本發明係關於一種具有組蛋白去乙醯酶6 (HDAC 6)抑制活性之新穎結構1,3,4-㗁二唑衍生化合物、其製備方法及其用途。The present invention relates to a novel 1,3,4-diazole derivative compound having histone deacetylase 6 (HDAC 6) inhibitory activity, a preparation method thereof and a use thereof.
在細胞中，轉譯後修飾(諸如乙醯化)係生物過程中心極為重要的調節模組且受多種酶嚴格控制。組蛋白係構成染色質之核心蛋白，且藉由作為DNA纏繞的軸幫助DNA縮合。另外，組蛋白乙醯化與去乙醯化之間的平衡在基因表現中起關鍵作用。In cells, post-translational modifications such as acetylation are extremely important regulatory modules at the heart of biological processes and are strictly controlled by a variety of enzymes. Histones are core proteins that make up chromatin and help DNA condense by acting as the axis around which DNA is wound. In addition, the balance between histone acetylation and deacetylation plays a key role in gene expression.
組蛋白去乙醯酶(HDAC)係移除構成染色質之組蛋白的離胺酸殘基的乙醯基的酶，並且已知與基因沈默相關並誘導細胞週期停滯、血管生成抑制、免疫調節、細胞死亡等(Hassig 等人，Curr. Opin. Chem. Biol. 1997, 1, 300-308)。此外，據報導，抑制HDAC酶功能可降低活體內癌細胞生存相關因子的活性並激活癌細胞死亡相關因子，從而誘導癌細胞自我死亡(Warrell等人，J. Natl. Cancer Inst. 1998, 90, 1621-1625)。Histone deacetylase (HDAC) is an enzyme that removes acetyl groups from lysine residues of histones constituting chromatin, and is known to be associated with gene silencing and induce cell cycle arrest, angiogenesis inhibition, immune regulation, cell death, etc. (Hassig et al., Curr. Opin. Chem. Biol. 1997, 1, 300-308). In addition, it is reported that inhibiting HDAC enzyme function can reduce the activity of cancer cell survival-related factors in vivo and activate cancer cell death-related factors, thereby inducing cancer cell self-death (Warrell et al., J. Natl. Cancer Inst. 1998, 90, 1621-1625).
在人類中，已知18種HDAC，並且根據與酵母HDAC的同源性將其分為四類。此處，使用鋅作為輔因子的11種HDAC可分為3組：I類(HDAC1、2、3及8)、II類(IIa：HDAC4、5、7及9；IIb：HDAC6及10)及IV類(HDAC 11)。此外，7種III類HDAC (SIRT 1-7)使用NAD+代替鋅作為輔因子(Bolden等人，Nat. Rev. Drug Discov. 2006, 5(9), 769-784)。In humans, 18 HDACs are known and are divided into four classes based on homology to yeast HDACs. Here, 11 HDACs that use zinc as a cofactor can be divided into three groups: class I (HDAC1, 2, 3, and 8), class II (IIa: HDAC4, 5, 7, and 9; IIb: HDAC6 and 10), and class IV (HDAC 11). In addition, 7 class III HDACs (SIRT 1-7) use NAD+ instead of zinc as a cofactor (Bolden et al., Nat. Rev. Drug Discov. 2006, 5(9), 769-784).
儘管各種HDAC抑制劑處於臨床前或臨床開發階段，但迄今為止，只有非選擇性HDAC抑制劑被稱為抗癌藥物，其中伏立諾他(vorinostat) (SAHA)及羅米地辛(romidepsin) (FK228)已被批准用於治療皮膚T細胞淋巴瘤，且帕比諾他(panobinostat) (LBH-589)已被批准用於治療多發性骨髓瘤。然而，眾所周知，非選擇性HDAC抑制劑在高劑量時會引起副作用，諸如疲勞、噁心等(Piekarz等人，Pharmaceuticals 2010, 3, 2751-2767)。據報導，此等副作用係由抑制I類HDAC引起的，並且由於此等副作用，非選擇性HDAC抑制劑在抗癌藥物以外的領域的藥物開發方面受到限制(Witt等人，Cancer Letters 277, (2009), 8-21)。Although various HDAC inhibitors are in the preclinical or clinical development stage, so far, only non-selective HDAC inhibitors are known as anticancer drugs, of which vorinostat (SAHA) and romidepsin (FK228) have been approved for the treatment of cutaneous T-cell lymphoma, and panobinostat (LBH-589) has been approved for the treatment of multiple myeloma. However, it is well known that non-selective HDAC inhibitors can cause side effects such as fatigue and nausea at high doses (Piekarz et al., Pharmaceuticals 2010, 3, 2751-2767). These side effects have been reported to be caused by the inhibition of class I HDACs, and due to these side effects, non-selective HDAC inhibitors have been limited in drug development in fields other than anticancer drugs (Witt et al., Cancer Letters 277, (2009), 8-21).
同時，據報導，選擇性II類HDAC抑制可能不會表現出I類HDAC抑制中所見的毒性，並且選擇性HDAC抑制劑的開發可解決諸如非選擇性HDAC抑制引起的毒性等副作用。因此，選擇性HDAC抑制劑有可能被開發為多種疾病的有效治療方法(Matthias等人，Mol. Cell. Biol. 2008, 28, 1688-1701)。At the same time, it has been reported that selective class II HDAC inhibition may not show the toxicity seen in class I HDAC inhibition, and the development of selective HDAC inhibitors may address side effects such as toxicity caused by non-selective HDAC inhibition. Therefore, selective HDAC inhibitors have the potential to be developed as effective treatments for a variety of diseases (Matthias et al., Mol. Cell. Biol. 2008, 28, 1688-1701).
HDAC6，IIb類HDAC之一，已知主要存在於細胞質中並參與許多非組蛋白受質(HSP90、皮層肌動蛋白(coractin)等)的去乙醯化，包括微管蛋白(Yao等人，Mol. Cell 2005, 18, 601-607)。HDAC6可能具有兩個催化域，且C端之鋅指域可與泛素化蛋白結合。已知由於HDAC6具有多種非組蛋白作為受質，所以其在諸如癌症、發炎性疾病、自體免疫疾病、神經性疾病及神經退化性疾病等各種疾病中發揮重要作用(Santo等人，Blood 2012 119, 2579-2589；Vishwakarma等人，International Immunopharmacology 2013, 16, 72-78；Hu等人，J. Neurol. Sci. 2011, 304, 1-8)。HDAC6, one of the class IIb HDACs, is known to be mainly present in the cytoplasm and is involved in the deacetylation of many non-histone substrates (HSP90, coractin, etc.), including tubulin (Yao et al., Mol. Cell 2005, 18, 601-607). HDAC6 may have two catalytic domains, and the C-terminal zinc finger domain can bind to ubiquitinated proteins. HDAC6 is known to play an important role in various diseases such as cancer, inflammatory diseases, autoimmune diseases, neurological diseases and neurodegenerative diseases because it has a variety of non-histone proteins as substrates (Santo et al., Blood 2012 119, 2579-2589; Vishwakarma et al., International Immunopharmacology 2013, 16, 72-78; Hu et al., J. Neurol. Sci. 2011, 304, 1-8).
各種HDAC抑制劑的共同結構特徵由封端基團、連接基團及鋅結合基團(ZBG)構成，如以下伏立諾他之結構中所示。許多研究人員透過封端基團及連接基團的結構修飾對酶的抑制活性及選擇性進行研究。已知鋅結合基團在酶抑制活性及選擇性中發揮更重要的作用(Wiest等人，J. Org. Chem. 2013 78: 5051-5065；Methot等人，Bioorg. Med. Chem. Lett. 2008, 18, 973-978)。The common structural features of various HDAC inhibitors are composed of a capping group, a linking group, and a zinc binding group (ZBG), as shown in the structure of vorinostat below. Many researchers have studied the inhibitory activity and selectivity of enzymes through structural modifications of the capping group and the linking group. It is known that the zinc binding group plays a more important role in enzyme inhibitory activity and selectivity (Wiest et al., J. Org. Chem. 2013 78: 5051-5065; Method et al., Bioorg. Med. Chem. Lett. 2008, 18, 973-978).
大部分鋅結合基團係異羥肟酸或苯甲醯胺，其中異羥肟酸衍生物顯示強HDAC抑制作用，但具有諸如生物利用度低及活性脫靶嚴重等問題。苯甲醯胺含有苯胺，且因此亦具有在活體內產生有毒代謝物的問題(Woster等人，Med. Chem. Commun. 2015, online publication)。Most zinc-binding groups are isohydroxyoxime or benzamide, of which isohydroxyoxime derivatives show strong HDAC inhibition, but have problems such as low bioavailability and severe off-target activity. Benzamide contains aniline and therefore also has the problem of producing toxic metabolites in vivo (Woster et al., Med. Chem. Commun. 2015, online publication).
因此，為了治療癌症、發炎性疾病、自體免疫疾病、神經性疾病及神經退化性疾病等，需要開發一種與具有副作用之非選擇性抑制劑不同的無副作用且生物利用度改良的具有鋅結合基團之選擇性HDAC6抑制劑。先前技術文獻WO 2011/091213: ACY-1215 WO 2011/011186: Tubastatin WO 2013/052110: Sloan-K WO 2013/041407: Cellzome WO 2013/134467: Kozi WO 2013/008162: Novartis WO 2013/080120: Novartis WO 2013/066835: Tempero WO 2013/066838: Tempero WO 2013/066833: Tempero WO 2013/066839: TemperoTherefore, in order to treat cancer, inflammatory diseases, autoimmune diseases, neurological diseases, neurodegenerative diseases, etc., it is necessary to develop a selective HDAC6 inhibitor having a zinc binding group that has no side effects and improved bioavailability, unlike non-selective inhibitors with side effects.Prior Art WO 2011/091213: ACY-1215 WO 2011/011186: Tubastatin WO 2013/052110: Sloan-K WO 2013/041407: Cellzome WO 2013/134467: Kozi WO 2013/008162: Novartis WO 2013/080120: Novartis WO 2013/066835: Tempero WO 2013/066838: Tempero WO 2013/066833: Tempero WO 2013/066839: Tempero
[技術問題][Technical issues]
本發明之目的為提供一種具有選擇性組蛋白去乙醯酶6 (HDAC6)抑制活性之化合物、其立體異構物或其醫藥學上可接受之鹽。The object of the present invention is to provide a compound having selective histone deacetylase 6 (HDAC6) inhibitory activity, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
本發明之另一目的為提供一種醫藥組合物，其包含具有選擇性HDAC6抑制活性之化合物、其立體異構物或其醫藥學上可接受之鹽。Another object of the present invention is to provide a pharmaceutical composition comprising a compound having selective HDAC6 inhibitory activity, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
本發明之又另一目標為提供其製備方法。Yet another object of the present invention is to provide a preparation method thereof.
本發明之又一目標為提供一種用於預防或治療HDAC6活性相關疾病的醫藥組合物。Another object of the present invention is to provide a pharmaceutical composition for preventing or treating diseases related to HDAC6 activity.
本發明之又一目標為提供其用於製備用以預防或治療HDAC6活性相關疾病之藥劑的用途。Another object of the present invention is to provide a use of the compound for preparing a medicament for preventing or treating diseases related to HDAC6 activity.
本發明之又一目標為提供一種用於預防或治療HDAC6活性相關疾病的方法，該方法包含投與治療有效量的如上文所描述之化合物。Another object of the present invention is to provide a method for preventing or treating diseases related to HDAC6 activity, which comprises administering a therapeutically effective amount of the compound as described above.
本發明之又一目標為提供用於預防或治療HDAC6活性相關疾病之用途。 [技術解決方案]Another object of the present invention is to provide a method for preventing or treating diseases related to HDAC6 activity.[Technical Solution]
本發明人發現具有組蛋白去乙醯酶6 (HDAC6)抑制活性之㗁二唑衍生化合物且使用該㗁二唑衍生化合物來抑制或治療HDAC6活性相關疾病，由此完成本發明。The inventors have discovered a oxadiazole derivative compound having histone deacetylase 6 (HDAC6) inhibitory activity and used the oxadiazole derivative compound to inhibit or treat diseases related to HDAC6 activity, thereby completing the present invention.
在下文中，將對其進行詳細描述。本文所揭示之各種要素之所有組合均在本發明之範疇內。此外，本發明之範疇不受以下具體描述限制。In the following, it will be described in detail. All combinations of various elements disclosed herein are within the scope of the present invention. In addition, the scope of the present invention is not limited by the following specific description.
1,3,4-㗁二唑衍生化合物在一個通用態樣中，本發明提供一種由以下化學式I表示之1,3,4-㗁二唑衍生化合物、其立體異構物或其醫藥學上可接受之鹽： [化學式I]在以上化學式I中， R1為-C1-4鹵烷基； X1至X4各獨立地為CRX或N； RX為-H、-C1-4烷基、-C1-4鹵烷基或-鹵基； Y為CRY或N； RY為-H或-C1-4烷基； Z為NRZ、O或S； RZ為-H或-C1-4烷基； W為O或S； m為0或1； 環V為芳基、雜芳基或氫化雜芳基{其中該芳基、雜芳基或氫化雜芳基環之至少一個H可經以下取代：-C1-4烷基、-C1-4胺基烷基、-C1-4羥基烷基、-C1-4鹵烷基、-鹵基、-(CH2)n-環烷基、-(CH2)n-雜環烷基或-(CH2)n-雜芳基[其中-(CH2)n-環烷基、-(CH2)n-雜環烷基或-(CH2)n-雜芳基環之至少一個H可經以下取代：-C1-4烷基、-C1-4鹵烷基、-鹵基、環烷基或雜環烷基(其中該環烷基或雜環烷基環之至少一個H可經-C1-4烷基取代)]}；及 n為0、1或2。1,3,4-oxadiazole derivative compound In a general aspect, the present invention provides a 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Chemical formula I] In the above chemical formula I,R1 is-C1-4 haloalkyl;X1 toX4 are each independently CRX or N;RX is -H,-C1-4 alkyl,-C1-4 haloalkyl or -halogen; Y is CRY or N;RY is -H or-C1-4 alkyl; Z is NRZ , O or S;RR is -H or-C1-4 alkyl; W is O or S; m is 0 or 1; Ring V is aryl, heteroaryl or hydrogenated heteroaryl {wherein at least one H of the aryl, heteroaryl or hydrogenated heteroaryl ring may be substituted by:-C1-4 alkyl,-C1-4 aminoalkyl,-C1-4 hydroxyalkyl,-C1-4 haloalkyl, -halogen, -(CH2 )n-cycloalkyl, -(CH2 )n-heterocycloalkyl or -(CH2 )n-heteroaryl [wherein at least one H of the -(CH2 )n-cycloalkyl, -(CH2 )n-heterocycloalkyl or -(CH2 )n-heteroaryl ring may be substituted by -C1-4 alkyl, -C1-4 haloalkyl, -halo, cycloalkyl or heterocycloalkyl (wherein at least one H of the cycloalkyl or heterocycloalkyl ring may be substituted by -C1-4 alkyl)]}; and n is 0, 1 or 2.
根據本發明之一實施例，由化學式I表示之化合物可在以下範圍內： R1為-C1-4鹵烷基； X1為N； X2至X4各獨立地為CRX； RX為-H或-鹵基； Y為CRY或N； RY為-H； Z為NRZ、O或S； RZ為-C1-4烷基； W為O或S； m為0或1； 環V為芳基、雜芳基或氫化雜芳基{其中該芳基、雜芳基或氫化雜芳基環之至少一個H可經以下取代：-C1-4烷基、-C1-4胺基烷基、-鹵基、-(CH2)n-環烷基、-(CH2)n-雜環烷基或-(CH2)n-雜芳基[其中-(CH2)n-環烷基、-(CH2)n-雜環烷基或-(CH2)n-雜芳基環之至少一個H可經以下取代：-C1-4烷基、-鹵基、環烷基或雜環烷基(其中該環烷基或雜環烷基環之至少一個H可經-C1-4烷基取代)]}；且 n為0或1。According to one embodiment of the present invention, the compound represented by Formula I may be within the following range:R1 is-C1-4 haloalkyl;X1 is N;X2 toX4 are each independentlyCRX ;RX is -H or -halogen; Y isCRY or N;RY is -H; Z isNRZ , O or S;RZ is-C1-4 alkyl; W is O or S; m is 0 or 1; Ring V is aryl, heteroaryl or hydrido heteroaryl {wherein at least one H of the aryl, heteroaryl or hydrido heteroaryl ring may be substituted by:-C1-4 alkyl,-C1-4 aminoalkyl, -halogen, -(CH2 )n-cycloalkyl, -(CH2 )n-heterocycloalkyl or -(CH2 )n-heteroaryl [wherein at least one H of -(CH2 )n-cycloalkyl, -(CH2 )n-heterocycloalkyl or -(CH2 )n-heteroaryl ring may be substituted by -C1-4 alkyl, -halogen, cycloalkyl or heterocycloalkyl (wherein at least one H of the cycloalkyl or heterocycloalkyl ring may be substituted by -C1-4 alkyl)]}; and n is 0 or 1.
另外，根據本發明之一實施例，由化學式I表示之化合物可在以下範圍內： R1為-CF2H或-CF3。In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range: R1 is -CF2 H or -CF3 .
另外，根據本發明之一實施例，由化學式I表示之化合物可在以下範圍內： X1為N；且 X2至X4各獨立地為CH或CF。In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range:X1 is N; andX2 toX4 are each independently CH or CF.
另外，根據本發明之一實施例，由化學式I表示之化合物可在以下範圍內： Y為CH或N； Z為N-C1-4烷基、O或S； W為O或S；且 m為0或1。In addition, according to one embodiment of the present invention, the compound represented by chemical formula I may be within the following ranges: Y is CH or N; Z is NC1-4 alkyl, O or S; W is O or S; and m is 0 or 1.
另外，根據本發明之一實施例，由化學式I表示之化合物可在以下範圍內： 環V為苯基、5員至10員雜芳基或9員至10員氫化雜芳基{其中該苯基、5員至10員雜芳基或9員至10員氫化雜芳基環之至少一個H可經以下取代：-C1-4烷基、-C1-4胺基烷基、-鹵基、-(CH2)n-環烷基、-(CH2)n-雜環烷基或-(CH2)n-雜芳基[其中-(CH2)n-環烷基、-(CH2)n-雜環烷基或-(CH2)n-雜芳基環之至少一個H可經以下取代：-C1-4烷基、-鹵基、4員至6員環烷基或4員至6員雜環烷基(其中該4員至6員環烷基或4員至6員雜環烷基環之至少一個H可經-C1-4烷基取代)]}；且 n為0或1。In addition, according to one embodiment of the present invention, the compound represented by Chemical Formula I may be within the following range: Ring V is phenyl, 5- to 10-membered heteroaryl or 9- to 10-membered hydridoaryl {wherein at least one H of the phenyl, 5- to 10-membered heteroaryl or 9- to 10-membered hydridoaryl ring may be substituted by: -C1-4 alkyl, -C1-4 aminoalkyl, -halogen, -(CH2 )n-cycloalkyl, -(CH2 )n-heterocycloalkyl or -(CH2 )n-heteroaryl [wherein at least one H of the -(CH2 )n-cycloalkyl, -(CH2 )n-heterocycloalkyl or -(CH2 )n-heteroaryl ring may be substituted by: -C wherein the present invention is selected from the group consisting of -C1-4 alkyl, -halogen, 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl (wherein at least one H of the 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl ring may be substituted with -C1-4 alkyl)]}; and n is 0 or 1.
另外，根據本發明之一實施例，由本發明之化學式I表示之特定化合物展示於下表1中： [表I]
在本發明中，除非另外規定，否則如本文中所使用之術語「烷基」可指其中連接碳原子之直鏈或分支鏈非環狀、環狀或飽和烴。舉例而言，「C1-4烷基」可意指含有1至4個碳原子的烷基。非環狀烷基可包括例如甲基、乙基、正丙基、正丁基、異丙基、二級丁基、異丁基、三級丁基以及其類似基團，但不限於此。在本說明書中，環狀烷基可與「環烷基」互換使用，且可包含例如環丙基、環丁基、環戊基、環己基、環庚基、環辛基及其類似基團，但不限於此。In the present invention, unless otherwise specified, the term "alkyl" as used herein may refer to a straight or branched chain non-cyclic, cyclic or saturated hydrocarbon in which carbon atoms are connected. For example, "C1-4 alkyl" may mean an alkyl group containing 1 to 4 carbon atoms. Non-cyclic alkyl groups may include, for example, methyl, ethyl, n-propyl, n-butyl, isopropyl, dibutyl, isobutyl, tertiary butyl and the like, but are not limited thereto. In the present specification, cyclic alkyl groups may be used interchangeably with "cycloalkyl" and may include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, but are not limited thereto.
在本發明中，「烷氧基」可指-(O-烷基)作為烷基醚基團，其中烷基與上文所定義相同。舉例而言，「C1-4烷氧基」可意指含有C1-4烷基之烷氧基，亦即-(O-C1-4烷基)；且該烷氧基之實例可包括(但不限於)甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、二級丁氧基、三級丁氧基及其類似基團。In the present invention, "alkoxy" may refer to -(O-alkyl) as an alkyl ether group, wherein the alkyl group is the same as defined above. For example, "C1-4 alkoxy" may refer to an alkoxy group containing a C1-4 alkyl group, i.e., -(OC1-4 alkyl); and examples of the alkoxy group may include (but are not limited to) methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, di-butoxy, tertiary butoxy and the like.
在本發明中，「鹵基」可為F、Cl、Br或I。In the present invention, the "halogen group" may be F, Cl, Br or I.
在本發明中，術語「鹵烷基」可意謂具有經至少一個如本文所定義之鹵基取代之碳原子的直鏈或分支鏈烷基(烴)。鹵烷基之實例包括(但不限於)獨立地經至少一個鹵素(諸如F、Cl、Br或I)取代之甲基、乙基、丙基、異丙基、異丁基或正丁基。In the present invention, the term "haloalkyl" may refer to a straight or branched chain alkyl (alkyl) group having at least one carbon atom substituted with a halogen as defined herein. Examples of halogenalkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl groups independently substituted with at least one halogen (such as F, Cl, Br or I).
在本發明中，術語「羥烷基」可指具有經-OH取代之碳原子的直鏈或分支鏈烷基(烴)。羥烷基之實例包括(但不限於)獨立地經至少一個羥基取代之甲基、乙基、丙基、異丙基、異丁基或正丁基。In the present invention, the term "hydroxyalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) group having a carbon atom substituted with -OH. Examples of hydroxyalkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl groups independently substituted with at least one hydroxyl group.
在本發明中，術語「胺基烷基」可指具有經胺基-(NR'R'')取代之碳原子的直鏈或分支鏈烷基(烴)。在本文中，R'及R''可各獨立地選自由氫及C1-4烷基組成之群，且選定的R'及R''可各獨立地經取代或未經取代。In the present invention, the term "aminoalkyl" may refer to a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted by an amino group -(NR'R''). Herein, R' and R'' may each independently be selected from the group consisting of hydrogen and C1-4 alkyl, and the selected R' and R'' may each independently be substituted or unsubstituted.
在本發明中，術語「雜環烷基」可意謂含有1至5個選自N、O及S之雜原子作為成環原子的環，且可為飽和的或部分不飽和的。在本文中，當不飽和時，雜環烷基可稱為雜環烯。除非另有說明，否則雜環烷基可為單環或多環，諸如螺環、橋環或稠環。此外，「3員至12員雜環烷基」可意謂含有3至12個成環原子的雜環烷基。雜環烷基之實例可包括(但不限於)吡咯啶、哌啶、咪唑啶、吡唑啶、丁內醯胺、戊內醯胺、咪唑啶酮、乙內醯脲、二氧雜環戊烷、鄰苯二甲醯亞胺、哌啶、嘧啶-2,4(1H,3H)-二酮、1,4-二㗁烷、𠰌啉、硫代𠰌啉、硫代𠰌啉-S-氧化物、硫代𠰌啉-S,S-氧化物、哌𠯤、哌喃、吡啶酮、3-吡咯啉、硫代哌喃、哌哢(pyrone)、四氫呋喃、四氫噻吩、奎寧環、䓬烷、2-氮雜螺[3.3]庚烷、(1R,5S)-3-氮雜雙環[3.2.1]辛烷、(1S,4S)-2氮雜雙環[2.2.2]辛烷或(1R,4R)-2-氧雜-5-氮雜雙環[2.2.2]辛烷及其類似物。In the present invention, the term "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as ring-forming atoms, and may be saturated or partially unsaturated. Herein, when unsaturated, the heterocycloalkyl may be referred to as a heterocycloalkene. Unless otherwise specified, the heterocycloalkyl may be a monocyclic or polycyclic ring, such as a spirocyclic ring, a bridged ring or a condensed ring. In addition, "3-membered to 12-membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 ring-forming atoms. Examples of heterocycloalkyl groups include, but are not limited to, pyrrolidine, piperidine, imidazolidinyl, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, iodine, thiodine, iodine-S-oxide, iodine-S,S-oxide, piperidine, pyran, pyridine, ketone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinine, hexane, 2-azaspiro[3.3]heptane, (1R,5S)-3-azabicyclo[3.2.1]octane, (1S,4S)-2-azabicyclo[2.2.2]octane or (1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and the like.
在本發明中，「芳烴」可意謂芳族烴環。芳烴可為單環芳烴或多環芳烴。芳烴中之環碳原子之數目可為5個或更多及30個或更少、5個或更多個及20個或更少、或5個或更多及15個或更少。芳烴之實例可包括(但不限於)苯、萘、茀、蒽、菲、聯苯、三苯、四苯、五苯、六苯、聯伸三苯、芘、苯并丙二烯合茀、䓛及其類似者。在本說明書中，藉由自以上「芳烴」移除一個氫原子而獲得的部分稱為「芳基」。In the present invention, "aromatic hydrocarbon" may mean an aromatic hydrocarbon ring. The aromatic hydrocarbon may be a monocyclic aromatic hydrocarbon or a polycyclic aromatic hydrocarbon. The number of ring carbon atoms in the aromatic hydrocarbon may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of aromatic hydrocarbons may include, but are not limited to, benzene, naphthalene, fluorene, anthracene, phenanthrene, biphenyl, triphenyl, tetraphenyl, pentyl, hexaphenyl, diphenyl, pyrene, benzophenone, chrysene, and the like. In the present specification, the portion obtained by removing one hydrogen atom from the above "aromatic hydrocarbon" is referred to as an "aryl group".
在本發明中，「雜芳烴」可為含有O、N、P、Si及S中之一或多者作為異質元素之環。雜芳烴之環碳原子之數目可為2個或更多及30個或更多，或2個或更多及20個或更少。雜芳烴可為單環雜芳烴或多環雜芳烴。多環雜芳烴可具有例如雙環或三環結構。雜芳烴之實例可包括(但不限於)噻吩、嘌呤、吡咯、吡唑、咪唑、噻唑、㗁唑、異噻唑、㗁二唑、三唑、吡啶、二吡啶基、三𠯤、吖啶基、嗒𠯤、吡𠯤、喹啉、喹唑啉、喹㗁啉、啡㗁 𠯤、呔𠯤、嘧啶、吡啶并嘧啶、吡啶并吡𠯤、吡𠯤并吡𠯤、異喹啉、吲哚、咔唑、咪唑并嗒𠯤、咪唑并吡啶、咪唑并嘧啶、吡唑并嘧啶、咪唑并吡𠯤或吡唑并吡啶、N-芳基咔唑、N-雜芳基咔唑、N-烷基咔唑、苯并㗁唑、苯并咪唑、苯并噻唑、苯并咔唑、苯并噻吩、二苯并噻吩、噻吩并噻吩、苯并呋喃、啡啉、異㗁唑、㗁二唑、噻二唑、苯并噻唑、四唑、啡噻𠯤、二苯并矽雜環戊二烯(dibenzosilole)、二苯并呋喃及其類似者。在本發明之一實施例中，雜芳烴亦可包括雙環雜環芳烴，其包括稠合至雜環烷基環之芳烴環或稠合至環烷基環之雜芳烴。在本說明書中，藉由自以上「雜芳烴」移除一個氫原子而獲得之部分稱為「雜芳基」。In the present invention, "heteroarene" may be a ring containing one or more of O, N, P, Si and S as a heterogeneous element. The number of ring carbon atoms of the heteroarene may be 2 or more and 30 or more, or 2 or more and 20 or less. The heteroarene may be a monocyclic heteroarene or a polycyclic heteroarene. The polycyclic heteroarene may have, for example, a bicyclic or tricyclic structure. Examples of heteroaromatic hydrocarbons may include, but are not limited to, thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxadiazole, isothiazole, oxadiazole, triazole, pyridine, dipyridyl, trioxadiazole, acridinium, pyridinium, pyridine, quinoline, quinazoline, quinoline, phenanthroline, pyrimidine, pyr ... oxadiazole, pyrimidine, pyridopyrimidine, pyridopyridine, pyridopyridine, isoquinoline, indole, carbazole, imidazothiazolidine, imidazopyridine, imidazopyrimidine, pyrazolopyridine, imidazopyridine or pyrazolopyridine, N-arylcarbazole, N-heteroarylcarbazole, N-alkylcarbazole, benzoxazole, benzimidazole, benzothiazole, benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoquinoline, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenathiothiazolidine, dibenzosilole, dibenzofuran and the like. In one embodiment of the present invention, the heteroarene may also include a bicyclic heterocyclic arene including an arene ring fused to a heterocycloalkyl ring or a heteroarene fused to a cycloalkyl ring. In the present specification, the moiety obtained by removing a hydrogen atom from the above "heteroarene" is referred to as a "heteroaryl group".
