TW202304881A - 經吡啶基取代之側氧基異吲哚啉化合物 - Google Patents
經吡啶基取代之側氧基異吲哚啉化合物 Download PDFInfo
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Abstract
Description
本發明大體上關於抑制Helios蛋白之經吡啶基取代之側氧基異吲哚啉化合物。本文中提供經吡啶基取代之側氧基異吲哚啉化合物,包含此等化合物之組合物,及其使用方法。本發明進一步關於包含根據本發明之至少一種化合物之醫藥組合物,其可用於治療增殖性病症(諸如癌症)及病毒感染。
調節性T細胞(Treg)於控制自身耐受及免疫穩態中起著必要作用,該控制經由在面對各種免疫及發炎反應時維持抑制活性及無能。通過保留穩定、無能及抑制性表現型,Treg減弱過度免疫反應及預防或改善自身免疫。許多報導已記載,Treg於人類腫瘤組織中之存在。研究證實,Treg之數目與T細胞浸潤至腫瘤及生存之間之明確負相關(Curiel等人,2004,
Nat. Med.10: 942-949;Viguier等人,2004,
J Immuno.1173:1444-1453;Beyer等人,2006,
Blood108: 804-811;Zou等人,2006,
Nat. Rev. Immunol.6: 295-307),這暗示Treg於防止有效抗腫瘤免疫之發展中之潛在關鍵作用。累積之證據指示,在嚙齒動物及人類中,Foxp3+CD25+CD4+Treg主要浸潤至腫瘤及顯然阻礙對腫瘤細胞之免疫反應。一旦藉由特異性抗原活化,Treg就以抗原非特異性及旁觀者方式活體外抑制響應T細胞(Takahashi等人,1998,
Int Immunol.10:1969–80;Thornton等人,1998,
J Exp. Med.188:287-96)。Foxp3+CD25+CD4+Treg顯然能抑制寬範圍之抗腫瘤免疫反應,涉及CD4+輔助T細胞、CD8+ T細胞、自然殺手細胞及自然殺手T細胞(Tanaka等人,2017,
Cell Research27:109-118)。CD25+CD4+Treg之腫瘤內耗盡誘導建立之腫瘤之消退,其中改變在腫瘤位點處之細胞激素環境(Yu等人,2005,
J Exp Med.201: 779-91)。此外,與含有Treg之T-細胞轉移相比,Treg耗盡之CD4+ T細胞之轉移顯著增強抗腫瘤免疫反應(Antony等人,2005,
J Immunol174:2591-601)。藉由腫瘤衍生之自抗原或腫瘤相關抗原活化之腫瘤浸潤性Treg可相似抑制特異性抗腫瘤免疫反應。關鍵因子控制Treg分化之活性之調節可代表用於治療某些疾病(包括癌症及病毒感染)之潛在治療策略。
FoxP3+CD4 Treg係明顯穩定的。研究仍演進為理解於擴增後在發炎、感染或自體免疫期間確保其表現型穩定性之遺傳機制。負責維持Treg之穩定免疫抑制表現型之轉錄因子(TF)可有助於此過程。Helios (IKZF2)基因(TF之Ikaros家族之一成員)不同於其他Ikaros家族成員,基於其藉由經歷陰性選擇之胸腺細胞以及藉由CD4及CD8 T細胞之調節譜系之選擇性表現。Helios藉由兩種調節性T-細胞譜系FoxP3+CD4+及Ly49+CD8+ Treg表現,該等Treg對維持自身耐受必需(Kim等人,2015,
Science350:334-339;Sebastian等人,2016,
J Immunol196:144-155)。有趣的是,最近研究表明,雖然Helios針對穩態下之Treg活性很大程度上可有可無,但是在發炎背景下FoxP3+ CD4 Treg之遺傳程式藉由Helios之控制對維持穩定表現型及強化抑制功能係必需的(Thornton等人,2010,
J Immunol.184:3433-3441;Kim等人,2015)。Helios藉由Treg之表現被證實於其在面對強烈發炎反應時維持抑制性且無能表現型之能力中係關鍵的。IL-2Rα-STAT5路徑之活化被證實為確保Treg生存及穩定性之關鍵貢獻者(Kim等人,2015)。Helios藉由發揮顯性淋巴細胞內在抑制於維持FoxP3+ CD4 Treg之表現型中起著不可或缺作用以防止在存在來自有皮屑小鼠之高度活化之自體反應性T細胞下之自體免疫性疾病,該等T細胞不具有FoxP3叉頭域。利用Helios–/–/有皮屑BM但是非Helios+/+/有皮屑BM細胞重新構成之骨髓(BM)嵌合體快速發展自體免疫(Kim等人,2015)。此等觀察結果指示,Helios對自體反應性T細胞選擇、分化及功能之重要貢獻。藉由Treg發揮之免疫抑制可阻礙抗腫瘤免疫反應。Helios於FoxP3+ CD4 Treg中之選擇性缺乏導致增加之Treg不穩定性及腫瘤內CD4 Treg轉化為效應T細胞(Teff)。腫瘤內Treg之不穩定性可增加腫瘤內之Teff細胞之數目,由於Treg轉化及降低之Treg抑制活性的組合結果。此外,於Helios缺乏之腫瘤內Treg中觀察到缺乏IL-2反應,其導致經活化Treg之數目減少及亦可有助於增加腫瘤內Teff活性。腫瘤細胞與浸潤免疫細胞之間之相互作用導致發炎介體(包括TNF-α、IL-6、IL-17、IL-1及TGF-β)之分泌及局部發炎性環境之形成(Kim等人,2015)。
Helios缺乏之Treg之譜系不穩定性亦伴隨減少之FoxP3表現及導致藉由產生促發炎性細胞激素獲取效應子表現型。Helios缺乏之Treg於腫瘤-組織微環境中之效應細胞轉化係與控制Teff表現型之基因之表現增加相關聯(Yates等人,2018,
PNAS, 2018, 115: 2162-2167)。藉由Helios缺乏獲取不穩定表現型僅於腫瘤微環境(TME)中發生,但是不在外周淋巴器官中發生(Nakagawa等人,2016,
PNAS113: 6248-6253)。在慢性發炎性TME中,Treg中之Helios缺乏可藉由上調T輔助細胞相關之TF及效應細胞激素急劇緩和與T輔助細胞分化相關之抑制之遺傳程式。Helios缺乏之Treg之此等遺傳變化於具有高自身抗原親和力之Treg亞群體中最明顯,如由增強之GITR/PD-1表現及對自身抗原之反應性增加所示。其組合效應可促進於TME中Treg至Teff之表現型轉化,與增加之T-細胞受體(TCR)接合及藉由Treg之共刺激受體表現,這表明作為Treg轉化之主要特徵之基因表現之更改係免疫環境依賴性(Yates等人,2018)。
FoxP3+ CD4 Treg中之Helios表現減少可允許記憶Treg細胞轉化為Teff細胞,該Teff細胞以針對腫瘤抗原之特異性表現自體反應性T-細胞受體。更改之Treg基因特徵可在生長腫瘤之慢性發炎條件中經選擇性誘導。Helios缺乏之Treg可顯示傾向針對自體肽/MHC之高親和力之TCR庫,其可促進TME中之穩健活化(Yates等人,2018)。鑑於CD4 Treg中之TCR之自體反應性與習知T細胞相比增加,Treg之轉化可產生高度強效效應CD4 T細胞,伴隨TME內之減弱之Treg介導之抑制。更有效策略可取決於將腫瘤內Treg選擇性轉化成Teff細胞而不影響系統性Treg群體之方法。作為維持Treg尺寸及對不同免疫擾動反應之功能穩定性的關鍵角色,Helios之藥理學干預可與加強目前腫瘤免疫療法之策略相關。因為Treg轉化為Teff可侷限於發炎性腫瘤內微環境,所以靶向Helios之基於抗體或小分子之方法可導致改善之Treg依賴性癌症免疫療法。重要的是,Helios缺乏之Treg之轉化僅於腫瘤之局部發炎性環境內發生。此方法可不激起與Treg之全身減少相關之自體免疫副作用。因此,特別利用腫瘤內Treg表現型之Helios依賴性控制之策略代表改善癌症免疫療法之重要前景。此外,亦報導移除Foxp3+Treg以增強疫苗誘導之抗腫瘤T-細胞反應(Nishikawa等人,2010,
Int. J. Cancer127: 759-767),這表明減少Helios含量於加強癌症疫苗之功效中可係有益。
除了抗腫瘤免疫療法外,在病毒感染期間,Treg細胞可限制因過度發炎所致之免疫病理學,又潛在抑制有效抗病毒T細胞反應及促進病毒持久性(Schmitz等人,2013,
PLOS Pathogens9: e1003362)。小鼠經淋巴細胞性脈絡叢腦膜炎病毒之慢性(但是非急性)感染導致Foxp3+ Treg之顯著擴增,這暗示某些感染劑可藉由活化及擴增Treg來逃避宿主免疫反應之潛在機制(Punkosdy等人,2011,
PNAS108: 3677-3682)。治療效益可藉由在與慢性病毒感染相關之背景中降低經活化Treg中之Helios含量來達成。
存在對可用作Helios蛋白之抑制劑之化合物的需求。
本發明提供式(I)之經吡啶基取代之側氧基異吲哚啉化合物或其鹽,其可用於降低細胞中之Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度。
本發明亦提供醫藥組合物,其包含式(I)化合物及/或其醫藥上可接受之鹽;及醫藥上可接受之載劑。
本發明亦提供一種藉由降低Helios蛋白活性來治療疾病或病症之方法,該方法包括向患者投與式(I)化合物及/或其醫藥上可接受之鹽。
本發明亦提供製備式(I)化合物及/或其鹽之方法及中間體。
本發明亦提供式(I)化合物及/或其醫藥上可接受之鹽,其用於療法中。
本發明亦提供式(I)化合物及/或其醫藥上可接受之鹽之用途,其用於製造降低細胞中之Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度以控制Treg分化之藥劑,用於治療某些疾病,包括癌症及病毒感染。
式(I)化合物及包含式(I)化合物之組合物可用於治療、預防或治癒病毒感染及各種增殖性病症,諸如癌症。包含此等化合物之醫藥組合物可用於治療、預防或減慢各種治療領域之疾病或病症(諸如病毒感染及癌症)之進展。
本發明之此等及其他特徵將隨著本發明繼續以擴展形式闡述。
交互參照
本申請案主張2021年4月6日申請之印度臨時申請案序列號202111016193及2021年5月17日申請之印度臨時申請案序列號202111022098的權益,各者之全文經併入本文中。
申請者已發現經取代之側氧基異吲哚啉化合物,其藉由促進Helios蛋白與對應E3泛素連接酶複合物(Cullin4-Cereblon,CUL4-CRBN)之間之相互作用來抑制Helios蛋白。此等化合物降低細胞中之Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度以控制Treg分化。此等化合物可用於治療某些疾病,包括癌症及病毒感染。提供化合物可用作具有所需穩定性、生物可利用率、治療指數及對其可成藥性重要之毒性值之藥物。
本發明之第一態樣提供至少一種式(I)化合物:
或其鹽,其中:
R
1為-NH
2或-NH(CH
3);
各R
2獨立地為F、Cl、-CN、C
1-4烷基、-CH
2F、-CHF
2、-CF
3、-OCH
3或環丙基;
各R
4獨立地為F、Cl、-CH
3、-CH
2F、-CHF
2、-CF
3或-OCH
3;
R
6為氫、C
1-2烷基或C
1-2氟烷基;
m為0、1、2或3;且
n為0、1、2或3;
附帶條件為當R
6為氫時,m為1、2或3。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH
2。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH(CH
3)。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為F、Cl、-CN、-CH
3、-CH
2CH
3、-CH(CH
3)
2、-CH
2CH
2CH
2CH
3、-CH
2F、-CHF
2、-CF
3、-OCH
3或環丙基。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為F、Cl、-CN、-CH
3、-CH
2CH
3、-CH(CH
3)
2、-CH
2CH
2CH
2CH
3、-CH
2F、-CHF
2或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為F、Cl、-CN、-CH
3、-CH
2CH
3、-CH
2F、-CHF
2或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為F、Cl、-CN、-CH
3或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為-CN、-CH
3或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為F、-CN、-CH
3或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為F、-CN或-CH
3。
一個實施例提供式(I)化合物或其鹽,其中n為0、1或2。
一個實施例提供式(I)化合物或其鹽,其中n為0或1。
一個實施例提供式(I)化合物或其鹽,其中n為1或2。
一個實施例提供式(I)化合物或其鹽,其中n為0。
一個實施例提供式(I)化合物或其鹽,其中n為1。
一個實施例提供式(I)化合物或其鹽,其中n為2。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為-CN、-CH
3或-CF
3;且n為0、1或2。包含於此實施例中為其中n為1或2之化合物。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為-CN、-CH
3或-CF
3;且n為0或1。包含於此實施例中為其中n為1之化合物。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為-CN、-CH
3或-CF
3;且n為2。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為-CN或-CH
3;且n為1或2。包含於此實施例中為其中n為1之化合物。亦包含於此實施例中為其中n為2之化合物。
一個實施例提供式(I)化合物或其鹽,其中各R
2獨立地為-CH
3;且n為1或2。包含於此實施例中為其中n為1之化合物。亦包含於此實施例中為其中n為2之化合物。
一個實施例提供式(I)化合物或其鹽,其中各R
4獨立地為F、Cl、-CH
3、-CH
2F、-CHF
2或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
4獨立地為F、-CH
3、-CH
2F、-CHF
2或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
4獨立地為F、-CH
3、-CHF
2或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中各R
4獨立地為F或-CH
3。
一個實施例提供式(I)化合物或其鹽,其中各R
4為F。包含於此實施例中為其中m為1之化合物。亦包含於此實施例中為其中m為2之化合物。
一個實施例提供式(I)化合物或其鹽,其中各R
4為-CH
3。包含於此實施例中為其中m為1之化合物。亦包含於此實施例中為其中m為2之化合物。
一個實施例提供式(I)化合物或其鹽,其中m為0、1或2。
一個實施例提供式(I)化合物或其鹽,其中m為0或1。
一個實施例提供式(I)化合物或其鹽,其中m為1或2。
一個實施例提供式(I)化合物或其鹽,其中m為1、2或3。
一個實施例提供式(I)化合物或其鹽,其中m為1。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;且m為1、2或3。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;且m為1或2。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;且m為1。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;且m為2。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;且m為3。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;m為1;且R
4為F、Cl、-CH
3、-CH
2F、-CHF
2或-CF
3。包含於此實施例中為其中R
4為F、-CH
3、-CHF
2或-CF
3之化合物。亦包含於此實施例中為其中R
4為F、-CH
3或-CF
3之化合物。另外,包含於此實施例中為其中R
4為F或-CH
3之化合物。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;m為1;且R
4為F。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;m為1;且R
4為-CH
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為氫;m為1或2;且R
4為F或-CH
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基或C
1-2氟烷基。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基、-CH
2F、-CF
2H、-CF
3或-CH
2CF
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基、-CH
2F、-CF
2H或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基。
一個實施例提供式(I)化合物或其鹽,其中R
6為-CH
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為-CH
2F、-CF
2H、-CF
3或-CH
2CF
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為-CH
2F、-CF
2H或-CF
3。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基或C
1-2氟烷基;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基、-CH
2F、-CF
2H、-CF
3或-CH
2CF
3;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基、-CH
2F、-CF
2H或-CF
3;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基或-CF
3;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為C
1-2烷基;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為-CH
3;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為-CH
2F、-CF
2H、-CF
3或-CH
2CF
3;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
6為-CH
2F、-CF
2H或-CF
3;且m為0。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH
2或-NH(CH
3);各R
2獨立地為-CN、-CH
3或-CF
3;各R
4獨立地為F或-CH
3;R
6為氫或-CH
3;m為0或1;且n為1或2;附帶條件為當R
6為氫時,m為1。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH
2;各R
2獨立地為-CN、-CH
3或-CF
3;R
4為F或-CH
3;R
6為氫或-CH
3;m為0或1;且n為1或2;附帶條件為當R
6為氫時,m為1。
一個實施例提供式(I)化合物或其鹽,其中R
1為–NH(CH
3);各R
2獨立地為-CN或-CH
3;R
4為F或-CH
3;R
6為氫或-CH
3;m為0或1;且n為1或2;附帶條件為當R
6為氫時,m為1。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH
2;各R
2獨立地為-CN、-CH
3或-CF
3;各R
4獨立地為F或-CH
3;R
6為-CH
3;m為1;且n為1或2。包含於此實施例中為其中各R
2為-CH
3之化合物。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH
2;各R
2獨立地為-CN或-CH
3;R
4為F或-CH
3;R
6為氫;m為1;且n為1或2。
一個實施例提供式(I)化合物或其鹽,其中R
1為-NH
2或-NH(CH
3);各R
2獨立地為-CH
3;R
4為F;R
6為氫或-CH
3;m為0或1;且n為1或2;附帶條件為當R
6為氫時,m為1。
一個實施例提供式(I)化合物或其鹽,其中該化合物為:2-胺基-6-(2-(2,6-二氧哌啶-3-基)-4-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(1);2-胺基-6-(2-(2,6-二氧哌啶-3-基)-6-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(2);2-胺基-6-(2-(2,6-二氧哌啶-3-基)-4-氟-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(3);3-(5-(6-胺基-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(4);3-(5-(6-胺基-4-(三氟乙基)吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(5);3-(4-氟-5-(4-甲基-6-(甲胺基)吡啶-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(6);3-(5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(7);3-((
S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(8);3-((
R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(9);2-胺基-6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(10);2-胺基-6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(11);3-((S)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(12);3-((R)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(13);6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈(14);6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈(15);3-((
S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(16);3-((
R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(17);3-(5-(6-胺基-3-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(18);3-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(19);3-(5-(6-胺基-3-氟-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(20);3-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(21-22);2-胺基-6-((3
R)-2-(2,6-二氧哌啶-3-基)-4-氟-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(23);3-(
(R)-5-(6-胺基-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(24);3-(
(R)-5-(6-胺基-4-(三氟甲基)吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(25);3-(
(R)-5-(6-胺基-3-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(26);3-(
(R)-5-(6-胺基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(27);
(R)-3-(
(R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(28);3-((R)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(29);或3-((
S)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(30)。
一個實施例提供式(I)化合物或其鹽,其中該化合物為3-((R)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。
一個實施例提供式(I)化合物或其鹽,其中該化合物為3-((S)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。
本發明可在不背離其精神或基本屬性下以其他特定形式體現。本發明包含本文中指定之本發明之態樣及/或實施例之所有組合。應瞭解,本發明之任何及所有實施例可結合任何其他實施例採用以描述另外實施例。亦應瞭解,該等實施例之各個別要素意欲與來自任何實施例之任何及所有其他要素組合以描述另外實施例。
本發明之特徵及優點可藉由一般技術者在閱讀下列實施方式後更容易理解。應瞭解,出於清楚原因,上文及下文在分開實施例之背景下描述之本發明之某些特徵亦可經組合以形成單一實施例。相反,出於簡潔原因,在單一實施例之背景下描述之本發明之各種特徵亦可經組合以便形成其子組合。本文中識別為示例性或較佳之實施例意欲係說明性且非限制性。
除非本文中另有明確指定,否則以單數進行之提及物亦可包含複數。例如,「一(a/an)」可係指一個或一或多個。
如本文中所用,短語「化合物及/或其鹽」係指至少一種化合物、至少一種化合物之鹽、或其組合。例如,式(I)化合物及/或其鹽包含式(I)化合物;兩種式(I)化合物;式(I)化合物之鹽;式(I)化合物及一或多種式(I)化合物之鹽;及兩種或更多種式(I)化合物之鹽。
