CN105793264B - 取代的二氢苯并呋喃‑哌啶‑甲酮衍生物、其制备及用途 - Google Patents
取代的二氢苯并呋喃‑哌啶‑甲酮衍生物、其制备及用途 Download PDFInfo
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- CN105793264B CN105793264B CN201580002731.2A CN201580002731A CN105793264B CN 105793264 B CN105793264 B CN 105793264B CN 201580002731 A CN201580002731 A CN 201580002731A CN 105793264 B CN105793264 B CN 105793264B
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- dihydrobenzofuranes
- pharmaceutically acceptable
- acceptable salt
- substituted
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
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Abstract
本发明涉及一种取代的二氢苯并呋喃‑哌啶‑甲酮衍生物、其制备及用途,具体的说涉及一种通式(A)所示的取代的二氢苯并呋喃‑哌啶‑甲酮衍生物、其立体异构体或药学上可以接受的盐、其制备方法以及含有它们的药物组合物以及在制备治疗癌症相关疾病的药物中的用途。
Description
技术领域
本发明涉及一种通式(A)所示的取代的二氢苯并呋喃-哌啶-甲酮衍生物、其立体异构体或药学上可以接受的盐、其制备方法以及含有它们的药物组合物以及在制备治疗癌症相关疾病的药物中的用途。
背景技术
本发明提供了一系列Wnt信号通路的抑制剂。这些抑制剂能够抑制肿瘤细胞增殖和阻止肿瘤转移。
Wnt信号通路是各种细胞进程中的关键调节器,包括干细胞的维持、干细胞命运的决定和细胞周期的控制等(Huang,Xie等,2006,J Immunol,176,4880-4887)。其在发育和成体稳态维持中发挥着重要的作用,同时在很多类型的肿瘤中也呈现异常活化的状态。经典的Wnt信号通路是通过其主要参与者连环蛋白β-catenin的稳定性进行调节的。而β-catenin的稳定性则是通过毁灭复合物所控制的。β-catenin具有许多重要的生物学功能。在细胞膜上,β-catenin与钙粘蛋白E-cadherin相连,参与粘附连接的形成。在细胞浆中,β-catenin能够与APC、AXIN、GSK3和CK1形成β-catenin毁灭复合物介导下游信号。当Wnt信号通路未被激活时,细胞浆中的β-catenin被复合物持续的磷酸化后降解。当Wnt激活Wnt信号通路时,β-catenin毁灭复合物降解,导致稳定的β-catenin进入细胞核之后不断积累,引起Wnt通路的靶基因(如c-myc、细胞周期蛋白D、Axin2和Nkd1等)转录激活。
在许多肿瘤中,Wnt蛋白的过表达或β-catenin毁灭复合物中各个组成蛋白的突变会使β-catenin变得稳定,导致Wnt通路的异常激活。尤其是肿瘤抑制因子APC的截短突变是结肠癌中最普遍的遗传学改变(Miyaki,Konishi等,1994,Cancer Res,54,3011-3020)。在人肝细胞癌和结肠癌中也分别发现有Axin1和Axin2的突变。这些突变导致非Wnt依赖的β-catenin稳定和β-catenin介导的转录持续活化(Taniguchi,Roberts等,2002,Oncogene,21,4863-4871)。除此之外,β-catenin的突变会导致β-catenin降解逆转和β-catenin信号的增加。其它许多类型的肿瘤中也都涉及到Wnt通路不受调控的激活,包括结直肠癌、黑色素瘤、乳腺癌、肝癌、肺癌和胃癌(Barker和Clevers,2006,Nat Rev Drug Discov,5,997-1014)。此肿瘤外,还有一些紊乱性疾病也与异常的Wnt通路有关,包括骨质疏松、关节炎、多囊性肾病、肺纤维化、糖尿病、精神分裂症、心血管疾病、非致癌的增生性疾病和神经变性疾病如阿尔兹海默病。多蛋白β-catenin毁灭复合物的有效组装依赖于其各个基本组成部分稳定态的水平。Axin呈浓度依赖的形式调节β-catenin毁灭复合物的功能(Salic,Lee等,2000,Mol Cell,5,523-532)。在表达APC截短突变的细胞系中增加Axin的表达能够增强β-catenin的降解(Behrens,Jerchow等,1998,Science,280,596-599)。因此,Axin蛋白的水平很可能受到严格的调控以确保产生适宜的Wnt通路信号。
Tankyrase蛋白是一种多功能的聚(ADP-核糖)聚合酶(PRAP),能够利用NAD+作为底物,将ADP-核糖聚合物转移到靶蛋白上进行翻译后修饰。Tankyrase能够直接结合Axin蛋白,调节其稳定性。研究发现通过抑制Tankyrase能够稳定Axin从而使β-catenin降解,抑制Wnt信号通路(Huang,Mishina等,2009,Nature,461,614-620)。Tankyrase的亚型都能与Axin的一段高保守序列反应,通过泛素-蛋白酶通路促进Axin的降解。Axin在广泛的生理学过程中具有重要的调节作用,包括髓鞘再生过程中脑胶质瘤祖细胞的分化(Fancy,Harrington等,2011,Nat Neurosci,14,1009-1016)和肺纤维化过程中上皮向间质的转化(Ulsamer,Wei等,2012,J Biol Chem,287,5164-5172)。抑制Tankyrase,能稳定Axin,抑制Wnt通路信号,利用这一过程可以开发与Wnt信号相关的紊乱疾病的治疗方法。Tankyrase具有多个蛋白伴侣,包括TRF1,一种双链端粒重复结合蛋白;NuMA,一种在有丝分裂纺锤体装配中起重要作用的蛋白;IRAP,一种对胰岛素应答的葡萄糖摄取相关的膜蛋白和Mcl-1,一种促凋亡蛋白。除了调节Wnt信号通路,通过与各种蛋白相互作用,Tankyrase蛋白具有各种不同的生物学功能。Tankyrase将TRF1从端粒释放,促使端粒接触端粒酶。由此可见,Tankyrase能够正调节端粒酶对端粒的延长(Cook,Dynek等,2002,Mol Cell Biol,22,332-342)。在正常细胞中,端粒酶的表达通常是被抑制的,而大部分的肿瘤细胞都表达端粒酶,导致其端粒延长稳定(Hahn,Stewart等,1999,Nat Med,5,1164-1170)。这表明Tankyrase能够作为肿瘤治疗的靶点,通过抑制端粒酶接近端粒而抑制肿瘤。Tankyrase的抑制剂能够作为有效的肿瘤治疗方法抑制各类肿瘤,包括白血病、淋巴瘤、多发性骨髓瘤、肺癌和乳腺癌等。Tankyrase在细胞有丝分裂过程中也发挥着重要作用:(1)调节NuMA在有丝分裂中对纺锤体极的调节功能(Chang,Dynek等,2005,Biochem J,391,177-184);(2)调节纺锤体的装配和结构(Chang,Jacobson等,2004,Nature,432,645-649);(3)维持姐妹染色单体的解离(Dynek和Smith,2004,Science,304,97-100)。抑制Tankyrase会引起细胞有丝分裂停滞或细胞老化,因此该策略能够被开发成为治疗有丝分裂异常的相关疾病,例如肿瘤(乳腺癌、肺癌、卵巢癌、白血病、淋巴瘤和黑色素瘤等)。除此之外,Tankyrase1是中心体聚集所需的一个重要的基因,肿瘤细胞具有多余的中心体以抑制多极有丝分裂而进行两极有丝分裂(Kwon,Godinho等,2008,Genes Dev,22,2189-2203)。因此抑制Tankyrase能够被开发成抑制中心体扩增的肿瘤,包括各种实体瘤和血液系统癌症,如乳腺癌、膀胱癌、肺癌、结肠癌和白血病等。
现有研究已公开了一些Tankyrase的合成抑制剂。其中一些研究发现Tankyrase的抑制剂能够阻断APC突变的结肠癌细胞中的Wnt信号(Chen,Dodge等,2009,Nat Chem Biol,5,100-107;Huang,Mishina等,2009,Nature,461,614-620)和乳腺癌中的Wnt信号(Bao,Christova等,2012,PLoS One,7,e48670)。尽管Wnt信号通路是抗肿瘤治疗的一个极具潜力的靶点,但目前有效的Tankyrase小分子抑制剂还较少。
WO2013012723描述了新的2-哌啶-2-基-乙酰胺衍生物及其作为Tankyrase抑制剂的用途,可用于治疗与Wnt、Tankyrase1和Tankyrase2相关的疾病,比如癌症。其中X为NH或O,Y为CH或N,R1a和R1b为烷基或一起形成可以被取代的5至7元环,R2为H或烷基,R3为H、烷基、炔基等,R5为可以被取代的苯、2,3-二氢苯并呋喃、喹啉等。不认为此专利中具体描述是本发明的一部分,其结构如下:
