TW202108141A - Fgfr抑制劑及其使用方法 - Google Patents
Fgfr抑制劑及其使用方法 Download PDFInfo
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- TW202108141A TW202108141A TW109115853A TW109115853A TW202108141A TW 202108141 A TW202108141 A TW 202108141A TW 109115853 A TW109115853 A TW 109115853A TW 109115853 A TW109115853 A TW 109115853A TW 202108141 A TW202108141 A TW 202108141A
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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- C07D498/04—Ortho-condensed systems
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Abstract
本發明係關於新穎化合物及其醫藥組合物,及使用本發明之化合物及組合物抑制FGFR酶活性的方法。本發明進一步關於(但不限於)使用本發明之化合物及組合物治療與FGFR信號傳導有關之病症的方法。
Description
纖維母細胞生長因子受體(FGFR1、FGFR2、FGFR3和FGFR4)為由細胞外配位體結合域及細胞內酪胺酸激酶域組成的受體酪胺酸激酶。FGF配位體的結合引起受體二聚合及胞內域構形變化,從而引起激酶域及細胞內尾部發生分子間轉磷酸化。磷酸化殘基充當接附蛋白的對接位點,其促進下游信號級聯,從而產生細胞行為,包括增殖、存活、分化、遷移及血管生成。失調的FGFR信號傳導可經由以下發生:FGFR
基因擴增或融合、FGFR
錯義突變、由表觀遺傳及/或轉錄調控因子之調節異常引起的受體過度表現,或FGF配位體在腫瘤微環境中的上調。FGFR表現於許多細胞類型中;因此,異常的FGFR信號傳導已牽涉到許多腫瘤類型的瘤形成、腫瘤進展及對治療的抗性。(關於FGFR信號傳導的評述,參見N. Turner及R. Grose,Nat. Rev. Cancer
2010, 10:116-129;及其中引用的參考文獻)。
泛FGFR1-3抑制劑已對FGFR改變的多種癌症產生臨床反應,然而,在靶毒性限制此等抑制劑之給與。泛FGFR抑制的最常見副作用之一為高磷酸鹽血症。磷酸鹽再吸收之調控係由FGFR3及FGFR1介導。因此,需要不傷害FGFR1的FGFR選擇性抑制劑。(J. Gattineni等人, Am. J. Physiol. Renal Physiol
. 2014, 306:F351-F358;X. Han等人, PLoS One
2016, 11:e0147845.)。含有FGFR2
基因融合體的癌症以及具有FGFR2
擴增及/或FGFR2
活化突變的癌症已對泛FGFR抑制展現反應,然而,反應的低速率及持續時間表明其受到毒性限制。因此,需要FGFR2選擇性抑制劑化合物及用此等化合物治療癌症及其它病症的方法。(關於泛FGFR1-3抑制劑及臨床反應的評述,參見I. S. Babina及N.C. Turner,Nat. Rev. Cancer
2017, 17:318-332;M. Katoh,Nat. Rev. Clin. Oncol
. 2019, 16:105-122;及其中引用的參考文獻)。
在一些實施例中,本發明提供一種醫藥組合物,其包含式I化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑、佐劑或稀釋劑。在一些實施例中,本發明提供一種醫藥組合物,其包含本發明化合物,例如式I-1化合物或其醫藥學上可接受之鹽,及醫藥學上可接受之載劑、佐劑或稀釋劑。
在一些實施例中,本發明提供一種治療FGFR介導性病症的方法,包含向有需要之患者投與式I化合物或包含該化合物的組合物。在一些實施例中,本發明提供一種治療FGFR介導性病症的方法,包含向有需要之患者投與本發明化合物,例如式I-1化合物,或包含該化合物的組合物。
在一些實施例中,本發明提供一種用於提供式I化合物或其合成中間物的方法。在一些實施例中,本發明提供一種用於提供本發明化合物(例如式I-1化合物)或其合成中間物的方法。
在一些實施例中,本發明提供一種用於提供包含式I化合物之醫藥組合物的方法。在一些實施例中,本發明提供一種用於提供包含本發明化合物(例如式I-1化合物)之醫藥組合物的方法。
相關申請案的交叉參考
本申請案主張2019年5月13日申請之美國臨時申請案第62/846,991號、2020年3月24日申請之美國臨時申請案第62/993,957號;及2020年4月17日申請之美國臨時申請案第63/011,469號的權益,所述美國臨時申請案中之每一者以引用的方式併入本文中。 1. 本發明之某些實施例的一般描述
本發明化合物及其醫藥組合物適用作FGFR2抑制劑。在一些實施例中,本發明提供一種式I-1化合物:
或其醫藥學上可接受之鹽,其中:
CyA
為 ,
其中表示連至R5
之鍵結且表示連至Cy6
之鍵結;
R5
為-R5A
-L5
-R5B
;
R5A
為RB
之二價基團,其中除-L5
-R5B
之外,R5A
亦經m個R5C
實例取代;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
Cy6
為伸苯基;3至14員飽和或部分不飽和二價碳環;具有1至4個獨立地選自氮、氧及硫之雜原子的3至14員飽和或部分不飽和二價雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至14員伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代;
RW
為鹵素、-CN、 、;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或
兩個R6
實例、一個R6
實例及一個RL
實例、一個R6
實例及一個RWA
實例,或一個R6
實例及一個R7a
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
R8
為H、-NR2
、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R9
為H、-NR2
、鹵素,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R10
為H或視情況經1至3個鹵素取代的C1 - 6
脂族;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈中的一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 6
伸環烷基、3至6員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;其中該C3 - 6
伸環烷基、3至6員伸雜環烷基及5至6員伸雜芳基中之每一者視情況經一個RA
或C1 - 6
脂族實例取代;
RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;其中該環經w個RC
實例取代;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;或
兩個R5C
實例、一個R5C
實例及一個R5D
實例,或兩個R5D
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該雜芳基環亦具有0至3個獨立地選自氮、氧及硫之雜原子;
m、n、p、q、r、t、u、v及w中之每一者獨立地為0、1、2、3或4。
在一些實施例中,本發明提供一種式I化合物:
或其醫藥學上可接受之鹽,其中:
R5
為-R5A
-L5
-R5B
;
R5A
為RB
之二價基團,其中除-L5
-R5B
之外,R5A
亦經m個R5C
實例取代;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
Cy6
為伸苯基或具有1至3個氮原子之6員伸雜芳基,其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代;
RW
為鹵素、-CN、 ;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或
兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;
RWA
、RWB
及RWC
中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代的基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該雜芳基環亦具有0至3個獨立地選自氮、氧及硫之雜原子;
m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。 2. 化合物及定義
本發明化合物包括本文中一般描述的彼等物,且根據本文所揭示之類別、子類及種類進一步說明。如本文所用,除非另有指示,否則以下定義應適用。出於本發明之目的,化學元素係根據元素週期表CAS版(Handbook of Chemistry and Physics第75版)來鑑別。此外,有機化學之一般原理描述於「Organic Chemistry」, Thomas Sorrell, University Science Books, Sausalito: 1999及「March's Advanced Organic Chemistry」第5版, 編者: Smith, M.B.及March, J., John Wiley & Sons, New York: 2001,所述文獻的全部內容以引用之方式併入本文中。化學名稱、通用名稱及化學結構可互換使用以描述相同結構。若使用化學結構與化學名稱提及化合物且結構與名稱存在分歧,則以結構為準。
如本文所用,術語「脂族」或「脂族基團」意謂經取代或未經取代之完全飽和或含有一或多個不飽和單元的直鏈(亦即,非分支鏈)或分支鏈烴鏈,或完全飽和或含有一或多個不飽和單元、但不為芳族(在本文中亦稱為「碳環」或「環脂族」)的單環烴或雙環烴,其具有連至分子之其餘部分的單個連接點。除非另外指定,否則脂族基團含有1至6個脂族碳原子。在一些實施例中,脂族基含有1至5個脂族碳原子。在其他實施例中,脂族基含有1至4個脂族碳原子。在另外的其他實施例中,脂族基含有1至3個脂族碳原子,且在又其他實施例中,脂族基含有1至2個脂族碳原子。在一些實施例中,「環脂族」(或「碳環」)係指完全飽和或含有一或多個不飽和單元,但不為芳族之單環C3
-C6
烴,其具有連至分子之其餘部分的單個連接點。適合的脂族基包括(但不限於)直鏈或分支鏈、經取代或未經取代之烷基、烯基、炔基及其混合物,諸如(環烷基)烷基、(環烯基)烷基或(環烷基)烯基。
除非另外指明,否則如本文所用,術語「烷基」係指具有直鏈、分支鏈、單環部分或多環部分或其組合之單價脂族烴基,其中該基團視情況在直鏈、分支鏈、單環部分或多環部分或其組合之一或多個碳原子處經各碳處之一或多個取代基取代,其中該一或多個取代基獨立地為C1
-C10
烷基。「烷基」之實例包括甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、己基、庚基、環丙基、環丁基、環戊基、環己基、環庚基、降冰片烷基及其類似基團。
術語「低碳數烷基」係指C1 - 4
直鏈或分支鏈烷基。例示性低碳數烷基為甲基、乙基、丙基、異丙基、丁基、異丁基及第三丁基。
術語「低碳數鹵烷基」係指經一或多個鹵素原子取代之C1 - 4
直鏈或分支鏈烷基。
術語「雜原子」意謂氧、硫、氮、磷或矽中之一或多者(包括氮、硫、磷或矽之任何氧化形式;任何鹼氮之四級銨化形式;或雜環之可取代氮,例如N (如3,4-二氫-2H
-吡咯基中)、NH (如吡咯啶基中)或NR+
(如N上經取代之吡咯啶基中))。
如本文所用,術語「不飽和」意謂部分具有一或多個不飽和單元。
如本文所用,術語「C1 - 8
(或C1 - 6
或C1 - 4
)飽和或不飽和、直鏈或分支鏈二價烴鏈」係指如本文所定義為直鏈或分支鏈之二價伸烷基、伸烯基及伸炔基鏈。
術語「伸烷基」係指二價烷基。「伸烷基鏈」為聚亞甲基,亦即-(CH2
)n
-,其中n為正整數,較佳為1至6、1至4、1至3、1至2或2至3。經取代之伸烷基鏈為其中一或多個亞甲基氫原子由取代基置換之聚亞甲基。適合取代基包括下文關於經取代之脂族基所述之彼等取代基。
術語「伸烯基」係指二價烯基。經取代之伸烯基鏈為含有至少一個雙鍵之聚亞甲基,其中一或多個氫原子經取代基置換。適合取代基包括下文關於經取代之脂族基所述之彼等取代基。
術語「鹵素」」意謂F、Cl、Br或I。
單獨使用或作為較大部分(如「芳烷基」、「芳烷氧基」或「芳氧基烷基」)的一部分使用的術語「芳基」係指具有總共五至十四個環成員之單環或雙環系統,其中系統中之至少一個環為芳族且其中系統中之各環含有3至7個環成員。術語「芳基」可與術語「芳環」互換使用。在本發明之某些實施例中,「芳基」係指可具有一或多個取代基的芳環系統,包括(但不限於)苯基、聯苯、萘基、蒽基及其類似基團。
除非另外定義,否則如本文所用,術語「雜芳基」或「雜芳族」係指含有一或多個雜原子(例如一至三個雜原子,諸如氮、氧及硫)的5至6員單環芳族環,或含有一或多個雜原子的8至10員多環環系統,其中多環環系統中的至少一個環為芳族,且多環環系統的連接點係經由芳族環上的環原子。雜芳基環可以經由碳或氮連接至相鄰基團。雜芳基環之實例包括(但不限於)呋喃、噻吩、吡咯、噻唑、噁唑、異噻唑、異噁唑、咪唑、吡唑、三唑、吡啶、嘧啶、吲哚等。舉例而言,除非另外定義,否則1,2,3,4-四氫喹啉為雜芳基環,條件為其連接點經由苯并環,例如:。
除非另外定義,否則術語「雜環基」或「雜環基團」係指飽和或部分不飽和的3至10員單環或7至14員多環環系統,包括橋連或稠合環,且其環系統包括一至四個雜原子,諸如氮、氧及硫。雜環基環可經由碳或氮連接至相鄰基團。
除非另外定義,否則術語「部分不飽和」在環的上下文中係指單環,或多環(例如雙環、三環等)環系統內的組成環,其中該組成環含有至少一個除環自身所提供之不飽和度之外的不飽和度,但不為芳族。部分不飽和環之實例包括(但不限於) 3,4-二氫-2H-哌喃、3-吡咯啉、2-噻唑啉等。在部分不飽和環為多環環系統之一部分的情況下,多環環系統中的其他組成環可為飽和、部分不飽和的或芳族,但多環環系統的連接點位於部分不飽和組成環上。舉例而言,除非另外定義,否則1,2,3,4-四氫喹啉為部分不飽和環,條件為其連接點係經由哌啶基環,例如:。
除非另外定義,否則術語「飽和」在環的上下文中係指3至10員單環或7至14員多環(例如雙環、三環等)環系統,其中該單環或作為多環環系統之連接點的組成環不含除環自身所提供之不飽和度之外的額外不飽和度。單環飽和環之實例包括(但不限於)氮雜環丁烷、氧雜環丁烷、環己烷等。在飽和環為多環環系統之一部分的情況下,多環環系統中的其他組成環可為飽和、部分不飽和的或芳族,但多環環系統的連接點位於飽和組成環上。舉例而言,除非另外定義,否則2-氮雜螺[3.4]辛-6-烯為飽和環,條件為其連接點係經由N-氮雜環丁烷基環,例如:。
如本文所用,術語「伸烷基」、「伸芳基」、「伸環烷基」、「伸雜芳基」、「伸雜環烷基」及具有前綴「伸-」的其他類似術語係指由該前綴修飾之基團的二價鍵結形式。舉例而言,「伸烷基」為二價烷基,其使基團連接至其所連接者。
如本文所用,術語「橋連雙環」係指具有至少一個橋鍵之任何飽和或部分不飽和雙環系統,亦即,碳環或雜環。如IUPAC所定義,「橋鍵」為多個原子或一個原子之未分支鏈或連接兩個橋頭之價鍵,其中「橋頭」為與三個或更多個骨架原子(除氫以外)鍵結之環系統的任何骨架原子。在一些實施例中,橋連雙環基團具有7至12個環成員及0至4個獨立地選自氮、氧或硫之雜原子。此類橋連雙環基團為此項技術中所熟知,且包括在下文中闡述之彼等基團,其中各基團在任何可取代碳或氮原子處與分子之其餘部分連接。除非另外說明,否則橋連雙環基團視情況經一或多個如關於脂族基闡述之取代基取代。或者或另外,橋連雙環基團之任何可取代氮視情況經取代。例示性橋連雙環包括: 。
如本文所述,本發明化合物可含有「視情況經取代」的部分。一般而言,術語「經取代」無論前面是否有術語「視情況」均意謂指定部分之一或多個氫經適合的取代基置換。除非另有指示,否則「視情況經取代」之基團可在基團之各可取代位置處具有適合的取代基,且當任何指定結構中之超過一個位置可經超過一個選自指定基團之取代基取代時,在每一位置處之取代基可相同或不同。本發明所設想之取代基之組合較佳為引起穩定或化學上可行之化合物形成的彼等取代基組合。如本文所用,術語「穩定」係指化合物在經受允許其產生、偵測及(在某些實施例中)其回收、純化及用於本文所揭示之一或多種目的之條件時不發生實質上改變。
「視情況經取代」之基團之可取代碳原子上的適合單價取代基獨立地為鹵素;-(CH2
)0 - 4
R°;-(CH2
)0 - 4
OR°;-O(CH2
)0 - 4
Ro
;-O-(CH2
)0 - 4
C(O)OR°;-(CH2
)0 - 4
CH(OR°)2
;-(CH2
)0 - 4
SR°;可經R°取代的-(CH2
)0 - 4
Ph;可經R°取代的-(CH2
)0 - 4
O(CH2
)0 - 1
Ph;可經R°取代的-CH=CHPh;可經R°取代的-(CH2
)0 - 4
O(CH2
)0 - 1
-吡啶基;-NO2
;-CN;-N3
;-(CH2
)0 - 4
N(R°)2
;-(CH2
)0 - 4
N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2
)0 - 4
N(R°)C(O)NR°2
;-N(R°)C(S)NR°2
;-(CH2
)0 - 4
N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2
;-N(R°)N(R°)C(O)OR°;-(CH2
)0 - 4
C(O)R°;-C(S)R°; -(CH2
)0 - 4
C(O)OR°;-(CH2
)0 - 4
C(O)SR°;-(CH2
)0 - 4
C(O)OSiR°3
;-(CH2
)0 - 4
OC(O)R°;-OC(O)(CH2
)0 - 4
SR°;-SC(S)SR°;-(CH2
)0 - 4
SC(O)R°;-(CH2
)0 - 4
C(O)NR°2
;-C(S)NR°2
;-C(S)SR°;-SC(S)SR°;-(CH2
)0 - 4
OC(O)NR°2
;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2
C(O)R°;-C(NOR°)R°;-(CH2
)0 - 4
SSR°;-(CH2
)0 - 4
S(O)2
R°;-(CH2
)0 - 4
S(O)2
OR°;-(CH2
)0 - 4
OS(O)2
R°;-S(O)2
NR°2
;-(CH2
)0 - 4
S(O)R°;-N(R°)S(O)2
NR°2
;-N(R°)S(O)2
R°;-N(OR°)R°;-C(NH)NR°2
;-P(O)(OR°)R°;-P(O)R°2
;-OP(O)R°2
;-OP(O)(OR°)2
;-SiR°3
;-(C1 - 4
直鏈或分支鏈伸烷基)O-N(R°)2
;或-(C1 - 4
直鏈或分支鏈伸烷基)C(O)O-N(R°)2
,其中各R°可如下文所定義經取代且獨立地為氫、C1 - 6
脂族、-CH2
Ph、-O(CH2
)0 - 1
Ph、-CH2
-(5至6員雜芳基環),或具有0至4個獨立地選自氮、氧或硫之雜原子的5至6員飽和、部分不飽和或芳環,或不管上述定義,兩個獨立出現的R°與其間插原子一起形成具有0至4個獨立地選自氮、氧或硫之雜原子的3至12員飽和、部分不飽和或芳基單環或雙環,該環可以如下文所定義經取代。
R°上之適合單價取代基(或兩個單獨出現之R°與其間插原子一起形成之環)獨立地為鹵素、-(CH2
)0 - 2
Rl
、-(鹵基Rl
)、-(CH2
)0 - 2
OH、-(CH2
)0 - 2
ORl
、-(CH2
)0 - 2
CH(ORl
)2
;-O(鹵基Rl
)、-CN、-N3
、-(CH2
)0 - 2
C(O)Rl
、-(CH2
)0 - 2
C(O)OH、-(CH2
)0 - 2
C(O)ORl
、-(CH2
)0 - 2
SRl
、-(CH2
)0 - 2
SH、-(CH2
)0 - 2
NH2
、-(CH2
)0 - 2
NHRl
、-(CH2
)0 - 2
NRl 2
、-NO2
、-SiRl 3
、-OSiRl 3
、-C(O)SRl
、-(C1 - 4
直鏈或分支鏈伸烷基)C(O)ORl
或-SSRl
,其中各Rl
未經取代或在冠有「鹵基」的情況下僅經一或多種鹵素取代,且獨立地選自C1 - 4
脂族、-CH2
Ph、-O(CH2
)0 - 1
Ph或具有0至4個獨立地選自氮、氧或硫之雜原子的5至6員飽和、部分不飽和或芳環。R°之飽和碳原子上的適合二價取代基包括=O及=S。
「視情況經取代」之基團之飽和碳原子上的適合二價取代基包括以下:=O、=S、=NNR* 2
、=NNHC(O)R*
、=NNHC(O)OR*
、=NNHS(O)2
R*
、=NR*
、=NOR*
、-O(C(R* 2
))2 - 3
O-或-S(C(R* 2
))2 - 3
S-,其中各單獨出現之R*
係選自氫、可如下文所定義經取代的C1 - 6
脂族,或具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之5至6員飽和、部分不飽和或芳環。結合至「視情況經取代之」基團之鄰位可取代碳的適合二價取代基包括:-O(CR* 2
)2 - 3
O-,其中各單獨出現之R*
係選自氫、可如下文所定義經取代之C1 - 6
脂族基,或具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之5至6員飽和、部分不飽和或芳環。
R*
之脂族基團上的適合取代基包括鹵素、-Rl
、-(鹵基Rl
)、-OH、-ORl
、-O(鹵基Rl
)、-CN、-C(O)OH、-C(O)ORl
、-NH2
、-NHRl
、-NRl 2
或-NO2
,其中各Rl
未經取代或在冠有「鹵基」的情況下僅經一或多個鹵素取代且獨立地為C1 - 4
脂族、-CH2
Ph、-O(CH2
)0 - 1
Ph,或具有0至4個獨立地選自氮、氧或硫之雜原子的5至6員飽和、部分不飽和或芳環。
「視情況經取代之」基團之可取代氮上的適合取代基包括-R†
、-NR† 2
、-C(O)R†
、-C(O)OR†
、-C(O)O(O)R†
、-C(O)CH2
C(O)R†
、-S(O)2
R†
、-S(O)2
NR† 2
、-C(S)NR† 2
、-C(NH)NR† 2
或-N(R†
)S(O)2
R†
;其中各R†
獨立地為氫、可如下文所定義經取代之C1 - 6
脂族、未經取代之-OPh或具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之5至6員飽和、部分不飽和或芳環;或不管上述定義,兩個單獨出現之R†
與其間插原子一起形成具有0至4個獨立地選自氮、氧或硫之雜原子的未經取代之3至12員飽和、部分不飽和或芳基單環或雙環。
R†
之脂族基團上的適合取代基獨立地為鹵素、-Rl
、-(鹵基Rl
)、-OH、-ORl
、-O(鹵基Rl
)、-CN、-C(O)OH、-C(O)ORl
、-NH2
、-NHRl
、-NRl 2
或-NO2
,其中各Rl
未經取代或在冠有「鹵基」的情況下僅經一或多個鹵素取代,且獨立地為C1 - 4
脂族、-CH2
Ph、-O(CH2
)0 - 1
Ph,具有0至4個獨立地選自氮、氧或硫之雜原子的5至6員飽和、部分不飽和或芳環。
如本文所用,術語「異構體」係指具有相同化學式、但結構或光學組態不同的化合物。如本文所用,術語「立體異構體」係指且包括具有相同分子式、但原子及/或官能基在空間中定位不同的異構分子。本發明化合物之所有立體異構體(例如,由於各個取代基上之不對稱碳而可能存在的彼等立體異構體),包括對映異構形式及非對映異構形式,涵蓋在本發明之範疇內。因此,除非另有說明,否則本發明化合物之單一立體化學異構體以及對映異構體、非對映異構體及幾何(或構象)異構體的混合物處於本發明之範疇內。
如本文所用,術語「互變異構體」為平衡存在且容易自一種異構形式轉化成另一種異構形式的兩種或更多種結構異構體之一。應理解,互變異構體涵蓋價態互變異構體及質子互變異構體(亦稱為質子移變的互變異構體)。價態互變異構體包括一些鍵結電子重組所引起的相互轉化。質子互變異構體包括經由質子遷移發生的相互轉化,諸如酮-烯醇及亞胺-烯胺異構化。除非另外說明,否則本發明化合物之所有互變異構體均在本發明之範疇內。
如本文所用,術語「同位素取代」係指原子經其同位素取代。如本文所用,術語「同位素」係指與自然界中主要存在的原子具有相同原子數、但質量數(中子數)與自然界中主要存在的原子之質量數不同的原子。應理解,具有同位素取代的化合物係指其中所含有的至少一個原子經其同位素取代的化合物。可經其同位素取代之原子包括(但不限於)氫、碳及氧。氫原子同位素之實例包括2
H (亦表示為D)及3
H。碳原子同位素之實例包括13
C及14
C。氧原子同位素之實例包括18
O。除非另外說明,否則本發明化合物之所有同位素取代均在本發明之範疇內。此類化合物適用作例如分析工具,用作生物分析中之探針,或用作根據本發明之治療劑。在某些實施例中,舉例而言,所提供之化合物的彈頭部分RW
包含一或多個氘原子。
如本文所用,術語「醫藥學上可接受的鹽」係指在合理醫學判斷的範圍內,適於與人類及低等動物的組織接觸使用而無過度毒性、刺激、過敏反應及類似情形且與合理的效益/風險比相稱的彼等鹽。例示性醫藥學上可接受之鹽見於例如Berge等人(J . Pharm . Sci .
1977, 66(1), 1;及Gould, P.L.,Int . J . Pharmaceutics
1986, 33, 201-217中;(每一者以全文引用之方式併入本文)。
本發明化合物之醫藥學上可接受之鹽包括衍生自適合無機及有機酸及鹼之彼等鹽。醫藥學上可接受之無毒性酸加成鹽之實例為胺基與無機酸(諸如鹽酸、氫溴酸、磷酸、硫酸及過氯酸)或與有機酸(諸如乙酸、草酸、順丁烯二酸、酒石酸、檸檬酸、丁二酸或丙二酸)形成之鹽,或藉由使用此項技術中所使用之其他方法(諸如離子交換)形成之鹽。其他醫藥學上可接受之鹽包括己二酸鹽、褐藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙烷磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、葡糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氫碘化物、2-羥基-乙烷磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、月桂基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲烷磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、特戊酸鹽、丙酸鹽、硬脂酸鹽、丁二酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一烷酸鹽、戊酸鹽及其類似鹽。
衍生自適當鹼的鹽包括鹼金屬、鹼土金屬、銨及N+
(C1 - 4
烷基)4
鹽。代表性鹼金屬或鹼土金屬鹽包括鈉鹽、鋰鹽、鉀鹽、鈣鹽、鎂鹽及其類似鹽。適當時,醫藥學上可接受之其他鹽包括無毒銨、季銨及使用諸如鹵離子、氫氧根、羧酸根、硫酸根、磷酸根、硝酸根、低碳烷基磺酸根及芳基磺酸根之相對離子形成之胺陽離子。
醫藥學上可接受之鹽亦意欲涵蓋半鹽,其中化合物:酸之比率分別為2:1。例示性半鹽為衍生自包含兩個羧酸基之酸的彼等鹽,該等酸諸如蘋果酸、反丁烯二酸、順丁烯二酸、丁二酸、酒石酸、戊二酸、草酸、己二酸及檸檬酸。其他例示性半鹽為衍生自二質子礦物酸(諸如硫酸)之彼等鹽。較佳例示性半鹽包括(但不限於)半順丁烯二酸鹽、半反丁烯二酸鹽及半丁二酸鹽。
如本文所用,術語「約」在本文中用於指大約、大致、在…左右或在…附近。當術語「約」結合數值範圍使用時,其藉由擴展界限高於及低於所述數值來修飾該範圍。一般而言,術語「約」在本文中用於修飾數值高於及低於所述值:向上或向下(更高或更低) 20%的偏差。
如本文所用,「有效量」、「足量」或「治療有效量」係足以實現有益或所要結果(包括臨床結果)之化合物的量。因此,有效量可足以例如減輕或改善與FGFR2信號傳導有關的疾患之嚴重程度及/或持續時間或其一或多種症狀;預防與FGFR2信號傳導有關的疾患相關病狀或症狀之進展;或者增強或以其他方式改善另一療法之預防或治療效果。有效量亦包括避免或實質上減弱非所要副作用之化合物的量。
如本文所用且如此項技術中所充分瞭解,「治療」為獲得有益或所需結果(包括臨床結果)之途徑。有益或所需臨床結果可以包括(但不限於)一或多種症狀或病狀之緩解或改善、疾病或病痛之程度減輕、疾病或病痛之狀態穩定(亦即不惡化)、疾病或病痛擴散之預防、疾病或病痛進展之延遲或減緩、疾病或病痛狀態之改善或緩和,以及緩解(無論部分或全部),無論可偵測或不可偵測。「治療」亦可意謂存活期與未接受治療之預期存活期相比延長。在一些實施例中,可在一或多種症狀已出現之後投與療法。在其他實施例中,療法可在不存在症狀之情況下投與。舉例而言,療法可在症狀發作之前投與易感個體(例如,根據症狀病史及/或根據遺傳或其他易感因素)。亦可在症狀已消退之後繼續治療,例如預防或延遲其復發。
片語「有需要」係指需要從與FGFR2信號傳導活性有關的病狀中出現有症狀的或無症狀的緩解,或可以其他方式藉由本發明之化合物及/或組合物緩解。 3. 例示性實施例之描述
如上文所述,在一些實施例中,本發明提供式I-1化合物:
或其醫藥學上可接受之鹽,其中:
CyA
為 ,
其中表示連至R5
之鍵結且表示連至Cy6
之鍵結;
R5
為-R5A
-L5
-R5B
;
R5A
為RB
之二價基團,其中除-L5
-R5B
之外,R5A
亦經m個R5C
實例取代;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
Cy6
為伸苯基;3至14員飽和或部分不飽和二價碳環;具有1至4個獨立地選自氮、氧及硫之雜原子的3至14員飽和或部分不飽和二價雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至14員伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代;
RW
為鹵素、-CN、 、;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代:或
兩個R6
實例、一個R6
實例及一個RL
實例、一個R6
實例及一個RWA
實例,或一個R6
實例及一個R7a
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環,其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
R8
為H、-NR2
、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R9
為H、-NR2
、鹵素,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R10
為H或視情況經1至3個鹵素取代的C1 - 6
脂族;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈中的一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 6
伸環烷基、3至6員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;其中該C3 - 6
伸環烷基、3至6員伸雜環烷基及5至6員伸雜芳基中之每一者視情況經一個RA
或C1 - 6
脂族實例取代;
RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;其中該環經w個RC
實例取代;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;或
兩個R5C
實例、一個R5C
實例及一個R5D
實例,或兩個R5D
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;
m、n、p、q、r、t、u、v及w中之每一者獨立地為0、1、2、3或4。
如上文一般性定義,CyA
為 ,其中表示連至R5
之鍵結且表示連至Cy6
之鍵結。在一些實施例中,CyA
為。在一些實施例中,CyA
為。在一些實施例中,CyA
為。在一些實施例中,CyA
為。在一些實施例中,CyA
為。在一些實施例中,CyA
為。在一些實施例中,CyA
為。在一些實施例中,CyA
為。
如上文一般所定義,Cy6
為伸苯基;飽和或部分不飽和3至14員二價碳環;具有1至4個獨立地選自氮、氧及硫之雜原子的飽和或部分不飽和二價3至14員雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至14員伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為伸苯基;3至7員飽和或部分不飽和二價單環碳環;8至14員飽和或部分不飽和二價雙環碳環;具有1至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和二價單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的8至14員飽和或部分不飽和二價雙環雜環;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環伸雜芳基;或具有1至4個獨立地選自氮、氧及硫之雜原子的9至10員雙環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為3至14員飽和或部分不飽和二價碳環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為3至7員飽和或部分不飽和二價單環碳環,或8至14員飽和或部分不飽和二價雙環碳環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為3至7員飽和或部分不飽和二價單環碳環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為8至14員飽和或部分不飽和二價雙環碳環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為具有1至4個獨立地選自氮、氧及硫之雜原子的3至14員飽和或部分不飽和二價雜環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和二價單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的8至14員飽和或部分不飽和二價雙環雜環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為具有1至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和二價單環雜環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至2個獨立地選自氮、氧及硫之雜原子的5至6員飽和或部分不飽和二價單環雜環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為二價吡咯啶或二氫吡咯啶環;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為具有1至4個獨立地選自氮、氧及硫之雜原子的5至14員伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環伸雜芳基;或具有1至4個獨立地選自氮、氧及硫之雜原子的9至10員雙環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至2個氮原子的5至6員單環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至2個氮原子的5員單環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
為1至4個獨立地選自氮、氧及硫之雜原子的9至10員雙環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至3個氮原子的9至10員雙環伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。
在一些實施例中,Cy6
係選自表1之化合物中所描繪之基團。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為: ,
其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為: ,
其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為: ,
其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。
如上文一般所定義,R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或兩個R6
實例、一個R6
實例及一個RL
實例、一個R6
實例及一個RWA
實例,或一個R6
實例及一個R7a
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC
實例取代。
在一些實施例中,兩個R6
實例、一個R6
實例及一個RL
實例、一個R6
實例及一個RWA
實例,或一個R6
實例及一個R7a
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC
實例取代。
在一些實施例中,一個R6
實例及一個RWA
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC
實例取代。在一些實施例中,一個R6
實例及一個R7a
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC
實例取代。
在一些實施例中,一個R6
實例及一個R7a
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC
實例取代。在一些實施例中,一個R6
實例及一個R7a
實例與其間插原子一起形成具有一個氮原子的4至8員部分不飽和環;其中該環視情況經1、2或3個獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-(C1 - 4
烷基)之取代基取代;其中各C1 - 4
烷基視情況經1、2或3個氟取代。在一些實施例中,一個R6
實例及一個R7a
實例與其間插原子一起形成4至8員部分不飽和環。在一些實施例中,一個R6
實例及一個R7a
實例與其間插原子一起形成具有一個氮原子的4至8員部分不飽和環。
在一些實施例中,各R6
係選自表1之化合物中所描繪之基團。
如上文一般所定義,R8
為H、-NR2
、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6
脂族。在一些實施例中,R8
為H。在一些實施例中,R8
為-NR2
。在一些實施例中,R8
為鹵素。在一些實施例中,R8
為-OH。在一些實施例中,R8
為視情況經1至3個鹵素取代的C1 - 6
脂族。
在一些實施例中,R8
為-NH2
。在一些實施例中,R8
為C1 - 4
烷基。在一些實施例中,R8
為甲基。在一些實施例中,R8
為-NH2
或甲基。在一些實施例中,R8
係選自表1中之化合物中所描繪之基團。
如上文一般所定義,R9
為H、-NR2
、鹵素,或視情況經1至3個鹵素取代的C1 - 6
脂族。在一些實施例中,R9
為H。在一些實施例中,R9
為-NR2
。在一些實施例中,R9
為-NH2
。在一些實施例中,R9
為鹵素。在一些實施例中,R9
為視情況經1至3個鹵素取代的C1 - 6
脂族。在一些實施例中,R9
為C1 - 4
烷基。在一些實施例中,R9
係選自表1中之化合物中所描繪之基團。
如上文一般所定義,R10
為H或視情況經1至3個鹵素取代的C1 - 6
脂族。在一些實施例中,R10
為H。在一些實施例中,R10
為視情況經1至3個鹵素取代的C1 - 6
脂族。在一些實施例中,R10
為C1 - 4
烷基。在一些實施例中,R10
為甲基。在一些實施例中,R10
為H或甲基。在一些實施例中,R10
係選自表1中之化合物中所描繪之基團。
如上文一般所定義,L6
為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 6
伸環烷基、3至6員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;其中該C3 - 6
伸環烷基、3至6員伸雜環烷基及5至6員伸雜芳基中之每一者視情況經一個RA
或C1 - 6
脂族實例取代。
在一些實施例中,L6
為C3 - 6
伸環烷基、3至6員伸雜環烷基,或5至6員伸雜芳基,其中之每一者視情況經一個RA
或C1 - 6
脂族實例取代。在一些實施例中,L6
為C3 - 6
伸環烷基、3至6員伸雜環烷基,或5至6員伸雜芳基。
在一些實施例中,L6
係選自表1之化合物中所描繪之基團。
如上文一般所定義,R5C
及R5D
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;或兩個R5C
實例、一個R5C
實例及一個R5D
實例,或兩個R5D
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC
實例取代。
在一些實施例中,兩個R5C
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC
實例取代。
在一些實施例中,一個R5C
實例及一個R5D
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC
實例取代。在一些實施例中,一個R5C
實例及一個R5D
實例與其間插原子一起形成經v個RC
實例取代之3至7員飽和或部分不飽和碳環。
在一些實施例中,兩個R5D
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC
實例取代。在一些實施例中,兩個R5D
實例與其間插原子一起形成經v個RC
實例取代之3至7員飽和或部分不飽和碳環。
在一些實施例中,R5C
及R5D
之各實例係選自表1之化合物中所描繪之基團。
如上文一般所定義,v為0、1、2、3或4。在一些實施例中,v為0。在一些實施例中,v為1。在一些實施例中,v為2。在一些實施例中,v為3。在一些實施例中,v為4。在一些實施例中,v為0或1。在一些實施例中,v為0、1或2。在一些實施例中,v為0、1、2或3。在一些實施例中,v為1或2。在一些實施例中,v為1、2或3。在一些實施例中,v為1、2、3或4。在一些實施例中,v為2或3。在一些實施例中,v為2、3或4。在一些實施例中,v為3或4。在一些實施例中,v係選自表1中之化合物所示的值。
如上文一般所定義,w為0、1、2、3或4。在一些實施例中,w為0。在一些實施例中,w為1。在一些實施例中,w為2。在一些實施例中,w為3。在一些實施例中,w為4。在一些實施例中,w 為0或1。在一些實施例中,w為0、1或2。在一些實施例中,w為0、1、2或3。在一些實施例中,w為1或2。在一些實施例中,w 為1、2或3。在一些實施例中,w為1、2、3或4。在一些實施例中,w為2或3。在一些實施例中,w為2、3或4。在一些實施例中,w為3或4。在一些實施例中,w係選自表1中之化合物所示的值。
在一些實施例中,本發明提供式I-1化合物,其中各變數如以下式I或式I-2之描述中所定義且以單獨及組合形式描述於本文實施例中。
如上文所述,在一些實施例中,本發明提供式I-2化合物:
或其醫藥學上可接受之鹽,其中:
R5
為-R5A
-L5
-R5B
;
R5A
為RB
之二價基團,其中除-L5
-R5B
之外,R5A
亦經m個R5C
實例取代;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
Cy6
為伸苯基或具有1至3個氮原子之6員伸雜芳基,其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代;
RW
為鹵素、-CN、 ;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或
兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;
RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;及
m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。
如上文一般所定義,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環。
在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
或-C(O)N(R)OR。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘或視情況經取代之C1 - 6
脂族。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、-C1 - 4
烷基、-(C1 - 4
烷基)-O-(C1 - 4
烷基),或-(C1 - 4
烷基)-N(C1 - 4
烷基)2
;其中各C1 - 4
烷基視情況經1、2或3個氟取代。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘,或視情況經1、2或3個氟取代的-C1 - 4
烷基。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘或-C1 - 4
烷基。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、氘或-CH3
。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫或氘。在一些實施例中,RWA
、RWB
及RWC
中之每一者為氘。
在一些實施例中,本發明提供式I-2化合物,其中各變數如以下式I之描述中所定義且以單獨及組合形式描述於本文實施例中。
如上文所述,在一些實施例中,本發明提供式I化合物:
或其醫藥學上可接受之鹽,其中:
R5
為-R5A
-L5
-R5B
;
R5A
為RB
之二價基團,其中除-L5
-R5B
之外,R5A
亦經m個R5C
實例取代;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
Cy6
為伸苯基或具有1至3個氮原子之6員伸雜芳基,其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代;
RW
為鹵素、-CN、 ;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或
兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;
RWA
、RWB
及RWC
中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代的基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;及
m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。
如上文一般所定義,R5A
為RB
之二價基團,其中除-L5
-R5B
之外,R5A
亦經m個R5C
實例取代;在一些實施例中,R5A
為二價C1 - 6
脂族,除-L5
-R5B
之外,其亦經m個R5C
實例取代。在一些實施例中,R5A
為伸苯基,除-L5
-R5B
之外,其亦經m個R5C
實例取代。在一些實施例中,R5A
為具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環伸雜芳基環,除-L5
-R5B
之外,該環亦經m個R5C
實例取代。在一些實施例中,R5A
為具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環伸雜芳基環,除-L5
-R5B
之外,該環亦經m個R5C
實例取代。在一些實施例中,R5A
為3至7員飽和或部分不飽和二價碳環,除-L5
-R5B
之外,該碳環亦經m個R5C
實例取代。在一些實施例中,R5A
為具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和二價單環雜環,除-L5
-R5B
之外,該單環雜環亦經m個R5C
實例取代。在一些實施例中,R5A
為具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和二價雙環雜環,除-L5
-R5B
之外,該雙環雜環亦經m個R5C
實例取代。在一些實施例中,R5A
係選自表1之化合物中所描繪之基團。
如上文一般所定義,L5
為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-。在一些實施例中,L5
為共價鍵。在一些實施例中,L5
為C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-。
在一些實施例中,L5
為C1 - 2
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-。在一些實施例中,L5
為C1 - 2
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經-O-、-C(O)-、-C(O)NH-或-C(O)N(RL
)-置換。
在一些實施例中,L5
為-O-、-C(O)-、-C(O)NH-或-C(O)N(RL
)-。在一些實施例中,L5
為-O-。在一些實施例中,L5
為-C(O)-。在一些實施例中,L5
為-C(O)NH-。在一些實施例中,L5
為-C(O)N(RL
)-。在一些實施例中,L5
係選自表1之化合物中所描繪之基團。
如上文一般所定義,R5B
為氫或RB
,其中R5B
經n個R5D
實例取代。在一些實施例中,R5B
為氫。在一些實施例中,R5B
為經n個R5D
實例取代之RB
。在一些實施例中,R5B
為經n個R5D
實例取代之C1 - 6
脂族。在一些實施例中,R5B
為經n個R5D
實例取代之苯基。在一些實施例中,R5B
為具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環,其經n個R5D
實例取代。在一些實施例中,R5B
為具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環,其經n個R5D
實例取代。在一些實施例中,R5B
為經n個R5D
實例取代之3至7員飽和或部分不飽和碳環。在一些實施例中,R5B
為具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環,該單環雜環經n個R5D
實例取代。在一些實施例中,R5B
為具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環,該雙環雜環經n個R5D
實例取代。
在一些實施例中,R5B
為具有1至2個獨立地選自氮、氧及硫之雜原子的4至6員飽和或部分不飽和單環雜環,該單環雜環經n個R5D
實例取代。在一些實施例中,R5B
為具有1至3個獨立地選自氮、氧及硫之雜原子的5員單環雜芳基環,該單環雜芳基環經n個R5D
實例取代。在一些實施例中,R5B
為具有1至2個獨立地選自氮、氧及硫之雜原子的6員單環雜芳基環,該單環雜芳基環經n個R5D
實例取代。在一些實施例中,R5B
選自表1之化合物中所描繪之基團。
如上文一般所定義,R5C
之各實例獨立地為RA
或RB
,且經u個RC
實例取代。在一些實施例中,R5C
之各實例為RA
。在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN、-OR、-S(O)2
NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-OC(O)R及-N(R)C(O)R。在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN、-OR及-C(O)NR2
。在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-C(O)N(C1 - 4
烷基)2
;其中各C1 - 4
烷基視情況經1、2或3個鹵素取代。在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-C(O)N(C1 - 4
烷基)2
。
在一些實施例中,R5C
之各實例為RB
,其中R5C
經u個RC
實例取代。在一些實施例中,R5C
之各實例為RB
,其中R5C
經一個RC
實例取代。在一些實施例中,R5C
之各實例獨立地選自C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者視情況經u個RC
實例取代。
在一些實施例中,R5C
之各實例獨立地選自C1 - 6
脂族;3至7員飽和或部分不飽和碳環;及具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者視情況經u個RC
實例取代。在一些實施例中,R5C
之各實例獨立地選自:視情況經一個RC
實例取代之C1 - 4
脂族;3至5員飽和碳環;及具有1個獨立地選自氮、氧及硫之雜原子的3至5員飽和單環雜環;其中之每一者視情況經1、2或3個鹵素取代。在一些實施例中,R5C
之各實例獨立地選自:視情況經-OH、-O-(C1 - 4
烷基)或-N(C1 - 4
烷基)2
之一個實例取代的C1 - 4
烷基;3至5員飽和碳環;及具有1個氧原子的3至5員飽和單環雜環;其中之每一者視情況經1、2或3個氟或氯取代。
在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN、-OR、-C(O)NR2
,及以下基團(其中之每一者視情況經u個RC
實例取代):C1 - 6
脂族;3至7員飽和或部分不飽和碳環;及具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環。在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN,及以下基團(其中之每一者視情況經1、2或3個鹵素取代):-O-(C1 - 4
烷基)、-C(O)N(C1 - 4
烷基)2
、視情況經一個RC
實例取代之C1 - 4
脂族;3至5員飽和碳環;及具有1個獨立地選自氮、氧及硫之雜原子的3至5員飽和單環雜環。在一些實施例中,R5C
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)、-C(O)N(C1 - 4
烷基)2
及以下基團(其中之每一者視情況經1、2或3個氟或氯取代):視情況經-OH、-O-(C1 - 4
烷基)或-N(C1 - 4
烷基)2
之一個實例取代的C1 - 4
烷基;3至5員飽和碳環;及具有1個氧原子的3至5員飽和單環雜環。在一些實施例中,R5C
係選自表1之化合物中所描繪之基團。
如上文一般所定義,R5D
之各實例獨立地為RA
或RB
,且經u個RC
實例取代。在一些實施例中,R5D
之各實例為RA
。在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN、-OR、-S(O)2
NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-OC(O)R,及-N(R)C(O)R。在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN、-OR及-C(O)NR2
。在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-C(O)N(C1 - 4
烷基)2
;其中各C1 - 4
烷基視情況經1、2或3個鹵素取代。在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-C(O)N(C1 - 4
烷基)2
。
在一些實施例中,R5D
之各實例為RB
,其中R5D
經u個RC
實例取代。在一些實施例中,R5D
之各實例為RB
,其中R5D
經一個RC
實例取代。在一些實施例中,R5D
之各實例獨立地選自C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者視情況經u個RC
實例取代。
在一些實施例中,R5D
之各實例獨立地選自C1 - 6
脂族;3至7員飽和或部分不飽和碳環;及具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者視情況經u個RC
實例取代。在一些實施例中,R5D
之各實例獨立地選自:視情況經一個RC
實例取代之C1 - 4
脂族;3至5員飽和碳環;及具有1個獨立地選自氮、氧及硫之雜原子的3至5員飽和單環雜環;其中之每一者視情況經1、2或3個鹵素取代。在一些實施例中,R5D
之各實例獨立地選自:視情況經-OH、-O-(C1 - 4
烷基)或-N(C1 - 4
烷基)2
之一個實例取代的C1 - 4
烷基;3至5員飽和碳環;及具有1個氧原子的3至5員飽和單環雜環;其中之每一者視情況經1、2或3個氟或氯取代。
在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN、-OR、-C(O)NR2
,及以下基團(其中之每一者視情況經u個RC
實例取代):C1 - 6
脂族;3至7員飽和或部分不飽和碳環;及具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環。在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN,及以下基團(其中之每一者視情況經1、2或3個鹵素取代):-O-(C1 - 4
烷基)、-C(O)N(C1 - 4
烷基)2
、視情況經一個RC
實例取代之C1 - 4
脂族;3至5員飽和碳環;及具有1個獨立地選自氮、氧及硫之雜原子的3至5員飽和單環雜環。在一些實施例中,R5D
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)、-C(O)N(C1 - 4
烷基)2
及以下基團(其中之每一者視情況經1、2或3個氟或氯取代):視情況經-OH、-O-(C1 - 4
烷基)或-N(C1 - 4
烷基)2
之一個實例取代的C1 - 4
烷基;3至5員飽和碳環;及具有1個氧原子的3至5員飽和單環雜環。在一些實施例中,R5D
係選自表1之化合物中所描繪之基團。
如上文一般所定義,在一些實施例中,本發明提供式I化合物,其中R5
為-R5A
-L5
-R5B
。在一些實施例中,R5
(亦即,-R5A
-L5
-R5B
結合在一起)為: ,
其中L5
、R5B
、R5C
及m中之每一者如在實施例以及本文的類別及子類中所定義。
在一些實施例中,R5
(亦即,-R5A
-L5
-R5B
結合在一起)係選自表1之化合物中所描繪之基團。
Cy6
為伸苯基或具有1至3個氮原子之6員伸雜芳基,其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為伸苯基,除-L6
-RW
之外,其亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至3個氮原子的6員伸雜芳基;其中除-L6
-RW
之外,Cy6
亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1至2個氮原子的6員伸雜芳基,除-L6
-RW
之外,其亦經p個R6
實例取代。在一些實施例中,Cy6
為具有1個氮原子的6員伸雜芳基,除-L6
-RW
之外,其亦經p個R6
實例取代。在一些實施例中,Cy6
為具有2個氮原子的6員伸雜芳基,除-L6
-RW
之外,其亦經p個R6
實例取代。在一些實施例中,Cy6
為具有2個氮原子的6員伸雜芳基,其僅經-L6
-RW
取代。在一些實施例中,Cy6
為具有1至2個氮原子的6員伸雜芳基,除-L6
之外,其亦經p個R6
實例取代,其中L6
為共價鍵,且-RW
為-CN或。在一些實施例中,Cy6
係選自表1之化合物中所描繪之基團。
如上文一般所定義,R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代。在一些實施例中,R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代。
在一些實施例中,兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代。在一些實施例中,兩個R6
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代。
在一些實施例中,一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代。在一些實施例中,一個R6
實例及一個RL
實例與其間插原子一起形成具有一個氮原子的4至7員部分不飽和環;其中該環視情況經1、2或3個獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-(C1 - 4
烷基)之取代基取代;其中各C1 - 4
烷基視情況經1、2或3個氟取代。在一些實施例中,一個R6
實例及一個RL
實例與其間插原子一起形成具有一個氮原子的4至7員部分不飽和環。
在一些實施例中,R6
之各實例為RA
。在一些實施例中,R6
之各實例獨立地選自鹵素、-CN、-OR、-S(O)2
NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-OC(O)R,及-N(R)C(O)R。在一些實施例中,R6
之各實例獨立地選自鹵素、-CN、-OR及-C(O)NR2
。在一些實施例中,R6
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-C(O)N(C1 - 4
烷基)2
;其中各C1 - 4
烷基視情況經1、2或3個鹵素取代。在一些實施例中,R6
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)及-C(O)N(C1 - 4
烷基)2
。
在一些實施例中,R6
之各實例為RB
,其中R6
經q個RC
實例取代。在一些實施例中,R6
之各實例為RB
,其中R6
經一個RC
實例取代。在一些實施例中,R6
之各實例獨立地選自C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者視情況經q個RC
實例取代。
在一些實施例中,R6
之各實例獨立地選自C1 - 6
脂族;3至7員飽和或部分不飽和碳環;及具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者視情況經q個RC
實例取代。在一些實施例中,R6
之各實例獨立地選自:視情況經一個RC
實例取代之C1 - 4
脂族;3至5員飽和碳環;及具有1個獨立地選自氮、氧及硫之雜原子的3至5員飽和單環雜環;其中之每一者視情況經1、2或3個鹵素取代。在一些實施例中,R6
之各實例獨立地選自:視情況經-OH、-O-(C1 - 4
烷基)或-N(C1 - 4
烷基)2
之一個實例取代的C1 - 4
烷基;3至5員飽和碳環;及具有1個氧原子的3至5員飽和單環雜環;其中之每一者視情況經1、2或3個氟或氯取代。
在一些實施例中,R6
之各實例獨立地選自鹵素、-CN、-OR、-C(O)NR2
,及以下基團(其中之每一者視情況經q個RC
實例取代):C1 - 6
脂族;3至7員飽和或部分不飽和碳環;及具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環。在一些實施例中,R6
之各實例獨立地選自鹵素、-CN,及以下基團(其中之每一者視情況經1、2或3個鹵素取代):-O-(C1 - 4
烷基)、-C(O)N(C1 - 4
烷基)2
、視情況經一個RC
實例取代之C1 - 4
脂族;3至5員飽和碳環;及具有1個獨立地選自氮、氧及硫之雜原子的3至5員飽和單環雜環。在一些實施例中,R6
之各實例獨立地選自鹵素、-CN、-O-(C1 - 4
烷基)、-C(O)N(C1 - 4
烷基)2
及以下基團(其中之每一者視情況經1、2或3個氟或氯取代):視情況經-OH、-O-(C1 - 4
烷基)或-N(C1 - 4
烷基)2
之一個實例取代的C1 - 4
烷基;3至5員飽和碳環;及具有1個氧原子的3至5員飽和單環雜環。在一些實施例中,R6
係選自表1之化合物中所描繪之基團。
如上文一般所定義,L6
為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-。在一些實施例中,L6
為共價鍵。在一些實施例中,L6
為C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-。
在一些實施例中,L6
為C1 - 2
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-。在一些實施例中,L6
為C1 - 2
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一個亞甲基單元視情況經-NH-或-N(RL
)-置換。
在一些實施例中,L6
為-NH-或-N(RL
)-。在一些實施例中,L6
為-NH-。在一些實施例中,L6
為-N(RL
)-。在一些實施例中,L6
為-NH-或-N(CH3
)-。在一些實施例中,L6
為-N(CH3
)-。在一些實施例中,L6
係選自表1之化合物中所描繪之基團。
在一些實施例中,RW
為鹵素。在一些實施例中,RW
為-CN。在一些實施例中,RW
為。在一些實施例中,RW
為 。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。
在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。在一些實施例中,RW
為。
在一些實施例中,RW
為 ;且RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環。
在一些實施例中,RW
為,且RWA
及RWB
或RWB
及RWC
與其間插原子一起形成具有0至1個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和環。在一些實施例中,RW
為;且RWA
及一個RL
實例與其間插原子一起形成具有0至1個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環。在一些實施例中,RW
為,且RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和環。在一些實施例中,RW
係選自表1之化合物中所描繪的基團。
不希望受任何特定理論束縛,咸信RW
為彈頭基團,尤其適於共價結合至蛋白激酶之硫氫基側鏈部分,例如FGFR2之Cys491。因此,在一些實施例中,RW
的特徵在於其能夠共價結合至半胱胺酸殘基,從而不可逆地抑制蛋白激酶。在一些實施例中,蛋白激酶為FGFR。在某些實施例中,蛋白激酶為FGFR2。在某些實施例中,蛋白激酶為FGFR2,且半胱胺酸殘基為Cys491。
如上文一般所定義,RWA
、RWB
及RWC
中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代的基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環。
在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環。在一些實施例中,RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環。
在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
,或-C(O)N(R)OR。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為選自以下之視情況經取代的基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環。
在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫或視情況經取代之C1 - 6
脂族。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫或視情況經取代之C1 - 6
脂族。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫、-C1 - 4
烷基、-(C1 - 4
烷基)-O-(C1 - 4
烷基),或-(C1 - 4
烷基)-N(C1 - 4
烷基)2
;其中各C1 - 4
烷基視情況經1、2或3個氟取代。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫或視情況經1、2或3個氟取代的-C1 - 4
烷基。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫或-C1 - 4
烷基。在一些實施例中,RWA
、RWB
及RWC
中之每一者獨立地為氫或-CH3
。
在一些實施例中,RWA
及RWB
或RWB
及RWC
與其間插原子一起形成具有0至1個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和環。在一些實施例中,RWA
及RWB
或RWB
及RWC
與其間插原子一起形成4至7員部分不飽和碳環。在一些實施例中,RWA
及一個RL
實例與其間插原子一起形成具有0至1個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環。在一些實施例中,RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和環。在一些實施例中,RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的5至6員部分不飽和環。在一些實施例中,RWA
、RWB
及RWC
中之每一者係選自表1之化合物中所描繪之基團。
如上文一般所定義,RWD
為鹵素或-OS(O)2
R。在一些實施例中,RWD
為鹵素。在一些實施例中,RWD
為氯或溴。在一些實施例中,RWD
為氯。在一些實施例中,RWD
為-OS(O)2
R。在一些實施例中,RWD
為-OS(O)2
-(視情況經取代之C1 - 3
烷基)。在一些實施例中,RWD
為-OS(O)2
CH3
或-OS(O)2
CF3
。在一些實施例中,RWD
為-OS(O)2
-(視情況經取代之苯基)。在一些實施例中,RWD
係選自表1之化合物中所描繪之基團。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,
其中L6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
、RW
及p中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
、R6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。在一些實施例中,-Cy6
-L6
-RW
結合在一起為:,其中L6
及RW
中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,-Cy6
-L6
-RW
係選自表1之化合物中所描繪之基團。
如上文一般所定義,R7
為H或RB
,其中R7
經t個R7A
實例取代。在一些實施例中,R7
為H。在一些實施例中,R7
為RB
,其中R7
經t個R7A
實例取代。在一些實施例中,R7
為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;3至7員飽和或部分不飽和碳環;或具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者經t個R7A
實例取代。在一些實施例中,R7
為C1 - 6
脂族;3至7員飽和或部分不飽和碳環;或具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;其中之每一者經t個R7A
實例取代。
在一些實施例中,R7
為C1 - 6
烷基;3至7員飽和碳環;或具有1至2個獨立地選自氮及氧之雜原子的3至7員飽和單環雜環;其中之每一者經0至1個R7A
實例及0至3個鹵素取代。在一些實施例中,R7
為經0至1個R7A
實例及0至3個鹵素取代之C1 - 6
烷基。在一些實施例中,R7
為-C1 - 4
烷基、-(C1 - 4
烷基)-OH、-(C1 - 4
烷基)-O-(C1 - 4
烷基),或-(C1 - 4
烷基)-N(C1 - 4
烷基)2
;其中各C1 - 4
烷基視情況經1、2或3個氟取代。在一些實施例中,R7
為視情況經1、2或3個氟取代之-C1 - 4
烷基。在一些實施例中,R7
為-CH3
。在一些實施例中,R7
為經0至1個RB
實例及0至3個鹵素取代之C1 - 6
烷基。
在一些實施例中,R7
為經0至1個R7A
實例及0至3個鹵素取代之3至7員飽和碳環。在一些實施例中,R7
為具有1至2個獨立地選自氮及氧之雜原子的3至7員飽和單環雜環;其經0至1個R7A
實例及0至3個鹵素取代。在一些實施例中,R7
為具有1個氧原子的5至6員飽和單環雜環;其經0至1個R7A
實例及0至3個鹵素取代。在一些實施例中,R7
為具有1個氧原子的5至6員飽和單環雜環;其經0至3個鹵素及0至1個選自-C1 - 4
烷基、-OH、-O-(C1 - 4
烷基)或N(C1 - 4
烷基)2
之基團取代;其中各C1 - 4
烷基視情況經1、2或3個氟取代。在一些實施例中,R7
為具有1個氧原子的5至6員飽和單環雜環。在一些實施例中,R7
係選自表1之化合物中所描繪之基團。
如上文一般所定義,m為0、1、2、3或4。在一些實施例中,m為0。在一些實施例中,m為1。在一些實施例中,m為2。在一些實施例中,m為3。在一些實施例中,m為4。在一些實施例中,m為0或1。在一些實施例中,m為0、1或2。在一些實施例中,m為0、1、2或3。在一些實施例中,m為1或2。在一些實施例中,m為1、2或3。在一些實施例中,m為1、2、3或4。在一些實施例中,m為2或3。在一些實施例中,m為2、3或4。在一些實施例中,m為3或4。在一些實施例中,m係選自表1中之化合物所示的值。
如上文一般所定義,n為0、1、2、3或4。在一些實施例中,n為0。在一些實施例中,n為1。在一些實施例中,n為2。在一些實施例中,n為3。在一些實施例中,n為4。在一些實施例中,n為0或1。在一些實施例中,n為0、1或2。在一些實施例中,n為0、1、2或3。在一些實施例中,n為1或2。在一些實施例中,n為1、2或3。在一些實施例中,n為1、2、3或4。在一些實施例中,n為2或3。在一些實施例中,n為2、3或4。在一些實施例中,n為3或4。在一些實施例中,n係選自表1中之化合物所示的值。
如上文一般所定義,p為0、1、2、3或4。在一些實施例中,p為0。在一些實施例中,p為1。在一些實施例中,p為2。在一些實施例中,p為3。在一些實施例中,p為4。在一些實施例中,p為0或1。在一些實施例中,p為0、1或2。在一些實施例中,p為0、1、2或3。在一些實施例中,p為1或2。在一些實施例中,p為1、2或3。在一些實施例中,p為1、2、3或4。在一些實施例中,p為2或3。在一些實施例中,p為2、3或4。在一些實施例中,p為3或4。在一些實施例中,p係選自表1中之化合物所示的值。
如上文一般所定義,q為0、1、2、3或4。在一些實施例中,q為0。在一些實施例中,q為1。在一些實施例中,q為2。在一些實施例中,q為3。在一些實施例中,q為4。在一些實施例中,q為0或1。在一些實施例中,q為0、1或2。在一些實施例中,q為0、1、2或3。在一些實施例中,q為1或2。在一些實施例中,q為1、2或3。在一些實施例中,q為1、2、3或4。在一些實施例中,q為2或3。在一些實施例中,q為2、3或4。在一些實施例中,q為3或4。在一些實施例中,q係選自表1中之化合物所示的值。
如上文一般所定義,r為0、1、2、3或4。在一些實施例中,r為0。在一些實施例中,r為1。在一些實施例中,r為2。在一些實施例中,r為3。在一些實施例中,r為4。在一些實施例中,r為0或1。在一些實施例中,r為0、1或2。在一些實施例中,r為0、1、2或3。在一些實施例中,r為1或2。在一些實施例中,r為1、2或3。在一些實施例中,r為1、2、3或4。在一些實施例中,r為2或3。在一些實施例中,r為2、3或4。在一些實施例中,r為3或4。在一些實施例中,r係選自表1中之化合物所示的值。
如上文一般所定義,t為0、1、2、3或4。在一些實施例中,t為0。在一些實施例中,t為1。在一些實施例中,t為2。在一些實施例中,t為3。在一些實施例中,t為4。在一些實施例中,t為0或1。在一些實施例中,t為0、1或2。在一些實施例中,t為0、1、2或3。在一些實施例中,t為1或2。在一些實施例中,t為1、2或3。在一些實施例中,t為1、2、3或4。在一些實施例中,t為2或3。在一些實施例中,t為2、3或4。在一些實施例中,t為3或4。在一些實施例中,t係選自表1中之化合物所示的值。
如上文一般所定義,u為0、1、2、3或4。在一些實施例中,u為0。在一些實施例中,u為1。在一些實施例中,u為2。在一些實施例中,u為3。在一些實施例中,u為4。在一些實施例中,u為0或1。在一些實施例中,u為0、1或2。在一些實施例中,u為0、1、2或3。在一些實施例中,u為1或2。在一些實施例中,u為1、2或3。在一些實施例中,u為1、2、3或4。在一些實施例中,u為2或3。在一些實施例中,u為2、3或4。在一些實施例中,u為3或4。在一些實施例中,u係選自表1中之化合物所示的值。
在一些實施例中,本發明提供式I - 1
化合物,包含吡咯并嘧啶、吡咯并三嗪、吡唑并吡嗪、吡咯并吡啶、呋喃并嘧啶、噻吩并嘧啶或吡咯并噠嗪酮,從而形成式Ia
、Ib
、Ic
、Id
、Ie
、、Ig
或Ih
化合物:
或其醫藥學上可接受之鹽,其中Cy6
、L6
、RW
、R5
、R7
、R8
、R9
及R10
中之每一者如本文的實施例以及各類別及子類中所定義。
在一些實施例中,本發明提供式I - 1
化合物,其中R5A
為伸苯基、伸吡啶基或伸環己烯基,從而形成式II - 1
、III - 1
、IV - 1
或V - 1
化合物:
或其醫藥學上可接受之鹽,其中CyA
、Cy6
、L5
、L6
、R5B
、R5C
、RW
及m中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式I - 1
化合物,其中Cy6
為伸苯基、伸吡啶基或伸嘧啶基,從而形成式VI - 1
、VII - 1
、VIII - 1
或IX - 1
化合物:
或其醫藥學上可接受之鹽,其中CyA
、L6
、R5
、RW
、R6
及p中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式II - 1
、III - 1
、IV - 1
或V - 1
化合物,其中Cy6
為伸苯基,從而分別形成式X - 1
、XI - 1
、XII - 1
或XIII - 1
化合物:
或其醫藥學上可接受之鹽,其中CyA
、L5
、L6
、R5B
、R5C
、RW
、R6
、m及p中之每一者如本文的實施例及各類別及子類中所定義。
舉例而言,在一些實施例中,本發明提供式X-1、XI-1、XII-1或XIII-1化合物:
或其醫藥學上可接受之鹽,其中:
CyA
為 ,
其中該CyA
中之表示連至以下之鍵結: ,並且CyA
中之表示連至之鍵結;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
RW
為鹵素、-CN、 ;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或
兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
R8
為H、-NR2
、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R9
為H、-NR2
、鹵素,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R10
為H或視情況經1至3個鹵素取代的C1 - 6
脂族;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;
RWA
、RWB
及RWC
中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代的基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;及
m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。
在一些實施例中,本發明提供式X-1、XI-1、XII-1或XIII-1化合物:
或其醫藥學上可接受之鹽,其中:
CyA
為 ,
其中CyA
中之表示連至以下之鍵結: ,且CyA
中之表示連至之鍵結;
R5B
為氫或RB
,其中R5B
經n個R5D
實例取代;
RW
為鹵素、-CN、 ;
R6
之各實例獨立地為RA
或RB
,其中R6
經q個RC
實例取代;或
兩個R6
實例,或一個R6
實例及一個RL
實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC
實例取代;
R7
為H或RB
,其中R7
經t個R7A
實例取代;
R8
為H、-NR2
、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R9
為H、-NR2
、鹵素,或視情況經1至3個鹵素取代的C1 - 6
脂族;
R10
為H或視情況經1至3個鹵素取代的C1 - 6
脂族;
L5
及L6
中之每一者獨立地為共價鍵,或C1 - 4
飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL
)-、-C(RL
)2
-、C3 - 5
伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL
)-、-NHC(O)-、-N(RL
)C(O)-、-C(O)NH-、-C(O)N(RL
)-、-NHS(O)2
-、-N(RL
)S(O)2
-、-S(O)2
NH-、-S(O)2
N(RL
)-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2
-;
RWA
、RWB
及RWC
中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或
RWA
及RWB
、RWB
及RWC
、RWA
及一個RL
實例,或RWC
及一個RL
實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;
RWD
為鹵素或-OS(O)2
R;
R5C
、R5D
、R7A
及RL
之各實例獨立地為RA
或RB
,且經u個RC
實例取代;
RA
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
或-N(R)S(O)2
R;
RB
之各實例獨立地為C1 - 6
脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環;
RC
之各實例獨立地為側氧基、鹵素、-CN、-NO2
、-OR、-SR、-NR2
、-S(O)2
R、-S(O)2
NR2
、-S(O)R、-S(O)NR2
、-S(O)2
F、-OS(O)2
F、-C(O)R、-C(O)OR、-C(O)NR2
、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2
、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2
、-N(R)C(NR)NR2
、-N(R)S(O)2
NR2
、-N(R)S(O)2
R,或選自以下之視情況經取代之基團:C1 - 6
脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;
各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6
脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或:
同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;及
m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。
在一些實施例中,本發明提供式II - 1
、III - 1
、IV - 1
或V - 1
化合物,其中Cy6
為伸吡啶基,從而分別形成式XIV - 1
、XV - 1
、XVI - 1
、XVII - 1
、XVIII - 1
、XIX - 1
、XX - 1
或XXI - 1
化合物:
或其醫藥學上可接受之鹽,其中CyA
、L5
、L6
、R5B
、R5C
、RW
、R6
、m及p中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式II - 1
、III - 1
、IV - 1
或V - 1
化合物,其中Cy6
為伸嘧啶基,從而分別形成式XXII - 1
、XXIII - 1
、XXIV - 1
或XXV - 1
化合物:
或其醫藥學上可接受之鹽,其中CyA
、L5
、L6
、R5B
、R5C
、RW
、R6
、m及p中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式I - 1 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中CyA
為 ,
其中表示連至之R5
一鍵且表示連至Cy6
之鍵結。
在一些實施例中,本發明提供式I - 1 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中CyA
為,其中表示連至R5
之鍵結且表示連至Cy6
之鍵結。
在一些實施例中,本發明提供I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L5
為-O-、-C(O)-、-C(O)NH-或-C(O)N(RL
)-。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L5
為-O-。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L5
為-C(O)-。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L5
為-C(O)NH-。在一些實施例中,本發明提供I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L5
為-C(O)N(RL
)-。
在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L6
為-NH-或-N(RL
)-。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中L6
為-NH-。
在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中m為0或1。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中m為0。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中m為1。
在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中p為0或1。在一些實施例中,本發明提供I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中p為0。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中p為1。
在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中RW
為。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1 或 XXV - 1
化合物,其中RW
為。在一些實施例中,本發明提供式I - 1 、 Ia 、 Ib 、 Ic 、 Id 、 Ie 、 If 、 Ig 、 Ih 、 II - 1 、 III - 1 、 IV - 1 、 V - 1 、 VI - 1 、 VII - 1 、 VIII - 1 、 IX - 1 、 X - 1 、 XI - 1 、 XII - 1 、 XIII - 1 、 XIV - 1 、 XV - 1 、 XVI - 1 、 XVII - 1 、 XVIII - 1 、 XIX - 1 、 XX - 1 、 XXI - 1 、 XXII - 1 、 XXIII - 1 、 XXIV - 1
或XXV - 1
化合物,其中RW
為。
在一些實施例中,本發明提供式I
化合物,其中R5A
為伸苯基、伸吡啶基或伸環己烯基,從而形成式II
、III
、IV
或V
化合物:
或其醫藥學上可接受之鹽,其中Cy6
、L5
、L6
、R5B
、R5C
、RW
、R7
及m中之每一者如本文的實施例及各類別及亞類中所定義。
在一些實施例中,本發明提供式I
化合物,其中Cy6
為伸苯基、伸吡啶基或伸嘧啶基,從而形成式VI
、VII
、VIII
或IX
化合物:
或其醫藥學上可接受之鹽,其中L6
、R5
、RW
、R6
、R7
及p中之每一者如本文的實施例及各類別及亞類中所定義。
在一些實施例中,本發明提供式II
、III
、IV
或V
化合物,其中Cy6
為伸苯基,從而分別形成式X
、XI
、XII
或XIII
化合物:
或其醫藥學上可接受之鹽,其中L5
、L6
、R5B
、R5C
、RW
、R6
、R7
、m及p中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式II
、III
、IV
或V
化合物,其中Cy6
為伸吡啶基,從而分別形成式XIV
、XV
、XVI
、XVII
、XVIII
、XIX
、XX
或XXI
化合物:
或其醫藥學上可接受之鹽,其中CyA
、L5
、L6
、R5B
、R5C
、RW
、R6
、m及p中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式II
、III
、IV
或V
化合物,其中Cy6
為伸嘧啶基,從而分別形成式XXII
、XXIII
、XXIV
或XXV
化合物:
或其醫藥學上可接受之鹽,其中CyA
、L5
、L6
、R5B
、R5C
、RW
、R6
、m及p中之每一者如本文的實施例及各類別及子類中所定義。
在一些實施例中,本發明提供式I
、II
、III
、IV
、V
、VI
、VII
、VIII
、IX
、X
、XI
、XII
或XIII
化合物,其中L5
為-O-、-C(O)-、-C(O)NH-或-C(O)N(RL
)-。在一些實施例中,本發明提供式I
、II
、III
、IV
、V
、VI
、VII
、VIII
、IX
、X
、XI
、XII
或XIII
化合物,其中L5
為-O-。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中L5
為-C(O)-。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中L5
為-C(O)NH-。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中L5
為-C(O)N(RL
)-。
在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中L6
為-NH-或-N(RL
)-。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中L6
為-NH-。
在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中m為0或1。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中m為0。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中m為1。
在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中p為0或1。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中p為0。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中p為1。
在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中RW
為。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中RW
為。在一些實施例中,本發明提供式I 、 II 、 III 、 IV 、 V 、 VI 、 VII 、 VIII 、 IX 、 X 、 XI 、 XII
或XIII
化合物,其中RW
為。
在一些實施例中,本發明提供XIV
、XV
、XVI
、XVII
、XVIII
、XIX
、XX
、XXI
、XXII
、XXIII
、XXIV
或XXV
化合物,其中L5
為-O-、-C(O)-、-C(O)NH-,或-C(O)N(RL
)-。在一些實施例中,本發明提供式XIV
、XV
、XVI
、XVII
、XVIII
、XIX
、XX
、XXI
、XXII
、XXIII
、XXIV
或XXV
化合物,其中L5
為-O-。在一些實施例中,本發明提供式XIV
、XV
、XVI
、XVII
、XVIII
、XIX
、XX
、XXI
、XXII
、XXIII
、XXIV
或XXV
化合物,其中L5
為-C(O)-。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中L5
為-C(O)NH-。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中L5
為-C(O)N(RL
)-。
在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中L6
為-NH-或-N(RL
)-。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中L6
為-NH-。
在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中m為0或1。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中m為0。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中m為1。
在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV 或 XXV
化合物,其中p為0或1。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中p為0。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中p為1。
在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中RW
為。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中RW
為。在一些實施例中,本發明提供式XIV 、 XV 、 XVI 、 XVII 、 XVIII 、 XIX 、 XX 、 XXI 、 XXII 、 XXIII 、 XXIV
或XXV
化合物,其中RW
為。
本發明之化合物之實例包括本文中之表及範例中所列的彼等化合物或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中,本發明包含選自下表1中所描繪之化合物的化合物或其醫藥學上可接受之鹽、立體異構體或立體異構體混合物。在一些實施例中,本發明提供下表1中所示之化合物或其醫藥學上可接受之鹽。在一些實施例中,本發明提供下表1中所示的化合物。表 1
.具有生物活性資料的本發明代表性化合物
.