除非另有指定,否則假設具有不滿足價之任何原子具有足以滿足價之氫原子。
本文中闡述之定義優先於以引用的方式併入本文中之任何專利、專利申請案及/或專利申請公開案中闡述之定義。
下文列出用於描述本發明之各種術語之定義。此等定義適用於該等術語,因為其在整篇本說明書中個別或作為更大基團之部分使用(除非其原本受限於特定實例)。
整篇本說明書,基團及其取代基可藉由熟習此項技術者選擇以提供穩定部分及化合物。
如本文中所用,術語「鹵基」及「鹵素」係指F、Cl、Br及I。
術語「氰基」係指基團-CN。
術語「胺基」係指基團-NH
2。
術語「側氧基」係指基團=O。
如本文中所用,術語「烷基」係指含有(例如) 1至12個碳原子,1至6個碳原子及1至4個碳原子之分支鏈及直鏈飽和脂族烴基二者。烷基之實例包括(但不限於)甲基(Me)、乙基(Et)、丙基(例如,n-丙基及i-丙基)、丁基(例如,n-丁基、i-丁基、sec-丁基及
t-丁基)及戊基(例如,n-戊基、異戊基、新戊基)、n-己基、2-甲基戊基、2-乙基丁基、3-甲基戊基及4-甲基戊基。當數字於符號「C」後之下標中出現時,該下標更具體限定特定基團可含有之碳原子之數目。例如,「C
1‑4烷基」表示具有1至4個碳原子之直鏈及分支鏈烷基。
如本文中所用,術語「氟烷基」意欲包含經一或多個氟原子取代之分支鏈及直鏈飽和脂族烴基二者。例如,「C
1‑4氟烷基」意欲包含經一或多個氟原子取代之C
1、C
2、C
3及C
4烷基。氟烷基之代表性實例包括(但不限於) -CF
3及-CH
2CF
3。
本發明之化合物包含於本發明化合物中出現之原子之所有同位素。同位素包括具有相同原子數但是不同質量數之彼等原子。經由一般實例且非限制性,氫之同位素包含氘(D)及氚(T)。碳之同位素包含
13C及
14C。本發明之同位素標記化合物一般可藉由熟習此項技術者已知之習知技術或藉由類似於本文中所述彼等之方法,使用適宜同位素標記試劑代替原本採用之非標記試劑來製備。
本文中採用短語「醫藥上可接受」係指在健全醫學判斷之範圍內,適用於與人類及動物之組織接觸而無過量毒性、刺激、過敏反應或與合理效益/風險比相稱之其他問題或併發症之彼等化合物、材料、組合物及/或劑型。
式(I)化合物可形成鹽,該等鹽亦於本發明之範圍內。除非另有指定,否則提及本發明化合物應理解為包含提及其一或多種鹽。術語「鹽」表示與無機及/或有機酸及鹼形成之酸性及/或鹼性鹽。此外,術語「鹽」可包含兩性離子(內鹽),例如,當式(I)化合物含有鹼性部分(諸如胺或吡啶或咪唑環),及酸性部分(諸如羧酸)時。醫藥上可接受(即,無毒生理上可接受)之鹽係較佳,諸如,例如,可接受之金屬及胺鹽,其中陽離子不顯著促進鹽之毒性或生物活性。然而,例如,在製備期間可採用之分離或純化步驟中之其他鹽可係可用,及因此,涵蓋於本發明之範圍內。式(I)化合物之鹽可(例如)藉由使式(I)化合物與一定量之酸或鹼(諸如當量)於諸如其中鹽沉澱者之介質中或於水性介質中反應,接著凍乾來形成。
示例性酸加成鹽包括乙酸鹽(諸如與乙酸或三鹵乙酸,例如三氟乙酸形成之彼等)、己二酸鹽、藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、富馬酸鹽、葡庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽(與鹽酸形成)、氫溴酸鹽(與溴化氫形成)、氫碘酸鹽、馬來酸鹽(與馬來酸形成)、2-羥基乙磺酸鹽、乳酸鹽、甲磺酸鹽(與甲磺酸形成)、2-萘磺酸鹽、菸酸鹽、硝酸鹽、草酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、新戊酸鹽、丙酸鹽、水楊酸鹽、琥珀酸鹽、硫酸鹽(諸如與硫酸形成之彼等)、磺酸鹽(諸如本文中提及彼等)、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽(toluenesulfonate/tosylate)、十一酸鹽及類似者。
示例性鹼性鹽包括銨鹽;鹼金屬鹽,諸如鈉、鋰及鉀鹽;鹼土金屬鹽,諸如鈣及鎂鹽;鋇、鋅及鋁鹽;與有機鹼(例如,有機胺),諸如三烷基胺(諸如三乙胺)、普魯卡因(procaine)、二苄基胺、N-苄基-β-苯乙胺、1-二苯羥甲胺、N,N′-二苄基乙-二胺、脫氫樅胺、N-乙基哌啶、苄胺、二環己胺或相似醫藥上可接受之胺之鹽及與胺基酸(諸如精胺酸、離胺酸及類似者)之鹽。鹼性含氮基團可經諸如以下之試劑季銨化:低碳數烷基鹵化物(例如,甲基、乙基、丙基及丁基氯化物、溴化物及碘化物)、硫酸二烷酯(例如,硫酸二甲酯、硫酸二乙酯、硫酸二丁酯及硫酸二戊酯)、長鏈鹵化物(例如,癸基、月桂基、肉豆蔻基及硬脂醯基氯化物、溴化物及碘化物)、芳烷基鹵化物(例如,苄基及苯乙基溴化物)及其他。
式(I)化合物可呈非晶型固體或結晶固體提供。可採用凍乾以提供呈固體之式(I)化合物。
應進一步瞭解,式(I)化合物之溶劑化物(例如,水合物)亦於本發明之範圍內。術語「溶劑化物」意指式(I)化合物與一或多種溶劑分子(無論有機或無機)之物理締合。此物理締合包含氫鍵結。於某些實例中,例如,當將一或多種溶劑分子併入結晶固體之晶格中時,溶劑化物將能分離。「溶劑化物」包含溶液相及可分離溶劑化物二者。示例性溶劑化物包括水合物、乙醇酸鹽、甲醇酸鹽、異丙酸鹽、乙腈溶劑化物及乙酸乙酯溶劑化物。溶劑化之方法係此項技術中已知。
各種形式之前藥係此項技術中熟知及述於Rautio, J.等人,
Nature Review Drug Discovery,17, 559-587 (2018)中。
此外,繼式(I)化合物之製備後,可將其分離及純化以獲得含有等於或大於99%之重量之量之式(I)化合物的組合物(「實質上純」),然後將其如本文中所述使用或調配。本文中亦考慮此「實質上純」式(I)化合物作為本發明之部分。
「穩定化合物」及「穩定結構」意欲指示足以穩健以自反應混合物生存分離至可用純度,及調配成有效治療劑之化合物。本發明意欲體現穩定化合物。
術語「Helios抑制劑」係指能降低細胞中之Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度以控制Treg分化之劑。Helios抑制劑可為可逆或不可逆抑制劑。
如本文中所用,「Helios」蛋白係指為鋅指蛋白之Ikaros家族之成員的蛋白。於人類中,Helios藉由IKZF2基因編碼。Helios亦稱作IKAROS家族鋅指2、ANF1A2、ZNF1A2、ZNFN1A2、鋅指蛋白亞科1A, 2及Ikaros家族鋅指蛋白2。此蛋白家族之成員包含Ikaros、Helios、Aiolos、Eos及Pegasus。如本文中所用,Helios蛋白包含各種同功異型物,其包含以下所列之同功異型物1至5。
同功異型物 1 (UniProt Q9UKS7-1)METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 1)
同功異型物 2 (UniProt Q9UKS7-2)METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 2)
同功異型物 4 (UniProt Q9UKS7-4)METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 3)
同功異型物 6 (UniProt Q9UKS7-6)METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVGKPHKCNYCGRSYKQRSSLEEHKERCHNYLQNVSMEAAGQVMSHHDS (SEQ ID NO: 4)
同功異型物 7 (UniProt Q9UKS7-7)METEAIDGYITCDNELSPEREHSNMAIDLTSSTPNGQHASPSHMTSTNSVKLEMQSDEECDRKPLSREDEIRGHDEGSSLEEPLIESSEVADNRKVQELQGEGGIRLPNGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCSYACRRRDALTGHLRTHSVPPMEDCKEQEPIMDNNISLVPFERPAVIEKLTGNMGKRKSSTPQKFVGEKLMRFSYPDIHFDMNLTYEKEAELMQSHMMDQAINNAITYLGAEALHPLMQHPPSTIAEVAPVISSAYSQVYHPNRIERPISRETADSHENNMDGPISLIRPKSRPQEREASPSNSCLDSTDSESSHDDHQSYQGHPALNPKRKQSPAYMKEDVKALDTTKAPKGSLKDIYKVFNGEGEQIRAFKCEHCRVLFLDHVMYTIHMGCHGYRDPLECNICGYRSQDRYEFSSHIVRGEHTFH (SEQ ID NO: 5)
以上所列之「Helios」同功異型物1、2、4、6及7包含降解決定子FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (加粗及加下劃線)。降解決定子為於調節蛋白質降解速率中起作用之蛋白質的一部分。
如本文中所用,「Eos」蛋白藉由IKZF4基因編碼,及亦稱作IKAROS家族鋅指4、ZNFN1A4、鋅指蛋白亞科1A, 4、Ikaros家族鋅指蛋白4及KIAA1782。「Eos」蛋白包含藉由下列兩種人類同功異型物1 (Q9H2S9-1)及2 (Q9H2S9-2)編碼之同功異型物:
同功異型物 1 (UniProt Q9H2S9-1)MHTPPALPRRFQGGGRVRTPGSHRQGKDNLERDPSGGCVPDFLPQAQDSNHFIMESLFCESSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 7)
同功異型物 2 (UniProt Q9H2S9-2)MDSRYLQLQLYLPSCSLLQGSGDSSLEKEFLGAPVGPSVSTPNSQHSSPSRSLSANSIKVEMYSDEESSRLLGPDERLLEKDDSVIVEDSLSEPLGYCDGSGPEPHSPGGIRLPNGKLKCDVCGMVCIGPNVLMVHKRSHTGERP
FHCNQCGASFTQKGNLLRHIKLH SGEKPFKCPFCNYACRRRDALTGHLRTHSVSSPTVGKPYKCNYCGRSYKQQSTLEEHKERCHNYLQSLSTEAQALAGQPGDEIRDLEMVPDSMLHSSSERPTFIDRLANSLTKRKRSTPQKFVGEKQMRFSLSDLPYDVNSGGYEKDVELVAHHSLEPGFGSSLAFVGAEHLRPLRLPPTNCISELTPVISSVYTQMQPLPGRLELPGSREAGEGPEDLADGGPLLYRPRGPLTDPGASPSNGCQDSTDTESNHEDRVAGVVSLPQGPPPQPPPTIVVGRHSPAYAKEDPKPQEGLLRGTPGPSKEVLRVVGESGEPVKAFKCEHCRILFLDHVMFTIHMGCHGFRDPFECNICGYHSQDRYEFSSHIVRGEHKVG (SEQ ID NO: 8)
以上所列之「Eos」蛋白同功異型物1及2包含降解決定子FHCNQCGASFTQKGNLLRHIKLH (SEQ ID NO: 6) (加粗及加下劃線),其與「Helios」蛋白之降解決定子相同。
如本文中所用,「Ikaros」蛋白藉由IKZF1基因編碼。Ikaros亦稱作IKAROS家族鋅指1、ZNFN1A1、鋅指蛋白亞科1A, 1、Ikaros家族鋅指蛋白1、IK1、淋巴轉錄因子LyF-1、Hs.54452、PPP1R92、蛋白磷酸酶1、調節亞單元92、PRO0758、CVID13及CLL相關抗原KW-6。Ikaros蛋白包含藉由胺基酸序列Q13422-1、Q13422-2、Q13422-3、Q13422-4、Q13422-7及Q13422-8編碼之同功異型物。Ikaros蛋白亦包含藉由胺基酸序列Q13422-5及Q13422-6編碼之同功異型物。
如本文中所用,「Aiolos」蛋白藉由IKZF3基因編碼。Aiolos蛋白亦稱作IKAROS家族鋅指3、ZNFN1A3、鋅指蛋白亞科1A, 3、Ikaros家族鋅指蛋白3及AIO。Aiolos蛋白包含藉由胺基酸序列Q9UKT9-1、Q9UKT9-3、Q9UKT9-4、Q9UKT9-6、Q9UKT9-7、Q9UKT9-8、Q9UKT9-9及Q9UKT9-14編碼之同功異型物。Aiolos蛋白亦包含藉由胺基酸序列Q9UKT9-2、Q9UKT9-5、Q9UKT9-10、Q9UKT9-11、Q9UKT9-12及Q9UKT9-13、Q9UKT9-15及Q9UKT9-16編碼之同功異型物。
如本文中所用,「Pegasus」蛋白亦稱作IKAROS家族鋅指5、ZNFN1A5、鋅指蛋白亞科1A, 5及Ikaros家族鋅指蛋白5。Pegasus藉由IKZF5基因編碼。
如本文中所用,術語「接觸」係指將指定部分一起帶入活體外系統或活體內系統。例如,使Helios蛋白與式(I)化合物「接觸」包括向具有Helios蛋白之個體或患者(諸如人類)投與本發明之化合物,以及例如將式(I)化合物引入含有細胞之樣品或含有Helios蛋白之經純化製劑。
如本文中所用,術語「治療(treat/treating/treatment)」係指在個體上進行之任何類型之干預或處理,或向個體投與活性劑,目標為逆轉、減輕、改善、抑制、或減慢下來或防止與疾病相關之症狀、併發症、病狀或生化標記之進展、發展、嚴重度或復發。相比之下,「預防(prophylaxis/prevention)」係指向未患有疾病之個體投與以防止疾病發生。「治療(treat/treating/treatment)」不包含預防(prophylaxis/prevention)。
「治療上有效量」意欲包含本發明化合物單獨之量或所主張化合物之組合之量或本發明化合物與有效降低細胞中之Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度或有效治療或預防病毒感染及增殖性病症(諸如癌症)之其他活性成分組合之量。
如本文中所用,術語「細胞」意欲係指活體外、離體或活體內細胞。於一些實施例中,離體細胞可為自生物體(諸如哺乳動物)切除之組織樣品之部分。於一些實施例中,活體外細胞可為細胞培養中之細胞。於一些實施例中,活體內細胞為於生物體(諸如哺乳動物)中生活之細胞。
術語「患者」包含人類及接受治療性或預防性治療之其他哺乳動物個體。
術語「個體」包含任何人類或非人類動物。例如,本文中所揭示之方法及組合物可用於治療患有癌症之個體。非人類動物包括所有脊椎動物,例如,哺乳動物及非哺乳動物,包括非人類靈長類動物、綿羊、犬、牛、雞、兩棲動物、爬行動物等。於一個實施例中,該個體為人類個體。
如本文中所用,短語「醫藥上可接受之載劑」意指醫藥上可接受之材料、組合物或媒劑,諸如液體或固體填料、稀釋劑、賦形劑、製造助劑(例如,潤滑劑、滑石、硬脂酸鎂、硬脂酸鈣或硬脂酸鋅、或硬脂酸),或涉及將主體化合物自身體之一個器官或部分攜帶或轉運至身體之另一器官或部分之溶劑封裝材料。各載劑在與調配物之其他成分相容之意義上必須係「可接受」,包括(即)佐劑、賦形劑或媒劑,諸如稀釋劑、防腐劑、填料、流動調節劑、崩解劑、潤濕劑、乳化劑、懸浮劑、甜味劑、調味劑、芳香劑、抗細菌劑、抗真菌劑、潤滑劑及分散劑,取決於投與模式之性質及劑型;且對患者無害。
術語「醫藥組合物」意指包含本發明之化合物與至少一種另外醫藥上可接受之載劑組合之組合物。
功用
式(I)化合物可用於治療癌症。
於一個實施例中,本發明提供式(I)化合物及/或其醫藥上可接受之鹽,其立體異構體或其互變異構體及附加治療劑之組合製劑同時、分開或依序用於治療及/或預防與Helios蛋白之活性相關之多種疾病或病症。該組合製劑可用於降低細胞中之Helios蛋白含量、Helios活性程度及/或Helios表現程度以控制Treg分化。
式(I)化合物及包含至少一種式(I)化合物之醫藥組合物可用於治療或預防與Helios蛋白之活性相關聯之任何疾病或病狀。此等包括病毒及其他感染(例如,皮膚感染、GI感染、泌尿道感染、泌尿生殖感染、全身感染)及增殖性疾病(例如,癌症)。式(I)化合物及包含至少一種式(I)化合物之醫藥組合物可向動物,較佳地哺乳動物(例如,家養動物、貓、犬、小鼠、大鼠),及更佳地人類投與。可使用任何投與方法以向患者遞送化合物或醫藥組合物。於某些實施例中,式(I)化合物或包含至少一種式(I)化合物之醫藥組合物係經口投與。於其他實施例中,式(I)或包含至少一種式(I)化合物之醫藥組合物係非經腸投與。
式(I)化合物可選擇性降低細胞中之Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度以控制Treg分化。例如,式(I)化合物可用於選擇性降低細胞中之Helios活性程度及/或抑制Helios表現程度以控制需要藉由投與抑制量之式(I)化合物或其鹽來降低Helios蛋白含量、降低Helios活性程度及/或抑制Helios表現程度之細胞或個體中之Treg分化。
於一個態樣中,該(等)式(I)化合物在投與免疫腫瘤學劑之前依序投與。於另一態樣中,式(I)化合物與免疫腫瘤學劑同時投與。於又一態樣中,式(I)化合物於投與免疫腫瘤學劑後依序投與。
於另一態樣中,式(I)化合物可與免疫腫瘤學劑共同調配。
免疫腫瘤學劑包括(例如)小分子藥物、抗體或其他生物或小分子。生物免疫腫瘤學劑之實例包括(但不限於)癌症疫苗、抗體及細胞激素。於一個態樣中,該抗體為單株抗體。於另一態樣中,該單株抗體係人源化或人類。
於一個態樣中,該免疫腫瘤學劑為(i)刺激性(包含共刺激)受體之促效劑或(ii) T細胞上之抑制性(包含共抑制)信號之拮抗劑,其二者均導致放大抗原特異性T細胞反應(通常稱作免疫檢查點調節劑)。
某些刺激性及抑制性分子為免疫球蛋白超家族(IgSF)之成員。結合至共刺激或共抑制受體之膜結合配位體之一個重要家族為B7家族,其包含B7-1、B7-2、B7-H1 (PD-L1)、B7-DC (PD-L2)、B7-H2 (ICOS-L)、B7-H3、B7-H4、B7-H5 (VISTA)及B7-H6。結合至共刺激或共抑制受體之膜結合配位體之另一家族為結合至同源TNF受體家族成員之分子之TNF家族,其包含CD40及CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137 (4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fn14、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTβR、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFR1, 淋巴毒素α/TNFβ、TNFR2、TNFα、LTβR、淋巴毒素α 1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
於一個態樣中,T細胞反應可藉由式(I)化合物及以下中之一或多者之組合刺激:(i)抑制T細胞活化之蛋白質之拮抗劑(例如,免疫檢查點抑制劑),諸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳凝素9、CEACAM-1、BTLA、CD69、半乳凝素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4,及(ii)刺激T細胞活化之蛋白質之促效劑,諸如B7-1、B7-2、CD28、4-1BB (CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3及CD28H。
可與式(I)化合物組合用於治療癌症之其他劑包括NK細胞上之抑制性受體之拮抗劑或NK細胞上之活化受體之促效劑。例如,式(I)化合物可與KIR之拮抗劑(諸如利魯單抗(lirilumab))組合。
組合療法之又其他劑包括抑制或耗盡巨噬細胞或單核細胞之劑,包括(但不限於) CSF-1R拮抗劑,諸如CSF-1R拮抗劑抗體,包括RG7155 (WO11/70024、WO11/107553、WO11/131407、WO13/87699、WO13/119716、WO13/132044)或FPA-008 (WO11/140249、WO13169264、WO14/036357)。
於另一態樣中,式(I)化合物可與下列中之一或多者使用:連接積極共刺激受體之促效劑、衰減通過抑制性受體之信號之阻斷劑、拮抗劑及系統性增加抗腫瘤T細胞之頻率之一或多種劑、克服腫瘤微環境內之不同免疫抑制路徑(例如,阻斷抑制性受體接合(例如,PD-L1/PD-1相互作用)、耗盡或抑制Treg (例如,使用抗CD25單株抗體(例如,達利珠單抗(daclizumab))或藉由離體抗CD25珠耗盡)、抑制代謝酶(諸如IDO)或逆轉/防止T細胞無能或耗盡)之劑及在腫瘤位點處觸發先天性免疫活化及/或發炎之劑。
於一個態樣中,該免疫腫瘤學劑為CTLA-4拮抗劑,諸如拮抗性CTLA-4抗體。適宜CTLA-4抗體包括(例如) YERVOY (伊匹單抗(ipilimumab))或曲美木單抗(tremelimumab)。
於另一態樣中,該免疫腫瘤學劑為PD-1拮抗劑,諸如拮抗性PD-1抗體。適宜PD-1抗體包括例如 OPDIVO
TM(納武單抗(nivolumab))、KEYTRUDA
TM(派姆單抗(pembrolizumab))或MEDI-0680 (AMP-514;WO2012/145493)。免疫腫瘤學劑亦可包括匹地利珠單抗(pidilizumab) (CT-011),儘管已質疑其對PD-1結合之特異性。靶向PD-1受體之另一方法為由PD-L2 (B7-DC)之細胞外域稠合至IgG1之Fc部分組成的重組蛋白(稱作AMP-224)。
於另一態樣中,該免疫腫瘤學劑為PD-L1拮抗劑,諸如拮抗性PD-L1抗體。適宜PD-L1抗體包括例如 MPDL3280A (RG7446;WO2010/077634)、德瓦魯單抗(durvalumab) (MEDI4736)、BMS-936559 (WO207/005874)及MSB0010718C (WO2013/79174)。
於另一態樣中,該免疫腫瘤學劑為LAG-3拮抗劑,諸如拮抗性LAG-3抗體。適宜LAG3抗體包括例如 BMS-986016 (WO10/ 19570、WO14/08218),或IMP-731或IMP-321 (WO08/132601、WO09/ 44273)。
於另一態樣中,該免疫腫瘤學劑為CD137 (4-1BB)促效劑,諸如促效性CD137抗體。適宜CD137抗體包括例如烏瑞蘆單抗(urelumab)及PF-05082566 (WO12/32433)。
於另一態樣中,該免疫腫瘤學劑為GITR促效劑,諸如促效性GITR抗體。適宜GITR抗體包括例如 BMS-986153、BMS-986156、TRX-518 (WO06/105021、WO09/009116)及MK-4166 (WO11/ 028683)。
於另一態樣中,該免疫腫瘤學劑為IDO拮抗劑。適宜IDO拮抗劑包括例如 INCB-024360 (WO206/122150、WO07/75598、WO 08/36653、WO08/36642)、吲哚莫德(indoximod),或NLG-919 (WO09/ 73620、WO09/1156652、WO11/56652、WO12/142237)。
於另一態樣中,該免疫腫瘤學劑為OX40促效劑,諸如促效性OX40抗體。適宜OX40抗體包括例如 MEDI-6383或MEDI-6469。
於另一態樣中,該免疫腫瘤學劑為OX40L拮抗劑,諸如拮抗性OX40抗體。適宜OX40L拮抗劑包括例如 RG-7888 (WO06/ 029879)。
於另一態樣中,該免疫腫瘤學劑為CD40促效劑,諸如促效性CD40抗體。於又一實施例中,該免疫腫瘤學劑為CD40拮抗劑,諸如拮抗性CD40抗體。適宜CD40抗體包括例如蘆卡木單抗(lucatumumab)或達西組單抗(dacetuzumab)。
於另一態樣中,該免疫腫瘤學劑為CD27促效劑,諸如促效性CD27抗體。適宜CD27抗體包括(例如)伐立魯單抗(varlilumab)。
於另一態樣中,該免疫腫瘤學劑為MGA271 (至B7H3) (WO11/109400)。
組合療法意欲包含以依序方式投與此等治療劑,即,其中各治療劑在不同時間投與,以及以實質上同時方式投與此等治療劑或該等治療劑中之至少兩者。實質上同時投與可(例如)藉由向個體投與具有固定比率之各治療劑之單一劑型或以針對治療劑各者之多個單一劑型來實現。各治療劑之依序或實質上同時投與可藉由任何適宜途徑實現,包括(但不限於)口服途徑、靜脈內途徑、肌肉內途徑及通過黏膜組織直接吸收。治療劑可藉由相同途徑或藉由不同途徑投與。例如,所選組合之第一治療劑可藉由靜脈內注射投與,而組合之其他治療劑可經口投與。或者,例如,所有治療劑可經口投與或所有治療劑可藉由靜脈內注射投與。組合療法亦可包含以與其他生物活性成分及非藥物療法(例如,手術或放射治療)之進一步組合投與如上所述之治療劑。在組合療法進一步包含非藥物治療之情況下,該非藥物治療可在任何適宜時間進行,只要達成來自治療劑及非藥物治療之組合之共同作用之有益效果。例如,在適宜情況下,當自投與治療劑暫時移除非藥物治療可能幾天或甚至幾週時,仍達成有益效果。
可利用式(I)化合物治療之癌症之類型包括(但不限於)腦癌、皮膚癌、膀胱癌、卵巢癌、乳癌、胃癌、胰癌、前列腺癌、結腸癌、血液癌、肺癌及骨癌。此等癌症類型之實例包括神經母細胞瘤、腸癌(諸如直腸癌、結腸癌、熟習腺瘤性息肉癌及遺傳性非息肉性結腸直腸癌)、食道癌、唇癌、喉癌、咽癌、舌癌、唾腺癌、胃癌、腺癌、髓樣甲狀腺癌、乳頭狀甲狀腺癌、腎癌、腎實質癌、卵巢癌、子宮頸癌、子宮體癌、子宮內膜癌、絨膜癌、胰癌、前列腺癌、睪丸癌、乳癌、尿道癌、黑色素瘤、腦瘤(諸如膠質母細胞瘤、星形細胞瘤、腦膜瘤、髓母細胞瘤及外周神經外胚瘤)、霍奇金氏(Hodgkin)淋巴瘤、非霍奇金氏淋巴瘤、伯基特氏(Burkitt)淋巴瘤、急性淋巴細胞性白血病(ALL)、慢性淋巴細胞性白血病(CLL)、急性骨髓性白血病(AML)、慢性骨髓性白血病(CML)、成人T-細胞白血病淋巴瘤、瀰漫性大B-細胞淋巴瘤(DLBCL)、肝細胞癌、膽囊癌、支氣管癌、小細胞肺癌、非小細胞肺癌、多發性骨髓瘤、基底細胞瘤、畸胎瘤、視網膜母細胞瘤、脈絡膜黑色素瘤、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、尤因氏(Ewing)肉瘤及漿細胞瘤。
一或多種另外醫藥劑或治療方法,諸如,例如,抗病毒劑、化療劑或其他抗癌劑、免疫增強劑、免疫抑制劑、輻射、抗腫瘤及抗病毒疫苗、細胞激素療法(例如,IL2及GM-CSF)及/或酪胺酸激酶抑制劑可視情況與式(I)化合物組合使用用於治療Helios蛋白相關之疾病、病症或病狀。該等劑可呈單一劑型與本發明化合物組合,或該等劑可呈單獨劑型同時或依序投與。
適宜化療劑或其他抗癌劑包括(例如)烷基化劑(包括不限於氮芥、乙烯亞胺衍生物、磺酸烷酯、亞硝基脲及三氮烯),諸如烏拉莫司汀(uracil mustard)、氮芥(chlormethine)、環磷醯胺(CYTOXAN
TM)、異環磷醯胺、美法崙(melphalan)、苯丁酸氮芥(chlorambucil)、哌泊溴烷(pipobroman)、三乙烯-三聚氰胺、三伸乙基硫代磷胺、白消安(busulfan)、卡莫司汀(carmustine)、羅莫司汀(lomustine)、鏈佐星(streptozocin)、達卡巴嗪(dacarbazine)及替莫唑胺(temozolomide)。
