TWI657083B - 用於抑制shp2活性之化合物及組合物 - Google Patents
用於抑制shp2活性之化合物及組合物 Download PDFInfo
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- TWI657083B TWI657083B TW104101593A TW104101593A TWI657083B TW I657083 B TWI657083 B TW I657083B TW 104101593 A TW104101593 A TW 104101593A TW 104101593 A TW104101593 A TW 104101593A TW I657083 B TWI657083 B TW I657083B
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- 229940094060 tykerb Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
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- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
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- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229940069559 votrient Drugs 0.000 description 1
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- 235000004416 zinc carbonate Nutrition 0.000 description 1
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- UGZADUVQMDAIAO-UHFFFAOYSA-L zinc hydroxide Chemical compound [OH-].[OH-].[Zn+2] UGZADUVQMDAIAO-UHFFFAOYSA-L 0.000 description 1
- 229940007718 zinc hydroxide Drugs 0.000 description 1
- 229910021511 zinc hydroxide Inorganic materials 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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- 239000002076 α-tocopherol Substances 0.000 description 1
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- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本發明係關於式I化合物,
其中p、q、Y1、Y2、R1、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R7及R8定義於發明內容中;該等式I化合物能夠抑制SHP2之活性。本發明進一步提供一種製備本發明化合物之方法、包含該等化合物之醫藥製劑及在管理與SHP2異常活性相關聯之疾病或病症中使用該等化合物及組合物之方法。
Description
本發明係關於能夠抑制SHP2活性之化合物。本發明進一步提供一種製備本發明化合物之方法、包含該等化合物之醫藥製劑及在管理與SHP2異常活性相關聯之疾病或病症中使用該等化合物及組合物之方法。
Src同源-2磷酸酶(SHP2)為由促成多種細胞功能(包括增殖、分化、細胞循環維持及遷移)之PTPN11基因編碼之非受體蛋白酪胺酸磷酸酶。SHP2涉及經由Ras有絲分裂原活化蛋白激酶、JAK-STAT或磷酸肌醇3-激酶-AKT路徑之信號傳導。
SHP2具有兩個N端Src同源2結構域(N-SH2及C-SH2)、催化結構域(PTP)及C端尾端。兩個SH2結構域控制SHP2之次細胞定位及功能調節。該分子以由包括來自N-SH2及PTP結構域之殘餘物的結合網狀物穩定之非活性、自抑制構形存在。舉例而言,細胞激素或生長因子刺激引起催化位點暴露,導致SHP2之酶活化。
已在數種人類疾病中鑑別出PTPN11基因突變及隨後SHP2突變,該等人類疾病諸如努南症候群(Noonan Syndrome)、豹皮症候群(Leopard Syndrome)、青少年骨髓單核細胞性白血病、神經母細胞瘤、黑素瘤、急性骨髓白血病及乳癌、肺癌及結腸癌。因此,SHP2代表研
發治療各種疾病之新穎療法之具有高度吸引力的目標。本發明化合物滿足抑制SHP2活性之小分子之需要。
在一個態樣中,本發明提供式I化合物:
其中:p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;R1為-XR1a;其中R1a選自C6-10芳基、C3-8環烷基、C3-8環烯基及含有1至4個獨立地選自N、C(O)、O及S之雜原子或基團之5-9員雜芳基;其中R1a之該芳基或雜芳基經1至5個獨立地選自鹵基、胺基、羥基、N3、C1-4烷基、二甲基-胺基、羥基取代之C1-4烷基、鹵基取代之C1-4烷基、胺基取代之C1-4烷基、-C(O)OR10及-NHC(O)R10之R9基團取代;且X選自一鍵、S(O)m、O、C(O)、COR11、CR10aR10b、NR11;其中m選自0、1及2;各R10a及R10b獨立地選自鹵基及C1-4烷基;且R11選自氫及C1-4烷基;R2a及R2b獨立地選自氫、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R3a及R3b獨立地選自鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R4a及R4b獨立地選自氫、鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R5a及R5b獨立地選自氫、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;其中選自R2a、R2b、R3a、R3b、R4a、R4g、R5a、R5b及R7之任何兩個基團可形成5至6員不飽和或部分飽
和環;R6選自氫、鹵基、氰基、C1-4烷基、C1-4烷氧基、胺基-羰基、鹵基取代之C1-4烷基、鹵基取代之C1-4烷氧基、羥基取代之C1-4烷基、胺基取代之C1-4烷基、-S(O)1-2R6a、-C(S)R6a、-C(O)NR6aR6b、-C(NH)NR6aR6b及-NR6aC(O)R6b;其中R6a及R6b獨立地選自氫及C1-4烷基;R7及R8連同其均連接之碳原子一起形成可視情況含有1至3個獨立地選自N、C(O)、O及S(O)m之雜原子或基團之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經1至3個獨立地選自胺基、羥基、甲氧基、鹵基、甲基、甲基-胺基及異丁醯氧基之基團取代。
在第二態樣中,本發明提供一種醫藥組合物,其含有與一或多種適合賦形劑混雜之式I化合物或其N-氧化物衍生物、互變異構體、個別異構體及異構體混合物;或其醫藥學上可接受之鹽。
在第三態樣中,本發明提供一種治療動物疾病之方法,其中調整SHP2活性可防止、抑制或改善疾病之病理學及/或症候學,該方法包含向動物投與治療有效量之式I化合物或其N-氧化物衍生物、個別異構體及異構體混合物或其醫藥學上可接受之鹽。
在第四態樣中,本發明提供一種治療動物疾病之方法,其中調整SHP2活性可防止、抑制或改善疾病之病理學及/或症候學,該方法包含與抗癌治療劑同時或依序組合,向動物投與治療有效量之式I化合物或其N-氧化物衍生物、個別異構體及異構體混合物或其醫藥學上可接受之鹽。
在第五態樣中,本發明提供式I化合物在製造用於治療SHP2活性促成疾病之病理學及/或症候學之動物疾病的藥物中的用途。
在第六態樣中,本發明提供一種製備式I化合物及其N-氧化物衍生物、前藥衍生物、經保護之衍生物、個別異構體及異構體混合物及其醫藥學上可接受之鹽之方法。
除非另外指定,否則上文及下文使用之通用術語在本發明之上下文內較佳具有以下含義,其中任何情況下使用之較通用術語可彼此獨立地經較具體定義置換或保持,從而定義本發明之較詳細實施例:「烷基」係指具有最多20個碳原子之完全飽和分支鏈或未分支烴部分。除非另外提供,否則烷基係指具有1至7個碳原子(C1-7烷基)或1至4個碳原子(C1-4烷基)之烴部分。烷基之代表性實例包括(但不限於)甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、異戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基、正癸基及類似基團。經取代之烷基為含有一或多個,諸如一個、兩個或三個選自鹵素、羥基或烷氧基之取代基之烷基。鹵基取代之烷基及鹵基取代之烷氧基可為直鏈或分支鏈且包括甲氧基、乙氧基、二氟甲基、三氟甲基、五氟乙基、二氟甲氧基、三氟甲氧基及其類似基團。
「芳基」意謂含有六至十個環碳原子之單環或稠合雙環芳環總成。舉例而言,芳基可為苯基或萘基,較佳為苯基。「伸芳基」意謂衍生自芳基之二價基團。
「雜芳基」係定義為其上一或多個環成員為雜原子之芳基。舉例而言,C5-10雜芳基為如由碳原子所指定但此等碳原子可經雜原子置換之最少5個成員。因此,C5-10雜芳基包括吡啶基、吲哚基、吲唑基、喹喏啉基、喹啉基、苯并呋喃基、苯并哌喃基、苯并硫哌喃基、苯并[1,3]間二氧雜環戊烯、咪唑基、苯并咪唑基、嘧啶基、呋喃基、噁唑基、異噁唑基、三唑基、四唑基、吡唑基、噻吩基等。
「環烷基」意謂含有指定環原子數目之飽和或部分不飽和、單環、稠合雙環或橋接多環環總成。舉例而言,C3-10環烷基包括環丙基、環丁基、環戊基、環己基、環己烯基等。
「雜環烷基」意謂如本申請案所定義之環烷基,其限制條件為所指定之一或多個環碳經選自-O-、-N=、-NR-、-C(O)-、-S-、-S(O)-或-S(O)2-(其中R為氫、C1-4烷基或氮保護基)之部分置換。舉例而言,如在本申請案中用於描述本發明化合物之C3-8雜環烷基包括N-嗎啉基、吡咯啶基、吡咯啶基-2-酮、哌嗪基、哌啶基、哌啶基酮、1,4-二氧雜-8-氮雜-螺[4.5]癸-8-基、硫N-嗎啉基、硫基N-嗎啉基、磺醯基N-嗎啉基等。
「鹵素」(或鹵基)較佳表示氯或氟,但亦可為溴或碘。
「SHP2」意謂「Src同源-2磷酸酶」且亦稱為SH-PTP2、SH-PTP3、Syp、PTP1D、PTP2C、SAP-2或PTPN11。
有「PTPN11突變」之癌症包括(但不限於):N58Y;D61Y、V;E69K;A72V、T、D;E76G、Q、K(ALL);G60A;D61Y;E69V;F71K;A72V;T73I;E76G、K;R289G;G503V(AML);G60R、D61Y、V、N;Y62D;E69K;A72T、V;T73I;E76K、V、G、A、Q;E139D;G503A、R;Q506P(JMML);G60V;D61V;E69K;F71L;A72V;E76A(MDS);Y63C(CMML);Y62C;E69K;T507K(神經母細胞瘤);V46L;N58S;E76V(肺癌);R138Q(黑素瘤);E76G(結腸癌)。
式I化合物可具有不同異構形式。舉例而言,任何不對稱碳原子可以(R)、(S)或(R,S)組態存在,較佳以(R)或(S)組態存在。在雙鍵或尤其環處之取代基可以順式(=Z)或反式(=E)形式存在。因此,該等化合物可以異構體混合物形式或較佳以純異構體形式,較佳以純非對映異構體或純對映異構體形式存在。
在使用複數形式(例如多種化合物、多種鹽)之情況下,此包括單數(例如單一化合物、單一鹽)。「一化合物」不排除(例如在醫藥調配物中)存在多於一種式I化合物(或其鹽),「一」僅表示不定冠詞。因此「一(a)」可較佳理解為「一或多個/種」,次佳地可替代性地理解為「一個/
種」。
在提及式I化合物之任何情況下,此進一步亦意欲包括該等化合物之N-氧化物及/或其互變異構體。
術語「及/或其N-氧化物、其互變異構體及/或其(較佳醫藥學上可接受之)鹽」尤其意謂式I化合物可按原樣或以與其N-氧化物之混合物形式,以互變異構體(例如由於酮-烯醇、內醯胺-內醯亞胺、醯胺-亞胺酸或烯胺-亞胺互變異構)形式或以與其互變異構體之(例如等效性反應引起)混合物形式,或以式I化合物之鹽及/或此等形式中之任一者或該等形式中之兩者或兩者以上之混合物形式存在。
本發明亦包括本發明化合物或其醫藥學上可接受之鹽之所有適合同位素變體。本發明化合物或其醫藥學上可接受之鹽之同位素變體定義為至少一個原子經具有相同原子數但原子質量與自然界中通常發現之原子質量不同之原子置換者。可併入本發明化合物及其醫藥學上可接受之鹽中之同位素之實例包括(但不限於)氫、碳、氮及氧之同位素,諸如2H、3H、11C、13C、14C、15N、17O、18O、35S、18F、36Cl及123I。本發明化合物及其醫藥學上可接受之鹽之某些同位素變體(例如,併入有諸如3H或14C之放射性同位素之彼等者)適用於藥物及/或基質組織分佈研究。在特定實例中,3H及14C同位素可因其易於製備及可偵測性而得以使用。在其他實例中,用諸如2H之同位素取代可獲得由較大代謝穩定性產生之某些治療優勢,諸如活體內半衰期增加或劑量需求減少。本發明化合物或其醫藥學上可接受之鹽之同位素變體一般可藉由習知程序使用適合試劑之適當同位素變體製備。舉例而言,本發明化合物可以如下所示之氘化形式存在:
本發明係關於能夠抑制SHP2活性之化合物。在本發明之一個態樣中,關於式I化合物,-XR1a為-SR1a且選自:
在本發明之另一態樣中,-XR1a為-SR1a且選自:
在本發明之另一態樣中,關於式I化合物:
係選自:
在另一態樣中,關於式I化合物,為式Ia化合物:
其中:n選自1、2、3及4;p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;Y4獨立地選自N、C(O)及CR9;其中僅一個Y4為C(O);R6選自氫、鹵基、甲基及胺基-羰基;R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經選自胺基、胺基-甲基及甲基-胺基之基團取代;R9選自鹵基、胺基、二甲基-胺基、羥基、N3、C1-4烷基、鹵基取代之C1-4烷基、C1-4烷氧基、-C(O)OR10及-NHC(O)R10;R10選自氫、苯基及萘基;其中R10之該苯基未經取代或經甲氧基取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中,R7及R8連同其均連接之碳原子一起形成可視情況含有1至2個獨立地選自N、O、C(O)及S(O)m之雜原子或基團之5員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經1至3個獨立地選自胺基、羥基、甲氧基、鹵基、甲基、甲基-胺基及異丁醯氧基之基團取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接受之鹽:
在本發明之另一態樣中為如下化合物:其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之6員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經選自胺基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接受之鹽:
在本發明之另一態樣中為如下化合物:其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之4員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經選自胺基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接
受之鹽:
在本發明之另一態樣中為p及q均為0之化合物;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接受之鹽:
在本發明之另一態樣中為式II化合物:
其中:p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;R1選自C6-10芳基、C3-8環烷基、C3-8環烯基及含有1至4個選自N、O及S之雜原子之5-9員雜芳基;其中R1a之該芳基或雜芳基經1至5個獨立地選自鹵基、胺基、羥基、N3、C1-4烷基、羥基取代之C1-4烷基、鹵基取代之C1-4烷基、胺基取代之C1-4烷基、-C(O)OR10及-NHC(O)R10之R9基團取代;其中m選自0、1及2;各R10a及R10b獨立地選自鹵基及C1-4烷基;且R11選自氫及C1-4烷基;R2a及R2b獨立地選自氫、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R3a及R3b獨立地選自鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R4a及R4b獨立地選自氫、鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R5a及R5b獨立地選自氫、羰
基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;其中選自R2a、R3a、R4、R5、R6a及R7a之任何兩個基團可形成5至6員不飽和或部分不飽和環;R6選自氫、鹵基、氰基、C1-4烷基、C1-4烷氧基、胺基-羰基、鹵基取代之C1-4烷基、鹵基取代之C1-4烷氧基、羥基取代之C1-4烷基及胺基取代之C1-4烷基;R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經選自胺基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為式IIa化合物:
其中:n選自1、2、3及4;p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;Y4選自N及CR9;R6選自氫、鹵基、甲基及胺基-羰基;R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經選自胺基、胺基-甲基及甲基-胺基之基團取代;R9選自鹵基、胺基、羥基、N3、C1-4烷基、鹵基取代之C1-4烷基、C1-4烷氧基、-C(O)OR10及-NHC(O)R10;R10選自氫、苯基及萘基;其中R10之該苯基未經取代或經甲氧基取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為如下化合物:其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之5員飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經選自胺基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接受之鹽:
在本發明之另一態樣中為如下化合物:其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之6員飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經選自胺基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接受文鹽:
在本發明之另一態樣中為如下化合物:其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之4員飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經胺基取代;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接
受之鹽:
在本發明之另一態樣中為p及q均為0之化合物;或其醫藥學上可接受之鹽。
在本發明之另一態樣中為選自以下之化合物或其醫藥學上可接受之鹽:
Src同源-2磷酸酶(SHP2)為由促成多種細胞功能(包括增殖、分
化、細胞循環維持及遷移)之PTPN11基因編碼之蛋白酪胺酸磷酸酶。SHP2涉及經由Ras有絲分裂原活化蛋白激酶、JAK-STAT或磷酸肌醇3-激酶-AKT路徑之信號傳導。SHP2藉由受體酪胺酸激酶(諸如ErbB1、ErbB2及c-Met)介導Erk1及Erk2(Erk1/2,Erk)MAP激酶之活化。
SHP2具有兩個N端Src同源2結構域(N-SH2及C-SH2)、催化結構域(PTP)及C端尾端。兩個SH2結構域控制SHP2之次細胞定位及功能調節。該分子以經由包括來自N-SH2及PTP結構域之殘餘物之結合網狀物抑制其自身活性之非活性構形存在。回應於生長因子刺激,SHP2經由其SH2結構域結合至停靠蛋白(諸如Gab1及Gab2)上之特異性酪胺酸磷酸化位點。此誘導引起SHP2活化之構形變化。
已在數種人類疾病中鑑別出PTPN11突變,該等人類疾病諸如努南症候群、豹皮症候群、青少年骨髓單核細胞性白血病、神經母細胞瘤、黑素瘤、急性骨髓白血病及乳癌、肺癌及結腸癌。SHP2為多種受體酪胺酸激酶、包括血小板衍生生長因子受體(PDGF-R)、纖維母細胞生長因子受體(FGF-R)及表皮生長因子受體(EGF-R)之重要下游信號傳導分子。SHP2亦為可導致細胞轉型(罹患癌症之先決條件)之有絲分裂原活化蛋白(MAP)激酶路徑之活化的重要下游信號傳導分子。阻斷SHP2基因表現顯著抑制具有SHP2突變或EML4/ALK易位之肺癌細胞株之細胞生長以及EGFR擴增乳癌及食道癌。SHP2亦在胃癌、退行性大細胞淋巴瘤及神經膠母細胞瘤中之致癌基因下游活化。
努南症候群(NS)及豹皮症候群(LS)-PTPN11突變導致LS(多發性雀斑、心電圖傳導異常、兩眼距離過遠、肺狹窄、生殖器異常、生長遲緩、感覺神經性耳聾)及NS(先天性異常,包括心臟缺陷、顱面異常及身材矮小)。兩種病症均為由正常細胞生長及分化所需之RAS/RAF/MEK/ERK有絲分裂原活化蛋白激酶路徑之組分之生殖系突變所引起的常染色體顯性症候群家族之部分。此路徑之異常調節尤其
對心臟發育具有深遠影響,導致各種異常,包括瓣膜中隔缺損及/或肥厚性心肌病(HCM)。已確定MAPK信號傳導路徑之擾亂對此等病症至關重要且已在人類中鑑別出沿此路徑之數種候選基因,包括KRAS、NRAS、SOS1、RAF1、BRAF、MEK1、MEK2、SHOC2及CBL之突變。在NS及LS中最常突變之基因為PTPN11。PTPN11(SHP2)之生殖系突變發現於約50%患有NS之病例及幾乎所有患有與NS共有某些特徵之LS之患者中。對於NS、Y62D及Y63C,蛋白質取代很大程度上恆定且為最常見突變之一。此等突變均在不擾亂磷酸酶與其磷酸化信號傳導搭配物之結合之情況下影響SHP2之催化非活性構形。
青少年骨髓單核細胞性白血病(JMML)-PTPN11(SHP2)之體細胞突變出現於約35%患有JMML,一種兒童骨髓增生病症(MPD)之患者中。此等功能獲得型突變通常為N-SH2結構域或磷酸酶結構域之點突變,其防止催化結構域與N-SH2結構域之間的自抑制,產生SHP2活性。
急性骨髓白血病-已於以下各者中鑑別到PTPN11突變:約10%兒科急性白血病,諸如骨髓發育不良症候群(MDS);約7% B細胞急性淋巴母細胞白血病(B-ALL);及約4%急性骨髓白血病(AML)。
NS及白血病突變導致位於由呈自抑制SHP2構形之N-SH2及PTP結構域形成之界面處的胺基酸變化,妨礙抑制性分子內相互作用,導致催化結構域之機能亢進。
SHP2充當受體酪胺酸激酶(RTK)信號傳導中之正調控劑。含有RTK改變(EGFR擴增、Her2擴增、FGFR擴增、Met擴增、易位/活化RTK,亦即ALK、BCR/ABL)之癌症包括食道癌、乳癌、肺癌、結腸癌、胃癌、神經膠質瘤癌、頭頸癌。
食道癌(esophageal cancer/oesophageal cancer)為食道惡性疾病。存在多種亞型,主要為鱗狀細胞癌(<50%)及腺癌。在食道腺癌及鱗狀細胞癌中存在高比率之RTK表現。本發明之SHP2抑制劑可因此用於創新
治療策略。
乳癌為癌症之主要類型且為女性死亡之主要病因,其中患者產生對當前藥物之抗性。存在乳癌之四種主要亞型,包括管狀A型、管狀B型、Her2樣及三陰性/基底樣。三陰性乳癌(TNBC)為缺乏特定靶向療法之侵襲性乳癌。表皮生長因子受體I(EGFR)作為TNBC之有前景之目標出現。經由SHP2抑制Her2以及EGFR可為乳癌之有前景之療法。
肺癌-NSCLC目前為癌症相關死亡之主要病因,其佔肺癌(主要為腺癌及鱗狀細胞癌)之約85%。儘管細胞毒性化學療法仍為治療之重要部分,但基於腫瘤之基因改變(諸如EGFR及ALK)之靶向療法較可能受益於靶向療法。
結腸癌-已知大約30%至50%結腸直腸腫瘤具有突變(異常)KRAS,且BRAF突變出現於10%至15%結腸直腸癌中。就表明結腸直腸腫瘤過度表現EGFR之患者之子集而言,此等患者展現出對抗EGFR療法之有利臨床反應。
胃癌為最流行之癌症類型之一。酪胺酸激酶之異常表現,如由胃癌細胞中之異常酪胺酸磷酸化所反映,在此項技術中已知。三種受體酪胺酸激酶c-met(HGF受體)、FGF受體2及erbB2/neu在胃癌中頻繁擴增。因此,不同信號路徑之破壞可促成不同類型胃癌之進展。
神經母細胞瘤為發育交感神經系統之兒科腫瘤,其佔兒童癌症之約8%。已假設退行性淋巴瘤激酶(ALK)基因之基因組改變促成神經母細胞瘤發病機制。
頭頸部鱗狀細胞癌(SCCHN). 高水準之EGFR表現與不良預後及對多種癌症,主要為頭頸部鱗狀細胞癌(SCCHN)之輻射療法之抗性相關。阻斷EGFR信號傳導引起受體刺激抑制、細胞增殖及減少之侵襲性及癌轉移。因此,EGFR為SCCHN之新穎抗癌療法之主要目標。
本發明係關於能夠抑制SHP2活性之化合物。本發明進一步提供一
種製備本發明化合物及包含該等化合物之醫藥製劑之方法。本發明之另一態樣係關於一種治療SHP2介導之病症之方法,其包含向有需要之患者投與治療有效量之如發明內容中所定義之式I化合物之步驟。
在某些實施例中,本發明係關於前述方法,其中該等SHP2介導之病症為選自(但不限於)以下之癌症:JMML、AML、MDS、B-ALL、神經母細胞瘤、食道癌、乳癌、肺癌、結腸癌、胃癌、頭頸癌。
本發明化合物亦可適用於治療與SHP2之異常活性相關之其他疾病或病狀。因此,作為另一態樣,本發明係關於一種治療選自以下之病症之方法:NS、LS、JMML、AML、MDS、B-ALL、神經母細胞瘤、食道癌、乳癌、肺癌、結腸癌、胃癌、頭頸癌。
本發明之SHP2抑制劑可有效地與另一藥理學上活性化合物組合,或與兩種或兩種以上其他藥理學上活性化合物組合,尤其在癌症治療中。舉例而言,如上所定義之式(I)化合物或其醫藥學上可接受之鹽可與一或多種選自以下之藥劑組合同時、依序或單獨投與:化學治療劑,例如有絲分裂抑制劑,諸如紫杉烷(taxane)、長春花屬生物鹼(vinca alkaloid)、太平洋紫杉醇(paclitaxel)、多烯紫杉醇(docetaxel)、長春新鹼(vincristine)、長春鹼(vinblastine)、長春瑞濱(vinorelbine)或長春氟寧(vinflunine);及其他抗癌劑,例如順鉑(cisplatin)、5-氟尿嘧啶或5-氟-2-4(1H,3H)-嘧啶二酮(5FU)、氟他胺(flutamide)或吉西他濱(gemcitabine)。
該等組合可在療法中提供顯著優勢,包括協同活性。
在某些實施例中,本發明係關於前述方法,其中該化合物非經腸投與。
在某些實施例中,本發明係關於前述方法,其中該化合物肌肉內、靜脈內、皮下、經口、經肺、鞘內、局部或鼻內投與。
在某些實施例中,本發明係關於前述方法,其中該化合物全身性
投與。
在某些實施例中,本發明係關於前述方法,其中該患者為哺乳動物。
在某些實施例中,本發明係關於前述方法,其中該患者為靈長類動物。
在某些實施例中,本發明係關於前述方法,其中該患者為人類。
在另一態樣中,本發明係關於一種治療SHP2介導之病症之方法,其包含如下步驟:向有需要之患者投與治療有效量之化學治療劑以及治療有效量之如發明內容中所定義之式I化合物。
在另一態樣中,本發明提供醫藥學上可接受之組合物,其包含治療有效量之與一或多種醫藥學上可接受之載劑(添加劑)及/或稀釋劑一起調配之一或多種上述化合物。如以下詳細描述,本發明之醫藥組合物可經特別調配以用於以固體或液體形式投與,包括適用於以下之彼等者:(1)經口投與,例如施用於舌頭之灌藥(水性或非水性溶液或懸浮液)、錠劑(例如,靶向經頰、舌下及全身性吸收之錠劑)、大丸劑、散劑、顆粒、糊劑;(2)非經腸投與,例如藉由皮下、肌肉內、靜脈內或硬膜外注射,如例如無菌溶液或懸浮液,或持續釋放調配物;(3)局部施用,例如以施用至皮膚之乳膏、軟膏或控制釋放貼片或噴霧形式;(4)陰道內或直腸內,例如以子宮托、乳膏或泡沫形式;(5)舌下;(6)經眼;(7)經皮;(8)經鼻;(9)經肺;或(10)鞘內。
如本文所用之片語「治療有效量」意謂可有效以適用於任何醫學治療之合理的效益/風險比在動物之至少一個細胞亞群中產生一些所需治療作用之包含本發明化合物之化合物、物質或組合物之量。
片語「醫藥學上可接受」在本文中用於指在合理醫學判斷範疇內,適用於與人類及動物之組織接觸而無過度毒性、刺激、過敏反應
或其他問題或併發症,與合理的效益/風險比相匹配之彼等化合物、物質、組合物及/或劑型。
如本文所用之片語「醫藥學上可接受之載劑」意謂涉及將本發明化合物自身體之一個器官或部分載運或傳輸至身體之另一器官或部分的醫藥學上可接受之物質、組合物或媒劑,諸如液體或固體填充劑、稀釋劑、賦形劑、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),或溶劑囊封物質。各載劑在與調配物之其他成分相容且對患者無害之意義上必須為「可接受的」。可充當醫藥學上可接受之載劑之物質之一些實例包括:(1)糖,諸如乳糖、葡萄糖及蔗糖;(2)澱粉,諸如玉米澱粉及馬鈴薯澱粉;(3)纖維素及其衍生物,諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素;(4)粉末狀黃蓍;(5)麥芽;(6)明膠;(7)滑石;(8)賦形劑,諸如可可脂及栓劑蠟;(9)油,諸如花生油、棉籽油、紅花油、芝麻油、橄欖油、玉米油及大豆油;(10)二醇,諸如丙二醇;(11)多元醇,諸如丙三醇、山梨糖醇、甘露糖醇及聚乙二醇;(12)酯,諸如油酸乙酯及月桂酸乙酯;(13)瓊脂;(14)緩衝劑,諸如氫氧化鎂及氫氧化鋁;(15)海藻酸;(16)無熱原質水;(17)等張鹽水;(18)林格氏溶液(Ringer's solution);(19)乙醇;(20)pH緩衝溶液;(21)聚酯、聚碳酸酯及/或聚酸酐;及(22)醫藥調配物中使用之其他無毒相容物質。
如上文所述,本發明化合物之某些實施例可含有鹼性官能基,諸如胺基或烷基胺基,且因此能夠與醫藥學上可接受之酸形成醫藥學上可接受之鹽。就此而言,術語「醫藥學上可接受之鹽」係指本發明化合物之相對無毒的無機及有機酸加成鹽。此等鹽可在投與媒劑或劑型製造過程中就地製備,或藉由使呈其游離鹼形式之經純化之本發明化合物與適合有機酸或無機酸單獨反應,且在隨後純化期間分離由此形成之鹽來製備。代表性鹽包括氫溴酸鹽、鹽酸鹽、硫酸鹽、硫酸氫鹽、
磷酸鹽、硝酸鹽、乙酸鹽、戊酸鹽、油酸鹽、棕櫚酸鹽、硬脂酸鹽、月桂酸鹽、苯甲酸鹽、乳酸鹽、磷酸鹽、甲苯磺酸鹽、檸檬酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、丁二酸鹽、酒石酸鹽、萘酸鹽(napthylate)、甲磺酸鹽、葡庚糖酸鹽、乳糖酸鹽及月桂基磺酸鹽及其類似物。(參見例如Berge等人(1977)「Pharmaceutical Salts」,J.Pharm.Sci.66:1-19)。
本發明化合物之醫藥學上可接受之鹽包括例如來自無毒有機或無機酸之化合物之習知無毒鹽或四級銨鹽。舉例而言,此類習知無毒鹽包括衍生自無機酸之鹽,該等無機酸諸如鹽酸、氫溴酸、硫酸、胺磺酸、磷酸、硝酸及其類似物;及自有機酸製備之鹽,該等有機酸諸如乙酸、丙酸、丁二酸、乙醇酸、硬脂酸、乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、棕櫚酸、順丁烯二酸、羥基順丁烯二酸、苯乙酸、麩胺酸、苯甲酸、水楊酸、對胺基苯磺酸、2-乙醯氧基苯甲酸、反丁烯二酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、異硫磺酸及其類似物。
在其他情況下,本發明化合物可含有一或多個酸性官能基且因此能夠與醫藥學上可接受之鹼形成醫藥學上可接受之鹽。在此等情況下,術語「醫藥學上可接受之鹽」係指本發明化合物之相對無毒的無機及有機鹼加成鹽。此等鹽可同樣在投與媒劑或劑型製造過程中就地製備,或藉由使呈其游離酸形式之純化化合物與適合鹼(諸如醫藥學上可接受之金屬陽離子的氫氧化物、碳酸鹽或碳酸氫鹽)、與氨或與醫藥學上可接受之有機一級、二級或三級胺單獨反應來製備。代表性鹼金屬鹽或鹼土金屬鹽包括鋰鹽、鈉鹽、鉀鹽、鈣鹽、鎂鹽及鋁鹽及其類似鹽。適用於形成鹼加成鹽之代表性有機胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪及其類似物。(參見例如Berge等人,前述文獻)
濕潤劑、乳化劑及潤滑劑(諸如月桂基硫酸鈉及硬脂酸鎂)以及著色劑、脫模劑、塗佈劑、甜味劑、調味劑及芳香劑、防腐劑及抗氧化
劑亦可存在於組合物中。
醫藥學上可接受之抗氧化劑之實例包括:(1)水溶性抗氧化劑,諸如抗壞血酸、半胱胺酸鹽酸鹽、硫酸氫鈉、偏亞硫酸氫鈉、亞硫酸鈉及其類似物;(2)油溶性抗氧化劑,諸如棕櫚酸抗壞血酸酯、丁基化羥基甲氧苯(BHA)、丁基化羥基甲苯(BHT)、卵磷脂、沒食子酸丙酯、α-生育酚及其類似物;及(3)金屬螯合劑,諸如檸檬酸、乙二胺四乙酸(EDTA)、山梨糖醇、酒石酸、磷酸及其類似物。
本發明調配物包括適用於經口、經鼻、局部(包括經頰及舌下)、直腸、陰道及/或非經腸投與之調配物。調配物宜以單位劑型呈現且可藉由藥劑學技術中熟知之任何方法來製備。可與載劑物質組合以產生單一劑型之活性成分之量將視所治療之主體、特定投與模式而定。可與載劑物質組合以產生單一劑型之活性成分之量一般將為產生治療作用之化合物之量。一般而言,在100%中,此量將在約0.1%至約99%、較佳約5%至約70%、最佳約10%至約30%之活性成分範圍內。
在某些實施例中,本發明調配物包含選自由以下組成之群之賦形劑:環糊精、纖維素、脂質體、微胞形成劑(例如膽汁酸)及聚合載劑(例如聚酯及聚酸酐);及本發明化合物。在某些實施例中,前述調配物使得本發明化合物具有口服生物可用性。
製備此等調配物或組合物之方法包括將本發明化合物與載劑及視情況存在之一或多種附屬成分結合之步驟。一般而言,藉由將本發明化合物與液體載劑或細粉狀固體載劑或兩者均勻且緊密結合且隨後必要時使產物成形來製備調配物。
適用於經口投與之本發明調配物可呈膠囊、扁囊劑、丸劑、錠劑、口含錠(使用調味基質,通常為蔗糖及阿拉伯膠或黃蓍)、散劑、顆粒形式,或呈水性或非水性液體中之溶液或懸浮液形式,或呈水包油或油包水液體乳液形式,或呈酏劑或糖漿形式,或呈片劑(使用惰性基
質,諸如明膠及丙三醇,或蔗糖及阿拉伯膠)及/或漱口劑形式及其類似形式,各含有預定量之本發明化合物作為活性成分。本發明化合物亦可以大丸劑、舐劑或糊劑形式投與。