在上表1之化學結構中,當立體異構中心用虛線或楔形鍵描繪且標記為「abs」(或未標記)時,化合物在該立體中心處基本上為單一異構體(而非等莫耳混合物),且絕對立體化學如化學結構中所示。(參見例如實例146之結構)。當立體異構中心用虛線或楔形鍵描繪且亦標記為「或1」時,化合物在該立體異構中心處為單一異構體,但該立體異構中心處的絕對立體化學尚未確定。(參見例如實例397及398之結構)。當立體異構中心用虛線或楔形鍵描繪且亦標記為「與1」或「及1」時,該化合物為該立體異構中心處之兩種異構體之混合物:如所繪示的結構,及其中該立體對稱中心具有相反組態的異構體。(參見例如實例581之結構)。
上表1中所描繪之某些化合物在室溫下之溶液中呈跨越聯芳基鍵的非互變滯轉異構體存在。當聯芳基鍵中的一個原子標記為「或1」時,此表示化合物在在室溫下之溶液中呈非互變滯轉異構體存在,且化合物基本上為單一滯轉異構體(而非等莫耳混合物)。(參見例如實例516及517之結構)。
在一些實施例中,本發明提供上表1中之化合物,其中該化合物具有之生物化學FGFR2 Caliper IC50
係以「A」表示。在一些實施例中,本發明提供上表1中的化合物,其中該化合物具有之生物化學FGFR2 Caliper IC50
係以「A」或「B」表示。在一些實施例中,本發明提供上表1中之化合物,其中該化合物具有之生物化學FGFR2 Caliper IC50
係以「A」或「B」或「C」表示。
在一些實施例中,本發明提供上表1中之化合物,其中化合物具有之細胞SNU-16 IC50
係以「A」表示。在一些實施例中,本發明提供上表1中之化合物,其中該化合物具有之細胞SNU-16 IC50
係以「A」或「B」表示。在一些實施例中,本發明提供上表1中之化合物,其中化合物具有之細胞SNU-16 IC50
係以「A」或「B」或「C」表示。 4. 提供本發明化合物之通用方法
本發明化合物一般可藉由熟習此項技術者已知用於類似化合物之合成及/或半合成方法及藉由本文實例中詳細描述之方法製備或分離。 5. 用途、配方及投藥 醫藥學上可接受之組合物
根據另一實施例,本發明提供一種組合物,其包含本發明化合物或其醫藥學上可接受之衍生物,及醫藥學上可接受之載劑、佐劑或媒劑。在一些實施例中,本發明提供一種醫藥組合物,其包含本發明化合物及醫藥學上可接受之載劑。本發明組合物中之化合物之量使得有效地可量測地抑制生物樣品或患者中之FGFR2蛋白激酶或其突變體。在某些實施例中,本發明組合物中之化合物之量使得有效地可量測地抑制生物樣品或患者中之FGFR2蛋白激酶或其突變體。在某些實施例中,本發明組合物經調配以投與需要此類組合物之患者。在一些實施例中,本發明組合物經調配以經口投與患者。
如本文所用,術語「個體」及「患者」意謂動物(亦即,動物界成員),較佳為哺乳動物,且最佳為人類。在一些實施例中,個體為人類、小鼠、大鼠、貓、猴、犬、馬或豬。在一些實施例中,個體為人類。在一些實施例中,個體為小鼠、大鼠、貓、猴、犬、馬或豬。
術語「醫藥學上可接受之載劑、佐劑或媒劑」係指不破壞與其一起調配之化合物之藥理學活性的無毒載劑、佐劑或媒劑。可用於本發明組合物中之醫藥學上可接受之載劑、佐劑或媒劑包括(但不限於)離子交換劑、氧化鋁、硬脂酸鋁、卵磷脂、血清蛋白(諸如人類血清白蛋白)、緩衝物質(諸如磷酸鹽)、甘胺酸、山梨酸、山梨酸鉀、飽和植物脂肪酸之部分甘油酯混合物、水、鹽或電解質(諸如魚精蛋白硫酸鹽、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽)、膠態二氧化矽、三矽酸鎂、聚乙烯基吡咯啶酮、基於纖維素之物質、聚乙二醇、羧甲基纖維素鈉、聚丙烯酸酯、蠟、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇及羊毛脂。
「醫藥學上可接受之衍生物」意謂本發明化合物之任何無毒的鹽、酯、酯之鹽或其他衍生物,其在投與接受者時,能夠直接地或間接地提供本發明化合物或其抑制活性代謝物或殘餘物。
如本文所用,術語「其抑制活性代謝物或殘餘物」意謂其代謝物或殘餘物亦為FGFR2蛋白激酶抑制劑或其突變體。
本發明之組合物可經口、非經腸、藉由吸入噴霧、體表、直腸、鼻、頰、陰道或經由植入式貯器投與。如本文所用,術語「非經腸」包括皮下、靜脈內、肌肉內、關節內、滑膜內、胸骨內、鞘內、肝內、病灶內及顱內注射或輸注技術。組合物較佳經口、腹膜內或靜脈內投與。
本發明組合物之無菌可注射形式可為水性或油性懸浮液。此等懸浮液可根據此項技術中已知之技術使用適合之分散劑或潤濕劑及懸浮劑來調配。無菌可注射製劑亦可為可接受之無毒非經腸稀釋劑或溶劑中之無菌可注射溶液或懸浮液,例如1,3-丁二醇中之溶液。在可接受之媒劑及溶劑中,可使用水、林格氏溶液(Ringer's solution)及等張氯化鈉溶液。另外,習知使用無菌不揮發油作為溶劑或懸浮介質。
出於此目的,可以使用任何溫和的不揮發油,包括合成單酸或二酸甘油酯。脂肪酸(諸如油酸及其甘油酯衍生物)適用於製備可注射劑,如醫藥學上可接受之天然油,諸如橄欖油或蓖麻油,尤其是其聚氧乙基化形式。此等油溶液或懸浮液亦可含有長鏈醇稀釋劑或分散劑,諸如羧甲基纖維素或常用於調配醫藥學上可接受之劑型(包括乳液及懸浮液)之類似分散劑。其他常用界面活性劑(諸如Tween、Span及其他乳化劑)或常用於製造醫藥學上可接受之固體、液體或其他劑型之生物可用性增強劑亦可用於調配之目的。
本發明之醫藥學上可接受之組合物可以可接受之任何口服劑型經口投與,包括(但不限於)膠囊、錠劑、水性懸浮液或溶液。在用於口服使用之錠劑之情況下,常用載劑包括乳糖及玉米澱粉。典型地亦添加潤滑劑,諸如硬脂酸鎂。以膠囊形式經口投與時,適用之稀釋劑包括乳糖及乾燥玉米澱粉。當口服使用需要水性懸浮液時,將活性成分與乳化劑及懸浮劑合併。必要時,亦可添加某些甜味劑、調味劑或著色劑。
或者,本發明之醫藥學上可接受之組合物可以直腸投與之栓劑形式投與。此等栓劑可藉由將藥劑與適合的無刺激性賦形劑混合來製備,該賦形劑在室溫下為固體,但在直腸或陰道溫度下為液體且因此將在直腸或陰道中熔融以釋放藥物。此類材料包括可可脂、蜂蠟及聚乙二醇。
本發明之醫藥學上可接受之組合物亦可體表投與,尤其當治療標靶包括藉由體表施用容易達到之區域或器官,包括眼睛、皮膚或低位腸道之疾病。容易製備適於此等區域或器官中之每一者的體表調配物。
低位腸道之體表施用可以直腸栓劑調配物(參見上文)或以適合的灌腸劑調配物實現。亦可使用體表經皮貼片。
對於體表施用而言,所提供的醫藥學上可接受之組合物可調配為含有懸浮或溶解於一或多種載劑中之活性組分之適合軟膏。用於體表投與本發明化合物的載劑包括(但不限於)礦物油、液體石蠟脂、白石蠟脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蠟及水。或者,所提供之醫藥學上可接受之組合物可以調配成適合洗劑或乳膏,其含有懸浮或溶解於一或多種醫藥學上可接受之載劑中的活性組分。適合載劑包括(但不限於)礦物油、去水山梨醇單硬脂酸酯、聚山梨醇酯60、鯨蠟酯蠟、鯨蠟硬脂醇、2-辛基十二醇、苯甲醇及水。
供眼科使用時,所提供的醫藥學上可接受之組合物可在防腐劑(諸如苯紮氯銨)存在或不存在下,在pH經調節的等張無菌生理鹽水中調配為微米尺寸化懸浮液,或較佳在pH經調節的等張無菌生理鹽水中調配為溶液。或者,供眼科使用時,醫藥學上可接受之組合物可調配為軟膏,諸如石蠟脂。
本發明之醫藥學上可接受之組合物亦可藉由鼻用氣溶膠或吸入劑來投藥。此類組合物係根據醫藥調配領域中熟知之技術製備,且可使用苯甲醇或其他適合防腐劑、增強生物可用性之吸收促進劑、氟碳化物及/或其他習知增溶劑或分散劑、於鹽水製備為溶液。
本發明之醫藥學上可接受之組合物較佳經調配以便經口投與。此類調配物可與食物一起或不一起投與。在一些實施例中,本發明之醫藥學上可接受之組合物不與食物一起投與。在其他實施例中,本發明之醫藥學上可接受之組合物與食物一起投與。
本發明化合物為了產生單一劑型之組合物而可與載劑物質合併的量將視所治療的患者、特定投藥模式而變化。所提供之組合物較佳應調配成可向接受此等組合物之患者投與劑量在每公斤體重每天0.01至100 mg之間的抑制劑。
亦應瞭解,任何特定患者之特定劑量及治療方案將視多種因素而定,包括所用特定化合物之活性、年齡、體重、一般健康、性別、膳食、投藥時間、排出速率、藥物組合,及治療醫師之判斷及所治療特定疾病之嚴重度。本發明化合物在組合物中之量亦視組合物中之特定化合物而定。
組合物中所用之確切劑量亦將視投藥途徑而定,且應根據從醫者判斷及各個體之情況決定。在本發明之特定實施例中,適於經口投與本發明化合物之劑量範圍通常為每天約1 mg至每天約1000 mg。在一些實施例中,口服劑量為每天約1 mg至每天約800 mg。在一些實施例中,口服劑量為每天約1 mg至每天約500 mg。在一些實施例中,口服劑量為每天約1 mg至每天約250 mg。在一些實施例中,口服劑量為每天約1 mg至每天約100 mg。在一些實施例中,口服劑量為每天約5 mg至每天約50 mg。在一些實施例中,口服劑量為每天約5 mg。在一些實施例中,口服劑量為約每天10 mg。在一些實施例中,口服劑量為每天約20 mg。在一些實施例中,口服劑量為每天約30 mg。在一些實施例中,口服劑量為每天約40 mg。在一些實施例中,口服劑量為每天約50 mg。在一些實施例中,口服劑量為每天約60 mg。在一些實施例中,口服劑量為每天約70 mg。在一些實施例中,口服劑量為每天約100 mg。應認識到,本文所列劑量中之任一者可構成上限或下限劑量範圍,且可與任何其他劑量組合以構成包含上限及下限之劑量範圍。
在一些實施例中,醫藥學上可接受的組合物含有所提供化合物及/或其醫藥學上可接受之鹽的濃度在以下範圍內:約0.01至約90 wt%、約0.01至約80 wt%、約0.01至約70 wt%、約0.01至約60 wt%、約0.01至約50 wt%、約0.01至約40 wt%、約0.01至約30 wt%、約0.01至約20 wt%、約0.01至約2.0 wt%、約0.01至約1 wt%、約0.05至約0.5 wt%、約1至約30 wt%,或約1至約20 wt%。組合物可調配為溶液、懸浮液、軟膏或膠囊及其類似者。醫藥組合物可製備成水溶液,且可含有其他組分,諸如防腐劑、緩衝劑、張力劑、抗氧化劑、穩定劑、黏度調節成分及其類似者。
醫藥學上可接受之載劑為熟習此項技術者所熟知,且包括例如佐劑、稀釋劑、賦形劑、填充劑、潤滑劑及媒劑。在一些實施例中,載劑為稀釋劑、佐劑、賦形劑或媒劑。在一些實施例中,載劑為稀釋劑、佐劑或賦形劑。在一些實施例中,載劑為稀釋劑或佐劑。在一些實施例中,載劑為賦形劑。
醫藥學上可接受之載劑之實例可包括例如水或生理鹽水溶液、聚合物(諸如聚乙二醇)、碳水化合物及其衍生物、油、脂肪酸或醇。作為醫藥載劑之油的非限制性實例包括石油、動物油、植物油或合成來源之油,諸如花生油、大豆油、礦物油、芝麻油及其類似者。醫藥載劑亦可為生理鹽水、阿拉伯膠(gum acacia)、明膠、澱粉糊、滑石、角蛋白、膠態二氧化矽、尿素及其類似者。此外,亦可使用助劑、穩定劑、增稠劑、潤滑劑及著色劑。適合的醫藥載劑之其他實例描述於例如以下文獻中:Remington's: The Science and Practice of Pharmacy, 第22版 (Allen, Loyd V., Jr編, Pharmaceutical Press (2012));Modern Pharmaceutics, 第5版 (Alexander T. Florence, Juergen Siepmann, CRC Press (2009));Handbook of Pharmaceutical Excipients, 第7版 (Rowe, Raymond C.; Sheskey, Paul J.;Cook, Walter G.;Fenton, Marian E.編, Pharmaceutical Press (2012)) (其中之每一者以全文引用之方式併入本文)。
本文所用的醫藥學上可接受之載劑可選自各種有機或無機物質,該等物質用作醫藥調配物之物質且作為鎮痛劑、緩衝劑、黏合劑、崩解劑、稀釋劑、乳化劑、賦形劑、增量劑、滑動劑、增溶劑、穩定劑、懸浮劑、張力劑、媒劑及黏度增加劑併入。亦可添加醫藥添加劑,諸如抗氧化劑、芳香劑、著色劑、風味改善劑、防腐劑及甜味劑。可接受的醫藥載劑之實例包括羧甲基纖維素、結晶纖維素、甘油、阿拉伯膠、乳糖、硬脂酸鎂、甲基纖維素、散劑、生理鹽水、褐藻酸鈉、蔗糖、澱粉、滑石及水以及其他。在一些實施例中,術語「醫藥學上可接受」意謂經聯邦政府或州政府之管制機構批准或在美國藥典或其他公認之藥典中列出適用於動物且更尤其適用於人類。
諸如洗滌劑之界面活性劑亦適用於調配物中。界面活性劑之特定實例包括聚乙烯吡咯啶酮、聚乙烯醇、乙酸乙烯酯及乙烯吡咯啶酮之共聚物、聚乙二醇、苯甲醇、甘露糖醇、甘油、山梨糖醇或去水山梨糖醇之聚氧乙烯化酯;卵磷脂或羧甲基纖維素鈉;或丙烯酸衍生物,諸如甲基丙烯酸酯及其他;陰離子界面活性劑,諸如鹼性硬脂酸鹽,特定言之,硬脂酸鈉、硬脂酸鉀或硬脂酸銨;硬脂酸鈣或硬脂酸三乙醇胺;烷基硫酸鹽,特定言之,月桂基硫酸鈉及鯨蠟基硫酸鈉;十二烷基苯磺酸鈉或二辛基磺基丁二酸鈉;或脂肪酸,特定言之,衍生自椰子油之彼等脂肪酸;陽離子界面活性劑,諸如具有式N+
R'R"R"'R""Y-
之水溶性四級銨鹽,其中R基團相同或不同,視情況為羥基化烴基,且Y-
為強酸之陰離子,諸如鹵離子、硫酸根及磺酸根陰離子;溴化鯨蠟基三甲銨為可使用的陽離子界面活性劑之一,其為具有式N+
R'R"R"'之胺鹽,其中R基團相同或不同,視情況為羥基化烴基;鹽酸十八烷基胺為可使用的陽離子界面活性劑之一;非離子界面活性劑,諸如視情況聚氧乙烯化之去水山梨糖醇酯,特定言之,聚山梨醇酯80或聚氧乙烯化烷基醚;聚乙二醇硬脂酸酯、聚氧乙烯化之蓖麻油衍生物、聚甘油酯、聚氧乙烯化脂肪醇、聚氧乙烯化脂肪酸或環氧乙烷及環氧丙烷之共聚物;兩性界面活性劑,諸如甜菜鹼之經取代月桂基化合物。
適合的醫藥載劑亦可包括賦形劑,諸如澱粉、葡萄糖、乳糖、蔗糖、明膠、麥芽、稻米、麵粉、白堊、矽膠、硬脂酸鈉、單硬脂酸甘油酯、滑石、氯化鈉、脫脂奶粉、甘油、丙烯、乙二醇、聚乙二醇300、水、乙醇、聚山梨醇酯20及其類似者。必要時,本發明組合物亦可含有少量濕潤劑或乳化劑,或pH緩衝劑。
錠劑及膠囊調配物可進一步含有一或多種佐劑、黏合劑、稀釋劑、崩解劑、賦形劑、填充劑或潤滑劑,其各自為此項技術中已知的。此類實例包括碳水化合物(諸如乳糖或蔗糖)、無水磷酸氫鈣、玉米澱粉、甘露糖醇、木糖醇、纖維素或其衍生物、微晶纖維素、明膠、硬脂酸鹽、二氧化矽、滑石、乙醇酸澱粉鈉、阿拉伯膠、調味劑、防腐劑、緩衝劑、崩解劑及著色劑。經口投與之組合物可含有一或多種視情況存在的藥劑,例如甜味劑,諸如果糖、阿斯巴甜糖(aspartame)或糖精;調味劑,諸如胡椒薄荷、冬青油或櫻桃;著色劑;及防腐劑,以提供醫藥學上適口的製劑。 化合物及醫藥學上可接受之組合物之用途
本文所述的化合物及組合物通常適用於抑制激酶或其突變體。在一些實施例中,被本文所述化合物及組合物抑制的激酶為纖維母細胞生長因子受體(FGFR)。在一些實施例中,被本文所述化合物及組合物抑制的激酶為FGFR1、FGFR2、FGFR3及FGFR4中之一或多者。在一些實施例中,被本文所述化合物及組合物抑制的激酶為FGFR2。
本發明之化合物或組合物可適用於得益於FGFR2磷酸酶之抑制的應用。舉例而言,本發明之FGFR2抑制劑通常適用於治療增生性疾病。
已在許多癌症中偵測到活化FGFR2基因融合體,包括肝內膽管癌、肝細胞癌、乳癌、前列腺癌、肺鱗狀細胞癌、甲狀腺癌、胃癌及卵巢癌。(I. S. Babina及N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332;Y-M Wu等人, Cancer Discov. 3:636-647;及其中引用的參考文獻)。
已描述胃癌、乳癌、三陰性乳癌及直腸癌中存在FGFR2擴增。(I. S. Babina及 N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332;M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122;及其中所引用之參考文獻)。
已在子宮內膜癌、非小細胞肺癌、肺鱗狀細胞癌、胃癌、乳癌及尿道上皮癌中偵測到活化FGFR2突變。最常見的突變包括細胞內激酶域中之彼等突變(例如N549K及K659N/M)及細胞外域中之彼等突變(S252W及P253R)。FGFR2抑制劑亦可靶向經泛FGFR1-3抑制劑治療之FGFR2中存在的抗性突變。此等突變包括V564F、E565A、N549K/H/T及L617V。(I. S. Babina及N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332;M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122;R. Porta等人, Crit. Rev. Oncol. Hematol. 2017, 113:256-267;及其中引用的參考文獻)。
抑制FGFR2亦對其中FGFR2配位體表現增強的腫瘤具有抗腫瘤活性(圖1-4、7、8、10、21-23)(N. Turner及R. Grose, Nat. Rev. Cancer 2010, 10:116-129;及其中引用的參考文獻)。
抑制FGFR2亦對其中FGFR接附蛋白FRS2擴增或過度表現的腫瘤具有抗腫瘤活性。(I. S. Babina及N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332;及其中引用的參考文獻)。
FGFR2的選擇性抑制通常可對其中泛FGFR1-3抑制劑有效的適應症有效。此類適應症描述於I. S. Babina及N.C. Turner, Nat. Rev. Cancer 2017, 17:318-332;M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122;R. Porta等人, Crit. Rev. Oncol. Hematol. 2017, 113:256-267;及其中引用的參考文獻。
FGFR2中的活化突變亦已在顱縫早閉症候群中偵測到,包括Crouzon、Apert、Pfeiffer、Antley-Bixler、Beare-Stevenson回狀顱皮、Jackson-Weiss、彎曲性骨骼發育不良,及Seathre-Chotzen樣症候群,其引起顱縫的過早融合。(S.C. Azoury等人, Int. J. Biol. Sci. 2017, 13:1479-1488;及其中引用的參考文獻)。FGFR2的抑制亦對此類顱縫早閉症候群有效。
本發明中所用之化合物作為FGFR激酶(例如FGFR2)或其突變體之抑制劑的活性可在活體外、活體內或細胞株中進行分析。活體外分析包括測定磷酸化活性及/或後續功能結果或活化FGFR2或其突變體之三磷酸腺苷酶活性之抑制的分析。替代的活體外分析對抑制劑結合至FGFR2之能力進行定量。可藉由在結合之前對抑制劑進行放射性標記、分離抑制劑/FGFR2複合物及測定放射性標記結合量來量測抑制劑結合。或者,可藉由運作競爭實驗來測定抑制劑結合,其中將新抑制劑與結合至已知放射性配位體之FGFR2一起培育。適用於分析FGFR2抑制劑的代表性活體外及活體內分析包括本文所述之專利及科學出版物中所述及所揭示的彼等分析。用於分析在本發明中用作FGFR2或其突變體之抑制劑之化合物的詳細條件闡述於以下實例中。病症治療
所提供之化合物為FGFR2抑制劑且因此適用於治療一或多種與FGFR2或其突變體之活性相關的病症。因此,在某些實施例中,本發明提供一種治療個體之FGFR2介導性病症的方法,包含向有需要的個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽,或前述任一者的醫藥學上可接受之組合物。在某些實施例中,本發明提供一種治療個體之FGFR2介導性病症的方法,其包含向有需要的受試者投與治療有效量之本發明化合物或其醫藥學上可接受之組合物。
如本文所用,術語「FGFR2介導性」病症、疾病及/或病狀意謂其中已知FGFR2或其突變體起作用的任何疾病或其他有害病狀。因此,本發明之另一實施例係關於治療其中已知FGFR2或其突變體起作用之一或多種疾病或減輕其嚴重程度。此類FGFR2介導性病症包括(但不限於)增生性病症(例如癌症)及顱縫早閉症候群。
在一些實施例中,本發明提供一種用於治療一或多種病症之方法,其中該等病症係選自增生性病症及顱縫早閉症候群,該方法包含向有需要之患者投與治療有效量之本發明化合物或其醫藥學上可接受之鹽,或前述任一者之醫藥學上可接受之組合物。在一些實施例中,本發明提供一種用於治療一或多種病症之方法,其中該等病症係選自增生性病症及顱縫早閉症候群,該方法包含向有需要之患者投與治療有效量之本發明化合物或其醫藥學上可接受之組合物。
在一些實施例中,本發明提供一種治療個體之病症的方法,該方法包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽,或前述任一者之醫藥組合物,其中該病症為膽管癌、肝癌、乳癌、前列腺癌、肺癌、甲狀腺癌、胃癌、卵巢癌、直腸癌、子宮內膜癌或尿道上皮癌。在一些實施例中,病症為肝內膽管癌。在一些實施例中,該病症為肝細胞癌。在一些實施例中,該病症為肺鱗狀細胞癌或非小細胞肺癌。
在一些實施例中,病症為膽管癌。在一些實施例中,膽管癌為肝內膽管癌。在一些實施例中,病症為肝癌。在一些實施例中,肝癌為肝細胞癌。在一些實施例中,病症為肺癌。在一些實施例中,肺癌為肺鱗狀細胞癌或非小細胞肺癌。
在一些實施例中,本發明提供一種治療個體之肝內膽管癌的方法,該方法包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽,或前述任一者之醫藥組合物。在一些實施例中,本發明提供一種治療個體之肝細胞癌的方法,該方法包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽或前述任一者之醫藥組合物。在一些實施例中,本發明提供一種治療個體之肺鱗狀細胞癌或非小細胞肺癌的方法,該方法包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之鹽或前述任一者之醫藥組合物。
在一些實施例中,該病症與FGFR2信號傳導相關。已知FGFR2及其他受體酪胺酸激酶(RTK)具有多個上游及下游信號傳導路徑(參見Turner及Grose, Nat. Rev. Cancer(2010)10, 116),並且抑制FGFR2可用於治療與彼等路徑內的信號傳導異常有關的病症。在一些實施例中,該病症與FGF信號傳導、JAK-STAT信號傳導、PI3K-Akt信號傳導、PLC-γ信號傳導或MAPK信號傳導相關。
在一些實施例中,治療方法包含以下步驟:i)鑑別需要此類治療之個體;(ii)提供所揭示之化合物或其醫藥學上可接受之鹽;及(iii)以治療有效量投與所提供之該化合物以治療、遏制及/或預防需要此類治療之個體的疾病狀態或病狀。
在一些實施例中,治療方法包含以下步驟:i)鑑別需要此類治療之個體;(ii)提供包含所揭示之化合物或其醫藥學上可接受之鹽的組合物;及(iii)以治療有效量投與該組合物以治療、遏制及/或預防需要此類治療之個體的疾病狀態或病狀。
本發明之另一態樣提供根據本文中之定義的化合物或其醫藥學上可接受之鹽,或前述任一者之醫藥組合物,其用於治療本文所述之病症。本發明之另一態樣提供根據本文中之定義的化合物或其醫藥學上可接受之鹽或前述任一者之醫藥組合物用於治療本文所述病症的用途。類似地,本發明提供根據本文中之定義的化合物或其醫藥學上可接受之鹽用於製備供治療本文所述病症之藥劑的用途。增生性病症
在一些實施例中,該病症為增生性病症。在一些實施例中,增生性病症為癌症。在一些實施例中,增生性病症為白血病、乳癌、肺癌、結腸直腸癌或其組合。在一些實施例中,增生性病症為白血病。在一些實施例中,增生性病症為乳癌。在一些實施例中,增生性病症為肺癌。在一些實施例中,增生性病症為結腸直腸癌。
在一些實施例中,增生性病症為肝內膽管癌、肝細胞癌、乳癌、前列腺癌、肺鱗狀細胞癌、甲狀腺癌、胃癌、卵巢癌、直腸癌、子宮內膜癌、非小細胞肺癌或尿道上皮癌。在一些實施例中,增生性病症為肝內膽管癌、肝細胞癌、乳癌、前列腺癌、肺鱗狀細胞癌、甲狀腺癌、胃癌或卵巢癌。在一些實施例中,增生性病症為胃癌、乳癌、三陰性乳癌或直腸癌。在一些實施例中,增生性病症為子宮內膜癌、非小細胞肺癌、肺鱗狀細胞癌、胃癌、乳癌或尿道上皮癌。
在一些實施例中,增生性病症與FGFR2中之一或多種活化突變相關。在一些實施例中,FGFR2中之活化突變為細胞內激酶域及胞外域中之一或多者的突變。在一些實施例中,FGFR2中之活化突變為細胞內激酶域之突變。在一些實施例中,FGFR2中之活化突變為胞外域之突變。在一些實施例中,FGFR2中之活化突變係選自N549K、K659N/M、S252W、P253R及其組合。在一些實施例中,FGFR2中之活化突變為N549K或K659N/M。在一些實施例中,FGFR2中之活化突變為N549K。在一些實施例中,FGFR2中之活化突變為K659N/M。在一些實施例中,FGFR2中之活化突變為S252W或P253R。在一些實施例中,FGFR2中之活化突變為S252W。在一些實施例中,FGFR2中之活化突變為P253R。
在一些實施例中,增生性病症與FGFR2中之一或多種抗性突變相關。在一些實施例中,FGFR2中之抗性突變選自V564F、E565A、N549K/H/T及L617V及其組合。在一些實施例中,FGFR2中之抗性突變為V564F。在一些實施例中,FGFR2中之抗性突變為E565A。在一些實施例中,FGFR2中之抗性突變為N549K/H/T。在一些實施例中,FGFR2中之抗性突變為L617V。投藥途徑及劑型
該等化合物及組合物可根據本發明之方法,使用有效治療病症(例如增生性病症或顱縫早閉症候群)或減輕其嚴重程度的任何量及任何投藥途徑投與。所需精確量將因個體而異,此視個體之物種、年齡及一般狀況、感染之嚴重度、特定藥劑、其投與模式及其類似因素而定。本發明之化合物較佳調配成容易投藥及均一給藥的單位劑型。如本文所用,表述「單位劑型」係指適於待治療患者之藥劑的實體不連續單元。然而應瞭解,本發明化合物及組合物之總日用量將由主治醫師在合理醫學判斷範圍內決定。用於任何特定患者或生物體之特定有效劑量水準將視多種因素而定,包括所治療之病症及病症嚴重度;所用特定化合物之活性;所用特定組合物;患者之年齡、體重、一般健康、性別及膳食;投藥時間、投藥途徑及所用特定化合物之排出比率;治療持續時間;與所用特定化合物組合或同時使用之藥物;及如醫學技術中熟知之因素。
本發明之醫藥學上可接受之組合物可經口、直腸、非經腸、腦池內、陰道內、腹膜內、體表(如藉由散劑、軟膏或滴劑)、經頰、作為口服或鼻用噴霧或其類似方式投與人類及其他動物。在某些實施例中,本發明化合物可以每公斤個體體重每天約0.01 mg至約50 mg及較佳約1 mg至約25 mg之劑量水準經口或非經腸一日投與一或多次以獲得所需治療效果。
經口投與之液體劑型包括(但不限於)醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。除活性化合物以外,液體劑型可含有此項技術中常用之惰性稀釋劑,諸如水或其他溶劑;增溶劑及乳化劑,諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲醯胺、油(特定言之,棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇及去水山梨糖醇之脂肪酸酯;及其混合物。除惰性稀釋劑之外,口服組合物亦可包括佐劑,諸如濕潤劑、乳化劑及懸浮劑、甜味劑、調味劑及芳香劑。
可根據已知技術、使用適合的分散劑或濕潤劑及懸浮劑來調配可注射製劑,例如無菌可注射水性或油性懸浮液。無菌可注射製劑亦可為可接受之無毒性非經腸稀釋劑或溶劑中之無菌可注射溶液、懸浮液或乳液,例如1,3-丁二醇中之溶液。在可接受之媒劑及溶劑中,可使用水、林格氏溶液、U.S.P.及等張氯化鈉溶液。另外,習知使用無菌不揮發油作為溶劑或懸浮介質。出於此目的,可使用任何溫和的不揮發油,包括合成的單酸甘油酯或二酸甘油酯。另外,使用脂肪酸(諸如油酸)製備可注射劑。
可注射調配物可例如藉由細菌截留過濾器過濾或藉由併入呈無菌固體組合物形式之滅菌劑來滅菌,所述無菌固體組合物在使用之前可溶解或分散於無菌水或其他無菌可注射介質中。
為延長本發明化合物之作用,通常需要減緩皮下或肌肉內注射之化合物的吸收。此可藉由使用水溶性不良之結晶或非晶形物質的液體懸浮液來實現。化合物吸收速率則視其溶出速率而定,溶出速率又可視晶體尺寸及結晶形式而定。或者,非經腸投與之化合物形式的延遲吸收係藉由將化合物溶解或懸浮於油性媒劑中來實現。藉由在諸如聚丙交酯-聚乙交酯之生物可降解聚合物中形成化合物之微膠囊基質來製備可注射儲槽形式。視化合物與聚合物之比率及所用特定聚合物的性質而定,可控制化合物釋放速率。其他生物可降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。可注射儲槽式調配物亦可藉由將化合物包覆於與身體組織相容之脂質體或微乳液中來製備。
用於直腸或陰道投與之組合物較佳為栓劑,其可藉由將本發明化合物與適合的非刺激性賦形劑或載劑(諸如可可脂、聚乙二醇或栓劑蠟)混合來製備,該等賦形劑或載劑在環境溫度下為固體,但在體溫下為液體且因此在直腸或陰道腔中熔融並釋放活性化合物。
經口投與之固體劑型包括膠囊、錠劑、丸劑、散劑及顆粒劑。在此類固體劑型中,將活性化合物與至少一種醫藥學上可接受之惰性賦形劑或載劑(諸如檸檬酸鈉或磷酸二鈣)及/或以下混合:(a)填充劑或增量劑,諸如澱粉、乳糖、蔗糖、葡萄糖、甘露糖醇及矽酸;(b)黏合劑,諸如羧甲基纖維素、褐藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖及阿拉伯膠;(c)保濕劑,諸如甘油;(d)崩解劑,諸如瓊脂--瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、褐藻酸、某些矽酸鹽及碳酸鈉;(e)阻溶劑,諸如石蠟;(f)吸收加速劑,諸如四級銨化合物;(g)濕潤劑,諸如鯨蠟醇及甘油單硬脂酸酯;(h)吸收劑,諸如高嶺土及膨潤土;及(i)潤滑劑,諸如滑石、硬脂酸鈣、硬脂酸鎂、固體聚乙二醇、月桂基硫酸鈉及其混合物。在膠囊、錠劑及丸劑之情況下,劑型亦可包含緩衝劑。
在使用諸如乳糖或奶糖之賦形劑以及高分子量聚乙二醇及其類似物的軟填充及硬填充明膠膠囊中,亦可使用類型相似的固體組合物作為填充劑。錠劑、糖衣藥丸、膠囊、丸劑及顆粒劑之固體劑型可製備有包衣及外殼,諸如腸溶包衣及醫藥調配技術中熟知之其他包衣。其可視情況含有乳濁劑,且亦可具有僅在或優先在腸道之某一部分中釋放或視情況以延遲方式釋放活性成分之組成。可使用之包埋組合物之實例包括聚合物質及蠟。在使用諸如乳糖或奶糖之賦形劑以及高分子量聚乙二醇及其類似物的軟填充及硬填充明膠膠囊中,可以使用類型相似的固體組合物作為填充劑。
活性成分可與一或多種如上文所指出之賦形劑一起呈微囊封形式。錠劑、糖衣藥丸、膠囊、丸劑及顆粒劑之固體劑型可製備有包衣及外殼,諸如腸溶包衣、釋放控制包衣及醫藥調配技術中熟知之其他包衣。在此類固體劑型中,可將活性化合物與至少一種惰性稀釋劑(諸如蔗糖、乳糖或澱粉)混合。如同一般實務,此類劑型亦可包含除惰性稀釋劑以外之其他物質,例如製錠潤滑劑及其他製錠助劑,諸如硬脂酸鎂及微晶纖維素。在膠囊、錠劑及丸劑之情況下,劑型可以包含緩衝劑。其可視情況含有乳濁劑,且亦可具有僅在或優先在腸道之某一部分中釋放或視情況以延遲方式釋放活性成分之組成。可使用之包埋組合物之實例包括聚合物質及蠟。
體表或經皮投與本發明化合物之劑型包括軟膏、糊劑、乳膏、洗劑、凝膠、散劑、溶液、噴霧劑、吸入劑或貼片。可在必要時,將活性組分在無菌條件下與醫藥學上可接受之載劑及任何必需防腐劑或緩衝劑混合。眼用調配物、滴耳劑和滴眼劑亦涵蓋於本發明的範疇內。另外,本發明涵蓋使用經皮貼片,其具有向身體提供化合物之可控遞送的額外優勢。此類劑型可藉由將化合物溶解或分配於適當介質中來製備。亦可使用吸收增強劑來增強化合物穿越皮膚之流動。可藉由提供速率控制膜或使化合物分散於聚合物基質或凝膠中來控制速率。給藥的量及療法
根據本發明之方法,向個體投與治療有效量之本發明之化合物,例如以減少或改善個體之病症之症狀。此量容易藉由熟習此項技術者基於已知程序判定,該等程序包括活體內確立之滴定曲線的分析以及本文所揭示的方法及分析。
在一些實施例中,方法包含投與治療有效劑量的本發明化合物。在一些實施例中,治療有效劑量為每公斤體重至少約0.0001 mg、每公斤體重至少約0.001 mg、每公斤體重至少約0.01 mg、每公斤體重至少約0.05 mg、每公斤體重至少約0.1 mg、每公斤體重至少約0.25 mg、每公斤體重至少約0.3 mg、每公斤體重至少約0.5 mg、每公斤體重至少約0.75 mg、每公斤體重至少約1 mg、每公斤體重至少約2 mg、每公斤體重至少約3 mg、每公斤體重至少約4 mg、每公斤體重至少約5 mg、每公斤體重至少約6 mg、每公斤體重至少約7 mg、每公斤體重至少約8 mg、每公斤體重至少約9 mg、每公斤體重至少約10 mg、每公斤體重至少約15 mg、每公斤體重至少約20 mg、每公斤體重至少約25 mg、每公斤體重至少約30 mg、每公斤體重至少約40 mg、每公斤體重至少約50 mg、每公斤體重至少約75 mg、每公斤體重至少約100 mg、每公斤體重至少約200 mg、每公斤體重至少約250 mg、每公斤體重至少約300 mg、每公斤體重至少約350 mg、每公斤體重至少約400 mg、每公斤體重至少約450 mg、每公斤體重至少約500 mg、每公斤體重至少約550 mg、每公斤體重至少約600 mg、每公斤體重至少約650 mg、每公斤體重至少約700 mg、每公斤體重至少約750 mg、每公斤體重至少約800 mg、每公斤體重至少約900 mg,或每公斤體重至少約1000 mg。應認識到,本文所列劑量中之任一者可構成上限或下限劑量範圍,且可與任何其他劑量組合以構成包含上限及下限之劑量範圍。
在一些實施例中,治療有效劑量的範圍為每公斤體重約0.1 mg至約10 mg、每公斤體重約0.1 mg至約6 mg、每公斤體重約0.1 mg至約4 mg或每公斤體重約0.1 mg至約2 mg之範圍內。
在一些實施例中,治療有效劑量的範圍為約1至500 mg、約2至150 mg、約2至120 mg、約2至80 mg、約2至40 mg、約5至150 mg、約5至120 mg、約5至80 mg、約10至150 mg、約10至120 mg、約10至80 mg、約10至40 mg、約20至150 mg、約20至120 mg、約20至80 mg、約20至40 mg、約40至150 mg、約40至120 mg或約40至80 mg。
在一些實施例中,方法包含單次給藥或投藥(例如單次注射或沈積)。或者,在一些實施例中,方法包含每日一次、每日兩次、每日三次或每日四次投與有需要之個體,歷時約2至約28天,或約7至約10天,或約7至約15天,或更久。在一些實施例中,方法包含長期投藥。在又其他實施例中,方法包含在數週、數月、數年或數十年之期間內投藥。在另其他實施例中,方法包含在數週之期間內投藥。在另其他實施例中,方法包含在數月之期間內投藥。在另其他實施例中,方法包含在數年之期間內投藥。在又其他實施例中,方法包含在數十年之期間內投藥。
投藥劑量可視已知因素而變化,諸如活性成分之藥效學特徵以及其投藥模式及途徑;活性成分之投與時間;接受者之年齡、性別、健康狀況及體重;症狀之性質及程度;並行治療之種類、治療頻率及所需效果;以及排出速率。此等因素皆容易確定且熟習此項技術者可利用此等因素來調整或滴定劑量及/或給藥方案。蛋白激酶的抑制
根據一個實施例,本發明係關於抑制生物樣品中之蛋白激酶活性的方法,其包含使該生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。
根據另一個實施例,本發明係關於一種抑制生物樣品中之FGFR2或其突變體之活性的方法,其包含使該生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。在某些實施例中,本發明係關於一種可逆地抑制生物樣品中之FGFR2或其突變體之活性的方法,其包含使該生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。在某些實施例中,本發明係關於不可逆地抑制生物樣品中之FGFR2或其突變體之活性的方法,其包含使該生物樣品與本發明化合物或包含該化合物之組合物接觸的步驟。
在一些實施例中,本發明係關於不可逆地抑制FGFR2或其突變體之方法,其中本發明化合物與FGFR2或其突變體形成共價鍵。在一些實施例中,本發明係關於不可逆地抑制FGFR2或其突變體的方法,其中本發明化合物在該化合物之RW
與FGFR2或其突變體之半胱胺酸之間形成共價鍵。在一些實施例中,本發明係關於不可逆地抑制FGFR2或其突變體之方法,其中本發明化合物在該化合物之RW
與FGFR2或其突變體之Cys491之間形成共價鍵。
根據另一實施例,本發明係關於被本發明化合物不可逆地抑制之FGFR2或其突變體。在一些實施例中,本發明係關於共價鍵結至本發明化合物之FGFR2或其突變體。在一些實施例中,本發明係關於共價鍵結至本發明化合物的FGFR2或其突變體,其中共價鍵介於該化合物之RW
與FGFR2或其突變體之半胱胺酸之間。在一些實施例中,本發明係關於共價鍵結至本發明化合物的FGFR2或其突變體,其中共價鍵介於該化合物之RW
與FGFR2或其突變體之Cys491之間。
在另一實施例中,本發明提供相對於FGFR1、FGFR3及FGFR4中之一或多者選擇性地抑制FGFR2的方法。在一些實施例中,本發明化合物相對於FGFR1、FGFR3及FGFR4具有超過5倍的選擇性。在一些實施例中,本發明化合物相對於FGFR1、FGFR3及FGFR4具有超過10倍的選擇性。在一些實施例中,本發明化合物相對於FGFR1、FGFR3及FGFR4具有超過50倍的選擇性。在一些實施例中,本發明化合物相對於FGFR1、FGFR3及FGFR4具有超過100倍的選擇性。在一些實施例中,本發明化合物相對於FGFR1、FGFR3及FGFR4具有超過200倍的選擇性。
如本文所用,術語「生物樣品」包括(不限於)細胞培養物或其提取物;獲自哺乳動物之切片材料或其提取物;及血液、唾液、尿液、糞便、精液、淚液或其他體液或其提取物。
抑制生物樣品中之FGFR2 (或其突變體)活性適用於熟習此項技術者已知的多種目的。此類目的之實例包括(但不限於)輸血、器官移植、生物樣本儲存及生物分析。
本發明之另一實施例係關於一種抑制患者中之蛋白激酶活性的方法,其包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。
根據另一個實施例,本發明係關於一種抑制患者中之FGFR2或其突變體之活性的方法,其包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。根據某些實施例,本發明係關於一種可逆地或不可逆地抑制患者中之FGFR2或其突變體中之一或多者之活性的方法,包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。根據另一個實施例,本發明係關於一種可逆地抑制患者中之FGFR2或其突變體中之一或多者之活性的方法,其包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。根據某些實施例,本發明係關於一種不可逆地抑制患者中之FGFR2或其突變體中之一或多者之活性的方法,包含向該患者投與本發明化合物或包含該化合物之組合物的步驟。
在一些實施例中,本發明係關於一種不可逆地抑制患者中之FGFR2或其突變體中之一或多者之活性的方法,包含向該患者投與本發明化合物或包含該化合物之組合物的步驟,其中該化合物與FGFR2或其突變體形成共價鍵。在一些實施例中,本發明係關於一種不可逆地抑制患者中之FGFR2或其突變體中之一或多者之活性的方法,包含向該患者投與本發明化合物或包含該化合物之組合物的步驟,其中該化合物在該化合物之RW
與FGFR2或其突變體之半胱胺酸之間形成共價鍵。在一些實施例中,本發明係關於一種不可逆地抑制患者中之FGFR2或其突變體中之一或多者之活性的方法,包含向該患者投與本發明化合物或包含該化合物之組合物的步驟,其中該化合物在該化合物之RW
與FGFR2或其突變體之Cys491之間形成共價鍵。
根據另一個實施例,本發明提供一種治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與根據本發明之化合物或其醫藥學上可接受之組合物的步驟。此類病症詳細描述於本文中。在一些實施例中,本發明提供一種用於治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與本發明化合物或其醫藥學上可接受之組合物的步驟,其中該化合物可逆地抑制FGFR2或其突變體。
在一些實施例中,本發明提供一種治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與本發明化合物或其醫藥學上可接受之組合物的步驟,其中該化合物不可逆地抑制FGFR2或其突變體。在一些實施例中,本發明提供一種用於治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與本發明化合物或其醫藥學上可接受之組合物的步驟,其中該化合物與FGFR2或其突變體形成共價鍵。在一些實施例中,本發明提供一種治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與本發明化合物或其醫藥學上可接受之組合物的步驟,其中該化合物在該化合物之RW
與FGFR2或其突變體之半胱胺酸之間形成共價鍵。在一些實施例中,本發明提供一種用於治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與本發明化合物或其醫藥學上可接受之組合物的步驟,其中該化合物在該化合物之RW
與FGFR2或其突變體之Cys491之間形成共價鍵。
根據另一個實施例,本發明提供一種抑制個體中之FGFR2或其突變體之信號傳導活性的方法,包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之組合物。在一些實施例中,本發明提供一種抑制個體中之FGFR2信號傳導活性的方法,該方法包含向有需要之個體投與治療有效量之本發明化合物或其醫藥學上可接受之組合物。
在一些實施例中,本發明提供一種用於治療有需要之患者之由FGFR2或其突變體介導之病症的方法,包含向該患者投與本發明化合物或其醫藥學上可接受之組合物的步驟,其中該化合物可逆地抑制FGFR2或其突變體。
本文所描述之化合物亦可經由併入催化FGFR2毀壞之藥劑中來抑制FGFR2功能。舉例而言,可將化合物併入靶向蛋白水解的嵌合體(PROTAC)中。PROTAC為雙官能分子,其中一個部分能夠接合E3泛蛋白連接酶且另一部分能夠結合意欲藉由細胞蛋白品質控制機制進行降解的靶蛋白。靶蛋白募集至特定E3連接酶使得其經標記用於毀壞(亦即,泛素化)且隨後藉由蛋白酶體降解。可使用任何E3連接酶。PROTAC中之與E3接合酶接合的部分經由連接子連接至PROTAC中之與靶蛋白接合的部分,該連接子由可變原子鏈組成。FGFR2募集至E3連接酶將因此毀壞FGFR2蛋白。可變原子鏈可包括例如環、雜原子及/或重複聚合物單元。其可為剛性或柔性的。其可使用有機合成技術中之標準技術連接至上述兩個部分。 組合療法
視待治療之特定病症、病狀或疾病而定,可將通常為了治療該病狀而投與的其他治療劑與本發明之化合物及組合物組合投與。如本文所用,通常為了治療特定疾病或病狀而投與的其他治療劑被稱為「適於所治療之疾病或病狀」。
因此,在某些實施例中,治療方法包含將本發明的化合物或組合物與一或多種其他治療劑組合投與。在某些其他實施例中,治療方法包含將本發明的化合物或組合物作為單獨的治療劑投與。
在一些實施例中,一或多種其他治療劑係選自抗體、抗體-藥物結合物、激酶抑制劑、免疫調節劑及組蛋白去乙醯酶抑制劑。在一些實施例中,一或多種其他治療劑係選自以下藥劑或其醫藥學上可接受之鹽:BCR-ABL抑制劑:例如伊馬替尼(imatinib)、伊羅替尼(inilotinib)、尼羅替尼(nilotinib)、達沙替尼(dasatinib)、伯舒替尼(bosutinib)、普納替尼(ponatinib)、巴氟替尼(bafetinib)、達魯舍替(danusertib)、塞卡替尼(saracatinib)、PF03814735;ALK抑制劑(參見Dardaei等人, 2018, Nat Med.;24(4):512-517):例如克卓替尼(crizotinib)、NVP-TAE684、色瑞替尼(ceritinib)、艾樂替尼(alectinib)、布加替尼(brigatinib)、恩曲昔尼(entrecinib)、羅拉替尼(lorlatinib);BRAF抑制劑(參見Prahallad等人, 2015, Cell Rep. 12, 1978-1985):例如維羅非尼(vemurafenib)、達拉非尼(dabrafenib);FGFR抑制劑:例如英非替尼(infigratinib)、多韋替尼(dovitinib)、厄達替尼(erdafitinib)、BLU-554、AZD4547;FLT3抑制劑:例如舒尼替尼(sunitinib)、米哚妥林(midostaurin)、丹魯替尼(tanutinib)、索拉非尼(sorafenib)、來他替尼(lestaurtinib)、喹雜替尼(quizartinib)及克諾拉尼(crenolanib);MEK抑制劑(參見Fedele等人, 2018, BioRxiv 307876;Torres-Ayuso等人, 2018, Cancer Discov. 8, 1210-1212;及Wong等人, 2016, Oncotarget. 2016年10月4日; 7(40): 65676-65695):例如曲美替尼(trametinib)、考比替尼(cobimetinib)、畢尼替尼(binimetinib)、司美替尼(selumetinib);ERK抑制劑,例如優立替尼(ulixertinib)、MK-8353、LY-3214996;VEGF受體抑制劑,例如貝伐單抗(bevacizumab)、阿西替尼(axitinib)、阿柏西普(aflibercept)、布立尼布(brivanib)、莫替沙尼(motesanib)、帕瑞肽(pasireotide)、索拉非尼(sorafenib);酪胺酸激酶抑制劑,例如埃羅替尼(erlotinib)、立尼法尼(linifanib)、舒尼替尼(sunitinib)、帕佐泮尼(pazopanib);表皮生長因子受體(EGFR)抑制劑:吉非替尼(gefitnib)、奧希替尼(osimertinib)、西妥昔單抗(cetuximab)、帕尼單抗(panitumumab);HER2受體抑制劑,例如曲妥珠單抗(trastuzumab)、來那替尼(neratinib)、拉帕替尼(lapatinib)、拉帕替尼;MET抑制劑:例如克卓替尼(crizotinib)、卡博替尼(cabozantinib);CD20抗體:例如利妥昔單抗(rituximab)、托西莫單抗(tositumomab)、奧伐木單抗(ofatumumab);DNA合成抑制劑:例如卡培他濱(capecitabine)、吉西他濱(gemcitabine)、奈拉濱(nelarabine)、羥基脲(hydroxycarbamide);抗贅生性藥劑:例如奧沙利鉑(oxaliplatin)、順鉑(cisplatin);HER二聚合抑制劑:例如帕妥珠單抗(pertuzumab);人類顆粒球群落刺激因子(G-CSF)調節劑:例如非格司亭(filgrastim);免疫調節劑:例如阿托珠單抗(afutuzumab)、來那度胺(lenalidomide)、沙立度胺(thalidomide)、泊利度胺(pomalidomide);CD40抑制劑:例如達西珠單抗(dacetuzumab);促細胞凋亡受體促效劑(PARA):例如杜拉樂明(dulanermin);熱休克蛋白(HSP)抑制劑:例如坦螺旋黴素(tanespimycin)(17-烯丙基胺基-17-去甲氧基格爾德黴素(desmethoxygeldanamycin));Hedgehog拮抗劑:例如維莫德吉(vismodegib);蛋白酶體抑制劑:硼替佐米(bortezomib);PI3K抑制劑:例如皮克昔布(pictilisib)、達妥昔布(dactolisib)、布帕昔布(buparlisib)、泰尼西布(taselisib)、艾德昔布(idelalisib)、杜維昔布(duvelisib)、溫布昔布(umbralisib);磷脂酶A2抑制劑:例如阿那格雷(anagrelide);BCL-2抑制劑:例如維納妥拉(venetoclax);芳香酶抑制劑:依西美坦(exemestane)、來曲唑(letrozole)、阿那曲唑(anastrozole)、法洛德克斯(faslodex)、他莫昔芬(tamoxifen);拓樸異構酶I抑制劑:例如伊立替康(irinotecan)、拓朴替康(topotecan);拓樸異構酶II抑制劑:例如依託泊苷(etoposide)、替尼泊苷(teniposide);mTOR抑制劑:例如坦羅莫司(temsirolimus)、地磷莫司(ridaforolimus)、依維莫司(everolimus)、西羅莫司(sirolimus);破骨骨骼再吸收抑制劑:例如唑來膦酸(zoledronic acid);CD33抗體藥物結合物:例如吉妥珠單抗奧佐米星(gemtuzumab ozogamicin);CD22抗體藥物結合物:例如英妥珠單抗奧佐米星(inotuzumab ozogamicin);CD20抗體藥物結合物:例如替伊莫單抗(ibritumomab tiuxetan);生長抑素類似物:例如奧曲肽(octreotide);介白素-11 (IL-11):例如奧普瑞白介素(oprelvekin);合成紅血球生成素:例如阿法達貝泊汀(darbepoetin alfa);核因子κ B之受體活化因子(RANK)抑制劑:例如地諾單抗(denosumab);血小板生成素模擬肽:例如羅米司亭(romiplostim);細胞生長刺激劑:例如帕利夫明(palifermin);抗胰島素樣生長因子-1受體(IGF-1R)抗體:例如非吉單抗(figitumumab);抗CSl抗體:例如埃羅妥珠單抗(elotuzumab);CD52抗體:例如阿侖單抗(alemtuzumab);CTLA-4抑制劑:例如曲美單抗(tremelimumab)、伊匹單抗(ipilimumab);PD1抑制劑:例如尼沃單抗(nivolumab)、派立珠單抗(pembrolizumab);免疫黏附素:例如皮立珠單抗(pidilizumab)、AMP-224;PDL1抑制劑:例如MSB0010718C、YW243.55.S70、MPDL3280A、MEDI-4736、MSB 0010718C或MDX-1105;LAG-3抑制劑:例如BMS-986016;GITR促效劑;GITR融合蛋白及抗GITR抗體;組蛋白去乙醯酶抑制劑(HDI):例如伏立諾他(voninostat);抗CTLA4抗體:例如曲美單抗(tremelimumab)、伊匹單抗(ipilimumab);烷基化劑:例如替莫唑胺(temozolomide)、放線菌素d (dactinomycin)、美法侖(melphalan)、六甲蜜胺卡莫司汀(altretamine carmustine)、苯達莫司汀(bendamustine)、白消安(busulfan)、卡鉑(carboplatin)、洛莫司汀(lomustine)、順鉑(cisplatin)、苯丁酸氮芥(chlorambucil)、環磷醯胺(cyclophosphamide)、達卡巴嗪(dacarbazine)、六甲蜜胺(altretamine)、異環磷醯胺(ifosfamide)、丙卡巴肼(procarbazine)、二氯甲二乙胺(mechlorethamine)、氮芥(mustine)及二氯甲基二乙胺(mechloroethamine)、鏈脲菌素(streptozocin)、噻替派(thiotepa);生物反應調節劑:例如卡介苗(bacillus calmette-guerin)、地尼白介素(denileukin diftitox);抗腫瘤抗生素:例如小紅莓(doxorubicin)、博萊黴素(bleomycin)、道諾黴素(daunorubicin)、道諾黴素脂質體、米托蒽醌(mitoxantrone)、表柔比星(epirubicin)、艾達黴素(idarubicin)、絲裂黴素C (mitomycin C);抗微管藥劑:例如雌氮芥(estramustine);組織蛋白酶K抑制劑:例如奧當卡替(odanacatib);埃坡黴素(Epothilone)類似物:例如伊沙匹隆(ixabepilone);TpoR促效劑:例如艾曲波帕(eltrombopag);抗有絲分裂藥劑:例如多烯紫杉醇(docetaxel);腎上腺類固醇抑制劑:例如胺魯米特(aminoglutethimide);抗雄激素:例如尼魯米特(nilutamide);雄激素受體抑制劑:例如恩雜魯胺(enzalutamide)、乙酸阿比特龍(abiraterone acetate)、奧特羅那(orteronel)、加利特隆(galeterone)及司維特奈(seviteronel)、比卡魯胺(bicalutamide)、氟他胺(flutamide);雄激素:例如氟羥甲基睪酮(fluoxymesterone);CDK1抑制劑:例如阿昔迪布(alvocidib)、帕柏西利(palbociclib)、利波西利(ribociclib)、曲拉西利(trilaciclib)、阿貝力布(abemaciclib);促性腺素釋放激素(GnRH)受體促效劑:例如亮丙立德(leuprolide)或乙酸亮丙立德;紫杉烷抗腫瘤劑:例如卡巴他賽(cabazitaxel)、拉洛他賽(larotaxel);5-HTla受體促效劑:例如紮利羅登(xaliproden);HPV疫苗:例如GlaxoSmithKline出售的Cervarix®、Merck出售的Gardasil®;鐵螯合劑:例如地拉羅司(deferasirox);抗代謝物:例如克拉屈濱(claribine)、5-氟尿嘧啶、6-硫鳥嘌呤、培美曲塞(pemetrexed)、阿糖胞苷(cytarabine)、阿糖胞苷脂質體、地西他濱(decitabine)、羥脲(hydroxyurea)、氟達拉賓(fludarabine)、氟尿苷(floxuridine)、克拉屈濱(cladribine)、甲胺喋呤(methotrexate)、噴司他汀(pentostatin);雙膦酸鹽:例如帕米膦酸鹽(pamidronate);去甲基化藥劑:例如5-阿紮胞苷、地西他濱(decitabine);抗腫瘤植物鹼:例如所結合的太平洋紫杉醇蛋白質(paclitaxel protein-bound);長春鹼(vinblastine)、長春新鹼(vincristine)、長春瑞賓(vinorelbine)、太平洋紫杉醇(paclitaxel);類視黃素:例如亞利崔托寧(alitretinoin)、維甲酸(tretinoin)、異維甲酸(isotretinoin)、貝瑟羅汀(bexarotene);糖皮質類固醇:例如氫化可的松(hydrocortisone)、地塞米松(dexamethasone)、潑尼松龍(prednisolone)、潑尼松(prednisone)、甲基潑尼松龍(methylprednisolone);細胞介素,例如介白素-2、介白素-11 (奧普瑞介白素(oprevelkin))、alpha干擾素α(IFN-α);雌激素受體下調劑:氟維司群(fulvestrant);抗雌激素:例如他莫昔芬(tamoxifen)、托瑞米芬(toremifene);選擇性雌激素受體調節劑(SERM):例如拉洛昔芬(raloxifene);促黃體生成激素釋放激素(LHRH)促效劑:例如戈舍瑞林(goserelin);孕酮:例如甲地孕酮(megestrol);細胞毒性劑:三氧化二砷、天冬醯胺酶(亦稱為L-天冬醯胺酶、歐文菌屬L-天冬醯胺酶;抗噁心藥物:例如NK-1受體拮抗劑(例如卡索匹坦(casopitant));細胞保護劑:例如阿米福汀(amifostine)、甲醯四氫葉酸(leucovorin);及免疫檢查點抑制劑。術語「免疫檢查點」係指CD4及CD8 T細胞之細胞表面上之一組分子。免疫檢查點分子包括(但不限於)程序性死亡1 (PD-1)、細胞毒性T淋巴球抗原4 (CTLA-4)、B7H1、B7H4、OX-40、CD 137、CD40及LAG3。可充當適用於本發明方法中之免疫檢查點抑制劑的免疫治療劑包括(但不限於) PD-L1、PD-L2、CTLA4、TIM3、LAG3、VISTA、BTLA、TIGIT、LAIR1、CD 160、2B4及/或TGFR β之抑制劑。
在一些實施例中,一或多種其他治療劑係選自以下藥劑:抗FGFR抗體;細胞毒性劑;靶向雌激素受體或其他內分泌療法、免疫檢查點抑制劑、CDK抑制劑、其他受體酪胺酸激酶抑制劑、BRAF抑制劑、MEK抑制劑、PI3K抑制劑、SHP2抑制劑及SRC抑制劑。(參見M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122;Y.K. Chae等人, Oncotarget 2017, 8:16052-16074;L. Formisano等人, Nat. Comm. 2019, 10:1373-1386;及其中引用的參考文獻)。
以代碼序號、屬類或商標名標識之活性化合物之結構可獲自正版標準概要「The Merck Index」或資料庫,例如Patents International (例如IMS World Publications)。
本發明化合物亦可與已知治療方法(例如投與激素或輻射)組合使用。在某些實施例中,所提供之化合物用作放射增敏劑,尤其用於治療對放射療法展現不良靈敏性之腫瘤。
本發明化合物可單獨或與一或多種其他治療化合物組合投與,可能的組合療法採用的形式為本發明化合物及一或多種其他治療化合物的固定組合或交錯或彼此獨立的投與,或固定組合與一或多種其他治療化合物的組合投與。此外或另外,本發明化合物可與化學療法、放射療法、免疫療法、光療法、手術介入或其組合進行組合,尤其用於腫瘤療法。如上文所述,在其他治療策略之背景下,長期療法同樣可能,輔助療法亦可能。其他可能的療法為在腫瘤消退後維持患者狀態之療法,或甚至為化學預防療法,例如對於風險下之患者。
彼等其他藥劑可作為多次給藥方案之一部分與含有本發明化合物之組合物分開投與。或者,彼等藥劑可為單一劑型之一部分,與本發明化合物一起混合成單一組合物。若作為多次給藥方案的一部分投與,則兩種活性劑可同時、依次或彼此間隔一定時間段(通常彼此間隔在五小時內)提供。
如本文所用,如本文所用,術語「組合(combination/combined」及相關術語係指同時或依次投與根據本發明的治療劑。舉例而言,本發明化合物可與另一治療劑以個別單位劑型同時或依次投與或以單一單位劑型一起投與。因此,本發明提供一種包含本發明化合物、另一種治療劑及醫藥學上可接受之載劑、佐劑或媒劑之單一單位劑型。
可與載劑物質組合產生單一劑型之本發明化合物及另一種治療劑(在包含如上文所述之另一種治療劑之彼等組合物中)的量將視所治療之宿主及特定投藥模式而變化。較佳地,本發明組合物應調配成使得本發明化合物的可投與劑量在每公斤體重每天0.01-100 mg之間。
在包含另一種治療劑之彼等組合物中,該另一種治療劑及本發明化合物可協同地起作用。因此,此類組合物中之另一種治療劑之量將小於僅利用該治療劑之單一療法中所需之量。在此類組合物中,另一種治療劑的可投與劑量在每公斤體重每天0.01-1,000 μg之間。
存在於本發明組合物中之其他治療劑的量將不超過通常在包含彼治療劑作為唯一活性劑之組合物中投與的量。另一種治療劑在本發明所揭示之組合物中的量較佳在通常存在於包含該藥劑作為唯一治療活性劑之組合物中之量的約50%至100%範圍內。
本發明化合物或其醫藥組合物亦可併入用於包覆可植入醫學裝置(諸如假肢、人工瓣膜、血管移植物、血管內支架及導管)的組合物中。血管內支架例如已用於克服再狹窄(損傷後的血管壁再狹窄)。然而,使用血管內支架或其他可植入裝置之患者具有凝塊形成或血小板活化之風險。可藉由用包含激酶抑制劑之醫藥學上可接受之組合物預包覆該裝置來預防或減輕此等非所需效應。用本發明化合物包覆之可植入裝置為本發明之另一實施例。
本發明之化合物及/或組合物中之任一者可提供於包含該等化合物及/或組合物之套組中。因此,在一些實施例中,本發明之化合物及/或組合物提供於套組中。
藉由以下非限制性實例進一步描述本發明。
實例
本文提供實例以促進對本發明之更透徹理解。以下實例用於說明製備及實施本發明之標的的例示性方式。然而,本發明之範疇不應理解為限於此等實例中所揭示之特定實施例,該等實例僅具說明性。
如以下實例中所描繪,在某些例示性實施例中,根據以下通用程序來製備化合物。應瞭解,儘管通用方法描繪本發明之某些化合物之合成,但以下通用方法及一般熟習此項技術者已知之其他方法可應用於如本文所述之此等化合物中之每一者的其他類別及子類及種類。本發明之其他化合物係藉由與本文在實例中所述之方法基本上類似的方法及熟習此項技術者已知之方法製備。
在下述合成方法之描述中,除非另有說明,否則應瞭解,所有反應條件(例如反應溶劑、氛圍、溫度、持續時間及處理程序)選自標準反應條件,除非另外指明。在通用流程中,熟習有機合成技藝者應瞭解,分子之各個部分上存在的官能基應與所提出之試劑及反應相容。與反應條件不相容的取代基對於熟習此項技術者而言將為顯而易見的,且因此指定替代方法(例如保護基團或替代反應的使用)。實例中的起始物質可市購或容易藉由標準方法自已知物質製備。
本文中鑑別為「中間物」之至少一些化合物作為本發明化合物涵蓋在內。
在一些實施例中,步驟1包含使Int-1與式X-R7
化合物縮合,從而形成式Int-2化合物,其中R7
在本文的實施例中定義且X為離去基。
在一些實施例中,步驟2包含使式Int-2化合物發生碘化。在一些實施例中,所用試劑為N-碘丁二醯亞胺。
在一些實施例中,步驟3包含使式Int-3化合物與經適合反應基官能化之包含Cy6
-L6
-RW
的合成組元偶合,從而形成式Int-4化合物。在一些實施例中,適合反應基為酸酯。在一些實施例中,適合反應基為頻哪醇酸酯。
在一些實施例中,步驟4包含使式Int-4化合物與經適合反應基官能化之包含R5
的合成組元偶合,從而形成式I化合物。在一些實施例中,適合反應基為酸或酸酯。
實例1
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟1:將5-溴-7H-吡咯并[2,3-d]嘧啶-4-胺(3 g,14.0 mmol)、Cs2
CO3
(9.10 g,28.0 mmol)、DMF (50 mL)及攪拌棒。將混合物冷卻至0℃且添加碘甲烷(1.98 g,14.0 mmol),且在0℃下攪拌溶液3小時。用H2
O (300 mL)稀釋反應混合物,且用EA (300 mL)萃取水相三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用MeOH/DCM = 1/80溶離)純化。真空濃縮,產生呈黃色結晶固體狀之5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(2.20 g,70%)。
5-溴-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 2 :
向圓底燒瓶中裝入5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(3 g,13.2 mmol)、TFA (7.52 g,66.0 mmol)、DCM (50 mL)及攪拌棒。將混合物冷卻至0℃且添加1-碘吡咯啶-2,5-二酮(2.96 g,13.2 mmol),且在室溫下攪拌溶液2小時。用飽和Na2
SO3
溶液(100 mL)稀釋反應混合物。用NaHCO3
飽和溶液將溶液pH調整至7~8。將固體過濾且用H2
O洗滌,接著用少量DCM洗滌且產生呈白色非晶形固體狀之5-溴-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(3.70 g,80%)。
N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
步驟 3
:向可再密封之反應瓶中裝入5-溴-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(3.7 g,10.51 mmol)、N-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)甲基丙烯醯胺(3.7 g,12.61 mmol)、Pd(PPh3
)4
(1.21 g,1.05 mmol)、K3
PO4
(6.68 g,31.53 mmol)、DMF (50 mL)、H2
O (3 mL)及攪拌棒,隨後抽真空並且用氮氣淨化三次。在50℃下攪拌混合物1小時。真空濃縮反應混合物。所得粗物質藉由矽膠層析(用MeOH/DCM = 1/100~1/20溶離)純化。真空濃縮,產生呈灰白色非晶形固體狀之N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(2.2 g,54%)。N -( 4 -( 4 - 胺基 - 5 -( 3 - 甲氧基 - 4 -( 嘧啶 - 2 - 基氧基 ) 苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 甲基丙烯醯胺
步驟 4
:向可再密封之反應瓶中裝入N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(120 mg,0.31 mmol)、2-(2-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)嘧啶(122 mg,0.373 mmol)、Pd(DtBPF)Cl2
(20.1 mg,0.031 mmol)、CsF (240 mg,0.930 mmol)、DMF (4 mL)、H2
O (0.5)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。真空濃縮反應混合物。所得粗物質藉由TLC (用MeOH/DCM = 1/15溶離)純化。真空濃縮,產生呈白色非晶形固體狀之N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(13.9 mg,9%)。
實例2N -( 4 -( 4 - 胺基 - 5 - 溴 - 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 甲基丙烯醯胺的替代途徑
6-(4-胺基苯基)-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 1
:向圓底燒瓶中裝入4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基胺基甲酸第三丁酯(20 g,47.8 mmol)、DCM (240 mL)及攪拌棒。添加TFA (60 mL)。在室溫下攪拌溶液4小時。反應混合物用Na2
CO3
飽和水溶液(40 mL)鹼化,且將固體濾出且真空濃縮。由此產生呈灰白色非晶形固體狀之6-(4-胺基苯基)-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(14 g,92.1%)。
N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
步驟 2
:向可再密封之反應瓶中裝入6-(4-胺基苯基)-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(10.0 g,31.4 mmol)、DMF/吡啶(4:1,200 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。且將溶液冷卻至0℃。隨後將甲基丙烯醯氯(4.0 g,37.7 mmol)溶解於DMF (10 mL)中且添加至上述溶液中,且在室溫下攪拌混合物1小時。反應混合物用H2
O (200 mL)稀釋,且水相用乙酸乙酯(200 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質用MeCN再結晶。真空濃縮,產生呈灰白色非晶形固體狀之N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(8.8 g,73%)。
實例34 -( 4 - 胺基 - 6 -( 4 - 甲基丙烯醯胺基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 5 - 基 )- N -( 氧雜環丁 - 2 - 基甲基 ) 苯甲醯胺 4 -( 4 - 胺基 - 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 5 - 基 ) 苯甲酸甲酯
步驟 1
:向可再密封之反應瓶中裝入5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(20 g,72.9 mmol)、[4-(甲氧基羰基)苯基]酸(15.7 g,87.4 mmol)、Pd(DtBPF)Cl2
(4.74 g,7.29 mmol)、CsF (33.1 g,218 mmol)、DMF (200 mL)、H2
O (25 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。反應混合物用H2
O (500 mL)稀釋,且水相用DCM (200 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。向反應混合物中添加MeCN (10 mL)且經由Celite®
墊過濾,用MeCN洗滌墊。真空濃縮濾液且所得固體為4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸甲酯(11.0 g,38.9 mmol),以黃色非晶形固體狀獲得。
4-(4-胺基-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸甲酯
步驟2:向圓底燒瓶中裝入4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸甲酯(10.9 g,38.6 mmol)、DCM (200 mL)、TFA (13.1 g,115 mmol)及攪拌棒。將混合物冷卻至0℃,添加NIS (9.53 g,42.4 mmol),且在室溫下攪拌溶液1小時。反應混合物用Na2
SO3
溶液稀釋,且水相用DCM (300 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。添加DCM (20 mL)且經由Celite®
墊過濾反應混合物,用少量DCM洗滌墊。真空濃縮濾液且所得固體為4-{4-胺基-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸甲酯(12.0 g,29.3 mmol),以灰白色非晶形固體狀獲得。4 -( 4 - 胺基 - 6 -( 4 - 甲基丙烯醯胺基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 5 - 基 ) 苯甲酸甲酯
步驟 3
:向可再密封之反應瓶中裝入4-{4-胺基-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸甲酯(11.9 g,29.1 mmol)、2-甲基-N-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-2-烯醯胺(10.0 g,34.9 mmol)、Pd(dppf)Cl2
(2.12 g,2.91 mmol)、K3
PO4
(18.5 g,87.3 mmol)、DMF (100 mL)、H2
O (12.5 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。反應混合物用H2
O (500 mL)稀釋,且水相用DCM (300 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用MeOH/DCM = 1/40溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸甲酯(7.70 g,17.4 mmol)。4 -( 4 - 胺基 - 6 -( 4 - 甲基丙烯醯胺基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 5 - 基 ) 苯甲酸
步驟 4
:向圓底燒瓶中裝入4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸甲酯(7.65 g,17.3 mmol)、MeOH (40 mL)、NaOH (2 N,40 mL)及攪拌棒。在室溫下攪拌溶液隔夜。用HCl (2 M)將反應混合物之pH調整至6~7。反應混合物經由Celite®
墊過濾,用H2
O洗滌墊。真空濃縮濾液且所得固體為4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸(6.50 g,15.2 mmol),以灰白色非晶形固體呈狀獲得。4 -( 4 - 胺基 - 6 -( 4 - 甲基丙烯醯胺基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 5 - 基 )- N -( 氧雜環丁 - 2 - 基甲基 ) 苯甲醯胺
步驟 5
:向圓底燒瓶中裝入4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}苯甲酸(60 mg,0.14 mmol)、1-(氧雜環丁-2-基)甲胺(13.4 mg,0.15 mmol)、HATU (58.7 mg,0.15 mmol)、DIEA (54.2 mg,0.42 mmol)及攪拌棒。添加二甲基甲醯胺(3 mL),且在25℃下攪拌溶液2小時。所得粗物質藉由HPLC純化(管柱:XBridge Prep Phenyl OBD管柱,19×150 mm,5 μm,13 nm)。凍乾產生呈灰白色非晶形固體狀之4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-N-[(氧雜環丁-2-基)甲基]苯甲醯胺(20.0 mg,0.040 mmol)。
根據實例1-3之方法製備的其他化合物描繪於下表2中。表 2 . 其他的例示性吲哚化合物
流程 2 實例 4 N -( 4 -( 4 - 胺基 - 7 - 甲基 - 5 -( 1 -( 2 , 2 , 2 - 三氟乙醯基 )- 1 , 2 , 3 , 6 - 四氫吡啶 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 丙烯醯胺 4 -( 6 -( 4 - 丙烯醯胺基苯基 )- 4 - 胺基 - 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 5 - 基 )- 3 , 6 - 二氫吡啶 - 1 ( 2H )- 甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.21 (s, 1H), 7.72 (d,J = 8.5 Hz, 2H), 7.66 (t,J = 7.8 Hz, 1H), 7.38 - 7.31 (m, 2H), 7.07 (d,J = 8.1 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.83 (dd,J = 8.0, 2.0 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.0 Hz, 1H), 6.06 (s, 2H), 5.78 (dd,J = 10.0, 2.1 Hz, 1H), 3.63 (s, 3H), 3.54 (s, 3H), 2.30 (s, 3H). | 507.3 | |
N-(3-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.23 (s, 1H), 7.75 (t,J = 1.9 Hz, 1H), 7.67 (ddd,J = 8.2, 2.2, 1.0 Hz, 1H), 7.62 (dd,J = 8.3, 7.4 Hz, 1H), 7.42 (t,J = 7.9 Hz, 1H), 7.13 (ddt,J = 13.0, 7.8, 1.0 Hz, 2H), 6.99 - 6.90 (m, 3H), 6.58 (dt,J = 8.3, 0.8 Hz, 1H), 6.48 - 6.32 (m, 2H), 5.80 (dd,J = 9.3, 2.5 Hz, 1H), 3.74 (s, 3H), 3.57 (s, 3H), 2.39 (s, 3H). | 507.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-N-甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 7.65 (dd,J = 8.2, 7.3 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.42 - 7.34 (m, 2H), 7.12 (d,J = 8.0 Hz, 1H), 7.01 (s, 2H), 6.96 - 6.91 (m, 2H), 6.88 (dd,J = 8.0, 2.0 Hz, 1H), 6.67 - 6.60 (m, 1H), 6.17 (dd,J = 16.8, 2.5 Hz, 1H), 6.08 (d,J = 11.3 Hz, 1H), 5.58 - 5.50 (m, 1H), 3.72 (s, 3H), 3.67(s, 3H), 3.28 (s, 3H), 2.29 (s, 3H). | 521.35 | |
N-(3-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.21 (s, 1H), 7.74 - 7.63 (m, 3H), 7.37 (t,J = 7.9 Hz, 1H), 7.33 - 7.23 (m, 2H), 7.17 - 6.97 (m, 4H), 6.75 (d,J = 8.2 Hz, 1H), 6.42 (dd,J = 16.9, 10.1 Hz, 1H), 6.26 (dd,J = 17.0, 2.1 Hz, 1H), 5.96 (s, 1H), 5.77 (dd,J = 10.0, 2.1 Hz, 1H), 3.62 (s, 3H), 2.33 (s, 3H). | 477.30 | |
1-(6-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,4-二氫喹啉-1(2H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 氯仿-d) δ 8.31 (s, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.20 (s, 1H), 7.17 - 7.08 (m, 3H), 6.88 (dd, J = 7.6, 3.0 Hz, 2H), 6.83 (d, J = 2.0 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 6.61 - 6.44 (m, 2H), 5.74 (dd, J = 9.4, 2.7 Hz, 1H), 3.90 (t, J = 6.5 Hz, 2H), 3.82 (s, 3H), 3.64 (s, 3H), 2.73 (t, J = 6.5 Hz, 2H), 2.42 (s, 3H), 2.01 (p, J = 6.5 Hz, 2H). | 547.4 | |
1-(5-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吲哚啉-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.18 (s, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.29 (s, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 7.4 Hz, 1H), 6.85 - 6.70 (m, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.32 (d, J = 16.5 Hz, 1H), 5.88 - 5.81 (m, 1H), 4.26 (s, 2H), 3.67 (s, 3H), 3.59 (s, 3H), 3.18 (d, J = 9.0 Hz, 2H), 2.31 (s, 3H). | 533.40 | |
1-(5-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)異吲哚啉-2-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.65 (t,J = 7.8 Hz, 1H), 7.43 (t,J = 3.9 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.07 (dd,J = 8.1, 1.0 Hz, 1H), 7.00 (d,J = 2.0 Hz, 1H), 6.92 (d,J = 7.3 Hz, 1H), 6.81 (dd,J = 8.0, 1.6 Hz, 1H), 6.67 (ddt,J = 21.6, 8.0, 4.6 Hz, 2H), 6.23 (dt,J = 16.8, 2.2 Hz, 1H), 6.05 (s, 1H), 5.76 (ddd,J = 10.3, 3.7, 2.3 Hz, 1H), 5.00 (s, 1H), 4.95 (s, 1H), 4.73 (d,J = 17.7 Hz, 2H), 3.62 (d,J = 1.7 Hz, 3H), 3.56 (s, 3H), 2.29 (d,J = 3.6 Hz, 3H). | 533.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-N-甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.73 (dd,J = 8.1, 7.4 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.37 - 7.22 (m, 4H), 7.14 - 6.96 (m, 3H), 6.78 (d,J = 8.1 Hz, 1H), 6.22 - 6.01 (m, 2H), 5.58 (dd,J = 9.9, 2.7 Hz, 1H), 3.65 (s, 3H), 3.27 (s, 3H), 2.33 (s, 3H). | 491.15 | |
1-(6-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,4-二氫異喹啉-2(1H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.73 (t,J = 7.7 Hz, 1H), 7.30 - 7.15 (m, 5H), 7.13 - 7.06 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.89 (dd,J = 16.7, 10.5 Hz, 1H), 6.77 (d,J = 8.2 Hz, 1H), 6.15 (dd,J = 16.7, 2.4 Hz, 1H), 5.88 (s, 2H), 5.72 (dd,J = 10.4, 2.4 Hz, 1H), 4.81 (s, 1H), 4.71 (s, 1H), 3.80 (d,J = 6.3 Hz, 2H), 3.62 (s, 3H), 2.83 (s, 2H), 2.33 (s, 3H). | 517.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 8.20 (s, 1H), 7.73 (t,J = 7.7 Hz, 1H), 7.62 (d,J = 8.2 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.23 (d,J = 2.0 Hz, 1H), 7.17 (dd,J = 8.3, 2.1 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.01 (d,J = 7.3 Hz, 1H), 6.77 (d,J = 8.1 Hz, 1H), 6.57 (dd,J = 17.0, 10.2 Hz, 1H), 6.26 (dd,J = 17.0, 2.1 Hz, 1H), 6.14 - 5.86 (m, 1H), 5.77 (dd,J = 10.2, 2.0 Hz, 1H), 3.63 (s, 3H), 2.34 (s, 3H), 2.20 (s, 3H). | 491.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氟苯基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.21 (s, 1H), 8.15 (t,J = 8.1 Hz, 1H), 7.74 (dd,J = 8.2, 7.4 Hz, 1H), 7.37 - 7.33 (m, 2H), 7.23 - 7.16 (m, 2H), 7.16 - 7.08 (m, 2H), 7.03 (dt,J = 7.4, 0.7 Hz, 1H), 6.77 (dt,J = 8.2, 0.7 Hz, 1H), 6.58 (dd,J = 17.0, 10.2 Hz, 1H), 6.42 (dd,J = 17.0, 1.8 Hz, 1H), 5.83 (dd,J = 10.2, 1.8 Hz, 1H), 3.73 (s, 3H), 2.43 (s, 3H). | 495.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲氧基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.45 (s, 1H), 8.21 (s, 1H), 8.14 (d,J = 8.3 Hz, 1H), 7.74 (t,J = 7.8 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.17 - 7.07 (m, 2H), 7.07 - 6.98 (m, 2H), 6.98 - 6.89 (m, 1H), 6.79 (d,J = 8.1 Hz, 1H), 6.73 (dd,J = 17.0, 10.2 Hz, 1H), 6.25 (dd,J = 17.1, 2.1 Hz, 1H), 5.92 (s, 1H), 5.73 (dd,J = 10.2, 2.1 Hz, 1H), 3.70 (d,J = 9.0 Hz, 6H), 2.34 (s, 3H). | 507.35 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.19 (d,J = 1.9 Hz, 1H), 7.77 - 7.66 (m, 3H), 7.41 - 7.30 (m, 2H), 7.21 (d,J = 2.2 Hz, 1H), 7.07 (dd,J = 8.2, 2.2 Hz, 1H), 6.97 (dd,J = 7.8, 5.7 Hz, 2H), 6.69 (d,J = 8.1 Hz, 1H), 6.45 (dd,J = 16.9, 10.1 Hz, 1H), 6.27 (dd,J = 16.9, 2.1 Hz, 1H), 5.92 (s, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.62 (s, 3H), 2.32 (s, 3H), 2.06 (s, 3H). | 491.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.56 (d,J = 4.8 Hz, 2H), 8.40 (s, 1H), 7.66 (d,J = 8.2 Hz, 2H), 7.48 (s, 1H), 7.30 (d,J = 2.1 Hz, 1H), 7.17 (d,J = 8.1 Hz, 1H), 7.05 (t,J = 4.8 Hz, 1H), 6.94 (dd,J = 8.1, 2.0 Hz, 1H), 6.86 (d,J = 1.9 Hz, 1H), 6.49 (dd,J = 16.9, 1.3 Hz, 1H), 6.29 (dd,J = 16.9, 10.2 Hz, 1H), 5.83 (dd,J = 10.2, 1.3 Hz, 1H), 5.27 (s, 2H), 3.75 (s, 3H), 3.57 (s, 3H) | 494.15 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.39 (s, 1H), 8.15 (ddd,J = 5.0, 2.0, 0.8 Hz, 1H), 7.72 (ddd,J = 8.3, 7.2, 2.0 Hz, 1H), 7.67 (d,J = 8.2 Hz, 2H), 7.44 (s, 1H), 7.30 (d,J = 1.9 Hz, 1H), 7.28 (s, 1H), 7.10 (d,J = 8.1 Hz, 1H), 7.00 (ddd,J = 7.2, 5.0, 0.9 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.86 (d,J = 2.0 Hz, 1H), 6.48 (dd,J = 16.8, 1.2 Hz, 1H), 6.28 (dd,J = 16.8, 10.2 Hz, 1H), 5.83 (dd,J = 10.2, 1.2 Hz, 1H), 5.35 (s, 2H), 3.75 (s, 3H), 3.60 (s, 3H). | 493.15 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-3-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.20 (s, 1H), 7.73 - 7.60 (m, 3H), 7.35 - 7.28 (m, 2H), 7.07 (d,J = 8.0 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.82 (dd,J = 8.1, 2.0 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 5.97 (ddt,J = 17.0, 10.1, 6.9 Hz, 1H), 5.19 (dq,J = 17.2, 1.8 Hz, 1H), 5.18 - 5.10 (m, 1H), 3.61 (s, 3H), 3.54 (s, 3H), 3.14 (dt,J = 7.0, 1.5 Hz, 2H), 2.30 (s, 3H). | 521.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-炔醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.75 (s, 1H), 8.20 (s, 1H), 7.70 - 7.54 (m, 3H), 7.32 (d,J = 8.2 Hz, 2H), 7.07 (d,J = 8.0 Hz, 1H), 7.02 - 6.88 (m, 2H), 6.82 (dd,J = 8.2, 1.9 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.02 (s, 2H), 3.57 (d,J = 32.6 Hz, 7H), 2.30 (s, 3H), 2.06 (s, 3H). | 519.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-N-甲基丁-2-炔醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.66 (dd,J = 8.2, 7.3 Hz, 1H), 7.43 (s, 4H), 7.08 (d,J = 8.0 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.87 (dd,J = 8.0, 1.9 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.06 (s, 2H), 3.65 (s, 3H), 3.53 (s, 4H), 3.23 (s, 2H), 2.30 (s, 3H), 2.11 (s, 1H), 1.66 (s, 2H). | 533.40 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.21 (s, 1H), 7.77 - 7.70 (m, 2H), 7.70 - 7.62 (m, 1H), 7.36 - 7.29 (m, 2H), 7.07 (d,J = 8.1 Hz, 1H), 6.99 - 6.89 (m, 2H), 6.82 (dd,J = 8.1, 1.9 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.62 (s, 3H), 3.55 (s, 3H), 2.30 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 521.35 | |
(E)-N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (d,J = 5.7 Hz, 1H), 8.20 (s, 1H), 7.66 (ddd,J = 21.5, 8.6, 3.9 Hz, 3H), 7.32 (dd,J = 8.7, 3.2 Hz, 2H), 7.07 (dd,J = 8.0, 1.7 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.88 - 6.75 (m, 2H), 6.64 (d,J = 8.2 Hz, 1H), 6.13 (dd,J = 15.1, 2.0 Hz, 1H), 6.0 (m, 1H), 5.25 - 5.10 (m, 1H), 3.62 (d,J = 3.0 Hz, 3H), 3.54 (s, 3H), 3.14 (dt,J = 6.8, 1.6 Hz, 1H), 2.30 (s, 3H), 1.88 (dd,J = 6.9, 1.6 Hz, 2H) | 521.35 | |
N-(4-(4-胺基-5-(3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 8.19 (s, 1H), 7.72 - 7.64 (m, 2H), 7.34 - 7.24 (m, 3H), 6.90 - 6.78 (m, 2H), 6.76 (dd,J = 2.6, 1.6 Hz, 1H), 6.44 (dd,J = 17.0, 10.1 Hz, 1H), 6.27 (dd,J = 17.0, 2.1 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 3H), 3.67 (s, 3H), 3.60 (s, 3H). | 400.1 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(間甲苯基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | .1 H NMR (400 MHz, DMSO-d 6 ) δ10.30 (s, 1H), 8.20 (s, 1H), 7.71 (d,J = 8.4 Hz, 2H), 7.32 (d,J = 8.4 Hz, 2H), 7.19 (t,J = 8.0 Hz, 1H), 6.90 - 6.97 (m, 2H), 6.76 - 6.88 (m, 2H), 6.71 (d,J = 2.0 Hz, 1H), 6.66-6.64 (m, 1H), 6.47-6.40 (m, 1H), 6.29-6.25 (m, 1H), 5.79-5.76 (m, 1H), 3.60 (d,J = 18.0 Hz, 6H), 2.27 (s, 3H). | 506.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(間甲苯基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 8.19 (s, 1H), 7.69 (d,J = 8.4 Hz, 2H), 7.35 - 7.17 (m, 6H), 7.02 - 6.80 (m, 5H), 6.44 (dd,J = 16.8, 10.0 Hz, 1H), 6.27 (dd,J = 16.8, 2.0 Hz, 1H), 6.16 - 5.66 (m, 2H), 3.61 (s, 3H), 2.30 (s, 3H). | 476.15 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.73 (t,J = 8.1 Hz, 3H), 7.33 - 7.22 (m, 4H), 7.13 - 7.05 (m, 2H), 7.01 (d,J = 7.3 Hz, 1H), 6.78 (d,J = 8.2 Hz, 1H), 5.80 (t,J = 1.0 Hz, 1H), 5.53 (t,J = 1.4 Hz, 1H), 3.62 (s, 3H), 3.32 (d,J = 0.7 Hz, 1H), 2.35 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 491.2 | |
N-(4-(4-胺基-7-甲基-5-(4-(間甲苯基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.19 (s, 1H), 7.71 (d,J = 8.2 Hz, 2H), 7.25 (dd,J = 18.4, 7.8 Hz, 5H), 6.95 (d,J = 8.2 Hz, 3H), 6.91 - 6.82 (m, 2H), 5.86 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.61 (s, 3H), 2.30 (s, 3H), 1.95 (s, 3H). | 490.15 | |
N-(4-(4-胺基-5-(3-甲氧基-4-苯氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.20 (s, 1H), 7.77 - 7.69 (m, 2H), 7.37 - 7.27 (m, 4H), 7.04 (t,J = 7.4 Hz, 1H), 7.00 - 6.93 (m, 2H), 6.93 - 6.86 (m, 2H), 6.80 (dd,J = 8.2, 2.0 Hz, 1H), 6.06 (s, 1H), 5.81 (s, 1H), 5.54 (d,J = 1.8 Hz, 1H), 3.60 (d,J = 10.8 Hz, 6H), 1.95 (d,J = 1.4 Hz, 3H). | 506.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(間甲苯基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.20 (s, 1H), 7.73 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.9 Hz, 1H), 6.98 - 6.90 (m, 2H), 6.85 (d, J = 7.5 Hz, 1H), 6.79 (dd, J = 8.1, 1.9 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.65 (dd, J = 8.2, 2.5 Hz, 1H), 6.04 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.60 (d, J = 12.6 Hz, 6H), 2.27 (s, 3H), 1.95 (s, 3H). | 519.23 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((5-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.44 (d, J = 0.8 Hz, 2H), 8.21 (s, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.86 (dd, J = 8.0, 2.0 Hz, 1H), 6.45 (dd, J = 16.8, 10.0 Hz, 1H), 6.32 - 6.21 (m, 1H), 5.79 (d, J = 11.6 Hz, 1H), 3.60 (s, 3H), 3.53 (s, 3H), 2.20 (s, 3H). | 508.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((4-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.44 (s, 2H), 8.22 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 10.0 Hz, 1H), 6.46 (dd, J = 17.2, 10.0 Hz, 1H), 6.29 (d, J = 18.8 Hz, 1H), 5.79 (d, J = 12.0 Hz, 1H), 3.60 (s, 3H), 3.53 (s, 3H), 2.20 (s, 3H). | 507.25 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(5-甲基吡啶-3-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.20 (s, 1H), 8.17 - 8.10 (m, 1H), 8.05 (d,J = 2.7 Hz, 1H), 7.78 - 7.66 (m, 2H), 7.38 - 7.26 (m, 2H), 7.12 (d,J = 2.5 Hz, 1H), 7.04 (d,J = 8.1 Hz, 1H), 6.98 (d,J = 1.9 Hz, 1H), 6.81 (dd,J = 8.1, 1.9 Hz, 1H), 6.45 (dd,J = 16.9, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.1 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 2H), 3.60 (d,J = 16.1 Hz, 6H), 2.27 (s, 3H). | 507.15 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(吡啶-4-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.41 (d, J = 5.5 Hz, 2H), 8.21 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.95 - 6.79 (m, 3H), 6.52 - 6.38 (m, 1H), 6.36 - 6.20 (m, 1H), 6.14 (s, 2H), 5.86 - 5.70 (m, 1H), 3.63 (s, 3H), 3.57 (s, 3H). | 493.15 | |
N-(4-(4-胺基-5-(4-((6-氯吡啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ10.28 (s, 1H), 8.21 (s, 1H), 7.84( t,J = 14.6 Hz, 1H), 7.72 (d,J = 8.4 Hz, 2H), 7.33 (d,J = 8.8 Hz, 2H), 7.19 (d,J = 7.2 Hz, 1H), 7.14 (d,J = 8.0 Hz, 1H), 6.98 (s, 1H), 6.91 (d,J = 8.0 Hz, 1H), 6.85 (dd,J = 6.0 Hz, 1H), 6.41 - 6.43 (m, 1H), 6.25 - 6.29 (m, 1H), 5.82 - 6.18 (br, 1H), 3.62 (s, 3H), 3.55 (s, 3H), 2.78 (t,J = 12.0 Hz, 1H). | 527.30 | |
N-(4-(4-胺基-5-(4-((6-乙基吡啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.39 (s, 1H), 7.61 (dd,J = 26.2, 7.9 Hz, 3H), 7.47 (s, 1H), 7.09 (d,J = 7.9 Hz, 1H), 6.87 (d,J = 25.9 Hz, 3H), 6.62 (d,J = 8.3 Hz, 1H), 6.48 (d,J = 16.9 Hz, 1H), 6.29 (t,J = 13.8 Hz, 1H), 5.82 (d,J = 10.2 Hz, 1H), 5.22 (s, 2H), 3.76 (s, 3H), 3.59 (s, 3H), 2.69 (d,J = 8.0 Hz, 2H), 1.20 (t,J = 7.7 Hz, 3H). | 521.2 | |
N-(4-(4-胺基-5-(4-((5,6-二甲基吡啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.20 (s, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.50 (d,J = 8.4 Hz, 1H), 7.34 (d,J = 8.4 Hz, 2H), 7.03 (d,J = 8.0 Hz, 1H), 6.95 (d,J = 2.0 Hz, 1H), 6.81 (dd,J = 8.2, 1.8 Hz, 1H), 6.57 (d,J = 8.2 Hz, 1H), 6.45 (dd,J = 17.0, 10.0 Hz, 1H), 6.32 - 6.23 (m, 1H), 5.78 (d,J = 11.8 Hz, 1H), 3.62 (s, 3H), 3.54 (s, 3H), 2.25 (s, 3H), 2.17 (s, 3H), 1.24 (s, 1H). | 521.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.41 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.73 (d,J = 8.6 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.17 - 7.07 (m, 2H), 6.97 (d,J = 1.8 Hz, 1H), 6.86 (dd,J = 8.0, 2.0 Hz, 1H), 6.45 (dd,J = 17.0, 10.2 Hz, 1H), 6.28 (dd,J = 17.0, 2.0 Hz, 1H), 5.78 (dd,J = 10.2, 2.0 Hz, 1H), 3.61 (s, 3H), 3.53 (s, 3H), 2.40 (s, 3H). | 508.15 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(5-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.71 - 7.73 (d,J = 8 Hz, 2H), 7.60 - 7.62 (d,J = 8 Hz, 1H), 7.34 - 7.36 (d,J = 8 Hz, 1H), 7.05-7.07 (d,J = 8 Hz, 1H), 6.94 (s, 1H), 6.82-6.86 (m, 2H), 6.41-6.48 (m, 1H), 6.25-6.30 (m, 1H), 5.97 (s, 1H), 5.77-5.79 (d,J = 8 Hz, 1H), 3.60 (s, 3H), 3.53 (s, 3H), 2.21 (s, 3H). | 507.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((3-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.21 (s, 1H), 7.88 (d,J = 4.9 Hz, 1H), 7.73 (d,J = 8.2 Hz, 2H), 7.65 (d,J = 7.2 Hz, 1H), 7.35 (dd,J = 17.4, 8.2 Hz, 2H), 7.08 (dd,J = 8.1, 2.8 Hz, 1H), 7.01 - 6.92 (m, 2H), 6.88 - 6.80 (m, 1H), 6.45 (dd,J = 17.0, 10.0 Hz, 1H), 6.28 (dd,J = 16.9, 2.0 Hz, 1H), 5.99 (s, 2H), 5.78 (dd,J = 9.9, 2.1 Hz, 1H), 3.60 (d,J = 5.7 Hz, 3H), 3.53 (s, 3H), 2.30 (s, 3H). | 507.2 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-3-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.20 (s, 1H), 8.13 (dd, J = 2.4, 1.2 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.38 - 7.27 (m, 2H), 7.26 - 7.16 (m, 2H), 7.06 - 6.93 (m, 2H), 6.79 (dd, J = 8.0, 2.0 Hz, 1H), 6.45 (dd, J = 17.2, 10.0 Hz, 1H), 6.28 (dd, J = 17.2, 2.0 Hz, 1H), 6.05 (s, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 3.62 (s, 3H), 3.59 (s, 3H), 2.42 (s, 3H). | 507.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.62 (d, J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.79 - 7.72 (m, 2H), 7.39 - 7.33 (m, 2H), 7.23 (t, J = 4.8 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.86 (dd, J = 8.0, 2.0 Hz, 1H), 6.01 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 3.55 (s, 3H), 1.96 (s, 3H). | 508.30 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.62 (d,J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.65 (d,J = 8.4 Hz, 2H), 7.33 (d,J = 8.4 Hz, 2H), 7.23 (t,J = 4.8 Hz, 1H), 7.17 (d,J = 8.1 Hz, 1H), 6.98 (d,J = 2.0 Hz, 1H), 6.85 (dd,J = 8.0, 1.9 Hz, 1H), 5.97 (s, 2H), 3.56 (d,J = 17.7 Hz, 6H), 2.33 (q,J = 7.5 Hz, 2H), 1.09 (t,J = 7.5 Hz, 3H). | 496.3 | |
