TWI515194B - Jak2抑制劑及其用於治療骨髓增生性疾病及癌症之用途 - Google Patents
Jak2抑制劑及其用於治療骨髓增生性疾病及癌症之用途 Download PDFInfo
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- TWI515194B TWI515194B TW103111993A TW103111993A TWI515194B TW I515194 B TWI515194 B TW I515194B TW 103111993 A TW103111993 A TW 103111993A TW 103111993 A TW103111993 A TW 103111993A TW I515194 B TWI515194 B TW I515194B
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- methyl
- ethyl
- pyrrolo
- dihydroimidazo
- pyridine
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Classifications
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Landscapes
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本發明係關於可用作抗癌/抗增生劑之新穎化合物。本發明亦係關於使用該等化合物治療諸如癌症等增生性疾病之方法以及含有該等化合物之醫藥組合物。
本申請案主張2009年9月3日申請之美國臨時申請案第61/239,501號之權利,該申請案之全文以引用方式併入本文中。
MPD患者中JAK-Stat信號傳導路徑之組成性激活的觀察結果鼓勵人們努力識別Ph(-)骨髓增生性疾病之新穎治療途徑。具體而言,已在大多數PV(95%)、ET(50-60%)及PMF(50-60%)患者中觀察到JAK2中殘基617處之單一纈胺酸至苯丙胺酸突變(JAK2-V617F)(表2,Kralovics等人,2005;Baxter等人,2005;Tefferi等人,2005)。該V617F突變位於編碼假激酶結構域之JAK2基因區域中,據認為該假激酶結構域用作自抑制結構域而調控JAK2酪胺酸激酶活性。亦以較低頻率(在PV及ET中小於5%)觀察到亦導致組成性JAK2激酶活性之JAK2外顯子12之突變,且其與JAK2V617F損害相互排斥(Pardanari等人,2007;Scott等人,2007)。JAK2係非受體酪胺酸激酶家族之成員,該家族亦包括JAK1、Tyk2及JAK3,且JAK2用作細胞因子受體信號傳導之介體(綜述請參見Murray,2007)。在細胞因子結合至其關聯受體後,受體結合之JAK家族成員被激活且磷酸化STAT,STAT係潛在的轉錄因子,其在JAK調介之磷酸化後經歷二聚並易位至細胞核中以調控基因表現。遺傳及生物化學研究已確定JAK家族成員與單個細胞因子受體之接合(engagement)的不同組合。例如,促紅細胞生成素
(EPO)、促血小板生成素(TPO)及粒細胞集落刺激因子(GM-CSF)受體接合導致JAK2之主要激活以調介下游信號傳導。與由JAK2-V617F突變引起之MPD病理生理異常一致,該等細胞因子促進分別作為PV、ET及PMF基礎之細胞類型之分化及擴增。與其他遺傳激活事件不同,JAK2-V617F之表現不足以在基於細胞之模型系統中促進轉化,且已顯示需要I型細胞因子受體之共表現,此突出了JAK-細胞因子受體相互作用之重要功能性相互依賴(Lu等人,2005)。令人感興趣的是,已在患有JAK2-V617F陰性PMF及ET之MPD患者(分別為5%及1%)中識別到TPO受體之激活突變(MPL,殘基515處色胺酸被白胺酸取代),導致組成性JAK2-Stat激活(Pikman等人,2006)。該等觀察結果表明,JAK-Stat信號轉導可通過在MPD中在路徑中之多個點處以相互排斥之方式突變而激活,且表明在JAK2-V617F及MPL-W515L陰性MPD中可能存在其他路徑突變。
JAK2信號傳導作為Ph(-)MPD驅動者之重要驗證自齧齒類動物模型出現,其中JAK2-V617F突變體信號傳導在造血幹細胞小室中重構。數個實驗室已證實,將JAK2-V617F病毒轉導(viral transduction)至小鼠骨髓中且隨後再移植至受體小鼠中可重構人類MPD之數個方面(Wernig等人,2006;Lacout等人,2006;Bumm等人,2006;Zaeleskas等人,2006)。該等特徵包括血細胞比容升高、由髓外血細胞生成造成之脾腫大、粒細胞增多及骨髓纖維化,所有該等特徵亦皆在真性紅細胞增多症中出現。令人感興趣的是,與人類病狀不同,在該等鼠科動物模型中未觀察到血小板增多,且表明血小板增多可歸因於促使血小板擴增之二級遺傳事件(Wernig等人,2006)。齧齒類動物骨髓中TPO受體突變(MPL-W515L)之類似重構所導致之骨髓增生性疾病之發作比JAK2-V617F動物更為快速,此與包括脾腫大、肝腫大及骨髓網狀纖維化之原發性骨髓纖維化類似(Pikman等人,2006)。亦與
JAK2-V617F模型不同的是,表現MPL-W515L之小鼠呈現明顯血小板增多,此或許表明在該譜系擴增中與JAK2-V617相比受體激活之功能更突出。雖然如此,該等觀察結果共同強調MPL-W515L及JAK2-V617F二者作為構成人類MPD進展之基礎之驅動突變的作用。
MPD遺傳基礎之一個重要問題係除JAK2及MPL外促使疾病進展之其他遺傳事件之作用。數個證據表明在MPD疾病進展中存在其他遺傳改變。事實上,在MPD患者中經常發生有絲分裂重組以產生兩種JAK2-V617F等位基因,此表明選擇突變激酶純合之細胞純系(Levine等人,2005)。就此而言,研發條件JAK2-V617F基因敲入動物並測定純合對雜合JAK2-V617F負荷(burden)之表型結果甚為重要。另外,有證據表明,在一些MPD患者中遺傳種系等位基因傾向於且易於使患者獲得JAK2-V617F(Goerttler等人,2005;Levine等人,2006)以及缺失染色體區域20q。儘管在臨床上以中等程度觀察到MPD轉化之AML,且在白血病中觀察到激活JAK染色體易位,但流行病學數據表明JAK2-V617F在該背景下係遺傳驅動者係可疑的,此表明完全白血病轉化需要其他遺傳改變(Theocharides等人,2007)。儘管存在該等觀察結果,但是使用小分子抑制劑抑制JAK2足以在臨床前動物模型中調節疾病進展,此表明JAK2激活足以保持MPD(Paradani等人,2007)。識別該等其他遺傳改變並破譯該等遺傳改變在JAK2-V617F及MPL-W515L背景下如何促使PV、ET及PMF疾病進展甚為重要。實施途徑以確定其他JAK2路徑組成部分(component)在與獲得JAK2-V617F、JAK2外顯子12或MPL-W515L突變無關之MPD患者中是否突變亦甚為重要。
專利公開案WO2006/122137揭示可用作IKK抑制劑之化合物。實例第A171號揭示具有下式之化合物:
已發現其在下文所述分析中具有較弱之抗JAK2活性。
本發明提供式I化合物、使用該等化合物之醫藥組合物以及使用該等化合物之方法。
根據本發明,揭示式I化合物
或其立體異構體、互變異構體或醫藥上可接受之鹽,其中:Y係C1-4烷基;X係C1-4烷基;R係
其中之任一者視情況與具有一個選自NR3或S之雜原子之5員或6員碳環或雜環稠合,該稠合碳環或雜環視情況經0-3個R1取代。
R1係H、鹵基、CN、經0-3個Rc取代之C1-6烷基、CF3、
CONRaRa、NRaRa、COORb、SO2-C1-4烷基、C(O)Rd、經0-3個Re取代之環烷基、呋喃基、四氫吡喃基或吡啶基;R2不存在,係H、經0-3個Rc取代之C1-6烷基、C(O)O-C1-4烷基、SO2-C1-4烷基、經0-3個Re取代之環烷基、或四氫吡喃基;R3不存在,係H或C(O)O-C1-4烷基;Ra係H、經0-3個Re取代之C1-6烷基、經0-3個Re取代之C3-6環烷基、四氫吡喃基或二側氧基四氫苯硫基;Rb係H或C1-6烷基;Rc係H、鹵基、CN、OH、O-C1-4烷基、O-C1-4烷基-O-C1-4烷基、NH2、N(C1-4烷基)2、C(O)N(C1-4烷基)2、SO2-C1-4烷基、或嗎啉基或六氫吡嗪基,其中之任一者視情況經0-1個C1-4烷基取代;Rd係C1-6烷基、或氮丙啶基、氮雜環丁基、吡咯啶基、六氫吡啶基、嗎啉基、六氫吡嗪基、二氧離子基硫嗎啉基或四氫吡喃基,其中之任一者經0-2個Re取代;且Re係H、鹵基、CN、C1-4烷基、OH、O-C1-4烷基、SO2-C1-4烷基、NHC(O)-C1-4烷基、嗎啉基、OC(O)-C1-4烷基、C(O)N(C1-4烷基)2或O-C1-4烷基-O-C1-4烷基。
在另一實施例中係式(I)化合物,其中:R係
其中之任一者視情況經0-3個R1取代。
在另一實施例中係式(I)化合物,其中:Y係甲基;且X係乙基。
在另一實施例中係式(I)化合物,其中:R係
在另一實施例中係式(I)化合物,其中:R係
其中之任一者視情況經0-2個R1取代。
在另一實施例中係式(I)化合物,其中
R係R1係H、鹵基、CN、經0-3個Rc取代之C1-6烷基、CF3、CONRaRa、COORb、SO2-C1-4烷基、C(O)Rd、經0-3個Re取代之環烷基、或吡啶基;Ra係H、經0-3個Re取代之C1-6烷基、經0-3個Re取代之C3-6環烷基、四氫吡喃基或二側氧基四氫苯硫基;Rb係H或C1-6烷基;Rc係H、鹵基、OH、O-C1-4烷基、SO2-C1-4烷基或嗎啉基;Rd係C1-6烷基、或氮雜環丁基、吡咯啶基、嗎啉基、六氫吡嗪基或二氧離子基硫嗎啉基,其中之任一者經0-2個Re取代;Re係H、鹵基、CN、OH、O-C1-4烷基、SO2-C1-4烷基、NHC(O)-C1-4烷基或嗎啉基。
在另一實施例中係式(I)化合物,其中:
R係R1係H、鹵基、經0-3個Rc取代之C1-6烷基、CF3、CONRaRa、COORb、C(O)Rd、經0-3個Re取代之環烷基、或呋喃基;R2係H、經0-3個Rc取代之C1-6烷基、SO2-C1-4烷基、經0-3個Re取代之環烷基、或四氫吡喃基;Ra係H或經0-3個Re取代之C1-6烷基;Rb係H或C1-6烷基;Rc係H、鹵基、CN、OH、O-C1-4烷基、O-C1-4烷基-O-C1-4烷基、NH2、N(C1-4烷基)2、C(O)N(C1-4烷基)2、SO2-C1-4烷基、或嗎啉基或六氫吡嗪基,其中之任一者視情況經0-1個C1-4烷基取代;Rd係C1-6烷基、或嗎啉基、六氫吡嗪基或二氧離子基硫嗎啉基,其中之任一者經0-2個Re取代;且Re係H、C1-4烷基、CN、OH、NHC(O)-C1-4烷基或嗎啉基。
在另一實施例中係式(I)化合物,其中:R係R1係經0-3個Rc取代之C1-6烷基;且R2係C1-6烷基。
在另一實施例中係式(I)化合物,其中該式(I)化合物選自例示性化合物。
在另一實施例中,本發明提供一種醫藥組合物,其包含醫藥上可接受之載劑及一或多種本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥。
在另一實施例中,本發明提供一種醫藥組合物,其包含式I化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑。
在另一實施例中,本發明提供一種醫藥組合物,其包含醫藥上可接受之載劑及治療有效量之一或多種本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥。
在另一實施例中,本發明提供用於治療增生性病症及/或癌症之方法,其包含向需要該治療之患者投予治療有效量之一或多種本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥、與一或多種其他抗癌劑、或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥。
在另一實施例中,本發明提供用於治療增生性病症及/或癌症之方法,其包含向需要該治療之患者投予治療有效量之一或多種本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥。
在另一實施例中,本發明提供治療需要增生性病症及/或癌症治療之患者的方法,其包含以有效治療該增生性病症及/或癌症的量投予本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥形式。
在另一實施例中,本發明提供治療骨髓增生性疾病(例如真性紅細胞增多症、特發性血小板減少及原發性骨髓纖維化)、胰腺癌、前列腺癌、肺癌、頭頸癌、乳癌、結腸癌、卵巢癌、胃癌實體腫瘤以及其他腫瘤類型之方法,該等其他腫瘤類型包括多發性骨髓瘤、黑色素瘤、神經母細胞瘤、膠質母細胞瘤、全身性肥大細胞增多症及血液惡性腫瘤,例如急性髓性白血病(包括難治性急性髓樣白血病)及急性淋巴性白血病。
在另一實施例中,本發明提供一種新穎方法,其包含以有效治
療增生性病症及/或癌症的量投予本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥形式。
在另一實施例中,本發明提供用於治療增生性病症及/或癌症之方法,其包含向需要該治療之患者投予治療有效量之式(I)化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥、與一或多種其他抗癌劑或抗增生劑及/或另一藥劑、或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥。
在另一實施例中,本發明提供用於治療增生性病症及/或癌症之方法,其包含向需要該治療之患者投予治療有效量之一或多種本發明化合物或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥、與一或多種其他抗癌劑、或其立體異構體、互變異構體、醫藥上可接受之鹽、溶劑合物或前藥。
在另一實施例中,本發明提供本發明化合物用於療法中。
在另一實施例中,本發明提供本發明化合物用於療法中以治療增生性病症及/或癌症。
在另一實施例中,本發明亦提供本發明式I化合物用以製造用於治療增生性病症及/或癌症之藥劑的用途。
本發明可以其他指定形式體現,此並不背離其精神或基本特徵。本發明涵蓋本文所提及之本發明較佳態樣及/或實施例之所有組合。應瞭解,本發明之任一及所有實施例可結合任一其他實施例來闡述其他更佳實施例。亦應瞭解,該等較佳實施例中之每一單個要素係其自身獨立之較佳實施例。而且,實施例之任一要素意欲與任一實施例之任一及所有其他要素組合以闡釋其他實施例。
圖1至4繪示本發明實施例之活體內分析數據。
以下係可用於本說明書中之術語的定義。除非另有說明,否則所提供本文基團或術語之初始定義適用於通篇本說明書中單獨或作為另一基團之一部分的該基團或術語。
本發明化合物可具有一或多個不對稱中心。除非另有說明,否則本發明化合物之所有對掌性(對映異構及非對映異構)及外消旋形式皆包括在本發明內。該等化合物中亦可存在烯烴、C=N雙鍵及諸如此類之多種幾何異構體,且所有該等穩定異構體皆涵蓋於本發明內。本發明化合物之順式及反式幾何異構體在本發明中有所闡述且可呈異構體混合物或分開的異構體形式分離。本發明化合物可呈光學活性或外消旋形式分離。業內已熟知如何製備光學活性形式,例如藉由拆分外消旋形式或藉由自光學活性起始材料合成來製備。除非明確指出具體立體化學或異構體形式,否則意欲涵蓋結構之所有對掌性(對映異構及非對映異構)及外消旋形式以及所有幾何異構體形式。
本文所用之術語「經取代」意指指定原子上之任一或多個氫經選自指定基團之基團替代,限制條件係不超過該指定原子之正常價數且該取代產生穩定的化合物。當取代基係酮基(即=O)時,則原子上之兩個氫被替代。酮基取代基不存在於芳香族部分上。本文所用之環雙鍵係形成於兩個相鄰環原子之間的雙鍵(例如,C=C、C=N或N=N)。
當任何變量(例如,R3)在化合物之任何組成或結構式中出現一次以上時,其每次出現時之定義均獨立於其在其他每種情況下出現時之定義。因此,例如,若顯示基團經0-2個R3取代,則該基團可視情況經至多兩個R3基團取代且R3在每次出現時獨立地選自R3之定義。同樣,取代基及/或變量之組合僅在該等組合產生穩定化合物時才容許存在。
當鍵結至取代基之鍵顯示為與連接環中兩個原子之鍵交叉時,
則該取代基可鍵結至該環之任一原子上。當列示取代基但未指明該取代基經由哪個原子鍵結至具有給定結構式之化合物的其餘部分上時,則該取代基可經由該取代基中之任一原子來鍵結。取代基及/或變量之組合僅在該等組合產生穩定化合物時才容許存在。
在本發明化合物上存在氮原子(例如,胺)之情形下,可藉由使用氧化劑(例如,MCPBA及/或過氧化氫)進行處理而將該等氮原子轉化成N-氧化物,以獲得本發明之其他化合物。因此,所有所顯示及主張之氮原子皆視為涵蓋所顯示氮及其N-氧化物(N→O)衍生物二者。
本文所用之術語「烷基」或「伸烷基」意欲包括具有指定碳原子數之具支鏈及直鏈飽和脂肪族烴基團。例如,「C1-10烷基」(或伸烷基)意欲包括C1、C2、C3、C4、C5、C6、C7、C8、C9及C10烷基。另外,例如,「C1-C6烷基」表示具有1至6個碳原子之烷基。烷基可未經取代或經取代,由此其一或多個氫被另一化學基團替代。烷基之實例包括(但不限於)甲基(Me)、乙基(Et)、丙基(例如,正丙基及異丙基)、丁基(例如,正丁基、異丁基、第三丁基)、戊基(例如,正戊基、異戊基、新戊基)及諸如此類。
「烯基」或「伸烯基」意欲包括具有直鏈或具支鏈構型且具有一或多個可存在於沿鏈之任一穩定點上之碳碳雙鍵的烴鏈。例如,「C2-6烯基」(或伸烯基)意欲包括C2、C3、C4、C5及C6烯基。烯基之實例包括(但不限於)乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基及諸如此類。
「炔基」或「伸炔基」意欲包括具有直鏈或具支鏈構型且具有一或多個可存在於沿鏈之任一穩定點上之碳碳三鍵的烴鏈。例如,「C2-6炔基」(或伸炔基)意欲包括C2、C3、C4、C5及C6炔基;例如乙炔基、丙炔基、丁炔基、戊炔基、己炔基及諸如此類。
「鹵基」或「鹵素」包括氟、氯、溴及碘。
術語「環烷基」係指環狀烷基,其包括單環狀、二環狀或多環狀環系統。C3-10環烷基意欲包括C3、C4、C5、C6及C7環烷基。環烷基之實例包括(但不限於)環丙基、環丁基、環戊基、環己基、降莰烷基及諸如此類。本文所用之「碳環」或「碳環殘基」意指任何穩定之3、4、5、6或7員單環狀或二環狀環或7、8、9、10、11、12或13員二環狀或三環狀環,其中之任一者可為飽和的、部分不飽和的、不飽和的或芳香族。該等碳環之實例包括(但不限於)環丙基、環丁基、環丁烯基、環戊基、環戊烯基、環己基、環庚烯基、環庚基、環庚烯基、金剛烷基、環辛基、環辛烯基、環辛二烯基、[3.3.0]二環辛烷、[4.3.0]二環壬烷、[4.4.0]二環癸烷、[2.2.2]二環辛烷、茀基、苯基、萘基、二氫茚基、金剛烷基、蒽基及四氫萘基(四氫萘)。如上文所示,橋接環亦包括於碳環定義內(例如,[2.2.2]二環辛烷)。除非另有說明,否則較佳之碳環係環丙基、環丁基、環戊基、環己基、苯基及二氫茚基。當使用術語「碳環」時,意欲包括「芳基」。當一或多個碳原子連接兩個非相鄰碳原子時,則產生橋接環。較佳之橋係一個或兩個碳原子。應注意,橋總是將單環狀環轉化成三環狀環。當環係橋接環時,所提及之環取代基亦可存在於橋上。
術語「芳基」係指在環部分中具有6至12個碳原子之單環狀或二環狀芳香族烴基團,例如苯基、萘基、聯苯基及二苯基,每一者均可經取代。
術語「經取代芳基」係指經例如1至4個取代基取代之芳基,該等取代基係例如烷基、經取代烷基、烯基、經取代烯基、炔基、經取代炔基、芳基、經取代芳基、芳基烷基、鹵基、三氟甲氧基、三氟甲基、羥基、烷氧基、烷醯基、烷醯基氧基、芳基氧基、芳基烷基氧基、胺基、烷基胺基、芳基胺基、芳基烷基胺基、二烷基胺基、烷醯
基胺基、巰基、烷硫基、脲基、硝基、氰基、羧基、羧基烷基、胺甲醯基、烷氧基羰基、烷基硫羰基(alkylthiono)、芳基硫羰基、芳基磺醯基胺、磺酸、烷基磺醯基、磺醯胺基、芳基氧基及諸如此類。該取代基可進一步經羥基、鹵基、烷基、烷氧基、烯基、炔基、芳基或芳基烷基取代。
術語「雜芳基」係指例如為4至7員單環狀、7至11員二環狀或10至15員三環狀環系統且具有含有至少一個雜原子及至少一個碳原子之環的視情況經取代之芳香族基團,例如,吡啶、四唑、吲唑。
本文所用之術語「雜環」、「雜環基」、「雜環系統」或「雜環基團」意指穩定的5、6或7員單環狀或二環狀環或7、8、9、10、11、12、13或14員二環狀雜環,其為飽和的、部分不飽和的或完全不飽和的,且其由碳原子及1、2、3或4個獨立地選自N、O及S之雜原子組成;且包括其中任一上文所定義雜環稠合至苯環之任何二環狀基團。氮及硫雜原子可視情況經氧化(即,N→O及S(O)p)。氮原子可經取代或未經取代(即,若定義,則為N或NR,其中R係H或另一取代基)。雜環可在任何雜原子或碳原子處與其側基附接,從而產生穩定結構。若所得化合物較穩定,則本文所述雜環可在碳或在氮原子上經取代。雜環中之氮可視情況經四級銨化。若雜環中之S及O原子總數超過1,則該等雜原子較佳彼此不相鄰。較佳地,雜環中之S及O原子總數不大於1。當使用術語「雜環」時,意欲包括雜芳基。
雜環實例包括(但不限於)吖啶基、氮基、苯并咪唑基、苯并呋喃基、苯并硫代呋喃基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并異噁唑基、苯并異噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、哢啉基、基、烯基、啉基、十氫喹啉基、2H,6H-1,5,2-二噻嗪基、二氫呋喃并[2,3-b]四氫呋喃、呋喃基、呋呫基、咪唑啶基、咪唑啉基、咪唑基、1H-吲唑基、假吲哚基
(indolenyl)、二氫吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛紅基(isatinoyl)、異苯并呋喃基、異基、異吲唑基、異二氫吲哚基、異吲哚基、異喹啉基、異噻唑基、異噻唑并吡啶基、異噁唑基、異噁唑并吡啶基、亞甲基二氧基苯基、嗎啉基、萘啶基、八氫異喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑啶基、噁唑基、羥吲哚基、嘧啶基、啡啶基、啡啉基、啡嗪基、啡噻嗪基、啡噁噻基、啡噁嗪基、呔嗪基、六氫吡嗪基、六氫吡啶基、六氫吡啶酮基、4-六氫吡啶酮基、胡椒基、喋啶基、嘌呤基、吡喃基、吡嗪基、吡唑啶基、吡唑啉基、吡唑基、嗒嗪基、吡啶并噁唑、吡啶并咪唑、吡啶并噻唑、吡啶基、嘧啶基、吡咯啶基、吡咯啉基、2-吡咯啶酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喏啉基、啶基、四氫呋喃基、四氫異喹啉基、四氫喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、苯硫基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基及呫噸基。亦包括含有(例如)上述雜環之稠合環及螺環化合物。
較佳之5員至10員雜環包括(但不限於)吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、六氫吡嗪基、六氫吡啶基、咪唑基、咪唑啶基、吲哚基、四唑基、異噁唑基、嗎啉基、噁唑基、噁二唑基、噁唑啶基、四氫呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基、三唑基、苯并咪唑基、1H-吲唑基、苯并呋喃基、苯并硫代呋喃基、苯并四唑基、苯并三唑基、苯并異噁唑基、苯并噁唑基、羥吲哚基、苯并噁唑啉基、苯并噻唑基、苯并異噻唑基、靛紅基、異喹啉基、八氫異喹啉基、四氫異喹啉基、四氫喹啉基、異噁唑并吡啶基、喹唑啉基、喹啉基、異噻唑并吡啶基、噻唑并吡啶基、噁唑并吡啶
基、咪唑并吡啶基及吡唑并吡啶基。
較佳之5員至6員雜環包括(但不限於)吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、六氫吡嗪基、六氫吡啶基、咪唑基、咪唑啶基、吲哚基、四唑基、異噁唑基、嗎啉基、噁唑基、噁二唑基、噁唑啶基、四氫呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基及三唑基。亦包括含有(例如)上述雜環之稠合環及螺環化合物。
在另一實施例中,雜環包括(但不限於)吡啶基(pyridyl)、吡啶基(pyridinyl)、異噁唑基、異喹啉基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、嗒嗪基、噁唑基、異噻唑基、噁二唑基、二氫茚酮基、六氫吡嗪基、吡喃基或吡咯基。
亦包括較小雜環,例如環氧化物及氮丙啶。
本文所用之術語「芳香族雜環基團」或「雜芳基」意指包括至少一個諸如硫、氧或氮等雜原子環成員之穩定的單環狀及多環狀芳香族烴。雜芳基包括(但不限於)吡啶基、嘧啶基、吡嗪基、嗒嗪基、三嗪基、呋喃基、喹啉基、異喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、異噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、異噻唑基、嘌呤基、咔唑基、苯并咪唑基、二氫吲哚基、苯并二氧戊環基、苯并二噁烷及諸如此類。雜芳基可經取代或未經取代。氮原子可經取代或未經取代(即,若定義,則為N或NR,其中R係H或另一取代基)。氮及硫雜原子可視情況經氧化(即,N→O及S(O)p)。應注意,芳香族雜環中之S及O原子總數不大於1。橋接環亦包括於雜環之定義內。當一或多個原子(即,C、O、N或S)連接兩個非相鄰碳或氮原子時,則產生橋接環。較佳之橋包括(但不限於)一個碳原子、兩個碳原子、一個氮原子、兩個氮原子及碳-氮基團。應注意,橋總是將單環狀環轉
化成三環狀環。當環係橋接環時,所提及之環取代基亦可存在於橋上。
術語「碳環(carbocyclic ring或carbocycle)」係指含有3-12個原子之穩定的飽和、部分飽和或不飽和的單環狀或二環狀烴環。具體而言,此包括含有5或6個原子之單環狀環或含有9或10個原子之二環狀環。適宜實例(value)包括環丙基、環丁基、環戊基、環己基、環庚基、二氫茚基及四氫萘基。當指代本文之「碳環(carbocyclic ring或carbocycle)」時,術語「視情況經取代」表示碳環可在一或多個可取代環位置上經一或多個獨立地選自以下之基團取代:烷基(較佳為低碳數烷基)、烷氧基(較佳為低碳數烷氧基)、硝基、單烷基胺基(較佳為低碳數烷基胺基)、二烷基胺基(較佳為二[低碳數]烷基胺基)、氰基、鹵基、鹵代烷基(較佳為三氟甲基)、烷醯基、胺基羰基、單烷基胺基羰基、二烷基胺基羰基、烷基醯胺基(較佳為低碳數烷基醯胺基)、烷氧基烷基(較佳為低碳數烷氧基[低碳數]烷基)、烷氧基羰基(較佳為低碳數烷氧基羰基)、烷基羰基氧基(較佳為低碳數烷基羰基氧基)及芳基(較佳為苯基),該芳基視情況經鹵基、低碳數烷基及低碳數烷氧基取代。
術語「雜原子」應包括氧、硫及氮。
式I化合物可以游離形式(未經離子化)存在或可形成鹽,該等鹽亦在本發明範圍內。醫藥上可接受之(即無毒性且生理學上可接受的)鹽較佳,但是其他鹽亦可用於(例如)分離或純化本發明化合物。
式I化合物可與鹼金屬(例如鈉、鉀及鋰)、與鹼土金屬(例如鈣及鎂)、與有機鹼(例如二環己基胺、三丁基胺、吡啶及胺基酸,例如精胺酸、離胺酸及諸如此類)形成鹽。該等鹽可以熟習此項技術者所習知之方式來形成。
式I化合物可與各種有機酸及無機酸形成鹽。該等鹽包括與鹽
酸、氫溴酸、甲烷磺酸、硫酸、乙酸、三氟乙酸、草酸、馬來酸、苯磺酸、甲苯磺酸形成之鹽及各種其他鹽(例如,硝酸鹽、磷酸鹽、硼酸鹽、酒石酸鹽、檸檬酸鹽、琥珀酸鹽、苯甲酸鹽、抗壞血酸鹽、水楊酸鹽及諸如此類)。該等鹽可以熟習此項技術者所習知之方式來形成。