在經口投與之本發明固體劑型(膠囊、錠劑、丸劑、糖衣藥丸、散劑、顆粒、口含錠及其類似物)中,活性成分與一或多種醫藥學上可接受之載劑(諸如檸檬酸鈉或磷酸二鈣)及/或以下任一者混合:(1)填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇及/或矽酸;(2)黏合劑,諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及/或阿拉伯膠;(3)保濕劑,諸如甘油;(4)崩解劑,諸如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽及碳酸鈉;(5)溶液阻滯劑,諸如石蠟;(6)吸收促進劑,諸如四級銨化合物,及界面活性劑,諸如泊洛沙姆(poloxamer)及月桂基硫酸鈉;(7)濕潤劑,諸如鯨蠟醇、單硬脂酸甘油酯及非離子界面活性劑;(8)吸收劑,諸如高嶺土及膨潤土;(9)潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉、硬脂酸鋅、硬脂酸鈉、硬脂酸及其混合物;(10)著色劑;及(11)控制釋放劑,諸如交聯普維酮(crospovidone)或乙基纖維素。在膠囊、錠劑及丸劑之情況下,醫藥組合物亦可包含緩衝劑。亦可使用諸如乳糖(lactose/milk sugar)以及高分子量聚乙二醇及其類似物之賦形劑將相似類型之固體組合物作為填充劑用於軟殼及硬殼明膠膠囊中。
可藉由視情況與一或多種附屬成分一起壓縮或模製來製造錠劑。可使用黏合劑(例如明膠或羥丙基甲基纖維素)、潤滑劑、惰性稀釋劑、防腐劑、崩解劑(例如羥基乙酸澱粉鈉或交聯羧甲基纖維素鈉)、表面活性劑或分散劑來製備壓縮錠劑。可藉由在適合機器中模製用惰性液體稀釋劑濕潤之粉末狀化合物之混合物來製造模製錠劑。
本發明醫藥組合物之錠劑及其他固體劑型(諸如糖衣藥丸、膠囊、
丸劑及顆粒)可視情況用包衣及外殼,諸如腸溶衣及醫藥調配技術中熟知之其他包衣得到或製備。其亦可使用例如不同比例之羥丙基甲基纖維素以提供所需釋放曲線、其他聚合物基質、脂質體及/或微球體來調配以便提供其中之活性成分之緩慢或控制釋放。其可經調配用於快速釋放,例如冷凍乾燥。其可藉由例如經由細菌截留過濾器過濾或藉由併入呈臨用前可溶解於無菌水或一些其他無菌可注射介質中之無菌固體組合物形式的滅菌劑來滅菌。此等組合物亦可視情況含有乳濁劑且可具有視情況以延遲方式僅僅或優先在胃腸道之某一部分中釋放活性成分之組成。可使用之包埋組合物之實例包括聚合物質及蠟。活性成分亦可適當時與一或多種上述賦形劑一起呈微囊封形式。
用於經口投與本發明化合物之液體劑型包括醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性成分以外,液體劑型可含有常用於此項技術中之惰性稀釋劑(諸如水或其他溶劑)、增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、油(尤其為棉籽油、花生油、玉米油、胚芽油、橄欖油、菌麻油及芝麻油)、甘油、四氫呋喃醇、聚乙二醇及脫水山梨糖醇之脂肪酸酯及其混合物。
除惰性稀釋劑之外,口服組合物亦可包括佐劑,諸如濕潤劑、乳化劑及懸浮劑、甜味劑、調味劑、著色劑、芳香劑及防腐劑。
除活性化合物以外,懸浮液亦可含有懸浮劑,例如乙氧基化異硬脂醇、聚氧乙烯山梨糖醇及脫水山梨糖醇酯、微晶纖維素、偏氫氧化鋁、膨潤土、瓊脂及黃蓍及其混合物。
用於直腸或陰道投與之本發明醫藥組合物之調配物可以栓劑形式呈現,其可藉由將一或多種本發明化合物與一或多種適合無刺激性賦形劑或載劑(包含例如可可脂、聚乙二醇、栓劑蠟或水楊酸酯)混合來製備,且其在室溫下為固體,但在體溫下為液體,且因此熔融於直
腸或陰道腔中且釋放活性化合物。
適用於陰道投與之本發明調配物亦包括含有諸如此項技術中已知適當之載劑之子宮托、棉塞、乳膏、凝膠、糊劑、泡沫或噴霧調配物。
用於局部或經皮投與本發明化合物之劑型包括散劑、噴霧、軟膏、糊劑、乳膏、洗劑、凝膠、溶液、貼片及吸入劑。活性化合物可在無菌條件下與醫藥學上可接受之載劑及與任何可能需要之防腐劑、緩衝液或推進劑混合。
除本發明之活性化合物以外,軟膏、糊劑、乳膏及凝膠可含有賦形劑,諸如動物及植物脂肪、油、蠟、石蠟、澱粉、黃蓍、纖維素衍生物、聚乙二醇、聚矽氧、膨潤土、矽酸、滑石及氧化鋅,或其混合物。
除本發明化合物以外,散劑及噴霧可含有賦形劑,諸如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣及聚醯胺粉末,或此等物質之混合物。噴霧可另外含有習用推進劑,諸如氯氟烴及揮發性未經取代之烴,諸如丁烷及丙烷。
經皮貼片具有提供本發明化合物向身體之控制傳遞之額外優勢。可藉由將化合物溶解或分散於適當介質中來製造該等劑型。亦可使用吸收增強劑來增加化合物通過皮膚之通量。該通量之速率可藉由提供速率控制膜或使化合物分散於聚合物基質或凝膠中來控制。
本發明之範疇內亦涵蓋眼用調配物、眼膏、散劑、溶液及其類似物。
適用於非經腸投與之本發明之醫藥組合物包含一或多種本發明化合物以及一或多種醫藥學上可接受之無菌等張水性或非水性溶液、分散液、懸浮液或乳液,或可僅在使用之前復原成無菌可注射溶液或分散液之無菌散劑,其可含有糖、醇、抗氧化劑、緩衝液、抑菌劑、
使得調配物與預期接受者之血液等張之溶質或懸浮劑或增稠劑。
可用於本發明之醫藥組合物之適合水性及非水性載劑之實例包括水、乙醇、多元醇(諸如甘油、丙二醇、聚乙二醇及其類似物)及其適合混合物、植物油(諸如橄欖油)及可注射有機酯(諸如油酸乙酯)。可例如藉由使用包衣物質(諸如卵磷脂)、在分散液之情況下藉由維持所需粒度及藉由使用界面活性劑來維持適當流動性。
此等組合物亦可含有佐劑,諸如防腐劑、濕潤劑、乳化劑及分散劑。防止微生物作用於本發明化合物可藉由包括各種抗細菌劑及抗真菌劑(例如對羥基苯甲酸酯、氯丁醇、苯酚、山梨酸及其類似物)來確保。亦可能需要在組合物中包括等張劑,諸如糖、氯化鈉及其類似物。另外,可注射醫藥形式之延長吸收可藉由包括延遲吸收劑(諸如單硬脂酸鋁及明膠)來達成。
在一些情況下,為延長藥物作用,需要減緩皮下或肌肉內注射之藥物之吸收。此可藉由使用具有不良水溶性之結晶或非晶形物質之液體懸浮液來實現。藥物吸收速率則視其溶解速率而定,而溶解速率又可視晶體尺寸及結晶形態而定。或者,非經腸投與之藥物形式之延遲吸收藉由將藥物溶解或懸浮於油性媒劑中來實現。
可注射積存形式藉由在諸如聚丙交酯-聚乙交酯之可生物降解聚合物中形成本發明化合物之微膠囊基質而製造。視藥物與聚合物之比及所用特定聚合物之性質而定,可控制藥物釋放之速率。其他可生物降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。積存可注射調配物亦藉由將藥物截留於與身體組織相容之脂質體或微乳液中來製備。
當本發明化合物以藥物形式向人類及動物投與時,其可本身給出或以含有例如0.1%至99%(更佳10%至30%)活性成分以及醫藥學上可接受之載劑之醫藥組合物形式給出。
本發明之製劑可經口、非經腸、局部或經直腸給出。其當然以適
用於各投與途徑之形式給出。舉例而言,其係以錠劑或膠囊形式投與,藉由注射、吸入投與,以眼部洗劑、軟膏、栓劑等形式投與,藉由注射、輸注或吸入投與,藉由洗劑或軟膏局部投與,及藉由栓劑經直腸投與。經口投與較佳。
如本文所用之片語「非經腸投與(parenteral administration/administered parenterally)」意謂除經腸及局部投與以外,通常藉由注射進行之投與模式,且包括(但不限於)靜脈內、肌肉內、動脈內、鞘內、囊內、眶內、心內、皮內、腹膜內、經氣管、皮下、表皮下、關節內、囊下、蛛網膜下、脊椎內及胸骨內注射及輸注。
如本文所用之片語「全身投與(systemic administration/administered systemically)」及「外周投與(peripheral administration/administered peripherally)」意謂化合物、藥物或其他物質除直接投至中樞神經系統外之投與,使得其進入患者系統且因此經受代謝及其他類似過程,例如皮下投與。
此等化合物可藉由任何適合投與途徑向人類及其他動物投與以用於療法,投與途徑包括經口、經鼻(如藉由例如噴霧)、經直腸、陰道內、非經腸、腦池內及局部(如藉由散劑、軟膏或滴劑,包括經頰及舌下)。
不考慮所選擇之投與途徑,可以適合水合形式使用之本發明化合物及/或本發明之醫藥組合物係藉由熟習此項技術者已知之習知方法調配成醫藥學上可接受之劑型。
本發明醫藥組合物中之活性成分之實際劑量水準可變化以獲得可有效達成特定患者、組合物及投與模式之所需治療反應而對患者無毒性的活性成分之量。
所選劑量水準將視多種因素而定,包括所用之特定本發明化合物或其酯、鹽或醯胺之活性、投與途徑、投與時間、所用特定化合物之
排泄或代謝速率、吸收速率及程度、治療持續時間、與所用特定化合物組合使用之其他藥物、化合物及/或物質、所治療之患者之年齡、性別、體重、病狀、一般健康及先前病史及醫學技術中熟知之類似因素。
一般熟習此項技術之醫師或獸醫可容易確定及開具所需醫藥組合物之有效量。舉例而言,醫師或獸醫可以低於為達成所需治療作用所需之水準起始給與醫藥組合物中所用之本發明化合物,且逐漸增加劑量直至達成所需作用。
一般而言,本發明化合物之適合日劑量為可有效產生治療作用之最低劑量的化合物的量。此類有效劑量一般將視上述因素而定。一般而言,對於患者而言,當用於指定止痛作用時,本發明化合物之經口、靜脈內、腦室內及皮下劑量將在每公斤體重每天約0.0001毫克至約100毫克之範圍內。
必要時,活性化合物之有效日劑量可以兩次、三次、四次、五次、六次或六次以上亞劑量投與,該等亞劑量視情況以單位劑型在全天內以適當時間間隔分開投與。較佳給藥為每日一次投與。
雖然本發明化合物可能單獨投與,但較佳以醫藥調配物(組合物)形式投與化合物。
藉由其他藥物類推,本發明化合物可經調配以任何適用於人類或獸醫藥物之便利方式投與。
在另一態樣中,本發明提供醫藥學上可接受之組合物,其包含與一或多種醫藥學上可接受之載劑(添加劑)及/或稀釋劑一起調配之治療有效劑量之上述一或多種本發明化合物。如以下詳細描述,本發明之醫藥組合物可經特別調配以用於以固體或液體形式投與,包括適用於以下之醫藥組合物:(1)經口投與,例如施用於舌頭之灌藥(水性或非水性溶液或懸浮液)、錠劑、大丸劑、散劑、顆粒、糊劑;(2)非經腸投與,例如藉由皮下、肌肉內或靜脈內注射,如例如無菌溶液或懸浮液;(3)
局部施用,例如以施用至皮膚、肺或黏膜之乳膏、軟膏或噴霧形式;或(4)陰道內或直腸內,例如以子宮托、乳膏或泡沫形式;(5)舌下或經頰;(6)經眼;(7)經皮;或(8)經鼻。
術語「治療」意欲亦包涵預防、治療及治癒。
接受此治療之患者為任何有需要之動物,包括靈長類,尤其人類,及其他哺乳動物,諸如馬、牛、豬及綿羊;且一般為家禽及寵物。
本發明化合物可按原樣或以與醫藥學上可接受之載劑之混雜物形式投與且亦可與抗微生物劑(諸如青黴素(penicillin)、頭胞菌素(cephalosporin)、胺基醣苷(aminoglycoside)及醣肽(glycopeptide))結合投與。因此結合療法包括以首先投與之活性化合物之治療作用在投與後一活性化合物時未完全消失之方式依序、同時及單獨投與活性化合物。
微乳化技術可改良一些親脂性(水不可溶)醫藥試劑之生物可用性。實例包括Trimetrine(Dordunoo,S.K.等人,Drug Development and Industrial Pharmacy,17(12),1685-1713,1991)及REV 5901(Sheen,P.C.等人,J Pharm Sci 80(7),712-714,1991)。微乳化藉由優先引導淋巴系統而非循環系統吸收,藉此繞過肝臟且防止化合物在肝膽循環中遭到破壞,尤其提供增強之生物可用性。
雖然涵蓋所有適合之兩親媒性載劑,但當前較佳載劑一般為具有普遍認為安全(Generally-Recognized-as-Safe;GRAS)狀態且當溶液與複雜水相(諸如發現於人類胃腸道中之水相)接觸時可溶解本發明化合物且後期將其微乳化之彼等載劑。通常,滿足此等要求之兩親媒性成分之HLB(親水-親脂平衡)值為2-20,且其結構含有在C-6至C-20範圍內之直鏈脂族基團。實例為聚乙二醇化之脂肪甘油酯及聚乙二醇。
尤其涵蓋市售兩親媒性載劑,包括Gelucire系列,Labrafil、Labrasol或Lauroglycol(所有均由Gattefosse Corporation,Saint Priest,France製
造及分配),PEG單油酸酯,PEG二油酸酯,PEG單月桂酸酯及二月桂酸酯,卵磷脂,聚山梨醇酯80等(由美國及全世界多個公司生產及分配)。
適用於本發明之親水性聚合物為易於溶於水,可共價連接至微脂粒形成脂質,且活體內可耐受而無毒性作用(亦即生物相容)之親水性聚合物。適合之聚合物包括聚乙二醇(PEG)、聚乳酸(亦稱為聚丙交酯)、聚乙醇酸(亦稱為聚乙交酯)、聚乳酸-聚乙醇酸共聚物及聚乙烯醇。較佳聚合物為分子量為約100道爾頓或120道爾頓至約5,000道爾頓或10,000道爾頓,且更佳為約300道爾頓至約5,000道爾頓之彼等聚合物。在一尤其較佳實施例中,聚合物為分子量為約100道爾頓至約5,000道爾頓,且更佳分子量為約300道爾頓至約5,000道爾頓之聚乙二醇。在一尤其較佳實施例中,聚合物為750道爾頓之聚乙二醇(PEG(750))。聚合物亦可由其中單體數目定義;本發明之一較佳實施例利用具有至少約三個單體之聚合物,該等PEG聚合物由三個單體(大約150道爾頓)組成。
可適用於本發明之其他親水性聚合物包括聚乙烯吡咯啶酮、聚甲基噁唑啉、聚乙基噁唑啉、聚羥丙基甲基丙烯醯胺、聚甲基丙烯醯胺、聚二甲基丙烯醯胺及衍生纖維素(諸如羥甲基纖維素或羥乙基纖維素)。
在某些實施例中,本發明調配物包含選自由以下組成之群之生物相容性聚合物:聚醯胺、聚碳酸酯、聚伸烷、丙烯酸酯與甲基丙烯酸酯之聚合物、聚乙烯聚合物、聚乙交酯、聚矽氧烷、聚胺基甲酸酯及其共聚物、纖維素、聚丙烯、聚乙烯、聚苯乙烯、乳酸與乙醇酸之聚合物、聚酸酐、聚(原酸)酯、聚(丁酸)、聚(戊酸)、聚(丙交酯-共-己內酯)、多醣、蛋白質、聚玻尿酸、聚氰基丙烯酸酯及其摻合物、混合物或共聚物。
環糊精為由希臘字母α、β或γ分別表示之6、7或8個葡萄糖單元組成之環狀寡醣。已知不存在具有少於六個葡萄糖單元之環糊精。葡萄糖單元由α-1,4-葡萄糖鍵連接。由於糖單元之椅式構形,所有二級羥基(在C-2、C-3處)位於環之一側上,而在C-6處之所有一級羥基位於另一側。因此,外部表面為親水性的,使得環糊精可溶於水。相比之下,環糊精之腔為疏水性的,因為其由原子C-3及C-5之氫及由類醚氧裝襯。此等基質允許與多種相對疏水性化合物,包括例如類固醇化合物(諸如17β-雌二醇)複合(參見例如,van Uden等人Plant Cell Tiss.Org.Cult.38:1-3-113(1994))。複合藉由凡得瓦爾力(Van der Waals)相互作用及藉由氫鍵形成來進行。關於環糊精之化學性質之一般綜述,參見Wenz,Agnew.Chem.Int.Ed.Engl.,33:803-822(1994)。
環糊精衍生物之物理化學特性強烈視取代之類型及程度而定。舉例而言,其於水中之溶解性在不可溶(例如三乙醯基-β-環糊精)至147%可溶(w/v)(G-2-β-環糊精)範圍內。另外,其可溶於多種有機溶劑中。環糊精之特性使得能夠藉由增加或降低其溶解性來控制各種調配物組分之溶解性。
已描述多種環糊精及其製備方法。舉例而言,Parmeter(I)等人(美國專利第3,453,259號)及Gramera等人(美國專利第3,459,731號)描述電中性環糊精。其他衍生物包括具有陽離子特性之環糊精[Parmeter(II),美國專利第3,453,257號]、不可溶交聯環糊精(Solms,美國專利第3,420,788號)及具有陰離子特性之環糊精[Parmeter(III),美國專利第3,426,011號]。在具有陰離子特性之環糊精衍生物中,已將羧酸、亞磷酸、亞膦酸、膦酸、磷酸、硫膦酸、硫亞磺酸及磺酸附加至親本環糊精[參見Parmeter(III),前述文獻]。此外,Stella等人(美國專利第5,134,127號)已描述磺烷基醚環糊精衍生物。
脂質體由至少一個封閉水性內部隔室之脂質雙層膜組成。脂質體
可由膜類型及尺寸表徵。單層小微脂粒(SUV)具有單個膜且直徑通常在0.02μm與0.05μm之間之範圍內;單層大微脂粒(LUV)通常大於0.05μm,寡層大微脂粒及多層微脂粒具有多個通常同心之膜層且通常大於0.1μm。具有數個非同心膜,亦即數個較小微脂粒含於較大微脂粒內之脂質體,稱為多囊泡微脂粒。
本發明之一個態樣係關於包含含有本發明化合物之脂質體之調配物,其中脂質體膜經調配以提供載運能力增加之脂質體。或者或另外,本發明化合物可含於脂質體之脂質體雙層內或吸附至脂質體之脂質體雙層上。本發明化合物可用脂質界面活性劑聚集且在脂質體內部空間內載運;在此等情況下,脂質體膜經調配以抵抗活性劑-界面活性劑聚集體之分裂作用。
根據本發明之一個實施例,脂質體之脂質雙層含有用聚乙二醇(PEG)衍生之脂質,以使得PEG鏈自脂質雙層之內表面延伸至藉由脂質體囊封之內部空間,且自脂質雙層之外部延伸至周圍環境。
本發明脂質體中所含有之活性劑呈溶解形式。界面活性劑與活性劑之聚集體(諸如含有相關活性劑之乳液或微胞)可截留於根據本發明之脂質體之內部空間內。界面活性劑起分散及溶解活性劑之作用,且可選自任何適合之脂族、環脂族或芳族界面活性劑,包括(但不限於)具有不同鏈長度(例如約C14至約C20)之生物相容性溶血磷脂醯膽鹼(LPC)。聚合物衍生之脂質(諸如PEG脂質)亦可用於形成微胞,因為其將起抑制微胞/膜融合之作用,且因為將聚合物添加至界面活性劑分子減少界面活性劑之CMC且輔助形成微胞。較佳為CMC在微莫耳範圍內之界面活性劑;較高CMC界面活性劑可用於製備截留於本發明脂質體內之微胞,然而,微胞界面活性劑單體可影響脂質體雙層穩定性且將為設計具有所需穩定性之脂質體中之因素。
根據本發明之脂質體可藉由此項技術中已知之任何多種技術製
備。參見例如美國專利第4,235,871號;公開PCT申請案WO 96/14057;New RRC,Liposomes:A practical approach,IRL Press,Oxford(1990),第33-104頁;Lasic DD,Liposomes from physics to applications,Elsevier Science Publishers BV,Amsterdam,1993。
舉例而言,本發明脂質體可藉由將用親水性聚合物衍生之脂質擴散於預先形成之脂質體中,諸如藉由將預先形成之脂質體暴露於由脂質接枝聚合物構成之微胞(脂質濃度對應於脂質體中所需之衍生脂質之最終莫耳百分比)來製備。含有親水性聚合物之脂質體亦可藉由如此項技術中已知之均質化、脂質領域水合作用或擠壓技術形成。
在本發明之一個態樣中,脂質體經製備具有在選定尺寸範圍內之實質上均勻尺寸。一種有效定尺寸方法涉及擠壓脂質體之水性懸浮液穿過一系列具有選定均勻孔隙尺寸之聚碳酸酯膜,該膜之孔隙尺寸將大致與藉由擠壓穿過彼膜產生之最大脂質體尺寸相對應。參見例如美國專利第4,737,323號(1988年4月12日)。
本發明調配物之釋放特徵視囊封材料、囊封藥物之濃度及釋放調節劑之存在而定。舉例而言,可例如使用僅在如胃中之低pH或如腸中之較高pH下釋放之pH敏感包衣將釋放操控為pH依賴性。可使用腸溶衣來防止釋放在通過胃之前發生。可使用囊封於不同材料中之多個氰胺包衣或混合物來獲得在胃中初始釋放,繼而隨後在腸中釋放。亦可藉由包括鹽或造孔劑來操控釋放,該等鹽或成孔劑可藉由自膠囊擴散來增加水吸收或藥物釋放。亦可使用調節藥物溶解性之賦形劑來控制釋放速率。亦可併入增強基質降解或自基質釋放之試劑。其可添加至藥物中,以單獨相(亦即以微粒形式)添加,或可視化合物而定共同溶解於聚合物相中。在所有情況下,量應該在0.1%與30%(w/w聚合物)之間。降解增強劑之類型包括無機鹽,諸如硫酸銨及氯化銨;有機酸,諸如檸檬酸、苯甲酸及抗壞血酸;無機鹼,諸如碳酸鈉、碳酸鉀、碳
酸鈣、碳酸鋅及氫氧化鋅;及有機鹼,諸如硫酸魚精蛋白、精胺、膽鹼、乙醇胺、二乙醇胺及三乙醇胺;及界面活性劑,諸如Tween®及Pluronic®。向基質添加微觀結構之造孔劑(亦即水溶性化合物,諸如無機鹽及糖)係以微粒形式添加。範圍應在1%與30%(w/w聚合物)之間。
亦可藉由改變粒子在消化道中之滯留時間來操控吸收。此可例如藉由用黏膜黏附聚合物包覆粒子或選擇黏膜黏附聚合物作為囊封材料來達成。實例包括大部分具有自由羧基之聚合物,諸如聚葡萄胺糖、纖維素,且尤其包括聚丙烯酸酯(如本文所用,聚丙烯酸酯係指包括丙烯酸酯基及經改質丙烯酸酯基(諸如氰基丙烯酸酯基及甲基丙烯酸酯基)之聚合物)。
本發明尤其關於式I化合物(或包含式I化合物之醫藥組合物)在治療本文中提及之一或多種疾病中之用途;其中如例如由疾病之一或多種症狀之部分或完全移除至完全治癒或緩解所展示,治療反應為有利的。
式(I)化合物亦可與以下化合物及抗體-藥物結合物組合使用:BCR-ABL抑制劑:伊馬替尼(Imatinib)(Gleevec®);鹽酸尼羅替尼(Inilotinib hydrochloride);尼羅替尼(Tasigna®);達沙替尼(Dasatinib)(BMS-345825);伯舒替尼(Bosutinib)(SKI-606);普納替尼(Ponatinib)(AP24534);巴氟替尼(Bafetinib)(INNO406);達魯舍替(Danusertib)(PHA-739358),AT9283(CAS 1133385-83-7);塞卡替尼(Saracatinib)(AZD0530);及N-[2-[(1S,4R)-6-[[4-(環丁基胺基)-5-(三氟甲基)-2-嘧啶基]胺基]-1,2,3,4-四氫萘-1,4-亞胺-9-基]-2-側氧基乙基]-乙醯胺(PF-03814735,CAS 942487-16-3);及LGX818。
ALK抑制劑:PF-2341066(XALKORI®;克卓替尼(crizotinib));5-氯-N4-(2-(異丙磺醯基)苯基)-N2-(2-甲氧基-4-(4-(4-甲基哌嗪-1-基)哌
啶-1-基)苯基)嘧啶-2,4-二胺;GSK1838705A;及CH5424802。
BRAF抑制劑:維羅非尼(Vemurafanib)(PLX4032);及達拉菲尼(Dabrafenib)。
FLT3抑制劑-蘋果酸舒尼替尼(sunitinib malate)(由Pfizer以商品名Sutent®出售);PKC412(米哚妥林(midostaurin));坦度替尼(tanutinib)、索拉非尼(sorafenib)、舒尼替尼、米哚妥林、來他替尼(lestaurtinib)、KW-2449、奎紮替尼(quizartinib)(AC220)及克諾蘭尼(crenolanib)。
MEK抑制劑-曲美替尼(trametinib)。
血管內皮生長因子(VEGF)受體抑制劑:貝伐單抗(Bevacizumab)(由Genentech/Roche以商標Avastin®出售)、阿西替尼(axitinib)(N-甲基-2-[[3-[(E)-2-吡啶-2-基乙烯基]-1H-吲唑-6-基]硫基]苯甲醯胺,其亦稱為AG013736且描述於PCT公開案第WO 01/002369號中)、丙胺酸布立尼布(Brivanib Alaninate)((S)-((R)-1-(4-(4-氟-2-甲基-1H-吲哚-5-基氧基)-5-甲基吡咯并[2,1-f][1,2,4]三嗪-6-基氧基)丙-2-基)2-胺基丙酸酯,亦稱為BMS-582664)、莫替沙尼(motesanib)(N-(2,3-二氫-3,3-二甲基-1H-吲哚-6-基)-2-[(4-吡啶基甲基)胺基]-3-吡啶甲醯胺,且描述於PCT公開案第WO 02/066470號中)、帕瑞肽(pasireotide)(亦稱為SOM230,且描述於PCT公開案第WO 02/010192號中)、索拉非尼(以商品名Nexavar®出售);HER2受體抑制劑:曲妥珠單抗(Trastuzumab)(由Genentech/Roche以商標Herceptin®出售)、來那替尼(neratinib)(亦稱為HKI-272,(2E)-N-[4-[[3-氯-4-[(吡啶-2-基)甲氧基]苯基]胺基]-3-氰基-7-乙氧基喹啉-6-基]-4-(二甲胺基)丁-2-烯醯胺,且描述於PCT公開案第WO 05/028443號中)、拉帕替尼(lapatinib)或二甲苯磺酸拉帕替尼(由GlaxoSmithKline以商標Tykerb®出售);曲妥珠單抗恩他新(Trastuzumab
emtansine)(在美國,阿多曲妥珠單抗恩他新(ado-trastuzumab emtansine),商標名Kadcyla)-一種由連接至細胞毒性劑美坦辛(mertansine)(DM1)之單株抗體曲妥珠單抗(Herceptin)組成之抗體-藥物結合物;CD20抗體:利妥昔單抗(Rituximab)(由Genentech/Roche以商標Riuxan®及MabThera®出售)、托西莫單抗(tositumomab)(由GlaxoSmithKline以商標Bexxar®出售)、奧伐木單抗(ofatumumab)(由GlaxoSmithKline以商標Arzerra®出售);酪胺酸激酶抑制劑:鹽酸埃羅替尼(Erlotinib hydrochloride)(由Genentech/Roche以商標Tarceva®出售)、利尼伐尼(Linifanib)(N-[4-(3-胺基-1H-吲唑-4-基)苯基]-N'-(2-氟-5-甲基苯基)脲,亦稱為ABT 869,獲自Genentech)、蘋果酸舒尼替尼(由Pfizer以商品名Sutent®出售)、伯舒替尼(4-[(2,4-二氯-5-甲氧苯基)胺基]-6-甲氧基-7-[3-(4-甲基哌嗪-1-基)丙氧基]喹啉-3-甲腈,亦稱為SKI-606,且描述於美國專利第6,780,996號中)、達沙替尼(由Bristol-Myers Squibb以商品名Sprycel®出售)、阿瑪拉(armala)(亦稱為帕唑帕尼(pazopanib),由GlaxoSmithKline以商品名Votrient®出售)、伊馬替尼及甲磺酸伊馬替尼(由Novartis以商品名Gilvec®及Gleevec®出售);DNA合成抑制劑:卡培他濱(Capecitabine)(由Roche以商標Xeloda®出售)、鹽酸吉西他濱(由Eli Lilly and Company以商標Gemzar®出售)、奈拉濱(nelarabine)((2R,3S,4R,5R)-2-(2-胺基-6-甲氧基-嘌呤-9-基)-5-(羥甲基)氧雜環戊烷-3,4-二醇,由GlaxoSmithKline以商品名Arranon®及Atriance®出售);抗腫瘤劑:奧沙利鉑(oxaliplatin)(由Sanofi-Aventis以商品名Eloxatin®出售且描述於美國專利第4,169,846號中);表皮生長因子受體(EGFR)抑制劑:吉非替尼(Gefitnib)(以商品名
Iressa®出售,N-[4-[(3-氯-4-氟苯基)胺基]-7-[[(3"S")-四氫-3-呋喃基]氧基]-6-喹唑啉基]-4(二甲胺基)-2-丁烯醯胺,由Boehringer Ingelheim以商品名Tovok®出售)、西妥昔單抗(cetuximab)(由Bristol-Myers Squibb以商品名Erbitux®出售)、帕尼單抗(panitumumab)(由Amgen以商品名Vectibix®出售);HER二聚抑制劑:帕妥珠單抗(Pertuzumab)(由Genentech以商標Omnitarg®出售);人類粒細胞群落刺激因子(G-CSF)調節劑:非格司亭(Filgrastim)(由Amgen以商品名Neupogen®出售);免疫調節劑:阿夫妥珠單抗(Afutuzumab)(獲自Roche®)、聚乙二醇非格司亭(pegfilgrastim)(由Amgen以商品名Neulasta®出售)、來那度胺(lenalidomide)(亦稱為CC-5013,以商品名Revlimid®出售)、沙立度胺(thalidomide)(以商品名Thalomid®出售);CD40抑制劑:達西珠單抗(Dacetuzumab)(亦稱為SGN-40或huS2C6,獲自Seattle Genetics,Inc);促凋亡受體促效劑(PARA):杜拉樂明(Dulanermin)(亦稱為AMG-951,獲自Amgen/Genentech);刺蝟拮抗劑:2-氯-N-[4-氯-3-(2-吡啶基)苯基]-4-(甲磺醯基)-苯甲醯胺(亦稱為GDC-0449,且描述於PCT公開案第WO 06/028958號中);PI3K抑制劑:4-[2-(1H-吲唑-4-基)-6-[[4-(甲磺醯基)哌嗪-1-基]甲基]噻吩并[3,2-d]嘧啶-4-基]嗎啉(亦稱為GDC 0941且描述於PCT公開案第WO 09/036082號及第WO 09/055730號中)、2-甲基-2-[4-[3-甲基-2-側氧基-8-(喹啉-3-基)-2,3-二氫咪唑并[4,5-c]喹啉-1-基]苯基]丙腈(亦稱為BEZ 235或NVP-BEZ 235,且描述於PCT公開案第WO 06/122806號中);磷脂酶A2抑制劑:阿那格雷(Anagrelide)(以商品名Agrylin®出
售);BCL-2抑制劑:4-[4-[[2-(4-氯苯基)-5,5-二甲基-1-環己烯-1-基]甲基]-1-哌嗪基]-N-[[4-[[(1R)-3-(4-嗎啉基)-1-[(苯硫基)甲基]丙基]胺基]-3-[(三氟甲基)磺醯基]苯基]磺醯基]苯甲醯胺(亦稱為ABT-263且描述於PCT公開案第WO 09/155386號中);有絲分裂原活化蛋白激酶激酶(MEK)抑制劑:XL-518(Cas號1029872-29-4,獲自ACC Corp.);芳香酶抑制劑:依西美坦(Exemestane)(由Pfizer以商標Aromasin®出售)、來曲唑(letrozole)(由Novartis以商品名Femara®出售)、阿那曲唑(anastrozole)(以商品名Arimidex®出售);拓撲異構酶(Topoisomerase)I抑制劑:伊立替康(Irinotecan)(由Pfizer以商標Camptosar®出售)、鹽酸拓朴替康(topotecan hydrochloride)(由GlaxoSmithKline以商品名Hycamtin®出售);拓撲異構酶II抑制劑:依託泊苷(etoposide)(亦稱為VP-16及磷酸依託泊苷,以商品名Toposar®、VePesid®及Etopophos®出售)、替尼泊甙(teniposide)(亦稱為VM-26,以商品名Vumon®出售);mTOR抑制劑:坦羅莫司(Temsirolimus)(由Pfizer以商品名Torisel®出售)、瑞達莫司(ridaforolimus)(正式稱為德非洛里莫司(deferolimus),二甲基亞膦酸(1R,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-二羥基-19,30-二甲氧基-15,17,21,23,29,35-六甲基-2,3,10,14,20-五側氧基-11,36-二氧雜-4-氮雜三環[30.3.1.04,9]三十六烷-16,24,26,28-四烯-12-基]丙基]-2-甲氧基環己酯,亦稱為AP23573及MK8669,且描述於PCT公開案第WO 03/064383號中)、依維莫司(everolimus)(由Novartis以商品名Afinitor®出售);破骨骨骼再吸收抑制劑:1-羥基-2-咪唑-1-基-膦醯乙基)膦酸單水
合物(由Novartis以商品名Zometa®出售);CD33抗體藥物結合物:吉妥單抗(Gemtuzumab ozogamicin)(由Pfizer/Wyeth以商品名Mylotarg®出售);CD22抗體藥物結合物:奧英妥珠單抗(Inotuzumab ozogamicin)(亦稱為CMC-544及WAY-207294,獲自Hangzhou Sage Chemical Co.,Ltd.);CD20抗體藥物結合物:替伊莫單抗(Ibritumomab tiuxetan)(以商品名Zevalin®出售);生長抑素類似物:奧曲肽(octreotide)(亦稱為乙酸奧曲肽,以商品名Sandostatin®及Sandostatin LAR®出售);合成介白素-11(IL-11):奧普瑞介白素(oprelvekin)(由Pfizer/Wyeth以商品名Neumega®出售);合成紅血球生成素:阿法達貝泊汀(Darbepoetin alfa)(由Amgen以商品名Aranesp®出售);核因子κ B受體活化劑(RANK)抑制劑:德諾單抗(Denosumab)(由Amgen以商品名Prolia®出售);血小板生成素模擬肽體:羅米司亭(Romiplostim)(由Amgen以商品名Nplate®出售);細胞生長刺激劑:帕利夫明(Palifermin)(由Amgen以商品名Kepivance®出售);抗胰島素樣生長因子-1受體(IGF-1R)抗體:非吉單抗(Figitumumab)(亦稱為CP-751,871,獲自ACC Corp)、羅妥木單抗(robatumumab)(CAS號934235-44-6);抗CS1抗體:埃羅茲單抗(Elotuzumab)(HuLuc63,CAS號915296-00-3);CD52抗體:阿侖單抗(Alemtuzumab)(以商品名Campath®出售);CTLA-4抑制劑:曲美單抗(Tremelimumab)(IgG2單株抗體,獲自
Pfizer,先前稱為替西單抗(ticilimumab),CP-675,206)、伊匹單抗(ipilimumab)(CTLA-4抗體,亦稱為MDX-010,CAS號477202-00-9);PD1抑制劑:尼沃單抗(Nivolumab)(在本文中亦稱為MDX-1106、MDX-1106-04、ONO-4538、BMS0936558,CAS登記號:946414-94-4),其揭示於例如US 8,008,449中且具有其中揭示之序列(或與其實質上一致或相似之序列,例如與US 8,008,449中指定之序列具有至少85%、90%、95%或95%以上一致性之序列);派立珠單抗(Pembrolizumab)(在本文中亦稱為拉立珠單抗(Lambrolizumab)、MK-3475、MK03475、SCH-900475或KEYTRUDA),其揭示於例如US 8,354,509及WO 2009/114335中,且具有其中揭示之序列(或與其實質上一致或相似之序列,例如與US 8,354,509及WO2009/114335中指定之序列具有至少85%、90%、95%或95%以上一致性之序列);免疫黏附素(例如包含融合至恆定區(例如免疫球蛋白序列之Fc區)之PD-L1或PD-L2之細胞外或PD-1結合部分之免疫黏附素;皮立珠單抗(Pidilizumab)(CT-011;Cure Tech)為結合至PD1之人類化IgG1k單株抗體(皮立珠單抗及其他人類化抗-PD-1單株抗體揭示於WO2009/101611中);及AMP-224(B7-DCIg;Amplimmune),其揭示於WO2010/027827及WO2011/066342中,為阻斷PD1與B7-H1之間的相互作用之PD-L2 Fc融合可溶受體;其他PD-1抑制劑,例如揭示於US 8,609,089、US 2010028330及/或US 20120114649中之抗PD1抗體。
PDL1抑制劑:MSB0010718C(亦稱為A09-246-2;Merck Serono)為結合至PD-L1之單株抗體且揭示於例如WO 2013/0179174中(且具有與其實質上一致或相似之序列,例如與WO 2013/0179174中指定之序列具有至少85%、90%、95%或95%以上一致性之序列);且選自YW243.55.S70、MPDL3280A(Genetech/Roche)之抗PD-L1結合拮抗劑為結合至PD-L1之人類Fc優化IgG1單株抗體(MDPL3280A及PD-L1之
其他人類單株抗體揭示於美國專利第7,943,743號及U.S公開案第20120039906號中);MEDI-4736、MSB-0010718C或MDX-1105(MDX-1105,亦稱為BMS-936559,為描述於WO2007/005874中之抗PD-L1抗體;抗體YW243.55.S70為描述於WO 2010/077634中之抗PD-L1抗體)。
LAG-3抑制劑:BMS-986016(亦稱為BMS986016;Bristol-Myers Squibb)為結合至LAG-3之單株抗體。BMS-986016及其他人類化抗LAG-3抗體揭示於US 2011/0150892、WO2010/019570及WO2014/008218中。