於治療黑色素瘤中,與式(I)化合物組合使用之適宜劑包括:達卡巴嗪(DTIC),視情況與其他化療藥物,諸如卡莫司汀(BCNU)及順鉑(cisplatin)一起;「Dartmouth方案」,其由DTIC、BCNU、順鉑及他莫昔芬(tamoxifen)組成;順鉑、長春鹼(vinblastine)及DTIC、替莫唑胺或YERVOY™之組合。式(I)化合物亦可與免疫療法藥物,包括細胞激素,諸如干擾素α、介白素2及腫瘤壞死因子(TNF)組合治療黑色素瘤。
式(I)化合物亦可與疫苗療法組合用於治療黑色素瘤。抗黑色素瘤疫苗在某些方面與抗病毒疫苗相似,其用於預防由病毒(諸如脊髓灰質炎(polio)、麻疹(measles)及流行性腮腺炎(mumps))引起之疾病。可將稱作抗原之變弱之黑色素瘤細胞或黑色素瘤細胞之部分注射至患者中以刺激身體之免疫系統以破壞黑色素瘤細胞。
侷限於手臂或腿之黑色素瘤亦可利用包含一或多種式(I)化合物之劑之組合使用高溫隔離肢體灌注技術治療。此治療協定暫時將涉及肢體之循環自身體之其餘部分分離及注射高劑量之化療劑至滋養肢體之動脈,因此對腫瘤區域提供高劑量而不將內部器官暴露於原本可引起嚴重副作用之此等劑量。通常將流體升溫至38.9℃至40℃。美法崙為此化療程序中最常用之藥物。此可利用稱作腫瘤壞死因子(TNF)之另一劑提供。
適宜化療劑或其他抗癌劑包括(例如)抗代謝劑(包括不限於葉酸拮抗劑、嘧啶類似物、嘌呤類似物及腺苷脫胺酶抑制劑),諸如胺甲喋呤(methotrexate)、5-氟尿嘧啶、氟尿苷、阿糖胞苷(cytarabine)、6-巰嘌呤、6-硫鳥嘌呤、磷酸氟達拉濱(fludarabine)、噴司他丁(pentostatine)及吉西他濱(gemcitabine)。
適宜化療劑或其他抗癌劑進一步包括(例如)某些天然產物及其衍生物(例如,長春花生物鹼、抗腫瘤抗生素、酶、淋巴啟動素及表鬼臼毒素),諸如長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、博來黴素(bleomycin)、更生黴素(dactinomycin)、道諾黴素(daunorubicin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、伊達比星(idarubicin)、ara-C、紫杉醇(paclitaxel) (Taxol)、光神黴素(mithramycin)、脫氧助間型黴素(deoxyco-formycin)、絲裂黴素(mitomycin)-C、L-天冬醯胺酶、干擾素(尤其IFN-a)、依託泊苷(etoposide)及替尼泊苷(teniposide)。
其他細胞毒性劑包括諾維本(navelbene)、CPT-11、阿那曲唑(anastrazole)、來曲唑(letrazole)、卡培他濱(capecitabine)、雷洛昔芬(reloxafine)及屈洛昔芬(droloxafine)。
亦適宜為細胞毒性劑,諸如表葉毒素(epidophyllotoxin)、抗腫瘤酶、拓撲異構酶抑制劑、丙卡巴嗪(procarbazine)、米托蒽醌(mitoxantrone)、鉑配合複合物(諸如順鉑及卡鉑(carboplatin))、生物反應調節劑、生長抑制劑、抗激素治療劑、甲醯四氫葉酸(leucovorin)、替加氟(tegafur)及造血生長因子。
其他抗癌劑包括抗體治療劑,諸如曲妥珠單抗(trastuzumab) (HERCEPTIN®)、共刺激分子(諸如CTLA-4、4-1BB及PD-1)之抗體或細胞激素(IL-1O或TGF-β)之抗體。
其他抗癌劑亦包含阻斷免疫細胞遷移之彼等,諸如趨化因子受體(包括CCR2及CCR4)之拮抗劑。
其他抗癌劑亦包含增強免疫系統之彼等,諸如佐劑或授受性T細胞轉移。
抗癌疫苗包括樹突狀細胞、合成肽、DNA疫苗及重組病毒。
本發明之醫藥組合物可視情況包含至少一種信號轉導抑制劑(STI)。「信號轉導抑制劑」為選擇性抑制癌細胞之正常功能中之信號路徑中之一或多個重要步驟的劑,從而導致細胞凋亡。適宜STI包括(但不限於):(i) bcr/abl激酶抑制劑,諸如,例如,STI 571 (GLEEVEC
TM);(ii)表皮生長因子(EGF)受體抑制劑,諸如,例如,激酶抑制劑(IRESSA
TM,SSI-774)及抗體(Imclone:C225 [Goldstein等人,
Clin. Cancer Res., 1:1311-1318 (1995)],及Abgenix:ABX-EGF);(iii) her-2/neu受體抑制劑,諸如法呢基轉移酶抑制劑(FTI),諸如,例如,L-744,832 (Kohl等人,
Nat. Med., 1(8):792-797 (1995));(iv) Akt家族激酶或Akt路徑之抑制劑,諸如,例如,雷帕黴素(rapamycin) (參見,例如,Sekulic等人,
Cancer Res., 60:3504-3513 (200));(v)細胞週期激酶抑制劑,諸如,例如,夫拉平度(flavopiridol)及UCN-O1 (參見,例如,Sausville,
Curr. Med. Chem. Anti-Canc. Agents, 3:47-56 (203));及(vi)磷脂醯肌醇激酶抑制劑,諸如,例如,LY294002 (參見,例如,Vlahos等人,
J. Biol. Chem., 269:5241-5248 (1994))。或者,至少一種STI及至少一種式(I)化合物可於分開醫藥組合物中。於本發明之特定實施例中,至少一種式(I)化合物及至少一種STI可同時或依序向患者投與。換言之,可首先投與至少一種式(I)化合物,可首先投與至少一種STI,或可同時投與至少一種式(I)化合物及至少一種STI。另外,當使用超過一種式(I)化合物及/或STI時,該等化合物可以任何順序投與。
本發明進一步提供用於治療患者之慢性病毒感染之醫藥組合物,其包含至少一種式(I)化合物,視情況,至少一種化療藥物,及視情況,至少一種抗病毒劑於醫藥上可接受之載劑中。
亦提供一種藉由投與有效量之以上醫藥組合物來治療患者之慢性病毒感染之方法。
於本發明之特定實施例中,至少一種式(I)化合物及至少一種化療劑同時或依序向患者投與。換言之,可首先投與至少一種式(I)化合物,可首先投與至少一種化療劑,或可同時投與至少一種式(I)化合物及至少一種STI。另外,當使用超過一種式(I)化合物及/或化療劑時,該等化合物可以任何順序投與。相似地,與投與式(I)化合物相比,任何抗病毒劑或STI亦可在任一點投與。
可使用本發明組合治療治療之慢性病毒感染包括(但不限於)由以下引起之疾病:C型肝炎病毒(HCV)、人類乳頭狀瘤病毒(HPV)、巨細胞病毒(CMV)、單純性疱疹病毒(HSV)、艾巴(Epstein-Barr)氏病毒(EBV)、水痘帶狀疱疹病毒、柯薩奇病毒、人類免疫缺陷病毒(HIV)。
考慮與式(I)化合物組合使用之適宜抗病毒劑可包括核苷及核苷酸逆轉錄酶抑制劑(NRTI)、非核苷酸逆轉錄酶抑制劑(NNRTI)、蛋白酶抑制劑及其他抗病毒藥物。
適宜NRTI之實例包括齊多夫定(zidovudine) (AZT)、地達諾新(didanosine) (ddl)、紮西他濱(zalcitabine) (ddC)、司他夫定(stavudine) (d4T)、拉米夫定(lamivudine) (3TC)、阿巴卡韋(abacavir) (1592U89)、阿德福韋酯(adefovir dipivoxil) [雙(POM)-PMEA]、洛布卡韋(lobucavir) (BMS-180194)、BCH-I0652、恩曲他濱(emitricitabine) [(-)-FTC]、β-L-FD4 (亦稱作β-L-D4C及稱作β-L-2′,3′-二脫氧基-5-氟-胞苷)、DAPD((-)-β-D-2,6-二胺基-嘌呤二噁茂烷)、及洛德諾新(lodenosine) (FddA)。典型適宜NNRTI包括奈韋拉平(nevirapine) (BI-RG-587)、地拉韋定(delaviradine) (BHAP,U-90152)、依法韋崙(efavirenz) (DMP-266)、PNU-142721、AG-1549、MKC-442 (1-(乙氧基-甲基)-5-(1-甲基乙基)-6-(苯基甲基)-(2,4(1H,3H)-嘧啶二酮)、及(+)-胡桐素(calanolide) A (NSC-675451)及B。典型適宜蛋白酶抑制劑包括沙奎那韋(saquinavir) (Ro 31-8959)、利托那韋(ritonavir) (ABT-538)、茚地那韋(indinavir) (MK-639)、奈非那韋(nelfnavir) (AG-1343)、安普那韋(amprenavir) (141W94)、拉西那韋(lasinavir) (BMS-234475)、DMP-450、BMS-2322623、ABT-378及AG-1549。其他抗病毒劑包括羥基脲、利巴韋林(ribavirin)、IL-2、IL-12、噴他夫西(pentafuside)及Yissum項編號11607。
組合療法意欲包含以依序方式投與此等治療劑,即,其中各治療劑在不同時間投與,以及以實質上同時方式投與此等治療劑或該等治療劑中之至少兩者。實質上同時投與可(例如)藉由向個體投與具有固定比率之各治療劑之單一劑型或以針對治療劑各者之多個單一劑型來實現。各治療劑之依序或實質上同時投與可藉由任何適宜途徑實現,包括(但不限於)口服途徑、靜脈內途徑、肌肉內途徑及通過黏膜組織直接吸收。治療劑可藉由相同途徑或藉由不同途徑投與。例如,所選組合之第一治療劑可藉由靜脈內注射投與,而組合之其他治療劑可經口投與。或者,例如,所有治療劑可經口投與或所有治療劑可藉由靜脈內注射投與。組合療法亦可包含以與其他生物活性成分及非藥物療法(例如,手術或放射治療)之進一步組合投與如上所述之治療劑。在組合療法進一步包含非藥物治療之情況下,該非藥物治療可在任何適宜時間進行,只要達成來自治療劑及非藥物治療之組合之共同作用之有益效果。例如,在適宜情況下,當自投與治療劑暫時移除非藥物治療可能幾天或甚至幾週時,仍達成有益效果。
醫藥組合物
本發明亦提供醫藥組合物,其包含治療上有效量之與一或多種醫藥上可接受之載劑(添加劑)及/或稀釋劑一起調配之式(I)化合物中的一或多者,及視情況,上述一或多種附加治療劑。
式(I)化合物可藉由任何適宜途徑,較佳地以適於此途徑之醫藥組合物之形式,及以針對意欲治療有效之劑量投與。該等化合物及式(I)化合物之組合物可針對本文中所述用途中之任一者藉由任何適宜方式投與,例如,口服,諸如錠劑、膠囊(其各者包含持續釋放或定時釋放調配物)、丸劑、粉末、顆粒、酏劑、酊劑、懸浮液(包括奈米懸浮液、微懸浮液、噴霧乾燥懸浮液)、糖漿及乳液;經舌下;經頰;非經腸,諸如藉由皮下、靜脈內、肌肉內或胸骨內注射或輸注技術(例如,呈無菌可注射水性溶液或非水性溶液或懸浮液);經鼻,包括向鼻膜投與,諸如藉由吸入噴霧;經局部,諸如以乳霜或軟膏之形式;或經直腸,諸如以栓劑之形式。其可單獨投與,但是一般與基於所選投與途徑及標準醫藥實務選擇之醫藥載劑投與。
針對口服投與,該醫藥組合物可呈(例如)錠劑、膠囊、液體膠囊、懸浮液或液體之形式。該醫藥組合物較佳地以含有特定量之活性成分之劑量單位之形式製備。例如,該醫藥組合物可呈包含約0.1至1000 mg,較佳地約0.25至250 mg,及更佳地約0.5至100 mg之範圍之量之活性成分的錠劑或膠囊提供。針對人類或其他哺乳動物之適宜每日劑量可取決於患者之狀況及其他因素廣泛變化,但是可使用常規方法測定。
本文中涵蓋之任何醫藥組合物可(例如)經由任何可接受且適宜口服製劑經口遞送。示例性口服製劑包括(但不限於)例如,錠劑、片劑、口含錠、水性及油性懸浮液、可分散粉末或顆粒、乳液、硬及軟膠囊、液體膠囊、糖漿及酏劑。意欲用於口服投與之醫藥組合物可根據此項技術中已知用於製造意欲用於口服投與之醫藥組合物之任何方法製備。為提供醫藥上可口的製劑,根據本發明之醫藥組合物可含有選自甜味劑、調味劑、著色劑、緩和劑、抗氧化劑及防腐劑之至少一種劑。
錠劑可(例如)藉由將至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽與適用於製造錠劑之至少一種無毒醫藥上可接受之賦形劑混合來製備。示例性賦形劑包括(但不限於)例如惰性稀釋劑,諸如,例如,碳酸鈣、碳酸鈉、乳糖、磷酸鈣及磷酸鈉;造粒及崩解劑,諸如,例如,微晶纖維素、交聯羧甲基纖維素鈉、玉米澱粉及藻酸;黏合劑,諸如,例如,澱粉、明膠、聚乙烯吡咯啶酮及阿拉伯膠;及潤滑劑,諸如,例如,硬脂酸鎂、硬脂酸及滑石。另外,錠劑可未經塗覆,或藉由已知技術塗覆以掩蓋不愉快品嘗藥物之壞口味,或延遲活性成分於胃腸道中之崩解及吸收,從而使活性成分之效應持續更長時間。示例性水溶性味道掩蓋材料包括(但不限於)羥丙基-甲基纖維素及羥丙基-纖維素。示例性時間延遲材料包括(但不限於)乙基纖維素及乙酸丁酸纖維素。
硬明膠膠囊可(例如)藉由將至少一種式(I)化合物及/或至少一種其鹽與至少一種惰性固體稀釋劑(諸如,例如,碳酸鈣、磷酸鈣及高嶺土)混合來製備。
軟明膠膠囊可(例如)藉由將至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽與至少一種水溶性載劑(諸如,例如,聚乙二醇)及至少一種油性介質(諸如,例如,花生油、液體石蠟及橄欖油)混合來製備。
水性懸浮液可(例如)藉由將至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽與適用於製造水性懸浮液之至少一種賦形劑混合來製備。適用於製造水性懸浮液之示例性賦形劑包括(但不限於)例如,懸浮劑,諸如,例如,羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、藻酸鈉、藻酸、聚乙烯吡咯啶酮、黃蓍膠及阿拉伯膠;分散或潤濕劑,諸如,例如,天然產生之磷脂,例如,卵磷脂;環氧烷烴與脂肪酸之縮合產物,諸如,例如,聚氧乙烯硬脂酸酯;環氧乙烷與長鏈脂肪醇之縮合產物,諸如,例如,十七乙烯-氧基鯨蠟醇;環氧乙烷與衍生自脂肪酸及己糖醇之偏酯之縮合產物,諸如,例如,聚氧乙烯山梨醇單油酸酯;及環氧乙烷與衍生自脂肪酸及己糖醇酐之偏酯之縮合產物,諸如,例如,聚乙烯脫水山梨糖醇單油酸酯。水性懸浮液亦可含有至少一種防腐劑,諸如,例如,對羥基苯甲酸乙酯及對羥基苯甲酸正丙酯;至少一種著色劑;至少一種調味劑;及/或至少一種甜味劑,包括(但不限於)例如,蔗糖、糖精及阿斯巴甜。
油性懸浮液可(例如)藉由將至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽懸浮於植物油(諸如,例如,花生油、橄欖油、芝麻油及椰子油)或礦物油(諸如,例如,液體石蠟)中來製備。油性懸浮液亦可含有至少一種增稠劑,諸如,例如,蜂蠟、硬石蠟及鯨蠟醇。為提供可口油性懸浮液,可將上文已述之甜味劑中之至少一者及/或至少一種調味劑添加至油性懸浮液中。油性懸浮液可進一步含有至少一種防腐劑,包括(但不限於)例如,抗氧化劑,諸如,例如,丁基化羥基苯甲醚及α-生育酚。
可分散粉末及顆粒可(例如)藉由將至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽與至少一種分散劑及/或潤濕劑、至少一種懸浮劑、及/或至少一種防腐劑混合來製備。以上已描述適宜分散劑、潤濕劑及懸浮劑。示例性防腐劑包括(但不限於)例如,抗氧化劑,例如,抗壞血酸。此外,可分散粉末及顆粒亦可含有至少一種賦形劑,包括(但不限於)例如,甜味劑、調味劑及著色劑。
至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽之乳液可(例如)呈水包油乳液製備。包含式(I)化合物之乳液之油相可以已知方式自已知成分構成。油相可藉由(但不限於)例如植物油(諸如,例如,橄欖油及花生油)、礦物油(諸如,例如,液體石蠟)及其混合物提供。雖然該相可僅包含乳化劑,但是其可包含至少一種乳化劑與脂肪或油或與脂肪及油二者之混合物。適宜乳化劑包括(但不限於)例如,天然產生之磷脂,例如,大豆卵磷脂;衍生自脂肪酸及己糖醇酐之酯或偏酯,諸如,例如,脫水山梨糖醇單油酸酯;及偏酯與環氧乙烷之縮合產物,諸如,例如,聚氧乙烯脫水山梨糖醇單油酸酯。較佳地,包含親水性乳化劑連同充當穩定劑之親脂性乳化劑。亦較佳地包含油及脂肪二者。一併考慮,具有或不具有穩定劑之該(等)乳化劑組成所謂之乳化蠟,及該蠟與油及脂肪一起組成所謂之乳化軟膏基,其形成乳霜調配物之油性分散相。乳液亦可含有甜味劑、調味劑、防腐劑及/或抗氧化劑。適用於本發明之調配物之乳化劑及乳液穩定劑包括Tween 60、Span 80、鯨蠟硬脂醇、肉豆蔻醇、單硬脂酸甘油酯、月桂基硫酸鈉、二硬脂酸甘油酯單獨或與蠟、或此項技術中熟知之其他物質。
式(I)化合物及/或至少一種其醫藥上可接受之鹽亦可(例如)經由任何醫藥上可接受且適宜可注射形式經靜脈內、經皮下及/或經肌肉內遞送。示例性可注射形式包括(但不限於)例如,包含可接受媒劑及溶劑(諸如,例如,水、林格氏(Ringer’s)溶液及等滲氯化鈉溶液)之無菌水性溶液、無菌水包油微乳液及水性或油性懸浮液。
用於非經腸投與之調配物可呈水性或非水性等滲無菌注射溶液或懸浮液之形式。此等溶液及懸浮液可自無菌粉末或顆粒使用用於口服投與之調配物提及之載劑或稀釋劑中之一或多者或藉由使用其他適宜分散或潤濕劑及懸浮劑來製備。可將化合物溶解於水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苄基醇、氯化鈉、黃蓍膠及/或各種緩衝劑中。其他佐劑及投與模式於醫藥技術中熟知且廣泛已知。活性成分亦可呈與適宜載劑,包括鹽水、右旋糖或水,或與環糊精(即,Captisol)、共溶劑增溶(即,丙二醇)或膠束增溶(即,Tween 80)之組合物藉由注射投與。
無菌可注射製劑亦可為含於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如,呈含於1,3-丁二醇中之溶液。可採用之可接受之媒劑及溶劑為水、林格氏溶液及等滲氯化鈉溶液。此外,習慣採用無菌固定油作為溶劑或懸浮介質。出於此目的,可採用任何溫和固定油,包括合成單甘油酯或二甘油酯。此外,發現脂肪酸(諸如油酸)用於可注射劑之製備中。
無菌可注射水包油微乳液可(例如)藉由以下製備:1)將至少一種式(I)化合物溶解於油相(諸如,例如,大豆油及卵磷脂之混合物)中;2)將含有油相之式(I)與水及甘油混合物組合;及3)將該組合處理,以形成微乳液。
無菌水性或油性懸浮液可根據此項技術中已知方法製備。例如,無菌水性溶液或懸浮液可利用無毒非經腸可接受之稀釋劑或溶劑(諸如,例如,1,3-丁二醇)製備;及無菌油性懸浮液可利用無菌無毒可接受之溶劑或懸浮介質(諸如,例如,無菌固定油,例如,合成單甘油酯或二甘油酯;及脂肪酸,諸如,例如,油酸)製備。
醫藥上可接受之載劑係根據一般技術者之權限內之許多因素調配。此等包括(不限於):正在調配之活性劑之類型及性質、待投與含劑組合物之個體、組合物之意欲投與途徑、及正在靶向之治療適應症。醫藥上可接受之載劑包括水性及非水性液體介質二者,以及各種固體及半固體劑型。此等載劑可包含許多不同成分及除了活性劑之添加劑,此等另外成分出於一般技術者熟知之各種原因(例如,穩定活性劑、黏合劑等)包含於調配物中。適宜醫藥上可接受之載劑及涉及其選擇之因素之描述見於各種易得資源,諸如,例如,Allen, L. V. Jr.等人,
Remington: The Science and Practice of Pharmacy (2 卷 ),第22版(2012), Pharmaceutical Press中。
可用於本發明之醫藥組合物中之醫藥上可接受之載劑、佐劑及媒劑包括(但不限於)離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、自乳化藥物遞送系統(SEDDS) (諸如d-α-生育酚聚乙二醇1000琥珀酸鹽)、用於醫藥劑型之表面活性劑(諸如Tween、聚乙氧基化蓖麻油(諸如CREMOPHOR
TM表面活性劑(BASF))或其他相似聚合物遞送基質)、血清蛋白(諸如人類血清白蛋白)、緩衝物質(諸如磷酸鹽)、甘油、山梨酸、山梨酸鉀、飽和植物脂肪酸之部分甘油酯混合物、水、鹽或電解質(諸如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽)、膠體二氧化矽、三矽酸鎂、聚乙烯吡咯啶酮、纖維素基物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇及羊毛脂。環糊精(諸如α-、β-及γ-環糊精)或經化學改性之衍生物(諸如羥烷基環糊精,包括2-及3-羥丙基環糊精)或其他增溶衍生物亦可有利地用於增強本文中所述式之化合物之遞送。
本發明之醫藥活性化合物可根據習知配藥方法處理以產生向患者(包括人類及其他哺乳動物)投與之醫藥劑。醫藥組合物可經歷習知醫藥操作(諸如滅菌)及/或可含有習知佐劑,諸如防腐劑、穩定劑、潤濕劑、乳化劑、緩衝劑等。錠劑及丸劑可另外利用腸塗層製備。此等組合物亦可包含佐劑,諸如潤濕劑、甜味劑、調味劑及芳香劑。
出於治療目的,本發明之活性化合物一般與適於指定投與途徑之一或多種佐劑組合。若經口投與,則可將化合物與乳糖、蔗糖、澱粉粉末、烷酸之纖維素酯、纖維素烷基酯、滑石、硬脂酸、硬脂酸鎂、氧化鎂、磷酸及硫酸之鈉及鈣鹽、明膠、阿拉伯膠、藻酸鈉、聚乙烯吡咯啶酮及/或聚乙烯醇混合,及然後製錠或封裝用於方便投與。此等膠囊或錠劑可含有控制釋放調配物,如可以含於羥丙基甲基纖維素中之活性化合物之分散液提供。
投與之化合物之量及利用本發明之化合物及/或組合物治療病狀之劑量方案取決於各種因素,包括個體之年齡、體重、性別、醫療狀況、疾病類型、疾病嚴重度、投與途徑及頻率及所採用之特定化合物。因此,劑量方案可廣泛變化,但是可使用標準方法常規確定。約0.001至100 mg/kg體重,較佳地約0.0025與約50 mg/kg體重之間及最佳地約0.005至10 mg/kg體重之每日劑量可係適宜。每日劑量可以每天1至4個劑量投與。其他給藥時程表包含每週一個劑量及每兩天週期一個劑量。
本發明之醫藥組合物包含至少一種式(I)化合物及/或至少一種其醫藥上可接受之鹽,及視情況選自任何醫藥上可接受之載劑、佐劑及媒劑之另外劑。本發明之替代組合物包含本文中所述之式(I)化合物或其前藥,及醫藥上可接受之載劑、佐劑或媒劑。
本發明亦包含可用於(例如)治療或預防Helios蛋白相關疾病或病症及本文中提及之其他疾病之醫藥套組,其包含含有醫藥組合物之一或多個容器,該醫藥組合物包含治療上有效量之式(I)化合物。若所需,則此等套組可進一步包含各種習知醫藥套組組件中之一或多者,諸如,例如,具有一或多種醫藥上可接受之載劑之容器、另外容器,如對熟習此項技術者顯而易見。作為插入物或標籤之指示待投與之組分之量、投與指導方針、及/或將組分混合之指導方針的說明書亦可包含於套組中。
本發明之化合物之劑量方案當然將取決於諸如以下之已知因素變化:特定劑之藥效動力學特徵及其投與模式及途徑;接受者之物種、年齡、性別、健康、醫療狀況及體重;症狀之性質及程度;合併治療之種類;治療頻率;投與途徑、患者之腎及肝功能及所需效應。
經由一般指導方針,當用於指定效應時,各活性成分之每日口服劑量範圍為約0.001至約5000 mg/天,較佳地約0.01至約1000 mg/天及最佳地約0.1至約250 mg/天。經靜脈內,在恆定速率輸注期間之最佳劑量範圍為約0.01至約10 mg/kg/分鐘。式(I)化合物可以單次每日劑量投與,或總每日劑量可以每日兩次、三次或四次之分開劑量投與。
該等化合物通常與相對於意欲投與形式,例如,口服錠劑、膠囊、酏劑及糖漿適宜選擇之適宜醫藥稀釋劑、賦形劑或載劑(本文中統稱作醫藥載劑)混合投與,且與習知醫藥實務一致。
適用於投與之劑型(醫藥組合物)可含有約1毫克至約200毫克活性成分/劑量單位。於此等醫藥組合物中,活性成分一般以基於組合物之總重量計約0.1至95重量%之量存在。
用於口服投與之典型膠囊含有式(I)化合物中之至少一者(250 mg)、乳糖(75 mg)及硬脂酸鎂(15 mg)。將混合物通過60目篩及封裝至1號明膠膠囊中。
典型可注射製劑藉由將式(I)化合物中之至少一者(250 mg)無菌放入小瓶中,無菌冷凍乾燥及密封。針對使用,將小瓶之內容物與2 mL生理鹽水混合,以產生可注射製劑。
本發明於其範圍內包含包含活性成分、治療上有效量之式(I)化合物中之至少一者單獨或與醫藥載劑組合之醫藥組合物。視情況,式(I)化合物可單獨,與其他式(I)化合物組合,或與一或多種其他治療劑(例如,抗癌劑或其他醫藥活性物質)組合使用。
不管所選投與途徑,可以適宜水合物形式使用之式(I)化合物及/或本發明之醫藥組合物藉由熟習此項技術者已知之習知方法調配成醫藥上可接受之劑型。
可改變本發明之醫藥組合物中之活性成分之實際劑量水平以便獲得一定量之活性成分,其有效達成對特定患者、組合物及投與模式之治療反應而對患者無毒。
所選劑量水平將取決於各種因素,包括所採用之特定式(I)化合物或其酯、鹽或醯胺之活性、投與途徑、投與時間、正在採用之特定化合物之排洩速率或代謝、吸收速率及程度、治療之持續時間、與所採用之特定化合物組合使用之其他藥物、化合物及/或物質、正在治療之患者之年齡、性別、體重、狀況、一般健康及先前醫療史及醫療技術中熟知之類似因素。
一般熟習此項技術之醫生或獸醫可容易確定所需醫藥組合物之有效量及開處方。例如,醫生或獸醫可以低於為達成治療效應所需之含量開始醫藥組合物中採用之式(I)化合物之劑量及逐漸增加劑量直至達成效應。
一般而言,式(I)化合物之適宜每日劑量將為有效產生治療效應之最低劑量之化合物的量。此有效劑量一般取決於上述因素。一般地,式(I)化合物針對患者之口服、靜脈內、腦室內及皮下劑量範圍為約0.01至約50 mg/kg體重/天。
若所需,則活性化合物之有效每日劑量可在整天以適宜間隔分開投與之兩個、三個、四個、五個、六個或更多個子劑量,視情況,以單位劑型投與。於本發明之某些態樣中,給藥為一次投與/天。
雖然式(I)化合物可單獨投與,但是較佳地呈醫藥調配物(組合物)投與化合物。
當與式(I)化合物組合採用時,以上其他治療劑可(例如)以Physicians’ Desk Reference (PDR)中所指示或如由一般技術者以其他方式測定之彼等量使用。於本發明之方法中,此等其他治療劑可在投與本發明化合物之前、同時或之後投與。
製備方法
本發明之化合物可以熟習有機合成技術者熟知之許多方法製備。本發明之化合物可使用下述方法,連同合成有機化學技術中已知之合成方法或如由熟習此項技術者所瞭解之其變型來合成。較佳方法包括(但不限於)下述彼等。本文中引用之所有參考文獻之全文係引用的方式併入本文中。
本發明之化合物可使用此節中所述之反應及技術製備。反應係於適於所採用之試劑及材料之溶劑中進行及適用於正在實現之轉化。同樣,於下述合成方法之描述中,應瞭解,選擇所有建議之反應條件,包括溶劑、反應氛圍、反應溫度、實驗之持續時間及處理程序之選擇為該反應之標準條件,其應容易由熟習此項技術者認識到。熟習有機合成技術者應瞭解,分子之各種部分上存在之官能基必須與建議之試劑及反應相容。與反應條件相容之取代基之此等限制將對熟習此項技術者顯而易見及然後必須使用替代方法。此有時需要判斷以修改合成步驟之順序或選擇一個特定製程方案優於另一者以獲得本發明之化合物。亦應知曉,在計劃此領域之任何合成途徑中之另一主要考量為明智選擇用於保護存在於本發明中所述化合物中之反應性官能基之保護基。對經訓練實務者描述許多替代之權威性報導為Greene及Wuts (
Protective Groups In Organic Synthesis,第4版,Wiley and Sons, 207)。
式(I)化合物可參考下列反應圖中所說明之方法製備。如其中所示,最終產物為具有與式(I)相同結構式之化合物。應瞭解,任何式(I)化合物可藉由反應圖藉由適宜選擇試劑與適宜取代產生。溶劑、溫度、壓力及其他反應條件可由一般技術者容易選擇。起始材料係市售或由一般技術者容易製備。化合物之成分係如本文中或本說明書其他地方所定義。
