CN101282930B - Fab I抑制剂及其制备方法 - Google Patents
Fab I抑制剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种有效抑制Fab I的化合物以及一种治疗细菌感染的方法。
Description
技术领域
本发明涉及一种用于抑制Fab I的新化合物,所述的Fab I参与细菌脂肪酸的生物合成。根据35U.S.C.119(e),本申请以2005年10月13日提交的发明名称为“新的Fab I抑制剂及其制备方法”的临时申请和2006年9月26日提交的临时申请60/827,029为优先权,并引入上述两件申请作为参考。
背景技术
脂肪酸合成酶(FAS)参与所有生物体中饱和脂肪酸的整个生物合成途径,但在这些生物体中,FAS的结构组织(structural organization)有相当大的变化。脊椎动物和酵母的FAS的区别性特征是所有的酶活性编码在一个或两个多肽链上,以及酰基载体蛋白(ACP)以配合物的形式存在。与此相反,在细菌的FAS中,每个合成步骤都被不同的单官能酶催化,以及所述的ACP是分立的(discrete)蛋白。因此,有可能使用抑制剂,通过阻断某一合成步骤对细菌的FAS进行选择性抑制。
在细菌脂肪酸生物合成每一循环所涉及的4个步骤中,依赖于NADH的烯酰基-ACP还原酶(Fab I)是参与最后一个步骤的酶(参见Payne等人,Drug Discovery Today,6,2001,537-544)。第一步,丙二酰基-ACP与乙酰基-CoA(Fab H)缩合,用β-酮脂酰基-ACP合成酶催化;第二步,酮酸酯被依赖于NADPH的β-酮脂酰基-ACP还原酶(Fab G)还原;接着,用β-羟酰基-ACP脱水酶(Fab A或Fab Z)脱水,得到反式-2-烯酰基-ACP;最后,在第四步中,用Fab I将反式-2-烯酰基-ACP转化为具有二个附加碳原子的酰基-ACP。重复此循环,最后得到棕榈酰基-ACP(16C),随之通过棕榈酰基-ACP对Fab I的抑制,使该循环停止(参见Heath等人,J.Biol.Chem.271,1996,1833-1836)。因此,在细菌脂肪酸生物合成的整个合成途径中,Fab I是生物合成酶。
近年来的研究表明Fab I是广谱抗菌剂的靶标,所述的广谱抗菌剂例如三氯生(triclosan)(参见McMurry等人,Nature,1998,394,531-532)或二氮杂烃基硼(diazaborine)(参见Baldock等人,Science,1996,274,2107-2110)。另外,已有报告称通过与Fab I形成共价配合物,二氮杂烃基硼用作Fab I的不可逆抑制剂(参见Baldock等人,Biochem.Pham.,1998,55,1541-1549),而三氯生是Fab I的可逆抑制剂(参见Ward等人,Biochem.,38,12514-12525)。
PCT公开号WO 200I/027103公开了Fab I抑制剂,其用下式或其药学上可接受的盐表示:
其中
B是H、C1-4烷基或C3-6环烷基;
D是H或C1-4烷基;
当与其相连接的键是双键时,E是CH2;或者,当与其相连接的键是单键时,E是H或C1-4烷基;
其中A是H或C1-4烷基;
F是H或C1-4烷基;
G是H、C1-4烷基或C0-6烷芳基;
I是O或NR′2;
Q是H、C1-4烷基、N(R′)2、NHC(O)R′、NHCH2C(O)R′或NHC(O)CH=CHR′;
X各自独立地是H、C1-4烷基、CH2OH、OR′、SR′、CN、N(R′)2、CH2N(R′)2、NO2、CF3、CO2R′、CON(R′)2、COR′、F、Cl、Br、I或-S(O)rCF3(r是0、1或2);
W是S或O;
M是CH2或O;
L是CH2或C(O);和
R′各自独立地是H、C1-4烷基或C0-6烷芳基。
此外,PCT公开号WO 2004/052890和WO 2004/064837,以及加拿大专利号2,444,957公开了用于细菌治疗的Fab I抑制剂。
本发明人开发了新的Fab I抑制剂,该抑制剂对革兰氏阳性菌具有广谱抗菌活性,所述的革兰氏阳性菌包括抗甲氧西林金黄色葡萄球菌(Staphylococcos Aureus)(MRSA)。
发明内容
本发明的目的是提供一种有效抑制Fab I,并可用于治疗细菌感染的新化合物。
按照本发明的一个方面,本发明提供了式(I)或(II)化合物,或其药学上可接受的类似物,所述的类似物选自盐、酸、酯、酰胺和腈:
其中
R1选自下述基团:
(a)H,
(b)C1-8烷基、C1-8链烯基、C1-8炔基,
(c)芳基、C3-8环烷基、C3-8环烯基,
(d)含有一个或多个选自N、S和/或O的杂原子的上述(c)组基团的类似物,和
(e)选自上述(b)、(c)和(d)组基团的取代类似物,所述的取代类似物含有一个或多个下述取代基:
羟基、卤素、C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基、芳基、杂芳基、取代芳基和取代杂芳基,
其中的取代芳基和取代杂芳基含有一个或多个下述取代基:C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基和芳基;
A选自C-R2和N;
R2选自下述基团:H、C1-5烷基、苄基和含有一个或多个取代基的取代C1-5烷基,所述取代基选自甲基、乙基、羟基、羟甲基和羟乙基;
B选自羰基、CH2和NH;
R4选自下述基团:
(a)C1-8烷基、C1-8链烯基、C1-8炔基,
(b)芳基、C3-8环烷基、C3-8环烯基,
(c)含有一个或多个选自N、S和O的杂原子的上述(b)组基团的类似物,和
(d)选自上述(a)、(b)和(c)组基团的取代类似物,所述的取代类似物含有一个或多个下述取代基:
羟基、卤素、C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基、芳基、杂芳基、取代芳基和取代杂芳基;
其中所述的取代芳基和取代杂芳基含有一个或多个下述取代基:C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷基氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基和芳基;
W选自C-R6和N;
Z选自C-R5和N;
R5和R6各自独立地选自下述基团:H、卤素、C1-5烷基和含有一个或多个取代基的取代C1-5烷基,所述取代基选自甲基、乙基、羟基、羟甲基和羟乙基;和
X选自C、N、O和S。
按照本发明的一个方面,本发明提供了式(I)或(II)的新化合物或其药学上可接受的盐。
本发明所用的术语“杂芳基”是指在环结构中含有一个或多个选自N、S或O的杂原子的芳基。杂芳基的实例包括由下述杂环化合物衍生的基团:吡咯、吡唑、咪唑、1,2,3-三唑、1,2,4-三唑、呋喃、异噁唑、噁唑、噻吩、异噻唑、噻唑烷、噻唑、1,2,5-噁二唑、1,2,3-噁二唑、1,2,5-噻二唑、1,2,3-噻二唑、1,3,4-噁二唑、1,3,4-噻二唑、吡啶、嘧啶、四唑和三嗪。
本发明所用的术语“与细菌有关的疾病”是指由细菌感染引起的,并且通过用Fab I抑制剂治疗可缓解或治愈的疾病或症状,包括但不限于尿道、呼吸或皮肤组织感染、脓血症等。
可以理解的是本发明的化合物可能含有R或S构型的不对称中心,因此本发明还包括式(I)或(II)化合物的几何异构体、立体异构体以及外消旋混合物。
本发明化合物药学上可接受的盐可以是用酸或碱制成的无毒的加成盐。本发明所用的酸的实例包括无机酸如盐酸、氢溴酸、磷酸和硫酸;以及有机酸如有机羧酸,例如乙酸、三氟乙酸、柠檬酸、甲酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸、苹果酸、甲磺酸和对甲苯磺酸。本发明所用碱的实例包括无机碱,如碱金属氢氧化物(例如氢氧化钠和氢氧化钾)、碱金属碳酸氢盐(例如碳酸氢钠和碳酸氢钾)、碱金属碳酸盐(例如碳酸钠、碳酸钾和碳酸钙)以及有机碱如胺类。
本发明化合物也可以具有适当的酯基或酰胺基的药学上可接受的衍生物或前药的形式被使用。优选的酯的例子是在活体内可以通过化学或生物化学方法水解的下述酯:茚满基、2-苯并[c]呋喃酮基、叔戊酰氧甲基(pivaloyloxymethyl)、甘氨酰氧甲基、苯基甘氨酰氧甲基和5-甲基-2-氧代-1,3-二氧杂环戊烯(dioxorene)-4-基甲基(ylmethyl)的酯。
本发明优选的化合物如下:
4-苄氧基-1-(2-氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(4-氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(4-硝基-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(2,5-二氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-2-(4-甲氧基-苄氧基)-吡啶;
4-苄氧基-1-(4-甲氧基-苄基)-1H-吡啶-2-酮;
4-苄氧基-2-(4-甲基-苄氧基)-吡啶;
4-苄氧基-1-(4-甲基-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(6-氯-吡啶-3-基甲基)-1H-吡啶-2-酮;
4-苄氧基-1-(3-氯-苄基)-1H-吡啶-2-酮;
1-苄基-4-苄氧基-1H-吡啶-2-酮;
1-(4-氨基-苄基)-4-苄氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮;
3-苄基-1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮;
4-(联苯-4-基甲氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2,4-二氯-苄氧基)-1H-吡啶-2-酮;
4-(2-氯-苄氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-甲氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-异丙氧基-1H-吡啶-2-酮;
4-环己基甲氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-丙氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-异丁氧基-1H-吡啶-2-酮;
4-丁氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-辛氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-戊氧基)-1H-吡啶-2-酮;
4-(丁-3-烯基氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧基]-乙酸乙酯;
1-(2,4-二氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-苄基-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-戊氧基-1-丙基-1H-吡啶-2-酮;
1-丁基-4-戊氧基-1H-吡啶-2-酮;
1-异丁基-4-戊氧基-1H-吡啶-2-酮;
1-(3-甲基-丁基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-己氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-庚氧基-1H-吡啶-2-酮;
1-(4-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-芳氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲氧基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-乙氨基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-乙氧基-乙氧基)-1H-吡啶-2-酮;
1-(3-甲基-丁-2-烯基)-4-戊氧基-1H-吡啶-2-酮;
4-戊氧基-1-噻唑-4-基甲基-1H-吡啶-2-酮;
4-戊氧基-1-吡啶-3-基甲基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-戊-3-烯基氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲氧基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-乙氧苯基氧基(phenetyloxy)-1H-吡啶-2-酮;
1-(2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-戊基-1-乙氧苯基-1H-吡啶-2-酮;
1-(2,4-二氯-5-氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3,4-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3,4-二氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(4-苄氧基-丁氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-羟基-丁氧基)-1H-吡啶-2-酮;
4-(5-苄氧基-戊氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(5-羟基-戊氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基(benzo[1,3]dioxol-5-ylmethyl))-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-甲基-苄氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-苄氧基)-1H-吡啶-2-酮;
1-(2-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
N-[2-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
4-戊氧基-1-(2-三氟甲基-苄基)-1H-吡啶-2-酮;
N-[4-(4-苄氧基-2-氧代-2H-吡啶-1-基甲基)-苯基]乙酰胺;
1-(2,4-二氯-苄基)-4-(萘-2-基甲氧基)-1H-吡啶-2-酮;
1-萘-2-基甲基-4-戊氧基-1H-吡啶-2-酮;
4-苄氧基-1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(2-甲基-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
4-(3-甲基-丁氧基)-1-(2-硝基-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-戊氨基-1H-吡啶-2-酮;
1-(2,3-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,3-二甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(5-苄氧基-戊氧基)-1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-1H-吡啶-2-酮;
1-(2-氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(3,4-二氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-5-氟-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-苄基-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(4-氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-戊氧基-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-戊氧基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-苯氧基-1H-嘧啶-2-酮;
4-(丁基-甲基-氨基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-二乙氨基-乙氧基)-1H-嘧啶-2-酮;
4-丁氧基-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,6-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-6-氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲基-3-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-甲氧基-3,5-二甲基-吡啶-2-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(5-羟基-戊氧基)-1H-吡啶-2-酮;
1-(2-甲氧基-5-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(5-氨基-2-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-乙基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(5-氨基-2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-甲氧基-2,3-二甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲基-吡啶-3-基甲基)-4-戊氧基-1H-吡啶-2-酮;
N-[4-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
1-(2,4-二氯-苄基)-4-(3-二甲氨基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-二甲氨基-丁氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(6-二甲氨基-己氧基)-1H-嘧啶-2-酮;
1-(2,4-二甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-三氟甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(3-环丙氧基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲基-戊氧基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-己-4-烯基氧基-1H-嘧啶-2-酮;
4-(2-环丙基-乙氧基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲基-戊氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(5-吗啉-4-基-戊氧基)-1H-吡啶-2-酮;
1-(2-氯-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-乙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-丙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-5-(2-羟基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
[4-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-氧基]-乙腈;
1-[5-(2-氨基-乙氧基)-2-氯-苄基]-4-戊氧基-1H-吡啶-2-酮;
N-[2-甲基-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
1-(2-甲基-3-甲氨基-苄基)-4-苯氧基-1H-吡啶-2-酮;
1-(3-二甲氨基-2-甲基-苄基)-4-苯氧基-1H-吡啶-2-酮;
1-(3-乙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-二乙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲基-3-丙氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-二丙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[3-(2-羟基-乙氨基)-2-甲基-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-甲氧基-4-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-氨基-2-氯-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
N-[5-氯-2-甲氧基-4-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
1-(2-氯-5-甲氧基-4-甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-4-二甲氨基-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-4-乙氨基-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-甲氧基-4-丙氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-4-(2-羟基-乙氨基)-5-甲氧基-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-(4-氨基-6-氯-3-甲氧基-2-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氨基-6-氯-3-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,5-二氯-6-甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苯磺酰基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-甲磺酰基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-氨基-2-氯-5-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(4-溴-丁氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
4-[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧基]-丁基铵;
1-(5-氯-2,6-二甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氨基-5-氯-6-甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(6-氨基-2,5-二氯-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
5-氯-6-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-3H-苯并噁唑-2-酮;
1-(2-氯-4-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-4-异丙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
2-[3-(2-氧代-4-戊氧基-2H-吡啶-1-基)-丙基]-异吲哚-1,3-二酮;
1-(3-氨基-丙基)-4-戊氧基-1H-吡啶-2-酮;
N-[3-(2-氧代-4-戊氧基-2H-吡啶-1-基)-丙基]-乙酰胺;
1-(3-二甲氨基-丙基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-6-甲基-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-6-甲基-3-戊基-4-戊氧基-1H-吡啶-2-酮;
1-(2-氨基-乙基)-4-戊氧基-1H-吡啶-2-酮;
N-[2-(2-氧代-4-戊氧基-2H-吡啶-1-基)-乙基]-乙酰胺;
N-[1,1-二甲基-2-(2-氧代-4-戊氧基-2H-吡啶-1-基)-乙基]-甲磺酰胺;
N-[1-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-丙基]-甲磺酰胺;
1-(7-硝基-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-氨基-2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
N-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
N-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-甲磺酰胺;
N,N’-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-二甲磺酰胺;
1-[2-氯-3-(2-羟基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
4-氯-2-(2-氯-苄基)-5-戊氧基-2H-哒嗪-3-酮;
2-(2-氯-苄基)-5-戊氧基-2H-哒嗪-3-酮;
1-(3-氨基-2,6-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-苄氧基-2-氯-4-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3,4-二甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3-羟基-4-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-4-甲氧基-3-(2-甲氧基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-4-甲氧基-3-(2-吡咯烷-1-基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-3-(2-二甲氨基-乙氧基)-4-甲氧基-苄基]-4-戊氧基-1H-吡啶-2-酮;
