TWI780944B - 作為jak激酶抑制劑的小分子化合物及其用途 - Google Patents
作為jak激酶抑制劑的小分子化合物及其用途 Download PDFInfo
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- TWI780944B TWI780944B TW110137632A TW110137632A TWI780944B TW I780944 B TWI780944 B TW I780944B TW 110137632 A TW110137632 A TW 110137632A TW 110137632 A TW110137632 A TW 110137632A TW I780944 B TWI780944 B TW I780944B
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- compound
- cycloalkyl
- alkyl
- hydrogen
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Classifications
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
本發明提供了一種小分子化合物,所述小分子化合物為由下式表示的
化合物,或其立體異構體、幾何異構體、互變異構體、水合物、溶劑化物、以及藥學上可接受的鹽或前藥,其中R1至R4各自獨立地選自C或N;並且其中R選自環烷基、取代的環烷基、雜環烷基、取代的雜環烷基、芳基、取代的芳基、雜芳基或取代的雜芳基。本發明的小分子化合物能夠抑制JAK激酶,更特別是作為JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑。
Description
本發明屬於小分子化合物領域,具體地,涉及一種能夠用於預防或治療緩解自身免疫性疾病如風濕性關節炎、潰瘍性結腸炎和系統性紅斑狼瘡等,或相關的炎症性皮膚病如銀屑病、濕疹、白癜風和斑禿等的小分子化合物。
JAK(Janus激酶,Janus Kinase)是細胞內非受體性酪氨酸蛋白激酶的一個家族,包括JAK1、JAK2、JAK3和Tyk2四個成員。JAK-STAT(轉錄蛋白的信號轉導和啟動劑,Signal Transducer and Activator of Transcription proteins)信號傳導通路是炎症性細胞因數和受體相結合之後激發的信號在細胞內傳導的主要通路。許多證據表明,JAK-STAT信號傳導通路在很多疾病的發病機理中起到不可或缺的驅動作用,特別是自身免疫性疾病如風濕性關節炎、紅斑狼瘡、炎症性腸病、多發性硬化、乾燥綜合征、銀屑病、斑禿和白癜風等;過敏性疾病如哮喘、過敏性鼻炎、過敏性結膜炎、特應性皮炎和濕疹等等。因此,利用高效的小分子對JAK激酶活性,特別是JAK1、TYK2激酶活性進行抑制可以阻斷參與炎症反應的細胞因數介導的信號通路,從而控制炎症,有效治療自身免疫性疾病和/或過敏性炎症性疾病。
不同炎症性疾病發病過程中T細胞會根據不同的炎症誘發因素如病毒或細菌感染而向不同的方向分化,形成Th1,Th2,Th17等T細胞亞群,這些T細胞相應地產生不同的細胞因數,如與病毒感染引起的急性炎症相關的Th1細胞產生IFNγ,IL-2;與過敏有關的Th2細胞產生IL-4,IL-5,IL-13;與自身免疫
有關的Th17細胞產生IL-17,IL-12,IL-21,IL-22,IL-23;這些細胞因數和細胞表面的受體結合後,通過細胞內的JAK傳遞炎症信號,驅動疾病的病理過程。更重要的是,很多病因不清楚的炎症性疾病發表機理複雜,在不同的階段甚至同一階段會涉及多種T細胞亞群,也就是會涉及多個JAK通路,這就對開發針對JAK的炎症性疾病治療藥物提出了新的要求。
雖然有研究報導JAK1抑制劑對Th2類過敏性炎症有特異性抑制,同時有效抑制JAK1和/或TYK2抑制劑的研究鮮有報導,尤其我們認為JAK1/Tyk2雙抑制劑和Tyk2抑制劑在臨床上有更廣泛的前途,尤其發病機制涉及到自身免疫異常的炎症性疾病。此外,更多的炎症性疾病尤其是炎症性皮膚病的發病機理可能涉及多個JAK,因此開發強效JAK1和Tyk2的單抑制劑或雙抑制劑具有重要意義,尤其用於皮膚病的外用治療,強效抑制劑在帶來很好的療效的同時又能避免系統用藥造成的副作用,但是這將同時需要很強的抑制活性才能實現。
本發明的目的旨在獲得高效的JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑,為不同的炎症性疾病提供有針對性的靶向治療,例如JAK1/Tyk2雙抑制劑可能適合於SLE、白癜風、IBD和濕疹等疾病,Tyk2特異性抑制劑可能更適合於治療類風濕性關節炎、銀屑病和斑禿等,同時克服由於抑制JAK2帶來的造血抑制和凝血異常。另外,選擇適合用於外用給藥途徑如針對炎症性皮膚病外用與疾病病因和症狀表現相關聯的不同性質的JAK家族成員抑制劑對疾病進行干預和症狀控制,能夠獲得好的治療效應。
