TWI531568B - 布魯頓氏(bruton's)酪胺酸激酶抑制劑 - Google Patents
布魯頓氏(bruton's)酪胺酸激酶抑制劑 Download PDFInfo
- Publication number
- TWI531568B TWI531568B TW103143354A TW103143354A TWI531568B TW I531568 B TWI531568 B TW I531568B TW 103143354 A TW103143354 A TW 103143354A TW 103143354 A TW103143354 A TW 103143354A TW I531568 B TWI531568 B TW I531568B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- phenoxy
- pyrazol
- amino
- phenyl
- Prior art date
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- 102000001714 Agammaglobulinaemia Tyrosine Kinase Human genes 0.000 title description 12
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- POEKHXLXMDTWCC-UHFFFAOYSA-N [5-amino-1-[4-(2,3-difluorophenoxy)-2-methylphenyl]pyrazol-4-yl]-(4-bromo-1H-indol-2-yl)methanone Chemical compound NC1=C(C=NN1C1=C(C=C(C=C1)OC1=C(C(=CC=C1)F)F)C)C(=O)C=1NC2=CC=CC(=C2C1)Br POEKHXLXMDTWCC-UHFFFAOYSA-N 0.000 claims description 6
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- KXOPUJVHXSJDAQ-UHFFFAOYSA-N [5-amino-1-[4-(2,3-difluorophenoxy)-2-methylphenyl]pyrazol-4-yl]-(4-thiophen-2-yl-1H-indol-2-yl)methanone Chemical compound NC1=C(C=NN1C1=C(C=C(C=C1)OC1=C(C(=CC=C1)F)F)C)C(=O)C=1NC2=CC=CC(=C2C1)C=1SC=CC1 KXOPUJVHXSJDAQ-UHFFFAOYSA-N 0.000 claims description 3
- JLQSKNLWSRKMTA-UHFFFAOYSA-N [5-amino-1-[4-(2,3-difluorophenoxy)-2-methylphenyl]pyrazol-4-yl]-[4-(3-chlorophenyl)-1H-indol-2-yl]methanone Chemical compound NC1=C(C=NN1C1=C(C=C(C=C1)OC1=C(C(=CC=C1)F)F)C)C(=O)C=1NC2=CC=CC(=C2C1)C1=CC(=CC=C1)Cl JLQSKNLWSRKMTA-UHFFFAOYSA-N 0.000 claims description 3
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Description
本發明係關於抑制Btk且適用於治療由異常B細胞活化引起之致癌、自體免疫及發炎疾病之新穎化合物的用途。
蛋白激酶構成人類酶之一個最大家族且藉由向蛋白質中添加磷酸酯基團而調節多個不同信號傳導過程(T.Hunter,Cell 1987 50:823-829)。特定言之,酪胺酸激酶磷酸化酪胺酸殘基之酚系部分上的蛋白質。酪胺酸激酶家族包括控制細胞生長、遷移及分化之成員。異常激酶活性已牽涉於多種人類疾病中,包括癌症、自身免疫及發炎疾病。由於蛋白激酶在細胞信號傳導之關鍵調節因子之中,故其提供由小分子激酶抑制劑調節細胞功能之目標且因此製成良好藥物設計標靶。除治療激酶介導之疾病過程以外,選擇性及有效激酶活性抑制劑亦適用於研究細胞信號傳導過程及鑑別治療關注之其他細胞標靶。
存在良好跡象表明B細胞在自身免疫及/或發炎疾病之發病機制中起重要作用。使B細胞缺失之基於蛋白質之治療劑(諸如Rituxan)有效抵抗自體抗體驅動之發炎疾病,諸如類風濕性關節炎(Rastetter等人Annu Rev Med 200455:477)。因此,在B細胞活化中起作用之蛋白激酶之抑制劑應為用於B細胞介導之疾病病理學,諸如自體抗體產生之有效治療劑。
經過B細胞受體(BCR)之信號傳導控制B細胞反應之範圍,包括增
殖及分化成成熟抗體產生細胞。BCR為B細胞活性之關鍵調節點且異常信號傳導可引起失調B細胞增殖及形成病原性自體抗體,由此產生多種自體免疫及/或發炎疾病。布魯頓氏酪胺酸激酶(Btk)為在BCR的膜近端且緊接下游的非BCR相關激酶。Btk之缺乏已顯示阻斷BCR信號傳導且因此Btk之抑制可為阻斷B細胞介導之疾病過程的有效治療方法。
Btk為酪胺酸激酶之Tec家族成員,且已顯示為早期B細胞發育及成熟B細胞活化及存活之關鍵調節因子(Khan等人Immunity 1995 3:283;Ellmeier等人J.Exp.Med.2000 192:1611)。人類中Btk之突變導致病狀X性聯無γ球蛋白血症(XLA)(回顧於Rosen等人New Eng.J.Med.1995333:431及Lindvall等人Immunol.Rev.2005203:200中)。此等患者為免疫功能不全且顯示減弱之B細胞成熟、減少之免疫球蛋白及周邊B細胞水準、減少之T細胞獨立免疫反應以及在BCR刺激之後減弱的鈣移動。
關於Btk在自體免疫及發炎疾病中之作用的證據亦已由Btk缺乏小鼠模型提供。在全身性紅斑性狼瘡症(SLE)之臨床前鼠類模型中,Btk缺乏小鼠顯示疾病進展之顯著的改善。此外,Btk缺乏小鼠對膠原蛋白誘導之關節炎具有抗性(Jansson及Holmdahl Clin.Exp.Immunol.1993 94:459)。選擇性Btk抑制劑已證實在小鼠關節炎模型中之劑量依賴性功效(Z.Pan等人,Chem.Med Chem.2007 2:58-61)。
Btk亦由除B細胞外可涉及疾病過程之細胞表現。舉例而言,Btk由肥大細胞表現且Btk缺乏骨髓源性肥大細胞展現減弱之抗原誘導去顆粒(Iwaki等人J.Biol.Chem.2005280:40261)。此顯示Btk可適用於治療病理性肥大細胞反應,諸如過敏及哮喘。此外,其中缺乏Btk活性之來自XLA患者之單核細胞顯示在刺激之後減少的TNFα產生(Horwood等人J Exp Med 197:1603,2003)。因此,TNFα介導之發炎
可由小分子Btk抑制劑調節。此外,已報導Btk在細胞凋亡中起作用(Islam及Smith Immunol.Rev.2000 178:49)且因此Btk抑制劑將適用於治療某些B細胞淋巴瘤及白血病(Feldhahn等人J.Exp.Med.2005 201:1837)。
本申請案提供式I之Btk抑制劑化合物、其使用方法,如下文所描述:本申請案提供式I化合物,
其中:R1為H或鹵基;R2為H、鹵基或氰基;R3為R4或R5;R4為鹵基或氰基;R5為苯基、雜芳基、-C(=O)R5'、低碳烷基或苯甲基,視情況經一或多個R5'取代;R5'為低碳烷基、氰基、羥基、雜環烷基、苯基、胺基、烷基胺基、二烷基胺基或低碳烷氧基;及X為低碳烷基或鹵基;或其醫藥學上可接受之鹽。
本申請案提供用於治療發炎及/或自體免疫病狀之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供包含與至少一種醫藥學上可接受之載劑、賦形劑或稀釋劑混合之式I化合物的醫藥組合物。
如本文所用之片語「一(a)」或「一(an)」種實體係指一或多種彼實體;舉例而言,一種化合物係指一或多種化合物或至少一種化合物。因而,術語「一(a)」(或「一(an)」)、「一或多種」及「至少一種」在本文中可互換使用。
片語「如上文所定義」係指如發明內容或最廣泛申請專利範圍所提供之每一基團的最廣泛定義。在下文提供之所有其他實施例中,可存在於每一實施例中且未明確定義之取代基保留發明內容中所提供之最廣泛定義。
如本說明書中所用,不論在過渡片語中或在申請專利範圍之主體中,術語「包含(comprise(s))」及「包含(comprising)」應解釋為具有開放式含義。亦即,該等術語應解釋為與片語「至少具有」或「至少包括」同義。當用於製程之情形下時,術語「包含」意謂該製程至少包括所述步驟,但可包括其他步驟。當用於化合物或組合物之情形下時,術語「包含」意謂該化合物或組合物至少包括所述特徵或組分,但亦可包括其他特徵或組分。
如本文所用,除非另外特定地指示,否則字語「或」以「及/或」之「包括」含義使用,而非以「或/或(either/or)」之「獨佔式」含義使用。
術語「獨立地」在本文中用於指示變數應用於任一情況中,而不考慮相同化合物內存在或不存在具有相同或不同定義之變數。因
此,在其中R"出現兩次且定義為「獨立地為碳或氮」之化合物中,兩個R"可為碳,兩個R"可為氮,或一個R"可為碳且另一R"可為氮。
在描繪及描述在本發明中所採用或主張之化合物之任一部分或式中,當任一變數出現一次以上時,其在每次出現時之定義獨立於其在每一另一次出現時之定義。此外,取代基及/或變數之組合僅當該等化合物產生穩定化合物時才容許。
在一鍵末端之符號「*」或經一鍵繪製之「------」各指官能基或其他化學部分與其為一部分之分子之剩餘部分的連接點。因此,例如:MeC(=O)OR4,其中或。
繪製至環系統中之一鍵(與在不同頂點處連接相反)指示該鍵可連接至任何適合之環原子。
如本文所用之術語「視情況選用之」或「視情況」意謂隨後描述之事件或情況可發生但無需發生,且該描述包括其中該事件或狀況發生之情形及其中其不發生之情形。舉例而言,「視情況經取代」意謂視情況經取代之部分可併入氫原子或取代基。
片語「視情況選用之鍵」意謂該鍵可存在或可不存在,且該描述包括單鍵、雙鍵或參鍵。若取代基經指定為「鍵」或「不存在」,則連接至取代基之原子直接連接。
術語「約」在本文中用以意謂大約、在範圍內、大致或左右。當術語「約」結合數值範圍使用時,其藉由使界限擴展至所闡述數值上方及下方來修改彼範圍。一般而言,術語「約」在本文中用於修改數值至陳述值上方及下方20%的偏差。
某些式I化合物可呈現互變異構。互變異構化合物可以兩種或兩種以上可轉化物質之形式存在。質子轉移互變異構體由共價鍵結之氫原子在兩個原子之間遷移產生。互變異構體一般以平衡狀態存在且分
離個別互變異構體之嘗試通常產生化學及物理特性與化合物之混合物一致的混合物。平衡位置取決於在分子內之化學特徵。舉例而言,在多種脂族醛及酮,諸如乙醛中,酮形式佔優勢;而在酚中,烯醇形式佔優勢。某些質子轉移互變異構體包括酮/烯醇(-C(=O)-CH--C(-OH)=CH-)、醯胺/醯亞胺酸(-C(=O)-NH--C(-OH)=N-)及脒(-C(=NR)-NH--C(-NHR)=N-)互變異構體。後兩者在雜芳基及雜環中尤其常見且本發明包含該等化合物之所有互變異構體形式。
除非另外定義,否則本文所使用之技術及科學術語具有熟習本發明所屬領域之技術者通常所理解之含義。本文中參考熟習此項技術者已知之各種方法及材料。闡述藥理學之一般原理之標準參考著作包括Goodman及Gilman之The Pharmacological Basis of Therapeutics,第10版,McGraw Hill Companies Inc.,New York(2001)。熟習此項技術者已知之任何適合之材料及/或方法均可用於進行本發明。然而,描述較佳材料及方法。除非另外說明,否則以下描述及實例中提及之材料、試劑及其類似物可獲自商業來源。
本文所述之定義可隨附以形成化學相關組合,諸如「雜烷基芳基」、「鹵烷基雜芳基」、「芳基烷基雜環基」、「烷基羰基」、「烷氧基烷基」及其類似組合。當術語「烷基」用作另一術語之後的字尾時,如在「苯基烷基」或「羥基烷基」中,此意欲指如上文所定義之烷基,經選自另一特定命名之基團的1至2個取代基取代。因此,例如「苯基烷基」係指具有1至2個苯基取代基之烷基,且因此包括苯甲基、苯乙基及聯苯基。「烷基胺基烷基」為具有1至2個烷基胺基取代基之烷基。「羥基烷基」包括2-羥基乙基、2-羥基丙基、1-(羥基甲基)-2-甲基丙基、2-羥基丁基、2,3-二羥基丁基、2-(羥基甲基)、3-羥基丙基等。因此,如本文所用,術語「羥基烷基」用於定義下文所定義之雜烷基之子集。術語-(芳)烷基係指未經取代之烷基或芳烷基。術語(雜)芳基
((hetero)aryl)或(雜)芳基((het)aryl)係指芳基或雜芳基。
如本文所用之術語「螺環烷基」意謂螺環環烷基,諸如螺[3.3]庚烷。如本文所用之術語螺雜環烷基意謂螺環雜環烷基,諸如2,6-二氮雜螺[3.3]庚烷。
如本文所用之術語「醯基」指示式-C(=O)R之基團,其中R為氫或如本文所定義之低碳烷基。如本文所用之術語「烷基羰基」指示式C(=O)R之基團,其中R為如本文所定義之烷基。術語C1-6醯基係指基團-C(=O)R含有6個碳原子。如本文所用之術語「芳基羰基」意謂式C(=O)R之基團,其中R為芳基;如本文所用之術語「苯甲醯基」意謂「芳基羰基」,其中R為苯基。
如本文所用之術語「酯」指示式-C(=O)OR之基團,其中R為如本文所定義之低碳烷基。
如本文所用之術語「烷基」指示含有1至10個碳原子之未分支或分支鏈、飽和、單價烴殘基。術語「低碳烷基」指示含有1至6個碳原子之直鏈或分支鏈烴殘基。如本文所用之「C1-10烷基」係指由1至10個碳構成之烷基。烷基之實例包括(但不限於)低碳烷基,包括甲基、乙基、丙基、異丙基、正丁基、異丁基、第三丁基或戊基、異戊基、新戊基、己基、庚基及辛基。
當術語「烷基」用作另一術語之後的字尾時,如在「苯基烷基」或「羥基烷基」中,此意欲指如上文所定義之烷基,經選自另一特定命名之基團之1至2個取代基取代。因此,例如「苯基烷基」指示基團R'R"-,其中R'為苯基,且R"為如本文所定義之伸烷基,應理解苯基烷基部分之連接點將在伸烷基上。芳基烷基之實例包括(但不限於)苯甲基、苯基乙基、3-苯基丙基。術語「芳基烷基」或「芳烷基」類似地解釋,除了R'為芳基。術語「(雜)芳基烷基」或「(雜)芳烷基」類似地解釋,除了R'視情況為芳基或雜芳基。
術語「鹵烷基」或「鹵基-低碳烷基」或「低碳鹵烷基」係指含有1至6個碳原子之直鏈或分支鏈烴殘基,其中一或多個碳原子經一或多個鹵素原子取代。
除非另外指示,否則如本文所用之術語「伸烷基」或「伸烯基」指示1至10個碳原子之二價飽和直鏈烴基(例如(CH2)n)或2至10個碳原子之分支鏈飽和二價烴基(例如-CHMe-或-CH2CH(i-Pr)CH2-)。除了在亞甲基之情況下,伸烷基之開放價態未連接至同一原子。伸烷基之實例包括(但不限於)亞甲基、伸乙基、伸丙基、2-甲基-伸丙基、1,1-二甲基-伸乙基、伸丁基、2-乙基伸丁基。
如本文所用之術語「烷氧基」意謂-O-烷基,其中烷基如上文所定義,諸如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第三丁氧基、戊氧基、己氧基,包括其異構體。如本文所用之「低碳烷氧基」指示具有如先前所定義之「低碳烷基」的烷氧基。如本文所用之「C1-10烷氧基」係指-O-烷基,其中烷基為C1-10。
術語「PCy3」係指經三個環狀部分三取代之膦。
術語「鹵烷氧基」或「鹵基-低碳烷氧基」或「低碳鹵烷氧基」係指低碳烷氧基,其中一或多個碳原子經一或多個鹵素原子取代。
如本文所用之術語「羥基烷基」指示如本文所定義之烷基,其中在不同碳原子上之1至3個氫原子經羥基置換。
如本文所用之術語「烷基磺醯基」及「芳基磺醯基」係指式-S(=O)2R之基團,其中R分別為烷基或芳基且烷基及芳基如本文所定義。如本文所用之術語「雜烷基磺醯基」在本文中指示式-S(=O)2R之基團,其中R為如本文所定義之「雜烷基」。
如本文所用之術語「烷基磺醯胺基」及「芳基磺醯胺基」係指式-NR'S(=O)2R之基團,其中R分別為烷基或芳基,R'為氫或C1-3烷基且烷基及芳基如本文所定義。
如本文所用之術語「環烷基」係指含有3至8個碳原子之飽和碳環,亦即環丙基、環丁基、環戊基、環己基、環庚基或環辛基。如本文所用之「C3-7環烷基」係指碳環由3至7個碳構成之環烷基。