WO2013008217描述了新的4-哌啶衍生物及其作为Tankyrase抑制剂的用途,可用于治疗与Wnt、Tankyrase1和Tankyrase2相关的疾病,如癌症。其中R1为可取代的苯基、5元杂环、8至10元杂环等,R4为H或可取代的苯基。不认为此专利中具体描述是本发明的一部分,其结构如下:
WO2013010092描述了新的4-氧代-3,5,7,8-四氢-4H-吡喃并[4,3-d]嘧啶衍生物及其作为Tankyrase抑制剂的用途,可用于治疗与Wnt、Tankyrase1和Tankyrase2相关的疾病,如癌症。其中R1为H或可取代的烷基,R2为R3-烯基-C(O)-、R3-烯基-S(O)2-或R3-烯基-C(O)O-,R3为可被取代的苯基、6元杂芳环或吲哚。不认为此专利中具体描述是本发明的一部分,其结构如下:
本发明目的是提供一种结构新颖的、有效的Tankyrase抑制剂,以及用于治疗癌症相关疾病的用途,其中所述癌症相关疾病包括膀胱癌、结肠癌、卵巢癌、黑色素瘤,白血病、淋巴瘤、多发性骨髓瘤、肺癌和乳腺癌等。
发明内容
本发明提供一种通式(A)所示的化合物、其立体异构体或药学上可以接受的盐,其中:
R1选自C 6-10碳环或5至10元杂环,所述杂环至少含有1至4个选自N、O或S的杂原子,所述碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、(=O)、氰基、羟基、羧基、氨基、硝基、R1a、NR1aR1b、COR1a、CONR1aR1b或NR1aCOR1b的取代基所取代;
R1a和R1b各自独立的选自H、C1-6烷基或C1-6烷氧基,所述烷基和烷氧基任选进一步被0至4个选自F、Cl、Br、I、氰基、羟基、羧基、氨基或硝基的取代基所取代;
R2、R3和R4各自独立的选自H、F、Cl、Br、I、氰基、羟基、羧基、氨基、硝基、C1-6烷基或C1-6烷氧基,所述烷基和烷氧基任选进一步被0至4个选自F、Cl、Br、I、氰基、羟基、羧基、氨基或硝基的取代基所取代;
R5、R6、R7和R8各自独立的选自H或C1-6烷基。
本发明优选方案,一种通式(A)所示的化合物、其立体异构体或药学上可以接受的盐,其中该化合物选自通式(I)所示的化合物、其立体异构体或药学上可以接受的盐:
本发明优选方案,一种通式(A)或通式(I)所示的化合物、其立体异构体或药学上可以接受的盐,其中,R1选自6元碳环、5元杂环、6元杂环、7元杂环、8元杂环、9元杂环或10元杂环,所述杂环至少含有1至4个选自N、O或S的杂原子,所述的碳环或杂环任选进一步被0至4个选自F、Cl、Br、I、(=O)、氰基、羟基、羧基、氨基、硝基、R1a、NR1aR1b或COR1a的取代基所取代;
R1a和R1b各自独立的选自H、C1-4烷基或C1-4烷氧基,所述烷基和烷氧基任选进一步被0至4个选自F、Cl、Br、I、氰基、羟基、羧基、氨基或硝基的取代基所取代。
本发明优选方案,一种通式(A)或通式(I)所示的化合物、其立体异构体或药学上可以接受的盐,其中,R1选自取代或未取代的如下结构之一:
当被取代时,任选进一步被1至4个选自F、Cl、Br、I、(=O)、氰基、羟基、羧基、氨基、硝基、R1a、NR1aR1b或COR1a的取代基所取代;
R1a和R1b各自独立的选自H、C1-4烷基或C1-4烷氧基,所述烷基和烷氧基任选进一步被0至4个选自F、Cl、Br、氰基或羟基的取代基所取代;
本发明优选方案,一种通式(A)或通式(I)所示的化合物、其立体异构体或药学上可以接受的盐,其中,R1选自取代或未取代的如下结构之一: 优选取代或未取代的
当被取代时,任选进一步被1至4个选自F、Cl、Br、氰基、羟基、羧基、氨基、硝基、甲基、乙基、三氟甲基、甲氧基或乙氧基的取代基所取代,优选被0至4个选自F、Cl、Br、氰基、甲基、乙基或三氟甲基的取代基所取代。
本发明优选方案,一种通式(A)或通式(I)所示的化合物、其立体异构体或药学上可以接受的盐,其中:R1选自取代或未取代的如下结构之一: 当被取代时,任选进一步被1至4个选自F、Cl、氰基、甲基、三氟甲基或甲氧基的取代基所取代;
R2、R3和R4各自独立的选自H、F、Cl或Br;
R5、R6、R7和R8各自独立的为H。
本发明优选方案,一种通式(I)所示的化合物、其立体异构体或药学上可以接受的盐,其中该化合物选自通式(II)所示的化合物、其立体异构体或药学上可以接受的盐:
本发明优选方案,一种通式(II)所示的化合物、其立体异构体或药学上可以接受的盐,其中:
R2、R3和R4各自独立的选自H、F、Cl、Br、三氟甲基、甲基、乙基、甲氧基或乙氧基,优选H、F、Cl或Br,更优选H或者F
R5、R6、R7和R8各自独立的选自H、甲基或乙基,优选H。
本发明优选方案,一种通式(I)所示的化合物、其立体异构体或药学上可以接受的盐,其中化合物选自,但不限于如下结构之一:
本发明提供一种药物组合物,所述药物组合物含有治疗有效剂量的本发明化合物及其立体异构体或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
进一步,本发明提供了本发明的化合物、其立体异构体或其药学上可以接受的盐,或本发明所述的药物组合物在制备治疗癌症相关药物中的用途。
更进一步,本发明还提供了一种治疗癌症的方法,所述方法包括给药本发明前面任意所述的化合物、其立体异构体或其药学上可以接受的盐,或本发明前面所述的药物组合物。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明涉及到被多个取代基取代时,各取代基可以相同或不相同。
本发明涉及到含有多个杂原子时,各杂原子可以相同或不相同。
本发明所述基团和衍生物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况,及本发明所述基团和衍生物中所涉及的元素碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
术语“烷基”是指饱和的脂肪族烃基团,包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基,非限制性实施例包括,甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、正壬基,及其各种支链异构体等;更优选的是含有1至4个碳原子的低级烷基,非限制性实施例包括甲基、乙基、丙基、异丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的,当被取代时,取代基优选为1至5个,独立地选自H、F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷巯基。
“烷氧基”是指-O-烷基,其中烷基如本文上面所定义。烷氧基可以是取代的或未取代的,其非限制性实施例包括,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基或己氧基,优选具有1至12元烷氧基。当被取代时,取代基优选为1至5个,独立地选自H、F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。
“碳环”是指饱和或者不饱和的芳香环或者非芳香环,芳香环或者非芳香可以是3至8元的单环,4至12元双环或者10至15元三环系统,碳环可以连接有桥环或者螺环,非限制性实施例包括环丙基、环丁基、环戊基、环己基、环己烯基、环庚基、环戊烯、环己二烯、环庚三烯、苯基、萘基、苯并环戊基、二环[3.2.1]辛烷基、二环[5.2.0]壬烷基、三环[5.3.1.1]十二烷基、金刚烷基或螺[3.3]庚烷基等。碳环可以被取代,当被取代时,取代基优选为1至5个,独立地选自H、F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷巯基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。
“杂环”是指取代的或未取代的饱和或者不饱和的芳香环或非芳香环,芳香环和非芳香环可以是3至8元的单环,4至12元双环或者10至15元三环系统,且由至少一个选自N、O或S的杂原子组成,优选3至10元杂环,杂环的环中选择性取代的N、S可被氧化成各种氧化态。杂环可以连接在杂原子或者碳原子上。杂环可以连接有桥环或者螺环,非限制性实施例包括,环氧乙烷、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环、1,4-二氧戊环、1,3-二氧六环、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷、二氢呋喃、二氢吡喃、二噻戊环、四氢呋喃、四氢吡咯基、四氢咪唑、四氢噻唑、四氢吡喃、苯并咪唑、苯并吡啶、吡咯并吡啶、苯并二氢呋喃、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基等;当被取代时,取代基优选为1至5个,取代基独立地选自H、F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、杂环烷基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯、杂环烷基巯基、-(CH2)nS(=O)pR6、-(CH2)n-烯基-R6或-(CH2)n-炔基-R6。