為了實現上述目的,在一方面,本發明提供了一種小分子化合物,所述小分子化合物為由如下所示的式I表示的化合物,或其立體異構體、幾何異構體、互變異構體、水合物、溶劑化物、以及藥學上可接受的鹽或前藥:
其中,R1至R4各自獨立地選自C或N;並且
其中,R選自環烷基、取代的環烷基、雜環烷基、取代的雜環烷基、芳基、取代的芳基、雜芳基或取代的雜芳基。
在一個實施方式中,R1至R4中的至多兩個為N。
在另一個實施方式中,R具有如下所示的式II表示的結構:
其中,R5選自C或N;
其中,R6選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R7選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在另一個實施方式中,R6和R7各自獨立地選自氫、烷基或環烷基。
在另一個實施方式中,R具有如下所示的式III表示的結構:
其中,R8選自C或N;
其中,R9選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R10選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在另一個實施方式中,R9和R10各自獨立地選自氫、烷基或環烷基。
在另一個實施方式中,所述烷基為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
在另一方面,本發明還提供了如上所述的小分子化合物在抑制JAK激酶中的用途。
在另一方面,本發明還提供了如上所述的小分子化合物在製備用於預防或治療JAK相關的自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥物中的用途。
在一個實施方式中,所述自身免疫性疾病選自類風濕性關節炎、強直性脊柱炎、潰瘍性結腸炎、克羅恩病、系統性紅斑狼瘡、皮肌炎、多發性硬化、I型糖尿病、乾燥綜合症和血管炎中的至少一種。
在另一個實施方式中,所述與免疫有關的炎症性皮膚疾病選自特應性皮炎、濕疹、斑禿、銀屑病、白癜風、扁平苔蘚、光澤苔蘚、硬化萎縮性苔蘚、脂膜炎、痤瘡和化膿性汗腺炎中的至少一種。
本發明的作用和效果:
本發明根據JAK激酶的蛋白結構,特別是Tyk2的蛋白結構,進行了
小分子化合物有目的的合理設計,合成的化合物首先進行JAK的激酶生化活性檢測,根據IC50建立SAR(structure-activity relationship),對IC50在200nM以下的強效抑制劑再進行細胞學的測試,並確定化合物的選擇性。參見具體活性實驗資料可以發現,本發明涉及的化合物具有良好的JAK激酶活性和細胞生物學活性的抑制能力。
以下對本發明的具體實施方式進行詳細說明。應當理解的是,此處所描述的具體實施方式僅用於說明和解釋本發明,並不用於限制本發明。
在本文中所披露的範圍的端點和任何值都不限於該精確的範圍或值,這些範圍或值應當理解為包含接近這些範圍或值的值。對於數值範圍來說,各個範圍的端點值之間、各個範圍的端點值和單獨的點值之間,以及單獨的點值之間可以彼此組合而得到一個或多個新的數值範圍,這些數值範圍應被視為在本文中具體公開。
在詳細描述本發明前,應瞭解,在此使用的術語只在於描述特定的實施方式,而不希望限制本發明的範圍,本發明的範圍僅由所附權利要求書限定。為
了更完全地瞭解在此描述的本發明,採用以下術語,它們的定義如下所示。除非另外定義,在此使用的所有技術和科學術語具有與本發明所屬領域的普通技術人員所理解的相同的含義。
在一方面,本發明提供了一種小分子化合物,所述小分子化合物為由如下所示的式I表示的化合物,或其立體異構體、幾何異構體、互變異構體、水合物、溶劑化物、以及藥學上可接受的鹽或前藥:
其中,R1至R4各自獨立地選自C或N;並且
其中,R選自環烷基、取代的環烷基、雜環烷基、取代的雜環烷基、芳基、取代的芳基、雜芳基或取代的雜芳基。
也就是說,R1、R2、R3和R4可以各自獨立地選自C或N。在一個優選的實施方式中,R1至R4中的至多兩個(即0、1或2個)可以為N。在另一個優選的實施方式中,R1至R4中的至多一個(即0或1個)可以為N。當R1至R4中的至多一個(即0或1個)為N時,它們將構成苯環或吡啶環。
根據本發明,在一個優選的實施方式中,R可以具有如下所示的式II表示的結構:
其中,R5可以選自C或N;
其中,R6選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R7選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在一個更優選的實施方式中,R6和R7可以各自獨立地選自氫、烷基或環烷基,進一步,所述烷基可以為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
例如,在一個具體的實施方式中,R5為N,R6為甲基,且R7為甲基。在這種情況下,R可以具有如下所示的結構:。
