CN102186822A - 新脲和硫脲衍生物 - Google Patents
新脲和硫脲衍生物 Download PDFInfo
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- CN102186822A CN102186822A CN200980137537XA CN200980137537A CN102186822A CN 102186822 A CN102186822 A CN 102186822A CN 200980137537X A CN200980137537X A CN 200980137537XA CN 200980137537 A CN200980137537 A CN 200980137537A CN 102186822 A CN102186822 A CN 102186822A
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- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明公开了式(I)的化合物,其中X是=O、=S、=NH、=NOH和=NO-Me;A是-C(=O)-、-S(=O)2-、-C(=S)-和P(=O)(R5)-;B是-O-、-(CH2)3-6-和O-(CH2)2-5-;D是-O-、-CR7R8-和-NR9;m是0-12,n是0-12,m+n是1-20;p是0-4;R1是任选地取代的杂芳基;和其药用可接受的盐,和其前药。本发明也公开了用作用于治疗由烟酰胺磷酸核糖基转移酶(NAMPRT)的水平升高引起的疾病或病况的药物的化合物,所述疾病或病况例如炎症性和组织修复障碍;皮肤病;自身免疫疾病、阿尔茨海默氏病、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症、恶病质、与感染和某些病毒感染相关的炎症,包括获得性免疫缺陷综合征(AIDS)、成人呼吸窘迫综合征、毛细血管扩张性运动失调。
Description
技术领域
本发明涉及脲和硫脲衍生物和这类衍生物的医学用途,所述脲和硫脲衍生物适用于抑制酶烟酰胺磷酸核糖基转移酶(NAMPRT)。
背景技术
对酶烟酰胺磷酸核糖基转移酶(NAMPRT)的抑制导致NF-kB的抑制,NF-kB的抑制是烟酰胺腺嘌呤二核苷酸(NAD)细胞浓度降低的结果(Beauparlant等人,(2007)AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics,2007Oct 22-26 Abstract nr A82;和Roulson等人,(2007)AACR-NCI-EORTCInternational Conference on Molecular Targets and Cancer Therapeutics,2007 Oct 22-26 Abstract nr A81)。肿瘤细胞具有升高的NAMPRT表达和有高的NAD周转率,这是由DNA修复、基因组稳定性和端粒维持所需要的高ADP-核糖基化活性所导致,这使肿瘤细胞比正常的细胞对NAMPRT抑制更敏感。这也提供了本发明的化合物与DNA损伤剂(damaging agent)组合用于未来临床试验的用途的理论基础。
NAD的生物合成途径显示于图1中。
NAMPRT涉及烟酰胺腺嘌呤二核苷酸(NAD)和NAD(P)的生物合成。在哺乳动物细胞中可以通过起始于色氨酸通过喹啉酸、从烟酸(尼克酸)或从烟酰胺(尼克酰胺)的3种不同途径合成NAD。
随后向单核苷酸中加入腺苷一磷酸,导致形成相应的二核苷酸:烟酸单核苷酸和尼克酰胺单核苷酸与三磷腺苷(ATP)反应分别形成烟酸腺嘌呤二核苷酸(dNAD)和尼克酰胺腺嘌呤二核苷酸(NAD)。两个反应尽管在不同途径发生,但是通过相同的酶NAD焦磷酸化酶催化。
需要另外的酰胺化步骤以将烟酸腺嘌呤二核苷酸(dNAD)转化为烟酰胺嘌呤二核苷酸(NAD)。催化该反应的酶是NAD合成酶NAD是烟酰胺腺嘌呤二核苷酸磷酸(NAD(P))的直接前体。该反应通过NAD激酶催化。具体参见,例如,Cory J.G.Purine and pyrimidine nucleotide metabolism In:Biochemistry and Clinical Correlations的第三版教材,ed.Devlin,T,Wiley,Brisbane 1992,pp 529-574。
正常细胞可以典型地将烟酸和烟酰胺这两种前体用于NAD(P)合成,在很多实例中还利用色氨酸或其代谢物。因此,鼠类神经胶质细胞利用烟酸、烟酰胺和喹啉酸(Grant等人,(1998)J.Neurochem.70:1759-1763)。人淋巴细胞利用烟酸和烟酰胺(Carson等人,(1987)J.Immunol.138:1904-1907;Ber ger等人,(1982)Exp.Cell Res.137;79-88)。大鼠肝细胞利用烟酸、烟酰胺和色氨酸(Yamada等人,(1983)Int.J.Vit.Nutr.Res.53:184-1291;Shin等人,(1995)Int.J.Vit.Nutr.Res.65:143-146;Dietrich(1971)Methods Enzymol.18B;144-149)。人红细胞利用烟酸和烟酰胺(Rocchigiani等人,(1991)Purine and pyrimidine metabolism in man VII Part B ed.Harkness等人,Plenum Press New York pp 337-3490)。豚鼠的白细胞利用烟酸(Flechner等人,(1970),Life Science 9:153-162)。
NAD(P)涉及多种对细胞关键的生物化学反应,因此已被深入研究。NAD(P)在肿瘤发展和生长中的作用也已被研究。已发现很多肿瘤细胞将烟酰胺用于细胞NAD(P)合成。认为在很多正常的细胞类型中构成可代替的前体的烟酸和色氨酸不能在肿瘤细胞中被利用,或至少不能达到足够细胞存活的程度。仅仅在烟酰胺途径(例如NAMPRT)的酶的选择性抑制将构成用于选择肿瘤特异性药物的方法。这通过已在临床试验中作为抗癌药的NAMPRT抑制剂而被例证,所述抗癌药即FK866/APO866,(参见Hasmann和Schemainda,Cancer Res63(21):7463-7442。),CHS828/GMX1778及其前药EB1627/GMX1777(参见Hjarnaa等人,Cancer Research 59;5751-5757;Binderup等人,Bioorg Med Chem Lett 15:2491-2494)。NAMPRT的其它抑制剂在下述文献中发现:WO 2006/066584、WO 2003/097602、WO2003/097601、WO 2002/094813、WO 2002/094265、WO 2002/042265、WO 2000/61561、WO2000/61559、WO 1997/048695、WO 1997/048696、WO 1997/048397、WO 1999/031063、WO 1999/031060和WO 1999/031087。
已知以特定方式取代的脲的不同衍生物具有药理学适用的性质。特别地,已知某些衍生物具有治疗活性。但是所有这些化合物与本发明的化合物结构不相似。
包括脲部分的化合物在下列公开文本中描述:
Budd等人(WO 2007/068473)描述了作为PI-3-激酶抑制剂的下列化合物:
Bruce等人(WO 2008/000421)描述了作为PI-3激酶δ抑制剂的下列结构的化合物:
PI-3激酶的其它抑制剂由Budd等人(WO 2007/134827)描述:
Weber等人(DE 2614189)描述了作为止痛剂的下列一般结构式的化合物。
Ashwell等人(2009)[WO 2009/026446]描述了作为组蛋白脱乙酰基酶抑制剂的下列化合物:
在2009年2月20日的Ambinter Stock Screening Collection中列举了下列化合物:
Fitzmaurice等人(2007)描述了下列化合物在极性溶剂中的性质[Organic & Biomolecular Chemistry(2007)5(11)1706-1714]
Morio等人(1998)[欧洲专利申请EP283040]描述了在摄影材料中使用的下列化合物:
Inoue等人(1998)[EP 283041]描述了在摄影材料中使用的下列化合物:
Schoue等人(1998)[WO 1998/54144]描述了作为细胞增殖的潜在抑制剂的下列化合物:
发明概述
相信本发明的新化合物作用于酶烟酰胺磷酸核糖基转移酶(NAMPRT),NF-kB的下游抑制是烟酰胺腺嘌呤二核苷酸(NAD)的细胞浓度降低的结果。
因此,本发明提供了根据权利要求1的通式(I)的化合物,以及这些化合物在药物中的应用,参照权利要求18、19、21和22。
酶NAMPRT的抑制剂可以用于癌症的治疗(WO 97/48696)以引起免疫抑制(WO 97/48397),用于涉及血管发生疾病的治疗(WO2003/80054),用于类风湿性关节炎或败血症性休克的治疗(WO2008/025857),或用于缺血的预防和治疗(EP 08102310.3(未公开的申请))。
附图概述
图1阐明了NAD生物合成的途径(Biedermann E.等人,WO00/50399)。
发明详述
本发明的化合物
本发明尤其涉及适用于抑制酶烟酰胺磷酸核糖基转移酶(NAMPRT)的特定的脲和硫脲衍生物。
本发明涉及式(I)的化合物和其药用可接受的盐,和其前药,
其中
X选自=O、=S、=NH、=NOH和=NO-Me;
A选自-C(=O)-、-S(=O)2-、-C(=S)-和-P(=O)(R5)-,其中R5选自C1-6-烷基、C1-6-烷氧基和羟基;
B选自单键、-(CH2)3-6-、-O-和-O-(CH2)2-5-;
D选自单键、-O-、-CR7R8-和-NR9,其中R7、R8和R9独立地选自氢、任选地经取代的C1-12-烷基、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;
m是0-12的整数且n是0-12的整数,其中m+n的和是1-20;
p是0-4的整数;
R1选自任选地经取代的杂芳基;
R2选自氢、任选地经取代的C1-12-烷基、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;和R3选自任选地经取代的C1-12-烷基、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;或R2和R3与插入的原子(即-N-B-)一同形成任选地经取代的含有N的杂环或杂芳环;
各R4和R4*独立选自氢、任选地经取代的C1-12-烷基和任选地经取代的C1-12-烯基;
条件是当p是0时,R1不是任选地经取代的噻唑-2-基;
和条件是化合物不是苯基-NH-C(=O)-(CH2)5-NH-C(=S)-NH-(4-吡啶基)。
特定地,
当X是=O且A是-SO2-时,B是-O-或-(CH2)3-6或-O-(CH2)2-5-;和
当X是=O、A是-C(=O)-和p=0时,B是-O-或-(CH2)3-6-或-O-(CH2)2-5-;和
当X是=O、A是-C(=O)-和p=0时,R1不是
当X是=O、A是-C(=O)-和p=1-4时,R1不是
当X是=S、A是-C(=O)-和p=1-4时,R3不是苄基或
定义
在本上下文中,术语“C1-12-烷基”和“C1-6-烷基”意指线性、环状或支化的分别具有1至12个碳原子和1至6个碳原子的烃基,例如甲基、乙基、丙基、异丙基、环丙基、丁基、异丁基、叔丁基、环丁基、戊基、环戊基、己基和环己基。
尽管术语“C3-12-环烷基”包含于术语“C1-12-烷基”,它特指单环和双环的对应物,包括具有环外原子的烷基基团,例如环己基-甲基。
类似地,术语“C2-12-烯基”和“C2-6-烯基”意欲包含线性、环状或支化的分别具有2至12个碳原子和2至6个碳原子的烃基,所述烃基包括(至少)1个不饱和键。烯基的实例是乙烯基、烯丙基、丁烯基、戊烯基、己烯基、庚烯基、辛烯基、十七碳烯基(heptadecaenyl)。烯基的优选实例是乙烯基、烯丙基、丁烯基,特别是烯丙基。
尽管术语“C3-12-环烯基”包含于术语“C2-12-烯基”,它特指单环和双环的对应物,包括具有环外原子的烯基基团,所述烯基基团例如环己烯基-甲基和环己基-烯丙基。
在本上下文中,即在结合术语“烷基”、“环烷基”、“烷氧基”、“烯基”、“环烯基”等时,术语“任选地经取代的”意指所谈论的基团可以用基团取代1次或若干次,优选1-3次,所述基团选自羟基(当与不饱和碳原子键合时其可以以互变异构体的酮的形式存在)、C1-6-烷氧基(即C1-6-烷基-氧基)、C2-6-烯氧基、羧基、氧代(形成酮或醛官能团)、C1-6-烷氧羰基、C1-6-烷基羰基、甲酰基、芳基、芳氧基、芳基氨基、芳基羰基、芳基氧基羰基、芳基羰基氧基、芳基氨基羰基、芳基羰基氨基、杂芳基、杂芳基氧基、杂芳基氨基、杂芳基羰基、杂芳基氧基羰基、杂芳基羰基氧基、杂芳基氨基羰基、杂芳基羰基氨基、杂环基、杂环氧基、杂环基氨基、杂环基羰基、杂环基氧基羰基、杂环基羰基氧基、杂环基氨基羰基、杂环基羰基氨基、氨基、单和二(C1-6-烷基)氨基、-N(C1-4-烷基)3 +、氨基甲酰基、单和二((C1-6-烷基)氨基羰基)、C1-6-烷基-羰基氨基、氰基、胍基、脲基、C1-6-烷基-磺酰基-氨基、芳基-磺酰基-氨基、杂芳基-磺酰基-氨基、C1-6-烷酰氧基、C1-6-烷基-磺酰基、C1-6-烷基-亚磺酰基、C1-6-烷基磺酰氧基、硝基、C1-6-烷硫基和卤素,其中任何芳基、杂芳基和杂环基可以如在下文中针对芳基、杂芳基和杂环基的特定描述被取代,且任何烷基、烷氧基等所表示的取代基可以用下述基团取代:羟基、C1-6-烷氧基、氨基、单和二(C1-6-烷基)氨基、羧基、C1-6-烷基羰基氨基、C1-6-烷基氨基羰基或卤素。
典型地,所述取代基选自羟基(当与不饱和碳原子键合时其可以以互变异构体的酮的形式存在)、C1-6-烷氧基(即C1-6-烷基-氧基)、C2-6-烯氧基、羧基、氧代(形成酮或醛官能团)、C1-6-烷基羰基、甲酰基、芳基、芳氧基、芳基氨基、芳基羰基、杂芳基、杂芳基氧基、杂芳基氨基、杂芳基羰基、杂环基、杂环基氧基、杂环基氨基、杂环基羰基、氨基、单和二(C1-6-烷基)氨基;氨基甲酰基、单和二(C1-6-烷基)氨基羰基、氨基-C1-6-烷基-氨基羰基、单和二(C1-6-烷基)氨基-C1-6-烷基-氨基羰基、C1-6-烷基羰基氨基、胍基、脲基、C1-6-烷基-磺酰基-氨基、C1-6-烷基-磺酰基、C1-6-烷基-亚磺酰基、C1-6-烷硫基、卤素,其中任何芳基、杂芳基和杂环基可以在下文描述中特定地经芳基、杂芳基和杂环基取代。
在某些实施方案中,取代基选自羟基、C1-6-烷氧基、氨基、单和二(C1-6-烷基)氨基、羧基、C1-6-烷基羰基氨基、C1-6-烷基氨基羰基或卤素。
术语“卤素”包括氟、氯、溴和碘代。
在上下文中,术语“芳基”意指全部或部分芳香族的碳环或环系统,例如苯基、萘基、1,2,3,4-四氢萘基、蒽基、菲基(phenanthracyl)、芘基、苯并芘基、芴基和呫吨基,其中苯基是优选的实例。