N-(4-(4-胺基-5-(3,4-二甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.18 (s, 1H), 7.69 (d, J = 8.4 Hz, 2H), 7.35 - 7.23 (m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 2H), 6.45 (dd, J = 17.2, 10.0 Hz, 1H), 6.28 (dd, J = 16.8, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 1H), 3.75 (s, 3H), 3.60 (d, J = 0.8 Hz, 6H). | 430.30 | |
N-(4-(4-胺基-5-(3-乙氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.62 (d, J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.85 - 7.68 (m, 2H), 7.56 - 7.29 (m, 2H), 7.23 (t, J = 4.8 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.91 - 6.81 (m, 1H), 6.51 - 6.39 (m, 1H), 6.35 - 6.21 (m, 1H), 5.98 (s, 2H), 5.82 - 5.73 (m, 1H), 3.88 - 3.74 (m, 2H), 3.60 (s, 3H), 0.93 (t, J = 7.0 Hz, 3H). | 508.35 | |
N-(4-(4-胺基-5-(3-乙基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.65 (d,J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.72 (d,J = 8.4 Hz, 2H), 7.35 (d,J = 8.4 Hz, 2H), 7.30 - 7.18 (m, 2H), 7.18 - 7.03 (m, 2H), 6.45 (dd,J = 16.9, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.1 Hz, 1H), 5.96 (s, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.60 (s, 3H), 2.47 - 2.31 (m, 2H), 0.97 (t,J = 7.5 Hz, 3H). | 492.15 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)-3-(三氟甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 8.72 - 8.66 (m, 2H), 8.23 (s, 1H), 7.74 (d,J = 8.3 Hz, 2H), 7.59 - 7.53 (m, 2H), 7.43 (d,J = 9.0 Hz, 1H), 7.39 - 7.30 (m, 3H), 6.45 (dd,J = 16.9, 10.1 Hz, 1H), 6.28 (dd,J = 16.7, 2.0 Hz, 1H), 6.03 (s, 2H), 5.83 - 5.75 (m, 1H), 3.59 (s, 3H). | 532.1 | |
N-(4-(4-胺基-5-(3-(二甲基胺基)-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.63 (d,J = 4.8 Hz, 2H), 8.20 (s, 1H), 7.73 (d,J = 8.4 Hz, 2H), 7.39 - 7.31 (m, 2H), 7.24 (t,J = 4.8 Hz, 1H), 7.07 (d,J = 8.0 Hz, 1H), 6.89 - 6.81 (m, 2H), 6.45 (dd,J = 16.8, 10.2 Hz, 1H), 6.28 (dd,J = 16.8, 2.2 Hz, 1H), 6.06 (s, 2H), 5.78 (dd,J = 10.0, 2.2 Hz, 1H), 3.60 (s, 3H), 2.53 (s, 6H). | 507.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)-3-(三氟甲氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.68 (d,J = 4.7 Hz, 2H), 8.23 (s, 1H), 7.74 (d,J = 8.5 Hz, 2H), 7.47 (d,J = 8.4 Hz, 1H), 7.40 - 7.19 (m, 6H), 6.53 - 6.36 (m, 1H), 6.30 (d,J = 2.0 Hz, 1H), 6.03 (s, 2H), 5.85 - 5.73 (m, 1H), 3.60 (s, 3H). | 548.25 | |
N-(4-(4-胺基-5-(3-(羥基甲基)-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 10.04 (s, 1H), 8.52 (dd,J = 4.2, 2.8 Hz, 1H), 8.16 (s, 1H), 8.02 (dd,J = 6.5, 2.8 Hz, 1H), 7.69 - 7.62 (m, 2H), 7.26 - 7.19 (m, 2H), 6.98 (d,J = 7.9 Hz, 2H), 6.80 (d,J = 8.0 Hz, 1H), 6.46 (dd,J = 16.9, 10.1 Hz, 1H), 6.39 (dd,J = 6.5, 4.1 Hz, 1H), 6.29 (dd,J = 16.9, 2.1 Hz, 1H), 5.79 (dd,J = 10.1, 2.1 Hz, 1H), 4.91 (s, 2H), 3.58 (s, 3H). | 494.3 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基硫基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.57 (d, J = 4.8 Hz, 2H), 8.23 (s, 1H), 7.81 - 7.70 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.44 - 7.32 (m, 2H), 7.20 (m, J = 4.8 Hz, 1H), 7.01 - 6.83 (m, 2H), 6.46 (dd, J = 17.2, 10.0 Hz, 1H), 6.29 (dd, J = 17.2, 2.0 Hz, 1H), 6.02 (s, 1H), 5.79 (dd, J = 10.0, 2.0 Hz, 1H), 3.60 (d, J = 17.2 Hz, 6H). | 510.10 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基胺基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.46-8.47 (d,J = 4.8 Hz, 1H), 8.16-8.19 (m, 2H), 8.04 (s, 1H), 7.69 - 7.71 (d,J = 8 Hz, 2H), 7.33-7.35 (d,J = 8 Hz, 2H), 6.83-6.87 (m, 3H), 6.40-6.49 (m, 1H), 6.24-6.29 (m, 1H), 5.98 (s, 1H), 5.76-5.78 (m, 1H), 3.70 (s, 3H), 3.60 (s, 3H). | 493.30 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(甲基(嘧啶-2-基)胺基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.29-8.31 (m, 2H), 8.19 (s, 1H), 7.75-7.77 (d,J = 8.2 Hz, 2H), 7.19-7.21 (d,J = 8.1 Hz, 1H), 6.85-6.92 (m, 2H), 6.64 - 6.69 (m, 1H), 6.42-6.49(m, 1H), 6.25-6.31 (m, 1H), 6.01 (s, 1H), 5.77-5.80 (m, 1H), 3.56-3.59 (m, 6H), 3.30 (s, 3H). | 507.35 | |
N-(4-(4-胺基-5-(3-甲氧基-5-甲基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.61 (d, J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.22 (t, J = 4.8 Hz, 1H), 6.85 - 6.77 (m, 2H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.28 (dd, J = 16.9, 2.0 Hz, 1H), 5.78 (dd, J = 10.1, 2.0 Hz, 1H), 3.59 (s, 3H), 3.50 (s, 3H), 2.05 (s, 3H). | 508.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.67 (d,J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.78 - 7.70 (m, 2H), 7.35 - 7.25 (m, 5H), 7.25 - 7.17 (m, 2H), 5.83 - 5.78 (m, 1H), 5.56 - 5.51 (m, 1H), 3.60 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 478.10 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基硫基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.61 (d,J = 4.8 Hz, 2H), 8.22 (s, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.59 (d,J = 8.1 Hz, 2H), 7.36 - 7.29 (m, 4H), 7.25 (t,J = 4.8 Hz, 1H), 6.44 (dd,J = 17.0, 10.2 Hz, 1H), 6.28 (dd,J = 17.0, 2.0 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.61 (s, 3H). | 480.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基硫基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.62 (d,J = 4.9 Hz, 2H), 8.22 (s, 1H), 7.74 (d,J = 8.6 Hz, 2H), 7.59 (d,J = 8.1 Hz, 2H), 7.37 - 7.28 (m, 4H), 7.25 (t,J = 4.8 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.61 (s, 3H), 1.95 (s, 3H). | 494.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 9.73 (s, 1H), 8.48 (d,J = 4.8 Hz, 2H), 8.18 (s, 1H), 7.76 (d,J = 8.3 Hz, 4H), 7.68 (d,J = 8.3 Hz, 2H), 7.30 (d,J = 8.6 Hz, 2H), 7.16 (d,J = 8.6 Hz, 2H), 6.84 (t,J = 4.7 Hz, 1H), 6.44 (dd,J = 17.0, 10.1 Hz, 1H), 6.27 (dd,J = 17.0, 2.1 Hz, 1H), 5.77 (dd,J = 10.0, 2.1 Hz, 2H), 3.61 (s, 4H). | 463.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 9.73 (s, 1H), 8.48 (d,J = 4.6 Hz, 2H), 8.19 (s, 1H), 8.02 - 7.52 (m, 5H), 7.22 (dd,J = 53.0, 7.6 Hz, 4H), 6.85 (s, 1H), 5.79 (s, 2H), 5.53 (s, 1H), 3.61 (s, 3H), 1.95 (s, 3H). | 477.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(甲基(嘧啶-2-基)胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.39 (d,J = 4.8 Hz, 2H), 8.20 (s, 1H), 7.71 (d,J = 8.3 Hz, 2H), 7.42 - 7.32 (m, 4H), 7.26 (d,J = 8.2 Hz, 2H), 6.75 (t,J = 4.7 Hz, 1H), 6.44 (dd,J = 16.9, 10.1 Hz, 1H), 6.27 (dd,J = 17.0, 2.0 Hz, 1H), 5.78 (dd,J = 9.9, 2.0 Hz, 2H), 3.59 (s, 3H), 3.47 (s, 3H). | 477.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(甲基(嘧啶-2-基)胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.40 (d,J = 4.7 Hz, 2H), 8.20 (s, 1H), 7.74 (d,J = 8.4 Hz, 2H), 7.35 (t,J = 8.9 Hz, 4H), 7.26 (d,J = 8.3 Hz, 2H), 6.75 (t,J = 4.7 Hz, 1H), 5.80 (s, 2H), 5.54 (s, 1H), 3.59 (s, 3H), 3.47 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 491.30 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.21 (s, 1H), 8.11 (dd, J = 5.0, 1.9 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.13 - 7.03 (m, 2H), 6.98 - 6.92 (m, 2H), 6.83 (dd, J = 8.0, 2.0 Hz, 1H), 5.99 (s, 2H), 3.59 (s, 3H), 3.54 (s, 3H), 2.34 (q, J = 7.6 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H). | 494.21 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.20 (s, 1H), 7.64 (d, J = 8.5 Hz, 3H), 7.30 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 6.98 - 6.89 (m, 2H), 6.82 (d, J = 7.9 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 6.01 (s, 2H), 3.61 (s, 3H), 3.54 (s, 3H), 2.32 (d, J = 14.9 Hz, 5H), 1.09 (t, J = 7.5 Hz, 3H). | 508.22 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.67 (d, J = 4.8 Hz, 2H), 8.20 (s, 1H), 7.67 - 7.60 (m, 2H), 7.33 - 7.25 (m, 5H), 7.24 - 7.17 (m, 2H), 5.90 (s, 2H), 3.59 (s, 3H), 2.33 (q, J = 7.5 Hz, 2H), 1.09 (t, J = 7.6 Hz, 3H). | 466.25 | |
N-(4-(4-胺基-5-(4-((5-(羥基甲基)嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.57 (s, 2H), 8.22 (s, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.35 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.47 (dd, J = 17.0, 9.4 Hz, 1H), 6.39 (dd, J = 17.2, 2.5 Hz, 1H), 5.81 (dd, J = 9.5, 2.4 Hz, 1H), 4.63 (s, 2H), 3.72 (s, 3H), 3.57 (s, 3H). | 524.30 | |
N-(4-(4-胺基-5-(4-(5-(羥基甲基)嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.59 (s, 2H), 8.21 (s, 1H), 7.78 - 7.71 (m, 2H), 7.36 - 7.25 (m, 4H), 7.22 - 7.14 (m, 2H), 5.80 (t,J = 1.1 Hz, 2H), 5.54 (t,J = 1.5 Hz, 1H), 5.38 (t,J = 5.6 Hz, 1H), 4.49 (d,J = 5.5 Hz, 2H), 3.60 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 508.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.67 (d,J = 4.8 Hz, 2H), 8.21 (s, 1H), 7.75 - 7.67 (m, 2H), 7.38 - 7.25 (m, 5H), 7.25 - 7.17 (m, 2H), 6.44 (dd,J = 16.8, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.2 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.60 (s, 3H). | 464.15 | |
N-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-炔醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.67 (d,J = 4.8 Hz, 2H), 8.20 (s, 1H), 7.63 (d,J = 8.3 Hz, 2H), 7.36 - 7.25 (m, 5H), 7.21 (d,J = 8.4 Hz, 2H), 5.89 (s, 2H), 3.59 (s, 3H), 2.07 (d,J = 9.3 Hz, 3H). | 476.2 | |
N-(4-(4-胺基-5-(3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.19 (s, 1H), 7.70 (d,J = 8.3 Hz, 2H), 7.27 (dd,J = 8.2, 5.8 Hz, 3H), 6.86 (dd,J = 8.3, 2.6 Hz, 1H), 6.81 (d,J = 7.5 Hz, 1H), 6.77 (t,J = 2.0 Hz, 1H), 5.78 (s, 2H), 5.53 (s, 1H), 3.67 (s, 3H), 3.60 (s, 3H), 1.95 (s, 3H). | 414.1 | |
(E)-N-(4-(4-胺基-5-(3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.07 (s, 1H), 8.19 (s, 1H), 7.70 - 7.62 (m, 2H), 7.32 - 7.24 (m, 3H), 6.90 - 6.74 (m, 4H), 6.17 - 6.08 (m, 1H), 5.91 (s, 1H), 3.67 (s, 3H), 3.60 (s, 3H), 1.88 (dd,J = 6.8, 1.6 Hz, 3H). | 414.15 | |
N-(4-(4-胺基-5-(3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-炔醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.19 (s, 1H), 7.60 (d,J = 8.4 Hz, 2H), 7.27 (dd,J = 8.4, 6.4 Hz, 3H), 6.86 (dd,J = 8.4, 2.8 Hz, 1H), 6.80 (d,J = 7.6 Hz, 1H), 6.78 - 6.73 (m, 1H), 5.91 (s, 1H), 3.67 (s, 3H), 3.59 (s, 3H), 2.06 (s, 3H). | 412.25 | |
N-(4-(4-胺基-5-(4-(羥基(鄰甲苯基)甲基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.22 (s, 1H), 7.71-7.43 (d,J = 8 Hz, 1H), 7.22-7.43 (m, 7H), 6.46-6.48 (m,J = 8 Hz, 1H), 6.26-6.44 (m, 2H), 5.77-5.80 (d,J = 8 Hz, 1H), 3.62 (s, 3H), 3.43 (s, 3H), 2.35 (s, 3H). | 518.20 | |
N-(4-(4-胺基-7-甲基-5-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.20 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 8.1, 6.6 Hz, 2H), 7.34 - 7.18 (m, 5H), 6.43 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.78 (dd, J = 10.1, 2.0 Hz, 1H), 3.61 (s, 3H). | 370.25 | |
N-(4-(4-胺基-7-甲基-5-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.19 (s, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.36 (t, J = 7.4 Hz, 2H), 7.30 - 7.18 (m, 5H), 5.79 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 1.95 (t, J = 1.2 Hz, 3H). | 384.20 | |
N-(4-(4-胺基-7-乙基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.20 (s, 1H), 7.73 (dd,J = 8.3, 6.6 Hz, 3H), 7.33 - 7.22 (m, 4H), 7.11 - 7.04 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.77 (d,J = 8.1 Hz, 1H), 5.88 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 4.12 (q,J = 7.0 Hz, 2H), 2.34 (s, 3H), 1.95 (s, 3H), 1.14 (t,J = 7.1 Hz, 3H). | 505.2 | |
N-(4-(4-胺基-7-(3-羥基環丁基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.83 - 7.66 (m, 3H), 7.22 (t,J = 8.2 Hz, 5H), 7.11 - 6.95 (m, 4H), 6.77 (d,J = 8.1 Hz, 1H), 5.79 (s, 1H), 5.54 (d,J = 1.8 Hz, 1H), 5.22 (d,J = 5.8 Hz, 1H), 4.33 - 4.00 (m, 1H), 3.82 (h,J = 7.0 Hz, 1H), 3.10 - 2.90 (m, 2H), 2.34 (s, 4H), 1.95 (s, 3H), 1.87 (s, 2H). | 547.25 | |
N-(4-(4-胺基-7-(2-(4-甲基哌嗪-1-基)乙基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.19 (s, 1H), 7.73 (dt,J = 8.2, 3.4 Hz, 3H), 7.35 - 7.28 (m, 2H), 7.28 - 7.12 (m, 2H), 7.11 - 7.04 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.77 (d,J = 8.2 Hz, 1H), 5.80 (t,J = 1.1 Hz, 1H), 5.53 (t,J = 1.4 Hz, 1H), 4.18 (t,J = 6.9 Hz, 2H), 2.47 (d,J = 7.0 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 8H), 2.09 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 603.3 | |
N-(4-(4-胺基-7-(2-羥乙基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.19 (s, 1H), 7.77 - 7.68 (m, 3H), 7.35 - 7.28 (m, 2H), 7.28 - 7.20 (m, 2H), 7.11 - 7.03 (m, 2H), 7.01 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 5.82 - 5.77 (m, 1H), 5.53 (t, J = 1.4 Hz, 1H), 4.90 (t, J = 5.6 Hz, 1H), 4.13 (t, J = 6.6 Hz, 2H), 3.58 (q, J = 6.4 Hz, 2H), 2.34 (s, 3H), 1.95 (t, J = 1.3 Hz, 3H). | 521.20 | |
N-(4-(4-胺基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7-(2-N-嗎啉基乙基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.19 (s, 1H), 7.73 (dt,J = 7.7, 3.5 Hz, 3H), 7.36 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 7.13 - 7.06 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.78 (d,J = 8.1 Hz, 1H), 5.91 (s, 1H), 5.81 (s, 1H), 5.53 (s, 1H), 4.21 (t,J = 7.0 Hz, 2H), 3.44 (t,J = 4.6 Hz, 4H), 2.48 (d,J = 7.0 Hz, 2H), 2.34 (s, 3H), 2.22 (t,J = 4.7 Hz, 4H), 1.95 (s, 3H). | 590.30 | |
N-(4-(4-胺基-7-(2-(二甲基胺基)乙基)-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.73 (t,J = 7.6 Hz, 3H), 7.31 (d,J = 8.6 Hz, 2H), 7.28 - 7.20 (m, 2H), 7.12 - 7.05 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.78 (d,J = 8.1 Hz, 1H), 5.90 (s, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 4.20 (t,J = 7.0 Hz, 2H), 2.38 (t,J = 7.1 Hz, 2H), 2.34 (s, 3H), 2.01 (s, 6H), 1.97 (s, 3H). | 548.25 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 9.83 (s, 1H), 8.12 (s, 1H), 7.77 (t,J = 7.8 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.42 - 7.34 (m, 2H), 7.34 - 7.26 (m, 2H), 7.23 - 7.15 (m, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.2 Hz, 1H), 5.78 (s, 1H), 5.52 (t,J = 1.5 Hz, 1H), 2.38 (s, 3H), 1.94 (d,J = 1.3 Hz, 3H). | 477.3 | |
N-(4-(4-胺基-5-(4-((5-氯嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.73 (s, 2H), 8.23 (s, 1H), 7.73 (d,J = 8.6 Hz, 2H), 7.44 - 7.31 (m, 2H), 7.20 (d,J = 8.1 Hz, 1H), 6.99 (d,J = 1.9 Hz, 1H), 6.92 - 6.84 (m,1H), 6.59 - 6.31 (m, 1H), 6.30 - 6.26 (m, 1H), 6.06 (s, 2H), 5.85 - 5.73 (m, 1H), 3.60 (s, 3H), 3.55 (s, 3H). | 528.20 | |
N-(4-(4-胺基-5-(4-((5-胺基嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (d,J = 14.0 Hz, 1H), 8.19 (d,J = 14.7 Hz, 1H), 7.93 (s, 2H), 7.81 - 7.58 (m, 2H), 7.48 - 7.20 (m, 2H), 7.06 (d,J = 8.0 Hz, 1H), 6.93 (d,J = 1.9 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.50 - 6.40 (m, 1H), 6.35 - 6.22 (m, 1H), 5.78 (d,J = 10.1 Hz, 1H), 5.12 (s, 2H), 3.67 - 3.57 (m, 4H), 3.53 (s, 3H). | 509.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(5-(甲基胺基)嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.21 (s, 1H), 7.93 (s, 2H), 7.73 (d,J = 8.6 Hz, 2H), 7.43 - 7.32 (m, 2H), 7.07 (d,J = 8.0 Hz, 1H), 6.94 (d,J = 2.0 Hz, 1H), 6.83 (dd,J = 8.1, 1.9 Hz, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.1 Hz, 1H), 5.96 (s, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 5.70 (q,J = 5.2 Hz, 1H), 3.60 (s, 3H), 3.53 (s, 3H), 2.67 (d,J = 5.2 Hz, 3H). | 523.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.71-8.72 (d,J = 4 Hz, 2H), 8.19 (s, 1H), 7.70-7.72 (d,J = 8 Hz, 2H), 7.30-7.34 (m, 3H), 7.03-7.05 (d,J = 8 Hz, 1H), 6.77-6.82 (m, 2H), 5.53-5.81 (m, 3H), 4.17 (s, 2H), 3.57-3.58 (m, 6H), 1.95 (s, 3H). | 506.35 | |
N-(4-(4-胺基-5-(4-(羥基(鄰甲苯基)甲基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.75-8.76 (d,J = 4 Hz, 2H), 8.19 (s, 1H), 7.70-7.72 (d,J = 8 Hz, 1H), 7.43-7.45 (d,J = 8 Hz, 1H), 7.30-7.37 (m, 3H), 6.78-6.87 (m, 1H), 6.77 (s, 1H), 5.99-6.01 (d,J = 8 Hz, 1H), 5.77-5.81 (m, 3H), 5.53 (s, 1H), 3.58 (s, 3H), 3.52 (s, 3H), 1.95 (s, 3H). | 522.25 | |
N-(4-(4-胺基-5-(3-乙基-5-羥基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (d, J = 10.6 Hz, 1H), 9.54 (s, 1H), 8.64 (m, J = 19.1, 4.8 Hz, 2H), 8.17 (d, J = 17.0 Hz, 1H), 7.85 - 7.63 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.20 (s, 1H), 6.92 - 6.48 (m, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 2.39 (q, J = 7.5 Hz, 2H), 1.96 (d, J = 3.4 Hz, 3H), 1.02 - 0.91 (m, 3H). | 522.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.22 (s, 1H), 7.79 - 7.65 (m, 4H), 7.40 (d, J = 8.4 Hz, 2H), 7.25 - 7.17 (m, 2H), 6.03 (s, 2H), 5.79 (s, 1H), 5.54 (s, 1H), 3.63 (s, 3H), 3.21 - 3.00 (m, 4H), 1.95 (d, J = 1.6 Hz, 3H), 1.72 - 1.52 (m, 4H). | 517.20 | |
N-(4-(5-(4-乙醯胺基-3-甲氧基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 9.12 (s, 1H), 8.19 (s, 1H), 7.93 (d,J = 8.2 Hz, 1H), 7.76 - 7.54 (m, 2H), 7.40 - 7.18 (m, 2H), 6.94 - 6.65 (m, 2H), 5.80 (t,J = 1.1 Hz, 1H), 5.59 - 5.35 (m, 1H), 3.67 (s, 3H), 3.61 (s, 3H), 2.08 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 471.15 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.77 - 7.66 (m, 2H), 7.55 - 7.43 (m, 2H), 7.33 - 7.20 (m, 4H), 5.92 (s, 1H), 5.83 - 5.77 (m, 1H), 5.53 (q,J = 1.4 Hz, 1H), 3.61 (s, 3H), 3.44 (dt,J = 16.1, 6.5 Hz, 4H), 1.95 (t,J = 1.3 Hz, 3H), 1.83 (dq,J = 18.0, 6.6 Hz, 4H). | 481.35 | |
N-(4-(4-胺基-5-(3-氟-4-((5-氟嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.78 (s, 2H), 8.22 (s, 1H), 7.85 - 7.71 (m, 2H), 7.42 - 7.29 (m, 3H), 7.21 (dd, J = 11.6, 2.0 Hz, 1H), 7.12 (dd, J = 8.4, 2.0 Hz, 1H), 6.00 (s, 1H), 5.81 (s, 1H), 5.55 (s, 1H), 3.59 (s, 3H), 1.96 (d, J = 1.6 Hz, 2H). | 514.35 | |
N-(4-(4-胺基-5-(3-氟-4-((5-氟吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.29 (s, 1H), 8.17 (d, J = 3.1 Hz, 1H), 7.86 (ddd, J = 9.0, 7.9, 3.1 Hz, 1H), 7.80 - 7.73 (m, 2H), 7.34 (s, 1H), 7.36 - 7.26 (m, 2H), 7.25 - 7.16 (m, 2H), 7.13 - 7.06 (m, 1H), 6.37 (s, 2H), 5.82 (s, 1H), 5.55 (d, J = 2.0 Hz, 1H), 3.62 (s, 3H), 1.96 (d, J = 1.2 Hz, 3H). | 513.20 | |
N-(4-(4-胺基-5-(3-氟-4-((5-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.42 (d,J = 5.6 Hz, 2H), 8.21 (s, 1H), 7.72 (d,J = 8.4 Hz, 2H), 7.31 (d,J = 8.4 Hz, 2H), 7.13 (d,J = 8.0 Hz, 1H), 7.01 (d,J = 2.0 Hz, 1H), 6.91 - 6.86 (m, 2H), 6.86 - 6.80 (m, 1H), 6.50 - 6.39 (m, 1H), 6.33 - 6.23 (m, 1H), 6.14 (s, 2H), 5.82 - 5.75 (m, 1H), 3.65 - 3.54 (d,J = 23.2 Hz, 6H). | 510.20 | |
N-(4-(4-胺基-5-(3,5-二氟-4-(吡嗪-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.94 (s, 1H), 8.77 (d, J = 1.4 Hz, 1H), 8.48 (d, J = 2.7 Hz, 1H), 8.27 (dd, J = 2.7, 1.5 Hz, 1H), 8.22 (s, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.16 (s, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 3.58 (s, 3H), 1.96 (s, 3H). | 514.20 | |
N-(4-(4-胺基-5-(4-((5-氯嘧啶-2-基)氧基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.81 (s, 2H), 8.22 (s, 1H), 7.76 (d,J = 8.3 Hz, 2H), 7.47 - 7.30 (m, 3H), 7.23 - 7.06 (m, 2H), 5.81 (s, 1H), 5.55 (s, 1H), 3.59 (s, 3H), 1.96 (s, 3H). | 530.15 | |
N-(4-(4-胺基-5-(3,5-二氟-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.22 (s, 1H), 8.15 (d,J = 5.4 Hz, 1H), 7.92 (td,J = 8.4, 7.8, 2.2 Hz, 1H), 7.78 (d,J = 8.6 Hz, 2H), 7.35 (d,J = 8.4 Hz, 2H), 7.25 - 7.15 (m, 2H), 7.05 (d,J = 8.8 Hz, 2H), 6.13 (s, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 3.58 (s, 3H), 1.96 (s, 3H). | 513.35 | |
N-(4-(4-胺基-5-(4-((5-氟吡啶-2-基)氧基)-3-羥基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 9.61 (s, 1H), 8.23 - 8.10 (m, 2H), 7.81 - 7.71 (m, 3H), 7.31 (d,J = 8.4 Hz, 2H), 7.09 - 6.96 (m, 2H), 6.81 (d,J = 2.2 Hz, 1H), 6.70 (dd,J = 8.0, 2.2 Hz, 1H), 5.81 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 1.96 (s, 3H). | 511.20 | |
N-(4-(4-胺基-5-(4-((5-氟嘧啶-2-基)氧基)-3-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.74 (s, 2H), 8.20 (s, 1H), 7.77 - 7.71 (m, 2H), 7.37 - 7.30 (m, 2H), 7.25 (s, 1H), 7.11 (d, J = 1.3 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 2.06 (s, 3H), 1.96 (t, J = 1.2 Hz, 3H). | 509.20 | |
N-(4-(4-胺基-5-(3-羥基-4-((5-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.90 (d, J = 3.1 Hz, 1H), 9.51 (d, J = 6.1 Hz, 1H), 8.17 (d, J = 14.7 Hz, 1H), 7.98 (s, 0H), 7.73 (dd, J = 8.6, 6.1 Hz, 2H), 7.65 - 7.56 (m, 1H), 7.30 (dd, J = 13.8, 8.6 Hz, 2H), 6.94 - 6.76 (m, 4H), 5.82 (s, 1H), 5.55 (s, 1H), 3.60 (d, J = 4.6 Hz, 3H), 2.22 (s, 3H), 1.97 (dd, J = 3.1, 1.8 Hz, 3H). | 507.20 | |
N-(4-(4-胺基-5-(3,5-二氟-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.72 (d, J = 4.8 Hz, 2H), 8.22 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.42 - 7.33 (m, 3H), 7.08 (d, J = 8.8 Hz, 2H), 6.13 (s, 2H), 5.82 (s, 1H), 5.55 (s, 1H), 3.57 (s, 3H), 1.96 (s, 3H). | 514.35 | |
N-(4-(4-胺基-5-(4-((6-氟-5-甲氧基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.86 - 7.65 (m, 3H), 7.28 (m,J = 12.2, 8.3 Hz, 4H), 7.11 (d,J = 8.3 Hz, 2H), 6.99 - 6.71 (m, 1H), 5.80 (s, 2H), 5.53 (s, 1H), 3.86 (s, 3H), 3.61 (s, 3H), 1.95 (s, 3H). | 525.15 | |
N-(4-(4-胺基-5-(3-胺基-4-((5-氟吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.20 - 8.13 (m, 2H), 7.83 - 7.73 (m, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.02 (dd, J = 9.1, 3.6 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.70 (d, J = 2.1 Hz, 1H), 6.41 (dd, J = 8.1, 2.1 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 5.01 (s, 2H), 3.60 (s, 3H), 2.08 (s, 1H), 1.96 (s, 3H). | 510.20 | |
N-(4-(4-胺基-5-(3-胺基-5-氟-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.25 - 8.07 (m, 2H), 7.91 - 7.70 (m, 3H), 7.35 (d,J = 8.4 Hz, 2H), 7.17 - 6.99 (m, 2H), 6.53 (s, 1H), 6.24 (dd,J = 10.8, 2.0 Hz, 1H), 5.82 (s, 1H), 5.54 (s, 1H), 5.34 (s, 2H), 3.59 (s, 3H), 1.96 (s, 3H). | 510.20 | |
N-(4-(4-胺基-5-(4-((5-氯吡啶-2-基)氧基)-3-羥基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (d, J = 4.6 Hz, 1H), 9.65 (d, J = 5.8 Hz, 1H), 8.25 - 8.10 (m, 2H), 7.92 - 7.85 (m, 1H), 7.73 (dd, J = 8.6, 6.5 Hz, 2H), 7.30 (dd, J = 11.6, 8.6 Hz, 2H), 7.07 - 6.92 (m, 2H), 6.92 - 6.77 (m, 2H), 6.20 (s, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 3.60 (d, J = 1.5 Hz, 3H), 1.97 (d, J = 3.3 Hz, 3H). | 527.30 | |
N-(4-(4-胺基-5-(3-氯-5-氟-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.71 (d, J = 4.8 Hz, 2H), 8.22 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.40 - 7.34 (m, 3H), 7.28 - 7.17 (m, 2H), 5.83 (s, 1H), 5.55 (s, 1H), 3.57 (s, 3H), 1.96 (s, 3H). | 530.15 | |
N-(4-(4-胺基-5-(3-羥基-5-甲基-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 9.42 (s, 1H), 8.21 - 8.06 (m, 2H), 7.76 (p,J = 11.6, 9.8 Hz, 3H), 7.32 (dd,J = 16.8, 8.4 Hz, 2H), 7.11 - 6.88 (m, 2H), 6.71 (dd,J = 49.6, 10.1 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.59 (d,J = 5.8 Hz, 3H), 2.15 - 1.89 (m, 6H). | 507.30 | |
N-(4-(4-胺基-5-(3-氟-4-((5-甲基吡嗪-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.50 (d, J = 1.3 Hz, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.33 (dd, J = 8.5, 3.7 Hz, 3H), 7.19 (dd, J = 11.6, 2.0 Hz, 1H), 7.10 (d, J = 9.2 Hz, 1H), 6.02 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 2.45 (s, 3H), 1.96 (s, 3H). | 510.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.19 (s, 1H), 7.72 (d,J = 8.7 Hz, 2H), 7.55 (d,J = 2.3 Hz, 1H), 7.30 (d,J = 8.6 Hz, 2H), 6.98 (d,J = 8.2 Hz, 1H), 6.92 (d,J = 2.1 Hz, 1H), 6.79 - 6.71 (m, 1H), 5.81 (s, 1H), 5.70 (d,J = 2.3 Hz, 1H), 5.54 (s, 1H), 3.71 (s, 3H), 3.64 (s, 3H), 3.60 (s, 3H), 2.00 - 1.89 (m, 3H). | 510.45 | |
N-(4-(4-胺基-5-(4-((5-氯嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.78 (s, 2H), 8.21 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.37 - 7.26 (m, 4H), 7.27 - 7.21 (m, 2H), 6.45 (dd, J = 17.2, 10.0 Hz, 1H), 6.28 (dd, J = 17.2, 2.0 Hz, 1H), 5.78 (dd, J = 10.0, 2.0 Hz, 2H), 3.60 (s, 3H). | 498.10 | |
N-(4-(4-胺基-5-(4-((5-氯嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.74 (s, 2H), 8.21 (s, 1H), 7.78 - 7.72 (m, 2H), 7.39 - 7.32 (m, 2H), 7.20 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.1, 1.9 Hz, 1H), 5.98 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.58 (d, J = 14.3 Hz, 6H), 1.96 (s, 3H). | 542.15 | |
N-(4-(4-胺基-5-(4-((5-氯-6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.28 (t, J = 8.4 Hz, 4H), 7.16 - 7.08 (m, 2H), 6.89 (d, J = 8.7 Hz, 1H), 5.94 (s, 3H), 5.80 (s, 1H), 5.54 (s, 1H), 3.62 (s, 3H), 2.40 (s, 3H), 1.95 (s, 3H). | 525.20 | |
N-(4-(4-胺基-5-(4-((5-氯吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.34 - 8.09 (m, 2H), 8.09 - 7.89 (m, 1H), 7.78 - 7.57 (m, 2H), 7.35 - 7.20 (m, 4H), 7.21 - 7.04 (m, 3H), 5.80 (d,J = 1.3 Hz, 3H), 5.54 (t,J = 1.4 Hz, 1H), 3.60 (d,J = 5.2 Hz, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 511.15 | |
N-(4-(4-胺基-5-(4-((5-氯-6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.20 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.34 - 7.23 (m, 4H), 7.15 - 7.08 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 16.9, 2.0 Hz, 1H), 5.96 (s, 2H), 5.78 (dd, J = 10.1, 2.1 Hz, 1H), 3.62 (s, 3H), 2.40 (s, 3H). | 511.20 | |
N-(4-(4-胺基-5-(4-((5-(二氟甲基)嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.87 (s, 2H), 8.22 (s, 1H), 7.73 (d,J = 8.3 Hz, 2H), 7.38 (d,J = 8.4 Hz, 2H), 7.22 (d,J = 8.0 Hz, 1H), 7.15 (s, 0H), 7.03 - 6.98 (m, 1H), 6.89 (dd,J = 8.0, 1.9 Hz, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.28 (dd,J = 16.9, 2.0 Hz, 1H), 6.00 (s, 2H), 5.78 (dd,J = 10.0, 2.1 Hz, 1H), 3.60 (s, 3H), 3.55 (s, 3H). | 544.2 | |
N-(4-(4-胺基-5-(4-((5-氟嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 8.71 (s, 2H), 8.21 (s, 1H), 7.73 (d,J = 8.6 Hz, 2H), 7.40 - 7.34 (m, 2H), 7.18 (d,J = 8.2 Hz, 1H), 6.99 (d,J = 1.8 Hz, 1H), 6.87 (dd,J = 8.0, 2.0 Hz, 1H), 6.45 (dd,J = 17.0, 10.2 Hz, 1H), 6.28 (dd,J = 17.0, 2.0 Hz, 1H), 5.99 (s, 1H), 5.79 (dd,J = 10.2, 2.0 Hz, 1H), 3.60 (s, 3H), 3.55 (s, 3H). | 512.30 | |
N-(4-(4-胺基-7-甲基-5-(2-甲基-4-(甲基磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.21 (s, 1H), 7.80 (d,J = 2.0 Hz, 1H), 7.75 - 7.63 (m, 3H), 7.45 (d,J = 8.0 Hz, 1H), 7.22 (d,J = 8.6 Hz, 2H), 5.78 (s, 1H), 5.72 (s, 2H), 5.52 (s, 1H), 3.66 (s, 3H), 3.30 (s, 1H), 3.23 (s, 3H), 2.08 (s, 3H), 1.93 (s, 3H). | 476.30 | |
N-(4-(4-胺基-7-甲基-5-(2-側氧基吲哚啉-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 9.88 (s, 1H), 8.17 (s, 1H), 7.69 (d,J = 8.3 Hz, 2H), 7.28 (d,J = 8.2 Hz, 2H), 7.10 (s, 1H), 7.03 (d,J = 8.0 Hz, 1H), 6.78 (d,J = 7.9 Hz, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 3.59 (s, 3H), 3.44 (s, 2H), 1.95 (s, 3H). | 439.3 | |
N-(4-(4-胺基-7-甲基-5-(4-(嗎啉-4-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.41 - 7.34 (m, 2H), 7.30 - 7.22 (m, 4H), 5.98 (s, 1H), 5.80 (s, 1H), 5.54 (d,J = 1.7 Hz, 1H), 3.32 (s, 11H), 1.95 (t,J = 1.2 Hz, 3H). | 497.20 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N,N-二甲基-1H-吲哚-2-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.60 (s, 1H), 9.83 (s, 1H), 8.18 (s, 1H), 7.68 - 7.61 (m, 2H), 7.50 (d,J = 1.6 Hz, 1H), 7.40 (d,J = 8.4 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.07 (dd,J = 8.4, 1.6 Hz, 1H), 6.86 (d,J = 2.1 Hz, 1H), 5.77 (s, 1H), 5.51 (d,J = 1.9 Hz, 1H), 3.63 (s, 3H), 3.11 (s, 6H), 1.93 (t,J = 1.2 Hz, 3H). | 494.30 | |
N-(4-(4-胺基-7-甲基-5-(6-(噁唑-2-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.41 (d,J = 2.2 Hz, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.05 (d,J = 8.1 Hz, 1H), 7.80 - 7.70 (m, 3H), 7.45 (s, 1H), 7.33 - 7.25 (m, 2H), 6.15 (s, 2H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.62 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 452.1 | |
N-(4-(5-(6-(1H-1,2,4-三唑-1-基)吡啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 9.37 (s, 1H), 8.32 - 8.25 (m, 2H), 8.23 (s, 1H), 7.85 (s, 1H), 7.73 (d,J = 8.4 Hz, 2H), 7.31 (d,J = 8.4 Hz, 2H), 6.17 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 1.95 (s, 3H). | 452.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(3-甲基異噁唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 6.85 (s, 1H), 5.97 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 2.50 (s, 3H), 1.94 (s, 3H). | 465.30 | |
N-(4-(4-胺基-7-甲基-5-(1-(哌啶-4-基甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.36 (s, 1H), 7.85 - 7.70 (m, 2H), 7.59 - 7.50 (m, 2H), 7.41 - 7.33 (m, 2H), 6.48 (dd,J = 17.0, 9.4 Hz, 2H), 8.85 (dd,J = 17.0, 2.5 Hz, 1H), 4.10 (dd,J = 9.4, 2.5 Hz, 2H), 3.80 (d,J = 7.1 Hz, 3H), 3.41 (s, 2H), 3.01 (d,J = 12.7 Hz, 2H), 2.20 - 2.01 (m, 1H), 1.81 - 1.61 (d,J = 14.0 Hz, 2H), 1.55 - 1.23 (m, 2H). | 457.3 | |
N-(4-(4-胺基-5-(4-胺基-3-(三氟甲氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.17 (s, 1H), 7.71 (d,J = 8.3 Hz, 2H), 7.26 (d,J = 8.3 Hz, 2H), 6.95-6.89 (m, 2H), 6.78 (d,J = 8.7 Hz, 1H), 5.90 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 5.44 (s, 2H), 3.58 (s, 3H), 1.96 (s, 3H). | 483.15 | |
N-(4-(4-胺基-5-(5-(羥基甲基)吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.40 (d,J = 2.0 Hz, 1H), 8.24 - 8.17 (m, 2H), 7.71 (d,J = 8.3 Hz, 2H), 7.64 (d,J = 2.5 Hz, 1H), 7.27 (d,J = 8.4 Hz, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 5.32 (t,J = 5.6 Hz, 1H), 4.53 (d,J = 5.6 Hz, 2H), 3.61 (s, 3H), 3.30 (s, 1H), 1.95 (s, 3H). | 415.2 | |
N-(4-(4-胺基-5-(4-(2-(二甲基胺基)-2-側氧基乙基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.19 (s, 1H), 7.69 (d,J = 8.4 Hz, 2H), 7.27 (d,J = 8.4 Hz, 2H), 7.17-7.22 (m, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 3.69 (s, 2H), 3.60 (s, 3H), 3.01 (s, 3H), 2.84 (s, 3H), 1.95 (s, 3H). | 469.20 | |
N-(4-(4-胺基-5-(4-(2-(二甲基胺基)-2-側氧基乙基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.75 - 7.69 (m, 2H), 7.33 - 7.26 (m, 2H), 7.22 (t,J = 7.9 Hz, 1H), 7.02 (dd,J = 7.7, 1.7 Hz, 1H), 6.97 (dd,J = 10.9, 1.7 Hz, 1H), 5.91 -5.81 (s, 2H), 5.54 (d,J = 2.0 Hz, 1H), 3.70 (s, 2H), 3.59 (s, 3H), 3.05 (s, 3H), 2.85 (s, 3H), 1.95 (s, 3H). | 487.20 | |
N-(4-(4-胺基-7-甲基-5-(1-(吡啶-3-基甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.52 - 8.43 (m, 2H), 8.16 (s, 1H), 7.84 (s, 1H), 7.74 (d,J = 8.5 Hz, 2H), 7.49 - 7.42 (m, 1H), 7.40 - 7.29 (m, 4H), 5.81 (s, 1H), 5.55 (s, 1H), 5.37 (s, 2H), 3.59 (s, 2H), 1.97 (s, 3H). | 465.4 | |
N-(4-(5-(4-((2H-四唑-5-基)甲基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.20 (s, 1H), 7.68 - 7.62 (m, 2H), 7.27 (d,J = 8.1 Hz, 6H), 5.82 (s, 1H), 5.54 (s, 1H), 4.27 (s, 2H), 3.70 (s, 3H), 2.04 (t,J = 1.2 Hz, 3H), 1.33 (d,J = 15.8 Hz, 1H). | 466.20 | |
2-(4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯氧基)乙酸 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.02 (s, 1H), 9.88 (s, 1H), 8.18 (s, 1H), 7.69 (d,J = 8.3 Hz, 2H), 7.28 (dd,J = 12.5, 8.1 Hz, 2H), 7.17 (d,J = 8.2 Hz, 2H), 6.90 (d,J = 8.1 Hz, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 4.65 (s, 2H), 3.60 (s, 3H), 1.95 (s, 3H). | 458.40 | |
4-(6-(4-乙醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 8.10 (s, 1H), 7.78 (dd,J = 7.8, 5.9 Hz, 3H), 7.44 (d,J = 8.5 Hz, 2H), 6.48 (dd,J = 17.0, 10.1 Hz, 2H), 6.30 (dd,J = 17.0, 2.1 Hz, 1H), 5.83 - 5.74 (m, 2H), 3.57 (s, 3H), 2.57 (d,J = 4.5 Hz, 3H), 2.45 (q,J = 6.2 Hz, 3H), 2.29 (s, 1H), 2.24 (s, 2H), 1.89 (s, 2H), 1.65 (d,J = 6.2 Hz, 2H). | 431.25 | |
N-(4-(5-(1-乙醯基-1,2,5,6-四氫吡啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (d,J = 6.3 Hz, 1H), 8.15 (d,J = 5.0 Hz, 1H), 7.82 (t,J = 8.2 Hz, 2H), 7.44 (dd,J = 10.6, 8.4 Hz, 2H), 6.35 (s, 2H), 6.05 - 5.81 (m, 2H), 5.56 (s, 1H), 3.78 (d,J = 34.2 Hz, 2H), 3.55 (t,J = 5.9 Hz, 4H), 3.48 (t,J = 5.7 Hz, 1H), 2.23 (d,J = 27.7 Hz, 2H), 1.99 (d,J = 11.9 Hz, 4H), 1.55 (s, 2H). | 431.25 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N,N-二甲基苯并[b]噻吩-2-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 8.21 (s, 1H), 7.95 (d,J = 8.3 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.71 - 7.64 (m, 2H), 7.32 - 7.23 (m, 3H), 5.78 (s, 1H), 5.52 (d,J = 1.9 Hz, 1H), 3.63 (s, 3H), 3.20 (s, 3H), 3.07 (s, 3H), 1.93 (s, 3H). | 511.2 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-1H-吲哚-2-甲酸 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.45 - 12.25 (s, 1H), 11.85 (s, 1H), 9.85 (d,J = 12.7 Hz, 1H), 8.25 (d,J = 12.7 Hz, 1H),7.78 - 7.65 (m, 2H), 7.54 (d,J = 1.6 Hz, 1H), 7.35 (d,J = 8.5 Hz, 1H), 7.35 - 7.20 (m, 2H), 7.20 - 7.01 (dd,J = 8.5, 1.7 Hz, 2H), 6.20 - 5.60 (d,J = 2.1 Hz, 2H), 5.60 - 5.40 (s, 1H), 3.65 (t,J = 1.5 Hz,3H), 1.95 (d,J = 1.4 Hz, 3H). | 467.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(噻唑-2-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.22 (s, 1H), 7.95 - 7.89 (m, 3H), 7.79 (d,J = 3.2 Hz, 1H), 7.72 (d,J = 8.3 Hz, 2H), 7.31 (dd,J = 18.0, 8.0 Hz, 4H), 5.79 (s, 2H), 5.53 (s, 1H), 3.62 (s, 3H), 1.94 (s, 3H), 1.18 (d,J = 13.5 Hz, 1H). | 467.20 | |
N-(4-(4-胺基-7-甲基-5-(1-(吡啶-4-基甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.54 - 8.48 (m, 2H), 8.17 (s, 1H), 7.83 (s, 1H), 7.78 (d,J = 8.4 Hz, 2H), 7.43 (s, 1H), 7.35 (d,J = 8.4 Hz, 2H), 6.96 (d,J = 5.4 Hz, 2H), 5.81 (s, 1H), 5.56 (s, 1H), 5.40 (s, 2H), 3.61 (s, 3H), 1.97 (s, 3H). | 465.2 | |
N-(4-(4-胺基-5-(6-(苯甲氧基)吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.20 (s, 1H), 8.01 (d,J = 2.4 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.57 (dd,J = 8.5, 2.4 Hz, 1H), 7.49 - 7.25 (m, 7H), 6.87 (d,J = 8.5 Hz, 1H), 5.94 (s, 1H), 5.81 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 5.31 (s, 2H), 3.60 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 491.30 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-4-(四氫呋喃-3-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.17 (d,J = 2.2 Hz, 1H), 7.67 (d,J = 8.4 Hz, 2H), 7.33 - 7.22 (m, 2H), 7.09 - 6.96 (m, 2H), 6.88 (d,J = 8.4 Hz, 1H), 6.44 (dd,J = 16.9, 10.1 Hz, 1H), 6.27 (dd,J = 16.9, 2.1 Hz, 1H), 5.81 - 5.74 (m, 1H), 5.01 (d,J = 5.6 Hz, 1H), 3.94 - 3.72 (m, 4H), 3.59 (d,J = 5.5 Hz, 3H), 2.19 (dt,J = 14.5, 7.0 Hz, 1H), 2.09 (s, 3H), 1.99 (d,J = 14.4 Hz, 1H). | 470.30 | |
N-(4-(4-胺基-5-(4-((3,5-二甲基-1H-吡唑-1-基)甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.18 (s, 1H), 7.73 - 7.65 (m, 2H), 7.29 - 7.18 (m, 4H), 7.05 (d,J = 8.0 Hz, 2H), 5.99 - 5.75 (s, 3H), 5.55 (m, 1H), 5.20 (m, 2H), 3.65 (s, 3H), 2.15 (s, 3H), 2.10 (d,J = 0.7 Hz, 3H), 1.95 (s, 3H). | 492.3 | |
N-(4-(4-胺基-7-甲基-5-(4-甲基-3,4-二氫-2H-吡啶并[3,2-b][1,4]噁嗪-7-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.17 (s, 1H), 7.76 - 7.68 (m, 2H), 7.50 (d,J = 1.9 Hz, 1H), 7.33 - 7.26 (m, 2H), 6.78 (d,J = 2.0 Hz, 1H), 5.91 (s, 2H), 5.81 (s, 1H), 5.54 (d,J = 1.8 Hz, 1H), 4.20 (t,J = 4.5 Hz, 2H), 3.57 (s, 3H), 3.43 (t,J = 4.5 Hz, 2H), 3.01 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 456.35 | |
N-(4-(5-(2-乙醯胺基-2,3-二氫-1H-茚-5-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 - 8.12 (m, 2H), 7.69 (d,J = 8.4 Hz, 2H), 7.28 (d,J = 8.4 Hz, 2H), 7.19 (d,J = 7.7 Hz, 1H), 7.12 (s, 1H), 7.02 (d,J = 7.8 Hz, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 4.45 (q,J = 6.8 Hz, 1H), 3.59 (s, 3H), 3.14 (td,J = 15.7, 7.6 Hz, 2H), 2.72 (td,J = 15.1, 5.8 Hz, 2H), 1.95 (s, 3H), 1.79 (s, 3H). | 481.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((3-甲基-2,4-二側氧基咪唑啶-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.19 (s, 1H), 7.69 (d,J = 8.6 Hz, 2H), 7.30 - 7.19 (m, 6H), 5.80 (s, 1H), 5.53 (s, 1H), 4.50 (s, 2H), 3.91 (s, 2H), 3.60 (s, 3H), 2.88 (s, 3H), 1.95 (s, 3H). | 510.2 | |
N-(4-(4-胺基-7-甲基-5-(6-(5-甲基-1,3,4-噁二唑-2-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.43 (d,J = 2.2 Hz, 1H), 8.24 (s, 1H), 8.09 (d,J = 8.1 Hz, 1H), 7.81 (dd,J = 8.1, 2.2 Hz, 1H), 7.77 - 7.70 (m, 2H), 7.32 - 7.25 (m, 2H), 6.20 (s, 2H), 5.80 (s, 1H), 5.54 (d,J = 1.7 Hz, 1H), 3.62 (s, 3H), 2.60 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 467.35 | |
N-(4-(4-胺基-5-(4-(異噁唑-3-基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 9.00 (d,J = 1.8 Hz, 1H), 8.22 (s, 1H), 7.90 - 7.84 (m, 2H), 7.75 - 7.68 (m, 2H), 7.39 - 7.32 (m, 2H), 7.32 - 7.25 (m, 2H), 7.15 (d,J = 1.7 Hz, 1H), 6.15 - 5.75 (s, 3H), 5.55 - 5.50 (m, 1H), 3.62 (s, 3H), 1.95 (s, 3H). | 451.2 | |
N-(4-(4-胺基-7-甲基-5-(6-(苯硫基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 - 8.14 (m, 2H), 7.76 - 7.70 (m, 2H), 7.64 - 7.57 (m, 2H), 7.49 (dt,J = 7.2, 2.1 Hz, 4H), 7.30 - 7.23 (m, 2H), 6.92 (d,J = 8.3 Hz, 1H), 6.02 (s, 2H), 5.81 (s, 1H), 5.55 (s, 1H), 3.58 (s, 2H), 1.96 (d,J = 1.4 Hz, 3H). | 493.30 | |
N-(4-(4-胺基-7-甲基-5-(1-甲基-1,2,3,4-四氫喹啉-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.15 (s, 1H), 7.68 (d,J = 8.3 Hz, 2H), 7.30 (d,J = 8.3 Hz, 2H), 6.86 (dd,J = 8.2, 2.1 Hz, 1H), 6.80 (d,J = 2.2 Hz, 1H), 6.53 (d,J = 8.4 Hz, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.27 (dd,J = 17.1, 2.1 Hz, 1H), 5.78 (dd,J = 10.0, 2.1 Hz, 1H), 3.58 (s, 3H), 3.19 (t,J = 5.6 Hz, 2H), 2.82 (s, 3H), 2.63 (t,J = 6.5 Hz, 2H), 1.87 (p,J = 6.1 Hz, 2H). | 439.30 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基吲哚啉-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.17 (s, 1H), 7.78 (d,J = 8.2 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.31 - 7.24 (m, 2H), 7.01 (d,J = 1.7 Hz, 1H), 6.95 (dd,J = 8.2, 1.9 Hz, 1H), 6.57 (q,J = 4.4 Hz, 1H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.86 (t,J = 8.7 Hz, 2H), 3.60 (s, 3H), 3.07 (t,J = 8.7 Hz, 2H), 2.66 (d,J = 4.3 Hz, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 482.30 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N,N-二甲基吡啶醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 7.72 (t,J = 9.9 Hz, 3H), 7.51 (d,J = 7.9 Hz, 1H), 7.27 (d,J = 8.2 Hz, 2H), 6.16 - 6.10 (m, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.62 (s, 3H), 2.99 (d,J = 4.8 Hz, 6H), 1.95 (s, 3H). | 456.25 | |
N-(4-(4-胺基-5-(4-(環丙基亞磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.22 (s, 1H), 7.71 (d,J = 8.5 Hz, 2H), 7.68 - 7.62 (m, 2H), 7.41 (d,J = 8.1 Hz, 2H), 7.31 - 7.24 (m, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 2.43 (s, 1H), 1.95 (s, 3H), 1.07 - 0.81 (m, 4H). | 472.1 | |
N-(4-(4-胺基-7-甲基-5-(4-((N-甲基乙醯胺基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.20 (d,J = 2.8 Hz, 1H), 7.66 (d,J = 8.2 Hz, 2H), 7.34 (d,J = 7.9 Hz, 1H), 7.31 - 7.22 (m, 5H), 5.81 (s, 1H), 5.54 (s, 1H), 4.63 (d,J = 15.5 Hz, 2H), 3.70 (d,J = 1.7 Hz, 3H), 3.04 (s, 2H), 2.94 (s, 1H), 2.18 (d,J = 6.6 Hz, 3H), 2.04 (s, 3H). | 469.35 | |
N-(4-(5-(6-(1H-吡唑-1-基)吡啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.60 (d,J = 2.6 Hz, 1H), 8.24 - 8.18 (m, 2H), 7.89 (d,J = 8.4 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.73 (d,J = 8.5 Hz, 2H), 7.30 (d,J = 8.5 Hz, 2H), 6.57 (t,J = 2.2 Hz, 1H), 6.12 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 1.94 (s, 3H). | 451.1 | |
N-(4-(4-胺基-7-甲基-5-(6-(3-(三氟甲基)苯氧基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.20 (s, 1H), 7.96 (d,J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.74 - 7.65 (m, 2H), 7.64 (d,J = 8.0 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.51 (d,J = 8.3 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.10 (d,J = 8.4 Hz, 1H), 6.08 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.32 (s, 3H), 1.95 (s, 3H). | 545.25 | |
N-(4-(4-胺基-5-(4-(4,5-二甲基噁唑-2-基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.87 - 7.80 (m, 2H), 7.74 - 7.67 (m, 2H), 7.35 - 7.28 (m, 2H), 7.31 - 7.23 (m, 2H), 5.94 (s, 2H), 5.82 - 5.77 (m, 1H), 5.55 - 5.50 (m, 1H), 3.62 (s, 3H), 2.31 (d,J = 1.2 Hz, 3H), 2.09 (d,J = 1.1 Hz, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 479.35 | |
N-(4-(5-(4-乙醯胺基環己-1-烯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 8.12 (s, 1H), 7.85 - 7.76 (m, 2H), 7.74 (d,J = 7.3 Hz, 1H), 7.49 - 7.41 (m, 2H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.36 - 6.21 (m, 3H), 5.80 (dd,J = 10.1, 2.1 Hz, 1H), 5.69 (d,J = 4.1 Hz, 1H), 3.80 (s, 1H), 3.57 (s, 3H), 2.34 (d,J = 16.4 Hz, 1H), 2.10 - 1.88 (m, 3H), 1.80 (s, 3H), 1.66 (d,J = 12.7 Hz, 1H), 1.46 (s, 1H). | 431.15 | |
N-(4-(4-胺基-5-(3,4-二乙氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.70 (d,J = 8.2 Hz, 2H), 7.28 (d,J = 8.2 Hz, 2H), 6.92 (d,J = 8.2 Hz, 1H), 6.79 - 6.70 (m, 2H), 6.13 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 4.01 (q,J = 7.0 Hz, 2H), 3.87 (q,J = 7.0 Hz, 2H), 3.33 (s, 3H), 1.95 (s, 3H), 1.32 (t,J = 7.0 Hz, 3H), 1.21 (t,J = 7.0 Hz, 3H). | 472.30 | |
N-(4-(4-胺基-7-甲基-5-(2-側氧基-1,2,3,4-四氫喹啉-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 9.89 (s, 1H), 8.17 (s, 1H), 7.73 - 7.67 (m, 2H), 7.32 - 7.25 (m, 2H), 7.09 (d,J = 1.9 Hz, 1H), 6.98 (dd,J = 8.0, 2.0 Hz, 1H), 6.80 (d,J = 8.1 Hz, 1H), 5.80 (s, 2H), 5.54 (d,J = 1.9 Hz, 1H), 3.59 (s, 3H), 2.83 (t,J = 7.5 Hz, 2H), 2.44 (dd,J = 8.5, 6.5 Hz, 2H), 1.95 (d,J = 1.3 Hz, 3H). | 453.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(噁唑-4-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.62 (d,J = 1.0 Hz, 1H), 8.47 (d,J = 1.0 Hz, 1H), 8.20 (s, 1H), 7.80 - 7.74 (m, 2H), 7.74 - 7.66 (m, 2H), 7.32 - 7.22 (m, 4H), 5.79 (s, 1H), 5.55 - 5.50 (m, 1H), 3.61 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 451.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((3-側氧基嗎啉基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.19 (s, 1H), 7.69 (d,J = 8.4 Hz, 2H), 7.25 (d,J = 18.7 Hz, 6H), 6.12 - 5.75 (s, 2H), 5.55 (s, 1H), 4.55 (s, 2H), 4.15(s, 2H), 3.91 - 3.75 (s, 2H), 3.60 (s, 3H), 3.29 (s, 2H), 1.95 (s, 3H). | 497.3 | |
N-(4-(4-胺基-7-甲基-5-(6-(2-甲基-2H-四唑-5-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.45 (s, 1H), 8.24 (s, 1H), 8.09 (d,J = 8.1 Hz, 1H), 7.84 - 7.77 (m, 1H), 7.73 (d,J = 8.3 Hz, 2H), 7.29 (d,J = 8.2 Hz, 2H), 6.15 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 4.45 (s, 3H), 3.32 (s, 2H), 2.08 (s, 0H), 1.95 (s, 3H). | 467.30 | |
N-(4-(5-(4-(1H-咪唑-2-基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.47 (s, 1H), 9.88 (s, 1H), 8.21 (s, 1H), 7.92 - 7.85 (m, 2H), 7.73 - 7.67 (m, 2H), 7.32 - 7.22 (m, 5H), 7.03 (s, 1H), 5.97 - 5.90 (m, 1H), 5.79 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 3.63 (s, 3H), 1.94 (s, 3H). | 450.30 | |
N-(4-(4-胺基-5-(6-(3-氟苯氧基)吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.20 (s, 1H), 7.98 (d,J = 2.4 Hz, 1H), 7.76 - 7.70 (m, 2H), 7.67 (dd,J = 8.4, 2.5 Hz, 1H), 7.44 (q,J = 8.0 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.11 (dt,J = 10.4, 2.4 Hz, 1H), 7.04 (dq,J = 8.3, 3.5, 2.3 Hz, 3H), 5.80 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 1.96 (s, 3H). | 495.15 | |
N-(4-(4-胺基-7-甲基-5-(4-(5-(三氟甲基)-1,3,4-噁二唑-2-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.25 (s, 1H), 8.13 - 8.06 (m, 2H), 7.73 - 7.65 (m, 2H), 7.56 - 7.50 (m, 2H), 7.35 - 7.27 (m, 2H), 5.81 (s, 1H), 5.54 (d,J = 1.7 Hz, 1H), 3.72 (s, 3H), 2.04 (d,J = 1.3 Hz, 3H). | 520.3 | |
N-(4-(4-胺基-7-甲基-5-(5-N-嗎啉基吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 (d,J = 11.4 Hz, 2H), 7.79 (s, 1H), 7.72 (d,J = 8.3 Hz, 2H), 7.29 (d,J = 8.2 Hz, 2H), 7.22 (d,J = 2.9 Hz, 1H), 6.12 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.75 (t,J = 4.8 Hz, 4H), 3.61 (s, 3H), 3.16 (t,J = 4.9 Hz, 4H), 1.96 (s, 3H). | 470.20 | |
N-(4-(4-胺基-7-甲基-5-(6-(4-甲基-1H-吡唑-1-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 8.17 (d,J = 2.2 Hz, 1H), 7.83 (d,J = 8.4 Hz, 1H), 7.79 - 7.69 (m, 3H), 7.64 (s, 1H), 7.29 (d,J = 8.5 Hz, 2H), 6.10 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 2.10 (s, 3H), 1.95 (s, 3H). | 465.30 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-2-側氧基-2,3-二氫-1H-苯并[d]咪唑-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 9.86 (s, 1H), 8.18 (s, 1H), 7.71 - 7.63 (m, 2H), 7.32 - 7.26 (m, 2H), 6.98 (d,J = 1.6 Hz, 1H), 6.93 (d,J = 7.9 Hz, 1H), 6.83 (dd,J = 7.9, 1.6 Hz, 1H), 5.79 (s, 1H), 5.55 - 5.50 (m, 1H), 3.61 (s, 3H), 3.20 (s, 3H), 1.94 (t,J = 1.2 Hz, 3H) | 454.30 | |
N-(4-(4-胺基-5-(4-(環丙基甲氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.17 (s, 1H), 7.72 - 7.65 (m, 2H), 7.26 (d,J = 8.4 Hz, 2H), 7.14 (d,J = 8.6 Hz, 2H), 6.90 (d,J = 8.3 Hz, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.80 (d,J = 7.0 Hz, 2H), 3.60 (s, 3H), 1.95 (s, 3H), 1.20 (ddd,J = 12.5, 7.9, 5.0 Hz, 1H), 0.61 - 0.52 (m, 2H), 0.32 (dd,J = 4.8, 1.6 Hz, 2H). | 454.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N,N-二甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.75 - 7.67 (m, 2H), 7.40 - 7.34 (m, 2H), 7.30 - 7.23 (m, 4H), 6.02 (s, 2H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.62 (s, 3H), 2.96 (s, 6H), 1.95 (d,J = 1.3 Hz, 3H). | 455.20 | |
N-(4-(4-胺基-5-(1-苯甲基-6-側氧基-1,6-二氫吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.24 (s, 1H), 7.81 - 7.73 (m, 2H), 7.60 (d,J = 7.0 Hz, 1H), 7.41 - 7.26 (m, 7H), 6.49 (d,J = 1.9 Hz, 1H), 6.23 (dd,J = 7.0, 1.9 Hz, 1H), 5.85 - 5.80 (m, 1H), 5.56 (d,J = 1.8 Hz, 1H), 5.18 (s, 2H), 3.68 (s, 3H), 2.08 - 2.03 (m, 3H). | 491.30 | |
N-(4-(4-胺基-5-(2,3-二甲基-1-側氧基異吲哚啉-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.22 (s, 1H), 7.73 - 7.66 (m, 2H), 7.59 (d,J = 7.7 Hz, 1H), 7.44 (s, 1H), 7.28 (td,J = 7.5, 6.9, 1.7 Hz, 3H), 5.79 (s, 1H), 5.53 (s, 1H), 4.50 (q,J = 6.6 Hz, 1H), 3.63 (s, 3H), 2.99 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H), 1.33 (d,J = 6.6 Hz, 3H). | 467.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(5-(甲基胺基)-1,3,4-噻二唑-2-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.87 (q,J = 4.8 Hz, 1H), 7.75 - 7.68 (m, 4H), 7.33 - 7.25 (m, 4H), 5.80 (s, 1H), 5.53 (t,J = 1.6 Hz, 1H), 3.61 (s, 3H), 2.93 (d,J = 4.8 Hz, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 497.20 | |
N-(4-(4-胺基-7-甲基-5-(1-(甲基磺醯基)-1H-吲哚-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.22 (s, 1H), 9.85 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.70 - 7.61 (m, 3H), 7.50 (d,J = 8.4 Hz, 1H), 7.31 - 7.24 (m, 2H), 7.14 (dd,J = 8.4, 1.7 Hz, 1H), 5.90 (s, 2H), 5.77 (s, 1H), 5.51 (t,J = 1.4 Hz, 1H), 3.63 (s, 3H), 3.02 (s, 3H), 1.93 (t,J = 1.2 Hz, 3H). | 501.35 | |
N-(4-(4-胺基-7-甲基-5-(4-甲基-3,4-二氫-2H-苯并[b][1,4]噁嗪-7-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.16 (s, 1H), 7.71 (d,J = 8.3 Hz, 2H), 7.28 (d,J = 8.3 Hz, 2H), 6.67 (s, 2H), 6.53 (s, 1H), 5.80 (s, 2H), 5.54 (s, 1H), 4.21 (t,J = 4.3 Hz, 2H), 3.31 (s, 2H), 3.24 (t,J = 4.5 Hz, 2H), 2.83 (s, 3H), 1.96 (s, 3H), 1.35 - 1.07 (m, 2H). | 455.30 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N,N-二甲基-2,3-二氫-1H-茚-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.18 (s, 1H), 7.74 - 7.66 (m, 2H), 7.33 - 7.25 (m, 2H), 7.15 (s, 1H), 7.09 - 6.98 (m, 2H), 5.80 (s, 2H), 5.53 (t,J = 1.5 Hz, 1H), 4.43 (t,J = 8.0 Hz, 1H), 3.59 (s, 3H), 3.32 (s, 3H), 3.19 (s, 4H), 2.94 (dt,J = 12.1, 4.4 Hz, 1H), 2.25 (s, 2H), 1.98 (dt,J = 16.0, 8.3 Hz, 3H). | 495.3 | |
N-(4-(4-胺基-5-(1-環丙基-6-側氧基-1,6-二氫吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.40 (s, 1H), 7.67 (dd,J = 9.7, 3.0 Hz, 3H), 7.30 (d,J = 2.6 Hz, 1H), 7.27 (dd,J = 8.5, 2.0 Hz, 2H), 7.14 (d,J = 2.6 Hz, 1H), 6.56 (d,J = 9.3 Hz, 1H), 5.86 (s, 1H), 5.55 (q,J = 1.5 Hz, 1H), 5.07 (s, 2H), 3.72 (s, 3H), 3.33 (tt,J = 7.6, 4.2 Hz, 1H), 2.11 (d,J = 1.3 Hz, 3H), 1.12 - 1.02 (m, 2H), 0.70 - 0.61 (m, 2H). | 441.15 | |
N-(4-(4-胺基-7-甲基-5-(2-甲基-2H-吲唑-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 8.33 (s, 1H), 8.20 (s, 1H), 7.71 - 7.62 (m, 3H), 7.42 (q,J = 1.2 Hz, 1H), 7.33 - 7.25 (m, 2H), 6.88 (dd,J = 8.5, 1.4 Hz, 1H), 5.78 (t,J = 1.1 Hz, 1H), 5.54 - 5.49 (m, 1H), 4.15 (s, 3H), 3.63 (s, 3H), 1.93 (t,J = 1.2 Hz, 3H). | 438.15 | |
N-(4-(4-胺基-5-(4-(環戊基磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.23 (s, 1H), 7.84 - 7.77 (m, 2H), 7.75 - 7.68 (m, 2H), 7.47 - 7.40 (m, 2H), 7.27 - 7.21 (m, 2H), 6.01 (s, 0H), 5.80 (s, 1H), 5.54 (s, 1H), 3.82 - 3.70 (m, 1H), 3.62 (s, 3H), 1.95 (d,J = 1.5 Hz, 3H), 1.84 (d,J = 8.8 Hz, 4H), 1.57 (q,J = 6.7, 6.1 Hz, 4H). | 516.25 | |
N-(4-(4-胺基-5-(6-(二甲基胺基)吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.92 (d,J = 2.4 Hz, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.37 (dd,J = 8.7, 2.5 Hz, 1H), 7.29 (d,J = 8.6 Hz, 2H), 6.63 (d,J = 8.7 Hz, 1H), 5.80 (s, 1H), 5.72 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 3.01 (s, 6H), 1.95 (s, 3H). | 428.35 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基-1H-吡唑-1-基)甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.71 (d,J = 8.4 Hz, 2H), 7.56 (s, 1H), 7.30 - 7.24 (m, 3H), 7.02 (d,J = 11.5 Hz, 3H), 5.92 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 5.29 (s, 2H), 3.58 (s, 3H), 2.01 (s, 3H), 1.96 (s, 3H). | 496.35 | |
N-(4-(4-胺基-7-甲基-5-(2-甲基-1-側氧基異吲哚啉-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.72 - 7.65 (m, 2H), 7.55 (d,J = 7.9 Hz, 1H), 7.42 (d,J = 7.1 Hz, 2H), 7.26 (d,J = 8.5 Hz, 2H), 5.79-5.76 (s, 2H), 5.53 (d,J = 1.9 Hz, 1H), 4.45 (s, 2H), 3.62 (s, 3H), 3.06 (s, 3H), 1.94 (s, 3H). | 453.20 | |
N-(4-(4-胺基-5-(4-((4,4-二氟哌啶-1-基)甲基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (d,J = 1.9 Hz, 1H), 7.68 (dd,J = 8.7, 2.0 Hz, 2H), 7.43 (t,J = 7.8 Hz, 1H), 7.29 (dd,J = 8.7, 2.0 Hz, 2H), 7.13 (d,J = 7.7 Hz, 1H), 7.01 (d,J = 10.8 Hz, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 3.72 - 3.65 (m, 5H), 3.33 (d,J = 9.1 Hz, 1H), 2.64 (d,J = 6.6 Hz, 4H), 2.07 - 1.95 (m, 7H). | 535.40 | |
N-(4-(4-胺基-5-(2,2-二氧離子基-1,3-二氫苯并[c]噻吩-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.36 - 7.25 (m, 4H), 7.19 (dd,J = 7.8, 1.8 Hz, 1H), 5.80 (s, 1H), 5.54 (d,J = 2.0 Hz, 1H), 4.48 (d,J = 4.6 Hz, 4H), 3.60 (s, 3H), 1.95 (s, 3H). | 474.15 | |
N-(4-(4-胺基-5-(4-((3-羥基吡咯啶-1-基)甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.19 (s, 1H), 7.69 (d,J = 8.3 Hz, 2H), 7.27 (dd,J = 8.2, 4.7 Hz, 4H), 7.19 (d,J = 7.7 Hz, 2H), 5.86 (s, 2H), 5.53 (s, 1H), 4.67 (d,J = 4.6 Hz, 1H), 4.19 (d,J = 7.1 Hz, 1H), 3.61 (s, 3H), 3.54 (d,J = 5.5 Hz, 2H), 2.67 (dd,J = 9.6, 6.2 Hz, 1H), 2.57 (t,J = 7.7 Hz, 1H), 2.40 (q,J = 7.5 Hz, 1H), 2.30 (dd,J = 9.8, 3.6 Hz, 1H), 2.06 - 1.95 (m, 4H), 1.65 - 1.41 (m, 1H). | 483.3 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基哌嗪-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.46 (s, 1H), 8.21 (s, 1H), 7.65 (d,J = 8.4 Hz, 2H), 7.36 (d,J = 7.9 Hz, 2H), 7.28 (t,J = 8.1 Hz, 4H), 5.81 (s, 1H), 5.55 (s, 1H), 3.68 (d,J = 18.2 Hz, 5H), 3.03 (s, 4H), 2.69 (s, 7H), 2.04 (s, 3H). | 496.35 | |