“氨基”是指-NH2,可以是取代的或未取代的,当被取代时,取代基优选为1至3个,独立地选自烷基、烯基、炔基、烷氧基、烷硫基、羟基、氨基、烷基氨基、烷基酰基氨基、杂环烷基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、羟基烷基、羧酸或羧酸酯。
“芳基”是指取代的或未取代的6至14元全碳单环或稠和多环基团,具有共轭的π电子体系的多环基团,优选6至10元芳香环,其非限定性实例包括苯基或萘基;所述芳基可以稠和与杂芳基、杂环基或环烷基,且与母体结构连接的部分为芳基,其非限定性实例包括苯并呋喃、苯并环戊烷基或苯并噻唑等。当被取代时,取代基优选为1至5个,取代基独立地选自H、F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。
“杂芳基”是指取代或未取代的5至15元芳香环,且含有1至3个选自N、O或S杂原子,优选5至10元芳香环,杂芳基的非限制性实施例包括吡啶基、呋喃基、噻吩基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并呋喃、苯并咪唑、苯并吡啶或吡咯并吡啶等。当被取代时,取代基优选为1至5个,取代基独立地选自H、F、Cl、Br、I、=O、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、巯基、羟基、硝基、氰基、氨基、烷基酰基氨基、环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷基巯基、羟基烷基、羧酸、羧酸酯或杂环烷基巯基。
“天然或可药用氨基酸”:蛋白质分子的基本骨架是氨基酸序列,组成蛋白质的基本氨基酸有20种,这20种基本氨基酸是生物进行蛋白后期修饰的基础,此外,在这些基本氨基酸的基础上,生物还会合成羟脯氨酸、羟赖氨酸等衍生出来的氨基酸类型,这些由生物合成的氨基酸统称为“天然氨基酸”;用人工方法合成的就是“非天然氨基酸”。“可药用氨基酸”是指在药学上可接受的天然或非天然氨基酸。
本发明的“=O”为本领域通常习惯用法,是指以双键相连的氧原子,譬如羰基中与碳原子相连的双键氧原子。
“药学上可接受的盐”是指药学上可接受的无毒酸或碱的盐,包括无机酸和碱、有机酸和碱的盐。
“共晶”是指活性药物成分(active pharmaceutical ingredient,API)和共晶形成物(cocrystal former,CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。所述“共晶形成物”包括但不限于各种药学上可接受的酸、碱、非离子化合物。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“药物组合物”表示一种或多种文本所述衍生物或其生理学/药学上可接受的盐或前体药物与其它化学组分的混合物,其它组分例如生理学/药学上可接受的载体和赋形剂。药物组合物的目的是促进化合物对生物体的给药。
“前药”是指可以在生理条件下或者通过溶剂解转化为具有生物活性的本发明衍生物。本发明的前药通过修饰在该衍生物中的功能基团来制备,该修饰可以按常规的操作或者在体内被除去,而得到母体化合物。前药包括本发明衍生物中的一个羟基、氨基或者巯基连接到任何基团上所形成的化合物,当本发明衍生物的前药被施予哺乳动物个体时,前药被割裂而分别形成游离的羟基、游离的氨基或者游离的疏基。前药的例子包括但不限于,本发明衍生物中的羟基或氨基功能基团与甲酸、乙酸或苯甲酸所形成的化合物。
“任选”、“任选的”或“任选地”意味着随后所描述地事件或环境可以但不必发生,包括该事件或环境发生或不发生的场合。例如,“芳基任选被烷基取代”意味着烷基可以但不必须存在,该说明包括芳基被烷基取代的情形和芳基不被烷基取代的情形。
“取代或未取代的”是指基团可以被取代或不被取代的情形,若在本发明中没有指出基团可以被取代,则表示该基团为未取代的情形。
“作为选择”是指“作为选择”之后的方案与“作为选择”之前的方案为并列关系,而不是在前方案中的进一步选择情形。
“取代”是指基团中一个或多个氢原子被其它基团取代的情形,如果所述的基团被氢原子取代,形成的基团与被氢原子取代的基团相同。基团被取代的情形,例如氨基、C1-4烷基、C1-4烷氧基、C3-6碳环、3至6元杂环任选进一步被0至4个选自H、F、Cl、Br、I、羟基、氰基、氨基、C1-4烷基或C1-4烷氧基的取代基所取代,形成的基团包括但不限于甲基、氯甲基、三氯甲基、羟基甲基、-CH2OCH3、-CH2SH、-CH2CH2CN、-CH2NH2、-NHOH、-NHCH3、-OCH2Cl、-OCH2OCH2CH3、-OCH2CH2NH2、-OCH2CH2SH、-OCH2CH2OH、1-羟基环丙基、2-羟基环丙基、2-氨基环丙基、4-甲基呋喃基、2-羟基苯基、4-氨基苯基或苯基。
具体实施方式
以下结合实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,反应在氮气氛下进行。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,为20℃~30℃。
实施例1
2-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3,5,7,8-四氢吡喃并[4,3-d]嘧啶-4-酮(化合物1)
2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one
第一步:4-甲氧基(甲基)氨基甲酰基)哌啶-1-甲酸叔丁酯(1B)
tert-butyl 4-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate
将N,N'-羰基二咪唑(21.0g,0.13mol)溶于无水二氯甲烷(200mL)中,滴加1-叔丁氧羰基哌啶-4-羧酸(1A)(23.0g,0.10mmol)的无水二氯甲烷(100mL)溶液,滴完搅拌30分钟,分批加入二甲羟胺盐酸盐(12.7g,0.13mol),常温反应3小时。向反应液中加入柠檬酸溶液(wt=10%,250mL),分液,有机相用饱和食盐水(300mL)洗涤,无水硫酸钠干燥,得到标题化合物4-甲氧基(甲基)氨基甲酰基)哌啶-1-甲酸叔丁酯(1B),浅黄色液体(25.0g,产率92%)。
1H NMR(400MHz,CDCl3)δ4.39–4.24(m,3H),3.71(t,2H),3.65–3.63(m,2H),3.55–3.53(m,2H),3.38(s,3H),1.44(s,9H),1.39(m,3H)。
LCMS m/z=217.0[M-55]。
第二步:4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-甲酸叔丁酯(1C)
tert-butyl 4-(2,3-dihydrobenzofuran-5-carbonyl)piperidine-1-carboxylate
将5-溴-2,3-二氢苯并呋喃(10.0g,50.2mmol)溶于无水四氢呋喃(80mL)中,氮气保护下,冷却至-78℃,滴加正丁基锂(31.3mL,50.2mmol),滴完搅拌30分钟,加入4-甲氧基(甲基)氨基甲酰基)哌啶-1-甲酸叔丁酯(1B)(3.1g,33.5mmol)的四氢呋喃(200mL)溶液,升常温反应1小时。向反应液中加入饱和氯化铵(150mL)溶液,分液,有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,浓缩,得到标题化合物4-甲氧基(甲基)氨基甲酰基)哌啶-1-甲酸叔丁酯(1C),浅黄色液体(10.0g,产率91%)。
1H NMR(400MHz,CDCl3)δ7.84(d,1H),7.79(dd,1H),6.81(d,1H),4.66(t,2H),4.16(m,2H),3.34(m,1H),3.26(t,2H),2.88(m,2H),1.81(m,2H),1.76–1.64(m,2H),1.47(s,9H)。
第三步:(2,3-二氢苯并呋喃-5-基)(哌啶-4-基)甲酮(1D)
(2,3-dihydrobenzofuran-5-yl)(piperidin-4-yl)methanone
将4-甲氧基(甲基)氨基甲酰基)哌啶-1-甲酸叔丁酯(1C)(4.0g,0.012mol)溶于无水二氯甲烷(50mL)中,冷却至0℃,加入三氟乙酸(13.7g,0.12mol),升常温反应4小时。向反应液中加入水(50mL),用氨水调节反应混合物至碱性,用二氯甲烷(100mL×2)萃取,合并有机层,用无水硫酸钠干燥,浓缩,得到标题化合物(2,3-二氢苯并呋喃-5-基)(哌啶-4-基)甲酮(1D),浅黄色固体(1.2g,产率43%)。