术语“杂芳基”意指全部或部分芳香化的碳环或环系统,其中1个或更多个碳原子被杂原子取代,所述杂原子例如氮(=N-或-NH-)、硫和/或氧原子。这类杂芳基基团的实例是唑基、异唑基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、香豆酸酰基(coumaryl)、呋喃基、噻吩基、喹啉基、苯并噻唑基、苯并三唑基、苯并二唑基、苯并唑基、酞嗪基、异苯并二氢呋喃基(phthalanyl)、三唑基、四唑基、异喹啉基、吖啶基、咔唑基、二苯并氮杂基、吲哚基、苯并吡唑基、吩嗪酮(phenoxazonyl)基。特别感兴趣的杂芳基基团是苯并咪唑基、唑基、异唑基、噻唑基、异噻唑基、吡咯基、咪唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、呋喃基、噻吩基、喹啉基、三唑基、四唑基、异喹啉基、吲哚基,特别是苯并咪唑基、吡咯基、咪唑基、吡啶基、嘧啶基、呋喃基、噻吩基、喹啉基、四唑基和异喹啉基。
术语“杂环基”意指非芳族的碳环或环系统,其中1个或更多个碳原子已被杂原子取代,所述杂原子例如氮(=N-或-NH-)、硫和/或氧原子。这类杂环基基团(根据环命名)的实例是咪唑烷、哌嗪、六氢哒嗪、六氢嘧啶、二氮杂环庚烷(diazepane)、二氮杂环辛烷(diazocane)、吡咯烷、哌啶、氮杂环庚烷、氮杂环辛烷、氮丙啶、氮杂环丙烯、氮杂环丁烷、吡咯啉、托烷、氧杂氮杂环己烷(oxazinane)(吗啉)、氮杂二氢吖庚因、四氢吖庚因、六氢吖庚因、氧杂氮杂环戊烷(oxazolane)、氧杂氮杂环庚烷(oxazepane)、氧杂氮杂环辛烷(oxazocane)、硫杂氮杂环戊烷(thiazolane)、硫杂氮杂环己烷(thiazinane)、硫杂氮杂环庚烷、硫杂氮杂环辛烷(thiazocane)、氧杂氮杂环丁烷(oxazetane)、二氮杂环丁烷(diazetane)、硫杂氮杂环丁烷(thiazetane)、四氢呋喃、四氢吡喃,氧杂环庚烷、四氢噻吩、四氢噻喃、硫杂环庚烷、二硫杂环己烷(dithiane)、二硫杂环庚烷(dithiepane)、二氧六环、二氧杂环庚烷(dioxepane)、氧杂硫杂环己烷(oxathiane)、氧杂硫杂环庚烷(oxathiepane)。最感兴趣的实例是四氢呋喃、四氢咪唑、哌嗪、六氢哒嗪、六氢嘧啶、二氮杂环庚烷、二氮杂环辛烷、吡咯烷、哌啶、氮杂环庚烷、氮杂环辛烷、氮杂环丁烷、托烷、氧杂氮杂环己烷(吗啉)、氧杂氮杂环戊烷、氧杂氮杂环庚烷、硫杂氮杂环戊烷、硫杂氮杂环己烷和硫杂氮杂环庚烷,特别是四氢呋喃、咪唑烷、哌嗪、六氢哒嗪、六氢嘧啶、二氮杂环庚烷、吡咯烷、哌啶、氮杂环庚烷、嗪烷(吗啉)和硫杂氮杂环己烷。
在本上下文中,即结合术语“芳基”、“杂芳基”、“杂环基”、“含有N、O的杂环或杂芳族的环”等(例如“芳氧基”、“杂芳基羰基”等),术语“任选地经取代的”意指所考虑的基团可以被取代1次或若干次,优选1-5次,特别是1-3次,所述基团选自羟基(其当存在于烯醇系统中时可以表示为互变异构体的酮的形式)、C1-6-烷基、C1-6-烷氧基、C2-6-烯氧基、氧代(其可以表示为互变异构体的烯醇形式)、氧化物(仅仅与N-氧化物相关)、羧基、C1-6-烷氧羰基、C1-6-烷基羰基、甲酰基、芳基、芳基氧基、芳基氨基、芳基氧基羰基、芳基羰基、杂芳基、杂芳基氨基、氨基、单和二(C1-6-烷基)氨基;氨基甲酰基、单和二(C1-6-烷基)氨基羰基、氨基-C1-6-烷基-氨基羰基、单和二(C1-6-烷基)氨基-C1-6-烷基-氨基羰基、C1-6-烷基羰基氨基、氰基、胍基、脲基、C1-6-烷酰氧基、C1-6-烷基-磺酰基-氨基、芳基-磺酰基-氨基、杂芳基-磺酰基-氨基、C1-6-烷基-磺酰基、C1-6-烷基-亚磺酰基、C1-6-烷基磺酰氧基、硝基、硫烷基(sulphanyl)、氨基、氨基-磺酰基、单和二(C1-6-烷基)氨基-磺酰基、二卤代-C1-4-烷基、三卤代-C1-4-烷基、卤素,其中芳基和杂芳基所表示的取代基可以经C1-4-烷基、C1-4-烷氧基、硝基、氰基、氨基或卤素取代1-3次,任何烷基、烷氧基等所表示的取代基可以经羟基、C1-6-烷氧基、C2-6-烯氧基、氨基、单和二(C1-6-烷基)氨基、羧基、C1-6-烷基羰基氨基、卤素、C1-6-烷硫基、C1-6-烷基-磺酰基-氨基或胍基取代。
典型地,所述取代基选自羟基、C1-6-烷基、C1-6-烷氧基、氧代(其可以表示为互变异构体的烯醇形式)、羧基、C1-6-烷基羰基、甲酰基、氨基、单和二(C1-6-烷基)氨基;氨基甲酰基、单和二(C1-6-烷基)氨基羰基、氨基-C1-6-烷基-氨基羰基、C1-6-烷基羰基氨基、胍基、脲基、C1-6-烷基-磺酰基-氨基、芳基-磺酰基-氨基、杂芳基-磺酰基-氨基、C1-6-烷基-磺酰基、C1-6-烷基-亚磺酰基、C1-6-烷基磺酰氧基、硫烷基、氨基、氨基-磺酰基、单和二(C1-6-烷基)氨基-磺酰基或卤素,其中任何烷基、烷氧基等所表示的取代基可以经羟基、C1-6-烷氧基、C2-6-烯氧基、氨基、单和二(C1-6-烷基)氨基、羧基、C1-6-烷基羰基氨基、卤素、C1-6-烷硫基、C1-6-烷基-磺酰基-氨基或胍基取代。在某些实施方案中,所述取代基选自C1-6-烷基、C1-6-烷氧基、氨基、单和二(C1-6-烷基)氨基、硫烷基、羧基或卤素,其中任何烷基、烷氧基等所表示的取代基可以经羟基、C1-6-烷氧基、C2-6-烯氧基、氨基、单和二(C1-6-烷基)氨基、羧基、C1-6-烷基羰基氨基、卤素、C1-6-烷硫基、C1-6-烷基-磺酰基-氨基或胍基取代。
包括C3-12-环烷基、C3-12-环烯基和/或芳基作为所述取代基的至少一部分的基团(例如R2和R3)被称为包括“碳环”。
包括杂环基或杂芳基作为所述取代基至少一部分的基团(例如R2和R3)被称为分别包括“杂环”和“杂芳族的环”。
术语“药用可接受的盐”意欲包括酸加成盐和碱式盐。酸加成盐的示例性的实例是与非毒性酸形成的药用可接受的盐。这类有机盐的实例是与马来酸、富马酸、苯甲酸、抗坏血酸、琥珀酸、草酸、双亚甲基水杨酸、甲磺酸、乙二磺酸、乙酸、丙酸、酒石酸、水杨酸、柠檬酸、葡萄糖酸、乳酸、苹果酸、杏仁酸、肉桂酸、柠康酸、天门冬氨酸、硬脂酸、棕榈酸、衣康酸、乙醇酸、对氨基苯甲酸、谷氨酸、苯磺酸和7-茶碱乙酸以及例如8-溴代茶碱的8-卤代茶碱形成的那些。这类无机盐的实例是与盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸形成的那些。碱式盐的实例是其中(残留的)反离子选自例如钠和钾的碱金属、例如钙的碱土金属和铵(+N(R)3R′,其中R和R′独立指代任选地经取代的C1-6-烷基、任选地经取代的C2-6-烯基、任选地经取代的芳基或任选地经取代的杂芳基)的盐。药用可接受的盐是,例如在Remington′s Pharmaceutical Sciences,17.Ed.Alfonso R.Gennaro(Ed.),Mack Publishing Company,Easton,PA,U.S.A.,1985以及更近的版本和Encyclopedia of Pharmaceutical Technology中描述的那些。因此,本文使用的术语“其酸加成盐或碱式盐”意欲含有这类盐。此外,化合物以及任何中间体或原料也可以在水合物形式中存在。
本文使用的术语“前药”意指暴露于生理环境中的化合物将释放衍生的所述化合物,其然后可以显示期望的生物学作用。通常的实例是不稳定的酯类(即潜在的羟基基团或潜在的酸基团)。
此外,应理解化合物可以以外消旋混合物或例如对映异构体或非对映异构体的单独的立体异构体的形式存在。本发明包括这类可能的立体异构体(例如对映异构体和非对映异构体)的各个和每个以及富含可能的立体异构体之一的外消旋体和混合物。
实施方案
在一个实施方案中,X选自=O和=S。
在关于此点的一个实施方案中,X是=O且B是-O-。在该实施方案的一个重要变体中,A是-S(=O)2-。在该实施方案的另一个重要变体中,A是-C(=O)-。
在另一个实施方案中,X是=S且B是-O-。在该实施方案的一个重要变体中,A是-S(=O)2-。在该实施方案的另一个重要变体中,A是-C(=O)-。
在另一个实施方案中,X选自=O和=S,B是单键。在该实施方案的一个重要变体中,A是-S(=O)2-。在该实施方案的另一个重要变体中,A是-C(=O)-。
在另一个实施方案中,B选自-(CH2)3-6和-O-(CH2)2-5-,优选自-(CH2)3-4-和-O-(CH2)1-3-。在该实施方案中,X优先选自=O和=S。
在上述实施方案中,D优先选自单键、-O-和-NR9。更特定的,D是单键。
关于R1,该取代基优先选自任选地经取代的吡啶-4-基、任选地经取代的嘧啶-4-基、任选地经取代的1,2,4-三嗪-3-基、任选地经取代的异唑-4-基、任选地经取代的吡嗪-2-基和任选地经取代的吡啶甲基;特别选自吡啶-4-基、嘧啶-4-基、1,2,4-三嗪-3-基、3,5-异唑-4-基、吡嗪-2-基和吡啶甲基。
R1和脲部分之间的距离取决于p。p是0-4的整数,但是优选0-2,特别是0。
在一个目前特别感兴趣的实施方案中,p是0且R1是吡啶-4-基。
在另一个特别感兴趣的实施方案中,p是1。
间隔元素的长度通过m和n定义。优选地,m是0-10的整数且n是0-10的整数,其中m+n的和是1-12;特别地m是1-8的整数且n是0-3的整数,其中m+n的和是3-8。在目前最优选的一个变体中,m是2-8的整数且n是0。
发现-除了D、A和B外-R2和R3(部分地也包括R4和R4*)对于本发明的化合物的功效发挥重要作用。因此,在一个特别感兴趣的实施方案中,R2和R3中至少一个包含碳环、杂环或杂芳环,或R2和R3与插入的原子一同形成任选地经取代的含有N的杂环或杂芳环。在该实施方案的一个特别感兴趣的变体中,R2是碳环,特别是环己基。在感兴趣的可代替的实施方案中,R2不是氢。
在关于此点的一个变体中,R2和R3与插入的原子一同形成任选地经取代的含有N、O的杂环或杂芳环。
此外,R4优先选自氢、C1-6-烷基和任选地经取代的苄基,R4*为氢。更特定地,R4和R4*优选均为氢。
在一个目前特别相关的实施方案中,
X选自=O和=S;
A选自-C(=O)-和-S(=O)2-;
B是-O-;
D选自单键、-O-和-NR9;
m是2-8的整数,n是0;
p是0-2的整数;
R2选自氢、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、-(CH2)0-2-(任选地经取代的芳基)、-(CH2)0-2-(任选地经取代的杂芳基)和-(CH2)0-2-(任选地经取代的杂环基);
R3选自任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;
R4选自氢、任选地经取代的C3-12-环烷基、-(CH2)0-2-(任选地经取代的芳基)、-(CH2)0-2-(任选地经取代的杂芳基)和-(CH2)0-2-(任选地经取代的杂环基);且
R4*为氢。
在另一个特别相关的实施方案中,
X选自=O和=S;
A选自-C(=O)-和-S(=O)2-;
B选自-(CH2)3-6-和-O-(CH2)2-5-,优选自-(CH2)3-4-和-O-(CH2)1-3-;
D选自单键、-O-和-NR9;
m是2-8的整数且n是0;
p是0-2的整数;
R2选自氢、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、-(CH2)0-2-(任选地经取代的芳基)、-(CH2)0-2-(任选地经取代的杂芳基)和-(CH2)0-2-(任选地经取代的杂环基);
R3选自任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;
R4选自氢、任选地经取代的C3-12-环烷基、-(CH2)0-2-(任选地经取代的芳基)、-(CH2)0-2-(任选地经取代的杂芳基)和-(CH2)0-2-(任选地经取代的杂环基);且
R4*为氢。
所述的目前最感兴趣的化合物是选自下列描述的化合物1001-1101的那些:
一般方法
可以使用下文概述的方法,连同有机合成有机化学领域已知的方法或那些本领域技术人员所理解的其变体合成本发明的化合物。优选的方法包括,但不限于,下文描述的那些。
可以使用在该部分描述的反应和技术制备式(I)的新化合物。该反应在适于所采用的反应物和材料且适于有效的转化的溶剂中进行。而且,在下文描述的合成方法中,应理解所有提议的反应条件,包括溶剂、反应气氛、试验过程中的反应温度和处理方法的选择选自该反应的标准条件,其应容易地被本领域技术人员识别。有机合成领域的技术人员应理解在离析分子的不同部位上存在的官能团必须与反应物和所提议的反应相容。不是所有属于特定类型的式(I)的分子都可以与在某些所述方法中需要的某些反应情况相容。这种对与反应情况相容的所述取代基的限制对于本领域技术人员将是容易而明显的,且可以使用可代替的方法。
根据本发明的是脲(Ia)的化合物(I)可以通过若干方法制备,例如通过通式(II)的胺类与1,1′-羰基二咪唑(CDI)或4-硝基苯基氯代甲酸酯反应,接着进行与通式(III)的胺类的反应。
根据本发明的是硫脲(Ib)的化合物(I)可以通过若干方法制备,例如通过胺类(III)与通式(IV)的异硫氰酸酯反应。异硫氰酸酯(IV)是商购可获得的,或可以通过通式(II)的胺类与二(2-吡啶基)硫代碳酸酯(thionocarbonate)(DPT)反应制备。
根据本发明的是烷氧基胍(Ic)的化合物(I)可以通过硫脲(Ib)转化为相应的碳二亚胺(V)而制备,例如通过与碳二亚胺(例如EDC或DCCI)或HgO反应,接着进行与O-烷氧基羟胺的反应。以类似的方式,分别用羟胺或受保护的羟胺、氨或氨的等效物代替O-烷氧基羟胺,可以制备根据本发明的是羟基胍(Id)或胍(Ie)的化合物(I)。如果采用受保护的羟胺或氨的等效物,必需有脱保护步骤。保护基团可以是例如基于四氢吡喃基(THP)、叔丁基、苄基或甲硅烷基的保护基团。
可代替地,可以将通式(Ib)的硫脲甲基化,且接着使其分别与O-甲氧基羟胺、羟胺或受保护的羟胺、氨或氨的等效物反应。如果采用受保护的羟胺或氨的等效物,必需有脱保护步骤。
根据本发明的是甲氧基胍(Ic)、羟基胍(Id)或胍(Ie)的化合物(I)也可以通过例如N-芳基磺酰基-S-甲基异硫脲、氰胺、吡唑-1-羰酰亚胺(carboximidamide)、三氟甲基磺酸胍、苯并三唑和含有咪唑的反应物制备(参见例如A.R.Katritzky等人:J.Org.Chem.(2006)71,6753-6778,且通过引用并入本文)。
通过使用肽偶联试剂(例如EDC或HATU)将通式(VII)的受保护的氨基酸(保护基团Pg例如Boc或邻苯二甲酰亚氨基)与羟胺或通式(VIII)的肼偶联,随后移除保护基团,可以制备是异羟肟酸酯、N-烷基-或N-芳基肼、N,N′-二烷基-或N,N′-二芳基肼(IIIa)的通式(III)的胺类。
在特定实例中,其中通式(IIIa)的胺类含有位于羰基基团α位的取代基,它们可以通过通式(X)的氨基酸或它们的对映异构体(根据文献例如K.S.Orwig等人:Tet.Lett.(2005)46 7007-7009的描述得到)制备,接着进行氨基基团的保护(例如用Boc、邻苯二甲酰亚氨基或其它),随后与羟胺或肼偶联,接着进行如上述描述的脱保护。