例如,在一個具體的實施方式中,R5為C,R6為甲基,且R7為乙基。在這種情況下,R可以具有如下所示的結構:。
例如,在一個具體的實施方式中,R5為N,R6為甲基,且R7為氫。在這種情況下,R可以具有如下所示的結構:。
根據本發明,在另一個優選的實施方式中,R可以具有如下所示的式III表示的結構:
其中,R8可以選自C或N;
其中,R9選自氫、鹵素、烷基、氨基、醯胺基、環烷基、雜環烷基、芳基或雜芳基;並且
R10選自氫、烷基、環烷基、雜環烷基、芳基或雜芳基。
在一個更優選的實施方式中,R9和R10可以各自獨立地選自氫、烷基或環烷基,進一步,所述烷基可以為甲基、乙基、丙基或異丙基,所述環烷基為環丙基、環丁基或環丙基甲基。
如本文所用,術語“藥學上可接受的”是指不影響本發明化合物的生物活性或性質的物質,並且相對無毒,即該物質可施用於個體而不造成不良的生物反應或以不良方式與組合物中包含的任意組分相互作用。在本發明中,“藥學上可接受的鹽”可以包括無機鹽和有機鹽,其中,所述有機鹽可以包括但不限於銨、鋰、鈉、鉀、銫、鈣、鎂、銅、鋁、鋅、鋇或季銨鹽,並且所述無機鹽可以包括但不限於精氨酸、叔丁胺、二甲胺、二乙醇胺、乙醇胺、乙二胺、咪唑、賴氨酸、甲胺、吡啶、吡啶甲酸酯、呱嗪、三乙胺、三乙醇胺、三甲胺或脲鹽。
在另一方面,本發明提供了上述小分子化合物在抑制JAK激酶中的用途,特別是作為JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑。
在另一方面,本發明還提供了上述小分子化合物在製備用於預防或治療自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥物中的用途。研究表明,這些疾病的發病機理均與JAK信號傳導的失調相關。
如本文所用,術語“治療”是指根據治療性方案的治療性試劑的任何施用,所述治療性方案達到所需效果,即部分或完全減輕、改善、緩解、抑制、延遲發作、降低嚴重程度和/或降低特定疾病、障礙和/或病症的一種或多種症狀或特徵的發生率;在一些實施方式中,根據治療性方案的治療性試劑的施用與所需效果的實現相關。這種治療可以針對沒有表現出相關疾病、障礙和/或病症的受試者和/或針對僅表現出疾病、障礙和/或病症的早期跡象的受試者。替代地或另外地,
這種治療可以針對表現出相關疾病、障礙和/或病症的一種或多種所確定跡象的受試者。在一些實施方式中,治療可以針對已被診斷患有相關疾病、障礙和/或病症的受試者。在一些實施方式中,治療可以針對已知具有一種或多種易感因素的受試者,所述易感因素在統計學上與相關疾病、障礙和/或病症發展的風險增加相關。
根據本發明,上述用途中制得的藥物可以包含有效量的本發明的小分子化合物,以及藥學上可接受的賦形劑、載體或稀釋劑。
如本文所用,術語“有效量”、“治療有效量”或“藥學有效量”是指對於治療的受試者以適用於任何藥物治療的合理受益/風險比賦予治療效果的治療性試劑的量。這樣的治療效果可以是客觀的(即可以通過某種測試或標記測量)或主觀的(即受試者給出指示或感覺到效果)。在一些實施方式中,“治療有效量”是指諸如通過改善與疾病有關的症狀、預防或延遲疾病發作和/或還減輕疾病症狀的嚴重性或頻率來有效治療、改善或預防(例如延遲發作)相關疾病或病症和/或表現出可檢測的治療或預防效果的治療性試劑或組合物的量。
本領域的技術人員將認識到,待施用的所述小分子化合物的治療有效量將根據以下各項而變化:受試者和疾病的性質和嚴重程度、受試者的身體狀況、治療方案(例如是否使用第二治療劑)、以及所選擇的施用途徑;合適的劑量可以由本領域的技術人員容易地確定。另外,該藥物的個體劑量的最佳數量和間隔將通過所治療的病狀的性質和程度、施用的形式、途徑和位置、以及所治療的特定受試者的年齡和病狀確定,並且醫師將最終確定待施用的合適劑量。此劑量可以視需要重複多次。如果出現副作用,則可以根據正常臨床實踐改變或減少劑量的量和/或頻率。
在本發明中,“藥學上可接受的賦形劑、載體或稀釋劑”包括但不限於任何被相關的政府管理部門許可為可接受供人類或家畜使用的佐劑、載體、賦形劑、助流劑、增甜劑、稀釋劑、防腐劑、染料/著色劑、矯味劑、表面活性劑、潤濕劑、分散劑、助懸劑、穩定劑、等滲劑、溶劑或乳化劑等。
根據本發明,進一步地,上述用途中制得的藥物除了可以包含本發明的小分子化合物作為有效成分之外,還可以包含其他可用於預防或治療自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥劑作為另一種有效成分。所述藥劑的實例包括但不限於維生素D衍生物、維生素A衍生物、糖皮質激素、鈣調神經磷酸酶抑制劑或非甾體類抗炎藥等。當該藥物包含多種有效成分時,各有效成分可以根據醫師的判斷同時、依次或分開施用。
另外,本發明的小分子化合物可以通過多種途徑施用于患者,這些途徑諸如口服、透皮、皮下、鼻內、靜脈內、肌內、鞘內、區域或局部(例如粘膜)。在任何給定情況下最適合的施用途徑將取決於受試者和疾病的性質和嚴重程度、以及受試者的身體狀況等。在一個實施方式中,本發明的小分子化合物可以經靜脈內施用。在另一個實施方式中,本發明的小分子化合物可以口服施用。相應地,根據不同的施用方式,本發明的藥物可以製備為不同的劑型。例如,在一個實施方式中,所述藥物可以製備為片劑、膠囊劑、丸劑、顆粒劑、霧化劑、噴霧劑或注射劑。