GITR促效劑:例示性GITR促效劑包括例如GITR融合蛋白及抗GITR抗體(例如二價抗GITR抗體),諸如美國專利第6,111,090號、歐洲專利第090505B1號、美國專利第8,586,023號、PCT公開案第WO 2010/003118號及第2011/090754號中所描述之GITR融合蛋白,或例如美國專利第7,025,962號、歐洲專利第1947183B1號、美國專利第7,812,135號、美國專利第8,388,967號、美國專利第8,591,886號、歐洲專利第EP 1866339號、PCT公開案第WO 2011/028683號、PCT公開案第WO 2013/039954號、PCT公開案第WO2005/007190號、PCT公開案第WO 2007/133822號、PCT公開案第WO2005/055808號、PCT公開案第WO 99/40196號、PCT公開案第WO 2001/03720號、PCT公開案第WO99/20758號、PCT公開案第WO2006/083289號、PCT公開案第WO 2005/115451號、美國專利第7,618,632號及PCT公開案第WO 2011/051726號中所描述之抗GITR抗體。
組蛋白脫乙醯基酶抑制劑(HDI):伏立諾他(Voninostat)(由Merck以商品名Zolinza®出售)。
抗CTLA4抗體包括曲美單抗(IgG2單株抗體,獲自Pfizer,先前稱為替西單抗,CP-675,206);及伊匹單抗(CTLA-4抗體,亦稱為
MDX-010,CAS號477202-00-9)。
抗TIM-3抗體或其抗原結合片段。
烷基化劑:替莫唑胺(Temozolomide)(由Schering-Plough/Merck以商品名Temodar®及Temodal®出售)、放線菌素d(dactinomycin)(亦稱為放線菌素-D(actinomycin-D)且以商品名Cosmegen®出售)、美法侖(melphalan)(亦稱為L-PAM、L-沙可來新(L-sarcolysin)及苯丙胺酸氮芥(phenylalanine mustard),以商品名Alkeran®出售)、六甲密胺(altretamine)(亦稱為六甲基三聚氰胺(HMM),以商品名Hexalen®出售)、卡莫司汀(carmustine)(以商品名BiCNU®出售)、苯達莫司汀(bendamustine)(以商品名Treanda®出售)、硫酸布他卡因(busulfan)(以商品名Busulfex®及Myleran®出售)、卡鉑(carboplatin)(以商品名Paraplatin®出售)、洛莫司汀(lomustine)(亦稱為CCNU,以商品名CeeNU®出售)、順鉑(亦稱為CDDP,以商品名Platinol®及Platinol®-AQ出售)、苯丁酸氮芥(chlorambucil)(以商品名Leukeran®出售)、環磷醯胺(cyclophosphamide)(以商品名Cytoxan®及Neosar®出售)、達卡巴嗪(dacarbazine)(亦稱為DTIC、DIC及咪唑甲醯胺,以商品名DTIC-Dome®出售)、六甲密胺(亦稱為六甲基三聚氰胺(HMM),以商品名Hexalen®出售)、異環磷醯胺(ifosfamide)(以商品名Ifex®出售)、丙卡巴肼(procarbazine)(以商品名Matulane®出售)、甲基二(氯乙基)胺(mechlorethamine)(亦稱為氮芥(nitrogen mustard/mustine)及鹽酸甲基二(氯乙基)胺,以商品名Mustargen®出售)、鏈佐星(streptozocin)(以商品名Zanosar®出售)、噻替派(thiotepa)(亦稱為硫磷醯胺(thiophosphoamide)、TESPA及TSPA,以商品名Thioplex®出售);生物反應調節劑:卡介苗(bacillus calmette-guerin)(以商品名theraCys®及TICE® BCG出售)、地尼介白素(denileukin diftitox)(以商品名Ontak®出售);
抗腫瘤抗生素:小紅莓(doxorubicin)(以商品名Adriamycin®及Rubex®出售)、博萊黴素(bleomycin)(以商品名lenoxane®出售)、道諾黴素(daunorubicin)(亦稱為鹽酸道諾黴素、柔紅黴素(daunomycin)及鹽酸紅比黴素(rubidomycin hydrochloride),以商品名Cerubidine®出售)、道諾黴素脂質體(檸檬酸道諾黴素脂質體,以商品名DaunoXome®出售)、米托蒽醌(mitoxantrone)(亦稱為DHAD,以商品名Novantrone®出售)、表柔比星(epirubicin)(以商品名EllenceTM出售)、艾達黴素(idarubicin)(以商品名Idamycin®、Idamycin PFS®出售)、絲裂黴素C(mitomycin C)(以商品名Mutamycin®出售);抗微管劑:雌氮芥(Estramustine)(以商品名Emcyl®出售);組織蛋白酶K抑制劑:奧當卡替(Odanacatib)(亦稱為MK-0822,N-(1-氰基環丙基)-4-氟-N2-{(1S)-2,2,2-三氟-1-[4'-(甲磺醯基)聯苯-4-基]乙基}-L-白胺醯胺,獲自Lanzhou Chon Chemicals,ACC Corp.及ChemieTek,且描述於PCT公開案第WO 03/075836號中);埃坡黴素B(Epothilone B)類似物:伊沙匹隆(Ixabepilone)(由Bristol-Myers Squibb以商品名Lxempra®出售);熱休克蛋白(HSP)抑制劑:坦螺旋黴素(Tanespimycin)(17-烯丙基胺基-17-去甲氧基格爾德黴素(geldanamycin),亦稱為KOS-953及17-AAG,獲自SIGMA,且描述於美國專利第4,261,989號中);TpoR促效劑:艾曲波帕(Eltrombopag)(由GlaxoSmithKline以商品名Promacta®及Revolade®出售);抗有絲分裂劑:多烯紫杉醇(由Sanofi-Aventis以商品名Taxotere®出售);腎上腺類固醇抑制劑:胺魯米特(aminoglutethimide)(以商品名Cytadren®出售);抗雄激素:尼魯米特(Nilutamide)(以商品名Nilandron®及
Anandron®出售)、比卡魯胺(bicalutamide)(以商品名Casodex®出售)、氟他胺(以商品名FulexinTM出售);雄激素:氟羥甲基睪酮(以商品名Halotestin®出售);蛋白酶體抑制劑:硼替佐米(Bortezomib)(以商品名Velcade®出售);CDK1抑制劑:阿昔迪布(Alvocidib)(亦稱為夫拉平度(flovopirdol)或HMR-1275,2-(2-氯苯基)-5,7-二羥基-8-[(3S,4R)-3-羥基-1-甲基-4-哌啶基]-4-烯酮,且描述於美國專利第5,621,002號中);促性腺激素釋放激素(GnRH)受體促效劑:亮丙瑞林(Leuprolide)或乙酸亮丙瑞林(由Bayer AG以商品名Viadure®、由Sanofi-Aventis以商品名Eligard®及由Abbott Lab以商品名Lupron®出售);紫杉烷抗腫瘤劑:卡巴他賽(Cabazitaxel)(1-羥基-7β,10β-二甲氧基-9-側氧基-5β,20-環氧紫杉-11-烯-2α,4,13α-三基-4-乙酸酯-2-苯甲酸酯-13-[(2R,3S)-3-{[(第三丁氧基)羰基]胺基}-2-羥基-3-苯基丙酸酯)、拉洛他賽(larotaxel)(苯甲酸(2α,3ξ,4α,5β,7α,10β,13α)-4,10-雙(乙醯氧基)-13-({(2R,3S)-3-(第三丁氧基羰基)胺基]-2-羥基-3-苯基丙醯基}氧基)-1-羥基-9-側氧基-5,20-環氧基-7,19-環紫杉-11-烯-2-酯);5HT1a受體促效劑:紮利羅登(Xaliproden)(亦稱為SR57746,1-[2-(2-萘基)乙基]-4-[3-(三氟甲基)苯基]-1,2,3,6-四氫吡啶,且描述於美國專利第5,266,573號中);HPC疫苗:由GlaxoSmithKline出售之Cervarix®、由Merck出售之Gardasil®;鐵螯合劑:地拉羅斯(Deferasinox)(由Novartis以商品名Exjade®出售);抗代謝物:克拉屈濱(Claribine)(2-氯去氧腺苷,以商品名leustatin®出售)、5-氟尿嘧啶(以商品名Adrucil®出售)、6-硫鳥嘌呤(以
商品名Purinethol®出售)、培美曲塞(pemetrexed)(以商品名Alimta®出售)、阿糖胞苷(cytarabine)(亦稱為阿糖胞苷(arabinosylcytosine)(Ara-C),以商品名Cytosar-U®出售)、阿糖胞苷脂質體(亦稱為脂質體Ara-C,以商品名DepoCytTM出售)、地西他濱(decitabine)(以商品名Dacogen®出售)、羥基脲(以商品名Hydrea®、DroxiaTM及MylocelTM出售)、氟達拉濱(fludarabine)(以商品名Fludara®出售)、氟尿苷(以商品名FUDR®出售)、克拉屈濱(cladribine)(亦稱為2-氯去氧腺苷(2-CdA),以商品名LeustatinTM出售)、甲胺喋呤(methotrexate)(亦稱為胺甲喋呤(amethopterin)、甲胺喋呤鈉(MTX),以商品名Rheumatrex®及TrexallTM出售)、噴司他丁(pentostatin)(以商品名Nipent®出售);雙膦酸鹽:帕米膦酸鹽(Pamidronate)(以商品名Aredia®出售)、唑來膦酸(zoledronic acid)(以商品名Zometa®出售);去甲基劑:5-阿紮胞苷(5-azacitidine)(以商品名Vidaza®出售)、地西他濱(以商品名Dacogen®出售);植物鹼:蛋白結合太平洋紫杉醇(以商品名Abraxane®出售)、長春鹼(亦稱為硫酸長春鹼、長春花鹼及VLB,以商品名Alkaban-AQ®及Velban®出售)、長春新鹼(亦稱為硫酸長春新鹼、LCR及VCR,以商品名Oncovin®及Vincasar Pfs®出售)、長春瑞濱(以商品名Navelbine®出售)、太平洋紫杉醇(以商品名紫杉醇及OnxalTM出售);類視黃素:亞利崔托寧(Alitretinoin)(以商品名Panretin®出售)、維甲酸(tretinoin)(全反式視黃酸,亦稱為ATRA,以商品名Vesanoid®出售)、異維甲酸(13-順式視黃酸,以商品名Accutane®、Amnesteem®、Claravis®、Clarus®、Decutan®、Isotane®、Izotech®、Oratane®、Isotret®及Sotret®出售)、貝瑟羅汀(bexarotene)(以商品名Targretin®出售);糖皮類固醇:氫皮質酮(亦稱為皮質酮、氫皮質酮丁二酸鈉、氫皮質酮磷酸鈉,且以商品名Ala-Cort®、磷酸氫皮質酮、Solu-Cortef®、
Hydrocort Acetate®及Lanacort®出售)、地塞米松(dexamethazone)((8S,9R,10S,11S,13S,14S,16R,17R)-9-氟-11,17-二羥基-17-(2-羥基乙醯基)-10,13,16-三甲基-6,7,8,9,10,11,12,13,14,15,16,17-十二氫-3H-環戊并[a]菲-3-酮)、潑尼龍(prednisolone)(以商品名Delta-Cortel®、Orapred®、Pediapred®及Prelone®出售)、潑尼松(prednisone)(以商品名Deltasone®、Liquid Red®、Meticorten®及Orasone®出售)、甲潑尼龍(亦稱為6-甲基潑尼龍、乙酸甲潑尼龍、甲潑尼龍丁二酸鈉,以商品名Duralone®、Medralone®、Medrol®、M-Prednisol®及Solu-Medrol®出售);細胞激素:介白素-2(亦稱為阿地介白素(aldesleukin)及IL-2,以商品名Proleukin®出售)、介白素-11(亦稱為奧普瑞介白素(oprevelkin),以商品名Neumega®出售)、α干擾素α(亦稱為IFN-α,以商品名Intron® A及Roferon-A®出售);雌激素受體下調劑:氟維司群(Fulvestrant)(以商品名Faslodex®出售);抗雌激素:他莫昔芬(tamoxifen)(以商品名Novaldex®出售);托瑞米芬(Toremifene)(以商品名Fareston®出售);選擇性雌激素受體調節劑(SERM):雷諾昔酚(Raloxifene)(以商品名Evista®出售);黃體生成激素釋放激素(LHRH)促效劑:戈舍瑞林(Goserelin)(以商品名Zoladex®出售);孕酮:甲地孕酮(亦稱為乙酸甲地孕酮,以商品名Megace®出售);雜項細胞毒性劑:三氧化二砷(以商品名Trisenox®出售)、天冬醯胺酶(亦稱為L-天冬醯胺酶、伊文氏桿菌屬(Erwinia)L-天冬醯胺酶,以商品名Elspar®及Kidrolase®出售);式(I)化合物亦可與以下輔助療法組合使用:
抗噁心藥:NK-1受體拮抗劑:卡索匹坦(Casopitant)(由GlaxoSmithKline以商品名Rezonic®及Zunrisa®出售);及細胞保護劑:阿米福汀(Amifostine)(以商品名Ethyol®出售)、甲醯四氫葉酸(亦稱為甲醯四氫葉酸鈣、嗜橙菌因子(citrovorum factor)及醛葉酸)。
免疫檢查點抑制劑:在一個實施例中,本文所揭示之組合療法包括免疫檢查點分子之抑制分子之抑制劑。術語「免疫檢查點」係指CD4及CD8 T細胞之細胞表面上之分子群。此等分子可有效充當「閘」來下調或抑制抗腫瘤免疫反應。免疫檢查點分子包括(但不限於)漸進式死亡1(PD-1)、細胞毒性T-淋巴細胞抗原4(CTLA-4)、B7H1、B7H4、OX-40、CD137、CD40及LAG3,其直接抑制免疫細胞,可充當適用於本發明方法之免疫檢查點抑制劑之免疫治療劑包括(但不限於)PD-L1、PD-L2、CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD160、2B4及/或TGFR β之抑制劑。抑制分子之抑制可藉由在DNA、RNA或蛋白質水準下抑制來進行。在實施例中,可使用抑制核酸(例如dsRNA、siRNA或shRNA)抑制抑制分子之表現。在其他實施例中,抑制信號之抑制劑為結合至抑制分子之多肽,例如可溶配位體或抗體或其抗原結合片段。
在某些實施例中,本文所述之抗PD-1分子與此項技術中已知之PD-1、PD-L1及/或PD-L2之一或多種其他抑制劑組合投與。拮抗劑可為抗體、其抗原結合片段、免疫黏附素、融合蛋白質或寡肽。
在某些實施例中,本文所揭示之組合療法包括共刺激分子或抑制分子之調節劑,例如,共抑制配位體或受體。
在一個實施例中,共刺激分子之共刺激調節劑(例如促效劑)選自OX40、CD2、CD27、CDS、ICAM-1、LFA-1(CD11a/CD18)、ICOS(CD278)、4-1BB(CD137)、GITR、CD30、CD40、BAFFR、HVEM、
CD7、LIGHT、NKG2C、SLAMF7、NKp80、CD160、B7-H3或CD83配位體之促效劑(例如促效抗體或其抗原結合片段或可溶融合體)。
在另一實施例中,本文所揭示之組合療法包括共刺激分子,例如,與包括CD28、CD27、ICOS及GITR之共刺激結構域之正信號相關聯之促效劑。
在一個實施例中,抗PD-1抗體分子在治療之後,例如在用有或無BRAF抑制劑(例如維羅非尼或達拉菲尼)之抗CTLA4抗體(例如伊匹單抗)治療黑素瘤之後投與。可使用之例示性劑量包括約1mg/kg至10mg/kg,例如3mg/kg之抗PD-1抗體分子之劑量,及約3mg/kg之抗CTLA-4抗體(例如伊匹單抗)之劑量。
在另一實施例中,抗PD-1或PD-L1抗體分子與抗LAG-3抗體或其抗原結合片段組合投與。在另一實施例中,抗PD-1或PD-L1抗體分子與抗TIM-3抗體或其抗原結合片段組合投與。在其他實施例中,抗PD-1或PD-L1抗體分子與抗LAG-3抗體及抗TIM-3抗體或其抗原結合片段組合投與。本文中所述之抗體之組合可例如以單獨抗體形式單獨投與,或例如以雙特異性或三特異性抗體分子形式連接。在一個實施例中,投與包括抗PD-1或PD-L1抗體分子及抗TIM-3或抗LAG-3抗體或其抗原結合片段之雙特異性抗體。在某些實施例中,本文中所述之抗體之組合用於治療癌症,例如,如本文所述之癌症(例如實體腫瘤)。可在此項技術中已知之動物模型中測試前述組合之功效。舉例而言,測試抗PD-1及抗LAG-3之協同作用之動物模型描述於例如Woo等人(2012)Cancer Res.72(4):917-27)中。
在一些實施例中,本文所揭示之組合療法(例如抗PD-1或PD-L1抗體分子)單獨或與另一免疫調節劑(例如抗LAG-3或抗TIM-3抗體分子)組合投與。在一個實施例中,抗PD-1或PD-L1抗體分子與抗LAG-3抗體或其抗原結合片段組合投與。在另一實施例中,抗PD-1或PD-L1抗
體分子與抗TIM-3抗體或其抗原結合片段組合投與。在其他實施例中,抗PD-1或PD-L1抗體分子與抗LAG-3抗體及抗TIM-3抗體或其抗原結合片段組合投與。本文中所述之抗體之組合可例如以單獨抗體形式單獨投與,或例如以雙特異性或三特異性抗體分子形式連接。在一個實施例中,投與包括抗PD-1或PD-L1抗體分子及抗TIM-3或抗LAG-3抗體或其抗原結合片段之雙特異性抗體。在某些實施例中,本文中所述之抗體之組合用於治療癌症,例如,如本文所述之癌症(例如實體腫瘤)。可在此項技術中已知之動物模型中測試前述組合之功效。舉例而言,測試抗PD-1及抗LAG-3之協同作用之動物模型描述於例如Woo等人(2012)Cancer Res.72(4):917-27).24中。
在某些實施例中,抗體分子呈雙特異性或多特異性抗體分子形式。在一個實施例中,雙特異性抗體分子具有對PD-1或PD-L1之第一結合特異性及第二結合特異性,例如對TIM-3、LAG-3或PD-L2之第二結合特異性。在一個實施例中,雙特異性抗體分子結合至PD-1或PD-L1及TIM-3。在另一實施例中,雙特異性抗體分子結合至PD-1或PD-L1及LAG-3。在另一實施例中,雙特異性抗體分子結合至PD-1或PD-L1。在另一實施例中,雙特異性抗體分子結合至PD-1及PD-L2。在另一實施例中,雙特異性抗體分子結合至TIM-3及LAG-3。可在多特異性抗體分子,例如,包括對PD-1或PD-1之第一結合特異性及對TIM-3、LAG-3或PD-L2中之兩者或兩者以上之第二及第三結合特異性之三特異性抗體中做出前述分子之任何組合。
在本發明內進行之對參考文獻之引用均不理解為承認所引用之參考文獻為將不利地影響本發明之專利性之先前技術。
本發明亦包括製備本發明化合物之方法。在所描述之反應中,可能需要保護反應性官能基以避免其在反應中之非吾人所樂見之參與,
該等反應性官能基例如羥基、胺基、亞胺基、硫基或羧基,其中在最終產物中需要此等基團。可根據標準實踐使用習知保護基,例如參見T.W.Greene及P.G.M.Wuts於「Protective Groups in Organic Chemistry」,John Wiley and Sons,1991中。
可藉由如在以下反應流程I中進行來製備式I化合物:
其中p、q、Y1、Y2、R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b、R7及R8如發明內容中關於式I所定義,Q為鹵素(如溴)或與化合物5上之鹵素反應之硫醇、酸酯或錫酸酯,且X為與Q反應之反應性基團(諸如酸酯、錫烷、醇、硫醇、鹵素及其類似者)。可藉由經由在適合酸或鹼條件下在過渡金屬之存在或不存在下在環境溫度下或在熱或微波條件下之反應,使化合物2與化合物3反應來製備化合物4。或者,化合物2之鹵素可由其他鹵素或適合活化基團,諸如三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯、九氟丁磺酸酯、酸酯、有機錫烷、有機矽烷基、有機鋅、鋰、鎂及其類似者置換。
式I化合物可藉由使化合物4與視X而定之適合偶合搭配物(例如化合物5)反應來製備。舉例而言,化合物5在反應流程I中顯示為經由X連接之經取代之苯基。或者,化合物5可為芳基-醇、芳基-硫基、芳基-酸酯、芳基-錫酸酯、雜芳基-醇、芳基-硫醇、雜芳基-硫醇、芳基-
酸酯、芳基-錫烷、烯烴或其他芳基-金屬或雜芳基-金屬及其類似者。偶合搭配物亦可經取代。此反應可在適合酸或鹼條件下,在過渡金屬(諸如鈀)存在或不存在下,在環境溫度下或在熱或微波條件下進行。可使用其他鹵素或適合活化基團(例如三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯及九氟丁磺酸酯)代替Br用於此等轉化。
或者,可將偶合搭配物逆轉且化合物2可衍生為錫烷、酸酯、有機鋅、有機鋰、有機鎂、有機矽、有機銅酸鹽且與適合芳基-鹵化物、雜芳基-鹵化物、烯烴或適合反應性官能基(例如三氟甲磺酸酯、甲磺酸酯、甲苯磺酸酯及九氟丁磺酸酯)及其類似者偶合。
此等反應可以所述順序或以逆向順序,在多種溶劑、溫度、壓力下且在適合氛圍下進行。反應可在酸、鹼及/或過渡金屬條件下進行。
式I化合物之合成之詳細實例可見於下文實例中。
本發明化合物可藉由使該化合物之游離鹼形式與醫藥學上可接受之無機酸或有機酸反應而製備成醫藥學上可接受之酸加成鹽。或者,本發明化合物之醫藥學上可接受之鹼加成鹽可藉由使該化合物之游離酸形式與醫藥學上可接受之無機鹼或有機鹼反應而製備。
亦可藉由附加適當官能基將式I化合物改質以增強選擇性生物特性。此類改質在此項技術中已知且包括增加滲透至給定生物系統(例如血液、淋巴系統、中樞神經系統、睪丸)中、增加生物可用性、增加溶解性以允許非經腸投與(例如注射、輸注)、改變代謝及/或改變分泌速率之彼等改質。此類型改質之實例包括(但不限於)例如用聚乙二醇酯化、用特戊醯基氧基或脂肪酸取代基衍生、轉化成胺基甲酸酯、芳環羥基化及在芳環中雜原子取代。在提及式I化合物及/或其N-氧化物、互變異構體及/或(較佳醫藥學上可接受之)鹽之任何情況下,此包含該等改質式,同時較佳意謂式I之分子、其N-氧化物、其互變異構體及/
或其鹽。
或者,可使用起始物質或中間物之鹽來製備本發明化合物之鹽形式。鑒於呈游離形式之新穎式I化合物與呈其鹽(包括可例如在純化或鑑別新穎化合物中用作中間物之彼等鹽)形式之式I化合物之間的緊密關係,將上文及下文中對式I化合物之任何提及應理解為係指呈游離形式之化合物及/或適當及有利時亦指其一或多種鹽,以及指一或多種溶劑合物,例如水合物。
較佳用有機酸或無機酸自具有鹼性氮原子之式I化合物形成鹽,例如酸加成鹽,尤其醫藥學上可接受之鹽。適合無機酸為例如氫鹵酸(諸如鹽酸)、硫酸或磷酸。適合有機酸為例如羧酸、膦酸、磺酸或胺磺酸,例如乙酸、丙酸、辛酸、癸酸、十二酸、乙醇酸、乳酸、反丁烯二酸、丁二酸、丙二酸、己二酸、庚二酸、辛二酸、壬二酸、蘋果酸、酒石酸、檸檬酸、胺基酸(諸如麩胺酸或天冬胺酸)、順丁烯二酸、羥基順丁烯二酸、甲基順丁烯二酸、環己羧酸、金剛烷羧酸、苯甲酸、水楊酸、4-胺基水楊酸、鄰苯二甲酸、苯乙酸、杏仁酸、肉桂酸、甲磺酸或乙磺酸、2-羥基乙磺酸、乙-1,2-二磺酸、苯磺酸、4-甲苯磺酸、2-萘磺酸、1,5-萘-二磺酸、2-甲基苯磺酸或3-甲基苯磺酸、甲基硫酸、乙基硫酸、十二基硫酸、N-環己基胺磺酸、N-甲基胺磺酸、N-乙基胺磺酸或N-丙基胺磺酸或其他有機質子酸(諸如抗壞血酸)。
出於分離或純化目的,亦有可能使用醫藥學上不可接受之鹽,例如苦味酸鹽或過氯酸鹽。就治療用途而言,僅使用醫藥學上可接受之鹽或游離化合物(適當時呈醫藥製劑形式),且因此醫藥學上可接受之鹽或游離化合物較佳。
本發明化合物之游離酸或游離鹼形式可分別自對應鹼加成鹽或酸加成鹽形式製備。舉例而言,可藉由用適合鹼(例如氫氧化銨溶液、氫氧化鈉及其類似物)處理將呈酸加成鹽形式之本發明化合物轉化成
對應游離鹼。可藉由用適合酸(例如鹽酸等)處理將呈鹼加成鹽形式之本發明化合物轉化成對應游離酸。
呈非氧化形式之本發明化合物可藉由在0℃至80℃下於適合惰性有機溶劑(例如乙腈、乙醇、二噁烷水溶液或其類似物)中,用還原劑(例如硫、二氧化硫、三苯膦、硼氫化鋰、硼氫化鈉、三氯化磷、三溴化物或其類似物)處理,自本發明化合物之N-氧化物製備。
本發明化合物之前藥衍生物可藉由一般技術者已知之方法來製備(例如關於其他細節,參見Saulnier等人,(1994),Bioorganic and Medicinal Chemistry Letters,第4卷,第1985頁)。舉例而言,可藉由使未衍生之本發明化合物與適合之胺基甲醯化試劑(例如,1,1-醯氧基烷基氯甲酸酯、碳酸對硝基苯酯或其類似物)反應來製備適當前藥。
本發明化合物之受保護衍生物可藉由一般技術者已知之方式製得。適用於保護基產生及其移除之技術之詳細描述可見於T.W.Greene,「Protecting Groups in Organic Chemistry」,第3版,John Wiley and Sons,Inc.,1999。
可在本發明方法期間便利地將本發明化合物製備為或形成為溶劑合物(例如,水合物)。可藉由使用諸如二氧雜環己烯、四氫呋喃或甲醇之有機溶劑,自水性/有機溶劑混合物再結晶來便利地製備本發明化合物之水合物。
可藉由使本發明化合物之外消旋混合物與光活性解析劑反應形成一對非對應異構化合物,分離非對映異構體且回收光學純對映異構體來將本發明化合物製備為其個別立體異構體。雖然可使用本發明化合物之共價非對映異構衍生物來進行對映異構體之解析,但可解離錯合物較佳(例如,結晶非對映異構鹽)。非對映異構體具有不同物理特性(例如熔點、沸點、溶解性、反應性等)且可易於藉由利用此等不同點分離。可藉由層析,或較佳藉由基於溶解性差異之分離/解析技術來
分離非對映異構體隨後藉由不會產生外消旋作用之任何實踐方式回收光學純對映異構體以及解析劑。適用於將化合物之立體異構體自其外消旋混合物解析之技術之較詳細描述可見於Jean Jacques,Andre Collet,Samuel H.Wilen,「Enantiomers,Racemates and Resolutions」,John Wiley And Sons,Inc.,1981。
總之,式I化合物可藉由涉及以下之方法製備:(a)反應流程I;及(b)視情況將本發明化合物轉化成醫藥學上可接受之鹽;(c)視情況將本發明化合物之鹽形式轉化成非鹽形式;(d)視情況將本發明化合物之非氧化形式轉化成醫藥學上可接受之N-氧化物;(e)視情況將本發明化合物之N-氧化物形式轉化成非氧化形式;(f)視情況將本發明化合物之個別異構體自異構體混合物解析;(g)視情況將未衍生之本發明化合物轉化成醫藥學上可接受之前藥衍生物;及(h)視情況將本發明化合物之前藥衍生物轉化成其未衍生形式。
在未具體描述起始物質之產生之情況下,化合物為已知的,或可類似於此項技術中已知之方法或如下文實例中所揭示來製備。
熟習此項技術者應瞭解以上轉化僅代表本發明化合物之製備方法,且可類似地使用其他熟知方法。
以下實例及中間物用以說明本發明而非限制其範疇。實例中使用之一些縮寫為如下:乙酸(AcOH);三乙胺(TEA);四氫呋喃(THF);水溶液(aq.);氛圍(atm.);2,2'-雙二苯基磷烷基-[1,1']聯萘基(BINAP);4-二甲胺基吡啶(DMAP);第三丁氧基羰基(Boc);1,1-羰基二咪唑(CDI);二碳酸二第三丁酯(BOC2O);六氟磷酸苯并三唑-1-基-氧-參-(二甲胺
基)-鏻(BOP);二氯甲烷(DCM);乙醚(Et2O);對甲苯磺酸(PTSA);乙酸乙酯(EtOAc);乙醇(EtOH);雙(三甲基矽烷基)胺基鋰(LHMDS);偶氮二甲酸二異丙酯(DIAD);N,N-二異丙基-乙胺(DIEA或DIPEA);N,N-二甲基甲醯胺(DMF);二甲亞碸(DMSO);二苯基磷醯基疊氮化物(DPPA);小時(h);六氟磷酸2-(1H-7-氮雜苯并三唑-1-基)-1,1,3,3-四甲(HATU);高效液相層析(HPLC);氫化鋰鋁(LAH);液相層析-質譜分析聯用(LCMS);二異丙基胺基鋰(LDA);甲醇(MeOH);毫升(mL);分鐘(min);微波(MW);正丁基鋰(n-BuLi);1,1-雙(二苯膦基)-二茂鐵二氯鈀(II)(PdCl2(dppf));參(二苯亞甲基丙酮)二鈀(0)(Pd2(dba)3);二氯雙(三苯膦)鈀(II)(PdCl2(PPh3)2);室溫(RT);三氟乙酸(TFA);四氫呋喃(THF);薄層層析法(TLC);滯留時間(tR);及4,5-雙(二苯膦基)-9,9-二甲基二苯并哌喃(Xantophos)。
步驟a:向3-溴-2-(三氟甲基)吡啶(1.0g,4.42mmol)、XantPhos(256mg,0.442mmol)、Pd2(dba)3(203mg,0.221mmol)於二噁烷(12mL)中之溶液中添加(在RT下且在N2下)2-乙基己基-3-巰基丙酸酯(1.1mL,4.87mmol),隨後添加DIPEA(1.55mL,8.85mmol)。將所得溶液於微波反應器中在110℃下攪拌1h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用EtOAc(25mL)洗滌。濃縮經合併之濾液且藉由矽膠層析(0至30%梯度之EtOAc/庚烷)純化所得殘餘物,得到3-((2-(三氟甲基)吡啶-3-基)硫基)丙酸2-乙基己酯(1.41g,3.88mmol)。MS m/z 364.0(M+H)+。
步驟b:在-78℃下且在N2下向3-((2-(三氟甲基)吡啶-3-基)硫基)丙酸2-乙基己酯(1.0g,2.75mmol)於THF(8mL)中之溶液中添加第三丁醇鉀(THF中1M,8.25mL,8.25mmol)。在-78℃下劇烈攪拌20min之後,將反應物用K2CO3水溶液(2M,500μL)淬滅且在減壓下移除揮發物。將所得殘餘物倒入含有K2CO3水溶液(2M,30mL)之分液漏斗中且將其用Et2O(2×20mL)萃取。將水相用6M HCl酸化直至pH 4且將所得混濁懸浮液用CHCl3:IPA(9:1;3×20mL)萃取,得到2-(三氟甲基)吡啶-3-硫醇(380mg,2.12mmol)。MS m/z 180.0(M+H)+。
步驟c:向2-(三氟甲基)吡啶-3-硫醇(285mg,1.591mmol)、3-溴-6-氯吡嗪-2-胺(414mg,1.988mmol)、XantPhos(101mg,0.175mmol)及Pd2(dba)3(72.8mg,0.08mmol)於二噁烷(2mL)中之溶液中添加(在RT下且在N2下)DIPEA(556μL,3.18mmol)。將所得溶液於微波反應器中在130℃下攪拌1.5h。在冷卻至RT之後,將反應物用EtOAc稀釋且將其經由矽藻土墊過濾,隨後用EtOAc(25mL)洗滌。濃縮經合併之濾液且藉由矽膠層析(0至30%梯度之EtOAc/庚烷)純化所得殘餘物,得到6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(1.41g,3.88mmol)。1H NMR(400MHz,氯仿-d)δ ppm 8.64(dd,J=4.55,1.26Hz,1 H),7.90(s,1 H),7.82(dd,J=8.08,0.76Hz,1 H),7.46(dd,J=8.08,4.80Hz,1 H);19F NMR(376MHz,氯仿-d)δ ppm -64.34(s,1 F)。MS m/z 307.1(M+H)+。
將3-溴-6-氯吡嗪-2-胺(1.2g,5.76mmol)、(2,3-二氯苯基)酸(1.1
g,5.76mmol)、磷酸鉀(3.67g,17.27mmol)及PdCl2(dppf).DCM加合物(235mg,0.288mmol)於MeCN:H2O(9:1,15mL,脫氣)中之懸浮液於微波反應器中在120℃下攪拌4h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用EtOAc(25mL)洗滌。濃縮經合併之濾液且藉由矽膠層析(0至30%梯度之EtOAc/庚烷)純化所得殘餘物,得到6-(4-胺基-4-甲基哌啶-1-基)-3-(2,3-二氯苯基)吡嗪-2-胺(633mg,2.306mmol)。MS m/z 276.4(M+H)+。
將3-溴-6-氯吡嗪-2-胺(5.0g,23.99mmol)、2,3-二氯苯硫酚(6.44g,36.0mmol)、碘化銅(I)(9l4mg,4.80mmol)、磷酸鉀(10.18g,48.0mmol)及1,10-啡啉(1.73mg,9.59mmol)於二噁烷(50mL,脫氣)中之混合物在85℃下攪拌16h。在冷卻至RT之後,將反應物用EtOAc稀釋且將其經由矽藻土墊過濾,隨後用EtOAc(50mL)洗滌。在減壓下移除揮發物且藉由矽膠層析(0至25%梯度之DCM/甲苯)純化所得殘餘物,得到6-氯-3-((2,3-二氯苯基)硫基)吡嗪-2-胺(3.7g,12.07mmol)。MS m/z 306.0(M+H)+。
步驟a:將1-胺基-7-氮雜螺[3.5]壬烷-7-甲酸第三丁酯(250mg,1.04mmol)、鄰苯二甲酸酐(193mg,1.3mmol)、活化分子篩(3埃,250mg)及DIPEA(545μL,3.12mmol)於甲苯(4mL)中之懸浮液在105℃下攪拌16h。在冷卻至RT之後,經由矽藻土墊過濾混合物,隨後用EtOAc(10mL)洗滌。在減壓下移除揮發物且藉由矽膠層析(5%至40%梯度之EtOAc/庚烷)純化所得殘餘物,得到1-(1,3-二側氧基異吲哚啉-2-基)-7-氮雜螺[3.5]壬烷-7-甲酸第三丁酯(233mg,0.629mmol)。MS m/z 370.4(M+H)+。
步驟b:將1-(1,3-二側氧基異吲哚啉-2-基)-7-氮雜螺[3.5]壬烷-7-甲酸第三丁酯(233mg,0.629mmol)及HCl(二噁烷中4M,800μL,3.21mmol)於二噁烷(5mL)中之溶液在RT下攪拌16h。在旋轉蒸發器上移除揮發物,得到標題化合物之鹽酸鹽(195mg,0.636mmol)。MS m/z 270.3(M+H)+。
步驟c:在以下條件下進行對掌性SFC純化;管柱:纖維素LUX-2 21×250mm,流動速率:75g/min,移動相:含50% MeOH及10mM NH4OH之CO2,偵測:220nm UV以獲得兩個峰值Rt(P1)=3.6min(對映異構體R);Rt(P2)=7.4min(對映異構體S)。
步驟a:將8-(第三丁氧基羰基)-1-硫雜-8-氮雜螺[4.5]癸烷-4-甲酸1,1-二氧化物(自4-側氧基哌啶-1-甲酸第三丁酯在如Carreira等人,Org Lett.,2011,13,6134-6136中所描述之4個步驟中製備;2.00g,6.00mmol)、二苯基磷醯基疊氮化物(2.0g,7.26mmol)及Et3N(1.0mL,7.26
mmol)於甲苯(37mL)中之溶液在115℃下攪拌1.5h。添加苯甲醇(1.50mL,14.52mmol)且將所得混合物在100℃下攪拌16h。在冷卻至RT之後,將反應混合物倒入含有NaHCO3飽和水溶液(30mL)之分液漏斗中且將其用EtOAc(3×20mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(10%至90%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之4-(((苯甲氧基)羰基)胺基)-1-硫雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯1,1-二氧化物(1.57g,3.58mmol)。MS m/z 339.4(M+H)+。
步驟b:將4-(((苯甲氧基)羰基)胺基)-1-硫雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯1,1-二氧化物(570mg,1.30mmol)及Pd/C(10%/木炭,138mg)於THF(8mL)中之懸浮液在H2氛圍下劇烈攪拌16h。將反應物經由矽藻土塞過濾,隨後用EtOAc(20mL)洗滌。在減壓下移除揮發物,得到4-胺基-1-硫雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯1,1-二氧化物,其不經進一步純化即用於下一步驟。