1H NMR(400MHz,CDCl3)δ7.84(d,1H),7.79(dd,1H),6.81(d,1H),4.66(t,2H),3.34(m,1H),3.25(t,2H),3.18(m,2H),2.77(td,2H),2.18(s,1H),1.83(m,2H),1.75–1.64(m,2H)。
LCMS m/z=232.0[M+1]。
第四步:(2-氧代吡咯烷-3-基)甲磺酸酯(1F)
2-oxopyrrolidin-3-yl methanesulfonate
将3-羟基-2-吡咯烷酮(1E)(5.0g,0.05mol)溶于无水二氯甲烷(50mL)中,加入三乙胺(10.1g,0.10mol),冷却至0℃,滴加甲基磺酰氯(6.8g,0.06mol),升至室温反应2小时。向反应液中加入饱和食盐水(50mL),用二氯甲烷(100mL×3)萃取,合并有机层,有机相用无水硫酸钠干燥,浓缩,得到标题化合物(2-氧代吡咯烷-3-基)甲磺酸酯(1F),白色固体(4.0g,产率45%)。
1H NMR(400MHz,CDCl3)δ6.64(s,1H),5.15(t,1H),3.54–3.48(m,1H),3.43–3.37(m,1H),3.26(s,3H),2.69–2.61(m,1H),2.41-2.31(m,1H)。
LCMS m/z=179.9[M+1]。
第五步:3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G)
3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)pyrrolidin-2-one
将(2-氧代吡咯烷-3-基)甲磺酸酯(1F)(1.0g,5.58mmol)溶于乙腈(30mL)中,加入(2,3-二氢苯并呋喃-5-基)(哌啶-4-基)甲酮(1D)(1.3g,5.58mmol)和N,N-二异丙基乙胺(1.3g,5.58mmol),升温至85℃反应4小时。将反应液浓缩,残留物用硅胶柱色谱分离提纯(甲醇:二氯甲烷(v/v)=0:1~5:95),得到标题化合物3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G),浅黄色固体(0.73g,产率42%)。
1H NMR(400MHz,CDCl3)δ7.83(d,1H),7.78(dd,1H),6.80(d,1H),5.99(s,1H),4.65(t,2H),3.50(t,1H),3.40–3.31(m,2H),3.25(m,3H),3.13(m,1H),2.98(m,2H),2.53(m,1H),2.32–2.15(m,2H),1.90(m,4H)。
LCMS m/z=315.0[M+1]。
第六步:2-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3,5,7,8-四氢吡喃并[4,3-d]嘧啶-4-酮(化合物1)
2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one
将3-4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G)(0.73g,2.32mmol)溶于四氢呋喃(20mL)中,加入2-(氯甲基)-7,8-二氢-3H-吡喃并[4,3-d]嘧啶-4(5H)-酮(512mg,2.55mol,参考WO2013008217中间体3的合成方法制备得到),冷却到0℃,氮气保护下,加入氢化钠(278mg,6.96mol),升温70℃,反应1小时。把反应液冷却到0℃,滴加甲醇淬灭过量的氢化钠,浓缩,残留物用硅胶柱色谱分离提纯(甲醇:二氯甲烷(v/v)=0:1~5:95)得到标题化合物2-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3,5,7,8-四氢吡喃并[4,3-d]嘧啶-4-酮(化合物1),白色固体(0.60g,产率55%)。
1H NMR(400MHz,CDCl3)δ7.83(d,1H),7.78(dd,1H),6.80(d,1H),4.66(t,2H),4.55(s,2H),4.39(s,2H),3.93(t,2H),3.66(t,1H),3.55–3.43(m,2H),3.25(m,3H),3.15(m,1H),3.05(m,2H),2.66(t,2H),2.54(m,1H),2.34(m,1H),2.20(m,1H),1.91(m,4H)。
LCMS m/z=478.9[M+1]。
实施例2
2-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3H-环庚并[d]咪唑-4-酮(化合物2)
2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]meth yl]-3H-cyclohepta[d]imidazol-4-one
第一步:
2-[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]乙腈(2B)
2-[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]acetonit rile
将3-4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G)(0.53g,1.68mmol)溶于干燥四氢呋喃(10mL)中,加入2-溴乙腈(0.61g,5.04m mol),氮气保护下冷却到0℃,把氢化钠(0.12g,5.04mol)加到反应液中,0℃反应30分钟。滴加水(10mL)淬灭反应,用二氯甲烷(20mL×2)萃取,合并有机层,用饱和氯化钠(10mL)洗涤一次,无水硫酸钠干燥,减压浓缩得粗品硅胶柱纯化(二氯甲烷:甲醇(v/v)=49:1~1:0),,得到标题化合物2-[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]乙腈(2B),黄色固体(0.30g,产率50%)。
1H NMR(400MHz,CDCl3)δ7.82(s,1H),7.77(dd,1H),6.80(d,1H),4.65(t,2H),4.27(q,2H),3.60–3.46(m,2H),3.46–3.38(m,1H),3.22(m,3H),3.06(dt,1H),2.92(dd,2H),2.47–2.38(m,1H),2.36–2.26(m,1H),2.19-2.09(m,1H),1.91–1.78(m,4H)。
LCMS m/z=354.1[M+1]。
第二步:
2-[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]乙脒盐酸盐(2C)
2-[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]aceta midine Hydrochloride salt
将2-[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]乙腈(2B)(0.3g,0.8m mol)溶解在无水甲醇(6mL)中,加入甲醇钠(0.005g,0.08mmol),25℃反应2小时后加入氯化铵(0.05g,1.0mmol),加完后,继续25℃反应2小时。减压浓缩至干得粗品悬浮在乙酸乙酯/石油醚的混合溶液(v/v=2/3,20mL)中,室温搅拌1小时,过滤,滤饼用乙酸乙酯/石油醚的混合溶液(v/v=2/3,20mL)洗涤,收集滤饼减压干燥得标题化合物2-[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]乙脒盐酸盐(2C),黄色固体(0.2g,产率58.1%)。
1H NMR(400MHz,DMSO)δ9.04(b,2H),7.88(s,1H),7.81(d,1H),7.36(b,2H),6.86(d,1H),4.63(t,2H),4.29(d,1H),4.11(m,1H),3.40-3.28(m,5H),3.23(t,2H),3.17(d,1H),2.84-2.74(m,1H),2.40-2.30(m,1H),2.23-2.13(m,1H),2.13–1.99(m,1H),1.82-1.66(m,2H),1.66-1.46(m,2H)。
LCMS m/z=371.1[M+1]。
第三步:
2-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3H-环庚并[d]咪唑-4-酮(化合物2)
2-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]meth yl]-3H-cyclohepta[d]imidazol-4-one
