CN103936690A - 氨基二氢噻嗪衍生物 - Google Patents

氨基二氢噻嗪衍生物 Download PDF

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CN103936690A
CN103936690A CN201410074667.6A CN201410074667A CN103936690A CN 103936690 A CN103936690 A CN 103936690A CN 201410074667 A CN201410074667 A CN 201410074667A CN 103936690 A CN103936690 A CN 103936690A
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CN103936690B (zh
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小林尚武
上田和生
伊藤尚弘
铃木慎司
阪口岳
加藤晃
行正显
堀章洋
郡山雄二
原口英和
安井健
神田泰彦
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Shionogi and Co Ltd
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

本发明涉及氨基二氢噻嗪衍生物。以式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物作为有效成分的BACE1抑制剂(式中，环A为可具有取代基的碳环式基团或可具有取代基的杂环式基团；E为低级亚烷基等；X为S、O或NR1；R1为氢或低级烷基；R2a、R2b、R3a、R3b、R4a和R4b各自独立表示氢、卤素、羟基等；n和m各自独立为0~3的整数，n+m为1~3；R5为氢、可具有取代基的低级烷基等)。

Description

氨基二氢噻嗪衍生物
本申请是原案申请日为2006年10月23日、原案申请号为200680048810.8(国际申请号为PCT/JP2006/321015)、发明名称为“氨基二氢噻嗪衍生物”的专利申请的分案申请。
技术领域
本发明涉及具有淀粉状β蛋白(amyloidβprotein)产生抑制作用、作为由淀粉状β蛋白的产生、分泌和/或沉积所诱发的疾病的治疗药有用的化合物。
背景技术
在阿尔茨海默病患者的脑内广泛确认到被称作淀粉状β蛋白的含有约40个氨基酸的肽蓄积在神经细胞外形成的不溶性斑点(老年斑)。认为该老年斑通过杀灭神经细胞而引发阿尔茨海默病，作为阿尔茨海默病治疗药，正在研究淀粉状β蛋白的分解促进剂、淀粉状β疫苗等。
分泌酶是在细胞内切断被称作淀粉状β蛋白前体(APP)的蛋白而生成淀粉状β蛋白的酶。掌管生成淀粉状β蛋白的N末端的酶称作BACE1(β位点APP裂解酶1，β分泌酶)，认为通过抑制该酶来抑制淀粉状β蛋白生成，能够成为阿尔茨海默病治疗药。
专利文献1中记载了结构与本发明化合物类似的化合物，并揭示其具有NO合成酶抑制活性、对痴呆有效。
专利文献2～4、非专利文献1和非专利文献2中记载了结构与本发明化合物类似的化合物，但记载各自作为升压药、***样镇痛剂或镇静剂等、药物中间体、镇痛剂是有用的。
作为BACE-1抑制剂，已知专利文献5～13等，但均具有不同于本发明化合物的骨架。
[专利文献1]国际公开第96/014842号小册子
[专利文献2]美国专利第3235551号说明书
[专利文献3]美国专利3227713号说明书
[专利文献4]日本特开平9-067355号公报
[专利文献5]国际公开第01/187293号小册子
[专利文献6]国际公开第04/014843号小册子
[专利文献7]日本特开2004-149429号公报
[专利文献8]国际公开第02/96897号小册子
[专利文献9]国际公开第04/043916号小册子
[专利文献10]国际公开第2005/058311号小册子
[专利文献11]国际公开第2005/097767号小册子
[专利文献12]国际公开第2006/041404号小册子
[专利文献13]国际公开第2006/041405号小册子
[非专利文献1]JournalofHeterocyclicChemistry,14卷,717页～723页(1977年)
[非专利文献2]JournalofOrganicChemistry,33卷,8号,3126页～3132页(1968年)
发明内容
发明所要解决的课题
提供具有淀粉状β蛋白产生抑制作用、特别是BACE1抑制作用，作为由淀粉状β蛋白的产生、分泌或沉积所诱发的疾病的治疗药有用的化合物。
解决课题的方法
本发明提供以下(a)～(x)：
(a)BACE1抑制剂，其以式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物作为有效成分，
[化学式1]
(式中，环A为可具有取代基的碳环式基团或可具有取代基的杂环式基团；
[化学式2]
Alk1为低级亚烷基或低级亚烯基；
R0为氢、低级烷基或酰基；
X为S、O或NR1；
R1为氢或低级烷基；
R2a和R2b各自独立表示氢、羟基、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的氨基、可具有取代基的脒基、可具有取代基的酰基、可具有取代基的氨基甲酰基、可具有取代基的氨基甲酰基羰基、可具有取代基的低级烷基磺酰基、可具有取代基的芳基磺酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；
R3a、R3b、R4a和R4b各自独立表示氢、卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的酰基、羧基、可具有取代基的低级烷氧基羰基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；
n和m各自独立表示0～3的整数，且n+m为1～3；
各R3a、各R3b、各R4a、各R4b可以不同；
R5表示氢、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的低级炔基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；
[化学式3]
(R5a和R5b各自独立表示氢或低级烷基；s为1～4的整数；各R5a、
各R5b可以不同)。
其中，n+m为2、R5为氢、且环A为未取代的苯基的化合物除外)。
(a1)BACE1抑制剂，其以式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物作为有效成分，
[化学式4]
(式中，环A为可具有取代基的碳环式基团或可具有取代基的杂环式基团；
[化学式5]
Alk1为低级亚烷基；
R0为氢、低级烷基或酰基；
X为S、O或NR1；
R1为氢或低级烷基；
R2a和R2b各自独立表示氢、羟基、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的氨基、可具有取代基的脒基、可具有取代基的酰基、可具有取代基的氨基甲酰基、可具有取代基的低级烷基磺酰基、可具有取代基的芳基磺酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；
R3a、R3b、R4a和R4b各自独立表示氢、卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的酰基、羧基、可具有取代基的低级烷氧基羰基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；
n和m各自独立表示0～3的整数，且n+m为1～3；
各R3a、各R3b、各R4a、各R4b可以不同；
R5表示氢、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的低级炔基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；
[化学式6]
(R5a和R5b各自独立表示氢或低级烷基；s为1～4的整数；各R5a、
各R5b可以不同)；
其中，n+m为2、R5为氢、且环A为未取代的苯基的化合物除外)。
(b)(a)的BACE1抑制剂，其中X为S。
(c)(a)的BACE1抑制剂，其中n为2、m为0。
(d)(a)的BACE1抑制剂，其中E为单键。
(e)式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物，
[化学式7]
(式中，各记号与(a)同义。其中，以下化合物除外：
i)n+m为2、R5为氢、环A为未取代的苯基的化合物；
ii)n为2、m为0、R2a为氢、R2b为氢或乙酰基、R5为甲基、环A为苯基或4-甲氧基苯基的化合物；
iii)n为2、m为0、R2a为氢、R2b为氢或乙酰基、R5为乙基、环A为3,4-二甲氧基苯基的化合物；
iv)n为2、m为0、R2a为氢、R2b为氢或乙酰基、R5和环A为苯基的化合物；
v)n为2、m为0、R2a和R2b为氢、R5和环A一起形成：
[化学式8]
的化合物(式中，Ｍe为甲基，各记号定义同上)；
vi)n+m为2、R5为氢、环A为只被选自羟基、卤素、低级烷基、低级烷氧基、硝基、氨基、低级烷基羰基氨基、巯基、低级烷硫基和氨基甲酰基的1～2个取代基取代的苯基、未取代的苯基或未取代的萘基的化合物)。
(f)(e)的化合物或其药学上可接受的盐或它们的溶剂合物，其中X为S。
(g)(e)或(f)的化合物或其药学上可接受的盐或它们的溶剂合物，其中n为2、m为0。
(h)(e)～(g)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中R5为可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的低级炔基、可具有取代基的碳环式基团或可具有取代基的杂环式基团。
(i)(e)～(h)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中R2a为氢，R2b为氢、可具有取代基的低级烷基、可具有取代基的酰基、可具有取代基的低级烷基磺酰基、可具有取代基的脒基。
(j)(e)～(h)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中NR2aR2b为：
[化学式9]
R6、R7和R8各自独立表示氢、低级烷基或酰基；
Y为可具有取代基的低级亚烷基、可具有取代基的低级亚烯基或可具有取代基的低级亚炔基；
Z为O或S。
(k)(e)～(j)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中环A为被取代的苯基。
(l)(e)～(j)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中环A为：
[化学式10]
(R9、R10和R11为氢或G，G为卤素、羟基、氰基、硝基、巯基、可具有取代基的低级烷基、可具有取代基的低级烷氧基、可具有取代基的低级烯基、可具有取代基的低级炔基、可具有取代基的酰基、可具有取代基的酰氧基、羧基、可具有取代基的低级烷氧基羰基、可具有取代基的低级烷氧基羰基氧基、可具有取代基的芳氧基羰基氧基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的氨基甲酰氧基、可具有取代基的低级烷硫基、可具有取代基的芳硫基、可具有取代基的低级烷基磺酰基、可具有取代基的芳基磺酰基、可具有取代基的低级烷基亚硫酰基、可具有取代基的芳基亚硫酰基、可具有取代基的低级烷基磺酰氧基、可具有取代基的芳基磺酰氧基、可具有取代基的碳环式基团、可具有取代基的碳环氧基、可具有取代基的杂环式基团或可具有取代基的杂环氧基，各G可以不同)。
(m)(l)的化合物或其药学上可接受的盐或它们的溶剂合物，其中G为：
[化学式11]
Q1、Q2和Q3各自独立表示单键、可具有取代基的低级亚烷基或可具有取代基的低级亚烯基；
Q4为可具有取代基的低级亚烷基或可具有取代基的低级亚烯基；
W1和W2各自独立表示O或S；
W3为O、S或NR12；
R12为氢、低级烷基、羟基低级烷基、低级烷氧基低级烷基、低级烷氧基羰基低级烷基、碳环低级烷基或酰基；
R14为氢或低级烷基；
环B为可具有取代基的碳环式基团或可具有取代基的杂环式基团；Alk2为可具有取代基的低级烷基；
p为1或2；
存在多个W1、多个W3、多个R12时，可以各自独立不同，(xii)中氧原子相对于取代基R14可以是顺式或反式的关系。
(n)(m)的化合物或其药学上可接受的盐或它们的溶剂合物，其中环B为可被选自卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基、可具有取代基的酰基、可具有取代基的氨基、氰基、可具有取代基的氨基甲酰基、可具有取代基的碳环式基团、可具有取代基的碳环氧基或可具有取代基的杂环式基团的一个以上基团分别取代的芳基或杂芳基。
(o)(m)的化合物或其药学上可接受的盐或它们的溶剂合物，其中G为：
[化学式12]
(式中，各记号定义同上)。
(p)(e)～(o)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中R5为C1～C3的烷基。
(q)(e)～(o)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中R5为甲基。
(r)(e)～(q)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中R3a和R3b各自独立表示氢、卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基或可具有取代基的芳基。
(s)(e)～(q)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物，其中R3a和R3b全部为氢。
(t)药物组合物，其特征在于：以(e)～(s)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物作为有效成分。
(u)BACE1抑制剂，其特征在于：以(e)～(s)中任一项的化合物或其药学上可接受的盐或它们的溶剂合物作为有效成分。
(v)(a)～(d)或(u)的BACE1抑制剂，该抑制剂为淀粉状β蛋白产生抑制剂。
(w)(a)～(d)、(u)或(v)中任一项的BACE1抑制剂，该抑制剂为由淀粉状β蛋白的产生、分泌和/或沉积所诱发的疾病的治疗药。
(x)(a)～(d)、(u)或(v)的BACE1抑制剂，该抑制剂为阿尔茨海默病治疗药。
本发明还提供以下(y)～(ab)：
(y)由淀粉状β蛋白的产生、分泌或沉积所诱发的疾病的治疗方法，其特征在于：给予上述(a)的式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物。
(z)上述(a)的式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物在制造用于治疗由淀粉状β蛋白的产生、分泌或沉积所诱发的疾病的药物中的应用。
(aa)阿尔茨海默病的治疗方法，其特征在于：给予上述(a)的式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物。
(ab)上述(a)的式(I)所示的化合物或其药学上可接受的盐或它们的溶剂合物在制备用于治疗阿尔茨海默病的药物中的应用。
发明效果
本发明的化合物作为由淀粉状β蛋白的产生、分泌或沉积所诱发的疾病(阿尔茨海默病等)的治疗药是有用的。
实施发明的最佳方式
本说明书中，“卤素”包含氟、氯、溴和碘。
“卤代低级烷基”、“卤代低级烷氧基”、“卤代酰基”、“卤代低级烷硫基”和“卤代低级烷氧基羰基”的卤素部分与上述“卤素”相同。
“低级烷基”包含碳原子数为1～15、优选碳原子数为1～10、更优选碳原子数为1～6、进一步优选碳原子数为1～3的直链或支链状的烷基，其例子有：甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、己基、异己基、正庚基、异庚基、正辛基、异辛基、正壬基和正癸基等。
“碳环低级烷基”、“低级烷氧基”、“卤代低级烷基”、“卤代低级烷氧基”、“卤代低级烷硫基”、“羟基低级烷基”、“低级烷氧基羰基”、“卤代低级烷氧基羰基”、“低级烷氧基羰基低级烷基”、“低级烷氧基羰基氧基”、“低级烷基氨基”、“低级烷基羰基氨基”、“低级烷氧基羰基氨基”、“低级烷氧基低级烷基”、“低级烷基氨基甲酰基”、“羟基低级烷基氨基甲酰基”、“氨基低级烷基”、“羟基亚氨基低级烷基”、“低级烷氧基亚氨基低级烷基”、“低级烷硫基”、“低级烷基磺酰基”、“低级烷基氨磺酰基”、“低级烷基亚硫酰基”、“低级烷基磺酰氧基”、“低级烷氧基羰基低级炔基”、“低级烷硫基低级烷基”、“芳基低级烷基”、“芳基低级烷基氨基”、“芳基低级烷氧基羰基”、“芳基低级烷基氨基甲酰基”、“杂环低级烷基氨基”和“杂环低级烷基氨基甲酰基”的低级烷基部分也与上述“低级烷基”相同。
作为环A的取代基的“可具有取代基的低级烷基”的例子有：可被选自取代基组α、羟基亚氨基和低级烷氧基亚氨基的一个以上基团取代的低级烷基；上述(i)、(ii)、(iv)、(vi)、(viii)、(x)所示的基团(各Q1为可具有取代基的低级亚烷基)；(iii)、(v)、(vii)、(ix)(各Q2为可具有取代基的低级亚烷基)、(xii)所示的基团。
除此以外的情况下，“可具有取代基的低级烷基”可以被选自取代基组α的一个以上基团取代。
其中，取代基组α包含：卤素、羟基、低级烷氧基、羟基低级烷氧基、低级烷氧基低级烷氧基、酰基、酰氧基、羧基、低级烷氧基羰基、氨基、酰基氨基、低级烷基氨基、低级烷硫基、氨基甲酰基、低级烷基氨基甲酰基、羟基低级烷基氨基甲酰基、氨磺酰基、低级烷基氨磺酰基、低级烷基亚硫酰基、氰基、硝基、芳基和杂环式基团。
特别是作为Alk2中的“可具有取代基的低级烷基”的取代基，优选卤素、羟基、低级烷氧基、低级烷氧基低级烷氧基、低级烷氧基羰基、氨基、酰基氨基、低级烷基氨基和/或低级烷硫基等。
作为环A的取代基的“可具有取代基的低级烷氧基”的例子有：可被选自上述取代基组α的一个以上基团取代的低级烷氧基和上述(iii)(Q1为可具有取代基的低级亚烷基，Q2为单键，W2为O)、(v)(Q1为可具有取代基的低级亚烷基，Q2为单键，W3为O)、(vi)(Q1为单键，Q2为可具有取代基的低级亚烷基，W2为O)或(xi)(Q4为可具有取代基的低级亚烷基，W2为O)所示的基团。
除此以外的情况下，作为“可具有取代基的低级烷氧基”以及“可具有取代基的低级烷氧基羰基”、“可具有取代基的低级烷氧基羰基氧基”、“可具有取代基的低级烷基磺酰基”、“可具有取代基的低级烷基亚硫酰基”、“可具有取代基的低级烷基磺酰氧基”和“可具有取代基的低级烷硫基”的取代基，可以列举出：选自上述取代基组α的一个以上的基团。
“低级烯基”包含在任意位置上具有一个以上双键的碳原子数为2～15、优选碳原子数为2～10、更优选碳原子数为2～6、进一步优选碳原子数为2～4的直链或支链状烯基。具体包含：乙烯基、烯丙基、丙烯基、异丙烯基、丁烯基、异丁烯基、异戊二烯基、丁二烯基、戊烯基、异戊烯基、戊二烯基、己烯基、异己烯基、己二烯基、庚烯基、辛烯基、壬烯基、癸烯基、十一碳烯基、十二碳烯基、十三碳烯基、十四碳烯基、十五碳烯基等。
“低级炔基”包含在任意位置上具有一个以上三键的碳原子数为2～10、优选碳原子数为2～8、进一步优选碳原子数为3～6的直链或支链状炔基。具体包含：乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基、癸炔基等。上述炔基可以进一步在任意位置上具有双键。
“低级烷氧基羰基低级炔基”的低级炔基部分也与上述“低级炔基”相同。
作为环A的取代基的「可具有取代基的低级烯基”的例子有：可被选自取代基组α的一个以上基团取代的低级烯基；上述(i)、(ii)、(iv)、(vi)、(viii)或(x)(Q1为可具有取代基的低级亚烯基)所示的基团；(iii)、(v)、(vii)或(ix)(Q2为可具有取代基的低级亚烯基)所示的基团。
除此以外的情况下，作为“可具有取代基的低级烯基”和“可具有取代基的低级炔基”的取代基，可以列举出：选自上述取代基组α的一个以上的基团。
作为环A的取代基的“可具有取代基的氨基”的例子有：可被选自低级烷基、酰基、羟基、低级烷氧基、低级烷氧基羰基、碳环式基团和杂环式基团的一个以上基团取代的氨基和上述(ii)(Q1为单键)、(iv)(Q1为单键)、(v)(Q2为单键，W3为NR12)、(ix)(Q2为单键)、(xiii)或(xiv)所示的基团。
作为环A的取代基的“可具有取代基的氨基甲酰基”的例子有：可被选自低级烷基、酰基、羟基、低级烷氧基、低级烷氧基羰基、碳环式基团和杂环式基团的一个以上基团取代的氨基甲酰基和上述(i)、
(viii)(各Q1为单键)或(xv)所示的基团。
除此以外的情况下，作为“可具有取代基的氨基”、“可具有取代基的脒基”、“可具有取代基的氨基甲酰基”、“可具有取代基的氨基甲酰基羰基”和“可具有取代基的氨基甲酰氧基”的取代基，可以列举出：选自低级烷基、酰基、羟基、低级烷氧基、低级烷氧基羰基、碳环式基团和杂环式基团等的1～2个的基团。
“酰基”包含碳原子数为1～10的脂肪族酰基、碳环羰基和杂环羰基。具体例示：甲酰基、乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、叔戊酰基、己酰基、丙烯酰基、丙酰基、甲基丙烯酰基、巴豆酰基、苯甲酰基、环己甲酰基、吡啶羰基、呋喃羰基、噻吩羰基、苯并噻唑羰基、哌嗪羰基、哌啶羰基、硫代吗啉基等。
“卤代酰基”、“酰基氨基”和“酰氧基”的酰基部分也与上述相同。
“可具有取代基的酰基”和“可具有取代基的酰氧基”的取代基的例子有：选自取代基组α的一个以上的基团。另外，碳环羰基和杂环羰基的环部分可以被选自低级烷基、取代基组α和被选自取代基组α的一个以上基团取代的低级烷基的一个以上基团取代。
“碳环式基团”包含环烷基、环烯基、芳基和非芳族缩合碳环式基团等。
“环烷基”是指碳原子数为3～10、优选碳原子数为3～8、更优选碳原子数为4～8的碳环式基团，例如包含环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基和环癸基等。
“环烯基”包含在上述环烷基的环中的任意位置上具有一个以上双键的环烯基，具体列举出：环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、环辛烯基和环己二烯基等。
“芳基”包含苯基、萘基、蒽基和菲基等，特别优选苯基。
“非芳族缩合碳环式基团”包含选自上述“环烷基”、“环烯基”和“芳基”的两个以上环状基团缩合的基团，具体列举出：茚满基、茚基、四氢萘基和芴基等。
“碳环氧基”、“碳环低级烷基”和“碳环低级烷基”的碳环部分也与“碳环式基团”相同。
“芳基低级烷基”、“芳氧基”、“芳氧基羰基”、“芳氧基羰基氧基”、“芳基低级烷氧基羰基”、“芳硫基”、“芳基氨基”、“芳基低级烷基氨基”、“芳基磺酰基”、“芳基磺酰氧基”、“芳基亚硫酰基”、“芳基氨磺酰基”、“芳基氨基甲酰基”和“芳基低级烷基氨基甲酰基”的芳基部分也与上述“芳基”相同。
“杂环式基团”包含环内具有一个以上任意选自O、S和N的杂原子的杂环式基团，具体包含：吡咯基、咪唑基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、***基、三嗪基、四唑基、异唑基、唑基、二唑基、异噻唑基、噻唑基、噻二唑基、呋喃基和噻吩基等5～6元杂芳基；吲哚基、异吲哚基、吲唑基、indolidinyl、吲哚啉基、异吲哚啉基、喹啉基、异喹啉基、噌啉基、酞嗪基、喹唑啉基、萘啶基(naphthridinyl)、喹喔啉基、嘌呤基、蝶啶基、苯并吡喃基、苯并咪唑基、苯并***基、苯并异唑基、苯并唑基、苯并二唑基、苯并异噻唑基、苯并噻唑基、苯并噻二唑基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并***基、咪唑并吡啶基、吡唑并吡啶基、***并吡啶基、咪唑并噻唑基、吡嗪并哒嗪基、喹唑啉基、喹啉基、异喹啉基、萘啶基(naphthyridinyl)、二氢苯并呋喃基、四氢喹啉基、四氢异喹啉基、二氢苯并嗪、四氢苯并噻吩基等二环的缩合杂环式基团；咔唑基、吖啶基、呫吨基、吩噻嗪基、啡噻基、吩嗪基、二苯并呋喃基、咪唑并喹啉基等三环的缩合杂环式基团；二烷基、硫杂丙环基(thiiranyl)、环氧乙烷基、oxathioranyl、azethidinyl、thianyl、噻唑烷、吡咯烷基,、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、吡唑啉基、哌啶基、哌嗪基、吗啉基(morpholinyl)、吗啉(morpholino)、硫代吗啉基(thiomorpholinyl)、硫代吗啉(thiomorpholino)、二氢吡啶基、二氢苯并咪唑基、四氢吡啶基、四氢呋喃基、四氢吡喃基、四氢噻唑基、四氢异噻唑基、二氢嗪基(dihydroxadinyl)、氮杂环庚烷基(hexahydroazepinyl)、tetrahydroazepyinyl等非芳族杂环式基团。优选为5～6元的杂芳基或非芳族杂环式基团。
