TW201601725A - Hsp70調節子及其製造及使用方法 - Google Patents
Hsp70調節子及其製造及使用方法 Download PDFInfo
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- TW201601725A TW201601725A TW104115328A TW104115328A TW201601725A TW 201601725 A TW201601725 A TW 201601725A TW 104115328 A TW104115328 A TW 104115328A TW 104115328 A TW104115328 A TW 104115328A TW 201601725 A TW201601725 A TW 201601725A
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 206010046766 uterine cancer Diseases 0.000 description 1
- 206010046885 vaginal cancer Diseases 0.000 description 1
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- 239000003981 vehicle Substances 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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- 229940053867 xeloda Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229950009268 zinostatin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
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Classifications
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本發明尤其提供用於調節Hsp70之化合物及其組合物。在一些實施例中,本發明提供一種抑制Hsp70活性之方法。在一些實施例中,本發明提供一種治療患有或易患對Hsp70抑制起反應之疾病、病症或病狀之個體的方法,其包含投與該個體治療有效量之所提供化合物。在一些實施例中,本發明提供一種治療或預防罹患癌症之個體的癌症的方法,其包含投與有需要之患者治療有效量之所提供化合物。
Description
本申請案主張2014年5月13日申請之美國臨時專利申請案第61/992,838號之優先權,其整個內容特此以引用之方式併入。
熱休克蛋白70(Hsp70)家族成員為在惡性病中具有重大作用之強力蛋白,該等作用諸如抑制細胞凋亡,誘導對化學療法之耐受性及調節癌蛋白之穩定性。特定言之,Hsp70表現以數種水準阻斷細胞凋亡,且就此而言,該伴隨蛋白抑制凋亡機構之關鍵效應子,且亦有助於蛋白酶體介導之細胞凋亡調節蛋白之降解。Hsp70同功異型物對腫瘤形成之貢獻主要經由其作為熱休克蛋白90(Hsp90)之共伴隨蛋白的作用進行,熱休克蛋白90為一種已知調控數種激酶及轉錄因子之轉型活性的熱休克蛋白。在此過程中,Hsp70會引發受質蛋白與Hsp90經由稱為HSP組織蛋白(HOP)之橋接蛋白結合。此等生物學功能提出將Hsp70作為重要標靶,其抑制或下調可引起大量癌細胞中之顯著細胞凋亡以及參與腫瘤形成及癌轉移之信號傳導路徑的抑制。由於此等功能,故Hsp70經常過度表現於癌症中並不意外,其中該高表現進一步被認為是對化學療法及其他療法之耐受性的原因。Hsp70(亦即Hsp90之共伴隨蛋白及抗細胞凋亡分子)在癌症中之此等雙重作用表明抑制Hsp70可提供有價值之抗癌策略,如由阻斷Hsp70基因表現研究所支
持。
最近大量工作已致力於發現Hsp70抑制劑,且不意外地,已報導來自多個化學類別之分子與Hsp70經由多種模式相互作用。此等先前工作集中於直接與ATP競爭,其獲得效能但具有有限細胞活性;或集中於別位機構。儘管據報導此等分子經由Hsp70機構引發其作用,但其亦可作用於多個其他不相關及迄今未規定之機構。此外,此等分子傾向於由不易控制之SAR阻礙,其中細微變化將引起活性急劇變化。
與Hsp90相比,Hsp70已證實為藥物之較困難標靶,其可歸因於多種原因。不同於Hsp90,並無結合Hsp70之晶體結構可用來引導藥物設計之藥物樣天然產物。此外,Hsp70之核苷酸結合袋比Hsp90之核苷酸結合袋的親水性大很多,從而需要ATP以更延展之構形與結合袋深處之極性接觸結合。由於Hsp70對ADP之高親和力及ATP之高胞內濃度,故可逆競爭性抑制劑開發起來尤其具有挑戰性。儘管Hsp90已證實高度易順從於鍵入臨床之多種小分子ATP競爭性抑制劑,但迄今為止尚無Hsp70抑制劑進入臨床試驗。
本發明尤其提供用於調節Hsp70之新穎化合物。在一些實施例中,本發明提供一種式I化合物:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
在一些實施例中,本發明提供一種式II化合物:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
在某些實施例中,本發明提供一種醫藥組合物,其包含式I化合物及醫藥學上可接受之載劑。在一些實施例中,本發明提供一種醫藥組合物,其包含式II化合物及醫藥學上可接受之載劑。
在一些實施例中,本發明提供一種抑制Hsp70活性之方法。在一些實施例中,本發明提供一種抑制Hsp70活性之方法,其包含使Hsp70與式I化合物或其組合物接觸。在一些實施例中,本發明提供一種抑制Hsp70活性之方法,其包含使Hsp70與式II化合物或其組合物接觸。在一些實施例中,本發明提供一種活化細胞中之卡斯蛋白酶的方法。在一些實施例中,本發明提供一種活化細胞中之卡斯蛋白酶的方法,其包含投與細胞式I化合物或其組合物。在一些實施例中,本發明提供一種活化細胞中之卡斯蛋白酶的方法,其包含投與細胞式II化合物或其組合物。在一些實施例中,本發明提供一種誘導細胞死亡之方法。在一些實施例中,本發明提供一種誘導細胞死亡之方法,其包含投與細胞式I化合物或其組合物。在一些實施例中,本發明提供一種誘導細胞死亡之方法,其包含投與細胞式II化合物或其組合物。在一些實施例中,本發明提供一種誘導細胞凋亡之方法。在一些實施例中,本發明提供一種誘導細胞凋亡之方法,其包含投與細胞式I化合物或其組合物。在一些實施例中,本發明提供一種誘導細胞凋亡之方法,其包含投與細胞式II化合物或其組合物。在一些實施例中,本發明提供一種抑制細胞生長之方法。在一些實施例中,本發明提供一種抑制細胞生長之方法,其包含投與細胞式I化合物或其組合物。在一些實施例中,本發明提供一種抑制細胞生長之方法,其包含投與細胞式II化合物或其組合物。在一些實施例中,所提供之方法中的細胞耐受Hsp90抑制劑。
在一些實施例中,本發明提供一種治療患有或易患對Hsp70抑制起反應之疾病、病症或病狀之個體的方法,其包含投與個體治療有效量之式I化合物或其組合物。在一些實施例中,本發明提供一種治療患有或易患對Hsp70抑制起反應之疾病、病症或病狀之個體的方法,其包含投與個體治療有效量之式II化合物或其組合物。
在一些實施例中,本發明提供一種治療或預防罹患癌症之個體的癌症的方法。在一些實施例中,本發明提供一種治療或預防罹患癌症之個體的癌症的方法,其包含投與有需要之患者治療有效量之式I化合物或其組合物。在一些實施例中,本發明提供一種治療或預防罹患癌症之個體的癌症的方法,其包含投與有需要之患者治療有效量之式II化合物或其組合物。在一些實施例中,所提供方法中之癌症用Hsp90抑制劑治療難治癒。
下文更詳細地描述本發明之某些化合物及特定官能基之定義。出於本發明之目的,根據元素週期表(Periodic Table of the Elements),CAS版,Handbook of Chemistry and Physics,第75版封面內頁來鑑別化學元素,且特定官能基一般係如其中所述來定義。另外,有機化學之通用原理以及特定官能部分及反應性描述於「Organic Chemistry」,Thomas Sorrell,University Science Books,Sausalito:1999中,其全部
內容以引用的方式併入本文中。
除非另外指定,否則如本文所用之以下定義應適用。
如本文所用之術語「脂族」或「脂族基」意謂完全飽和或含有一或多個不飽和單元之直鏈(亦即無分支鏈)或分支鏈、經取代或未經取代之烴鏈,或完全飽和或含有一或多個不飽和單元、但不為芳族之單環烴、雙環或多環烴(本文中亦稱為「碳環」、「環脂族」或「環烷基」),其與分子剩餘部分具有單一連接點。除非另外規定,否則脂族基含有1-20個脂族碳原子。在一些實施例中,脂族基含有1-12個脂族碳原子。在一些實施例中,脂族基含有1-6個脂族碳原子。在一些實施例中,脂族基含有1-5個脂族碳原子。在其他實施例中,脂族基含有1-4個脂族碳原子。在其他實施例中,脂族基含有1-3個脂族碳原子,且在其他實施例中,脂族基含有1-2個脂族碳原子。在一些實施例中,「環脂族基」(或「碳環」或「環烷基」)係指完全飽和或含有一或多個不飽和單元,但不為芳族之單環C3-C6烴,其與分子剩餘部分具有單一連接點。適合脂族基包括(但不限於)直鏈或分支鏈、經取代或未經取代之烷基、烯基、炔基及其混合物,諸如(環烷基)烷基、(環烯基)烷基或(環烷基)烯基。
如本文所用之術語「環脂族基」係指如本文所述之飽和或部分不飽和環脂族單環、雙環或多環環系統,其具有3至14個成員,其中脂族環系統視情況如上文所定義及本文所述經取代。環脂族基包括(但不限於)環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環庚基、環庚烯基、環辛基、環辛烯基、降冰片烷基、金剛烷基及環辛二烯基。在一些實施例中,環烷基具有3-6個碳。術語「環脂族基」亦可包括與一或多個芳族或非芳族環稠合之脂族環,諸如十氫萘基或四氫萘基,其中連接之基團或點在脂族環上。在一些實施例中,碳環基為雙環。在一些實施例中,碳環基為三環。在一些實施例
中,碳環基為多環。在一些實施例中,「環脂族基」(或「碳環」或「環烷基」)係指單環C3-C6烴;或完全飽和或含有一或多個不飽和單元,但不為芳族之C8-C10雙環烴,其與分子剩餘部分具有單一連接點;或完全飽和或含有一或多個不飽和單元,但不為芳族之C9-C16三環烴,其與分子剩餘部分具有單一連接點。
如本文所用之術語「烷基」以此項技術中之其一般含義給出,且可包括飽和脂族基,包括直鏈烷基、分支鏈烷基、環烷基(脂環族基)、經烷基取代之環烷基及經環烷基取代之烷基。在某些實施例中,直鏈或分支鏈烷基在其主鏈中具有約1-20個碳原子(例如對於直鏈為C1-C20,對於分支鏈為C2-C20)且或者約1-10個碳原子。在一些實施例中,環烷基環在其環結構中具有約3-10個碳原子,其中此類環為單環或雙環,且或者在環結構中具有約5、6或7個碳。在一些實施例中,烷基可為低碳烷基,其中低碳烷基包含1-4個碳原子(例如對於直鏈低碳烷基為C1-C4)。
如本文所用,術語「鹵烷基」係指經一或多個鹵素取代之烷基。
如本文所用,術語「烯基」係指如本文所定義之烷基,其具有一或多個雙鍵。
如本文所用,術語「炔基」係指如本文所定義之烷基,其具有一或多個參鍵。
術語「雜烷基」以此項技術中其一般含義給出且係指如本文所述之烷基,其中一或多個碳原子經雜原子(例如氧、氮、硫及其類似雜原子)置換。雜烷基之實例包括(但不限於)烷氧基、聚(乙二醇)-、經烷基取代之胺基、四氫呋喃基、哌啶基、嗎啉基等。
術語「雜原子」意謂氧、硫、氮、磷或矽中之一或多者(包括:氮、硫、磷或矽之任何氧化形式;任何鹼性氮之四級銨化形式;或雜
環之可經取代氮,例如N(如在3,4-二氫-2H-吡咯基中)、NH(如在吡咯啶基中)或NR+(如在N經取代之吡咯啶基中))。
如本文所用之術語「不飽和」意謂部分具有一或多個不飽和單元。
術語「鹵素」意謂F、Cl、Br或I。
單獨使用或作為較大部分(如在「芳烷基」、「芳烷氧基」或「芳氧基烷基」中)之一部分使用的術語「芳基」係指具有總共五至十四個環成員之單環、雙環及三環系統,其中系統中之至少一個環為芳族環且其中系統中之各環含有3至7個環成員。術語「芳基」可與術語「芳環」互換使用。
在本發明之某些實施例中,「芳基」係指包括(但不限於)苯基、聯苯、萘基、蒽基及其類似基團之芳族環系統,其可具有一或多個取代基。在於本文中使用時,術語「芳基」之範疇內亦包括芳族環與一或多個非芳族環(諸如茚滿基、鄰苯二甲醯亞胺基、萘醯亞胺基、啡啶基或四氫萘基及其類似基團)稠合之基團。
單獨或以較大部分之一部分使用之術語「雜芳基」及「雜芳-」(例如「雜芳烷基」或「雜芳烷氧基」)係指具有5至14個環原子,較佳5、6或9個環原子;具有環狀陣列中共用之6、10或14個π電子;且除碳原子以外具有一至五個雜原子之基團。術語「雜原子」係指氮、氧或硫,且包括氮或硫之任何氧化形式,及鹼性氮之任何四級銨化形式。雜芳基包括(但不限於)噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噁唑基、異噁唑基、噁二唑基、噻唑基、異噻唑基、噻二唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、吲嗪基、嘌呤基、啶基及喋啶基。如本文所用之術語「雜芳基」及「雜芳-」亦包括雜芳環與一或多個芳基、環脂族或雜環基環稠合的基團,其中連接之基團或點在雜芳族環上。非限制性實例包括吲哚基、異吲哚基、
苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、異喹啉基、啉基、酞嗪基、喹唑啉基、喹喏啉基、4H-喹嗪基、咔唑基、吖啶基、啡嗪基、啡噻嗪基、啡噁嗪基、四氫喹啉基、四氫異喹啉基及吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。雜芳基可為單環或雙環的。術語「雜芳基」可與術語「雜芳基環」、「雜芳基」或「雜芳族基」互換使用,該等術語中之任一者包括視情況經取代之環。術語「雜芳烷基」及「雜芳基烷基」係指經雜芳基部分取代之烷基,其中烷基及雜芳基部分獨立地視情況經取代。
如本文所用,術語「雜環(heterocycle)」、「雜環基」、「雜環基團」及「雜環(heterocyclic ring)」可互換使用且如上文所定義係指為飽和或部分不飽和,且除碳原子以外具有一或多個,較佳一至四個雜原子之穩定3至14員單環或7-14員雙環或多環雜環部分。當關於雜環之環原子使用時,術語「氮」包括經取代之氮。舉例而言,在具有0-3個選自氧、硫或氮之雜原子之飽和或部分不飽和環中,氮可為N(如在3,4-二氫-2H-吡咯基中)、NH(如在吡咯啶基中)或+NR(如在N經取代之吡咯啶基中)。
雜環可在任何雜原子或碳原子處連接至其側基,從而產生穩定結構,且任何環原子可視情況經取代。此類飽和或部分不飽和雜環基團之實例包括(但不限於)四氫呋喃基、四氫噻吩基吡咯啶基、哌啶基、吡咯啉基、四氫喹啉基、四氫異喹啉基、十氫喹啉基、噁唑啶基、哌嗪基、二氧雜環己烷基、二氧戊環基、二氮呯基、噁氮呯基、噻氮呯基、嗎啉基及啶基。術語「雜環」、「雜環基(heterocyclyl)」、「雜環基環」、「雜環基(heterocyclic group)」、「雜環部分」及「雜環基團」在本文中可互換使用,且亦包括雜環基環與一或多個芳基、雜芳基或環脂族環稠合之基團,諸如二氫吲哚基、3H-吲哚基、烷基、啡啶基或四氫喹啉基,其中連接之基團或點在雜環
基環上。雜環基可為單環或雙環的。術語「雜環基烷基」係指經雜環基取代之烷基,其中烷基及雜環基部分獨立地視情況經取代。
如本文所用之術語「部分不飽和」係指包括至少一個雙鍵或參鍵之環部分。術語「部分不飽和」欲涵蓋具有多個不飽和位點之環,但不欲包括如本文所定義之芳基或雜芳基部分。
在另一態樣中,本發明提供「醫藥學上可接受之」組合物,其包含與一或多種醫藥學上可接受之載劑(添加劑)及/或稀釋劑一起調配的治療有效量之一或多種本文所述化合物。如詳細描述,本發明之醫藥組合物可經特別調配以用於以固體或液體形式投與,其包括適合於以下之彼等者:經口投與,例如用於施用於舌的大劑量藥液(水性或非水性溶液或懸浮液)、錠劑(例如,針對經頰、舌下及全身性吸收之劑型)、大丸劑、粉末、顆粒、糊劑;非經腸投與,例如藉由以如例如無菌溶液或懸浮液或持續釋放調配物形式皮下、肌肉內、靜脈內或硬膜外注射;局部施用,例如以施用於皮膚、肺或口腔之乳膏、軟膏或控制釋放貼片或噴霧形式;陰道內或直腸內,例如以子宮托、乳膏或泡沫形式;舌下;經眼;經皮;或經鼻;經肺;及施用於其他黏膜表面。
片語「醫藥學上可接受」在本文中係用於指在合理醫學判斷之範疇內適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應或其他問題或併發症,與合理益處/風險比相匹配的彼等化合物、物質、組合物及/或劑型。
如本文所用之片語「醫藥學上可接受之載劑」意謂如下醫藥學上可接受之物質、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑或溶劑囊封材料,其參與自一個器官或身體之部分運載或輸送本發明化合物至另一器官或身體之部分。就與調配物之其他成分相容而言,各載劑必須「可接受」且對患者無害。可充當醫藥學上可接受
之載劑的材料之一些實例包括:糖,諸如乳糖、葡萄糖及蔗糖;澱粉,諸如玉米澱粉及馬鈴薯澱粉;纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;粉末狀黃蓍;麥芽;明膠;滑石;賦形劑,諸如可可油及栓劑蠟;油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;二醇,諸如丙二醇;多元醇,諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇;酯,諸如油酸乙酯及月桂酸乙酯;瓊脂;緩衝劑,諸如氫氧化鎂及氫氧化鋁;褐藻酸;無熱原質水;等張生理食鹽水;林格氏溶液(Ringer's solution);乙醇;pH緩衝溶液;聚酯、聚碳酸酯及/或聚酸酐;及醫藥調配物中採用之其他無毒相容物質。
除非另外說明,否則本文中所描繪之結構亦意欲包括該結構之所有異構(例如對映異構、非對映異構及幾何異構(或構形異構))形式;舉例而言,對於各立構中心之R及S構型、Z及E雙鍵異構體、及Z及E構形異構體。因此,本發明化合物之單一立體化學異構體以及對映異構體、非對映異構體及幾何異構體(或構形異構體)混合物係在本發明之範疇內。除非另外說明,否則本發明化合物之所有互變異構形式係在本發明之範疇內。
舉例而言,若需要本發明化合物之特定對映異構體,則其可藉由不對稱合成、對掌性層析法或藉由經對掌性助劑衍生來製備,其中分離所得非對映異構混合物且使助劑基團斷裂以得到純所要對映異構體。或者,在分子含有鹼性官能基(諸如胺基)或酸性官能基(諸如羧基)的情況下,與適當光學活性酸或鹼形成非對映異構鹽,接著藉由此項技術中熟知之分步結晶或層析方法解析由此形成之非對映異構體,隨後回收純對映異構體。
此外,除非另外說明,否則本文所述之結構亦意欲包括僅在一或多個同位素富集原子之存在方面不同之化合物。舉例而言,包括氫
由氘或氚替換或碳由富含13C或14C之碳替換的具有本發明結構之化合物係在本發明之範疇內。此類化合物適用作例如分析工具,用作生物分析中之探針,或用作本發明之治療劑。
一般技術者應瞭解,如本文所述之合成方法利用多種保護基團。如本文所用之術語「保護基」意謂特定官能部分(例如O、S或N)經遮蔽或阻斷以在必要時准許反應在多官能化合物中另一反應性位點處選擇性進行。在較佳實施例中,保護基選擇性地以良好產率反應以得到對預計反應穩定之受保護基質;保護基較佳可藉由容易獲得、較佳不攻擊其他官能基之無毒試劑選擇性移除;保護基形成可分離衍生物(更佳在無新立體對稱中心產生之情況下);且保護基較佳具有最小額外官能性以避開其他反應位點。如本文詳述,可使用氧、硫、氮及碳保護基。作為非限制性實例,羥基保護基包括甲基、甲氧基甲基(MOM)、甲基硫基甲基(MTM)、第三丁基硫基甲基、(苯基二甲基矽烷基)甲氧基甲基(SMOM)、苯甲氧基甲基(BOM)、對甲氧基苯甲氧基甲基(PMBM)、(4-甲氧基苯氧基)甲基(p-AOM)、愈創木酚甲基(GUM)、第三丁氧基甲基、4-戊烯氧基甲基(POM)、矽烷氧基甲基、2-甲氧基乙氧基甲基(MEM)、2,2,2-三氯乙氧基甲基、雙(2-氯乙氧基)甲基、2-(三甲基矽烷基)乙氧基甲基(SEMOR)、四氫哌喃基(THP)、3-溴四氫哌喃基、四氫硫哌喃基、1-甲氧基環己基、4-甲氧基四氫哌喃基(MTHP)、4-甲氧基四氫硫哌喃基、4-甲氧基四氫硫哌喃基S,S-二氧化物、1-[(2-氯-4-甲基)苯基]-4-甲氧基哌啶-4-基(CTMP)、1,4-二氧雜環己烷-2-基、四氫呋喃基、四氫硫基呋喃基、2,3,3a,4,5,6,7,7a-八氫-7,8,8-三甲基-4,7-亞甲基苯并呋喃-2-基、1-乙氧基乙基、1-(2-氯乙氧基)乙基、1-甲基-1-甲氧基乙基、1-甲基-1-苯甲氧基乙基、1-甲基-1-苯甲氧基-2-氟乙基、2,2,2-三氯乙基、2-三甲基矽烷基乙基、2-(苯基氫硒基)乙基、第三丁基、烯丙基、對氯苯基、對甲氧基苯基、2,4-二
硝基苯基、苯甲基、對甲氧基苯甲基、3,4-二甲氧基苯甲基、鄰硝基苯甲基、對硝基苯甲基、對鹵基苯甲基、2,6-二氯苯甲基、對氰基苯甲基、對苯基苯甲基、2-吡啶甲基、4-吡啶甲基、3-甲基-2-吡啶甲基N-氧離子基、二苯基甲基、對,對'-二硝基二苯甲基、5-二苯并環庚基、三苯基甲基、α-萘基二苯基甲基、對甲氧基苯基二苯基甲基、二(對甲氧基苯基)苯基甲基、三(對甲氧基苯基)甲基、4-(4'-溴苯甲醯甲氧基苯基)二苯基甲基、4,4',4"-參(4,5-二氯鄰苯二醯亞胺基苯基)甲基、4,4',4"-參(乙醯丙醯氧基苯基)甲基、4,4',4"-參(苯甲醯氧基苯基)甲基、3-(咪唑-1-基)雙(4',4"-二甲氧基苯基)甲基、1,1-雙(4-甲氧基苯基)-1'-芘基甲基、9-蒽基、9-(9-苯基)基、9-(9-苯基-10-側氧基)蒽基、1,3-苯并二硫雜環戊烷-2-基、苯并異噻唑基S,S-二氧離子基、三甲基矽烷基(TMS)、三乙基矽烷基(TES)、三異丙基矽烷基(TIPS)、二甲基異丙基矽烷基(IPDMS)、二乙基異丙基矽烷基(DEIPS)、二甲基第三己基矽烷基、第三丁基二甲基矽烷基(TBDMS)、第三丁基二苯基矽烷基(TBDPS)、三苯甲基矽烷基、三-對二甲苯基矽烷基、三苯基矽烷基、二苯基甲基矽烷基(DPMS)、第三丁基甲氧基苯基矽烷基(TBMPS)、甲酸酯、苯甲醯基甲酸酯、乙酸酯、氯乙酸酯、二氯乙酸酯、三氯乙酸酯、三氟乙酸酯、甲氧基乙酸酯、三苯基甲氧基乙酸酯、苯氧基乙酸酯、對氯苯氧基乙酸酯、3-苯基丙酸酯、4-側氧基戊酸酯(乙醯丙酸酯)、4,4-(伸乙基二硫基)戊酸酯(乙醯丙醯基二硫縮醛)、新戊酸酯、金剛酸酯、巴豆酸酯、4-甲氧基巴豆酸酯、苯甲酸酯、對苯基苯甲酸酯、2,4,6-三甲基苯甲酸酯(均三甲苯酸酯基)、碳酸烷酯甲酯、碳酸9-茀基甲酯(Fmoc)、碳酸烷酯乙酯、碳酸烷酯2,2,2-三氯乙酯(Troc)、碳酸2-(三甲基矽烷基)乙酯(TMSEC)、碳酸2-(苯基磺醯基)酯乙酯(Psec)、碳酸2-(三苯基磷鎓基)酯乙酯(Peoc)、碳酸烷酯異丁酯、碳酸烷酯乙烯酯、碳酸烷酯烯丙酯、碳酸烷酯對硝基
苯酯、碳酸烷酯苯甲酯、碳酸烷酯對甲氧基苯甲酯、碳酸烷酯3,4-二甲氧基苯甲酯、碳酸烷酯鄰硝基苯甲酯、碳酸烷酯對硝基苯甲酯、硫代碳酸烷酯S-苯甲酯、碳酸4-乙氧基-1-萘酯、二硫代碳酸甲酯、2-碘苯甲酸酯、4-疊氮基丁酸酯、4-硝基-4-甲基戊酸酯、鄰(二溴甲基)苯甲酸酯、2-甲醯基苯磺酸酯、2-(甲基硫基甲氧基)乙基、4-(甲基硫基甲氧基)丁酸酯、2-(甲基硫基甲氧基甲基)苯甲酸酯、2,6-二氯-4-甲基苯氧基乙酸酯、2,6-二氯-4-(1,1,3,3-四甲基丁基)苯氧基乙酸酯、2,4-雙(1,1-二甲基丙基)苯氧基乙酸酯、氯二苯基乙酸酯、異丁酸酯、單丁二酸酯、(E)-2-甲基-2-丁烯酸酯、鄰(甲氧羰基)苯甲酸酯、α-萘甲酸酯、硝酸酯、N,N,N',N'-四甲基磷二醯胺酸烷酯、N-苯基胺基甲酸烷酯、硼酸酯、二甲基膦基亞硫醯基、2,4-二硝基苯基亞磺酸烷酯、硫酸酯、甲烷磺酸酯(甲磺酸酯)、苯甲基磺酸酯及甲苯磺酸酯(Ts)。
為保護1,2-或1,3-二醇,保護基包括亞甲基縮醛、亞乙基縮醛、1-第三丁基亞乙基縮酮、1-苯基亞乙基縮酮、(4-甲氧基苯基)亞乙基縮醛、2,2,2-三氯亞乙基縮醛、縮丙酮化物、亞環戊基縮酮、亞環己基縮酮、亞環庚基縮酮、苯亞甲基縮醛、對甲氧基苯亞甲基縮醛、2,4-二甲氧基苯亞甲基縮酮、3,4-二甲氧基苯亞甲基縮醛、2-硝基苯亞甲基縮醛、甲氧基亞甲基縮醛、乙氧基亞甲基縮醛、原酸二甲氧基亞甲酯、原酸1-甲氧基亞乙酯、原酸1-乙氧基亞乙酯、原酸1,2-二甲氧基亞乙酯、原酸α-甲氧基苯亞甲酯、1-(N,N-二甲胺基)亞乙基衍生物、α-(N,N'-二甲基胺基)苯亞甲基衍生物、原酸2-噁亞環戊酯、二-第三丁基亞矽烷基(DTBS)、1,3-(1,1,3,3-四異丙基二矽氧烷亞基)衍生物(TIPDS)、四-第三丁氧基二矽氧烷基-1,3-二亞基衍生物(TBDS)、環狀碳酸酯、環狀酸酯、酸乙酯及酸苯酯。
保護基包括胺基甲酸甲酯、胺基甲酸乙酯、胺基甲酸9-茀基甲酯(Fmoc)、胺基甲酸9-(2-磺酸基)茀基甲酯、胺基甲酸9-(2,7-二溴)茀基
甲酯、胺基甲酸2,7-二-第三丁基-[9-(10,10-二側氧基-10,10,10,10-四氫噻噸基)]甲酯(DBD-Tmoc)、胺基甲酸4-甲氧基苯甲醯甲酯(Phenoc)、胺基甲酸2,2,2-三氯乙酯(Troc)、胺基甲酸2-三甲基矽烷基乙酯(Teoc)、胺基甲酸2-苯基乙酯(hZ)、胺基甲酸1-(1-金剛烷基)-1-甲基乙酯(Adpoc)、胺基甲酸1,1-二甲基-2-鹵基乙酯、胺基甲酸1,1-二甲基-2,2-二溴乙酯(DB-t-BOC)、胺基甲酸1,1-二甲基-2,2,2-三氯乙酯(TCBOC)、胺基甲酸1-甲基-1-(4-聯苯基)乙酯(Bpoc)、胺基甲酸1-(3,5-二-第三丁基苯基)-1-甲基乙酯(t-Bumeoc)、胺基甲酸2-(2'-及4'-吡啶基)乙酯(Pyoc)、胺基甲酸2-(N,N-二環己基甲醯胺基)乙酯、胺基甲酸第三丁酯(BOC)、胺基甲酸1-金剛烷酯(Adoc)、胺基甲酸乙烯酯(Voc)、胺基甲酸烯丙酯(Alloc)、胺基甲酸1-異丙基烯丙酯(Ipaoc)、胺基甲酸肉桂酯(Coc)、胺基甲酸4-硝基肉桂酯(Noc)、胺基甲酸8-喹啉酯、胺基甲酸N-羥基哌啶酯、胺基甲酸烷基二硫酯、胺基甲酸苯甲酯(Cbz)、胺基甲酸對甲氧基苯甲酯(Moz)、胺基甲酸對硝基苯甲酯、胺基甲酸對溴苯甲酯、胺基甲酸對氯苯甲酯、胺基甲酸2,4-二氯苯甲酯、胺基甲酸4-甲基亞磺醯基苯甲酯(Msz)、胺基甲酸9-蒽基甲酯、胺基甲酸二苯基甲酯、胺基甲酸2-甲基硫基乙酯、胺基甲酸2-甲基磺醯基乙酯、胺基甲酸2-(對甲苯磺醯基)乙酯、胺基甲酸[2-(1,3-二噻烷基)]甲酯(Dmoc)、胺基甲酸4-甲基硫基苯酯(Mtpc)、胺基甲酸2,4-二甲基硫基苯酯(Bmpc)、胺基甲酸2-磷鎓基乙酯(Peoc)、胺基甲酸2-三苯基磷鎓基異丙酯(Ppoc)、胺基甲酸1,1-二甲基-2-氰基乙酯、胺基甲酸間氯-對醯氧基苯甲酯、胺基甲酸對(二羥基氧硼基)苯甲酯、胺基甲酸5-苯并異噁唑基甲酯、胺基甲酸2-(三氟甲基)-6-色酮基甲酯(Tcroc)、胺基甲酸間硝基苯酯、胺基甲酸3,5-二甲氧基苯甲酯、胺基甲酸鄰硝基苯甲酯、胺基甲酸3,4-二甲氧基-6-硝基苯甲酯、胺基甲酸苯基(鄰硝基苯基)甲酯、啡噻嗪基-(10)-羰基衍生物、N'-對甲苯磺醯基胺基羰
基衍生物、N'-苯基胺基硫基羰基衍生物、胺基甲酸第三戊酯、硫胺基甲酸S-苯甲酯、胺基甲酸對氰基苯甲酯、胺基甲酸環丁酯、胺基甲酸環己酯、胺基甲酸環戊酯、胺基甲酸環丙基甲酯、胺基甲酸對癸氧基苯氧酯、胺基甲酸2,2-二甲氧基羰基乙烯酯、胺基甲酸鄰(N,N-二甲基甲醯胺基)苯甲酯、胺基甲酸1,1-二甲基-3-(N,N-二甲基甲醯胺基)丙酯、胺基甲酸1,1-二甲基丙炔酯、胺基甲酸二(2-吡啶基)甲酯、胺基甲酸2-呋喃基甲酯、胺基甲酸2-碘乙酯、胺基甲酸異冰片酯、胺基甲酸異丁酯、胺基甲酸異菸鹼酯、胺基甲酸對(對'-甲氧基苯基偶氮基)苯甲酯、胺基甲酸1-甲基環丁酯、胺基甲酸1-甲基環己酯、胺基甲酸1-甲基-1-環丙基甲酯、胺基甲酸1-甲基-1-(3,5-二甲氧基苯基)乙酯、胺基甲酸1-甲基-1-(對苯基偶氮基苯基)乙酯、胺基甲酸1-甲基-1-苯基乙酯、胺基甲酸1-甲基-1-(4-吡啶基)乙酯、胺基甲酸苯酯、胺基甲酸對(苯基偶氮基)苯甲酯、胺基甲酸2,4,6-三-第三丁基苯酯、胺基甲酸4-(三甲基銨)苯甲酯、胺基甲酸2,4,6-三甲基苯甲酯、甲醯胺、乙醯胺、氯乙醯胺、三氯乙醯胺、三氟乙醯胺、苯基乙醯胺、3-苯基丙醯胺、吡啶甲醯胺、3-吡啶基甲醯胺、N-苯甲醯基苯基丙胺醯基衍生物、苯甲醯胺、對苯基苯甲醯胺、鄰硝基苯基乙醯胺、鄰硝基苯氧基乙醯胺、乙醯乙醯胺、(N'-二硫基苯甲氧基羰基胺基)乙醯胺、3-(對羥基苯基)丙醯胺、3-(鄰硝基苯基)丙醯胺、2-甲基-2-(鄰硝基苯氧基)丙醯胺、2-甲基-2-(鄰苯基偶氮基苯氧基)丙醯胺、4-氯丁醯胺、3-甲基-3-硝基丁醯胺、鄰硝基肉桂醯胺、N-乙醯基甲硫胺酸衍生物、鄰硝基苯甲醯胺、鄰(苯甲醯氧基甲基)苯甲醯胺、4,5-二苯基-3-噁唑啉-2-酮、N-鄰苯二甲醯亞胺、N-二硫雜丁二醯亞胺(Dts)、N-2,3-二苯基順丁烯二醯亞胺、N-2,5-二甲基吡咯、N-1,1,4,4-四甲基二矽烷基氮雜環戊烷加合物(STABASE)、5-取代之1,3-二甲基-1,3,5-三氮雜環己-2-酮、5-取代之1,3-二苯甲基-1,3,5-三氮雜環己-2-酮、1-取代之3,5-二硝
基-4-吡啶酮、N-甲胺、N-烯丙胺、N-[2-(三甲基矽烷基)乙氧基]甲基胺(SEM)、N-3-乙氧基丙胺、N-(1-異丙基-4-硝基-2-側氧基-3-吡咯啉-3-基)胺、四級銨鹽、N-苯甲胺、N-二(4-甲氧基苯基)甲胺、N-5-二苯并環庚胺、N-三苯基甲胺(Tr)、N-[(4-甲氧基苯基)二苯基甲基]胺(MMTr)、N-9-苯基茀基胺(PhF)、N-2,7-二氯-9-茀基亞甲胺、N-二茂鐵基甲基胺基(Fcm)、N-2-吡啶甲基胺基N'-氧化物、N-1,1-二甲基硫基亞甲胺、N-苯亞甲胺、N-對甲氧基苯亞甲胺、N-二苯基亞甲胺、N-[(2-吡啶基)均三甲苯基]亞甲胺、N-(N',N'-二甲基胺基亞甲基)胺、N,N'-異亞丙基二胺、N-對硝基苯亞甲基胺、N-亞水楊胺、N-5-氯亞水楊胺、N-(5-氯-2-羥基苯基)苯基亞甲胺、N-亞環己胺、N-(5,5-二甲基-3-側氧基-1-環己烯基)胺、N-硼烷衍生物、N-二苯基硼酸衍生物、N-[苯基(五羰基鉻-或鎢)羰基]胺、N-銅螯合物、N-鋅螯合物、N-硝胺、N-亞硝胺、胺N-氧化物、二苯基膦醯胺(Dpp)、二甲基硫基膦醯胺(Mpt)、二苯基硫基膦醯胺(Ppt)、二烷基磷醯胺酸、二苯甲基磷醯胺酸、二苯基磷醯胺酸、苯次磺醯胺、鄰硝基苯次磺醯胺(Nps)、2,4-二硝基苯次磺醯胺、五氯苯次磺醯胺、2-硝基-4-甲氧基苯次磺醯胺、三苯基甲基次磺醯胺、3-硝基吡啶次磺醯胺(Npys)、對甲苯磺醯胺(Ts)、苯磺醯胺、2,3,6,-三甲基-4-甲氧基苯磺醯胺(Mtr)、2,4,6-三甲氧基苯磺醯胺(Mtb)、2,6-二甲基-4-甲氧基苯磺醯胺(Pme)、2,3,5,6-四甲基-4-甲氧基苯磺醯胺(Mte)、4-甲氧基苯磺醯胺(Mbs)、2,4,6-三甲基苯磺醯胺(Mts)、2,6-二甲氧基-4-甲基苯磺醯胺(iMds)、2,2,5,7,8-五甲基烷-6-磺醯胺(Pmc)、甲烷磺醯胺(Ms)、β-三甲基矽烷基乙烷磺醯胺(SES)、9-蒽磺醯胺、4-(4',8'-二甲氧基萘基甲基)苯磺醯胺(DNMBS)、苯甲基磺醯胺、三氟甲基磺醯胺及苯甲醯甲基磺醯胺。例示性保護基詳述於本文中,然而,應瞭解本發明並不意欲限於此等保護基;相反地,多種其他等效保護基可使用以上標準容易地鑑別且
可用於本發明之方法中。另外,多種保護基已為此項技術中所熟知且包括詳細描述於Protecting Groups in Organic Synthesis,T.W.Greene及P.G.M.Wuts,第3版,John Wiley及Sons,1999中之保護基,該文獻之全部內容以引用的方式併入本文中。
如本文所述,本發明之化合物可含有「視情況經取代」之部分。一般而言,術語「經取代」無論前面是否有術語「視情況」均意謂指定部分之一或多個氫經適合取代基替換。除非另外指示,否則「視情況經取代」之基團可在該基團之各可取代位置具有取代基,且當任何給定結構中之一個以上位置可經一個以上選自規定基團之取代基取代時,各位置之取代基可相同或不同。由本發明預想之取代基之組合較佳為使得形成穩定或化學上可行之化合物的彼等取代基。如本文所用之術語「穩定」係指化合物在經受允許其產生、偵測及在某些實施例中其回收、純化及用於本文所揭示之一或多個目的之條件時不發生實質上改變。
除非另外指示,否則「視情況經取代」之基團之可取代碳原子上的適合單價取代基獨立地為鹵素、C1-4烷基或C1-4鹵烷基。
當用作化學鍵時,「」應理解為描繪在碳中心具有非限定立體化學之單個碳-碳鍵。因此,連接於具有「」鍵之碳原子的取代基係指取代基自紙平面出來之實施例、取代基進入紙平面後之實施例及其組合(亦即,立體化學混合物)。
如本文及申請專利範圍中所用,除非上下文以另外的方式明確
指示,否則單數形式「一」及「該」包括複數個提及物。因此,例如,提及「化合物」包括複數種此類化合物。
如本文所使用之片語「非經腸投藥」意謂除經腸及局部投藥之外的投藥模式,通常為注射,且包括(但不限於)靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表
皮下、關節內、囊下、蛛膜下、脊柱內及胸骨內注射及輸注。
如本文所用之術語「治療有效量」意謂當作為治療方案之一部分投與時引發所要生物反應之物質(例如治療劑、組合物及/或調配物)的量。在一些實施例中,物質之治療有效量為當投與罹患或易患疾病、病症及/或病狀之個體時足以治療疾病、病症及/或病狀之量。如由一般技術者所瞭解,物質之有效量可視諸如所要生物學終點、欲傳遞之物質、標靶細胞或組織等的因素而變化。舉例而言,調配物中化合物治療疾病、病症及/或病狀之有效量為緩解、改善、減輕、抑制、預防疾病、病症及/或病狀、延遲其發作、降低其嚴重性及/或降低其一或多種症狀或特徵之發生的量。在一些實施例中,治療有效量以單次劑量投與;在一些實施例中,需要多次單位劑量以傳遞治療有效量。
如本文所用之術語「治療」係指用於部分或完全緩解、改善、減輕、抑制、預防疾病、病症及/或病狀、延遲其發作、降低其嚴重性及/或降低其一或多種症狀或特徵之發生的任何方法。可向未呈現疾病、病症及/或病狀之病徵的個體施與治療。在一些實施例中,可向僅呈現疾病、病症及/或病狀之早期病徵的個體施與治療以降低產生與該疾病、病症及/或病狀有關之病變的風險。
如本文所用之表述「單位劑量」係指適合於待治療個體之調配物的物理離散單位。然而,應瞭解,本發明調配物之總日用量由主治醫師在合理醫學判斷之範疇內決定。對於任何特定個體或生物體之特定有效劑量可取決於多種因素,包括所治療之病症及病症之嚴重性;所用特定活性化合物之活性;所用特定組合物;個體之年齡、體重、一般健康狀況、性別及飲食;投藥時間及所用特定活性化合物之排泄速率;治療持續時間;與所用特定化合物組合或同時使用之藥物及/或其他療法,及醫療技術中熟知之類似因素。特定單位劑量可含有或
可不含治療有效量之治療劑。
「罹患」疾病、病症及/或病狀之個體已診斷患有該疾病、病症及/或病狀及/或呈現其一或多種症狀。
「易患」疾病、病症及/或病狀之個體尚未診斷患有該疾病、病症及/或病狀。在一些實施例中,易患疾病、病症及/或病狀之個體可呈現該疾病、病症及/或病狀之症狀。在一些實施例中,易患疾病、病症及/或病狀之個體可不呈現該疾病、病症及/或病狀之症狀。在一些實施例中,易患疾病、病症及/或病狀之個體將產生該疾病、病症及/或病狀。在一些實施例中,易患疾病、病症及/或病狀之個體將不產生該疾病、病症及/或病狀。
圖1. A:Hsp70調控數種抗細胞凋亡蛋白質複合物;作用由化合物32處理恢復。用Hsp70抑制劑化合物32或Hsp90抑制劑PU-H71處理MDA-MB-468三陰性乳癌細胞且藉由西方墨點法分析蛋白質。B:化合物32在誘導出對PU-H71之耐受性的彌漫性大B細胞淋巴瘤(DLBCL)細胞中保留活性。C:PU-H71及化合物32敏感性DLBCL之譜圖不重疊。
本發明涵蓋如下認識:設計Hsp70之有力且有效調節子為具有挑戰性之嘗試,其係鑒於缺乏已知結合Hsp70之天然產物及候選調節子所面臨之一般競爭性及結合袋困難,尤其在可逆Hsp70調節子之情形下。
本發明尤其提供用於調節Hsp70之新穎化合物。在一些實施例中,本發明提供Hsp70之意外有效可逆抑制劑。基於嘧啶之特定不可逆衍生物已預先展示選擇性結合癌細胞中所存在之Hsp70,在不反饋誘導Hsp70下誘導Hsp90/Hsp70複合致癌受質蛋白降解及誘導細胞凋亡(參見例如WO 2011/022440)。然而,在本發明之前,基於嘧啶之化合物尚未展現出在低於約1.0μM之濃度下在特定Hsp70模型系統中展示活性。本發明意外地提供在低於約1.0μM之濃度下在此類模型系統中展示活性的化合物。在一些實施例中,所提供之化合物在低於約0.5μM之濃度下在此類模型系統中展示活性。在一些實施例中,所提供化合物在低於約0.4μM之濃度下在此類模型系統中展示活性。在一些實施例中,所提供之化合物在低於約0.2μM之濃度下在此類模型系統
中展示活性。在一些實施例中,所提供之化合物在低於約0.1μM之濃度下在此類模型系統中展示活性。在一些實施例中,所提供之化合物在低於約0.01μM之濃度下在此類模型系統中展示活性。在一些實施例中,所提供化合物展示此等活性之模型系統為卡斯蛋白酶裂解分析。
在一些實施例中,所提供之本發明化合物選擇性抑制腫瘤細胞中之Hsp70。在一些實施例中,所提供化合物選擇性抑制腫瘤特異性Hsp70及/或Hsp70複合物。測試腫瘤特異性Hsp70及/或Hsp70複合物之選擇性抑制的分析為此項技術中廣泛已知,包括(但不限於)WO 2011/022440中所述之分析。
在某些實施例中,本發明提供式I化合物:
或其醫藥學上可接受之鹽,其中:X為-N=或-CH=;X1為-N=或-C(R5)=;
R1為或
R1a為或C1-6脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基;各R1b獨立地為氫、C1-4烷基,或兩個R1b基團視情況一起形成側氧基;R1c及R1d各獨立地為氫或C1-4烷基;
R2為-O-CH2-環A、-NH-CH2-環A或-O-CH2CH2-環A;
環A為未經取代之苯基、未經取代之呋喃某、 或視情況經RA5取代之吡啶基;
RA1各獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基;各R獨立地為氫或視情況經一或多個鹵素取代之C1-4烷基;RA2為-Cl、-Br、-I、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基;n為1至4;RA3為-H或-F;RA4為-F或-OR;RA5為-OR或-N(R)2;R3為-C(O)N(R3a)2、-OR3b、-C(O)H、-C(O)OR或-N(R3c)2;各R3a獨立地為氫或視情況經一或多個獨立地選自鹵素或1-吡咯啶基之基團取代之C1烷基;R3b為氫或視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基;各R3c獨立地為氫或視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基;R4為R、鹵素或-N(R)2;且
R5為氫、甲基或-N(R)2。
在某些實施例中,所提供之式I化合物在低於約1.0μM下在卡斯蛋白酶裂解分析(例如以達成最大卡斯蛋白酶裂解之50%所要的化合物濃度形式量測)中具有活性。在某些實施例中,所提供之式I化合物在低於約0.5μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式I化合物在低於約0.4μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式I化合物在低於約0.2μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式I化合物在低於約0.1μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式I化合物在低於約0.01μM下在卡斯蛋白酶裂解分析中具有活性。
在某些實施例中,本發明提供式II化合物:
或其醫藥學上可接受之鹽,其中:Y為-S-、-O-或-CR2-;
R1為
R1a為或C1-6脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基;各R1b獨立地為氫、C1-4烷基,或兩個R1b基團視情況一起形成側氧基;R1c及R1d各獨立地為氫或C1-4烷基;
R2為-O-CH2-環A、-NH-CH2-環A或-O-CH2CH2-環A;
環A為未經取代之苯基、未經取代之呋喃基、 或視情況經RA5取代之吡啶基;
RA1各獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基;各R獨立地為氫或視情況經一或多個鹵素取代之C1-4烷基;RA2為-Cl、-Br、-I、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基;n為1至4;RA3為-H或-F;RA4為-F或-OR;RA5為-OR或-N(R)2;且
環B為 、視情況經-C(O)R取代之噻吩基或視情況經-
C(O)R取代之呋喃基。
在某些實施例中,所提供之式II化合物在低於約1.0μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式II化合物在低於約0.5μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例
中,所提供之式II化合物在低於約0.4μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式II化合物在低於約0.2μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式II化合物在低於約0.1μM下在卡斯蛋白酶裂解分析中具有活性。在某些實施例中,所提供之式II化合物在低於約0.01μM下在卡斯蛋白酶裂解分析中具有活性。
在一些實施例中,X為-N=。在一些實施例中,X為-CH=。
在一些實施例中,X1為-N=。在一些實施例中,X為-C(R5)=。在一些實施例中,X為-C(R5)=,其中R5為氫。在一些實施例中,X為-C(R5)=,其中R5為甲基。在一些實施例中,X為-C(R5)=,其中R5為-N(R)2。在一些實施例中,X為-C(R5)=,其中R5為-NH2。
在一些實施例中,R1為或
。在一些實施例中,R1為或
。在一些實施例中,R1為。在一些實施例中,R1為
。在一些實施例中,R1為。在一些實施例中,
R1為。在一些實施例中,R1為。在一些實施例中,R1為
。在一些實施例中,R1為
在一些實施例中,R1為。在一些實施例中,各R1b為
氫。在一些實施例中,R1為。在一些實施例中,R1為
,其中各R1b獨立地為C1-4烷基。在一些實施例中,兩個R1b
一起形成側氧基。在一些實施例中,R1為。在一些實施例
中,R1為
在一些實施例中,R1a為。
在一些實施例中,R1a為C1-6脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。在一些實施例中,R1a為C1-6直鏈脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。在一些實施例中,R1a為C1-6直鏈脂族基,其視情況經一個獨立地選自以下之基團取代:-OH、環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。
在一些實施例中,R1a為C1-6脂族基。在一些實施例中,R1a為直鏈C1-6脂族基。在一些實施例中,R1a為直鏈C1-6烷基。在一些實施例中,R1a為甲基。在一些實施例中,R1a為直鏈烯基。在一些實施例中,R1a為-CH2CH=CH2。在一些實施例中,R1a為直鏈C1-6炔基。在一
些實施例中,R1a為-(CH2)nC≡CH,其中n為1-4。在一些實施例中,R1a為-CH2C≡CH。在一些實施例中,R1a為-(CH2)3C≡CH。在一些實施例中,R1a為-(CH2)4C≡CH。在一些實施例中,R1a為-CH2C≡CCH2OH。
在一些實施例中,R1a為分支鏈C1-6脂族基。在一些實施例中,R1a為分支鏈炔基。在一些實施例中,R1a為具有末端-C≡CH基團之分支鏈炔基。在一些實施例中,R1a為-CH(CH3)C≡CH。在一些實施例中,R1a為異丙基。
在一些實施例中,R1a為C1-6直鏈脂族基,其經一個獨立地選自以下之基團取代:-OH、環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。在一些實施例中,R1a為經環丙基或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基取代之甲基。在一些實施例中,R1a為經環丙基取代之甲基。在一些實施例中,R1a為經具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基取代之甲基。在一些
實施例中,R1a為經取代之甲基。在一些實施例中,R1a為經
取代之甲基。在一些實施例中,R1a為經取代之甲基。在一些實
施例中,R1a為2-羥基乙基。
在一些實施例中,R1a為C1-6環脂族基。在一些實施例中,R1a為環丙基。
在一些實施例中,R1a係選自甲基、2-羥基乙基、-CH2C≡CH、-(CH2)3C≡CH、-(CH2)4C≡CH、-CH(CH3)C≡CH、異丙基、-
CH2CH=CH2、、環丙基、或
。在一些實施例中,R1a係選自甲基、2-羥基乙基、-CH2C≡CH、-
(CH2)3C≡CH、-(CH2)4C≡CH、-CH(CH3)C≡CH、異丙基、-
CH2CH=CH2、、環丙基、或。在一些實
施例中,R1a係選自甲基、2-羥基乙基、-CH2C≡CH、-(CH2)3C≡CH、-
(CH2)4C≡CH、-CH(CH3)C≡CH、-CH2CH=CH2、、環丙基、
或。在一些實施例中,R1a係選自甲基、2-羥
基乙基、-CH2C≡CH、-(CH2)3C≡CH、-(CH2)4C≡CH、-
CH(CH3)C≡CH、-CH2CH=CH2、、環丙基、或
在一些實施例中,R1a不在與哌嗪氮連接點相鄰處置放四級碳。
在一些實施例中,各R1b獨立地為氫,或兩個R1b基團視情況一起形成側氧基。在一些實施例中,各R1b為氫。
在一些實施例中,R1b為C1-4烷基。在一些實施例中,各R1b為C1-4烷基。在一些實施例中,各R1b為甲基。在一些實施例中,R1為
。在一些實施例中,R1為
在一些實施例中,兩個R1b基團視情況一起形成側氧基。
在一些實施例中,R1為
在一些實施例中,R1為
在一些實施例中,各R1c獨立地為氫或C1-4烷基。在一些實施例中,R1c為氫。在一些實施例中,R1c為C1-4烷基。在一些實施例中,R1c為甲基。在一些實施例中,各R1c為氫。在一些實施例中,一個R1c為氫,且另一個R1c為C1-4烷基。在一些實施例中,各R1c獨立地為C1-4烷基。在一些實施例中,各R1c為甲基。在一些實施例中,R1為
。在一些實施例中,R1為
在一些實施例中,R1為
在一些實施例中,R1d為氫或C1-4烷基。在一些實施例中,R1d為氫。在一些實施例中,R1d為C1-4烷基。在一些實施例中,R1d為甲基。在一些實施例中,各R1c獨立地為氫或C1-4烷基,且各R1d獨立地為C1-4烷基。
在一些實施例中,R1為。在一些實施例中,R1為
。在一些實施例中,R1為,其中R1c及R1d各獨立地為
氫或C1-4烷基。
在一些實施例中,R1c及R1d各為氫。在一些實施例中,R1為
。在一些實施例中,R1為。在一些實施例中,R1為
實施例中,R1為,其中R1c為氫或C1-4烷基,且R1d為C1-4烷
在一些實施例中,R1c為氫或C1-4烷基,且R1d為C1-4烷基。在一些
基。在一些實施例中,R1為,其中R1c為氫或C1-4烷基,且R1d
為C1-4烷基。在一些實施例中,R1為,其中R1c為氫或C1-4烷
基,且R1d為C1-4烷基。
在一些實施例中,R1c為氫,且R1d為C1-4烷基。在一些實施例
中,R1為,其中R1c為氫,且R1d為C1-4烷基。在一些實施例
中,R1為,其中R1c為氫,且R1d為C1-4烷基。在一些實施例
中,R1為,其中R1c為氫,且R1d為C1-4烷基。在一些實施例
中,R1c為氫,且R1d為甲基。在一些實施例中,R1為。在一些實
施例中,R1為。在一些實施例中,R1為
中,R1為,其中R1c及R1d各獨立地為C1-4烷基。在一些實施例
在一些實施例中,R1c及R1d各獨立地為C1-4烷基。在一些實施例
中,R1為,其中R1c及R1d各獨立地為C1-4烷基。在一些實施例
中,R1為,其中R1c及R1d各獨立地為C1-4烷基。在一些實施例
中,R1c及R1d為甲基。在一些實施例中,R1為。在一些實施例
中,R1為。在一些實施例中,R1為
例示性R1基團如下所示:
在一些實施例中,R1選自下表1中之基團。
在一些實施例中,R2為-O-CH2-環A、-NH-CH2-環A或-O-CH2CH2-環A。在一些實施例中,R2為-O-CH2-環A。在一些實施例中,R2為-NH-CH2-環A。在一些實施例中,R2為-O-CH2CH2-環A。
在一些實施例中,環A為未經取代之苯基。在一些實施例中,環
A為未經取代之呋喃基。在一些實施例中,環A為。在一些
實施例中,環A為。在一些實施例中,環A為。在
一些實施例中,環A為視情況經RA5取代之吡啶基。
在一些實施例中,環A為苯基。在一些實施例中,環A為-C6D5。
在一些實施例中,R2為。在一些實施例中,R2為
。在一些實施例中,R2為
在一些實施例中,環A為呋喃基。在一些實施例中,環A為1-呋喃基。在一些實施例中,環A為2-呋喃基。在一些實施例中,R2為
。在一些實施例中,R2為
在一些實施例中,環A為
在一些實施例中,RA1各獨立地為鹵素、-CN、-C(O)N(R)2、-
N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA1各獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA1各獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3或視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA1各獨立地為鹵素、-N(R)2、-OR或視情況經一或多個鹵素取代之C1-4烷基。
在某些實施例中,一個RA1為-F,且另一個RA1獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。在某些實施例中,一個RA1為-F,且另一個RA1獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。
在某些實施例中,一個RA1為-F,且另一個RA1獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3或視情況經一或多個鹵素取代之C1-4烷基。在某些實施例中,一個RA1為-F,且另一個RA1獨立地為鹵素、-N(R)2、-OR或視情況經一或多個鹵素取代之C1-4烷基。在一