羟胺(VIII,B=O))是商购可获得的或可以通过将N-羟基邻苯二甲酰亚胺(或可代替地是叔丁基羟基氨基甲酸酯)与卤化物和碱(例如DBU)进行烷化反应或与醇(使用例如DEAD)进行三信反应,接着与肼或甲基肼进行脱保护而制备,得到羟胺(VIIIa)。当R2不是氢时,按照文献(例如B.J.Mavunkel等人:Eur.J.Med.Chem.(1994)29,659-666;T.Ishikawa等人:J.Antibiotics(2000),53(10),1071-1085;J.Ishwara Bhat等人:J.Chem.Soc.,Perkin Trans.2(2000),1435-1446)的描述,所得羟胺(VIIIa)可以与醛或酮进行还原性胺化作用,接着进行与例如氰基硼氢化钠的还原。可代替地,在用例如2-硝基苯基磺酰氯保护之后,通过三信反应或烷化反应,随后移除保护基团(使用例如苯硫酚和碳酸铯),可以实现羟胺(VIIIa)的烷化反应。
肼(VIII,B=O)是商购可获得的或可以-在R2是H的实例中-根据文献步骤(例如D.J.Drain等人:J.Med.Chem.(1963)6 63-9;G.B.Marini-Bettolo等人:Rend.Ist.Super.Sanita(1960)231110-27),在碱的存在下将水合肼通过烷化反应制备。可以如下得到N,N′-二取代肼:根据文献步骤(例如H.Dorn等人:Zeitschrift für Chemie(1972)12(4)129-30;R.L.Hinman:JACS(1957)79414-417;J.A.Blair:JCS(Section)C:Organic(1970)(12)1714-17),通过将单取代肼(VIIIa)与醛或酮反应,接着进行与例如氢、LiAlH4或硼烷的还原,或可代替地在氢化钠的存在下,通过Boc-保护水合肼,与卤代烷进行烷化反应,在氢化钠的存在下接着与另一种卤代烷进行二次烷化反应,最后移除Boc-保护基团(L.Ling等人:Bioorg.Med.Chem.Lett.(2001)(11)2715-2717)。
可以根据文献步骤(例如Thomsen等人:Org.Synth.(1984)62,158,R.A.Cherkasov等人:Tet.(1985)41,2567;M.P.Cava,M.J.Levinson Tet.(1985)41,5061),通过将相应的羰基化合物(IIIa)用拉韦松试剂处理,制备通式(III)的胺类,所述胺类是N-烷氧基-或N-芳基氧基硫代酰胺,或硫代肼(IIIb)。
可代替地,根据文献步骤(M.A:Shalaby等人:J.Org.Chem.(1996)61 9045-48),通式(VII)的受保护的氨基酸(保护基团例如Boc或邻苯二甲酰亚氨基)可以转化为通式(XI)的活化的物质,接着能够与通式(VIII)的羟胺或肼反应,接着进行脱保护,得到通式(IIIb)的胺类。
在碱(例如三乙胺或N-甲基吗啉)的存在下,通过邻苯二甲酰亚氨基链烷磺酰氯(XII)(根据文献,例如G.J.Atwell等人:J.Med.Chem.(1977)20(9)1128-134;J.Humljan等人i:Tet.Letters,464069-4072的描述制备)分别与羟胺、胺或肼(VIII)反应,接着与水合肼进行脱保护,可以得到通式(III)的胺类,所述胺类是N-烷氧基或N-芳氧基磺酰胺、磺酰胺或磺酰肼(IIIc)。可以使用除邻苯二甲酰亚氨基之外的其它保护基团。
在碱的存在下通过邻苯二甲酰亚氨基保护的膦酰氯(XIII)(根据文献,例如S.Gobec等人:Tet.Lett.(2002)43167-170;U.Urleb等人:Lett.In Peptide Science(1995)2 193-197的描述制备)分别与羟胺、胺类或肼(VIII)反应,接着与水合肼进行脱保护,可以得到通式(III)的胺类,其是N-烷氧基-P-烷基氨基磷酸酯或N-芳氧基-P-烷基氨基磷酸酯、P-烷基氨基磷酸酯或P-烷基膦酰肼(IIId)。可以采用除邻苯二甲酰亚氨基之外的其它保护基团。
通过在碱的存在下邻苯二甲酰亚氨基保护的烷基次膦酰氯(XIV)(例如S.Gobec等人:Lett.In Peptide Science(1998)5 109-114)分别与羟胺、胺类或肼(VIII)反应,接着与水合肼进行脱保护,可以得到通式(III)的胺类,所述胺类是N-烷氧基-P-烷基次膦酰胺或N-芳氧基-P-烷基次膦酰胺、P-烷基次膦酰胺或P-烷基次膦酰肼(IIIe)。可以采用除邻苯二甲酰亚氨基之外的其它保护基团。
根据已知文献步骤(例如B.等人:J.Med.&Pharm.Chem.(1962)5 231-9;R.Tull等人JCS Section C:Organic(1967)(8)701-2;B.Loev:J.Med.Chem.(1963)6(5)506-8;D.R.Cassady等人:J.Org.Chem.(1958)23 923-6;D.Freitag:Tetrahedron(2005)61 5615-21;Y.Kanbe等人:Bioorg.Med.Chem.Lett.(2006)164090-94;I.Ubarretxena-Belandia等人:Eur.J.Biochem.(1999)260 794-800;B.D.Roth等人:Bioorg.Med.Chem.Lett.(1995)5(20)2367-70),例如通过适当地保护的氨基链烷磺酰氯(XII)与氨的等效物或胺反应,接着在碱的存在下进行与烷基氯代甲酸酯的反应,得到通式(XVI)的氨基甲酸酯,其接着能够与胺类R3R6NH2反应,得到通式(XVII)的磺酰脲,可以制备是磺酰脲(IIIf)的通式(III)的胺类。可代替地,通式(XV)的磺酰胺可以直接与异氰酸酯反应,得到受保护的磺酰脲(XVIIa)。接着移除保护基团(例如邻苯二甲酰亚氨基、Boc或其它)。
如下文描述,通过受保护的氨基烷基4-硝基苯基碳酸酯(XVIII)(保护基团例如Boc或邻苯二甲酰亚氨基)与羟胺或肼(VIII)反应,接着进行脱保护,可以得到通式(III)的胺类,所述胺类是N-烷氧基-或N-芳氧基氨基甲酸酯或烷基-或芳基肼羧酸酯(Ig)。
通过对于本领域技术人员已知的用于制备脲的方法,可以制备通式(III)的胺类,所述胺类是N-烷氧基-、N-芳氧基脲、烷基-或芳基肼甲酰胺(IIIh)。一种该方法是,如下文描述,受保护的4-硝基苯基氨基烷基氨基甲酸酯(XX)(保护基团例如Boc或邻苯二甲酰亚氨基)与羟胺或肼(VIII)反应,接着进行脱保护。
作为4-硝基苯基氨基烷基氨基甲酸酯(XX)的代替物,可以采用N-(氨基烷基)-1H-咪唑-1-甲酰胺(XXII)。
医学用途
相信本发明的化合物特别适用于通过抑制NAMPRT下调NAD,因此这类化合物特别适用于治疗涉及NF-κB的激活的疾病。这种方法适用于治疗多种疾病,所述疾病包括炎症性障碍和组织修复障碍;特别是类风湿性关节炎、炎症性肠病、哮喘和CPOD(慢性阻塞性肺病)、骨关节炎、骨质疏松和纤维化病;皮肤病,所述皮肤病包括银屑病、特应性皮炎和紫外线导致的皮肤损伤;自身免疫疾病,所述疾病包括系统性红斑狼疮、多发性硬化、银屑病性关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏病、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,特别地癌症选自乳腺癌、前列腺癌、肺癌、结肠癌、子宫颈癌、卵巢癌、皮肤癌、CNS的癌症、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金氏病、恶病质、与感染和某些病毒感染相关的炎症,包括获得性免疫缺陷综合征(AIDS)、成人呼吸窘迫综合征、毛细血管扩张性运动失调。
因此,本发明提供了用作药物的式(I)的化合物;更特定地是用作用于治疗由烟酰胺磷酸核糖基转移酶(NAMPRT)的水平升高引起的疾病或病况的药物,特别是用于治疗上述提及的疾病和病况的药物。
此外,本发明也提供了在哺乳动物中抑制烟酰胺磷酸核糖基转移酶(NAMPRT)的酶促活性的方法,所述方法包括给予所述哺乳动物药学相关量的通式(I)的化合物的步骤。
此外,本发明提供了治疗在哺乳动物中由烟酰胺磷酸核糖基转移酶(NAMPRT)的水平升高引起的疾病或病况(特别是上述提及的疾病和病况)的方法,所述方法包括给予所述哺乳动物药学相关量的通式(I)的化合物的步骤。
在该方法中,化合物可以与DNA损伤剂组合给予。
药物组合物的配制
将通式(I)的化合物适当地配制在药物组合物中以适于期望的给药途径。
化合物的给药途径可以是任何适合的途径,所述途径导致在血液或组织中相应于治疗有效浓度的浓度。因此,例如,下列给药途径可以是适用的,尽管本发明不限于此:口服途径、肠胃外途径、皮肤途径、鼻途径、直肠途径、阴道途径和眼途径。本领域技术人员应清楚给药途径取决于所讨论的特定的化合物;特别是给药途径的选择取决于化合物的物理化学性质以及患者的年龄和重量和特定的疾病或病况和所述疾病或病况的严重性。
化合物可以以任何适当的量包含在药物组合物中,且通常包含在占组合物总重的约1-95重量%的量中,例如1-10重量%。组合物可以存在于适于口服、肠胃外、直肠、皮肤、鼻、阴道和/或眼给药途径的剂型中。因此,组合物可以在如下形式中:例如,片剂、胶囊、丸剂、粉剂、颗粒剂、混悬剂、乳剂、溶液、包括水凝胶的凝胶剂、糊剂、软膏、乳膏、硬膏剂、浸液(drench)、递送装置、栓剂、灌肠剂、注射剂、植入剂、喷雾剂、气雾剂和其它适合的形式。
可以根据常规药学实践配制药物组合物,参见,例如,Swarbrick,J.& J.C.Boylan,Marcel Dekker,Inc.编辑的“Remington′s Pharmaceutical Sciences”和“Encyclopedia of Pharmaceutical Technology”,New York,1988。典型地,采用(至少)一种药用可接受的载体或赋形剂配制在此定义的化合物。药用可接受的载体或赋形剂是本领域技术人员已知的那些。根据之前所述,式(I)的化合物适合的盐的形成也将是显而易见的。
因此,在另外的方面本发明提供了包含通式(I)的化合物与药用可接受的载体组合的药物组合物。
根据本发明的药物组合物可以配制为在给药后基本上立即或在给药之后的任何基本上预定的时间或时段释放活性化合物。后者类型的组合物通常已知作为控释配制剂。
在本上下文中,术语“控释配制剂”包括i)在持续的时段在体内产生基本上恒定的药物浓度的配制剂,ii)在持续的时段在体内在预定的延滞时间之后产生基本上恒定的药物浓度的配制剂,iii)在预定的时段,通过在体内维持相对恒定的有效药物水平以维持药物作用,同时将与活性药物物质的血浆水平的波动(锯齿状动力图)相关的不期望的副作用最小化的配制剂,iv)试图通过,例如,与患病组织或器官相邻或在患病组织或器官中的控释组合物的空间放置定位药物作用的配制剂,v)试图通过使用载体或化学衍生物递送药物至特定的靶细胞类型从而靶向药物作用的配制剂。
控释配制剂也可以指“持续释放”、“延长释放”、“程序化释放”、“定时释放”、“控制速率”和/或“靶向释放”的配制剂。
控释药物组合物可以存在于适合的剂型中,特别是在意欲用于口服、肠胃外、皮肤、鼻、直肠、阴道和/或眼给药的剂型中。实例包括单个或多个单位的片剂或胶囊组合物、油溶液剂、混悬剂、乳剂、微囊、微球、纳米粒、脂质体、递送装置,例如意欲用于口服、肠胃外、皮肤、鼻,阴道或眼使用的那些递送装置。
用于口服使用、控释口服剂型、液体组合物、肠胃外组合物、控释肠胃外组合物、直肠组合物、鼻组合物、经皮和局部组合物、控释经皮和局部组合物和用于眼部给药的组合物的固体剂型的制备对于那些药学配制领域的技术人员将是众所周知的。特定配制剂可以参见“Remington′s Pharmaceutical Sciences”。
胶囊、片剂和丸剂等可以含有例如下列化合物:作为粘合剂的微晶纤维素、树胶或明胶;作为赋形剂的淀粉或乳糖;作为润滑剂的硬脂酸盐;多种甜味剂或矫味剂。对于胶囊,剂量单元可以含有例如脂肪油的液体载体。同样地糖包衣或肠包衣的制剂可以是剂量单元的一部分。药物组合物也可以是化合物和脂质形成胶束乳液(micellular emulsion)的乳剂。
对于肠胃外、皮下、皮内或局部给药,药物组合物可以包括无菌的稀释剂、缓冲剂、张度调节剂和抗菌剂。可以用防止降解或立即从体内消除的载体制备活性化合物,所述载体包括具有控释性质的植入体或微囊。对于静脉内给药,优选的载体是生理盐水或磷酸缓冲盐水。
剂量
在一个实施方案中,药物组合物在单位剂型中。在这类实施方案中,各单位剂型典型地包含0.1-500mg,例如0.1-200mg,例如0.1-100mg的化合物。
更通常地,化合物优选以每kg体重每天约0.1-250mg的量给予,例如每kg体重每天约0.5-100mg。
对于适于口服给药全身使用的组合物,根据被治疗的疾病,剂量通常是每剂量0.5mg至1g,每日给予1-4次,给予1周至12个月。
对于口服给药以预防疾病或病况的组合物,剂量通常是每kg体重每天1mg至100mg。剂量可以在暴露至疾病之前1周开始直到暴露之后4周的时间段每日给予1次或2次。
对于适于直肠给药用于预防疾病的组合物,通常优选稍高量的化合物,即每kg体重每天大约1mg至100mg。
对于肠胃外给药,每kg体重每天约0.1mg至约100mg的剂量是方便的。对于静脉内给药,每kg体重每天约0.1mg至约20mg的给予1天至3个月的剂量是方便的。对于关节内给药,每kg体重每天约0.1mg至约50mg的剂量是通常优选的。对于通常的肠胃外给药,可以采用在水性介质中0.5-2%或更多的活性成分的溶液。
对于皮肤局部给药,每日给予1-10次的约1mg至约5g的给予1周至12个月的剂量是通常优选的。
实施例
一般步骤,制备物和实例
对于核磁共振,引用1H NMR光谱(300MHz)和13C NMR(75.6)化学位移值(δ)(ppm),除非另有说明,其中氘代氯仿溶液相对于四甲基硅烷(δ=0.0)、氯仿(δ=7.25)或氘代氯仿(13C NMR δ=76.81)标准。给出定义(双峰(d)、三重峰(t)、双二重峰(dd)、双三重峰(dt)、四重峰(q)),或不定义(m)在大约中点的多重峰值,除非引用了范围。(bs)意指宽单峰。
使用Bruker Esquire 3000+ESI Iontrap的LC-MS,采用Agilent1200 HPLC系统,进行MS。
使用X-Btidge Prep C18 OBD 19x150mm柱,使用缓冲剂A(在H2O中0.1%TFA)和缓冲剂B(在乙腈中0.1%TFA)的梯度,进行HPLC纯化。
使用的有机溶剂是无水的。
下列缩略语已被贯穿全文使用:
一般方法1:通式(II)的胺类与CDI反应,接着进行与通式(III)的胺类的反应,得到通式(Ia)的脲。
将通式(II)的胺(1.0当量)加入至CDI(1.1当量)在THF中的溶液中,将混合物在RT搅拌过夜。将通式(III)的胺(1.0当量)加入至反应混合物,将反应在RT搅拌过夜。在真空中蒸去溶剂,通过色谱法(氯仿∶甲醇∶NH3(25%水溶液)96∶4∶0.4或MeCN-H2O-AcOH 3∶1∶1)纯化残余物,得到通式(Ia)的脲。
通过将通式(Ia)的化合物(1当量)溶解在MeCN中和加入草酸(2当量)在MeCN中的溶液可以得到通式(Ia)的脲的草酸盐。将沉淀过滤和干燥,得到通式(Ia)的脲的草酸盐。
通过将通式(Ia)的化合物(1当量)溶解在1N HCl/MeOH(2当量)中可以得到通式(Ia)的脲的HCl-盐,蒸去溶剂,将残余物用DCM洗涤,接着用Et2O洗涤,干燥,得到通式(Ia)的脲的HCl-盐。
一般方法2:通式(II)的胺类与4-硝基苯基氯代甲酸酯反应,接着进行与通式(III)的胺类的反应,得到通式(Ia)的脲。