N-(4-(4-胺基-5-(1-異丙基-1H-吲唑-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.84 (s, 1H), 8.19 (s, 1H), 8.04 (s, 1H), 7.70 - 7.61 (m, 4H), 7.28 (d,J = 8.6 Hz, 2H), 7.21 (dd,J = 8.6, 1.6 Hz, 1H), 5.77 (s, 2H), 5.51 (s, 1H), 4.97 (p,J = 6.6 Hz, 1H), 3.62 (s, 3H), 1.93 (s, 3H), 1.49 (d,J = 6.6 Hz, 6H). | 466.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(2-側氧基哌啶-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.75 - 7.67 (m, 2H), 7.41 - 7.21 (m, 6H), 5.85 (m, 2H), 5.55 (d,J = 1.2 Hz, 1H), 3.65 (d,J = 8.1 Hz, 5H), 2.55 - 2.31 (t,J = 6.3 Hz, 2H), 1.95 (t,J = 1.2 Hz, 3H), 1.91 - 1.77 (m, 4H). | 481.3 | |
N-(4-(4-胺基-7-甲基-5-(1-(1-甲基氮雜環丁-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.38 (s, 1H), 7.63 (d,J = 8.3 Hz, 2H), 7.56 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 5.84 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 5.08 (s, 2H), 4.87 (p,J = 6.9 Hz, 1H), 3.86 - 3.75 (m, 2H), 3.70 (s, 3H), 3.54 - 3.45 (m, 2H), 2.45 (s, 3H), 2.11 (s, 3H). | 443.20 | |
N-(4-(4-胺基-7-甲基-5-(6-(2-側氧基吡咯啶-1-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.28 (d,J = 8.6 Hz, 1H), 8.23 - 8.14 (m, 2H), 7.75 - 7.63 (m, 3H), 7.28 (d,J = 8.3 Hz, 2H), 5.95 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.97 (t,J = 7.1 Hz, 2H), 3.61 (s, 3H), 2.57 (t,J = 8.0 Hz, 2H), 2.04 (q,J = 7.5 Hz, 2H), 1.95 (s, 3H). | 468.35 | |
N-(4-(4-胺基-5-(5-氟-2-甲氧基吡啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.21 (s, 1H), 8.04 (d,J = 1.4 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.30 - 7.23 (m, 2H), 6.70 (d,J = 5.0 Hz, 1H), 6.16 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.82 (s, 3H), 3.62 (s, 3H), 1.95 (s, 3H). | 433.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(2-側氧基咪唑啶-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.18 (s, 1H), 7.69 (d,J = 8.6 Hz, 2H), 7.55 (d,J = 8.6 Hz, 2H), 7.31 - 7.24 (m, 2H), 7.18 (d,J = 8.6 Hz, 2H), 6.96 (s, 1H), 5.94 (s, 2H), 5.79 (s, 1H), 5.55 - 5.50 (m, 1H), 3.84 (dd,J = 9.2, 6.6 Hz, 2H), 3.40 (t,J = 7.9 Hz, 3H), 3.32 (s, 2H), 1.95 (s, 3H). | 468.30 | |
N-(4-(4-胺基-5-(2,5-二甲氧基吡啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.70 (d,J = 8.4 Hz, 2H), 7.23 (d,J = 8.4 Hz, 2H), 6.51 (s, 1H), 5.88 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.76 (s, 3H), 3.60 (d,J = 2.3 Hz, 6H), 1.95 (s, 3H). | 445.25 | |
N-(4-(4-胺基-5-(咪唑并[1,2-a]吡啶-7-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.44 (d,J = 7.0 Hz, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.72 (d,J = 8.5 Hz, 2H), 7.56 - 7.51 (m, 1H), 7.36 - 7.28 (m, 3H), 6.63 (dd,J = 7.0, 1.7 Hz, 1H), 6.15 (s, 2H), 5.78 (d,J = 11.5 Hz, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 1.94 (s, 3H). | 424.25 | |
N-(4-(4-胺基-7-甲基-5-(6-(1-甲基哌啶-4-基氧基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.97 (d,J = 2.5 Hz, 1H), 7.75 - 7.70 (m, 2H), 7.52 (dd,J = 8.5, 2.5 Hz, 1H), 7.32 - 7.24 (m, 2H), 6.75 (d,J = 8.5 Hz, 1H), 5.92 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.95 (tt,J = 8.8, 4.1 Hz, 1H), 3.60 (s, 3H), 2.66 (dd,J = 12.9, 5.5 Hz, 2H), 2.19 - 2.08 (m, 5H), 1.99 - 1.93 (m, 5H), 1.69 (ddt,J = 14.5, 9.2, 4.8 Hz, 2H). | 498.25 | |
N-(4-(4-胺基-5-(8-氮雜雙環[3.2.1]辛-2-烯-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.37 (s, 1H), 7.90 (d,J = 8.4 Hz, 2H), 7.50 (d,J = 8.4 Hz, 2H), 6.21 (d,J = 5.6 Hz, 1H), 5.87 (s, 1H), 5.60 (s, 1H), 4.37 (t,J = 5.5 Hz, 1H), 4.10 (s, 1H), 3.75 (s, 3H), 2.93 - 2.84 (m, 1H), 2.31 - 2.12 (m, 4H), 2.07 (s, 3H), 1.99 - 1.90 (m, 1H), 1.57 (s, 1H), 1.30 (d,J = 13.5 Hz, 1H). | 415.30 | |
N-(4-(4-胺基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-N-甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.17 (s, 1H), 8.14 (s, 1H), 7.74-7.78 (m, 1H), 7.41-7.47 (m, 4H), 7.21-7.24 (m, 4H), 6.84-6.86 (d,J = 8 Hz, 1H), 5.17-6.18 (m, 5H), 3.23 (s, 3H), 2.36 (s, 3H). | 477.35 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.82 (s, 1H), 8.13 (s, 1H), 7.59 (d, J = 8.3 Hz, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.6 Hz, 2H), 5.79 (s, 1H), 5.52 (s, 1H), 3.48 (dt, J = 11.2, 6.4 Hz, 4H), 1.96 - 1.81 (m, 7H). | 467.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 8.21 (s, 1H), 7.72 - 7.65 (m, 2H), 7.55 - 7.46 (m, 2H), 7.28 (dd,J = 8.6, 6.8 Hz, 4H), 6.44 (dd,J = 17.0, 10.2 Hz, 1H), 6.27 (dd,J = 17.0, 2.2 Hz, 1H), 5.78 (dd,J = 10.2, 2.2 Hz, 2H), 3.62 (s, 3H), 3.44 (dt,J = 17.8, 6.6 Hz, 4H), 1.84 (ddd,J = 17.8, 12.8, 6.8 Hz, 4H). | 467.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-炔醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.72 (s, 1H), 8.21 (s, 2H), 7.59 -7.61 (d,J = 8 Hz, 2H), 7.47-7.49 (d,J = 8 Hz, 2H), 7.26 (m, 4H), 5.91 (s, 1H), 3.59 (s, 3H), 3.16-3.45 (m, 4H), 2.05 (s, 3H), 1.82-1.86 (m, 4H). | 479.35 | |
N-(4-(4-胺基-5-(3-乙氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.83 (s, 1H), 8.13 (s, 1H), 7.70 (m, 1H), 7.66 - 7.60 (m, 2H), 7.39 - 7.30 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 2.0 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 5.79 (s, 2H), 5.53 (s, 1H), 3.93-3.88 (m, 2H), 2.34 (s, 3H), 1.95 (s, 3H), 1.23 - 1.13 (m, 3H). | 521.25 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-炔醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.66 (s, 1H), 8.13 (s, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.8 Hz, 2H), 7.37 - 7.25 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.04 - 6.88 (m, 2H), 6.72 (d, J = 8.4 Hz, 1H), 5.84 (s, 2H), 3.62 (s, 3H), 2.34 (s, 3H), 2.05 (s, 3H). | 505.25 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 10.19 (s, 1H), 8.12 (s, 1H), 7.77 (t,J = 7.8 Hz, 1H), 7.60 (d,J = 8.6 Hz, 2H), 7.42 - 7.35 (m, 2H), 7.32 (d,J = 8.5 Hz, 2H), 7.23 - 7.16 (m, 2H), 7.04 (d,J = 7.3 Hz, 1H), 6.85 (d,J = 8.2 Hz, 1H), 6.43 (dd,J = 17.0, 10.1 Hz, 1H), 6.26 (dd,J = 17.0, 2.0 Hz, 1H), 5.76 (dd,J = 10.1, 2.0 Hz, 1H), 2.38 (s, 3H). | 463.4 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)異丁醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 9.87 (s, 1H), 8.12 (s, 1H), 7.76 (t,J = 7.8 Hz, 1H), 7.54 (d,J = 8.6 Hz, 2H), 7.40 - 7.33 (m, 2H), 7.31 - 7.25 (m, 2H), 7.22 - 7.15 (m, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.84 (d,J = 8.2 Hz, 1H), 5.74 (s, 2H), 2.59 (q,J = 6.7 Hz, 1H), 2.38 (s, 3H), 1.09 (d,J = 6.8 Hz, 6H). | 479.4 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.20 (s, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.34 - 7.23 (m, 4H), 7.15 - 7.08 (m, 2H), 6.89 (d, J = 8.6 Hz, 1H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 16.9, 2.0 Hz, 1H), 5.96 (s, 2H), 5.78 (dd, J = 10.1, 2.1 Hz, 1H), 3.62 (s, 3H), 2.40 (s, 3H). | 453.30 | |
N-(4-(4-胺基-5-(4-((6-氟吡啶-3-基)氧基)-3-羥基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 9.61 (s, 1H), 8.23 - 8.10 (m, 2H), 7.81 - 7.71 (m, 3H), 7.31 (d,J = 8.4 Hz, 2H), 7.09 - 6.96 (m, 2H), 6.81 (d,J = 2.2 Hz, 1H), 6.70 (dd,J = 8.0, 2.2 Hz, 1H), 5.81 (s, 1H), 3.60 (s, 3H), 1.96 (s, 3H). | 511.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 7.78 - 7.60 (m, 3H), 7.55 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H), 7.01 - 6.95 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.75 (m, J = 8.2, 2.2 Hz, 1H), 6.45 (m, J = 17.0, 10.1 Hz, 1H), 6.21 - 6.12 (m, 1H), 5.78 (dd, J = 10.1, 2.0 Hz, 1H), 5.69 (d, J = 2.3 Hz, 1H), 3.71 (s, 3H), 3.62 (d, J = 9.0 Hz, 6H). | 496.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 7.6 Hz, 1H), 6.90 (s, 1H), 6.83 (d, J = 7.6 Hz, 1H) , 6.11 (s, 1H), 5.82 (s, 1H), 5.54 (s, 1H), 3.63 (d, J = 12.4 Hz, 6H), 3.43 (t, J = 6.8 Hz, 2H), 3.16-3.13 (m, 2H), 1.96 (s, 3H), 1.87-1.77 (m, 4H). | 511.35 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.27 (s, 1H), 8.21 (s, 1H), 7.70 (d,J = 8.4 Hz, 2H), 7.31 (d,J = 8.5 Hz, 2H), 7.14 (d,J = 7.6 Hz, 1H), 6.88 (d,J = 1.5 Hz, 1H), 6.82 (dd,J = 7.7, 1.4 Hz, 1H), 6.44 (dd,J = 17.0, 10.1 Hz, 1H), 6.27 (dd,J = 17.0, 2.1 Hz, 1H), 6.02 (s, 2H), 5.78 (dd,J = 10.0, 2.0 Hz, 1H), 3.62 (d,J = 6.3 Hz, 6H), 3.42 (t,J = 6.9 Hz, 2H), 3.13 (t,J = 6.5 Hz, 2H), 1.82 (dq,J = 19.6, 7.0 Hz, 4H). | 497.3 | |
N-(4-(4-胺基-7-甲基-5-(3-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.21 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.53 - 7.35 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 2.0 Hz, 1H), 5.78 (s, 1H), 5.54 (s, 1H), 3.61 (s, 3H), 3.37 (t, J = 7.0 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H), 1.95 (s, 3H), 1.81 - 1.73 (m, 2H), 1.67 - 1.59 (m, 2H). | 481.35 | |
N-(4-(4-胺基-7-甲基-5-(1-(吡咯啶-1-羰基)哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.11 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 6.38 (s, 2H), 5.83 (s, 1H), 5.56 (s, 1H), 3.60 (d, J = 12.7 Hz, 2H), 3.36 (s, 3H), 3.18 (d, J = 6.3 Hz, 4H), 3.05 (s, 1H), 2.73 (t, J = 12.3 Hz, 2H), 1.98 (s, 3H), 1.72 (d, J = 4.9 Hz, 4H), 1.68 - 1.49 (m, 4H). | 488.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(3-甲基氮雜環丁烷-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.63 - 7.57 (m, 2H), 7.27 (t, J = 8.4 Hz, 4H), 5.80 (s, 1H), 5.53 (t, J = 1.6 Hz, 1H), 4.42 (t, J = 8.3 Hz, 1H), 4.15 (t, J = 8.8 Hz, 1H), 3.88 (s, 1H), 3.61 (s, 3H), 3.32 (s, 1H), 2.75 - 2.66 (m, 1H), 1.95 (d, J = 1.2 Hz, 3H), 1.20 (d, J = 6.8 Hz, 3H). | 481.20 | |
N-(4-(4-胺基-5-(4-(4,4-二氟哌啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.81 - 7.64 (m, 2H), 7.41 (d,J = 8.1 Hz, 2H), 7.34 - 7.18 (m, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 2.09 - 1.97 (m, 4H), 1.95 (d,J = 1.3 Hz, 3H). | 531.20 | |
N-(4-(4-胺基-5-(4-(3,3-二氟吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.51 (s, 2H), 7.30 - 7.23 (m, 2H), 5.98 (s, 2H), 5.80 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 3.93 (s, 2H), 3.72 (t,J = 7.4 Hz, 2H), 3.61 (s, 3H), 2.50 - 2.32 (m, 2H), 1.95 (d,J = 1.2 Hz, 3H). | 517.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(十氫環戊并[c]吡咯-2-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.71 (d,J = 8.5 Hz, 2H), 7.45 (d,J = 7.9 Hz, 2H), 7.26 (dd,J = 8.4, 2.1 Hz, 4H), 5.93 (s, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 3.69 (s, 1H), 3.61 (s, 4H), 3.22 (s, 2H), 2.62 (s, 2H), 1.95 (s, 3H), 1.84 - 1.60 (m, 3H), 1.60 - 1.20 (m, 3H). | 521.30 | |
N-(4-(4-胺基-5-(4-(3-羥基吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.49 (dd, J = 8.3, 2.3 Hz, 2H), 7.27 (dd, J = 8.3, 1.8 Hz, 4H), 5.80 (s, 3H), 5.53 (t, J = 1.5 Hz, 1H), 4.96 (dd, J = 27.0, 3.5 Hz, 1H), 4.28 (d, J = 36.6 Hz, 1H) , 3.66 (s, 3H), 3.32 (s, 3H), 3.24 (d, J = 11.0 Hz, 1H), 1.95 (t, J = 1.2 Hz, 5H). | 497.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.68 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.27 (dd, J = 8.3, 1.4 Hz, 4H), 5.95 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.68 - 3.36 (m, 7H), 1.96 (t, J = 1.2 Hz, 3H), 1.62 (d, J = 6.4 Hz, 2H), 1.51 (s, 4H). | 495.35 | |
N-(4-(4-胺基-7-甲基-5-(1-(哌啶-4-基甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.37 (s, 1H), 7.77 - 7.70 (m, 2H), 7.59 (s, 1H), 7.54 (s, 1H), 7.40 - 7.33 (m, 2H), 5.84 (s, 1H), 5.58 (d,J = 1.8 Hz, 1H), 4.10 (d,J = 7.1 Hz, 2H), 3.79 (s, 3H), 3.46 - 3.37 (m, 2H), 2.96 (td,J = 12.9, 3.0 Hz, 2H), 2.16 (ddd,J = 11.4, 7.6, 3.9 Hz, 1H), 2.06 (s, 3H), 1.72 - 1.63 (m, 2H), 1.55 - 1.25 (m, 2H). | 471.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.10 (s, 1H), 7.84 - 7.75 (m, 3H), 7.46 - 7.39 (m, 2H), 5.83 (s, 1H), 5.77 (s, 1H), 5.56 (d,J = 1.6 Hz, 1H), 3.57 (s, 3H), 2.57 (d,J = 4.5 Hz, 3H), 2.45 (q,J = 6.2 Hz, 1H), 2.29 (s, 1H), 2.24 (s, 1H), 1.98 (t,J = 1.2 Hz, 3H), 1.89 (s, 2H), 1.65 (d,J = 6.3 Hz, 2H). | 445.30 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-4-(四氫呋喃-3-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.17 (s, 1H), 7.69 (d,J = 8.4 Hz, 2H), 7.28 (d,J = 8.3 Hz, 2H), 7.07 (s, 1H), 7.01 (d,J = 8.7 Hz, 1H), 6.88 (d,J = 8.4 Hz, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 5.00 (d,J = 5.8 Hz, 1H), 3.94 - 3.72 (m, 4H), 3.59 (s, 3H), 2.20 (dq,J = 14.5, 7.7 Hz, 1H), 2.09 (s, 3H), 1.99 (d,J = 7.1 Hz, 1H), 1.95 (s, 3H), 1.16 (t,J = 13.1 Hz, 1H). | 484.35 | |
N-(4-(4-胺基-7-甲基-5-(1-甲基-1,2,3,4-四氫喹啉-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.15 (s, 1H), 7.70 (d,J = 8.3 Hz, 2H), 7.29 (d,J = 8.3 Hz, 2H), 6.86 (dd,J = 8.3, 2.2 Hz, 1H), 6.81 (d,J = 2.2 Hz, 1H), 6.53 (d,J = 8.3 Hz, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 3.58 (s, 3H) 3.20 (t,J = 5.6 Hz, 2H), 2.82 (s, 3H), 2.63 (t,J = 6.5 Hz, 2H), 1.95 (s, 3H), 1.87 (p,J = 6.2 Hz, 2H). | 453.40 | |
(E)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-(二甲基胺基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.17 (s, 1H), 8.20 (s, 1H), 7.67 (d,J = 8.3 Hz, 2H), 7.49 (d,J = 7.9 Hz, 2H), 7.26 (dd,J = 8.3, 1.9 Hz, 4H), 6.74 (dt,J = 15.5, 5.8 Hz, 1H), 6.31 - 6.23 (m, 1H), 5.92 (s, 1H), 3.61 (s, 3H), 3.43 (dt,J = 17.9, 6.6 Hz, 4H), 3.28 (s, 1H), 3.09 - 3.03 (m, 1H), 2.18 (s, 6H), 1.89 - 1.78 (m, 4H). | 524.45 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.21 (s, 1H), 7.60 (d,J = 8.2 Hz, 1H), 7.49 (d,J = 8.1 Hz, 2H), 7.28 (d,J = 8.1 Hz, 2H), 7.20 (d,J = 2.1 Hz, 1H), 7.13 (dd,J = 8.2, 2.1 Hz, 1H), 6.56 (dd,J = 16.9, 10.2 Hz, 1H), 6.26 (dd,J = 17.0, 2.0 Hz, 1H), 5.76 (dd,J = 10.1, 2.0 Hz, 2H), 3.43 (dt,J = 21.9, 6.5 Hz, 4H), 3.33 (s, 3H), 2.18 (s, 3H), 1.84 (dq,J = 18.5, 7.1 Hz, 4H). | 481.45 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氟苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.22 (s, 1H), 8.08 (t,J = 8.3 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.32 - 7.23 (m, 3H), 7.14 (dd,J = 8.3, 1.9 Hz, 1H), 6.64 (dd,J = 17.0, 10.2 Hz, 1H), 6.29 (dd,J = 17.0, 2.0 Hz, 1H), 5.79 (dd,J = 10.1, 2.0 Hz, 1H), 3.62 (s, 3H), 3.44 (dt,J = 19.1, 6.5 Hz, 4H), 1.85 (dp,J = 18.1, 6.7 Hz, 4H). | 485.1 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,6-二氟苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 8.23 (s, 1H), 7.53 (d,J = 7.9 Hz, 2H), 7.31 (d,J = 7.8 Hz, 2H), 7.18 (d,J = 8.4 Hz, 2H), 6.55 - 6.40 (m, 1H), 6.27 (dd,J = 17.2, 1.9 Hz, 1H), 5.82 (dd,J = 10.2, 1.9 Hz, 2H), 3.69 (s, 3H), 3.48 (q,J = 9.0, 6.9 Hz, 2H), 3.41 (t,J = 6.5 Hz, 2H), 1.90 - 1.79 (m, 4H). | 503.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.21 (s, 1H), 7.58 (d,J = 8.3 Hz, 2H), 7.49 - 7.42 (m, 2H), 7.27 (d,J = 8.1 Hz, 1H), 7.24 - 7.18 (m, 2H), 6.44 (dd,J = 17.0, 10.1 Hz, 1H), 6.27 (dd,J = 17.0, 2.1 Hz, 1H), 5.77 (dd,J = 10.0, 2.1 Hz, 1H), 3.41 (d,J = 6.3 Hz, 7H), 1.91 (s, 3H), 1.83 (dt,J = 18.0, 6.5 Hz, 4H). | 481.2 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 8.22 (s, 1H), 7.79 (dd,J = 12.2, 2.0 Hz, 1H), 7.49 (d,J = 7.8 Hz, 2H), 7.37 (dd,J = 8.5, 2.0 Hz, 1H), 7.32 - 7.24 (m, 2H), 7.24 (s, 1H), 6.43 (dd,J = 17.0, 10.0 Hz, 1H), 6.30 (dd,J = 17.0, 2.0 Hz, 1H), 6.03 (s, 2H), 5.82 (dd,J = 10.1, 2.1 Hz, 1H), 3.55 (s, 3H), 3.43 (dt,J = 18.4, 6.6 Hz, 4H), 1.83 (dq,J = 12.9, 6.8 Hz, 4H). | 485.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.61 (s, 1H), 8.22 (s, 1H), 7.59 (t,J = 8.2 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.32 - 7.24 (m, 3H), 7.13 (dd,J = 8.3, 1.9 Hz, 1H), 5.88 (s, 1H), 5.56 (s, 1H), 3.65 (s, 3H), 3.44 (dt,J = 16.9, 6.5 Hz, 4H), 1.95 (s, 3H), 1.84 (dq,J = 18.5, 7.0 Hz, 4H). | 499.2 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,6-二氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.66 (s, 1H), 8.23 (s, 1H), 7.53 (d,J = 8.0 Hz, 2H), 7.31 (d,J = 7.9 Hz, 2H), 7.23 - 7.13 (m, 2H), 5.91 (s, 1H), 5.60 (s, 1H), 3.44 (dt,J = 19.8, 6.5 Hz, 4H), 3.33 (s, 2H), 1.94 (s, 3H), 1.84 (dq,J = 18.4, 6.7 Hz, 3H). | 517.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環戊基-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.73 - 7.67 (m, 2H), 7.32 (d,J = 7.8 Hz, 2H), 7.26 (dd,J = 8.4, 2.4 Hz, 4H), 6.33 - 5.71 (s, 3H), 5.53 (d,J = 1.8 Hz, 1H), 4.99 - 3.92 (s, 1H), 3.65 (s, 3H), 2.82 (s, 3H), 1.95 (d,J = 1.6 Hz, 3H), 1.90 - 1.58 (s, 6H), 1.57 - 1.33 (s, 2H). | 509.4 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環戊基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.29 - 8.19 (m, 2H), 7.81 (d,J = 8.2 Hz, 2H), 7.79 - 7.66 (m, 2H), 7.27 (t,J = 8.4 Hz, 4H), 6.31 - 5.45(s, 4H), 4.22 (q,J = 6.9 Hz, 1H), 3.65 (s, 3H), 1.95 (t,J = 1.2 Hz,3H), 1.87 (s, 2H), 1.69 (s, 2H), 1.53 (q,J = 11.7, 8.4 Hz, 4H). | 495.35 | |
N-(4-(5-(4-(2-氮雜雙環[2.2.2]辛烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.71 - 7.64 (m, 2H), 7.44 - 7.35 (m, 4H), 7.28 (dd,J = 9.4, 2.7 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.70 (s, 4H), 3.58 (d,J = 2.5 Hz, 2H), 2.08 - 2.02 (m, 4H), 1.92 (s, 2H), 1.81 - 1.68 (m, 6H). | 521.40 | |
N-(4-(4-胺基-5-(4-(氮雜環庚烷-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.73 - 7.67 (m, 2H), 7.32 (d,J = 8.1 Hz, 2H), 7.25 (dd,J = 8.3, 1.6 Hz, 4H), 5.93 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 3.55 (t,J = 5.7 Hz, 2H), 1.95 (d,J = 1.5 Hz, 3H), 1.70 (s, 2H), 1.55 (s, 6H). | 509.4 | |
N-(4-(5-(4-(2-氮雜螺[3.3]庚烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.74 - 7.68 (m, 2H), 7.62 - 7.56 (m, 2H), 7.31 - 7.23 (m, 4H), 5.80 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 4.29 (s, 2H), 4.00 (s, 2H), 3.61 (s, 3H), 2.15 (t,J = 7.6 Hz, 4H), 1.95 (s, 3H), 1.86 (s, 1H), 1.76 (td,J = 7.8, 3.7 Hz, 2H). | 507.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(2-側氧基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.21 (s, 1H), 7.72 (d,J = 8.6 Hz, 2H), 7.54 (d,J = 8.2 Hz, 2H), 7.27 (dd,J = 8.2, 5.8 Hz, 4H), 5.80 (s, 1H), 5.70 (s, 2H), 5.53 (s, 1H), 3.67 (t,J = 5.7 Hz, 2H), 3.61 (s, 3H), 2.50(s,2H)1.95 (s, 3H), 1.87 (tt,J = 11.7, 6.3 Hz, 4H). | 509.25 | |
N-(4-(5-(4-(3-氮雜雙環[4.1.0]庚烷-3-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.71 (d,J = 8.5 Hz, 2H), 7.32 (d,J = 7.9 Hz, 2H), 7.26 (d,J = 8.3 Hz, 4H), 5.95 (s, 2H), 5.80 (s, 1H), 5.53 (d,J = 1.7 Hz, 1H), 3.68 (d,J = 12.5 Hz, 2H), 3.61 (s, 4H), 3.08 (s, 1H), 1.95 (s, 4H), 1.70 - 1.64 (m, 1H), 1.06 (s, 2H), 0.64 (s, 1H), 0.21 (s, 1H). | 507.40 | |
N-(4-(5-(4-(2-氮雜雙環[4.1.0]庚烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.73 - 7.66 (m, 2H), 7.52 (d,J = 7.9 Hz, 1H), 7.34 (d,J = 7.9 Hz, 1H), 7.26 (dd,J = 8.2, 4.2 Hz, 4H), 6.25 - 5.70 (s, 3H), 5.53 (t,J = 1.5 Hz, 1H), 4.05 (d,J = 12.6 Hz, 1H), 3.65 (d,J = 7.1 Hz, 3H), 3.02 (t,J = 12.6 Hz, 1H),2.52 (t,J = 12.6 Hz, 1H), 1.95 (s, 3H), 1.85 (s, 2H), 1.83 - 1.55 (m, 1H), 1.35 (d,J = 13.8 Hz, 2H), 0.37 (s, 1H). | 507.4 | |
N-(4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)環戊烷甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (d,J = 11.0 Hz, 2H), 8.18 (s, 1H), 7.72 - 7.65 (m, 2H), 7.62 - 7.55 (m, 2H), 7.29 - 7.22 (m, 2H), 7.18 - 7.11 (m, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 2.76 (p,J = 7.8 Hz, 1H), 1.95 (d,J = 1.5 Hz, 3H), 1.85 (ddd,J = 14.1, 8.3, 4.3 Hz, 2H), 1.77 - 1.62 (m, 4H), 1.61 - 1.51 (m, 2H). | 495.20 | |
N-(4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-N-甲基環戊烷甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.80 - 7.62 (m, 2H), 7.36 - 7.19 (m, 6H), 5.78 (s, 1H), 5.53 (s, 1H), 3.63 (s, 3H), 3.17 (d,J = 2.9 Hz, 3H), 1.94 (t,J = 1.2 Hz, 3H), 1.65 - 1.30 (s, 9H). | 509.30 | |
N-(4-(5-(4-(3-氮雜雙環[3.1.0]己烷-3-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.75 (d,J = 8.4 Hz, 2H), 7.45 (d,J = 7.9 Hz, 2H), 7.26 (dd,J = 8.2, 4.4 Hz, 4H), 6.25 - 5.75 (s, 2H), 5.53 (s, 1H), 3.95 (d,J = 11.9 Hz, 1H), 3.66 (d,J = 10.7 Hz, 1H), 3.58 (s, 3H), 3.38 (d,J = 10.8 Hz, 2H), 1.95 (s, 3H), 1.69 - 1.51 (m, 2H), 0.65 (q,J = 4.3 Hz, 1H) , 0.08 (q,J = 4.3 Hz, 1H). | 493.35 | |
N-(4-(5-(4-(5-氮雜螺[2.4]庚烷-5-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.70 (dd,J = 8.8, 3.4 Hz, 2H), 7.50 (dd,J = 12.8, 7.8 Hz, 2H), 7.26 (dt,J = 8.2, 4.5 Hz, 4H), 6.04 (s, 1H), 5.92- 5.80 (s, 1H), 5.53 (s, 1H), 3.66 - 3.55 (m, 5H), 3.37 (d,J = 8.4 Hz, 2H), 1.95 (s, 3H), 1.81 (t,J = 7.1 Hz, 1H), 1.76 (t,J = 6.7 Hz, 1H), 0.54 (d,J = 3.4 Hz, 4H). | 507.45 | |
N-(4-(5-(4-(2-氮雜雙環[3.1.0]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.70 (d,J = 8.4 Hz, 2H), 7.59 (d,J = 7.7 Hz, 2H), 7.44 (s, 1H), 7.28 (t,J = 8.9 Hz, 3H), 5.95 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.96 (d,J = 12.2 Hz, 1H), 3.61 (s, 3H), 3.31-3.21 (s, 1H), 3.13 (d,J = 12.0 Hz, 1H), 2.06 (s, 1H), 1.95 (s, 4H), 1.60 (s, 1H), 0.77 (t,J = 6.5 Hz, 2H). | 493.40 | |
N-(4-(5-(4-((1R,4R)-2-氧雜-5-氮雜雙環[2.2.2]辛烷-5-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (d,J = 2.7 Hz, 1H), 7.75 (d,J = 8.3 Hz, 2H), 7.59 - 7.25 (d,J = 7.8 Hz, 2H), 7.23 (dd,J = 8.3, 4.7 Hz, 4H), 6.25 - 5.72 (s, 3H), 5.53 (s, 1H), 4.06 (d,J = 17.0 Hz, 2H), 3.95 - 3.72 (dd,J = 18.0, 9.0 Hz, 3H), 3.65 (m, 3H), 3.51 (d,J = 3.7 Hz, 1H), 2.05 (d,J = 10.8 Hz, 2H), 1.95 (s, 3H), 1.85 - 1.64 (m, 2H). | 523.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(3-甲基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.36 - 7.22 (m, 6H), 5.79 (s, 1H), 5.53 (s, 1H), 4.28 (s, 1H), 3.62 (s, 4H), 2.96 (s, 1H), 1.95 (s, 3H), 1.78 (d,J = 12.6 Hz, 1H), 1.57 (s, 2H), 1.42 (d,J = 13.0 Hz, 1H), 1.17 (t,J = 11.1 Hz, 1H), 0.77 (s, 3H). | 509.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(4-甲基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.33 (d,J = 8.1 Hz, 2H), 7.26 (d,J = 8.3 Hz, 4H), 5.95 (s, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 4.42 (s, 1H), 3.61 (s, 4H), 2.99 (s, 1H), 2.72 (s, 1H), 1.95 (s, 3H), 1.62 (s, 3H), 1.14 - 1.07 (m, 1H), 1.05 (s, 1H), 0.92 (d,J = 6.2 Hz, 3H). | 509.3 | |
N-(4-(4-胺基-7-甲基-5-(4-(2-甲基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.4 Hz, 2H), 7.31 (d,J = 8.0 Hz, 2H), 7.26 (d,J = 9.0 Hz, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 4.45 (s, 1H), 3.61 (s, 3H), 3.30 (s, 1H), 2.98 (s, 1H), 1.95 (s, 3H), 1.62 (dd,J = 19.7, 7.5 Hz, 5H), 1.36 (d,J = 12.8 Hz, 1H), 1.18 (d,J = 6.9 Hz, 3H). | 509.4 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環丁基-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.32 - 7.23 (m, 6H), 5.97 (s, 0H), 5.79 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 4.32 (s, 1H), 3.62 (s, 3H), 2.93 (s, 3H), 2.22 (dq,J = 12.2, 9.4 Hz, 2H), 1.95 (s, 5H), 1.60 (s, 1H). | 495.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環丁基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.59 (d,J = 7.6 Hz, 1H), 8.21 (s, 1H), 7.79 (d,J = 8.2 Hz, 2H), 7.73 - 7.67 (m, 2H), 7.32 - 7.23 (m, 4H), 5.92 (s, 2H), 5.79 (s, 1H), 5.54 (s, 1H), 4.40 (q,J = 8.2 Hz, 1H), 3.61 (s, 3H), 2.20 (d,J = 8.7 Hz, 3H), 2.12 - 1.98 (m, 2H), 1.95 (d,J = 1.4 Hz, 3H), 1.65 (td,J = 10.7, 9.4, 6.1 Hz, 2H). | 481.35 | |
N-(4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)環丁烷甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 9.76 (s, 1H), 8.18 (s, 1H), 7.69 (d,J = 8.3 Hz, 2H), 7.59 (d,J = 8.1 Hz, 2H), 7.25 (d,J = 8.2 Hz, 2H), 7.15 (d,J = 8.1 Hz, 2H), 5.79 (s, 1H), 5.58 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 3.26 - 3.17 (m, 1H), 2.22 (t,J = 9.5 Hz, 2H), 2.10 (d,J = 9.3 Hz, 2H), 1.95 (s, 4H), 1.80 (d,J = 10.6 Hz, 1H). | 481.20 | |
N-(4-(5-(4-(5-氮雜螺[2.5]辛烷-5-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.2 Hz, 2H), 7.26 (s, 6H), 5.79 (s, 2H), 5.53 (s, 1H), 3.62 (s, 3H), 3.39 (s, 2H), 3.30 (s, 1H), 3.09 (s, 1H), 1.95 (s, 3H), 1.60 (s, 2H), 1.46 (s, 2H), 0.46 (s, 1H), 0.29 (s, 2H), 0.11 (s, 1H). | 521.40 | |
N-(4-(5-(4-(6-氮雜螺[2.5]辛烷-6-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.3 Hz, 2H), 7.41 (d,J = 7.8 Hz, 2H), 7.26 (dd,J = 8.4, 2.6 Hz, 4H), 6.25 - 5.75 (s, 2H), 5.53 (s, 1H), 3.85 - 3.35 (s, 7H), 1.95 (s, 3H), 1.35 (s, 4H), 0.35 (s, 4H). | 521.4 | |
N-(4-(4-胺基-7-甲基-5-(1-側氧基異吲哚啉-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.51 (s, 1H), 8.21 (s, 1H), 7.73 - 7.66 (m, 2H), 7.59 (d,J = 7.7 Hz, 1H), 7.43 (s, 1H), 7.35 - 7.23 (m, 3H), 5.91 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 4.33 (s, 2H), 3.62 (s, 3H), 1.95 (s, 3H). | 439.25 | |
N-(4-(4-胺基-5-(4-(環戊基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.17 (s, 1H), 7.73 - 7.66 (m, 2H), 7.30 - 7.23 (m, 2H), 7.18 - 7.09 (m, 2H), 6.92 - 6.83 (m, 2H), 5.80 (s, 1H), 5.53 (d,J = 1.9 Hz, 1H), 4.79 (td,J = 6.0, 3.0 Hz, 1H), 3.60 (s, 3H), 1.97 - 1.86 (m, 5H), 1.75 - 1.65 (m, 4H), 1.58 (q,J = 6.0, 3.6 Hz, 2H). | 468.30 | |
N-(4-(4-胺基-5-(4-(環戊基甲氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.17 (s, 1H), 7.72 - 7.66 (m, 2H), 7.29 - 7.23 (m, 2H), 7.17 - 7.10 (m, 2H), 6.94 - 6.87 (m, 2H), 5.79 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.83 (d,J = 6.9 Hz, 2H), 3.60 (s, 3H), 2.28 (dq,J = 14.7, 7.4 Hz, 1H), 2.08 (s, 1H), 1.95 (t,J = 1.2 Hz, 3H), 1.76 (ddd,J = 11.9, 9.2, 4.7 Hz, 2H), 1.65 - 1.47 (m, 4H), 1.39 - 1.26 (m, 2H). | 482.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(十氫-1H-異吲哚-2-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.37 (s, 1H), 7.72 (d,J = 8.6 Hz, 2H), 7.52 (d,J = 8.0 Hz, 2H), 7.27 (d,J = 8.0 Hz, 4H), 6.74 (s, 3H), 5.80 (s, 1H), 5.54 (s, 1H), 3.66 (s, 3H), 3.51 - 3.41 (m, 2H), 3.39 - 3.26 (m, 1H), 3.31 (s, 1H), 2.25 (d,J = 6.9 Hz, 1H), 2.16 (s, 1H), 1.95 (s, 3H), 1.49 (d,J = 9.3 Hz, 5H), 1.33 - 1.26 (m, 3H). | 535.50 | |
N-(4-(4-胺基-5-(4-(4-氟哌啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.29 (s, 1H), 7.75 - 7.68 (m, 2H), 7.41 - 7.34 (m, 2H), 7.27 (dd,J = 8.4, 2.4 Hz, 4H), 5.80 (s, 1H), 5.54 (s, 1H), 4.97 (s, 1H), 4.85 (s, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 1.95 (s, 3H), 1.73 (s, 3H). | 513.40 | |
N-(4-(4-胺基-5-(4-(4-甲氧基哌啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.74 - 7.67 (m, 2H), 7.35 (d,J = 7.8 Hz, 2H), 7.26 (d,J = 8.1 Hz, 4H), 5.96 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.89 (s, 1H), 3.61 (s, 3H), 1.95 (s, 3H), 1.84 (s, 2H), 1.44 (s, 2H). | 525.45 | |
N-(4-(4-胺基-5-(4-(3,3-二氟氮雜環丁烷-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.75 - 7.63 (m, 4H), 7.34 - 7.23 (m, 4H), 5.96 (s, 1H), 5.80 (t,J = 1.0 Hz, 1H), 5.54 (t,J = 1.4 Hz, 1H), 4.78 (s, 2H), 4.52 (s, 2H), 3.61 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 503.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 9.09 (t,J = 6.3 Hz, 1H), 8.36 (s, 1H), 7.87 (d,J = 8.2 Hz, 2H), 7.76 - 7.68 (m, 2H), 7.33 (d,J = 8.2 Hz, 2H), 7.30 - 7.24 (m, 2H), 6.69 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 4.08 (td,J = 9.9, 6.3 Hz, 2H), 3.65 (s, 3H), 1.95 (s, 3H). | 509.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-羥乙基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.70 (d,J = 8.4 Hz, 2H), 7.38 (d,J = 7.9 Hz, 2H), 7.30 - 7.23 (m, 4H), 5.94 (s, 0H), 5.80 (s, 1H), 5.53 (s, 1H), 4.77 (s, 1H), 3.62 (s, 4H), 3.50 (s, 2H), 3.32 (s, 1H), 2.98 (s, 3H), 1.95 (s, 3H), 1.25 (s, 1H). | 485.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基乙基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.73 - 7.67 (m, 2H), 7.35 (d,J = 8.1 Hz, 2H), 7.26 (d,J = 8.2 Hz, 4H), 5.80 (s, 2H), 5.53 (s, 1H), 3.62 (s, 3H), 3.41 (s, 2H), 3.29 (s, 1H), 3.11 (s, 2H), 2.97 (s, 3H), 1.95 (d,J = 1.5 Hz, 3H). | 499.40 | |
(R)-N-(4-(4-胺基-5-(4-(3-甲氧基吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.67 (d,J = 8.4 Hz, 2H), 7.52 (dd,J = 8.2, 2.1 Hz, 2H), 7.38 (d,J = 8.0 Hz, 2H), 7.31 - 7.24 (m, 2H), 5.85 (s, 1H), 5.54 (d,J = 2.1 Hz, 1H),4.20 - 4.00 (dq,J = 4.2, 2.3 Hz, 1H), 3.75 (s, 4H), 3.55 (s, 3H), 3.35 (dd,J = 7.7, 4.6 Hz, 2H), 3.25(m, 2H), 2.31 - 1.89 (m, 5H). | 511.4 | |
(S)-N-(4-(4-胺基-5-(4-(3-甲氧基吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.74 - 7.66 (m, 2H), 7.48 (dd,J = 7.9, 5.6 Hz, 2H), 7.26 (dd,J = 8.2, 1.7 Hz, 4H), 5.93 (s, 1H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.97 (d,J = 32.6 Hz, 1H), 3.61 (s, 3H), 3.51 (d,J = 11.3 Hz, 3H), 3.26 (s, 2H), 3.17 (s, 2H), 2.01 - 1.92 (m, 5H). | 511.45 | |
N-(4-(5-(4-(2-氮雜雙環[2.2.1]庚烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (d,J = 1.7 Hz, 1H), 7.68 (dd,J = 8.7, 2.4 Hz, 2H), 7.50 (dd,J = 8.3, 2.8 Hz, 2H), 7.39 (dd,J = 11.2, 8.1 Hz, 2H), 7.29 (dq,J = 8.6, 2.1 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.18 (s, 1H), 3.71 (d,J = 1.8 Hz, 3H), 3.55 (d,J = 11.3 Hz, 1H), 3.19 (dd,J = 11.3, 1.7 Hz, 1H), 2.70 (s, 1H), 2.08 - 2.02 (m, 3H), 1.80 (q,J = 12.8, 10.8 Hz, 3H), 1.70 (d,J = 10.3 Hz, 1H), 1.59 (s, 1H), 1.52 (d,J = 9.7 Hz, 1H). | 507.40 | |
N-(4-(5-(4-(3-氮雜-雙環[3.2.1]辛烷-3-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.74 - 7.67 (m, 2H), 7.28 (q,J = 8.1 Hz, 6H), 5.94 (s, 2H), 5.80 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 4.29 (s, 1H), 3.38 (s, 1H), 3.32 (s, 2H), 3.17 (s, 1H), 2.79 (s, 1H), 2.28 - 2.19 (m, 2H), 2.12 (s, 1H), 1.95 (d,J = 1.4 Hz, 3H), 1.60 (d,J = 10.5 Hz, 3H), 1.49 (s, 3H), 1.39 (s, 1H). | 521.40 | |
(R)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1-環丙基-2-羥乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 8.14 (d,J = 8.4 Hz, 1H), 7.82 (d,J = 8.1 Hz, 2H), 7.70 (d,J = 8.5 Hz, 2H), 7.32 - 7.23 (m, 4H), 5.79 (s, 2H), 5.53 (s, 1H), 4.63 (t,J = 5.7 Hz, 1H), 3.62 (s, 3H), 3.58 - 3.39 (m, 3H), 1.95 (s, 3H), 0.98 (d,J = 8.1 Hz, 1H), 0.48 - 0.42 (m, 1H), 0.38 - 0.13 (m, 3H). | 511.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(嘧啶-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.73 (d,J = 4.8 Hz, 2H), 8.22 (s, 1H), 7.96 - 7.89 (m, 2H), 7.77 - 7.69 (m, 2H), 7.38 - 7.30 (m, 2H), 7.33 - 7.22 (m, 3H), 5.98 (s, 1H), 5.80 (t,J = 1.0 Hz, 1H), 5.53 (t,J = 1.4 Hz, 1H), 3.62 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 505.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-(嘧啶-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.52 (d,J = 4.8 Hz, 2H), 8.19 (s, 1H), 7.75 - 7.68 (m, 2H), 7.25 - 7.08 (m, 7H), 5.82 (d,J = 1.3 Hz, 2H), 5.56 (t,J = 1.4 Hz, 1H), 3.61 (s, 3H), 3.54 (s, 3H), 1.97 (d,J = 1.3 Hz, 3H), 1.24 (s, 1H). | 519.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.40 (s, 1H), 7.73 (d,J = 8.4 Hz, 2H), 7.35 (s, 2H), 7.30 - 7.23 (m, 4H), 5.80 (s, 1H), 5.54 (s, 1H), 3.99 - 3.89 (m, 1H), 3.78 (dd,J = 9.6, 3.9 Hz, 1H), 3.67 (s, 3H), 3.42 (s, 1H), 2.87 (s, 3H), 2.11 (s, 1H), 1.95 (s, 3H). | 511.40 | |
N-(4-(5-(4-(2-氮雜雙環[2.1.1]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.75 - 7.67 (m, 2H), 7.64 (d,J = 7.8 Hz, 1H), 7.40 (d,J = 7.7 Hz, 1H), 7.27 (d,J = 8.0 Hz, 4H), 5.95 (s, 1H), 5.80 (t,J = 1.0 Hz, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.69 - 4.33 (d,J = 6.8 Hz, 1H), 3.61 (s, 3H), 3.45 (d,J = 9.0 Hz, 2H), 2.93 - 2.84 (m, 1H), 1.95 (d,J = 1.2 Hz, 4H), 1.47 (s, 1H), 1.33 (s, 1H). | 493.25 | |
N-(4-(5-(4-(2-氮雜螺[3.4]辛烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.66 (dd,J = 10.2, 8.2 Hz, 4H), 7.42 (d,J = 7.9 Hz, 2H), 7.28 (d,J = 8.3 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.22 (s, 2H), 4.02 (s, 2H), 3.70 (s, 3H), 2.05 (d,J = 4.9 Hz, 3H), 1.87 (d,J = 6.6 Hz, 4H), 1.68 - 1.64 (m, 4H). | 521.4 | |
N-(4-(4-胺基-5-(4-(六氫-1H-呋喃并[3,4-c]吡咯-5-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.69 (m, 2H), 7.55 (m, 2H), 7.39 (d,J = 8.1 Hz, 2H), 7.25 (m, 2H), 5.81 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 4.05 - 3.72 (s, 4H), 3.70 (s, 5H), 3.55 (s, 1H), 3.42 (d,J = 11.6 Hz, 1H), 3.03 (s, 2H), 2.04 (d,J = 1.6 Hz, 3H). | 523.4 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((1-甲基-1H-吡唑-4-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.5 Hz, 2H), 7.58 (s, 1H), 7.37 (d,J = 8.0 Hz, 2H), 7.26 (dd,J = 8.1, 3.7 Hz, 4H), 5.80 (s, 2H), 5.56 - 5.51 (m, 1H), 4.44 (s, 1H), 4.28 (s, 1H), 3.80 (s, 3H), 3.61 (s, 3H), 2.87 (s, 3H), 1.95 (s, 3H). | 535.45 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1,2,4-噁二唑-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.52 (s, 1H), 9.91 (s, 1H), 9.01 (s, 1H), 8.23 (s, 1H), 8.07 - 8.00 (m, 2H), 7.76 - 7.68 (m, 2H), 7.47 - 7.40 (m, 2H), 7.32 - 7.25 (m, 2H), 6.04 (s, 2H), 5.80 (s, 1H), 5.54 (d,J = 1.7 Hz, 1H), 3.62 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 495.2 | |
N-((1,2,4-噁二唑-3-基)甲基)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 9.62 (s, 1H), 8.20 (d,J = 2.6 Hz, 1H), 7.73 - 7.67 (m, 2H), 7.44 - 7.37 (m, 2H), 7.26 (d,J = 8.5 Hz, 4H), 5.97 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 4.85 (s, 1H), 4.73 (s, 1H), 3.32 (s, 3H), 3.05 (s, 1H), 2.98 (s, 1H), 1.95 (t,J = 1.3 Hz, 3H). | 523.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.3 Hz, 2H), 7.42 (s, 2H), 7.26 (d,J = 8.4 Hz, 3H), 5.80 (s, 1H), 5.53 (s, 1H), 4.91 (s, 2H), 3.61 (s, 3H), 3.29 (s, 1H), 3.11 (s, 3H), 2.35 (s, 3H), 1.95 (s, 3H). | 537.45 | |
N-(4-(5-(4-(2-氧雜-6-氮雜螺[3.4]辛烷-6-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.71 (dd,J = 8.7, 3.5 Hz, 2H), 7.49 (t,J = 7.0 Hz, 2H), 7.27 (t,J = 7.5 Hz, 4H), 5.96 (s, 1H), 5.80 (t,J = 1.0 Hz, 1H), 5.56 - 5.51 (m, 1H), 4.62 (d,J = 6.0 Hz, 1H), 4.47 (q,J = 7.7, 6.8 Hz, 3H), 3.70 (s, 2H), 3.61 (s, 3H), 3.46 (q,J = 7.3 Hz, 2H), 2.14 (dt,J = 12.1, 7.0 Hz, 2H), 1.95 (t,J = 1.2 Hz, 3H). | 523.25 | |
N-{4-[4-胺基-5-(4-{6-氮雜螺[3.4]辛烷-6-羰基}苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.38 (s, 1H), 7.73 (dd,J = 8.7, 2.7 Hz, 2H), 7.50 (d,J = 8.1 Hz, 2H), 7.31 - 7.23 (m, 4H), 6.80 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.43 (dd,J = 11.9, 5.6 Hz, 5H), 2.03 (s, 1H), 1.95 (s, 3H), 1.89 (dd,J = 18.8, 5.4 Hz, 8H). | 521.45 | |
N-(4-(5-(4-(3-氮雜雙環[3.2.0]庚烷-3-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.52 - 7.45 (m, 2H), 7.31 - 7.23 (m, 4H), 5.80 (s, 2H), 5.53 (t,J = 1.4 Hz, 1H), 3.96 (s, 1H), 3.61 (s, 3H), 3.32 (s, 5H), 2.91 (s, 2H), 2.14 (s, 2H), 1.95 (d,J = 1.2 Hz, 3H), 1.60 (s, 2H). | 507.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((四氫呋喃-2-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.33 (s, 2H), 7.26 (dd,J = 8.5, 2.9 Hz, 4H), 5.79 (s, 1H), 5.56 - 5.50 (m, 1H), 4.09 (s, 1H), 4.03 (s, 1H), 3.79 (s, 1H), 3.62 (s, 3H), 2.99 (s, 3H), 1.95 (d,J = 1.5 Hz, 3H), 1.54 (s, 1H). | 525.45 | |
N-{4-[4-胺基-7-甲基-5-(4-{1-氧雜-6-氮雜螺[3.3]庚烷-6-羰基}苯基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.71 (d,J = 8.5 Hz, 2H), 7.60 (d,J = 8.2 Hz, 2H), 7.31 - 7.23 (m, 4H), 5.91 (s, 3H), 5.80 (s, 1H), 5.54 (s, 1H), 4.53 (s, 1H), 4.40 (t,J = 7.5 Hz, 2H), 4.31 (s, 1H), 4.12 (s, 1H), 3.61 (s, 3H), 2.83 (t,J = 7.4 Hz, 2H), 1.95 (s, 3H). | 509.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(3-(四氫呋喃-3-基)氮雜環丁烷-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.61 (d,J = 7.9 Hz, 2H), 7.27 (t,J = 8.6 Hz, 4H), 5.93 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 4.39 (d,J = 8.1 Hz, 1H), 4.20 - 3.90 (m, 2H), 3.73 (d,J = 7.4 Hz, 3H), 3.61 (s, 4H), 3.30 (s, 2H), 2.59 (s, 1H), 1.95 (s, 4H), 1.45 (s, 1H). | 537.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3,3-二氟環丁基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.37 (d,J = 7.7 Hz, 2H), 7.31 - 7.23 (m, 4H), 6.05 (s, 2H), 5.80 (s, 1H), 5.53 (d,J = 1.9 Hz, 1H), 4.45 (s, 1H), 3.62 (s, 3H), 3.01 - 2.69 (m, 7H), 1.95 (d,J = 1.5 Hz, 3H). | 531.40 | |
4-(6-(4-乙醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基環己烷-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 8.07 (s, 1H), 7.89 (d,J = 4.4 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.39 - 7.32 (m, 2H), 6.93 (s, 2H), 6.49 (dd,J = 17.0, 10.1 Hz, 1H), 6.31 (dd,J = 17.0, 2.0 Hz, 1H), 5.80 (dd,J = 10.0, 2.0 Hz, 1H), 3.43 (s, 3H), 2.60 (d,J = 4.6 Hz, 4H), 2.45 (s, 1H), 2.21 - 2.10 (m, 2H), 1.83 (d,J = 12.9 Hz, 2H), 1.52 - 1.39 (m, 4H). | 433.35 | |
4-(6-(4-乙醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環戊基環己-3-烯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 8.10 (s, 1H), 7.78 (dd,J = 8.2, 6.6 Hz, 3H), 7.48 - 7.40 (m, 2H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.30 (dd,J = 17.0, 2.1 Hz, 1H), 5.83 - 5.75 (m, 2H), 3.99 (p,J = 6.8 Hz, 1H), 3.57 (s, 3H), 2.45 (t,J = 6.0 Hz, 1H), 2.28 (s, 1H), 2.19 (d,J = 17.9 Hz, 1H), 1.90 - 1.84 (m, 2H), 1.82 - 1.69 (m, 2H), 1.62 (s, 4H), 1.47 (q,J = 7.0 Hz, 2H), 1.35 (s, 1H), 1.32 (s, 1H). | 485.2 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.10 (s, 1H), 7.82 - 7.75 (m, 2H), 7.49 - 7.42 (m, 2H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.30 (dd,J = 17.0, 2.1 Hz, 1H), 5.83 - 5.73 (m, 2H), 3.58 (s, 3H), 3.51 (dt,J = 10.0, 6.6 Hz, 1H), 3.43 (dt,J = 10.0, 6.7 Hz, 1H), 3.32 - 3.20 (m, 2H), 2.82 (q,J = 6.0 Hz, 1H), 2.27 (d,J = 12.9 Hz, 2H), 1.89 (s, 4H), 1.76 (p,J = 6.7 Hz, 2H), 1.63 (d,J = 6.1 Hz, 2H). | 471.2 | |
4-(6-(4-乙醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N,N-二甲基環己-3-烯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.30 (s, 1H), 8.10 (s, 1H), 7.82 - 7.75 (m, 2H), 7.49 - 7.41 (m, 2H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.29 (dd,J = 17.0, 2.1 Hz, 1H), 5.83 - 5.73 (m, 2H), 3.58 (s, 3H), 3.02 (s, 3H), 3.08 - 2.97 (m, 1H), 2.82 (s, 3H), 2.27 (d,J = 12.9 Hz, 2H), 1.90 (s, 1H), 1.83 (d,J = 17.4 Hz, 1H), 1.61 (d,J = 6.0 Hz, 2H). | 445.2 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-5,6-二氫吡啶-1(2H)-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.13 (s, 1H), 7.84 - 7.78 (m, 2H), 7.44 - 7.38 (m, 2H), 6.34 (d,J = 4.5 Hz, 1H), 6.25 (s, 2H), 5.83 (s, 1H), 5.78 (s, 1H), 5.55 (d,J = 1.8 Hz, 1H), 3.91 (d,J = 3.3 Hz, 2H), 3.56 (s, 3H), 2.57 (d,J = 4.3 Hz, 3H), 1.97 (d,J = 1.4 Hz, 3H), 1.95 (s, 2H). | 446.35 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-基磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.21 (s, 1H), 9.85 (s, 1H), 8.14 (s, 1H), 7.88 - 7.81 (m, 2H), 7.62 - 7.52 (m, 4H), 7.16 (d,J = 8.8 Hz, 2H), 5.86 (s, 2H), 5.78 (s, 1H), 5.52 (s, 1H), 3.24 - 3.12 (m, 2H), 1.94 (d,J = 1.2 Hz, 3H), 1.71 - 1.63 (m, 3H), 1.57 (s, 1H), 1.32 (q,J = 7.2 Hz, 1H), 0.94 (t,J = 7.2 Hz, 1H). | 503.15 | |
N-(4-(4-胺基-5-(3-氟-4-((5-氟嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 12.14 (s, 1H), 9.85 (s, 1H), 8.81 (s, 2H), 8.14 (s, 1H), 7.68 - 7.61 (m, 2H), 7.48 (t, J = 8.4 Hz, 1H), 7.38 - 7.27 (m, 3H), 7.24 (dd, J = 8.3, 2.0 Hz, 1H), 5.80 (s, 1H), 5.75 (s, 1H), 5.53 (d, J = 1.6 Hz, 1H), 1.95 (s, 3H). | 500.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.18 (s, 1H), 7.72 - 7.62 (m, 3H), 7.32 - 7.25 (m, 2H), 7.25 - 7.16 (m, 2H), 7.07 - 6.98 (m, 2H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.88 (d, J = 2.3 Hz, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H), 3.75 (s, 3H), 3.60 (s, 3H). | 466.30 | |
N-(4-(5-(4-((1H-吡唑-1-基)甲基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.19 (s, 1H), 7.84 (d,J = 2.2 Hz, 1H), 7.72 - 7.64 (m, 2H), 7.48 (d,J = 1.8 Hz, 1H), 7.31 - 7.20 (m, 4H), 7.14 (d,J = 8.0 Hz, 2H), 6.28 (t,J = 2.0 Hz, 1H), 5.80 (s, 2H), 5.53 (t,J = 1.6 Hz, 1H), 5.35 (s, 2H), 3.59 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 464.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((3-甲基-1H-吡唑-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.19 (s, 1H), 7.69 (dd, J = 5.4, 3.1 Hz, 3H), 7.30 - 7.18 (m, 4H), 7.14 (d, J = 8.2 Hz, 2H), 6.04 (d, J = 2.2 Hz, 1H), 5.91 (s, 2H), 5.80 (s, 1H), 5.53 (t, J = 1.5 Hz, 1H), 5.24 (s, 2H), 3.59 (s, 3H), 2.15 (s, 3H), 1.95 (t, J = 1.3 Hz, 3H). | 478.35 | |
N-(4-(4-胺基-5-(4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.13 (s, 1H), 8.12 (d, J = 13.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.59 - 7.52 (m, 2H), 7.46 - 7.39 (m, 2H), 7.23 - 7.14 (m, 3H), 6.57 - 6.37 (m, 1H), 6.31-6.11 (m, 1H), 5.96 (s, 2H), 5.81 - 5.69 (m, 1H), 3.80 (s, 3H). | 452.15 | |
N-(4-(4-胺基-7-甲基-5-(4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.18 (s, 1H), 7.74 - 7.67 (m, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.31 - 7.23 (m, 2H), 7.23 - 7.16 (m, 2H), 7.06 - 6.98 (m, 2H), 5.88 (d, J = 2.3 Hz, 1H), 5.85 - 5.77 (m, 3H), 5.56 - 5.51 (m, 1H), 3.75 (s, 3H), 3.60 (s, 3H), 1.95 (d, J = 1.1 Hz, 3H). | 480.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基-1H-吡唑-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.19 (s, 1H), 7.72 - 7.65 (m, 2H), 7.58 (s, 1H), 7.27 (s, 2H), 7.27 - 7.17 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 5.80 (s, 1H), 5.71 (s, 1H), 5.56 - 5.51 (m, 1H), 5.25 (s, 2H), 3.59 (s, 3H), 2.01 (s, 3H), 1.95 (d, J = 1.1 Hz, 3H). | 478.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((5-甲基-1H-吡唑-1-基)甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.18 (s, 1H), 7.72 - 7.64 (m, 2H), 7.35 (d, J = 1.7 Hz, 1H), 7.29 - 7.17 (m, 4H), 7.04 (d, J = 7.9 Hz, 2H), 6.07 (d, J = 1.9 Hz, 1H), 5.96 (s, 1H), 5.80 (s, 1H), 5.78 (s, 1H), 5.53 (t, J = 1.5 Hz, 1H), 5.30 (s, 2H), 3.59 (s, 3H), 2.21 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H). | 478.35 | |
N-(4-(4-胺基-5-(4-((3,5-二甲基-1H-吡唑-1-基)甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.18 (s, 1H), 7.70 - 7.63 (m, 2H), 7.30 - 7.21 (m, 2H), 7.24 - 7.16 (m, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.95 (s, 2H), 5.85 (s, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H), 5.19 (s, 2H), 3.59 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H). | 478.40 | |
N-((1,2,4-噁二唑-3-基)甲基)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 9.55 (s, 1H), 9.16 (t,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.36 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 5.92 (s, 1H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.62 (d,J = 5.7 Hz, 2H), 3.32 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 509.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(2-甲基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.34 - 7.22 (m, 6H), 5.79 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H), 1.61 (d,J = 16.0 Hz, 3H), 1.50 (s, 2H), 1.36 (d,J = 12.6 Hz, 1H), 1.18 (d,J = 7.0 Hz, 3H). | 509.45 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(2-甲基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.34 - 7.22 (m, 6H), 5.79 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 2.98 (s, 1H), 1.95 (d,J = 1.3 Hz, 3H), 1.63 (s, 1H), 1.59 (s, 2H), 1.51 (s, 1H), 1.37 (s, 1H), 1.18 (d,J = 6.9 Hz, 3H). | 509.45 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.51 (d,J = 6.5 Hz, 1H), 8.21 (s, 1H), 7.84 - 7.78 (m, 2H), 7.74 - 7.66 (m, 2H), 7.32 - 7.22 (m, 4H), 5.91 (s, 1H), 5.79 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 4.44 (d,J = 8.0 Hz, 1H), 3.84 (td,J = 8.7, 6.7 Hz, 2H), 3.71 (td,J = 8.1, 5.7 Hz, 1H), 3.61 (s, 3H), 3.57 (dd,J = 8.9, 4.4 Hz, 1H), 2.20 - 2.06 (m, 1H), 1.97 - 1.85 (m, 4H). | 497.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2,2-二氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.84 (t,J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.83 (d,J = 7.9 Hz, 2H), 7.70 (d,J = 8.4 Hz, 2H), 7.31 (d,J = 8.0 Hz, 2H), 7.26 (d,J = 8.3 Hz, 2H), 6.33 - 5.63 (m, 4H), 5.53 (s, 1H), 3.72 - 3.61 (m, 3H), 3.32 (s, 2H), 1.95 (s, 3H). | 491.15 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-羥基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (d,J = 9.3 Hz, 2H), 7.85 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.33 - 7.23 (m, 4H), 5.92 (s, 1H), 5.80 (s, 1H), 5.56 - 5.51 (m, 1H), 4.53 (s, 1H), 3.61 (s, 3H), 3.24 (d,J = 6.1 Hz, 2H), 1.95 (d,J = 1.2 Hz, 3H), 1.10 (s, 6H). | 499.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (d,J = 5.4 Hz, 2H), 7.84 - 7.77 (m, 2H), 7.74 - 7.67 (m, 2H), 7.33 - 7.24 (m, 4H), 5.90 (s, 1H), 5.80 (s, 1H), 5.53 (d,J = 1.9 Hz, 1H), 3.61 (s, 3H), 3.32 (d,J = 6.5 Hz, 1H), 3.15 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H), 1.11 (s, 6H). | 513.50 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.39 (s, 2H), 7.27 (dd,J = 13.3, 8.2 Hz, 4H), 5.98 (s, 2H), 5.80 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 3.32 (s, 2H), 3.07 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 523.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(氧雜環丁-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 9.08 (d,J = 6.4 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.80 (m, 2H), 7.75 - 7.67 (m, 2H), 7.35 - 7.22 (m, 4H), 5.92- 5.79 (s, 2H), 5.54 (t,J = 1.5 Hz, 1H), 4.99 (h,J = 6.9 Hz, 1H), 4.76 (dd,J = 7.5, 6.3 Hz, 2H), 4.58 (t,J = 6.4 Hz, 2H), 3.61 (s, 3H), 1.95 (d,J = 1.1 Hz, 3H). | 483.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-異丁基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.43 (t,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.79 (d,J = 8.0 Hz, 2H), 7.70 (d,J = 8.6 Hz, 2H), 7.28 (dd,J = 11.2, 8.4 Hz, 4H), 5.79 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 3.07 (t,J = 6.4 Hz, 2H), 1.95 (d,J = 1.2 Hz, 3H), 1.83 (dt,J = 13.6, 6.8 Hz, 1H), 0.89 (d,J = 6.7 Hz, 6H). | 483.40 | |
N-(4-(4-胺基-5-(4-(N-環戊基胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.22 (s, 1H), 7.77 - 7.66 (m, 4H), 7.57 (d,J = 7.7 Hz, 1H), 7.38 (d,J = 8.2 Hz, 2H), 7.22 (d,J = 8.5 Hz, 2H), 5.96 (s, 0H), 5.78 (s, 1H), 5.53 (s, 1H), 3.63 (s, 3H), 3.42 (q,J = 7.0 Hz, 1H), 3.32 (s, 1H), 1.94 (s, 3H), 1.53 (s, 3H), 1.37 (s, 2H), 1.21 (d,J = 6.0 Hz, 2H). | 531.35 | |
N-(4-(4-胺基-5-(4-(N-(2-羥基-2-甲基丙基)胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.22 (s, 1H), 7.73 (t,J = 8.3 Hz, 4H), 7.45 (t,J = 6.5 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.29 - 7.21 (m, 2H), 5.80 (s, 1H), 5.53 (t,J = 1.6 Hz, 1H), 4.38 (s, 1H), 3.61 (s, 3H), 3.32 (s, 2H), 2.66 (d,J = 6.5 Hz, 2H), 1.95 (t,J = 1.3 Hz, 3H), 1.03 (s, 6H). | 535.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(N-(2,2,2-三氟乙基)胺磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.59 (s, 1H), 8.22 (s, 1H), 7.80 - 7.68 (m, 4H), 7.40 (d,J = 8.1 Hz, 2H), 7.26 (d,J = 8.3 Hz, 2H), 5.99 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.74 (d,J = 9.4 Hz, 2H), 3.69 (d,J = 9.5 Hz, 1H), 3.53 (s, 3H), 1.95 (s, 3H). | 545.30 | |
N-(4-(4-胺基-5-(4-(N-異丁基胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.75 - 7.68 (m, 4H), 7.55 (t,J = 6.1 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.27 - 7.20 (m, 2H), 5.95 (s, 2H), 5.79 (d,J = 1.3 Hz, 1H), 5.56 - 5.51 (m, 1H), 3.62 (s, 3H), 2.58 (t,J = 6.4 Hz, 2H), 1.95 (t,J = 1.3 Hz, 3H), 1.58 (hept,J = 6.7 Hz, 1H), 0.78 (d,J = 6.7 Hz, 6H). | 519.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(N-(氧雜環丁-3-基)胺磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.49 (d,J = 7.4 Hz, 1H), 8.22 (s, 1H), 7.75 - 7.67 (m, 4H), 7.42 - 7.35 (m, 2H), 7.27 - 7.19 (m, 2H), 5.97 (m, 2H), 5.82 - 5.77 (m, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.46 (dd,J = 7.6, 5.6 Hz, 2H), 4.40 (q,J = 7.1 Hz, 1H), 4.21 (t,J = 6.0 Hz, 2H), 3.62 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 519.35 | |
N-(4-(4-胺基-5-(4-(N-環戊基胺磺醯亞胺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.85 - 7.79 (m, 2H), 7.68 (d,J = 8.6 Hz, 2H), 7.37 - 7.31 (m, 2H), 7.23 (d,J = 8.3 Hz, 2H), 6.85 (d,J = 8.0 Hz, 1H), 5.90 (br, 2H), 5.77 (s, 1H), 5.55 (s, 1H), 4.04 (s, 1H), 3.63 (s, 3H), 3.40 - 3.60(m, 1H), 1.94 (t,J = 1.2 Hz, 3H), 1.49 (s, 4H), 1.33 (s, 2H), 1.15 (s, 2H). | 530.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-磺醯亞胺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.22 (s, 1H), 7.82 - 7.76 (m, 2H), 7.73 - 7.66 (m, 2H), 7.41 - 7.34 (m, 2H), 7.26 - 7.18 (m, 2H), 5.79 (s, 3H), 5.56 - 5.50 (m, 1H), 4.37 (s, 1H), 3.63 (s, 3H), 3.06 (d,J = 6.4 Hz, 4H), 1.95 (d,J = 1.3 Hz, 3H), 1.61 - 1.53 (m, 4H). | 516.30 | |
N-(4-(4-胺基-5-(4-(N-環戊基-N-甲基胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.75 - 7.65 (m, 4H), 7.43 - 7.36 (m, 2H), 7.25 - 7.17 (m, 2H), 5.98 (s, 2H), 5.78 (t,J = 1.1 Hz, 1H), 5.56 - 5.51 (m, 1H), 4.17 (q,J = 8.0 Hz, 1H), 3.64 (s, 3H), 2.64 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H), 1.52 (q,J = 5.0, 4.5 Hz, 2H), 1.42 (d,J = 11.8 Hz, 4H), 1.32 - 1.23 (m, 2H). | 545.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(N-甲基-N-(2,2,2-三氟乙基)胺磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.23 (s, 1H), 7.83 - 7.76 (m, 2H), 7.76 - 7.69 (m, 2H), 7.45 - 7.38 (m, 2H), 7.29 - 7.21 (m, 2H), 5.83 - 5.78 (m, 1H), 5.54 (t,J = 1.4 Hz, 1H), 4.02 (q,J = 9.2 Hz, 2H), 3.62 (s, 3H), 2.83 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 559.40 | |
N-(4-(4-胺基-5-(4-(環戊基甲磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.23 (s, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.68 (m, 2H), 7.47 - 7.40 (m, 2H), 7.27 - 7.21 (m, 2H), 5.79 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 3.62 (s, 3H), 3.37 - 3.27 (m, 2H), 2.10 (hept,J = 7.5 Hz, 1H), 1.95 (d,J = 1.1 Hz, 3H), 1.75 - 1.63 (m, 2H), 1.54 (qd,J = 9.4, 8.0, 3.0 Hz, 2H), 1.45 (qt,J = 7.1, 2.6 Hz, 2H), 1.16 (dq,J = 11.8, 7.7 Hz, 2H). | 530.4 | |
N-(4-(4-胺基-7-甲基-5-(4-(3,3,3-三氟丙基磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.23 (s, 1H), 7.90 - 7.84 (m, 2H), 7.76 - 7.69 (m, 2H), 7.47 - 7.41 (m, 2H), 7.29 - 7.22 (m, 2H), 5.80 (s, 1H), 5.54 (d,J = 1.8 Hz, 1H), 3.61 (s, 4H), 3.65 - 3.57 (m, 1H), 2.73 - 2.58 (m, 2H), 1.95 (s, 3H). | 544.3 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基環戊基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.33 (d,J = 7.7 Hz, 1H), 8.21 (s, 1H), 7.79 (d,J = 7.9 Hz, 2H), 7.70 (d,J = 8.2 Hz, 2H), 7.28 (dd,J = 12.1, 8.1 Hz, 4H), 5.92 (s, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 4.18 (dd,J = 11.6, 6.3 Hz, 1H), 3.69 (dd,J = 6.7, 3.4 Hz, 1H), 3.33 (s, 3H), 3.25 (s, 3H), 1.98 (d,J = 7.7 Hz, 1H), 1.95 (s, 3H), 1.88 (dq,J = 13.8, 7.0 Hz, 1H), 1.69 (s, 1H), 1.70 - 1.59 (m, 0H), 1.58 (s, 2H), 1.52 (dq,J = 14.1, 7.4, 6.3 Hz, 1H). | 525.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-羥基環戊基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (d,J = 7.7 Hz, 2H), 7.83 - 7.76 (m, 2H), 7.73 - 7.67 (m, 2H), 7.32 - 7.22 (m, 4H), 5.90 (s, 1H), 5.79 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 4.74 (d,J = 3.8 Hz, 1H), 3.98 (s, 2H), 3.61 (s, 3H), 2.03 - 1.92 (m, 4H), 1.91 - 1.78 (m, 1H), 1.65 (p,J = 7.8, 6.8 Hz, 2H), 1.47 (dd,J = 13.4, 7.0 Hz, 2H). | 511.25 | |
N-(4-(4-胺基-5-(4-(N-(2-甲氧基環戊基)胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.22 (s, 1H), 7.78 - 7.66 (m, 4H), 7.43 - 7.36 (m, 2H), 7.27 - 7.19 (m, 2H), 5.96 (s, 2H), 5.80 - 5.75 (m, 1H), 5.56 - 5.51 (m, 1H), 3.62 (s, 3H), 3.41 - 3.28 (m, 2H), 2.97 (s, 3H), 2.08 (s, 1H), 1.94 (d,J = 1.3 Hz, 3H), 1.76 - 1.57 (m, 1H), 1.61 - 1.44 (m, 1H), 1.48 - 1.36 (m, 3H), 1.21 (dt,J = 12.2, 6.4 Hz, 1H). | 561.45 | |