經發明人研究發現,本發明的小分子化合物或其制得的藥物在用於預防或治療JAK相關的自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病能夠發揮優異的效果。具體地,所述自身免疫性疾病可以包括但不限於類風濕性關節炎、強直性脊柱炎、潰瘍性結腸炎、克羅恩病、系統性紅斑狼瘡、皮肌炎、多發性硬
化、I型糖尿病、乾燥綜合症和血管炎等;而所述與免疫有關的炎症性皮膚疾病可以包括但不限於特應性皮炎、濕疹、斑禿、銀屑病或白癜風、扁平苔蘚、光澤苔蘚、硬化萎縮性苔蘚、脂膜炎、痤瘡和化膿性汗腺炎等。
以下,將通過實施例對本發明的特定小分子化合物的效果進行詳細描述。
實施例
實施例1合成化合物1的一般方法(TDM-180972)
步驟1:化合物1c(4-(2-氯嘧啶-4-基)苯胺)的製備
向三口燒瓶加入化合物1a(2g,9.129mmol),化合物1b(1.36g,9.129mmol),四三苯基膦鈀(527g,0.45mmol),碳酸鉀(2.5g,18.258mmol),二氧六環(20mL)和水(20mL),用氮氣置換數次,然後將混合物加熱至80℃並攪拌45分鐘。反應結束減壓濃縮反應物,殘餘物通過矽膠色譜法進行純化(石油醚/乙酸乙酯=0-60%),以得到淡黃色固體目標化合物(化合物1c,394mg,收率21%)。LCMS[M+1]+=206。
步驟2:化合物1e((S)-N-(4-(2-氯嘧啶-4-基)苯基)-2,2-二氟環丙烷-1-羧醯胺)的製備
向三口燒瓶中加入化合物1c(300mg,1.459mmol)和化合物1d(187mg,1.531mmol),將混合物用氮氣置換幾次,然後在0℃下加入吡啶(10mL)和三氯氧磷(335.6mg,2.189mmol)。將混合物在室溫攪拌1h,然後減壓濃縮,殘餘物用乙酸乙酯(30mL*3)萃取,合併有機層,並用水(50mL*3)和飽和鹽水(50mL*2)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,殘餘物通過矽膠色譜法進行純化(石油醚/乙酸乙酯=0-12%),以得到黃色固體目標化合物(化合物1e,327.7mg,收率72.5%)。LCMS[M+H]+=310。
步驟3:化合物1((S)-4-((4-(4-(4-(2,2-二氟環丙烷-1-羧醯胺基)苯基)嘧啶-2-基)氨基)-N-乙基苯甲醯胺)的製備
向化合物1e(80mg,0.258mmol)的正丁醇(8mL)溶液加入化合物1f(85mg,0.517mmol)和對甲苯磺酸一水合物(98mg,0.517mmol)。將所得混合物加熱至110℃並攪拌3小時。反應結束將混合物在減壓下濃縮,殘餘物通過製備型HPLC(甲酸)純化,以得到黃色固體目標化合物TDM-180972(化合物1,19.7mg,收率17.5%)。LCMS[M+H]+=438.2。
1H NMR(400MHz,DMSO)δ 10.70(s,1H),9.91(s,1H),8.57(d,J=5.3Hz,1H),8.28(t,J=5.5Hz,1H),8.19(d,J=8.8Hz,2H),7.92(d,J=8.9Hz,2H),7.83(d,J=8.9Hz,2H),7.78(d,J=8.8Hz,2H),7.44(d,J=5.3Hz,1H),3.28(dt,J=12.7,6.4Hz,2H),2.86(ddd,J=13.6,10.8,8.0Hz,1H),2.12-1.94(m,2H),1.13(t,J=7.2Hz,3H)。
實施例2合成化合物2的一般方法(TDM-180974)
步驟1:化合物2((S)-5-((4-(4-(4-(2,2-二氟環丙烷-1-羧醯胺基)苯基)嘧啶-2-基)氨基)-3-甲基吡啶啉)的製備
向化合物2a(80mg,0.258mmol)的正丁醇(8mL)溶液加入化合物2b(78mg,0.517mmol)和對甲苯磺酸一水合物(98mg,0.517mmol),將混合物加熱至115℃並攪拌過夜。反應結束將混合物在減壓下濃縮,向殘餘物中加入甲醇,通過過濾收集固體,通過製備型HPLC(甲酸)純化固體,以得到白色固體目標化合物TDM-180974(化合物2,18.9mg,收率10.6%)。LCMS[M+H]+=425.2。
1H NMR(400MHz,DMSO)δ 10.73(s,1H),10.08(s,1H),8.89(d,J=2.2Hz,1H),8.60(d,J=5.3Hz,1H),8.23(d,J=2.0Hz,1H),8.18(d,J=8.8Hz,2H),7.90(s,1H),7.79(d,J=8.8Hz,2H),7.49(d,J=5.3Hz,1H),7.26(s,1H),2.87(ddd,J=13.6,10.8,8.1Hz,1H),2.61(s,3H),2.10-1.96(m,2H)。
實施例3合成化合物3的一般方法(TDM-180977)