些實施例中,環A為。在一些實施例中,環A為
在某些實施例中,一個RA1為RA2,且另一個RA1獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。在某些實施例中,一個RA1
為RA2,且另一個RA1為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的5或6員雜環基或雜芳基、或視情況獨立地經一或多個鹵素取代之C1-4烷基。
在某些實施例中,一個RA1為RA2,且另一個RA1獨立地為鹵素、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3或視情況經一或多個鹵素取代之C1-4烷基。在某些實施例中,一個RA1為RA2,且另一個RA1獨立地為鹵素、-N(R)2、-OR或視情況經一或多個鹵素取代之C1-4烷基。在一
些實施例中,環A為。在一些實施例中,環A為
在一些實施例中,環A為
在一些實施例中,RA1為視情況經一或多個鹵素取代之C1-4烷
基。在一些實施例中,環A為,其中RA1為視情況經一或多
個鹵素取代之C1-4烷基。在一些實施例中,環A為,其中RA1
為視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,環A為
,其中RA1為視情況經一或多個鹵素取代之C1-4烷基。在一些
實施例中,RA1為C1-4烷基。在一些實施例中,RA1為經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA1為經一或多個-F取代之C1-4烷基。在一些實施例中,RA1為-CF3。在一些實施例中,環A為
。在一些實施例中,R2為
在一些實施例中,RA1為鹵素。在一些實施例中,環A為
,其中RA1為鹵素。在一些實施例中,環A為,其中
RA1為鹵素。在一些實施例中,環A為,其中RA1為鹵素。在
一些實施例中,環A為,其中RA1為鹵素。在一些實施例中,
環A為,其中RA1為鹵素。在一些實施例中,RA1為-F。在一
些實施例中,RA1為-Cl。在一些實施例中,RA1為-Br。在一些實施例中,RA1為-I。在一些實施例中,一個RA1為-F,且其他RA1基團各獨立
地選自-F、-Cl、-Br或-I。在一些實施例中,環A為。在一些
實施例中,R2為。在一些實施例中,環A為。在
一些實施例中,R2為。在一些實施例中,環A為
。在一些實施例中,R2為。在一些實施例中,環
A為。在一些實施例中,R2為。在一些實施例中,環
A為。在一些實施例中,R2為
在一些實施例中,RA1為-CN。在一些實施例中,RA1為-C(O)N(R)2。
在一些實施例中,RA1為-N(R)2。在一些實施例中,RA1為-N(R)2,其中各R獨立地為視情況經一或多個鹵素取代之C1-4烷基。在
一些實施例中,RA1為-N(R)2,其中各R獨立地為C1-4烷基。在一些實
施例中,環A為。在一些實施例中,環A為,其
中各R獨立地為視情況經一或多個鹵素取代之C1-4烷基。在一些實施
例中,環A為,其中各R獨立地為C1-4烷基。在一些實施例
中,環A為。在一些實施例中,環A為,其中
RA1為-N(R)2。在一些實施例中,環A為,其中RA1為-N(R)2。
在一些實施例中,環A為,其中RA1為-N(R)2。在一些實施例
中,RA1為-NH2。在一些實施例中,環A為。在一些實施例
中,R2為。在一些實施例中,RA1為-N(CH3)2。在一些實
施例中,環A為。在一些實施例中,R2為
在一些實施例中,RA1為-OR。在一些實施例中,環A為
。在一些實施例中,環A為,其中RA1為-OR。在
一些實施例中,環A為,其中RA1為-OR。在一些實施例中,
環A為,其中RA1為-OR。在一些實施例中,環A為
其中RA1為-OR。在一些實施例中,環A為,其中RA1為-OR。
在一些實施例中,環A為,其中RA1為-OR。在一些實施例
中,RA1為-OH。在一些實施例中,環A為。在一些實施例
中,R2為。在一些實施例中,RA1為-OR,其中R為視情況
經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA1為-OR,其中R為C1-4烷基。在一些實施例中,RA1為-OR,其中R為甲基。在一些實
施例中,RA1為-OMe。在一些實施例中,環A為。在一些實
施例中,環A為。在一些實施例中,R2為。在一
些實施例中,環A為。在一些實施例中,R2為
在一些實施例中,環A為。在一些實施例中,R2為
在一些實施例中,環A為。在一些實施例中,R2為
在一些實施例中,n為1-4。在一些實施例中,n為1-2。在一些實施例中,n為1-3。在一些實施例中,n為2-3。在一些實施例中,n為2-4。在一些實施例中,n為1。在一些實施例中,n為2。在一些實施例中,n為3。在一些實施例中,n為4。
在一些實施例中,環A為,其中RA2為-F、-Cl、-Br、-
I、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,環
A為,其中RA2為-Cl、-Br、-I、-CN、-C(O)N(R)2、-N(R)2、-
OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。
在一些實施例中,RA2為-Cl、-I、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA2為-I、-CN、-C(O)N(R)2、-N(R)2、-OR、-C(O)R、-N3、具有一或兩個獨立地選自氮、氧或硫之雜原子的5或6員雜環基或雜芳基、或視情況經一或多個鹵素取代之C1-4烷基。
在一些實施例中,RA2為-Cl。在一些實施例中,環A為
在一些實施例中,R2為。在一些實施例中,RA2為-I。在一
些實施例中,環A為。在一些實施例中,R2為。在一
些實施例中,RA2為-F。在一些實施例中,R2為。在一些實
施例中,RA2為-Br。在一些實施例中,R2為
在一些實施例中,RA2為-CN。在一些實施例中,環A為
在一些實施例中,R2為
在一些實施例中,RA2為-N(R)2。在一些實施例中,RA2為-
N(R)2,其中各R為氫。在一些實施例中,環A為。在一些實施
例中,R2為。在一些實施例中,RA2為-N(R)2,其中各R獨立
地為C1-4烷基。在一些實施例中,環A為。在一些實施例中,R2
為。在一些實施例中,RA2為-N(R)2,其中一個R為氫,且另
一個R為C1-4烷基。在一些實施例中,RA2為-N(R)2,其中一個R為氫,
且另一個R為C1-4環烷基。在一些實施例中,環A為。在一些實
施例中,R2為
在一些實施例中,RA2為-C(O)N(R)2。在一些實施例中,RA2為-
C(O)N(R)2,其中各R為氫。在一些實施例中,環A為。在一些
實施例中,R2為
在一些實施例中,RA2為-OR。在一些實施例中,RA2為-OR,其
中各R為氫。在一些實施例中,環A為。在一些實施例中,R2為
。在一些實施例中,RA2為-OR,其中R為視情況經一或多個
鹵素取代之C1-4烷基。在一些實施例中,RA2為-OR,其中R為C1-4烷
基。在一些實施例中,環A為。在一些實施例中,R2為
。在一些實施例中,RA2為-OR,其中R為經一或多個鹵素
取代之C1-4烷基。在一些實施例中,RA2為-OR,其中R為經一或多個-F取代之C1-4烷基。在一些實施例中,R為-CF3。在一些實施例中,環
A為。在一些實施例中,R2為。在一些實施例中,R
為-CHF2。在一些實施例中,環A為。在一些實施例中,R2為
在一些實施例中,RA2為-C(O)R。在一些實施例中,RA2為-C(O)R,其中各R為C1-4烷基。在一些實施例中,R為甲基。在一些實
施例中,環A為。在一些實施例中,R2為
在一些實施例中,RA2為-N3。在一些實施例中,環A為
在一些實施例中,R2為
在一些實施例中,RA2為視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA2為C1-4烷基。在一些實施例中,RA2為經一或多個鹵素取代之C1-4烷基。在一些實施例中,RA2為經一或多個-F取代之C1-4烷基。在一些實施例中,RA2為-CF3。在一些實施例中,環A
為。在一些實施例中,R2為
在一些實施例中,RA2為苯甲基位置無分支鏈之C1-4烷基。
在一些實施例中,RA2為具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5或6員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個獨立地選自氮、氧或硫之雜原子的5或6員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個氮原子的視情況經取代之5或6員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個氮原子的5或6員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個獨立地選自氮、氧或硫之雜原子的視情況經取代之5員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個獨立地選自氮、氧或硫之雜原子的5員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個氮原子的視情況經取代之5員雜環基或雜芳基。在一些實施例中,RA2為具有一或兩個氮原子的5員雜環基或雜芳基。在一些實施例
中,RA2為具有一或兩個氮原子的視情況經取代之5員雜環基。在一些實施例中,RA2為具有一或兩個氮原子的5員雜環基。在一些實施例中,RA2為具有一個氮原子的視情況經取代之5員雜環基。在一些實施例中,RA2為具有一個氮原子之5員雜環基。在一些實施例中,RA2為具有兩個氮原子的視情況經取代之5員雜環基。在一些實施例中,RA2為具有兩個氮原子之5員雜環基。在一些實施例中,RA2為具有一或兩個氮原子的視情況經取代之5員雜芳基。在一些實施例中,RA2為具有一或兩個氮原子之5員雜芳基。在一些實施例中,RA2為具有一個氮原子的視情況經取代之5員雜芳基。在一些實施例中,RA2為具有一個氮原子之5員雜芳基。在一些實施例中,RA2為具有兩個氮原子的視情況經取代之5員雜芳基。在一些實施例中,RA2為具有兩個氮原子之5員
雜芳基。在一些實施例中,RA2為。在一些實施例中,環A為
。在一些實施例中,R2為。在一些實施例中,RA2為
。在一些實施例中,環A為。在一些實施例中,R2為
在一些實施例中,RA2為-I、-CN、-NH2、-N(CH3)2、-NH(環丙基)、-C(O)NH2、-OH、-OMe、-OCF3、-OCHF2、-C(O)Me、-N3、-CF3、
在一些實施例中,環A為
一些實施例中,環A為。在一些實施例中,RA3為-F。在一些
在一些實施例中,RA3為-H或-F。在一些實施例中,RA3為-H。在
實施例中,環A為
在一些實施例中,RA4為-F或-OR。在一些實施例中,RA4為-F。
在一些實施例中,環A為。在一些實施例中,環A為
。在一些實施例中,R2為。在一些實施例中,環
A為。在一些實施例中,R2為。在一些實施例中,
RA4為-OR。在一些實施例中,環A為。在一些實施例中,
RA4為-OR,其中R為C1-4烷基。在一些實施例中,RA4為-OMe。在一
些實施例中,環A為。在一些實施例中,R2為
在一些實施例中,環A為視情況經RA5取代之吡啶基。在一些實施例中,環A為吡啶基。在一些實施例中,環A為經RA5取代之吡啶基。
在一些實施例中,RA5為-OR或-N(R)2。在一些實施例中,RA5為-OR。在一些實施例中,環A為經RA5取代之吡啶基,其中RA5為-OR。在一些實施例中,RA5為-OR,其中R為C1-4烷基。在一些實施例中,環A為經RA5取代之吡啶基,其中RA5為-OR,其中R為C1-4烷基。在一
些實施例中,RA5為-OMe。在一些實施例中,環A為經-OMe取代之吡
啶基。在一些實施例中,環A為。在一些實施例中,R2為
。在一些實施例中,環A為。在一些實施例中,R2為
。在一些實施例中,環A為。在一些實施例中,R2為
。在一些實施例中,環A為。在一些實施例中,R2為
。在一些實施例中,RA5為-N(R)2。在一些實施例中,環A
為經RA5取代之吡啶基,其中RA5為-N(R)2。在一些實施例中,RA5為-N(R)2,其中各R為氫。在一些實施例中,環A為經RA5取代之吡啶
基,其中RA5為-NH2。在一些實施例中,環A為。在一些實施例
中,R2為
例示性環A基團描述於下表2中。
在一些實施例中,R2為-NH-CH2-環A。在一些實施例中,R2為
。在一些實施例中,R2為
在一些實施例中,R2為-O-CH2CH2-環A。
例示性R2基團描述於下表3中。
在一些實施例中,R3為-C(O)N(R3a)2、-OR3b、-C(O)H、-C(O)OR或-N(R3c)2。在一些實施例中,R3為-C(O)N(R3a)2。在一些實施例中,R3為-OR3b。在一些實施例中,R3為-C(O)H。在一些實施例中,R3為-
C(O)OR。在一些實施例中,R3為-N(R3c)2。
在一些實施例中,各R3a獨立地為氫或視情況經一或多個獨立地選自鹵素或1-吡咯啶基之基團取代之C1烷基。
在一些實施例中,R3a為氫。在一些實施例中,各R3a為氫。在一些實施例中,R3為-C(O)NH2。
在一些實施例中,R3a為視情況經一或多個獨立地選自鹵素或1-吡咯啶基之基團取代之C1烷基。在一些實施例中,R3a為視情況經1-吡咯啶基取代之C1烷基。在一些實施例中,R3a為甲基。在一些實施
例中,R3a為
在一些實施例中,一個R3a為氫,且另一個R3a為視情況經一或多個獨立地選自鹵素或1-吡咯啶基之基團取代之C1烷基。在一些實施例中,一個R3a為氫,且另一個R3a為視情況經1-吡咯啶基取代之C1烷基。在一些實施例中,一個R3a為氫,且另一個R3a為甲基。在一些實施例中,R3為-CONH(CH3)。在一些實施例中,一個R3a為氫,且另一
個R3a為。在一些實施例中,R3為
在一些實施例中,R3b為氫或視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。在一些實施例中,R3b為氫或C1-4烷基。
在一些實施例中,R3b為氫。在一些實施例中,R3為-OH。
在一些實施例中,R3b為視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。在一些實施例中,R3b為C1-4烷基。在一些實施例中,R3b為甲基。在一些實施例中,R3為-OMe。在一些實施例中,R3b為-CH(CH3)C(O)NH2。在一些實施例中,R3為-OCH(CH3)C(O)NH2。
在一些實施例中,R3為-C(O)H。
在一些實施例中,R3為-C(O)OR,其中R為C1-4烷基。在一些實施例中,R為甲基。在一些實施例中,R3為-C(O)OMe。
在一些實施例中,各R3c獨立地為氫或視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。
在一些實施例中,R3c為氫。在一些實施例中,各R3c為氫。在一些實施例中,R3為NH2。
在一些實施例中,R3c為視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。在一些實施例中,一個R3c為氫,且另一個R3c為視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。在一些實施例中,一個R3c為氫,且另一個R3c為視情況經一或多個獨立地選自側氧基或-N(R)2之基團取代之C1-4烷基。在一些實施例中,R3為-NHC(O)CH2NH2。
在一些實施例中,R4為R或鹵素。在一些實施例中,R4為R。在一些實施例中,R4為氫。在一些實施例中,R4為視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,R4為C1-4烷基。在一些實施例中,R4為甲基。在一些實施例中,R4為經一或多個鹵素取代之C1-4烷基。在一些實施例中,R4為-CF3。
在一些實施例中,R4為鹵素。在一些實施例中,R4為-F。在一些實施例中,R4為-Cl。在一些實施例中,R4為-Br。在一些實施例中,R4為-I。
在一些實施例中,R4為-N(R)2。在一些實施例中,R4為-N(R)2,其中各R為氫。在一些實施例中,R4為-NH2。
在一些實施例中,R5為氫、甲基或-N(R)2。在一些實施例中,R5
為氫。在一些實施例中,R5為甲基。在一些實施例中,R5為-N(R)2。在一些實施例中,R5為-N(R)2,其中各R為氫。在一些實施例中,R5為-NH2。
在一些實施例中,各R獨立地為氫或視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,各R獨立地為氫或未經取代之C1-4烷基。在一些實施例中,各R獨立地為氫或視情況經一或多個-F取代之C1-4烷基。
在一些實施例中,R為氫。在一些實施例中,R為視情況經一或多個鹵素取代之C1-4烷基。在一些實施例中,R為氫或視情況經一或多個-F取代之C1-4烷基。在一些實施例中,R為氫或C1-4烷基。在一些實施例中,R為C1-4烷基。在一些實施例中,R為甲基。在一些實施例中,R為氫或經一或多個鹵素取代之C1-4烷基。在一些實施例中,R為氫或經一或多個-F取代之C1-4烷基。在一些實施例中,R為-CF3。在一些實施例中,R為-CHF2。
在一些實施例中,式I之右手側為。在一
些實施例中,為。在一些實施例中,
為。在一些實施例中,為。在一些實施
例中,為。在一些實施例中,為
。在一些實施例中,為。在一些實施
例中,為。在一些實施例中,不為
例示性部分描述於下表4中。
在一些實施例中,式I化合物具有式I-a之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如
本文之類別及亞類中獨立地描述。在一些實施例中,R1a為或直
鏈C1-6脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基、-C≡CH或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜
芳基。
在一些實施例中,式I化合物具有式I-a-1之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。在一些實施例中,R1a為或直鏈C1-6脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基、-C≡CH或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。
在一些實施例中,式I化合物具有式I-a-2之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。在一些實施例中,R1a為或直鏈C1-6脂族基,其視情況經一或多個獨立地選自以下之基團取代:-OH、環丙基、-C≡CH或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。
在一些實施例中,式I化合物具有式I-b之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
在一些實施例中,式I化合物具有式I-c之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。在一些實施例中,R1c及R1d各為甲基。在一些實施例中,R1c為氫,且R1d為甲基。
在一些實施例中,式I化合物具有式I-c-1之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。在一些實施例中,R1c及R1d各為甲基。在一些實施例中,R1c為氫,且R1d為甲基。
在一些實施例中,式I化合物具有式I-d之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。在一些實施例中,RA2為-OMe。在
一些實施例中,RA2為-N(R)2,其中各R獨立地為C1-4烷基。在一些實施例中,RA2為-N(CH3)2。在一些實施例中,RA2為-Cl,RA1為-F,且n為1。
在一些實施例中,式I化合物具有式I-e之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
在一些實施例中,式I化合物具有式I-e-1之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
在一些實施例中,式I化合物具有式I-f之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。在一些實施例中,RA2為-OMe。在一些實施例中,RA2為-N(R)2,其中各R獨立地為C1-4烷基。在一些實
施例中,RA2為-N(CH3)2。在一些實施例中,RA2為-Cl。
在一些實施例中,式I化合物具有式I-g之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
例示性式I化合物描述於下表5中。
在某些實施例中,本發明提供一種式II化合物或其醫藥學上可接受之鹽。
在一些實施例中,Y為-S-。在一些實施例中,Y為-O-。在一些
實施例中,式II化合物為或其醫藥學上可接受
之鹽。在一些實施例中,Y為-CR2-。在一些實施例中,Y為-CH2-。
在一些實施例中,式II化合物為或其醫藥學上
可接受之鹽。
在一些實施例中,環B為。在一些實施例中,環B為
。在一些實施例中,環B為。在一些實施例中,環
B為。在一些實施例中,環B為。在一些實施例
中,環B為。在一些實施例中,環B為。在一些
實施例中,環B為。在一些實施例中,環B為。在一
些實施例中,環B為。在一些實施例中,環B為視情況經-C(O)R
取代之噻吩基。在一些實施例中,環B為視情況經-C(O)Me取代之噻
吩基。在一些實施例中,環B為。在一些實施例中,環B為
視情況經-C(O)R取代之呋喃基。在一些實施例中,環B為視情況經-
C(O)H取代之呋喃基。在一些實施例中,環B為
在一些實施例中,式II化合物具有式II-a之結構:
或其醫藥學上可接受之鹽,其中各變數以單獨與組合之方式如本文之類別及亞類中獨立地描述。
例示性式II化合物描述於下表6中。
在一些實施例中,式I及/或II之化合物適用於醫學。在一些實施例中,本發明提供一種治療罹患或易患對Hsp70抑制起反應之疾病、病症或病狀之個體的方法,該方法包含投與個體治療有效量之如本文所述化合物。在一些實施例中,疾病、病症或病狀為增生性疾病、病症或病狀。在一些實施例中,疾病、病症或病狀為癌症。
在某些實施例中,已發現所提供化合物具有抗增生活性,因此被認為可用於治療增生性病症(諸如癌症)及與不受控之細胞增殖有關的其他病症。如本文所定義,在本發明標的物之範疇內,以非限制性實例形式,抗增生作用可藉由活體外或活體內抑制細胞增殖特定基因標靶或在活體外全細胞分析中、活體內動物模型中或在人類臨床投藥中抑制細胞增殖的能力展現。
所提供之化合物可用於活體外或活體內。在一些實施例中,所提供化合物尤其可適用於在活體內治療贅瘤或其他增生性疾病。然而,上述所提供化合物亦可在活體外用於研究或臨床目的(例如,判定患者之疾病對所提供化合物之敏感性,研究作用機制,說明細胞路徑或過程)。在某些實施例中,贅瘤為良性贅瘤。在其他實施例中,贅瘤為惡性贅瘤。
在某些實施例中,惡性病為血液惡性病。血液惡性病為影響血液、骨髓及/或淋巴結之癌症類型。可使用所提供化合物治療之血液惡性病之實例包括(但不限於)急性淋巴母細胞性白血病(ALL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、慢性淋巴細胞性白血病(CLL)、毛細胞白血病、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、皮膚T細胞淋巴瘤(CTCL)、周邊T細胞淋巴瘤(PTCL)、套細胞淋巴瘤、B細胞淋巴瘤、急性淋巴母細胞性T細胞白血病(T-ALL)、急性前髓細胞性白血病及多發性骨髓瘤。在某些實施例中,所提供化合物為用於治療多發性骨髓瘤、神經膠母細胞瘤、上皮癌、頸腺癌或高分化型脂肪肉瘤。在某些特定實施例中,癌症為復發性及/或難治性多發性骨髓瘤。在其他實施例中,所提供化合物用於治療慢性淋巴細胞性白血病(CLL)。在某些實施例中,所提供化合物用於治療急性淋巴母細胞性白血病(ALL)。在某些實施例中,所提供化合物用於治療急性骨髓性白血病(AML)。在某些實施例中,癌症為慢性骨髓性白血病(CML)。在某些實施例中,癌症為皮膚T細胞淋巴瘤。在其他實施例中,癌症為周邊T細胞淋巴瘤。所提供化合物亦可用於治療難治性或復發性惡性病。在某些實施例中,癌症為難治性及/或復發性血液惡性病。在某些實施例中,癌症具有多藥耐藥性。舉例而言,癌症可耐受特定化學治療劑。
除血液惡性病以外,其他癌症亦可使用所提供化合物治療。在某些實施例中,癌症為實體腫瘤。僅舉數例,可使用所提供化合物治療之例示性癌症包括結腸癌、肺癌、骨癌、胰臟癌、胃癌、食道癌、皮膚癌、腦癌、肝癌、卵巢癌、頸癌、子宮癌、睾丸癌、前列腺癌、膀胱癌、腎癌、神經內分泌癌、乳癌、胃癌、眼癌、膽囊癌、喉癌、口腔癌、陰莖癌、腺腫瘤、直腸癌、小腸癌、肉瘤、癌瘤、黑色素瘤、尿道癌、陰道癌。
在一些實施例中,所提供化合物亦可用於活體外治療及/或殺滅細胞。在某些實施例中,使細胞毒性濃度之所提供化合物與細胞接觸以殺滅該細胞。在其他實施例中,使用半致命濃度之所提供化合物處理該等細胞。在某些實施例中,所提供化合物之濃度在0.01nM至100nM範圍內。在某些實施例中,所提供化合物之濃度在0.1nM至50nM範圍內。在某些實施例中,所提供化合物之濃度在1nM至10nM範圍內。在某些實施例中,所提供化合物之濃度在1nM至10nM範圍內,更尤其在1nM至5nM範圍內。
可用所提供化合物測試或殺滅任何類型之細胞。細胞可處於分化或發育之任何階段。在某些實施例中,細胞為動物細胞。在某些實施例中,細胞為脊椎動物細胞。在某些實施例中,細胞為哺乳動物細胞。在某些實施例中,細胞為人類細胞。細胞可來源於任何發育階段之男性或女性人類。在某些實施例中,細胞為靈長類細胞。在其他實施例中,細胞來源於嚙齒動物(例如,小鼠、大鼠、天竺鼠、倉鼠、沙鼠)。在某些實施例中,細胞來源於馴養動物,諸如狗、貓、牛、羊、豬等。細胞亦可來源於基因工程改造動物或植物,諸如轉基因小鼠。
所用細胞可為野生型或突變細胞。細胞可經基因工程改造。在某些實施例中,細胞為正常細胞。在某些實施例中,細胞為血液細
胞。在某些實施例中,細胞為白血球。在某些特定實施例中,細胞為白血球之前驅物(例如,幹細胞、祖細胞、母細胞)。在某些實施例中,細胞為贅生性細胞。在某些實施例中,細胞為癌細胞。在某些實施例中,細胞來源於血液惡性病。在其他實施例中,細胞來源於實體腫瘤。舉例而言,細胞可來源於患者之腫瘤(例如,來自生檢或外科切除術)。在某些實施例中,細胞來源於個體之血液樣品或骨髓生檢。在某些實施例中,細胞來源於淋巴結生檢。此類細胞毒性測試可適用於判定患者之疾病是否對特定療法起反應。此類測試亦可適用於確定治療惡性病所需之劑量。患者之癌症對所提供化合物之敏感性的此測試將防止不必要地投與藥物而對患者無作用。在患者之癌症對化合物尤其敏感時,該測試亦可使得可使用較低劑量之本發明化合物。
在一些實施例中,細胞來源於癌細胞株。在某些實施例中,細胞來自血液惡性病,諸如本文所述之血液惡性病。人類白血病細胞株包括U937、HL-60、HL-60/RV+(過表現P-醣蛋白之多藥耐藥性HL-60變異體,其藉由持續暴露於長春花生物鹼長春新鹼(vincristine)來選擇)、THP-1、Raji、CCRF-CEM、ALL3(自在Memorial Sloan Kettering Cancer Center中治療且特徵為費城染色體(Philadelphia chromosome)陽性之患者分離的急性淋巴母細胞性白血病)及Jurkat。
例示性CLL細胞株包括JVM-3及MEC-2。例示性骨髓瘤細胞株包括MM1.S、MM1.R(耐地塞米松(dexamethasone))、RPMI8226、NCI-H929及U266。例示性淋巴瘤細胞株包括NCEB1(套細胞淋巴瘤)、JEKO(B細胞淋巴瘤)、Karpas、SUDH-6、SUDH-16、L428、KMH2及Granta套細胞淋巴瘤細胞株。在某些實施例中,細胞為AML細胞或多發性骨髓瘤(CD138+)細胞。在某些實施例中,細胞為造血幹細胞或祖細胞。舉例而言,在某些實施例中,細胞為造血祖細胞,諸如CD34+骨髓細胞。在某些實施例中,細胞為MOLT-3(急性淋巴母細胞
性T細胞)、SKNLP(神經母細胞瘤)、PC9(腺癌)、H1650(腺癌)、H1975(腺癌)、H2030(腺癌)、H3255(腺癌)、TC71(尤文氏肉瘤(Ewing's sarcoma))、HTP-15(神經膠母細胞瘤)、A431(上皮癌)、HeLa(頸腺癌)或WD0082(高度分化型脂肪肉瘤)細胞。在一些實施例中,細胞為HL-60/RV+細胞。在某些實施例中,細胞株耐受特定化學治療劑。
在一些實施例中,癌症用Hsp90抑制劑治療難治癒。耐受Hsp90抑制劑之癌症可尤其難以治療。意外地發現所提供化合物在投與耐受Hsp90抑制劑之細胞時活化卡斯蛋白酶、誘導細胞死亡及/或抑制細胞生長。在一些實施例中,本發明提供一種在耐受Hsp90抑制劑之細胞中活化卡斯蛋白酶的方法,其包含投與該細胞所提供化合物或組合物。在一些實施例中,本發明提供一種在耐受Hsp90抑制劑之細胞中誘導細胞死亡的方法,其包含投與該細胞所提供化合物或組合物。在一些實施例中,本發明提供一種在耐受Hsp90抑制劑之細胞中誘導細胞凋亡的方法,其包含投與該細胞所提供化合物或組合物。在一些實施例中,本發明提供一種在耐受Hsp90抑制劑之細胞中抑制細胞生長的方法,其包含投與該細胞所提供化合物或組合物。
在某些實施例中,所提供化合物適用於治療臨床緩解之個體,其中該個體已藉由手術治療或患有侷限性未切除疾病。在一些實施例中,個體已藉由Hsp90抑制劑預先治療。
在另一態樣中,本發明提供醫藥組合物,其包含式I或II之化合物與醫藥學上可接受之賦形劑(例如,載劑)的組合。
醫藥組合物包括本文所揭示化合物之光學異構體、非對映異構體或醫藥學上可接受之鹽。醫藥組合物中所包括之所提供化合物可共價連接於上述載劑部分。或者,醫藥組合物中包括之所提供化合物不
共價連接於載劑部分。
如本文所用之「醫藥學上可接受之載劑」係指適用於經腸或非經腸施用的不會不利地與活性劑反應的醫藥賦形劑(例如醫藥學上、生理學上可接受之有機或無機載劑物質)。醫藥學上可接受之適合載劑包括水、鹽溶液(諸如林格氏溶液(Ringer's solution))、醇、油、明膠及碳水化合物(諸如乳糖、直鏈澱粉或澱粉、脂肪酸酯、羥基甲基纖維素及聚乙烯基吡咯啶)。此類製劑可滅菌且必要時與不會不利地與本發明化合物反應之助劑(諸如潤滑劑、防腐劑、穩定劑、潤濕劑、乳化劑、影響滲透壓之鹽、緩衝劑、染色劑及/或芳族物質及其類似物)混合。
本發明化合物可單獨投與或可共投與個體。共投與意欲包括同時或依序以個別或組合(一種以上化合物)形式投與化合物。製劑亦可在需要時與其他活性物質組合(例如以減少代謝降解)。
本發明化合物可以經口、非經腸及局部劑型中之多種形式製備且投與。因此,本發明化合物可藉由注射(例如靜脈內、肌肉內、皮內、皮下、十二指腸內或腹膜內注射)投與。本文所述之化合物亦可藉由吸入(例如鼻內)投與。另外,本發明化合物可經皮投與。亦設想可使用多種投藥途徑(例如,肌肉內、經口、經皮)投與本發明化合物。
為自本發明化合物製備醫藥組合物,醫藥學上可接受載劑可為固體或液體。固體形式製劑包括粉末、錠劑、丸劑、膠囊、扁囊劑、栓劑及可分散顆粒。固體載劑可為一或多種物質,其亦可充當稀釋劑、調味劑、黏合劑、防腐劑、錠劑崩解劑或囊封材料。
在粉末中,載劑為與細粉狀活性組分混合的細粉狀固體。在錠劑中,活性組分以合適比例與具有必需黏合特性之載劑混合且壓緊為所要形狀及大小。
粉末及錠劑較佳含有5%至70%活性化合物。適合載劑包括碳酸鎂、硬脂酸鎂、滑石、糖、乳糖、果膠、糊精、澱粉、明膠、黃蓍、甲基纖維素、羧基甲基纖維素鈉、低熔點蠟、可可油及其類似物。術語「製備」意欲包括用囊封材料作為載劑調配活性化合物,從而得到膠囊,其中含或不含載劑之活性組分由載劑包圍,因此與載劑結合。
類似地,包括扁囊劑及口含劑。錠劑、粉末、膠囊、丸劑、扁囊劑及口含錠可以適合於經口投與之固體劑型使用。
為製備栓劑,首先將諸如脂肪酸甘油酯之混合物或可可油的低熔點蠟熔融,且將活性組分如藉由攪拌均勻分散於其中。接著將熔融均勻混合物傾倒於適宜尺寸之模具中,使其冷卻,從而凝固。
液體形式製劑包括溶液、懸浮液及乳液,例如水或水-丙二醇溶液。為進行非經腸注射,液體製劑可以於聚乙二醇水溶液中之溶液形式調配。
在必需或需要非經腸施用時,本發明化合物之尤其適合混合物為可注射無菌溶液,較佳油性溶液或水溶液,以及懸浮液、乳液或植入物,包括栓劑。詳言之,用於非經腸投藥之載劑包括右旋糖、生理食鹽水、純水、乙醇、甘油、丙二醇、花生油、芝麻油、聚氧乙烯-嵌段聚合物及其類似物之水溶液。安瓿為適宜單位劑量。本發明化合物亦可併入脂質體中或經由經皮泵或貼片投與。適用於本發明之醫藥混合物包括例如Pharmaceutical Sciences(第17版,Mack Pub.Co.,Easton,PA)及WO 96/05309中所述之醫藥混合物,其教示以引用的方式併入本文中。
適用於經口使用之水溶液可藉由將活性組分溶解於水中且視需要添加適合著色劑、調味劑、穩定劑及增稠劑來製備。適用於經口使用之水性懸浮液可藉由將細粉狀活性組分與黏性材料(諸如天然或合成樹膠、樹脂、甲基纖維素、羧基甲基纖維素鈉及其他熟知懸浮劑)
一起分散於水中來製備。
亦包括固體形式製劑,欲在使用前不久將其轉化成液體形式製劑以經口投與。此類液體形式包括溶液、懸浮液及乳液。除活性組分外,此等製劑亦可含有著色劑、調味劑、穩定劑、緩衝劑、人工及天然甜味劑、分散劑、增稠劑、增溶劑及其類似物。
醫藥製劑較佳呈單位劑型。在此類形式中,將製劑再分成含有適當量活性組分之單位劑量。單位劑型可為包裝製劑,該包裝含有離散量之製劑,諸如包裝錠劑、膠囊及小瓶或安瓿裝粉末。單位劑型亦可為膠囊、錠劑、扁囊劑或口含劑本身,或其可為適當數目之包裝形式之此等單位劑型中之任一者。
單位劑量製劑中活性組分之量可根據特定應用及活性組分之效能在0.1mg至10000mg、更通常1.0mg至1000mg、最通常10mg至500mg中變化或調節。組合物必要時亦可含有其他相容治療劑。
一些化合物在水中可具有有限溶解度,因此在組合物中可能需要界面活性劑或其他適當共溶劑。此類共溶劑包括:Polysorbate 20、60及80;Pluronic F-68、F-84及103;環糊精;及聚乙二醇35蓖麻油。此類共溶劑通常以約0.01重量%至約2重量%之含量使用。
可能需要黏度大於簡單水溶液之黏度以降低施配調配物時之變化性,降低調配物之懸浮液或乳液之組分的實體分離及/或以其他方式改良調配物。此類黏度構建劑包括例如聚乙烯醇、聚乙烯基吡咯啶酮、甲基纖維素、羥基丙基甲基纖維素、羥基乙基纖維素、羧基甲基纖維素、羥基丙基纖維素、硫酸軟骨素及其鹽、玻尿酸及其鹽及上述物質之組合。此類藥劑通常以約0.01重量%至約2重量%之含量使用。
本發明之組合物可另外包括提供持續釋放及/或舒適度之組分。此類組分包括高分子量陰離子型黏膜模擬(mucomimetic)聚合物、膠凝化多醣及細粉狀藥物載劑基質。此等組分更詳細地論述在美國專利
第4,911,920號;第5,403,841號;第5,212,162號;及第4,861,760號中。此等專利之全部內容以全文引用的方式併入本文中。
由本發明提供之醫藥組合物包括如下組合物,其中含有治療有效量(亦即有效達成其預期目的之量)之活性成分。有效用於特定應用之實際量尤其取決於所治療病狀。舉例而言,當在方法中投與以治療癌症時,此類組合物應含有有效達成所要結果(例如降低個體之癌細胞數)之量的活性成分。
所投與化合物之劑量及頻率(單次或多次劑量)可視多種因素而變化,包括投藥路徑;接受者之身材、年齡、性別、健康狀況、體重、身體質量指數;所治療疾病之症狀的性質及程度(例如,對Hsp70抑制起反應之疾病);其他疾病或其他健康相關問題之存在;同時治療之種類;及任何疾病或治療方案之併發症。其他治療方案或藥劑可與本發明之方法及化合物結合使用。
對於本文所述之任何化合物,治療有效量可首先由細胞培養物分析確定。標靶濃度為活性化合物之可降低例如使用所述方法量測之酶活性的濃度。
適用於人類之治療有效量可由動物模型確定。舉例而言,用於人類之劑量可調配至達成已發現在動物中有效之濃度。人類中之劑量可藉由監測抑制及如上述向上或向下調節劑量來調節。在某些實施例中,所投與劑量在每天約1mg至約1000mg範圍內,每天一次、兩次或兩次以上。在某些實施例中,所投與劑量在每天每公斤約0.001至約100mg範圍內。在某些實施例中,所投與劑量在每天每公斤約0.001至約10mg範圍內。在某些實施例中,所投與劑量在每天每公斤約0.0001至約100mg範圍內。在某些實施例中,所投與劑量在每天每公斤約0.0001至約10mg範圍內。在某些實施例中,所投與劑量在每
天每公斤約0.01至約10mg範圍內。
在某些實施例中,較佳治療有效劑量為獲得如下血清(但更佳腫瘤)濃度所要的本發明標的物之化合物的量,該濃度等效於在本文所述之任何分析中達成表型作用(諸如(但不限於)誘導細胞凋亡,如由卡斯蛋白酶所表明)的濃度。在一些實施例中,此類濃度選自由以下組成之群:小於200μM;小於100μM;小於50μM;小於25μM;小於15μM;小於10μM;小於5μM;小於2μM;小於1μM;小於500nM;小於200nM;或小於100nM。在一些實施例中,表型作用為分析之IC50值。
劑量可視患者之需要及所用化合物而變化。在本發明之情形下,投與患者之劑量應足以隨時間在患者體內實現有益治療反應。劑量大小亦藉由任何不良副作用之存在、性質及程度來確定。一般而言,治療係以小於化合物最佳劑量之較小劑量開始。隨後,劑量以小幅增量增加直至在一定情形下達到最佳作用。在一些實施例中,劑量範圍為0.001w/v%至10w/v%。在一些實施例中,劑量範圍為0.1w/v%至5w/v%。
可個別地調節劑量之量及間隔時間以提供對所治療之特定臨床適應症有效的所投與化合物之含量。此將提供與個體之疾病病況的嚴重性相對應的治療方案。
在一些實施例中,根據本文所述標的物之醫藥組合物可為靜脈內形式或經口劑型,例如封裝在例如多次使用或單次使用包裝(包括例如容器或瓶、泡殼封裝)中的膠囊、錠劑、液體及/或粉末。可製備含有每天一次或每次治療一次之量的醫藥組合物的單次劑量套組及包裝。單次劑量、單位劑量及每天一次拋棄式容器的本發明醫藥組合物涵蓋在本發明標的物之範疇內。
在一些實施例中,本發明醫藥組合物可與另一醫藥劑型組合使用以提高其在治療如本文所述之疾病、病症或病狀中之有效性。就此而言,本發明組合物可作為另外包括此項技術中已知有效治療如本文所述之疾病、病症或病狀的任何其他醫藥及/或醫藥劑型的方案的一部分投與。類似地,除本文指定成分以外之醫藥活性成分可添加至本發明組合物中以提高其在治療如本文所述之疾病、病症或病狀中的有效性。因此,此另一醫藥活性成分或另一醫藥劑型可直接或間接且與本文所述之組合物同時或依序投與患者。
舉例而言,可與本發明之所提供化合物及組合物組合使用的其他療法、醫藥劑型及/或抗癌劑包括手術、放射療法(僅舉數例,γ-輻射、中子束放射療法、電子束放射療法、質子療法、近接療法及全身放射性同位素)、內分泌療法、生物反應調節劑(僅舉數例,干擾素、介白素及腫瘤壞死因子(TNF))、高溫處理及冷凍療法、減少任何不良作用之藥劑(例如,止吐藥)及其他批准化學治療藥物,僅舉數例,包括(但不限於)烷化藥(氮芥、苯丁酸氮芥、環磷醯胺、美法侖(Melphalan)、異環磷醯胺)、抗代謝物(甲胺喋呤(Methotrexate))、嘌呤拮抗劑及嘧啶拮抗劑(6-巰基嘌呤、5-氟尿嘧啶、阿糖胞苷、吉西他濱(Gemcitabine))、紡錘體毒劑(長春鹼(Vinblastine)、長春新鹼(Vincristine)、長春瑞賓(Vinorelbine)、太平洋紫杉醇(Paclitaxel))、足葉草毒素(依託泊苷(Etoposide)、伊立替康(Irinotecan)、拓朴替康(Topotecan))、抗生素(小紅莓(Doxorubicin)、博萊黴素(Bleomycin)、絲裂黴素(Mitomycin))、亞硝基脲(卡莫司汀(Carmustine)、洛莫司汀(Lomustine))、無機離子(順鉑(Cisplatin)、卡鉑(Carboplatin))、酶(天冬醯胺酶)及激素(他莫昔芬(Tamoxifen)、亮丙立德(Leuprolide)、氟他胺(Flutamide)及甲地孕酮(Megestrol))。在某些實施例中,抗癌劑為埃坡黴素(epothilone)、紫杉醇(taxol)、根赤殼菌素(radicicol)或TMC-
95A/B。在某些實施例中,埃坡黴素為12,13-去氧埃坡黴素B、(E)-9,10-去氫-12,13-去氧EpoB及26-CF3-(E)-9,10-去氫-12,13-去氧EpoB。
另外,本發明亦涵蓋當前在臨床試驗中且可最終經FDA批准的某些細胞毒性劑或抗癌劑(包括(但不限於)埃博黴素及其類似物及格爾德黴素(geldanamycins)及其類似物)的用途。
在一些實施例中,所提供化合物與一或多種其他抗癌劑組合投與。在一些實施例中,抗癌劑選自由以下組成之群:有絲分裂抑制劑、烷基化劑、抗代謝物、嵌入型抗生素、生長因子抑制劑、細胞週期抑制劑、酶、拓撲異構酶抑制劑、生物反應調節劑、抗激素、血管生成抑制劑及抗雄激素。非限制性實例為化學治療劑、細胞毒性劑及非肽小分子(諸如Gleevec(甲磺酸伊馬替尼(Imatinib Mesylate))、Velcade(Velcade)(硼替佐米(bortezomib))、Casodex(Casodex)(比卡魯胺(bicalutamide))、Iressa(吉非替尼(gefitinib))及Adriamycin)以及大量化學治療劑。化學治療劑之非限制性實例包括烷基化劑,諸如噻替派(thiotepa)及環磷醯胺(CYTOXANTM);磺酸烷酯,諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan);氮丙啶,諸如苯唑多巴(benzodopa)、卡波醌(carboquone)、米特多巴(meturedopa)及尤利多巴(uredopa);乙烯亞胺及甲基三聚氰胺,包括六甲蜜胺(altretamine)、曲他胺(triethylenemelamine)、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三甲密胺(trimethylolomelamine);氮芥,諸如苯丁酸氮芥(chlorambucil)、萘氮芥(chlornaphazine)、氯磷醯胺、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、氮芥(mechlorethamine)、氮芥氧化物鹽酸鹽、美法侖、新氮芥(novembichin)、芬司特瑞(phenesterine)、潑尼氮芥(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亞硝基脲,諸如卡莫司汀(carmustine)、氯脲菌素(chlorozotocin)、福莫司汀(fotemustine)、洛莫
司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,諸如阿克拉黴素(aclacinomysin)、放射菌素(actinomycin)、安麯黴素(authramycin)、偶氮絲胺酸(azaserine)、博來黴素(bleomycins)、放線菌素C(cactinomycin)、卡奇黴素(calicheamicin)、卡拉比辛(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、CasodexTM、色黴素(chromomycins)、放線菌素(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、小紅莓(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、艾達黴素(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycins)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、潑非黴素(potfiromycin)、嘌呤黴素(puromycin)、奎那黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑黴素(streptonigrin)、鏈脲菌素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、左柔比星(zorubicin);抗代謝物,諸如甲胺喋呤及5-氟尿嘧啶(5-FU);葉酸類似物,諸如迪諾特寧(denopterin)、甲胺喋呤、蝶羅呤(pteropterin)、曲美沙特(trimetrexate);嘌呤類似物,諸如氟達拉賓(fludarabine)、6-巰基嘌呤、硫米嘌呤(thiamiprine)、硫鳥嘌呤(thioguanine);嘧啶類似物,諸如安西他濱(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、雙去氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine);雄激素,諸如卡魯睾酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺,諸如胺格魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,諸如亞葉酸;醋葡醛內酯(aceglatone);
醛磷醯胺糖苷;胺基乙醯丙酸;安吖啶(amsacrine);貝斯布西(bestrabucil);比山群(bisantrene);艾達曲克(edatraxate);得弗伐胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);依洛尼塞(elfomithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;蘑菇多醣(lentinan);氯尼達明(lonidamine);丙脒腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);二胺硝吖啶(nitracrine);噴司他汀(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸;2-乙基醯肼;丙卡巴肼(procarbazine);PSK®;雷佐生(razoxane);西佐喃(sizofuran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2"-三氯三乙胺;尿烷(urethan);長春地辛(vindesine);達卡巴嗪(dacarbazine);甘露氮芥(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加西托星(gacytosine);阿拉伯糖苷(「Ara-C」);環磷醯胺;噻替派;紫杉烷(taxane),例如太平洋紫杉醇(paclitaxel)(例如,TAXOLTM,Bristol-Myers Squibb Oncology,Princeton,N.J.;ABRAXANETM,Celgene Corporation,Summit,N.J.)及多烯紫杉醇(docetaxel)(TAXOTERETM,Rhone-Poulenc Rorer,Antony,France);視黃酸;埃斯波黴素(esperamicin);卡培他濱(capecitabine);及醫藥學上可接受之鹽,以上任一者之酸或衍生物。
亦包括如下適合化學治療細胞調節劑作為用於組合之適合藥劑,諸如用於調節或抑制腫瘤上之激素作用的抗激素劑,包括抗雌激素,例如(tamoxifen)(NolvadexTM)、雷洛昔芬(raloxifene)、抑制芳香酶之4(5)-咪唑、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、雷洛昔芬(keoxifene)、LY 117018、奧那司酮(onapristone)及托瑞米芬(toremifene)(Fareston);及抗雄激素,諸如氟他胺(flutamide)、尼魯
胺(nilutamide)、比卡魯胺(bicalutamide)、亮丙立德(leuprolide)及戈舍瑞林(goserelin)。用於組合之其他抗癌劑包括苯丁酸氮芥(chlorambucil);吉西他濱(gemcitabine);6-硫代鳥嘌呤(6-thioguanine);巰基嘌呤(mercaptopurine);甲胺喋呤;鉑類似物,諸如順鉑及卡鉑;長春鹼(vinblastine);鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺(ifosfamide);絲裂黴素C(mitomycin C);米托蒽醌(mitoxantrone);長春新鹼(vincristine);長春瑞賓(vinorelbine);溫諾平(navelbine);米托蒽醌(novantrone);替尼泊甙(teniposide);柔紅黴素(daunomycin);胺基喋呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);喜樹鹼-11(CPT-11));拓撲異構酶抑制劑RFS 2000);二氟甲基鳥胺酸(DMFO)。在一些實施例中,本發明之化合物或醫藥組合物可與通常開處之抗癌藥(諸如Herceptin®、Avastin®、Erbitux®、Rituxan®、Taxol®、Arimidex®、Taxotere®及Velcade®)組合使用。
在一些實施例中,另外涵蓋除上述化合物以外之適用於本文所述之組合療法的抗癌劑、抗惡性病劑或抗增生性病症劑。本文涵蓋任何前述藥劑或其醫藥學上可接受之鹽或衍生物之組合。
在一些實施例中,本發明組合物及另一醫藥劑型可同時投與患者。在某些實施例中,本發明組合物及另一醫藥劑型中之一者可在早晨投與,且另一者可在晚間投與。
在一些實施例中,當前所述之化合物可以多種醫藥劑型投與有需要之患者。此組合療法可使本發明組合物在治療癌症、惡性病或增生性病症中之有效性達最大。
為了能更全面地理解本文所述之發明,闡述以下實例。應瞭解,此等實例僅用於說明性目的,且不應理解為以任何方式限制本發明。
通則. 在Bruker AV-III-500或600MHz NMR光譜儀上記錄NMR譜。化學位移以δ值(距內標TMS之低場ppm數)報導。1H資料如下報導:化學位移,多重性(s=單峰,d=二重峰,t=三重峰,q=四重峰,br=寬峰,m=多重峰),耦合常數(Hz),積分。13C化學位移以δ值(距內標TMS之低場ppm數)報導。在Waters LCT Premier系統上記錄高解析度質譜。在具有電噴霧電離及SQ偵測器之Waters Acquity超高效LC上獲得低解析度質譜。在具有PDA、MicroMass ZQ及ELSD偵測器之Waters自動純化系統上執行分析型HPLC。在250μM矽膠F254板上執行分析型薄層層析。在1000μM矽膠F254板上執行製備型薄層層析。採用230-400目矽膠執行急驟管柱層析。溶劑為HPLC級。所有試劑購自Aldrich,Acros,Oakwood或Matrix Scientific且在不純化下使用。所有反應均在氬氣保護下執行。
流程2. 合成10、11、13、14、18、19及22-25.
