TW202400578A - 新穎的化合物及其用於抑制檢查點激酶2的用途 - Google Patents
新穎的化合物及其用於抑制檢查點激酶2的用途 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Abstract
本發明提供一種新穎化合物、其用於抑制檢查點激酶2 (Chk2)之用途及其用於預防或治療癌症之用途。本發明化合物具有高Chk2選擇性,且因此其可克服對PARP抑制劑之抗性及毒性,且可有效地用於預防或治療癌症。
Description
發明領域
本發明係關於一種新穎化合物、其製備方法、醫藥組成物、其用於抑制檢查點激酶2之用途及使用其預防或治療由檢查點激酶2活化介導之疾病(例如癌症)的方法。
發明背景
為了維持基因體完整性,細胞活化檢查點路徑以停止細胞週期且接著修復DNA損傷,且當受損部分未得到恰當修復時,通常誘導細胞凋亡。若基因毒性損傷未被適當處理,則會引起經修飾基因的積聚,其可直接引起癌症的發展。視引起之DNA損傷而定,檢查點激酶1或2 (Chk1或Chk2)被ATM (毛細血管擴張性失調突變)或ATR (ATM/Rad3相關)磷酸化。一般而言,Chk1在存在DNA單股損傷之情況下活化,且Chk2在存在雙股損傷之情況下活化。被ATM磷酸化後,活化之Chk2激酶充當信號轉導子且使各種受質磷酸化,包括Cdc25磷酸酶、p53、PML、E2F-1及BRCA1,該等受質參與諸如細胞週期停滯、DNA修復及DNA損傷後細胞凋亡等功能。
Chk2藉由經磷酸化調節腫瘤抑制因子BRCA1 (乳癌1)之功能來參與DNA修復。已知活化之BRCA1協調HR (同源重組) DNA修復路徑之功能,同時其抑制NHEJ (非同源末端接合)路徑(Nature, 2000, 第404卷, 第201-204頁;Cancer research, 2006,第66卷, 第1401-1408頁)。為了經由HR促進DNA修復,BRCA1與BRCA2形成複合物且與HR DNA修復路徑中之關鍵蛋白質Rad51重組酶直接相互作用。此Chk2對BRCA1之調節支持自NHEJ至HR路徑之轉變。另外,BRCA1與DNA錯配修復蛋白Msh2相關,且Chk2與Msh2相互作用,此意謂Chk2及BRCA1亦參與DNA錯配修復(Mol. Cell. Bio, 2004, 第24卷, 第2期, 第708-718頁)。
另一方面,聚(ADP-核糖)聚合酶1 (PARP1)係一種DNA損傷感測器,且當活化時,藉由經聚ADP-核糖基化(PAR基化)募集下游蛋白質來參與DNA修復。最近的一項研究報告了PARP1及Chk2之免疫共沈澱、二種蛋白質之間的相互作用在氧化DNA損傷後增加以及總體多聚ADP核糖基化因Chk2耗竭而降低(Oncogene, 2019, 第38卷, 第8期, 第1166-1182頁)。另外,經由Chk2 SCD域與PARP1 BRCT域之相互作用,Chk2經由Chk2依賴性磷酸化刺激PARP1之聚-ADP核糖基化活性。換言之,Chk2在氧化應激期間對PARP1具有多效性作用,以便促進DNA修復及細胞存活。
作為基於BRCA突變之合成致死策略開發之奧拉帕尼(Olaparib)係一種PARP1抑制劑,已在乳癌、卵巢癌、前列腺癌及胰臟癌患者群體中取得了臨床成功。然而,儘管取得了此成功,但由於PARP抑制劑之使用已引起抗性及毒性問題,因此已作出各種嘗試來克服此等問題。特定言之,已知Chk2與與PARP抑制劑抗性相關之目標蛋白相互作用,Chk2被認為係克服PARP抑制劑抗性之主要靶標。
因此,在此項技術中迫切需要開發具有高選擇性之Chk2抑制劑。
發明概要
技術問題
本發明之目標為提供一種具有檢查點激酶2抑制活性之新穎化合物。
本發明之另一目標為提供一種用於預防或治療癌症之醫藥組成物,其包含具有檢查點激酶2抑制活性之新穎化合物。
本發明之另一目標為提供一種使用具有檢查點激酶2抑制活性之新穎化合物抑制檢查點激酶2之方法。
本發明之另一目標為提供一種使用具有檢查點激酶2抑制活性之新穎化合物預防或治療癌症的方法。
問題的解決方案 定義
應理解,在適當時,結合本發明之特定態樣、實施例或實例描述之任何特徵、整數、特性、化合物、化學部分或基團可應用於本文描述之任何另一態樣、實施例或實例。亦即,除了相互排斥的組合外,本文中所揭露之各種要素之所有組合均屬於本申請案之範疇內。另外,本申請案之範疇不應解釋為受下文所闡述之特定實施例限制。
在本說明書之描述及申請專利範圍通篇中,字語「包含」及「含有」及其變化形式係指「包括但不限於」,此意謂不排除其他結構、取代基、添加劑、組分、整數或步驟。在本說明書之描述及申請專利範圍通篇中,除非上下文另外要求,否則單數形式包括複數形式。特定言之,當使用不定冠詞時,應理解,除非上下文另外要求,否則本說明書涵蓋複數形式以及單數形式。
如本文所用,當提及數值或數值範圍時,術語「約」意謂所提及之數值或數值範圍在實驗偏差(或統計誤差)範圍內,且在一些情況下可意謂所提及之數值或數值範圍的±1%至±20%、±5%至±15%或±10%。
除非另外規定,否則如本文所用,以下術語具有以下含義。
術語「烷基」係指完全飽和分支鏈或非分支鏈(或直鏈或線性)烴。烷基可為經取代或未經取代之烷基。如本文所用,術語「烷基」可指例如C
1-C
8烷基、C
1-C
6烷基、C
1-C
5烷基、C
1-C
3烷基及其類似基團。C
1-C
6烷基可為C
1至C
5、C
1至C
4、C
1至C
3或C
1至C
2烷基。該C
1-C
6烷基之非限制性實例可為甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、正戊基、異戊基、新戊基、異戊基或正己基。
術語「環烷基」或「環狀環」係指飽和或部分不飽和非芳族單環或雙環烴基。雙環環烷基可為稠合、橋連及/或螺環結構。環狀環基團可含有例如3至10、3至8、3至6或3至5個碳原子。單環基團可為例如環戊基、環戊烯基、環己基或環己烯基或其類似基團。雙環基團包括例如冰片基、十氫萘基、雙環[2.1.1]己基、雙環[2.2.1]庚基、雙環[2.2.1]庚烯基或雙環[2.2.2]辛基或其類似基團。
術語「鹵素」原子係指屬於元素週期表之第17族之原子。鹵素原子包括氟(F)、氯(Cl)、溴(Br)、碘(I)及其類似者。術語「鹵素」可與術語「鹵基」互換使用,鹵基意謂由鹵素構成之單價官能基。
術語「羥基(hydroxy)」係指-OH官能基(羥基(hydroxyl group))。
術語「胺基」係指-NH
2,其中氫鍵結至氮原子。
術語「硝基」係指-NO
2。
術語「氰基」係指-CN,且係指由碳原子與氮原子之間的參鍵組成之官能基。
術語「側氧基」係指=O,且「經側氧基取代」意謂碳原子具有呈-C(=O)-形式之=O取代基。
除非另外說明,否則術語「烷氧基」係指經取代或未經取代之直鏈或分支鏈烷基部分藉由氧鍵聯至另一化學結構的取代基。如本文所用,術語「烷氧基」可指例如C
1-C
8烷氧基、C
1-C
6烷氧基、C
1-C
5烷氧基、C
1-C
3烷氧基及其類似基團。烷氧基可包括其所有可能的異構物,諸如甲氧基、乙氧基、丙氧基以及丁氧基,或異丙氧基、異丁氧基以及三級丁氧基,但不限於此。
術語「烯基」係指具有至少一個碳-碳雙鍵之分支鏈或非分支鏈烴。如本文所用,術語「烯基」可包括例如C
2-C
8烯基、C
2-C
6烯基、C
2-C
5alken烯基、C
2-C
3烯基及其類似基團。烯基之非限制性實例可包括乙烯基、3-丙烯基、1-丙烯基、異丙烯基、丁烯-4-基及其類似基團。
術語「芳基」係指芳族烴環基團且亦包括環與一或多個碳環稠合之基團。舉例而言,芳基可為C
6至C
10芳基。芳基可為苯基、萘基或四氫萘基。
術語「雜芳基」係指含有一或多個雜原子(亦即,選自氧、氮及硫之一或多個環雜原子)且其餘環原子為碳之單環或雙環芳族基。雜芳基可含有例如1至5、1至3、1或2個雜原子且可含有5至10個環元素。「雜芳基」可為例如吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、異㗁唑基、噻唑基、異噻唑基、吡啶基、嘧啶基、吡𠯤基、嗒𠯤基、吲哚基、苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并㗁唑基、苯并異㗁唑基、苯并噻唑基或苯并異噻唑基,或其類似基團。
術語「雜環烷基」、「雜環基」或「雜環」係指在環中具有一或多個雜原子(亦即,選自氧、氮及硫之一或多個環雜原子)之飽和或部分不飽和非芳族單環或非芳族多環系統。除非另外規定,否則雜環烷基具有約3至12個環原子、3至10個環原子、3至8個環原子、3至6個環原子、3至5個環原子、4至6個環原子或5至6個環原子。多環雜環烷基在價數要求允許時可具有稠合、橋連或螺環結構。雜環烷基可包括但不限於氮雜環丁烷、氮丙啶、咪唑啶、嗎啉、環氧乙烷(環氧化物)、氧雜環丁烷、環硫烷、哌𠯤、哌啶、吡唑啶、哌啶、吡咯啶、1,4-氧氮雜環庚烷-6-基、1,4-二氮雜環庚烷-6-基、吡咯啶酮、四氫呋喃、四氫噻吩、二氫吡啶、四氫吡啶、𪡓啶、2-氧雜-6-氮雜螺[3.3]庚-6-基、6-氧雜-1-氮雜螺[3.3]庚-1-基、2-硫雜-6-氮雜螺[3.3]庚-6-基、2,6-二氮雜螺[3.3]庚-2-基、2-氮雜雙環[3.1.0]己-2-基、3-氮雜雙環[3.1.0]己基、2-氮雜雙環[2.1.1]己基、2-氮雜雙環[2.2.1]庚-2-基、4-氮雜螺[2.4]庚基、5-氮雜螺[2.4]庚基、4-氮雜螺[2.5]辛-6-基及其類似基團。雜環烷基可未經取代或經取代。
如本文所用,「任擇地經取代」中之術語「取代」係指當有機化合物中之一或多個氫原子經另一原子團取代以形成衍生物時引入替代氫原子,且「取代基」係指引入之原子團。本文中表示為「經取代」之化學結構假定滿足指定取代基及經其取代之原子之價數,且藉由取代形成化學穩定結構。
在本說明書中,當取代基組合提及為一個基團,例如芳基烷基、環烷基烷基或其類似基團時,最後提及之基團通常含有連接至分子之其餘部分的原子。
在本說明書中,「-」用於指示取代基鍵結至化合物之其餘部分的位置。舉例而言,若-指示於取代基之末端,則意謂末端連接至化合物之剩餘部分。另外,當二個或更多個取代基藉由「-」連接時,其意謂緊接在「-」之前的取代基鍵結至緊接在「-」之後的取代基之可取代原子。
在本說明書中之各個位置,化合物之取代基指定為基團或範圍。特定言之,本說明書意欲包括以上群組及範圍元素之各個別子組合。舉例而言,特定言之,術語「C
1-C
6烷基」個別地表示C
1、C
2、C
3、C
4、C
5、C
6、C
1-C
6、C
1-C
5、C
1-C
4、C
1-C
3、C
1-C
2、C
2-C
6、C
2-C
5、C
2-C
4、C
2-C
3、C
3-C
6、C
3-C
5、C
3-C
4、C
4-C
6、C
4-C
5及C
5-C
6烷基。
如本文所用,術語「治療(treating)」或「治療(treatment)」係指抑制疾病,例如抑制經歷或呈現疾病、病狀或病症之病變或病徵之個體的疾病、病狀或病症,亦即防止病變及/或病徵進一步發展;或改善疾病,例如改善經歷或呈現疾病、病狀或病症之病變或病徵之個體的疾病、病狀或病症,亦即逆轉病變及/或病徵,例如減輕疾病之嚴重程度。需要治療之個體包括已呈現症狀或病徵之個體、更可能具有症狀或病徵之個體或需要預防之個體。
如本文所用,術語「預防(preventing)」或「預防(prevention)」係指預防疾病,例如預防可能易患疾病、病狀或病症但尚未經歷或呈現疾病之病變或病徵之個體的疾病、病狀或病症。
術語「癌症」係指哺乳動物中之生理症狀、病症或疾病,其特徵通常為細胞之異常或不可控生長。
術語「醫藥學上可接受」意謂在化學上及/或毒理學上與構成化合物或組成物之其他成分相容。
術語「治療有效量」或「有效量」係指足以產生有益或所要臨床結果的量,例如足以緩解、改善、穩定化、逆轉、減緩或延遲疾病進展之量。
化合物
在本發明之一個態樣中,提供一種以下式A化合物,或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽:
[式A]
其中,
環A為C
6-C
10芳基或含有1至3個氮原子之5至10員雜芳基;
環B為C
3-C
10單環或雙環環烷基或單環或雙環3至10員雜環烷基,其中該雜環烷基含有1至3個選自N、O及S之雜原子;
R
1及R
2各自獨立地為鹵素、-OH、-CN、胺基、硝基、側氧基、C
1-C
8烷基、C
1-C
8烷氧基、任擇地經一或多個R'取代之直鏈或分支鏈C
1-C
8烷基或任擇地經一或多個R'取代之C
3-C
8環烷基,或
當R
1及R
2連接至相鄰環元素時,其可與其所連接之碳原子及氮原子一起形成吡咯啶環,其中該吡咯啶環任擇地經一或多個R'取代;
R'為一或多個獨立地選自由以下組成之群的取代基:鹵素、-OH、-CN、胺基、硝基、側氧基、C
1-C
8烷基及C
1-C
8烷氧基;
R
3選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C
1-C
8烷基、C
3-C
8環烷基及C
1-C
8烷氧基;
R
4選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C
1-C
8烷基、C
1-C
8烷氧基、-CO-(C
1-C
8烷基)、-CO-(C
2-C
8烯基)、-COOH及-COO-C
1-C
8烷基,其中該C
1-C
8烷基、C
1-C
8烷氧基及C
2-C
8烯基可任擇地經一或多個鹵素、-OH或-CN取代;
R
5為H或直鏈或分支鏈C
1-C
8烷基;
n為0至2之整數,且其中當n為2時,R
3可各自鍵結至相同或不同環原子;且
m為0至3之整數,且其中當m為2或更大時,R
4可各自鍵結至相同或不同環原子。
在上式A中,環A可為苯基。另外,環A可為含有1至2個氮原子之5或6員雜芳基。在一個實施例中,環A可為吡啶基或嘧啶基。
在上式A中,環B可為單環3至10員雜環烷基。另外,環B可為螺環3至10員雜環烷基。在一個實施例中,環B可為單環3至8員雜環烷基。在一個實施例中,環B可為螺環3至8員雜環烷基。單環或螺環雜環烷基可含有一個氮原子(N)。另外,除一個N以外,單環或螺環雜環烷基亦可任擇地含有1或2個選自N、O及S之雜原子。舉例而言,雜環烷基可含有但不限於2個N、1個N及1個O或1個N及1個S。
另外,在本發明之一個態樣中,提供一種以下式I化合物,或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽:
[式I]
。
適用於與下文所述之式I相關之實施例的內容亦可適用於上文之式A。
在上式I中,X、Y以及Z可各自獨立地為C或N。X可為C或N。Y可為C或N。Z可為C或N。X、Y及Z中之至少一者可為C。舉例而言,X及Z可為N,且Y可為C。Y及Z可為N,且X可為C。X可為N,且Y及Z可為C。Y可為N,且X及Z皆可為C。X、Y及Z均可為C。
在上式I中,R
1可為任擇地經一或多個R'取代之直鏈或分支鏈C
1-C
8烷基或任擇地經一或多個R'取代之C
3-C
8環烷基。此處,R'可為一或多個獨立地選自由以下組成之群的取代基:鹵素、-OH、CN、胺基、硝基、側氧基、C
1-C
8烷基及C
1-C
8烷氧基。R
1可為任擇地經一或多個鹵素、-OH或-CN取代之直鏈或分支鏈C
1-C
5烷基,或任擇地經一或多個鹵素、-OH或-CN取代之C
3-C
5環烷基。R
1可為H、甲基、乙基、-CH
2-CF
3、-CH
2-CN、-CH
2-C(CH
3)
2OH或環丙基。
在上式I中,R
2可為H或直鏈或分支鏈C
1-C
8烷基。R
2可為H。
在上式I中,R
1可為-CH
2-CF
3、-CH
2-CN、-CH
3、-CH
2-C(CH
3)
2OH或環丙基,且R
2可為H。
在上式I中,R
1及R
2可與其各自所連接之氮原子及碳原子一起形成吡咯啶環,其中吡咯啶環可任擇地經一或多個R'取代;此處,R'可為一或多個獨立地選自由以下組成之群的取代基:鹵素、-OH、CN、胺基、硝基、C
1-C
8烷基及C
1-C
8烷氧基。R
1及R
2可與其各自所連接之氮原子及碳原子一起形成吡咯啶環,其中吡咯啶環可任擇地經一或多個C
1-C
5烷基取代。
可具有
之結構。
在上式I中,R
3可選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C
1-C
8烷基、C
3-C
8環烷基及C
1-C
8烷氧基。R
3可選自由以下組成之群:鹵素、-OH、-CN、C
1-C
5烷基及C
1-C
5烷氧基。R
3可選自由以下組成之群:F、-OH及甲基。
在上式I中,R
4可選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C
1-C
8烷基、C
1-C
8烷氧基、-CO-C
1-C
8烷基、-CO-C
2-C
8烯基、-COOH及-COO-C
1-C
8烷基,其中該C
1-C
8烷基、C
1-C
8烷氧基及C
2-C
8烯基可任擇地經一或多個鹵素、-OH-或CN取代。R
4可選自由以下組成之群:鹵素、-OH、-CN、C
1-C
5烷基及C
1-C
5烷氧基。R
4可為F或-OH。
在上式I中,R
3可選自由以下組成之群:鹵素、-OH、-CN、C
1-C
5烷基及C
1-C
5烷氧基,且R
4可選自由以下組成之群:鹵素、-OH、-CN、C
1-C
5烷基及C
1-C
5烷氧基。
在上式I中,n可為0至2之整數,且其中當n為2時,二個R
3可各自鍵結至相同或不同環原子。
在上式I中,m可為0至2之整數,且其中當m為2時,二個R
4可各自鍵結至相同或不同環原子。
在上式I中,p可為1至5、2至4或3至4之整數。
在上式I中,W可為C,且其中當p為2或更大時,W中之一者可任擇地經選自N、O或S之雜原子置換。在此情況下,W中之一者可與另一碳原子一起形成C
3-C
5環烷基環。W可全部為C,或W中之一者可經O置換,或W中之一者可與另一碳原子一起形成環丙基環。雜原子可為選自由N、O及S組成之群的任何一或多者。
在上式I中,p可為2至4之整數,且W可全部為C,或W中之一者可經O置換,或W中之一者可與另一碳原子一起形成環丙基環。
在上式I中,
可具有選自由以下組成之群的結構:
、
、
及
。
式I化合物可為選自由以下化合物組成之群的化合物:
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及
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鏡像異構物、水合物、溶劑合物及醫藥學上可接受之鹽
「鏡像異構物」中之術語「異構物」係指具有相同分子式但分子中組成原子之連接方法或空間排列不同的化合物。異構物包括例如結構異構物及鏡像異構物。鏡像異構物可為非鏡像異構物或鏡像異構物。鏡像異構物係指不與其鏡像重疊之異構物,諸如左手與右手之間的關係,且亦稱為光學異構物。當對掌性中心碳上的四個或更多個取代基彼此不同時,鏡像異構物分類為R (右:順時針)及S (左:逆時針)。非鏡像異構物係與鏡像無關之鏡像異構物,且係由原子之空間排列差異產生之異構物。非鏡像異構物可分為順反異構物及構形異構物或構形物。
當本發明化合物含有對掌性中心時,其可以不同鏡像異構形式存在。本發明化合物可為但不限於鏡像異構物、非鏡像異構物、外消旋混合物及其類似物。當未指定本文中所描繪之結構中之任何特定對掌性原子的立體化學時,所有鏡像異構物均包括為本發明化合物。
另外,當本發明化合物含有能夠互變異構化之基團時,所有互變異構形式均包括於本發明之範疇內。舉例而言,2-羥基吡啶可包括2-吡啶酮,且所有此類異構物形式均包括於本發明中。
如本文所用,術語「溶劑合物」可指包含化學計量或非化學計量之量的藉由非共價分子間力結合之溶劑的本發明化合物或其鹽。就此而言,較佳溶劑可為揮發性、無毒及/或適合於向人類投予之任何溶劑。溶劑合物為例如水合物。本發明化合物可以非溶劑化形式、與水溶劑化之水合物、與醫藥學上可接受之溶劑(諸如乙醇)溶劑化之溶劑合物等形式存在,且所有此類形式均意欲包括於本發明之範疇內。
如本文所用,術語「鹽」可包括母體化合物之無機及有機酸加成鹽或鹼加成鹽。醫藥學上可接受之鹽可為對化合物所投予之生物體不造成嚴重刺激且不損害化合物之生物活性及物理特性的鹽。其可包括但不限於鹼性部分諸如胺、鹼(土)金屬之無機或有機酸鹽,或酸部分諸如羧酸之有機鹽,及其類似物。無機酸鹽可為鹽酸鹽、溴酸鹽、磷酸鹽、硫酸鹽或硫酸氫鹽。有機酸鹽可為甲酸鹽、乙酸鹽、丙酸鹽、乳酸鹽、草酸鹽、酒石酸鹽、蘋果酸鹽、順丁烯二酸鹽、檸檬酸鹽、反丁烯二酸鹽、苯磺酸鹽(besylate)、樟腦磺酸鹽、乙二磺酸鹽、三氯乙酸鹽、三氟乙酸鹽、苯甲酸鹽、葡糖酸鹽、甲磺酸鹽、乙醇酸鹽、丁二酸鹽、4-甲苯磺酸鹽、半乳糖醛酸鹽、雙羥萘酸鹽、麩胺酸鹽、乙磺酸鹽、苯磺酸鹽(benzenesulfonate)、對甲苯磺酸鹽或天冬胺酸鹽。金屬鹽可為鈣鹽、鈉鹽、鎂鹽、鍶鹽或鉀鹽。
化合物之製備方法
本發明化合物(包括鏡像異構物、溶劑合物及鹽)可藉由已知有機合成方法製備且可經由多種合成途徑合成。