如本文所用之術語羧基-烷基係指烷基部分,其中一個氫原子已經羧基置換,應理解該雜烷基之連接點係經過碳原子。術語「羧基(carboxy)」或「羧基(carboxyl)」係指-CO2H部分。
如本文所用之術語「雜芳基」或「雜芳族」意謂具有至少一個芳族或部分不飽和環之5至12個環原子之單環或雙環基團,每個環含有4至8個原子,併有一或多個N、O或S雜原子,剩餘環原子為碳,應理解該雜芳基之連接點將在芳族或部分不飽和環上。熟習此項技術者應熟知,雜芳基環與其全碳相對部分相比具有較低程度之芳族特徵。因此,出於本發明之目的,雜芳基僅需要具有一些程度之芳族特徵。雜芳基部分之實例包括具有5至6個環原子及1至3個雜原子之單環芳族雜環,包括(但不限於)吡啶基、嘧啶基、吡嗪基、噁嗪基、吡咯基、吡唑基、咪唑基、噁唑基、4,5-二氫-噁唑基、5,6-二氫-4H-[1,3]噁唑基、異噁唑、噻唑、異噻唑、***啉、噻二唑及噁二唑啉(oxadiaxoline),其可視情況經一或多個、較佳地1或2個選自羥基、氰基、烷基、烷氧基、硫基、低碳鹵烷氧基、烷硫基、鹵基、低碳鹵烷基、烷基亞磺醯基、烷基磺醯基、鹵素、胺基、烷基胺基、二烷基胺基、胺基烷基、烷基胺基烷基及二烷基胺基烷基、硝基、烷氧羰基及胺甲醯基、烷基胺甲醯基、二烷基胺甲醯基、芳基胺甲醯基、烷基羰基胺基及芳基羰基胺基之取代基取代。雙環部分之實例包括(但不限於)喹啉基、異喹啉基、苯并呋喃基、苯并噻吩基、苯并噁唑、苯并異噁唑、苯并噻唑、啶基、5,6,7,8-四氫-[1,6]啶基及苯并異噻唑。雙環部分可視情況在任一環上經取代,然而連接點在含有雜原子之環上。
除非另外指示,否則如本文所用之術語「雜環基」、「雜環烷基」或「雜環」指示單價飽和環狀基團,由一或多個環、較佳地1至2個環組成,包括螺環系統,每個環具有3至8個原子,併有一或多個環雜原子(選自N、O或S(O)0-2),且其可視情況獨立地經一或多個、較佳地1或2個選自羥基、側氧基、氰基、低碳烷基、低碳烷氧基、低碳鹵烷氧基、烷硫基、鹵基、低碳鹵烷基、羥基烷基、硝基、烷氧羰基、胺基、烷基胺基、烷基磺醯基、芳基磺醯基、烷基胺基磺醯基、芳基胺基磺醯基、烷基磺醯胺基、芳基磺醯胺基、烷基胺基羰基、芳基胺基羰基、烷基羰基胺基、芳基羰基胺基及其離子形式之取代基取代。雜環基團之實例包括(但不限於)嗎啉基、哌嗪基、哌啶基、氮雜環丁烷基、吡咯啶基、六氫氮呯基、氧雜環丁烷基、四氫呋喃基、四氫噻吩基、噁唑啶基、噻唑啶基、異噁唑啶基、四氫哌喃基、硫代嗎啉基、啶基及咪唑啉基及其離子形式。實例亦可為雙環,諸如3,8-二氮雜-雙環[3.2.1]辛烷、2,5-二氮雜-雙環[2.2.2]辛烷或八氫-吡嗪并[2,1-c][1,4]噁嗪。
本申請案提供式I化合物,
其中:R1為H或鹵基;R2為H、鹵基或氰基;R3為R4或R5;
R4為鹵基或氰基;R5為苯基、雜芳基、-C(=O)R5'、低碳烷基或苯甲基,視情況經一或多個R5'取代;R5'為低碳烷基、氰基、羥基、雜環烷基、苯基、胺基、烷基胺基、二烷基胺基或低碳烷氧基;及X為低碳烷基或鹵基;或其醫藥學上可接受之鹽。
本申請案提供式I化合物,其中X為甲基。
本申請案提供式I化合物,其中X為鹵基。
本申請案提供式I化合物,其中X為甲基且R5為雜芳基,視情況經一或多個R5'取代。
本申請案提供式I化合物,其中R5為噻吩基,視情況經一或多個R5'取代。
本申請案提供式I化合物,其中R5為吡啶基,視情況經一或多個R5'取代。
本申請案提供任何以上式I化合物,其中R1為F且R2為F。
本申請案或者提供任何以上式I化合物,其中R1為H且R2為氰基。
本申請案提供式I化合物,其中R5為-C(=O)R5'。
本申請案提供式I化合物,其中R5'為嗎啉基、哌啶基、低碳烷基哌啶基或低碳烷氧基。
本申請案提供式I化合物,其中R1為F且R2為F。
本申請案提供式I化合物,其中R1為H且R2為氰基。
本申請案提供式I化合物,其中R5為苯基或苯甲基,視情況經一或多個R5'取代。
本申請案提供式I化合物,其中R5為低碳伸烷基,視情況經一或
多個R5'取代。
本申請案提供以上式I化合物中之任一者,其中R1為F且R2為F。
本申請案或者提供以上式I化合物中之任一者,其中R1為H且R2為氰基。
本申請案提供式I化合物,選自由以下組成之群:{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-苯基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-噻吩-3-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-吡唑-1-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-噻吩-2-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(嗎啉-4-羰基)-1H-吲哚-2-基]-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(1-甲基-1H-吡唑-4-基)-1H-吲哚-2-基]-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-吡啶-2-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-苯甲基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(1H-吡唑-4-基)-1H-吲哚-2-基]-甲酮;3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰
基}-1H-吲哚-4-基)-苯甲腈;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(3-氯-苯基)-1H-吲哚-2-基]-甲酮;3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-基甲基)-苯甲腈;3-(4-{5-胺基-4-[4-(1H-吡唑-4-基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;3-(4-{5-胺基-4-[4-(嗎啉-4-羰基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;3-(4-{5-胺基-4-[4-(4-甲基-哌嗪-1-羰基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;3-(4-{5-胺基-4-[4-(3-甲氧基-苯甲基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-甲酸甲酯;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-嗎啉-4-基甲基-1H-吲哚-2-基)-甲酮;3-{4-[5-胺基-4-(4-氰基甲基-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈;及2-{5-胺基-1-[4-(3-氰基-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-甲酸甲基醯胺。
本申請案提供一種用於治療發炎及/或自體免疫病狀之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供一種用於治療類風濕性關節炎之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供一種用於治療哮喘之方法,其包含向有需要之患
者投與治療有效量之式I化合物。
本申請案提供一種用於治療癌症之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供包含式I化合物之醫藥組合物。
本申請案提供包含與至少一種醫藥學上可接受之載劑、賦形劑或稀釋劑混合之式I化合物之醫藥組合物。
本申請案提供式I化合物作為治療活性物質的用途。
本申請案提供式I化合物用於製造用於治療發炎病症之藥劑的用途。
本申請案提供式I化合物用於製造用於治療自體免疫病症之藥劑的用途。
本申請案提供式I化合物用於製造用於治療類風濕性關節炎之藥劑的用途。
本申請案提供式I化合物用於製造用於治療哮喘之藥劑的用途。
本申請案提供如上文所述之化合物用於治療發炎及/或自體免疫病狀的用途。
本申請案提供如上文所述之化合物用於治療類風濕性關節炎的用途。
本申請案提供如上文所述之化合物用於治療哮喘的用途。
本申請案提供如上文所述之化合物用於治療發炎及/或自體免疫病狀的用途。
本申請案提供如上文所述之化合物用於治療類風濕性關節炎的用途。
本申請案提供如上文所述之化合物用於治療哮喘的用途。
本申請案提供用於治療發炎及/或自體免疫病狀之如上文所述之化合物。
本申請案提供用於治療類風濕性關節炎之如上文所述之化合物。
本申請案提供用於治療哮喘之如上文所述之化合物。
本申請案提供如本文所述之化合物、方法或組合物。
下表中提供由本發明包涵且在本發明之範圍內的代表性化合物之實例。提供下文之此等實例及製備以使得熟習此項技術者能更清楚地理解且實施本發明。其不應被視為限制本發明之範疇,而僅為本發明之說明及代表。
一般而言,用於本申請案之命名法係基於AUTONOMTM v.4.0,一種用於產生IUPAC系統命名之Beilstein Institute電腦化系統。若在所描繪之結構與給出彼結構之名稱之間存在不一致,則所描繪之結構應佔更高權重。此外,若結構或結構之一部分之立體化學未用例如粗體或虛線指示,則該結構或該結構之部分應解釋為包涵其所有立體異構體。
表I描繪根據通式I之化合物之實例:
本發明化合物可藉由任何習知方式製備。用於合成此等化合物之適合之製程提供於實例中。一般而言,本發明化合物可根據以下流程製備。
式11化合物(其中R1及R2如上文在式I之種類中所述)可使用流程1中所概述之途徑製備。根據此程序,市售之式1化合物4-溴吲哚可轉化成式2之苯基磺醯胺。用強鹼及二氧化碳處理會提供羧酸3,其經由酸氯化物4轉化成甲酯5。酯5可接著與源於乙腈之陰離子反應以生成式6之氰基乙醯基衍生物。與二甲基甲醯胺二甲基縮醛之反應提供丙烯腈衍生物7,且此衍生物與式8之苯肼衍生物反應以生成式9之胺基
吡唑。R2基團可接著使用過渡金屬催化之偶合反應或如下文所概述之親核芳族取代反應***,以生成式10化合物。苯基磺醯基保護基之移除隨後提供式11之本發明化合物。
4-溴吲哚(式1化合物)宜用諸如氫化鈉之鹼在諸如四氫呋喃之惰性溶劑中在約0℃溫度下處理以生成相應陰離子。此可用苯磺醯氯處理且混合物在室溫下攪拌約1小時以生成式2之苯磺醯胺衍生物。
式2化合物可接著用正丁基鋰在四氫呋喃中在低溫下,諸如在約-78℃下處理,且相應陰離子用過量固體二氧化碳處理以生成式3之羧酸。
式3之羧酸轉化為式5之甲酯可使用一般熟習有機合成技術者所熟知之多種方法之一來實現。多種適合之方法列舉於Greene's Protective Groups in Organic Synthesis[Wuts,P.G.M及Greene,T.W.,第4版,Wiley-Interscience,New York,2006,553頁及以下各頁]中。舉例而言,該轉化宜藉由用氯化劑(諸如亞硫醯二氯)純淨地或在諸如苯之惰性溶劑中在約50℃與約回流溫度之間之溫度下處理式3之羧酸來進行。所得式4之酸氯化物可隨後用甲醇在諸如三乙胺或二異丙基乙胺或吡啶之鹼存在下使用甲醇作為溶劑或在諸如四氫呋喃之惰性溶劑中在約室溫下處理。
用於製備式5化合物之特定條件可發現於該文獻中,發現於Mahboobi,S.等人J.Med.Chem. 2006,49,3101-3115中。
式5化合物宜藉由用乙腈與諸如二異丙基胺基鋰或雙(三甲基矽烷)胺基鋰之強鹼的混合物在諸如四氫呋喃之溶劑中在低溫下,諸如在約-78℃下處理而轉化為式6之氰基乙醯基衍生物。用於此類反應之條件見於專利文獻中,例如於Taka,N.等人US 20120208811第163頁中。
式6化合物可藉由用N,N-二甲基甲醯胺二甲基縮醛在諸如芳族烴
(例如甲苯)或四氫呋喃之惰性溶劑中在約室溫下處理而轉化為式7之丙烯腈衍生物。用於此類反應之條件可發現於專利文獻中,例如發現於Taka,N.等人US 20120208811第132頁中。
式7之丙烯腈衍生物可藉由用式8之中間物(其中R1如上文在式I之種類中所述)在諸如甲醇或乙醇或異丙醇之醇溶劑中在該溶劑之約回流溫度下處理而轉化為式9之胺基吡唑衍生物。用於此類反應之條件可發現於專利文獻中,例如發現於Taka,N.等人US 20120208811第94頁中。
式9化合物與式R 2 -X化合物(其中X代表酸、酸酯、三氟硼酸鉀、三甲基錫或三正丁基錫)反應生成式10化合物可使用一般熟習此項技術者所熟知之鈴木(Suzuki)或Stille或Negishi偶合條件來實現。舉例而言,在鈴木反應中,反應宜藉由使式9化合物與式R 2 -B(OH) 2 化合物在諸如極性非質子溶劑(例如N,N-二甲基甲醯胺)或醚(例如二噁烷)或水之便利惰性溶劑中或實際上在此類溶劑的混合物中,在催化量之鈀(0)前驅體(例如乙酸鈀(II)或氯化雙(三苯膦)鈀(II))存在下,在催化量之膦配位體(例如三鄰甲苯基膦或三第三丁基膦)之視情況額外存在下或者在鈀(0)與膦配位體之預成型錯合物(諸如雙(三環己基膦)鈀、肆(三苯膦)-鈀(0)或[1,1-雙(二苯膦基)二茂鐵]二氯鈀(II))存在下,且亦在例如鹼金屬碳酸鹽、碳酸氫鹽或磷酸鹽(例如磷酸鉀或碳酸鈉)之無機鹼存在下在約室溫與約100度之間且較佳地在約室溫與約50度之間的溫度下反應來進行。鈴木反應為一般熟習有機合成技術者所熟習,且已回顧數次,尤其在Miyaura,N.;Suzuki,A.Chem.Rev. 1995,95,2457-2483中且最近在Alonso,F.;Beletskaya,I.P.;Yus,M.Tetrahedron 2008,64,3047-3101中。適用於鈴木偶合之特定條件之實例可發現於該文獻中之多個參考文獻中,包括:Tiede,S.等人Angew.Chem.Intl.Edn. 2010,49,3972-3975;Schmidt,A.及Rahimi,A.Chem.Commun. 2010,46,2995-2997;Lee,S.H.等人US 20100063281;及Tobisu,M.等人J.Org.Chem. 2010,75,4835-4840(支持資訊)。Stille偶合為一般熟習有機合成技術者所熟知,且可用作鈴木偶合之替代,針對該偶合之條件之實例已提供於上文。Stille偶合已經回顧,包括於Farina,V.等人Org.Reactions 1997,50,1-652中。已用於Stille偶合之特定條件之實例可發現於該文獻中,例如發現於Littke,A.F.等人J.Am.Chem.Soc. 2002,124,5343-6348中;發現於Alberati-Giani,D.等人US 7,462,617中;及發現於Robl,J.A.US 5,072,023中。舉例而言,反應可藉由用式R 2 -SnA 3 化合物(其中A表示低碳烷基,諸如甲基或正丁基)於諸如極性非質子溶劑(例如N,N-二甲基甲醯胺)或芳族烴(例如甲苯)或乙腈或二甲氧基乙烷之便利惰性溶劑中,在催化量之鈀催化劑(諸如肆(三苯膦)鈀(0)或氯化雙(三苯膦)鈀(II)或雙(乙酸根)雙(三苯膦)鈀(0)或參(二亞苄基丙酮)二鈀(0))存在下在約80℃與約180℃之間的溫度下處理式9化合物來進行。
式10化合物(其中R2代表具有連接至吲哚環之羰基碳的羧醯胺或酯官能基)宜使用過渡金屬催化之羰化偶合反應製備。根據此製程,式9化合物與胺(以生成羧醯胺產物)或低級醇(以生成羧酸酯產物)一起在一氧化碳氣體及催化量之鈀催化劑(諸如肆(三苯膦)鈀(0))或鈀催化劑(諸如二氯化雙(苯甲腈)鈀(II))與配位體(諸如1,1'-雙(二苯基膦基)二茂鐵)之組合存在下於諸如四氫呋喃或甲苯之溶劑中於密封管中在約80℃與約100℃之間的溫度下加熱。可用於此類反應之特定條件之實例可發現於該文獻中,例如發現於Kumar,K.等人Org.Letters 2004,6,7-10中。
式10化合物(其中R2表示芳烷基,諸如苯甲基或經取代苯甲基)宜使用過渡金屬催化之偶合反應,諸如Negishi反應製備。根據此製程,式9化合物與芳烷基鋅試劑一起在催化量之具有配位體(諸如2-二