反應圖1至2中說明本發明中所述化合物之一般途徑,其中R
1、R
2、R
4及R
6先前於文本中定義或為可轉化成最終取代基之官能基。取代基X為離去基團,諸如鹵化物(較佳地I、Br或Cl)或三氟甲磺酸鹽。取代基M為適宜偶合搭檔,諸如硼酸、硼酸酯或錫烷。取代基R為羧酸保護基,諸如第三丁基、甲基、乙基或苄基。如反應圖1中所示,用於製備本發明之化合物之一般程序涉及以經適宜取代之芳基氟
1開始。當利用適宜親核試劑,諸如中間體
2(其中M可為MgBr或Li)處理時,可產生經取代之芳基鹵,諸如
3。鹵化,較佳地溴化可藉由將
3用諸如N-溴琥珀醯亞胺之試劑處理以得到溴化物
4來實現。在鹼性條件(諸如碳酸鉀)下將
4用胺
5處理將導致二級溴化物之初始置換,接著環化,以得到內醯胺
6。
反應圖1
當M為錫烷時,
6可與經適宜取代之雜環
7於施蒂勒(Stille)偶合反應中使用適宜觸媒體系(例如,Pd(PPh
3)
4或雙(三苯基膦)二氯化鈀(II)/CuI)聯合,以得到
8。或者,可藉由熟習此項技術者熟知之條件將
6轉化成硼酸或硼酸酯
9。該硼酸或硼酸酯
9可與經適宜取代之雜環
10於鈴木-宮浦(Suzuki-Miyaura)偶合反應中使用適宜鈀觸媒(例如,Pd(PPh
3)
4或1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II))在存在適宜鹼(例如,碳酸銫、磷酸鉀或碳酸氫鈉)下聯合,以得到
8。
取決於中間體
8中之酸保護基R之特定選擇,可需要不同條件以將其轉化成化合物
11(反應圖2)。例如,在R =甲基、乙基或苄基之情況下,使用適宜鹼(例如LiHMDS)於適宜溶劑(例如,四氫呋喃)中鹼誘導之
8之環化針對將
8直接轉化為
11可係較佳。在R =第三丁基之情況下,使用適宜酸(例如,苯磺酸)於適宜溶劑(例如,乙腈)中酸誘導之
12之環化針對
8直接轉化為
11可係較佳。於一些情況下,使用兩步程序可係較佳,首先使用適用於特定酸保護基R之條件將對應於
8之游離羧酸釋放。此等方法為一般熟習有機合成技術者熟知。例如,在R=第三丁基之情況下,使用適宜酸(例如,三氟乙酸或鹽酸)之酸性水解可係較佳。在R=甲基、乙基或苄基之情況下,使用適宜鹼(例如,LiOH)之鹼性水解可係較佳。於其他情況下,在R=苄基之情況下,藉由鈀催化之氫解之作用脫去保護基可係有利的。一旦釋放,羧酸就可朝向藉由側鏈一級醯胺之分子內攻擊藉由亞硫醯氯/二甲基甲醯胺或羰二咪唑/二甲胺基吡啶之作用經活化,以得到
11。
反應圖2
實例
下列實例說明本發明之特定實施例且不限制本發明之範圍。除非另有指定,否則化學縮略語及符號以及科學縮略語及符號具有其通常且習慣含義。以上定義實例及本申請案之其他地方中所採用之另外縮略語。常見中間體一般可用於製備超過一個實例。實例之化合物藉由製備其之實例及步驟(例如,「1-A」表示實例1,步驟A)或在化合物為實例之標題化合物之情況下僅由實例(例如,「1」表示實例1之標題化合物)識別。於一些實例中,描述中間體或實例之替代製法。熟習合成技術之化學家可頻繁地設計替代製法,其基於一或多個考量,諸如更短反應時間、更少昂貴起始物質、容易操作或分離、提高產率、服從催化、避免毒性試劑、專用儀器之可及性及減少之線性步驟數等可係所需。描述替代製法之意圖為進一步使能製備本發明之實例。於一些實例中,實例及申請專利範圍中概述之一些官能基可藉由此項技術中已知之熟知生物電子等排替換來替換,例如,將羧酸基團用四唑或磷酸酯部分替換。
縮略語
ACN 乙腈
AIBN 2,2-偶氮二異丁腈
n-BuLi 正丁基鋰
DCE 二氯乙烷
DCM 二氯甲烷
DIPEA
N,
N-二異丙基乙胺
DMF 二甲基甲醯胺
DMSO 二甲亞碸
dppf 雙(二苯基膦基)二茂鐵
EtOH 乙醇
EtOAc 乙酸乙酯
Hex 己烷
H-Glu(OtBu)-NH
2HCl (4S)-4,5-二胺基-5-側氧基戊酸第三丁酯鹽酸鹽
HPLC 高效液相層析法
亨氏(Hunig’s)鹼
N,
N-二異丙基乙胺
LiHMDS 雙(三甲基矽基)醯胺鋰
MeCN 乙腈
min 分鐘
mL 毫升
NBS n-溴琥珀醯亞胺
Pd(dppf)
2Cl
2[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)
Pd(dtbpf)Cl
2[1,1′-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II)
Pd(PPh
3)
4肆(三苯基膦)鈀
PhSO
3H 苯磺酸
PTSOH 對甲苯磺酸
TEA 三乙胺
THF 四氫呋喃
XPhos Pd G2 氯(2-二環己基膦基-2′,4′,6′-三異丙基-1,1′-聯苯基)[2-(2′-胺基-1,1′-聯苯基)]鈀(II)
製備型HPLC方法1:XBridge C18,200 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與10-mM乙酸銨;流動相B:95:5乙腈:水與10-mM乙酸銨;梯度:0分鐘保持在15% B下,15至50% B歷時25分鐘,然後在100% B下保持6分鐘;流率:20 mL/min;管柱溫度:25℃。藉由MS信號觸發溶離份收集。
實例1
2-胺基-6-(2-(2,6-二氧哌啶-3-基)-4-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈
製備1A:(S)-5-胺基-4-(5-溴-4-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯。
在0℃下,向含於乙腈(30 ml)中之(S)-4,5-二胺基-5-側氧基戊酸第三丁酯鹽酸鹽(2.162 g,6.06 mmol)之懸浮液中添加添加DIPEA (3.018 ml,17.28 mmol)。於攪拌20分鐘後,將反應混合物用含於MeCN (10 mL)中之4-溴-2-(溴甲基)-3-甲基苯甲酸甲酯(2.650 g,8.22 mmol)之溶液處理。將反應混合物在0℃下攪拌5分鐘。移除冰浴及允許將反應混合物升溫至室溫及在室溫下攪拌1小時。將反應混合物升溫至60℃及在該溫度下保持過夜。將反應混合物濃縮,溶解於EtOAc中,用水洗滌兩次,然後用1.5M K
2HPO
4洗滌,及亦用鹽水洗滌,及然後經MgSO
4乾燥,過濾及濃縮。將物質使用矽膠及利用30至100% EtOAc/Hex溶離純化。將所得物質用8 mL乙醚研磨,以獲得33.7%產率之標題產物。
1H NMR (400 MHz,氯仿-d) δ 7.70 (d, J=8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 6.23 (br s, 1H), 5.31 (br s, 1H), 4.92 (dd, J=8.6, 6.4 Hz, 1H), 4.55-4.47 (m, 1H), 4.45-4.36 (m, 1H), 2.41 (s, 3H), 2.41-2.14 (m, 4H), 1.45 (s, 9H)。
製備1B:(S)-5-胺基-4-(4-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環(dioxaborolan)-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向乾燥燒瓶中放入(S)-5-胺基-4-(5-溴-4-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(300 mg,0.730 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼戊環) (278 mg,1.094 mmol)及乙酸鉀及乙酸鉀(214 mg,2.188 mmol)及用氮沖洗。將固體懸浮於二噁烷及用氮氣沖洗。將固體懸浮於二噁烷(10 mL)中及用氮氣流脫氣5分鐘,同時攪拌。將反應混合物用Pd(dppf)Cl
2(16.02 mg,21.88 µmol)處理。將燒瓶脫氣5分鐘,密封及在氮氣下加熱至60℃持續18小時。將反應混合物用EtOAc稀釋,用鹽水洗滌,及經MgSO
4乾燥。將其濃縮及藉由40 g矽膠管柱藉由ISCO,利用0至40% B/DCM (其中B= 15% EtOH/EtOAc+0.1% TEA)溶離純化,以得到99%產率之產物。MS (ES): m/z = 459.3 [M+H]
+。
實例1:
向2 mL微波小瓶中放入2-胺基-6-溴-4-甲基菸鹼甲腈(12 mg,0.057 mmol)、(S)-5-胺基-4-(4-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(28.5 mg,0.062 mmol)、Pd(dtbpf)Cl
2(1.106 mg,1.698 µmol)、二噁烷(1.5 mL)及K
3PO
4水溶液(0.075 mL,0.226 mmol)。將小瓶密封及將空氣用氮氣置換。將反應混合物在120℃下微波15分鐘。於冷卻至室溫後,將反應混合物用EtOAc稀釋,用鹽水洗滌,及分離有機層及濃縮。將所獲得之殘留物溶解於1 mL含於MeCN中之PhSO
3H溶液(1.44 g/40 mL)中及在120℃下微波10分鐘。將物質濃縮至乾,及將殘留物溶解於1.9 mL DMSO中,及藉由製備型HPLC方法1純化,以得到49%產率之標題化合物。MS (ES): m/z = 390.3 [M+H]
+。
1H NMR (500 MHz, DMSO-
d 6) δ ppm 11.03 (s, 1 H) 7.66 (d,
J=7.63 Hz, 1 H) 7.53 (d,
J=7.93 Hz, 1 H) 6.91 (s, 2 H) 6.78 (s, 1 H) 5.18 (br dd,
J=13.43, 5.19 Hz, 1 H) 4.52 (br d,
J=17.09 Hz, 1 H) 4.35 (br d,
J=17.40 Hz, 1 H) 2.91-3.01 (m, 1 H) 2.65 (br d,
J=16.78 Hz, 1 H) 2.47 (br dd,
J=13.12, 4.27 Hz, 1 H) 2.43 (s, 3 H) 2.33 (s, 3 H) 2.03-2.10 (m, 1 H)。
實例2
2-胺基-6-(2-(2,6-二氧哌啶-3-基)-6-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈
製備2A:4-溴-2-(溴甲基)-5-甲基苯甲酸甲酯。
在室溫下,向4-溴-2,5-二甲基苯甲酸(5.0 g,21.82 mmol)之溶液中添加SOCl
2(31.66 mL,436 mmol)及攪拌2小時。使用LCMS證實醯基氯之形成,及然後濃縮至乾。在室溫下添加甲醇(30 mL)及攪拌0.5小時及然後再次濃縮至乾。向所獲得之甲酯中添加CCl
4(180 mL),接著1-溴吡咯啶-2,5-二酮(4.08 g,22.92 mmol)及然後AIBN (0.108 g,0.654 mmol)。將所得混合物加熱至80℃,同時攪拌過夜。於冷卻至室溫後,將混合物濃縮,溶解於EtOAc中,用鹽水洗滌,及經MgSO
4乾燥。LCMS顯示兩個主要峰。將所獲得之區域異構體之混合物(5.4 g)用於下個步驟。
製備2B:(S)-5-胺基-4-(5-溴-6-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向含於乙腈(100 mL)中之4-溴-2-(溴甲基)-5-甲基苯甲酸甲酯(5.4 g,16.76 mmol)之懸浮液中添加(S)-4,5-二胺基-5-側氧基戊酸第三丁酯HCl (4.00 g,16.76 mmol),接著亨氏鹼(5.84 mL,33.52 mmol)。於室溫下攪拌1小時後,將反應混合物放入40℃浴中及在該溫度下攪拌6天。將反應混合物冷卻至室溫及用EtOAc稀釋,用鹽水洗滌,經MgSO
4乾燥,過濾及濃縮。將殘留物藉由ISCO [120 g管柱],利用EtOAc/DCM自0至100%溶離純化,以獲得2.80 g所需化合物。此外,將兩種其他副產物((S)-5-(((1-胺基-5-(第三丁氧基)-1,5-二氧戊-2-基)胺基)甲基)-4-溴-2-甲基苯甲酸甲酯及(S)-5-胺基-4-(((2-((R)-1-胺基-5-(第三丁氧基)-1,5-二氧戊-2-基)-6-溴-3-側氧基異吲哚啉-5-基)甲基)胺基)-5-側氧基戊酸第三丁酯)分離。MS (ES): m/z = 411.0 [M+H]
+。
1H NMR (400 MHz,氯仿-
d) δ ppm 7.70 (d,
J=6.44 Hz, 2 H) 6.31 (br s, 1 H) 5.36 (br s, 1 H) 4.90 (dd,
J=8.68, 6.34 Hz, 1 H) 4.51 (d,
J=16.98 Hz, 1 H) 4.41 (d,
J=16.98 Hz, 1 H) 2.51 (s, 3 H) 2.21-2.43 (m, 3 H) 2.12-2.19 (m, 1 H) 1.44 (s, 9 H)。
製備2C:(S)-5-胺基-4-(6-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向40 mL壓力小瓶中放入(S)-5-胺基-4-(5-溴-6-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(600 mg,1.458 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼戊環) (556 mg,2.188 mmol)及乙酸鉀(430 mg,4.376 mmol)及用氮氣沖洗。將固體懸浮於二噁烷(20 mL)中及用氮氣流脫氣5分鐘,同時攪拌。將反應混合物用Pd(dppf)Cl
2(32.02 mg,0.044 mmol)處理及脫氣5分鐘。將小瓶密封,及在氮氣下加熱至95℃持續3小時。將反應混合物冷卻至室溫,用EtOAc稀釋,用鹽水洗滌,及經MgSO
4乾燥。將濾液濃縮及藉由40 g矽膠管柱藉由ISCO,利用(0%至40% B/DCM,其中B= 15% EtOH/EtOAc+0.1% TEA)溶離純化,以得到95%產率之標題化合物。MS (ES): m/z = 459.3 [M+H]
+。
實例2:
向2 mL微波小瓶中放入2-胺基-6-溴-4-甲基菸鹼甲腈(12 mg,0.057 mmol)、(S)-5-胺基-4-(6-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(28.5 mg,0.062 mmol)、Pd(dtbpf)Cl
2(1.106 mg,1.698 µmol)、二噁烷(1.5 mL)及K
3PO
4水溶液(0.075 mL,0.226 mmol)。將小瓶密封及將空氣用氮氣置換。將反應混合物在120℃下微波15分鐘。於冷卻至室溫後,將反應混合物用EtOAc稀釋,用鹽水洗滌,及分離有機層及濃縮。將所獲得之殘留物溶解於1 mL含於MeCN中之PhSO
3H溶液(1.44 g/40 mL)中及在120℃下微波10分鐘。將混合物濃縮至乾,及將殘留物溶解於1.7 mL DMSO中,及藉由製備型HPLC方法1純化,以得到35%產率之標題化合物。MS (ES): m/z = 390.3 [M+H]
+。
1H NMR (500 MHz, DMSO-
d 6) δ ppm 10.97-11.02 (m, 1 H) 7.65 (s, 1 H) 7.55 (s, 1 H) 6.76 (s, 1 H) 5.13 (dd,
J=13.31, 5.18 Hz, 1 H) 4.39-4.51 (m, 1 H) 4.28-4.39 (m, 1 H) 2.87-2.98 (m, 1 H) 2.58-2.65 (m, 1 H) 2.51 (d,
J=1.74 Hz, 3 H) 2.42-2.46 (m, 1 H) 2.41 (br s, 3 H) 2.39-2.40 (m, 1 H) 1.99-2.06 (m, 1 H)。
實例3
2-胺基-6-(2-(2,6-二氧哌啶-3-基)-4-氟-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈
中間體3A:5-溴-4-氟-3-羥基異苯并呋喃-1(3
H)-酮
在0℃下,向經攪拌之含於THF (150 mL)中之2,2,6,6-四甲基哌啶(7.07 mL,41.6 mmol)之溶液中添加2.5M n-BuLi之己烷溶液(16 mL,40.0 mmol)。將反應混合物在0℃下攪拌30分鐘。在-50℃下,向此中逐滴添加含於無水THF (100 mL)中之4-溴-3-氟苯甲酸(3.5 g,15.98 mmol)之溶液。將反應混合物在相同溫度下攪拌3小時。在-50℃添加無水DMF (2.48 mL,32.0 mmol)及使反應混合物達到室溫及攪拌16小時。將反應用1.5 N HCl (100 mL)淬滅。將反應混合物用乙酸乙酯(3 x 30 mL)萃取。將合併之有機層用鹽水洗滌,經無水Na
2SO
4乾燥,過濾及在減壓下蒸發。將殘留物藉由急驟層析法(SiO
2,120 g管柱,0至50% EtOAc/石油醚)純化,以得到呈黃色固體之5-溴-4-氟-3-羥基異苯并呋喃-1(3
H)-酮(1.0 g,23%產率)。LCMS (方法A):滯留時間0.48 min,[M+H]
+245.1, 247.1;
1H NMR (400 MHz,乙腈-d
3) δ 7.93 (dd,
J= 8.0, 5.5 Hz, 1H), 7.59 (d,
J= 8.0 Hz, 1H), 6.74 (br s, 1H), 5.94 (br s, 1H)。
中間體3B:(
S)-5-胺基-4-(5-溴-4-氟-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
在0℃下,向經攪拌之含於DMF (30 mL)中之5-溴-4-氟-3-羥基異苯并呋喃-1(3
H)-酮(1.7 g,6.88 mmol)及(
S)-4,5-二胺基-5-側氧基戊酸第三丁酯HCl (1.67 g,8.26 mmol)之溶液中添加三乙醯氧基硼氫化鈉(3.65 g,17.21 mmol)。允許使反應混合物達到室溫及攪拌48小時。將反應混合物用冰水(50 mL)稀釋及將所得白色固體過濾及在減壓下乾燥,以得到呈白色固體之(
S)-5-胺基-4-(5-溴-4-氟-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(1.6 g,50%產率)。LCMS (方法A):滯留時間1.39 min,[M+H]
+413.9, 415.3;
1H NMR (400 MHz, DMSO-d
6) δ 7.85 (dd,
J= 8.0, 6.0 Hz, 1H), 7.59 (br s, 1H), 7.51 (d,
J= 8.0 Hz, 1H), 7.23 (br s, 1H), 4.77-4.59 (m, 3H), 2.26-2.13 (m, 3H), 2.08-1.96 (m, 1H), 1.34 (s, 9H)。
中間體3C:(
S)-5-胺基-4-(5-(6-胺基-5-氰基-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
將2-胺基-6-氯-4-甲基菸鹼甲腈(50 mg,0.30 mmol)及六甲基二錫(0.093 mL,0.45 mmol)於甲苯(2 mL)中之經攪拌溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II) (9.72 mg,0.015 mmol)。將反應混合物在100℃攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,得到粗產物。[M+H]
+298.2。向粗產物於二噁烷(2 mL)中之溶液中添加(
S)-5-胺基-4-(5-溴-4-氟-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(98 mg,0.24 mmol)。將反應混合物用氬氣沖洗5分鐘,添加雙(三苯基膦)氯化鈀(II) (16.60 mg,0.024 mmol),及將反應混合物在100℃加熱16小時。將反應混合物冷卻至室溫,過濾,及將濾液在減壓下濃縮,得到粗產物,將其藉由急驟層析法(SiO
2,80 g管柱,0至100% B (B = 15% EtOH/EtOAc,0.5%TEA)/氯仿)純化,得到(
S)-5-胺基-4-(5-(6-胺基-5-氰基-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(60 mg,40.7%產率)。LCMS (方法A):滯留時間1.35 min, [M+H]
+468.3。
實例3:
向中間體3C (60 mg,0.13 mmol)於乙酸(2 mL)中之經攪拌溶液中添加苯磺酸(20.30 mg,0.13 mmol)。將反應混合物在微波照射下加熱至150℃持續10分鐘。在減壓下移除揮發物,及將所得粗產物經由製備型LC-MS (管柱:Waters XBridge C18,19 x 150 mm,5 μm粒子;流動相A:0.1%三氟乙酸於水中;流動相B:乙腈;梯度:10至40% B歷時20分鐘,然後在100% B保持5分鐘;流率:15 mL/min)純化。將所需溶離份凍乾,得到2-胺基-6-(2-(2,6-二氧哌啶-3-基)-4-氟-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(15 mg,29%產率)。LCMS (方法G):滯留時間1.62 min,[M+H]
+394.2;
1H NMR (400 MHz, DMSO-d
6) δ 11.01 (br s, 1H), 8.01 (t, J=7.3 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.06 (d, J=1.5 Hz, 1H), 6.99 (s, 2H), 5.14 (dd, J=13.3, 5.1 Hz, 1H), 4.74-4.38 (m, 2H), 3.05-2.85 (m, 1H), 2.75-2.57 (m, 2H), 2.46 (s, 3H), 2.13-1.95 (m, 1H)。
一般程序2:將經攪拌之含於二噁烷(5 mL/mmol)中之中間體3B (1 eq.)及芳基錫烷試劑(1 eq.)之溶液用氬氣沖洗5分鐘。添加雙(三苯基膦)氯化鈀(II) (0.1 eq.)及將反應混合物在100℃下加熱16小時。將反應混合物冷卻至室溫,通過矽藻土墊過濾及將濾液在減壓下濃縮。將粗物質轉移至微波小瓶中,添加PhSO
3H (2 eq.)及乙酸(5 mL/mmol)及將混合物在微波反應器中在150℃下加熱10分鐘。將混合物濃縮及將殘留物藉由製備型HPLC純化。
實例4
3-(5-(6-胺基-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體4A:4-甲基-6-(三甲基錫烷基)吡啶-2-胺
將經攪拌之含於甲苯(5 mL)中之6-溴-4-甲基吡啶-2-胺(75 mg,0.382 mmol)及六甲基二錫(0.119 mL,0.57 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II) (12.4 mg,0.02 mmol)。將反應混合物在100℃下攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到4-甲基-6-(三甲基錫烷基)吡啶-2-胺(130 mg,89%產率)。LCMS (方法A):滯留時間1.62 min,[M+H]
+273.1。
實例4:
施蒂勒偶合及環化藉由下列一般程序2利用製備4A及製備3B實現。MS (ES): m/z = [M+H]
+369.1;
1H NMR (400 MHz, DMSO-d
6) δ = 11.02 (s, 1H), 8.02 (t,
J= 7.2 Hz, 1H), 7.65 (d,
J= 7.8 Hz, 1H), 6.84 (s, 1H), 6.34 (s, 1H), 6.03 (s, 2H), 5.15 (dd,
J= 5.0, 13.3 Hz, 1H), 4.66-4.57 (m, 1H), 4.49-4.38 (m, 1H), 3.02-2.85 (m, 1H), 2.62 (br d,
J= 17.4 Hz, 1H), 2.49-2.40 (m, 1H), 2.22 (s, 3H), 2.07-1.98 (m, 1H)。
實例5
3-(5-(6-胺基-4-(三氟乙基)吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體5A:
將經攪拌之含於甲苯(5 mL)中之6-氯-4-(三氟甲基)吡啶-2-胺(75 mg,0.382 mmol)及六甲基二錫(0.119 mL,0.57 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二-第三丁基膦基)二茂鐵]二氯化鈀(II) (12.4 mg,0.02 mmol)。將反應混合物在100℃下攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到4-(三氟甲基)-6-(三甲基錫烷基)吡啶-2-胺(130 mg,89%產率)。LCMS (方法A):滯留時間1.92 min,[M+H]
+327.1。
實例5:
施蒂勒偶合及環化藉由下列一般程序1利用中間體5A及中間體3B實現。MS (ES): m/z = [M+H]
+423.3;
1H NMR (400 MHz, DMSO-d
6) δ = 11.02 (s, 1H), 8.05 (t,
J= 7.3 Hz, 1H), 7.69 (d,
J= 7.8 Hz, 1H), 7.15 (s, 1H), 6.78 (d,
J= 11.8 Hz, 3H), 5.15 (dd,
J= 5.0, 13.3 Hz, 1H), 4.68-4.57 (m, 1H), 4.52-4.39 (m, 1H), 2.99-2.82 (m, 1H), 2.67-2.58 (m, 1H), 2.48-2.39 (m, 1H), 2.12-1.93 (m, 1H)。
實例6
3-(4-氟-5-(4-甲基-6-(甲胺基)吡啶-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體6A:
N,4-二甲基-6-(三甲基錫烷基)吡啶-2-胺
將經攪拌之含於甲苯(10 mL)中之6-氯-
N,4-二甲基吡啶-2-胺(100 mg,0.64 mmol)及六甲基二錫(0.199 mL,0.96 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II) (20.8 mg,0.032 mmol)。將反應混合物在100℃下攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到
N,4-二甲基-6-(三甲基錫烷基)吡啶-2-胺(250 mg,55.0%產率)。LCMS (方法A):滯留時間1.29 min,[M+H]
+287.1。
實例6:
施蒂勒偶合及環化藉由下列一般程序2利用中間體6A及中間體3B實現。MS (ES): m/z = [M+H]