另外,可形成兩性離子(「內鹽」)。
本發明涵蓋本發明化合物之所有立體異構體,其係呈混合物形式或呈純淨形式或呈基本上純淨之形式。本發明化合物之定義涵蓋所有可能的立體異構體及其混合物。其尤其涵蓋具有特定活性之外消旋形式及分離的光學異構體。外消旋形式可藉由物理方法進行拆分,例如,分段結晶、分離或結晶非對映異構衍生物或藉由對掌性管柱層析進行分離。單個光學異構體可藉由習用方法自外消旋物獲得,例如與光學活性酸形成鹽隨後進行結晶。
本發明意欲包括在本發明化合物中出現之原子的所有同位素。同位素包括彼等具有相同原子序數但不同質量數的原子。概括舉例而言但不加以限制,氫之同位素包括氘及氚。碳之同位素包括13C及14C。同位素標記之本發明化合物通常可藉由熟習此項技術者所習知之習用技術來製備,或可藉由與本文所述方法類似之方法使用適當同位素標記試劑代替原本採用之未標記試劑來製備。
式I化合物亦可具有前藥形式。由於吾人已知前藥可增強藥物之多種期望品質(例如,溶解性、生物利用度、製造性等),因此本發明化合物可以前藥形式遞送。因此,本發明意欲涵蓋本發明所主張化合物之前藥、遞送其之方法以及含有其之組合物。「前藥」意欲包括當將該前藥投予至哺乳動物個體時在活體內釋放本發明活性母體藥物之任何共價鍵結之載體(carrier)。本發明之前藥係藉由以下方式來製備:修飾存於化合物中之官能團,以使該等修飾形式可在常規處理中
或在活體內裂解成母體化合物。前藥包括其中羥基、胺基或巰基鍵結至任何基團且當將本發明前藥投予至哺乳動物個體時其裂解以分別形成游離羥基、游離胺基或游離巰基之本發明化合物。前藥之實例包括(但不限於)存於本發明化合物中之醇及胺官能團的乙酸酯、甲酸酯及苯甲酸酯衍生物。
前藥之各種形式已為熟習此項技術者所熟知。該等前藥衍生物之實例可參見:a)Design of Prodrugs,H.Bundgaard編輯,(Elsevier,1985)及Methods in Enzymology,第112卷,第309-396頁,K.Widder等人編輯(Academic Press,1985);b)A Textbook of Drug Design and Development,Krosgaard-Larsen及H.Bundgaard編輯,第5章,「Design and Application of Prodrugs」,H.Bundgaard,第113-191頁(1991);及c)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992)。
應進一步瞭解,式I化合物之溶劑合物(例如,水合物)亦在本發明範圍內。溶劑化方法已為熟習此項技術者普遍習知。
「穩定化合物」及「穩定結構」意指一種穩健至足以自反應混合物以有用的純度分離並調配成有效治療劑之化合物。較佳地,本發明所提及之化合物不含有N-鹵基、S(O)2H或S(O)H基團。
本文所用之「治療(treating或treatment)」涵蓋哺乳動物(尤其人類)之疾病狀態之治療,且包括:(a)在哺乳動物中、尤其在該哺乳動物易患疾病狀態但尚未診斷出患有該疾病狀態時預防該疾病狀態發生;(b)抑制疾病狀態,即阻止其發展;及/或(c)減輕疾病狀態,即,使疾病狀態減退。
「治療有效量」意欲包括當單獨或組合投予時有效之本發明化
合物的量。「治療有效量」亦意欲包括可有效治療疾病之化合物組合的量。
本發明進一步包括包含一或多種本發明化合物及醫藥上可接受之載劑的組合物。
「醫藥上可接受之載劑」係指業內普遍接受之用於將生物活性劑遞送至動物(尤其為哺乳動物)之介質。根據熟習此項技術者範圍內之諸多因素來調配醫藥上可接受之載劑。該等因素包括(但不限於):所調配活性劑之類型及性質;含有活性劑之組合物擬投予之個體;組合物之預期投予途徑;及所靶向之治療適應症。醫藥上可接受之載劑包括水性及非水性液體介質以及各種固體及半固體劑型。該等載劑除活性劑外亦可包括諸多不同成份及添加劑,該等其他成份出於熟習此項技術者所熟知之各種原因包括於調配物中,例如,穩定活性劑、黏合劑等。關於適宜的醫藥上可接受之載劑及載劑選擇中所涉及之因素的描述可參見多個容易獲得之來源,例如,Remington's Pharmaceutical Sciences,第17版,Mack Publishing Company,Easton,PA,1985,其全文以引用方式併入本文中。
本發明係基於某些化合物係蛋白激酶抑制劑之發現。更具體而言,化合物(例如本發明中所述者)抑制JAK受體家族成員之蛋白酪胺酸激酶活性。該等抑制劑可用於治療依賴於藉由一或多種該等受體進行信號傳導之增生性疾病。該等疾病包括骨髓增生性疾病、胰腺、前列腺、肺、頭頸、乳房、結腸、卵巢之實體腫瘤以及其他腫瘤類型,該等其他腫瘤類型包括多發性骨髓瘤、黑色素瘤、神經母細胞瘤、膠質母細胞瘤及血液惡性腫瘤,例如急性髓性白血病。
本發明亦係關於包含式I化合物或其醫藥上可接受之鹽及醫藥上可接受之載劑的醫藥組合物用於治療哺乳動物之過度增生性病症。具
體而言,該醫藥組合物預期可抑制與Flt-3(Fms樣激酶-3)、JAK2、JAK3及JAK1有關之原發性及復發性實體腫瘤之生長及/或轉移,尤其彼等生長及擴散明顯依賴於JAK2之腫瘤,包括例如血液癌症、甲狀腺癌、乳癌、結腸癌、胰腺癌、或包括多發性骨髓瘤、黑色素瘤、神經母細胞瘤及膠質母細胞瘤在內之各種腫瘤類型。除JAK2活性外,抗JAK3/JAK1或TYK2抑制活性可用於治療具有炎症成份之某些癌症。
因此,根據本發明之又一態樣,提供式I化合物或其醫藥上可接受之鹽於製造用於在溫血動物(例如人類)中產生抗增生效應之藥劑的用途。
根據本發明之又一特徵,提供在需要治療之溫血動物(例如人類)中產生抗增生效應之方法,其包含向該動物投予有效量之如上文所定義之式I化合物或其醫藥上可接受之鹽。
由於本發明化合物能夠抑制Flt-3、JAK2及JAK3激酶,故其可用於治療增生性疾病(包括癌症)。
因此,本發明提供治療各種癌症之方法,該等癌症包括(但不限於)以下:癌瘤,包括膀胱癌瘤(包括加速(accelerated)及轉移性膀胱癌)、乳房癌瘤、結腸癌瘤(包括結腸直腸癌)、腎癌瘤、肝癌瘤、肺癌瘤(包括小及非小細胞肺癌及肺腺癌)、卵巢癌瘤、前列腺癌瘤、睾丸癌瘤、泌尿生殖道癌瘤、淋巴系統癌瘤、直腸癌瘤、喉癌瘤、胰腺癌瘤(包括外分泌胰腺癌)、食管癌瘤、胃癌瘤、膽囊癌瘤、子宮頸癌瘤、甲狀腺癌瘤及皮膚癌瘤(包括鱗狀細胞癌);淋巴譜系之造血性腫瘤,包括白血病、急性淋巴細胞白血病、急性淋巴母細胞白血病、B細胞淋巴瘤、T細胞淋巴瘤、何傑金氏淋巴瘤(Hodgkin's lymphoma)、非何傑金氏淋巴瘤、毛細胞淋巴瘤、組
織細胞淋巴瘤及伯基特氏淋巴瘤(Burkett's lymphoma);骨髓譜系之造血性腫瘤,包括急性及慢性骨髓性白血病、骨髓增生異常綜合症、髓樣白血病及前髓細胞性白血病;中樞及外周神經系統腫瘤,包括星形細胞瘤、神經母細胞瘤、神經膠質瘤及許旺氏細胞瘤(schwannoma);間質來源之腫瘤,包括纖維肉瘤、橫紋肌肉瘤及骨肉瘤;及其他腫瘤,包括黑色素瘤、著色性幹皮病、角化棘皮瘤、精原細胞瘤、甲狀腺濾泡癌及畸胎癌。
本發明提供治療白血病、骨髓增生性疾病(例如真性紅細胞增多症、特發性血小板減少及骨髓纖維化)、多發性骨髓瘤、結腸癌、乳癌及胃癌之方法。
上文定義之抗增生治療可作為唯一療法應用,或者除本發明化合物外亦可包括一或多種其他物質及/或治療。該治療可藉由同時、依序或分開投予治療之單獨組份而達成。本發明化合物亦可與已知抗癌劑及細胞毒性劑及治療(包括輻射)組合使用。若以固定劑量進行調配,則該等組合產品使用下文所述劑量範圍內之本發明化合物及批准劑量範圍內之其他醫藥活性劑。當組合調配物不合適時,可依序使用式I化合物與已知抗癌劑或細胞毒性劑及治療(包括輻射)。
術語「抗癌」劑包括可用於治療癌症之任何已知藥劑,包括以下:17α-炔雌醇(17α-ethinylestradiol)、己烯雌酚(diethylstilbestrol)、睪酮(testosterone)、潑尼松(prednisone)、氟甲睪酮(fluoxymesterone)、丙酸屈他雄酮(dromostanolone propionate)、睪內酯(testolactone)、乙酸甲地孕酮(megestrolacetate)、甲潑尼龍(methylprednisolone)、甲基睪酮(methyltestosterone)、潑尼松龍(prednisolone)、曲安西龍(triamcinolone)、氯烯雌醚(chlorotrianisene)、羥孕酮(hydroxyprogesterone)、胺魯米特
(aminoglutethimide)、雌莫司汀(estramustine)、乙酸甲羥孕酮(medroxyprogesterone-acetate)、亮丙瑞林(leuprolide)、氟他胺(flutamide)、托瑞米芬(toremifene)、諾雷德(Zoladex);基質金屬蛋白酶抑制劑;VEGF抑制劑,例如抗VEGF抗體(Avastin®)及小分子,例如ZD6474及SU6668;瓦他拉尼(Vatalanib)、BAY-43-9006、SU11248、CP-547632及CEP-7055;HER 1及HER 2抑制劑,包括抗HER2抗體(赫賽汀(Herceptin));EGFR抑制劑,包括吉非替尼(gefitinib)、厄洛替尼(erlotinib)、ABX-EGF、EMD72000、11F8及西妥昔單抗(cetuximab);Eg5抑制劑,例如SB-715992、SB-743921及MKI-833;pan Her抑制劑,例如卡奈替尼(canertinib)、EKB-569、CI-1033、AEE-788、XL-647、mAb 2C4及GW-572016;激酶抑制劑,例如Gleevec®及達沙替尼(dasatinib)(Sprycel®);Casodex®(比卡魯胺(bicalutamide)、阿斯利康(Astra Zeneca))、他莫昔芬(Tamoxifen);MEK-1激酶抑制劑、MAPK激酶抑制劑、PI3激酶抑制劑;PDGF抑制劑,例如伊馬替尼(imatinib);抗血管生成及抗血管劑,其藉由干擾血液流動至實體腫瘤藉由剝奪癌細胞之營養而使癌細胞靜止;閹割,其使雄激素依賴性癌瘤非增生性;非受體及受體酪胺酸激酶抑制劑;整聯蛋白信號傳導抑制劑;微管蛋白作用劑(tubulin acting agent),例如長春鹼(vinblastine)、長春新鹼(vincristine)、長春瑞濱(vinorelbine)、長春氟寧(vinflunine)、紫杉醇(paclitaxel)、多西他賽(docetaxel)、7-O-甲硫基甲基紫杉醇、4-去乙醯基-4-甲基碳酸鹽紫杉醇、3'-第三丁基-3'-N-第三丁基氧基羰基-4-去乙醯基-3'-去苯基-3'-N-去苯甲醯基-4-O-甲氧基羰基-紫杉醇、C-4甲基碳酸鹽紫杉醇、埃坡黴素A(epothilone A)、埃坡黴素B、埃坡黴素C、埃坡黴素D、去氧埃坡黴素A、去氧埃坡黴素B、[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-二羥基-
8,8,10,12,16-五甲基-3-[1-甲基-2-(2-甲基-4-噻唑基)乙烯基]-4-氮雜-17-氧雜二環[14.1.0]十七烷-5,9-二酮(伊沙匹隆(ixabepilone))、[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(胺基甲基)-4-噻唑基]-1-甲基乙烯基]-7,11-二羥基-8,8,10,12,16-五甲基-4,17-二氧雜二環[14.1.0]-十七烷-5,9-二酮及其衍生物;CDK抑制劑、抗增生細胞週期抑制劑、表鬼臼毒素(epidophyllotoxin)、依託泊苷(etoposide)、VM-26;抗腫瘤酶,例如,拓撲異構酶I抑制劑、喜樹鹼(camptothecin)、托泊替康(topotecan)、SN-38;丙卡巴肼(procarbazine);米托蒽醌(mitoxantrone);鉑配位錯合物,例如順鉑(cisplatin)、卡鉑(carboplatin)及奧沙利鉑(oxaliplatin);生物反應調節劑;生長抑制劑;抗激素治療劑;甲醯四氫葉酸(leucovorin);替加氟(tegafur);抗代謝物,例如嘌呤拮抗劑(例如6-硫鳥嘌呤及6-巰基嘌呤;麩醯胺酸拮抗劑,例如DON(AT-125;d-側氧基-正白胺酸);核糖核苷酸還原酶抑制劑;mTOR抑制劑;及造血生長因子。
其他細胞毒性劑包括環磷醯胺(cyclophosphamide)、多柔比星(doxorubicin)、柔紅黴素(daunorubicin)、米托蒽醌、美法侖(melphalan)、六甲蜜胺(hexamethyl melamine)、噻替哌(thiotepa)、阿糖胞苷(cytarabin)、依達曲沙(idatrexate)、三甲曲沙(trimetrexate)、達卡巴嗪(dacarbazine)、L-天冬醯胺酶、比卡魯胺、亮丙瑞林、吡啶并苯并吲哚衍生物、干擾素及白細胞介素。
在醫學腫瘤學領域中,常用做法係使用不同治療形式之組合來治療每一癌症患者。在醫學腫瘤學中,除上文所定義之抗增生治療外該治療之其他組成部分可為手術、放射療法或化學療法。該化學療法可涵蓋三種主要治療劑種類:(i)抗血管生成劑,其藉由上文所定義之不同機制起作用(例
如,利諾胺(linomide)、整聯蛋白αvβ3功能抑制劑、血管抑制素(angiostatin)、雷佐生(razoxane));(ii)細胞抑制劑,例如抗雌激素藥(例如,他莫昔芬、托瑞米芬、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、艾多昔芬(iodoxifene))、孕激素(progestogen)(例如,乙酸甲地孕酮)、芳香酶抑制劑(例如,阿那曲唑(anastrozole)、來曲唑(letrozole)、硼嗪(borazole)、依西美坦(exemestane))、抗激素藥、抗孕激素藥(antiprogestogen)、抗雄激素藥(例如,氟他胺、尼魯米特(nilutamide)、比卡魯胺、乙酸環丙孕酮(cyproterone acetate))、LHRH激動劑及拮抗劑(例如,乙酸戈舍瑞林(gosereline acetate)、亮丙瑞林)、睪酮5α-二氫還原酶抑制劑(例如,非那雄胺(finasteride))、法尼基轉移酶抑制劑、抗侵襲劑(例如,金屬蛋白酶抑制劑,例如馬立馬司他(marimastat)及尿激酶纖維蛋白溶酶原激活劑受體功能抑制劑)及生長因子功能抑制劑(該等生長因子包括例如EGF、FGF、血小板衍生之生長因子及肝細胞生長因子,該等抑制劑包括生長因子抗體、生長因子受體抗體,例如Avastin®(貝伐珠單抗(bevacizumab))及Erbitux®(西妥昔單抗);酪胺酸激酶抑制劑及絲胺酸/蘇胺酸激酶抑制劑);及(iii)醫學腫瘤學中所使用之抗增生/抗腫瘤藥物及其組合,例如抗代謝物(例如,抗葉酸劑,例如胺甲蝶呤(methotrexate)、氟嘧啶(fluoropyrimidine),例如5-氟尿嘧啶、嘌呤及腺苷類似物、胞嘧啶阿糖核苷(cytosine arabinoside));嵌入抗腫瘤抗生素(例如,蒽環抗生素(anthracycline),例如多柔比星、道諾黴素(daunomycin)、表柔比星(epirubicin)及伊達比星(idarubicin)、絲裂黴素(mitomycin-C)、更生黴素(dactinomycin)、光輝黴素(mithramycin));鉑衍生物(例如,順鉑、卡鉑);烷基化劑(例如,氮芥(nitrogen mustard)、美法侖、苯丁酸氮
芥(chlorambucil)、白消安(busulphan)、環磷醯胺、異環磷醯胺(ifosfamide)、亞硝基脲(nitrosourea)、噻替哌;抗有絲分裂劑(例如,長春花生物鹼,例如長春新鹼、長春瑞濱、長春鹼及長春氟甯)及紫杉烷,例如Taxol®(紫杉醇)、Taxotere®(多西他賽)及新穎微管劑,例如埃坡黴素類似物(伊沙匹隆)、迪克德莫利得(discodermolide)類似物及艾榴素(eleutherobin)類似物;拓撲異構酶抑制劑(例如,表鬼臼毒素(epipodophyllotoxin),例如依託泊苷及替尼泊苷(teniposide)、安吖啶(amsacrine)、托泊替康、伊立替康(irinotecan));細胞週期抑制劑(例如,黃酮吡多(flavopyridol));生物反應調節劑及蛋白酶體抑制劑,例如Velcade®(硼替佐米(bortezomib))。
如上文所述,本發明之式I化合物因其抗增生效應而令人感興趣。預期該等本發明化合物可用於寬範圍之疾病狀態,包括癌症、牛皮癬及類風濕性關節炎。
更具體而言,該等式I化合物可用於治療各種癌症,包括(但不限於)以下:- 癌瘤,包括前列腺、胰腺導管腺癌、乳房、結腸、肺、卵巢、胰腺及甲狀腺癌瘤;- 中樞及外周神經系統腫瘤,包括神經母細胞瘤、膠質母細胞瘤及髓母細胞瘤;- 血液惡性腫瘤,例如急性髓性白血病(AML);及- 其他腫瘤,包括黑色素瘤及多發性骨髓瘤。
由於激酶總體調控細胞增生之重要作用,抑制劑可用作可逆的細胞抑制劑而用於治療特徵在於異常細胞增生之任何疾病過程,例如,良性前列腺增生、家族性腺瘤性息肉病、神經纖維瘤病、肺纖維化、關節炎、牛皮癬、腎小球腎炎、血管成形術或血管手術後再狹窄、肥厚性瘢痕形成及炎性腸病。
式I化合物尤其可用於治療具有較高酪胺酸激酶活性發生率之腫瘤,例如前列腺、結腸、腦、甲狀腺及胰腺腫瘤。藉由投予本發明化合物之組合物(或組合)來降低哺乳動物宿主中腫瘤之發生。
式I化合物亦可用於治療其他癌性疾病(例如急性髓性白血病)。
含有活性成份之本發明醫藥組合物可呈適於經口使用之形式,例如,錠劑、口含錠、菱形錠、水性或油性懸浮液、可分散粉劑或顆粒劑、乳液、硬質或軟質膠囊、或糖漿或酏劑。
當本發明化合物投予人類個體時,日劑量通常由處方醫師來確定,該劑量通常視各患者之年齡、體重、性別及反應以及患者症狀之嚴重程度而有所變化。
若以固定劑量進行調配,則該等組合產品使用上文所述劑量範圍內之本發明化合物及批准劑量範圍內之其他醫藥活性劑或治療。當組合調配物不合適時,亦可依序投予式I化合物與已知抗癌劑或細胞毒性劑。本發明在投予順序方面並無限制;式I化合物可在已知抗癌劑或細胞毒性劑投予之前或之後投予。
該等化合物可以約0.05至200mg/kg/天、較佳小於100mg/kg/天之劑量範圍以單次劑量或以2至4次分開劑量投予。
本發明化合物可呈諸如錠劑、膠囊(每一者包括緩釋或定時釋放調配物)、丸劑、粉劑、顆粒劑、酏劑、酊劑、懸浮液、糖漿及乳液等經口劑型投予。其亦可呈靜脈內(團藥或輸注)、腹膜內、皮下或肌內形式投予,所有此等形式均使用醫藥領域之技術人員所熟知之劑型。其可單獨投予,但通常與根據所選投予途徑及標準醫藥作法而選擇之醫藥載劑一起投予。
當然,本發明化合物之劑量療程應端視諸如下述習知因素而有所變化:特定藥劑之藥效特徵及其投予方式及途徑;接受者之物種、
年齡、性別、健康狀況、醫學病症及體重;症狀之性質及程度;並存治療之種類;治療頻率;投予途徑;患者之腎及肝功能;以及期望效果。醫師或獸醫可確定及開列治療癌症所需藥物之有效量。
作為一般指導,當用於指定效果時,各活性成份之日口服劑量應介於約0.001至1000mg/kg體重範圍內,較佳介於約0.001至100mg/kg體重/天範圍內,且最佳介於約0.001至20mg/kg/天範圍內。以靜脈內方式投予時,最佳劑量介於約0.1至約10mg/kg範圍內。本發明化合物可依單一日劑量投予,或者總日劑量可依每天兩次、三次或四次分開劑量投予。
本發明化合物可呈鼻內形式經由局部使用適宜鼻內媒劑或經由穿皮途徑,使用穿皮皮膚貼劑投予。當以穿皮遞送系統形式投予時,在整個劑量療程期間之劑量投予當然應為連續式而間斷式。
該等化合物通常以與根據預期投予形式(即口服錠劑、膠囊、酏劑、糖漿及諸如此類)適當選擇且與習用醫藥作法相符合之適宜醫藥稀釋劑、賦形劑或載劑(在本文中統稱為醫藥載劑)之混合物形式進行投予。
例如,以錠劑或膠囊形式經口投予時,活性藥物組份可與經口無毒性的醫藥上可接受之惰性載劑組合,該等載劑係例如乳糖、澱粉、蔗糖、葡萄糖、甲基纖維素、硬脂酸鎂、磷酸二鈣、硫酸鈣、甘露醇、山梨醇及諸如此類;以液體形式經口投予時,經口藥物組份可與任何經口無毒性的醫藥上可接受之惰性載劑組合,該等載劑係例如乙醇、甘油、水及諸如此類。此外,當期望或需要時,亦可將適宜黏合劑、潤滑劑、崩解劑及著色劑納入混合物中。適宜黏合劑包括澱粉、明膠、天然糖類(例如葡萄糖或β-乳糖)、玉米甜味劑、天然及合成膠(例如阿拉伯膠、黃蓍膠或藻酸鈉)、羧甲基纖維素、聚乙二醇、蠟及諸如此類。該等劑型中所用之潤滑劑包括油酸鈉、硬脂酸鈉、硬
脂酸鎂、苯甲酸鈉、乙酸鈉、氯化鈉及諸如此類。崩解劑包括(但不限於)澱粉、甲基纖維素、瓊脂、膨潤土、黃原膠及諸如此類。
本發明化合物亦可以脂質體遞送系統形式進行投予,例如單層小囊泡、單層大囊泡及多層囊泡。脂質體可自多種磷脂(例如膽固醇、硬脂胺或磷脂醯膽鹼)形成。
本發明化合物亦可與作為可靶向藥物載體之可溶性聚合物偶合。此等聚合物可包括經棕櫚醯殘基取代之聚乙烯吡咯啶酮、吡喃共聚物、聚羥丙基甲基丙烯醯胺苯酚、聚羥乙基天冬醯胺苯酚或聚環氧乙烷-聚離胺酸。此外,本發明化合物可與一類可用於達成藥物受控釋放之生物可降解聚合物偶合,例如,聚乳酸、聚乙醇酸、聚乳酸與聚乙醇酸之共聚物、聚ε己內酯、聚羥基丁酸、聚原酸酯、聚縮醛、聚二氫吡喃、聚氰基丙烯酸酯及水凝膠之交聯或兩親性嵌段共聚物。
適於投予之劑型(醫藥組合物)每一劑量單元可含有約1毫克至約1000毫克活性成份。在該等醫藥組合物中,活性成份通常以佔組合物總重量約0.1-95重量%的量存在。
明膠膠囊可含有活性成份及粉末狀載劑,例如乳糖、澱粉、纖維素衍生物、硬脂酸鎂、硬脂酸及諸如此類。可使用類似稀釋劑來製備壓縮錠劑。錠劑及膠囊二者均可製造成緩釋產品,以保證在數小時時間段內持續釋放藥物。壓縮錠劑可塗敷糖或塗敷薄膜以掩蓋任何令人不快的味道並保護錠劑遠離空氣,或者塗敷腸溶衣以在胃腸道中選擇性崩解。
用於經口投予之液體劑型可含有著色劑及矯味劑以提高患者接受度。
通常,水、適宜油、鹽水、水性右旋糖(葡萄糖)及相關糖溶液及二醇(例如丙二醇或聚乙二醇)係非經腸溶液之適宜載劑。用於非經腸投予之溶液較佳含有活性成份之水溶性鹽、適宜穩定劑及(若需要)緩
衝物質。諸如亞硫酸氫鈉、亞硫酸鈉或抗壞血酸(單獨或組合)等抗氧化劑係適宜的穩定劑。亦使用檸檬酸及其鹽及EDTA鈉鹽。另外,非經腸溶液可含有防腐劑,例如苯紮氯銨、對羥基苯甲酸甲酯或對羥基苯甲酸丙酯、及氯丁醇。
適宜醫藥載劑闡述於此領域之標準參考文本Remington's Pharmaceutical Sciences,Mack Publishing Company中。
在V形底384孔板中實施分析。最終分析體積係30μL,其自15μL酶及受質(螢光肽及ATP)及測試化合物存於分析緩衝液(100mM HEPES pH 7.4、10mM MgCl2、25mM β-甘油磷酸鹽、0.015% Brij35及4mM DTT)中之添加物製備。藉由將JAK2與受質及測試化合物組合來開始反應。將反應物在室溫下培育60min,並藉由向每一試樣中添加45μL 35mM EDTA來終止反應。在Caliper LabChip 3000上藉由電泳分離螢光受質及磷酸化產物來分析反應混合物。藉由與100%抑制之無酶對照反應及0%抑制之僅媒劑反應進行比較來計算抑制數據。分析中之最後試劑濃度係ATP,30μM;JAK2螢光肽,1.5μM;JAK2,1nM;及DMSO,1.6%。製作劑量反應曲線以確定抑制50%之激酶活性所需要的濃度(IC50)。將化合物以10mM溶解於二甲基亞碸(DMSO)中,並以11種濃度(每種濃度一式兩份)進行評價。藉由非線性回歸分析來獲得IC50值。
在V形底384孔板中實施分析。最終分析體積係30μL,其自15μL酶及受質(螢光肽及ATP)及測試化合物存於分析緩衝液(100mM HEPES pH 7.4、10mM MgCl2、25mM β-甘油磷酸鹽、0.015% Brij35及4mM DTT)中之添加物製備。藉由將JAK3與受質及測試化合物組
合來開始反應。將反應物在室溫下培育60min,並藉由向每一試樣中添加45μL 35mM EDTA來終止反應。在Caliper LabChip 3000上藉由電泳分離螢光受質及磷酸化產物來分析反應混合物。藉由與100%抑制之無酶對照反應及0%抑制之僅媒劑反應進行比較來計算抑制數據。分析中之最後試劑濃度係ATP,8μM;JAK3螢光肽,1.5μM;JAK3,2.5nM;及DMSO,1.6%。製作劑量反應曲線以確定抑制50%之激酶活性所需要的濃度(IC50)。將化合物以10mM溶解於二甲基亞碸(DMSO)中,並以11種濃度(每種濃度一式兩份)進行評價。藉由非線性回歸分析來獲得IC50值。
利用量測分裂細胞DNA中之胸甘納入(其與細胞數量直接相關)之分析來評價化合物抑制細胞增生之能力。將SET-2細胞以10000個細胞/孔鋪板於96孔板中,並在補加有20%胎牛血清之RPMI-1640中培養24h,隨後添加測試化合物。將化合物稀釋於培養基中,以使二甲基亞碸之最終濃度決不超過0.1%。添加化合物後,將細胞再培養72h,然後藉由利用3H-胸苷納入量測DNA合成來測定細胞增生。
在上文所述JAK2及細胞增生抑制分析中測試本文所述之化合物。獲得以下結果。
已在一或多種上文所確定分析中對本文所述化合物進行測試,且發現其具有活性。
將調配於合適媒劑中之化合物以經口濃注或經腹膜內或皮下注射至小鼠之方式投予至Balb/C小鼠中。通過在化合物投予後多個時間點實施眼采血或心臟穿刺來採集血液試樣。將血液分液(90μL)置於96孔板中。將鼠科動物促血小板生成素(mTPO;Peprotech)之稀釋溶液(5ul)(以1:1000稀釋於dPBS/BSA中,2μL於2ml dPBS/BSA中)遞送至
每一孔中以實施路徑刺激。將板在37℃下於水浴中培育10分鐘。向每一孔中添加1.5ml固定/裂解溶液(來自BD Biosciences)。隨後將試樣在37℃下培育15分鐘以確保紅細胞(RBC)裂解。將該等板在2000rpm下離心5分鐘並使用V&P 96孔抽吸器進行抽吸。使用dPBS洗滌細胞,再次離心,再懸浮並轉移至標準96孔板中。使用dPBS洗滌細胞兩次,隨後添加CD61 FITC(來自eBiosciences)以在黑暗中於室溫下實施表面受體染色45min。隨後在dPBS中洗滌細胞並如下實施滲透化處理以進行pSTAT5染色:添加200μL滲透化緩衝液III(來自BD Bioscience),並將試樣在冰上培育30分鐘,且隨後使用dPBS/1%BSA洗滌試樣兩次並再懸浮於100μL含有Stat5(pY695)Alexa 647抗體之dPBS/BSA中。將試樣在室溫下於黑暗中培育45分鐘,洗滌兩次並再懸浮於10μL所用Stat5(pY695)Alexa 647抗體中並添加至試樣中。將試樣再懸浮於200μL dPBS/BSA中,並在FACSCanto上進行分析,使用Diva 6及FlowJo 8.5.3分析軟體對試樣圖像進行處理。
在製備方法及實例中可使用以下縮略語:h=小時
DCM=二氯甲烷
THF=四氫呋喃
HPLC=高效液相層析
DIEA=二異丙基乙胺
i-PrOH=異丙醇
TFA=三氟乙酸
min=分鐘
DMF=二甲基甲醯胺
EDC=N-(3-二甲基胺基丙基)N'-乙基碳化二亞胺
HOBt=羥基苯并三唑
NMP=N-甲基吡咯啶酮
EtOAc=乙酸乙酯
AcOH=乙酸
BOP試劑=六氟磷酸苯并三唑-1-基-氧基-叁-(二甲基胺基)-鏻鹽
鹽水=飽和氯化鈉水溶液
Et3N=三乙胺
tR=保留時間
rt=室溫
NCS=N-氯代琥珀醯胺
NBS=N-溴代琥珀醯胺
NIS=N-碘代琥珀醯胺
R基團係噻唑(如在Ia1中)且R1及R2基團係CF3或烷基或環烷基或組合以形成飽和碳環或雜環或R2基團係COORb之通式I化合物可使用繪示於反應圖1中之通用方法來製備。二氯中間體II(使用報導於WO200612237中之程序來製備)可與2,4-二甲氧基苄基組合,並使用適宜保護基團(Boc)來封端所得二級胺(III)。可通過二苯甲酮亞胺中間體將第二個氯原子轉化成對應胺(IV)。胺基化合物可鹵化成中間體V。可對V實施過渡金屬調介之吲哚環形成反應,並使用碘乙烷封端所得吲哚氮,獲得VI。酯水解隨後醯胺鍵形成及利用酸處理裂解保護基團將獲得胺VII。可藉由首先與異硫氰酸苯甲醯酯偶合、隨後使用水性鹼進行處理將胺VII轉化成硫脲VIII。可藉由與α-溴酮衍生物(R1CHBrCOR2)縮合來形成噻唑。