步驟1:化合物3b(4-氨基-N-乙基-2-甲基苯甲醯胺)的製備
向化合物3a(1.8g,11.91mmol)的N,N-二甲基甲醯胺(80mL)溶液中加入2-(7-氮雜苯並三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(5.4g,14.289mmol)和N,N-二異丙基乙胺(3.8g,29.775mmol),將混合物攪拌5分鐘,然後加入乙胺的四氫呋喃(2M)(9mL,18mmol)溶液,將混合物在室溫攪拌過夜。減壓濃縮混合物除去一些溶劑,向殘餘物中加入水並用乙酸乙酯(100mL*3)萃取,合併有機相,用水(150mL*3)和飽和鹽水(150mL)洗滌,用硫酸鈉乾燥,減壓濃縮濾液,通過矽膠色譜法純化(石油醚/乙酸乙酯=0%-50%),以得到黃色油狀目標化合物(化合物3b,1.32g,收率62.2%)。LCMS[M+1]+=179。
步驟2:化合物3((S)-4-((4-(4-(4-(2,2-二氟環丙烷-1-羧醯胺基)苯基)嘧啶-2-基)氨基)-N-乙基-2-甲基苯甲醯胺)的製備
向化合物3c(80mg,0.258mmol)的正丁醇(8mL)溶液加入化合物3b(92mg,0.517mmol)和對甲苯磺酸一水合物(98mg,0.517mmol)。將所得混合物加熱至110℃並攪拌3小時。反應結束將混合物在減壓下濃縮,殘餘物通過製備型HPLC(甲酸)純化,以得到白色固體目標化合物TDM-180977(化合物3,19.4mg,收率13.3%。LCMS[M+H]+=425.2。
1H NMR(400MHz,DMSO)δ10.70(s,1H),9.72(s,1H),8.54(d,J=5.3Hz,1H),8.18(d,J=8.8Hz,2H),8.08(d,J=5.6Hz,1H),7.81-7.67(m,4H),7.40(d,J=5.3Hz,1H),7.32(d,J=8.4Hz,1H),3.28-3.17(m,2H),2.86(ddd,J=13.6,10.8,8.1Hz,1H),2.37(s,3H),2.14-1.93(m,2H),1.11(t,J=7.2Hz,3H)。
實施例4合成化合物4的一般方法(TDM-180981)
步驟1:化合物4((S)-5-((4-(4-(4-(2,2-二氟環丙烷-1-羧醯胺基)苯基)嘧啶-2-基)氨基)-N,3-二甲基吡啶啉醯胺)的製備
以與實施例3相似的方法製備得到化合物4(白色固體,3.5mg,收率1.6%)。
1H NMR(400MHz,DMSO)δ10.74(s,1H),10.06(s,1H),8.92(d,J=2.2Hz,1H),8.60(d,J=5.3Hz,1H),8.48(d,J=4.8Hz,1H),8.22-8.18(m,2H),8.17(s,1H),7.78(d,J=8.8Hz,2H),7.49(d,J=5.3Hz,1H),2.87(ddd,J=13.6,10.8,8.0Hz,1H),2.78(d,J=4.8Hz,3H),2.61(s,3H),2.03(ddd,J=18.1,11.7,6.0Hz,2H)。LCMS[M+H]+=439.2。
實施例5合成化合物5的一般方法(TDM-180989)
步驟1:化合物5c(2-(5-硝基吡啶-2-基)丙二酸1-(叔丁基)3-甲基酯)的製備
在室溫下向化合物5a(10g,63.076mmol)的N,N-二甲基甲醯胺(100mL)溶液中加入碳酸鉀(17.435g,126.152mmol)和化合物5b(13.185g,75.691mmol),混合物用氮氣置換幾次。將混合物加熱至100℃並攪拌過夜。反應結束將混合物冷卻至室溫,然後添加飽和氯化銨溶液(150mL),將混合物過濾,將濾液用乙酸乙酯(300mL*3)萃取,合併有機層,用飽和鹽水(200mL*2)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,殘餘物通過矽膠色譜法進行純化(石油醚/乙酸乙酯=0%-6%),以得到黃色油狀目標化合物(化合物5c,7.286g,收率39%)。LCMS[M-C4H9]+=241.1。
步驟2:化合物5d(1-(叔丁基)3-甲基-2-甲基-2-(5-硝基吡啶-2-基)丙二酸酯)的製備
在0℃下,向化合物5c(7g,23.626mmol)的N,N-二甲基甲醯胺(150mL)溶液中加入碳酸銫(15.4g,47.252mmol)。然後將混合物溫熱至室溫並攪拌10分鐘,添加碘甲烷(13.4g,94.505mmol),在室溫攪拌3小時。反應結束在0℃下向混合物中加入水(150mL),並用乙酸乙酯(150mL*3)萃取,合併有機層,並用飽和鹽水(250mL*2)洗滌,用硫酸鈉乾燥,將濾液減壓濃縮,殘留物通過矽膠色譜純化(石油醚/乙酸乙酯=0%-3%),得到黃色油狀目標化合物(化合物5d,6.026g,收率82.2%)。LCMS[M-C4H9]+=255.1。
步驟3:化合物5e(2-(5-硝基吡啶-2-基)丙酸丙酯)的製備