“杂环氧基”、“杂环硫基”、“杂环羰基”、“杂环氨基”、“杂环羰基氨基”、“杂环氨磺酰基”、“杂环磺酰基”、“杂环氨基甲酰基”、“杂环氧基羰基”、“杂环低级烷基氨基”和“杂环低级烷基氨基甲酰基”的杂环部分也与上述“杂环式基团”相同。
作为环A的“可具有取代基的碳环式基团”和“可具有取代基的杂环式基团”的取代基，可以被选自下述基团的一种以上基团取代，可以列举出：
取代基组α(优选卤素、羟基、酰基、酰氧基、羧基、低级烷氧基羰基、氨基甲酰基、氨基、低级烷基氨基、低级烷硫基等)；
可被选自取代基组α的一个以上基团取代的低级烷基(其中，取代基优选卤素、羟基、低级烷氧基、低级烷氧基羰基等)；
被选自取代基组α的一个以上基团取代的氨基低级烷基(其中取代基为酰基、低级烷基和/或低级烷氧基等)；
羟基亚氨基低级烷基、低级烷氧基亚氨基低级烷基；
可被选自取代基组α的一个以上基团取代的低级烯基(取代基优选低级烷氧基羰基、卤素和/或卤代低级烷氧基羰基等)；
可被选自取代基组α的一个以上基团取代的低级炔基(取代基优选低级烷氧基羰基等)；
可被选自取代基组α的一个以上基团取代的低级烷氧基(取代基优选低级烷基氨基甲酰基和/或羟基低级烷基氨基甲酰基等)；
可被选自取代基组α的一个以上基团取代的低级烷硫基；
被选自取代基组α的一个以上基团取代的低级烷基氨基；
可被选自取代基组α的一个以上基团取代的低级烷基磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基低级烷氧基羰基；
被选自取代基组α的一个以上基团取代的酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的环烷基；
可被选自取代基组α的一个以上基团取代的低级烷基亚硫酰基；
氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基；可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环式基团；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳氧基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氧基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳硫基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环硫基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基氨基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氨基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基低级烷基氨基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环低级烷基氨基；
可被选自取代基组α的一个以上基团取代的低级烷基氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基低级烷基氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环低级烷基氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳氧基羰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氧基羰基；
可被卤素取代的低级亚烷基二氧基；氧基(oxo)；叠氮基；
[化学式13]
(Q1、Q2和Q3各自独立表示单键、可具有取代基的低级亚烷基或可具有取代基的低级亚烯基；
Q4为可具有取代基的低级亚烷基或可具有取代基的低级亚烯基；
W1和W2各自独立表示O或S；
W3为O、S或NR12；
R12为氢、低级烷基、羟基低级烷基、低级烷氧基低级烷基、低级烷氧基羰基低级烷基、碳环低级烷基或酰基；
R14为氢或低级烷基；
环B为可具有取代基的碳环式基团或可具有取代基的杂环式基团；
Alk2为可具有取代基的低级烷基)所示的基团等。
存在多个W1、多个W3、多个R12等时，可以各自独立不同。
在(xii)中，氧原子相对于取代基R14可以是顺式或反式的关系。
“被取代的苯基”的取代基也同上，优选为被选自取代基组α和(i)～(xv)所示基团的1～2个基团取代的苯基。
作为环B中的“可具有取代基的碳环式基团”或“可具有取代基的杂环式基团”的取代基，可以被选自下述基团的一种以上基团取代，可以列举如：
取代基组α(优选卤素、羟基、低级烷氧基、羧基、低级烷氧基羰基、酰基、氨基、低级烷基氨基、酰基氨基、氨基甲酰基、低级烷基氨基甲酰基、氰基、硝基等)；
可被选自取代基组α的一个以上基团取代的低级烷基(其中取代基优选卤素、羟基、低级烷氧基等)；
被选自取代基组α的一个以上基团取代的氨基低级烷基、羟基亚氨基低级烷基、低级烷氧基亚氨基低级烷基；
可被选自取代基组α的一个以上基团取代的低级烯基；
可被选自取代基组α的一个以上基团取代的低级炔基；
可被选自取代基组α的一个以上基团取代的低级烷氧基(取代基优选卤素、羟基等)；
可被选自取代基组α的一个以上基团取代的低级烷硫基(取代基优选卤素)；
可被选自取代基组α的一个以上基团取代的低级烷基氨基(取代基优选氨基)；
可被选自取代基组α的一个以上基团取代的低级烷基磺酰基；
可被选自取代基组α和低级烷基的一个以上基团取代的芳基低级烷氧基羰基；
可被选自取代基组α的一个以上基团取代的酰基(取代基优选卤素)；
可被选自取代基组α的一个以上基团取代的低级烷基磺酰基；
氨磺酰基；
可被选自取代基组α的一个以上基团取代的低级烷基氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的环烷基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基；可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环式基团(取代基优选卤素、低级烷基等)；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳氧基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氧基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳硫基(取代基优选卤素、羟基、低级烷氧基、酰基等)；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环硫基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基氨基(取代基优选卤素、羟基、低级烷氧基、酰基等)；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氨基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基低级烷基氨基(取代基优选卤素、羟基、低级烷氧基、酰基等)；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环低级烷基氨基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氨磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环磺酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳基低级烷基氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环低级烷基氨基甲酰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的芳氧基羰基；
可被选自取代基组α、叠氮基和低级烷基的一个以上基团取代的杂环氧基羰基；
可被卤素取代的低级亚烷基二氧基；氧基等。
除上述情况外，作为“可具有取代基的碳环式基团”、“可具有取代基的杂环式基团”、“可具有取代基的碳环氧基”、“可具有取代基的芳基磺酰基”、“可具有取代基的芳氧基羰基氧基”、“可具有取代基的杂环氧基”、“可具有取代基的芳基亚硫酰基”、“可具有取代基的芳基磺酰氧基”、“可具有取代基的芳硫基”的取代基，可以列举出：可被选自低级烷基和取代基组α的一个以上基团取代的基团。
“杂芳基”包含上述“杂环式基团”中的芳族环式基团。
“可具有取代基的5～6元杂芳基”的取代基与上述环B中的“可具有取代基的杂环式基团”的取代基相同。优选为选自低级烷基和取代基组α的一种以上的基团。
“低级亚烷基”包含碳原子数为1～10、优选碳原子数为1～6、更优选碳原子数为1～3的直链状或支链状的二价碳链。具体有亚甲基、二亚甲基、三亚甲基、四亚甲基、甲基三亚甲基等。
“低级亚烷基二氧基”的低级亚烷基部分也与上述“低级亚烷基”相同。
“低级亚烯基”包含在任意位置上具有双键的直链或支链状的碳原子数为2～10、优选碳原子数为2～6、更优选碳原子数为2～4的二价碳链。具体有亚乙烯基、亚丙烯基、亚丁烯基、亚丁二烯基、甲基亚丙烯基、亚戊烯基和亚己烯基等。
“低级亚炔基”包含在任意位置上具有三键且可以进一步具有双键的直链或支链状的碳原子数为2～10、更优选碳原子数为2～6、更优选碳原子数为2～4的二价碳链。具体可以列举出：亚乙炔基、亚丙炔基、亚丁炔基、亚戊炔基和亚己炔基等。
作为“可具有取代基的低级亚烷基”、“可具有取代基的低级亚烯基”、“可具有取代基的低级亚炔基”的取代基，可以列举出取代基组α，优选为卤素、羟基等。
“各R3a、各R3b、各R4a、各R4b可以不同”意思是指：当n为2或3时，两个或三个R3a各自可以不同，两个或三个R3b各自可以不同。同样当m为2或3时，两个或三个R4a各自可以不同，两个或三个R4b各自可以不同。
[化学式14]
的情况例如包含以下情形。
[化学式15]
(各记号定义同上)
优选为R5a、R5b全部为氢的基团。
本说明书中，“溶剂合物”包含例如与有机溶剂的溶剂合物、水合物等。形成水合物时，可以和任意数目的水分子配位。
化合物(I)包含药学上可接受的盐。可以列举如：与碱金属(锂、钠或钾等)、碱土金属(镁或钙等)、氨、有机碱和氨基酸的盐；或者与无机酸(盐酸、硫酸、硝酸、氢溴酸、磷酸或氢碘酸等)和有机酸(乙酸、三氟乙酸、枸橼酸、乳酸、酒石酸、草酸、马来酸、富马酸、扁桃酸、戊二酸、苹果酸、苯甲酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、甲磺酸或乙磺酸等)的盐。特别优选盐酸、磷酸、酒石酸或甲磺酸等。上述盐可以按照通常进行的方法来形成。
另外，化合物(I)并不限于特定的异构体，包括所有可能的异构体(酮-烯醇异构体、亚胺-烯胺异构体、非对映异构体、光学异构体和旋转异构体等)或外消旋体。例如R2a为氢的化合物(I)包含以下互变异构体。
[化学式16]
本发明的化合物(I)例如可以按照非专利文献1所记载的方法或下述方法进行制备。
氨基二氢噻嗪环的合成A法
[化学式17]
(式中，R2b和R2c中至少一个为氢；R3c和R3d各自独立表示氢、卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烯基、可具有取代基的酰基、羧基、可具有取代基的低级烷氧基羰基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；其他各记号定义同上)
步骤一
在-100℃～50℃、优选-80℃～0℃下，向***、四氢呋喃等溶剂或***-四氢呋喃等混合溶剂中加入市售或利用公知方法可以制备的化合物a和氯化乙烯基镁、溴化乙烯基镁、溴化丙烯基镁等具有对应于目标化合物的取代基的格利雅试剂，使之反应0.2小时～24小时、优选0.5小时～5小时，可以得到化合物b。
步骤二
在甲苯等溶剂的存在或非存在下，向乙酸、三氟乙酸、氯化氢、硫酸等酸或它们的混合物中加入硫脲或N-甲基硫脲、N,N’-二甲基硫脲等具有对应于目标化合物的取代基的取代硫脲，使其与化合物b在-20℃～100℃、优选0℃～50℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物c。
步骤三
在甲苯等溶剂的存在或非存在下，向化合物c中加入三氟乙酸、甲磺酸、三氟甲磺酸等酸或它们的混合物，在-20℃～100℃、优选0℃～50℃下反应0.5～120小时、优选1小时～72小时，当R2b为氢时可以得到(I-2)，当R2c为氢时可以得到(I-1)。
氨基二氢噻嗪环的合成B法
[化学式18]
(式中，L为卤素或磺酰氧基等离去基团，其他记号定义同上)
步骤一
在甲苯、氯仿、四氢呋喃等溶剂中，在水和盐酸、硫酸等酸的存在下，使市售或利用公知方法可以制备的化合物d与硫氰酸钠、硫氰酸铵等硫氰酸盐在0℃～150℃、优选20℃～100℃下反应0.5小时～24小时、优选1小时～12小时，可以得到化合物e。
步骤二
在磷酸二氢钠等缓冲剂的存在或非存在下，向四氢呋喃、甲醇、乙醇、水等溶剂中或乙醇-水等混合溶剂中加入硼氢化钠等还原剂，使与化合物e在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时，可以得到化合物f。
步骤三
在甲苯、二氯甲烷等溶剂的存在或非存在下，使化合物f与亚硫酰氯、氯氧化磷、四溴化碳-三苯基膦等卤化剂在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时，或者在甲苯、二氯甲烷等溶剂中，在三乙胺等碱的存在下使甲磺酰氯、对甲苯磺酰氯等磺化剂与化合物f在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时，可以得到化合物g。
步骤四
在甲醇、乙醇、水等溶剂中或甲醇-水等混合溶剂中，使氨或甲胺等伯胺与化合物g在-20℃～80℃、优选0℃～40℃下反应0.5小时～48小时、优选1小时～24小时，可以得到化合物(I-3)。
氨基二氢噻嗪环的合成C法
[化学式19]
(式中，R为氢或羧基的保护基，其他记号定义同上)
步骤一
使市售或利用公知方法可以制备的化合物h与氢化锂铝、氢化二异丙基铝等还原剂在四氢呋喃、二***等溶剂中在-80℃～150℃、优选25℃～100℃下反应0.1小时～24小时、优选0.5小时～12小时，可以得到化合物i。
步骤二
在甲苯、氯仿、四氢呋喃等溶剂中，在二异丙基乙胺、三乙胺、吡啶、氢氧化钠等碱的存在下或非存在下，使4-甲氧基苄基异硫氰酸酯、叔丁基异硫氰酸酯等对应于目标化合物的异硫氰酸酯或N,N-二甲基硫代氨基甲酰氯、N,N-二乙基硫代氨基甲酰氯等对应于目标化合物的硫代氨基甲酰卤与化合物i在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物j。
步骤三
在乙腈、甲苯、二氯甲烷等溶剂中，使化合物j与亚硫酰氯、氯氧化磷、四溴化碳-三苯基膦等卤化剂在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时，或者在甲苯、二氯甲烷等溶剂中，在三乙胺等碱的存在下使甲磺酰氯、对甲苯磺酰氯等磺化剂与化合物j在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时。使二异丙基乙胺、碳酸钾、碳酸氢钠、氢化钠、氢氧化钠等碱与所得卤化物或磺酰基化合物在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物(I-4)。
氨基二氢噻嗪环的合成Ｄ法
氨基噻唑啉环的合成A法
氨基四氢噻唑环的合成A法
[化学式20]
(式中，L为卤素或磺酰氧基等离去基团，m为1～3的整数，其他记号定义同上)
步骤一
在二甲基甲酰胺、四氢呋喃等溶剂中加入叠氮化钠等叠氮化剂，使与市售或利用公知方法可以制备的化合物k在0℃～200℃、优选40℃～150℃下反应0.5小时～24小时、优选1小时～12小时，可以得到化合物l。
步骤二
使化合物l和氢化锂铝、氢化二异丁基铝等还原剂在四氢呋喃、二***等溶剂中在-80℃～150℃、优选25℃～100℃下反应0.1小时～24小时、优选0.5小时～12小时，可以得到化合物m。
步骤三
在甲苯、氯仿、四氢呋喃等溶剂中，使甲基异硫氰酸酯、乙基异硫氰酸酯等对应于目标化合物的异硫氰酸酯或N,N-二甲基硫代氨基甲酰氯、N,N-二乙基硫代氨基甲酰氯等对应于目标化合物的硫代氨基甲酰卤与化合物m在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物n。
步骤四
使化合物n与亚硫酰氯、氯氧化磷、四溴化碳-三苯基膦等卤化剂在乙腈、甲苯、二氯甲烷等溶剂中在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时，或者在甲苯、二氯甲烷等溶剂中，在二异丙基乙胺、三乙胺等碱的存在下使甲磺酰氯、对甲苯磺酰氯等磺酰化剂与化合物n在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时。使碳酸钾、碳酸氢钠、氢化钠、氢氧化钠等碱与所得卤化物或磺酸酯衍生物在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物(I-5)。
氨基二氢噻嗪环的合成E法
氨基噻唑啉环的合成B法
氨基四氢噻唑环的合成B法
[化学式21]
(式中，R2b和R2c中的至少一个为氢，n为1～3的整数，其他记号定义同上)
步骤一
在乙醇、甲醇、四氢呋喃、甲苯等溶剂中，使硫脲或N-甲基硫脲、N,N-二甲基硫脲、N,N’-二甲基硫脲等对应于目标化合物的取代硫脲与市售或利用公知方法可以制备的化合物o在-20℃～200℃、优选0℃～150℃下反应0.5小时～200小时、优选1小时～120小时，可以得到化合物p。
步骤二
在-100℃～50℃、优选-80℃～30℃下，向醚、四氢呋喃等溶剂中或它们的混合溶剂中加入化合物p和甲基氯化镁、乙基溴化镁、苄基溴化镁等对应于目标化合物的格利雅试剂，使之反应0.2小时～24小时、优选0.5小时～5小时，可以得到化合物q。
步骤三
在甲苯等溶剂的存在或非存在下，加入三氟乙酸、甲磺酸、三氟甲磺酸等酸或它们的混合物，使与化合物q在-20℃～100℃、优选0℃～50℃下反应0.5小时～200小时、优选1小时～150小时，可以得到化合物(I-6)(R2c=H)或化合物(I-7)(R2b=H)。
氨基二氢噻嗪环的合成F法
[化学式22]
(式中，各记号定义同上)
步骤一
使氯化铵和利用公知方法可以制备的化合物r在乙酸等溶剂中在0℃～200℃、优选10℃～100℃下反应0.1小时～100小时、优选0.5小时～24小时，可以得到化合物s。
步骤二
使化合物s与氢化锂铝、氢化二异丁基铝等还原剂在四氢呋喃、二***等溶剂中在-80℃～150℃、优选0℃～100℃下反应0.1小时～24小时、优选0.5小时～12小时，可以得到化合物t。
步骤三
在甲苯、氯仿、四氢呋喃等溶剂中，在二异丙基乙胺、三乙胺、吡啶、氢氧化钠等碱的存在或非存在下，使4-甲氧基苄基异硫氰酸酯、叔丁基异硫氰酸酯等对应于目标化合物的异硫氰酸酯或N,N-二甲基硫代氨基甲酰氯、N,N-二乙基硫代氨基甲酰氯等对应于目标化合物的氨基甲酰卤与化合物t在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物u。
步骤四
使化合物u和亚硫酰氯、氯氧化磷、四溴化碳-三苯基膦等卤化剂在乙腈、甲苯、二氯甲烷等溶剂中在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时，或者在甲苯、二氯甲烷等溶剂中，在三乙胺等碱的存在下，使甲磺酰氯、对甲苯磺酰氯等磺酰化剂和化合物u在-80℃～50℃、优选-20℃～20℃下反应0.1小时～24小时、优选0.5小时～12小时。使二异丙基乙胺、碳酸钾、碳酸氢钠、氢化钠、氢氧化钠等碱与所得卤化物或磺酸酯衍生物在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物(I-8)。
氨基二氢嗪环的合成A法
氨基四氢氧氮杂环的合成A法
[化学式23]
(式中，各记号定义同上)
步骤一
使甲基碘、二乙基硫酸、苄基溴等烷基化剂与氨基二氢噻嗪环的合成D法的步骤三(m至n)得到的化合物n在甲醇、乙醇、二甲基甲酰胺、四氢呋喃等溶剂中，在二异丙基乙胺、三乙胺、吡啶、氢氧化钠等碱的存在或非存在下，在0℃～200℃、优选40℃～150℃下反应0.1小时～48小时、优选0.5小时～24小时，可以得到化合物v。
步骤二
使氧化银、***、二氧化锰等金属氧化物和化合物v在二甲基甲酰胺、四氢呋喃、二氯甲烷等溶剂中，在二异丙基乙胺、三乙胺、吡啶、氢氧化钠等碱的存在或非存在下，在0℃～200℃、优选10℃～150℃下反应1小时～120小时、优选0.5小时～100小时，可以得到化合物(I-9)。
氨基二氢嗪环的合成B法
氨基唑啉环的合成
氨基四氢氧氮杂环的合成B法
[化学式24]
(式中，R15为可具有取代基的低级烷基(叔丁基、苄基等)；R16为氢或低级烷基；n为1～3的整数；其他记号定义同上)
步骤一
在甲苯、叔丁醇、四氢呋喃等溶剂中，在二异丙基乙胺、三乙胺、吡啶等碱的存在下，使叠氮化磷酸二苯酯等叠氮化剂与市售或利用公知方法可以制备的化合物w在0℃～200℃、优选40℃～150℃下反应1小时～48小时、优选0.5小时～24小时，可以得到化合物x。
步骤二
使叔丁醇、3,4-二甲氧基苄醇、4-甲氧基苄醇等醇与化合物x在甲苯、二甲苯、二甲基甲酰胺、四氢呋喃等溶剂中，在0℃～300℃、优选50℃～200℃下反应1小时～800小时、优选5小时～500小时，可以得到化合物y。
步骤三
在水、甲苯、二氯甲烷、甲醇、1,4-二烷、乙酸、乙酸乙酯等溶剂的存在或非存在下，在盐酸、硫酸、氢溴酸、三氟乙酸等酸的存在下，使化合物y在0℃～200℃、优选25℃～150℃下反应0.1小时～48小时、优选0.5小时～24小时，可以得到化合物z。
步骤四
在甲苯、氯仿、四氢呋喃等溶剂中，在二异丙基乙胺、三乙胺、吡啶等碱的存在下，使甲基异硫氰酸酯、乙基异硫氰酸酯等对应于目标化合物的异硫氰酸酯或N,N-二甲基硫代氨基甲酰氯、N,N-二乙基硫代氨基甲酰氯等对应于目标化合物的硫代氨基甲酰卤与化合物z在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物aa。
步骤五
在甲醇、乙醇、二甲基甲酰胺、四氢呋喃等溶剂中，在二异丙基乙胺、三乙胺、吡啶、氢氧化钠等碱的存在或非存在下，使甲基碘、二乙基硫酸、苄基溴等烷基化剂与化合物aa在0℃～200℃、优选40℃～150℃下反应1小时～48小时、优选0.5小时～24小时，可以得到化合物ab。
步骤六
使氧化银、***、二氧化锰等金属氧化物与化合物ab在二甲基甲酰胺、四氢呋喃、二氯甲烷等溶剂中，在二异丙基乙胺、三乙胺、吡啶、氢氧化钠等碱的存在下，在0℃～200℃、优选10℃～150℃下反应1小时～120小时、优选0.5小时～100小时，可以得到化合物(I-10)。
氨基四氢嘧啶环的合成
[化学式25]
(式中，各记号定义同上)
步骤一
向二甲基甲酰胺、甲醇等溶剂中加入利用公知方法可以制备的化合物ac和叠氮化钠、叠氮化锂等叠氮化剂，使之在20℃～150℃、优选50℃～100℃下反应0.5小时～120小时、优选1小时～72小时，可以得到化合物ad。
步骤二
在氮气环境下，将氢化锂铝悬浮在四氢呋喃或二***等溶剂中，在-80℃～20℃、优选-30℃～0℃下加入将化合物ad溶解在四氢呋喃或二乙基醚等溶剂中的溶液，反应1分钟～10小时、优选10分钟～1小时，或者在乙醇、异丙醇、正丁醇等溶剂中在10℃～110℃、优选50℃～80℃下加入拉尼镍，使之与化合物ad反应1分钟～10小时、优选10分钟～1小时，可以得到化合物ae。