2-{3-[2-氯-6-甲氧基-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯氧基]-丙基}-异吲哚-1,3-二酮;
1-[3-(2-二甲氨基-乙氧基)-2-甲基-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-3-(2-二甲氨基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(2-羟基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(2-二甲氨基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(3-羟基-丙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(3-二甲氨基-丙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[3-(3-氨基-丙氨基)-2,6-二氯-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-(3-氟-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3-二甲氨基甲基-4-氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,6-二氯-3-甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,6-二氯-3-二甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯氨基]-乙酸;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(吡啶-4-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(6-氯-吡啶-3-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(4-甲氧基-3,5-二甲基吡啶-2-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-甲基-吡啶-3-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(噻唑-4-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(吡啶-2-基甲氧基)-1H-吡啶-2-酮;
戊酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
己酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
1-(2-氯-3-三氟甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
噻吩-2-羧酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
甲苯-4-磺酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(4,4,5,5,5-五氟-戊氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-二甲氨基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(5-氟-戊氧基)-1H-吡啶-2-酮;
3-[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧甲基]-吲哚-1-羧酸四-丁基酯;
1-(2,4-二氯-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-噻吩-3-基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-吡咯-1-基-丙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(4-甲基-噻唑-5-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-(5-溴噻吩-2-基)-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-(5-氟噻吩-2-基)-乙氧基)-1H-吡啶-2-酮;
1-[3-(2-羟基-乙氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙酰胺;
1-[3-(环丙基甲基-氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙腈;
N-(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙基)-乙酰胺;
1-[2-甲基-3-(2-吡咯-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-氧代-2-吡咯烷-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-氧代-2-哌啶-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N,N-二甲基-2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙酰胺;
1-{2-甲基-3-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-吗啉-4-基-2-氧代-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-呋喃-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-氯-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-[2-(3-甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-苯并[b]噻吩-3-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-氯-3-甲基-苯并[b]噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(3-甲基-苯并[b]噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基-呋喃-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-乙基-呋喃-2-基)-乙氧基]-1H-吡啶-2-酮;
5-[1-(3-氨基-2-甲基-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧甲基]-呋喃-2-羧酸乙酯;
1-[3-(2-二甲氨基-乙氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基硫烷基(sulfanyl)-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-苯并呋喃-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(3-甲基-异噁唑-5-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(4,5-二甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-乙基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2,6-二氯-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯基}-乙酰胺;
1-[2-甲基-3-(2-哌啶-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-吗啉-4-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯基}-甲磺酰胺;
1-(3-氨基-2-甲基-苄基)-4-[2-(4-溴-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-吡咯烷-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙基)-乙酰胺;
1-{2-甲基-3-[(吡啶-3-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯基酯;
1-{2-甲基-3-[(吡啶-4-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{2-甲基-3-[(噻唑-4-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[3-(4-甲氧基-苄氧基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{3-[(3,5-二甲基-异噁唑-4-基甲基)-氨基]-2-甲基-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-羟基-2-甲基-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{2-甲基-3-[(1-甲基-吡咯烷-2-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{2-甲基-3-[2-(1-甲基-吡咯烷-2-基)-乙氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙基)-膦酸二乙酯;
4-(异丁硫基)-1-(2-甲基-3-硝基苄基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(异丁硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(呋喃-2-基甲硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(戊硫基)吡啶-2-(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(苯乙硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(丁硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(噻吩-2-基甲硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(戊硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(丙硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(1-甲基丁硫基)吡啶-2(1H)-酮;
N,N-二甲基-3-(2-甲基-3-((2-氧代-4-(2-(噻吩-2-基)乙氧基)吡啶-1(2H)-基)甲基)苯氨基)丙烷-1-磺酰胺;
1-(3-氨基-2-甲基苄基)-4-(2-(噻吩-2-基)乙氨基)吡啶-2-(1H)-酮。
本发明的式(I)或(II)化合物可用哒嗪衍生物、嘧啶酮衍生物、三嗪酮衍生物或吡啶酮衍生物通过简单的烷基化或芳基化作用制备。
式(I)化合物的优选实例是吡啶酮化合物,该化合物可通过反应流程1或2制备。本文中所使用的NaH是氢化钠,TsCl是对甲苯磺酰氯,Ac2O是乙酸酐,BuOH是丁醇,t-BuOH是叔丁醇,Pd/C是钯/碳,KOtBu是叔丁醇钾,以及Zn是锌粉。
反应流程1
试剂:(a)NaH,苄氧基丙基溴,DMF;(b)Pd/C,H2,MeOH;(c)TsCl,TEA,DCM;(d)环丙胺,MeOH
反应流程2
试剂:(a)NaH,2-甲基-3-硝基苄基氯,DMF;(b)肼,Zn,EtOH;(c)乙酸酐,TEA,DCM
以上用作原料的吡啶酮衍生物可分别由反应流程3或4制备。
反应流程3
试剂:(a)BnCl,NaH,DMF;(b)Pd/C,H2,MeOH
反应流程4
试剂:(a)BuOH,KOtBu,t-BuOH;(b)Ac2O,回流
式(I)化合物的另一优选实例是用甲基取代的吡啶酮化合物,该化合物可按照反应流程5制备。
反应流程5
试剂:(a)NaH,戊基溴,DMF;(b)苯甲胺,EtOH,回流
上式化合物的另一优选实例是哒嗪化合物,可按照反应流程6制备。
反应流程6
试剂:(a)NaH,戊醇,DMF;(b)2,4-二氯苄基氯NaH,DMF;(c)Pd/C,H2,MeOH
在反应流程6中,用4-甲基戊醇代替戊醇可以得到产品2-(2,4-二氯苄基)-5-(4-甲基戊氧基)哒嗪-3(2H)酮:
2-(2,4-二氯苄基)-5-(4-甲基戊氧基)哒嗪-3(2H)酮
式(I)或(II)能有效地抑制Fab I活性。因此,本发明提供了一种抑制Fab I活性的方法,该方法包括将体液如血液、尿液和淋巴液与本发明的式(I)或(II)化合物相接触。
本发明还提供了一种药物组合物,该组合物含有对治疗或预防与细菌有关的疾病有效量的式(I)或(II)化合物作为有效成分。
本发明的药物组合物还可含有药学上可接受的载体、稀释剂、辅剂(adjuvants)或赋形剂(vehicles),示例性的载体、稀释剂、辅剂和赋形剂包括但不限于离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清白蛋白,缓冲物质如磷酸盐、氨基乙酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物,水,盐或电解质如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠或锌盐,胶态二氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素基物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜡,聚乙烯-聚氧丙烯嵌段聚合物,聚乙二醇,羊毛脂,对羟基苯甲酸酯,氯丁醇,苯酚,山梨酸,单硬脂酸铝,明胶等。还可根据需要包括等渗剂,例如糖、氯化钠等。
本发明的各种制剂可用表面活性剂例如TWEENsTM或SPANsTM、乳化剂、补充剂(extenders)等制备,并可通过下述途径给药:口服、舌下、肠胃外、吸入喷雾、局部、直肠、鼻内、口含、阴道或通过植入储库(implanted reservoir)给药。本发明所用的术语“肠胃外”包括皮下、静脉内、肌肉内、关节内、滑膜腔内、胸骨内、鞘内、肝内、病灶内和颅内注射,或灌输技术。优选地,所述的组合物经口服、腹膜内、皮下、肌肉内或静脉内给药。
无菌注射制剂可以是水悬浮液或油悬浮液的形式。这些悬浮液可以通过常规方法,使用例如下述适当的分散剂或湿润剂和悬浮剂诸如水、乙醇、多元醇类(丙二醇、聚乙二醇、甘油等)或其适当的混合物、植物油(例如橄榄油)、注射用有机酯如油酸乙酯配制。通过例如下述的方法可保持适当的流动性:使用诸如卵磷脂的包衣、在分散时维持所要求的颗粒大小,以及使用表面活性剂。
适用于口服给药的制剂可以是胶囊剂、片剂、丸剂、粉剂或颗粒剂的形式。在这些固体剂型中,所述的活性化合物可以与至少一种惰性载体混合,所述的惰性载体例如是柠檬酸钠或磷酸二钙;或与填充剂、补充剂、粘合剂、保湿剂、崩解剂如碳酸钙或某些硅酸络盐(complexsilicates)、溶液缓凝剂如石蜡、吸收加速剂如季铵化合物、湿润剂如十六烷醇或单硬脂酸甘油酯、吸附剂以及润滑剂如硬脂酸镁、固体聚乙二醇等,或其混合物。为胶囊剂的形式时,所述的活性化合物可与缓冲剂混合,也可以与赋形剂如乳糖以及高分子量的聚乙二醇等混合。
适于口服给药的制剂还可以是水悬浮液、溶液、糖浆等形式。当需要口服水悬浮剂时,使活性成分与乳化剂和悬浮剂混合。如果需要,还可以加入甜味剂、芳香剂或着色剂。
适于口服的制剂还可以有包衣,以及还可以与某些试剂一起制剂,以便能够在消化道的特定部位释放活性化合物。
局部给药的制剂可用于需要治疗的靶位,所述的靶位包括通过局部应用可容易到达的位置或器官,例如眼睛、皮肤或下消化道。局部经皮贴剂也可用于局部给药。
对于皮肤或下消化道的局部应用而言,本发明的组合物可以制剂成膏剂、洗剂、霜剂或喷雾剂形式,其中含有悬浮于或溶解于一种或多种适当载体的活性成分。所述的膏剂可含有矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯、乳化蜡、或水作为适当的载体。所述的洗剂、霜剂或喷雾剂可含有矿物油、失水山梨糖醇单硬脂酸酯、多乙氧基醚60、十六烷基酯蜡、鲸蜡硬脂醇(cetearyl alcohol)、2-辛基十二烷醇、苯甲醇或水作为适当的载体。
对于眼科使用,所述的组合物可制剂成超微细化的悬浮液或是溶解于等渗的、pH受到调节的无菌盐水的溶液剂,其中含有或不含有诸如苯扎氯铵(benzaikonium chloride)的防腐剂。另外,该组合物还可以用例如凡士林制成眼药膏。
适用于鼻内气雾或吸入给药的制剂可以是盐水溶液剂的形式。该溶液剂可含有苯甲醇或其它适当的防腐剂、增强生物利用率的吸收促进剂、碳氟化合物和/或其它常规的增溶剂或分散剂。
适用于直肠或阴道给药的制剂可通过将本发明的化合物与适当的非刺激性赋形剂或载体混合制备,所述赋形剂或载体诸如在体温下可熔化的栓剂用蜡、可可脂或聚乙二醇。
如果需要,本发明化合物可以与其它的抗菌剂如青霉素或头孢菌素一起使用。
虽然用药剂量可根据患者的年龄、体重和症状变化,但是本发明式(I)或(II)化合物的单一剂量可在大约50-1,500mg范围内。本发明式(I)或(II)化合物典型的成人日剂量可在大约50-5,000mg范围内,或在大约150-3,000mg范围内,或在大约50-2000mg范围内,或在大约100-2000mg范围内,或在大约300-2500mg范围内,或在大约500-4000mg范围内,或在大约500-5000mg范围内。
进一步地,本发明提供了治疗与细菌相关的疾病的方法,该方法包括给需要进行该治疗的患者给予有效量的式(I)或(II)化合物。上述方法所治疗的患者包括人或非人哺乳动物。
具体实施方式
下面通过实施例对本发明作更详细的描述,但可以理解的是这些具体的实施例并不限制本发明。
制备实施例1:合成4-戊氧基-1H-吡啶基-2-酮
将戊醇(2.7g,31mmol)和在叔丁醇溶剂中的叔丁醇金属化物(tert-butoxide)(3.5g,31mmol)溶液在室温下搅拌1小时,接着加入4-硝基吡啶-N-氧化物(4g,28.6mmol)。反应后,将所得到的溶液用乙酸乙酯和水精制、分离,并将有机溶剂彻底干燥。加入甲苯,减压除去溶剂。在残余混合物中加入乙酸酐(40ml),回流3小时。将乙酸酐彻底干燥,接着加入MeOH(20ml)和3N NaOH(5ml),搅拌1小时。将MeOH充分干燥,然后用6N HCl将残余混合物调至中性。得到的溶液用乙酸乙酯(80ml)萃取,用硅胶色谱(乙酸乙酯/MeOH,10∶1)处理,得到标题化合物(2.3g,56%)。
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.33-1.44(m,4H),1.72-1.79(m,2H),3.91(t,2H),5.91-6.08(m,2H),7.40(d,1H)
实施例1:4-苄氧基-1-(2-氯-苄基)-1H-吡啶-2-酮
将4-苄氧基-1H-吡啶酮(300mg,1.49mmol)和在DMF溶剂中的NaH(60mg,1.49mmol)溶液搅拌30分钟,接着加入2-氯苄基氯(240mg,1.49mmol),室温下再搅拌30分钟。所得到的溶液用水和二氯甲烷精制,用柱色谱纯化(乙酸乙酯/己烷,1∶1),得到标题化合物(320mg,67%)。
1H NMR(CDCl3,300MHz.)δ5.00(s,2H),5.20(s,2H),5.97(dd,1H),6.04(d,1H),7.17-7.39(m,10H)
实施例2-13:除起始原料以外,重复实施例1的方法,得到所述的标题
化合物。
实施例2:4-苄氧基-1-(4-氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.96(s,2H),5.01(s,2H),5.93(dd,1H),5.99(d,1H),7.09(d,1H),7.19(d,2H),7.24(d,2H),7.28-7.36(m,5H)
实施例3:4-苄氧基-1-(4-硝基-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.08(s,2H),5.47(s,2H),6.39-6.60(m,2H),7.35-7.59(m,7H),7.95(d,1H),8.18-8.23(m,2H)
实施例4:4-苄氧基-1-(2,5-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.98(s,2H),5.12(s,2H),5.96-6.03(m,2H),7.14-7.39(m,9H)
实施例5:4-苄氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.00(s,2H),5.14(s,2H),5.97-6.03(m,2H),7.18-7.41(m,9H)
实施例6:4-苄氧基-2-(4-甲氧基-苄氧基)-吡啶
1H NMR(CDCl3,300MHz)δ3.80(s,3H),5.05(s,2H),5.28(s,2H),6.31(d,1H),6.55(dd,1H),6.90(d,1H),7.29-7.40(m,7H),7.99(d,1H)
实施例7:4-苄氧基-1-(4-甲氧基-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.79(s,3H),4.98(s,2H),5.01(s,2H),5.92(dd,1H),6.01(d,1H),6.86(d,2H),7.11(d,1H),7.22-7.26(m,3H),7.34-7.38(m,4H)
实施例8:4-苄氧基-2-(4-甲基-苄氧基)-吡啶
1H NMR(CDCl3,300MHz)δ2.37(s,3H),5.06(s,2H),5.33(s,2H),6.34(d,1H),6.56(dd,1H),7.19(d,2H),7.34-7.41(m,7H),8.00(d,1H)
实施例9:4-苄氧基-1-(4-甲基-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.33(s,3H),4.98(s,2H),5.04(s,2H),5.93(dd,1H),6.02(d,1H),7.10-7.19(m,5H),7.34-7.38(m,5H)
实施例10:4-苄氧基-1-(6-氯-吡啶-3-基甲基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.99(s,2H),5.04(s,2H),6.00-6.02(m,2H),7.15-7.38(m,7H),7.66(dd,1H),8.34-8.37(m,1H)
实施例11:4-苄氧基-1-(3-氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.96(s,2H),5.01(s,2H),5.94(dd,1H),6.00(d,1H),7.09-7.36(m,10H)
实施例12:1-苄基-4-苄氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.96(s,2H),5.06(s,2H),5.92(dd,1H),6.01(d,1H),7.10(d,1H),7.24-7.36(m,10H)
实施例13:1-(4-氨基-苄基)-4-苄氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.73(br s,2H),4.95(s,2H),4.97(s,2H),5.90(dd,1H),6.00(d,1H),6.63(d,2H),7.08-7.37(m,8H)
实施例14:1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮
将按照实施例1同样方法合成的4-苄氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮用Pd/C氢化,得到所述的标题化合物。
1H NMR(CD3OD,300MHz)δ5.17(s,2H),5.86(d,1H),6.10(dd,1H),6.99(d,1H),7.27-7.32(m,1H),7.50-7.52(m,2H)
实施例15:3-苄基-1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮
将实施例14合成的1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮溶于DMF,接着加入NaH和苄基溴,得到比例为1∶1的4-苄氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮和所述的标题化合物。
1H NMR(CDCl3,300MHz)δ4.00(s,2H),5.13(s,2H),5.87(d,1H),7.25-7.33(m,9H)
实施例16-225:除起始原料外,重复实施例1的方法,得到所述的标
题化合物。
实施例16:4-(联苯-4-基甲氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.04(s,2H),5.15(s,2H),6.01(dd,1H),6.06(d,1H),7.22-7.63(m,13H)
实施例17:1-(2,4-二氯-苄基)-4-(2,4-二氯-苄氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.06(s,2H),5.15(s,2H),5.99-6.01(m,2H),7.15-7.44(m,7H)
实施例18:4-(2-氯-苄氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.11(s,2H),5.16(s,2H),6.00-6.04(m,2H),7.21-7.47(m,8H)
实施例19:1-(2,4-二氯-苄基)-4-甲氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.78(s,3H),5.14(s,2H),5.91-5.94(m,2H),7.16-7.22(m,3H),7.41(s,1H)
实施例20:1-(2,4-二氯-苄基)-4-异丙氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.34(d,6H),4.47-4.55(m,1H),5.86-5.91(m,2H),7.15-7.21(m,3H),7.41(s,1H)