用於製備本發明化合物之反應可在可由一般熟習有機合成技術者適當選擇之適合溶劑中進行。適合之溶劑為在反應發生之溫度下基本上不與起始物質(反應物)、中間物或目標材料發生反應之溶劑。一般熟習此項技術者將能夠適當地選擇適用於特定反應步驟之溶劑。
各種官能基之保護及脫保護可在本發明化合物合成期間進行。一般熟習此項技術者將易於選擇保護及脫保護及適當保護基之需求。
各反應可藉由此項技術中已知之適當方法監測。舉例而言,目標化合物之合成可藉由光譜方法,諸如NMR (例如,
1H或
13C)、質譜或層析(HPLC或TLC)等來監測。
必要時,本發明化合物可藉由例如層析、自溶劑或溶劑混合物結晶、蒸餾、萃取及其類似方法純化。層析可為例如逆相、正相、尺寸排阻、離子交換、製備型或急驟層析,但不限於此。一般熟習此項技術者將能夠容易地選擇對於目標材料之純化最佳的技術。
當本發明化合物為鏡像異構物時,其可視需要藉由任何適當方法自外消旋混合物分離。舉例而言,可使用:使用對掌性化合物形成離子及非鏡像異構鹽,且藉由分步結晶等分離;使用對掌性衍生化試劑形成非鏡像異構物且在分離之後轉化為純鏡像異構物;及在對掌性條件下直接分離基本上純的鏡像異構物,及其類似方法。
本發明化合物可根據以下實例中所描述之合成方法合成,且基於此等實例,任何目標化合物可藉由取決於目標化合物之結構適當改變反應物及反應條件來製備。
一般而言,式I化合物可經由以下反應流程1之合成方法製備。本發明之式A化合物亦可由一般熟習此項技術者藉由適當地修改以下反應流程1及本文中之實例來容易地製備。
[反應流程1]
(在以上反應流程1中,Hal為鹵素,諸如Br、I、Cl或F,且R表示烷基。)
在步驟1中,使用適當試劑(例如雙(頻哪醇根基)二硼)在適當鹼(例如KOAc)及適當催化劑(例如PdCl
2(dppf)·DCM)存在下將吡𠯤羧酸鹽化合物酯化為頻哪醇酸酯。步驟1之反應可在90℃下在適當有機溶劑(諸如二㗁烷)中進行15小時。
在步驟2中,使用適當試劑(例如4-溴-2-氯-5-氟吡啶、4-溴-2-氯吡啶、2,4-二溴-1-氟苯、1,3-二溴苯、2-溴-4-氯苯酚、4-溴-2-碘-1-甲基苯、2,4-二溴嘧啶),在適當鹼(例如1M碳酸鈉水溶液)及適當催化劑(例如PdCl
2(dppf)·DCM)存在下經由頻哪醇酸酯化合物進行鈴木-宮浦偶合反應。步驟2之反應可在90℃下在適當有機溶劑(諸如二㗁烷)中進行15小時。
在步驟3中,使用適當試劑(例如4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環(dioxaborolan)-2-基)-1-(2,2,2-三氟乙基)-1H-吡唑、[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯、1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑、1-環-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑、2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑-1-基)乙腈、5,5-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-5,6-二氫-4H-吡咯并[1,2-b]吡唑),在適當鹼(例如1M碳酸鈉水溶液)及適當催化劑(例如PdCl
2(dppf)·DCM)存在下進行鈴木-宮浦偶合反應。步驟3之反應可在90℃下在適當有機溶劑(諸如二㗁烷)中進行15小時。
在步驟4中,使用適當試劑(例如(
S)-3-胺基哌啶-1-甲酸酯、tert-butyl (3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯、(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯、反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯、4-氮雜螺[2.5]辛-6-胺、(3R,4R)-3-胺基-4-羥基吡咯啶-1-甲酸三級丁酯、6-胺基-4-氮雜螺[2.5]辛烷-甲酸三級丁酯),在適當鹼(例如三乙胺)及適當催化劑(例如HBTU)存在下經由羧酸化合物進行醯胺偶合反應。步驟4之反應可在25℃下在適當有機溶劑(諸如N,N-二甲基甲醯胺)中進行15小時。
在步驟5中,使用適當酸(例如4M HCl)使胺之三級丁氧羰基(Boc)脫除保護基。步驟5之反應可在25℃下在適當有機溶劑(諸如二氯甲烷)中進行約1小時至15小時。
醫藥組成物及醫療用途
在另一態樣中,提供一種用於預防或治療由檢查點激酶2活化介導之疾病的醫藥組成物,該醫藥組成物包含根據一個態樣之化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽。
化合物、鏡像異構物、水合物、溶劑合物及鹽與上文所描述相同。
檢查點激酶2 (Chk2)可為編碼Chk2 (一種絲胺酸-蘇胺酸激酶)之腫瘤抑制蛋白。Chk2可參與響應於DNA損傷之DNA修復、細胞週期停滯或細胞凋亡。儘管正常細胞可在Chk2抑制後激活其他檢查點,但癌細胞通常缺乏一或多個基因體完整性檢查點。因此,具有Chk2抑制活性之本發明之化合物或組成物可進一步增加抗癌療法(諸如γ-輻射或DNA損傷劑)之腫瘤細胞選擇性。另外,具有Chk2抑制活性之本發明之化合物或組成物可在其刺激Chk2依賴性細胞週期檢查點時增強各種抗癌劑之活性。另外,具有Chk2抑制活性之本發明之化合物或組成物可克服對PARP抑制劑之抗性且降低毒性。
由檢查點激酶2活化介導之疾病可為癌症。由於Chk2抑制劑可增加各種抗癌劑之活性,因此各種類型之癌症將能夠藉由本發明之化合物、組成物及方法治療。癌症可為實體癌症或非實體癌症。實體癌症係指已出現在器官,例如肝、肺、乳房及皮膚中之癌性腫瘤。非實體癌症為血液中已出現之癌症,且亦稱為血液學癌症。癌症可為癌瘤、肉瘤、造血細胞源性癌症、生殖細胞腫瘤或母細胞瘤。
由檢查點激酶2活化介導之疾病可為具有ATM、CHK2及/或編碼p53蛋白之TP53基因之畸變的癌症。例如,上述基因畸變可包括ATM之同型接合生殖細胞突變(例如毛細血管擴張性失調)、ATM之體細胞突變(例如淋巴惡性腫瘤)、ATM表現缺失(例如大腸直腸癌、乳癌、非小細胞肺癌、肺腺癌或胰臟癌)、由於11q缺失導致ATM異型接合性喪失(例如乳癌、慢性淋巴球性白血病及其他淋巴惡性腫瘤、兒童神經母細胞瘤)、CHK2突變(例如結腸癌、腎癌、乳癌、前列腺癌)、同型接合生殖細胞CHK2突變、TP53基因突變(例如李-弗美尼症候群(Li-Fraumeni syndrome))、通過17p對偶基因缺失導致的TP53異型接合性喪失及其類似者。
可藉由本發明化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽預防或治療之癌症可選自由以下組成之群:例如卵巢癌、子宮頸癌、子宮內膜癌、子宮肉瘤、外陰癌、乳癌、皮膚癌、頭頸癌、胰臟癌、肺癌(例如小細胞肺癌、非小細胞肺癌、肺腺癌、鱗狀細胞癌或大細胞癌)、大腸癌、大腸直腸癌、結腸癌、胃癌、前列腺癌、膀胱癌、尿道癌、肝癌、腎癌、皮膚癌、腦脊髓腫瘤、腦癌、胸腺瘤、間皮瘤、支氣管癌、鼻咽癌、喉癌、食道癌、膽道癌、睾丸癌、生殖細胞腫瘤、甲狀腺癌、副甲狀腺癌、淋巴瘤、骨髓發育不良症候群(MDS)、骨髓纖維化、急性骨髓白血病(AML)、急性淋巴球性白血病(ALL)、慢性骨髓白血病(CML)、慢性淋巴球性白血病(CLL)、多發性骨髓瘤、內分泌癌、肉瘤、毛細血管擴張性失調、兒童神經母細胞瘤及李-弗美尼症候群。
醫藥組成物可進一步包含具有抗癌活性之已知活性成分。醫藥組成物可為單一組成物或單獨的組成物。舉例而言,根據一個態樣之醫藥組成物可為口服劑型之組成物,且具有抗癌活性之已知活性成分可為非經腸劑型之組成物。
醫藥組成物可包含醫藥學上可接受之載劑。載劑用作包括賦形劑、稀釋劑或助劑之含義。載劑可選自由以下組成之群:例如乳糖、右旋糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藻糖醇、麥芽糖醇、澱粉、阿拉伯膠、海藻酸鹽、明膠、磷酸鈣、矽酸鈣、纖維素、甲基纖維素、聚乙烯吡咯啶酮、水、生理鹽水、緩衝劑(諸如PBS)、羥基苯甲酸甲酯、羥基苯甲酸丙酯、滑石、硬脂酸鎂及礦物油。組成物可包含填充劑、抗聚結劑、潤滑劑、濕潤劑、調味劑、乳化劑、防腐劑或其組合。
醫藥組成物可根據習知方法以任何劑型製備。組成物可調配為例如口服劑型(例如,散劑、錠劑、膠囊、糖漿、丸劑或顆粒)或非經腸劑型(例如,注射劑)。另外,組成物可製備為全身劑型或局部劑型。
在醫藥組成物中,用於經口投予之固體製劑可為錠劑、丸劑、散劑、顆粒或膠囊。固體製劑可進一步包含賦形劑。賦形劑可為例如澱粉、碳酸鈣、蔗糖、乳糖或明膠。另外,固體製劑可進一步包含潤滑劑,諸如硬脂酸鎂或滑石。在醫藥組成物中,用於經口投予之液體製劑可為懸浮液、內部溶液、乳液或糖漿。液體製劑可包含水或液體石蠟。液體製劑可包含賦形劑,諸如濕潤劑、甜味劑、調味劑或防腐劑。在醫藥組成物中,用於非經腸投予之製劑可為滅菌水溶液、非水性溶液、懸浮液、乳液、冷凍乾燥製劑及/或栓劑。非水性溶液或懸浮液可包含植物油或酯。植物油可為例如丙二醇、聚乙二醇或橄欖油。酯可為例如油酸乙酯。栓劑之基質可為witepsol、聚乙二醇、吐溫61、可可脂、月桂脂或甘油明膠。
醫藥組成物包含治療有效量之根據一個態樣之化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽作為活性成分。「活性成分」係指用於實現藥理學活性(例如,癌症治療)之生理學活性物質。
醫藥組成物可包含有效量之根據一個態樣之化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽。有效量可由一般熟習此項技術者根據待選擇之細胞或個體來適當地選擇。醫藥組成物之較佳劑量視個體之病狀及體重、疾病之嚴重程度、藥物之類型、投予途徑及持續時間而變化,但可由一般熟習此項技術者適當地選擇。然而,化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽可以例如約0.0001 mg/kg至約100 mg/kg或約0.001 mg/kg至約100 mg/kg之量投予,該量可分成一天1至24次、2天至1週內1至7次,或1個月至12個月內1至24次。舉例而言,投予可一天一次、一天多次或一週一次、每2週一次、每3週一次或每4週一次至一年一次地進行。在醫藥組成物中,按整個組成物之總重量計,化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽的含量可為約0.0001重量%至約10重量%,或約0.001重量%至約1重量%。
投予方法可為經口或非經腸投予。投予方法可為例如經口、經皮、皮下、經直腸、靜脈內、動脈內、腹膜內、肌內、胸骨內、局部、鼻內、氣管內或皮內途徑。組成物可全身性或局部投予,且可單獨或與其他醫藥學上活性化合物組合投予。
組合投予
在一些實施例中,根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽可單獨或與具有抗癌活性之額外治療劑組合投予。額外治療劑可為例如經由不同機制具有互補或協同藥理學活性而不減弱本發明化合物之藥理學活性的藥劑。額外治療劑可與本發明化合物一起以單一醫藥組成物形式投予,或可分開投予。當分開投予時,本發明化合物及額外治療劑可同時或按任何次序依序投予。額外治療劑可包括手術療法及電離輻射。
舉例而言,額外治療劑可選自由以下組成之群:手術療法、電離輻射、化學治療劑(例如烷基化劑、抗代謝物、拓樸異構酶抑制劑、微管抑制劑、抗生素或植物生物鹼、激素劑)、靶向抗癌劑、免疫檢查點抑制劑、細胞治療劑、抗體治療劑、抗癌病毒及其組合,但不限於此。
烷基化劑可包括例如順鉑、卡鉑、奧沙利鉑、白消安、苯丁酸氮芥、環磷醯胺、異環磷醯胺、美法侖、噻替派、六甲蜜胺、丙卡巴肼、達卡巴嗪、鏈佐黴素、卡莫司汀(carmustine)、洛莫司汀(lomustine)、尿嘧啶氮芥、三伸乙基三聚氰胺、替莫唑胺及2-氯乙基-3-肌胺酸醯胺-1-亞硝基脲及其類似物。
抗代謝物可包括氯去氧腺苷、阿糖胞苷、卡培他濱(capecitabine)、2'-去氧助間型黴素、磷酸氟達拉濱(fludarabine phosphate)、5-氟尿嘧啶(5-FU)、5-氟-2'-去氧尿苷、吉西他濱(gemcitabine)、喜樹鹼、6-巰基嘌呤、甲胺喋呤、4-甲基硫苯丙胺、培美曲唑(pemetrexed)及硫鳥嘌呤及其類似物,但不限於此。
拓樸異構酶抑制劑可包括拓朴替康(topotecan)、伊立替康(irinotecan)、依託泊苷(etoposide)、博萊黴素(bleomycin)、阿德力黴素(adriamycin)、道諾黴素(daunorubicin)及其類似物,但不限於此。
微管抑制劑包括多西他賽(docetaxel)、紫杉醇、長春鹼、長春新鹼、長春瑞濱以及其類似物,但不限於此。
抗癌抗生素或植物生物鹼可包括放線菌素-D、博萊黴素、念珠藻環肽、道諾黴素、小紅莓、艾達黴素、伊立替康、L-天冬醯胺酶、絲裂黴素-C、光神黴素、溫諾平(navelbine)、紫杉醇、多西他賽、拓朴替康、長春鹼、長春新鹼、替尼泊苷(VM-26)及依託泊苷(VP-16)及其類似物,但不限於此。
激素劑包括5α-還原酶抑制劑、胺魯米特(aminoglutethimide)、阿那曲唑(anastrozole)、比卡魯胺(bicalutamide)、氯三芳乙烯、己烯雌酚(DES)、屈他雄酮、雌莫司汀(estramustine)、乙炔基雌二醇、氟他胺、氟甲睾酮、戈舍瑞林(goserelin)、羥基孕酮、來曲唑、亮丙立德、乙酸甲羥孕酮、乙酸甲地孕酮、甲基普賴蘇濃(methylprednisolone)、甲睾酮、米托坦、尼魯米特(nilutamide)、普賴蘇濃、阿佐昔芬(arzoxifene) (SERM-3)、他莫昔芬(tamoxifen)、托瑞米芬(toremifene)、氟維司群(fulvestrant)、依西美坦(exemestane)、睾內酯、睪固酮、曲安西龍(triamcinolone)、諾雷德(zoladex)及其類似物,但不限於此。
靶向抗癌劑為藉由靶向僅出現在癌細胞中之特定蛋白質或特定基因之變化而阻斷與癌症生長及發展有關之信號而特異性殺死癌細胞的治療劑。將其歸類為在細胞外部反應之單株抗體及在細胞內部起作用之小分子物質。單株抗體為阻斷癌細胞誘導信號傳輸至細胞外部且作用於與增殖、死亡及其類似者有關之起始信號的抗癌劑,且小分子物質作用於細胞內發生的複雜信號轉導。
特定而言,待靶向之蛋白質可為EGFR、VEGFR、CD20、CD38、RNAK-L、BTK、Bcr-abl、PDGFR/FGFR家族、MEK/RAF/KRAS、HER2/Neu、泛素、JAK、ALK、PARP、TGFβRI、蛋白酶體、Bcl-2、C-Met、VR1、VR2、VR3、c-kit、AXL、RET、Braf、DNMT、CDK4/6、STING及其類似物。
術語「表皮生長因子受體(EGFR)」為調節細胞生長、分裂、存活及死亡之細胞膜受體,且EGFR之表現在各種癌症之腫瘤組織中增加。已知EGFR增加之腫瘤組織具有高侵襲性、轉移性及抗癌劑耐藥性。EGFR抑制劑為抑制EGFR之物質,且在一個實施例中可為西妥昔單抗(cetuximab)、曲妥珠單抗(trastuzumab)、帕妥珠單抗(pertuzumab)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、奧希替尼(osimertinib)或帕尼單抗(panitumumab)。
術語「血管內皮生長因子受體(VEGFR)」為誘發血管生成之血管內皮生長因子之細胞膜受體,且VEGFR抑制劑抑制血管生成,從而抑制腫瘤生長及轉移。在一個實施例中,VEGF抑制劑或VEGFR抑制劑可為阿西替尼(axitinib)、樂伐替尼(lenvatinib)、貝伐單抗(bevacizumab)、雷莫蘆單抗(ramucirumab)或阿柏西普(aflibercept)。
術語「CD20 (B淋巴球抗原CD20)」為表現於B細胞表面上之蛋白質且作為目標蛋白用於治療B細胞淋巴瘤。靶向CD20之抑制劑可為利妥昔單抗或阿托珠單抗(obinutuzumab)。
術語「CD38 (分化叢集38)」為調節細胞增殖及死亡、同時充當免疫細胞中之信號轉導受體的蛋白質,且靶向此蛋白質之抑制劑可為達土木單抗(daratumumab)。
術語「RNAK-L (核因子κ-B配位體之受體活化劑」為破骨細胞表面上所表現之RANK受體,且當藉由結合至配位體而活化時,其用以引起骨破壞。RANK-L抑制劑主要用於罹患骨轉移或骨質疏鬆症的癌症患者,且可為例如德諾單抗(Denosumab)。
術語「BTK (布魯頓氏酪胺酸激酶)」係一種參與B細胞增殖之酶,且在過度表現時,其可發展為血液學癌症。在一個實施例中,靶向BTK之抑制劑可為依魯替尼(ibrutinib)。
術語「Bcr-abl」為在患有慢性骨髓性白血病之患者中高度表現且已知誘導血細胞之異常增殖的融合蛋白。特定言之,此蛋白質之抑制劑可為達沙替尼(dasatinib)、尼羅替尼(nilotinib)、伊馬替尼(imatinib)或伯舒替尼(bosutinib)。
術語「腫瘤生長因子β受體(TGFβR)」為用於腫瘤生長因子之細胞膜受體,且調節上皮細胞及造血細胞之生長、遷移、分化及死亡及其類似者。靶向TGFβR之抑制劑可包括加盧色替(galunisertib)或瓦妥色替(vactosertib),但不限於此。
術語「PDGFR (血小板衍生生長因子受體)」為頻繁表現於癌細胞中且已知參與血管生成以調節癌症生長、轉移及耐藥性之PDGF之細胞膜受體。FGFR (纖維母細胞生長因子受體)為纖維母細胞生長因子(FGF)之受體且調節各種生物過程,包括細胞生長、分化及遷移及其類似者。FGFR基因頻繁發生突變,且此等突變體通常在乳癌、子宮癌、卵巢癌、子宮頸癌及其類似者中觀測到。靶向PDGFR或FGFR之抑制劑可為尼達尼布(nintedanib)、舒尼替尼(sunitinib)、索拉非尼(sorafenib)、卡博替尼(cabozantinib)、樂伐替尼(lenvatinib)、瑞戈非尼(regorafenib)、馬賽替尼(masitinib)、司馬沙尼(semaxanib)、替沃紮尼(tivozanib)、凡德他尼(vandetanib)、阿西替尼(axitinib)或帕唑帕尼(pazopanib)。
術語「MEK/RAF/KRAS」為參與細胞增殖、細胞週期調節、細胞存活、血管生成、細胞遷移及其類似者之細胞內信號轉導介體,且在癌細胞中過度活化。靶向MEK/RAF/KRAS之抑制劑可為曲美替尼(trametinib)、達拉非尼(dabrafenib)或索妥昔布(sotorasib)。
術語「HER-2/neu (人類表皮生長因子受體2)藉由PI3K/AkT之活化來調節細胞增殖。其過度表現於轉移性乳癌及卵巢癌及其類似者中,且已知誘導對抗癌劑之抗性。Her2/neu靶向抗癌劑可為曲妥珠單抗、阿法替尼(afatinib)、拉帕替尼(lapatinib)或來那替尼(neratinib)。
術語「泛素」藉由結合至其他蛋白質且誘導蛋白酶體(一種蛋白分解酶)之蛋白水解(泛素蛋白酶體系統,UPS)來維持細胞穩態。在各種腫瘤中觀測到UPS之異常表現或活性,且UPS之抑制劑展現抗癌活性。特定言之,靶向泛素或蛋白酶體之抑制劑可為來那度胺(lenalidomide)或伊沙佐米(ixazomib)。
術語「JAK (Janus激酶)」為STAT之上游蛋白質,其為調節細胞增殖、細胞存活、細胞遷移及免疫反應之轉錄因子,且已知JAK抑制劑經由抑制STAT活性而減少細胞增殖且誘導細胞死亡。靶向JAK之抑制劑可為蘆可替尼(ruxolitinib)、來他替尼(lestaurtinib)或帕瑞替尼(pacritinib)。
術語「MAP2K (促分裂原活化蛋白激酶)」為藉由MAPK之磷酸化參與細胞增殖、細胞週期調節、細胞存活、血管生成、細胞遷移及其類似者之細胞內信號轉導介體,且在癌細胞中過度活化。靶向MAP2K之抑制劑可為考比替尼(cobimetinib)、司美替尼(selumetinib)、曲美替尼(trametinib)或畢尼替尼(binimetinib)。
術語「ALK (間變性淋巴瘤激酶)」為促進細胞增殖、細胞遷移及血管生成且抑制細胞死亡之信號轉導介體,且在各種癌症組織中過度活化。靶向ALK之抑制劑可為阿來替尼(alectinib)或克卓替尼(crizotinib)。
術語「Bcl-2」為抑制細胞死亡之蛋白質,且在各種癌症組織中過度表現或過度活化。靶向Bcl-2之抑制劑可為維納妥拉(venetoclax)。
術語「C-Met」為肝細胞生長因子(HGF)之受體,且活化與細胞生長、形成、運動、存活及血管生成及其類似者相關之信號轉導。C-Met靶向抗癌劑可為克卓替尼或卡博替尼。