R1基團係CONRaRa之通式Ia2化合物可使用反應圖2來製備。可使硫脲中間體(VIII)與EtO2CCHBrCOR1組合以獲得噻唑酯(IX)。可使酯水解並使酸與胺偶合以獲得噻唑醯胺衍生物(Ia)。
類似地,R1基團係CONRaRa之通式Ia3化合物可使用繪示於反應圖3中之通用方案來製備。
R1係鹵素(Cl、Br或I)之通式Ia化合物可藉由如反應圖4中所繪示縮合a,a'-二鹵代酮來製備。
或者,硫脲衍生物VIII可在室溫下轉化成C-5未經取代之噻唑XI,並隨後使用親電鹵素源或通過金屬化隨後使用親電鹵化劑驟冷而直接鹵化(反應圖5)。
R1係SO2Rb之通式Ia5化合物可使用反應圖6中所顯示之通用合成途徑來合成。
R1與R2組合形成芳香族或雜芳香族環之通式Ia化合物可利用反應圖7來製備。
或者,該等化合物可藉由首先使苯胺或雜苯胺(XVI)與異硫氰酸酯(XV)偶合、隨後氧化環化來製備(反應圖8)。
通式Ib1化合物可使用繪示於反應圖9中之通用合成途徑來製備。可在鹼性條件下使苯胺VII與γ-二硫代甲基酮化合物XVII(在室溫下使用報導於Synlett,第2331頁(2008)中之程序來製備)組合以獲得XVIII。使經Boc保護之肼衍生物逐步縮合將得到需要之吡唑Ib1。
通式Ib1或If1及1f化合物亦可利用過渡金屬催化之反應藉由使C-4鹵代衍生物(XIX)與經適當取代之2-胺基吡唑衍生物(XX)偶合來製備(反應圖10)。
R2基團係CONRaRa之通式Ib2化合物可利用反應圖11來合成。可
使苯胺VII與γ-二硫代甲基酮衍生物XXII(使用Tetrahedron,第2631頁(2003)之程序來製備)組合以獲得中間體XXIII。使經Boc保護之肼衍生物逐步縮合將得到需要之吡唑醛XXIV。可使用過硫酸氫鉀製劑(oxone)或次氯酸鈉來氧化醛以獲得羧酸XXV。使酸XXV與胺偶合將得到吡唑醯胺Ib2。
通式Ic1化合物可使用如反應圖12中所顯示之通用方案來製備。可使苯胺VII與氯乙醯氯偶合,並可使用硫代醯胺(R2CSNH2)處理所得醯胺以獲得噻唑Ic1。
通式1d1化合物可按照反應圖13來製備。可使先前所述之異硫氰酸酯衍生物XV與脒XXV在脫水反應條件下組合以得到1,2,4-噻二唑(Id1)。
通式1e1化合物可使用如反應圖14中所顯示之合成途徑來製備。可使異硫氰酸酯XV與疊氮化物XXVI於膦存在下組合以獲得1,3-噁唑Ie1。
通式1g1化合物可使用如反應圖15中所顯示之合成途徑來製備。可使胺VII與異硫氰酸醯基酯XXVII組合。可使醯基硫脲基與肼衍生物縮合以獲得1,2,4-三唑衍生物1g1。
1A 製備6-氯-N-(2,4-二甲氧基苄基)-1-甲基-1H-咪唑并[4,5-c]吡啶-4-胺
在200mL圓底燒瓶中,將4,6-二氯-1-甲基-1H-咪唑并[4,5-c]吡啶(15g,74.2mmol)(按照WO2006122137實例A1.5來製備)溶解於2,4-二甲氧基苄基胺(25mL,166mmol)中。將反應混合物加熱至110℃,保持3h,並冷卻至室溫。添加水且沉澱出棕褐色固體。真空過濾,獲得棕褐色固體。使用乙酸乙酯及己烷洗滌固體,獲得奶油色固體狀6-氯-N-(2,4-二甲氧基苄基)-1-甲基-1H-咪唑并[4,5-c]吡啶-4-胺(23.459g,95%產率)。
MS(ESI)m/z 333.0(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 8.05(s,1 H),7.17(t,1 H,J=6.19Hz),7.06(d,1 H,J=8.25Hz),6.87(s,1 H),6.55(d,1 H,J=2.47Hz),6.42(dd,1 H,J=8.52,2.47Hz),4.54(d,2 H,J=5.77Hz),3.82(s,3 H),3.74(s,3 H),3.72(s,3 H)。
1B 製備6-氯-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯
向6-氯-N-(2,4-二甲氧基苄基)-1-甲基-1H-咪唑并[4,5-c]吡啶-4-胺(實例1A,0.63g,1.893mmol)存於冷卻至-78℃之四氫呋喃(38mL)中之溶液中緩慢添加NaHMDS(1.0M THF,2.366mL,2.366mmol)。於-78℃下攪拌30min後,添加BOC2O(0.483mL,2.082mmol)。移除冷卻浴並使反應物升溫至室溫,保持過夜。藉由HPLC觀測到約50%轉化。將溶液再次冷卻至-78℃。添加NaHMDS(1.0M THF,2.366mL,2.366mmol),並將混合物攪拌30min,隨後添加BOC2O(0.483mL,2.082mmol)。移除冷卻浴並使反應物升溫至室溫,保持5h。在減壓下移除溶劑,並將殘留物分配於乙酸乙酯與水之間。有機層用水洗滌兩次,經無水硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 40g管柱使用50-100%乙酸乙酯/己烷溶析對粗殘留物進行純化,獲得發泡體狀白色固體6-氯-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(0.638g,78%產率)。
MS(ESI)m/z 433.0(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.91(s,1 H),7.47(d,1 H,J=8.31Hz),7.19(s,1 H),6.38(dd,1 H,J=8.31,2.52Hz),6.32(d,1 H,J=2.52Hz),5.13(s,2 H),3.80(s,3 H),3.74(s,3 H),3.59(s,3 H),1.40(s,9 H)。
1C 製備2,4-二甲氧基苄基(6-(二苯基亞甲基胺基)-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基)胺基甲酸第三丁基酯
將無水二噁烷(4mL)添加至6-氯-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(實例1B,0.638g,1.474mmol)、二苯甲酮亞胺(0.297mL,1.769mmol)、Pd2(dba)3(0.270g,0.295mmol)、9,9-二甲基-4,5-雙(二苯基膦基)呫噸(0.256g,0.442mmol)及碳酸銫(0.672g,2.063mmol)之混合物中。將反應混合物加熱至90℃,保持過夜。冷卻至室溫後,在真空中移除溶劑。將殘留物分配於乙酸乙酯與水之間。有機層用水洗滌兩次,經無水硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 40g管柱使用50-100%乙酸乙酯/己烷溶析對粗殘留物進行純化,提供淡黃色固體狀2,4-二甲氧基苄基(6-(二苯基亞甲基胺基)-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基)胺基甲酸第三丁基酯(0.757g,89%產率)。
MS(ESI)m/z 414.0(M-CPh2+2H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.16(s,1 H),7.67(dd,2 H,J=8.56,1.51Hz),7.44-7.60(m,3 H),7.25(d,1 H,J=8.31Hz),6.96-7.11(m,4 H),6.87(s,1 H),6.46(d,1 H,J=2.52Hz),6.33(dd,1 H,J=8.56,2.27Hz),4.52(s,2 H),3.70(s,3 H),3.69(s,3 H),3.67(s,3 H),1.25(s,9 H)。
1D 製備6-胺基-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯
在1000mL圓底燒瓶中,在THF(50mL)中攪拌2,4-二甲氧基苄基(6-(二苯基亞甲基胺基)-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基)胺基甲酸第三丁基酯(實例1C,9.2g,15.93mmol)。添加1N HCl(33mL)。2min後,用1N NaOH(65mL)及乙酸乙酯(100mL)驟冷反應物。分離有機層,經無水硫酸鈉乾燥,過濾並在真空中濃縮。將殘留物在真空中乾燥1h並使用醚研磨(4x)。分離得到奶油色固體狀6-胺基-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(6.587g,15.93mmol,100%產率)。物質未經進一步純化即用於下一步驟中。
MS(ESI)m/z 413.0(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 7.93(s,1 H),7.44(d,1 H,J=8.31Hz),6.44(d,1 H,J=2.27Hz),6.35(dd,1 H,J=8.56,2.27Hz),6.25(s,1 H),5.58(s,2 H),4.87(s,2 H),3.67(s,6 H),3.63(s,3 H),1.30(s,9 H)。
1E 製備6-胺基-7-碘-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯
在圓底燒瓶中,將6-胺基-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(實例1D,7.887g,19.08mmol)溶解於MeCN(200mL)中並冷卻至0℃。將N-碘代琥珀醯亞胺(4.51g,20.03mmol)溶解於剩餘MeCN(50mL)中,並經40min逐滴添加至反應混合物中。將反應混合物在0℃下再攪拌10min,並使用2M亞硫酸氫鈉(125mL)驟冷。攪拌及溫度保持50min。將混合物轉移至分液漏
斗中。使用CH2Cl2(3×100mL)萃取水性層。合併之有機層用水及鹽水洗滌,經Na2SO4乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 120g管柱使用20-100%乙酸乙酯/CH2Cl2溶析對粗殘留物進行純化,提供淺黃色固體狀6-胺基-7-碘-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(8.436g,82%產率)。
MS(ESI)m/z 539.0(M)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.00(s,1 H),7.40(d,1 H,J=8.06Hz),6.43(d,1 H,J=2.52Hz),6.31-6.39(m,1 H),5.73(s,2 H),4.86(s,2 H),3.95(s,3 H),3.67(s,3 H),3.64(s,3 H),1.30(s,9 H)。
1F 製備4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸乙酯
向裝有存於DMA(43.1mL)中之6-胺基-7-碘-1-甲基-1H-咪唑并[4,5-c]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(實例1E,3.49g,6.47mmol)之燒瓶中添加Pd2(dba)3(0.474g,0.518mmol)、丙酮酸乙酯(7.22mL,64.7mmol)及N-甲基二環己基胺(2.77mL,12.94mmol)。向反應混合物中通氬氣10min並在60℃下加熱6h。藉由LCMS測定反應完成。冷卻至室溫後,用乙酸乙酯及飽和NaHCO3水溶液稀釋反應混合物。通過矽藻土墊真空過濾所得乳液,並轉移至分液漏斗中。用乙酸乙酯萃取水性層。使用10% LiCl水溶液(2 x)洗滌合併之有機層。有機相經MgSO4乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 120g管柱使用40-80%乙酸乙酯/己烷溶析對褐色殘留物進行純化,獲得4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-1-甲基-
1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸乙酯(2.830g,86%產率)。
MS(ESI)m/z 510.0(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.83(s,1 H),7.57(d,1 H,J=8.31Hz),7.39(d,1 H,J=2.27Hz),6.40(dd,1 H,J=8.44,2.39Hz),6.32(d,1 H,J=2.52Hz),5.16(s,2 H),4.43(q,2 H,J=7.05Hz),4.09(s,3 H),3.74(s,3 H),3.56(s,3 H),1.43(t,3 H,J=7.18Hz),1.40(s,9 H)。
1G 製備4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸乙酯
向4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸乙酯(實例1F,5.046g,9.90mmol)存於DMF(49.5mL)中之溶液中添加碘乙烷(1.601mL,19.81mmol)及碳酸銫(6.45g,19.81mmol)。將反應混合物在60℃下加熱60min,並冷卻至室溫。使用乙酸乙酯稀釋反應混合物,並實施真空過濾以移除碳酸銫。添加飽和碳酸氫鈉水溶液,並使用乙酸乙酯(2x)萃取水性層。合併之有機層使用10%氯化鋰(3 x)洗滌,經無水硫酸鎂乾燥,過濾並在真空中濃縮。粗產物用於下一步驟中。
MS(ESI)m/z 538.1(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.79(s,1 H),7.62(d,1 H J=8.28Hz),7.43(s,1 H),6.39(dd,1 H,J=8.41,2.38Hz),6.32(d,1 H,J=2.26Hz),5.20(s,2 H),4.79(q,2 H,J=7.03Hz),4.41(q,2 H,J=7.28Hz),4.07(s,3 H),3.74(s,3 H),3.61(s,3 H),1.44(t,3 H,J=7.15Hz),1.41
(s,9 H),1.37(t,3 H,J=7.03Hz)。
1H 製備4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸
向4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸乙酯(實例1G,5.32g,9.9mmol)存於乙醇(49.5mL)中之溶液中添加1N NaOH水溶液(49.5mL)。將反應混合物在60℃下加熱3h並冷卻至室溫。藉由在真空中濃縮來移除乙醇。使用1N HCl酸化殘留物,並藉由真空過濾來收集產物。在真空中乾燥後分離得到白色固體狀4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸(4.3g,8.44mmol,經兩步驟產率為85%)。
MS(ESI)m/z 510.0(M+H)。
1I 製備7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯
向4-(第三丁氧基羰基(2,4-二甲氧基苄基)胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲酸(實例1H,0.89g,1.747mmol)存於乙腈(17.47mL)中之混合物中添加二環丙基胺鹽酸鹽(0.303g,2.271mmol)、N-甲基嗎啉(0.499mL,4.54mmol)、DMAP
(0.021g,0.175mmol)及HATU(0.797g,2.096mmol)。將反應混合物在室溫下攪拌5h並加熱至50℃,保持45min。將反應物冷卻至室溫。在真空中移除乙腈,並將殘留物分配於飽和碳酸氫鈉水溶液與二氯甲烷之間。用二氯甲烷萃取水性層。合併之有機層經無水硫酸鈉乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 80g管柱使用1-4% MeOH/CH2Cl2溶析對粗固體進行純化,獲得米色固體狀7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(0.8g,78%產率)。
MS(ESI)m/z 589.0(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.78(s,1 H),7.67(d,1 H,J=8.28Hz),6.85(s,1 H),6.40(dd,1 H,J=8.41,2.38Hz),6.33(d,1 H,J=2.51Hz),5.20(s,2 H),4.58(q,2 H,J=7.03Hz),4.02(s,3 H),3.74(s,3 H),3.62(s,3 H),2.77-2.85(m,2 H),1.42(s,9 H),1.39(t,3 H,J=7.40Hz),0.80-0.89(m,4 H),0.72-0.78(m,4 H)。
1J 製備4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基(2,4-二甲氧基苄基)胺基甲酸第三丁基酯(實例1I,2.66g,4.51mmol)存於二氯甲烷(33.8mL)中之溶液中添加TFA(11.28mL)。將反應混合物在室溫下攪拌45min,並在真空中濃縮。將粗殘留物分配於乙酸乙酯與飽和碳酸氫鈉水溶液之間。使用乙酸乙酯(2 x)萃取水性層,並將合併之有機物經無水硫酸鈉乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 40g管柱使用4-10%
MeOH/CH2Cl2溶析對粗固體進行純化,獲得淺黃色固體狀4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(1.2g,3.55mmol,79%產率)。
MS(ESI)m/z 339.2(M+H)。
1H NMR(400MHz,MeOD)δ ppm 7.95(s,1 H),7.15(s,1 H),4.51(q,2 H J=7.13Hz),4.04(s,3 H),2.89-2.98(m,2 H),1.35(t,3 H),0.82-0.91(m,4 H),0.70-0.81(m,4 H)。
1 製備N,N-二環丙基-6-乙基-1-甲基-4-(噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,30mg,0.089mmol)、2-溴噻唑(11.98μL,0.133mmol)、Pd2(dba)3(12.18mg,0.013mmol)、BINAP(24.84mg,0.040mmol)及第三丁醇鈉(13.63mg,0.142mmol)之混合物中添加PhMe(887μL)。向混合物中通氬氣5min並加熱至85℃,保持5.5h。通過矽藻土塞過濾反應混合物並濃縮。藉由製備型HPLC對粗殘留物進行純化,提供N,N-二環丙基-6-乙基-1-甲基-4-(噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(4mg,10.49%產率)與一些回收的起始材料。
MS(ESI)m/z 423.0(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 8.14(s,1H),7.47(d,1H,J=3.57Hz),7.24(s,1H),7.14(d,1H,J=3.57Hz),4.63(q,2H,J=6.87Hz),4.05(s,3H),2.88-2.99(m,2H),1.39(t,3H,J=7.01Hz),0.73-0.81(m,4H),0.64-0.70(m,4H)。
2A 製備4-(3-苯甲醯基硫脲基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,234mg,0.69mmol)及異硫氰酸苯甲醯酯(0.1ml,0.83mmol)存於丙酮(3ml)中之溶液在室溫下攪拌3h。將反應混合物冷卻至0℃並添加水。藉由過濾收集所得褐色固體並實施空氣乾燥,得到4-(3-苯甲醯基硫脲基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(306mg,88%產率)。
MS(ESI)rt=1.86min,m/z 502(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.44(br.s.,1 H)7.99-8.07(m,2 H)7.64-7.74(m,1 H)7.58(t,J=7.65Hz,2 H)7.34(s,1 H)4.47(br.s.,2 H)4.11(s,3 H)2.90-2.99(m,2 H)2.08(s,1 H)1.28(br.s.,3 H)0.64-0.81(m,8 H)。
2B 製備N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將存於10ml EtOH中之4-(3-苯甲醯基硫脲基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2A,306mg,0.61mmol)及1N NaOH(10ml,10.00mmol)在60℃下加熱1h。將反應物冷卻至室溫並濃縮。使用乙酸乙酯萃取(3x)剩餘水溶液。有機相經Na2SO4乾燥,過濾並濃縮。藉由矽膠層析(二氯甲烷/甲醇0-4%)進行純化,得到黃色固體狀N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(199mg,82%產率)。
MS(ESI)m/z 398(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 11.02(br.s.,1 H)9.27(s,2 H)7.75(s,1 H)6.89(s,1 H)4.52(q,J=7.12Hz,2 H)4.06(s,3 H)2.77-2.90(m,2 H)1.45(t,J=7.15Hz,3 H)0.73-0.97(m,8 H)。
2 製備N,N-二環丙基-6-乙基-1-甲基-4-(4-甲基噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將存於EtOH(2ml)中之N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B,40mg,0.10mmol)及氯丙酮(62.4mg,0.40mmol)在80℃下加熱20min。將反應物冷卻至室溫並在真空中移除溶劑。添加飽和NaHCO3溶液,並使用二氯甲烷萃取(3x)水性層。合併有機層,經Na2SO4乾燥,過濾並濃縮。藉由矽膠層析(二氯甲烷/甲醇0-7%)對粗物質進行純化,提供白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(4-甲基噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(9mg,12%產率)。
MS(CI)m/z 436.1(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 10.70(br s,1H),8.12(s,1H),7.23(s,1H),6.69(s,1H),4.61(q,2H,J=7.19Hz),4.04(s,3H),2.88-2.98(m,2H),2.29(s,3H),1.38(t,3H,J=7.15Hz),0.72-0.81(m,4H),0.62-0.70(m,4H)。
3A 製備1-溴-3-氟丙-2-酮
將溴(0.36ml,7.02mmol)逐滴添加至1-氟丙-2-酮(0.51ml,7.02mmol)存於四氯化碳(25ml)中之溶液中。將溶液在45℃下加熱3h。將反應物冷卻至室溫並用水驟冷。使用二氯甲烷(3x)萃取後,合併之有機層經Na2SO4乾燥,過濾並濃縮。藉由矽膠層析(0-20% EtOAc/己烷)進行純化,得到黃色油狀1-溴-3-氟丙-2-酮(118mg,65%)。
1H NMR(400MHz,氯仿-d)δ ppm 5.14(s,1 H)5.02(s,1 H)4.10(d,J=2.86Hz,2 H)。
3 製備N,N-二環丙基-6-乙基-4-(4-(氟甲基)噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
使用與2相同之程序自N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)及1-溴-3-氟丙-2-酮(實例3A)製備。
MS(ESI)rt=1.94min,m/z 454(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 9.34(br.s.,1 H)7.75(s,1 H)6.96(d,J=3.52Hz,1 H)6.90(s,1 H)5.27-5.53(m,2 H)4.75(q,J=7.12Hz,2 H)3.98-4.11(m,3 H)2.76-2.91(m,2 H)1.54(t,J=7.04Hz,3 H)0.70-0.94(m,8 H)。
使用與對於2所報告程序相同之程序自N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)及1-氯-3,3-二甲基丁-2-酮製備。
MS(ESI)rt=1.99min,m/z 478(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.74(s,1 H)6.90(s,1 H)6.48(s,1 H)4.74(q,J=7.03Hz,1 H)4.04(s,3 H)2.77-2.90(m,2 H)1.53(t,J=7.03Hz,3 H)1.37(s,9 H)0.70-0.96(m,8 H)。
5A 製備1-氯-1-(異丙基磺醯基)丙-2-酮
在0℃下,將磺醯氯(0.248mL,3.05mmol)逐滴添加至1-(異丙基磺醯基)丙-2-酮(418mg,2.55mmol)存於1:1 AcOH/DCM(16ml)中之溶液中。將反應物在室溫下攪拌4h。在真空中移除溶劑,隨後使用二氯甲烷稀釋。有機層使用飽和NaHCO3溶液洗滌(2x),經Na2SO4乾燥,過濾並濃縮,留下800mg無色油狀物。該物質未經進一步純化即使用。
1H NMR(500MHz,氯仿-d)δ ppm 5.19(s,1 H)3.65(dt,J=13.66,6.90Hz,1 H)2.56(s,3 H)1.45(dd,J=6.94,3.05Hz,6 H)。
5 製備N,N-二環丙基-6-乙基-4-(4-(異丙基磺醯基甲基)噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
使用與對於2所報告程序相同之程序自N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)及1-氯-1-(異丙基磺醯基)丙-2-酮(實例5a)製備。
MS(ESI)rt=1.84min,m/z 542(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.82(s,1 H)7.01(s,1 H)6.90(s,1 H)4.73(q,J=7.04Hz,2 H)4.35(s,2 H)4.06(s,3 H)3.36(quin,J=6.88Hz,1 H)2.79-2.91(m,2 H)1.53(t,J=7.04Hz,3 H)1.43(d,J=6.82Hz,6 H)0.74-0.92(m,8 H)。