实施例21:4-环己基甲氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.86-1.83(m,11H),3.71(d,2H),5.14(s,2H),5.90-5.94(m,2H),7.15-7.23(m,3H),7.40(s,1H)
实施例22:3-(2-氯-苄基)-4-羟基-1H-吡啶-2-酮
1H NMR(CD3OD,300MHz)δ3.82(s,2H),6.12(d,1H),7.06-7.28(m,5H)
实施例23:1-(2,4-二氯-苄基)-4-丙氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.02(t,3H),1.74-1.85(m,2H),3.88(t,2H),5.14(s,2H),5.91-5.94(m,2H),7.15-7.24(m,3H),7.40(s,1H)
实施例24:1-(2,4-二氯-苄基)-4-异丁氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.00(d,6H),2.03-2.12(m,1H),3.68(d,2H),5.14(s,2H),5.90-5.95(m,2H),7.15-7.23(m,3H),7.41(s,1H)
实施例25:4-丁氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.97(t,3H),1.40-1.52(m,2H),1.71-1.80(m,2H),3.92(t,2H),5.14(s,2H),5.90-5.92(m,2H),7.15-7.23(m,3H),7.41(s,1H)
实施例26:1-(2,4-二氯-苄基)-4-辛氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.84(t,3H),1.24-1.52(m,10H),1.67-1.76(m,2H),3.86(t,2H),5.09(s,2H),5.86-5.89(m,2H),7.10-7.18(m,3H),7.36(s,1H)
实施例27:1-(2,4-二氯-苄基)-4-(4-甲基-戊氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.86(d,6H),1.24-1.29(m,2H),1.50-1.59(m,1H),1.67-1.77(m,2H),3.86(t,2H),5.10(s,2H),5.87-5.90(m,2H),7.11-7.16(m,3H),7.36(s,1H)
实施例28:4-(丁-3-烯基氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.48(q,2H),3.93(t,2H),5.06-5.15(m,4H),5.76-5.89(m,3H),7.11-7.15(m,3H),7.36(s,1H)
实施例29:1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.78-1.87(m,2H),2.16(q,2H),3.89(t,2H),4.95-5.09(m,4H),5.71-5.88(m,3H),7.11-7.15(m,3H),7.36(s,1H)
实施例30:1-(2,4-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.33-1.44(m,4H),1.72-1.79(m,2H),3.91(t,2H),5.14(s,2H),7.16-7.22(m,3H),7.40(d,1H)
实施例31:[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧基]-乙酸乙
酯
1H NMR(CDCl3,300MHz)δ3.77(s,3H),4.54(s,2H),5.09(s,2H),5.77(d,1H),5.99(dd,1H),7.17-7.22(m,3H),7.37(s,1H)
实施例32:1-(2,4-二氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.87(d,6H),1.54-1.76(m,3H),3.86(t,2H),5.00(s,2H),5.79(dd,1H),5.86(d,1H),7.04(d,1H),7.13-7.27(m,3H)
实施例33:1-苄基-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.40(m,4H),1.75-1.79(m,2H),3.92(t,2H),5.10(s,2H),5.87-5.93(m,2H),7.11(d,1H),7.25-7.32(m,5H)
实施例34:1-(2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.31-1.42(m,4H),1.72-1.79(m,2H),3.91(t,2H),5.19(S,2H),5.89-5.92(m,2H),7.14-7.26(m,4H),7.37-7.40(m,1H)
实施例35:4-戊氧基-1-丙基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90-0.96(m,6H),1.28-1.38(m,4H),1.67-1.80(m,4H),3.82(t,2H),3.89(t,2H),5.87(d,2H),7.07-7.10(m,1H)
实施例36:1-丁基-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.89-0.96(m,6H),1.29-1.42(m,6H),1.64-1.78(m,4H),3.83-3.91(m,4H),5.86-5.88(m,2H),7.07-7.10(m,1H)
实施例37:1-异丁基-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91-0.93(m,9H),1.33-1.39(m,4H),1.71-1.78(m,2H),2.10-2.19(m,1H),3.65(d,2H),3.89(t,2H),5.84-5.87(m,2H),7.05(d,1H)
实施例38:1-(3-甲基-丁基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90-0.96(m,9H),1.33-1.39(m,4H),1.55-1.78(m,5H),3.84-3.91(m,4H),5.86-5.88(m,2H),7.07-7.10(m,1H)
实施例39:1-(2,4-二氯-苄基)-4-己氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90(t,3H),1.25-1.34(m,4H),1.71-1.80(m,2H),3.91(t,2H),5.14(s,2H),5.91-5.93(m,2H),7.14-7.23(m,3H),7.40(s,1H)
实施例40:1-(2,4-二氯-苄基)-4-庚氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.75(t,3H),1.09-1.54(m,8H),1.71-1.80(m,2H),3.91(t,2H),5.13(s,2H),5.86-5.92(m,2H),7.14-7.22(m,3H),7.40(s,1H)
实施例41:1-(4-氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.42(m,4H),1.71-1.80(m,2H),3.90(t,2H),5.04(s,2H),5.87-5.91(m,2H),7.08(d,1H),7.20(d,2H),7.30(d,2H)
实施例42:4-芳氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.48(d,2H),5.14(s,2H),5.32-5.45(m,2H),5.94-6.07(m,3H),7.18-7.20(m,3H),7.41(s,1H)
实施例43:1-(2,4-二氯-苄基)-4-(3-甲氧基-丙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.01-2.07(m,2H),3.35(s,3H),3.52(t,2H),4.02(t,2H),5.14(s,2H),5.91-5.94(m,2H),7.16-7.20(m,3H),7.41(s,1H)
实施例44:1-(2,4-二氯-苄基)-4-(3-乙氨基-丙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.25-1.52(m,5H),2.92-3.05(m,4H),4.03(t,2H),5.13(s,2H),5.91-5.93(m,2H),7.17-7.19(m,3H),7.41(s,1H),8.48(br s,1H)
实施例45:1-(2,4-二氯-苄基)-4-(2-乙氧基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.25(t,3H),3.58(q,2H),3.77(t,2H),4.08(t,2H),5.14(s,2H),5.92(d,1H),5.99(dd,1H),7.16-7.23(m,3H),7.41(s,1H)
实施例46:1-(3-甲基-丁-2-烯基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.38(m,4H),1.71-1.73(m,2H),1.76(s,6H),3.89(t,2H),4.47(d,2H),5.27(t,1H),5.87-5.88(m,2H),7.10-7.13(m,1H)
实施例47:5-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-呋喃-2-羧酸乙酯
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.44(m,7H),1.73-1.80(m,2H),3.89(t,2H),4.34(q,2H),5.09(s,2H),5.86(d,1H),5.92(dd,1H),6.47(d,1H),7.09(d,1H),7.29(d,1H)
实施例48:5-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-呋喃-2-羧酸
1H NMR(CD3OD,300MHz)δ0.94(t,3H),1.37-1.45(m,4H),1.73-1.80(m,2H),3.97(t,2H),5.13(s,2H),5.89(d,1H),6.11(dd,1H),6.41(d,1H),6.93(d,1H),7.65(d,1H)
实施例49:4-戊氧基-1-噻唑-4-基甲基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.32-1.44(m,4H),1.70-1.80(m,2H),3.89(t,2H),5.22(s,2H),5.88(d,1H),5.92(dd,1H),7.38-7.42(m,2H),8.76(s,1H)
实施例50:4-戊氧基-1-吡啶-3-基甲基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.45(m,4H),1.74-1.83(m,2H),3.96(t,2H),5.55(s,2H),6.29(d,1H),6.50(dd,1H),7.40(s,1H),7.96(d,1H),8.84(d,1H)
实施例51:1-(2,4-二氯-苄基)-4-(4-甲基-戊-3-烯基氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.65(s,3H),1.73(s,3H),2.46(q,2H),3.89(t,2H),5.14(s,2H),5.91-5.94(m,2H),7.15-7.13(m,3H),7.27(s,1H),7.41(s,1H)
实施例52:1-(2,4-二氯-苄基)-4-(3-甲氧基-丙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.88(d,6H),1.18-1.26(m,4H),1.37-1.77(m,5H),3.92(t,2H),5.14(s,2H),5.91-5.93(m,2H),7.15-7.23(m,3H),7.41(s,1H)
实施例53:1-(2,4-二氯-苄基)-4-乙氧苯基氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.09(t,2H),4.15(t,2H),5.14(s,2H),5.91-5.99(m,2H),7.16-7.40(m,9H)
实施例54:1-(2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.33-1.43(m,4H),1.75-1.79(m,2H),2.28(s,3H),3.92(t,2H),5.08(s,2H),5.86(dd,1H),5.94(d,1H),6.93(d,1H),7.03(d,1H),7.15-7.23(m,3H)
实施例55:4-戊基-1-乙氧苯基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.86(t,3H),1.27-1.33(m,4H),1.65-1.72(m,2H),2.96(t,2H),3.83(t,2H),4.01(t,2H),5.65(dd,1H),5.83(d,1H),6.65(d,1H),7.08(d,1H),7.13-7.25(m,3H)
实施例56:1-(2,4-二氯-5-氟-苄基)-4-戊氢基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.31-1.43(m,4H),1.73-1.80(m,2H),3.92(t,2H),5.10(s,2H),5.92-5.96(m,2H),7.02(d,1H),7.16(d,1H),7.44(d,1H)
实施例57:1-(3,4-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.31-1.46(m,4H),1.73-1.82(m,2H),3.92(t,2H),5.02(s,2H),5.92-5.95(m,2H),7.10-7.15(m,2H),7.36-7.42(m,2H)
实施例58:1-(3,4-二氟-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.43(m,4H),1.73-1.80(m,2H),3.92(t,2H),5.02(s,2H),5.91-5.94(m,2H),7.03-7.17(m,4H)
实施例59:4-(4-苄氧基-丁氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.68-1.94(m,4H),3.54(t,2H),3.96(t,2H),4.53(s,2H),5.15(s,2H),5.90-5.93(m,2H),7.16-7.42(m,9H)
实施例60:1-(2,4-二氯-苄基)-4-(4-羟基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.70-1.91(m,4H),3.72(t,2H),3.98(t,2H),5.14(s,2H),5.92-5.94(m,2H),7.16-7.25(m,3H),7.41(s,1H)
实施例61:4-(5-苄氧基-戊氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.52-1.85(m,6H),3.51(t,2H),3.94(t,2H),4.53(s,2H),5.15(s,2H),5.90-5.94(m,2H),7.16-7.42(m,9H)
实施例62:1-(2,4-二氯-苄基)-4-(5-羟基-戊氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.44-1.83(m,6H),3.70(t,2H),3.93(t,2H),5.14(s,2H),5.91-5.92(m,2H),7.15-7.20(m,3H),7.41(s,1H)
实施例63:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-戊氧基-1H-吡
啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.35-1.43(m,4H),1.74-1.79(m,2H),3.91(t,2H),5.10(s,2H),5.88-5.91(m,2H),5.96(s,2H),6.81(s,1H),6.84(s,1H),7.18(dd,1H)
实施例64:1-(2,4-二氯-苄基)-4-(2-甲基-苄氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.35(s,3H),4.99(s,2H),5.16(s,2H),5.98(dd,1H),6.08(d,1H),7.20-7.42(m,8H)
实施例65:1-(2,4-二氯-苄基)-4-(4-甲基-苄氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.37(s,3H),4.95(s,2H),5.15(s,2H),5.98(dd,1H),6.03(d,1H),7.18-7.30(m,8H)
实施例66:1-(2-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.43(m,4H),1.73-1.82(m,2H),3.93(t,2H),5.46(s,2H),5.93(d,1H),5.98(dd,1H),7.10(d,1H),7.17(d,1H),7.44(t,1H),7.56(t,1H),8.10(d,1H)
实施例67:1-(2-氨基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.30-1.39(m,4H),1.69-1.76(m,2H),3.89(t,2H),4.75(br s,2H),5.00(s,2H),5.89-5.93(m,2H),6.62-6.70(m,2H),7.09-7.23(m,3H)
实施例68:N-[2-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.26-1.38(m,4H),1.74-1.78(m,2H),2.29(s,3H),3.91(t,2H),5.01(s,2H),5.94(d,1H),6.01(dd,1H),7.08(t,1H),7.31-7.38(m,3H),8.20(d,1H),10.56(br s,1H)
实施例69:4-戊氧基-1-(2-三氟甲基-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.31-1.42(m,4H),1.75-1.81(m,2H),3.95(t,2H),5.32(s,2H),5.93(dd,1H),5.98(d,1H),7.04(d,1H),7.15(d,1H),7.38(t,1H),7.49(t,1H),7.69(d,1H)
实施例70:N-[4-(4-苄氧基-2-氧代-2H-吡啶-1-基甲基)-苯基]乙酰胺
1H NMR(CDCl3,300MHz)δ2.18(s,3H),4.99(s,2H),5.04(s,2H),5.98(dd,1H),6.02(d,1H),7.14-7.46(m,10H),7.82(br s,1H)
实施例71:1-(2,4-二氯-苄基)-4-(萘-2-基甲氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.15(s,2H),5.16(s,2H),5.99-6.09(m,2H),7.18-7.55(m,7H),7.83-7.90(m,4H)
实施例72:1-萘-2-基甲基-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.35-1.43(m,4H),1.73-1.76(m,2H),3.91(t,2H),5.24(s,2H),5.84-5.96(m,2H),7.13(d,1H),7.26-7.49(m,3H),7.70(s,1H),7.79-7.83(m,3H)
实施例73:4-苄氧基-1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-1H-吡
啶-2-酮
1H NMR(CDCl3,300MHz)δ4.99(s,2H),5.10(s,2H),5.94-6.03(m,4H),6.84(d,2H),7.20(d,1H),7.33-7.39(m,5H)
实施例74:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(3-甲基-丁氧
基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(d,6H),1.58-1.66(m,3H),3.92(t,2H),5.07(s,2H),5.86(dd,1H),5.90(d,1H),5.93(s,2H),6.80(d,2H),7.14(d,1H)
实施例75:1-(2-甲基-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(d,6H),1.63(q,2H),1.72-1.81(m,1H),3.93(t,2H),5.05(s,2H),5.82(dd,1H),5.92(d,1H),6.90(d,1H),7.01(d,1H),7.13-7.20(m,3H)
实施例76:4-(3-甲基-丁氧基)-1-(2-硝基-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(d,6H),1.65(q,2H),1.69-1.78(m,1H),3.95(t,2H),5.45(s,2H),5.93-5.96(m,2H),7.11(d,1H),7.14(d,1H),7.44(t,1H),7.53(t,1H),8.08(d,1H)
实施例77:1-(2,4-二氯-苄基)-4-戊氨基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.88(t,3H),1.24-1.34(m,4H),1.57-1.84(m,2H),3.19(br s,1H),3.47(q,2H),5.03(s,2H),5.56(d,1H),7.15-7.38(m,4H)
实施例78:1-(2,3-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90(t,3H),1.28-1.40(m,4H),1.70-1.77(m,2H),3.89(t,2H),5.17(s,2H),5.89-5.92(m,2H),7.01(d,1H),7.11-7.16(m,2H),7.37(d,1H)
实施例79:1-(2-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90(t,3H),1.27-1.36(m,4H),1.68-1.77(m,2H),3.83(s,3H),3.87(t,2H),5.05(s,2H),5.81(dd,1H),5.86(d,1H),6.84-6.92(m,2H),7.18-7.27(m,3H)
实施例80:1-(2,3-二甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.89(t,3H),1.29-1.38(m,4H),1.67-1.74(m,2H),3.81-3.88(m,8H),5.08(s,2H),5.80(dd,1H),5.86(d,1H),6.82-6.87(m,2H),6.98(t,1H),7.18(d,1H)
实施例81:4-(5-苄氧基-戊氧基)-1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲
基)-1H-吡啶-2-酮
1H NMR(CD3OD,300MHz)δ1.47-1.53(m,2H),1.61-1.66(m,2H),1.74-1.78(m,2H),3.48(t,2H),3.96(t,2H),4.45(s,2H),5.06(s,2H),5.90(s,1H),5.94(s,2H),6.06(dd,1H),6.61(s,1H),6.90(s,1H),7.22-7.29(m,5H),7.42(d,1H)
实施例82:1-(2-氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(d,6H),1.60-1.82(m,3H),3.94(t,2H),5.17(s,2H),5.86-5.94(m,2H),7.12-7.40(m,5H)
实施例83:1-(3,4-二氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(d,6H),1.63(q,2H),1.72-1.81(m,1H),3.92(t,2H),4.99(s,2H),5.87-5.90(m,2H),7.05-7.12(m,2H),7.33-7.38(m,2H)
实施例84:1-(2,4-二氯-5-氟-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(d,6H),1.64(q,2H),1.71-1.82(m,1H),3.93(t,2H),5.08(s,2H),5.90-5.92(m,2H),7.00(d,1H),7.12-7.15(m,1H),7.42(d,1H)
实施例85:1-苄基-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.95(d,6H),1.59-1.78(m,3H),3.93(t,2H),5.08(s,2H),5.83-5.93(m,2H),7.07-7.36(m,6H)
实施例86:1-(4-氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(d,6H),1.62(q,2H),1.71-1.80(m,1H),3.91(t,2H),5.01(s,2H),5.85(dd,1H),5.89(d,1H),7.06(d,1H),7.19(d,2H),7.27(d,2H)
实施例87:1-(2,4-二氯-苄基)-4-戊氧基-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ0.88(t,3H),1.32-1.36(m,4H),1.61-1.73(m,2H),4.33(t,2H),5.07(s,2H),5.83(d,1H),7.22(d,1H),7.35-7.45(m,3H)
实施例88:1-(2,4-二氯-苄基)-4-(4-甲基-戊氧基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ0.89(d,6H),1.20-1.76(m,5H),4.34(t,2H),5.09(s,2H),5.85(d,1H),7.22(d,1H),7.26-7.47(m,3H)
实施例89:1-(2,4-二氯-苄基)-4-苯氧基-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ5.11(d,2H),6.07(d,1H),7.12-7.65(m,9H)