試劑及條件:a.芳基硫醇,噻吩-2-甲酸銅(I),K2CO3,DMF,120-130℃,3-24小時。
合成10、11、13、14、18、19及22-25之通用程序. 將芳碘9(1當量)、芳基硫醇(1.2當量)及K2CO3(2當量)於DMF中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.4當量),抽空且用氬氣回填兩次。在氬氣下在120℃下加熱反應混合物24小時或在130℃下加熱3
小時。在減壓下移除溶劑,且藉由管柱層析純化殘餘物,得到所要產物。
4-(4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基硫基)苯胺[10]. 遵循以上通用程序,在於120℃下加熱24小時後獲得10,產率為75%。1H NMR(500MHz,CDCl3):δ 8.17(s,1H),7.20-7.30(m,5H),7.13(d,J=8.4Hz,2H),6.54(d,J=8.4Hz,2H),5.37(s,2H),3.80(m,4H),3.66(br s,2H),2.42(m,4H),2.32(s,3H);13C NMR(125MHz,CDCl3):δ 167.8,162.4,161.0,158.1,145.7,136.8,132.4,128.3,127.7,127.5,123.9,115.6,67.6,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C22H26N5OS之計算值,408.1858;實驗值408.1839。
5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-甲氧基苯胺[11]. 遵循以上通用程序,在於120℃下加熱24小時後獲得11,產率為64%。1H NMR(500MHz,CDCl3)δ 8.20(s,1H),7.22-7.28(m,5H),6.61-6.67(m,2H),6.58(s,1H),5.38(s,2H),3.81-3.83(m,4H),3.80(s,3H),3.69(br s,2H),2.43-2.45(m,4H),2.33(s,3H);13C NMR(125MHz,CDCl3):168.3,163.4,161.3,146.6,137.0,136.9,128.5,127.9,127.8,127.7,120.0,116.3,110.9,102.7,67.8,55.8,55.0,46.4,44.0;MS(m/z):[M+H]+ 438.2。
3-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[13]. 遵循以上通用程序,在於120℃下加熱24小時後獲得13,產率為26%。1H NMR(500MHz,CDCl3)δ 8.19(s,1H),7.95(d,J=6.5Hz,1H),7.51(d,J=7.5Hz,1H),7.31-7.36(m,5H),6.50(dd,J=7.5,5.2Hz,1H),5.36(s,2H),5.01(br s,2H),3.82-3.84(m,4H),2.44-2.46(m,4H),2.34(s,3H);HRMS(ESI)m/z[M+H]+ C21H25N6OS之計算值,409.1811;實驗值409.1804。
4-(苯甲氧基)-5-((6-甲氧基-5-硝基吡啶-3-基)硫基)-2-(4-甲基哌嗪-1-基)嘧啶[14]. 遵循以上通用程序,在於120℃下加熱24小時後獲得14,產率為63%。1H NMR(500MHz,CDCl3)δ 8.19(s,2H),7.60(s,1H),7.19-7.31(m,5H),5.27(s,2H),3.77-3.79(m,4H),3.22(s,3H),2.37-2.39(m,4H),2.27(s,3H);13C NMR(125MHz,CDCl3):168.2,162.7,161.5,153.9,148.5,143.0,138.0,136.1,128.9,128.8,128.5,110.2,101.0,68.5,54.9,46.3,44.0,38.6;HRMS(ESI)m/z[M+H]+ C22H25N6O4S之計算值,469.1658;實驗值469.1662。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-3-甲基苯甲腈[18]. 遵循以上通用程序,在於120℃下加熱24小時後獲得18,產率為76%。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.39(s,1H),7.12-7.32(m,6H),6.76(d,J=8.2Hz,1H),5.39(s,2H),3.86-3.94(m,4H),2.46-2.52(m,4H),2.43(s,3H),2.38(s,3H);13C NMR(125MHz,CDCl3):δ 168.7,165.2,161.8,144.7,136.3,135.7,132.8,129.6,128.4,128.0,127.6,125.4,119.2,107.8,96.6,67.8,54.8,46.2,43.9,19.7;HRMS(ESI)m/z[M+H]+ C24H26N5OS之計算值,432.1858;實驗值432.1840。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-甲基苯甲腈[19]. 遵循以上通用程序,在於120℃下加熱24小時後獲得19,產率為78%。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.36(d,J=8.1Hz,1H),7.23-7.30(m,3H),7.11-7.18(m,2H),6.96(s,1H),6.90(d,J=8.0Hz,1H),5.30(s,2H),3.85-3.93(m,4H),2.44-2.50(m,4H),2.41(s,3H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 168.6,165.0,161.7,145.2,142.1,136.3,132.5,128.4,128.0,127.5,127.1,123.5,118.3,108.9,97.1,67.8,54.8,46.2,43.9,20.4;HRMS(ESI)m/z[M+H]+ C24H26N5OS之計算值,432.1858;實驗值432.1840。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-溴苯甲腈[22]. 遵循以上通用程序,在於120℃下加熱24小時後獲得22,產率為52%。1H NMR(500MHz,CDCl3):δ 8.22(s,1H),7.38(d,J=8.2Hz,1H),7.24-7.31(m,4H),7.14-7.19(m,2H),6.85-7.04(m,1H),5.37(s,2H),3.83-3.97(m,4H),2.44-2.54(m,4H),2.37(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,165.1,161.8,147.6,136.1,133.8,129.2,128.5,128.1,127.5,125.5,124.6,117.4,111.4,95.9,68.0,54.7,46.1,43.9;HRMS(ESI)m/z[M+H]+ C23H22BrN5OS之計算值,496.0807;實驗值496.0816。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氯苯甲腈[23]. 遵循以上通用程序,在於120℃下加熱24小時後獲得23,產率為39%。1H NMR(500MHz,CDCl3):δ 8.22(s,1H),7.39(d,J=8.3Hz,1H),7.25-7.31(m,3H),7.15-7.20(m,2H),7.10(d,J=1.7Hz,1H),6.98(dd,J=8.3,1.7Hz,1H),5.37(s,2H),3.86-3.95(m,4H),2.45-2.54(m,4H),2.36(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,165.1,161.8,147.7,137.1,136.1,133.5,128.5,128.1,127.6,126.2,124.1,116.2,109.0,95.9,68.0,54.7,46.1,43.9;HRMS(ESI)m/z[M+H]+ C23H22ClN5OS之計算值,452.1312;實驗值452.1303。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氟苯甲腈[24]. 遵循以上通用程序,在於130℃下加熱3小時後獲得24,產率為92%。MS(ESI)m/z[M+H]+ 436.3。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-碘苯甲腈[25]. 遵循以上通用程序,在於130℃下加熱3小時後獲得25,產率為57%。MS(ESI)m/z[M+H]+ 544.2。
流程3. 合成29-32、36、37、40、43-45、47-49.
試劑及條件:a.(4-甲氧基苯基)甲烷硫醇,噻吩-2-甲酸銅(I),CuI,K2CO3,DMF,135℃,18小時;b. HgO,TFA,室溫,1小時;c.芳碘,K2CO3,新亞銅試劑,CuI,DMF,135℃,1.5小時。
4-(苯甲氧基)-5-((4-甲氧基苯甲基)硫基)-2-(4-甲基哌嗪-1-基)嘧 啶[26]. 將9(0.400g,1.0mmol)及K2CO3(0.552g,4.0mmol)於DMF(10mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.076g,0.4mmol)及CuI(0.078g,0.4mmol),抽空且用氬氣回填兩次。添加(4-甲氧基苯基)甲烷硫醇(0.185g,1.2mmol)且在135℃下加熱反應混合物18小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化殘餘物,得到0.340mg(78%)26。HRMS(ESI)m/z[M+H]+ C24H29N4O2S之計算值,437.2011;實驗值437.2025。
雙((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)汞[27]. 向26(5.0g,11.5mmol)於TFA(30mL)中之溶液中添加HgO(1.25g,5.7mmol)且在室溫下攪拌混合物1小時。在減壓下濃縮反應混合物且藉由管柱層析(CH2Cl2:MeOH,9:1)純化所得殘餘物,得到4.5g(95%)27。1H NMR(500MHz,CDCl3):δ 8.10(s,2H),7.26-7.38(m,10H),5.32(s,4H),3.86(m,8H),2.61(m,8H),2.40(s,6H);MS(m/z):[M+H]+ 483.1。
合成29-32、36、37、40、43-45、47-49之通用程序. 在氬氣下在135℃下加熱27(1當量)、芳碘(1.2當量)、K2CO3(4當量)、新亞銅試劑(0.5當量)及CuI(1當量)於DMF中之混合物1.5小時。在減壓下移除溶劑,且藉由管柱層析純化殘餘物,得到所要產物。
5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)呋喃-2-甲醛[29]. 遵循以上通用程序獲得29,產率為72%。1H NMR(500MHz,CDCl3):δ 9.45(s,1H),8.27(s,1H),7.30(m,5H),7.10(d,J=3.6Hz,
1H),6.31(d,J=3.2Hz,1H),5.39(s,2H),3.85(m,4H),2.45(m,4H),2.33(s,3H);13C NMR(125MHz,CDCl3):δ 176.6,168.0,163.9,161.5,155.7,153.8,136.3,128.4,128.0,127.6,122.2,113.7,96.7,68.0,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C21H23N4O3S之計算值,411.1491;實驗值411.1510。
1-(5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)噻吩-2-基)乙酮[30]. 遵循以上通用程序獲得30,產率為68%。1H NMR(500MHz,CDCl3):δ 8.26(s,1H),7.45(d,J=3.9Hz,1H),7.25-7.32(m,5H),6.90(d,J=3.9Hz,1H),5.39(s,2H),3.84-3.90(m,4H),2.44-2.49(m,7H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 189.6,168.0,164.1,161.5,150.4,143.7,136.3,133.0,128.4,127.9,127.6,127.3,100.1,68.0,54.8,46.2,43.9,26.3;HRMS(ESI)m/z[M+H]+ C22H25N4O2S2之計算值,441.1419;實驗值441.1418。
6-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-3-胺[31]. 遵循以上通用程序獲得31,產率為65%。1H NMR(500MHz,CDCl3):δ 8.27(s,1H),7.92(s,1H),7.17-7.30(m,5H),6.79(s,2H),5.37(s,2H),3.80-3.88(m,4H),3.59(br s,2H),2.42-2.49(m,4H),2.34(s,3H);HRMS(ESI)m/z[M+H]+ C21H25N6OS,409.1811之計算值;實驗值409.1806。
5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[32]. 遵循以上通用程序獲得32,產率為59%。1H NMR(500MHz,CDCl3):δ 8.20(s,1H),8.12(s,1H),7.36-7.42(m,1H),7.23-7.36(m,5H),6.33(d,J=8.5Hz,1H),5.36(s,2H),4.49(br s,2H),3.77-3.84(m,4H),2.38-2.47(m,4H),2.37(s,3H);HRMS(ESI)m/z[M+H]+ C21H25N6OS之計算值,409.1811;實驗值409.1810。
1-(4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯基)乙酮[36]. 遵循以上通用程序獲得36,產率為52%。1H NMR(500MHz,CDCl3):δ 8.26(s,1H),7.77(d,J=8.5Hz,2H),7.23(m,3H),7.14(m,2H),7.12(d,J=8.5Hz,2H),5.36(s,2H),3.88(m,4H),2.54(s,3H),2.47(m,4H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 197.2,168.6,165.0,161.7,145.3,136.4,134.0,128.7,128.3,127.8,127.4,125.7,97.7,67.8,54.8,46.2,43.9,26.5;HRMS(ESI)m/z[M+H]+ C24H27N4O2S之計算值,435.1855;實驗值435.1866。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)酚[37]. 遵循以上通用程序獲得37,產率為54%。1H NMR(500MHz,CDCl3):δ
8.15(s,1H),7.26(m,3H),7.25(m,2H),7.16(d,J=8.5Hz,2H),6.05(d,J=8.5Hz,2H),5.34(s,2H),3.82(m,4H),2.48(m,4H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 167.9,162.3,160.9,155.8,136.5,132.3,128.3,127.8,127.5,125.9,116.2,103.6,67.8,54.7,46.0,43.6;HRMS(ESI)m/z[M+H]+ C22H25N4O2S之計算值,409.1698;實驗值409.1696。
4-(苯甲氧基)-5-((4-甲氧基-2-硝基苯基)硫基)-2-(4-甲基哌嗪-1-基)嘧啶[40]. 遵循以上通用程序獲得40,產率為59%。1H NMR(500MHz,CDCl3):δ 8.26(s,1H),7.72(d,J=2.7Hz,1H),7.22-7.28(m,3H),7.12-7.18(m,2H),6.91(dd,J=9.0,2.8Hz,1H),6.81(d,J=9.0Hz,1H),5.35(s,2H),3.86-3.94(m,4H),3.84(s,3H),2.46-2.51(m,4H),2.36(s,3H);HRMS(ESI)m/z[M+H]+ C23H26N5O4S之計算值,468.1706;實驗值468.1697。
3-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醛[43]. 遵循以上通用程序獲得43,產率為59%。1H NMR(500MHz,CDCl3):δ 9.86(s,1H),8.29(s,1H),7.63(d,J=7.2Hz,1H),7.57(s,1H),7.38(m,2H),7.22(m,3H),7.11(m,2H),5.34(s,2H),4.04(m,4H),2.80(m,4H),2.56(s,3H);13C NMR(125MHz,CDCl3):δ 191.8,
168.6,164.5,161.3,139.4,130.9,136.2,132.9,129.4,128.4,128.0,127.9,127.4,126.9,99.7,68.0,54.2,45.3,42.7;HRMS(ESI)m/z[M+H]+ C23H25N4O2S之計算值,421.1698;實驗值421.1703。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[44]. 遵循以上通用程序獲得44,產率為72%。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.42(d,J=8.5Hz,2H),7.25(m,3H),7.13(m,2H),7.10(d,J=8.5Hz,2H),5.36(s,2H),3.95(m,4H),2.60(m,4H),2.40(s,3H);13C NMR(125MHz,CDCl3):δ 168.0,165.0,161.7,145.5,136.1,132.1,128.4,128.0,127.5,126.2,118.9,108.3,97.3,67.9,54.2,45.4,43.2;HRMS(ESI)m/z[M+H]+ C23H24N5OS之計算值,418.1702;實驗值418.1713。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醛[45]. 遵循以上通用程序獲得45,產率為52%。1H NMR(500MHz,CDCl3):δ 9.90(s,1H),8.26(s,1H),7.67(d,J=8.3Hz,2H),7.11-7.28(m,7H),5.37(s,2H),3.86-3.96(m,4H),2.45-2.53(m,4H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 191.2,168.7,165.1,161.7,147.4,136.3,133.5,130.0,128.3,127.9,127.5,125.8,97.2,67.8,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C23H25N4O2S之計算值,421.1698;實驗值421.1690。
3-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[47]. 遵循以上通用程序獲得47,產率為70%。1H NMR(500MHz,CDCl3):δ 8.27(s,1H),7.37(t,J=7.3Hz,1H),7.36(d,J=8.6Hz,1H),7.23-7.33(m,5H),7.14-7.18(m,2H),5.37(s,2H),3.85-3.91(m,4H),2.37-2.61(m,4H),2.37(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,164.9,161.6,140.5,136.2,130.8,129.5,129.2,128.7,128.4,128.0,127.4,118.5,112.9,97.4,67.9,54.8,46.2,43.9;MS(m/z):418.2[M+H]+。
6-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)菸鹼腈[48]. 遵循以上通用程序獲得48,產率為65%。1H NMR(500MHz,CDCl3):δ 8.57(s,1H),8.25(s,1H),7.59(d,J=8.3Hz,1H),7.21-7.31(m,5H),6.98(d,J=8.4Hz,1H),5.40(s,2H),3.90-3.94(m,4H),2.45-2.52(m,4H),2.38(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,166.9,164.9,161.8,152.1,138.4,136.3,128.4,128.0,127.6,119.8,116.9,104.9,95.7,67.8,54.8,46.2,43.9;MS(m/z):419.1[M+H]+。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲酸甲酯[49]. 遵循以上通用程序獲得49,產率為72%。1H NMR(500MHz,CDCl3,TMS)δ 8.26(s,1H),7.84(d,J=8.6Hz,2H),7.23(m,3H),7.11(m,4H),5.36(s,2H),3.89(m,7H),2.48(m,4H),2.36(s,3H);13C NMR(125MHz,CDCl3)δ 168.6,166.8,165.0,161.7,144.9,136.4,129.9,128.3,127.8,127.4,126.8,125.6,97.9,67.8,54.8,52.0,46.2,43.9;MS(m/z):451.1[M+H]+。
流程5. 合成56.
試劑及條件:a.丙烯醯氯,Et3N,CH2Cl2,室溫,2小時。
N-(5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-基)丙烯醯胺[56]. 向32(20mg,0.049mmol)及Et3N(49mg,0.49mmol)於CH2Cl2(0.5mL)中之溶液中添加丙烯醯氯(44mg,0.49mmol)且在室溫下攪拌混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3,15:1)純化所得殘餘物,得到15.9mg(70%)56。1H NMR(500MHz,CDCl3):δ 8.27(s,1H),8.16(d,J=2.2Hz,1H),8.14(d,J=8.8Hz,1H),8.08(br s,1H),7.53(dd,J=8.7,2.4Hz,1H),7.25-7.31(m,3H),7.18-7.22(m,2H),6.45(dd,J=16.9,0.8Hz,1H),6.24(dd,J=16.9,10.3Hz,1H),5.81(dd,J=10.3,0.8Hz,1H),5.34(s,2H),3.82-3.90(m,4H),2.42-2.50(m,4H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 168.3,163.8,163.4,161.4,149.5,148.0,139.2,136.3,130.9,129.4,128.6,128.4,128.0,127.6,114.1,100.1,68.0,54.7,46.1,43.8;HRMS(ESI)m/z[M+H]+ C24H27N6O2S之計算值,
463.1916;實驗值463.1930。
流程6. 合成58.
試劑及條件:a. Boc-甘胺酸,DCC,THF,室溫,隔夜,隨後CH2Cl2:TFA(4:1),室溫,45分鐘。
2-胺基-N-(4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯基)乙醯胺[58]. 向10(19mg,0.047mmol)於THF(1.5mL)中之溶液中添加Boc-甘胺酸(9.1mg,0.052mmol)及DCC(10.7mg,0.052mmol)。在室溫下攪拌隔夜後,蒸發THF且添加1mL CH2Cl2:TFA(4:1)。攪拌溶液45分鐘,隨後在減壓下濃縮至乾,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化,得到13.5mg(62%)58。1H NMR(500MHz,CDCl3):δ 9.34(br s,1H),8.24(s,1H),7.47(d,J=8.6Hz,2H),7.24-7.30(m,3H),7.15-7.21(m,4H),5.35(s,2H),3.81-3.89(m,4H),3.46(s,2H),2.42-2.48(m,4H),2.34(s,3H);13C NMR(125MHz,CDCl3):δ 170.6,168.4,163.9,161.3,136.6,135.9,132.2,129.1,128.3,127.7,127.4,119.9,101.0,67.7,54.8,46.2,45.1,43.9;HRMS(ESI)m/z[M+H]+ C24H29N6O2S之計算值,465.2073;實驗值465.2076。
流程7. 合成62-63.
試劑及條件:a. Zn,AcOH,CH2Cl2,室溫,2小時;b.亞硫酸氫鈉,二噁烷,室溫,1小時。
2-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-5-甲氧基苯胺[62]. 在室溫下攪拌40(50mg,0.123mmol)、AcOH(50μL)及Zn粉於CH2Cl2(2mL)中之混合物2小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,9:1)純化,得到44mg(82%)62。1H NMR(500MHz,CDCl3):δ 8.04(s,1H),7.45(m,4H),7.32(m,1H),7.30(m,1H),6.22(m,1H),6.17(m,1H),5.36(s,2H),3.87(m,4H),3.73(s,3H),2.65(m,4H),2.42(s,3H);13C NMR(125MHz,CDCl3):δ 167.2,161.7,160.5,160.3,149.8,137.9,136.4,128.5,128.1,128.0,108.2,105.0,104.8,100.3,68.1,55.2,53.7,44.7,42.6;HRMS(ESI)m/z[M+H]+ C23H28N5O2S之計算值,438.1964;實驗值438.1963。
5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-甲氧基吡啶-3-胺[63]. 向14(10mg,0.021mmol)於2mL無水二噁烷中之溶液中添加12mg(0.064mmol)亞硫酸氫鈉。在室溫下攪拌所得混合物1小時。隨後在減壓下濃縮反應物且藉由製備型TLC(CH2Cl2:MeOH-
NH3(7N),15:1)純化殘餘物,得到5.8mg(62%)63。1H NMR(500MHz,CDCl3)δ 8.14(s,1H),7.19-7.27(m,7H),6.74(s,1H),6.37(s,1H),5.29(s,2H),4.01(s,2H),3.75-3.77(m,4H),3.28(s,3H),2.37-2.39(m,4H),2.26(s,3H);HRMS(ESI)m/z[M+H]+ C22H27N6O2S之計算值,439.1916;實驗值439.1909。
流程8. 合成64及65.
試劑及條件:a. 2-溴丙酸甲酯,K2CO3,CH3CN,80℃,1小時;b. MeOH-NH3(7N),室溫,12小時。
2-(4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯氧基)丙酸甲酯[64]. 在80℃下加熱37(50mg,0.123mmol)、2-溴丙酸甲酯(102mg 0.613mmol)及K2CO3於乙腈(1mL)中之混合物1小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH,20:1)純化,得到42mg(69%)64。1H NMR(500MHz,CDCl3):δ 8.21(s,1H),7.27(m,3H),7.18(m,2H),7.16(d,J=8.6Hz,2H),6.73(d,J=8.6Hz,2H),5.36(s,2H),4.70(q,J=6.5Hz,1H),3.83(m,4H),3.73(s,3H),2.44(m,4H),2.34(s,3H),1.60(d,J=6.2Hz,3H);13C NMR(125MHz,CDCl3):δ 172.5,168.2,163.5,161.2,156.4,136.6,130.8,128.9,128.3,127.7,127.5,115.7,101.9,72.8,67.7,54.8,52.4,46.2,43.8,18.6;HRMS(ESI)m/z[M+H]+ C26H31N4O4S之計算值,495.2066;實驗值495.2062。
2-(4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯氧基)丙醯胺[65]. 在室溫下攪拌64(30mg,0.061mmol)於3mL MeOH-NH3
(7N)中之溶液12小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH,10:1)純化,得到26mg(89%)65。1H NMR(500MHz,CDCl3):δ 8.22(s,1H),7.25-7.30(m,3H),7.15-7.23(m,4H),6.76(d,J=8.8Hz,2H),6.32(br s,1H),5.39(br s,1H),5.36(s,2H),4.60(q,J=6.8Hz,1H),3.80-3.87(m,4H),2.43-2.48(m,4H),2.34(s,3H),1.57(d,J=6.8Hz,3H);13C NMR(125MHz,CDCl3):δ 174.6,168.2,163.6,161.3,155.6,136.6,130.7,129.7,128.3,127.8,127.4,116.0,103.5,75.0,67.7,54.8,46.2,43.8,18.6;HRMS(ESI)m/z [M+H]+ C25H30N5O3S之計算值,480.2069;實驗值480.2075。
流程9. 合成66-68、70、72、73、74、77-80.
試劑及條件:a. KOH,t-BuOH,80℃,1小時。
合成66-80之通用程序. 在80℃下加熱腈(1當量)及KOH(25當量)於t-BuOH中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC純化殘餘物,得到所要產物。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[66]. 遵循以上通用程序獲得66,產率為83%。1H NMR(500MHz,CDCl3):δ 8.26(s,1H),7.63(d,J=8.4Hz,2H),7.22-7.26(m,3H),7.11-7.15(m,4H),5.94(br s,1H),5.56(br s,1H),5.36(s,2H),3.85-
3.92(m,4H),2.44-2.50(m,4H),2.36(s,3H);HRMS(ESI)m/z[M+H]+ C23H26N5O2S之計算值,436.1807;實驗值436.1801。
3-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[67]. 遵循以上通用程序獲得67,產率為78%。1H NMR(500MHz,CDCl3):δ 8.19(s,1H),7.50(s,1H),7.48(t,J=5.5Hz,1H),7.15-7.18(m,1H),7.06(d,J=7.3Hz,1H),7.05(d,J=5.8Hz,1H),6.01(br s,2H),5.27(s,2H),3.77-3.79(m,4H),2.37-2.39(m,4H),2.26(s,3H);13C NMR(125MHz,CDCl3):δ 169.0,168.5,164.5,161.5,138.8,136.4,134.1,130.7,129.0,128.4,127.9,127.4,126.1,124.7,99.1,67.8,54.7,46.1,43.8;MS(m/z):436.2[M+H]+。
5-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氟苯甲醯胺[68]. 遵循以上通用程序獲得68,產率為76%。1H NMR(500MHz,CDCl3):δ 8.19(s,1H),7.87(dd,J=7.2,2.6Hz,1H),7.13-7.22(m,4H),7.08-7.12(m,2H),6.87(dd,J=11.4,8.7Hz,1H),6.51(br s,1H),5.92(br s,1H),5.28(s,2H),3.78(m,4H),2.38(m,4H),2.27(s,3H);13C NMR(125MHz,CDCl3):δ 168.4,164.3,164.2,161.5,159.3(d,J=246Hz),136.4,134.5(d,J=2.5Hz),133.0(d,J=9.1Hz),131.2,128.3,127.8,127.5,120.5(d,J=12.5Hz),116.5(d,J=26.3
Hz),99.5,67.8,54.8,46.2,43.9.MS(m/z):454.0[M+H]+。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[70]. 遵循以上通用程序獲得70,產率為70%。1H NMR(500MHz,CDCl3):δ 8.18(s,1H),7.36-7.39(m,1H),7.31(d,J=8.1Hz,1H),7.17-7.23(m,3H),7.11-7.15(m,1H),7.06-7.10(m,2H),6.02(br s,1H),5.71(br s,1H),5.28(s,2H),3.81(m,4H),2.39(m,4H),2.27(s,3H);MS(m/z):503.9[M+H]+。
6-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)菸鹼醯胺[72]. 遵循以上通用程序獲得72,產率為84%。1H NMR(500MHz,CDCl3):δ 8.64(s,1H),8.19(s,1H),7.80(dd,J=8.4,2.0Hz,1H),7.16-7.20(m,3H),7.10-7.15(m,2H),6.88(d,J=8.4Hz,1H),5.65(br s,2H),5.31(s,2H),3.83(m,4H),2.42(m,4H),2.30(s,3H);MS(m/z):437.0[M+H]+。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-3-甲基苯甲醯胺[73]. 遵循以上通用程序獲得73,產率為88%。1H NMR(500
MHz,CDCl3)δ 8.23(s,1H),7.58(s,1H),7.38(dd,J=8.2,1.4Hz,1H),7.21-7.28(m,3H),7.12-7.18(m,2H),6.79(d,J=8.2Hz,1H),5.94(br s,1H),5.61(br s,1H),5.36(s,2H),3.80-4.00(m,4H),2.45-2.51(m,4H),2.44(s,3H),2.35(s,3H);MS(m/z):[M+H]+ 450.2。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-甲基苯甲醯胺[74]. 遵循以上通用程序獲得74,產率為81%。1H NMR(500MHz,CDCl3)δ 8.25(s,1H),7.20-7.30(m,5H),7.16(d,J=6.7Hz,2H),6.97(s,1H),6.92(d,J=8.1Hz,1H),5.65(br s,2H),5.37(s,2H),3.87(m,4H),2.48(m,4H),2.41(s,3H),2.35(s,3H);MS(m/z):[M+H]+ 450.0。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-溴苯甲醯胺[77]. 遵循以上通用程序獲得77,產率為49%。1H NMR(600MHz,CD2Cl2/MeOH-d 4 ):δ 8.17(s,1H),7.32(d,J=8.2Hz,1H),7.17-7.24(m,4H),7.10-7.14(m,2H),7.01(dd,J=8.1,1.8Hz,1H),5.29(s,2H),3.55-4.15(m,4H),2.20-2.75(m,7H);HRMS(ESI)m/z[M+H]+ C23H24BrN5O2S之計算值,514.0912;實驗值514.0902。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氯苯甲醯胺[78]. 遵循以上通用程序獲得78,產率為56%。1H NMR(500MHz,CD2Cl2/MeOH-d 4 ):δ 8.16(s,1H),7.41(d,J=8.2Hz,1H),7.15-7.25(m,3H),7.09-7.14(m,2H),7.02(s,1H),6.97(d,J=8.2Hz,1H),5.26(s,2H),3.77-3.88(m,4H),2.40-2.53(m,4H),2.29(s,3H);13C NMR(125MHz,CD2Cl2/MeOH-d 4 ):δ 169.2,169.1,165.2,162.0,143.7,136.8,131.8,131.4,130.5,128.8,128.3,127.8,127.5,125.0,98.1,68.5,54.8,45.7,43.7;HRMS(ESI)m/z[M+H]+ C23H24ClN5O2S之計算值,470.1417;實驗值470.1422。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氟苯甲醯胺[79]. 遵循以上通用程序獲得79,產率為53%。1H NMR(500MHz,CDCl3)δ 8.25(s,1H),7.94-7.97(m,1H),7.26-7.27(m,3H),7.17(m,2H),6.96(d,J=8.3Hz,1H),6.77(d,J=12.6Hz,1H),6.57(bs,1H),5.89(bs,1H),5.38(s,2H),3.92(m,4H),2.52(m,4H),2.39(s,3H);13C NMR(125MHz,CDCl3)δ 168.8,165.3,164.6,161.9,146.9,136.4,132.6,128.6,128.2,127.7,122.2,116.6,113.2,112.9,97.3,68.1,54.9,46.3,44.0;HRMS(ESI)m/z[M+H]+ C23H25FN5O2S之計算值454.1713;實驗值454.1713。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-碘苯甲醯胺[80]. 遵循以上通用程序獲得80,產率為52%。1H NMR(500MHz,CDCl3)δ 8.20(s,1H),7.57(s,1H),7.21-7.26(m,4H),7.13(d,J=7.4Hz,2H),7.03(d,J=8.0Hz,1H),5.70(br s,2H),5.31(s,2H),3.91(m,4H),2.55(m,4H),2.37(s,3H);HRMS(ESI)m/z[M+H]+ C23H25IN5O2S之計算值562.0774;實驗值562.0787。
流程10. 合成83-84.
試劑及條件:a. LiOH,THF,H2O,室溫,1.5小時;b.乙二醯氯,CH2Cl2,室溫,5小時;c.胺,CH2Cl2,室溫,2小時。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲酸[81]. 在室溫下攪拌49(100mg,0.222mmol)及LiOH(27mg,1.11mmol)於3mL THF:H2O(2:1)中之混合物1.5小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,9:1)純化,得到
93mg(96%)81。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.18(s,1H),7.76(d,J=8.5Hz,2H),7.10-7.15(m,3H),6.95-7.02(m,4H),5.23(s,2H),3.40(m,4H),2.81(m,4H),2.18(s,3H);HRMS(ESI)m/z[M+H]+ C23H25N4O3S之計算值,437.1647;實驗值437.1654。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯氯[82]. 向81(90mg,0.206mmol)於CH2Cl2中之混合物中添加乙二醯氯(35μL,0.412mmol)且在室溫下攪拌反應混合物5小時。在減壓下濃縮反應混合物且乾燥,得到定量產率之82,其不經進一步純化即使用。
合成83-84之通用程序. 向82(1當量)於CH2Cl2(1mL)中之溶液中添加胺(3當量)且在室溫下攪拌2小時。在減壓下移除溶劑且藉由製備型TLC純化所得殘餘物。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-N-甲基苯甲醯胺[83]. 遵循以上通用程序獲得83,產率為93%。1H NMR(500MHz,CDCl3):δ 8.29(s,1H),7.61(d,J=8.5Hz,2H),7.24-7.28(m,3H),7.12-7.17(m,4H),6.14(br s,1H),5.37(s,2H),3.97(m,4H),3.02(d,J=4.8Hz,3H),2.61(m,4H),2.45(s,3H);13C NMR(125MHz,CDCl3):δ 168.7,167.6,164.8,161.5,142.5,136.3,131.4,128.4,127.8,127.4,127.2,126.3,98.8,67.9,54.4,45.6,43.3,26.8;MS(m/z):450.2[M+H]+。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-N,N-二甲基苯甲醯胺[84]. 遵循以上通用程序獲得84,產率為88%。1H NMR(500MHz,CDCl3):δ 7.27(s,1H),7.25-7.30(m,7H),7.13(d,J=6.9Hz,2H),5.38(s,2H),3.84-3.93(m,4H),3.01(s,3H),2.88(s,3H),2.47-2.49(m,4H),2.36(s,3H);13C NMR(125MHz,CDCl3):δ 171.2,168.6,164.8,161.5,140.2,136.4,133.1,129.8,128.3,127.7,127.4,
126.3,98.6,67.8,61.3,54.8,46.2,43.8;MS(m/z):464.0[M+H]+。
流程11. 合成92及93.
試劑及條件:a. t-BuOH,吡咯啶,福馬林,室溫1小時,隨後回流2小時;b. t-BuOH,哌啶,福馬林,室溫1小時,隨後回流2小時。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-N-(吡咯啶-1-基甲基)苯甲醯胺[92]. 向66(20mg,0.046mmol)於t-BuOH(2mL)中之溶液中添加吡咯啶(8.3μL,0.10mmol)及福馬林(10μL,0.134mmol)。在室溫下攪拌反應混合物1小時,隨後回流2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3,20:1)純化殘餘物,得到8.6mg(36%)92。1H NMR(500MHz,CDCl3)δ 8.26(s,1H),7.60(d,J=8.4Hz,2H),7.23-7.24(m,3H),7.11-7.14(m,4H),6.55(br s,1H),5.35(s,2H),4.38(d,J=6.0Hz,2H),3.86-3.87(m,4H),2.69-2.71(m,4H),2.45-2.47(m,4H),2.35(s,3H),1.79-1.80(m,4H);13C NMR(125MHz,CDCl3)δ 168.6,167.0,164.9,161.6,143.1,136.4,131.0,128.5,127.4,127.2,126.3,126.0,98.1,67.8,58.8,54.8,51.0,46.2,43.9,23.7;HRMS(ESI)m/z[M+H]+ C28H35N6O2S之計算值519.2542;實驗值519.2549。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-N-(哌啶-1-基甲基)苯甲醯胺[93]. 向66(20mg,0.046mmol)於t-BuOH(2mL)中之溶液中添加哌啶(10μL,0.10mmol)及福馬林(10μL,0.134mmol)。在室溫下攪拌反應混合物1小時,隨後回流2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3,20:1)純化殘餘物,得到9.1mg(37%)93。1H NMR(500MHz,CDCl3)δ 8.23(s,1H),7.61(d,J=8.4Hz,2H),7.22-7.24(m,3H),7.11-7.13(m,4H),6.52(br s,1H),5.36(s,2H),4.25(d,J=6.2Hz,2H),3.86-3.88(m,4H),2.56-2.58(m,4H),2.45-2.47(m,4H),2.35(s,3H),1.57-1.62(m,4H),1.44-1.45(m,2H);13C NMR(125MHz,CDCl3)δ 168.6,167.2,164.9,161.6,143.1,136.4,130.9,128.4,127.4,127.2,126.3,126.0,98.1,67.6,62.5,54.8,51.5,46.2,43.9,25.8,24.1;HRMS(ESI)m/z[M+H]+ C29H37N6O2S之計算值533.2699;實驗值533.2686。
流程12. 合成99a-j、m-o及q-x及100a-j、m-o及q-x.