使用與對於2所報告程序相同之程序自N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)及1-溴戊-2-酮製備。
MS(ESI)rt=1.94min,m/z 464(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.43-9.78(m,1 H)7.71(s,1 H)6.89(s,1 H)6.48(s,1 H)4.75(q,J=7.04Hz,2 H)4.04(s,3 H)2.76-2.92(m,2 H)2.68(t,J=7.37Hz,2 H)1.76(dq,J=14.94,7.42Hz,2 H)1.53(t,J=7.04Hz,3 H)1.01(t,J=7.26Hz,3 H)0.69-0.94(m,8 H)。
使用與對於2所報告程序相同之程序自N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)及1-溴丁-2-酮製備。
MS(ESI)m/z 450(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.71(s,1 H)6.89(s,1 H)6.49(s,1 H)4.75(q,J=7.03Hz,2 H)4.04(s,3 H)2.80-2.88(m,2 H)2.75(q,J=7.45Hz,1 H)1.54(t,J=7.15Hz,2 H)1.33(t,J=7.40Hz,2 H)0.82(br.s.,8 H)。
將4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,70mg,0.21mmol)及異硫氰酸苯甲醯酯(36μl,0.27mmol)存於丙酮(1ml)中之溶液在室溫下攪拌1.5h。在真空中移除溶劑,將殘留物溶解於EtOH(1.5ml)中,並添加K2CO3(40mg,0.290mmol)。將反應物在60℃下加熱3h。冷卻至室溫後,添加2-溴-1-(吡啶-2-基)乙酮氫溴酸鹽(139.4mg,0.50mmol),並將反應物在80℃下加熱24h。將反應混合物冷卻至室溫並濃縮。藉由矽膠層析(0-7% MeOH/二氯甲烷)對殘留物進行純化。藉由製備型HPLC再次純化,提供10.2mg(10%產率)褐色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(4-(吡啶-2-基)噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)rt=1.78min,m/z 499(M+H)。
1H NMR(DMSO-d6)δ ppm 10.9(s,1 H),8.2(bs,1 H),7.81(d,1 H),7.75(s,1H),3.92(m,4H),3.77(q,2H,J=7.8Hz),2.52-2.81(m,7H)。
按照實例2使用3-溴-1,1,1-三氟丙酮來製備該化合物,以提供N,N-二環丙基-6-乙基-1-甲基-4-(4-(三氟甲基)噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)m/z 490.0(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 11.71(s,1H),8.16(s,1H),7.86(s,1H),7.27(s,1H),4.63(q,2H),4.05(s,3H),2.89-2.98(m,2H),1.40(t,3H,J=6.87Hz),0.74-0.80(m,4H),0.64-0.71(m,4H)。
將4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,86.3mg,0.255mmol)溶解於丙酮中,並添加異硫氰酸苯甲醯酯(37.8μL,0.281mmol)。將反應物在室溫下攪拌2h。在真空中移除溶劑。將殘留物溶解於乙醇(1500μL)中,並添加K2CO3(49.3mg,0.357mmol)。將反應混合物升溫至60℃,保持3h。添加2-溴丙醛(45.4mg,0.332mmol)。3h後,再添加2-溴丙醛(約100mg)。在60℃下攪拌16h。再添加2-溴丙醛,並將反應混合物在60℃下攪拌3h。藉由在真空中濃縮來移除乙醇。藉由急驟層析使用Isco 12g管柱使用2-10% MeOH/CH2Cl2溶析對粗殘留物進行純化。經由製備型HPLC再次實施純化。分離得到白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(20mg,17.47%產率)。
MS(ESI)m/z 436.0(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 10.56(br s,1H),8.12(s,1H),7.23(s,1H),7.12(s,1H),4.62(q,2H,J=6.78Hz),4.04(s,3H),2.87-2.99(m,2H),2.39(s,3H),1.35-1.46(m,3H),0.72-0.81(m,4H),0.59-0.71(m,4H)。
使用與實例8相同之程序自2-溴丁醛及4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J)製備。
MS(ESI)rt=1.86min,m/z 450(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 8.91-9.22(m,1 H)7.71(s,1 H)7.14(s,1 H)6.89(s,1 H)4.75(q,J=6.94Hz,2 H)4.05(s,3 H)2.80-2.89(m,4 H)1.55(t,J=5.00Hz,3 H)1.37(t,J=7.49Hz,3 H)0.73-0.92(m,8 H)。
12A 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-4-甲酸
將存於丙酮(4ml)中之4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-
二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(1J,300mg,0.89mmol)及異硫氰酸苯甲醯酯(0.16ml,1.15mmol)在室溫下攪拌1.5h。在真空中移除溶劑,並將殘留物溶解於EtOH(6ml)中。添加K2CO3(172mg,1.241mmol),並將反應物在60℃下加熱3h。將反應物冷卻至室溫,並添加3-溴-2-側氧基丙酸乙酯(692mg,3.55mmol)。將反應物在70℃下加熱過夜。環化步驟完成後,向反應混合物中添加1N NaOH(6.3ml,6.30mmol),並在60℃下加熱4h。將反應物冷卻至室溫,並在真空中移除溶劑。將剩餘水溶液酸化至pH 1並藉由真空過濾移除沉澱,使用水、EtOAc及隨後二氯甲烷洗滌,獲得褐色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-4-甲酸(325mg,79%產率)。
MS(ESI)rt=1.85min,m/z 466(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.16(s,1 H)7.94(s,1 H)7.26(s,1 H)4.63(q,J=6.94Hz,2 H)4.05(s,3 H)3.36(br.S.,1 H)2.89-2.99(m,2 H)1.40(t,J=7.03Hz,3 H)0.61-0.83(m,8 H)。
12 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N-二甲基噻唑-4-甲醯胺
向存於DMF(2ml)中之2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-4-甲酸(實例12A,44mg,0.095mmol)中添加HATU(108mg,0.284mmol)、DIPEA(0.066mL,0.378mmol)及二甲基胺(0.013mL,0.189mmol)。將反應物在室溫下攪拌3h,隨後在真空中移除溶劑。藉由製備型HPLC對殘留物進行純化,得到褐色固體狀2-(7-(二環丙基胺甲醯基)-
6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N-二甲基噻唑-4-甲醯胺(10mg,21%產率)。
MS(ESI)m/z 493(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 9.45(br.S.,1 H)7.81(s,1 H)7.43(s,1 H)6.90(s,1 H)4.74(q,J=7.03Hz,2 H)4.05(s,3 H)3.31(br.S.,3 H)3.13(br.S.,3 H)2.75-2.90(m,2 H)1.54(t,J=7.15Hz,3 H)0.65-0.96(m,8 H)。
使用對於實例12所述之程序來製備實例13-17。
MS(ESI)rt=1.99min,m/z 505(M+H)。
1H NMR(400MHz,MeOD)δ ppm 8.07(s,1 H)7.74(s,1 H)7.26(s,1 H)4.73(q,J=7.03Hz,1 H)4.13(s,3 H)2.94-3.04(m,2 H)2.85-2.93(m,1 H)1.51(t,J=7.03Hz,2 H)0.67-0.95(m,12 H)。
MS(ESI)rt=1.87min,m/z 535(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 9.21(br.s.,1 H)7.76(s,1 H)7.56
(s,1 H)6.81-6.94(m,1 H)4.74(q,J=7.11Hz,2 H)4.07(s,3 H)3.79(br.s.,4 H)3.50(d,J=4.52Hz,2 H)2.74-2.90(m,2 H)1.60(s,2 H)1.54(t,J=7.03Hz,3 H)0.70-0.94(m,8 H)。
MS(ESI)rt=1.88min,m/z 583(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 9.31(br.s.,1 H)7.77(s,1 H)7.69-7.75(m,1 H)6.91(s,1 H)4.85-4.99(m,1 H)4.64-4.81(m,2 H)4.07(s,3 H)3.45-3.61(m,2 H)3.35(br.s.,1 H)3.19(dt,J=13.36,8.12Hz,2 H)2.75-2.91(m,2 H)2.57-2.72(m,1 H)2.42(ddd,J=14.49,7.53,7.34Hz,1 H)1.54(t,J=6.90Hz,3 H)0.69-0.94(m,8 H)。
MS(ESI)rt=2.05min,m/z 555(M+H)。
1H NMR(400MHz,MeOD)δ ppm 8.00(s,1 H)7.73(s,1 H)7.70(s,1 H)7.19(s,1 H)4.68(q,J=7.03Hz,2 H)4.51(t,J=12.80Hz,1 H)4.34(t,J=7.40Hz,1 H)4.06(s,3 H)3.96(t,J=13.18Hz,1 H)3.86(t,
J=7.65Hz,1 H)2.87-3.02(m,2 H)2.34-2.59(m,2 H)1.45(t,J=6.90Hz,3 H)0.72-0.95(m,8 H)。
MS(ESI)rt=1.95min,m/z 505(M+H)。
1H NMR(400MHz,MeOD)δ ppm 8.03(s,1 H)7.70(s,1 H)7.21(s,1 H)4.78(t,J=7.53Hz,2 H)4.69(q,J=7.03Hz,2 H)4.19(t,J=7.78Hz,2 H)4.08(s,3 H)2.95(ddd,J=7.22,3.45,3.14Hz,2 H)2.27-2.48(m,2 H)1.47(t,J=7.03Hz,3 H)0.69-0.93(m,8 H)。
按照實例2使用溴丙酮酸乙酯及N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)來製備該化合物,以獲得黃色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-4-甲酸乙酯。
MS(ESI)m/z 494.1(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 11.42(br s,1H),8.14(s,1H),
8.00(s,1H),7.25(s,1H),4.62(q,2H),4.30(q,2H,J=7.15Hz),4.05(s,3H),2.89-2.97(m,2H),1.39(t,3H,J=7.01Hz),1.32(t,3H,J=7.15Hz),0.74-0.80(m,4H),0.64-0.70(m,4H)。
按照實例2使用2-氯-2-甲醯基乙酸乙酯及N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B)來製備該化合物,以提供淺黃色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸乙酯(18.5mg,17%產率)。
MS(ESI)m/z 494.0(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 11.95(s,1H),8.20(s,1H),8.14(s,1H),7.28(s,1H),4.63(q,2H,J=7.19Hz),4.28(q,2H,J=7.19Hz),4.06(s,3H),2.88-3.00(m,2H),1.44(t,3H,J=7.03Hz),1.32(t,3H,J=7.15Hz),0.73-0.81(m,4H),0.63-0.70(m,4H)。
20A 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸
向2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸乙酯(實例19,14.6mg,0.030mmol)存於EtOH(296μL)中之溶液中添加1N NaOH水溶液(296μL)。將反應混合物在室溫下攪拌3h並在50℃下攪拌18h。冷卻至室溫後,藉由在真空中濃縮來移除乙醇。使用1N HCl酸化殘留物,並藉由過濾來收集固體產物。分離得到淺黃色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸,其未經處理即用於下一反應中。
MS(ESI)m/z 465.9(M+H)。
20 製備N-環丙基-2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲醯胺
向2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸(實例20A,13.97mg,0.030mmol)存於DMF(300μL)中之混合物中添加環丙基胺(4.16μL,0.060mmol)、HATU(14.83mg,0.039mmol)及Hünig鹼(15.72μL,0.090mmol)。將反應混合物在室溫下攪拌1h,並在真空中濃縮。將殘留物溶解於MeOH中並藉由製備型HPLC進行純化。分離得到白色固體狀N-環丙基-2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲醯胺(3mg,19.82%產率)。
MS(ESI)m/z 505.0(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.36(br s,1H),8.15(s,1H),8.02(s,1H),7.25(s,1H),4.63(q,2H,J=7.11Hz),4.05(s,3H),2.89-3.00(m,2H),2.76(tq,1H,J=7.25,3.70Hz),1.41(t,3H,J=7.03Hz),0.74-0.81(m,4H),0.64-0.72(m,6H),0.51-0.59(m,2H)。
按照實例20使用嗎啉及2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸(實例20A)來製備該化合物,以提供白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(5-(嗎啉-4-羰基)噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)m/z 535.1(M+H)。
1H NMR(400MHz,MeOD)δ ppm 8.08(s,1H),7.79-7.93(m,1H),7.26(s,1H),4.74(q,2H,J=7.28Hz),4.12(s,3H),3.81-3.88(m,2H),3.72-3.80(m,2H),2.91-3.02(m,2H),1.52(t,3H,J=7.15Hz),0.83-0.93(m,4H),0.72-0.84(m,4H)。
按照實例20使用吡咯啶及2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸(實例20A)來製備該化合物,以提供N,N-二環丙基-6-乙基-1-甲基-4-(5-(吡咯啶-1-羰基)噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)m/z 519.1(M+H)。
1H NMR(400MHz,甲醇-d4)δ 8.58(s,1H),7.97(s,1H),7.28(s,1H),4.71(q,J=6.7Hz,2H),4.20(s,3H),3.87(t,J=6.5Hz,2H),3.67(t,J=6.7Hz,2H),2.97-3.05(m,2H),2.10-2.19(m,2H),1.98-2.07(m,2H),1.51(t,J=7.2Hz,3H),0.88-0.95(m,4H),0.80-0.86(m,4H)。
按照實例20使用N-甲基丙-2-胺及2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸(實例20A)來製備該化合物,以提供2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N-異丙基-N-甲基噻唑-5-甲醯胺。
MS(ESI)m/z 521.1(M+H)。
1H NMR(400MHz,甲醇-d4)δ:8.68(s,1H),7.87(s.,1H),7.32(s,1H),4.74(q,J=7.0Hz,2H),4.24(s,3H),3.18(br.s.,3H),2.99-3.06(m,2H),1.53(t,J=7.0Hz,3H),1.35(d,J=6.8Hz,6H),0.89-0.96(m,4H),0.81-0.88(m,4H)。
按照實例20使用N,N-二甲基胺及2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)噻唑-5-甲酸(實例20A)來製備該化合物,以得到2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N-二甲基噻唑-5-甲醯胺。
MS(ESI)m/z 493.1(M+H)。
1H NMR(400MHz,甲醇-d4)δ:8.56(s,1H),7.91(s,1H),7.31(s,1H),4.72(q,J=7.0Hz,1H),4.22(s,3H),3.15-3.45(br.S,6 H),2.97-3.05(m,2H),2.91(s,1H),1.54(t,J=7.0Hz,3H),0.88-0.95(m,4H),0.80-0.86(m,4H)。
按照實例20來製備該化合物。
MS(ESI)m/z 597.0(M+H)。
1H NMR(400MHz,甲醇-d4)δ:8.74(s,1H),7.99(s,1H),7.37(s,1H),5.34-5.45(m,1H),4.78(q,J=6.9Hz,2H),4.28(s,3H),4.05(s,3H),3.49-3.59(m,1H),3.22-3.33(m,1H),3.00-3.10(m,2H),2.94(s,1H),2.47-2.66(m,2H),1.57(t,J=6.9Hz,3H),1.34-1.45(M,1H),0.91-0.99(m,J=6.5Hz,4H),0.83-0.90(m,4H)。
按照實例2使用3-溴-2-丁酮(0.034mL,0.323mmol)來製備該化合物,以提供淺黃色固體狀N,N-二環丙基-4-(4,5-二甲基噻唑-2-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(59.17mg,44.3%產率)。
MS(ESI)m/z 450.1(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.15(s,1H),7.23(s,1H),4.61(q,2H,J=7.03Hz),4.04(s,3H),2.88-2.98(m,2H),2.29(s,3H),2.19(s,3H),1.38(t,3H,J=7.03Hz),0.73-0.80(m,4H),0.62-0.71(m,4H)。
使用與實例2類似之程序來製備。
MS(ESI)rt=1.95min,m/z 462(M+H)。
1H NMR(500MHz,MeOD)δ ppm 8.12(s,1 H)7.22(s,1 H)4.68(q,J=7.12Hz,2 H)4.10(s,3 H)2.86-3.02(m,4 H)2.80(t,J=7.07Hz,2 H)2.43-2.61(m,2 H)1.46(t,J=7.07Hz,3 H)0.70-0.90(m,8 H)。
28A 製備2-溴戊-3-酮
按照闡述於Chem.Comm.2004,470-471中之程序來製備。
28 製備N,N-二環丙基-6-乙基-4-(4-乙基-5-甲基噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
使用與實例2類似之程序自實例26A來製備。
MS(ESI)m/z 464(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.81-9.19(m,1 H)7.69(s,1 H)6.89(s,1 H)4.75(q,J=7.12Hz,2 H)4.03(s,3 H)2.78-2.93(m,2 H)2.63(q,J=7.48Hz,2 H)2.37(s,3 H)1.53(t,J=7.04Hz,3 H)1.26(t,J=7.48Hz,3 H)0.73-0.95(m,8 H)。
按照實例2使用3-溴-1,1,1-三氟丁-2-酮來製備該化合物,以提供白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基-4-(三氟甲基)噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)m/z 504.0(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 8.14(s,1H),7.25(s,1H),4.62(q,2H,J=6.97Hz),4.04(s,3H),2.89-2.98(m,2H),1.40(t,3H,J=6.87Hz),0.73-0.80(m,4H),0.65-0.71(m,4H)。
30A 製備1-溴-1-(甲基磺醯基)丙-2-酮
向圓底燒瓶中存於AcOH(7.34mL)及二氯甲烷(11.02mL)中之甲烷磺醯基丙酮(0.5g,3.67mmol)溶液中逐滴添加溴(0.189mL,3.67mmol)。將反應混合物在室溫下攪拌90min。在真空中移除溶劑。將殘留物溶解於醚中並用飽和碳酸氫鈉水溶液(2 x)洗滌。在真空中濃縮有機物。分離得到油狀1-溴-1-(甲基磺醯基)丙-2-酮(0.332g,42%產率)。
MS(CI)m/z 215.0(M+H)。
30 製備N,N-二環丙基-6-乙基-1-甲基-4-(4-甲基-5-(甲基磺醯基)
噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
按照實例1使用1-溴-1-(甲基磺醯基)丙-2-酮(28A,32.5mg,0.151mmol)來製備該化合物,以提供米色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(4-甲基-5-(甲基磺醯基)噻唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(12.5mg,0.023mmol,30.6%產率)。
MS(ESI)m/z 514.1(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 12.00(br s,1H),8.18(s,1H),7.27(s,1H),4.59(q,2H,J=6.78Hz),4.06(s,3H),3.29(s,3H),2.88-2.98(m,2H),2.53(s,3H),1.41(t,3H,J=6.90Hz),0.72-0.81(m,4H),0.62-0.71(m,4H)。
按照實例2使用1,1-二氯丙-2-酮(14.26μL,0.147mmol)來製備該化合物,以提供淺綠色固體狀4-(5-氯-4-甲基噻唑-2-基胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(4.35mg,18.9%產率)。
MS(ESI)m/z 470.1(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 11.34(s,1H),8.14(s,1H),7.25(s,1H),4.58(q,2H,J=7.28Hz),4.04(s,3H),2.88-2.98(m,2H),2.25(s,3H),1.40(t,3H,J=6.90Hz),0.73-0.81(m,4H),0.63-0.70(m,4H)。
按照實例2使用2-氯-5,5-二甲基環己烷-1,3-二酮(34.9mg,0.200mmol)來製備該化合物,以提供淺黃色固體狀N,N-二環丙基-4-(5,5-二甲基-7-側氧基-4,5,6,7-四氫苯并[d]噻唑-2-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(11.24mg,21.7%產率)。
MS(ESI)m/z 518.2(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 11.93(s,1H),8.19(s,1H),7.28(s,1H),4.62(q,2H),4.06(s,3H),2.89-2.98(m,2H),2.80(s,2H),2.40(s,2H),1.41(t,3H,J=7.03Hz),1.09(s,6H),0.73-0.80(m,4H),0.63-0.71(m,4H)。
33A 製備3-溴二氫-2H-噻喃-4(3H)-酮
向四氫噻喃-4-酮(0.5g,4.30mmol)存於二氯甲烷(51.2mL)及甲醇(20.49mL)中之混合物中添加四正丁基三溴化銨(2.283g,4.73mmol)。將反應混合物在室溫下攪拌2.5h。在真空中移除溶劑。使用醚(3 x)研磨粗固體。合併之醚層經無水硫酸鎂乾燥,過濾並在真空中濃縮。分離得到淺橙色油狀產物。物質直接用於下一反應中。