实施例90:4-(丁基-甲基-氨基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90(t,3H),1.19-1.56(m,4H),2.81-3.11(m,3H),3.22-3.27(m,1H),3.59-3.62(m,1H),4.98(s,2H),5.72-5.75(m,1H),7.12-7.31(m,4H)
实施例91:1-(2,4-二氯-苄基)-4-(2-二乙氨基-乙氧基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ1.04(t,6H),2.62(q,4H),2.84(t,2H),4.46(t,2H),5.09(s,2H),5.90(d,1H),7.21-7.54(m,4H)
实施例92:4-丁氧基-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ0.95(t,3H),1.39-1.46(m,2H),1.69-1.74(m,2H),4.37(t,2H),5.10(s,2H),5.87(d,1H),7.23-7.48(m,4H)
实施例93:1-(2,6-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.32-1.44(m,4H),1.70-1.80(m,2H),3.90(t,2H),5.37(s,2H),5.79(dd,1H),5.91(d,1H),6.71(d,1H),7.25-7.41(m,3H)
实施例94:1-(2-氯-6-氟-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.30-1.44(m,4H),1.70-1.77(m,2H),3.89(t,2H),5.24(s,2H),5.82(dd,1H),5.88(d,1H),6.92(d,1H),7.05(t,1H),7.24-7.33(m,2H)
实施例95:1-(2-甲基-3-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.43(m,4H),1.75(m,2H),2.40(s,3H),3.92(t,2H),5.13(s,2H),5.92-5.95(m,2H),6.98(dd,1H),7.16(d,1H),7.28(t,1H),7.69(d,1H)
实施例96:1-(3-氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.43(m,4H),1.71-1.80(m,2H),2.01(s,3H),3.72(s,2H),3.91(t,2H),5.05(s,2H),5.81(dd,1H),5.92(d,1H),6.56(d,1H),6.69(d,1H),6.90(d,1H),7.01(t,1H)
实施例97:1-(4-甲氧基-3,5-二甲基-吡啶-2-基甲基)-4-戊氧基-1H-吡啶
-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.30-1.41(m,4H),1.70-1.77(m,2H),2.23(s,3H),2.30(s,3H),3.75(s,3H),3.89(t,2H),5.16(s,2H),5.85-5.88(m,2H),7.28-7.30(m,1H),8.19(s,1H)
实施例98:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(5-羟基-戊氧基)
-1H-吡啶-2-酮
1H NMR(CD3OD,300MHz)δ1.48-1.58(m,4H),1.75-1.80(m,2H),3.54(t,2H),3.97(t,2H),5.06(s,2H),5.89(d,1H),5.94(s,2H),6.07(dd,1H),6.61(s,1H),6.90(s,1H),7.43(d,1H)
实施例99:1-(2-甲氧基-5-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.36-1.44(m,4H),1.74-1.80(m,2H),3.91(t,2H),3.97(S,3H),5.07(s,2H),5.90-5.95(m,2H),7.17(d,1H),7.21(d,1H),8.03(d,1H),8.19(dd,1H)
实施例100:1-(5-氨基-2-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.24-1.39(m,4H),1.73-1.78(m,2H),3.79(s,2H),3.90(t,2H),5.02(s,2H),5.83(dd,1H),5.89(d,1H),6.59-6.74(m,3H),7.23-7.27(m,3H)
实施例101:1-(2-乙基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.18(t,3H),1.34-1.43(m,4H),1.73-1.79(m,2H),2.63(q,2H),3.93(t,2H),5.12(s,2H),5.84(dd,1H),5.94(d,1H),6.92(d,1H),7.05(d,1H),7.16-7.32(m,3H)
实施例102:1-(2-氯-5-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.46(m,4H),1.72-1.82(m,2H),3.94(t,2H),5.19(s,2H),5.94(dd,1H),6.00(d,1H),7.18(d,1H),7.55(d,1H),7.96(d,1H),9.09(dd,1H)
实施例103:1-(5-氨基-2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.31-1.43(m,4H),1.72-1.79(m,2H),3.91(t,2H),5.11(s,2H),5.87-5.91(m,2H),6.52-6.55(m,2H),7.11-7.18(m,2H)
实施例104:1-(4-甲氧基-2,3-二甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.31-1.42(m,4H),1.72-1.81(m,2H),2,12(s,3H),2.16(s,3H),3.82(s,3H),3.91(t,2H),5.04(s,2H),5.80(dd,1H),5.93(d,1H),6.71(d,1H),6.85(d,1H),6.97(d,1H)
实施例105:1-(2-甲基-吡啶-3-基甲基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.47(m,4H),1.73-1.83(m,2H),2.56(s,3H),3.93(t,2H),5.09(s,2H),5.91-5.94(m,2H),7.00(d,1H),7.08-7.13(m,1H),7.26-7.28(m,1H),8.43(d,1H)
实施例106:N-[4-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苄基]-乙酰
胺
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.29-1.45(m,4H),1.71-1.78(m,2H),2.10(s,3H),3.87(t,2H),5.16(s,2H),5.89(d,1H),5.99(dd,1H),7.26-7.33(m,3H),7.77(d,1H),8.43(br s,1H)
实施例107:1-(2,4-二氯-苄基)-4-(3-二甲氨基-丙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.87-1.97(m,2H),2.25(s,6H),2.40(t,2H),4.42(t,2H),5.10(s,2H),5.87(d,1H),7.23-7.49(m,4H)
实施例108:1-(2,4-二氯-苄基)-4-(4-二甲氨基-丁氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.52-1.81(m,4H),2.22(s,6H),2.29(t,2H),4.38(t,2H),5.10(s,2H),5.86(d,1H),7.23-7.48(m,4H)
实施例109:1-(2,4-二氯-苄基)-4-(6-二甲氨基-己氧基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ1.34-1.78(m,8H),2.24-2.30(m,8H),4.35(t,2H),5.10(s,2H),5.86(d,1H),7.23-7.47(m,4H)
实施例110:1-(2,4-二甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.42(m,4H),1.71-1.76(m,2H),2.22(s,3H),2.31(s,3H),3.91(t,2H),5.03(s,2H),5.83(dd,1H),5.92(d,1H),6.89-7.20(m,4H)
实施例111:1-(2-氯-5-三氟甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.46(m,4H),1.74-1.83(m,2H),3.93(t,2H),5.21(s,2H),5.94-6.15(m,2H),7.17(d,1H),7.43-7.54(m,3H)
实施例112:1-(2-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.29-1.43(m,4H),1.70-1.79(m,2H),3.90(t,2H),4.99(s,2H),5.97(d,1H),6.04(dd,1H),6.83(t,1H),6.95(dd,1H),7.19-7.24(m,2H),7.38(d,1H),10.45(br s,1H)
实施例113:4-(3-环-丙氧基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ1.27-1.25(m,2H),1.51-1.82(m,9H),4.37(t,2H),5.10(s,2H),5.85(d,1H),7.22(d,1H),7.38-7.47(m,3H)
实施例114:1-(2,4-二氯-苄基)-4-(3-甲基-戊氧基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ0.85-2.03(m,11H),4.39(t,2H),5.10(s,2H),5.85(d,1H),7.22-7.47(m,4H)
实施例115:1-(2,4-二氯-苄基)-4-己-4-烯基氧基-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ1.25-2.10(m,7H),4.35(t,2H),5.10(s,2H),5.40-5.46(m,2H),5.86(d,1H),7.23-7.47(m,4H)
实施例116:4-(2-环丙基-乙氧基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮
1H NMR(CDCl3,300MHz)δ0.42-0.96(m,3H),1.25-1.66(m,4H),4.43(t,2H),5.10(s,2H),5.87(d,1H),7.22-7.47(m,4H)
实施例117:1-(2,4-二氯-苄基)-4-(3-甲基-戊氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.85-0.91(m,6H),1.17-1.24(m,1H),1.33-1.39(m,1H),1.51-1.58(m,2H),1.78-1.80(m,1H),3.93(t,2H),5.12(s,2H),5.88-5.92(m,2H),7.14-7.20(m,3H),7.38(s,1H)
实施例118:1-(2,4-二氯-苄基)-4-(5-吗啉-4-基-戊氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.46-1.61(m,4H),1.75-1.84(m,2H),2.36(t,2H),2.44(br s,4H),3.73(t,4H),3.92(t,2H),5.14(s,2H),5.90-5.92(m,2H),7.16-7.23(m,3H),7.41(s,1H)
实施例119:1-(2-氯-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.33-1.43(m,4H),1.72-1.79(m,2H),.74(s,3H),3.91(t,2H),5.15(s,2H),5.88-5.93(m,2H),6.76-6.79(m,2H),7.15(d,1H),7.27(d,1H)
实施例120:1-(2-氯-5-乙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.25-1.40(m,7H),1.72-1.81(m,2H),3.89-3.99(m,4H),5.15(s,2H),5.89-5.92(m,2H),6.75-6.77(m,2H),7.15(d,1H),7.26(d,1H)
实施例121:1-(2-氯-5-丙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.00(t,3H),1.33-1.43(m,4H),1.70-1.81(m,4H),3.84(t,2H),3.92(t,2H),5.15(s,2H),5.88-5.93(m,2H),6.74-6.78(m,2H),7.15(d,1H),7.26(d,1H)
实施例122:1-[2-氯-5-(2-羟基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90(t,3H),1.25-1.43(m,4H),1.72-1.79(m,2H),2.13(t,1H),3.91(t,4H),4.01(t,2H),5.15(s,2H),5.86-5.92(m,2H),6.76-6.83(m,2H),7.18(d,1H),7.28(d,1H)
实施例123:[4-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-氧基]-乙腈
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.33-1.43(m,4H),1.73-1.82(m,2H),3.92(t,2H),4.71(s,2H),5.16(s,2H),5.92-5.95(m,2H),6.84-6.88(m,2H),7.20(d,1H),7.35(dd,1H)
实施例124:1-[5-(2-氨基-乙氧基)-2-氯-苄基]-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.41-1.44(m,4H),1.78-1.82(m,2H),3.93(t,2H),4.01(t,4H),5.17(s,2H),5.96(d,1H),7.13(dd,1H),6.60(s,1H),6.90(d,1H),7.34(d,1H),7.49(d,1H)
实施例125:N-[2-甲基-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苄基]-
乙酰胺
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.44(m,4H),1.73-1.82(m,2H),2.07(s,3H),2.22(s,3H),3.92(t,2H),5.05(s,2H),5.89(dd,1H),5.93(d,1H),6.84(d,1H),6.94(d,1H),7.18(t,1H),7.49(brs,1H),7.56(d,1H)
实施例126:1-(2-甲基-3-甲氨基-苄基)-4-苄氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.27-1.40(m,4H),1.73-1.78(m,2H),1.98(s,3H),2.90(s,3H),3.69(br s,1H),3.90(t,2H),5.07(s,2H),5.80(dd,1H),5.93(d,1H),6.57(d,1H),6.65(d,1H),6.89(d,1H),7.16(t,1H)
实施例127:1-(3-二甲氨基-2-甲基-苄基)-4-苯氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.36-1.43(m,4H),1.75-1.79(m,2H),2.22(s,3H),2.69(s,6H),3.92(t,2H),5.07(s,2H),5.86(dd,1H),5.95(d,1H),6.72(d,1H),6.93(d,1H),7.05(d,1H),7.15(t,1H)
实施例128:1-(3-乙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.31(t,3H),1.33-1.42(m,4H),1.71-1.78(m,2H),1.97(s,3H),3.19(q,2H),3.48(br s,1H),3.90(t,2H),5.06(s,2H),5.79(dd,1H),5.93(d,1H),6.56(d,1H),6.65(d,1H),6.89(d,1H),7.13(t,1H)
实施例129:1-(3-二乙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.96(t,9H),1.34-1.44(m,4H),1.75-1.80(m,2H),2.21(s,3H),2.95(q,4H),3.92(t,2H),5.08(s,2H),5.87-5.95(m,2H),6.73(d,1H),6.95-7.16(m,3H)
实施例130:1-(2-甲基-3-丙氨基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.02(t,3H),1.33-1.42(m,4H),1.66-1.80(m,4H),1.97(s,3H),3.12(t,2H),3.57(br s,1H),3.91(t,2H),5.06(s,2H),5.80(dd,1H),5.93(d,1H),6.55(d,1H),6.65(d,1H),6.90(d,1H),7.13(t,1H)
实施例131:1-(3-二丙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.83(t,6H),0.93(t,3H),1.34-1.47(m,8H),1.75-1.80(m,2H),2.22(s,3H),2.82-2.87(m,4H),3.93(t,2H),5.07(s,2H),5.87(dd,1H),5.96(d,1H),6.69(d,1H),6.94(d,1H),7.07-7.15(m,2H)
实施例132:1-[3-(2-羟基-乙氨基)-2-甲基-苄基]-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.32-1.41(m,4H),1.71-1.78(m,2H),1.83(br s,1H),2.01(s,3H),3.34(t,2H),3.90(t,4H),4.02(br s,1H),5.06(s,2H),5.81(dd,1H),5.92(d,1H),6.57(d,1H),6.67(d,1H),6.89(d,1H),7.12(t,1H)
实施例133:1-(2-氯-5-甲氧基-4-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.37-1.44(m,4H),1.76-1.81(m,2H),3.91(s,3H),3.93(t,2H),5.20(s,2H),5.93(d,1H),5.97(dd,1H),7.18(s,1H),7.26(d,1H),7.93(s,1H)
实施例134:1-(4-氨基-2-氯-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.32-1.42(m,4H),1.71-1.78(m,2H),3.81(t,3H),3.87-3.93(m,4H),5.09(s,2H),5.85(dd,1H),5.90(d,1H),6.69(s,1H),6.91(s,1H),7.21(d,1H)
实施例135:N-[5-氯-2-甲氧基-4-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-
苄基]-乙酰胺
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.35-1.42(m,4H),1.74-1.78(m,2H),2.21(s,3H),3.84(s,3H),3.90(t,2H),5.15(s,2H),5.88-5.93(m,2H),7.04(s,1H),7.29(d,1H),7.77(br s,1H),8.46(s,1H)
实施例136:1-(2-氯-5-甲氧基-4-甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.30-1.43(m,4H),1.70-1.77(m,2H),2.85(s,3H),3.81(s,3H),3.92(t,2H),4.95(s,2H),5.89-6.03(m,2H),6.53(s,1H),6.89(s,1H),7.28(d,1H)
实施例137:1-(2-氯-4-二甲氨基-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.95(t,3H),1.40-1.44(m,4H),1.75-1.81(m,2H),2.76(s,6H),3.80(s,3H),3.99(t,2H),5.14(s,2H),5.95(d,1H),6.10(dd,1H),6.85(s,1H),7.00(s,1H),7.47(d,1H)
实施例138:1-(2-氯-4-乙氨基-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.28(t,3H),1.36-1.41(m,4H),1.71-1.77(m,2H),3.13(t,2H),3.80(s,3H),3.89(t,2H),4.23(br s,1H),5.10(s,2H),5.84(dd,1H),5.90(d,1H),6.52(s,1H),6.87(s,1H),7.22(d,1H)
实施例139:1-(2-氯-5-甲氧基-4-丙氨基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.00(t,3H),1.34-1.41(m,4H),1.62-1.77(m,4H),3.05(t,2H),3.80(s,3H),3.89(t,2H),4.31(br s,1H),5.09(s,2H),5.83(dd,1H),5.89(d,1H),6.51(s,1H),6.86(s,1H),7.21(d,1H)
实施例140:1-[2-氯-4-(2-羟基-乙氨基)-5-甲氧基-苄基]-4-戊氧基-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.32-1.42(m,4H),1.70-1.77(m,2H),1.96(br s,1H),3.30(t,2H),3.79(s,3H),3.82-3.91(m,4H),4.73(br s,1H),5.09(s,2H),5.85(dd,1H),5.90(d,1H),6.57(s,1H),6.88(s,1H),7.21(d,1H)
实施例141:1-(4-氨基-6-氯-3-甲氧基-2-硝基-苄基)-4-戊氧基-1H-吡啶
-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.28-1.41(m,4H),1.69-1.79(m,2H),3.84(s,3H),3.88(t,2H),4.35(br s,2H),4.96(s,2H),5.82-5.85(m,2H),6.92-7.02(m,2H)
实施例142:1-(2,4-二氨基-6-氯-3-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.30-1.39(m,4H),1.73-1.77(m,2H),3.69(s,3H),3.79(br s,2H),3.89(t,2H),5.16(s,2H),5.30(br s,2H),5.88-5.94(m,2H),6.17(s,1H),7.56(d,1H)
实施例143:1-(2,5-二氯-6-甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-
酮
H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.45(m,4H),1.73-1.82(m,2H),3.92(t,2H),4.08(s,3H),5.14(s,2H),5.86(d,1H),5.96(dd,1H),7.19(d,1H)
实施例144:1-(2,4-二氯-苯磺酰基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.90(t,3H),1.32-1.40(m,4H),1.72-1.79(m,2H),3.89(t,2H),5.60(d,1H),6.05(dd,1H),7.47-7.51(m,2H),7.95(d,1H),8.35(d,1H)
实施例145:1-(4-甲磺酰基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.34-1.45(m,4H),1.74-1.83(m,2H),3.04(s,3H),3.94(t,2H),5.22(s,2H),5.93(d,1H),5.99(dd,1H),7.20(d,1H),7.32(d,1H),7.76(dd,1H),7.97(d,1H)
实施例146:1-(4-氨基-2-氯-5-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.29-1.41(m,4H),1.66-1.75(m,2H),3.78(t,2H),5.13(s,2H),5.85(d,1H),5.94(dd,1H),6.68(s,1H),7.18(s,1H),7.44(d,1H)
实施例147:4-(4-溴-丁氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.88-2.08(m,4H),3.46(t,2H),3.95(t,2H),5.13(s,2H),5.88-5.92(m,2H),7.16-7.24(m,3H),7.40(s,1H)
实施例148:4-[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧基]-丁基
铵
1H NMR(CD3OD,300MHz)δ1.82-1.90(m,4H),3.00(t,2H),4.07(t,2H),5.19(s,2H),5.97(s,1H),6.14(dd,1H),7.05(d,1H),7.31(dd,1H),7.53-7.57(m,2H)
实施例149:1-(5-氯-2,6-二甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.40(m,4H),1.73-1.80(m,2H),3.80(s,3H),3.91(t,2H),4.04(s,3H),5.15(s,2H),5.89(d,1H),5.93(dd,1H),7.16(d,1H)