+383.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.03 (s, 1H), 8.02 (s, 1H), 7.72 (d,
J= 7.5 Hz, 1H), 6.93 (s, 1H), 6.58 (br s, 1H), 5.16 (dd,
J= 13.1, 5.0 Hz, 1H), 4.82-4.40 (m, 3H), 2.89 (s, 3H), 2.75-2.63 (m, 1H), 2.64-2.57 (m, 1H), 2.46-2.41 (m, 1H), 2.36-2.28 (m, 3H), 2.06-2.00 (m, 1H)。19/19
實例7
3-(5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體7A:3,4-二甲基-6-(三甲基錫烷基)吡啶-2-胺
將經攪拌之含於甲苯(3 mL)中之6-氯-3,4-二甲基吡啶-2-胺(75 mg,0.48 mmol)及六甲基二錫(0.149 mL,0.72 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II) (15.6 mg,0.024 mmol)。將反應混合物在100℃下攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到3,4-二甲基-6-(三甲基錫烷基)吡啶-2-胺(150 mg,55.0%產率)。LCMS (方法A):滯留時間1.16 min,[M+H]
+287.2。
實例7:
施蒂勒偶合及環化藉由下列一般程序1利用中間體7A及中間體3B實現。MS (ES): m/z = [M+H]
+383.0;
1H NMR (400 MHz, DMSO-d
6) δ 11.01 (br s, 1H), 8.05 (t,
J= 7.3 Hz, 1H), 7.65 (d,
J= 7.9 Hz, 1H), 6.93 (d,
J= 1.5 Hz, 1H), 5.81 (s, 2H), 5.14 (dd,
J= 13.3, 5.1 Hz, 1H), 4.71-4.34 (m, 2H), 3.01-2.88 (m, 1H), 2.67-2.58 (m, 2H), 2.46-2.41 (m, 1H), 2.23 (s, 3H), 2.04 (s, 3H)。
實例8及9
3-((
S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮及3-((
R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體8A:4-溴-2-乙基苯甲酸
在-78℃下,於15分鐘內向含於無水THF (100 mL)中之4-溴-2-氟苯甲酸(5 g,22.83 mmol)之溶液中添加1M乙基溴化鎂之THF溶液(22.83 mL,68.5 mmol)。將反應混合物緩慢升溫至室溫及在氮氣氛圍下攪拌12小時。將反應混合物冷卻至0℃。將反應利用逐滴添加MeOH (15 mL)淬滅。將反應混合物在減壓下濃縮。將所得殘留物分配在EtOAc與2M HCl水溶液之間。分離層及將水層用EtOAc萃取兩次。將合併之有機層用鹽水洗滌,經無水Na
2SO
4乾燥,過濾及在減壓下濃縮,以得到粗產物。將粗產物藉由急驟層析法(SiO
2,80 g管柱,0至30% EtOAc/石油醚)純化,以得到4-溴-2-乙基苯甲酸(4 g,76%產率)。LCMS (方法D):滯留時間2.49 min,[M+H]
+228.8, 230.0;
1H NMR (400 MHz, DMSO-d
6) δ 13.04 (br s, 1H), 7.71 (d,
J= 8.5 Hz, 1H), 7.55 (d,
J= 2.0 Hz, 1H), 7.49 (dd,
J= 8.0, 2.0 Hz, 1H), 2.92 (q,
J= 7.2 Hz, 2H), 1.15 (t,
J= 7.5 Hz, 3H)。
中間體8B:4-溴-2-乙基苯甲酸甲酯
向經攪拌之含於DMF (40 mL)中之4-溴-2-乙基苯甲酸(4.0 g,17.46 mmol)及Cs
2CO
3(11.38 g,34.9 mmol)之混合物中添加碘甲烷(2.18 mL,34.9 mmol)。將反應混合物在室溫下攪拌14小時,通過矽藻土墊過濾及在減壓下濃縮。將殘留物藉由急驟層析法(SiO
2,80 g管柱,0至50% EtOAc/石油醚)純化,以得到呈無色油之4-溴-2-乙基苯甲酸甲酯(3.3 g,78%產率)。
1H NMR (400 MHz,氯仿-d) δ 7.76 (d,
J= 8.5 Hz, 1H), 7.46 (d,
J= 1.5 Hz, 1H), 7.40 (dd,
J= 8.5, 2.0 Hz, 1H), 3.91 (s, 3H), 2.99 (q,
J= 7.5 Hz, 2H), 1.26 (t,
J= 7.5 Hz, 3H)。
中間體8C:4-溴-2-(1-溴乙基)苯甲酸甲酯
向經攪拌之含於苯(40 mL)中之4-溴-2-乙基苯甲酸甲酯(3.0 g,12.34 mmol)之溶液中添加NBS (3.29 g,18.51 mmol),接著添加AIBN (0.405 g,2.47 mmol)。將反應混合物在85℃下加熱15小時。將反應混合物冷卻至室溫,用EtOAc稀釋,用飽和10%硫代硫酸鈉溶液及鹽水溶液洗滌。將有機層經無水Na
2SO
4乾燥,過濾及在減壓下濃縮。將殘留物藉由急驟層析法(SiO
2,40 g管柱,0至30% EtOAc/石油醚)純化,以得到4-溴-2-(1-溴乙基)苯甲酸甲酯(2.1 g,53%產率)。
1H NMR (400 MHz,氯仿-d) δ 7.96 (d,
J= 2.0 Hz, 1H), 7.73 (s, 1H), 7.49 (dd,
J= 8.5, 2.0 Hz, 1H), 6.28 (q,
J= 7.0 Hz, 1H), 3.95 (s, 3H)。
中間體8D:(4
S)-5-胺基-4-(5-溴-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向經攪拌之含於乙腈(30 mL)中之4-溴-2-(1-溴乙基)苯甲酸甲酯(1.0 g,3.11 mmol)及H-Glu(OtBu)-NH
2HCl (0.754 g,3.73 mmol)之溶液中添加DIPEA (2.71 mL,15.53 mmol)。將所得反應混合物在85℃下加熱15小時。將反應混合物冷卻至室溫及在減壓下濃縮。將殘留物藉由急驟層析法(SiO
2,40 g管柱,0至10% MeOH/DCM)純化,以得到呈半固體之(4
S)-5-胺基-4-(5-溴-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(650 mg,51%產率)。LCMS (方法A):滯留時間1.45 min,[M+H]
+411.3, 413.3。
中間體8E:5-胺基-4-(5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
將經攪拌之含於甲苯(6 mL)中之6-氯-3,4-二甲基吡啶-2-胺(200 mg,1.28 mmol)及六甲基二錫(544 mg,1.66 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二-第三丁基膦基)二茂鐵]二氯化鈀(II) (83 mg,0.13 mmol)。將反應混合物在100℃下攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到粗產物。[M+H]
+287.0。向含於二噁烷(4 mL)中之此粗產物之溶液中添加5-胺基-4-(5-溴-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(0.289 g,0.70 mmol)。將反應混合物用氬氣沖洗5分鐘。添加雙(1,2-雙(二苯基膦基)乙烷)鈀(0) (0.063 g,0.07 mmol)及將反應混合物在100℃下加熱16小時。將反應混合物冷卻至室溫,過濾及將濾液在減壓下濃縮,以得到粗產物,將其藉由急驟層析法(SiO
2,80 g管柱,0至100% B (B = 15% EtOH / EtOAc + 0.5%TEA)/氯仿)純化,以得到5-胺基-4-(5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(110 mg,34.6%產率)。LCMS (方法A):滯留時間1.40 min,[M+H]
+453.3。
中間體8F:3-(5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
向經攪拌之含於乙腈(5 mL)中之5-胺基-4-(5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(110 mg,0.243 mmol,34.6%產率)之溶液中添加對甲苯磺酸(84 mg,0.442 mmol)。將反應混合物在微波照射下加熱至120℃持續30分鐘。在減壓下移除揮發物及將粗產物經由製備型HPLC (管柱:Hypersil gold c18 (19 X 250 mm),5 μm,流動相A- 10 mM乙酸銨/水,流動相B:ACN,流率:20 mL T/B%:0/20,18/80,19/100,21/100,22/20,24/20)純化。將所需溶離份凍乾,以得到3-(5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮。LCMS (方法D):滯留時間2.15 min,[M+H]
+379.0。
實例8及9:
使3-(5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(100 mg)經歷SFC分離(管柱Welk-01(R,R)(250*4.6) mm,5 μm;% CO
2:45%;共溶劑%:含5 mM乙酸銨之甲醇及乙腈(1:1);流率:4 g/min;溫度:30℃;UV:237 nm),將在2.64 min滯留時間溶離之第一峰溶離份濃縮至乾及凍乾,得到3-((S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(12 mg,15%產率)。LCMS (方法D):滯留時間2.112 min,[M+H]
+379.0;
1H NMR (400 MHz, DMSO-d
6) δ 11.10-10.71 (s, 1H), 8.19 (s, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 5.73 (s, 2H), 4.93-4.67 (m, 2H), 2.85-2.71 (m, 2H), 2.25 (s, 3H), 2.04 (s, 3H), 1.51 (d, J=6.6 Hz, 3H),及將在4.03 min滯留時間溶離之第二峰溶離份濃縮至乾及凍乾,得到3-((R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(8 mg,10%產率)。LCMS (方法D):滯留時間2.162 min,[M+H]
+379.0;
1H NMR (400 MHz, DMSO-d
6) δ 11.00-10.89 (s, 1H), 8.18 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.13 (s, 1H), 5.73 (s, 2H), 4.84-4.68 (m, 2H), 2.91-2.65 (m, 3H), 2.25 (s, 3H), 2.04 (s, 3H), 1.51-1.46 (m, 3H)。
實例10及11
2-胺基-6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈及2-胺基-6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈
中間體10A及11A:
將經攪拌之含於甲苯(10 mL)中之2-胺基-6-氯-4-甲基菸鹼甲腈(300 mg,1.790 mmol)及1,1,1,2,2,2-六甲基二錫烷(762 mg,2.327 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II) (117 mg,0.179 mmol)。將反應混合物在100℃下攪拌2小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到粗產物。[M+H]
+298.0。將該粗物質溶解於二噁烷中,添加中間體8D (0.695 g,1.689 mmol)。將反應混合物用氬氣沖洗5分鐘及添加雙(二苯基膦基)乙烷)鈀(0) (0.153 g,0.169 mmol)。將反應混合物加熱至100℃及攪拌16小時。將反應混合物冷卻至室溫,過濾及將濾液在減壓下濃縮,以得到粗產物,將其藉由急驟層析法(SiO
2,80 g管柱,0至100% B (B = 15% EtOH / EtOAc,0.5%TEA)/氯仿)純化,以得到5-胺基-4-(5-(6-胺基-5-氰基-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(200 mg,0.431 mmol,25.5%產率)。LCMS (方法A):滯留時間1.47 min,[M+H]
+464.3。
實例10及11:
向經攪拌之含於乙腈(10 mL)中之5-胺基-4-(5-(6-胺基-5-氰基-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(200 mg,0.431 mmol)之溶液中添加對甲苯磺酸(164 mg,0.863 mmol)。將反應混合物在微波照射下加熱至120℃持續30分鐘。在減壓下移除揮發物,及將所得粗產物藉由製備型HPLC (管柱:Hypersil gold c18 (19 X 250 mm),5 μm,流動相A-含10 mM乙酸銨之水;流動相B:ACN,流率:20 mL T/B%:0/20,18/80,19/100,21/100,22/20,24/20)純化。將所需溶離份凍乾,以得到呈非對映異構體之混合物之2-胺基-6-(2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈LCMS (方法D):滯留時間1.66 min,[M+H]
+390.2。將該等非對映異構體藉由SFC (管柱Welk-01(R,R)(250*4.6) mm,5 μm;%CO
2:45%;共溶劑%:含5 mM乙酸銨之甲醇及乙腈(1:1);流率:4 g/min;溫度:30℃;UV:237 nm)分離,將在2.28 min滯留時間之第一溶離異構體溶離份濃縮至乾及凍乾,以得到2-胺基-6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(20 mg,12%產率)。LCMS (方法D):滯留時間1.64 min,[M+H]
+390.0;
1H NMR (400 MHz, DMSO-d
6) δ 11.01-10.72 (s, 1H), 8.28 (s, 1H), 8.19 (dd, J=8.0, 1.3 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 6.92 (s, 2H), 4.94-4.68 (m, 2H), 2.65-2.58 (m, 2H), 2.44 (s, 3H), 2.14-1.91 (m, 2H), 1.51 (d, J=6.6 Hz, 3H);及將在3.25 min滯留時間之第二溶離異構體溶離份濃縮至乾及凍乾,以得到2-胺基-6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(20 mg,12%產率)。LCMS (方法D):滯留時間1.66 min,[M+H]
+390.0;
1H NMR (400 MHz, DMSO-d
6) δ 11.01-10.72 (s, 1H), 8.27 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.34 (s, 1H), 6.90 (s, 2H), 4.84-4.70 (m, 2H), 2.84-2.67 (m, 2H), 2.44 (s, 3H), 2.14-1.91 (m, 2H), 1.49 (br d, J=6.6 Hz, 3H)。
實例12及13
3-((S)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮及3-((R)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體12A及13A:
向含於二噁烷(8 mL)中之中間體8D (350 mg,0.764 mmol)之溶液中添加6-氯-N,3,4-三甲基吡啶-2-胺(130 mg,0.764 mmol),接著添加3M磷酸氫二鉀水(0.764 mL,2.291 mmol)溶液。將反應混合物在室溫下用氮氣沖洗15分鐘。在氮氣下添加PdCl
2(dppf)-CH
2Cl
2加合物(62.4 mg,0.076 mmol)及將反應混合物在100℃下加熱12小時。將反應混合物冷卻至室溫,通過矽藻土墊過濾及在減壓下濃縮。將殘留物藉由急驟層析法(SiO
2,24 g管柱,0至10% MeOH\DCM)純化,以得到呈灰白色固體之(4S)-5-胺基-4-(5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(230 mg,0.493 mmol,64.6%產率)。LCMS (方法A):滯留時間1.81 min,[M+H]
+467.4。
實例12及13:
向經攪拌之含於乙酸(1 mL)中之5-胺基-4-(5-(4,5-二甲基-6-(甲胺基) 吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(200 mg,0.429 mmol)之溶液中添加苯磺酸(67.8 mg,0.429 mmol)。將反應混合物在微波照射下加熱至120℃持續30分鐘。在減壓下移除揮發物,及將所得粗產物經由製備型HPLC (管柱:X Select CSH C18 (250*20 mm),5 μm,流動相:A:10 mM乙酸銨,B:ACN T/B:0/20,18/85,20/100,21/20,23/20,流率:20 mL/min)純化。將所需溶離份凍乾,以得到呈非對映異構體之混合物之3-(5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮LCMS (方法A):滯留時間1.47 min,[M+H]
+393.4。將該等非對映異構體藉由SFC (管柱,Chiralpak IC (250*4.6) mm,5 μm;%CO
2:45%;%共溶劑:含5 mM乙酸銨之甲醇及乙腈(1:1);流率:4 g/min;溫度:30℃;UV:237 nm)分離,將在8.65 min滯留時間之第一溶離異構體溶離份濃縮至乾及凍乾,以得到3-((S)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(3 mg,2%產率),LCMS (方法D):滯留時間1.743 min,[M+H]
+393.4;
1H NMR (400 MHz, DMSO-d
6) δ 11.07-10.81 (m, 1H), 8.35-8.12 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 6.03 (br d, J=4.0 Hz, 1H), 4.88-4.69 (m, 2H), 2.96 (d, J=4.5 Hz, 3H), 2.78-2.63 (m, 3H), 2.26 (s, 3H), 2.03 (s, 4H), 1.49 (d, J=6.5 Hz, 3H)及將在11.18 min滯留時間溶離之第二峰溶離份濃縮至乾及凍乾,以得到3-((R)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(3 mg,2%產率) LCMS (方法D):滯留時間1.669 min,[M+H]
+393.4;
1H NMR (400 MHz, DMSO-d
6) δ 11.07-10.81 (m, 1H), 8.35-8.12 (m, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.14 (s, 1H), 6.03 (br d, J=4.0 Hz, 1H), 4.88-4.69 (m, 2H), 2.96 (d, J=4.5 Hz, 3H), 2.78-2.63 (m, 3H), 2.26 (s, 3H), 2.03 (s, 4H), 1.49 (d, J=6.5 Hz, 3H)。
實例14及15
6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈及6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈
中間體14A及15A:
向含於二噁烷(8 mL)中之中間體8D (200 mg,0.436 mmol)之溶液中添加6-氯-4-甲基-2-(甲胺基)菸鹼甲腈(79 mg,0.436 mmol),接著添加K
3PO
4(0.291 mL,0.873 mmol 3M水溶液)。將反應混合物在室溫下用氮氣沖洗15分鐘。在氮氣氛圍下添加Xphos Pd G4 (37.6 mg,0.044 mmol)及將反應混合物在80℃下加熱12小時。將反應混合物冷卻至室溫,通過矽藻土墊過濾及在減壓下濃縮。將殘留物藉由急驟層析法(SiO
2,24 g管柱,0至10% MeOH\DCM)純化,以得到呈灰白色固體之(4S)-5-胺基-4-(5-(5-氰基-4-甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(75 mg,0.157 mmol,36.0%產率)。LCMS (方法A):滯留時間1.59 min,[M+H]
+478.2。
實例14及15:
在室溫下,向含於乙腈(3 mL)中之(4S)-5-胺基-4-(5-(5-氰基-4-甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(60 mg,0.126 mmol)之溶液中添加苯磺酸(19.87 mg,0.126 mmol)。將反應混合物於微波反應器中加熱至120℃持續45分鐘。將反應混合物冷卻至室溫及在減壓下濃縮,以得到粗產物。將該粗產物藉由急驟層析法(SiO
2,24 g管柱,0至10% MeOH/DCM)純化,以得到呈灰白色固體之呈非對映異構體之混合物之6-(2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈。LCMS (方法A):滯留時間1.22 min,[M+H]
+404.1。將該等非對映異構體藉由SFC (管柱Welk-01(R,R)(250*4.6) mm,5 μm;%CO
2:45%;共溶劑%:含5 mM乙酸銨之甲醇及乙腈(1:1);流率:4 g/min;溫度:30℃;UV:237 nm)分離,將在2.91 min滯留時間之第一溶離異構體溶離份濃縮至乾及凍乾,以得到6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈(6 mg,12%產率),LCMS (方法D):滯留時間2.071 min,[M+H]
+404.2;
1H NMR (400 MHz, DMSO-d
6) δ 11.27-10.74 (m, 1H), 8.35 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.37 (s, 1H), 7.12 (br d, J=4.5 Hz, 1H), 4.87 (q, J=6.2 Hz, 1H), 4.81-4.71 (m, 1H), 3.00 (d, J=4.5 Hz, 3H), 2.68 (s, 1H), 2.44 (s, 3H), 1.72 (s, 3H), 1.52 (d, J=7.0 Hz, 3H)及將在4.74 min滯留時間溶離之第二峰溶離份濃縮至乾及凍乾,以得到6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈(8 mg,16%產率)。LCMS (方法D):滯留時間2.063 min,[M+H]
+404.2;1H NMR (400 MHz, DMSO-d
6) δ 11.08-10.87 (m, 1H), 8.34 (s, 1H), 8.28 (d, J=8.3 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.36 (s, 1H), 7.19-7.05 (m, 1H), 4.91-4.71 (m, 2H), 2.99 (d, J=4.5 Hz, 3H), 2.76-2.57 (m, 3H), 2.44 (s, 3H), 1.71 (s, 1H), 1.49 (d, J=6.8 Hz, 3H)。
實例16及17
3-((
S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮及3-((
R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體16A:4-溴-2-乙基-3-氟苯甲酸
將於四氫呋喃(40 mL)中之4-溴-2,3-二氟苯甲酸(2.0 g,8.44 mmol)之溶液冷卻至-78℃及逐滴添加乙基溴化鎂於THF中之1M溶液(8.44 mL,25.3 mmol)。使反應混合物達到室溫及在氮氣氛圍下攪拌12小時。將反應藉由在0℃下逐滴添加MeOH (15 mL)淬滅。在減壓下移除揮發物及將殘留物分配在EtOAc與2M HCl水溶液之間。分離層及用EtOAc萃取。將合併之有機層用鹽水洗滌,經無水Na
2SO
4乾燥,過濾及在減壓下濃縮,以得到粗產物。將該粗產物藉由急驟層析法(SiO
2,40 g管柱,0至80% EtOAc/石油醚)純化,以得到4-溴-2-乙基-3-氟苯甲酸(1 g,48%產率)。LCMS (方法A):滯留時間0.69 min,[M-H]
+245.1, 247.1;
1H NMR (300 MHz, DMSO-d
6) δ 13.36 (s, 1H), 7.68-7.53 (m, 2H), 2.95 (qd, J = 7.4, 2.6 Hz, 2H), 1.24-1.06 (m, 3H)。
中間體16B:4-溴-2-乙基-3-氟苯甲酸甲酯
在室溫下,向經攪拌之含於丙酮(15 mL)中之4-溴-2-乙基-3-氟苯甲酸(0.7 g,2.83 mmol)及K
2CO
3(0.783 g,5.67 mmol)之混合物中逐滴添加硫酸二甲酯(0.541 mL,5.67 mmol)。將反應混合物在50℃下攪拌14小時及通過矽藻土墊過濾。將濾液在真空下濃縮及藉由急驟層析法(SiO
2,24 g管柱,0至50% EtOAc/石油醚)純化,以得到呈無色油之4-溴-2-乙基-3-氟苯甲酸甲酯(0.51 g,69%產率)。
