TW202237101A - Ctla-4小分子降解劑及其應用 - Google Patents
Ctla-4小分子降解劑及其應用 Download PDFInfo
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- TW202237101A TW202237101A TW111110135A TW111110135A TW202237101A TW 202237101 A TW202237101 A TW 202237101A TW 111110135 A TW111110135 A TW 111110135A TW 111110135 A TW111110135 A TW 111110135A TW 202237101 A TW202237101 A TW 202237101A
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Abstract
本發明實施例涉及一種CTLA-4小分子降解劑及其應用,所述CTLA-4
小分子降解劑為具備式I結構的化合物或其藥學上可接受的鹽、酯、氘代物、異構體、溶劑化物、前藥或同位素標記物:
Description
本發明屬於醫藥化學領域,具體涉及一種通過抑制LRBA蛋白和CTLA-4蛋白相互作用從而導致CTLA-4蛋白降解的小分子降解劑、其製備方法、藥物組合物以及在醫藥方面的用途。
PD-1/PD-L1抑制劑是目前最重要的腫瘤免疫類藥物之一,但是臨床反應率比較低(10-30%),對於大部分腫瘤患者無效,臨床需新的解決方案。PD-1/PD-L1抑制劑與其它腫瘤治療藥物進行聯合給藥,可能是較好策略。
CTLA-4(細胞毒性T淋巴細胞相關蛋白-4)是一種蛋白受體,其作為免疫檢查點起作用並下調免疫應答。它在T細胞,尤其調節性T細胞中組成型高表達,當與抗原呈遞細胞表面上的CD80或CD86結合時,起到“關閉”開關的作用。CTLA-4抑制劑可以啟動抗腫瘤免疫反應,用於腫瘤的免疫治療。CTLA-4抑制劑伊匹木單抗(Yervoy,“Y”藥)已經用於黑色素瘤等多種腫瘤的治療。
考慮到CTLA-4和PD-1/PD-L1於腫瘤免疫反應不同階段協同調控免疫反應:CTLA-4,腫瘤免疫反應早中期階段;PD-1,腫瘤免疫反應後期階段,所以CTLA-4與PD-1/PD-L1抑制劑聯合給藥是可行的,並且此聯合給藥策略已
在臨床中獲得充分驗證:如FDA已經批准了肝細胞癌、非小細胞肺癌等6個臨床適應症。如伊匹木單抗(Yervoy,“Y”藥)與PD-1抑制劑納武單抗(OPDIVO,“O”藥)聯合給藥時客觀緩解率(ORR)與“O”藥單藥相比,得到顯著提高。Y藥與O藥的雙免疫治療組合,是首個也是目前唯一獲得FDA批准的雙免疫療法。
但目前的CTLA-4抑制劑如“Y”藥等是抗體藥物,該抗體及該類抗體藥物存在一些固有局限性:1)副作用大,臨床上54%左右聯用患者會產生3-4級免疫治療相關的嚴重副作用(irAEs),極大限制了此類藥物的臨床使用,同時該副作用作用與抗體的ADCC作用和免疫原性有關;2)瘤內擴散難:CTLA-4抗體藥物作為大分子藥物,實體瘤內浸潤比較困難,限制了單用或者聯合用藥的治療效果;3)依從性差:CTLA-4抗體藥物的給藥方式以靜脈、皮下或者肌肉注射給藥為主,無法口服給藥,患者依從性差。
為瞭解決上述至少部分問題和缺陷,本發明實施例提供了一種CTLA-4小分子降解劑及其應用。
為瞭解決上述至少部分問題和缺陷,本發明實施例提供了以下技術方案:一種CTLA-4小分子降解劑,具備式I結構:
,其中,A、B、C、D、E、F、G、H、I、
J、K、L和M分別選自直連鍵、CR6、CR6R14、N、NR7、O、S和C=O;每一個R1、R2、R3、R6、R7和R14分別選自氫、氘、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的炔基、未取代或取代的環烷基、未取代或取代的環雜烷基、鹵素、-OH、未取代或取代的烷氧基、未取代或取代的芳基烷基、未取代或取代的芳雜基烷基、未取代或取代的芳基醚基、未取代或取代的芳雜基醚基、-CN、-N(R4R5)、-NO2、-N3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲醯基、未取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的硫醚基、未取代或取代的亞碸基、未取代或取代的碸基、
未取代或取代的磺醯胺基、、、未取代或取代
的膦酸酯基,其中R4、R5、R8、R9、R10和R11分別選自氫、氘、未取代或取代的C1-6烷基、C3-7環烷基、未取代或取代的芳基、未取代或取代的芳雜基,且R4和R5、R8和R9可與相鄰的氮原子或碳原子連接成環;或相鄰的兩個R1和/或相鄰的兩個R3也可連接成環烷基、環雜烷基、芳基或芳雜基;m、n、o分別選自0~4的整數;W選自直連鍵、未取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的環烷基、未取
代或取代的環雜烷基、未取代或取代的橋環烷基、未取代或取代的橋環雜烷基、未取代或取代的螺環烷基、未取代或取代的螺環雜烷基、未取代或取代的烷基、未取代或取代的雜烷基、未取代或取代的烯基、未取代或取代的雜烯基、未取代或取代的炔基、未取代或取代的雜炔基、未取代或取代的-N(R12R13)、未取代或取代的胺基烷基、未取代或
取代的胺基烷基胺基、未取代或取代的、未取代或取代的
,其中R12和R13分別選自氫、氘、C1-6烷基、C3-7環烷基、
未取代或取代的烷基胺基、未取代或取代的芳基、取代或未取代的芳雜基,或R12和R13可連接成環;Q為-H、-NH2、-OH、-烷基-NHC(=O)H、環烷基、未取代或取代的烷基醯基、未取代或取代的烷基羥基、未取代或取代的烯基羥基、未取代或取代的炔基羥基、未取代或取代的烷基胺基、未取代或取代的磺醯胺基、未取代或取代的烷基磺醯胺基、
氨基酸殘基、、磺醯胺基、磺醯肼基、未取代或取代的芳基、
未取代或取代的芳雜基、未取代或取代的、未取代或取代的
、取代或未取代的-(CH2)n1-(M)n2-(CH2)n3-(M)n4-(CH2)n 5-(M)n6,其中每個M分別選自O、OH、S、SO、SO2和未取代或取代的胺基,每個n1、n2、n3、n4、n5和n6分別選自0-6的整數;或W和Q可以連接或融合成取代或非取代的環烷基、環雜烷基、芳基或芳雜基。
在本發明的一個實施例中,所述C、G、I中至少一個為N原子。
在本發明的一個實施例中,所述J、K、M中至少一個為N原子。
在本發明的一個實施例中,所述I、J、K均為N原子,或I、M、K均為N原子。
在本發明的一個實施例中,每一個R1、R2、R3、R6、R7和R14分別選自氫、氘、未取代或取代的C1-6烷基、未取代或取代的C2-6烯基、未取代或取代的C2-6炔基、未取代或取代的C3-7環烷基、未取代或取代的3-7元環雜烷基、鹵素、-OH、未取代或取代的C1-6烷氧基、未取代或取代的C6-10芳基乙基、未取代或取代的5-10元芳雜基乙基、未取代或取代的C6-10芳基醚基、未取代或取代的5-10元芳雜基醚基、-CN、-NH2、-NO2、-N3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲醯基、未取代或取代的C6-10芳基、未取代或取代的5-10元芳雜基、未取代或取代的硫醚基、未取代或取代的亞碸
基、未取代或取代的碸基、未取代或取代的磺醯胺基、、、
未取代或取代的膦酸酯基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個實施例中,所述W選自直連鍵、取代或非取代的芳基、芳雜基、環烷基、環雜烷基、橋烷基、橋環雜環烷基、螺環烷基、螺環雜烷基、烷基、雜烷基、烯基、雜烯基、炔基、雜炔基、-N(R12R13)、胺基烷基、
胺基烷基胺基、未取代或取代的、未取代或取代的,
所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、
C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個實施例中,所述W選自取代或非取代的5-7元環雜烷基、取代或非取代的-胺基-C1-6烷基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個實施例中,所述W中與含J、K的環相連的原子為N。
在本發明的一個實施例中,W選自取代或非取代的5-7元環雜烷基,所述5-7元雜環烷基至少包含一個氮原子,更優選的,所述5-7元雜環烷基為呱啶基或呱嗪基。
在本發明的一個實施例中,所述Q為-H、-NH2、-OH、-C1-6烷基-HNC(=O)H、未取代或取代的C1-6烷基羥基、未取代或取代的C2-6烯基羥基、未取代或取代的C2-6炔基羥基、未取代或取代的烷基胺基、磺醯胺基和磺醯肼基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個實施例中,所述W和Q可以連接或融合成環,所述環為取代或非取代的5-7元環烷基、取代或非取代的5-7元的環雜烷基、取代或非取代的C6-10芳基、取代或非取代的5-10元芳雜基。
在本發明的一個實施例中,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、接基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個實施例中,所述式II結構的化合物為:
在本發明的一個實施例中,所述式III結構的化合物為:
本發明實施例提供的CTLA-4小分子降解劑在體外研究中,對CTLA-4在納摩爾(nM)水準即顯示出良好活性,以及具有優秀的抑瘤效果。
本發明實施例提供了一種CTLA-4小分子降解劑,其具有其獨特優勢:1)顯著減少毒副作用:CTLA-4小分子降解劑通過降解CTLA-4蛋白達到解除免疫抑制的目的,本身對T細胞其他活性沒有影響,並且小分子沒有抗體的ADCC作用和免疫原性,因此副作用會大大降低;2)瘤內易擴散:小分子藥物較容易浸潤到實體瘤內,大大提高單用或者聯合用藥的治療效果;3)依從性好:小分子藥物可以口服用藥;4)價格優勢:小分子藥物生產成本低。
本文中使用的術語“直連鍵”指的是與直連鍵相連的兩個原子或基團直接通過化學鍵相連,優選的,所述化學鍵包括單鍵和雙鍵。
除非另有定義,本文使用的術語“取代”是被下列取代基所取代:烷基、環烷基、芳基、雜環基、鹵素、羥基、烷氧基、硼酸基、硼酸酯、膦酸酯、酯基、氧代、烷醯基、芳基氧基、烷醯基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的胺基(其中2個氨基取代基選自烷基、芳基或芳基烷基)、烷醯基氨基、芳醯基氨基、芳烷醯基氨基、取代的烷醯基氨基、取代的芳基氨基、取代的芳烷醯基氨基、硫基、烷基硫基、芳基硫基、芳基烷基硫基、芳基硫羰基、芳基烷基硫羰基、烷基磺醯基、芳基磺醯基、芳基烷基磺醯基、磺醯氨基例如-SO2NH2、取代的磺醯氨基、硝基、氰基、羧基、氨基甲醯基例如-CONH2、取代的氨基甲醯基例如-CONH烷基、-CONH芳基、-CONH芳基烷基或在氮上具有兩個選自烷基、芳基或芳基烷基的取代基的情況、烷氧基羰基、芳基、取代的芳基、胍基、雜環基例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、呱啶基、嗎啉基、呱嗪基、高呱嗪基等和取代的雜環基。
本文使用的術語“烷基”或“亞烷基”均意欲包括具有指定碳原子數的支鏈和直鏈飽和脂族烴基團。例如,“C1-6烷基”表示具有1個至6個碳原子的烷基。烷基的實例包括但不限於甲基(Me)、乙基(Et)、丙基(例如正丙基和異丙基)、丁基(例如正丁基、異丁基、叔丁基)和戊基(例如正戊基、異戊基、新戊基)。
術語“雜烷基”或“烷雜基”是指烷基上的1-4個碳原子被雜原子所取代,優選的,烷基上的1-3個碳原子被雜原子所取代,更優選的,烷基上的1-2個碳原子被雜原子所取代;優選的,被雜原子取代前的烷基為C2-10烷基,更優選的,被雜原子取代前的烷基為C2-6烷基;雜原子取代的位置可以為烷基的端位,也可以為烷基的中間位置,所述雜原子分別獨立地選自N、O、S、P等。
術語“烯基”表示含一個或多個雙鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如,“C2-6烯基”含有兩個至六個碳原子。烯基包括但不限於例如乙烯基、丙烯基、丁烯基、1-甲基-2-丁烯-1-基、己烯基等。
術語“炔基”表示含一個或多個三鍵且通常長度為2至20個碳原子的直鏈或支鏈的烴基。例如,“C2-6炔基”含有兩個至六個碳原子。代表性炔基包括但不限於例如乙炔基、1-丙炔基、1-丁炔基、戊炔基、己炔基等。
術語“雜烯基”表示上述定義的“烯基”中的一個或多個碳原子被選自N、O、S的雜原子替換,或者被含有選自N、O、S的雜原子基團所取代。
術語“雜炔基”表示上述定義的“炔基”中的一個或多個碳原子被選自N、O、S的雜原子替換,或者被含有選自N、O、S的雜原子基團所取代。
術語“烷氧基”或“烷基氧基”是指-O-烷基。“C1-10烷氧基”(或烷基氧基)意欲包括C1-C10的烷氧基。烷氧基的實例包括但不限於甲氧基、乙氧基、丙氧基(例如正丙氧基和異丙氧基)和叔丁氧基,同時烷氧基中可以帶有
多個氧原子如1-10個氧原子。類似地,“烷基硫基”或“硫代烷氧基”表示具有指定數量碳原子的經硫橋連接的如上文所定義的烷基;例如甲基-S-和乙基-S-。
術語“羰基”和“醯基”是指由碳和氧兩種原子通過雙鍵連接而成的有機官能團(C=O)。
術語“酯基”是包括接酸酯基、磷酸酯基、亞磷酸酯基、矽酸酯基、硼酸酯基等,例如-COOR,B(OR)2,其中R為烷基。
術語“環烷基”是指單環或二環的環狀烷基。單環的環狀烷基指C3-8的環狀烷基,包括但不限於環丙基、環丁基、環戊基、環己基和降莰烷基等。支化環烷基諸如1-甲基環丙基和2-甲基環丙基包括在“環烷基”的定義中。二環的環狀烷基包括橋環、螺環或融合環的環烷基。
術語“環烯基”是指單環或二環的環狀烯基。單環的環狀烯基指C3-8的環狀烯基,包括但不限於環丙烯基、環丁烯基、環戊烯基、環己烯基和降莰烯基。支化環烯基諸如1-甲基環丙烯基和2-甲基環丙烯基包括在“環烯基”的定義中。二環的環狀烯基包括橋環、螺環或融合環的環狀烯基。
“鹵代”或“鹵素”包括氟、、溴和碘。“鹵代烷基”意欲包括具有指定碳原子數且取代有1個或多個鹵素的支鏈和直鏈飽和脂族烴基團。鹵代烷基的實例包括但不限於氟甲基、二氟甲基、三氟甲基、三甲基、五氟乙基、五乙基、2,2,2-三氟乙基、七氟丙基和七丙基。鹵代烷基的實例還包括意欲包括具有指定碳原子數且取代有1個或多個氟原子的支鏈和直鏈飽和脂族烴基團的“氟烷基”。
“鹵代烷氧基”或“鹵代烷基氧基”表示具有指定數量碳原子的經氧橋連接的如上文所定義的鹵代烷基。例如,“C1-6鹵代烷氧基”意欲包括C1、C2、C3、C4、C5和C6鹵代烷氧基。鹵代烷氧基的實例包括但不限於三氟甲
氧基、2,2,2-三氟乙氧基和五氟乙氧基。類似地,“鹵代烷基硫基”或“硫代鹵代烷氧基”表示具有指定數量碳原子的經硫橋連接的如上文所定義的鹵代烷基;例如三氟甲基-S-和五氟乙基-S-。
術語“芳基”/“亞芳基”,單獨或作為較大部分諸如“芳烷基”、“芳烷氧基”或“芳基氧基烷基”的部分,是指具有總計6至10個環成員的單環、二環或三環的環系統,其中所述系統中的至少一個環為芳族的且其中所述系統中的每個環含有3至7個環成員。在本發明的某些實施方案中,“芳基”是指芳族環系統,其包括但不限於苯基、茚滿基、1-萘基、2-萘基和四氫萘基。稠合的芳基可在環烷基環或芳族環的合適位置上連接至另一基團。例如從環系統中畫出的箭頭線表明鍵可連接至任意合適的環原子。
術語“雜芳基”/“亞雜芳基”、“雜芳環”、“亞芳雜基”、“芳雜基”、“雜芳環基”或“雜芳環基團”意指穩定的3元、4元、5元、或7元芳香單環或芳香二環或7元、8元、9元、10元、11元、12元、13元或14元芳香多環雜環,其為完全不飽和的、部分不飽和的,且其含有碳原子和1個、2個、3個或4個獨立地選自N、O和S的雜原子;且包括任何以下多環基團,其中上文所定義的任意雜環與苯環稠合。氮和硫雜原子可任選地被氧化。氮原子為取代的或未取代的(即N或NR,其中R為H或如果被定義,則為另一取代基)。雜環可在得到穩定結構的任何雜原子或碳原子處連接至其側基。如果所得化合物是穩定的,則本文所述的雜環基可在碳或氮原子上被取代。雜環中的氮可任選地被季銨化。優選地,當雜環中S和O原子的總數超過1時,則這些雜原子彼此不相鄰。優選地,雜環中S和O原子的總數不大於1。芳雜環的實施例包括但不限於吖啶基、氮雜環丁基、吖辛因基、苯並咪唑基、苯並呋喃基、苯並硫代呋喃基、苯並噻吩基、苯並噁唑基、苯並噁唑啉基、苯並噻
唑基、苯並***基、苯並四唑基、苯並異噁唑基、苯並異噻唑基、苯並咪唑啉基、哢唑基、4aH-哢唑基、哢啉基、色滿基、色烯基、噌啉基、十氫喹啉基、2H,6H-1,5,2-二噻嗪基、二氫呋喃並[2,3-b]四氫呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、咪唑並吡啶基、假吲25哚基(indolenyl)、二氫吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛紅醯基(isatinoyl)、異苯並呋喃基、異色滿基、異吲唑基、異二氫吲哚基、異吲哚基、異喹啉基、異噻唑基、異噻唑並吡啶基、異噁唑基、異噁唑並吡啶基、亞甲基二氧基苯基、嗎啉基、二氮雜萘基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、噁唑並吡啶基、噁唑烷基、萘嵌間二氮雜苯基、羥吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、吩噁噻基、吩噁嗪基、酞嗪基、呱嗪基、呱啶基、呱啶酮基、4-呱啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑並吡啶基、吡唑基、噠嗪基、吡啶並噁唑基、吡啶並咪唑基、吡啶並噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎寧環基、四唑基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻唑並吡啶基、噻吩並噻唑基、噻吩並噁唑基、噻吩並咪唑基、噻吩基、三嗪基、1,2,3-***基、1,2,4-***基、1,2,5-***基、1,3,4-***基和呫噸基、喹啉基、異喹啉基、酞嗪基、喹唑啉基、吲哚基、異吲哚基、二氫吲哚基、1H-吲唑基、苯並咪唑基、1,2,3,4-四氫喹啉基、1,2,3,4-四氫異喹啉基、5,6,7,8-四氫-喹啉基、2,3-二
氫-苯並呋喃基、色滿基、1,2,3,4-四氫-喹喔啉基和1,2,3,4-四氫-喹唑啉基。本發明還包括含有例如上述雜環的稠環和螺環化合物。