向化合物5d(6g,19.366mmol)的二氯甲烷(150mL)溶液中加入三氟乙酸(50mL)。將混合物在室溫攪拌3小時。反應結束將混合物在減壓下濃縮,殘餘物通過矽膠色譜法純化(石油醚/乙酸乙酯=0%-6%),得到黃色油狀目標化合物(化合物5e,3.671g,收率90.3%)。LCMS[M+1]+=211.1。
步驟4:化合物5f(2-(5-氨基吡啶-2-基)丙酸甲酯)的製備
在室溫下向化合5e(3.67g,17.460mmol)的甲醇(120mL)溶液中加入合適的鈀碳,混合物用氫氣置換幾次,然後在室溫下攪拌2小時。反應結束將混合物過濾並將濾液減壓濃縮,殘餘物通過矽膠色譜法純化(石油醚/乙酸乙酯=0%-50%),以得到黃色油狀目標化合物(化合物5f,2.6025g,收率82.7%)。
LCMS[M+1]+=181。
步驟5:化合物5g(2-(5-氨基吡啶-2-基)丙-1-醇)的製備
在100mL三頸燒瓶中,用氮氣置換瓶內空氣,在冰浴下加入氫化鋁鋰(1.8g,47.26mmol),然後逐滴加入四氫呋喃(180mL),然後加入化合物5f(1.31g,7.27mmol)的四氫呋喃(20mL)溶液。將反應溫熱至室溫並攪拌2小時。反應結束將反應液在冰浴中冷卻,並依次滴加1.8mL水、1.8mL的15%氫氧化鈉水溶液和5.4mL水。將混合物過濾以獲得濾液,並將濾餅用乙酸乙酯洗滌。將濾液用無水硫酸鈉乾燥,過濾並濃縮,以獲得黃色油狀目標化合物(化合物5g,1.2g,收率95%)。LCMS[M+1]+=153。
步驟6:化合物5((1S)-2,2-二氟-N-(4-(2-((6-(1-(1-羥基丙烷-2-基)吡啶-3-基)氨基)嘧啶-4-基)苯基)環丙烷-1-羧醯胺)的製備
向化合物389h(100mg,0.323mmol),化合物389g(98mg,0.646mmol),醋酸鈀(7.3mg,0.032mmol),4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(37.4mg,0.065mmol)和碳酸銫(316mg,0.969mmol)的混合物中加入二氧六環(25mL),將混合物用氬氣置換幾次,將混合物加熱至100℃並攪拌1小時。反應結束向反應混合物中加入水(30mL),並用乙酸乙酯(30mL*3)萃取,合併有機層,然後用水(60mL)和飽和鹽水(60mL)洗滌,用硫酸鈉乾燥,將濾液在減壓下濃
縮,殘餘物通過製備型HPLC(甲酸)進行純化,以得到淡黃色固體目標化合物TDM-180989(化合物5,30.3mg,收率18.4%)。LCMS[M+H]+=426.1。
1H NMR(400MHz,DMSO)δ 10.70(s,1H),9.71(s,1H),8.86(d,J=2.5Hz,1H),8.52(d,J=5.3Hz,1H),8.20-8.10(m,3H),7.77(d,J=8.8Hz,2H),7.39(d,J=5.3Hz,1H),7.22(d,J=8.5Hz,1H),4.60(s,1H),3.64(dd,J=10.3,6.6Hz,1H),3.50(dd,J=10.3,7.0Hz,1H),2.98-2.81(m,2H),2.13-1.94(m,2H),1.20(d,J=7.0Hz,3H)。
實施例6合成化合物6的一般方法(TDM-180971)
步驟1:化合物6c(5-(2-氯嘧啶-4-基)吡啶-2-胺)的製備
向250mL的三口燒瓶中加入化合物6a(1.5g,10mmol),化合物6b(2.21g,1.01mmol),四(三苯基膦)鈀(1.16g,1mmol),碳酸鉀(2.76g,20mmol),1,4-二氧六環(60mL)和水(60mL),反應液用氮氣置換數次,升溫至80℃攪拌45分鐘,LCMS[M+H]+=227,檢測反應完全。後處理:反應液濃縮拉幹,得到的粗品過柱,[洗脫劑:(EA/PE)=0-70%]得到黃色固體目標化合物(化合物6c,1.47g,收率71.36%),LCMS[M+1]+=207。
步驟2:化合物6e((S)-N-(5-(2-氯嘧啶-4-基)吡啶-2-基)-2,2-二氟環丙烷-1-羧醯胺)的製備
向化合物6c(1.47g,7.11mmol)的無水吡啶(50ml)溶液加入化合物6d(910mg,7.47mmol)和三氯氧磷(1.64g,10.67mmol)。反應液在室溫下攪拌1小時,LCMS[M+H]+=311,檢測反應完全。後處理:反應液濃縮拉幹,殘餘物加水和乙酸乙酯(3*100mL)萃取三次,合併有機相,並用飽和食鹽水洗,無水硫酸鈉乾燥,過濾,濃縮拉幹,得到的粗品過柱,[洗脫劑:(EA/PE)=0-30%],粗品再重結晶,以得到黃色固體目標化合物(化合物6e,1.73g,收率78.6%),LCMS[M+H]+=311。
步驟3:化合物6((S)-4-((4-(6-(2,2-二氟環丙烷-1-甲醯胺基)吡啶-3-基)嘧啶-2-基)氨基)-N-乙基苯甲醯胺)的製備
向化合物6e(100mg,0.32mmol)的正丁醇(10ml)溶液中加入化合物6f(105.7mg,0.64mmol)和一水合對甲苯磺酸(122.5mg,0.64mmol)。反應液升溫至110℃攪拌2小時,LCMS[M+H]+=439,檢測反應完全。後處理:反應液濃縮拉幹,製備得到黃色固體目標化合物(化合物6,12.3mg,收率8.7%),LCMS[M+H]+=439.2。