33B 製備3-溴-1,1-二側氧基-四氫-1λ
6
-噻喃-4-酮
向存於二氯甲烷(20.27mL)中之經冷卻(0℃)3-溴二氫-2H-噻喃-4(3H)-酮(實例33A,0.791g,4.05mmol)中緩慢添加mCPBA(1.749g,10.14mmol)。使反應混合物升溫至室溫。使用飽和碳酸氫鈉水溶液驟冷反應混合物。用二氯甲烷(2 x)萃取水性層。合併之有機物經無水硫酸鎂乾燥,過濾並在真空中濃縮,獲得白色固體狀3-溴-1,1-二側氧基-四氫-1λ6-噻喃-4-酮,其直接用於下一反應中。
33 製備4-(5,5-二側氧基-4,5,6,7-四氫-5λ
6
-噻喃并[4,3-d]噻唑-2-基胺基)-6-乙基-1-甲基-1,6-二氫-1,3,5,6-四氮雜-不對稱-引達省-7-甲酸二環丙基醯胺
按照實例1使用3-溴-1,1-二側氧基-四氫-1λ6-噻喃-4-酮(實例33B,32.5mg,0.151mmol)來製備該化合物,以提供淺棕褐色固體狀4-(5,5-二側氧基-4,5,6,7-四氫-5λ6-噻喃并[4,3-d]噻唑-2-基胺基)-6-乙基-1-甲基-1,6-二氫-1,3,5,6-四氮雜-不對稱-引達省-7-甲酸二環丙基醯胺(9mg,17.56%產率)。
MS(ESI)m/z 526.2(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.16(s,1H),7.25(s,1H),4.61(q,2H,J=6.78Hz),4.54(s,2H),4.04(s,3H),3.49(7,2H,J=6.02Hz),
3.16(t,2H,J=8.16Hz),2.89-2.97(m,2H),1.38(t,3H,J=7.03Hz),0.73-0.79(m,4H),0.61-0.70(m,4H)。
按照實例2使用3-氯-2,4-戊烷二酮(36.0μL,0.302mmol)來製備該化合物,以提供淺黃色固體狀4-(5-乙醯基-4-甲基噻唑-2-基胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(76mg,100%產率)。
MS(ESI)m/z 478.2(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.31(s,1H),7.28(s,1H),4.62(q,2H,J=6.94Hz),4.08(s,3H),2.89-2.99(m,2H),2.61(s,3H),1.44(t,3H,J=7.03Hz),0.72-0.81(m,4H),0.64-0.72(m,4H)。
35A 製備3-溴六氫吡啶-2,4-二酮
向六氫吡啶-2,4-二酮(0.072g,0.637mmol)存於乙酸(1.591mL)中
之混合物中逐滴添加溴(0.033mL,0.637mmol)。將反應混合物在室溫下攪拌70min。添加二氯甲烷,並在真空中濃縮該渾濁混合物。使用乙基醚處理殘留溶液。沉墜出白色固體,並輕輕倒出AcOH/醚。推測為產物之白色固體用於下一步驟中。在暴露於光及靜置後,白色固體迅速開始液化並變成紅色。
35 製備N,N-二環丙基-6-乙基-1-甲基-4-(4-側氧基-4,5-二氫噻唑并[5,4-c]吡啶-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
按照實例2使用3-溴六氫吡啶-2,4-二酮(實例35A)來製備該化合物,以提供白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(4-側氧基-4,5-二氫噻唑并[5,4-c]吡啶-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(4.51mg,12.3%產率),其含有10%的N,N-二環丙基-6-乙基-1-甲基-4-(4-側氧基-4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)m/z 489.1(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.20(s,1H),7.32-7.47(m,1H),7.29(s,1H),6.62(d,1H,J=7.03Hz),4.66(q,2H,J=7.19Hz),4.07(s,3H),2.88-3.06(m,2H),1.44(t,3H,J=7.03Hz),0.72-0.85(m,4H),0.60-0.72(m,4H)。
按照實例2使用3-溴-4-側氧基-六氫吡啶-1-甲酸乙酯來製備該化合物,以提供白色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-6,7-二氫噻唑并[5,4-c]吡啶-5(4H)-甲酸乙酯(5mg,15.36%產率)。
MS(ESI)m/z 549.2(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 10.83(br s,1H),8.12(s,1H),7.23(s,1H),4.56-4.67(m,4H),4.10(q,2H,J=7.19Hz),4.04(s,3H),3.72(t,2H,J=5.52Hz),2.87-2.98(m,2H),2.64-2.73(m,2H),1.38(t,3H,J=7.03Hz),1.22(t,3H,J=7.15Hz),0.71-0.81(m,4H),0.60-0.71(m,4H)。
按照實例2使用3-溴六氫吡啶-4-酮氫溴酸鹽(33.8mg,0.130mmol)來製備該化合物,以提供淺黃色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(4,5,6,7-四氫噻唑并[5,4-c]吡啶-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(30mg,60%產率)。
MS(ESI)m/z 477.3(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 9.08(br s,2H),8.25(s,1H),7.27(s,1H),4.63(q,2H,J=6.78Hz),4.38(br s,2H),4.06(s,3H),2.85-2.98(m,4H),1.38(t,3H,J=7.03Hz),0.73-0.81(m,4H),0.62-0.71(m,4H)。
向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,60mg,0.177mmol)、2-氯噻唑-5-甲腈(38.5mg,0.266mmol)、Pd2(dba)3(24.4mg,0.027mmol)、BINAP(49.7mg,0.080mmol)及第三丁醇鈉(27.3mg,0.284mmol)之混合物中添加DME(1ml)。混合物用氬氣吹掃5min並加熱至85℃,保持3h。藉由HPLC顯示反應混合物約60%轉化,通過矽藻土塞進行過濾並濃縮。藉由製備型HPLC對粗產物進行純化,獲得米色固體狀4-(5-氰基噻唑-2-基胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。
MS(ESI)m/z 447.2(M+H)。
1H NMR(500MHz,CD3OD-CDCl3)δ:8.60(s,1H),8.04(s,1H),7.56(s,4H),7.13(s,1H),4.71(q,J=7.1Hz,2H),4.20(s,3H),2.84-2.91(m,2H),1.52(t,J=7.1Hz,3H),0.83-0.90(m,5H),0.74-0.80(m,4H)。
向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,21.2mg,0.063mmol)存於DMF
(626μL)中之溶液中一次性添加氫化鈉(10.02mg,0.251mmol)。20min後,添加2-溴-1,3-苯并噻唑(53.6mg,0.251mmol)。將反應混合物在室溫下攪拌16h。反應混合物用水驟冷並用乙酸乙酯稀釋。用乙酸乙酯萃取水性層。合併之有機物用10% LiCl洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 4g管柱使用0-5% MeOH/CH2Cl2溶析對粗殘留物進行純化,獲得米色固體狀4-(苯并[d]噻唑-2-基胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(6.8mg,21.87%產率)。
MS(ESI)m/z 472.2(M+H)。
1H NMR(500MHz,DMSO-d6)δ ppm 8.17(s,1H),7.95(d,1H,J=7.97Hz),7.67(d,1H,J=8.25Hz),7.39(t,1H,J=7.97Hz),7.27(s,1H),7.22(t,1H,J=8.52Hz),4.70(q,2H,J=7.06Hz),4.06(s,3H),2.88-2.99(m,2H),1.65(br s,1H),1.45(t,3H,J=7.01Hz),0.74-0.84(m,4H),0.64-0.73(m,4H)。
40A 製備5-氟-2-(甲硫基)苯并[d]噻唑
向5-氟-2-巰基苯并噻唑(0.15g,0.810mmol)存於THF(8.10mL)中之冷卻至0℃的溶液中添加氫化鈉(0.036g,0.891mmol)。攪拌10min後,添加碘甲烷(0.076mL,1.215mmol),並使反應混合物經2h緩慢
升溫至室溫。反應物用乙酸乙酯稀釋並用飽和碳酸氫鈉水溶液驟冷。有機層用鹽水洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮。分離得到白色固體狀5-氟-2-(甲硫基)苯并[d]噻唑(0.178g,110%產率)。物質未經任何進一步純化即使用。
MS(ESI)m/z 200.0(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.68(dd,1H,J=8.81,5.04Hz),7.56(dd,1H,J=9.57,2.52Hz),7.07(td,1H,J=8.81,2.52Hz),2.80(s,3H)。
40B 製備5-氟-2-(甲基亞磺醯基)苯并[d]噻唑
將5-氟-2-(甲硫基)苯并[d]噻唑(實例40A,0.178g,0.893mmol)溶解於CH2Cl2(5.96mL)中。一次性添加mCPBA(0.154g,0.893mmol),並在室溫下攪拌反應混合物。反應物用飽和碳酸氫鈉水溶液驟冷並用二氯甲烷稀釋。用二氯甲烷(2 x)萃取水性層。合併之有機物用鹽水洗滌,經無水硫酸鎂乾燥,過濾並在真空中濃縮。分離得到白色固體狀5-氟-2-(甲基亞磺醯基)苯并[d]噻唑(0.180g,94%產率),其未經進一步純化即使用。
MS(ESI)m/z 216.0(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 7.97(dd,1H,J=9.07,4.95Hz),7.76(dd,1H,J=9.07,2.47Hz),7.27-7.34(m,1H),3.10(s,3H)。
40 製備N,N-二環丙基-6-乙基-4-(5-氟苯并[d]噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,50mg,0.148mmol)存於DMF(1.5mL)中之溶液中添加氫化鈉(17.73mg,0.443mmol)。20min後,一次
性添加5-氟-2-(甲基亞磺醯基)苯并[d]噻唑(實例40B,95mg,0.443mmol)。在室溫下攪拌反應混合物。反應混合物用乙酸乙酯稀釋並用水驟冷。使用乙酸乙酯(2 x)萃取水性層。合併之有機層使用10%氯化鋰溶液(2 x)洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮。藉由急驟層析使用Isco 12g管柱使用0-5% MeOH/CH2Cl2溶析對粗殘留物進行純化,以提供N,N-二環丙基-6-乙基-4-(5-氟苯并[d]噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(13mg,17.07%產率)。
MS(CI)m/z 490.2(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 11.53(br s,1H),8.19(s,1H),7.95-8.02(m,1H),7.47(d,1H,J=9.82Hz),7.28(s,1H),7.09(t,1H,J=8.18Hz),4.69(q,2H,J=7.13Hz),4.06(s,3H),2.89-3.02(m,2H),1.45(t,3H,J=7.05Hz),0.74-0.81(m,4H),0.63-0.71(m,4H)。
41A 製備N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
在圓底燒瓶中於氮氣中,向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(194.5mg,0.575
mmol)存於二氯甲烷(2874μL)中之混合物中添加1,1'-硫代羰基二-2(1H)-吡啶酮(133mg,0.575mmol)。將反應混合物在室溫下攪拌16h。在減壓下濃縮反應混合物。分離得到黃色黏性固體狀N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺。物質按原樣用於隨後反應中。
MS(ESI)m/z 381.1(M+H)。
41B 製備N,N-二環丙基-4-(3-(1,3-二甲基-1H-吡唑-5-基)硫脲基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向裝有N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例41A,0.0342g,0.090mmol)之燒瓶中添加THF(0.449mL)。添加5-胺基-1,3-二甲基吡唑(0.012g,0.108mmol),隨後添加氫化鈉(3.60mg,0.090mmol)。將反應混合物在室溫下攪拌16h。反應混合物用乙酸乙酯稀釋並用飽和碳酸氫鈉水溶液驟冷。用乙酸乙酯萃取水性層。合併之有機物經無水硫酸鈉乾燥,過濾並在真空中濃縮。粗物質未經進一步純化即使用。
MS(ESI)m/z 492.2(M+H)。
41 製備N,N-二環丙基-4-(1,3-二甲基-1H-吡唑并[3,4-d]噻唑-5-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將N,N-二環丙基-4-(3-(1,3-二甲基-1H-吡唑-5-基)硫脲基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例41B,41mg,0.083mmol)溶解於氯仿(2780μL)中並冷卻至0℃。緩慢添加NIS(18.76mg,0.083mmol),並使反應物升溫至室溫。濃縮反應混合
物。添加甲醇及醚,並過濾混合物。靜置一週後,自溶液中沉澱出產物。用甲醇研磨產物。分離得到淺黃色固體狀N,N-二環丙基-4-(1,3-二甲基-1H-吡唑并[3,4-d]噻唑-5-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(8.1mg,20%產率)。
MS(ESI)m/z 490.3(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 11.39(s,1H),8.17(s,1H),7.26(s,1H),4.66(q,2H,J=7.03Hz),4.05(s,3H),3.85(s,3H)2.88-3.00(m,2H),2.33(s,3H),1.43(t,3H,J=7.03Hz),0.72-0.82(m,4H),0.61-0.73(m,4H)。
將3-溴-2-側氧基丁酸甲酯(320mg,1.642mmol)添加至N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B,435mg,1.094mmol)存於EtOH(10ml)中之懸浮液中,並將反應混合物在65℃下加熱2h。在真空中移除溶劑,並藉由矽膠層析(2-10% MeOH/二氯甲烷)對殘留物進行純化,得到黃色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-5-甲基噻唑-4-甲酸甲酯(380mg,70%產率)。
MS(ESI)rt=0.87min,m/z 494(M+H)。
1H NMR(氯仿-d)δ:9.41(br.s.,1H),7.78(s,1H),6.89(s,1H),4.73(q,J=7.0Hz,2H),4.03(s,3H),3.95(s,3H),2.80-2.87(m,2H),2.77(s,
3H),1.54(t,J=7.0Hz,3H),0.83-0.90(m,4H),0.73-0.80(m,4H)。
43A 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-5-甲基噻唑-4-甲酸
將1N NaOH水溶液(0.962mL,0.962mmol)添加至2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-5-甲基噻唑-4-甲酸甲酯(實例41,0.19g,0.385mmol)存於乙醇(2mL)中之懸浮液中,並將混合物在60℃下加熱2h。將反應物冷卻至室溫並使用1N HCl酸化至pH 4。濃縮反應混合物並使用甲醇研磨殘留物5次。濃縮合併之甲醇洗滌物,並使用2:1醚/二氯甲烷洗滌剩餘固體3次,提供2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-5-甲基噻唑-4-甲酸(105mg,57%產率)。
MS(ESI)rt=0.79min,m/z 480(M+H)。
43 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N,5-三甲基噻唑-4-甲醯胺
將2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-5-甲基噻唑-4-甲酸(43A,30mg,0.063
mmol)、二甲基胺之40%水溶液(0.016mL,0.125mmol)及HATU(35.7mg,0.094mmol)存於DMF(1mL)中之混合物在室溫下攪拌3h。蒸發溶劑,並藉由矽膠層析(2-10% MeOH/二氯甲烷)對殘留物進行純化。藉由製備型HPLC對物質進行進一步純化,得到米色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N,5-三甲基噻唑-4-甲醯胺(20mg,62.5%產率)。
MS(ESI)m/z 507(M+H)。
1H NMR(400MHz,氯仿-d)δ:7.79(s,1H),6.90(s,1H),4.73(q,J=7.0Hz,2H),4.05(s,3H),3.12(s.,3H),3.11(s,3H),2.80-2.87(m,2H),2.53(s,3H),1.53(t,J=7.2Hz,3H),0.83-0.91(m,4H),0.74-0.80(m,4H)。
使用與對於實例42所述類似之方案來製備實例44-49。
MS(ESI)m/z 546(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 9.34(br.s.,1 H)7.75(d,J=5.94Hz,1 H)6.90(s,1 H)4.74(q,J=7.04Hz,2 H)4.06(s,3 H)3.80(t,J=6.71Hz,2 H)3.11-3.32(m,3 H)2.95(t,J=6.71Hz,2 H)2.78-2.91(m,2 H)2.58(d,J=15.85Hz,3 H)1.54(t,J=7.04Hz,3 H)0.70-0.94(m,8 H)。
MS(ESI)m/z 493(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 7.84(s,1 H)7.40(d,J=4.99Hz,1 H)6.90(s,1 H)4.73(q,J=6.94Hz,2 H)4.08(s,3 H)2.99(d,J=4.99Hz,3 H)2.73-2.91(m,5 H)2.14(s,1 H)1.53(t,J=7.07Hz,3 H)0.66-0.97(m,8 H)。
MS(ESI)m/z 551(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 7.73(d,J=3.05Hz,1 H)6.90(s,1 H)4.74(q,J=7.21Hz,2 H)4.05(s,3 H)3.72(dd,J=13.73,4.58Hz,2 H)3.61-3.68(m,1 H)3.57(t,J=5.41Hz,1 H)3.27-3.45(m,3 H)3.17(d,J=8.32Hz,3 H)2.79-2.88(m,2 H)2.54(d,J=5.83Hz,3 H)1.54(t,J=7.07Hz,3 H)0.73-0.92(m,8 H)。
MS(ESI)m/z 519(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 8.50-9.65(m,1 H)8.00(s,1 H)6.88(s,1 H)4.68(q,J=7.21Hz,2 H)4.59(t,J=7.63Hz,2 H)4.18(t,J=7.77Hz,2 H)4.09(s,3 H)2.78-2.89(m,2 H)2.72(s,3 H)2.30(quin,J=7.70Hz,2 H)1.49(t,J=7.07Hz,3 H)0.72-0.92(m,8 H)。
MS(ESI)m/z 521(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.77(s,1 H)6.89(s,1 H)4.74(q,J=7.04Hz,2 H)4.04(s,3 H)3.36-3.66(m,2 H)3.07(d,J=14.09Hz,3 H)2.72-2.90(m,2 H)2.51(s,3 H)2.11(s,1 H)1.54(t,J=7.04Hz,3 H)1.13-1.35(m,3 H)0.66-0.90(m,8 H)。
MS(ESI)m/z 508(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.78(s,1 H)6.89(s,1 H)4.73(q,J=7.04Hz,2 H)4.42(q,J=7.12Hz,2 H)4.04(s,3 H)2.78-2.91(m,2
H)2.75(s,3 H)2.15(s,1 H)1.54(t,J=7.04Hz,3 H)1.44(t,J=7.04Hz,3 H)0.68-0.91(m,8 H)。
50A 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-甲基噻唑-5-甲酸甲酯
將2-溴-3-側氧基丁酸甲酯(213mg,1.094mmol,按照Abu T.Khan等人,Tetrahedron Letters 2006,47,2751-2754所述之程序來製備)添加至N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B,290mg,0.730mmol)存於乙醇(5ml)中之懸浮液中,並將反應混合物在65℃下加熱2h。LC/MS顯示反應完成(反應物始終保持為懸浮液)。濃縮反應混合物以移除乙醇,並溶解於二氯甲烷中。使用飽和碳酸氫鈉洗滌溶液,並使用二氯甲烷反萃取水性層。合併之有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析使用自動化ISCO系統(40g管柱,使用0-5%甲醇/二氯甲烷溶析)對粗物質進行純化,獲得白色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-甲基噻唑-5-甲酸甲酯(301mg,0.610mmol,84%產率)。
MS(ESI)m/z 494.4(M+H)。
1H NMR(400MHz,氯仿-d)δ:7.75(s,1H),6.92(s,1H),4.76(q,J=7.0Hz,2H),4.08(s,3H),3.92(s,3H),2.82-2.89(m,2H),2.71(s,3H),1.59(t,J=7.0Hz,3H),0.85-0.93(m,4H),0.75-0.82(m,4H)
50B 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-甲基噻唑-5-甲酸
將2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-甲基噻唑-5-甲酸甲酯(實例50A,288mg,0.583mmol)及1N NaOH(5.83mL,5.830mmol)存於甲醇(5mL)中之混合物在65℃下加熱18h。蒸發出甲醇,並使用1N HCl將水溶液酸化至pH 4,自溶液中沉墜出固體,且在過濾後保留,獲得純淨形式之期望酸。隨後使用二氯甲烷萃取水性混合物。有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析使用自動化ISCO系統(40g管柱,使用0-8%甲醇/二氯甲烷溶析)對粗物質進行純化。總共獲得260mg黃色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-甲基噻唑-5-甲酸(93%產率)。
MS(ESI)m/z 480.2(M+H)。
1H NMR(500MHz,DMSO-d6)δ:8.03(br.s.,1H),7.06(s,1H),4.40(q,J=7.0Hz,2H),3.86(s,3H),2.96(s,1H),2.69-2.76(m,2H),2.36(s,3H),1.20(t,J=6.9Hz,3H),0.56(d,J=5.5Hz,4H),0.45-0.50(m,4H)。
50 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N,4-三甲基噻唑-5-甲醯胺
將2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-
d]吡咯并[2,3-b]吡啶-4-基胺基)-4-甲基噻唑-5-甲酸(實例50B,51mg,0.106mmol)、二甲基胺(40%,於水中,0.027mL,0.213mmol)、HATU(52.6mg,0.138mmol)及2,6-二甲基吡啶(0.025mL,0.213mmol)存於DMF(1mL)中之混合物在室溫下攪拌2h。蒸發溶劑,並藉由急驟層析在矽膠上使用自動化ISCO系統(24g管柱,使用2-8%甲醇/二氯甲烷溶析)對殘留物進行純化。藉由製備型HPLC對產物進行進一步純化。獲得米色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-N,N,4-三甲基噻唑-5-甲醯胺(17mg,0.032mmol,30.0%產率)。
MS(ESI)m/z 507.1(M+H)。
1H NMR(400MHz,甲醇-d4)δ:8.75(s,1H),7.27(s,1H),4.66(q,J=7.0Hz,2H),4.21(s,3H),3.19(s,6H),2.95-3.02(m,2H),2.39(s,3H),1.47(t,J=7.2Hz,3H),0.86-0.93(m,4H),0.78-0.84(m,4H)。
使用與對於50所用方法相同之方法來合成實例51-55。
MS(ESI)m/z 546.1(M+H)。