本文使用的術語“雜環烷基”和“環雜烷基”指的是一個單環雜環烷基體系,或為一個二環雜環烷基體系。單環的雜環烷基指的是3-12元(優選3-8元,更優選5-7元)、且至少含一個選自O、N、S、P的飽和或不飽和但不為芳香性的環狀烷基體系。二環雜烷基體系指的是一個雜環烷基融合到一個苯基、或一個環烷基、或一個環烯基、或一個環雜烷基、或一個雜芳基。所述雜環烷基包括但不限於氮丙啶基、氮雜環丁基、氧雜環丁基、吡咯烷基、四氫呋喃基、四氫噻吩基、呱啶基、嗎啉基、呱嗪基、硫代嗎啉基、四氫吡喃基、1,1-二氧硫代嗎啉基、1,4-二氮烷基等。
本文使用的術語“橋環烷基”指的是5至20元,任意兩個環共用兩個不直接連接的碳原子的全碳多環基團,其可以含有一個或多個雙鍵。優選為6至14元,更優選為7至10元(例如7、8、9或10元)。根據組成環的數目可以分為雙環、三環、四環或多環橋環烷基,優選為雙環、三環或四環,更優選為雙環或三環。
本文使用的術語“橋雜環烷基”、“雜橋環烷基”和“橋環雜烷基”指的是共用兩個或兩個以上碳原子或雜原子的多環化合物,所述“橋雜環烷基”、“雜橋環烷基”和“橋環雜烷基”至少含一個選自O、N、S、P等的雜原子。可分為二環雜橋環烷基及多環雜橋環烷基,前者由兩個脂環共用兩個以上碳原子或雜原子所構成;後者是由三個以上的環組成的雜橋環烷基。
本文使用的術語“螺環烴”、“螺環烷基”指的是單環之間共用一個碳原子(稱螺原子)的多環烴、多環烷基。
本文使用的術語“螺環雜烷基”指的是5至20元,單環之間共用一個原子(稱螺原子)的多環雜環基團,其中一個或多個環原子為選自氮、氧和硫的雜原子,所述的硫可任選被氧代(即形成亞碸或碸),其餘環原子為碳。其可以含有一個或多個雙鍵。優選為6至14元,更優選為7至10元(例如7、8、9或10元)。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基,優選為單螺雜環基和雙螺雜環基。更優選為3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元單螺雜環基。
本文中使用的術語“異構體”中包括了“互變異構體”、“立體異構體”等,“互變異構體”指的是具有不同能量的,可通過低能壘互相轉化的結構異構體。若互變異構是可能的(如在溶液中),則可以達到互變異構體的化學平衡。例如,質子互變異構體(或稱質子轉移互變異構體)包括但不限於通過質子遷移來進行的互相轉化,如酮-烯醇異構化、亞胺-烯胺異構化、醯胺-亞胺醇異構化等。“立體異構體”指的是具有相同化學構造,但原子或基團在空間上排列方式不同的化合物。立體異構體包括對映異構體、非對映異構體、構象異構體(旋轉異構體)、幾何(順/反)異構體、阻轉異構體,等等。除非另外指出,本發明的化合物的所有互變異構體、立體異構體形式都在本發明的範圍之內。
本文中所用的術語“取代”意指至少一個氫原子被非氫基團替代,條件是維持正常化合價且所述取代得到穩定的化合物。本文所用的環雙鍵為在兩個相鄰環原子之間形成的雙鍵(例如C=C、C=N或N=N)。
在本發明化合物上存在氮原子(例如胺)的情形下,可通過使用氧化劑(例如mCPBA和/或過氧化氫)進行處理來將這些氮原子轉化成N-氧化物以獲得本發明的其他化合物。因此,所顯示和要求保護的氮原子視為均涵蓋所顯示氮及其N-氧化物(N→O)衍生物。
當任何變數在化合物的任何組成或式中出現一次以上時,其每次出現時的定義均獨立於其在其他每種情況下出現時的定義。因此,例如如果顯示基團取代有0-3個R,則所述基團可任選地取代有至多三個R基團,且在每次出現時R獨立地選自R的定義。此外,取代基和/或變數的組合僅在上述組合可產生穩定的化合物時才容許存在。
當鍵合至取代基的鍵顯示為與連接環中的兩個原子的鍵交叉時,則上述取代基可鍵合至該環上的任一原子。當列舉取代基但未指明該取代基中鍵合至具有給定式的化合物的其餘部分上的原子時,則上述取代基可經由該取代基中的任一原子來鍵合。取代基和/或變數的組合僅在上述組合可產生穩定的化合物時才容許存在。
術語“C1-6烷基胺基”單獨或者以組合方式表示如上所定義的胺基基團,其中胺基基團的氫原子被至少一個C1-6烷基所取代,其中“烷基”表示如以上所定義,相應地,“C1-6烷基胺基”包括甲基胺基、乙基胺基、丙基胺基、異丙基胺基、正丁基胺基、異丁基胺基、2-丁基胺基、叔丁基胺基、正戊基胺基、2-戊基胺基、3-戊基胺基、2-甲基-2-丁基胺基、3-甲基-2-丁基胺基、3-甲基-1-丁基胺基、2-甲基-1-丁基胺基、正己基胺基、2-己基胺基、3-己基胺基、2-甲基-2-戊基胺基、3-甲基-2-戊基胺基、4-甲基-2-戊基胺基、3-甲基-3-戊基胺基、2-甲基-3-戊基胺基、2,3-二甲基-2-丁基胺基、3,3-二甲基-2-丁基胺基等。特別的“C1-6烷基胺基”是甲基胺基、乙基胺基、異丙基胺基、叔丁基胺基等。
術語“(C1-6烷基)2胺基”單獨或者以組合方式表示如上所定義的胺基基團,其中氨基基團的氫原子被兩個C1-6烷基所取代,其中“烷基”表示
如以上所定義,相應地,“(C1-6烷基)2胺基”包括二甲胺基、二乙胺基、甲基乙基胺基等。
本文使用的術語“氨基酸殘基”指的是一個氨基酸的碳端羧基或胺基參與了鍵的形成而失去一分子水,此氨基酸單位稱為氨基酸殘基。
本文使用的術語“[Cu]”在本文中指的是含一價銅(Cu+)或二價銅(Cu2+)試劑,如CuI、CuBr、CuCl、CuI2、CuBr2、CuCl2等。
術語“異構體”包含所有的同分異構形式包括對映異構體、非對映異構體、互變異構體和幾何異構體(包括順反異構體)。因此,本發明中所設計的化合物的單個立體化學異構體或其對映異構體、非對映異構體、互變異構體或幾何異構體(或順反異構體)的混合物都屬於本發明的範圍。
本文使用的“藥學上可接受的鹽”是指本發明化合物的衍生物,其中母體化合物通過製備其酸或堿鹽來修飾。藥用鹽的實例包括但不限於鹼性基團(諸如胺)的無機或有機酸鹽;及酸性基團(諸如羧酸)的鹼金屬鹽或有機鹽。藥用鹽包括由(例如)無毒的無機或有機酸形成的母體化合物的常規無毒鹽或季銨鹽。例如,上述常規無毒鹽包括衍生自例如以下無機酸的那些:鹽酸、氫溴酸、硫酸、氨基磺酸、磷酸和硝酸;及由例如以下有機酸製備的鹽:乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、撲酸、馬來酸、羥基馬來酸、苯乙酸、穀氨酸、苯甲酸、水楊酸、磺胺酸、2-乙醯氧基苯甲酸、富馬酸、苯磺酸、甲磺酸、乙二磺酸、草酸和羥乙磺酸等。
本發明的藥學上可接受的鹽可通過常規化學方法自含有鹼性或酸性部分的母體化合物合成。通常,可通過在水或有機溶劑或二者的混合物中使這些化合物的遊離酸或堿形式與化學計量的適合堿或酸反應來製備上述鹽;通常,優選如***、乙酸乙酯、乙醇、異丙醇或乙腈等非水性介質。合適鹽的列
表可參見Remington:The Science and Practice of Pharmacy,22nd Edition,25 Allen,L.V.Jr.,Ed.;Pharmaceutical Press,London,UK(2012),通過引用的方式將其披露內容併入本文中。
術語“溶劑化物”意指本發明化合物與一個或多個溶劑分子(無論有機的還是無機的)的物理締合。該物理締合包括氫鍵。在某些情形中,例如當一個或多個溶劑分子納入結晶固體的晶格中時,溶劑化物將能夠被分離。溶劑化物中的溶劑分子可按規則排列和/或無序排列存在。溶劑化物可包含化學計量或非化學計量的溶劑分子。“溶劑合物”涵蓋溶液相和可分離的溶劑化物。示例性溶劑化物包括但不限於水合物、乙醇合物、甲醇合物和異丙醇合物。溶劑化方法是本領域公知的。
術語“酯”用於表示有機酯,包括單酯、二酯、三酯、和更通常地多酯。
術語“同位素衍生物”表示通式(I)中的氫原子被1-6個氘原子(D)所取代得到的同位素衍生物、通式(I)中的碳原子被1-3個碳14原子(14C)所取代得到的同位素衍生物。
本文使用的術語“治療”包括導致改善病症、疾病、障礙等的任何效果,例如減輕、減少、調節、改善或消除,或改善其症狀。
本文使用的術語“藥物組合物”是指活性劑與惰性或活性的載體的組合,使得所述組合物尤其適用於體內或離體診斷或治療。堿的實例包括但不限於鹼金屬(例如鈉)氫氧化物、鹼土金屬(例如鎂)氫氧化物、氨等。對於治療用途,本發明化合物的鹽對於治療用途,本發明化合物的鹽預期為是藥用的。然而,非藥用的酸和堿的鹽也可用於例如藥用化合物的製備或純化中。
特定藥學及醫學術語
術語“癌症”,如本文所用,指一種不能控制的細胞的異常生長,並且在某種條件下能夠轉移(傳播)。這種類型的癌症包括但不限於,固體腫瘤(如膀胱、腸、腦、胸、子宮、心臟、腎、肺、淋巴組織(淋巴瘤)、卵巢、胰腺或其他內分泌器官(如甲狀腺)、***、皮膚(黑色素瘤)或血液瘤(如非白血性白血病)。
藥物組合物和劑量
本發明實施例還提供了一種藥用組合物,其包含治療有效量的與一種或多種藥用載體(添加劑)和/或稀釋劑一起配製的一種或多種式(I)化合物,和任選的一種或多種上述其他治療劑。可通過任意合適方式給予本發明化合物以用於任意上述用途,例如口服,諸如片劑、膠囊劑(各包括持續釋放或定時釋放製劑)、丸劑、粉劑、顆粒劑、酏劑、酊劑、懸浮液(包括納米懸浮液、微懸浮液、噴霧乾燥的分散液)、糖漿和乳液;經舌下;含服;經腸胃外,諸如通過皮下、靜脈內、肌內或胸骨內注射或輸注技術(例如以無菌可注射水性或非水性溶液或懸浮液形式);經鼻,包括向鼻膜給藥,諸如通過吸入噴霧;局部,諸如以乳膏劑或軟膏劑形式;或經直腸,諸如以栓劑形式。它們可單獨給藥,但通常使用基於所選給藥途徑和標準藥學實踐選擇的藥物載體給藥。
根據本領域技術人員認識範圍內的諸多因素來調配藥用載體。這些因素包括,但不限於:所調配活性劑的類型和性質;含有活性劑的組合物所要給藥的受試者;組合物的預期給藥途徑;及所靶向的治療適應症。藥用載體包括水性和非水性液體介質及各種固體和半固體劑型。
上述載體可包括除活性劑外的諸多不同成分和添加劑,上述其他成分出於本領域技術人員公知的各種原因包括於製劑中,例如穩定活性劑、粘合劑等。關於合適的藥用載體和載體選擇中所涉及的因素的描述可參見多個容易
獲得的來源,例如Allen,L.V.Jr.et.al.Remington:The Science and Practice of Pharmacy(2 Volumes),22nd Edition(2012),Pharmaceutical Press。
當然,本發明化合物的劑量方案取決於已知因素而有所變化,諸如具體藥劑的藥效學特性及其給藥模式和途徑;接受者的物種、年齡、性別、健康狀況、醫學病狀和重量;症狀的性質和程度;同時治療的種類;治療頻率;給藥途徑、患者的腎和肝功能及期望效應。根據一般指導,當用於指定效應時,各活性成分的日口服劑量應為約0.001mg/天至約10-5000mg/天,優選地為約0.01mg/天至約1000mg/天,且最優選地為約0.1mg/天至約600mg/天。在恒速輸注期間,靜脈內最優選劑量應為約0.01mg/kg/分鐘至約10mg/kg/分鐘。本發明化合物可以單一日劑量給藥,或可以每日兩次、三次或四次的分開劑量給藥總日劑量。
所述化合物通常以與根據預期給藥形式(例如口服片劑、膠囊劑、酏劑和糖漿劑)適當地選擇且與常規藥學實踐相符合的合適藥物稀釋劑、賦形劑或載體(在本文中統稱為藥物載體)的混合物形式進行給藥。
適於給藥的劑型(藥物組合物)可含有約0.1毫克至約2000毫克活性成分/劑量單位。在這些醫藥組合物中,以組合物的總重量計,活性成分通常將以約0.1-95重量%的量存在。
典型的可注射製劑可如下製備:以無菌方式將至少一種本發明化合物(250mg)置於瓶中、以無菌方式凍幹並密封。為進行使用,將瓶內容物與2mL生理鹽水混合,以產生可注射製劑。
本發明範圍包括(單獨或與藥物載體組合)包含治療有效量的至少一種本發明化合物作為活性成分的藥物組合物。任選地,本發明化合物可單獨
使用、與本發明其他化合物組合使用或與一種或多種其他治療劑(例如抗癌劑或其他藥學活性物質)組合使用。
不考慮所選擇的給藥路徑,通過本領域技術人員已知的常規方法來將本發明的化合物(其可以合適的水合形式使用)和/或本發明的藥物組合物配製成藥用劑量形式。
可改變活性成分在本發明的藥物組合物中的實際劑量水準,從而獲得對於實現特定患者的期望的治療回應、組成和給藥模式有效的而對患者無毒的活性成分量。
選定的劑量水準會取決於多種因素,包括所用的本發明的特定化合物或其酯、鹽或醯胺的活性;給藥路徑;給藥時間;所用的特定化合物的***速率;吸收速率和程度;治療的持續時間;與所用的特定化合物組合使用的其他藥物、化合物和/或物質;所治療的患者的年齡、性別、重量、狀況、一般健康和先前的醫學史等醫學領域公知的因素。
具有本領域普通技術的醫生或獸醫可容易地確定並開出有效量的所需藥物組合物。例如,為了達到所期望的治療效果,醫師或獸醫可在低於所需的水準開始藥物組合物中所用的本發明化合物的較量,並逐步增加劑量直至實現所期望的效果。通常,合適日劑量的本發明化合物將是有效產生治療效果的最低劑量的化合物的量。此種有效劑量通常取決於上述因素。通常,口服、靜脈內、肌肉注射、腦室內和皮下劑量的用於患者的本發明化合物的範圍為約0.01至約1000mg/kg體重/天。如果需要的話,有效日劑量的活性化合物可以兩個、三個、四個、五個、六個或更多個亞劑量在一天當中的適當的間隔分別給藥,任選地呈單位劑型形式。在本發明的某些方面中,服藥為每天一次給藥。
雖然本發明化合物可單獨給藥,但優選以藥物製劑(組合物)形式給予化合物。
本發明提到的上述特徵,或實施例提到的特徵可以任意組合。本案說明書所揭示的所有特徵可與任何組合物形式並用,說明書中所揭示的各個特徵,可以任何可提供相同、均等或相似目的的替代性特徵取代。因此除有特別說明,所揭示的特徵僅為均等或相似特徵的一般性例子。
首先,本發明實施例提供了一種CTLA-4小分子降解劑,具備式I結構:
每一個R1、R2、R3、R6、R7和R14分別選自氫、氘、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的炔基、未取代或取代的環烷基、未取代或取代的環雜烷基、鹵素、-OH、未取代或取代的烷氧基、未取代或取代的芳基烷基、未取代或取代的芳雜基烷基、未取代或取代的芳基醚基、未取代或取代的芳雜基醚基、-CN、-N(R4R5)、-NO2、-N3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲醯基、未取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的硫醚基、未取代或取代的亞碸
基、未取代或取代的碸基、未取代或取代的磺醯胺基、、、
未取代或取代的膦酸酯基,其中R4、R5、R8、R9、R10和R11分別選自氫、氘、
未取代或取代的C1-6烷基、C3-7環烷基、未取代或取代的芳基、未取代或取代的芳雜基,且R4和R5、R8和R9可與相鄰的氮原子或碳原子連接成環。
或相鄰的兩個R1和/或相鄰的兩個R3也可連接成環烷基、環雜烷基、芳基或芳雜基。
m、n、o分別選自0~4的整數。
W選自直連鍵、未取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的環烷基、未取代或取代的環雜烷基、未取代或取代的橋環烷基、未取代或取代的橋環雜烷基、未取代或取代的螺環烷基、未取代或取代的螺環雜烷基、未取代或取代的烷基、未取代或取代的雜烷基、未取代或取代的烯基、未取代或取代的雜烯基、未取代或取代的炔基、未取代或取代的雜炔基、未取代或取代的-N(R12R13)、未取代或取代的胺基烷基、未取代或取代的胺基烷基胺
基、未取代或取代的、未取代或取代的,其中R12和
R13分別選自氫、氘、C1-6烷基、C3-7環烷基、未取代或取代的烷基胺基、未取代或取代的芳基、取代或未取代的芳雜基,或R12和R13可連接成環。
Q為-H、-NH2、-OH、-烷基-NHC(=O)H、環烷基、未取代或取代的烷基醯基、未取代或取代的烷基羥基、未取代或取代的烯基羥基、未取代或取代的炔基羥基、未取代或取代的烷基胺基、未取代或取代的磺醯胺基、未取
代或取代的烷基磺醯胺基、氨基酸殘基、、磺醯胺基、磺醯肼基、未
取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的、未
取代或取代的、取代或未取代的-(CH2)n1-(M)n2-(CH2)n3-(M)n4
-(CH2)n5-(M)n6,其中每個M分別選自O、OH、S、SO、SO2和未取代或取代的胺基,每個n1、n2、n3、n4、n5和n6分別選自0-6的整數。
或W和Q可以連接或融合成取代或非取代的環烷基、環雜烷基、芳基或芳雜基。
在本發明的一個優選的實施方案中,所述C、G、I中至少一個為N原子,例如C、G、I中的任一個為N原子,或C、G、I中的任意兩個為N原子(即,C和G為N原子,或C和I為N原子,或G和I為N原子),或C、G、I均為N原子。
在本發明的一個優選的實施方案中,所述J、K、M中至少一個為N原子,例如,J為N原子或K為N原子,或J、K均為N原子。
在本發明的一個優選的實施方案中,所述I、J、K均為N原子,或,或I、M、K均為N原子。
在本發明的一個優選的實施方案中,每一個R1、R2、R3、R6、R7和R14分別選自氫、氘、未取代或取代的C1-6烷基、未取代或取代的C2-6烯基、未取代或取代的C2-6炔基、未取代或取代的C3-7環烷基、未取代或取代的3-7元環雜烷基、鹵素、-OH、未取代或取代的C1-6烷氧基、未取代或取代的C6-10芳基乙基、未取代或取代的5-10元芳雜基乙基、未取代或取代的C6-10芳基醚基、未取代或取代的5-10元芳雜基醚基、-CN、-NH2、-NO2、-N3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲醯基、未取代或取代的C6-10芳基、未取代或取代的5-10元芳雜基、未取代或取代的硫醚基、未取代
或取代的亞碸基、未取代或取代的碸基、未取代或取代的磺醯胺基、、
、未取代或取代的膦酸酯基,所述取代是被選自氫、氘、鹵素、
C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個優選的實施方案中,所述W選自直連鍵、取代或非取代的芳基、芳雜基、環烷基、環雜烷基、橋環烷基、橋環雜烷基、螺環烷基、螺環雜烷基、烷基、雜烷基、烯基、雜烯基、炔基、雜炔基、-N(R12R13)、
胺基烷基、胺基烷基胺基、未取代或取代的、未取代或取代的
,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6
炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個優選的實施方案中,所述W選自取代或非取代的5-7元環雜烷基、取代或非取代的-胺基-C1-6烷基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個優選的實施方案中,所述W中與含J、K的環相連的原子為N。
在本發明的一個優選的實施方案中,W選自取代或非取代的5-7元環雜烷基,所述5-7元雜環烷基至少包含一個氮原子,更優選的,所述5-7元雜環烷基為呱啶基或呱嗪基。