1H NMR(400MHz,DMSO)δ 11.30(s,1H),9.99(s,1H),9.25-9.06(m,1H),8.62(d,J=5.2Hz,1H),8.57(dd,J=8.8,2.4Hz,1H),8.34-8.17(m,2H),7.90(d,J=8.9Hz,2H),7.82(d,J=8.9Hz,2H),7.53(d,J=5.2Hz,1H),3.28(dt,J=12.7,6.4Hz,2H),3.04(dd,J=8.8,5.7Hz,1H),2.12-1.98(m,2H),1.13(t,J=7.2Hz,3H)。
實施例7合成化合物7的一般方法(TDM-180979)
步驟1:化合物7((S)-5-((4-(6-(2,2-二氟環丙烷-1-羧醯胺基)吡啶-3-基)嘧啶-2-基)氨基)-N,3-二甲基吡啶啉醯胺)的製備
向化合物7a(100mg,0.32mmol)的二氧六環(25ml)溶液中加入化合物7b(106.3mg,0.64mmol),乙酸鈀(3.6mg,0.02mmol),4,5-雙(二苯基膦)-9,9-二甲基氧雜蒽(18.6mg,0.03mmol)和碳酸銫(314.7mg,0.97mmol)。反應液用氬氣置換數次,並升溫至100℃攪拌2小時,LCMS[M+H]+=440,檢測反應完全。後處理:將反應液濃縮至幹,殘留物用甲醇打漿,粗品製備得到黃色固體目標化合物(化合物7,6.4mg,收率3.2%),LCMS[M+1]+=440.0。
1H NMR(400MHz,DMSO)δ 11.34(s,1H),10.15(s,1H),9.17(d,J=2.0Hz,1H),8.87(d,J=2.2Hz,1H),8.65(d,J=5.2Hz,1H),8.56(dd,J=8.8,2.4Hz,1H),8.50(d,J=4.8Hz,1H),8.30-8.18(m,2H),7.58(d,J=5.3Hz,1H),3.04(dd,J=8.9,3.5Hz,1H),2.77(d,J=4.8Hz,3H),2.61(s,3H),2.05(dt,J=10.7,5.2Hz,2H)。
實施例8合成化合物8的一般方法(TDM-180980)
步驟1:化合物8((S)-5-((4-(6-(2,2-二氟環丙烷-1-羧醯胺基)吡啶-3-基)嘧啶-2-基)氨基)-3-甲基吡啶啉醯胺)的製備
以相似的方法製備得到化合物8(2.3mg,黃色固體,收率1.2%)。1H NMR(400MHz,DMSO)δ 11.35(s,1H),10.16(s,1H),9.18(d,J=2.0Hz,1H),8.84(d,J=2.2Hz,1H),8.66(d,J=5.2Hz,1H),8.56(dd,J=8.8,2.4Hz,1H),8.25(dd,J=8.2,5.5Hz,2H),7.90(s,1H),7.58(d,J=5.3Hz,1H),7.25(s,1H),3.13-2.94(m,1H),2.61(s,3H),2.06(d,J=9.6Hz,2H)。LCMS[M+H]+=426.1。
實施例9合成化合物9的一般方法(TDM-180984)
步驟1:化合物9((S)-4-((4-(6-(2,2-二氟環丙烷-1-羧醯胺基)吡啶-3-基)嘧啶-2-基)氨基)-N-乙基-2-甲基苯甲醯胺)的製備
以相似的方法製備得到化合物9(26.6mg,黃色固體,收率13.04%)。1H NMR(400MHz,DMSO)δ 11.33(s,1H),9.80(s,1H),9.17(d,J=1.8Hz,1H),8.68-8.49(m,2H),8.22(d,J=8.7Hz,1H),8.09(t,J=5.6Hz,1H),7.80-7.61(m,2H),7.50(d,J=5.2Hz,1H),7.32(d,J=8.4Hz,1H),3.28-3.19(m,2H),3.04(dt,J=13.5,9.8Hz,1H),2.37(s,3H),2.12-2.00(m,2H),1.11(t,J=7.2Hz,3H)。LCMS[M+H]+=453.2。
實施例10合成化合物10的一般方法(TDM-180987)
步驟1:化合物10((1S)-2,2-二氟-N-(5-(2-((6-(1-(羥丙基-2-基)吡啶基-3-基)氨基)嘧啶基-4-基)吡啶基-2-基環丙烷-1-羧醯胺)的製備
以相似的方法製備得到化合物10(79mg,類白色固體,收率27.8%)。
1H NMR(400MHz,DMSO)δ 11.30(s,1H),9.79(s,1H),9.13(d,J=2.1Hz,1H),8.84(d,J=2.5Hz,1H),8.65-8.46(m,2H),8.30-8.07(m,2H),7.48(d,J=5.2Hz,1H),7.22(d,J=8.5Hz,1H),4.59(t,J=5.3Hz,1H),3.71-3.43(m,2H),3.04(dt,J=13.5,9.9Hz,1H),2.91(dt,J=14.0,7.0Hz,1H),2.13-1.95(m,2H),1.20(d,J=6.9Hz,3H)。LCMS[M+H]+=427.1。