術語「VR (香草精類受體)」亦稱為TRPV (瞬時受體電位香草精類),且以VR1、VR2、VR3、VR4、VR5及VR6之形式存在。已知VR在癌症進展過程之各階段調節癌細胞之增殖、死亡、遷移、浸潤及血管生成。
術語「c-kit」亦稱為CD117,且誘導信號轉導,從而活化細胞存活、增殖及分化。c-kit為原致癌基因,且此基因之過度表現或突變與癌症發展相關。
術語「AXL (酪胺酸-蛋白激酶受體UFO)」係一種酪胺酸激酶受體,其存在於細胞表面上且介導參與細胞增殖及存活之信號轉導。已知其參與抗癌治療中對抗癌劑之耐藥性。在一個實施例中,AXL靶向抗癌劑可為貝西替尼(bemcentinib)或吉列替尼(gilteritinib)。
術語「RET (在轉染期間重排)」為介導參與細胞增殖、細胞死亡及存活之信號的受體,且已知RET中之突變參與癌症發展。靶向RET之抑制劑可為塞帕替尼(selpercatinib)或普拉替尼(pralsetinib),但不限於此。
術語「Braf」為參與細胞增殖、細胞週期調節、細胞存活、血管生成、細胞遷移及其類似者之MAPK信號轉導介體,且在癌細胞中觀測到其基因突變。靶向Braf之抑制劑可為維羅非尼(vemurafenib)。
術語「PARP (聚[ADP-核糖]聚合酶)」為藉由識別細胞核中之受損DNA而活化且接著活化DNA修復相關蛋白質之蛋白質。靶向PARP之抑制劑藉由抑制癌細胞中之DNA修復來抑制癌細胞增殖。在一個實施例中,靶向PARP之抑制劑可為奧拉帕尼(olaparib)、拉唑帕尼(talazoparib)、尼拉帕尼(niraparib)或盧卡帕尼(rucaparib)。
術語「DNA甲基轉移酶(DNMT)」為將甲基附著於包裹DNA之組蛋白的酶,且經由此過程,基因之表現受到抑制。靶向DMNT之抑制劑藉由抑制癌症抑制基因之高甲基化及誘導癌症抑制基因之正常表現而展現抗癌活性。在一個實施例中,靶向DNMT之抑制劑可為阿紮胞苷(azacitidine)、地西他濱(decitabine)或瓜達西汀(guadecitabine)。
術語「CDK (細胞週期素依賴性激酶) 4/6」為藉由調節細胞週期而促進細胞生長之蛋白質,且在各種惡性腫瘤之發展及進展期間過度活化。靶向CDK4/6之抑制劑藉由抑制癌細胞之細胞週期、抑制細胞增殖及誘導細胞死亡來展現抗癌活性。靶向CDK4/6之抑制劑可為阿貝西利(abemaciclib)、利波西利(ribociclib)或帕柏西利(palbociclib)。
術語「STING (干擾素基因刺激蛋白)」係一種活體內感測器,其識別來自癌細胞之DNA片段,且藉由刺激干擾素基因活化體內之免疫細胞,諸如樹突狀細胞。STING促效劑展現免疫增強作用及癌症血管生成抑制作用。舉例而言,STING促效劑可為CDN、SB11285、DMXAA及其類似物。
靶向抗癌劑包括曲妥珠單抗、雷莫蘆單抗、維莫德吉(bismodegib)、索尼得吉(sonidegib)、貝伐單抗、拉帕替尼、來那替尼、帕妥株單抗、曲妥珠單抗美坦新、帕柏西利、西妥昔單抗、帕尼單抗、阿柏西普、瑞戈非尼、甲磺酸伊馬替尼、尼達尼布、舒尼替尼、卡博替尼、瑞戈非尼、馬賽替尼、司馬沙尼、替沃紮尼、凡德他尼、德諾單抗、亞利崔托寧(alitretinoin)、阿西替尼、樂伐替尼、帕佐泮尼、曲美替尼、達拉非尼、坦羅莫司、依維莫司、視網酸、達沙替尼、尼羅替尼、伊馬替尼、伯舒替尼、加盧色替、瓦妥色替、利妥昔單抗、阿侖單抗、奧伐木單抗、阿托珠單抗、達土木單抗、依魯替尼、艾德昔布、博納吐單抗、索拉非尼、克卓替尼、厄洛替尼、吉非替尼、索妥昔布、阿法替尼、塞利替尼、來那度胺、伊沙佐米、蘆可替尼、來他替尼、帕瑞替尼、考比替尼、司美替尼、畢尼替尼、阿來替尼、維納妥拉、貝西替尼、吉列替尼、塞帕替尼、普拉替尼、維羅非尼、奧拉帕尼、拉唑帕尼、尼拉帕尼、盧卡帕尼、阿紮胞苷、地西他濱、瓜達西汀、阿貝西利、利波西利、帕柏西利、奧希替尼及耐昔妥珠單抗(necitumumab)及其類似物,但不限於此。
額外治療劑可為免疫檢查點抑制劑。術語「免疫檢查點抑制劑」為抑制免疫檢查點蛋白(其抑制免疫細胞之分化、增殖及活性)之活性的物質,且已知藉由預防癌細胞發揮逃避免疫系統之功能來消除該等癌細胞。免疫檢查點抑制劑可為選自由以下組成之群的任一者:抗CTLA-4抗體、抗PD-1抗體、抗PD-L1抗體、抗PD-L2抗體、抗B7-H4抗體、抗HVEM抗體、抗TIM3抗體、抗GAL9抗體、抗LAG3抗體、抗VISTA抗體、抗KIR抗體、抗BTLA抗體及抗TIGIT抗體。在一個實施例中,免疫檢查點抑制劑可為伊匹單抗(ipilimumab)、帕博利珠單抗(pembrolizumab)、納武單抗(nivolumab)、西米普利單抗(cemiplimab)、阿特珠單抗(Atezolizumab)、阿維魯單抗(Avelumab)及度伐魯單抗(Duralumab)及其類似物,但不限於此。
額外治療劑可為細胞治療劑。術語「細胞治療劑」為藉由使用免疫細胞,諸如樹突狀細胞、自然殺手細胞、T細胞及其類似物活化體內免疫反應而展現抗癌作用之治療劑。免疫細胞治療劑係藉由以下方式使用:在體內提取免疫細胞,且對其進行增強或基因修飾且接著將其注射回體內。代表性免疫細胞治療劑可包括T細胞受體修飾之T細胞(TCR-T)、嵌合抗原受體修飾之T細胞(CAR-T)及其類似物。特定而言,其可為但不限於替沙津魯(Tisagenlecleucel)或西卡思羅(Axicabtagene Ciloleucel)。
額外治療劑可為抗體治療劑。術語「抗體治療劑」為使用識別癌細胞之特定蛋白質作為抗原之抗體展現抗癌作用的治療劑。抗體治療劑可為西妥昔單抗、曲妥珠單抗、利妥昔單抗、布突默單抗(ibritumomab)、托西莫單抗(tositumomab)、本妥昔單抗(brentuximab)、奧伐木單抗、阿托珠單抗、耐昔妥珠單抗、貝伐單抗、雷莫蘆單抗、納武單抗、帕博利珠單抗、阿特珠單抗、度伐魯單抗、伊匹單抗及其類似物。
抗體治療劑可包括抗體藥物結合物(ADC)。術語「ADC (抗體藥物結合物)」為藉由抗體與細胞毒性藥物之化學結合進行靶向遞送而展現高抗癌作用之治療劑。其可為吉妥珠單抗-奧佐米星(gemtuzumab-ozogamicin)、本妥昔單抗-維多汀(brentuximab-vedotin)、曲妥珠單抗-美坦新(trastuzumab-emtansine)、伊珠單抗-奧佐米星(inotuzumab-ozogamicin)及其類似物。
額外治療劑可為抗癌病毒治療劑。術語「抗癌病毒治療劑」為藉由將靶向癌細胞之特定基因插入至能夠增殖且具有感染性之病毒中來殺死癌症的治療劑。抗癌病毒治療劑可為塔里穆尼拉赫韋克(Talimogene Laherparepvec)。
在一個實施例中,額外治療劑可為DNA損傷劑,諸如烷基化劑、抗代謝物、拓樸異構酶抑制劑、微管抑制劑、抗生素或植物生物鹼。眾所周知,由DNA修復缺陷引起之癌症可對DNA損傷劑敏感。因此,本發明化合物可增強DNA損傷劑之抗癌活性。舉例而言,DNA損傷劑可包括輻射、順鉑、奧沙利鉑、卡鉑、阿德力黴素或小紅莓、道諾黴素、伊立替康、吉西他濱、替莫唑胺、卡培他濱、拓朴替康、喜樹鹼、阿糖胞苷、5-FU (氟尿嘧啶)、環磷醯胺、依託泊苷或磷酸依託泊苷、替尼泊苷、道諾黴素、培美曲唑及其類似物。在某些實施例中,DNA損傷劑可選自由以下組成之群:輻射、順鉑、小紅莓、伊立替康、替莫唑胺、卡培他濱、喜樹鹼、Ara-C及5-FU。在某些實施例中,DNA損傷劑可為輻射、順鉑或小紅莓。
在一個實施例中,額外治療劑可為PARP抑制劑。在一個實施例中,PARP抑制劑可為奧拉帕尼、拉唑帕尼、尼拉帕尼或盧卡帕尼。
「PARP (聚[ADP-核糖]聚合酶)」為藉由識別細胞核中之受損DNA而活化且活化DNA修復相關蛋白質之蛋白質。PARP抑制劑藉由抑制癌細胞中之DNA修復來抑制癌細胞增殖。特定言之,已知同源重組修復(HRR)功能喪失之細胞高度取決於PARP活性。在具有BRCA1/2 (其在HRR中起重要作用)之突變的患者中,PARP抑制劑之抗癌作用已得到臨床證實(N. Engl. J. Med. 361, 123, 2009)。然而,當投予PARP抑制劑時,諸如網狀紅血球、B細胞前驅體細胞及不成熟胸腺細胞之減少及骨髓抑制的血液學毒性係有問題的。另外,PARP抑制劑亦經由以下機制引起耐藥性表現的問題:同源重組(HR)的恢復、複製叉的穩定、PAR基化活性的增加或外排轉運體對藥物的消除(Cancer Drug Resist., 2, 665-79, 2019)。
在此情形下,已知Chk2與參與對PARP抑制劑之抗性的蛋白質相互作用。舉例而言,已報導Chk2參與經由與BRCA1相互作用而活化HR功能、經由與PARP1相互作用而活化PAR基化及經由與Msh2相互作用而使複製穩定。另外,已報導與CHK2抑制劑組合會降低PARK抑制劑之血液學毒性。因此,具有Chk2抑制活性之本發明化合物在與PARP抑制劑組合時可展現更有利的抗癌作用。
額外治療劑可包括一或多種抗癌劑。特定言之,根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽可與二種抗癌劑組合。舉例而言,二種抗癌劑可為化學治療劑及靶向抗癌劑;化學治療劑及抗癌病毒;靶向抗癌劑及抗體治療劑;化學治療劑及細胞治療劑;以及化學治療劑及免疫檢查點抑制劑。另外,二種抗癌劑可為靶向抗癌劑及抗癌病毒;靶向抗癌劑及抗體治療劑;靶向抗癌劑及細胞治療劑;靶向抗癌劑及免疫檢查點抑制劑。另外,二種抗癌劑可為抗癌病毒及抗體治療劑;抗癌病毒及細胞治療劑;以及抗癌病毒及免疫檢查點抑制劑。另外,二種抗癌劑可為抗體治療劑及細胞治療劑;以及抗體治療劑及免疫檢查點抑制劑。
化合物、其溶劑合物、鏡像異構物或醫藥學上可接受之鹽可與三種抗癌劑組合。除二種抗癌劑之前述組合以外,亦可進一步包括不同抗癌劑。
根據一個實施例,化合物、其溶劑合物、鏡像異構物或醫藥學上可接受之鹽可與二種或更多種化學治療劑及免疫檢查點抑制劑一起使用。舉例而言,二種或更多種化學治療劑可包括烷基化劑及抗代謝物。
化合物、其溶劑合物、鏡像異構物或醫藥學上可接受之鹽可與四種、五種或六種抗癌劑一起使用。除三種抗癌劑之前述組合以外,亦可進一步包括不同抗癌劑。
抑制Chk2
之
方法、治療方法等
在另一態樣中,提供一種抑制檢查點激酶2 (Chk2)之方法,其包含將根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽活體外添加至細胞中。
該方法可在活體外進行。在該方法中,根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽可1000 nM或更小、100 nM或更小或10 nM或更小之IC
50。
在另一態樣中,提供一種抑制檢查點激酶2活化之方法,其包含向個體投予根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽。
化合物、鏡像異構物、水合物、溶合物、鹽及檢查點激酶2與上文所述相同。
在另一態樣中,提供一種用於預防或治療癌症之方法,其包含向個體投予根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽。化合物、鏡像異構物、水合物、溶合物、鹽、癌症、預防及治療與上文所描述相同。
個體可為哺乳動物,諸如人類、小鼠、大鼠、牛、馬、豬、犬、猴、綿羊、山羊、猿或貓。個體可為罹患或高度可能罹患與癌症相關之症狀的個體。
該方法可進一步包含向該個體投予具有抗癌活性之額外治療劑。額外治療劑可與根據一個態樣之化合物、其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽組合同時、分開或依序向個體投予。
上述方法中之劑量、投予方法、投予週期等與上文關於醫藥組成物所描述的相同。
在另一態樣中,提供根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其用於預防或治療癌症。
在另一態樣中,提供一種醫藥組成物,其包含根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其用於預防或治療癌症。
在另一態樣中,提供根據一個態樣之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽的用途,其用於製造供預防或治療癌症用之藥劑。
化合物、鏡像異構物、水合物、溶合物、鹽、癌症、預防及治療與上文所描述相同。
本發明之作用
根據一個態樣之化合物、其用於抑制檢查點激酶2 (Chk2)之用途及其用於預防或治療癌症之用途,本發明化合物具有高Chk2選擇性,且因此其可克服對PARP抑制劑之抗性及與其使用相關之毒性,且可有效用於預防或治療癌症。
較佳實施例之詳細說明
在下文中,將藉助於實例更詳細地描述本發明。然而,以下實例僅用於說明本發明,且本發明之範疇不限於以下實例。
製備實例1 : 製備(S)-4- 氮雜螺[2.5] 辛-6- 胺 步驟1 :製備(S)- 苯甲基(1- 苯甲基-6- 側氧基哌啶-3- 基) 胺基甲酸三級丁酯
將(S)-(6-側氧基哌啶-3-基)胺基甲酸三級丁酯(9 g,42 mmol)溶解於DMF (90 mL)中,且接著在0℃下以小份添加氫化鈉(1.5 g,63 mmol)。攪拌混合物30分鐘,且接著添加苯甲基溴(8 mL,67 mmol),且在室溫下攪拌混合物15小時。將水(500 mL)及乙酸乙酯(EA) (500 mL)添加至反應溶液,且接著藉由添加1 M鹽酸水溶液將反應溶液中和至pH 7。將有機層合併,經無水硫酸鎂乾燥且過濾,且接著在減壓下移除溶劑。藉由矽膠管柱層析(EA)純化殘餘物,得到(S)-苯甲基(1-苯甲基-6-側氧基哌啶-3-基)胺基甲酸三級丁酯(3.3 g,20%)。
1H NMR (400 MHz, CDCl
3) δ 7.31 - 7.20 (m, 7H), 7.17 - 7.11 (m, 4H), 4.69 - 3.82 (m, 5H), 3.13 (d,
J= 10.0 Hz, 2H), 2.55 (ddd,
J= 17.6, 5.8, 2.8 Hz, 1H), 2.49 - 2.38 (m, 1H), 1.98 (td,
J= 12.2, 5.9 Hz, 1H), 1.86 - 1.76 (m, 1H), 1.37 (s, 9H); MS (ESI) m/z = 215 [M+H]
+。
步驟2 :製備(S)- 苯甲基(4- 苯甲基-4- 氮雜螺[2.5] 辛-6- 基) 胺基甲酸三級丁酯
將溴化乙基鎂(8.3 mL,25.1 mmol)溶解於THF (100 mL)中且接著冷卻至-78℃。添加異丙醇鈦(3.22 mL,10.8 mmol)且接著攪拌10分鐘,且接著逐滴添加溶解於THF (10 mL)中之(S)-苯甲基(1-苯甲基-6-側氧基哌啶-3-基)胺基甲酸三級丁酯(3.3 g,8.37 mmol)。在將溫度緩慢升高至室溫之後,使混合物在70℃下回流15小時。藉由添加10% (v/v)氫氧化鈉水溶液終止反應。藉由添加THF (30 mL)萃取混合物,經無水硫酸鎂乾燥,且過濾,且接著在減壓下移除溶劑。藉由矽膠管柱層析(EA)純化殘餘物,得到(S)-苯甲基(4-苯甲基-4-氮雜螺[2.5]辛-6-基)胺基甲酸三級丁酯(2.38 g,70%)。MS (ESI) m/z = 407 [M+H]
+。
步驟3 :製備(S)-4- 氮雜螺[2.5] 辛-6- 胺
將(S)-苯甲基(4-苯甲基-4-氮雜螺[2.5]辛-6-基)胺基甲酸三級丁酯(2.38 g,5.86 mmol)溶解於MeOH (30 mL)中,且接著添加5%鹽酸水溶液(57.3 mL, 0.12 mmol)。添加Pd/C (238 mg,2.24 mmol),且接著在氫氣球下在室溫下攪拌混合物15小時。反應完成後,其經矽藻土過濾,且接著在減壓下濃縮濾液,得到中間物A (628 mg,85%)。
1H NMR (400 MHz, DMSO-
D 6) δ 8.49 (s, 2H), 3.46 (d,
J= 9.9 Hz, 2H), 2.93 (d,
J= 11.9 Hz, 1H), 2.04 (dt,
J= 12.0, 7.3 Hz, 2H), 1.68 (qd,
J= 12.4, 3.9 Hz, 1H), 1.40 - 1.31 (m, 1H), 1.01 (ddt,
J= 22.5, 11.5, 5.6 Hz, 2H), 0.69 (ddt,
J= 51.5, 10.4, 5.7 Hz, 2H); MS (ESI) m/z = 127 [M+H]
+。
實例1 :製備(S)-3- 胺基-6-(5- 氟-2-(1-(2,2,2- 三氟乙基)-1H- 吡唑-4- 基) 吡啶-4- 基)-N-( 哌啶-3- 基) 吡 𠯤-2- 甲醯胺 步驟1 :製備3- 胺基-6-(4,4,5,5- 四甲基-1,3,2- 二氧雜硼戊環-2- 基) 吡 𠯤-2- 甲酸甲酯
將3-胺基-溴吡𠯤-2-甲酸甲酯(5 g,21.5 mmol)溶解於二㗁烷(70 mL)中,且接著添加PdCl
2(dppf)·DCM (176 mg,0.21 mmol)、雙(頻哪醇根基)二硼(7.11 g,28.0 mmol)及乙酸鉀(3.81 g,38.8 mmol),且進行氬氣鼓泡10分鐘。此後,使其回流15小時。混合物經由矽藻土過濾器過濾,且接著用正己烷(200 mL)洗滌殘餘物。在減壓下濃縮濾液,得到殘餘物。在將乙酸乙酯(7 mL)添加至殘餘物中之後,過濾固體,得到呈棕色粉末狀之3-胺基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡𠯤-2-甲酸甲酯(4.15 g,69%)。
1H NMR (400 MHz, DMSO-
d 6): δ 8.31 (s, 1H), 7.44 (s, 2H), 3.82 (s, 3H), 1.20 (s, 12H); MS (ESI) m/z = 197 [M+H]
+。
步驟2 :製備3- 胺基-6-(2- 氯-5- 氟吡啶-4- 基) 吡 𠯤-2- 甲酸
將3-胺基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡𠯤-2-甲酸甲酯(219 mg,0.78 mmol)溶解於二㗁烷(5 mL)中,且接著添加PdCl
2(dppf)·DCM (8.4 mg,0.05 mmol)、4-溴-2-氯-5-氟吡啶(150 mg,0.71 mmol)、1M碳酸鈉水溶液(2.14 mL, 2.14 mmol),且進行氬氣鼓泡10分鐘。此後,使其回流15小時。在減壓下濃縮混合物,得到殘餘物。在向殘餘物中添加水(40 mL)之後,將其用EA (40 mL)萃取。將水層合併且藉由添加1 M鹽酸水溶液而酸化至pH 3,且接著用EA (40 mL×2)萃取。將有機層用氯化鈉水溶液(40 mL)洗滌,接著經無水硫酸鎂乾燥,且過濾,且接著在減壓下移除溶劑且無需純化過程即用於步驟3中(產率89%)。
1H NMR (400 MHz, 甲醇-
D 4) δ 8.80 - 8.79 (d,
J= 1.8 Hz, 1H), 8.35 - 8.34 (d,
J= 3.0 Hz, 1H), 8.23 - 8.22 (d,
J= 5.7 Hz, 1H), 8.20 - 8.19 (d,
J= 2.4 Hz, 1H), 7.85 - 7.84 (d,
J= 2.4 Hz, 1H); MS (ESI) m/z = 269 [M+H]
+。
步驟3 :製備3- 胺基-6-(5- 氟-2-(1-(2,2,2- 三氟乙基)-1H- 吡唑-4- 基) 吡啶-4- 基) 吡 𠯤-2- 甲酸
將3-胺基-6-(2-氯-5-氟吡啶-4-基)吡𠯤-2-甲酸(168 mg,0.63 mmol)溶解於二㗁烷(3 mL)中,且接著添加PdCl
2(dppf)·DCM (33.7 mg,0.04 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1-(2,2,2-三氟乙基)-1H-吡唑(190 mg,0.69 mmol)及1 M碳酸鈉水溶液(1.88 mL, 1.88 mmol),且進行氬氣鼓泡10分鐘。此後,使其回流15小時。在減壓下濃縮混合物,得到殘餘物。在向殘餘物中添加水(30 mL)之後,將其用EA (30 mL)萃取。將水層合併且藉由添加1 M鹽酸水溶液而酸化至pH 3,且接著用EA (30 mL×2)萃取。將有機層用氯化鈉水溶液(30 mL)洗滌,且接著經無水硫酸鎂乾燥且過濾,且接著在減壓下移除溶劑且無需純化過程即用於步驟4中(產率58%)。
1H NMR (400 MHz, DMSO-
d 6) δ 8.76 (s, 1H), 8.58 (s, 1H), 8.40 (s, 1H), 8.22 (m, 1H), 8.14 (s, 1H), 7.85 (s, 1H), 7.80 (bs, 2H), 5.22 - 5.15 (q,
J= 9.1 Hz, 2H); MS (ESI) m/z = 393 [M+H]
+。