实施例150:1-(2-氨基-5-氯-6-甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡
啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.43(m,4H),1.73-1.80(m,2H),3.92(t,2H),3.95(s,3H),4.81(br s,2H),5.08(s,2H),5.90-5.93(m,2H),7.10(d,1H)
实施例151:1-(6-氨基-2,5-二氯-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.95(t,3H),1.31-1.44(m,4H),1.73-1.79(m,2H),3.91(t,2H),5.08(s,2H),5.60(br s,2H),5.86(d,1H),5.95(dd,1H),7.22(d,1H)
实施例152:5-氯-6-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-3H-苯并噁唑
-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.38-1.46(m,4H),1.76-2.05(m,2H),3.97(t,2H),5.11(s,2H),6.01-6.07(m,2H),6.72(s,1H),6.73(s,1H),7.22(d,1H),9.35(br s,1H)
实施例153:1-(2-氯-4-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.30-1.41(m,4H),1.70-1.80(m,2H),3.90(t,2H),5.09(s,2H),5.94-6.01(m,2H),6.60(dd,1H),6.88(d,1H),7.00(d,1H),7.28(d,1H),9.75(br s,1H)
实施例154:1-(2-氯-4-异丙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.31(d,6H),1.35-1.45(m,4H),1.73-1.80(m,2H),3.90(t,2H),4.46-4.54(m,1H),5.11(s,2H),5.85-5.91(m,2H),6.74(dd,1H),6.91(d,1H),7.16(d 1H),7.23(d,1H)
实施例155:2-[3-(2-氧代-4-戊氧基-2H-吡啶-1-基)-丙基]-异吲哚-1,3-二
酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.20-1.33(m,4H),1.71-1.80(m,2H),2.09-2.18(m,2H),3.75(t,2H),3.87-3.94(m,4H),5.86(d,1H),5.91(dd,1H),7.27(s,1H),7.72-7.76(m,2H),7.83-7.87(m,2H)
实施例156:1-(3-氨基-丙基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.36-1.44(m,4H),1.75-1.80(m,2H),2.26-2.30(m,2H),3.00(t,2H),3.91(t,2H),4.10(t,2H),5.90(d,1H),6.02(d,1H),7.25(d,1H)
实施例157:N-[3-(2-氧代-4-戊氧基-2H-吡啶-1-基)-丙基]-乙酰胺
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.44(m,4H),1.73-1.89(m,4H),2.01(s,3H),3.15-3.21(m,2H),3.92(t,2H),3.98(t,2H),5.89(d,1H),5.98(dd,1H),7.08(br s,1H),7.14(d,1H)
实施例158:1-(3-二甲氨基-丙基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.37-1.42(m,4H),1.72-1.78(m,4H),2.31-2.39(m,2H),3.16-3.20(m,2H),3.40(s,6H),3.90(t,2H),4.11(t,2H),5.84(s,1H),5.97(d,1H),7.55(d,1H)
实施例159:1-(2,4-二氯-苄基)-6-甲基-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.44(m,4H),1.73-1.92(m,2H),2.13(s,3H),3.93(t,2H),5.28(d,2H),5.82(d,1H),5.88(d,1H),6.72(d,1H),7.13(d,1H),7.40(d,1H)
实施例160:1-(2,4-二氯-苄基)-6-甲基-3-戊基-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.85-0.98(m,6H),1.30-1.48(m,10H),1.75-1.78(m,2H),2.18(s,3H),2.55(t,2H),3.99(t,2H),5.33(s,2H),5.94(s,1H),6.65(d,1H),7.12(dd,1H),7.39(d,1H)
实施例161:1-(2-氨基-乙基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3+数滴CD3OD,300MHz)δ0.93(t,3H),1.31-1.40(m,4H),1.75-1.79(m,2H),2.95(t,2H),3.81-4.00(m,4H),5.83-5.91(m,2H),7.08(d,1H)
实施例162:N-[2-(2-氧代-4-戊氧基-2H-吡啶-1-基)-乙基]-乙酰胺
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.31-1.42(m,4H),1.72-1.79(m,2H),1.96(s,3H),3.53(q,2H),3.90(t,2H),4.05(t,2H),5.87(d,1H),5.94(dd,2H),6.89(br s,1H),7.13(d,1H)
实施例163:N-[1,1-二甲基-2-(2-氧代-4-戊氧基-2H-吡啶-1-基)-乙基]-
甲磺酰胺
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.29-1.46(m,10H),1.75-1.80(m,2H),2.98(s,3H),3.92(t,2H),3.99(s,2H),5.91-5.97(m,2H),6.56(br s,1H),7.23(d,1H)
施例164:N-[1-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-丙基]-甲磺酰胺
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.05(t,3H),1.30-1.40(m,4H),1.59-1.81(m,4H),2.75(s,3H),3.65-4.15(m,6H),5.75(d,1H),5.91(d,1H),5.97(dd,1H),7.19(d,1H)
实施例165:1-(7-硝基-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-戊氧基-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.95(t,3H),1.32-1.42(m,4H),1.75-1.82(m,2H),3.95(t,2H),5.42(s,2H),5.94-6.00(m,2H),6.09(s,2H),6.55(s,1H),7.18(d,1H),7.63(s,1H)
实施例166:1-(2-氯-3-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.97(t,3H),1.27-1.53(m,4H),1.77-1.82(m,2H),3.95(t,2H),5.25(s,2H),5.96-6.00(m,2H),7.22(d,1H),7.35-7.44(m,2H),7.73(d,1H)
实施例167:1-(3-氨基-2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.37-1.43(m,4H),1.72-1.76(m,2H),3.89(t,2H),4.13(br s),5.12(s,2H),5.86-5.92(m,2H),6.47(d,1H),6.70(d,1H),6.96-7.07(m,2H)
实施例168:N-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰
胺
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.27-1.44(m,4H),1.74-1.81(m,2H),2.26(s,3H),3.93(t,2H),5.19(s,2H),5.90-5.94(m,2H),6.87(d,1H),7.06(d,1H),7.23(d,1H),7.69(br s,1H),8.30(d,1H)
实施例169:N-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-甲
磺酰胺
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.37-1.43(m,4H),1.75-1.81(m,2H),3.03(s,3H),3.94(t,2H),5.18(s,2H),5.94-5.97(m,2H),6.90(d,1H),7.00(br s,1H),7.12(d,1H),7.28(d,1H),7.60(d,1H)
实施例170:N,N’-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯
基]-二甲磺酰胺
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.26-1.41(m,4H),1.76-1.81(m,2H),3.49(s,6H),3.94(t,2H),5.23(s,2H),5.94-5.96(m,2H),7.15(d,1H),7.25-7.38(m,3H)
实施例171:1-[2-氯-3-(2-羟基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.28-1.38(m,4H),1.74-1.79(m,2H),2.00(br s,1H),3.37(br s,2H),3.89-3.94(m,4H),4.74(br s,1H),5.15(s,2H),5.87(dd,1H),5.93(d,1H),6.48(d,1H),6.66(d,1H),7.05-7.12(m,2H)
实施例172:4-氯-2-(2-氯-苄基)-5-戊氧基-2H-哒嗪-3-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.30-1.47(m,4H),1.70-1.79(m,2H),4.59(t,2H),5.43(s,2H),7.07-7.10(m,1H),7.18-7.26(m,2H),7.38(dd,1H),7.74(s,1H)
实施例173:2-(2-氯-苄基)-5-戊氧基-2H-哒嗪-3-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.26-1.49(m,4H),1.85-1.94(m,2H),3.99(t,2H),5.49(s,2H),6.38(d,1H),7.16-7.39(m,4H),7.67(d,1H)
实施例174:1-(3-氨基-2,6-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.25-1.44(m,4H),1.70-1.80(m,2H),3.90(t,2H),4.19(s,2H),5.33(s,2H),5.79(dd,1H),5.92(d,1H),6.74(dd,2H),7.18(d,1H)
实施例175:1-(3-苄氧基-2-氯-4-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.35-1.43(m,4H),1.72-1.79(m,2H),3.84(s,3H),3.90(t,2H),5.02(s,2H),5.12(s,2H),5.84-5.91(m,2H),6.79(d,1H),7.01(d,1H),7.11(d,1H),7.33-7.40(m,3H),7.49-7.54(m,2H)
实施例176:1-(2-氯-3,4-二甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.27-1.41(m,4H),1.74-1.80(m,2H),3.86-3.94(m,8H),5.13(s,2H),5.87-5.92(m,2H),6.80(d,1H),7.03(d,1H),7.18(d,1H)
实施例177:1-(2-氯-3-羟基-4-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.95(t,3H),1.26-1.39(m,4H),1.73-1.76(m,2H),3.89-3.93(m,5H),5.13(s,2H),5.86-5.90(m,2H),6.75(d,1H),6.83(d,1H),7.13(d,1H)
实施例178:-[2-氯-4-甲氧基-3-(2-甲氧基-乙氧基)-苄基]-4-戊氧基-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.26-1.39(m,4H),1.74-1.82(m,2H),3.45(s,3H),3.74(t,2H),3.84(s,3H),3.91(t,2H),4.15(t,2H),5.12(s,2H),5.86-5.91(m,2H),6.78(d,1H),7.00(d,1H),7.15(d,1H)
实施例179:1-[2-氯-4-甲氧基-3-(2-吡咯烷-1-基-乙氧基)-苄基]-4-戊氧
基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.33-1.39(m,4H),1.77-1.84(m,6H),2.71(m,4H),2.97(t,2H),3.83(s,3H),3.91(t,2H),4.13(t,2H),5.12(s,2H),5.86-5.92(m,2H),6.78(d,1H),7.00(d,1H),7.15(d,1H)
实施例180:1-[2-氯-3-(2-二甲氨基-乙氧基)-4-甲氧基-苄基]-4-戊氧基
-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.33-1.42(m,4H),1.75-1.82(m,2H),2.41(s,6H),2.83(t,2H),3.97(t,2H),4.11(t,2H),5.13(s,2H),5.94(s,1H),6.04(dd,1H),6.87(dd,1H),6.94(dd,1H),7.27(d,1H)
实施例181:2-{3-[2-氯-6-甲氧基-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲
基)-苯氧基]-丙基}-异吲哚-1,3-二酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.28-1.38(m,4H),1.73-1.77(m,2H),3.59(s,3H),3.89(t,2H),4.12(t,2H),4.26(t,2H),5.03(s,2H),5.85-5.91(m,2H),6.69(d,1H),6.95(d,1H),7.08(d,1H),7.74(d,2H),7.87(d,2H)
实施例182:1-[3-(2-二甲氨基-乙氧基)-2-甲基-苄基]-4-戊氧基-1H-吡啶
-2-酮
1H NMR(CDCl3,300MHz)δ0.94(t,3H),1.26-1.35(m,4H),1.75-1.79(m,2H),2.15(s,3H),2.37(s,6H),2.79(t,2H),3.93(t,2H),4.09(t,2H),5.08(s,2H),5.83-5.94(m,2H),6.70(d,1H),6.83-6.92(m,2H),7.15(t,1H),7.28(s,1H)
实施例183:1-[2-氯-3-(2-二甲氨基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.30-1.40(m,4H),1.55-1.59(m,2H),2.29(s,6H),2.62(t,2H),3.20(t,2H),3.92(t,2H),5.00(br s,1H),5.16(s,2H),5.86-5.93(m,2H),6.47(d,1H),6.61(d,1H),7.06-7.13(m,2H)
实施例184:1-[2,6-二氯-3-(2-羟基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.91(t,3H),1.32-1.42(m,4H),1.72-1.79(m,2H),2.54(t,1H),3.36(q,2H),3.87-3.94(m,4H),4.84(t,1H),5.27(s,2H),5.78(dd,1H),5.91(d,1H),6.68-6.71(m,2H),7.23(d,1H)
实施例185:1-[2,6-二氯-3-(2-二甲氨基-乙氨基)-苄基]-4-戊氧基-1H-吡
啶-2-酮
1H NMR(CD3OD,300MHz)δ0.93(t,3H),1.38-1.46(m,4H),1.75-1.80(m,2H),2.55(s,6H),2.91(t,2H),3.46(t,2H),3.99(t,2H),5.32(s,2H),5.96(d,1H),6.02(dd,1H),6.88(d,1H),6.93(d,1H),7.35(d,1H)
实施例186:1-[2,6-二氯-3-(3-羟基-丙氨基)-苄基]-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CD3OD,300MHz)δ0.93(t,3H),1.38-1.45(m,4H),1.75-1.90(m,4H),3.48-3.53(m,2H),3.69(t,2H),3.98(t,2H),5.31(s,2H),5.95(d,1H),6.01(dd,1H),6.83(d,1H),6.90(d,1H),7.30(d,1H)
实施例187:1-[2,6-二氯-3-(3-二甲氨基-丙氨基)-苄基]-4-戊氧基-1H-吡
啶-2-酮
1H NMR(CDCl3+数滴CD3OD,300MHz)δ0.79(t,3H),1.13-1.30(m,4H),1.61-1.77(m,4H),2.20(s,6H),2.38(t,2H),3.11(t,2H),3.80(t,2H),5.18(s,2H),5.76(dd,1H),5.81(d,1H),6.54(d,1H),6.64(d,1H),7,13(d,1H)
实施例188:1-[3-(3-氨基-丙氨基)-2,6-二氯-苄基]-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CD3OD,300MHz)δ0.94(t,3H),1.38-1.46(m,4H),1.75-1.80(m,2H),1.94-2.01(m,2H),3.01-3.06(m,2H),3.32-3.39(m,2H),3.99(t,2H),5.31(s,2H),5.95(d,1H),6.02(dd,1H),6.87(d,1H),6.92(d,1H),7.33(d,1H)
实施例189:1-(3-氟-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.32-1.46(m,4H),1.75-1.78(m,2H),2.19(s,3H),3.93(t,2H),5.08(s,2H),5.86-5.94(m,2H),6.82(d,1H),6.92-7.02(m,2H),7.10-7.15(m,1H)
实施例190:1-(2-氯-3-二甲氨基甲基-4-氟-苄基)-4-戊氧基-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.33-1.45(m,4H),1.72-1.86(m,2H),3.55(s,6H),3.91(t,2H),4.91(s,2H),5.19(s,2H),5.88(d,1H),5.98(dd,1H),7.12-7.42(m,3H)
实施例191:1-(2,6-二氯-3-甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.32-1.42(m,4H),1.75-1.79(m,2H),2.91(d,3H),3.90(t,2H),4.49(q,1H),5.33(s,2H),5.78(dd,1H),5.92(d,1H),6.63(d,1H),6.70(d,1H),7.28(d,1H)
实施例192:1-(2,6-二氯-3-二甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.92(t,3H),1.34-1.41(m,4H),1.72-1.78(m,2H),2.80(s,6H),3.90(t,2H),5.38(s,2H),5.79(dd,1H),5.93(d,1H),6.69(d,1H),7.08(d,1H),7.33(d,1H)
实施例193:[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯氨基]-乙酸
1H NMR(DMSO-d6,300MHz)δ0.89(t,3H),1.32-1.37(m,4H),1.67-1.71(m,2H),3.90-3.97(m,4H),5.03(s,2H),5.69(br s,1H),5.83(s,1H),5.99(d,1H),6.05(d,1H),6.52(d,1H),7.05(t,1H),7.51(d,1H)
实施例194:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(吡啶-4-基甲
氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.02(s,2H),5.09(s,2H),5.95-6.01(m,4H),6.84(d,1H)7.21-7.31(m,4H),8.62(d,2H)
实施例195:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基-4-(6-氯-吡啶-3-
基甲氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.98(s,2H),5.09(s,2H),5.92-5.99(m,4H),6.83(d,1H),7.22-7.40(m,3H),7.70(dd,1H),8.40(dd,1H)
实施例196:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(4-甲氧基-3,5-
二甲基吡啶-2-基甲氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.27(s,6H),3.78(s,3H),5.09(s,4H),6.09-6.10(m,4H),6.84(s,2H),7.17(s,1H),7.21(s,1H),8.25(s,1H)
实施例197:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-甲基-吡啶
-3-基甲氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.58(s,3H),5.00(s,2H),5.13(s,2H),5.96-5.98(m,3H),6.05(d,1H),6.87(d,2H),7.19(dd,1H),7.25-7.29(m,1H),7.67(d,1H),8.51(d,1H)
实施例198:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(噻唑-4-基甲
氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.12(s,2H),5.21(s,2H),5.98(s,2H),6.01(dd,1H),6.07(d,1H),6.86(d,2H),7.24(d,1H),7.43(s,1H),8.87(s,1H)
实施例199:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(吡啶-2-基甲
氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.12(s,2H),5.16(s,2H),5.98(s,2H),6.03-6.05(m,2H),6.86(d,2H),7.25-7.29(m,2H),7.45(d,1H),7.75(td,1H),8.63(d,1H)
实施例200:戊酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代
-1,2-二氢-吡啶-4-基酯
1H NMR(CDCl3,300MHz)δ0.97(t,3H),1.39-1.47(m,2H),1.68-1.75(m,2H),2.54(t,2H),5.15(s,2H),5.98(s,2H),6.09(dd,1H),6.38(d,1H),6.86(s,1H),6.91(s,1H),7.37(d,1H)
实施例201:己酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代
-1,2-二氢-吡啶-4-基酯
1H NMR(CDCl3,300MHz)δ0.93(t,3H),1.34-1.38(m,4H),1.70-1.76(m,2H),2.54(t,2H),5.16(s,2H),5.98(s,2H),6.10(dd,1H),6.40(d,1H),6.87(s,1H),6.91(s,1H),7.37(d,1H)
实施例202:1-(2-氯-3-三氟甲基-苄基)-4-戊氧基-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.95(t,3H),1.37-1.45(m,4H),1.78-1.81(m,2H),3.94(t,2H),5.25(s,2H),5.95-5.98(m,2H),7.19-7.38(m,3H),7.65(d,1H)
实施例203:噻吩-2-羧酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-
氧代-1,2-二氢-吡啶-4-基酯
1H NMR(CDCl3,300MHz)δ5.19(s,2H),6.00(s,2H),6.24(dd,1H),6.53(d,1H),6.88(s,1H),6.94(s,1H),7.21(t,1H),7.42(d,1H),7.72(d,1H),7.98(d,1H)
实施例204:甲苯-4-磺酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-
氧代-1,2-二氢-吡啶-4-基酯
1H NMR(CDCl3,300MHz)δ2.48(s,3H),5.10(s,2H),6.00(s,2H),6.14-6.15(m,2H),6.84(s,1H),6.87(s,1H),7.34-7.35(m,1H),7.38(d,2H),7.81(d,2H)