在本發明的一個優選的實施方案中,所述Q為-H、-NH2、-OH、-C1-6烷基-HNC(=O)H、未取代或取代的C1-6烷基羥基、未取代或取代的C2-6烯基羥基、未取代或取代的C2-6炔基羥基、未取代或取代的烷基胺基、磺醯胺基和磺醯肼基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個優選的實施方案中,所述W和Q可以連接或融合成環,所述環為取代或非取代的5-7元環烷基、取代或非取代的5-7元的環雜烷基、取代或非取代的C6-10芳基、取代或非取代的5-10元芳雜基。
在本發明的一個更優選的實施方案中,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
在本發明的一個優選的實施方案中,所述式II結構的化合物為:
在本發明的一個優選的實施方案中,所述式III結構的化合物為:
在本發明的一個優選的實施方案中,本發明還提供了如下化合物或其藥學上可接受的鹽、酯、氘代物、異構體、溶劑化物、前藥或同位素標記物,所述化合物選自:
本發明還提供了一種藥物組合物,該藥物組合物包含上述任一所述的化合物或其藥學上可接受的鹽、酯、氘代物、異構體、溶劑化物、前藥或同位素標記物和藥學上可接受的賦形劑。
在本發明的一個優選的實施方案中,所述藥物組合物的形式為水性分散劑、液體、啫哩、糖漿、西也劑、藥漿、懸浮液、氣霧劑、控釋劑、即溶劑、泡騰劑、凍幹劑、片劑、粉末、藥丸、糖衣完、膠囊、延遲釋放劑、延長釋放劑、脈衝控釋劑、多微粒劑或立即釋放劑中的任一種。
本發明實施例還提供了上述任一所述的化合物或其藥學上可接受的鹽、酯、異構體、溶劑化物、前藥或同位素標記物,或者上述任一所述的藥物組合物在製備治療CTLA-4相關疾病的藥物中的應用。
在本發明的一個優選的實施方案中,所述CTLA-4相關疾病包括癌症、自身免疫疾病、免疫缺陷疾病、病毒感染、器官移植排斥。
在本發明的一個更優選的實施方案中,所述癌症選自皮膚癌、膀胱癌、乳腺癌、胰腺癌、骨癌、腦癌、神經細胞瘤、食管癌、唇癌、喉癌、下嚥癌、舌癌、唾液腺癌、腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、絨毛膜癌、胰腺癌、泌尿癌、腦腫瘤諸如成膠質細胞瘤、星形細胞瘤、腦膜瘤、成神經管細胞瘤和外周神經外胚層腫瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、成人T細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤(DLBCL)、膽囊癌、支氣管癌、多發性骨髓瘤、基底細胞瘤、畸胎瘤、成視網膜細胞瘤、脈絡膜黑素瘤、精原細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肪肉瘤、纖維肉瘤、尤因肉瘤或漿細胞瘤、乳頭狀瘤、芽狀神經膠質瘤、肉瘤(包括但不限於軟骨肉瘤、組織肉瘤、惡性纖維性組織細胞瘤、淋巴肉瘤以及橫紋肌肉瘤)、黑素瘤、血管瘤、瘢痕瘤、鱗狀細胞癌、星細胞瘤、淋巴瘤(包括但不限於非霍奇金淋巴瘤、AIDS相關淋巴瘤、皮膚T細胞淋巴瘤、霍奇金病以及中樞神經系統淋巴瘤)、呼吸道癌(包括但不限於肺癌,例如小細胞及非小細胞肺癌,以及支氣管腺瘤和胸膜肺母細胞瘤)、頭頸癌(包括但不限於頭癌、頸癌、喉癌、下嚥癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌)、膀胱癌、乳癌(包括但不限於浸潤性導管癌、浸潤性小葉癌、原位導管癌和原位小葉癌)、消化道癌(包括但不限於肛門癌、結腸癌、結腸直腸癌、食道癌、膽囊癌、直腸癌、胃癌、小腸癌以及唾液腺癌)、甲狀腺癌、副甲狀腺癌及其遠距離轉移灶、胰腺癌、肝癌(包括但不限於肝細胞癌、具有或不具有纖維板層形式的肝細胞癌、膽管細胞癌以及混合型肝細胞膽管細胞癌)、白血病(包括但不限於急性成淋巴細胞白血病、慢性淋巴細胞白血病、急性骨髓性白血病、慢性骨髓性白血病以及絨毛細胞白血病)、腦癌(包
括但不限於腦幹和垂體神經膠質瘤、成神經管細胞瘤、小腦和大腦星細胞瘤、室鼓膜瘤以及神經外胚瘤和松果腺瘤)、生殖器官癌(包括但不限於***癌、睾丸癌、卵巢癌、子宮內膜癌、宮頸癌、子宮內膜癌、***癌和外陰癌以及子宮肉瘤)、尿道癌、眼癌(包括但不限於眼內黑素瘤和成視網膜細胞瘤)、皮膚癌(包括但不限於卡波西肉瘤、鱗狀細胞瘤、惡性黑素瘤、梅克爾細胞皮膚癌以及非黑素瘤皮膚癌)、腎實質癌、腎癌(也稱為腎細胞癌和腎腺癌)等相關癌症。
本發明提到的上述技術特徵,或實施例提到的特徵可以任意組合。本案說明書所揭示的所有技術特徵可與任何組合物形式並用,說明書中所揭示的各個技術特徵,可以任何可提供相同、均等或相似目的的替代性技術特徵取代。因此除有特別說明,所揭示的技術特徵僅為均等或相似技術特徵的一般性例子。
下麵結合具體實施例,進一步闡述本發明。應理解,這些實施例僅用於說明本發明而不用於限制本發明的範圍。下列實施例中未注明具體條件的實驗方法,通常按照常規條件或按照製造廠商所建議的條件。除非另外說明,否則所有的百分數、比率、比例、或份數按重量計。
本發明中的重量體積百分比中的單位是本領域技術人員所熟知的,例如是指在100毫升的溶液中溶質的重量。
除非另行定義,文中所使用的所有專業與科學用語與本領域熟練人員所熟悉的意義相同。此外,任何與所記載內容相似或均等的方法及材料皆可應用於本發明方法中。文中所述的較佳實施方法與材料僅作示範之用。
這些實施例僅供例證說明的目的,並不限定在此提供的權利要求的範圍。
1H-NMR譜Bruker-400或OXFORD-AS500核磁共振儀,化學位移的單位是百萬分之一,內標是四甲基矽烷。耦合常數(J)接近0.1Hz。使用的縮略語如下說明:s:單重峰;d:雙重峰;t:三重峰;q:四重峰;qu:五重峰;m:多重峰;brs:寬峰。質譜使用Quattro MicroTM API三重四極杆質譜儀。
實施例1(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺(化合物1)的製備
將喹啉-3-基硼酸(5.0g,33.58mmoL)和2,4-二嘧啶(5.8g,33.58mmoL)加入到乙腈(100mL)中,再加入2M碳酸鈉水溶液(50mL),最後加入Pd(dppf)Cl2(492mg,0.67mmol)。加料完畢後置換三次氮氣,升溫至80℃反應。TLC檢測反應完全後,將反應體系用矽藻土過濾,濾液濃縮。加入乙酸乙酯,分液。有機相經減壓蒸去溶劑,殘留物用快速柱層析法分離,洗脫體系為石油醚/乙酸乙酯=2/1。得目標產物6.2g,收率為77%。
1H NMR(400MHz,CDCl3)δ 9.51(d,J=4.0Hz,1H),8.95(d,J=4.0Hz,1H),8.73(d,J=4.0Hz,1H),8.17(d,J=8.0Hz,1H),7.97(d,J=8.0Hz,1H),7.86-7.79(m,2H),7.68-7.60(m,1H)。
化合物1
將3-(2-嘧啶-4-基)喹啉(1.1g,4.56mmoL)和呱啶-4-基甲胺(0.52g,4.56mmoL)加入到DMSO(10mL)中,再加入DIPEA(1.2g,9.12mmoL)。加料完畢後升溫至80℃反應。2小時(h)後TLC檢測反應完全,加入到水(30mL)中,乙酸乙酯萃取分液,有機相用飽和食鹽水洗,水洗後濃縮,殘留物用快速柱層析分離,洗脫體系為二甲烷/甲醇=10/1。得到目標產物600mg,收率為40%。
1H NMR(400MHz,DMSO-d6)δ 9.59(d,J=4.0Hz,1H),9.07(d,J=4.0Hz,1H),8.50(d,J=4.0Hz,1H),8.15(d,J=8.0Hz,1H),8.08(d,J=8.0Hz,1H),7.87-7.81(m,1H),7.74-7.65(m,1H),7.38(d,J=4.0Hz,1H),4.86(d,J=12.0Hz,2H),3.16(s,2H),3.02-2.88(m,2H),1.87-1.76(m,2H),1.68-1.52(m,1H),1.19-1.02(m,2H)。
MS-ESI:320.5[M+H]+。
實施例2 N-((1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲基)甲醯胺(化合物2)的製備
除了反應時間用24小時替代2小時外,化合物2的製備同化合物1。收率為26%。
1H NMR(400MHz,DMSO-d6)δ 9.58(d,J=4.0Hz,1H),9.06(d,J=2.0Hz,1H),8.49(d,J=4.0Hz,1H),8.13(d,J=8.0Hz,1H),8.06(dd,
J=12.0,8.0Hz,3H),7.87-7.79(m,1H),7.67(t,J=8.0Hz,1H),7.37(d,J=8.0Hz,1H),4.83(d,J=12.0Hz,2H),3.06-3.00(m,2H),2.94(t,J=12.0Hz,2H),1.75(d,J=12.0Hz,2H),1.20-1.07(m,2H)。
MS-ESI:348.6[M+H]+。
實施例3(1-(4-(喹啉-6-基)嘧啶-2-基)呱啶-4-基)甲胺(化合物3)的製備
1H NMR(400MHz,CDCl3)δ 9.01(dd,J=4.0,2.0Hz,1H),8.72(d,J=8.0Hz,1H),8.68(d,J=2.0Hz,1H),8.36(dd,J=8.0,4.0Hz,1H),8.32(d,J=8.0Hz,1H),8.24(d,J=8.0Hz,1H),7.80(d,J=4.0Hz,1H),7.50(dd,J=8.0,4.0Hz,1H)。
MS-ESI:242.4[M+H]+。
化合物3
1H NMR(400MHz,DMSO-d6)δ 8.95(dd,J=4.0,2.0Hz,1H),8.77(d,J=4.0Hz,1H),8.55-8.44(m,3H),8.12(d,J=8.0Hz,1H),7.59(dd,J=8.0,4.0Hz,1H),7.32(d,J=4.0Hz,1H),485(d,J=12.0Hz,2H),2.93(td,J=12.0,4.0Hz,2H),2.53(d,J=4.0Hz,2H),1.89-1.76(m,2H),1.70-1.57(m,1H),1.20-1.06(m,2H)。
MS-ESI:320.5[M+H]+。
實施例4 N-((1-(4-(喹啉-6-基)嘧啶-2-基)呱啶-4-基)甲基)甲醯胺(化合物4)的製備
1H NMR(400MHz,DMSO-d6)δ 8.95(dd,J=4.0,2.0Hz,1H),8.76(d,J=4.0Hz,1H),8.54-8.44(m,3H),8.11(d,J=8.0Hz,1H),8.03(s,1H),7.59(dd,J=8.0,4.0Hz,1H),7.32(d,J=4.0Hz,1H),4.83(d,J=12.0Hz,2H),3.03(t,J=8.0Hz,2H),2.93(t,J=12.0Hz,2H),178-1.70(m,3H),1.20-1.05(m,2H)。
MS-ESI:348.6[M+H]+。
實施例5(1-(4-(喹啉-2-基)嘧啶-2-基)呱啶-4-基)甲胺(化合物5)的製備
1-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)乙-1-酮
除了用1-(2-嘧啶-4-基)乙-1-酮替代實施例(4-1)中3-(2-嘧啶-4-基)喹啉外,1-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)乙-1-酮的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為98%。
MS-ESI:235.4[M+H]+。
(1-(4-(喹啉-2-基)嘧啶-2-基)呱啶-4-基)甲胺
將鄰氨基苯甲醛(197mg,1.63mmol)和1-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)乙-1-酮(380mg,1.63mmol)溶於EtOH(10mL)中,再加入氫氧化鉀(182mg,3.25mmol)。加料完畢,80℃反應過夜。次日TLC檢測反應完全。減壓蒸去溶劑,殘留物中加入乙酸乙酯和水,分液,有機相用水洗。減壓蒸去溶劑,殘留物用快速柱層析分離,得產物450mg,收率為86%。
1H NMR(400MHz,CDCl3)δ 8.50(t,J=6.8Hz,2H),8.25(d,J=8.6Hz,1H),8.17(d,J=8.6Hz,1H),7.84(d,J=8.0Hz,1H),7.73(t,J=7.2Hz,2H),7.56(t,J=7.4Hz,1H),4.97(d,J=13.2Hz,2H),3.01-2.94(m,2H),2.67(d,J=6.6Hz,2H),2.32(brs,2H),1.89(d,J=13.2Hz,2H),1.75-1.65(m,1H),1.32-1.19(m,2H)。
MS-ESI:320.5[M+H]+。
實施例6 (1-(4-(喹喔啉-2-基)嘧啶-2-基)呱啶-4-基)甲胺(化合物6)的製備
除了用2-(4,4,5,5-四甲基-1,3,2-二氧雜環芳烴-2-基)喹喔啉化合物替代實施例1中喹啉-3-基硼酸外,化合物2-(2-嘧啶-4-基)喹喔啉的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為57%。
MS-ESI:243.2[M+H]+。
化合物6
MS-ESI:321.2[M+H]+。
實施例7 (1-(4-(6-氟喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺(化合物7)的製備
除了用6-氟-3-(4,4,5,5-四甲基-1,3,2-二氧雜環芳烴-2-基)喹啉化合物替代實施例1中喹啉-3-基硼酸外,化合物3-(2-嘧啶-4-基)-6-氟喹啉的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為56%。
1H NMR(400MHz,CD3OD)δ 9.54(d,J=4.0Hz,1H),9.13(d,J=4.0Hz,1H),8.80(d,J=8.0Hz,1H),8.17(d,J=8.0Hz,1H),8.16-8.12(m,1H),7.79(dd,J=8.0,4.0Hz,1H),7.73-7.66(m,1H)。
MS-ESI:260.3[M+H]+。
化合物7
1H NMR(400MHz,CD3OD)δ 9.51(d,J=4.0Hz,1H),8.97(d,J=4.0Hz,1H),8.44(d,J=8.0Hz,1H),8.15-8.10(m,1H),7.76(dd,J=12.0,4.0Hz,1H),7.66(td,J=8.0,4.0Hz,1H),7.25(d,J=4.0Hz,1H),4.96(d,J=12.0Hz,2H),3.00(td,J=12.0,4.0Hz,2H),2.66(d,J=8.0Hz,2H),1.89(d,J=12.0Hz,2H),1.86-1.72(m,1H),1.30-1.18(m,2H)。
MS-ESI:338.4[M+H]+。
實施例8 (1-(3-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)喹啉-2-基)呱啶-4-基)甲胺(化合物8)
1H NMR(400MHz,CD3OD)δ 9.28(d,J=8.0Hz,1H),8.82(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),8.05(dd,J=8.0,4.0Hz,1H),7.97-7.85(m,2H),7.69(t,J=8.0Hz,1H)。
MS-ESI:260.3[M+H]+。
化合物8
1H NMR(400MHz,CD3OD)δ 8.40-8.32(m,2H),7.81(dd,J=8.0,4.0Hz,2H),7.65(t,J=8.0Hz,1H),7.39(t,J=8.0Hz,1H),7.19(d,J=8.0Hz,1H),4.96(d,J=16.0Hz,2H),3.79(d,J=16.0Hz,2H),3.01(t,J=12.0Hz,2H),2.93-2.85(m,6H),2.08-1.96(m,1H),1.94-1.74(m,5H),1.46-1.26(m,4H)。
MS-ESI:432.5[M+H]+。
實施例9 (1-(4-(2-甲氧基喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺(化合物9)的製備
1H NMR(400MHz,CDCl3):δ 9.00(s,1H),8.67(d,J=4.0Hz,1H),8.17(d,J=8.0Hz,1H),7.94-7.85(m,2H),7.72(t,J=8.0Hz,1H),7.46(t,J=4.0Hz,1H),4.21(s,3H)。
MS-ESI:272.3[M+H]+。
化合物9
1H NMR(400MHz,CDCl3):δ 8.75(s,1H),8.37(d,J=4.0Hz,1H),7.85(t,J=7.0Hz,2H),7.65(t,J=7.6Hz,1H),7.40(t,J=8.0Hz,1H),7.27(s,1H),4.93(d,J=16.0Hz,2H),4.15(s,3H),3.71(q,J=7.0Hz,2H),
2.94(t,J=12.8Hz,2H),2.65(d,J=4.0Hz,2H),1.86(d,J=16.0Hz,2H),1.78-1.60(m,1H),1.31-1.17(m,2H)。
MS-ESI:350.4[M+H]+。
實施例10 3-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)喹啉-2-醇(化合物10)的製備
將化合物9(300mg,0.86mmoL)和DCM(6mL)加入至封管中,隨後加入三溴化硼(539mg,2.16mmoL),50℃加熱反應。TLC監測反應完全後,加水分液,有機相依次用飽和碳酸氫鈉和水。減壓蒸去溶劑,殘留物用用快速柱層析分離。得化合物10為155mg,收率為54%。
1H NMR(400MHz,DMSO-d6)δ 8.86(s,1H),8.39(d,J=4.0Hz,1H),7.90(d,J=8.0Hz,1H),7.74(d,J=4.0Hz,1H),7.60-7.54(m,1H),7.36(d,J=8.0Hz,1H),7.25-7.9(m,1H),4.78(d,J=12.0Hz,2H),3.47-3.42(m,2H),2.97-2.76(m,4H),1.75(d,J=16.0Hz,2H),1.70-1.60(m,1H)。
MS-ESI:336.4[M+H]+。
實施例11 (1-(4-(喹啉-3-基-2-d)嘧啶-2-基)呱啶-4-基)甲胺(化合物11)的製備
1H NMR(400MHz,CD3OD)δ 9.01(s,1H),8.43(d,J=4.0Hz,1H),8.09(d,J=4.0Hz,2H),7.90-7.78(m,1H),7.73-7.64(m,1H),7.27(d,J=4.0Hz,1H)。
MS-ESI:243.2[M+H]+。
化合物11