步驟c:將4-胺基-1-硫雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯1,1-二氧化物(415mg,1.363mmol)、鄰苯二甲酸酐(252mg,1.704mmol)及活化分子篩(3埃,500mg)於甲苯(7mL)中之懸浮液在115℃下劇烈攪拌16h。在冷卻至RT之後,經由矽藻土墊過濾混合物,隨後用EtOAc(10mL)洗滌,且在減壓下移除揮發物。藉由矽膠層析(0至10%梯度之MeOH/DCM)純化所得殘餘物,得到呈白色泡沫狀之4-(1,3-二側氧基異吲哚啉-2-基)-1-硫雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯1,1-二氧化物(385mg,0.886mmol)。MS m/z 433.1(M-H)-。
步驟d:將4-(1,3-二側氧基異吲哚啉-2-基)-1-硫雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯1,1-二氧化物(385mg,0.886mmol)及HCl(二噁烷中4M,2.22mL,8.86mmol)於二噁烷(4mL)中之溶液在RT下攪拌16h。將混合物用二噁烷(20mL)稀釋且過濾,得到呈白色固體狀之
2-(1,1-二氧離子基-1-硫雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮(鹽酸鹽,328mg,0.884mmol)。MS m/z 335.4(M+H)+。
步驟a:將1-側氧基-7-氮雜螺[3.5]壬烷-7-甲酸第三丁酯(5.24g,21.9mmol)、異丙醇鈦(IV)(16.2mL,54.7mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(3.45g,28.5mmol)於THF(99mL)中之溶液在65℃下攪拌12h。在冷卻至-78℃之後,添加MeOH(9.9mL),隨後添加硼氫化鋰(1.43g,65.7mmol)。將所得混合物在-78℃下攪拌3h及在RT下攪拌1h。緩慢添加MeOH以淬滅過量硼氫化物,隨後添加鹽水。將所得混合物攪拌15min且隨後經由矽藻土過濾。用EtOAc(3×20mL)萃取水性混合物。將有機相經MgSO4乾燥,過濾,且在減壓下移除揮發物。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之1-((R)-1,1-二甲基乙基亞磺醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸(S)-第三丁酯(4.79g.13.90mmol)。MS m/z 345.3(M+H)+。
步驟b:將1-((R)-1,1-二甲基乙基亞磺醯胺基)-7-氮雜螺[3.5]壬烷-7-甲酸(S)-第三丁酯(0.4g,1.16mmol)及TFA(450μL,5.81mmol)於DCM(3.5mL)中之溶液在40℃下攪拌30min。添加Na2CO3飽和水溶液直至pH 11且用DCM(3×15mL)萃取水性混合物。將合併之有機相用鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下移除揮發物,得到呈白色固體狀之(R)-2-甲基-N-((S)-7-氮雜螺[3.5]壬-1-基)丙烷-2-亞磺醯胺(237mg,0.97mmol)。MS m/z 245.5(M+H)+。
步驟a:向1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(1.8g,7.11mmol)及(4-甲氧基苯基)甲胺(1.07g,7.82mmol)於DCE(7mL)中之溶液中逐份添加氰基硼氫化鈉(2.23g,35.5mmol)且在RT下攪拌65h。將混合物用碳酸氫鈉飽和水溶液(10mL)稀釋且用EtOAc(3×20mL)萃取。將合併之有機相用鹽水洗滌且濃縮。藉由矽膠層析(0至2%梯度之MeOH/DCM,0.25%經改質之Et3N,隨後0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈無色蠟狀之1-((4-甲氧基苯甲基)胺基)-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(1.1g,2.94mmol)。MS m/z 375.3(M+H)+。
步驟b:將1-((4-甲氧基苯甲基)胺基)-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(1.1g,2.94mmol)及TFA(2mL)於DCM(2mL)中之溶液在0℃下攪拌15min。在減壓下移除揮發物。將所得殘餘物用NaHCO3水溶液(10mL)稀釋且用EtOAc(4×10mL)萃取,得到呈無色油狀物之N-(4-甲氧基苯甲基)-8-氮雜螺[4.5]癸-1-胺(0.8g,2.92mmol)。MS m/z 275.2(M+H)+。
在以上程序之後,以7-側氧基-3-氮雜螺[5.5]十一烷-3-甲酸第三丁酯為起始物質,獲得N-(4-甲氧基苯甲基)-3-氮雜螺[5.5]十一-7-胺。
步驟a:向1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(1.15g,4.54mmol)及(R)-1-(4-甲氧基苯基)乙胺(961mg,6.36mmol)於DCE(3mL)中之溶液中逐份添加氰基硼氫化鈉且在RT下攪拌16h。將混合物用碳酸氫鈉飽和水溶液(5mL)稀釋且用EtOAc(3×10mL)萃取。將合併之有機相用鹽水洗滌且濃縮。藉由矽膠層析(0至20%梯度之EtOAc/庚烷)純化含有9:1非對映異構體混合物之所得殘餘物,得到純的1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(主要非對映異構體;431mg,1.11mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 7.18-7.24(m,2 H),6.81-6.86(m,2 H),3.76(d,J=13.64Hz,1 H),3.72(s,3 H),3.64-3.70(m,2 H),2.65-2.92(m,2 H),2.05-2.14(m,1 H),1.80-1.91(m,1 H),1.65-1.75(m,1 H),1.42-1.60(m,4 H),1.40(s,9 H),1.28-1.35(m,1 H),1.20(d,J=6.57Hz,3 H),1.09-1.17(m,2 H),0.80(d,J=11.37Hz,1 H)。MS m/z 389.6(M+H)+。
步驟b:向1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(主要非對映異構體;431mg,1.11mmol)於DCM(2mL)中之溶液中添加TFA(2mL)且在RT下攪拌10min。藉由進一步添加DCM將反應物濃縮,隨後用NaHCO3飽和水溶液稀釋且用DCM(3×20mL)萃取。將有機物用鹽水洗滌,經Na2SO4乾燥,過濾且濃縮,得到N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺。1H NMR(400MHz,甲醇-d 4)δ 7.25(d,J=8.6Hz,2 H),6.87(d,J=8.7Hz,2 H),
3.85-3.78(m,1 H),3.78(s,3 H),3.35(m,1 H),3.28(m,1 H),3.03(m,2 H),2.63(dd,J=9.6,7.3Hz,1 H),2.06-1.85(m,2 H),1.83-1.69(m,2 H),1.62(m,1 H),1.54-1.38(m,4 H),1.33(d,J=6.6Hz,3 H),1.31-1.23(m,1 H)。MS m/z 289.5(M+H)+。
步驟a:向4-側氧基-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(自4-側氧基哌啶-1-甲酸第三丁酯在如Carreira等人,Org Lett.,2013,15,4766-4769中所描述之3個步驟中製備;200mg,0.78mmol)及(R)-1-(4-甲氧基苯基)乙胺(474mg,3.13mmol)於DCE(1mL)中之溶液中逐份添加氰基硼氫化鈉(393mg,3.13mmol)。將所得反應物在RT下攪拌16h。添加硼氫化鋰(34mg,1.6mmol)且將混合物在RT下攪拌30min。將混合物用MeOH(2mL)稀釋且在減壓下移除揮發物(兩次)。添加NaHCO3飽和水溶液(5mL)且用DCM(3×20mL)萃取混合物。將合併之有機相經Na2SO4乾燥,過濾,且在減壓下移除揮發物。藉由矽膠層析(0至40%梯度之EtOAc/庚烷)純化所得9:1非對映異構體混合物,得到非對映異構純之4-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(65mg,0.17mmol)。主要非對映異構體:1H NMR(400MHz,CDCl3)δ ppm 7.15(d,J=8.6Hz,2 H),6.79(d,J=8.6Hz,2 H),3.96-3.76(m,2 H),3.77-3.66(m,5 H),3.60(t,J=8.1Hz,1 H),2.98(m,2 H),2.76(t,J=7.8Hz,1 H),1.95(m,1 H),1.67-1.41(m,4 H),1.40(s,9 H),1.33(d,J=3.1Hz,1 H),1.21(d,J=6.5Hz,3 H),1.08-0.92(m,1
H)。MS m/z 391.6(M+H)+。
步驟b:將4-(((R)-1-(4-甲氧基苯基)乙基)胺基)-1-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(主要非對映異構體,65mg,0.17mmol)及TFA(2mL)於DCM(2mL)中之溶液在RT下攪拌10min。在減壓下移除揮發物,將其用NaHCO3飽和水溶液(5mL)稀釋,且用DCM(3×20mL)萃取。將合併之有機相用鹽水洗滌,經Na2SO4乾燥,過濾且在減壓下移除揮發物,得到N-((R)-1-(4-甲氧基苯基)乙基)-1-氧雜-8-氮雜螺[4.5]癸-4-胺(40mg,0.13mmol),其不經進一步純化即使用。MS m/z 291.5(M+H)+。
步驟a:藉由如Marie等人,Molecules,2012,17,10683-10707中所描述之程序a將市售2,3-二氯-4-碘吡啶轉化成3-氯-4-碘吡啶-2-胺。
步驟b:向3-胺基-5-氯吡嗪-2-硫醇(100mg,0.619mmol)、3-氯-4-碘吡啶-2-胺(315mg,1.238mmol)、XantPhos(35.8mg,0.062mmol)及Pd2(dba)3(28.3mg,0.03mmol)於二噁烷(3mL)中之溶液中添加(在RT下且在N2下)DIPEA(324μL,1.856mmol)。將所得溶液於微波反應器中在100℃下攪拌2.5h。在冷卻至RT之後,將反應物用EtOAc稀釋且將其經由矽藻土墊過濾,隨後用EtOAc(10mL)洗滌。濃縮經合併之濾液且藉由矽膠層析(0至5%梯度之MeOH/DCM)純化所得殘餘物,得到3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(1.41g,3.88mmol)。1H
NMR(400MHz,甲醇-d 4)δ ppm 7.88(s,1 H),7.68(d,J=5.56Hz,1 H),6.06(d,J=5.56Hz,1 H),1.35-1.43(m,2 H)。MS m/z 288.2(M+H)+。
步驟a:將3-溴-6-氯吡嗪-2-胺(4.95g,23.74mmol)於二噁烷(119mL)中之溶液用氮氣充氣10min。隨後添加3-巰基丙酸2-乙基己酯(3.79mL,24.92mmol)、Xantphos(1.37g,2.37mmol)、Pd2(dba)3(1.08g,1.19mmol)及DIPEA(8.29mL,47.5mmol)。將所得混合物在105℃下攪拌24h且將反應混合物經由矽藻土過濾且濃縮。藉由矽膠層析(0-40%梯度之EtOAc/庚烷)純化粗產物,得到呈黃色油狀物之3-((3-胺基-5-氯吡嗪-2-基)硫基)丙酸2-乙基己酯(6.24g,18.04mmol)。1H NMR(400MHz,氯仿-d)δ ppm 7.82(s,1 H),4.93(br.s.,2 H),4.14-3.96(m,2 H),3.47(t,J=6.9Hz,2 H),2.78(t,J=6.9Hz,2 H),1.67-1.51(m,1 H),1.44-1.20(m,8 H),0.90(t,J=7.4Hz,6 H)。MS m/z 346.0(M+H)+。
步驟b:在-78℃下向3-((3-胺基-5-氯吡嗪-2-基)硫基)丙酸2-乙基己酯(2.3g,6.65mmol)於THF(33mL)中之溶液中添加第三丁醇鉀(THF中1M,19.95mL,19.95mmol)且將所得混合物在-78℃下攪拌1h。添加MeOH(20mL)且濃縮所得混合物。將粗產物溶解於MeOH中,過濾且藉由HPLC(梯度溶離5-20%,乙腈/水,0.1% TFA改質劑)純化,得到呈黃色固體狀之3-胺基-5-氯吡嗪-2-硫醇(TFA鹽:1.3g,4.72mmol)。MS m/z 162.0(M+H)+。
將3-胺基-5-氯吡嗪-2-硫醇(TFA鹽:0.158g,0.978mmol)於二噁烷(4.9mL)中之溶液用氮氣充氣10min。隨後添加3-氯-4-碘吡啶(0.468g,1.955mmol)、Xantphos(0.057g,0.098mmol)、Pd2(dba)3(0.045g,0.049mmol)及DIPEA(0.512mL,2.93mmol)。將所得混合物在105℃下攪拌10h,經由矽藻土過濾且濃縮。藉由矽膠層析(0-40%梯度之EtOAc/庚烷;庚烷含有2% Et3N)純化粗產物,得到呈白色固體狀之6-氯-3-((3-氯吡啶-4-基)硫基)吡嗪-2-胺(75mg,0.274mmol)。1H NMR(400MHz,氯仿-d)δ ppm 8.46(s,1 H),8.22(d,J=5.3Hz,1 H),7.96(s,1 H),6.68(d,J=5.3Hz,1 H),5.17(br.s.,2 H)。MS m/z 273.0(M+H)+。
將3-胺基-5-氯吡嗪-2-硫醇(TFA鹽:0.2g,1.238mmol)於二噁烷(6.2mL)中之溶液用氮氣充氣10min。隨後添加2-氯-3-碘吡啶(0.593g,2.475mmol)、Xantphos(0.072g,0.124mmol)、Pd2(dba)3(0.057g,0.062mmol)及DIPEA(0.65mL,3.71mmol)。將所得混合物在105℃下攪拌10h,經由矽藻土過濾且濃縮。藉由矽膠層析(0-40%梯度之EtOAc/庚烷,含有2% Et3N)純化粗產物,得到呈白色固體狀之6-氯-3-((2-氯吡啶-3-基)硫基)吡嗪-2-胺(95mg,0.348mmol)。1H NMR(400MHz,氯仿-d)δ ppm 8.28-8.38(m,1 H),7.91(s,1 H),7.51-7.59(m,1 H),7.22(dd,J=7.9,4.6Hz,1 H),5.25(br.s.,2 H)。MS m/z 273.0(M+H)+。
將3-胺基-5-氯吡嗪-2-硫醇(TFA鹽:0.50g,1.814mmol)於二噁烷(90mL)中之溶液用氮氣脫氣10min。隨後添加2,3-二氯-4-碘吡啶(0.0.99g,3.63mmol)、Xantphos(0.105g,0.181mmol)、Pd2(dba)3(0.083g,0.091mmol)及DIPEA(0.95mL,5.44mmol)。將所得混合物在105℃下攪拌10h,經由矽藻土過濾且濃縮。藉由矽膠層析(0-10%梯度之EtOAc/DCM)純化粗產物。1H NMR(400MHz,DMSO-d 6)δ ppm 8.13(d,J=5.3Hz,1 H),7.95(s,1 H),7.30(br.s,2 H),6.83(d,J=5.3Hz,1 H)。MS m/z 306.9(M+H)+。
將3-胺基-5-氯吡嗪-2-硫醇(TFA鹽:50mg,0.181mmol)於二噁烷(1.8mL)中之溶液用氮氣充氣10min。隨後添加3-氯-2-氟-4-碘吡啶(0.140g,0.544mmol)、Xantphos(11mg,0.018mmol)、Pd2(dba)3(8mg,0.009mmol)及DIPEA(95μL,0.544mmol)。將所得混合物在100℃下攪拌10h,經由矽藻土過濾且濃縮。藉由矽膠層析(0至40%梯度之EtOAc/庚烷;庚烷含有2% Et3N)純化粗產物,得到呈白色固體狀之6-氯-3-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-胺(41mg,0.137mmol)。1H NMR(400MHz,氯仿-d)δ ppm 8.06(s,1 H),7.91(d,J=5.3Hz,1 H),6.63(d,J=5.3Hz,1 H),5.30(br.s,2 H)。MS m/z 291.0(M+H)+。
遵循Dirat等人,PCT國際申請案20044078750,2004年9月16日之程序,製備4-羥基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯。1H NMR(400MHz,氯仿-d)δ 4.13(dd,J=10.1,4.6Hz,1 H),4.03(dd,J=4.6,2.0Hz,1 H),3.78-3.71(m,2 H),3.69(d,J=8.6Hz,1 H),3.67-3.58(m,2 H),3.29(m,1 H),3.16(m,1 H),1.78(m,2 H),1.58(m,1 H),1.50(m,2 H),1.47(s,9 H)。來自四個步驟中之哌啶-1,4-二甲酸1-第三丁酯4-乙酯之MS m/z 258.1(M-H)+,隨後在如下兩個步驟中轉化成2-(2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮。
步驟a:向4-羥基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(306mg,1.19mmol)、鄰苯二甲醯亞胺(262mg,1.78mmol)及三苯膦(468mg,1.78mmol)於THF(10mL)中之溶液中添加氮雜二甲酸二異丙酯(0.374mL,1.78mmol)且攪拌16h。濃縮且藉由矽膠層析(0至50%梯度之乙酸乙酯/庚烷)純化,獲得外消旋4-(1,3-二側氧基異吲哚啉-2-基)-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(190mg,0.49mmol)。1H NMR(400MHz,氯仿-d)δ 7.88(dd,J=5.4,3.0Hz,2 H),7.77(dd,J=5.5,3.0Hz,2 H),4.65(dd,J=8.7,5.6Hz,1 H),4.40(dd,J=9.5,5.6Hz,1 H),4.26(t,J=9.0Hz,1 H),4.08(d,J=8.5Hz,1 H),3.98(d,J=8.5Hz,1 H),3.84(m,1 H),3.58(m,1 H),3.20(m,1 H),2.94(m,1 H),1.73(m,2 H),1.56(s,9 H),1.42-1.36(m,2 H)。
步驟b:向外消旋4-(1,3-二側氧基異吲哚啉-2-基)-2-氧雜-8-氮雜螺
[4.5]癸烷-8-甲酸第三丁酯(190mg,0.49mmol)於二氯甲烷(3mL)中之溶液中添加三氟乙酸(1mL)。藉由進一步相繼添加二氯甲烷、乙腈進行濃縮,獲得呈TFA鹽形式之2-(2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮(定量)。MS m/z 287.0(M+H)+。不經進一步表徵即使用。
步驟a:將2-氯-3-氟苯甲腈(3.15g,20.25mmol)、2-甲基丙烷-2-硫醇(2.283mL,20.25mmol)及Cs2CO3(6.598g,20.25mmol)於DMF(100mL)中之混合物在22℃下攪拌48h。將反應混合物用水(200mL)及EtOAc(300mL)稀釋。將EtOAc層用水(3×300mL)、鹽水(3×100mL)洗滌,經Na2SO4乾燥,過濾且濃縮。藉由HPLC(梯度溶離:45%至70%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到3-(第三丁硫基)-2-氯苯甲腈(1.33g,5.89mmol)。MS m/z 226.1(M+H)+。
步驟b:將3-(第三丁硫基)-2-氯苯甲腈(217mg,0.961mmol)及NaOH(1N,2.88mL,2.88mmol)於MeOH(11mL)中之混合物於微波反應器中在90℃下照射35min。在冷卻至RT之後,將反應物濃縮且溶解於MeOH中。過濾出固體且將濾液濃縮至幾乎乾燥且藉由HPLC(梯度溶離:25%至50%乙腈/水,5mM NH4OH改質劑)純化,得到3-(第三丁硫基)-2-氯苯甲醯胺(93.6mg,0.384mmol)。MS m/z 244(M+H)+。
步驟c:將3-(第三丁硫基)-2-氯苯甲醯胺(190mg,0.779mmol)與濃HCl(2.36mL,78mmol)之混合物在85℃下攪拌45min。在冷卻至RT之後,將反應物濃縮至乾燥,產生粗2-氯-3-巰基苯甲醯胺(鹽酸鹽:156
mg,0.651mmol)。MS m/z 188(M+H)+。
使用上述標準程序將2-(2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮TFA鹽與6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(151mg,0.492mmol)偶合。用DCM稀釋且藉由矽膠層析(0至60%梯度之乙酸乙酯/庚烷)純化,獲得2-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮(0.140g,0.178mmol)。MS m/z 557.1(M+H)+。如下進行對掌性SFC純化;管柱:OJ-H21×250mm,流動速率:80g/min,移動相:含45% MeOH及5mM NH4OH之CO2,偵測:觸發質量以獲得單一對映異構體峰值1(P1),Rt:2.77min,MS m/z 557.1(M+H)+,及峰值2(P2),Rt:3.91min,MS m/z 557.2(M+H)+。不經進一步表徵即單獨地對各對映異構體進行鄰苯二甲醯亞胺脫除保護基。
將3-氯-2-氟-4-碘吡啶(0.26g,1.01mmol)及二甲胺(THF中2M,1.5mL,3.03mmol)於DMSO(3.4mL)中之溶液在70℃下攪拌2h。在冷
卻至RT之後,添加水且用EtOAc萃取水性混合物。將合併之有機相用水、鹽水洗滌,用Na2SO4乾燥,過濾且減壓濃縮,得到呈無色油狀物之3-氯-4-碘-N,N-二甲基吡啶-2-胺(0.26g,0.922mmol)。1H NMR(400MHz,氯仿-d)δ ppm 7.75(d,J=5.3Hz,1 H),7.33(d,J=5.0Hz,1 H),3.00(s,6 H)。MS m/z 282.9(M+H)+。
將3-氯-2-氟-4-碘吡啶(150mg,0.571mmol)及NaOMe(MeOH中0.5M,3.4mL,1.71mmol)於DMSO(1.9mL)中之溶液在70℃下攪拌1h。在冷卻至RT之後,添加水且用EtOAc萃取水性混合物。將合併之有機相用水、鹽水洗滌,經Na2SO4乾燥,過濾且在減壓下濃縮,得到呈無色油狀物之3-氯-4-碘-2-甲氧基吡啶(123mg,0.456mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 7.81(d,J=5.3Hz,1 H),7.55(d,J=5.3Hz,1 H),3.92(s,3 H)。MS m/z 269.9(M+H)+。
將3-胺基-5-氯吡嗪-2-硫醇(750mg,4.09mmol)、4-溴-3-(三氟甲基)吡啶(1.63g,5.31mmol)、Xantphos(236mg,0.409mmol)、Pd2(dba)3(187mg,0.204mmol)及DIPEA(2.14mL,12.26mmol)於二噁烷(脫氣,50mL)中之混合物在100℃下攪拌16h。在冷卻至RT之後,反應物經由
矽藻土墊過濾,隨後用EtOAc(25mL)洗滌。在減壓下濃縮經合併之濾液且藉由矽膠層析(0至40%梯度之EtOAc/DCM)純化所得殘餘物,得到呈淡黃色固體狀之6-氯-3-((3-(三氟甲基)吡啶-4-基)硫基)吡嗪-2-胺(722mg,2.35mmol)。MS m/z 307.0(M+H)+。
使用以上程序或對以上程序之修改,使用對應碘-吡啶基或溴-吡啶基及硫醇鹽合成以下化合物。
將3-胺基-5-氯吡嗪-2-硫醇(100mg,0.545mmol)、3,4-二氯噠嗪(81mg,0.545mmol)及DIPEA(0.142mL,0.817mmol)於MeCN(5.5mL)中之混合物在50℃下攪拌12h。在冷卻至RT之後,藉由真空過濾收集沈澱物,得到呈棕色固體狀之6-氯-3-((3-氯噠嗪-4-基)硫基)吡嗪-2-胺(101mg,0.368mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 8.90(d,J=5.4Hz,1 H),7.95(s,1 H),7.31(s,2 H),7.15(d,J=5.3Hz,1 H)。MS m/z 274.1(M+H)+。
步驟a:將4-甲醯基哌啶-1-甲酸第三丁酯(35.0g,164mmol)、第三丁醇鋰(15.77g,197mmol)及烯丙基溴(11.54mL,189mmol)於DMF(328mL)中之混合物在0℃下攪拌1h。將混合物倒入含有NH4Cl飽和水溶液:H2O(1:1,500mL)之分液漏斗中且將其用Et2O(5×50mL)萃取。將合併之有機相經MgSO4乾燥,過濾,且在減壓下移除揮發物。藉由矽膠層析(0至25%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈無色油狀物之4-烯丙基-4-甲醯基哌啶-1-甲酸第三丁酯(24g,95mmol)。1H NMR(400MHz,氯仿-d)δ ppm 9.52(s,1 H),5.53-5.76(m,1 H),4.96-5.19(m,2 H),3.80(br.s.,2 H),2.97(t,J=11.49Hz,2 H),2.26(d,J=7.33Hz,2 H),1.95(dt,J=13.71,3.13Hz,2 H),1.38-1.58(m,11 H)。
步驟b:向4-烯丙基-4-甲醯基哌啶-1-甲酸第三丁酯(24g,95mmol)於THF(300mL)中之溶液中添加(在-78℃下且在N2下)溴化乙烯基鎂(THF中1M,118mL,118mmol)。在1h內將所得溶液緩慢升溫至RT。將混合物倒入含有NH4Cl飽和水溶液(250mL)之分液漏斗中且將其用EtOAc(4×50mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物,得到呈無色油狀物之4-烯丙基-4-(1-羥基烯丙基)哌啶-1-甲酸第三丁酯(26.7g,95mmol)。1H NMR(400MHz,氯仿-d)δ ppm 9.52(s,1 H),5.56-5.75(m,1 H),5.05-5.18(m,2 H),3.80(br.s.,2 H),2.97(t,J=11.49Hz,2 H),2.26(d,J=7.33Hz,2 H),1.96(dt,J=13.83,3.06Hz,2 H),1.49-1.60(m,2 H),1.41-1.49(m,9 H)。此化合物不經進一步純化即用於下一步驟。
步驟c:將4-烯丙基-4-(1-羥基烯丙基)哌啶-1-甲酸第三丁酯(26.7g,95mmol)及戴斯-馬丁高碘烷(Dess-Martin periodinane)(44.3g,105mmol)於DCM(380mL)中之混合物在RT下攪拌1h。將混合物倒入含有NaHCO3飽和水溶液:Na2SO3(1:1,300mL)之分液漏斗中且將其用DCM(4×50mL)萃取。將合併之有機相經MgSO4乾燥,過濾,且在減壓下移除揮發物,得到白色固體。將此固體懸浮於庚烷(250mL)中且音波處理5min。經由矽藻土墊過濾白色懸浮液且在減壓下移除揮發物,得到呈黃色油狀物之4-丙烯醯基-4-烯丙基哌啶-1-甲酸第三丁酯(26.5g,95mmol)。1H NMR(400MHz,氯仿-d)δ ppm 6.81(dd,J=16.93,10.36Hz,1 H),6.40(dd,J=16.80,1.89Hz,1 H),5.71(dd,J=10.36,2.02Hz,1 H),5.46-5.66(m,1 H),4.91-5.14(m,2 H),3.78(br.s.,2 H),2.96(br.s.,2 H),2.25-2.39(m,2 H),1.97-2.15(m,2 H),1.37-1.57(m,11 H)。此化合物不經進一步純化即用於下一步驟。
步驟d:向4-丙烯醯基-4-烯丙基哌啶-1-甲酸第三丁酯(26.5g,95mmol)於甲苯(脫氣,850mL)中之溶液中添加含格拉布斯II催化劑(Grubbs II catalyst)(2.02g,2.38mmol)之甲苯(脫氣,100mL)。將所得混合物在85℃下攪拌45min。在減壓下移除溶劑且藉由矽膠層析(0至40%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈棕色固體狀之1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(20.76g,83mmol)。將此化合物及DDQ(565mg,2.49mmol)於甲苯(540mL)中之溶液在RT下攪拌15min。經由矽藻土墊過濾所得亮紅色溶液。添加木炭(200g)且將所得懸浮液在RT下攪拌2h。經由矽藻土墊過濾混合物且在減壓下移除揮發物。藉由矽膠層析(0至40%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(15.6g,62.3mmol)。1H NMR(400MHz,氯仿-d)δ ppm 7.63-7.74(m,1 H),6.20(dt,J=5.81,2.15Hz,1 H),3.99-4.25(m,2 H),2.92(t,J=11.62
Hz,2 H),2.63(s,2 H),1.72-1.86(m,2 H),1.49(s,9 H),1.29(d,J=12.88Hz,2 H)。
步驟a:向1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(4.2g,16.71mmol)及CuI(6.37g,33.4mmol)於Et2O(100mL)中之懸浮液中添加(在0℃下且在N2下)MeLi(THF中1.6M,31.3mL,50.1mmol)。在0℃下攪拌90min之後,將混合物倒入含有NH4Cl飽和水溶液之分液漏斗中且將其用EtOAc(3×15mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈無色油狀物之3-甲基-1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(4.23g,15.82mmol)。1H NMR(400MHz,氯仿-d)δ ppm 3.89-4.00(m,1 H),3.83(d,J=13.39Hz,1 H),3.11(ddd,J=13.64,10.36,3.28Hz,1 H),2.99(ddd,J=13.58,10.42,3.54Hz,1 H),2.47-2.59(m,1 H),2.19-2.36(m,2 H),1.74-1.97(m,2 H),1.50-1.65(m,2 H),1.48(s,9 H),1.33-1.44(m,2 H),1.17(d,J=6.32Hz,3 H)。
步驟b:將3-甲基-1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(502mg,1.878mmol)、乙醇鈦(IV)(1.57mL,7.51mmol)及2-甲基丙烷-2-亞磺醯胺(455mg,3.76mmol)於THF(12.5mL)中之溶液在65℃下攪拌16h。在冷卻至0℃之後,添加MeOH(3mL),隨後添加硼氫化鋰
(123g,5.63mmol)。將所得混合物在0℃下攪拌1h。緩慢添加NH4Cl飽和水溶液以淬滅過量硼氫化物,隨後添加EtOAc(30mL)。將所得混合物劇烈攪拌15min且隨後經由矽藻土墊過濾。在減壓下移除揮發物且藉由矽膠層析(0至75%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之1-(1,1-二甲基乙基亞磺醯胺基)-3-甲基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(463mg,1.243mmol)。
步驟a:將3-甲基-1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(4.23g,15.82mmol)及TFA(17mL)於DCM(80mL)中之混合物在RT下攪拌30min。在減壓下移除揮發物。將所得殘餘物、DIPEA(13.82mL,79mmol)及氯甲酸苯甲酯(3.39mL,23.73mmol)於DCM(80mL)中之混合物在RT下攪拌16h。將混合物倒入含有NH4Cl飽和水溶液之分液漏斗中且將其用DCM(3×25mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至40%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈淡黃色油狀物之3-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸苯甲酯(4.58g,15.20mmol)。MS m/z 302.2(M+H)+。
步驟b:3-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸苯甲酯(4.58g,15.20mmol)藉由對掌性SFC如下進行進一步純化:管柱:IA 21×250mm,流動速率:70g/min,移動相:含45%(9:1 EtOH:MeCN)之CO2,偵測:220nm UV,得到3-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-苯甲酯(2.02g,6.70mmol),Rt:2.0min;及3-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(S)-苯甲酯(2.11g,7.0mmol),Rt:3.6min。
步驟c:將3-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-苯甲酯(2.02g,6.70mmol)、乙醇鈦(IV)(5.62mL,26.8mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(1.625g,13.4mmol)於THF(67mL)中之溶液在65℃下攪拌16h。在冷卻至-78℃之後,添加MeOH(12mL),隨後添加硼氫化鋰(0.438g,20.11mmol)。將所得混合物在-78℃下攪拌16h至RT。緩慢添加NH4Cl飽和水溶液以淬滅過量硼氫化物,隨後添加EtOAc(100mL)。將所得混合物劇烈攪拌15min且隨後經由矽藻土墊過濾。在減壓下移除揮發物且藉由矽膠層析(5%至90%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-苯甲酯(1.94g,4.77mmol)。MS m/z 407.3(M+H)+。
步驟c(自對映異構體):以3-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(S)-苯甲酯為起始物質,遵循相同程序,得到1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3S)-苯甲酯。