步骤三
在四氢呋喃、二氯甲烷等溶剂中，在乙酸、丙酸等酸的存在下，使化合物ae与氰化硼氢化钠、三乙酰氧基硼氢化钠等还原剂在-50℃～100℃、优选0℃～50℃下反应0.1小时～48小时、优选0.5小时～24小时，或者在四氢呋喃、二甲基甲酰胺等溶剂中，在1-乙基-3-(3-二甲氨基丙基)碳二亚胺-N-羟基苯并***、羰基二咪唑等脱水缩合剂存在下，以及三乙胺、碳酸钾等碱的存在下或非存在下，使化合物ae与甲酸、乙酸等羧酸在-50℃～100℃、优选0℃～50℃下反应0.1小时～48小时、优选0.5小时～16小时，可以得到酰胺衍生物。接着，在氮气环境下，将氢化锂铝悬浮在四氢呋喃或二***等溶剂中，在-50℃～60℃、优选0℃～50℃下加入将上述酰胺衍生物溶解在四氢呋喃或二***等溶剂中的溶液，反应1分钟～48小时、优选10分钟～10小时，可以得到化合物af。
步骤四
使化合物ae或af与3,5-二甲基吡唑-1-羧基脒或S-甲基硫脲等在乙腈、四氢呋喃、二甲基甲酰胺等溶剂中，在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～24小时，可以得到化合物ag。
步骤五
在甲苯等溶剂的存在或非存在下，向化合物ag(R2b和R2c中的至少一个为氢)中加入三氟乙酸、甲磺酸、三氟甲磺酸等酸或它们的混合物，在-20℃～100℃、优选0℃～50℃下反应0.5～120小时、优选1小时～72小时，当R2b为氢时可以得到(I-2)；当R2c为氢时可以得到(I-1)。其中，当R2a、R2b、R2c具有在叔丁氧基羰基等的酸性条件下容易分解的结构时，化合物(I-1)、(I-2)中的R2a、R2b、R2c有时会转化为氢。
氨基噻唑啉环的合成C法
[化学式26]
(式中，Hal为卤素，其他各记号定义同上)
步骤一
在甲苯、氯仿、四氢呋喃等溶剂中或氯仿-水等混合溶剂中，在碘、溴、氯等卤素和硫氰酸钠、硫氰酸铵等硫氰酸盐以及根据需要在四丁基溴化铵等相转移催化剂的存在下，使市售或利用公知方法可以制备的化合物ah在0℃～150℃、优选20℃～100℃下反应0.5小时～48小时、优选1小时～24小时，可以得到化合物ai。
步骤二
向甲苯、氯仿、四氢呋喃等溶剂中加入化合物ai、和氨或甲胺、二乙胺等具有对应于目标化合物的取代基的胺，使之在0℃～150℃、优选20℃～100℃下反应0.5小时～48小时、优选1小时～24小时，可以得到化合物(I-11)。
酰基氨基衍生物-1
[化学式27]
(式中，R17为可具有取代基的低级烷基、可具有取代基的烃环或可具有取代基的杂环式基团等，其他记号定义同上)
在四氢呋喃、二氯甲烷等溶剂的存在或非存在下，在吡啶、三乙胺等碱的存在或非存在下，使R2b为氢的化合物(I-12)与苯甲酰氯、2-糠酰氯、乙酸酐等具有对应于目标化合物的取代基的酰化剂在-80℃～100℃、优选-20℃～40℃下反应0.1小时～24小时、优选1小时～12小时，或者使化合物(I-12)与氨基酸、羟基乙酸等具有对应于目标化合物的取代基的羧酸在二甲基甲酰胺、四氢呋喃、二氯甲烷等溶剂中，在二环己基碳二亚胺、羰基二咪唑等脱水缩合剂的存在下，在-80℃～100℃、优选-20℃～40℃下反应0.1小时～24小时、优选1小时～12小时，可以得到化合物(I-13)和/或(I-14)(R2a为氢时)。
胍基衍生物
[化学式28]
(式中，各记号定义同上)
在乙腈、四氢呋喃、二甲基甲酰胺等溶剂中，在三乙胺、碳酸氢钠等碱的存在或非存在下，使R2b为氢的化合物(I-12)与3,5-二甲基吡唑-1-羧基脒或S-甲基异硫脲等在0℃～150℃、优选20℃～100℃下反应0.5小时～120小时、优选1小时～24小时，可以得到化合物(I-15)。
氨基甲酰基衍生物
[化学式29]
(式中，CONR18R19为可具有取代基的氨基甲酰基，其他记号定义同上)
在二甲基甲酰胺、四氢呋喃、二氯甲烷等溶剂中，在二环己基碳二亚胺、羰基二咪唑、二环己基碳二亚胺-N-羟基苯并***等脱水缩合剂的存在下，使具有羧基的化合物(I-16)作为环A的取代基与具有对应于目标化合物的取代基的伯胺或仲胺(苯胺、2-氨基吡啶、二甲胺等)在-80℃～100℃、优选-20℃～40℃下反应0.1小时～24小时、优选1小时～12小时，可以得到化合物(I-17)。
酰基氨基衍生物-2
[化学式30]
(式中，NHR20为可具有取代基的氨基；NR20COR21为可具有取代基的酰基氨基、可具有取代基的脲基、氧上具有取代基的羧基氨基；其他各记号定义同上)
使环A中具有可具有取代基的氨基的化合物(I-18)与具有对应于目标化合物的取代基的酰氯类、酸酐、氯碳酸酯类、异氰酸酯类等反应剂(苯甲酰氯、2-糠酰氯、乙酸酐、氯碳酸苄酯、二碳酸二叔丁酯、苯基异氰酸酯等)在四氢呋喃、二氯甲烷等溶剂的存在或非存在下，在吡啶、三乙胺等碱的存在或非存在下，在-80℃～100℃、优选-20℃～40℃下反应0.1小时～24小时、优选1小时～12小时，或者使化合物(I-18)与苯甲酸、2-吡啶碳酸等具有对应于目标化合物的取代基的羧酸在二甲基甲酰胺、四氢呋喃、二氯甲烷等溶剂中，在二环己基碳二亚胺、羰基二咪唑、二环己基碳二亚胺-N-羟基苯并***等脱水缩合剂的存在下，在-80℃～100℃、优选-20℃～40℃下反应0.1小时～24小时、优选1小时～12小时，可以得到化合物(I-19)。
烷基氨基衍生物
[化学式31]
(式中，NHR20为可具有取代基的氨基，R22为低级烷基)
在二氯甲烷，四氢呋喃等溶剂中，在乙酸等酸的存在下或非存在下，使环A中具有氨基的化合物(I-18)与苯甲醛、吡啶-2-甲醛等具有对应于目标化合物的取代基的醛和氰基三氢硼酸钠、三乙酰氧基硼氢化钠等还原剂在-80℃～100℃、优选0℃～40℃下反应0.5小时～150小时、优选1小时～24小时，可以得到化合物(I-20)。
取代烷氧基衍生物
[化学式32]
(式中，R23为可具有取代基的低级烷基、可具有取代基的碳环式基团或可具有取代基的杂环式基团等，其他记号定义同上)
在二甲基甲酰胺、四氢呋喃等溶剂中，在碳酸钾、氢氧化钠、氢化钠等碱的存在下，使具有羟基的化合物(I-21)作为A环的取代基与苄基氯、甲基碘等具有对应于目标化合物的取代基的烷基化剂在-80℃～100℃、优选0℃～40℃下反应0.5小时～150小时、优选1小时～24小时，或者使化合物(I-18)与2-氨基乙醇等醇类在二甲基甲酰胺、四氢呋喃等溶剂中、在三苯基膦-偶氮二羧酸二乙酯等Ｍitsunobu反应试剂的存在下，在-80℃～100℃、优选0℃～40℃下反应0.5小时～72小时、优选1小时～24小时，可以得到化合物(I-22)。
通过钯偶联反应导入取代基
[化学式33]
(式中，Hal为卤素；G为可具有取代基的低级烯基、可具有取代基的低级炔基、可具有取代基的低级烷氧基羰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团等；其他记号定义同上)
在四氢呋喃、二甲基甲酰胺、1，2-二甲氧基乙烷、甲醇等溶剂中，在三乙胺、碳酸钠等碱、乙酸钯、氯化钯等钯催化剂和三苯基膦等配位子的存在下，使具有卤素的化合物(I-23)作为环A的取代基与具有对应于目标化合物的取代基的化合物(苯乙烯、丙炔醇、芳基硼酸、一氧化碳等)在微波的照射下或非照射下在-80℃～150℃、优选0℃～100℃下反应0.5小时～72小时、优选1小时～24小时，可以得到化合物(I-24)。
肟衍生物
[化学式34]
(式中，R24为氢或可具有取代基的低级烷基等；R25为氢、可具有取代基的低级烷基、可具有取代基的低级烯基或可具有取代基的碳环式基团或可具有取代基的杂环式基团等；其他记号定义同上)
在甲醇或乙醇等溶剂中，在乙酸钾等添加剂的存在或非存在下，使具有酰基的化合物(I-25)作为环A的取代基与具有对应于目标化合物的取代基的羟胺类(羟胺、甲氧基胺、邻苄基羟胺等)或其盐在-80℃～100℃、优选0℃～40℃下反应0.5小时～150小时、优选1小时～72小时，可以得到化合物(I-26)。
在上述所有步骤中，当具有成为反应障碍的取代基(例如羟基、巯基、氨基、甲酰基、羰基、羧基等)时，可以按照有机合成中的保护基(ProtectiveGroupsinOrganicSynthesis)TheodoraWGreen(JohnWiley&Sons)等中记载的方法预先进行保护，在希望的阶段除去该保护基。
本发明的化合物(I)中，特别优选X为S、E为单键或亚甲基的以下化合物。
1)式(I’)所示的化合物：
[化学式35]
(式中，t为0或1；其他各记号与上述(a)同义，其中以下化合物除外。
i)n+m为2、R5为氢、环A为未取代的苯基的化合物；
ii)n为2、m为0、R2a为氢、R2b为氢或乙酰基、R5为甲基、环A为苯基或4-甲氧基苯基的化合物；
iii)n为2、m为0、R2a为氢、R2b为氢或乙酰基、R5为乙基、环A为3,4-二甲氧基苯基的化合物；
iv)n为2、m为0、R2a为氢、R2b为氢或乙酰基、R5和环A为苯基的化合物；
v)n为2、m为0、R2a和R2b为氢、R5和环A一起形成：
[化学式36]
的化合物；
vi)n+m为1或2、R5为氢、环A为只被选自羟基、卤素、低级烷基、低级烷氧基、硝基、氨基、低级烷基羰基氨基、巯基、低级烷硫基、氨基甲酰基、低级烷基氨基、低级烷基氨基甲酰基和低级烷氧基羰基的1～2个取代基取代的苯基、未取代的苯基或未取代的萘基的化合物)。
另外，式(I’)中优选以下化合物。
2)n为1、m为0的化合物(以下该化合物由nm-1表示)；
3)n为2、m为0的化合物(以下该化合物由nm-2表示)；
4)n为3、m为0的化合物(以下该化合物由nm-3表示)；
5)R2a为氢，R2b为氢、可具有取代基的低级烷基、可具有取代基的酰基、可具有取代基的低级烷基磺酰基、可具有取代基的脒基的化合物(以下该化合物由R2-1表示)；
6)R2a为氢，R2b为氢、可具有取代基的低级烷基或可具有取代基的酰基的化合物(以下该化合物由R2-2表示)；
7)NR2aR2b为：
[化学式37]
(各记号定义同上)；R6、R7和R8各自独立表示氢、低级烷基或酰基；Y为可具有取代基的低级亚烷基、可具有取代基的低级亚烯基或可具有取代基的低级亚炔基；Z为O或S的化合物(以下该化合物由R2-3表示)；
8)NR2aR2b为NH2的化合物(以下该化合物由R2-4表示)；
9)环A为取代的苯基或取代的吡啶基的化合物(以下该化合物由A-1表示)；
10)环A为：
[化学式38]
(R9、R10和R11为氢或G；
G为卤素、羟基、氰基、硝基、巯基、可具有取代基的低级烷基、可具有取代基的低级烷氧基、可具有取代基的低级烯基、可具有取代基的低级炔基、可具有取代基的酰基、可具有取代基的酰氧基、羧基、可具有取代基的低级烷氧基羰基、可具有取代基的低级烷氧基羰基氧基、可具有取代基的芳氧基羰基氧基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的氨基甲酰氧基、可具有取代基的低级烷硫基、可具有取代基的芳硫基、可具有取代基的低级烷基磺酰基、可具有取代基的芳基磺酰基、可具有取代基的低级烷基亚硫酰基、可具有取代基的芳基亚硫酰基、可具有取代基的低级烷基磺酰氧基、可具有取代基的芳基磺酰氧基、可具有取代基的氨磺酰基、可具有取代基的碳环式基团、可具有取代基的碳环氧基、可具有取代基的杂环式基团或可具有取代基的杂环氧基；各G可以不同)(以下由A-2表示)；
11)环A为：
[化学式39]
(R9和R10各自独立表示氢、卤素、羟基、可具有取代基的低级烷基、氰基、硝基、可具有取代基的低级烷氧基、可具有取代基的酰基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的氨基甲酰氧基、可具有取代基的低级烷基磺酰基、可具有取代基的芳基磺酰基、可具有取代基的低级烷基磺酰氧基、可具有取代基的芳基磺酰氧基、可具有取代基的碳环式基团、可具有取代基的碳环氧基、可具有取代基的杂环式基团或可具有取代基的杂环氧基；G与上述10同义)的化合物(以下该化合物由A-3表示)；
12)环A为：
[化学式40]
(R9和R10与11)同义，G与上述10)同义)的化合物(以下该化合物由A-4表示)；
13)环A、R9和R10为11)所定义的基团、G为可具有取代基的氨基的化合物(以下该化合物由A-5表示)；
14)环A、R9和R10为11)定义的基团、G为可具有取代基的芳基羰基氨基或可具有取代基的杂环羰基氨基的化合物；
15)环A、R9和R10为11)所定义的基团、G为可具有取代基的杂环羰基氨基的化合物(以下该化合物由A-6表示)；
16)环A为11)所定义的基团、G为：
[化学式41]
(Q1、Q2和Q3各自独立表示单键、可具有取代基的低级亚烷基或可具有取代基的低级亚烯基；
Q4为可具有取代基的低级亚烷基或可具有取代基的低级亚烯基；
W1和W2各自独立表示O或S；
W3为O、S或NR12；
R12为氢、低级烷基、羟基低级烷基、低级烷氧基低级烷基、低级烷氧基羰基低级烷基、碳环低级烷基或酰基；
R14为氢或低级烷基；
环B为可具有取代基的碳环式基团或可具有取代基的杂环式基团；
Alk2为可具有取代基的低级烷基)、R9和R10与11)同义的化合物(以下该化合物由A-7表示)；
17)环A、R9和R10为11)所定义的基团、G为16)所定义的基团、环B为可被选自卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基、可具有取代基的酰基、可具有取代基的氨基、氰基、可具有取代基的氨基甲酰基、可具有取代基的碳环式基团、可具有取代基的碳环氧基或可具有取代基的杂环式基团的一个以上基团分别
取代的芳基或杂芳基、其他记号与16)同义的化合物(以下该化合物由A-8表示)；
18)环A、R9和R10为11)所定义的基团、G为：
[化学式42]
(式中，各记号与16)同义)的化合物(以下该化合物由A-9表示)；
19)环A为：
[化学式43]
G为16)所定义的基团，环B为可具有取代基的芳基或可具有取代基的杂芳基，R9和R10的其中之一为氢；且另一个为氢、卤素、可具有取代基的低级烷基、氰基、硝基、可具有取代基的低级烷氧基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的低级烷基磺酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团的化合物(以下该化合物由A-10表示)；
20)环A为：
[化学式44]
G为18)所定义的基团、其他记号与19)同义的化合物(以下该化合物由A-11表示)；
21)环A为：
[化学式45]
G为16)所定义的基团、环B为分别可以具有取代基的苯基、5～6元杂芳基、苯并噻二唑基或苯并噻吩基、R9和R10与19)同义的化合物(以下该化合物由A-12表示)；
22)环A为：
[化学式46]
G为18)所定义的基团、环B与21)同义、R9和R10与19)同义的化合物(以下该化合物由A-13表示)；
23)环A为：
[化学式47]
(式中，R9为氢、卤素、可具有取代基的低级烷基、氰基、硝基、可具有取代基的低级烷氧基、可具有取代基的氨基、可具有取代基的氨基甲酰基、可具有取代基的低级烷基磺酰基、可具有取代基的碳环式基团或可具有取代基的杂环式基团；环B与21)同义；R12为氢或低级烷基)的化合物(以下该化合物由A-14表示)；
24)R5为氢或C1～C3烷基的化合物(以下该化合物由R5-1表示)；
25)R5为C1～C3烷基的化合物(以下该化合物由R5-2表示)；
26)R5为甲基的化合物(以下该化合物由R5-3表示)；
27)R3a和R3b各自独立表示氢、卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基或可具有取代基的芳基的化合物(以下该化合物由R3-1表示)；
28)R3a为氢、卤素、羟基、可具有取代基的低级烷基、可具有取代基的低级烷氧基或可具有取代基的芳基，R3b为氢，当n为2时1个R3a为氢，当n为3时1～2个R2a为氢的化合物(以下该化合物由R3-2表示)；
29)R3a和R3b全部为氢的化合物(以下该化合物由R3-3表示)；
式(I’)中，n、m、R2a、R2b、环A、R5、R3a和R3b的组合(nm、R2、A、R5、R3)为以下组合的化合物。
(nm、R2、A、R5、R3)＝(nm-1,R2-1,A-1,R5-1,R3-1),(nm-1,R2-1,A-1,R5-1,R3-2),(nm-1,R2-1,A-1,R5-2,R3-1),(nm-1,R2-1,A-1,R5-2,R3-2),(nm-1,R2-1,A-1,R5-3,R3-1),(nm-1,R2-1,A-1,R5-3,R3-2),(nm-1,R2-1,A-2,R5-1,R3-1),(nm-1,R2-1,A-2,R5-1,R3-2),(nm-1,R2-1,A-2,R5-2,R3-1),(nm-1,R2-1,A-2,R5-2,R3-2),(nm-1,R2-1,A-2,R5-3,R3-1),(nm-1,R2-1,A-2,R5-3,R3-2),(nm-1,R2-1,A-3,R5-1,R3-1),(nm-1,R2-1,A-3,R5-1,R3-2),(nm-1,R2-1,A-3,R5-2,R3-1),(nm-1,R2-1,A-3,R5-2,R3-2),(nm-1,R2-1,A-3,R5-3,R3-1),(nm-1,R2-1,A-3,R5-3,R3-2),(nm-1,R2-1,A-4,R5-1,R3-1),(nm-1,R2-1,A-4,R5-1,R3-2),(nm-1,R2-1,A-4,R5-2,R3-1),(nm-1,R2-1,A-4,R5-2,R3-2),(nm-1,R2-1,A-4,R5-3,R3-1),(nm-1,R2-1,A-4,R5-3,R3-2),(nm-1,R2-1,A-5,R5-1,R3-1),(nm-1,R2-1,A-5,R5-1,R3-2),(nm-1,R2-1,A-5,R5-2,R3-1),(nm-1,R2-1,A-5,R5-2,R3-2),(nm-1,R2-1,A-5,R5-3,R3-1),(nm-1,R2-1,A-5,R5-3,R3-2),(nm-1,R2-1,A-6,R5-1,R3-1),(nm-1,R2-1,A-6,R5-1,R3-2),(nm-1,R2-1,A-6,R5-2,R3-1),(nm-1,R2-1,A-6,R5-2,R3-2),(nm-1,R2-1,A-6,R5-3,R3-1),(nm-1,R2-1,A-6,R5-3,R3-2),(nm-1,R2-1,A-7,R5-1,R3-1),(nm-1,R2-1,A-7,R5-1,R3-2),(nm-1,R2-1,A-7,R5-2,R3-1),(nm-1,R2-1,A-7,R5-2,R3-2),(nm-1,R2-1,A-7,R5-3,R3-1),(nm-1,R2-1,A-7,R5-3,R3-2),(nm-1,R2-1,A-8,R5-1,R3-1),(nm-1,R2-1,A-8,R5-1,R3-2),(nm-1,R2-1,A-8,R5-2,R3-1),(nm-1,R2-1,A-8,R5-2,R3-2),(nm-1,R2-1,A-8,R5-3,R3-1),(nm-1,R2-1,A-8,R5-3,R3-2),(nm-1,R2-1,A-9,R5-1,R3-1),(nm-1,R2-1,A-9,R5-1,R3-2),(nm-1,R2-1,A-9,R5-2,R3-1),(nm-1,R2-1,A-9,R5-2,R3-2),(nm-1,R2-1,A-9,R5-3,R3-1),(nm-1,R2-1,A-9,R5-3,R3-2),(nm-1,R2-1,A-10,R5-1,R3-1),(nm-1,R2-1,A-10,R5-1,R3-2),(nm-1,R2-1,A-10,R5-2,R3-1),(nm-1,R2-1,A-10,R5-2,R3-2),(nm-1,R2-1,A-10,R5-3,R3-1),(nm-1,R2-1,A-10,R5-3,R3-2),(nm-1,R2-1,A-11,R5-1,R3-1),(nm-1,R2-1,A-11,R5-1,R3-2),(nm-1,R2-1,A-11,R5-2,R3-1),(nm-1,R2-1,A-11,R5-2,R3-2),(nm-1,R2-1,A-11,R5-3,R3-1),(nm-1,R2-1,A-11,R5-3,R3-2),(nm-1,R2-1,A-12,R5-1,R3-1),(nm-1,R2-1,A-12,R5-1,R3-2),(nm-1,R2-1,A-12,R5-2,R3-1),(nm-1,R2-1,A-12,R5-2,R3-2),(nm-1,R2-1,A-12,R5-3,R3-1),(nm-1,R2-1,A-12,R5-3,R3-2),(nm-1,R2-1,A-13,R5-1,R3-1),(nm-1,R2-1,A-13,R5-1,R3-2),(nm-1,R2-1,A-13,R5-2,R3-1),(nm-1,R2-1,A-13,R5-2,R3-2),(nm-1,R2-1,A-13,R5-3,R3-1),(nm-1,R2-1,A-13,R5-3,R3-2),(nm-1,R2-1,A-14,R5-1,R3-1),(nm-1,R2-1,A-14,R5-1,R3-2),(nm-1,R2-1,A-14,R5-2,R3-1),(nm-1,R2-1,A-14,R5-2,R3-2),(nm-1,R2-1,A-14,R5-3,R3-1),(nm-1,R2-1,A-14,R5-3,R3-2),(nm-1,R2-2,A-1,R5-1,R3-1),(nm-1,R2-2,A-1,R5-1,R3-2),(nm-1,R2-2,A-1,R5-2,R3-1),(nm-1,R2-2,A-1,R5-2,R3-2),(nm-1,R2-2,A-1,R5-3,R3-1),(nm-1,R2-2,A-1,R5-3,R3-2),(nm-1,R2-2,A-2,R5-1,R3-1),(nm-1,R2-2,A-2,R5-1,R3-2),(nm-1,R2-2,A-2,R5-2,R3-1),(nm-1,R2-2,A-2,R5-2,R3-2),(nm-1,R2-2,A-2,R5-3,R3-1),(nm-1,R2-2,A-2,R5-3,R3-2),(nm-1,R2-2,A-3,R5-1,R3-1),(nm-1,R2-2,A-3,R5-1,R3-2),(nm-1,R2-2,A-3,R5-2,R3-1),(nm-1,R2-2,A-3,R5-2,R3-2),(nm-1,R2-2,A-3,R5-3,R3-1),(nm-1,R2-2,A-3,R5-3,R3-2),(nm-1,R2-2,A-4,R5-1,R3-1),(nm-1,R2-2,A-4,R5-1,R3-2),(nm-1,R2-2,A-4,R5-2,R3-1),(nm-1,R2-2,A-4,R5-2,R3-2),(nm-1,R2-2,A-4,R5-3,R3-1),(nm-1,R2-2,A-4,R5-3,R3-2),(nm-1,R2-2,A-5,R5-1,R3-1),(nm-1,R2-2,A-5,R5-1,R3-2),(nm-1,R2-2,A-5,R5-2,R3-1),(nm-1,R2-2,A-5,R5-2,R3-2),(nm-1,R2-2,A-5,R5-3,R3-1),(nm-1,R2-2,A-5,R5-3,R3-2),(nm-1,R2-2,A-6,R5-1,R3-1),(nm-1,R2-2,A-6,R5-1,R3-2),(nm-1,R2-2,A-6,R5-2,R3-1),(nm-1,R2-2,A-6,R5-2,R3-2),(nm-1,R2-2,A-6,R5-3,R3-1),(nm-1,R2-2,A-6,R5-3,R3-2),(nm-1,R2-2,A-7,R5-1,R3-1),(nm-1,R2-2,A-7,R5-1,R3-2),(nm-1,R2-2,A-7,R5-2,R3-1),(nm-1,R2-2,A-7,R5-2,R3-2),(nm-1,R2-2,A-7,R5-3,R3-1),(nm-1,R2-2,A-7,R5-3,R3-2),(nm-1,R2-2,A-8,R5-1,R3-1),(nm-1,R2-2,A-8,R5-1,R3-2),(nm-1,R2-2,A-8,R5-2,R3-1),(nm-1,R2-2,A-8,R5-2,R3-2),(nm-1,R2-2,A-8,R5-3,R3-1),(nm-1,R2-2,A-8,R5-3,R3-2),(nm-1,R2-2,A-9,R5-1,R3-1),(nm-1,R2-2,A-9,R5-1,R3-2),(nm-1,R2-2,A-9,R5-2,R3-1),(nm-1,R2-2,A-9,R5-2,R3-2),(nm-1,R2-2,A-9,R5-3,R3-