本發明的由化學式I表示之化合物可含有至少一個不對稱碳且因此可以外消旋物、外消旋混合物、單一鏡像異構物、非鏡像異構混合物及各非鏡像異構物的形式存在。此等立體異構物可藉由習知技術分離，且例如，由化學式I表示之化合物可藉由管柱層析、HPLC或其類似者分離。除此以外，由化學式I表示之化合物之各立體異構物可使用光學純起始物質及/或具有已知組態之試劑以立體特異方式合成。The compounds represented by Formula I of the present invention may contain at least one asymmetric carbon and thus may exist as racemates, racemic mixtures, single mirror image isomers, non-mirror image isomer mixtures and each non-mirror image isomer. Such stereoisomers may be separated by known techniques, and for example, the compounds represented by Formula I may be separated by column chromatography, HPLC or the like. In addition, each stereoisomer of the compound represented by Formula I may be synthesized in a stereospecific manner using optically pure starting materials and/or reagents with known configurations.
在本發明中，如本文所使用之術語「鏡像異構物」意謂具有相同化學式或分子式但在空間排列方面不同的化合物或其鹽。此等鏡像異構物及其混合物中之每一者亦包括在本發明之範疇內。除非另有規定，否則連接至不對稱碳原子之實線鍵(-)可包括楔形實線鍵或楔形虛線鍵，其表示立體中心之絕對排列。In the present invention, the term "mirror image isomer" as used herein means a compound or a salt thereof having the same chemical formula or molecular formula but different in spatial arrangement. Each of these mirror image isomers and mixtures thereof are also included in the scope of the present invention. Unless otherwise specified, a solid line bond (-) connected to an asymmetric carbon atom may include a wedge-shaped solid line bond. or Dashed Wedge Key , which represents the absolute arrangement of the stereocenter.
本發明之由化學式I表示之化合物可以「醫藥學上可接受之鹽」形式存在。作為鹽，由醫藥學上可接受之游離酸形成之酸加成鹽係有用的。如本文所用，術語「醫藥學上可接受之鹽」係指對患者具有相對無毒且無害的有效作用之濃度，其包括由化學式I表示之化合物之任何有機酸或無機酸加成鹽，其中由此等鹽引起之副作用不降低化合物之有益功效。The compounds represented by Formula I of the present invention may exist in the form of "pharmaceutically acceptable salts". As salts, acid addition salts formed from pharmaceutically acceptable free acids are useful. As used herein, the term "pharmaceutically acceptable salt" refers to a concentration that has an effective effect that is relatively non-toxic and harmless to patients, including any organic or inorganic acid addition salts of the compounds represented by Formula I, wherein the side effects caused by such salts do not reduce the beneficial effects of the compound.
酸加成鹽係藉由習知方法來製備的，例如藉由將化合物溶解於過量酸水溶液中且使用可與水混溶之有機溶劑(諸如甲醇、乙醇、丙酮或乙腈)沈澱鹽。可加熱等莫耳量之化合物及酸或醇之水溶液，且隨後可將混合物蒸發至乾燥，或所沈澱的鹽可經抽吸過濾。Acid addition salts are prepared by known methods, for example by dissolving the compound in an excess of aqueous acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equimolar amounts of the compound and the aqueous acid or alcohol solution may be heated, and the mixture may then be evaporated to dryness, or the precipitated salt may be filtered with suction.
在此情況下，作為游離酸，可使用有機酸或無機酸，其中，無機酸可包括鹽酸、磷酸、硫酸、硝酸及其類似酸，且有機酸可包括甲磺酸、對甲苯磺酸、乙酸、三氟乙酸、順丁烯二酸、丁二酸、草酸、苯甲酸、酒石酸、反丁烯二酸、杏仁酸、丙酸、檸檬酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、麩胺酸、戊二酸、葡糖醛酸、天冬胺酸、抗壞血酸、碳酸、香草酸、氫碘酸及其類似酸。然而，有機酸及無機酸不限於此。In this case, as the free acid, an organic acid or an inorganic acid may be used, wherein the inorganic acid may include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid and the like, and the organic acid may include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like. However, the organic acid and the inorganic acid are not limited thereto.
此外，可使用鹼製備醫藥學上可接受之金屬鹽。例如藉由將化合物溶解於過量鹼金屬氫氧化物或鹼土金屬氫氧化物溶液中及過濾未溶解的化合物鹽，然後蒸發及乾燥濾液獲得鹼金屬鹽或鹼土金屬鹽。此處，作為金屬鹽，鈉鹽、鉀鹽或鈣鹽尤其適合於醫藥態樣，但金屬鹽不限於此。此外，對應銀鹽可藉由使鹼金屬或鹼土金屬鹽與適合銀鹽(例如硝酸銀)反應來獲得。In addition, a pharmaceutically acceptable metal salt can be prepared using a base. For example, the alkali metal salt or alkali earth metal salt can be obtained by dissolving the compound in an excess alkali metal hydroxide or alkali earth metal hydroxide solution and filtering the undissolved compound salt, and then evaporating and drying the filtrate. Here, as the metal salt, sodium salt, potassium salt or calcium salt is particularly suitable for pharmaceutical use, but the metal salt is not limited thereto. In addition, the corresponding silver salt can be obtained by reacting an alkali metal or alkali earth metal salt with a suitable silver salt (e.g., silver nitrate).
除非另有指示，否則本發明之醫藥學上可接受之鹽包括可存在於由以上化學式I表示之化合物中的酸性或鹼性基團之鹽。舉例而言，醫藥學上可接受之鹽可包括羥基之鈉鹽、鈣鹽及鉀鹽，且胺基之其他醫藥學上可接受之鹽可包括氫溴酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、磷酸氫鹽、磷酸二氫鹽、乙酸鹽、丁二酸鹽、檸檬酸鹽、酒石酸鹽、乳酸鹽、杏仁酸鹽、甲磺酸鹽(methanesulfonate/mesylate)及對甲苯磺酸鹽(p-toluenesulfonate/tosylate)及其類似鹽，其可經由此項技術中已知的鹽製備方法製備。Unless otherwise indicated, the pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups which may be present in the compounds represented by the above Chemical Formula I. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxyl groups, and other pharmaceutically acceptable salts of amine groups may include hydrobromates, sulfates, hydrogen sulfates, phosphates, hydrogen phosphates, dihydrogen phosphates, acetates, succinates, citrates, tartrates, lactates, mandelates, methanesulfonates (mesylate) and p-toluenesulfonates (tosylate) and the like, which can be prepared by salt preparation methods known in the art.
製備1,3,4-㗁二唑衍生化合物之方法本發明提供一種製備由以下化學式I表示之1,3,4-㗁二唑衍生化合物、其立體異構物或其醫藥學上可接受之鹽的方法： [化學式I]化學式I如上文所定義。Method forpreparing1,3,4-oxadiazole derivative compounds The present invention provides a method for preparing a 1,3,4-oxadiazole derivative compound represented by the following chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Chemical formula I] Formula I is as defined above.
在本發明中，製備由化學式I表示之㗁二唑衍生化合物、其立體異構物或其醫藥學上可接受之鹽的較佳方法展示於以下[反應流程1]至[反應流程8]中，且其經修改至熟習此項技術者顯而易見之程度的製備方法亦包括於其中。 [反應流程1]In the present invention, a preferred method for preparing the oxadiazole derivative compound represented by Chemical Formula I, its stereoisomers or pharmaceutically acceptable salts thereof is shown in the following [Reaction Scheme 1] to [Reaction Scheme 8], and the preparation methods thereof modified to the extent obvious to those skilled in the art are also included therein. [Reaction Scheme 1]
根據以上反應流程1，將肼添加至化合物1-1中以製備化合物1-2，然後與三氟乙酸酐或二氟乙酸酐反應以製備化合物1-3，且接著進行溴化反應以合成化合物1-4。化合物1-4係HDAC 6抑制劑之Zn-黏合劑部分且在所有化合物之合成中用作中間物。 [反應流程2]According to the above reaction scheme 1, hydrazine is added to compound 1-1 to prepare compound 1-2, which is then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare compound 1-3, and then subjected to bromination reaction to synthesize compound 1-4. Compound 1-4 is the Zn-binder part of the HDAC 6 inhibitor and is used as an intermediate in the synthesis of all compounds. [Reaction Scheme 2]
根據以上反應流程2，使用肼由化合物2-1製備化合物2-2，且接著藉由採用CDI且使用1,3,4-㗁二唑-2(3H)-酮及乙基黃原酸鉀製備1,3,4-㗁二唑-2(3H)-硫酮化合物2-4。此外，可藉由將勞森氏試劑添加至化合物2-2中來製備化合物2-3，且接著可藉由使用CDI來製備1,3,4-噻二唑-2(3H)-酮化合物2-4。經由與化合物2-4及化合物1-4發生取代反應來製備化合物2-5。待藉由以上反應流程2製備的化合物2-5的實例可包括化合物1號、5號、15號、16號、17號、18號、42號、43號、44號、45號、46號、47號、48號、49號、50號、51號、52號、53號、54號、59號、60號、61號、62號及其類似者。 [反應流程3]According to the above reaction scheme 2, compound 2-2 is prepared from compound 2-1 using hydrazine, and then 1,3,4-thiadiazole-2(3H)-thione compound 2-4 is prepared by using CDI and using 1,3,4-thiadiazole-2(3H)-one and potassium ethylxanthate. In addition, compound 2-3 can be prepared by adding Lawson's reagent to compound 2-2, and then 1,3,4-thiadiazole-2(3H)-one compound 2-4 can be prepared by using CDI. Compound 2-5 is prepared by a substitution reaction with compound 2-4 and compound 1-4. Examples of compound 2-5 to be prepared by the above reaction scheme 2 may include compound No. 1, No. 5, No. 15, No. 16, No. 17, No. 18, No. 42, No. 43, No. 44, No. 45, No. 46, No. 47, No. 48, No. 49, No. 50, No. 51, No. 52, No. 53, No. 54, No. 59, No. 60, No. 61, No. 62 and the like. [Reaction Scheme 3]
在反應流程3中，對具有醛結構的化合物3-1進行還原胺化以製備化合物3-2，接著使用肼製備化合物3-3，且接著使用CDI製備1,3,4-㗁二唑-2(3H)-酮化合物3-4。接著，可經由與化合物1-4發生取代反應製備化合物3-5。待藉由以上反應流程3製備的化合物3-5的實例可包含化合物2號及4號以及其類似者。 [反應流程3-1]In reaction scheme 3, compound 3-1 having an aldehyde structure is subjected to reductive amination to prepare compound 3-2, then hydrazine is used to prepare compound 3-3, and then CDI is used to prepare 1,3,4-oxadiazol-2(3H)-one compound 3-4. Then, compound 3-5 can be prepared through a substitution reaction with compound 1-4. Examples of compound 3-5 to be prepared by the above reaction scheme 3 may include compounds No. 2 and No. 4 and the like. [Reaction scheme 3-1]
在反應流程3-1中，使用乙二醇，由化合物3-1製備保護醛結構之二氧雜環戊烷化合物3-1-1，且接著使用肼製備化合物3-1-2。隨後，藉由採用CDI且使用1,3,4-㗁二唑-2(3H)-酮及乙基黃原酸鉀製備1,3,4-㗁二唑-2(3H)-硫酮化合物3-1-3。隨後，經由與化合物1-4發生取代反應製備化合物3-1-4，且藉由使用六水合氯化鐵(III)移除二氧雜環戊烷(醛保護基)來製備化合物3-1-5。隨後，可經由還原胺化製備化合物3-5。待藉由反應流程3-1製備之化合物3-5之實例可包括化合物84號、85號、86號、87號、88號、89號、90號、91號、92號、93號、94號、95號、96號、97號、98號、99號、107號、108號、109號、110號、111號、112號、113號、114號、117號、118號、119號、120號、121號、122號、123號、124號、125號、128號、129號、130號、131號、132號、133號、134號及其類似者。 [反應流程3-2]In reaction scheme 3-1, ethylene glycol is used to prepare a dioxacyclopentane compound 3-1-1 with an aldehyde structure protected from compound 3-1, and then hydrazine is used to prepare compound 3-1-2. Subsequently, 1,3,4-oxadiazole-2(3H)-thione compound 3-1-3 is prepared by using CDI and 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate. Subsequently, compound 3-1-4 is prepared by a substitution reaction with compound 1-4, and compound 3-1-5 is prepared by removing the dioxacyclopentane (aldehyde protecting group) using iron (III) chloride hexahydrate. Subsequently, compound 3-5 can be prepared by reductive amination. Examples of compound 3-5 to be prepared by reaction scheme 3-1 may include compound No. 84, No. 85, No. 86, No. 87, No. 88, No. 89, No. 90, No. 91, No. 92, No. 93, No. 94, No. 95, No. 96, No. 97, No. 98, No. 99, No. 107, No. 108, No. 109, No. 110, No. 111, No. 112, No. 113, No. 114, No. 117, No. 118, No. 119, No. 120, No. 121, No. 122, No. 123, No. 124, No. 125, No. 128, No. 129, No. 130, No. 131, No. 132, No. 133, No. 134 and the like. [Reaction scheme 3-2]
在反應流程3-2中，對具有醛結構之化合物3-1進行還原胺化以製備化合物3-2-1，接著使用肼製備化合物3-2-2，且接著藉由採用CDI及使用1,3,4-㗁二唑-2(3H)-酮及乙基黃原酸鉀來製備1,3,4-㗁二唑-2(3H)-硫酮化合物3-2-4。此外，藉由將勞森氏試劑添加至化合物3-2-2中來製備化合物3-2-3，且接著藉由使用CDI來製備1,3,4-噻二唑-2(3H)-酮化合物3-2-4。接著，使用與化合物3-2-4及化合物1-4的取代反應製備化合物3-2-5，且藉由移除胺保護基來製備化合物3-2-6，然後進行還原胺化，以製備化合物3-2-7。待藉由以上反應流程3-2製備之化合物3-2-7的實例可包括化合物63號、64號、65號、66號、67號、68號、77號、78號、79號、83號及其類似者。 [反應流程4]In reaction scheme 3-2, compound 3-1 having an aldehyde structure is subjected to reductive amination to prepare compound 3-2-1, then compound 3-2-2 is prepared using hydrazine, and then 1,3,4-oxadiazole-2(3H)-thione compound 3-2-4 is prepared by using CDI and using 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate. In addition, compound 3-2-3 is prepared by adding Lawson's reagent to compound 3-2-2, and then 1,3,4-thiadiazol-2(3H)-one compound 3-2-4 is prepared by using CDI. Next, compound 3-2-5 is prepared using a substitution reaction with compound 3-2-4 and compound 1-4, and compound 3-2-6 is prepared by removing the amine protecting group, followed by reductive amination to prepare compound 3-2-7. Examples of compound 3-2-7 to be prepared by the above reaction scheme 3-2 may include compound Nos. 63, 64, 65, 66, 67, 68, 77, 78, 79, 83 and the like. [Reaction Scheme 4]
在反應流程4中，使具有鹵素元素之酯化合物4-1發生C-C偶合(鈴木偶合)反應以製備化合物4-2，然後進行還原反應以製備化合物4-3。此外，經由C-N偶合(布赫瓦爾德反應)及取代反應由化合物4-1製備化合物4-3。隨後，使用肼製備化合物4-4，且接著藉由採用CDI及使用1,3,4-㗁二唑-2(3H)-酮及乙基黃原酸鉀製備1,3,4-㗁二唑-2(3H)-硫酮化合物4-6。此外，藉由將勞森氏試劑添加至化合物4-4中來製備化合物4-5，且接著藉由使用CDI來製備1,3,4-噻二唑-2(3H)-酮化合物4-6。接下來，經由與化合物1-4發生取代反應來製備化合物4-7，且接著藉由移除胺保護基來製備化合物4-8。化合物4-8之實例可包括化合物20號、23號及36號，以及其類似者。隨後，可經由還原胺化製備化合物4-9。待藉由以上反應流程4製備之化合物4-9之實例可包括化合物8號、9號、10號、21號、22號、24號、25號、26號、29號、30號、37號、38號、39號、40號、41號、55號、56號、57號、58號、75號、76號、80號、81號、82號、100號、101號、102號、103號、104號、105號、106號、115號、116號、126號、127號及其類似者。In Reaction Scheme 4, the ester compound 4-1 having a halogen element is subjected to C-C coupling (Suzuki coupling) reaction to prepare compound 4-2, and then subjected to reduction reaction to prepare compound 4-3. In addition, compound 4-3 is prepared from compound 4-1 via C-N coupling (Buchwald reaction) and substitution reaction. Subsequently, compound 4-4 is prepared using hydrazine, and then 1,3,4-oxadiazole-2(3H)-thione compound 4-6 is prepared by using CDI and using 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate. In addition, compound 4-5 is prepared by adding Lawson's reagent to compound 4-4, and then 1,3,4-thiadiazol-2(3H)-one compound 4-6 is prepared by using CDI. Next, compound 4-7 is prepared by a substitution reaction with compound 1-4, and then compound 4-8 is prepared by removing the amine protecting group. Examples of compound 4-8 may include compounds No. 20, No. 23 and No. 36, and the like. Subsequently, compound 4-9 may be prepared by reductive amination. Examples of compounds 4-9 to be prepared by the above reaction scheme 4 may include compounds No. 8, No. 9, No. 10, No. 21, No. 22, No. 24, No. 25, No. 26, No. 29, No. 30, No. 37, No. 38, No. 39, No. 40, No. 41, No. 55, No. 56, No. 57, No. 58, No. 75, No. 76, No. 80, No. 81, No. 82, No. 100, No. 101, No. 102, No. 103, No. 104, No. 105, No. 106, No. 115, No. 116, No. 126, No. 127 and the like.
此外，可經由還原胺化由根據反應流程4製備之化合物4-8來製備化合物4-10，且可藉由移除胺保護基來製備化合物4-11，然後進行還原胺化以製備化合物4-12。化合物4-12之實例可包括化合物27號、28號及其類似者。 [反應流程4-1]In addition, compound 4-10 can be prepared from compound 4-8 prepared according to reaction scheme 4 via reductive amination, and compound 4-11 can be prepared by removing the amine protecting group and then performing reductive amination to prepare compound 4-12. Examples of compound 4-12 may include compound No. 27, No. 28 and the like. [Reaction scheme 4-1]
在反應流程4-1中，使用肼，由具有鹵素元素之酯化合物4-1製備化合物4-2，且使用CDI製備1,3,4-㗁二唑-2(3H)-酮化合物4-3。隨後，經由與化合物1-4發生取代反應來製備化合物4-4，然後進行胺取代反應來製備化合物4-9。待藉由反應流程4-1製備之化合物的實例可包括化合物6號、7號及其類似者。 [反應流程5]In reaction scheme 4-1, compound 4-2 is prepared from ester compound 4-1 having a halogen element using hydrazine, and 1,3,4-oxadiazol-2(3H)-one compound 4-3 is prepared using CDI. Subsequently, compound 4-4 is prepared by a substitution reaction with compound 1-4, and then an amine substitution reaction is performed to prepare compound 4-9. Examples of the compound to be prepared by reaction scheme 4-1 may include compound No. 6, No. 7, and the like. [Reaction scheme 5]
在反應流程5中，使含胺化合物5-1受胺保護基保護且進行烷化反應以製備化合物5-2，接著使用肼製備化合物5-3，且接著藉由採用CDI及使用1,3,4-㗁二唑-2(3H)-酮及乙基黃原酸鉀來製備1,3,4-㗁二唑-2(3H)-硫酮化合物5-4。接著，可經由與化合物1-4發生取代反應製備化合物5-5。待藉由反應流程5製備之化合物5-5的實例可包括化合物19號、31號、32號及其類似者。In Reaction Scheme 5, the amine-containing compound 5-1 is protected with an amine protecting group and subjected to an alkylation reaction to prepare the compound 5-2, followed by the use of hydrazine to prepare the compound 5-3, and then by using CDI and using 1,3,4-oxadiazole-2(3H)-one and potassium ethylxanthate to prepare the 1,3,4-oxadiazole-2(3H)-thione compound 5-4. Then, the compound 5-5 can be prepared via a substitution reaction with the compound 1-4. Examples of the compound 5-5 to be prepared by Reaction Scheme 5 may include Compound Nos. 19, 31, 32, and the like.
此外，可藉由移除根據反應流程5製備之化合物5-5的胺保護基來製備化合物5-6，且化合物5-6之實例可包括化合物3號、11號、33號、34號、35號及其類似者。In addition, compound 5-6 can be prepared by removing the amine protecting group of compound 5-5 prepared according to reaction scheme 5, and examples of compound 5-6 may include compound No. 3, No. 11, No. 33, No. 34, No. 35 and the like.
隨後，可經由還原胺化製備化合物5-7。待藉由以上反應流程5製備之化合物5-7的實例可包括化合物12號、13號、14號、135號、136號、137號、138號、139號、140號、141號及其類似者。 [反應流程6]Subsequently, compound 5-7 can be prepared by reductive amination. Examples of compound 5-7 to be prepared by the above reaction scheme 5 may include compound No. 12, No. 13, No. 14, No. 135, No. 136, No. 137, No. 138, No. 139, No. 140, No. 141 and the like. [Reaction Scheme 6]
在反應流程6中，經由取代反應由溴化合物6-1製備乙酸鹽化合物6-2，然後進行取代反應以製備甲酸肼化合物6-3，且接著藉由使用乙醇化鈉製備1,3,4-㗁二唑-2-酮化合物6-4。接著，可經由與化合物1-4發生取代反應製備化合物6-5。待藉由反應流程6製備之化合物6-5的實例可包括化合物69號、70號、71號、72號、73號、74號及其類似者。 [反應流程7]In Reaction Scheme 6, acetate compound 6-2 is prepared from bromine compound 6-1 through substitution reaction, then substitution reaction is performed to prepare hydrazine formate compound 6-3, and then 1,3,4-oxadiazol-2-one compound 6-4 is prepared by using sodium ethanolate. Next, compound 6-5 can be prepared through substitution reaction with compound 1-4. Examples of compound 6-5 to be prepared by Reaction Scheme 6 may include compound Nos. 69, 70, 71, 72, 73, 74 and the like. [Reaction Scheme 7]
在反應流程7中，製備受化合物7-1之胺保護基保護的化合物7-2，接著經由與化合物7-3發生取代反應製備參鍵化合物7-4，且接著使用雙(三氟甲磺醯基)亞胺銀製備㗁唑-2(3H)-酮化合物7-5。接下來，可使用肼製備化合物7-6，然後與三氟乙酸酐或二氟乙酸酐反應以製備化合物7-7。待藉由反應流程7製備之化合物的實例可包括化合物142號、143號及其類似者。 [反應流程8]In Reaction Scheme 7, Compound 7-2 protected by the amine protecting group of Compound 7-1 is prepared, and then a key compound 7-4 is prepared by a substitution reaction with Compound 7-3, and then oxazol-2(3H)-one compound 7-5 is prepared using silver bis(trifluoromethanesulfonyl)imide. Next, Compound 7-6 may be prepared using hydrazine, and then reacted with trifluoroacetic anhydride or difluoroacetic anhydride to prepare Compound 7-7. Examples of the compound to be prepared by Reaction Scheme 7 may include Compound Nos. 142, 143, and the like. [Reaction Scheme 8]
在反應流程8中，可經由與化合物1-4發生取代反應，由咪唑2-酮化合物8-1製備化合物8-2。待藉由反應流程8製備之化合物的實例可包括化合物144號及其類似者。In Reaction Scheme 8, Compound 8-2 can be prepared from imidazol-2-one Compound 8-1 via a substitution reaction with Compound 1-4. Examples of the compound to be prepared by Reaction Scheme 8 may include Compound No. 144 and the like.
1,3,4-㗁二唑衍生化合物之用途本發明提供由以下化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽的用途： [化學式I]化學式I如上文所定義。Use of1,3,4-oxadiazole derivative compounds The present invention provides uses of a compound represented by the following chemical formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof: [Chemical formula I] Formula I is as defined above.
根據本發明之一實施例，本發明提供一種醫藥組合物，其包含由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽作為活性成分。According to one embodiment of the present invention, the present invention provides a pharmaceutical composition comprising a compound represented by Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
另外，根據本發明之一實施例，本發明提供一種用於預防或治療組蛋白去乙醯酶6活性相關疾病之醫藥組合物，其包含如上所述之由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽作為活性成分。本發明之醫藥組合物選擇性地抑制組蛋白去乙醯酶6，由此顯示出在預防或治療組蛋白去乙醯酶6活性相關疾病方面的顯著作用。In addition, according to one embodiment of the present invention, the present invention provides a pharmaceutical composition for preventing or treating diseases related to histone deacetylase 6 activity, which comprises the compound represented by chemical formula I as described above, its stereoisomer or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition of the present invention selectively inhibits histone deacetylase 6, thereby showing a significant effect in preventing or treating diseases related to histone deacetylase 6 activity.
除了與組蛋白去乙醯酶功能異常相關之症狀或疾病以外，組蛋白去乙醯酶6 (HDAC6)活性相關疾病亦包括癌症、發炎性疾病、自體免疫疾病、神經性疾病或神經退化性疾病，且具體而言係肺癌、大腸癌、乳癌、前列腺癌、肝癌、腦癌、卵巢癌、胃癌、皮膚癌、胰臟癌、神經膠質瘤、神經母細胞瘤、白血病、淋巴瘤、多發性骨髓瘤、實體癌、威爾遜氏病(Wilson's disease)、脊髓小腦失調、普里昂疾病(prion disease)、帕金森氏病(Parkinson's disease)、亨廷頓氏症(Huntington's disease)、肌萎縮性側索硬化、澱粉樣變性、阿茲海默症(Alzheimer's disease)、酒精性肝病、脊髓性肌萎縮、類風濕性關節炎或骨關節炎。In addition to symptoms or diseases associated with abnormal histone deacetylase function, diseases associated with histone deacetylase 6 (HDAC6) activity also include cancer, inflammatory diseases, autoimmune diseases, neurological diseases or neurodegenerative diseases, and specifically lung cancer, colorectal cancer, breast cancer, prostate cancer, liver cancer, brain cancer, ovarian cancer, stomach cancer, skin cancer, pancreatic cancer, neuroglioma, neuroblastoma, leukemia, lymphoma, multiple myeloma, solid cancer, Wilson's disease, spinocerebellar disorders, prion diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, amyloid degeneration, Alzheimer's disease, disease), alcoholic liver disease, spinal muscular atrophy, rheumatoid arthritis, or osteoarthritis.