实施例205:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(4,4,5,5,5-五
氟-戊氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.08-2.28(m,4H),4.01(t,2H),5.12(s,2H),5.91-5.93(m,2H),5.98(s,2H),6.84(s,1H),6.87(s,1H),7.22-7.24(m,1H)
实施例206:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-二甲氨基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.33(s,6H),2.73(t,2H),4.03(t,2H),5.11(s,2H),5.94-5.97(m,4H),6.83(s,1H),6.86(s,1H),7.19(d,1H)
实施例207:4-氯-2-(2,4-二氯-苄氧基)-吡啶
1H NMR(CDCl3,300MHz)δ5.17(s,2H),6.83(dd,1H),6.93(d,1H),7.28-7.47(m,3H),8.23(d,1H)
实施例208:4-氯-1-(2,4-二氯-苄基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ5.17(s,2H),6.21(dd,1H),6.65(s,1H),7.22-7.42(m,3H),7.43(s,1H)
实施例209:1-(2,4-二氯-苄基)-4-(5-氟-戊氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.58-1.61(m,2H),1.74-1.88(m,4H),3.96(t,2H),4.44(t,1H),4.54(t,1H),5.16(s,2H),5.93-5.94(m,2H),7.18-7.22(m,3H),7.42(s,1H)
实施例210:3-[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧甲基]-
吲哚-1-羧酸4-丁基酯
1H NMR(CDCl3,300MHz)δ1.61(s,9H),5.18(s,2H),5.40(s,2H),5.95(dd,1H),6.15(d,1H),7.21-7.60(m,7H),8.23(d,1H)
实施例211:1-(2,4-二氯-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.30(t,2H),4.15(t,2H),5.13(s,2H),5.90-5.97(m,2H),6.87-6.98(m,2H),7.15-7.22(m,4H),7.41(s,1H)
实施例212:1-(2,4-二氯-苄基)-4-(2-噻吩-3-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.12(t,2H),4.15(t,2H),5.12(s,2H),5.88-5.97(m,2H),6.95-7.41(m,7H)
实施例213:1-(2,4-二氯-苄基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.18(t,2H),4.28(t,2H),5.14(s,2H),5.82-5.97(m,2H),6.70-6.80(m,2H),7.10-7.25(m,3H),7.40(s,1H)
实施例214:1-(2,4-二氯-苄基)-4-(3-吡咯-1-基-丙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.20(m,2H),3.82(t,2H),4.03(t,2H),5.14(s,2H),5.86(d,1H),5.94(dd,1H),6.12-6.18(m,2H),6.60-6.66(m,2H),7.18-7.24(m,3H),7.40(s,1H)
实施例215:1-(3-氨基-2-甲基-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ2.01(s,3H),3.28(t,2H),3.65(br s,2H),4.14(t,2H),5.04(s,2H),5.84(dd,1H),5.95(d,1H),6.57(d,1H),6.70(d,1H),6.88-7.02(m,4H),7.16(dd,1H)
实施例216:1-(3-氨基-2-甲基-苄基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ2.01(s,3H),4.16(t,2H),4.25(t,2H),5.04(s,2H),5.83(dd,1H),5.90(d,1H),6.16(t,2H),6.57(d,1H),6.71-6.75(m,3H),6.91(d,1H),7.02(t,1H)
实施例217:1-(3-氨基-2-甲基-苄基)-4-[2-(4-甲基-噻唑-5-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.98(s,3H),2.40(s,3H),3.20(t,2H),3.46(br s,2H),4.06(t,2H),5.02(s,2H),5.81(dd,1H),5.92(d,1H),6.53(d,1H),6.68(d,1H),6.91(d,1H),6.99(t,1H),8.56(s,1H)
实施例218:1-(3-氨基-2-甲基-苄基)-4-(2-(5-溴噻吩-2-基)-乙氧基)-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.95(s,3H),3.14(t,2H),3.49(br s,2H),4.05(t,2H),4.99(s,2H),5.81(dd,1H),5.88(m,1H),6.49(d,1H),6.60(m,1H),6.64(d,1H),6.83(m,1H),6.89(dd,1H),6.96(t,1H)
实施例219:1-(3-氨基-2-甲基-苄基)-4-(2-(5-氟噻吩-2-基)-乙氧基)-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.02(s,3H),3.12(dt,2H),4.09(t,2H),5.05(s,2H),5.85(dd,1H),5.93(d,1H),6.28(dd,1H),6.46(d,1H),6.58(d,1H),6.72(d,1H),6.92(d,1H),7.03(t,1H)
实施例220:1-[3-(2-羟基-乙氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧
基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.96(s,3H),3.29(m,4H),3.88(t,2H),4.12(t,2H),5.02(s,2H),5.84(dd,1H),5.93(d,1H),6.53(d,1H),6.66(d,1H),6.92(m,3H),7.10(t,1H),7.16(dd,1H)
实施例221:2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基
甲基]-苯氨基}-乙酰胺
1H NMR(CDCl3,300MHz)δ2.01(s,3H),3.22(t,2H),3.60(d,2H),4.17(t,2H),4.97(s,2H),5.86(m,1H),5.94(dd,1H),6.20(d,1H),6.29(d,1H),6.95(m,3H),7.33(m,2H)
实施例222:1-[3-(环丙基甲基-氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧
基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ0.25(dt,2H),0.57(dt,2H),1.06-1.19(m,1H),2.01(s,3H),2.98(d,2H),3.27(t,2H),3.73(br s,1H),4.14(t,2H),5.05(s,2H),5.82(dd,1H),5.94(d,1H),6.87-6.95(m,3H),7.10(t,1H)
实施例223:N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-
基甲基]-苯氨基}-乙腈
1H NMR(CDCl3,300MHz)δ2.00(s,3H),3.28(t,2H),4.14(m,4H),5.07(s,2H),5.87(dd,1H),5.93(d,1H),6.66(d,1H),6.71(d,1H),6.93-6.96(m,3H),7.15-7.19(m,2H)
实施例224:N-(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-
基甲基]-苯氨基}-乙基)-乙酰胺
1H NMR(CDCl3,300MHz)δ1.99(m,6H),3.26-3.32(m,4H),3.53-3.59(m,2H),4.14(t,2H),5.05(s,2H),5.82(dd,1H),5.94(d,1H),6.52(d,1H),6.61(d,1H),6.89-6.69(m,3H),7.10(t,1H),7.15(d,1H)
实施例225:1-[2-甲基-3-(2-吡咯-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙
氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.85(s,3H),3.28(t,2H),3.51(t,3H),4.14(t,4H),5.05(s,2H),5.84(dd,1H),5.93(d,1H),6.17(m,2H),6.56(d,1H),6.65(m,3H),6.90(m,3H),7.10-7.17(m,2H)
实施例226:合成1-[2-甲基-3-(2-氧代-2-吡咯烷-1-基-乙氨基)-苄基]
-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮
将{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙酸(50mg,0.13mmol)、TBTU(60mg,0.19mmol)、吡咯烷(0.02ml,0.25mmol)和三乙胺(0.09ml,0.63mmol)的混合物溶于N,N-二甲基甲酰胺(0.5ml),于室温下搅拌。1小时后,使得到的溶液蒸发,用二氯甲烷(20ml)萃取,并用硅胶柱色谱(乙酸乙酯/MeOH,20∶1)处理,得到所述的标题化合物(41mg,71%)。
1H NMR(CDCl3,300MHz)δ1.88-1.95(m,2H),1.99-2.09(m,5H),3.27(t,2H),3.44(t,2H),3.55(t,2H),3.81(s,2H),4.14(t,2H),5.06(s,2H),5.83(dd,1H),5.95(d,1H),6.51(d,1H),6.54(d,1H),6.87-6.94(m,3H),7.10(t,1H)7.16(dd,1H)
实施例227-230:除起始原料外,重复实施例226的方法,得到所述的
标题化合物。
实施例227:1-[2-甲基-3-(2-氧代-2-哌啶-1-基-乙氨基)-苄基]-4-(2-噻吩
-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.53-1.74(m,6H),2.07(s,3H),3.27(t,2H),3.39(t,2H),3.62(t,2H),3.88(s,2H),4.14(t,2H),5.06(s,2H),5.83(dd,1H),5.95(d,1H),6.52(d,1H),6.84-6.96(m,3H),7.10(t,1H)7.16(dd,1H)
实施例228:N,N-二甲基-2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧
基)-2H-吡啶-1-基甲基]-苯氨基}-乙酰胺
1H NMR(CDCl3,300MHz)δ2.08(s,3H),3.05(s,6H),3.28(t,2H),3.88(s,2H),4.15(t,2H),5.07(s,2H),5.83(dd,1H),5.94(d,1H),6.50-6.55(m,2H),6.89-6.96(m,3H),7.08-7.17(m,2H)
实施例229:1-{2-甲基-3-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙氨基]-苄
基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.07(s,3H),2.33(s,3H),2.45(d,4H),3.28(t,2H),3.48(d,2H),3.70(d,2H),3.89(s,2H),4.14(t,2H),5.06(s,2H),5.83(dd,1H),5.94(d,1H),6.52(dd,2H),6.88-6.97(m,3H),7.08-7.17(m,2H)
实施例230:1-[2-甲基-3-(2-吗啉-4-基-2-氧代-乙氨基)-苄基]-4-(2-噻吩
-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.08(s,3H),2.28(t,2H),3.48(t,2H),3.62-3.79(m,6H),3.90(s,2H),4.15(t,2H),5.07(s,2H),5.83(dd,1H),5.94(d,1H),6.48(d,1H),6.54(d,1H),6.88-6.96(m,3H),7.08-7.18(m,2H)
实施例231-266:除起始原料外,重复实施例1的方法,得到所述的标
题化合物。
实施例231:1-(3-氨基-2-甲基-苄基)-4-(2-呋喃-2-基-乙氧基)-1H-吡啶-2-
酮
1H NMR(CDCl3,300MHz)δ2.01(s,3H),3.10(t,2H),4.17(t,2H),5.05(s,2H),5.81(dd,1H),5.95(d,1H),6.10(d,1H),6.30(d,1H),6.57(d,1H),6.69(d,1H),6.90(d,1H),7.02(t,1H),7.29(d,1H)
实施例232:1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基-噻吩-2-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CD3OD,300MHz)δ2.02(s,3H),2.40(s,3H),3.19(t,2H),4.16(t,2H),5.07(s,2H),5.96(d,1H),6.06(dd,1H),6.40(d,1H),6.57(dd,1H),6.67(d,1H),6.73(d,1H),6.95(t,1H),7.21(d,1H)
实施例233:1-(3-氨基-2-甲基-苄基)-4-[2-(5-氯-噻吩-2-基)-乙氧基]-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.01(s,3H),3.18(t,2H),3.70(br s,2H),4.10(t,2H),5.05(s,2H),5.84(dd,1H),2.92(d,1H),6.57(d,1H),6.65(d,1H),6.69(d,1H),6.74(d,1H),6.92(d,1H),7.02(t,1H)
实施例234:1-(2,4-二氯-苄基)-4-[2-(3-甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.20(s,3H),3.20(t,2H),4.10(t,2H),5.14(s,2H),5.93-5.97(m,2H),6.80(d,1H),7.07(d,1H),7.17-7,20(m,3H),7.40(s,1H)
实施例235:1-(3-氨基-2-甲基-苄基)-4-(2-苯并[b]噻吩-3-基-乙氧基)-1H-
吡啶-2-酮
1H NMR(CD3OD,300MHz)δ2.00(s,3H),3.31(t,2H),4.31(t,2H),5.04(s,2H),5.96-6.01(m,2H),6.37(d,1H),6.72(d,1H),6.93(t,1H),7.14-7.42(m,5H),7.84(t,1H)
实施例236:1-(3-氨基-2-甲基-苄基)-4-[2-(5-氯-3-甲基-苯并[b]噻吩-2-
基)-乙氧基]-1H-吡啶-2-酮
1H NMR(CD3OD+数滴CDCl3,300MHz)δ1.97(s,3H),2.32(s,3H),3.32(t,2H),4.20(t,2H),5.01(s,2H),5.92-5.97(m,2H),6.45(d,1H),6.71(d,1H),6.96(t,1H),7.02(d,1H),7.21(dd,1H),7.55(d,1H),7.65(d,1H)
实施例237:1-(3-氨基-2-甲基-苄基)-4-[2-(3-甲基-苯并[b]噻吩-2-基)-乙
氧基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.00(s,3H),2.36(s,3H),3.33(t,2H),3.73(br s,2H),4.18(t,2H),5.05(s,2H),5.82(dd,1H),5.95(d,1H),6.56(d,1H),6.69(d,1H),6.91(d,1H),7.02(t,1H),7.27-7.39(m,2H),7.63(d,1H),7.77(d,1H)
实施例238:1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基-呋喃-2-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.00(s,3H),2.24(s,3H),3.03(t,2H),4.13(t,2H),5.03(s,2H),5.80-5.86(m,2H),5.94-5.96(m,2H),6.53(d,1H),6.66(d,1H),6.89(d,1H),7.00(t,1H)
实施例239:1-(3-氨基-2-甲基-苄基)-4-[2-(5-乙基-呋喃-2-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.20(t,3H),1.99(s,3H),2.59(q,2H),3.04(t,2H),3.68(br s,2H),4.14(t,2H),5.04(s,2H),5.80(dd,1H),5.86(d,1H),5.94(d,1H),5.97(d,1H),6.55(d,1H),6.67(d,1H),6.89(d,1H),7.00(t,1H)
实施例240:5-[1-(3-氨基-2-甲基-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧甲
基]-呋喃-2-羧酸乙酯
1H NMR(CDCl3,300MHz)δ1.37(t,3H),2.00(s,3H),4.36(q,2H),4.97(s,2H),5.05(s,2H),5.84(dd,1H),6.01(d,1H),6.55-6.58(m,2H),6.69(d,1H),6.93(d,1H),7.02(t,1H),7.14(d,1H)
实施例241:1-[3-(2-二甲氨基-乙氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙
氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.99(s,3H),2.30(s,6H),2.60(t,2H),3.17(t,2H),3.28(t,2H),4.14(t,2H),5.06(s,2H),5.83(dd,1H),5.94(d,1H),6.88-6.96(m,3H),7.09-7.18(m,2H)
实施例242:1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基硫烷基-噻吩-2-基)-乙
氧基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.01(s,3H),2.45(s,3H),3.21(t,2H),3.70(br s,2H),4.12(t,2H),5.05(s,2H),5.84(dd,1H),5.93(d,1H),6.57(d,1H),6.69-6.73(m,2H),6.91-6.93(m,2H),7.02(t,1H)
实施例243:1-(3-氨基-2-甲基-苄基)-4-(2-苯并呋喃-2-基-乙氧基)-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.05(s,3H),3.25(t,2H),4.29(t,2H),5.05(s,2H),5.82(d,1H),6.00(s,1H),6.51-6.71(m,3H),6.91(d,1H),7.04(t,1H),7.17-7.28(m,2H),7.42(d,1H),7.50(d,1H)
实施例244:1-(3-氨基-2-甲基-苄基)-4-[2-(3-甲基-异噁唑-5-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CDCl3+数滴CD3OD,300MHz)δ1.86(s,3H),1.93(s,3H),2.63(t,2H),4.14(t,2H),4.96(s,2H),5.82(dd,1H),5.90(d,1H),6.46(d,1H),6.64(d,1H),6.86(d,1H),6.94(t,1H),7.26(s,1H)
实施例245:1-(3-氨基-2-甲基-苄基)-4-[2-(4,5-二甲基-噻吩-2-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.00(s,3H),2.07(s,3H),2.78(s,3H),3.14(t,2H),4.09(t,2H),5.05(s,2H),5.85(dd,1H),5.95(d,1H),6.55(s,1H),6.56(d,1H),6.69(d,1H),6.91(d,1H),7.01(t,1H)
实施例246:1-(3-氨基-2-甲基-苄基)-4-[2-(5-乙基-噻吩-2-基)-乙氧
基]-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.28(t,3H),2.00(s,3H),2.78(q,2H),3.20(t,2H),3.69(br s,2H),4.11(t,2H),5.04(s,2H),5.84(dd,1H),5.94(d,1H),6.55-6.70(m,4H),6.91(d,1H),7.01(t,1H)
实施例247:1-(3-氨基-2,6-二氯-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶
-2-酮
1H NMR(CDCl3,300MHz)δ3.25(t,2H),4.12(t,2H),4.30(br s,2H),5.30(s,2H),5.81(dd,1H),5.92(d,1H),6.70-6.93(m,4H),7.13-7.16(m,2H)
实施例248:N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-
基甲基]-苯基}-乙酰胺
1H NMR(DMSO-d6,300MHz)δ2.02(s,3H),2.08(s,3H),3.22(t,2H),4.17(t,2H),5.00(s,2H),5.87(d,1H),5.99(dd,1H),6.57(d,1H),6.94-6.96(m,2H),7.07(t,1H),7.19(d,1H),7.32-7.34(m,1H),7.43(d,1H)
实施例249:1-[2-甲基-3-(2-哌啶-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙
氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.59(br s,2H),1.83-1.87(m,4H),2.07(s,3H),2.90-2.94(m,4H),3.06(t,2H),3.28(t,2H),3.52(t,2H),4.13(t,2H),4.60(br s,1H),5.03(s,2H),5.86(dd,1H),5.92(d,1H),6.46(d,1H),6.59(d,1H),6.88-6.96(m,3H),7.07(t,1H),7.16(dd,1H)
实施例250:1-[2-甲基-3-(2-吗啉-4-基-乙基氨基)-苄基]-4-(2-噻吩-2-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.00(s,3H),2.47(t,4H),2.69(t,2H),3.18(t,2H),3.28(t,2H),3.70(t,4H),4.14(t,2H),5.06(s,2H),5.83(dd,1H),5.94(d,1H),6.53(d,1H),6.61(d,1H),6.88-6.95(m,3H),7.10(d,1H),7.15(t,1H)
实施例251:N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-
基甲基]-苄基}-甲磺酰胺
1H NMR(CDCl3,300MHz)δ2.15(s,3H),2.95(s,3H),3.30(t,2H),4.17(t,2H),5.01(s,2H),5.97(dd,2H),6.03(d,1H),6.74(d,1H),6.89-6.96(m,2H),7.01(d,1H),7.09(t,1H),7.16(dd,1H),7.28(t,1H),7.60(br s,1H)
实施例252:1-(3-氨基-2-甲基-苄基)-4-[2-(4-溴-噻吩-2-基)-乙氧基]-1H-
吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.99(s,3H),3.22(t,2H),3.69(br s,2H),4.10(t,2H),5.04(s,2H),5.83(dd,1H),5.92(d,1H),6.55(d,1H),6.68(d,1H),6.80(s,1H),6.91(d,1H),6.98-7.06(m,2H)
实施例253:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-吡咯-1-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ4.15(t,2H),4.25(t,2H),5.07(s,2H),5.85-5.90(m,2H),5.94(s,2H),6.15-6.16(m,2H),6.60-6.72(m,2H),6.79(s,1H),6.83(s,1H),7.18(d,1H)
实施例254:1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-噻吩-2-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ3.26(t,2H),4.12(t,2H),5.06(s,2H),5.89-5.92(m,4H),6.78-6.94(m,4H),7.14-7.18(m,2H)