将2-[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]乙脒盐酸盐(2C)(0.2g,0.49mmol)悬浮在甲苯(20mL)中,加入2-对甲苯磺酰基氧基环庚三烯酮(0.135g,0.49mmol),加入四丁基溴化铵(0.063g,0.19mmol),再加入30%的氢氧化钠(0.078g,1.9mmol)水溶液,加完后,加热至30℃反应过夜。分液,弃甲苯收集水层,加入二氯甲烷(20mL),分液,水层再用甲醇/二氯甲烷混合溶剂(v/v=1/9,20mL)萃取,合并有机层,用饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,减压浓缩所得粗品硅胶柱纯化(二氯甲烷:甲醇(v/v)=97:3~1:0)得标题化合物2-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3H-环庚并[d]咪唑-4-酮(化合物2),浅黄色固体(0.01g,产率4%)。
1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.78-7.72(t,2H),7.40-7.36(t,1H),7.29(d,1H),7.07–6.96(m,1H),6.80(d,1H),4.76(s,2H),4.65(t,2H),3.66-3.56(m,1H),3.55-3.40(m,2H),3.24(t,3H),3.18-3.08(m,1H),3.05-2.90(m,2H),2.55-2.45(m,1H),2.35-2.25(m,1H),2.20-2.09(m,2H),1.92-1.80(m,4H)。
LCMS m/z=473.3[M+1]。
实施例3
2-[[3-[4-(6-氟-2,3-二氢苯并呋喃-7-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3,5,7,8-四氢吡喃并[4,3-d]嘧啶-4-酮(化合物3)
2-[[3-[4-(6-fluoro-2,3-dihydrobenzofuran-7-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one
第一步:5-溴-6-氟-2,3-二氢苯并呋喃(3B)
5-bromo-6-fluoro-2,3-dihydrobenzofuran
室温下在6-氟-2,3-二氢苯并呋喃-5-胺(3A)(10.0g,65.30mmol)中加入48%的氢溴酸溶液(160mL),搅拌溶解。冷却到0℃,缓慢滴加亚硝酸钠(9.79g,142mmol)的水溶液(160mL),1小时滴完。升温到室温搅拌30分钟,再次冷却到0℃,分批加入溴化亚铜(14.20g,98.99mmol),加完后室温反应40分钟,加热到140℃反应1.5小时。冷却到室温,用二氯甲烷萃取(100mL×3),合并有机相,有机相用水洗(200mL×2),无水硫酸钠干燥,浓缩,残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(v/v)=100:0~20:1)得到标题化合物5-溴-6-氟-2,3-二氢苯并呋喃(化合物3B),白色固体(4.50g,产率31.8%)。
1H NMR(400MHz,CDCl3)δ7.32–7.23(m,1H),6.57(d,1H),4.62(t,2H),3.22–3.11(m,2H)。
第二步:4-(6-氟-2,3-二氢苯并呋喃-7-羰基)哌啶-1-甲酸叔丁酯(3C)
tert-butyl 4-(6-fluoro-2,3-dihydrobenzofuran-7-carbonyl)piperidine-1-carboxylate
在-78℃下,往5-溴-6-氟-2,3-二氢苯并呋喃(3B)(2.17g,10.0mmol)的四氢呋喃(30mL)溶液中缓慢滴加正丁基锂的正己烷溶液(5.00mL,12.5mmol),搅拌30分钟,加入4-[甲氧基(甲基)氨基甲酰基]哌啶-1-甲酸叔丁酯(2.50g,9.18mmol),加完继续反应1小时。加入20mL饱和氯化铵水溶液,乙酸乙酯萃取(100mL×2),合并有机相,无水硫酸钠干燥,旋干,残留物用硅胶柱色谱分离纯化(石油醚:乙酸乙酯(v/v)=100:0~20:1)得到标题化合物4-(6-氟-2,3-二氢苯并呋喃-7-羰基)哌啶-1-甲酸叔丁酯(3C),淡黄色固体(1.90g,产率54.4%)。
1H NMR(400MHz,CDCl3)δ7.68(d,1H),6.50(d,1H),4.69(t,2H),4.15-4.09(m,2H),3.27-3.15(m,3H),2.90–2.85(m,2H),1.87(d,2H),1.66-1.60(m,2H),1.46(s,9H)。
LCMS m/z=372.1[M+23]。
第三步:(6-氟-2,3-二氢苯并呋喃-7-基)(哌啶-4-基)甲酮(3D)
(6-fluoro-2,3-dihydrobenzofuran-7-yl)(piperidin-4-yl)methanone
室温下在4-(6-氟-2,3-二氢苯并呋喃-7-羰基)哌啶-1-甲酸叔丁酯(3C)(1.90g,5.4mmol)的二氯甲烷(8mL)溶液中加入三氟乙酸(4mL),反应1小时。缓慢加入20mL饱和碳酸氢钠水溶液,二氯甲烷萃取(100mL,×3),合并有机相,有机相用无水硫酸钠干燥,旋干粗品直接用于下一步,黄色粘稠物(1.1g,产率81.4%)。
LCMS m/z=250.1[M+1]。
第四步:3-[4-(6-氟-2,3-二氢苯并呋喃-7-羰基)-1-哌啶基]吡咯烷-2-酮(3E)
3-[4-(6-fluoro-2,3-dihydrobenzofuran-7-carbonyl)-1-piperidyl]pyrrolidin-2-one
室温下在(6-氟-2,3-二氢苯并呋喃-7-基)(哌啶-4-基)甲酮(3D)(0.5g,2.0mmol)的20mL乙腈溶液中加入(2-氧代吡咯-3-基)甲磺酸酯(0.7g,4.0mmol)和二异丙基乙胺(0.5g,4.0mmol),加完后升温到80℃反应5小时。加入30mL水,乙酸乙酯萃取(100mL×2),合并有机相,有机相用水洗(100mL×2),无水硫酸钠干燥,浓缩。残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1~30:1)得到标题化合物3-[4-(6-氟-2,3-二氢苯并呋喃-7-羰基)-1-哌啶基]吡咯烷-2-酮(3E),淡黄色固体(0.35g,产率52.2%)。
1H NMR(400MHz,CDCl3)δ7.16–7.13(m,1H),6.56(dd,1H),6.05(s,1H),4.71–4.64(m,2H),3.47-3.43(t,1H),3.38–3.24(m,2H),3.19-3.14(q,2H),3.05-2.99(m,2H),2.92-2.85(m,1H),2.80-2.74(m,1H),2.45-2.37(m,1H),2.29–2.09(m,2H),1.99–1.88(m,2H),1.86–1.71(m,2H)。
LCMS m/z=333.3[M+1]。
第五步:2-[[3-[4-(6-氟-2,3-二氢苯并呋喃-7-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3,5,7,8-四氢吡喃并[4,3-d]嘧啶-4-酮(化合物3)
2-[[3-[4-(6-fluoro-2,3-dihydrobenzofuran-7-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]-3,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-4-one
室温下在化合物3-[4-(6-氟-2,3-二氢苯并呋喃-7-羰基)-1-哌啶基]吡咯烷-2-酮(3D)(0.35g,1.05mmol)的四氢呋喃(15mL)中加入2-(氯甲基)-7,8-二氢-3H-吡喃并[4,3-d]嘧啶-4(5H)-酮(0.25g,1.26mmol,参考WO2013008217中间体3的合成方法制备得到),加完后加入氢化钠(0.05g,1.26mmol),加完升温到80℃反应2小时。冷却到0℃加入5mL甲醇淬灭反应,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1~30:1)得到标题化合物2-[[3-[4-(6-氟-2,3-二氢苯并呋喃-7-羰基)-1-哌啶基]-2-氧代-吡咯烷-1-基]甲基]-3,5,7,8-四氢吡喃并[4,3-d]嘧啶-4-酮(化合物3),白色固体(0.03g,产率5.7%)。
1H NMR(400MHz,CDCl3)δ7.18–7.12(m,1H),6.56(dd,1H),4.70-4.66(t,2H),4.54(s,2H),4.40-4.38(m,2H),3.94-3.91(t,2H),3.63-3.59(t,1H),3.50-3.46(m,2H),3.19-3.15(t,2H),3.07–2.98(m,2H),2.92-2.87(m,1H),2.82-2.77(m,1H),2.66-2.64(t,2H),2.45-2.37(m,1H),2.31–2.20(m,1H),2.17-2.07(m,1H),1.94-1.89(m,2H),1.83–1.69(m,2H)。