根據本發明之一實施例，組蛋白去乙醯酶介導之疾病的實例可包括傳染病；贅瘤；內分泌、營養性及代謝性疾病；精神及行為障礙；神經性疾病；眼睛及眼部附件疾病；循環系統疾病；呼吸道疾病；消化系統疾病；皮膚及皮下組織疾病；肌肉骨胳及結締組織疾病；或先天性畸形、變形及染色體異常。此外，組蛋白去乙醯酶介導之疾病包括與組蛋白去乙醯酶6之功能異常相關之症狀或疾病。According to one embodiment of the present invention, examples of histone deacetylase-mediated diseases may include infectious diseases; tumors; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; eye and ocular adnexa diseases; circulatory system diseases; respiratory diseases; digestive system diseases; skin and subcutaneous tissue diseases; musculoskeletal and connective tissue diseases; or congenital malformations, deformations and chromosomal abnormalities. In addition, histone deacetylase-mediated diseases include symptoms or diseases associated with abnormal function of histone deacetylase 6.
在本發明中，傳染病可為普里昂疾病。此外，贅瘤可為良性腫瘤(例如骨髓發育不良症候群)或惡性腫瘤(例如多發性骨髓瘤、淋巴瘤、白血病、肺癌、結腸直腸癌、大腸癌、前列腺癌、尿道上皮細胞癌、乳癌、黑色素瘤、皮膚癌、肝癌、腦癌、胃癌、卵巢癌、胰臟癌、頭頸癌、口腔癌或神經膠質瘤)。此外，內分泌、營養性及代謝性疾病可為威爾遜氏病、澱粉樣變性或糖尿病。另外，精神及行為障礙為抑鬱症或雷特氏症候群(rett syndrome)。此外，神經性疾病可包括中樞神經系統萎縮(例如亨廷頓氏症、脊髓性肌萎縮(SMA)、脊髓小腦失調(SCA))、神經退化性疾病(例如阿茲海默症)、運動障礙(例如帕金森氏病)、神經病變(例如，遺傳性神經病變(恰克-馬利-杜斯氏病(Charcot-Marie-Tooth disease)、偶發性神經病變、發炎性神經病變、藥物誘導性神經病變)、運動神經元疾病(例如肌萎縮性側索硬化(ALS))、或中樞神經系統髓鞘脫失病(例如多發性硬化(MS))。此外，眼睛及眼部附件疾病可為葡萄膜炎。另外，循環系統疾病可為心房微顫或中風。此外，呼吸道疾病可為哮喘。另外，消化道疾病可為酒精性肝病、發炎性腸病、克羅恩氏病(Crohn's disease)或潰瘍性腸病。此外，皮膚及皮下組織疾病可為牛皮癬。另外，肌肉骨胳及結締組織疾病可為類風濕性關節炎、骨關節炎或全身性紅斑狼瘡症(SLE)。此外，先天性畸形、變形及染色體異常可為常染色體顯性多囊性腎病。In the present invention, the infectious disease may be a prion disease. In addition, the tumor may be a benign tumor (e.g., myelodysplastic syndrome) or a malignant tumor (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colorectal cancer, prostate cancer, urothelial cell cancer, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or neuroglioma). In addition, the endocrine, nutritional, and metabolic diseases may be Wilson's disease, amyloidosis, or diabetes. In addition, the mental and behavioral disorders may be depression or Rett syndrome. In addition, neurological diseases may include central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative diseases (e.g., Alzheimer's disease), movement disorders (e.g., Parkinson's disease), neuropathies (e.g., hereditary neuropathies (Charcot-Marie-Tooth disease ... In addition, the disease of the eye and ocular adnexa may be uveitis. In addition, the disease of the circulatory system may be atrial fibrillation or stroke. In addition, the disease of the respiratory tract may be asthma. In addition, the disease of the digestive tract may be alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or Diseases of the skin and subcutaneous tissues may be psoriasis. Diseases of the musculoskeletal and connective tissues may be rheumatoid arthritis, osteoarthritis or systemic lupus erythematosus (SLE). Congenital malformations, deformations and chromosomal abnormalities may be autosomal dominant polycystic nephropathy.
立體異構物及醫藥學上可接受之鹽係如上文所描述的由化學式I表示之化合物的立體異構物及醫藥學上可接受之鹽。Stereoisomers and pharmaceutically acceptable salts are stereoisomers and pharmaceutically acceptable salts of the compound represented by Formula I as described above.
為了投與，除了由化學式I表示之化合物、其立體異構物或醫藥學上可接受之鹽以外，本發明之醫藥組合物可進一步包含至少一或多種醫藥學上可接受之載劑。醫藥學上可接受之載劑可為生理食鹽水、無菌水、林格氏溶液(Ringer's solution)、緩衝鹽水、右旋糖溶液、麥芽糊精溶液、甘油、乙醇或此等成分中之一或多者之混合物，且必要時，可含有其他習知添加劑，諸如抗氧化劑、緩衝劑、抑菌劑及其類似物。此外，可另外添加稀釋劑、分散劑、界面活性劑、黏合劑及潤滑劑且可將其調配成可注射調配物，諸如水溶液、懸浮液、乳液及其類似物、丸劑、膠囊、顆粒劑或錠劑。因此，本發明之醫藥組合物可為貼劑、液體、丸劑、膠囊、顆粒劑、錠劑、栓劑或其類似者。此等調配物可藉由此項技術中用於調配之習知方法或文獻[參見Remington's Pharmaceutical Science (最新版本), Mack Publishing Company, Easton PA]中所揭示之方法製備，且視每種疾病或組分而定，可調配成多種調配物。For administration, in addition to the compound represented by Formula I, its stereoisomers or pharmaceutically acceptable salts, the pharmaceutical composition of the present invention may further comprise at least one or more pharmaceutically acceptable carriers. The pharmaceutically acceptable carrier may be physiological saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol or a mixture of one or more of these components, and may contain other known additives, such as antioxidants, buffers, antibacterial agents and the like, if necessary. In addition, diluents, dispersants, surfactants, adhesives and lubricants may be added and may be formulated into injectable formulations, such as aqueous solutions, suspensions, emulsions and the like, pills, capsules, granules or tablets. Thus, the pharmaceutical composition of the present invention may be a patch, liquid, pill, capsule, granule, tablet, suppository or the like. Such formulations may be prepared by methods known in the art for formulation or disclosed in the literature [see Remington's Pharmaceutical Science (latest edition), Mack Publishing Company, Easton PA] and may be formulated into a variety of formulations depending on each disease or component.
本發明之組合物可根據所需方法經口或非經腸投與(例如靜脈內、皮下、腹膜內或局部施用)，且劑量視患者體重、年齡、性別、健康狀況、飲食、投與時間、投與方法、排泄率及疾病嚴重程度而變化。本發明的由化學式I表示之化合物的日劑量為約1至1000 mg/kg，較佳地為5至100 mg/kg，並且可為分次的且一日一次或數次投與。The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage varies depending on the patient's weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. The daily dosage of the compound represented by Formula I of the present invention is about 1 to 1000 mg/kg, preferably 5 to 100 mg/kg, and can be divided and administered once or several times a day.
除了由化學式I表示之化合物、其立體異構物或醫藥學上可接受之鹽以外，本發明之醫藥組合物可進一步包含至少一種表現出相同或相似功效的活性成分。In addition to the compound represented by Formula I, its stereoisomers or pharmaceutically acceptable salts, the pharmaceutical composition of the present invention may further comprise at least one active ingredient exhibiting the same or similar efficacy.
根據本發明之一實施例，本發明提供一種預防或治療組蛋白去乙醯酶6活性相關疾病之方法，其包含：向有需要個體投與治療有效量的由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽。個體可為哺乳動物，包括人類。According to one embodiment of the present invention, the present invention provides a method for preventing or treating a disease associated with histone deacetylase 6 activity, comprising: administering a therapeutically effective amount of a compound represented by chemical formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject may be a mammal, including a human.
預防或治療組蛋白去乙醯酶6活性相關疾病之方法包含不僅在症狀發作之前應對疾病本身，而且藉由投與由化學式I表示之化合物、其立體異構物或醫藥學上可接受之鹽抑制或避免其症狀。另外，本發明之預防或治療組蛋白去乙醯酶6活性相關疾病之方法可進一步投與治療有效量之另一種活性劑，該另一種活性劑有助於與由化學式I表示之化合物一起治療疾病，其中該另一種活性劑可與由以上化學式I表示之化合物一起表現出協同或輔助作用。The method for preventing or treating a disease related to histone deacetylase 6 activity includes not only treating the disease itself before the onset of symptoms, but also inhibiting or avoiding its symptoms by administering a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In addition, the method for preventing or treating a disease related to histone deacetylase 6 activity of the present invention may further administer a therapeutically effective amount of another active agent, which helps to treat the disease together with the compound represented by Formula I, wherein the other active agent may exhibit a synergistic or adjuvant effect with the compound represented by the above Formula I.
本文所用之術語「治療有效量」係指可有效治療或預防組蛋白去乙醯酶6活性相關疾病的由化學式I表示之化合物的量。具體言之，「醫藥學上有效量」意謂在適用於醫學治療之合理益處/風險比下足以治療疾病之量，且有效劑量水準可視包括以下之因素而定：個體類型及嚴重程度、年齡、性別、疾病類型、藥物活性、對藥物之敏感性、投與時間、投與途徑、排泄率、治療持續時間、同時使用之藥物及醫學領域中熟知之其他因素。本發明之醫藥組合物可作為單獨治療劑或與其他治療劑組合投與，或可與市售治療劑依序或同時投與。此外，本發明之醫藥組合物可單次或以多次劑量投與。考慮到所有上述因素，重要的是投與能夠以最小量獲得最大作用而無副作用之量，該量可由熟習此項技術者容易地確定。本發明之醫藥組合物之投與劑量可由專家根據各種因素(諸如患者之狀況、年齡、性別、併發症及其類似者)來確定。由於本發明之醫藥組合物之活性成分具有極佳安全性，因此可甚至超過預定劑量來使用活性成分。The term "therapeutically effective amount" used herein refers to the amount of the compound represented by Chemical Formula I that can effectively treat or prevent diseases related to histone deacetylase 6 activity. Specifically, "pharmaceutically effective amount" means an amount sufficient to treat the disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level can be determined according to factors including: individual type and severity, age, sex, disease type, drug activity, sensitivity to the drug, administration time, administration route, excretion rate, duration of treatment, drugs used simultaneously, and other factors well known in the medical field. The pharmaceutical composition of the present invention can be administered as a single therapeutic agent or in combination with other therapeutic agents, or can be administered sequentially or simultaneously with commercially available therapeutic agents. In addition, the pharmaceutical composition of the present invention can be administered in a single or multiple doses. Taking all of the above factors into account, it is important to administer an amount that can achieve the maximum effect with the minimum amount without side effects, which can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention can be determined by an expert based on various factors such as the patient's condition, age, sex, complications, and the like. Since the active ingredients of the pharmaceutical composition of the present invention have excellent safety, the active ingredients can be used even in excess of the predetermined dosage.
根據本發明之一實施例，本發明提供一種選擇性抑制組蛋白去乙醯酶6 (HDAC6)之方法，其藉由向哺乳動物(包括人類)投與由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽進行。According to one embodiment of the present invention, the present invention provides a method for selectively inhibiting histone deacetylase 6 (HDAC6), which is performed by administering a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof to a mammal (including a human).
根據本發明之一實施例，本發明提供由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽的用途。According to one embodiment of the present invention, the present invention provides the use of a compound represented by Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.
根據本發明之一實施例，本發明提供由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽的用途，其用於製造治療組蛋白去乙醯酶6活性相關疾病之藥物。用於製造藥劑的由化學式I表示之化合物可與可接受佐劑、稀釋劑、載劑及其類似物混合，且可與其他活性劑一起製備為組合製劑，以具有活性成分之協同作用。According to one embodiment of the present invention, the present invention provides the use of a compound represented by Formula I, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease associated with the activity of histone deacetylase 6. The compound represented by Formula I used for the manufacture of a medicament can be mixed with an acceptable adjuvant, diluent, carrier and the like, and can be prepared as a combination preparation together with other active agents to have a synergistic effect of the active ingredients.
根據本發明之一實施例，本發明提供由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽的用途，其係用於預防或治療組蛋白去乙醯酶6介導之疾病。用於預防或治療組蛋白去乙醯酶6介導之疾病的由化學式I表示之化合物可與可接受佐劑、稀釋劑、載劑及其類似物混合，且可與其他活性劑一起製備為組合製劑，以具有活性成分之協同作用。According to one embodiment of the present invention, the present invention provides the use of a compound represented by Formula I, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for preventing or treating a disease mediated by histone deacetylase 6. The compound represented by Formula I for preventing or treating a disease mediated by histone deacetylase 6 can be mixed with an acceptable adjuvant, diluent, carrier, and the like, and can be prepared as a combination preparation together with other active agents to have a synergistic effect of the active ingredients.
本發明之用途、組合物及治療方法中提及之物質同樣適用，只要其不彼此矛盾即可。The substances mentioned in the uses, compositions and treatment methods of the present invention are equally applicable, as long as they do not conflict with each other.
本發明之例示性實施例可修改成各種其他形式，且本發明之範疇不限於下文所描述的例示性實施例。此外，提供本發明之例示性實施例以更完整地向一般熟習此項技術者闡釋本發明。此外，除非另有說明，否則整個說明書中的「包含」組分並不意謂排除其他組分，而是意謂可進一步包含其他組分。 [有利作用]The exemplary embodiments of the present invention can be modified into various other forms, and the scope of the present invention is not limited to the exemplary embodiments described below. In addition, the exemplary embodiments of the present invention are provided to more completely explain the present invention to those who are generally familiar with this technology. In addition, unless otherwise stated, the "comprising" components throughout the specification do not mean to exclude other components, but mean that other components can be further included. [Beneficial effects]
本發明之由化學式I表示之化合物、其立體異構物或其醫藥學上可接受之鹽可選擇性地抑制HDAC6，從而對組蛋白去乙醯酶6活性相關疾病具有顯著極佳的預防或治療作用。The compound represented by chemical formula I, its stereoisomers or pharmaceutically acceptable salts thereof of the present invention can selectively inhibit HDAC6, thereby having a significant and excellent preventive or therapeutic effect on diseases related to histone deacetylase 6 activity.
在下文中，將經由實例及實驗實例更詳細地描述本發明。然而，此等實例及其類似者僅作為本發明之實例呈現，且本發明之範疇不僅限於此等實例。Hereinafter, the present invention will be described in more detail by way of examples and experimental examples. However, these examples and the like are presented only as examples of the present invention, and the scope of the present invention is not limited to these examples.
1,3,4-㗁二唑衍生化合物之製備如下描述用於製備由化學式I表示之化合物的特定方法。Preparation of1,3,4-oxadiazole derivative compounds A specific method for preparing the compound represented by Formula I is described below.
實例5：合成化合物5，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(2-噻吩基)-1,3,4-㗁二唑-2-酮[步驟1]合成6-甲基菸鹼醯肼Example5: Synthesis ofCompound5,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-thienyl)-1,3,4-oxadiazol- 2-one[Step1]Synthesis of6-methylnicotinylhydrazine
向6-甲基菸鹼酸甲酯(10.000 g，66.151 mmol)在室溫溶解於乙醇(200 mL)中之溶液中添加單水合肼(32.151 mL，661.507 mmol)，且在相同溫度攪拌混合物18小時。自反應混合物中減壓移除溶劑，得到濃縮物。向濃縮物中倒入水，然後用二氯甲烷萃取。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。所得產物不經進一步純化即使用(8.248 g，82.5%，白色固體)。To a solution of methyl 6-methylnicotinate (10.000 g, 66.151 mmol) dissolved in ethanol (200 mL) at room temperature, hydrazine monohydrate (32.151 mL, 661.507 mmol) was added, and the mixture was stirred at the same temperature for 18 hours. The solvent was removed from the reaction mixture under reduced pressure to obtain a concentrate. Water was poured into the concentrate, and then extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (8.248 g, 82.5%, white solid).
[步驟2]合成2-(二氟甲基)-5-(6-甲基吡啶-3-基)-1,3,4-㗁二唑[Step2]Synthesis of2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole
向步驟1中合成之6-甲基菸鹼醯肼(8.248 g，54.561 mmol)在0℃溶解於四氫呋喃(200 mL)中之溶液中添加三乙胺(38.024 mL，272.805 mmol)且在相同溫度攪拌10分鐘。向反應混合物中添加2,2-二氟乙酸酐(20.349 mL，163.683 mmol)且進一步在80℃攪拌3小時，且隨後藉由將溫度降低至室溫來終止反應。將碳酸氫鈉飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，80 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到呈黃色固體形式之標題化合物(8.019 g，69.6%)。To a solution of 6-methylnicotinyl hydrazide (8.248 g, 54.561 mmol) synthesized in step 1 dissolved in tetrahydrofuran (200 mL) at 0°C, triethylamine (38.024 mL, 272.805 mmol) was added and stirred at the same temperature for 10 minutes. 2,2-Difluoroacetic anhydride (20.349 mL, 163.683 mmol) was added to the reaction mixture and further stirred at 80°C for 3 hours, and then the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 80 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (8.019 g, 69.6%) as a yellow solid.
[步驟3]合成2-(6-(溴甲基)-吡啶-3-基)-5-(二氟甲基)-1,3,4-㗁二唑[Step3]Synthesis of2-(6-(bromomethyl)-pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole
將步驟2中合成之2-(二氟甲基)-5-(6-甲基吡啶-3-基)-1,3,4-㗁二唑(8.019 g，37.974 mmol)、1-溴吡咯啶-2,5-酮(NBS，8.110 g，45.569 mmol)及偶氮二異丁腈(AIBN，0.624 g，3.797 mmol)在室溫溶解於1,2-二氯乙烷(120 mL)中之溶液在相同溫度攪拌6小時。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，80 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到呈棕色固體形式之標題化合物(3.960 g，36.0%)。A solution of 2-(difluoromethyl)-5-(6-methylpyridin-3-yl)-1,3,4-oxadiazole (8.019 g, 37.974 mmol), 1-bromopyrrolidin-2,5-one (NBS, 8.110 g, 45.569 mmol), and azobisisobutyronitrile (AIBN, 0.624 g, 3.797 mmol) synthesized in step 2 was dissolved in 1,2-dichloroethane (120 mL) at room temperature and stirred at the same temperature for 6 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 80 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (3.960 g, 36.0%) as a brown solid.
[步驟4]合成噻吩-2-卡肼[Step4]Synthesis of Thiophene-2-Carbohydrazide
向噻吩-2-甲酸甲酯(100.00%溶液，0.163 mL，1.410 mmol)在室溫溶解於乙醇(10 mL)中之溶液中添加單水合肼(100.00%溶液，1.367 mL，28.100 mmol)，且在60℃攪拌5小時，且接著藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑，得到濃縮物。向濃縮物中倒入碳酸氫鈉飽和水溶液，且用二氯甲烷萃取反應混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。所得產物不經進一步純化即使用(0.2 g，99.8%，淺黃色固體)。To a solution of thiophene-2-carboxylic acid methyl ester (100.00% solution, 0.163 mL, 1.410 mmol) dissolved in ethanol (10 mL) at room temperature, hydrazine monohydrate (100.00% solution, 1.367 mL, 28.100 mmol) was added, and stirred at 60° C. for 5 hours, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure to obtain a concentrate. A saturated aqueous solution of sodium bicarbonate was poured into the concentrate, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was used without further purification (0.2 g, 99.8%, light yellow solid).
[步驟5]合成5-(2-噻吩基)-3H-1,3,4-㗁二唑-2-酮[Step5]Synthesis of5-(2-thienyl)-3H-1,3,4-oxadiazol-2-one
向步驟4中合成之噻吩-2-卡肼(100.00%，0.200 g，1.407 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.274 g，1.690 mmol)在室溫溶解於四氫呋喃(10 mL)中之溶液中添加三乙胺(100.00%溶液，0.273 mL，2.000 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到呈淺黃色固體之標題化合物(0.143 g，60.450%)。To a solution of thiophene-2-carbohydrazide (100.00%, 0.200 g, 1.407 mmol) and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.274 g, 1.690 mmol) synthesized in step 4 dissolved in tetrahydrofuran (10 mL) at room temperature, triethylamine (100.00% solution, 0.273 mL, 2.000 mmol) was added, and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.143 g, 60.450%) as a light yellow solid.
[步驟6]合成化合物5[Step6]Synthesis of Compound5
向步驟5中合成之5-(2-噻吩基)-3H-1,3,4-㗁二唑-2-酮(100.00%，0.063 g，0.350 mmol)及碳酸鉀(100.00%，0.049 g，0.494 mmol)在室溫溶解於N,N-二甲基甲醯胺(2 mL)中之溶液中添加步驟3中合成之2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.122 g，0.421 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，且接著藉由層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)再次純化所得產物且濃縮，得到標題化合物(0.036 g，26.44%，黃色固體)。To a solution of 5-(2-thienyl)-3H-1,3,4-oxadiazole-2-one (100.00%, 0.063 g, 0.350 mmol) synthesized in step 5 and potassium carbonate (100.00%, 0.049 g, 0.494 mmol) dissolved in N,N-dimethylformamide (2 mL) at room temperature was added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.122 g, 0.421 mmol) synthesized in step 3, and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%), and then the obtained product was purified and concentrated again by chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) to give the title compound (0.036 g, 26.44%, yellow solid).
1H NMR(400 MHz, CDCl3)δ9.34-9.33 (m, 1H), 8.44 (dd,J= 8.2, 2.2 Hz, 1H), 7.65 (dd,J= 4.0, 1.2 Hz, 1H), 7.55-7.52 (m, 2H), 7.17-7.15 (m, 1H), 6.96 (t,J= 51.6 Hz, 1H), 5.22 (s, 2H);LRMS(ES) m/z 378.7 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.34-9.33 (m, 1H), 8.44 (dd,J = 8.2, 2.2 Hz, 1H), 7.65 (dd,J = 4.0, 1.2 Hz, 1H), 7.55-7.52 (m, 2H), 7.17-7.15 (m, 1H), 6.96 (t,J = 51.6 Hz, 1H), 5.22 (s, 2H);LRMS (ES) m/z 378.7 (M+ +1).
下表2中之化合物係根據與實例5中實質上相同的方法合成。 [表2]
實例45：合成化合物45，3-((5-(5-(二氟甲基)-1,3,4-㗁二唑-2-基)吡啶-2-基)甲基)-5-苯基-1,3,4-㗁二唑-2(3H)-硫酮[步驟1]合成苯肼Example45: Synthesis of Compound45,3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-5-phenyl-1,3,4-oxadiazole-2(3H)-thione[Step1]Synthesis of Phenylhydrazine
將苯甲酸甲酯(0.500 g，2.203 mmol)及單水合肼(0.920 mL，7.308 mmol)在室溫溶解於乙醇(12 mL)中之溶液加熱至回流18小時，且接著藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.500 g，100.0%，白色固體)。A solution of methyl benzoate (0.500 g, 2.203 mmol) and hydrazine monohydrate (0.920 mL, 7.308 mmol) dissolved in ethanol (12 mL) at room temperature was heated to reflux for 18 hours, and then the reaction was quenched by lowering the temperature to room temperature. After removing the solvent from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.500 g, 100.0%, white solid).
[步驟2]合成5-苯基-1,3,4-㗁二唑-2(3H)-硫酮向步驟1中合成之苯甲醯肼(100.00%，0.500 g，3.672 mmol)在室溫溶解於乙醇(12 mL)中之溶液中添加乙基黃原酸鉀(100.00%，0.589 g，3.674 mmol)，且將混合物在相同溫度進行攪拌。自反應混合物中減壓移除溶劑之後，過濾所沈澱之固體且用水洗滌，然後乾燥，得到呈淺黃色固體之標題化合物(0.45 g，68.759%)。[Step2]Synthesis of5-phenyl-1,3,4-oxadiazole-2(3H)-thione To a solution of benzoyl hydrazide (100.00%, 0.500 g, 3.672 mmol) synthesized in step 1 dissolved in ethanol (12 mL) at room temperature, potassium ethylxanthate (100.00%, 0.589 g, 3.674 mmol) was added, and the mixture was stirred at the same temperature. After the solvent was removed from the reaction mixture under reduced pressure, the precipitated solid was filtered and washed with water, and then dried to obtain the title compound (0.45 g, 68.759%) as a light yellow solid.
[步驟3]合成化合物45向步驟1中合成之5-苯基-1,3,4-㗁二唑-2(3H)-硫酮(100.00%，50.000 mg，0.281 mmol)在室溫溶解於N,N-二甲基甲醯胺(2 mL)中之溶液中添加碳酸鉀(100.00%，40.000 mg，0.404 mmol)，且在相同溫度攪拌0.3小時。向反應混合物中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，100.000 mg，0.345 mmol)且在35℃進一步攪拌18小時。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；己烷/乙酸乙酯=100%至50%)純化濃縮物且濃縮，得到呈白色固體形式之標題化合物(58 mg，53.36%)。[Step3]Synthesis of compound45 To a solution of 5-phenyl-1,3,4-oxadiazole-2(3H)-thione (100.00%, 50.000 mg, 0.281 mmol) synthesized in step 1 dissolved in N,N-dimethylformamide (2 mL) at room temperature was added potassium carbonate (100.00%, 40.000 mg, 0.404 mmol), and stirred at the same temperature for 0.3 hours. To the reaction mixture was added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 100.000 mg, 0.345 mmol) and further stirred at 35° C. for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; hexane/ethyl acetate = 100% to 50%) and concentrated to give the title compound (58 mg, 53.36%) as a white solid.
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.6 Hz, 1H), 8.40 (dd,J= 8.2, 2.2 Hz, 1H), 8.01 (dd,J= 8.2, 1.4 Hz, 2H), 7.83 (d,J= 8.4 Hz, 1H), 7.56-7.51 (m, 3H), 6.96 (t,J= 51.6 Hz, 1H), 4.75 (s, 2H);LRMS(ES) m/z 388.8 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.6 Hz, 1H), 8.40 (dd,J = 8.2, 2.2 Hz, 1H), 8.01 (dd,J = 8.2, 1.4 Hz, 2H), 7.83 (d,J = 8.4 Hz, 1H), 7.56-7.51 (m, 3H), 6.96 (t,J = 51.6 Hz, 1H), 4.75 (s, 2H);LRMS (ES) m/z 388.8 (M+ +1).
下表3中之化合物係根據與實例45中實質上相同的方法合成。 [表3]
實例43：合成化合物43，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-苯基-1,3,4-噻二唑-2-酮[步驟1]合成苯甲醯肼Example43: Synthesis of Compound43,3-[[5-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-2-pyridyl]methyl]-5-phenyl-1,3,4-thiadiazole-2-one[Step1]Synthesis of benzoylhydrazine
將苯甲酸甲酯(100.00%，1.000 g，7.345 mmol)及單水合肼(100.00%，3.677 g，73.452 mmol)在90℃溶解於乙醇(80 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑，得到濃縮物。向濃縮物中倒入水，然後用二氯甲烷萃取。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。所得產物不經進一步純化即使用(0.88 g，88.000%，白色固體)。A solution of methyl benzoate (100.00%, 1.000 g, 7.345 mmol) and hydrazine monohydrate (100.00%, 3.677 g, 73.452 mmol) dissolved in ethanol (80 mL) at 90° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. The solvent was removed from the reaction mixture under reduced pressure to obtain a concentrate. Water was poured into the concentrate, and then extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.88 g, 88.000%, white solid).
[步驟2]合成苯硫代卡肼[Step2]Synthesis of phenylthiocarbazide
將步驟1中合成之苯甲醯肼(100.00%，0.500 g，3.672 mmol)及勞森氏試劑(100.00%，1.782 g，4.406 mmol)在100℃溶解於甲苯(20 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.31 g，55.455%，白色固體)。A solution of benzyl hydrazide (100.00%, 0.500 g, 3.672 mmol) synthesized in step 1 and Lawson's reagent (100.00%, 1.782 g, 4.406 mmol) dissolved in toluene (20 mL) at 100° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.31 g, 55.455%, white solid).
[步驟3]合成5-苯基-3H-1,3,4-噻二唑-2-酮[Step3]Synthesis of5-phenyl-3H-1,3,4-thiadiazole-2-one
將步驟2中合成之苯硫代卡肼(100.00%，0.280 g，1.839 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.358 g，2.208 mmol)在50℃溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.25 g，76.264%，白色固體)。A solution of phenylthiocarbazide (100.00%, 0.280 g, 1.839 mmol) synthesized in step 2 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.358 g, 2.208 mmol) dissolved in dichloromethane (20 mL) at 50°C was stirred at the same temperature overnight. Subsequently, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.25 g, 76.264%, white solid).