1H NMR(400MHz,CD3OD)δ 9.01(s,1H),8.43(d,J=4.0Hz,1H),8.13-8.03(m,2H),7.89-7.81(m,1H),7.72-7.63(m,1H),7.27(d,J=4.0Hz,1H),4.96(d,J=16.0Hz,2H),2.99(td,J=12.0,4.0Hz,2H),2.59(d,J=8.0Hz,2H),1.94-1.84(m,2H),1.80-1.66(m,1H),1.27-1.19(m,2H)。
MS-ESI:321.3[M+H]+。
實施例12(1-(4-(喹啉-3-基)吡啶-2-基)呱啶-4-基)甲胺(化合物12)的製備
1H NMR(400MHz,DMSO-d6)δ 9.37(d,J=4.0Hz,1H),8.94(d,J=4.0Hz,1H),8.57(d,J=4.0Hz,1H),8.13(s,1H),8.10(d,J=12.0Hz,2H),8.00(dd,J=8.0,4.0Hz,1H),7.89-7.83(m,1H),7.71(t,J=8.0Hz,1H)。
MS-ESI:241.2[M+H]+。
化合物12
1H NMR(400MHz,DMSO-d6)δ 9.29(d,J=4.0Hz,1H),8.77(d,J=4.0Hz,1H),8.22(d,J=8.0Hz,1H),8.06(d,J=12.0Hz,2H),7.80(t,J=8.0Hz,1H),7.66(t,J=8.0Hz,1H),7.28(s,1H),7.10(d,J=4.0Hz,1H),4.49(d,J=12.0Hz,2H),2.84(t,J=12.0Hz,2H),2.63(d,J=4.0Hz,2H),1.78(d,J=12.0Hz,2H),1.75-1.65(m,1H),1.26-1.14(m,2H)。
MS-ESI:319.3[M+H]+。
實施例13 2-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)-4氫-苯並吡喃-4-酮(化合物13)的製備
2-(4-((叔丁氧羰基)氨基)甲基)呱啶-1-基)嘧啶-4-羧酸甲酯
除了用2-嘧啶-4-羧酸甲酯替代實施例1中3-(2-嘧啶-4-基)喹啉外,2-(4-((叔丁氧羰基)氨基)甲基)呱啶-1-基)嘧啶-4-羧酸甲酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為88%。
MS-ESI:351.2[M+H]+。
((1-(4-(羥甲基)嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯
將2-(4-((叔丁氧羰基)氨基)甲基)呱啶-1-基)嘧啶-4-羧酸甲酯(1.56g,4.5mmoL)溶於DCM(30mL)攪拌,在-70℃條件下緩慢加入DIBAL-H(4.5mL,6.7mmoL)。次日TLC監測還有原料剩餘,補加DIBAL-H(3mL),3h後反應完全,加入MeOH(5mL)淬滅反應。加飽和NaHCO3分液,減壓蒸餾,殘留物用快速柱層析分離。得目標產物760mg,收率為55%。
1H NMR(400MHz,CDCl3):δ 8.21(dd,J=8.0,0.6Hz,1H),6.35(d,J=4.0Hz,1H),4.79(d,J=16.0Hz,2H),4.65(s,1H),4.54(d,J=4.0Hz,2H),3.73-3.71(m,1H),3.05-3.02(m,2H),2.86(t,J=12.0,7.6Hz,2H),1.79-1.75(m,2H),1.45(s,9H),1.18(dd,J=12.2,3.8Hz,2H)。
MS-ESI:323.4[M+H]+。
((1-(4-甲醯嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯
將((1-(4-(羥甲基)嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯(760mg,0.24mmoL)溶於DCM(30mL)中,再將PCC(1.5g,7.0mmoL)和矽膠(1.5g)混合均勻加入反應體系,3h後TLC監測反應完全。過濾,濾液進行分液,有機相用鹽水洗,減壓蒸去溶劑,殘留物用快速柱層析分離。得目標產物360mg,收率為46%。
1H NMR(400MHz,CDCl3):δ 9.81(s,1H),8.50(d,J=4.0Hz,1H),6.92(d,J=4.0Hz,1H),4.87(d,J=12.0Hz,2H),3.07-3.04(m,2H),2.86(t,J=12.0,7.6Hz,2H),1.87-1.74(m,3H),1.45(s,9H),1.29-1.11(m,2H)。
MS-ESI:321.6[M+H]+。
((1-(4-(1-羥基-3-(2-羥基苯基)-3-氧丙基)嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯
將((1-(4-甲醯嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯(360mg,0.1mmoL)和1-(2-羥基苯基)乙烷-1-酮(184mg,0.1mmoL)溶於MeOH(20mL)中,再加入KOH(126mg,0.2mmoL),3h後TLC監測反應完全。用2M的HCl溶液將pH調至6~7。減壓蒸去溶劑,殘留物經高真空乾燥得粗品。不做純化,直接進行下步反應。
MS-ESI:457.5[M+H]+。
((1-(4-(4-氧代-4H-鉻烯-2-基)嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯
將((1-(4-(1-羥基-3-(2-羥基苯基)-3-氧丙基)嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯溶於DMSO(6mL)中,加入I2(5mg)。加料完畢後,體系溫度升至100℃,次日TLC監測反應基本完全,加入水,用DCM提取。有機相用飽和碳酸氫鈉洗,減壓蒸去溶劑。殘留物用快速柱層析分離。得到目標產物40mg,收率為38%。
1H NMR(400MHz,CDCl3):δ 8.41(d,J=4.0Hz,1H),7.82-7.79(m,1H),7.71-7.67(m,1H),7.32(d,J=8.0Hz,1H),7.29-7.27(m,1H),7.24-7.21(m,1H),6.77-6.72(m,1H),4.89-4.79(m,2H),3.78-3.66(m,1H),3.08-3.02(m,2H),2.92-2.86(m,2H),1.80(d,J=12.0Hz,2H),1.44(s,9H),1.33-1.15(m,2H)。
MS-ESI:437.4[M+H]+。
化合物13
將((1-(4-(4-氧代-4H-鉻烯-2-基)嘧啶-2-基)呱啶-4-基)甲基)氨基甲酸叔丁酯(40mg,0.09mmoL)溶於HCl-Dioxane(6mL)中,1h後TLC監測反應完全。減壓旋幹溶劑,加入飽和碳酸氫鈉將PH調至6~7,殘留物用快速柱層析分離。得化合物13為20mg,收率為65%。
1H NMR(400MHz,CD3OD):δ 8.44(d,J=4.0Hz,1H),7.81(t,J=7.4Hz,2H),7.45(d,J=8.0Hz,1H),7.36(dd,J=16.0,6.4Hz,2H),6.61(s,1H),4.59(s,2H),2.95(t,J=12.0,7.4Hz,2H),2.87(d,J=8.0Hz,2H),2.0-1.90(m,1H),1.86(d,J=12.8Hz,2H),1.35-1.22(m,2H)。
MS-ESI:337.3[M+H]+。
實施例14 (1-(6-(喹啉-3-基)吡啶-2-基)呱啶-4-基)甲胺(化合物14)的製備
(1-(6-溴吡啶-2-基)呱啶-4-基)甲胺
將2,6-二溴吡啶(1.7g,7.17mmoL)和呱啶-4-基甲胺(0.9g,7.88mmoL)溶於1,4-二氧六環(15mL)中,並加入磷酸鉀(1.52g,7.17mmoL)。隨後置換三次氮氣,加熱至105℃反應。8h後基本反應完畢,將體系濃縮,加入乙酸乙酯和水。分液,有機相經減壓蒸去溶劑殘留物用快速柱層析分離。得產物1.36g,收率為70%。
1H NMR(400MHz,DMSO-d6)δ 7.41-7.33(m,1H),6.77(d,J=12.0Hz,1H),6.70(d,J=8.0Hz,1H),4.21(d,J=16.0Hz,2H),2.76(td,J=12.0,4.0Hz,2H),2.42(d,J=8.0Hz,2H),1.73(d,J=12.0Hz,2H),1.55-1.40(m,1H),1.03(qd,J=12.0,4.0Hz,2H)。
化合物14
1H NMR(400MHz,DMSO-d6)δ 9.57(d,J=4.0Hz,1H),8.93(d,J=4.0Hz,1H),8.11(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.82-7.74(m,1H),7.73-7.60(m,2H),7.42(d,J=4.0Hz,1H),6.92(d,J=8.0Hz,1H),4.50(d,J=12.0Hz,2H),2.88(t,J=12.0Hz,3H),2.69(d,J=4.0Hz,3H),1.95-1.85(d,J=11.3Hz,3H),1.33-1.14(m,2H)。
MS-ESI:319.3[M+H]+。
實施例15 (1-(3-(喹啉-3-基)苯基)呱啶-4-基)甲胺(化合物15)的製備
3-(3-溴苯基)喹啉
1H NMR(400MHz,DMSO-d6)δ 9.26(d,J=4.0Hz,1H),8.71(d,J=4.0Hz,1H),8.11(t,J=4.0Hz,1H),8.06(d,J=8.0Hz,2H),7.91(d,J=8.0Hz,1H),7.82-7.76(m,1H),7.69-7.63(m,2H),7.51(t,J=8.0Hz,1H)。
化合物15
將化合物3-(3-溴苯基)喹啉(630mg,2.22mmoL)、呱啶-4-基甲胺(380mg,3.33mmoL)和XPhos(21mg,0.044mmoL)加入至THF(10mL)中,隨後向體系緩慢加入2.0M NaHMDS(1.42g,7.77mmoL),最後再加入Pd(dba)3(41mg,0.044mmoL)置換三次氮氣,70℃反應7h,TLC監測基本反應完全。加入鹽酸將調節pH調至中性。將反應體系濃縮,加入DCM和水分液。有機相經減壓蒸去溶劑,殘留物用快速柱層析分離。得產物150mg,收率為21%。
1H NMR(400MHz,DMSO-d6)δ 9.23(d,J=4.0Hz,1H),8.64(d,J=4.0Hz,1H),8.05(t,J=8.0Hz,1H),7.76(d,J=8.0Hz,2H),7.67-7.61(m,1H),7.38(d,J=4.0Hz,1H),7.23(d,J=8.0Hz,1H),7.10(d,J=12.0Hz,1H),7.06-6.98(m,1H),3.87(d,J=12.0Hz,2H),2.80-2.64(m,4H),1.90-1.80(m,3H),1.38-1.26(m,2H)。
實施例16 3-(2-(4-(氨基甲基)呱啶-1-基)嘧啶-4-基)喹啉-2-胺(化合物16)的製備
除了用化合物3-(4,4,5,5-四甲基-1,3,2-二氧苯甲醛-2-基)喹啉-2-胺替代實施例1中喹啉-3-基硼酸外,化合物3-(2-嘧啶-4-基)喹啉-2-胺的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為64%。
1H NMR(400MHz,CDCl3)δ 8.92(d,J=8.0Hz,1H),8.51(d,J=4.0Hz,1H),8.14(s,1H),8.08(d,J=8.0Hz,1H),7.81(d,J=8.0Hz,2H),7.57(t,J=8.0Hz,1H),7.39(s,1H)。
MS-ESI:257.3[M+H]+。
化合物16
1H NMR(400MHz,DMSO-d6)δ 8.29(s,1H),8.12(s,1H),7.85(d,J=8.0Hz,2H),7.79-7.68(m,1H),7.66-7.58(m,1H),7.54-7.46(m,1H),4.73(d,J=12.0Hz,2H),3.11(t,J=12.0Hz,2H),2.90(d,J=8.0Hz,2H),2.09-1.99(m,1H),1.92(d,J=16.0Hz,2H),1.38(dd,J=12.0,4.0Hz,2H)。
MS-ESI:335.4[M+H]+。
實施例17 1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-胺(化合物17)的製備
除了用呱啶-4-胺替代實施例1中呱啶-4-基甲胺外,化合物17的合成同實施例1中的化合物1。收率為65%。
1H NMR(400MHz,DMSO-d6)δ 9.63(d,J=4.0Hz,1H),9.11(d,J=4.0Hz,1H),8.54(d,J=4.0Hz,1H),8.18(d,J=8.0Hz,1H),8.11(d,J=8.0Hz,1H),7.91-7.84(m,1H),7.71(t,J=8.0Hz,1H),7.42(d,J=4.0Hz,1H),4.75(d,J=8.0Hz,2H),3.11(t,J=12.0Hz,2H),3.04-2.94(m,1H),1.89(d,J=8.0Hz,2H),1.40-1.20(m,2H)。
MS-ESI:306.3[M+H]+。
實施例18 3-(2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物18)的製備
4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺外,4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為95%。
MS-ESI:392.2[M+H]+。
化合物18
向4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯(6.1g,15.56mmoL)中加入4M鹽酸/1,4-二氧六環溶液(50mL),室溫攪拌30分鐘。TLC監測反應完全,將反應體系濃縮,加入甲醇鈉的甲醇溶液將產物遊離出來。減壓蒸去溶劑,殘留物用快速柱層析分離得到產物4.55g,收率為98%。
1H NMR(400MHz,DMSO-d6)δ 9.65(d,J=4.0Hz,1H),9.15(d,J=4.0Hz,1H),8.60(d,J=8.0Hz,1H),8.17-8.12(m,1H),8.09(d,J=8.0Hz,1H),7.86(t,J=8.0Hz,1H),7.70(t,J=8.0Hz,1H),7.56(d,J=8.0Hz,1H),4.15-4.08(m,4H),3.25-3.12(m,4H)。
MS-ESI:292.2[M+H]+。
實施例19 2-(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)乙胺(化合物19)的製備
除了用呱啶-4-基乙胺替代實施例1中呱啶-4-基甲胺外,化合物19的合成同實施例1中的化合物1。收率為36%。
1H NMR(400MHz,DMSO-d6)δ 9.60(d,J=4.0Hz,1H),9.09(d,J=4.0Hz,1H),8.51(d,J=4.0Hz,1H),8.15(d,J=8.0Hz,1H),8.09(d,J=8.0Hz,1H),7.88-7.83(m,1H),769(t,J=8.0Hz,1H),4.86(d,J=12.0Hz,2H),2.98-2.92(m,2H),2.90-2.83(m,2H),2.54(s,2H),1.79(d,J=8.0Hz,2H),1.54-1.48(m,1H),1.20-1.12(m,2H)。
MS-ESI:334.2[M+H]+。
實施例20 (1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲醇(化合物20)的製備
除了用呱啶-4-基甲醇替代實施例1中的呱啶-4-基甲胺外,化合物20的合成同實施例1中的化合物1。收率為83%。
1H NMR(400MHz,DMSO-d6)δ 9.58(d,J=4.0Hz,1H),9.07(d,J=4.0Hz,1H),8.49(d,J=4.0Hz,1H),8.14(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.88-7.79(m,1H),7.73-7.63(m,1H),7.36(d,J=4.0Hz,1H),4.85(d,J=12.0Hz,2H),4.51(t,J=8.0Hz,1H),3.31-3.24(m,2H),2.98-2.86(m,2H),1.76(d,J=12.0Hz,2H),1.72-1.63(m,1H),1.11(qd,J=12.0,4.0Hz,2H)。
MS-ESI:321.2[M+H]+。
實施例21 (1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)乙醇(化合物21)的製備
除了用呱啶-4-基乙醇替代實施例1中呱啶-4-基甲胺外,化合物21的合成同實施例1中的化合物1。收率為49%。
1H NMR(400MHz,DMSO-d6)δ 9.57(d,J=4.0Hz,1H),9.05(d,J=1.9Hz,1H),8.48(d,J=4.0Hz,1H),8.13(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.88-7.77(m,1H),7.67(t,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),4.81(d,J=12.0Hz,2H),4.40(s,1H),3.47(d,J=4.0Hz,1H),2.91(t,J=12.0Hz,1H),1.82-1.63(m,3H),1.38(q,J=8.0Hz,2H),1.17-0.99(m,2H)。
MS-ESI:335.3[M+H]+。
實施例22 3-(2-((3S,5R)-3,5-二甲基呱嗪-1-基)嘧啶-4-基)喹啉(化合物22)的製備
除了用(2S,6R)-2,6-二甲基呱嗪替代實施例1中呱啶-4-基甲胺外,化合物22的合成同實施例1中的化合物1。收率為83%。
1H NMR(400MHz,DMSO-d6):δ 9.61(d,J=2.2Hz,1H),9.08(d,J=2.2Hz,1H),8.51(d,J=5.2Hz,1H),8.15(d,J=8.2Hz,1H),8.09(d,J=8.4Hz,1H),7.89-7.81(m,1H),7.69(t,J=7.4Hz,1H),7.40(d,J=5.2Hz,1H),4.72(d,J=12.4Hz,2H),2.81-2.74(m,2H),2.45(t,J=12.0Hz,2H),1.09(s,3H),1.07(s,3H)。