N-(4-(4-胺基-5-(4-(N-(2-羥基環戊基)胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.22 (s, 1H), 7.78 - 7.67 (m, 4H), 7.50 (d,J = 7.5 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.27 - 7.20 (m, 2H), 5.94 (s, 1H), 5.78 (s, 1H), 5.53 (s, 1H), 4.66 (d,J = 4.4 Hz, 1H), 3.75 (dt,J = 8.7, 4.5 Hz, 1H), 3.58 (s, 1H), 3.32 (s, 2H), 3.24 - 3.17 (m, 1H), 1.95 (t,J = 1.2 Hz, 3H), 1.77 - 1.64 (m, 1H), 1.63 - 1.49 (m, 1H), 1.49 (d,J = 7.3 Hz, 2H), 1.35 (dt,J = 11.7, 5.7 Hz, 1H), 1.11 (dt,J = 13.1, 6.6 Hz, 1H). | 547.35 | |
N-(4-(4-胺基-5-(4-(N-環丁基胺磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.87 (d,J = 9.1 Hz, 1H), 7.75 - 7.65 (m, 4H), 7.38 (d,J = 8.3 Hz, 2H), 7.25 - 7.18 (m, 2H), 5.78 (s, 1H), 5.53 (s, 1H), 3.63 (s, 3H), 3.59 (d,J = 8.3 Hz, 0H), 3.32 (s, 1H), 1.94 (d,J = 1.5 Hz, 3H), 1.89 - 1.77 (m, 2H), 1.74 - 1.60 (m, 2H), 1.57 - 1.40 (m, 2H). | 517.35 | |
(R)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.51 (d,J = 6.5 Hz, 1H), 8.21 (s, 1H), 7.81 (d,J = 8.2 Hz, 2H), 7.70 (d,J = 8.6 Hz, 2H), 7.32 - 7.23 (m, 4H), 5.79 (s, 1H), 5.53 (s, 1H), 4.44 (d,J = 7.2 Hz, 1H), 3.89 - 3.79 (m, 2H), 3.73 (m, 1H), 3.68 - 3.61 (m, 3H), 3.56 (dd,J = 8.8, 4.4 Hz, 1H), 2.18 - 2.07 (m, 1H), 1.97 - 1.87 (m, 4H). | 497.20 | |
(S)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.23 (s, 1H), 7.83 - 7.78 (m, 2H), 7.70 - 7.64 (m, 2H), 7.40 - 7.35 (m, 2H), 7.30 - 7.25 (m, 2H), 5.87 - 5.77 (m, 1H), 5.54 (dt,J = 2.0, 1.0 Hz, 1H), 4.59 (ddt,J = 8.0, 6.0, 4.1 Hz, 1H), 4.02 - 3.94 (m, 2H), 3.86 (td,J = 8.3, 5.8 Hz, 1H), 3.77 - 3.69 (m, 4H), 2.38 - 2.23 (m, 1H), 2.04 - 1.93 (d,J = 1.3 Hz, 4H). | 497.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3,3,3-三氟-2-羥基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.70 (t,J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.85 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.34 - 7.23 (m, 4H), 6.47 (d,J = 6.4 Hz, 1H), 5.92 (s, 1H), 5.79 (s, 1H), 5.53 (t,J = 1.4 Hz, 1H), 4.22 - 4.16 (m, 2H), 3.62 (s, 3H), 3.58 (d,J = 5.2 Hz, 1H), 1.95 (d,J = 1.2 Hz, 3H). | 539.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((3-氟氧雜環丁-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.78 (t,J = 6.0 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.34 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 5.79 (s, 1H), 5.53 (d,J = 2.1 Hz, 1H), 4.70 (d,J = 8.0 Hz, 1H), 4.65 (q,J = 3.4 Hz, 2H), 4.59 (d,J = 8.0 Hz, 1H), 3.82 (d,J = 6.0 Hz, 1H), 3.77 (d,J = 6.0 Hz, 1H), 3.61 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 515.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((四氫呋喃-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.40 (s, 1H), 7.71 (d,J = 7.9 Hz, 2H), 7.63 - 7.55 (m, 3H), 7.34 (d,J = 8.0 Hz, 2H), 7.25 - 7.19 (m, 2H), 6.39 (t,J = 5.5 Hz, 1H), 5.82 (s, 1H), 5.52 (d,J = 2.0 Hz, 1H), 5.03 (s, 2H), 3.95 (td,J = 8.3, 5.2 Hz, 1H), 3.86 (dd,J = 8.9, 6.9 Hz, 1H), 3.82 - 3.72 (m, 4H), 3.66 (dd,J = 8.9, 4.9 Hz, 1H), 3.50 (dd,J = 7.2, 5.3 Hz, 2H), 2.63 (p,J = 6.9 Hz, 1H), 2.19 - 2.05 (m, 4H), 1.78 - 1.66 (m, 1H). | 511.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-羥基環丙基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.38 (t,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.33 - 7.23 (m, 4H), 5.80 (d,J = 1.4 Hz, 3H), 5.53 (t,J = 1.6 Hz, 1H), 5.40 (s, 1H), 3.67(s, 3H),3.42 (d,J = 5.7 Hz, 2H), 1.95 (t,J = 1.3 Hz, 3H), 0.55 (q,J = 2.2 Hz, 4H). | 497.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-羥基環丙基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.38 (t,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.33 - 7.23 (m, 4H), 5.80 (d,J = 1.4 Hz, 3H), 5.53 (t,J = 1.6 Hz, 1H), 5.40 (s, 1H), 3.67(s, 3H),3.42 (d,J = 5.7 Hz, 2H), 1.95 (t,J = 1.3 Hz, 3H), 0.55 (q,J = 2.2 Hz, 4H). | 497.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-羥基-2,2-二甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.38 (t,J = 6.2 Hz, 1H), 8.21 (s, 1H), 7.82 - 7.75 (m, 2H), 7.74 - 7.67 (m, 2H), 7.34 - 7.24 (m, 4H), 6.07 - 5.75 (m, 2H), 5.53 (t,J = 1.4 Hz, 1H), 4.58 (t,J = 6.1 Hz, 1H), 3.61 (s, 3H), 3.17 - 3.09 (m, 4H), 1.95 (t,J = 1.2 Hz, 3H), 0.83 (s, 6H). | 513.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-(羥基甲基)環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.53 (d,J = 7.5 Hz, 1H), 8.21 (s, 1H), 7.79 (dd,J = 8.4, 1.7 Hz, 2H), 7.73 - 7.67 (m, 2H), 7.32 - 7.22 (m, 4H), 5.79 (d,J = 1.3 Hz, 2H), 5.54 (d,J = 1.8 Hz, 1H), 4.51 - 4.38 (m, 1H), 4.27 (q,J = 8.4 Hz, 1H), 3.61 (s, 3H), 3.50 - 3.42 (m, 1H), 3.36 (t,J = 5.7 Hz, 2H), 2.25 (d,J = 8.8 Hz, 2H), 2.13 - 2.04 (m, 2H), 1.95 (d,J = 1.3 Hz, 3H), 1.82 - 1.70 (m, 1H). | 511.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-(氧雜環丁-3-基)乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.49 (d,J = 7.3 Hz, 2H), 7.27 (d,J = 7.6 Hz, 4H), 5.80 (s, 2H), 5.53 (s, 1H), 4.67 (dd,J = 20.8, 5.0 Hz, 1H), 3.61 (s, 3H), 3.58 - 3.36 (m, 4H), 3.32 - 3.22 (m, 2H), 2.40 - 2.20 (m, 1H), 1.95 (t,J = 1.2 Hz, 3H), 1.88 (s, 1H), 1.64 (s, 1H). | 511.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(氮雜環丁-3-基甲基)苯甲醯胺2,2,2-三氟乙酸鹽 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.68 (t,J = 5.8 Hz, 1H), 8.64 - 8.41 (m, 3H), 7.87 - 7.80 (m, 2H), 7.77 - 7.69 (m, 2H), 7.37 - 7.25 (m, 4H), 5.80 (s, 1H), 5.55 (d,J = 1.9 Hz, 1H), 3.95 (t,J = 10.1 Hz, 2H), 3.80 (q,J = 8.9, 7.9 Hz, 2H), 3.67 (s, 3H), 3.48 (t,J = 6.1 Hz, 2H), 3.01 (p,J = 7.5 Hz, 1H), 1.95 (t,J = 1.3 Hz, 3H). | 496.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-氧雜雙環[3.1.0]己-6-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.46 (d,J = 4.2 Hz, 1H), 8.21 (s, 1H), 7.79 - 7.73 (m, 2H), 7.73 - 7.66 (m, 2H), 7.32 - 7.22 (m, 4H), 5.90 (s, 1H), 5.79 (s, 1H), 5.56 - 5.51 (m, 1H), 3.86 (d,J = 8.4 Hz, 2H), 3.63 (d,J = 13.4 Hz, 5H), 2.59 (q,J = 2.9 Hz, 1H), 1.95 (t,J = 1.2 Hz, 3H),, 1.87 (s, 2H). | 509.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-甲氧基環丁基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.27 (t,J = 6.1 Hz, 1H), 8.21 (s, 1H), 7.81 (d,J = 7.9 Hz, 2H), 7.70 (d,J = 8.3 Hz, 2H), 7.28 (dd,J = 11.9, 8.1 Hz, 4H), 5.80 (s, 2H), 5.53 (s, 1H), 3.53 (d,J = 6.0 Hz, 2H), 3.33 (s, 3H), 3.13 (s, 3H), 1.96 (d,J = 9.9 Hz, 7H), 1.70 - 1.64 (m, 1H), 1.63 - 1.54 (m, 1H). | 525.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-氰基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.78 (t,J = 6.4 Hz, 1H), 8.22 (s, 1H), 7.86 - 7.80 (m, 2H), 7.75 - 7.67 (m, 2H), 7.36 - 7.24 (m, 4H), 5.80 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 3.61 (s, 3H), 3.46 (d,J = 6.4 Hz, 2H), 1.95 (d,J = 1.3 Hz, 3H), 1.33 (s, 6H). | 508.2 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1-環丙基-3-羥基丙-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 8.06 (d,J = 8.4 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.74 - 7.67 (m, 2H), 7.32 - 7.23 (m, 4H), 5.95 (s, 2H), 5.79 (s, 1H), 5.56 - 5.51 (m, 1H), 4.63 (t,J = 5.8 Hz, 1H), 4.05 - 3.98 (m, 1H), 3.61 (s, 3H), 3.53 - 3.36 (m, 3H), 1.94 (d,J = 1.3 Hz, 3H), 1.44 (h,J = 7.4 Hz, 2H), 0.72 (s, 1H), 0.42 - 0.33 (m, 2H), 0.11 (d,J = 8.8 Hz, 1H). | 525.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(氧雜環丁-3-基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.60 (t,J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.82 - 7.75 (m, 2H), 7.74 - 7.67 (m, 2H), 7.33 - 7.23 (m, 4H), 5.92 (s, 1H), 5.80 (t,J = 1.0 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.63 (dd,J = 7.8, 6.0 Hz, 2H), 4.34 (t,J = 6.0 Hz, 2H), 3.61 (s, 3H), 3.53 (dd,J = 6.9, 5.7 Hz, 2H), 3.16 (dq,J = 13.7, 6.9 Hz, 1H), 1.95 (t,J = 1.2 Hz, 3H). | 497.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(氰基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 9.18 (t,J = 5.5 Hz, 1H), 8.21 (s, 1H), 7.85 - 7.79 (m, 2H), 7.74 - 7.67 (m, 2H), 7.36 - 7.29 (m, 2H), 7.29 - 7.22 (m, 2H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.30 (d,J = 5.4 Hz, 2H), 3.61 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 466.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(四氫-2H-哌喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (d,J = 6.9 Hz, 2H), 7.83 - 7.76 (m, 2H), 7.74 - 7.66 (m, 2H), 7.32 - 7.22 (m, 4H), 5.91 (s, 2H), 5.79 (s, 1H), 5.56 - 5.51 (m, 1H), 3.93 - 3.86 (m, 1H), 3.83 - 3.72 (m, 2H), 3.61 (s, 3H), 3.28 - 3.22 (m, 1H), 3.14 (dd,J = 10.7, 9.5 Hz, 1H), 1.95 (t,J = 1.2 Hz, 4H), 1.69 (s, 1H), 1.58 (t,J = 9.3 Hz, 2H). | 511.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(氧雜環丁-2-基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.61 (t,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.82 (d,J = 8.3 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.33 - 7.23 (m, 4H), 5.91 (s, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 4.85 - 4.77 (m, 1H), 4.55 - 4.38 (m, 2H), 3.61 (s, 3H), 3.60 - 3.51 (m, 1H), 3.51 - 3.41 (m, 1H), 2.68 - 2.55 (m, 1H), 2.47 - 2.37 (m, 1H), 1.95 (d,J = 1.2 Hz, 3H). | 497.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-羥乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.81 (d,J = 8.0 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.27 (dd,J = 11.7, 8.3 Hz, 4H), 5.79 (s, 1H), 5.53 (s, 1H), 4.69 (t,J = 5.7 Hz, 1H), 3.61 (s, 3H), 3.50 (q,J = 6.2 Hz, 2H), 1.95 (s, 3H). | 471.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-羥基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.42 (t,J = 5.6 Hz, 1H), 8.21 (s, 1H), 7.82 - 7.75 (m, 2H), 7.74 - 7.67 (m, 2H), 7.32 - 7.23 (m, 4H), 5.91 (s, 0H), 5.80 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 4.46 (t,J = 5.2 Hz, 1H), 3.61 (s, 3H), 3.46 (q,J = 6.0 Hz, 2H), 3.34 (d,J = 6.0 Hz, 2H), 1.95 (t,J = 1.2 Hz, 3H), 1.67 (p,J = 6.6 Hz, 2H). | 485.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-甲氧基丙基)苯甲醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.40 (s, 1H), 7.75 - 7.68 (m, 2H), 7.65 (s, 1H), 7.62 - 7.55 (m, 2H), 7.37 - 7.29 (m, 2H), 7.26 - 7.18 (m, 2H), 6.96 - 6.88 (m, 1H), 5.82 (s, 1H), 5.51 (q,J = 1.6 Hz, 1H), 5.03 (s, 2H), 3.74 (s, 3H), 3.59 (q,J = 5.8 Hz, 4H), 3.41 (s, 3H), 2.09 (t,J = 1.2 Hz, 3H), 1.96 - 1.86 (m, 2H). | 499.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1,3-二氟丙-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.65 (d,J = 7.2 Hz, 1H), 8.21 (s, 1H), 7.87 - 7.81 (m, 2H), 7.74 - 7.67 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 5.94 (s, 1H), 5.80 (s, 1H), 5.53 (d,J = 1.9 Hz, 1H), 4.64 (t,J = 5.1 Hz, 2H), 4.53 (s, 3H), 3.62 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 505.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(吡咯啶-3-基)苯甲醯胺2,2,2-三氟乙酸鹽 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.84 (s, 2H), 8.60 (d,J = 6.2 Hz, 1H), 8.46 (d,J = 1.5 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.76 - 7.70 (m, 2H), 7.37 - 7.31 (m, 2H), 7.31 - 7.24 (m, 2H), 5.80 (s, 1H), 5.55 (t,J = 1.5 Hz, 1H), 4.50 (hept,J = 6.0, 5.4 Hz, 1H), 3.67 (s, 3H), 3.41 (ddt,J = 28.8, 12.4, 6.4 Hz, 2H), 3.31 - 3.22 (m, 1H), 3.21 - 3.12 (m, 1H), 2.26 - 2.13 (m, 1H), 2.01 (dt,J = 13.1, 6.4 Hz, 1H), 1.95 (t,J = 1.2 Hz, 3H). | 496.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丙基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.67 (dd,J = 7.2, 3.8 Hz, 1H), 8.21 (s, 1H), 7.79 (dd,J = 8.3, 2.7 Hz, 2H), 7.70 (d,J = 8.6 Hz, 2H), 7.33 - 7.22 (m, 4H), 5.92 (s, 2H), 5.79 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 3.97 (q,J = 7.9 Hz, 1H), 3.61 (s, 3H), 2.72 (ddd,J = 9.6, 6.5, 3.1 Hz, 1H), 2.46 (s, 1H), 2.33 - 2.20 (m, 1H), 1.94 (d,J = 1.4 Hz, 3H). | 481.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1-(甲氧基甲基)環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.34 (s, 1H), 8.21 (s, 1H), 7.84 - 7.78 (m, 2H), 7.74 - 7.66 (m, 2H), 7.30 - 7.22 (m, 4H), 5.80 (d,J = 1.3 Hz, 1H), 5.56 - 5.51 (m, 1H), 3.61 (d,J = 1.4 Hz, 5H), 3.31 (d,J = 13.6 Hz, 3H), 2.30 - 2.18 (m, 2H), 2.18 - 2.09 (m, 2H), 1.95 (d,J = 1.3 Hz, 3H), 1.85 (dd,J = 9.4, 4.8 Hz, 1H), 1.84 - 1.72 (m, 1H). | 525.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-氟環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.67 (dd,J = 7.2, 3.8 Hz, 1H), 8.21 (s, 1H), 7.79 (dd,J = 8.3, 2.7 Hz, 2H), 7.70 (d,J = 8.6 Hz, 2H), 7.33 - 7.22 (m, 4H), 5.92 (s, 2H), 5.79 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 3.97 (q,J = 7.9 Hz, 1H), 3.61 (s, 3H), 2.72 (ddd,J = 9.6, 6.5, 3.1 Hz, 1H), 2.46 (s, 1H), 2.33 - 2.20 (m, 1H), 1.94 (d,J = 1.4 Hz, 3H). | 499.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((3-羥基環丁基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.43 (t,J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.78 (d,J = 8.0 Hz, 2H), 7.70 (d,J = 8.5 Hz, 2H), 7.28 (dd,J = 10.3, 8.3 Hz, 4H), 5.79 (s, 3H), 5.53 (s, 1H), 4.92 (s, 1H), 3.91 - 3.83 (m, 1H), 3.61 (s, 3H), 3.25 (t,J = 6.2 Hz, 2H), 2.23 (p,J = 7.6, 7.1 Hz, 2H), 1.95 - 1.90 (s, 4H), 1.59 - 1.47 (m, 2H), 1.24 (s, 0H). | 511.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-氰基環丙基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.87 (t,J = 6.1 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.35 - 7.29 (m, 2H), 7.29 - 7.23 (m, 2H), 5.92 (s, 2H), 5.79 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 3.61 (s, 3H), 3.42 (d,J = 5.9 Hz, 2H), 1.94 (t,J = 1.3 Hz, 3H), 1.21 (q,J = 3.9, 2.9 Hz, 2H), 1.18 - 1.08 (m, 2H). | 506.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-羥基環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.55 (t,J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.79 (dd,J = 8.4, 2.0 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.27 (td,J = 8.7, 2.2 Hz, 4H), 5.79 (s, 1H), 5.56 - 5.51 (m, 1H), 5.07 (d,J = 5.5 Hz, 1H), 3.86 (d,J = 7.7 Hz, 1H), 3.61 (s, 3H), 2.30 - 2.21 (m, 1H), 2.01 - 1.83 (m, 4H). | 497.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1-羥基丙-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 8.07 (d,J = 8.2 Hz, 1H), 7.80 (d,J = 8.2 Hz, 2H), 7.70 (d,J = 8.5 Hz, 2H), 7.27 (t,J = 8.8 Hz, 4H), 5.89 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 4.69 (t,J = 5.8 Hz, 1H), 4.01 (q,J = 6.7 Hz, 1H), 3.61 (s, 3H), 3.45 (dt,J = 11.2, 5.8 Hz, 1H), 3.37 - 3.27 (m, 1H), 1.95 (t,J = 1.3 Hz, 3H), 1.12 (d,J = 6.7 Hz, 3H). | 485.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-(羥基甲基)環丙基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.37 (s, 1H), 7.78 - 7.69 (m, 3H), 7.57 (d,J = 8.4 Hz, 2H), 7.30 (d,J = 8.0 Hz, 2H), 7.19 (d,J = 8.4 Hz, 2H), 7.13 (t,J = 5.9 Hz, 1H), 5.83 (s, 1H), 5.51 (d,J = 1.8 Hz, 1H), 5.09 (s, 2H), 3.73 (s, 3H), 3.51 - 3.43 (m, 4H), 2.08 (s, 3H), 0.60 - 0.49 (m, 4H). | 511.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((4-甲基嗎啉-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.37 (t,J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.81 - 7.74 (m, 2H), 7.73 - 7.66 (m, 2H), 7.33 - 7.23 (m, 4H), 5.79 (s, 1H), 5.53 (s, 1H), 3.74 - 3.62 (m, 2H), 3.61 (s, 3H), 3.57 - 3.41 (m, 2H), 3.23 (dd,J = 11.3, 9.3 Hz, 1H), 3.13 (dt,J = 13.3, 6.4 Hz, 1H), 2.63 (d,J = 11.7 Hz, 1H), 2.29 (s, 3H), 2.21 - 2.11 (m, 2H), 1.94 (t,J = 1.2 Hz, 3H). | 540.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.68 (d,J = 6.1 Hz, 1H), 8.21 (s, 1H), 7.82 (d,J = 7.9 Hz, 2H), 7.70 (d,J = 8.4 Hz, 2H), 7.28 (dd,J = 16.5, 8.1 Hz, 4H), 5.80 (s, 2H), 5.53 (s, 1H), 4.59 (t,J = 5.2 Hz, 1H), 4.47 (t,J = 5.2 Hz, 1H), 3.62 (s, 3H), 3.59 (d,J = 5.4 Hz, 1H), 3.59 - 3.50 (m, 1H), 1.95 (s, 3H). | 473.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-胺基乙基)-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.46 (s, 1H), 7.86 (s, 3H), 7.73 (d,J = 8.5 Hz, 2H), 7.43 (d,J = 7.9 Hz, 2H), 7.29 (dd,J = 19.9, 8.0 Hz, 4H), 5.80 (s, 1H), 5.54 (d,J = 1.7 Hz, 1H), 4.25 (s, 2H), 3.68 (m, 5H), 3.08 (s, 2H), 1.94 (d,J = 1.5 Hz, 3H). | 552.2 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-羥基環丁基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.31 (t,J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.83 (d,J = 8.3 Hz, 2H), 7.74 - 7.67 (m, 2H), 7.33 - 7.23 (m, 4H), 5.92 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 5.15 (s, 1H), 3.61 (s, 3H), 3.41 (d,J = 6.0 Hz, 2H), 2.10 - 1.99 (m, 2H), 1.95 (d,J = 1.3 Hz, 3H), 1.89 (dd,J = 11.6, 8.9 Hz, 2H), 1.63 (d,J = 9.9 Hz, 1H), 1.48 (q,J = 9.2 Hz, 1H). | 511.40 | |
N-(4-(4-胺基-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.22 (s, 1H), 7.75 - 7.71 (m, 3H), 7.35 - 7.33 (m, 1H), 7.22 (t, J = 8.4 Hz, 1H), 7.16 - 7.11 (m, 2H), 7.00 (d, J = 7.3 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 5.83 (s, 1H), 5.55 (s, 1H), 3.71 (s, 3H), 2.39 (s, 3H), 2.05 (s, 3H). | 509.30 | |
N-(4-(4-胺基-5-(3-(2-甲氧基乙氧基)-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.20 (s, 1H), 7.78 - 7.71 (m, 2H), 7.70 - 7.62 (m, 1H), 7.35 - 7.28 (m, 2H), 7.08 (d,J = 8.2 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.84 (dd,J = 8.2, 2.0 Hz, 1H), 6.66 (d,J = 8.2 Hz, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 3.88 (dd,J = 5.6, 3.8 Hz, 2H), 3.62 (s, 3H), 3.31 - 3.25 (m, 2H), 3.06 (s, 3H), 2.30 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 565.40 | |
N-(4-(4-胺基-7-甲基-5-(2-((6-甲基吡啶-2-基)氧基)嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.39 (s, 2H), 8.21 (s, 1H), 7.91 - 7.64 (m, 3H), 7.31 (d,J = 8.6 Hz, 2H), 7.18 (d,J = 7.4 Hz, 1H), 7.01 (d,J = 8.0 Hz, 1H), 6.33 (s, 2H), 5.82 (s, 1H), 5.55 (d,J = 1.9 Hz, 1H), 3.60 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H). | 493.20 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.78 - 7.66 (m, 2H), 7.33 (m, J = 8.6, 2.3 Hz, 3H), 7.21 - 7.16 (m, 2H), 7.12 (s, 0H), 5.80 (s, 1H), 5.54 (d, J = 1.7 Hz, 1H), 3.59 (s, 3H), 2.42 (s, 3H), 1.95 (d, J = 1.2 Hz, 3H). | 510.20 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.82 - 7.68 (m, 2H), 7.37 - 7.26 (m, 4H), 7.24 - 7.12 (m, 3H), 5.79 (s, 1H), 5.53 (d, J = 1.8 Hz, 1H), 3.60 (s, 3H), 2.41 (s, 3H), 1.95 (t, J = 1.3 Hz, 3H). | 492.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(5-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.50 (d,J = 0.9 Hz, 2H), 8.20 (s, 1H), 7.81 - 7.67 (m, 2H), 7.39 - 7.25 (m, 4H), 7.25 - 7.12 (m, 2H), 6.2 - 5.67 (t,J = 1.0 Hz, 2H), 5.54 (t,J = 1.5 Hz, 1H), 3.60 (s, 3H), 2.22 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 492.20 | |
N-(4-(4-胺基-7-(2-甲氧基乙基)-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.19 (s, 1H), 7.73 (dd,J = 8.4, 7.3 Hz, 3H), 7.34 - 7.27 (m, 2H), 7.31 - 7.21 (m, 2H), 7.10 - 7.03 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.77 (d,J = 8.1 Hz, 1H), 5.82 - 5.77 (m, 1H), 5.69 (s, 1H), 5.53 (t,J = 1.4 Hz, 1H), 4.25 (t,J = 6.0 Hz, 2H), 3.50 (t,J = 6.0 Hz, 2H), 3.09 (s, 3H), 2.34 (s, 3H), 2.08 (s, 1H), 1.95 (t,J = 1.2 Hz, 3H). | 535.25 | |
N-(4-(4-胺基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7-(氧雜環丁-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.20 (s, 1H), 7.77 - 7.68 (m, 3H), 7.24 (dd,J = 8.6, 3.1 Hz, 4H), 7.10 - 7.05 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.78 (d,J = 8.1 Hz, 1H), 5.79 (s, 1H), 5.63 - 5.51 (m, 2H), 5.15 (t,J = 6.9 Hz, 2H), 4.61 (dd,J = 7.9, 6.2 Hz, 2H), 2.34 (s, 3H), 1.95 (d,J = 1.6 Hz, 3H). | 533.2 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.83 (s, 1H), 8.20 (s, 1H), 7.71 (t,J = 7.8 Hz, 1H), 7.65 - 7.56 (m, 2H), 7.26 (d,J = 8.2 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.09 - 7.02 (m, 2H), 7.00 (d,J = 7.3 Hz, 1H), 6.76 (d,J = 8.2 Hz, 1H), 5.79 (s, 1H), 5.52 (t,J = 1.5 Hz, 1H), 3.32 (s, 3H), 2.33 (s, 3H), 1.97 - 1.91 (m, 6H). | 505.25 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.21 (s, 1H), 7.81 - 7.69 (m, 2H), 7.51 (dd,J = 8.5, 2.0 Hz, 1H), 7.34 - 7.21 (m, 3H), 7.09 (d,J = 8.7 Hz, 2H), 7.02 (d,J = 7.4 Hz, 1H), 6.78 (d,J = 8.1 Hz, 1H), 5.82 (s, 1H), 5.58 (s, 1H), 3.55 (s, 3H), 2.34 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 509.50 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 8.19 (s, 1H), 7.72 (t,J = 7.8 Hz, 1H), 7.35 (d,J = 8.1 Hz, 1H), 7.30 - 7.21 (m, 3H), 7.16 (d,J = 8.2 Hz, 1H), 7.09 (d,J = 8.1 Hz, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.76 (d,J = 8.2 Hz, 1H), 5.85 (s, 1H), 5.50 (s, 1H), 3.32 (s, 2H), 2.34 (s, 3H), 2.17 (s, 3H), 1.96 (s, 3H). | 505.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲氧基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.20 (s, 1H), 7.92 (d,J = 8.2 Hz, 1H), 7.73 (t,J = 7.8 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.13 - 7.06 (m, 2H), 7.04 - 6.93 (m, 3H), 6.79 (d,J = 8.1 Hz, 1H), 5.95 (s, 1H), 5.84 (s, 1H), 5.51 (d,J = 1.7 Hz, 1H), 3.69 (d,J = 6.4 Hz, 6H), 2.33 (s, 3H), 1.96 (d,J = 1.5 Hz, 3H). | 521.10 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.21 (s, 1H), 7.81 - 7.69 (m, 2H), 7.51 (dd,J = 8.6, 2.1 Hz, 1H), 7.27 (dd,J = 23.5, 8.5 Hz, 3H), 7.09 (d,J = 8.5 Hz, 1H), 7.02 (d,J = 7.4 Hz, 1H), 6.78 (d,J = 8.2 Hz, 1H), 5.82 (s, 1H), 5.58 (s, 1H), 3.55 (s, 3H), 2.34 (s, 3H), 1.95 (s, 3H). | 509.50 | |
N-(4-(4-胺基-5-(4-((6-胺基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.19 (s, 1H), 7.75 - 7.68 (m, 2H), 7.40 (t, J = 7.8 Hz, 1H), 7.33 - 7.27 (m, 2H), 7.27 - 7.19 (m, 2H), 7.05 - 6.97 (m, 2H), 6.18 (d, J = 7.9 Hz, 1H), 6.05 - 5.97 (m, 3H), 5.80 (s, 1H), 5.67 (s, 2H), 5.53 (t, J = 1.5 Hz, 1H), 3.60 (s, 3H), 1.95 (t, J = 1.3 Hz, 3H). | 492.25 | |
N-(4-(4-胺基-5-(4-((6-氰基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.21 (s, 1H), 8.09 (dd, J = 8.4, 7.2 Hz, 1H), 7.81 (d, J = 7.2 Hz, 1H), 7.77 - 7.67 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.35 - 7.26 (m, 4H), 7.26 - 7.08 (m, 2H), 5.80 (s, 2H), 5.58 - 5.45 (m, 1H), 3.61 (s, 3H), 1.95 (t, J = 1.2 Hz, 3H). | 502.20 | |
N-(4-(4-胺基-5-(4-((6-(羥基甲基)吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.85 (t,J = 7.8 Hz, 1H), 7.76 - 7.68 (m, 2H), 7.33 - 7.21 (m, 5H), 7.14 - 7.06 (m, 2H), 6.84 (d,J = 8.1 Hz, 1H), 5.93 (s, 2H), 5.80 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 5.38 (t,J = 5.8 Hz, 1H), 4.42 (d,J = 5.0 Hz, 2H), 3.62 (s, 3H), 1.96 (d,J = 1.3 Hz, 3H). | 507.30 | |
N-(4-(4-胺基-5-(4-((6-(甲氧基甲基)吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.86 (t,J = 7.8 Hz, 1H), 7.77 - 7.68 (m, 2H), 7.33 - 7.22 (m, 4H), 7.20 - 7.05 (m, 3H), 6.91 (d,J = 8.2 Hz, 1H), 5.80 (s, 1H), 5.56 - 5.51 (m, 1H), 4.35 (s, 2H), 3.62 (s, 3H), 3.33 (d,J = 6.5 Hz, 4H), 1.95 (t,J = 1.3 Hz, 3H). | 521.25 | |
N-(4-(4-胺基-5-(4-((6-甲氧基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.75 - 7.62 (m, 3H), 7.33 - 7.19 (m, 4H), 7.15 - 7.01 (m, 2H), 6.52 (d, J = 7.9 Hz, 2H), 6.26 - 5.68 (m, 1H), 5.57 - 5.43 (m, 1H), 3.62 (s, 5H), 1.95 (d, J = 1.3 Hz, 3H). | 507.20 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-(甲氧基甲基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 8.19 (s, 1H), 7.84 - 7.58 (m, 3H), 7.35 - 7.20 (m, 4H), 7.13 - 7.05 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.78 (d,J = 8.1 Hz, 1H), 5.94 (s, 1H), 5.70 (s, 1H), 4.15 (s, 2H), 3.61 (s, 3H), 3.31 (d,J = 7.2 Hz, 3H), 2.34 (s, 3H). | 521.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((5-甲基-1,3,4-噁二唑-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.21 (s, 1H), 7.69 - 7.67 (m, 2H), 7.40 (s, 4H), 7.31 - 7.29 (m, 2H), 5.82 (s, 1H), 5.54 (d, J = 1.6 Hz, 1H), 3.71 (s, 3H), 2.50 (s, 3H), 2.04 (s, 3H). | 482.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((5-甲基-1,3,4-噁二唑-2-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.40 (s, 1H), 7.62 - 7.56 (m, 3H), 7.48 (d,J = 8.0 Hz, 2H), 7.34 (d,J = 8.0 Hz, 2H), 7.23 (d,J = 8.4 Hz, 2H), 5.83 (s, 1H), 5.52 (s, 1H), 5.04 (s, 2H), 4.94 (s, 2H), 3.74 (s, 3H), 3.14 (s, 3H), 2.58 (s, 3H), 2.09 (t,J = 1.3 Hz, 3H) | 537.35 | |
N-((1,2,4-噁二唑-5-基)甲基)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 9.60 (s, 1H), 8.21 (s, 1H), 8.17 - 8.10 (m, 2H), 7.74 - 7.67 (m, 2H), 7.34 - 7.23 (m, 4H), 5.91 (s, 1H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.15 (s, 2H), 3.62 (s, 3H), 3.07 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 523.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((5-甲基-1,2,4-噁二唑-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.40 (d,J = 8.2 Hz, 2H), 7.26 (d,J = 8.4 Hz, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 4.76 (s, 1H), 4.62 (s, 1H), 3.61 (s, 3H), 3.03 (s, 2H), 2.96 (s, 1H), 2.60 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 537.2 | |
(R)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1-環丙基-2-甲氧基乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.27 (d,J = 8.5 Hz, 1H), 8.21 (s, 1H), 7.83 - 7.77 (m, 2H), 7.73 - 7.67 (m, 2H), 7.32 - 7.23 (m, 4H), 5.79 (s, 3H), 5.53 (d,J = 1.7 Hz, 1H), 3.68 - 3.61 (m, 4H), 3.48 (qd,J = 9.9, 6.2 Hz, 2H), 3..24(s, 3H), 1.95 (d,J = 1.2 Hz, 3H), 0.95 (dd,J = 8.1, 5.0 Hz, 1H), 0.45 (dt,J = 8.7, 4.1 Hz, 1H), 0.37 - 0.22 (m, 3H). | 525.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-羥基-2-甲基丙基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.35 (s, 1H), 7.60 (d,J = 8.0 Hz, 3H), 7.44 (d,J = 7.8 Hz, 2H), 7.32 (d,J = 7.8 Hz, 2H), 7.22 (d,J = 8.3 Hz, 2H), 5.83 (s, 1H), 5.52 (d,J = 1.5 Hz, 1H), 3.75 (s, 3H), 3.62 (s, 2H), 3.14 (s, 3H), 2.09 (t,J = 1.2 Hz, 3H), 1.33 (s, 6H), 1.01 (s, 1H). | 513.45 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-(甲氧基甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.38 (s, 1H), 8.20 (s, 1H), 7.85 - 7.63 (m, 2H), 7.51 - 7.18 (m, 4H), 7.15 - 7.06 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.76 (d,J = 8.2 Hz, 1H), 5.85 (s, 1H), 5.54 (t,J = 1.6 Hz, 1H), 4.45 (s, 2H), 3.63 (s, 3H), 3.20 (s, 3H), 2.33 (d,J = 5.9 Hz, 3H), 1.98 (s, 3H). | 535.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-((二甲基胺基)甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.28 (d, J = 8.4 Hz, 1H), 8.19 (s, 1H), 7.72 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 8.5, 2.0 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.10 - 7.04 (m, 3H), 7.01 (d, J = 7.3 Hz, 1H), 6.74 (d, J = 8.1 Hz, 1H), 5.85 (s, 1H), 5.71 (s, 2H), 5.54 (t, J = 1.6 Hz, 1H), 3.65 (s, 3H), 3.47 (s, 2H), 2.35 (s, 3H), 2.14 (s, 6H), 1.99 (s, 3H). | 548.30 | |
N-(4-(4-胺基-7-甲基-5-(5-((6-甲基吡啶-2-基)氧基)吡嗪-2-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 7.83 (dd,J = 31.7, 8.0 Hz, 3H), 7.66 (s, 1H), 7.59 - 7.28 (m, 4H), 7.12 (d,J = 7.4 Hz, 1H), 6.97 (d,J = 8.1 Hz, 1H), 5.83 (s, 1H), 5.56 (s, 1H), 3.57 (s, 3H), 2.35 (s, 3H), 1.97 (s, 3H). | 493.20 | |
N-(4-(4-胺基-5-(3-氰基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ: 9.92 (s, 1H), 8.27 (s, 1H), 7.82 (t,J = 7.8 Hz, 1H), 7.76 (d,J = 8.6 Hz, 2H), 7.71 (s, 1H), 7.47 (dd,J = 8.7, 2.2 Hz, 1H), 7.30 (d,J = 8.6 Hz, 2H), 7.23 (d,J = 8.6 Hz, 1H), 7.11 (d,J = 7.3 Hz, 1H), 6.97 (d,J = 8.1 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.63 (s, 3H), 2.35 (s, 3H), 1.96 (s, 3H).2.44 (s, 3H), 1.96 (d,J = 1.2 Hz, 3H). | 516.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.23 (s, 1H), 7.71 - 7.69 (m, 2H), 7.64 (t, J = 7.8 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.21 (dd, J1 = 8.0Hz, J2 = 1.2 Hz, 1H), 7.09 (dd, J1 = 11.6Hz, J2 = 1.2 Hz, 1H), 5.82 (t, J = 1.0 Hz, 1H), 5.55 (d, J = 1.8 Hz, 1H), 4.58 - 4.55(m, 1H), 3.98 - 3.93 (m, 2H), 3.87 - 3.83 (m, 1H), 3.75 - 3.71 (m, 1H), 3.70 (s, 1H), 2.33 - 2.30(m, 1H), 2.05(s, 3H), 1.97 - 1.96(m, 1H). | 515.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)氰胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 8.19 (s, 1H), 7.73 (t,J = 7.8 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.28 - 7.21 (m, 2H), 7.13 - 7.05 (m, 2H), 7.02 (d,J = 7.3 Hz, 1H), 6.98 - 6.91 (m, 2H), 6.78 (d,J = 8.1 Hz, 1H), 5.90 (s, 2H), 3.60 (s, 3H), 2.35 (s, 3H). | 448.20 | |
5-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)嘧啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.97 (s, 2H), 8.26 (s, 1H), 7.75 (s, 1H), 7.47 - 7.26 (m, 2H), 7.25 - 7.10 (m, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.83 (d,J = 8.2 Hz, 1H), 3.76 (s, 3H), 2.36 (s, 3H). | 435.20 | |
(S)-N-(4-(4-胺基-5-(1-(4-(二甲基胺基)-2-甲基丁醯基)哌啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.15 (s, 1H), 7.81 - 7.79 (m, 2H), 7.56 - 7.48 (m, 3H), 6.77 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.87 - 5.85 (m, 2H), 5.57 - 5.56 (m, 1H), 5.39 - 5.37 (m, 1H), 3.67 (s, 3H), 2.67 - 2.62 (m, 1H), 2.47 - 2.45 (m, 1H), 2.41(s, 3H), 2.28 - 2.23 (m, 1H), 2.08 (s, 3H), 2.07 - 2.02 (m, 2H), 1.86 (d,J = 6.4 Hz, 1H). | 495.40 | |
(R)-N-(4-(4-胺基-5-(1-(4-(二甲基胺基)-2-甲基丁醯基)哌啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.15 (s, 1H), 7.81 - 7.79 (m, 2H), 7.56 - 7.48 (m, 3H), 6.78 (d, J = 7.2 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 5.87 - 5.85 (m, 2H), 5.57 (d, J = 1.7 Hz, 1H), 5.39 - 5.37 (m, 1H), 3.67 (s, 3H), 2.67 - 2.62 (m, 1H), 2.47 - 2.45 (m, 1H), 2.41(s, 3H), 2.28 - 2.23 (m, 1H), 2.08 (s, 3H), 2.07 - 2.02 (m, 2H), 1.86 (m, 1H). | 495.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.82 (s, 1H), 8.21 (s, 1H), 7.61 (s, 2H), 7.45 (d,J = 8.2 Hz, 2H), 7.23 (dd,J = 18.0, 8.2 Hz, 3H), 5.80 (s, 2H), 5.52 (s, 1H), 3.43 (s, 7H), 1.95 (s, 3H), 1.90 (s, 3H), 1.88 - 1.68 (m, 4H). | 495.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.22 (s, 1H), 7.76 (dd,J = 12.4, 2.0 Hz, 1H), 7.48 (dd,J = 8.4, 1.6 Hz, 3H), 7.31 - 7.21 (m, 3H), 6.01 (s, 1H), 5.82 (s, 1H), 5.57 (s, 1H), 3.55 (s, 3H), 3.43 (dt,J = 17.2, 6.6 Hz, 4H), 1.95 (t,J = 1.2 Hz, 3H), 1.83 (dt,J = 17.8, 7.4 Hz, 4H). | 499.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.31 (s, 1H), 8.21 (s, 1H), 7.63 - 7.40 (m, 2H), 7.34 (d,J = 8.1 Hz, 1H), 7.30 - 7.24 (m, 2H), 7.22 (d,J = 2.0 Hz, 1H), 7.12 (dd,J = 8.0, 2.0 Hz, 1H), 5.85 (s, 1H), 5.50 (s, 1H), 3.62 (s, 3H), 3.43 (d,J = 21.0 Hz, 4H), 2.15 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H), 1.88 - 1.68 (m, 4H). | 495.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲氧基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.21 (s, 1H), 7.89 (d,J = 8.8 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.33 - 7.26 (m, 2H), 6.94 (d,J = 6.6 Hz, 2H), 5.85 (s, 1H), 5.54 - 5.48 (m, 1H), 3.67 (d,J = 2.8 Hz, 6H), 3.44 (dt,J = 18.4, 6.6 Hz, 4H), 1.96 (d,J = 1.4 Hz, 3H), 1.90 - 1.79 (m, 4H). | 511.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-(1-甲基-2-側氧基吡咯啶-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.74 - 7.66 (m, 2H), 7.38 (d,J = 7.7 Hz, 2H), 7.29 - 7.22 (m, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 4.58 (t,J = 9.3 Hz, 1H), 3.61 (s, 3H), 3.32 (d,J = 8.7 Hz, 1H), 3.18 (d,J = 8.7 Hz, 1H), 2.77 (t,J = 13.3 Hz, 6H), 2.16 (s, 2H), 1.95 (s, 3H). | 538.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1-甲基-2-側氧基吡咯啶-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.72 (d,J = 8.4 Hz, 1H), 8.21 (s, 1H), 7.81 (d,J = 8.2 Hz, 2H), 7.72 - 7.66 (m, 2H), 7.29 (d,J = 8.1 Hz, 2H), 7.27 - 7.21 (m, 2H), 5.93 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 4.57 (q,J = 9.0 Hz, 1H), 3.62 (s, 3H), 3.34 (s, 2H), 2.77 (s, 3H), 2.32 (s, 1H), 1.94 (s, 4H). | 524.30 | |
N-(4-(4-胺基-7-甲基-5-(6-(吡咯啶-1-羰基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.31 (dd,J = 1.9, 1.1 Hz, 1H), 8.23 (s, 1H), 7.79 - 7.64 (m, 4H), 7.33 - 7.16 (m, 2H), 6.09 (s, 2H), 5.86 - 5.76 (m, 1H), 5.54 (q,J = 1.5 Hz, 1H), 3.63 (d,J = 10.6 Hz, 5H), 3.52 - 3.42 (m, 2H), 1.95 (t,J = 1.2 Hz, 3H), 1.83 (dqd,J = 5.1, 3.7, 1.7 Hz, 4H). | 482.35 | |
(R)-N-(4-(4-胺基-5-(4-(2-(甲氧基甲基)吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.45 (d,J = 7.8 Hz, 2H), 7.26 (dd,J = 8.4, 2.8 Hz, 4H), 5.80 (s, 2H), 5.53 (t,J = 1.5 Hz, 1H), 4.25 (s, 1H), 3.62 (s, 4H), 3.50 - 3.35 (m, 3H), 3.30 (s, 2H), 2.91 (s, 1H), 2.04 - 1.95 (m, 1H), 1.95 (d,J = 1.2 Hz, 3H), 1.85 (s, 2H), 1.70 (s, 1H). | 525.40 | |
(S)-N-(4-(4-胺基-5-(4-(2-(甲氧基甲基)吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.45 (d,J = 7.7 Hz, 2H), 7.26 (dd,J = 8.4, 2.8 Hz, 4H), 5.95 (s, 2H), 5.80 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 4.25 (s, 1H), 4.04 (s, 0H), 3.62 (s, 3H), 3.42 (d,J = 7.1 Hz, 1H), 2.90 (s, 1H), 2.04 - 1.92 (m, 4H), 1.85 (s, 3H), 1.70 (s, 1H). | 525.45 | |
(R)-N-(4-(4-胺基-5-(4-(2-氰基吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (s, 1H), 7.74 - 7.68 (m, 2H), 7.57 (d,J = 7.8 Hz, 2H), 7.33 - 7.23 (m, 4H), 5.80 (s, 1H), 5.53 (d,J = 2.0 Hz, 1H), 4.88 (t,J = 6.7 Hz, 1H), 3.70 - 3.60 (m, 4H), 3.59 - 3.50 (m, 1H), 2.33 (s, 1H), 2.18 (dq,J = 12.2, 6.1 Hz, 1H), 2.05 - 1.90 (m, 5H). | 506.20 | |
(R)-N-(4-(4-胺基-5-(4-(3-甲氧基哌啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.24 (s, 1H), 7.70 (d,J = 8.3 Hz, 2H), 7.33 (s, 2H), 7.26 (dd,J = 8.3, 6.1 Hz, 4H), 6.14 (s, 2H), 5.79 (s, 1H), 5.53 (d,J = 1.6 Hz, 1H), 3.62 (s, 4H), 3.52 (s, 3H), 3.22 (s, 3H), 2.98 (s, 1H), 1.94 (d,J = 1.5 Hz, 3H), 1.67 (s, 3H), 1.42 (s, 1H). | 525.35 | |
(S)-N-(4-(4-胺基-5-(4-(3-甲氧基哌啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.69 (d,J = 8.4 Hz, 2H), 7.33 (d,J = 7.8 Hz, 2H), 7.30 - 7.22 (m, 4H), 5.95 (s, 0H), 5.79 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 3.97-3.63 (m, 4H), 3.62-3.31 (m, 3H), 3.29-3.13 (m, 3H), 2.98 (s, 1H), 1.94 (t,J = 1.3 Hz, 3H), 1.85 (s, 1H), 1.67 (s, 1H), 1.57 (s, 1H), 1.41 (s, 1H). | 525.45 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.19 (d,J = 14.1 Hz, 2H), 7.75 - 7.69 (m, 2H), 7.61 (d,J = 7.8 Hz, 1H), 7.34 - 7.26 (m, 2H), 6.93 (d,J = 1.5 Hz, 1H), 6.86 (dd,J = 7.8, 1.5 Hz, 1H), 6.02 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.43 (d,J = 7.0 Hz, 1H), 3.82 (td,J = 10.2, 9.7, 6.7 Hz, 2H), 3.71 (s, 3H), 3.71 (td,J = 8.2, 5.6 Hz, 1H), 3.60 (s, 3H), 3.55 (dd,J = 8.9, 4.0 Hz, 1H), 2.15 (dq,J = 12.6, 7.6 Hz, 1H), 1.95 (d,J = 1.2 Hz, 3H), 1.89 - 1.80 (m, 1H). | 527.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-(氧雜環丁-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.24 - 8.15 (m, 2H), 7.70 (d,J = 8.2 Hz, 2H), 7.59 (d,J = 7.8 Hz, 1H), 7.25 (d,J = 8.3 Hz, 2H), 6.93 (s, 1H), 6.84 (d,J = 7.9 Hz, 1H), 5.80 (s, 1H), 5.59 - 5.51 (m, 2H), 5.15 (t,J = 6.8 Hz, 2H), 4.60 (t,J = 6.9 Hz, 2H), 4.42 (s, 1H), 3.81 (td,J = 10.1, 9.6, 6.5 Hz, 2H), 3.70 (s, 4H), 3.54 (dd,J = 8.8, 4.0 Hz, 1H), 2.14 (dq,J = 14.6, 7.6 Hz, 1H), 1.95 (s, 3H), 1.84 (s, 1H). | 569.40 | |
N-(4-(4-胺基-5-(4-(2-氰基吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.57 (d,J = 7.7 Hz, 2H), 7.28 (dd,J = 13.0, 8.2 Hz, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 4.87 (s, 1H), 3.61 (s, 3H), 3.55 (s, 1H), 2.22 - 2.14 (m, 1H), 1.94 (d,J = 1.5 Hz, 3H). | 506.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(1,3-二氟丙-2-基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.22 (s, 1H), 7.74 - 7.67 (m, 2H), 7.37 (s, 1H), 7.27 (dd,J = 8.7, 6.8 Hz, 5H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.95 - 4.30 (dd,J = 8.7, 6.8 Hz, 5H), 3.62 (s, 3H), 2.96 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 519.4 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-(二甲基胺基)乙基)-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.41 (s, 1H), 7.56 (dd,J = 7.5, 5.7 Hz, 3H), 7.41 (d,J = 7.9 Hz, 2H), 7.35 (d,J = 8.2 Hz, 2H), 7.26 - 7.18 (m, 2H), 5.83 (d,J = 1.2 Hz, 1H), 5.52 (d,J = 1.6 Hz, 1H), 4.26 (s, 2H), 3.74 (s, 3H), 3.61 (s, 2H), 2.46 (s, 2H), 2.24 - 2.05 (m, 9H). | 580.3 | |
N-(4-(4-胺基-5-(4-(2-(甲氧基甲基)哌啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.73 - 7.66 (m, 2H), 7.32 (d,J = 7.8 Hz, 2H), 7.29 - 7.22 (m, 4H), 5.94 (s, 2H), 5.79 (s, 1H), 5.53 (d,J = 1.9 Hz, 1H), 3.61 (s, 3H), 3.32 (s, 4H), 2.94 (s, 1H), 1.94 (t,J = 1.2 Hz, 3H), 1.57 (s, 4H), 1.38 (s, 1H). | 539.25 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)吡啶醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.73 (t,J = 6.2 Hz, 1H), 8.33 (d,J = 2.1 Hz, 1H), 8.23 (s, 1H), 7.97 (d,J = 8.0 Hz, 1H), 7.77 (dd,J = 8.0, 2.2 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.30 - 7.24 (m, 2H), 6.13 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.61 (s, 3H), 3.32 (d,J = 13.5 Hz, 1H), 2.55 (d,J = 7.4 Hz, 1H), 2.01 - 1.90 (m, 1H), 1.95 (s, 4H), 1.88 - 1.76 (m, 2H), 1.76 - 1.64 (m, 2H). | 496.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.42 (t,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.78 (d,J = 8.0 Hz, 2H), 7.70 (d,J = 8.5 Hz, 2H), 7.28 (dd,J = 10.3, 8.3 Hz, 4H), 5.91 -5.80 (s, 2H), 5.53 (s, 1H), 3.61 (s, 3H), 3.28 (t,J = 6.4 Hz, 3H), 2.05 - 1.94 (m, 1H), 1.99 (s, 2H), 1.95 (s, 2H), 1.82 (p,J = 7.2, 6.3 Hz, 2H), 1.71 (p,J = 8.6, 7.8 Hz, 2H). | 495.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.21 (s, 1H), 8.07 (t,J = 5.8 Hz, 1H), 7.75 - 7.69 (m, 2H), 7.66 (d,J = 7.9 Hz, 1H), 7.34 - 7.27 (m, 2H), 6.93 (d,J = 1.5 Hz, 1H), 6.86 (dd,J = 7.9, 1.5 Hz, 1H), 6.01 (s, 1H), 5.81 (s, 1H), 5.54 (s, 1H), 3.72 (s, 3H), 3.34 - 3.26 (m, 5H), 2.00 (dd,J = 8.5, 3.9 Hz, 1H), 1.96 (s, 4H), 1.90 - 1.78 (m, 2H), 1.1-1.73 (ddd,J = 17.0, 8.4, 4.5 Hz, 3H). | 525.30 | |
2-乙醯基-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.75 - 7.67 (m, 2H), 7.51 (d,J = 7.7 Hz, 1H), 7.45 (d,J = 1.4 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.24 (dd,J = 7.7, 1.5 Hz, 1H), 6.20 (s, 1H), 5.79 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.61 (s, 3H), 3.45 (dd,J = 14.0, 7.6 Hz, 1H), 3.38 - 3.28 (m, 1H), 2.74 (q,J = 7.6 Hz, 1H), 2.03 - 1.97 (m, 1H), 1.98 (s, 1H), 1.95 (t,J = 1.2 Hz, 3H), 1.84 - 1.72 (m, 4H), 1.51 (s, 3H). | 537.4 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)-2-氟苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.25 (dt,J = 6.0, 2.9 Hz, 1H), 8.22 (s, 1H), 7.78 - 7.70 (m, 2H), 7.54 (t,J = 7.8 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.10 (dd,J = 7.9, 1.6 Hz, 1H), 7.06 (dd,J = 11.4, 1.6 Hz, 1H), 5.81 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.59 (s, 3H), 3.27 (dd,J = 7.0, 5.8 Hz, 2H), 2.48 (s, 1H), 2.04 - 1.92 (m, 5H), 1.89 - 1.77 (m, 2H), 1.80 - 1.65 (m, 2H). | 513.2 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟-N-(2-甲氧基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.21 (s, 1H), 8.00 (q,J = 4.3, 2.8 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.56 (t,J = 8.0 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.12 - 7.03 (m, 2H), 5.80 (t,J = 1.0 Hz, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.59 (s, 3H), 3.31 (d,J = 6.0 Hz, 2H), 3.13 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H), 1.12 (s, 6H). | 531.3 | |
5-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)吡啶醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.37 (d,J = 2.1 Hz, 1H), 8.30 (t,J = 6.2 Hz, 1H), 8.22 (s, 1H), 7.99 (d,J = 8.0 Hz, 1H), 7.81 - 7.69 (m, 3H), 7.30 - 7.24 (m, 2H), 6.12 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 3.36 (d,J = 6.2 Hz, 2H), 3.15 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H), 1.11 (s, 6H). | 514.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-甲基-1H-吡唑-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.86 (t,J = 5.9 Hz, 1H), 8.21 (s, 1H), 7.83 (d,J = 8.0 Hz, 2H), 7.70 (d,J = 8.6 Hz, 2H), 7.56 (d,J = 2.2 Hz, 1H), 7.32 - 7.23 (m, 4H), 6.12 (d,J = 2.2 Hz, 1H), 5.91 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 4.39 (d,J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.61 (s, 3H), 1.95 (s, 3H), 1.29 (s, 1H). | 521.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((四氫呋喃-2-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.50 (t,J = 5.9 Hz, 1H), 8.22 (s, 1H), 7.84 - 7.77 (m, 2H), 7.74 - 7.66 (m, 2H), 7.32 - 7.23 (m, 4H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.97 (p,J = 6.3 Hz, 1H), 3.82 - 3.73 (m, 1H), 3.67 - 3.57 (m, 1H), 3.62 (s, 3H), 3.25 (s, 2H), 1.95 (t,J = 1.2 Hz, 3H), 1.94 - 1.85 (m, 1H), 1.85 - 1.77 (m, 2H), 1.65 - 1.54 (m, 1H). | 511.3 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-甲基吡咯啶-2-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.35 (s, 1H), 8.21 (s, 1H), 7.82 - 7.75 (m, 2H), 7.74 - 7.66 (m, 2H), 7.33 - 7.23 (m, 4H), 5.80 (d,J = 1.4 Hz, 1H), 5.56 - 5.51 (m, 1H), 3.61 (s, 3H), 3.46 (dt,J = 12.9, 5.0 Hz, 1H), 3.16 (s, 1H), 2.97 (s, 1H), 2.34 (s, 4H), 2.17 (s, 1H), 1.95 (t,J = 1.2 Hz, 3H), 1.85 (s, 1H), 1.63 (s, 3H). | 524.3 | |
N-(4-(4-胺基-7-甲基-5-(4-(1-甲基-1H-吡唑-3-基氧基)環己-1-烯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.13 (s, 1H), 7.85 - 7.79 (m, 2H), 7.49 - 7.42 (m, 3H), 5.83 (s, 1H), 5.68 (dd,J = 11.6, 3.0 Hz, 2H), 5.58 - 5.53 (m, 1H), 4.83 - 4.74 (m, 1H), 3.66 (s, 3H), 3.59 (s, 3H), 2.55 (s, 1H), 2.33 (d,J = 18.3 Hz, 1H), 2.16 - 2.06 (m, 1H), 2.01 - 1.91 (m, 4H), 1.89 (q,J = 6.4 Hz, 1H), 1.80 (d,J = 9.1 Hz, 1H). | 484.4 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(1-甲基-1H-吡唑-3-基氧基)環己-1-烯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.13 (s, 1H), 7.86 - 7.79 (m, 2H), 7.50 - 7.42 (m, 3H), 5.83 (d,J = 1.4 Hz, 1H), 5.72 - 5.64 (m, 2H), 5.56 (t,J = 1.5 Hz, 1H), 4.78 (q,J = 2.7 Hz, 1H), 3.66 (s, 3H), 3.58 (s, 3H), 2.55 (d,J = 8.1 Hz, 1H), 2.33 (d,J = 18.2 Hz, 1H), 2.18 - 2.06 (m, 1H), 2.03 - 1.93 (m, 4H), 1.89 (q,J = 6.3 Hz, 1H), 1.83 - 1.73 (m, 1H). | 484.3 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(1-甲基-1H-吡唑-3-基氧基)環己-1-烯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.13 (s, 1H), 7.86 - 7.79 (m, 2H), 7.49 - 7.42 (m, 3H), 5.83 (s, 1H), 5.71 - 5.64 (m, 2H), 5.56 (t,J = 1.5 Hz, 1H), 4.81 - 4.75 (m, 1H), 3.66 (s, 3H), 3.59 (s, 3H), 2.52 (s, 1H), 2.33 (d,J = 18.3 Hz, 1H), 2.12 (d,J = 17.4 Hz, 1H), 2.04 - 1.93 (m, 4H), 1.88 (q,J = 6.3 Hz, 1H), 1.80 (d,J = 8.6 Hz, 1H). | 484.3 | |
N-(4-(5-(4-(3-氮雜雙環[3.2.1]辛烷-3-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.09 (s, 1H), 7.90 - 7.76 (m, 2H), 7.43 (d,J = 8.2 Hz, 2H), 6.52 (s, 2H), 5.83 (s, 1H), 5.75 (s, 1H), 5.55 (s, 1H), 4.17 (d,J = 12.6 Hz, 1H), 4.08 (d,J = 12.8 Hz, 0H), 3.73 (s, 1H), 3.58 (s, 3H), 3.14 - 3.02 (m, 2H), 2.57 (d,J = 12.0 Hz, 1H), 2.19 (s, 4H), 1.97 (s, 3H), 1.86 (s, 1H), 1.65 (s, 1H), 1.54 (s, 7H), 1.30 (s, 1H), 1.24 (s, 1H). | 525.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.01 (s, 1H), 8.38 (s, 1H), 8.26 (s, 1H), 7.90 (t,J = 6.1 Hz, 1H), 7.88 - 7.82 (m, 2H), 7.51 - 7.44 (m, 2H), 5.89 (s, 1H), 5.84 (s, 1H), 5.57 (d,J = 1.9 Hz, 1H), 3.67 (s, 3H), 3.25 (dd,J = 13.6, 6.8 Hz, 1H), 3.08 (s, 3H), 3.01 (dd,J = 13.6, 5.3 Hz, 1H), 2.74 (d,J = 4.7 Hz, 1H), 2.28 (s, 1H), 1.98 (d,J = 1.1 Hz, 3H), 1.92 (d,J = 12.0 Hz, 1H), 1.80 (d,J = 12.8 Hz, 2H), 1.66 (d,J = 11.7 Hz, 1H), 1.03 (d,J = 5.3 Hz, 6H). | 517.25 | |
N-(4-(4-胺基-7-甲基-5-(4-((S)-2-甲基哌啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (d,J = 1.8 Hz, 1H), 8.10 (s, 1H), 7.84 - 7.77 (m, 2H), 7.46 - 7.40 (m, 2H), 6.54 (s, 2H), 5.83 (s, 1H), 5.80 - 5.73 (m, 1H), 5.55 (d,J = 2.0 Hz, 1H), 4.76 (s, 1H), 4.31 (s, 1H), 3.75 (d,J = 12.4 Hz, 1H), 3.58 (s, 3H), 3.07 (s, 1H), 3.01 (s, 1H), 2.60 (s,2H), 2.31 (s, 1H), 2.23 (s, 2H), 2.08 (s, 1H), 1.98 (d,J = 1.5 Hz, 4H), 1.91 (s, 1H), 1.81 (d,J = 17.7 Hz, 1H), 1.60 (s, 6H), 1.51 (d,J = 14.5 Hz, 1H), 1.20 (s, 2H), 1.08 - 0.98 (m, 2H). | 513.35 | |
N-(4-(4-胺基-5-(4-(5-氟嘧啶-2-基氧基)環己-1-烯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.68 (s, 2H), 8.13 (s, 1H), 7.87 - 7.79 (m, 2H), 7.50 - 7.42 (m, 2H), 5.83 (t,J = 1.0 Hz, 1H), 5.74 - 5.67 (m, 1H), 5.55 (t,J = 1.5 Hz, 1H), 5.24 - 5.18 (m, 1H), 3.58 (s, 3H), 2.67 - 2.63 (s, 1H), 2.40 (s, 1H), 2.13 - 2.02 (m, 2H), 1.98 (t,J = 1.2 Hz, 3H), 1.93 - 1.83 (m, 2H). | 500.2 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)環己-3-烯-1-甲醯胺 | 31 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.10 (s, 1H), 7.85 - 7.77 (m, 3H), 7.46 - 7.39 (m, 2H), 6.45 (s, 2H), 5.83 (s, 1H), 5.81 - 5.75 (m, 1H), 5.58 - 5.53 (m, 1H), 3.57 (s, 3H), 3.13 (dt,J = 13.0, 6.4 Hz, 1H), 3.02 (dt,J = 13.0, 6.0 Hz, 1H), 2.47 (t,J = 5.9 Hz, 1H), 2.43 - 2.33 (m, 1H), 2.35 - 2.26 (m, 1H), 2.22 (d,J = 5.3 Hz, 1H), 1.98 (d,J = 1.2 Hz, 3H), 1.98 - 1.86 (m, 4H), 1.85 - 1.70 (m, 2H), 1.68 - 1.55 (m, 4H). (m, 1H) | 499.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-氟-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.59 (t,J = 6.3 Hz, 1H), 8.21 (s, 1H), 7.96 - 7.79 (m, 2H), 7.76 - 7.60 (m, 2H), 7.43 - 6.93 (m, 4H), 5.79 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 3.61 (s, 3H), 3.49 (d,J = 6.2 Hz, 1H), 3.44 (d,J = 6.2 Hz, 1H), 1.94 (t,J = 1.3 Hz, 3H), 1.35 (s, 3H), 1.29 (s, 3H). | 501.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-N-甲基甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.79 - 7.69 (m, 1H), 7.39 - 7.32 (m, 2H), 7.32 - 7.26 (m, 2H), 7.26 - 7.19 (m, 2H), 7.13 - 7.05 (m, 2H), 7.02 (d,J = 7.3 Hz, 1H), 6.76 (d,J = 8.1 Hz, 1H), 5.93 (s, 2H), 5.04 (p,J = 1.6 Hz, 1H), 4.86 (t,J = 1.3 Hz, 1H), 3.62 (s, 3H), 3.27 (s, 3H), 2.35 (s, 3H), 1.69 (d,J = 1.3 Hz, 3H). | 505.25 | |
4-(4-胺基-7-甲基-6-(4-(N-甲基甲基丙烯醯胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 2H), 7.86 - 7.76 (m, 2H), 7.39 - 7.19 (m, 6H), 5.95 (s, 2H), 5.09 - 5.04 (m, 1H), 4.86 (s, 1H), 3.62 (s, 3H), 3.34 (s, 2H), 3.27 (s, 3H), 3.15 (s, 3H), 1.70 (d,J = 1.5 Hz, 3H), 1.11 (s, 6H). | 527.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2,6-二氟-N-(2-甲氧基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.50 (t,J = 6.1 Hz, 1H), 8.22 (s, 1H), 7.77 (d,J = 2.0 Hz, 1H), 7.38 - 7.28 (m, 2H), 6.94 (d,J = 8.1 Hz, 2H), 6.08 (s, 2H), 5.82 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 3.30 (d,J = 6.2 Hz, 2H), 3.12 (s, 3H), 1.96 (d,J = 1.2 Hz, 3H), 1.12 (s, 6H). | 549.45 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((3-氟氧雜環丁-3-基)甲基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.77 - 7.65 (m, 2H), 7.37 (d,J = 7.8 Hz, 2H), 7.33 - 7.21 (m, 4H), 5.95 (s, 1H), 5.80 (t,J = 1.1 Hz, 1H), 5.53 (t,J = 1.5 Hz, 1H), 4.66 (d,J = 20.1 Hz, 4H), 4.06 (d,J = 22.7 Hz, 2H), 3.62 (s, 3H), 2.97 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 529.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3-甲氧基-2,2-二甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.22 (d,J = 12.8 Hz, 2H), 7.88 - 7.71 (m, 2H), 7.74 - 7.50 (m, 2H), 7.40 - 6.99 (m, 4H), 5.79 (s, 3H), 5.53 (d,J = 1.9 Hz, 1H), 3.61 (s, 3H), 3.32 (s, 3H), 3.26 (s, 2H), 3.17 (d,J = 6.3 Hz, 2H), 1.94 (d,J = 1.5 Hz, 3H), 0.86 (s, 6H). | 527.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.10 (s, 1H), 7.84 - 7.77 (m, 2H), 7.47 - 7.39 (m, 2H), 6.51 (s, 2H), 5.83 (s, 1H), 5.77 (s, 1H), 5.55 (d,J = 1.9 Hz, 1H), 3.58 (s, 3H), 3.55 - 3.48 (m, 1H), 3.47 - 3.39 (m, 1H), 3.31 - 3.22 (m, 2H), 2.83 (t,J = 6.0 Hz, 1H), 2.26 (s, 2H), 1.98 (d,J = 1.3 Hz, 3H), 1.88 (dd,J = 13.4, 6.6 Hz, 4H), 1.77 (q,J = 6.7 Hz, 2H), 1.63 (d,J = 6.2 Hz, 2H). | 485.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.10 (s, 1H), 7.84 - 7.77 (m, 2H), 7.47 - 7.39 (m, 2H), 6.51 (s, 2H), 5.83 (s, 1H), 5.77 (s, 1H), 5.55 (d,J = 1.9 Hz, 1H), 3.58 (s, 3H), 3.55 - 3.48 (m, 1H), 3.47 - 3.39 (m, 1H), 3.31 - 3.22 (m, 2H), 2.83 (t,J = 6.0 Hz, 1H), 2.26 (s, 2H), 1.98 (d,J = 1.3 Hz, 3H), 1.88 (dd,J = 13.4, 6.6 Hz, 4H), 1.77 (q,J = 6.7 Hz, 2H), 1.63 (d,J = 6.2 Hz, 2H). | 485.25 | |
N-(4-(4-胺基-5-(3-氰基-4-((5-氟嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.83 (s, 2H), 8.22 (s, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.76 - 7.73 (m, 2H), 7.55 - 7.53 (m, 1H), 7.45 (s, 1H), 7.33 (d, J = 8.6 Hz, 2H), 6.05 (s, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 3.59 (s, 3H), 1.96 (t, J = 1.2 Hz, 3H). | 521.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.41 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.75 (d, 2H), 7.35 (d, 2H), 7.16 - 7.07 (m, 2H), 6.98 (d,J = 2.0 Hz, 1H), 6.85 (dd,J = 8.1, 1.9 Hz, 1H), 5.96 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.61 (s, 3H), 3.55 (s, 3H), 2.40 (s, 3H), 1.96 (s, 3H). | 528.20 | |
N-(4-(4-胺基-5-(4-((5-氟嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.76 (s, 2H), 8.20 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.32 - 7.29 (m, 3H), 7.21 (d, J = 8.7 Hz, 2H), 5.80 (t, J = 1.1 Hz, 2H), 5.54 (t, J = 1.5 Hz, 1H), 3.60 (s, 3H), 1.95 (t, J = 1.2 Hz, 3H). | 496.15 | |
N-(4-(4-胺基-5-(4-((5-氟嘧啶-2-基)氧基)-3-甲基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.12 (s, 1H), 8.73 (s, 2H), 8.22 (s, 1H), 7.79 (dd,J = 12.4, 2.0 Hz, 1H), 7.53 (dd,J = 8.4, 2.0 Hz, 1H), 7.34 (t,J = 8.4 Hz, 1H), 7.24 (s, 1H), 7.11 (d,J = 2.3 Hz, 2H), 5.83 (s, 1H), 5.59 (s, 1H), 3.53 (s, 3H), 2.06 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 528.35 | |
N-(4-(4-胺基-5-(3,5-二氟-4-((5-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.54 (s, 2H), 8.22 (s, 1H), 7.82 - 7.76 (m, 2H), 7.39 - 7.33 (m, 2H), 7.07 (d,J = 8.8 Hz, 2H), 6.12 (s, 2H), 5.83 (s, 1H), 5.56 (s, 1H), 3.58 (s, 3H), 2.24 (s, 3H), 1.97 (d,J = 1.2 Hz, 3H). | 528.15 | |
N-(4-(4-胺基-5-(3,5-二氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.51 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.78 (d,J = 8.7 Hz, 2H), 7.34 (d, 2H), 7.24 (d,J = 5.0 Hz, 1H), 7.06 (d,J = 8.8 Hz, 2H), 6.12 (s, 2H), 5.82 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 2.44 (s, 3H), 1.96 (d,J = 1.2 Hz, 3H). | 520.25 | |
N-(4-(4-胺基-5-(4-((5-(二甲基胺基)嘧啶-2-基)氧基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.20 (d,J = 9.0 Hz, 3H), 7.87 - 7.65 (m, 2H), 7.45 - 7.24 (m, 3H), 7.21 - 7.03 (m, 2H), 5.68 (d,J = 108.0 Hz, 2H), 3.59 (s, 3H), 2.89 (s, 6H), 1.96 (s, 3H). | 539.30 | |
N-(4-(4-胺基-5-(4-((5-甲氧基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.43 (s, 2H), 8.20 (s, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.34 - 7.25 (m, 4H), 7.19 - 7.12 (m, 2H), 5.80 (s, 1H), 5.54 (d, J = 1.8 Hz, 1H), 3.86 (s, 3H), 3.60 (s, 3H), 1.95 (t, J = 1.3 Hz, 3H). | 508.20 | |
N-(4-(4-胺基-5-(3-(二甲基胺基)-4-((5-氟嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.72 (s, 2H), 8.20 (s, 1H), 7.91 - 7.63 (m, 2H), 7.34 (d,J = 8.6 Hz, 2H), 7.16 - 6.99 (m, 1H), 6.86 (s, 2H), 5.81 (s, 1H), 5.55 (d,J = 1.9 Hz, 1H), 3.59 (s, 3H), 2.55 (s, 6H), 1.96 (t,J = 1.2 Hz, 3H). | 539.30 | |