步驟4 :製備(S)-3-(3- 胺基-6-(5- 氟-2-(1-(2,2,2- 三氟乙基)-1H- 吡唑-4- 基) 吡啶-4- 基) 吡 𠯤-2- 甲醯胺基) 哌啶-1- 甲酸三級丁酯
將3-胺基-6-(5-氟-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲酸(33.5 mg,0.09 mmol)溶解於
N,N-二甲基甲醯胺(1 mL)中,且添加三乙胺(14.7 μL, 0.11 mmol)、HBTU (39.9 mg,0.11 mmol)及(
S)-3-胺基哌啶-1-甲酸三級丁酯(17.6 mg,0.09 mmol)且在室溫下攪拌15小時。反應完成後,在減壓下濃縮混合物,得到殘餘物。在向殘餘物中添加水(20 mL)之後,將其用EA (20 mL×2)萃取,且接著經無水硫酸鈉乾燥,且過濾。在減壓下移除溶劑,且接著藉由矽膠管柱層析(50% EA/正己烷)純化殘餘物,得到(S)-3-(3-胺基-6-(5-氟-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺基)哌啶-1-甲酸三級丁酯(38 mg,77%)。
1H NMR (400 MHz, CDCl
3) δ 8.79 (d,
J= 1.5 Hz, 1H), 8.48 (d,
J= 2.9 Hz, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 8.10 (d,
J= 2.4 Hz, 1H), 7.75 (d,
J= 2.4 Hz, 1H), 4.81 (s, 2H), 3.85 - 3.80 (m, 1H), 3.40 (d,
J= 13.8 Hz, 1H), 3.16 (t,
J= 11.2 Hz, 1H), 1.88 (q,
J= 4.3 Hz, 2H), 1.76 - 1.52 (m, 4H), 1.22 (d,
J= 2.0 Hz, 9H); MS (ESI) m/z = 565 [M+H]
+。
步驟5 :製備(S)-3- 胺基-6-(5- 氟-2-(1-(2,2,2- 三氟乙基)-1H- 吡唑-4- 基) 吡啶-4- 基)-N-( 哌啶-3- 基) 吡 𠯤-2- 甲醯胺
將(S)-3-(3-胺基-6-(5-氟-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺基)哌啶-1-甲酸三級丁酯(37 mg,0.07 mmol)溶解於二氯甲烷(1 mL)中,且接著添加4 M HCl (0.33 mL, 1.3 mmol),且使混合物在室溫下反應1小時。反應完成後,在減壓下濃縮混合物以得到殘餘物,其藉由製備型管柱層析純化,得到呈黃色粉末狀之實例1之化合物(20 mg,66%)。
1H NMR (400 MHz, 甲醇-
D 4) δ 8.75 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 8.28 - 8.26 (d,
J= 6.3 Hz, 1H), 8.16 (s, 1H), 5.04 - 4.98 (q,
J= 8.7 Hz, 2H), 4.28 (bs, 1H), 3.50 (m, 1H), 3.34 (m, 1H), 3.05 (m, 1H), 2.96 (m, 1H), 2.10 (m, 2H), 1.86 (m, 2H); MS (ESI) m/z = 465 [M+H]
+。
實例2 至41
使用對應於下表3中所示之目標化合物之結構的起始物質以與實例1中相同之方式製備實例2至41之化合物。然而,當中間物A用於步驟4中時,在步驟4中藉由製備型管柱層析對其進行純化,且在無步驟5之情況下直接獲得目標化合物。
[表1]
[表2]
[表3]
實例42 :製備(S)-3- 胺基-6-(3-(5,5- 二甲基-5,6- 二氫-4H- 吡咯并[1,2-b] 吡唑-3- 基) 苯基)-N-( 哌啶-3- 基) 吡 𠯤-2- 甲醯胺 步驟1 :製備3- 胺基-6-(3- 溴苯基) 吡 𠯤-2- 甲酸甲酯
實例編號 | 化學結構 | 化合物名稱 |
2 | 3-胺基-6-(5-氟-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
3 | 3-胺基-6-(5-氟-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
4 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(5-氟-2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
5 | (S)-3-胺基-6-(2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
6 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
7 | (S)-3-胺基-6-(2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
8 | (S)-3-胺基-6-(2-氟-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
9 | 3-胺基-6-(2-氟-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
10 | 3-胺基-6-(2-氟-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
11 | 3-胺基-6-(2-氟-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)-N-((3R,4R)-4-羥基吡咯啶-3-基)吡𠯤-2-甲醯胺 | |
12 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(2-氟-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)吡𠯤-2-甲醯胺 | |
13 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
14 | 3-胺基-N-((3R,4R)-4-羥基哌啶-3-基)-6-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
15 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
16 | (S)-3-胺基-6-(3-(1-甲基-1H-吡唑-4-基)苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
17 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(3-(1-甲基-1H-吡唑-4-基)苯基)吡𠯤-2-甲醯胺 | |
18 | (S)-3-胺基-6-(2-氟-5-(1-甲基-1H-吡唑-4-基)苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
19 | 3-胺基-6-(2-氟-5-(1-甲基-1H-吡唑-4-基)苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
20 | (S)-3-胺基-6-(2-(1-環丙基-1H-吡唑-4-基)吡啶-4-基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
21 | (S)-3-胺基-N-(哌啶-3-基)-6-(2-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
22 | 3-胺基-6-(5-氟-2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
23 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(2-羥基-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)吡𠯤-2-甲醯胺 | |
24 | (S)-3-胺基-6-(2-羥基-5-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
25 | 3-胺基-6-(3-(1-(氰基甲基)-1H-吡唑-4-基)苯基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
26 | 3-胺基-6-(3-(1-(氰基甲基)-1H-吡唑-4-基)苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
27 | (S)-3-胺基-6-(3-(1-(氰基甲基)-1H-吡唑-4-基)苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
28 | 3-胺基-6-(3-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)苯基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
29 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(3-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)苯基)吡𠯤-2-甲醯胺 | |
30 | (S)-3-胺基-6-(3-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
31 | (S)-3-胺基-6-(5-(1-環丙基-1H-吡唑-4-基)-2-氟苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
32 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(5-氟-2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
33 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
34 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(2-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)吡啶-4-基)吡𠯤-2-甲醯胺 | |
35 | 3-胺基-6-(2-氟-5-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
36 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(2-氟-5-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)苯基)吡𠯤-2-甲醯胺 | |
37 | 3-胺基-N-((3S,5S)-5-氟哌啶-3-基)-6-(5-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)-2-甲基苯基)吡𠯤-2-甲醯胺 | |
38 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(5-(1-(2-羥基-2-甲基丙基)-1H-吡唑-4-基)-2-甲基苯基)吡𠯤-2-甲醯胺 | |
39 | (S)-3-胺基-N-(哌啶-3-基)-6-(4-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)嘧啶-2-基)吡𠯤-2-甲醯胺 | |
40 | 3-胺基-6-(2-氟-5-(1-甲基-1H-吡唑-4-基)苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
41 | 3-胺基-6-(3-(1-甲基-1H-吡唑-4-基)苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 |
實例編號 | LC/MS (ESI) m/z: [M+H] + | NMR |
2 | 483 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.75 (s, 1H), 8.73 - 8.71 (d, J= 8.2 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 8.27 - 8.25 (d, J= 6.2 Hz, 1H), 8.17 (s, 1H), 5.29 - 5.18 (d, J= 45.0 Hz, 1H), 5.04 - 4.98 (q, J= 8.7, 2H), 4.64 (m, 1H), 3.63 (m, 1H), 3.55 (m, 1H), 3.12 (m, 2H), 2.47 (bs, 1H), 2.13 (m, 1H)。 |
3 | 481 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.76 (s, 1H), 8.68 - 8.66 (d, J= 8.2 Hz, 1H), 8.48 (s, 1H), 8.32 (s, 1H), 8.30 - 8.28 (d, J= 6.2 Hz, 1H), 8.18 (s, 1H), 5.04 - 4.98 (q, J= 8.7 Hz, 2H), 4.12 (m, 1H), 3.98 (m, 1H), 3.59 (m, 1H), 3.46 (m, 2H), 3.09 (m, 1H), 2.26 (m, 1H), 1.82 (m, 1H)。 |
4 | 501 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.80 - 8.79 (d, J= 7.0 Hz, 1H), 8.79 (s, 1H), 8.49 (s, 1H), 8.31 (s, 1H), 8.28 - 8.26 (d, J= 6.3 Hz, 1H), 8.16 (s, 1H), 5.03 - 4.97 (q, J= 8.6 Hz, 2H), 4.63 (m, 1H), 3.72 (m, 1H), 3.57 (m, 2H), 3.35 (m, 1H), 2.59 (m, 2H)。 |
5 | 437 | 1H NMR (400 MHz, DMSO-d 6) δ 9.17 (s, 1H), 8.81 - 8.79 (d, J= 8.4 Hz, 1H), 8.77 - 8.74 (d, J= 11.1 Hz, 1H), 8.64 - 8.61 (d, J= 10.8 Hz, 1H), 8.59 - 8.58 (d, J= 5.6 Hz, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.99 (bs, 1H), 4.20 (m, 1H), 4.06 (s, 2H), 3.32 - 3.22 (dd, J= 29.3, 12.0 Hz, 2H), 3.06 - 2.98 (q, J= 10.8 Hz, 1H), 2.79 (m, 1H), 1.89 (m, 2H), 1.73 (m, 2H), 1.08 (s, 6H)。 |
6 | 455 | 1H NMR (400 MHz, DMSO-d 6) δ 9.27 (bs, 1H), 9.17 (s, 1H), 9.08 (bs, 1H), 8.92 - 8.89 (d, J= 8.7 Hz, 1H), 8.59 - 8.57 (d, J= 5.6 Hz, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 8.12 - 8.11 (d, J= 5.6 Hz, 1H), 7.98 (bs, 1H), 5.28 - 5.17 (d, J= 45.2 Hz, 1H), 4.47 (m, 1H), 4.06 (s, 2H), 3.57 - 3.51 (d, J= 13.1 Hz, 1H), 3.32 - 3.29 (d, J= 11.8 Hz, 1H), 3.23 - 3.20 (d, J= 11.8 Hz, 1H), 3.11 (m, 1H), 2.19 (m, 1H), 2.06 (m, 1H), 1.07 (s, 6H)。 |
7 | 463 | 1H NMR (400 MHz, DMSO-d 6) δ 9.40 (bs, 1H), 9.21 (s, 1H), 8.94 - 8.91 (d, J= 11.0 Hz, 1H), 8.89 - 8.87 (d, J= 8.6 Hz, 1H), 8.62 - 8.61 (d, J= 5.8 Hz, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.24 (m, 2H), 8.10 (bs, 1H), 4.29 (m, 1H), 4.08 (s, 2H), 3.34 (m, 1H), 3.16 (m, 1H), 2.09 (m, 1H), 1.94 (m, 1H), 1.42 (m, 1H), 1.03 (s, 6H), 0.97 (m, 2H), 0.78 (m, 2H)。 |
8 | 490 | 1H NMR (400 MHz, DMSO-d 6) δ 9.27 (bs, 1H), 8.77 (m, 2H), 8.63 - 8.62 (d, J= 2.3 Hz, 1H), 8.31 (s, 1H), 8.14 (m, 1H), 8.09 (s, 1H), 7.74 (bs, 1H), 7.64 (m, 1H), 7.33 (m, 1H), 5.17 - 5.10 (q, J= 9.1, 2H), 4.28 (m, 1H), 3.33 (m, 1H), 3.14 (m, 1H), 2.04 (m, 1H), 1.91 (m, 2H), 1.43 (m, 1H), 0.83 (m, 4H)。 |
9 | 482 | 1H NMR (400 MHz, DMSO-d 6) δ 9.20 (bs, 1H), 9.09 (bs, 1H), 8.80 - 8.78 (d, J= 8.6 Hz, 1H), 8.61 (s, 1H), 8.19 (m, 2H), 7.65 (m, 2H), 7.32 (m, 1H), 5.25 (bs, 1H), 5.16 - 5.09 (q, J= 9.1, 2H), 4.45 (m, 1H), 3.52 (m, 1H), 3.25 (m, 1H), 3.08 (m, 2H), 2.24 (m, 1H), 2.05 (m, 1H)。 |
10 | 480 | 1H NMR (400 MHz, DMSO-d 6) δ 8.62 (m, 4H), 8.30 (s, 1H), 8.12 (m, 1H), 8.08 (s, 1H), 7.71 (bs, 1H), 7.63 (m, 1H), 7.33 (m, 1H), 5.16 - 5.09 (q, J= 9.2 Hz, 2H), 4.01 (m, 1H), 3.78 (m, 1H), 3.51 (m, 1H), 3.13 (m, 1H), 2.98 (m, 1H), 2.86 (m, 1H), 2.00 (m, 1H), 1.63 (m, 1H)。 |
11 | 466 | 1H NMR (400 MHz, DMSO-d 6) δ 9.15 (bs, 1H), 8.80 (bs, 1H), 8.80 - 8.78 (d, J= 7.1 Hz, 1H), 8.63 - 8.62 (d, J= 2.3 Hz, 1H), 8.31 (s, 1H), 8.13 (m, 1H), 8.08 (s, 1H), 7.69 (bs, 1H), 7.63 (m, 1H), 7.32 (m, 1H), 5.16 - 5.09 (q, J= 9.1, 2H), 4.37 (m, 2H), 3.55 (m, 2H), 3.31 (m, 1H), 3.10 (m, 1H)。 |
12 | 500 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.75 - 8.73 (d, J= 7.9 Hz, 1H), 8.64 (m, 1H), 8.13 (s, 1H), 8.09 (m, 1H), 7.98 (s, 1H), 7.59 (m, 1H), 7.23 (m, 1H), 4.98 - 4.92 (q, J= 8.7 Hz, 2H), 4.62 (m, 1H), 3.68 (m, 1H), 3.52 (m, 1H), 3.32 (m, 1H), 2.60 (m, 1H), 2.48 (m, 1H)。 |