環己基膦基-2',6'-二甲氧基聯苯(S-Phos)之鈀催化劑(諸如乙酸鈀(II))存在下或使用肆(三苯膦)-鈀(0)於諸如四氫呋喃或甲苯之溶劑中在約50℃與約90℃之間的溫度下加熱。可用於此類反應之特定條件之實例可發現於該文獻中,例如發現於Ellsworth,B.A.等人US 20110082165第51頁中。
式10化合物(其中R2表示氰基甲基)宜使用過渡金屬催化之與三丁基錫烷基-乙腈或氰基乙酸低碳烷基酯之偶合反應製備。與三丁基錫烷基-乙腈之反應可藉由用三丁基錫烷基-乙腈在鈀催化劑(諸如二氯化雙(三苯基膦基)鈀(II)或二氯化雙(三鄰甲苯基膦)鈀(II))存在下於甲苯或二甲苯中在約110℃與約130℃之間之溫度下處理式9化合物來進行。用於此類反應之條件可發現於該文獻中,例如發現於Ettaoussi,M.等人Eur.J.Med.Chem. 2012,49,310-323中及發現於Song,D.等人WO 2011117211第118頁中。與氰基乙酸低碳烷基酯之反應可藉由用氰基乙酸低碳烷基酯在鈀催化劑(諸如雙(三-第三丁基膦)鈀(0))或鈀催化劑(諸如參-(二亞苄基丙酮)二鈀(0)或雙(二亞苄基丙酮)鈀(0))及配位體(諸如第三丁基膦)及鹼(諸如磷酸三鈉)的混合物存在下於諸如甲苯之溶劑中於密封管中在約70℃與約100℃之間的溫度下處理式9化合物來進行。在氰基乙酸低碳烷基酯為氰基乙酸第三丁酯之情況下,第三丁基可在反應條件下經歷去羧反應以生成所需式10化合物(其中R2代表氰基甲基)。在氰基乙酸低碳烷基酯為氰基乙酸甲酯或氰基乙酸乙酯之情況下,需要額外水解步驟且此步驟宜藉由在約70℃下加熱鈀催化的與含3M鹽酸之二甲亞碸之偶合之產物持續數小時來影響。可用於此類反應之條件之實例可發現於該文獻中,例如發現於Alargova,R.G等人US 20120015999第10頁中。
式10化合物轉化為式11之本發明化合物可使用任何習知程序實現。舉例而言,該反應可藉由用鹼(諸如碳酸銫)及低級醇(諸如甲醇)
的混合物於諸如四氫呋喃之溶劑中在約室溫與該混合物之約回流溫度之間的溫度下處理式10化合物來進行。可用於此類反應之條件之實例可發現於該文獻中,例如發現於Zhang,B及Wee.A.G.H.Org.Biomol.Chem. 2012,10,4597-4608補充資訊中;發現於Alam,M.等人US 20110071150第54頁中;及發現於Taka,N.等人US 20120208811第55頁中。
一般熟習有機合成技術者應顯而易知,如流程2中所概述,若自式9化合物而非自式10化合物移除保護基,則亦可容易獲得多種式11化合物。
根據此製程,脫除保護基反應可藉由用鹼(諸如碳酸銫)及低級醇(諸如甲醇)的混合物於諸如四氫呋喃之溶劑中在約室溫與該混合物之約回流溫度之間的溫度下處理式9化合物來進行。可用於此類反應之條件之實例可發現於該文獻中,例如發現於Zhang,B及Wee.A.G.H.Org.Biomol.Chem. 2012,10,4597-4608補充資訊中;發現於Alam,M.等人US 20110071150第54頁中;及發現於Taka,N.等人US 20120208811第55頁中。
所得式12化合物可隨後用式R 2 -B(OH) 2 化合物在上文針對式9化合物之鈴木反應所述的條件下處理以生成所需式11化合物。
式11化合物(其中R2表示N連接之雜環,諸如吡唑-1-基)亦宜使用流程2製備。根據此製程,式12化合物用N連接之雜環(諸如吡唑)在鹼(諸如碳酸鉀)存在下,在銅催化劑(諸如碘化銅(I))存在下且在L-脯胺酸存在下,於諸如二甲亞碸之惰性溶劑中在約100℃與約130℃之間的溫度下處理。可用於此類反應之條件之實例可發現於該文獻中,例如發現於Sun,X.等人Bioorg.Med.Chem.Lett. 2011,21,3671-3675補充資訊中;及發現於Yokotani,J.等人US 20110275797第31頁中。
式21化合物(其中R3代表二級胺基,諸如二烷基胺基(例如二甲基胺基或二乙基胺基)或環狀二級胺基,諸如N-吡咯啶基、N-哌啶基、嗎啉-4-基、1-甲基-哌嗪-4-基或其類似基團)可使用流程3中所概述之製程製備。根據此製程,1-苯磺醯基-1H-吲哚-4-甲醇,即式13化合物(其為已知化合物,可根據Castro Pineiro,J.L.等人US 6187805第15欄中概述之程序或使用以下實例中所述之程序製備)轉化為式14之相應氯甲基吲哚衍生物。此衍生物用胺進行取代反應以生成式15化合物。一系列羧化、酯化及與乙腈之陰離子反應,隨後生成式18之氰基乙醯基衍生物。與二甲基甲醯胺二甲基縮醛反應,生成式19之丙烯腈衍生物,該衍生物與式8之芳基肼進行反應以生成式20之胺基吡唑衍生物。移除苯基磺醯基保護基,隨後生成式21之本發明化合物。
式13化合物可用甲烷磺醯氯在鹼(諸如三乙胺或二異丙基乙胺)存在下於諸如四氫呋喃之溶劑中在約室溫之溫度下處理以生成式14化合物。
式14化合物可用二級胺,諸如二烷基胺(例如二甲胺鹽酸鹽或二乙胺),或環狀二級胺基,諸如吡咯啶、哌啶、嗎啉或1-甲基-哌嗪,在無機鹼(諸如碳酸鉀或碳酸銫)存在下於諸如乙腈之惰性溶劑中在約50℃與約80℃之間的溫度下處理以生成式15之胺。
式15化合物可隨後用強鹼(諸如二異丙基胺基鋰或雙(三甲基矽烷)胺基鋰)於四氫呋喃中在低溫下,諸如在約-78℃下處理,且相應陰離子用過量固體二氧化碳處理以生成式16之羧酸。
式16之羧酸轉化為式17之甲酯可使用一般熟習有機合成技術者
所熟知之多種方法之一來實現。多種適合之方法列舉於Greene's Protective Groups in Organic Synthesis[Wuts,P.G.M及Greene,T.W.,第4版,Wiley-Interscience,New York,2006,553頁及以後各頁]中。舉例而言,該轉化宜藉由用氯化劑(諸如亞硫醯二氯)純淨地或於諸如苯之惰性溶劑中在約50℃與約回流溫度之間的溫度下處理式16之羧酸來進行。所得酸氯化物可隨後用甲醇在鹼(諸如三乙胺或二異丙基乙胺或吡啶)存在下使用甲醇作為溶劑或於諸如四氫呋喃之惰性溶劑中在約室溫下處理以生成式17之酯。
式17化合物宜藉由用乙腈及強鹼(諸如二異丙基胺基鋰或雙(三甲基矽烷)胺基鋰)的混合物於諸如四氫呋喃之溶劑中在低溫下,諸如在約-78℃下處理而轉化為式18之氰基乙醯基衍生物。用於此類反應之條件可發現於專利文獻中,例如發現於Taka,N.等人US 20120208811第163頁中。
式18化合物可藉由用N,N-二甲基甲醯胺二甲基縮醛於諸如芳族烴(例如甲苯)或四氫呋喃之惰性溶劑中在約室溫下處理而轉化為式19之丙烯腈衍生物。用於此類反應之條件可發現於專利文獻中,例如發現於Taka,N.等人US 20120208811第163頁中。
式19之丙烯腈衍生物可藉由用式8之中間物(其中R1如上文在式I之種類中所述)在諸如甲醇或乙醇或異丙醇之醇溶劑中在該溶劑之約回流溫度下處理而轉化為式20之胺基吡唑衍生物。用於此類反應之條件可發現於專利文獻中,例如發現於Taka,N.等人US 20120208811第94頁中。
式20化合物轉化為式21之本發明化合物可使用任何習知程序實現。舉例而言,該反應可藉由用鹼(諸如碳酸銫)及低級醇(諸如甲醇)的混合物於諸如四氫呋喃之溶劑中在約室溫與該混合物之約回流溫度之間的溫度下處理式20化合物來進行。可用於此類反應之條件之實例
可發現於該文獻中,例如發現於Zhang,B及Wee.A.G.H.Org.Biomol.Chem. 2012,10,4597-4608補充資訊中;發現於Alam,M.等人US 20110071150第54頁中;及發現於Taka,N.等人US 20120208811第55頁中。
式8之中間物(其中R1如上文於式I之種類中所述)可根據流程4製備。式22化合物4-氯-2-甲基-1-硝基-苯與式23之酚衍生物進行親核芳族取代反應以生成式24化合物。還原式24化合物中之硝基,接著重氮化及還原,生成式8之芳基-肼衍生物。
4-氯-2-甲基-1-硝基-苯(22)可用式23之酚在鹼(諸如碳酸鉀或碳酸銫)存在下於諸如二甲基甲醯胺之惰性溶劑中在約100℃與約150℃之間的溫度下,視情況在微波照射下處理,以生成式24之硝基化合物。可用於此類反應之特定條件之實例可發現於該文獻中,例如發現於Chee,G.-L等人US 20040266738第5頁中;及發現於Cui,S.-L.等人Synlett 2004,1829-1831中。
還原式24化合物中之硝基可使用一般熟習有機合成技術者所熟知之多種程序來實現。此等程序中之多種概述於Larock,R.C.Comprehensive Organic Transformations John Wiley & Sons Inc.NY 1999,第823頁及以後各頁中。一種便利方法係用氫氣在貴金屬催化
劑(諸如鈀/碳)存在下於諸如醇(例如甲醇或乙醇)之溶劑中在約一個大氣壓之氫氣與約三個大氣壓之氫氣之間的壓力下在約室溫下處理式24化合物。可用於此類反應之特定條件之實例可發現於該文獻中,例如發現於Chee,G.-L等人US 20040266738第5頁中;及發現於Schoenafinger,K.等人US 20030236288第18頁中。
式25化合物中之苯胺基團之重氮化及還原可使用任何習知程序進行。舉例而言,反應宜藉由用含亞硝酸鈉之水溶液在無機酸(諸如鹽酸)存在下在低於約5℃且較佳地低於約0℃之溫度下處理式25化合物,接著在約相同溫度下添加還原劑(諸如氯化錫(II)或連二亞硫酸鈉)來進行。可用於此類反應之特定條件之實例可發現於該文獻中,例如發現於Wipf,P.及Qiming,J.WO 2012078859第47頁中;發現於Rewolinski,M.V.等人WO 2009055721第82頁中;及發現於Schoenafinger,K.等人US 20030236288第18頁中。
本發明化合物可在各種經口投與劑型及載劑中調配。經口投與可呈錠劑、包覆包衣之錠劑、糖衣藥丸、硬及軟明膠膠囊、溶液、乳液、糖漿或懸浮液之形式。在其他投與途徑中,當藉由包括連續(靜脈內滴液)表面非經腸、肌肉內、靜脈內、皮下、經皮(其可包括穿透增強劑)、經頰、經鼻、吸入及栓劑投與之其他投與途徑投與時,本發明化合物為有效的。較佳投與方式一般為使用便利每日給藥方案經口投與,該給藥方案可根據病痛之程度及患者對活性成分的反應來調節。
本發明化合物以及其醫藥學上可使用的鹽連同一或多種習知賦形劑、載劑或稀釋劑可置於醫藥組合物及單元劑量之形式中。醫藥組合物及單位劑型可以習知比例包含習知成分,具有或不具有額外活性化合物或原理,且單位劑型可含有與欲採用之預期每日劑量範圍相稱
的任何適合有效量之活性成分。醫藥組合物可用作固體(諸如錠劑或填充膠囊)、半固體、散劑、持續釋放調配物,或液體(諸如溶液、懸浮液、乳劑、酏劑),或用於經口使用之填充膠囊;或呈用於經直腸或經***投與之栓劑形式;或呈用於非經腸使用之無菌可注射溶液形式。典型製劑將含有約5%至約95%活性化合物(w/w)。術語「製劑」或「劑型」意欲包括活性化合物之固體及液體調配物且熟習此項技術者應理解活性成分可以不同製劑存在,取決於標靶器官或組織及所需劑量及藥物動力學參數。
如本文所用之術語「賦形劑」係指適用於製備醫藥組合物之化合物,一般安全、無毒且在生物學上或在其他方面均合乎需要,且包括可接受用於獸醫使用以及人類醫藥使用之賦形劑。本發明化合物可單獨投與,但一般將以與一或多種關於預期投與途徑及標準醫藥規範選擇的適合醫藥賦形劑、稀釋劑或載劑的混合物形式投與。
「醫藥學上可接受」意謂其適用於製備醫藥組合物,該醫藥組合物通常為安全、無毒且在生物學上或在其他方面均合乎需要,且包括可接受用於獸醫以及人類醫藥使用之醫藥組合物。
活性成分之「醫藥學上可接受之鹽」形式亦可最初對該活性成分賦予在非鹽形式中不存在之所需藥物動力學特性,且關於其在體內之治療活性,甚至可正面地影響活性成分之藥效學。片語化合物之「醫藥學上可接受之鹽」意謂醫藥學上可接受且具有母體化合物之所需藥理學活性之鹽。該等鹽包括:(1)與無機酸形成之酸加成鹽,該等無機酸諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似酸;或與有機酸形成之酸加成鹽,該等有機酸諸如乙酸、丙酸、己酸、環戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、丁二酸、蘋果酸、順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、3-(4-羥基苯甲醯基)苯甲酸、肉桂酸、杏仁酸、甲烷磺酸、乙烷磺酸、1,2-乙烷-二磺酸、2-
羥基乙烷磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟腦磺酸、4-甲基雙環[2.2.2]-辛-2-烯-1-甲酸、葡糖庚酸、3-苯基丙酸、三甲基乙酸、第三丁基乙酸、月桂基硫酸、葡萄糖酸、麩胺酸、羥基萘甲酸、水楊酸、硬脂酸、黏康酸及其類似酸;或(2)當母體化合物中存在之酸性質子置換為金屬離子(例如鹼金屬離子、鹼土金屬離子或鋁離子)時形成之鹽;或與有機鹼(諸如乙醇胺、二乙醇胺、三乙醇胺、緩血酸胺、N-甲基還原葡糖胺及其類似鹼)配位時形成之鹽。
固體形式製劑包括散劑、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、增溶劑、潤滑劑、懸浮劑、黏合劑、防腐劑、錠劑崩解劑或囊封材料。在散劑中,載劑一般為細粉狀固體,其為含細粉狀活性組分的混合物。在錠劑中,活性組分一般與具有必需結合能力的載劑以適合比例混合且按所需形狀及大小壓緊。適合之載劑包括(但不限於)碳酸鎂、硬脂酸鎂、滑石、糖、乳糖、果膠、糊精、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、低熔點蠟、可可脂及其類似物。固體形式製劑除了活性組分以外,亦可含有著色劑、調味劑、穩定劑、緩衝液、人工及天然甜味劑、分散劑、增稠劑、增溶劑及其類似物。
液體調配物亦適用於經口投與,包含包括乳液、糖漿、酏劑、水溶液、水性懸浮液在內之液體調配物。此等液體調配物包括意欲在使用之前不久轉化為液體形式製劑的固體形式製劑。乳液可在溶液中,例如在丙二醇水溶液中製備或可含有乳化劑,諸如卵磷脂、脫水山梨糖醇單油酸酯或***膠。可藉由將活性組分溶解於水中且添加適合之著色劑、調味劑、穩定劑及增稠劑製備水溶液。水性懸浮液可藉由將細粉狀活性組分分散於具有黏稠材料之水中來製備,該黏稠材料諸如天然或合成膠、樹脂、甲基纖維素、羧甲基纖維素鈉及其他熟
知懸浮劑。
本發明化合物可經調配用於非經腸投與(例如,藉由注射,例如快速注射或連續輸注),且可在安瓿、預填充注射器、小體積輸注中或在具有附加防腐劑之多劑量容器中以單位劑型呈遞。該等組合物可採用諸如油性或水性媒劑中之懸浮液、溶液或乳液之形式,例如水性聚乙二醇中之溶液。油性或非水性載劑、稀釋劑、溶劑或媒劑之實例包括丙二醇、聚乙二醇、植物油(例如橄欖油)及可注射有機酯(例如油酸乙酯),且可含有調配劑,諸如保持劑、濕潤劑、乳化或懸浮劑、穩定劑及/或分散劑。或者,活性成分可呈粉末形式,其藉由無菌隔離無菌固體或藉由自在使用之前用適合媒劑(例如,無菌、無熱原質之水)構成之溶液凍乾獲得。
本發明化合物可經調配用於以軟膏、乳膏或洗劑之形式或以經皮貼片之形式表面投與至表皮。軟膏及乳膏可例如用添加適合增稠劑及/或膠凝劑之水性或油性基質調配。洗劑可用水性或油性基質調配且一般而言亦應含有一或多種乳化劑、穩定劑、分散劑、懸浮劑、增稠劑或著色劑。適用於在口中表面投與之調配物包括在調味基質(通常為蔗糖及***膠或黃蓍膠)中包含活性成分之***錠;在惰性基質(諸如明膠及甘油或蔗糖及***膠)中包含活性成分之片劑;及在適合之液體載劑中包含活性成分之漱口劑。
本發明化合物可經調配用於以栓劑形式投與。首先熔融低熔點蠟,諸如脂肪酸甘油酯或可可脂的混合物,且均勻分散活性組分,例如藉由攪拌。然後將熔融的均質混合物傾入適宜大小的模具中,使其冷卻且固化。
本發明化合物可經調配用於經***投與。此項技術中已知,除了活性成分以外亦含有該等載劑的子宮托、棉塞、乳膏、凝膠、糊劑、發泡體或噴霧劑為適當的。
本發明化合物可經調配用於經鼻投與。藉由習知方式,例如用滴管、移液管或噴霧器將溶液或懸浮液直接施用於鼻腔。可以單劑量或多劑量形式提供調配物。在滴管或移液管之後一情況中,此可藉由向患者投與適當之預定體積之溶液或懸浮液實現。在噴霧器情況下,此可例如藉助於計量霧化噴霧泵實現。