1H NMR(CDCl3)δ:7.77(s,1H),6.89(s,1H),4.71(q,J=6.9Hz,2H),4.05(s,3H),3.81(t,J=6.6Hz,2H),3.31(s,3H),2.78-2.86(m,4H),2.44(s,3H),1.53(t,J=7.0Hz,3H),0.83-0.90(m,4H),0.73-0.79(m,4H)。
MS(ESI)m/z 521.1(M+H)。
1H NMR(400MHz,CDCl3)δ:7.74(s,1H),6.88(s,1H),4.72(q,J=7.0Hz,2H),4.04(s,3H),3.57(q,J=7.2Hz,2H),3.11(s,3H),2.79-2.86(m,2H),2.40(s,3H),1.51(t,J=7.0Hz,3H),1.25(t,J=7.2Hz,3H),0.82-0.90(m,4H),0.73-0.79(m,4H)。
MS(ESI)m/z 537.1(M+H)。
1H NMR(400MHz,CDCl3)δ:7.74(s,1H),6.89(s,1H),6.13(t,J=4.7Hz,1H),4.74(q,J=7.0Hz,2H),4.05(s,3H),3.65(q,J=5.1Hz,2H),3.58(t,J=4.8Hz,2H),3.42(s,3H),2.79-2.87(m,2H),2.65(s,3H),1.58(t,J=7.0Hz,3H),0.83-0.90(m,4H),0.73-0.80(m,4H)。
MS(ESI)m/z 493.1(M+H)。
1H NMR(400MHz,CDCl3)δ:7.77(s,1H),6.86(s,1H),5.87-5.94(m,J=4.6Hz,1H),4.66(q,J=7.1Hz,2H),4.04(s,3H),3.04(d,J=4.6Hz,3H),2.79-2.87(m,2H),2.62(s,3H),1.51(t,J=7.0Hz,3H),0.83-0.90(m,4H),0.73-0.80(m,4H)。
MS(ESI)m/z 519.1(M+H)。
1H NMR(400MHz,CDCl3)δ:7.73(s,1H),6.90(s,1H),4.73(q,J=7.0Hz,2H),4.33(br.s.,4H),4.05(s,3H),2.80-2.87(m,2H),2.66(s,3H),2.33-2.43(m,2H),1.55(t,J=7.2Hz,3H),0.83-0.90(m,4H),0.73-0.80(m,4H)。
使用與對於50所用程序相同之程序來合成實例56-70。
分析條件-管柱-Mac-Mod Halo 4.6×50mm 2.7um;梯度-4min,自0%B至100%B;流速-4mL/min;溶劑-A=5:95乙腈:水;B=90:5乙腈:水;改性劑=10mM NH4OAc。
71A 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-乙基噻唑-5-甲酸甲酯
在室溫下,向N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(103mg,0.259mmol)存於
EtOH(5ml)中之攪拌懸浮液中添加剛製備之2-溴-3-側氧基戊酸甲酯1(81mg,0.389mmol)。隨後將漿液在65℃下攪拌2h。隨後將反應混合物冷卻至室溫並在真空中濃縮,獲得黃色固體。隨後將固體溶解於二氯甲烷中並使用飽和碳酸氫鈉水溶液洗滌。有機相經無水硫酸鎂乾燥並在真空中濃縮。隨後藉由矽膠急驟層析使用Isco 40g管柱自0-5%甲醇/二氯甲烷溶析來對粗殘留物進行純化,獲得白色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-乙基噻唑-5-甲酸甲酯(37.5mg,28.5%產率)。
MS(ESI)m/z 508.4(M+H)。
1H NMR(CDCl3)δ ppm 9.38(br s,1 H),7.75(s,1 H),6.92(s,1 H),4.76(q,2 H,J=6.94Hz),4.08(s,3H),3.92(s,3H),3.14(q,2H,J=7.68Hz),2.85(m,2H),1.59(t,3H,J=6.94Hz),1.34(t,3H,J=7.49Hz),0.78-0.91(m,8H)
71B 製備2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-乙基噻唑-5-甲酸
向2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-乙基噻唑-5-甲酸甲酯(實例71A,103mg,0.203mmol)存於MeOH(2mL)中之攪拌溶液中添加NaOH(1.420mL,1.420mmol)。隨後將溶液在65℃下攪拌18hr。隨後將反應混合物冷卻至室溫並在真空中濃縮,獲得黃色漿液。隨後用水稀釋混合物,使用1N HCl使其pH為4,並藉由真空過濾收集沉澱。隨後使用CH2Cl2萃取濾液;有機層經無水硫酸鎂乾燥並在真空中濃縮。隨後藉由矽膠急驟層析使用Isco 40g管柱自0-8% MeOH/CH2Cl2溶析對粗
殘留物進行純化。將期望流份與所收集沉澱合併,並濃縮,獲得橙色/黃色固體狀2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-乙基噻唑-5-甲酸(126mg,126%產率)。
MS(ESI)m/z 494.2(M+H)。
1H NMR(CDCl3)δ ppm 8.23(s,1 H),7.28(s,1H),4.62(q,2 H,J=6.94Hz),4.07(s,3H),3.04(q,2H,J=7.49Hz),3.00(m,2H),1.42(t,3H,J=7.07Hz),1.23(t,3H,J=7.63Hz),0.67-0.79(m,8H)。
71 製備N,N-二環丙基-6-乙基-4-(4-乙基-5-(1,1-二側氧基硫嗎啉-4-羰基)噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向2-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4-乙基噻唑-5-甲酸(實例69B,33mg,0.067mmol)、HATU(50.8mg,0.134mmol)、2,6-二甲基吡啶(0.020mL,0.174mmol)及DMF(1mL)之攪拌溶液中添加硫嗎啉1,1-二氧化物(27.1mg,0.201mmol)。隨後將溶液在50℃下攪拌1.5hr。隨後將反應物冷卻至室溫並使用二氯甲烷稀釋。隨後使用飽和碳酸氫鈉水溶液、存於H2O中之10% LiCl及再次飽和碳酸氫鈉水溶液洗滌該溶液。有機相經無水硫酸鎂乾燥並在真空中濃縮。隨後藉由矽膠急驟層析使用Isco 40g管柱自0-6% MeOH/CH2Cl2溶析對粗殘留物進行純化,得到淺黃色固體狀N,N-二環丙基-6-乙基-4-(4-乙基-5-(1,1-二側氧基硫嗎啉-4-羰基)噻唑-2-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(21.7mg,52.6%產率)。
MS(ESI)m/z 611.3(M+H)。
1H NMR(CDCl3)δ ppm 7.68(s,1 H),6.83(s,1 H),4.65(q,2 H,J=7.04),4.13(m,4H),3.99(s,3H),3.05(m,4H),2.76(m,2H),2.68(q,
2H,J=7.56Hz),1.46(t,3H,J=7.04Hz),1.25(t,3H,J=7.59Hz),0.68-0.80(m,8H)。
72A 製備4,4-雙(甲硫基)丁-3-烯-2-酮
將丙酮(2.205mL,30.0mmol)存於二硫化碳(1.81mL,30.0mmol)中之溶液添加至第三丁醇鈉(5.76g,60.0mmol)存於苯(30mL)中之懸浮液中,同時保持反應溫度不超過10℃。將反應混合物在室溫下攪拌3h,並在10℃下添加碘甲烷(3.75mL,60.0mmol)。將所得反應混合物在室溫下攪拌過夜。反應混合物用乙酸乙酯稀釋並用水洗滌兩次。有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析在矽膠上使用自動化ISCO系統(80g管柱,使用10-35%乙酸乙酯/己烷溶析)對粗產物進行純化,得到黃色固體狀4,4-雙(甲硫基)丁-3-烯-2-酮(3.456g,71.0%產率)。
1H NMR(400MHz,CDCl3)δ:6.04(s,1H),2.47(s,3H),2.45(s,3H),2.20(s,3H)。
72B 製備(Z)-N,N-二環丙基-6-乙基-1-甲基-4-(1-(甲硫基)-3-側氧基丁-1-烯基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將氫化鈉(2.84g,71.1mmol)添加至4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,8.02g,23.70mmol)存於DMF(60mL)中之溶液中,並將反應混合物在室溫下攪拌1h。添加存於DMF(10ml)中之4,4-雙(甲硫基)丁-3-烯-2-酮(實例70A,5.77g,35.5mmol),並持續攪拌3天。LC/MS顯示約75%完成。反應混合物用乙酸乙酯稀釋並添加水。形成米色沉澱,藉由過濾進行收集以得到5.1g產物。將濾液轉移至分液漏斗中。分離各層,並使用二氯甲烷(3x50ml)萃取水性層,合併之有機層使用飽和碳酸氫鈉洗滌並經硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析在矽膠上使用ISCO系統(220g管柱,使用2-8%甲醇/二氯甲烷溶析)對粗產物進行純化,得到(Z)-N,N-二環丙基-6-乙基-1-甲基-4-(1-(甲硫基)-3-側氧基丁-1-烯基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(6.6g,61.5%產率)與2.2g回收之1J。
MS(ESI)m/z 453.3(M+H)。
1H NMR(400MHz,DMSO-d6)δ:14.42(s,1H),8.16(s,1H),7.24(s,1H),5.54(s,1H),4.52(q,J=7.0Hz,2H),4.05(s,3H),2.89-2.97(m,2H),2.43(s,3H),2.14(s,3H),1.34(t,J=7.0Hz,3H),0.71-0.80(m,4H),0.63-0.70(m,4H)。
72 製備N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基異噁唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將(Z)-N,N-二環丙基-6-乙基-1-甲基-4-(1-(甲硫基)-3-側氧基丁-1-烯基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(22mg,0.049mmol)及羥胺(50%水溶液,3.13μL,0.051mmol)存於乙醇(1
mL)中之混合物回流加熱3h,且LC/MS顯示反應完成。反應混合物使用甲醇稀釋並藉由製備型HPLC進行純化,獲得白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基異噁唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(9mg,43.3%產率)。
MS(ESI)m/z 420.1(M+H)。
1H NMR(400MHz,甲醇-d4)δ:8.45(s,1H),7.26(s,1H),6.58(s,1H),4.63(q,J=7.2Hz,2H),4.17(s,3H),2.94-3.02(m,2H),2.33(s,3H),1.47(t,J=7.2Hz,3H),0.85-0.92(m,4H),0.77-0.84(m,4H)。
將(Z)-N,N-二環丙基-6-乙基-1-甲基-4-(1-(甲硫基)-3-側氧基丁-1-烯基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例72B,70mg,0.155mmol)及1-甲基肼甲酸第三丁基酯(0.046mL,0.309mmol)存於乙酸(1mL)中之混合物在35℃下攪拌4h(藉由LC/MS進行監測,直至無起始材料剩餘)。添加甲酸(0.5mL)並在60℃下攪拌6h。蒸發溶劑,並藉由急驟層析在矽膠上使用自動化ISCO系統(12g管柱,使用2-10%甲醇/二氯甲烷溶析)對粗產物進行純化。藉由製備型HPLC對不純淨產物進行進一步純化,得到米色固體狀N,N-二環丙基-4-(1,5-二甲基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(45mg,63.9%產率)。
MS(ESI)m/z 433.2(M+H)。
1H NMR(500MHz,CDCl3)δ:8.19(s,1H),7.63(s,1H),6.94(s,1H),
6.85(s,1H),4.65(q,J=7.0Hz,2H),3.99(s,3H),3.71(s,3H),2.79-2.85(m,2H),2.33(s,3H),1.49(t,J=7.2Hz,3H),0.82-0.87(m,4H),0.72-0.78(m,4H)。
73A 製備4-碘-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
在60℃下,向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(34.4mg,0.102mmol)存於二碘甲烷(102μL)中之攪拌懸浮液中緩慢添加亞硝酸異戊酯(27.4μL,0.203mmol)。將反應混合物在60℃下攪拌5h。冷卻至室溫後,使用二氯甲烷稀釋反應混合物。添加飽和碳酸氫鈉水溶液,並使用二氯甲烷(3x)萃取水性層。合併之有機物經無水硫酸鈉乾燥,過濾並在真空中濃縮。將粗殘留物置於幫浦上達16h以移除任何額外的二碘甲烷。LCMS認為足夠純淨可不經處理用於下一步驟中。該產物直接用於下一反應中。
MS(ESI)m/z 450.1(M+H)。
73 製備N,N-二環丙基-6-乙基-1-甲基-4-(1,5-二甲基-1H-吡唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向含有1,5-二甲基-1H-吡唑-3-胺(13.60mg,0.122mmol)、Pd2(dba)3(4.67mg,5.10μmol)、Xantphos(5.90mg,10.20μmol)及碳酸銫(100mg,0.306mmol)之小瓶中添加存於DME(1020μL)中之N,N-二環丙基-6-乙基-4-碘-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(45.8mg,0.102mmol)。向反應混合物中通氬氣5min,給
小瓶蓋上蓋子,並將反應混合物在90℃下加熱1h。反應混合物使用二氯甲烷稀釋並通過矽藻土進行真空過濾。在真空中濃縮濾液。經由急驟管柱層析使用ISCO 12g管柱使用1-10% MeOH/CH2Cl2溶析對粗殘留物進行純化。分離得到米色固體狀N,N-二環丙基-4-(1,5-二甲基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(14mg,31.7%產率)。
MS(ESI)m/z 433.2(M+H)。
1H NMR(500MHz,CDCl3)δ:8.19(s,1H),7.63(s,1H),6.94(s,1H),6.85(s,1H),4.65(q,J=7.0Hz,2H),3.99(s,3H),3.71(s,3H),2.79-2.85(m,2H),2.33(s,3H),1.49(t,J=7.2Hz,3H),0.82-0.87(m,4H),0.72-0.78(m,4H)。
74A 製備1,3-二側氧基異二氫吲哚-2-基(乙基)胺基甲酸第三丁基酯
在0℃下,將偶氮二甲酸二異丙酯(2.92mL,15.00mmol)一次性添加至1,3-二側氧基異二氫吲哚-2-基胺基甲酸第三丁基酯(2.62g,10mmol,按照Nicolas Brosse等人,Eur.J.Org.Chem.4757-4764,2003闡述之程序來製備)、三苯基膦(3.93g,15.00mmol)及乙醇(0.691g,15.00mmol)存於THF(20mL)中之溶液中,並將反應溶液在室溫下攪
拌1h(藉由TLC進行監測,直至完成)。蒸發溶劑,並藉由急驟層析在矽膠上使用自動化ISCO系統(80g管柱,使用5-35%乙酸乙酯/己烷溶析)對殘留物進行純化,提供白色固體狀1,3-二側氧基異二氫吲哚-2-基(乙基)胺基甲酸第三丁基酯(2.6g,90%產率),其按原樣用於下一步驟中。
74B 製備1-乙基肼甲酸第三丁基酯
在0℃下,將甲基肼(1.415mL,26.9mmol)添加至1,3-二側氧基異二氫吲哚-2-基(乙基)胺基甲酸第三丁基酯(實例74A,5.2g,17.91mmol)存於THF(40mL)中之溶液中,並將反應混合物在室溫下攪拌過夜。形成白色沉澱,並通過矽藻土墊過濾出來。在真空中濃縮濾液。將殘留物溶解於乙酸乙酯(50ml)中並使用1N HCl(3x30ml)萃取,酸性層使用乙酸乙酯(50ml)洗滌並藉由添加20% NaOH鹼化至pH 10。隨後使用乙酸乙酯(3x50ml)萃取鹼性溶液,且合併之有機層使用鹽水洗滌,經硫酸鎂乾燥,過濾並在真空中濃縮,得到無色油狀1-乙基肼甲酸第三丁基酯(2.5g,87%產率)。
1H NMR(400MHz,CDCl3)δ:3.90(br.s.,2H),3.35(q,J=7.0Hz,2H),1.42(s,9H),1.07(t,J=7.0Hz,3H)。
74 製備N,N-二環丙基-6-乙基-4-(1-乙基-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將(Z)-N,N-二環丙基-6-乙基-1-甲基-4-(1-(甲硫基)-3-側氧基丁-1-烯基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例74B,70mg,0.155mmol)及1-乙基肼甲酸第三丁基酯(49.6mg,0.309mmol)存於乙酸(1mL)中之混合物在35℃下攪拌4h(藉由LC/MS進行監測,直至無起始材料剩餘)。添加甲酸(1mL)並將反應混合物在60℃
下攪拌6h。蒸發溶劑,並藉由急驟層析在矽膠上使用自動化ISCO系統(12g管柱,使用2-10%甲醇/二氯甲烷溶析)對粗產物進行純化。藉由製備型HPLC對物質進行進一步純化,獲得米色固體狀N,N-二環丙基-6-乙基-4-(1-乙基-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(38mg,53.4%產率)。
MS(ESI)m/z 447.3(M+H)。
1H NMR(500MHz,CDCl3)δ:8.08(s,1H),7.61(s,1H),6.93(s,1H),6.84(s,1H),4.66(q,J=7.1Hz,2H),4.02(q,J=7.2Hz,2H),3.98(s,3H),2.79-2.85(m,2H),2.34(s,3H),1.49(t,J=7.1Hz,3H),1.41(t,J=7.2Hz,3H),0.82-0.87(m,4H),0.72-0.78(m,4H)。
標題化合物係使用與用於製備實例74之方法類似之方法來製備。
MS(ESI)m/z 472.2(M+H)。
1H NMR(400MHz,CDCl3)δ:8.05(s,1H),7.64(s,1H),6.99(s,1H),6.85(s,1H),4.65(q,J=7.0Hz,2H),4.25(t,J=6.8Hz,2H),4.01(s,3H),2.92(t,J=6.7Hz,2H),2.79-2.86(m,2H),2.41(s,3H),1.49(t,J=7.2Hz,3H),0.82-0.88(m,4H),0.72-0.80(m,4H)。
標題化合物係使用與用於製備實例74之方法類似之方法來製備。
MS(ESI)m/z 477.2(M+H)。
1H NMR(500MHz,CDCl3)δ:8.09(s,1H),7.61(s,1H),6.94(s,1H),6.84(s,1H),4.66(q,J=6.8Hz,2H),4.12(t,J=5.5Hz,2H),3.98(s,3H),3.74(t,J=5.8Hz,2H),3.32(s,3H),2.78-2.86(m,2H),2.36(s,3H),1.49(t,J=7.1Hz,3H),0.81-0.89(m,4H),0.71-0.80(m,4H)。
N,N-二環丙基-6-乙基-4-(1-(2-異丙氧基乙基)-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
77A 製備甲烷磺酸2-異丙氧基乙酯
向圓底燒瓶中裝入2-異丙氧基乙醇(0.5mL,4.34mmol)及二氯甲烷(21.68mL)並冷卻至0℃。添加三乙胺(1.208mL,8.67mmol)與一管嘴(tip)DMAP。逐滴添加甲烷磺醯氯(0.338mL,4.34mmol)。使反應混合物經2h緩慢升溫至室溫。反應混合物使用飽和氯化銨水溶液驟
冷並轉移至分液漏斗中。用二氯甲烷(2 x)萃取水性層。合併之有機物用鹽水洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮。分離得到澄清油狀甲烷磺酸2-異丙氧基乙酯(1g),其直接用於下一反應中。
1H NMR(400MHz,氯仿-d)δ ppm 4.34-4.40(m,2H),3.67-3.71(m,2H),3.60-3.67(m,1H),3.07(s,3H),1.18(d,6H,J=8.0Hz)。
77B 製備1,3-二側氧基異二氫吲哚-2-基(2-異丙氧基乙基)胺基甲酸第三丁基酯
在氮氣氣氛中攪拌裝有存於乙腈(21.70mL)中之甲烷磺酸2-異丙氧基乙酯(實例77A,0.791g,4.34mmol)的圓底燒瓶。添加1,3-二側氧基異二氫吲哚-2-基胺基甲酸第三丁基酯(1.138g,4.34mmol)與碳酸鉀(2.399g,17.36mmol)及苄基三乙基氯化銨(0.198g,0.868mmol)。將反應混合物在50℃下加熱24h並冷卻至室溫,保持整個週末。用乙酸乙酯及水稀釋反應混合物。用乙酸乙酯萃取水性層。合併之有機物用鹽水洗滌,經無水硫酸鈉乾燥,通過矽膠塞進行真空過濾並在真空中濃縮。粗油狀物未經額外純化即使用(1.26g,83%產率)。
MS(ESI)m/z 249.2(M-C4H9CO2)。
1H NMR(400MHz,氯仿-d)(作為旋轉異構體之混合物)δ ppm 1H NMR(400MHz,氯仿-d)d ppm 7.86-7.94(m,2 H),7.73-7.82(m,2 H),3.79-3.90(m,2 H),3.58-3.66(m,2 H),3.41-3.55(m,1 H),1.31-1.56(m,9 H),0.87-1.05(m,6 H)。
77C 製備1-(2-異丙氧基乙基)肼甲酸第三丁基酯
在0℃下,向1,3-二側氧基異二氫吲哚-2-基(2-異丙氧基乙基)胺基甲酸第三丁基酯(實例77B,1.262g,3.62mmol)存於四氫呋喃(24.15mL)中之溶液中緩慢添加甲基肼(0.289mL,5.43mmol)。將反應混合物在0℃下攪拌3h。過濾反應混合物以移除白色沉澱並在真空中濃縮濾液。使用乙酸乙酯(2 x)研磨半固體,並在真空中濃縮研磨物。重複此過程,最終提供黃色油狀1-(2-異丙氧基乙基)肼甲酸第三丁基酯(0.665g,84%產率)。
1H NMR(400MHz,氯仿-d)δ ppm 3.52-3.65(m,5 H),1.48(s,9 H),1.15(d,6 H,J=6.27Hz)
77 製備N,N-二環丙基-6-乙基-4-(1-(2-異丙氧基乙基)-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
按照實例73使用1-(2-異丙氧基乙基)肼甲酸第三丁基酯(實例77C,29.8mg,0.137mmol)來製備該化合物,以提供白色固體狀N,N-二環丙基-6-乙基-4-(1-(2-異丙氧基乙基)-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(16.72mg,48.7%產率)。
MS(ESI)m/z 505.4(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.89(s,1 H),6.99(s,1 H),6.88(s,1H),4.65(q,2 H,J=7.03Hz),4.22(t,2H,J=5.27Hz),4.06(s,3 H),3.78(t,2H,J=5.27Hz),3.52(dt,1H,J=12.11,6.12Hz),2.79-2.88(m,2 H),2.41(s,3H),1.50(t,3 H,J=7.03Hz),1.09(d,6H,J=6.27Hz),0.82-0.91(m,4 H),0.71-0.81(m,4 H)。
N,N-二環丙基-6-乙基-4-(1-(2-(2-甲氧基乙氧基)乙基)-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
78A 製備1,3-二側氧基異二氫吲哚-2-基(2-(2-甲氧基乙氧基)乙基)胺基甲酸第三丁基酯
按照實例77B使用1-溴-2-(2-甲氧基乙氧基)乙烷(0.259mL,1.906mmol)來製備該化合物,以提供淺黃色油狀1,3-二側氧基異二氫吲哚-2-基(2-(2-甲氧基乙氧基)乙基)胺基甲酸第三丁基酯(0.583g,84%產率)。
MS(ESI)m/z 265.2(M-C4H9CO2)。
1H NMR(400MHz,氯仿-d)(作為旋轉異構體之混合物)δ ppm 7.85-7.94(m,2 H),7.73-7.82(m,2 H),3.83-3.93(m,2 H),3.67-3.74(m,2 H),3.48-3.59(m,2 H),3.30-3.43(m,2 H),3.16-3.28(m,3 H),1.29-1.55(m,9 H)。
78B 製備1-(2-(2-乙氧基乙氧基)乙基)肼甲酸第三丁基酯
按照實例77C使用1,3-二側氧基異二氫吲哚-2-基(2-(2-甲氧基乙氧基)乙基)胺基甲酸第三丁基酯(0.583g,1.600mmol)來製備該化合物,以提供黃色油狀1-(2-(2-甲氧基乙氧基)乙基)肼甲酸第三丁基酯(0.4g,107%產率)。
1H NMR(400MHz,氯仿-d)δ ppm 3.51-3.70(m,8 H),3.39(s,3 H),1.48(s,9 H)。
78 製備N,N-二環丙基-6-乙基-4-(1-(2-(2-甲氧基乙氧基)乙基)-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
按照實例74使用1-(2-(2-甲氧基乙氧基)乙基)肼甲酸第三丁基酯(實例78B,43.2mg,0.184mmol)來製備該化合物,以提供白色固體狀N,N-二環丙基-6-乙基-4-(1-(2-(2-甲氧基乙氧基)乙基)-5-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(17.34mg,36%產率)。
MS(ESI)m/z 521.4(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.85(br s,1 H),6.91(s,1 H),6.87(s,1H),4.65(q,2 H,J=7.03Hz),4.20(t,2H,J=5.27Hz),4.05(s,3 H),3.87(t,2H,J=5.65Hz),3.53-3.59(m,2H),3.50(ddd,2H,J=5.40,2.89,2.76Hz),2.77-2.87(m,2 H),2.38(s,3H),1.50(t,3 H,J=7.03Hz),0.82-0.91(m,4 H),0.71-0.79(m,4 H)。