13 | 483 | 1H NMR (400 MHz, 甲醇- D 4) δ 9.06 - 9.05 (d, J= 2.3 Hz, 1H), 8.91 - 8.89 (d, J= 8.0 Hz, 1H), 8.57 (m, 3H), 8.32 - 8.31 (d, J= 2.3 Hz, 1H), 8.23 (m, 1H), 5.11 - 5.05 (q, J= 8.6 Hz, 2H), 4.63 (m, 1H), 3.73 (m, 1H), 3.56 (m, 2H), 3.34 (m, 1H), 2.57 (m, 2H)。 |
14 | 463 | 1H NMR (400 MHz, DMSO- D 6) δ 9.14 (s, 1H), 8.74 (s, 1H), 8.66 (t, J= 9.6 Hz, 2H), 8.60 (d, J= 5.4 Hz, 1H), 8.52 (s, 1H), 8.43 (d, J= 1.7 Hz, 1H), 8.31 (s, 1H), 8.08 (dd, J= 5.4, 1.7 Hz, 1H), 5.22 (q, J= 9.1 Hz, 2H), 4.04 (qd, J= 9.2, 4.3 Hz, 1H), 3.84 (dt, J= 9.7, 5.0 Hz, 1H), 3.33 - 3.25 (m, 2H), 3.03 (q, J= 10.9 Hz, 1H), 2.88 (q, J= 9.2, 6.3 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.68 - 1.54 (m, 1H)。 |
15 | 465 | 1H NMR (400 MHz, DMSO- D 6) δ 9.24 (bs, 1H), 9.13 (s, 1H), 9.08 (bs, 1H), 8.89 - 8.87 (d, J= 8.7 Hz, 1H), 8.60 - 8.59 (d, J= 5.4 Hz, 1H), 8.51 (s, 1H), 8.42 - 8.41 (d, J= 1.6 Hz, 1H), 8.31 (s, 1H), 8.08 (m, 1H), 7.93 (bs, 1H), 5.22 (m, 3H), 4.47 (m, 1H), 3.30 (m, 1H), 3.20 (m, 1H), 3.10 (m, 2H), 2.16 (m, 2H)。 |
16 | 378 | 1H NMR (400 MHz, DMSO- D 6) δ 8.93 (s, 1H), 8.65 (m, 3H), 8.21 (m, 2H), 7.97 (s, 1H), 7.95 (m, 1H), 7.61 (bs, 1H), 7.54 (m, 1H), 7.42 (m, 1H), 4.20 (m, 1H), 3.85 (s, 3H), 3.31 - 3.20 (dd, J= 30.9, 12.0 Hz, 1H), 3.08 - 2.99 (q, J= 10.7 Hz, 1H), 2.77 (m, 1H), 1.88 (m, 2H), 1.73 (m, 2H)。 |
17 | 396 | 1H NMR (400 MHz, DMSO- D 6) δ 9.24 (bs, 1H), 9.05 (bs, 1H), 8.94 (s, 1H), 8.79 - 8.77 (d, J= 8.7 Hz, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 7.98 (s, 1H), 7.96 (m, 1H), 7.61 (bs, 1H), 7.54 (m, 1H), 7.42 (m, 1H), 5.27 - 5.16 (d, J= 45.3 Hz, 1H), 4.48 (m, 1H), 3.85 (s, 3H), 3.51 (m, 1H), 3.30 (m, 1H), 3.15 (m, 2H), 2.15 (m, 2H)。 |
18 | 396 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.58 - 8.57 (d, J= 2.3 Hz, 1H), 8.08 (m, 2H), 7.96 - 7.95 (d, J= 4.4 Hz, 1H), 7.58 (m, 1H), 7.22 (m, 1H), 4.28 (m, 1H), 3.95 (s, 3H), 3.48 (m, 1H), 3.32 (m, 1H), 3.06 (m, 1H), 2.97 (m, 1H), 2.05 (m, 2H), 1.85 (m, 2H)。 |
19 | 414 | 1H NMR (400 MHz, DMSO- D 6) δ 9.19 (s, 1H), 9.04 (d, J= 10.7 Hz, 1H), 8.78 (d, J= 8.7 Hz, 1H), 8.60 (d, J= 2.4 Hz, 1H), 8.14 (s, 1H), 8.04 (dd, J= 7.6, 2.4 Hz, 1H), 7.90 (s, 1H), 7.69 (s, 1H), 7.57 (ddd, J= 8.5, 4.7, 2.4 Hz, 1H), 7.29 (dd, J= 11.1, 8.5 Hz, 1H), 5.20 (d, J= 45.2 Hz, 1H), 4.51 - 4.38 (m, 1H), 3.83 (s, 4H), 3.49 (d, J= 12.5 Hz, 1H), 3.32 - 3.01 (m, 3H), 2.24 (s, 1H), 2.14 - 1.93 (m, 1H)。 |
20 | 405 | 1H NMR (400 MHz, DMSO- D 6) δ 9.14 (s, 1H), 8.78 (m, 2H), 8.64 - 8.62 (d, J= 10.1 Hz, 1H), 8.59 - 8.58 (d, J= 5.6 Hz, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 8.16 (s, 1H), 8.12 - 8.10 (d, J= 5.6 Hz, 1H), 4.18 (m, 2H), 3.32 - 3.22 (dd, J= 27.7, 12.2 Hz, 2H), 3.02 (m, 1H), 2.79 (m, 1H), 1.90 (m, 2H), 1.80 (m, 2H), 1.06 (m, 2H), 1.01 (m, 2H)。 |
21 | 447 | 1H NMR (400 MHz, DMSO- D 6) δ 9.14 (s, 1H), 8.79 (m, 2H), 8.63 (m, 2H), 8.53 (s, 1H), 8.45 (s, 1H), 8.33 (s, 1H), 8.11 (m, 1H), 5.26 - 5.20 (q, J= 9.1 Hz, 2H), 4.18 (m, 1H), 3.32 - 3.22 (dd, J= 28.5, 12.2 Hz, 2H), 3.03 (m, 1H), 2.78 (m, 1H), 1.86 (m, 2H), 1.72 (m, 2H)。 |
22 | 473 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.94 (s, 1H), 8.55 (dd, J= 5.4, 0.8 Hz, 1H), 8.35 - 8.28 (m, 1H), 8.17 (d, J= 0.8 Hz, 1H), 7.89 (dd, J= 5.4, 1.7 Hz, 1H), 4.40 (m 1H), 4.20 (s, 2H), 3.19 - 3.03 (m, 3H), 2.91 (dd, J= 13.2, 7.0 Hz, 1H), 2.56 - 2.21 (m, 3H), 1.26 (s, 6H)。 |
23 | 480 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.81 (s, 1H), 8.73 - 8.71 (d, J= 8.2 Hz, 2H), 8.56 (s, 1H), 8.31 (s, 1H), 7.78 - 7.71 (d, J= 6.1 Hz, 1H), 7.21 - 7.18 (d, J= 5.3 Hz, 1H), 4.94 - 4.81 (q, J= 7.6 Hz, 2H), 4.03 - 3.87 (m, 1H), 3.63 - 3.51 (m, 1H), 3.40 - 2.69 (m, 4H), 2.08 - 1.67 (m, 2H)。 |
24 | 462 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.82 (s, 1H), 8.74 - 8.71 (d, J= 8.2 Hz, 2H), 8.46 (s, 1H), 8.22 (s, 1H), 7.80 - 7.69 (d, J= 7.4 Hz, 1H), 7.25 - 7.19 (d, J= 6.2 Hz, 1H), 4.94 - 4.81 (m, 2H), 3.81 - 3.70 (m, 1H), 3.63 - 2.69 (m, 4H), 1.98 - 1.78 (m, 2H), 1.68 - 1.42 (m, 2H)。 |
25 | 419 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.86 (s, 1H), 8.50 (d, J= 6.4 Hz, 2H), 8.33 (s, 1H), 8.20 (s, 1H), 7.77 - 7.64 (m, 2H), 4.85 - 4.80 (m, 2H), 4.27 - 4.24 (m, 1H) 3.70 - 3.63 (m, 1H), 3.00 - 2.92 (m, 2H), 2.84 - 2.69 (m, 4H), 1.78 - 1.53 (m, 2H)。 |
26 | 421 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.86 (s, 1H), 8.51 - 8.49 (m, 2H), 8.32 (s, 1H), 8.19 (s, 1H), 7.78 - 7.71 (m, 2H), 4.85 - 4.80 (q, J= 9.6 Hz, 2H), 3.63 - 3.51 (m, 3H), 3.47 - 2.85 (m, 4H), 2.18 - 1.88 (m, 1H)。 |
27 | 403 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.81 (s, 1H), 8.54 - 8.48 (m, 2H), 8.33 (s, 1H), 8.20 (s, 1H), 7.75 - 7.70 (m, 2H), 4.86 - 4.82 (q, J= 7.7 Hz, 2H), 3.74 - 3.66 (m, 1H), 3.12 - 2.85 (m, 2H), 2.78 - 2.63 (m, 2H), 1.82 - 1.63 (m, 4H)。 |
28 | 452 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.90 (s, 1H), 8.53 (dd, J= 6.4, 1.3 Hz, 2H), 8.34 - 8.20 (m, 1H), 8.14 (d, J= 1.8 Hz, 1H), 7.89 - 7.63 (m, 1H), 4.42 (m 1H), 3.89 - 3.75 (m, 2H), 3.64 (tt, J= 13.1, 7.8 Hz, 1H), 3.16 - 3.03 (m, 4H), 1.86 - 1.64 (m, 4H), 1.25 (s, 6H)。 |
29 | 454 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.84 (s, 1H), 8.51 (dd, J= 5.4, 2.3 Hz, 2H), 8.24 - 8.21 (m, 1H), 8.06 (d, J= 1.9 Hz, 1H), 7.86 - 7.60 (m, 1H), 3.80 - 3.76 (m, 2H), 3.60 - 3.12 (m, 4H), 3.10 - 2.88 (m, 2H), 1.86 - 1.64 (m, 2H), 1.23 (s, 6H)。 |
30 | 436 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.81 (s, 1H), 8.57 - 8.50 (m, 2H), 8.20 - 8.18 (m, 1H), 8.04 (d, J= 2.0 Hz, 1H), 7.87 - 7.66 (m, 1H), 3.81 - 3.78 (m, 2H), 3.60 - 3.55 (m, 1H), 3.15 - 2.93 (m, 4H), 1.89 - 1.60 (m, 4H), 1.26 (s, 6H)。 |
31 | 422 | 1H NMR (400 MHz, 甲醇- D 4) δ 9.10 (s, 1H), 8.73 - 8.61 (m, 1H), 8.37 (s, 1H), 8.24 (s, 1H), 7.97 - 7.83 (m, 2H), 3.72 - 3.64 (m, 1H), 3.60 - 3.13 (m, 4H), 2.76 - 2.55 (m, 1H), 1.90 - 1.54 (m, 4H), 1.28 - 1.12 (m, 4H)。 |
32 | 491 | 1H NMR (400 MHz, DMSO- D 6) δ 8.79 (d, J= 1.6 Hz, 1H), 8.75-8.73 (m, 1H), 8.590 (d, J= 3.6 Hz, 1H), 8.259 (t, J= 6.4 Hz, 2H), 8.04 (s, 1H), 7.95 (bs, 2H), 4.74 (s, 1H), 4.21-4.18 (m, 1H), 4.078 (s, 2H), 2.99-2.91 (m, 4H), 2.83-2.66 (m, 1H), 2.35-2.20 (m, 1H), 1.11 (s, 6H)。 |
33 | 473 | 1H NMR (400 MHz, DMSO- D 6) δ 9.09 (s, 1H), 8.72 (d, J= 9.2 Hz, 1H), 8.55 (d, J= 5.2 Hz, 1H), 8.30 (s, 2H), 8.11 (s, 1H), 7.92-7.91 (m, 2H), 4.75 (s, 1H), 4.18-4.15 (m, 1H), 4.05 (s, 2H), 3.15-2.82 (m, 3H), 2.71-2.65 (m, 2H), 2.33-2.19 (m, 2H), 1.09 (s, 6H)。 |
34 | 455 | 1H NMR (400 MHz, DMSO- D 6) δ 9.08 (s, 1H), 8.58-8.54 (m, 2H), 8.31 (s, 2H), 8.12 (s, 1H), 7.95-7.89 (m, 2H), 4.86 (s, 1H), 4.75 (s, 1H), 4.17-4.13 (m, 1H), 4.06 (s, 2H), 2.93-2.91 (m, 2H), 2.76-2.61 (m, 3H), 2.10-1.97 (m, 2H), 1.08 (s, 6H)。 |
35 | 472 | 1H NMR (400 MHz, DMSO- D 6) δ 8.64 (d, J= 2 Hz, 1H), 8.50 (d, J= 8.8 Hz, 1H), 8.149-8.121 (m,2H), 7.94 (s, 1H), 7.83 (s, 1H), 7.65-7.61 (m, 1H), 7.34-7.29 (m, 1H), 4.85 (s, 1H), 4.73 (s, 1H), 4.19-4.09 (m, 1H), 4.04 (s, 2H) 2.96-2.61 (m, 5H), 2.09-1.98 (m, 2H), 1.10 (s, 6H)。 |
36 | 490 | 1H NMR (400 MHz, DMSO- D 6) δ 8.69-8.66 (m, 2H) , 8.14-8.11 (m, 2H), 7.93 (s, 1H), 7.65-7.61 (m, 2H), 7.35-7.30 (m, 1H), 4.73 (s, 1H), 4.19 (m, 1H), 4.04 (s, 2H), 2.95-2.89 (m, 3H), 2.69-2.67 (m, 2H), 2.33-2.25 (m, 2H), 1.10 (s, 6H)。 |
37 | 468 | 1H NMR (400 MHz, DMSO- D 6) δ 8.44 (s, 1H), 8.33 (d, J= 9.2 Hz, 1H), 8.09 (s, 1H), 7.88 (s, 1H), 7.64-7.48 (m, 3H), 7.28-7.26 (m, 1H), 4.76-7.64 (m, 2H), 4.13-4.00 (m, 3H), 2.86-2.65 (m, 4H), 2.58-2.48 (m, 1H), 2.32 (s, 3H), 2.05-1.94 (m, 2H), 1.07 (s, 6H)。 |
38 | 486 | 1H NMR (400 MHz, DMSO- D 6) δ 8.50 (d, J= 9.2 Hz, 1H), 8.45 (s, 1H) , 8.09 (s, 1H), 7.88 (s, 1H), 7.64-7.60 (m, 2H), 7.50-7.48 (m, 1H), 7.27 (d, J= 8 Hz 1H), 4.70 (s, 1H), 4.14 (s, 1H), 4.00 (s, 2H), 2.95-2.75 (m, 4H), 2.65-2.59 (m, 1H), 2.32 (s, 3H), 2.23-2.10 (m, 2H), 1.07 (s, 6H)。 |
39 | 448 | 1H NMR (400 MHz, 甲醇- D 4) δ 9.59 (d, J= 7.4 Hz, 1H), 9.42 (s, 1H), 8.80 (d, J= 5.5 Hz, 1H), 8.67 (s, 1H), 8.35 (s, 1H), 7.69 (d, J= 5.5 Hz, 1H), 5.06 (q, J= 8.6 Hz, 2H), 4.26 (s, 1H), 3.52 (dd, J= 12.3, 4.1 Hz, 1H), 3.37 - 3.31 (m, 1H), 3.01 (t, J= 11.2 Hz, 2H), 2.12 (dd, J= 9.4, 5.3 Hz, 2H), 1.85 (q, J= 10.1, 9.6 Hz, 2H)。 |
40 | 422 | 1H NMR (400 MHz, DMSO- D 6) δ 9.26 (t, J= 10.5 Hz, 1H), 8.95 (s, 1H), 8.74 (dd, J= 17.3, 10.0 Hz, 2H), 8.22 (d, J= 2.2 Hz, 2H), 8.02 - 7.95 (m, 2H), 7.69 - 7.56 (m, 1H), 7.54 (dt, J= 7.8, 1.4 Hz, 1H), 7.43 (t, J= 7.7 Hz, 1H), 4.29 (s, 2H), 3.85 (s, 3H), 3.34 (d, J= 11.9 Hz, 1H), 3.18 (q, J= 10.6 Hz, 1H), 2.11 - 2.03 (m, 1H), 1.93 (dd, J= 9.5, 3.8 Hz, 2H), 1.42 (d, J= 14.0 Hz, 1H), 0.95 (ddd, J= 25.8, 10.9, 5.2 Hz, 2H), 0.77 (ddd, J= 24.2, 9.7, 4.9 Hz, 2H)。 |
41 | 404 | 1H NMR (400 MHz, DMSO- D 6) δ 9.27 (d, J= 10.8 Hz, 1H), 8.97 (s, 1H), 8.77 (d, J= 8.7 Hz, 2H), 8.34 (dd, J= 7.4, 2.4 Hz, 1H), 8.20 (d, J= 2.4 Hz, 1H), 8.08 - 8.02 (m, 2H), 7.64 (s, 1H), 7.33 (dd, J= 11.0, 8.7 Hz, 1H), 4.29 (s, 1H), 3.88 (s, 4H), 3.33 (d, J= 11.9 Hz, 1H), 3.17 (q, J= 10.7 Hz, 1H), 2.11 - 2.02 (m, 1H), 1.91 (d, J= 4.2 Hz, 2H), 1.42 (d, J= 14.1 Hz, 1H), 1.03 - 0.89 (m, 2H), 0.85 - 0.70 (m, 2H)。 |