1),(nm-1,R2-2,A-9,R5-3,R3-2),(nm-1,R2-2,A-10,R5-1,R3-1),(nm-1,R2-2,A-10,R5-1,R3-2),(nm-1,R2-2,A-10,R5-2,R3-1),(nm-1,R2-2,A-10,R5-2,R3-2),(nm-1,R2-2,A-10,R5-3,R3-1),(nm-1,R2-2,A-10,R5-3,R3-2),(nm-1,R2-2,A-11,R5-1,R3-1),(nm-1,R2-2,A-11,R5-1,R3-2),(nm-1,R2-2,A-11,R5-2,R3-1),(nm-1,R2-2,A-11,R5-2,R3-2),(nm-1,R2-2,A-11,R5-3,R3-1),(nm-1,R2-2,A-11,R5-3,R3-2),(nm-1,R2-2,A-12,R5-1,R3-1),(nm-1,R2-2,A-12,R5-1,R3-2),(nm-1,R2-2,A-12,R5-2,R3-1),(nm-1,R2-2,A-12,R5-2,R3-2),(nm-1,R2-2,A-12,R5-3,R3-1),(nm-1,R2-2,A-12,R5-3,R3-2),(nm-1,R2-2,A-13,R5-1,R3-1),(nm-1,R2-2,A-13,R5-1,R3-2),(nm-1,R2-2,A-13,R5-2,R3-1),(nm-1,R2-2,A-13,R5-2,R3-2),(nm-1,R2-2,A-13,R5-3,R3-1),(nm-1,R2-2,A-13,R5-3,R3-2),(nm-1,R2-2,A-14,R5-1,R3-1),(nm-1,R2-2,A-14,R5-1,R3-2),(nm-1,R2-2,A-14,R5-2,R3-1),(nm-1,R2-2,A-14,R5-2,R3-2),(nm-1,R2-2,A-14,R5-3,R3-1),(nm-1,R2-2,A-14,R5-3,R3-2),(nm-1,R2-3,A-1,R5-1,R3-1),(nm-1,R2-3,A-1,R5-1,R3-2),(nm-1,R2-3,A-1,R5-2,R3-1),(nm-1,R2-3,A-1,R5-2,R3-2),(nm-1,R2-3,A-1,R5-3,R3-1),(nm-1,R2-3,A-1,R5-3,R3-2),(nm-1,R2-3,A-2,R5-1,R3-1),(nm-1,R2-3,A-2,R5-1,R3-2),(nm-1,R2-3,A-2,R5-2,R3-1),(nm-1,R2-3,A-2,R5-2,R3-2),(nm-1,R2-3,A-2,R5-3,R3-1),(nm-1,R2-3,A-2,R5-3,R3-2),(nm-1,R2-3,A-3,R5-1,R3-1),(nm-1,R2-3,A-3,R5-1,R3-2),(nm-1,R2-3,A-3,R5-2,R3-1),(nm-1,R2-3,A-3,R5-2,R3-2),(nm-1,R2-3,A-3,R5-3,R3-1),(nm-1,R2-3,A-3,R5-3,R3-2),(nm-1,R2-3,A-4,R5-1,R3-1),(nm-1,R2-3,A-4,R5-1,R3-2),(nm-1,R2-3,A-4,R5-2,R3-1),(nm-1,R2-3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(nm-3,R2-3,A-4,R5-3,R3-1),(nm-3,R2-3,A-4,R5-3,R3-2),(nm-3,R2-3,A-5,R5-1,R3-1),(nm-3,R2-3,A-5,R5-1,R3-2),(nm-3,R2-3,A-5,R5-2,R3-1),(nm-3,R2-3,A-5,R5-2,R3-2),(nm-3,R2-3,A-5,R5-3,R3-1),(nm-3,R2-3,A-5,R5-3,R3-2),(nm-3,R2-3,A-6,R5-1,R3-1),(nm-3,R2-3,A-6,R5-1,R3-2),(nm-3,R2-3,A-6,R5-2,R3-1),(nm-3,R2-3,A-6,R5-2,R3-2),(nm-3,R2-3,A-6,R5-3,R3-1),(nm-3,R2-3,A-6,R5-3,R3-2),(nm-3,R2-3,A-7,R5-1,R3-1),(nm-3,R2-3,A-7,R5-1,R3-2),(nm-3,R2-3,A-7,R5-2,R3-1),(nm-3,R2-3,A-7,R5-2,R3-2),(nm-3,R2-3,A-7,R5-3,R3-1),(nm-3,R2-3,A-7,R5-3,R3-2),(nm-3,R2-3,A-8,R5-1,R3-1),(nm-3,R2-3,A-8,R5-1,R3-2),(nm-3,R2-3,A-8,R5-2,R3-1),(nm-3,R2-3,A-8,R5-2,R3-2),(nm-3,R2-3,A-8,R5-3,R3-1),(nm-3,R2-3,A-8,R5-3,R3-2),(nm-3,R2-3,A-9,R5-1,R3-1),(nm-3,R2-3,A-9,R5-1,R3-2),(nm-3,R2-3,A-9,R5-2,R3-1),(nm-3,R2-3,A-9,R5-2,R3-2),(nm-3,R2-3,A-9,R5-3,R3-1),(nm-3,R2-3,A-9,R5-3,R3-2),(nm-3,R2-3,A-10,R5-1,R3-1),(nm-3,R2-3,A-10,R5-1,R3-2),(nm-3,R2-3,A-10,R5-2,R3-1),(nm-3,R2-3,A-10,R5-2,R3-2),(nm-3,R2-3,A-10,R5-3,R3-1),(nm-3,R2-3,A-10,R5-3,R3-2),(nm-3,R2-3,A-11,R5-1,R3-1),(nm-3,R2-3,A-11,R5-1,R3-2),(nm-3,R2-3,A-11,R5-2,R3-1),(nm-3,R2-3,A-11,R5-2,R3-2),(nm-3,R2-3,A-11,R5-3,R3-1),(nm-3,R2-3,A-11,R5-3,R3-2),(nm-3,R2-3,A-12,R5-1,R3-1),(nm-3,R2-3,A-12,R5-1,R3-2),(nm-3,R2-3,A-12,R5-2,R3-1),(nm-3,R2-3,A-12,R5-2,R3-2),(nm-3,R2-3,A-12,R5-3,R3-1),(nm-3,R2-3,A-12,R5-3,R3-2),(nm-3,R2-3,A-13,R5-1,R3-1),(nm-3,R2-3,A-13,R5-1,R3-2),(nm-3,R2-3,A-13,R5-2,R3-1),(nm-3,R2-3,A-13,R5-2,R3-2),(nm-3,R2-3,A-13,R5-3,R3-1),(nm-3,R2-3,A-13,R5-3,R3-2),(nm-3,R2-3,A-14,R5-1,R3-1),(nm-3,R2-3,A-14,R5-1,R3-2),(nm-3,R2-3,A-14,R5-2,R3-1),(nm-3,R2-3,A-14,R5-2,R3-2),(nm-3,R2-3,A-14,R5-3,R3-1),(nm-3,R2-3,A-14,R5-3,R3-2),(nm-3,R2-4,A-1,R5-1,R3-1),(nm-3,R2-4,A-1,R5-1,R3-2),(nm-3,R2-4,A-1,R5-2,R3-1),(nm-3,R2-4,A-1,R5-2,R3-2),(nm-3,R2-4,A-1,R5-3,R3-1),(nm-3,R2-4,A-1,R5-3,R3-2),(nm-3,R2-4,A-2,R5-1,R3-1),(nm-3,R2-4,A-2,R5-1,R3-2),(nm-3,R2-4,A-2,R5-2,R3-1),(nm-3,R2-4,A-2,R5-2,R3-2),(nm-3,R2-4,A-2,R5-3,R3-1),(nm-3,R2-4,A-2,R5-3,R3-2),(nm-3,R2-4,A-3,R5-1,R3-1),(nm-3,R2-4,A-3,R5-1,R3-2),(nm-3,R2-4,A-3,R5-2,R3-1),(nm-3,R2-4,A-3,R5-2,R3-2),(nm-3,R2-4,A-3,R5-3,R3-1),(nm-3,R2-4,A-3,R5-3,R3-2),(nm-3,R2-4,A-4,R5-1,R3-1),(nm-3,R2-4,A-4,R5-1,R3-2),(nm-3,R2-4,A-4,R5-2,R3-1),(nm-3,R2-4,A-4,R5-2,R3-2),(nm-3,R2-4,A-4,R5-3,R3-1),(nm-3,R2-4,A-4,R5-3,R3-2),(nm-3,R2-4,A-5,R5-1,R3-1),(nm-3,R2-4,A-5,R5-1,R3-2),(nm-3,R2-4,A-5,R5-2,R3-1),(nm-3,R2-4,A-5,R5-2,R3-2),(nm-3,R2-4,A-5,R5-3,R3-1),(nm-3,R2-4,A-5,R5-3,R3-2),(nm-3,R2-4,A-6,R5-1,R3-1),(nm-3,R2-4,A-6,R5-1,R3-2),(nm-3,R2-4,A-6,R5-2,R3-1),(nm-3,R2-4,A-6,R5-2,R3-2),(nm-3,R2-4,A-6,R5-3,R3-1),(nm-3,R2-4,A-6,R5-3,R3-2),(nm-3,R2-4,A-7,R5-1,R3-1),(nm-3,R2-4,A-7,R5-1,R3-2),(nm-3,R2-4,A-7,R5-2,R3-1),(nm-3,R2-4,A-7,R5-2,R3-2),(nm-3,R2-4,A-7,R5-3,R3-1),(nm-3,R2-4,A-7,R5-3,R3-2),(nm-3,R2-4,A-8,R5-1,R3-1),(nm-3,R2-4,A-8,R5-1,R3-2),(nm-3,R2-4,A-8,R5-2,R3-1),(nm-3,R2-4,A-8,R5-2,R3-2),(nm-3,R2-4,A-8,R5-3,R3-1),(nm-3,R2-4,A-8,R5-3,R3-2),(nm-3,R2-4,A-9,R5-1,R3-1),(nm-3,R2-4,A-9,R5-1,R3-2),(nm-3,R2-4,A-9,R5-2,R3-1),(nm-3,R2-4,A-9,R5-2,R3-2),(nm-3,R2-4,A-9,R5-3,R3-1),(nm-3,R2-4,A-9,R5-3,R3-2),(nm-3,R2-4,A-10,R5-1,R3-1),(nm-3,R2-4,A-10,R5-1,R3-2),(nm-3,R2-4,A-10,R5-2,R3-1),(nm-3,R2-4,A-10,R5-2,R3-2),(nm-3,R2-4,A-10,R5-3,R3-1),(nm-3,R2-4,A-10,R5-3,R3-2),(nm-3,R2-4,A-11,R5-1,R3-1),(nm-3,R2-4,A-11,R5-1,R3-2),(nm-3,R2-4,A-11,R5-2,R3-1),(nm-3,R2-4,A-11,R5-2,R3-2),(nm-3,R2-4,A-11,R5-3,R3-1),(nm-3,R2-4,A-11,R5-3,R3-2),(nm-3,R2-4,A-12,R5-1,R3-1),(nm-3,R2-4,A-12,R5-1,R3-2),(nm-3,R2-4,A-12,R5-2,R3-1),(nm-3,R2-4,A-12,R5-2,R3-2),(nm-3,R2-4,A-12,R5-3,R3-1),(nm-3,R2-4,A-12,R5-3,R3-2),(nm-3,R2-4,A-13,R5-1,R3-1),(nm-3,R2-4,A-13,R5-1,R3-2),(nm-3,R2-4,A-13,R5-2,R3-1),(nm-3,R2-4,A-13,R5-2,R3-2),(nm-3,R2-4,A-13,R5-3,R3-1),(nm-3,R2-4,A-13,R5-3,R3-2),(nm-3,R2-4,A-14,R5-1,R3-1),(nm-3,R2-4,A-14,R5-1,R3-2),(nm-3,R2-4,A-14,R5-2,R3-1),(nm-3,R2-4,A-14,R5-2,R3-2),(nm-3,R2-4,A-14,R5-3,R3-1),(nm-3,R2-4,A-14,R5-3,R3-2),(nm-3,R2-4,A-14,R5-3,R3-3)。
式(I’)中，n、m、R2a、R2b、环A、R5、R3a和R3b的组合(nm、R2、A、R5、R3)为上述任一组合、E为单键的化合物。
本发明的化合物对由淀粉状β蛋白的产生、分泌或沉积所诱发的疾病有用，例如对阿尔茨海默型痴呆(阿尔茨海默病、阿尔茨海默型老年痴呆等)、唐氏综合征、记忆障碍、朊毒病(早老痴呆症等)、轻度认知障碍(MCI)、荷兰型遗传性淀粉状脑出血、脑淀粉状血管障碍、其他变性痴呆、血管性变性混合型痴呆、帕金森病所伴随的痴呆、进行性核上麻痹所伴随的痴呆、皮质基底核变性症所伴随的痴呆、弥漫性路易小体型阿尔茨海默病、老年黄斑病变、帕金森病、淀粉状血管病等的治疗和/或予防、症状改善有效。
给予本发明化合物时，可以和其他药物(例如乙酰胆碱酯酶等其他阿尔茨海默病治疗药等)结合使用。例如可以和盐酸多奈培齐、他可林、加兰他敏、利凡斯的明、扎那培齐(Zanapezil)、美金刚、长春西汀等抗痴呆药等结合使用。
对人给予本发明化合物时，可以作为散剂、颗粒剂、片剂、胶囊剂、丸剂、溶液剂等进行口服给药；或者作为注射剂、栓剂、经皮吸收剂、吸入剂等进行非口服给药。还可以根据需要向有效量的本化合物中混合适合该剂型的赋形剂、粘合剂、润湿剂、崩解剂、润滑剂等药用添加剂制成药物制剂。
给药量根据疾病的状态、给药途径、患者的年龄或体重而异，对成人口服给药时，通常为0.1μg～1g/天，优选为0.01～200mg/天；非口服给药时，通常为1μg～10g/天，优选为0.1～2g/天。
以下例举出实施例和试验例来进一步详细说明本发明，但本发明并不受限于此。
实施例中各缩写的意思如下。
Ｍe：甲基
Et：乙基
iPr、Prｉ：异丙基
Ph：苯基
Bn：苄基
Boc：叔丁氧基羰基
TBDPS：叔丁基二苯基甲硅烷基
[实施例1]
化合物588的合成
[化学式48]
步骤一
在氮气环境下，将7.98g化合物(1-1)溶解在330ml二乙基醚-36ml四氢呋喃的混合溶剂中，边用干冰-丙酮浴冷却边加入44.8ml(1.32mol/L)的乙烯基氯化镁的四氢呋喃溶液，搅拌20分钟。之后，将反应液在冰冷下搅拌30分钟、在室温下搅拌35分钟。加入饱和氯化铵水溶液，用乙酸乙酯进行提取，有机层经饱和氯化铵水溶液、饱和碳酸氢钠水溶液、饱和食盐水依次洗涤，之后用无水硫酸镁干燥，减压下馏去溶剂。残余物用中压硅胶柱层析进行纯化，得到6.00g化合物
(1-2)。
1H-NMR(CDCl3):1.63(3H,s),2.08(1H,br),5.20(1H,dd,J=10.6,1.6Hz),5.31(1H,dd,J=17.1,1.6Hz),6.09(1H,m),7.46(1H,m),7.52(1H,dd,J=3.4,2.6Hz),7.80(1H,dd,J=3.9,2.6Hz),8.06(1H,br).
步骤二
将6.36g化合物(1-2)溶解在30ml乙酸中，加入1.50g硫脲、20.7ml(1mol/L)的盐酸乙酸溶液，在室温下搅拌3小时、在40℃下搅拌3小时，进一步在室温下搅拌66小时、在40℃下搅拌19小时。追加0.450g硫脲、7.53ml(1mol/L)的盐酸乙酸溶液，在40℃下搅拌23小时。确认化合物(1-2)消失后，减压下馏去溶剂，使残余物从甲醇/二乙基醚中结晶，得到5.23g为晶体的化合物(1-3)。另外，将母液在减压下浓缩干固，得到3.00g作为固体粗产物的化合物(1-3)。
1H-NMR(DMSO-d6):2.09(3H,s),4.10(2H,d,J=7.3Hz),5.94(1H,t,J=7.7Hz),7.50(1H,s),7.75(1H,s),7.87(1H,s),9.17(3H,br),11.46(1H,s).
步骤三
将5.23g化合物(1-3)溶解在25ml三氟乙酸中，冰冷下边搅拌边滴加2.14ml三氟甲磺酸。滴加结束后，将反应液升温至室温，搅拌3.5小时，确认化合物(1-3)消失后，减压下馏去溶剂。向所得残余物中加入水和碳酸钠，用乙酸乙酯提取。有机层经饱和碳酸氢钠水溶液洗涤后，用无水硫酸镁干燥，减压下浓缩干固，得到4.90g作为粗产物的化合物(1-4)。
1H-NMR(CDCl3):1.53(3H,s),1.90(1H,m),2.09(1H,m),2.74(1H,m),2.97(1H,m),4.32(2H,br),7.34(1H,t,J=1.6Hz),7.37(1H,t,J=1.8Hz),7.86(1H,t,J=1.8Hz).
步骤四
在氮气环境下，将4.90g化合物(1-4)溶解在30ml四氢呋喃中，冰冷下边搅拌边加入2.97g二碳酸二叔丁酯、1.89ml三乙胺，搅拌2小时。将反应液升温至室温，进一步搅拌3小时后加入水，用乙酸乙酯提取。有机层用水洗涤，并用无水硫酸镁干燥，之后减压下馏去溶剂。使所得残余物从乙酸乙酯/二乙基醚中结晶，得到4.62g化合物(1-5)。
1H-NMR(CDCl3):1.36(9H,s),1.72(3H,s),2.10(1H,m),2.41(1H,m),2.62(1H,m),2.75(1H,m),7.22(1H,s),7.48(1H,s),8.29(1H,s).
步骤五
将1.00g化合物(1-5)溶解在8.7ml四氢呋喃中，加入4.43ml(1mol/L)的氢氧化锂水溶液，在50℃下搅拌4小时。向反应液中加入水，用乙酸乙酯提取，有机层用水、饱和食盐水依次洗涤，并用无水硫酸镁干燥，之后减压下馏去溶剂。将所得残余物进行中压硅胶柱层析，得到0.668g化合物(1-6)。
1H-NMR(CDCl3):1.51(9H,s),1.63(3H,s),2.06(1H,m),2.40(1H,m),2.68-2.74(2H,m),3.83(2H,br),6.51(1H,t,J=1.8Hz),6.72-6.74(2H,m).
步骤六
将20.0mg化合物(1-6)溶解在4mol/L盐酸-1,4-二烷溶液中，搅拌16小时。减压浓缩反应液，使所得残余物从甲醇/二乙基醚中结晶，得到14.7mg化合物(588)。
1H-NMR(DMSO-d6):1.59(3H,s),2.09-2.76(4H,m),6.44(1H,t,J=1.6Hz),6.60(1H,tJ=1.9Hz),6.71(1H,t,J=2.0Hz),10.4(1H,s).
[实施例2]
化合物835的合成
[化学式49]
步骤一
将2020mg化合物(2-1)溶解在20ml氯仿中，室温下边搅拌边加入4ml水、1470mg硫氰酸钠，之后在冰冷下滴加1.94ml硫酸。滴加结束后将反应液升温至室温，搅拌345分钟，之后在60℃下搅拌一夜。为了利用TLC来确认化合物(2-1)的残留，将反应液冷却至室温，之后依次加入1470mg硫氰酸钠、5ml水、1.94ml硫酸。将反应液升温至60℃后搅拌1天。冰冷下加入饱和碳酸氢钠水溶液使反应液呈碱性，之后用乙酸乙酯提取。有机层经饱和食盐水洗涤后用硫酸镁干燥。减压馏去溶剂，将所得残余物通过硅胶柱层析进行纯化，得到968mg化合物(2-2)。
1H-NMR(CDCl3,270MHz):1.99(3H,s),3.55(1H,d,J=16.1Hz),3.69(1H,d,J=16.1Hz),7.12-7.64(8H,m),7.82-7.95(2H,m).
步骤二
将842mg化合物(2-2)溶解在8.4ml乙醇中，冰冷下边搅拌边依次加入1600mg磷酸二氢钠、113.2mg硼氢化钠的2.8ml水溶液，之后在相同温度下搅拌30分钟。通过TLC确认化合物(2-2)消失后，在冰冷下加入乙酸乙酯和水，搅拌数分钟，之后用乙酸乙酯提取。有机层经水、饱和食盐水依次洗涤后用硫酸镁干燥。减压馏去溶剂，得到904.8mg作为粗产物的化合物(2-3)。
步骤三
将900mg化合物(2-3)溶解在10ml甲苯中，冰冷下边搅拌边加入0.7ml亚硫酰氯的5ml甲苯溶液，之后在相同温度下搅拌1小时。通过TLC确认化合物(2-3)消失后，在减压下浓缩反应液，得到1076.8mg作为粗产物的化合物(2-4)。
步骤四
在室温下将1070mg化合物(2-4)溶解在约7mol/L的氨的20ml甲醇溶液中，在相同温度下搅拌1天。经TLC确认化合物(2-4)消失后，减压下浓缩反应液，得到2633mg作为粗产物的化合物(835)。
[实施例3]
化合物561的合成
[化学式50]
步骤一
冰冷搅拌下向30ml四氢呋喃中少量多次加入0.63g氢化锂铝，之后滴加1.94g化合物(3-1)的40ml四氢呋喃溶液。在室温下反应20分钟、在加热回流下反应3小时后，冰冷搅拌下少量多次加入冰，在室温下搅拌一昼夜。过滤反应液，之后减压下馏去滤液，残余物通过硅胶柱层析进行纯化，得到0.90g化合物(3-2)。
1H-NMR(CDCl3):1.22(3H,s),3.08(1H,d,J=12.5Hz),3.34(1H,d,J=12.5Hz),3.85(1H,d,J=11.0Hz),4.11(1H,d,J=11.0Hz),7.21-7.25(1H,m),7.34-7.40(2H,m),7.46-7.50(2H,m).
步骤二
将0.90g化合物(3-2)溶解在15ml四氢呋喃中，冰冷搅拌下加入0.69g叔丁基异硫氰酸酯的5ml四氢呋喃溶液。在室温下搅拌3天，之后加入水，用二氯甲烷提取，有机层用无水硫酸钠进行干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到1.33g化合物
(3-3)。
1H-NMR(CDCl3):1.12(9H,s),1.34(3H,s),3.15(1H,br),3.76(1H,d,J=11.2Hz),3.87(1H,dd,J=14.2,4.6Hz),4.13(1H,d,J=11.2Hz),4.23(1H,dd,J=14.2,6.6Hz),5.18(1H,br),6.01(1H,br),7.23-7.28(1H,m),7.34-7.41(4H,m).
步骤三
将315mg化合物(3-3)溶解在3ml乙腈中，冰冷搅拌下加入440mg三苯基膦和520mg四氯化碳的3ml乙腈溶液。在室温下搅拌1小时，之后在冰冷搅拌下加入460mg碳酸钾，在室温下搅拌2天后加入水，用二氯甲烷提取，有机层用无水硫酸钠进行干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.23g化合物(3-4)。
1H-NMR(CDCl3):1.30(9H,s),1.36(3H,s),3.13(1H,d,J=12.2Hz),3.24(1H,dd,J=12.2,2.3Hz),3.51(1H,br),3.53(1H,d,J=15.2Hz),3.99(1H,dd,J=15.2,2.3Hz),7.20-7.25(1H,m),7.30-7.36(2H,m),7.39-7.43(2H,m).
步骤四
向0.22g化合物(3-4)中加入4.5ml浓盐酸，加热回流下搅拌2小时，之后减压下馏去反应液。残余物用甲醇/二乙基醚进行结晶，得到0.16g化合物561。
1H-NMR(DMSO-d6):1.33(3H,s),3.33-3.49(2H,m),3.65-3.96(2H,m),7.29(1H,t.J=7.6Hz),7.40(2H,t.J=7.6Hz),7.48(2H,t.J=7.6Hz).
[实施例4]
化合物534的合成
[化学式51]
步骤一
将0.72g化合物(4-1)溶解在15mlN,N-二甲基甲酰胺中，加入0.31g叠氮化钠。在100℃下搅拌13小时，之后加入水，用二乙基醚提取，有机层用无水硫酸钠进行干燥，减压下馏去溶剂，得到0.71g作为粗产物的化合物(4-2)。
步骤二
冰冷搅拌下向0.71g化合物(4-2)的10ml四氢呋喃溶液中少量多次加入0.14g氢化锂铝，之后在室温下搅拌2小时。反应结束后，在冰冷搅拌下少量多次加入冰，室温下搅拌18小时。过滤反应液，之后在减压下馏去滤液，得到0.89g作为粗产物的化合物(4-3)。
步骤三
将0.89g化合物(4-3)溶解在10ml四氢呋喃中，冰冷搅拌下加入0.56g叔丁基异硫氰酸酯的5ml四氢呋喃溶液。室温下搅拌4小时，之后加入水，用二氯甲烷提取，有机层用无水硫酸钠进行干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.72g化合物
(4-4)。
1H-NMR(CDCl3):1.39(9H,s),2.08(3H,s),2.09-2.15(2H,m),3.37-3.44(1H,m),3.80-3.87(1H,m),5.97(1H,br.),6.86(1H,br.),7.28-7.43(5H,m).