MS-ESI:320.2[M+H]+。
實施例23 3-(2-(4-甲基呱嗪-1-基)嘧啶-4-基)喹啉(化合物23)的製備
除了用1-甲基呱嗪替代實施例1中呱啶-4-基甲胺外,化合物23的合成同實施例1中的化合物1。收率為78%。
1H NMR(400MHz,CD3OD):δ 9.56(d,J=4.0Hz,1H),9.05(d,J=2.4Hz,1H),8.48(d,J=8.0Hz,1H),8.10(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.80(t,J=7.2Hz,1H),7.64(t,J=7.2Hz,1H),7.39(d,J=8.0Hz,1H),3.86-3.79(m,4H),2.41-2.34(m,4H),2.20(s,3H)。
MS-ESI:306.4[M+H]+。
實施例24 3-(2-(1,4-二氮雜-1-基)嘧啶-4-基)喹啉(化合物24)的製備
4-(4-(喹啉-3-基)嘧啶-2-基)-1,4-二氮烷-1-羧酸叔丁酯
除了用1,4-二氮烷-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺外,4-(4-(喹啉-3-基)嘧啶-2-基)-1,4-二氮烷-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為71%。
MS-ESI:406.3[M+H]+。
化合物24
除了用4-(4-(喹啉-3-基)嘧啶-2-基)-1,4-二氮烷-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物24的合成同實施例18中的化合物18。收率為84%。
1H NMR(400MHz,CDCl3)δ 9.59(d,J=4.0Hz,1H),8.75(d,J=4.0Hz,1H),8.45(d,J=4.0Hz,1H),8.15(d,J=8.0Hz,1H),7.94(d,J=8.0Hz,1H),7.82-7.74(m,1H),7.60(t,J=8.0Hz,1H),7.07(d,J=8.0Hz,1H),4.12-3.84(m,4H),3.13(s,2H),3.03-2.86(m,2H),2.38-2.20(m,1H),2.00(s,2H)。
MS-ESI:306.2[M+H]+。
實施例253-(2-(3,8-二氮雜二環[3.2.1]辛烷-3-基)嘧啶-4-基)喹啉(化合物25)的製備
8-(4-(喹啉-3-基)嘧啶-2-基)-3,8-二氮雜二環[3.2.1]辛烷-3-羧酸叔丁酯
除了用3,8-二氮雜二環[3.2.1]辛烷-3-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺外,8-(4-(喹啉-3-基)嘧啶-2-基)-3,8-二氮雜二環[3.2.1]辛烷-3-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為41%。
MS-ESI:418.2[M+H]+。
化合物25
除了用8-(4-(喹啉-3-基)嘧啶-2-基)-3,8-二氮雜二環[3.2.1]辛烷-3-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物25的合成同實施例18中的化合物18。收率為63%。
1H NMR(400MHz,CDCl3)δ 9.56(d,J=4.0Hz,1H),8.76(d,J=4.0Hz,1H),8.46(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.78(t,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,1H),3.22(d,J=12.0Hz,2H),2.84(d,J=12.0Hz,2H),2.20-1.99(m,6H)。
MS-ESI:318.2[M+H]+。
實施例26 N-(4-(喹啉-3-基)嘧啶-2-基)乙烷-1,2-二胺(化合物26)的製備
(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)乙基)氨基甲酸叔丁酯
除了用(2-氨基乙基)氨基甲酸叔丁酯替代實施例1中呱啶-4-基甲胺外,(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)乙基)氨基甲酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為64%。
MS-ESI:366.2[M+H]+。
化合物26
除了用(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)乙基)氨基甲酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物26的合成同實施例18中的化合物18。收率為79%。
1H NMR(400MHz,CDCl3)δ 9.54(s,1H),8.78(s,1H),8.42(d,J=8.0Hz,1H),8.15(d,J=12.0Hz,1H),7.94(d,J=8.0Hz,1H),7.78(t,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.14(d,J=8.0Hz,1H),3.68-3.56(m,2H),3.02(t,J=8.0Hz,2H)。
MS-ESI:266.2[M+H]+。
實施例27 N-(4-(喹啉-3-基)嘧啶-2-基)丙烷-1,3-二胺(化合物27)的製備
(3-((4-(喹啉-3-基)嘧啶-2-基)氨基)丙基)氨基甲酸叔丁酯
除了用(2-氨基丙基)氨基甲酸叔丁酯替代實施例1中呱啶-4-基甲胺外,(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)丙基)氨基甲酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為50%。
MS-ESI:380.2[M+H]+。
化合物27
除了用(2-((4-(喹啉-3-基)嘧啶-2-基)氨基)丙基)氨基甲酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物27的合成同實施例18中的化合物18。收率為98%。
1H NMR(400MHz,CDCl3)δ 9.54(s,1H),8.78(d,J=4.0Hz,1H),8.41(d,J=8.0Hz,1H),8.15(d,J=8.0Hz,1H),7.94(d,J=8.0Hz,1H),7.81-7.75(m,1H),7.60(t,J=8.0Hz,1H),7.11(d,J=4.0Hz,1H),5.68(s,1H),3.67-3.62(m,2H),2.88(t,J=8.0Hz,2H),1.82(p,J=8.0Hz,2H),1.41(s,2H)。
MS-ESI:280.3[M+H]+。
實施例28 7-(2-(呱嗪-1-基)嘧啶-4-基)-2,3-二氫-[1,4]二氧基[2,3-b]吡啶(化合物28)的製備
將化合物2,4-二嘧啶(3.72g,21.5mmoL)、4-甲基呱嗪-1-羧酸叔丁酯(4.3g,21.5mmoL)溶於甲苯(50mL)中,回流反應過夜,次日TLC檢測反應完全。減壓蒸去溶劑,將正丙醇/水(55mL/83mL)加入至殘留物中,升溫至90℃,體系溶清。降溫至室溫析出固體,過濾,正丙醇/水(1v/1.5v,30mL×3)洗滌,高真空乾燥。得到產物4.0g,收率為62%。
1H NMR(400MHz,CDCl3)δ 8.16(d,J=5.2Hz,1H),6.52(d,J=5.2Hz,1H),3.85-3.72(m,4H),3.52-3.41(m,4H),1.48(s,9H)。
7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氫-[1,4]二惡英[2,3b]吡啶
將化合物7-溴-2,3-二氫-[1,4]二惡英[2,3-b]吡啶(180mg,0.84mmoL)、連頻哪醇硼酸酯(318mg,1.26mmoL)、醋酸鉀(329mg,3.36mmoL)和Pd(dppf)Cl2(61mg,0.084mmoL)加入到1,4-二氧六環(5mL)中,在氮氣保護下於90℃反應過夜。次日TLC檢測反應。將反應體系用矽藻土過濾,減壓蒸
發去溶劑,殘留物中加入乙酸乙酯。分液,減壓蒸去溶劑。殘留物用用快速柱層析分離。得目標產物186mg,收率為84%。
1H NMR(400MHz,CDCl3)δ 8.19(d,J=1.6Hz,1H),7.53(d,J=1.6Hz,1H),7.26(s,1H),4.48-4.41(m,2H),4.27-4.20(m,2H),1.33(s,12H)。
MS-ESI:264.4[M+H]+。
4-(4-(2,3-二氫-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氫-[1,4]二惡英[2,3b]吡啶替代喹啉-3-基硼酸,以及用4-(4-嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代2,4-二嘧啶外,4-(4-(2,3-二氫-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為46%。
1H NMR(400MHz,CDCl3)δ 8.47(d,J=2.2Hz,1H),8.36(d,J=5.2Hz,1H),7.88(d,J=2.2Hz,1H),6.89(d,J=5.2Hz,1H),4.54-4.44(m,2H),4.37-4.26(m,2H),3.94-3.84(m,4H),3.56-3.46(m,4H),1.49(s,9H)。
MS-ESI:400.5[M+H]+。
化合物28
除了用4-(4-(2,3-二氫-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物28的合成同實施例18中的化合物18。收率為92%。
1H NMR(400MHz,DMSO-d6)δ 8.52(d,J=2.2Hz,1H),8.39(d,J=5.2Hz,1H),7.95(d,J=2.2Hz,1H),7.18(d,J=5.2Hz,1H),4.52-4.42(m,2H),4.33-4.27(m,2H),3.77-3.69(m,4H),2.83-2.72(m,4H)。
實施例29 4-(2,3-二氫苯並[b][1,4]二惡英-6-基)-2-(呱嗪-1-基)嘧啶(化合物29)的製備
4-(4-(2,3-二氫苯並[b][1,4]二惡英-6-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用(2,3-二氫苯並[b][1,4]二惡英-6-基)硼酸替代替代實施例1中喹啉-3-硼酸外,化合物4-(4-(2,3-二氫苯並[b][1,4]二惡英-6-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施列1中的3-(2-嘧啶-4-基)喹啉。收率為57%。
1H NMR(400MHz,CDCl3)δ 8.32(d,J=5.2Hz,1H),7.63(d,J=2.2Hz,1H),7.55(dd,J=8.4,2.2Hz,1H),6.94(d,J=8.4Hz,1H),6.88(d,J=5.2Hz,1H),4.36-4.20(m,4H),3.89(t,J=5.2Hz,4H),3.52(t,J=5.2Hz,4H),1.50(s,9H)。
MS-ESI:399.5[M+H]+。
化合物29
除了用4-(4-(2,3-二氫苯並[b][1,4]二惡英-6-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物29的合成同實施例18中的化合物18。收率為53%。
1H NMR(400MHz,CDCl3)δ 8.32(d,J=5.2Hz,1H),7.63(d,J=2.2Hz,1H),7.54(dd,J=8.4,2.2Hz,1H),6.93(d,J=8.4Hz,1H),6.86(d,J=5.2Hz,1H),4.36-4.26(m,4H),3.95-3.88(m,4H),3.00-2.98(m,4H)。
MS-ESI:299.5[M+H]+。
實施例30 4-(5,6-二甲氧基-吡啶-3-基)-2-呱嗪-1-基-嘧啶(化合物30)的製備
2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶
除了用5-溴-2,3-二甲氧基吡啶替代7-溴-2,3-二氫-[1,4]二惡英[2,3-b]吡啶外,2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶的合成同實施例28中的7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氫-[1,4]二惡英[2,3b]吡啶。收率為93%。
1H NMR(400MHz,CDCl3)δ 8.12(s,1H),7.34(s,1H),4.04(s,3H),3.89(s,3H),1.34(s,12H)。
MS-ESI:266.4[M+H]+。
4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁酯
除了用2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶替換7-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)2,3-二氫-[1,4]二惡英[2,3b]吡啶外,4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁酯的合成實施與實施例28中的4-(4-(2,3-二氫-[1,4]二氧代[2,3-b]吡啶-7-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯。收率為54%。
1H NMR(400MHz,CDCl3)δ 8.39(d,J=1.8Hz,1H),8.36(d,J=5.2Hz,1H),7.74(d,J=1.8Hz,1H),6.91(d,J=5.2Hz,1H),4.08(s,3H),3.97(s,3H),3.93-3.85(m,4H),3.59-3.49(m,4H),1.50(s,9H)。
MS-ESI:402.5[M+H]+。
化合物30
除了用4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物30的合成同實施例18中的化合物18。收率為40%。
1H NMR(400MHz,DMSO-d6)δ 8.50(d,J=1.8Hz,1H),8.41(d,J=5.2Hz,1H),7.87(d,J=1.8Hz,1H),7.23(d,J=5.2Hz,1H),3.93(s,3H),3.87(s,3H),3.82-3.76(m,4H),2.90-2.80(m,4H)。
MS-ESI:302.4[M+H]+。
實施例31 4-(3,4-二甲氧基-苯基)-2-呱嗪-1-基-嘧啶(化合物31)的製備
4-[4-(3,4-二甲氧基-苯基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁酯
除了用2-(3,4-二甲氧基-苯基)-4,4,5,5-四甲基-[1,3,2]二氧硼烷替代2,3-二甲氧基-5-(4,4,5,5-四甲基-[1,3,2]二氧硼烷-2-基)-吡啶外,4-[4-(3,4-二甲氧基-苯基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁酯的合成實施同實施例30的4-[4-(5,6-二甲氧基-吡啶-3-基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁。收率為60%。
1H NMR(400MHz,CDCl3)δ 8.33(d,J=5.2Hz,1H),7.67-7.60(m,2H),6.94(d,J=8.4Hz,1H),6.92(d,J=5.2Hz,1H),3.98(s,3H),3.94(s,3H),3.92-3.86(m,4H),3.57-3.50(m,4H),1.49(s,9H)。
MS-ESI:401.5[M+H]+。
化合物31
除了用4-[4-(3,4-二甲氧基-苯基)-嘧啶-2-基]-呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物31的合成同實施例18中的化合物18。收率為51%。
1H NMR(400MHz,DMSO-d6)δ 8.36(d,J=5.2Hz,1H),7.72(dd,J=8.4,1.8Hz,1H),7.68(d,J=1.8Hz,1H),7.16(d,J=5.2Hz,1H),7.06(d,
J=8.4Hz,1H),3.84(s,3H),3.82(s,3H),3.79-3.72(m,4H),2.83-2.76(m,4H)。
MS-ESI:301.5[M+H]+。
實施例32 3-(2-(呱嗪-1-基)嘧啶-4-基)-1H吲哚(化合物32)的製備
3-(2-(4-(叔丁氧羰基)呱嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯
除了用3-(4,4,5,5-四甲基-1,3,2-二氧雜環戊烷-2-基)-1H-吲哚-1-羧酸叔丁酯替代實施例1中喹啉-3-硼酸外,化合物3-(2-(4-(叔丁氧羰基)呱嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為69%。
1H NMR(400MHz,CDCl3):δ 8.40-8.36(m,1H),8.34(d,J=8.0Hz,1H),8.19(s,2H),7.39-7.5(m,2H),6.93(d,J=8.0Hz,1H),3.93(t,J=8.0Hz,4H),3.57(t,J=8.0Hz,4H),1.71(s,9H),1.51(s,9H)。
MS-ESI:480.6[M+H]+。
3-(2-(呱嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯
將化合物3-(2-(4-(叔丁氧羰基)呱嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯(284mg,0.59mmoL)溶於DCM(8mL)中,加入HCl/1,4-二氧六環(4M,
5mL),室溫反應30min,TLC檢測反應完全。減壓蒸去溶劑,殘留物中加入水(5mL),用NaOH(3M)調節pH至14。減壓蒸去溶劑,殘留物用快速柱層析法分離。得目標產物210mg,收率為93%。