LCMS m/z=497.1[M+1]。
实施例4
2-氯-5-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代吡咯烷-1-基]甲基]苯甲腈(化合物4)
2-chloro-5-[[3-[4-(2,3-dihydrobenzofuran-5-carbonyl)-1-piperidyl]-2-oxo-pyrrolidin-1-yl]methyl]benzonitrile
将3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G)(0.314g,1.0mmol)溶于四氢呋喃(10mL)中,加入5-溴甲基-2-氯苯甲腈(276mg,1.2mol),冷却到0℃,氮气保护,加入氢化钠(120mg,3.0mol),升温至70℃,反应1小时。把反应液冷却到0℃,滴加甲醇淬灭过量的氢化钠,减压浓缩,残留物用硅胶柱色谱分离提纯(甲醇:二氯甲烷(v/v)=0:1~5:95),得到标题化合物2-氯-5-[[3-[4-(2,3-二氢苯并呋喃-5-羰基)-1-哌啶基]-2-氧代吡咯烷-1-基]甲基]苯甲腈(化合物4),浅黄色固体(0.60g,产率54.5%)。
1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.78(dd,1H),7.55(d,1H),7.47(q,2H),6.81(d,1H),4.66(t,2H),4.51(d,1H),4.40(d,1H),3.57(t,1H),3.21(ddd,5H),3.11(s,1H),3.00(s,2H),2.48(s,1H),2.24(s,1H),2.07(s,1H),1.90(s,4H)。
LCMS m/z=464.3[M+1]。
实施例5
2-((3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)甲基)-6,7-二氢-3H-环戊并[d]嘧啶-4(5H)-酮(化合物5)
2-((3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)met hyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one
第一步:2-(氯甲基)-6,7-二氢-3H-环戊并[d]嘧啶-4(5H)-酮(5B)
2-(chloromethyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one
室温下在2-氧代环戊烷甲酸甲酯(5A)(7.10g,49.9mmol)的甲醇(150mL)溶液中加入三乙胺(4.20g,41.5mmol)和2-氯乙基脒(3.00g,0.649mmol),加完后室温反应5小时。反应完毕后加入水(200mL),用二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1~30:1)得到标题化合物2-(氯甲基)-6,7-二氢-3H-环戊并[d]嘧啶-4(5H)-酮(5B),淡黄色固体(1.00g,产率10.8%)。
1HNMR(400MHz,DMSO)δ12.58(s,1H),4.46(s,2H),2.76(t,2H),2.63(t,2H),2.04-1.90(m,2H)。
LCMSm/z=185.1[M+1]。
第二步:2-((3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)甲基)-6,7-二氢-3H-环戊并[d]嘧啶-4(5H)-酮(化合物5)
2-((3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)met hyl)-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one
0℃,在化合物3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G)(0.314g,1.00mmol)的四氢呋喃(10mL)溶液中加入2-(氯甲基)-6,7-二氢-3H-环戊并[d]嘧啶-4(5H)-酮(5B)(0.400g,2.17mmol),加完后,分批加入氢化钠(0.100g,4.17mmol),升温到80℃反应1小时。冷却到零度加入甲醇(5mL)淬灭反应,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1~30:1)得到标题化合物2-((3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)甲基)-6,7-二氢-3H-环戊并[d]嘧啶-4(5H)-酮(化合物5)白色固体(80mg,产率17.0%)。
1HNMR(400MHz,CDCl3)δ11.17(s,1H),7.83(s,1H),7.79(d,1H),6.80(d,1H),4.66(t,2H),4.40(dd,2H),3.64(t,1H),3.45(t,2H),3.25(t,3H),3.05(d,3H),2.89–2.74(m,4H),2.48(s,1H),2.32(s,1H),2.07(m,3H),1.87(s,4H)。
LCMSm/z=463.3[M+1]。
实施例6
2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)-N-(5,6-二氢噻唑[2,3-c][1,2,4]三氮唑-3-基)乙酰胺(化合物6)
2-(3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)-N-(5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-yl)acetamide
第一步:2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)乙酸甲酯(6B)
methyl2-(3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)acetate
将3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(1G)(1.0g,3.18mmol)溶于四氢呋喃(10mL)中,再加入溴乙酸乙酯(6A)(1.06g,6.36mol),冷却到0℃,氮气保护,加入氢化钠(153m g,6.36mol),0℃反应0.5小时。把反应液冷却到0℃,滴加甲醇淬灭过量的氢化钠,减压浓缩,残留物硅胶柱色谱分离提纯(甲醇:二氯甲烷(v/v)=0:1~5:95),得到标题化合物2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)乙酸甲酯(6B),黄色油状(0.370g,产率30.1%)。
1HNMR(400MHz,CDCl3)δ7.82(s,1H),7.77(dd,1H),6.80(d,1H),4.65(t,2H),4.13(d,1H),4.02(d,1H),3.74(s,3H),3.65–3.55(m,1H),3.48–3.34(m,2H),3.31–3.16(m,3H),3.11(d,1H),3.00(d,2H),2.58-2.43(m,1H),2.28(ddd,1H),2.21–2.07(m,1H),1.87(t,4H)。
LCMSm/z=387.1[M+1]。
第二步:2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)乙酸(6C)
2-(3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)aceti c acid
将2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)乙酸甲酯(6B)(0.370g,0.958mmol)溶于甲醇(8mL)中,加入氢氧化钠(0.0153g,0.383mmol)的水溶液(2mL),室温反应1小时。反应液加入盐酸(1mol/L)调节反应液至pH至4,减压浓缩。向反应液中加入二氯甲烷(10mL)和饱和食盐水溶液(3mL),分液,水相用二氯甲烷(10mL×3)萃取,合并有机相,无水硫酸钠干燥,浓缩,得到标题化合物2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)乙酸(6C),白色固体(0.310g,产率86.9%)。
1HNMR(400MHz,DMSO)δ13.03(s,1H),7.93(s,1H),7.86(d,1H),6.88(d,1H),4.65(t,2H),4.36(s,1H),4.05(s,2H),3.77(d,1H),3.68(s,1H),3.46(dd,3H),3.24(t,2H),3.15(d,1H),2.49–2.28(m,3H),1.93(d,4H)。