N-(4-(4-胺基-5-(3-氟-4-((5-甲氧基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.43 (s, 2H), 8.21 (s, 1H), 7.80 - 7.73 (m, 2H), 7.38 - 7.29 (m, 3H), 7.18 (dd, J = 11.6, 2.0 Hz, 1H), 7.10 (dd, J = 8.4, 2.0 Hz, 1H), 5.99 (s, 2H), 5.81 (s, 1H), 5.54 (d, J = 1.9 Hz, 1H), 3.86 (s, 3H), 3.59 (s, 3H), 1.96 (t, J = 1.2 Hz, 3H). | 526.20 | |
N-(4-(4-胺基-5-(4-((5-氟嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.12 (s, 1H), 8.76 (s, 2H), 8.22 (s, 1H), 7.82 - 7.73 (m, 1H), 7.56 - 7.49 (m, 1H), 7.36 - 7.24 (m, 3H), 7.24 - 7.19 (m, 2H), 5.83 (s, 1H), 5.59 (d,J = 2.1 Hz, 1H), 3.54 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 514.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-((二甲基胺基)甲基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.21 (s, 1H), 8.20 (s, 1H), 7.73 (t,J = 7.8 Hz, 1H), 7.66 - 7.62 (m, 2H), 7.35 - 7.29 (m, 2H), 7.28 - 7.23 (m, 2H), 7.13 - 7.06 (m, 2H), 7.01 (d,J = 7.3 Hz, 1H), 6.79 (d,J = 8.1 Hz, 1H), 6.02 (d,J = 1.8 Hz, 3H), 5.58 (d,J = 1.6 Hz, 1H), 3.62 (s, 3H), 3.23 (s, 2H), 2.35 (s, 3H), 2.25 (s, 6H). | 534.25 | |
N-(6-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.09 (s, 1H), 10.04 (s, 1H), 8.90 (d,J = 2.5 Hz, 1H), 8.13 (s, 1H), 7.91 (dd,J = 8.8, 2.5 Hz, 1H), 7.78 (t,J = 7.8 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.35 - 7.16 (m, 2H), 7.07 (t,J = 7.6 Hz, 2H), 6.88 (d,J = 8.1 Hz, 1H), 5.85 (s, 1H), 5.58 (s, 1H), 2.39 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 478.30 | |
N-(4-(4-胺基-5-(2-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.20 (s, 1H), 7.71 (d,J = 8.7 Hz, 3H), 7.40 - 7.21 (m, 3H), 7.12 - 7.00 (m, 2H), 6.96 (dd,J = 8.4, 2.4 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 5.80 (s, 3H), 5.53 (t,J = 1.5 Hz, 1H), 3.65 (s, 3H), 2.37 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 509.25 | |
N-(4-(4-胺基-7-甲基-5-(5-((6-甲基吡啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (s, 1H), 7.65 (dd,J = 8.2, 7.3 Hz, 1H), 7.54 - 7.44 (m, 2H), 7.42 - 7.34 (m, 2H), 7.12 (d,J = 8.0 Hz, 1H), 7.01 (s, 2H), 6.96 - 6.91 (m, 2H), 6.88 (dd,J = 8.0, 2.0 Hz, 1H), 6.67 - 6.60 (m, 1H), 6.17 (dd,J = 16.8, 2.5 Hz, 1H), 6.08 (d,J = 11.3 Hz, 1H), 5.58 - 5.50 (m, 1H), 3.72 (s, 3H), 3.67(s, 3H), 3.28 (s, 3H), 2.29 (s, 3H). | 492.25 | |
N-(4-(4-胺基-5-(3-((二甲基胺基)甲基)-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.76 - 7.66 (m, 3H), 7.35 (d,J = 2.4 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.16 (dd,J = 8.4, 2.4 Hz, 1H), 6.99 (dd,J = 18.4, 7.8 Hz, 2H), 6.71 (d,J = 8.2 Hz, 1H), 5.98 (s, 2H), 5.79 (s, 1H), 5.53 (t,J = 1.6 Hz, 1H), 3.63 (s, 3H), 3.30 (s,2H), 2.31 (s, 3H), 2.00 (s, 6H), 1.95 (t,J = 1.2 Hz, 3H). | 548.30 | |
N-(4-(4-胺基-7-甲基-5-(1-((6-甲基吡啶-2-基)甲基)-2-側氧基-1,2-二氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.22 (s, 1H), 7.85 - 7.76 (m, 2H), 7.69 - 7.61 (m, 2H), 7.39 - 7.31 (m, 2H), 7.15 (d,J = 7.6 Hz, 1H), 6.93 (d,J = 7.7 Hz, 1H), 6.32 (s, 2H), 6.21 (d,J = 1.9 Hz, 1H), 6.00 (dd,J = 7.0, 2.0 Hz, 1H), 5.82 (d,J = 1.3 Hz, 1H), 5.55 (d,J = 1.6 Hz, 1H), 5.09 (s, 2H), 3.59 (s, 3H), 2.44 (s, 3H), 1.97 (t,J = 1.2 Hz, 3H). | 506.20 | |
N-(4-(4-胺基-7-甲基-5-(1-((6-甲基吡啶-2-基)甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.18 (s, 1H), 7.84 (s, 1H), 7.80 - 7.72 (m, 2H), 7.63 (t,J = 7.8 Hz, 1H), 7.39 - 7.31 (m, 3H), 7.15 (d,J = 7.8 Hz, 1H), 6.63 (d,J = 7.8 Hz, 1H), 6.06 (s, 2H), 5.84 - 5.79 (m, 1H), 5.56 (t,J = 1.4 Hz, 1H), 5.38 (s, 2H), 3.61 (s, 3H), 2.44 (s, 3H), 1.98 (t,J = 1.2 Hz, 3H). | 479.35 | |
N-(4-(4-胺基-5-(4-((S)-2-氰基吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.23 (s, 1H), 7.77 (dd,J = 12.5, 2.0 Hz, 1H), 7.57 (d,J = 7.8 Hz, 2H), 7.49 (dd,J = 8.5, 2.0 Hz, 1H), 7.32 - 7.22 (m, 3H), 5.82 (t,J = 1.0 Hz, 1H), 5.58 (d,J = 2.0 Hz, 1H), 4.87 (t,J = 6.6 Hz, 1H), 3.65 (s, 1H), 3.56 (s, 4H), 2.32 (s, 1H), 2.17 (ddd,J = 12.7, 11.5, 6.1 Hz, 1H), 1.95 (t,J = 1.3 Hz, 5H). | 524.2 | |
(S)-N-(4-(4-胺基-5-(4-(2-氰基吡咯啶-1-羰基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 (s, 1H), 7.74 (d,J = 8.4 Hz, 2H), 7.42 (t,J = 7.5 Hz, 1H), 7.27 (d,J = 8.4 Hz, 2H), 7.08 (d,J = 9.3 Hz, 2H), 5.82 (s, 1H), 5.54 (s, 1H), 4.95 - 4.87 (m, 1H), 3.60 (s, 3H), 1.96 (s, 4H). | 524.40 | |
4-(4-胺基-6-(2-氟-4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((3-氟氧雜環丁-3-基)甲基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.22 (s, 1H), 7.76 (dd,J = 12.5, 2.0 Hz, 1H), 7.49 (dd,J = 8.4, 2.0 Hz, 1H), 7.37 (s, 2H), 7.30 - 7.21 (m, 3H), 5.82 (s, 1H), 5.58 (s, 1H), 4.64(s, 5H), 4.09 (s, 1H), 4.03 (s, 1H), 3.55 (s, 3H), 2.96 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 547.30 | |
4-(4-胺基-6-(2-氟-4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.22 (s, 1H), 7.76 (dd,J = 12.4, 2.0 Hz, 1H), 7.48 (dd,J = 8.5, 2.0 Hz, 1H), 7.43 (s, 2H), 7.28 (s, 3H), 7.25 (d,J = 8.5 Hz, 1H), 6.04 (s, 2H), 5.83 (s, 1H), 5.58 (s, 1H), 4.91 (s, 2H), 3.55 (s, 3H), 3.10 (s, 3H), 2.35 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 555.30 | |
4-(4-胺基-6-(2-氟-4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-氰基環丙基)甲基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.23 (s, 1H), 7.77 (dd,J = 12.5, 2.0 Hz, 1H), 7.49 (dd,J = 8.5, 2.0 Hz, 1H), 7.37 (d,J = 7.5 Hz, 2H), 7.28 (d,J = 8.2 Hz, 3H), 6.04 (s, 2H), 5.83 (s, 1H), 5.57 (s, 1H), 3.32 (s, 3H), 3.06 (s, 3H), 1.95 (d,J = 1.5 Hz, 3H), 1.29 (s, 2H), 1.16 (t,J = 13.2 Hz, 2H). | 538.40 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((四氫呋喃-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.35 (s, 2H), 7.30 - 7.22 (m, 4H), 5.92 (s, 2H), 5.80 (s, 1H), 5.56 - 5.50 (m, 1H), 3.76 (s, 1H), 3.62 (s, 4H), 3.53 (s, 2H), 3.22 (s, 1H), 2.95 (s, 3H), 2.62 (s, 0.5H), 1.95 (d,J = 1.2 Hz, 3H), 1.82 (s, 0.5H), 1.60 (s, 0.5H), 1.31 (s, 0.5H). | 525.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-異丁基-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.35 (s, 2H), 7.27 (d,J = 7.9 Hz, 2H), 7.26 (s, 2H), 5.79 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.62 (s, 3H), 3.28 (s, 1H), 3.05 (s, 1H), 2.92 (s, 3H), 2.03 - 1.85 (s, 1H), 1.95 (t,J = 1.2 Hz, 3H), 0.91 (d,J = 6.6 Hz, 3H), 0.68 (s, 3H). | 497.3 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-甲氧基環丙基)甲基)-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.23 (s, 1H), 7.67 (d,J = 8.3 Hz, 2H), 7.46 - 7.37 (m, 4H), 7.28 (d,J = 7.7 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.83 (s, 1H), 3.71 (s, 3H), 3.59 (s, 1H), 3.39 (s, 2H), 3.11 (s, 3H), 2.86 (s, 1H), 2.04 (d,J = 1.3 Hz, 3H), 0.88 (s, 1H), 0.82 (s, 1H), 0.73 (s, 1H), 0.52 (s, 1H). | 525.45 | |
N-(4-(5-(4-((1R,5S)-2-氮雜雙環[3.1.0]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.23 (s, 1H), 7.77 (dd,J = 12.4, 2.0 Hz, 1H), 7.60 (d,J = 7.6 Hz, 1H), 7.49 (dd,J = 8.5, 2.0 Hz, 1H), 7.28 (d,J = 8.3 Hz, 3H), 6.05 (s, 2H), 5.83 (s, 1H), 5.58 (s, 1H), 3.97 (s, 1H), 3.56 (s, 3H), 3.14 (s, 1H), 2.06 (s, 1H), 1.96 (d,J = 1.2 Hz, 3H), 1.70 (s, 1H), 0.77 (s, 2H). | 511.30 | |
N-(4-(5-(4-((1S,5R)-2-氮雜雙環[3.1.0]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.23 (s, 1H), 7.77 (dd,J = 12.5, 2.0 Hz, 1H), 7.60 (d,J = 7.7 Hz, 1H), 7.49 (dd,J = 8.4, 2.0 Hz, 2H), 7.28 (d,J = 8.3 Hz, 3H), 6.03 (s, 1H), 5.83 (s, 1H), 5.58 (s, 1H), 3.97 (s, 1H), 3.56 (s, 4H), 3.14 (s, 1H), 2.06 (s, 1H), 1.96 (d,J = 1.2 Hz, 4H), 1.70 (s, 1H), 0.77 (s, 2H). | 511.30 | |
N-(4-(5-(4-(2-氮雜雙環[2.1.1]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.22 (s, 1H), 7.77 (dd,J = 12.5, 2.0 Hz, 1H), 7.64 (d,J = 8.9 Hz, 1H), 7.49 (dd,J = 8.4, 2.0 Hz, 1H), 7.40 (d,J = 7.9 Hz, 1H), 7.26 (d,J = 7.3 Hz, 3H), 6.02 (s, 1H), 5.83 (s, 1H), 5.57 (s, 1H), 4.33 (d,J = 6.9 Hz, 1H), 3.55 (s, 3H), 3.44 (s, 2H), 2.89 (d,J = 17.1 Hz, 1H), 1.95 (s, 5H), 1.47 (s, 1H), 1.33 (s, 1H). | 511.40 | |
4-(4-胺基-6-(2-氟-4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-(氧雜環丁-3-基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.22 (s, 1H), 7.76 (dd,J = 12.6, 1.9 Hz, 1H), 7.48 (dd,J = 8.4, 2.0 Hz, 1H), 7.34 (d,J = 7.7 Hz, 2H), 7.25 (d,J = 7.8 Hz, 3H), 5.82 (s, 1H), 5.76 (s, 1H), 5.58 (s, 1H), 4.65 (s, 2H), 4.40 (s, 1H), 4.15 (s, 1H), 3.76 (s, 1H), 3.55 (s, 4H), 3.22 (s, 1H), 2.88 (s, 3H), 1.95 (s, 3H). | 529.30 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(2-甲基哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.22 (s, 1H), 7.76 (dd,J = 12.5, 2.0 Hz, 1H), 7.48 (dd,J = 8.5, 2.0 Hz, 1H), 7.31 (d,J = 8.3 Hz, 2H), 7.29 - 7.21 (m, 3H), 6.02 (s, 1H), 5.82 (s, 1H), 5.57 (s, 1H), 3.55 (s, 5H), 2.98 (s, 1H), 1.95 (d,J = 1.3 Hz, 3H), 1.64 (d,J = 10.9 Hz, 1H), 1.59 (s, 3H), 1.51 (s, 1H), 1.36 (d,J = 12.8 Hz, 1H), 1.18 (d,J = 6.9 Hz, 3H). | 527.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(N-嗎啉基甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 (s, 1H), 7.80 (dd,J = 8.3, 2.2 Hz, 1H), 7.75 (d,J = 2.2 Hz, 1H), 7.45 (d,J = 7.9 Hz, 2H), 7.41 (d,J = 8.3 Hz, 1H), 7.23 (d,J = 7.9 Hz, 2H), 6.02 (s, 2H), 5.83 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 3.48 - 3.35 (m, 3H), 3.15 (d,J = 13.8 Hz, 1H), 2.75 (d,J = 13.7 Hz, 1H), 2.05 (d,J = 6.7 Hz, 2H), 1.96 (t,J = 1.2 Hz, 5H), 1.83 (dt,J = 19.2, 6.4 Hz, 3H). | 580.50 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(四氫呋喃-2-基)苯基)甲基丙烯醯胺(滯轉異構體1) | 滯轉異構體1 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.24 (s, 1H), 7.84 (d,J = 2.2 Hz, 1H), 7.74 (dd,J = 8.3, 2.3 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.38 (dd,J = 13.8, 8.2 Hz, 3H), 5.86 - 5.81 (m, 1H), 5.55 (d,J = 1.8 Hz, 1H), 4.47 (dd,J = 7.9, 6.8 Hz, 1H), 4.05 (q,J = 7.2 Hz, 1H), 3.75 (q,J = 7.6 Hz, 1H), 3.59 (t,J = 7.0 Hz, 2H), 3.55 (s, 3H), 3.47 (t,J = 6.6 Hz, 2H), 2.08 - 2.01 (m, 3H), 1.96 (dq,J = 27.5, 6.8 Hz, 5H), 1.87 - 1.74 (m, 1H), 1.61 (dq,J = 12.7, 7.0 Hz, 1H), 1.34 (dq,J = 12.5, 8.1 Hz, 1H). | 551.40 |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(四氫呋喃-2-基)苯基)甲基丙烯醯胺(滯轉異構體1) | 滯轉異構體2 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.24 (s, 1H), 7.84 (d,J = 2.2 Hz, 1H), 7.74 (dd,J = 8.3, 2.3 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.38 (dd,J = 13.8, 8.2 Hz, 3H), 5.86 - 5.81 (m, 1H), 5.55 (d,J = 1.8 Hz, 1H), 4.47 (dd,J = 7.9, 6.8 Hz, 1H), 3.91 (q,J = 7.2 Hz, 1H), 3.75 (q,J = 7.6 Hz, 1H), 3.59 (t,J = 7.0 Hz, 2H), 3.55 (s, 3H), 3.47 (t,J = 6.6 Hz, 2H), 2.08 - 2.01 (m, 3H), 1.96 (dq,J = 27.5, 6.8 Hz, 5H), 1.87 - 1.74 (m, 1H), 1.61 (dq,J = 12.7, 7.0 Hz, 1H), 1.34 (dq,J = 12.5, 8.1 Hz, 1H). | 551.40 |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氯苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.23 (s, 1H), 8.03 (d,J = 2.0 Hz, 1H), 7.65 (dd,J = 8.4, 2.1 Hz, 1H), 7.47 (d,J = 8.2 Hz, 2H), 7.33 (d,J = 8.4 Hz, 1H), 7.24 (d,J = 8.1 Hz, 2H), 6.02 (s, 1H), 5.83 (d,J = 1.4 Hz, 1H), 5.58 (s, 1H), 3.48 (s, 3H), 3.42 (dt,J = 18.3, 6.6 Hz, 4H), 1.98 - 1.93 (m, 3H), 1.83 (dt,J = 18.7, 6.6 Hz, 4H). | 515.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氰基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 8.26 (s, 1H), 8.20 (d,J = 2.2 Hz, 1H), 8.03 (dd,J = 8.6, 2.3 Hz, 1H), 7.62 (d,J = 8.6 Hz, 1H), 7.49 (d,J = 7.9 Hz, 2H), 7.22 (d,J = 7.8 Hz, 2H), 6.12 (s, 1H),5.86 (s, 1H), 5.61 (s, 1H), 3.56 (s, 3H), 3.49 - 3.38 (m, 4H), 1.96 (s, 3H), 1.88 - 1.78 (m, 4H). | 506.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(二氟甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.24 (s, 1H), 8.07 (d,J = 2.2 Hz, 1H), 8.00 - 7.93 (m, 1H), 7.52 (d,J = 8.4 Hz, 1H), 7.45 (d,J = 8.2 Hz, 2H), 7.23 (d,J = 8.1 Hz, 2H), 6.51 (d,J = 5.6 Hz, 1H), 6.02 (s, 1H), 5.86 (d,J = 1.3 Hz, 1H), 5.58 (d,J = 1.7 Hz, 1H), 3.44 (d,J = 13.6 Hz, 6H), 1.96 (t,J = 1.2 Hz, 3H), 1.82 (dq,J = 19.2, 6.7 Hz, 4H). | 531.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲氧基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.19 (s, 1H), 7.62 (d,J = 1.9 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.26 (dd,J = 8.3, 1.9 Hz, 1H), 7.25 - 7.18 (m, 2H), 6.99 (d,J = 8.2 Hz, 1H), 5.92 (s, 1H), 5.81 (t,J = 1.0 Hz, 1H), 5.54 (t,J = 1.4 Hz, 1H), 3.70 (s, 3H), 3.47 (s, 4H), 3.45 - 3.37 (m, 3H), 1.96 (t,J = 1.2 Hz, 3H), 1.83 (dt,J = 17.0, 6.4 Hz, 4H). | 511.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-環丙基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 8.32 (s, 1H), 7.61 (dd,J = 8.3, 2.1 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.28 - 7.16 (m, 4H), 5.80 (s, 1H), 5.53 (t,J = 1.6 Hz, 1H), 3.52 (s, 3H), 3.43 (dt,J = 17.2, 6.6 Hz, 4H), 1.94 (t,J = 1.2 Hz, 3H), 1.83 (dq,J = 18.6, 6.8 Hz, 4H), 1.52 - 1.40 (m, 1H), 0.84 (ddt,J = 10.2, 8.7, 4.0 Hz, 1H), 0.72 - 0.52 (m, 2H), 0.44 - 0.34 (m, 1H). | 521.4 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-環丙基苯基)甲基丙烯醯胺 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 8.29 (s, 1H), 7.60 (dd,J = 8.3, 2.1 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.28 - 7.17 (m, 4H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.52 (s, 3H), 3.43 (dt,J = 17.3, 6.6 Hz, 4H), 1.95 (d,J = 1.2 Hz, 3H), 1.90 - 1.75 (m, 4H), 1.46 (td,J = 8.5, 4.4 Hz, 1H), 0.84 (p,J = 4.9 Hz, 1H), 0.63 (ddt,J = 29.5, 9.2, 4.5 Hz, 2H), 0.39 (p,J = 4.8 Hz, 1H). | 521.3 |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-環丙基苯基)甲基丙烯醯胺 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.77 (s, 1H), 8.21 (s, 1H), 7.59 (dd,J = 8.4, 2.1 Hz, 1H), 7.49 - 7.43 (m, 2H), 7.32 - 7.16 (m, 4H), 5.80 (s, 1H), 5.55 - 5.50 (m, 1H), 3.49 (s, 3H), 3.47 - 3.38 (m, 4H), 1.95 (t,J = 1.3 Hz, 3H), 1.83 (dq,J = 17.3, 6.5 Hz, 4H), 1.48 (td,J = 8.3, 4.5 Hz, 1H), 0.85 (s, 1H), 0.66 (d,J = 13.8 Hz, 1H), 0.58 (dt,J = 10.1, 5.2 Hz, 1H), 0.43 - 0.36 (m, 1H). | 521.3 |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-乙基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.21 (s, 1H), 7.70 - 7.61 (m, 2H), 7.48 - 7.42 (m, 2H), 7.32 (d,J = 8.3 Hz, 1H), 7.26 - 7.19 (m, 2H), 6.19 - 5.79 (m, 3H), 5.53 (t,J = 1.6 Hz, 1H), 3.48 - 3.35 (m, 7H), 2.29 (dt,J = 15.1, 7.4 Hz, 1H), 2.10 (dq,J = 15.0, 7.5 Hz, 1H), 1.96 (t,J = 1.2 Hz, 3H), 1.84 (dq,J = 18.9, 6.8 Hz, 4H), 0.83 (t,J = 7.5 Hz, 3H). | 509.3 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-乙基苯基)甲基丙烯醯胺 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.22 (s, 1H), 7.71 - 7.62 (m, 2H), 7.49 - 7.42 (m, 2H), 7.32 (d,J = 8.3 Hz, 1H), 7.23 (d,J = 8.2 Hz, 2H), 5.82 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.48 - 3.35 (m, 7H), 2.30 (dt,J = 15.0, 7.5 Hz, 1H), 2.10 (dq,J = 14.9, 7.5 Hz, 1H), 1.96 (t,J = 1.2 Hz, 3H), 1.85 (dq,J = 18.9, 6.8 Hz, 4H), 0.83 (t,J = 7.5 Hz, 3H). | 509.3 |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-乙基苯基)甲基丙烯醯胺 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.22 (s, 1H), 7.71 - 7.62 (m, 2H), 7.49 - 7.42 (m, 2H), 7.32 (d,J = 8.2 Hz, 1H), 7.23 (d,J = 8.2 Hz, 2H), 5.82 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.48 - 3.35 (m, 7H), 2.30 (dt,J = 15.0, 7.5 Hz, 1H), 2.10 (dq,J = 14.9, 7.5 Hz, 1H), 1.96 (d,J = 1.2 Hz, 3H), 1.82 (dq,J = 18.6, 6.6 Hz, 4H), 0.83 (t,J = 7.5 Hz, 3H). | 509.3 |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.80 - 7.76 (m, 1H), 7.53 - 7.51 (m, 1H), 7.36 - 7.26 (m, 3H), 7.23 - 7.13 (m, 3H), 5.82 (s, 1H), 5.58 (d,J = 1.8 Hz, 1H), 3.54 (s, 3H), 2.41 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 510.20 | |
N-(4-(4-胺基-5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.50 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.76 - 7.66 (m, 2H), 7.38 (t,J = 8.5 Hz, 1H), 7.31 - 7.27 (m, 2H), 7.22 - 7.15 (m, 2H), 7.09 - 7.07 (m, 1H), 5.80 (d,J = 1.3 Hz, 1H), 5.53 (d,J = 1.7 Hz, 1H), 3.64 (s, 3H), 2.43 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 510.20 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.11 (s, 1H), 8.40 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.80 (dd,J = 12.5, 2.0 Hz, 1H), 7.54 (dd,J = 8.4, 2.0 Hz, 1H), 7.36 (t,J = 8.5 Hz, 1H), 7.14 (d,J = 8.1 Hz, 1H), 7.09 (d,J = 5.1 Hz, 1H), 6.97 (d,J = 2.0 Hz, 1H), 6.85 (dd,J = 8.1, 2.0 Hz, 1H), 5.83 (s, 1H), 5.58 (s, 1H), 3.55 (d,J = 5.1 Hz, 6H), 2.39 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 540.25 | |
N-(4-(4-胺基-5-(4-((5-氟嘧啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.71 (s, 2H), 8.21 (s, 1H), 7.75 (d,J = 8.7 Hz, 2H), 7.35 (d,J = 8.6 Hz, 2H), 7.18 (d,J = 8.1 Hz, 1H), 6.99 (d,J = 2.0 Hz, 1H), 6.86 (dd,J = 8.1, 2.0 Hz, 1H), 5.81 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 3.56 (s, 3H), 1.96 (d,J = 1.3 Hz, 3H). | 526.20 | |
N-(4-(4-胺基-7-甲基-5-(6-((6-甲基吡啶-2-基)氧基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.21 (s, 1H), 7.99 (d,J = 2.4 Hz, 1H), 7.75 (t,J = 8.2 Hz, 4H), 7.42 - 7.24 (m, 2H), 7.08 (dd,J = 14.6, 7.9 Hz, 2H), 6.92 (d,J = 8.1 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.61 (s, 3H), 2.38 (s, 3H), 1.96 (t,J = 1.3 Hz, 3H). | 492.30 | |
N-(4-(4-胺基-5-(6-((5-氟嘧啶-2-基)氧基)吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.83 (s, 2H), 8.22 (s, 1H), 8.07 (d,J = 2.4 Hz, 1H), 7.76 (dd,J = 9.4, 2.5 Hz, 3H), 7.43 - 7.26 (m, 2H), 7.23 (s, 1H), 5.92 (d,J = 81.4 Hz, 3H), 5.55 (d,J = 1.8 Hz, 1H), 3.60 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 497.25 | |
N-(4-(4-胺基-5-(5-((5-氟嘧啶-2-基)氧基)吡啶-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.02 (s, 1H), 8.78 (s, 2H), 8.60 (d,J = 2.8 Hz, 1H), 8.17 (s, 1H), 7.93 - 7.85 (m, 2H), 7.50 (dd,J = 8.8, 2.8 Hz, 1H), 7.46 - 7.38 (m, 2H), 6.94 (d,J = 8.8 Hz, 1H), 5.84 (t,J = 1.0 Hz, 1H), 5.57 (t,J = 1.6 Hz, 1H), 3.52 (s, 3H), 1.98 (t,J = 1.2 Hz, 3H). | 497.30 | |
N-(4-(4-胺基-7-甲基-5-(2-甲基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.19 (s, 1H), 7.70 (d,J = 8.6 Hz, 2H), 7.28 (dd,J = 8.6, 2.3 Hz, 3H), 7.15 (d,J = 5.1 Hz, 1H), 7.10 - 7.00 (m, 2H), 5.78 (s, 1H), 5.53 (s, 1H), 3.66 (s, 3H), 2.42 (s, 3H), 1.97 (s, 3H), 1.94 (s, 3H). | 540.25 | |
N-(4-(5-((4R)-4-(3-氮雜雙環[3.2.1]辛烷-3-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.09 (s, 1H), 7.90 - 7.76 (m, 2H), 7.43 (d,J = 8.2 Hz, 2H), 6.52 (s, 2H), 5.83 (s, 1H), 5.75 (s, 1H), 5.55 (s, 1H), 4.17 (d,J = 12.6 Hz, 1H), 4.08 (d,J = 12.8 Hz, 0H), 3.73 (s, 1H), 3.58 (s, 3H), 3.14 - 3.02 (m, 2H), 2.57 (d,J = 12.0 Hz, 1H), 2.19 (s, 4H), 1.97 (s, 3H), 1.86 (s, 1H), 1.65 (s, 1H), 1.54 (s, 7H), 1.30 (s, 1H), 1.24 (s, 1H). | 525.30 | |
N-(4-(5-((4S)-4-(3-氮雜雙環[3.2.1]辛烷-3-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.09 (s, 1H), 7.90 - 7.76 (m, 2H), 7.43 (d,J = 8.2 Hz, 2H), 6.52 (s, 2H), 5.83 (s, 1H), 5.75 (s, 1H), 5.55 (s, 1H), 4.17 (d,J = 12.6 Hz, 1H), 4.08 (d,J = 12.8 Hz, 0H), 3.73 (s, 1H), 3.58 (s, 3H), 3.14 - 3.02 (m, 2H), 2.57 (d,J = 12.0 Hz, 1H), 2.19 (s, 4H), 1.97 (s, 3H), 1.86 (s, 1H), 1.65 (s, 1H), 1.54 (s, 7H), 1.30 (s, 1H), 1.24 (s, 1H). | 525.30 | |
(R)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.10 (s, 1H), 7.85 - 7.77 (m, 2H), 7.70 (t,J = 6.2 Hz, 1H), 7.47 - 7.39 (m, 2H), 6.44 (s, 1H), 5.83 (t,J = 1.1 Hz, 1H), 5.78 (s, 1H), 5.58 - 5.53 (m, 1H), 3.57 (s, 3H), 3.19 (dd,J = 13.6, 6.5 Hz, 1H), 3.08 (s, 3H), 3.03 (dd,J = 13.6, 5.6 Hz, 1H), 2.61 (d,J = 6.3 Hz, 1H), 2.29 (s, 1H), 2.21 (d,J = 18.0 Hz, 1H), 1.98 (t,J = 1.2 Hz, 3H), 1.90 (s, 2H), 1.66 (d,J = 6.1 Hz, 2H), 1.03 (d,J = 4.0 Hz, 6H). | 517.25 | |
(S)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.12 (s, 1H), 7.85 - 7.77 (m, 2H), 7.70 (t,J = 6.0 Hz, 1H), 7.47 - 7.39 (m, 2H), 6.50 (s, 1H), 5.86 - 5.76 (m, 2H), 5.55 (t,J = 1.4 Hz, 1H), 3.58 (s, 3H), 3.19 (dd,J = 13.6, 6.5 Hz, 1H), 3.08 (s, 3H), 3.03 (dd,J = 13.6, 5.6 Hz, 1H), 2.65 - 2.58 (m, 1H), 2.26 (d,J = 22.4 Hz, 2H), 1.98 (t,J = 1.2 Hz, 3H), 1.94 - 1.87 (m, 2H), 1.66 (s, 2H), 1.24 (s, 0H), 1.03 (d,J = 4.0 Hz, 6H). | 517.30 | |
(S)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((四氫呋喃-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.71 - 7.64 (m, 2H), 7.40 (s, 5H), 7.28 (d,J = 8.2 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.96 - 3.87 (m, 1H), 3.80 (d,J = 7.6 Hz, 2H), 3.71 (s, 3H), 3.60 (d,J = 6.9 Hz, 3H), 3.10 (s, 1H), 3.05 (s, 2H), 2.77 (s, 1H), 2.11 (s, 1H), 2.04 (t,J = 1.3 Hz, 3H), 1.76 (s, 1H). | 525.30 | |
(R)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((四氫呋喃-3-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.71 - 7.64 (m, 2H), 7.40 (s, 5H), 7.28 (d,J = 8.2 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.96 - 3.87 (m, 1H), 3.80 (d,J = 7.6 Hz, 2H), 3.71 (s, 3H), 3.60 (d,J = 6.9 Hz, 3H), 3.10 (s, 1H), 3.05 (s, 2H), 2.77 (s, 1H), 2.11 (s, 1H), 2.04 (t,J = 1.3 Hz, 3H), 1.76 (s, 1H). | 525.30 | |
N-(4-(5-(4-(2-氮雜雙環[3.1.0]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.22 (s, 1H), 7.76 (dd,J = 12.5, 2.0 Hz, 1H), 7.59 (d,J = 7.8 Hz, 1H), 7.48 (dd,J = 8.4, 2.1 Hz, 2H), 7.28 (d,J = 8.6 Hz, 3H), 6.03 (s, 1H), 5.82 (d,J = 1.1 Hz, 1H), 5.58 (s, 1H), 3.95 (d,J = 10.7 Hz, 1H), 3.55 (s, 3H), 3.13 (s, 2H), 2.05 (s, 1H), 1.95 (d,J = 1.3 Hz, 4H), 1.69 (s, 4H), 1.59 (s, 1H) , 0.76 (s, 2H). | 511.35 | |
N-(4-(5-(4-(3-氮雜雙環[3.1.0]己烷-3-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.22 (s, 1H), 7.77 (dd,J = 12.5, 2.0 Hz, 1H), 7.49 (dd,J = 8.5, 2.0 Hz, 1H), 7.41 (d,J = 8.1 Hz, 2H), 7.31 - 7.20 (m, 3H), 5.83 (s, 1H), 5.76 (s, 1H), 5.58 (d,J = 2.0 Hz, 1H), 3.95 (d,J = 11.9 Hz, 1H), 3.66 (d,J = 10.0 Hz, 1H), 3.55 (s, 3H), 3.3 - 3.2 (m, 2H), 1.95 (t,J = 1.2 Hz, 3H), 1.54 (s, 2H), 0.68 - 0.59 (m, 1H), 0.07 (q,J = 4.3 Hz, 1H). | 511.30 | |
N-(4-(4-胺基-5-(3-氟-4-((2-甲基嘧啶-4-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.60 (d,J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.78 - 7.72 (m, 2H), 7.35 (t,J = 8.3 Hz, 1H), 7.33 - 7.28 (m, 2H), 7.21 (dd,J = 11.4, 2.1 Hz, 1H), 7.10 (d,J = 8.1 Hz, 1H), 7.03 (d,J = 5.7 Hz, 1H), 6.05 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.62 (s, 3H), 2.46 (s, 3H), 1.95 (s, 3H). | 510.20 | |
N-(4-(4-胺基-5-(3-氟-4-((6-甲基吡嗪-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.45 - 8.14 (m, 3H), 7.81 - 7.70 (m, 2H), 7.42 - 7.24 (m, 3H), 7.24 - 7.02 (m, 2H), 6.27 - 5.90 (m, 1H), 5.80 (t,J = 1.1 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.61 (s, 3H), 2.35 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 510.20 | |
N-(4-(4-胺基-5-(4-((4-氯嘧啶-2-基)氧基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.66 (d,J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.76 (d,J = 8.5 Hz, 2H), 7.54 (d,J = 5.3 Hz, 1H), 7.42 (t,J = 8.4 Hz, 1H), 7.33 (d,J = 8.5 Hz, 2H), 7.23 (d,J = 13.3 Hz, 1H), 7.13 (d,J = 8.4 Hz, 1H), 6.21 - 5.90 (m, 1H), 5.5.81 (s, 1H), 5.55 (s, 1H), 3.60 (s, 3H), 1.96 (s, 3H). | 530.20 | |
N-(4-(4-胺基-5-(4-((4-(二氟甲基)嘧啶-2-基)氧基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.90 (d,J = 4.9 Hz, 1H), 8.22 (s, 1H), 7.80 - 7.72 (m, 2H), 7.59 (d,J = 5.0 Hz, 1H), 7.42 (t,J = 8.4 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.23 (dd,J = 11.4, 2.0 Hz, 1H), 7.15 - 7.06 (m, 1H), 6.88 (d,J = 54.0 Hz, 1H), 5.99 (s, 1H), 5.81 (t,J = 1.1 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.60 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 546.40 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲氧基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.34 (d,J = 5.7 Hz, 1H), 8.21 (s, 1H), 7.74 (d,J = 8.6 Hz, 2H), 7.45 - 7.24 (m, 3H), 7.20 (t,J = 11.4, 2.0 Hz, 1H), 7.11 (d,J = 8.2 Hz, 1H), 6.72 (d,J = 5.7 Hz, 1H), 5.81 (s, 1H), 5.55 (s, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 526.25 | |
N-(4-(4-胺基-5-(4-((4-氰基嘧啶-2-基)氧基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 9.03 (d,J = 4.8 Hz, 1H), 8.22 (s, 1H), 7.97 (d,J = 4.8 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.42 (t,J = 8.4 Hz, 1H), 7.33 (d,J = 8.6 Hz, 2H), 7.25 (dd,J = 11.4, 2.0 Hz, 1H), 7.14 (dd,J = 8.2, 1.8 Hz, 1H), 6.01 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.59 (s, 3H), 1.96 (t,J = 1.4 Hz, 3H). | 521.25 | |
N-(4-(4-胺基-5-(3-氟-4-((4-(羥基甲基)嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.61 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.80 - 7.72 (m, 2H), 7.34 (dd,J = 8.3, 5.4 Hz, 4H), 7.19 (dd,J = 11.4, 2.0 Hz, 1H), 7.11 (dt,J = 8.3, 1.4 Hz, 1H), 5.84 - 5.79 (m, 1H), 5.67 (t,J = 6.0 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.50 (d,J = 5.9 Hz, 2H), 3.60 (s, 3H), 3.32 (s, 2H), 1.96 (t,J = 1.2 Hz, 3H). | 526.10 | |
N-(4-(4-胺基-5-(3-氟-4-((4-(甲氧基甲基)嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.63 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.79 - 7.73 (m, 2H), 7.41 - 7.31 (m, 2H), 7.32 (d,J = 2.0 Hz, 1H), 7.28 (d,J = 5.0 Hz, 1H), 7.19 (dd,J = 11.4, 2.0 Hz, 1H), 7.11 (dd,J = 8.4, 2.1 Hz, 1H), 5.98 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.45 (s, 2H), 3.60 (s, 3H), 3.39 (s, 3H), 1.96 (s, 3H). | 540.20 | |
N-(4-(4-胺基-5-(3-氟-4-((5-氟-4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.57 (d,J = 1.4 Hz, 1H), 8.21 (s, 1H), 7.80 - 7.71 (m, 2H), 7.41 - 7.30 (m, 3H), 7.20 (dd,J = 11.5, 2.0 Hz, 1H), 7.14 - 7.08 (m, 1H), 5.98 (s, 1H), 5.81 (t,J = 1.1 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.60 (s, 3H), 2.43 (d,J = 2.5 Hz, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 528.40 | |
N-(4-(4-胺基-5-(3-氯-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.77 (d,J = 8.5 Hz, 2H), 7.41 (d,J = 2.1 Hz, 1H), 7.34 (d,J = 8.4 Hz, 3H), 7.30 - 7.20 (m, 1H), 7.18 (d,J = 5.0 Hz, 1H), 5.97 (s, 1H), 5.81 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 2.43 (s, 3H), 1.96 (d,J = 1.2 Hz, 3H). | 526.15 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.44 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.74 (d,J = 8.7 Hz, 2H), 7.33 (d,J = 8.7 Hz, 2H), 7.24 (d,J = 2.0 Hz, 1H), 7.14 - 7.05 (m, 3H), 5.80 (d,J = 1.3 Hz, 2H), 5.54 (s, 1H), 3.60 (s, 3H), 2.41 (s, 3H), 2.04 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 506.25 | |
N-(4-(4-胺基-5-(3-(甲氧基甲基)-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.44 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.73 (d,J = 8.3 Hz, 2H), 7.39 - 7.26 (m, 3H), 7.23 - 7.21 (m, 1H), 7.17 - 7.09 (m, 2H), 5.79 (s, 2H), 5.53 (s, 1H), 4.29 (s, 2H), 3.61 (s, 3H), 3.08 (s, 3H), 2.41 (s, 3H), 1.95 (s, 3H). | 536.40 | |
N-(4-(4-胺基-5-(3-氰基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.52 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.82 - 7.69 (m, 3H), 7.53 (t,J = 8.6, 2.2 Hz, 1H), 7.41 (d,J = 8.6 Hz, 1H), 7.33 (d,J = 8.6 Hz, 2H), 7.25 (d,J = 5.1 Hz, 1H), 5.81 (s, 1H), 5.55 (s, 1H), 3.60 (s, 3H), 2.45 (s, 3H), 1.96 (t,J = 1.3 Hz, 3H). | 517.25 | |
N-(4-(4-胺基-5-(3-(二甲基胺基)-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.43 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.84 - 7.58 (m, 2H), 7.43 - 7.27 (m, 2H), 7.10 (d,J = 5.0 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.83 (d,J = 6.7 Hz, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.60 (s, 3H), 2.55 (s, 6H), 2.40 (s, 3H), 1.96 (s, 3H). | 535.45 | |
N-(4-(4-胺基-5-(3-乙氧基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.42 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.74 (d,J = 8.6 Hz, 2H), 7.34 (d,J = 8.6 Hz, 2H), 7.18 - 7.05 (m, 2H), 6.94 (d,J = 2.0 Hz, 1H), 6.84 (dd,J = 8.1, 1.9 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 3.81 (d,J = 7.0 Hz, 2H), 3.61 (s, 3H), 2.44 - 2.31 (m, 3H), 1.96 (t,J = 1.3 Hz, 3H), 0.94 (t,J = 6.9 Hz, 3H). | 536.45 | |
N-(4-(4-胺基-5-(3-甲氧基-5-甲基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.39 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.87 - 7.69 (m, 2H), 7.43 - 7.30 (m, 2H), 7.09 (d,J = 5.0 Hz, 1H), 6.84 - 6.77 (m, 2H), 5.81 (s, 2H), 5.54 (d,J = 1.5 Hz, 1H), 3.60 (s, 3H), 3.50 (s, 3H), 2.41 (s, 3H), 2.03 (s, 3H), 1.96 (s, 3H). | 536.45 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.14 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.80 (dd,J = 12.5, 2.0 Hz, 1H), 7.55 (dd,J = 8.5, 2.0 Hz, 1H), 7.35 (td,J = 8.4, 2.4 Hz, 2H), 7.22 - 7.16 (m, 2H), 7.13 - 7.08 (m, 1H), 6.07 (s, 2H), 5.83 (s, 1H), 5.59 (s, 1H), 3.54 (s, 3H), 2.42 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 528.35 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.13 (s, 1H), 8.44 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.80 (dd,J = 12.4, 1.9 Hz, 1H), 7.53 (dd,J = 8.5, 2.0 Hz, 1H), 7.35 (t,J = 8.4 Hz, 1H), 7.23 (s, 1H), 7.14(d,J = 4.0 Hz, 1H), 7.16 - 7.09 (m, 2H), 5.97 (s, 1H), 5.84 (s, 1H), 5.59 (s, 1H), 3.54 (s, 3H), 2.42 (s, 3H), 2.04 (s, 3H), 1.96 (d,J = 1.5 Hz, 3H). | 524.35 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(羥基甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.91 (d,J = 2.2 Hz, 1H), 7.74 (dd,J = 8.3, 2.3 Hz, 1H), 7.36 - 7.27 (m, 2H), 7.20 - 7.11 (m, 2H), 7.08 (dd,J = 8.4, 2.0 Hz, 1H), 6.05 (s, 1H), 5.83 (s, 1H), 5.54 (s, 1H), 5.17 (t,J = 5.3 Hz, 1H), 4.17 (dd,J = 13.9, 5.3 Hz, 1H), 4.02 (dd,J = 13.8, 5.3 Hz, 1H), 2.41 (s, 3H), 1.96 (d,J = 1.6 Hz, 3H). | 540.40 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(羥基甲基)苯基)甲基丙烯醯胺 | 滯轉異構體A | 1 H NMR (400 MHz, 氯仿-d ) δ 8.41 - 8.32 (m, 2H), 7.82 (dd,J = 8.3, 2.2 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.33 (d,J = 8.3 Hz, 1H), 7.22 (t,J = 8.2 Hz, 1H), 7.06 (t,J = 8.2 Hz, 2H), 6.95 (d,J = 5.1 Hz, 1H), 5.85 (s, 1H), 5.60 (s, 1H), 5.54 (d,J = 1.7 Hz, 1H), 4.36 (d,J = 13.2 Hz, 1H), 4.25 (d,J = 13.2 Hz, 1H), 3.59 (s, 3H), 2.51 (s, 3H), 2.13 - 2.08 (m, 3H). | 540.40 |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(羥基甲基)苯基)甲基丙烯醯胺 | 滯轉異構體B | 1 H NMR (400 MHz, 氯仿-d ) δ 8.39 (s, 1H), 8.34 (d,J = 5.0 Hz, 1H), 7.82 (dd,J = 8.3, 2.1 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.33 (d,J = 8.3 Hz, 1H), 7.21 (t,J = 8.2 Hz, 1H), 7.06 (t,J = 8.0 Hz, 2H), 6.94 (d,J = 5.0 Hz, 1H), 5.85 (s, 1H), 5.53 (d,J = 1.6 Hz, 2H), 4.36 (d,J = 13.3 Hz, 1H), 4.25 (d,J = 13.3 Hz, 1H), 3.59 (s, 3H), 2.51 (s, 3H), 2.10 (t,J = 1.2 Hz, 3H). | 540.45 |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(甲氧基甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.86 - 7.76 (m, 2H), 7.38 (d,J = 8.3 Hz, 1H), 7.31 (t,J = 8.4 Hz, 1H), 7.20 - 7.10 (m, 2H), 7.07 (dd,J = 8.3, 2.2 Hz, 1H), 6.06 (s, 1H), 5.84 (t,J = 1.1 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.12 (d,J = 12.7 Hz, 1H), 3.91 (d,J = 12.7 Hz, 1H), 3.42 (s, 3H), 3.10 (s, 3H), 2.40 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 554.25 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(甲氧基甲基)苯基)甲基丙烯醯胺 | 滯轉異構體A | 1 H NMR (400 MHz, 氯仿-d ) δ 8.41 (s, 1H), 8.35 (d,J = 5.0 Hz, 1H), 7.89 - 7.82 (m, 1H), 7.64 - 7.56 (m, 2H), 7.32 (d,J = 8.3 Hz, 1H), 7.22 (t,J = 8.2 Hz, 1H), 7.06 (d,J = 10.7 Hz, 2H), 6.94 (d,J = 5.0 Hz, 1H), 5.84 (s, 1H), 5.53 (s, 1H), 5.37 (s, 1H), 4.14 (d,J = 12.4 Hz, 1H), 3.99 (d,J = 12.3 Hz, 1H), 3.57 (s, 3H), 3.21 (s, 3H), 2.50 (s, 3H), 2.10 (t,J = 1.2 Hz, 3H). | 554.45 |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(甲氧基甲基)苯基)甲基丙烯醯胺 | 滯轉異構體B | 1 H NMR (400 MHz, 氯仿-d ) δ 8.41 (s, 1H), 8.35 (d,J = 5.0 Hz, 1H), 7.85 (dd,J = 8.3, 2.2 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.32 (d,J = 8.3 Hz, 1H), 7.22 (t,J = 8.2 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.94 (d,J = 5.0 Hz, 1H), 5.84 (s, 1H), 5.53 (d,J = 1.5 Hz, 1H), 5.40 (s, 2H), 4.14 (d,J = 12.4 Hz, 1H), 3.99 (d,J = 12.4 Hz, 1H), 3.57 (s, 3H), 3.21 (s, 3H), 2.50 (s, 3H), 2.13 - 2.08 (m, 3H). | 554.45 |
N-(4-(4-胺基-5-(3-氟-4-(4-甲基嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-乙基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.47 (d,J = 5.1 Hz, 1H), 8.23 (s, 1H), 7.70 (d,J = 6.2 Hz, 2H), 7.39 - 7.28 (m, 2H), 7.18 (d,J = 5.1 Hz, 1H), 7.13 (d,J = 11.3 Hz, 1H), 7.07 (d,J = 8.7 Hz, 1H), 5.82 (s, 1H), 5.54 (s, 1H), 2.40 (s, 3H), 2.17 (dd,J = 14.9, 7.2 Hz, 1H), 1.97 (s, 3H), 0.90 (t,J = 7.6 Hz, 3H). | 538.25 | |
2-(4-胺基-5-(3-氟-4-(4-甲基嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-5-甲基丙烯醯胺基-N,N-二甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.04 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.85 (dd,J = 8.5, 2.3 Hz, 1H), 7.72 (d,J = 2.1 Hz, 1H), 7.64 (d,J = 8.3 Hz, 1H), 7.34 (t,J = 8.4 Hz, 1H), 7.17 (d,J = 5.1 Hz, 1H), 7.12 - 7.05 (m, 1H), 7.03 (d,J = 8.6 Hz, 1H), 5.85 (d,J = 1.2 Hz, 1H), 5.57 (d,J = 1.8 Hz, 1H), 3.45 (s, 3H), 2.71 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 581.3 | |
N-(4-(4-胺基-5-(3-(二氟甲基)-4-(4-甲基嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.43 (d,J = 5.1 Hz, 1H), 8.23 (s, 1H), 7.71 (d,J = 8.3 Hz, 2H), 7.58 (s, 1H), 7.48 (d,J = 8.6 Hz, 1H), 7.33 (d,J = 8.3 Hz, 2H), 7.25 (d,J = 8.4 Hz, 1H), 7.18 (d,J = 5.1 Hz, 1H), 7.00 - 6.71 (m, 1H), 5.83 (s, 1H), 5.55 (s, 1H), 3.72 (s, 3H), 2.51 (s, 3H), 2.05 (s, 3H). | 542.2 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(二氟甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.14 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 8.13 (d,J = 1.9 Hz, 1H), 7.99 (d,J = 8.4 Hz, 1H), 7.55 (d,J = 8.4 Hz, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.07 (dd,J = 8.3, 2.1 Hz, 1H), 6.58 (s, 1H), 6.06 (s, 1H), 5.86 (s, 1H), 5.58 (d,J = 1.8 Hz, 1H), 3.42 (s, 3H), 2.40 (s, 3H), 1.97 (d,J = 1.2 Hz, 3H). | 560.40 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(二氟甲基)苯基)甲基丙烯醯胺 | 滯轉異構體A | 1 H NMR (400 MHz, 氯仿-d ) δ 8.43 (s, 1H), 8.36 (d,J = 5.0 Hz, 1H), 8.03 (d,J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.39 (d,J = 8.3 Hz, 1H), 7.23 (t,J = 8.2 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.94 (d,J = 5.0 Hz, 1H), 6.31 (s, 1H), 5.87 (s, 1H), 5.56 (d,J = 1.5 Hz, 1H), 5.29 (s, 2H), 3.57 (s, 3H), 2.50 (s, 3H), 2.11 (dd,J = 1.6, 0.9 Hz, 3H). | 560.35 |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-(二氟甲基)苯基)甲基丙烯醯胺 | 滯轉異構體B | 1 H NMR (400 MHz, 氯仿-d ) δ 8.42 (s, 1H), 8.36 (d,J = 5.0 Hz, 1H), 8.03 (d,J = 8.4 Hz, 1H), 7.80 (d,J = 2.2 Hz, 1H), 7.72 (s, 1H), 7.39 (d,J = 8.4 Hz, 1H), 7.23 (t,J = 8.3 Hz, 1H), 7.09 - 7.00 (m, 2H), 6.94 (d,J = 5.0 Hz, 1H), 6.31 (s, 1H), 5.87 (s, 1H), 5.56 (q,J = 1.6 Hz, 1H), 5.40 (s, 2H), 3.58 (s, 3H), 2.50 (s, 3H), 2.11 (d,J = 1.3 Hz, 3H). | 560.40 |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-((二甲基胺基)甲基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.21 (d,J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.79 (d,J = 8.3 Hz, 1H), 7.37 (d,J = 8.3 Hz, 1H), 7.30 (t,J = 8.4 Hz, 1H), 7.16 (d,J = 5.0 Hz, 1H), 7.11 (d,J = 11.5 Hz, 1H), 7.06 (d,J = 8.3 Hz, 1H), 6.07 (s, 2H), 5.84 (s, 1H), 5.53 (s, 1H), 3.4 (d,J = 14.1 Hz, 3H), 3.15 (d,J = 14.1 Hz, 1H), 2.79 (d,J = 14.0 Hz, 1H), 2.39 (s, 3H), 1.95 (d,J = 5.1 Hz, 9H). | 567.30 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲氧基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.47 (d,J = 5.1 Hz, 1H), 8.20 (s, 1H), 7.63 (d,J = 1.9 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.18 (d,J = 5.0 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.08 - 7.01 (m, 1H), 6.00 (s, 2H), 5.82 (s, 1H), 5.55 (s, 1H), 3.71 (s, 3H), 3.47 (s, 3H), 2.41 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 540.25 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.86 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.69 - 7.59 (m, 2H), 7.36 - 7.27 (m, 2H), 7.18 (d,J = 5.1 Hz, 1H), 7.12 (dd,J = 11.5, 2.1 Hz, 1H), 7.06 (dd,J = 8.4, 2.1 Hz, 1H), 6.04 (s, 2H), 5.81 (s, 1H), 5.54 (d,J = 1.8 Hz, 1H), 3.43 (s, 3H), 2.41 (s, 3H), 1.96 (d,J = 1.4 Hz, 6H). | 524.25 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 滯轉異構體A | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.69 - 7.60 (m, 2H), 7.32 (t,J = 7.7 Hz, 2H), 7.18 (d,J = 5.0 Hz, 1H), 7.15 - 7.09 (m, 1H), 7.06 (d,J = 8.6 Hz, 1H), 5.81 (s, 2H), 5.53 (s, 1H), 3.43 (s, 3H), 2.41 (s, 3H), 1.96 (s, 6H). | 524.25 |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 滯轉異構體B | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.47 (d,J = 5.1 Hz, 1H), 8.23 (s, 1H), 7.69 - 7.60 (m, 2H), 7.32 (dd,J = 8.5, 7.1 Hz, 2H), 7.18 (d,J = 5.1 Hz, 1H), 7.12 (d,J = 12.5 Hz, 1H), 7.06 (d,J = 8.4 Hz, 1H), 5.81 (s, 2H), 5.53 (s, 1H), 3.43 (s, 3H), 2.41 (s, 3H), 1.96 (s, 6H). | 524.25 |
N-(4-(4-胺基-5-(3-氟-4-(4-甲基嘧啶-2-基氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.19 (s, 1H), 7.80 - 7.73 (m, 2H), 7.35 - 7.27 (m, 3H), 7.23 - 7.15 (m, 2H), 7.10 (dd,J = 8.3, 2.0 Hz, 1H), 5.81 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.33 (p,J = 6.8 Hz, 1H), 2.41 (s, 3H), 1.96 (t,J = 1.3 Hz, 3H), 1.59 (d,J = 6.8 Hz, 6H). | 538.2 | |
N-(4-(4-胺基-7-乙基-5-(3-氟-4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.81 - 7.74 (m, 2H), 7.38 - 7.28 (m, 3H), 7.23 - 7.15 (m, 2H), 7.11 (dd,J = 8.3, 2.1 Hz, 1H), 5.81 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.10 (q,J = 7.0 Hz, 2H), 2.42 (s, 3H), 1.96 (d,J = 1.4 Hz, 3H), 1.22 - 1.10 (m, 3H). | 524.4 | |
N-(4-(4-胺基-5-(3-氟-4-(4-甲基嘧啶-2-基氧基)苯基)-7-(2-羥乙基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.79 - 7.72 (m, 2H), 7.37 (s, 1H), 7.39 - 7.29 (m, 2H), 7.21 - 7.13 (m, 2H), 7.10 (dd,J = 8.1, 2.0 Hz, 1H), 5.99 (s, 2H), 5.81 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 4.90 (t,J = 5.5 Hz, 1H), 4.11 (t,J = 6.6 Hz, 2H), 3.58 (t,J = 6.2 Hz, 2H), 2.42 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 540.40 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-(四氫呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.78 (d,J = 8.3 Hz, 2H), 7.32 (dd,J = 8.5, 3.5 Hz, 3H), 7.24 - 7.15 (m, 2H), 7.11 (dd,J = 8.2, 2.0 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 4.75 - 4.62 (m, 1H), 4.18 (dt,J = 14.4, 8.0 Hz, 2H), 3.96 (t,J = 8.2 Hz, 1H), 3.83 (q,J = 7.3 Hz, 1H), 2.77 (dq,J = 14.1, 7.3 Hz, 1H), 2.41 (s, 3H), 2.24 - 2.11 (m, 1H), 1.96 (s, 3H). | 566.45 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-(四氫呋喃-2-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.47 (d,J = 5.1 Hz, 1H), 8.21 (s, 1H), 7.74 (d,J = 8.3 Hz, 2H), 7.31 (d,J = 8.6 Hz, 3H), 7.25 - 7.15 (m, 2H), 7.11 (d,J = 8.2 Hz, 1H), 5.94 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.09 (d,J = 7.7 Hz, 1H), 3.78 (s, 1H), 2.81 (s, 1H), 2.41 (s, 3H), 2.20 (d,J = 29.2 Hz, 2H), 1.95 (s, 3H), 1.89 (s, 1H). | 566.45 | |
N-(6-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 9.02 - 8.97 (m, 1H), 8.22 (s, 1H), 8.00 (dd,J = 8.6, 2.6 Hz, 1H), 7.74 (dd,J = 8.2, 7.4 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.17 - 7.06 (m, 3H), 7.02 (d,J = 7.4 Hz, 1H), 6.81 (d,J = 8.2 Hz, 1H), 5.86 (t,J = 1.0 Hz, 1H), 5.59 (t,J = 1.6 Hz, 1H), 3.77 (s, 3H), 2.36 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 492.20 | |
1-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-1H-吡咯-2(5H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.82 (d,J = 8.5 Hz, 2H), 7.49 (d,J = 8.0 Hz, 3H), 7.35 (d,J = 8.4 Hz, 2H), 7.28 (d,J = 7.8 Hz, 2H), 6.25 (dt,J = 6.1, 1.9 Hz, 1H), 5.92 (s, 2H), 4.61 (d,J = 2.0 Hz, 2H), 3.62 (s, 3H), 3.44 (dt,J = 13.7, 6.5 Hz, 4H), 1.85 (dt,J = 11.2, 6.2 Hz, 3H), 1.79 (d,J = 6.8 Hz, 1H). | 479.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)環戊-1-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.20 (s, 1H), 7.73 - 7.67 (m, 2H), 7.52 - 7.45 (m, 2H), 7.26 (dd,J = 8.5, 3.0 Hz, 4H), 6.70 (p,J = 2.2 Hz, 1H), 5.93 (s, 2H), 3.61 (s, 3H), 3.43 (dt,J = 16.5, 6.4 Hz, 4H), 2.57 (tt,J = 6.9, 2.2 Hz, 2H), 2.51 (tt,J = 6.9, 2.2 Hz, 2H), 1.97 - 1.76 (m, 6H). | 507.40 | |
5-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d,J = 5.1 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.62 (dd,J = 5.1, 1.7 Hz, 1H), 7.54 (d,J = 8.0 Hz, 2H), 7.30 (d,J = 8.0 Hz, 2H), 3.73 (s, 3H), 3.47 (t,J = 6.8 Hz, 2H), 3.41 (t,J = 6.3 Hz, 2H), 1.84 (dt,J = 19.3, 6.8 Hz, 4H). | 424.30 | |
(4-(4-胺基-6-(4-(1,1-二氧離子基異噻唑-2(3H)-基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (d,J = 2.0 Hz, 1H), 7.50 (d,J = 7.8 Hz, 2H), 7.39 (dd,J = 13.6, 8.3 Hz, 4H), 7.28 (t,J = 7.0 Hz, 4H), 5.96 (s, 1H), 4.62 (s, 2H), 3.61 (s, 3H), 3.43 (dt,J = 13.0, 6.5 Hz, 4H), 1.84 (dt,J = 18.6, 6.9 Hz, 4H). | 515.35 | |
(4-(4-胺基-6-(4-(1,1-二氧離子基-3,4-二氫-2H-1,2-噻嗪-2-基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.49 (d,J = 7.8 Hz, 2H), 7.41 - 7.18 (m, 6H), 5.93 (dd,J = 80.2, 10.4 Hz, 4H), 4.52 - 4.21 (m, 2H), 3.86 (d,J = 4.3 Hz, 2H), 3.62 (s, 3H), 3.43 (dt,J = 20.3, 6.5 Hz, 4H), 1.84 (dt,J = 18.5, 6.7 Hz, 4H). | 529.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)環丁-1-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.83 (s, 1H), 8.21 (s, 1H), 7.74 - 7.67 (m, 2H), 7.52 - 7.45 (m, 2H), 7.31 - 7.21 (m, 4H), 6.80 (d,J = 1.3 Hz, 1H), 5.93 (s, 2H), 3.62 (s, 3H), 3.44 (dt,J = 18.5, 6.5 Hz, 4H), 2.74 - 2.68 (m, 2H), 2.46 - 2.40 (m, 2H), 1.83 (dq,J = 18.0, 6.9 Hz, 4H). | 493.20 | |
1-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-5,6-二氫吡啶-2(1H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.55 - 7.45 (m, 2H), 7.42 - 7.25 (m, 6H), 6.83 (dt,J = 9.7, 4.2 Hz, 1H), 5.91 (dt,J = 9.7, 1.8 Hz, 3H), 3.83 (t,J = 6.9 Hz, 2H), 3.63 (s, 3H), 3.44 (dt,J = 13.7, 6.5 Hz, 4H), 2.48 (d,J = 10.1 Hz, 1H), 1.84 (dq,J = 18.2, 6.8 Hz, 4H). | 493.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-亞環丁基乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.20 (s, 1H), 7.66 - 7.56 (m, 2H), 7.54 - 7.42 (m, 2H), 7.32 - 7.15 (m, 4H), 5.81 (t,J = 2.3 Hz, 1H), 3.61 (s, 3H), 3.47 - 3.32 (m, 4H), 3.10 (t,J = 8.2 Hz, 2H), 2.83 (t,J = 7.9 Hz, 2H), 2.05 (p,J = 7.9 Hz, 2H), 1.92 - 1.75 (m, 4H). | 507.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-亞環戊基乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.20 (s, 1H), 7.67 - 7.60 (m, 2H), 7.52 - 7.45 (m, 2H), 7.29 - 7.20 (m, 4H), 6.01 (q,J = 2.4 Hz, 1H), 5.93 (s, 2H), 3.61 (s, 3H), 3.43 (dt,J = 15.8, 6.4 Hz, 4H), 2.75 (t,J = 7.2 Hz, 2H), 2.43 (t,J = 7.2 Hz, 2H), 1.84 (dp,J = 17.8, 6.6 Hz, 4H), 1.64 (dp,J = 34.2, 7.0 Hz, 4H). | 521.40 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-((二甲基胺基)甲基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.22 (s, 1H), 8.21 (s, 1H), 7.71 - 7.59 (m, 2H), 7.54 - 7.44 (m, 2H), 7.28 (t,J = 8.0 Hz, 4H), 6.02 (s, 2H), 5.59 (s, 1H), 3.62 (s, 3H), 3.62 - 3.41 (m, 4H), 3.23 (s, 2H), 2.25 (s, 6H), 1.89 - 1.80 (m, 4H). | 524.35 | |
(E)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-(二甲基胺基)-2-甲基丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.20 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.28 - 7.05 (m, 4H), 6.89 (t, J = 1.6Hz, 1H), 6. 03 - 5.80 (m 1H), 3.60 (s, 3H),3.47 - 3.41 (m, 4H), 3.04 (d, J = 6.0 Hz, 2H), 2.20 (s, 6H), 1.87 (s, 3H), 1.85 - 1.72 (m, 4H). | 538.30 | |
N-(4-(4-胺基-5-(2-氟-4-(吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.20 (s, 1H), 7.71 - 7.64 (m, 2H), 7.36 - 7.30 (m, 3H), 7.27 - 7.21 (m, 2H), 5.92 (s, 2H), 5.80 (d,J = 1.4 Hz, 1H), 5.53 (t,J = 1.4 Hz, 1H), 3.65 (s, 3H), 3.45 (q,J = 7.2 Hz, 4H), 1.95 (t,J = 1.2 Hz, 3H), 1.92 - 1.77 (m, 4H). | 499.25 | |
N-(4-(4-胺基-5-(2,3-二氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.51 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.75 (d,J = 8.4 Hz, 2H), 7.42 - 6.94 (m, 5H), 6.04 (s, 2H), 5.80 (s, 1H), 5.54 (s, 1H), 3.64 (s, 3H), 2.43 (s, 3H), 1.95 (s, 3H). | 528.30 | |
N-(4-(4-胺基-5-(2,5-二氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.51 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.81 - 7.71 (m, 2H), 7.43 - 7.27 (m, 4H), 7.22 (d,J = 5.1 Hz, 1H), 6.00 (s, 2H), 5.85 - 5.77 (m, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.63 (s, 3H), 2.43 (s, 3H), 1.96 (t,J = 1.3 Hz, 3H). | 528.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((1-甲基-1H-吡唑-4-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.18 (s, 1H), 7.77 (s, 1H), 7.74 - 7.67 (m, 2H), 7.39 (s, 1H), 7.30 - 7.23 (m, 2H), 7.23 - 7.15 (m, 2H), 7.00 - 6.92 (m, 2H), 5.80 (s, 2H), 5.54 (d,J = 1.8 Hz, 1H), 3.81 (s, 3H), 3.59 (s, 3H),, 1.95 (d,J = 1.5 Hz, 3H). | 480.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(1-甲基-2-氮雜-雙環[2.1.1]己烷-2-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.21 (s, 1H), 7.73 - 7.67 (m, 2H), 7.50 (d,J = 7.7 Hz, 2H), 7.29 - 7.22 (m, 4H), 5.80 (s, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.62 (s, 3H), 3.40 (s, 2H), 2.71 (d,J = 3.1 Hz, 1H), 1.95 (d,J = 1.4 Hz, 3H), 1.76 (d,J = 4.8 Hz, 2H), 1.60 (s, 3H), 1.50 (dd,J = 4.5, 1.9 Hz, 2H). | 507.3 | |
N-(4-(4-胺基-5-(4-(1-(羥基甲基)-2-氮雜-雙環[2.1.1]己烷-2-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.21 (s, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.57 (d,J = 7.9 Hz, 2H), 7.27 (dd,J = 8.4, 3.0 Hz, 4H), 5.80 (s, 1H), 5.53 (s, 1H), 5.12 (t,J = 6.5 Hz, 1H), 3.93 (d,J = 6.4 Hz, 2H), 3.62 (s, 3H), 3.46 (s, 2H), 2.74 (d,J = 3.2 Hz, 1H), 1.95 (s, 3H), 1.93 - 1.87 (m, 2H), 1.47 (dd,J = 4.6, 1.8 Hz, 2H). | 523.2 | |
N-(4-(4-胺基-5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.77 (dd,J = 12.5, 2.0 Hz, 1H), 7.50 (dd,J = 8.5, 2.0 Hz, 1H), 7.26 (t,J = 8.4 Hz, 2H), 7.18 (d,J = 5.0 Hz, 2H), 7.07 (d,J = 8.3 Hz, 1H), 5.82 (s, 1H), 5.58 (s, 1H), 3.57 (s, 3H), 2.42 (s, 3H), 1.95 (d,J = 1.2 Hz, 3H). | 528.40 | |
(4-(4-胺基-7-甲基-6-(2-乙烯基嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 2H), 8.25 (s, 1H), 7.54 (d,J = 7.9 Hz, 2H), 7.33 (d,J = 7.9 Hz, 2H), 6.84 (dd,J = 17.3, 10.5 Hz, 1H), 6.57 (dd,J = 17.3, 2.0 Hz, 1H), 5.81 (dd,J = 10.5, 2.0 Hz, 1H), 3.72 (s, 3H), 3.45 (dt,J = 16.8, 6.5 Hz, 4H), 1.84 (dq,J = 18.7, 6.8 Hz, 4H). | 462.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-氯乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.21 (s, 1H), 7.68 (s, 3H), 7.61 (d,J = 8.1 Hz, 2H), 7.49 (d,J = 7.7 Hz, 2H), 7.28 (dd,J = 15.1, 7.9 Hz, 4H), 5.94 (s, 2H), 4.27 (s, 2H), 3.61 (s, 3H), 3.45 (dd,J = 16.0, 8.9 Hz, 4H), 1.84 (dd,J = 18.3, 6.3 Hz, 5H). | 489.35 | |
(R)-N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-(四氫呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.81 - 7.74 (m, 2H), 7.37 - 7.28 (m, 3H), 7.24 - 7.15 (m, 2H), 7.11 (dd,J = 8.2, 2.0 Hz, 1H), 5.95 (s, 1H), 5.80 (s, 1H), 5.54 (d,J = 1.8 Hz, 1H), 4.68 (p,J = 8.2 Hz, 1H), 4.18 (dt,J = 15.3, 8.2 Hz, 2H), 3.96 (t,J = 8.2 Hz, 1H), 3.83 (q,J = 7.5 Hz, 1H), 2.77 (dq,J = 14.1, 7.2 Hz, 1H), 2.41 (s, 3H), 2.17 (dd,J = 10.1, 4.9 Hz, 1H), 1.96 (t,J = 1.2 Hz, 3H). | 566.25 | |
(S)-N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-(四氫呋喃-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.81 - 7.74 (m, 2H), 7.37 - 7.28 (m, 3H), 7.25 - 7.15 (m, 2H), 7.14 - 7.07 (m, 1H), 6.12 (s, 1H), 5.80 (s, 1H), 5.55 (d,J = 1.9 Hz, 1H), 4.68 (q,J = 8.3 Hz, 1H), 4.24 - 4.12 (m, 2H), 3.97 (t,J = 8.2 Hz, 1H), 3.83 (q,J = 7.4 Hz, 1H), 2.76 (dq,J = 14.2, 7.3 Hz, 1H), 2.41 (s, 3H), 2.19 (s, 1H), 1.96 (t,J = 1.2 Hz, 3H). | 566.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-(環戊-1-烯-1-基)乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.20 (s, 1H), 7.64 - 7.57 (m, 2H), 7.52 - 7.45 (m, 2H), 7.29 - 7.21 (m, 4H), 5.92 (s, 2H), 5.52 (s, 1H), 3.60 (s, 3H), 3.43 (dt,J = 18.2, 6.4 Hz, 4H), 3.13 (s, 2H), 2.30 (t,J = 7.6 Hz, 4H), 1.84 (tdd,J = 12.4, 7.0, 3.8 Hz, 6H). | 521.35 | |
2-((4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)胺基)乙腈 | 1 H NMR (400 MHz, CDCl3 ):δ 8.41-8.36 (m, 2H), 8.21 (s, 1H), 7.48 (s, 1H), 7.41-7.38 (m, 2H), 7.31-7.28 (m, 2H), 6.96 (s, 1H), 5.14 (s, 2H), 4.28 (m, 2H), 3.21 (s, 1H), 2.85-2.81 (m, 2H), 2.54 (s, 3H), 2.40-2.36 (m, 2H) | 460.3 | |
(2E )-4-{[4-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]胺基}丁-2-烯甲酯 | 1 H NMR (400 MHz, CD3 OD):δ 8.42 (d,J = 5.2 Hz, 1H), 8.19 (s, 1H), 7.29-7.25 (m, 1H), 7.18-7.02 (m, 6H), 6.65 (d,J = 8.4 Hz, 2H), 6.03(d,J = 15.6 Hz, 1H), 3.99-3.97 (m, 2H), 3.71 (s, 3H), 3.68 (s, 3H), 2.51 (s, 3H). | 540.3 | |
N -[(3S )-1--[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]吡咯啶-3-基]丙-2-烯醯胺 | 1 H NMR (400 MHz, CDCl3 ):δ 8.37 (s, 1 H), 7.62 - 7.54 (m, 1H), 7.33 - 7.26 (m, 2H), 7.08 - 7.04 (m, 2H), 6.93 - 6.88 (m, 2H), 6.70 - 6.62 (m, 2H), 6.59 - 6.52 (m, 1H), 6.38 - 6.25 (m, 2H), 6.10 - 5.99 (m, 1H), 5.93 - 5.83 (m, 1H) , 5.05 - 4.96 (m, 2H), 4.76 - 4.63 (m, 1H), 3.75 (s, 3H) 3.53 - 3.45 (m, 1H), 3.39 - 3.05 (m, 3H), 2.45 (s, 3H), 2.36 - 2.26 (m, 1H), 2.06 - 1.96 (m, 1H). | 546.1 | |
N -[(3R )-1-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]吡咯啶-3-基]丙-2-烯醯胺 | 1 H NMR (400 MHz, CDCl3 ):δ 8.37 (s, 1 H), 7.62 - 7.54 (m, 1H), 7.33 - 7.26 (m, 2H), 7.08 - 7.04 (m, 2H), 6.93 - 6.88 (m, 2H), 6.70 - 6.62 (m, 2H), 6.59 - 6.52 (m, 1H), 6.38 - 6.25 (m, 2H), 6.10 - 5.99 (m, 1H), 5.93 - 5.83 (m, 1H) , 5.05 - 4.96 (m, 2H), 4.76 - 4.63 (m, 1H), 3.75 (s, 3H) 3.53 - 3.45 (m, 1H), 3.39 - 3.05 (m, 3H), 2.45 (s, 3H), 2.36 - 2.26 (m, 1H), 2.06 - 1.96 (m, 1H) | 546.1 | |
1-{4-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]哌嗪-1-基}丙-2-烯-1-酮鹽酸鹽 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 7.73-7.70 (m, 1H), 7.63-7.60 (d,J = 8.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.35-7.28 (m, 3H), 7.32-7.28 (m, 3H), 7.14-7.10 (m, 2H), 7.02-7.00 (d,J = 7.6 Hz, 1H), 6.79-6.76 (m, 1H), 6.69-6.59 (m, 1H), 6.49 (s, 1H), 6.23-6.15 (m, 1H), 5.75-5.70 (m, 1H), 4.69 (s, 1H), 4.55-4.47 (d,J = 32.4 Hz, 2H), 4.32 (s, 1H), 3.75-3.73 (d,J = 6.8 Hz, 3H), 2.31-2.29 (d,J = 7.2 Hz, 3H). | 529.3 | |
N -{[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]甲基}丙-2-烯醯胺鹽酸鹽 | 1 H NMR (400 MHz, DMSO-d6 ):δ 8.71-8.67 (m, 1H), 8.58 (s, 1H), 7.76 (t,J = 7.8 Hz, 1H), 7.44 - 7.20 (m, 6H), 7.15 - 7.00 (m, 3H), 6.81 (d,J = 8.0 Hz, 1H), 6.32 - 6.23 (m, 1H), 6.16 - 6.05 (m, 1H), 5.61 (dd,J = 2.1, 10.0 Hz, 1H), 4.36 (d,J = 6.0 Hz, 2H), 3.69 (s, 3H), 2.37 (s, 3H). | 491.1 | |
N -[2-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]丙-2-烯醯胺鹽酸鹽 | 1 H NMR (400 MHz, CD3 OD):δ 8.10 (s, 1H), 7.66 - 7.55 (m, 2H), 7.40 - 7.32 (m, 2H), 7.28 - 7.19 (m, 1H), 7.11 (br d,J = 7.8 Hz, 2H), 6.90 (t,J = 7.2 Hz, 3H), 6.63 (d,J = 8.4 Hz, 1H), 6.17 - 5.99 (m, 2H), 5.58 - 5.50 (m, 1H), 5.10 (s, 1H), 4.88 - 4.82 (m, 4H), 4.51 (s, 11H), 3.54 (s, 4H), 2.36 - 2.27 (m, 3H) | 477.2 | |
N -[5-(4-胺基-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H 吡咯并[2,3-d ]嘧啶-6-基)-1-甲基-1H -吡唑-3-基]丙-2-烯醯胺 | 1 HNMR (400 MHz, 甲醇-d 4 ):δ 8.30 (d,J = 5.0 Hz, 1H), 8.14 (s, 1H), 7.29 (d,J = 8.4 Hz, 2H), 7.13 (d,J = 8.8 Hz, 2H), 7.02 (d,J = 5.0 Hz, 1H), 6.82 (s, 1H), 6.40 - 6.23 (m, 2H), 5.68 (dd,J = 2.4, 9.8 Hz, 1H), 4.50 (s, 4H), 3.61 - 3.56 (m, 3H), 2.38 (s, 3H). | 482.3 | |