[步驟4]合成化合物43[Step4]Synthesis of compound43
將步驟3中合成之5-苯基-3H-1,3,4-噻二唑-2-酮(100.00%，0.050 g，0.281 mmol)及碳酸鉀(100.00%，0.058 g，0.420 mmol)溶解於N,N-二甲基甲醯胺(5 mL)中之溶液在室溫攪拌30分鐘。隨後，添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.085 g，0.293 mmol)及碘化鉀(100.00%，0.023 g，0.139 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.054 g，49.68%，白色固體)。A solution of 5-phenyl-3H-1,3,4-thiadiazol-2-one (100.00%, 0.050 g, 0.281 mmol) synthesized in step 3 and potassium carbonate (100.00%, 0.058 g, 0.420 mmol) dissolved in N,N-dimethylformamide (5 mL) was stirred at room temperature for 30 minutes. Subsequently, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-thiadiazole (100.00%, 0.085 g, 0.293 mmol) and potassium iodide (100.00%, 0.023 g, 0.139 mmol) were added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.054 g, 49.68%, white solid).
1H NMR(400 MHz, CDCl3)δ9.33 (d,J= 1.6 Hz, 1H), 8.42 (dd,J= 8.2, 2.2 Hz, 1H), 7.71-7.69 (m, 2H), 7.48-7.43 (m, 4H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.43 (s, 2H);LRMS(ES) m/z 388.0 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.33 (d,J = 1.6 Hz, 1H), 8.42 (dd,J = 8.2, 2.2 Hz, 1H), 7.71-7.69 (m, 2H), 7.48-7.43 (m, 4H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.43 (s, 2H);LRMS (ES) m/z 388.0 (M+ +1).
下表4中之化合物係根據與實例43中實質上相同的方法合成。 [表4]
實例4：合成化合物4，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-4-[(4-甲基-1-哌啶基)甲基]苯基]-1,3,4-㗁二唑-2-酮[步驟1]合成2-氟-4-[(4-甲基-1-哌啶基)甲基]苯甲酸甲酯Example4: Synthesis of Compound4,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]phenyl]-1,3,4-oxadiazol-2-one[Step1]Synthesis of2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzoic acid methyl ester
將2-氟-4-甲醯基-苯甲酸甲酯(100.00%，0.300 g，1.647 mmol)、4-甲基哌啶(100.00%，2.000 equiv.，3.294 mmol)及三乙醯氧基硼氫化鈉(100.00%，2.000 equiv.，3.294 mmol)在室溫溶解於二氯甲烷(10 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至100%)純化濃縮物且濃縮，得到標題化合物(0.43 g，98.41%，黃色油狀物)。A solution of 2-fluoro-4-formyl-benzoic acid methyl ester (100.00%, 0.300 g, 1.647 mmol), 4-methylpiperidine (100.00%, 2.000 equiv., 3.294 mmol) and sodium triacetoxyborohydride (100.00%, 2.000 equiv., 3.294 mmol) dissolved in dichloromethane (10 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.43 g, 98.41%, yellow oil).
[步驟2]合成2-氟-4-[(4-甲基-1-哌啶基)甲基]苯甲醯肼[Step2]Synthesis of2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzohydrazide
將步驟1中合成之2-氟-4-[(4-甲基-1-哌啶基)甲基]苯甲酸甲酯(100.00%，0.420 g，1.583 mmol)及單水合肼(100.00%，10.000 equiv.，15.830 mmol)在80℃溶解於乙醇(10 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.42 g，100.0%，白色固體)。A solution of methyl 2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzoate (100.00%, 0.420 g, 1.583 mmol) synthesized in step 1 and hydrazine monohydrate (100.00%, 10.000 equiv., 15.830 mmol) dissolved in ethanol (10 mL) at 80° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.42 g, 100.0%, white solid).
[步驟3]合成5-[2-氟-4-[(4-甲基-1-哌啶基)甲基]苯基]-3H-1,3,4-㗁二唑-2-酮將步驟2中合成之2-氟-4-[(4-甲基-1-哌啶基)甲基]苯甲醯肼(100.00%，0.420 g，1.583 mmol)、三光氣(100.00%，0.400 equiv.，0.633 mmol)及N,N-二異丙基乙胺(100.00%，2.000 equiv.，3.166 mmol)在室溫溶解於二氯甲烷(10 mL)中之溶液在相同溫度進行攪拌。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至100%)純化濃縮物且濃縮，得到標題化合物(0.275 g，59.63%，白色固體)。[Step3]Synthesis of5-[2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]phenyl]-3H-1,3,4-oxadiazol-2-one A solution of 2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]benzhydrazide (100.00%, 0.420 g, 1.583 mmol) synthesized in step 2, triphosgene (100.00%, 0.400 equiv., 0.633 mmol) and N,N-diisopropylethylamine (100.00%, 2.000 equiv., 3.166 mmol) dissolved in dichloromethane (10 mL) at room temperature was stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.275 g, 59.63%, white solid).
[步驟4]合成化合物4[Step4]Synthesis of Compound4
將步驟3中合成之5-[2-氟-4-[(4-甲基-1-哌啶基)甲基]苯基]-3H-1,3,4-㗁二唑-2-酮(100.00%，0.090 g，0.309 mmol)、2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，1.200 equiv.，0.371 mmol)、碳酸鉀(100.00%，2.000 equiv.，0.618 mmol)及碘化鉀(100.00%，1.100 equiv.，0.340 mmol)在室溫溶解於N,N-二甲基甲醯胺(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至100%)純化濃縮物且濃縮，得到標題化合物(0.07 g，45.27%，白色固體)。A solution of 5-[2-fluoro-4-[(4-methyl-1-piperidinyl)methyl]phenyl]-3H-1,3,4-oxadiazol-2-one (100.00%, 0.090 g, 0.309 mmol) synthesized in step 3, 2-[6-(bromomethyl)-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equiv., 0.371 mmol), potassium carbonate (100.00%, 2.000 equiv., 0.618 mmol) and potassium iodide (100.00%, 1.100 equiv., 0.340 mmol) dissolved in N,N-dimethylformamide (5 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.07 g, 45.27%, white solid).
1H NMR(400 MHz, CDCl3)δ9.25 (s, 1H), 8.37 (d,J= 10.0 Hz, 1H), 7.69 (t,J= 7.6 Hz, 1H), 7.49 (d,J= 8.0 Hz, 1H), 7.21-7.18 (m, 2H), 6.93 (t,J= 51.6 Hz, 1H), 5.22 (s, 2H), 3.47 (s, 2H), 2.76 (d,J= 11.2 Hz, 2H), 1.95 (t,J= 10.8 Hz, 2H), 1.57 (d,J= 12.0 Hz, 2H), 1.34-1.20 (m, 3H), 0.89 (d,J= 6.0 Hz, 3H);LRMS(ES) m/z 501.4 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.25 (s, 1H), 8.37 (d,J = 10.0 Hz, 1H), 7.69 (t,J = 7.6 Hz, 1H), 7.49 (d,J = 8.0 Hz, 1H), 7.21-7.18 (m, 2H), 6.93 (t,J = 51.6 Hz, 1H), 5.22 (s, 2H), 3.47 (s, 2H), 2.76 (d,J = 11.2 Hz, 2H), 1.95 (t,J = 10.8 Hz, 2H), 1.57 (d,J = 12.0 Hz, 2H), 1.34-1.20 (m, 3H), 0.89 (d,J = 6.0 Hz, 3H);LRMS (ES) m/z 501.4 (M++ 1).
下表5中之化合物係根據與實例4中實質上相同的方法合成。 [表5]
實例84：合成化合物84，3-((5-(5-(二氟甲基)-1,3,4-㗁二唑-2-基)吡啶-2-基)甲基)-5-(3-((二甲基胺基)甲基)苯基)-1,3,4-㗁二唑-2(3H)-硫酮[步驟1]合成3-(1,3-二氧戊環-2-基)苯甲酸甲酯Example84: Synthesis of Compound84,3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-5-(3-((dimethylamino)methyl)phenyl)-1,3,4-oxadiazole-2(3H)-thione[Step1]Synthesis of3-(1,3-dioxolan-2-yl)benzoic acid methyl ester
在室溫將3-甲醯基苯甲酸甲酯(100.00%，2.000 g，12.183 mmol)、乙二醇(100.00%，3.781 g，60.920 mmol)及4-甲基苯磺酸水合物(100.00%，0.232 g，1.220 mmol)溶解於甲苯(120 mL)中，且將所得混合物加熱至回流隔夜。將混合物冷卻至室溫，且將水倒入反應混合物中，然後用乙酸乙酯萃取。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，80 g卡管；乙酸乙酯/己烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(1.8 g，70.959%，白色固體)。Methyl 3-methylbenzoate (100.00%, 2.000 g, 12.183 mmol), ethylene glycol (100.00%, 3.781 g, 60.920 mmol), and 4-methylbenzenesulfonic acid hydrate (100.00%, 0.232 g, 1.220 mmol) were dissolved in toluene (120 mL) at room temperature, and the resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 80 g cartridge; ethyl acetate/hexane = 0% to 10%) and concentrated to give the title compound (1.8 g, 70.959%, white solid).
[步驟2]合成3-(1,3-二氧戊環-2-基)苯甲醯肼[Step2]Synthesis of3-(1,3-dioxolane-2-yl)benzylhydrazine
將步驟1中合成之3-(1,3-二氧戊環-2-基)苯甲酸甲酯(100.00%，1.130 g，5.427 mmol)及單水合肼(100.00%，2.717 g，54.275 mmol)在80℃溶解於乙醇(80 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(1.1 g，97.345%，白色固體)。A solution of methyl 3-(1,3-dioxolan-2-yl)benzoate (100.00%, 1.130 g, 5.427 mmol) synthesized in step 1 and hydrazine monohydrate (100.00%, 2.717 g, 54.275 mmol) dissolved in ethanol (80 mL) at 80° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (1.1 g, 97.345%, white solid).
[步驟3]合成5-[3-(1,3-二氧戊環-2-基)苯基]-3H-1,3,4-㗁二唑-2-硫酮[Step3]Synthesis of5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thione
將步驟2中合成之3-(1,3-二氧戊環-2-基)苯甲醯肼(100.00%，0.900 g，4.323 mmol)及乙基黃原酸鉀(100.00%，0.762 g，4.754 mmol)在80℃溶解於乙醇(50 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.7 g，64.70%，白色固體)。A solution of 3-(1,3-dioxolan-2-yl)benzylhydrazine (100.00%, 0.900 g, 4.323 mmol) and potassium ethylxanthate (100.00%, 0.762 g, 4.754 mmol) synthesized in step 2 dissolved in ethanol (50 mL) at 80°C was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.7 g, 64.70%, white solid).
[步驟4]合成3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[3-(1,3-二氧戊環-2-基)苯基]-1,3,4-㗁二唑-2-硫酮[Step4]Synthesis of3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[3-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-thione
將步驟3中合成之5-[3-(1,3-二氧戊環-2-基)苯基]-3H-1,3,4-㗁二唑-2-硫酮(100.00%，0.350 g，1.398 mmol)、2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.426 g，1.469 mmol)、碳酸鉀(100.00%，0.208 g，2.099 mmol)及碘化鉀(100.00%，0.116 g，0.699 mmol)溶解於N,N-二甲基甲醯胺(30 mL)中之溶液在室溫攪拌30分鐘，且接著在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.51 g，79.39%，白色固體)。A solution of 5-[3-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazole-2-thione (100.00%, 0.350 g, 1.398 mmol) synthesized in step 3, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.426 g, 1.469 mmol), potassium carbonate (100.00%, 0.208 g, 2.099 mmol) and potassium iodide (100.00%, 0.116 g, 0.699 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 minutes, and then further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.51 g, 79.39%, white solid).
[步驟5]合成3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]苯甲醛[Step5]Synthesis of3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]benzaldehyde
將步驟4中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[3-(1,3-二氧戊環-2-基)苯基]-1,3,4-㗁二唑-2-硫酮(100.00%，0.500 g，1.088 mmol)及六水合氯化鐵(100.00%，1.030 g，3.811 mmol)溶解於二氯甲烷(30 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到呈白色固體形式之標題化合物(0.350 g，77.41%)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[3-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazole-2-thione (100.00%, 0.500 g, 1.088 mmol) synthesized in step 4 and iron chloride hexahydrate (100.00%, 1.030 g, 3.811 mmol) dissolved in dichloromethane (30 mL) was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.350 g, 77.41%) as a white solid.
[步驟6]合成化合物84[Step6]Synthesis of compound84
向步驟5中合成之4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]苯甲醛(100.00%，0.030 g，0.072 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液中添加N-甲基甲胺(100.00%，0.007 g，0.155 mmol)，且在相同溫度攪拌30分鐘。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.011 g，34.27%，白色固體)。To a solution of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]benzaldehyde (100.00%, 0.030 g, 0.072 mmol) synthesized in step 5 dissolved in dichloromethane (5 mL) at room temperature, N-methylmethylamine (100.00%, 0.007 g, 0.155 mmol) was added, and stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.011 g, 34.27%, white solid).
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.7 Hz, 1H), 8.39 (dd,J= 8.2, 2.2 Hz, 1H), 7.94-7.90 (m, 2H), 7.83 (d,J= 8.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.74 (s, 2H), 3.50 (s, 2H), 2.28 (s, 6H);LRMS(ES) m/z 445.23 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.7 Hz, 1H), 8.39 (dd,J = 8.2, 2.2 Hz, 1H), 7.94-7.90 (m, 2H), 7.83 (d,J = 8.2 Hz, 1H), 7.52-7.45 (m, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.74 (s, 2H), 3.50 (s, 2H), 2.28 (s, 6H);LRMS (ES) m/z 445.23 (M+ +1).
下表6中之化合物係根據與實例84中實質上相同的方法合成。 [表6]
實例132：合成化合物132，5-[4-(氮雜環丁-1-基甲基)苯基]-3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-1,3,4-㗁二唑-2-酮[步驟1]合成4-(1,3-二氧戊環-2-基)苯甲酸甲酯Example132: Synthesis of Compound132,5-[4-(Azocyclobutan-1-ylmethyl)phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazol-2-one[Step1]Synthesis of4-(1,3-dioxolan-2-yl)benzoic acid methyl ester
在室溫將4-甲醯基苯甲酸甲酯(100.00%，3.000 g，18.275 mmol)、乙二醇(100.00%，5.672 g，91.380 mmol)及4-甲基苯磺酸水合物(100.00%，0.348 g，1.830 mmol)溶解於甲苯(150 mL)中，且將所得混合物加熱至回流隔夜。將混合物冷卻至室溫，且將水倒入反應混合物中，然後用乙酸乙酯萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，80 g卡管；乙酸乙酯/己烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(3.5 g，91.984%，白色固體)。Methyl 4-methylbenzoate (100.00%, 3.000 g, 18.275 mmol), ethylene glycol (100.00%, 5.672 g, 91.380 mmol) and 4-methylbenzenesulfonic acid hydrate (100.00%, 0.348 g, 1.830 mmol) were dissolved in toluene (150 mL) at room temperature, and the resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 80 g cartridge; ethyl acetate/hexane = 0% to 10%) and concentrated to give the title compound (3.5 g, 91.984%, white solid).
[步驟2]合成4-(1,3-二氧戊環-2-基)苯甲醯肼[Step2]Synthesis of4-(1,3-dioxolane-2-yl)benzylhydrazine
在室溫將步驟1中合成之4-(1,3-二氧戊環-2-基)苯甲酸甲酯(100.00%，2.000 g，9.606 mmol)及單水合肼(100.00%，4.809 g，96.065 mmol)溶解於乙醇(100 mL)中且將所得混合物加熱至回流隔夜。將混合物冷卻至室溫，且將水倒入反應混合物中，然後用二氯甲烷萃取。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，40 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(1.8 g，90,000 %，白色固體)。Methyl 4-(1,3-dioxolan-2-yl)benzoate (100.00%, 2.000 g, 9.606 mmol) synthesized in Step 1 and hydrazine monohydrate (100.00%, 4.809 g, 96.065 mmol) were dissolved in ethanol (100 mL) at room temperature and the resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 40 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (1.8 g, 90,000%, white solid).
[步驟3]合成5-[4-(1,3-二氧戊環-2-基)苯基]-3H-1,3,4-㗁二唑-2-酮[Step3]Synthesis of5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazol-2-one
在室溫將步驟2中合成之4-(1,3-二氧戊環-2-基)苯甲醯肼(100.00%，0.650 g，3.122 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.607 g，3.744 mmol)溶解於二氯甲烷(50 mL)中，且將所得混合物加熱至回流隔夜。將混合物冷卻至室溫，且將水倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.45 g，61.545%，白色固體)。4-(1,3-Dioxolan-2-yl)benzylhydrazine (100.00%, 0.650 g, 3.122 mmol) synthesized in step 2 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.607 g, 3.744 mmol) were dissolved in dichloromethane (50 mL) at room temperature, and the resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.45 g, 61.545%, white solid).
[步驟4]合成3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(1,3-二氧戊環-2-基)苯基]-1,3,4-㗁二唑-2-酮[Step4]Synthesis of3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazol-2-one
向步驟3中之合成之5-[4-(1,3-二氧戊環-2-基)苯基]-3H-1,3,4-㗁二唑-2-酮(100.00%，0.500 g，2.135 mmol)及碳酸鉀(100.00%，0.443 g，3.205 mmol)在室溫溶解於N,N-二甲基甲醯胺(30 mL)中之溶液中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.650 g，2.241 mmol)及碘化鉀(100.00%，0.177 g，1.066 mmol)，且在相同溫度攪拌30分鐘。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。向濃縮物中添加乙酸乙酯(5 mL)且攪拌以沈澱固體，且過濾沈澱固體，用己烷洗滌且乾燥，得到標題化合物(0.74 g，78.18%，白色固體)。To a solution of 5-[4-(1,3-dioxolan-2-yl)phenyl]-3H-1,3,4-oxadiazol-2-one (100.00%, 0.500 g, 2.135 mmol) synthesized in step 3 and potassium carbonate (100.00%, 0.443 g, 3.205 mmol) dissolved in N,N-dimethylformamide (30 mL) at room temperature, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.650 g, 2.241 mmol) and potassium iodide (100.00%, 0.177 g, 1.066 mmol) were added, and the mixture was stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate (5 mL) was added to the concentrate and stirred to precipitate a solid, and the precipitated solid was filtered, washed with hexane and dried to obtain the title compound (0.74 g, 78.18%, white solid).
[步驟5]合成4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]苯甲醛[Step5]Synthesis of4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxadiazol-1,3,4-oxadiazol-2-yl]benzaldehyde
將步驟4中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(1,3-二氧戊環-2-基)苯基]-1,3,4-㗁二唑-2-酮(100.00%，0.280 g，0.632 mmol)及六水合氯化鐵(100.00%，0.512 g，1.894 mmol)溶解於二氯甲烷(30 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.18 g，71.39%，白色固體)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(1,3-dioxolan-2-yl)phenyl]-1,3,4-oxadiazol-2-one (100.00%, 0.280 g, 0.632 mmol) synthesized in step 4 and ferric chloride hexahydrate (100.00%, 0.512 g, 1.894 mmol) in dichloromethane (30 mL) was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.18 g, 71.39%, white solid).
[步驟6]合成化合物132[Step6]Synthesis of compound132
將步驟5中合成之4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]苯甲醛(100.00%，0.030 g，0.075 mmol)及氮雜環丁烷鹽酸鹽(100.00%，0.014 g，0.150 mmol)溶解於二氯甲烷(5 mL)中之溶液在室溫攪拌30分鐘。隨後，添加三乙醯氧基硼氫化鈉(100.00%，0.048 g，0.227 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.019 g，57.42%，白色固體)。A solution of 4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]benzaldehyde (100.00%, 0.030 g, 0.075 mmol) synthesized in step 5 and azocyclobutane hydrochloride (100.00%, 0.014 g, 0.150 mmol) in dichloromethane (5 mL) was stirred at room temperature for 30 minutes. Subsequently, sodium triacetoxyborohydride (100.00%, 0.048 g, 0.227 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.019 g, 57.42%, white solid).
1H NMR(400 MHz, CDCl3)δ9.33 (d,J= 1.5 Hz, 1H), 8.43 (dd,J= 8.2, 2.2 Hz, 1H), 7.82 (d,J= 8.3 Hz, 2H), 7.55-7.52 (m, 1 H), 7.43 (d,J= 8.1 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.24 (s, 2H), 3.67 (s, 2H), 3.32-3.28 (m, 4H), 2.19-2.12 (m, 2H);LRMS(ES) m/z 441.3 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.33 (d,J = 1.5 Hz, 1H), 8.43 (dd,J = 8.2, 2.2 Hz, 1H), 7.82 (d,J = 8.3 Hz, 2H), 7.55-7.52 (m, 1 H), 7.43 (d,J = 8.1 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.24 (s, 2H), 3.67 (s, 2H), 3.32-3.28 (m, 4H), 2.19-2.12 (m, 2H);LRMS (ES) m/z 441.3 (M+ +1).
下表7中之化合物係根據與實例132中實質上相同的方法合成。 [表7]
實例83：合成化合物83，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-[(4-異丙基哌𠯤-1-基)甲基]苯基]-1,3,4-㗁二唑-2-酮[步驟1]合成4-[(4-甲氧基羰基苯基)甲基]哌𠯤-1-甲酸三級丁酯Example83: Synthesis of Compound83,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperidin-1-yl)methyl]phenyl]-1,3,4-oxadiazol-2-one[Step1]Synthesis of4-[(4-methoxycarbonylphenyl)methyl]piperidin-1-carboxylicacid tributyl ester
將4-甲醯基苯甲酸甲酯(100.00%，0.500 g，3.046 mmol)、哌𠯤-1-甲酸三級丁酯(100.00%，0.681 g，3.656 mmol)及三乙醯氧基硼氫化鈉(100.00%，1.291 g，6.091 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.89 g，87.38%，白色固體)。A solution of methyl 4-formylbenzoate (100.00%, 0.500 g, 3.046 mmol), tributyl piperidine-1-carboxylate (100.00%, 0.681 g, 3.656 mmol) and sodium triacetoxyborohydride (100.00%, 1.291 g, 6.091 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.89 g, 87.38%, white solid).
[步驟2]合成4-[[4-(肼羰基)苯基]甲基]哌𠯤-1-甲酸三級丁酯[Step2]Synthesis of4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperidinium-1-carboxylicacid tributyl ester
將步驟1中合成之4-[(4-甲氧基羰基苯基)甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.300 g，0.897 mmol)及單水合肼(100.00%，0.449 g，8.969 mmol)在90℃溶解於乙醇(20 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。所得產物不經進一步純化即使用(0.29 g，96.67%，白色固體)。A solution of tributyl 4-[(4-methoxycarbonylphenyl)methyl]piperidinium-1-carboxylate (100.00%, 0.300 g, 0.897 mmol) synthesized in step 1 and hydrazine monohydrate (100.00%, 0.449 g, 8.969 mmol) dissolved in ethanol (20 mL) at 90° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.29 g, 96.67%, white solid).
[步驟3]合成4-[[4-(2-側氧基-3H-1,3,4-㗁二唑-5-基)苯基]甲基]哌𠯤-1-甲酸三級丁酯[Step3]Synthesis of4-[[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]methyl]piperidin-1-carboxylicacid tributyl ester
向步驟2中合成之4-[[4-(肼羰基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.500 g，1.495 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.291 g，1.795 mmol)在室溫溶解於四氫呋喃(10 mL)中之溶液中添加三乙胺(100.00%溶液，0.29 mL，2.100 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.468 g，86.85%，白色固體)。To a solution of tributyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperidinium-1-carboxylate (100.00%, 0.500 g, 1.495 mmol) synthesized in step 2 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.291 g, 1.795 mmol) dissolved in tetrahydrofuran (10 mL) at room temperature, triethylamine (100.00% solution, 0.29 mL, 2.100 mmol) was added, and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.468 g, 86.85%, white solid).
[步驟4]合成4-[[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]苯基]甲基]哌𠯤-1-甲酸三級丁酯[Step4]Synthesis of4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperidin-1-carboxylicacid tributyl ester
向步驟3中合成之4-[[4-(2-側氧基-3H-1,3,4-㗁二唑-5-基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.236 g，0.655 mmol)及碳酸鉀(100.00%，0.091 g，0.918 mmol)在室溫溶解於N,N-二甲基甲醯胺(3 mL)中之溶液中添加實例5之步驟3中製備的2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.228 g，0.786 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至60%)純化濃縮物且濃縮，且接著藉由層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)再次純化所得產物且濃縮，得到標題化合物(0.37 g，99.20%，白色固體)。To a solution of tributyl 4-[[4-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]methyl]piperidin-1-carboxylate (100.00%, 0.236 g, 0.655 mmol) synthesized in Step 3 and potassium carbonate (100.00%, 0.091 g, 0.918 mmol) dissolved in N,N-dimethylformamide (3 mL) at room temperature was added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.228 g, 0.786 mmol) prepared in Step 3 of Example 5, and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified and concentrated by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 60%), and then the obtained product was purified and concentrated again by chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) to give the title compound (0.37 g, 99.20%, white solid).
[步驟5]合成3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(哌𠯤-1-基甲基)苯基]-1,3,4-㗁二唑-2-酮[Step5]Synthesis of3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(piperidin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-2-one
將步驟4中合成之4-[[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.370 g，0.650 mmol)及三氟乙酸(100.00%溶液，0.497 mL，6.490 mmol)在室溫溶解於二氯甲烷(3 mL)中之溶液在相同溫度攪拌隔夜。將碳酸氫鈉飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。所得產物不經進一步純化即使用(0.3 g，98.39%，黃色油狀物)。A solution of tributyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperidin-1-carboxylate (100.00%, 0.370 g, 0.650 mmol) and trifluoroacetic acid (100.00% solution, 0.497 mL, 6.490 mmol) synthesized in step 4 was dissolved in dichloromethane (3 mL) at room temperature and stirred at the same temperature overnight. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was used without further purification (0.3 g, 98.39%, yellow oil).
[步驟6]合成化合物83[Step6]Synthesis of compound83
將步驟5中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(哌𠯤-1-基甲基)苯基]-1,3,4-㗁二唑-2-酮(100.00%，0.075 g，0.160 mmol)、丙酮(100.00%溶液，0.019 mL，0.257 mmol)及N-乙基-N-異丙基-丙-2-胺(100.00%溶液，0.056 mL，0.322 mmol)溶解於二氯甲烷(1 mL)中之溶液在室溫攪拌30分鐘。隨後，添加三乙醯氧基硼氫化鈉(100.00%，0.101 g，0.479 mmol)且在相同溫度進一步攪拌18小時。將碳酸氫鈉飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到呈淺黃色固體之標題化合物(0.014 g，17.13%)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[4-(piperidin-1-ylmethyl)phenyl]-1,3,4-oxadiazol-2-one (100.00%, 0.075 g, 0.160 mmol) synthesized in step 5, acetone (100.00% solution, 0.019 mL, 0.257 mmol) and N-ethyl-N-isopropyl-propan-2-amine (100.00% solution, 0.056 mL, 0.322 mmol) in dichloromethane (1 mL) was stirred at room temperature for 30 minutes. Subsequently, sodium triacetoxyborohydride (100.00%, 0.101 g, 0.479 mmol) was added and further stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.014 g, 17.13%) as a light yellow solid.
