TWI812302B - 作為ron抑制劑之新穎尿素衍生物化合物 - Google Patents
作為ron抑制劑之新穎尿素衍生物化合物 Download PDFInfo
- Publication number
- TWI812302B TWI812302B TW111123538A TW111123538A TWI812302B TW I812302 B TWI812302 B TW I812302B TW 111123538 A TW111123538 A TW 111123538A TW 111123538 A TW111123538 A TW 111123538A TW I812302 B TWI812302 B TW I812302B
- Authority
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- Taiwan
- Prior art keywords
- phenyl
- oxy
- pyridin
- imidazo
- dihydro
- Prior art date
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- -1 urea derivative compound Chemical class 0.000 title claims description 79
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- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
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- JFLKFZNIIQFQBS-FNCQTZNRSA-N trans,trans-1,4-Diphenyl-1,3-butadiene Chemical group C=1C=CC=CC=1\C=C\C=C\C1=CC=CC=C1 JFLKFZNIIQFQBS-FNCQTZNRSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Bioinformatics & Cheminformatics (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本發明關於一種作為蛋白激酶抑制劑(特別是RON抑制劑)之新穎化合物。
Description
本發明關於一種作為蛋白激酶抑制劑之新穎化合物。具體來說,本發明關於一種作為RON抑制劑之新穎化合物。
本申請案主張於2021年6月24日在韓國智慧財產局提出申請之韓國專利申請案第10-2021-0082700號的權益,其揭示係以全文引用方式併入本文中。
已知有至少400種的催化從三磷酸腺苷(ATP)至蛋白質受質的磷酸化轉變反應之蛋白激酶。在磷醯基轉移至其的靶蛋白中,特異性胺基酸為酪胺酸、絲胺酸或蘇胺酸,因此蛋白激酶通常稱為蛋白酪胺酸激酶(PTK)或絲胺酸/蘇胺酸激酶(STK)。
蛋白激酶構成負責控制細胞內的多種信號通
路之結構相關族群的大家族。信號通路包括藉由將磷醯基轉移到靶蛋白的許多其他信號通路。此等磷酸化事件充當可調節靶蛋白或蛋白複合物的生物功能之分子開/關開關。信號通路中適合的蛋白激酶功能為活化或去活化代謝酶、調節蛋白、受體、細胞骨架蛋白、離子通道和泵、轉錄因子、等等。由於蛋白磷酸化的缺陷控制而不受控制的信號涉及許多疾病,包括發炎、癌症、過敏/氣喘、免疫系統的疾病、中樞神經系統的疾病、血管生成、等等。
幾乎所有激酶都包括類似的250-300個胺基酸催化結構域。激酶可藉由彼等磷酸化的受質來分類,且已經鑑定通常對應於此等激酶家族中各個的序列模體(sequence motif)。
同時,源自南特(nante)RON的受體,其為酪胺酸蛋白激酶受體之一,也稱為巨噬細胞刺激1受體(MST1R),且據報導其促進癌細胞的侵襲和轉移。也已知RON的過表現出現在多種腫瘤類型中。
酪胺酸蛋白激酶(諸如腫瘤細胞中的RON)之活化增加腫瘤細胞的增生、侵襲和轉移,並增加腫瘤細胞對凋亡和細胞毒治療的抵抗力。因此,靶向酪胺酸蛋白激酶(諸如RON)的選擇性小分子激酶調節劑具有治療癌症的治療潛力,其中RON受體等等的活化在原發性腫瘤的發育和進展及繼發性轉移中起關鍵作用。因此,對用於選擇性抑制酪胺酸蛋白之一的RON中的激酶活性之各種抑製劑正進行持續研究。
本發明之一態樣提供一種具有蛋白激酶抑制活性之新穎化合物。
本發明之另一態樣提供一種可用於預防或治療癌症之化合物。
本發明之再一態樣提供一種可用於預防或治療免疫相關疾病之化合物。
本發明之又一態樣提供一種可用作為RON抑制劑之化合物。
為了達到上述目的,根據本發明之一態樣,提供一種下述式1之吡啶衍生物化合物或其醫藥上可接受的鹽。
在式1中,
上述X為O,上述Y為氫、鹵素、C1-C6烷基、或C3-C6環烷基,上述R1為氫、C1-C6烷基、C3-C12環烷基、或C2-C11雜環烷基,上述R2為氫或C1-C6烷基,上述A為-Ar或-(CH2)n-Ar,其中Ar為經取代或未經取代之C6-C10芳基、或經取代或未經取代之5-員雜芳基,其包括1至4個選自由下列所組成之群組的雜環原子:氮、硫和氧,其中取代基為選自下列之一或多者:鹵素、胺、C1-C6烷基、C3-C12環烷基、鹵素取代之C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羥基、羧酸、C1-C6烷羰基、C1-C6烷氧羰基、C1-C6烷羰氧基、硝基、氰基、胺甲醯基、尿素、巰基、和NR3R4,且上述n為1至3的整數,上述R3和R4各自獨立地為氫或C1-C6烷基,上述B為氫、C1-C6烷基、經取代之C1-C6烷基、C3-C12環烷基、經取代之C3-C12環烷基、C3-C11雜環烷基、經取代之C3-C11雜環烷基、C6-C20芳基、經取代之C6-C20芳基,其中取代基為鹵素、C1-C6烷基、C3-C7環烷基、鹵素取代之C1-C6烷基、C1-C6烷氧基、C3-C11雜環烯基、或C6-C10芳基,其中該鹵素係選自由下列所組成之群組:F、Cl、Br、和I。
根據本發明之另一態樣,提供一種醫藥組成物,其包括上述式1之化合物或其醫藥上可接受的鹽,和醫藥上可接受的載劑。
根據本發明,一種新穎化合物或其藥學上可接受的鹽,其藉由抑制蛋白激酶(特別是RON受體的蛋白激酶)的活性而可有效地使用於治療各種免疫媒介的疾病,包括抗癌劑,但本發明不限於此。
根據一態樣,本發明提供一種上述定義的式1之新穎尿素衍生物化合物或其醫藥上可接受的鹽。
在本發明中,化合物包括但不限於式1化合物、其立體異構物(諸如鏡像異構物和非鏡像異構物)、溶劑合物和前驅藥。
在式1中,
上述X為O,上述Y為氫、鹵素、C1-C6烷基、或C3-C6環烷基,上述R1為氫、C1-C6烷基、C3-C12環烷基、或C2-C11雜環烷基,上述R2為氫或C1-C6烷基,上述A為-Ar或-(CH2)n-Ar,其中Ar為經取代或未經取代之C6-C10芳基、或經取代或未經取代之5-員雜芳基,其包括1至4個選自由下列所組成之群組的雜環原子:氮、硫和氧,其中取代基為選自下列之一或多者:鹵素、胺、C1-C6烷基、C3-C12環烷基、鹵素取代之C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羥基、羧酸、C1-C6烷羰基、C1-C6烷氧羰基、C1-C6烷羰氧基、硝基、氰基、胺甲醯基、尿素、巰基、和NR3R4,且上述n為1至3的整數,上述R3和R4各自獨立地為氫或C1-C6烷基,上述B為氫、C1-C6烷基、經取代之C1-C6烷基、C3-C12環烷基、經取代之C3-C12環烷基、C3-C11雜環烷基、經取代之C3-C11雜環烷基、C6-C20芳基、經取代之C6-C20芳基,其中取代基為鹵素、C1-C6烷基、C3-C7環烷基、鹵素取代之C1-C6烷基、C1-C6烷氧基、C3-C11雜環烯基、或C6-C10芳基,其中該鹵素係選自由下列所組成之群組:F、Cl、Br、和I。
在本說明書中,術語“取代”意指與結構中的碳原子鍵結的氫原子被改變為另一個取代基,且取代發生的位置不受限制,只要其為氫原子被取代的位置,即,取代基可被取代的位置,及在二或更多個位置被取代時,二或更多個取代基彼此可為相同或不同。
在本說明書中,除非另有定義,“取代基”可為一或更多個選自由下列所組成之群組:氘、鹵素、羥基、C1-C10烷基、C3-C12環烷基、C1-C10烷氧基、C5-C12芳氧基、C1-C10烷硫基(alkylthioxy)、C5-C12芳硫基(arylthioxy)、C1-C10烷基亞磺醯基(alkylsulfoxy)、C5-C12芳基亞磺醯基(arylsulfoxy)、C1-C10鹵烷基、C2-C20烯基、C0-C10胺、腈、硝基、醯亞胺、醯胺、側氧基、羰基、甲酸、胺甲醯基、酯、C5-C12芳基、和C5-C12雜芳基。
在本說明書中,“烷基”可為直鏈或支鏈,且較佳具有1至20個碳原子,除非另有定義。其實例可包括甲基、乙基、丙基、正丙基、異丙基、丁基、正丁基、異丁基、三級-丁基、二級-丁基、1-甲基丁基、乙基丁基、戊基、正戊基、異戊基、新戊基、三級-戊基、己基、正己基、甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基、庚基、正庚基、1-甲基己基、環戊基甲基、環己基甲基、辛基、正辛基、三級-辛基、1-甲基庚基、2-乙基己基、2-丙基戊基、正壬基、2,2-二甲基庚基、1-乙基丙基、二甲基丙基、異己基、2-甲基戊基、4-甲基己基、5-甲基己基、等等,但不限於此。
在本說明書中,“環烷基”可意指環狀飽和烴,且較佳具有3至20個碳原子,除非另有定義。其實例可包括環丙基、環丁基、環戊基、3-甲基環戊基、2,3-二甲基環戊基、環己基、3-甲基環己基、4-甲基環己基、2,3-二甲基環己基、3,4,5-三甲基環己基、4-三級-丁基環己基、環庚基、環辛基、等等,但不限於此。
在本說明書中,“烷氧基”可為直鏈、支鏈或環狀,且較佳具有1至20個碳原子,除非另有定義。其實例可包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、三級-丁氧基、二級-丁氧基、正戊氧基、新戊氧基、異戊氧基、正己氧基、3,3-二甲基丁氧基、2-乙基丁氧基、正辛氧基、正壬氧基、正癸氧基、苄氧基、對-甲基苄氧基、等等、但不限於此。