79A 製備1-丙基肼甲酸第三丁基酯
在圓底燒瓶中於氮氣中,向丙基肼草酸鹽(0.5g,3.05mmol)存於乙醇(3mL)中之溶液中添加三乙胺(0.425mL,3.05mmol)。將反應混合物冷卻至0℃,並經10min逐滴添加溶解於乙醇(1mL)中之BOC2O(0.707mL,3.05mmol)。使反應混合物升溫至室溫,保持16h。藉由在真空中濃縮來移除乙醇。將殘留物溶解於水及乙酸乙酯中。用乙酸乙酯(3x)萃取水性層。合併之有機物經無水硫酸鈉乾燥,過濾並在真空中濃縮。粗產物原樣用於下一反應中。
1H NMR(400MHz,氯仿-d)δ ppm 3.30-3.36(m,2 H),1.59(dq,3 H,J=14.40,7.33Hz),1.48(s,9 H),0.88(t,3 H,J=7.40Hz)。
79 製備N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基-1-丙基-1H-吡唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
按照實例74使用1-丙基肼甲酸第三丁基酯(實例79A,19.87mg,0.114mmol)來製備該化合物,以提供白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基-1-丙基-1H-吡唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(15.6mg,59%產率)。
MS(ESI)m/z 461.4(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 7.74(br s,1 H),6.92(s,1 H),6.86(s,1 H),4.66(q,2 H,J=7.11Hz),4.03(s,3 H),3.95(t,2 H,J=7.15Hz),2.78-2.87(m,2 H),2.34(s,3 H),1.87(dq,3 H,J=14.49,7.30Hz),1.50(t,3 H,J=7.15Hz),0.96(t,3 H,J=7.40Hz),0.83-0.89(m,4 H),0.72-0.79(m,4 H)。
80A 製備2,2-二氟乙基(1,3-二側氧基異二氫吲哚-2-基)胺基甲酸第三丁基酯
標題化合物係使用與用於製備實例77A之方法類似之方法來製備。
80B 製備1-(2,2-二氟乙基)肼甲酸第三丁基酯
標題化合物係使用與用於製備實例77B之方法類似之方法來製備。
1H NMR(400MHz,氯仿-d)δ:5.94(tt,J=56.3,4.4Hz,1H),3.74(td,J=13.8,4.4Hz,2H),1.48(s,9H)。
80 製備N,N-二環丙基-4-(1-(2,2-二氟乙基)-5-甲基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例73之方法類似之方法來製備。
MS(ESI)m/z 483.3(M+H)。
1H NMR500MHz,(氯仿-d)δ:8.17(br.s.,1H),7.66(s,1H),7.01(s,
1H),6.85(s,1H),6.05(tt,J=56.0,4.4Hz,1H),4.65(q,J=6.9Hz,2H),4.30(td,J=13.2,4.3Hz,2H),3.99(s,3H),2.79-2.86(m,2H),2.36(s,3H),1.49(t,J=7.1Hz,3H),0.81-0.88(m,4H),0.72-0.79(m,4H)。
81A 製備1-環丁基肼甲酸第三丁基酯
按照So Ok Park等人,J.Comb.Chem.11,315-326,2009闡述之程序來製備標題化合物。
81 製備4-(1-環丁基-5-甲基-1H-吡唑-3-基胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例73之方法類似之方法來製備。
MS(ESI)m/z 473.4(M+H)。
1H NMR(500MHz,氯仿-d)δ:8.05(s,1H),6.91(s,1H),6.79(s,1H),4.68(quin,J=8.4Hz,1H),4.61(q,J=7.1Hz,2H),4.07(s,3H),2.80-2.87(m,2H),2.69-2.79(m,2H),2.37-2.47(m,2H),2.32(s,3H),1.78-1.98(m,2H),1.47(t,J=7.1Hz,3H),0.82-0.91(m,4H),0.72-0.80(m,4H)。
如實例77中所述來製備。
MS(ESI)m/z 491(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.18(br.s.,1 H)7.63(s,1 H)6.93(s,1 H)6.85(s,1 H)4.66(q,J=7.04Hz,2 H)4.29-4.48(m,J=13.31,6.82,6.82,6.71Hz,1 H)4.00(s,3 H)3.55-3.79(m,2 H)3.29(s,3 H)2.72-2.92(m,2 H)2.36(s,3 H)1.49(t,J=7.04Hz,3 H)1.46(d,J=6.82Hz,2 H)0.68-0.93(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 503(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 8.12(s,1 H)7.64(s,1 H)6.95(s,1 H)6.86(s,1 H)4.66(q,J=7.21Hz,2 H)4.09-4.23(m,3 H)4.01(s,3 H)3.55(td,J=12.00,1.80Hz,2 H)2.73-2.89(m,2 H)2.37(s,3 H)2.25-2.36(m,2 H)1.84(dd,J=12.76,2.22Hz,2 H)1.50(t,J=7.07Hz,3 H)0.71-0.91(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 490(M+H)。
1H NMR(500MHz,氯仿-d)δ ppm 8.08(s,1 H)7.64(s,1 H)6.96(s,1 H)6.86(s,1 H)4.65(q,J=7.21Hz,2 H)4.24(br.s.,2 H)4.01(s,3 H)3.01-3.22(m,2 H)2.70-2.89(m,2 H)2.50(br.s.,6 H)2.37(s,3 H)1.49(t,J=7.07Hz,3 H)0.71-0.91(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 463(M+H)。
1H NMR(500MHz,MeOD)δ ppm 7.93(s,1 H)7.16(s,1 H)6.88(s,1 H)4.60(q,J=7.21Hz,2 H)4.09(t,J=5.55Hz,2 H)4.05(s,3 H)3.88(t,J=5.55Hz,2 H)2.88-3.00(m,2 H)2.37(s,3 H)1.43(t,J=7.07Hz,3 H)0.62-0.98(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 504(M+H)。
1H NMR(500MHz,MeOD)δ ppm 7.93(s,1 H)7.16(s,1 H)6.99(s,1 H)4.97(s,2 H)4.61(q,J=6.94Hz,2 H)4.05(s,3 H)3.15(s,3 H)2.98(s,3 H)2.79-2.97(m,2 H)2.29(s,3 H)1.44(t,J=7.07Hz,3 H)0.72-0.91(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 458(M+H)。
1H NMR(400MHz,氯仿-d)TM ppm 8.17(s,1 H)7.67(s,1 H)7.10(s,1 H)6.87(s,1 H)4.93(s,2 H)4.65(q,J=7.04Hz,2 H)4.01(s,3 H)2.76-2.92(m,2 H)2.43(s,3 H)1.50(t,J=7.04Hz,3 H)0.68-0.93(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 491(M+H)。
1H NMR(400MHz,氯仿-d)TM ppm 8.11(s,1 H)7.62(s,1 H)6.92(s,1 H)6.78-6.89(m,1 H)4.66(q,J=7.04Hz,2 H)4.06(t,J=6.60Hz,2 H)3.98(s,3 H)3.29-3.39(m,4 H)2.75-2.91(m,2 H)2.34(s,3 H)2.08(dq,J=6.38,6.16Hz,2 H)1.50(t,J=7.04Hz,3 H)0.70-0.94(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 461(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.15(s,1 H)7.62(s,1 H)6.91(s,1 H)6.85(s,1 H)4.66(q,J=7.19Hz,2 H)4.25-4.48(m,1 H)3.99(s,3 H)2.66-2.90(m,J=7.13,7.13,3.85,3.47Hz,2 H)2.34(s,3 H)1.38-1.58(m,9 H)0.68-0.91(m,8 H)。
使用與實例77類似之程序來製備。
MS(ESI)m/z 475(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.11(s,1 H)7.62(s,1 H)6.93(s,1 H)6.85(s,1 H)4.66(q,J=7.04Hz,2 H)3.99(s,3 H)3.74(d,J=7.48Hz,2 H)2.74-2.89(m,2 H)2.33(s,3 H)2.18-2.29(m,1 H)1.50(t,J=7.04Hz,3 H)0.94(d,J=6.60Hz,6 H)0.72-0.88(m,8 H)。
使用與實例72類似之方案自肼製備。
MS(ESI)m/z 419.3(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.70(br s,1 H),7.91(br s,1 H),6.87(s,1 H),6.09(br s,1 H),4.64(q,2 H,J=7.03Hz),4.08(s,3 H),2.74-2.95(m,2 H),2.41(s,3 H),1.51(t,3 H,J=7.15Hz),0.81-0.95(m,4 H),0.70-0.81(m,4 H)
使用與實例77所用程序相同之程序來製備。
MS(ESI)m/z 525.3(M+H)。
1H NMR(CDCl3)δ ppm 8.25(br s,1H),7.75(s,1H),6.86(s,1H),6.77(s,1H),4.54(q,2H,J=8Hz),4.36(t,2H,J=8Hz),3.97(s,3H),3.58(t,2H,J=8Hz),2.71-2.77(m,2H),2.44(s,3H),2.34(s,3H),1.41(t,3H,J=8Hz),0.75-0.78(m,4H),0.67-0.71(m,4H)。
使用與實例77所用程序相同之程序來製備。
MS(ESI)m/z 517.4(M+H)。
1H NMR(CDCl3)δ ppm 8.14(br s,1H),7.56(s,1H),6.83(s,1H),6.76(s,1H),4.59(q,2H,J=8Hz),4.01-4.02(m,1H),3.93(s,3H),3.88-3.93(m,1H),2.73-2.77(m,2H),2.28(s,3H),2.25-2.33(m,2H),1.93-1.96(m,2H),1.59-1.73(m,4H),1.42(t,3H,J=8Hz),0.73-0.78(m,4H),0.66-0.70(m,4H)。
使用與實例77所用程序相同之程序來製備。
MS(ESI)m/z 497.3(M+H)。
1H NMR(CDCl3)δ ppm 8.46(br s,1H),7.75(s,1H),7.16(s,1H),6.78(s,1H),4.54(q,2H,J=8Hz),3.97(s,3H),3.19(s,3H),2.72-2.76(m,2H),2.51(s,3H),1.41(t,3H,J=8Hz),0.72-0.78(m,4H),0.66-0.69(m,4H)。
95A 製備4-甲基-1,1-雙(甲硫基)戊-1-烯-3-酮
標題化合物係使用與用於製備實例70A之方法類似之方法來製備。
1H NMR(400MHz,CDCl3)δ:6.08(s,1H),2.47(s,3H),2.46(s,3H),1.14(s,3H),1.12(s,3H)。
95B 製備(Z)-N,N-二環丙基-6-乙基-1-甲基-4-(4-甲基-1-(甲硫
基)-3-側氧基戊-1-烯基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例70B之方法類似之方法來製備。
MS(ESI)m/z 481.4(M+H)。
95 製備N,N-二環丙基-6-乙基-4-(5-異丙基-1-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例73之方法類似之方法來製備。
MS(ESI)m/z 461.4(M+H)。
1H NMR(500MHz,CDCl3)δ:7.80(s,1H),7.07(s,1H),6.86(s,1H),4.60(q,J=6.9Hz,2H),4.02(s,3H),3.79(s,3H),2.93-3.01(m,1H),2.79-2.86(m,2H),1.52(t,J=7.1Hz,3H),1.35(d,J=6.9Hz,6H),0.82-0.89(m,4H),0.72-0.78(m,4H)。
96A 製備1-環丙基-3,3-雙(甲硫基)丙-2-烯-1-酮
標題化合物係使用與用於製備實例72A之方法類似之方法來製備。
1H NMR(400MHz,CDCl3)δ:6.23(s,1H),2.50(s,3H),2.48(s,3H),1.86-1.94(m,1H),1.09(quin,J=3.7Hz,2H),0.82-0.88(m,2H)。
96B 製備(Z)-N,N-二環丙基-4-(3-環丙基-1-(甲硫基)-3-側氧基丙-1-烯基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例72B之方法類似之方法來製備。
MS(ESI)m/z 479.3(M+H)。
1H NMR(400MHz,CDCl3)δ:14.81(s,1H),7.75(s,1H),6.85(s,1H),5.58(s,1H),4.62(q,J=7.0Hz,2H),4.00(s,3H),2.75-2.85(m,2H),2.45(s,3H),1.76-1.86(m,1H),1.46(t,J=7.0Hz,3H),1.17-1.28(m,2H),0.69-0.91(m,10H)。
96 製備N,N-二環丙基-4-(5-環丙基-1-乙基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例73之方法類似之方法來製備。
MS(ESI)m/z 473.3(M+H)。
97A 製備4-溴-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
在氮氣氣氛中使用二溴甲烷(397μL)處理裝有4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(134.4mg,0.397mmol)之圓底燒瓶。添加硝酸異戊酯(107μL,0.794mmol),並將反應混合物在60℃下加熱3.5h並冷卻至室溫。反應混合物使用乙酸乙酯稀釋並使用飽和碳酸氫鈉水溶液洗滌。有機物經無水硫酸鈉乾燥,過濾並在真空中濃縮。分離得到褐色玻璃狀固體4-溴-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(0.156g,0.388mmol,98%產率)。該產物直接用於下一反應中。
MS(ESI)m/z 404.2(M+H)。
97 製備N,N-二環丙基-6-乙基-1-甲基-4-(1-甲基-1H-吡唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向含有1-甲基-1H-吡唑-3-胺(11.89mg,0.122mmol)、Pd2(dba)3(4.67mg,5.10μmol)、Xantphos(5.90mg,10.20μmol)及碳酸銫(100mg,0.306mmol)之小瓶中添加存於DME(1020μL)中之4-溴-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例97A,41.0mg,0.102mmol)。向反應混合物中通氬氣5min,給小瓶蓋上蓋子,並將反應混合物在60℃下加熱4h及在80℃下加熱16h。在真空中濃縮反應混合物。藉由急驟管柱層析使用Isco 40g管
柱使用0-5% MeOH/CH2Cl2溶析對粗殘留物進行純化,隨後藉由製備型HPLC再次純化。分離得到白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(1-甲基-1H-吡唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(13mg,0.030mmol,29.5%產率)。
MS(ESI)m/z 419.3(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.17(s,1 H),7.64(s,1 H),7.31(d,1H,J=2.26Hz),7.16(d,1 H,J=2.26Hz),6.86(s,1 H),4.65(q,2 H,J=7.03Hz),4.01(s,3 H),3.85(s,3H),2.78-2.87(m,2 H),1.49(t,3 H,J=7.15Hz),0.81-0.89(m,4 H),0.71-0.80(m,4 H)
使用與實例97所用程序類似之程序來製備。
1H NMR(500MHz,氯仿-d)δ:8.15(s,1H),7.72(s,1H),7.67(s,1H),7.66(br.s.,1H),6.85(s,1H),4.65(q,J=7.2Hz,2H),4.01(s,3H),3.95(s,3H),2.79-2.86(m,2H),1.50(t,J=7.1Hz,3H),0.81-0.89(m,4H),0.73-0.79(m,4H)。
以與實例73所用方法類似之方法來製備。
MS(ESI)m/z 485.4(M+H)。
1H NMR(CDCl3)δ ppm 8.03(br s,1H),7.58(s,1H),7.48(m,1H),7.35(s,1H),6.79(s,1H),6.54(d,1H,J=3.3Hz),6.47(m,1H),4.58(q,2 H,J=7.04Hz),3.94(s,3H),3.93(s,3H),2.74(m,2H),1.44(t,3H),0.69-0.79(m,8H)。
N,N-二環丙基-6-乙基-1-甲基-4-((1-甲基-5-(三氟甲基)-1H-吡唑-3-基)胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
以與實例73所用方法類似之方法來製備。
MS(ESI)m/z 487.3(M+H)。
1H NMR(CDCl3)δ ppm 7.41(s,1 H),7.12(s,1H),6.78(s,1 H),4.52(q,2H,J=7.04Hz),4.11(s,3H),3.86(s,3H),2.74(m,2H),1.42(t,3H,J=7.15Hz),0.67-0.80(m,8H)。
101A 製備(Z)-N,N-二環丙基-4-(4,4-二甲氧基-1-(甲硫基)-3-側氧基丁-1-烯基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
在室溫下,將氫化鈉(142mg,3.55mmol)添加至存於DMF(7mL)中之4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,400mg,1.182mmol)中,並將混合物攪拌30min,添加1,1-二甲氧基-4,4-雙(甲硫基)丁-3-烯-2-酮(394mg,1.773mmol)並持續攪拌過夜。反應混合物使用乙酸乙酯稀釋並使用水、10%氯化鋰及水洗滌。有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析在矽膠上使用自動化ISCO系統(80g管柱,使用2-5%甲醇/二氯甲烷溶析)對粗產物進行純化。獲得黃色固體狀(Z)-N,N-二環丙基-4-(4,4-二甲氧基-1-(甲硫基)-3-側氧基丁-1-烯基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(484mg,0.944mmol,80%產率)。
101B 製備(Z)-2-(1-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4,4-二甲氧基-3-側氧基丁-1-烯基)-1-乙基肼甲酸第三丁基酯
將(Z)-N,N-二環丙基-4-(4,4-二甲氧基-1-(甲硫基)-3-側氧基丁-1-烯基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例101A,160mg,0.312mmol)及1-乙基肼甲酸第三丁基酯(125mg,0.780mmol)存於乙酸(2mL)中之混合物在35℃下攪拌過夜。蒸發溶劑,並藉由急驟層析在矽膠上使用自動化ISCO系統(40g管柱,使用2-8%甲醇/二氯甲烷溶析)對粗產物進行純化。獲得黃色固體
狀(Z)-2-(1-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4,4-二甲氧基-3-側氧基丁-1-烯基)-1-乙基肼甲酸第三丁基酯(195mg,0.312mmol,100%產率)。
MS(ESI)m/z 625.5(M+H)。
101C 製備N,N-二環丙基-6-乙基-4-(1-乙基-5-甲醯基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將(Z)-2-(1-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4,4-二甲氧基-3-側氧基丁-1-烯基)-1-乙基肼甲酸第三丁基酯(187mg,0.299mmol)與TFA(25%,於二氯乙烷中,1.0mL,2.99mmol)之混合物在60℃下加熱0.5h,且LC/MS顯示反應完成。蒸發溶劑,並將殘留物分配於飽和碳酸氫鈉與二氯甲烷之間。分離各層,並使用二氯甲烷萃取水性層兩次以上。合併之有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由急驟層析在矽膠上使用自動化ISCO系統(24g管柱,使用1-5%甲醇/二氯甲烷溶析)對粗產物進行純化。獲得黃色固體狀N,N-二環丙基-6-乙基-4-(1-乙基-5-甲醯基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(80mg,0.174mmol,58.0%產率)。
MS(ESI)m/z 461.4(M+H)。
1H NMR(500MHz,CDCl3)δ:9.88(s,1H),8.25(s,1H),7.76(s,1H),7.67(s,1H),6.87(s,1H),4.67(d,J=7.2Hz,2H),4.52(q,J=7.1Hz,2H),4.02(s,3H),2.80-2.86(m,2H),1.52(t,J=7.1Hz,3H),1.44(t,J=7.2Hz,3H),0.83-0.89(m,4H),0.73-0.79(m,4H)。
101 製備3-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪
唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-1-乙基-1H-吡唑-5-甲酸
將N,N-二環丙基-6-乙基-4-(1-乙基-5-甲醯基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例101C,27mg,0.059mmol)及過硫酸氫鉀製劑(79mg,0.129mmol)存於DMF中之混合物在室溫下攪拌20hr。添加水,並將混合物用二氯甲烷萃取三次。有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由製備型HPLC對粗產物進行純化,得到3-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-1-乙基-1H-吡唑-5-甲酸(20mg,98%產率)。
MS(ESI)m/z 477.4(M+H)。
1H NMR(500MHz,甲醇-d4)δ:7.96(s,1H),7.48(s,1H),7.18(s,1H),4.70(q,J=6.9Hz,2H),4.60(q,J=7.2Hz,2H),4.09(s,3H),2.94-3.00(m,2H),1.45(t,J=6.94Hz,3H),1.44(t,J=7.21Hz,3H),0.85-0.92(m,4H),0.77-0.82(m,4H)。
N,N-二環丙基-6-乙基-4-(1-乙基-5-(羥基甲基)-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
在室溫下,將硼氫化鈉(佔氧化鋁之10wt%,13.14mg,0.035mmol)添加至存於甲醇(1mL)中之N,N-二環丙基-6-乙基-4-(1-乙基-5-甲醯基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例101C,16mg,0.035mmol)中,並將反應混合物攪拌0.5h。過濾出固體氧化鋁並在真空中濃縮濾液。藉由急驟層析在矽膠上使用自動化ISCO系統(4g管柱,使用2-10%甲醇/二氯甲烷溶
析)對粗產物進行純化。獲得白色固體狀N,N-二環丙基-6-乙基-4-(1-乙基-5-(羥基甲基)-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(14mg,86%產率)。
MS(ESI)m/z 563.4(M+H)。
1H NMR(500MHz,CDCl3)δ:8.09(s,1H),7.59(s,1H),7.08(s,1H),6.81(s,1H),4.72(d,J=4.7Hz,2H),4.57(q,J=7.2Hz,2H),4.15(q,J=7.3Hz,2H),3.97(s,3H),2.76-2.84(m,3H),1.46(t,J=7.2Hz,3H),1.41(t,J=7.1Hz,3H),0.81-0.87(m,4H),0.71-0.76(m,4H)。
將3-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-1-乙基-1H-吡唑-5-甲酸(實例101,28mg,0.059mmol)、HATU(26.8mg,0.071mmol)及二甲基胺(2M,於THF中,59μL,0.118mmol)存於DMF(1mL)中之混合物在室溫下攪拌2h。添加水,並將反應混合物用乙酸乙酯萃取三次。合併之有機層使用10%氯化鋰洗滌兩次,經硫酸鎂乾燥,過濾並在真空中濃縮。藉由製備型HPLC(Phenomenex Luna 5u C18管柱,21.2×250mm管柱,保留時間為15.317min,梯度為經20分鐘含有10mM乙酸銨之30-100%甲醇水溶液,流速為20ml/min並在254nm下進行檢測)對粗物質進行純化。獲得米色固體狀N,N-二環丙基-4-(5-(二甲基胺甲醯基)-1-乙基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(20mg,66.9%產率)。