實例編號 | 所用起始物質 |
2 | 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
3 | 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
4 | 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
5 | 步驟2:4-溴-2-氯吡啶 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 |
6 | 步驟2:4-溴-2-氯吡啶 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
7 | 步驟2:4-溴-2-氯吡啶 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:中間物A |
8 | 步驟2:2,4-二溴-1-氟苯 步驟4:中間物A |
9 | 步驟2:2,4-二溴-1-氟苯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
10 | 步驟2:2,4-二溴-1-氟苯 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
11 | 步驟2:2,4-二溴-1-氟苯 步驟4:(3R,4R)-3-胺基-4-羥基吡咯啶-1-甲酸三級丁酯 |
12 | 步驟2:2,4-二溴-1-氟苯 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
13 | 步驟2:4-溴-2-氯吡啶 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
14 | 步驟2:4-溴-2-氯吡啶 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
15 | 步驟2:4-溴-2-氯吡啶 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
16 | 步驟2:1,3-二溴苯 步驟3:1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑 |
17 | 步驟2:1,3-二溴苯 步驟3:1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
18 | 步驟2:2,4-二溴-1-氟苯 步驟3:1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑 |
19 | 步驟2:2,4-二溴-1-氟苯 步驟3:1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
20 | 步驟2:4-溴-2-氯吡啶 步驟3:1-環-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑 |
21 | 步驟2:4-溴-2-氯吡啶 |
22 | 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
23 | 步驟2:2-溴-4-氯苯酚 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
24 | 步驟2:2-溴-4-氯苯酚 |
25 | 步驟2:1,3-二溴苯 步驟3:2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑-1-基)乙腈 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
26 | 步驟2:1,3-二溴苯 步驟3:2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑-1-基)乙腈 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
27 | 步驟2:1,3-二溴苯 步驟3:2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑-1-基)乙腈 |
28 | 步驟2:1,3-二溴苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
29 | 步驟2:1,3-二溴苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
30 | 步驟2:1,3-二溴苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 |
31 | 步驟2:2,4-二溴-1-氟苯 步驟3:1-環-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1H-吡唑 |
32 | 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
33 | 步驟2:4-溴-2-氯吡啶 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
34 | 步驟2:4-溴-2-氯吡啶 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
35 | 步驟2:2,4-二溴-1-氟苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
36 | 步驟2:2,4-二溴-1-氟苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
37 | 步驟2:4-溴-2-碘-1-甲基苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
38 | 步驟2:4-溴-2-碘-1-甲基苯 步驟3:[1-(2-羥基-2-甲基-丙基)吡唑-4-基]酸頻哪醇酯 步驟4:(5S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
39 | 步驟2:2,4-二溴嘧啶 |
40 | 步驟2:2,4-二溴-1-氟苯 步驟4:4-氮雜螺[2.5]辛-6-胺(使用外消旋體) |
41 | 步驟2:1,3-二溴苯 步驟4:4-氮雜螺[2.5]辛-6-胺(使用外消旋體) |
將3-胺基-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡𠯤-2-甲酸甲酯(500 mg,1.79 mmol)溶解於二㗁烷(10 mL)中,且接著添加PdCl
2(dppf)·DCM (97 mg,0.12 mmol)、1,3-二溴苯(0.43 mL, 3.58 mmol)及1M碳酸鈉水溶液(5.37 mL, 5.37 mmol),且進行氬氣鼓泡10分鐘。此後,使其回流2小時。在減壓下濃縮混合物,得到殘餘物。在向殘餘物中添加水(70 mL)之後,將其用EA (70 mL×2)萃取。有機層經無水硫酸鎂乾燥且過濾,且接著在減壓下移除溶劑。藉由矽膠管柱層析(30% EA/正己烷)純化殘餘物,得到3-胺基-6-(3-溴苯基)吡𠯤-2-甲酸甲酯(86 mg,16%)。將水層合併且藉由添加1 M鹽酸水溶液而酸化至pH 3,且接著用EA (70 mL×2)萃取。有機層經無水硫酸鎂乾燥且過濾,且接著在減壓下移除溶劑,無需純化過程即得到3-胺基-6-(3-溴苯基)吡𠯤-2-甲酸(150 mg,28%)。
1H NMR (400 MHz, CDCl
3) δ 8.63 (s, 1H), 8.07 (t,
J= 1.8 Hz, 1H), 7.81 (ddd,
J= 7.8, 1.7, 1.0 Hz, 1H), 7.50 (ddd,
J= 8.0, 2.0, 1.0 Hz, 1H), 7.32 (t,
J= 7.9 Hz, 1H), 4.01 (s, 3H); MS (ESI) m/z = 309 [M+H]
+。
步驟2 :製備3- 胺基-6-(3- 溴苯基) 吡 𠯤-2- 甲酸
將3-胺基-6-(3-溴苯基)吡𠯤-2-甲酸甲酯(86 mg,0.28 mmol)溶解於甲醇(1 mL)、四氫呋喃(1 mL)及水(0.5 mL)中,且接著添加氫氧化鈉(33.5 mg,0.84 mmol)且在室溫下攪拌15小時。藉由添加1M鹽酸水溶液將反應溶液酸化至pH 2,且接著用EA萃取。有機層經無水硫酸鎂乾燥且過濾,且接著在減壓下移除溶劑且無需純化過程即用於步驟3中(產率90%)。MS (ESI) m/z = 295 [M+H]
+。
步驟3 :製備3- 胺基-6-(3-(5,5- 二甲基-5,6- 二氫-4H- 吡咯并[1,2-b] 吡唑-3- 基) 苯基) 吡 𠯤-2- 甲酸
將3-胺基-6-(3-溴苯基)吡𠯤-2-甲酸(100 mg,0.34 mmol)溶解於二㗁烷(3 mL)中,且接著添加PdCl
2(dppf)·DCM (18.3 mg,0.02 mmol)、5,5-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-5,6-二氫-4H-吡咯并[1,2-b]吡唑(89.1 mg,0.34 mmol)及1 M碳酸鈉水溶液(1 mL,1.00 mmol),且進行氬氣鼓泡10分鐘。此後,使其回流3小時。在減壓下濃縮混合物,得到殘餘物。在向殘餘物中添加水(30 mL)之後,將其用EA (30 mL)萃取。將水層合併且藉由添加1M鹽酸水溶液而酸化至pH 3,且接著用EA (30 mL×2)萃取。有機層經無水硫酸鎂乾燥且過濾,且接著在減壓下移除溶劑且無需純化過程即用於步驟4中(產率84%)。
1H NMR (400 MHz, DMSO-
D 6) δ 8.91 (s, 1H), 8.09 (s, 1H), 7.96 (s, 1H), 7.86 - 7.80 (m, 1H), 7.56 - 7.38 (m, 5H), 3.85 (s, 2H), 2.94 (s, 2H), 1.24 (s, 6H); MS (ESI) m/z = 350 [M+H]
+。
步驟4 :製備(S)-3-(3- 胺基-6-(3-(5,5- 二甲基-5,6- 二氫-4H- 吡咯并[1,2-b] 吡唑-3- 基) 苯基) 吡 𠯤-2- 甲醯胺基) 哌啶-1- 甲酸三級丁酯
將3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)吡𠯤-2-甲酸(30 mg,0.09 mmol)溶解於
N,N-二甲基甲醯胺(1 mL)中,且添加三乙胺(14 μL, 0.11 mmol)、HBTU (39 mg,0.11 mmol)及(
S)-3-胺基哌啶-1-甲酸三級丁酯(17.2 mg,0.09 mmol)且在室溫下攪拌15小時。反應完成後,在減壓下濃縮混合物,得到殘餘物。在向殘餘物中添加水(30 mL)之後,將其用EA (30 mL×2)萃取,且接著經無水硫酸鈉乾燥,且過濾。在減壓下移除溶劑,且接著藉由矽膠管柱層析(60% EA/正己烷)純化殘餘物,得到(S)-3-(3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)吡𠯤-2-甲醯胺基)哌啶-1-甲酸三級丁酯(37 mg,81%)。
1H NMR (400 MHz, CDCl
3) δ 8.63 (s, 1H), 8.01 (s, 2H), 7.89 (s, 1H), 7.85 (s, 1H), 7.65 (s, 1H), 7.46 - 7.43 (m, 2H), 4.11 - 4.02 (m, 1H), 3.95 (s, 2H), 3.79 (dd,
J= 13.1, 3.6 Hz, 1H), 3.54 (s, 1H), 3.31 (dd,
J= 13.0, 7.5 Hz, 2H), 1.73 (s, 4H), 1.62 (s, 2H), 1.36 (d,
J= 4.6 Hz, 15H); MS (ESI) m/z = 532 [M+H]
+。
步驟5 :製備(S)-3- 胺基-6-(3-(5,5- 二甲基-5,6- 二氫-4H- 吡咯并[1,2-b] 吡唑-3- 基) 苯基)-N-( 哌啶-3- 基) 吡 𠯤-2- 甲醯胺
將(S)-3-(3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)吡𠯤-2-甲醯胺基)哌啶-1-甲酸三級丁酯(35 mg,0.065 mmol)溶解於二氯甲烷(1 mL)中,且接著添加4 M HCl (0.35 mL, 1.3 mmol),且將混合物在室溫下反應2小時。反應完成後,在減壓下濃縮混合物以得到殘餘物,其藉由製備型管柱層析純化,得到實例42之化合物(10 mg,33%)。
1H NMR (400 MHz, DMSO-
D 6) δ 8.90 (s, 1H), 8.70 (d,
J= 8.6 Hz, 2H), 8.60 (d,
J= 11.0 Hz, 1H), 8.10 (t,
J= 1.8 Hz, 1H), 7.99 (s, 1H), 7.89 (dt,
J= 7.5, 1.6 Hz, 1H), 7.61 (s, 1H), 7.49 - 7.38 (m, 2H), 4.19 (dd,
J= 10.0, 4.9 Hz, 1H), 3.86 (s, 2H), 3.26 (dd,
J= 28.5, 11.6 Hz, 2H), 3.04 - 2.91 (m, 3H), 2.75 (d,
J= 10.9 Hz, 1H), 1.97 - 1.82 (m, 2H), 1.73 (q,
J= 12.5 Hz, 2H), 1.24 (d,
J= 2.2 Hz, 6H); MS (ESI) m/z = 432 [M+H]
+。
實例43 至66
使用對應於下表6中所示之目標化合物之結構的起始物質以與實例42中相同之方式製備實例43至66之化合物。然而,當中間物A用於步驟4中時,在步驟4中藉由製備型管柱層析對其進行純化,且在無步驟5之情況下直接獲得目標化合物。
[表4]
[表5]
[表6]
實驗實例1 : 評估化合物之Chk1 及Chk2 抑制活性
實例編號 | 化學結構 | 化合物名稱 |
43 | (S)-3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-氟苯基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
44 | 3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-氟苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
45 | 3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
46 | (S)-3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-氟苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
47 | 3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-氟苯基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
48 | 3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-4-基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
49 | (S)-3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-4-基)-N-(哌啶-3-基)吡𠯤-2-甲醯胺 | |
50 | (S)-3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-4-基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
51 | (S)-3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
52 | 3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
53 | 3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-4-基)-N-((3R,4R)-4-羥基哌啶-3-基)吡𠯤-2-甲醯胺 | |
54 | 3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-4-基)-N-((3R,4R)-4-羥基吡咯啶-3-基)吡𠯤-2-甲醯胺 | |
55 | 3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-羥基苯基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
56 | (S)-3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-羥基苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
57 | 3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-羥基苯基)-N-((3R,4R)-4-羥基吡咯啶-3-基)吡𠯤-2-甲醯胺 | |
58 | 3-胺基-N-(4,4-二氟哌啶-3-基)-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)吡𠯤-2-甲醯胺 | |
59 | (S)-3-胺基-N-(5,5-二氟哌啶-3-基)-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b])吡唑-3-基)苯基)吡𠯤-2-甲醯胺 | |
60 | 3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-((3R,4R)-4-羥基吡咯啶-3-基)吡𠯤-2-甲醯胺 | |
61 | 3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-(1,4-氧氮雜環庚烷-6-基)吡𠯤-2-甲醯胺 | |
62 | 3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-((3S,4S)-4-氟吡咯啶-3-基)吡𠯤-2-甲醯胺 | |
63 | (S)-3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)嘧啶-4-基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
64 | 3-胺基-6-(2-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)嘧啶-4-基)-N-((3S,5S)-5-氟哌啶-3-基)吡𠯤-2-甲醯胺 | |
65 | 3-胺基-6-(3-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 | |
66 | 3-胺基-6-(5-(5,5-二甲基-5,6-二氫-4H-吡咯并[1,2-b]吡唑-3-基)-2-氟苯基)-N-(4-氮雜螺[2.5]辛-6-基)吡𠯤-2-甲醯胺 |
實例編號 | LC/MS (ESI) m/z: [M+H] + | NMR |
43 | 450 | 1H NMR (400 MHz, DMSO-d 6) δ 8.61 (d, J= 2.4 Hz, 1H), 8.52 (d, J= 7.8 Hz, 1H), 7.96 (dd, J= 7.4, 2.4 Hz, 1H), 7.87 (s, 1H), 7.48 (m, 1H), 7.20 (m, 1H), 4.27 (m, 1H), 3.91 (s, 2H), 3.50 (dd, J= 12.2, 4.2 Hz, 1H), 3.32 (m, 1H), 2.95 (m, 4H), 2.05 (m, 2H), 1.85 (m, 2H), 1.33 (s, 3H), 1.32 (s, 3H)。 |