将通式(II)的胺(1.0当量)溶解在EtOAc中,加入DIEA(1.2当量),将混合物在冰浴上冷却,加入4-硝基苯基氯代甲酸酯(1.1当量)并搅拌。在4小时(或胺(II)消耗完)之后,将反应混合物连续用5%Na2CO3(2次)、H2O、盐水洗涤,用Mg2SO4干燥,过滤和浓缩。将所得4-硝基苯基氨基甲酸酯(1.0当量)溶解在DMF中,加入通式(III)的胺(1.0当量),接着加入HOBT(2.0eq)和DI EA(0.5当量),在40℃加热过夜。将混合物浓缩,通过色谱法(氯仿∶甲醇∶NH3(25%水溶液)98∶2∶0.2至96∶4∶0.4)纯化以提供通式(Ia)的脲。
通过将通式(Ia)的化合物(1当量)溶解在MeCN中,加入草酸(2当量)在MeCN中的溶液,可以得到通式(Ia)的脲的草酸盐。将沉淀过滤和干燥,得到通式(Ia)的脲的草酸盐。
一般方法3:通式(II)的胺类与DPT反应,接着进行与通式(III)的胺类的反应,得到通式(Ib)的硫脲
将通式(II)的胺(1.0当量)溶解在THF中,将反应混合物在冰浴上冷却,边搅拌边加入NaH(1.1当量)。在2h之后,加入DPT(1.0当量),使混合物逐渐达到rt。在另外3h(或原料消耗完)之后,将所得异硫氰酸酯通过色谱法(石油醚和ETOAc的混合物)纯化或直接使用。
将通式(III)的胺(1.0当量)和DIEA(1.1当量)加入至异硫氰酸酯(1.0当量)在THF中的溶液中,将混合物在RT搅拌过夜,浓缩,通过色谱法(在DCM中1-5%甲醇)纯化以提供通式(Ib)的硫脲。
通过将通式(Ib)的化合物(1当量)溶解在MeCN中和加入草酸(2当量)在MeCN中的溶液可以得到通式(Ib)的硫脲的草酸盐。将沉淀过滤和干燥,得到通式(Ib)的脲的草酸盐。
一般方法4:通式(XX)的4-硝基苯氧基氨基甲酸酯与羟胺或肼(VIII)反应,随后脱保护。
将通式(XX)的4-硝基苯氧基氨基甲酸酯(1.0当量)溶解在DMF中,加入羟胺或肼(2.0当量)、HOBt(2当量)和DIEA(0.5当量,或如果羟胺或肼是盐时1.5当量),将混合物加热至500℃,搅拌4h或直到氨基甲酸酯消耗完。将混合物浓缩,通过色谱法(含1-5%MeOH的DCM)纯化。将所得Boc-保护的通式(XXIa)的化合物溶解在MeOH中,加入含3N HC1的MeOH并搅拌。在2h之后,将混合物浓缩,化合物作为HCl-盐直接使用,或通过色谱法(氯仿∶甲醇∶NH3(25%水溶液)95∶5∶1)纯化以提供通式(IIIh)的化合物。
一般方法5:通过邻苯二甲酰亚氨基链烷磺酰氯(XII)与羟胺、胺类或肼(VIII)反应,随后脱保护,制备通式(IIIc)的胺类。
在-20℃边搅拌边将邻苯二甲酰亚氨基烷磺酰氯(XII)(1.0当量)(按照文献,例如G.J.Atwell等人i:J.Med.Chem.(1977)20(9)1128-134;J.Humljan等人:Tet.Letters,464069-4072的描述制备)少量分次加入至羟胺、胺或肼(VIII)(1.02当量)和三乙胺或N-甲基吗啉(1.1当量,或如果羟胺或胺是盐时2.2当量)在DCM中的溶液中。使混合物逐渐达到rt,搅拌过夜,浓缩。通过色谱法(在DCM中1%的甲醇或石油醚和EtOAc的混合物)纯化,得到邻苯二甲酰亚氨基-保护的中间体。
脱保护:将邻苯二甲酰亚氨基保护的中间体(1.0当量)溶解在乙醇中,加入水合肼(2.9当量),将混合物在微波炉中在120℃加热直到原料消耗完(典型地10-30min)。将混合物过滤,用乙醇洗涤滤饼,浓缩滤液,通过色谱法(氯仿∶甲醇∶NH3(25%水溶液)98∶2∶02或90∶10∶1)纯化以提供通式(IIIc)的胺类。
制备1:叔丁基5-((4-硝基苯氧基)羰基氨基)戊基氨基甲酸酯(化合物1)。
将叔丁基5-氨基戊基氨基甲酸酯(2.02g,10mmol)溶解在EtOAc中,加入4-硝基苯基碳酰氯(2.22g,11mmol),将混合物在冰浴上冷却,边搅拌边加入DIEA(2.05mL,12mmol),使混合物逐渐达到rt,搅拌3小时。将混合物转移至含有EtOAc和H2O的分液漏斗中,振摇。将有机相用1N HCl、H2O、5%Na2CO3、H2O(3次)、盐水萃取,用Mg2SO4干燥,过滤和浓缩,得到化合物9。
1H-NMR(CDCl3):δ8.24(m,2H),7.39(m,2H),5.32(bs,1H),4.56(bs,1H),3.29(q,2H),3.14(m,2H),1.7-1.3(m,6H),1.44(s,9H)。
制备2:N-(5-氨基戊基)吗啉-2-甲酰胺盐酸盐(化合物2)。
1H-NMR(CD3OD):δ3.94(m,2H),3.52(m,2H),3.17(t,2H),2.90(t,2H),1.75-1.60(m,6H),1.54(m,2H),1.39(m,2H)。
制备3:3-(5-氨基戊基)-1-环己基-1-(2-吗啉基乙氧基)脲二盐酸盐(化合物3)。
一般方法4。原料:化合物1和N-环己基-O-(2-吗啉基乙基羟胺(参见,例如,WO 2009/086835)。
1H-NMR(DMSO-d6):δ11.44(bs,1H),7.97(bs,3H),4.22(t,2H),4.09(t,2H),3.97(m,2H),3.83(m,2H),3.72(m,1H),3.40(m,4H),3.14(m,2H),2.77(m,2H),1.8-1.0(m,16)。
制备4:3-(5-氨基戊基)-1-异丙基-1-(2-吗啉基乙氧基)脲二盐酸盐(化合物4)。
一般方法4。原料:化合物1和N-异丙基-O-(2-吗啉基乙基羟胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ4.28(t,2H),4.20(m,1H),4.09(m,2H),3.95(m,2H),3.56(m,4H),3.26(m,4H),2.95(t,2H),1.71(m,2H),1.63(m,2H),1.45(m,2H),1.23(d,6H)。
实施例
实施例1:N-(环己基甲氧基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1001)。
一般方法1。原料:4-氨基吡啶和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),3.75(d,2H),3.22(m,4H),1.9-1.15(m,17H),0.99(m,2H)。
实施例2:N-环己基-N-(2-吗啉基乙氧基)-7-(3-吡啶-4-基脲基)庚酰胺(化合物1002)。
一般方法1。原料:4-氨基吡啶和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
MS[M+H]+=476.3,[M-H]-=574.3.3,[M-H+HCOOH]-=520.5。
实施例3:N-(环己基甲氧基)-6-(3-嘧啶-4-基硫脲基)己烷-1-磺酰胺(化合物1003)。
一般方法3.原料:4-氨基嘧啶和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
MS[M+H]+=430.2,[M-H]-=528.3。
实施例4:N-(环己基甲氧基)-6-(3-(吡啶-4-基甲基)脲基)己烷-1-磺酰胺(化合物1004)。
一般方法2。原料:4-吡啶甲基胺和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):8.47(m,2H),7.36(m,2H),4.39(s,2H),3.75(d,2H),3.16(m,4H),1.9-1.15(m,17H),1.00(m,2H)。
实施例5:N-环己基-N-(2-吗啉基乙氧基)-6-(3-吡啶-4-基硫脲基)己烷-1-磺酰胺草酸盐(化合物1005)。
一般方法3。原料:4-氨基吡啶和6-氨基-N-环己基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(200MHz)(DMSO-d6:10.99(b s,1H),9.21(t,1H),8.44(d,2H),7.88(d,2H),4.11(t,2H),3.74-3.60(m,4H),3.58-3.39(m,3H),3.42(t,2H),2.90(t,2H),2.83-2.67(m,4H),1.96-1.65(m,5H),1.90-1.65(13H)。
实施例6:N-环己基-N-(2-吗啉基乙氧基)-7-(3-嘧啶-4-基硫脲基)庚酰胺(化合物1006)。
一般方法3。原料:4-氨基嘧啶和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.79(bs,1H),8.48(m,1H),7.01(m,1H),4.10(m,1H),4.08(t,2H),3.71(m,6H),2.67(t,2H),2.56(m,4H),2.51(t,2H),1.95-1.05(m,18H)。
实施例7:1-(6-(吗啉代磺酰基)己基)-3-(吡啶-4-基)脲盐酸盐(化合物1007)。
一般方法1。原料:4-氨基吡啶和6-(吗啉代磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(200MHz)(DMSO-d6):δ14.36(bs,1H),10.85(bs,1H),8.51(d,2H),7.84(d,2H),7.22(b s,1H),4.03(t,2H),3.02-3.44(m,6H),1.90-1.54(m,6H),1.54-1.21(m,6H)。
实施例8:N-环己基-N-(2-吗啉基乙氧基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺草酸盐(化合物1008)。
一般方法1。原料:4-氨基吡啶和6-氨基-N-环己基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(200MHz)(DMSO-d6):10.25-9.50(bs,1H),8.36bs,2H),7.56(bs,2H),7.23-6.78(m,1H),4.40-3.92(m,6H),3.40-3.70(m,3H),3.35-2.97(m,4H),2.80-2.59(m,4H),2.00-1.64(m,5H),1.64-0.91(m,13H)。
实施例9:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(吡啶-3-基甲基)脲基)庚酰胺(化合物1009)。
一般方法2。原料:3-吡啶甲基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.50(d,1H),8.43(dd,1H),7.80(dt,1H),7.41(m,1H),4.37(s,2H),4.14(bs,1H),4.08(t,2H),3.72(m,4H),3.15(t,2H),2.68(t,2H),2.56(m,4H),2.49(t,2H),1.95-1.1(18H)。
实施例10:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(吡啶-4-基甲基)脲基)庚酰胺(化合物1010)。
一般方法2。原料:4-吡啶甲基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.47(m,2H),7.36(m,mH),4.379(s,2H),4.14(bs,1H),4.08(t,2H),3.72(m,4H),3.16(t,2H),2.67(t,2H),2.56(m,4H),2.50(t,2H),1.95-1.05(18H)。
实施例11:6-(3-1,2,4-三嗪-3-基硫脲基)-N-(环己基甲氧基)己烷-1-磺酰胺(化合物1011)。
一般方法3。原料:1,2,4-三嗪-3-胺和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(DMSO-d6):δ11.12(bs,1H),10.96(t,1H),9.97(bs,1H),9.08(d,1H),8.72(d,1H),3.65(m,4H),3.12(m,2H),1.65(m,10H),1.41(m,4H),1.16(m,3H),0.90(m,2H)。
实施例12:7-(3-1,2,4-三嗪-3-基硫脲基)-N-环己基)-N-(2-吗啉基乙氧基)庚酰胺(化合物1012)。
一般方法3。原料:1,2,4-三嗪-3-胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.98(d,2H),8.63(d,2H),4.14(bs,1H),3.76(t,2),3.72(m,4H),2.68(t,2H),2.57(m,4H),2.51(m,2H),1.9-1.25(m,17H),1.20(m,1H)。
实施例13:N-(环己基甲氧基)-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1013)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(环己基甲氧基)-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
13C-NMR(CD3OD):δ160.99,148.94,148.38,137.47,125.26,83.80,73.00,71.59,71.42,71.38,68.74,59.14,53.53、46.11,42.18,40.92、38.37,31.04,29.29,27.56,27.39,26.88,23.53。
实施例14:N-(环己基甲氧基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1014)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(b s,1H),8.43(d,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.75(d,2H),3.16(m,4H),1.85-1.1(m,17),1.00(m,2H)。
实施例15:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(吡啶-3-基甲基)硫脲基)庚酰胺(化合物1015)。
一般方法3。原料:3-吡啶甲基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.52(bs,1H),8.43(d,1H),7.85(m,1H),7.42(m,1H),4.82(s,2H),4.13(bs,1H),4.08(t,2H),3.72(m,4H),3.46(m,2H),2.68(m,2H),2.56(m,4H),2.49(t,2H),1.95-1.1(m,18H)。
1H-NMR(DMSO-d6):δ9.96(s,1H),8.67(bs,1H),7.74(bs,1H),3.66(d,2H),3.42(m,2H),3.11(m,2H),2.21(s,3H),2.06(s,3H),1.80-0.8(m,19)。
1H-NMR(DMSO-d6):δ8.65(b s,1H),7.73(bs,1H),4.03(bs,1H),3.95(t,2H),3.57(m,4H),3.40(m,2H),2.53(m,2H),2.43(m,4H),2.39(t,2H),2.21(s,3H),2.05(s,3H),1.8-1.1(m,18H)。
实施例18:1-(6-吗啉基磺酰基)己基)-3-(吡啶-3-基甲基)脲盐酸盐(化合物1018)。