MS(ESI)m/z 504.5(M+H)。
1H NMR(500MHz,CDCl3)δ:8.38(br.S,1H),7.75(s,1H),7.28(s,1H),6.86(s,1H),4.61(q,J=7.2Hz,2H),4.27(q,J=7.0Hz,5H),4.03(s,3H),3.27(s,3H),3.17(s,3H),2.79-2.86(m,2H),1.47(t,J=7.14Hz,3H),1.46(t,J=7.14Hz,3H),0.83-0.89(m,4H),0.73-0.78(m,4H)。
實例104
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 546.5(M+H)。
1H NMR(500MHz,CDCl3)δ:7.95(s,1H),7.19(s,1H),6.87(s,1H),4.60(q,J=6.9Hz,2H),4.28(q,J=7.2Hz,5H),4.07(s,3H),3.82(br.s.,5H),3.76(br.s.,3H),2.74-2.93(m,4H),1.48(t,J=7.14Hz,3H),1.47(t,J=7.14Hz,3H),0.84-0.90(m,4H),0.74-0.78(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 594.5(M+H)。
1H NMR(500MHz,CDCl3)δ:7.95(s,1H),7.19(s,1H),6.83(s,1H),4.55(q,J=7.03Hz,2H),4.20-4.34(m,6H),4.06(s,3H),3.13(br.s.,4H),2.77-2.89(m,2H),1.46(t,J=7.21Hz,3H),1.43(t,J=7.21Hz,3H),0.82-0.88(m,4H),0.72-0.77(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 589.6(M+H)。
1H NMR(500MHz,CDCl3)δ:8.18(s,1H),7.68(s,1H),7.45(s,1H),6.87(s,1H),4.64(q,J=6.9Hz,2H),4.54(q,J=7.2Hz,2H),4.03(s,3H),3.77(br.s.,4H),3.61(br.s.,2H),2.80-2.87(m,2H),2.67(br.s.,2H),2.57(br.s.,3H),1.71(br.s.,3H),1.53(t,J=7.1Hz,3H),1.46(t,J=7.1Hz,3H),0.84-0.90(m,4H),0.74-0.79(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 559.5(M+H)。
1H NMR(500MHz,CDCl3)δ:8.19(s,1H),7.66(s,1H),7.26(s,1H),6.87(s,1H),4.63(q,J=6.9Hz,2H),4.26(q,J=7.2Hz,2H),4.02(s,3H),3.88(br.s.,4H),2.80-2.86(m,2H),2.54(br.s.,4H),2.40(br.s.,3H),1.48(t,J=7.1Hz,3H),1.47(t,J=7.1Hz,3H),0.82-0.90(m,4H),0.73-0.79(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 529.3(M+H)。
1H NMR(500MHz,CDCl3)δ:8.37(br.s.,1H),7.77(s,1H),7.39(s,1H),6.86(s,1H),4.62(q,J=7.2Hz,2H),4.54(br.s.,2H),4.27-4.34
(m,1H),4.04(s,3H),3.41(br.s.,3H),2.79-2.86(m,2H),1.47(t,J=7.2Hz,6H),0.83-0.89(m,4H),0.73-0.78(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 561.5(M+H)。
1H NMR(500MHz,CDCl3)δ:7.77(br.s.,2H),7.40(s,1H),6.72(s,1H),4.48-4.56(m,4H),3.99(s,3H),3.61-3.66(m,2H),3.52-3.58(m,2H),2.81(m,2H),2.02(s,3H),1.44(t,J=7.1Hz,3H),1.34(t,J=6.9Hz,3H),1.26(s,1H),0.82-0.90(m,4H),0.70-0.77(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 532.4(M+H)。
1H NMR(500MHz,CDCl3)δ:8.29(br.S.,1H),7.70(s,1H),7.23(s,1H),6.85(s,1H),4.62(q,J=6.9Hz,2H),4.20(q,J=7.2Hz,2H),4.00(s,3H),3.51-3.62(m,4H),2.77-2.85(m,2H),1.40-1.47(m,6H),1.27(t,J=7.1Hz,6H),0.80-0.88(m,4H),0.72-0.77(m,4H)。
標題化合物係使用與用於製備實例103之方法類似之方法來製備。
MS(ESI)m/z 574.4(M+H)。
1H NMR(500MHz,CDCl3)δ:8.30(br.S.,1H),7.72(s,1H),7.21(s,1H),6.86(s,1H),4.62(q,J=6.9Hz,2H),4.21-4.28(m,2H),4.07-4.20(m,2H),4.01(s,3H),3.61(br.s,2H),2.91(br.s,1H),2.79-2.85(m,2H),2.60(br.S.1H),1.47(t,J=7.2Hz,3H),1.45(t,J=7.2Hz,3H),1.07-1.36(m,6H),0.81-0.88(m,4H),0.72-0.78(m,4H)。
112A 製備(Z)-2-(1-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-4,4-二甲氧基-3-側氧基丁-1-烯基)-1-甲基肼甲酸第三丁基酯
標題化合物係使用與用於製備實例101B之方法類似之方法來製備。
MS(ESI)m/z 611.7(M+H)。
112B 製備N,N-二環丙基-6-乙基-4-(5-甲醯基-1-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
標題化合物係使用與用於製備實例101C之方法類似之方法來製備。
MS(ESI)m/z 447.3(M+H)。
112C 製備3-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-1-甲基-1H-吡唑-5-甲酸
標題化合物係使用與用於製備實例101之方法類似之方法來製備。
MS(ESI)m/z 463.3(M+H)。
112 製備N,N-二環丙基-4-(5-(二甲基胺甲醯基)-1-甲基-1H-吡
唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將3-(7-(二環丙基胺甲醯基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-4-基胺基)-1-甲基-1H-吡唑-5-甲酸(39.8mg,0.086mmol)、HATU(49.0mg,0.129mmol)及二甲基胺(2M,於THF中)(0.086mL,0.172mmol)存於DMF(2mL)中之混合物在室溫下攪拌2h。添加水,並將反應混合物用乙酸乙酯萃取三次。合併之有機層使用10%氯化鋰洗滌兩次,經硫酸鎂乾燥,過濾並在真空中濃縮。藉由製備型HPLC對粗物質進行純化,得到米色固體狀N,N-二環丙基-4-(5-(二甲基胺甲醯基)-1-甲基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(23mg,54.1%產率)。
MS(ESI)m/z 490.2(M+H)。
1H NMR(400MHz,CDCl3)δ:8.28(s,1H),7.67(s,1H),7.34(s,1H),6.86(s,1H),4.61(q,J=7.0Hz,2H),4.01(s,3H),3.95(s,3H),3.29(s,3H),3.16(s,3H),2.79-2.86(m,2H),1.47(t,J=7.0Hz,3H),0.82-0.89(m,4H),0.72-0.79(m,4H)。
標題化合物係使用與用於製備實例112之方法類似之方法來製備。
MS(ESI)m/z 580.3(M+H)。
1H NMR(400MHz,CDCl3)δ:8.29(s.,1H),7.69(s,1H),7.30(s,1H),6.83(s,1H),4.57(q,J=6.8Hz,2H),4.31(br.s.,4H),4.00(s,3H),3.93(s,3H),3.15(br.s.,4H),2.77-2.88(m,2H),1.45(t,J=7.0Hz,3H),0.80-0.91(m,4H),0.69-0.80(m,4H)。
標題化合物係使用與用於製備實例112之方法類似之方法來製備,只是使用實例80A。
MS(ESI)m/z 540.4(M+H)。
1H NMR(400MHz,氯仿-d)δ:8.41(br.s.,1H),7.73(s,1H),7.43(s,1H),6.86(s,1H),6.17(tt,J=55.9,4.2Hz,1H),4.57-4.72(m,4H),4.01(s,3H),3.30(s,3H),3.16(s,3H),2.78-2.86(m,2H),1.47(t,J=7.0Hz,3H),0.80-0.89(m,4H),0.71-0.80(m,4H)。
標題化合物係藉由與實例102所用方法類似之方法來製備。
MS(ESI)m/z 449.3(M+H)。
1H NMR(CDCl3)δ ppm 8.11(br s,1H),7.67(s,1 H),7.16(s,1 H),6.88(s,1 H),4.75(d,2 H,J=5.94Hz),4.67(q,2H,J=7.26Hz),4.03(s,3H),3.89(s,3H),2.84(m,2H),1.68(t,3H,J=6.16Hz),1.50(t,3H,J=7.15Hz),0.75-0.89(m,8H)
向N,N-二環丙基-6-乙基-4-(5-甲醯基-1-甲基-1H-吡唑-3-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例112B,22mg,0.049mmol)及分子篩4Å(30mg)存於MeOH(2mL)中之攪拌溶液中添加嗎啉(0.017mL,0.197mmol)。將溶液在室溫下攪拌12hr後,添加硼氫化鈉(7.46mg,0.197mmol)並攪拌3hr。使用1N HCl使溶液達到pH=4,使用飽和碳酸氫鈉水溶液中和,且隨後使用CH2Cl2萃取。有機層經無水硫酸鎂乾燥並在真空中濃縮。藉由矽膠急驟層析使用Isco 40g管柱自0-10% MeOH/CH2Cl2溶析對殘留物進行純化,獲得白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(1-甲基-5-(N-嗎啉基甲基)-1H-吡唑-3-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(14.3mg,0.027mmol,54.9%產率)。
MS(ESI)m/z 518.3(M+H)。
1H NMR(CDCl3)δ ppm 7.99(br s,1 H),7.57(s,1 H),6.99(s,1 H),6.78(s,1H),4.56(q,2 H J=7.04Hz),3.93(s,3H),3.77(s,3H),3.64(m,4H),3.48(s,2H),2.75(m,2H),2.45(m,4H),1.42(t,3H J=7.02
Hz),0.66-0.80(m,8H)。
使用與用於製備實例116之方法類似之方法來合成。
MS(ESI)m/z 531.4(M+H)。
1H NMR(CDCl3)δ ppm 8.05(br s,1 H),7.60(s,1 H),7.01(s,1H),6.78(s,1 H),4.56(q,2 H J=6.75Hz),3.95(s,3H),3.72(s,3H),3.61(s,2H),2.96(m,4H),2.76(m,4H),2.74(m,2H),2.71(s,3H),1.42(t,3H,J=7.04Hz),0.67-0.80(m,8H)。
使用與用於製備實例116之方法類似之方法來合成。
MS(ESI)m/z 476.4(M+H)。
1H NMR(CDCl3)δ ppm 7.45(s,1 H),7.33(s,1H),6.84(s,1 H),4.52(q,2H,J=7.04Hz),4.25(s,2H),3.98(s,3H),3.90(s,3H),2.80(s,6H),2.77(m,2H),1.37(t,3H,J=6.82Hz),0.64-0.87(m,8H)。
使用中間體101B及實例116所用之程序來製備。
MS(ESI)m/z 545.4(M+H)。
1H NMR(CDCl3)δ ppm 8.03(s,1 H),7.57(s,1 H),7.00(s,1H),6.78(s,1 H),4.55(q,2 H,J=7.04Hz),4.03(q,2H,J=5.72Hz),3.94(s,3H),3.60(s,2H),2.93(br s,3H),2.63-2.84(br m,10H),1.42(t,3H,J=7.04Hz),1.35(t.3H,J=7.26Hz),0.69-0.79(m,8H)。
120A 製備4-(2-氯乙醯胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向裝有4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,47.2mg,0.139mmol)之圓底燒瓶中添加二氯甲烷(697μL)及三乙胺(35.0μL,0.251mmol)。逐滴添
加氯乙醯氯(12.20μL,0.153mmol)。將反應混合物在室溫下攪拌16h。再添加氯乙醯氯(12.20μL,0.153mmol)。用二氯甲烷稀釋反應混合物。有機物用水洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮。分離得到橙色糊狀4-(2-氯乙醯胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(58.5mg,101%產率)。物質未經進一步純化即用於隨後反應中。
MS(ESI)m/z 415.0(M+H)。
1H NMR(400MHz,氯仿-d)δ ppm 8.04(br s,1H),6.90(s,1H),5.31(s,2H),4.62(q,2H,J=7.11Hz),4.24(s,3H),2.77-2.88(m,2H),1.47(t,3H,J=7.03Hz),0.83-0.92(m,4H),0.71-0.80(m,4H)。
120 製備N,N-二環丙基-6-乙基-1-甲基-4-(2-甲基噻唑-4-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向4-(2-氯乙醯胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(58.5mg,0.141mmol)存於DMF(176μL)中之溶液中添加硫代乙醯胺(12.71mg,0.169mmol)。給小瓶蓋上蓋子,並將反應混合物在80℃下加熱3h。在真空中濃縮反應混合物。將粗殘留物溶解於MeOH中並藉由製備型HPLC進行純化。分離得到米色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(2-甲基噻唑-4-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(4.05mg,6.6%產率)。
MS(ESI)m/z 436.0(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 8.78(s,1H),8.08(s,1H),7.74(s,1H),7.20(s,1H),4.55(q,2H,J=7.19Hz),4.03(s,3H),2.87-2.98(m,2H),2.65(s,3H),1.34(t,3H,J=7.03Hz),0.73-0.81(m,4H),0.62-0.69(m,4H)。
121A 製備1-疊氮基丙-2-酮
向氯丙酮(0.680mL,8.53mmol)存於丙酮(10mL)及水(5.00mL)中之溶液中添加疊氮化鈉(0.555g,8.53mmol)。將反應混合物在室溫下攪拌3.5h。在減壓下濃縮反應混合物。使用二氯甲烷(2 x)萃取剩餘水溶液。合併之有機物使用鹽水洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮,獲得褐色油狀1-疊氮基丙-2-酮(0.641g,6.47mmol,76%產率)。該物質未經任何純化即使用。
1H NMR(400MHz,氯仿-d)δ ppm 3.96(s,2H),2.21(s,3H)。
121B 製備N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
在圓底燒瓶中於氮氣中,向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,194.5mg,0.575mmol)存於二氯甲烷(2874μL)中之混合物中添加1,1'-硫代羰基二-2(1H)-吡啶酮(133mg,0.575mmol)。將反應混合物在室溫下攪拌16h。在減壓下濃縮反應混合物。分離得到黃色黏性固體狀N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(180mg,94%產率)。該物質按原樣用於隨後反
應中。
MS(ESI)m/z 381.1(M+H)。
121 製備N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基噁唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例121B,45.7mg,0.120mmol)存於二噁烷(343μL)中之溶液中添加1-疊氮基丙-2-酮(14.28mg,0.144mmol)及三苯基膦(37.8mg,0.144mmol)。將燒瓶所含物浸沒至預加熱油浴中達35min,並冷卻至室溫。殘留物使用乙酸乙酯稀釋並使用飽和碳酸氫鈉水溶液驟冷。用乙酸乙酯萃取水性層。合併之有機物用鹽水洗滌,經無水硫酸鈉乾燥,過濾並在真空中濃縮。藉由急驟層析在Isco 12g管柱上使用1-10% MeOH/CH2Cl2溶析對粗殘留物進行純化。將淺黃色固體溶解於MeOH中並藉由製備型HPLC進行進一步純化。分離得到白色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(5-甲基噁唑-2-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(10mg,25%產率)。
MS(ESI)m/z 420.0(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 9.86(s,1H),8.05(s,1H),7.18(s,1H),6.66(d,1H,J=1.51Hz),4.41(q,2H,J=7.28Hz),4.02(s,3H),2.85-2.98(m,2H),2.21-2.29(m,3H),1.27(t,3H,J=7.15Hz),0.71-0.80(m,4H),0.60-0.70(m,4H)。
N,N-二環丙基-6-乙基-1-甲基-4-(3-甲基-1,2,4-噻二唑-5-基胺基)-1,6-
二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將N,N-二環丙基-6-乙基-4-異硫氰酸基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例121B,0.042g,0.111mmol)、乙脒鹽酸鹽(10.49mg,0.111mmol)及Hünig鹼(0.058mL,0.333mmol)存於DMF(0.617mL)中之混合物在室溫下攪拌過夜。添加偶氮二甲酸二乙酯(0.088mL,0.222mmol),並在室溫下持續攪拌16h。濃縮反應混合物。將殘留物溶解於MeOH中並藉由製備型HPLC進行純化。分離得到淺黃色固體狀N,N-二環丙基-6-乙基-1-甲基-4-(3-甲基-1,2,4-噻二唑-5-基胺基)-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(4.32mg,9%產率)。
MS(ESI)m/z 437.1(M+H)。
1H NMR(400MHz,MeOD)δ ppm 8.10(s,1 H),7.28(s,1 H),4.73(q,2 H,J=7.19Hz),4.13(s,3 H),2.93-3.01(m,2 H),2.53(s,3 H),1.53(t,3 H,J=7.03Hz),0.83-0.92(m,4 H),0.76-0.83(m,4 H)。
按照實例122使用異丁基亞胺醯胺鹽酸鹽(15.08mg,0.123mmol)及偶氮二甲酸二異丙酯(47.8μL,0.246mmol)來製備該化合物。分離得到米色固體狀N,N-二環丙基-6-乙基-4-(3-異丙基-1,2,4-噻二唑-5-基胺基)-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(21mg,34.9%產率)。
MS(ESI)m/z 465.3(M+H)。
1H NMR(400MHz,DMSO-d6)δ ppm 12.24(s,1H),8.18(s,1H),7.28(s,1H),4.64(q,2H,J=6.94Hz),4.06(s,3H),3.10(ddd,1H,J=13.93,6.90,6.78Hz),2.86-3.00(m,2H),1.42(t,3H,J=7.03Hz),1.32(s,3H),1.31(s,3H),0.72-0.81(m,4H),0.63-0.71(m,4H)。
將N,N-二環丙基-6-乙基-1-甲基-4-硫脲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例2B,30mg,0.075mmol)與1,1-二甲氧基-N,N-二甲基甲胺(1g,8.39mmol)之混合物在50℃下加熱2h。在真空中蒸發出過量1,1-二甲氧基-N,N-二甲基甲胺,並將粗實例物質溶解於二氯甲烷(1mL)中,並添加O-(三甲苯基磺醯基)羥胺(24.4mg,0.113mmol)。將反應混合物在室溫下攪拌3h。添加水並分離各層。有機層經硫酸鎂乾燥,過濾並在真空中濃縮。藉由製備型HPLC對粗殘留物進行純化,得到黃色固體狀4-(1,2,4-噻二唑-5-基胺基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(7mg,19.20%產率)。
MS(ESI)m/z 423.0(M+H)。
1H NMR(500MHz,CD3OD)δ:8.32(s,1H),8.27(s,1H),7.38(d,J=4.4Hz,1H),7.28(s,1H),4.74(q,J=7.0Hz,2H),4.15(s,3H),2.94-3.00(m,2H),1.53(t,J=7.0Hz,3H),0.82-0.89(m,4H),0.75-0.82(m,4H)。
125A 製備4-(3-乙醯基硫脲基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
向4-胺基-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例1J,60mg,0.177mmol)存於丙酮(1.182mL)中之溶液中添加異硫氰酸乙醯酯(0.020mL,0.230mmol)。將反應混合物在室溫下攪拌6h。LC/MS顯示仍然有一半起始材料剩餘。再添加0.5當量異硫氰酸乙醯酯,並將反應混合物在35℃下加熱過夜。蒸發溶劑,並藉由急驟層析在矽膠上使用自動化ISCO系統(24g管柱,使用2-8%甲醇/二氯甲烷溶析)對粗產物進行純化。獲得黃色固體狀4-(3-乙醯基硫脲基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(34mg,43.6%產率)。
MS(ESI)m/z 440.1(M+H)。
125 製備N,N-二環丙基-4-(1,5-二甲基-1H-1,2,4-三唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺
將4-(3-乙醯基硫脲基)-N,N-二環丙基-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(實例125A,17mg,0.039mmol)及甲基肼(2.486μL,0.046mmol)存於乙酸(0.5mL)中之混合物在80℃下加熱4h,LC/MS顯示起始材料仍有剩餘。再添加甲基肼(2.486
μL,0.046mmol),並再持續加熱2h,反應完成。蒸發溶劑,並藉由製備型HPLC對粗物質進行純化,獲得米色固體狀N,N-二環丙基-4-(1,5-二甲基-1H-1,2,4-三唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺(5.2mg,30.7%產率)。
MS(ESI)m/z 434.3(M+H)。
1H NMR(CDCl3)δ:7.96(s,1H),7.65(s,1H),6.83(s,1H),4.67(q,J=7.1Hz,2H),4.01(s,3H),3.82(s,3H),2.77-2.84(m,2H),2.43(s,3H),1.48(t,J=7.2Hz,3H),0.79-0.86(m,4H),0.71-0.77(m,4H)。
Claims (7)
- 一種化合物N,N-二環丙基-4-(1,5-二甲基-1H-吡唑-3-基胺基)-6-乙基-1-甲基-1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶-7-甲醯胺,其具有下式,
- 一種醫藥組合物,其包含如請求項1之化合物及醫藥上可接受之載劑。
- 一種如請求項1之化合物的用途,其用以製造用於治療以下疾病之藥劑:骨髓增生性疾病;胰腺癌、前列腺癌、肺癌、頭頸癌、乳癌、結腸癌、卵巢癌、胃癌之實體腫瘤;多發性骨髓瘤、黑色素瘤、神經母細胞瘤、膠質母細胞瘤、全身性肥大細胞增多症及血液惡性腫瘤。
- 如請求項3之用途,其中該骨髓增生性疾病係真性紅細胞增多症、特發性血小板減少或原發性骨髓纖維化。
- 如請求項3之用途,其用以製造用於治療急性髓性白血病或急性淋巴性白血病之藥劑。
- 如請求項5之用途,其中該急性髓性白血病包括難治性急性髓樣白血病。
- 如請求項3之用途,其中該藥劑進一步包含一或多種其他抗癌劑或細胞毒性劑或與該一或多種其他抗癌劑或細胞毒性劑組合使用。
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