LCMSm/z=373.3[M+1]。
第三步:5-((2-溴乙基)硫基)-4H-1,2,4-三氮唑-3-氨(6E)
5-((2-bromoethyl)thio)-4H-1,2,4-triazol-3-amine
将原料3-氨基-5-巯基-1,2,4-三氮唑(6D)(2.320g,19.98mmol)溶于甲醇(25mL)中,加入甲醇钠(1.079g,19.98mmol),在加入1,2-二溴乙烷(30.02g,159.8mmol),室温反应3.5小时。反应完全后,直接减压浓缩,残留物用硅胶柱层析分离(二氯甲烷:甲醇(v:v)=100:1~100:3)得到标题化合物5-((2-溴乙基)硫基)-4H-1,2,4-三氮唑-3-氨(6E),白色固体(2.1g,产率47.1%)。
1HNMR(400MHz,DMSO)δ12.03(s,1H),6.11(s,2H),3.73–3.65(m,2H),3.37(m,2H)。
LCMSm/z=224.9[M+1]。
第四步:3-氨基-5,6-二氢噻唑并[2,3-C][1,2,4]三氮唑氢溴酸盐(6F)
5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-aminehydrobromide
将原料5-((2-溴乙基)硫基)-4H-1,2,4-三氮唑-3-氨(6E)(2.1g,9.41mmol)溶于N,N-二甲基甲酰胺(10mL)中,加热至50℃反应3.5小时。反应结束后,有白色固体析出,过滤固体,得到标题化合物3-氨基-5,6-二氢噻唑并[2,3-C][1,2,4]三氮唑氢溴酸盐(6F),白色固体(1.2g,产率57%)。
1HNMR(400MHz,DMSO)δ13.47(s,1H),8.49(s,2H),4.20–4.13(m,2H),4.09–4.02(m,2H)。
LCMSm/z=143.2[M+1]。
第五步:2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)-N-(5,6-二氢噻唑[2,3-c][1,2,4]三氮唑-3-基)乙酰胺(化合物6)
2-(3-(4-(2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)-N-(5,6-dihydrothiazolo[2,3-c][1,2,4]triazol-3-yl)acetamide
将2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)乙酸(6C)(0.300g,0.806mmol)溶于无水二氯甲烷(10mL)中,加入3-氨基-5,6-二氢噻唑并[2,3-C][1,2,4]三氮唑氢溴酸盐(6F)(0.198g,0.886mmol)和二异丙基乙基胺(0.416g,3.22mmol),搅拌下加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)(0.337g,0.886mmol)室温反应48小时。反应液浓缩,残余物用硅胶柱色谱分离提纯(甲醇:二氯甲烷(v/v)=0:1~10:90),得到标题化合物2-(3-(4-(2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)-N-(5,6-二氢噻唑[2,3-c][1,2,4]三氮唑-3-基)乙酰胺(化合物6),白色固体(0.070g,产率17%)。
1HNMR(400MHz,DMSO)δ9.21(s,1H),7.88(s,1H),7.84–7.76(m,1H),6.85(d,1H),4.63(t,2H),4.17–3.95(m,6H),3.57(dd,2H),3.41–3.33(m,2H),3.23(t,2H),3.11(dd,2H),2.81(s,2H),2.16(d,1H),1.99(s,1H),1.73(s,2H),1.57(s,2H)。
LCMSm/z=497.1[M+1]。
实施例7
2-((3-(4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)甲基)-7,8-二氢-3H-吡喃并[4,3-d]嘧啶-4(5H)-酮(化合物7)
2-((3-(4-(6-fluoro-2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one
第一步:4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-甲酸叔丁酯(7C)
tert-butyl4-(6-fluoro-2,3-dihydrobenzofuran-5-carbonyl)piperidine-1-carboxylate
在-78℃下,往5-溴-6-氟-2,3-二氢苯并呋喃(3B)(2.17g,10.0mmol)的四氢呋喃(30mL)溶液中缓慢滴加正丁基锂的正己烷溶液(5.00mL,12.5mmol),搅拌30分钟,加入4-[甲氧基(甲基)氨基甲酰基]哌啶-1-甲酸叔丁酯(2.50g,9.18mmol,CAS:139290-70-3),加完继续反应1小时。加入饱和氯化铵水溶液(20mL),用乙酸乙酯(100mL×2)萃取,合并有机相,无水硫酸钠干燥,旋干。残留物用硅胶柱色谱分离纯化(石油醚:乙酸乙酯(v/v)=100:0~20:1)得到标题化合物4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-甲酸叔丁酯(7C),淡黄色固体(1.10g,产率31.5%)。
1HNMR(400MHz,CDCl3)δ7.68(d,1H),6.50(d,1H),4.69(t,2H),4.12(m,2H),3.21(m,3H),2.96–2.80(m,2H),1.87(d,2H),1.61(m,2H),1.46(s,9H)。
LCMSm/z=372.1[M+23]。
第二步:(6-氟-2,3-二氢苯并呋喃-5-基)(哌啶-4-基)甲酮(7D)
(6-fluoro-2,3-dihydrobenzofuran-5-yl)(piperidin-4-yl)methanone
室温下在4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-甲酸叔丁酯(7C)(1.10g,3.15mmol)的二氯甲烷(8mL)溶液中加入三氟乙酸(4mL),反应1小时。缓慢加入饱和碳酸氢钠水溶液(20mL),二氯甲烷(100mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,旋干得标题化合物(6-氟-2,3-二氢苯并呋喃-5-基)(哌啶-4-基)甲酮(7D),白色固体(0.750g,产率95.6%)。
1HNMR(400MHz,DMSO)δ7.68(d,1H),6.78(d,1H),4.69(t,2H),3.28(dd,1H),3.18(dd,4H),2.80(m,2H),1.83(d,2H),1.55(m,2H)。
LCMSm/z=250.1[M+1]。
第三步:3-(4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(7E)
3-(4-(6-fluoro-2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)pyrrolidin-2-one
室温下在(6-氟-2,3-二氢苯并呋喃-5-基)(哌啶-4-基)甲酮(7D)(0.400,1.60mmol)的乙腈(20mL)溶液中加入(2-氧代吡咯-3-基)甲磺酸酯(1F)(1.20g,6.70mmol)和二异丙基乙胺(0.850g,6.58mmol),加完后升温到80℃反应5小时。加入水(30mL),乙酸乙酯(100mL×2)萃取,合并有机相,有机相用水(100mL×2)洗涤,无水硫酸钠干燥,浓缩。残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1~30:1)得到标题化合物3-(4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(7E),淡黄色固体(0.400g,产率75.0%)。
1HNMR(400MHz,DMSO)δ8.17(d,1H),7.66(d,1H),6.76(d,1H),4.68(t,2H),3.37–3.22(m,3H),3.23–3.08(m,3H),3.02(m,2H),2.74(s,1H),2.29(d,1H),2.17–2.01(m,2H),1.76(m,2H),1.59–1.38(m,2H)。
LCMSm/z=333.3[M+1]。
第四步:2-((3-(4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)甲基)-7,8-二氢-3H-吡喃并[4,3-d]嘧啶-4(5H)-酮(化合物7)