44 | 468 | 1H NMR (400 MHz, DMSO-d 6) δ 8.59 (m, 2H), 7.94 (m, 1H), 7.87 (s, 1H), 7.47 (m, 1H), 7.20 (m, 1H), 5.23 (m, 1H), 4.61 (m, 1H), 3.90 (s, 2H), 3.55 (m, 2H), 3.11 (m, 2H), 2.94 (s, 2H), 2.45 (m, 1H), 2.08 (m, 1H), 1.33 (s, 3H), 1.32 (s, 3H)。 |
45 | 450 | 1H NMR (400 MHz, DMSO- D 6) δ 9.15 (d, J= 73.6 Hz, 1H), 8.94 - 8.77 (m, 2H), 8.10 (q, J= 1.6 Hz, 1H), 7.99 (s, 1H), 7.91 (dq, J= 7.2, 1.5 Hz, 1H), 7.60 (s, 2H), 7.47 - 7.38 (m, 2H), 5.25 (dd, J= 45.2, 28.9 Hz, 1H), 4.58 - 4.39 (m, 1H), 3.85 (s, 2H), 3.50 (d, J= 11.9 Hz, 1H), 3.30 (d, J= 12.1 Hz, 1H), 3.10 (t, J= 22.2 Hz, 2H), 2.97 (d, J= 4.1 Hz, 2H), 2.85 (s, 1H), 2.32 - 1.99 (m, 2H), 1.25 (s, 6H)。 |
46 | 476 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.61 (d, J= 2.4 Hz, 1H), 8.54 (d, J= 7.7 Hz, 1H), 7.97 (dd, J= 7.4, 2.4 Hz, 1H), 7.87 (s, 1H), 7.49 (ddd, J= 8.6, 4.6, 2.4 Hz, 1H), 7.21 (dd, J= 11.1, 8.6 Hz, 1H), 4.35 (td, J= 10.1, 5.6 Hz, 1H), 3.91 (s, 2H), 3.54 - 3.48 (m, 1H), 3.20 (t, J= 11.1 Hz, 1H), 2.96 (d, J= 1.6 Hz, 2H), 2.23 - 2.11 (m, 2H), 2.04 - 1.93 (m, 1H), 1.61 (dt, J= 15.0, 4.4 Hz, 1H), 1.08 - 0.81 (m, 4H)。 |
47 | 466 | 1H NMR (400 MHz, DMSO- D 6) δ 8.73 (s, 1H), 8.68 - 8.55 (m, 3H), 7.94 (dd, J= 7.5, 2.4 Hz, 1H), 7.91 (s, 1H), 7.71 (s, 1H), 7.52 (ddd, J= 8.6, 4.7, 2.4 Hz, 1H), 7.29 (dd, J= 11.1, 8.5 Hz, 1H), 5.31 (s, 1H), 4.03 (ddt, J= 13.4, 9.0, 4.4 Hz, 1H), 3.84 (s, 2H), 3.75 (td, J= 9.8, 4.3 Hz, 1H), 3.28 (d, J= 14.1 Hz, 2H), 2.95 (d, J= 5.9 Hz, 2H), 2.82 (d, J= 11.6 Hz, 1H), 2.04 - 1.93 (m, 1H), 1.64 (q, J= 10.4 Hz, 1H), 1.23 (d, J= 2.6 Hz, 6H)。 |
48 | 451 | 1H NMR (400 MHz, DMSO- D 6) δ 9.33 (s, 1H), 9.10 (s, 2H), 8.90 (d, J= 8.7 Hz, 1H), 8.57 (dd, J= 5.5, 0.7 Hz, 1H), 8.20 (t, J= 1.2 Hz, 1H), 8.17 (s, 1H), 8.04 - 7.89 (m, 2H), 5.22 (d, J= 45.1 Hz, 1H), 4.48 (dt, J= 8.2, 4.1 Hz, 1H), 3.89 (s, 2H), 3.54 (t, J= 12.7 Hz, 1H), 3.32 (d, J= 11.0 Hz, 1H), 3.19 (s, 1H), 3.13 - 3.00 (m, 4H), 2.28 (d, J= 13.8 Hz, 1H), 2.10 (dt, J= 44.5, 13.2 Hz, 1H), 1.25 (s, 6H)。 |
49 | 433 | 1H NMR (400 MHz, DMSO- D 6) δ 9.10 (s, 1H), 8.79 (d, J= 8.5 Hz, 2H), 8.66 (d, J= 11.2 Hz, 1H), 8.57 (d, J= 5.5 Hz, 1H), 8.22 - 8.15 (m, 2H), 8.04 - 7.87 (m, 2H), 4.19 (s, 1H), 3.90 (s, 2H), 3.28 (dd, J= 28.9, 12.2 Hz, 2H), 3.13 - 2.90 (m, 3H), 2.76 (d, J= 11.4 Hz, 1H), 1.89 (d, J= 15.6 Hz, 2H), 1.73 (td, J= 11.9, 6.5 Hz, 2H), 1.25 (d, J= 2.4 Hz, 6H)。 |
50 | 459 | 1H NMR (400 MHz, DMSO- D 6) δ 9.34 (s, 1H), 9.10 (s, 1H), 8.82 (dd, J= 21.2, 9.8 Hz, 2H), 8.58 (d, J= 5.5 Hz, 1H), 8.23 - 8.14 (m, 2H), 7.99 (t, J= 17.7 Hz, 2H), 4.35 - 4.25 (m, 2H), 3.90 (s, 3H), 3.35 (d, J= 11.8 Hz, 1H), 3.17 - 2.99 (m, 3H), 2.12 (q, J= 8.0, 4.8 Hz, 1H), 1.94 (d, J= 7.8 Hz, 2H), 1.41 (s, 1H), 1.25 (d, J= 2.6 Hz, 6H), 1.04 - 0.65 (m, 4H)。 |
51 | 458 | 1H NMR (400 MHz, DMSO- D 6) δ 9.24 (d, J= 11.7 Hz, 1H), 8.91 (s, 1H), 8.83 - 8.73 (m, 1H), 8.63 (s, 1H), 8.14 - 8.09 (m, 1H), 7.99 (s, 1H), 7.91 (dt, J= 7.6, 1.6 Hz, 1H), 7.62 (s, 1H), 7.49 - 7.39 (m, 2H), 4.29 (s, 1H), 3.86 (s, 2H), 3.13 (d, J= 10.6 Hz, 1H), 3.04 - 2.92 (m, 2H), 2.64 - 2.58 (m, 1H), 2.10 (s, 1H), 1.93 (s, 2H), 1.40 (d, J= 14.0 Hz, 1H), 1.25 (d, J= 2.3 Hz, 6H), 0.98 (dd, J= 10.6, 5.3 Hz, 1H), 0.90 (d, J= 5.8 Hz, 1H), 0.83 - 0.77 (m, 1H), 0.70 (dd, J= 9.8, 5.3 Hz, 1H)。 |
52 | 448 | 1H NMR (400 MHz, DMSO- D 6) δ 8.91 (s, 1H), 8.74 (d, J= 10.7 Hz, 1H), 8.63 (d, J= 10.5 Hz, 1H), 8.57 (d, J= 8.5 Hz, 1H), 8.09 (d, J= 1.9 Hz, 1H), 7.99 (s, 1H), 7.90 (dt, J= 7.4, 1.6 Hz, 1H), 7.62 (s, 1H), 7.48 - 7.39 (m, 2H), 4.06 - 4.03 (m, 1H), 3.85 (s, 2H), 3.80 (d, J= 4.3 Hz, 1H), 3.31 (t, J= 13.3 Hz, 2H), 3.00 (dd, J= 15.1, 5.3 Hz, 3H), 2.89 - 2.79 (m, 1H), 2.07 - 1.97 (m, 1H), 1.68 (d, J= 14.2 Hz, 1H), 1.25 (d, J= 2.6 Hz, 6H)。 |
53 | 449 | 1H NMR (400 MHz, DMSO- D 6) δ 9.10 (s, 1H), 8.81 (s, 1H), 8.68 (d, J= 8.6 Hz, 2H), 8.58 (d, J= 5.5 Hz, 1H), 8.21 (d, J= 1.7 Hz, 1H), 8.17 (s, 1H), 8.02 (dd, J= 5.6, 1.6 Hz, 1H), 4.07 - 4.01 (m, 1H), 3.90 (s, 2H), 3.84 - 3.79 (m, 1H), 3.32 (d, J= 12.4 Hz, 2H), 3.08 - 2.94 (m, 3H), 2.85 (d, J= 11.6 Hz, 1H), 2.08 - 2.00 (m, 1H), 1.65 (d, J= 12.7 Hz, 1H), 1.25 (d, J= 3.0 Hz, 6H)。 |
54 | 435 | 1H NMR (400 MHz, DMSO- D 6) δ 9.22 (s, 2H), 9.11 (s, 1H), 8.88 (d, J= 7.1 Hz, 1H), 8.57 (d, J= 5.6 Hz, 1H), 8.23 - 8.17 (m, 2H), 8.06 (dd, J= 5.7, 1.7 Hz, 1H), 7.96 (s, 1H), 4.44 (dt, J= 5.3, 2.9 Hz, 1H), 4.36 (dt, J= 6.9, 3.4 Hz, 1H), 3.90 (s, 2H), 3.63 - 3.52 (m, 1H), 3.49 - 3.40 (m, 1H), 3.35 (dq, J= 11.9, 6.1, 5.4 Hz, 1H), 3.13 (t, J= 7.5 Hz, 1H), 3.06 (s, 2H), 1.25 (s, 6H)。 |
55 | 466 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.81 (s, 1H), 7.83 - 7.74 (m, 2H), 7.31 (dd, J= 8.4, 2.3 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 5.20 (d, J= 44.8 Hz, 1H), 4.60 (ddd, J= 12.1, 7.8, 4.3 Hz, 1H), 3.88 (s, 2H), 3.65 - 3.50 (m, 2H), 3.27 - 3.14 (m, 1H), 3.04 (t, J= 11.9 Hz, 1H), 2.91 (s, 2H), 2.44 (s, 1H), 2.17 - 1.99 (m, 1H), 1.31 (s, 6H)。 |
56 | 474 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.85 (s, 1H), 7.83 - 7.76 (m, 2H), 7.33 (dd, J= 8.4, 2.2 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 4.33 (s, 1H), 3.88 (s, 2H), 3.51 (d, J= 11.9 Hz, 1H), 3.21 (t, J= 10.9 Hz, 1H), 2.93 (s, 2H), 2.17 - 2.09 (m, 2H), 2.03 - 1.92 (m, 1H), 1.63 (d, J= 13.6 Hz, 1H), 1.32 (s, 7H), 1.09 - 0.95 (m, 2H), 0.89 (ddd, J= 25.2, 9.7, 5.8 Hz, 2H)。 |
57 | 450 | 1H NMR (400 MHz, 甲醇- D 4) δ 8.78 (s, 1H), 7.82 - 7.69 (m, 2H), 7.32 (dd, J= 8.4, 2.3 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 4.86 (s, 1H), 4.53 (dd, J= 4.4, 2.2 Hz, 1H), 4.37 (d, J= 7.0 Hz, 1H), 3.88 (s, 2H), 3.76 (dd, J= 12.5, 6.9 Hz, 1H), 3.59 - 3.49 (m, 2H), 2.91 (s, 2H), 1.32 (s, 7H)。 |
58 | 468 | 1H NMR (400 MHz, DMSO- D 6) δ 8.93 (s, 1H), 8.44 (d, J= 9.6 Hz, 1H), 8.05 (s, 1H), 7.96 (s, 1H), 7.82-7.80 (m, 1H), 7.62 (s, 2H), 7.54-7.52 (m, 1H), 7.46-7.42 (m, 1H), 4.44 (m, 1H) 3.88 (s, 2H), 3.22-3.04 (m, 4H), 2.74-2.65 (m, 2H), 2.08 (m, 3H), 1.27 (m, 6H)。 |
59 | 468 | 1H NMR (400 MHz, DMSO- D 6) δ 8.91 (s, 1H), 8.67 (d, J= 8.8 Hz, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 7.87 (d, J= 8.0 Hz, 1H), 7.62 (bs, 2H), 7.52 - 7.50 (m, 1H), 7.47 - 7.43 (m, 1H), 4.20 - 4.16 (m, 1H), 3.89 (s, 2H), 3.03 - 2.93 (m, 4H), 2.82 - 2.70 (m, 2H), 2.68 - 2.65 (m, 1H), 2.35 - 2.32 (m, 1H), 2.28 - 2.24 (m, 1H), 1.29 (s, 6H)。 |
60 | 434 | 1H NMR (400 MHz, DMSO- D 6) δ 8.89 (s, 1H), 8.53 (d, J= 8 Hz, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 7.88 (d, J= 8 Hz, 1H), 7.75-7.60 (m, 2H), 7.52 (d, J= 8 Hz, 1H), 7.45 (t, J= 8 Hz, 1H), 4.15-4.10 (m, 2H), 3.89 (s, 2H), 3.20-3.10 (m, 1H), 3.09-3.05 (m, 1H), 3.03 (s, 2H), 2.72-2.70 (m, 2H), 2.64-2.60 (m, 2H), 1.30 (s, 6H)。 |
61 | 448 | 1H NMR (400 MHz, DMSO- D 6) δ 8.90 (s, 1H), 8.75 - 8.72 (m, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.83 (d, J= 7.6 Hz, 1H), 7.63 (bs, 2H), 7.51 - 7.44 (m, 2H), 4.20 - 4.15 (m, 1H), 3.99 - 3.88 (m, 3H), 3.75 - 3.66 (m, 3H), 3.06 - 3.00 (m, 3H), 2.95 - 2.82 (m, 4H), 1.29 (s, 6H)。 |
62 | 436 | 1H NMR (400 MHz, DMSO- D 6) δ 8.89 (s, 1H), 8.78 (d, J= 4 Hz, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.89 (d, J= 8 Hz, 1H), 7.60 (bs, 2H), 7.49 (d, J= 8 Hz, 1H), 7.43 (t, J= 8 Hz, 1H), 5.24 (s, 1H), 5.11 (s, 1H), 4.43-4.35 (m, 1H), 3.87 (s, 2H), 3.18-3.00 (m, 4H), 2.81-2.77 (m, 2H), 1.26-2.21 (m, 6H)。 |
63 | 460 | 1H NMR (400 MHz, DMSO- D 6) δ 9.28 (s, 2H), 8.84 - 8.78 (m, 2H), 8.70 (d, J= 11.5 Hz, 1H), 8.21 (d, J= 5.3 Hz, 1H), 8.13 (s, 1H), 4.31 (s, 1H), 3.90 (s, 2H), 3.32 (s, 1H), 3.15 (t, J= 10.9 Hz, 1H), 3.03 (s, 2H), 2.11 (dd, J= 14.8, 7.9 Hz, 1H), 1.96 - 1.88 (m, 2H), 1.44 - 1.33 (m, 1H), 1.27 (s, 6H), 0.96 (ddd, J= 31.4, 10.4, 5.0 Hz, 2H), 0.86 - 0.70 (m, 2H)。 |
64 | 452 | 1H NMR (400 MHz, DMSO- D 6) δ 9.35 (s, 1H), 9.26 (s, 1H), 9.09 (s, 1H), 8.87 (d, J= 8.8 Hz, 1H), 8.77 (d, J= 5.3 Hz, 1H), 8.18 (d, J= 5.3 Hz, 1H), 8.12 (s, 1H), 5.22 (d, J= 45.1 Hz, 1H), 4.48 (dd, J= 8.3, 4.1 Hz, 2H), 3.90 (s, 2H), 3.54 (t, J= 12.7 Hz, 1H), 3.35 - 3.06 (m, 3H), 3.03 (s, 2H), 2.18 (dd, J= 25.6, 12.8 Hz, 1H), 1.26 (s, 6H)。 |
65 | 458 | 1H NMR (400 MHz, DMSO- D 6) δ 9.30 (t, J= 10.8 Hz, 1H), 8.91 (s, 1H), 8.76 (t, J= 11.9 Hz, 2H), 8.11 (t, J= 1.8 Hz, 1H), 7.99 (s, 1H), 7.92 (dt, J= 7.5, 1.6 Hz, 1H), 7.63 (s, 1H), 7.49 - 7.40 (m, 2H), 4.29 (s, 1H), 3.86 (s, 2H), 3.38 - 3.30 (m, 1H), 3.13 (q, J= 10.8 Hz, 1H), 2.99 (q, J= 15.7 Hz, 2H), 2.11 (dt, J= 14.8, 7.8 Hz, 1H), 1.93 (dd, J= 7.9, 3.9 Hz, 2H), 1.39 (d, J= 13.9 Hz, 1H), 1.24 (d, J= 2.3 Hz, 6H), 1.03 - 0.94 (m, 1H), 0.90 (dt, J= 10.0, 5.1 Hz, 1H), 0.85 - 0.77 (m, 1H), 0.75 - 0.64 (m, 1H)。 |
66 | 476 | 1H NMR (400 MHz, 甲醇- D 4) δ 9.29 (d, J= 2.4 Hz, 1H), 9.22 (d, J= 7.7 Hz, 1H), 8.65 (dd, J= 7.4, 2.4 Hz, 1H), 8.55 (s, 1H), 8.16 (ddd, J= 8.6, 4.6, 2.4 Hz, 1H), 7.88 (dd, J= 11.1, 8.5 Hz, 1H), 5.10 - 4.94 (m, 1H), 4.58 (s, 2H), 4.19 (ddd, J= 12.0, 4.2, 1.4 Hz, 1H), 3.88 (dd, J= 12.0, 10.1 Hz, 1H), 3.64 (d, J= 1.6 Hz, 2H), 2.91 - 2.75 (m, 2H), 2.71 - 2.58 (m, 1H), 2.28 (dt, J= 15.0, 4.4 Hz, 1H), 2.00 (d, J=1.9 Hz, 7H), 1.76 - 1.48 (m, 4H)。 |
實例編號 | 所用起始物質 |
43 | 步驟1:2,4-二溴-1-氟苯 |
44 | 步驟1:2,4-二溴-1-氟苯 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
45 | 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
46 | 步驟1:2,4-二溴-1-氟苯 步驟4:中間物A |