实施例255:1-[2-甲基-3-(2-吡咯烷-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.78(br s,4H),1.98(s,3H),2.55(br s,4H),2.79(t,2H),3.23(t,2H),3.28(t,2H),4.14(t,2H),4.33(br s,1H),5.05(s,2H),5.81-5.85(m,1H),5.94(d,1H),6.53(d,1H),6.63(d,1H),6.88-6.96(m,3H),7.09-7.18(m,2H)
实施例256:N-(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-
基甲基]-苯氨基}-乙基)-乙酰胺
1H NMR(CDCl3,300MHz)δ1.94(s,6H),3.25(t,4H),3.49(q,2H),4.10(t,2H),5.00(s,2H),5.83-5.89(m,2H),6.44(d,1H),6.58(d,1H),6.73(t,1H),6.87-6.94(m,3H),7.06(t,1H),7.14(d,1H)
实施例257:1-{2-甲基-3-[(吡啶-3-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.03(s,3H),3.28(t,2H),4.14(t,2H),4.42(s,2H),5.07(s,2H),5.86(dd,1H),5.93(d,1H),6.56(d,2H),6.88-6.96(m,3H),7.07(t,1H),7.16(dd,1H),7.30-7.34(m,1H),7.73(d,1H),8.54(s,1H),8.64(s,1H)
实施例258:2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲
基]-苯基酯
1H NMR(CDCl3,300MHz)δ2.26(s,3H),3.16(s,3H),3.27(t,2H),4.14(t,2H),5.06(s,2H),5.93-5.95(m,2H),6.88-7.00(m,4H),7.14-7.26(m,3H)
实施例259:1-{2-甲基-3-[(吡啶-4-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.07(s,3H),3.28(t,2H),4.14(t,2H),4.44(s,2H),5.08(s,2H),5.86(dd,1H),5.94(d,1H),6.42(d,2H),6.54(d,1H),6.88-7.11(m,4H),7.16(dd,1H),7.30(d,2H),8.55(d,2H)
实施例260:1-{2-甲基-3-[(噻唑-4-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-
乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.04(s,3H),3.28(t,2H),4.14(t,2H),4.56(s,2H),5.06(s,2H),5.84(dd,1H),5.94(d,1H),6.55(d,1H),6.65(d,1H),6.88-7.20(m,6H),8.85(s,1H)
实施例261:1-[3-(4-甲氧基-苄氧基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧
基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ2.15(s,3H),3.29(t,2H),3.81(s,3H),4.16(t,2H),4.99(s,2H),5.08(s,2H),5.88(dd,1H),6.00(d,1H),6.68(d,1H),6.90-6.96(m,6H),7.11-7.18(m,2H),7.35(d,2H)
实施例262:1-{3-[(3,5-二甲基-异噁唑-4-基甲基)-氨基]-2-甲基-苄
基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.98(s,3H),2.26(s,3H),2.37(s,3H),3.28(t,2H),4.04(s,2H),4.15(t,2H),5.07(s,2H),5.85-5.95(m,2H),6.62(d,1H),6.74(d,1H),6.88-6.96(m,3H),7.14-7.19(m,2H)
实施例263:1-(3-羟基-2-甲基-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-
酮
1H NMR(CDCl3+数滴CD3OD,300MHz)δ1.96(s,3H),3.16(t,2H),4.05(t,2H),4.91(s,2H),5.85-5.88(m,2H),6.41(d,1H),6.66(d,1H),6.76-6.90(m,4H),7.04(d,1H)
实施例264:1-{2-甲基-3-[(1-甲基-吡咯烷-2-基甲基)-氨基]-苄基}-4-(2-
噻吩-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3+数滴CD3OD,300MHz)δ1.57-1.67(m,3H),1.79-1.89(m,6H),2.25(s,3H),2.47-2.50(m,1H),2.98-3.04(m,2H),3.13(t,2H),4.01(t,2H),4.88(s,2H),5.78-5.81(m,2H),6.32(d,1H),6.47(d,1H),6.73-6.85(m,3H),6.94(t,1H),7.00(d,1H)
实施例265:1-{2-甲基-3-[2-(1-甲基-吡咯烷-2-基)-乙氨基]-苄基}-4-(2-
噻吩-2-基-乙氧基)-1H-吡啶-2-酮
1H NMR(CDCl3,300MHz)δ1.67-1.79(m,3H),1.90-1.98(m,6H),2.24(q,2H),2.40(s,3H),3.10-3.30(m,5H),4.14(t,2H),4.88(br s,1H),5.04(s,2H),5.82(dd,1H),5.93(d,1H),6.52(d,1H),6.60(d,1H),6.88-6.96(m,3H),7.08-7.17(m,2H)
实施例266:(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-
基甲基]-苯氨基}-乙基)-膦酸二乙酯
1H NMR(CDCl3,300MHz)δ1.32(t,6H),2.02(s,3H),2.10-2.20(m,2H),3.28(t,2H),3.42-3.53(m,2H),4.07-4.17(m,6H),5.06(s,2H),5.85(dd,1H),5.96(s,1H),6.57(d,1H),6.68(d,1H),6.88-6.96(m,3H),7.10-7.17(m,2H)
制备4-(异丁硫基)吡啶1-氧化物:将在30ml DMF中的5.80g异丁基硫醇溶液在室温下搅拌,加入2.55g NaOMe。30分钟后加入6.0g N-氧化物,将反应混合物加热回流15小时。将该混合物冷却,蒸发溶液,用二氯甲烷萃取,并用硅胶柱色谱处理(己烷/乙酸乙酯),得到5.8g 4-(异丁硫基)吡啶1-氧化物。
1H NMR(CDCl3,300MHz)δ0.99(s,3H),1.01(s,3H),1.85-1.89(m,1H),2.78(d,J=6.9Hz,2H),7.04(d,J=7.2Hz,2H),8.01(d,J=7.5Hz,2H)
制备4-(异丁硫基)吡啶-2(1H)-酮:将500mg 4-(异丁硫基)吡啶-N-氧化物和5ml乙酸酐的混合物加热回流10小时。然后,冷却该混合物,加入MeOH,滴加3N NaOH至pH9-11,搅拌。1小时后,蒸发溶液,滴加3N HCl至pH6.5-7.5,用乙酸乙酯萃取,用硅胶柱色谱处理(己烷/乙酸乙酯),得到所述的化合物(90mg)。
1H NMR(CDCl3,300MHz)δ1.05(s,3H),1.07(s,3H),1.95-2.00(m,1H),2.79(d,J=6.9Hz,2H),6.19(dd,1H),6.31(s,1H),7.21(d,J=6.9Hz,1H)
实施例267:4-(异丁硫基)-1-(2-甲基-3-硝基苄基)吡啶-2(1H)-酮
制备4-(异丁硫基)-1-(2-甲基-3-硝基苄基)吡啶-2(1H)-酮:将100mg4-(异丁硫基)吡啶-2(1H)-酮、2ml DMF、65mg t-BuOK的混合物在室温下搅拌,向其中加入105mg 2-甲基-3-硝基苄基氯。3小时后,蒸发得到的溶液,用二氯甲烷萃取,并用硅胶柱色谱处理(己烷/乙酸乙酯),得到所述的化合物(90mg)。
1H NMR(CDCl3,300MHz)δ1.06(s,3H),1.08(s,3H),1.94-2.03(m,1H),2.42(s,3H),2.80(,J=6.9Hz,2H),5.15(s,2H),6.07(dd,1H),6.35(s,1H),6.93(,J=7.5Hz,1H),7.19-7.33(m,2H),7.71(,J=8.1Hz,1H)
实施例268-280:除起始原料外,重复实施例267的方法,得到所述的
标题化合物。
实施例268:1-(3-氨基-2-甲基苄基)-4-(异丁硫基)吡啶-2(1H)-酮
将400mg 1-(3-氨基-2-甲基苄基)-4-(异丁硫基)吡啶-2(1H)-酮、5ml乙醇、3ml溶于水的阮内镍的混合物于室温下搅拌,并滴加3.5ml的NH2NH2H2O。1小时后,通过C盐(Celite)过滤除去催化剂,蒸发得到的溶液,用二氯甲烷萃取,得到所述的标题化合物(200mg)。
1H NMR(CDCl3,300MHz)δ1.01-1.07(m,6H),1.95-1.99(m,1H),2.13(s,3H),2.77(d,J=6.9Hz,2H),5.07(s,2H),5.97(dd,1H),6.32(s,1H),6.70(d,J=7.8Hz,1H),6.85-6.92(m,2H),7.08(t,J=7.8Hz,1H)
实施例269:1-(3-氨基-2-甲基苄基)-4-(呋喃-2-基甲硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ2.03(s,3H),4.14(s,2H),5.05(s,2H),5.96(dd,1H),6.31(s,2H),6.45(d,J=7.8Hz,1H),6.76(d,J=7.5Hz,1H),6.88(d,J=6.9Hz,1H),7.04(t,J=7.8Hz,1H),7.36(s,1H)
实施例270:1-(3-氨基-2-甲基苄基)-4-(戊硫基)吡啶-2-(1H)-酮
1H NMR(CDCl3,300MHz)δ0.89-0.93(m,3H),1.31-1.44(m,4H),1.66-1.73(m,2H),2.03(s,3H),2.85-2.90(m,2H),5.05(s,2H),5.92-5.95(m,1H),6.33(s,1H),6.60(d,J=7.2Hz,1H),6.73(d,J=7.8Hz,1H),6.85(q,1H),7.03(t,J=7.8Hz,1H)
实施例271:1-(3-氨基-2-甲基苄基)-4-(苯乙硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ2.13(s,3H),3.00(t,J=7.5Hz,2H),3.16(t,J=7.5Hz,2H),5.06(s,2H),5.94-5.97(dd,1H),6.39(s,1H),6.66(bs,1H),6.88(d,J=7.5Hz,2H),7.06-7.10(m,1H),7.19-7.35(m,3H)
实施例272:1-(3-氨基-2-甲基苄基)-4-(丁硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ0.95(t,J=7.2Hz,3H),1.43-1.50(m,2H),1.67-1.72(m,2H),2.04(s,3H),2.89(t,J=7.3Hz,2H),5.05(s,2H),5.94(dd,1H),6.33(s,1H),6.61(d,J=7.6Hz,1H),6.75(d,J=8.1Hz,1H),6.86(d,J=7.2Hz,1H),7.04(t,J=7.6Hz,1H)
实施例273:1-(3-氨基-2-甲基苄基)-4-(噻吩-2-基甲硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ2.03(s,3H),4.34(s,2H),5.04(s,2H),5.95(dd,1H),6.41(bs,1H),6.60(d,J=7.5Hz,1H),6.75(d,J=7.5Hz,1H),6.87-6.95(m,2H),7.01-7.05(m,2H),7.21-7.26(m,1H)
实施例274:1-(3-氨基-2-甲基苄基)-4-(戊硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ0.92(t,J=6.8Hz,3H),1.32-1.46(m,4H),1.68-1.78(m,2H),2.43(s,3H),2.91(t,J=7.3Hz,2H),5.15(s,2H),6.07(dd,1H),6.38-6.39(m,1H),6.94(d,J=7.2Hz,1H),7.20-7.31(m,2H),7.72(d,J=8.1Hz,2H)
实施例275:1-(3-氨基-2-甲基苄基)-4-(丙硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ1.05(t,J=7.5Hz,3H),1.71-1.78(m,2H),2.02(s,3H),2.87(t,J=7.3Hz,2H),5.06(s,2H),5.94(dd,1H),6.33(d,J=1.8Hz,1H),6.59(d,J=7.8Hz,1H),6.70(d,J=7.5Hz,1H),6.86(d,J=7.2Hz,1H),7.03(t,J=7.8Hz,1H)
实施例276:1-(3-氨基-2-甲基苄基)-4-(1-甲基丁硫基)吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ0.93-1.02(m,6H),1.55-1.62(m,2H),1.68-1.75(m,1H),2.06(s,3H),2.89(t,J=7.5Hz,2H),5.06(s,2H),5.94(dd,1H),6.33(s,1H),6.63(d,J=7.2Hz,1H),6.78(d,J=8.1Hz,1H),6.86(d,J=7.2Hz,1H),7.04(t,J=7.6Hz,1H)
实施例277:N,N-二甲基-3-(2-甲基-3-((2-氧代-4-(2-(噻吩-2-基)乙氧基)
吡啶-1(2H)-基)甲基)苯氨基)丙烷-1-磺酰胺
1H NMR(CDCl3,300MHz)δ2.06(s,3H),2.23(t,J=6.8Hz,2H),2.87(s,6H),3.06(t,J=7.2Hz,2H),3.29(t,J=6.5Hz,2H),3.39(t,J=6.7Hz,2H),3.62-3.68(m,1H),4.14-4.18(m,2H),5.06(s,2H),5.87(dd,1H),5.97(d,J=2.1Hz,1H),6.60(d,J=7.5Hz,1H),6.80(bs,1H),6.90(bs,1H),6.93-6.96(m,2H),7.10-7.18(m,2H)
实施例278:1-(3-硝基-2-甲基苄基)-4-氯吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ2.38(s,3H),5.38(s,2H),6.54(dd,1H),7.27(d,J=7.8Hz,1H),7.45(t,J=7.9Hz,1H),7.79(d,J=7.8Hz,2H),8.21(s,1H)
实施例279:1-(3-氨基-2-甲基苄基)-4-氯吡啶-2(1H)-酮
1H NMR(CDCl3,300MHz)δ1.94(s,3H),5.08(s,2H),6.23-6.28(m,2H),6.63(d,J=7.8Hz,1H),6.90(t,J=7.8Hz,1H),8.11(s,1H)
实施例280:1-(3-氨基-2-甲基苄基)-4-(2-(噻吩-2-基)乙氨基)吡啶
-2-(1H)-酮
1H NMR(CDCl3,300MHz)δ2.02(s,3H),3.07(t,J=6.8Hz,2H),3.37(t,J=6.5Hz,2H),4.97(s,2H),5.64(d,J=8.1Hz,2H),6.55(d,J=7.5Hz,1H),6.75-6.83(m,3H),6.88-6.91(m,1H),7.00(t,J=7.5Hz,1H),7.12(d,J=5.1Hz,1H)
试验实施例1:最小抑制浓度(MIC)
实施例合成的所述化合物的抗菌活性通过测定其对标准菌株的最小抑制浓度MIC值进行评价。具体地,通过下述步骤测量MIC值:按照双倍稀释方法稀释试验化合物;在Müller-Hinton琼脂肉汤中分散得到的稀释液;接种2ml具有浓度为107cfu(集落形成单位)/ml的标准菌株培养物;该混合物在37℃培养20小时。得到的MIC值在128-0.2μg/ml范围内,优选1-0.2μg/ml。上述结果表明:本发明化合物对各种感染性细菌菌株包括MRSA菌株具有良好的抗菌活性。
Claims (22)
1.一种具有式(I)的化合物及其药学上可接受的的物质,所述物质选自盐:
其中
R1选自下述基团:
C1-8烷基、C1-8链烯基和芳基,上述基团任选含有一个或多个下述取代基:
羟基、卤素、C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基、芳基、杂芳基、取代芳基和取代杂芳基,
其中所述的取代芳基和取代杂芳基含有一个或多个下述取代基:C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基和芳基;
A为C-R2;
R2选自下述基团:H、C5烷基和苄基;
B选自CH2;
R4选自下述基团:
C1-8烷基、C1-8链烯基和芳基,上述基团任选含有一个或多个下述取代基:
羟基、卤素、C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基、芳基、杂芳基、取代芳基和取代杂芳基;
其中所述的取代芳基和取代杂芳基含有一个或多个下述取代基:C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷基氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基和芳基;
W为CH;
Z为C-R5;
R5选自下述基团:H和甲基;和
X选自NH、O和S。
2.按照权利要求1所述的化合物,其中所述R1和R4中的烷基和链烯基基团是直链的。
3.按照权利要求1所述的化合物,其中所述R1和R4中的烷基和链烯基基团是支链的。
4.选自下述化合物的化合物:
4-苄氧基-1-(2-氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(4-氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(4-硝基-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(2,5-二氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
4-苄氧基-2-(4-甲氧基-苄氧基)-吡啶;
4-苄氧基-1-(4-甲氧基-苄基)-1H-吡啶-2-酮;
4-苄氧基-2-(4-甲基-苄氧基)-吡啶;
4-苄氧基-1-(4-甲基-苄基)-1H-吡啶-2-酮;
4-苄氧基-1-(6-氯-吡啶-3-基甲基)-1H-吡啶-2-酮;
4-苄氧基-1-(3-氯-苄基)-1H-吡啶-2-酮;
1-苄基-4-苄氧基-1H-吡啶-2-酮;
1-(4-氨基-苄基)-4-苄氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮;
3-苄基-1-(2,4-二氯-苄基)-4-羟基-1H-吡啶-2-酮;
4-(联苯-4-基甲氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2,4-二氯-苄氧基)-1H-吡啶-2-酮;
4-(2-氯-苄氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氨-苄基)-4-甲氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-异丙氧基-1H-吡啶-2-酮;
4-环己基甲氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-丙氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-异丁氧基-1H-吡啶-2-酮;
4-丁氧基-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-辛氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-戊氧基)-1H-吡啶-2-酮;
4-(丁-3-烯基氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧基]-乙酸乙酯;
1-(2,4-二氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-苄基-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-戊氧基-1-丙基-1H-吡啶-2-酮;
1-丁基-4-戊氧基-1H-吡啶-2-酮;
1-异丁基-4-戊氧基-1H-吡啶-2-酮;
1-(3-甲基-丁基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-己氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-庚氧基-1H-吡啶-2-酮;
1-(4-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲氧基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-乙氨基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-乙氧基-乙氧基)-1H-吡啶-2-酮;
1-(3-甲基-丁-2-烯基)-4-戊氧基-1H-吡啶-2-酮;
4-戊氧基-1-噻唑-4-基甲基-1H-吡啶-2-酮;
4-戊氧基-1-吡啶-3-基甲基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-戊-3-烯基氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲氧基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-乙氧苯基氧基-1H-吡啶-2-酮;
1-(2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-戊基-1-乙氧苯基-1H-吡啶-2-酮;
1-(2,4-二氯-5-氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3,4-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3,4-二氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(4-苄氧基-丁氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-羟基-丁氧基)-1H-吡啶-2-酮;
4-(5-苄氧基-戊氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(5-羟基-戊氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-甲基-苄氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-苄氧基)-1H-吡啶-2-酮;
1-(2-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
N-[2-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
4-戊氧基-1-(2-三氟甲基-苄基)-1H-吡啶-2-酮;
N-[4-(4-苄氧基-2-氧代-2H-吡啶-1-基甲基)-苯基]乙酰胺;
1-(2,4-二氯-苄基)-4-(萘-2-基甲氧基)-1H-吡啶-2-酮;
1-萘-2-基甲基-4-戊氧基-1H-吡啶-2-酮;
4-苄氧基-1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(2-甲基-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
4-(3-甲基-丁氧基)-1-(2-硝基-苄基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-戊氨基-1H-吡啶-2-酮;
1-(2,3-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,3-二甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(3,4-二氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-5-氟-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-苄基-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(4-氯-苄基)-4-(3-甲基-丁氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-戊氧基-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-甲基-戊氧基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-苯氧基-1H-嘧啶-2-酮;
4-(丁基-甲基-氨基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-二乙氨基-乙氧基)-1H-嘧啶-2-酮;
4-丁氧基-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,6-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-6-氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲基-3-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-甲氧基-3,5-二甲基-吡啶-2-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(5-羟基-戊氧基)-1H-吡啶-2-酮;
1-(2-甲氧基-5-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(5-氨基-2-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-乙基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(5-氨基-2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-甲氧基-2,3-二甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲基-吡啶-3-基甲基)-4-戊氧基-1H-吡啶-2-酮;