在本說明書中“烯基”可為直鏈或支鏈,且較佳具有2至20個碳原子,除非另有定義。其實例可包括乙烯基、1-丙烯基、異丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、3-甲基-1-丁烯基、1,3-丁二烯基、烯丙基、1-苯基乙烯基-1-基、2-苯基乙烯基-1-基、2,2-二苯基乙烯基-1-基、2-苯基-2-(萘基-1-基)乙烯基-1-基、2,2-雙(二苯基-1-基)乙烯基-1-基、二苯乙烯基、苯乙烯基、等等,但不限於此。
在本說明書中,“芳基”可為單芳基、聯芳基或三或更多個環的多環芳基,且當包括二或更多個環狀結構時,各環可稠合或包括螺環形式,且較佳具有5至12個
碳原子,除非另有定義。其實例可包括苯基、聯苯基、聯三苯基、萘基、蒽基、菲基、芘基、苝基、等等,但不限於此。
在本說明書中,“雜環原子”意指環中所包括的非碳原子。除非另有定義,雜環原子可包括一或多個選自氧、氮、硒和硫之原子。
在本說明書中,“雜環烷基”可意指包括雜環原子之環狀飽和烴,且較佳具有2至20個碳原子,除非另有定義。
在本說明書中,“雜芳基”可意指包括雜環原子之芳族烴。雜芳基可為單環或多環,且當包括二或更多個環狀結構時,各環可稠合或包括螺環形式,且較佳具有5至12個碳原子,除非另有定義。其實例可包括噻吩基、呋喃基、吡咯基、咪唑基、噻唑基、唑基、二唑基、吡啶基、聯吡啶基、嘧啶基、三基、三唑基、吖啶基、嗒基、吡基、喹啉基、喹唑啉基、喹啉基、呔基、吡啶并嘧啶基、吡啶并吡基、吡并吡基、異喹啉基、吲哚基、咔唑基、苯并唑基、苯并咪唑基、苯并噻唑基、等等、但不限於此。
根據一實施態樣,本發明提供一種下述式2之新穎尿素衍生物化合物或其醫藥上可接受的鹽。
該取代基與式1中所定義者相同。
根據一實施態樣,在上述式1中,上述A可為-Ar或-(CH2)n-Ar,其中上述Ar可為經取代或未經取代之C6-C10芳基或經取代或未經取代之5-員雜芳基。此時,關於結構A,術語‘芳基’並不意指僅其中A為單價官能基的結構,即在上述式1中其中B為氫的結構,和當上述B具有氫之外的結構時,上述Ar可為經取代或未經取代之C6-C10伸芳基或經取代或未經取代之5-員伸雜芳基。
根據一實施態樣,在上述式1中,上述A可為經取代或未經取代之5-員雜芳基,且具體來說,可包括至少二個雜環原子。此時所包括的雜環原子彼此可為相同或不同,但不限於此。
根據另一實施態樣,在上述式1中,上述Ar可包括至少一個氮原子作為雜環原子,且可進一步包括至少一個選自氮和硫之雜環原子。
根據另一實施態樣,上述Ar可包括一或二個選自由下列所組成之群組的雜芳基:吡唑、咪唑、和噻唑,其中雜芳基可經取代或未經取代,且經取代之雜芳基
具有的取代基可為鹵素、胺、C1-C6烷基、鹵素取代之C1-C6烷基、C6-C10芳基、C1-C6烷氧基、C1-C6烷硫基、羥基、羧酸、C1-C6烷羰基、C1-C6烷氧羰基、C1-C6烷羰氧基、硝基、氰基、胺甲醯基、尿素、巰基、和NR3R4。此時,上述R3和R4係如上述所定義。
根據另一實施態樣,在上述式1中,上述A可為經取代或未經取代之C6-C10芳基,且具體來說,可為經取代或未經取代之苯基。此時,經取代之苯基具有的取代基可為一或多個選自鹵素和鹵素取代之C1-C6烷基。更具體地說,經取代之苯基具有的取代基可為一或多個選自氟基、溴基、和三氟甲基。
根據另一實施態樣,在上述式1中,A可為-(CH2)n-Ar,其中n可為1至3的整數,及例如,n可為1。
根據一實施態樣,在上述式1中,上述B可為氫、C1-C6烷基、經取代之C1-C6烷基、C3-C7環烷基、苯基、經取代之苯基、苄基、或萘 四氫哌喃、哌啶或經取代之哌啶,其中取代基可為一種化合物,其為鹵素、C1-C3烷基、鹵化C1-C3烷基、C3-C5環烷基、或C1-C3烷氧基。
根據一實施態樣,在上述式1中,上述Y為氟基。
根據一實施態樣,在上述式1中,上述R1為C1-C6烷基、C3-C6環烷基、或C4-C6雜環烷基。
根據另一實施態樣,在上述式1中,上述R1
為氫、甲基、乙基、異丙基、環戊基、或四氫呋喃基。
根據一實施態樣,在上述式1中,上述R2為氫。
根據一實施態樣,上述式1之化合物可選自由下列所組成之群組:N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-乙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-乙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-甲基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-甲基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-
1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,5-乙基-N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲醯胺,5-乙基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-
1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-苯基噻唑-5-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-苯基噻唑-2-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(對-)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1,5-二苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氫-2H-哌喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑
并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺,4-溴-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,3-溴-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺,1-環己基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氫-2H-哌喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-(三級-丁基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-環庚基-N-(3-氟-4-((1-異丙基-2-側氧基-
2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-(2-氯苯基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-(2,6-二氟苯基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-1-(四氫呋喃-3-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-側氧基-
2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-3-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-1,2,3-三唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-1,2,3-三唑-4-甲醯胺,和N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-1H-1,2,3-三唑-4-甲醯胺,及其結構係如下表1中所示。
在本發明中,“醫藥上可接受的鹽”包括通常用於形成鹼金屬鹽和形成游離酸或游離鹼的加成鹽之鹽。該等鹽的性質並不重要,但該等鹽應為醫藥上可接受的。適合於式1化合物之醫藥上可接受的酸加成鹽可從無機酸或有機酸製備。無機酸的實例可包括鹽酸、氫溴酸、氫碘酸、硝酸、碳酸、硫酸及磷酸。適合的有機酸可選自脂族、環脂族、芳族、芳脂族、雜環族、羧酸和磺酸類之有機酸,及其實例可包括甲酸、乙酸、己二酸、丁酸、丙酸、琥珀酸、乙醇酸、葡萄糖酸,乳酸、蘋果酸、酒石酸、檸檬酸、抗壞血酸、葡萄糖醛酸、順丁烯二酸、反丁烯二酸、丙酮酸、天冬胺酸、麩胺酸、苯甲酸、鄰胺苯甲酸、甲磺酸、4-羥基苯甲酸、苯乙酸、杏仁酸、撲酸(embonic acid)(撲酸(pamoic acid))、甲磺酸、乙磺酸、乙二磺酸、苯磺酸、泛酸、2-羥基乙磺酸、甲苯磺酸、對胺苯磺酸、環己基胺基磺酸、樟腦二酸、樟腦磺酸、二葡萄糖酸、環戊烷丙酸、十二基磺酸、糖庚酸、糖磷酸、庚酸、己酸、2-羥基-乙磺酸、菸鹼酸、2-萘磺酸、草酸、棕櫚酸、果膠酯酸、過硫酸、2-苯基丙酸、苦味酸、三甲基乙酸、丙酸、琥珀酸、酒石酸、硫氰酸、甲磺酸、十一
酸、硬脂酸、藻酸、β-羥基丁酸、水楊酸、半乳糖二酸和半乳糖醛酸。適合於式1化合物之醫藥上可接受的鹼加成鹽可為金屬鹽,例如,自鋁、鈣、鋰、鎂、鉀、鈉或鋅製得之鹽,或從有機鹼(包括經取代之胺,包括一級胺、二級胺或三級胺及環狀胺,例如咖啡因、精胺酸、二乙胺、N-乙基哌啶、組胺酸、葡糖胺、異丙胺、離胺酸、嗎啉、N-乙基嗎啉、哌、哌啶、三乙胺、三甲胺)製得之鹽。此等鹽可藉由一般方式從本發明之對應化合物製備,諸如使適當酸或鹼與式1化合物反應。當鹼性基團和酸性基團存在於同一分子中時,式1化合物也可形成內鹽。在本發明中,“溶劑合物”可包括水合物、與有機溶劑(諸如甲醇、乙醇、2-丙醇、1,2-丙二醇、1,3-丙二醇、正丁醇、1,4-丁二醇、三級-丁醇、乙酸、丙酮、乙酸丁酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級-丁酯、乙酸異丁酯、甲基乙基酮、2-戊酮、四氫呋喃、乙腈、氯仿、甲苯及其混合物)的溶劑合物。