本發明化合物可經調配用於氣霧劑投與,尤其投與至呼吸道,且包括鼻內投與。化合物一般應具有小粒徑,例如約五(5)微米或五(5)微米以下。此類粒徑可藉由此項技術中已知之方式,例如藉由微粉化獲得。活性成分係提供於含適合推進劑之加壓包裝中,該推進劑諸如氯氟碳化物(chlorofluorocarbon,CFC),例如二氯二氟甲烷、三氯氟甲烷或二氯四氟乙烷,或二氧化碳或其他適合氣體。氣霧劑亦宜含有諸如卵磷脂之界面活性劑。藥物劑量可藉由計量閥控制。或者,活性成分可以乾燥粉末之形式提供,例如化合物於適合粉末基質中之粉末混合物,該基質諸如乳糖、澱粉、澱粉衍生物(諸如羥丙基甲基纖維素)及聚乙烯吡咯啶酮(polyvinylpyrrolidine,PVP)。粉末載劑將在鼻腔中形成凝膠。粉末組合物可以單位劑型例如在例如明膠之膠囊或藥筒或泡殼包裝中呈遞,粉末可藉助於吸入器自其投與。
必要時,可用經調適用於持續或控制釋放投與活性成分之腸溶衣製備調配物。舉例而言,本發明化合物可在經皮或皮下藥物遞送裝置中調配。當有必要持續釋放化合物且當患者順應治療方案至關重要時,此等遞送系統為有利的。經皮遞送系統中之化合物常常附著於皮膚黏著性固體載劑。所關注之化合物亦可與穿透增強劑,例如氮酮(Azone)(1-十二烷基氮雜-環庚-2-酮)組合。持續釋放遞送系統藉由手術或注射經皮下***皮下層中。皮下植入物將化合物囊封於脂質可溶膜(例如聚矽氧橡膠)或生物可降解聚合物(例如聚乳酸)中。
適合之調配物連同醫藥載劑、稀釋劑及賦形劑描述於Remington: The Science and Practice of Pharmacy 1995,由E.W.Martin編輯,Mack Publishing Company,第19版,Easton,Pennsylvania中。熟練的調配科學家可在本說明書之教示內容內修改調配物以提供用於特定投與途徑而不使本發明組合物不穩定或損害其治療活性的大量調配物。
舉例而言,可藉由充分在此項技術之一般技能內的細微修改(鹽調配、酯化等)容易地使本發明化合物改質以使其更可溶於水或其他媒劑中。針對患者中之最大有益作用修改特定化合物之投與途徑及給藥方案以便管理本發明化合物的藥物動力學亦充分在此項技術之一般技能內。
如本文所用之術語「治療有效量」意謂減少個體中之疾病症狀所需的量。該劑量將在各特定情形中針對個體需求經調節。彼劑量可在寬界限內變化,取決於多種因素,諸如欲治療之疾病的嚴重程度、患者之年齡及一般健康狀況、治療患者所用之其他藥劑、投與途徑及形式及所牽涉的醫學從業者之偏好及經歷。關於經口投與,在每日約0.01與約1000mg/kg體重之間之每日劑量應在單一療法中及/或在組合療法中為適當的。較佳每日劑量在每日約0.1與約500mg/kg體重之間,更佳在每日0.1與約100mg/kg體重之間且最佳在每日1.0與約10mg/kg體重之間。因此,關於投與至70kg個人,劑量範圍將為每日約7mg至0.7g。每日劑量可以單一劑量或以分次劑量投與,典型地在每日1個劑量與5個劑量之間。一般而言,治療以比化合物之最佳劑量小之劑量起始。其後,該劑量以小增量增加直至關於個別患者達到最佳效應。一般熟習治療本文所述疾病之技能者將能夠確定本發明化合物關於既定疾病及患者之治療有效量,而無需不當實驗及依賴於個人知識、經歷及本申請案之揭示內容。
醫藥製劑較佳地呈單位劑型。在該形式中,將製劑再分為含有適量活性組分之單位劑量。單位劑型可為經封裝之製劑,該封裝含有
個別量之製劑,諸如經封包之錠劑、膠囊及在小瓶或安瓿中之散劑。又,單位劑型可為膠囊、錠劑、扁囊劑或***錠自身,或其可為適當數目之呈封裝形式的此等單位劑型中之任一者。
通式I之化合物抑制布魯頓氏酪胺酸激酶(Btk)。藉由上游激酶活化Btk引起磷脂酶-Cγ活化,其又刺激促炎性介體釋放。式I化合物適用於治療關節炎及其他抗發炎及自體免疫疾病。根據式I之化合物因此適用於治療關節炎。式I化合物適用於抑制細胞中之Btk且適用於調節B細胞發育。本發明進一步包含含有與醫藥學上可接受之載劑、賦形劑或稀釋劑混合之式I化合物的醫藥組合物。
本文所述之化合物為激酶抑制劑,特定言之Btk抑制劑。此等抑制劑可適用於治療哺乳動物中之一或多種回應於激酶抑制之疾病,包括回應於Btk抑制及/或B細胞增殖抑制之疾病。不希望束縛於任何特定理論,咸信本發明化合物與Btk之相互作用引起Btk活性之抑制且因此產生此等化合物之醫藥效用。因此,本發明包括一種治療具有回應於Btk活性抑制及/或抑制B細胞增殖之疾病的哺乳動物(例如人類)之方法,其包含向具有此類疾病之哺乳動物投與有效量的至少一種本文所提供之化學實體。有效濃度可以實驗方式,例如藉由分析該化合物之血液濃度,或在理論上藉由計算生物可用性來確定。除Btk之外亦可受影響之其他激酶包括(但不限於)其他酪胺酸激酶及絲胺酸/蘇胺酸激酶。
激酶在控制基礎細胞過程,諸如增殖、分化及死亡(細胞凋亡)之信號傳導路徑中起顯著的作用。異常激酶活性已牽涉於多種疾病中,包括多種癌症、自體免疫及/或發炎疾病及急性發炎反應。激酶在關鍵細胞信號傳導路徑中之多層面作用提供鑑別靶向激酶及信號傳導路徑之新穎藥物的顯著機會。
一實施例包括一種治療具有自體免疫及/或發炎疾病或回應於Btk活性及/或B細胞增殖之抑制之急性發炎反應的患者之方法。
可使用根據本發明之化合物及組合物來影響的自體免疫及/或發炎疾病包括(但不限於):牛皮癬、過敏、克羅恩病、大腸急躁症、休格連氏病、組織移植排斥及移植器官之超急性排斥、哮喘、全身性紅斑性狼瘡症(及相關絲球體腎炎)、皮肌炎、多發性硬化、硬皮病、血管炎(ANCA相關及其他血管炎)、自體免疫溶血性及血小板減少性狀態、古巴士德氏症候群(及相關絲球體腎炎及肺出血)、動脈粥樣硬化、類風濕性關節炎、慢性特發性血小板減少性紫癜(ITP)、艾迪森氏病、帕金森氏病、阿爾茨海默氏病、糖尿病、敗血性休克及重症肌無力。
本文中包括治療方法,其中至少一種本文所提供之化學實體與消炎劑組合投與。消炎劑包括(但不限於)NSAID、非特異性及COX-2特異性環加氧酶抑制劑、金化合物、皮質類固醇、甲胺喋呤、腫瘤壞死因子受體(TNF)受體拮抗劑、免疫抑制劑及甲胺喋呤。
NSAID之實例包括(但不限於)布洛芬、氟比洛芬、萘普生及萘普生鈉、雙氯芬酸、雙氯芬酸鈉與米索前列醇之組合、舒林酸、奧沙普嗪、二氟尼柳、吡羅昔康、吲哚美辛、依託度酸、非諾洛芬鈣、酮基布洛芬、鈉萘丁美酮、柳氮磺胺吡啶、托美丁鈉及羥氯喹。NSAID之實例亦包括COX-2特異性抑制劑,諸如塞內昔布、伐地昔布、盧米昔布及/或依託昔布。
在一些實施例中,消炎劑為水楊酸鹽。水楊酸鹽包括(但不限於)乙醯基水楊酸或阿司匹靈、水楊酸鈉及膽鹼及水楊酸鎂。
消炎劑亦可為皮質類固醇。舉例而言,皮質類固醇可為可的松、***、甲潑尼龍、潑尼松龍、潑尼松龍磷酸鈉或潑尼松。
在額外實施例中,消炎劑為金化合物,諸如硫代蘋果酸金鈉或
金諾芬。
本發明亦包括其中消炎劑為代謝抑制劑,諸如二氫葉酸還原酶抑制劑(諸如甲胺喋呤)或二氫乳清酸去氫酶抑制劑(諸如來氟米特)之實施例。
本發明之其他實施例係關於組合,其中至少一種消炎化合物為抗C5單株抗體(諸如艾庫組單抗或培克珠單抗)、TNF拮抗劑(諸如依那西普)或英利昔單抗(其為抗TNFα單株抗體)。
本發明之其他實施例係關於組合,其中至少一種活性劑為免疫抑制劑化合物,諸如選自甲胺喋呤、來氟米特、環孢靈、他克莫司、硫唑嘌呤及黴酚酸嗎啉乙酯之免疫抑制劑化合物。
表現BTK之B細胞及B細胞前驅體已牽涉於B細胞惡性疾病之病理學中,該等B細胞惡性疾病包括(但不限於)B細胞淋巴瘤、淋巴瘤(包括霍奇金氏及非霍奇金氏淋巴瘤)、毛細胞淋巴瘤、多發性骨髓瘤、慢性及急性骨髓性白血病及慢性及急性淋巴球性白血病。
BTK已顯示為B譜系淋巴細胞中Fas/APO-1(CD-95)死亡誘發信號傳導複合物(DISC)之抑制劑。白血病/淋巴瘤細胞之命運可在由DISC活化之卡斯蛋白酶的相對促細胞凋亡效應與涉及BTK及/或其受質之上游抗細胞凋亡調節機制之間保持平衡(Vassilev等人,J.Biol.Chem.1998,274,1646-1656)。
亦已發現BTK抑制劑適用作化學增敏劑且因此適於與其他化學治療藥物,特定言之誘發細胞凋亡之藥物組合。可與化學增敏BTK抑制劑組合使用之其他化學治療藥物之實例包括拓撲異構酶I抑制劑(喜樹鹼或拓朴替康)、拓撲異構酶II抑制劑(例如道諾黴素及依託泊苷)、烷基化劑(例如環磷醯胺、美法侖及BCNU)、微管蛋白導向劑(例如紫杉醇及長春鹼)及生物劑(例如抗體,諸如抗CD20抗體、IDEC 8、免疫毒素及細胞因子)。
Btk活性亦已與一些由染色體9及22之部分易位引起之表現bcr-abl融合基因的白血病相關。此異常通常在慢性骨髓性白血病中觀察到。Btk藉由起始下游存活信號之bcr-abl激酶組成性磷酸化,該激酶在bcr-abl細胞中防止細胞凋亡。(N.Feldhahn等人J.Exp.Med.2005201(11):1837-1852)。
本申請案提供一種用於治療發炎及/或自體免疫病狀之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供一種用於治療發炎病狀之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供一種用於治療類風濕性關節炎之方法,其包含向有需要之患者投與治療有效量之式I化合物。
本申請案提供一種用於治療哮喘之方法,其包含向有需要之患者投與治療有效量之式I。
本申請案提供一種用於治療發炎及/或自體免疫病狀之方法,其包含向有需要之患者投與治療有效量之式I之Btk抑制劑化合物。
本申請案提供一種用於治療關節炎之方法,其包含向有需要之患者投與治療有效量之式I之Btk抑制劑化合物。
本申請案提供一種用於治療哮喘之方法,其包含向有需要之患者投與治療有效量之式I之Btk抑制劑化合物。
本申請案提供一種用於治療癌症之方法,其包含向有需要之患者投與治療有效量之式I之Btk抑制劑化合物。
本申請案提供一種抑制B細胞增殖之方法,其包含向有需要之患者投與治療有效量之式I之Btk抑制劑化合物。
本申請案提供一種用於抑制Btk活性之方法,其包含投與式I中之任一者的Btk抑制劑化合物,其中該Btk抑制劑化合物在Btk活性之活
體外生物化學分析中呈現50微莫耳濃度或低於50微莫耳濃度之IC50。
在以上方法之一種變化形式中,該Btk抑制劑化合物在Btk活性之活體外生物化學分析中呈現100奈莫耳濃度或低於100奈莫耳濃度之IC50。
在以上方法之另一變化形式中,該化合物在Btk活性之活體外生物化學分析中呈現10奈莫耳濃度或低於10奈莫耳濃度之IC50。
本申請案提供一種用於治療發炎病狀之方法,其包含與式I之Btk抑制劑化合物組合向有需要之患者共投與治療有效量之消炎化合物。
本申請案提供一種用於治療關節炎之方法,其包含與式I之Btk抑制劑化合物組合向有需要之患者共投與治療有效量之消炎化合物。
本申請案提供一種藉由向有需要之患者投與治療有效量之式I之Btk抑制劑化合物來治療淋巴瘤或BCR-ABL1+白血病細胞之方法。
常用縮寫包括:乙醯基(Ac),偶氮-雙-異丁腈(AIBN),大氣壓(Atm),9-硼雜雙環[3.3.1]壬烷(9-BBN或BBN),2,2'-雙(二苯基膦基)-1,1'-聯萘(BINAP),第三丁氧羰基(Boc),焦碳酸酯二-第三丁酯或boc酐(BOC2O),苯甲基(Bn),丁基(Bu),化學文摘登記號(CASRN),苯甲氧羰基(CBZ或Z),羰基二咪唑(CDI),1,4-二氮雜雙環[2.2.2]辛烷(DABCO),二乙基胺基三氟化硫(DAST),二亞苄基丙酮(dba),1,5-二氮雜雙環[4.3.0]壬-5-烯(DBN),1,8-二氮雜雙環[5.4.0]十一-7-烯(DBU),N,N'-二環己基碳化二亞胺(DCC),1,2-二氯乙烷(DCE),二氯甲烷(DCM),2,3-二氯-5,6-二氰基-1,4-苯醌(DDQ),偶氮二甲酸二乙酯(DEAD),偶氮二甲酸二-異丙酯(DIAD),二-異丁基氫化鋁(DIBAL或DIBAL-H),二-異丙基乙胺(DIPEA),N,N-二甲基乙醯胺(DMA),4-N,N-二甲基胺基吡啶(DMAP),N,N-二甲基甲醯胺(DMF),二甲亞
碸(DMSO),1,1'-雙-(二苯基膦基)乙烷(dppe),1,1'-雙-(二苯基膦基)二茂鐵(dppf),1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺鹽酸鹽(EDCI),2-乙氧基-1-乙氧羰基-1,2-二氫喹啉(EEDQ),乙基(Et),乙酸乙酯(EtOAc),乙醇(EtOH),2-乙氧基-2H-喹啉-1-甲酸乙酯(EEDQ),二***(Et2O),乙基異丙基醚(EtOiPr),六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N'N'-四甲基鎓乙酸(HATU),乙酸(HOAc),1-N-羥基苯并***(HOBt),高壓液相層析(HPLC),異丙醇(IPA),異丙基氯化鎂(iPrMgCl),六甲基二矽氮烷(HMDS),液相層析質譜(LCMS),六甲基二矽氮烷鋰(LiHMDS),間氯過氧苯甲酸(m-CPBA),甲醇(MeOH),熔點(mp),MeSO2-(甲磺醯基或Ms),甲基(Me),乙腈(MeCN),間氯過苯甲酸(MCPBA),質譜(ms),甲基第三丁基醚(MTBE),甲基四氫呋喃(MeTHF),N-溴丁二醯亞胺(NBS),正丁基鋰(nBuLi),N-羧基酐(NCA),N-氯丁二醯亞胺(NCS),N-甲基嗎啉(NMM),N-甲基吡咯啶酮(NMP),氯鉻酸吡啶鎓(PCC),二氯-((雙-二苯基膦基)二茂鐵基)鈀(II)(Pd(dppf)Cl2),乙酸鈀(II)(Pd(OAc)2),參(二亞苄基丙酮)二鈀(0)(Pd2(dba)3),二鉻酸吡啶鎓(PDC),苯基(Ph),丙基(Pr),異丙基(i-Pr),磅/平方吋(psi),吡啶(pyr),1,2,3,4,5-五苯基-1'-(二-第三丁基膦基)二茂鐵(Q-Phos),室溫(環境溫度、rt或RT),第二丁基鋰(sBuLi),第三丁基二甲基矽烷基或t-BuMe2Si(TBDMS),四-正丁基氟化銨(TBAF),三乙胺(TEA或Et3N),2,2,6,6-四甲基哌啶1-氧基(TEMPO),三甲基矽烷基乙氧基甲基(SEM),三氟甲磺酸鹽或CF3SO2-(Tf),三氟乙酸(TFA),1,1'-雙-2,2,6,6-四甲基庚烷-2,6-二酮(TMHD),四氟硼酸O-苯并***-1-基-N,N,N',N'-四甲基鎓(TBTU),薄層層析(TLC),四氫呋喃(THF),三甲基矽烷基或Me3Si(TMS),對甲苯磺酸單水合物(TsOH或pTsOH),4-Me-C6H4SO2-或甲苯磺醯基(Ts),及N-胺基甲酸酯-N-羧基酐(UNCA)。包括字首正(n)、異(i-)、第二(sec-)、第三(tert-)
及新之習知命名法在與烷基部分一起使用時具有其慣用含義。(J.Rigaudy及D.P.Klesney,Nomenclature in Organic Chemistry,IUPAC 1979 Pergamon Press,Oxford.)。
本發明化合物可以市售起始材料為起始物藉由利用熟習此項技術者已知之一般合成技術及程序來製備。以下概述為適用於製備該等化合物之反應流程。進一步例證可發現於特定實例中。
試劑購自Aldrich,Oakwood,Matrix或其他供應商且不經進一步純化即使用。使用Personal Chemistry Emrys Optimizer系統或CEM Discovery系統進行使用微波照射來加熱之反應。藉由熟習此項技術者已知之方法,諸如矽膠急驟管柱之溶離來進行多毫克至多公克規模之純化;亦在一些情況下藉由使用用CombiFlash系統溶離之拋棄式預包裝多公克矽膠管柱(RediSep)來實現製備型急驟管柱純化。BiotageTM及ISCOTM亦為已可用於本發明中以純化中間物之急驟管柱儀器。
出於判斷化合物身分及純度之目的,使用以下系統記錄LC/MS(液相層析/質譜)譜。關於質譜量測,該系統由Micromass Platform II光譜儀組成:呈正離子模式之ES電離(質量範圍:150-1200)。用以下HPLC系統實現同時層析分離:ES Industries Chromegabond WR C-18 3u 120Å(3.2 x 30mm)管柱筒;移動相A:水(0.02% TFA)及相B:乙腈(0.02% TFA);梯度10% B至90% B,在3分鐘中;1分鐘之平衡時間;2mL/分鐘之流動速率。
多種式1化合物亦藉由逆相HPLC,使用熟習此項技術者熟知之方法來純化。在一些情況下,使用控制連接至Shimadzu製備型HPLC系
統及Leap自動注射器之Gilson 215收集器的PE Sciex 150 EX Mass Spec進行製備型HPLC純化。使用LC/MS偵測以正離子偵測自溶離流收集化合物:使用經10分鐘溶劑(A)0.05% TFA/H2O及溶劑(B)0.035% TFA/乙腈之適當線性梯度模式自C-18管柱(2.0×10cm,在20mL/min下溶離)溶離化合物。關於注射至HPLC系統上,將粗樣品溶解於甲醇、乙腈及DMSO之混合物中。