步骤四
将120mg化合物(4-4)溶解在2ml乙腈中，冰冷搅拌下加入170mg三苯基膦和200mg四氯化碳的1ml乙腈溶液。室温下搅拌5小时，之后在冰冷搅拌下加入177mg碳酸钾，在室温下搅拌5天，之后加入水，用二氯甲烷提取，有机层用无水硫酸钠进行干燥，并减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.06g化合物(4-5)。
1H-NMR(CDCl3):1.35(9H,s),1.59(3H,s),1.91(1H,ddd,J=13.5,8.8,5.0Hz),2.06(1H,dt,J=13.5,5.0Hz),3.00(1H,ddd,J=15.1,8.8,5.0Hz),3.30(1H,dt,J=15.1,5.0Hz),7.24-7.38(5H,m).
步骤五
向0.06g化合物(4-5)中加入3ml浓盐酸，加热回流下搅拌1小时，之后减压下馏去反应液。残余物用甲醇/水进行结晶，得到0.02g化合物534。
1H-NMR(DMSO-d6):1.43(3H,s),1.77(1H,dt.J=8.4,3.4Hz),2.11(1H,d.J=9.2Hz),2.48-2.50(1H,m),2.83-2.99(1H,m),6.12(1H,br),6.65(1H,br),7.21-7.24(1H,m),
7.31-7.37(4H,m).
[实施例5]
化合物1008的合成
[化学式52]
步骤一
将3.00g化合物(5-1)溶解在30ml乙醇中，加入1.13g硫脲，加热回流26小时，之后减压下馏去反应液。残余物用乙酸乙酯/己烷进行结晶，得到4.03g化合物(5-2)。
1H-NMR(DMSO-d6):1.95(2H,quint,J=6.8Hz),3.13(2H,t,J=6.8Hz),3.21(2H,t,J=6.8Hz),3.85(3H,s),7.06(2H,d,J=8.8Hz),7.95(2H,d,J=8.8Hz),9.18(4H,br).
步骤二
将1.00g化合物(5-2)溶解在25ml四氢呋喃中，加入1.74g二碳酸二叔丁酯和0.88g三乙胺，室温下搅拌3小时，之后加入水，用二氯甲烷提取，有机层用无水硫酸钠干燥，并减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到1.24g化合物(5-3)。
1H-NMR(CDCl3):1.50(9H,s),2.07-2.17(2H,m),2.98(2H,t,J=7.8Hz),3.09(2H,t,J=6.3Hz),6.95(2H,d,J=8.9Hz),7.95(2H,d,J=8.9Hz).
步骤三
将1.18g化合物(5-3)溶解在12ml四氢呋喃中，用乙腈/干冰浴进行冷却，搅拌下加入10.1ml(0.9mol/L)的甲基溴化镁/四氢呋喃溶液，搅拌1小时，之后在室温下搅拌30分钟。反应后在冰冷搅拌下加入饱和氯化铵水溶液，用二乙基醚进行提取，有机层用无水硫酸钠干燥，并减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.39g化合物(5-4)。
1H-NMR(CDCl3):1.51(9H,s),1.63(3H,s),1.55-1.65(2H,m),1.87-1.91(2H,m),2.96-3.12(2H,m),6.86(2H,d,J=8.9Hz),7.36(2H,d,J=8.9Hz).
步骤四
将0.24g化合物(5-4)溶解在6ml三氟乙酸中，室温下搅拌20小时，之后减压下馏去反应液。向残余物中加入水和饱和碳酸氢钠水溶液，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，并减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.06g化合物1008。
1H-NMR(CDCl3):1.54(3H,s),1.77-1.87(1H,m),1.90-1.97(1H,m),2.20-2.36(2H,m),2.67-2.79(2H,m),3.81(3H,s),5.30(2H,br),6.87(2H,d,J=9.0Hz),7.33(2H,d,J=9.0Hz).
[实施例6]
化合物783的合成
[化学式53]
步骤一
将0.55g化合物(6-1)溶解在7ml甲醇中，室温搅拌下加入0.36g甲基碘。在室温下搅拌18小时，之后减压下馏去反应液，得到0.92g作为粗产物的化合物(6-2)。
步骤二
将0.92g化合物(6-2)溶解在7ml四氢呋喃中，加入0.24g三乙胺和1.1g氧化银。室温下搅拌3天后滤除不溶物，减压下浓缩滤液，之后残余物通过硅胶柱层析进行纯化，得到0.31g化合物(6-3)。
1H-NMR(CDCl3):1.35(9H,s),1.60(3H,s),1.92(1H,ddd,J=9.2,5.8,3.4Hz),2.07(1H,dt,J=9.2,3.4Hz),3.00(1H,ddd,J=9.2,5.8,3.4Hz),3.30(1H,dt,J=9.2,3.4Hz),7.24-7.38(5H,m).
步骤三
向0.29g化合物(6-3)中加入3ml浓盐酸，加热回流下搅拌1小时，之后减压下馏去反应液。向残余物中加入水进行结晶，得到0.13g化合物783。
1H-NMR(DMSO-d6):1.44(3H,s),1.78(1H,dt.J=12.4,4.2Hz),2.12(1H,d.J=8.9Hz),2.51-2.52(1H,m),2.96(1H,d.J=4.2Hz),6.12(1H,br),6.66(1H,br),7.21-7.24(1H,m),7.32-7.37(4H,m).
[实施例7]
化合物69的合成
[化学式54]
步骤一
将1.93g化合物(7-1)、1.60g叠氮化磷酸二苯酯、0.59g三乙胺的20ml甲苯溶液在80℃下搅拌3小时，之后加入水，用二乙基醚进行提取，有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到1.69g化合物(7-2)。
1H-NMR(CDCl3):1.00(9H,s),1.72(3H,s),2.17-2.22(2H,m),3.49-3.58(1H,m),3.70-3.80(1H,m),7.20-7.42(10H,m),7.58-7.63(5H,m).
步骤二
将1.68g化合物(7-2)溶解在9ml甲苯中，加入0.79g3,4-二甲氧基苄醇，加热回流8天，之后加入水，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，并减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到2.09g化合物(7-3)。
1H-NMR(CDCl3):1.03(9H,s),1.87(3H,s),2.04(2H,m),3.48(1H,m),3.51(1H,m),3.62(3H,s),3.65(3H,s),4.95(1H,d,J=12.2Hz),5.03(1H,d,J=12.2Hz),6.80-7.09(3H,m),7.22-7.42(10H,m),7.56-7.64(5H,m).
步骤三
将2.09g化合物(7-3)溶解在15ml1,4-二烷中，加入15ml4mol/L-盐酸/1,4-二烷溶液，室温下搅拌24小时，之后加入水和1mol/L-氢氧化钠溶液，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.45g化合物(7-4)。
1H-NMR(CDCl3):1.57(3H,s),1.07-1.98(2H,m),3.48-3.56(1H,m),3.72-3.86(1H,m),7.23-7.45(15H,m).
步骤四
将0.44g化合物(7-4)溶解在15ml四氢呋喃中，加入0.41g叔丁基异硫氰酸酯和0.46g二异丙基乙胺。室温下搅拌3天，之后加入水，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.17g化合物(7-5)。
1H-NMR(CDCl3):1.79(3H,s),1.82-2.20(2H,m),3.71-3.81(2H,m),5.09(1H,br),7.30-7.52(5H,m).
步骤五
将0.17g化合物(7-5)溶解在3.4ml四氢呋喃中，室温搅拌下加入0.11g甲基碘。室温下搅拌23小时，之后减压下馏去反应液，得到0.28g作为粗产物的化合物(7-6)。
步骤六
将0.28g化合物(7-6)溶解在5ml四氢呋喃中，加入74mg三乙胺和0.34g氧化银。室温下搅拌20小时后滤除不溶物，减压下浓缩滤液，之后残余物通过硅胶柱层析进行纯化，得到0.14g化合物(7-7)。
1H-NMR(CDCl3):1.36(9H,s),1.49(3H,s),1.96-2.09(2H,m),2.77-3.83(1H,m),4.05-4.10(1H,m),7.19(1H,t,J=7.3Hz),7.31(2H,t,J=7.3Hz),7.44(2H,d,J=7.3Hz).
步骤七
向0.12g化合物(7-7)中加入9ml浓盐酸，加热回流下搅拌1小时，之后减压下馏去反应液。残余物用甲醇/水进行结晶，得到0.10g化合物69。
1H-NMR(DMSO-d6):1.65(3H,s),2.28-2.35(1H,m),2.39-2.44(1H,m),3.97(1H,dt,J=7.8,3.0Hz),4.53(1H,dt,J=7.8,3.0Hz),7.32-7.44(5H,m),8.44(2H,br),10.33(1H,s).
[实施例8]
化合物256的合成
[化学式55]
步骤一
将4890mg化合物(8-1)溶解在100ml二甲基甲酰胺中，室温下边搅拌边加入5720mg叠氮化钠，之后将反应液升温至80℃，搅拌12小时。经TLC确认化合物(8-1)消失后，将反应液冷却至室温，加入二乙基醚和水，用二乙基醚进行提取。有机层经饱和食盐水洗涤后用硫酸镁干燥。减压馏去溶剂，得到4940mg作为粗产物的化合物(8-2)。步骤二
在氮气环境下、冰冷下向1080mg氢化锂铝的90ml四氢呋喃悬浮液中加入4940mg化合物(8-2)的15ml四氢呋喃溶液，之后在相同温度下搅拌30分钟。经TLC确认化合物(8-2)消失后，在冰冷下加入1mol/L的氢氧化钠水溶液，并搅拌片刻。滤除生成的凝胶，母液用二乙基醚进行提取。有机层经饱和食盐水依次洗涤后用硫酸镁干燥。减压馏去溶剂，得到4219.1mg作为粗产物的化合物(8-3)。
步骤三
将800mg化合物(8-3)溶解在16ml乙腈中，室温下边搅拌边加入1840mg化合物(8-4)，之后在相同温度下搅拌13小时。经TLC确认化合物(8-3)消失后，减压下浓缩反应液，所得残余物通过硅胶柱层析进行纯化，得到1550.7mg化合物(8-5)。
8-5-(Z):1H-NMR(CDCl3,270MHz):1.49(18H,s),2.06(3H,d,J=1.4Hz),3.91-4.00(2H,m),5.54(1H,td,J=7.1,1,4Hz),7.12-7.41(5H,m),8.17-8.25(1H,m),11.47(1H,s).
8-5-(E):1H-NMR(CDCl3,270MHz):1.49(9H,s),1.52(9H,s),2.09(3H,d,J=1.5Hz),4.24(2H,dd,J=6.6,5.3Hz),5.80(1H,td,J=6.6,1,5Hz),7.21-7.48(5H,m),8.28-8.38(1H,m),11.51(1H,s).
步骤四
冰冷下将474.1mg化合物(8-5)溶解在4.5ml三氟乙酸中，升温至室温后搅拌4小时。经NMR确认化合物(8-5)消失后，将反应液注入到漂浮有冰的1mol/L氢氧化钠水溶液中进行中和，用乙酸乙酯进行提取。有机层经饱和食盐水洗涤后用硫酸镁干燥。减压馏去溶剂，得到326.4mg作为粗产物的化合物(8-6)。
步骤五
将326.4mg化合物(8-6)溶解在2.4ml1,4-二烷中，室温下边搅拌边依次加入195mg氢氧化钠、1.2ml水，之后在冰冷下加入0.84ml二碳酸二叔丁酯。升温至室温并搅拌15小时，之后通过LC-MS确认化合物(8-6)的消失。加入水后用乙酸乙酯提取反应液。有机层经饱和食盐水洗涤后用硫酸镁干燥。减压馏去溶剂，所得残余物通过硅胶柱层析进行纯化，得到113.6mg化合物(8-7)。
1H-NMR(CDCl3,400MHz):1.46(9H,s),1.51(9H,s),1.64(3H,s),2.06(1H,ddd,J=13.4,11.4,5.0Hz),2.27(1H,dt,J=13.4,4.6Hz),3.15(1H,ddd,J=12.9,11.3,4.6Hz),3.70(1H,dt,J=12.9,4.7Hz),7.23-7.29(1H,m),7.33-7.38(4H,m).
步骤六
冰冷下将110mg化合物(8-7)溶解在1ml(4mol/L)的氯化氢的1,4-二烷溶液中，升温至室温后搅拌2天。经LC-MS确认化合物(8-7)消失后，室温下向反应液中加入二乙基醚和水。分离二乙基醚层，之后减压下浓缩水层。向所得残余物中加入甲醇，滤除生成的晶体。通过减压馏去母液的甲醇，得到69mg化合物(256)。
1H-NMR(DMSO-d6,400MHz):1.57(3H,s),1.87-1.96(1H,m),2.30(1H,dt,J=13.6,3.8Hz),2.60(1H,td,J=12.0,3.7Hz),3.25(1H,ddd,J=12.8,8.2,4.4Hz),6.93(2H,s),7.27-7.44(5H,m),7.94(1H,s),8.63(1H,s).
[实施例9]
化合物24的合成
[化学式56]
步骤一
将0.39g化合物(9-1)溶解在20ml氯仿中，室温搅拌下加入1.53g碘、1.25g硫氰酸钾、催化剂量的四丁基氯化铵和1ml水，搅拌15小时。反应后加入10%硫代硫酸钠水溶液和水，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到0.56g化合物(9-2)。
1H-NMR(CDCl3):1.95(3H,s),3.62(2H,s),7.30-7.40(4H,m).
步骤二
向0.56g化合物(9-2)的10ml四氢呋喃溶液中加入0.24g叔丁胺，室温下搅拌18小时，之后减压下馏去反应液，残余物通过硅胶柱层析进行纯化，得到190mg化合物(9-3)。
1H-NMR(CDCl3):1.43(9H,s),1.56(3H,s),3.27(1H,d,J=10.6Hz),3.36(1H,d,J=10.6Hz),7.28(2H,d,J=8.2Hz),7.43(2H,d,J=8.2Hz).
步骤三
向190mg化合物(9-3)中加入3ml浓盐酸，在100℃下搅拌7小时，之后在冰冷搅拌下加入6mol/L-氢氧化钠水溶液进行中和，用二氯甲烷进行提取，之后有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化后，用二氯甲烷/正己烷进行结晶，得到110mg化合物24。
1H-NMR(CDCl3):1.62(3H,s),3.47(1H,d,J=10.6Hz),3.52(1H,d,J=10.6Hz),4.59(2H,br),7.29(2H,d,J=8.6Hz),7.39(2H,d,J=8.6Hz).
[实施例10]
化合物48的合成
[化学式57]
步骤一
将79.6mg化合物(10-1)和120mg(10-2)溶解在3ml二甲基甲酰胺中，室温下边搅拌边加入54.6mg1-羟基苯并***和0.063mlN,N’-二异丙基碳二亚胺。之后，将反应液在室温下搅拌一夜，确认化合物(10-1)消失后加入水，用乙酸乙酯进行提取，有机层经饱和食盐水洗涤后用无水硫酸镁干燥，减压下馏去溶剂。残余物用硅胶柱层析进行纯化，得到110.2mg作为非对映体的混合物的化合物(10-3)。
1H-NMR(CDCl3):0.78-1.00(6H,m,),1.14(9/2H,s),1.16(9/2H,s)1.52(3/2H,s),1.54(3/2H,s)1.86-2.28(3H,m),2.56-2.89(2H,m),3.80(3/2H,s),3.81(3/2H,s)4.04-4.14(1H,m),6.80-6.91(2H,m),7.08-7.22(2H,m),7.30-7.51(6H,m),7.61-7.76(4H,m).
步骤二
在氮气流下将100mg化合物(10-3)溶解在3ml四氢呋喃中，0℃下边搅拌边加入0.18ml四丁基氟化铵的1mol/L的四氢呋喃溶液。之后将反应液在0℃下搅拌5分钟，确认化合物(10-3)消失后加入水，用乙酸乙酯进行提取，有机层经饱和食盐水洗涤后用无水硫酸镁干燥，减压下馏去溶剂。残余物用硅胶柱层析进行纯化，得到40.7mg作为非对映体的混合物的化合物48。
1H-NMR(CDCl3):0.80-0.90(3H,m,)1.01-1.12(3H,m)1.70(3H,m),2.02-2.31(2H,m)2.39--2.55(1H,m),2.61-2.90(2H,m)3.53-3.70(1H,m)3.81(3H,m),3.96-4.08(1H,m)6.87-6.96(2H,m),7.13-7.22(2H,m).
[实施例11]
化合物707的合成
[化学式58]
步骤一
将150mg化合物(11-1)溶解在5ml乙腈中，室温下边搅拌边加入219.6mg化合物(11-2)，之后将反应液升温至60℃，搅拌25小时。通过TLC确认化合物(11-1)的残留。减压下浓缩反应液，所得残余物通过硅胶柱层析进行纯化，得到211.4mg化合物(11-3)。
1H-NMR(CDCl3,400MHz):1.46(9H,s),1.50(9H,s),1.57(3H,s),1.90(1H,ddd,J=13.7,10.0,3.8Hz)2.11(1H,ddd,J=13.7,6.5,3.7Hz)2.68-2.76(1H,m),2.86-2.93(1H,m),3.88(3H,s),6.91(1H,t,J=8.6Hz)6.99-7.03(1H,m),7.06(1H,dd,J=
13.0,2.2Hz),10.14(1H,s),13.93(1H,s).
步骤二
冰冷下将210mg化合物(11-3)溶解在4mol/L的氯化氢的4ml1,4-二烷溶液中，升温至室温后搅拌67小时。通过LC-MS确认化合物(11-3)消失后，减压下浓缩反应液。所得残余物用甲醇-二乙基醚进行结晶，之后过滤收集晶体，用二乙基醚洗涤，得到140.2mg化合物(707)。
1H-NMR(DMSO-d6,400MHz):1.56(3H,s),1.90-2.01(1H,m),2.43-2.62(2H,m),2.95-3.03(1H,m),3.84(3H,s),7.10-7.27(3H,m),7.76(3H,brs),8.26(1H,brs),9.42(1H,s).
[实施例12]
化合物845的合成
[化学式59]
步骤一
将50mg化合物(12-1)和17.9mg哌啶溶解在2ml二甲基甲酰胺中，室温下边搅拌边加入79.8mg邻(7-氮杂苯并***-1-基)-1,1,3,3-四甲基脲六氟磷酸酯。之后，将反应液在室温下搅拌40小时，确认化合物(12-1)消失后，加热减压下馏去溶剂。向残余物中加入饱和碳酸氢钠水溶液，用乙酸乙酯提取，有机层经饱和食盐水洗涤后用无水硫酸镁干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到30.7mg化合物845。
1H-NMR(CDCl3):1.60(3H,s),1.51-1.82(6H,m),1.87-1.98(1H,m),2.09-2.19(1H,m),2.91-2.97(2H,m),3.64-3.68(4H,m),6.73(1H,d,J=4.05Hz),7.14(1H,d,J=4.05Hz).
[实施例13]
化合物1262的合成
[化学式60]
步骤一
在氮气环境下将50.0mg化合物(13-1)溶解在1ml四氢呋喃中，冰冷下加入19μl三乙胺、30.1mg4-溴苯甲酰氯，搅拌40分钟。减压下浓缩反应液，所得残余物溶解在乙酸乙酯中，用饱和碳酸氢钠水溶液洗涤，并用无水硫酸镁干燥后减压浓缩。过滤收集析出的晶体，得到57.2mg化合物(13-2)。
1H-NMR(CDCl3):1.48(9H,s),1.68(3H,s),2.08(1H,m),2.44(1H,m),2.65(1H,m),2.76(1H,m),7.18(1H,s),7.32(1H,s),7.64(2H,d,J=8.2Hz),7.78(2H,d,J=8.2Hz),8.15(1H,s),8.25(1H,br).
步骤二
将62.3mg化合物(13-2)溶解在4mol/L的盐酸1,4-二烷溶液中，搅拌24小时。减压浓缩反应液，所得残余物从甲醇/二乙基醚中结晶，得到44.7mg化合物(1262)。
1H-NMR(DMSO-d6):1.67(3H,s),2.10(1H,m),2.50-2.61(3H,m),7.33(1H,s),7.74(1H,s),7.77(2H,d,J=8.6Hz),7.91(2H,d,J=8.6Hz),8.08(1H,s),10.6(1H,s).
[实施例14]
化合物753的合成
[化学式61]
步骤一
将46mg化合物(14-1)溶解在2ml二氯甲烷中，加入20mg4-氯苯甲醛和17mg乙酸，室温下搅拌20分钟，之后在冰冷下边搅拌边加入45mg三乙酰氧基硼氢化钠。室温下搅拌14小时后加入水，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到52mg化合物(14-2)。
1H-NMR(CDCl3):1.50(9H,s),1.64(3H,s),2.02-2.10(1H,m),2.40(1H,dt,J=14.0,4.1Hz),2.62-2.74(2H,m),4.30(2H,s),6.49(1H,ddd,J=,7.8,2.0,0.8Hz),6.52(1H,t,J=2.0Hz),6.60(1H,ddd,J=,7.8,2.0,0.8Hz),7.16(1H,t,J=7.8Hz),7.18-7.33(4H,m).
步骤二
向52mg化合物(14-2)中加入4ml4mol/L-盐酸/1,4-二烷溶液，室温下搅拌4天，之后减压下馏去反应液。残余物用甲醇/二乙基醚进行结晶，得到42mg化合物753。
1H-NMR(DMSO-d6):1.58(3H,s),2.00(1H,ddd,J=,14.3,11.3,3.3Hz),2.49-2.57(2H,m),3.07(1H,dt,J=12.7,3.3Hz),4.27(2H,s),6.47(1H,d,J=8.2Hz),6.51-6.53(2H,m),7.08(1H,t,J=8.2Hz),7.37(4H,s),8.80(2H,br).
[实施例15]
化合物1135的合成
[化学式62]
步骤一
向101mg化合物(15-1)、56μl2-丙醇、189mg三苯基膦的2ml四氢呋喃溶液中滴加328μl偶氮二羧酸二乙酯的2.2mol/L的甲苯溶液。滴加结束后，在室温下搅拌1小时，确认化合物(15-1)消失，之后减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到280mg作为三苯基氧化膦和肼二羧酸二乙酯的混合物的化合物(15-2)。
步骤二
向47mg5-氯吡啶-2-羧酸的1ml甲苯悬浮液中加入1滴二甲基甲酰胺和91μl亚硫酰氯，在100℃下搅拌1小时。减压下馏去溶剂，将残余物溶解在1ml四氢呋喃中，在0℃下滴加280mg化合物(15-2)的混合物和194μl吡啶的0.5ml四氢呋喃溶液。室温下搅拌10分钟，确认化合物(15-2)消失后加入水，用乙酸乙酯进行提取。有机层用水洗涤，之后减压下馏去溶剂。所得残余物通过硅胶柱层析进行纯化，得到68mg作为与肼二羧酸二乙酯的混合物的化合物(15-3)。
步骤三
向作为与肼二羧酸二乙酯的混合物的68mg化合物(15-3)中加入1ml4mol/L-盐酸/1,4-二烷溶液，室温下搅拌16小时，确认化合物(44)消失，之后减压下馏去反应液。残余物用2-丙醇/***进行结晶，得到36mg化合物1135。
1H-NMR(DMSO-d6):1.30(3H,d,J=6.4Hz),1.31(3H,d,J=6.4Hz),1.65(3H,s),2.04-2.11(1H,m),2.50-2.64(2H,m),3.12-3.16(1H,m),4.61(1H,sep,J=6.4Hz),6.66(1H,t,J=2.0Hz),7.48(1H,t,J=2.0Hz),7.60(1H,t,J=2.0Hz),8.16(1H,dd,J=8.4,0.8Hz),8.22(1H,dd,J=8.4,2.4Hz),8.79(1H,dd,J=2.4,0.8Hz),10.33(1H,s),10.72(1H,s).