根據另一態樣,本發明提供一種醫藥組成物,其包括上述定義之新穎式1化合物或其醫藥上可接受的鹽,和醫藥上可接受的載劑。
醫藥組成物可用於預防或治療蛋白激酶媒介的疾病,但本發明的用途不限於此等疾病。
在一個實施態樣中,醫藥組成物可用於預防或治療RON媒介的疾病。
根據本發明之醫藥組成物包括治療有效量的
上述式1化合物或其醫藥上可接受的鹽。
在一個實施態樣中,疾病可為選自由下列所組成之群組的癌症:肺癌、乳癌、大腸直腸癌、腎癌、胰臟癌、頭癌、子宮頸癌、遺傳性乳頭狀腎細胞癌、小兒肝細胞癌、和胃癌,但不限於此。
在另一實施態樣中,疾病可為選自由下列所組成之群組的免疫疾病:發炎性病症、心血管疾病、病毒引起的疾病、循環系統疾病、纖維增生性疾病和痛覺,但不限於此。
為了治療上述疾病,可將醫藥組成物投予至需要預防或治療上述疾病的個體。
在本說明書中,術語“預防”意指降低感染疾病或病症的風險,且其意指藉由防止暴露於或易患該疾病但尚未患有該疾病或表現出該疾病的症狀之個體中超過一種類型的疾病臨床症狀之進展來抑制或延遲疾病發作的任何作用。
在本說明書中,術語“治療”意指減輕疾病或病症,且意指藉由停止或減少疾病或其一種或多種臨床症狀的進展來減輕或有利地改變疾病症狀的任何作用。
在本說明書中,術語“載劑”意指促進化合物引入細胞或組織中的化合物。醫藥組成物可藉由使用醫藥上可接受的載劑調配而製備成單位劑量形式,或可藉由引入多劑量容器中來製備。此時,調配物可為在油或水介質中的溶液、懸浮液或乳液的形式,或可為萃取物、粉末、
顆粒、錠劑、膠囊或凝膠(例如水凝膠)的形式,且可另外含有分散劑或穩定劑。
此外,醫藥組成物中包括的以式1表示之化合物或其醫藥上可接受的鹽可載於醫藥上可接受的載劑(諸如膠體懸浮液、粉末、鹽水溶液、脂質、脂質體、微球或奈米球粒子)中。上述可與輸送方式形成複合物或與之結合,且可使用該項技術已知的輸送系統(諸如脂質、脂質體、微粒、金、奈米粒子、聚合物、縮合反應器、多醣、聚胺基酸、樹枝狀聚合物、皂素、吸附增強物質或脂肪酸)帶入體內。
此外,醫藥上可接受的載劑可包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、澱粉、阿拉伯膠、橡膠、磷酸鈣、海藻酸鹽、明膠、矽酸鈣、微晶纖維素、聚乙烯吡咯啶酮、纖維素、水、糖漿、甲基纖維素、羥基苯甲酸甲酯、羥基苯甲酸丙酯、滑石、硬脂酸鎂、礦物油、等等,其通常用於調配物中,但不限於此。此外,除了上述組分可額外包括潤滑劑、潤濕劑、甜味劑、調味劑、乳化劑、懸浮劑、防腐劑、等等。
根據本發明之醫藥組成物在臨床投予時可口服或腸胃外投予,且可以一般醫藥調配物的形式使用。即,本發明之醫藥組成物在實際臨床投予時可以口服和腸胃外的各種調配物投予,且在調配時,使用常用的稀釋劑或賦形劑諸如填充劑、增量劑、黏合劑、潤濕劑、崩解劑、表面活性劑、等等來製備。用於口服投予的固體調配
物包括錠劑、丸劑、酸、粒劑、膠囊、等等,且該等固體調配物可藉由將至少一種賦形劑例如澱粉、碳酸鈣、蔗糖或乳糖、明膠、等等混合在草藥萃取物或草藥發酵產物中而製備。此外,除了簡單賦形劑之外,也可使用潤滑劑諸如硬脂酸鎂、滑石。用於口服投予的液體調配物可包括懸浮液、內用液體、乳液、糖漿、等等,且除了常用的簡單稀釋劑水和液體石蠟外,也可包括各種賦形劑諸如潤濕劑、甜味劑、矯味劑、香料、防腐劑、等等。用於腸胃外投予之調配物可包括無菌水溶液、非水溶劑、懸浮劑、乳液、凍乾調配物和栓劑。非水溶劑和懸浮液之實例可包括丙二醇、聚乙二醇、植物油(諸如橄欖油)、和可注射酯(諸如油酸乙酯)。作為栓劑的基質,可使用witepsol、macrogol、tween 61、可可脂、三月桂酸甘油酯脂肪(laurin fat)、甘油、明膠、等等。
當醫藥組成物因臨床目的而投予時,式1化合物或其醫藥上可接受的鹽之有效劑量可取決於諸如調配方法、投予模式、患者的年齡、體重、性別、病理狀況、和飲食、投予時間、投予途徑、排泄率、藥物混合、和反應敏感性之因素而改變,但一般情況下,醫藥組成物可投予0.01至20mg/天,較佳1至10mg/天,每1kg成年患者體重,並且可每天分期投予數次,較佳每天2至3次,根據醫生或藥劑師的判斷定期進行。
在另一態樣中,本發明提供一種治療蛋白激酶媒介的疾病(特別是RON媒介的疾病)之方法,該方法包
括將治療有效量的上述式1化合物或其醫藥上可接受的鹽投予至個體。
在另一態樣中,本發明提供一種抑制RON受體的活性之方法,該方法包括將治療有效量的上述式1化合物或其醫藥上可接受的鹽投予至個體。
在本說明書中,術語“治療有效量”意指各調配物的量,其在以各調配物本身治療期間達到降低疾病嚴重程度和疾病發作頻率之目的,但避免通常與其他療法相關的有害副作用。例如,用於腫瘤治療的有效藥劑係有效延長患者的存活期、抑制與腫瘤相關的快速增生細胞之生長或使腫瘤消退。
在下文中,根據下列方法可製備本發明之實例化合物,但本發明之化合物不受限於製備方法。
製備例1. 7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
在下文中,根據下述反應式1製備製備例1之化合物。
條件:a)Boc-酐,THF,RT;b)4-氯-3-硝基吡啶-2-胺,NaH,DMSO.100℃;c)Pd/C,H,MeOH/THF,RT;d)氯甲酸乙酯,DIPEA,THF,RT;e)TFA,DCM,RT;f)NaH,2-溴丙烷,DNF,0℃至RT;g)乙醇鈉,EtOH,100℃
步驟1)(3-氟-4-羥基苯基)胺甲酸三級-丁基酯
將4-胺基-2-氟酚(10g,79mmol)溶解在THF(100mmol)中並接著將Boc-酐(34.3g,158mmol)加至其中,及將混合物在室溫下攪拌12小時。將反應混合物濃縮,並藉由管柱層析法純化殘餘物以獲得標題化合物(13g,產率:72%)。
MS m/z:228[M+H]。
步驟2)(4-((2-胺基-3-硝基吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯
將上述步驟1中所得之化合物(3-氟-4-羥基苯基)胺甲酸三級-丁基酯(12.5g,55mmol)和4-氯-3-硝基吡啶-2-胺(9.55g,55mmol)溶解在60ml的DMSO中,及接著將NaH(2.64g,66mmol)在0℃下加至其中,並將混合物在100℃下攪拌12小時。將反應混合物用乙酸乙酯稀釋,用水和鹽水洗滌,並接著濃縮。藉由管柱層析法純化殘餘物以獲得標題化合物(15g,產率:75%)。
MS m/z:365[M+H]。
步驟3)(4-((2,3-二胺基吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯
將上述步驟2中所得之化合物(4-((2-胺基-3-硝基吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯在室溫下溶解在甲醇/THF混合溶劑中,並接著將Pd/C加至其中,並將混合物在氫氣條件下攪拌12小時。將反應混合物通過矽藻土過濾器過濾並接著濃縮。藉由管柱層析法純化殘餘物以獲得標題化合物(11.5g,產率:84%)。
MS m/z:335[M+H]。
步驟4)(4-((2-胺基-3-((乙氧羰基)胺基)吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯
將上述步驟3中所得之化合物(4-((2,3-二胺基吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯(10g,29.9mmol)和吡啶(4.73g,59.8mmol)溶解在THF中,並接著將氯甲酸乙酯(3.57g,32.9mmol)在0℃下緩慢加至其中。將混合物攪拌12小時,並接著將反應混合物用乙酸乙酯稀釋,用水和鹽水洗滌,並接著濃縮。藉由管柱層析法純化
殘餘物以獲得標題化合物(4.5g,產率:37%)。
MS m/z:407[M+H]。
步驟5)(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)胺甲酸乙基酯
將上述步驟4中所得之化合物(4-((2-胺基-3-((乙氧羰基)胺基)吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯(3.5g,8.61mmol)溶解在TFA/DCM 1:5混合溶劑中並在室溫下攪拌5小時。將反應混合物用乙酸乙酯稀釋,用水和鹽水洗滌,並藉由管柱層析法純化以獲得標題化合物(1.9g,產率:72%)。
MS m/z:307[M+H]。
步驟6)(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)(異丙基)胺甲酸乙基酯
將上述步驟5中所得之化合物(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)胺甲酸乙基酯(1.9g,6.2mmol)溶解在DMF中,並接著將NaH(0.273g,6.82mmol)在
0℃下加至其中,接著將2-溴丙烷(0.84g,6.82mmol)緩慢加至其中。將混合物攪拌12小時,並接著將反應混合物用乙酸乙酯稀釋,用水和鹽水洗滌,並接著濃縮。藉由管柱層析法純化殘餘物以獲得標題化合物(1.25g,產率:58%)。
MS m/z:349[M+H]。
步驟7)7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
將上述步驟6中所得之化合物(2-胺基-4-(4-胺基-2-氟苯氧基)吡啶-3-基)(異丙基)胺甲酸乙酯(1.25g,3.59mmol)和乙醇鈉(0.488g,7.18mmol)溶解在乙醇中並將混合物在微波條件和120℃下攪拌4小時。將水加至反應混合物中,使混合物結晶,從而得到標題化合物(1.0g,產率:92%)。
1H NMR(500MHz,MeOH-d4)δ 7.76(d,1H),7.03(t,1H),6.62(dd,1H),6.57(dd,1H),6.33(d,1H),5.02(m,1H),1.58(s,3H),1.07(s,3H);MS m/z:303[M+H]。