1H NMR(400 MHz, CD3OD)δ9.25 (d,J= 1.6 Hz, 1H), 8.53 (dd,J= 8.2, 2.2 Hz, 1H), 7.85 (d,J= 8.4 Hz, 2H), 7.72 (d,J= 8.0 Hz, 1H), 7.53 (d,J= 8.4 Hz, 2H), 7.26 (t,J= 51.6 Hz, 1H), 5.26 (s, 2H), 3.63 (s, 2H), 2.74-2.59 (m, 9H), 1.15 (d,J= 6.8 Hz, 6H);LRMS(ES) m/z 512.8 (M++1)。1H NMR (400 MHz, CD3 OD)δ 9.25 (d,J = 1.6 Hz, 1H), 8.53 (dd,J = 8.2, 2.2 Hz, 1H), 7.85 (d,J = 8.4 Hz, 2H), 7.72 (d,J = 8.0 Hz, 1H), 7.53 (d,J = 8.4 Hz, 2H), 7.26 (t,J = 51.6 Hz, 1H), 5.26 (s, 2H), 3.63 (s, 2H), 2.74-2.59 (m, 9H), 1.15 (d,J = 6.8 Hz, 6H);LRMS (ES) m/z 512.8 (M+ +1).
實例66：合成化合物66，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(4-異丙基哌𠯤-1-基)苯基]-1,3,4-噻二唑-2-酮[步驟1]合成4-[[4-(胺基硫代胺基甲醯基)苯基]甲基]哌𠯤-1-甲酸三級丁酯Example66: Synthesis of Compound66,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(4-isopropylpiperidin-1-yl)phenyl]-1,3,4-thiadiazol-2-one[Step1]Synthesis of4-[[4-(aminothiocarbamoyl)phenyl]methyl]piperidin-1-carboxylicacid tributyl ester
將實例86之步驟2中合成之4-[[4-(肼羰基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，1.000 g，2.990 mmol)及勞森氏試劑(100.00%，1.451 g，3.587 mmol)在80℃溶解於甲苯(40 mL)中之溶液在相同溫度攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至60%)純化濃縮物且濃縮，得到標題化合物(0.61 g，58.20%，白色固體)。A solution of tributyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperidinium-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) synthesized in Step 2 of Example 86 and Lawson's reagent (100.00%, 1.451 g, 3.587 mmol) dissolved in toluene (40 mL) at 80° C. was stirred at the same temperature overnight. Thereafter, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.61 g, 58.20%, white solid).
[步驟2]合成4-[[4-(2-側氧基-3H-1,3,4-噻二唑-5-基)苯基]甲基]哌𠯤-1-甲酸三級丁酯[Step2]Synthesis of4-[[4-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]methyl]piperidin-1-carboxylicacid tributyl ester
將步驟1中合成之4-[[4-(胺基硫代胺基甲醯基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.500 g，1.427 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.278 g，1.715 mmol)在50℃溶解於二氯甲烷(30 mL)中之溶液在相同溫度攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.25 g，46.55%，白色固體)。A solution of tributyl 4-[[4-(aminothiocarbamoyl)phenyl]methyl]piperidinium-1-carboxylate (100.00%, 0.500 g, 1.427 mmol) synthesized in step 1 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.278 g, 1.715 mmol) dissolved in dichloromethane (30 mL) at 50°C was stirred at the same temperature overnight. Thereafter, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.25 g, 46.55%, white solid).
[步驟3]合成4-[[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-噻二唑-2-基]苯基]甲基]哌𠯤-1-甲酸三級丁酯[Step3]Synthesis of4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]phenyl]methyl]piperidin-1-carboxylicacid tributyl ester
將步驟2中合成之4-[[4-(2-側氧基-3H-1,3,4-噻二唑-5-基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.100 g，0.266 mmol)及碳酸鉀(100.00%，0.055 g，0.398 mmol)溶解於N,N-二甲基甲醯胺(10 mL)中之溶液在室溫攪拌30分鐘。隨後，添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.081 g，0.279 mmol)及碘化鉀(100.00%，0.022 g，0.133 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.095 g，61.08%，白色固體)。A solution of tributyl 4-[[4-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]methyl]piperidinium-1-carboxylate (100.00%, 0.100 g, 0.266 mmol) synthesized in step 2 and potassium carbonate (100.00%, 0.055 g, 0.398 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 30 minutes. Subsequently, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.081 g, 0.279 mmol) and potassium iodide (100.00%, 0.022 g, 0.133 mmol) were added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.095 g, 61.08%, white solid).
[步驟4]合成2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(哌𠯤-1-基甲基)苯基]-1,3,4-噻二唑-2-酮[Step4]Synthesis of2,2,2-trifluoroacetic acid3-[[5-[5-(difluoromethyl)-1,3,4-thiadiazole- 2-yl]-2-pyridyl]methyl]-5-[4-(piperidin-1-ylmethyl)phenyl]-1,3,4-thiadiazole-2-one
將步驟3中合成之4-[[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-噻二唑-2-基]苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.090 g，0.154 mmol)及三氟乙酸(100.00%，0.053 g，0.465 mmol)在室溫溶解於中二氯甲烷(10 mL)中之溶液在相同溫度攪拌隔夜。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.088 g，95.51%，黃色油狀物)。A solution of tributyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]phenyl]methyl]piperidin-1-carboxylate (100.00%, 0.090 g, 0.154 mmol) and trifluoroacetic acid (100.00%, 0.053 g, 0.465 mmol) synthesized in step 3 was dissolved in dichloromethane (10 mL) at room temperature and stirred at the same temperature overnight. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.088 g, 95.51%, yellow oil).
[步驟5]合成化合物66[Step5]Synthesis of compound66
將步驟4中合成之2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(哌𠯤-1-基甲基)苯基]-1,3,4-噻二唑-2-酮(100.00%，0.030 g，0.051 mmol)、丙酮(100.00%，0.006 g，0.103 mmol)、N-乙基二異丙胺(100.00%溶液，0.018 mL，0.103 mmol)及三乙醯氧基硼氫化鈉(100.00%，0.033 g，0.156 mmol)溶解於二氯甲烷(5 mL)中之溶液在室溫攪拌30分鐘，且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.011 g，41.80%，白色固體)。2,2,2-Trifluoroacetic acid 3-[[5-[5-(difluoromethyl)-1,3,4-thiadiazol-2-yl]-2-pyridyl]methyl]-5-[4-(piperidin-1-ylmethyl)phenyl]-1,3,4-thiadiazol-2-one (100.00%, 0.030 g, 0.051 mmol) synthesized in step 4, acetone (100.00%, 0.006 g, 0.103 mmol), N-ethyldiisopropylamine (100.00% solution, 0.018 mL, 0.103 mmol) and sodium triacetoxyborohydride (100.00%, 0.033 g, 0.156 mmol) were dissolved in dichloromethane (5% ethanol). The solution in 40 mL) was stirred at room temperature for 30 minutes, and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.011 g, 41.80%, white solid).
1H NMR(400 MHz, CDCl3)δ9.33 (d,J= 1.6 Hz, 1H), 8.41 (dd,J= 8.2, 2.2 Hz, 1H), 7.64 (d,J= 8.2 Hz, 2H), 7.47 (d,J= 8.2 Hz, 1H), 7.41 (d,J= 8.2 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.42 (s, 2H), 3.56 (s, 2H), 2.78-2.77 (m, 1H), 2.64-2.48 (m, 8H), 1.11 (d,J= 6.5 Hz, 6H);LRMS(ES) m/z 529.35 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.33 (d,J = 1.6 Hz, 1H), 8.41 (dd,J = 8.2, 2.2 Hz, 1H), 7.64 (d,J = 8.2 Hz, 2H), 7.47 (d,J = 8.2 Hz, 1H), 7.41 (d,J = 8.2 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 5.42 (s, 2H), 3.56 (s, 2H), 2.78-2.77 (m, 1H), 2.64-2.48 (m, 8H), 1.11 (d,J = 6.5 Hz, 6H);LRMS (ES) m/z 529.35 (M++ 1).
下表8中之化合物係根據與實例66中實質上相同的方法合成。 [表8]
實例77：合成化合物77，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-[(4-異丙基哌𠯤-1-基)甲基]苯基]-1,3,4-㗁二唑-2-硫酮[步驟1]合成4-(4-(5-硫酮基-4,5-二氫-1,3,4-㗁二唑-2-基)苯甲基)哌𠯤-1-甲酸三級丁酯Example77: Synthesis of Compound77,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[4-[(4-isopropylpiperidin-1-yl)methyl]phenyl]-1,3,4-oxadiazole-2-thione[Step1]Synthesis of4-(4-(5-thionyl-4,5-dihydro- 1,3,4-oxadiazol-2-yl)benzyl)piperidin-1 -carboxylicacid tributyl ester
將實例86之步驟2中製備之4-[[4-(肼羰基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，1.000 g，2.990 mmol)及乙基黃原酸鉀(100.00%，0.575 g，3.587 mmol)在室溫下混合於乙醇(80 mL)中之混合物加熱至回流隔夜。將混合物冷卻至室溫，且將水倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.85 g，75.50%，白色固體)。A mixture of tributyl 4-[[4-(hydrazinecarbonyl)phenyl]methyl]piperidinium-1-carboxylate (100.00%, 1.000 g, 2.990 mmol) prepared in step 2 of Example 86 and potassium ethylxanthate (100.00%, 0.575 g, 3.587 mmol) in ethanol (80 mL) was heated to reflux overnight at room temperature. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.85 g, 75.50%, white solid).
[步驟2]合成4-[[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]苯基]甲基]哌𠯤-1-甲酸三級丁酯[Step2]Synthesis of4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperidin-1-carboxylicacid tributyl ester
將步驟1中合成之4-[[4-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.500 g，1.328 mmol)及碳酸鉀(100.00%，0.197 g，1.988 mmol)溶解於N,N-二甲基甲醯胺(30 mL)中之溶液在室溫攪拌30分鐘。隨後，添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.404 g，1.393 mmol)及碘化鉀(100.00%，0.110 g，0.663 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.65 g，83.58%，白色固體)。A solution of tributyl 4-[[4-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]methyl]piperidin-1-carboxylate (100.00%, 0.500 g, 1.328 mmol) synthesized in step 1 and potassium carbonate (100.00%, 0.197 g, 1.988 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 minutes. Subsequently, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.404 g, 1.393 mmol) and potassium iodide (100.00%, 0.110 g, 0.663 mmol) were added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.65 g, 83.58%, white solid).
[步驟3]合成2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(哌𠯤-1-基甲基)苯基]-1,3,4-㗁二唑-2-硫酮[Step3]Synthesis of2,2,2-trifluoroacetic acid3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole- 2-yl]-2-pyridyl]methyl]-5-[4-(piperidin-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thione
將步驟2中合成之4-[[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]苯基]甲基]哌𠯤-1-甲酸三級丁酯(100.00%，0.300 g，0.512 mmol)及三氟乙酸(100.00%，0.175 g，1.535 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌3小時。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.28 g，91.17%，黃色油狀物)。A solution of tributyl 4-[[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]phenyl]methyl]piperidin-1-carboxylate (100.00%, 0.300 g, 0.512 mmol) and trifluoroacetic acid (100.00%, 0.175 g, 1.535 mmol) synthesized in step 2 was dissolved in dichloromethane (20 mL) at room temperature and stirred at the same temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.28 g, 91.17%, yellow oil).
[步驟4]合成化合物77[Step4]Synthesis of compound77
將步驟3中合成之2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(哌𠯤-1-基甲基)苯基]-1,3,4-㗁二唑-2-硫酮(100.00%，0.050 g，0.083 mmol)、丙酮(100.00%，0.010 g，0.172 mmol)及N-乙基二異丙胺(100.00%溶液，0.029 mL，0.167 mmol)溶解於二氯甲烷(5 mL)中之溶液在室溫攪拌30分鐘。隨後，添加三乙醯氧基硼氫化鈉(100.00%，0.053 g，0.250 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.022 g，50.00%，白色固體)。A solution of 2,2,2-trifluoroacetic acid 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridinyl]methyl]-5-[4-(piperidin-1-ylmethyl)phenyl]-1,3,4-oxadiazole-2-thione (100.00%, 0.050 g, 0.083 mmol) synthesized in step 3, acetone (100.00%, 0.010 g, 0.172 mmol) and N-ethyldiisopropylamine (100.00% solution, 0.029 mL, 0.167 mmol) in dichloromethane (5 mL) was stirred at room temperature for 30 minutes. Subsequently, sodium triacetoxyborohydride (100.00%, 0.053 g, 0.250 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.022 g, 50.00%, white solid).
1H NMR(400 MHz, CDCl3)δ9.31 (d,J= 2.2 Hz, 1H), 8.39 (dd,J= 8.2, 2.2 Hz, 1H), 7.95 (d,J= 8.3 Hz, 2H), 7.82 (d,J= 8.2 Hz, 1H), 7.46 (d,J= 8.3 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.60 (s, 2H), 3.16-2.92 (m, 1H), 2.81-2.76 (m, 8H), 1.19 (d,J= 6.5 Hz, 6H);LRMS(ES) m/z 528.87 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.31 (d,J = 2.2 Hz, 1H), 8.39 (dd,J = 8.2, 2.2 Hz, 1H), 7.95 (d,J = 8.3 Hz, 2H), 7.82 (d,J = 8.2 Hz, 1H), 7.46 (d,J = 8.3 Hz, 2H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.60 (s, 2H), 3.16-2.92 (m, 1H), 2.81-2.76 (m, 8H), 1.19 (d,J = 6.5 Hz, 6H);LRMS (ES) m/z 528.87 (M++ 1).
下表9中之化合物係根據與實例77中實質上相同的方法合成。 [表9]
實例26：合成化合物26，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-[1-(氧雜環丁-3-基)-4-哌啶基]苯基]-1,3,4-㗁二唑-2-酮[步驟1]合成4-(2-氟-3-甲氧基羰基-苯基)-3,6-二氫-2H-吡啶-1-甲酸三級丁酯Example26: Synthesis of Compound26,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(oxadiazol-3-yl)-4-piperidinyl]phenyl]-1,3,4-oxadiazol-2-one[Step1]Synthesis of4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tributyl ester
將3-溴-2-氟-苯甲酸甲酯(100.00%，1.000 g，4.291 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊-2-基)-3,6-二氫-2H-吡啶-1-甲酸三級丁酯(100.00%，1.460 g，4.722 mmol)、雙(三苯基膦)二氯化鈀(II) (100.00%，0.301 g，0.429 mmol)及碳酸鈉(100.00%，1.365 g，12.879 mmol)在室溫溶解於N,N-二甲基甲醯胺(20 mL)/水(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(1.100 g，76.43%，白色固體)。A solution of methyl 3-bromo-2-fluoro-benzoate (100.00%, 1.000 g, 4.291 mmol), tributyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (100.00%, 1.460 g, 4.722 mmol), bis(triphenylphosphine)palladium(II) dichloride (100.00%, 0.301 g, 0.429 mmol) and sodium carbonate (100.00%, 1.365 g, 12.879 mmol) dissolved in N,N-dimethylformamide (20 mL)/water (5 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (1.100 g, 76.43%, white solid).
[步驟2]合成4-(2-氟-3-甲氧基羰基-苯基)哌啶-1-甲酸三級丁酯[Step2]Synthesis of4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylic acid tributyl ester
將步驟1中合成之4-(2-氟-3-甲氧基羰基-苯基)-3,6-二氫-2H-吡啶-1-甲酸三級丁酯(100.00%，0.900 g，2.683 mmol)及Pd/C (100.00%，0.286 g，2.688 mmol)溶解於甲醇(20 mL)中之溶液在相同溫度攪拌隔夜。經由矽藻土濾片過濾反應混合物以移除固體，且自濾液中減壓移除溶劑。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.74 g，81.73%，黃色油狀物)。A solution of 4-(2-fluoro-3-methoxycarbonyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tributyl ester (100.00%, 0.900 g, 2.683 mmol) synthesized in step 1 and Pd/C (100.00%, 0.286 g, 2.688 mmol) dissolved in methanol (20 mL) was stirred at the same temperature overnight. The reaction mixture was filtered through a diatomaceous earth filter pad to remove the solid, and the solvent was removed from the filtrate under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.74 g, 81.73%, yellow oil).
[步驟3]合成4-[2-氟-3-(肼羰基)苯基]哌啶-1-甲酸三級丁酯[Step3]Synthesis of4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylic acid tributyl ester
將步驟2中合成之4-(2-氟-3-甲氧基羰基-苯基)哌啶-1-甲酸三級丁酯(100.00%，0.700 g，2.075 mmol)及單水合肼(100.00%，1.039 g，20.755 mmol)在室溫溶解於乙醇(30 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。所得產物不經進一步純化即使用(0.65 g，92.86%，白色固體)。A solution of 4-(2-fluoro-3-methoxycarbonyl-phenyl)piperidine-1-carboxylic acid tributyl ester (100.00%, 0.700 g, 2.075 mmol) synthesized in step 2 and hydrazine monohydrate (100.00%, 1.039 g, 20.755 mmol) dissolved in ethanol (30 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.65 g, 92.86%, white solid).
[步驟4]合成4-[2-氟-3-(2-側氧基-3H-1,3,4-㗁二唑-5-基)苯基]哌啶-1-甲酸三級丁酯[Step4]Synthesis of4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylic acid tributyl ester
將步驟3中合成之4-[2-氟-3-(肼羰基)苯基]哌啶-1-甲酸三級丁酯(100.00%，0.700 g，2.075 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.404 g，2.492 mmol)在室溫溶解於二氯甲烷(30 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.55 g，72.95%，白色固體)。A solution of tributyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.700 g, 2.075 mmol) synthesized in step 3 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.404 g, 2.492 mmol) dissolved in dichloromethane (30 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.55 g, 72.95%, white solid).
[步驟5]合成4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-2-氟-苯基]哌啶-1-甲酸三級丁酯[Step5]Synthesis of4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2 -fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester
向步驟4中合成之4-[2-氟-3-(2-側氧基-3H-1,3,4-㗁二唑-5-基)苯基]哌啶-1-甲酸三級丁酯(100.00%，0.400 g，1.101 mmol)及碳酸鉀(100.00%，0.164 g，1.655 mmol)在室溫溶解於N,N-二甲基甲醯胺(20 mL)中之溶液中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.335 g，1.155 mmol)及碘化鉀(100.00%，0.091 g，0.548 mmol)，且在相同溫度進行攪拌。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.54 g，85.69%，白色固體)。To a solution of tributyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-oxadiazole-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.400 g, 1.101 mmol) and potassium carbonate (100.00%, 0.164 g, 1.655 mmol) synthesized in step 4 in N,N-dimethylformamide (20 mL) at room temperature were added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.335 g, 1.155 mmol) and potassium iodide (100.00%, 0.091 g, 0.548 mmol), and the mixture was stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.54 g, 85.69%, white solid).
[步驟6]合成2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-㗁二唑-2-酮[Step6]Synthesis of2,2,2-trifluoroacetic acid3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazol-2-one
將步驟5中合成之4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-2-氟-苯基]哌啶-1-甲酸三級丁酯(100.00%，0.300 g，0.524 mmol)及2,2,2-三氟乙酸(100.00%，0.179 g，1.570 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌3小時。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.3 g，97.63%，黃色油狀物)。A solution of 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester (100.00%, 0.300 g, 0.524 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 0.179 g, 1.570 mmol) synthesized in step 5 in dichloromethane (20 mL) was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.3 g, 97.63%, yellow oil).
[步驟7]合成化合物26[Step7]Synthesis of compound26
將步驟6中之合成之2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-㗁二唑-2-酮(100.00%，0.050 g，0.085 mmol)、N-乙基二異丙胺(100.00%溶液，0.03 mL，0.172 mmol)、氧雜環丁-3-酮(100.00%，0.012 g，0.167 mmol)及三乙醯氧基硼氫化鈉(100.00%，0.054 g，0.255 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.031 g，68.79%，白色固體)。2,2,2-Trifluoroacetic acid 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazol-2-one (100.00%, 0.050 g, 0.085 mmol), N-ethyldiisopropylamine (100.00% solution, 0.03 mL, 0.172 mmol), oxadiazol-3-one (100.00%, 0.012 g, 0.167 mmol) and sodium triacetoxyborohydride (100.00%, 0.054 g, 0.255 mmol) prepared in step 6 were dissolved in dichloromethane (5% ethanol, 1% ethanol, 0.050 g, 0.085 mmol) at room temperature. The solution in 40 mL) was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.031 g, 68.79%, white solid).
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.6 Hz, 1H), 8.43 (dd,J= 8.2, 2.2 Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d.J= 8.2 Hz, 1H), 7.47-7.43 (m, 1H), 7.26-7.23 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 4.71-4.64 (m, 4H), 3.56-3.50 (m, 1H), 3.00-2.94 (m, 1H), 2.91-2.88 (m, 2H), 2.02-1.96 (m, 2H), 1.87-1.81 (m, 4H);LRMS(ES) m/z 529.82 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.6 Hz, 1H), 8.43 (dd,J = 8.2, 2.2 Hz, 1H), 7.70-7.66 (m, 1H), 7.53 (d.J = 8.2 Hz, 1H), 7.47-7.43 (m, 1H), 7.26-7.23 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 4.71-4.64 (m, 4H), 3.56-3.50 (m, 1H), 3.00-2.94 (m, 1H), : 2.91-2.88 (m, 2H), 2.02-1.96 (m, 2H), 1.87-1.81 (m, 4H);LRMS (ES) m/z 529.82 (M++ 1).
下表10中之化合物係根據與實例26中實質上相同的方法合成。 [表10]
實例27：合成化合物27，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-[1-(1-甲基氮雜環丁-3-基)-4-哌啶基]苯基]-1,3,4-㗁二唑-2-酮[步驟1]合成3-[4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-2-氟-苯基]-1-哌啶基]氮雜環丁-1-甲酸三級丁酯Example27: Synthesis of Compound27,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-[1-(1-methylazinocyclobutane-3-yl)-4-piperidinyl]phenyl]-1,3,4-oxadiazol-2-one[Step1]Synthesis of3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4 -oxadiazol-2-yl]-2 -fluoro-phenyl]-1-piperidinyl]azinocyclobutane-1-carboxylicacid tributyl ester
將實例26之步驟6中合成之2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-㗁二唑-2-酮(100.00%，0.150 g，0.256 mmol)、N-乙基二異丙胺(100.00%溶液，0.089 mL，0.511 mmol)、3-側氧基氮雜環丁-1-甲酸三級丁酯(100.00%，0.088 g，0.514 mmol)及三乙醯氧基硼氫化鈉(100.00%，0.163 g，0.769 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.11 g，68.52%，白色固體)。2,2,2-trifluoroacetic acid 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazol-2-one synthesized in step 6 of Example 26 (100.00%, 0.150 g, 0.256 mmol), N-ethyldiisopropylamine (100.00% solution, 0.089 mL, 0.511 mmol), 3-oxazolidinone-1-carboxylic acid tributyl ester (100.00%, 0.088 g, 0.514 mmol) and sodium triacetoxyborohydride (100.00%, 0.163 g, 0.769 mmol) was dissolved in dichloromethane (5 mL) at room temperature and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.11 g, 68.52%, white solid).
[步驟2]合成2,2,2-三氟乙酸5-[3-[1-(氮雜環丁-3-基)-4-哌啶基]-2-氟-苯基]-3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-1,3,4-㗁二唑-2-酮[Step2]Synthesis of2,2,2-trifluoroacetic acid5-[3-[1-(azacyclobutane-3-yl)-4-piperidinyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazol-2-one
將步驟1中合成之3-[4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-2-氟-苯基]-1-哌啶基]氮雜環丁-1-甲酸三級丁酯(100.00%，0.110 g，0.175 mmol)及2,2,2-三氟乙酸(100.00%，0.060 g，0.526 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.100 g，88.94%，黃色油狀物)。A solution of 3-[4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]-1-piperidinyl]azinecyclobutane-1-carboxylic acid tributyl ester (100.00%, 0.110 g, 0.175 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 0.060 g, 0.526 mmol) synthesized in step 1 in dichloromethane (5 mL) was stirred at the same temperature overnight. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.100 g, 88.94%, yellow oil).
[步驟3]合成化合物27[Step3]Synthesis of compound27
將步驟2中合成之2,2,2-三氟乙酸5-[3-[1-(氮雜環丁-3-基)-4-哌啶基]-2-氟-苯基]-3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-1,3,4-㗁二唑-2-酮(100.00%，0.050 g，0.078 mmol)、甲醛(100.00%，0.005 g，0.167 mmol)、N-乙基二異丙胺(100.00%溶液，0.027 mL，0.155 mmol)及三乙醯氧基硼氫化鈉(100.00%，0.050 g，0.236 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.029 g，68.71%，白色固體)。2,2,2-Trifluoroacetic acid 5-[3-[1-(Azocyclobutan-3-yl)-4-piperidinyl]-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazol-2-one (100.00%, 0.050 g, 0.078 mmol), formaldehyde (100.00%, 0.005 g, 0.167 mmol), N-ethyldiisopropylamine (100.00% solution, 0.027 mL, 0.155 mmol) and sodium triacetoxyborohydride (100.00%, 0.050 g, 0.236 mmol) synthesized in step 2 were dissolved in dichloromethane (5% ethanol, 1% ethanol, 0.050 g, 0.078 mmol) at room temperature. The solution in 40 mL) was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.029 g, 68.71%, white solid).
1H NMR(400 MHz, CDCl3)δ9.31 (d,J= 1.6 Hz, 1H), 8.43 (dd,J= 8.2, 2.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.53 (d.J= 8.2 Hz, 1H), 7.45-7.41 (m, 1H), 7.25-7.21 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 3.76 (brs, 2H), 3.09 (brs, 3H), 2.99-2.90 (m, 3H), 2.50 (s, 3H), 2.09-1.94 (m, 2H), 1.87-1.80 (m, 4H);LRMS(ES) m/z 542.86 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.31 (d,J = 1.6 Hz, 1H), 8.43 (dd,J = 8.2, 2.2 Hz, 1H), 7.69-7.65 (m, 1H), 7.53 (d.J = 8.2 Hz, 1H), 7.45-7.41 (m, 1H), 7.25-7.21 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H) 5.26 (s, 2H), 3.76 (brs, 2H), 3.09 (brs, 3H), 2.99-2.90 (m, 3H), 2.50 (s, 3H), 2.09-1.94 (m, 2H), 1.87-1.80 (m, 4H);LRMS (ES) m/z 542.86 (M++ 1).
下表11中之化合物係根據與實例27中實質上相同的方法合成。 [表11]
實例81：合成化合物81，5-[3-(1-環丁基-4-哌啶基)-2-氟-苯基]-3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-1,3,4-㗁二唑-2-硫酮[步驟1]合成4-[2-氟-3-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)苯基]哌啶-1-甲酸三級丁酯Example81: Synthesis of Compound81,5-[3-(1-cyclobutyl-4-piperidinyl)-2-fluoro-phenyl]-3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-1,3,4-oxadiazole-2-thione[Step1]Synthesis of4-[2-fluoro-3-(2-thione-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylic acid tributyl ester
將實例26之步驟3中製備之4-[2-氟-3-(肼羰基)苯基]哌啶-1-甲酸三級丁酯(100.00%，1.100 g，3.260 mmol)及乙基黃原酸鉀(100.00%，0.627 g，3.911 mmol)在室溫混合於乙醇(80 mL)中之混合物加熱至回流隔夜。將混合物冷卻至室溫，且將水倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.9 g，72.76%，白色固體)。A mixture of tributyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 1.100 g, 3.260 mmol) prepared in step 3 of Example 26 and potassium ethylxanthate (100.00%, 0.627 g, 3.911 mmol) in ethanol (80 mL) was heated to reflux overnight at room temperature. The mixture was cooled to room temperature, and water was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.9 g, 72.76%, white solid).
[步驟2]合成4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]-2-氟-苯基]哌啶-1-甲酸三級丁酯[Step2]Synthesis of4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl]-2-pyridyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]-2 -fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester
將步驟1中合成之4-[2-氟-3-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)苯基]哌啶-1-甲酸三級丁酯(100.00%，0.500 g，1.318 mmol)及碳酸鉀(100.00%，0.196 g，1.978 mmol)溶解於N,N-二甲基甲醯胺(20 mL)中之溶液在室溫攪拌30分鐘。隨後，添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.401 g，1.383 mmol)及碘化鉀(100.00%，0.109 g，0.657 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.61 g，78.64%，白色固體)。A solution of tributyl 4-[2-fluoro-3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.500 g, 1.318 mmol) synthesized in step 1 and potassium carbonate (100.00%, 0.196 g, 1.978 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 30 minutes. Subsequently, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.401 g, 1.383 mmol) and potassium iodide (100.00%, 0.109 g, 0.657 mmol) were added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.61 g, 78.64%, white solid).