1H NMR(400MHz,CDCl3):δ 8.39-8.36(m,1H),8.33(d,J=4.0Hz,1H),8.19(d,J=8.0Hz,2H),7.39-7.34(m,2H),6.92(d,J=4.0Hz,1H),3.98(t,J=12.0Hz,4H),3.05(t,J=12.0Hz,4H),1.71(s,9H)。
MS-ESI:380.5[M+H]+。
化合物32
將化合物3-(2-(呱嗪-1-基)嘧啶-4-基)-1H-吲哚-1-羧酸叔丁酯(210mg,0.551mmoL)溶於正丁醇(2.1mL)和水(1.2mL)的混合體系中,加入濃鹽酸(0.23mL),加熱反應過夜,TLC檢測反應完全。減壓蒸去溶劑。殘留物中加入水(5mL),用NaOH(3M)調節pH至14。減壓蒸去旋幹溶劑,殘留物用快速柱層析法得到目標產物124mg,收率為80%。
1H NMR(400MHz,CDCl3)δ 8.53(s,1H),8.44-8.38(m,1H),8.29(d,J=4.0Hz,1H),7.88(d,J=2.0Hz,1H),7.45-7.39(m,1H),7.29(s,1H),6.88(d,J=5.2Hz,1H),3.96-3.90(m,4H),3.03-3.00(m,4H)。
MS-ESI:280.5[M+H]+。
實施例33 4-(苯並呋喃-3-基)-2-(呱嗪-1-某)嘧啶(化合物33)的製備
4-(4-(苯並呋喃-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用苯並呋喃-3-基硼酸替代喹啉-3-基硼酸,以及用4-(4-嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代2,4-二嘧啶外,4-(4-(苯並呋喃-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為84%。
1H NMR(400MHz,CDCl3)δ 8.36(d,J=5.1Hz,1H),8.23(q,J=4.3,3.4Hz,2H),7.67-7.50(m,1H),7.43-7.30(m,2H),6.89(d,J=5.1Hz,1H),4.01-3.85(m,4H),3.57(dd,J=6.5,4.0Hz,4H),1.50(s,9H)。
MS-ESI:381.5[M+H]+。
化合物33
除了用4-(4-(苯並呋喃-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物33的合成同實施例18中的化合物18。收率為86%。
1H NMR(400MHz,CDCl3)δ 8.35(d,J=5.1Hz,1H),8.24(d,J=10.3Hz,2H),7.65-7.50(m,1H),7.43-7.31(m,2H),6.86(d,J=5.1Hz,1H),3.98-3.89(m,4H),3.01(dd,J=6.0,4.2Hz,4H)。
MS-ESI:281.4[M+H]+。
實施例34 3-甲氧基-5-(2-呱嗪-1-基-嘧啶-4-基)-吡啶-2-醇(化合物34)的製備
化合物34
除了將鹽酸脫Boc的反應時間延長至過夜,化合物34的合成實施同實施例30的4-(5,6-二甲氧基-吡啶-3-基)-2-呱嗪-1-基-嘧啶。產率為50%。
1H NMR(400MHz,DMSO)δ 8.31(d,J=5.2Hz,1H),7.87(d,J=2.2Hz,1H),7.44(d,J=2.2Hz,1H),7.07(d,J=5.4Hz,1H),3.79(s,3H),3.76-3.64(m,4H),2.83-2.68(m,4H)。
MS-ESI:288.4[M+H]+。
實施例35 3-(4-(呱嗪-1-基)-1,3,5-三嗪-2-基)喹啉(化合物35)的製備
4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用2,4-二-1,3,5-三嗪替代實施例1中3-(2-嘧啶-4-基)喹啉,以及用呱嗪-1-羧酸叔丁酯代替呱啶-4-基甲胺外,4-(4--1,3,5-三嗪-2-
基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為46%。
MS-ESI:300.3[M+H]+。
4-(4-(喹啉-3-基)-1,3,5-三嗪-2-基)呱嗪-1-羧酸叔丁酯
除了用4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯代替實施例1中喹啉-3-硼酸外,化合物4-(4-(喹啉-3-基)-1,3,5-三嗪-2-基)呱嗪-1-羧酸叔丁酯的合成同實施列1中的3-(2-嘧啶-4-基)喹啉。收率為42%。
1H NMR(400MHz,CDCl3)δ:9.92(d,J=4.0Hz,1H),9.25(d,J=4.0Hz,1H),8.78(s,1H),8.25(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.87(t,J=8.0Hz,1H),7.68(t,J=8.0Hz,1H),4.07(d,J=44.0Hz,4H),3.65(d,J=8.0Hz,4H),1.58(s,9H)。
MS-ESI:393.4[M+H]+。
化合物35
除了用4-(4-(喹啉-3-基)-1,3,5-三嗪-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物35的合成同實施例18中的化合物18。收率為72%。
1H NMR(400MHz,DMSO-d6)δ:9.75(d,J=4.0Hz,1H),9.30(s,1H),8.74(s,1H),8.22(d,J=8.0Hz,1H),8.11(d,J=8.0Hz,1H),7.88(t,J=8.0Hz,1H),7.70(t,J=8.0Hz,1H),3.89(d,J=28.0Hz,4H),2.81(d,J=16.0Hz,4H),1.23(s,1H)。
MS-ESI:293.4[M+H]+。
實施例36 2-(呱嗪-1-基)-4-(喹啉-3-基)喹唑啉(化合物36)的製備
1H NMR(400MHz,CDCl3)δ 9.32(d,J=4.0Hz,1H),8.67(d,J=2.0Hz,1H),8.25(d,J=8.0Hz,1H),8.19-8.10(m,2H),8.05-7.97(m,2H),7.88(t,J=8.0Hz,1H),7.69(t,J=8.0Hz,2H)。
MS-ESI:292.4[M+H]+。
4-(4-(喹啉-3-基)喹唑啉-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺外,4-(4-(喹啉-3-基)喹唑啉-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為84%。
1H NMR(400MHz,CDCl3)δ 9.30(d,J=2.0Hz,1H),8.54(d,J=2.0Hz,1H),8.22(d,J=8.0Hz,1H),7.96(d,J=8.0Hz,1H),7.91-7.80(m,2H),7.73-7.62(m,3H),7.25-7.20(m,1H),4.10-3.97(m,4H),3.64-3.52(m,4H),1.50(s,9H)。
MS-ESI:442.5[M+H]+。
化合物36
除了用化合物4-(4-(喹啉-3-基)喹唑啉-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物36的合成同實施例18中的化合物18。收率為82%。
1H NMR(400MHz,DMSO-d6)δ 9.23(d,J=4.0Hz,1H),8.80(d,J=2.0Hz,1H),8.20-8.13(m,2H),7.95-7.85(m,2H),7.80-7.70(m,2H),7.62(d,J=8.0Hz,1H),7.28(t,J=8.0Hz,1H),3.96-3.84(m,4H),2.92-2.81(m,4H)。
MS-ESI:342.3[M+H]+。
實施例37 2-(呱嗪-1-基)-4-(喹啉-3-基)-5,6,7,8-四氫喹唑(化合物37)的製備
1H NMR(400MHz,CDCl3)δ:9.09(d,J=2.4Hz,1H),8.39(d,J=2.4Hz,1H),8.14(d,J=8.0Hz,1H),7.87(d,J=8.0Hz,1H),7.78(t,J=7.5Hz,1H),7.59(t,J=7.5Hz,1H),2.98(t,J=8.0Hz,2H),2.81(t,J=8.0Hz,2H),2.00-1.87(m,2H),1.82-1.69(m,2H)。
MS-ESI:296.4[M+H]+。
4-(4-(喹啉-3-基)-5,6,7,8-四氫喹唑啉-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,以及用2--4-(喹啉-3-基)-5,6,7,8-四氫喹唑代替實施例1中3-(2-嘧啶-4-基)喹啉外,4-(4-(喹啉-3-基)-5,6,7,8-四氫喹唑啉-2-基)呱嗪-1-羧酸叔丁酯的合成實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為78%。
1H NMR(400MHz,CDCl3)δ:9.14(d,J=4.0Hz,1H),8.33(d,J=4.0Hz,1H),8.15(d,J=8.0Hz,1H),7.88(d,J=8.0Hz,1H),7.76(t,J=8.0Hz,1H),7.59(t,J=8.0Hz,1H),3.88-3.77(m,4H),3.57-3.42(m,4H),2.81(t,J=8.0Hz,2H),2.70(t,J=8.0Hz,2H),1.95-1.83(m,2H),1.79-1.67(m,2H),1.48(s,9H)。
MS-ESI:446.6[M+H]+。
化合物37
除了用4-(4-(喹啉-3-基)-5,6,7,8-四氫喹唑啉-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物37的合成同實施例18中的化合物18。收率為73%。
1H NMR(400MHz,DMSO-d6)δ:9.07(d,J=4.0Hz,1H),8.58(d,J=2.4Hz,1H),8.08(t,J=8.0Hz,2H),7.83(t,J=8.0Hz,1H),7.67(t,J=8.0Hz,1H),3.71-3.63(m,4H),2.80-2.69(m,6H),2.66(t,J=8.0Hz,2H),1.86-1.77(m,2H),1.71-1.62(m,2H),1.23(s,1H)。
MS-ESI:346.5[M+H]+。
實施例38 3-(5-氨基-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物38)的製備
1H NMR(400MHz,CDCl3)δ:9.19(d,J=2.2Hz,1H),8.76(d,J=2.2Hz,1H),8.29(s,1H),8.14-8.05(m,2H),7.90-7.80(m,1H),7.69(t,J=8.0Hz,1H),5.95(s,2H)。
MS-ESI:257.3[M+H]+。
4-(5-氨基基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代呱啶-4-基甲胺,以及用3-(2--5-氨基基嘧啶-4-基)喹啉代替3-(2-嘧啶-4-基)喹啉外,4-(5-氨基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為42%。
1H NMR(400MHz,DMSO-d6)δ:9.36(d,J=2.2Hz,1H),8.85(d,J=2.2Hz,1H),8.22(s,1H),8.16-8.06(m,2H),7.86-7.82(m,1H),7.71-7.66(m,1H),4.88(s,2H),3.68-3.61(m,4H),3.48-3.42(m,4H),1.45(s,9H)。
MS-ESI:407.4[M+H]+。
化合物38
除了用4-(5-氨基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物38的合成同實施例18中的化合物18。收率63%。
1H NMR(400MHz,DMSO)δ:9.32(d,J=2.2Hz,1H),8.82(d,J=2.2Hz,1H),8.18(s,1H),8.09-8.03(m,2H),7.81(t,J=7.6Hz,1H),
7.66(t,J=7.6Hz,1H),4.80(s,2H),3.59(t,J=5.0Hz,4H),2.82(t,J=5.0Hz,4H)。
MS-ESI:307.4[M+H]+。
實施例39 3-(6-甲氧基-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物39)的製備
1H NMR(400MHz,CDCl3)δ:9.44(d,J=2.4Hz,1H),8.90(d,J=2.4Hz,1H),8.17(d,J=8.6Hz,1H),8.00-7.93(m,1H),7.81(t,J=8.6Hz,1H),7.67-7.58(m,1H),7.21(s,1H),4.10(s,3H)。
MS-ESI:272.3[M+H]+。
4-(4-甲氧基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,以及用3-(2--6-甲氧基嘧啶-4-基)喹啉代替實施例1中3-(2-嘧啶-4-基)喹啉外,4-(4-甲氧基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率55%。
1H NMR(400MHz,DMSO-d6)δ:9.58(d,J=2.2Hz,1H),9.07(d,J=2.2Hz,1H),8.12(d,J=8.0Hz,1H),8.07(d,J=8.0Hz,1H),7.90-7.78(m,1H),7.68(t,J=7.4Hz,1H),6.93(s,1H),3.94(s,3H),3.91-3.81(m,4H),3.54-3.43(m,4H),1.44(s,9H)。
MS-ESI:422.5[M+H]+。
化合物39
除了用4-(4-甲氧基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物39的合成同實施例18中的化合物18。收率為60%。
1H NMR(400MHz,DMSO)δ:9.56(d,J=2.2Hz,1H),9.04(d,J=2.2Hz,1H),8.12(d,J=8.4Hz,1H),8.07(d,J=8.4Hz,1H),7.82(t,J=8.4Hz,1H),7.67(t,J=8.4Hz,1H),6.87(s,1H),3.92(s,3H),3.82(t,J=5.0Hz,4H),2.81(t,J=5.0Hz,4H)。
MS-ESI:322.5[M+H]+。
實施例40 3-(2-(呱嗪-1-基)-6-(三氟甲基)嘧啶-4-基)喹啉(化合物40)的製備
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,以及用2,4-二-6-(三氟甲基)嘧啶代替3-(2-嘧啶-4-基)喹啉外,4-(4--6-(三氟甲基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率40%。
1H NMR(400MHz,CDCl3):δ 6.79(s,1H),3.86-3.83(m,4H),3.52-3.50(m,4H),1.49(s,9H)。
4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代2,4-二嘧啶,以及用1,4-二氧六環替代乙醇外,4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為85%。
1H NMR(400MHz,CDCl3):δ 9.58(d,J=2.0Hz,1H),8.79(m,d,J=2.0Hz,1H),8.19(d,J=8.0Hz,1H),7.96-7.95(m,1H),7.84-7.80(m,1H),7.66-7.64(m,1H),7.37(s,1H),4.00-3.99(m,4H),3.60-3.57(m,4H),1.51(s,9H)。
化合物40
除了用4-(4-(喹啉-3-基)-6-(三氟甲基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物40的合成同實施例18中的化合物18。收率為83%。
1H NMR(400MHz,DMSO-d6):δ 9.67(d,J=4.0Hz,1H),9.25(d,J=2.0Hz,1H),8.17-8.15(m,1H),8.10(d,J=8.0Hz,1H),7.90-7.86(m,1H),7.82(s,1H),7.73-7.71(m,1H),3.90-3.84(m,4H),2.85-2.83(m,4H)。
MS-ESI:360.3[M+H]+。
實施例41 3-(5-(呱嗪-1-基)咪唑並[1,2-c]嘧啶-7-基)喹啉(化合物41)的製備
除了用5,7-二咪唑並[1,2-c]嘧啶代替實施例1中3-(2-嘧啶-4-基)喹啉,用呱嗪-1-羧酸叔丁酯代替呱啶-4-基甲胺,以及用TEA代替DIPEA外,4-(7-咪唑並[1,2-c]嘧啶-5-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為90%。
1H NMR(400MHz,CDCl3)δ:7.60(s,1H),7.40(s,1H),7.21(s,1H),3.68-3.62(m,4H),3.51-3.44(m,4H),1.49(s,9H)。
(7-(喹啉-3-基)咪唑並[1,2-c]嘧啶-5-基)呱嗪-1-羧酸叔丁酯
除了用4-(7-咪唑並[1,2-c]嘧啶-5-基)呱嗪-1-羧酸叔丁酯代替2,4-二嘧啶,以及用1,4-二氧六環代替乙醇外,4-(7-(喹啉-3-基)咪唑並[1,2-c]嘧啶-5-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為31%。
1H NMR(400MHz,CDCl3)δ:9.59(s,1H),8.77(s,1H),8.15(d,J=8.0Hz,1H),7.95(d,J=8.0Hz,1H),7.84(s,1H),7.75(t,J=8.0Hz,1H),7.70(s,1H),7.60(t,J=8.0Hz,1H),7.49(s,1H),3.74(m,4H),3.62-3.55(m,4H),1.52(s,9H)。
化合物41
除了用4-(7-(喹啉-3-基)咪唑並[1,2-c]嘧啶-5-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物41的合成同實施例18中的化合物18。收率為53%。
1H NMR(400MHz,DMSO)δ:9.68(d,J=2.0Hz,1H),9.07(d,J=2.0Hz,1H),8.12-8.04(m,3H),7.89(s,1H),7.83-7.76(m,1H),7.71-7.63(m,2H),3.60-3.54(m,4H),3.12-3.06(m,4H)。