試劑及條件:a. 4-巰基苯甲腈,噻吩-2-甲酸銅(I),K2CO3,
DMF,120℃,20小時;b. KOH,t-BuOH,80℃,1小時;c. TFA,CH2Cl2,室溫,12小時;d. POCl3,75℃,1小時;e. ROH,NaH,CH3CN,室溫,3小時。
4-(4-(4-甲氧基苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基硫基)苯甲腈[95]. 將94(1.0g,2.27mmol)及K2CO3(0.628g,4.54mmol)於DMF(32mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.173g,0.908mmol),抽空且用氬氣回填。添加4-巰基苯甲腈(0.496g,2.72mmol)且在120℃下加熱反應混合物20小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,200:1至40:1)純化殘餘物,得到0.867g(85%)95。1H NMR(500MHz,CDCl3):δ 8.22(s,1H),7.39(d,J=8.3Hz,2H),7.03-7.11(m,4H),6.78(d,J=8.6Hz,2H),5.30(s,2H),3.90(m,4H),3.79(s,3H),2.49(m,4H),2.36(s,3H);13C NMR(125MHz,CDCl3):δ 168.6,165.0,161.8,159.5,145.7,132.1,129.4,128.2,126.1,119.0,113.7,108.1,96.9,67.7,55.3,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C24H26N5O2S之計算值,448.1807;實驗值448.1823。
4-((4-((4-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[96]. 在80℃下加熱95(11.2mg,0.025mmol)及KOH(20mg,0.357mmol)於t-BuOH(500μL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到9.8mg(84%)96。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.19(s,1H),7.56(d,J=8.5Hz,2H),6.97-7.06(m,4H),6.72(d,J=8.6Hz,2H),5.24(s,2H),3.80-3.88(m,4H),3.73(s,3H),2.41-2.49(m,4H),2.32(s,3H);13C NMR(125MHz,CDCl3):δ 169.5,168.8,164.9,161.7,159.5,143.7,130.0,129.5,128.5,127.9,126.2,113.9,98.5,67.8,55.4,54.9,46.2,43.9;HRMS(ESI)m/z[M+H]+ C24H28N5O3S之計算值,
466.1913;實驗值466.1924。
4-((4-羥基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[97]. 向95(0.800g,1.79mmol)於CH2Cl2(4mL)中之溶液中經5分鐘逐滴添加TFA(4mL)且在室溫下攪拌12小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,10:1至7:1)純化,得到0.546g(93%)97。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.10(s,1H),7.49(d,J=8.5Hz,2H),7.22(d,J=8.5Hz,2H),3.68-3.79(m,4H),2.42-2.51(m,4H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 155.5,145.8,132.3,131.2,129.0,126.0,119.0,108.1,101.7,54.3,45.8,44.4;HRMS(ESI)m/z[M+H]+ C16H18N5OS之計算值,328.1232;實驗值328.1234。
4-((4-氯-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[98]. 在75℃下加熱97(0.419g,1.28mmol)及POCl3(2mL)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×50mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(CH2Cl2:MeOH,50:1至40:1)純化,得到0.426g(86%)98。1H NMR(500MHz,CDCl3):δ 8.38(s,1H),7.51(d,J=8.5Hz,2H),7.13(d,J=8.4Hz,2H),3.85-3.94(m,4H),2.43-2.51(m,4H),2.36(s,3H);MS(m/z):[M+H]+ 346.0/348.0。
合成99a-j、m-o及q-x之通用程序. 向溶解於CH3CN中之醇(4.25當量)中添加NaH(4當量)且在室溫下攪拌所得懸浮液10分鐘。隨後添加98(1當量)且在室溫下攪拌反應混合物3小時。在減壓下移除溶劑,且藉由管柱層析純化殘餘物,得到所要產物。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99a]. 遵循以上通用程序獲得99a,其混雜有未反應之醇。MS(m/z):[M+H]+ 461.2。
4-((2-(4-甲基哌嗪-1-基)-4-((3-(吡咯啶-1-基)苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[99b]. 遵循以上通用程序獲得99b,產率為89%。1H NMR(500MHz,CDCl3):δ 8.20(s,1H),7.36(d,J=8.4Hz,2H),7.08(t,J=7.8Hz,1H),7.05(d,J=8.4Hz,2H),6.41-6.46(m,2H),6.35(br s,1H),5.31(s,2H),3.81-3.95(m,4H),3.06-3.13(m,4H),2.43-2.48(m,4H),2.34(s,3H),1.91-2.00(m,4H);MS(m/z):[M+H]+ 487.2。
4-((4-((3-(二甲基胺基)-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99c]. 遵循以上通用程序獲得99c,其混雜有未反應之醇。MS(m/z):[M+H]+ 479.2。
4-((4-(1-(3-(二甲基胺基)苯基)乙氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99d].遵循以上通用程序獲得99d,其混雜有未反應之醇。MS(m/z):[M+H]+ 475.1。
4-((4-((3-(環丙基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99c].遵循以上通用程序獲得99e,其混雜有未反應之醇。MS(m/z):[M+H]+ 473.3。
4-((4-((3-(1H-吡唑-1-基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99f]. 遵循以上通用程序獲得99f,產率為98%。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.77(d,J=2.5Hz,1H),7.73(d,J=1.6Hz,1H),7.58-7.60(m,1H),7.54-7.57(m,1H),7.38(d,J=8.5Hz,2H),7.34(t,J=7.9Hz,1H),7.05-7.12(m,3H),6.49(t,J=2.2Hz,1H),5.41(s,2H),3.84-3.92(m,4H),2.42-2.48(m,4H),2.34(s,3H);MS(m/z):[M+H]+ 484.3。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99g].遵循以上通用程序獲得99g,其混雜有未反應之醇。MS(m/z):[M+H]+ 448.3。
4-((2-(4-甲基哌嗪-1-基)-4-苯乙氧基嘧啶-5-基)硫基)苯甲腈[99h].遵循以上通用程序獲得99h,產率為89%。1H NMR(500MHz,CDCl3):δ 8.14(s,1H),7.33(d,J=8.3Hz,2H),7.06-7.12(m,3H),6.99-7.03(m,2H),6.97(d,J=8.4Hz,2H),4.43(t,J=6.8Hz,2H),3.76-3.84(m,
4H),2.87(t,J=6.8Hz,2H),2.37-2.44(m,4H),2.29(s,3H);MS(m/z):[M+H]+ 432.2。
4-((4-(呋喃-2-基甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99i]. 遵循以上通用程序獲得99i,產率為96%。1H NMR(500MHz,CDCl3):δ 8.16(s,1H),7.33(d,J=8.6Hz,2H),7.26(s,1H),6.97(d,J=8.6Hz,2H),6.21-6.27(m,1H),6.20(d,J=3.1Hz,1H),5.27(s,2H),3.79-3.90(m,4H),2.37-2.46(m,4H),2.30(s,3H);MS(m/z):[M+H]+ 408.2。
4-((4-(呋喃-3-基甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99j]. 遵循以上通用程序獲得99j,產率為76%。1H NMR(500MHz,CDCl3):δ 8.17(s,1H),7.35(d,J=8.6Hz,2H),7.22-7.28(m,2H),7.00(d,J=8.6Hz,2H),6.12(s,1H),5.18(s,2H),3.78-3.88(m,4H),2.37-2.48(m,4H),2.30(s,3H);MS(m/z):[M+H]+ 408.2。
4-((4-((4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99m]. 遵循以上通用程序獲得99m,產率為70%。1H NMR(500MHz,CDCl3):δ 8.17(s,1H),7.35(d,J=8.4Hz,2H),7.04-7.07(m,4H),7.01(d,J=8.4Hz,2H),6.86-6.88(m,2H),5.24(s,2H),3.81-3.85(m,4H),2.40-2.45(m,4H),2.30(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,165.2,161.7,145.6,132.1,129.4,129.3,126.0,118.9,115.4,115.2,108.3,96.8,67.2,54.7,46.1,43.8;MS(m/z):[M+H]+ 436.0。
(S)-4-((4-(1-(4-氟苯基)乙氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99n]. 遵循以上通用程序獲得99n,產率為55%。1H NMR(500MHz,CDCl3):δ 8.14(s,1H),7.37(d,J=8.2Hz,2H),7.02-7.07(m,4H),6.83-6.87(m,2H),6.01-6.02(m,1H),3.73-3.79(m,4H),2.36-2.40(m,4H),2.26(s,3H),1.40(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3):δ 168.0,164.9,161.7,145.8,137.9,132.1,127.4,126.2,118.9,115.3,115.1,108.2,97.0,73.6,54.7,46.2,43.9,22.7;MS
(m/z):[M+H]+ 450.1。
(R)-4-((4-(1-(4-氟苯基)乙氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99o]. 遵循以上通用程序獲得99o,產率為52%。1H NMR(500MHz,CDCl3):δ 8.14(s,1H),7.37(d,J=8.3Hz,2H),7.02-7.05(m,4H),6.83-6.87(m,2H),5.99-6.02(m,1H),3.73-3.79(m,4H),2.36-2.39(m,4H),2.27(s,3H),1.39(d,J=6.5Hz,3H);13C NMR(125MHz,CDCl3):δ 168.0,164.9,161.7,143.8,137.9,132.1,127.5,126.2,118.9,115.3,115.1,108.2,97.0,73.7,54.7,46.2,43.9,22.7;MS(m/z):[M+H]+ 450.1。
4-((4-((3-乙醯基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99q].遵循以上通用程序獲得99q,其混雜有未反應之醇。MS(m/z):[M+H]+ 460.2。
4-((4-((2-胺基吡啶-4-基)甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99r]. 遵循以上通用程序獲得99r,其混雜有未反應之醇。MS(m/z):[M+H]+ 434.2。
4-((4-((3-碘苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99s]. 遵循以上通用程序獲得99s,產率為92%。MS(m/z):[M+H]+ 444.2。
4-((4-(苯甲氧基-d 5 )-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99t].遵循以上通用程序獲得99t,產率為82%。MS(ESI)m/z[M+H]+ 423.4。
4-((4-(苯甲氧基-d 2 )-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99u]. 遵循以上通用程序獲得99u,產率為78%。MS(ESI)m/z [M+H]+ 420.4。
4-((4-((4-碘苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99v]. 遵循以上通用程序獲得99v,產率為72%。MS(ESI)m/z [M+H]+ 544.2。
3-(((5-((4-氰基苯基)硫基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)氧基)甲基)苯甲腈[99w]. 遵循以上通用程序獲得99w,產率為63%。MS(ESI)m/z[M+H]+ 443.2。
4-((4-((3-胺基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[99x]. 遵循以上通用程序獲得99x,產率為96%。1H NMR(500MHz,CDCl3):δ 8.16(s,1H),7.35(d,J=8.5Hz,2H),7.02(d,J=8.5Hz,2H),6.96(t,J=7.8Hz,1H),6.50(dd,J=7.9,2.2Hz,1H),6.47(d,J=7.6Hz,1H),6.33(s,1H),5.20(s,2H),3.82-3.85(m,4H),3.51(br s,2H),2.42-2.45(m,4H),2.30(s,3H);MS(ESI)m/z[M+H]+ 433.1。
合成100a-j、m-o及q-x之通用程序. 在80℃下加熱腈(1當量)及KOH(25當量)於t-BuOH中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC純化殘餘物,得到醯胺。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100a]. 遵循以上通用程序獲得100a,產率為944%。1H NMR(500MHz,CDCl3):δ 8.23(s,1H),7.57(d,J=8.5Hz,2H),7.00-7.12(m,3H),6.46-6.62(m,3H),5.97(br s,1H),5.64(br s,1H),5.32(s,2H),3.82-3.91(m,4H),2.79(m,6H),2.41-2.50(m,
4H),2.34(s,3H);13C NMR(125MHz,CDCl3):δ 168.9,168.7,165.0,161.7,150.6,143.8,137.1,129.7,129.0,127.7,125.7,115.8,112.1,111.7,97.7,68.3,54.8,46.2,43.9,40.5;HRMS(ESI)m/z[M+H]+ C25H31N6O2S之計算值,479.2229;實驗值479.2234。
4-((2-(4-甲基哌嗪-1-基)-4-((3-(吡咯啶-1-基)苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[100b]. 遵循以上通用程序獲得100b,產率為92%。1H NMR(500MHz,CDCl3):δ 8.23(s,1H),7.58(d,J=8.3Hz,2H),7.04-7.10(m,3H),6.45(d,J=7.4Hz,1H),6.41(d,J=8.2Hz,1H),6.39(br s,1H),5.93(br s,1H),5.60(br s,1H),5.31(s,2H),3.84-3.91(m,4H),3.03-3.12(m,4H),2.42-2.49(m,4H),2.34(s,3H),1.87-1.94(m,4H);13C NMR(125MHz,CDCl3):δ 168.9,168.6,165.0,161.8,148.0,143.9,137.2,129.6,129.0,128.0,125.7,114.5,111.2,110.6,97.7,68.4,54.8,47.5,46.2,43.9,25.4;HRMS(ESI)m/z[M+H]+ C27H33N6O2S之計算值,505.2386;實驗值505.2362。
4-((4-((3-(二甲基胺基)-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100c]. 遵循以上通用程序獲得100c,產率為77%。1H NMR(500MHz,CDCl3):δ 8.23(s,1H),7.56(d,J=8.5Hz,2H),7.02(d,J=8.5Hz,2H),6.82-6.88(m,1H),6.71(dd,J=8.6,2.0Hz,1H),6.61-6.67(m,1H),6.10(br s,1H),5.77(br s,1H),5.27(s,2H),3.82-3.92(m,4H),2.67(s,6H),2.42-2.50(m,4H),2.34(s,3H);13C NMR(125MHz,CDCl3):δ 168.8,168.7,165.1,161.7,154.6(d,J=245Hz),143.6,140.5(d,J=9.0Hz),132.4(d,J=3.6Hz),129.9,127.7,125.6,120.3(d,J=8.4Hz),117.8(d,J=3.7Hz),115.9(d,J=21.5Hz),97.7,67.5,54.8,46.2,43.9,42.6(d,J=3.8Hz);HRMS(ESI)m/z[M+H]+ C25H30FN6O2S之計算值,497.2135;實驗值497.2152。
4-((4-(1-(3-(二甲基胺基)苯基)乙氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100d]. 遵循以上通用程序獲得100d,產率為85%。1H NMR(600MHz,CDCl3):δ 8.20(s,1H),7.59(d,J=8.4Hz,2H),7.05-7.11(m,3H),6.54-6.58(m,2H),6.48(d,J=7.4Hz,1H),6.05(q,J=6.5Hz,1H),6.04(br s,1H),5.72(br s,1H),3.75-3.87(m,4H),2.81(s,6H),2.38-2.47(m,4H),2.32(s,3H),1.48(d,J=6.5Hz,3H);13C NMR(150MHz,CDCl3):δ 168.8,168.4,164.8,161.7,150.5,144.0,143.2,130.0,129.0,128.0,126.0,114.2,111.8,110.0,98.1,74.8,
54.8,46.2,43.8,40.5,22.9;HRMS(ESI)m/z[M+H]+ C26H33N6O2S之計算值,493.2386;實驗值493.2394。
4-((4-((3-(環丙基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100e]. 遵循以上通用程序獲得100e,產率為75%。1H NMR(600MHz,CDCl3):δ 8.23(s,1H),7.59(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),7.04(t,J=7.8Hz,1H),6.66(dd,J=8.0,1.7Hz,1H),6.52(d,J=7.5Hz,1H),6.46(s,1H),6.00(br s,1H),5.60(br s,1H),5.27(s,2H),4.06(br s,1H),3.80-3.93(m,4H),2.43-2.50(m,4H),2.34(s,3H),2.25-2.30(m,1H),0.62-0.67(m,2H),0.41-0.45(m,2H);13C NMR(150MHz,CDCl3):δ 168.75,168.72,164.9,161.7,148.8,143.8,137.3,129.8,129.0,127.7,126.0,116.8,112.5,112.2,97.9,68.0,54.8,46.2,43.8,25.2,7.4;HRMS(ESI)m/z[M+H]+ C26H31N6O2S之計算值,491.2229;實驗值491.2243。
4-((4-((3-(1H-吡唑-1-基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100f]. 遵循以上通用程序獲得100f,產率為70%。1H NMR(500MHz,CDCl3):δ 8.27(s,1H),7.73(d,J=2.5Hz,1H),7.70(d,J=1.7Hz,1H),7.53-7.59(m,4H),7.32(t,J=7.8Hz,1H),7.10(t,J=8.4Hz,2H),7.06(t,J=7.7Hz,1H),6.45(t,J=2.2Hz,1H),6.07(br s,1H),5.65(br s,1H),5.41(s,2H),3.84-3.93(m,4H),2.43-2.50(m,4H),2.34(s,3H);13C NMR(125MHz,CDCl3):δ 168.7,168.5,165.0,161.6,143.4,141.2,140.2,138.0,130.0,129.5,127.8,126.9,125.9,125.4,118.7,118.3,107.8,97.9,67.3,54.7,46.1,43.9;HRMS(ESI)m/z[M+H]+ C26H28N7O2S之計算值,502.2025;實驗值502.2022。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100g]. 遵循以上通用程序獲得100g,產率為60%。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.61(d,J=8.3Hz,2H),7.16(t,J=7.8Hz,1H),7.10(d,J=8.2Hz,2H),6.78(d,J=8.2Hz,1H),6.75(d,J=7.5Hz,1H),6.67(s,1H),6.06(br s,1H),5.65(br s,1H),5.33(s,2H),3.86-3.92(m,4H),3.68(s,3H),2.46-2.51(m,4H),2.36(s,3H);13C NMR(150MHz,CDCl3):δ 168.8,168.6,165.0,161.7,160.0,143.6,137.9,129.9,129.4,127.8,125.9,119.8,113.3,113.2,97.9,67.7,
55.2,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C24H28N5O3S之計算值,466.1913;實驗值466.1904。
4-((2-(4-甲基哌嗪-1-基)-4-苯乙氧基嘧啶-5-基)硫基)苯甲醯胺[100h]. 遵循以上通用程序獲得100h,產率為99%。1H NMR(500MHz,CDCl3):δ 8.22(s,1H),7.60(d,J=8.7Hz,2H),7.11-7.17(m,3H),7.02-7.10(m,4H),5.95(br s,1H),5.72(br s,1H),4.47(t,J=7.0Hz,2H),3.80-3.89(m,4H),2.91(t,J=7.0Hz,2H),2.40-2.50(m,4H),2.34(s,3H);13C NMR(125MHz,CDCl3):δ 169.2,168.9,165.2,162.0,144.0,138.1,130.0,129.2,128.6,127.9,126.6,125.8,97.7,67.4,55.0,46.4,44.0,35.3;HRMS(ESI)m/z[M+H]+ C24H28N5O2S之計算值,450.1964;實驗值450.1951。
4-((4-(呋喃-2-基甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100i]. 遵循以上通用程序獲得100i,產率為76%。1H NMR
(500MHz,CDCl3):δ 8.23(s,1H),7.57(d,J=8.4Hz,2H),7.30(s,1H),7.05(d,J=8.4Hz,2H),6.26-6.29(m,1H),6.24(d,J=3.2Hz,1H),5.94(br s,1H),5.62(br s,1H),5.31(s,2H),3.84-3.93(m,4H),2.43-2.52(m,4H),2.35(s,3H);13C NMR(125MHz,CDCl3):δ 168.9,168.7,165.3,161.7,150.0,143.7,143.1,130.0,127.9,126.2,110.6,110.4,98.2,60.1,55.0,46.4,44.1;HRMS(ESI)m/z[M+H]+ C21H24N5O3S之計算值,426.1600;實驗值426.1598。
4-((4-(呋喃-3-基甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100j]. 遵循以上通用程序獲得100j,產率為82%。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.17(s,1H),7.57(d,J=8.5Hz,2H),7.18-7.26(m,2H),7.02(d,J=8.5Hz,2H),6.12(br s,1H),5.17(s,2H),3.78-3.87(m,4H),2.42-2.49(m,4H),2.31(s,3H);13C NMR(125MHz,CDCl3):δ 169.8,168.7,164.9,161.6,143.5,143.3,141.1,129.9,127.9,126.0,120.7,110.3,98.4,60.0,54.8,46.0,43.7;HRMS(ESI)m/z[M+H]+ C21H24N5O3S之計算值,426.1600;實驗值426.1596。
4-((4-((4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100m]. 遵循以上通用程序獲得100m,產率為85%。1H NMR(500MHz,CDCl3):δ 8.19(s,1H),7.55(d,J=8.4Hz,2H),7.01-7.05(m,4H),6.80-6.88(m,2H),5.92(br s,1H),5.70(br s,1H),5.24(s,2H),3.80-3.85(m,4H),2.40-2.43(m,4H),2.29(s,3H);13C NMR(125MHz,CDCl3):δ 168.6,168.5,164.9,161.6,143.6,132.1,129.9,129.3,127.7,126.0,115.3,115.2,98.0,67.1,54.8,46.2,43.9;MS(m/z):[M+H]+ 454.1。
(S)-4-((4-(1-(4-氟苯基)乙氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100n]. 遵循以上通用程序獲得100n,產率為83%。1H NMR(600MHz,CDCl3):δ 8.16(s,1H),7.57(d,J=8.5Hz,2H),7.06(d,J=8.5Hz,2H),6.99-7.02(m,2H),6.81-6.85(m,2H),5.98-6.02(m,1H),3.68-3.79(m,4H),2.37-2.39(m,4H),2.27(s,3H),1.39(d,J=6.6Hz,3H);13C NMR(150MHz,CDCl3):δ 168.7,168.0,164.7,161.6,143.8,138.0,129.9,127.7,127.5,126.2,115.2,115.1,98.2,73.6,54.7,46.2,43.8,22.8;MS(m/z):[M+H]+ 468.2。
(R)-4-((4-(1-(4-氟苯基)乙氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100o]. 遵循以上通用程序獲得100o,產率為78%。1H NMR(600MHz,CDCl3):δ 8.16(s,1H),7.57(d,J=8.5Hz,2H),7.06(d,J=8.5Hz,2H),6.99-7.02(m,2H),6.81-6.85(m,2H),5.98-6.02(m,1H),3.72-3.79(m,4H),2.37-2.40(m,4H),2.27(s,3H),1.39(d,J=6.6Hz,3H);13C NMR(150MHz,CDCl3):δ 168.7,168.0,164.7,161.5,143.8,138.0,129.9,127.7,127.4,126.2,115.2,115.0,98.3,73.6,54.7,46.2,43.8,22.8;MS(m/z):[M+H]+ 468.2。
4-((4-((3-乙醯基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100q]. 遵循以上通用程序獲得100q,產率為55%。1H NMR(600MHz,CDCl3):δ 8.28(s,1H),7.81-7.83(m,1H),7.78(s,1H),7.63-7.67(m,2H),7.37(d,J=5.0Hz,2H),7.09-7.13(m,2H),6.43(br s,1H),5.54(br s,1H),5.39(s,2H),3.89(m,4H),2.54(s,3H),
2.51(m,4H),2.38(s,3H);HRMS(ESI)m/z[M+H]+ C25H27N5O3S之計算值,478.1913;實驗值478.1911。
4-((4-((2-胺基吡啶-4-基)甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100r]. 遵循以上通用程序獲得100r,產率為48%。1H NMR(600MHz,CDCl3/MeOH-d 4 ):δ 8.29(s,1H),7.89(d,J=5.3Hz,1H),7.67(d,J=8.3Hz,2H),7.17(d,J=8.5Hz,2H),6.42(d,J=5.2,1H),5.94(s,1H),5.23(s,2H),3.86(m,4H),2.48(m,4H),2.36(s,3H);13C NMR(150MHz,CDCl3/MeOH-d 4 ):δ 169.3,168.2,164.9,161.7,158.7,147.8,147.6,143.6,130.4,127.9,126.5,112.1,98.2,66.2,54.9,46.3,43.9;HRMS(ESI)m/z[M+H]+ C22H26N7O2S之計算值,452.1869;實驗值452.1860。
4-((4-((3-碘苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100s]. 遵循以上通用程序獲得100s,產率為35%。1H NMR(500MHz,CDCl3)δ 8.27(s,1H),7.66(d,J=8.3Hz,2H),7.57(d,J=7.8Hz,1H),7.52(s,1H),7.13(d,J=8.3Hz,2H),7.08(d,J=7.6Hz,
1H),6.98(t,J=7.8Hz,1H),6.02(br s,1H),5.67(br s,1H),5.28(s,2H),3.86-3.88(m,4H),2.47-2.49(m,4H),2.36(s,3H);13C NMR(150MHz,CDCl3)δ 168.7,168.3,165.0,161.6,143.4,138.7,136.9,136.3,130.1,130.0,127.9,126.6,125.9,97.8,94.2,66.8,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C23H25IN5O2S之計算值562.0774;實驗值562.0758。
4-((4-(苯甲氧基-d 5 )-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100t]. 遵循以上通用程序獲得100t,產率為67%。1H NMR(600MHz,CDCl3)δ 8.26(s,1H),7.62(d,J=8.4Hz,1H),7.12(d,J=8.4Hz,2H),6.02(br s,1H),5.73(br s,1H),5.36(s,2H),3.87-3.89(m,4H),2.46-2.48(m,4H),2.35(s,3H);13C NMR(150MHz,CDCl3)δ 168.7,168.6,164.9,161.6,143.7,136.2,129.8,127.8,127.7,127.3,127.0,126.0,97.9,67.7,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C23H21D5N5O2S之計算值441.2121;實驗值441.2122。
4-((4-(苯甲氧基-d 2 )-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100u]. 遵循以上通用程序獲得100u,產率為77%。1H NMR(600MHz,CDCl3)δ 8.26(s,1H),7.62(d,J=8.3Hz,2H),7.24-7.25(m,3H),7.11-7.14(m,4H),6.03(br s,1H),5.76(br s,1H),3.86-3.88(m,4H),2.46-2.48(m,4H),2.35(s,3H);13C NMR(150MHz,CDCl3)δ 168.7,168.6,164.9,161.6,143.7,136.2,129.8,128.3,127.9,127.7,127.5,126.0,97.9,67.6,54.8,46.2,43.9;HRMS(ESI)m/z[M+H]+ C23H24D2N5O2S之計算值438.1933;實驗值438.1928。
4-((4-((4-碘苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100v]. 遵循以上通用程序獲得100v,產率為68%。1H NMR(600MHz,CDCl3/MeOD-d 4)δ 8.24(s,1H),7.63(d,J=8.4Hz,2H),7.54(d,J=8.2Hz,2H),7.08(d,J=8.4Hz,2H),6.84(d,J=8.2Hz,2H),5.26(s,2H),3.87(s,4H),2.51(s,4H),2.20(s,3H);13C NMR(150MHz,CDCl3/MeOD-d 4)δ 169.2,168.4,164.9,161.4,143.4,137.4,136.0,129.9,129.2,127.8,126.0,93.4,67.2,54.5,45.9,43.5;HRMS(ESI)m/z[M+H]+ C23H25IN5O2S之計算值562.0774;實驗值562.0797。
3-(((5-((4-胺甲醯基苯基)硫基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)氧基)甲基)苯甲醯胺[100w]. 遵循以上通用程序獲得100w,產率為53%。1H NMR(600MHz,CDCl3/MeOH-d 4 )δ 8.24(s,1H),7.63-7.69(m,4H),7.25-7.29(m,2H),7.05(d,J=8.5Hz,2H),5.36(s,2H),3.96(m,4H),2.79(m,4H),2.55(s,3H);HRMS(ESI)m/z[M+H]+ C24H27N6O3S之計算值479.1865;實驗值479.1855。
4-((4-((3-胺基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[100x]. 遵循以上通用程序獲得100x,產率為64%。1H NMR(600MHz,CDCl3/MeOD-d 4)δ 8.25(s,1H),7.63(d,J=8.5Hz,2H),7.10(d,J=8.5Hz,2H),7.01(t,J=7.7Hz,1H),6.53-6.57(m,2H),6.22(s,1H),5.24(s,2H),3.91(m,4H),2.55(m,4H),2.39(s,3H);13C NMR(150MHz,CDCl3/MeOD-d 4)δ 169.6,168.7,164.7,161.6,146.5,143.5,137.5,130.2,129.3,127.9,126.3,118.0,115.0,114.2,98.6,68.0,54.7,45.9,43.6;HRMS(ESI)m/z[M+H]+ C23H27N6O2S之計算值451.1916;實驗值451.1908。
流程13. 合成101.
試劑及條件:a. NaNO2,NaN3,p-TsOH,CH3CN,H2O,室溫,4小時。
4-((4-((3-疊氮基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[101]. 向100x(20mg,0.044mmol)及p-TsOH(22mg,0.131mmol)於CH3CN(1mL)及H2O(2滴)中之溶液中添加NaNO2(8mg,0.118mmol)及NaN3(15mg,0.231)且在室溫下攪拌4小時。在減壓下濃縮反應混合物至乾,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化,得到5.5mg(26%)101。1H NMR(600MHz,CDCl3)δ 8.29(s,1H),7.65(d,J=8.5Hz,2H),7.24(t,J=7.9Hz,1H),7.12(d,J=8.6Hz,2H),6.91-6.94(m,2H),6.80(s,1H),6.04(br s,1H),5.64(br s,1H),5.24(s,2H),4.00(m,4H),2.70(m,4H),2.49(s,3H);13C NMR(150MHz,CDCl3)δ 168.8,168.7,165.2,161.6,143.4,140.4,138.5,130.3,130.0,128.1,126.2,124.0,118.7,118.1,98.9,67.5,54.6,53.7,43.3;HRMS(ESI)m/z[M+H]+ C23H25N8O2S之計算值477.1821;實驗值477.1811。
流程14. 合成102.
試劑及條件:a.苯甲胺,CH3CN,80℃,2小時;b. KOH,t-BuOH,80℃,1小時。
4-((4-(苯甲基胺基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[102]. 在80℃下加熱98(20mg,0.058mmol)及苯甲胺(18.6mg,0.174mmol)於乙腈(500μL)中之混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到殘餘物。向其中添加t-BuOH(650μL)及KOH(81mg,1.45mmol)且在80℃下加熱混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到16.4mg(65%)102。1H NMR(600MHz,CDCl3):δ 8.03(s,1H),7.59(d,J=8.5Hz,2H),7.14-7.21(m,3H),7.04-7.09(m,4H),5.93(br s,1H),5.83(t,J=5.8Hz,1H),5.53(br s,1H),4.53(d,J=5.8Hz,2H),3.74-3.83(m,4H),2.33-2.42(m,4H),2.28(s,3H);13C NMR(150MHz,CDCl3):δ 168.5,163.5,162.0,161.8,142.8,138.8,130.2,128.6,128.0,127.30,127.29,125.3,93.8,54.9,46.2,44.5,43.7;MS(m/z):[M+H]+ 435.0。
流程16. 合成108-118及121-126.
試劑及條件:a. 2-氯-4-巰基苯甲腈,噻吩-2-甲酸銅(I),K2CO3,DMF,120℃,17小時;b. TFA,CH2Cl2,室溫,12小時;c. POCl3,75℃,1小時;d. ROH,NaH,CH3CN,室溫,3小時;e. KOH,t-BuOH,80℃,1小時。
2-氯-4-((4-((4-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[105]. 將94(0.920g,2.09mmol)及K2CO3(0.866g,6.27mmol)於DMF(27mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.159g,0.832mmol)且用氬氣回填兩次。添加2-氯-4-巰基苯甲腈(0.425g,2.51mmol)且在120℃下加熱反應混合物17小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化殘餘物,得到0.504g(50%)105。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.39(d,J=8.3Hz,1H),7.09-7.13(m,2H),7.06(d,J=1.7Hz,1H),6.97(dd,J=8.3,1.8Hz,1H),6.79-6.83(m,2H),5.30(s,2H),3.91-3.96(m,4H),3.80(s,3H),2.51-2.56(m,4H),2.39(s,
3H);13C NMR(150MHz,CDCl3):δ 168.5,165.0,161.8,159.5,147.6,137.0,133.4,129.5,128.0,126.2,124.1,116.2,113.8,108.9,96.0,67.8,55.3,54.7,46.1,43.8;HRMS(ESI)m/z[M+H]+ C24H24ClN5O2S之計算值,482.1417;實驗值482.1406。
2-氯-4-((4-羥基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[106]. 向105(0.500g,1.04mmol)於CH2Cl2(4mL)中之溶液中經5分鐘逐滴添加TFA(4mL)且在室溫下攪拌12小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,0-15% MeOH)純化,得到0.354g(94%)106。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.14(s,1H),7.50(d,J=8.3Hz,1H),7.18(d,J=1.7Hz,1H),7.11(dd,J=8.3,1.7Hz,1H),3.85-4.28(m,4H),3.09-3.27(m,4H),2.82(s,3H);MS(ESI)m/z 362.2/364.3[M+H]+。
2-氯-4-((4-氯-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[107]. 在75℃下加熱106(0.354g,0.978mmol)及POCl3(2mL)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(3×100mL)萃取,經MgSO4乾燥,過濾且濃縮,得到0.337g(91%)107,其不經進一步純化即使用。1H NMR(500MHz,CDCl3):δ 8.38(s,1H),7.51(d,J=8.3Hz,1H),7.13(d,J=1.8Hz,1H),7.02(dd,J=8.3,1.8Hz,1H),3.90-4.00(m,4H),2.47-2.58(m,4H),2.38(s,3H);MS(ESI)m/z 380.1/382.1[M+H]+。
合成108-118及121-126之通用程序. 向溶解於CH3CN中之醇(4.25當量)中添加NaH(4當量)且在室溫下攪拌所得懸浮液10分鐘。隨後添加107(1當量)且在室溫下攪拌反應混合物3小時。在減壓下移除溶劑,且藉由管柱層析純化殘餘物,得到中間物腈。在80℃下加熱腈(1當量)及KOH(25當量)於t-BuOH中之混合物1小時。在減壓下移除溶
劑且藉由製備型TLC純化殘餘物,得到所要醯胺。
2-氯-4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[108]. 遵循以上通用程序獲得108,產率為26%。1H NMR(600MHz,CDCl3):δ 8.25(s,1H),7.65(d,J=8.2Hz,1H),7.20(t,J=7.9Hz,1H),7.08(d,J=1.8Hz,1H),7.00(dd,J=8.3,1.9Hz,1H),6.77-6.82(m,2H),6.66(s,1H),6.52(br s,1H),5.98(br s,1H),5.34(s,2H),3.87-3.93(m,4H),3.72(s,3H),2.47-2.52(m,4H),2.36(s,3H);13C NMR(150MHz,CDCl3):δ 168.5,167.5,164.9,161.7,159.5,143.9,137.8,131.3,131.1,129.8,129.4,127.0,124.5,119.8,113.23,113.20,97.1,67.7,55.2,54.7,46.2,43.8;HRMS(ESI)m/z[M+H]+ C24H26ClN5O3S之計算值,500.1523;實驗值500.1510。
2-氯-4-((4-((2-氟-5-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[109]. 遵循以上通用程序獲得109,產率為
50%。1H NMR(600MHz,CDCl3):δ 8.24(s,1H),7.62(d,J=8.2Hz,1H),7.06(d,J=1.8Hz,1H),6.98(dd,J=8.2,1.8Hz,1H),6.88-6.93(m,1H),6.69-6.74(m,1H),6.54-6.58(m,1H),6.47(br s,1H),5.97(br s,1H),5.37(s,2H),3.91-4.02(m,4H),3.63(s,3H),2.52-2.65(m,4H),2.42(s,3H);HRMS(ESI)m/z[M+H]+ C24H25ClFN5O3S之計算值,518.1429;實驗值518.1432。
2-氯-4-((4-((3-氟-5-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[110]. 遵循以上通用程序獲得110,產率為43%。1H NMR(600MHz,CD2Cl2/MeOH-d 4 ):δ 8.18(s,1H),7.48(d,J=8.2Hz,1H),7.02(d,J=1.8Hz,1H),6.97(dd,J=8.2,1.8Hz,1H),6.42-6.46(m,2H),6.36-6.39(m,1H),5.22(s,2H),3.79-3.85(m,4H),3.63(s,3H),2.40-2.47(m,4H),2.28(s,3H);HRMS(ESI)m/z[M+H]+ C24H25ClFN5O3S之計算值,518.1429;實驗值518.1423。
2-氯-4-((4-((4-氟-3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[111]. 遵循以上通用程序獲得111,產率為62%。1H NMR(600MHz,CDCl3/MeOH-d 4 ):δ 8.28(s,1H),7.55(d,J=8.2Hz,1H),7.08(s,1H),7.00-7.06(m,2H),6.86-6.91(m,1H),6.77-6.81(m,1H),5.35(s,2H),3.89-3.97(m,4H),3.76(s,3H),2.51-2.57(m,4H),2.38(s,3H);13C NMR(150MHz,CDCl3/MeOH-d 4 ):δ 168.9,168.5,165.5,162.1,152.4(d,J=244Hz),147.93,147.86,144.0,133.2(d,J=3.8Hz),131.8,131.0,130.7,127.1,124.6,120.4(d,J=7.0Hz),116.1(d,J=18.4Hz),113.3(d,J=2.0Hz),67.9,56.4,54.9,46.0,43.9;HRMS(ESI)m/z[M+H]+ C24H25ClFN5O3S之計算值,518.1429;實驗值518.1418。
2-氯-4-((4-((2,4-二氟-3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[112]. 遵循以上通用程序獲得112,產率為62%。1H NMR(600MHz,CDCl3):δ 8.19(s,1H),7.58(d,J=8.0Hz,1H),6.93-6.99(m,2H),6.68-6.77(m,2H),6.43(br s,1H),5.97(br s,1H),5.30(s,2H),3.85-3.97(m,7H),2.47-2.58(m,4H),2.36(s,3H);13C NMR(150MHz,CDCl3):δ 168.3,167.4,165.0,161.5,155.6(dd,J=247.8,4.9Hz),153.8(dd,J=248.4,5.5Hz),143.6,136.3(t,J=14.1Hz),131.3,131.1,130.1,127.1,124.7,122.8,120.4(dd,J=12.9,3.4
Hz),112.0(dd,J=19.4,3.5Hz),97.5,62.0,61.2,54.6,45.8,43.5;HRMS(ESI)m/z[M+H]+ C24H24ClF2N5O3S之計算值,536.1335;實驗值536.1337。
2-氯-4-((4-((3-氯-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[113]. 遵循以上通用程序獲得113,產率為48%。1H NMR(500MHz,CDCl3):δ 8.25(s,1H),7.69(d,J=8.3Hz,1H),7.20(dd,J=7.0,1.8Hz,1H),6.97-7.07(m,4H),6.41(br s,1H),5.92(br s,1H),5.26(s,2H),3.87-4.02(m,4H),2.53-2.68(m,4H),2.43(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,167.3,165.3,161.7,157.9(d,J=248.1Hz),143.8,133.5(d,J=3.9Hz),131.7,130.2,130.0,127.5,127.43,127.37,124.9,121.2(d,J=17.9Hz),116.9(d,J=21.2Hz),97.9,66.8,54.7,45.9,43.6;HRMS(ESI)m/z[M+H]+ C23H22Cl2FN5O2S之計算值,522.0934;實驗值522.0920。
4-((4-((3-溴-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氯苯甲醯胺[114]. 遵循以上通用程序獲得114,產率為47%。1H NMR(500MHz,CDCl3):δ 8.25(s,1H),7.70(d,J=8.2Hz,1H),7.37(dd,J=6.5,1.9Hz,1H),6.98-7.08(m,4H),6.41(br s,1H),5.91(br s,1H),5.26(s,2H),3.89-4.05(m,4H),2.53-2.70(m,4H),2.45(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,167.3,165.3,161.7,158.9(d,J=246.6Hz),143.8,133.8(d,J=3.8Hz),133.0,131.69,131.66,130.2,128.3(d,J=7.4Hz),127.4,124.9,116.8(d,J=22.3Hz),109.2(d,J=21.2Hz),98.0,66.7,54.6,45.8,43.5;HRMS(ESI)m/z[M+H]+ C23H22BrClFN5O2S之計算值,566.0428;實驗值566.0413。
2-氯-4-((4-((4-氟-3-(三氟甲基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[115]. 遵循以上通用程序獲得115,產率為52%。1H NMR(600MHz,CDCl3):δ 8.24(s,1H),7.66(d,J=8.2Hz,1H),7.48(dd,J=6.5,1.6Hz,1H),7.28-7.32(m,1H),7.09-7.14(m,1H),7.02(d,J=1.8Hz,1H),6.99(dd,J=8.3,1.9Hz,1H),6.40(br s,1H),6.09(br s,1H),5.32(s,2H),3.83-3.99(m,4H),2.48-2.59(m,4H),2.39(s,3H);13C NMR(150MHz,CDCl3):δ 168.3,167.3,165.2,161.5,159.3(d,J=255.5Hz),143.7,133.0(d,J=8.6Hz),132.5(d,J=3.8Hz),131.4,131.3,130.0,127.0,126.4,124.5,122.4(q,J=270.8Hz),
118.2,117.3(d,J=20.8Hz),97.2,66.5,54.5,45.9,43.6;HRMS(ESI)m/z[M+H]+ C24H22ClF4N5O2S之計算值,556.1197;實驗值556.1182。
2-氯-4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[116]. 遵循以上通用程序獲得116,產率為67%。1H NMR(600MHz,CDCl3):δ 8.22(s,1H),7.61(d,J=8.2Hz,1H),7.10-7.14(m,1H),7.04(d,J=1.8Hz,1H),6.96(dd,J=8.2,1.8Hz,1H),6.61(dd,J=8.3,2.4Hz,1H),6.57(s,1H),6.54(d,J=7.5Hz,1H),6.47(br s,1H),5.99(br s,1H),5.31(s,2H),3.88-3.97(m,4H),2.82(s,6H),2.49-2.58(m,4H),2.38(s,3H);13C NMR(150MHz,CDCl3):δ 169.0,167.6,165.2,161.9,150.8,144.3,137.2,131.5,131.4,129.8,129.3,127.0,124.6,115.9,112.4,111.8,97.4,68.7,54.8,46.1,43.8,40.7;HRMS(ESI)m/z[M+H]+ C25H29ClN6O2S之計算值,513.1839;實驗值513.1833。
4-((4-((3-胺基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氯苯甲醯胺[117].遵循以上通用程序獲得117,產率為29%。1H NMR(600MHz,CD2Cl2/MeOH-d 4 ):δ 8.15(s,1H),7.35(d,J=8.2Hz,1H),7.03(d,J=1.7Hz,1H),6.93-6.99(m,4H),6.50-6.56(m,2H),6.28(s,1H),5.17(s,2H),3.75-3.88(m,4H),2.40-2.52(m,4H),2.27(s,3H);13C NMR(150MHz,CD2Cl2/MeOH-d 4 ):δ 168.8,167.9,163.8,161.0,146.3,142.3,136.7,130.8,130.6,129.0,128.5,126.4,123.9,117.0,114.3,113.4,97.1,67.5,53.8,44.8,42.7;HRMS(ESI)m/z[M+H]+ C23H25ClN6O2S之計算值,485.1526;實驗值485.1527。
4-((4-((3-胺基-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-氯苯甲醯胺[118].遵循以上通用程序獲得118,產率為53%。1H NMR(500MHz,CD2Cl2/MeOH-d 4 ):δ 8.15(s,1H),7.34(d,J=8.1Hz,1H),7.01(d,J=1.5Hz,1H),6.94(dd,J=8.1,1.5Hz,1H),6.75-6.82(m,1H),6.43-6.49(m,1H),6.35-6.41(m,1H),5.13(s,2H),3.75-3.84(m,4H),2.40-2.46(m,4H),2.26(s,3H);HRMS(ESI)m/z[M+H]+ C23H24ClFN6O2S之計算值,503.1432;實驗值503.1430。
2-氯-4-((4-((3-(二氟甲氧基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[121].遵循以上通用程序獲得121,產率為46%。1H NMR(600MHz,CDCl3):δ 8.20(s,1H),7.62(d,J=8.2Hz,1H),7.21(t,J=7.9Hz,1H),7.02(d,J=1.8Hz,1H),6.93-6.97(m,3H),6.85-6.88(m,1H),6.39(t,J=73.7Hz,1H),6.36(br s,1H),5.77(br s,1H),5.28(s,2H),3.78-3.86(m,4H),2.39-2.45(m,4H),2.30(s,3H);HRMS(ESI)m/z[M+H]+ C24H24ClF2N5O3S之計算值,536.1335;實驗值536.1324。
2-氯-4-((4-((3-羥基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[122].獲得122作為合成121之副產物,產率為52%。1H NMR(600MHz,CDCl3):δ 8.18(s,1H),7.44(s,1H),7.08-7.11(m,1H),7.04(t,J=7.9Hz,1H),6.94(dd,J=8.2,1.7Hz,1H),6.66-6.70(m,2H),6.39(br s,1H),6.07-6.13(m,1H),5.99(d,J=1.7Hz,1H),
5.11(s,2H),3.78-3.86(m,4H),2.44-2.47(m,4H),2.30(s,3H);13C NMR(150MHz,CDCl3):δ 169.2,167.9,163.6,161.6,156.5,143.5,137.3,131.0,130.5,130.1,129.3,128.0,125.7,120.1,116.1,114.8,98.4,68.2,54.7,46.1,43.7;HRMS(ESI)m/z[M+H]+ C23H24ClN5O3S之計算值,486.1367;實驗值486.1361。
2-氯-4-((4-((6-甲氧基吡啶-2-基)甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[123].遵循以上通用程序獲得123,產率為49%。1H NMR(600MHz,CDCl3):δ 8.20(s,1H),7.62(d,J=8.2Hz,1H),7.37-7.42(m,1H),7.04(d,J=1.7Hz,1H),7.00(dd,J=8.2,1.8Hz,1H),6.57(d,J=7.3Hz,1H),6.53(d,J=8.2Hz,1H),6.38(br s,1H),6.00(br s,1H),3.76-3.83(m,7H),2.36-2.41(m,4H),2.28(s,3H);13C NMR(150MHz,CDCl3):δ 168.5,167.4,165.2,163.5,161.7,154.1,144.1,139.1,131.4,131.3,129.8,127.0,124.6,113.2,109.4,96.8,68.3,54.7,53.4,46.2,43.8;HRMS(ESI)m/z[M+H]+ C23H25ClN6O3S之計算值,501.1476;實驗值501.1472。
2-氯-4-((4-((2-甲氧基吡啶-4-基)甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[124].遵循以上通用程序獲得124,產率為46%。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.99(d,J=5.3Hz,1H),7.63(d,J=8.2Hz,1H),7.04(d,J=1.8Hz,1H),6.99(dd,J=8.2,1.9Hz,1H),6.60(dd,J=5.3,1.3Hz,1H),6.44(br s,1H),6.34(s,1H),5.95(br s,1H),5.23(s,2H),3.83(s,3H),3.79(m,4H),2.40(m,4H),2.28(s,3H);13C NMR(150MHz,CDCl3):δ 168.1,167.5,165.1,164.4,161.6,148.2,147.0,143.6,131.5,131.2,130.2,127.2,124.7,114.8,108.4,97.2,66.0,54.7,53.5,46.2,43.9;HRMS(ESI)m/z[M+H]+ C23H25ClN6O3S之計算值,501.1476;實驗值501.1462。
2-氯-4-((4-((5-甲氧基吡啶-3-基)甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[125].遵循以上通用程序獲得125,產率為49%。1H NMR(600MHz,CDCl3):δ 8.22(s,1H),8.08(br s,1H),7.49
(br s,2H),7.42(d,J=8.1Hz,1H),7.00(d,J=1.7Hz,1H),6.95(dd,J=8.1,1.8Hz,1H),6.91-6.93(m,1H),5.94(br s,1H),5.25(s,2H),3.87-3.94(m,4H),3.72(s,3H),2.51-2.59(m,4H),2.38(s,3H);13C NMR(150MHz,CDCl3):δ 168.3,167.8,164.3,161.4,155.4,142.4,141.1,136.5,132.4,131.8,131.4,130.2,127.8,125.4,120.4,98.9,65.1,55.6,54.5,45.8,43.4;HRMS(ESI)m/z[M+H]+ C23H25ClN6O3S之計算值,501.1476;實驗值501.1467。
2-氯-4-((4-((4-甲氧基吡啶-2-基)甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[126].遵循以上通用程序獲得126,產率為39%。1H NMR(600MHz,CDCl3):δ 8.25(d,J=5.7Hz,1H),8.22(s,1H),7.63(d,J=8.3Hz,1H),7.09(d,J=1.8Hz,1H),7.01(dd,J=8.3,1.8Hz,1H),6.61(dd,J=5.8,2.5Hz,1H),6.52(d,J=2.3Hz,1H),6.40(br s,1H),5.98(br s,1H),5.36(s,2H),3.81-3.92(m,4H),3.65(s,3H),2.45-2.55(m,4H),2.35(s,3H);13C NMR(150MHz,CDCl3):δ 167.3,166.2,165.4,164.2,160.6,157.1,149.3,142.9,130.5,130.4,128.9,125.9,123.4,107.5,105.6,96.0,67.3,54.0,53.5,44.7,42.3;HRMS(ESI)m/z[M+H]+ C23H25ClN6O3S之計算值,501.1476;實驗值501.1487。
流程17. 合成127.