[实施例16]
化合物161的合成
[化学式63]
步骤一
在氮气环境下将200mg化合物(16-1)、4.7mg乙酸钯、12.5mg三邻甲硅烷基膦溶解在2ml二甲基甲酰胺中，室温下边搅拌边加入0.196ml正丁胺、0.074ml对氯苯乙烯，之后将反应液升温至80℃，搅拌3小时。经TLC确认化合物(16-1)消失后冷却至室温，加入饱和氯化铵水溶液。用乙酸乙酯进行提取，有机层经水、饱和食盐水洗涤后用硫酸镁干燥。减压馏去溶剂，所得残余物通过硅胶柱层析进行纯化，得到213.1mg化合物(16-2)。
1H-NMR(CDCl3,400MHz):1.54(18H,s),1.64(3H,s),1.96(1H,ddd,J=13.7,9.1,4.0Hz)2.10(1H,ddd,J=13.7,8.1,3.4Hz)2.86(1H,ddd,J=12.3,9.1,3.4Hz),3.03(1H,ddd,J=12.3,8.1,4.0Hz),7.08(1H,d,J=16.4Hz)7.15(1H,d,J=16.4Hz),7.27-7.40(5H,m)7.44(2H,d,J=8.8Hz),7.58(1H,s).
步骤二
冰冷下将213mg化合物(16-2)溶解在4mol/L的氯化氢的5ml1,4-二烷溶液中，升温至室温后搅拌63小时。经LC-MS确认化合物(16-2)消失后，用二***稀释反应液。过滤收集析出的晶体，用二乙基醚洗涤，得到108.6mg化合物(161)。
1H-NMR(DMSO-d6,400MHz):1.69(3H,s),2.08-2.18(1H,m),2.56-2.70(2H,m),3.13-3.20(1H,m),7.23(1H,d,J=8.0Hz),7.31(1H,d,J=17.0Hz),7.35(1H,d,J=17.0Hz),7.45(2H,d,J=8.6Hz),7.46(1H,t,7.6Hz),7.59(1H,d,J=2.0Hz),7.61-7.64(1H,m),7.64(2H,d,J=8.6Hz),8.53-9.50(2H,br),10.67(1H,brs).
[实施例17]
化合物597的合成
[化学式64]
步骤一
将135mg化合物(17-1)、39mg盐酸甲氧基胺、27mg乙酸钾的3ml甲醇溶液在室温下搅拌16小时，之后加入水，用二氯甲烷进行提取，有机层用无水硫酸钠干燥，减压下馏去溶剂。残余物通过硅胶柱层析进行纯化，得到110mg化合物(17-2)。
1H-NMR(CDCl3):1.51(9H,s),1.70(3H,s),2.14(1H,ddd,J=14.4,11.4,3.4Hz),2.22(3H,s),2.48(1H,m),2.65(1H,dt,J=12.6,11.4Hz),2.78(1H,ddd,J=12.6,5.6,3.4Hz),4.00(3H,s),7.30(1H,d,J=7.8Hz),7.38(1H,d,J=7.8Hz),7.54-7.57(2H,m).
步骤二
向110mg化合物(17-2)中加入4.5ml4mol/L-盐酸/1,4-二烷溶液，在室温下搅拌4天，之后减压下馏去反应液。残余物用甲醇/二乙基醚进行结晶，得到65mg化合物597。
1H-NMR(DMSO-d6):1.67(3H,s),2.08-2.15(1H,m),2.20(3H,s),2.56-2.64(2H,m),3.14-3.17(1H,m),3.92(3H,s),7.37(1H,d,J=8.0Hz),7.48(1H,d,J=8.0Hz),7.56(1H,s),7.62(1H,d,J=8.0Hz).
同样操作来合成其他化合物。以下显示结构式和物理常数。
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[化学式65]
[表136]
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[表168]
[化学式66]
上述式(Ia)～(Ih)中，NR2aR2b、R3c、R3d、R5和G的组合(NR2aR2b、R3c、R3d、R5、G)为以下组合的化合物。
(NHMe,H,H,Me,CONHPh),(NHMe,H,H,Me,CONH-3-吡啶基),(NHMe,H,H,Me,NHCOPh),(NHMe,H,H,Me,NHCO-2-呋喃基),(NHMe,H,H,Me,NHCONHPh),(NHMe,H,H,Me,NHCOCONHPh),(NHMe,H,H,Et,CONHPh),(NHMe,H,H,Et,CONH-3-吡啶基),(NHMe,H,H,Et,NHCOPh),(NHMe,H,H,Et,NHCO-2-呋喃基),(NHMe,H,H,Et,NHCONHPh),(NHMe,H,H,Et,NHCOCONHPh),(NHMe,H,H,CH2OH,CONHPh),(NHMe,H,H,CH2OH,CONH-3-吡啶基),(NHMe,H,H,CH2OH,NHCOPh),(NHMe,H,H,CH2OH,NHCO-2-呋喃基),(NHMe,H,H,CH2OH,NHCONHPh),(NHMe,H,H,CH2OH,NHCOCONHPh),(NHMe,H,Me,Me,CONHPh),(NHMe,H,Me,Me,CONH-3-吡啶基),(NHMe,H,Me,Me,NHCOPh),(NHMe,H,Me,Me,NHCO-2-呋喃基),(NHMe,H,Me,Me,NHCONHPh),(NHMe,H,Me,Me,NHCOCONHPh),(NHMe,H,Me,Et,CONHPh),(NHMe,H,Me,Et,CONH-3-吡啶基),(NHMe,H,Me,Et,NHCOPh),(NHMe,H,Me,Et,NHCO-2-呋喃基),(NHMe,H,Me,Et,NHCONHPh),(NHMe,H,Me,Et,NHCOCONHPh),(NHMe,H,Me,CH2OH,CONHPh),(NHMe,H,Me,CH2OH,CONH-3-吡啶基),(NHMe,H,Me,CH2OH,NHCOPh),(NHMe,H,Me,CH2OH,NHCO-2-呋喃基),(NHMe,H,Me,CH2OH,NHCONHPh),(NHMe,H,Me,CH2OH,NHCOCONHPh),(NHMe,H,Ph,Me,CONHPh),(NHMe,H,Ph,Me,CONH-3-吡啶基),(NHMe,H,Ph,Me,NHCOPh),(NHMe,H,Ph,Me,NHCO-2-呋喃基),(NHMe,H,Ph,Me,NHCONHPh),(NHMe,H,Ph,Me,NHCOCONHPh),(NHMe,H,Ph,Et,CONHPh),(NHMe,H,Ph,Et,CONH-3-吡啶基),(NHMe,H,Ph,Et,NHCOPh),(NHMe,H,Ph,Et,NHCO-2-呋喃基),(NHMe,H,Ph,Et,NHCONHPh),(NHMe,H,Ph,Et,NHCOCONHPh),(NHMe,H,Ph,CH2OH,CONHPh),(NHMe,H,Ph,CH2OH,CONH-3-吡啶基),(NHMe,H,Ph,CH2OH,NHCOPh),(NHMe,H,Ph,CH2OH,NHCO-2-呋喃基),(NHMe,H,Ph,CH2OH,NHCONHPh),(NHMe,H,Ph,CH2OH,NHCOCONHPh),(NHMe,H,OH,Me,CONHPh),(NHMe,H,OH,Me,CONH-3-吡啶基),(NHMe,H,OH,Me,NHCOPh),(NHMe,H,OH,Me,NHCO-2-呋喃基),(NHMe,H,OH,Me,NHCONHPh),(NHMe,H,OH,Me,NHCOCONHPh),(NHMe,H,OH,Et,CONHPh),(NHMe,H,OH,Et,CONH-3-吡啶基),(NHMe,H,OH,Et,NHCOPh),(NHMe,H,OH,Et,NHCO-2-呋喃基),(NHMe,H,OH,Et,NHCONHPh),(NHMe,H,OH,Et,NHCOCONHPh),(NHMe,H,OH,CH2OH,CONHPh),(NHMe,H,OH,CH2OH,CONH-3-吡啶基),(NHMe,H,OH,CH2OH,NHCOPh),(NHMe,H,OH,CH2OH,NHCO-2-呋喃基),(NHMe,H,OH,CH2OH,NHCONHPh),(NHMe,H,OH,CH2OH,NHCOCONHPh),(NHMe,Me,H,Me,CONHPh),(NHMe,Me,H,Me,CONH-3-吡啶基),(NHMe,Me,H,Me,NHCOPh),(NHMe,Me,H,Me,NHCO-2-呋喃基),(NHMe,Me,H,Me,NHCONHPh),(NHMe,Me,H,Me,NHCOCONHPh),(NHMe,Me,H,Et,CONHPh),(NHMe,Me,H,Et,CONH-3-吡啶基),(NHMe,Me,H,Et,NHCOPh),(NHMe,Me,H,Et,NHCO-2-呋喃基),(NHMe,Me,H,Et,NHCONHPh),(NHMe,Me,H,Et,NHCOCONHPh),(NHMe,Me,H,CH2OH,CONHPh),(NHMe,Me,H,CH2OH,CONH-3-吡啶基),(NHMe,Me,H,CH2OH,NHCOPh),(NHMe,Me,H,CH2OH,NHCO-2-呋喃基),(NHMe,Me,H,CH2OH,NHCONHPh),(NHMe,Me,H,CH2OH,NHCOCONHPh),(NHMe,Me,Me,Me,CONHPh),(NHMe,Me,Me,Me,CONH-3-吡啶基),(NHMe,Me,Me,Me,NHCOPh),(NHMe,Me,Me,Me,NHCO-2-呋喃基),(NHMe,Me,Me,Me,NHCONHPh),(NHMe,Me,Me,Me,NHCOCONHPh),(NHMe,Me,Me,Et,CONHPh),(NHMe,Me,Me,Et,CONH-3-吡啶基),(NHMe,Me,Me,Et,NHCOPh),(NHMe,Me,Me,Et,NHCO-2-呋喃基),(NHMe,Me,Me,Et,NHCONHPh),(NHMe,Me,Me,Et,NHCOCONHPh),(NHMe,Me,Me,CH2OH,CONHPh),(NHMe,Me,Me,CH2OH,CONH-3-吡啶基),(NHMe,Me,Me,CH2OH,NHCOPh),(NHMe,Me,Me,CH2OH,NHCO-2-呋喃基),(NHMe,Me,Me,CH2OH,NHCONHPh),(NHMe,Me,Me,CH2OH,NHCOCONHPh),(NHMe,Me,Ph,Me,CONHPh),(NHMe,Me,Ph,Me,CONH-3-吡啶基),(NHMe,Me,Ph,Me,NHCOPh),(NHMe,Me,Ph,Me,NHCO-2-呋喃基),(NHMe,Me,Ph,Me,NHCONHPh),(NHMe,Me,Ph,Me,NHCOCONHPh),(NHMe,Me,Ph,Et,CONHPh),(NHMe,Me,Ph,Et,CONH-3-吡啶基),(NHMe,Me,Ph,Et,NHCOPh),(NHMe,Me,Ph,Et,NHCO-2-呋喃基),(NHMe,Me,Ph,Et,NHCONHPh),(NHMe,Me,Ph,Et,NHCOCONHPh),(NHMe,Me,Ph,CH2OH,CONHPh),(NHMe,Me,Ph,CH2OH,CONH-3-吡啶基),(NHMe,Me,Ph,CH2OH,NHCOPh),(NHMe,Me,Ph,CH2OH,NHCO-2-呋喃基),(NHMe,Me,Ph,CH2OH,NHCONHPh),(NHMe,Me,Ph,CH2OH,NHCOCONHPh),(NHMe,Me,OH,Me,CONHPh),(NHMe,Me,OH,Me,CONH-3-吡啶基),(NHMe,Me,OH,Me,NHCOPh),(NHMe,Me,OH,Me,NHCO-2-呋喃基),(NHMe,Me,OH,Me,NHCONHPh),(NHMe,Me,OH,Me,NHCOCONHPh),(NHMe,Me,OH,Et,CONHPh),(NHMe,Me,OH,Et,CONH-3-吡啶基),(NHMe,Me,OH,Et,NHCOPh),(NHMe,Me,OH,Et,NHCO-2-呋喃基),(NHMe,Me,OH,Et,NHCONHPh),(NHMe,Me,OH,Et,NHCOCONHPh),(NHMe,Me,OH,CH2OH,CONHPh),(NHMe,Me,OH,CH2OH,CONH-3-吡啶基),(NHMe,Me,OH,CH2OH,NHCOPh),(NHMe,Me,OH,CH2OH,NHCO-2-呋喃基),(NHMe,Me,OH,CH2OH,NHCONHPh),(NHMe,Me,OH,CH2OH,NHCOCONHPh),(NHMe,Ph,H,Me,CONHPh),(NHMe,Ph,H,Me,CONH-3-吡啶基),(NHMe,Ph,H,Me,NHCOPh),(NHMe,Ph,H,Me,NHCO-2-呋喃基),(NHMe,Ph,H,Me,NHCONHPh),(NHMe,Ph,H,Me,NHCOCONHPh),(NHMe,Ph,H,Et,CONHPh),(NHMe,Ph,H,Et,CONH-3-吡啶基),(NHMe,Ph,H,Et,NHCOPh),(NHMe,Ph,H,Et,NHCO-2-呋喃基),(NHMe,Ph,H,Et,NHCONHPh),(NHMe,Ph,H,Et,NHCOCONHPh),(NHMe,Ph,H,CH2OH,CONHPh),(NHMe,Ph,H,CH2OH,CONH-3-吡啶基),(NHMe,Ph,H,CH2OH,NHCOPh),(NHMe,Ph,H,CH2OH,NHCO-2-呋喃基),(NHMe,Ph,H,CH2OH,NHCONHPh),(NHMe,Ph,H,CH2OH,NHCOCONHPh),(NHMe,Ph,Me,Me,CONHPh),(NHMe,Ph,Me,Me,CONH-3-吡啶基),(NHMe,Ph,Me,Me,NHCOPh),(NHMe,Ph,Me,Me,NHCO-2-呋喃基),(NHMe,Ph,Me,Me,NHCONHPh),(NHMe,Ph,Me,Me,NHCOCONHPh),(NHMe,Ph,Me,Et,CONHPh),(NHMe,Ph,Me,Et,CONH-3-吡啶基),(NHMe,Ph,Me,Et,NHCOPh),(NHMe,Ph,Me,Et,NHCO-2-呋喃基),(NHMe,Ph,Me,Et,NHCONHPh),(NHMe,Ph,Me,Et,NHCOCONHPh),(NHMe,Ph,Me,CH2OH,CONHPh),(NHMe,Ph,Me,CH2OH,CONH-3-吡啶基),(NHMe,Ph,Me,CH2OH,NHCOPh),(NHMe,Ph,Me,CH2OH,NHCO-2-呋喃基),(NHMe,Ph,Me,CH2OH,NHCONHPh),(NHMe,Ph,Me,CH2OH,NHCOCONHPh),(NHMe,Ph,Ph,Me,CONHPh),(NHMe,Ph,Ph,Me,CONH-3-吡啶基),(NHMe,Ph,Ph,Me,NHCOPh),(NHMe,Ph,Ph,Me,NHCO-2-呋喃基),(NHMe,Ph,Ph,Me,NHCONHPh),(NHMe,Ph,Ph,Me,NHCOCONHPh),(NHMe,Ph,Ph,Et,CONHPh),(NHMe,Ph,Ph,Et,CONH-3-吡啶基),(NHMe,Ph,Ph,Et,NHCOPh),(NHMe,Ph,Ph,Et,NHCO-2-呋喃基),(NHMe,Ph,Ph,Et,NHCONHPh),(NHMe,Ph,Ph,Et,NHCOCONHPh),(NHMe,Ph,Ph,CH2OH,CONHPh),(NHMe,Ph,Ph,CH2OH,CONH-3-吡啶基),(NHMe,Ph,Ph,CH2OH,NHCOPh),(NHMe,Ph,Ph,CH2OH,NHCO-2-呋喃基),(NHMe,Ph,Ph,CH2OH,NHCONHPh),(NHMe,Ph,Ph,CH2OH,NHCOCONHPh),(NHMe,Ph,OH,Me,CONHPh),(NHMe,Ph,OH,Me,CONH-3-吡啶基),(NHMe,Ph,OH,Me,NHCOPh),(NHMe,Ph,OH,Me,NHCO-2-呋喃基),(NHMe,Ph,OH,Me,NHCONHPh),(NHMe,Ph,OH,Me,NHCOCONHPh),(NHMe,Ph,OH,Et,CONHPh),(NHMe,Ph,OH,Et,CONH-3-吡啶基),(NHMe,Ph,OH,Et,NHCOPh),(NHMe,Ph,OH,Et,NHCO-2-呋喃基),(NHMe,Ph,OH,Et,NHCONHPh),(NHMe,Ph,OH,Et,NHCOCONHPh),(NHMe,Ph,OH,CH2OH,CONHPh),(NHMe,Ph,OH,CH2OH,CONH-3-吡啶基),(NHMe,Ph,OH,CH2OH,NHCOPh),(NHMe,Ph,OH,CH2OH,NHCO-2-呋喃基),(NHMe,Ph,OH,CH2OH,NHCONHPh),(NHMe,Ph,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,H,Me,CONHPh),(NHCH2CH2OH,H,H,Me,CONH-3-吡啶基),(NHCH2CH2OH,H,H,Me,NHCOPh),(NHCH2CH2OH,H,H,Me,NHCO-2-呋喃基),(NHCH2CH2OH,H,H,Me,NHCONHPh),(NHCH2CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH2OH,H,H,Et,CONHPh),(NHCH2CH2OH,H,H,Et,CONH-3-吡啶基),(NHCH2CH2OH,H,H,Et,NHCOPh),(NHCH2CH2OH,H,H,Et,NHCO-2-呋喃基),(NHCH2CH2OH,H,H,Et,NHCONHPh),(NHCH2CH2OH,H,H,Et,NHCOCONHPh),(NHCH2CH2OH,H,H,CH2OH,CONHPh),(NHCH2CH2OH,H,H,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,H,H,CH2OH,NHCOPh),(NHCH2CH2OH,H,H,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,H,H,CH2OH,NHCONHPh),(NHCH2CH2OH,H,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Me,Me,CONHPh),(NHCH2CH2OH,H,Me,Me,CONH-3-吡啶基),(NHCH2CH2OH,H,Me,Me,NHCOPh),(NHCH2CH2OH,H,Me,Me,NHCO-2-呋喃基),(NHCH2CH2OH,H,Me,Me,NHCONHPh),(NHCH2CH2OH,H,Me,Me,NHCOCONHPh),(NHCH2CH2OH,H,Me,Et,CONHPh),(NHCH2CH2OH,H,Me,Et,CONH-3-吡啶基),(NHCH2CH2OH,H,Me,Et,NHCOPh),(NHCH2CH2OH,H,Me,Et,NHCO-2-呋喃基),(NHCH2CH2OH,H,Me,Et,NHCONHPh),(NHCH2CH2OH,H,Me,Et,NHCOCONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONHPh),(NHCH2CH2OH,H,Me,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,H,Me,CH2OH,NHCOPh),(NHCH2CH2OH,H,Me,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,H,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,H,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Me,CONHPh),(NHCH2CH2OH,H,Ph,Me,CONH-3-吡啶基),(NHCH2CH2OH,H,Ph,Me,NHCOPh),(NHCH2CH2OH,H,Ph,Me,NHCO-2-呋喃基),(NHCH2CH2OH,H,Ph,Me,NHCONHPh),(NHCH2CH2OH,H,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,H,Ph,Et,CONHPh),(NHCH2CH2OH,H,Ph,Et,CONH-3-吡啶基),(NHCH2CH2OH,H,Ph,Et,NHCOPh),(NHCH2CH2OH,H,Ph,Et,NHCO-2-呋喃基),(NHCH2CH2OH,H,Ph,Et,NHCONHPh),(NHCH2CH2OH,H,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONHPh),(NHCH2CH2OH,H,Ph,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,H,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,H,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,H,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,H,OH,Me,CONHPh),(NHCH2CH2OH,H,OH,Me,CONH-3-吡啶基),(NHCH2CH2OH,H,OH,Me,NHCOPh),(NHCH2CH2OH,H,OH,Me,NHCO-2-呋喃基),(NHCH2CH2OH,H,OH,Me,NHCONHPh),(NHCH2CH2OH,H,OH,Me,NHCOCONHPh),(NHCH2CH2OH,H,OH,Et,CONHPh),(NHCH2CH2OH,H,OH,Et,CONH-3-吡啶基),(NHCH2CH2OH,H,OH,Et,NHCOPh),(NHCH2CH2OH,H,OH,Et,NHCO-2-呋喃基),(NHCH2CH2OH,H,OH,Et,NHCONHPh),(NHCH2CH2OH,H,OH,Et,NHCOCONHPh),(NHCH2CH2OH,H,OH,CH2OH,CONHPh),(NHCH2CH2OH,H,OH,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,H,OH,CH2OH,NHCOPh),(NHCH2CH2OH,H,OH,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,H,OH,CH2OH,NHCONHPh),(NHCH2CH2OH,H,OH,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,H,Me,CONHPh),(NHCH2CH2OH,Me,H,Me,CONH-3-吡啶基),(NHCH2CH2OH,Me,H,Me,NHCOPh),(NHCH2CH2OH,Me,H,Me,NHCO-2-呋喃基),(NHCH2CH2OH,Me,H,Me,NHCONHPh),(NHCH2CH2OH,Me,H,Me,NHCOCONHPh),(NHCH2CH2OH,Me,H,Et,CONHPh),(NHCH2CH2OH,Me,H,Et,CONH-3-吡啶基),(NHCH2CH2OH,Me,H,Et,NHCOPh),(NHCH2CH2OH,Me,H,Et,NHCO-2-呋喃基),(NHCH2CH2OH,Me,H,Et,NHCONHPh),(NHCH2CH2OH,Me,H,Et,NHCOCONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONHPh),(NHCH2CH2OH,Me,H,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,Me,H,CH2OH,NHCOPh),(NHCH2CH2OH,Me,H,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,Me,H,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,H,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Me,CONHPh),(NHCH2CH2OH,Me,Me,Me,CONH-3-吡啶基),(NHCH2CH2OH,Me,Me,Me,NHCOPh),(NHCH2CH2OH,Me,Me,Me,NHCO-2-呋喃基),(NHCH2CH2OH,Me,Me,Me,NHCONHPh),(NHCH2CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Me,Et,CONHPh),(NHCH2CH2OH,Me,Me,Et,CONH-3-吡啶基),(NHCH2CH2OH,Me,Me,Et,NHCOPh),(NHCH2CH2OH,Me,Me,Et,NHCO-2-呋喃基),(NHCH2CH2OH,Me,Me,Et,NHCONHPh),(NHCH2CH2OH,Me,Me,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONHPh),(NHCH2CH2OH,Me,Me,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Me,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Me,CONHPh),(NHCH2CH2OH,Me,Ph,Me,CONH-3-吡啶基),(NHCH2CH2OH,Me,Ph,Me,NHCOPh),(NHCH2CH2OH,Me,Ph,Me,NHCO-2-呋喃基),(NHCH2CH2OH,Me,Ph,Me,NHCONHPh),(NHCH2CH2OH,Me,Ph,Me,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,Et,CONHPh),(NHCH2CH2OH,Me,Ph,Et,CONH-3-吡啶基),(NHCH2CH2OH,Me,Ph,Et,NHCOPh),(NHCH2CH2OH,Me,Ph,Et,NHCO-2-呋喃基),(NHCH2CH2OH,Me,Ph,Et,NHCONHPh),(NHCH2CH2OH,Me,Ph,Et,NHCOCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCO-2-呋喃基),(NHCH2CH2OH,Me,Ph,CH2OH,NHCONHPh),(NHCH2CH2OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Me,CONHPh),(NHCH2CH2OH,Me,OH,Me,CONH-3-吡啶基),(NHCH2CH2OH,Me,OH,Me,NHCOPh),(NHCH2CH2OH,Me,OH,Me,NHCO-2-呋喃基),(NHCH2CH2OH,Me,OH,Me,NHCONHPh),(NHCH2CH2OH,Me,OH,Me,NHCOCONHPh),(NHCH2CH2OH,Me,OH,Et,CONHPh),(NHCH2CH2OH,Me,OH,Et,CONH-3-吡啶基),(NHCH2CH2OH,Me,OH,Et,NHCOPh),(NHCH2CH2OH,Me,OH,Et,NHCO-2-呋喃基),(NHCH2CH2OH,Me,OH,Et,NHCONHPh),(NHCH2CH2OH,Me,OH,Et,NHCOCONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONHPh),(NHCH2CH2OH,Me,OH,CH2OH,CONH-3-吡啶基),(NHCH2CH2OH,Me,OH,CH2OH,NHCO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)CH2OH,Me,Me,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,Et,CONHPh),(NHCH(Me)CH2OH,Me,Me,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,Me,Et,NHCOPh),(NHCH(Me)CH2OH,Me,Me,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,CONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,Me,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,CONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,Ph,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Me,OH,Me,CONHPh),(NHCH(Me)CH2OH,Me,OH,Me,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,OH,Me,NHCOPh),(NHCH(Me)CH2OH,Me,OH,Me,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Me,OH,Et,CONHPh),(NHCH(Me)CH2OH,Me,OH,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,OH,Et,NHCOPh),(NHCH(Me)CH2OH,Me,OH,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,OH,Et,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Me,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,Me,CONHPh),(NHCH(Me)CH2OH,Ph,H,Me,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,H,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,H,Me,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,H,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,H,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,Et,CONHPh),(NHCH(Me)CH2OH,Ph,H,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,H,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,H,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,H,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,H,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,H,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,CONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,Me,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,Me,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,Me,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,CONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,Me,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,Me,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,CONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,OH,Me,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,Me,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,OH,Me,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,Me,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,CONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,OH,Et,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,Et,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,OH,Et,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,Et,NHCOCONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,CONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,CONH-3-吡啶基),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCOPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCONHPh),(NHCH(Me)CH2OH,Ph,OH,CH2OH,NHCOCONHPh),