MS-ESI:331.5[M+H]+。
實施例42 3-(6-氰基-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物42)的製備
將化合物2,6-二嘧啶-4-腈(125mg,0.72mmoL)、4-甲基呱嗪-1-羧酸叔丁酯(144mg,0.72mmoL)溶於甲苯(5mL)中,回流反應1.5h,TLC檢測反應完全。減壓蒸去溶劑,殘留物用快速柱層析分離。得目標產物156mg,收率為67%。
1H NMR(400MHz,CDCl3)δ 6.79(s,1H),3.93-3.72(m,4H),3.58-3.43(m,4H),1.49(s,9H)。
MS-ESI:224.3[M-100]+。
4-(4-氰基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用4-(4--6-氰基嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例1中2,4-二嘧啶外,4-(4-氰基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為94%。
1H NMR(400MHz,CDCl3)δ 9.53(d,J=2.2Hz,1H),8.75(d,J=1.8Hz,1H),8.18(d,J=8.6Hz,1H),7.97(d,J=8.2Hz,1H),7.86-7.80(m,1H),7.64(t,J=7.6Hz,1H),7.37(s,1H),4.03-3.91(m,4H),3.65-3.51(m,4H),1.51(s,9H)。
MS-ESI:417.5[M+H]+。
化合物42
除了用4-(4-氰基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物42的合成同實施例18中的化合物18。收率為60%。
1H NMR(400MHz,DMSO-d6)δ 9.62(d,J=2.0Hz,1H),9.19(s,1H),8.13(d,J=8.2Hz,1H),8.10(d,J=8.4Hz,1H),7.99(s,1H),7.88(t,J=7.4Hz,1H),7.71(t,J=7.4Hz,1H),3.87-3.75(m,4H),2.88-2.76(m,4H)。
MS-ESI:317.4[M+H]+。
實施例43 3-(5-甲氧基-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物43)的製備
1H NMR(400MHz,CDCl3)δ 9.62(d,J=2.2Hz,1H),8.95(d,J=1.8Hz,1H),8.39(s,1H),8.15(d,J=8.4Hz,1H),7.94(d,J=8.0Hz,1H),7.85-7.75(m,1H),7.65-7.58(m,1H),4.07(s,3H)。
MS-ESI:272.3[M+H]+。
4-(5-甲氧基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,3-(2--5-甲氧基嘧啶-4-基)喹啉代替實施例1中3-(2-嘧啶-4-基)喹啉外,4-(5-甲氧基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為68%。
1H NMR(400MHz,CDCl3)δ 9.63(s,1H),8.91(s,1H),8.26(s,1H),8.14(d,J=8.8Hz,1H),7.93(d,J=8.2Hz,1H),7.79-7.73(m,1H),7.62-7.56(m,1H),3.90(s,3H),3.86-3.80(m,4H),3.58-3.51(m,4H),1.50(s,9H)。
MS-ESI:422.5[M+H]+。
化合物43
除了用4-(5-甲氧基-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物43的合成同實施例18中的化合物18。收率為79%。
1H NMR(400MHz,DMSO-d6)δ 9.48(d,J=2.2Hz,1H),8.96(d,J=1.8Hz,1H),8.44(s,1H),8.11(d,J=7.8Hz,1H),8.06(d,J=8.4Hz,1H),7.86-7.79(m,1H),7.70-7.62(m,1H),3.88(s,3H),3.72-3.63(m,4H),2.85-2.75(m,4H)。
MS-ESI:322.5[M+H]+。
實施例44 3-(6-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物44)的製備
1H NMR(400MHz,DMSO-d6)δ:9.68(d,J=4.0Hz,1H),9.27(d,J=4.0Hz,1H),9.20(d,J=4.0Hz,1H),8.58(d,J=2.0Hz,1H),8.13(dd,J=20.0,8.0Hz,2H),7.94-7.86(m,1H),7.77-7.69(m,1H)。
MS-ESI:242.4[M+H]+。
4-(6-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,用3-(6-嘧啶-4-基)喹啉代替實施例1中3-(2-嘧啶-4-基)喹啉,以及用TEA替代DIPEA外,4-(6-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為95%。
1H NMR(400MHz,DMSO-d6)δ:9.64(d,J=2.0Hz,1H),9.12(d,J=2.0Hz,1H),8.68(s,1H),8.10(t,J=8.0Hz,2H),7.84(t,J=8.0Hz,1H),7.69(t,J=8.0Hz,1H),7.60(s,1H),3.82-3.75(m,4H),3.50-3.44(m,4H),1.44(s,9H)。
MS-ESI:392.4[M+H]+。
化合物44
除了用4-(6-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物44的合成同實施例18中的化合物18。收率為85%。
1H NMR(400MHz,DMSO-d6)δ:9.62(d,J=2.0Hz,1H),9.11(d,J=2.0Hz,1H),8.63(s,1H),8.09(t,J=8.0Hz,2H),7.87-7.78(m,1H),7.72-7.64(m,1H),7.54(s,1H),3.74-3.66(m,4H),2.84-2.76(m,4H)。
MS-ESI:292.5[M+H]+。
實施例45 3-(9-甲基-2-(呱嗪-1-基)-9H-嘌呤-6-基)喹啉(化合物45)的製備
1H NMR(400MHz,DMSO-d6)δ:10.11(d,J=2.2Hz,1H),9.63(d,J=2.2Hz,1H),8.74(s,1H),8.23(d,J=8.4Hz,1H),8.12(d,J=8.4Hz,1H),7.91(t,J=8.2,Hz,1H),7.72(t,J=8.2Hz,1H),3.87(s,3H)。
MS-ESI:296.3[M+H]+。
4-(9-甲基-6-(喹啉-3-基)-9H-嘌呤-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,3-(2--9-甲基-9H-嘌呤-6-基)喹啉代替實施例1中3-(2-嘧啶-4-基)喹啉外,4-(9-甲基-6-(喹啉-3-基)-9H-嘌呤-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為84%。
1H NMR(400MHz,DMSO-d6)δ:10.14(d,J=2.1Hz,1H),9.67(d,J=2.2Hz,1H),8.29(s,1H),8.18(d,J=8.0Hz,1H),8.10(d,J=8.8Hz,
1H),7.86(t,J=8.6Hz,1H),7.70(t,J=8.0Hz,1H),3.96-3.89(m,4H),3.73(s,3H),3.55-3.47(m,4H)。
MS-ESI:446.5[M+H]+。
化合物45
除了用4-(9-甲基-6-(喹啉-3-基)-9H-嘌呤-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物45的合成同實施例18中的化合物18。收率為92%。
1H NMR(400MHz,DMSO-d6)δ:10.12(d,J=2.0Hz,1H),9.64(d,J=2.0Hz,1H),8.26(s,1H),8.17(d,J=8.2Hz,1H),8.10(d,J=8.4Hz,1H),7.86(t,J=8.2Hz,1H),7.69(t,J=8.2Hz,1H),3.86(t,J=5.0Hz,4H),3.72(s,3H),2.86(t,J=5.0Hz,4H)。
MS-ESI:346.4[M+H]+。
實施例46 3-(5-氟-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物46)的製備
MS-ESI:260.7[M+H]+。
4-(5-氟-4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,用3-(2--5-氟嘧啶-4-基)喹啉代替實施例1中3-(2-嘧啶-4-基)喹啉,以及用TEA替代DIPEA外4-(5-氟-4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為95%。
1H NMR(400MHz,DMSO-d6)δ:9.48(d,J=2.0Hz,1H),9.00(s,1H),8.63(d,J=4.0Hz,1H),8.18(d,J=8.0Hz,1H),8.10(d,J=8.0Hz,1H),7.93-7.85(m,1H),7.71(m,1H),3.84-3.77(m,4H),3.49-3.44(m,4H),1.43(s,9H)。
MS-ESI:410.5[M+H]+。
化合物46
除了用4-(5-氟-4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物46的合成同實施例18中的化合物18。收率為75%。
1H NMR(400MHz,DMSO-d6)δ:9.46(s,1H),8.97(s,1H),8.59(d,J=4.0Hz,1H),8.18(d,J=8.0Hz,1H),8.10(d,J=8.0Hz,1H),7.92-7.84(m,1H),7.70(m,1H),3.77-3.70(m,4H),2.84-2.76(m,4H)。
MS-ESI:310.4[M+H)+。
實施例47 2-(呱嗪-1-基)-6-(喹啉-3-基)嘧啶-4-胺(化合物47)的製備
將化合物4-(4-氨基-6-嘧啶-2-基)呱嗪-1-羧酸叔丁酯(395mg,1.26mmoL)溶於二甲烷(5mL)中,再加入三乙胺(254mg,2.52mmoL)。在冰浴下緩慢滴加二碳酸二叔丁酯(412mg,1.89mmoL),滴加完畢後逐漸升溫至室溫反應。反應1h後,TLC監測反應基本未反應,加入DMAP(40mg,0.33mmoL),室溫繼續反應。TLC監測反應基本完全。減壓蒸去溶劑,殘留物用快速柱層析分離。得目標產物487mg,收率為93%。
1H NMR(400MHz,CDCl3):δ 6.89(s,1H),3.76-3.73(m,4H),3.47-3.44(m,4H),1.49(s,9H),1.46(s,9H)。
4-(4-((叔丁氧羰基)氨基)-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用4-(4-((叔丁氧基羰基)氨基)-6-嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例1中2,4-二嘧啶,用1,4-二氧六環替代乙醇外,4-(4-((叔丁
氧羰基)氨基)-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為92%。
1H NMR(400MHz,CDCl3):δ 9.62-9.57(m,1H),8.77-8.75(m,1H),8.17-8.14(m,1H),7.96-7.93(m,1H),7.83-7.75(m,1H),7.61-7.58(m,1H),7.07-7.06(m,1H),3.90-3.87(m,4H),3.54-3.51(m,4H),1.58(s,9H),1.50(s,9H)。
化合物47
除了用4-(4-((叔丁氧羰基)氨基)-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物47的合成同實施例18中的化合物18。收率為43%。
1H NMR(400MHz,DMSO-d6):δ 9.42(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.12(d,J=8.0Hz,1H),8.06(d,J=8.0Hz,1H),7.82-7.79(m,1H),7.67-7.64(m,1H),6.61(s,2H),6.46(s,1H),3.78-3.75(m,4H),2.82-2.80(m,4H)。
MS-ESI:307.4[M+H]+。
實施例48 6-(呱嗪-1-基)-2-(喹啉-3-基)嘧啶-4-胺(化合物48)的製備
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,用2,6-二嘧啶-4-胺代替實施例1中3-(2-嘧啶-4-基)喹啉,4-(6-氨基-2-嘧啶-4-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為13%。
1H NMR(400MHz,CDCl3):δ 5.41(s,1H),3.56-3.48(m,8H),1.48(s,9H)。
4-(6-氨基-2-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯
除了用4-(6-氨基-2-嘧啶-4-基)呱嗪-1-羧酸叔丁酯替代實施例1中2,4-二嘧啶,以及用1,4-二氧六環替代乙醇外,4-(6-氨基-2-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為46%。
1H NMR(400MHz,CDCl3):δ 9.84(d,J=2.0Hz,1H),9.06(d,J=2.0Hz,1H),8.15(d,J=12.0Hz,1H),7.95-7.93(m,1H),7.76-7.72(m,1H),7.58-7.54(m,1H),5.59(s,1H),4.70(s,2H),3.72-3.69(m,4H),3.59-3.56(m,4H),1.50(s,9H)。
化合物48
除了用4-(6-氨基-2-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物48的合成同實施例18中的化合物18。收率為53%。
MS-ESI:307.3[M+H]+。
實施例49 4-(2-(呱嗪-1-基)-6-(喹啉-3-基)嘧啶-4-基)嗎啉(化合物49)的製備
除了用呱嗪-1-羧酸叔丁酯替代呱啶-4-基甲胺,以及用4-(2,6-二嘧啶-4-基)嗎啉替代3-(2-嘧啶-4-基)喹啉外,4-(4--6-嗎啉嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為89%。
1H NMR(400MHz,CDCl3)δ 5.85(s,1H),3.78-3.70(m,8H),3.58-3.51(m,4H),3.49-3.42(m,4H)。
MS-ESI:384.4[M+H]+。
4-(4-嗎啉-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用4-(4--6-嗎啉嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例1中2,4-二嘧啶,以及用1,4-二氧六環替代乙醇外,4-(4-嗎啉-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的3-(2-嘧啶-4-基)喹啉。收率為74%。
1H NMR(400MHz,CDCl3)δ 9.47(d,J=2.2Hz,1H),8.73(d,J=1.6Hz,1H),8.15(d,J=8.6Hz,1H),7.93(d,J=8.2Hz,1H),7.79-7.71(m,1H),7.59(t,J=7.6Hz,1H),6.44(s,1H),3.94-3.86(m,4H),3.86-3.80(m,4H),3.72-3.66(m,4H),3.57-3.51(m,4H),1.50(s,9H)。
MS-ESI:477.5[M+H]+。
化合物49
除了用4-(4-嗎啉-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物49的合成同實施例18中的化合物18。收率為81%。
1H NMR(400MHz,DMSO-d6)δ 9.58(d,J=2.1Hz,1H),9.03(d,J=1.8Hz,1H),8.08(t,J=9.1Hz,2H),7.86-7.76(m,1H),7.66(t,J=7.1Hz,1H),6.89(s,1H),3.81-3.72(m,4H),3.71-3.63(m,8H),2.84-2.78(m,4H)。
MS-ESI:377.5[M+H]+。
實施例50 3-(5-環丙基-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物50)的製備
1H NMR(400MHz,CDCl3)δ 9.36(d,J=2.2Hz,1H),8.66(d,J=1.7Hz,1H),8.40(s,1H),8.18(d,J=8.4Hz,1H),7.94(d,J=8.1Hz,1H),7.86-7.76(m,1H),7.66-7.61(m,1H),2.05(tt,J=8.5,5.5Hz,1H),1.15-1.08(m,2H),0.80(q,J=5.2Hz,2H)。
MS-ESI:282.4[M+H]+。
4-(5-環丙基-4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代實施例1中呱啶-4-基甲胺,3-(2--5-環丙基嘧啶-4-基)喹啉代替實施例1中3-(2-嘧啶-4-基)喹啉外,4-(5-環丙基-4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為79%。