測試例1 JAK激酶小分子抑制劑的酶活性抑制檢測
實驗方案
1、試劑準備
激酶反應緩衝液:配置激酶反應緩衝液,組分如下:50mM HEPES,pH 7.5,1mM EGTA,10mM MgCl2,2mM DTT,0.01% Tween20。1X檢測緩衝液:配置檢測緩衝液,去離子水9:1稀釋10X檢測緩衝液至1X。4X激酶溶液:激酶反應緩衝液稀釋JAK激酶至4X終濃度(JAK1:80nM,JAK2/JAK3/Tyk2:4nM)。4X底物溶液:激酶反應緩衝液稀釋ULightTM-JAK(Tyr1023)底物至200nM(終濃度:50nM)。4XATP溶液:激酶反應緩衝液稀釋ATP至4X終濃度(JAK1:160μM,JAK2/JAK3/Tyk2:40μM)。4X測試化合物溶液:DMSO溶解測試用化合物至10mM儲存液,3倍梯度稀釋配置成所需濃度,每個化合物設置10個濃度點,測試化合物終濃度範圍為:10μM-0.5nM。4X酶反應終止液:1X檢測緩衝液溶解EDTA至40mM(EDTA終濃度:10mM)。4X檢測抗體溶液:1X檢測緩衝液稀釋Eu標記檢測抗體(抗磷酸酪氨酸(PT66))至8nM(抗體終濃度:2nM)。
2、實驗過程
向384微孔板中依次加入2.5μL的4X激酶溶液和2.5μL已經稀釋好的不同濃度的4X測試化合物溶液,每個濃度設置2個複孔,同時設置酶溶液空白
對照組和陰性對照組(DMSO組)。震盪384多孔板,混勻酶和化合物,1000轉,離心1分鐘,在室溫下孵育60分鐘。向384多孔板中加入2.5μL,4X底物溶液,1000轉離心1分鐘。向384多孔板中加入2.5μL,4XATP溶液,1000轉離心1分鐘,起始酶反應。JAK1室溫反應2小時,JAK2/JAK3/Tyk2室溫反應1小時。JAK1反應的各組分終濃度分別為:JAK1:20nM,底物:50nM,ATP:40uM,測試化合物終濃度範圍為:10μM-0.5nM。JAK2/JAK3/Tyk2反應的各組分終濃度分別為:JAK2:1nM,底物:50nM,ATP:10μM,測試化合物終濃度範圍為:10μM-0.5nM。酶反應結束後,向384多孔板每孔中加入5μL,4X酶反應終止液,1000轉,離心1分鐘,在室溫下孵育5分鐘。向384多孔板每孔中加入5μL,4X檢測抗體溶液,(檢測抗體終濃度為2nM),1000轉,離心1分鐘,室溫條件下孵育1小時。抗體孵育結束後,在Envision讀板儀上測定各孔的信號值。
3、資料分析
以酶溶液空白對照組為100%抑制率和陰性對照組(DMSO組)為0%抑制率,計算檢測各個濃度對應的百分比抑制率。在GraphPad Prism軟體中對檢測化合物的濃度對數值和相對應的百分比抑制率進行非線性回歸分析,得到檢測化合物的半數抑制濃度(IC50),針對實施例1-10的化合物所測得的實驗結果列在下表1中。
從上表1的結果可以看出,本申請的化合物的酶活性資料非常優異,以上具體化合物測得的半數抑制濃度較低,特別是針對Tyk2、JAK1和JAK2時基本上達到小於0.03μM,尤其是化合物TDM-180972、TDM-180974、TDM-180977、TDM-180981、TDM-180971和TDM-180984,其半數抑制濃度均小於0.01μM。因此,通過以上實驗已經證明了本申請的小分子化合物是一類針對JAK家族靶向性強、酶活性優異的化合物,能夠作為JAK1/Tyk2雙抑制劑和Tyk2特異性抑制劑。
以上詳細描述了本發明的優選實施方式,但是,本發明並不限於上述實施方式中的具體細節,在本發明的技術構思範圍內,可以對本發明的技術方案進行多種簡單變型,這些簡單變型均屬於本發明的保護範圍。
另外需要說明的是,在上述具體實施方式中所描述的各個具體技術特徵,在不矛盾的情況下,可以通過任何合適的方式進行組合,為了避免不必要的重複,本發明對各種可能的組合方式不再另行說明。
此外,本發明的各種不同的實施方式之間也可以進行任意組合,只要其不違背本發明的思想,其同樣應當視為本發明所公開的內容。
Claims (7)
- 如請求項1所述的小分子化合物,其中,R6選自氫、烷基或環烷基。
- 如請求項1所述的小分子化合物,其中,R9選自氫、烷基或環烷基。
- 如請求項1-3中任一項所述的小分子化合物在製備用於抑制JAK激酶的藥物中的用途。
- 如請求項1-3中任一項所述的小分子化合物在製備用於預防或治療自身免疫性疾病、以及與免疫有關的炎症性皮膚疾病的藥物中的用途,其中,這些疾病的發病機理均與JAK信號傳導的失調相關。
- 如請求項5所述的用途,其中,所述自身免疫性疾病選自類風濕性關節炎、強直性脊柱炎、潰瘍性結腸炎、克羅恩病、系統性紅斑狼瘡、皮肌炎、多發性硬化、I型糖尿病、乾燥綜合症和血管炎中的至少一種。
- 如請求項5所述的用途,其中,所述與免疫有關的炎症性皮膚疾病選自特應性皮炎、濕疹、斑禿、銀屑病、白癜風、扁平苔蘚、光澤苔蘚、硬化萎縮性苔蘚、脂膜炎、痤瘡和化膿性汗腺炎中的至少一種。
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