N -[5-(4-胺基7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)-1-甲基-1H -吡唑-3-基]丙-2-烯醯胺 | 1 HNMR (400 MHz, DMSO-d6 ):δ 10.73 (s, 1H), 8.28 (s, 1H), 7.85 (t,J = 7.6 Hz, 1H), 7.62 (d,J = 2.0 Hz, 1H), 7.54 - 7.45 (m, 3H), 7.35 (d,J = 8.4 Hz, 2H), 7.13 (d,J = 7.6 Hz, 1H), 7.00 - 6.94 (m, 1H), 6.93 - 6.87 (m, 1H), 6.58 (d,J = 2.4 Hz, 1H), 4.01 (s, 3H), 3.88 - 3.75 (m, 4H), 2.45 (s, 3H). | 481.3 | |
[3-[4-胺基-7-甲基-5-[4-[(6-甲基-2-吡啶基)氧基]苯基]吡咯并[2,3-d ]嘧啶-6-基]苯基]氰胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.72 (t,J = 7.6 Hz, 1H), 7.38 (t,J = 8.0 Hz, 1H), 7.2 (d,J = 8.8 Hz, 2H), 7.09 (d,J = 7.6 Hz, 2H), 7.04-7.00 (m, 2H), 6.98-6.93 (m, 1H), 6.81 (s, 1H), 6.77 (d,J = 8.0 Hz, 1H), 5.93 (br, 1H), 3.60 (s, 3H), 2.35 (s, 3H). | 448.2 | |
4-{4-胺基-7-甲基-6-[3-(丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-N-[(3-氟氧雜環丁-3-基)甲基]苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.24 (s, 1H), 8.83-8.77 (m, 1H), 8.22 (s, 1H), 7.82 (d,J = 8.0 Hz, 2H), 7.73-7.64 (m, 2H), 7.38-7.29 (m, 3H), 6.99 (d,J = 7.6 Hz, 1H), 6.47-6.35 (m, 1H), 6.30-6.21 (m, 1H), 5.98 (s, 1H), 5.79-5.73 (m, 1H), 4.73-4.55(m, 4H), 3.82 (d,J = 6.0 Hz, 1H), 3.76 (d,J = 6.0 Hz 1H), 3.60 (s, 3H). | 501.1 | |
4-{4-胺基-7-甲基-6-[4-(丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-N-[(3-氟氧雜環丁-3-基)甲基]苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 10.27 (s, 1H), 8.82-8.74 (m, 1H),8.20 (s, 1H), 7.82 (d,J = 8.0 Hz, 2H), 7.67 (d,J = 8.0 Hz, 2H), 7.33-7.24 (m, 4H), 6.48-6.38 (m, 1H), 6.30-6.23 (m, 1H), 5.93 (br, 1H), 5.80-5.74 (m, 1H), 4.71-4.52 (m, 4H), 3.83-3.73 (m, 2H), 3.60 (s, 3H). | 501.1 | |
4-[4-胺基-6-[3-(2-甲基丙-2-烯醯基胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基]-N-[(3-氟氧雜環丁-3-基)甲基]苯甲醯胺 | 1 HNMR (400 MHz, DMSO-d 6 ):δ 12.16 (br, 1H), 9.81 (s, 1H), 8.86 (t,J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.92 (d,J = 8.4 Hz, 2H), 7.81 (s, 1H), 7.57 (d,J = 8.0 Hz, 1H), 7.42 (d,J = 8.4 Hz, 2H), 7.21 (m, 1H), 6.89 (d,J = 8.0 Hz, 1H), 5.75 (s, 1H), 5.51(s, 1H), 4.74-4.59 (m, 4H), 3.82 (dd,J = 19.6 Hz, 6.6 Hz, 2H), 1.92 (s, 3H). | 501.1 | |
4-{4-胺基-7-甲基-6-[3-(2-甲基丙-2-烯醯胺基)苯基]-7H -吡咯并[2,3-d ]嘧啶-5-基}-N -[(3-氟氧雜環丁-3-基)甲基]苯甲醯胺 | 1 HNMR (400 MHz, DMSO-d 6 ):δ 9.88 (s, 1H), 8.81-8.78 (m, 1H), 8.22 (s, 1H), 7.82 (d,J = 8.4 Hz, 2H), 7.72 (d,J = 8.8 Hz, 2H), 7.34-7.29 (m, 3H), 6.95 (d,J = 7.6 Hz, 1H), 5.78 (s, 1H), 5.52 (s, 1H), 4.70-4.57 (m, 4H), 3.82-3.75 (m, 2H), 3.60 (s, 3H), 1.93 (s, 3H). | 515.1 | |
(2E )-N -(3-{4-胺基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-4-(二甲基胺基)丁-2-烯醯胺鹽酸鹽 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 10.99 (s, 1H), 10.72 (s, 1H), 8.60 (s, 1H), 7.77-7.73 (m, 2H), 7.49 (d,J = 8.4 Hz, 2H), 7.72 (d,J = 8.8 Hz, 2H), 7.43-7.39 (m, 1H), 7.28 (d,J = 8.4 Hz, 2H), 7.07 (d,J = 7.6 Hz, 1H), 6.83-6.76 (m, 1H), 6.50 (d,J = 7.2 Hz, 1H), 3.92-3.89 (m, 2H), 3.71 (s, 3H), 3.45-3.40 (m, 4H), 2.74 (d,J = 4.0 Hz, 6H), 1.88-1.76 (m, 4H). | 524.4 | |
4-[4-胺基-6-(4-{2-[(二甲基胺基)甲基]丙-2-烯醯胺基}苯基)-7-甲基-7H -吡咯并[2,3-d]嘧啶-5-基]-N -[(3-氟氧雜環丁-3-基)甲基]苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 8.83-8.74 (m, 1H), 8.16 (s, 1H), 7.80 (d,J = 8.0 Hz, 2H), 7.28 (d,J = 8.0 Hz, 2H), 6.99 (d,J = 8.0 Hz, 2H), 6.58 (d,J = 8.0 Hz, 2H), 6.30-6.20 (m, 1H), 5.83 (br, 1H), 5.36 (s, 1H), 5.12 (s, 1H), 4.74-4.53 (m, 4H), 3.89-3.70 (m, 4H), 3.57 (s, 3H), 2.91-2.78 (d,J = 16.0 Hz, 6H). | 558.2 | |
4-{4-胺基-7-甲基-6-[4-(丙-2-烯醯胺基)苯基]-7H -吡咯并[2,3-d ]嘧啶-5-基}-N -(2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 8.40 (s, 1H), 7.81 (d,J = 8.4 Hz, 2H), 7.71 (d,J = 8.8 Hz, 2H), 7.40 (d,J = 8.4 Hz, 2H), 7.30 (d,J = 8.4 Hz, 2H), 6.47-6.34 (m, 2H), 5.81-5.78 (m, 2H), 3.8 (s, 3H), 3.19 (d,J = 6.8 Hz, 1H), 1.95-1.88 (m, 1H), 0.95 (d,J = 6.4 Hz, 6H). | 469.2 | |
(1S )-4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-N-[(3-氟氧雜環丁-3-基)甲基]環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ):δ 9.95 (s, 1H), 8.35-8.24 (m, 1H), 8.10 (s, 1H), 7.81 (d,J = 12.0 Hz, 2H), 7.43 (d,J = 12.0 Hz, 2H), 6.60 - 6.24 (m, 2H), 5.92 - 5.72 (m, 2H), 5.55 (s, 1H), 4.68 - 4.43 (m, 4H), 3.63 - 3.53 (m, 4H), 2.59 - 2.53 (m, 1H), 2.38 - 2.16 (m, 2H), 1.97 (s, 3H), 1.91-1.84 (m, 2H), 1.75-1.60 (m, 2H). | 519.1 | |
(1R )-4-{4-胺基-7-甲基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-N-[(3-氟氧雜環丁-3-基)甲基]環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 9.96 (s, 1H), 8.26 (t,J = 6.0 Hz, 1H), 8.10 (s, 1H), 7.81 (d,J = 8.4 Hz, 2H), 7.43 (d,J = 8.4 Hz, 2H), 6.44 (br s, 2H), 5.88 - 5.70 (m, 2H), 5.55 (s, 1H), 4.64 - 4.46 (m, 4H), 3.62 - 3.53 (m, 4H), 2.59 - 2.54 (m, 1H), 2.39 - 2.16 (m, 2H), 1.97 (s, 3H), 1.93-83 (m, 2H), 1.72-1.60 (m, 2H). | 519.1 | |
N -{3-[4-胺基-7-甲基-5-(1-甲基-1,2,3,4-四氫喹啉-6-基)-7H -吡咯并[2,3-d]嘧啶-6-基]苯基}丙-2-烯醯胺鹽酸鹽 | 1 H NMR (400 MHz, DMSO-d6 ):δ 10.60 - 10.32 (m, 1H), 8.59 - 8.40 (m, 1H), 7.78 (s, 1H), 7.70 (d,J = 7.6 Hz, 1H), 7.42 - 7.33 (m, 1H), 7.06 - 7.00 (m, 1H), 6.93 - 6.84 (m, 2H), 6.59 (d,J = 8.4 Hz, 1H), 6.52 - 6.41 (m, 1H), 6.25 (dd,J = 1.6, 16.8 Hz, 1H), 5.80 - 5.71 (m, 1H), 3.65 - 3.64 (m, 3H), 3.27 - 3.16 (m, 2H), 2.83 (s, 3H), 2.68 - 2.59 (m, 2H), 1.86 (m, 2H) | 439.1 | |
N -(3-{4-胺基-7-甲基-5-[(4S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H -吡咯并[2,3-d]嘧啶-6-基}苯基)丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d6 ):δ 10.27 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.66 (dd,J = 8.0 Hz, 1H), 7.44 (t,J = 8.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.530 (br, 2H), 6.491-6.423 (m, 1H), 6.35 - 6.21 (m, 1H), 5.83 - 5.71 (m, 2H), 3.69 - 3.53 (m, 3H), 3.52 - 3.40 (m, 2H), 3.42 - 3.40 (m, 1H), 3.29 - 3.20 (m, 2H), 2.81 (m, 1H), 2.37 - 2.13 (m, 2H), 1.98 - 1.58 (m, 8H). | 471.1 | |
N -(3-{4-胺基-7-甲基-5-[(4R )-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H -吡咯并[2,3-d]嘧啶-6-基}苯基)丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 10.28 (s, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.67 (dd,J = 8.0 Hz, 1H), 7.44 (t,J = 8.0 Hz, 1H), 7.20 (d,J = 7.6 Hz, 1H), 6.526 (br, 2H), 6.493-6.425(m, 1H), 6.33 - 6.22 (m, 1H), 5.85 - 5.69 (m, 2H), 3.60 (s, 3H), 3.52 - 3.40 (m, 4H), 3.34 - 3.20 (m, 3H), 2.88 - 2.74 (m, 1H), 2.38 - 2.14 (m, 2H), 2.01 - 1.56 (m, 8H). | 471.1 | |
N -(4-{4-胺基-7-甲基-5-[(1R )-3'-側氧基-1',3'-二氫螺[環己烷-1,2'-茚]-3-烯-4-基]-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 H NMR (400MHz, 甲醇-d 4 ) δ 8.16 (s, 1H), 7.83 (d,J = 8.8 Hz, 2H), 7.75 - 7.64 (m, 2H), 7.58 - 7.48 (m, 3H), 7.47 - 7.39 (m, 1H), 5.98 (s, 1H), 5.87 (s, 1H), 5.58 (d,J = 0.8 Hz, 1H), 3.68 (s, 3H), 3.01 (s, 2H), 2.70 - 2.43 (m, 1H), 2.37 - 2.17 (m, 2H), 2.09 (s, 3H), 2.06 - 1.96 (m, 1H), 1.86-1.78 (m, 1H), 1.69 - 1.56 (m, 1H). | 504.1 | |
N -(4-{4-胺基-7-甲基-5-[(1S )-3'-側氧基-1',3'-二氫螺[環己烷-1,2'-茚]-3-烯-4-基]-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 HNMR (400MHz, 甲醇-d 4 ) δ 8.06 (s, 1H), 7.79 - 7.66 (m, 2H), 7.64 - 7.50 (m, 2H), 7.46 - 7.36 (m, 3H), 7.35 - 7.28 (m, 1H), 5.87 (s, 1H), 5.75 (s, 1H), 5.46 (d,J = 0.8 Hz, 1H), 3.58 (s, 3H), 2.89 (s, 2H), 2.55 - 2.34 (m, 1H), 2.27 - 2.04 (m, 2H), 1.97 (s, 3H), 1.94 - 1.87 (m, 1H), 1.72-1.66 (m, 1H), 1.58 - 1.47 (m, 1H). | 504.1 | |
N -(4-{4-胺基-5-[(1R )-2'-甲氧基-7'-側氧基-5',7'-二氫螺[環己烷-1,6'-環戊并[b ]吡啶]-3-烯-4-基]-7-甲基-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 H NMR (400MHz, DMSO-d 6 ):δ 9.97 (s, 1H), 8.13 (s, 1H), 7.93 (d,J = 8.4 Hz, 1H), 7.84 (d,J = 8.4 Hz, 2H), 7.48 (d,J = 8.4 Hz, 2H), 7.12 (d,J = 8.4 Hz, 1H), 6.51 (br, 2H), 5.87-5.78 (m, 2H), 5.56 (s, 1H), 3.88 (s, 3H), 3.60 (s, 3H), 2.89-2.74 (m, 2H), 2.47-2.42 (m, 2H), 2.14-2.09 (m, 2H), 2.05-1.98 (m, 4H), 1.83 - 1.66 (m, 1H), 1.58 - 1.45 (m, 1H). | 535.1 | |
N -(4-{4-胺基-5-[(1S )-2'-甲氧基-7'-側氧基-5',7'-二氫螺[環己烷-1,6'-環戊并[b]吡啶]-3-烯-4-基]-7-甲基-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 H NMR (400MHz, DMSO-d 6 ):δ 9.99 (s, 1H), 8.13 (s, 1H), 7.94 (d,J = 8.4 Hz, 1H), 7.85 (d,J = 8.8 Hz, 2H), 7.48 (d,J = 8.4 Hz, 2H), 7.13 (d,J = 8.4 Hz, 1H), 6.53 (br, 2H), 5.90 - 5.80 (m, 2H), 5.56 (s, 1H), 3.89 (s, 3H), 3.61 (s, 3H), 2.92-2.77 (m, 2H), 2.47-2.43 (m, 1H), 2.14-2.10 (m, 2H), 2.02-1.99 (m, 4H), 1.81-1.69 (m, 1H), 1.57-1.46 (m, 1H). | 535.1 | |
N -(4-{4-胺基-7-甲基-5-[(1R )-2'-甲基-7'-側氧基-5',7'-二氫螺[環己烷-1,6'-環戊并[b ]吡啶]-3-烯-4-基]-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 H NMR (400MHz, CDCl3 ):δ 8.33 (s, 1H), 7.79 - 7.67 (m, 3H), 7.61 (s, 1H), 7.44 (d,J = 8.4 Hz, 2H), 7.35 (d,J = 8.0 Hz, 1H), 5.96 (br, 1H), 5.86 (s, 1H), 5.54 (s, 1H), 3.70 (s, 3H), 2.93 (s, 2H), 2.68 (s, 3H), 2.61-2.56 (m, 1H), 2.45 - 2.15 (m, 3H), 2.12 (s, 3H), 2.05 - 1.92 (m, 1H), 1.89 - 1.78 (m, 1H) | 519.1 | |
N -(4-{4-胺基-7-甲基-5-[(1S )-2'-甲基-7'-側氧基-5',7'-二氫螺[環己烷-1,6'-環戊并[b ]吡啶]-3-烯-4-基]-7H -吡咯并[2,3-d ]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 H NMR (400MHz, CDCl3 ):δ 8.28 (s, 1H), 7.79 - 7.69 (m, 3H), 7.65 (s, 1H), 7.43 (d,J = 8.4 Hz, 2H), 7.36 (d,J = 8.0 Hz, 1H), 5.96 (s, 1H), 5.86 (s, 1H), 5.54 (s, 1H), 3.72 (s, 3H), 2.94 (s, 2H), 2.68 (s, 3H), 2.59-2.53 (m, 1H), 2.43 - 2.26 (m, 3H), 2.12 (s, 3H), 2.02-1.92 (m, 1H), 1.82-1.71 (m, 1H). | 519.1 |
步驟 1
:向圓底燒瓶中裝入N-(4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}苯基)丙-2-烯醯胺(200 mg,537 µmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(199 mg,644 µmol)、Pd(dtbpf)Cl2
(34.9 mg,53.7 µmol)、K3
PO4
(341 mg,1.61 mmol)、5 mL DMF及攪拌棒。在90℃下攪拌溶液2小時。反應混合物用水(50 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(2 g管柱;用庚烷/乙酸乙酯3:1溶離)。真空濃縮,產生呈黃色油狀之4-{4-胺基-7-甲基-6-[4-(丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(121 mg,48%)。N -( 4 -( 4 - 胺基 - 7 - 甲基 - 5 -( 1 , 2 , 3 , 6 - 四氫吡啶 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 丙烯醯胺
步驟 2
:向圓底燒瓶中裝入4-{4-胺基-7-甲基-6-[4-(丙-2-烯醯胺基)苯基]-7H-吡咯并[2,3-d]嘧啶-5-基}-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(30 mg,63.2 µmol)、0.2 mL TFA、0.8 mL DCM及攪拌棒。在室溫下攪拌溶液1小時。將反應混合物過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水/0.1%甲酸)。凍乾產生呈白色非晶形固體狀之N-{4-[4-胺基-7-甲基-5-(1,2,3,6-四氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}丙-2-烯醯胺(16.8 mg,71%)。N -( 4 -( 4 - 胺基 - 7 - 甲基 - 5 -( 1 -( 2 , 2 , 2 - 三氟乙醯基 )- 1 , 2 , 3 , 6 - 四氫吡啶 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 丙烯醯胺
步驟 3
:向圓底燒瓶中裝入N-{4-[4-胺基-7-甲基-5-(1,2,3,6-四氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}丙-2-烯醯胺(40 mg,106 µmol)、TEA (32.1 mg,318 µmol)、DMAP (1.29 mg,10.6 µmol)、5 mL DCM及攪拌棒。在0℃下逐滴添加TFAA。在室溫下攪拌溶液1小時。反應混合物用水(30 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水/0.1%甲酸)。凍乾產生呈白色非晶形固體狀之N-(4-{4-胺基-7-甲基-5-[1-(2,2,2-三氟乙醯基)-1,2,3,6-四氫吡啶-4-基]-7H-吡咯并[2,3-d]嘧啶-6-基}苯基)丙-2-烯醯胺(27.9 mg,37%)。
根據實例4之方法製備的其他化合物描繪於下表3中。表 3 . 其他例示性化合物
流程 3
實例5N -( 4 -( 4 - 胺基 - 7 - 甲基 - 5 -( 1 -( 吡咯啶 - 1 - 羰基 ) 哌啶 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 甲基丙烯醯胺
4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3,6-二氫吡啶-1(2H)-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-7-甲基-5-(1-(2,2,2-三氟乙醯基)-1,2,3,6-四氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (d, J = 2.8 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.87 - 7.68 (m, 2H), 7.47 - 7.39 (m, 2H), 6.49 - 6.28 (m, 3H), 5.85 - 5.70 (m, 2H), 4.30 - 4.09 (m, 2H), 3.65 - 3.52 (m, 5H), 2.09 (s, 2H). | 471.1 | |
N-(4-(4-胺基-7-甲基-5-(1,2,3,6-四氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (d, J = 28.0 Hz, 1H), 8.21 - 8.08 (m, 1H), 7.80 - 7.56 (m, 2H), 7.44-7.39 (m, 2H), 6.56 - 6.05 (m, 2H), 5.80 (d, J = 10.4 Hz, 1H), 3.57-3.46 (m, 4H), 3.16 (d, J = 46.0 Hz, 2H), 2.77 - 2.63 (m, 2H), 2.00 (m, J = 46.4 Hz, 2H). | 375.2 |
步驟 1
:向圓底燒瓶中裝入5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(3.00 g,10.9 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(4.01 g,13.0 mmol)、Pd(dtbpf)Cl2
(710 mg,1.09 mmol)、K3
PO4
(6.91 g,32.6 mmol)及攪拌棒。添加DMF (45 mL)及H2
O (3 mL),且在90℃下攪拌溶液3小時。混合物用EtOAc (300 mL)稀釋且用水(3*100 mL)洗滌,濃縮有機相且藉由使用DCM:MeOH = 25:1的矽膠管柱純化粗產物,得到呈棕色油狀之4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(2.97 g,83%)。
4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯
步驟 2
:向圓底燒瓶中裝入4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}-1,2,3,6-四氫吡啶-1-甲酸第三丁酯(1.70 g,5.16 mmol)、Pd/C (326 mg,154 µmol)及攪拌棒。添加MeOH (50 mL),且在50℃下、在H2
下攪拌溶液48小時。過濾混合物且用MeOH洗滌5次,濃縮濾液且獲得呈棕色油狀之4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}哌啶-1-甲酸第三丁酯(900 mg,53%)。
4-(4-胺基-6-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯
步驟 3
:向圓底燒瓶中裝入4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}哌啶-1-甲酸第三丁酯(800 mg,2.41 mmol)、NBS (428 mg,2.41 mmol)及攪拌棒。添加ACN (20 mL),且在25℃下攪拌溶液0.5小時。在減壓下濃縮混合物且獲得呈棕色固體狀之產物4-{4-胺基-6-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}哌啶-1-甲酸第三丁酯(500 mg,51%)。粗產物不經進一步純化即用於下一步驟中。6 - 溴 - 7 - 甲基 - 5 -( 哌啶 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 4 - 胺
步驟 4
:向圓底燒瓶中裝入4-{4-胺基-6-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}哌啶-1-甲酸第三丁酯(500 mg,1.21 mmol)、DCM (5 mL)及攪拌棒。添加TFA (0.5 mL),且在25℃下攪拌溶液2小時。在減壓下濃縮混合物,且用DCM (30 mL)稀釋,用NaHCO3
飽和水溶液(3*15 mL)洗滌,濃縮有機相且獲得呈棕色油狀之產物6-溴-7-甲基-5-(哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(310 mg,83%)。
(4-(4-胺基-6-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-基)(吡咯啶-1-基)甲酮
步驟 5
:向圓底燒瓶中裝入6-溴-7-甲基-5-(哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(280 mg,902 µmol)、DIEA (580 mg,4.50 mmol)、DCM (10 mL)及攪拌棒。添加三光氣(106 mg,360 µmol),且在室溫下攪拌溶液1小時,接著添加吡咯啶(512 mg,7.21 mmol)且在室溫下攪拌1小時。移除溶劑且藉由C18 Flash純化粗產物,得到呈灰白色固體狀之6-溴-7-甲基-5-[1-(吡咯啶-1-羰基)哌啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(160 mg,21%)。
N-(4-(4-胺基-7-甲基-5-(1-(吡咯啶-1-羰基)哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
步驟 6
:向可再密封之反應瓶中裝入6-溴-7-甲基-5-[1-(吡咯啶-1-羰基)哌啶-4-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(140 mg,0.34 mmol)、N-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙烯醯胺(112 mg,0.41 mmol)、Pd(dppf)Cl2
(25.1 mg,34.3 µmol)、K3
PO4
(216 mg,1.02 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF (1 mL)及H2O (0.1 mL),且在90℃下攪拌混合物3小時。所得混合物經由C18管柱純化。所得粗物質藉由HPLC純化。凍乾產生呈白色非晶形固體狀之N-(4-{4-胺基-7-甲基-5-[1-(吡咯啶-1-羰基)哌啶-4-基]-7H-吡咯并[2,3-d]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺(24.3 mg,15%)。
根據實例5之方法製備的其他化合物描繪於下表4中。表 4 . 例示性化合物
流程 4
實例6
N-(4-(4-胺基-7-甲基-5-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺
4-(6-(4-丙烯醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-7-甲基-5-(1-(吡咯啶-1-羰基)哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.11 (s, 1H), 7.83 (d,J = 8.4 Hz, 2H), 7.35 (d,J = 8.3 Hz, 2H), 6.38 (s, 2H), 5.83 (s, 1H), 5.56 (s, 1H), 3.58 - 3.61 (m, 2H), 3.55 (s, 3H), 3.26 - 3.38 (m, 4H), 3.02 - 3.05 (m, 1H), 2.68 - 2.76 (m, 2H), 2.08 (s, 3H), 1.63 - 1.66 (m, 4H), 1.48 - 1.57 (m, 4H). | 488.3 |
步驟1:向圓底燒瓶中裝入4-(4-胺基-6-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯(700 mg,1.7 mmol)、N-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙烯醯胺(559 mg,2.0 mmol)、Pd(dtbpf)Cl2 (124 mg,0.17 mmol)、K3
PO4
(1.08 g,5.1 mmol)及攪拌棒。添加DMF (10 mL)及H2
O (1 mL),且在90℃下攪拌溶液3小時。混合物用EtOAc (100 mL)稀釋且用水(3*100 mL)洗滌,且濃縮有機相且藉由使用DCM:MeOH=25:1的矽膠管柱純化粗產物,得到呈黃色固體狀之4-(6-(4-丙烯醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯(340 mg,42%)。
4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯
步驟 2
:向圓底燒瓶中裝入4-(6-(4-丙烯醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯(340 mg,0.71 mmol)、DCM (5 mL)及攪拌棒。添加TFA (0.5 mL),且在25℃下攪拌溶液2小時。在減壓下濃縮混合物,且用DCM (30 mL)稀釋,用NaHCO3
飽和水溶液(3*15 mL)洗滌,濃縮有機相且獲得呈棕色油狀之產物4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯(240 mg,89%)。
N-(4-(4-胺基-7-甲基-5-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺
步驟 3
:向圓底燒瓶中裝入4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)哌啶-1-甲酸第三丁酯(120 mg,0.32 mmol)、NaBH(OAc)3
(81 mg,0.38 mmol)、(CH2
O)n (20 mg,0.64 mmol)及攪拌棒。添加DCM (5 mL)及AcOH (0.5 mL),且在室溫下攪拌溶液隔夜。反應混合物用水(50 mL)稀釋,且水相用DCM (20 mL)萃取三次。合併之有機層經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化。凍乾產生呈白色非晶形固體狀之N-(4-{4-胺基-7-甲基-5-[1-(吡咯啶-1-羰基)哌啶-4-基]-7H-吡咯并[2,3-d]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺(8 mg,6%)。
根據實例6之方法製備的其他化合物描繪於下表5中。表 5 . 例示性化合物
流程 5
實例7N -( 4 -( 4 - 胺基 - 7 - 甲基 - 5 -( 1 -(( 甲基胺甲醯基 ) 甘胺醯基 ) 哌啶 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 ) 苯基 ) 丙烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-7-甲基-5-(1-甲基哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.11 (s, 1H), 7.85 - 7.78 (m, 2H), 7.40 - 7.29 (m, 2H), 6.49 (dd, J = 17.0, 10.1 Hz, 1H), 6.37-6.28 (m, 3H), 5.81 (dd, J = 10.0, 2.0 Hz, 1H), 3.37 (s, 3H), 2.75 (d, J = 10.9 Hz, 3H), 2.50-2.31 (m, 3H), 2.14 (s, 3H), 1.93-1.91 (m, 2H), 1.65 (s, 4H). | 391.2 |
向可再密封之反應瓶中裝入N-{4-[4-胺基-7-甲基-5-(哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}丙-2-烯醯胺(100 mg,0.265 mmol)、2-[(甲基胺甲醯基)胺基]乙酸(35.0 mg,0.265 mmol)、HATU (121 mg,0.32 mmol)、DIEA (68.5 mg,0.53 mmmol)及攪拌棒。添加二甲基甲醯胺(5 mL),且在室溫下攪拌混合物1小時。反應混合物用水(10 mL)稀釋,且水相用二氯甲烷(15 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水/0.1%甲酸)。凍乾產生呈白色非晶形固體狀之N-{4-[4-胺基-7-甲基-5-(1-{2-[(甲基胺甲醯基)胺基]乙醯基}哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}丙-2-烯醯胺(6.00 mg,5%)。
根據實例7之方法製備的其他化合物描繪於下表6中。表 6 . 其他例示性化合物
實例8流程 6 5 -( 4 - 甲氧基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 4 - 胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-7-甲基-5-(1-((甲基胺甲醯基)甘胺醯基)哌啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.47 (dd, J = 17.0, 10.2 Hz, 1H), 6.39 (s, 2H), 6.30 (d, J = 16.8 Hz, 1H), 6.10 (s, 1H), 5.92 (s, 1H), 5.80 (d, J = 10.5 Hz, 1H), 3.78-3.66 (m, 3H), 3.45-3.37 (m, 1H), 3.31 (s, 3H), 3.21-3.08 (m, 2H), 2.55-2.53 (m, 1H), 2.51 (s, 3H), 1.86-1.73 (m, 2H), 1.45-1.24 (m, 2H). | 491.2 | |
(R)-N-(4-(4-胺基-5-(1-(4-(二甲基胺基)-2-甲基丁醯基)哌啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.2 Hz, 2H), 6.53 - 6.42 (m, 3H), 6.30 (dd, J = 16.8, 2.1 Hz, 1H), 5.80 (dd, J = 10.0, 2.0 Hz, 1H), 4.37 (s, 1H), 3.88 (s, 1H), 3.28 (s, 3H), 3.09 (t, J = 13.6 Hz, 1H), 2.75-2.61 (m, 2H), 2.06 (s, 4H), 2.01 (s, 4H), 1.76-1.48 (m, 4H), 1.29-1.22 (m, 3H), 0.91-0.82 (m, 3H). | 504.4 |
步驟 1
:向可再密封之反應瓶中裝入5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(20 g,72.9 mmol)、(4-甲氧基苯基)酸(13.3 g,87.5 mmol)、Pd(DtBPF)Cl2
(4.74 g,7.29 mmol)、CsF (33.1 g,218 mmol)、DMF (200 mL)、H2
O (25 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。反應混合物用H2
O (500 mL)稀釋,且水相用DCM (200 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。向反應混合物中添加MeCN (10 mL)且經由Celite®
墊過濾,用MeCN洗滌墊。真空濃縮濾液且所得固體為5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(10.2 g,55%),以黃色非晶形固體狀獲得。6 - 碘 - 5 -( 4 - 甲氧基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 4 - 胺
步驟2:向圓底燒瓶中裝入5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(9.8 g,38.5 mmol)、DCM (200 mL)、TFA (13.1 g,115 mmol)及攪拌棒。將混合物冷卻至0℃,添加NIS (9.53 g,42.4 mmol),且在室溫下攪拌溶液1小時。反應混合物用Na2
SO3
溶液稀釋,且水相用DCM (300 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。添加DCM (20 mL)且經由Celite®
墊過濾反應混合物,用少量DCM洗滌墊。真空濃縮濾液且所得固體為6-碘-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(10.9 g,74%),以灰白色非晶形固體呈狀獲得。4 -( 4 -( 4 - 胺基 - 5 -( 4 - 甲氧基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 )- 1H - 吡唑 - 1 - 基 ) 哌啶 - 1 - 甲酸第三丁酯
步驟 3
:向可再密封之反應瓶中裝入6-碘-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(1 g,2.63 mmol)、4-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(1.2 g,3.16 mmol)、Pd(dppf)Cl2
(190 mg,0.26 mmol)、K3
PO4
(1.5 g,6.9 mmol)、DMF (20 mL)、H2
O (2 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。反應混合物用H2
O (100 mL)稀釋,且水相用DCM (100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用MeOH/DCM = 1/40溶離)純化。真空濃縮,產生呈黃色固體狀的4-(4-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(800 mg,61%)。5 -( 4 - 甲氧基苯基 )- 7 - 甲基 - 6 -( 1 ( 哌啶 - 4 - 基 )- 1H - 吡唑 - 4 - 基 )- 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 4 - 胺三氟乙酸鹽
步驟 4
:向圓底燒瓶中裝入4-(4-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-甲酸第三丁酯(800 mg,1.6 mmol)、DCM (20 mL)及攪拌棒。添加TFA (5 mL)。在室溫下攪拌反應混合物1小時。真空移除溶劑,產生呈深色油狀之5-(4-甲氧基苯基)-7-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺三氟乙酸鹽(795 mg,100%)。1 -( 4 -( 4 -( 4 - 胺基 - 5 -( 4 - 甲氧基苯基 )- 7 - 甲基 - 7H - 吡咯并 [ 2 , 3 - d ] 嘧啶 - 6 - 基 )- 1H - 吡唑 - 1 - 基 ) 哌啶 - 1 - 基 ) 丙 - 2 - 烯 - 1 - 酮
步驟 5
:向圓底燒瓶中裝入5-(4-甲氧基苯基)-7-甲基-6-(1-(哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺三氟乙酸鹽(120 mg,0.24 mmol)、Et3
N (72.9 mg,0.72 mmol)、DCM (10 mL)及攪拌棒。將混合物冷卻至-30℃,逐滴添加丙-2-烯醯氯(21.6 mg,0.24 mmol)且在-30℃下攪拌溶液0.5小時。反應混合物用MeOH淬滅且真空濃縮。所得粗物質藉由製備型HPLC純化。凍乾產生呈白色非晶形固體狀之1-(4-(4-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮(33 mg,30%)。
根據實例8之方法製備的其他化合物描繪於下表7中。表 7 . 其他例示性化合物
實例9流程 7
N-(4-(4-胺基吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-(4-(4-(4-胺基-7-甲基-5-(4-苯氧基苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 1.63 - 1.88 (m, 2H), 2.01 (t, J = 14.8 Hz, 2H), 2.35 (q, J = 7.6 Hz, 2H), 2.73 (t, J = 12.4 Hz, 1H), 3.16 (t, J = 12.8 Hz, 1H), 3.70 (s, 3H), 3.93 (d, J = 14.0 Hz, 1H), 4.43 (td, J = 5.6, 11.5 Hz, 2H), 5.85 (s, 1H), 7.02 - 7.07 (m, 2H), 7.07 - 7.12 (m, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.27 - 7.35 (m, 2H), 7.39 - 7.46 (m, 3H), 7.89 (s, 1H), 8.15 (s, 1H). | 522.23 | |
1-(4-(4-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.95 (s, 1H), 7.36 (s, 1H), 7.29 - 7.21 (m, 2H), 7.04 - 6.96 (m, 2H), 6.85 (m, 1H), 6.12 (m, 1H), 5.70 (m, 1H), 4.47 (t, J = 7.2 Hz, 2H), 4.13 (d, J = 13.6 Hz, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.24 (d, J = 13.6 Hz, 1H), 2.83 (t, J = 12.4 Hz, 1H), 2.04 (d, J = 12.4 Hz, 2H), 1.79 (d, J = 16.8 Hz, 2H). | 458.22 | |
1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)-2-甲基哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.77 (s, 1H), 7.80 - 7.72 (m, 1H), 7.48 (s, 1H), 7.38 - 7.25 (m, 2H), 7.16 - 7.10 (m, 2H), 7.05 (d,J = 7.4 Hz, 1H), 6.82 (d,J = 8.2 Hz, 1H), 6.66 (s, 1H), 6.01 (d,J = 16.4 Hz, 1H), 5.60 (d,J = 10.4 Hz, 1H), 5.01 (s, 1H), 4.38 (s, 1H), 4.07 (s, 1H), 3.66 (s, 3H), 3.32 (s, 1H), 3.07 (s, 1H), 2.37 (s, 3H), 2.15 (s, 2H), 1.49 (s, 1H), 1.38 (s, 1H), 1.31 (d,J = 6.8 Hz, 3H). | 549.25 | |
1-(3-(4-(4-胺基-7-甲基-5-(4-苯氧基苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)-2-甲基哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.77 (s, 1H), 7.80 - 7.72 (m, 1H), 7.48 (s, 1H), 7.38 - 7.25 (m, 2H), 7.16 - 7.10 (m, 2H), 7.05 (d,J = 7.4 Hz, 1H), 6.82 (d,J = 8.2 Hz, 1H), 6.66 (s, 1H), 6.01 (d,J = 16.4 Hz, 1H), 5.60 (d,J = 10.4 Hz, 1H), 5.01 (s, 1H), 4.38 (s, 1H), 4.07 (s, 1H), 3.66 (s, 3H), 3.32 (s, 1H), 3.07 (s, 1H), 2.15 (s, 2H), 1.49 (s, 1H), 1.38 (s, 1H), 1.31 (d,J = 6.8 Hz, 3H). | 534.25 | |
1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.96 (s, 1H), 7.79 - 7.71 (m, 1H), 7.47 (s, 1H), 7.38 - 7.31 (m, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H), 6.38 - 5.91 (m, 1H), 5.67 (dd, J = 10.4, 32.3 Hz, 1H), 4.51 - 3.93 (m, 3H), 3.70 (s, 3H), 3.56 (s, 0H), 3.17 (s, 1H), 2.98 (s, 0H), 2.36 (s, 3H), 2.09 (d, J = 17.2 Hz, 2H), 1.77 (s, 1H), 1.50 (s, 1H). | 535.25 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.95 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 5.00 (s, 1H), 4.46 (t, J = 11.6 Hz, 1H), 3.94 (s, 1H), 3.70 (s, 3H), 2.84 (s, 1H), 2.35 (s, 3H), 2.04 (d, J = 12.8 Hz, 2H), 1.86 (s, 3H), 1.79 (d, J = 12.8 Hz, 2H). | 549.26 | |
(E)-1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-4-(二甲基胺基)丁-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.95 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 2.8 Hz, 2H), 4.45 (s, 2H), 4.13 (s, 1H), 3.69 (s, 3H), 3.02 (d, J = 4.0 Hz, 2H), 2.80 (s, 2H), 2.35 (s, 3H), 2.14 (s, 6H), 2.03 (s, 2H), 1.78 (s, 3H). | 592.41 | |
1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.98 (d, J = 18.1 Hz, 1H), 7.78 - 7.75 (m, 1H), 7.50 - 7.44 (m, 1H), 7.37 - 7.30 (m, 2H), 7.14 (dd, J = 8.6, 1.9 Hz, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 6.57 (dt, J = 16.7, 10.6 Hz, 1H), 6.14 (ddd, J = 16.7, 5.5, 2.4 Hz, 1H), 5.66 (ddd, J = 12.8, 10.3, 2.4 Hz, 1H), 5.09 - 4.96 (m, 1H), 3.92 - 3.78 (m, 1H), 3.70 (s, 5H), 3.62 - 3.42 (m, 3H), 2.36 (s, 4H). | 521.20 | |
1-(4-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,2,4-噁二唑-5-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.76 (t,J = 7.7 Hz, 1H), 7.42 (d,J = 8.2 Hz, 2H), 7.17 (d,J = 8.1 Hz, 2H), 7.05 (d,J = 7.4 Hz, 1H), 6.79 (dd,J = 17.3, 9.7 Hz, 2H), 6.09 (dd,J = 16.6, 2.5 Hz, 1H), 5.66 (dd,J = 10.3, 2.5 Hz, 1H), 4.15 (d,J = 13.0 Hz, 1H), 3.92 (s, 2H), 3.22 (d,J = 45.6 Hz, 4H), 3.03 (d,J = 12.4 Hz, 1H), 2.37 (s, 3H), 2.12 - 1.96 (m, 2H), 1.64 (s, 2H). | 537.40 | |
1-(4-(5-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,3,4-噁二唑-2-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.41 - 1.68 (m, 2H), 1.80 - 1.92 (m, 2H), 2.38 (s, 3H), 2.92 - 3.00 (m, 1H), 3.10 - 3.26 (m, 2H), 3.85 - 3.98 (m, 1H), 4.04 (s, 3H), 4.04 - 4.09 (m, 1H), 5.63 (dd,J = 2.8 Hz, 1H), 6.07 (dd,J = 2.4 Hz, 1H), 6.70 - 6.77 (m, 1H), 6.83 (d,J = 8.0 Hz, 1H), 7.06 (d,J = 7.2 Hz, 1H), 7.24 (d,J = 11.2 Hz, 1H), 7.48 (d,J = 4.8 Hz, 1H), 7.79 (t,J = 15.6 Hz, 1H), 8.28 (s, 1H) | 537.40 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 8.01 (s, 1H), 7.77 - 7.70 (m, 1H), 7.25 (d,J = 8.5 Hz, 2H), 7.11 (d,J = 8.6 Hz, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.89 - 6.75 (m, 2H), 6.12 (dd,J = 16.7, 2.4 Hz, 1H), 5.71 - 5.66 (m, 1H), 4.49 (d,J = 12.4 Hz, 1H), 4.39 (d,J = 11.2 Hz, 1H), 4.14 (d,J = 13.5 Hz, 1H), 3.55 (s, 3H), 3.32 (s, 2H), 3.23 (s, 1H), 2.83 (t,J = 13.1 Hz, 1H), 2.34 (s, 3H), 2.07 (d,J = 10.1 Hz, 2H), 1.88 - 1.75 (m, 2H), 1.70 (s, 3H). | 549.40 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((5-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.03 (dd, J = 2.1, 1.1 Hz, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.71 (dd, J = 8.2, 2.5 Hz, 1H), 7.45 (d, J = 0.7 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.17 - 7.09 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.51 - 4.41 (m, 2H), 4.14 (d, J = 13.9 Hz, 1H), 3.70 (s, 3H), 3.23 (t, J = 12.9 Hz, 1H), 2.84 (t, J = 12.5 Hz, 1H), 2.27 (s, 3H), 2.04 (s, 2H), 1.78 (t, J = 13.6 Hz, 2H). | 535.3 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((4-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 8.05 (d,J = 5.2 Hz, 1H), 7.95 (s, 1H), 7.45 (s, 1H), 7.36 - 7.31 (m, 2H), 7.16 - 7.12 (m, 2H), 7.02 - 6.99 (m, 1H), 6.91 (s, 1H), 6.85 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd,J = 16.7, 2.5 Hz, 1H), 5.69 (dd,J = 10.4, 2.4 Hz, 1H), 4.46 (t,J = 10.8 Hz, 1H), 4.14 (d,J = 13.7 Hz, 1H), 3.70 (s, 3H), 3.21 (d,J = 12.9 Hz, 1H), 2.83 (t,J = 12.6 Hz, 1H), 2.35 (s, 4H), 2.04 (s, 2H), 1.80 (d,J = 13.6 Hz, 2H). | 535.40 | |
1-(4-(4-(4-胺基-5-(4-((6-氟吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.05 (q, J = 8.1 Hz, 1H), 7.92 (s, 1H), 7.46 (s, 1H), 7.42 - 7.34 (m, 2H), 7.27 - 7.19 (m, 2H), 6.97 (dd, J = 7.9, 1.7 Hz, 1H), 6.92 (dd, J = 7.9, 2.4 Hz, 1H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.85 (s, 2H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.46 (ddd, J = 15.3, 11.3, 3.9 Hz, 1H), 4.14 (d, J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.22 (t, J = 12.9 Hz, 1H), 2.83 (t, J = 12.6 Hz, 1H), 2.05 (d, J = 12.4 Hz, 2H), 1.79 (t, J = 12.8 Hz, 2H). | 539.3 | |
1-(4-(4-(4-胺基-5-(4-((6-甲氧基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)乙-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.98 (s, 1H), 7.76 (t,J = 7.9 Hz, 1H), 7.41 - 7.30 (m, 3H), 7.25 - 7.16 (m, 2H), 6.85 (dd,J = 16.7, 10.4 Hz, 1H), 6.55 (dd,J = 7.9, 5.0 Hz, 2H), 6.12 (dd,J = 16.6, 2.5 Hz, 1H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.47 (td,J = 12.2, 11.3, 6.8 Hz, 2H), 4.14 (d,J = 13.6 Hz, 1H), 3.69 (d,J = 15.3 Hz, 6H), 3.21 (d,J = 13.0 Hz, 1H), 2.83 (t,J = 12.6 Hz, 1H), 2.04 (d,J = 12.5 Hz, 2H), 1.89 - 1.65 (m, 2H). | 551.35 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-(吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.25 - 8.13 (m, 2H), 7.94 (s, 1H), 7.88 (ddd,J = 8.2, 7.2, 2.0 Hz, 1H), 7.46 (s, 1H), 7.38 - 7.30 (m, 2H), 7.22 - 7.11 (m, 3H), 7.07 (dd,J = 8.3, 1.0 Hz, 1H), 6.84 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd,J = 16.7, 2.4 Hz, 1H), 5.86 (s, 1H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.47 (td,J = 11.1, 5.5 Hz, 2H), 4.14 (d,J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.23 (t,J = 12.9 Hz, 1H), 2.83 (t,J = 12.7 Hz, 1H), 2.12 - 1.98 (m, 2H), 1.78 (t,J = 12.9 Hz, 2H). | 521.35 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.8 Hz, 2H), 8.17 (s, 1H), 7.96 (s, 1H), 7.48 (d, J = 0.7 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.34 - 7.23 (m, 3H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.6, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 4.49 (d, J = 12.4 Hz, 2H), 4.15 (d, J = 13.7 Hz, 1H), 3.70 (s, 3H), 3.24 (s, 1H), 2.84 (t, J = 12.3 Hz, 1H), 2.07 (d, J = 12.4 Hz, 2H), 1.81 (d, J = 14.3 Hz, 2H). | 522.2 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-(吡嗪-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J = 1.4 Hz, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.26 (dd, J = 2.7, 1.4 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 0.7 Hz, 1H), 7.46 (d, J = 0.7 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.31 - 7.23 (m, 2H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.5, 2.4 Hz, 1H), 4.47 (m, 2H), 4.14 (d, J = 13.5 Hz, 1H), 3.70 (s, 3H), 3.23 (t, J = 12.9 Hz, 1H), 2.84 (t, J = 12.8 Hz, 1H), 2.04 (s, 2H), 1.80 (d, J = 13.6 Hz, 2H). | 522.2 | |
N-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)環丁基)-N-甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.17 (d, J = 1.4 Hz, 1H), 8.02 (s, 1H), 7.75 (td, J = 7.7, 2.3 Hz, 1H), 7.50 (d, J = 12.4 Hz, 1H), 7.36 (dd, J = 8.7, 2.6 Hz, 2H), 7.18 - 7.14 (m, 2H), 7.04 - 7.00 (m, 1H), 6.82 (dd, J = 8.1, 3.2 Hz, 1H), 6.19 - 5.57 (m, 3H), 5.14 (d, J = 106.7 Hz, 1H), 4.90 (dt, J = 9.0, 4.8 Hz, 1H) 3.71 (d, J = 2.7 Hz, 3H), 3.16 - 2.91 (m, 3H), 2.90 - 2.54 (m, 6H), 2.35 (s, 3H). | 535.40 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-5-甲基-1H-吡唑-1-基)哌啶-1- | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.74 (t,J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.22 (d,J = 8.2 Hz, 2H), 7.10 (d,J = 8.2 Hz, 2H), 7.02 (d,J = 7.4 Hz, 1H), 6.85 (dd,J = 16.8, 10.6 Hz, 1H), 6.79 (d,J = 8.2 Hz, 1H), 6.12 (dd,J = 16.8, 2.4 Hz, 1H), 6.01 (s, 2H), 5.69 (dd,J = 10.4, 2.4 Hz, 1H), 4.50 (d,J = 13.2 Hz, 1H), 4.40 (s, 1H), 4.16 (d,J = 13.6 Hz, 1H), 3.58 (s, 3H), 3.20 (t,J = 12.2 Hz, 1H), 2.79 (s, 1H), 2.35 (s, 3H), 1.83 (s, 4H), 1.78 (s, 3H). | 549.25 | |
(E)-2-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-羰基)丁-2-烯腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.82 - 1.93 (m, 3H), 2.07 - 2.09 (m, 5H), 2.25 - 2.36 (m, 5 H), 2.80 - 3.08 (br, 1H), 3.70 (s, 3H), 3.82 - 4.70 (m, 3H), 5.50 - 6.10 (br, 1 H), 6.69 - 6.92 (m, 1H), 6.92 - 7.16 (m, 4H), 7.33 - 7.36 (m , 2H), 7.45 (s, 1H), 7.72 - 7.80 (m, 1H), 7.97 (s, 1H), 8.10 (s, 1H). | 574.40 | |
1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)吡咯啶-1-基)丁-2-炔-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 2.00 (d, J = 14.4 Hz, 3H), 2.36 (s, 5H), 3.31 (s, 1H), 3.49 (m, 1H), 3.62 - 3.80 (m, 5H), 3.88 - 4.05 (m, 1H), 5.04 (s, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 7.11 - 7.19 (m, 2H), 7.30 - 7.39 (m, 2H), 7.48 (d, J = 2.8 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.99 (d, J = 9.6 Hz, 1H), 8.17 (d, J = 0.8 Hz, 1H). | 533.23 | |
(E)-1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)吡咯啶-1-基)丁-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 1.82 (m, 3H), 2.36 (s, 5H), 3.51 (m, 1H), 3.70 (s, 4H), 3.80 - 4.05 (m, 1H), 4.95 - 5.11 (m, 1H), 6.25 (m, 1H), 6.64 - 6.73 (m, 1H), 6.82 (d, J = 8.4 Hz, 1H), 7.03 (d, J = 7.2 Hz, 1H), 7.11 - 7.18 (m, 2H), 7.34 (m, 2H), 7.48 (d, J = 4.4 Hz, 1H), 7.72 - 7.79 (m, 1H), 7.96 (d, J = 26.4 Hz, 1H), 8.16 (d, J = 0.8 Hz, 1H). | 535.2 | |
(E)-1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)氮雜環丁-1-基)-4-(二甲基胺基)-2-甲基丁-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 11.3 Hz, 2H), 7.76 (t, J = 7.8 Hz, 1H), 7.51 (s, 1H), 7.40 - 7.32 (m, 2H), 7.20 - 7.12 (m, 2H), 7.03 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.92 (td, J = 6.5, 1.6 Hz, 2H), 5.27 (ddd, J = 13.4, 8.2, 5.2 Hz, 1H), 4.70 - 4.05 (m, 4H), 3.71 (s, 3H), 3.31 (s, 1H), 2.98 (d, J = 6.5 Hz, 2H), 2.36 (s, 3H), 2.14 (s, 6H), 1.75 (d, J = 1.4 Hz, 3H). | 578.45 | |
(E)-1-(3-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)氮雜環丁-1-基)丁-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.82 - 1.84 (m, 4H), 2.36 (s, 1H), 3.71 (s, 1H), 4.12 - 4.19 (m, 1H), 4.31 - 4.58 (m, 2H), 4.61 - 4.69 (m, 1 H), 5.27 - 5.33 (m, 1H), 6.01 - 6.06 (m, 1 H), 6.66 - 6.68 (m, 1H), 6.82 (d,J = 8.0 Hz, 1H), 7.03 (d,J = 8.0 Hz, 1H), 7.15 (dd,J = 2.0 Hz, 2H), 7.35 (dd,J = 2.0 Hz, 2H), 7.52 (s, 1H), 7.76 (t,J = 15.6 Hz, 1H), 8.13 (s, 1H), 8.17 (s, 1H). | 521.20 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-2-(N-嗎啉基甲基) 丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.81 (s, 2H), 2.04 (d,J = 12.5 Hz, 2H), 2.35 (s, 4H), 2.37 (s, 3H), 2.85 (s, 1H), 3.10 (s, 1H), 3.22 (s, 1H), 3.54 (t,J = 4.8 Hz, 4H), 3.70 (s, 3H), 3.98 (s, 1H), 4.38 - 4.51 (m, 2H), 5.20 (s, 1H), 5.35 (s, 1H), 6.81 (d,J = 8.0 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 7.12 - 7.18 (m, 2H), 7.32 - 7.38 (m, 2H), 7.47 (d,J = 0.8 Hz, 1H), 7.75 (m, 1H), 7.94 (s, 1H), 8.16 (s, 1H). | 634.5 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丁-2-炔-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.73 (m, 1H), 1.86 (m, 1H), 2.03 (s, 4H), 2.10 (d,J = 13.2 Hz, 1H), 2.36 (s, 3H), 2.80 - 2.92 (m, 1H), 3.27 (d,J = 2.8 Hz, 1H), 3.70 (s, 3H), 4.34 (m, 2H), 4.41 - 4.52 (m, 1H), 6.21 (d,J = 273.6 Hz, 1H), 6.81 (d,J = 8.4 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 7.10 - 7.21 (m, 2H), 7.31 - 7.40 (m, 2H), 7.44 (d,J = 0.7 Hz, 1H), 7.75 (dd,J = 7.3, 8.2 Hz, 1H), 7.97 (s, 1H), 8.16 (s, 1H). | 547.25 | |
(E)-1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丁-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.94 (d,J = 0.7 Hz, 1H), 7.75 (dd,J = 8.2, 7.4 Hz, 1H), 7.44 (d,J = 0.7 Hz, 1H), 7.37 - 7.32 (m, 2H), 7.17 - 7.13 (m, 2H), 7.03 (d,J = 7.3 Hz, 1H), 6.80 (d,J = 8.1 Hz, 1H), 6.75 - 6.64 (m, 1H), 6.54 (dd,J = 14.9, 1.7 Hz, 1H), 6.20 - 5.50 (m, 1H), 4.53 - 4.37 (m, 2H), 4.14 (s, 1H), 3.70 (s, 3H), 3.24 - 3.12 (m, 1H), 2.78 (s, 1H), 2.36 (s, 3H), 2.14 - 1.98 (m, 2H), 1.84 (dd,J = 6.7, 1.5 Hz, 3H), 1.77 (s, 2H). | 549.25 | |
(E)-1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-4-N-嗎啉基丁-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.79 (d,J = 18.2=4 Hz, 2H), 2.06 (d,J = 16.0 Hz, 2H), 2.36 (s, 6H), 3.09 (d,J = 5.6 Hz, 4H), 3.58 (t,J = 4.8 Hz, 4H), 3.70 (s, 3H), 4.12 (d,J = 13.6 Hz, 1H), 4.46 (m, 2H), 5.84 (s, 1H), 6.53 - 6.72 (m, 2H), 6.80 (d,J = 8.0 Hz, 1H), 7.03 (d,J = 7.2 Hz, 1H), 7.15 (d,J = 8.5 Hz, 2H), 7.24 - 7.40 (m, 2H), 7.44 (s, 1H), 7.95 (s, 1H), 8.15 (d,J = 4.4 Hz, 2H) | 634.3 | |
(E)-1-(4-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-4-(二甲基胺基)-2-甲基丁-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.97 (s, 1H), 7.75 (t,J = 7.8 Hz, 1H), 7.45 (s, 1H), 7.37 - 7.31 (m, 2H), 7.19 - 7.13 (m, 2H), 7.03 (d,J = 7.3 Hz, 1H), 6.81 (d,J = 8.1 Hz, 1H), 5.51 (td,J = 6.6, 1.7 Hz, 2H), 4.60 - 4.33 (m, 1H), 4.38 - 3.79 (m, 1H), 3.70 (s, 3H), 3.34 (s, 1H), 2.93 (d,J = 6.7 Hz, 4H), 2.35 (s, 3H), 2.13 (s, 6H), 2.04 (d,J = 12.7 Hz, 2H), 1.88 - 1.72 (m, 5H). | 606.45 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-苯氧基苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.49 - 7.38 (m, 3H), 7.36 - 7.28 (m, 2H), 7.17 (t,J = 7.4 Hz, 1H), 7.11 - 7.07 (m, 2H), 7.07 - 7.02 (m, 2H), 5.84 (s, 2H), 5.24 - 5.12 (m, 1H), 5.01 (t,J = 1.3 Hz, 1H), 4.51 - 4.34 (m, 2H), 3.91 (d,J = 28.7 Hz, 1H), 3.70 (s, 3H), 3.22 (s, 1H), 2.86 (s, 1H), 2.04 (d,J = 12.6 Hz, 2H), 1.88 (d,J = 1.4 Hz, 3H), 1.78 (tt,J = 12.2, 6.1 Hz, 2H). | 534.40 | |
1-(4-(4-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.94 (s, 1H), 7.36 (s, 1H), 7.28 - 7.22 (m, 2H), 7.07 - 6.90 (m, 2H), 5.76 (s, 2H), 5.26 - 5.14 (m, 1H), 5.01 (t,J = 1.3 Hz, 1H), 4.44 (ddt,J = 11.1, 8.0, 4.0 Hz, 2H), 3.97 (s, 1H), 3.79 (s, 3H), 3.70 (s, 3H), 3.03 (d,J = 139.1 Hz, 2H), 2.04 (d,J = 12.5 Hz, 2H), 1.88 (d,J = 1.4 Hz, 3H), 1.78 (qd,J = 12.1, 4.4 Hz, 2H). | 472.35 | |
7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-6-(1-(1-(乙烯基磺醯基)哌啶-4-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.97 - 7.94 (m, 1H), 7.75 (dd,J = 8.2, 7.3 Hz, 1H), 7.46 (d,J = 0.7 Hz, 1H), 7.38 - 7.32 (m, 2H), 7.20 - 7.12 (m, 2H), 7.03 (d,J = 7.3 Hz, 1H), 6.91 - 6.79 (m, 2H), 6.21 - 6.09 (m, 2H), 5.85 (s, 2H), 4.33 (dt,J = 7.2, 4.1 Hz, 0H), 3.70 (s, 3H), 3.60 (d,J = 12.4 Hz, 2H), 2.84 (td,J = 12.2, 2.7 Hz, 2H), 2.36 (s, 3H), 2.10 (d,J = 12.9 Hz, 2H), 1.95 (qd,J = 12.0, 4.2 Hz, 2H). | 571.15 | |
1-(4-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.98 (s, 1H), 7.67 (dd,J = 8.2, 7.4 Hz, 1H), 7.49 (d,J = 0.8 Hz, 1H), 7.14 (d,J = 8.0 Hz, 1H), 7.03 (d,J = 2.0 Hz, 1H), 6.97 - 6.90 (m, 2H), 6.85 (dd,J = 16.8, 10.6 Hz, 1H), 6.66 (d,J = 8.2 Hz, 1H), 6.12 (dd,J = 16.8, 2.6 Hz, 1H), 5.93 (s, 2H), 5.69 (dd,J = 10.6, 2.4 Hz, 1H), 4.54 - 4.43 (m, 2H), 4.15 (d,J = 13.8 Hz, 1H), 3.70 (s, 3H), 3.61 (s, 3H), 3.23 (t,J = 13.4 Hz, 1H), 2.83 (t,J = 12.4 Hz, 1H), 2.32 (s, 3H), 2.06 (d,J = 18.0 Hz, 2H), 1.87 - 1.71 (m, 2H). | 565.25 | |
1-(4-(4-(4-胺基-5-(3-甲氧基-4-(間甲苯基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.79 (m, 2H), 2.03 (s, 2H), 2.29 (s, 3H), 2.83 (m, 1H), 3.23 (m, 1H), 3.67 (d,J = 20.4 Hz, 6H), 4.14 (d,J = 14.0 Hz, 1H), 4.40 - 4.54 (m, 2H), 5.69 (m, 1H), 6.12 (m, 1H), 6.66 (m, 1H), 6.76 - 6.91 (m, 4H), 7.02 (m, 2H), 7.20 (d,J = 8.0 Hz, 1H), 7.47 (s, 1H), 7.95 (s, 1H), 8.16 (s, 1H). | 564.45 | |
1-(4-(4-(4-胺基-5-(3-甲氧基-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 8.11 (dd, J = 5.2, 2.0 Hz, 1H), 7.96 (s, 1H), 7.82 (ddd, J = 8.4, 7.2, 2.1 Hz, 1H), 7.52 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (ddd, J = 7.2, 4.9, 0.9 Hz, 1H), 7.03 - 6.92 (m, 3H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.95 (s, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.57 - 4.36 (m, 2H), 4.13 (t, J = 11.7 Hz, 1H), 3.69 (s, 3H), 3.60 (s, 3H), 3.29 - 3.14 (m, 1H), 2.84 (t, J = 12.7 Hz, 1H), 2.05 (s, 2H), 1.79 (t, J = 13.1 Hz, 2H). | 551.20 | |
1-(4-(3-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-5-甲基-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.69 (t, J = 7.7 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 2H), 5.86 (s, 1H), 5.68 (dd, J = 10.4, 2.5 Hz, 1H), 4.57 - 4.43 (m, 2H), 4.16 (d, J = 13.7 Hz, 1H), 3.84 (s, 3H), 3.63 (s, 3H), 3.25 (d, J = 12.7 Hz, 1H), 2.86 (t, J = 12.0 Hz, 1H), 2.30 (d, J = 17.8 Hz, 6H), 1.90 (d, J = 22.3 Hz, 4H). | 579.45 | |
1-(4-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-5-甲基-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.73 - 7.63 (m, 2H), 7.13 (d,J = 8.0 Hz, 1H), 6.94 (d,J = 7.3 Hz, 1H), 6.90 - 6.78 (m, 3H), 6.68 (d,J = 8.2 Hz, 1H), 6.12 (dd,J = 16.6, 2.4 Hz, 2H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.56 - 4.35 (m, 2H), 4.17 (d,J = 13.7 Hz, 1H), 3.60 (s, 3H), 3.47 (s, 3H), 3.20 (t,J = 13.1 Hz, 1H), 2.79 (s, 1H), 2.31 (s, 3H), 1.78 (s, 7H). | 579.45 | |
1-(4-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)-2-甲基哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (d,J = 1.3 Hz, 1H), 8.04 (s, 1H), 7.71 - 7.62 (m, 1H), 7.53 (s, 1H), 7.13 (dd,J = 9.2, 8.0 Hz, 1H), 7.04 (dd,J = 6.3, 1.9 Hz, 1H), 6.97 - 6.88 (m, 2H), 6.88 - 6.70 (m, 1H), 6.66 (dd,J = 8.3, 4.5 Hz, 1H), 6.10 (dd,J = 16.6, 2.4 Hz, 1H), 5.95 (s, 1H), 5.72 - 5.62 (m, 1H), 4.46 (s, 1H), 4.06 (s, 1H), 3.69 (s, 3H), 3.62 (d,J = 3.7 Hz, 3H), 2.31 (d,J = 1.9 Hz, 3H), 2.28 - 2.18 (m, 1H), 2.07 (dd,J = 16.7, 8.8 Hz, 2H), 1.32 - 1.18 (m, 1H), 0.84 (d,J = 6.8 Hz, 2H). | 578.677 | |
1-(4-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d,J = 4.8 Hz, 2H), 8.17 (s, 1H), 7.30 - 7.22 (m, 2H), 7.10 (s, 1H), 6.98 (d,J = 8.1 Hz, 1H), 6.80 (ddd,J = 28.0, 16.6, 10.4 Hz, 1H), 6.31 - 5.87 (m, 3H), 5.69 (t,J = 8.7 Hz, 1H), 4.20 (d,J = 31.7 Hz, 2H), 3.66 (d,J = 5.4 Hz, 8H), 2.18 (s, 2H). | 484.25 | |
1-(4-(4-胺基-5-(4-((6-乙基吡啶-2-基)氧基)-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J = 11.4, 7.8 Hz, 2H), 6.75 (dd, J = 38.1, 9.5 Hz, 2H), 6.38 - 5.84 (m, 3H), 5.69 (t, J = 9.3 Hz, 1H), 4.42 - 4.06 (m, 2H), 3.66 (d, J = 3.1 Hz, 8H), 2.57 (q, J = 7.5 Hz, 2H), 2.18 (s, 2H), 1.08 (t, J = 7.5 Hz, 3H). | 511.25 | |
1-(4-(4-胺基-5-(3-甲氧基-4-((5-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.94 (s, 1H), 7.64 (dd,J = 8.5, 2.4 Hz, 1H), 7.16 (d,J = 8.1 Hz, 1H), 7.07 (s, 1H), 6.95 (d,J = 8.1 Hz, 1H), 6.90 - 6.71 (m, 2H), 6.30 - 5.85 (m, 3H), 5.68 (d,J = 9.9 Hz, 1H), 4.20 (d,J = 32.5 Hz, 2H), 3.66 (d,J = 3.5 Hz, 8H), 2.24 (s, 3H), 2.17 (s, 2H). | 497.35 | |
1-(4-(4-胺基-5-(3-甲氧基-4-((5-甲基吡啶-3-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 - 8.07 (m, 3H), 7.18 - 7.08 (m, 3H), 6.96 (dd,J = 8.0, 1.9 Hz, 1H), 6.79 (ddd,J = 26.9, 16.6, 10.4 Hz, 1H), 6.17 - 6.07 (m, 2H), 5.96 (d,J = 18.9 Hz, 1H), 5.74 - 5.64 (m, 1H), 4.19 (d,J = 33.2 Hz, 2H), 3.71 (s, 3H), 3.66 (s, 5H), 2.29 (s, 3H), 2.16 (s, 2H), 2.08 (s, 1H). | 497.20 | |
1-(3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (dd,J = 12.3, 4.7 Hz, 2H), 8.19 (d,J = 1.1 Hz, 1H), 7.51 - 7.41 (m, 2H), 7.38 - 7.27 (m, 3H), 6.62 - 6.25 (m, 2H), 6.15 (dd,J = 16.8, 2.4 Hz, 1H), 5.89 (s, 2H), 5.69 (ddd,J = 14.8, 10.2, 2.4 Hz, 1H), 4.56 (dt,J = 4.8, 2.4 Hz, 1H), 4.35 - 4.22 (m, 2H), 4.05 (q,J = 2.4 Hz, 1H), 3.78 (d,J = 4.1 Hz, 3H). | 440.15 | |
1-(3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (t,J = 4.6 Hz, 2H), 8.18 (s, 1H), 7.49 - 7.41 (m, 2H), 7.38 - 7.28 (m, 3H), 6.28 (dd,J = 39.5, 2.3 Hz, 1H), 5.86 (s, 2H), 5.32 - 4.93 (m, 2H), 4.50 - 4.28 (m, 2H), 4.06 (d,J = 10.4 Hz, 2H), 3.79 (d,J = 4.9 Hz, 3H), 1.90 - 1.72 (m, 3H). | 454.15 | |
4-(6-(1-(1-丙烯醯基哌啶-4-基)-1H-吡唑-4-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-羥基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (t,J = 6.1 Hz, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.92 - 7.81 (m, 2H), 7.43 - 7.35 (m, 3H), 6.84 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd,J = 16.7, 2.4 Hz, 1H), 5.82 (s, 1H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.55 (s, 1H), 4.51 - 4.43 (m, 1H), 4.13 (d,J = 13.6 Hz, 1H), 3.69 (s, 3H), 3.27 (d,J = 6.2 Hz, 2H), 2.82 (d,J = 12.1 Hz, 1H), 2.05 (d,J = 12.7 Hz, 2H), 1.79 (s, 2H), 1.12 (s, 6H). | 543.35 | |
4-(6-(1-(1-丙烯醯基哌啶-4-基)-1H-吡唑-4-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d,J = 6.4 Hz, 1H), 8.17 (s, 1H), 8.00 (s, 1H), 7.92 - 7.86 (m, 2H), 7.43 - 7.33 (m, 3H), 6.85 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd,J = 16.7, 2.4 Hz, 1H), 5.83-5.69 (dd,J = 10.4, 2.4 Hz, 2H), 4.52 - 4.41 (m, 3H), 4.14 (d,J = 13.6 Hz, 1H), 3.87 (dd,J = 8.8, 6.5 Hz, 2H), 3.73 (td,J = 8.1, 5.8 Hz, 1H), 3.68 (s, 3H), 3.59 (dd,J = 8.8, 4.3 Hz, 1H), 3.23 (t,J = 13.1 Hz, 1H), 2.83 (t,J = 12.9 Hz, 1H), 2.16 (dq,J = 12.4, 7.5 Hz, 1H), 2.05 (d,J = 12.4 Hz, 2H), 1.94 (tt,J = 12.4, 5.6 Hz, 1H), 1.78 (d,J = 13.0 Hz, 2H). | 541.25 | |
1-(4-(4-(5-(4-(2-氮雜雙環[2.1.1]己烷-2-羰基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.69 (d,J = 7.7 Hz, 1H), 7.46 (d,J = 7.8 Hz, 1H), 7.44 - 7.33 (m, 3H), 6.84 (dd,J = 16.7, 10.4 Hz, 1H), 6.12 (dd,J = 16.7, 2.5 Hz, 1H), 5.87 (s, 1H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.50 - 4.40 (m, 2H), 4.13 (d,J = 13.8 Hz, 1H), 3.69 (s, 3H), 3.47 (s, 2H), 3.32 - 3.17 (m, 1H), 2.89 (s, 1H), 2.81 (d,J = 12.3 Hz, 1H), 2.10 - 1.95 (m, 5H), 1.77 (s, 2H), 1.49 (s, 1H), 1.36 (s, 1H). | 537.45 | |
4-(6-(1-(1-丙烯醯基哌啶-4-基)-1H-吡唑-4-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-甲基-N-((3-甲基-1,2,4-噁二唑-5-基)甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.39 (d,J = 14.2 Hz, 5H), 6.84 (dd,J = 16.7, 10.5 Hz, 1H), 6.11 (dd,J = 16.7, 2.4 Hz, 1H), 5.89 (s, 1H), 5.69 (dd,J = 10.5, 2.4 Hz, 1H), 4.94 (s, 2H), 4.45 (s, 2H), 4.12 (d,J = 13.8 Hz, 1H), 3.69 (s, 3H), 3.17 (d,J = 33.9 Hz, 4H), 2.82 (t,J = 12.9 Hz, 1H), 2.37 (s, 3H), 2.05 (d,J = 26.0 Hz, 2H), 1.78 (d,J = 13.9 Hz, 2H). | 581.30 | |
1-(4-(4-(4-胺基-7-甲基-5-(4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1H-吡唑-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.83 (s, 1H), 7.55 (s, 1H), 7.46 - 7.38 (m, 2H), 7.26 (s, 1H), 7.20 - 7.16 (m, 2H), 6.87 - 6.80 (m, 1H), 6.11 (dd,J = 16.7, 2.4 Hz, 1H), 6.07 - 5.99 (m, 1H), 5.70 - 5.66 (m, 1H), 4.56 - 4.38 (m, 2H), 4.18 - 4.09 (m, 1H), 3.79 (s, 3H), 3.74 (s, 3H), 3.21 (t,J = 12.7 Hz, 1H), 2.81 (t,J = 12.7 Hz, 1H), 2.02 (d,J = 12.5 Hz, 2H), 1.84 - 1.68 (m, 2H). | 524.35 | |
4-(6-(1-(1-丙烯醯基哌啶-4-基)-1H-吡唑-4-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(2-甲氧基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 8.00 (s, 2H), 7.88 (d,J = 7.9 Hz, 2H), 7.43 - 7.35 (m, 3H), 6.84 (dd,J = 16.8, 10.7 Hz, 1H), 6.12 (d,J = 16.6 Hz, 1H), 5.69 (d,J = 10.8 Hz, 2H), 4.48 (d,J = 14.5 Hz, 2H),4.13(s, 1H) 3.68 (s, 3H), 3.40-3.23 (s, 3H), 3.16 (s, 3H), 2.83 (s, 1H), 2.04 (s, 2H), 1.79 (s, 2H), 1.13 (s, 6H). | 557.45 | |
1-(4-{4-[4-胺基-5-(2-氯-4-苯氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]-1H-吡唑-1-基}哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.88 (s, 1H), 7.47 (t,J = 7.7 Hz, 1H), 7.40 (d,J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.28 - 7.14 (m, 4H), 7.00 (dd,J = 8.4, 2.6 Hz, 1H), 6.85 (dd,J = 16.7, 10.4 Hz, 1H), 6.13 (dd,J = 16.8, 2.4 Hz, 1H), 5.77 (s, 2H), 4.47 (tt,J = 11.4, 4.1 Hz, 2H), 4.14 (d,J = 13.7 Hz, 1H), 3.76 (s, 3H), 3.24 (t,J = 12.8 Hz, 1H), 2.85 (t,J = 12.7 Hz, 1H), 2.03 (s, 2H), 1.78 (t,J = 12.6 Hz, 2H). | 554.05 | |
1-(4-{4-[4-胺基-5-(3-甲氧基-4-苯氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]-1H-吡唑-1-基}哌啶-1-基)丙-2-烯-1-酮;甲酸 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.92 (s, 1H), 7.49 (s, 1H), 7.34 (t,J = 7.7 Hz, 2H), 7.10 - 7.00 (m, 3H), 7.00 - 6.79 (m, 4H), 6.13 (dd,J = 16.7, 2.4 Hz, 1H), 5.70 (dd,J = 10.4, 2.4 Hz, 1H), 4.49 (tt,J = 11.6, 4.1 Hz, 2H), 4.14 (d,J = 13.8 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.24 (t,J = 12.9 Hz, 1H), 2.85 (t,J = 12.7 Hz, 1H), 2.03 (s, 2H), 1.80 (t,J = 12.6 Hz, 2H). | 595.66 | |
1-(4-{4-[4-胺基-5-(4-氯-3-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]-1H-吡唑-1-基}哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.98 (d,J = 0.8 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.00 (d,J = 1.9 Hz, 1H), 6.91 - 6.85 (m, 1H), 6.89 - 6.80 (m, 1H), 6.12 (dd,J = 16.7, 2.4 Hz, 1H), 5.92 (s, 2H), 5.70 (dd,J = 10.5, 2.4 Hz, 1H), 4.53 - 4.43 (m, 1H), 4.14 (d,J = 14.0 Hz, 1H), 3.76 (s, 3H), 3.67 (s, 3H), 3.23 (t,J = 13.2 Hz, 1H), 2.84 (t,J = 12.9 Hz, 1H), 2.04 (d,J = 12.8 Hz, 2H), 1.80 (s, 2H). | 491.98 | |
1-(4-{4-[4-胺基-5-(2-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]-1H-吡唑-1-基}哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.87 (s, 1H), 7.40 (t,J = 7.8 Hz, 1H), 7.29 (s, 1H), 7.20 (d,J = 7.3 Hz, 1H), 7.12 (d,J = 8.3 Hz, 1H), 7.00 (t,J = 7.4 Hz, 1H), 6.84 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd,J = 16.5, 2.4 Hz, 1H), 5.69 (dd,J = 10.3, 2.4 Hz, 1H), 5.57 (s, 2H), 4.42 (dt,J = 15.2, 5.3 Hz, 2H), 4.12 (d,J = 13.8 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 2.82 (t,J = 12.9 Hz, 3H), 2.02 (d,J = 12.5 Hz, 2H), 1.81 - 1.70 (m, 2H). | 457.538 | |
1-(4-{4-[4-胺基-5-(5-氯-2H-1,3-苯并二唑-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]-1H-吡唑-1-基}哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.96 (s, 1H), 7.37 (s, 1H), 7.04 (d,J = 8.4 Hz, 2H), 7.00 (d,J = 8.4 Hz, 1H), 6.85 (dd,J = 16.7, 10.5 Hz, 1H), 6.12 (dd,J = 16.7, 2.4 Hz, 1H), 6.01 (d,J = 1.0 Hz, 1H), 5.96 (d,J = 1.0 Hz, 1H), 5.70 (dd,J = 10.5, 2.4 Hz, 1H), 4.53 - 4.43 (m, 2H), 4.13 (d,J = 13.8 Hz, 1H), 3.80 (s, 3H), 3.25 (d,J = 13.6 Hz, 1H), 2.83 (t,J = 12.6 Hz, 1H), 2.04 (d,J = 12.5 Hz, 2H), 1.79 (s, 2H). | 505.96 |
步驟 1
:向可再密封之反應瓶中裝入6-溴吡咯并[2,1-f][1,2,4]三嗪-4-胺(500 mg,2.34 mmol)、2-甲基-N-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-2-烯醯胺(804 mg,2.80 mmol)、K3PO4 (1.48 g,7.02 mmol)、Pd(dppf)Cl2
(171 mg,234 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF/H2O (10 mL),且在90℃下攪拌混合物1小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC (用二氯甲烷/甲醇15:1溶離)來純化。真空濃縮,產生呈灰白色非晶形固體狀之N-(4-{4-胺基吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺(280 mg,34%)。
N-(4-{4-胺基-5,7-二溴吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺
步驟2:向圓底燒瓶中裝入N-(4-{4-胺基吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺(260 mg,886 µmol),添加二甲基甲醯胺(5 mL),接著在0℃下添加NBS (313 mg,1.77 mmol),且在0℃下攪拌溶液1小時。反應混合物用Na2SO3 (水溶液)(10 mL)稀釋,且水相用二氯甲烷(10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC (用二氯甲烷/甲醇20:1溶離)來純化。真空濃縮,產生呈橙色非晶形固體狀之N-(4-{4-胺基-5,7-二溴吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺(350 mg,87%)。N -( 4 -( 4 - 胺基 - 5 - 溴吡咯并 [ 2 , 1 - f ][ 1 , 2 , 4 ] 三嗪 - 6 - 基 ) 苯基 ) 甲基丙烯醯胺
步驟3:向可再密封之反應瓶中裝入N-(4-{4-胺基-5,7-二溴吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺(300 mg,665 µmol),添加四氫呋喃(6 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在-78℃下添加n-BuLi (0.8 mL,2 mmol),且在-78℃下攪拌混合物5分鐘。反應混合物用水(5 mL)稀釋,且水相用二氯甲烷(5 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由TLC (用二氯甲烷/甲醇15:1溶離)來純化。真空濃縮,產生呈灰白色非晶形固體狀之N-(4-{4-胺基-5-溴吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺(100 mg,40%)。
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺
步驟 4
:向可再密封之反應瓶中裝入N-(4-{4-胺基-5-溴吡咯并[2,1-f][1,2,4]三嗪-6-基}苯基)-2-甲基丙-2-烯醯胺(90.0 mg,241 µmol)、2-甲基-6-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(82.4 mg,265 µmol)、K3
PO4
(153 mg,722 µmol)、Pd(dppf)Cl2
(17.6 mg,24.1 µmol),添加DMF/H2
O (4 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在90℃下攪拌混合物1小時。反應混合物用水(10 mL)稀釋,且水相用二氯甲烷(10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(管柱:XBridge製備型OBD C18管柱,30×150 mm 5 um;移動相A:未定義,移動相B:未定義;流量:60 mL/min;梯度:35 B至50 B,歷時8分鐘;220nm;RT1:7.54;RT2:;注射體積:ml;操作次數:;)。凍乾產生呈灰白色非晶形固體狀之N-[4-(4-胺基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基]-2-甲基丙-2-烯醯胺(7.62 mg,6%)。
根據實例9之方法製備的其他化合物描繪於下表8中。表 8. 其他例示性化合物
實例10流程 8.