1H NMR(400MHz,CDCl3)δ 9.37(d,J=2.0Hz,1H),8.62(d,J=1.8Hz,1H),8.24(s,1H),8.17(d,J=8.5Hz,1H),7.92(d,J=8.1Hz,1H),779(t,J=7.7Hz,1H),7.59(dd,J=20.7,13.5Hz,1H),3.90-3.80(m,4H),3.58-3.46(m,4H),1.93(dq,J=8.4,5.4Hz,1H),1.49(s,10H),0.90(s,2H),0.57(d,J=5.4Hz,2H)。
化合物50
除了用4-(5-環丙基-4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物50的合成同實施例18中的化合物18。收率為81%。
1H NMR(400MHz,DMSO-d6)δ 9.27(d,J=2.2Hz,1H),8.79(d,J=1.9Hz,1H),8.29(s,1H),8.13-8.01(m,2H),7.86-7.79(m,1H),7.68(t,J=7.5Hz,1H),3.79-3.66(m,4H),2.84-2.70(m,4H),2.06-1.94(m,2H),0.87-0.71(m,3H),0.53(q,J=5.9Hz,2H)。
MS-ESI:331.4[M+H]+。
實施例51 3-(6-(4-甲氧基苯基)-2-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物51)的製備
1H NMR(400MHz,CDCl3)δ:9.57(d,J=4.0Hz,1H),8.99(d,J=4.0Hz,1H),8.26-8.13(m,3H),8.11(s,1H),8.00(d,J=8.0Hz,1H),7.83(t,J=8.0Hz,1H),7.65(t,J=8.0Hz,1H),7.06(d,J=8.0Hz,2H),3.92(s,3H)。
MS-ESI:348.4[M+H]+。
4-(4-(4-甲氧基苯基)-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代呱啶-4-基甲胺,以及用3-(2--6-(4-甲氧基苯基)嘧啶-4-基)喹啉代替3-(2-嘧啶-4-基)喹啉外,4-(4-(4-甲氧基苯基)-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為70%。
1H NMR(400MHz,CDCl3)δ:9.61(d,J=4.0Hz,1H),8.84(d,J=4.0Hz,1H),8.19-8.13(m,3H),7.97(d,J=8.0Hz,1H),7.78(t,J=8.0Hz,
1H),7.62(t,J=8.0Hz,1H),7.51(s,1H),7.03(d,J=8.0Hz,2H),4.15-3.99(m,4H),3.90(s,3H),3.66-3.55(m,4H),1.52(s,9H)。
MS-ESI:498.4[M+H]+。
化合物51
除了用4-(4-(4-甲氧基苯基)-6-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物51的合成同實施例18中的化合物18。收率為74%。
1H NMR(400MHz,DMSO-d6)δ:9.73(d,J=4.0Hz,1H),9.23(d,J=4.0Hz,1H),8.30(d,J=8.0Hz,2H),8.13(dd,J=19.3,8.1Hz,2H),7.95(s,1H),7.85(t,J=8.0Hz,1H),7.70(t,J=8.0Hz,1H),7.10(d,J=8.0Hz,2H),3.96-3.87(m,4H),3.86(s,3H),2.89-2.82(m,4H),1.23(s,1H)。
MS-ESI:398.4[M+H]+。
實施例52 3-(1-甲基-6-(呱嗪-1-基)-1H-吡唑並[3,4-d]嘧啶-4-基)喹啉(化合物52)的製備
除了用4,6-二-1-甲基-1H-吡唑[3,4-d]嘧啶替代2,4-二嘧啶,以及用1,4-二氧六環替代乙腈外,3-(6--1-甲基-1H-吡唑並[3,4-d]嘧啶-4-基)喹啉的合成同實施例1中的中的3-(2-嘧啶-4-基)喹啉。未作純化直接進行下步反應。
MS-ESI:296.2[M+H]+。
4-(1-甲基-4-(喹啉-3-基)-1H-吡唑[3,4-d]嘧啶-6-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代呱啶-4-基甲胺外,3-(6--1-甲基-1H-吡唑並[3,4-d]嘧啶-4-基)喹啉的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為91%。
MS-ESI:296.2[M+H]+。
化合物52
除了用化合物4-(1-甲基-4-(喹啉-3-基)-1H-吡唑[3,4-d]嘧啶-6-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物52的合成同實施例18中的化合物18。收率為82%。
1H NMR(400MHz,DMSO-d6)δ 9.66(d,J=2.0Hz,1H),9.18(d,J=2.0Hz,1H),8.55(s,1H),8.27(d,J=8.0Hz,1H),8.11(d,J=8.0Hz,1H),7.92-7.84(m,1H),7.74-7.69(m,1H),3.93-23.89(m,4H),3.88(s,3H),2.90-2.79(m,4H)。
MS-ESI:346.4[M+H]+。
實施例53 3-(5-甲基-6-(呱嗪-1-基)嘧啶-4-基)喹啉(化合物53)的製備
1H NMR(400MHz,CDCl3):δ 9.12(d,J=4.0Hz,1H),8.95(s,1H),8.41(d,J=2.0Hz,1H),8.19(dd,J=16.0,4.0Hz,1H),7.92(dd,J=8.0,2.0Hz,1H),7.85-7.80(m,1H),7.66-7.62(m,1H),2.53(s,3H)。
MS-ESI:256.3[M+H]+。
4-(5-甲基-6-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯
除了用呱嗪-1-羧酸叔丁酯替代呱啶-4-基甲胺,用3-(6--5-甲基嘧啶-4-基)喹啉代替3-(2-嘧啶-4-基)喹啉,以及用TEA替代DIPEA外,4-(5-甲基-6-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯的合成同實施例1中的(1-(4-(喹啉-3-基)嘧啶-2-基)呱啶-4-基)甲胺。收率為89%。
1H NMR(400MHz,CDCl3):δ 9.15(d,J=8.0Hz,1H),8.76(s,1H),8.44-8.43(m,1H),8.16(d,J=2.0Hz,1H),7.91(dd,J=8.0,4.0Hz,1H),7.81-7.77(m,1H),7.63-7.59(m,1H),3.62-3.59(m,4H),3.48-3.45(m,4H),2.31(s,3H),1.50(s,9H)。
化合物53
除了用4-(5-甲基-6-(喹啉-3-基)嘧啶-4-基)呱嗪-1-羧酸叔丁酯替代實施例18中4-(4-(喹啉-3-基)嘧啶-2-基)呱嗪-1-羧酸叔丁酯外,化合物53的合成同實施例18中的化合物18。收率為82%。
1H NMR(400MHz,DMSO-d6):δ 9.17(d,J=4.0Hz,1H),8.69-8.66(m,2H),8.09(d,J=8.0Hz,2H),7.87-7.83(m,1H),7.69(t,J=8.0Hz,1H),3.42-3.35(m,4H),2.85(t,J=8.0Hz,4H),2.27(s,3H)。
MS-ESI:306.3[M+H]+。
實施例54 CTLA-4小分子降解劑活性檢測(蛋白-蛋白相互作用報告系統檢測法,CTLA-4蛋白表達水準初篩)
將HEK293細胞鋪於96孔板,24h後將LRBA和CTLA-4報告系統共轉入HEK293細胞,24h後再加入終濃度分別為0.01、0.033、0.10、0.33、1.00、3.33、10.00、33.33、100.00μM的不同化合物。加藥24小時(h)後,去除
細胞培養基並用冷PBS清洗細胞,再用雙螢光素酶檢測試劑盒檢測化合物的活性,根據檢測結果計算IC50。
對於活性強的化合物(IC50<200nM)待用蛋白質免疫印跡方法(Western Blot)進一步檢測對CTLA-4蛋白降解作用。
IC50:抑制50%報告系統活性的化合物濃度
IC50大小分成四個層次:
++++,IC50<200nM;+++,IC50為200-1000nM;++,IC50為1000-2000nM;+,IC50>2000nM。
本發明化合物IC50,如下表1所示。
表1 化合物對CTLA-4蛋白表達水準的影響(蛋白-蛋白相互作用報告系統)
實施例55 移植瘤模型(MC-38)體內活性研究
細胞培養:小鼠結腸癌MC-38細胞體外貼壁培養,培養條件為RPMI-1640培養基中加10%胎牛血清,100U/mL青黴素和100μg/mL鏈黴素,37℃ 5%CO2孵箱培養。一周兩到三次常規處理傳代。當細胞飽和度為80%-90%,數量到達要求時,收取細胞計數,調整細胞濃度後用於實驗接種。
動物:C57BL/6小鼠,雌性,7周齡,體重18-20克,每組8只。
腫瘤接種:0.02mL(0.2×106個)MC-38細胞皮下接種於每只小鼠的右後背。接種後第7天,測量動物腫瘤體積,然後根據腫瘤體積大小隨機化分組並開始給藥。
實驗指標:實驗指標是考察腫瘤生長是否被抑制、延緩或治癒。每週兩到三次用遊標卡尺測量腫瘤直徑。腫瘤體積的計算公式為:V=0.5a×b2,a和b分別表示腫瘤的長徑和短徑。化合物的抑瘤療效用TGI(%)。TGI(%),反映腫瘤生長抑制率。TGI(%)的計算:TGI(%)=[(1-(某處理組給藥結束時平均瘤
體積一該處理組開始給藥時平均瘤體積))/(溶劑對照組治療結束時平均瘤體積一溶劑對照組開始治療時平均瘤體積)]×100%。
動物實驗分組、給藥方案及實驗結果:
應當理解,以上實施例均為示例性的,不用於包含權利要求所包含的所有可能的實施方式。在不脫離本公開的範圍的情況下,還可以在以上實施例的基礎上做出各種變形和改變。同樣的,也可以對以上實施例的各個技術特徵進行任意組合,以形成可能沒有被明確描述的本發明的另外的實施例。因此,上述實施例僅表達了本發明的幾種實施方式,不對本發明專利的保護範圍進行限制。
Claims (20)
- 一種CTLA-4小分子降解劑,具備式I結構:其中,A、B、C、D、E、F、G、H、I、J、K、L和M分別選自直連鍵、CR6、CR6R14、N、NR7、O、S和C=O;每一個R1、R2、R3、R6、R7和R14分別選自氫、氘、未取代或取代的烷基、未取代或取代的烯基、未取代或取代的炔基、未取代或取代的環烷基、未取代或取代的環雜烷基、鹵素、-OH、未取代或取代的烷氧基、未取代或取代的芳基烷基、未取代或取代的芳雜基烷基、未取代或取代的芳基醚基、未取代或取代的芳雜基醚基、-CN、-N(R4R5)、-NO2、-N3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲醯基、未取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的硫醚基、未取代或取代的亞碸基、未取代或取代 的碸基、未取代或取代的磺醯胺基、、、未取代或取 代的膦酸酯基,其中R4、R5、R8、R9、R10和R11分別選自氫、氘、C1-6烷基、C3-7環烷基、未取代或取代的芳基、未取代或取代的芳雜基,且R4和R5、R8和R9可與相鄰的氮原子或碳原子連接成環;或相鄰的兩個R1和/或相鄰的兩個R3也可連接成未取代或取代的環烷基、未取代或取代的環雜烷基、未取代或取代的芳基或未取代或取代的芳雜基;m、n、o分別選自0~4的整數;W選自直連鍵、未取代或取代的芳基、未取代或取代的芳雜基、未取代或取代的環烷基、未取代或取代的環雜烷基、未取代或取代的橋環烷基、未取代或取代的橋環雜烷基、未取代或取代的螺環烷基、未取代或取代的螺環雜烷基、未取代或取代的烷基、未取代或取代的雜烷基、未取代或取代的烯基、未取代或取代的雜烯基、未取代或取代的炔基、未取代或取代的雜炔基、未取代或取代的-N(R12R13)、未取代或取代的胺基烷基、未取代或取代的胺基烷基胺基、未 取代或取代的、未取代或取代的,其中R12和R13分別 選自氫、氘、未取代或取代的C1-6烷基、C3-7環烷基、未取代或取代的烷基胺基、未取代或取代的芳基、取代或未取代的芳雜基,或R12和R13可連接成環;Q為-H、-NH2、-OH、-烷基-NHC(=O)H、環烷基、未取代或取代的烷基醯基、未取代或取代的烷基羥基、未取代或取代的烯基羥基、未取代或取代的炔基羥基、未取代或取代的烷基胺基、未取代或取代的磺醯胺基、未取代或取代 的烷基磺醯胺基、氨基酸殘基、、磺醯胺基、磺醯肼基、未取代或取 代的芳基、未取代或取代的芳雜基、未取代或取代的、未取代或取代 的、取代或未取代的-(CH2)n1-(M)n2-(CH2)n3-(M)n4-(CH2)n5-(M)n 6,其中每個M分別選自O、OH、S、SO、SO2和未取代或取代的胺基,每個n1、n2、n3、n4、n5和n6分別選自0~6的整數;或W和Q可以連接或融合成取代或非取代的環烷基、環雜烷基、芳基或芳雜基。
- 如請求項1所述之CTLA-4小分子降解劑,其中,C、G、I中至少一個為N原子。
- 如請求項1所述之CTLA-4小分子降解劑,其中,所述J、K、M至少一個為N原子。
- 如請求項1所述之CTLA-4小分子降解劑,其中,I、J、K均為N原子,或I、M、K均為N原子。
- 如請求項1所述之CTLA-4小分子降解劑,其中,每一個R1、R2、R3、R6、R7和R14分別選自氫、氘、未取代或取代的C1-6烷基、未取代或取代的C2-6烯基、未取代或取代的C2-6炔基、未取代或取代的C3-7環烷基、未取代或取代的3-7元環雜烷基、鹵素、-OH、未取代或取代的C1-6烷氧基、未取代或取代的C6-10芳基乙基、未取代或取代的5-10元芳雜基乙基、未取代或取代的C6-10芳基醚基、未取代或取代的5-10元芳雜基醚基、-CN、-NH2、-NO2、-N3、硼酸基、未取代或取代的硼酸酯基、羧基、酯基、未取代或取代的胺基甲醯基、未取代或取代的C6-10芳基、未取代或取代的5-10元芳雜基、未取代或取代的硫醚基、未取代或取代的亞碸基、未取代或取代的碸基、未取代或取代的磺醯胺 基、、、未取代或取代的膦酸酯基,所述取代是被選 自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、 C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
- 如請求項1所述之CTLA-4小分子降解劑,其中,W選自直連鍵、取代或非取代的芳基、芳雜基、環烷基、環雜烷基、橋環烷基、橋環雜烷基、螺環烷基、螺環雜烷基、烷基、雜烷基、烯基、雜烯基、炔基、雜炔基、-N(R12R13)、 胺基烷基、胺基烷基胺基、未取代或取代的、未取代或取代的 ,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔 基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
- 如請求項6所述之CTLA-4小分子降解劑,其中,W選自取代或非取代的5-7元環雜烷基、取代或非取代的-胺基-C1-6烷基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
- 如請求項7所述之CTLA-4小分子降解劑,其中,W中與含J、K的環相連的原子為N。
- 如請求項7所述之CTLA-4小分子降解劑,其中,W選自取代或非取代的5-7元環雜烷基,所述5-7元雜環烷基至少包含一個氮原子,優選的,所述5-7元雜環烷基為呱啶基或呱嗪基。
- 如請求項1所述之CTLA-4小分子降解劑,其中,Q為-H、-NH2、-OH、-C1-6烷基-HNC(=O)H、未取代或取代的C1-6烷基羥基、未取代或取代的C2-6烯基羥基、未取代或取代的C2-6炔基羥基、未取代或取代的烷基胺基、磺醯胺基和磺醯肼基,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
- 如請求項1所述之CTLA-4小分子降解劑,其中,W和Q可以連接或融合成環,所述環為取代或非取代的5-7元環烷基、取代或非取代的5-7元的環雜烷基、取代或非取代的C6-10芳基、取代或非取代的5-10元芳雜基。
- 如請求項11所述之CTLA-4小分子降解劑,其中,所述取代是被選自氫、氘、鹵素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6鹵代烷基、C1-6鹵代烯基、C1-6鹵代炔基、C3-7環烷基、3-7元雜環烷基、鹵素、-OH、C1-6烷氧基、C1-6鹵代烷氧基、-CN、-NH2、-NO2、-N3、硼酸基、羧基、酯基、甲醯胺基、C1-6烷基醯胺基、C6-10芳基、5-10元芳雜基、烷基胺基的取代基所取代。
- 一種藥物組合物,包含如請求項1-15中任意一項所述之CTLA-4小分子降解劑。
- 如請求項16所述之藥物組合物,其中,所述藥物組合物的形式為水性分散劑、液體、啫哩、糖漿、西也劑、藥漿、懸浮液、氣霧劑、控釋劑、即溶劑、泡騰劑、凍幹劑、片劑、粉末、藥丸、糖衣完、膠囊、延遲釋放劑、延長釋放劑、脈衝控釋劑、多微粒劑或立即釋放劑中的任一種。
- 一種組合物在製備治療CTLA-4相關疾病的藥物中之應用,包含如請求項1-15中任意一項所述之CTLA-4小分子降解劑。
- 如請求項18所述之應用,其中,所述CTLA-4相關疾病包括癌症、自身免疫疾病、免疫缺陷疾病、病毒感染、器官移植排斥。
- 如請求項19所述之應用,其中,所述癌症選自皮膚癌、膀胱癌、乳腺癌、胰腺癌、骨癌、腦癌、神經細胞瘤、食管癌、唇癌、喉癌、下嚥癌、舌癌、唾液腺癌、腺癌、甲狀腺髓樣癌、乳頭狀甲狀腺癌、絨毛膜癌、胰腺癌、泌尿癌、腦腫瘤諸如成膠質細胞瘤、星形細胞瘤、腦膜瘤、成神經管細胞瘤和外周神經外胚層腫瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、成人T細胞白血病淋巴瘤、彌漫性大B細胞淋巴瘤、膽囊癌、支氣管癌、多發性骨髓瘤、基底細胞瘤、畸胎瘤、成視網膜細胞瘤、脈絡膜黑素瘤、精原細胞瘤、橫紋肌肉瘤、顱咽管瘤、骨肉瘤、軟骨肉瘤、肌肉瘤、脂肪肉瘤、纖維肉瘤、尤因肉瘤或漿細胞瘤、乳頭狀瘤、芽狀神經膠質瘤、肉瘤(包括但不限於軟骨肉瘤、組織肉瘤、惡性纖維性組織細胞瘤、淋巴肉瘤以及橫紋肌肉瘤)、黑素瘤、血管瘤、瘢痕瘤、鱗狀細胞癌、星細胞瘤、淋巴瘤、呼吸道癌、頭頸癌(包括但不限於頭癌、頸癌、喉癌、下嚥癌、鼻咽癌和/或口咽癌以及嘴唇和口腔癌)、膀胱癌、乳癌、消化道癌、甲狀腺癌、副甲狀腺癌及其遠距離轉移灶、胰腺癌、 肝癌、白血病、腦癌、生殖器官癌、尿道癌、眼癌、皮膚癌、腎實質癌、腎癌等相關癌症。
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