試劑及條件:a. BCl3.S(CH3)2,1,2-二氯乙烷,80℃,隔夜。
2-氯-4-((4-((4-氟-3-羥基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[127].在80℃下加熱111(19mg,0.0367mmol)及三氯化硼甲基硫醚錯合物(26mg,0.147mmol)於1,2-二氯乙烷(1mL)中之混合物隔夜。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化所得殘餘物,得到2.8mg(15%)127。1H NMR(600MHz,CDCl3):δ 8.25(s,1H),7.55(d,J=8.2Hz,1H),7.12(d,J=1.7Hz,1H),7.01(dd,J=8.2,1.8Hz,1H),6.91-6.96(m,1H),6.66-6.70(m,1H),6.41(br s,1H),6.31(d,J=8.3Hz,1H),5.99(br s,1H),5.17(s,2H),3.86-3.93(m,4H),2.48-2.52(m,4H),2.36(s,3H);HRMS(ESI)m/z[M+H]+ C23H23ClFN5O3S之計算值,504.1272;實驗值504.1263。
流程18. 合成131-139.
試劑及條件:a. 4-巰基-2-(三氟甲基)苯甲腈,噻吩-2-甲酸銅(I),K2CO3,DMF,120℃,23小時;b. TFA,CH2Cl2,室溫,5小時;c. POCl3,75℃,1小時;d. ROH,NaH,CH3CN,室溫,3小時;e. KOH,t-BuOH,80℃,1小時。
4-((4-((4-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[128].將94(1.5g,3.4mmol)及K2CO3(1.41g,10.2mmol)於DMF(44mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.259g,1.36mmol),抽空且用氬氣回填兩次。添加4-巰基-2-(三氟甲基)苯甲腈(0.829g,4.08mmol)且在120℃下加熱反應混合物23小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化殘餘物,得到1.66g(95%)128。1H NMR(600MHz,CDCl3):δ 8.29(s,1H),7.57(d,J=8.2Hz,1H),7.44(s,1H),7.19(d,J=8.2Hz,1H),7.08(d,J=8.5Hz,2H),6.82(d,J=8.6Hz,2H),5.31(s,2H),3.70-3.88(m,7H),2.73(m,4H),1.60(s,
3H);MS(ESI)m/z 516.2[M+H]+。
4-((4-羥基-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[129].向128(1.66g,3.2mmol)於CH2Cl2(15mL)中之溶液中經5分鐘逐滴添加TFA(15mL)且在室溫下攪拌5小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,0-20% MeOH)純化,得到1.21g(95%)129。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.11(s,1H),7.64(d,J=8.2Hz,1H),7.48(d,J=2.7Hz,1H),7.34(dd,J=8.2,1.6Hz,1H),3.91(m,4H),2.73(m,4H),2.54(s,1H);MS(ESI)m/z 396.1[M+H]+。
4-((4-氯-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[130].在75℃下加熱129(0.826g,2.09mmol)及POCl3(5mL)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(3×100mL)萃取,經MgSO4乾燥,過濾且濃縮,得到0.707g(82%)130,其不經進一步純化即使用。1H NMR(500MHz,CDCl3):δ 8.36(s,1H),7.61(d,J=8.2Hz,1H),7.39(s,1H),7.17(d,J=8.2Hz,1H),3.90(m,4H),2.59(m,4H),1.48(s,3H);MS(ESI)m/z 414.1[M+H]+。
合成131-139之通用程序.向溶解於CH3CN中之醇(4.25當量)中添加NaH(4當量)且在室溫下攪拌所得懸浮液10分鐘。隨後添加130(1當量)且在室溫下攪拌反應混合物3小時。在減壓下移除溶劑,且藉由管柱層析純化殘餘物,得到中間物腈。在80℃下加熱腈(1當量)及KOH(25當量)於t-BuOH中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC純化殘餘物,得到所要醯胺。
4-((4-((3-氯苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[131].遵循以上通用程序獲得131,產率為47%。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.36-7.39(m,2H),7.13-7.17(m,3H),7.07(s,1H),6.95-6.98(m,1H),5.87(br s,1H),5.73(br s,1H),5.24(s,2H),3.82-3.97(m,4H),2.47-2.60(m,4H),2.37(s,3H);13C NMR(150MHz,CDCl3):δ 169.1,168.4,165.0,161.5,141.9,138.2,134.2,131.6,129.9,129.21,129.18,128.1,127.8(d,J=31.9Hz),127.5,125.4,123.9(q,J=5.2Hz),123.2(q,J=272.4Hz),97.5,67.1,54.5,45.7,43.4;HRMS(ESI)m/z[M+H]+ C24H23ClF3N5O2S之計算值,538.1291;實驗值538.1287。
4-((4-((3-氯-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[132].遵循以上通用程序獲得132,產率為48%。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.34-7.39(m,2H),
7.13-7.17(m,2H),6.98-7.02(m,1H),6.93-6.97(m,1H),5.91(br s,1H),5.73(br s,1H),5.21(s,2H),3.83-3.98(m,4H),2.48-2.64(m,4H),2.37(s,3H);13C NMR(150MHz,CDCl3):δ 169.1,168.3,165.1,161.5,158.5,156.9,141.9,133.2(d,J=3.9Hz),131.6,129.8,129.2,127.6(q,J=32.0Hz),127.3(d,J=7.2Hz),123.9(q,J=5.2Hz),123.2(q,J=272.3Hz),120.9(d,J=17.8Hz),116.7(d,J=21.0Hz),97.4,66.6,54.5,45.8,43.4;HRMS(ESI)m/z[M+H]+ C24H22ClF4N5O2S之計算值,556.1197;實驗值556.1200。
4-((4-((5-氯-2-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[133].遵循以上通用程序獲得133,產率為53%。1H NMR(500MHz,CDCl3):δ 8.22(s,1H),7.36-7.42(m,2H),7.12-7.18(m,2H),7.01-7.05(m,1H),6.87-6.93(m,1H),5.90(br s,1H),5.73(br s,1H),5.30(s,2H),3.88-4.06(m,4H),2.55-2.72(m,4H),2.43(s,3H);HRMS(ESI)m/z[M+H]+ C24H22ClF4N5O2S之計算值,556.1197;實驗值556.1199。
4-((4-((3-溴-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[134].遵循以上通用程序獲得134,產率為51%。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.38(d,J=8.1Hz,1H),7.35(d,J=1.4Hz,1H),7.33(dd,J=6.7,1.7Hz,1H),7.14(dd,J=8.1,1.6Hz,1H),6.96-7.01(m,2H),5.89(br s,1H),5.73(br s,1H),5.21(s,2H),3.83-4.02(m,4H),2.49-2.67(m,4H),2.40(s,3H);13C NMR(150MHz,CDCl3):δ 169.1,168.3,165.1,161.5,159.5,157.9,141.8,133.6(d,J=3.8Hz),132.7,131.6,129.2(d,J=5.1Hz),128.1(d,J=7.3Hz),127.8(q,J=32.0Hz),123.9(q,J=5.2Hz),123.2(q,J=272.3Hz),116.6(d,J=22.4Hz),108.9(d,J=21.3Hz),97.5,66.6,54.4,45.7,43.3;HRMS(ESI)m/z[M+H]+ C24H22BrF4N5O2S之計算值,600.0692;實驗值600.0697。
4-((4-((2,4-二氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫 基)-2-(三氟甲基)苯甲醯胺[135].遵循以上通用程序獲得135,產率為57%。1H NMR(600MHz,CDCl3):δ 8.20(s,1H),7.33-7.37(m,2H),7.14-7.18(m,1H),6.98-7.04(m,1H),6.67-6.75(m,2H),5.87(br s,1H),5.71(br s,1H),5.29(s,2H),3.80-4.05(m,4H),2.46-2.68(m,4H),2.38(3,3H);13C NMR(150MHz,CDCl3):δ 169.1,168.3,165.0,162.8(dd,J=248.3,11.9Hz),161.5,160.6(dd,J=248.9,12.0Hz),141.9,131.6,130.7(dd,J=9.7,5.4Hz),129.5,129.1,127.7(q,J=31.9Hz),124.2(q,J=5.1Hz),123.2(q,J=272.3Hz),119.3(dd,J=14.5,3.8Hz),111.5(dd,J=21.1,3.5Hz),103.8(t,J=25.4Hz),97.7,61.2,54.5,45.7,43.3;HRMS(ESI)m/z[M+H]+ C24H22F5N5O2S之計算值,540.1493;實驗值540.1476。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[136].遵循以上通用程序獲得136,產率為52%。1H NMR(600MHz,CDCl3):δ 8.20(s,1H),7.38(d,J=1.4Hz,1H),7.30(d,J=8.1Hz,1H),7.11-7.15(m,1H),7.09(dd,J=8.1,1.5Hz,1H),6.68-6.74(m,2H),6.49(s,1H),5.92(br s,1H),5.87(br s,1H),5.24(s,2H),3.82-3.97(m,4H),3.64(s,3H),2.46-2.58(m,4H),2.36(s,3H);13C NMR(150MHz,CDCl3):δ 169.3,168.4,164.8,161.6,159.4,142.5,137.7,131.5,129.5,129.1,129.0,127.7(q,J=32.0Hz),
124.0(q,J=5.2Hz),123.2(q,J=272.4Hz),119.9,113.5,113.1,97.6,67.8,55.2,54.5,45.8,43.5;HRMS(ESI)m/z[M+H]+ C25H26F3N5O3S之計算值,534.1787;實驗值534.1787。
4-((4-((4-氟-3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[137].遵循以上通用程序獲得137,產率為63%。1H NMR(600MHz,CDCl3)δ 2.40(s,3H),2.54(m,4H),3.72(s,3H),3.94(m,4H),5.31(s,2H),5.95(bs,2H),6.74-6.77(m,2H),6.97-7.00(m,1H),7.10(dd,J=8.1,1.7Hz,1H),7.34(d,J=8.2Hz,1H),7.41(d,J=1.7Hz,1H),8.27(s,1H);13C NMR(150MHz,CDCl3)δ 43.9,46.2,54.9,56.5,67.6,97.2,113.4,116.1,120.6,123.9,127.9,128.9,129.2,131.7,132.7,142.3,147.6,151.5,53.1,161.9,165.3,168.7,169.3;HRMS(ESI)m/z[M+H]+ C25H26F4N5O3S之計算值552.1692;實驗值552.1687。
4-((4-((2-氟-5-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[138].遵循以上通用程序獲得138,產率為60%。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.39(d,J=1.6Hz,1H),7.32(d,J=8.1Hz,1H),7.10(dd,J=8.1,1.7Hz,1H),6.86(m,1H),6.65-6.69(m,1H),6.41-6.44(m,1H),5.93(br s,1H),5.88(br s,1H),5.30(s,2H),3.90(m,4H),3.59(s,3H),2.53(s,4H),2.37(s,3H);HRMS(ESI)m/z[M+H]+ C25H25F4N5O3S之計算值,552.1692;實驗值552.1699。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[139].遵循以上通用程序獲得139,產率為68%。1H NMR(600MHz,CDCl3):δ 8.18(s,1H),7.37(d,J=1.5Hz,1H),7.24(d,J=8.1Hz,1H),7.05-7.09(m,1H),7.03(dd,J=8.1,1.6Hz,1H),6.56-6.59(m,1H),6.47-6.52(m,2H),5.88(br s,1H),5.84(br s,1H),5.26(s,2H),3.83-3.96(m,4H),2.76(s,6H),2.45-2.55(m,4H),2.35(s,3H);HRMS(ESI)m/z[M+H]+ C26H29F3N6O2S之計算值,547.2103;實驗值547.2090。
流程19. 合成141.
試劑及條件:a. 3-氯苯甲基胺,CH3CN,75℃,3小時;b. KOH,t-BuOH,80℃,1小時。
4-((4-((3-氯苯甲基)胺基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[140].在75℃下加熱130(15mg,0.036245mmol)、3-氯苯甲胺(22.1μL,0.181mmol)於CH3CN(500μL)中之溶液3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化,得到6mg(32%)140。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 8.00(s,1H),7.58(d,J=8.3Hz,1H),7.42(d,J=1.3Hz,1H),7.11-7.19(m,3H),7.07(s,1H),6.95-7.00(m,1H),5.90(t,J=5.9Hz,1H),4.50(d,J=5.9Hz,2H),3.75-3.89(m,4H),2.40-2.45(m,4H),2.29(s,3H);MS(ESI)m/z 519.1[M+H]+。
4-((4-((3-氯苯甲基)胺基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[141].在80℃下加熱140(6mg,0.0116mmol)及KOH(49mg,0.87mmol)於t-BuOH(400μL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到4.6mg(74%)141。1H NMR(600MHz,CDCl3):δ 8.05(s,1H),7.43(d,J=8.1Hz,1H),7.36(d,J=1.3Hz,1H),7.11-7.16(m,3H),7.07(s,1H),6.95-6.99(m,1H),5.90-5.95(t,J=5.5Hz,1H),5.78(br s,1H),5.72(br s,1H),4.49(d,J=5.9Hz,2H),3.99(m,4H),2.72
(m,4H),2.52(s,3H);HRMS(ESI)m/z[M+H]+ C24H24ClF3N6OS之計算值,537.1451;實驗值537.1459。
流程20. 合成146c、e、g、h.
試劑及條件:a.(4-甲氧基苯基)甲烷硫醇,CuI,新亞銅試劑,K2CO3,DMF,135℃,18小時;b. HgO,TFA,60℃,1小時;c. CuI,新亞銅試劑,K2CO3,DMF,140℃,1小時。
5-((4-甲氧基苯甲基)硫基)吡啶-2-胺[143].將142(0.220g,1.0mmol)、K2CO3(0.552g,4.0mmol)、CuI(0.078g,0.4mmol)及新亞銅試劑(0.090g,0.4mmol)於DMF(5mL)中之混合物抽空且用氬氣回填三次。添加(4-甲氧基苯基)甲烷硫醇(0.185g,1.2mmol)且在135℃下加熱反應混合物18小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化殘餘物,得到185mg(75%)143。MS(m/z):[M+H]+ 247.1。
雙((6-胺基吡啶-3-基)硫基)汞[144].向143(1.0g,4.1mmol)於TFA(10mL)中之溶液中添加HgO(0.45g,2.05mmol)且加熱混合物
至60℃後維持1小時。在減壓下濃縮反應混合物且藉由管柱層析(CH2Cl2:MeOH,9:1)純化所得殘餘物,得到0.85g(92%)144。
合成146c/e/g/h之通用程序.在氬氣下在140℃下加熱145c/e/g/h(1當量)、144(1.2當量)、K2CO3(4當量)、CuI(1.0當量)及新亞銅試劑(0.2當量)於DMF中之混合物1小時。在減壓下濃縮反應混合物且藉由製備型TLC純化。
5-((4-((4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[146c].遵循以上通用程序獲得146c,產率為63%。1H NMR(500MHz,CDCl3):δ 8.13(s,1H),8.03(s,1H),7.30(dd,J=8.5,1.8Hz,1H),7.15-7.19(m,2H),6.92-6.95(m,2H),6.26(d,J=8.5Hz,1H),5.24(s,2H),4.38(s,2H),3.74-3.76(m,4H),2.27-2.39(m,4H),2.27(s,3H);MS(m/z):[M+H]+ 427.0。
5-((2-(4-甲基哌嗪-1-基)-4-((3-(三氟甲基)苯甲基)氧基)嘧啶-5-基)硫基)吡啶-2-胺[146e].遵循以上通用程序獲得146e,產率為52%。1H NMR(600MHz,CDCl3):δ 8.17(s,1H),8.07(s,1H),7.57(d,J=7.6Hz,1H),7.40(t,J=7.5Hz,1H),7.37(dd,J=8.6,2.3Hz,1H),7.28-7.32(m,2H),6.31(d,J=8.5Hz,1H),5.32(s,2H),4.39(s,2H),3.67-
3.70(m,4H),2.28-2.33(m,4H),2.24(s,3H);13C NMR(150MHz,CDCl3):δ 167.5,162.8,160.9,157.5,151.1,141.5,135.4,132.1,128.0,127.5,126.9,125.7,120.7,108.8,63.6,54.7,46.2,43.8;MS(m/z):[M+H]+ 477.0。
5-((4-((3,4-二氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[146g].遵循以上通用程序獲得146g,產率為68%。MS(m/z):[M+H]+ 444.9。
5-((4-((3,5-雙(三氟甲基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[146h].遵循以上通用程序獲得146h,產率為47%。MS(m/z):[M+H]+ 545.0。
流程21. 合成151-158.
試劑及條件:a. 6-硝基吡啶-3-硫醇,噻吩-2-甲酸銅(I),K2CO3,DMF,130℃,3小時;b. TFA,CH2Cl2,室溫,隔夜;c. POCl3,80℃,1小時;d.鐵,AcOH,室溫,2小時;e. ROH,NaH,CH3CN,室溫,3小時。
4-((4-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)-5-((6-硝基吡啶-3-基)硫基)嘧啶[147].將94(0.760g,1.726mmol)及K2CO3(0.714g,5.178mmol)於DMF(20mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.132g,0.690mmol),抽空且用氬氣回填兩次。添加6-硝基吡啶-3-硫醇(0.350g,2.24mmol)且在130℃下加熱反應混合物3小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化殘餘物,得到0.600g(74%)147。MS(m/z):[M+H]+ 469.0。
2-(4-甲基哌嗪-1-基)-5-((6-硝基吡啶-3-基)硫基)嘧啶-4-醇[148].向147(0.600g,1.28mmol)於CH2Cl2(10mL)中之溶液中經5分鐘逐滴
添加TFA(1mL)且在室溫下攪拌隔夜。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,0-20% MeOH)純化,得到0.280g(63%)148。1H NMR(500MHz,DMSO-d 6):δ 8.37(d,J=2.4Hz,1H),8.22(s,1H),8.19(d,J=8.7Hz,1H),7.80(dd,J=8.6,2.5Hz,1H),3.25-3.28(m,4H),2.78(s,3H),2.49-2.51(m,4H);MS(m/z):[M+H]+ 349.1。
4-氯-2-(4-甲基哌嗪-1-基)-5-((6-硝基吡啶-3-基)硫基)嘧啶[149].在80℃下加熱148(0.240g,0.69mmol)及POCl3(5mL)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(3×75mL)萃取,經MgSO4乾燥過濾且濃縮,得到0.180g(71%)149,其不經進一步純化即使用。MS(ESI)m/z[M+H]+ 367.1。
5-((4-氯-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[150].在室溫下攪拌149(140mg,0.382mmol)、鐵(10mg,0.179mmol)於AcOH(1mL)中之混合物2小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化,得到70mg(54%)150。MS(ESI)m/z[M+H]+ 337.1。
合成151-158之通用程序.向溶解於CH3CN中之醇(4.25當量)中添加NaH(4當量)且在室溫下攪拌所得懸浮液10分鐘。隨後添加150(1當量)且在室溫下攪拌反應混合物3小時。在減壓下移除溶劑且藉由製備型TLC純化殘餘物,得到所要產物。
5-((4-((4-氟-3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[151].遵循以上通用程序獲得151,產率為81%。1H NMR(500MHz,CDCl3)δ 8.22(s,1H),8.11(s,1H),7.38-7.40(m,1H),7.01-7.05(m,1H),6.93-6.95(m,1H),6.82-6.84(m,1H),6.32(d,J=8.5Hz,1H),5.31(s,2H),4.49(br s,2H),3.85(m,7H),2.49-2.52(m,4H),2.38(s,3H);13C NMR(125MHz,CDCl3)δ 168.0,162.7,161.2,157.7,151.3,147.8,141.7,133.0,120.7,120.3,116.1,115.9,113.1,108.9,103.4,67.6,56.4,54.9,46.2,43.8;HRMS(ESI)m/z[M+H]+ C22H26FN6O2S之計算值457.1822;實驗值457.1809。
3-(((5-((6-胺基吡啶-3-基)硫基)-2-(4-甲基哌嗪-1-基)嘧啶-4-基)氧基)甲基)苯甲腈[152].遵循以上通用程序獲得152,產率為70%。1H NMR(500MHz,CDCl3)δ 8.26(s,1H),8.10(d,J=2.2Hz,1H),7.58(d,J=7.6Hz,1H),7.50(m,1H),7.41-7.46(m,2H),7.39(s,1H),6.45(d,J=8.5Hz,1H),5.37(s,2H),4.56(br s,2H),3.85(m,4H),2.51(m,4H),2.39(s,3H);13C NMR(125MHz,CDCl3)δ 167.6,162.8,161.0,157.9,151.3,141.5,138.4,131.9,131.7,131.1,129.4,120.4,118.8,112.8,109.2,103.2,66.6,54.8,46.1,43.7;HRMS(ESI)m/z[M+H]+ C22H24N7O2S之計算值434.1763;實驗值434.1751。
5-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[153].遵循以上通用程序獲得153,產率為75%。1H NMR(500MHz,CDCl3)δ 8.19(s,1H),8.14(d,J=2.0Hz,1H),7.42(dd,J=8.5,2.4Hz,1H),7.20(t,J=7.9Hz,1H),6.74(s,1H),6.66-6.68(m,2H),6.33(d,J=8.5Hz,1H),5.34(s,2H),4.46(br s,2H),3.86(m,4H),2.94(s,6H),2.47-2.49(m,4H),2.37(s,3H);13C NMR(125MHz,CDCl3)δ 168.2,162.6,161.2,157.7,151.4,150.9,141.9,137.5,129.3,120.9,116.1,112.2,111.9,108.9,103.4,68.7,54.9,46.2,43.8,40.8;HRMS(ESI)m/z[M+H]+ C23H30N7OS之計算值452.2233;實驗值452.2215。
5-((4-((3-氯-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[154].遵循以上通用程序獲得154,產率為80%。1H NMR(500MHz,CDCl3)δ 8.22(s,1H),8.10(d,J=2.1Hz,1H),7.39(dd,J=8.5,2.4Hz,1H),7.30(dd,J=7.0,1.9Hz,1H),7.07-7.14(m,2H),6.36(d,J=8.5Hz,1H),5.29(s,2H),4.48(br s,2H),3.80-3.82(m,4H),2.43-2.45(m,4H),2.33(s,3H);13C NMR(125MHz,CDCl3)δ
167.7,162.8,161.1,157.8,156.9,151.3,141.6,133.9,130.2,127.7,120.7,116.8,116.7,108.9,103.2,66.5,55.0,46.4,44.1;HRMS(ESI)m/z[M+H]+ C21H23ClFN6OS之計算值461.1327;實驗值461.1316。
5-((4-((3-溴-4-氟苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[155].遵循以上通用程序獲得155,產率為73%。1H NMR(500MHz,CDCl3)δ 8.22(s,1H),8.11(s,1H),7.48(dd,J=6.5,1.9Hz,1H),7.40(dd,J=8.5,2.3Hz,1H),7.17-7.20(m,1H),7.07(t,J=8.4Hz,1H),6.39(d,J=8.5Hz,1H),5.29(s,2H),4.50(br s,2H),3.86(m,4H),2.51(m,4H),2.38(s,3H);13C NMR(125MHz,CDCl3)δ 167.7,162.7,161.0,157.9,157.8,151.4,141.7,134.2,133.1,128.6,128.5,116.7,116.6,109.2,109.1,66.5,54.8,46.1,43.8;HRMS(ESI)m/z[M+H]+ C21H23BrFN6OS之計算值505.0821;實驗值505.0821。
5-((4-((4-氟-3-(三氟甲基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[156].遵循以上通用程序獲得156,產率為68%。1H NMR(500MHz,CDCl3)δ 8.21(s,1H),8.08(d,J=2.0Hz,1H),7.55(d,J=6.6Hz,1H),7.40-7.43(m,1H),7.37(dd,J=8.5,2.3Hz,1H),7.16(t,J=9.3Hz,1H),6.34(d,J=8.5Hz,1H),5.34(s,2H),4.49
(br s,2H),3.84(m,4H),2.48-2.50(m,4H),2.37(s,3H);HRMS(ESI)m/z[M+H]+ C22H23F4N6OS之計算值495.1590;實驗值495.1577。
5-((4-((2-氟-5-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[157].遵循以上通用程序獲得157,產率為96%。1H NMR(500MHz,CDCl3)δ 8.19(s,1H),8.12(s,1H),7.42(dd,J=8.5,2.2Hz,1H),6.96(t,J=9.2Hz,1H),6.84-6.86(m,1H),6.76-6.79(m,1H),6.34(d,J=8.5Hz,1H),5.40(s,2H),4.48(br s,2H),3.83(m,4H),3.73(s,3H),2.45-2.47(m,4H),2.34(s,3H);13C NMR(125MHz,CDCl3)δ 167.9,162.8,161.1,157.8,155.9,151.4,141.8,124.6,120.7,116.0,115.9,114.9,114.3,109.0,103.3,61.7,56.0,54.9,46.2,43.9;HRMS(ESI)m/z[M+H]+ C22H26FN6O2S之計算值457.1822;實驗值457.1817。
5-((4-((2,4-二氟-3-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)吡啶-2-胺[158].遵循以上通用程序獲得158,產率為95%。1H NMR(500MHz,CDCl3)δ 8.21(s,1H),8.10(s,1H),7.40(dd,J=8.5,2.2Hz,1H),6.80-6.91(m,2H),6.35(d,J=8.5Hz,1H),5.38(s,2H),4.49(br s,2H),4.00(s,3H),3.85(m,4H),2.49-2.50(m,4H),
2.37(s,3H);HRMS(ESI)m/z[M+H]+ C22H25F2N6O2S之計算值475.1728;實驗值475.1718。
流程23. 合成166-168.
試劑及條件:a. 4-巰基苯甲腈,CuI,新亞銅試劑,K2CO3,DMF,120℃,20小時;b. KOH,t-BuOH,80℃,1小時;c.乙酸酐,DMAP,110℃ 2小時。
4-((4-(苯甲氧基)-2-(哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[166].在120℃下加熱162(75mg,0.189mmol)、K2CO3(52.2mg,0.378mmol)、新亞銅試劑(11.8mg,0.0567mmol)、CuI(10.8mg,0.0567mmol)及4-巰基苯甲腈(31.9mg,0.236mmol)於DMF(2mL)中之混合物20小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到24.6mg(32%)166。1H NMR(500MHz,CDCl3):δ 8.17(s,1H),7.34(d,J=8.3Hz,2H),7.15-7.21(m,
3H),7.05-7.09(m,2H),7.02(d,J=8.3Hz,2H),5.29(s,2H),3.74-3.80(m,4H),2.84-2.89(m,4H);13C NMR(125MHz,CDCl3):δ 168.6,165.1,161.8,145.7,136.3,132.1,128.4,128.0,127.5,126.1,119.0,108.2,96.7,67.8,45.9,45.2;HRMS(ESI)m/z[M+H]+ C22H22N5OS之計算值,404.1545;實驗值404.1537。
4-((4-(苯甲氧基)-2-(哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[167].在80℃下加熱166(18.5mg,0.0458mmol)及KOH(56.5mg,1.01mmol)於t-BuOH(500μL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到15mg(78%)167。1H NMR(500MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.3Hz,2H),7.21-7.25(m,3H),7.10-7.16(m,4H),5.97(br s,1H),5.80(br s,1H),5.36(s,2H),3.80-3.87(m,4H),2.90-2.97(m,4H);13C NMR(125MHz,CDCl3):δ 168.8,168.6,164.9,161.7,143.7,136.4,129.9,128.3,127.8,127.7,127.4,126.1,97.9,67.8,45.9,45.1;HRMS(ESI)m/z[M+H]+ C22H24N5O2S之計算值,422.1651;實驗值422.1644。
4-((2-(4-乙醯基哌嗪-1-基)-4-(苯甲氧基)嘧啶-5-基)硫基)苯甲醯胺[168].在110℃下攪拌167(10mg,0.023mmol)及DMAP(0.001mmol,2mg)於2mL乙酸酐中之溶液2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:己烷:EtOAc:MeOH-NH3(7N),4:4:2:1)純化殘餘物,得到6.8mg(61%)168。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.62(d,J=8.6Hz,2H),7.17-7.20(m,3H),7.05-7.07(m,4H),5.95(br s,1H),5.75(br s,1H),5.29(s,2H),3.80-3.83(m,2H),3.76-3.83(m,2H),3.61-3.63(m,4H),3.45-3.48(m,2H),2.09(s,3H);13C NMR(150MHz,CDCl3):δ 169.3,168.7,168.6,164.8,161.5,143.3,136.2,130.0,128.4,127.9,127.8,127.3,126.2,99.0,68.0,45.9,43.7,41.1.HRMS(ESI)m/z[M+H]+ C24H26N5O2S之計算值,464.1721;實驗
值464.1728。
流程25. 合成179a及c.
試劑及條件:a. 4-巰基苯甲腈,噻吩-2-甲酸銅(I),K2CO3,DMF,130℃,16小時;b. POCl3,DIEA,100℃,1小時;c. BnOH,KOH,18-冠-6,室溫,12小時,甲苯;d.胺,DMF,90℃,2小時;e. KOH,t-BuOH,80℃,1小時。
4-((2,4-二羥基嘧啶-5-基)硫基)苯甲腈[175].將5-碘嘧啶-2,4-二醇174(1g,4.2mmol)、4-巰基苯甲腈(0.68g,5.04mmol)及K2CO3(1.74g,12.6mmol)於DMF(30mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.32g,1.68mmol),抽空且用氬氣回填兩次,且在130℃下加熱反應混合物16小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:CH3OH:CH3COOH,25:1:0.3)純化,得到0.65g(63%)175。1H NMR(500MHz,DMSO-d 6):δ 8.03(s,1H),7.69(d,J=7.9Hz,2H),7.31(d,J=8.6Hz,2H);13C NMR(125MHz,DMSO-d 6):δ 162.6,151.6,150.8,144.9,132.4,125.7,118.8,107.2,99.1;HRMS(ESI)m/z[M-H]+ C11H6N3O2S之計算值,244.0181;實驗值244.0178。
4-((2,4-二氯嘧啶-5-基)硫基)苯甲腈[176].在攪拌下在100mL含有0.65g(2.65mmol)175之圓底燒瓶中添加12.1mL POCl3(20.34g,
132.65mmol)。向此混合物中緩慢添加1.15mL DIEA(0.85g,6.63mmol)且在100℃下加熱反應物1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×75mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(己烷:EtOAc,80:20)純化,得到0.56g(86%)176。1H NMR(500MHz,CDCl3):δ 8.34(s,1H),7.61(d,J=8.2Hz,2H),7.34(d,J=8.2Hz,2H);13C NMR(125MHz,CDCl3):δ 163.5,161.9,159.9,137.9,133.5,131.1,128.8,118.0,112.5;MS(ESI)m/z[M+H]+ 282.1。
4-((4-(苯甲氧基)-2-氯嘧啶-5-基)硫基)苯甲腈[177].向溶解於甲苯(10mL)中之176(0.16g,0.57mmol)中添加苯甲醇(59μL,61.5mg,0.57mmol)。依序添加KOH(32mg,0.57mmol)及18-冠-6(7.5mg,0.03mmol)且在室溫下攪拌反應物12小時。隨後在減壓下濃縮反應混合物,得到殘餘物,向其中添加50mL EtOAc。將其轉移至分液漏斗中且依序用0.1N HCl(30mL)及H2O(2×30mL)洗滌,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(己烷:EtOAc,90:10至80:20)純化,得到67mg(34%)177。MS(m/z):[M+H]+ 354.2。
4-((4-(苯甲氧基)-2-嗎啉并嘧啶-5-基)硫基)苯甲腈[178a].向177(15.0mg,0.039mmol)中添加嗎啉(4.1mg,0.047mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,75:25)純化殘餘物,得到7.8mg(45%)178a。MS(m/z):[M+H]+ 405.5。
(S)-4-((4-(苯甲氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲腈[178c].向177(10.0mg,0.028mmol)中添加(S)-N,N-二甲基吡咯啶-3-胺(3.9mg,0.034mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到5.8mg(48%)178c。MS(m/z):[M+H]+ 432.3。
4-((4-((4-(苯甲氧基)-2-嗎啉并嘧啶-5-基)硫基)苯甲醯胺[179a].在80℃下加熱178a(7.8mg,0.019mmol)及KOH(23.8mg,0.425mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,75:25,兩次)純化殘餘物,得到4.7mg(59%)179a。1H NMR(600MHz,CDCl3):δ 8.21(s,1H),7.56(d,J=8.5Hz,2H),7.17-7.19(m,3H),7.04-7.06(m,4H),5.91(br s,1H),5.51(br s,1H),5.29(s,2H),3.76-3.79(m,4H),3.69-3.70(m,4H);13C NMR(150MHz,CDCl3):δ 168.9,168.8,165.1,161.9,143.8,136.5,130.1,128.6,128.1,127.9,127.6,126.3,98.8,68.1,66.9,44.6;HRMS(ESI)m/z[M+H]+ C22H23N4O3S之計算值,423.1491;實驗值423.1481。
(S)-4-((4-(苯甲氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲醯胺(179c).在80℃下加熱178c(5.8mg,0.014mmol)及KOH(16.6mg,0.30mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到4.1mg(63%)179c。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.62(d,J=8.5Hz,2H),7.24(t,J=8.5Hz,3H),7.16(s,2H),7.11(J=8.4Hz,2H),5.98(br s,1H),5.58(br s,1H),5.39(s,2H),3.82-3.98(m,2H),3.49-3.54(m,1H),3.31-3.36(m,1H),2.78-2.82(m,1H),2.34(s,3H),2.32(s,3H),2.20-2.25(m,1H),1.88-1.95(m,1H);13C NMR(150MHz,CDCl3):δ 168.6,168.5,164.9,160.2,143.9,136.6,136.5,129.7,128.3,127.8,127.7,127.6,125.8,97.4,67.8,65.4,51.3,46.1,44.4,30.4;HRMS(ESI)m/z[M+H]+ C24H28N5O2S之計算值,450.1964;實驗值450.1956。
流程26. 合成182.
試劑及條件:a.反-2,5-二甲基哌嗪,Et3N,DMF,90℃,2小時;b.甲醛,NaBH3CN,NaOAc,MeOH,50℃,5小時;c. KOH,
t-BuOH,80℃,1小時。
4-((4-(苯甲氧基)-2-((2R,5S)-2,5-二甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[180].向177(20mg,0.056mmol)中添加反-2,5-二甲基哌嗪(8mg,0.0672mmol)及Et3N(15μl,0.11mmol)於DMF(3mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到20mg(82%)180。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.42(d,J=8.3Hz,2H),7.23-7.27(m,3H),7.10-7.16(m,4H),5.41(d,J=12.6Hz,1H),5.31(d,J=12.6Hz,1H),4.76(m,1H),4.29(d,J=13.4Hz,1H),3.29-3.39(m,3H),2.64(d,J=13.0Hz,1H),1.83-1.87(m,1H),1.27(d,J=6.5Hz,3H),1.19(d,J=6.7Hz,3H);MS(m/z):[M+H]+ 432.0。
4-((4-(苯甲氧基)-2-((2R,5S)-2,4,5-三甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[181].向180(20mg,0.046mmol)於MeOH(3mL)中之溶液中添加福馬林(20μL,0.269mmol)、乙酸鈉(20mg,0.244mmol)及氰基硼氫化鈉(20mg,0.095mmol)且在50℃下加熱5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到16mg(77%)181。MS(ESI)m/z[M+H]+ 446.4。
4-((4-(苯甲氧基)-2-((2R,5S)-2,4,5-三甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[182].在80℃下加熱181(16mg,0.036mmol)及KOH(40mg,0.71mmol)於t-BuOH(3mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到9mg(54%)182。1H NMR(600MHz,CDCl3)δ 8.19(s,1H),7.56(d,J=8.4
Hz,2H),7.16-7.19(m,3H),7.06-7.08(m,4H),5.95(br s,1H),5.62(br s,1H),5.33(d,J=12.6Hz,1H),5.22(d,J=12.6Hz,1H),4.79(s,1H),4.35(d,J=13.2Hz,1H),3.38(d,J=12.0Hz,1H),2.97(s,1H),2.74(dd,J=12.0,4.6Hz,1H),2.34(d,J=10.9Hz,1H),2.30(s,3H),1.24(d,J=6.6Hz,3H),0.88(d,J=6.5Hz,3H);13C NMR(150MHz,CDCl3)δ 168.7,168.6,165.0,162.1,143.8,136.5,129.8,128.3,127.8,127.7,127.3,126.0,97.4,67.7,54.3,52.0,46.9,44.0,42.8,15.7,7.8;HRMS(ESI)m/z[M+H]+ C25H30N5O2S之計算值464.2120;實驗值464.2104。
流程27. 合成185a、b、d及e.
試劑及條件:a. 3-二甲基胺基苯甲醇,KOH,18-冠-6,甲苯,室溫,12小時;b.胺,DMF,90℃,2小時;c. KOH,t-BuOH,80℃,1小時。
4-((2-氯-4-((3-(二甲基胺基)苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[183].向溶解於甲苯(12mL)中之176(0.26g,0.935mmol)中添加3-二甲基胺基苯甲醇(134μL,141.0mg,0.935mmol)。依序添加KOH(78mg,1.4mmol)及18-冠-6(12mg,0.047mmol)且在室溫下攪拌反應物12小時。隨後在減壓下濃縮反應混合物,得到殘餘物,向其中添加100mL EtOAc。將其轉移至分液漏斗中且依序用0.1N HCl(50mL)及H2O(2×50mL)洗滌,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(己烷:EtOAc,90:10至80:20)純化,得到0.11g(30%)183。1H
NMR(500MHz,CDCl3):δ 8.36(s,1H),7.35(d,J=8.4Hz,2H),7.09(t,J=8.0Hz,1H),7.07(d,J=8.4Hz,2H),6.61(dd,J=8.6,2.3Hz,1H),6.52(s,1H),6.42(d,J=7.3Hz,1H),5.32(s,2H),2.84(s,6H);MS(ESI)m/z[M+H]+ 397.2。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-嗎啉并嘧啶-5-基)硫基)苯甲腈[184a].向183(10.0mg,0.0252mmol)中添加嗎啉(2.64mg,0.0303mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,7:3)純化殘餘物,得到6.2mg(64%)184a。MS(m/z):[M+H]+ 448.3。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-異丙基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[184b].向183(10.0mg,0.0252mmol)中添加N-異丙基哌嗪(4.2mg,0.033mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS(m/z):[M+H]+ 489.4。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(2-羥基乙基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[184d].向183(10.0mg,0.0252mmol)中添加2-(哌嗪-1-基)乙醇(4.3mg,0.033mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS(m/z):[M+H]+ 491.4。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(己-5-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[184e].向183(10.0mg,0.0252mmol)中添加1-(己-5-炔-1-基)哌嗪(5.5mg,0.033mmol)及Et3N(100μL)於DMF(2mL)中之溶液且在室溫下攪拌隔夜。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。1H NMR(500MHz,CDCl3)δ 8.22(s,1H),7.39(d,J=8.5Hz,2H),7.13(t,J=7.8Hz,1H),7.06(d,J=8.5Hz,2H),6.63(dd,J=8.3,2.2Hz,1H),6.50-6.56(m,2H),5.33(s,2H),3.90(m,4H),2.84(s,6H),2.52(m,4H),2.42(t,J=7.0Hz,2H),2.25(td,J=7.0,2.6Hz,2H),1.97(t,J=2.5Hz,1H),1.66-1.71(m,2H),1.57-1.62(m,2H);MS(m/z):[M+H]+ 527.1。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-嗎啉并嘧啶-5-基)硫基)苯甲醯胺[185a].在80℃下加熱184a(6.2mg,0.014mmol)及KOH(17.1mg,0.305mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:1)純化殘餘物,得到4.1mg(63%)185a。1H NMR(600MHz,CDCl3):δ 8.19(s,1H),7.53(d,J=8.4Hz,2H),7.05(t,J=8.4Hz,1H),7.02(d,J=8.4Hz,2H),6.56(dd,J=8.9,2.6Hz,1H),6.50(s,1H),6.46(d,J=7.4Hz,1H),5.97(br s,1H),5.49(br s,1H),5.27(s,2H),3.78-3.79(m,4H),3.69-3.71(m,4H),2.75(s,6H);13C NMR(150MHz,CDCl3):δ 168.9,168.6,164.9,161.8,150.6,143.6,137.1,129.7,129.0,127.7,125.7,115.7,112.1,111.6,98.2,68.4,66.7,44.4,40.5;HRMS(ESI)m/z[M+H]+ C24H25N5O3S之計算值,466.1913;實驗值466.1901。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-異丙基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[185b].在80℃下加熱184b及KOH(31.0mg,0.055mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得
到9.2mg(72%)185b。1H NMR(600MHz,CDCl3):δ 8.17(s,1H),7.52(d,J=10.0Hz,2H),7.04(t,J=9.6Hz,1H),7.01(d,J=10.4Hz,2H),6.55(dd,J=10.0,2.9Hz,1H),6.51(s,1H),6.47(d,J=9.2Hz,1H),5.95(br s,1H),5.47(br s,1H),5.26(s,2H),3.82-3.84(m,4H),2.74(s,6H),2.66-2.70(m,1H),2.52-2.54(m,4H),1.02(d,J=7.9Hz,6H);13C NMR(150MHz,CDCl3):δ 168.9,168.8,164.9,161.6,150.6,143.8,137.1,129.7,128.9,127.7,125.7,115.8,112.1,111.7,97.6,68.3,54.7,48.5,44.2,40.5,18.4;HRMS(ESI)m/z[M+H]+ C27H35N6O2S之計算值,507.2542;實驗值507.2543。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(2-羥基乙基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[185d].在80℃下加熱184d及KOH(31.0mg,0.055mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到10.2mg(80%)185d。1H NMR(600MHz,CDCl3):δ 8.18(s,1H),7.53(d,J=8.5Hz,2H),7.05(t,J=7.5Hz,1H),7.02(d,J=8.5Hz,2H),6.56(dd,J=8.5,2.3Hz,1H),6.51(s,1H),6.47(d,J=7.6Hz,1H),5.26(s,2H),3.83-3.84(m,4H),3.62-3.63(m,4H),2.74(s,6H),2.53-2.57(m,6H);13C NMR(150MHz,CDCl3):δ 169.1,168.9,164.9,161.6,150.6,143.7,137.1,129.7,128.9,127.7,125.7,115.8,112.2,111.7,97.9,68.4,59.6,57.7,43.8,40.5;HRMS(ESI)m/z[M+H]+ C26H33N6O3S之計算值,509.2335;實驗值509.2336。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(己-5-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[185e].在80℃下加熱184e(12mg,0.023mmol)及KOH(28mg,0.5mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到5.7mg(46%)185e。1H NMR(600MHz,CDCl3)δ 8.25(s,1H),7.59(d,J=8.4Hz,2H),7.12(t,J=7.9Hz,1H),7.07(d,J=8.4Hz,2H),6.61-6.63(m,1H),6.57(s,1H),6.54(d,J=7.5Hz,1H),6.09(br s,1H),5.68(br s,1H),5.34(s,2H),3.90(m,4H),2.81(s,6H),2.53(m,4H),2.40-2.45(m,2H),2.25(td,J=7.0,2.6Hz,2H),1.98(t,J=2.6Hz,1H),1.64-1.71(m,2H),1.55-1.63(m,2H);13C NMR(150MHz,CDCl3)δ 168.8,165.0,161.6,150.5,143.8,137.1,129.5,129.0,127.7,125.5,115.8,112.0,111.6,97.4,84.2,68.6,68.2,58.0,52.9,43.8,40.5,26.3,25.8,18.3;HRMS(ESI)m/z[M+H]+ C30H37N6O2S之計算值545.2699;實驗值545.2701。
流程28. 合成187.