使用Bruker或Varian 300或400MHz NMR光譜儀進行1H-NMR表徵。
本發明化合物可根據已知技術合成。提供以下實例及參考文獻以輔助理解本發明。然而,該等實例不意欲限制本發明,其真實範圍闡述於隨附申請專利範圍中。該等實例中之最終產物之名稱使用Isis AutoNom 2000產生。
4-氯-2-甲基-1-硝基-苯(5g,29.1mmol)、2,3-二氟苯酚(4.55g,35.0mmol)及Cs2CO3(14.2g,43.7mmol)於DMF(10mL)中之混合物在密封管中在微波烘箱中在150℃下加熱30分鐘。添加EtOAc(300mL)且混合物用水(150mL)及鹽水洗滌。有機層經乾燥(Na2SO4),過
濾,且蒸發。粗材料藉由急驟層析(矽膠,10%乙酸乙酯/己烷)來純化以生成呈淺黃色油狀物之4-(2,3-二氟-苯氧基)-2-甲基-1-硝基-苯(5.6g,72%)。
4-(2,3-二氟-苯氧基)-2-甲基-1-硝基-苯(5.28g,19.9mmol)及鈀/碳(587mg)於MeOH(55mL)中之混合物在30psi氫氣下在Parr震盪器中震盪4小時。混合物經矽藻土過濾且矽藻土用MeOH洗滌。蒸發濾液以生成4-(2,3-二氟-苯氧基)-2-甲基-苯胺(4.56g,97%),其不經進一步純化即用於下一步驟中。
4-(2,3-二氟-苯氧基)-2-甲基-苯胺(546mg,2.32mmol)及濃HCl(0.6mL)於MeOH(1mL)及水(2mL)中之混合物在冰浴中冷卻。緩慢添加NaNO2(168mg,2.44mmol)於水(0.4mL)中之溶液且混合物攪拌30分鐘。反應混合物藉由移液管轉移至氯化錫(II)二水合物(2.25g,10mmol)於濃HCl(5mL)中之經攪拌溶液中且混合物攪拌4小時。添加MeOH(4mL),繼而添加10M NaOH直至pH達到7-8。在減壓下蒸發溶劑且殘餘物在真空下乾燥1小時。殘餘物用10% MeOH/CH2Cl2濕磨且濾出固體且用10% MeOH/CH2Cl2洗滌。在減壓下蒸發濾液以生成呈黃色油狀物之[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-肼(495mg,68%)。此材料不經進一步純化即用於下一步驟中。
3-(4-胺基-3-甲基-苯氧基)-苯甲腈(其可如Akama,T.等人Bioorg.Med.Chem.Lett. 2009,19,2129-2132中所述來製備;2.2g,9.8mmol)及濃HCl(3.5mL)於MeOH(7mL)及水(5mL)中之混合物在冰浴中冷卻。緩慢添加NaNO2(1.35g,19.6mmol)於水(6mL)中之溶液且混合物攪拌30分鐘。反應混合物藉由移液管轉移至氯化錫(II)二水合物(8.85g,39.2mmol)於濃HCl(7mL)中之經攪拌溶液中且混合物攪拌30分鐘。添加MeOH(10mL),繼而添加10M NaOH直至pH達到7-8。添加水(100mL)且混合物用EtOAc(500mL)萃取。有機層用鹽水(Na2SO4)洗滌,過濾,且蒸發以生成呈油狀物之3-(4-肼基-3-甲基-苯氧基)-苯甲腈(2.2g,94%)。此材料不經進一步純化即用於下一步驟中。
DIPEA(2.6mL,14.8mmol)及MeOH(3mL,74.2mmol)添加至1-苯磺醯基-4-溴-1H-吲哚-2-碳醯氯(其可如Mahboobi,S.等人J.Med.Chem. 2006,49,3101-3115中所述來製備;1.97g,4.94mmol)之溶液中。混合物在室溫下攪拌隔夜,且溶劑在減壓下蒸發。殘餘物用15% EtOAc/己烷濕磨,過濾,用15% EtOAc/己烷洗滌,且在真空下乾燥隔夜以生成1-苯磺醯基-4-溴-1H-吲哚-2-甲酸甲酯(1.78g,91%)。
4-溴-1-(苯基磺醯基)-1H-吲哚-2-甲酸甲酯(970mg,2.46mmol)及乙腈(770μL,14.8mmol)於THF(25mL)中之溶液冷卻至-78℃。經5分鐘緩慢添加LDA(2M/THF)(2.5ml,5mmol)。反應混合物在-78℃下攪拌30分鐘且隨後添加飽和NH4Cl溶液(40mL)。添加水(150mL)且混合物用EtOAc(500mL)萃取。有機層用鹽水洗滌,乾燥(Na2SO4),過濾,且蒸發。殘餘物藉由層析(矽膠,30% EtOAc/己烷)來純化以生成呈泡沫之3-(4-溴-1-(苯基磺醯基)-1H-吲哚-2-基)-3-側氧基丙腈(650mg,66%)。
N,N-二甲基甲醯胺二甲基縮醛(465mg,3.9mmol)添加至3-(4-溴-1-(苯基磺醯基)-1H-吲哚-2-基)-3-側氧基丙腈(1.21g,3.00mmol)於甲苯(20mL)中之溶液中,且混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,70% EtOAc/己烷)來純化以生成呈黃色泡沫之(E)-2-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-3-二甲基胺基-丙烯腈(1.06g,77%)。
[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-肼(其可如關於中間物1所述來製備;816mg,3.26mmol)、(E)-2-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-3-二甲基胺基-丙烯腈(650mg,1.42mmol)及EtOH(25mL)的混合物在回流下加熱隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,30% EtOAc/己烷)來純化以生成呈泡沫之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(820mg,87%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(275mg,0.414mmol)、Cs2CO3(540mg,1.66mmol)、THF(10mL)及MeOH(5mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈灰白色固體狀之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(210mg,97%)。1H NMR(400MHz,DMSO-d 6)δ ppm 12.10(s,1 H),8.28(s,1 H),7.51(d,J=8.3Hz,1 H),7.25-7.42(m,4 H),7.15-7.23(m,3 H),7.09(t,J=7.5Hz,1 H),7.03(d,J=8.5Hz,1 H),6.96(br.s.,2 H),2.09(s,3 H)。關於C25H18BrF2N4O2之MS計算值[(M+H)+]523,觀測值522.9。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-
苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;30mg,0.045mmol)、苯基酸(11mg,0.09mmol)、Pd(PPh3)4(5.2mg,0.004mmol)、K2CO3(25mg,0.18mmol)、水(0.5mL)、甲苯(1mL)及EtOH(1mL)的混合物在90℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,30% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-苯基-1H-吲哚-2-基)-甲酮(28mg,94%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-苯基-1H-吲哚-2-基)-甲酮(28mg,0.04mmol)、Cs2CO3(41.4mg,0.13mmol)、THF(2mL)及MeOH(1mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈淺黃色油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-苯基-1H-吲哚-2-基)-甲酮(20mg,86%)。1H NMR(400MHz,CDCl3)δ ppm 9.65(s,1 H),8.17(s,1 H),7.72(dd,J=8.4,1.4Hz,2 H),7.48-7.56(m,3 H),7.37-7.46(m,3 H),7.31(d,J=8.6Hz,1 H),7.26(s,1 H),7.23(dd,J=6.8,1.4Hz,1 H),7.07(d,J=5.5Hz,2 H),6.99(d,J=2.7Hz,1 H),6.92(dt,J=8.1,2.6Hz,2 H),2.17(s,3 H)。關於C31H23F2N4O2之MS計算值[(M+H)+]521,觀測值521.1。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;95mg,0.14mmol)、噻吩-3-酸(37mg,0.29mmol)、Pd(PPh3)4(16.5mg,0.014mmol)、K2CO3(79.2mg,0.57mmol)、水(1.5mL)、甲苯(3mL)及EtOH(3mL)的混合物在90℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-噻吩-3-基-1H-吲哚-2-基)-甲酮(94mg,92%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-噻吩-3-基-1H-吲哚-2-基)-甲酮(94mg,0.14mmol)、Cs2CO3(137mg,0.42mmol)、THF(6mL)及MeOH(3mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈灰白色固體狀之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-噻吩-3-基-1H-吲哚-2-基)-甲酮(70mg,88%)。1H NMR(400MHz,CDCl3)δ ppm 9.40(s,1 H),8.20(s,1 H),7.59-7.61(m,1 H),7.54(dd,J=2.3,0.8Hz,1 H),7.48-7.53(m,2 H),7.40-7.44(m,1 H),7.35-7.40(m,1 H),7.27-7.34(m,2 H),7.03-7.13(m,2 H),7.00(d,J=2.7Hz,1 H),6.89-6.96(m,2 H),2.17(s,3 H)。關於C29H21F2N4O2S之MS計算值[(M+H)+]527,觀測值527。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟5中所述來製備;100mg,0.15mmol)、吡唑(20.5mg,0.3mmol)、L-脯胺酸(7mg,0.06mmol)、碘化銅(I)(6mg,0.03mmol)及K2CO3(62.5mg,0.45mmol)
於DMSO(2mL)中的混合物用氬氣沖洗。該混合物在130℃下加熱40小時且隨後藉由製備型HPLC來純化以生成呈黃色粉末之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-吡唑-1-基-1H-吲哚-2-基)-甲酮(6mg,8%)。1H NMR(400MHz,CDCl3)δ ppm 9.44(br.s.,1 H),8.29(s,1 H),8.08(dd,J=2.5,0.5Hz,1 H),7.83-7.93(m,2 H),7.71(s,1 H),7.39-7.48(m,2 H),7.31-7.37(m,2 H),7.05-7.17(m,2 H),7.03(d,J=2.8Hz,1 H),6.91-7.00(m,2 H),6.57-6.59(m,1 H),2.20(s,3 H)。關於C28H21F2N6O2之MS計算值[(M+H)+]511,觀測值511。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;60mg,0.09mmol)、2-(三丁基錫烷基)噻吩(67.5mg,0.18
mmol)、Pd(PPh3)4(10.4mg,0.009mmol)及甲苯(2mL)的混合物在100℃下加熱隔夜。蒸發溶劑。殘餘物藉由層析(矽膠,35% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-噻吩-2-基-1H-吲哚-2-基)-甲酮(46mg,76%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-噻吩-2-基-1H-吲哚-2-基)-甲酮(46mg,0.07mmol)、Cs2CO3(67.4mg,0.21mmol)、THF(2mL)及MeOH(1mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈灰白色固體狀之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-噻吩-2-基-1H-吲哚-2-基)-甲酮(32mg,88%)。1H NMR(400MHz,CDCl3)δ ppm 9.41(br.s.,1 H),8.24(s,1 H),7.73(dd,J=2.0,0.8Hz,1 H),7.49(dd,J=3.5,1.2Hz,1 H),7.40-7.44(m,2 H),7.36-7.39(m,2 H),7.30-7.36(m,2 H),7.20(dd,J=5.1,3.5Hz,1 H),7.02-7.13(m,2 H),7.00(d,J=2.7Hz,1 H),6.88-6.96(m,2 H),2.18(s,3 H)。關於C29H21F2N4O2S之MS計算值[(M+H)+]527,觀測值526.9。
在可密封管中,一氧化碳氣體鼓泡通過{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟5中所述來製備;94mg,0.18mmol)、嗎啉(313mg,3.6mmol)、Pd(PPh3)4(62.3mg,0.054mmol)及THF(10mL)的混合物持續5分鐘。該管經密封且在90℃下加熱2小時。蒸發溶劑且殘餘物藉由製備型HPLC來純化以生成呈淺黃色粉末之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(嗎啉-4-羰基)-1H-吲哚-2-基]-甲酮三氟乙酸鹽(24mg,24%)。1H NMR(400MHz,CDCl3)δ ppm 9.52(s,1 H),8.23(s,1 H),7.51(d,J=8.2Hz,1 H),7.30-7.38(m,3 H),7.18(dd,J=7.2,1.0Hz,1 H),7.02-7.15(m,2 H),7.00(d,J=2.7Hz,1 H),6.88-6.96(m,2 H),3.41-4.00(m,8 H),2.17(s,3 H)。關於C30H26F2N5O4之MS計算值[(M+H)+]558,觀測值558。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;65mg,0.098mmol)、1-甲基-1H-吡唑-4-酸鹽酸鹽(32mg,0.196mmol)、Pd(PPh3)4(11.3mg,0.01mmol)、K2CO3(54.2mg,0.39mmol)、水(1mL)、甲苯(2mL)及EtOH(2mL)的混合物在90℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[1-苯磺醯基-4-(1-甲基-1H-吡唑-3-基)-1H-吲哚-2-基]-甲酮(31mg,48%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[1-苯磺醯基-4-(1-甲基-1H-吡唑-3-基)-1H-吲哚-2-基]-甲酮(31mg,0.046mmol)、Cs2CO3(60.8mg,0.19mmol)、THF(1.5mL)及MeOH(0.75mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層