步驟a:將CuCl(142mg,1.432mmol)、(S)-TolBINAP(972mg,1.432mmol)及第三丁醇鈉(138mg,1.432mmol)於THF(60mL)中之混合物在RT下攪拌30min。添加含B2pin2(13.34g,52.5mmol)之THF(20mL)且將所得混合物在RT下攪拌10min。添加含1-側氧基-8-氮雜螺[4.5]癸-2-烯-8-甲酸第三丁酯(12.0g,47.7mmol)之THF(50mL),隨後添加MeOH(3.9mL,95mmol)。將所得混合物在RT下攪拌16h。添加H2O(150mL),隨後添加過硼酸鈉(36.7g,239mmol)且將所得混合物在RT下劇烈攪拌1h。將所得綠色懸浮液經由矽藻土墊過濾,倒入含有NaHCO3飽和水溶液:Na2SO3飽和水溶液(1:1,300mL)之分液漏斗中且用EtOAc(4×40mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物,得到3-羥基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-第三丁酯粗產物。此混合物之對映異構測定顯示90% ee(Rt(S):1.59min,Rt(R):1.80min;對掌性SFC;管柱:IA 4.6×100mm,流動速率:70g/min,移動相:含5-55% MeOH之CO2,偵測:220nm UV)。
將3-羥基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-第三丁酯粗產物(理論47.7mmol)、咪唑(4.87g,71.6mmol)及TBSCl(8.99g,59.6mmol)於DMF(120mL)中之混合物在RT下攪拌16h。將反應混合物倒入含有NH4Cl飽和水溶液:H2O(1:1,250mL)之分液漏斗中且將其用Et2O(5×50mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至30%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈無色油狀物之3-((第三丁基二甲基矽烷基)氧基)-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-第三丁酯(13.115g,34.2mmol),其在
靜置之後凝固。
步驟b:將3-((第三丁基二甲基矽烷基)氧基)-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-第三丁酯(8g,20.86mmol)、乙醇鈦(IV)(17.49mL,83.0mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(5.06g,41.7mmol)於THF(100mL)中之溶液在65℃下攪拌16h。在冷卻至-78℃之後,添加MeOH(15mL),隨後添加硼氫化鋰(1.363g,62.6mmol)。將所得混合物在-78℃下攪拌16h。緩慢添加NH4Cl飽和水溶液以淬滅過量硼氫化物,隨後添加EtOAc(100mL)。將所得混合物劇烈攪拌15min且隨後經由矽藻土墊過濾。在減壓下移除揮發物且藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之3-((第三丁基二甲基矽烷基)氧基)-1-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯(5.3g,10.84mmol)。MS m/z 489.3(M+H)+。
步驟a:將3-((第三丁基二甲基矽烷基)氧基)-1-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯(3.84g,7.86mmol)及TBAF(THF中1M;8.64mL,8.64mmol)於THF(40mL)中之混合物在RT下攪拌30min。在減壓下移除揮發物且藉由矽膠層析(0至10%梯度之MeOH/DCM)純化所得殘餘物,得到1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯
(2.94g,7.86mmol)。MS m/z 375.3(M+H)+。
步驟b:向1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-羥基-8-氮雜螺14.5]癸烷-8-甲酸(1R,3R)-第三丁酯(3.0g,8.01mmol)、三苯膦(4.2g,16.02mmol)及異喹啉-1-甲酸(4.16g,24.03mmol)於THF(80mL)中之溶液中添加DIAD(3.1mL,16.02mmol)。將所得混合物在RT下攪拌1h。將反應物用EtOAc(50mL)稀釋,經由矽藻土墊過濾,倒入含有NaHCO3飽和水溶液之分液漏斗中且用EtOAc(3×25mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至4%梯度之MeOH/DCM)純化所得殘餘物,得到呈橙色固體狀之異喹啉-1-甲酸(2S,4R)-8-(第三丁氧基羰基)-4-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸-2-酯(3.65g,6.89mmol)。MS m/z 530.3(M+H)+。
步驟c:將異喹啉-1-甲酸(2S,4R)-8-(第三丁氧基羰基)-4-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸-2-酯(3.65g,6.89mmol)及氫氧化鋰(2.95g,68.9mmol)於THF:H2O(1:1,70mL)中之混合物在RT下攪拌2h。將混合物倒入含有NH4Cl飽和水溶液之分液漏斗中且將其用EtOAc(3×15mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至10%梯度之MeOH/DCM)純化所得殘餘物,得到呈白色固體狀之1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3S)-第三丁酯(2.35g,6.27mmol)。MS m/z 275.2(M+H-Boc)+。
向1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯(200mg,0.534mmol)、三苯膦(280mg,1.068mmol)及異丁酸(146μL,1.602mmol)於THF(5mL)中之溶液中添加DIAD(208μL,1.068mmol)。將所得混合物在RT下攪拌16h。將反應物用EtOAc(50mL)稀釋,經由矽藻土墊過濾,倒入含有NaHCO3飽和水溶液之分液漏斗中且用EtOAc(3×10mL)萃取。將合併之有機相經MgsO4乾燥,過濾,且在減壓下移除揮發物。藉由矽膠層析(0至7%梯度之MeOH/DCM)純化所得殘餘物,得到1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-(異丁醯氧基)-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3S)-第三丁酯(237mg,0.534mmol)。MS m/z 345.3(M+H-Boc)+。
將1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯(142mg,0.378mmol)及NaH(於礦物油中之60%分散液,19mg,0.473mmol)於THF中之混合物在0℃下攪拌20
min。添加碘甲烷(47μL,0.756mmol)且將所得混合物在RT下攪拌4h。在減壓下移除揮發物且藉由HPLC(梯度溶離25-50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到1-((R)-N,2-二甲基丙-2-基亞磺醯胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯(15.0mg,0.039mmol)。MS m/z 289.2(M+H-Boc)+;1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲氧基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯。MS m/z 289.2(M+H-Boc)+;及1-((R)-N,2-二甲基丙-2-基亞磺醯胺基)-3-甲氧基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯。MS m/z 303.2(M+H-Boc)+。
將1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3S)-第三丁酯(500mg,1.335mmol)、氧化銀(I)(340mg,1.468mmol)及碘甲烷(250μL,4.0mmol)於DCM(5mL)中之混合物在RT下攪拌(避光)24h且在45℃下攪拌(避光)24h。在冷卻至RT之後,經由矽藻土墊過濾混合物,在減壓下移除揮發物,且藉由矽膠層析(0至5%梯度之MeOH/DCM)純化所得殘餘物,得到1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲氧基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3S)-第三丁酯(248mg,0.638mmol)。MS m/z 289.2(M+H-Boc)+。
步驟a:將3-((第三丁基二甲基矽烷基)氧基)-1-(1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(365mg,0.746mmol)及HCl(二噁烷中4M,1.86mL,7.46mmol)於MeOH(4mL)中之混合物在40℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物得到白色固體。MS m/z 171.1(M+H)+。將此殘餘物、DIPEA(2.6mL,14.92mmol)及Boc2O(407mg,1.865mmol)於THF(15mL)中之混合物在RT下攪拌16h。將混合物倒入含有NH4Cl飽和水溶液之分液漏斗中且將其用Et2O(5×10mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(10%至80%梯度之EtOAc/庚烷)純化所得殘餘物,得到1-((第三丁氧基羰基)胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(275mg,0.742mmol)。MS m/z 271.3(M+H-Boc)+。
步驟b:將1-((第三丁氧基羰基)胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(275mg,0.742mmol)及戴斯-馬丁高碘烷(472mg,1.113mmol)於DCM(7.5mL)中之混合物在0℃下攪拌2h。將混合物倒入含有NaHCO3飽和水溶液之分液漏斗中且將其用DCM(3×10mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(5%至75%梯度之EtOAc/庚烷)純化所得殘餘物,得到1-((第三丁氧基羰基)胺基)-3-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(135mg,0.366mmol)。1H NMR(400MHz,氯仿-d)δ ppm 4.57(d,J=9.09Hz,1 H),4.16(d,J=8.08Hz,1 H),3.89-4.08(m,2 H),2.77-2.93(m,2 H),2.71(dd,J=18.95,8.08Hz,1 H),2.50(d,J=18.19Hz,1 H),2.07-2.24(m,2
H),1.76(td,J=12.82,4.67Hz,1 H),1.58-1.70(m,1 H),1.42-1.53(m,18 H),1.25-1.38(m,1 H)。
步驟c:將1-((第三丁氧基羰基)胺基)-3-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(95mg,0.258mmol)及脫氧加氟物(DeoxoFluor)(190μL,1.031mmol)於DCM(1mL)中之混合物在50℃下攪拌48h。將混合物倒入含有NaHCO3飽和水溶液/冰之分液漏斗中且將其用EtOAc(3×5mL)萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至30%梯度之EtOAc/庚烷)純化所得殘餘物,得到1-((第三丁氧基羰基)胺基)-3,3-二氟-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(52mg,0.133mmol)。1H NMR(400MHz,氯仿-d)δ ppm 4.55(d,J=9.35Hz,1 H),3.78-4.02(m,3 H),2.64-2.86(m,2 H),2.38-2.59(m,1 H),2.10-2.32(m,1 H),1.79-2.10(m,2 H),1.58(qd,J=12.72,3.79Hz,1 H),1.27-1.52(m,21 H)。
使用以上程序或對以上程序之修改,使用對掌性純之3-((第三丁基二甲基矽烷基)氧基)-1-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯作為起始物質合成以下化合物。
步驟a:將二異丙胺(0.320mL,2.245mmol)於THF(4mL)中之溶液冷卻至-78℃且用正丁基鋰(1.3mL,2.080mmol)處理,隨後在-78℃下攪拌5min且升溫至0℃,得到隨後使用之LDA溶液。向4-氰基哌啶-1-甲酸第三丁酯(153mg,0.728mmol)於THF(10mL)中之-78℃溶液中逐滴添加所製備之LDA溶液(2.8mL)且將所得混合物在-78℃下攪拌10min,隨後在-10℃下攪拌10min。將反應物再冷卻至-78℃且逐滴添加烯丙基溴(80μL,0.924mmol)於THF(2mL)中之溶液。將所得反應混合物在RT下攪拌1h且在減壓下移除揮發物。將水溶液用EtOAc萃取,將合併之有機相用水、鹽水洗滌,經Na2SO4乾燥,過濾且減壓濃縮。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化殘餘物,得到呈無色油狀物之4-烯丙基-4-氰基哌啶-1-甲酸第三丁酯(40mg,0.16mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 5.99-5.70(m,1 H),5.23(q,J=1.1Hz,1 H),5.20(dtd,J=3.3,2.1,1.1Hz,1 H),3.96(d,J=13.7Hz,2 H),2.86(s,2 H),2.36(dt,J=7.5,1.3Hz,2 H),1.84(dq,J=13.7,2.6Hz,2 H),1.40(s,11 H)。
步驟b:將4-烯丙基-4-氰基哌啶-1-甲酸第三丁酯(22mg,0.088mmol)於DCM(1.5mL)及NaOH(MeOH中2.5M,0.176mL,0.439mmol)中之溶液在-78℃下用臭氧充氣(擴散充氣器)30分鐘。將反應物用氧氣淨化,隨後分配於水與DCM之間。分離各相,收集有機相且用DCM(2×5mL)萃取水相。將合併之有機相在減壓下濃縮。將所得殘餘物溶解於MeOH中且在65℃下攪拌24h。在冷卻至RT之後,在減壓下移除揮
發物且藉由矽膠層析(0至70%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈無色油狀物之4-氰基-4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯(21mg,0.074mmol)。1H NMR(400MHz,氯仿-d)δ ppm 4.14(s,2 H),3.75(s,3 H),3.08(t,J=12.9Hz,2 H),2.62(s,2 H),2.15-2.02(m,2 H),1.59-1.48(m,2 H),1.46(s,9 H)。TLC(50% EtOAc/庚烷(染色w/KMnO4),Rf=0.5)。
步驟c:將4-氰基-4-(2-甲氧基-2-側氧基乙基)哌啶-1-甲酸第三丁酯(287mg,1.017mmol)及NH3(MeOH中7N,3.0mL,21.00mmol)於MeOH(5mL)中之溶液於密封管中在120℃下攪拌48h。在冷卻至RT之後,在減壓下移除揮發物得到白色固體。將固體用EtOAc濕磨且過濾,得到呈白色固體狀之1-胺基-3-側氧基-2,8-二氮雜螺[4.5]癸-1-烯-8-甲酸第三丁酯(157mg,0.587mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 8.44(s,1 H),8.02(s,1 H),3.98(d,J=13.3Hz,2 H),2.71(s,2 H),2.34(s,2 H),1.81(td,J=12.9,4.6Hz,2 H),1.49-1.30(m,11 H)。MS m/z 268(M+H)+。
向NaHMDS(THF中1M,8.68mL,8.68mmol)之-78℃溶液中添加1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(2.0g,7.89mmol)於THF(5mL)中之溶液。在此溫度下攪拌30min之後,添加N-氟苯磺醯胺(2.49
g,7.89mmol)於THF(10mL)中之溶液。在-78℃下攪拌3h之後,將其用NaHCO3飽和水溶液(100mL)稀釋且用DCM(3×100mL)萃取。將合併之有機相用鹽水洗滌,經Na2SO4乾燥,過濾且在減壓下濃縮。藉由矽膠層析(0至25%梯度之EtOAc/庚烷)純化所得殘餘物,得到外消旋2-氟-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(351mg,1.29mmol),MS m/z 272.1(M+H)+及與起始物質共溶離之二氟酮。藉由矽膠層析(0至5%梯度之MeOH/DCM)再純化二氟酮/起始物質之經合併之共溶離部分,得到2,2-二氟-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(573mg,1.98mmol)。MS m/z 290.1(M+H)+。
步驟a:將4-羥基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(544mg,2.11mmol)及戴斯-馬丁高碘烷(1.39g,3.17mmol)於DCM(10mL)中之溶液在0℃下攪拌2h。添加NaHCO3飽和水溶液:Na2S2O3飽和水溶液(1:1,10mL),分離有機相且將水相用DCM(3×10mL)萃取。將合併之有機相經Na2SO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈無色油狀物之4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(470mg,1.84mmol),其在靜置之後結晶。1H NMR(400MHz,氯仿-d)δ ppm 4.08(s,2 H),4.05(s,2 H),3.88(dt,J=13.7,4.9Hz,2 H),3.12(ddd,J=13.6,
9.8,3.6Hz,2 H),1.75(ddd,J=13.9,9.7,4.2Hz,2 H),1.58-1.51(m,2 H),1.48(s,9 H)。MS m/z 256.2(M+H)+。
步驟b:將4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(220mg,0.86mmol)、乙醇鈦(IV)(725μL,3.45mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(209mg,1.72mmol)於THF(4mL)中之溶液在90℃下攪拌1h。在冷卻至0℃之後,添加硼氫化鋰(23mg,1.06mmol)。在攪拌30min之後,藉由添加MeOH淬滅反應混合物。在減壓下移除揮發物。將所得殘餘物用鹽水稀釋且將其用EtOAc(4×10mL)萃取。將合併之有機相經Na2SO4乾燥,過濾,在減壓下移除揮發物,且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到4-((R)-1,1-二甲基乙基亞磺醯胺基)-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(S)-第三丁酯(170mg,0.47mmol)。MS m/z 361.1(M+H)+。
使用以上程序或對以上程序之修改,使用對應酮及亞磺醯胺合成以下化合物。
步驟a:在0-5℃下向1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(2.2g,8.68mmol)於THF(24mL)中之溶液中添加LiHMDS(THF中1M,8.68mL,8.68mmol)。在此溫度下將混合物攪拌30min之後,添加碘甲烷(0.543mL,8.68mmol)。使所得混合物升溫至RT且將其攪拌2h。將反應混合物用EtOAc稀釋且用NaHCO3飽和水溶液淬滅。將有機相用鹽水洗滌,經Na2SO4乾燥,過濾且在減壓下濃縮。藉由矽膠層析(0至25%梯度之EtOAc/庚烷)純化所得棕色油狀物,得到2-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(1.3g,4.86mmol)。MS m/z 268.1(M+H)+。
步驟b:將2-甲基-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(267mg,0.999mmol)、乙醇鈦(IV)(837μL,3.99mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(242mg,1.997mmol)於THF(10mL)中之溶液在85℃下攪拌24h。在冷卻至-78℃之後,添加MeOH(12mL),隨後添加硼氫化鋰(65.3mg,3.00mmol)。將所得混合物在-78℃下攪拌16h至RT。緩慢添加NH4Cl飽和水溶液以淬滅過量硼氫化物,隨後添加EtOAc(100mL)。將所得混合物劇烈攪拌15min且隨後經由矽藻土墊過濾。在減壓下移除揮發物且藉由矽膠層析(0至60%梯度之EtOAc/庚烷(含有0.25% Et3N))純化所得殘餘物,得到1-((R)-1,1-二甲基乙基亞磺醯胺基)-2-甲基-8-氮雜螺[4.5]癸烷-8-甲酸(1R)-第三丁酯(92mg,0.247mmol)。MS m/z 373.1(M+H)+。
步驟a:在-78℃下向4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(2.47g,9.67mmol)於THF(24mL)中之溶液中添加LiHMDS(THF中1M,9.67mL,9.67mmol)。在此溫度下將混合物攪拌30min之後,添加含碘甲烷(0.605mL,9.67mmol)之THF(10mL)。使所得混合物升溫至RT且將其攪拌1h。將反應混合物用EtOAc稀釋且用NaHCO3飽和水溶液淬滅。將有機相用鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下濃縮。藉由矽膠層析(0至20%梯度之EtOAc/庚烷)純化所得棕色油狀物,得到3-甲基-4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(318mg,1.181mmol)。MS m/z 270.2(M+H)+。
步驟b:將3-甲基-4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(318mg,1.181mmol)、乙醇鈦(IV)(990μL,4.72mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(286mg,2.361mmol)於THF(4mL)中之溶液在90℃下攪拌90min。在冷卻至0℃之後,一次性添加硼氫化鋰(65.3mg,3.00mmol)且將所得混合物在RT下攪拌16h。緩慢添加NH4Cl飽和水溶液以淬滅過量硼氫化物,隨後添加EtOAc(25mL)。將所得混合物劇烈攪拌15min且隨後經由矽藻土墊過濾。將有機相用NaHCO3飽和水溶液、鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下移除揮發物。藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(4S)-第三丁酯(88mg,0.235mmol)。MS m/z 375.2(M+H)+。
步驟c:藉由對掌性SFC如下分離非對映異構體:管柱:LUXC4 30
×250mm,流動速率:80g/min,移動相:含20% MeOH之CO2,偵測:210nm,得到4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3R,4S)-第三丁酯,Rt=4.0min;及4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S,4S)-第三丁酯,Rt=4.55min。
步驟a:向二異丙胺(23.4mL,166mmol)於THF(220mL)中之-10℃溶液中逐滴添加nBuLi(己烷中2.5M,64.1mL,160mmol)。在此溫度下攪拌30min之後,逐滴添加含哌啶-1,4-二甲酸1-第三丁酯4-乙酯(27.5g,107mmol)之THF(50mL)且將所得混合物在0℃下攪拌30min。添加(S)-2-((第三丁基二甲基矽烷基)氧基)丙醛(20.47mL,102mmol)且將混合物在0℃下攪拌1h且在RT下攪拌1h。用NaHCO3飽和水溶液:H2O(1:4,125mL)稀釋反應物,添加EtOAc(50mL)且分離各相。用EtOAc(3×100mL)進一步萃取水相。將合併之有機相經Na2SO4乾燥,過濾,且在減壓下移除溶劑。所得殘餘物不經進一步純化即用於下一步驟。MS m/z 346.4(M+H-Boc)+。
步驟b:向粗4-((2S)-2-((第三丁基二甲基矽烷基)氧基)-1-羥丙基)哌啶-1,4-二甲酸1-第三丁酯4-乙酯(95g,214mmol)於THF(600mL)中
之溶液中逐份添加LiBH4(7.0g,321mmol)且將所得混合物在RT下攪拌16h。在冷卻至0℃之後,添加NaHCO3飽和水溶液:H2O(1:2,150mL)且劇烈攪拌所得混合物直至不再觀察到起泡。添加EtOAc(100mL),過濾混合物,分離各相,且用EtOAc(3×50mL)進一步萃取水相。將合併之有機相用鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下移除揮發物,得到4-((2S)-2-((第三丁基二甲基矽烷基)氧基)-1-羥丙基)-4-(2-羥乙基)哌啶-1-甲酸第三丁酯(64.8g,161mmol),其不經進一步純化即用於下一步驟。
步驟c:將4-((2S)-2-((第三丁基二甲基矽烷基)氧基)-1-羥丙基)-4-(2-羥乙基)哌啶-1-甲酸第三丁酯(64.8g,161mmol)及TBAF(THF中1M,242mL,242mmol)於THF(500mL)中之溶液在RT下攪拌2h。添加NaHCO3飽和水溶液:H2O(1:2,150mL),分離各相,且用EtOAc(3×100mL)進一步萃取水相。將合併之有機相用鹽水洗滌,經Na2SO4乾燥,過濾,且在減壓下移除揮發物。藉由矽膠層析(20%至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈半固體無色油狀物之4-((2S)-1,2-二羥丙基)-4-(2-羥乙基)哌啶-1-甲酸第三丁酯(39.25g,136mmol)。
步驟d:向NaH(10.60g,424mmol)於THF(600mL)中之0℃懸浮液中逐滴添加4-((2S)-1,2-二羥丙基)-4-(2-羥乙基)哌啶-1-甲酸第三丁酯(35.06g,121mmol)及TsCl(23.10g,121mmol)於THF(200mL)中之溶液。將所得混合物在0℃下攪拌1h。在-20℃下緩慢添加NH4Cl飽和水溶液(約5mL)且劇烈攪拌反應物直至不再觀察到起泡。此時,添加NH4Cl飽和水溶液(100mL),隨後添加鹽水(100mL)且用EtOAc(3×100mL)萃取混合物。將合併之有機相經Na2SO4乾燥,過濾,且在減壓下移除溶劑,得到4-羥基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S)-第三丁酯(32.19g,119mmol),其不經進一步純化即用於下一步
驟。MS m/z 171.1(M-Boc)-。
步驟e:將4-羥基-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S)-第三丁酯(32.19g,119mmol)及戴斯-馬丁高碘烷(67.4g,154mmol)於DCM(300mL)中之溶液在0℃下攪拌2h。在升溫至RT之後,在減壓下移除揮發物且藉由矽膠層析(0至40%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈淺黃色油狀物之3-甲基-4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(S)-第三丁酯(27.68g,92mmol)。1H NMR(400MHz,氯仿-d)δ ppm 4.09(d,J=9.60Hz,1 H),3.66-3.86(m,4 H),3.03(ddd,J=13.77,9.73,3.79Hz,1 H),2.90(ddd,J=13.64,10.23,3.41Hz,1 H),1.68(ddd,J=13.83,9.92,4.29Hz,1 H),1.41-1.59(m,2 H),1.30-1.40(m,10 H),1.20-1.25(m,3 H)。
步驟f:將3-甲基-4-側氧基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S)-第三丁酯(22.52gmg,84mmol)、乙醇鈦(IV)(70.1mL,334mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(21g,173mmol)於THF(300mL)中之溶液在90℃下攪拌21h。在冷卻至-4℃之後,添加MeOH(30mL),隨後逐滴添加(將反應溫度維持在2℃以下)硼氫化鋰(1.82g,84mmol)且將所得混合物在-4℃下攪拌1h。緩慢添加NH4Cl飽和水溶液以淬滅過量硼氫化物(形成明膠型),隨後添加EtOAc(500mL)。將所得混合物在RT下劇烈攪拌15min且隨後經由矽藻土墊過濾,隨後用EtOAc(500mL)洗滌。在減壓下移除揮發物且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈95:5非對映異構混合物(次要非對映異構體4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3R,4S)-第三丁酯)之4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S,4S)-第三丁酯。
步驟g:藉由對掌性SFC如下分離非對映異構體:管柱:LC-4 30×250mm,流動速率:100g/min,移動相:含30% MeOH之CO2,偵測:
225nm,Rt:0.95min(次要非對映異構體Rt:0.55min),得到4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S,4S)-第三丁酯(19g,50.68mmol)。MS m/z 375.2。
步驟a:將(2R,4R)-4-胺基-8-氮雜螺[4.5]癸-2-醇二鹽酸鹽(623mg,2.56mmol)、Na2CO3(1357mg,12.80mmol)及CbzCl(1048mg,6.14mmol)於H2O(5mL)中之混合物在RT下劇烈攪拌30min。添加THF(0.5mL)且將所得混合物在RT下攪拌18h。用水及DCM稀釋混合物。將分離之水相用DCM(2×10mL)萃取。將合併之有機相經Na2SO4乾燥,過濾,且在減壓下濃縮,且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色泡沫狀之1-(((苯甲氧基)羰基)胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-苯甲酯(940mg,2.14mmol)。MS m/z 439.3(M+H)+。
步驟b:將1-(((苯甲氧基)羰基)胺基)-3-羥基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-苯甲酯(440mg,1.003mmol)及戴斯-馬丁高碘烷(638mg,1.505mmol)於DCM(6mL)中之混合物在0℃下攪拌1h且在RT下
攪拌18h。將反應混合物用NaHCO3飽和水溶液:Na2S2O3飽和水溶液(1:1,25mL)稀釋。將分離之水相用DCM(3×15mL)萃取。將合併之有機相用鹽水洗滌,經MgSO4乾燥,且在減壓下濃縮。藉由矽膠層析(0至70%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色泡沫狀之1-(((苯甲氧基)羰基)胺基)-3-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-苯甲酯(415mg,0.951mmol)。MS m/z 437.2(M+H)+。
步驟c:在-30℃至-40℃下向MeLi(THF中1.2M,2.61mL,3.13mmol)於THF(15mL)中之溶液中逐滴添加含1-(((苯甲氧基)羰基)胺基)-3-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸(R)-苯甲酯(415mg,0.951mmol)之THF(5mL)。將所得混合物在-30℃至-40℃下攪拌20min。將混合物用NaHSO4(10%水溶液)稀釋,用EtOAc稀釋,且使其在劇烈攪拌下升溫至RT。將混合物用NaHCO3飽和水溶液稀釋且將分離之水相用EtOAc(1×15mL)萃取。將合併之有機相經Na2SO4乾燥,過濾,且在減壓下濃縮。將所得殘餘物(313mg)、Na2CO3(498mg,4.70mmol)及CbzCl(295mg,1.729mmol)於水(10mL)及THF(1mL)中之溶液在RT下劇烈攪拌3天。將混合物用EtOAc稀釋且將分離之水相用EtOAc(3×15mL)萃取。在減壓下濃縮合併之有機相。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到兩種非對映異構體:呈無色半固體狀之非對映異構體A(112mg,0.25mmol),MS m/z 453.3(M+H)+及呈白色泡沫/固體狀之非對映異構體B(45mg,0.010mmol),MS m/z 453.3(M+H)+。
步驟d:將非對映異構體A(50mg,0.11mmol)及Pd/C(10重量%;12mg,0.011mmol)於MeOH(8mL)中之混合物在氫氣氛圍下劇烈攪拌2h。添加矽藻土且經由矽藻土墊過濾混合物,隨後用DCM洗滌。在減壓下濃縮濾液,得到呈無色固體狀之(4R)-4-胺基-2-甲基-8-氮雜螺[4.5]癸-2-醇,其不經進一步純化即使用。MS m/z 185.2(M+H)+。