製備例2. 7-(4-胺基-2-氟苯氧基)-1-乙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
以類似於製備例1的方式藉由使用碘乙烷代替製備例1之步驟6中的2-溴丙烷獲得標題化合物(63mg,產率:56%)。
MS m/z:289[M+H]。
製備例3. 7-(4-胺基-2-氟苯氧基)-1-甲基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
以類似於製備例1的方式藉由使用碘甲烷代替製備例1之步驟6中的2-溴丙烷獲得標題化合物(90mg,產率:74%)。
MS m/z:275[M+H]。
製備例4. 7-(4-胺基-2-氟苯氧基)-1-環戊基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
以類似於製備例1的方式藉由使用溴環戊烷代替製備例1之步驟6中的2-溴丙烷獲得標題化合物(150mg,產率:86%)。
MS m/z:329[M+H]。
製備例5. 7-(4-胺基-2-氟苯氧基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
在下文中,根據下述反應式2製備製備例5之化合物。
步驟1)(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)胺甲酸三級-丁基酯
將(4-((2,3-二胺基吡啶-4-基)氧基)-3-氟苯基)胺甲酸三級-丁基酯(250mg,0.75mmol)溶解在THF中,並將混合物冷卻至0℃。將三光氣(225mg,0.75mmol)加至其中,並將混合物在0℃下攪拌30分鐘。將飽和NaHCO3加至其中,並將混合物用乙酸乙酯萃取3次。將有機層用鹽水洗滌並濃縮,及藉由管柱層析法純化殘餘物以獲得標題化合物(85mg,產率:32%)。
MS m/z:361[M+H]。
步驟2)7-(4-胺基-2-氟苯氧基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮
將上述步驟1中所得之化合物(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)胺甲酸三級-丁基酯(80mg,0.22mmol)溶解在3ml的DCM中,並將1.5ml的TFA加至其中。將反應混合物在室溫下攪拌2小時。將反應混合物濃縮,用乙酸乙酯稀釋,並用飽和
NaHCO3洗滌。將有機層用鹽水洗滌及濃縮以獲得標題化合物(40mg,產率:69%)。
MS m/z:261[M+H]。
製備例6. 1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸
在下文中,根據下述反應式3製備製備例6之化合物。
步驟1)2-(乙氧基亞甲基)-4,4,4-三氟-3-側氧基丁酸乙酯
將4,4,4-三氟-3-側氧基丁酸乙酯(2.0g,10.9mmol)和三乙氧基甲烷(2.0g,14.1mmol)溶解在乙酐(3.3g,32.6mmol)中,並將混合物在130℃下攪拌4小時。將反應混合物濃縮以獲得標題化合物(2.0g,產率:77%)。
MS m/z:241[M+H]。
步驟2)1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯
將上述步驟1中所得之化合物2-(乙氧基亞甲基)-4,4,4-三氟-3-側氧基丁酸乙酯(0.5g,2.1mmol)和(2-氟苯基)肼(0.263g,2.1mmol)溶解在7ml的乙醇中並將混合物在70℃下攪拌4小時。將反應混合物用乙酸乙酯和水萃取及濃縮。藉由管柱層析法純化殘餘物以獲得標題化合物(0.38g,產率:60%)。
MS m/z:303[M+H]。
步驟3)1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸
將上述步驟2中所得之化合物1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸乙酯(0.38g,1.3mmol)溶解在4ml乙醇中,並接著將2ml的6N氫氧化鈉溶液在室溫下加至其中,並將混合物攪拌1小時。過濾藉由將冰水加至反應產物中所形成的固體以獲得標題化合物(0.18g,產率:52%)。
MS m/z:275[M+H]。
實施例1. N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺
在下文中,根據下述反應式4製備實施例1之化合物。
將上述製備例5中所得之化合物7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮(20mg,0.07mmol)、1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸(20mg,0.08mmol)、和HATU(40mg,0.10mmol)溶解在2ml的DMF中,並接著將DIPEA(17μl,0.10mmol)加至其中,及將混合物在室溫下攪拌12小時。將反應混合物用乙
酸乙酯稀釋,用水和鹽水洗滌,並接著濃縮。藉由prep-HPLC(在水/乙腈中之0.1%甲酸)純化殘餘物以獲得標題化合物(11mg,產率:30%)。
1H NMR(500MHz,DMSO-d6)δ 11.30(brs,1H),10.77(s,1H),8.35(s,1H),8.04(m,1H),7.78(d,1H),7.72(m,1H),7.60(m,3H),7.39(t,1H),6.37(d,1H);MS m/z:499[M+H]。
實施例2. N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例1的方式藉由使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例1之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(9mg,產率:28%)。
1H NMR(500MHz,DMSO-d6)δ 10.84(s,1H),8.34(s,1H),7.93(dd,1H),7.78(d,1H),7.64(m,3H),7.56(m,3H),7.40(t,1H),6.38(d,1H);MS m/z:499[M+H]。
實施例3. N-(4-((1-乙基-2-側氧基-2,3-二氫-
1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺
以類似於實施例1的方式藉由使用製備例2中所得之7-(4-胺基-2-氟苯氧基)-1-乙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例1之7-(4-胺基-2-氟苯氧基)-1H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(35mg,產率:64%)。
1H NMR(500MHz,DMSO-d6)δ 11.64(brs,1H),10.74(s,1H),8.31(s,1H),8.01(d,1H),7.98(d,1H),7.75(m,1H),7.59(m,5H),7.41(t,1H),6.36(d,1H),3.97(q,2H),1.26(t,3H);MS m/z:527[M+H]。
實施例4. N-(4-((1-乙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例3的方式藉由使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例3之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(33mg,產率:60%)。
1H NMR(500MHz,DMSO-d6)δ 11.62(brs,1H),10.81(s,1H),8.30(s,1H),7.90(d,1H),7.77(d,1H),7.59(m,3H),7.52(m,3H),7.43(t,1H),6.37(d,1H),3.97(q,2H),1.26(t,3H);MS m/z:527[M+H]。
實施例5. N-(3-氟-4-((1-甲基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺
以類似於實施例1的方式藉由使用製備例3中所得之7-(4-胺基-2-氟苯氧基)-1-甲基-1,3-二氫-2H-咪唑并
[4,5-b]吡啶-2-酮代替根據實施例1之7-(4-胺基-2-氟苯氧基)-1-H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(15mg,產率:26%)。
1H NMR(500MHz,DMSO-d6)δ 11.63(brs,1H),10.73(s,1H),8.31(s,1H),7.97(d,1H),7.76(d,1H),7.63(m,1H),7.48(m,5H),7.38(t,1H),6.38(d,1H),3.47(s,3H);MS m/z:513[M+H]。
實施例6. N-(3-氟-4-((1-甲基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例5的方式藉由使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例5之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(15mg,產率:21%)。
1H NMR(500MHz,DMSO-d6)δ 11.64(brs,1H),10.80(s,1H),8.30(s,1H),7.88(d,1H),7.76(d,1H),7.59(m,3H),7.50(m,3H),7.40(t,1H),6.38(d,1H),3.46(s,3H);MS m/z:513[M+H]。
實施例7. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例1的方式藉由使用製備例1中所得之7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例1之7-(4-胺基-2-氟苯氧基)-1-H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(10mg,產率:11%)。