試劑及條件:a. 3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡咯-
1-甲酸第三丁酯,NaHCO3,PdCl2(PPh3)2,DMF,H2O,90℃,16小時;b. TFA,CH2Cl2,室溫,20小時;c. KOH,t-BuOH,80℃,1小時。
3-(5-((4-氰基苯基)硫基)-4-((3-(二甲基胺基)苯甲基)氧基)嘧啶-2-基)-1H-吡咯-1-甲酸第三丁酯[186].向圓底燒瓶中183(20mg,0.038mmol)於DMF(2mL)中之溶液中依序添加3-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡咯-1-甲酸第三丁酯(18.0mg,0.076mmol)及NaHCO3(9.5mg,0.113mmol)。隨後向反應混合物施加真空,繼而用氬氣回填燒瓶。再執行此真空-氬氣循環兩次。隨後將PdCl2(PPh3)2(5.3mg,0.0076mmol)及0.1mL經脫氣蒸餾水添加至反應混合物中。隨後反應混合物再進行兩次真空-氬氣循環且在90℃下加熱16小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,8:2)純化所得殘餘物,得到10mg(71%)186。MS(m/z):[M+H]+ 528.1。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(1H-吡咯-3-基)嘧啶-5-基)硫基)苯甲醯胺[187].向溶解於CH2Cl2(2mL)中之186(10mg,0.019mmol)中添加140μL TFA且在室溫下攪拌反應混合物20小時。在減壓下移除溶劑,得到殘餘物(MS(m/z):[M+H]+ 428.20),依序添加t-BuOH(1mL)及KOH(20mg,0.36mmol)且在80℃下加熱反應混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到5.3mg(61%)187。1H NMR(600MHz,CDCl3):δ 8.75(s,1H),7.70-7.71(m,1H),7.60(d,J=8.5Hz,2H),7.14(d,J=8.5Hz,2H),7.13(t,J=9.1Hz,1H),6.97-6.98(m,1H),6.85-6.86(m,1H),6.66(s,1H),6.64(dd,J=9.1,2.2Hz,1H),6.61(d,J=9.1,2.2Hz,1H),5.49(s,2H),2.84(s,6H);13C NMR(150MHz,CDCl3):δ 173.5,168.9,167.9,163.6,162.6,150.6,141.4,136.8,129.1,127.8,127.1,123.9,121.5,119.2,116.4,112.4,112.3,108.9,108.5,
68.7,40.6;HRMS(ESI)m/z[M+H]+ C24H24N5O2S之計算值,446.1651;實驗值446.1647。
流程29. 合成190a、b、d-h、j、k及m-v.
試劑及條件:a. 3-甲氧基苯甲醇,KOH,18-冠-6,甲苯,室溫,12小時;b.胺,Et3N,DMF,90℃,2小時;c. KOH,t-BuOH,80℃,1小時。
4-((2-氯-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[188].向溶解於甲苯(18mL)中之176(0.3g,1.07mmol)中添加3-甲氧基苯甲醇(133μL,147.3mg,1.07mmol)。依序添加KOH(68mg,1.28mmol)及18-冠-6(14.1mg,0.054mmol)且在室溫下攪拌反應物12小時。隨後在減壓下濃縮反應混合物,得到殘餘物,向其中添加120mL EtOAc。將其轉移至分液漏斗中且依序用0.1N HCl(60mL)及H2O(2×60mL)洗滌,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(己烷:EtOAc,90:10至80:20)純化,得到0.13g(32%)188。1H NMR(600MHz,CDCl3):δ 8.41(s,1H),7.43(d,J=8.6Hz,2H),7.18(t,J=8.2Hz,1H),7.16(d,J=8.6Hz,2H),6.82(dd,J=8.2,1.8Hz,1H),6.70(d,J=7.7Hz,1H),6.62(s,1H),5.36(s,2H),3.75(s,3H);13C NMR(150MHz,CDCl3):δ 168.6,162.7,160.8,159.7,140.7,135.9,132.7,129.7,128.8,120.6,118.5,114.4,113.7,113.4,110.4,69.9,55.3.MS(ESI)m/z[M+H]+ 384.2。
4-((4-((4-((3-甲氧基苯甲基)氧基)-2-嗎啉并嘧啶-5-基)硫基)苯甲腈[189a].向188(10.0mg,0.026mmol)中添加嗎啉(2.7mg,0.031mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS(m/z):[M+H]+ 435.37。
4-((2-(4-異丙基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189b].向188(10.0mg,0.026mmol)中添加N-異丙基哌嗪(4.0mg,0.031mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS(m/z):[M+H]+ 476.2。
4-((2-(4-(二甲基胺基)哌啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189d].向188(9.0mg,0.023mmol)中添加N,N-二
甲基哌啶-4-胺(3.9mg,0.03mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS(m/z):[M+H]+ 476.2。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189e].向188(9.0mg,0.023mmol)中添加(R)-N,N-二甲基吡咯啶-3-胺(3.4mg,0.03mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到9.7mg(89%)189e。MS(m/z):[M+H]+ 462.1。
(S)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189f].向188(9.0mg,0.023mmol)中添加(S)-N,N-二甲基吡咯啶-3-胺(3.4mg,0.03mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到9.5mg(88%)189f。MS(m/z):[M+H]+ 462.2。
4-((2-((2-(二甲基胺基)乙基)(甲基)胺基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189g].向188(9.0mg,0.023mmol)中添加N 1 ,N 1 ,N 2 -三甲基乙烷-1,2-二胺(3.1mg,0.03mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到7mg(66%)189g。MS(m/z):[M+H]+ 450.2。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基-1,4-二氮雜環庚烷-1-基)嘧啶-5-基)硫基)苯甲腈[189h].向188(9.0mg,0.023mmol)中添加1-甲基-1,4-二氮雜環庚烷(3.9mg,0.03mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到10.1mg(93%)189h。MS(m/z):[M+H]+ 462.1。
4-((2-(4-(己-5-炔-1-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189j].向188(20mg,0.0521mmol)中添加1-(己-5-炔-1-基)哌嗪(17.3mg,0.104mmol)及Et3N(100μL,0.72mmol)於DMF(3mL)中之溶液且在室溫下攪拌隔夜。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到24.6mg(92%)189j。1H NMR(500MHz,CDCl3):δ 8.16(s,1H),7.34(d,J=8.6Hz,2H),7.10(t,J=7.9Hz,1H),7.02(d,J=8.6Hz,2H),6.72(dd,J=8.2,2.5Hz,1H),6.66(d,J=7.6Hz,1H),6.59(s,1H),5.22(s,2H),3.79-3.81(m,4H),3.65(s,3H),2.43-2.45(m,4H),2.35(t,J=7.6Hz,2H),2.17(td,J=7.0,2.7Hz,2H),1.89(t,J=2.6Hz,1H),1.60(m,2H),1.52(m,2H);MS(m/z):[M+H]+ 514.3。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(戊-4-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[189k].向188(15mg,0.039mmol)中添加1-(戊-4-炔-1-基)哌嗪(7.6mg,0.05mmol)及Et3N(10μL,0.072mmol)於DMF(3mL)中之溶液且在90℃下加熱3小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,30:1)純化殘餘物,得到18mg(92%)189k。MS(ESI)m/z[M+H]+ 500.3。
4-((2-(3-(二甲基胺基)氮雜環丁烷-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189m].向188(10mg,0.026mmol)中添加N,N-二甲基氮雜環丁烷-3-胺(13mg,0.13mmol)及Et3N(20μL,0.144mmol)於DMF(3mL)中之溶液且在90℃下加熱3小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,30:1)純化殘餘物,得到定量產率之189m。1H NMR(500MHz,CDCl3):δ 8.15(s,1H),7.34(d,J=8.5Hz,2H),7.10(t,J=7.9Hz,1H),6.99(d,J=8.5Hz,2H),6.72(dd,J=8.2,2.4,1H),6.67(d,J=7.6Hz,1H),6.61(s,1H),5.26(s,2H),4.12(dd,J=9.4,8.5Hz,2H),3.96(dd,J=9.4,7.3Hz,2H),3.66(s,3H),3.16(五重峰,J=5.5Hz,1H),2.19(s,6H);MS(ESI)m/z[M+H]+ 448.0。
4-((2-(4-(丁-3-炔-2-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189n].向188(10mg,0.026mmol)中添加1-(丁-3-炔-2-基)哌嗪(18mg,0.13mmol)及Et3N(200μL,1.44mmol)於DMF(3mL)中之溶液且在90℃下加熱3小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,30:1)純化殘餘物,得到12mg(94%)189n。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.42(d,J=8.5Hz,2H),7.18(t,J=7.9Hz,1H),7.10(d,J=8.5Hz,2H),6.80(dd,J=8.3,2.4,1H),6.74(d,J=7.6Hz,1H),6.67(m,1H),5.34(s,2H),3.86-3.95(m,4H),3.72(s,3H),3.55-3.60(m,1H),2.71-2.76(m,2H),2.53-2.57(m,2H),2.29(d,J=2.1Hz,1H),1.41(d,J=7.1Hz,3H);MS(ESI)
m/z[M+H]+ 486.3。
4-((2-(4-烯丙基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189o].向188(10mg,0.026mmol)中添加1-烯丙基哌嗪(16.4mg,0.13mmol)及Et3N(200μL,1.44mmol)於DMF(3mL)中之溶液且在90℃下加熱3小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,30:1)純化殘餘物,得到11mg(89%)189o。1H NMR(500MHz,CDCl3):δ 8.24(s,1H),7.42(d,J=8.4Hz,2H),7.17(t,J=7.9Hz,1H),7.09(d,J=8.4Hz,2H),6.79(dd,J=8.2,2.2Hz,1H),6.73(d,J=7.5Hz,1H),6.67(m,1H),5.86-5.93(m,1H),5.33(s,2H),5.17-5.22(m,2H),3.88-3.90(m,4H),3.72(s,3H),3.05(d,J=6.6Hz,2H),2.50-2.53(m,4H);MS(ESI)m/z[M+H]+ 474.1。
4-((2-(4-環丙基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189p].向188(10mg,0.026mmol)中添加1-環丙基哌嗪二鹽酸鹽(26mg,0.130mmol)、DMF(1mL)及Et3N(50μL,0.358mmol)且在90℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:1)純化殘餘物,得到12mg(97%)189p。MS(m/z):[M+H]+ 474.2。
4-((2-(4-(環丙基甲基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189q].向188(10mg,0.026mmol)於DMF(1mL)中之溶液中添加1-(環丙基甲基)哌嗪(19.3μL,0.130mmol)且在90℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到9.6mg(76%)189q。MS(m/z):[M+H]+ 488.3。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(氧雜環丁烷-3-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[189r].向188(14mg,0.036mmol)於DMF(1mL)中之溶液中依序添加1-(氧雜環丁烷-3-基)哌嗪(二)三氟乙酸酯(184mg,0.50mmol)及Et3N(50μL,0.358mmol)且在90℃下加熱反應混合物4小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),40:1)純化殘餘物,得到10mg(57%)189r。MS(m/z):[M+H]+ 490.0。
4-((4-((3-甲氧基苯甲基)氧基)-2-(3,3,4-三甲基哌嗪-1-基)嘧啶-5- 基)硫基)苯甲腈[189s].向188(10mg,0.026mmol)、1,2,2-三甲基哌嗪(67mg,0.52mmol)中添加DMF(1mL)且在90℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到7.4mg(60%)189s。MS(m/z):[M+H]+ 476.2。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基-3-側氧基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[189t].向188(10mg,0.026mmol)於DMF(800μL)中之溶液中添加1-甲基哌嗪-2-酮(14.8mg,0.130mmol)且在90℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到10mg(83%)189t。MS(m/z):[M+H]+ 462.1。
4-((2-(4-(呋喃-2-基甲基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[189u].向188(10mg,0.026mmol)中添加1-(呋喃-2-基甲基)哌嗪(二)三氟乙酸酯(36.4mg,0.092mmol)、DMF(1mL)及Et3N(50μL,0.358mmol)且在90℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:1)純化殘餘物,得到10mg(75%)189u。MS(m/z):[M+H]+ 514.3。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(噻唑-2-基甲基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[189v].向188(10mg,0.026mmol)中添加2-(哌啶-4-基甲基)噻唑(二)三氟乙酸酯(38.6mg,0.094mmol)、DMF(1mL)及Et3N(50μL,0.358mmol)且在90℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:1)純化殘餘物,得到12mg(87%)189v。MS(m/z):[M+H]+ 531.1。
4-((4-((3-甲氧基苯甲基)氧基)-2-嗎啉并嘧啶-5-基)硫基)苯甲醯胺[190a].在80℃下加熱中間物189a(11mg,0.025mmol)及KOH(32.0mg,0.057mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到9.4mg(80%)190a。1H NMR(600MHz,CDCl3):δ 8.28(s,1H),7.62(d,J=8.6Hz,2H),7.17(t,J=7.8Hz,1H),7.10(d,J=8.4Hz,2H),6.78(d,J=8.1Hz,1H),6.74(d,J=7.6Hz,1H),6.67(s,1H),6.06(br s,1H),5.68(br s,1H),5.33(s,2H),3.83-3.85(m,4H),3.75-3.77(m,4H),3.68(s,3H);13C NMR(150MHz,CDCl3):δ 168.8,168.6,164.8,161.7,159.5,143.4,137.8,129.9,129.4,127.7,125.9,119.7,
113.2,113.1,98.4,67.7,66.7,55.2,44.3;HRMS(ESI)m/z[M+H]+ C23H25N4O4S之計算值,453.1597;實驗值453.1599。
4-((2-(4-異丙基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190b].在80℃下加熱189b及KOH(32.0mg,0.057mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到8.1mg(64%)190b。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.61(d,J=8.3Hz,2H),7.16(t,J=7.9Hz,1H),7.10(d,J=8.4Hz,2H),6.78(dd,J=8.2,2.4Hz,1H),6.75(d,J=7.6Hz,1H),6.68(s,1H),6.05(br s,1H),5.63(br s,1H),5.34(s,2H),3.87-3.88(m,4H),3.68(s,3H),2.75(septet,J=6.4,1H),2.57-2.59(m,4H),1.08(d,J=6.5Hz,6H);13C NMR(150MHz,CDCl3):δ 169.0,168.8,165.2,161.8,159.7,143.9,138.1,130.1,129.5,127.9,126.0,119.9,113.5,113.3,97.7,67.8,55.4,54.8,48.6,44.5,18.7;HRMS(ESI)m/z[M+H]+ C26H32N5O3S之計算值,494.2226;實驗值494.2215。
4-((2-(4-(二甲基胺基)哌啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶- 5-基)硫基)苯甲醯胺[190d].在80℃下加熱中間物189d及KOH(26.0mg,0.046mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1×2)純化殘餘物,得到5.3mg(53%)190d。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.4Hz,2H),7.16(t,J=7.9Hz,1H),7.11(d,J=8.3Hz,2H),6.78(dd,J=8.3,2.4Hz,1H),6.76(d,J=8.5Hz,1H),6.68(s,1H),6.05(br s,1H),5.57(br s,1H),5.34(s,2H),4.81(d,J=13.2Hz,2H),3.68(s,3H),2.88-2.96(m,2H),2.47-2.51(m,1H),2.34(s,6H),1.93-1.95(m,2H),1.43-1.49(m,2H);13C NMR(150MHz,CDCl3):δ 169.2,168.6,164.9,161.4,159.5,143.6,137.9,129.8,129.3,127.7,125.8,119.7,113.2,113.1,97.6,67.6,62.5,55.1,43.4,41.3,27.8;HRMS(ESI)m/z[M+H]+ C26H32N5O3S之計算值,494.2226;實驗值494.2232。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190e].在80℃下加熱189e(9.7mg,0.021mmol)及KOH(24.0mg,0.42mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到7.0mg(70%)190e。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.61(d,J=8.1Hz,2H),7.16(t,J=8.0Hz,1H),7.09(d,J=8.0Hz,2H),6.77(dd,J=8.0,2.0Hz,2H),6.69(s,1H),6.05(br s,1H),5.61(br s,1H),5.36(s,2H),3.82-3.96(m,2H),
3.67(s,3H),3.49-3.55(m,1H),3.31-3.35(m,1H),2.76-2.82(m,1H),2.34(s,3H),2.33(s,3H),2.21-2.24(m,1H),1.88-1.95(m,1H);13C NMR(150MHz,CDCl3):δ 168.8,168.5,164.9,160.2,159.5,143.8,138.2,129.8,129.3,127.7,125.7,119.9,113.3,113.2,97.3,67.6,65.4,55.2,51.3,46.1,44.4,30.4;HRMS(ESI)m/z[M+H]+ C25H30N5O3S之計算值,480.2069;實驗值480.2079。
(S)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190f].在80℃下加熱189f(9.5mg,0.021mmol)及KOH(24.0mg,0.42mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到6.4mg(64%)190f。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.61(d,J=8.3Hz,2H),7.16(t,J=7.9Hz,1H),7.09(d,J=8.5Hz,2H),6.77(dd,J=8.1,2.2Hz,2H),6.69(s,1H),6.06(br s,1H),5.63(br s,1H),5.36(s,2H),3.84-3.96(m,2H),3.68(s,3H),3.49-3.54(m,1H),3.32-3.35(m,1H),2.77-2.79(m,1H),2.34(s,3H),2.33(s,3H),2.20-2.24(m,1H),1.89-1.93(m,1H);13C NMR(150MHz,CDCl3):δ 168.8,168.4,164.9,160.2,159.5,143.8,138.2,129.8,129.3,127.7,125.7,119.9,113.3,113.2,97.3,67.6,65.5,55.1,51.3,46.1,44.4,30.4;HRMS(ESI)m/z[M+H]+ C25H30N5O3S之計算值,480.2069;實驗值480.2063。
4-((2-((2-(二甲基胺基)乙基)(甲基)胺基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190g].在80℃下加熱189g(7.0mg,0.018mmol)及KOH(22.5mg,0.40mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1,隨後15:1)純化殘餘物,得到4.7mg(64%)190g。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.63(d,J=8.1Hz,2H),7.16(t,J=7.8Hz,1H),7.12(d,J=7.8Hz,2H),6.78(dd,J=8.2,2.3Hz,2H),6.67(s,1H),6.07(br s,1H),5.62(br s,1H),5.36(s,2H),3.81-3.90(m,2H),3.68(s,3H),3.22(s,3H),2.63-2.84(m,2H),2.54(s,3H),2.38(s,3H);13C NMR(150MHz,CDCl3):δ 168.9,168.7,165.0,162.2,159.8,143.8,138.2,130.1,129.6,127.9,126.1,119.4,113.3,113.2,97.9,67.7,56.1,55.4,45.4,45.0,36.2;HRMS(ESI)m/z[M+H]+ C25H30N5O3S之計算值,468.2069;實驗值468.2074。
(4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基-1,4-二氮雜環庚烷-1-基)嘧啶-5-基)硫基)苯甲醯胺[190h].在80℃下加熱189h(10.1mg,0.022mmol)及KOH(24.5mg,0.44mmol)於t-BuOH(1mL)中之混合
物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1,隨後15:1)純化殘餘物,得到6.5mg(62%)190h。1H NMR(600MHz,CDCl3):δ 8.18(s,1H),7.61(d,J=8.2Hz,2H),7.09(t,J=7.8Hz,1H),7.05(d,J=7.5Hz,2H),6.73(dd,J=8.2,2.4Hz,1H),6.67(d,J=8.5Hz,1H),6.65(s,1H),5.26(s,2H),3.73-3.81(m,4H),3.58(s,3H),3.16-3.17(m,2H),2.61-2.67(m,2H),2.54-2.56(m,2H),2.28(s,3H);13C NMR(150MHz,CDCl3):δ 170.0,169.8,166.4,163.1,160.9,144.4,139.8,131.7,130.7,129.3,126.5,120.9,114.5,114.1,98.2,68.9,58.5,57.9,56.0,47.3,47.1,46.8,27.8;HRMS(ESI)m/z[M+H]+ C25H30N5O3S之計算值,480.2069;實驗值480.2069。
4-((2-(4-(己-5-炔-1-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190j].在80℃下加熱189j(20mg,0.039mmol)及KOH(48mg,0.86mmol)於t-BuOH(3mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到17.2mg(83%)190j。1H NMR(500MHz,CDCl3)δ 8.26(s,1H),7.61(d,J=8.5Hz,2H),7.17(t,J=7.9Hz,1H),7.09(d,J=8.5Hz,2H),6.77(dd,J=8.2,2.5Hz,1H),6.75(d,J=7.6Hz,1H),6.67(s,1H),6.15(br s,1H),5.93(br s,1H),5.33(s,2H),3.88(m,4H),3.67(s,3H),2.52(m,4H),2.40-2.43(m,2H),2.25(td,J=7.2,2.6Hz,2H),1.98(t,J=2.6Hz,1H),1.63-1.71(m,2H),1.57-1.61(m,2H);13C NMR(125MHz,CDCl3)δ 169.1,168.7,165.1,161.7,159.6,143.7,
138.0,130.0,129.5,127.9,125.9,119.9,113.4,113.3,97.8,84.4,68.8,67.8,58.2,55.3,53.1,44.0,26.5,26.0,18.5;HRMS(ESI)m/z[M+H]+ C29H34N5O3S之計算值532.2382;實驗值532.2366。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(戊-4-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[190k].在80℃下加熱189k(18mg,0.0360mmol)及KOH(44mg,0.792mmol)於t-BuOH(3mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到12.4mg(67%)190k。1H NMR(500MHz,CDCl3)δ 8.27(s,1H),7.62(d,J=8.5Hz,2H),7.17(t,J=7.9Hz,1H),7.11(d,J=8.5Hz,2H),6.78(dd,J=8.3,2.4Hz,1H),6.75(d,J=7.6Hz,1H),6.69(s,1H),6.05(br s,1H),5.68(br s,1H),5.34(s,2H),3.91(m,4H),3.69(s,3H),2.56(m,6H),2.30(td,J=7.0,2.5Hz,2H),1.98(t,J=2.6Hz,1H),1.80(m,2H);13C NMR(125MHz,CDCl3)δ 169.0,168.8,165.1,161.8,159.8,143.7,138.1,130.2,129.6,128.0,126.1,120.0,113.5,113.4,84.0,69.0,67.9,57.4,55.4,53.6,53.1,43.9,16.6;HRMS(ESI)m/z[M+H]+ C28H32N5O3S之計算值518.2226;實驗值518.2233。
4-((2-(3-(二甲基胺基)氮雜環丁烷-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190m].在80℃下加熱189m(11.5mg,0.026mmol)及KOH(32mg,0.57mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到7.1mg(59%)190m。1H NMR(600MHz,CDCl3)δ 8.25(s,1H),7.61(d,J=8.5Hz,2H),7.17(t,J=7.9Hz,1H),7.07(d,J=8.5Hz,2H),6.74-6.81(m,2H),6.69(s,1H),6.10(br s,1H),5.71(br s,1H),5.34(s,2H),4.19-4.23(m,2H),4.04-4.07(m,2H),3.69(s,3H),3.27(m,1H),2.28(s,6H);13C NMR(150MHz,CDCl3)δ 169.03,168.98,165.1,162.7,159.7,143.6,138.0,130.1,129.5,128.0,126.0,120.3,113.7,113.5,98.8,67.9,56.0,55.4,54.3,42.0;HRMS(ESI)m/z[M+H]+ C24H28N5O3S之計算值466.1913;實驗值466.1927。
4-((2-(4-(丁-3-炔-2-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190n].在80℃下加熱189n(12mg,0.025mmol)及KOH(30mg,0.54mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到8.6mg(68%)190n。1H NMR(600MHz,CDCl3)δ 8.27(s,1H),7.62(d,J=8.5Hz,2H),7.17(t,J=7.9Hz,1H),7.11(d,J=8.5Hz,2H),6.77-6.80(m,1H),6.75(d,J=7.5Hz,1H),6.68(s,1H),6.06(br s,1H),5.68(br s,1H),5.34(s,2H),3.85-3.96(m,4H),3.68(s,3H),3.55-3.61(m,1H),2.70-2.77(m,2H),2.52-2.59(m,2H),2.29(d,J
=2.2Hz,1H),1.40(d,J=7.0Hz,3H);13C NMR(150MHz,CDCl3)δ 168.8,168.6,164.9,161.5,159.5,143.6,137.9,129.9,129.3,127.7,125.8,119.8,113.3,113.1,97.7,81.8,73.1,67.6,55.1,51.8,48.7,43.9,19.1;HRMS(ESI)m/z[M+H]+ C27H30N5O3S之計算值504.2069;實驗值504.2090。
4-((2-(4-烯丙基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190o].在80℃下加熱189o(11mg,0.023mmol)及KOH(28.3mg,0.51mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到10.2mg(90%)190o。1H NMR(500MHz,CDCl3)δ 8.26(s,1H),7.61(d,J=8.4Hz,2H),7.16(t,J=7.9Hz,1H),7.10(d,J=8.4Hz,2H),6.74-6.80(m,2H),6.68(s,1H),6.05(br s,1H),5.85-5.95(m,1H),5.74(br s,1H),5.33(s,2H),5.19-5.24(m,2H),3.87-3.89(m,4H),3.68(s,3H),3.05(d,J=6.5Hz,2H),2.51-2.53(m,4H);13C NMR(125MHz,CDCl3)δ 168.8,168.6,164.9,161.6,159.6,143.6,137.9,134.6,130.0,129.3,127.7,125.9,119.8,118.5,113.3,113.1,97.8,67.6,61.8,55.2,52.8,43.9;HRMS(ESI)m/z[M+H]+ C26H30N5O3S之計算值492.2069;實驗值492.2052。
4-((2-(4-環丙基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190p].在80℃下加熱189p(12mg,0.025mmol)及KOH(28.4mg,0.50mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到8.2mg(67%)190p。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.5Hz,2H),7.16(t,J=7.9Hz,1H),7.11(d,J=8.5Hz,2H),6.78(dd,J=8.2,2.4Hz,1H),6.76(d,J=7.6Hz,1H),6.68(s,1H),6.05(br s,1H),5.57(br s,1H),5.34(s,2H),3.83(m,4H),3.68(s,3H),2.67(m,4H),1.65(m,1H),0.48-0.52(m,4H);13C NMR(150MHz,CDCl3):δ 168.7,168.5,164.9,161.6,159.5,143.6,137.9,129.8,129.3,127.7,125.8,119.7,113.2,113.1,97.6,67.6,55.1,53.1,43.9,38.5,5.9;HRMS(ESI)m/z[M+H]+ C26H30N5O3S之計算值,492.2069;實驗值492.2051。
4-((2-(4-(環丙基甲基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190q].在80℃下加熱189q(9.6mg,0.0196mmol)及KOH(22mg,0.392mmol)於t-BuOH(2mL)中之混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到8.0mg(81%)190q。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.5Hz,2H),7.16(t,J=7.9Hz,1H),7.11(d,J=8.5Hz,2H),6.78(dd,J=8.2,2.3Hz,1H),6.76(d,J=7.6Hz,1H),6.68(s,1H),6.03(br s,1H),5.57(br s,1H),5.33(s,2H),
3.91(m,4H),3.68(s,3H),2.61(m,4H),2.33(m,2H),0.92(m,1H),0.56(m,2H),0.15(m,2H);13C NMR(150MHz,CDCl3):δ 168.7,168.5,164.9,161.5,159.5,143.5,137.8,129.8,129.3,127.7,125.8,119.7,113.2,113.1,97.7,67.6,63.7,55.1,52.9,43.8,8.2,4.0;HRMS(ESI)m/z[M+H]+ C27H32N5O3S之計算值,506.2226;實驗值506.2209。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(氧雜環丁烷-3-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[190r].在80℃下加熱189r(10mg,0.020mmol)及KOH(22.4mg,0.4mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到4.5mg(44%)190r。1H NMR(600MHz,MeOH-d 4 ):δ 8.25(s,1H),7.72(d,J=3.3Hz,2H),7.14(t,J=7.9Hz,1H),7.10(d,J=8.5Hz,2H),6.78(dd,J=8.1,2.4Hz,1H),6.72(d,J=8.1Hz,1H),6.68(s,1H),5.32(s,2H),4.71(t,J=6.7Hz,2H),4.64(t,J=6.2Hz,2H),3.90(m,4H)3.64(s,3H),3.51-3.55(m,1H),2.42(m,4H);13C NMR(150MHz,MeOH-d 4 ):δ 171.7,170.1,165.9,162.9,161.1,144.6,139.4,131.7,130.4,129.2,126.8,120.6,114.3,113.9,99.8,76.5,68.9,60.3,55.6,50.4,44.6;HRMS(ESI)m/z[M+H]+ C26H30N5O4S之計算值,508.2019;實驗值508.2014。
4-((4-((3-甲氧基苯甲基)氧基)-2-(3,3,4-三甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[190s].在80℃下加熱中間物189s(7.4mg,0.015mmol)及KOH(16.8mg,0.3mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到6.9mg(93%)190s。MS(m/z):[M+H]+ 494.1。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-甲基-3-側氧基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[190t].在80℃下加熱189t(10mg,0.021mmol)及KOH(24.2mg,0.433mmol)於t-BuOH(2mL)中之混合物45分鐘。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到3.0mg(30%)190t。1H NMR(600MHz,MeOH-d 4 ):δ 8.30(s,1H),7.72(d,J=8.6Hz,2H),7.14(t,J=7.9Hz,1H),7.11(d,J=8.6Hz,2H),6.78(dd,J=8.2,2.3Hz,1H),6.72(d,J=7.6Hz,1H),6.69(s,1H),5.36(s,2H),4.40(s,2H),4.10(t,J=5.4Hz,2H),3.65(s,3H),3.47(t,J=5.4Hz,2H),3.01(s,3H);13C NMR(150MHz,MeOH-d 4 ):δ 171.6,170.2,168.4,165.9,162.2,161.2,144.3,139.3,131.8,130.4,129.3,126.9,120.6,114.5,113.8,100.9,69.1,55.6,
41.7,34.7;HRMS(ESI)m/z[M+H]+ C24H26N5O4S之計算值,480.1706;實驗值480.1702。
4-((2-(4-(呋喃-2-基甲基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[190u].在80℃下加熱189u(10mg,0.0194mmol)及KOH(22mg,0.39mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到8.8mg(85%)190u。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.5Hz,2H),7.41(m,1H),7.16(t,J=7.9Hz,1H),7.10(d,J=8.5Hz,2H),6.78(dd,J=8.2,2.3Hz,1H),6.74(d,J=7.6Hz,1H),6.66(s,1H),6.34(m,1H),6.24(d,J=3.0Hz,1H),6.03(br s,1H),5.60(br s,1H),5.44(s,2H),3.90(m,4H),3.66(s,3H),3.61(s,2H),2.54(m,4H);13C NMR(150MHz,CDCl3):δ 168.7,168.5,164.9,161.5,159.5,143.5,142.4,137.8,129.8,129.3,127.7,125.8,119.7,113.2,113.1,110.1,109.1,97.7,67.6,55.1,54.8,52.8,43.7;HRMS(ESI)m/z[M+H]+ C28H30N5O4S之計算值,532.2019;實驗值532.2020。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(噻唑-2-基甲基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[190v].在80℃下加熱189u(12mg,0.023mmol)及KOH(25.2mg,0.45mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到9.6mg(76%)190v。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.74(d,J=3.3Hz,1H),7.62(d,J=8.5Hz,2H),7.33(d,J=3.3Hz,1H),7.16(t,J=7.9Hz,1H),7.11(d,J=8.5Hz,2H),6.78(dd,J=8.2,2.3Hz,1H),6.74(d,J=7.6Hz,1H),6.68(s,1H),6.05(br s,1H),5.51(br s,1H),5.44(s,2H),4.05(s,2H),3.90(m,4H),3.66(s,3H),2.66(m,4H);13C NMR(150MHz,CDCl3):δ 169.4,168.7,168.5,164.9,161.5,159.5,143.5,142.5,137.8,129.9,129.3,127.7,125.8,119.7,113.2,113.1,97.8,67.6,59.5,55.1,52.8,43.9;HRMS(ESI)m/z[M+H]+ C27H29N6O3S2之計算值,549.1743;實驗值549.1761。
流程30. 合成193.
試劑及條件:a.(S)-1-N-Boc-2-甲基哌嗪,DMF,Et3N,90℃,2小時;b. TFA,CH2Cl2,室溫,4小時;c.福馬林,氰基硼氫化鈉,乙酸鈉,MeOH,50℃,5小時;d. KOH,t-BuOH,80℃,1小時。
(R)-4-((4-((3-甲氧基苯甲基)氧基)-2-(2-甲基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[191].向188(15mg,0.039mmol)於DMF(3mL)中之溶液中添加(S)-1-N-Boc-2-甲基哌嗪(9.4mg,0.047mmol)及Et3N(10
μL,0.072mmol)且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到定量產率之經Boc保護中間物。向其中添加1mL CH2Cl2:TFA(7:3)之溶液且在室溫下攪拌4小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到17mg(98%)191。1H NMR(500MHz,CDCl3):δ 8.17(s,1H),7.35(d,J=8.4Hz,2H),7.10(t,J=7.8Hz,1H),7.04(d,J=8.4Hz,2H),6.72(dd,J=8.1,1.7,1H),6.67(d,J=7.5Hz,1H),6.60(s,1H),5.29(d,J=12.7Hz,1H),5.24(d,J=12.7Hz,1H),4.76(m,1H),4.42-4.47(m,1H),3.65(s,3H),3.00-3.12(m,2H),2.84-2.94(m,2H),2.67-2.73(m,1H),1.22(d,J=6.8Hz,3H);MS(ESI)m/z[M+H]+ 448.3。
(R)-4-((2-(2,4-二甲基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[192].向191(17mg,0.038mmol)於MeOH(5mL)中之溶液中添加福馬林(20μL,0.269mmol)、乙酸鈉(20mg,0.244mmol)及氰基硼氫化鈉(20mg,0.095mmol)且在50℃下加熱5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到15mg(86%)192。MS(ESI)m/z[M+H]+ 462.2。
(R)-4-((2-(2,4-二甲基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[193].在80℃下加熱192(15mg,0.0325mmol)及KOH(40mg,0.71mmol)於t-BuOH(3mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到12.2mg(78%)193。1H NMR(500MHz,CDCl3)δ 8.28(s,1H),7.62(d,J=8.2Hz,2H),7.12-7.18(m,3H),6.75-6.79(m,2H),6.69(s,1H),6.07(br s,1H),5.81(br s,1H),5.35(d,J=12.0Hz,1H),5.29(d,J=12.0Hz,1H),4.87(s,1H),4.53(d,J=13.0Hz,1H),3.69(s,3H),3.28(t,J=12.6Hz,1H),2.90(d,J=10.6Hz,1H),2.76(d,J=
11.2Hz,1H),2.32(s,3H),2.23(d,J=10.6Hz,1H),2.03(t,J=11.5Hz,1H),1.31(d,J=6.6Hz,3H);13C NMR(125MHz,CDCl3)δ 169.1,168.8,165.2,161.5,159.8,143.8,138.2,130.1,129.5,128.0,126.1,119.9,113.4,113.2,97.8,67.8,60.1,55.4,55.3,47.1,46.7,39.3,15.6;HRMS(ESI)m/z[M+H]+ C25H30N5O3S之計算值480.2069;實驗值480.2054。
流程31. 合成195.
試劑及條件:a.(i)2,5-二氮雜雙環[2.2.1]庚烷-2-甲酸第三丁酯,DMF,90℃,2小時;(ii)TFA,CH2Cl2,室溫,2小時;b. 37%甲醛,NaBH(OAc)3,CH3COONa,CH3OH,50℃,5小時;c. KOH,t-BuOH,80℃,1小時。
4-((4-((3-甲氧基苯甲基)氧基)-2-(5-甲基-2,5-二氮雜雙環[2.2.1]庚-2-基)嘧啶-5-基)硫基)苯甲腈[194].向188(15.0mg,0.039mmol)於DMF(2mL)中之溶液中添加2,5-二氮雜雙環[2.2.1]庚烷-2-甲酸第三丁酯(11.6mg,0.0585mmol)且在90℃下加熱2小時。在減壓下移除溶劑,向殘餘物中依序經5分鐘逐滴添加CH2Cl2(3mL)及TFA(1mL)且在室溫下攪拌反應混合物2小時。在減壓下濃縮反應混合物且在高真空下乾燥隔夜。將此殘餘物溶解於CH3OH(3mL)中且向其中添加37%甲醛(40μL,15mg,0.495mmol)、三乙醯氧基硼氫化鈉(35mg,0.165mmol)及乙酸鈉(27mg,0.330mmol)且在50℃下加熱反應物5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化
殘餘物,得到16.2mg(91%)194。MS(m/z):[M+H]+ 460.18。
4-((4-((2-胺基吡啶-4-基)甲氧基)-2-(5-甲基-2,5-二氮雜雙環[2.2.1]庚-2-基)嘧啶-5-基)硫基)苯甲醯胺[195].在80℃下加熱194(16.2mg,0.0353mmol)及KOH(39.5mg,0.706mmol)於t-BuOH(3mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到10.0mg(60%)195。1H NMR(600MHz,CDCl3):δ 8.19(s,1H),7.55(d,J=8.2Hz,2H),7.09(t,J=7.9Hz,1H),7.03(d,J=8.2Hz,2H),6.68-6.72(m,2H),6.61(s,1H),5.99(br s,1H),5.62(br s,1H),5.52(s,2H),4.73-4.78(m,1H),3.35-3.74(m,3H),3.61(s,3H),2.96(m,1H),2.50-2.70(m,1H),2.41(s,3H),1.78-1.99(m,2H);HRMS(ESI)m/z[M+H]+ C25H28N5O3S之計算值,478.1913;實驗值478.1897。
流程32. 合成198.
試劑及條件:a.(i)哌嗪,Et3N,DMF,90℃,2小時。(ii)TFA,CH2Cl2,室溫,2小時;b.丙炔基溴,Et3N,DMF,90℃,1小時;c. KOH,t-BuOH,80℃,1小時。
4-((4-((3-甲氧基苯甲基)氧基)-2-(哌嗪-1-基)嘧啶-5-基)硫基)苯甲 腈[196].向188(75mg,0.195mmol)中添加哌嗪(47mg,0.254mmol)及Et3N(50μL,0.36mmol)於DMF(4mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到定量產率之經Boc保護中間物。向其中添加5mL CH2Cl2:TFA(7:3)之溶液且在室溫下攪拌2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到58mg(69%)196。MS(ESI)m/z[M+H]+ 434.3。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[197].在90℃下加熱196(20mg,0.046mmol)、丙炔基溴(80%甲苯溶液;8.2mg,0.055mol)及Et3N(14mg,0.138mmol)於DMF(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),30:1)純化殘餘物,得到14mg(63%)197。MS(ESI)m/z[M+H]+ 472.3。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[198].在80℃下加熱197(10mg,0.021mmol)及KOH(26mg,0.466mmol)於t-BuOH(3mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到3.6mg(35%)198。1H NMR(500MHz,CDCl3)δ 8.29(s,1H),7.63(d,J=8.5Hz,2H),7.18(t,J=7.9Hz,1H),7.12(d,J=8.5Hz,2H),6.79(dd,J=8.2,2.3Hz,1H),6.75(d,J=7.6Hz,1H),6.68(s,1H),6.04(br s,1H),5.60(br s,1H),5.34(s,2H),4.06(m,4H),
3.70(s,3H),3.57(s,2H),2.85(m,4H),2.42(s,1H);HRMS(ESI)m/z[M+H]+ C26H28N5O3S之計算值490.1913;實驗值490.1899
流程33. 合成205-208.
試劑及條件:a.(R)-N,N-二甲基吡咯啶-3-胺,DMF,90℃,2小時;b. NIS,TFA,ACN,室溫;c. 4-巰基苯甲腈,噻吩-2-甲酸銅(I),K2CO3,DMF,120℃,20小時;d. TFA,CH2Cl2,室溫,12小時;e. POCl3,100℃,1小時;f. ROH,NaH,CH3CN,室溫,3小時;g. KOH,t-BuOH,80℃,1小時。
(R)-1-(4-((4-甲氧基苯甲基)氧基)嘧啶-2-基)-N,N-二甲基吡咯啶-3-胺[200].向2-氯-4-((4-甲氧基苯甲基)氧基)嘧啶(199;0.9g,3.60mmol)於DMF(10mL)中之溶液中添加(R)-N,N-二甲基吡咯啶-3-胺(0.67mL,0.62g,5.4mmol)且在90℃下加熱2小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH-NH3(7N),50:1)純化粗產物,得到1.12g(86%)油狀物200。1H NMR(500MHz,CDCl3):δ 8.05(d,J=5.7Hz,1H),7.37(d,J=8.5Hz,2H),6.89(d,J=8.5Hz,2H),5.99(d,J=5.7,2H),5.31(s,2H),3.91-3.96(m,1H),3.83-3.88(m,1H),3.81(s,3H),3.46-3.53(m,1H),3.28-3.32(m,1H),2.73-2.81(m,1H),2.33(s,6H),2.18-2.24(m,1H),1.84-1.95(m,1H);13C NMR(125MHz,
CDCl3):δ 169.4,160.3,159.6,158.2,130.1,129.2,114.0,96.4,67.2,65.7,55.5,51.1,45.9,44.6,30.6;MS(ESI)m/z[M+H]+ 329.2。
(R)-1-(5-碘-4-((4-甲氧基苯甲基)氧基)嘧啶-2-基)-N,N-二甲基吡咯啶-3-胺[201].向200(1.12g,3.41mmol)於乙腈(17mL)中之溶液中添加N-碘丁二醯亞胺(0.917g,4.09mmol)及TFA(1.02mL,1.56g,13.65mmol),且在室溫下攪拌反應混合物1.5小時。用Na2CO3(pH約8)鹼化反應混合物,濃縮至乾且將殘餘物溶解於EtOAc(150mL)中,且用10%硫代硫酸鈉(50mL)及鹽水(2×40mL)洗滌。經MgSO4乾燥有機層,過濾且濃縮,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH-NH3(7N),50:1)純化,得到1.13g(76%)201。1H NMR(500MHz,CDCl3):δ 8.26(s,1H),7.38(d,J=8.6Hz,2H),6.89(d,J=8.6Hz,2H),5.36(s,2H),3.83-3.89(m,1H),3.81(s,3H),3.73-3.79(m,1H),3.43-3.51(m,1H),3.28-3.33(m,1H),2.78-2.84(m,1H),2.34(s,6H),2.18-2.24(m,1H),1.86-1.96(m,1H);MS(ESI)m/z[M+H]+ 455.1。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((4-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[202].將201(0.7g,1.54mmol)、4-巰基苯甲腈(0.25g,1.85mmol)及K2CO3(0.64g,4.62mmol)於DMF(20mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.12g,0.61mmol),抽空且用氬氣回填兩次,且在130℃下加熱反應混合物16小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:CH3OH,10:1)純化,得到0.42g(58%)202。MS(ESI)m/z[M+H]+ 462.1。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-羥基嘧啶-5-基)硫基)苯甲腈[203].將3mL CH2Cl2及4mL TFA添加至202(0.42g,0.9mmol)中且在室溫下攪拌2小時。在減壓下濃縮反應混合物且藉由急驟管柱層析(CH2Cl2:CH3OH,10:1)純化殘餘物,得到0.30g(97%)203。MS(m/z):[M+H]+ 342.1。
(R)-4-((4-氯-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲腈[204].在100℃下加熱203(0.12g,0.35mmol)及POCl3(2mL)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×50mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(CH2Cl2:MeOH,40:1至20:1)純化,得到0.12g(95%)204。1H NMR(500MHz,CDCl3):δ 8.40(s,1H),7.51(d,J=8.3Hz,2H),7.12(d,J=8.4Hz,2H),3.94-3.99(m,1H),3.83-3.91(m,1H),3.53-3.60(m,1H),3.41-3.45(m,1H),2.84-2.91(m,1H),2.37(s,6H),2.24-2.30(m,1H),1.96-2.03(m,1H);MS(ESI)m/z[M+H]+ 360.10。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-(三氟甲氧基)苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[205].向溶解於CH3CN(1mL)中之(3-(三氟甲氧基)苯基)甲醇(6.3μL,8.1mg,0.042mmol)中添加NaH(2.8mg,0.116mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加204(10mg,0.0289mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)部分純化,得到8.2mg中間物腈(MS(m/z):[M+H]+ 516.2)。在80℃下加熱其與KOH(20.0mg,0.35mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)
純化殘餘物,得到6.6mg(78%)205。1H NMR(600MHz,CDCl3):δ 8.23(s,1H),7.64(d,J=8.5Hz,2H),7.25(d,J=7.9Hz,1H),7.12(d,J=8.5Hz,2H),7.09(d,J=8.7,1H),7.07(t,J=7.3,1H),7.05(s,1H),6.00(br s,1H),5.62(br s,1H),5.37(s,2H),3.93-3.99(m,1H),3.78-3.87(m,1H),3.45-3.56(m,1H),3.03-3.40(m,1H),2.77-2.86(m,1H),2.34(s,6H),2.20-2.25(m,1H),1.90-1.96(m,1H);13C NMR(150MHz,CDCl3+CD3OD):δ 168.6,168.2,165.1,160.2,149.1,143.7,138.9,129.9,129.7,127.8,125.7,125.6,125.5,121.9(q,J=255.6Hz),120.2,119.9,97.3,66.7,65.4,51.1,45.9,44.3,30.1;HRMS(ESI)m/z[M+H]+ C25H27F3N5O3S之計算值,534.1787;實驗值534.1782。
(R)-4-((4-((2-胺基吡啶-4-基)甲氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲醯胺[206].向溶解於CH3CN(1mL)中之((2-胺基吡啶-4-基)甲醇(5.4mg,0.042mmol)中添加NaH(2.8mg,0.116mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加204(10mg,0.0289mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到8.0mg中間物腈(MS(m/z):[M+H]+ 448.2)。在80℃下加熱其與KOH(22.0mg,0.39mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到4.8mg(58%)206。1H NMR(600MHz,CDCl3):δ 8.31(s,1H),7.92(s,
1H),7.66(d,J=8.3Hz,2H),7.17(d,J=8.2Hz,2H),6.43(m,1H),6.10(br s,1H),5.93(m,1H),2H),5.62(br s,1H),5.25(s,2H),4.46(br s,2H),3.75-3.98(m,2H),3.42-3.56(m,1H),3.27-3.38(m,1H),2.75-2.82(m,1H),2.33(s,6H),2.20-2.25(m,1H),1.86-1.96(m,1H);HRMS(ESI)m/z[M+H]+ C23H28N7O2S之計算值,466.2025;實驗值466.2020。
(R)-4-((4-(苯甲氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲醯胺[207].向溶解於CH3CN(1mL)中之苯甲醇(4.34μL,4.54mg,0.042mmol)中添加NaH(2.8mg,0.116mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加204(10mg,0.0289mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到8.0mg中間物腈(MS(m/z):[M+H]+ 432.2)。在80℃下加熱其與KOH(22.0mg,0.39mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到5.2mg(63%)207。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.62(d,J=8.5Hz,2H),7.22-7.24(m,3H0,7.15(m,2H),7.11(d,J=8.5Hz,2H),5.99(br s,1H),5.62(br s,1H),5.39(s,2H),3.81-3.98(m,2H),3.48-3.55(m,1H),3.31-3.37(m,1H),2.76-2.83(m,1H),2.34(s,6H),2.19-2.25(m,1H),1.88-1.96(m,1H);HRMS(ESI)m/z[M+H]+ C24H28N5O2S之計算值,450.1964;實驗值450.1962。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((4-氟-3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[208].向溶解於CH3CN(1mL)中之(4-氟-3-甲氧基苯基)甲醇(5.52μL,6.6mg,0.042mmol)中添加NaH(2.8mg,0.116mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加204(10mg,0.0289mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到7.2mg中間物腈(MS(m/z):[M+H]+ 480.2)。在80℃下加熱其與KOH(18.5mg,0.33mmol)於t-BuOH(1mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到4.1mg(55%)208。1H NMR(600MHz,CDCl3):δ 8.28(s,1H),7.60(d,J=8.5Hz,2H),7.06(d,J=8.5Hz,2H),6.93-6.97(m,1H),6.74-6.79(m,2H),6.01(br s,1H),5.55(br s,1H),5.34(s,2H),3.83-3.99(m,2H),3.52-3.57(m,1H),3.35-3.40(m,1H),2.79-2.85(m,1H),2.35(s,6H),2.20-2.27(m,1H),1.92-2.05(m,1H);13C NMR(150MHz,CDCl3):δ 168.5,165.1,160.3,152.8,151.2,147.5,143.9,132.8,129.7,127.7,125.4,120.6,115.6,113.0,97.1,67.3,65.3,56.1,51.1,45.9,44.3,30.1;HRMS(ESI)m/z[M+H]+ C25H29FN5O3S之計算值,498.1975;實驗值498.1980。
流程34. 合成212-214.