(NHCH(Me)CONHMe,H,H,Me,CONHPh),(NHCH(Me)CONHMe,H,H,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,H,Me,NHCOPh),(NHCH(Me)CONHMe,H,H,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,H,Me,NHCONHPh),(NHCH(Me)CONHMe,H,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,H,Et,CONHPh),(NHCH(Me)CONHMe,H,H,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,H,Et,NHCOPh),(NHCH(Me)CONHMe,H,H,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,H,Et,NHCONHPh),(NHCH(Me)CONHMe,H,H,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,H,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,Me,CONHPh),(NHCH(Me)CONHMe,H,Me,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,Me,Me,NHCOPh),(NHCH(Me)CONHMe,H,Me,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,Me,Me,NHCONHPh),(NHCH(Me)CONHMe,H,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,Et,CONHPh),(NHCH(Me)CONHMe,H,Me,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,Me,Et,NHCOPh),(NHCH(Me)CONHMe,H,Me,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,Me,Et,NHCONHPh),(NHCH(Me)CONHMe,H,Me,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,Me,CONHPh),(NHCH(Me)CONHMe,H,Ph,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,Ph,Me,NHCOPh),(NHCH(Me)CONHMe,H,Ph,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,Ph,Me,NHCONHPh),(NHCH(Me)CONHMe,H,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,Et,CONHPh),(NHCH(Me)CONHMe,H,Ph,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,Ph,Et,NHCOPh),(NHCH(Me)CONHMe,H,Ph,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,Ph,Et,NHCONHPh),(NHCH(Me)CONHMe,H,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,Me,CONHPh),(NHCH(Me)CONHMe,H,OH,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,OH,Me,NHCOPh),(NHCH(Me)CONHMe,H,OH,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,H,OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,Et,CONHPh),(NHCH(Me)CONHMe,H,OH,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,OH,Et,NHCOPh),(NHCH(Me)CONHMe,H,OH,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,H,OH,Et,NHCOCONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCOPh),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,H,OH,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,H,Me,CONHPh),(NHCH(Me)CONHMe,Me,H,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,H,Me,NHCOPh),(NHCH(Me)CONHMe,Me,H,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,H,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,H,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,H,Et,CONHPh),(NHCH(Me)CONHMe,Me,H,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,H,Et,NHCOPh),(NHCH(Me)CONHMe,Me,H,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,H,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,H,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,H,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,H,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,H,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,Me,CONHPh),(NHCH(Me)CONHMe,Me,Me,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,Me,Me,NHCOPh),(NHCH(Me)CONHMe,Me,Me,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,Me,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,Et,CONHPh),(NHCH(Me)CONHMe,Me,Me,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,Me,Et,NHCOPh),(NHCH(Me)CONHMe,Me,Me,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,Me,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,Me,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,CONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,Ph,Me,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,Ph,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,CONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,Ph,Et,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,Ph,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCOPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCONHPh),(NHCH(Me)CONHMe,Me,Ph,CH2OH,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,Me,CONHPh),(NHCH(Me)CONHMe,Me,OH,Me,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,OH,Me,NHCOPh),(NHCH(Me)CONHMe,Me,OH,Me,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,OH,Me,NHCONHPh),(NHCH(Me)CONHMe,Me,OH,Me,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,Et,CONHPh),(NHCH(Me)CONHMe,Me,OH,Et,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,OH,Et,NHCOPh),(NHCH(Me)CONHMe,Me,OH,Et,NHCO-2-呋喃基),(NHCH(Me)CONHMe,Me,OH,Et,NHCONHPh),(NHCH(Me)CONHMe,Me,OH,Et,NHCOCONHPh),(NHCH(Me)CONHMe,Me,OH,CH2OH,CONHPh),(NHCH(Me)CONHMe,Me,OH,CH2OH,CONH-3-吡啶基),(NHCH(Me)CONHMe,Me,OH,CH2OH,NH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Me,Ph,Me,Me,NHCOCONHPh),(NHSO2Me,Ph,Me,Et,CONHPh),(NHSO2Me,Ph,Me,Et,CONH-3-吡啶基),(NHSO2Me,Ph,Me,Et,NHCOPh),(NHSO2Me,Ph,Me,Et,NHCO-2-呋喃基),(NHSO2Me,Ph,Me,Et,NHCONHPh),(NHSO2Me,Ph,Me,Et,NHCOCONHPh),(NHSO2Me,Ph,Me,CH2OH,CONHPh),(NHSO2Me,Ph,Me,CH2OH,CONH-3-吡啶基),(NHSO2Me,Ph,Me,CH2OH,NHCOPh),(NHSO2Me,Ph,Me,CH2OH,NHCO-2-呋喃基),(NHSO2Me,Ph,Me,CH2OH,NHCONHPh),(NHSO2Me,Ph,Me,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,Ph,Me,CONHPh),(NHSO2Me,Ph,Ph,Me,CONH-3-吡啶基),(NHSO2Me,Ph,Ph,Me,NHCOPh),(NHSO2Me,Ph,Ph,Me,NHCO-2-呋喃基),(NHSO2Me,Ph,Ph,Me,NHCONHPh),(NHSO2Me,Ph,Ph,Me,NHCOCONHPh),(NHSO2Me,Ph,Ph,Et,CONHPh),(NHSO2Me,Ph,Ph,Et,CONH-3-吡啶基),(NHSO2Me,Ph,Ph,Et,NHCOPh),(NHSO2Me,Ph,Ph,Et,NHCO-2-呋喃基),(NHSO2Me,Ph,Ph,Et,NHCONHPh),(NHSO2Me,Ph,Ph,Et,NHCOCONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONHPh),(NHSO2Me,Ph,Ph,CH2OH,CONH-3-吡啶基),(NHSO2Me,Ph,Ph,CH2OH,NHCOPh),(NHSO2Me,Ph,Ph,CH2OH,NHCO-2-呋喃基),(NHSO2Me,Ph,Ph,CH2OH,NHCONHPh),(NHSO2Me,Ph,Ph,CH2OH,NHCOCONHPh),(NHSO2Me,Ph,OH,Me,CONHPh),(NHSO2Me,Ph,OH,Me,CONH-3-吡啶基),(NHSO2Me,Ph,OH,Me,NHCOPh),(NHSO2Me,Ph,OH,Me,NHCO-2-呋喃基),(NHSO2Me,Ph,OH,Me,NHCONHPh),(NHSO2Me,Ph,OH,Me,NHCOCONHPh),(NHSO2Me,Ph,OH,Et,CONHPh),(NHSO2Me,Ph,OH,Et,CONH-3-吡啶基),(NHSO2Me,Ph,OH,Et,NHCOPh),(NHSO2Me,Ph,OH,Et,NHCO-2-呋喃基),(NHSO2Me,Ph,OH,Et,NHCONHPh),(NHSO2Me,Ph,OH,Et,NHCOCONHPh),(NHSO2Me,Ph,OH,CH2OH,CONHPh),(NHSO2Me,Ph,OH,CH2OH,CONH-3-吡啶基),(NHSO2Me,Ph,OH,CH2OH,NHCOPh),(NHSO2Me,Ph,OH,CH2OH,NHCO-2-呋喃基),(NHSO2Me,Ph,OH,CH2OH,NHCONHPh),(NHSO2Me,Ph,OH,CH2OH,NHCOCONHPh),(NH2,H,H,Me,CONHPh),(NH2,H,H,Me,CONH-3-吡啶基),(NH2,H,H,Me,NHCOPh),(NH2,H,H,Me,NHCO-2-呋喃基),(NH2,H,H,Me,NHCONHPh),(NH2,H,H,Me,NHCOCONHPh),(NH2,H,H,Et,CONHPh),(NH2,H,H,Et,CONH-3-吡啶基),(NH2,H,H,Et,NHCOPh),(NH2,H,H,Et,NHCO-2-呋喃基),(NH2,H,H,Et,NHCONHPh),(NH2,H,H,Et,NHCOCONHPh),(NH2,H,H,CH2OH,CONHPh),(NH2,H,H,CH2OH,CONH-3-吡啶基),(NH2,H,H,CH2OH,NHCONHPh),(NH2,H,H,CH2OH,NHCOCONHPh),(NH2,H,Me,Me,CONHPh),(NH2,H,Me,Me,CONH-3-吡啶基),(NH2,H,Me,Me,NHCONHPh),(NH2,H,Me,Me,NHCOCONHPh),(NH2,H,Me,Et,CONHPh),(NH2,H,Me,Et,CONH-3-吡啶基),(NH2,H,Me,Et,NHCOPh),(NH2,H,Me,Et,NHCO-2-呋喃基),(NH2,H,Me,Et,NHCONHPh),(NH2,H,Me,Et,NHCOCONHPh),(NH2,H,Me,CH2OH,CONHPh),(NH2,H,Me,CH2OH,CONH-3-吡啶基),(NH2,H,Me,CH2OH,NHCONHPh),(NH2,H,Me,CH2OH,NHCOCONHPh),(NH2,H,Ph,Me,CONHPh),(NH2,H,Ph,Me,CONH-3-吡啶基),(NH2,H,Ph,Me,NHCONHPh),(NH2,H,Ph,Me,NHCOCONHPh),(NH2,H,Ph,Et,CONHPh),(NH2,H,Ph,Et,CONH-3-吡啶基),(NH2,H,Ph,Et,NHCOPh),(NH2,H,Ph,Et,NHCO-2-呋喃基),(NH2,H,Ph,Et,NHCONHPh),(NH2,H,Ph,Et,NHCOCONHPh),(NH2,H,Ph,CH2OH,CONHPh),(NH2,H,Ph,CH2OH,CONH-3-吡啶基),(NH2,H,Ph,CH2OH,NHCONHPh),(NH2,H,Ph,CH2OH,NHCOCONHPh),(NH2,H,OH,Me,CONHPh),(NH2,H,OH,Me,CONH-3-吡啶基),(NH2,H,OH,Me,NHCONHPh),(NH2,H,OH,Me,NHCOCONHPh),(NH2,H,OH,Et,CONHPh),(NH2,H,OH,Et,CONH-3-吡啶基),(NH2,H,OH,Et,NHCOPh),(NH2,H,OH,Et,NHCO-2-呋喃基),(NH2,H,OH,Et,NHCONHPh),(NH2,H,OH,Et,NHCOCONHPh),(NH2,H,OH,CH2OH,CONHPh),(NH2,H,OH,CH2OH,CONH-3-吡啶基),(NH2,H,OH,CH2OH,NHCONHPh),(NH2,H,OH,CH2OH,NHCOCONHPh),(NH2,Me,H,Me,CONHPh),(NH2,Me,H,Me,CONH-3-吡啶基),(NH2,Me,H,Me,NHCONHPh),(NH2,Me,H,Me,NHCOCONHPh),(NH2,Me,H,Et,CONHPh),(NH2,Me,H,Et,CONH-3-吡啶基),(NH2,Me,H,Et,NHCOPh),(NH2,Me,H,Et,NHCO-2-呋喃基),(NH2,Me,H,Et,NHCONHPh),(NH2,Me,H,Et,NHCOCONHPh),(NH2,Me,H,CH2OH,CONHPh),(NH2,Me,H,CH2OH,CONH-3-吡啶基),(NH2,Me,H,CH2OH,NHCONHPh),(NH2,Me,H,CH2OH,NHCOCONHPh),(NH2,Me,Me,Me,CONHPh),(NH2,Me,Me,Me,CONH-3-吡啶基),(NH2,Me,Me,Me,NHCONHPh),(NH2,Me,Me,Me,NHCOCONHPh),(NH2,Me,Me,Et,CONHPh),(NH2,Me,Me,Et,CONH-3-吡啶基),(NH2,Me,Me,Et,NHCOPh),(NH2,Me,Me,Et,NHCO-2-呋喃基),(NH2,Me,Me,Et,NHCONHPh),(NH2,Me,Me,Et,NHCOCONHPh),(NH2,Me,Me,CH2OH,CONHPh),(NH2,Me,Me,CH2OH,CONH-3-吡啶基),(NH2,Me,Me,CH2OH,NHCONHPh),(NH2,Me,Me,CH2OH,NHCOCONHPh),(NH2,Me,Ph,Me,CONHPh),(NH2,Me,Ph,Me,CONH-3-吡啶基),(NH2,Me,Ph,Me,NHCOPh),(NH2,Me,Ph,Me,NHCO-2-呋喃基),(NH2,Me,Ph,Me,NHCONHPh),(NH2,Me,Ph,Me,NHCOCONHPh),(NH2,Me,Ph,Et,CONHPh),(NH2,Me,Ph,Et,CONH-3-吡啶基),(NH2,Me,Ph,Et,NHCOPh),(NH2,Me,Ph,Et,NHCO-2-呋喃基),(NH2,Me,Ph,Et,NHCONHPh),(NH2,Me,Ph,Et,NHCOCONHPh),(NH2,Me,Ph,CH2OH,CONHPh),(NH2,Me,Ph,CH2OH,CONH-3-吡啶基),(NH2,Me,Ph,CH2OH,NHCONHPh),(NH2,Me,Ph,CH2OH,NHCOCONHPh),(NH2,Me,OH,Me,CONHPh),(NH2,Me,OH,Me,CONH-3-吡啶基),(NH2,Me,OH,Me,NHCONHPh),(NH2,Me,OH,Me,NHCOCONHPh),(NH2,Me,OH,Et,CONHPh),(NH2,Me,OH,Et,CONH-3-吡啶基),(NH2,Me,OH,Et,NHCOPh),(NH2,Me,OH,Et,NHCO-2-呋喃基),(NH2,Me,OH,Et,NHCONHPh),(NH2,Me,OH,Et,NHCOCONHPh),(NH2,Me,OH,CH2OH,CONHPh),(NH2,Me,OH,CH2OH,CONH-3-吡啶基),,(NH2,Me,OH,CH2OH,NHCONHPh),(NH2,Me,OH,CH2OH,NHCOCONHPh),(NH2,Ph,H,Me,CONHPh),(NH2,Ph,H,Me,CONH-3-吡啶基),(NH2,Ph,H,Me,NHCONHPh),(NH2,Ph,H,Me,NHCOCONHPh),(NH2,Ph,H,Et,CONHPh),(NH2,Ph,H,Et,CONH-3-吡啶基),(NH2,Ph,H,Et,NHCOPh),(NH2,Ph,H,Et,NHCO-2-呋喃基),(NH2,Ph,H,Et,NHCONHPh),(NH2,Ph,H,Et,NHCOCONHPh),(NH2,Ph,H,CH2OH,CONHPh),(NH2,Ph,H,CH2OH,CONH-3-吡啶基),(NH2,Ph,H,CH2OH,NHCONHPh),(NH2,Ph,H,CH2OH,NHCOCONHPh),(NH2,Ph,Me,Me,CONHPh),(NH2,Ph,Me,Me,CONH-3-吡啶基),(NH2,Ph,Me,Me,NHCONHPh),(NH2,Ph,Me,Me,NHCOCONHPh),(NH2,Ph,Me,Et,CONHPh),(NH2,Ph,Me,Et,CONH-3-吡啶基),(NH2,Ph,Me,Et,NHCOPh),(NH2,Ph,Me,Et,NHCO-2-呋喃基),(NH2,Ph,Me,Et,NHCONHPh),(NH2,Ph,Me,Et,NHCOCONHPh),(NH2,Ph,Me,CH2OH,CONHPh),(NH2,Ph,Me,CH2OH,CONH-3-吡啶基),(NH2,Ph,Me,CH2OH,NHCONHPh),(NH2,Ph,Me,CH2OH,NHCOCONHPh),(NH2,Ph,Ph,Me,CONHPh),(NH2,Ph,Ph,Me,CONH-3-吡啶基),(NH2,Ph,Ph,Me,NHCOPh),(NH2,Ph,Ph,Me,NHCO-2-呋喃基),(NH2,Ph,Ph,Me,NHCONHPh),(NH2,Ph,Ph,Me,NHCOCONHPh),(NH2,Ph,Ph,Et,CONHPh),(NH2,Ph,Ph,Et,CONH-3-吡啶基),(NH2,Ph,Ph,Et,NHCOPh),(NH2,Ph,Ph,Et,NHCO-2-呋喃基),(NH2,Ph,Ph,Et,NHCONHPh),(NH2,Ph,Ph,Et,NHCOCONHPh),(NH2,Ph,Ph,CH2OH,CONHPh),(NH2,Ph,Ph,CH2OH,CONH-3-吡啶基),(NH2,Ph,Ph,CH2OH,NHCOPh),(NH2,Ph,Ph,CH2OH,NHCO-2-呋喃基),(NH2,Ph,Ph,CH2OH,NHCONHPh),(NH2,Ph,Ph,CH2OH,NHCOCONHPh),(NH2,Ph,OH,Me,CONHPh),(NH2,Ph,OH,Me,CONH-3-吡啶基),(NH2,Ph,OH,Me,NHCONHPh),(NH2,Ph,OH,Me,NHCOCONHPh),(NH2,Ph,OH,Et,CONHPh),(NH2,Ph,OH,Et,CONH-3-吡啶基),(NH2,Ph,OH,Et,NHCOPh),(NH2,Ph,OH,Et,NHCO-2-呋喃基),(NH2,Ph,OH,Et,NHCONHPh),(NH2,Ph,OH,Et,NHCOCONHPh),(NH2,Ph,OH,CH2OH,CONHPh),(NH2,Ph,OH,CH2OH,CONH-3-吡啶基),(NH2,Ph,OH,CH2OH,NHCOPh),(NH2,Ph,OH,CH2OH,NHCO-2-呋喃基),(NH2,Ph,OH,CH2OH,NHCONHPh),(NH2,Ph,OH,CH2OH,NHCOCONHPh),
(NHCH2CH(OH)CH2OH,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,CONH-3-吡啶基),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCO-2-呋喃基),(NHCH2CH(OH)CH2OH,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OH,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,CONH-3-吡啶基),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCO-2-呋喃基),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2OMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,CONH-3-吡啶基),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCO-2-呋喃基),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NH2,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,CONH-3-吡啶基),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCO-2-呋喃基),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NHMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,CONH-3-吡啶基),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCO-2-呋喃基),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2NHCOMe,H,H,Me,NHCOCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,CONH-3-吡啶基),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCO-2-呋喃基),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCONHPh),(NHCH2CH(OH)CH2N(Me)Me,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NH2,H,H,Me,CONHPh),(NHC(O)C(O)NH2,H,H,Me,CONH-3-吡啶基),(NHC(O)C(O)NH2,H,H,Me,NHCOPh),(NHC(O)C(O)NH2,H,H,Me,NHCO-2-呋喃基),(NHC(O)C(O)NH2,H,H,Me,NHCONHPh),(NHC(O)C(O)NH2,H,H,Me,NHCOCONHPh),(NHC(O)C(O)NHMe,H,H,Me,CONHPh),(NHC(O)C(O)NHMe,H,H,Me,CONH-3-吡啶基),(NHC(O)C(O)NHMe,H,H,Me,NHCOPh),(NHC(O)C(O)NHMe,H,H,Me,NHCO-2-呋喃基),(NHC(O)C(O)NHMe,H,H,Me,NHCONHPh),(NHC(O)C(O)NHMe,H,H,Me,NHCOCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,CONH-3-吡啶基),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCO-2-呋喃基),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCONHPh),(NHC(O)C(O)N(Me)Me,H,H,Me,NHCOCONHPh)。