2-((3-(4-(6-fluoro-2,3-dihydrobenzofuran-5-carbonyl)piperidin-1-yl)-2-oxopyrrolidin-1-yl)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one
0℃,在化合物3-(4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)吡咯烷-2-酮(7E)(0.334g,1.00mmol)的四氢呋喃(15mL)中加入2-(氯甲基)-7,8-二氢-3H-吡喃并[4,3-d]嘧啶-4(5H)-酮(0.500g,2.49mmol,参考WO2013008217中间体3合成方法制备得到),加完后分批加入氢化钠(0.100g,4.17mmol),加完升温到80℃反应1小时。冷却到0℃加入甲醇(5mL)淬灭反应,浓缩,残留物用硅胶柱色谱分离提纯(二氯甲烷:甲醇(v/v)=100:1~30:1)得到标题化合物2-((3-(4-(6-氟-2,3-二氢苯并呋喃-5-羰基)哌啶-1-基)-2-氧代吡咯烷-1-基)甲基)-7,8-二氢-3H-吡喃并[4,3-d]嘧啶-4(5H)-酮(化合物7),白色固体(110mg,产率22.0%)。
1HNMR(400MHz,CDCl3)δ7.67(d,1H),6.48(d,1H),4.68(t,2H),4.55(s,2H),4.39(d,2H),3.93(t,2H),3.61(t,1H),3.51–3.42(m,2H),3.38(dd,1H),3.19(t,2H),3.09(d,2H),2.94(d,1H),2.66(t,2H),2.38(t,1H),2.32–2.21(m,1H),2.20–2.09(m,1H),1.93(d,2H),1.79(dd,2H)。
LCMSm/z=497.2[M+1]。
测试例
测试例1:通过报告基因检测方法测试化合物对wnt信号通路活性的抑制作用
Super-TOpFlash(STF)是对wnt信号通路特异响应的荧光素酶报告基因系统。将Super-TOpFlash(STF)质粒转入HEK293细胞,使用报告基因检测方法,可以反映化合物对细胞内wnt信号通路活性的抑制情况。连续培养的HEK293细胞种于六孔板中,于37℃,5%CO2二氧化碳孵箱培养过夜;当细胞达到90%融合时,使用Lipofectamine2000(Invitrogen)转染试剂转染报告基因质粒到细胞中,4.5小时后,细胞铺板至96孔板,每孔10000个细胞,于37℃,5%CO2二氧化碳孵箱中培养过夜,第二天加测试化合物。化合物溶于DMSO,最高浓度10μM,以细胞培养基5倍稀释,10个浓度,同时每孔加入50%wnt3A条件培养基,于37℃,5%CO2二氧化碳孵箱中培养24小时,使用荧光素酶报告基因检测试剂(Luciferase AssaySystem Freezer Pack,Promega,Cat.#E4530)和珀金埃尔默公司Envision酶标仪检测荧光强度,计算IC50值。测试结果见表1。
表1:化合物对wnt信号通路活性的抑制活性
化合物编号 | STF IC50(nM) |
1 | 8.27 |
2 | 1.51 |
3 | 66.17 |
4 | 24.99 |
5 | 5.74 |
6 | 21.69 |
7 | 4.62 |
结论:本发明化合物对wnt信号通路具有显著的抑制活性。
Claims (9)
1.一种通式(A)所示的化合物或药学上可以接受的盐,其中:
R1选自当被取代时,任选进一步被1至4个选自F、Cl、Br、I或氰基的取代基所取代;
或者R1选自
R2、R3和R4各自独立的选自H、F、Cl、Br或I;
R5、R6、R7和R8各自独立的选自H或C1-6烷基。
2.根据权利要求1所述的化合物或药学上可以接受的盐,其中该化合物选自通式(I)所述的化合物或药学上可以接受的盐:
3.根据权利要求1或2所述的化合物或药学上可以接受的盐,其中:
R1选自取代或未取代的如下结构之一: 当被取代时,任选进一步被1至4个选自F、Cl或氰基的取代基所取代;
或者R1选自
R2、R3和R4各自独立的选自H、F、Cl或Br;
R5、R6、R7和R8各自独立选自H。
4.根据权利要求3所述的化合物或药学上可以接受的盐,其中该化合物选自通式(II)所示的化合物或药学上可以接受的盐,其中:
5.根据权利要求4所述的化合物或药学上可以接受的盐,其中
R2、R3和R4各自独立的选自H、F、Cl或Br;
R5、R6、R7和R8各自独立的选自H、甲基或乙基。
6.根据权利要求1或2所述的化合物或药学上可以接受的盐,其中
R1选自
R2、R3和R4各自独立的选自H或F;
R5、R6、R7和R8各自独立的选自H。
7.根据权利要求1所述化合物或药学上可以接受的盐,其中化合物选自如下结构之一:
8.一种药物组合物,所述药物组合物含有治疗有效剂量的根据权 利要求1~7中任一项所述的化合物或药学上可以接受的盐,以及药学上可接受的载体或者赋形剂。
9.权利要求1-7中任一项所述的化合物或其药学上可以接受的盐,或权利要求8所述的药物组合物在制备治疗癌症相关药物中的用途。
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WO2004033427A1 (en) * | 2002-10-11 | 2004-04-22 | Astrazeneca Ab | 1,4-disubstituted piperidine derivatives and their use as 11-betahsd1 inhibitors |
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WO2007127726A2 (en) * | 2006-04-25 | 2007-11-08 | Eli Lilly And Company | Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
WO2013008217A1 (en) * | 2011-07-13 | 2013-01-17 | Novartis Ag | 4 - piperidinyl compounds for use as tankyrase inhibitors |
WO2013012723A1 (en) * | 2011-07-13 | 2013-01-24 | Novartis Ag | Novel 2-piperidin-1-yl-acetamide compounds for use as tankyrase inhibitors |
WO2013134079A1 (en) * | 2012-03-05 | 2013-09-12 | Amgen Inc. | Oxazolidinone compounds and derivatives thereof |
WO2014036022A1 (en) * | 2012-08-29 | 2014-03-06 | Amgen Inc. | Quinazolinone compounds and derivatives thereof |
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WO2004033427A1 (en) * | 2002-10-11 | 2004-04-22 | Astrazeneca Ab | 1,4-disubstituted piperidine derivatives and their use as 11-betahsd1 inhibitors |
CN101001836A (zh) * | 2004-05-07 | 2007-07-18 | 詹森药业有限公司 | 作为11-β羟基类固醇脱氢酶抑制剂的吡咯烷-2-酮和哌啶-2-酮衍生物 |
WO2007127726A2 (en) * | 2006-04-25 | 2007-11-08 | Eli Lilly And Company | Inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
WO2013008217A1 (en) * | 2011-07-13 | 2013-01-17 | Novartis Ag | 4 - piperidinyl compounds for use as tankyrase inhibitors |
WO2013012723A1 (en) * | 2011-07-13 | 2013-01-24 | Novartis Ag | Novel 2-piperidin-1-yl-acetamide compounds for use as tankyrase inhibitors |
WO2013134079A1 (en) * | 2012-03-05 | 2013-09-12 | Amgen Inc. | Oxazolidinone compounds and derivatives thereof |
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