析(矽膠,90% EtOAc/己烷)來純化以生成呈灰白色固體狀之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(1-甲基-1H-吡唑-3-基)-1H-吲哚-2-基]-甲酮(21mg,86%)。1H NMR(400MHz,CDCl3)δ ppm 9.29(s,1 H),8.21(s,1 H),7.93(s,1 H),7.78(s,1 H),7.47-7.50(m,1 H),7.30-7.37(m,3 H),7.22(dd,J=6.4,1.8Hz,1 H),7.02-7.14(m,2 H),7.00(d,J=2.7Hz,1 H),6.86-6.96(m,2 H),4.05(s,3 H),2.18(s,3 H)。關於C29H23F2N6O2之MS計算值[(M+H)+]525,觀測值525。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;64mg,0.097mmol)、2-(三丁基錫烷基)吡啶(71mg,0.19mmol)、Pd(PPh3)4(11.1mg,0.01mmol)及甲苯(2mL)的混合物在100℃
下加熱隔夜。蒸發溶劑。殘餘物藉由層析(矽膠,45% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-吡啶-2-基-1H-吲哚-2-基)-甲酮(27mg,42%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-吡啶-2-基-1H-吲哚-2-基)-甲酮(27mg,0.041mmol)、Cs2CO3(53.2mg,0.16mmol)、THF(2mL)及MeOH(1mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,50% EtOAc/己烷)來純化以生成呈灰白色固體狀之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-吡啶-2-基-1H-吲哚-2-基)-甲酮(19mg,79%;純度88%)。1H NMR(400MHz,CDCl3)δ ppm9.37(br.s.,1 H),8.87(d,J=4.8Hz,1 H),8.29(s,1 H),7.91(d,J=18.1Hz,3 H),7.44-7.65(m,3 H),7.35(d,J=8.5Hz,2 H),7.04-7.18(m,2 H),7.01-7.04(m,1 H),6.88-6.99(m,2 H),2.20(s,3 H)。關於C30H22F2N5O2之MS計算值[(M+H)+]522,觀測值522。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;65mg,0.098mmol)、Pd(OAc)2(2.8mg,0.012mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(Aldrich;9mg,0.022mmol)及THF(2mL)的混合物用氬氣沖洗3分鐘且隨後在室溫下攪拌5分鐘。添加苯甲基溴化鋅(II)(Aldrich;0.5M於THF中;0.3mL;0.15mmol)且混合物在75℃下加熱2小時。蒸發溶劑。殘餘物藉由層析(矽膠,35% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-苯甲基-1H-吲哚-2-基)-甲酮(66mg,82%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-苯甲基-1H-吲哚-2-基)-甲酮(63mg,0.093mmol)、Cs2CO3(122mg,0.37mmol)、THF(5mL)及MeOH(2.5mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈黃色油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-苯甲基-1H-吲哚-2-基)-甲酮(42mg,84%)。1H NMR(400MHz,CDCl3)δ ppm 9.26(br.s.,1 H),8.06(s,1 H),7.30-7.42(m,8 H),7.25(dd,J=2.1,0.9Hz,2 H),7.05-7.17(m,2 H),6.91-7.04(m,4 H),4.36(s,2 H),2.19(s,3 H)。關於C32H25F2N4O2之MS計算值[(M+H)+]535,觀測值536。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟5中所述來製備;55mg,0.105mmol)、第三丁氧羰基-1H-吡唑-4-酸(44.6mg,0.21mmol)、Pd(PPh3)4(12.1mg,0.011mmol)、K2CO3(58.1mg,0.42mmol)、水(0.75mL)、甲苯(1.5mL)及EtOH(1.5mL)的混合物在90℃下加熱隔
夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,60% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(1H-吡唑-4-基)-1H-吲哚-2-基]-甲酮(30mg,56%)。1H NMR(400MHz,DMSO-d 6)δ ppm 13.04(br.s.,1 H),11.78(s,1 H),8.39-8.47(m,2 H),8.07(s,1 H),7.23-7.49(m,7 H),7.17(d,J=2.8Hz,1 H),6.99-7.13(m,2 H),6.90(s,2 H),2.10(s,3 H)。關於C28H21F2N6O2之MS計算值[(M+H)+]511,觀測值511。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟5中所述來製備;55mg,0.105mmol)、3-氰基苯基酸(30.9mg,0.21mmol)、Pd(PPh3)4(12.1mg,0.011mmol)、K2CO3(58.1mg,0.42mmol)、水(0.75mL)、甲苯(1.5mL)及EtOH(1.5mL)的混合物在90℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,35% EtOAc/己烷)來純化以生成呈油狀物之3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-基)-苯甲腈(38mg,66%)。1H NMR(400MHz,CDCl3)δ ppm 9.43(s,1 H),8.15(s,1 H),7.96-8.01(m,2 H),7.73-7.78(m,1 H),7.64-7.70(m,1 H),7.53-7.57(m,1 H),7.42-7.49(m,1 H),7.32-7.38(m,2 H),
7.23(dd,J=7.2,0.9Hz,1 H),7.05-7.17(m,2 H),7.02(d,J=3.0Hz,1 H),6.91-6.99(m,2 H),2.20(s,3 H)。關於C32H22F2N5O2之MS計算值[(M+H)+]546,觀測值546。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟5中所述來製備;55mg,0.105mmol)、3-氯苯基酸(32.9mg,0.21mmol)、Pd(PPh3)4(12.1mg,0.011mmol)、K2CO3(58.1mg,0.42mmol)、水(0.75mL)、甲苯(1.5mL)及EtOH(1.5mL)的混合物在90℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,35% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(3-氯-苯基)-1H-吲哚-2-基]-甲酮(54mg,87%)。1H NMR(400MHz,CDCl3)δ ppm 9.41(br.s.,1 H),8.17(s,1 H),7.71(t,J=1.8Hz,1 H),7.63(dt,J=7.5,1.4Hz,1 H),7.48-7.53(m,2 H),7.41-7.47(m,3 H),7.34(d,J=8.5Hz,1 H),7.24(dd,J=7.3,1.0Hz,1 H),7.05-7.16(m,2 H),7.02(d,J=2.5Hz,1 H),6.90-6.99(m,2 H),2.20(s,3 H)。關於C31H22ClF2N4O2之MS計算值[(M+H)+]555,觀測值555。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟4中所述來製備;65mg,0.098mmol)、Pd(OAc)2(2.8mg,0.012mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(Aldrich;9mg,0.022mmol)及THF(2mL)的混合物用氬氣沖洗3分鐘且隨後在室溫下攪拌5分鐘。添加(3-氰基-苯甲基)溴化鋅(II)(Aldrich;0.5M於THF中;0.3mL;0.15mmol)且混合物在75℃下加熱2小時。添加水(3mL)且混合物用EtOAc(2×5mL)萃取。蒸發經合併之有機層。殘餘物藉由層析(矽膠,35% EtOAc/己烷)來純化以生成呈油狀物之3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1-苯磺醯基-1H-吲哚-4-基甲基)-苯甲腈(64mg,93%)。
3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1-苯磺醯基-1H-吲哚-4-基甲基)-苯甲腈(64mg,0.092mmol)、Cs2CO3(119mg,0.37mmol)、THF(5mL)及MeOH(2.5mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈黃色油狀物之3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-基甲基)-苯甲腈(40mg,78%)。1H NMR(400MHz,CDCl3)δ ppm 9.30(br.s.,1 H),8.07(s,1 H),7.50-7.60(m,3 H),7.43(dd,J=11.2,8.2Hz,2 H),7.30-7.36(m,2 H),7.20(s,1 H),7.10(ddd,J=15.2,8.7,5.9Hz,2 H),7.02(d,J=2.5Hz,1 H),6.90-6.98(m,3 H),4.39(s,2 H),2.19(s,3 H)。關於C33H24F2N5O2之MS計算值[(M+H)+]560,觀測值560.1。
3-(4-肼基-3-甲基-苯氧基)-苯甲腈(其可如關於中間物2所述來製備;789mg,3.3mmol)、(E)-2-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-3-二甲基胺基-丙烯腈(其可如實例I-1步驟3中所述來製備;510mg,1.11mmol)及EtOH(30mL)的混合物在回流下加熱隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,30% EtOAc/己烷)來純化以生成呈泡沫之3-{4-[5-胺基-4-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(598mg,82%)。
3-{4-[5-胺基-4-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(450mg,0.69mmol)、Cs2CO3(899mg,2.76mmol)、THF(15mL)及MeOH(7.5mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成3-{4-[5-胺基-4-(4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈。
3-{4-[5-胺基-4-(4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(55mg,0.107mmol)、1-第三丁氧羰基-1H-吡唑-4-酸(Combi-Blocks Inc.,7949 Silverton Avenue,Suite 915,San Diego,CA 92126,USA;45.5mg,0.22mmol)、Pd(PPh3)4(12.4mg,0.011mmol)、K2CO3(59.3mg,0.43mmol)、水(0.75mL)、甲苯(1.5mL)及EtOH(1.5mL)的混合物在90℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發有機層。殘餘物藉由層析(矽膠,80% EtOAc/己烷)來純化以生成呈油狀物之3-(4-{5-胺基-4-[4-(1H-吡唑-4-基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈(30mg,56%)。1H NMR(400MHz,DMSO-d 6)δ ppm 13.04(br.s.,1 H),11.78(s,1 H),8.38-8.49(m,2 H),8.08(br.s.,1 H),7.56-7.71(m,3 H),7.35-7.52(m,4 H),7.19-7.30(m,3 H),7.08(dd,J=8.5,2.8Hz,1 H),6.92(s,2 H),2.11(s,3 H)。關於C29H22N7O2之MS計算值[(M+H)+]500,觀測值500。
在可密封管中,一氧化碳氣體鼓泡通過3-{4-[5-胺基-4-(4-溴-1H-
吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(其可如實例I-14步驟2中所述來製備;53mg,0.10mmol)、嗎啉(180mg,2.1mmol)、Pd(PPh3)4(35.9mg,0.031mmol)及THF(10mL)的混合物持續5分鐘。密封該管且在90℃下加熱隔夜。蒸發溶劑且殘餘物藉由製備型HPLC來純化以生成呈淺黃色粉末狀之3-(4-{5-胺基-4-[4-(嗎啉-4-羰基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈(21mg,37%)。關於C31H27N6O4之MS計算值[(M+H)+]547,觀測值546.9。
在可密封管中,一氧化碳氣體鼓泡通過3-{4-[5-胺基-4-(4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(其可如實例I-14步驟2中所述來製備;53mg,0.10mmol)、1-甲基哌嗪(155mg,1.55mmol)、Pd(PPh3)4(35.9mg,0.031mmol)及THF(10mL)的混合物持續5分鐘。密封該管且在90℃下加熱隔夜。蒸發溶劑且殘餘物藉由製備型HPLC來純化以生成呈灰白色泡沫之3-(4-{5-胺基-4-[4-(4-甲基-哌嗪-1-羰基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈(32mg,55%)。關於C32H30N7O3之MS計算值[(M+H)+]560,觀測值560。
3-{4-[5-胺基-4-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(其可如實例I-14步驟1中所述來製備;65mg,0.10mmol)、Pd(OAc)2(2.8mg,0.012mmol)、2-二環己基膦基-2',6'-二甲氧基聯苯(Aldrich;9mg,0.022mmol)及THF(2mL)的混合物用氬氣沖洗5分鐘且隨後在室溫下攪拌5分鐘。添加(3-甲氧基-苯甲基)溴化鋅(II)(Aldrich;0.5M於THF中;0.3mL;0.15mmol)且混合物在75℃下加熱2小時。添加水(3mL)且混合物用EtOAc(2×5mL)萃取。蒸發經合併之有機層。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈油狀物之3-(4-{5-胺基-4-[1-苯磺醯基-4-(3-甲氧基-苯甲基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈(62mg,90%)。