步驟a:將6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(200mg,0.652mmol)及N-(4-甲氧基苯甲基)-8-氮雜螺[4.5]癸-1-胺(358mg,1.304mmol)於DIPEA(3mL)中之溶液在130℃下攪拌60h。在冷卻至RT之後,在減壓下移除揮發物。將所得殘餘物溶解於TFA(3mL)中且將溶液於微波反應器中在160℃下攪拌1h且在180℃下攪拌15min。在減壓下移除揮發物且藉由HPLC(梯度溶離25-50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到6-(4-(胺甲基)-4-甲基哌啶-1-基)-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(73mg,0.482mmol;基於HRMS,83%純)。藉由HPLC(梯度溶離25-50%乙腈/水,0.1% TFA改質劑)進一步純化19mg此化合物,得到純標題化合物(9.5mg)。1H NMR(400MHz,甲醇-d 4)δ ppm 8.29(dd,J=4.42,1.39Hz,1 H),7.48(s,1 H),7.19-7.41(m,2 H),4.06-4.26(m,2 H),2.89-3.14(m,2 H),2.71(t,J=7.33Hz,1 H),1.86-2.00(m,1 H),1.73-1.84(m,1 H),1.43-1.72(m,5 H),1.27-1.42(m,2 H),1.17-1.27(m,1 H)。19F NMR(376MHz,甲醇-d 4)δ ppm -66.45(s)。C19H24N6F3S(M+H)+之HRMS計算值425.1735,實驗值425.1753。IC50為0.023μM。
步驟b:如下進行以上標題化合物之對掌性SFC純化;管柱:ID 21
×250mm,流動速率:75g/min,移動相:含35% MeOH及10mM NH4OH之CO2,偵測:270nm UV,獲得單一對映異構體Rt(P1)=4.9min;IC50為0.011μM及Rt(P2)=6.4min;IC50為0.167μM。
使用以上程序或對以上程序之修改,使用對應硫吡嗪-2-胺衍生物及經保護之胺製造如表4中所鑑別之以下式I化合物。
步驟a:將6-氯-3-((2,3-二氯苯基)硫基)吡嗪-2-胺(140mg,0.457mmol)及2-氮雜螺[3.3]庚-5-基胺基甲酸第三丁酯(鹽酸鹽,125mg,0.502mmol)於DIPEA(1mL)中之溶液在130℃下攪拌24h。在冷卻至RT之後,在減壓下移除揮發物。將所得殘餘物溶解於DCM(5mL)中,添加TFA(0.5mL)且將所得混合物在RT下攪拌30min。在減壓下移除揮發物且藉由HPLC(梯度溶離25-50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到2-(6-胺基-5-((2,3-二氯苯基)硫基)吡嗪-2-基)-2-氮雜螺[3.3]庚-5-胺(75mg,0.186mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.31(dd,J=8.03,1.51Hz,1 H),7.18(s,1 H),7.11(t,J=8.03Hz,1 H),6.60(dd,J=8.03,1.51Hz,1 H),4.45(d,J=8.78Hz,1 H),4.03(d,J=9.03Hz,1 H),3.96(d,J=9.03Hz,1 H),3.90(d,J=8.78Hz,1 H),3.34-3.39(與溶劑部分重疊,m,1 H),2.12-2.25(m,1 H),1.90-2.11(m,2 H),1.52-1.67(m,1 H)。C16H18Cl2N5S(M+H)+之HRMS計算值382.0660,實驗值382.0585。IC50為5.36μM。
步驟b:將2-(6-胺基-5-((2,3-二氯苯基)硫基)吡嗪-2-基)-2-氮雜螺[3.3]庚-5-胺(53.9mg,0.141mmol)藉由對掌性SFC進一步純化;管柱:OJ-H 21×250mm,流動速率:80g/min,移動相:含26% MeOH及10mM NH4OH之CO2,偵測:269nm UV,獲得單一對映異構體Rt(P1)=3.7min;IC50為17.49μM及Rt(P2)=4.7min;IC50為3.31μM。
使用以上程序或對以上程序之修改,使用對應吡嗪-2-胺衍生物及經保護之胺製造如表5中所鑑別之以下式I化合物。
將6-氯-3-((2,3-二氯苯基)硫基)吡嗪-2-胺(140mg,0.457mmol)及2-(7-氮雜螺[3.5]壬-1-基)異吲哚啉-1,3-二酮(鹽酸鹽,154mg,0.502mmol)於DIPEA(1mL)中之溶液在130℃下攪拌16h。在冷卻至RT之後,在減壓下移除揮發物。將所得殘餘物及水合肼(29μL,0.602mmol)於THF:MeOH(1:1,1mL)中之溶液在55℃下攪拌16h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離35-60%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到標題化合物(78mg,0.502
mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.59(s,1 H),7.31(dd,J=8.03,1.51Hz,1 H),7.12(t,J=8.03Hz,1 H),6.62(dd,J=8.03,1.51Hz,1 H),4.37(d,J=13.55Hz,1 H),4.26(d,J=13.55Hz,1 H),3.24-3.30(與溶劑部分重疊,m,1 H),3.07-3.20(m,1 H),2.923.06(m,1 H),2.26-2.39(m,1 H),1.87-2.07(m,2 H),1.57-1.87(m,4 H),1.34-1.42(m,1 H)。C18H22Cl2N5S(M+H)+之HRMS計算值410.0973,實驗值410.1018(外消旋)。IC50為0.056μM。
如下進行以上標題化合物之對掌性SFC純化;管柱:AD-H 21×250mm,流動速率:80g/min,移動相:含46% MeOH及10mM NH4OH之CO2,偵測:274nm UV,獲得單一對映異構體Rt(P1)=4.0min及Rt(P2)=5.5min(P1(S對映異構體(藉由X射線測定));IC50為0.019μM;(P2(R對映異構體));IC50為0.414μM。
使用以上程序或對以上程序之修改,使用對應吡嗪-2-胺衍生物及鄰苯二甲醯胺保護之胺製造如表6中所鑑別之以下式I化合物。
步驟a:將6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(230mg,0.750mmol)及(R)-2-甲基-N-((S)-7-氮雜螺[3.5]壬-1-基)丙烷-2-亞磺醯胺(238mg,0.975mmol)於DIPEA(3.7mL)中之混合物在105℃下攪拌10h。在冷卻至RT之後,在減壓下移除揮發物且藉由矽膠層析(5%至70%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色固體狀之(R)-N-((S)-7-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-7-氮雜螺[3.5]壬-1-基)-2-甲基丙烷-2-亞磺醯胺(172mg,0.334mmol)。MS m/z 515.2(M+H)+。
步驟b:將(R)-N-((S)-7-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-7-氮雜螺[3.5]壬-1-基)-2-甲基丙烷-2-亞磺醯胺(142mg,0.376mmol)及HCl(二噁烷中4M,414μL,1.66mmol)於DCM(1.4mL)
中之溶液在40℃下攪拌20min。在冷卻至RT之後,添加HCl(H2O中1M)且將所得水性混合物用DCM萃取。用NH4OH(H2O中28%)鹼化水相直至pH 12且將其用DCM(3×20mL)萃取。將合併之有機層用鹽水洗滌,經MgSO4乾燥,過濾且在減壓下移除揮發物,得到(S)-7-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-7-氮雜螺[3.5]壬-1-胺(93mg,0.227mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 8.40-8.53(m,1 H),7.61-7.69(m,1 H),7.55(dd,J=8.0,4.5Hz,1 H),7.29(d,J=8.0Hz,1 H),6.19(s,2 H),4.11-4.24(m,1 H),3.99-4.06(m,1 H),3.06-3.20(m,2 H),2.90-3.06(m,2 H),1.50-1.74(m,4 H),1.33-1.49(m,2 H)。C18H21F3N6S(M+H)+之HRMS計算值411.1566,實驗值411.1579。IC50為0.038μM。
步驟a:在0℃下向6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(1.2g,2.119mmol)於DCM(30mL)中之溶液中一次性添加NBS(745mg,4.19mmol)。將所得混合物在0℃下劇烈攪拌30min且在RT下劇烈攪拌1h。將澄清溶液用水淬滅且用DCM萃取。將合併之有機層隨後用水、鹽水洗滌,經Na2SO4乾燥,過濾且濃縮。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到5-溴-6-氯-3-((2-(三氟甲基)
吡啶-3-基)硫基)吡嗪-2-胺(938mg,2.51mmol)。MS m/z 387.2(M+H)+。
步驟b:將5-溴-6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(750mg,1.945mmol)及氰化銅(I)(348mg,3.89mmol)於DMF(7mL)中之混合物在120℃下攪拌14h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用MeOH(50mL)洗滌。在減壓下移除揮發物且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到5-胺基-3-氯-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲腈(301mg,0.907mmol)。MS m/z 332.3(M+H)+。
步驟c:將5-胺基-3-氯-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲腈(52mg,0.157mmol)及(S)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(90mg,0.314mmol)於DIPEA(0.246mL)中之混合物在135℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到5-胺基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲腈(77mg,0.132mmol)。MS m/z 584.5(M+H)+。
步驟d:將5-胺基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲腈(77mg,0.132mmol)及NaOH(H2O中1M,1.451mL,1.451mmol)於MeOH(3.5mL)中之混合物於微波反應器中在110℃下攪拌35min。在冷卻至RT之後,在減壓下移除揮發物,得到5-胺基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲醯胺(79mg,0.132mmol),其不經進一步純化即用於下一步驟。MS m/z 602.5(M+H)+。
步驟e:於微波反應器中在100℃下攪拌5-胺基-3-((S)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶
-3-基)硫基)吡嗪-2-甲醯胺(79mg,0.132mmol)於TFA(1.2mL,15.76mmol)中之溶液直至無起始物質剩餘(3h,藉由LCMS監控)。在減壓下移除揮發物且藉由HPLC(梯度溶離25-50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(S)-5-胺基-3-(1-胺基-8-氮雜螺[4.5]癸-8-基)-6-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-甲醯胺(18.8mg,0.039mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 8.43(dd,J=4.5,1.4Hz,1 H),7.57(dd,J=8.1,1.3Hz,1 H),7.46(dd,J=8.2,4.5Hz,1 H),3.92-3.88(m,2 H),3.20-3.08(m,2 H),2.77(t,J=7.4Hz,1 H),2.04-1.96(m,1 H),1.829-1.82(m,1 H),1.78-1.61(m,4 H),1.53(ddd,J=12.3,9.2,5.7Hz,1 H),1.43(ddd,J=9.8,4.9,2.0Hz,1 H),1.39-1.32(m,1 H),1.30-1.23(m,1 H)。C20H25F3N7OS(M+H)+之HRMS計算值468.1715,實驗值468.1761;IC50為0.010μM。
使用以上程序或對以上程序之修改,使用對應胺及脫除胺之保護基方法製造如表7中所鑑別之以下式I化合物。
步驟a:將3-氯-1,2,4-三嗪-5-胺(70mg,0.536mmol)、(S)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(247mg,0.644mmol)及N-甲基嗎啉(177μL,1.609mmol)於MeCN(1mL)及NMP(0.1mL)中之混合物於微波反應器中在90℃下照射45min。在冷卻至RT之後,藉由矽膠層析(0至5%梯度之MeOH/DCM)直接純化所得殘餘物,得到(S)-8-(5-胺基-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺,其不經進一步純化即用於下一步驟。MS m/z 383.5(M+H)+。
步驟b:在0℃下向(S)-8-(5-胺基-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(194mg,0.507mmol)於DCM(8mL)中之溶液中一次性添加NBS(97mg,0.543mmol)。在0℃下攪拌20min之後,將澄清溶液用幾滴Na2CO3水溶液淬滅且將其用DCM萃取。將合併之有機層經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到(S)-8-(5-胺基-6-溴-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(77.9mg,0.169mmol)。MS m/z 463.4(M+H)+。
步驟c:將(S)-8-(5-胺基-6-溴-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(54.1mg,0.117mmol)、2-(三氟甲基)吡啶-3-硫醇(21mg,0.117mmol)、XantPhos(7.46mg,0.013mmol)、Pd2(dba)3(5.37mg,0.0058mmol)及DIPEA(0.041mL,0.234mmol)於二噁烷(1mL)中之混合物於微波反應器中在130℃下攪拌1.5h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用EtOAc(10mL)洗滌。在
減壓下移除揮發物,得到(S)-8-(5-胺基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(65mg,0.116mmol)。MS m/z 560.5(M+H)+。
步驟d:在100℃下攪拌(S)-8-(5-胺基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(65mg,0.116mmol)於TFA(1.253mL,16.26mmol)中之溶液直至無起始物質剩餘(1.5h,藉由LC/MS監控),在減壓下移除揮發物,將所得殘餘物用水稀釋且將其用Et2O(3×10mL)萃取。使用NH4OH(水中28%)將水層鹼化至pH 12,且將其用DCM(3×10mL)萃取。將合併之有機層用鹽水洗滌,經Na2SO4乾燥,過濾且在減壓下移除揮發物。藉由HPLC(梯度溶離25-50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(S)-8-(5-胺基-6-((2-(三氟甲基)吡啶-3-基)硫基)-1,2,4-三嗪-3-基)-8-氮雜螺[4.5]癸-1-胺(14.5mg,0.032mmol)。1H NMR(400MHz,甲醇-d 4 )δ ppm 8.50-8.45(m,1 H),7.60-7.54(m,1 H),7.53-7.46(m,1 H),4.64-4.50(m,2 H),3.22-3.09(m,2 H),2.88(t,J=7.3Hz,1 H),2.11-2.00(m,1 H),1.94-1.86(m,1 H),1.84-1.74(m,1 H),1.74-1.63(m,3 H),1.59-1.46(m,2 H),1.45-1.39(m,1 H),1.39-1.31(m,1 H)。C18H23F3N7S(M+H)+之HRMS計算值426.1688,實驗值426.1667。IC50為0.290μM。
步驟a:將2-(三氟甲基)吡啶-3-硫醇(150mg,0.837mmol)、2-氯-5-碘嘧啶-4-胺(267mg,1.047mmol)、XantPhos(53.3mg,0.092mmol)、Pd2(dba)3(38.3mg,0.042mmol)及DIPEA(0.292mL,1.674mmol)於二噁烷(1mL)中之混合物於微波反應器中在130℃下攪拌1.5h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用EtOAc(10mL)洗滌。在減壓下移除揮發物,得到2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4-胺(141mg,0.460mmol)。MS m/z 307.4(M+H)+。
步驟b:將2-氯-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-4-胺(70mg,0.228mmol)及(S)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(105mg,0.274mmol)於DIPEA(0.359mL)中之混合物於微波反應器中在135℃下攪拌1.5h。在冷卻至RT之後,在減壓下移除揮發物,得到(S)-8-(4-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(128mg,0.228mmol)。MS m/z 559.5(M+H)+。
步驟c:在100℃下攪拌(S)-8-(4-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2-基)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(128mg,0.229mmol)於TFA(2.471mL,32.1mmol)中之溶液直至無起始物質剩餘(1.5h,藉由LCMS監控),在減壓下移除揮發物,將所得殘餘物用水稀釋,且隨後將其用Et2O(3×10mL)萃取。使用NH4OH(水中28%)將水層鹼化至pH 12,且將其用DCM(3×10mL)萃取。將合併之有機層用鹽水洗滌,經Na2SO4乾燥,過濾且在減壓下移除揮發物。
藉由HPLC(梯度溶離35-60%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(S)-8-(4-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)嘧啶-2-基)-8-氮雜螺[4.5]癸-1-胺(32mg,0.072mmol)。1H NMR(400MHz,甲醇-d 4 )δ ppm 8.41-8.35(m,1 H),8.00(s,1 H),7.47-7.43(m,2 H),4.66-4.45(m,2 H),3.18-3.06(m,2 H),2.81(t,J=7.3Hz,1 H),2.09-1.97(m,1 H),1.94-1.86(m,1 H),1.81-1.72(m,1 H),1.69-1.62(m,2 H),1.59-1.53(m,2 H),1.49-1.44(m,1 H),1.40-1.35(m,1 H),1.33-1.25(m,1 H)。C19H24F3N6S(M+H)+之HRMS計算值425.1735,實驗值425.1741;IC50為2.78μM。
步驟a:將5-胺基-3-氯吡嗪-2-甲腈(1.55g,10.0mmol)及(R)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(2.88g,10.0mmol)於DIPEA(10μL)及NMP(5mL)中之溶液在110℃下攪拌16h。在冷卻至RT之後,將反應混合物倒入含有NaHCO3水溶液之分液漏斗中且將其用EtOAc萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物。藉由矽膠層析(0至5%梯度之MeOH/DCM)純化所得殘餘物,得到5-胺基-3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)吡嗪-2-甲腈(2.74g,6.74mmol)。MS m/z 407.3(M+H)+。
步驟b:(注意:此反應在各500mg之4個批料中操作)。將5-胺基
-3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)吡嗪-2-甲腈(500mg,1.23mmol)於MeOH(8mL)及NaOH(H2O中2.5M,5mL,12.3mmol)中之溶液於微波反應器中在130℃下攪拌90min。在冷卻至RT之後,藉由HPLC(35-60%梯度之乙腈/水,5mM NH4OH改質劑)純化所得混合物,得到5-胺基-3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)吡嗪-2-甲醯胺(160mg/反應,總共640mg,1.51mmol)。MS m/z 425.3(M+H)+。
步驟c:將5-胺基-3-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)吡嗪-2-甲醯胺(615mg,1.45mmol)於TFA(11mL)中之溶液在100℃下攪拌1h。在減壓下移除揮發物。將所得殘餘物、DIPEA(1.2mL,6.89mmol)及Boc2O(330mg,1.516mmol)於DCM(15mL)中之溶液在RT下攪拌2h。在減壓下移除揮發物且藉由矽膠層析(1%至10%梯度之MeOH/DCM)純化所得殘餘物,得到(8-(6-胺基-3-胺甲醯基吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(538mg,1.378mmol)。MS m/z 391.0(M+H)+。
步驟d:將(8-(6-胺基-3-胺甲醯基吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(538mg,1.378mmol)及NBS(270mg,1.516mmol)於DCM(5mL)中之溶液在0℃下攪拌20min。將反應混合物用MeOH(2mL)淬滅且在RT下攪拌20min。將所得混合物倒入含有NaHCO3水溶液之分液漏斗中且將其用DCM萃取。將合併之有機相經MgSO4乾燥,過濾且在減壓下移除揮發物,得到(8-(6-胺基-5-溴-3-胺甲醯基吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(627mg,1.336mmol)。MS m/z 471.2(M+H)+。
步驟e:向(8-(6-胺基-5-溴-3-胺甲醯基吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(627mg,1.336mmol)、XantPhos(77mg,0.134mmol)及Pd2(dba)3(61.2mg,0.067mmol)於二噁烷(3mL)中之溶
液中添加(在RT下且在N2下)2-乙基己基-3-巰基丙酸酯(334μL,1.469mmol),隨後添加DIPEA(467μL,2.67mmol)。將所得溶液於微波反應器中在90℃下攪拌1h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用EtOAc(5mL)洗滌。濃縮經合併之濾液且藉由矽膠層析(0至10%梯度之MeOH/DCM)純化所得殘餘物,得到3-((3-胺基-5-((R)-1-((第三丁氧基羰基)胺基)-8-氮雜螺[4.5]癸-8-基)-6-胺甲醯基吡嗪-2-基)硫基)丙酸2-乙基己酯(574mg,0.946mmol)。MS m/z 607.4(M+H)+。
步驟f:向3-((3-胺基-5-((R)-1-((第三丁氧基羰基)胺基)-8-氮雜螺[4.5]癸-8-基)-6-胺甲醯基吡嗪-2-基)硫基)丙酸2-乙基己酯(574mg,0.946mmol)於THF(3mL)中之溶液中添加(在-78℃下且在N2下)第三丁醇鉀(THF中1M,2.84mL,2.84mmol)。在-78℃下劇烈攪拌10min之後,用K2CO3水溶液(2M,500μL)淬滅反應物且在減壓下移除揮發物。藉由HPLC(15%至40%梯度之乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(8-(6-胺基-3-胺甲醯基-5-巰基吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(280mg,0.663mmol)。MS m/z 423.4(M+H)+。
步驟g:向(8-(6-胺基-3-胺甲醯基-5-巰基吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(88mg,0.208mmol)、3-氯-4-碘-2-(三氟甲基)吡啶(80mg,0.260mmol)、XantPhos(12.1mg,0.021mmol)及Pd2(dba)3(9.6mg,0.01mmol)於二噁烷(0.5mL)中之溶液中添加(在RT下且在N2下)DIPEA(110μL,0.625mmol)。將所得溶液於微波反應器中在90℃下攪拌1h。在冷卻至RT之後,將反應物用EtOAc稀釋且將其經由矽藻土墊過濾,隨後用EtOAc(5mL)洗滌。將合併之濾液濃縮且在真空下乾燥。將所得殘餘物於DCM(1mL)及TFA(400μL)中之溶液在RT下攪拌10min。在減壓下移除揮發物且藉由HPLC(梯度溶離
25-50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(R)-5-胺基-3-(1-胺基-8-氮雜螺[4.5]癸-8-基)-6-((3-氯-2-(三氟甲基)吡啶-4-基)硫基)吡嗪-2-甲醯胺(60mg,0.120mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 8.18(d,J=5.05Hz,1 H).6.85(d,J=5.31Hz,1 H).3.87(t,J=13.89Hz,2 H).2.98-3.14(m,2 H),2.72(t,J=7.33Hz,1 H).1.86-2.02(m,1 H).1.73-1.81(m,1 H).1.43-1.72(m,5 H).1.17-1.41(m,3 H)。19F NMR(376MHz,甲醇-d 4)δ ppm -67.22(s,1F)。C20H24ClF3N7OS(M+H)+之HRMS計算值502.1404,實驗值502.1398。IC50為0.058μM。
(R)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺
將3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(67mg,0.233mmol)及(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(120mg,0.465mmol)於DIPEA(2mL)中之混合物在130℃下攪拌5h。在冷卻至RT之後,在減壓下移除揮發物。將所得殘餘物於二噁烷(5mL)及HCl(二噁烷中4M,1mL)中之溶液在40℃下攪拌1h。在減壓下移除揮發物且將所得殘餘物藉由HPLC(梯度溶離25-50%乙腈/水,5mM NH4OH改質劑)純化。藉由SFC(Princeton DEAP 20×150mm,流動速率:80g/min,移動相:含20-40% MeOH之CO2,在5.7min內,觸發質量收集,烘箱溫度40℃,背壓120巴)進一步純化所得殘餘物,得到(R)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(23mg,0.057mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm
7.50-7.64(m,2 H),5.91(d,J=5.77Hz,1 H),4.26(t,J=13.18Hz,2 H),3.03-3.20(m,2 H),2.79(t,J=7.53Hz,1 H),1.95-2.11(m,1 H),1.83-1.95(m,1 H),1.52-1.82(m,5 H),1.37-1.52(m,2 H),1.32(dd,J=13.30,2.01Hz,1 H)。C18H25ClN7S(M+H)+之HRMS計算值406.1581,實驗值406.1576。IC50為0.014μM。
使用以上程序或對以上程序之修改,使用對應胺保護之胺合成以下化合物。
步驟a:向6-氯-3-((3-氯吡啶-4-基)硫基)吡嗪-2-胺(53mg,0.194mmol)於DIPEA(2mL)中之懸浮液中添加(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(65mg,0.252mmol)。將所得混合物在90℃下攪拌10h且隨後濃縮。藉由矽膠層析(0-50%梯度之EtOAc/庚烷;EtOAc含有10% MeOH,庚烷含有2% Et3N)純化粗產物,得到呈灰白色固體狀之(R)-N-((R)-8-(6-胺基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-
基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(40mg,0.081mmol)。MS m/z 495.0(M+H)+。
步驟b:向(R)-N-((R)-8-(6-胺基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(40mg,0.081mmol)於DCM(0.8mL)中之溶液中添加HCl(二噁烷中4M,101μL,0.404mmol)溶液且將所得混合物在40℃下攪拌1h。添加HCl(2M,2mL)水溶液且用DCM(2×)萃取所得混合物。將水性混合物用氫氧化銨(水中28%)鹼化直至pH=12且將其用DCM(3×)萃取。將有機層合併,用鹽水洗滌,經Na2SO4乾燥,過濾且濃縮,得到(R)-8-(6-胺基-5-((3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(24mg,0.061mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 8.49(s,1 H),8.25(d,J=5.3Hz,1 H),7.66(s,1 H),6.56(d,J=5.3Hz,1 H),6.24(s,2 H),4.07-4.26(m,2 H),2.98-3.13(m,2 H),2.70(t,J=7.4Hz,1 H),1.11-1.94(m,10 H)。C18H24ClN6S(M+H)+之HRMS計算值391.1472,實驗值391.1480。IC50為0.023μM。
步驟a:向6-氯-3-((2-氯吡啶-3-基)硫基)吡嗪-2-胺(85mg,0.311mmol)於DIPEA(1.6mL)中之懸浮液中添加(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(105mg,0.405mmol)。將所得混合物在90℃下攪拌10h且隨後濃縮。藉由矽膠層析(0-50%梯度之EtOAc/庚烷;EtOAc含有10% MeOH,庚烷含有2% Et3N)純化粗產物,得到呈灰
白色固體狀之(R)-N-((R)-8-(6-胺基-5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(40mg,0.081mmol)。1H NMR(400MHz,甲醇-d)δ ppm 8.15(dd,J=4.5,1.8Hz,1 H),7.64(s,1 H),7.01-7.18(m,2 H),4.87(br.s,2 H),4.24(s,2 H),3.29-3.45(m,1 H),3.20(d,J=5.8Hz,1 H)2.98-3.13(m,2 H),1.98-2.21(m,1 H),1.36-1.94(m,9 H),1.22(s,9 H)。MS m/z 495.0(M+H)+。
步驟b:向(R)-N-((R)-8-(6-胺基-5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(66mg,0.133mmol)於DCM(2mL)中之溶液中添加HCl(二噁烷中4M,167μL,0.667mmol)溶液且將所得混合物在40℃下攪拌1h。添加HCl(2M,2mL)水溶液且用DCM(2×)萃取所得混合物。將水性混合物用氫氧化銨(水中28%)鹼化直至pH=12且將其用DCM(3×)萃取。將有機層合併,用鹽水洗滌,經Na2SO4乾燥,過濾且濃縮,得到呈棕褐色固體狀之(R)-8-(6-胺基-5-((2-氯吡啶-3-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(24mg,0.062mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 8.01(dd,J=4.8,1.8Hz,1 H),7.43-7.52(m,1 H),7.12(dd,J=7.9,4.6Hz,1 H),7.00(dd,J=7.9,1.6Hz,1 H),4.11-4.26(m,2 H),2.96-3.10(m,2 H),2.67-2.81(m,1 H),1.06-2.05(m,10 H)。C18H24ClN6S(M+H)+之HRMS計算值391.1472,實驗值391.1470。IC50為0.015μM。