1H NMR (300 MHz,氯仿-d) δ 7.58-7.51 (m, 1H), 7.49-7.37 (m, 1H), 3.90 (s, 3H), 3.01 (qd, J = 7.4, 2.6 Hz, 2H), 1.23 (t, J = 7.4 Hz, 3H)。
中間體16C:4-溴-2-(1-溴乙基)-3-氟苯甲酸甲酯
向經攪拌之含於DCE (10 mL)中之4-溴-2-乙基-3-氟苯甲酸甲酯(0.515 g,1.972 mmol)之溶液中添加NBS (0.386 g,2.170 mmol),接著添加AIBN (0.065 g,0.394 mmol)。將反應混合物在85℃下加熱15小時。將反應混合物用乙酸乙酯稀釋,用飽和10%硫代硫酸鈉溶液及鹽水溶液洗滌。將有機層經無水硫酸鈉乾燥,過濾及在真空下濃縮。將所得殘留物藉由急驟層析法(SiO
2,24 g管柱,0至30% EtOAc/石油醚)純化,以得到呈白色固體之4-溴-2-(1-溴乙基)-3-氟苯甲酸甲酯(0.6 g,89%產率)。
1H NMR (300 MHz,氯仿-d) δ 7.70-7.53 (m, 1H), 7.52-7.44 (m, 1H), 6.16-5.87 (m, 1H), 3.93 (s, 3H), 1.95 (dd, J = 7.0, 1.3 Hz, 3H)。
中間體16D:(4S)-5-胺基-4-(5-溴-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向經攪拌之含於乙腈(15 mL)中之4-溴-2-(1-溴乙基)-3-氟苯甲酸甲酯(0.86 g,2.53 mmol)及H-Glu(OtBu)-NH
2HCl (0.845 g,3.54 mmol)之溶液中添加DIPEA (1.325 mL,7.59 mmol)。將反應混合物在85℃下加熱15小時。在減壓下移除揮發物及藉由急驟層析法(SiO
2,40 g管柱,0至10% MeOH/DCM)純化,以得到呈淺黃色固體之(4S)-5-胺基-4-(5-溴-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(0.23 g,21%產率)。LCMS (方法A):滯留時間1.19 min,[M+23H]
+451.3, 453.4。
中間體16E:(4
S)-5-胺基-4-(5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向經攪拌之含於1,4-二噁烷(20 mL)中之(4
S)-5-胺基-4-(5-溴-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(350 mg,0.815 mmol)之溶液中添加3,4-二甲基-6-(三甲基錫烷)吡啶-2-胺(232 mg,0.815 mmol)。將混合物用氬氣沖洗5分鐘及添加雙(三苯基膦)氯化鈀(II) (57.2 mg,0.082 mmol)。將反應混合物在100℃下加熱16小時,冷卻至室溫及用乙酸乙酯稀釋。將混合物用鹽水溶液洗滌及將有機層經無水硫酸鈉乾燥,過濾及在真空下濃縮,得到粗製化合物。將該粗製化合物藉由急驟層析法(SiO
2,24 g管柱,0至5% MeOH/DCM)純化,將合併之產物溶離份在減壓下濃縮,以得到呈淺棕色固體之(4
S)-5-胺基-4-(5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(270 mg,70.4%產率)。LCMS (方法A):滯留時間1.64 min,[M+H]
+471.2
1H NMR (400 MHz, DMSO-d
6) δ 7.99 (t, J=6.9 Hz, 1H), 7.59 (s, 1H), 7.47 (br s, 1H), 7.30-7.13 (m, 2H), 6.90 (s, 1H), 5.74 (br d, J=5.3 Hz, 2H), 4.89 (q, J=6.1 Hz, 1H), 4.50-4.37 (m, 1H), 2.31-2.19 (m, 6H), 2.04 (s, 3H), 1.55-1.45 (m, 3H), 1.37 (d, J=2.9 Hz, 9H)。
實例16及17:
向經攪拌之含於乙腈(10 mL)中之(4S)-5-胺基-4-(5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(270 mg,0.574 mmol)之溶液中添加PTSOH (218 mg,1.148 mmol)。將反應混合物在120℃下在微波照射下加熱30分鐘。在減壓下移除揮發物及將所得粗產物經由製備型HPLC使用極性有機方法(纖維素-2 [250 x 4.6 mm],含10 mM乙酸銨之MeOH,流率:23 mL/min (等梯度))純化,將在9.73 min滯留時間之第一溶離異構體溶離份濃縮至乾及凍乾,以得到3-(
(S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(60 mg,27%產率)。LCMS (方法G):滯留時間1.83 min,[M+H]
+397.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.10-10.87 (m, 1H), 8.01 (t, J=7.3 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 5.78 (s, 2H), 5.01 (q, J=6.5 Hz, 1H), 4.73 (br dd, J=12.3, 4.8 Hz, 1H), 2.82-2.67 (m, 1H), 2.64-2.55 (m, 2H), 2.23 (s, 3H), 2.04 (s, 3H), 1.54 (d, J=7.0 Hz, 3H)。將在13.96 min滯留時間之第二溶離峰溶離份濃縮至乾及凍乾,以得到3-((
R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(70 mg,31%產率)。LCMS (方法G):滯留時間1.84 min,[M+H]
+397.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.07-10.89 (m, 1H), 8.01 (t, J=7.1 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 6.91 (s, 1H), 5.79 (s, 2H), 4.89 (q, J=6.5 Hz, 1H), 4.80 (dd, J=12.6, 5.1 Hz, 1H), 2.94-2.78 (m, 1H), 2.73-2.59 (m, 2H), 2.22 (s, 3H), 2.03 (s, 3H), 1.51 (d, J=6.8 Hz, 3H)。
方法A:ACQUITY UPLC® BEH C18 (3.0 x 50 mm) 1.7 μm;流動相A:95:5水:乙腈與2.5 mM NH
4OAc;流動相B:5:95水:乙腈與2.5 mM NH
4OAc;溫度:40℃;梯度:20%B至100%B歷時2分鐘;流率:0.7 mL/min;檢測:MS及UV (220 nm)。
方法B:管柱:XBridge BEH XP C18 (50 x 2.1) mm,2.5 μm;流動相A:95:5水:乙腈與10 mM NH
4OAc;流動相B:5:95水:乙腈與10 mM NH
4OAc;溫度:50℃;梯度:0%B至100%B歷時3分鐘;流率:1.1 mL/min;檢測:MS及UV (220 nm)。
方法D:管柱-Kinetex XB-C18 (75 X 3 mm-2.6 μm);流動相A:含5 mM NH
4COOH之水;流動相B:乙腈;梯度:10%B至50%B歷時3分鐘,流率:1.0 mL/min;50%B至100%B上至4.1 min,流率:1.0 mL/min;保持直至4.5 min;4.5 min至5.0 min 90%B流率:1.5 mL/min;檢測:MS及UV (220 nm)。
方法G:管柱-Kinetex XB-C18 (75 X 3 mm-2.6 μm);流動相A:含5 mM NH
4CO
2H之水;流動相B:乙腈;梯度:20%B至100%B歷時4分鐘,流率:1.0 mL/min;保持至4.6 min,流率:1.5 mL/min;保持直至4.7 min;4.7 min至5.0 min 20%B,流率:1.0 mL/min;檢測:MS及UV (220 nm)。
實例18
3-(5-(6-胺基-3-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例18係自6-氯吡啶-2-胺及中間體3B使用一般程序2合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間0.98 min,[M+H]
+369.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.04 (s, 1H), 7.77 (br d,
J= 7.6 Hz, 2H), 7.74-7.68 (m, 1H), 6.93-6.87 (m, 1H), 5.17 (dd,
J= 13.3, 5.1 Hz, 1H), 4.67 (d,
J= 17.6 Hz, 1H), 4.55-4.47 (m, 1H), 3.01-2.89 (m, 2H), 2.67-2.61 (m, 1H), 2.47-2.39 (m, 1H), 2.04 (s, 3H)。
一般程序4:
在室溫下,將芳基鹵(1 eq.)、芳基硼酸頻哪醇酯(1.0 eq.)、碳酸鉀(1.5 eq.)、二噁烷(4 mL/mmol)及水(0.4 mL/mmol)之混合物用氬氣沖洗5分鐘。添加[1,1'-雙(二苯基膦基)二茂鐵]二氯化鈀(II)二氯甲烷複合物(0.05 eq.)及將反應混合物在110℃下加熱2小時。將反應混合物冷卻至室溫,用EtOAc稀釋及通過矽藻土墊過濾。將濾液用鹽水溶液洗滌,經無水Na
2SO
4乾燥,過濾及在減壓下濃縮。將殘留物藉由急驟層析法純化。將經分離之產物溶解於乙腈中,添加pTSA•H
2O (2 eq.)及將混合物於微波反應器中在120℃下加熱1.5小時。將反應混合物冷卻至室溫及在減壓下濃縮及將粗產物藉由製備型HPLC純化,以得到所需產物。
實例19
3-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體19A及19B:6-溴-3-氟-4-甲基吡啶-2-胺及6-溴-5-氟-4-甲基吡啶-2-胺
向含於氯仿(100 mL)及水(100 mL)中之6-溴-4-甲基吡啶-2-胺(2.6 g,13.90 mmol)之溶液中添加Selectfluor (2.462 g,6.95 mmol)。將反應混合物在室溫下攪拌48小時。將反應混合物用DCM (200 mL)稀釋,用鹽水溶液洗滌,經無水Na
2SO
4乾燥,過濾及在減壓下濃縮。將所獲得之殘留物藉由急驟層析法(SiO
2,80 g管柱,0至30% EtOAc/石油醚)純化,以得到中間體19A:6-溴-3-氟-4-甲基吡啶-2-胺(600 mg,19.6%產率);LCMS (方法A):滯留時間1.21 min,[M+H]
+207.1。
1H NMR (300 MHz, DMSO-d
6) δ 6.60 (d,
J =4.2 Hz, 1H), 6.55 (s, 2H), 2.13 (d,
J =1.9 Hz, 3H);及中間體19B:6-溴-5-氟-4-甲基吡啶-2-胺(500 mg,4.4%產率);LCMS (方法A):滯留時間1.14,[M+H]
+207.1;
1H NMR (300 MHz,氯仿-d) δ 6.25 (d,
J= 4.2 Hz, 1H), 4.52-4.22 (m, 2H), 2.23 (d,
J= 1.1 Hz, 3H)。
實例19:
實例19藉由使用一般程序4利用6-溴-3-氟-4-甲基吡啶-2-胺及(S)-5-胺基-4-(4-氟-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)合成。將粗產物藉由製備型LCMS (管柱:YMC EXRS 250 mm x 21 mm,流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法D):滯留時間1.56 min,[M+H]
+387.15;
1H NMR (400 MHz, DMSO-d
6) δ 11.02 (s, 1H), 8.09-7.92 (m, 1H), 7.66 (d,
J= 8.0 Hz, 1H), 7.32-6.78 (m, 1H), 5.14(dd,
J= 13.8, 5.8 Hz,1H), 4.74-4.33 (m, 2H), 2.98-2.86 (m, 1H), 2.68-2.56 (m, 2H), 2.24 (s, 3H), 22.09-2.05(m, 1H)。
實例20
3-(5-(6-胺基-3-氟-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例20藉由使用一般程序4利用6-溴-5-氟-4-甲基吡啶-2-胺及(S)-5-胺基-4-(4-氟-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.03 min,[M+H]
+387.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.04 (s, 1H), 7.74-7.57 (m, 2H), 6.46 (d,
J= 4.5 Hz, 1H), 5.97 (s, 2H), 5.16 (dd,
J= 5.0, 13.3 Hz, 1H), 4.65 (d,
J= 17.5Hz, 1H), 4.52-4.42 (m, 1H), 3.03-2.86 (m, 1H), 2.68-2.59 (m, 1H), 2.49-2.41 (m, 1H), 2.21 (s, 3H), 2.12-1.99 (m, 1H)。
實例21及22
3-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
中間體21A:(4
S)-5-胺基-4-(3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
在室溫下,將含於無水DME (15 mL)中之中間體8D (1.0 g,2.43 mmol)、乙酸鉀(0.239 g,2.43 mmol)及Bispin (0.617 g,2.43 mmol)之混合物用氬氣沖洗10分鐘。在氬氣氛圍下添加PdCl
2(dppf)-CH
2Cl
2加合物(0.159 g,0.195 mmol)。將小瓶密封及將混合物在90℃下加熱12小時。將反應混合物冷卻至室溫,通過矽藻土墊過濾及將濾液在減壓下濃縮。將殘留物溶解於乙醚中及通過矽藻土墊過濾。將濾液在減壓下濃縮,以得到(4S)-5-胺基-4-(3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(1.0 g,90%產率)。LCMS (方法A):滯留時間1.70 min,[M+H]
+459.1。
製備21B及22B:(4
S)-5-胺基-4-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯
向含於二噁烷(10 mL)中之(4
S)-5-胺基-4-(3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(0.241 g,0.527 mmol)之溶液中添加6-溴-3-氟-4-甲基吡啶-2-胺(0.09 g,0.44 mmol),接著添加碳酸氫鈉(0.5M溶液,2.195 mL,1.097 mmol)。在室溫下,將反應混合物用氮氣沖洗15分鐘,在氮氣下添加雙(三苯基膦)氯化鈀(II) (0.031 g,0.044 mmol)及在100℃下加熱12小時。將反應混合物冷卻至室溫,通過矽藻土墊過濾及在減壓下濃縮。將殘留物藉由急驟層析法(SiO
2,24 g管柱,50至100% EtOAc/DCM)純化,以得到呈非對映異構體之混合物之(4S)-5-胺基-4-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(150 mg)。將該等非對映異構體藉由SFC (管柱Chiral Pak IG (250*4.6) mm,5 μm;%CO
2:45%;共溶劑%:含5 mM乙酸銨之甲醇及乙腈(1:1);流率:4 g/min;溫度:30℃;UV:237 nm)分離,將在3.4 min滯留時間之第一溶離異構體溶離份濃縮至乾,以得到(4
S)-5-胺基-4-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(40 mg,20%產率)。LCMS (方法A):滯留時間1.41,[M+H]
+457.1及將在4.6 min滯留時間溶離之第二峰溶離份濃縮,以得到(4S)-5-胺基-4-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(50 mg,25%產率)。LCMS (方法A):滯留時間1.40,[M+H]
+457.4。
實例21:
向經攪拌之含於乙腈(10 mL)中之(
4S)-5-胺基-4-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(0.04 g,0.088 mmol)之溶液中添加苯磺酸(0.028 g,0.175 mmol)。將反應混合物在微波照射下在120℃下加熱30分鐘。將反應混合物冷卻至室溫,在減壓下濃縮及藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.19 min,[M+H]
+383.1;
1H NMR (400 MHz, DMSO-d
6) δ 10.95 (s, 1H), 8.14 (s, 1H), 8.07 (dd,
J= 1.1, 8.1 Hz, 1H), 7.72 (d,
J= 8.0 Hz, 1H), 7.17 (d,
J= 4.4 Hz, 1H),4.82-4.67 (m, 2H), 2.93-2.79 (m, 1H), 2.71-2.59 (m, 2H), 2.26 (s, 3H), 2.05-1.96 (m, 1H), 1.48 (d,
J= 6.6 Hz, 3H)。
實例22:
向經攪拌之含於乙腈(10 mL)中之(
4S)-5-胺基-4-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(0.04 g,0.088 mmol)之溶液中添加苯磺酸(0.028 g,0.175 mmol)。將反應混合物在微波照射下在120℃下加熱30分鐘。將反應混合物冷卻至室溫,在減壓下濃縮及將殘留物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.19 min,[M+H]
+383.1;
1H NMR (400 MHz, DMSO-d
6) δ 10.92 (s, 1H), 8.16 (s, 1H), 8.07 (dd,
J= 1.1, 8.0 Hz, 1H), 7.70 (d,
J= 8.0 Hz, 1H), 7.17 (d,
J= 4.3 Hz, 1H),6.26 (br s, 2H), 4.83 (q,
J= 6.6 Hz, 1H), 4.74 (br dd,
J= 4.3, 11.3 Hz, 1H), 2.83-2.71 (m, 1H), 2.64-2.55 (m, 2H), 2.25 (d,
J= 1.5 Hz, 3H), 2.09 -1.96 (m, 1H), 1.50 (d,
J= 6.6 Hz, 3H)。
實例23
2-胺基-6-((3
R)-2-(2,6-二氧哌啶-3-基)-4-氟-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈
實例23係自2-胺基-6-氯-4-甲基菸鹼甲腈及
(S)-5-胺基-4-(
(R)-4-氟-3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)使用一般程序4合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.19 min,[M+H]
+408.0;
1H NMR (400 MHz, DMSO-d
6) δ 11.00 (s, 1H), 8.17-7.85 (m, 1H), 7.73-7.52 (m, 1H), 7.05 (s, 1H), 6.99 (s, 2H), 5.08-4.89 (m, 1H), 4.86-4.72 (m, 1H), 2.90-2.75 (m, 1H), 2.74-2.58 (m, 2H), 2.42 (s, 3H), 2.12-2.00 (m, 1H), 1.57-1.47 (m, 3H)。
實例24
3-(
(R)-5-(6-胺基-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例24係自6-氯-4-甲基吡啶-2-胺及
(S)-5-胺基-4-(
(R)-4-氟-3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)使用一般程序4合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.20 min,[M+H]
+383.2;
1H NMR (400 MHz, DMSO-d
6) δ 11.00 (d,
J= 0.8 Hz, 1H), 8.01-7.84 (m, 1H), 7.71 (d,
J= 7.8 Hz, 1H), 6.96 (br d,
J= 1.0 Hz, 1H), 6.71-6.54 (m, 1H), 4.99-4.91 (m, 1H), 4.87-4.78 (m, 1H), 2.86 (br dd,
J= 4.4, 3.4 Hz, 1H), 2.75-2.62 (m, 2H), 2.47-2.44 (m, 1H), 2.34 (s, 4H), 1.94 (d,
J= 16.0 Hz, 1H), 1.53 (d,
J= 6.8 Hz, 3H)。
實例25
3-(
(R)-5-(6-胺基-4-(三氟甲基)吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例25係自6-氯-4-(三氟甲基)吡啶-2-胺及
(S)-5-胺基-4-(
(R)-4-氟-3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)使用一般程序4合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.39 min,[M+H]
+438.1;
1H NMR (400 MHz, DMSO-d
6) δ 10.99 (s, 1H), 8.13-7.95 (m, 1H), 7.65 (d,
J= 7.8 Hz, 1H), 7.15 (s, 1H), 6.79 (s, 2H), 4.98-4.88 (m, 1H), 4.86-4.77 (m, 1H), 2.85 (br s, 1H), 2.93-2.78 (m, 1H), 2.72-2.59 (m, 2H), 2.08-2.00 (m, 1H), 1.52 (d,
J= 6.8 Hz, 3H)。
實例26
3-(
(R)-5-(6-胺基-3-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例26係自6-氯-5-甲基吡啶-2-胺及
(S)-5-胺基-4-(
(R)-4-氟-3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)使用一般程序4合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.07 min,[M+H]
+383.1;
1H NMR (400 MHz, DMSO-d
6) δ 11.01 (s, 1H), 7.90-7.77 (m, 1H), 7.74-7.61 (m, 2H), 6.86 (br dd,
J= 5.5, 3.9 Hz, 1H), 4.96 (q,
J= 6.5 Hz, 1H), 4.84 (dd,
J= 12.6, 5.1 Hz, 1H), 3.01-2.82 (m, 2H), 2.71-2.60 (m, 2H), 2.12-2.01 (m, 5H), 1.51 (d,
J= 6.6 Hz, 3H)。
實例27
3-(
(R)-5-(6-胺基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例27係自6-氯吡啶-2-胺及
(S)-5-胺基-4-(
(R)-4-氟-3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)使用一般程序4合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.01 min,[M+H]
+369.1;
1H NMR (400 MHz, DMSO-d
6) δ 7.95 (t,
J= 7.1 Hz, 1H), 7.81-7.62 (m, 2H), 7.22 (s, 1H), 7.09 (s, 1H), 7.04 (br d,
J= 7.0 Hz, 1H), 6.97 (s, 1H), 6.78-6.72 (m, 1H), 4.93 (q,
J= 6.5 Hz, 1H), 4.82 (dd,
J= 12.4, 5.3 Hz, 1H), 2.91-2.83 (m, 1H), 2.75-2.60 (m, 2H), 2.36-2.32 (m, 1H), 1.52 (d,
J= 6.8 Hz, 3H)。
實例28
(R)-3-(
(R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
向經攪拌之含於乙腈(4 mL)中之實例17 (250 mg,0.531 mmol)之溶液中添加TFA (1 mL,13.81 mmol)。將反應混合物在90℃下加熱2小時。將反應混合物在減壓下濃縮及將粗產物藉由製備型SFC (Chiral Pak IC (250 X 50) mm,5 μm;%CO
2:50%;共溶劑%:50%之含5 mM乙酸銨之ACN:MEOH (50:50);流率:300.0 g/min;溫度:40℃;UV:240 nm)純化,將在6.9 min滯留時間之第一溶離異構體溶離份濃縮至乾及凍乾,以得到
(R)-3-(
(R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(15 mg,7%產率)。LCMS (方法D):滯留時間1.28 min,[M+H]
+397.1;
1H NMR (400 MHz, DMSO-d
6) δ 10.97-10.89 (m, 1H), 7.99 (br d,
J= 6.8 Hz, 1H), 7.57 (d,
J= 8.0 Hz, 1H), 6.91 (s, 1H), 5.80 (s, 2H), 5.00 (q,
J= 6.7 Hz, 1H), 4.76-4.67 (m, 1H), 2.82-2.70 (m, 1H), 2.67-2.55 (m, 2H), 2.22 (s, 3H), 2.03 (s, 4H), 1.53 (d,