[步驟3]合成2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-㗁二唑-2-硫酮[Step3]Synthesis of2,2,2-trifluoroacetic acid3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazole-2-thione
將步驟2中合成之4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]-2-氟-苯基]哌啶-1-甲酸三級丁酯(100.00%，0.400 g，0.680 mmol)及三氟乙酸(100.00%，0.232 g，2.035 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌3小時。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.37 g，90.37%，黃色油狀物)。A solution of 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester (100.00%, 0.400 g, 0.680 mmol) and trifluoroacetic acid (100.00%, 0.232 g, 2.035 mmol) synthesized in step 2 in dichloromethane (20 mL) was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.37 g, 90.37%, yellow oil).
[步驟4]合成化合物81[Step4]Synthesis of compound81
將步驟3中合成之2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-㗁二唑-2-硫酮(100.00%，0.050 g，0.083 mmol)、環丁酮(100.00%，0.012 g，0.171 mmol)及N-乙基二異丙胺(100.00%溶液，0.029 mL，0.167 mmol)溶解於二氯甲烷(5 mL)中之溶液在室溫攪拌30分鐘。隨後，添加三乙醯氧基硼氫化鈉(100.00%，0.053 g，0.250 mmol)且在相同溫度進一步攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.029 g，64.40%，白色固體)。A solution of 2,2,2-trifluoroacetic acid 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridinyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-oxadiazole-2-thione (100.00%, 0.050 g, 0.083 mmol) synthesized in step 3, cyclobutanone (100.00%, 0.012 g, 0.171 mmol) and N-ethyldiisopropylamine (100.00% solution, 0.029 mL, 0.167 mmol) in dichloromethane (5 mL) was stirred at room temperature for 30 minutes. Subsequently, sodium triacetoxyborohydride (100.00%, 0.053 g, 0.250 mmol) was added and further stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.029 g, 64.40%, white solid).
1H NMR(400 MHz, CDCl3)δ9.31 (d,J= 2.1 Hz, 1H), 8.38 (dd,J= 8.2, 2.3 Hz, 1H), 7.83-7.79 (m, 2H), 7.49-7.45 (m, 1H), 7.26-7.22 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.15-3.12 (m, 2H), 3.03-3.00 (m, 1H), 2.88-2.84 (m, 1H), 2.12-2.02 (m, 6H), 1.98-1.88 (m, 4H), 1.79-1.68 (m, 2H);LRMS(ES) m/z 543.90 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.31 (d,J = 2.1 Hz, 1H), 8.38 (dd,J = 8.2, 2.3 Hz, 1H), 7.83-7.79 (m, 2H), 7.49-7.45 (m, 1H), 7.26-7.22 (m, 1H), 7.08 (s, 0.2H), 6.95 (s, 0.5H), 6.82 (s, 0.2H), 4.73 (s, 2H), 3.15-3.12 (m, 2H), 3.03-3.00 (m, 1H), 2.88-2.84 (m, 1H), 2.12-2.02 (m, 6H), 1.98-1.88 (m, 4H), 1.79-1.68 (m, 2H);LRMS (ES) m/z 543.90 (M++ 1).
下表12中之化合物係根據與實例81中實質上相同的方法合成。 [表12]
實例100：合成化合物100，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[6-(4-乙基哌𠯤-1-基)-2-吡啶基]-1,3,4-㗁二唑-2-硫酮[步驟1]合成4-(6-甲氧基羰基-2-吡啶基)哌𠯤-1-甲酸三級丁酯Example100: Synthesis of Compound100,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridinyl]methyl]-5-[6-(4-ethylpiperidin-1-yl)-2-pyridinyl]-1,3,4-oxadiazole-2-thione[Step1]Synthesis of4-(6-methoxycarbonyl-2-pyridinyl)piperidin-1-carboxylicacid tributyl ester
將6-氟吡啶-2-甲酸甲酯(100.00%，0.500 g，3.223 mmol)、哌𠯤-1-甲酸三級丁酯(100.00%，1.200 g，6.443 mmol)及N,N-二異丙基乙胺(100.00%溶液，0.844 mL，4.800 mmol)在130℃溶解於二甲亞碸(15 mL)中之溶液在相同溫度攪拌隔夜，且藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至60%)純化濃縮物且濃縮，得到標題化合物(0.736 g，71.05%，黃色固體)。A solution of methyl 6-fluoropyridine-2-carboxylate (100.00%, 0.500 g, 3.223 mmol), tributyl piperidine-1-carboxylate (100.00%, 1.200 g, 6.443 mmol) and N,N-diisopropylethylamine (100.00% solution, 0.844 mL, 4.800 mmol) dissolved in dimethyl sulfoxide (15 mL) at 130° C. was stirred at the same temperature overnight, and the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.736 g, 71.05%, yellow solid).
[步驟2]合成4-[6-(肼羰基)-2-吡啶基]哌𠯤-1-甲酸三級丁酯[Step2]Synthesis of4-[6-(hydrazinecarbonyl)-2-pyridyl]piperidinium-1-carboxylicacid tributyl ester
向步驟1中合成之4-(6-甲氧基羰基-2-吡啶基)哌𠯤-1-甲酸三級丁酯(100.00%，0.736 g，2.290 mmol)在室溫溶解於乙醇(10 mL)中之溶液中添加單水合肼(100.00%溶液，1.113 mL，22.900 mmol)且在60℃攪拌18小時。隨後，藉由將溫度降低至室溫來終止反應。將氯化銨飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.73 g，99.18%，黃色固體)。To a solution of tributyl 4-(6-methoxycarbonyl-2-pyridyl)piperidinium-1-carboxylate (100.00%, 0.736 g, 2.290 mmol) synthesized in step 1 dissolved in ethanol (10 mL) at room temperature, hydrazine monohydrate (100.00% solution, 1.113 mL, 22.900 mmol) was added and stirred at 60°C for 18 hours. Thereafter, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.73 g, 99.18%, yellow solid).
[步驟3]合成4-[6-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)-2-吡啶基]哌𠯤-1-甲酸三級丁酯[Step3]Synthesis of tributyl4-[6-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)-2-pyridinyl]piperidin-1-carboxylate
將步驟2中合成之4-[6-(肼羰基)-2-吡啶基]哌𠯤-1-甲酸三級丁酯(100.00%，0.730 g，2.271 mmol)及乙基黃原酸鉀(100.00%，0.364 g，2.271 mmol)在室溫溶解於乙醇(10 mL)中之溶液在90℃攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。將氯化銨飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，40 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.604 g，73.18%，黃色固體)。A solution of tributyl 4-[6-(hydrazinecarbonyl)-2-pyridinyl]piperidinium-1-carboxylate (100.00%, 0.730 g, 2.271 mmol) synthesized in step 2 and potassium ethylxanthate (100.00%, 0.364 g, 2.271 mmol) dissolved in ethanol (10 mL) at room temperature was stirred at 90°C overnight. Subsequently, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 40 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.604 g, 73.18%, yellow solid).
[步驟4]合成4-[6-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]-2-吡啶基]哌𠯤-1-甲酸三級丁酯[Step4]Synthesis of4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl]-2-pyridinyl]methyl]-5-thioxo-1,3,4-oxadiazol-2-yl]-2-pyridinyl]piperidin-1-carboxylicacid tributyl ester
將步驟3中合成之4-[3-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)苯基]哌𠯤-1-甲酸三級丁酯(100.00%，0.700 g，1.932 mmol)、2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，1.000 equiv.，1.932 mmol)、碳酸鉀(100.00%，2.000 equiv.，3.863 mmol)及碘化鉀(100.00%，2.000 equiv.，3.863 mmol)在室溫溶解於N,N-二甲基甲醯胺(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.14 g，12.68%，黃色固體)。A solution of tributyl 4-[3-(2-thioxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidin-1-carboxylate (100.00%, 0.700 g, 1.932 mmol) synthesized in step 3, 2-[6-(bromomethyl)-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.000 equiv., 1.932 mmol), potassium carbonate (100.00%, 2.000 equiv., 3.863 mmol) and potassium iodide (100.00%, 2.000 equiv., 3.863 mmol) dissolved in N,N-dimethylformamide (5 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.14 g, 12.68%, yellow solid).
[步驟5]合成3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(6-哌𠯤-1-基-2-吡啶基)-1,3,4-㗁二唑-2-硫酮[Step5]Synthesis of3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridyl]methyl]-5-(6-piperidin-1-yl-2-pyridyl)-1,3,4-oxadiazole-2-thione
將步驟4中合成之4-[6-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]-2-吡啶基]哌𠯤-1-甲酸三級丁酯(100.00%，0.384 g，0.671 mmol)及三氟乙酸(100.00%溶液，0.513 mL，6.700 mmol)在室溫溶解於二氯甲烷(3 mL)中之溶液在相同溫度攪拌隔夜。將碳酸氫鈉飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。所得產物不經進一步純化即使用(0.31 g，97.83%，黃色油狀物)。A solution of tributyl 4-[6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]-2-pyridinyl]piperidin-1-carboxylate (100.00%, 0.384 g, 0.671 mmol) and trifluoroacetic acid (100.00% solution, 0.513 mL, 6.700 mmol) dissolved in dichloromethane (3 mL) at room temperature was stirred at the same temperature overnight. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was used without further purification (0.31 g, 97.83%, yellow oil).
[步驟6]合成化合物100[Step6]Synthesis of compound100
在室溫將步驟5中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(6-哌𠯤-1-基-2-吡啶基)-1,3,4-㗁二唑-2-硫酮(100.00%，0.100 g，0.212 mmol)、乙醛(100.00%溶液，0.024 mL，0.429 mmol)及N-乙基-N-異丙基-丙-2-胺(100.00%溶液，0.074 mL，0.425 mmol)溶解於二氯甲烷(1 mL)中之溶液攪拌30分鐘，且添加三乙醯氧基硼氫化鈉(100.00%，0.134 g，0.635 mmol)，且在相同溫度進一步攪拌18小時。將碳酸氫鈉飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.026 g，24.55%，黃色固體)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-2-pyridinyl]methyl]-5-(6-piperidin-1-yl-2-pyridinyl)-1,3,4-oxadiazole-2-thione (100.00%, 0.100 g, 0.212 mmol), acetaldehyde (100.00% solution, 0.024 mL, 0.429 mmol) and N-ethyl-N-isopropyl-propan-2-amine (100.00% solution, 0.074 mL, 0.425 mmol) dissolved in dichloromethane (1 mL) was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.134 g, 0.635 mmol) was added. mmol), and further stirred at the same temperature for 18 hours. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.026 g, 24.55%, yellow solid).
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.6 Hz, 1H), 8.37 (dd,J= 8.2, 2.2 Hz, 1H), 7.84 (d,J= 8.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.43 (d,J= 7.2 Hz, 1H), 6.96 (t,J= 51.6 Hz, 1H), 6.78 (d,J= 8.8 Hz, 1H), 4.75 (s, 2H), 3.69 (t,J= 5.0 Hz, 4H), 2.59 (t,J= 5.0 Hz, 4H), 2.50 (q,J= 7.2 Hz, 2H), 1.16 (t,J= 7.2 Hz, 3H);LRMS(ES) m/z 501.5 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.6 Hz, 1H), 8.37 (dd,J = 8.2, 2.2 Hz, 1H), 7.84 (d,J = 8.4 Hz, 1H), 7.63-7.59 (m, 1H), 7.43 (d,J = 7.2 Hz, 1H), 6.96 (t,J = 51.6 Hz, 1H), 6.78 (d,J = 8.8 Hz, 1H), 4.75 (s, 2H), 3.69 (t,J = 5.0 Hz, 4H), 2.59 (t,J = 5.0 Hz, 4H), 2.50 (q,J = 7.2 Hz, 2H), 1.16 (t,J = 7.2 Hz, 3H);LRMS (ES) m/z 501.5 (M++ 1).
下表13中之化合物係根據與實例100中實質上相同的方法合成。 [表13]
實例41：合成化合物41，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(1-甲基-4-哌啶基)苯基]-1,3,4-噻二唑-2-酮[步驟1]合成4-[3-(胺基硫代胺基甲醯基)-2-氟-苯基]哌啶-1-甲酸三級丁酯Example41: Synthesis of Compound41,3-[[5-[5-(difluoromethyl)-1,3,4-thiazol-2-yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(1-methyl-4-piperidinyl)phenyl]-1,3,4-thiadiazol-2-one[Step1]Synthesis of4-[3-(aminothiocarbamoyl)-2-fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester
將實例26之步驟3中合成之4-[2-氟-3-(肼羰基)苯基]哌啶-1-甲酸三級丁酯(100.00%，0.200 g，0.593 mmol)及勞森氏試劑(100.00%，0.288 g，0.712 mmol)在室溫溶解於甲苯(20 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。所得產物不經進一步純化即使用(0.11 g，52.51%，黃色油狀物)。A solution of tributyl 4-[2-fluoro-3-(hydrazinecarbonyl)phenyl]piperidine-1-carboxylate (100.00%, 0.200 g, 0.593 mmol) and Lawson's reagent (100.00%, 0.288 g, 0.712 mmol) synthesized in step 3 of Example 26 dissolved in toluene (20 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.11 g, 52.51%, yellow oil).
[步驟2]合成4-[2-氟-3-(2-側氧基-3H-1,3,4-噻二唑-5-基)苯基]哌啶-1-甲酸三級丁酯[Step2]Synthesis of4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylic acid tributyl ester
將步驟1中合成之4-[3-(胺基硫代胺基甲醯基)-2-氟-苯基]哌啶-1-甲酸三級丁酯(100.00%，0.200 g，0.566 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，0.110 g，0.678 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(0.15 g，69.86%，白色固體)。A solution of 4-[3-(aminothiocarbamoyl)-2-fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester (100.00%, 0.200 g, 0.566 mmol) synthesized in step 1 and 1,1'-carbonylbis-1H-imidazole (100.00%, 0.110 g, 0.678 mmol) dissolved in dichloromethane (20 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (0.15 g, 69.86%, white solid).
[步驟3]合成4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-噻二唑-2-基]-2-氟-苯基]哌啶-1-甲酸三級丁酯[Step3]Synthesis of4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-thiadiazol-2 -yl]-2-pyridyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]-2 -fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester
向步驟2中合成之4-[2-氟-3-(2-側氧基-3H-1,3,4-噻二唑-5-基)苯基]哌啶-1-甲酸三級丁酯(100.00%，0.073 g，0.192 mmol)及碳酸鉀(100.00%，0.029 g，0.293 mmol)在室溫溶解於N,N-二甲基甲醯胺(20 mL)中之溶液中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.059 g，0.203 mmol)及碘化鉀(100.00%，0.016 g，0.096 mmol)，且在相同溫度攪拌30分鐘。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化銨飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.05 g，44.15%，白色固體)。To a solution of tributyl 4-[2-fluoro-3-(2-oxo-3H-1,3,4-thiadiazol-5-yl)phenyl]piperidine-1-carboxylate (100.00%, 0.073 g, 0.192 mmol) synthesized in step 2 and potassium carbonate (100.00%, 0.029 g, 0.293 mmol) in N,N-dimethylformamide (20 mL) at room temperature were added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-thiadiazole (100.00%, 0.059 g, 0.203 mmol) and potassium iodide (100.00%, 0.016 g, 0.096 mmol), and the mixture was stirred at the same temperature for 30 minutes. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.05 g, 44.15%, white solid).
[步驟4]合成2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-噻二唑-2-酮[Step4]Synthesis of2,2,2-trifluoroacetic acid3-[[5-[5-(difluoromethyl)-1,3,4-thiadiazole-2 -yl]-2-pyridyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-thiadiazole-2-one
將步驟3中合成之4-[3-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-噻二唑-2-基]-2-氟-苯基]哌啶-1-甲酸三級丁酯(100.00%，0.058 g，0.099 mmol)及三氟乙酸(100.00%，0.034 g，0.298 mmol)在室溫溶解於二氯甲烷(10 mL)中之溶液在相同溫度攪拌3小時。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.055 g，92.64%，黃色油狀物)。A solution of 4-[3-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-thiadiazol-2-yl]-2-fluoro-phenyl]piperidine-1-carboxylic acid tributyl ester (100.00%, 0.058 g, 0.099 mmol) and trifluoroacetic acid (100.00%, 0.034 g, 0.298 mmol) synthesized in step 3 in dichloromethane (10 mL) was stirred at room temperature for 3 hours. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.055 g, 92.64%, yellow oil).
[步驟5]合成化合物41[Step5]Synthesis of compound41
將步驟4中合成之2,2,2-三氟乙酸3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[2-氟-3-(4-哌啶基)苯基]-1,3,4-噻二唑-2-酮(100.00%，0.055 g，0.091 mmol)、N-乙基二異丙胺(100.00%溶液，0.032 mL，0.184 mmol)、甲醛(100.00%，0.005 g，0.167 mmol)及三乙醯氧基硼氫化鈉(100.00%，0.039 g，0.184 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用碳酸氫鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾，且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至5%)純化濃縮物且濃縮，得到標題化合物(0.031 g，67.58%，白色固體)。A solution of 2,2,2-trifluoroacetic acid 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[2-fluoro-3-(4-piperidinyl)phenyl]-1,3,4-thiadiazol-2-one (100.00%, 0.055 g, 0.091 mmol) synthesized in step 4, N-ethyldiisopropylamine (100.00% solution, 0.032 mL, 0.184 mmol), formaldehyde (100.00%, 0.005 g, 0.167 mmol) and sodium triacetoxyborohydride (100.00%, 0.039 g, 0.184 mmol) in dichloromethane (5 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 5%) and concentrated to give the title compound (0.031 g, 67.58%, white solid).
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.6 Hz, 1H), 8.41 (dd,J= 8.2, 2.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.46 (d,J= 8.2 Hz, 1H), 7.40-7.36 (m, 1H), 7.28-7.17 (m, 1H), 5.44 (s, 2H), 3.13-3.10 (m, 2H), 2.99-2.92 (m, 1H), 2.43 (s, 3H), 2.26-2.20 (m, 2H), 1.98-1.86 (m, 4H);LRMS(ES) m/z 503.7 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.6 Hz, 1H), 8.41 (dd,J = 8.2, 2.2 Hz, 1H), 7.77-7.73 (m, 1H), 7.46 (d,J = 8.2 Hz, 1H), 7.40-7.36 (m, 1H), 7.28-7.17 (m, 1H), 5.44 (s, 2H), 3.13-3.10 (m, 2H), 2.99-2.92 (m, 1H), 2.43 (s, 3H), 2.26-2.20 (m, 2H), 1.98-1.86 (m, 4H);LRMS (ES) m/z 503.7 (M+ +1).
下表14中之化合物係根據與實例41中實質上相同的方法合成。 [表14]
實例20：合成化合物20，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(4-哌𠯤-1-基苯基)-1,3,4-㗁二唑-2-酮[步驟1]合成4-(4-甲氧基羰基苯基)哌𠯤-1-甲酸三級丁酯Example20: Synthesis of Compound20,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(4-piperidin-1-ylphenyl)-1,3,4-oxadiazol-2-one[Step1]Synthesis of4-(4-methoxycarbonylphenyl)piperidin-1-carboxylicacid tributyl ester
將4-溴苯甲酸甲酯(100.00%，0.500 g，2.325 mmol)、哌𠯤-1-甲酸三級丁酯(100.00%，1.200 equiv.，2.790 mmol)、參(二苯亞甲基丙酮)二鈀(100.00%，5.000 mol%，0.116 mmol)、Xphos (100.00%，5.000 mol%，0.116 mmol)及碳酸銫(100.00%，2.000 equiv.，4.650 mmol)在110℃溶解於甲苯(50 mL)中之溶液在相同溫度攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.73 g，97.99%，棕色固體)。A solution of methyl 4-bromobenzoate (100.00%, 0.500 g, 2.325 mmol), tributyl piperidine-1-carboxylate (100.00%, 1.200 equiv., 2.790 mmol), dipalladium tris(benzylideneacetone) (100.00%, 5.000 mol%, 0.116 mmol), Xphos (100.00%, 5.000 mol%, 0.116 mmol) and cesium carbonate (100.00%, 2.000 equiv., 4.650 mmol) dissolved in toluene (50 mL) at 110° C. was stirred at the same temperature overnight. Subsequently, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.73 g, 97.99%, brown solid).
[步驟2]合成4-[4-(肼羰基)苯基]哌𠯤-1-甲酸三級丁酯[Step2]Synthesis of4-[4-(hydrazinecarbonyl)phenyl]piperidinium-1-carboxylicacid tributyl ester
將步驟1中合成之4-(4-甲氧基羰基苯基)哌𠯤-1-甲酸三級丁酯(100.00%，0.770 g，2.403 mmol)及單水合肼(100.00%，10.000 equiv.，24.030 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度進行攪拌。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.77 g，100.0%，黃色固體)。A solution of tributyl 4-(4-methoxycarbonylphenyl)piperidinium-1-carboxylate (100.00%, 0.770 g, 2.403 mmol) synthesized in step 1 and hydrazine monohydrate (100.00%, 10.000 equiv., 24.030 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.77 g, 100.0%, yellow solid).
[步驟3]合成4-[4-(2-側氧基-3H-1,3,4-㗁二唑-5-基)苯基]哌𠯤-1-甲酸三級丁酯[Step3]Synthesis of tributyl4-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidin-1-carboxylate
將步驟2中合成之4-[4-(肼羰基)苯基]哌𠯤-1-甲酸三級丁酯(100.00%，0.770 g，2.403 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，1.500 equiv.，3.605 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在回流下加熱隔夜。隨後，藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至100%)純化濃縮物且濃縮，得到標題化合物(0.5 g，60.06%，黃色固體)。A solution of tributyl 4-[4-(hydrazinecarbonyl)phenyl]piperidinium-1-carboxylate (100.00%, 0.770 g, 2.403 mmol) synthesized in step 2 and 1,1'-carbonylbis-1H-imidazole (100.00%, 1.500 equiv., 3.605 mmol) dissolved in dichloromethane (5 mL) at room temperature was heated under reflux overnight. Subsequently, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.5 g, 60.06%, yellow solid).
[步驟4]合成4-[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]苯基]哌𠯤-1-甲酸三級丁酯[Step4]Synthesis of4-[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2 -yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]piperidin-1-carboxylicacid tributyl ester
將步驟3中合成之4-[4-(2-側氧基-3H-1,3,4-㗁二唑-5-基)苯基]哌𠯤-1-甲酸三級丁酯(100.00%，0.500 g，1.443 mmol)及2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，1.200 equiv.，1.732 mmol)、碳酸鉀(100.00%，2.000 equiv.，2.887 mmol)及碘化鉀(100.00%，1.100 equiv.，1.588 mmol)在室溫溶解於N,N-二甲基甲醯胺(25 mL)中之溶液在相同溫度進行攪拌。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.9 g，112.2%，黃色固體)。A solution of tributyl 4-[4-(2-oxo-3H-1,3,4-oxadiazol-5-yl)phenyl]piperidin-1-carboxylate (100.00%, 0.500 g, 1.443 mmol) synthesized in step 3 and 2-[6-(bromomethyl)-3-pyridinyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equiv., 1.732 mmol), potassium carbonate (100.00%, 2.000 equiv., 2.887 mmol) and potassium iodide (100.00%, 1.100 equiv., 1.588 mmol) dissolved in N,N-dimethylformamide (25 mL) at room temperature was stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.9 g, 112.2%, yellow solid).
[步驟5]合成化合物20，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(4-哌𠯤-1-基苯基)-1,3,4-㗁二唑-2-酮[Step5]Synthesis of compound20,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-(4-piperidin-1-ylphenyl)-1,3,4-oxadiazol-2-one
將步驟4中合成之4-[4-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]苯基]哌𠯤-1-甲酸三級丁酯(100.00%，0.900 g，1.620 mmol)及2,2,2-三氟乙酸(100.00%，10.000 equiv.，16.200 mmol)在室溫溶解於二氯甲烷(50 mL)中之溶液在相同溫度進行攪拌。將N-碳酸氫鈉水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.12 g，16.26%，白色固體)。A solution of tributyl 4-[4-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]phenyl]piperidin-1-carboxylate (100.00%, 0.900 g, 1.620 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 10.000 equiv., 16.200 mmol) prepared in step 4 dissolved in dichloromethane (50 mL) was stirred at the same temperature. A sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.12 g, 16.26%, white solid).
1H NMR(400 MHz, CDCl3) δ 9.29 (s, 1H), 8.39 (d,J= 10.0 Hz, 1H), 7.70 (d,J= 8.8 Hz, 2H), 7.49 (d,J= 8.0 Hz, 1H), 7.06-6.80 (m, 3H), 5.18 (s, 2H), 3.27 (s, 4H), 3.02 (s, 4H);LRMS(ES) m/z 455.5 (M++1)。1H NMR (400 MHz, CDCl3 ) δ 9.29 (s, 1H), 8.39 (d,J = 10.0 Hz, 1H), 7.70 (d,J = 8.8 Hz, 2H), 7.49 (d,J = 8.0 Hz, 1H), 7.06-6.80 (m, 3H), 5.18 (s, 2H), 3.27 (s, 4H), 3.02 (s, 4H);LRMS (ES) m/z 455.5 (M+ +1).
下表15中之化合物係根據與實例20中實質上相同的方法合成。 [表15]
實例21：合成化合物21，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[4-(4-甲基哌𠯤-1-基)苯基]-1,3,4-㗁二唑-2-酮Example21: Synthesis of Compound21,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[4-(4-methylpiperidin-1-yl)phenyl]-1,3,4-oxadiazol-2-one
將實例20之步驟5中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(4-哌𠯤-1-基苯基)-1,3,4-㗁二唑-2-酮(100.00%，0.060 g，0.132 mmol)、三乙醯氧基硼氫化鈉(100.00%，2.000 equiv.，0.264 mmol)及甲醛(37.00%，2.000 equiv.，0.264 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度進行攪拌。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.025 g，40.42%，黃色固體)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-(4-piperidin-1-ylphenyl)-1,3,4-oxadiazol-2-one (100.00%, 0.060 g, 0.132 mmol) synthesized in Step 5 of Example 20, sodium triacetoxyborohydride (100.00%, 2.000 equiv., 0.264 mmol) and formaldehyde (37.00%, 2.000 equiv., 0.264 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.025 g, 40.42%, yellow solid).
1H NMR(400 MHz, CDCl3)δ9.29 (s, 1H), 8.39 (d,J= 10.4 Hz, 1H), 7.70 (d,J= 8.8 Hz, 2H), 7.50 (d,J= 8.0 Hz, 1H), 6.93-6.80 (m, 3H), 5.18 (s, 2H), 3.34 (s, 4H), 2.59 (s, 4H), 2.36 (s, 3H);LRMS(ES) m/z 470.6 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.29 (s, 1H), 8.39 (d,J = 10.4 Hz, 1H), 7.70 (d,J = 8.8 Hz, 2H), 7.50 (d,J = 8.0 Hz, 1H), 6.93-6.80 (m, 3H), 5.18 (s, 2H), 3.34 (s, 4H), 2.59 (s, 4H), 2.36 (s, 3H);LRMS (ES) m/z 470.6 (M+ +1).
下表16中之化合物係根據與實例21中實質上相同的方法合成。 [表16]
實例6：合成化合物6，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-[6-(4-異丙基哌𠯤-1-基)-2-吡啶基]-1,3,4-㗁二唑-2-酮[步驟1]合成6-氟吡啶-2-卡肼Example6: Synthesis of Compound6,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-[6-(4-isopropylpiperidin-1-yl)-2-pyridinyl]-1,3,4-oxadiazol-2-one[Step1]Synthesis of6-fluoropyridine-2-carboxylic acid hydrazide
向6-氟吡啶-2-甲酸甲酯(100.00%，1.000 g，6.446 mmol)在室溫溶解於乙醇(30 mL)中之溶液中添加單水合肼(100.00%溶液，6.266 mL，129.000 mmol)，且在相同溫度攪拌隔夜。向藉由自反應混合物中減壓移除溶劑而獲得之濃縮物中倒入碳酸氫鈉飽和水溶液，且用二氯甲烷萃取所得混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。所得產物不經進一步純化即使用(1 g，100.00%，淺黃色固體)。To a solution of methyl 6-fluoropyridine-2-carboxylate (100.00%, 1.000 g, 6.446 mmol) dissolved in ethanol (30 mL) at room temperature, hydrazine monohydrate (100.00% solution, 6.266 mL, 129.000 mmol) was added, and stirred at the same temperature overnight. A saturated aqueous solution of sodium bicarbonate was poured into a concentrate obtained by removing the solvent from the reaction mixture under reduced pressure, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained product was used without further purification (1 g, 100.00%, light yellow solid).