47 | 步驟1:2,4-二溴-1-氟苯 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
48 | 步驟1:4-溴-2-氯吡啶 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
49 | 步驟1:4-溴-2-氯吡啶 |
50 | 步驟1:4-溴-2-氯吡啶 步驟4:中間物A |
51 | 步驟4:中間物A |
52 | 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
53 | 步驟1:4-溴-2-氯吡啶 步驟4:反-3-胺基-4-羥基-哌啶-1-甲酸三級丁酯 |
54 | 步驟1:4-溴-2-氯吡啶 步驟4:(3R,4R)-3-胺基-4-羥基吡咯啶-1-甲酸三級丁酯 |
55 | 步驟1:2-溴-4-氯苯酚 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
56 | 步驟1:2-溴-4-氯苯酚 步驟4:中間物A |
57 | 步驟1:2-溴-4-氯苯酚 步驟4:(3R,4R)-3-胺基-4-羥基吡咯啶-1-甲酸三級丁酯 |
58 | 步驟4:3-胺基-4,4-二氟哌啶-1-甲酸三級丁酯 |
59 | 步驟4:(S)-5-胺基-3,3-二氟哌啶-1-甲酸三級丁酯 |
60 | 步驟4:(3R,4R)-3-胺基-4-羥基吡咯啶-1-甲酸三級丁酯 |
61 | 步驟4:6-胺基-1,4-氧氮雜環庚烷-4-甲酸三級丁酯 |
62 | 步驟4:(3S,4S)-3-胺基-4-氟吡咯啶-1-甲酸三級丁酯 |
63 | 步驟1:2,4-二溴嘧啶 步驟4:中間物A |
64 | 步驟1:2,4-二溴嘧啶 步驟4:(3S,5S)-3-胺基-5-氟哌啶-1-甲酸三級丁酯 |
65 | 步驟4:6-胺基-4-氮雜螺[2.5]辛烷-甲酸三級丁酯 |
66 | 步驟1:2,4-二溴-1-氟苯 步驟4:6-胺基-4-氮雜螺[2.5]辛烷-甲酸三級丁酯 |
將實例1至實例66之化合物以各種濃度稀釋且轉移5 μl至384孔盤,且將10 μl Chk1激酶(Thermo,P3040)或Chk2激酶(Thermo,PV3367)及受質(Thermo,PV3508)之混合溶液(2×)添加至用化合物處理之孔中。將5 μl 4×濃度之ATP溶液添加至測試孔中且在室溫下反應1小時。將20 μl LanthaScreen Terbium-CREB p-Ser 133抗體(Thermo,PV3542)添加至反應孔中且在室溫下培育30分鐘。藉由EnVision 2014多標記讀取器(PerkinElmer)量測轉化資料。各濃度之活性由各波長之發光波長值中520 nm處之值除以490 nm處之值(Em520/Em490)所獲得之值的比率(FRET比率=FR)確定。化合物之各濃度所獲得之結果為在二個孔中獲得之平均值,且使用PRIZM軟體計算化合物之IC
50值以用於分析結果。所量測之IC
50值展示於下表7中。表7中之IC
50分級如下。
A級:IC
50≤ 10 nM,B級:100 nM ≥ IC
50> 10 nM,C級:1000 nM ≥ IC
50> 100 nM,D級:IC
50> 1000 nM
由表7之結果可確認,本發明化合物對Chk1及/或chk2具有極佳抑制活性,且特定言之選擇性地抑制chk2。
[表7]
實驗實例2 : 癌細胞生長抑制測試
實例編號 | 激酶抑制活性(IC 50) | 實例編號 | 激酶抑制活性(IC 50) | ||
Chk1 | Chk2 | Chk1 | Chk2 | ||
1 | B | 34 | B | A | |
2 | C | B | 35 | D | B |
3 | A | 36 | D | D | |
4 | D | B | 37 | D | B |
5 | A | 38 | D | D | |
6 | A | 39 | C | A | |
7 | A | 40 | B | A | |
8 | B | 41 | B | A | |
9 | B | 42 | B | A | |
10 | B | 43 | C | A | |
11 | B | 44 | A | B | |
12 | D | 45 | C | A | |
13 | C | 46 | D | B | |
14 | C | B | 47 | B | |
15 | C | A | 48 | A | |
16 | B | A | 49 | A | |
17 | B | A | 50 | A | |
18 | D | B | 51 | A | |
19 | C | B | 52 | B | |
20 | B | B | 53 | B | |
21 | B | A | 54 | A | |
22 | D | 55 | A | ||
23 | A | 56 | A | ||
24 | A | 57 | B | ||
25 | D | B | 58 | A | |
26 | C | B | 59 | D | B |
27 | B | B | 60 | A | |
28 | D | A | 61 | A | |
29 | B | A | 62 | B | |
30 | B | A | 63 | A | |
31 | C | B | 64 | D | A |
32 | D | D | 65 | B | B |
33 | D | C | 66 | D | B |
用胰蛋白酶處理且收穫人類乳癌細胞株MCF-7。對細胞數目進行計數,且將約3000個細胞/80 μl/孔接種至96孔盤(Corning)中,且接著在37℃恆溫箱中培育24小時。此後,實例化合物在培養溶液中以各種濃度稀釋,且各孔用20 μl處理且在細胞培養恆溫箱中儲存72小時。在組合投予組之情況下,將實例化合物及順鉑或小紅莓在培養溶液中以各種濃度稀釋,且用20 μl處理各孔。72小時後,各孔用30 μl CellTiter-Glo溶液(Promega)處理,且在Victor3多標記讀取器(PerkinElmer)上讀取發光。
相對存活率(%) = (各測試孔的值/僅用DMSO處理之孔的值) × 100
各實例化合物之各濃度所獲得之結果為獲自三個孔之平均值,且PRIZM軟體用於分析結果。
基於細胞之分析中量測實例化合物之細胞增殖抑制活性之結果展示於表8中。表8中之IC
50分級如下。
A級:IC
50≤ 10 μM,B級:100 μM ≥ IC
50> 10 μM,C級:IC
50> 100 μM
由表8之結果可確認,本發明化合物展現極佳細胞增殖抑制活性。
[表8]
實例編號 | Celltiter glo分析(IC 50) | 實例編號 | Celltiter glo分析(IC 50) |
1 | B | 34 | B |
2 | B | 35 | B |
3 | B | 36 | B |
4 | B | 37 | C |
5 | C | 38 | B |
6 | B | 39 | B |
7 | B | 40 | C |
8 | B | 41 | C |
9 | B | 42 | B |
10 | B | 43 | B |
11 | B | 44 | A |
12 | A | 45 | B |
13 | A | 46 | B |
14 | C | 47 | B |
15 | A | 48 | B |
16 | B | 49 | B |
17 | B | 50 | B |
18 | B | 51 | B |
19 | B | 52 | B |
20 | B | 53 | C |
21 | B | 54 | C |
22 | B | 55 | B |
23 | B | 56 | B |
24 | B | 57 | C |
25 | C | 58 | B |
26 | C | 59 | A |
27 | C | 60 | C |
28 | C | 61 | C |
29 | B | 62 | B |
30 | C | 63 | B |
31 | B | 64 | B |
32 | B | 65 | C |
33 | B | 66 | A |
另一方面,與順鉑或小紅莓組合投予時之細胞增殖抑制活性的量測結果展示於表9中。如表9中所示,當與順鉑或小紅莓組合投予時,本發明化合物展現協同細胞增殖抑制活性。
[表9]
實驗實例 3 :使用小鼠之藥物動力學測試
化合物 | 單獨投予 (IC 50,μM) | 與順鉑組合投予(IC 50,μM) | 與小紅莓組合投予(IC 50,μM) |
順鉑 | 26 | ||
小紅莓 | 1.5 | ||
實例4 | 48.1 | 3.44 | 0.67 |
實例13 | 8.59 | 2.93 | 0.91 |
實例15 | 11.8 | 2.27 | 3.05 |
實例32 | 33.1 | 4.58 | 0.91 |
使體重22-29 g之6至8週齡雄性Balb/C小鼠適應環境約1週,且接著將各組之12隻小鼠分成靜脈內投予組及經口投予組且用於實驗中。在投予化合物之前使小鼠禁食且允許隨意飲水。在投予化合物後2小時提供飼料。
藉由將1.264 mg實例9之化合物溶解於6.257 mL DMSO : solutol及乙醇之混合溶液(1:1) :生理鹽水(5:5:90% v/v)中來製備靜脈內注射製劑(0.2 mg/mL)。藉由將5.916 mg實例9之化合物懸浮於5.857 mL含有0.1 Tween 80之0.5%甲基纖維素(0.5:99.5% v/v)中來製備經口投予製劑(1 mg/mL)。
對於靜脈內投予,實例9之化合物以1 mg/kg之劑量投予,且對於經口投予,使用經口管飼針(oral zonde)以10 mg/kg之劑量投予。
在靜脈內投予之情況下,在投予化合物之後5分鐘、15分鐘、30分鐘、1小時、2小時、4小時、8小時及24小時收集血液。在經口投予之情況下,在投予化合物之後15分鐘、30分鐘、1小時、2小時、4小時、8小時、10小時及24小時收集血液。自收集之血液中分離血漿,且藉由LC-MS/MS法量測血液中化合物之含量,且使用Phoenix軟體8.1版計算PK參數。
化合物之平均血液濃度隨時間的變化量示於圖1中,且計算之PK參數示於下表10中。
[表10]
在以上描述中,出於解釋之目的,已闡述眾多具體細節以便提供對實施例之透徹理解。然而,一般熟習此項技術者將顯而易見,可在無此等具體細節中之一些的情況下實踐一或多個其他實施例。亦應理解,在本說明書通篇中,對「一個實施例」、「一實施例」、具有序數名稱之實施例或其類似者之引用意謂可在本發明之實踐中包括特定特徵、結構或特性。應進一步理解,在本發明中,出於簡化描述且促進對各個發明態樣之理解的目的,有時在單個實施例、圖式或其描述中將各種特徵分組在一起,且在適當時在本發明之實踐中,可實踐來自一個實施例之一或多個特徵或具體細節以及來自其他實施例之一或多個特徵或具體細節。
儘管已關於視為例示性實施例之內容描述本發明,但本發明不限於所描述之實施例,而是意欲涵蓋可包括於如申請專利範圍中所闡述之本發明範疇內的所有修改、替代方案及等效物。
(無)
圖1為展示在小鼠中靜脈內投予(IV)或經口投予(PO)時實例9之化合物隨時間(h)之平均血液濃度(ng/mL)的圖式。
Claims (22)
- 一種以下式A化合物或其一鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽: [式A] 其中, 環A為一C 6-C 10芳基或含有1至3個氮原子之一5至10員雜芳基; 環B為一C 3-C 10單環或雙環環烷基或一單環或雙環3至10員雜環烷基,其中該雜環烷基含有1至3個選自N、O及S之雜原子; R 1及R 2各自獨立地為鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基、C 1-C 8烷氧基、任擇地經一或多個R'取代之一直鏈或分支鏈C 1-C 8烷基或任擇地經一或多個R'取代之一C 3-C 8環烷基,或 當R 1及R 2連接至相鄰環元素時,其可與其所連接之碳原子及氮原子一起形成一吡咯啶環,其中該吡咯啶環任擇地經一或多個R'取代; R'為一或多個獨立地選自由以下組成之群的取代基:鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基及C 1-C 8烷氧基; R 3選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基、C 3-C 8環烷基及C 1-C 8烷氧基; R 4選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基、C 1-C 8烷氧基、-CO-(C 1-C 8烷基)、-CO-(C 2-C 8烯基)、-COOH及-COO-C 1-C 8烷基,其中該C 1-C 8烷基、C 1-C 8烷氧基及C 2-C 8烯基可任擇地經一或多個鹵素、-OH或-CN取代; R 5為H或一直鏈或分支鏈C 1-C 8烷基; n為0至2之一整數,且其中當n為2時,R 3可各自鍵結至相同或不同環原子;且 m為0至3之一整數,且其中當m為2或更大時,R 4可各自鍵結至相同或不同環原子。
- 如請求項1之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中環A為苯基、吡啶基或嘧啶基。
- 如請求項1之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中環B為一單環或螺環3至10員雜環烷基。
- 如請求項3之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中除一個N以外,該單環或螺環3至10員雜環烷基亦任擇地含有1或2個選自N、O及S之雜原子。
- 如請求項1之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中該式A化合物為以下之一式I化合物: [式I] 其中, X、Y及Z各自獨立地為C或N; R 1為任擇地經一或多個R'取代之一直鏈或分支鏈C 1-C 8烷基或任擇地經一或多個R'取代之一C 3-C 8環烷基;且 R 2為H或一直鏈或分支鏈C 1-C 8烷基;或 R 1及R 2可與其各自所連接之氮原子及碳原子一起形成一吡咯啶環,其中該吡咯啶環任擇地經一或多個R'取代; R'為一或多個獨立地選自由以下組成之群的取代基:鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基及C 1-C 8烷氧基; R 3選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基、C 3-C 8環烷基及C 1-C 8烷氧基; R 4選自由以下組成之群:鹵素、-OH、-CN、胺基、硝基、側氧基、C 1-C 8烷基、C 1-C 8烷氧基、-CO-C 1-C 8烷基、-CO-C 2-C 8烯基、-COOH及-COO-C 1-C 8烷基,其中該C 1-C 8烷基、C 1-C 8烷氧基及C 2-C 8烯基可任擇地經一或多個鹵素、-OH或-CN取代; n為0至2之一整數,且其中當n為2時,二個R 3可各自鍵結至相同或不同環原子; m為0至2之一整數,且其中當m為2時,二個R 4可各自鍵結至相同或不同環原子; p為1至5之一整數;且 W為C,且其中當p為2或更大時,W中之一者可任擇地經選自N、O或S之一雜原子置換,或W中之一者可與一額外碳原子一起形成一C 3-C 5環烷基環。
- 如請求項5之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 X及Z為N,且Y為C; Y及Z為N,且X為C; X為N,且Y及Z為C; Y為N,且X及Z為C;或 X、Y及Z均為C。
- 如請求項5之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 R 1為任擇地經一或多個鹵素、-OH或-CN取代之一直鏈或分支鏈C 1-C 5烷基,或任擇地經一或多個鹵素、-OH或-CN取代之一C 3-C 5環烷基;且 R 2為H。
- 如請求項7之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 R 1為-CH 2-CF 3、-CH 2-CN、-CH 3、-CH 2-C(CH 3) 2OH或環丙基;且 R 2為H。
- 如請求項5之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 R 1及R 2與其各自所連接之氮原子及碳原子一起形成一吡咯啶環,其中該吡咯啶環任擇地經一或多個C 1-C 5烷基取代,或 具有 之一結構。
- 如請求項5之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 R 3選自由以下組成之群:鹵素、-OH、-CN、C 1-C 5烷基及C 1-C 5烷氧基;且 R 4選自由以下組成之群:鹵素、-OH、-CN、C 1-C 5烷基及C 1-C 5烷氧基。
- 如請求項5之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 p為2至4之一整數;且 W全部為C,或W中之一者經O置換,或W中之一者與一額外碳原子一起形成一環丙基環。
- 如請求項11之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中 具有選自以下之一結構: 、 、 及 。
- 如請求項1之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽,其中該化合物為選自以下化合物之任一者: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 及 。
- 一種用於預防或治療由檢查點激酶2活化介導之一疾病的醫藥組成物,其包含如請求項1至13中任一項之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽作為一活性成分。
- 如請求項14之醫藥組成物,其中該由檢查點激酶2活化介導之疾病為癌症。
- 如請求項15之醫藥組成物,其中該癌症選自由以下組成之群:卵巢癌、子宮頸癌、子宮內膜癌、子宮肉瘤、外陰癌、乳癌、皮膚癌、頭頸癌、胰臟癌、肺癌、大腸癌、大腸直腸癌、胃癌、前列腺癌、膀胱癌、尿道癌、肝癌、腎癌、皮膚癌、腦脊髓腫瘤、腦癌、胸腺瘤、間皮瘤、支氣管癌、鼻咽癌、喉癌、食道癌、膽道癌、睾丸癌、生殖細胞腫瘤、甲狀腺癌、副甲狀腺癌、淋巴瘤、骨髓發育不良症候群(MDS)、骨髓纖維化、急性骨髓白血病(AML)、急性淋巴球性白血病(ALL)、慢性骨髓白血病(CML)、慢性淋巴球性白血病(CLL)、多發性骨髓瘤、內分泌癌、肉瘤、毛細血管擴張性失調、兒童神經母細胞瘤及李-弗美尼症候群(Li-Fraumeni syndrome)。
- 如請求項15之醫藥組成物,其中該醫藥組成物與至少一種具有抗癌活性之藥劑同時或依序投予。
- 如請求項17之醫藥組成物,其中該具有抗癌活性之藥劑為選自以下之一DNA損傷劑:輻射、順鉑、奧沙利鉑、卡鉑、阿德力黴素(adriamycin)或小紅莓(doxorubicin)、道諾黴素(daunorubicin)、伊立替康(irinotecan)、吉西他濱(gemcitabine)、替莫唑胺(temozolomide)、卡培他濱(capecitabine)、拓朴替康(topotecan)、喜樹鹼、阿糖胞苷、5-氟尿嘧啶、環磷醯胺、依託泊苷(etoposide)或磷酸依託泊苷、替尼泊苷(teniposide)、道諾黴素及培美曲唑(pemetrexed)。
- 如請求項17之醫藥組成物,其中該具有抗癌活性之藥劑為一PARP抑制劑,或靶向選自由以下組成之群的一蛋白質之一藥劑:EGFR、VEGFR、CD20、CD38、RNAK-L、BTK、Bcr-abl、PDGFR/FGFR、MEK/RAF/KRAS、HER2/Neu、泛素、JAK、ALK、TGFβRI、蛋白酶體、Bcl-2、C-Met、VR1、VR2、VR3、c-kit、AXL、RET、Braf、DNMT、CDK4/6及STING;一免疫檢查點抑制劑;一細胞治療劑;一抗體治療劑;或一抗癌病毒治療劑。
- 一種用於預防或治療癌症之方法,其包含向一個體投予如請求項1至13中任一項之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽。
- 一種抑制檢查點激酶2活化之方法,其包含向一個體投予如請求項1至13中任一項之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽。
- 一種如請求項1至13中任一項之化合物或其鏡像異構物、水合物、溶劑合物或醫藥學上可接受之鹽之用途,其用於製造供預防或治療癌症用之一藥劑。
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