試劑及條件:a. 2-氯-4-巰基苯甲腈,噻吩-2-甲酸銅(I),K2CO3,DMF,130℃,16小時;b. POCl3,DIEA,100℃,4小時;c.(4-氟-3-甲氧基苯基)甲醇,NaH,CH3CN,室溫,2.5小時;d.胺,Et3N,DMF,90℃,2小時;e. KOH,t-BuOH,80℃,1小時。
2-氯-4-((2,4-二羥基嘧啶-5-基)硫基)苯甲腈[209].將5-碘嘧啶-2,4-二醇(174;2.7g,0.011mmol)、2-氯-4-巰基苯甲腈(2.5g,0.015mmol)及K2CO3(4.71g,0.034mmol)於DMF(80mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.865g,0.0046mmol),抽空且用氬氣回填兩次,且在130℃下加熱反應混合物16小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:CH3OH:CH3COOH,15:1:0.1)純化,得到2.0g(65%)209。MS(ESI)m/z 278.0[M-H]-。
2-氯-4-((2,4-二氯嘧啶-5-基)硫基)苯甲腈[210].向209(2.0g,7.14mmol)及POCl3(25mL)之混合物中添加DIEA(3.11mL,2.31g,17.9mmol)且在100℃下加熱反應物4小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×100mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(己
烷:EtOAc,80:20)純化,得到0.935g(41%)210。
2-氯-4-((2-氯-4-((4-氟-3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[211].向溶解於CH3CN(5mL)中之(4-氟-3-甲氧基苯基)甲醇(75.9μL,90.7mg,0.5809mmol)中添加NaH(17.0mg,0.6971mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加210(183mg,0.5809mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(正己烷:EtOAc,8:2)純化,得到59.2mg 211。1H NMR(500MHz,CDCl3):δ 8.42(s,1H),7.41(d,J=8.2Hz,1H),7.09(s,1H),6.92-6.98(m,2H),6.86(d,J=8.0Hz,1H),6.66-6.84(m,1H),5.32(s,2H),3.79(s,3H);13C NMR(125MHz,CDCl3):δ 168.7,163.7,161.5,153.7,151.7,147.7,142.8,134.1,130.6,128.4,126.1,121.5,116.4,115.7,114.3,112.1,111.1,70.0,56.4;MS(ESI)m/z[M+H]+ 436.0。
(R)-2-氯-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((4-氟-3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[212].向211(10.0mg,0.023mmol)中添加(R)-N,N-二甲基吡咯啶-3-胺(11μL,10.5mg,0.0919mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到8.7mg(74%)中間物腈(MS(m/z):[M+H]+ 514.1)。在80℃下加熱其與KOH(18.0mg,0.318mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3
(7N),20:1)純化殘餘物,得到7.2mg(80%)212。1H NMR(600MHz,CD2Cl2):δ 8.16(s,1H),7.48(d,J=8.1Hz,1H),6.90-6.94(m,2H),6.88(d,J=8.2Hz,1H),6.76(dd,J=8.2,1.6Hz,1H),6.71(s,1H),6.27(br s,1H),5.81(br s,1H),5.27(s,2H),3.73-3.88(m,2H),3.63(s,3H),3.42-3.46(m,1H),3.26-3.33(m,1H),2.76-2.80(m,1H),2.26(s,3H),2.25(s,3H),2.12-2.15(m,1H),1.86-2.90(m,1H);13C NMR(150MHz,CD2Cl2):δ 168.8,165.6,160.9,153.2,151.2,147.8,144.5,133.4,131.7,131.1,130.6,126.9,124.5,120.6,116.1,113.4,96.5,67.7,65.6,56.5,51.3,46.4,44.3,30.2;HRMS(ESI)m/z[M+H]+ C25H28ClFN5O3S之計算值,532.1585;實驗值532.1592。
(R)-4-((2-(3-胺基吡咯啶-1-基)-4-((4-氟-3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)-2-氯苯甲醯胺[213].向211(30.0mg,0.069mmol)中添加(R)-N,N-二甲基吡咯啶-3-胺(18.1μL,17.8mg,0.206mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化,得到28.0mg(84%)中間物腈(MS(m/z):[M+H]+ 486.1)。在80℃下加熱其與KOH(64.6mg,1.154mmol)於t-BuOH(5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到25.7mg(86%)213。1H NMR(600MHz,CDCl3/MeOH-d 4 ):δ 8.15(s,1H),7.45(d,J=8.1Hz,1H),6.84-6.92(m,3H),6.67-6.76(m,2H),5.27(s,2H),3.73-3.80(m,2H),3.67(s,3H),
3.58-3.62(m,1H),3.27-3.34(m,2H),2.10-2.14(m,1H),1.78-1.82(m,1H);13C NMR(150MHz,CDCl3/MeOH-d 4 ):δ 168.5,164.7,160.3,152.8,151.2,147.4,143.7,132.5,131.4,130.4,130.2,126.6,124.1,120.2,115.7,112.9,96.7,67.4,56.1,54.5,50.5,45.1,33.2;HRMS(ESI)m/z[M+H]+ C23H24ClFN5O3S之計算值,504.1272;實驗值504.1275。
(R)-2-氯-4-((4-((4-氟-3-甲氧基苯甲基)氧基)-2-(3-(甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲醯胺[214].向211(12.0mg,0.0276mmol)中添加(R)-N-甲基吡咯啶-3-胺(9.7μL,9.1mg,0.206mmol)於DMF(2mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到11.6mg(84%)中間物腈(MS(m/z):[M+H]+ 500.1)。在80℃下加熱其與KOH(26.0mg,0.465mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到7.6mg(64%)214。1H NMR(500MHz,CD2Cl2/MeOH-d 4 ):δ 8.15(s,1H),7.45(d,J=8.1Hz,1H),6.90-6.94(m,2H),6.77(dd,J=1.9及8.1Hz,1H),6.68-6.72(m,1H),5.27(s,2H),3.63-3.76(m,2H),3.65(s,3H),3.55-3.56(m,1H),3.25-3.41(m,2H),2.41(s,3H),2.12-2.19(m,1H),1.82-1.86(m,1H);HRMS(ESI)m/z[M+H]+ C24H26ClFN5O3S之計算值,518.1278;實驗值518.1280。
流程35. 合成218及225-229.
試劑及條件:a. 4-巰基-2-(三氟甲基)苯甲腈,噻吩-2-甲酸銅(I),K2CO3,DMF,130℃,16小時;b. POCl3,DIEA,100℃ 4小時;c. 3-氯苯甲醇,CH3CN,NaH,室溫4小時;d.胺,Et3N,DMF,90℃,2小時;e. KOH,t-BuOH,80℃,1小時。
4-((2,4-二羥基嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[215].將5-碘嘧啶-2,4-二醇174(3.77g,15.8mmol)、4-巰基-2-(三氟甲基)苯甲腈(3.86g,19.0mmol)及K2CO3(6.55g,47.4mmol)於DMF(100mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(1.21g,6.32mmol),抽空且用氬氣回填兩次,且在130℃下加熱反應混合物16小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:CH3OH:CH3COOH,25:1:0.3)純化,得到2.54g(51%)215。MS(ESI)m/z 312.0[M-H]-。
4-((2,4-二氯嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[216].在攪拌下向0.320g(1.022mmol)215中添加7mL POCl3(4g,25.55mmol)。向此混合物中緩慢添加450μL DIEA(0.33g,2.55mmol)且在100℃下反應物4小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×75mL)萃取,經MgSO4乾
燥,過濾且濃縮成固體,藉由管柱層析(己烷:EtOAc,80:20)純化,得到0.25g(70%)216。1H NMR(600MHz,CDCl3):δ 8.64(s,1H),7.83(d,J=8.2Hz,1H),7.69(d,J=1.7Hz,1H),7.45(dd,J=1.7,8.2Hz,1H);MS(ESI)m/z 383.8/385.8[M+Cl]-。
4-((2-氯-4-((3-氯苯甲基)氧基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[217].向溶解於CH3CN(2mL)中之3-氯苯甲醇(101mg,0.71mmol)中添加NaH(22mg,0.923mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加216(0.250g,0.71mmol)且在室溫下攪拌反應混合物4小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(己烷:CH2Cl2,40:60)純化,得到110mg(34%)217。MS(ESI)m/z[M+H]+ 456.1。
合成218及225-229之通用程序.向217(1當量)中添加胺(1.5當量)及Et3N(2當量)於DMF中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC純化殘餘物,得到中間物腈。在80℃下加熱腈(1當量)及KOH(25當量)於t-BuOH中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC純化殘餘物,得到所要醯胺。
(R)-4-((4-((3-氯苯甲基)氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[218].遵循以上通用程序獲得218,產率為51%。1H NMR(600MHz,CDCl3)δ 8.28(s,1H),7.41-7.45(m,2H),7.16-7.24(m,4H),7.03-7.07(m,1H),5.96(br s,1H),5.83(br s,1H),5.29-5.38(m,2H),3.81-4.00(m,2H),3.48-3.56(m,
1H),3.35-3.43(m,1H),2.88-2.89(m,1H),2.38(d,J=12.1Hz,6H),2.23-2.27(m,1H),1.94-2.03(m,1H);HRMS(ESI)m/z[M+H]+ C25H26ClF3N5O2S之計算值552.1448;實驗值552.1457。
4-((4-((3-氯苯甲基)氧基)-2-(3-(二甲基胺基)氮雜環丁烷-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[225].遵循以上通用程序獲得225,產率為36%。1H NMR(600MHz,CD2Cl2)δ 8.25(s,1H),7.44(d,J=1.5Hz,1H),7.41(d,J=8.2Hz,1H),7.22-7.26(m,2H),7.18-7.22(m,2H),7.06-7.09(m,1H),5.77(br s,2H),5.33(s,2H),4.16-4.19(m,2H),4.03(m,2H),3.28(br s,1H),2.26(s,6H);13C NMR(150MHz,CD2Cl2)δ 169.2,169.1,165.7,163.2,142.5,139.1,134.4,132.3,130.3,129.6,129.5,128.5,128.4,128.2(q,J=31.9Hz),126.4,124.4(q,J=5.1Hz),123.9(q,J=272.3Hz),98.0,67.7,56.4,54.6,42.0;HRMS(ESI)m/z[M+H]+ C24H24ClF3N5O2S之計算值538.1291;實驗值538.1306。
4-((4-((3-氯苯甲基)氧基)-2-(4-(己-5-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[226].遵循以上通用程序獲得226,產率為48%。1H NMR(600MHz,CDCl3)δ 8.27(s,1H),7.42-7.46(m,
2H),7.18-7.26(m,3H),7.14(s,1H),7.01-7.06(m,1H),5.93(br s,1H),5.82(br s,1H),5.32(s,2H),3.88(m,4H),2.52(m,4H),2.40-2.45(m,2H),2.25(td,J=7.0,2.6Hz,2H),1.98(t,J=2.6Hz,1H),1.64-1.70(m,2H),1.56-1.62(m,2H);13C NMR(150MHz,CDCl3)δ 169.4,168.5,165.3,161.7,142.2,138.5,134.3,131.6,130.0,129.3,129.1,128.3,128.0(q,J=29.7Hz),127.7,125.6,124.0(q,J=5.2Hz),123.4(q,J=271.3Hz),96.9,84.4,68.8,67.2,58.2,53.0,44.1,26.5,25.9,18.5;HRMS(ESI)m/z[M+H]+ C29H30ClF3N5O2S之計算值604.1761;實驗值604.1786。
4-((4-((3-氯苯甲基)氧基)-2-(4-環丙基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[227].遵循以上通用程序獲得227,產率為69%。1H NMR(600MHz,CDCl3)δ 8.27(s,1H),7.45(m,1H),7.43(d,J=8.2Hz,1H),7.20-7.24(m,3H),7.15(s,1H),7.04(m,1H),5.79-5.81(d,J=8.4Hz,2H),5.32(s,2H),3.82(m,4H),2.67(m,4H),1.65(m,1H),0.48-0.52(m,4H);13C NMR(150MHz,CDCl3)δ 169.1,168.3,165.1,161.6,142.1,138.3,134.1,131.4,129.8,129.2,129.0,128.1,127.8(q,J=31.9Hz),127.5,125.4,123.8(q,J=5.3Hz),123.2(q,J=272.3Hz),96.7,67.0,53.0,44.0,31.0,5.9;HRMS(ESI)m/z[M+H]+ C26H26ClF3N5O2S之計算值564.1448;實驗值564.1456。
4-((4-((3-氯苯甲基)氧基)-2-(4-(呋喃-2-基甲基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[228].遵循以上通用程序獲得228,產率為47%。1H NMR(600MHz,CDCl3)δ 8.26(s,1H),7.41-7.44(m,3H),7.19-7.26(m,3H),7.13(s,1H),7.02-7.03(m,1H),6.34(m,1H),6.24(d,J=3.0Hz,1H),5.78(br s,2H),5.30(s,2H),3.89(m,4H),3.60(s,2H),2.53-2.55(m,4H);13C NMR(150MHz,CDCl3)δ 169.1,168.3,165.1,161.6,151.0,142.5,142.1,138.3,134.1,131.4,129.8,129.2,129.0,128.1,127.8(q,J=32.0Hz),127.5,125.4,123.8(q,J=5.3Hz),123.2(q,J=272.6Hz),110.1,109.2,96.8,67.0,54.9,52.4,43.8;HRMS(ESI)m/z[M+H]+ C28H26ClF3N5O3S之計算值604.1397;實驗值604.1404。
4-((4-((3-氯苯甲基)氧基)-2-(4-(噻唑-2-基甲基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[229].遵循以上通用程序獲得229,產率為48%。1H NMR(600MHz,CDCl3)δ 8.27(s,1H),7.74(d,J=3.1Hz,1H),7.43-7.44(m,2H),7.35(d,J=3.1Hz,1H),7.20-7.24(m,3H),7.13(s,1H),7.02-7.03(m,1H),5.78-5.80(d,J=12.8Hz,2H),5.30(s,2H),3.94(s,2H),3.91(m,4H),2.65-2.67(m,4H);13C NMR(150MHz,
CDCl3)δ 169.4,169.0,168.3,165.1,161.6,142.5,142.0,138.3,134.1,131.5,129.8,129.2,129.1,128.1,127.8(q,J=32.0Hz),127.4,125.4,123.8(q,J=5.0Hz),123.2(q,J=272.6Hz),119.7,97.0,67.0,59.5,52.8,44.0;HRMS(ESI)m/z[M+H]+ C27H25ClF3N6O2S2之計算值621.1121;實驗值621.1139。
流程44. 合成282.
試劑及條件:a.溴乙酸乙酯,K2CO3,CH3CN,80℃,12小時;b.甲酸乙酯,NaH,THF,0℃至室溫,20小時;c.乙醇,硫脲,回流,18小時,隨後1M HCl(水溶液);d. Et3N,DMF,0℃至室溫,隔夜;e. POCl3,75℃,1小時;f. BnOH,NaH,CH3CN,室溫,2.5小時;g. m-CPBA,CH2Cl2,室溫3小時;h. N-甲基哌嗪,DMF,80℃,1小時;i. KOH,t-BuOH,80℃,1小時。
2-(4-氰基苯氧基)乙酸乙酯[276].加熱4-氰基酚(275;4.0g,33.6mmol)、溴乙酸乙酯(5.05g,30.2mmol)及K2CO3(5.8g,42.2mmol)於乙腈(50mL)中之混合物至80℃後維持12小時。在減壓下濃縮反應混合物且藉由管柱層析(己烷:EtOAc,0-40% EtOAc)純化,得到4.7g(75%)276。1H NMR(500MHz,CDCl3):δ 7.63(d,J=8.8Hz,
2H),6.99(d,J=8.8Hz,2H),4.69(s,2H),4.31(q,J=7.2Hz,2H),1.32(t,J=7.2Hz,3H);13C NMR(125MHz,CDCl3):δ 167.9,161.0,134.1,118.9,115.4,105.2,65.2,61.7,14.1;MS(m/z):[M+H]+ 205.9。
4-((4-羥基-2-巰基嘧啶-5-基)氧基)苯甲腈[277].在0℃下將276(2.05g,10mmol)及甲酸乙酯(2.70g,45mmol)於THF(50mL)中之溶液經1小時逐滴添加至NaH(0.36g,15mmol)於THF(10mL)中之懸浮液中。之後,移除冰浴且在室溫下持續攪拌20小時。在減壓下移除溶劑且將所得殘餘物溶解於乙醇(10mL)中,與硫脲(0.91g,12mmol)組合且回流反應物18小時。隨後添加1M HCl(水溶液)且過濾沈澱之固體,用水及己烷洗滌,得到1.66g(71%)277。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 7.76(d,J=8.0Hz,2H),7.75(s,1H),7.18(d,J=8.0Hz,2H);13C NMR(125MHz,CDCl3):δ 174.4,160.5,157.2,134.4,134.2,132.6,118.8,116.4,104.9;MS(m/z):[M-H]- 244.1。
4-((4-羥基-2-(甲基硫基)嘧啶-5-基)氧基)苯甲腈[278].在0℃下向277(500mg,2mmol)及Et3N(212mg,2.1mmol)於DMF(5mL)中之混合物中添加甲基碘(282mg,2mmol)。之後,移除冰浴且在室溫下持續攪拌隔夜。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,0-10% MeOH)純化,得到461mg(89%)278。1H NMR(500MHz,CDCl3/MeOH-d 4 ):δ 7.72(s,1H),7.50(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),2.47(s,3H);13C NMR(125MHz,CDCl3):δ;MS(m/z):[M+H]+ 260.0。
4-((4-氯-2-(甲基硫基)嘧啶-5-基)氧基)苯甲腈[279].在75℃下加熱278(0.200g,0.77mmol)及POCl3(1mL)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×25mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由
管柱層析(CH2Cl2:MeOH,50:1至40:1)純化,得到0.173g(81%)279。MS(m/z):[M+H]+ 277.9/279.9。
4-((4-(苯甲氧基)-2-(甲基硫基)嘧啶-5-基)氧基)苯甲腈[280].向溶解於CH3CN(500μL)中之苯甲醇(46.7mg,0.432mmol)中添加NaH(10.4mg,0.432mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加279(30mg,0.108mmol,0.0289mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)部分純化,得到28.5mg 280。1H NMR(500MHz,CDCl3):δ 8.21(s,1H),7.58(d,J=8.9Hz,2H),7.31-7.39(m,3H),7.16-7.18(m,2H),6.94(d,J=8.8Hz,2H),5.45(s,2H),2.60(s,3H);13C NMR(125MHz,CDCl3):δ 168.2,160.9,149.8,140.9,135.3,134.1,133.8,128.6,128.5,128.4,127.9,127.7,127.0,118.6,116.6,106.4,68.6,14.7;MS(m/z):[M+H]+ 350.0。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)苯甲腈[281].在室溫下攪拌280(35mg,0.1mmol)及m-CPBA(34.4mg,0.2mmol)於CH2Cl2(2mL)中之溶液3小時。隨後,在減壓下移除溶劑,將所得殘餘物溶解於DMF(1mL)中,且在80℃下與N-甲基哌嗪(26mg,0.3mmol)反應1小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH-NH3(7N),100:1至50:1)純化,得到26mg(65%)281。1H NMR(500MHz,CDCl3):δ 7.92(s,1H),7.47(d,J=7.4Hz,2H),7.18-7.21(m,3H),7.06-7.09(m,2H),6.85(d,J=7.4Hz,2H),5.27(s,2H),3.73-3.78(m,4H),2.39-2.43(m,4H),2.29(s,3H);13C NMR(125MHz,CDCl3):δ 162.1,161.3,158.9,150.8,136.1,133.9,128.4,128.1,127.6,127.4,127.0,118.8,116.1,105.6,67.7,54.9,46.2,43.1;MS(m/z):[M+H]+ 402.2。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)苯甲醯胺[282].在80℃下加熱281(10mg,0.025mmol)及KOH(35mg,0.62mmol)於t-BuOH(500μL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到8.8mg(84%)282. 1H NMR(500MHz,CDCl3):δ 7.93(s,1H),7.66(d,J=8.8Hz,2H),7.16-7.19(m,3H),7.07-7.09(m,2H),6.84(d,J=8.8Hz,2H),5.83(br s,1H),5.54(br s,1H),5.28(s,2H),3.74-3.78(m,4H),2.42-2.45(m,4H),2.30(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,161.7,161.5,158.6,150.8,136.3,129.2,128.3,128.1,128.0,127.5,127.0,115.4,67.6,54.8,46.1,44.0;MS(m/z):[M+H]+ 420.2。
化合物283及284以類似於流程44中所示之282之方式合成。
4-((4-((4-甲氧基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)苯甲醯胺[283]. 1H NMR(500MHz,CDCl3):δ 7.91(s,1H),7.65(d,J=8.7Hz,2H),7.04(d,J=8.6Hz,2H),6.82(d,J=8.7Hz,2H),6.72(d,J=8.6Hz,2H),5.73(br s,2H),5.23(s,2H),3.75(m,4H),3.71(s,3H),2.42(m,4H),2.32(s,3H);13C NMR(125MHz,CDCl3):δ 168.6,161.7,161.6,159.4,158.6,150.7,129.4,129.2,128.3,128.1,127.0,115.4,113.7,67.4,55.3,54.9,46.2,44.1;MS(m/z):[M+H]+ 450.2。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)氧基)苯甲醯胺[284]. 1H NMR(500MHz,CDCl3):δ 7.92(s,1H),7.64(d,J=8.7Hz,2H),7.05(t,J=8.6Hz,1H),6.83(d,J=8.7Hz,2H),6.54(dd,J=8.0,2.1Hz,1H),6.47(s,2H),5.86(br s,1H),5.48(br s,1H),5.24(s,2H),3.74-3.77(m,4H),2.76(s,6H),2.39-2.42(m,4H),2.28(s,3H);13C NMR(125MHz,CDCl3):δ 168.5,161.7,161.5,158.7,150.7,150.6,137.0,129.2,129.0,127.9,126.9,115.7,115.3,112.1,111.6,68.1,54.9,46.3,44.2,40.5。
流程45. 合成299.
試劑及條件:a.吡啶,哌啶,110℃,2小時;b. KOH,t-BuOH,80℃,3小時;c. H2SO4,EtOH,80℃,12小時;d. EtOH,Pd/C(10%),室溫,12小時;e. HCOOEt,NaH,THF,0℃至室溫,
24小時;f.硫脲,EtOH,回流,8小時;g. CH3I,Et3N,DMF,室溫,2小時;h. POCl3,80℃,1小時;i. BnOH,NaH,CH3CN,室溫,2.5小時;j. NaOH,EtOH,回流,8小時;k.乙二醯氯,DMF,室溫,5小時;l. NH3(g),-78℃至室溫,30分鐘;m. m-CPBA,CH2Cl2,攪拌,2小時;n. N-甲基哌嗪,K2CO3,DMF,100℃,1小時。
(E)-3-(4-氰基苯基)丙烯酸[287].向丙二酸(285;2.02g,19.47mmol)、4-甲醯基苯甲腈(286;2.55g,19.47mmol)及吡啶之混合物中添加哌啶(0.2mL)。在110℃下加熱反應混合物2小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,50:1至10:1)純化殘餘物,得到3.2g(95%)287。MS m/z[M+H]+ 174.3。
(E)-3-(4-胺甲醯基苯基)丙烯酸[288].在80℃下加熱287(3.2mg,18.5mmol)及KOH(6.0g,107.14mmol)於t-BuOH(50mL)中之混合物3小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH:CH3COOH,15:1:0.1)純化殘餘物,得到2.5g(72%)288。MS m/z[M+H]+ 192.3。
(E)-4-(3-乙氧基-3-側氧基丙-1-烯-1-基)苯甲酸乙酯[289].在80℃下加熱288(2.5g,13.1mmol)及H2SO4(6.0g,107.14mmol)於EtOH(100mL)中之混合物12小時。在減壓下移除溶劑且將殘餘物溶解於CH2Cl2(150mL)中,用水(50mL)及鹽水(2×50mL)洗滌,經MgSO4乾燥,過濾且濃縮,得到油狀物,藉由管柱層析(己烷:EtOAc:1:1)純化,得到0.72g(23%)289。MS m/z[M+H]+ 249.1。
4-(3-乙氧基-3-側氧基丙基)苯甲酸乙酯[290].向289(0.72g,2.90mmol)於EtOH(50mL)中之溶液中添加Pd/C(10%)(80mg)且在室溫下攪拌12小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,50:1至10:1)純化殘餘物,得到0.71g(97%)290。MS
m/z[M+H]+ 251.4。
4-(3-乙氧基-2-甲醯基-3-側氧基丙基)苯甲酸乙酯[291].在0℃下將290(0.5g,2mmol)及甲酸乙酯(0.67g,9mmol)於3mL THF中之混合物經30分鐘添加至NaH(0.1g,4.1mmol)於2mL THF中之懸浮液中。在添加結束時,在室溫下攪拌反應混合物24小時。在減壓下移除溶劑且藉由管柱層析(己烷:EtOAc,1:1)純化殘餘物,得到0.43g(78%)291。MS m/z[M+H]+ 279.2。
4-((4-羥基-2-巰基嘧啶-5-基)甲基)苯甲酸乙酯[292].使291(0.4g,1.43mmol)及硫脲(0.11g,1.43mmol)於40mL EtOH中之混合物回流8小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH:CH3COOH,40:1:0.1至10:1:0.1)純化殘餘物,得到0.13g(30%)292。MS m/z[M+H]+ 291.1。
4-((4-羥基-2-(甲基硫基)嘧啶-5-基)甲基)苯甲酸乙酯[293].向292(0.12g,0.414mmol)於DMF(5mL)中之溶液中添加Et3N(0.2mL)且攪拌10分鐘。隨後向反應混合物中添加甲基碘(62mg,0.43mmol)且在室溫下攪拌反應混合物2小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,10:1)純化殘餘物,得到60mg(49%)293。MS m/z[M+H]+ 305.1。
4-((4-氯-2-(甲基硫基)嘧啶-5-基)甲基)苯甲酸乙酯[294].在80℃下加熱293(60mg,0.197mmol)及POCl3(2mL)之混合物1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×25mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由製備型TLC(己烷:EtOAc,8:2)純化,得到56mg(88%)294。MS(m/z):[M+H]+ 323.0/325.0。
4-((4-(苯甲氧基)-2-(甲基硫基)嘧啶-5-基)甲基)苯甲酸乙酯[295].
向溶解於CH3CN(500μL)中之苯甲醇(10.7μL,11.3mg,0.104mmol)中添加NaH(2.8mg,0.116mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加294(28mg,0.0869mmol)且在室溫下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到31.2mg(91%)295。(MS(m/z):[M+H]+ 395.2。
4-((4-(苯甲氧基)-2-(甲基硫基)嘧啶-5-基)甲基)苯甲酸[296].使295(31mg,0.0786mmol)及NaOH(9.5mg,0.236mmol)於10mL EtOH中之混合物回流8小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS m/z[M+H]+ 367.1。
4-((4-(苯甲氧基)-2-(甲基硫基)嘧啶-5-基)甲基)苯甲醯胺[297].在室溫下向296(28mg,0.0765mmol)於DMF(2mL)中之溶液中添加乙二醯氯(6.6μL,9.6mg,0.0765mmol)且攪拌5小時,得到酸氯化物。隨後在-78℃下向反應混合物NH3(g)中鼓泡且在室溫下攪拌反應混合物30分鐘。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到24mg(86%)297。MS m/z[M+H]+ 366.2。
4-((4-(苯甲氧基)-2-(甲基磺醯基)嘧啶-5-基)甲基)苯甲醯胺[298].向297(24mg,0.0655mmol)於CH2Cl2(5mL)中之溶液中添加m-CPBA(22.6mg,0.1314mmol)且在室溫下攪拌2小時。在減壓下移除溶劑且所得碸不經進一步純化即進一步反應。MS m/z[M+H]+ 398.1。
4-((4-(苯甲氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)甲基)苯甲醯胺[299].向298(26mg,0.0656mmol)於DMF(2mL)中之溶液中添加N-
甲基哌嗪(20.5μL,18.1mg,0.181mmol)及K2CO3(7.3mg,0.1312mmol)且在100℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到20mg(69%)299。
1H NMR(500MHz,CDCl3):δ 7.86(s,1H),7.60(d,J=8.2Hz,2H),7.12-7.23(m,7H),5.24(s,2H),3.64-3.75(m,6H),2.34-2.41(m,4H),2.26(s,3H);13C NMR(125MHz,CDCl3):δ 169.1,167.1,160.9,157.5,144.9,136.8,131.0,128.9,128.4,127.9,127.7,127.4,108.4,67.3,54.9,46.2,43.9,32.8;MS m/z[M+H]+ 418.1。
流程46. 合成304.
試劑及條件:a. 4-CNBnOH,NaH,CH3CN,室溫,2.5小時;b. NaOH,EtOH,回流,8小時;b.乙二醯氯,DMF,室溫,5小時;c. NH3(g),-78℃至室溫,30分鐘;d. m-CPBA,CH2Cl2,室溫,2小時;e. N-甲基哌嗪,K2CO3,DMF,100℃,1小時。
4-((4-((4-氰基苯甲基)氧基)-2-(甲基硫基)嘧啶-5-基)甲基)苯甲酸乙酯[300].向溶解於CH3CN(500μL)中之4-氰基苯甲醇(11.9μL,13.8mg,0.104mmol)中添加NaH(2.8mg,0.116mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加294(28mg,0.0869mmol)且在室溫
下攪拌反應混合物2.5小時。添加MeOH(1mL)且攪拌5分鐘,隨後在減壓下濃縮反應混合物,得到殘餘物,其藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到29.2mg(81%)300(MS(m/z):[M+H]+ 420.2)。
4-((4-((4-氰基苯甲基)氧基)-2-(甲基硫基)嘧啶-5-基)甲基)苯甲酸[301].使300(29mg,0.0692mmol)及NaOH(8.3mg,0.2076mmol)於10mL EtOH中之混合物回流8小時。在減壓下移除溶劑且殘餘物不經進一步純化即用於下一步驟中。MS m/z[M+H]+ 392.1。
4-((4-((4-氰基苯甲基)氧基)-2-(甲基硫基)嘧啶-5-基)甲基)苯甲醯胺[302].在室溫下向301(27mg,0.069mmol)於DMF(2mL)中之溶液中添加乙二醯氯(5.9μL,8.7mg,0.069mmol)且攪拌5小時,得到酸氯化物。隨後在-78℃下向反應混合物NH3(g)中鼓泡且在室溫下攪拌反應混合物30分鐘。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到23mg(85%)302。MS m/z[M+H]+ 391.2。
4-((4-((4-氰基苯甲基)氧基)-2-(甲基磺醯基)嘧啶-5-基)甲基)苯甲醯胺[303].向302(23mg,0.0588mmol)於CH2Cl2(5mL)中之溶液中添加m-CPBA(20.2mg,0.1176mmol)且在室溫下攪拌2小時。在減壓下移除溶劑且所得碸不經進一步純化即進一步反應。MS m/z[M+H]+ 423.1。
4-((4-((4-氰基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)甲基)苯甲醯胺[304].向303(25mg,0.0591mmol)於DMF(2mL)中之溶液中添加N-甲基哌嗪(19.7μL,17.7mg,0.177mmol)及K2CO3(6.6mg,0.1182mmol)且在100℃下加熱混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到17mg(65%)304。1H NMR(500MHz,CDCl3):δ 7.87(s,1H),7.66
(d,J=8.4Hz,2H),7.51(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),7.16(d,J=8.4Hz,2H),5.29(s,2H),3.75(s,2H),3.66-3.71(m,4H),2.37-2.43(m,4H),2.27(s,3H);MS m/z[M+H]+ 443.1。
流程47. 合成306-308.
試劑及條件:a. Ac2O,CH2Cl2,0℃,30分鐘;b. EtMgBr,MeTi(O-i-Pr)3,THF,-78℃至室溫;c. TFA,CH2Cl2,室溫,24小時。
4-乙醯基哌嗪-1-甲酸第三丁酯[306].經兩分鐘向冷卻至0℃之305(1g,5.36mmol)於CH2Cl2(10mL)中之溶液中添加乙酸酐(557μL,5.9mmol)。在0℃下攪拌反應混合物30分鐘。在減壓下移除溶劑,用飽和NaHCO3(40mL)處理粗物質且用乙醚(3×30mL)萃取。經MgSO4乾燥經合併之有機萃取物且濃縮溶劑,得到0.86g(70%)呈透明油狀之306,其不經進一步純化即使用。MS(m/z):[M+Na]+ 251.5。
4-(1-甲基環丙基)哌嗪-1-甲酸第三丁酯[307].將306(850mg,3.72mmol)溶解於無水THF(10mL)中且在氬氣下冷卻至-78℃。經3分鐘向其中添加MeTi(O-i-Pr)3溶液(4.5mL 1M THF溶液),繼而經7分鐘添加EtMgBr(4.8mL 3M Et2O溶液)。使反應混合物溫至室溫且再攪拌30分鐘,隨後用水(10mL)及羅謝爾鹽(Rochelle salt)溶液(30mL,20%水溶液)謹慎地稀釋。劇烈攪拌混合物15分鐘,隨後用EtOAc(3×)萃取且在MgSO4下乾燥經合併之有機層。在減壓下移除溶劑且藉由層
析(0-20% EtOAc之己烷溶液)純化殘餘物,得到307(0.358g,40%)。MS(m/z):[M+H]+ 241.1。
1-(1-甲基環丙基)哌嗪[308].向307(300mg,1.24mmol)於CH2Cl2(6mL)中之溶液中添加TFA(800μL)且在室溫下攪拌反應混合物24小時。濃縮溶劑,得到定量產率之二TFA鹽形式之308且不經任何進一步純化即使用。MS(m/z):[M+H]+ 141.8。
流程48. 合成310-325
試劑及條件:a.胺,Et3N,DMF,90℃,2小時;b. KOH,t-BuOH,80℃,1小時。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(1-甲基環丙基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[310].向309(8.2mg,0.021mmol)中添加308(106.6mg,0.29mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱2小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,8:2)純化殘餘物,得到8.6mg(84%)310。MS(ESI)m/z[M+H]+ 488.2。
4-((2-(4-(2-環丙基丙-2-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[312].向309(10mg,0.026mmol)中添加1-(2-環丙基丙-2-基)哌嗪(8.8mg,0.052mmol)於DMF(1.5mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到6mg(45%)312。MS(ESI)m/z[M+H]+ 516.2。
(S)-4-((2-(4-(1-環丙基乙基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[314].向309(10mg,0.026mmol)中添加(S)-1-(1-環丙基乙基)哌嗪(20.1mg,0.130mmol)於DMF(2mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到12mg(92%)314。MS(ESI)m/z[M+H]+ 502.2。
(R)-4-((2-(4-(1-環丙基乙基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[316].向309(10mg,0.026mmol)中添加(R)-1-(1-環丙基乙基)哌嗪(20.1mg,0.130mmol)於DMF(2mL)中之溶液
且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到8.5mg(65%)316。MS(ESI)m/z[M+H]+ 502.2。
4-((4-((3-甲氧基苯甲基)氧基)-2-(3-側氧基哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[318].向309(11.1mg,0.0289mmol)中添加哌嗪-2-酮(14.5mg,0.145mmol)及Et3N(21μL,0.145mmol)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到9.7mg(75%)318。MS(ESI)m/z[M+H]+ 448.0。
4-((2-(4-(環丙基甲基)-3-側氧基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[320].向309(9.9mg,0.0258mmol)中添加1-(環丙基甲基)哌嗪-2-酮(36mg,0.129mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到10.3mg(80%)320。MS(ESI)m/z[M+H]+ 502.0。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(噁唑-2-基甲基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[322].向309(13.8mg,0.0360mmol)中添加2-(哌嗪-1-基甲基)噁唑(30.1mg,0.18mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到15.5mg(84%)322。MS(ESI)m/z[M+H]+ 515.1。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[324].向309(14.9mg,0.0389mmol)中添加1-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪(37.1mg,0.1995mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:4)純化殘餘物,得到12.3mg(54%)324。MS(ESI)m/z[M+H]+ 586.1。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(1-甲基環丙基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[311].在80℃下加熱310(8.6mg,0.0176mmol)及KOH(19.7mg,0.352mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到6.1mg(68%)311。1H NMR(600MHz,
CDCl3):δ 8.30(s,1H),7.64(d,J=8.3Hz,2H),7.19(t,J=7.9Hz,1H),7.14(d,J=8.3Hz,2H),6.80(d,J=8.3Hz,1H),6.73(d,J=7.6Hz,1H),6.62(s,1H),6.49(br s,1H),6.25(br s,1H),5.44(s,2H),4.89(m,2H),3.71(s,3H),3.53(m,4H),3.09(m,2H),1.59(t,J=6.1Hz,2H),1.37(s,3H),0.78(t,J=6.2Hz,2H);13C NMR(150MHz,CDCl3):δ 170.0,168.8,164.4,161.4,160.8,159.6,143.3,137.5,129.5,127.9,126.4,119.6,113.3,113.1,100.5,68.2,55.2,49.2,43.8,40.8,15.8,12.7;HRMS(ESI)m/z[M+H]+ C27H32N5O3S之計算值,506.2226;實驗值506.2208。
4-((2-(4-(2-環丙基丙-2-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[313].在70℃下加熱312(6mg,0.0116mmol)及KOH(13mg,0.232mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到5.8mg(94%)313。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.4Hz,2H),7.17(t,J=7.9Hz,1H),7.11(d,J=8.5Hz,2H),6.79(d,J=8.2Hz,1H),6.76(d,J=7.5Hz,1H),6.69(s,1H),6.04(br s,1H),5.50(br s,1H),5.34(s,2H),3.87(m,4H),3.68(s,3H),2.77(m,4H),1.22(m,1H),0.88(s,6H),0.45(m,2H),0.25(m,2H);HRMS(ESI)m/z[M+H]+ C29H36N5O3S之計算值,534.2539;實驗值534.2537。
(S)-4-((2-(4-(1-環丙基乙基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[315].在80℃下加熱314(12mg,0.0239mmol)及KOH(27mg,0.478mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到12mg(97%)315。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=8.8Hz,2H),7.17(t,J=6.6Hz,1H),7.11(d,J=8.8Hz,2H),6.74-6.80(m,2H),6.69(s,1H),6.03(br s,1H),5.60(br s,1H),5.34(s,2H),3.89(m,4H),3.68(s,3H),2.81(m,2H),2.64(m,2H),1.72(m,1H),1.20(d,J=6.5Hz,3H),0.73-0.80(m,1H),0.59-0.67(m,1H),0.46-0.53(m,1H),0.27-0.34(m,1H),0.01-0.08(m,1H);HRMS(ESI)m/z[M+H]+ C28H34N5O3S之計算值,520.2382;實驗值520.2360。
(R)-4-((2-(4-(1-環丙基乙基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[317].在80℃下加熱316(8.5mg,0.0169mmol)及KOH(19mg,0.338mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到8mg(91%)317。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.62(d,J=6.8Hz,2H),7.17(t,J=7.9Hz,1H),7.11(d,
J=8.7Hz,2H),6.79(dd,J=8.2,2.5Hz,1H),6.76(d,J=7.6Hz,1H),6.69(s,1H),6.01(br s,1H),5.51(br s,1H),5.34(s,2H),3.89(m,4H),3.68(s,3H),2.81(m,2H),2.64(m,2H),1.72(m,1H),1.21(m,3H),0.77(m,1H),0.63(m,1H),0.49(m,1H),0.31(m,1H),0.05(m,1H);HRMS(ESI)m/z[M+H]+ C28H34N5O3S之計算值,520.2382;實驗值520.2396。
4-((4-((3-甲氧基苯甲基)氧基)-2-(3-側氧基哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[319].在70℃下加熱318(9.7mg,0.0217mmol)及KOH(24.3mg,0.433mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到6.6mg(65%)319。1H NMR(600MHz,MeOH-d 4 ):δ 8.23(s,1H),7.63(d,J=6.7Hz,2H),7.05(t,J=7.8Hz,1H),7.02(d,J=6.7Hz,2H),6.66-6.70(m,1H),6.64(d,J=7.6Hz,1H),6.60(s,1H),5.27(s,2H),4.30(s,2H),3.94-3.98(m,2H),3.55(s,3H),3.28-3.33(m,2H);13C NMR(150MHz,MeOH-d 4 ):171.7,170.6,170.2,165.9,162.3,161.2,144.3,139.3,131.8,130.4,129.3,126.9,120.7,114.5,113.8,100.9,69.2,55.6,49.6,41.6,41.4;HRMS(ESI)m/z[M+H]+ C23H24N5O4S之計算值,466.1549;實驗值466.1550。
4-((2-(4-(環丙基甲基)-3-側氧基哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[321].A在70℃下加熱320(10.3mg,0.0205mmol)及KOH(23.1mg,0.411mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到6.6mg(62%)321。1H NMR(600MHz,CDCl3):δ 8.31(s,1H),7.64(d,J=8.4Hz,2H),7.17(t,J=9.5Hz,1H),7.12(d,J=8.0Hz,2H),6.74-6.80(m,2H),6.68(s,1H),6.00(br s,1H),5.50(br s,1H),5.41(s,2H),4.48(s,2H),4.10-4.13(m,2H),3.73(s,3H),3.52-3.56(m,2H),3.37(d,J=7.0Hz,2H),0.98-1.04(m,1H),0.50-0.58(m,2H),0.27-0.31(m,2H);13C NMR(150MHz,CDCl3):168.7,168.6,165.5,164.8,160.6,159.6,143.1,137.9,130.1,129.4,127.8,126.1,119.7,113.5,112.9,99.4,67.9,55.2,51.1,48.2,45.9,40.9,9.1,3.6;HRMS(ESI)m/z[M+H]+ C27H30N5O4S之計算值,520.2019;實驗值520.1994。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(噁唑-2-基甲基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[323].在70℃下加熱322(15.5mg,0.0301mmol)及KOH(16.9mg,0.301mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到10mg(63%)323。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.67(s,1H),7.61(d,J=8.4Hz,2H),7.16(t,J=7.8Hz,1H),7.08-7.13(m,3H),6.78(d,J=8.2Hz,1H),6.74(d,J=7.5Hz,1H),6.66(s,1H),6.06(br s,1H),5.63(br s,1H),5.32(s,2H),
3.90-3.93(m,4H),3.79(s,2H),3.68(s,3H),2.61-2.64(m,4H);13C NMR(150MHz,CDCl3):168.8,168.6,164.9,161.5,160.9,159.5,143.5,139.2,139.8,129.9,129.3,127.7,127.2,125.9,119.7,113.2,113.1,97.9,67.6,55.1,54.7,52.6,43.7;HRMS(ESI)m/z[M+H]+ C27H29N6O4S之計算值,533.1971;實驗值533.1979。
4-((4-((3-甲氧基苯甲基)氧基)-2-(4-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[325].在70℃下加熱324(12.3mg,0.0210mmol)及KOH(11.8mg,0.210mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到7.6mg(60%)325。MS(ESI)m/z[M+H]+ 604.1。
流程49. 合成326.
試劑及條件:a. PPTS,EtOH,60℃,隔夜。
4-((2-(4-(4-羥基丁-2-炔-1-基)哌嗪-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[326].向325(7.6mg,0.0126mmol)於EtOH(1mL)中之混合物中添加PPTS(1mg,0.004mmol)且在60℃下攪拌反應物隔夜。在減壓下移除溶劑且藉由製備型TLC
(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到3.7mg(57%)326。1H NMR(600MHz,CDCl3/MeOH-d 4 ):δ 8.24(s,1H),7.72(d,J=8.6Hz,1H),7.16(t,J=7.9Hz,1H),7.12(d,J=8.6Hz,2H),6.78(d,J=8.2Hz,1H),6.74(d,J=7.5Hz,1H),6.70(s,1H),5.34(s,2H),4.23(s,2H),3.90-3.93(m,4H),3.67(s,3H),3.41(t,J=1.7Hz,2H),2.65-2.68(m,4H);13C NMR(150MHz,CDCl3/MeOH-d 4 ):171.7,170.2,166.1,162.9,161.1,144.7,139.4,131.5,130.6,129.3,126.9,120.9,114.6,113.9,99.9,85.7,79.9,69.1,55.9,52.9,51.0,48.1,44.8;HRMS(ESI)m/z[M+H]+ C27H30N5O4S之計算值,520.2019;實驗值520.2003。
流程50. 合成328-333.