[步驟2]合成5-(6-氟-2-吡啶基)-3H-1,3,4-㗁二唑-2-酮[Step2]Synthesis of5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazol-2-one
向步驟1中合成之6-氟吡啶-2-卡肼(100.00%，1.000 g，6.446 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，1.254 g，7.734 mmol)在室溫溶解於四氫呋喃(30 mL)中之溶液中添加三乙胺(100.00%溶液，1.251 mL，9.000 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.21 g，17.987%，黃色固體)。To a solution of 6-fluoropyridine-2-carbohydrazide (100.00%, 1.000 g, 6.446 mmol) synthesized in step 1 and 1,1'-carbonylbis-1H-imidazole (100.00%, 1.254 g, 7.734 mmol) dissolved in tetrahydrofuran (30 mL) at room temperature, triethylamine (100.00% solution, 1.251 mL, 9.000 mmol) was added, and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.21 g, 17.987%, yellow solid).
[步驟3]合成3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(6-氟-2-吡啶基)-1,3,4-㗁二唑-2-酮[Step3]Synthesis of3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-(6-fluoro-2-pyridinyl)-1,3,4 -oxadiazol-2-one
向步驟2中合成之5-(6-氟-2-吡啶基)-3H-1,3,4-㗁二唑-2-酮(100.00%，0.210 g，1.160 mmol)及碳酸鉀(100.00%，0.244 g，1.765 mmol)在室溫溶解於N,N-二甲基甲醯胺(5 mL)中之溶液中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.404 g，1.393 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.185 g，40.88%，淺黃色固體)。To a solution of 5-(6-fluoro-2-pyridyl)-3H-1,3,4-oxadiazole-2-one (100.00%, 0.210 g, 1.160 mmol) synthesized in step 2 and potassium carbonate (100.00%, 0.244 g, 1.765 mmol) dissolved in N,N-dimethylformamide (5 mL) at room temperature was added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.404 g, 1.393 mmol), and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.185 g, 40.88%, light yellow solid).
[步驟4]合成化合物6[Step4]Synthesis of Compound6
將步驟3中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(6-氟-2-吡啶基)-1,3,4-㗁二唑-2-酮(100.00%，0.040 g，0.103 mmol)、1-異丙基哌𠯤(100.00%溶液，0.029 mL，0.203 mmol)及N,N-二異丙基乙胺(100.00%溶液，0.027 mL，0.150 mmol)在130℃溶解於二甲亞碸(1 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到呈橙色固體形式之標題化合物(0.02 g，39.15%)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridinyl]methyl]-5-(6-fluoro-2-pyridinyl)-1,3,4-oxadiazol-2-one (100.00%, 0.040 g, 0.103 mmol), 1-isopropylpiperidinium (100.00% solution, 0.029 mL, 0.203 mmol) and N,N-diisopropylethylamine (100.00% solution, 0.027 mL, 0.150 mmol) synthesized in step 3 dissolved in dimethyl sulfoxide (1 mL) at 130° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (0.02 g, 39.15%) as an orange solid.
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.6 Hz, 1H), 8.43 (dd,J= 8.2, 2.2 Hz, 1H), 7.61-7.57 (m, 1H), 7.52 (d,J= 8.0 Hz, 1H), 7.23 (d,J= 7.6 Hz, 1H), 6.96 (t,J= 51.6 Hz, 1H), 6.78 (d,J= 8.8 Hz, 1H), 5.27 (s, 2H), 3.76 (s, 4H), 2.89-2.75 (m, 5H), 1.18 (d,J= 5.6 Hz, 6H);LRMS(ES) m/z 499.8 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.6 Hz, 1H), 8.43 (dd,J = 8.2, 2.2 Hz, 1H), 7.61-7.57 (m, 1H), 7.52 (d,J = 8.0 Hz, 1H), 7.23 (d,J = 7.6 Hz, 1H), 6.96 (t,J = 51.6 Hz, 1H), 6.78 (d,J = 8.8 Hz, 1H), 5.27 (s, 2H), 3.76 (s, 4H), 2.89-2.75 (m, 5H), 1.18 (d,J = 5.6 Hz, 6H);LRMS (ES) m/z 499.8 (M+ +1).
下表17中之化合物係根據與實例6中實質上相同的方法合成。 [表17]
實例19：合成化合物19，3-((5-(5-(二氟甲基)-1,3,4-㗁二唑-2-基)吡啶-2-基)甲基)-5-(1-甲基-1H-吲哚-5-基)-1,3,4-㗁二唑-2(3H)-硫酮[步驟1]合成1-甲基吲哚-5-甲酸甲酯Example19: Synthesis of Compound19,3-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridin-2-yl)methyl)-5-(1-methyl-1H-indol-5-yl)-1,3,4 -oxadiazole-2(3H)-thione[Step1]Synthesis of1-methylindole-5-carboxylic acid methyl ester
向1H-吲哚-5-甲酸甲酯(100.00%，0.500 g，2.854 mmol)在0℃溶解於N,N-二甲基甲醯胺(7 mL)中之溶液中添加氫化鈉(60.00%，140.000 mg，3.500 mmol)，且在相同溫度攪拌0.2小時。將碘甲烷(100.00%溶液，0.27 mL，4.340 mmol)添加至反應混合物中且進一步在室溫攪拌4小時。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.27 g，49.996%，白色固體)。To a solution of 1H-indole-5-carboxylic acid methyl ester (100.00%, 0.500 g, 2.854 mmol) dissolved in N,N-dimethylformamide (7 mL) at 0°C was added sodium hydroxide (60.00%, 140.000 mg, 3.500 mmol), and stirred at the same temperature for 0.2 hours. Iodomethane (100.00% solution, 0.27 mL, 4.340 mmol) was added to the reaction mixture and further stirred at room temperature for 4 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.27 g, 49.996%, white solid).
[步驟2]合成1-甲基吲哚-5-卡肼[Step2]Synthesis of1-methylindole-5-carbohydrazide
將步驟1中合成之1-甲基吲哚-5-甲酸甲酯(100.00%，160.000 mg，0.846 mmol)溶解於乙醇(2.5 mL)中，且在室溫添加單水合肼(100.00%溶液，0.8 mL，16.490 mmol)，且在60℃攪拌18小時。隨後，藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(160 mg，100.00%，淺黃色固體)。Methyl 1-methylindole-5-carboxylate (100.00%, 160.000 mg, 0.846 mmol) synthesized in step 1 was dissolved in ethanol (2.5 mL), and hydrazine monohydrate (100.00% solution, 0.8 mL, 16.490 mmol) was added at room temperature, and stirred at 60°C for 18 hours. Then, the reaction was terminated by lowering the temperature to room temperature. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (160 mg, 100.00%, light yellow solid).
[步驟3]合成5-(1-甲基吲哚-5-基)-3H-1,3,4-㗁二唑-2-酮[Step3]Synthesis of5-(1-methylindol-5-yl)-3H-1,3,4-oxadiazol-2-one
向步驟2中合成之1-甲基吲哚-5-卡肼(100.00%，160.000 mg，0.846 mmol)及N,N-二異丙基乙胺(DIPEA，100.00%溶液，0.3 mL，1.700 mmol)在0℃溶解於二氯甲烷(3 mL)中之溶液中添加三光氣(100.00%，100.000 mg，0.337 mmol)，且在相同溫度進行攪拌。自反應混合物中減壓移除溶劑之後，藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=10%至50%)純化濃縮物且濃縮，得到標題化合物(270 mg，148.36%，白色固體)。To a solution of 1-methylindole-5-carboxylic acid hydrazide (100.00%, 160.000 mg, 0.846 mmol) synthesized in step 2 and N,N-diisopropylethylamine (DIPEA, 100.00% solution, 0.3 mL, 1.700 mmol) dissolved in dichloromethane (3 mL) at 0°C, triphosgene (100.00%, 100.000 mg, 0.337 mmol) was added, and stirring was performed at the same temperature. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane=10% to 50%) and concentrated to give the title compound (270 mg, 148.36%, white solid).
[步驟4]合成化合物19[Step4]Synthesis of compound19
向步驟3中合成之5-(1-甲基吲哚-5-基)-3H-1,3,4-㗁二唑-2-酮(100.00%，50.000 mg，0.232 mmol)在室溫溶解於N,N-二甲基甲醯胺(2 mL)中之溶液中添加碳酸鉀(100.00%，35.000 mg，0.353 mmol)，且在相同溫度攪拌0.3小時。向反應混合物中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，80.000 mg，0.276 mmol)且在35℃進一步攪拌18小時。將氯化鈉飽和水溶液倒入反應混合物中，且用乙酸乙酯萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；己烷/乙酸乙酯=100%至50%)純化濃縮物且濃縮，得到標題化合物(43 mg，43.61%，白色固體)。To a solution of 5-(1-methylindol-5-yl)-3H-1,3,4-oxadiazole-2-one (100.00%, 50.000 mg, 0.232 mmol) synthesized in step 3 dissolved in N,N-dimethylformamide (2 mL) at room temperature was added potassium carbonate (100.00%, 35.000 mg, 0.353 mmol), and stirred at the same temperature for 0.3 hours. To the reaction mixture was added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 80.000 mg, 0.276 mmol) and further stirred at 35° C. for 18 hours. A saturated aqueous solution of sodium chloride was poured into the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; hexane/ethyl acetate = 100% to 50%) and concentrated to give the title compound (43 mg, 43.61%, white solid).
1H NMR(400 MHz, CD3OD)δ9.27 (d,J= 1.2 Hz, 1H), 8.52 (dd,J= 8.4, 2.4 Hz, 1H), 8.10 (d,J= 0.8 Hz, 1H), 7.80 (s, 1H), 7.70 (t,J= 8.8 Hz, 1H), 7.48 (d,J= 8.8 Hz, 1H), 7.26 (d,J= 3.2 Hz, 1H), 7.21 (t,J= 51.6 Hz, 1H), 6.57 (dd,J= 3.2, 0.4 Hz, 1H), 5.25 (s, 2H), 3.86 (s, 3H);LRMS(ES) m/z 425.7 (M++1)。1H NMR (400 MHz, CD3 OD)δ 9.27 (d,J = 1.2 Hz, 1H), 8.52 (dd,J = 8.4, 2.4 Hz, 1H), 8.10 (d,J = 0.8 Hz, 1H), 7.80 (s, 1H), 7.70 (t,J = 8.8 Hz, 1H), 7.48 (d,J = 8.8 Hz, 1H), 7.26 (d,J = 3.2 Hz, 1H), 7.21 (t,J = 51.6 Hz, 1H), 6.57 (dd,J = 3.2, 0.4 Hz, 1H), 5.25 (s, 2H), 3.86 (s, 3H);LRMS (ES) m/z 425.7 (M++ 1).
下表18中之化合物係根據與實例19中實質上相同的方法合成。 [表18]
實例33：合成化合物33，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(1H-吲哚-6-基)-1,3,4-㗁二唑-2-酮[步驟1]合成1-三級丁氧基羰基吲哚-6-甲酸Example33: Synthesis of Compound33,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-one[Step1]Synthesis of1-tert-butyloxycarbonylindole-6- carboxylicacid
向1H-吲哚-6-甲酸(100.00%，1.000 g，6.205 mmol)及二碳酸二-三級丁酯(100.00%，2.000 g，9.164 mmol)在室溫溶解於四氫呋喃(12 mL)中之溶液中添加4-(二甲基胺基)吡啶(100.00%，0.150 g，1.228 mmol)，且在相同溫度攪拌18小時。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.8 g，49.34%，白色固體)。To a solution of 1H-indole-6-carboxylic acid (100.00%, 1.000 g, 6.205 mmol) and di-tert-butyl dicarbonate (100.00%, 2.000 g, 9.164 mmol) dissolved in tetrahydrofuran (12 mL) at room temperature, 4-(dimethylamino)pyridine (100.00%, 0.150 g, 1.228 mmol) was added, and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.8 g, 49.34%, white solid).
[步驟2]合成6-(肼羰基)-1H-吲哚-1-甲酸三級丁酯[Step2]Synthesis of6-(hydrazinecarbonyl)-1H-indole-1-carboxylic acid tributyl ester
向步驟1中合成之1-三級丁氧基羰基吲哚-6-甲酸(100.00%，250 mg，0.9568 mmol)在室溫溶解於四氫呋喃(5 mL)中之溶液中添加1,1'-羰基雙-1H-咪唑(100.00%，200.000 mg，1.233 mmol)，且在相同溫度攪拌3小時。將單水合肼(100.00%，145.000 mg，2.897 mmol)添加至反應混合物中，且在相同溫度進一步攪拌18小時。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(混合物，淺黃色固體)。To a solution of 1-tert-butoxycarbonylindole-6-carboxylic acid (100.00%, 250 mg, 0.9568 mmol) synthesized in step 1 dissolved in tetrahydrofuran (5 mL) at room temperature, 1,1'-carbonylbis-1H-imidazole (100.00%, 200.000 mg, 1.233 mmol) was added, and stirred at the same temperature for 3 hours. Hydrazine monohydrate (100.00%, 145.000 mg, 2.897 mmol) was added to the reaction mixture, and further stirred at the same temperature for 18 hours. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (mixture, light yellow solid).
[步驟3]合成6-(2-側氧基-3H-1,3,4-㗁二唑-5-基)吲哚-1-甲酸三級丁酯[Step3]Synthesis of6-(2-oxo-3H-1,3,4-oxadiazol-5-yl)indole-1-carboxylic acid tributyl ester
將步驟2中合成之6-(肼羰基)吲哚-1-甲酸三級丁酯(100.00%，450.000 mg，1.635 mmol)及N,N-二異丙基乙胺(100.00%溶液，0.56 mL，3.200 mmol)溶解於二氯甲烷(5 mL)中，且在0℃添加三光氣(100.00%，190.000 mg，0.640 mmol)且在室溫攪拌18小時。自反應混合物中減壓移除溶劑之後，藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=10%至50%)純化濃縮物且濃縮，得到標題化合物(270 mg，54.82%，白色固體)。Tributyl 6-(hydrazinecarbonyl)indole-1-carboxylate (100.00%, 450.000 mg, 1.635 mmol) synthesized in step 2 and N,N-diisopropylethylamine (100.00% solution, 0.56 mL, 3.200 mmol) were dissolved in dichloromethane (5 mL), and triphosgene (100.00%, 190.000 mg, 0.640 mmol) was added at 0°C and stirred at room temperature for 18 hours. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane=10% to 50%) and concentrated to give the title compound (270 mg, 54.82%, white solid).
[步驟4]合成6-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]吲哚-1-甲酸三級丁酯[Step4]Synthesis of6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]indole-1-carboxylic acid tributyl ester
向步驟3中合成之6-(2-側氧基-3H-1,3,4-㗁二唑-5-基)吲哚-1-甲酸三級丁酯(100.00%，55.000 mg，0.183 mmol)在室溫溶解於N,N-二甲基甲醯胺(2 mL)中之溶液中添加碳酸鉀(100.00%，25.000 mg，0.252 mmol)，且在相同溫度攪拌0.3小時。向反應混合物中添加2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，64,000 mg，0.221 mmol)且在35℃進一步攪拌18小時。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；己烷/乙酸乙酯=100%至50%)純化濃縮物且濃縮，得到標題化合物(58 mg，62.25%，白色固體)。To a solution of tributyl 6-(2-oxo-3H-1,3,4-oxadiazole-5-yl)indole-1-carboxylate (100.00%, 55.000 mg, 0.183 mmol) synthesized in step 3 dissolved in N,N-dimethylformamide (2 mL) at room temperature was added potassium carbonate (100.00%, 25.000 mg, 0.252 mmol), and stirred at the same temperature for 0.3 hours. To the reaction mixture was added 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 64,000 mg, 0.221 mmol) and further stirred at 35° C. for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; hexane/ethyl acetate = 100% to 50%) and concentrated to give the title compound (58 mg, 62.25%, white solid).
[步驟5]合成化合物33[Step5]Synthesis of compound33
將步驟4中合成之6-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]吲哚-1-甲酸三級丁酯(100.00%，50.000 mg，0.098 mmol)在室溫溶解於二氯甲烷(1 mL)中之溶液中添加三氟乙酸(100.00%溶液，0.3 mL，3.918 mmol)，且在相同溫度攪拌1小時。向藉由自反應混合物中減壓移除溶劑而獲得之濃縮物中倒入碳酸氫鈉飽和水溶液，且用乙酸乙酯萃取所得混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=100%至80%)純化濃縮物且濃縮，得到標題化合物(34 mg，84.59%，淺黃色固體)。To a solution of tributyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]indole-1-carboxylate (100.00%, 50.000 mg, 0.098 mmol) synthesized in step 4 dissolved in dichloromethane (1 mL) at room temperature, trifluoroacetic acid (100.00% solution, 0.3 mL, 3.918 mmol) was added, and stirred at the same temperature for 1 hour. To the concentrate obtained by removing the solvent from the reaction mixture under reduced pressure was poured a saturated aqueous sodium bicarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 100% to 80%) and concentrated to give the title compound (34 mg, 84.59%, light yellow solid).
1H NMR(400 MHz, CD3OD)δ9.27 (d,J= 1.6 Hz, 1H), 8.54 (dd,J= 8.2, 2.2 Hz, 1H), 7.93 (d,J= 0.8 Hz, 1H), 7.73 (d,J= 8.4 Hz, 1H), 7.67 (d,J= 8.4 Hz, 1H), 7.53 (dd,J= 8.4, 1.6 Hz, 1H), 7.44 (d,J= 1.2 Hz, 1H), 7.26 (t,J= 51.6 Hz, 1H), 5.26 (s, 2H);LRMS(ES) m/z 412.8 (M++1)。1H NMR (400 MHz, CD3 OD)δ 9.27 (d,J = 1.6 Hz, 1H), 8.54 (dd,J = 8.2, 2.2 Hz, 1H), 7.93 (d,J = 0.8 Hz, 1H), 7.73 (d,J = 8.4 Hz, 1H), 7.67 (d,J = 8.4 Hz, 1H), 7.53 (dd,J = 8.4, 1.6 Hz, 1H), 7.44 (d,J = 1.2 Hz, 1H), 7.26 (t,J = 51.6 Hz, 1H), 5.26 (s, 2H);LRMS (ES) m/z 412.8 (M+ +1).
下表19中之化合物係根據與實例33中實質上相同的方法合成。 [表19]
實例11：合成化合物11，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(1,2,3,4-四氫異喹啉-6-基)-1,3,4-㗁二唑-2-酮[步驟1]合成7-(肼羰基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯Example11: Synthesis of Compound11,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazol-2-one[Step1]Synthesis of7-(hydrazinecarbonyl)-3,4 -dihydro-1H-isoquinoline-2-carboxylic acid tributyl ester
將3,4-二氫-1H-異喹啉-2,7-二甲酸2-三級丁酯7-甲酯(100.00%，0.603 g，2.070 mmol)及單水合肼(100.00%，10.000 equiv.，20.700 mmol)在70℃溶解於乙醇(20 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.603 g，100.0%，白色固體)。A solution of 2-tert-butyl 7-methyl 3,4-dihydro-1H-isoquinoline-2,7-dicarboxylate (100.00%, 0.603 g, 2.070 mmol) and hydrazine monohydrate (100.00%, 10.000 equiv., 20.700 mmol) dissolved in ethanol (20 mL) at 70° C. was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.603 g, 100.0%, white solid).
[步驟2]合成7-(2-側氧基-3H-1,3,4-㗁二唑-5-基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯[Step2]Synthesis of7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4 -dihydro-1H-isoquinoline-2-carboxylic acid tributyl ester
將步驟1中合成之7-(肼羰基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(100.00%，0.640 g，2.197 mmol)及1,1'-羰基雙-1H-咪唑(100.00%，1.500 equiv.，3.296 mmol)在50℃溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜，且接著藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至100%)純化濃縮物且濃縮，得到標題化合物(0.42 g，60.25%，白色固體)。A solution of tributyl 7-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.640 g, 2.197 mmol) synthesized in step 1 and 1,1'-carbonylbis-1H-imidazole (100.00%, 1.500 equiv., 3.296 mmol) dissolved in dichloromethane (5 mL) at 50°C was stirred at the same temperature overnight, and then the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.42 g, 60.25%, white solid).
[步驟3]合成7-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯[Step3]Synthesis of7-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-3,4 -dihydro-1H -isoquinoline-2- carboxylicacid tributyl ester
將步驟2中合成之7-(2-側氧基-3H-1,3,4-㗁二唑-5-基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(100.00%，0.420 g，1.324 mmol)、2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，1.200 equiv.，1.588 mmol)、碳酸鉀(100.00%，2.000 equiv.，2.647 mmol)及碘化鉀(100.00%，1.100 equiv.，1.456 mmol)在室溫溶解於N,N-二甲基甲醯胺(25 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至100%)純化濃縮物且濃縮，得到標題化合物(0.55 g，78.92%，黃色固體)。Tributyl 7-(2-oxo-3H-1,3,4-oxadiazol-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.420 g, 1.324 mmol) synthesized in step 2, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 1.200 equiv., 1.588 mmol), potassium carbonate (100.00%, 2.000 equiv., 2.647 mmol) and potassium iodide (100.00%, 1.100 equiv., 1.456 mmol) were dissolved in N,N-dimethylformamide (25 mL) at room temperature. The solution in 40 mL) was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 100%) and concentrated to give the title compound (0.55 g, 78.92%, yellow solid).
[步驟4]合成化合物11[Step4]Synthesis of compound11
將步驟3中合成之7-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(100.00%，0.550 g，1.045 mmol)及2,2,2-三氟乙酸(100.00%，10.000 equiv.，10.450 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液在相同溫度攪拌隔夜。將N-碳酸氫鈉水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.42 g，94.29%，黃色固體)。A solution of tributyl 7-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.550 g, 1.045 mmol) and 2,2,2-trifluoroacetic acid (100.00%, 10.000 equiv., 10.450 mmol) synthesized in step 3 dissolved in dichloromethane (20 mL) was stirred at room temperature overnight. Aqueous N-bicarbonate solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.42 g, 94.29%, yellow solid).
1H NMR(400 MHz, CDCl3)δ9.31 (s, 1H), 8.42 (d,J= 8.4 Hz, 1H), 7.60 (s, 2H), 7.51 (d,J= 7.6 Hz, 1H), 7.12 (d,J= 8.4 Hz, 1H), 6.93 (t,J= 51.6 Hz, 1H), 5.21 (s, 2H), 4.09 (s, 2H), 3.19 (s, 2H), 2.88 (s, 2H);LRMS(ES) m/z 427.4 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.31 (s, 1H), 8.42 (d,J = 8.4 Hz, 1H), 7.60 (s, 2H), 7.51 (d,J = 7.6 Hz, 1H), 7.12 (d,J = 8.4 Hz, 1H), 6.93 (t,J = 51.6 Hz, 1H), 5.21 (s, 2H), 4.09 (s, 2H), 3.19 (s, 2H), 2.88 (s, 2H);LRMS (ES) m/z 427.4 (M+ +1).
實例12：合成化合物12，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(2-甲基-3,4-二氫-1H-異喹啉-7-基)-1,3,4-㗁二唑-2-酮Example12: Synthesis of Compound12,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinolin-7-yl)-1,3,4-oxadiazol-2-one
將實例11之步驟4中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(1,2,3,4-四氫異喹啉-7-基)-1,3,4-㗁二唑-2-酮(100.00%，0.080 g，0.188 mmol)、甲醛(100.00%，1.500 equiv.，0.281 mmol)及三乙醯氧基硼氫化鈉(100.00%，2.000 equiv.，0.375 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度進行攪拌。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.02 g，24.21%，黃色固體)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,3,4-oxadiazol-2-one (100.00%, 0.080 g, 0.188 mmol) synthesized in Step 4 of Example 11, formaldehyde (100.00%, 1.500 equiv., 0.281 mmol) and sodium triacetoxyborohydride (100.00%, 2.000 equiv., 0.375 mmol) dissolved in dichloromethane (5 mL) at room temperature was stirred at the same temperature. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.02 g, 24.21%, yellow solid).
1H NMR(400 MHz, CDCl3)δ9.27 (s, 1H), 8.38 (d,J= 10.4 Hz, 1H), 7.57 (d,J= 8.0 Hz, 1H), 7.52 (d,J= 25.6 Hz, 2H), 7.17 (d,J= 8.0 Hz, 1H), 6.93 (t,J= 51.6 Hz, 1H), 5.18 (s, 2H), 3.60 (s, 2H), 2.95 (t,J= 5.6 Hz, 2H), 2.72 (t,J= 6.0 Hz, 2H), 2.45 (s, 3H);LRMS(ES) m/z 441.4 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.27 (s, 1H), 8.38 (d,J = 10.4 Hz, 1H), 7.57 (d,J = 8.0 Hz, 1H), 7.52 (d,J = 25.6 Hz, 2H), 7.17 (d,J = 8.0 Hz, 1H), 6.93 (t,J = 51.6 Hz, 1H), 5.18 (s, 2H), 3.60 (s, 2H), 2.95 (t,J = 5.6 Hz, 2H), 2.72 (t,J = 6.0 Hz, 2H), 2.45 (s, 3H);LRMS (ES) m/z 441.4 (M+ +1).
下表20中之化合物係根據與實例12中實質上相同的方法合成。 [表20]
實例135：合成化合物135，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-3-氟-2-吡啶基]甲基]-5-(2-甲基-3,4-二氫-1H-異喹啉-6-基)-1,3,4-㗁二唑-2-硫酮[步驟1]合成6-(肼羰基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯Example135: Synthesis of Compound135,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3 -fluoro-2-pyridyl]methyl]-5-(2-methyl-3,4-dihydro-1H-isoquinolin -6-yl)-1,3,4-oxadiazole-2-thione[Step1]Synthesis of6-(hydrazinecarbonyl)-3,4 -dihydro-1H-isoquinoline-2-carboxylic acid tributyl ester
向3,4-二氫-1H-異喹啉-2,6-二甲酸2-三級丁酯6-甲酯(100.00%，1.000 g，3.433 mmol)在室溫溶解於乙醇(20 mL)中之溶液中添加單水合肼(100.00%溶液，1.668 mL，34.320 mmol)，且在60℃攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑之後，藉由管柱層析(SiO2，24 g卡管；甲醇/二氯甲烷=0%至10%)純化濃縮物且濃縮，得到標題化合物(1 g，100.0%，白色固體)。To a solution of 2-tert-butyl 6-methyl 3,4-dihydro-1H-isoquinoline-2,6-dicarboxylate (100.00%, 1.000 g, 3.433 mmol) dissolved in ethanol (20 mL) at room temperature, hydrazine monohydrate (100.00% solution, 1.668 mL, 34.320 mmol) was added, and stirred at 60°C overnight. Subsequently, the reaction was terminated by lowering the temperature to room temperature. After the solvent was removed from the reaction mixture under reduced pressure, the concentrate was purified by column chromatography (SiO2 , 24 g cartridge; methanol/dichloromethane = 0% to 10%) and concentrated to give the title compound (1 g, 100.0%, white solid).
[步驟2]合成6-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯[Step2]Synthesis of6-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)-3,4 -dihydro-1H-isoquinoline-2-carboxylic acid tributyl ester
將步驟1中合成之6-(肼羰基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(100.00%，0.642 g，2.204 mmol)及乙基黃原酸鉀(100.00%，0.353 g，2.202 mmol)在室溫溶解於乙醇(10 mL)中之溶液在90℃攪拌隔夜。隨後，藉由將溫度降低至室溫來終止反應。將氯化銨飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.03 g，4.083%，無色油狀物)。A solution of tributyl 6-(hydrazinecarbonyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.642 g, 2.204 mmol) and potassium ethylxanthate (100.00%, 0.353 g, 2.202 mmol) synthesized in step 1 dissolved in ethanol (10 mL) was stirred at 90°C overnight. Subsequently, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.03 g, 4.083%, colorless oil).