3-(4-{5-胺基-4-[1-苯磺醯基-4-(3-甲氧基-苯甲基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈(62mg,0.089mmol)、Cs2CO3(116mg,0.36mmol)、THF(5mL)及MeOH(2.5mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈黃色泡沫之3-(4-{5-胺基-4-[4-(3-甲氧基-苯甲基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈(41mg,83%)。1H NMR(400MHz,CDCl3)δ ppm 9.28(s,1 H),8.11(s,1 H),7.44-7.56(m,2 H),7.37-7.42(m,2 H),7.30-7.37(m,4 H),7.25(d,J=8.0Hz,1 H),6.91-7.08(m,5 H),6.77-6.87(m,2 H),4.34(s,2 H),3.78(s,3 H),2.22(s,3 H)。關於C34H28N5O3之MS計算值[(M+H)+]554,觀測值554.1。
在可密封管中,一氧化碳氣體鼓泡通過{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮(其可如實例I-1步驟5中所述來製備;200mg,0.38mmol)、MeOH(2.5mL,62mmol)、Pd(PPh3)4(132mg,0.115mmol)及THF(20mL)的混合物持續5分鐘。密封該管且在90℃下加熱隔夜。蒸發溶劑且殘餘物
藉由層析(矽膠,45% EtOAc/己烷)來純化以生成呈油狀物之2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-甲酸甲酯(101mg,45%;85%純度)。1H NMR(400MHz,CDCl3)δ ppm 9.52(br.s.,1 H),8.26(s,1 H),7.87-7.95(m,2 H),7.60(d,J=8.3Hz,2 H),7.43(d,J=5.5Hz,2 H),7.23-7.35(m,3 H),7.19(s,2 H),7.11(d,J=7.5Hz,2 H),6.96-7.05(m,3 H),6.94(d,J=2.8Hz,1 H),6.79-6.90(m,2 H),3.96(s,3 H),2.11(s,3 H)。關於C27H21F2N4O4之MS計算值[(M+H)+]503,觀測值502.9。
向含有1-苯磺醯基-4-溴-1H-吲哚(其可如Bell,I.M.等人WO 2007061694第103頁中所述來製備;5.18g,59.5mmol)、Pd(PPh3)4(1.37g,1.19mmol)及THF(125mL)之密封管中饋入40psi之一氧化碳。混合物在95℃下加熱隔夜且隨後蒸發溶劑。殘餘物藉由層析(矽膠,80% EtOAc/己烷)來純化以生成呈泡沫之(1-苯磺醯基-1H-吲哚-4-
基)-嗎啉-4-基-甲酮(2.67g,61%)。
(1-苯磺醯基-1H-吲哚-4-基)-嗎啉-4-基-甲酮(2.07g,5.59mmol)於THF(50mL)中之溶液冷卻至-20℃且逐滴添加LiAlH4(2M於THF中;6.2mL,12.4mmol)。混合物攪拌30分鐘且添加MeOH(20ML)。添加NaBH4(634mg,16.8mmol)且混合物攪拌30分鐘。添加EtOAc(300mL)且混合物用鹽水洗滌。有機層經乾燥(Na2SO4),過濾,且蒸發以生成呈油狀物之(1-苯磺醯基-1H-吲哚-4-基)-甲醇(1.41g,88%),該油狀物無需進一步純化直接用於下一步驟。
DIPEA(3.17g,24.5mmol)及甲烷磺醯氯(1.69g,14.7mmol)添加至(1-苯磺醯基-1H-吲哚-4-基)-甲醇(1.41g,4.91mmol)於THF(40mL)中之溶液中。混合物在室溫下攪拌隔夜。在減壓下蒸發溶劑。殘餘物藉由層析(矽膠,20% EtOAc/己烷)來純化以生成呈油狀物之1-苯磺醯基-4-氯甲基-1H-吲哚(1.4g,93%)。
1-苯磺醯基-4-氯甲基-1H-吲哚(1.4g,4.58mmol)、嗎啉(1.2mL,13.7mmol)、K2CO3(3.16g,22.9mmol)及CH3CN(60mL)的混合物在65℃下加熱隔夜。添加EtOAc(250mL)且混合物用水及鹽水洗滌,乾燥(Na2SO4),過濾,且蒸發。殘餘物藉由層析(矽膠,60% EtOAc/己烷)來純化以生成呈油狀物之1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚(1.45g,89%)。
1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚(600mg,1.68mmol)於THF(12mL)中之溶液冷卻至-78℃。添加LDA(2M於THF中;1.7mL,3.4mmol)且混合物攪拌1小時。添加過量固體CO2。在-78℃下30分鐘之後,反應混合物升溫至室溫且添加2N HCl。用CH2Cl2(3×150mL)萃取混合物。有機層經乾燥(Na2SO4),過濾,且蒸發以生成呈泡沫之1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-甲酸(670mg,99%),其無需進一步純化直接用於下一步驟。
1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-甲酸(670mg,1.67mmol)及SOCl2(10mL,137mmol)的混合物在回流下加熱1小時。在減壓下蒸發溶劑且殘餘物在真空下乾燥1小時。添加THF(20mL),繼而添加McOH(1.5mL)且反應混合物在室溫下攪拌1小時。在減壓下蒸發溶劑。殘餘物藉由層析(矽膠,60% EtOAc/己烷)來純化以生成呈油狀物之1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-甲酸甲酯(486mg,70%)。
1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-甲酸甲酯(486mg,1.17mmol)、CH3CN(0.37mL,7.0mmol)及THF(10mL)的混合物冷卻至-78℃。添加LDA(2M於THF中;1.2mL,2.4mmol)且混合物在-78℃下攪拌30分鐘。相繼添加飽和NH4Cl水溶液(10mL)及水(50mL)。混合物用EtOAc(350mL)萃取。有機層用鹽水洗滌,乾燥(Na2SO4),過濾,且蒸發以生成呈油狀物之3-(1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-基)-3-側氧基-丙腈(506mg,93%),其無需進一步純化直接用於
下一步驟。
3-(1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-基)-3-側氧基-丙腈(506mg,1.17mmol)、N,N-二甲基甲醯胺二甲基縮醛(0.21mL,1.55mmol)及甲苯(10mL)的混合物在室溫下攪拌隔夜。蒸發溶劑。殘餘物藉由層析(矽膠,100% EtOAc)來純化以生成呈黃色泡沫之(E)-2-(1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-羰基)-3-二甲基胺基-丙烯腈(285mg,50%)。
[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-肼(其可如關於中間物1所述來製備;130mg,0.52mmol)、(E)-2-(1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-羰基)-3-二甲基胺基-丙烯腈(60mg,0.125mmol)及EtOH(10mL)的混合物在回流下加熱隔夜。在減壓下移除溶劑。殘餘物藉
由層析(矽膠,50% EtOAc/己烷)來純化以生成呈油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-基)-甲酮(56mg,65%)。
{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(1-苯磺醯基-4-嗎啉-4-基甲基-1H-吲哚-2-基)-甲酮(56mg,0.082mmol)、Cs2CO3(133mg,0.41mmol)、THF(4mL)及MeOH(2mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,70% EtOAc/己烷)來純化以生成呈淺黃色油狀物之{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-嗎啉-4-基甲基-1H-吲哚-2-基)-甲酮(35mg,79%)。1H NMR(400MHz,CDCl3)δ ppm 9.27(br,s.,1 H),8.27(s,1 H),7.62(s,1 H),7.39(d,J=8.0Hz,1 H),7.35(d,J=8.5Hz,1 H),7.30(d,J=7.3Hz,1 H),3.86(br.s.,2 H),3.75(br.s.,4 H),2.54(br.s.,3 H),2.20(s,3 H)。關於C30H28F2N5O3之MS計算值[(M+H)+]544,觀測值544.1。
3-{4-[5-胺基-4-(1-苯磺醯基-4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(其可如關於實例I-14步驟1所述來製備;107mg,0.164mmol)、氰基乙酸第三丁酯(81mg,0.57mmol)、雙(三-第三丁基膦)鈀(0)(Strem Chemicals;29.5mg,0.058mmol)、磷酸三鈉(121mg,0.74mmol)及甲苯(2mL)的混合物在密封管中在100℃下加熱隔夜。添加水(2mL),且混合物用EtOAc(2×5mL)萃取。蒸發經合併之有機層。殘餘物藉由層析(矽膠,40% EtOAc/己烷)來純化以生成呈油狀物之3-{4-[5-胺基-4-(1-苯磺醯基-4-氰基甲基-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(34mg,34%)。
3-{4-[5-胺基-4-(1-苯磺醯基-4-氰基甲基-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(34mg,0.056mmol)、Cs2CO3(81.4mg,0.25mmol)、THF(4mL)及MeOH(2mL)的混合物在室溫下攪拌隔夜。在減壓下移除溶劑。殘餘物藉由層析(矽膠,40% EtOAc/己烷)
來純化以生成呈淺黃色固體狀之3-{4-[5-胺基-4-(4-氰基甲基-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(11mg,42%)。1H NMR(400MHz,CDCl3)δ ppm 9.38(br.s.,1 H),8.31(s,1 H),7.46-7.58(m,4 H),7.31-7.45(m,7 H),7.22-7.26(m,1 H),6.99-7.11(m,3 H),4.10(s,2 H),2.25(s,4 H)。關於C28H21N6O2之MS計算值[(M+H)+]473,觀測值473。
向含有3-{4-[5-胺基-4-(4-溴-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈(其可如實例I-14步驟2中所述來製備;160mg,0.31mmol)、Pd(PPh3)4(108mg,0.094mmol)、甲胺(2M於THF中;2mL,4mmol)及THF(20mL)之密封管中饋入30psi之一氧化碳。混合物在95℃下加熱隔夜且隨後蒸發溶劑。殘餘物藉由製備型HPLC來純化以生成呈灰白色凍乾粉末之2-{5-胺基-1-[4-(3-氰基-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-甲酸甲基醯胺三氟乙酸鹽(73mg,48%)。1H NMR(400MHz,CDCl3)δ ppm 9.43(s,1 H),8.36(s,1 H),7.89(dd,J=2.1,0.9Hz,1 H),7.60-7.64(m,1 H),7.44-7.55(m,3 H),7.38-7.44(m,2 H),7.31-7.37(m,2 H),7.07(d,J=2.8Hz,1 H),7.01(dd,J=8.4,2.4Hz,1 H),3.15(d,J=4.8Hz,3 H),2.22(s,3 H)。關於C28H21F2N6O2之MS計算值[(M+H)+]511,觀測值511。
該分析為經由過濾捕獲放射性33P磷酸化產物。Btk、生物素標記SH2肽受質(Src同源)及ATP之相互作用引起該肽受質之磷酸化。生物素標記產物為結合之抗生蛋白鏈菌素瓊脂糖珠粒。所有結合之放射性標記產物均藉由閃爍計數器偵測。
所分析之板為96孔聚丙烯(Greiner)及96孔1.2μm親水性PVDF濾板(Millipore)。此處報告之濃度為最終分析濃度:在DMSO(Burdick and Jackson)中之10-100μM化合物,5-10nM Btk酶(His標記,全長),30μM肽受質(生物素-Aca-AAAEEIYGEI-NH2),100μM ATP(Sigma),8mM咪唑(Sigma,pH 7.2),8mM甘油-2-磷酸(Sigma),200μM EGTA(Roche Diagnostics),1mM MnCl2(Sigma),20mM MgCl2(Sigma),0.1mg/ml BSA(Sigma),2mM DTT(Sigma),1μCi 33P ATP(Amersham),20%抗生蛋白鏈菌素瓊脂糖珠粒(Amersham),50mM EDTA(Gibco),2M NaCl(Gibco),2M NaCl w/1%磷酸(Gibco),microscint-20(Perkin Elmer)。
利用由標準96孔板分析模板產生的數據,自每個化合物10個數據點計算IC50測定值。在每一板上測試一種對照化合物及七種未知抑制劑且每一板進行兩次。典型地,以半-對數(half-log)稀釋化合物,以100μM開始且以3nM結束。對照化合物為星形孢菌素。在肽受質不存在下對背景計數。在肽受質存在下測定總活性。以下方案用於測定Btk抑制。
1)樣品製備:測試化合物以半-對數增量在分析緩衝液(咪唑、甘油-2-磷酸、EGTA、MnCl2、MgCl2、BSA)中稀釋。
2)珠粒製備
a.)藉由在500g下離心來沖洗珠粒
b.)用PBS及EDTA復原珠粒以產生20%珠粒漿液
3)在30℃下預培育不含受質之反應混合物(分析緩衝液、DTT、ATP、33P ATP)及含受質之混合物(分析緩衝液、DTT、ATP、33P ATP、肽受質)持續15分鐘。
4)為開始分析,在室溫下預培育在酶緩衝液(咪唑、甘油-2-磷酸、BSA)中之10μL Btk及10μL測試化合物持續10分鐘。
5)向Btk及化合物中添加30μL不含或含受質之反應混合物。
6)在30℃下培育50μL總分析混合物持續30分鐘。
7)轉移40μL分析液至濾板中之150μL珠粒漿液中以停止反應。
8)30分鐘後洗滌濾板,使用以下步驟
a. 3 x 250μL NaCl
b. 3 x 250μL NaCl,含有1%磷酸
c. 1 x 250μL H2O
9)在65℃下乾燥板持續1小時或在室溫下乾燥板隔夜
10)添加50μL microscint-20且在閃爍計數器上計數33P cpm。
由原始數據(cpm)計算活性百分比
活性百分比=(樣品-bkg)/(總活性-bkg)x 100
使用單位點劑量反應S型模型,由活性百分比計算IC50
y=A+((B-A)/(1+((x/C)D))))
x=化合物濃度,y=%活性,A=min,B=max,C=IC50,D=1(希爾斜率)
此BTK競爭分析使用FRET(Förster/螢光共振能量轉移)技術量測針對布魯頓氏酪胺酸激酶之不活化狀態的化合物效能(IC50)。BTK-Eu錯合物在以50nM BTK-BioeaseTm:10nM Eu-抗生蛋白鏈菌素(Perkin-Elmer目錄號AD0062)之開始濃度使用之前一小時在冰上保溫。分析緩衝液由20mM HEPES(pH 7.15)、0.1mM DTT、10mM MgCl2、具