試劑及條件:a. ROH,NaH,CH3CN,室溫,3小時;b. KOH,t-BuOH,80℃,1小時。
4-((4-((3-甲基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[328].向間甲苯基甲醇(20.5μL,0.170mmol)於CH3CN(1mL)中之溶液中添加NaH(3.5mg,0.148mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加327(15.6mg,0.037mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘
物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到7.5mg(41%)328。MS(ESI)m/z[M+H]+ 500.0。
4-((4-((3-異丙基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[330].向(3-異丙基苯基)甲醇(17.9mg,0.119mmol)於CH3CN(1mL)中之溶液中添加NaH(2.5mg,0.106mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加327(11mg,0.0265mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到13.5mg(97%)330。MS(ESI)m/z[M+H]+ 528.2。
4-((4-((3-乙基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[332].向溶解於CH3CN(1mL)中之(3-乙基苯基)甲醇(16.2mg,0.119mmol)中添加NaH(2.5mg,0.106mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加327(11mg,0.0265mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到9.4mg(69%)332。MS(ESI)m/z[M+H]+ 514.2。
4-((4-((3-甲基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[329].在80℃下加熱328(7.5mg,0.015mmol)及KOH(16.8mg,0.30mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到4.7mg(61%)329。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.45(s,1H),7.41(d,J=8.2Hz,1H),7.20(d,J=8.1Hz,1H),7.17(t,J=7.6Hz,1H),7.07(d,J=7.6Hz,1H),7.02(s,1H),6.96(d,J=7.6Hz,1H),5.68-5.80(m,2H),5.32(s,2H),3.90(m,4H),2.49(m,4H),2.37(s,3H),2.28(s,3H);13C NMR(150MHz,CDCl3):δ 169.0,168.6,164.9,161.7,142.3,138.0,136.1,131.3,129.2,129.1,128.7,128.32,128.28,127.6(q,J=31.9Hz),123.9(q,J=5.1Hz),123.2(q,J=272.5Hz),97.0,68.0,54.7,46.2,43.8,21.4;HRMS(ESI)m/z[M+H]+ C25H27F3N5O2S之計算值,518.1838;實驗值518.1834。
4-((4-((3-異丙基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[331].在80℃下加熱330(13.5mg,0.0255mmol)及KOH(28.6mg,0.511mmol)於t-BuOH(2mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到7.8mg(56%)331。1H NMR(600MHz,
CDCl3):δ 8.27(s,1H),7.46(s,1H),7.41(d,J=8.2Hz,1H),7.20(t,J=7.8Hz,2H),7.10-7.15(m,2H),6.97(d,J=7.6Hz,1H),5.80(br s,1H),5.73(br s,1H),5.35(s,2H),3.90(m,4H),2.83(septet,J=6.9Hz,1H),2.49(m,4H),2.36(s,3H),1.19(d,J=6.9Hz,6H);13C NMR(150MHz,CDCl3):δ 169.1,168.7,165.0,161.8,149.0,142.4,136.2,131.3,129.2,129.0,128.4,127.7(q,J=31.8Hz),126.0,125.5,124.8,123.8(q,J=5.3Hz),123.2(q,J=272.3Hz),96.9,68.2,54.7,46.2,43.8,34.0,23.9;HRMS(ESI)m/z[M+H]+ C27H31F3N5O2S之計算值,546.2151;實驗值546.2159。
4-((4-((3-乙基苯甲基)氧基)-2-(4-甲基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[333].在80℃下加熱332(9.4mg,0.0183mmol)及KOH(21mg,0.366mmol)於t-BuOH(1.5mL)中之混合物1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到5mg(52%)333。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.45(s,1H),7.41(d,J=8.1Hz,1H),7.16-7.23(m,2H),7.10(d,J=7.6Hz,1H),7.07(s,1H),6.97(d,J=7.6Hz,1H),5.77(br s,1H),5.72(br s,1H),5.34(s,2H),3.90(m,4H),2.58(q,J=7.6Hz,2H),2.49(m,4H),2.37(s,3H),1.18(t,J=7.6Hz,3H);13C NMR(150MHz,CDCl3):δ 169.0,168.7,165.0,161.7,144.4,142.3,136.2,131.3,129.14,129.08,128.4,127.7(q,J=31.9Hz),127.5,127.0,124.7,123.8(q,J=5.3Hz),123.2(q,J=272.3Hz),97.0,68.1,54.7,46.1,43.8,28.7,15.5;HRMS(ESI)m/z[M+H]+ C26H29F3N5O2S之計算值,
532.1994;實驗值532.1994。
流程51. 合成335及336.
試劑及條件:a. 1-(丙-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,80℃,1.5小時。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[335].向334(16.5mg,0.0416mmol)中添加1-(丙-2-炔-1-基)哌嗪(46mg,0.208mmol)及Et3N(75μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到14.4mg(71%)335。MS(ESI)m/z[M+H]+ 485.1。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[336].在80℃下加熱335(14.4mg,0.03mmol)及KOH(33.3mg,0.594mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到10.9mg(73%)336。1H NMR(600MHz,CDCl3):δ 8.26(s,1H),7.59(d,J=8.4Hz,2H),7.12(t,J=7.9Hz,1H),7.07(d,J=7.7Hz,2H),6.62(d,J=8.3Hz,1H),6.58(s,1H),6.54(d,J=7.4Hz,1H),6.02(br s,1H),5.58(br s,1H),5.34(s,2H),3.91-3.94(m,4H),3.38(s,2H),2.81(s,6H),2.63-2.67(m,4H),2.29(t,J=2.3Hz,1H);13C NMR(150MHz,CDCl3):δ 168.8,168.7,164.9,161.7,150.6,143.7,137.1,129.6,129.0,127.7,125.7,115.7,112.1,111.7,97.8,78.4,73.7,68.3,51.6,47.0,43.9,40.6;MS(ESI)m/z [M+H]+ 503.1。
流程52. 合成338-345.
試劑及條件:a.胺,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,80℃,1.5小時。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[338].向337(23.2mg,0.05mmol)中添加1-(丙-2-炔-1-基)哌嗪(88mg,0.250mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到19.7mg(72%)338。MS(ESI)m/z[M+H]+ 553.0。
4-((2-(4-環丙基哌嗪-1-基)-4-((3-(二甲基胺基)苯甲基)氧基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[340].向337(28.6mg,0.0615mmol)中添加1-環丙基哌嗪(61.2mg,0.3076mmol)及Et3N(100μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到25.7mg(75%)340。MS(ESI)m/z[M+H]+ 555.1。
4-((2-(4-(環丙基甲基)哌嗪-1-基)-4-((3-(二甲基胺基)苯甲基)氧基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[342].向337(24.5mg,0.0527mmol)中添加1-(環丙基甲基)哌嗪(36.9mg,0.263mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到23.7mg(79%)342。MS(ESI)m/z[M+H]+ 569.1。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基-3-側氧基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[344].向337(31.8mg,0.0684mmol)中添加1-甲基哌嗪-2-酮(51.5mg,0.342mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,20:1)純化殘餘物,得到31.8mg(86%)344。MS(ESI)m/z[M+H]+ 543.1。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[339].在80℃下加熱338(19.7mg,0.0356mmol)及KOH(40mg,0.713mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到7.8mg(38%)339。1H NMR(600MHz,CDCl3):δ 8.25(s,1H),7.44(s,1H),7.31(d,J=8.1Hz,1H),7.14(t,J=7.8Hz,1H),7.11(d,J=8.1Hz,1H),6.64(d,J=8.3Hz,1H),6.55-6.58(m,2H),5.93(br s,1H),5.79(br s,1H),5.33(s,2H),3.92-3.95(m,4H),3.39(s,2H),2.82(s,6H),2.64-2.66(m,4H),2.28(t,J=2.3Hz,1H);13C NMR(150MHz,CDCl3):169.2,168.7,164.9,161.7,150.6,142.2,136.9,131.2,129.1,129.0,128.8,127.6(q,J=31.9Hz),123.7(q,J=5.0Hz),123.2(q,J=272.3Hz),116.1,112.4,111.9,97.0,78.3,73.6,68.4,51.6,46.9,43.8,40.6;HRMS(ESI)m/z[M+H]+ C28H30F3N6O2S之計算值,571.2103;實驗值571.2086。
4-((2-(4-環丙基哌嗪-1-基)-4-((3-(二甲基胺基)苯甲基)氧基)嘧啶- 5-基)硫基)-2-(三氟甲基)苯甲醯胺[341].在80℃下加熱340(25.7mg,0.0463mmol)及KOH(52mg,0.927mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到19mg(72%)341。1H NMR(600MHz,CDCl3):δ 8.25(s,1H),7.45(s,1H),7.31(d,J=8.1Hz,1H),7.14(t,J=7.9Hz,1H),7.10(dd,J=8.1,1.4Hz,1H),6.65(dd,J=8.2,2.2Hz,1H),6.55-6.59(m,2H),5.93(s,1H),5.84(s,1H),5.34(s,2H),3.86(m,4H),2.83(s,6H),2.69(m,4H),1.63-1.69(m,1H),0.46-0.53(m,4H);13C NMR(150MHz,CDCl3):δ 169.3,168.7,164.9,161.7,150.6,142.3,137.0,131.2,129.05,128.99,128.8,127.6(q,J=31.9Hz),123.7(q,J=5.0Hz),123.2(q,J=272.3Hz),116.1,112.4,112.0,96.7,68.3,53.1,43.9,40.6,38.5,5.9;HRMS(ESI)m/z[M+H]+ C28H32F3N6O2S之計算值,573.2260;實驗值573.2264。
4-((2-(4-(環丙基甲基)哌嗪-1-基)-4-((3-(二甲基胺基)苯甲基)氧基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[343].在80℃下加熱342(23.7mg,0.0417mmol)及KOH(46.8mg,0.833mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到15.4mg(63%)343。1H NMR(600MHz,CDCl3):δ 8.25(s,1H),7.45(s,1H),7.31(d,J=8.1Hz,1H),7.14(t,J=7.9Hz,1H),7.10(dd,J=8.0,1.5Hz,1H),
6.64(dd,J=8.2,2.3Hz,1H),6.55-6.59(m,2H),5.94(s,1H),5.88(s,1H),5.34(s,2H),3.93(m,4H),2.83(s,6H),2.61(m,4H),2.33(d,J=6.6Hz,2H),0.88-0.95(m,1H),0.54-0.59(m,2H),0.13-0.16(m,2H);13C NMR(150MHz,CDCl3):δ 169.3,168.7,164.9,161.7,150.6,142.2,137.0,131.2,129.1,129.0,128.8,127.6(q,J=31.8Hz),123.7(q,J=5.0Hz),123.2(q,J=272.4Hz),116.1,112.4,112.0,96.7,68.3,63.8,53.0,43.9,40.6,8.3,4.0;HRMS(ESI)m/z[M+H]+ C29H34F3N6O2S之計算值,587.2416;實驗值587.2416。
4-((4-((3-(二甲基胺基)苯甲基)氧基)-2-(4-甲基-3-側氧基哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[345].在80℃下加熱344(31.8mg,0.0586mmol)及KOH(65.8mg,1.172mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到22.7mg(69%)345。1H NMR(600MHz,CDCl3):δ 8.29(s,1H),7.44(s,1H),7.33(d,J=8.1Hz,1H),7.15(t,J=7.9Hz,1H),7.12(d,J=8.1Hz,1H),6.65(d,J=8.3Hz,1H),6.58(s,1H),6.54(d,J=7.5Hz,1H),5.92(br s,1H),5.68(br s,1H),5.35(s,2H),4.47(s,2H),4.11-4.14(m,2H),3.45-3.47(m,2H),3.06(s,3H),2.85(s,6H);HRMS(ESI)m/z[M+H]+ C26H28F3N6O3S之計算值,561.1896;實驗值561.1902。
流程53. 合成347及348.
試劑及條件:a. 1-(丙-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,80℃,1.5小時。
4-((4-((3-氯苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[347].向346(24.2mg,0.0623mmol)中添加1-(丙-2-炔-1-基)哌嗪(68.9mg,0.3116mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到17.5mg(59%)347。MS(ESI)m/z[M+H]+ 476.0。
4-((4-((3-氯苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[348].在80℃下加熱347(17.5mg,0.0368mmol)及
KOH(41.3mg,0.735mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到9.4mg(52%)348。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.66(d,J=8.4Hz,2H),7.17-7.32(m,2H),7.14(d,J=8.4Hz,2H),7.09(s,1H),7.02(d,J=7.5Hz,1H),6.01(br s,1H),5.61(br s,1H),5.31(s,2H),3.98-4.02(m,4H),3.38(s,2H),2.60-2.65(m,4H),2.28(t,J=2.3Hz,1H);13C NMR(150MHz,CDCl3):δ 168.7,168.3,164.9,161.5,143.4,138.4,134.2,129.9,129.6,128.0,127.8,127.4,125.9,125.4,97.9,78.4,73.7,66.9,51.6,46.8,43.8;HRMS(ESI)m/z[M+H]+ C25H25ClN5O2S之計算值,494.1417;實驗值494.1411。
流程54. 合成350及351.
試劑及條件:a. 1-(丙-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,80℃,1.5小時。
4-((4-((3-氯苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[350].向349(12.5mg,0.0274mmol)中添加1-(丙-2-炔-1-基)哌嗪(30.3mg,0.137mmol)及Et3N(50μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到12.5mg(84%)350。MS(ESI)m/z[M+H]+ 544.0。
4-((4-((3-氯苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[351].在80℃下加熱350(12.5mg,0.023mmol)及KOH(26mg,0.459mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到6.2mg(48%)351。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.40-7.45(m,2H),7.20-7.25(m,3H),7.14(s,1H),7.04(d,J=6.7Hz,1H),5.79(br s,2H),5.32(s,2H),3.88-3.92(m,4H),3.38(s,2H),2.62-2.65(m,4H),2.28(t,J=2.2Hz,1H);13C NMR(150MHz,CDCl3):δ 169.1,168.3,165.1,161.6,142.0,138.2,134.2,131.4,129.8,129.2,129.1,128.1,127.7(q,J=31.9Hz),127.5,125.4,123.8(q,J=5.1Hz),123.2(q,J=272.3Hz),96.9,78.3,73.6,67.0,51.5,46.9,43.8;HRMS(ESI)m/z[M+H]+ C26H24ClF3N5O2S之計算值,562.1291;實驗值562.1298。
流程55. 合成353及354.
試劑及條件:a. 1-(丙-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,80℃,1.5小時。
4-((4-((3-氯-4-氟苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[353].向352(24.7mg,0.0608mmol)中添加1-(丙-2-炔-1-基)哌嗪(67.2mg,0.304mmol)及Et3N(100μL)於DMF(1
mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到24.5mg(82%)353。MS(ESI)m/z[M+H]+ 494.0。
4-((4-((3-氯-4-氟苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[354].在80℃下加熱353(24.5mg,0.05mmol)及KOH(56mg,0.99mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到19.1mg(75%)354。1H NMR(600MHz,CDCl3):δ 8.28(s,1H),7.67(d,J=8.4Hz,2H),7.14(d,J=7.0Hz,1H),7.12(d,J=8.4Hz,2H),6.98-7.03(m,2H),6.02(br s,1H),5.70(br s,1H),5.27(s,2H),3.90-3.95(m,4H),3.39(s,2H),2.62-2.66(m,4H),2.29(t,J=2.3Hz,1H);13C NMR(150MHz,CDCl3):δ 168.4(d,J=52.7Hz),165.0,161.4,158.4,156.8,143.4,133.4,130.1,129.7,127.9,127.2(d,J=11.9Hz),125.9,120.9(d,J=17.9Hz),116.4(d,J=23.9Hz),98.0,78.3,73.8,66.5,51.7,47.2,43.9;HRMS(ESI)m/z[M+H]+ C25H24ClFN5O2S之計算值,512.1323;實驗值512.1330。
流程56. 合成356及357.
試劑及條件:a. 1-(丙-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,80℃,1.5小時。
4-((4-((3-碘苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5- 基)硫基)-2-(三氟甲基)苯甲腈[356].向355(46.7mg,0.0853mmol)中添加1-(丙-2-炔-1-基)哌嗪(94.3mg,0.426mmol)及Et3N(100μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH,40:1)純化殘餘物,得到37.5mg(69%)356。MS(ESI)m/z[M+H]+ 636.2。
4-((4-((3-碘苯甲基)氧基)-2-(4-(丙-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[357].在80℃下加熱356(37.5mg,0.059mmol)及KOH(66.2mg,1.18mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化殘餘物,得到21.7mg(56%)357。1H NMR(600MHz,CDCl3):δ 8.28(s,1H),7.59(d,J=8.0Hz,1H),7.58(s,1H),7.43-7.47(m,2H),7.21(d,J=8.1Hz,1H),7.11(d,J=7.7Hz,1H),7.03(t,J=7.7Hz,1H),5.80(br s,1H),5.78(br s,1H),5.29(s,2H),3.89-3.92(m,4H),3.39(s,2H),2.63-2.66(m,4H),2.28(t,J=2.4Hz,1H);13C NMR(150MHz,CDCl3):δ 169.0,168.4,165.1,161.6,142.1,138.6,136.9,136.4,131.4,130.3,129.3,128.9,127.7(q,J=31.9Hz),126.5,123.8(q,J=5.2Hz),123.2(q,J=272.6Hz),96.9,94.1,78.3,73.6,66.9,51.5,46.9,43.8;HRMS(ESI)m/z[M+H]+ C26H24F3IN5O2S之計算值,654.0648;實驗值654.0644。
流程57. 合成358-360.
試劑及條件:a. 1-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,70℃,1.5小
時;c. PPTS,EtOH,60℃,隔夜。
4-((4-((3-碘苯甲基)氧基)-2-(4-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲腈[358].向355(45.8mg,0.0836mmol)中添加1-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪(79.7mg,0.33mmol)及Et3N(100μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:4)純化殘餘物,得到45.9mg(73%)358。MS(ESI)m/z[M+H]+ 750.2。
4-((4-((3-碘苯甲基)氧基)-2-(4-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[359].在70℃下加熱358(45.9mg,0.0612mmol)及KOH(68.7mg,1.22mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到22.9mg(49%)359。MS(ESI)m/z[M+H]+ 768.1。
4-((2-(4-(4-羥基丁-2-炔-1-基)哌嗪-1-基)-4-((3-碘苯甲基)氧基)嘧啶-5-基)硫基)-2-(三氟甲基)苯甲醯胺[360].向359(22.9mg,0.03mmol)於EtOH(1mL)中之混合物中添加PPTS(1mg,0.004mmol)且在60℃下攪拌反應物隔夜。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到12.0mg(59%)360。1H NMR(600MHz,CDCl3):δ 8.27(s,1H),7.57-7.61(m,2H),7.44-7.47(m,2H),7.21(d,J=8.0Hz,1H),7.11(d,J=7.7Hz,1H),7.03(t,J=7.7,1H),5.78(br s,2H),5.29(s,2H),4.31(s,2H),3.89-3.95(m,4H),3.41(s,2H),2.61-2.65(m,4H);13C NMR(150MHz,CDCl3):δ 169.0,168.4,165.1,161.6,142.1,138.5,136.9,136.4,131.4,130.3,129.3,129.0,127.7(q,J=31.9Hz),126.6,123.8(q,J=5.0Hz),123.2(q,J=272.4Hz),96.9,94.1,83.7,80.5,66.9,51.7,51.2,47.3,
43.8;HRMS(ESI)m/z[M+H]+ C27H26F3IN5O3S之計算值,684.0753;實驗值684.0753。
流程58. 合成362-369.
試劑及條件:a.(3-氟苯基)甲醇,NaH,CH3CN,室溫,3小時;b. KOH,t-BuOH,70℃,1小時。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-氟苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[362].向溶解於CH3CN(3mL)中之(3-氟苯基)甲醇(34μL,0.311mmol)中添加NaH(7.0mg,0.292mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加361(26.3mg,0.0731mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),40:1)純化,得到24.8mg(77%)362。MS(ESI)m/z[M+H]+ 450.0。
(R)-4-((4-((3-氯苯甲基)氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲腈[364].向溶解於CH3CN(3mL)中之(3-氟苯基)甲醇(35μL,0.296mmol)中添加NaH(6.7mg,0.279mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加361(25.1mg,0.07mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),40:1)純化,得到22.6mg(69%)364。MS(ESI)m/z[M+H]+ 466.0。
(R)-4-((4-((3-溴苯甲基)氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲腈[366].向溶解於CH3CN(3mL)中之(3-溴苯基)甲醇(35μL,0.296mmol)中添加NaH(6.7mg,0.279mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加361(25.1mg,0.07mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),40:1)純化,得到29.3mg(82%)366。MS(ESI)m/z[M+H]+ 510.0/512.0。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-碘苯甲基)氧基)嘧啶-5-基)硫基)苯甲腈[368].向(3-碘苯基)甲醇(40μL,0.311mmol)於CH3CN(3mL)中之溶液中添加NaH(7.0mg,0.292mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加361(26.3mg,0.0731mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘
物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),40:1)純化,得到33.8mg(83%)368。MS(ESI)m/z[M+H]+ 558.1。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-氟苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[363].在70℃下加熱362(24.8mg,0.0552mmol)及KOH(61.91mg,1.1033mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到21.1mg(82%)363。1H NMR(600MHz,CDCl3):δ 8.29(s,1H),7.65(d,J=8.4Hz,2H),7.18-7.23(m,1H),7.12(d,J=8.4Hz,2H),6.89-6.94(m,2H),6.75(d,J=9.2Hz,1H),6.05(br s,1H),5.72(br s,1H),5.35(s,2H),3.93-3.97(m,1H),3.79-3.86(m,1H),3.48-3.53(m,1H),3.30-3.37(m,1H),2.79-2.82(m,1H),2.33(s,6H),2.20-2.25(m,1H),1.90-1.95(m,1H);13C NMR(150MHz,CDCl3):δ 168.8,168.2,164.9,163.5,161.9,160.2,143.6,139.2,129.8(d,J=27.8Hz),127.8,125.9,122.9,114.6(d,J=24.9Hz),114.2(d,J=27.8Hz),97.6,66.8,65.3,51.3,45.9,44.3,30.1;MS(ESI)m/z[M+H]+ 468.1。
(R)-4-((4-((3-氯苯甲基)氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲醯胺[365].在70℃下加熱364(22.6mg,0.0485mmol)及KOH(54.43mg,0.97mmol)於t-BuOH(2mL)中之混合物1.5
小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到17.4mg(74%)365。1H NMR(600MHz,CDCl3):δ 8.29(s,1H),7.66(d,J=8.4Hz,2H),7.21-7.22(m,1H),7.17(t,J=7.6Hz,1H),7.10-7.13(m,3H),7.02(d,J=7.3Hz,1H),6.04(br s,1H),5.69(br s,1H),5.33(s,2H),3.93-3.97(m,1H),3.79-3.87(m,1H),3.47-3.53(m,1H),3.29-3.37(m,1H),2.79-2.82(m,1H),2.34(d,J=9.4Hz,6H),2.21-2.25(m,1H),1.88-1.96(m,1H);13C NMR(150MHz,CDCl3):δ 168.8,168.2,164.9,160.2,143.6,138.7,134.2,129.9,129.6,127.9,127.8,127.6,125.8,125.6,97.4,66.9,65.3,51.2,45.9,44.3,30.2;HRMS(ESI)m/z[M+H]+ C24H27ClN5O2S之計算值,484.1574;實驗值484.1588。
(R)-4-((4-((3-溴苯甲基)氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)苯甲醯胺[367].在70℃下加熱366(29.3mg,0.0574mmol)及KOH(64.4mg,1.148mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到15.9mg(52%)367。1H NMR(600MHz,CDCl3):δ 8.29(s,1H),7.66(d,J=8.4Hz,2H),7.36(d,J=7.8Hz,1H),7.29(s,1H),7.06-7.13(m,4H),6.04(br s,1H),5.67(br s,1H),5.32(s,2H),3.93-3.97(m,1H),3.79-3.87(m,1H),3.49-3.53(m,1H),3.30-3.36(m,1H),2.78-2.82(m,1H),2.34(d,J=10.9Hz,6H),2.22-2.25(m,1H),1.90-1.95(m,1H);13C NMR(150MHz,CDCl3):δ 168.7,168.2,164.9,160.2,143.6,138.9,130.9,130.6,130.5,129.9,127.8,
126.1,125.7,122.3,97.3,66.8,65.3,51.2,45.9,44.3,30.4;HRMS(ESI)m/z[M+H]+ C24H27BrN5O2S之計算值,528.1069;實驗值528.1052。
(R)-4-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-碘苯甲基)氧基)嘧啶-5-基)硫基)苯甲醯胺[369].在70℃下加熱368(33.8mg,0.0606mmol)及KOH(68.04mg,1.212mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到18.8mg(54%)369。1H NMR(600MHz,CDCl3):δ 8.28(s,1H),7.67(d,J=8.3Hz,2H),7.57(d,J=7.9Hz,1H),7.53(s,1H),7.08-7.18(m,3H),6.98(t,J=7.7Hz,1H),6.07(s,1H),5.77(s,1H),5.30(s,2H),3.95(m,1H),3.84(m,1H),3.51(m,1H),3.33(m,1H),2.80(m,1H),2.34(d,J=13.4Hz,6H),2.23(m,1H),1.92(m,1H);HRMS(ESI)m/z[M+H]+ C24H27IN5O2S之計算值,576.0930;實驗值576.0952。
流程59. 合成371-375.
試劑及條件:a. 6-硝基吡啶-3-硫醇,噻吩-2-甲酸銅(I),K2CO3,DMF,120℃,20小時;b. TFA,CH2Cl2,室溫,16小時;c. POCl3,DIEA,75℃,1小時;d. Fe粉,AcOH,室溫,隔夜;e.(3-甲氧基苯基)甲醇,NaH,CH3CN,室溫,3小時。
(R)-1-(4-(苯甲氧基)-5-((6-硝基吡啶-3-基)硫基)嘧啶-2-基)-N,N-二甲基吡咯啶-3-胺[371].將370(0.768g,1.69mmol)及K2CO3(0.701g,5.07mmol)於DMF(5mL)中之混合物抽空且用氬氣回填三次。添加噻吩-2-甲酸銅(I)(0.129g,0.676mmol),抽空且用氬氣回填兩次。添加6-硝基吡啶-3-硫醇(0.343g,2.2mmol)且在120℃下加熱反應混合物20小時。在減壓下移除溶劑且藉由管柱層析(CH2Cl2:MeOH,200:1至40:1)純化殘餘物,得到0.649g(80%)371。MS(ESI)m/z[M+H]+ 483.2。
(R)-2-(3-(二甲基胺基)吡咯啶-1-基)-5-((6-硝基吡啶-3-基)硫基)嘧啶-4-醇[372].向371(0.649g,1.34mmol)於CH2Cl2(4mL)中之溶液中經5分鐘逐滴添加TFA(4mL)且在室溫下攪拌16小時。在減壓下濃縮反應混合物,得到殘餘物,藉由管柱層析(CH2Cl2:MeOH,9:1至8:2)純化,得到0.351g(72%)372。MS(ESI)m/z[M+H]+ 363.2。
(R)-1-(4-氯-5-((6-硝基吡啶-3-基)硫基)嘧啶-2-基)-N,N-二甲基吡咯啶-3-胺[373].在75℃下加熱372(0.351g,0.968mmol)、POCl3(3.4mL)及DIEA(0.423mL,2.42mmol)1小時。冷卻至室溫之後,將反應混合物添加至含有冰碴之燒杯中。完全淬滅POCl3之後,謹慎地添加固體Na2CO3直至pH值達約9。將其轉移至分液漏斗中且用CH2Cl2(4×50mL)萃取,經MgSO4乾燥,過濾且濃縮成固體,藉由管柱層析(CH2Cl2:MeOH,100:0至95:5)純化,得到139.5mg(38%)373。MS(ESI)m/z[M+H]+ 381.0。
(R)-5-((4-氯-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)吡啶-2-胺[374].在室溫下攪拌373(139.5mg,0.366mmol)及鐵粉(82mg,1.465mmol)於乙酸(1mL)中之混合物隔夜。在減壓下濃縮反應混合物且藉由管柱層析(CH2Cl2:MeOH,100:0至90:10)純化,得到78.1mg(61%)374。MS(ESI)m/z[M+H]+ 351.1。
(R)-5-((2-(3-(二甲基胺基)吡咯啶-1-基)-4-((3-甲氧基苯甲基)氧基)嘧啶-5-基)硫基)吡啶-2-胺[375].向(3-甲氧基苯基)甲醇(42μL,
0.338mmol)於CH3CN(3mL)中之溶液中添加NaH(9.5mg,0.394mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加374(39.5mg,0.113mmol)且在室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到12mg(23%)375。1H NMR(600MHz,CDCl3):δ 8.23(s,1H),8.13(s,1H),7.40(dd,J=8.5,2.3Hz,1H),7.23(t,J=7.9Hz,1H),6.85-6.90(m,2H),6.82(dd,J=8.3,2.2Hz,1H),6.34(d,J=8.5Hz,1H),5.37(s,2H),4.45(s,2H),3.79(s,3H),3.46(m,1H),3.27(m,1H),2.74(m,1H),2.31(s,6H),2.19(s,1H),1.76-1.88(m,3H);HRMS(ESI)m/z[M+H]+ C23H29N6O2S之計算值,453.2073;實驗值453.2051。
流程60. 合成376.
試劑及條件:a.(3-氯苯基)甲醇,NaH,CH3CN,室溫,3小時。
(R)-5-((4-((3-氯苯甲基)氧基)-2-(3-(二甲基胺基)吡咯啶-1-基)嘧啶-5-基)硫基)吡啶-2-胺[376].向(3-氯苯基)甲醇(41μL,0.351mmol)於CH3CN(3mL)中之溶液中添加NaH(9.8mg,0.410mmol)且在室溫下攪拌所得懸浮液10分鐘。隨後添加374(41.1mg,0.117mmol)且在
室溫下攪拌反應混合物3小時。在減壓下濃縮反應混合物,得到殘餘物,藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),20:1)純化,得到9mg(17%)376。1H NMR(600MHz,CDCl3):δ 8.25(s,1H),8.12(s,1H),7.39(d,J=8.5Hz,1H),7.22-7.26(m,3H),7.13-7.16(m,1H),6.37(d,J=8.5Hz,1H),5.34(s,2H),4.46(br s,2H),3.75-3.88(m,2H),3.41-3.44(m,1H),3.25-3.28(m,1H),2.73-2.79(m,1H),2.31(s,6H),2.16-2.21(m,1H),1.83-1.91(m,1H);HRMS(ESI)m/z[M+H]+ C22H26ClN6OS之計算值,457.1577;實驗值457.1561。
流程61. 合成377-379.
試劑及條件:a. 1-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪,Et3N,DMF,90℃,1小時;b. KOH,t-BuOH,70℃,1.5小時;c. PPTS,EtOH,60℃,隔夜。
4-((4-((3-氯苯甲基)氧基)-2-(4-(4-((四氫-2H-哌喃-2-基)氧基)丁- 2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲腈[377].向346(24.9mg,0.065mmol)中添加1-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪(55.5mg,0.233mmol)及Et3N(100μL)於DMF(1mL)中之溶液且在90℃下加熱1小時。在減壓下移除溶劑且藉由製備型TLC(己烷:EtOAc,1:4)純化殘餘物,得到28.2mg(73%)377。MS(ESI)m/z[M+H]+ 590.1。
4-((4-((3-氯苯甲基)氧基)-2-(4-(4-((四氫-2H-哌喃-2-基)氧基)丁-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[378].在70℃下加熱377(28.2mg,0.0478mmol)及KOH(26.8mg,0.478mmol)於t-BuOH(2mL)中之混合物1.5小時。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),15:1)純化殘餘物,得到22mg(46%)378。MS(ESI)m/z[M+H]+ 608.3。
4-((4-((3-氯苯甲基)氧基)-2-(4-(4-羥基丁-2-炔-1-基)哌嗪-1-基)嘧啶-5-基)硫基)苯甲醯胺[379].向378(13.4mg,0.022mmol)於EtOH(1mL)中之混合物中添加PPTS(1mg,0.004mmol)且在60℃下攪拌反應物隔夜。在減壓下移除溶劑且藉由製備型TLC(CH2Cl2:MeOH-NH3(7N),10:1)純化殘餘物,得到6.2mg(54%)379。1H NMR(600MHz,CDCl3/MeOH-d 4 ):δ 8.26(s,1H),7.74-7.77(m,2H),7.19-7.24(m,2H),
7.14(d,J=8.8Hz,2H),7.11(m,1H),7.04(m,1H),5.34(s,2H),4.23(s,2H),3.91(m,4H),3.41(s,2H),2.66(m,4H);13C NMR(150MHz,CDCl3/MeOH-d 4 ):δ 171.3,169.4,165.4,162.3,144.0,139.6,135.0,131.2,130.5,129.0,128.6,128.1,126.6,126.2,99.5,85.3,79.4,67.9,52.3,50.6,47.6,44.3;HRMS(ESI)m/z[M+H]+ C26H27ClN5O3S之計算值,524.1523;實驗值524.1508。
卡斯蛋白酶3、7活化.將MOLM-13細胞(30,000個細胞/孔)塗佈於黑色96孔盤(Corning目錄號3603)中之40μL RPMI培養基中,且置於培育箱(37℃,5% CO2)中高達24小時。將細胞用於50μL培養基中所要濃度之化合物或DMSO(對照)處理16小時。將藥物添加至三個孔中。使細胞暴露於Hsp70抑制劑後,將50μL含有10mM HEPES(pH 7.5)、2mM EDTA、0.1% CHAPS及25μM卡斯蛋白酶受質Z-DEVD-R110之緩衝液添加至各孔中。培育培養盤直至信號穩定為止,隨後在Analyst GT微量盤讀取器中量測各孔之螢光信號。藉由比較由經處理細胞獲得之螢光讀數與由對照細胞獲得之螢光讀數計算凋亡細胞之增加百分比。
例示性結果描述於下表7中。
細胞株:MDA-MB-468細胞獲自美國菌種保藏中心(American Type Culture Collection)。DLBCL細胞描述於以下文獻中:Cerchietti LC等人,BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.J Clin Invest.,2010年12月1日;120(12):4569-4582;及Cerchietti LC等人,A purine scaffold Hsp90 inhibitor destabilizes BCL-6 and has specific antitumor activity in BCL-6-dependent B cell lymphomas.Nat Med.,2009年12月;15(12):1369-76。MDA-MB-468細胞生長於具有10%
FBS及1%青黴素及鏈黴素之DME/F12中。藉由在次優濃度之PU-H71(如下所描繪)存在下連續培育OCI-LY1細胞,隨後選擇抗性純系而得到OCI-LY1R細胞。在補充有20% FBS、1%格魯塔瑪(glutamax)及1%青黴素及鏈黴素之IMDM中培養OCI-LY1、OCI-LY1R及OCI-LY7細胞。OCI-LY3、FARAGE、HBL1、Karpas422、MD901、U2932、SU-DHL4、SU-DHL6、RCK8及TMD8細胞生長於具有10% FBS、1%格魯塔瑪及1%青黴素及鏈黴素之RPMI中。
西方墨點法:塗佈細胞且第二天用指定藥物濃度處理24小時。
收集細胞且在20mM Tris pH 7.4、25mM NaCl、1% NP-40緩衝液中提取蛋白質。對30-50μg總蛋白進行SDS-PAGE,轉移至硝化纖維膜上且在指定抗體存在下培育。P-Akt、BID、Mcll、卡斯蛋白酶9、卡斯蛋白酶3、卡斯蛋白酶7及Bcl-XL抗體購自Cell Signaling Technology;Bax抗體購自Santa Cruz Biotechnology;已裂解PARP Ab購自Promega;且β-肌動蛋白Ab購自Sigma。墨點用TBS-0.1% Tween 20洗滌且在HRP結合之適當二次抗體存在下培育。使用增強化學發光偵測系統(Amersham Biosciences)根據製造商之說明偵測化學發光信號。
生長抑制:將5,000個細胞/孔塗佈於黑色96孔微量滴定盤中且第二天用1/2連續稀釋之指定化合物處理。培育培養盤72小時,之後使
用CellTiter-Glo發光細胞活力分析(Promega)根據製造商之說明量測生長情況。藉由比較由經處理細胞獲得之發光讀數與由對照細胞獲得之發光讀數來計算佔初始細胞群體之細胞生長抑制百分比。使用Analyst GT微量盤讀取器(Molecular Devices)量測各孔中之發光信號。
意外地發現所提供之本發明化合物可在耐受Hsp90抑制劑之癌細胞中活化卡斯蛋白酶,誘導細胞死亡且抑制細胞生長(圖1)。
儘管在本文中已描述且說明本發明之若干實施例,但一般技術者應容易設想多種其他方法及/或結構來執行功能及/或獲得結果及/或一或多種本文所述之優勢,且此類變化及/或修改各可視為在本發明之範疇內。更一般而言,熟習此項技術者應容易瞭解,本文所述之所有參數、尺寸、材料及構型均欲為例示性的且實際參數、尺寸、材料及/或構型取決於使用本發明教示之特定應用。熟習此項技術者應識別或能夠僅僅使用常規實驗確定本文所述之本發明之特定實施例的多個等效物。因此應瞭解,前述實施例僅以實例方式呈現且在隨附申請專利範圍及其等效物之範疇內,本發明可以不同於特別描述及主張之其他方式來實踐。本發明係關於本文所述之各個別特徵、系統、物品、材料、套組及/或方法。另外,若此類特徵、系統、物品、材料、套組及/或方法不會相互矛盾,則兩種或兩種以上此類特徵、系統、物品、材料、套組及/或方法之任何組合均包括於本發明之範疇內。
Claims (112)
- 一種式I化合物,
- 如請求項1之化合物,其中X為-N=。
- 如請求項1之化合物,其中X為-CH=。
- 如前述請求項中任一項之化合物,其中R3為-C(O)N(R3a)2。
- 如前述請求項中任一項之化合物,其中R3為-C(O)NH2。
- 如請求項4之化合物,其中一個R3a為氫,且另一個R3a為視情況經一或多個獨立地選自鹵素或1-吡咯啶基之基團取代之C1烷基。
- 如請求項4之化合物,其中各R3a為甲基。
- 如請求項1至3中任一項之化合物,其中R3為-OR3b。
- 如請求項8之化合物,其中R3b為氫。
- 如請求項8之化合物,其中R3b為視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。
- 如請求項8之化合物,其中R3b為C1-4烷基。
- 如請求項11之化合物,其中R3b為甲基。
- 如請求項10之化合物,其中R3b為-CH(CH3)C(O)NH2。
- 如請求項1至5中任一項之化合物,其中R3為-C(O)H。
- 如請求項1至5中任一項之化合物,其中R3為-C(O)OR。
- 如請求項1至5中任一項之化合物,其中R3為-N(R3c)2。
- 如請求項16之化合物,其中各R3c為氫。
- 如請求項16之化合物,其中一個R3c為氫,且另一個R3c為視情況經一或多個獨立地選自鹵素、C1-4烷基、C1-4鹵基烷基、側氧基或-N(R)2之基團取代之C1-4烷基。
- 如前述請求項中任一項之化合物,其中R4為R或鹵素。
- 如前述請求項中任一項之化合物,其中R4為R。
- 如前述請求項中任一項之化合物,其中R4為氫。
- 如請求項1至20中任一項之化合物,其中R4為C1-4烷基。
- 如請求項22之化合物,其中R4為甲基。
- 如請求項1至19中任一項之化合物,其中R4為視情況經一或多個鹵素取代之C1-4烷基。
- 如請求項24之化合物,其中R4為-CF3。
- 如請求項1至19中任一項之化合物,其中R4為鹵素。
- 如請求項1至19中任一項之化合物,其中R4為-F。
- 如請求項1至19中任一項之化合物,其中R4為-Cl。
- 如請求項1至19中任一項之化合物,其中R4為-Br。
- 如請求項1至19中任一項之化合物,其中R4為-I。
- 如前述請求項中任一項之化合物,其中X1為-C(R5)=。
- 如前述請求項中任一項之化合物,其中R5為氫。
- 如請求項1至31中任一項之化合物,其中R5為甲基。
- 如請求項1至31中任一項之化合物,其中R5為-NH2。
- 如請求項1至30中任一項之化合物,其中X1為-N=。
- 如請求項1之化合物,其中為選自表4之基團。
- 一種式II化合物:
- 如請求項37之化合物,其中Y為-S-。
- 如請求項37之化合物,其中Y為-O-。
- 如請求項37之化合物,其中Y為-CH2-。
- 如請求項37之化合物,其中環B為
- 如前述請求項中任一項之化合物,其中R1為
- 如前述請求項中任一項之化合物,其中R1為
- 如前述請求項中任一項之化合物,其中各R1b獨立地為氫或兩個R1b基團視情況一起形成側氧基。
- 如前述請求項中任一項之化合物,其中R1a為或C1-4直鏈脂 族基,其視情況經一或多個獨立地選自以下之基團取代:-OH或具有1-2個獨立地選自氮、氧或硫之雜原子的5員雜芳基。
- 如請求項1至41中任一項之化合物,其中R1為
- 如請求項1至41中任一項之化合物,其中R1為
- 如請求項1至41、46及47中任一項之化合物,其中各R1c獨立地為C1-4烷基。
- 如請求項1至41、46、47及48中任一項之化合物,其中各R1c為甲 基。
- 如請求項1至41中任一項之化合物,其中R1為
- 如請求項1至41中任一項之化合物,其中R1為
- 如請求項1至41中任一項之化合物,其中R1為
- 如請求項1至41及51至52中任一項之化合物,其中各R1c獨立地為氫或C1-4烷基,且R1d獨立地為C1-4烷基。
- 如請求項51或52之化合物,其中R1為
- 如請求項51或52之化合物,其中R1為
- 如請求項1至41中任一項之化合物,其中R1為選自表1之基團。
- 如前述請求項中任一項之化合物,其中R2為-O-CH2-環A。
- 如請求項1至56中任一項之化合物,其中R2為-NH-CH2-環A。
- 如請求項1至56中任一項之化合物,其中R2為-O-CH2CH2-環A。
- 如請求項1至59中任一項之化合物,其中環A為苯基。
- 如請求項1至59中任一項之化合物,其中環A為呋喃基。
- 如請求項1至59中任一項之化合物,其中環A為1-呋喃基。
- 如請求項1至59中任一項之化合物,其中環A為2-呋喃基。
- 如請求項1至59中任一項之化合物,其中環A為
- 如請求項64之化合物,其中環A為
- 如請求項65之化合物,其中環A為
- 如請求項64至66中任一項之化合物,其中RA1為-Cl或-OR。
- 如請求項64至67中任一項之化合物,其中RA1為-OR,其中R為C1-4烷基。
- 如請求項64至68中任一項之化合物,其中RA1為-OCH3。
- 如請求項1至66中任一項之化合物,其中RA1為-N(R)2,其中各R獨立地為C1-4烷基。
- 如請求項1至66及70中任一項之化合物,其中RA1為-N(CH3)2。
- 如請求項1至59中任一項之化合物,其中環A為
- 如請求項72之化合物,其中RA2為-F、-Br或-OR。
- 如請求項72或73之化合物,其中RA2為-OR,其中R為C1-4烷基。
- 如請求項72至74中任一項之化合物,其中RA2為-OCH3。
- 如請求項1至59中任一項之化合物,其中環A為
- 如請求項76之化合物,其中RA3為-H或-F。
- 如請求項76或77之化合物,其中RA4為-F或-OCH3。
- 如請求項1至59中任一項之化合物,其中環A為視情況經RA5取代之吡啶基。
- 如請求項1至59中任一項之化合物,其中環A為經RA5取代之吡啶基。
- 如請求項79或80之化合物,其中RA5為-N(R)2。
- 如請求項81之化合物,其中RA5為-NH2。
- 如請求項79或80之化合物,其中RA5為-OR。
- 如請求項83之化合物,其中R為C1-4烷基。
- 如請求項83或84之化合物,其中R為甲基。
- 如請求項1至56中任一項之化合物,其中R2為選自表3之基團。
- 一種選自表5之化合物,或其醫藥學上可接受之鹽。
- 一種選自表6之化合物,或其醫藥學上可接受之鹽。
- 如前述請求項中任一項之化合物,其中該化合物在約1.0μM或低於約1.0μM下在卡斯蛋白酶裂解分析中具有活性。
- 如前述請求項中任一項之化合物,其中該化合物在低於約0.5μM下在卡斯蛋白酶裂解分析中具有活性。
- 如前述請求項中任一項之化合物,其中該化合物在低於約0.4μM下在卡斯蛋白酶裂解分析中具有活性。
- 如前述請求項中任一項之化合物,其中該化合物在低於約0.2μM下在卡斯蛋白酶裂解分析中具有活性。
- 如前述請求項中任一項之化合物,其中該化合物在低於約0.1μM下在卡斯蛋白酶裂解分析中具有活性。
- 如前述請求項中任一項之化合物,其中該化合物在低於約0.05μM下在卡斯蛋白酶裂解分析中具有活性。
- 如前述請求項中任一項之化合物,其中該化合物在低於約0.01μM下在卡斯蛋白酶裂解分析中具有活性。
- 一種醫藥組合物,其包含如請求項1至95中任一項之化合物及醫藥學上可接受之載劑。
- 一種治療患有或易患對Hsp70抑制起反應之疾病、病症或病狀之個體的方法,該方法包含投與該個體治療有效量之如請求項1至95中任一項之化合物或其組合物。
- 如請求項97之方法,其中該疾病、病症或病狀為增生性疾病、病症或病狀。
- 如請求項98之方法,其中該疾病、病症或病狀為癌症。
- 如請求項99之方法,其中該癌症以Hsp90抑制劑治療是難治性的。
- 如請求項99或100之方法,其進一步包含投與該個體治療有效量之第二化學治療劑。
- 如請求項99至101中任一項之方法,其中該個體處於臨床緩解中,或其中該個體已藉由手術治療,患有侷限性未切除疾病。
- 一種抑制Hsp70活性之方法,該方法包含使Hsp70與如請求項1至95中任一項之化合物或其組合物接觸。
- 如請求項103之方法,其中該方法用於離體抑制Hsp70。
- 如請求項103之方法,其中該方法用於抑制患者之Hsp70。
- 一種治療或預防罹患癌症之個體的癌症的方法,該方法包含投與有需要之患者治療有效量之如請求項1至95中任一項之化合物或其組合物。
- 如請求項106之方法,其中該個體處於臨床緩解中,或其中該個體已藉由手術治療,患有侷限性未切除疾病。
- 如請求項106或107之方法,其中該癌症以Hsp90抑制劑治療是難治性的。
- 一種活化細胞中卡斯蛋白酶之方法,其包含投與該等細胞如請求項1至95中任一項之化合物或其組合物。
- 一種誘導細胞中細胞凋亡之方法,其包含投與該等細胞如請求項1至95中任一項之化合物或其組合物。
- 一種抑制細胞生長之方法,其包含投與該等細胞如請求項1至95中任一項之化合物或其組合物。
- 如請求項109至111中任一項之方法,其中該等細胞耐受Hsp90抑制劑。
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US9878987B2 (en) | 2018-01-30 |
WO2015175707A1 (en) | 2015-11-19 |
PH12016502244A1 (en) | 2017-01-09 |
TWI699204B (zh) | 2020-07-21 |
EA201692155A1 (ru) | 2017-04-28 |
BR112016026470A8 (pt) | 2021-07-20 |
US20180170883A1 (en) | 2018-06-21 |
CA2948621A1 (en) | 2015-11-19 |
JP6607870B2 (ja) | 2019-11-20 |
CN107074806B (zh) | 2021-04-23 |
KR20170005095A (ko) | 2017-01-11 |
EP3143013A1 (en) | 2017-03-22 |
AU2015259173A1 (en) | 2016-12-08 |
AU2015259173B2 (en) | 2019-09-05 |
JP2017515857A (ja) | 2017-06-15 |
BR112016026470A2 (pt) | 2017-08-15 |
KR102461419B1 (ko) | 2022-11-02 |
US10647683B2 (en) | 2020-05-12 |
SG11201609336PA (en) | 2016-12-29 |
CN107074806A (zh) | 2017-08-18 |
ES2774975T3 (es) | 2020-07-23 |
IL248792A0 (en) | 2017-01-31 |
US20170233352A1 (en) | 2017-08-17 |
IL248792B (en) | 2020-01-30 |
EP3143013B1 (en) | 2019-12-18 |
US10160729B2 (en) | 2018-12-25 |
US20190241526A1 (en) | 2019-08-08 |
MX2016014755A (es) | 2017-03-27 |
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