一般方法1。原料:3-吡啶甲基胺和6-(吗啉代磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz)(DMSO-d6):δ8.75-8.67(m,2H),8.27(m,1H),7.88(m,1H),6.59(bs,1H),6.22(bs,1H),4.34(s,2H),4.03(t,2H),3.27(m,2H),3.18(m,2H),2.98(t,2H),1.79(m,2H),1.69(m,2H),1.61(m,2H),1.44-1.31(m,4H),1.20-1.31(m,2H)。
实施例19:N-(环己基甲氧基)-6-(3-吡嗪-2-基硫脲基)己烷-1-磺酰胺(化合物1019)。
一般方法3。原料:吡嗪-2-胺和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.38(d,1H),8.24(m,1H),8.19(d,1H),3.74(m,4H),3.20(m,2H),1.9-1.4(m,13),1.26(m,4H),0.99(m,2H)。
实施例20:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(2-吡啶-3-基)乙基)脲基)庚酰胺(化合物1020)。
一般方法2。原料:2-(吡啶-3-基)乙胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.42(d,1H),8.40(dd,1H),7.75(dt,1H),7.39(m,1H),4.15(bs,1H),4.08(t,2H),3.72(m,4H),3.39(t,2H),3.10(t,2H),2.83(t,2H),2.67(m,2H),2.56(m,4H),2.49(t,2H),1.95-1.05(m,18H)。
实施例21:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(2-吡啶-4-基)乙基)脲基)庚酰胺(化合物1021)。
一般方法2。原料:2-(吡啶-4-基)乙胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.44(m,2H),7.33(m,2H),4.15(bs,1H),4.08(t,2H),3.72(m,4H),3.42(t,2H),3.10(t,2H),2.85(t,2H),2.67(m,2H),2.56(m,4H),2.49(t,2H),1.95-1.25(m,17H),1.10(m,1H)。
实施例22:N-异丙基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1022)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-异丙基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.18(t,2H),3.98(m,1H),3.71(m,4H),3.22(m,2H),3.16(t,2H),2.66(m,2H),2.55(m,4H),1.87(m,2H),1.51(m,4H),1.41(m,2H),1.29(d,6H)。
实施例23:N-(5-(3-(吡啶-3-基甲基)脲基)戊基)吗啉-2-甲酰胺(化合物1023)。
一般方法2。原料:3-吡啶甲基胺和化合物2。
1H-NMR(CD3OD):δ8.50(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),6.98(t,1H),4.37(s,2H),3.97(m,2H),3.55(m,2H),3.16(m,4H),1.73(m,4H),1.53(m,4H),1.37(m,2H)。
实施例24:N-(5-(3-吡啶-4-基脲基)戊基)吗啉-2-甲酰胺(化合物1024)。
一般方法1。原料4-氨基吡啶和化合物2。
1H-NMR(CD3OD):δ8.28(m,2H),7.47(m,2H),3.96(t,2H),3.55(t,2H),3.22(m,4H),1.72(m,4H),1.57(m,4H),(m,2H)。
实施例25:N-环己基-N-(3-吗啉基丙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1025)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环己基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.50(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),3.71(m,4H),3.52(m,1H),3.24(m,2H),3.15(t,2H),3.02(m,2H),2.49(m,4H),2.40(t,2H),1.9-1.25(m,19H),1.18(m,1H)。
实施例26:N-环己基-N-(3-吗啉基丙基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1026)。
一般方法1。原料:4-氨基吡啶和6-氨基-N-环己基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),3.70(m,4H),3.51(m,1H),3.23(m,4H),3.03(m,2H),2.47(m,4H),2.37(t,2H),1.82(m,8H),1.7-1.25(m,11H),1.17(m,1H)。
实施例27:N-环己基-N-(2-吗啉基乙氧基)-7-(3-吡嗪-2-基硫脲基)庚酰胺(化合物10127)。
一般方法3。原料:吡嗪-2-胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.38(d,1H),8.23(dd,1H),8.20(d,1H),4.14(b s,1H),4.07(t,2H),3.71(m,6H),2.67(t,2H),2.55(m,4H),2.51(t,2H),1.9-1.25(m,17H),1.20(m,1H)。
实施例28:N-(环己基甲氧基)-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)-6-(3-(吡啶-3-基甲基)硫脲基)己烷-1-磺酰胺(化合物1028)。
一般方法3。原料:3-吡啶甲基胺和6-氨基-N-(环己基甲氧基)-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.53(d,1H),8.44(dd,1H),7.85(dt,1H),7.42(m,1H),4.82(s,2H),3.87(d,2H),3.72(t,2H),3.66(m,6H),3.6-3.4(m,6H),3.37(s,3H),3.18(m,2H),1.87(m,2H),1.85-1.15(m,15H),1.05(m,2H)。
实施例29:N-(环己基甲氧基)-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1029)。
一般方法1。原料:4-氨基吡啶和6-氨基-N-(环己基甲氧基)-N-(2-(2-(2-甲氧基乙氧基)乙氧基)乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),3.87(d,2H),3.72(t,2H),3.66(m,6H),3.55(m,2H),3.44(t,2H),3.37(s,3H),3.21(m,4H),1.89(m,2H),1.8-1.1(m,15H),1.04(m,2H)。
实施例30:N-(环己基甲氧基)-N-(2-吗啉基乙基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1030)。
一般方法1。原料:4-氨基吡啶和6-氨基-N-(环己基甲氧基)-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),3.89(d,2H),3.71(m,4H),3.42(t,2H),3.22(m,4H),2.67(t,2H),2.53(m,4H),1.95-1.15(m,17),1.05(m,2H)。
实施例31:N-(环己基甲氧基)-N-(2-吗啉基乙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1031)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(环己基甲氧基)-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.90(d,2H),3.71(m,4H),3.42(t,2H),3.16(m,4H),2.68(t,2H),2.54(m,4H),1.87(m,2H),1.83-1.58(m,6H),1.52(m,4H),1.39(m,2H),1.26(m,3H),1.06(m,2H)。
实施例32:N-(环己基甲氧基)-N-(2-吗啉基乙基)-6-(3-(2-(吡啶-3-基)乙基)脲基)己烷-1-磺酰胺(化合物1032)。
一般方法2。原料:2-(吡啶-3-基)乙胺和6-氨基-N-(环己基甲氧基)-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.42(d,1H),8.40(dd,1H),7.75(dt,1H),7.39(m,1H),3.90(d,2H),3.71(m,4H),3.39(m,4H),3.19(m,2H),3.11(t,2H),2.84(t,2H),2.68(t,2H),2.53(m,4H),1.87(m,2H),1.85-1.1(m,15H),1.05(m,2H)。
实施例33:N-(环己基甲氧基)-6-(3-(2-(吡啶-3-基)乙基)脲基)己烷-1-磺酰胺(化合物1033)。
一般方法2。原料:2-(吡啶-3-基)乙胺和6-氨基-N-(环己基甲氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.41(m,2H),7.75(m,1H),7.39(m,1H),3.75(d,2H),3.39(t,2H),3.18(m,2H),3.10(t,2H),2.84(t,2H),1.85-1.1(m,17H),1.0(m,2H)。
实施例34:N-环己基-N-(2-吗啉基乙氧基)-5-(3-吡啶-4-基脲基)戊烷-1-磺酰胺(化合物1034)。
一般方法1。原料:4-氨基吡啶和5-氨基-N-环己基-N-(2-吗啉基乙氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),4.16(m,2H),3.70(m,4H),3.56(m,1H),3.24(m,4H),2.64(t,2H),2.54(m,4H),2.00-1.05(m,16H)。
实施例35:N-环己基-N-(2-吗啉基乙氧基)-7-(3-吡啶-4-基脲基)庚烷-1-磺酰胺(化合物1035)。
一般方法1。原料:4-氨基吡啶和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),4.16(m,2H),3.71(m,4H),3.58(m,1H),3.19(m,4H),2.65(t,2H),2.55(m,4H),2.00-1.05(m,20H)。
实施例36:N-(环己基甲氧基)-6-(3-嘧啶-4-基脲基)己烷-1-磺酰胺(化合物1036)。
将化合物1003(225mg,0.52mmol)溶解在DCM中,加入EDC(301mg,1.56mmol),将混合物加热,在45℃搅拌过夜。加入少量水,将混合物浓缩,通过色谱法(在DCM中1-5%的甲醇)纯化残余物,得到化合物1036。
1H-NMR(CDCl3):δ9.55(b s,1H),9.04(t,1H),8.75(m,1H),8.42(d,1H),7.76(s,1H),6.89(m,1H),3.79(d,2H),3.38(m,2H),3.20(m,2H),1.83(m,2H),1.75-1.05(m,15H),0.93(m,2H)。
实施例37:1-环己基-1-(2-吗啉基乙氧基)-3-(5-(3-(吡啶-3-基甲基)脲基)戊基)脲(化合物1037)。
一般方法2。原料:3-吡啶甲基胺和化合物3。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.98(t,2H),3.82(m,1H),3.76(m,4H),3.22(t,2H),3.14(t,2H),2.83(t,2H),2.77(m,4H),1.9-1.45(m,11),1.36(m,4H),1.15(m,1H)。
实施例38:1-环己基-1-(2-吗啉基乙氧基)-3-(5-(3-(2-(吡啶-3-基)乙基)脲基)戊基)脲(化合物1038)。
一般方法2。原料:2-(吡啶-3-基)乙胺和化合物3。
1H-NMR(CD3OD):δ8.42(d,1H),8.40(dd,1H),7.76(dt,1H),7.40(m,1H),3.96(t,2H),3.85(m,1H),3.74(m,4H),3.39(t,2H),3.23(t,2H),3.10(t,2H),2.84(t,2H),2.62(t,2H),2.58(m,4H),1.9-1.05(m,16)。
实施例39:N-环己基-N-(2-吗啉基乙氧基)-7-(3-嘧啶-4-基脲基)庚酰胺(化合物1039)。
将化合物1006(39mg,0.08mmol)溶解在DCM中,加入EDC(46mg,0.24mmol),将混合物加热,在45℃搅拌过夜。加入少量水,将混合物浓缩,通过色谱法(在DCM中1-5%的甲醇)纯化残余物,得到化合物1039。
1H-NMR(CD3OD):δ8.73(bs,1H),8.43(d,1H),7.30(m,1H),4.30(m,1H),4.08(m,2H),3.71(m,6H),2.67(t,2H),2.56(m,4H),2.50(t,2H),1.95-0.75(m,18H)。
实施例40:N-(环己基甲氧基)-N-(2-吗啉基乙基)-6-(3-(2-(吡啶-2-基)乙基)脲基)己烷-1-磺酰胺(化合物1040)。
一般方法2。原料:2-(吡啶-2-基)乙胺和6-氨基-N-(环己基甲氧基)-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.48(dd,1H),7.78(dt,1H),7.35(d,1H),7.28(m,1H),3.90(d,2H),3.71(m,4H),3.49(t,2H),3.42(t,2H),3.19(m,2H),3.11(t,2H),2.96(t,2H),2.68(t,2H),2.53(m,4H),1.95-1.1(m,17),1.05(m,2H)。
实施例41:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(2-(吡啶-2-基)乙基)脲基)庚酰胺(化合物1041)。