[化学式67]
上述式(Ii)或(Ij)中，B、接头、A、R5的组合(B、接头、A、R5为以下组合的化合物。
[表169]
(B、接头、A、R5)＝(B1,L1,A1,R51),(B1,L1,A1,R52),(B1,L1,A1,R53),(B1,L1,A1,R54),(B1,L1,A1,R55),(B1,L1,A1,R56),(B1,L1,A2,R51),(B1,L1,A2,R52),(B1,L1,A2,R53),(B1,L1,A2,R54),(B1,L1,A2,R55),(B1,L1,A2,R56),(B1,L1,A3,R51),(B1,L1,A3,R52),(B1,L1,A3,R53),(B1,L1,A3,R54),(B1,L1,A3,R55),(B1,L1,A3,R56),(B1,L1,A4,R51),(B1,L1,A4,R52),(B1,L1,A4,R53),(B1,L1,A4,R54),(B1,L1,A4,R55),(B1,L1,A4,R56),(B1,L1,A5,R51),(B1,L1,A5,R52),(B1,L1,A5,R53),(B1,L1,A5,R54),(B1,L1,A5,R55),(B1,L1,A5,R56),(B1,L2,A1,R51),(B1,L2,A1,R52),(B1,L2,A1,R53),(B1,L2,A1,R54),(B1,L2,A1,R55),(B1,L2,A1,R56),(B1,L2,A2,R51),(B1,L2,A2,R52),(B1,L2,A2,R53),(B1,L2,A2,R54),(B1,L2,A2,R55),(B1,L2,A2,R56),(B1,L2,A3,R51),(B1,L2,A3,R52),(B1,L2,A3,R53),(B1,L2,A3,R54),(B1,L2,A3,R55),(B1,L2,A3,R56),(B1,L2,A4,R51),(B1,L2,A4,R52),(B1,L2,A4,R53),(B1,L2,A4,R54),(B1,L2,A4,R55),(B1,L2,A4,R56),(B1,L2,A5,R51),(B1,L2,A5,R52),(B1,L2,A5,R53),(B1,L2,A5,R54),(B1,L2,A5,R55),(B1,L2,A5,R56),(B1,L3,A1,R51),(B1,L3,A1,R52),(B1,L3,A1,R53),(B1,L3,A1,R54),(B1,L3,A1,R55),(B1,L3,A1,R56),(B1,L3,A2,R51),(B1,L3,A2,R52),(B1,L3,A2,R53),(B1,L3,A2,R54),(B1,L3,A2,R55),(B1,L3,A2,R56),(B1,L3,A3,R51),(B1,L3,A3,R52),(B1,L3,A3,R53),(B1,L3,A3,R54),(B1,L3,A3,R55),(B1,L3,A3,R56),(B1,L3,A4,R51),(B1,L3,A4,R52),(B1,L3,A4,R53),(B1,L3,A4,R54),(B1,L3,A4,R55),(B1,L3,A4,R56),(B1,L3,A5,R51),(B1,L3,A5,R52),(B1,L3,A5,R53),(B1,L3,A5,R54),(B1,L3,A5,R55),(B1,L3,A5,R56),(B1,L4,A1,R51),(B1,L4,A1,R52),(B1,L4,A1,R53),(B1,L4,A1,R54),(B1,L4,A1,R55),(B1,L4,A1,R56),(B1,L4,A2,R51),(B1,L4,A2,R52),(B1,L4,A2,R53),(B1,L4,A2,R54),(B1,L4,A2,R55),(B1,L4,A2,R56),(B1,L4,A3,R51),(B1,L4,A3,R52),(B1,L4,A3,R53),(B1,L4,A3,R54),(B1,L4,A3,R55),(B1,L4,A3,R56),(B1,L4,A4,R51),(B1,L4,A4,R52),(B1,L4,A4,R53),(B1,L4,A4,R54),(B1,L4,A4,R55),(B1,L4,A4,R56),(B1,L4,A5,R51),(B1,L4,A5,R52),(B1,L4,A5,R53),(B1,L4,A5,R54),(B1,L4,A5,R55),(B1,L4,A5,R56),(B1,L5,A1,R51),(B1,L5,A1,R52),(B1,L5,A1,R53),(B1,L5,A1,R54),(B1,L5,A1,R55),(B1,L5,A1,R56),(B1,L5,A2,R51),(B1,L5,A2,R52),(B1,L5,A2,R53),(B1,L5,A2,R54),(B1,L5,A2,R55),(B1,L5,A2,R56),(B1,L5,A3,R51),(B1,L5,A3,R52),(B1,L5,A3,R53),(B1,L5,A3,R54),(B1,L5,A3,R55),(B1,L5,A3,R56),(B1,L5,A4,R51),(B1,L5,A4,R52),(B1,L5,A4,R53),(B1,L5,A4,R54),(B1,L5,A4,R55),(B1,L5,A4,R56),(B1,L5,A5,R51),(B1,L5,A5,R52),(B1,L5,A5,R53),(B1,L5,A5,R54),(B1,L5,A5,R55),(B1,L5,A5,R56),(B2,L1,A1,R51),(B2,L1,A1,R52),(B2,L1,A1,R53),(B2,L1,A1,R54),(B2,L1,A1,R55),(B2,L1,A1,R56),(B2,L1,A2,R51),(B2,L1,A2,R52),(B2,L1,A2,R53),(B2,L1,A2,R54),(B2,L1,A2,R55),(B2,L1,A2,R56),(B2,L1,A3,R51),(B2,L1,A3,R52),(B2,L1,A3,R53),(B2,L1,A3,R54),(B2,L1,A3,R55),(B2,L1,A3,R56),(B2,L1,A4,R51),(B2,L1,A4,R52),(B2,L1,A4,R53),(B2,L1,A4,R54),(B2,L1,A4,R55),(B2,L1,A4,R56),(B2,L1,A5,R51),(B2,L1,A5,R52),(B2,L1,A5,R53),(B2,L1,A5,R54),(B2,L1,A5,R55),(B2,L1,A5,R56),(B2,L2,A1,R51),(B2,L2,A1,R52),(B2,L2,A1,R53),(B2,L2,A1,R54),(B2,L2,A1,R55),(B2,L2,A1,R56),(B2,L2,A2,R51),(B2,L2,A2,R52),(B2,L2,A2,R53),(B2,L2,A2,R54),(B2,L2,A2,R55),(B2,L2,A2,R56),(B2,L2,A3,R51),(B2,L2,A3,R52),(B2,L2,A3,R53),(B2,L2,A3,R54),(B2,L2,A3,R55),(B2,L2,A3,R56),(B2,L2,A4,R51),(B2,L2,A4,R52),(B2,L2,A4,R53),(B2,L2,A4,R54),(B2,L2,A4,R55),(B2,L2,A4,R56),(B2,L2,A5,R51),(B2,L2,A5,R52),(B2,L2,A5,R53),(B2,L2,A5,R54),(B2,L2,A5,R55),(B2,L2,A5,R56),(B2,L3,A1,R51),(B2,L3,A1,R52),(B2,L3,A1,R53),(B2,L3,A1,R54),(B2,L3,A1,R55),(B2,L3,A1,R56),(B2,L3,A2,R51),(B2,L3,A2,R52),(B2,L3,A2,R53),(B2,L3,A2,R54),(B2,L3,A2,R55),(B2,L3,A2,R56),(B2,L3,A3,R51),(B2,L3,A3,R52),(B2,L3,A3,R53),(B2,L3,A3,R54),(B2,L3,A3,R55),(B2,L3,A3,R56),(B2,L3,A4,R51),(B2,L3,A4,R52),(B2,L3,A4,R53),(B2,L3,A4,R54),(B2,L3,A4,R55),(B2,L3,A4,R56),(B2,L3,A5,R51),(B2,L3,A5,R52),(B2,L3,A5,R53),(B2,L3,A5,R54),(B2,L3,A5,R55),(B2,L3,A5,R56),(B2,L4,A1,R51),(B2,L4,A1,R52),(B2,L4,A1,R53),(B2,L4,A1,R54),(B2,L4,A1,R55),(B2,L4,A1,R56),(B2,L4,A2,R51),(B2,L4,A2,R52),(B2,L4,A2,R53),(B2,L4,A2,R54),(B2,L4,A2,R55),(B2,L4,A2,R56),(B2,L4,A3,R51),(B2,L4,A3,R52),(B2,L4,A3,R53),(B2,L4,A3,R54),(B2,L4,A3,R55),(B2,L4,A3,R56),(B2,L4,A4,R51),(B2,L4,A4,R52),(B2,L4,A4,R53),(B2,L4,A4,R54),(B2,L4,A4,R55),(B2,L4,A4,R56),(B2,L4,A5,R51),(B2,L4,A5,R52),(B2,L4,A5,R53),(B2,L4,A5,R54),(B2,L4,A5,R55),(B2,L4,A5,R56),(B2,L5,A1,R51),(B2,L5,A1,R52),(B2,L5,A1,R53),(B2,L5,A1,R54),(B2,L5,A1,R55),(B2,L5,A1,R56),(B2,L5,A2,R51),(B2,L5,A2,R52),(B2,L5,A2,R53),(B2,L5,A2,R54),(B2,L5,A2,R55),(B2,L5,A2,R56),(B2,L5,A3,R51),(B2,L5,A3,R52),(B2,L5,A3,R53),(B2,L5,A3,R54),(B2,L5,A3,R55),(B2,L5,A3,R56),(B2,L5,A4,R51),(B2,L5,A4,R52),(B2,L5,A4,R53),(B2,L5,A4,R54),(B2,L5,A4,R55),(B2,L5,A4,R56),(B2,L5,A5,R51),(B2,L5,A5,R52),(B2,L5,A5,R53),(B2,L5,A5,R54),(B2,L5,A5,R55),(B2,L5,A5,R56),(B3,L1,A1,R51),(B3,L1,A1,R52),(B3,L1,A1,R53),(B3,L1,A1,R54),(B3,L1,A1,R55),(B3,L1,A1,R56),(B3,L1,A2,R51),(B3,L1,A2,R52),(B3,L1,A2,R53),(B3,L1,A2,R54),(B3,L1,A2,R55),(B3,L1,A2,R56),(B3,L1,A3,R51),(B3,L1,A3,R52),(B3,L1,A3,R53),(B3,L1,A3,R54),(B3,L1,A3,R55),(B3,L1,A3,R56),(B3,L1,A4,R51),(B3,L1,A4,R52),(B3,L1,A4,R53),(B3,L1,A4,R54),(B3,L1,A4,R55),(B3,L1,A4,R56),(B3,L1,A5,R51),(B3,L1,A5,R52),(B3,L1,A5,R53),(B3,L1,A5,R54),(B3,L1,A5,R55),(B3,L1,A5,R56),(B3,L2,A1,R51),(B3,L2,A1,R52),(B3,L2,A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),(B5,L3,A2,R51),(B5,L3,A2,R52),(B5,L3,A2,R53),(B5,L3,A2,R54),(B5,L3,A2,R55),(B5,L3,A2,R56),(B5,L3,A3,R51),(B5,L3,A3,R52),(B5,L3,A3,R53),(B5,L3,A3,R54),(B5,L3,A3,R55),(B5,L3,A3,R56),(B5,L3,A4,R51),(B5,L3,A4,R52),(B5,L3,A4,R53),(B5,L3,A4,R54),(B5,L3,A4,R55),(B5,L3,A4,R56),(B5,L3,A5,R51),(B5,L3,A5,R52),(B5,L3,A5,R53),(B5,L3,A5,R54),(B5,L3,A5,R55),(B5,L3,A5,R56),(B5,L4,A1,R51),(B5,L4,A1,R52),(B5,L4,A1,R53),(B5,L4,A1,R54),(B5,L4,A1,R55),(B5,L4,A1,R56),(B5,L4,A2,R51),(B5,L4,A2,R52),(B5,L4,A2,R53),(B5,L4,A2,R54),(B5,L4,A2,R55),(B5,L4,A2,R56),(B5,L4,A3,R51),(B5,L4,A3,R52),(B5,L4,A3,R53),(B5,L4,A3,R54),(B5,L4,A3,R55),(B5,L4,A3,R56),(B5,L4,A4,R51),(B5,L4,A4,R52),(B5,L4,A4,R53),(B5,L4,A4,R54),(B5,L4,A4,R55),(B5,L4,A4,R56),(B5,L4,A5,R51),(B5,L4,A5,R52),(B5,L4,A5,R53),(B5,L4,A5,R54),(B5,L4,A5,R55),(B5,L4,A5,R56),(B5,L5,A1,R51),(B5,L5,A1,R52),(B5,L5,A1,R53),(B5,L5,A1,R54),(B5,L5,A1,R55),(B5,L5,A1,R56),(B5,L5,A2,R51),(B5,L5,A2,R52),(B5,L5,A2,R53),(B5,L5,A2,R54),(B5,L5,A2,R55),(B5,L5,A2,R56),(B5,L5,A3,R51),(B5,L5,A3,R52),(B5,L5,A3,R53),(B5,L5,A3,R54),(B5,L5,A3,R55),(B5,L5,A3,R56),(B5,L5,A4,R51),(B5,L5,A4,R52),(B5,L5,A4,R53),(B5,L5,A4,R54),(B5,L5,A4,R55),(B5,L5,A4,R56),(B5,L5,A5,R51),(B5,L5,A5,R52),(B5,L5,A5,R53),(B5,L5,A5,R54),(B5,L5,A5,R55),(B5,L5,A5,R56)。
试验例β分泌酶抑制作用的测定
向96孔half-area平板(黑色平板，Costar公司制)的各孔中加入48.5μl底物肽(Biotin-XSEVNLDAEFRHDSGC-Eu：X=ε-氨基正己酸、Eu=铕穴合物(Europiumcryptate))溶液，分别添加0.5μl受试化合物(N,N’-二甲基甲醛溶液)和1μl重组人BACE-1(R&Dsystems公司制)，之后在30℃下反应3小时。底物肽通过使CryptateTBPCOOHmonoSMP(CISbiointernational公司制)与Biotin-XSEVNLDAEFRHDSGC(Peptide研究所制)反应来合成。底物肽的最终浓度为18nM、重组人BACE-1的最终浓度为7.4nM，反应缓冲液使用乙酸钠缓冲液(50mM乙酸钠pH5.0、0.008%TritonX-100)。反应结束后，向各孔中添加50μl溶解在磷酸缓冲液(150mMK2HPO4-KH2PO4pH7.0、0.008%TritonX-100、0.8MKF)中的8.0μg/ml的Streptavidin-XL665(CISbiointernational公司制)，在30℃下静置1小时。之后，使用Wallac1420多标计数仪(PerkinElmerlifesciences公司制)测定荧光强度(激发波长320nm、测定波长620nm和665nm)。酶活性由各测定波长的计数率(10000×计数665/计数620)求出，算出50%抑制酶活性的用量(IC50)。受试物质的IC50值如表170所示。
[表170]
通过相同的试验，以下化合物的IC50值也显示100μM以下。
3,4,6,8,12,17,18,30,31,35,36,38,39,42,43,57,61,67,67,71,77,78,80,85,97,99,105,106,113,114,115,117,120,121,125,128,129,130,134,139,144,154,157,159,164,172,175,178,181,182,186,189,200,200,201,204,207,209,211,214,215,216,228,232,240,241,243,243,243,251,255,259,267,,273,275,278,279,281,282,,293,298,299,300,302,303,307,314,319,321,322,326,328,330,333,335,339,341,344,345,346,348,352,353,357,358,359,359,359,360,361,363,369,370,373,378,380,383,389,390,393,396,397,402,405,406,409,410,413,415,426,442,443,444,451,452,454,456,463,467,469,472,472,479,480,482,482,483,491,493,497,500,501,502,509,511,515,516,517,527,528,532,542,544,549,550,551,558,560,568,569,575,578,584,586,588,591,600,607,608,611,613,618,620,629,634,634,637,643,646,652,657,661,671,677,681,687,691,708,711,719,720,723,725,728,729,730,732,735,743,746,756,758,761,770,775,781,787,788,790,791,792,796,797,802,803,804,808,809,813,816,819,820,824,833,835,836,847,850,861,865,866,871,876,887,893,894,900,905,906,908,910,919,922,928,932,933,935,936,939,941,943,944,946,947,949,959,966,971,984,986,988,990,1004,1005,1007,1009,1013,1020,1028,1034,1039,1046,1055,1062,1063,1069,1074,1077,1084,1089,1096,1099,1108,1109,1114,1124,1125,1131,1140,1142,1145,1147,1148,1150,1164,1165,1172,1174,1184,1185,1193,1211,1217,1221,1237,1241,1243,1255,1256,1257,1258,1261,1263,1264,1265,1266,1268,1269,1270,1271,1272,1274等。
制剂例1
制备含有以下成分的颗粒剂。
将式(I)所示的化合物和乳糖过60目的筛。将玉米淀粉过120目的筛。用V型混合机混合上述成分。向混合粉末中添加HPC-L(低粘度羟丙基纤维素)水溶液，进行混合、制粒(挤出制粒，孔径0.5～1mm)、干燥步骤。将所得干燥颗粒用振动筛(12/60目)过筛，得到颗粒剂。
制剂例2
制备含有以下成分的胶囊填充用颗粒剂。
将式(I)所示的化合物、乳糖过60目的筛。将玉米淀粉过120目的筛。混合上述成分，向混合粉末中添加HPC-L溶液，进行混合、制粒、干燥。所得干燥颗粒整粒后，将该150mg填充到4号硬明胶胶囊中。
制剂例3
制备含有以下成分的片剂。
将式(I)所示的化合物、乳糖、微晶纤维素、CMC-Na(羧甲基纤维素钠盐)过60目的筛，进行混合。向混合粉末中混合硬脂酸镁，得到制片用混合粉末。将该混合粉末直接压片，得到150mg的片剂。
制剂例4
将以下成分加热混合，然后灭菌，制备注射剂。
成分  式(I)所示的化合物   3mg
      非离子表面活性剂   15mg
      注射用纯净水       1ml
产业实用性
本发明化合物作为由淀粉状β蛋白的产生、分泌和/或沉积所诱发的疾病的治疗药是有用的药物。

Claims (17)

1.BACE1抑制剂，该抑制剂以式(I)所示的化合物或其药学上可接受的盐作为有效成分，
式中，
环A为被选自组<A-1>和组<A-2>的一个以上取代基取代的碳环式基团或可被选自组<A-1>和组<A-2>的一个以上取代基取代的杂环式基团；
组<A-1>：
卤素；羟基；C1-C15烷氧基；氨基；酰基氨基；氰基；可被选自卤素、羟基、C1-C15烷氧基、C1-C15烷氧基羰基和酰基氨基的一个以上取代基取代的C1-C15烷基；
羟基亚氨基C1-C15烷基；
C1-C15烷氧基亚氨基C1-C15烷基；
可被选自卤素和C1-C15烷氧基羰基的一个以上取代基取代的C2-C15烯基；
可被C1-C15烷氧基羰基取代的C2-C10炔基；
C1-C15烷基磺酰基；
C1-C10亚烷基二氧基；以及
氧基；
组<A-2>：
式中，Q2为C1-C10亚烷基；
式中，Q1为单键、C1-C10亚烷基、C2-C10亚烯基、或卤代C2-C10亚烯基；
式中，Q2为单键、C1-C10亚烷基或C2-C10亚烯基；
式中，Q1为C1-C10亚烷基；
式中，Q1和Q2各自独立为C1-C10亚烷基；
；
式中，Q1为C1-C10亚烷基或卤代C1-C10亚烷基；
式中，Q1为单键或C1-C10亚烷基；
式中，Q3为C1-C10亚烷基；
；
式中，Q1为单键或C1-C10亚烷基；
式中，Q1为单键或C1-C10亚烷基；
式中，Q2为C1-C10亚烷基；
式中，Q2为C1-C10亚烷基；
式中，Q1和Q3各自独立为C1-C10亚烷基；
p为1或2的整数；
式中，Q1为单键或C1-C10亚烷基；
式中，Q4为C1-C10亚烷基；
式中，R14为氢或C1-C15烷基，且Q1为单键或C1-C10亚烷基；
式中，Alk2为卤代C1-C15烷基或C1-C15烷氧基C1-C15烷基；
式中，Alk2为C1-C15烷基；
式中，Q2为C1-C10亚烷基；
；和 
式中，R12为氢或C1-C15烷基；环B为可被选自组<I>的一个以上取代基取代的碳环式基团或可被选自组<I>的一个以上取代基取代的杂环式基团；
组<I>：
卤素、羟基、C1-C15烷氧基、酰基、C1-C15烷氧基羰基、氨基、酰基氨基、C1-C15烷基氨基、C1-C15烷硫基、氨基甲酰基、氰基、硝基、芳基、以及杂环式基团；
可被选自卤素、羟基和C1-C15烷氧基的一个以上取代基取代的C1-C15烷基；
可被选自卤素和芳基的一个以上取代基取代的C1-C15烷氧基；
被选自羟基、C1-C15烷氧基、芳基和杂环式基团的一个以上取代基取代的C1-C15烷基氨基；
可被选自卤素的一个以上取代基取代的芳基；
可被选自卤素的一个以上取代基取代的杂环式基团；
芳氧基；
C1-C10亚烷基二氧基；以及
氧基；X为O；
R2a和R2b各自独立表示氢或脒基；
R3a、R3b、R4a和R4b各自独立表示氢、C1-C15烷基或碳环式基团；
n和m各自独立表示0-3的整数；
n+m为3的整数、或者n为2且m为0；
各R3a、各R3b、各R4a、各R4b可以不同；
R5表示氢或C1-C15烷基；
其中，“碳环式基团”为C3-C10环烷基、C3-C10环烯基、芳基和非芳族缩合碳环式基团；
“芳基”为苯基、萘基、蒽基或菲基；
“非芳族缩合碳环式基团”为与选自上述C3-C10环烷基、C3-C10环烯基和芳基的两个以上环状基团缩合的基团；
“杂环式基团”为环内具有一个以上任意选自O、S和N的杂原子的杂环式基团。
2.权利要求1的BACE1抑制剂，其中n为2且m为0。
3.式(I)所示的化合物或其药学上可接受的盐，
式中，
各记号与权利要求1的定义相同，但以下化合物除外：
ii) 其中n为2、m为0、R2a为氢、R2b为氢、R5为甲基、环A为4-甲氧基苯基的化合物；
iii) 其中n为2、m为0、R2a为氢、R2b为氢、R5为乙基、环A为3,4-二甲氧基苯基的化合物；
vi) 其中n+m为2、R5为氢、环A为被选自羟基、卤素、C1-C15烷基、C1-C15烷氧基、硝基、氨基、C1-C15烷基羰基氨基、巯基、C1-C15烷硫基和氨基甲酰基的1或2个取代基取代的苯基的化合物。
4.权利要求3的化合物或其药学上可接受的盐，其中n为2且m为0。
5.权利要求3的化合物或其药学上可接受的盐，其中R5为C1-C15烷基。
6.权利要求3的化合物或其药学上可接受的盐，其中R2a为氢且R2b为氢。
7.权利要求3的化合物或其药学上可接受的盐，其中环A为被选自组<A-1>和组<A-2>的一个以上取代基取代的苯基，所述组<A-1>和组<A-2>与权利要求1的定义相同。
8.权利要求3的化合物或其药学上可接受的盐，其中环A为：
式中，
R9和R10为氢或G；
R11为G；
G为：
卤素；
羟基；
氰基；
可被选自卤素、羟基、C1-C15烷氧基、C1-C15烷氧基羰基和酰基氨基的一个以上取代基取代的C1-C15烷基；
羟基亚氨基C1-C15烷基；
C1-C15烷氧基亚氨基C1-C15烷基；
C1-C15烷氧基；
可被选自卤素和C1-C15烷氧基羰基的一个以上取代基取代的C2-C15烯基；
可被C1-C15烷氧基羰基取代基的C2-C10炔基；
C1-C15烷基磺酰基；或
组<A-2>；
其中，组<A-2>与权利要求1的定义相同，
各G可以不同。
9.权利要求3的化合物或其药学上可接受的盐，其中环A为：
式中，
R9、R10和R11为：
氢；卤素；羟基；氰基；
可被选自卤素、羟基、C1-C15烷氧基、C1-C15烷氧基羰基和酰基氨基的一个以上取代基取代的C1-C15烷基；
羟基亚氨基C1-C15烷基；
C1-C15烷氧基亚氨基C1-C15烷基；
C1-C15烷氧基；
可被选自卤素和C1-C15烷氧基羰基的一个以上取代基取代的C2-C15烯基；
可被C1-C15烷氧基羰基取代的C2-C10炔基；
C1-C15烷基磺酰基；或
可被选自组<I>的一个以上取代基取代的碳环式基团；
条件是R11不为氢；以及
G为组<A-2>；
其中，所述组<A-2>和组<I>与权利要求1的定义相同。
10.权利要求9的化合物或其药学上可接受的盐，其中环B为芳基或杂芳基，所述芳基或杂芳基可以被选自下述的一个以上取代基取代：
卤素；
羟基；
可被选自卤素、羟基和C1-C15烷氧基的一个以上取代基取代的C1-C15烷基；
可被选自卤素和芳基的一个以上取代基取代的C1-C15烷氧基；
酰基；
氨基；
酰基氨基；
可被选自羟基、C1-C15烷氧基、芳基和杂环式基团的一个以上取代基取代的C1-C15烷基氨基；
氰基；
氨基甲酰基；
可被选自卤素的一个以上取代基取代的芳基；
芳氧基；以及
可被选自卤素的一个以上取代基取代的杂环式基团，
其中，“芳基”为苯基、萘基、蒽基或菲基；
“杂环式基团”为环内具有一个以上任意选自O、S和N的杂原子的杂环式基团；
“杂芳基”为环内具有一个以上任意选自O、S和N的杂原子的杂环式基团。
11.权利要求9的化合物或其药学上可接受的盐，其中Ｇ为：
式中，Q1为单键、C1-C10亚烷基、C2-C10亚烯基或卤代C2-C10亚烯基；
；
式中，Q1为C1-C10亚烷基或卤代C1-C10亚烷基；
式中，Q1为单键或C1-C10亚烷基；或者
式中，Q1为单键或C1-C10亚烷基；
其中，R12为氢或C1-C15烷基。
12.权利要求3~11中任一项的化合物或其药学上可接受的盐，其中R5为C1-C3烷基。
13.权利要求3~11中任一项的化合物或其药学上可接受的盐，其中R5为甲基。
14.权利要求3~11中任一项的化合物或其药学上可接受的盐，其中R3a和R3b各自独立表示氢、C1-C15烷基或芳基，其中芳基为苯基、萘基、蒽基或菲基。
15.权利要求3~11中任一项的化合物或其药学上可接受的盐，其中R3a和R3b全部为氢。
16.药物组合物，其特征在于：以权利要求3~15中任一项的化合物或其药学上可接受的盐作为有效成分。
17.BACE1抑制剂，其特征在于：以权利要求3~15中任一项的化合物或其药学上可接受的盐作为有效成分。
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JP2013116902A (ja) 2013-06-13
CN103936690B (zh) 2016-06-08
US20090082560A1 (en) 2009-03-26
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US8815851B2 (en) 2014-08-26
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US20120016116A1 (en) 2012-01-19
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