1H NMR(500MHz,MeOH-d4)δ 8.13(s,1H),7.89(m,2H),7.58(m,6H),7.36(t,1H),6.45(d,1H),5.01(m,1H),1.57(d,6H);MS m/z:541[M+H]。
實施例8. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(36mg,產率:50%)。
1H NMR(500MHz,DMSO-d6)δ 11.68(brs,1H),10.78(s,1H),8.35(s,1H),8.06(m,1H),7.81(d,1H),7.76(m,1H),7.62(m,5H),7.42(t,1H),6.42(d,1H),4.90(m,1H),1.49(d,6H),1.47(s,3H);MS m/z:541[M+H]。
實施例9. 5-乙基-N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲醯胺
以類似於實施例1的方式藉由使用5-乙基-1-
苯基-1H-吡唑-4-甲酸代替根據實施例1之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(26mg,產率:53%)。
1H NMR(500MHz,DMSO-d6)δ 11.41(brs,1H),11.23(brs,1H),10.14(s,1H),8.32(s,1H),7.98(d,1H),7.78(d,1H),7.62(m,4H),7.51(m,2H),7.38(t,1H),6.36(d,1H),2.98(q,2H),1.08(t,3H);MS m/z:459[M+H]。
實施例10. 5-乙基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用5-乙基-1-苯基-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(26mg,產率:53%)。
1H NMR(500MHz,DMSO-d6)δ 11.68(brs,1H),10.15(s,1H),8.34(s,1H),8.01(d,1H),7.82(d,1H),7.60(m,3H),7.51(m,3H),7.45(t,1H),6.41(d,1H),4.90(m,1H),2.99(q,2H),1.09(t,3H);MS m/z:501[M+H]。
實施例11. N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺
以類似於實施例1的方式藉由使用7-(4-胺基-2-氟苯氧基)-1-(四氫-2H-哌喃-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例1之7-(4-胺基-2-氟苯氧基)-1-H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(1.4mg,產率:12%)。
MS m/z:583[M+H]。
實施例12. N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲醯胺
以類似於實施例1的方式藉由使用3,5-二甲基-1-苯基-1H-吡唑-4-甲酸代替根據實施例1之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(25mg,產率:48%)。
1H NMR(500MHz,DMSO-d6)δ 11.41(brs,1H),11.27(brs,1H),10.14(s,1H),7.93(d,1H),7.77(d,1H),7.57(m,2H),7.52(m,4H),7.34(t,1H),6.35(d,1H),2.43(s,3H),2.38(s,3H);MS m/z:459[M+H]。
實施例13. N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用3,5-二甲基
-1-苯基-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(9mg,產率:22%)。
1H NMR(500MHz,MeOH-d4)δ 7.92(d,1H),7.86(d,1H),7.61(m,2H),7.49(m,4H),7.37(t,1H),6.49(d,1H),5.08(m,1H),2.48(s,3H),2.46(s,3H),1.62(d,6H);MS m/z:501[M+H]。
實施例14. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用5-甲基-1-苯基-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(15mg,產率:23%)。
1H NMR(500MHz,DMSO-d6)δ 10.15(s,1H),8.34(s,1H),7.98(dd,1s),7.87(d,1H),7.61-7.51(m,6H),7.43(t,1H),6.40(d,1H),4.88(m,1H),2.57(s,3H),1.50(1s,3H),1.49(1s,3H);MS m/z:487[M+H]。
實施例15. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-苯基噻唑-5-甲醯胺
以類似於實施例7的方式藉由使用2-苯基噻唑-5-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(20mg,產率:31%)。
1H NMR(500MHz,DMSO-d6)δ 11.70(s,1H),10.77(s,1H),8.71(s,1H),8.06-8.05(m,2H),7.95(dd,1H),7.82(d,1H),7.62-7.56(m,4H),7.47(t,1H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:490[M+H]。
實施例16. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-苯基噻唑-2-甲醯胺
以類似於實施例7的方式藉由使用5-苯基噻唑-5-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(10mg,產率:18%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),11.17(s,1H),8.56(s,1H),8.06(dd,1H),7.86-7.80(m,4H),7.54-7.44(m,4H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.47(s,3H);MS m/z:490[M+H]。
實施例17. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(對-)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
類似於實施例7的方式藉由使用1-(對-甲苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(15mg,產率:20%)。
1H NMR(400MHz,DMSO-d6)δ 11.65(s,1H),10.80(s,1H),8.27(s,1H),7.88(dd,1H),7.76(d,1H),7.52(d,1H),7.46-7.35(m,5H),6.36(d,1H),4.83(m,1H),2.31(s,3H),1.45(s,3H),1.43(s,3H);MS m/z:555[M+H]。
實施例18. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(30mg,產率:40%)。
1H NMR(400MHz,DMSO-d6)δ 11.55(brs,1H),10.73(s,1H),8.30(s,1H),7.89(dd,1H),7.76(d,1H),7.58-7.53(m,2H),7.43-7.38(m,2H),7.25(d,1H),7.10(t,1H),6.36(d,1H),4.83(m,1H),3.75(s,3H),1.44(s,3H),1.43(s,3H);MS m/z:571[M+H]。
實施例19. N-(3-氟-4-((1-異丙基-2-側氧基-
2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1,5-二苯基-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1,5-二苯基-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(14mg,產率:19%)。
1H NMR(400MHz,DMSO-d6)δ 10.23(s,1H),8.35(s,1H),7.83(dd,1H),7.74(d,1H),7.46(d,1H),7.36-7.26(m,9H),7.19(dd,2H),6.31(d,1H),4.81(m,1H),1.43(s,3H),1.42(s,3H);MS m/z:549[M+H]。
實施例20. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氫-2H-哌喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(四氫-2H-哌喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(24mg,產率:33%)。
MS m/z:549[M+H]。
實施例21. N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺
以類似於實施例1的方式藉由使用製備例4中所得之7-(4-胺基-2-氟苯氧基)-1-環戊基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例1之7-(4-胺基-2-氟苯氧基)-1-H-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(35mg,產率:64%)。
1H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),10.74(s,1H),8.31(s,1H),7.99(dd,1H),7.77(d,1H),7.71(d,1H),7.59-7.54(m,5H),7.39(t,1H),6.36(d,1H),4.94(m,1H),2.08-1.99(m,2H),1.94-1.87(m,2H),1.71-1.69(m,2H),1.59-1.54(m,2H);MS m/z:567[M+H]。
實施例22. N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例21的方式藉由使用1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例21之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(20mg,產率:29%)。
1H NMR(400MHz,DMSO-d6)δ 11.72(s,1H),10.85(s,1H),8.34(s,1H),7.92(dd,1H),7.82(d,1H),7.64-7.63(m,3H),7.57-7.55(m,3H),7.46(t,1H),6.41(d,1H),2.09-2.05(m,2H),1.98-1.97(m,2H),1.76-1.75(m,2H),1.61-1.60(m,2H);MS m/z:567[M+H]。
實施例23. N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-苯基-1H-吡唑-4-甲醯胺
以類似於實施例21的方式藉由使用5-乙基-1-
苯基-1H-吡唑-4-甲酸代替根據實施例21之1-苯基-5-(三氟甲基)-1H-咪唑-4-甲酸獲得標題化合物(22mg,產率:36%)。
1H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),10.11(s,1H),8.29(s,1H),7.94(dd,1H),7.78(d,1H),7.58-7.46(m,6H),7.38(t,1H),6.36(d,1H),4.95(m,1H),2.92(q,2H),2.05-2.00(m,2H),1.94-1.90(m,2H),1.71-1.69(m,2H),1.56-1.55(m,2H),1.03(t,3H);MS m/z:527[M+H]。
實施例24. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺
以類似於實施例7的方式藉由使用2-(三氟甲基)苯甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(32mg,產率:51%)。
1H NMR(500MHz,DMSO-d6)δ 11.68(s,1H),10.90(s,1H),7.91-7.74(m,6H),7.53(d,1H),7.44(t,1H),6.42(d,1H),4.87(m,1H),1.49(s,3H),1.47(s,3H);MS m/z:475[M+H]。
實施例25. 4-溴-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺
以類似於實施例7的方式藉由使用4-溴-2-(三氟甲基)苯甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(27mg,產率:37%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.94(s,1H),8.11(s,1H),8.07(d,1H),7.87(dd,1H),7.81(d,1H),7.73(d,1H),7.50(d,1H),7.45(t,1H),6.41(d,1H),4.87(m,1H),1.48(s,3H),1.47(s,3H);MS m/z:553[M],555[M+2]。
實施例26. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(45mg,產率:58%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.90(s,1H),8.49(s,1H),8.25(d,1H),8.15(d,1H),7.95(dd,1H),7.81(d,1H),7.78(d,1H),7.77-7.59(m,4H),7.48(t,1H),7.13(d,1H),6.43(d,1H),4.88(m,1H),1.50(s,3H),1.48(s,1H);MS m/z:591[M+H]。
實施例27. 3-溴-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺
以類似於實施例7的方式藉由使用3-溴-2-(三氟甲基)苯甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(100mg,產率:27%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.96(s,1H),8.05(d,1H),7.86-7.73(m,2H),7.70(m,2H),7.49-7.43(m,2H),6.41(d,1H),4.87(m,1H),1.48(s,3H),1.47(s,3H);MS m/z:553[M],555[M+2]。
實施例28. 1-環己基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-環己基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(24mg,產率:33%)。
1H NMR(500MHz,DMSO-d6)δ 11.70(s,1H),10.76(s,1H),8.07(s,1H),7.88(d,1H),7.80(d,1H),7.51(d,1H),7.43(t,1H),6.39(d,1H),1.94-1.85(m,6H),1.70-1.68(m,1H),1.48(s,3H),1.47(s,3H),1.43-1.40(m,1H),1.28-1.20(m,2H);MS m/z:547[M+H]。
實施例29. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氫-2H-哌喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(四氫-2H-哌喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(41mg,產率:57%)。
1H NMR(500MHz,DMSO-d6)δ 11.70(s,1H),10.78(s,1H),8.11(s,1H),7.88(dd,1H),7.80(d,1H),7.51(d,1H),7.43(t,1H),6.39(d,1H),4.78(m,1H),4.62(m,1H),3.99(dd,2H),3.54(t,2H),2.15(m,2H),1.90(dd,2H),1.48(s,3H),1.47(s,3H);MS m/z:549[M+H]。
實施例30. 1-(三級-丁基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(三級-丁基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(30mg,產率:44%)。
1H NMR(500MHz,DMSO-d6)δ 11.70(s,1H),10.82(s,1H),7.96(s,1H),7.88(dd,1H),7.50(d,1H),7.43(t,
1H),6.39(d,1H),4.86(m,1H),1.67(s,9H),1.48(s,3H),1.47(s,3H);MS m/z:520[M+H]。
實施例31. 1-環庚基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-環庚基-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(28mg,產率:38%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.76(s,1H),8.06(s,1H),7.88(d,1H),7.80(d,1H),7.51(d,1H),7.43(t,1H),6.39(d,1H),4.86(m,1H),4.52(m,1H),2.10-1.99(m,4H),1.81(m,1H),1.62-1.53(m,6H),1.48(s,3H),1.47(s,3H);MS m/z:561[M+H]。
實施例32. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙醯胺
以類似於實施例7的方式藉由使用2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(16mg,產率:22%)。
1H NMR(500MHz,DMSO-d6)δ 10.90(s,1H),8.90(d,1H),8.39(s,1H),7.90(d,1H),7.77(d,1H),7.68(d,1H),7.53(d,1H),7.38(t,1H),6.43(s,2H),5.96(d,1H),2.61(s,3H),2.55(s,3H);MS m/z:555[M+H]。