[步驟3]合成6-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-3-氟-2-吡啶基]甲基]-5-側氧基-1,3,4-㗁二唑-2-基]-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯[Step3]Synthesis of6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-oxo-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tributyl ester
向步驟2中合成之6-(2-硫酮基-3H-1,3,4-㗁二唑-5-基)-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(100.00%，0.550 g，1.650 mmol)及碳酸鉀(100.00 %，0.229 g，2.311 mmol)在室溫溶解於N,N-二甲基甲醯胺(10 mL)中之溶液中添加2-[6-(溴甲基)-5-氟-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.610 g，1.980 mmol)，且在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至60%)純化濃縮物且濃縮，得到標題化合物(0.395 g，42.71%，黃色固體)。To a solution of tributyl 6-(2-thioxo-3H-1,3,4-oxadiazole-5-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.550 g, 1.650 mmol) synthesized in step 2 and potassium carbonate (100.00%, 0.229 g, 2.311 mmol) dissolved in N,N-dimethylformamide (10 mL) at room temperature was added 2-[6-(bromomethyl)-5-fluoro-3-pyridyl]-5-(difluoromethyl)-1,3,4-oxadiazole (100.00%, 0.610 g, 1.980 mmol), and stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.395 g, 42.71%, yellow solid).
[步驟4]合成3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-3-氟-2-吡啶基]甲基]-5-(1,2,3,4-四氫異喹啉-6-基)-1,3,4-㗁二唑-2-硫酮[Step4]Synthesis of3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazole-2-thione
將步驟3中合成之6-[4-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-3-氟-2-吡啶基]甲基]-5-硫酮基-1,3,4-㗁二唑-2-基]-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(100.00%，0.395 g，0.705 mmol)及三氟乙酸(100.00%溶液，0.539 mL，7.040 mmol)在室溫溶解於二氯甲烷(5 mL)中之溶液在相同溫度攪拌隔夜。將N-碳酸氫鈉水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。所得產物不經進一步純化即使用(0.32 g，98.64%，黃色油狀物)。A solution of tributyl 6-[4-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-fluoro-2-pyridyl]methyl]-5-thionyl-1,3,4-oxadiazol-2-yl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (100.00%, 0.395 g, 0.705 mmol) and trifluoroacetic acid (100.00% solution, 0.539 mL, 7.040 mmol) synthesized in step 3 dissolved in dichloromethane (5 mL) was stirred at the same temperature overnight. A sodium bicarbonate aqueous solution was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The product was used without further purification (0.32 g, 98.64%, yellow oil).
[步驟5]合成化合物135[Step5]Synthesis of compound135
將步驟4中合成之3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-3-氟-2-吡啶基]甲基]-5-(1,2,3,4-四氫異喹啉-6-基)-1,3,4-㗁二唑-2-硫酮(100.00%，0.060 g，0.130 mmol)、甲醛(37.00%溶液，0.026 mL，0.261 mmol)及N-乙基-N-異丙基-丙-2-胺(100.00%溶液，0.045 mL，0.258 mmol)溶解於二氯甲烷(1 mL)中之溶液在室溫攪拌30分鐘，且添加三乙醯氧基硼氫化鈉(100.00%，0.082 g，0.389 mmol)且進一步在相同溫度攪拌18小時。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=0%至10%)純化濃縮物且濃縮，得到標題化合物(0.021 g，33.96%，淺黃色固體)。A solution of 3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazole-2-yl]-3-fluoro-2-pyridyl]methyl]-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,3,4-oxadiazole-2-thione (100.00%, 0.060 g, 0.130 mmol) synthesized in step 4, formaldehyde (37.00% solution, 0.026 mL, 0.261 mmol) and N-ethyl-N-isopropyl-propan-2-amine (100.00% solution, 0.045 mL, 0.258 mmol) in dichloromethane (1 mL) was stirred at room temperature for 30 minutes, and sodium triacetoxyborohydride (100.00%, 0.082 g, 0.389 mmol) and further stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 0% to 10%) and concentrated to give the title compound (0.021 g, 33.96%, light yellow solid).
1H NMR(400 MHz, CDCl3)δ9.12 (s, 1H), 8.15 (dd,J= 9.0, 1.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.17 (d,J= 8.0 Hz, 1H), 6.96 (t,J= 52.2 Hz, 1H), 4.80 (d,J= 1.6 Hz, 2H), 3.65 (s, 2H), 3.01 (t,J= 5.8 Hz, 2H), 2.76-2.73 (m, 2H), 2.50 (s, 3H);LRMS(ES) m/z 475.9 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.12 (s, 1H), 8.15 (dd,J = 9.0, 1.8 Hz, 1H), 7.79-7.76 (m, 2H), 7.17 (d,J = 8.0 Hz, 1H), 6.96 (t,J = 52.2 Hz, 1H), 4.80 (d,J = 1.6 Hz, 2H), 3.65 (s, 2H), 3.01 (t,J = 5.8 Hz, 2H), 2.76-2.73 (m, 2H), 2.50 (s, 3H);LRMS (ES) m/z 475.9 (M+ +1).
下表21中之化合物係根據與實例135中實質上相同的方法合成。 [表21]
實例69：合成化合物69，3-[[5-[5-(二氟甲基)-1,3,4-㗁二唑-2-基]-2-吡啶基]甲基]-5-(2-噻吩基)-6H-1,3,4-㗁二𠯤-2-酮[步驟1]合成乙酸[2-側氧基-2-(2-噻吩基)乙酯]Example69: Synthesis of Compound69,3-[[5-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-2-pyridyl]methyl]-5-(2-thienyl)-6H-1,3,4-oxadiazol-2-one[Step1]Synthesis of[2-oxo-2-(2-thienyl)ethyl acetate]
向2-溴-1-(2-噻吩基)乙酮(100.00%，0.500 g，2.438 mmol)在室溫溶解於N,N-二甲基甲醯胺(10 mL)中之溶液中添加乙酸鉀(100.00%，0.718 g，7.316 mmol)及碘化鉀(100.00%，0.405 g，2.440 mmol)，且在相同溫度攪拌18小時。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。所得產物不經進一步純化即使用(0.445 g，99.078%，黃色油狀物)。To a solution of 2-bromo-1-(2-thienyl)ethanone (100.00%, 0.500 g, 2.438 mmol) dissolved in N,N-dimethylformamide (10 mL) at room temperature, potassium acetate (100.00%, 0.718 g, 7.316 mmol) and potassium iodide (100.00%, 0.405 g, 2.440 mmol) were added, and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained product was used without further purification (0.445 g, 99.078%, yellow oil).
[步驟2]合成乙酸[(2E)-2-(甲氧基羰基亞肼基)-2-(2-噻吩基)乙酯][Step2]Synthesis of(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl acetate
向步驟1中合成之乙酸[2-側氧基-2-(2-噻吩基)乙酯](100.00%，0.445 g，2.416 mmol)及氯化氫(1.00 M溶液，0.048 mL，0.048 mmol)在室溫溶解於甲醇(10 mL)中之溶液中添加肼基甲酸甲酯(100.00%，0.239 g，2.653 mmol)，且在相同溫度攪拌18小時。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至50%)純化濃縮物且濃縮，得到標題化合物(0.425 g，68.648%，黃色固體)。To a solution of [2-oxo-2-(2-thienyl)ethyl acetate] (100.00%, 0.445 g, 2.416 mmol) and hydrogen chloride (1.00 M solution, 0.048 mL, 0.048 mmol) synthesized in step 1 dissolved in methanol (10 mL) at room temperature, methyl carbazate (100.00%, 0.239 g, 2.653 mmol) was added, and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 50%) and concentrated to give the title compound (0.425 g, 68.648%, yellow solid).
[步驟3]合成5-(2-噻吩基)-3,6-二氫-1,3,4-㗁二𠯤-2-酮[Step3]Synthesis of5-(2-thienyl)-3,6-dihydro-1,3,4-dioxadien-2-one
將步驟2中合成之乙酸[(2E)-2-(甲氧基羰基亞肼基)-2-(2-噻吩基)乙酯](100.00%，0.425 g，1.658 mmol)及乙醇鈉(約20%於乙醇中，20.00%溶液，0.962 mL，2.500 mmol)在室溫溶解於乙醇(10 mL)中之溶液在相同溫度攪拌30分鐘。將氯化銨飽和水溶液倒入反應混合物中，然後用二氯甲烷萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.2 g，66.192%，黃色固體)。A solution of [(2E)-2-(methoxycarbonylhydrazono)-2-(2-thienyl)ethyl acetate] (100.00%, 0.425 g, 1.658 mmol) and sodium ethoxide (about 20% in ethanol, 20.00% solution, 0.962 mL, 2.500 mmol) synthesized in step 2 was dissolved in ethanol (10 mL) at room temperature and stirred at the same temperature for 30 minutes. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.2 g, 66.192%, yellow solid).
[步驟4]合成化合物69[Step4]Synthesis of compound69
將步驟3中合成之5-(2-噻吩基)-3,6-二氫-1,3,4-㗁二𠯤-2-酮(100.00%，0.045 g，0.247 mmol)、2-[6-(溴甲基)-3-吡啶基]-5-(二氟甲基)-1,3,4-㗁二唑(100.00%，0.075 g，0.259 mmol)、碳酸鉀(100.00%，0.037 g，0.373 mmol)及碘化鉀(100.00%，0.020 g，0.120 mmol)在室溫溶解於N,N-二甲基甲醯胺(1 mL)中之溶液在相同溫度攪拌隔夜。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鎂乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至60%)純化濃縮物且濃縮，得到標題化合物(0.042 g，43.45%，淺黃色固體)。A solution of 5-(2-thienyl)-3,6-dihydro-1,3,4-dioxadiazole (100.00%, 0.045 g, 0.247 mmol) synthesized in step 3, 2-[6-(bromomethyl)-3-pyridyl]-5-(difluoromethyl)-1,3,4-dioxadiazole (100.00%, 0.075 g, 0.259 mmol), potassium carbonate (100.00%, 0.037 g, 0.373 mmol) and potassium iodide (100.00%, 0.020 g, 0.120 mmol) dissolved in N,N-dimethylformamide (1 mL) at room temperature was stirred at the same temperature overnight. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 60%) and concentrated to give the title compound (0.042 g, 43.45%, light yellow solid).
1H NMR(400 MHz, CDCl3)δ9.32 (d,J= 1.6 Hz, 1H), 8.40 (dd,J= 8.2, 2.2 Hz, 1H), 7.53 (d,J= 8.4 Hz, 1H), 7.47 (dd,J= 5.2, 1.2 Hz, 1H), 7.25-7.24 (m, 1H), 7.11-7.09 (m, 1H), 6.96 (t,J= 51.6 Hz, 1H), 5.27 (s, 2H), 5.25 (s, 2H);LRMS(ES) m/z 392.3 (M++1)。1H NMR (400 MHz, CDCl3 )δ 9.32 (d,J = 1.6 Hz, 1H), 8.40 (dd,J = 8.2, 2.2 Hz, 1H), 7.53 (d,J = 8.4 Hz, 1H), 7.47 (dd,J = 5.2, 1.2 Hz, 1H), 7.25-7.24 (m, 1H), 7.11-7.09 (m, 1H), 6.96 (t,J = 51.6 Hz, 1H), 5.27 (s, 2H), 5.25 (s, 2H);LRMS (ES) m/z 392.3 (M+ +1).
下表22中之化合物係根據與實例69中實質上相同的方法合成。 [表22]
實例142：合成化合物142，3-((5-(5-(二氟甲基)-1,3,4-㗁二唑-2-基)吡啶-2-基)甲基)-5-苯基㗁唑-2(3H)-酮[步驟1]合成6-(((三級丁氧基羰基)胺基)甲基)菸鹼酸甲酯Example142: Synthesis of Compound142,3-((5-(5-(difluoromethyl)-1,3,4-oxadiazol- 2-yl)pyridin-2-yl)methyl)-5-phenyloxadiazol-2(3H)-one[Step1]Synthesis of6-(((tert-butyloxycarbonyl)amino)methyl)nicotinic acid methyl ester
向6-(胺基甲基)菸鹼酸甲酯(2.000 g，12.035 mmol)在室溫溶解於二氯甲烷(20 mL)中之溶液中添加二碳酸二-三級丁酯(3.152 g，14.442 mmol)及三乙胺(2.516 mL，18.053 mmol)，且在相同溫度攪拌18小時。將水倒入反應混合物中，且用二氯甲烷萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，24 g卡管；乙酸乙酯/己烷=0%至40%)純化濃縮物且濃縮，得到標題化合物(1.700 g，53.0%，白色固體)。To a solution of methyl 6-(aminomethyl)nicotinate (2.000 g, 12.035 mmol) dissolved in dichloromethane (20 mL) at room temperature, di-tributyl dicarbonate (3.152 g, 14.442 mmol) and triethylamine (2.516 mL, 18.053 mmol) were added, and stirred at the same temperature for 18 hours. Water was poured into the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 24 g cartridge; ethyl acetate/hexane = 0% to 40%) and concentrated to give the title compound (1.700 g, 53.0%, white solid).
[步驟2]合成6-(((三級丁氧基羰基)(苯基乙炔基)胺基)甲基)菸鹼酸甲酯[Step2]Synthesis of methyl6-(((tert-butyloxycarbonyl)(phenylethynyl)amino)methyl)nicotinate
在室溫將(溴乙炔基)苯(0.200 g，1.105 mmol)溶解於甲苯(5 mL)及步驟1中合成之6-(((三級丁氧基羰基)胺基)甲基)菸鹼酸甲酯(0.353 g，1.326 mmol)中，添加五水合硫酸銅(II)(0.055 g，0.221 mmol)、磷酸鉀(0.563 g，2.651 mmol)及1,10-啡啉(0.080 g，0.442 mmol)，且在80℃攪拌36小時。隨後，藉由將溫度降低至室溫來終止反應。經由矽藻土濾片過濾反應混合物以移除固體，且自濾液中減壓移除溶劑。隨後，藉由管柱層析(SiO2，12 g卡管；乙酸乙酯/己烷=0%至70%)純化濃縮物且濃縮，得到標題化合物(0.110 g，27.2%，淺黃色固體)。(Bromoethynyl)benzene (0.200 g, 1.105 mmol) was dissolved in toluene (5 mL) and methyl 6-(((tert-butyloxycarbonyl)amino)methyl)nicotinate (0.353 g, 1.326 mmol) synthesized in step 1 at room temperature, copper (II) sulfate pentahydrate (0.055 g, 0.221 mmol), potassium phosphate (0.563 g, 2.651 mmol) and 1,10-phenanthroline (0.080 g, 0.442 mmol) were added, and stirred at 80° C. for 36 hours. Subsequently, the reaction was terminated by lowering the temperature to room temperature. The reaction mixture was filtered through a diatomaceous earth filter to remove the solid, and the solvent was removed from the filtrate under reduced pressure. Subsequently, the concentrate was purified by column chromatography (SiO2 , 12 g cartridge; ethyl acetate/hexane = 0% to 70%) and concentrated to obtain the title compound (0.110 g, 27.2%, light yellow solid).
[步驟3]合成6-((2-側氧基-5-苯基㗁唑-3(2H)-基)甲基)菸鹼酸甲酯[Step3]Synthesis of methyl6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinate
向步驟2中合成之6-(((三級丁氧基羰基)(苯基乙炔基)胺基)甲基)菸鹼酸甲酯(0.050 g，0.136 mmol)在室溫溶解於二氯甲烷(0.5 mL)中之溶液中添加雙(三氟甲磺醯基)亞胺銀(0.003 g，0.007 mmol)，且在相同溫度攪拌1小時。將氯化銨飽和水溶液倒入反應混合物中且用乙酸乙酯萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；乙酸乙酯/己烷=0%至30%)純化濃縮物且濃縮，得到標題化合物(0.030 g，70.8%，黃色固體)。To a solution of methyl 6-(((tert-butyloxycarbonyl)(phenylethynyl)amino)methyl)nicotinate (0.050 g, 0.136 mmol) synthesized in step 2 dissolved in dichloromethane (0.5 mL) at room temperature, silver bis(trifluoromethanesulfonyl)imide (0.003 g, 0.007 mmol) was added, and stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride was poured into the reaction mixture and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; ethyl acetate/hexane = 0% to 30%) and concentrated to give the title compound (0.030 g, 70.8%, yellow solid).
[步驟4]合成6-((2-側氧基-5-苯基㗁唑-3(2H)-基)甲基)菸鹼醯肼[Step4]Synthesis of6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinylhydrazine
將步驟3中合成之6-((2-側氧基-5-苯基㗁唑-3(2H)-基)甲基)菸鹼酸甲酯(0.016 g，0.052 mmol)及單水合肼(0.050 mL，1.031 mmol)在80℃溶解於乙醇(1 mL)中之溶液在相同溫度攪拌18小時。隨後，藉由將溫度降低至室溫來終止反應。自反應混合物中減壓移除溶劑之後，所得產物不經進一步純化即使用(0.016 g，100.0%，白色固體)。A solution of methyl 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinate (0.016 g, 0.052 mmol) synthesized in step 3 and hydrazine monohydrate (0.050 mL, 1.031 mmol) dissolved in ethanol (1 mL) at 80° C. was stirred at the same temperature for 18 hours. Subsequently, the reaction was terminated by lowering the temperature to room temperature. After the solvent was removed from the reaction mixture under reduced pressure, the obtained product was used without further purification (0.016 g, 100.0%, white solid).
[步驟5]合成化合物142[Step5]Synthesis of compound142
向步驟4中合成之6-((2-側氧基-5-苯基㗁唑-3(2H)-基)甲基)菸鹼醯肼(0.015 g，0.048 mmol)及三乙胺(0.040 mL，0.290 mmol)在室溫溶解於四氫呋喃(0.7 mL)中之溶液中添加2,2-二氟乙酸酐(0.024 mL，0.193 mmol)，且在80℃攪拌6小時。隨後，藉由將溫度降低至室溫來終止反應。將碳酸氫鈉飽和水溶液倒入反應混合物中，然後用乙酸乙酯萃取。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。藉由管柱層析(SiO2，4 g卡管；己烷/乙酸乙酯=100%至50%)純化濃縮物且濃縮，得到標題化合物(0.008 g，44.7%，白色固體)。To a solution of 6-((2-oxo-5-phenyloxazol-3(2H)-yl)methyl)nicotinoid hydrazide (0.015 g, 0.048 mmol) synthesized in step 4 and triethylamine (0.040 mL, 0.290 mmol) dissolved in tetrahydrofuran (0.7 mL) at room temperature, 2,2-difluoroacetic anhydride (0.024 mL, 0.193 mmol) was added, and stirred at 80° C. for 6 hours. Subsequently, the reaction was terminated by lowering the temperature to room temperature. A saturated aqueous solution of sodium bicarbonate was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; hexane/ethyl acetate = 100% to 50%) and concentrated to give the title compound (0.008 g, 44.7%, white solid).
1H NMR(400 MHz, CD3OD)δ9.28 (s, 1H), 8.53 (dd,J= 7.8, 2.2 Hz, 1H), 7.67 (d,J= 8.4 Hz, 1H), 7.56 (d,J= 7.6 Hz, 2H), 7.44-7.40 (m, 3H), 7.33 (t,J= 7.4 Hz, 1H), 7.26 (t,J= 51.4 Hz, 1H), 7.26 (t,J= 51.4 Hz, 1H), 5.09 (s, 2H);LRMS(ES) m/z 371.2 (M++1)。1H NMR (400 MHz, CD3 OD)δ 9.28 (s, 1H), 8.53 (dd,J = 7.8, 2.2 Hz, 1H), 7.67 (d,J = 8.4 Hz, 1H), 7.56 (d,J = 7.6 Hz, 2H), 7.44-7.40 (m, 3H), 7.33 (t,J = 7.4 Hz, 1H), 7.26 (t,J = 51.4 Hz, 1H), 7.26 (t,J = 51.4 Hz, 1H), 5.09 (s, 2H);LRMS (ES) m/z 371.2 (M+ +1).
下表23中之化合物係根據與實例142中實質上相同的方法合成。 [表23]
實例144：合成化合物144：1-((5-(5-(二氟甲基)-1,3,4-㗁二唑-2-基)吡啶-2-基)甲基)-3-甲基-4-苯基-1,3-二氫-2H-咪唑-2-酮Example144: Synthesis of Compound144:1-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-3 -methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one
向1-甲基-5-苯基-1,3-二氫-2H-咪唑-2-酮(0.050 g，0.287 mmol)及2-(6-(溴甲基)吡啶-3-基)-5-(二氟甲基)-1,3,4-㗁二唑(0.100 g，0.345 mmol)在室溫溶解於N,N-二甲基甲醯胺(1 mL)中之溶液中添加碳酸鉀(0.060 g，0.431 mmol)及碘化鉀(0.010 g，0.057 mmol)，且在80℃攪拌18小時。隨後，藉由將溫度降低至室溫來終止反應。將水倒入反應混合物中，且用乙酸乙酯萃取混合物。將有機層用氯化鈉飽和水溶液洗滌，經無水硫酸鈉乾燥，過濾且減壓濃縮。經由管柱層析(SiO2，4 g卡管；二氯甲烷/甲醇=100%至80%)純化濃縮物且濃縮，得到標題化合物(0.012 g，10.9%，白色固體)。To a solution of 1-methyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one (0.050 g, 0.287 mmol) and 2-(6-(bromomethyl)pyridin-3-yl)-5-(difluoromethyl)-1,3,4-oxadiazole (0.100 g, 0.345 mmol) dissolved in N,N-dimethylformamide (1 mL) at room temperature, potassium carbonate (0.060 g, 0.431 mmol) and potassium iodide (0.010 g, 0.057 mmol) were added, and stirred at 80° C. for 18 hours. Subsequently, the reaction was terminated by lowering the temperature to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2 , 4 g cartridge; dichloromethane/methanol = 100% to 80%) and concentrated to give the title compound (0.012 g, 10.9%, white solid).
1H NMR(400 MHz, CDCl3)δ8.18 (d,J= 8.4 Hz, 2H), 8.15 (dd,J= 4.2, 1.8 Hz, 1H), 7.71 (d,J= 8.0 Hz, 2H), 7.62 - 7.57 (m, 2H), 7.51 - 7.37 (m, 3H), 6.95 (t,J= 51.8 Hz, 1H), 6.79 (s, 1H), 5.66 (s, 2H), 3.51 (s, 3H);LRMS(ES) m/z 384.2 (M++1)。1H NMR (400 MHz, CDCl3 )δ 8.18 (d,J = 8.4 Hz, 2H), 8.15 (dd,J = 4.2, 1.8 Hz, 1H), 7.71 (d,J = 8.0 Hz, 2H), 7.62 - 7.57 (m, 2H), 7.51 - 7.37 (m, 3H), 6.95 (t,J = 51.8 Hz, 1H), 6.79 (s, 1H), 5.66 (s, 2H), 3.51 (s, 3H);LRMS (ES) m/z 384.2 (M+ +1).
根據本發明之化合物之活性量測及分析方案＜實驗實例1＞HDAC酶活性抑制之確認(活體外)進行以下實驗以經由HDAC1及HDAC6酶活性抑制測試確認本發明之由化學式I表示之化合物的HDAC6選擇性。Activity measurement and analysis scheme of the compounds of the present invention<Experimental Example1>Confirmation ofHDAC enzyme activity inhibition(in vitro) The following experiment was performed to confirm the HDAC6 selectivity of the compounds represented by Chemical Formula I of the present invention through HDAC1 and HDAC6 enzyme activity inhibition tests.
HDAC酶活性係使用由Enzo Life Science製造之HDAC螢光測定藥物發現套組(BML-AK511，516)來量測。對於HDAC1酶活性測試，將人類重組HDAC1 (BML-SE456)用作酶來源，且將Fluor de Lys-"SIRT1 (BNL-KI177)用作受質。將5倍稀釋之化合物分配於96孔盤中，添加0.3 μg酶及10 μM受質至各孔中，且在30℃反應60分鐘，添加Fluor de LysDeveloper II(BML-KI176)且反應30分鐘以完成反應。隨後，使用多盤讀取器(Flexstation 3, Molecular Device)量測螢光值(Ex 360，Em 460)。使用與HDAC1酶活性測試方法相同之方案，採用來自Calbiochem之人類重組HDAC6 (382180)測試HDAC6酶。對於最終結果，使用GraphPad Prism 4.0程式計算各IC50值。其結果顯示於下表24中。 [表24]
如上表24中所描述，從HDAC1及HDAC6活性抑制測試之結果確認，本發明之1,3,4-㗁二唑衍生化合物、其立體異構物或其醫藥學上可接受之鹽表現出約185至約3497倍的優異選擇性HDAC6抑制活性。As described in Table 24 above, the results of the HDAC1 and HDAC6 activity inhibition assays confirmed that the 1,3,4-oxadiazole derivative compound of the present invention, its stereoisomers or pharmaceutically acceptable salts thereof exhibited an excellent HDAC6 inhibitory activity of about 185 to about 3497 times selectivity.
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020220114318AKR20240035172A (en) | 2022-09-08 | 2022-09-08 | 1,3,4-Oxadiazole Derivative Compounds as Histone Deacetylase 6 Inhibitor, and Uses thereof |
| KR10-2022-0114318 | 2022-09-08 |
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| TW112134022ATWI867736B (en) | 2022-09-08 | 2023-09-07 | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and uses thereof |
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| JP (1) | JP2025530834A (en) |
| KR (1) | KR20240035172A (en) |
| CN (1) | CN119816495A (en) |
| AU (1) | AU2023338505A1 (en) |
| MX (1) | MX2025002435A (en) |
| TW (1) | TWI867736B (en) |
| WO (1) | WO2024054071A1 (en) |
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| CA2787756C (en) | 2010-01-22 | 2019-06-18 | Acetylon Pharmaceuticals, Inc. | Reverse amide compounds as protein deacetylase inhibitors and methods of use thereof |
| AU2013230881A1 (en) | 2012-03-07 | 2014-10-30 | Board Of Trustees Of The University Of Illinois | Selective histone deactylase 6 inhibitors |
| PT3330259T (en)* | 2015-07-27 | 2020-09-03 | Chong Kun Dang Pharmaceutical Corp | 1,3,4-oxadiazole amide derivative compound as histone deacetylase 6 inhibitor, and pharmaceutical composition containing same |
| ES2774510T3 (en)* | 2015-07-27 | 2020-07-21 | Chong Kun Dang Pharmaceutical Corp | 1,3,4-Oxadiazole sulfamide derivatives as histone deacetylase 6 inhibitors and pharmaceutical composition comprising the same |
| CN107922362B (en)* | 2015-07-27 | 2021-06-15 | 株式会社钟根堂 | 1,3, 4-oxadiazole sulfonamide derivative compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions containing the same |
| WO2017023133A2 (en)* | 2015-08-04 | 2017-02-09 | Chong Kun Dang Pharmaceutical Corp. | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same |
| EP3475275B1 (en)* | 2016-06-23 | 2024-04-10 | Merck Sharp & Dohme LLC | 3-aryl and heteroaryl substituted 5-trifluoromethyl oxadiazoles as histone deacetylase 6 (hdac6) inhibitors |
| CN114269739B (en)* | 2019-04-17 | 2025-04-22 | 奎马特里克斯公司 | 1,3,4-oxadiazole derivatives as histone deacetylase inhibitors |
| CA3139026A1 (en)* | 2019-05-31 | 2020-12-03 | Chang Sik Lee | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same |
| PH12023550101A1 (en)* | 2020-07-14 | 2024-06-24 | Chong Kun Dang Pharmaceutical Corp | Novel compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same |
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| WO2024054071A1 (en) | 2024-03-14 |
| MX2025002435A (en) | 2025-04-02 |
| AU2023338505A1 (en) | 2025-02-13 |
| CN119816495A (en) | 2025-04-11 |
| TWI867736B (en) | 2024-12-21 |
| KR20240035172A (en) | 2024-03-15 |
| EP4584263A1 (en) | 2025-07-16 |
| JP2025530834A (en) | 2025-09-17 |
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