一般方法2。原料:2-(吡啶-2-基)乙胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.48(dd,1H),7.78(dt,1H),7.35(d,1H),7.28(m,1H),4.15(m,1H),4.08(t,2H),3.72(m,4H),3.49(t,2H),3.10(t,2H),2.96(t,2H),2.67(t,2H),2.56(m,4H),2.49(m,2H),1.95-1.05(m,18H)。
实施例42:N-环己基-N-(2-吗啉基乙氧基)-5-(3-(吡啶-3-基)甲基)脲基)戊烷-1-磺酰胺(化合物1042)。
一般方法2。原料:3-吡啶甲基胺和5-氨基-N-环己基-N-(2-吗啉基乙氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.80(dt,1H),7.42(m,1H),4.37(s,2H),4.16(t,2H),3.71(m,4H),3.59(m,1H),3.19(m,4H),2.65(t,2H),2.55(m,4H),1.90(m,6H),1.75-1.25(m,9),1.19(m,1H)。
实施例43:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(吡啶-3-基)甲基)脲基)庚烷-1-磺酰胺(化合物1043)。
一般方法2。原料:3-吡啶甲基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.80(dt,1H),7.42(m,1H),4.37(s,2H),4.16(t,2H),3.71(m,4H),3.58(m,1H),3.17(m,4H),2.65(t,2H),2.55(m,4H),2.0-1.1(m,20H)。
实施例44:1-异丙基-1-(2-吗啉基乙氧基)-3-(5-(3-(吡啶-3-基甲基)脲基)戊基)脲(化合物1044)。
一般方法2。原料:3-吡啶甲基胺和化合物4。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.22(m,1H),3.99(t,2H),3.72(m,4H),3.22(t,2H),3.13(t,2H),2.63(t,2H),2.58(m,4H),1.52(m,4),1.38(m,2H),1.18(d,6H)。
实施例45:1-异丙基-1-(2-吗啉基乙氧基)-3-(5-(3-(吡啶-3-基乙基)脲基)戊基)脲(化合物1045)。
一般方法2。原料:2-(吡啶-3-基)乙胺和化合物4。
1H-NMR(CD3OD):δ8.41(m,2H),7.77(dt,1H),7.40(m,1H),4.25(m,1H),3.98(t,2H),3.74(m,4H),3.39(t,2H),3.23(t,2H),3.10(t,2H),2.83(t,2H),2.63(t,2H),2.57(m,4H),1.53(m,4),1.36(m,2H),1.17(d,6H)。
实施例46:1-异丙基-1-(2-吗啉基乙氧基)-3-(5-(3-(吡啶-4-基)脲基)戊基)脲(化合物1046)。
一般方法1。原料:4-吡啶基胺和化合物4。
1H-NMR(CD3OD):δ8.29(m,2H),7.46(m,2H),4.25(m,1H),3.97(t,2H),3.73(m,4H),3.24(m,4H),2.60(t,2H),2.55(m,4H),1.60(m,4),1.42(m,2H),1.16(d,6H)。
实施例47:N-异丙基-N-(3-吗啉基丙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1047)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-异丙基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.22(m,1H),3.99(t,2H),3.72(m,4H),3.22(t,2H),3.13(t,2H),2.63(t,2H),2.58(m,4H),1.52(m,4H),1.38(m,2H),1.18(d,6H)。
实施例48:N-异丙基-N-(3-吗啉基丙基)-6-(3-(2-(吡啶-3-基)乙基)脲基)己烷-1-磺酰胺(化合物1048)。
一般方法2。原料:2-(吡啶-3-基)乙胺和6-氨基-N-异丙基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.41(m,2H),7.75(dt,1H),7.40(m,1H),3.99(m,1H),3.70(m,4H),3.39(t,2H),3.21(t,2H),3.10(t,2H),3.02(m,2H),2.84(t,2H),2.47(m,4H),2.39(t,2H),1.82(m,4H),1.47(m,4H),1.37(m,2H),1.25(d,6H)。
实施例49:N-异丙基-N-(3-吗啉基丙基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1049)。
一般方法1。原料:4-吡啶基胺和6-氨基-N-异丙基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),3.99(m,1H),3.71(m,4H),3.22(m,4H),3.02(m,2H),2.47(m,4H),2.39(t,2H),1.82(m,4H),1.49(m,6H),1.25(d,6H)。
实施例50:N-环戊基-N-(3-吗啉基丙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1050)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环戊基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),4.07(m,1H),3.70(m,4H),3.17(m,4H),3.03(m,2H),2.48(m,4H),2.39(t,2H),1.95-1.30(m,18H)。
实施例51:N-(环己基甲氧基)-5-(3-(吡啶-3-基甲基)脲基)戊烷-1-磺酰胺(化合物1051)。
一般方法2。原料:3-吡啶甲基胺和5-氨基-N-(环己基甲氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.75(d,2H),3.17(m,4H),1.75(m,8H),1.51(m,4H),1.26(m,3H),0.99(m,2H)。
实施例52:1-(5-(吗啉磺酰基)戊基)-3-(3-(吡啶-3-基甲基)脲(化合物1052)。
一般方法2。原料:3-吡啶甲基胺和5-(吗啉磺酰基)戊烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.10(t,2H),3.36(t,2H),3.19(m,4H),1.87(m,4H),1.71(m,2H),1.51(m,4H)。
实施例53:N-(环己基甲氧基)-7-(3-(吡啶-3-基甲基)脲基)庚烷-1-磺酰胺(化合物1053)。
一般方法2。原料:3-吡啶甲基胺和7-氨基-N-(环己基甲氧基)庚烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.75(d,2H),3.16(m,4H),1.76(m,8H),1.6-1.1(m,11H),0.99(m,2H)。
实施例54:1-(7-(吗啉磺酰基)庚基)-3-(3-(吡啶-3-基甲基)脲(化合物1054)。
一般方法2。原料:3-吡啶甲基胺和7-(吗啉磺酰基)庚烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.11(t,2H),3.36(t,2H),3.17(m,4H),1.86(m,4H),1.71(m,2H),1.49(m,4H),1.37(m,4H)。
实施例55:N-环己基-N-(2-吗啉基乙氧基)-7-(3-(吡啶-2-基甲基)脲基)庚酰胺(化合物1055)。
一般方法2。原料:2-吡啶甲基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.48(d,1H),7.82(t,1H),7.42(d,1H),7.30(m,1H),4.44(s,2H),4.17(m,1H),4.10(t,2H),3.73(m,4H),3.16(t,2H),2.8-2.4(m,8H),1.9-1.25(m,17H),1.21(m,1H)。
实施例56:N-环戊基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1056)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环戊基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.20(bs,2H),4.04(m,1H),3.70(t,4H),3.21(bs,2H),3.16(t,2H),2.65(t,2H),2.54(t,4H),2.0-1.3(m,16H)。
实施例57:N-环庚基-N-(3-吗啉基丙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1057)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环庚基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),3.71(m,4H),3.65(m,1H),3.23(m,2H),3.15(t,2H),3.01(m,2H),2.47(m,4H),2.38(t,4H),2.0-1.3(m,22H)。
实施例58:N-环庚基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1058)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环庚基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
MS[M+H]+=540.3,[M-H+HCOOH]-=584.5。
实施例59:N-环丁基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1059)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环丁基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),4.24(m,1H),4.20(m,2H),3.71(t,4H),3.15(t,2H),3.07(t,2H),2.70(t,2H),2.57(t,4H),2.41(m,2H),2.15(m,2H),1.84(m,2H),1.74(m,2H),1.50(m,4H),1.39(m,2H)。
实施例60:N-环丁基-N-(3-吗啉基丙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1060)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环丁基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),4.21(m,1H),3.71(m,4H),3.29(m,2H),3.15(t,2H),2.97(m,2H),2.48(m,4H),2.41(t,2H),2.21(m,4H),1.74(m,6H),1.43(m,6H)。
实施例61:N-环己基-N-(3-(二甲基氨基)丙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1061)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环己基-N-(3-二甲基氨基)丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),3.51(m,1H),3.17(m,4H),3.02(m,2H),2.35(t,2H),2.26(s,6H),1.9-1.25(m,19H),1.18(m,1H)。
实施例62:N-环己基-N-(2-吗啉基乙氧基)-7-(3-吡啶-3-基硫脲基)庚酰胺(化合物1062)。
一般方法3。原料:3-吡啶基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.59(d,1H),8.30(d,1H),8.04(bd,1H),7.42(m,1H),4.15(m,1H),4.10(t,2H),3.73(m,4H),3.60(m,2H),2.8-2.4(m,8H),1.9-1.25(m,17H),1.20(m,1H)。
实施例63:N-环己基-N-(2-吗啉基乙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1063)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环己基-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),3.70(m,4H),3.51(m,1H),3.34(t,2H),3.14(m,4H),2.54(m,6H),1.9-1.25(m,17H),1.18(m,1H)。
实施例64:N-环戊基-N-(3-吗啉基丙基)-6-(3-吡啶-4-基硫脲基)己烷-1-磺酰胺(化合物1064)。
一般方法3。原料:4-吡啶基胺和6-氨基-N-环戊基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.35(m,2H),7.74(m,2H),4.07(m,1H),3.70(m,4H),3.62(t,2H),3.18(m,2H),3.05(m,2H),2.47(m,4H),2.38(t,2H),1.95-1.35(m,18H)。
实施例65:N-环己基-N-(2-吗啉基乙氧基)-7-(3-吡啶-3-基脲基)庚酰胺(化合物1065)。
一般方法1。原料:3-吡啶基胺和7-氨基-N-环己基-N-(2-吗啉基乙氧基)庚酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.55(d,1H),8.14(dd,1H),7.96(dt,1H),7.35(m,1H),4.15(m,1H),4.09(t,2H),3.72(t,4H),3.23(t,2H),2.67(t,2H),2.56(t,4H),2.51(t,2H),1.9-1.1(m,18H)。
实施例66:N-环戊基-N-(3-吗啉基丙基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1066)。
一般方法1。原料:4-吡啶基胺和6-氨基-N-环戊基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.28(m,2H),7.46(m,2H),4.07(m,1H),3.70(m,4H),3.23(t,2H),3.18(m,2H),3.04(m,2H),2.47(m,4H),2.38(t,2H),1.95-1.15(m,18H)。