有3%激酶穩定劑(Fremont Biosolutions,目錄號STB-K02)之0.5mg/ml BSA組成。1小時之後,來自上文之反應混合物在分析緩衝液中10倍稀釋以製備5nM BTK:1nM Eu-抗生蛋白鏈菌素錯合物(供體螢光團)。隨後將18μl具有單獨BTK-Eu而無陰性對照物之0.11nM BTK-Eu及0.11nM激酶示蹤劑178(Invitrogen,目錄號PV5593,)的混合物分配於384孔平底板(Greiner,784076)中。欲在分析中測試之化合物以10×濃度製備且在DMSO中以半-對數增量進行連續稀釋以生成10點曲線。為起始FRET反應,將以DMSO中之10×儲備液製備的化合物添加至板中且該等板在14℃下保溫18-24小時。
在培育之後,該等板在BMG Pherastar螢光板讀取器(或等效物)上讀數且用於量測來自銪供體螢光團(620nm發射)及FRET(665nm發射)之發射能量。對陰性對照孔值求平均值以獲得平均最小值。對陽性「無抑制劑」對照孔求平均值以獲得平均最大值。最大FRET之百分比使用以下等式計算:% max FRET=100 x[(FSR化合物-FSR平均最小值)/(FSR平均最大值-FSR平均最小值)]
其中FSR=FRET信號比率。在Activity Base(Excel)中繪製% Max FRET曲線且測定IC50(%)、希爾斜率、z'及%CV。平均IC50及標準差將使用Microsoft Excel自雙重複曲線(來自2次獨立稀釋之單一抑制曲線)獲得。
關於此分析之代表性化合物數據列於下文表II中。
測試Btk抑制劑抑制人類血液中B細胞受體介導之B細胞活化之能力的程序如下:人類全血(HWB)獲自健康志願者,具有以下限制:24小時沒有使用藥物、無抽菸者。藉由靜脈穿刺將血液收集至用肝素鈉抗凝結之Vacutainer管中。測試化合物在PBS中稀釋至10倍所需開始藥物濃度,繼而在PBS(20x)中之10% DMSO中三倍連續稀釋以產生9點劑量-反應曲線。將5.5μl之每種化合物稀釋液一式兩份添加至2ml 96孔V型底之板(Analytical Sales and Services,#59623-23)中;將5.5μl之在PBS中之10% DMSO添加至對照及無刺激孔中。將HWB(100μl)添加至各孔中,且在混合之後,使板在37℃、5% CO2、100%濕度下培育30分鐘。在混合下將山羊F(ab')2抗人類IgM(Southern Biotech,#2022-14)(10μl 500μg/ml溶液,50μg/ml最終濃度)添加至各孔(除了無刺激孔)中且該等板再培育20小時。
在20小時培育結束時,樣品與螢光探針標記之抗體(15μl PE小鼠抗人類CD20,BD Pharmingen,#555623,及/或20μl APC小鼠抗人類CD69,BD Pharmingen #555533)一起在37℃、5% CO2、100%濕度下培育30分鐘。包括用於補充調節及初始電壓設置之誘導對照、未染色及單染色劑。樣品隨後用1ml 1X Pharmingen溶解緩衝液(BD
Pharmingen # 555899)溶解,且板在1800rpm下離心5分鐘。上清液經由抽汲移除且剩餘集結粒再次用另外1ml 1X Pharmingen溶解緩衝液溶解,且板如之前短暫離心。抽吸上清液且剩餘集結粒在FACs緩衝液(PBS+1% FBS)中洗滌。在最終旋轉之後,移除上清液且集結粒再懸浮於180μl FACs緩衝液中。將樣品轉移至適合在BD LSR II流式細胞儀上之HTS 96孔系統上運行的96孔板中。
使用關於所用螢光團之適當激發及發射波長,獲取數據且使用Cell Quest Software獲得百分比陽性細胞值。最初藉由FACS分析軟體(Flow Jo)分析結果。測試化合物之IC50定義為使CD69陽性細胞之百分比減小50%的濃度,該等CD69陽性細胞在藉由抗IgM刺激之後亦為CD20陽性(8個對照孔之平均值,在扣除8個無刺激背景之孔的平均值之後)。使用XLfit軟體版本3,等式201計算IC50值。
藉由測定測試化合物對抗IgM刺激之B細胞反應的影響,來證實本發明化合物抑制B細胞活化。
B細胞FLIPR分析為基於細胞之功能方法,該方法測定潛在抑制劑對於由抗IgM抗體刺激所致之細胞內鈣增加的影響。在生長培養基(描述如下)中培養Ramos細胞(人類伯基特氏淋巴瘤細胞株.ATCC-No.CRL-1596)。在分析之前一天,使Ramos細胞再懸浮於新鮮生長培養基(與上述相同)中且以0.5×106/mL之濃度設置於組織培養燒瓶中。在分析當天,將細胞計數且以1×106/mL之濃度設置於組織培養燒瓶中補充有1μM FLUO-3AM(TefLabs目錄號0116,在無水DMSO及10%普朗尼克酸中製備)之生長培養基中,且在37℃(4% CO2)下培育1小時。為了移除細胞外染料,藉由離心(5分鐘,1000rpm)收集細胞,以1×106個細胞/mL再懸浮於FLIPR緩衝液(描述如下)中且隨後以每孔1×105個細胞分配於96孔聚-D-離胺酸塗佈之黑色/透明板(BD目錄號
356692)中。添加在100μM至0.03μM範圍內之各種濃度(7種濃度,以下詳情)的測試化合物,且使其與細胞一起在室溫下培育30分鐘。藉由添加10μg/mL抗IgM(Southern Biotech,目錄號2020-01)刺激Ramos細胞Ca2+信號傳導且在FLIPR(Molecular Devices,使用具有在480nM激發的氬雷射之CCD相機捕獲96孔板之影像)上量測。
培養基/緩衝液:生長培養基:RPMI 1640培養基,其具有L-麩醯胺酸(Invitrogen,目錄號61870-010)、10%胎牛血清(FBS,Summit Biotechnology目錄號FP-100-05);1mM丙酮酸鈉(Invitrogen目錄號11360-070)。
FLIPR緩衝液:HBSS(Invitrogen,目錄號141175-079)、2mM CaCl2(Sigma目錄號C-4901)、HEPES(Invitrogen,目錄號15630-080)、2.5mM丙磺舒(Sigma,目錄號P-8761)、0.1% BSA(Sigma,目錄號A-7906)、11mM葡萄糖(Sigma,目錄號G-7528)
化合物稀釋詳情:為了獲得100μM之最高最終分析濃度,直接將24μL之10mM化合物儲備溶液(在DMSO中製得)添加至576μL之FLIPR緩衝液中。測試化合物稀釋於FLIPR緩衝液中(使用Biomek 2000機器人吸移管管理器),產生以下稀釋方案:媒劑,1.00×10-4M、1.00×10-5、3.16×10-6、1.00×10-6、3.16×10-7、1.00×10-7、3.16×10-8。
使用最大-最小統計(使用Molecular Devices FLIPR對照及統計輸出軟體,自藉由添加刺激抗體引起之峰減去靜止基線)報導鈣之細胞內增加。使用非線性曲線擬合(GraphPad Prism軟體)測定IC50。
在第0天,小鼠用II型膠原蛋白(i.d.)在完全弗氏佐劑(CFA)中之乳
液在尾巴基部或在背部上之數個點處注射。在膠原蛋白免疫之後,動物將在約21至35天發展關節炎。關節炎之發作藉由在第21天全身性投與在不完全弗氏佐劑(IFA;i.d.)中之膠原蛋白而同步(增強)。在第20天之後每天檢查動物之輕微關節炎(1或2分;參見以下記分描述)的任何發作,其為增強之信號。在增強之後,對小鼠記分且將候選治療劑以規定的時間(典型地2-3週)及給藥頻率給藥,每天一次(QD)或每天兩次(BID)。
在第0天,大鼠用在不完全弗氏佐劑(IFA)中之牛II型膠原蛋白之乳液皮內注射(i.d.)在背部上之數個位置處。在約第7天,在尾巴基部或在背部上之替代位點處提供膠原蛋白乳液之加強注射(i.d.)。一般在初始膠原蛋白注射之後12-14天觀察到關節炎。自第14天起,可如下文所述(關節炎之評估)評估動物之關節炎發展。動物用候選治療劑以預防性方式在二次激發時開始給藥且以規定的時間典型地2-3週)及給藥頻率給藥,每天一次(QD)或每天兩次(BID)。
在兩種模型中,使用記分系統對爪及肢關節之發展的炎症進行定量,該記分系統包括根據下文所述之準則分析4隻爪:
記分:1=爪或一個趾之腫脹及/或發紅。
2=兩個或兩個以上關節腫脹。
3=爪之總體腫脹,涉及兩個以上關節。
4=整個爪及趾之嚴重關節炎。
如下進行評估:在第0天進行基線量測且在第一個徵候或腫脹時再次開始,每週多達三次直至實驗結束。藉由將4個各別爪記分相加來獲得每隻小鼠之關節炎指數,每隻動物之最大記分為16。
用在0.2ml礬中之100μg卵白蛋白(OA)腹膜內(i.p.)敏化雄性Brown-Norway大鼠,每週一次,持續三週(第0、7及14天)。在第21天(最後一次敏化之後一週),大鼠在OA氣霧劑激發(1% OA,持續45分鐘)之前0.5小時用媒劑或化合物調配物皮下q.d.給藥且在激發之後4或24小時終止。在處死時,自所有動物收集血清及血漿,分別用於血清學及PK。***氣管插管且肺用PBS灌洗3次。對BAL流體分析總白血球數目及差異白血球計數。藉由Coulter Counter測定細胞之等分試樣(20-100μl)中之總白血球數目。對於差異白血球計數,50-200μl之樣品在Cytospin中離心且載片用Diff-Quik染色。使用標準形態準則根據光學顯微法對單核細胞、嗜酸性球、嗜中性白血球及淋巴細胞之比例計數且表述為百分比。如與對照水準相比,Btk之代表性抑制劑在OA敏化及激發之大鼠之BAL中顯示減少之總白血球計數。
上述發明已藉助於說明及實例較詳細地加以描述,以達成清楚及理解之目的。熟習此項技術者將顯而易知,可在隨附申請專利範圍之範圍內進行改變及修改。因此,應理解,以上描述意欲為說明性而非限制性的。因此,本發明的範圍不應參考以上描述來確定,而應參考以下隨附申請專利範圍連同由該等申請專利範圍授權之等效物的全部範圍來確定。
本申請案中所引用之所有專利、專利申請案及出版物藉此以引用的方式全文併入以達成所有目的,其併入程度就如同各個別專利、專利申請案或出版物單獨地如此指示一般。
Claims (22)
- 一種式I化合物或其醫藥學上可接受之鹽,
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中X為甲基且R5為雜芳基,視情況經一或多個R5'取代。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R5為噻吩基,視情況經一或多個R5'取代。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R5為吡啶基,視情況經一或多個R5'取代。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R1為F且R2為F。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其中R1為H且R2為氰基。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R5為-C(=O)R5'。
- 如請求項7之化合物或其醫藥學上可接受之鹽,其中R5'為嗎啉基、哌啶基、低碳烷基哌啶基或低碳烷氧基。
- 如請求項8之化合物或其醫藥學上可接受之鹽,其中R1為F且R2為F。
- 如請求項8之化合物或其醫藥學上可接受之鹽,其中R1為H且R2為氰基。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R5為苯基或苯甲基,視情況經一或多個R5'取代。
- 如請求項1之化合物或其醫藥學上可接受之鹽,其中R5為低碳烷基,視情況經一或多個R5'取代。
- 如請求項11之化合物或其醫藥學上可接受之鹽,其中R1為F且R2為F。
- 如請求項11之化合物或其醫藥學上可接受之鹽,其中R1為H且R2為氰基。
- 如請求項1或2之化合物或其醫藥學上可接受之鹽,其選自由以下組成之群:{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-溴-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-苯基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-噻吩-3-基-1H-吲哚-2-基)-甲酮; {5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-吡唑-1-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-噻吩-2-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(嗎啉-4-羰基)-1H-吲哚-2-基]-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(1-甲基-1H-吡唑-4-基)-1H-吲哚-2-基]-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-吡啶-2-基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-苯甲基-1H-吲哚-2-基)-甲酮;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(1H-吡唑-4-基)-1H-吲哚-2-基]-甲酮;3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-基)-苯甲腈;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-[4-(3-氯-苯基)-1H-吲哚-2-基]-甲酮;3-(2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-基甲基)-苯甲腈;3-(4-{5-胺基-4-[4-(1H-吡唑-4-基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;3-(4-{5-胺基-4-[4-(嗎啉-4-羰基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;3-(4-{5-胺基-4-[4-(4-甲基-哌嗪-1-羰基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈; 3-(4-{5-胺基-4-[4-(3-甲氧基-苯甲基)-1H-吲哚-2-羰基]-吡唑-1-基}-3-甲基-苯氧基)-苯甲腈;2-{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-甲酸甲酯;{5-胺基-1-[4-(2,3-二氟-苯氧基)-2-甲基-苯基]-1H-吡唑-4-基}-(4-嗎啉-4-基甲基-1H-吲哚-2-基)-甲酮;3-{4-[5-胺基-4-(4-氰基甲基-1H-吲哚-2-羰基)-吡唑-1-基]-3-甲基-苯氧基}-苯甲腈;及2-{5-胺基-1-[4-(3-氰基-苯氧基)-2-甲基-苯基]-1H-吡唑-4-羰基}-1H-吲哚-4-甲酸甲基醯胺。
- 一種如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造用於治療發炎及/或自體免疫病狀的藥劑。
- 一種如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造用於治療發炎病狀的藥劑。
- 一種如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造用於治療類風濕性關節炎的藥劑。
- 一種如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造用於治療哮喘的藥劑。
- 一種醫藥組合物,其包含與至少一種醫藥學上可接受之載劑、賦形劑或稀釋劑混合的如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽。
- 如請求項1、2及7至10中任一項之化合物或其醫藥學上可接受之鹽,其用作治療活性物質。
- 如請求項1、2或7至10中任一項之化合物或其醫藥學上可接受之鹽,其用於治療發炎及/或自體免疫病狀。
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