步驟a:向6-氯-3-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-胺(34mg,0.111mmol)於DIPEA(0.55mL)中之懸浮液中添加(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(37mg,0.144mmol)。將所得混合物在90℃下攪拌10h且隨後濃縮。藉由矽膠層析(0-50%梯度之EtOAc/庚烷;EtOAc含有10% MeOH,庚烷含有2% Et3N)純化粗產物,得到呈灰白色固體狀之(R)-N-((R)-8-(6-胺基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(33mg,0.062mmol)。1H NMR(400MHz,氯仿-d)δ ppm 8.02(d,J=5.3Hz,1 H),7.66(s,1 H),6.60(d,J=5.3Hz,1 H),4.82(s,2 H),4.21-4.34(m,2 H),3.34-3.42(m,1 H),3.20(d,J=5.8Hz,1 H),2.99-3.15(m,2 H),2.08-2.21(m,1 H),1.26-1.97(m,9 H),1.23(s,9 H)。MS m/z 529.1(M+H)+。
步驟b:向(R)-N-((R)-8-(6-胺基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(20mg,0.038mmol)於DCM(0.38mL)中之溶液中添加HCl(二噁烷中4M,47μL,0.189mmol)溶液且將所得混合物在40℃下攪拌1h。將反應混合物濃縮且溶解於MeOH中。藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化粗產物,得到呈白色固體狀之(R)-8-(6-胺基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(7mg,0.016mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.91-8.04(m,1 H),7.52-7.65(m,1 H),6.61(d,J=5.3Hz,1 H),4.29(t,J=14.2Hz,2 H),3.06-3.22(m,2 H),2.88(t,J=7.4Hz,1 H),1.21-2.17(m,10 H)。C18H23Cl2N6S(M+H)+之HRMS計算值425.1082,實驗值425.1095。IC50為0.003μM。
步驟a:向6-氯-3-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-胺(54mg,0.176mmol)於DIPEA(1.8mL)中之懸浮液中添加(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(86mg,0.351mmol)。將所得混合物在90℃下攪拌10h且隨後濃縮。藉由矽膠層析(0-50%梯度之EtOAc/庚烷;EtOAc含有10% MeOH,庚烷含有2% Et3N)純化粗產物,得到呈灰白色固體狀之(R)-N-((S)-7-(6-胺基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-7-氮雜螺[3.5]壬-1-基)-2-甲基丙烷-2-亞磺醯胺(52mg,0.102mmol)。MS m/z 514.9(M+H)+。
步驟b:向(R)-N-((S)-7-(6-胺基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-7-氮雜螺[3.5]壬-1-基)-2-甲基丙烷-2-亞磺醯胺(20mg,0.039mmol)於DCM(0.38mL)中之溶液中添加HCl(二噁烷中4M,47μL,0.189mmol)溶液且將所得混合物在40℃下攪拌1h。將反應混合物濃縮且溶解於MeOH中。藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化粗產物,得到呈白色固體狀之(S)-7-(6-胺基-5-((2,3-二氯吡啶-4-基)硫基)吡嗪-2-基)-7-氮雜螺[3.5]壬-1-胺(7mg,0.017mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.89(d,J=5.5Hz,1 H),7.50(s,1 H),6.51(d,J=5.5Hz,1 H),3.94-4.31(m,2 H),2.76-3.11(m,3 H),2.06-2.24(m,1 H),1.36-1.82(m,7 H)。C17H21Cl2N6S(M+H)+之HRMS計算值411.0925,實驗值411.0938。IC50為0.028μM。
步驟a:向3-((3-胺基-2-氯苯基)硫基)-6-氯吡嗪-2-胺(60mg,0.209mmol)於DIPEA(1.5mL)中之懸浮液中添加(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(70mg,0.272mmol)。將所得混合物在90℃下攪拌10h且隨後濃縮。藉由矽膠層析(0-50%梯度之EtOAc/庚烷;庚烷含有2% Et3N)純化粗產物,得到呈灰白色固體狀之(R)-N-((R)-8-(6-胺基-5-((3-胺基-2-氯苯基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(31mg,0.061mmol)。MS m/z 509.0(M+H)+。
步驟b:向(R)-N-((R)-8-(6-胺基-5-((3-胺基-2-氯苯基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(31mg,0.061mmol)於DCM(0.6mL)中之溶液中添加HCl(二噁烷中4M,76μL,0.304mmol)溶液且將所得混合物在40℃下攪拌1h。添加HCl(2M,2mL)水溶液且用DCM(2×)萃取所得混合物。將水性混合物用氫氧化銨(水中28%)鹼化直至pH=12且將其用DCM(3×)萃取。將有機層合併,用鹽水洗滌,經Na2SO4乾燥,過濾且濃縮,得到呈黃色固體狀之(R)-8-(6-胺基-5-((3-胺基-2-氯苯基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(18mg,0.042mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.40(s,1 H),6.73(t,J=8.0Hz,1 H),6.50(dd,J=8.1,1.3Hz,1 H),5.90(dd,J=7.8,1.3Hz,1 H),4.02-4.18(m,2 H),3.21(dt,J=3.2,1.5Hz,1 H),2.98(d,J=11.4Hz,2 H),2.67(t,J=7.5Hz,1 H),1.04-2.02(m,10 H)。C19H26ClN6S(M+H)+之HRMS計算值405.1628,實驗值405.1639。IC50為0.011μM。
向6-氯-3-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-胺(40mg,0.137mmol)於DIPEA(0.7mL)中之懸浮液中添加(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(71mg,0.0275mmol)。將所得混合物在90℃下攪拌10h且隨後濃縮。將粗產物溶解於DCM(0.7mL)中,添加HCl(二噁烷中4M,34μL,0.137mmol)溶液且將所得混合物在40℃下攪拌1h。濃縮反應混合物且藉由HPLC(梯度溶離15%至40%乙腈/水,0.1% TFA改質劑)純化粗產物,得到(R)-8-(6-胺基-5-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(TFA鹽:17mg,0.042mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 7.94(d,J=5.3Hz,1 H),7.79(br.s.,3 H),7.69(br.s.,1 H),6.51(d,J=5.5Hz,1 H),6.34(br.s.,2 H),4.12-4.32(m,2 H),2.99-3.24(m,3 H),2.00-2.12(m,1 H),1.30-1.90(m,9 H)。C18H23ClFN6S(M+H)+之HRMS計算值409.1377,實驗值409.1385。IC50為0.005μM。
步驟a:向2-側氧基-1,8-二氮雜螺[4.5]癸烷-8-甲酸第三丁酯(300mg,1.180mmol)於二氯甲烷(3mL)中之RT溶液中添加五硫化磷(110mg,0.495mmol),隨後添加六甲基二矽氧烷(2.256mL,10.62mmol)。將反應物在RT下攪拌3h,隨後用EtOAc稀釋且經由矽藻土過濾。在減壓下濃縮濾液。藉由矽膠層析(0至80%梯度之EtOAc/庚烷)純化粗產物,得到呈白色固體狀之1-硫酮基-2,8-二氮雜螺[4.5]癸烷-8-甲酸第三丁酯(0.290g,1.07mmol)。1H NMR(400MHz,DMSO-d 6 )δ 10.39(s,1 H),3.66(dt,J=13.6,4.9Hz,2 H),3.09(s,2 H),2.78(t,J=7.8Hz,2 H),1.95(t,J=7.8Hz,2 H),1.57(dd,J=6.6,4.8Hz,4 H),1.39(s,9 H)。MS m/z 271(M+H)+。
步驟b:向1-硫酮基-2,8-二氮雜螺[4.5]癸烷-8-甲酸酯(100mg,0.370mmol)於THF(3mL)中之溶液中逐滴添加碘甲烷(0.231mL,3.70mmol)。將所得溶液在RT下攪拌16h。在反應過程中,混合物顏色慢慢變得較黃且在攪拌所分配之反應時間之後產生淡黃色沈澱物。將反應混合物濃縮且在真空下乾燥,得到黃色固體。將黃色固體溶解於MeOH(2mL)中且用含7M氨之甲醇(3mL)處理,隨後在密封管中加熱至100℃,持續8h。將反應物冷卻至RT且在減壓下濃縮,得到固體,將其用乙腈音波處理且過濾。濃縮濾液且藉由矽膠層析(0至30%梯度之MeOH/DCM)純化殘餘物,得到1-胺基-2,8-二氮雜螺[4.5]癸-1-烯-8-甲酸第三丁酯(87mg,0.343mmol)。1H NMR(400MHz,DMSO-d 6 )δ 9.38(s,1 H),8.81(d,J=25.2Hz,2 H),3.98(s,2 H),3.55(t,J=7.0Hz,2 H),2.82(s,2 H),2.12(t,J=7.1Hz,2 H),1.74(td,J=12.9,4.7Hz,2 H),1.57(d,J=12.7Hz,2H),1.41(s,9 H)。MS m/z 254(M+H)+。
步驟c:在RT下向1-胺基-2,8-二氮雜螺[4.5]癸-1-烯-8-甲酸第三丁酯(86mg,0.339mmol)於DCM(3mL)中之溶液中添加含HCl之二噁烷(4M,0.500mL,2.0mmol)且將反應物攪拌16h。濃縮反應混合物且
將殘餘物自乙腈濕磨且過濾,得到呈棕褐色固體狀之2,8-二氮雜螺[4.5]癸-1-烯-1-胺(57.7mg,0.254mmol)。1H NMR(400MHz,DMSO-d 6 )δ 9.64(s,1 H),9.39-9.23(m,1 H),9.15(s,1 H),9.07(s,1 H),8.70(d,J=12.5Hz,1 H),3.54(t,J=6.9Hz,2 H),3.32(d,J=13.3Hz,2 H),3.05-2.88(m,2 H),2.18(t,J=6.9Hz,2 H),2.01(td,J=13.7,4.3Hz,2 H),1.80(d,J=13.8Hz,2 H)。MS m/z 154(M+H)+。
步驟d:向6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(250mg,0.815mmol)及2,8-二氮雜螺[4.5]癸-1-烯-1-胺(210mg,1.371mmol)於N-甲基-2-吡咯啶酮(4mL)中之懸浮液中添加DIPEA(1.4mL,8.02mmol)且將反應物加熱至140℃,持續16h。將所得深色混合物冷卻至RT且用EtOAc及水稀釋。分配各層且丟棄有機物。用20%異丙醇/氯仿混合物(2×30mL)萃取水層,將合併之有機物經Na2SO4乾燥,過濾且濃縮。使用製備型HPLC(梯度溶離,5%至40% ACN/水,0.1% TFA改質劑)純化粗殘餘物且將一半混合溶離份凍乾,得到8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,8-二氮雜螺[4.5]癸-1-烯-1-胺(TFA鹽:61.4mg,0.082mmol)。將剩餘溶離份合併且用50%飽和NaHCO3藉由劇烈攪拌10分鐘中和。用20%異丙醇/氯仿混合物(3×30mL)萃取所得溶液,將合併之有機物經Na2SO4乾燥,過濾且濃縮,得到呈游離鹼形式之8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,8-二氮雜螺[4.5]癸-1-烯-1-胺(22mg,0.052mmol)。1H NMR(400MHz,DMSO-d 6 )δ 8.46(d,J=4.4Hz,1 H),7.67(s,1 H),7.55(dd,J=8.2,4.5Hz,1 H),7.31(d,J=8.1Hz,1 H),6.19(s,2 H),5.74(s,2 H),4.40(d,J=13.4Hz,2 H),3.43-3.34(m,2 H),2.90(t,J=12.2Hz,2 H),1.97-1.89(m,2 H),1.83(td,J=13.0,4.1Hz,2 H),1.36(d,J=12.9Hz,2 H)。MS m/z 424.1541(M+H)+。IC50為0.032μM。
使用以上胺製造以下化合物且使用本文所述之標準程序偶合。
將外消旋-2-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮(40mg,0.072mmol)溶解於5mL錐形微波瓶中之乙醇(1mL)中,添加水合肼(0.070mL,1.44mmol),加蓋且在90℃鋁珠浴上加熱2h。經由0.45μm PTFE膜真空過濾懸浮液且用乙醇洗滌。HPLC純化(梯度溶離15%至40%乙腈/水,0.1% TFA改質劑),隨後用EtOAc稀釋且相繼用碳酸氫鹽飽和水溶液、鹽水洗滌。濃縮,用1mL DCM稀釋且添加HCl(100μL,二噁烷中4M)以獲得沈澱物。濃縮,獲得8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-胺(鹽酸鹽:1mg,0.002mmol)。1H NMR(400MHz,甲醇-d 4)δ 8.43-8.39(m,1 H),7.65(s,1 H),7.46-7.39(m,2 H),4.35-4.14(m,2 H),3.98(d,J=9.2Hz,1 H),3.90(d,
J=9.2Hz,1 H),3.58(d,J=5.3Hz,1 H),3.29-3.12(m,3 H),1.76(m,4 H)。C18H22F3N6OS(M+H)+之HRMS計算值427.1528,實驗值427.1537。IC50為0.07μM。
將單一對映異構體P1,2-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮(49mg,0.088mmol)溶解於5mL錐形微波瓶中之乙醇(1mL)中,添加水合肼(0.080mL,1.65mmol),加蓋且在90℃鋁珠浴上加熱2h。經由0.45μm PTFE膜真空過濾懸浮液且用乙醇洗滌。HPLC純化(梯度溶離15%至40%乙腈/水,5mM NH4OH改質劑)引起8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-胺(13mg,0.029mmol)分離。對掌性分析型HPLC:LC-3 4.6×100mm,5μm,移動相:具有10mM氨之45% MeOH,5mL/min,單一對映異構體峰值1(P1),Rt:0.88min,>99%單一對映異構體。1H NMR(400MHz,甲醇-d4)δ 8.39(dd,J=4.3,1.6Hz,1 H),7.60(s,1 H),7.41(m,2 H),4.21-4.07(m,3 H),3.86(d,J=8.7Hz,1 H),3.79(d,J=8.7Hz,1 H),3.51(dd,J=9.0,5.2Hz,1 H),3.24(m,2 H),3.15(m,1 H),1.73(m,2 H),1.59(m,1.8Hz,2 H)。C18H22F3N6OS(M+H)+之HRMS計算值427.1528,實驗值427.1542。IC50為0.025μM。
將單一對映異構體P2,2-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-基)異吲哚啉-1,3-二酮(42mg,0.075mmol)溶解於5mL錐形微波瓶中之乙醇(1mL)中,添加水合肼(0.080mL,1.65mmol),加蓋且在90℃鋁珠浴上加熱2h。經由0.45μm PTFE膜真空過濾懸浮液且用乙醇洗滌。HPLC純化(梯度溶離15%至40%乙腈/水,5mM NH4OH改質劑)引起8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氧雜-8-氮雜螺[4.5]癸-4-胺(13mg,0.029mmol)分離。對掌性分析型HPLC:LC-3 4.6×100mm,5μm,移動相:具有10mM氨之45% MeOH,5mL/min,單一對映異構體峰值2(P2),Rt:1.33min,>99%單一對映異構體。1H NMR(400MHz,甲醇-d4)δ 8.39(dd,J=4.3,1.6Hz,1 H),7.60(s,1 H),7.41(m,2 H),4.21-4.07(m,3 H),3.86(d,J=8.6Hz,1 H),3.79(d,J=8.8Hz,1 H),3.50(dd,J=9.0,5.2Hz,1 H),3.24(m,2 H),3.15(m,1 H),1.80-1.67(m,2 H),1.64-1.50(m,2 H)。C18H22F3N6OS(M+H)+之HRMS計算值427.1528,實驗值427.1536。IC50為0.983μM。
步驟a:向2,6-二氯吡啶-3-甲醯胺(0.728g,3.81mmol)於1-甲基吡咯啶酮(7mL)中之溶液中添加N-甲基嗎啉(1.14mL,10.40mmol)及(R)-N-((R)-1-(4-甲氧基苯基)乙基)-8-氮雜螺[4.5]癸-1-胺(1g,3.47mmol)。在回流條件下將所得混合物加熱至100℃,持續24h。將反應混合物用乙酸乙酯稀釋,用濃碳酸氫鈉處理且過濾。將有機層分離,經硫酸鈉乾燥,過濾且在減壓下濃縮。藉由矽膠層析(0至50%梯度之乙酸乙酯/庚烷(含有0.25%三乙胺))純化所得深紅色油狀物,得到6-氯-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺(0.998g,2.25mmol)。1H NMR(400MHz,甲醇-d 4)δ 7.81(d,J=7.8Hz,1 H),7.26(d,J=8.6Hz,2 H),6.86(m,3 H),3.82(m,1 H),3.77(s,3 H),3.75-3.63(m,2 H),3.03(m,2 H),2.59(m,1 H),2.01-1.92(m,1 H),1.88-1.52(m,5 H),1.51-1.36(m,3 H),1.32(d,J=6.5Hz,3 H),1.25(m,2 H)。MS m/z 442.9(M+H)+。
步驟b:向6-氯-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺(242mg,0.546mmol)於甲苯(11mL)中之溶液中添加Pd2(dba)3(97mg,0.169mmol)及(氧基雙(2,1-伸苯基))雙(二苯膦)(103mg,0.191mmol)。將反應混合物用氮氣充氣且在氮氣下添加二苯甲酮亞胺(0.11mL,0.656mmol)及第三丁醇鉀(0.710mL,四氫呋喃中1M,0.710mmol)。將反應混合物加熱至80℃持續2h,且使混合物冷卻至RT,經由矽藻土墊過濾,且用乙酸乙酯洗滌。在減壓下濃縮濾液,且藉由矽膠層析(0至50%梯度之乙酸乙酯/庚烷)純化殘餘物,得到6-((二苯亞甲基)胺基)-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺(250mg,0.425mmol)。MS m/z 588.3(M+H)+。
步驟c:向6-((二苯亞甲基)胺基)-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺(130mg,0.221mmol)於THF(6mL)中之懸浮液中添加HCl(2M,0.1mL,0.200mmol)且將所得溶液在RT下攪拌30分鐘。在減壓下濃縮反應混合物且藉由矽膠層析(0至50%梯度之乙酸乙酯/庚烷(含有0.25%三乙胺))純化殘餘物,得到6-胺基-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺(43mg,0.102mmol)。MS m/z 424.1(M+H)+。
步驟d:將6-胺基-2-((R)-1-(((R)-1-(4-甲氧基苯基)乙基)胺基)-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺(199mg,0.470mmol)於三氟乙酸(3mL)中之溶液加熱至100℃,持續30min。在減壓下濃縮混合物且殘餘物不經進一步純化即用於下一步驟。(R)-6-胺基-2-(1-胺基-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺。MS m/z 290.2(M+H)+。
步驟e:向(R)-6-胺基-2-(1-胺基-8-氮雜螺[4.5]癸-8-基)菸鹼醯胺於二氯甲烷(2mL)中之溶液中添加三乙胺(0.196mL,1.410mmol)及二碳酸二第三丁酯(113mg,0.517mmol)且將所得混合物在RT下攪拌2h。
在減壓下濃縮反應混合物,且藉由矽膠層析(0至50%梯度之乙酸乙酯/庚烷(含有0.25%三乙胺))純化殘餘物,得到(8-(6-胺基-3-胺甲醯基吡啶-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(147mg,0.377mmol)。1H NMR(400MHz,甲醇-d 4)δ 7.88(d,J=8.5Hz,1 H),6.19(d,J=8.5Hz,1 H),3.66(t,J=7.7Hz,1 H),3.27-3.15(m,2 H),2.98(t,J=12.4Hz,2 H),2.05-1.94(m,1 H),1.86-1.46(m,8 H),1.45(s,9 H),1.41(d,J=6.0Hz,1 H)。MS m/z 390.3(M+H)+。
步驟f:向(8-(6-胺基-3-胺甲醯基吡啶-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(136mg,0.349mmol)於二氯甲烷(5mL)中之在冰浴上冷卻之溶液中添加N-碘丁二醯亞胺(86mg,0.384mmol)。將所得混合物在5℃下攪拌2h。藉由添加2mL甲醇淬滅反應物且使混合物升溫至RT。在減壓下移除溶劑。將粗產物用二氯甲烷萃取且用鹽水洗滌。將有機層經硫酸鈉乾燥,過濾且在減壓下濃縮,得到(8-(6-胺基-3-胺甲醯基-5-碘吡啶-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(170mg,0.330mmol),其不經進一步純化即用於下一步驟。MS m/z 516.1(M+H)+。
步驟g:向(8-(6-胺基-3-胺甲醯基-5-碘吡啶-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(177mg,0.343mmol)於二噁烷(10mL)中之溶液中添加Pd2(dba)3(31.4mg,0.034mmol)、(9,9-二甲基-9H-二苯并哌喃-4,5-二基)雙(二苯膦)(39.7mg,0.069mmol)、2-(三氟甲基)吡啶-3-硫醇(67.7mg,0.378mmol)及N,N-二異丙基乙胺(0.120mL,0.687mmol)。將所得混合物加熱至120℃持續2h,隨後使其冷卻至RT。將反應混合物用乙酸乙酯稀釋且經由短矽藻土墊過濾。將濾液在減壓下濃縮且藉由矽膠層析(0至50%之梯度乙酸乙酯/庚烷(含有0.25%三乙胺))純化,得到(8-(6-胺基-3-胺甲醯基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡啶-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(115mg,0.203
mmol)。MS m/z 567.2(M+H)+。
步驟h:向(8-(6-胺基-3-胺甲醯基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡啶-2-基)-8-氮雜螺[4.5]癸-1-基)胺基甲酸(R)-第三丁酯(110mL,0.194mmol)於二氯甲烷(2mL)中之溶液中添加三氟乙酸(2mL,26mmol)且使所得混合物在RT下攪拌1h。在減壓下移除溶劑,且藉由HPLC(梯度溶離:35%至60%乙腈/水,5mM NH4OH改質劑)純化殘餘物,得到(R)-6-胺基-2-(1-胺基-8-氮雜螺[4.5]癸-8-基)-5-((2-(三氟甲基)吡啶-3-基)硫基)菸鹼醯胺(40mg,0.084mmol)。1H NMR(400MHz,甲醇-d 4)δ 8.38(dd,J=4.1,1.9Hz,1 H),7.93(s,1 H),7.56-7.31(m,2 H),3.77-3.55(m,2 H),3.16-2.98(m,2 H),2.82(t,J=7.4Hz,1 H),2.03(m,1 H),1.94-1.60(m,5 H),1.60-1.20(m,4 H)。19F NMR(376MHz,甲醇-d 4)δ -66.48。C21H26F3N6OS(M+H)+之HRMS計算值467.1841,實驗值467.1837。IC50為0.118μM。
步驟a:將2-氯-3-巰基苯甲醯胺(鹽酸鹽,145mg,0.647mmol)、3-溴-6-氯吡嗪-2-胺(299mg,1.436mmol)、碘化銅(I)(49.3mg,0.259mmol)、磷酸鉀(412mg,1.941mmol)及1,10-啡啉(58.3mg,0.324mmol)
於二噁烷(5mL,脫氣)中之混合物於微波反應器中在130℃下攪拌4h。在冷卻至RT之後,反應物經由矽藻土墊過濾,隨後用EtOAc(50mL)洗滌。濃縮經合併之濾液且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到3-((3-胺基-5-氯吡嗪-2-基)硫基)-2-氯苯甲醯胺(140mg,0.444mmol)。MS m/z 315.0(M+H)+。
步驟b:將3-((3-胺基-5-氯吡嗪-2-基)硫基)-2-氯苯甲醯胺(130mg,0.412mmol)及(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(139mg,0.536mmol)於DIPEA(0.648mL)中之混合物於微波反應器中在95℃下攪拌14h。在冷卻至RT之後,在減壓下移除揮發物且藉由矽膠層析(0至100%梯度之MeOH/DCM(含有0.25% TEA))純化所得殘餘物,得到3-((3-胺基-5-((R)-1-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯甲醯胺(65mg,0.121mmol)。MS m/z 537.2(M+H)+。
步驟c:將3-((3-胺基-5-((R)-1-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯甲醯胺(65mg,0.121mmol)溶解於HCl/二噁烷(4M,0.121mL,0.484mmol)中且在22℃下攪拌直至無起始物質剩餘(1h,藉由LCMS監控)。在減壓下移除揮發物且藉由HPLC(梯度溶離:25%至50%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(R)-3-((3-胺基-5-(1-胺基-8-氮雜螺[4.5]癸-8-基)吡嗪-2-基)硫基)-2-氯苯甲醯胺(25.5mg,0.058mmol)。1H NMR(400MHz,DMSO-d 6 )δ 7.90(s,1 H),7.63(s,1 H),7.62(br.s.,1 H),7.28-7.18(m,1 H),7.18-7.09(m,1 H),6.64(dd,J=1.6,7.9Hz,1 H),6.08(s,2 H),4.18-4.07(m,2 H),3.12-2.95(m,2 H),2.74-2.64(m,1 H),1.91-1.73(m,2 H),1.66-1.47(m,4 H),1.39-1.14(m,4 H)。C20H26ClN6OS(M+H)+之HRMS計算值433.1577,實驗值433.1598;IC50為0.016μM。
步驟a:將3-((第三丁基二甲基矽烷基)氧基)-1-((R)-1,1-二甲基乙基亞磺醯胺基)-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-第三丁酯(100mg,0.205mmol)及HCl(二噁烷中4M,510μL,2.05mmol)於MeOH(1mL)中之混合物在40℃下攪拌1h。在減壓下移除揮發物且將所得白色殘餘物在真空下乾燥1h。MS m/z 171.1(M+H)+。
步驟b:將此白色殘餘物及3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(65mg,0.226mmol)於DIPEA:NMP(2:1;1.5mL)中之混合物在100℃下劇烈攪拌40h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離7.5-20%乙腈/水,0.1% TFA改質劑)純化所得粗產物。在減壓下移除揮發物且藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)進一步純化所得殘餘物,得到呈白色固體狀之(2R,4R)-4-胺基-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-2-醇(44mg,0.102mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.51-7.64(m,2 H),5.92(d,J=5.56Hz,1 H),4.16-4.39(m,3 H),3.00-3.21(m,2 H),2.80(dd,J=8.08,7.07Hz,1 H),2.33(dt,J=13.45,6.79Hz,1 H),1.95(dd,J=13.89,7.58Hz,1 H),1.83(dd,J=14.02,4.17Hz,1 H),1.61-1.74(m,3 H),1.56(ddd,J=13.39,8.08,5.81Hz,1 H),1.30(d,J=13.14Hz,1 H)。C18H25ClN7OS(M+H)+之HRMS計算值422.1557,實驗值422.1569。IC50為0.007μM。
使用以上程序或對以上程序之修改,使用對應經保護之胺及氯-吡嗪中間物合成以下表9化合物。
步驟a:將4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3R,4S)-第三丁酯(53mg,0.142mmol)及HCl(二噁烷中4M,354μL,1.415mmol)於MeOH(5mL)中之混合物在40℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物,得到(3R,4S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺,其不經進一步純化即用於下一步驟。MS m/z 171.1(M+H)+。
步驟b:將(3R,4S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺粗產物、3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(35.5mg,0.123mmol)及DIPEA(193μL,1.11mmol)於DMSO(600μL)中之混合物在100℃下攪拌16h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(3R,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺(13mg,0.030mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.72-7.51(m,2 H),5.92(d,J=5.5Hz,1 H),4.31(m,2 H),4.01-3.78(m,2 H),3.58(dq,J=8.1,6.0Hz,1 H),3.04(m,2 H),2.48(d,J=8.1Hz,1 H),1.75(m,2 H),1.61-1.47(m,2 H),1.31(d,J=6.1Hz,3 H)。C18H25ClN7OS(M+H)+之HRMS計算值422.1530,實驗值422.1505。IC50為0.010μM。
步驟a:將4-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-8-甲酸(3S,4S)-第三丁酯(51mg,0.136mmol)及HCl(二噁烷中4M,340μL,1.362mmol)於MeOH(5mL)中之混合物在40℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物,得到(3S,4S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺,其不經進一步純化即用於下一步驟。MS m/z 171.1(M+H)+。
步驟b:將(3S,4S)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸烷-4-胺粗產物、3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(35.5mg,0.123mmol)及DIPEA(193μL,1.11mmol)於DMSO(600μL)中之混合物在100℃下攪拌16h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(3S,4S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-2-氧雜-8-氮雜螺[4.5]癸-4-胺(11mg,0.026mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.67-7.47(m,2 H),5.91(d,J=5.5Hz,1 H),4.22(qd,J=6.4,4.8Hz,1 H),4.03(ddt,J=13.5,8.9,4.7Hz,2 H),3.86(d,J=8.7Hz,1 H),3.71(d,J=8.7Hz,1 H),3.37(td,J=9.9,4.9Hz,1 H),3.29-3.23(m,1 H),3.00(d,J=5.0Hz,1H)1.91-1.56(m,4 H),1.21(d,J=6.4Hz,3 H)。C18H25ClN7OS(M+H)+之HRMS計算值422.1530,實驗值422.1514。IC50為0.010μM。