N-[4-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
1-(2,4-二氯-苄基)-4-(3-二甲氨基-丙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(4-二甲氨基-丁氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(6-二甲氨基-己氧基)-1H-嘧啶-2-酮;
1-(2,4-二甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-三氟甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(3-环丙氧基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲基-戊氧基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-己-4-烯基氧基-1H-嘧啶-2-酮;
4-(2-环丙基-乙氧基)-1-(2,4-二氯-苄基)-1H-嘧啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-甲基-戊氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(5-吗啉-4-基-戊氧基)-1H-吡啶-2-酮;
1-(2-氯-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-乙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-丙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-5-(2-羟基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
[4-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-氧基]-乙腈;
1-[5-(2-氨基-乙氧基)-2-氯-苄基]-4-戊氧基-1H-吡啶-2-酮;
N-[2-甲基-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
1-(2-甲基-3-甲氨基-苄基)-4-苯氧基-1H-吡啶-2-酮;
1-(3-二甲氨基-2-甲基-苄基)-4-苯氧基-1H-吡啶-2-酮;
1-(3-乙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-二乙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-甲基-3-丙氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-二丙氨基-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[3-(2-羟基-乙氨基)-2-甲基-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-甲氧基-4-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-氨基-2-氯-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
N-[5-氯-2-甲氧基-4-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
1-(2-氯-5-甲氧基-4-甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-4-二甲氨基-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-4-乙氨基-5-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-5-甲氧基-4-丙氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-4-(2-羟基-乙氨基)-5-甲氧基-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-(4-氨基-6-氯-3-甲氧基-2-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氨基-6-氯-3-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,5-二氯-6-甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苯磺酰基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-甲磺酰基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(4-氨基-2-氯-5-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮;
4-(4-溴-丁氧基)-1-(2,4-二氯-苄基)-1H-吡啶-2-酮;
4-[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧基]-丁基铵;
1-(5-氯-2,6-二甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氨基-5-氯-6-甲氧基-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(6-氨基-2,5-二氯-嘧啶-4-基甲基)-4-戊氧基-1H-吡啶-2-酮;
5-氯-6-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-3H-苯并噁唑-2-酮;
1-(2-氯-4-羟基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-4-异丙氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
2-[3-(2-氧代-4-戊氧基-2H-吡啶-1-基)-丙基]-异吲哚-1,3-二酮;
1-(3-氨基-丙基)-4-戊氧基-1H-吡啶-2-酮;
N-[3-(2-氧代-4-戊氧基-2H-吡啶-1-基)-丙基]-乙酰胺;
1-(3-二甲氨基-丙基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-6-甲基-4-戊氧基-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-6-甲基-3-戊基-4-戊氧基-1H-吡啶-2-酮;
1-(2-氨基-乙基)-4-戊氧基-1H-吡啶-2-酮;
N-[2-(2-氧代-4-戊氧基-2H-吡啶-1-基)-乙基]-乙酰胺;
N-[1,1-二甲基-2-(2-氧代-4-戊氧基-2H-吡啶-1-基)-乙基]-甲磺酰胺;
N-[1-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-丙基]-甲磺酰胺;
1-(7-硝基-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3-硝基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-氨基-2-氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
N-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-乙酰胺;
N-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-甲磺酰胺;
N,N’-[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯基]-二甲磺酰胺;
1-[2-氯-3-(2-羟基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
4-氯-2-(2-氯-苄基)-5-戊氧基-2H-哒嗪-3-酮;
2-(2-氯-苄基)-5-戊氧基-2H-哒嗪-3-酮;
1-(3-氨基-2,6-二氯-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(3-苄氧基-2-氯-4-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3,4-二甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3-羟基-4-甲氧基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-4-甲氧基-3-(2-甲氧基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-4-甲氧基-3-(2-吡咯烷-1-基-乙氧基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-3-(2-二甲氨基-乙氧基)-4-甲氧基-苄基]-4-戊氧基-1H-吡啶-2-酮;
2-{3-[2-氯-6-甲氧基-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯氧基]-丙基}-异吲哚-1,3-二酮;
1-[3-(2-二甲氨基-乙氧基)-2-甲基-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2-氯-3-(2-二甲氨基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(2-羟基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(2-二甲氨基-乙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(3-羟基-丙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[2,6-二氯-3-(3-二甲氨基-丙氨基)-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-[3-(3-氨基-丙氨基)-2,6-二氯-苄基]-4-戊氧基-1H-吡啶-2-酮;
1-(3-氟-2-甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2-氯-3-二甲氨基甲基-4-氟-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,6-二氯-3-甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
1-(2,6-二氯-3-二甲氨基-苄基)-4-戊氧基-1H-吡啶-2-酮;
[2-氯-3-(2-氧代-4-戊氧基-2H-吡啶-1-基甲基)-苯氨基]-乙酸;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(吡啶-4-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(6-氯-吡啶-3-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(4-甲氧基-3,5-二甲基吡啶-2-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-甲基-吡啶-3-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(噻唑-4-基甲氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(吡啶-2-基甲氧基)-1H-吡啶-2-酮;
戊酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
己酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
1-(2-氯-3-三氟甲基-苄基)-4-戊氧基-1H-吡啶-2-酮;
噻吩-2-羧酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
甲苯-4-磺酸1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-2-氧代-1,2-二氢-吡啶-4-基酯;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(4,4,5,5,5-五氟-戊氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-二甲氨基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(5-氟-戊氧基)-1H-吡啶-2-酮;
3-[1-(2,4-二氯-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧甲基]-吲哚-1-羧酸四-丁基酯;
1-(2,4-二氯-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-噻吩-3-基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-(3-吡咯-1-基-丙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(4-甲基-噻唑-5-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-(5-溴噻吩-2-基)-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-(5-氟噻吩-2-基)-乙氧基)-1H-吡啶-2-酮;
1-[3-(2-羟基-乙氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙酰胺;
1-[3-(环丙基甲基-氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙腈;
N-(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙基)-乙酰胺;
1-[2-甲基-3-(2-吡咯-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-氧代-2-吡咯烷-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-氧代-2-哌啶-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N,N-二甲基-2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙酰胺;
1-{2-甲基-3-[2-(4-甲基-哌嗪-1-基)-2-氧代-乙氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-吗啉-4-基-2-氧代-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-呋喃-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-氯-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(2,4-二氯-苄基)-4-[2-(3-甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-苯并[b]噻吩-3-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-氯-3-甲基-苯并[b]噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(3-甲基-苯并[b]噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基-呋喃-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-乙基-呋喃-2-基)-乙氧基]-1H-吡啶-2-酮;
5-[1-(3-氨基-2-甲基-苄基)-2-氧代-1,2-二氢-吡啶-4-基氧甲基]-呋喃-2-羧酸乙酯;
1-[3-(2-二甲氨基-乙氨基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-甲基硫烷基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-(2-苯并呋喃-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(3-甲基-异噁唑-5-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(4,5-二甲基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2-甲基-苄基)-4-[2-(5-乙基-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(3-氨基-2,6-二氯-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯基}-乙酰胺;
1-[2-甲基-3-(2-哌啶-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-吗啉-4-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯基}-甲磺酰胺;
1-(3-氨基-2-甲基-苄基)-4-[2-(4-溴-噻吩-2-基)-乙氧基]-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-吡咯-1-基-乙氧基)-1H-吡啶-2-酮;
1-(6-氯-苯并[1,3]二氧杂环戊烯-5-基甲基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[2-甲基-3-(2-吡咯烷-1-基-乙氨基)-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
N-(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙基)-乙酰胺;
1-{2-甲基-3-[(吡啶-3-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯基酯;
1-{2-甲基-3-[(吡啶-4-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{2-甲基-3-[(噻唑-4-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-[3-(4-甲氧基-苄氧基)-2-甲基-苄基]-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{3-[(3,5-二甲基-异噁唑-4-基甲基)-氨基]-2-甲基-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-(3-羟基-2-甲基-苄基)-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{2-甲基-3-[(1-甲基-吡咯烷-2-基甲基)-氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
1-{2-甲基-3-[2-(1-甲基-吡咯烷-2-基)-乙氨基]-苄基}-4-(2-噻吩-2-基-乙氧基)-1H-吡啶-2-酮;
(2-{2-甲基-3-[2-氧代-4-(2-噻吩-2-基-乙氧基)-2H-吡啶-1-基甲基]-苯氨基}-乙基)-膦酸二乙酯;
4-(异丁硫基)-1-(2-甲基-3-硝基苄基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(异丁硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(呋喃-2-基甲硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(戊硫基)吡啶-2-(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(苯乙硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(丁硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(噻吩-2-基甲硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(戊硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(丙硫基)吡啶-2(1H)-酮;
1-(3-氨基-2-甲基苄基)-4-(1-甲基丁硫基)吡啶-2(1H)-酮;
N,N-二甲基-3-(2-甲基-3-((2-氧代-4-(2-(噻吩-2-基)乙氧基)吡啶-1(2H)-基)甲基)苯氨基)丙烷-1-磺酰胺;
1-(3-氨基-2-甲基苄基)-4-(2-(噻吩-2-基)乙氨基)吡啶-2-(1H)-酮。
5.一种权利要求1所述化合物的制备方法,该方法包括以下步骤:
制备含有醇或胺官能团的吡啶酮衍生物和在DMF中的NaH或叔丁醇钾的溶液;
将上述溶液与式k-m-h的卤化物混合,其中h是氯或溴;m是苄基;
以及k是2-氯、3-氯、4-氯、4-硝基、2,5-二氯、2,4-二氯、4-甲氧基、4-甲基、6-氯-吡啶-3-或4-氨基;
将上述混合物于室温下搅拌30分钟,形成反应产物,所述的反应产物含有一种或多种权利要求1所述的化合物。
6.按照权利要求5所述的方法,其中还包括:通过柱色谱法从所述的反应产物中分离出所述的一种或多种权利要求1所述的化合物。
7.一种权利要求6所述的方法,其中还包括:将所述的分离产物用Pd/C氢化,形成具有羟基取代基的化合物。
8.按照权利要求7所述的方法,其中还包括:
用选自下述的取代基取代所述的羟基取代基:
C1-8烷基、C1-8链烯基和芳基,所述的基团含有一个或多个选自下述的取代基:羟基、卤素、C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基、芳基和杂芳基。
9.一种抗菌组合物,其中含有权利要求1所述的化合物作为活性成分。
10.权利要求9所述的抗菌组合物,该组合物为含有50-5,000mg的权利要求1化合物的制剂形式,所述的制剂选自口服、舌下、吸入、局部、直肠和注射制剂。
11.权利要求10所述的抗菌组合物,该组合物为含有150-3,000mg的权利要求1化合物的制剂形式。
12.权利要求10所述的抗菌组合物,该组合物为含有50-2,000mg的权利要求1化合物的制剂形式。
13.权利要求1所述的化合物在生产用于抑制Fab I活性的制剂方面的用途。
14.权利要求1所述的化合物在生产用于治疗与细菌有关的疾病的制剂方面的用途。
15.权利要求14所述的用途,其中所述的制剂是片剂、胶囊剂或丸剂的形式。
16.权利要求14所述的用途,其中所述制剂选自皮下制剂、静脉内制剂、肌肉内制剂、关节内制剂、滑膜腔内制剂、胸骨内制剂、鞘内制剂、肝内制剂、病灶内制剂和颅内注射制剂。
17.一种用于治疗与细菌有关的疾病的试剂盒,其中包括:(a)权利要求10所述的抗菌组合物,和(b)注射器。
18.一种在治疗与细菌有关的疾病的方法中使用的试剂盒,其中包括粉末剂、颗粒剂或浓缩剂形式的权利要求10所述的抗菌组合物,和用于重悬所述药物组合物以提供口服剂型的溶剂。
19.权利要求1所述的化合物,其中X是O。
20.权利要求19所述的化合物,其中:
A是CH;
B是CH2;
Z是CH;和
W是CH。
21.权利要求20所述的化合物,其中:
R4选自下述基团:
芳基和含有一个或多个取代基的取代芳基,所述取代基选自下述基团:羟基、卤素、C1-6烷基、C3-8环烷基、C3-8杂环烷基、烷氧基、氨基、烷氨基、羧基、硝基、磺酰胺、烷基磺酰基、酰胺、二氧代异吲哚、三卤代烷基和芳基。
22.权利要求1所述的化合物,其中:
X是S;
A是CH;
B是CH2;
Z是CH;和
W是CH。
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WO2003068230A1 (en) * | 2002-02-14 | 2003-08-21 | Pharmacia Corporation | Substituted pyridinones as modulators of p38 map kinase |
US20050020594A1 (en) * | 2003-07-18 | 2005-01-27 | Pharmacia Corporation | Substituted pyridazinones |
Also Published As
Publication number | Publication date |
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CA2625962C (en) | 2014-11-04 |
ES2576579T3 (es) | 2016-07-08 |
EP1948601A4 (en) | 2011-04-06 |
BRPI0617268A2 (pt) | 2011-07-19 |
KR20080068060A (ko) | 2008-07-22 |
WO2007043835A1 (en) | 2007-04-19 |
JP2009511575A (ja) | 2009-03-19 |
JP5049977B2 (ja) | 2012-10-17 |
US7973060B2 (en) | 2011-07-05 |
KR101502335B1 (ko) | 2015-03-16 |
US20070135465A1 (en) | 2007-06-14 |
CN101282930A (zh) | 2008-10-08 |
KR20140029550A (ko) | 2014-03-10 |
EP1948601B1 (en) | 2016-04-13 |
KR101522713B1 (ko) | 2015-05-26 |
CA2625962A1 (en) | 2007-04-19 |
EP1948601A1 (en) | 2008-07-30 |
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