实施例67:N-环己基-P-(6-(3-吡啶-3-基甲基)脲基)氨基磷酸乙酯(化合物1067)。
一般方法2。原料:3-吡啶甲基胺和P-氨基己基-N-环己基氨基磷酸乙酯(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.99(m,2H),3.14(t,2H),2.97(m,1H),1.89(m,2H),1.8-1.05(m,21H)。
实施例68:1-(6-(3,4-二氢异喹啉-2(1H)-基磺酰基)己基)-3-(吡啶-3-基甲基)脲(化合物1068)。
一般方法2。原料:3-吡啶甲基胺和6-(3,4-二氢异喹啉-2(1H)-基磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(DMSO-d6):δ8.45(d,1H),8.42(dd,1H),7.63(dt,1H),7.33(m,1H),7.17(m,4H),6.37(t,1H),5.98(t,1H),4.39(s,2H),4.19(d,2H),3.47(t,2H),3.09(m,2H),2.97(m,2H),2.87(t,2H),1.64(m,2H),1.34(m,4H),1.25(m,2H)。
实施例69:N-环戊基-N-(3-吗啉基丙基)-5-(3-(吡啶-3-基甲基)脲基)戊烷-1-磺酰胺(化合物1069)。
一般方法2。原料:3-吡啶甲基胺和5-氨基-N-环戊基-N-(3-吗啉基丙基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.07(m,1H),3.70(m,4H),3.17(m,4H),3.03(m,2H),2.47(m,4H),2.38(t,2H),1.95-1.40(m,16H)。
实施例70:N-环丁基-N-(3-吗啉基丙基)-5-(3-(吡啶-3-基甲基)脲基)戊烷-1-磺酰胺(化合物1070)。
一般方法2。原料:3-吡啶甲基胺和5-氨基-N-环丁基-N-(3-吗啉基丙基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.21(m,1H),3.71(t,4H),3.29(m,2H),3.15(t,2H),2.97(m,2H),2.48(t,4H),2.41(t,2H),2.20(m,4H),1.9-1.35(m,10H)。
实施例71:N-环丁基-N-(2-吗啉基乙氧基)-5-(3-(吡啶-3-基甲基)脲基)戊烷-1-磺酰胺(化合物1071)。
一般方法2。原料:3-吡啶甲基胺和5-氨基-N-环丁基-N-(2-吗啉基乙氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),4.25(m,1H),4.20(m,2H),3.72(t,4H),3.16(t,2H),3.07(t,2H),2.70(t,2H),2.57(t,4H),2.41(m,2H),2.15(m,2H),2.87(m,2H),1.75(m,2H),1.52(m,4H)。
实施例72:吗啉基(6-(3-吡啶-3-基甲基)脲基)己基)次膦酸乙酯(化合物1072)。
一般方法2。原料:3-吡啶甲基胺和6-氨基己基(吗啉基)次膦酸乙酯(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.10(m,2H),3.97(t,2H),3.37(m,2H),3.15(t,2H),1.95-1.25(m,17H)。
实施例73:1-(6-(4-乙酰基哌嗪-1-基磺酰基)己基)-3-(吡啶-3-基甲基)脲(化合物1073)。
一般方法2。原料:3-吡啶甲基胺和1-(4-(6-氨基己基磺酰基)哌嗪-1-基)乙酮(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),3.64(m,4H),3.32(m,2H),3.26(t,2H),3.15(t,2H),3.04(m,2H),2.14(s,3H),1.79(m,2H),1.89(m,4H),1.39(m,2H)
实施例74:N-环戊基-N-(2-吗啉基乙氧基)-5-(3-(吡啶-3-基甲基)脲基)戊烷-1-磺酰胺(化合物1074)。
一般方法2。原料:3-吡啶甲基胺和5-氨基-N-环戊基-N-(2-吗啉基乙氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.80(dt,1H),7.42(m,1H),4.37(s,2H),4.20(b s,2H),4.04(m,1H),3.70(t,4H),3.17(m,4H),2.65(t,2H),2.54(t,4H),2.0-1.45(m,14H)。
实施例75:N-环己基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺草酸盐(化合物1075)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-环己基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,DMSO-d6):δ8.46(d,1H),8.43(dd,1H),7.63(dt,1H),7.33(m,1H),6.36(t,1H),5.99(t,1H),4.21(d,2H),4.09(t,2H),3.69-3.61(m,4H),3.50(m,1H),3.22(t,2H),2.99(m,2H),2.88-2.78(m,2H),2.76-2.64(m,4H),1.92-1.81(m,2H),1.80-1.65(m,4H),1.63-1.32(m,7H),1.32-1.19(m,4H),1.16-1.00(m,1H)。
实施例76:N-苯基-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1076)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-苯基己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.48(d,1H),8.42(dd,1H),7.78(dt,1H),7.41(m,1H),7.33(m,2H),7.25(m,2H),7.12(m,1H),4.36(s,2H),3.08(m,4H),1.77(m,2H),1.5-1.2(m,6H)。
实施例77:N-(苄基氧基)-N-甲基-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1077)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(苄基氧基)-N-甲基己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.42(dd,1H),7.79(dt,1H),7.40(m,6H),4.94(s,2H),4.36(s,2H),3.15(m,4H),2.92(s,3H),1.86(m,2H),1.49(m,4H),1.37(m,2H)。
实施例78:N-(苄基氧基)-N-(2-吗啉基乙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1078)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(苄基氧基)-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.42(dd,1H),7.79(dt,1H),7.40(m,6H),5.06(s,2H),4.36(s,2H),3.68(m,4H),3.40(t,2H),3.22(t,2H),3.14(t,2H),2.53(t,2H),2.46(t,4H),1.88(m,2H),1.51(m,4H),1.39(m,2H)。
实施例79:N-(4-氯苯基)-N-甲基-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1079)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(4-氯苯基)-N-甲基己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.42(dd,1H),7.78(dt,1H),7.42(m,5H),4.36(s,2H),3.32(s,3H),3.11(m,4H),1.76(m,2H),1.46(m,4H),1.35(m,2H)。
实施例80:N-(4-氯苯基)-N-(2-吗啉基乙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1080)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(4-氯苯基)-N-(2-吗啉基乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.42(dd,1H),7.77(m,1H),7.44(m,5H),4.36(s,2H),3.85(m,2H),3.63(m,4H),3.14(m,4H),2.44(m,6H),1.79(m,2H),1.47(m,4H),1.36(m,2H)。
实施例81:N-环己基-N-(3-吗啉基丙基)-6-(3-(吡啶-4-基硫脲基)己烷-1-磺酰胺草酸盐(化合物1081)。
一般方法3。原料:4-吡啶基胺和6-氨基-N-环己基-N-(3-吗啉基丙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,DMSO-d6):δ10.16(b s,1H),8.53(b s,1H),8.38(d,2H),7.67(d,2H),3.70(bs,4H),3.51-3.36(m,3H),3.13(t,2H),3.02(t,2H),2.85(bs,4H),2.73(t,2H),1.86-1.20(m,19H),1.15-1.00(m,1H)。
实施例82:N-环戊基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-4-基硫脲基)己烷-1-磺酰胺(化合物1082)。
一般方法3。原料:4-吡啶基胺和6-氨基-N-环戊基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,DMSO-d6):δ10.29(bs,1H),8.63(bs,1H),8.41(d,2H),7.75-7.70(m,2H),4.12(t,2H),3.94(m,1H),3.66-3.60(m,4H),3.48(m,2H),3.19(t,2H),2.78(t,2H),2.65(bs,4H),1.91-1.80(m,2H),1.80-1.68(m,4H),1.68-1.61(m,2H),1.57(m,2H),1.52-1.40(m,4H),1.40-1.29(m,2H)。
实施例83:N-环戊基-N-(2-吗啉基乙氧基)-5-(3-(吡啶-4-基硫脲基)戊烷-1-磺酰胺草酸盐(化合物1083)。
一般方法3。原料:4-吡啶基胺和5-氨基-N-环戊基-N-(2-吗啉基乙氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,DMSO-d6):δ10.52(bs,1H),8.81(bs,1H),8.44-8.38(m,2H),7.76(d,2H),4.13(t,2H),3.94(m,1H),3.66-3.60(m,4H),3.49(m,2H),3.21(t,2H),2.80(t,2H),2.71-2.62(m,4H),1.92-1.69(m,6H),1.69-1.55(m,4H),1.55-1.40(m,4H)。
实施例84:N-环戊基-N-(2-吗啉基乙氧基)-5-(3-(吡啶-4-基脲基)戊烷-1-磺酰胺(化合物1084)。
一般方法1。原料:4-吡啶基胺和5-氨基-N-环戊基-N-(2-吗啉基乙氧基)戊烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,CDCl3):δ8.37(d,2H),7.46(s,1H),7.34(d,2H),5.33(t,1H),4.19(bs,2H),4.01(m,1H),3.71(t,4H),3.28(m,2H),3.09(b s,2H),2.63(t,2H),2.52(t,4H),1.99-1.63(m,8H),1.63-1.46(m,6H)。
实施例85:吗啉基(6-(3-(吡啶-4-基硫脲基)己基)次膦酸乙酯草酸盐(化合物1085)。
一般方法3。原料:4-吡啶基胺和6-氨基己基(吗啉基)次膦酸乙酯(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,DMSO-d6):δ10.32(bs,1H),8.65(bs,1H),8.41(d,2H),7.77-7.72(m,2H),3.81-4.05(m,4H),3.47(m,2H),3.29-3.19(m,2H),1.82-1.43(m,10H),1.43-1.27(m,4H),1.22(t,3H)。
实施例86:吗啉基(6-(3-(吡啶-4-基脲基)己基)次膦酸乙酯(化合物1086)。
一般方法1。原料:4-吡啶基胺和6-氨基己基(吗啉基)次膦酸乙酯(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,DMSO-d6):δ9.76(bs,1H),8.36(d,2H),7.57(d,2H),6.93(t,1H),4.04-3.88(m,2H),3.88-3.81(m,2H),3.29-3.16(m,2H),3.09(m,2H),1.81-1.16(m,14H),1.21(t,3H)。
实施例87:N-(环己基甲氧基)-N-(2-氟代乙基)-6-(3-吡啶-4-基硫脲基)己烷-1-磺酰胺(化合物1087)。
一般方法3。原料:4-吡啶基胺和6-氨基-N-(环己基甲氧基)-N-(2-氟代乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.35(m,2H),7.72(m,2H),4.62(dt,2H),3.88(d,2H),3.60(m,3H),3.51(t,1H),3.21(m,2H),1.91(m,2H),1.8-1.1(m,15H),1.05(m,2H)。
实施例88:N-(环己基甲氧基)-N-(2-氟代乙基)-6-(3-吡啶-4-基脲基)己烷-1-磺酰胺(化合物1088)。
一般方法1。原料:4-吡啶基胺和6-氨基-N-(环己基甲氧基)-N-(2-氟代乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.27(m,2H),7.46(m,2H),4.61(dt,2H),3.88(d,2H),3.55(dt,2H),3.21(m,4H),1.89(m,2H),1.8-1.1(m,15H),1.03(m,2H)。
实施例89:N-(环己基甲氧基)-N-(2-氟代乙基)-6-(3-(吡啶-3-基甲基)脲基)己烷-1-磺酰胺(化合物1089)。