步驟a:將1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3R)-苯甲酯(100mg,0.246mmol)及HCl(二噁烷中4M,1.5mL,6.5mmol)於MeOH(1.5mL)中之混合物於微波反應器中在140℃下攪拌14h。在冷卻至RT之後,在減壓下移除揮發物,得到(1R,3R)-3-甲基-8-氮雜螺[4.5]癸-1-胺,其不經進一步純化即用於下一步驟。MS m/z 169.2(M+H)+。
步驟b:將(1R,3R)-3-甲基-8-氮雜螺[4.5]癸-1-胺粗產物(理論0.246mmol)及3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(70.9mg,0.246mmol)於DIPEA(1mL)及DMSO(0.5mL)中之混合物在130℃下攪拌2h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到(1R,3R)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-8-氮雜螺[4.5]癸-1-胺(23mg,0.055mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.51-7.64(m,2 H),5.91(d,J=5.31Hz,1 H),4.18-4.37(m,2 H),3.02-3.18(m,2 H),2.82(dd,J=9.60,6.32Hz,1 H),2.09-2.20(m,1 H),2.00-2.09(m,1 H),1.91-2.00(m,1 H),1.58-1.74(m,2 H),1.24-1.48(m,3 H),1.09-1.20(m,1 H),1.01-1.09(m,3 H)。C19H27ClN7S(M+H)+之HRMS計算值420.1737,實驗值420.1719。IC50為0.005μM。
步驟a:將1-((R)-1,1-二甲基乙基亞磺醯胺基)-3-甲基-8-氮雜螺[4.5]癸烷-8-甲酸(1R,3S)-苯甲酯(600mg,1.476mmol)及Pd(OH)2(104mg,0.148mmol)於EtOAc:THF(1:275mL)中之懸浮液在H2氛圍下劇烈攪拌48h。將反應混合物經由矽藻土墊過濾,隨後用MeOH(50mL)洗滌。在減壓下移除揮發物。將所得殘餘物及HCl(二噁烷中4M,1.0mL,4.0mmol)之溶液在45℃下攪拌2h。在冷卻至RT之後,在減壓下移除揮發物。將所得殘餘物及Pd/C(木炭中10%,200mg)於MeOH(20mL)中之懸浮液在60psi H2氛圍下震盪2h。將反應混合物經由矽藻土墊過濾,隨後用MeOH(50mL)洗滌。在減壓下移除揮發物,得到(1R,3S)-3-甲基-8-氮雜螺[4.5]癸-1-胺,其不經進一步純化即用於下一步驟。MS m/z 169.1(M+H)+。
步驟b:將(1R,3S)-3-甲基-8-氮雜螺[4.5]癸-1-胺粗產物(0.729mmol)及3-((2-胺基-3-氯吡啶-4-基)硫基)-6-氯吡嗪-2-胺(150mg,0.521mmol)於DIPEA(3.2mL)及DMA(6mL)中之混合物在100℃下攪拌14h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離10-30%乙腈/水,0.1% TFA改質劑)純化所得殘餘物,得到粗固體。藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)進一步純化此粗固體,得到(1R,3S)-8-(6-胺基-5-((2-胺基-3-氯吡啶-4-基)硫基)吡嗪-2-基)-3-甲基-8-氮雜螺[4.5]癸-1-胺(80mg,0.189mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.65-7.49(m,2 H),5.91(d,J=5.5Hz,1 H),4.30
(ddt,J=12.4,9.7,3.6Hz,2 H),3.34(s,1 H),3.19-2.95(m,1 H),2.92-2.80(m,1 H),2.34-2.16(m,2 H),1.85-1.49(m,4 H),1.41(dq,J=13.5,2.7Hz,1 H),1.30(dq,J=13.5,2.6Hz,1 H),1.13-0.92(m,4 H)。C19H27ClN7S(M+H)+之HRMS計算值420.1737,實驗值420.1716。IC50為0.005μM。
步驟a:將6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(70mg,0.304mmol)、((4-羥基哌啶-4-基)甲基)胺基甲酸第三丁酯(103mg,0.336mmol)及DIPEA(2.0mL,11.45mmol)於NMP(1mL)中之溶液在120℃下攪拌3h。在冷卻至RT之後,用EtOAc稀釋反應物,將有機相用水、鹽水洗滌,經Na2SO4乾燥且在減壓下移除揮發物,得到棕色油狀殘餘物。將此殘餘物溶解於DCM(5mL)中且以兩份形式添加HCl(二噁烷中4M;760μL,3.04mmol)(一半在開始反應時且另一半在3h後)。將反應物攪拌總共4h。在減壓下移除揮發物且用MeCN濕磨所得殘餘物,得到棕色固體。將所得粗產物以游離鹼形式懸浮於5% MeOH/DCM中且添加NaHCO3飽和水溶液。分離所得層且再次用5% MeOH/DCM萃取水溶液。在減壓下濃縮經合併之有機相,得到呈灰白色-棕褐色固體狀之1-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-4-(胺甲基)哌啶-4-醇(65mg,0.149mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 8.47(dd,J=4.6,1.4Hz,1 H),7.68(s,1 H),7.55(dd,
J=8.3,4.5Hz,1H)7.32(dd,J=8.3,1.4Hz,1 H),4.04(dt,J=13.8,4.2Hz,2 H),3.38-3.28(m,2 H),2.83(s,2 H),1.70-1.48(m,4 H)。MS m/z 401.2(M+H)+。
步驟b:相繼接連用溴化氰(0.541mL,1.623mmol)、NaHCO3(68.2mg,0.812mmol)處理1-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-4-(胺甲基)哌啶-4-醇(65mg,0.162mmol)於EtOH(3mL)中之溶液且將所得混合物在RT下攪拌16h。在減壓下移除揮發物且藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-1-氧雜-3,8-二氮雜螺[4.5]癸-2-烯-2-胺(12.5mg,0.029mmol)。1H NMR(400MHz,DMSO-d 6)δ ppm 8.46(dd,J=4.5,1.4Hz,1 H),7.68(s,1 H),7.55(dd,J=8.3,4.6Hz,1 H),7.31(dd,J=8.2,1.5Hz,1 H),6.22(s,2 H),5.78(s,2 H),3.94-3.73(m,2 H),3.64-3.45(m,2 H),3.36(s,2 H),1.88-1.56(m,4 H)。C17H19F3N7OS(M+H)+之HRMS計算值426.1318,實驗值426.1296。IC50為0.193μM。
使用以上程序或對以上程序之修改,使用對應經保護之胺及氯-吡嗪中間物合成以下表10化合物。
步驟a:將6-溴-3-((3-氯-2-(二甲胺基)吡啶-4-基)硫基)吡嗪-2-胺(124mg,0.392mmol)及(R)-2-甲基-N-((R)-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(111mg,0.431mmol)於DIPEA(2.6mL)中之混合物在90℃下攪拌10h。在冷卻至RT之後,在減壓下移除揮發物且藉由矽膠層析(0至10%梯度之EtOAc(含有10% MeOH)/庚烷(含有25% Et3N))純化所得殘餘物,得到(R)-N-((R)-8-(6-胺基-5-((3-氯-2-(二甲胺基)吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(75mg,0.139mmol)。MS m/z 538.3(M+H)+。
步驟b:將(R)-N-((R)-8-(6-胺基-5-((3-氯-2-(二甲胺基)吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(75mg,0.139mmol)及HCl(二噁烷中4M,174μL,0.697mmol)於DCM(2mL)中之混合物在RT下攪拌30min。在減壓下移除揮發物且藉由HPLC(梯度溶離35-60%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到呈白色固體狀之(R)-8-(6-胺基-5-((3-氯-2-(二甲胺基)吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-胺(28mg,0.064mmol)。1H NMR(400
MHz,DMSO-d 6)δ ppm 7.85-7.92(m,1 H),7.63(s,1 H),6.16(br.s,2 H),6.04-6.10(m,1 H),4.06-4.23(m,2 H),2.97-3.15(m,2 H),2.87(s,6 H),2.64-2.73(m,1 H),1.11-1.97(m,10 H)。C20H29ClN7S(M+H)+之HRMS計算值434.1894,實驗值434.1883。IC50為0.010μM。
使用以上程序或對以上程序之修改,使用對應經保護之胺及氯-吡嗪中間物合成以下表11化合物。
將(S)-N-((R)-8-(6-胺基-5-((3-氯-2-氟吡啶-4-基)硫基)吡嗪-2-基)-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(17mg,0.033mmol)、氫氧化鋰(2mg,0.040mmol)及水(0.07mL)於DMSO(0.3mL)中之混合物於微波反應器中在90℃下攪拌45min。在冷卻至RT之後,添加MeOH(0.5mL),隨後添加HCl(二噁烷中4M,2.0mL,8.0mmol)且將所得混合物在40℃下攪拌1h。在減壓下移除揮發物且藉由HPLC(梯度溶離15-40%乙腈/水,5mM NH4OH改質劑)純化所得殘餘物,得到呈白色固體狀之(R)-4-((3-胺基-5-(1-胺基-8-氮雜螺[4.5]癸-8-基)吡嗪-2-基)硫基)-3-氯吡啶-2(1H)酮(5mg,0.012mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 7.53-7.61(m,1 H),7.19(d,J=7.1Hz,1 H),5.72
(d,J=7.1Hz,1 H),4.26(t,J=13.1Hz,2 H),3.06-3.20(m,2 H),2.81(t,J=7.5Hz,1 H),1.27-2.11(m,10 H)。C18H24ClN6OS(M+H)+之HRMS計算值407.1448,實驗值407.1433。IC50為0.020μM。
步驟a:將2,2-二氟-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(220mg,0.76mmol)、外消旋2-甲基丙烷-2-亞磺醯胺(184mg,1.52mmol)及乙醇鈦(IV)(0.640mL,3.0mmol)於THF(4mL)中之溶液在90℃下攪拌30min。在冷卻至0℃之後,一次性添加硼氫化鋰(33mg,1.5mmol)。在攪拌30min之後,藉由添加MeOH淬滅反應混合物。在減壓下移除揮發物。將所得殘餘物用鹽水稀釋,將其用EtOAc(4×10mL)萃取,將合併之有機相經Na2SO4乾燥,過濾且在減壓下濃縮。藉由矽膠層析(10%至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈白色粉末狀之1-(1,1-二甲基乙基亞磺醯胺基)-2,2-二氟-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(190mg,0.48mmol)。MS m/z 395.2(M+H)+。
步驟b:將1-(1,1-二甲基乙基亞磺醯胺基)-2,2-二氟-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(190mg,0.48mmol)及TFA(1mL)於DCM(4mL)中之溶液在0℃下攪拌20min。在減壓下移除揮發物,得到N-(2,2-二氟-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺,其不經進一步純化即用於下一步驟。
步驟c:將N-(2,2-二氟-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(理論0.48mmol)及6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-
胺(148mg,0.480mmol)於DIPEA(0.8mL)中之溶液在100℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物且藉由矽膠層析(0至100%梯度之EtOAc/庚烷)純化所得殘餘物,得到呈橙色粉末狀之N-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2-二氟-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(174mg,0.28mmol)。此物質之一部分繼續進行步驟d,剩餘物質藉由對掌性層析(參見實例83)分離。
步驟d:將N-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2-二氟-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(54mg,0.096mmol)及HCl(二噁烷中4M,0.239mL,0.96mmol)於DCM(1mL)中之溶液在40℃下攪拌30min。在冷卻至RT之後,在減壓下移除揮發物。用MeCN濕磨此殘餘物,得到呈淡棕褐色粉末狀之外消旋-8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2-二氟-8-氮雜螺[4.5]癸-1-胺(鹽酸鹽,38mg,0.075mmol)。1H NMR(400MHz,甲醇-d 4)δ ppm 8.52-8.38(m,1 H),7.71(s,1 H),7.50-7.43(m,2 H),4.44(dd,J=21.0,14.2Hz,2 H),3.67(dd,J=15.1,11.2Hz,1 H),3.23-3.08(m,2 H),2.47-2.34(m,2 H),2.27(dt,J=14.6,7.4Hz,1 H),2.01-1.88(m,2 H),1.75-1.54(m,3 H)。C19H22F5N6S(M+H)+之HRMS計算值461.1547,實驗值461.1540。IC50為0.380μM。
步驟a:藉由對掌性SFC如下進一步純化N-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2,2-二氟-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(100mg,0.177mmol):管柱:WHO-1 21×250mm,流動速率:80g/min,移動相:含45% MeOH及5mM NH4OH之CO2,偵測:觸發質量,獲得單一對映異構體Rt(對映異構體R):2.6min(44mg,0.078mmol)及Rt(對映異構體S):5.8min(41mg,0.073mmol)。
步驟b:將純對映異構體及HCl(二噁烷中4M,200μL,0.8mmol)於DCM(2mL)中之混合物在40℃下攪拌1h。在減壓下移除揮發物且用MeCN濕磨所得殘餘物,得到呈鹽酸鹽形式之標題化合物:
(R)-對映異構體:1H NMR(400MHz,甲醇-d 4)δ ppm 8.46(dd,J=3.7,2.3Hz,1 H),7.73(s,1 H),7.53-7.45(m,2 H),4.52-4.36(m,2 H),3.68(dd,J=15.0,11.2Hz,1 H),3.24-3.09(m,2 H),2.47-2.34(m,2 H),2.32-2.21(m,1 H),2.05-1.90(m,2 H),1.74-1.55(m,3 H)。19F NMR(376MHz,甲醇-d 4)δ -66.19,-98.51(d,J=234.5Hz),-101.83(d,J=234.6Hz)。C19H22F5N6S(M+H)+之HRMS計算值461.1547,實驗值461.1540。IC50為0.882μM。
(S)-對映異構體:1H NMR(400MHz,甲醇-d 4)δ ppm 8.50-8.41(m,1 H),7.70(s,1 H),7.47(m,2 H),4.52-4.35(m,2 H),3.67(dd,J=15.1,11.2Hz,1 H),3.24-3.05(m,2 H),2.49-2.32(m,2 H),2.31-2.19(m,1 H),2.02-1.88(m,2 H),1.73-1.51(m,3 H)。19F NMR(376MHz,甲醇
-d 4)δ -66.24,-98.47(d,J=234.4Hz),-101.77(d,J=234.6Hz)。C19H22F5N6S(M+H)+之HRMS計算值461.1547,實驗值461.1541。IC50為0.306μM。
步驟a:將外消旋2-氟-1-側氧基-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(78mg,0.28mmol)、乙醇鈦(IV)(235μL,1.1mmol)及(R)-2-甲基丙烷-2-亞磺醯胺(68mg,0.56mmol)於THF(1.5mL)中之溶液在90℃下攪拌1h。在冷卻至0℃之後,一次性添加硼氫化鋰(12mg,0.56mmol)。在攪拌30min之後,藉由添加MeOH淬滅反應混合物。在減壓下移除揮發物。將所得殘餘物用鹽水稀釋,將其用EtOAc(4×10mL)萃取,將合併之有機相經Na2SO4乾燥,過濾且在減壓下濃縮。藉由矽膠層析(0至50%梯度之EtOAc/庚烷)純化所得殘餘物,得到1-((R)-1,1-二甲基乙基亞磺醯胺基)-2-氟-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(64mg,0.17mmol)。MS m/z 377.3(M+H)+。
步驟b:將1-((R)-1,1-二甲基乙基亞磺醯胺基)-2-氟-8-氮雜螺[4.5]癸烷-8-甲酸第三丁酯(64mg,0.17mmol)及TFA(1mL)於DCM(4mL)
中之混合物在0℃下攪拌10min。在減壓下移除揮發物且所得殘餘物不經進一步純化即用於下一步驟。
步驟c:將之前的殘餘物及6-氯-3-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-胺(51mg,0.17mmol)於DIPEA(0.3mL)中之混合物在100℃下攪拌2h。在冷卻至RT之後,在減壓下移除揮發物且藉由矽膠層析(0至10%梯度之MeOH/DCM(含有0.25% Et3N))純化所得殘餘物,以非對映異構體混合物形式得到N-(8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-氟-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺(41mg,0.075mmol)。MS m/z 547.2(M+H)+。使用對掌性SFC如下進行進一步純化:管柱:ID 21×250mm,流動速率:80g/min,移動相:含45% iPrOH及10mM NH4OH之CO2,偵測:觸發質量,得到單一對映異構體Rt(P1)=2.7min(17mg,0.031mmol)及Rt(對映異構體-P1)=4.4min(17mg,0.031mmol)。
步驟d:將各純異構體及HCl(二噁烷中4M,100μL,0.4mmol)於DCM(0.1mL)中之溶液在40℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物且用MeCN濕磨所得殘餘物,得到呈鹽酸鹽形式之標題化合物。
步驟a:將1-((R)-1,1-二甲基乙基亞磺醯胺基)-2-甲基-8-氮雜螺[4.5]癸烷-8-甲酸(1R)-第三丁酯(32mg,0.086mmol)及TFA(0.2mL,2.60mmol)於DCM(2mL)中之溶液在RT下攪拌30min。在減壓下移除
揮發物,得到(R)-2-甲基-N-((1R)-2-甲基-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺。MS m/z 273.0(M+H)+。粗產物不經進一步純化即用於下一步驟。
步驟b:將(R)-2-甲基-N-((1R)-2-甲基-8-氮雜螺[4.5]癸-1-基)丙烷-2-亞磺醯胺(23mg,0.084mmol)、6-氯-3-((2-(三氟甲基)吡啶-3-基))吡嗪-2-胺(23mg,0.075mmol)及NMP(0.1mL)於DIPEA(1mL)中之混合物在115℃下攪拌6h。在冷卻至RT之後,在減壓下移除揮發物,得到呈黑色油狀物之(R)-N-((1R)-8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-甲基-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺,其不經純化即用於下一步驟。
步驟c:將(R)-N-((1R)-8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-甲基-8-氮雜螺[4.5]癸-1-基)-2-甲基丙烷-2-亞磺醯胺及HCl(二噁烷中4M,84μL,0.338mmol)於DCM(2mL)中之混合物在40℃下攪拌1h。在冷卻至RT之後,在減壓下移除揮發物且藉由HPLC(梯度溶離35-60%乙腈/水,0.1% TFA改質劑)純化所得殘餘物,得到8-(6-胺基-5-((2-(三氟甲基)吡啶-3-基)硫基)吡嗪-2-基)-2-甲基-8-氮雜螺[4.5]癸-1-胺TFA鹽。C20H26F3N6S(M+H)+之HRMS計算值439.1892,實驗值439.1872。IC50為0.0010μM。
步驟d:對掌性分離(關於細節參見表13)。
可使用以上方法及適當起始物質製造以下表14之實例:
評估本發明化合物選擇性抑制SHP2活性之能力。本文所述之本發明化合物之抑制特性可藉由在以下分析中之任一者中測試來證明。
SHP2經由將雙酪胺醯基磷酸化肽結合至其Src同源2(SH2)結構域異位活化。後一活化步驟引起SHP2之自身抑制界面之釋放,其又使得SHP2蛋白酪胺酸磷酸酶(PTP)活化且可用於受質識別及反應催化。使用瞬時螢光分析格式之代用受質DiFMUP監控SHP2之催化活性。
更特定言之,在室溫下於平底、低凸緣、非結合表面384孔黑色聚苯乙烯培養盤(Corning,目錄號3575)中使用25μL之最終反應體積及以下分析緩衝液條件進行磷酸酶反應:60mM HEPES(pH 7.2)、75mM NaCl、75mM KCl、1mM EDTA、0.05% P-20、5mM DTT。
使用其中0.5nM SHP2與0.5μM肽IRS1_pY1172(dPEG8)pY1222(序列:H2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-醯胺)一起培育之分析來監控本發明化合物(濃度在0.003-100μM之間變化)對SHP2之抑制。在25℃下培育30-60分鐘之後,將代用受質DiFMUP(Invitrogen,
目錄號D6567)添加至反應中且在25℃下培育30分鐘。隨後藉由添加5μl 160μM bpV(Phen)溶液(Enzo Life Sciences目錄號ALX-270-204)淬滅反應物。使用微定量盤式讀取器(Envision,Perki-Elmer),使用分別為340nm及450nm之激勵及發射波長,監控螢光信號。使用與基於對照之標準化擬合之標準化IC50回歸曲線分析抑制劑劑量反應曲線。本發明化合物之IC50結果顯示於以上實例及表1-7中。
p-ERK細胞分析使用AlphaScreen® SureFireTM磷酸化ERK 1/2套組(PerkinElmer):使KYSE-520細胞(每孔30,000個細胞)生長於96孔板中培養隔夜且用Shp2抑制劑以20μM、6.6μM、2.2μM、0.74μM、0.24μM、0.08μM、0.027μM之濃度在37℃下處理2h。藉由添加與SureFire磷酸化細胞外信號調節激酶(pERK)分析套組(PerkinElmer)一起供應之30μL溶解緩衝液(PerkinElmer)終止培育。根據製造商之說明處理樣品。使用2101多標記讀取器(Perkin Elmer Envision)一式兩份地量測來自pERK之螢光信號。將抑制百分比針對總ERK信號標準化且與DMSO媒劑對照相比較。
將KYSE-520細胞(每孔1500個細胞)塗覆至24孔板上300μL培養基(含有10% FBS之RPMI-1640,Lonza)中。就藥物治療而言,在細胞塗覆之後24小時及5天,添加各種濃度(20μM、10μM、5μM、2.5μM、1.25μM)之本發明化合物。在第11天,用0.2%結晶紫(MP Biomedicals)對群落進行染色且隨後將其溶解於20%乙酸中以便使用Spectramax讀取器(Thermo Scientific)定量。在細胞增殖分析中,將細胞(每孔1500個細胞)塗覆至96孔板上100μL培養基(含有10% FBS之RPMI-1640,Lonza)中。在第6天,添加50μL Celltiter-Glo試劑(Promega),且根據供應商之指示(Promega)測定發光信號。
應理解,本文所述之實例及實施例僅出於說明之目的,且鑒於其而進行之各種修改或變化應由熟習此項技術者提出且包括在本申請案之精神及範圍及所附申請專利範圍之範疇內。
Claims (27)
- 一種式I化合物,其中:p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;R1為-XR1a;其中R1a選自C6-10芳基、C3-8環烷基、C3-8環烯基及含有1至4個獨立地選自N、C(O)、O及S之雜原子或基團之5-9員雜芳基;其中R1a之該芳基或雜芳基經1至5個獨立地選自鹵基、胺基、羥基、N3、C1-4烷基、C1-4烷氧基、二甲基-胺基、羥基取代之C1-4烷基、鹵基取代之C1-4烷基、胺基取代之C1-4烷基、-C(O)OR10、-C(O)NH2及-NHC(O)R10之R9基團取代;其中R10選自氫、苯基及萘基;其中R10之苯基為未經取代或經甲氧基取代;且X選自一鍵、S(O)m、O、C(O)、COR11、CR10aR10b、NR11;其中m選自0、1及2;各R10a及R10b獨立地選自鹵基及C1-4烷基;且R11選自氫及C1-4烷基;R2a及R2b獨立地選自氫、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R3a及R3b獨立地選自氫、鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R4a及R4b獨立地選自氫、鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R5a及R5b獨立地選自氫、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;其中選自R2a、R2b、R3a、R3b、R4a、R4b、R5a、R5b及R7之任何兩個基團可形成5至6員不飽和或部分飽和環;R6選自氫、鹵基、氰基、C1-4烷基、C1-4烷氧基、胺基-羰基、鹵基取代之C1-4烷基、鹵基取代之C1-4烷氧基、羥基取代之C1-4烷基、胺基取代之C1-4烷基、-S(O)1-2R6a、-C(S)R6a、-C(O)NR6aR6b、-C(NH)NR6aR6b及-NR6aC(O)R6b;其中R6a及R6b獨立地選自氫及C1-4烷基;R7及R8連同其均連接之碳原子一起形成可視情況含有1至3個獨立地選自N、C(O)、O及S(O)m之雜原子或基團之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經1至3個獨立地選自胺基、羥基、甲氧基、鹵基、甲基、胺基-甲基、甲基-胺基及異丁醯氧基之基團取代;或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其具有式Ia:其中:n選自1、2、3及4;p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;各Y4獨立地選自N、C(O)及CR9;其中僅一個Y4為C(O);R6選自氫、鹵基、甲基及胺基-羰基;R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、C(O)、O及S(O)m之雜原子之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經1至3個獨立地選自胺基、鹵基、甲基、羥基、甲氧基、胺基-甲基、甲基-胺基及異丁醯氧基之基團取代;R9選自鹵基、胺基、羥基、N3、二甲基-胺基、C1-4烷基、鹵基取代之C1-4烷基、C1-4烷氧基、-C(O)OR10、-C(O)NH2及-NHC(O)R10;R10選自氫、苯基及萘基;其中R10之該苯基未經取代或經甲氧基取代;或其醫藥學上可接受之鹽。
- 如請求項2之化合物,其中R7及R8連同其均連接之碳原子一起形成可視情況含有1至2個獨立地選自N、O、C(O)及S(O)m之雜原子或基團之5員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經1至3個獨立地選自胺基、羥基、甲氧基、鹵基、甲基、胺基-甲基、甲基-胺基及異丁醯氧基之基團取代;或其醫藥學上可接受之鹽。
- 如請求項2之化合物,其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之6員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經胺基取代;或其醫藥學上可接受之鹽。
- 如請求項2之化合物,其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之4員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經選自胺基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
- 如請求項2之化合物,其中p及q均為0;或其醫藥學上可接受之鹽。
- 如請求項1之化合物,其具有式II:其中:p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;R1選自C6-10芳基、C3-8環烷基、C3-8環烯基及含有1至4個選自N、O及S之雜原子之5-9員雜芳基;其中R1a之該芳基或雜芳基經1至5個獨立地選自鹵基、胺基、羥基、N3、C1-4烷基、羥基取代之C1-4烷基、鹵基取代之C1-4烷基、胺基取代之C1-4烷基、C1-4烷氧基、-C(O)NH2、-C(O)OR10及-NHC(O)R10之R9基團取代;其中R10選自氫、苯基及萘基;其中R10之苯基未經取代或經甲氧基取代;R2a及R2b獨立地選自氫、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R3a及R3b獨立地選自氫、鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R4a及R4b獨立地選自氫、鹵基、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;R5a及R5b獨立地選自氫、羰基、C1-4烷基、C1-4烷氧基、胺基、羥基、C3-8環烷基及C1-4烷基-胺基;其中選自R2a、R3a、R4、R5、R6a及R7a之任何兩個基團可形成5至6員不飽和或部分不飽和環;R6選自氫、鹵基、氰基、C1-4烷基、C1-4烷氧基、胺基-羰基、鹵基取代之C1-4烷基、鹵基取代之C1-4烷氧基、羥基取代之C1-4烷基及胺基取代之C1-4烷基;R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經1至3個獨立地選自胺基、鹵基、羥基、胺基-甲基及甲基-胺基之基團取代;或其醫藥學上可接受之鹽。
- 如請求項11之化合物,其具有式IIa:其中:n選自1、2、3及4;p選自0及1;q選自0及1;Y1選自CH及N;Y2選自CR6及N;Y4選自N及CR9;R6選自氫、鹵基、甲基及胺基-羰基;R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之3至7員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環可未經取代或經選自胺基、胺基-甲基及甲基-胺基之基團取代;R9選自鹵基、胺基、羥基、N3、C1-4烷基、鹵基取代之C1-4烷基、C1-4烷氧基、-C(O)OR10、-C(O)NH2及-NHC(O)R10;R10選自氫、苯基及萘基;其中R10之該苯基未經取代或經甲氧基取代;或其醫藥學上可接受之鹽。
- 如請求項12之化合物,其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之5員飽和或部分不飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經胺基取代;或其醫藥學上可接受之鹽。
- 如請求項12之化合物,其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之6員飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經胺基取代;或其醫藥學上可接受之鹽。
- 如請求項12之化合物,其中R7及R8連同其均連接之碳原子一起形成可視情況含有選自N、O及S(O)m之雜原子之4員飽和環;其中m選自0、1及2;其中由R7及R8形成之該飽和環經胺基取代;或其醫藥學上可接受之鹽。
- 如請求項12之化合物,其中p及q均為0;或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含如請求項1至20中任一項之化合物或其醫藥學上可接受之鹽,及至少一種醫藥學上可接受之載劑。
- 一種如請求項1至20中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製造預防性或治療性治療藉由SHP2之活性介導之疾病或病症的藥物。
- 如請求項22之用途,其中該藉由SHP2之活性介導之疾病或病症選自努南症候群(Noonan Syndrome)、豹皮症候群(Leopard Syndrome)、青少年骨髓單核細胞性白血病、神經母細胞瘤、黑素瘤、急性骨髓白血病、乳癌、食道癌、肺癌、結腸癌、頭部癌、神經母細胞瘤、頭頸部鱗狀細胞癌、胃癌、退行性大細胞淋巴瘤及神經膠母細胞瘤。
- 一種如請求項24之化合物之用途,其用於製造治療肺癌之藥物。
- 一種如請求項24之化合物之用途,其用於製造治療頭頸部鱗狀細胞癌之藥物。
- 一種如請求項24之化合物之用途,其用於製造治療退行性大細胞淋巴瘤之藥物。
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