實施例33. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(1-甲基哌啶-3-基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例
7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(2mg,產率:4%)。
MS m/z:562[M+H]。
實施例34. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用製備例6中所得之化合物1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(25mg,產率:45%)。
1H NMR(500MHz,DMSO-d6)δ 11.70(s,1H),10.87(s,1H),8.44(s,1H),7.93(dd,1H),7.81(d,1H),7.73(m,2H),7.58(m,2H),7.76(m,2H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:559[M+H]。
實施例35. 1-(2-氯苯基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(2-氯苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(12mg,產率:21%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.84(s,1H),8.45(s,1H),7.94(d,1H),7.80(m,2H),7.71(m,2H),7.60(m,2H),7.46(t,1H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:575[M+H]。
實施例36. 1-(2,6-二氟苯基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(2,6-二氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲酸代替根據實施例7之
1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(22mg,產率:39%)。
1H NMR(500MHz,DMSO-d6)δ 11.68(s,1H),10.93(s,1H),8.52(s,1H),7.92(d,1H),7.87-7.81(m,2H),7.57-7.51(m,3H),7.46(t,1H),6.41(d,1H),4.87(m,1H),1.49(s,3H),1.48(s,3H);MS m/z:577[M+H]。
實施例37. N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用7-(4-胺基-2-氟苯氧基)-1-(四氫-2H-哌喃-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例7之7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(30mg,產率:59%)。
1H NMR(500MHz,DMSO-d6)δ 11.78(brs,1H),10.86(s,1H),8.35(s,1H),7.94(d,1H),7.83(d,1H),7.63(m,3H),7.57(m,3H),7.47(m,1H),6.43(d,1H),4.71(m,1H),3.97(m,2H),3.43(m,2H),2.43(m,2H),1.73(m,2H);
MS m/z:583[M+H]。
實施例38. N-(3-氟-4-((2-側氧基-1-(四氫呋喃-3-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用7-(4-胺基-2-氟苯氧基)-1-(四氫呋喃-3-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例7之7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(25mg,產率:49%)。
1H NMR(500MHz,DMSO-d6)δ 11.81(s,1H),10.85(s,1H),8.35(s,1H),7.94(d,1H),7.84(m,1H),7.63(m,3H),7.58(m,3H),7.47(m,1H),6.43(d,1H),5.29(m,1H),4.03(m,1H),3.93(m,3H),2.43(m,1H),2.29(m,1H);MS m/z:569[M+H]。
實施例39. N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺
以類似於實施例7的方式藉由使用7-(4-胺基-2-氟苯氧基)-1-(1-甲基哌啶-4-基)-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮代替根據實施例7之7-(4-胺基-2-氟苯氧基)-1-異丙基-1,3-二氫-2H-咪唑并[4,5-b]吡啶-2-酮獲得標題化合物(0.7mg,產率:4%)。
MS m/z:596[M+H]。
實施例40. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-3-甲醯胺
以類似於實施例7的方式藉由使用1-苯基-1H-吡唑-3-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(27mg,產率:48%)。
1H NMR(500MHz,DMSO-d6)δ 11.67(s,1H),
10.47(s,1H),8.68(s,1H),8.12(d,1H),8.07(m,2H),7.81(m,2H),7.60(m,2H),7.43(m,2H),7.08(s,1H),6.41(d,1H),4.86(m,1H),1.49(d,6H)。
實施例41. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-1,2,3-三唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-苯基-1H-1,2,3-三唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(27mg,產率:48%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.97(s,1H),9.50(s,1H),8.09(m,3H),7.81(s,2H),7.67(m,2H),7.58(m,1H),7.47(m,1H),6.41(d,1H),4.86(m,1H),1.49(d,6H)。
實施例42. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-1,2,3-三唑-4-甲醯胺
以類似於實施例7的方式藉由使用5-甲基-1-苯基-1H-1,2,3-三唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(35mg,產率:61%)。
1H NMR(500MHz,DMSO-d6)δ 11.68(s,1H),10.90(s,1H),8.10(d,1H),7.84(t,2H),7.68(m,5H),7.45(t,1H),6.41(d,1H),4.86(m,1H),2.60(s,3H),1.49(d,6H)。
實施例43. N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-1H-1,2,3-三唑-4-甲醯胺
以類似於實施例7的方式藉由使用1-(2-氟苯基)-5-甲基-1H-1,2,3-三唑-4-甲酸代替根據實施例7之1-苯基-5-(三氟甲基)-1H-吡唑-4-甲酸獲得標題化合物(38mg,產率:64%)。
1H NMR(500MHz,DMSO-d6)δ 11.69(s,1H),10.94(s,1H),8.09(d,1H),7.84(m,4H),7.65(m,1H),7.54(m,1H),7.46(m,1H),6.41(d,1H),4.86(m,1H),2.50(s,3H),1.49(d,6H)。
實驗例1. 對抗RON和MET的抑制活性之評估
[1-1]對抗RON的抑制活性之評估
為了測量實施例的各化合物對抗RON的抑制活性,使用時間解析螢光能量轉移化學(TR)測量各化合物的IC50。
具體來說,用100% DMSO將化合物製備成1mM之濃度,並透過3倍稀釋以逐步方式稀釋10倍。將2ul之以逐步方式稀釋的化合物加至含有48ul的1x的激酶反應緩衝液(50mM HEPES(pH 7.4)、0.01% Tween-20、5mM DTT、0.5mM Na3VO4、2mM EGTA、10mM MgCl2)的96孔盤。
用RON儲存緩衝液(50mM Tris-HCl(pH 7.5)、150mM NaCl、0.5mM EDTA、0.02% Triton X-100)將RON蛋白稀釋至49.3nM的濃度,並接著使用1x激酶反應緩衝液再次稀釋至0.4nM的濃度。作為受質混合物(cocktail),RON特異性受質混合物(40uM ULight標記的Poly GT,100nM ATP),濃度為2倍最終反應濃度。
之後,製備384孔盤,並將2.5μl的各稀釋的實施例化合物加至實驗組孔的對應孔中,及將2.5μl的4%
DMSO溶液分配到高對照組孔和低對照組孔中。
之後,將2.5μL的0.4nM RON分配到高對照組孔和實驗組孔中,並將2.5μL的1x激酶反應緩衝液加至低對照組孔,及將RON和反應緩衝液在室溫下以1000RPM離心40秒,並接著在室溫下培養20至30分鐘。接著,將5uL的受質混合物(cocktail)(2x)分配到所有孔中,在室溫下以1000RPM離心40秒,並接著在室溫下培養60分鐘。