一般方法2。原料:3-吡啶甲基胺和6-氨基-N-(环己基甲氧基)-N-(2-氟代乙基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.42(dd,1H),7.79(dt,1H),7.42(m,1H),4.62(dt,2H),4.37(s,2H),3.88(d,2H),3.55(dt,2H),3.17(m,4H),1.95-1.05(m,19H)。
实施例90:N-环戊基-N-(2-吗啉基乙氧基)-6-(3-(吡啶-4-基脲基)己烷-1-磺酰胺(化合物1090)。
一般方法1。原料:4-吡啶基胺和6-氨基-N-环戊基-N-(2-吗啉基乙氧基)己烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(400MHz,CDCl3):δ8.38(m,2H),7.34(m,2H),7.24(s,1H),5.11(t,1H),4.19(bs,2H),4.01(m,1H),3.71(t,4H),3.28(m,2H),3.09(bs,2H),2.62(t,2H),2.51(t,4H),1.96-1.66(m,8H),1.60-1.46(m,6H),1.39(m,2H)。
实施例91:N-环戊基-N-(3-吗啉基丙基)-4-(3-(吡啶-3-基甲基)脲基)丁烷-1-磺酰胺(化合物1091)。
一般方法2。原料:3-吡啶甲基胺和4-氨基-N-环戊基-N-(3-吗啉基丙基)丁烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),4.06(m,1H),3.70(t,4H),3.19(m,4H),3.06(m,2H),2.47(t,4H),2.38(t,2H),2.0-1.5(m,14H)。
实施例92:N-环丁基-N-(3-吗啉基丙基)-4-(3-(吡啶-3-基甲基)脲基)丁烷-1-磺酰胺(化合物1092)。
一般方法2。原料:3-吡啶甲基胺和4-氨基-N-环丁基-N-(3-吗啉基丙基)丁烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.41(m,1H),4.37(s,2H),4.19(m,1H),3.71(t,4H),3.28(m,2H),3.18(m,2H),3.00(m,2H),2.48(t,4H),2.40(t,2H),2.19(m,4H),1.9-1.5(m,8H)。
实施例93:N-环戊基-N-(3-吗啉基丙基)-4-(3-吡啶-4-基硫脲基)丁烷-1-磺酰胺(化合物1093)。
一般方法3。原料:4-氨基吡啶和4-氨基-N-环戊基-N-(3-吗啉基丙基)丁烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.37(m,2H),7.73(m,2H),4.08(m,1H),3.70(m,6H),3.17(m,4H),2.47(t,4H),2.39(t,2H),2.0-1.5(m,14H)。
实施例94:N-环丁基-N-(3-吗啉基丙基)-4-(3-吡啶-4-基硫脲基)丁烷-1-磺酰胺(化合物1094)。
一般方法3。原料:4-氨基吡啶和4-氨基-N-环丁基-N-(3-吗啉基丙基)丁烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.36(m,2H),7.72(m,2H),4.21(m,1H),3.70(m,6H),3.30(t,2H),3.08(m,2H),2.48(t,4H),2.40(t,2H),2.20(m,4H),1.82(m,6H),1.66(m,2H)。
实施例95:N-环戊基-N-(3-吗啉基丙基)-4-(3-(2-(吡啶-3-基)乙基脲基)丁烷-1-磺酰胺(化合物1095)。
一般方法2。原料:2-(吡啶-3-基)乙胺和4-氨基-N-环戊基-N-(3-吗啉基丙基)丁烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.43(d,1H),8.40(dd,1H),7.75(dt,1H),7.40(m,1H),4.07(m,1H),3.69(m,4H),3.39(t,2H),3.17(m,4H),3.06(m,2H),2.84(t,2H),2.46(t,4H),2.38(t,2H),2.0-1.5(m,14H)。
实施例96:N-环丁基-N-(3-吗啉基丙基)-4-(3-(2-(吡啶-3-基)乙基脲基)丁烷-1-磺酰胺(化合物1096)。
一般方法2。原料:2-(吡啶-3-基)乙胺和4-氨基-N-环丁基-N-(2-吗啉基丙基)丁烷-1-磺酰胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.43(d,1H),8.40(dd,1H),7.76(dt,1H),7.40(m,1H),4.21(m,1H),3.70(m,4H),3.40(t,2H),3.30(t,2H),3.14(t,2H),3.00(m,2H),2.84(t,2H),2.47(t,4H),2.41(t,2H),2.21(m,4H),1.9-1.5(m,8H)。
实施例97:1-(6-(吗啉磺酰基)己基)-3-(吡啶-3-基甲基)脲(化合物1097)。
一般方法2。原料:3-吡啶甲基胺和6-(吗啉磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.40(m,1H),4.37(s,2H),3.73(t,4H),3.25(t,4H),3.15(t,2H),3.03(m,2H),1.80(m,2H),1.55-1.25(m,6H)。
实施例98:1-(6-(氮杂环庚烷-1-基磺酰基)己基)-3-(吡啶-3-基甲基)脲(化合物1098)。
一般方法2。原料:3-吡啶甲基胺和6-(氮杂环庚烷-1-基磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),3.37(m,4H),3.15(t,4H),3.03(m,2H),1.76(m,6H),1.66(m,4H),1.6-1.25(m,6H)。
实施例99:1-(吡啶-3-基甲基)-3-(6-(吡咯烷-1-基磺酰基)己基)脲(化合物1099)。
一般方法2。原料:3-吡啶甲基胺和6-(吡咯烷-1-基磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.49(d,1H),8.43(dd,1H),7.79(dt,1H),7.42(m,1H),4.37(s,2H),3.34(m,4H),3.15(t,4H),3.06(m,2H),1.95(m,4H),1.79(m,2H),1.6-1.25(m,6H)。
实施例100:1-(6-(哌啶-1-基磺酰基)己基)-3-(吡啶-4-基)硫脲(化合物1100)。
一般方法3。原料:4-氨基吡啶和6-(哌啶-1-基磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.35(m,2H),7.73(m,2H),3.62(t,2H),3.24(m,4H),3.01(m,2H),1.82(m,2H),1.8-1.35(m,12H)。
实施例101:1-(6-(吗啉磺酰基)己基)-3-(吡啶-4-基)硫脲(化合物1101)。
一般方法3。原料:4-氨基吡啶和6-(吗啉代磺酰基)己烷-1-胺(参见,例如,WO 2009/086835)。
1H-NMR(CD3OD):δ8.35(m,2H),7.72(m,2H),4.11(t,2H),3.62(t,2H),3.37(t,2H),3.22(m,2H),1.88(m,4H),1.71(m,4H),1.52(m,4H)。
实施例102:体外细胞增殖测试(WST-1测试)
以3x103细胞/孔,每孔100μL培养基,将A2780细胞种在96孔板中,8孔留空用于培养基仅作对照。
在24小时之后,在单独的稀释板中通过在培养基中连续稀释通式(I)的化合物,进行化合物滴定(titration)。将100μL各稀释液加入至板中的细胞中,各做三份,包括对照(例如DMSO和空白)。将板在37℃CO2培养箱中温育24小时。在24小时之后在单独的稀释板中重复进行化合物滴定。然后将培养基和化合物从测试板中吸出。然后将100μL培养基加入至所有孔,接着进行100μL各化合物的稀释。将板在37℃CO2培养箱中再温育48小时(总温育时间72小时)。然后使用细胞增殖试剂WST-1测定活细胞的数量。将10μLWST-1试剂加入至各孔,在37℃CO2培养箱中温育1至4小时。测量吸光度(450nm/690nm)。
通式(I)的化合物降低活细胞的数量的活性计算为:
%活性=[(Sc-B)/(So-B)]x100
Sc指的是在待测化合物的存在下测量的信号,So指的是不存在化合物时检测到的信号,B指的是背景信号,其在仅仅含有培养基的空白孔中测得。使用GraphPad Prism分析数据。
结果可见表1。
表1-体外细胞增殖测试(按照在实施例102中的描述的WST-1测试)
Claims (24)
1.式(I)的化合物
其中
X选自=O、=S、=NH、=NOH和=NO-Me;
A选自-C(=O)-、-S(=O)2-、-C(=S)-和-P(=O)(R5)-,其中R5选自C1-6-烷基、C1-6-烷氧基和羟基;
B选自单键、-(CH2)3-6-、-O-和-O-(CH2)2-5-;
D选自单键、-O-、-CR7R8-和-NR9,其中R7、R8和R9独立选自氢、任选地经取代的C1-12-烷基、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;
m是0-12的整数和n是0-12的整数,其中m+n的和是1-20;
p是0-4的整数;
R1选自任选地经取代的杂芳基;
R2选自氢、任选地经取代的C1-12-烷基、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;R3选自任选地经取代的C1-12-烷基、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;或R2和R3与插入的原子(即-N-B-)一同形成任选地经取代的含有N的杂环或杂芳环;
各R4和R4*独立选自氢、任选地经取代的C1-12-烷基和任选地经取代的C1-12-烯基;
条件是当p是0时,R1不是任选地经取代的噻唑-2-基;
且条件是化合物不是苯基-NH-C(=O)-(CH2)5-NH-C(=S)-NH-(4-吡啶基);
和其药用可接受的盐,和其前药。
2.根据权利要求1的化合物,其中X选自=O和=S。
3.根据前述权利要求任一项的化合物,其中B是-O-。
4.根据前述权利要求任一项的化合物,其中A选自-S(=O)2-和-C(=O)。
5.根据权利要求2-4任一项的化合物,其中D是单键。
6.根据权利要求1的化合物,其中B选自-(CH2)3-6-和-O-(CH2)2-5-。
7.根据权利要求6的化合物,其中A是-S(=O)2-。
8.根据前述权利要求任一项的化合物,其中D选自单键、-O-和-NR9。
10.根据前述权利要求任一项的化合物,其中p是0-2,特别是0或1。
11.根据权利要求10的化合物,其中p是0且R1是吡啶-4-基。
12.根据前述权利要求任一项的化合物,其中m是0-10的整数且n是0-10的整数,其中m+n的和是1-12。
13.根据权利要求12的化合物,其中m是2-8的整数且n是0。
14.根据前述权利要求任一项的化合物,其中R2和R3中至少一个包括碳环、杂环或杂芳环,或R2和R3与插入的原子一同形成任选地经取代的含有N的杂环或杂芳环。
15.根据权利要求14的化合物,其中R2和R3与插入的原子一同形成任选地经取代的含有N、O的杂环或杂芳环。
16.根据权利要求1的化合物,其中
X选自=O和=S;
A选自-C(=O)-和-S(=O)2-;
B选自-O-、-(CH2)3-6-和-O-(CH2)2-5-;
D选自单键、-O-和-NR9;
m是2-8的整数且n是0;
p是0-2的整数;
R2选自氢、任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、-(CH2)0-2-(任选地经取代的芳基)、-(CH2)0-2-(任选地经取代的杂芳基)和-(CH2)0-2-(任选地经取代的杂环基);
R3选自任选地经取代的C3-12-环烷基、-[CH2CH2O]1-10-(任选地经取代的C1-6-烷基)、任选地经取代的C1-12-烯基、任选地经取代的芳基、任选地经取代的杂环基和任选地经取代的杂芳基;
R4选自氢、任选地经取代的C3-12-环烷基、-(CH2)0-2-(任选地经取代的芳基)、-(CH2)0-2-(任选地经取代的杂芳基)和-(CH2)0-2-(任选地经取代的杂环基);和
R4*为氢。
17.根据权利要求1的化合物,其选自本文描述的化合物1001-1101。
18.根据前述权利要求任一项的化合物,所述化合物用作药物。
19.根据权利要求1-17任一项的化合物,所述化合物用作用于治疗由烟酰胺磷酸核糖基转移酶(NAMPRT)的水平升高引起的疾病或病况的药物。
20.根据权利要求19的化合物,其中所述疾病或病况是1个或更多个选自下述的疾病或病况:炎症性和组织修复障碍,特别是类风湿性关节炎、炎症性肠病、哮喘和CPOD(慢性阻塞性肺病)、骨关节炎、骨质疏松和纤维化病;皮肤病,包括银屑病、特应性皮炎和紫外线导致的皮肤损伤;自身免疫疾病,包括系统性红斑狼疮、多发性硬化、银屑病性关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏病、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,特别地其中癌症选自乳腺癌、前列腺癌、肺癌、结肠癌、子宫颈癌、卵巢癌、皮肤癌、CNS的癌症、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金氏病、恶病质、与感染和某些病毒感染相关的炎症,包括获得性免疫缺陷综合征(AIDS)、成人呼吸窘迫综合征、毛细血管扩张性运动失调。
21.在哺乳动物中抑制烟酰胺磷酸核糖基转移酶(NAMPRT)的酶促活性的方法,所述方法包括下述步骤:给予所述哺乳动物药学相关量的在权利要求1-17任一项中定义的化合物。
22.在哺乳动物中治疗由烟酰胺磷酸核糖基转移酶(NAMPRT)的水平升高引起的疾病或病况的方法,所述方法包括下述步骤:给予所述哺乳动物药学相关量的在权利要求1-17任一项中定义的化合物。
23.根据权利要求22的方法,其中化合物与DNA损伤剂组合给予。
24.根据权利要求22-23任一项的方法,其中所述疾病或病况是1个或更多个选自下述的疾病和病况:炎症性和组织修复障碍,特别是类风湿性关节炎、炎症性肠病、哮喘和COPD(慢性阻塞性肺病)、骨关节炎、骨质疏松和纤维化病;皮肤病,包括银屑病、特应性皮炎和紫外线导致的皮肤损伤;自身免疫疾病,包括系统性红斑狼疮、多发性硬化、银屑病性关节炎、关节强硬性脊椎炎、组织和器官排斥、阿尔茨海默氏病、中风、动脉粥样硬化、再狭窄、糖尿病、肾小球肾炎、癌症,特别地其中癌症选自乳腺癌、前列腺癌、肺癌、结肠癌、子宫颈癌、卵巢癌、皮肤癌、CNS的癌症、膀胱癌、胰腺癌、白血病、淋巴瘤或霍奇金氏病、恶病质、与感染和某些病毒感染相关的炎症,包括获得性免疫缺陷综合征(AIDS)、成人呼吸窘迫综合征、毛细血管扩张性运动失调。
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