J= 6.8 Hz, 3H)。
實例29
3-((R)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
實例29係自6-氯-3-氟-4-甲基吡啶-2-胺及
(S)-5-胺基-4-(
(R)-4-氟-3-甲基-1-側氧基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)異吲哚啉-2-基)-5-側氧基戊酸第三丁酯(藉由實例2中所示之程序以4-溴-3-氟-2-甲基苯甲酸開始合成)使用一般程序4合成。將粗產物藉由製備型LCMS (管柱:Waters XBridge C18,150 mm x 19 mm,5-μm粒子;流動相A:5:95乙腈:水與0.1%三氟乙酸;流動相B:95:5乙腈:水與0.1%三氟乙酸;梯度:在10% B下保持0分鐘,10至30% B歷時20分鐘,然後在100% B下保持5分鐘;流率:20 mL/min)純化。LCMS (方法B):滯留時間1.18 min,[M+H]
+401.3;
1H NMR (400 MHz, DMSO-d
6) δ 10.98 (s, 1H), 7.95 (t,
J= 7.1 Hz, 1H), 7.60 (d,
J= 7.8 Hz, 1H), 6.93 (d,
J= 3.3 Hz, 1H), 4.90 (q,
J= 6.6 Hz, 1H), 4.80 (dd,
J= 4.9, 12.9 Hz, 1H), 2.89-2.78 (m, 1H), 2.70-2.60 (m, 2H), 2.24 (s, 3H), 2.07-1.97 (m, 1H), 1.51 (d,
J= 6.5 Hz, 3H)。
實例30
3-((
S)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮
製備30A:3-氟-4-甲基-6-(三甲基錫烷)吡啶-2-胺
將經攪拌之含於甲苯(3 mL)中之6-溴-3-氟-4-甲基吡啶-2-胺(0.05 g,0.24 mmol)及六甲基二錫(0.076 mL,0.366 mmol)之溶液用氬氣沖洗5分鐘,接著添加[1,1’-雙(二第三丁基膦基)二茂鐵]二氯化鈀(II) (0.016 g,0.024 mmol)。將反應混合物在100℃下攪拌15小時,冷卻至室溫及過濾。將濾液在減壓下濃縮,以得到3-氟-4-甲基-6-(三甲基錫烷)吡啶-2-胺(69 mg,82%產率)。LCMS (方法A):滯留時間1.68,[M+H]
+289.2。
實例30:
施蒂勒偶合及環化係藉由下列一般程序2利用中間體30A及中間體16D實現。LCMS (方法D):滯留時間1.17 min,[M+H]
+401.3;
1H NMR (400 MHz, DMSO-d
6) δ 10.94 (s, 1H), 7.94 (t,
J= 7.3 Hz, 1H), 7.58 (d,
J= 8.0 Hz, 1H), 6.93 (d,
J= 3.3 Hz, 1H), 6.31 (br s, 2H), 5.01 (q,
J= 6.6 Hz, 1H), 4.72 (dd,
J= 4.9, 11.9 Hz, 1H), 2.79-2.67 (m, 1H), 2.64-2.55 (m, 2H), 2.24 (s, 3H), 2.07-1.98 (m, 1H), 1.53 (d,
J=6.8 Hz, 3H)。
生物學分析
本發明之化合物之藥理學性質可藉由許多生物學分析證實。下列例示生物學分析已利用本發明之化合物進行。
Helios細胞降解分析
將Jurkat細胞於384孔細胞培養板中於40 µL RPMI + 10% FBS中以80,000個細胞/孔平板接種,之後使用聲學分配技術以添加所關注之化合物。將細胞培養物在37℃及5% CO
2下培育72小時。為便於分析,將細胞培養物以200 rpm旋轉沉降5分鐘及遺棄上清液。於將板振盪以移走細胞集結塊後,在室溫下,將細胞再懸浮於50 µL固定緩衝液(eBioScience FoxP3緩衝設置00-5523-00)中持續60分鐘。於離心及遺棄上清液後,在室溫下,將細胞用50 µL滲透緩衝液(eBioScience FoxP3緩衝設置00-5523-00)滲透10分鐘。於滲透後,將細胞旋轉沉降及將上清液用20 µL含於1x滲透緩衝液中之螢光標記之抗Helios、Ikaros及Aiolos之抗體或對應同型對照(Ikaros-Alexa488 [Biolegend,目錄號368408,1:50]、Helios-PE [CST,目錄號29360,1:50]、Aiolos-Alexa647 [Biolegend,目錄號371106Biolegend,1:25])更換及將染色反應在室溫下培育1小時;避光。隨後,添加30 µL 1x滲透緩衝液,之後將細胞離心及遺棄上清液。將經染色細胞再懸浮於25 µL流動式細胞測量術染色緩衝液(PBS + 0.2%BSA)中及使用Intellicyt Ique Plus流動式細胞儀分析。
表4
實例編號 | Helios Jurkat IC 50(μM) | Ikaros Jurkat IC 50(μM) |
1 | 1.4 | >10 |
3 | 0.003 | >10 |
7 | 0.001 | >10 |
9 | 0.003 | >10 |
10 | 0.31 | >10 |
11 | 0.006 | >10 |
12 | 0.033 | >10 |
13 | 2.8 | >10 |
14 | 1.0 | >10 |
15 | 0.057 | >10 |
16 | 0.56 | >10 |
17 | 0.007 | >10 |
19 | 0.0035 | >10 |
20 | 490 | >10 |
21 | 0.0058 | >10 |
22 | 0.20 | >10 |
23 | 0.035 | >10 |
24 | 0.16 | >10 |
25 | 1.3 | >10 |
29 | 0.024 | >10 |
30 | 0.70 | >10 |
<![CDATA[<110> 美商必治妥美雅史谷比公司(BR]]>ISTOL-MYERS SQUIBB COMPANY) <![CDATA[<120> 經吡啶基取代之側氧基異吲哚啉化合物]]> <![CDATA[<130> 13954-NP]]> <![CDATA[<150> IN 202111016193]]> <![CDATA[<151> 2022-04-06]]> <![CDATA[<150> IN 202111022098]]> <![CDATA[<151> 2022-05-17]]> <![CDATA[<160> 8 ]]> <![CDATA[<170> PatentIn version 3.5]]> <![CDATA[<210> 1]]> <![CDATA[<211> 526]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 1]]> Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu 1 5 10 15 Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser 20 25 30 Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn 35 40 45 Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro 50 55 60 Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu 65 70 75 80 Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val 85 90 95 Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu 100 105 110 Lys Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met 115 120 125 Val His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln 130 135 140 Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys 145 150 155 160 Leu His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Ser Tyr Ala 165 170 175 Cys Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val 180 185 190 Gly Lys Pro His Lys Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Arg 195 200 205 Ser Ser Leu Glu Glu His Lys Glu Arg Cys His Asn Tyr Leu Gln Asn 210 215 220 Val Ser Met Glu Ala Ala Gly Gln Val Met Ser His His Val Pro Pro 225 230 235 240 Met Glu Asp Cys Lys Glu Gln Glu Pro Ile Met Asp Asn Asn Ile Ser 245 250 255 Leu Val Pro Phe Glu Arg Pro Ala Val Ile Glu Lys Leu Thr Gly Asn 260 265 270 Met Gly Lys Arg Lys Ser Ser Thr Pro Gln Lys Phe Val Gly Glu Lys 275 280 285 Leu Met Arg Phe Ser Tyr Pro Asp Ile His Phe Asp Met Asn Leu Thr 290 295 300 Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser His Met Met Asp Gln Ala 305 310 315 320 Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala Glu Ala Leu His Pro Leu 325 330 335 Met Gln His Pro Pro Ser Thr Ile Ala Glu Val Ala Pro Val Ile Ser 340 345 350 Ser Ala Tyr Ser Gln Val Tyr His Pro Asn Arg Ile Glu Arg Pro Ile 355 360 365 Ser Arg Glu Thr Ala Asp Ser His Glu Asn Asn Met Asp Gly Pro Ile 370 375 380 Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln Glu Arg Glu Ala Ser Pro 385 390 395 400 Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser Glu Ser Ser His Asp Asp 405 410 415 His Gln Ser Tyr Gln Gly His Pro Ala Leu Asn Pro Lys Arg Lys Gln 420 425 430 Ser Pro Ala Tyr Met Lys Glu Asp Val Lys Ala Leu Asp Thr Thr Lys 435 440 445 Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr Lys Val Phe Asn Gly Glu 450 455 460 Gly Glu Gln Ile Arg Ala Phe Lys Cys Glu His Cys Arg Val Leu Phe 465 470 475 480 Leu Asp His Val Met Tyr Thr Ile His Met Gly Cys His Gly Tyr Arg 485 490 495 Asp Pro Leu Glu Cys Asn Ile Cys Gly Tyr Arg Ser Gln Asp Arg Tyr 500 505 510 Glu Phe Ser Ser His Ile Val Arg Gly Glu His Thr Phe His 515 520 525 <![CDATA[<210> 2]]> <![CDATA[<211> 500]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 2]]> Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu 1 5 10 15 Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser 20 25 30 Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn 35 40 45 Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro 50 55 60 Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu 65 70 75 80 Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val 85 90 95 Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg 100 105 110 Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn 115 120 125 Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys 130 135 140 Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His 145 150 155 160 Leu Arg Thr His Ser Val Gly Lys Pro His Lys Cys Asn Tyr Cys Gly 165 170 175 Arg Ser Tyr Lys Gln Arg Ser Ser Leu Glu Glu His Lys Glu Arg Cys 180 185 190 His Asn Tyr Leu Gln Asn Val Ser Met Glu Ala Ala Gly Gln Val Met 195 200 205 Ser His His Val Pro Pro Met Glu Asp Cys Lys Glu Gln Glu Pro Ile 210 215 220 Met Asp Asn Asn Ile Ser Leu Val Pro Phe Glu Arg Pro Ala Val Ile 225 230 235 240 Glu Lys Leu Thr Gly Asn Met Gly Lys Arg Lys Ser Ser Thr Pro Gln 245 250 255 Lys Phe Val Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp Ile His 260 265 270 Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser 275 280 285 His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala 290 295 300 Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile Ala Glu 305 310 315 320 Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His Pro Asn 325 330 335 Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His Glu Asn 340 345 350 Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln 355 360 365 Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser 370 375 380 Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro Ala Leu 385 390 395 400 Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp Val Lys 405 410 415 Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr 420 425 430 Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys Cys Glu 435 440 445 His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile His Met 450 455 460 Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys Gly Tyr 465 470 475 480 Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu 485 490 495 His Thr Phe His 500 <![CDATA[<210> 3]]> <![CDATA[<211> 452]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 3]]> Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu 1 5 10 15 Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser 20 25 30 Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn 35 40 45 Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro 50 55 60 Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu 65 70 75 80 Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val 85 90 95 Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg 100 105 110 Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn 115 120 125 Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys 130 135 140 Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His 145 150 155 160 Leu Arg Thr His Ser Val Gly Lys Pro His Lys Cys Asn Tyr Cys Gly 165 170 175 Arg Ser Tyr Lys Gln Arg Ser Ser Leu Glu Glu His Lys Glu Arg Cys 180 185 190 His Asn Tyr Leu Gln Asn Val Ser Met Glu Ala Ala Gly Gln Val Met 195 200 205 Ser His His Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp Ile His 210 215 220 Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met Gln Ser 225 230 235 240 His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu Gly Ala 245 250 255 Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile Ala Glu 260 265 270 Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His Pro Asn 275 280 285 Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His Glu Asn 290 295 300 Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg Pro Gln 305 310 315 320 Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr Asp Ser 325 330 335 Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro Ala Leu 340 345 350 Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp Val Lys 355 360 365 Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp Ile Tyr 370 375 380 Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys Cys Glu 385 390 395 400 His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile His Met 405 410 415 Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys Gly Tyr 420 425 430 Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu 435 440 445 His Thr Phe His 450 <![CDATA[<210> 4]]> <![CDATA[<211> 239]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 4]]> Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu 1 5 10 15 Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser 20 25 30 Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn 35 40 45 Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro 50 55 60 Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu 65 70 75 80 Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val 85 90 95 Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu 100 105 110 Lys Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met 115 120 125 Val His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln 130 135 140 Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys 145 150 155 160 Leu His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Ser Tyr Ala 165 170 175 Cys Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val 180 185 190 Gly Lys Pro His Lys Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Arg 195 200 205 Ser Ser Leu Glu Glu His Lys Glu Arg Cys His Asn Tyr Leu Gln Asn 210 215 220 Val Ser Met Glu Ala Ala Gly Gln Val Met Ser His His Asp Ser 225 230 235 <![CDATA[<210> 5]]> <![CDATA[<211> 454]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 5]]> Met Glu Thr Glu Ala Ile Asp Gly Tyr Ile Thr Cys Asp Asn Glu Leu 1 5 10 15 Ser Pro Glu Arg Glu His Ser Asn Met Ala Ile Asp Leu Thr Ser Ser 20 25 30 Thr Pro Asn Gly Gln His Ala Ser Pro Ser His Met Thr Ser Thr Asn 35 40 45 Ser Val Lys Leu Glu Met Gln Ser Asp Glu Glu Cys Asp Arg Lys Pro 50 55 60 Leu Ser Arg Glu Asp Glu Ile Arg Gly His Asp Glu Gly Ser Ser Leu 65 70 75 80 Glu Glu Pro Leu Ile Glu Ser Ser Glu Val Ala Asp Asn Arg Lys Val 85 90 95 Gln Glu Leu Gln Gly Glu Gly Gly Ile Arg Leu Pro Asn Gly Glu Arg 100 105 110 Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn 115 120 125 Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys 130 135 140 Pro Phe Cys Ser Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His 145 150 155 160 Leu Arg Thr His Ser Val Pro Pro Met Glu Asp Cys Lys Glu Gln Glu 165 170 175 Pro Ile Met Asp Asn Asn Ile Ser Leu Val Pro Phe Glu Arg Pro Ala 180 185 190 Val Ile Glu Lys Leu Thr Gly Asn Met Gly Lys Arg Lys Ser Ser Thr 195 200 205 Pro Gln Lys Phe Val Gly Glu Lys Leu Met Arg Phe Ser Tyr Pro Asp 210 215 220 Ile His Phe Asp Met Asn Leu Thr Tyr Glu Lys Glu Ala Glu Leu Met 225 230 235 240 Gln Ser His Met Met Asp Gln Ala Ile Asn Asn Ala Ile Thr Tyr Leu 245 250 255 Gly Ala Glu Ala Leu His Pro Leu Met Gln His Pro Pro Ser Thr Ile 260 265 270 Ala Glu Val Ala Pro Val Ile Ser Ser Ala Tyr Ser Gln Val Tyr His 275 280 285 Pro Asn Arg Ile Glu Arg Pro Ile Ser Arg Glu Thr Ala Asp Ser His 290 295 300 Glu Asn Asn Met Asp Gly Pro Ile Ser Leu Ile Arg Pro Lys Ser Arg 305 310 315 320 Pro Gln Glu Arg Glu Ala Ser Pro Ser Asn Ser Cys Leu Asp Ser Thr 325 330 335 Asp Ser Glu Ser Ser His Asp Asp His Gln Ser Tyr Gln Gly His Pro 340 345 350 Ala Leu Asn Pro Lys Arg Lys Gln Ser Pro Ala Tyr Met Lys Glu Asp 355 360 365 Val Lys Ala Leu Asp Thr Thr Lys Ala Pro Lys Gly Ser Leu Lys Asp 370 375 380 Ile Tyr Lys Val Phe Asn Gly Glu Gly Glu Gln Ile Arg Ala Phe Lys 385 390 395 400 Cys Glu His Cys Arg Val Leu Phe Leu Asp His Val Met Tyr Thr Ile 405 410 415 His Met Gly Cys His Gly Tyr Arg Asp Pro Leu Glu Cys Asn Ile Cys 420 425 430 Gly Tyr Arg Ser Gln Asp Arg Tyr Glu Phe Ser Ser His Ile Val Arg 435 440 445 Gly Glu His Thr Phe His 450 <![CDATA[<210> 6]]> <![CDATA[<211> 23]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 6]]> Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu 1 5 10 15 Leu Arg His Ile Lys Leu His 20 <![CDATA[<210> 7]]> <![CDATA[<211> 585]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 7]]> Met His Thr Pro Pro Ala Leu Pro Arg Arg Phe Gln Gly Gly Gly Arg 1 5 10 15 Val Arg Thr Pro Gly Ser His Arg Gln Gly Lys Asp Asn Leu Glu Arg 20 25 30 Asp Pro Ser Gly Gly Cys Val Pro Asp Phe Leu Pro Gln Ala Gln Asp 35 40 45 Ser Asn His Phe Ile Met Glu Ser Leu Phe Cys Glu Ser Ser Gly Asp 50 55 60 Ser Ser Leu Glu Lys Glu Phe Leu Gly Ala Pro Val Gly Pro Ser Val 65 70 75 80 Ser Thr Pro Asn Ser Gln His Ser Ser Pro Ser Arg Ser Leu Ser Ala 85 90 95 Asn Ser Ile Lys Val Glu Met Tyr Ser Asp Glu Glu Ser Ser Arg Leu 100 105 110 Leu Gly Pro Asp Glu Arg Leu Leu Glu Lys Asp Asp Ser Val Ile Val 115 120 125 Glu Asp Ser Leu Ser Glu Pro Leu Gly Tyr Cys Asp Gly Ser Gly Pro 130 135 140 Glu Pro His Ser Pro Gly Gly Ile Arg Leu Pro Asn Gly Lys Leu Lys 145 150 155 160 Cys Asp Val Cys Gly Met Val Cys Ile Gly Pro Asn Val Leu Met Val 165 170 175 His Lys Arg Ser His Thr Gly Glu Arg Pro Phe His Cys Asn Gln Cys 180 185 190 Gly Ala Ser Phe Thr Gln Lys Gly Asn Leu Leu Arg His Ile Lys Leu 195 200 205 His Ser Gly Glu Lys Pro Phe Lys Cys Pro Phe Cys Asn Tyr Ala Cys 210 215 220 Arg Arg Arg Asp Ala Leu Thr Gly His Leu Arg Thr His Ser Val Ser 225 230 235 240 Ser Pro Thr Val Gly Lys Pro Tyr Lys Cys Asn Tyr Cys Gly Arg Ser 245 250 255 Tyr Lys Gln Gln Ser Thr Leu Glu Glu His Lys Glu Arg Cys His Asn 260 265 270 Tyr Leu Gln Ser Leu Ser Thr Glu Ala Gln Ala Leu Ala Gly Gln Pro 275 280 285 Gly Asp Glu Ile Arg Asp Leu Glu Met Val Pro Asp Ser Met Leu His 290 295 300 Ser Ser Ser Glu Arg Pro Thr Phe Ile Asp Arg Leu Ala Asn Ser Leu 305 310 315 320 Thr Lys Arg Lys Arg Ser Thr Pro Gln Lys Phe Val Gly Glu Lys Gln 325 330 335 Met Arg Phe Ser Leu Ser Asp Leu Pro Tyr Asp Val Asn Ser Gly Gly 340 345 350 Tyr Glu Lys Asp Val Glu Leu Val Ala His His Ser Leu Glu Pro Gly 355 360 365 Phe Gly Ser Ser Leu Ala Phe Val Gly Ala Glu His Leu Arg Pro Leu 370 375 380 Arg Leu Pro Pro Thr Asn Cys Ile Ser Glu Leu Thr Pro Val Ile Ser 385 390 395 400 Ser Val Tyr Thr Gln Met Gln Pro Leu Pro Gly Arg Leu Glu Leu Pro 405 410 415 Gly Ser Arg Glu Ala Gly Glu Gly Pro Glu Asp Leu Ala Asp Gly Gly 420 425 430 Pro Leu Leu Tyr Arg Pro Arg Gly Pro Leu Thr Asp Pro Gly Ala Ser 435 440 445 Pro Ser Asn Gly Cys Gln Asp Ser Thr Asp Thr Glu Ser Asn His Glu 450 455 460 Asp Arg Val Ala Gly Val Val Ser Leu Pro Gln Gly Pro Pro Pro Gln 465 470 475 480 Pro Pro Pro Thr Ile Val Val Gly Arg His Ser Pro Ala Tyr Ala Lys 485 490 495 Glu Asp Pro Lys Pro Gln Glu Gly Leu Leu Arg Gly Thr Pro Gly Pro 500 505 510 Ser Lys Glu Val Leu Arg Val Val Gly Glu Ser Gly Glu Pro Val Lys 515 520 525 Ala Phe Lys Cys Glu His Cys Arg Ile Leu Phe Leu Asp His Val Met 530 535 540 Phe Thr Ile His Met Gly Cys His Gly Phe Arg Asp Pro Phe Glu Cys 545 550 555 560 Asn Ile Cys Gly Tyr His Ser Gln Asp Arg Tyr Glu Phe Ser Ser His 565 570 575 Ile Val Arg Gly Glu His Lys Val Gly 580 585 <![CDATA[<210> 8]]> <![CDATA[<211> 544]]> <![CDATA[<212> PRT]]> <![CDATA[<213> 智人]]> <![CDATA[<400> 8]]> Met Asp Ser Arg Tyr Leu Gln Leu Gln Leu Tyr Leu Pro Ser Cys Ser 1 5 10 15 Leu Leu Gln Gly Ser Gly Asp Ser Ser Leu Glu Lys Glu Phe Leu Gly 20 25 30 Ala Pro Val Gly Pro Ser Val Ser Thr Pro Asn Ser Gln His Ser Ser 35 40 45 Pro Ser Arg Ser Leu Ser Ala Asn Ser Ile Lys Val Glu Met Tyr Ser 50 55 60 Asp Glu Glu Ser Ser Arg Leu Leu Gly Pro Asp Glu Arg Leu Leu Glu 65 70 75 80 Lys Asp Asp Ser Val Ile Val Glu Asp Ser Leu Ser Glu Pro Leu Gly 85 90 95 Tyr Cys Asp Gly Ser Gly Pro Glu Pro His Ser Pro Gly Gly Ile Arg 100 105 110 Leu Pro Asn Gly Lys Leu Lys Cys Asp Val Cys Gly Met Val Cys Ile 115 120 125 Gly Pro Asn Val Leu Met Val His Lys Arg Ser His Thr Gly Glu Arg 130 135 140 Pro Phe His Cys Asn Gln Cys Gly Ala Ser Phe Thr Gln Lys Gly Asn 145 150 155 160 Leu Leu Arg His Ile Lys Leu His Ser Gly Glu Lys Pro Phe Lys Cys 165 170 175 Pro Phe Cys Asn Tyr Ala Cys Arg Arg Arg Asp Ala Leu Thr Gly His 180 185 190 Leu Arg Thr His Ser Val Ser Ser Pro Thr Val Gly Lys Pro Tyr Lys 195 200 205 Cys Asn Tyr Cys Gly Arg Ser Tyr Lys Gln Gln Ser Thr Leu Glu Glu 210 215 220 His Lys Glu Arg Cys His Asn Tyr Leu Gln Ser Leu Ser Thr Glu Ala 225 230 235 240 Gln Ala Leu Ala Gly Gln Pro Gly Asp Glu Ile Arg Asp Leu Glu Met 245 250 255 Val Pro Asp Ser Met Leu His Ser Ser Ser Glu Arg Pro Thr Phe Ile 260 265 270 Asp Arg Leu Ala Asn Ser Leu Thr Lys Arg Lys Arg Ser Thr Pro Gln 275 280 285 Lys Phe Val Gly Glu Lys Gln Met Arg Phe Ser Leu Ser Asp Leu Pro 290 295 300 Tyr Asp Val Asn Ser Gly Gly Tyr Glu Lys Asp Val Glu Leu Val Ala 305 310 315 320 His His Ser Leu Glu Pro Gly Phe Gly Ser Ser Leu Ala Phe Val Gly 325 330 335 Ala Glu His Leu Arg Pro Leu Arg Leu Pro Pro Thr Asn Cys Ile Ser 340 345 350 Glu Leu Thr Pro Val Ile Ser Ser Val Tyr Thr Gln Met Gln Pro Leu 355 360 365 Pro Gly Arg Leu Glu Leu Pro Gly Ser Arg Glu Ala Gly Glu Gly Pro 370 375 380 Glu Asp Leu Ala Asp Gly Gly Pro Leu Leu Tyr Arg Pro Arg Gly Pro 385 390 395 400 Leu Thr Asp Pro Gly Ala Ser Pro Ser Asn Gly Cys Gln Asp Ser Thr 405 410 415 Asp Thr Glu Ser Asn His Glu Asp Arg Val Ala Gly Val Val Ser Leu 420 425 430 Pro Gln Gly Pro Pro Pro Gln Pro Pro Pro Thr Ile Val Val Gly Arg 435 440 445 His Ser Pro Ala Tyr Ala Lys Glu Asp Pro Lys Pro Gln Glu Gly Leu 450 455 460 Leu Arg Gly Thr Pro Gly Pro Ser Lys Glu Val Leu Arg Val Val Gly 465 470 475 480 Glu Ser Gly Glu Pro Val Lys Ala Phe Lys Cys Glu His Cys Arg Ile 485 490 495 Leu Phe Leu Asp His Val Met Phe Thr Ile His Met Gly Cys His Gly 500 505 510 Phe Arg Asp Pro Phe Glu Cys Asn Ile Cys Gly Tyr His Ser Gln Asp 515 520 525 Arg Tyr Glu Phe Ser Ser His Ile Val Arg Gly Glu His Lys Val Gly 530 535 540
Claims (20)
- 如請求項1之化合物或其鹽、立體異構體、互變異構體或水合物,其中R 1為-NH 2。
- 如請求項1之化合物或其鹽、立體異構體、互變異構體或水合物,其中R 1為-NH(CH 3)。
- 如請求項1至3中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中各R 2獨立地為F、-CN、-CH 3或-CF 3。
- 如請求項1至4中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中R 6為C 1-2烷基、-CH 2F、-CF 2H、-CF 3或-CH 2CF 3。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中R 6為-CH 3。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中: R 6為C 1-2烷基、-CH 2F、-CF 2H、-CF 3或-CH 2CF 3;且 m為0。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中: R 6為-CH 3;且 m為0。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中各R 4獨立地為F、-CH 3、-CHF 2或-CF 3。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中: 各R 4為F、-CH 3、-CHF 2或-CF 3; R 6為氫;且 m為1或2。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中: 各R 4為F或-CH 3; R 6為氫;且 m為1或2。
- 如請求項1至5中任一項之化合物或其鹽、立體異構體、互變異構體或水合物,其中: R 4為F或-CH 3; R 6為氫;且 m為1。
- 如請求項1之化合物或其鹽、立體異構體、互變異構體或水合物,其中該化合物為: 2-胺基-6-(2-(2,6-二氧哌啶(dioxopiperidin)-3-基)-4-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(1); 2-胺基-6-(2-(2,6-二氧哌啶-3-基)-6-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(2); 2-胺基-6-(2-(2,6-二氧哌啶-3-基)-4-氟-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(3); 3-(5-(6-胺基-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(4); 3-(5-(6-胺基-4-(三氟乙基)吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(5); 3-(4-氟-5-(4-甲基-6-(甲胺基)吡啶-2-基)-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(6); 3-(5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(7); 3-(( S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(8); 3-(( R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(9); 2-胺基-6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(10); 2-胺基-6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(11); 3-((S)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(12); 3-((R)-5-(4,5-二甲基-6-(甲胺基)吡啶-2-基)-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(13); 6-((3S)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈(14); 6-((3R)-2-(2,6-二氧哌啶-3-基)-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基-2-(甲胺基)菸鹼甲腈(15); 3-(( S)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(16); 3-(( R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(17); 3-(5-(6-胺基-3-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(18); 3-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(19); 3-(5-(6-胺基-3-氟-4-甲基吡啶-2-基)-4-氟-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(20); 3-(5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(21-22); 2-胺基-6-((3 R)-2-(2,6-二氧哌啶-3-基)-4-氟-3-甲基-1-側氧基異吲哚啉-5-基)-4-甲基菸鹼甲腈(23); 3-( (R)-5-(6-胺基-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(24); 3-( (R)-5-(6-胺基-4-(三氟甲基)吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(25); 3-( (R)-5-(6-胺基-3-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(26); 3-( (R)-5-(6-胺基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(27); (R)-3-( (R)-5-(6-胺基-4,5-二甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(28); 3-((R)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(29);或 3-(( S)-5-(6-胺基-5-氟-4-甲基吡啶-2-基)-4-氟-3-甲基-1-側氧基異吲哚啉-2-基)哌啶-2,6-二酮(30)。
- 一種醫藥組合物,其包含如請求項1至13中任一項之化合物或其鹽、立體異構體、互變異構體或水合物;及醫藥上可接受之載劑。
- 一種如請求項1至13中任一項之化合物或其鹽、立體異構體、互變異構體或水合物於製造用於治療癌症之藥劑的用途。
- 如請求項15之用途,其中該癌症選自結腸癌、胃癌、胰癌、乳癌、前列腺癌、肺癌、卵巢癌、子宮頸癌、腎癌、頭頸癌、淋巴瘤、白血病及黑色素瘤。
- 一種降低細胞中之Helios蛋白含量、Helios活性程度或Helios表現程度之方法,其包括使該Helios蛋白與如請求項1至13中任一項之化合物或其鹽、立體異構體、互變異構體或水合物接觸。
- 如請求項17之方法,其中Helios蛋白為由SEQ ID NO: 1、2、3、4或5編碼之胺基酸序列。
- 一種降低細胞中之Eos蛋白含量、Eos活性程度或Eos表現程度之方法,其包括使該Eos蛋白與如請求項1至13中任一項之化合物或其鹽、立體異構體、互變異構體或水合物接觸。
- 如請求項19之方法,其中Eos蛋白為由SEQ ID NO: 7或8編碼之胺基酸序列。
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2022
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- 2022-04-05 JP JP2023561684A patent/JP2024515243A/ja active Pending
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- 2022-04-05 IL IL307343A patent/IL307343A/en unknown
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- 2022-04-05 BR BR112023020077A patent/BR112023020077A2/pt unknown
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AR125298A1 (es) | 2023-07-05 |
US20220324840A1 (en) | 2022-10-13 |
CL2023002966A1 (es) | 2024-02-23 |
KR20230165815A (ko) | 2023-12-05 |
BR112023020077A2 (pt) | 2023-11-14 |
JP2024515243A (ja) | 2024-04-08 |
CA3214244A1 (en) | 2022-10-13 |
CO2023013321A2 (es) | 2023-10-19 |
US20230303527A1 (en) | 2023-09-28 |
WO2022216644A1 (en) | 2022-10-13 |
EP4320112A1 (en) | 2024-02-14 |
US11718601B2 (en) | 2023-08-08 |
IL307343A (en) | 2023-11-01 |
MX2023011715A (es) | 2023-10-12 |
PE20231941A1 (es) | 2023-12-05 |
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