之後,將5uL的30mM EDTA加至所有孔以終止反應,並接著再次在室溫下培養5分鐘。之後,將5uL的含有銪之4x磷酸酪胺酸(phosphotyrosine)抗體(Perkin Elmer)加至所有孔中,並接著在室溫下培養60分鐘。培養後,用Vison讀板器讀取384孔盤。此時,激發波長為340nm,及發射波長為620nm和665nm。使用GraphPd Prism7程式得出各實施例之化合物的IC50值。
[1-2]對抗MET的抑制活性之評估
此外,為了測量cMET的酶活性抑制,進行RON的酶活性抑制測量實驗。
具體來說,用100% DMSO將化合物製備成1mM之濃度,並透過3倍稀釋以逐步方式稀釋10倍。將2ul之以逐步方式稀釋的化合物加至含有48ul 1x激酶反應緩衝液(50mM HEPES(pH 7.4)、0.05% BSA、0.005% Tween-20、1mM DTT、0.5mM MnCl2、20mM MgCl2)的96孔盤。
用cMET儲存緩衝液(50mM Tris-HCl(pH 7.5)、150mM NaCl、0.05% Brij35、1mM DTT、10%
Glycerol)將cMET蛋白稀釋至263nM的濃度,並接著使用1x激酶反應緩衝液再次稀釋至2nM的濃度。作為受質混合物(cocktail),MET特異性受質混合物(5uM TK肽,10mM ATP),濃度為2倍最終反應濃度。
之後,製備384孔盤,並將2.5μl的各稀釋的實施例化合物加至實驗組孔的對應孔中,及將2.5μl的4% DMSO溶液分配到高對照組孔和低對照組孔中。
之後,將2.5μL的2nM cMET分配到高對照組孔和實驗組孔中,並將2.5μL的1x激酶反應緩衝液加至低對照組孔,及將RON和反應緩衝液在室溫下以1000RPM離心40秒,並接著在室溫下培養20至30分鐘。接著,將5uL的受質混合物(cocktail)(2x)分配到所有孔中,在室溫下以1000RPM離心40秒,並接著在室溫下培養60分鐘。之後,將5uL的90mM EDTA加至所有孔以終止反應,並接著再次在室溫下培養5分鐘。之後,將5uL的含有銪之4x磷酸酪胺酸(phosphotyrosine)抗體(Perkin Elmer)加至所有孔中,並接著在室溫下培養60分鐘。培養後,用Vison讀板器讀取384孔盤。此時,激發波長為340nm,及發射波長為620nm和665nm。使用GraphPd Prism7程式得出各實施例之化合物的IC50值。
評估實施例之化合物的抑制活性之結果係顯示於下表2中。
(A:<50nM,B:50至500nM,C:500至5000nM,D:>5,000nM)。
Claims (8)
- 一種下述式2之尿素衍生物化合物或其醫藥上可接受的鹽:
- 如請求項1之尿素衍生物化合物或其醫藥上可接受的鹽,其中上述A為經取代或未經取代之5-員雜芳基化合物。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受的鹽,其中上述B為氫、C1-C6烷基、經取代之C1-C6烷基、C3-C7環烷基、苯基、經取代之苯基、苄基、或萘四氫哌喃、哌啶或經取代之哌啶,其中取代基為化合物,其為鹵素、C1-C3烷基、鹵素取代之C1-C3烷基、C3-C5環烷基、或C1-C3烷氧基。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受的鹽,其中上述Y為氟。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受的鹽,其中上述R1為氫、C1-C6烷基、C3-C6環烷基、或C4-C6雜環烷基。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受的鹽,其中上述R2為氫。
- 如請求項1之尿素衍生物化合物或其醫藥上可接受的鹽,其中該化合物為選自由下列所組成之群組的化合物:N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-乙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(4-((1-乙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-甲基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(3-氟-4-((1-甲基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,5-乙基-N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲醯胺,5-乙基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-3,5-二甲基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-苯基噻唑-5-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-苯基噻唑-2-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并 [4,5-b]吡啶-7-基)氧基)苯基)-1-(對-甲苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-甲氧基苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1,5-二苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氫-2H-哌喃-3-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-咪唑-4-甲醯胺,N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(4-((1-環戊基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)-3-氟苯基)-5-乙基-1-苯基-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺,4-溴-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯 胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(萘-1-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,3-溴-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(三氟甲基)苯甲醯胺,1-環己基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(四氫-2H-哌喃-4-基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-(三級-丁基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-環庚基-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-2-(1-苯基-5-(三氟甲基)-1H-吡唑-4-基)乙醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(1-甲基哌啶-3-基)-5-(三氟 甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-(2-氯苯基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,1-(2,6-二氟苯基)-N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-1-(四氫-2H-哌喃-4-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((2-側氧基-1-(四氫呋喃-3-基)-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-(1-甲基哌啶-4-基)-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-5-(三氟甲基)-1H-吡唑-4-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-吡唑-3-甲醯胺,N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-苯基-1H-1,2,3-三唑-4-甲醯胺, N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-5-甲基-1-苯基-1H-1,2,3-三唑-4-甲醯胺,及N-(3-氟-4-((1-異丙基-2-側氧基-2,3-二氫-1H-咪唑并[4,5-b]吡啶-7-基)氧基)苯基)-1-(2-氟苯基)-1H-1,2,3-三唑-4-甲醯胺。
- 一種醫藥組成物,其包含根據請求項1至7中任一項之化合物或其醫藥上可接受的鹽、和醫藥上可接受的載劑。
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WO2007125330A1 (en) * | 2006-04-26 | 2007-11-08 | Cancer Research Technology Limited | Imidazo[4, 5-b]pyridin-2-one and oxazolo[4, 5-b]pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds |
TWI520962B (zh) * | 2012-06-29 | 2016-02-11 | As the c-Met tyrosine kinase inhibitors novel fused pyridine derivatives |
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