4-(4-胺基-7-(羥基甲基)-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺
4-(4-胺基-7-(羥基甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.77 (t,J = 7.8 Hz, 1H), 7.60 - 7.53 (m, 2H), 7.41 - 7.34 (m, 2H), 7.23 - 7.13 (m, 4H), 7.05 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 5.77 (s, 1H), 5.50 (s, 1H), 2.38 (s, 3H), 1.94 (s, 3H). | 477.20 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.64 - 7.51 (m, 4H), 7.42 - 7.36 (m, 2H), 7.14 - 7.08 (m, 2H), 5.77 (d,J = 1.3 Hz, 1H), 5.50 (t,J = 1.5 Hz, 1H), 3.48 (dt,J = 13.3, 6.3 Hz, 4H), 2.01 - 1.71 (m, 7H). | 467.35 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-基磺醯基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.04 (s, 1H), 7.94 (s, 1H), 7.85 (d,J = 8.2 Hz, 2H), 7.54 (dd,J = 8.4, 5.8 Hz, 4H), 7.01 (d,J = 8.6 Hz, 2H), 5.76 (s, 1H), 5.50 (s, 1H), 3.25 - 3.13 (m, 4H), 1.96 - 1.89 (m, 3H), 1.77 - 1.57 (m, 4H). | 503.35 | |
N-(4-(4-胺基-5-(3-氟-4-((5-氟嘧啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1H), 8.81 (s, 2H), 8.02 (s, 1H), 7.93 (s, 1H), 7.62 - 7.56 (m, 2H), 7.49 (t, J = 8.3 Hz, 1H), 7.36 (dd, J = 11.2, 2.0 Hz, 1H), 7.24 (dd, J = 8.3, 2.1 Hz, 1H), 7.21 - 7.10 (m, 2H), 5.79 (s, 1H), 5.54 - 5.45 (m, 1H), 1.95 (t, J = 1.3 Hz, 3H). | 500.30 | |
1-(3-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 7.86 (d, J = 1.5 Hz, 1H), 7.84 - 7.72 (m, 2H), 7.45 (dd, J = 8.6, 2.6 Hz, 2H), 7.29 - 7.19 (m, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.55 (ddd, J = 16.8, 13.5, 10.3 Hz, 1H), 6.12 (dt, J = 16.9, 2.0 Hz, 1H), 5.65 (ddd, J = 9.8, 6.9, 2.4 Hz, 1H), 4.70 (d, J = 8.6 Hz, 1H), 3.91 - 3.59 (m, 2H), 3.59 - 3.42 (m, 1H), 3.37 (s, 1H), 3.28 - 3.14 (m, 2H), 2.37 (d, J = 3.0 Hz, 3H), 2.25 - 1.85 (m, 2H). | 441.30 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.81 - 7.73 (m, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.44 - 7.32 (m, 2H), 7.24 - 7.13 (m, 4H), 7.05 (d, J = 7.4 Hz, 1H), 6.84 (s, 1H), 6.42 (dd, J = 16.9, 10.1 Hz, 1H), 6.24 (dd, J = 17.0, 2.0 Hz, 1H), 5.75 (dd, J = 10.1, 2.1 Hz, 1H), 2.38 (s, 3H). | 463.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 7.96 (s, 1H), 7.83 - 7.71 (m, 1H), 7.64 - 7.57 (m, 2H), 7.35 - 7.24 (m, 2H), 7.16 - 7.06 (m, 4H), 7.02 (d,J = 7.4 Hz, 1H), 6.80 (d,J = 8.1 Hz, 1H), 5.77 (t,J = 1.1 Hz, 1H), 5.60 - 5.39 (m, 1H), 2.46 (s, 3H), 2.35 (s, 3H), 1.94 (d,J = 1.2 Hz, 3H). | 491.30 |
步驟 1
:向可再密封之反應瓶中裝入(4-胺基-5-溴吡咯并[2,1-f][1,2,4]三嗪-7-基)甲醇(600 mg,2.49 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-N-(2,2,2-三氟乙基)苯甲醯胺(983 mg,2.99 mmol)、Pd(dtbpf)Cl2
(162 mg,249 µmol)、CsF (1.14 g,7.47 mmol)、DMF:水=16:1 (8 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取。分離有機相且經Na2
SO4
乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC純化。真空濃縮,產生呈黃色油狀之4-(4-胺基-7-(羥基甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(400 mg,44%)。
4-(4-胺基-7-(((第三丁基二甲基矽烷基)氧基)甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺
步驟 2
:向可再密封之反應瓶中裝入4-(4-胺基-7-(羥基甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(380 mg,1.04 mmol)、咪唑(283 mg,4.16 mmol)、DMF (5 mL)及攪拌棒。添加TBSCl (314 mg,2.08 mmol),且在室溫下攪拌溶液1小時。所得混合物經由C18管柱純化。真空濃縮,產生呈黃色非晶形固體狀之4-(4-胺基-7-(((第三丁基二甲基矽烷基)氧基)甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(420 mg,84%)。
4-(4-胺基-6-溴-7-(((第三丁基二甲基矽烷基)氧基)甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺
步驟 3
:向圓底燒瓶中裝入4-(4-胺基-7-(((第三丁基二甲基矽烷基)氧基)甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(400 mg,0.84 mmol)、二甲基甲醯胺(5 mL)及攪拌棒。添加NBS (225 mg,1.00 mmol),且在室溫下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取。分離有機相且經Na2
SO4
乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色非晶形固體狀之4-(4-胺基-6-溴-7-(((第三丁基二甲基矽烷基)氧基)甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(450 mg,94%)。
6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟4:向可再密封之反應瓶中裝入4-(4-胺基-6-溴-7-(((第三丁基二甲基矽烷基)氧基)甲基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(200 mg,0.36 mmol)、N-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)甲基丙烯醯胺(124 mg,0.43 mmol)、Pd(dtbpf)Cl2
(23.4 mg,36 µmol)、CsF (164 mg,1.08 mmol)、DMF:水=16:1 (4 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下、在N2
下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取。收集有機相且經Na2
SO4
乾燥,過濾且真空濃縮。所得粗物質藉由製備型HPLC純化(管柱:XBridge製備型OBD C18管柱,19*250 mm,5 um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:25 mL/min;梯度:20 B至50 B,歷時8分鐘;220 nm;RT1:7.23;)。凍乾產生呈灰白色非晶形固體狀之4-(4-胺基-7-(羥基甲基)-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺(30.4 mg,16%)。
根據實例10之方法製備的其他化合物描繪於下表9中。表 9 . 其他例示性化合物
實例11流程 9
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7H-環戊并[d]嘧啶-5-基)苯甲酸甲酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-7-氰基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.46 (s, 1H), 8.20 (s, 1H), 7.80 - 7.63 (m, 3H), 7.36 (d,J = 8.4 Hz, 2H), 7.25 - 7.14 (m, 4H), 7.04 (d,J = 7.3 Hz, 1H), 6.84 (d,J = 8.2 Hz, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 2.36 (s, 3H), 1.94 (s, 3H). | 502.35 | |
N-(4-(4-胺基-7-(羥基甲基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 7.99 (s, 1H), 7.75 (t,J = 7.8 Hz, 1H), 7.64 - 7.55 (m, 2H), 7.32 - 7.26 (m, 2H), 7.22 - 7.10 (m, 4H), 7.03 (d,J = 7.4 Hz, 1H), 6.81 (d,J = 8.1 Hz, 1H), 5.77 (s, 1H), 5.51 (s, 1H), 5.17 (t,J = 5.0 Hz, 1H), 4.69 (d,J = 4.9 Hz, 2H), 2.36 (s, 3H), 1.94 (s, 3H). | 507.35 | |
N-(4-(4-胺基-7-(羥基甲基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.14 (s, 1H), 7.99 (s, 1H), 7.75 (t,J = 7.7 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.33 - 7.25 (m, 2H), 7.24 - 7.17 (m, 2H), 7.17 - 7.09 (m, 2H), 7.03 (d,J = 7.3 Hz, 1H), 6.81 (d,J = 8.1 Hz, 1H), 6.43 (dd,J = 17.0, 10.1 Hz, 1H), 6.25 (dd,J = 17.0, 2.1 Hz, 1H), 5.75 (dd,J = 10.1, 2.1 Hz, 1H), 5.16 (t,J = 5.0 Hz, 1H), 4.69 (d,J = 5.0 Hz, 2H), 2.36 (s, 3H). | 493.35 | |
4-(4-胺基-7-(羥基甲基)-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.13 (s, 1H), 8.01 (s, 1H), 7.93 - 7.83 (m, 2H), 7.61 - 7.54 (m, 2H), 7.43 - 7.30 (m, 2H), 7.18 - 7.08 (m, 2H), 5.77 (d, J = 1.2 Hz, 1H), 5.51 (s, 0H), 5.16 (t, J = 4.9 Hz, 1H), 4.68 (d, J = 5.0 Hz, 2H), 4.19 - 4.00 (m, 2H), 1.93 (t, J = 1.2 Hz, 3H). | 525 | |
N-(4-(4-胺基-7-(羥基甲基)-5-(4-(哌啶-1-羰基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.76 (s, 1H), 7.99 (s, 1H), 7.60 - 7.53 (m, 2H), 7.37 (d,J = 8.1 Hz, 2H), 7.32 - 7.26 (m, 2H), 7.15 - 7.09 (m, 2H), 5.77 (s, 1H), 5.50 (d,J = 1.9 Hz, 1H), 5.17 (s, 1H), 4.68 (s, 2H), 3.57- 3.35 (d,J = 2.8 Hz, 4H), 1.93 (t,J = 1.2 Hz, 3H), 1.69 - 1.40 (m, 6H). | 511.40 | |
N-(4-(4-胺基-7-(甲氧基甲基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 8.00 (s, 1H), 7.74 (t,J = 7.7 Hz, 1H), 7.61 (d,J = 8.6 Hz, 2H), 7.36 - 7.25 (m, 2H), 7.12 (d,J = 8.3 Hz, 4H), 7.03 (d,J = 7.4 Hz, 1H), 6.81 (d,J = 8.1 Hz, 1H), 5.77 (s, 1H), 5.50 (s, 1H), 4.60 (s, 2H), 3.31 (s, 3H), 2.35 (s, 3H), 1.94 (d,J = 1.3 Hz, 3H). | 521.40 | |
N-(4-(4-胺基-7-((二甲基胺基)甲基)-5-(4-((6-甲基吡啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 7.96 (s, 1H), 7.79 - 7.70 (m, 1H), 7.62 - 7.56 (m, 2H), 7.34 - 7.26 (m, 2H), 7.26 - 7.20 (m, 2H), 7.15 - 7.07 (m, 2H), 7.03 (d,J = 7.4 Hz, 1H), 6.80 (d,J = 8.1 Hz, 1H), 5.77 (s, 1H), 5.50 (t,J = 1.5 Hz, 1H), 3.71 (s, 2H), 2.36 (s, 3H), 2.11 (s, 6H), 1.94 (d,J = 1.2 Hz, 3H). | 534.35 |
步驟 1
:向圓底燒瓶中裝入N-(4-{4-胺基-5-溴-7H-環戊并[d]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺(800 mg,2.15 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯甲酸甲酯(731 mg,2.79 mmol)、Pd(dtbpf)Cl2 (139 mg,215 µmol)、CsF (980 mg,6.45 mmol)、DMF:H2
O=16:1 (8 mL)及攪拌棒。在90℃下、在N2
下攪拌溶液2小時。反應混合物用水(50 mL)稀釋且用EtOAc (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色非晶形固體狀之4-{4-胺基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-環戊并[d]嘧啶-5-基}苯甲酸甲酯(600 mg,56%)。
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7H-環戊并[d]嘧啶-5-基)苯甲酸
步驟 2
:向圓底燒瓶中裝入4-{4-胺基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-環戊并[d]嘧啶-5-基}苯甲酸甲酯(580 mg,1.35 mmol)、THF:LiOH (2M)=1:1 (6 mL)及攪拌棒。在室溫下攪拌溶液3小時。溶液pH值用HCl水溶液調整至6~7。藉由添加HCl而使產物沈澱且乾燥。此產生呈灰白色非晶形固體狀之4-{4-胺基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7H-環戊并[d]嘧啶-5-基}苯甲酸(350 mg,63%)。
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2-羥基-2-甲基丙基)苯甲醯胺
步驟 3
:向可再密封之反應瓶中裝入4-{4-胺基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]-7aH-環戊并[d]嘧啶-5-基}苯甲酸(60 mg,145 μmol)、1-胺基-2-甲基丙-2-醇(15.5 mg,174 μmol)、HATU (55.2 mg,145 μmol)、DIEA (37.4 mg,290 μmol)、二甲基甲醯胺(10 mL)及攪拌棒。在室溫下攪拌混合物1小時。反應混合物用水淬滅且藉由HPLC純化(管柱:XBridge製備型C18 OBD管柱,5um,19*150 mm;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:25 mL/min;梯度:15 B至50 B,歷時7分鐘;254/220 nm;RT1:7.58;)。凍乾產生呈白色非晶形固體狀之4-{4-胺基-6-[4-(2-甲基丙-2-烯醯胺基)苯基]吡咯并[2,1-f][1,2,4]三嗪-5-基}-N-(2-羥基-2-甲基丙基)苯甲醯胺(40.2 mg,56.4%)。
根據實例11之方法製備的其他化合物描繪於下表10中。表 10 . 其他例示性化合物
實例12流程 10
N-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 9.18 (t,J = 6.3 Hz, 1H), 8.03 (s, 1H), 8.00 - 7.89 (m, 3H), 7.59 - 7.51 (m, 2H), 7.51 - 7.37 (m, 2H), 7.14 - 7.03 (m, 2H), 5.77 (d,J = 1.1 Hz, 1H), 5.50 (t,J = 1.5 Hz, 1H), 4.12 (qd,J = 9.7, 6.1 Hz, 2H), 1.93 (t,J = 1.2 Hz, 3H). | 485.25 | |
N-(4-(4-胺基-5-(4-(哌啶-1-羰基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.63 - 7.50 (m, 2H), 7.50 - 7.28 (m, 4H), 7.17 - 7.03 (m, 2H), 5.77 (s, 1H), 5.57 - 5.46 (m, 1H), 3.48 (d,J = 89.5 Hz, 4H), 1.75 - 1.37 (m, 6H). | 481.40 | |
N-(4-(4-胺基-5-(4-(哌啶-1-羰基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 10.11 (s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.55 - 7.48 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.14 - 7.03 (m, 2H), 6.56 - 6.35 (m, 1H), 6.24 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 3.59 (s, 4H), 1.64 (s, 2H), 1.54 (s, 4H). | 467.35 | |
4-(6-(4-丙烯醯胺基苯基)-4-胺基吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 10.11 (s, 1H), 9.18 (t, J = 6.3 Hz, 1H), 8.03 (s, 1H), 8.01 - 7.89 (m, 3H), 7.56 - 7.50 (m, 2H), 7.50 - 7.33 (m, 2H), 7.17 - 7.05 (m, 2H), 6.41 (dd, J = 17.0, 10.1 Hz, 1H), 6.24 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.0, 2.1 Hz, 1H), 4.21 - 4.03 (m, 2H). | 481.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-環丁基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.75 (s, 1H), 8.70 (d, J = 7.4 Hz, 1H), 8.03 (s, 1H), 7.91 (d, J = 8.3 Hz, 3H), 7.53 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 5.76 (s, 1H), 5.50 (s, 1H), 4.53 - 4.26 (m, 1H), 2.22 (s, 2H), 2.09 (t, J = 10.6 Hz, 2H), 1.93 (s, 3H), 1.68 (s, 2H). | 467.35 | |
N-(4-(4-胺基-5-(4-(N-環丁基胺磺醯基)苯基)吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.75 (s, 1H), 8.04 (s, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.87 - 7.80 (m, 2H), 7.55 - 7.49 (m, 4H), 7.08 - 7.01 (m, 2H), 5.75 (s, 1H), 5.50 (t,J = 1.5 Hz, 1H), 3.68 (s, 1H), 2.02 - 1.85 (m, 5H), 1.79 - 1.65 (m, 2H), 1.63 - 1.38 (m, 2H). | 503.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N,N-二甲基環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.82 (s, 1H), 7.90 (s, 1H), 7.78 (s, 1H), 7.75 - 7.66 (m, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.25 (s, 1H), 5.90 (d, J = 4.4 Hz, 1H), 5.81 (t, J = 1.1 Hz, 1H), 5.52 (t, J = 1.5 Hz, 1H), 3.20 (d, J = 13.7 Hz, 1H), 3.06 (s, 3H), 2.85 (s, 3H), 2.36 (s, 2H), 1.97 (t, J = 1.2 Hz, 3H), 1.90 (s, 2H), 1.77 (s, 1H). | 445.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2-羥基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.74 (s, 1H), 8.34 (t, J = 6.2 Hz, 1H), 8.03 (s, 1H), 7.93 (d, J = 8.5 Hz, 3H), 7.56 - 7.48 (m, 2H), 7.45 - 7.39 (m, 2H), 7.18 - 7.06 (m, 2H), 5.76 (d, J = 1.4 Hz, 1H), 5.53 - 5.43 (m, 1H), 4.56 (s, 1H), 3.28 (d, J = 6.1 Hz, 2H), 1.92 (t, J = 1.2 Hz, 3H), 1.12 (s, 6H). | 485.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(四氫呋喃-3-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.74 (s, 1H), 8.62 (d, J = 6.4 Hz, 1H), 8.03 (s, 1H), 7.93 (d, J = 8.0 Hz, 3H), 7.62 - 7.49 (m, 2H), 7.46 - 7.39 (m, 2H), 7.14 - 7.04 (m, 2H), 5.76 (s, 1H), 5.49 (t, J = 1.5 Hz, 1H), 4.51 - 4.41 (m, 1H), 3.87 (dd, J = 9.0, 6.6 Hz, 2H), 3.73 (td, J = 8.1, 5.7 Hz, 1H), 3.61 (dd, J = 8.9, 4.4 Hz, 1H), 2.16 (dq, J = 12.6, 7.6 Hz, 1H), 1.99 - 1.81 (m, 4H). | 483.15 | |
N-(4-(5-(4-(2-氮雜雙環[2.1.1]己烷-2-羰基)苯基)-4-胺基吡咯并[2,1-f][1,2,4]三嗪-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.74 (s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.57 - 7.47 (m, 3H), 7.39 (d, J = 7.3 Hz, 2H), 7.17 - 7.06 (m, 2H), 5.77 (d, J = 1.5 Hz, 1H), 5.49 (t, J = 1.5 Hz, 1H), 4.55 (dd, J = 147.8, 7.0 Hz, 1H), 3.48 (d, J = 10.6 Hz, 2H), 2.91 (d, J = 16.9 Hz, 1H), 2.05 - 1.84 (m, 5H), 1.51 (s, 1H), 1.37 (s, 1H). | 479.35 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)吡咯并[2,1-f][1,2,4]三嗪-5-基)-N-(2-甲氧基-2-甲基丙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.33 (t,J = 6.2 Hz, 1H), 8.03 (s, 1H), 7.95 - 7.88 (m, 3H), 7.54 (d,J = 8.8 Hz, 2H), 7.43 (d,J = 1.9 Hz, 2H), 7.15 - 7.06 (m, 2H), 5.76 (s, 1H), 5.49 (s, 1H), 3.35 (d,J = 6.2 Hz, 2H), 3.16 (s, 3H), 1.92 (t,J = 1.2 Hz, 3H), 1.13 (s, 6H). | 499.25 |
步驟 1
:向圓底燒瓶中裝入3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯胺(10 g,42.8 mmol)、丙-2-烯醯氯(3.87 g,42.8 mmol)、吡啶(10.1 g,128 mmol)、二氯甲烷(150 mL)及攪拌棒。在0℃下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取。有機相經Na2
SO4
乾燥,過濾且真空蒸發。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色油狀之N-(3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙烯醯胺(12 g,98%)。
N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺
步驟 2
:向圓底燒瓶中裝入N-[3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-2-烯醯胺(1 g,3.48 mmol)、5-溴-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(1.22 g,3.48 mmol)、Pd(dppf)Cl2
(254 mg,348 µmol)、K3
PO4
(2.20 g,10.4 mmol)、DMF/H2
O (16:1)(15 mL)及攪拌棒。在50℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,過濾且真空蒸發。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色非晶形固體狀之N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺(440 mg,33%)。
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺
步驟 3
:向可再密封之反應瓶中裝入N-(4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3-甲基苯基)丙-2-烯醯胺(200 mg,517 µmol)、1-[(1R)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-羰基]吡咯啶(156 mg,517 µmol)、Pd(pddf)Cl2
(37.8 mg,517 µmol)、Na2
CO3
(164 mg,1.55 mmol)、DMF (10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,過濾且真空蒸發。所得粗物質藉由製備型HPLC純化(管柱:YMC-Actus Triart C18,30*250,5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:50 mL/min;梯度:40 B至62 B,歷時8分鐘;220 nm;RT1:6.83)。凍乾產生呈灰白色非晶形固體狀之(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺(40 mg,16%)。
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺
步驟 4
:向可再密封之反應瓶中裝入N-(4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3-甲基苯基)丙-2-烯醯胺(240 mg,621 µmol)、Pd(dppf)Cl2
(45.4 mg,62.1 µmol)、Na2
CO3
(197 mg,1.86 mmol)、1-[(1S)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-羰基]吡咯啶(189240 mg,621 µmol)、二甲基甲醯胺/H2
O (8 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,過濾且真空蒸發。所得粗物質藉由製備型HPLC純化(管柱:YMC-Actus Triart C18,30*250,5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:50 mL/min;梯度:40 B至60 B,歷時8分鐘;220 nm;RT1:7.67;RT2:;注射體積:ml;操作次數:;)。凍乾產生呈灰白色非晶形固體狀之(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺(39 mg,14%)。
根據實例12之方法製備的其他化合物描繪於下表11中。表 11. 其他例示性化合物
實例13流程 11
N-(2-(4-溴苯基)丙-2-基)丙烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(5-甲基-7-(4-((6-甲基吡啶-2-基)氧基)苯基)-5H-吡咯并[3,2-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.03 (s, 1H), 9.16 (s, 1H), 8.94 (s, 1H), 7.88 (d,J = 8.4 Hz, 2H), 7.72 (t,J = 7.8 Hz, 1H), 7.48 (dd,J = 20.9, 8.5 Hz, 4H), 7.08 - 6.96 (m, 3H), 6.75 (d,J = 8.2 Hz, 1H), 5.85 (s, 1H), 5.57 (s, 1H), 3.75 (s, 3H), 2.34 (s, 3H), 1.98 (s, 3H). | 476.15 | |
N-(4-(4-胺基-7-側氧基-3-(4-(吡咯啶-1-羰基)苯基)-6,7-二氫-1H-吡咯并[2,3-d]噠嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.72 (s, 1H), 11.38 (s, 1H), 9.83 (s, 1H), 7.62 - 7.54 (m, 4H), 7.45 - 7.35 (m, 2H), 7.28 - 7.21 (m, 2H), 5.78 (s, 1H), 5.52 (s, 1H), 4.55 (s, 2H), 3.46 (dt,J = 23.1, 6.3 Hz, 4H), 1.98 - 1.80 (m, 7H). | 483.25 | |
N-(4-(4-胺基-1-甲基-7-側氧基-3-(4-(吡咯啶-1-羰基)苯基)-6,7-二氫-1H-吡咯并[2,3-d]噠嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.41 (s, 1H), 9.91 (s, 1H), 7.69 (d,J = 8.2 Hz, 2H), 7.47 (d,J = 7.7 Hz, 2H), 7.26 (dd,J = 12.9, 8.1 Hz, 4H), 5.79 (s, 1H), 5.53 (s, 1H), 4.59 (s, 2H), 3.98 (s, 3H), 3.45 (t,J = 7.0 Hz, 2H), 1.93 (s, 3H), 1.82 (dt,J = 18.4, 7.0 Hz, 4H). | 497.35 | |
N-(4-(4-胺基-1,6-二甲基-7-側氧基-3-(4-(吡咯啶-1-羰基)苯基)-6,7-二氫-1H-吡咯并[2,3-d]噠嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 7.73 - 7.66 (m, 2H), 7.47 (d,J = 8.1 Hz, 2H), 7.31 - 7.21 (m, 4H), 5.79 (s, 1H), 5.53 (s, 1H), 4.72 (s, 2H), 3.98 (s, 3H), 3.55 (s, 3H), 3.45 (t,J = 6.8 Hz, 2H), 3.37 (t,J = 6.4 Hz, 2H), 1.94 (s, 3H), 1.84 (m,J = 18.4 Hz, 4H). | 511.25 | |
N-(4-(4-胺基-7-甲基-5-(2-側氧基-4-(吡咯啶-1-羰基)吡啶-1(2H)-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.21 (s, 1H), 7.84 - 7.71 (m, 2H), 7.44 (d,J = 7.0 Hz, 1H), 7.36 - 7.25 (m, 2H), 6.49 (d,J = 1.7 Hz, 1H), 6.32 (s, 2H), 6.14 (dd,J = 7.0, 1.8 Hz, 1H), 5.88 - 5.79 (m, 1H), 5.54 (d,J = 1.8 Hz, 1H), 3.65 (s, 3H), 3.40 (td,J = 11.7, 11.3, 5.5 Hz, 3H), 1.95 (d,J = 1.2 Hz, 3H), 1.89 - 1.80 (m, 4H). | 498.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(2-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) 8.15 (s, 1H), 7.82 - 7.75 (m, 2H), 7.46 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 5.85 (t, J = 1.0 Hz, 1H), 5.59 - 5.53 (m, 1H), 3.67 (s, 4H), 3.60 - 3.45 (m, 1H), 3.49 - 3.35 (m, 2H), 2.98 (s, 1H), 2.46 (d, J = 9.9 Hz, 1H), 2.37 (s, 1H), 2.07 (t, J = 1.2 Hz, 3H), 2.01 - 1.90 (m, 5H), 1.72 (s, 1H), 1.55 (d, J = 12.8 Hz, 1H), 0.90 (s, 3H). | 499.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(2-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, 甲醇-d 4 ) 8.15 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 5.97 (s, 1H), 5.87 - 5.82 (m, 1H), 5.56 (q, J = 1.6 Hz, 1H), 3.67 (s, 4H), 3.60 - 3.51 (m, 1H), 3.50 - 3.35 (m, 2H), 2.98 (s, 1H), 2.60 - 2.46 (d, J = 10.4 Hz, 1H), 2.37 (s, 1H), 2.07 (t, J = 1.3 Hz, 3H), 2.00 (p, J = 6.5 Hz, 2H), 1.95 - 1.85 (m, 2H), 1.80 - 1.60 (s, 1H),1.59 - 1.50 (m, 1H), 1.1 - 0.45 (m, 3H). | 499.25 | |
(S)-N-(4-(4-胺基-7-甲基-5-(2-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, 甲醇-d 4 ) 8.15 (s, 1H), 7.83 - 7.75 (m, 2H), 7.52 - 7.45 (m, 2H), 6.03 (t, J = 3.1 Hz, 1H), 5.85 (t, J = 0.9 Hz, 1H), 5.57 (d, J = 1.9 Hz, 1H), 3.66 (s, 3H), 3.63 (s, 1H), 3.62 - 3.49 (m, 1H), 3.48 - 3.35 (m, 2H), 2.75 (s, 1H), 2.49 (s, 1H), 2.37 (s, 1H), 2.07 (t, J = 1.2 Hz, 3H), 1.99 (q, J = 6.6 Hz, 3H), 1.95 - 1.85 (m, 2H), 1.84 (s, 1H), 1.55 (q, J = 11.1 Hz, 1H), 0.74 (d, J = 7.1 Hz, 3H). | 499.20 | |
(S)-N-(4-(4-胺基-7-甲基-5-(2-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) 8.15 (s, 1H), 7.83 - 7.75 (m, 2H), 7.51 - 7.45 (m, 2H), 6.06 - 6.00 (m, 1H), 5.85 (t, J = 1.0 Hz, 1H), 5.57 (q, J = 1.8 Hz, 1H), 3.66 (s, 3H), 3.61 - 3.48 (m, 2H), 3.43 - 3.35 (m, 2H), 3.13 - 2.71 (s, 1H), 2.75 (s, 1H), 2.37 (s, 1H), 2.10 - 1.91 (m, 6H), 1.89 (dd, J = 10.4, 4.4 Hz, 2H), 1.84 (s, 1H), 1.62 - 1.49 (m, 1H), 0.74 (d, J = 7.1 Hz, 3H). | 499.30 | |
(S)-N-(4-(4-胺基-5-(2-氟-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) 8.15 (d, J = 11.9 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.48 - 7.40 (m, 2H), 5.85 (s, 1H), 5.57 (s, 1H), 3.69 (d, J = 5.4 Hz, 3H), 3.67 - 3.50 (m, 1H), 3.52 - 3.36 (m, 2H), 3.16 (d, J = 1.7 Hz, 2H), 2.48 (t, J = 16.7 Hz, 2H), 2.15 (s, 1H), 2.10 - 1.69 (m, 10H). | 503.25 | |
(R)-N-(4-(4-胺基-5-(2-氟-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) 8.16 (d, J = 8.6 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.48 - 7.40 (m, 2H), 5.85 (t, J = 1.0 Hz, 1H), 5.57 (d, J = 2.0 Hz, 1H), 3.69 (d, J = 3.1 Hz, 3H), 3.67 - 3.55 (m, 1H), 3.55 - 3.35 (m, 3H), 3.16 (s, 1H), 2.50 (d, J = 11.2 Hz, 2H), 2.15 (s, 1H), 2.07 (t, J = 1.2 Hz, 3H), 1.99 (p, J = 6.5 Hz, 2H), 1.94 - 1.86 (m, 4H), 1.69 (s, 1H). | 503.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(2-甲基-1-側氧基-2-氮雜螺[4.5]癸-7-烯-8-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.11 (s, 1H), 7.84 - 7.77 (m, 2H), 7.47 - 7.41 (m, 2H), 6.65 (s, 1H), 5.83 (s, 1H), 5.71 (d,J = 4.0 Hz, 1H), 5.56 (d,J = 1.8 Hz, 1H), 3.59 (s, 3H), 3.26 (ddt,J = 9.7, 7.1, 3.4 Hz, 2H), 2.73 (s, 3H), 2.27 (d,J = 17.7 Hz, 1H), 2.17 - 2.01 (m, 2H), 1.97 (s, 3H), 1.90 (s, 1H), 1.87 - 1.72 (m, 3H), 1.45 - 1.31 (m, 1H). | 471.25 | |
N-(4-(4-胺基-7-甲基-5-(3-(6-甲基吡啶-2-基)-2,3-二氫苯并呋喃-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.77 - 7.64 (m, 3H), 7.34 - 7.24 (m, 2H), 7.21 - 7.12 (m, 2H), 7.06 (d,J = 7.6 Hz, 1H), 6.73 (d,J = 1.5 Hz, 1H), 6.69 (dd,J = 16.4, 1.5 Hz, 1H), 6.25 - 5.61 (m, 2H), 5.61 - 5.50 (m, 1H), 4.97 - 4.68 (m, 3H), 3.58 (s, 3H), 2.45 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 517.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(3-(6-甲基吡啶-2-基)-2,3-二氫苯并呋喃-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.78 - 7.63 (m, 3H), 7.39 - 7.25 (m, 2H), 7.13 (t,J = 7.0 Hz, 2H), 7.06 (d,J = 7.6 Hz, 1H), 6.72 (dd,J = 7.6, 1.5 Hz, 1H), 6.67 (d,J = 1.4 Hz, 1H), 5.80 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 5.00 - 4.69 (m, 3H), 3.58 (s, 3H), 2.45 (s, 3H), 1.95 (d,J = 1.4 Hz, 3H). | 517.25 | |
(S)-N-(4-(4-胺基-7-甲基-5-(3-(6-甲基吡啶-2-基)-2,3-二氫苯并呋喃-6-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.18 (s, 1H), 7.79 - 7.61 (m, 3H), 7.33 - 7.27 (m, 2H), 7.13 (t,J = 7.0 Hz, 2H), 7.06 (d,J = 7.6 Hz, 1H), 6.72 (dd,J = 7.6, 1.5 Hz, 1H), 6.67 (d,J = 1.5 Hz, 1H), 5.80 (s, 1H), 5.54 (t,J = 1.6 Hz, 1H), 4.98 - 4.74 (m, 3H), 3.58 (s, 3H), 2.45 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 517.25 | |
(S)-N-(4-(4-胺基-7-甲基-5-(1-(6-甲基吡啶-2-基)-1,3-二氫異苯并呋喃-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.74 - 7.62 (m, 3H), 7.33 - 7.19 (m, 5H), 7.19 - 7.09 (m, 2H), 6.68 - 5.38 (m, 5H), 5.29 (dd,J = 12.7, 2.8 Hz, 1H), 5.14 (d,J = 12.6 Hz, 1H), 3.59 (s, 3H), 2.50 (s, 3H), 1.94 (d,J = 1.4 Hz, 3H). | 517.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(1-(6-甲基吡啶-2-基)-1,3-二氫異苯并呋喃-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.20 (s, 1H), 7.81 - 7.61 (m, 3H), 7.35 - 7.10 (m, 7H), 6.75 - 5.41 (m, 5H), 5.29 (dd,J = 12.8, 2.8 Hz, 1H), 5.14 (d,J = 12.6 Hz, 1H), 3.59 (s, 3H), 2.50 (s, 3H), 1.94 (s, 3H). | 517.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(2-甲基-1-側氧基-2-氮雜螺[4.5]癸-7-烯-8-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (s, 1H), 7.83 - 7.77 (m, 2H), 7.47 - 7.41 (m, 2H), 6.61 (s, 2H), 5.83 (s, 1H), 5.72 (d,J = 3.8 Hz, 1H), 5.55 (s, 1H), 3.58 (s, 3H), 3.32 - 3.21 (m, 2H), 2.73 (s, 3H), 2.27 (d,J = 17.4 Hz, 1H), 2.15 - 2.01 (m, 2H), 1.97 (s, 3H), 1.90 (s, 1H), 1.87 - 1.72 (m, 3H), 1.45 - 1.31 (m, 1H). | 471.25 | |
(R)-N-(4-(5-(4-(5-氮雜螺[2.4]庚烷-5-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.10 (s, 1H), 7.81 (dd,J = 8.7, 2.5 Hz, 2H), 7.43 (dd,J = 8.4, 3.6 Hz, 2H), 6.51 (s, 2H), 5.83 (s, 1H), 5.77 (s, 1H), 5.55 (s, 1H), 3.67 (t,J = 7.3 Hz, 1H), 3.58 (d,J = 1.8 Hz, 3H), 3.32 - 3.21 (m, 1H),, 2.88 (t,J = 6.0 Hz, 1H),, 2.28 (s, 2H), 1.98 (s, 3H), 1.90 (s, 2H), 1.82 (d,J = 4.4 Hz, 1H), 1.75 - 1.68 (m, 2H), 1.63 (dd,J = 15.1, 6.7 Hz, 2H), 0.63 - 0.53 (m, 4H). | 511.30 | |
(S)-N-(4-(5-(4-(5-氮雜螺[2.4]庚烷-5-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.10 (s, 1H), 7.81 (dd,J = 8.7, 2.6 Hz, 2H), 7.43 (dd,J = 8.6, 3.5 Hz, 2H), 6.51 (s, 2H), 5.83 (s, 1H), 5.77 (s, 1H), 5.55 (s, 1H), 3.71 - 3.60 (m, 1H), 3.58 (d,J = 1.9 Hz, 3H), 3.42 (dd,J = 17.0, 11.4 Hz, 1H), 3.32 - 3.13 (m, 1H), 2.73 (q,J = 6.0 Hz, 1H), 2.28 (s, 2H), 1.98 (s, 3H), 1.90 (s, 2H), 1.82 (dt,J = 10.1, 4.6 Hz, 1H), 1.72 (td,J = 7.0, 4.0 Hz, 1H), 1.63 (dd,J = 14.8, 6.3 Hz, 2H), 0.61 (d,J = 6.4 Hz, 1H), 0.56 (d,J = 5.7 Hz, 3H). | 511.35 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-氯乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.10 (s, 1H), 7.88 - 7.75 (m, 2H), 7.57 - 7.40 (m, 2H), 6.55 (s, 1H), 5.77 (d,J = 3.1 Hz, 1H), 4.29 (s, 2H), 3.58 (s, 3H), 3.56 - 3.48 (m, 1H), 3.48 - 3.40 (m, 1H), 3.32 - 3.23 (m, 3H), 2.82 (q,J = 6.0 Hz, 1H), 2.38 - 2.10 (m, 2H), 1.87 (h,J = 6.4 Hz, 4H), 1.76 (p,J = 6.3 Hz, 2H), 1.63 (d,J = 5.9 Hz, 2H). | 493.20 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-氯乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.48 (s, 1H), 8.10 (s, 1H), 7.85 - 7.69 (m, 2H), 7.53 - 7.44 (m, 2H), 6.55 (s, 1H), 5.76 (d,J = 4.0 Hz, 1H), 4.29 (s, 2H), 3.58 (s, 3H), 3.51 (dt,J = 10.1, 6.7 Hz, 1H), 3.47 - 3.41 (m, 1H), 3.32 (d,J = 9.3 Hz, 3H), 2.83 (p,J = 5.9 Hz, 1H), 2.37 - 2.14 (m, 2H), 1.87 (p,J = 6.8 Hz, 4H), 1.76 (p,J = 6.3 Hz, 2H), 1.63 (d,J = 6.1 Hz, 2H). | 493.20 | |
(S)-N-(4-(4-胺基-7-甲基-5-(6-(吡咯啶-1-羰基)-5,6-二氫-2H-哌喃-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.99 (s, 1H), 8.12 (s, 1H), 7.81 (d,J = 8.2 Hz, 2H), 7.42 (d,J = 8.4 Hz, 2H), 6.63 (s, 2H), 5.94 (d,J = 4.2 Hz, 1H), 5.82 (s, 1H), 5.56 (s, 1H), 4.55 (t,J = 5.0 Hz, 1H), 3.77 (d,J = 2.9 Hz, 2H), 3.55 (s, 3H), 3.50 (s, 3H), 3.29 (td,J = 6.8, 3.1 Hz, 2H), 2.45 (d,J = 17.9 Hz, 1H), 2.31 (dt,J = 17.1, 4.2 Hz, 1H), 1.97 (s, 3H), 1.79 (dp,J = 24.9, 6.9 Hz, 4H), 1.19 (s, 1H). | 487.30 | |
(R)-N-(4-(4-胺基-7-甲基-5-(6-(吡咯啶-1-羰基)-5,6-二氫-2H-哌喃-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.11 (s, 1H), 7.85 - 7.78 (m, 2H), 7.46 - 7.39 (m, 2H), 6.55 (s, 2H), 5.94 (s, 1H), 5.85 - 5.80 (m, 1H), 5.56 (d,J = 1.8 Hz, 1H), 4.54 (t,J = 5.0 Hz, 1H), 3.77 (s, 2H), 3.55 (s, 3H), 3.52 - 3.41 (m, 2H), 3.39 - 3.28 (m, 3H), 2.43 (s, 1H), 2.29 (s, 1H), 1.97 (s, 3H), 1.77 (ddt,J = 24.2, 11.8, 5.5 Hz, 4H), 1.19 (s, 1H). | 487.20 | |
N-(4-(4-胺基-7-甲基-5-(1-(吡咯啶-1-羰基)-1,2,3,6-四氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 8.13 (s, 1H), 7.84 - 7.78 (m, 2H), 7.46 - 7.39 (m, 2H), 6.3 (s, 1H), 5.81 (d,J = 11.2 Hz, 2H), 5.56 (s, 1H), 3.83 (d,J = 3.3 Hz, 2H), 3.57 (s, 3H), 3.23 (s, 1H), 1.97 (d,J = 1.2 Hz, 5H), 1.77 - 1.70 (m, 4H). | 486.25 | |
N-(4-(4-胺基-5-(1-(環戊烷羰基)-1,2,3,6-四氫吡啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 8.13 (s, 1H), 7.84 - 7.78 (m, 2H), 7.46 - 7.39 (m, 2H), 6.3 (s, 1H), 5.81 (d,J = 11.2 Hz, 2H), 5.56 (s, 1H), 3.83 (d,J = 3.3 Hz, 2H), 3.57 (s, 3H), 3.23 (s, 1H), 2.45 (s, 1H), 1.97 (d,J = 1.2 Hz, 5H), 1.77 - 1.70 (m, 4H). | 485.25 | |
N-(4-(4-胺基-5-((R)-4-((S)-2-乙炔基吡咯啶-1-羰基)環己-1-烯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, 甲醇-d4) δ 8.15 (d, J = 3.5 Hz, 1H), 7.91-7.65 (m, 2H), 7.54-7.38 (m, 2H), 5.94 (s, 1H), 5.89-5.73 (m, 1H), 5.64-5.44 (m, 1H), 4.90-4.65 (m, 1H), 3.70-3.60 (m, 3H), 3.60-3.50 (m, 1H), 3.50-3.40 (m, 1H), 3.10-2.88 (m, 1H), 2.88-2.60 (m, 1H), 2.55-2.30 (m, 2H), 2.30-2.10 (m, 2H), 2.10-1.98 (m, 7H), 1.90-1.80 (m, 1H), 1.80-1.70 (m, 1H), 1.40-1.30 (m, 1H). | 509.25 | |
N-(4-{4-胺基-5-[(4R)-4-[(2R)-2-乙炔基吡咯啶-1-羰基]環己-1-烯-1-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1H NMR (400 MHz, 甲醇-d4) δ 8.14 (d, J = 3.4 Hz, 1H), 7.79 (dq, J = 9.1, 2.5 Hz, 2H), 7.47 (dd, J = 8.7, 2.1 Hz, 2H), 5.93 (d, J = 9.6 Hz, 1H), 5.85 (dt, J = 2.0, 1.0 Hz, 1H), 5.59 - 5.54 (m, 1H), 4.77 - 4.71 (m, 1H), 3.70 - 3.65 (m, 3H), 3.65 - 3.55 (m, 1H), 3.55 - 3.40 (m, 1H), 3.20 - 2.55 (m, 2H), 2.53 - 2.30 (m, 2H), 2.20-2.10 (m, 2H) 2.10 - 1.93 (m,7H), 1.90-1.60 (m, 2H), 1.40 - 1.30 (m,1H). | 509.25 | |
N-(4-{4-胺基-7-甲基-5-[(4S)-4-{2-氧雜-5-氮雜螺[3.4]辛烷-5-羰基}環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-6-基}苯基)-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.11 (s, 1H), 7.84 - 7.78 (m, 2H), 7.47 - 7.38 (m, 2H), 6.48 (s, 2H), 5.83- 5.79 (m, 2H), 5.56 (d,J = 2.0 Hz, 1H), 5.33-5.28 (m, 2H), 4.18 (dd,J = 4.9, 3.0 Hz, 2H), 3.58 (s, 3H), 3.55 (dt,J = 9.6, 6.1 Hz, 1H), 3.46 (dt,J = 9.6, 6.8 Hz, 1H), 2.85 (s, 1H), 2.40-2.30 (m,1H), 2.30-2.10 (m,3H),2.0-1.80 (m,5H),1.80-1.50 (m,4H). | 527.30 | |
N-{4-[4-胺基-7-甲基-5-(4-{7-氧雜-1-氮雜螺[4.4]壬烷-1-羰基}環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.13 (s, 1H), 7.85 - 7.72 (m, 2H), 7.52 - 7.42 (m, 2H), 5.93 (s, 1H), 5.85 (s, 1H), 5.57 (s, 1H), 4.15 (q,J = 7.7 Hz, 1H), 3.99 (d,J = 8.1 Hz, 1H), 3.92 (td,J = 7.8, 5.1 Hz, 1H), 3.66 (s, 5H), 3.53 - 3.43 (m, 1H), 2.87 (t,J = 6.0 Hz, 1H), 2.73 (ddd,J = 12.6, 7.9, 5.1 Hz, 1H), 2.38 (q,J = 19.0 Hz, 2H), 2.13 - 1.90 (m, 8H), 1.89 - 1.66 (m, 4H), 1.31 (s, 1H). | 541.25 | |
N-{4-[4-胺基-7-甲基-5-(4-{7-氧雜-1-氮雜螺[4.4]壬烷-1-羰基}環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.13 (s, 1H), 7.82 - 7.73 (m, 2H), 7.53 - 7.41 (m, 2H), 5.93 (s, 1H), 5.85 (s, 1H), 5.57 (s, 1H), 4.15 (q,J = 7.7 Hz, 1H), 3.99 (d,J = 8.1 Hz, 1H), 3.92 (td,J = 7.8, 5.1 Hz, 1H), 3.66 (s, 5H), 3.53 - 3.41 (m, 1H), 2.96 - 2.81 (m, 1H), 2.73 (ddd,J = 12.6, 7.9, 5.1 Hz, 1H), 2.38 (q,J = 19.0 Hz, 2H), 2.07 (d,J = 1.2 Hz, 3H), 2.02 (q,J = 8.5, 7.3 Hz, 3H), 1.98 - 1.81 (m, 2H), 1.81 - 1.71 (m, 4H), 1.31 (s, 1H). | 541.25 | |
N-(4-(4-胺基-5-(6,6-二氟-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.16 (s, 1H), 7.76 (d,J = 8.4 Hz, 2H), 7.40 (d,J = 8.4 Hz, 2H), 6.32 (s, 1H), 5.87 - 5.82 (m, 1H), 5.59 - 5.54 (m, 1H), 5.20 (s, 1H), 3.63 (s, 3H), 3.59 (s, 2H), 3.44 (t,J = 6.9 Hz, 2H), 3.40 (s, 1H), 2.47 (s, 2H), 2.31 (s, 1H), 2.09 - 1.97 (m, 5H), 2.00 - 1.87 (m, 2H). | 521.30 | |
N-[4-(4-胺基-5-{4-[(2R)-2-乙炔基吡咯啶-1-羰基]環己-1-烯-1-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基]-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.14 (d,J = 3.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.47 (dt,J = 8.7, 2.1 Hz, 2H), 5.93 (d,J = 9.7 Hz, 1H), 5.85 (dt,J = 2.1, 1.0 Hz, 1H), 5.57 (d,J = 1.8 Hz, 1H), 4.74 (dd,J = 24.7, 7.0 Hz, 1H), 3.67 (d,J = 1.8 Hz, 3H), 3.59 (t,J = 8.8 Hz, 1H), 3.45 - 3.35 (m, 1H), 3.20 - 2.55 (m, 2H), 2.50 - 2.30 (m, 2H), 2.25 - 1.98 (m, 9H), 1.90-1.70 (m, 2H). | 509.25 | |
N-(4-(4-胺基-5-((S)-4-((S)-2-乙炔基吡咯啶-1-羰基)環己-1-烯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.14 (d,J = 3.4 Hz, 1H), 7.82 - 7.74 (m, 2H), 7.47 (dt,J = 8.7, 2.1 Hz, 2H), 5.93 (d,J = 9.7 Hz, 1H), 5.85 (dt,J = 2.1, 1.0 Hz, 1H), 5.57 (d,J = 1.8 Hz, 1H), 4.74 (dd,J = 24.7, 7.0 Hz, 1H), 3.67 (d,J = 1.8 Hz, 3H), 3.59 (t,J = 8.8 Hz, 1H), 3.45 - 3.35 (m, 1H), 3.20 - 2.55 (m, 2H), 2.50 - 2.30 (m, 2H), 2.25 - 1.98 (m, 9H), 1.90-1.70 (m, 2H). | 509.25 | |
N-{4-[4-胺基-7-甲基-5-(4-{2-氧雜-5-氮雜螺[3.4]辛烷-5-羰基}環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.12 (s, 1H), 7.84 - 7.77 (m, 2H), 7.47 - 7.40 (m, 2H), 6.52 (s, 1H), 5.83 (s, 1H), 5.78 (s, 1H), 5.56 (t,J = 1.5 Hz, 1H), 5.33 (d,J = 4.9 Hz, 1H), 5.28 (d,J = 4.9 Hz, 1H), 4.18 (dd,J = 4.9, 3.1 Hz, 2H), 3.59 (s, 3H), 3.57 - 3.50 (m, 1H), 3.46 (dt,J = 9.7, 6.8 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.33 (s, 1H), 2.30 - 2.14 (m, 3H), 1.97 (t,J = 1.2 Hz, 3H), 1.92 -1.86 (m, 2H), 1.72 (q,J = 6.7 Hz, 2H), 1.64 (s, 2H). | 527.25 | |
N-{4-[4-胺基-7-甲基-5-(4-{7-氧雜-1-氮雜螺[4.4]壬烷-1-羰基}環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.31 (s, 1H), 7.72 - 7.65 (m, 2H), 7.62 (s, 1H), 7.47 - 7.39 (m, 2H), 6.35-5.95 (m, 2H), 5.90-5.75 (s,1H), 5.65-5.45 (m,1H),4.13 (q,J = 8.0 Hz, 1H), 4.02 - 3.92 (m, 2H), 3.70 (s, 3H), 3.64 (t,J = 8.2 Hz, 1H), 3.55 - 3.45 (m, 1H), 3.43 (d,J = 8.0 Hz, 1H), 2.81 (s, 1H), 2.64 (ddd,J = 11.5, 7.5, 3.3 Hz, 1H), 2.51 (d,J = 18.0 Hz, 1H), 2.35 - 2.25 (m, 1H),2.15 - 2.10(m, 3H), 2.10-1.82 (m,6H), 1.80-1.70 (m,3H). | 541.30 | |
N-{4-[4-胺基-7-甲基-5-(4-{7-氧雜-1-氮雜螺[4.4]壬烷-1-羰基}環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基]苯基}-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.32 (s, 1H), 7.76 - 7.65 (m, 3H), 7.46 - 7.39 (m, 2H), 5.96- 5.87 (m, 3H), 5.54 (d,J = 1.7 Hz, 1H), 4.18 (q,J = 8.0 Hz, 1H), 3.98 (td,J = 8.0, 3.7 Hz, 1H), 3.88 (d,J = 8.0 Hz, 1H), 3.70 (s, 3H), 3.55 (dtd,J = 15.7, 10.0, 9.6, 6.8 Hz, 2H), 3.42 (d,J = 8.0 Hz, 1H), 2.77 (tt,J = 7.9, 3.8 Hz, 2H), 2.59 - 2.40 (m, 1H), 2.40 - 2.25 (m, 1H),2.10 - 2.15 (m, 3H), 2.10 - 1.82 (m, 6H), 1.80 - 1.72 (m, 3H). | 541.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 8.10 (s, 1H), 7.78 (d,J = 8.7 Hz, 2H), 7.49 - 7.42 (m, 2H), 6.47 (dd,J = 17.0, 10.1 Hz, 2H), 6.29 (dd,J = 17.0, 2.0 Hz, 1H), 5.79 (dd,J = 10.1, 2.1 Hz, 1H), 5.76 (s, 1H), 3.60 (s, 3H), 3.54 - 3.47 (m, 1H), 3.47 - 3.37 (m, 1H), 3.30 - 3.20 (m, 2H), 2.83 (t,J = 5.9 Hz, 1H), 2.26 (s, 2H), 1.91 - 1.81 (m, 4H), 1.76 (q,J = 6.6 Hz, 2H), 1.63 (d,J = 6.2 Hz, 2H). | 471.20 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 8.09 (s, 1H), 7.82 - 7.75 (m, 2H), 7.48 - 7.42 (m, 2H), 6.47 (dd,J = 17.0, 10.1 Hz, 2H), 6.29 (dd,J = 17.0, 2.0 Hz, 1H), 5.79 (dd,J = 10.1, 2.0 Hz, 1H), 5.76 (s, 1H), 3.58 (s, 3H), 3.56 - 3.47 (m, 1H), 3.47 - 3.37 (m, 1H), 3.31 - 3.20 (m, 2H), 2.82 (t,J = 5.9 Hz, 1H), 2.26 (s, 2H), 1.90 - 1.81 (m, 4H), 1.76 (p,J = 6.6 Hz, 2H), 1.63 (d,J = 5.7 Hz, 2H). | 471.20 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基磺醯基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.13 (s, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.49 - 7.37 (m, 2H), 6.42 (s, 1H), 5.84 (s, 1H), 5.71 (d, J = 4.8 Hz, 1H), 5.55 (t, J = 1.5 Hz, 1H), 3.62 (s, 1H), 3.58 (s, 3H), 3.42 - 3.22 (m, 4H), 2.47 - 2.31 (m, 2H), 2.10 (d, J = 12.2 Hz, 1H), 2.03 - 1.90 (m, 5H), 1.90 - 1.75 (m, 4H), 1.63 (s, 1H). | 521.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基磺醯基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.13 (s, 1H), 7.81 (d, J = 2.0 Hz, 2H), 7.49 - 7.37 (m, 2H), 6.42 (s, 1H), 5.84 (s, 1H), 5.71 (d, J = 4.8 Hz, 1H), 5.55 (t, J = 1.5 Hz, 1H), 3.62 (s, 1H), 3.58 (s, 3H), 3.42 - 3.22 (m, 4H), 2.47 - 2.31 (m, 2H), 2.10 (d, J = 12.2 Hz, 1H), 2.03 - 1.90 (m, 5H), 1.90 - 1.75 (m, 4H), 1.63 (s, 1H). | 521.25 | |
N-(4-(4-胺基-5-(4-(環戊基磺醯基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.33 (s, 1H), 7.69 (t,J = 8.4 Hz, 3H), 7.38 (d,J = 8.2 Hz, 2H), 5.92 (s, 1H), 5.87 (s, 1H), 5.55 (s, 3H), 3.68 (s, 3H), 3.50 (m,J = 8.2 Hz, 1H), 3.20 (d,J = 7.6 Hz, 1H), 2.73 (s, 1H), 2.66 (s, 1H), 2.31 (d,J = 15.8 Hz, 1H), 2.12 (s, 3H), 2.01 (d,J = 19.2 Hz, 6H), 1.85 (s, 3H), 1.70 (d,J = 8.4 Hz, 2H). | 520.25 | |
(S)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環戊基環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.11 (s, 1H), 7.80 (t,J = 7.9 Hz, 3H), 7.43 (d,J = 8.6 Hz, 2H), 6.52 (s, 1H), 5.83 (s, 1H), 5.78 (s, 1H), 5.56 (s, 1H), 3.98 (q,J = 6.9 Hz, 1H), 3.57 (s, 3H), 2.45 (s, 1H), 2.28 (s, 1H), 2.21 (s, 1H), 1.98 (s, 3H), 1.88 (s, 2H), 1.76 (dt,J = 12.8, 6.6 Hz, 2H), 1.62 (dd,J = 12.4, 5.7 Hz, 2H), 1.47 (q,J = 6.8 Hz, 2H), 1.39 - 1.31 (m, 1H), 1.34 - 1.22 (m, 1H). | 499.25 | |
(R)-4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環戊基環己-3-烯-1-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (s, 1H), 8.11 (s, 1H), 7.80 (t,J = 7.9 Hz, 3H), 7.46 - 7.39 (m, 2H), 6.52 (s, 1H), 5.83 (s, 1H), 5.78 (s, 1H), 5.56 (s, 1H), 3.98 (q,J = 6.8 Hz, 1H), 3.57 (s, 3H), 2.44 (s, 1H), 2.28 (s, 1H), 2.21 (s, 1H), 1.98 (d,J = 1.2 Hz, 3H), 1.88 (s, 2H), 1.76 (dt,J = 12.5, 6.5 Hz, 2H), 1.61 (dt,J = 13.2, 6.0 Hz, 3H), 1.47 (q,J = 7.0 Hz, 2H), 1.35 (s, 2H), 1.31 (dd,J = 13.2, 6.9 Hz, 1H). | 499.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(3,3-二氟環丁基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.47 (d,J = 6.8 Hz, 1H), 8.22 (s, 1H), 7.76 - 7.69 (m, 2H), 7.62 (d,J = 7.9 Hz, 1H), 7.35 - 7.27 (m, 2H), 6.93 (d,J = 1.5 Hz, 1H), 6.87 (dd,J = 7.8, 1.5 Hz, 1H), 6.01 (s, 1H), 5.81 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.71 (s, 3H), 3.61 (s, 3H), 3.00 - 2.85 (m, 2H), 2.82 - 2.68 (m, 2H), 2.08 (s, 1H), 1.96 (d,J = 1.2 Hz, 3H). | 547.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環丁基-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.23 (d,J = 11.7 Hz, 2H), 7.76 - 7.68 (m, 2H), 7.60 (d,J = 7.8 Hz, 1H), 7.34 - 7.26 (m, 2H), 6.92 (d,J = 1.5 Hz, 1H), 6.85 (dd,J = 7.9, 1.5 Hz, 1H), 6.01 (s, 1H), 5.81 (d,J = 1.3 Hz, 1H), 5.57 - 5.51 (m, 1H), 4.39 (h,J = 8.2 Hz, 1H), 3.72 (s, 3H), 3.60 (s, 3H), 2.21 (dtt,J = 8.9, 6.9, 3.0 Hz, 2H), 2.06 - 1.93 (m, 5H), 1.66 (tt,J = 10.5, 6.3 Hz, 2H). | 511.45 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1s,3s)-3-氟環丁基)-2-(甲氧基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.65 (d,J = 6.9 Hz, 1H), 8.21 (s, 1H), 7.71 (d,J = 8.5 Hz, 2H), 7.40 (d,J = 7.8 Hz, 1H), 7.35 (d,J = 1.8 Hz, 1H), 7.29 (d,J = 8.5 Hz, 2H), 7.20 (dd,J = 7.9, 1.8 Hz, 1H), 5.85 (s, 1H), 5.79 (s, 1H), 5.54 (s, 1H), 5.32 - 5.14 (m, 1H), 4.51 (s, 2H), 4.45 (s, 1H), 3.60 (s, 3H), 3.16 (s, 3H), 2.53 - 2.35 (m, 4H), 1.95 (s, 3H). | 543.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-(二氟甲氧基)-N-((1r,3r)-3-氟環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.62 (d,J = 7.0 Hz, 1H), 8.22 (s, 1H), 7.78 - 7.70 (m, 2H), 7.47 (d,J = 7.9 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.17 - 7.01 (m, 3H), 6.01 (s, 2H), 5.80 (d,J = 1.3 Hz, 1H), 5.55 (d,J = 1.7 Hz, 1H), 5.31 (ddd,J = 10.5, 6.4, 4.2 Hz, 1H), 5.17 (ddd,J = 11.0, 6.6, 4.3 Hz, 1H), 3.59 (s, 3H), 2.55 (dd,J = 9.2, 4.2 Hz, 1H), 2.51 - 2.29 (m, 2H), 1.95 (d,J = 1.2 Hz, 3H). | 565.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1r,3r)-3-氟環丁基)-2-(甲氧基甲基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.90 (s, 1H), 8.62 (d,J = 7.5 Hz, 1H), 8.21 (s, 1H), 7.71 (dd,J = 8.7, 2.2 Hz, 2H), 7.40 (d,J = 7.8 Hz, 1H), 7.35 (d,J = 1.8 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.20 (dd,J = 7.8, 1.8 Hz, 1H), 5.98 (s, 1H), 5.79 (s, 1H), 5.54 (d,J = 2.0 Hz, 1H), 4.92 - 4.78 (p,J = 6.8 Hz, 1H), 4.51 (s, 2H), 3.92 (p,J = 7.9 Hz, 1H), 3.60 (s, 3H), 3.16 (s, 3H), 2.73 (ddq,J = 12.7, 6.0, 3.1 Hz, 2H), 2.29 - 2.11 (m, 2H), 1.95 (d,J = 1.2 Hz, 3H). | 543.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1s,3s)-3-氟環丁基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.32 (d,J = 7.7 Hz, 1H), 8.21 (s, 1H), 7.72 (d,J = 8.3 Hz, 2H), 7.59 (d,J = 7.8 Hz, 1H), 7.30 (d,J = 8.7 Hz, 2H), 6.92 (s, 1H), 6.86 (d,J = 7.8 Hz, 1H), 6.01 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 5.02 - 4.65 (m, 1H), 3.96 (q,J = 8.0 Hz, 1H), 3.66 (d,J = 43.5 Hz, 6H), 2.72 (dd,J = 11.6, 5.5 Hz, 2H), 2.37 - 2.11 (m, 2H), 1.95 (s, 3H). | 529.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1r,3r)-3-氟環丁基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.32 (d,J = 7.7 Hz, 1H), 8.21 (s, 1H), 7.72 (d,J = 8.3 Hz, 2H), 7.59 (d,J = 7.8 Hz, 1H), 7.30 (d,J = 8.7 Hz, 2H), 6.92 (s, 1H), 6.86 (d,J = 7.8 Hz, 1H), 6.01 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 5.02 - 4.65 (m, 1H), 3.96 (q,J = 8.0 Hz, 1H), 3.66 (d,J = 43.5 Hz, 6H), 2.72 (dd,J = 11.6, 5.5 Hz, 2H), 2.37 - 2.11 (m, 2H), 1.95 (s, 3H). | 529.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基-N-(1-(甲氧基甲基)環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.40 (s, 1H), 8.14 (s, 1H), 7.75 (t,J = 8.1 Hz, 3H), 7.35 - 7.27 (m, 2H), 7.04- 6.99 (m, 1H), 6.86 (dd,J = 7.9, 1.5 Hz, 1H), 5.81 (s, 1H), 5.55 (d,J = 1.6 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 3.58 (s, 2H), 3.33 (s,3H),2.43 - 2.33 (m, 2H), 2.07 (s, 2H), 1.95 (d,J = 1.5 Hz, 3H), 1.93 - 1.72 (m, 2H). | 555.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-異丁基-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.21 (s, 1H), 8.10 (t,J = 5.9 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.65 (d,J = 7.9 Hz, 1H), 7.34 - 7.27 (m, 2H), 6.94 (d,J = 1.5 Hz, 1H), 6.86 (dd,J = 7.9, 1.5 Hz, 1H), 6.02 (s, 1H), 5.81 (s, 1H), 5.54 (d,J = 1.9 Hz, 1H), 3.72 (s, 3H), 3.60 (s, 3H), 3.10 (t,J = 6.4 Hz, 2H), 1.95 (t,J = 1.2 Hz, 3H), 1.81 (hept,J = 6.7 Hz, 1H), 0.89 (d,J = 6.7 Hz, 6H). | 513.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-(二氟甲氧基)-N-((1s,3s)-3-氟環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.58 (d,J = 7.7 Hz, 1H), 8.22 (s, 1H), 7.74-7.73 (d,J = 6.8 Hz, 2H), 7.46 (d,J = 7.8 Hz, 1H), 7.33 - 7.25 (m, 2H), 7.13-6.84 (dd,J = 7.9, 1.6 Hz, 3H), 6.03 (s, 1H), 5.80 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.78 (p,J = 7.0 Hz, 1H), 3.93 (q,J = 8.0 Hz, 1H), 3.59 (s, 3H), 2.73 (dq,J = 9.6, 3.0 Hz, 1H), 2.27 - 2.06 (m, 2H), 1.95 (t,J = 1.2 Hz, 3H), | 565.20 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-環丙氧基-N-((1s,3s)-3-氟環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 (s, 1H), 8.16 (d,J = 7.0 Hz, 1H), 7.81 - 7.66 (m, 2H), 7.55 (d,J = 7.9 Hz, 1H), 7.39 - 7.28 (m, 2H), 7.23 (d,J = 1.6 Hz, 1H), 6.91 (dd,J = 7.8, 1.5 Hz, 1H), 5.85 - 5.75 (m, 1H), 5.58 - 5.51 (m, 1H), 5.23 (dddd,J = 56.7, 10.2, 6.5, 3.8 Hz, 1H), 4.48 (q,J = 7.7 Hz, 1H), 3.73 (tt,J = 6.1, 3.0 Hz, 1H), 3.61 (s, 3H), 2.48 - 2.38 (m, 2H), 2.38 - 2.28 (m, 2H), 1.96 (t,J = 1.3 Hz, 3H), 0.66 (t,J = 5.8 Hz, 2H), 0.61 (d,J = 3.2 Hz, 2H). | 555.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-環丙氧基-N-((1r,3r)-3-氟環丁基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 (s, 1H), 8.12 (d,J = 7.7 Hz, 1H), 7.82 - 7.67 (m, 2H), 7.54 (d,J = 7.8 Hz, 1H), 7.34 - 7.26 (m, 2H), 7.22 (d,J = 1.5 Hz, 1H), 6.90 (dd,J = 7.9, 1.5 Hz, 1H), 5.81 (t,J = 1.1 Hz, 1H), 5.54 (t,J = 1.4 Hz, 1H), 4.84 (dp,J = 56.8, 6.8 Hz, 1H), 3.92 (dt,J = 15.3, 7.6 Hz, 1H), 3.72 (dq,J = 6.2, 3.0 Hz, 1H), 3.61 (s, 3H), 2.81 - 2.64 (m, 2H), 2.29 - 2.03 (m, 2H), 1.95 (t,J = 1.2 Hz, 3H), 0.64 (dd,J = 24.4, 4.7 Hz, 4H). | 555.30 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-氟環丁基)甲基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 8.24 (d,J = 18.2 Hz, 2H), 7.75 - 7.68 (m, 3H), 7.33 - 7.27 (m, 2H), 6.95 (d,J = 1.4 Hz, 1H), 6.87 (dd,J = 7.9, 1.5 Hz, 1H), 6.04 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 3.73 (s, 3H), 3.71 - 3.60 (m, 2H), 3.60 (s, 3H), 2.26 - 2.13 (m, 4H), 2.08 (s, 1H), 1.95 (t,J = 1.2 Hz, 3H), 1.75 (dd,J = 11.4, 6.3 Hz, 1H), 1.53 (q,J = 8.8 Hz, 1H). | 543.30 | |
6-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-(環丁基甲基)-2-甲氧基菸鹼醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 8.18 (d, J = 11.9 Hz, 2H), 7.86 - 7.69 (m, 3H), 7.40 - 7.28 (m, 4H), 6.55 (d, J = 7.9 Hz, 1H), 5.83 (s, 1H), 5.56 (d, J = 1.9 Hz, 1H), 4.03 (s, 3H), 3.55 (s, 3H), 3.28 (d, J = 6.3 Hz, 2H), 2.53 (s, 1H), 1.82 (q, J = 6.7, 6.2 Hz, 2H), 1.77 - 1.67 (m, 2H). | 526.30 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氯苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.12 (s, 1H), 8.11 (d,J = 3.9 Hz, 1H), 8.07 (d,J = 2.0 Hz, 1H), 7.74 (ddd,J = 8.4, 3.5, 2.1 Hz, 1H), 7.37 (dd,J = 8.4, 6.3 Hz, 1H), 6.55 (d,J = 47.7 Hz, 2H), 5.87 (s, 1H), 5.75 - 5.63 (m, 1H), 5.60 (s, 1H), 3.51 - 3.41 (m, 2H), 3.40 (d,J = 2.0 Hz, 3H), 3.27 (ddt,J = 12.1, 8.4, 4.6 Hz, 2H), 2.75 (qt,J = 7.7, 3.4 Hz, 1H), 2.34 - 2.03 (m, 3H), 1.97 (s, 4H), 1.84 (qd,J = 6.7, 3.3 Hz, 2H), 1.76 (qd,J = 6.7, 2.2 Hz, 2H), 1.71 - 1.45 (m, 2H). | 519.20 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.15 (s, 1H), 8.12 (s, 1H), 7.83 (dd,J = 12.6, 2.0 Hz, 1H), 7.59 (dd,J = 8.4, 2.1 Hz, 1H), 7.37 (t,J = 8.5 Hz, 1H), 6.57 (s, 2H), 5.86 (s, 1H), 5.69 (s, 1H), 5.60 (s, 1H), 3.55 - 3.40 (m, 5H), 3.28 (d,J = 6.5 Hz, 1H), 2.79 (t,J = 6.1 Hz, 1H), 2.21 (d,J = 17.2 Hz, 2H), 1.97 (d,J = 1.3 Hz, 3H), 1.81 (dq,J = 35.8, 6.8 Hz, 4H), 1.63 (s, 2H). | 503.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.10 (s, 1H), 7.71 (t,J = 2.7 Hz, 1H), 7.62 (ddd,J = 8.0, 5.6, 2.2 Hz, 1H), 7.18 (dd,J = 8.3, 6.6 Hz, 1H), 6.48 (d,J = 17.0 Hz, 2H), 5.91 - 5.79 (m, 1H), 5.66 (ddt,J = 14.5, 4.1, 2.2 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.56 - 3.39 (m, 2H), 3.34 (s, 3H), 3.27 (q,J = 6.9 Hz, 2H), 2.73 (p,J = 6.3 Hz, 1H), 2.21 (q,J = 15.7, 12.1 Hz, 2H), 2.06 (s, 3H), 2.01 - 1.80 (m, 7H), 1.80 - 1.70 (m, 2H), 1.56 (q,J = 7.9, 7.0 Hz, 2H). | 499.35 | |
(R)-N-(4-(5-(4-(2-氧雜-5-氮雜螺[3.4]辛烷-5-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.14 (s, 1H), 7.84 (dd,J = 12.6, 2.0 Hz, 1H), 7.59 (dd,J = 8.4, 2.0 Hz, 1H), 7.37 (t,J = 8.5 Hz, 1H), 6.55 (s, 2H), 5.86 (t,J = 1.1 Hz, 1H), 5.71 (s, 1H), 5.60 (d,J = 1.9 Hz, 1H), 5.30 (dd,J = 13.7, 4.9 Hz, 2H), 4.19 (d,J = 4.9 Hz, 2H), 3.60 - 3.43 (m, 5H), 2.97 - 2.78 (m, 1H), 2.44 - 2.07 (m, 4H), 1.98 (t,J = 1.2 Hz, 5H), 1.70 (dq,J = 19.5, 7.6, 7.1 Hz, 4H). | 545.25 | |
(S)-N-(4-(5-(4-(2-氧雜-5-氮雜螺[3.4]辛烷-5-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.14 (s, 1H), 7.84 (dd,J = 12.6, 2.0 Hz, 1H), 7.59 (dd,J = 8.5, 2.0 Hz, 1H), 7.37 (t,J = 8.5 Hz, 1H), 6.55 (s, 2H), 5.86 (t,J = 1.0 Hz, 1H), 5.71 (s, 1H), 5.60 (d,J = 1.8 Hz, 1H), 5.30 (dd,J = 13.7, 4.9 Hz, 2H), 4.19 (d,J = 4.9 Hz, 2H), 3.61 - 3.40 (m, 5H), 2.93 - 2.78 (m, 1H), 2.37 - 2.13 (m, 4H), 1.98 (t,J = 1.2 Hz, 5H), 1.70 (td,J = 15.9, 14.6, 7.9 Hz, 4H). | 545.25 | |
(R)-N-(4-(5-(4-(2-氧雜-5-氮雜螺[3.4]辛烷-5-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.11 (s, 1H), 7.73-7.70 (m, 1H), 7.63-7.62 (m, 1H), 7.20-7.17 (m, 1H), 6.51 (d, J = 28.6 Hz, 2H), 5.83 (s, 1H), 5.68 (d, J = 10.9 Hz, 1H), 5.55 (t, J = 1.5 Hz, 1H), 5.31-5.26 (m, 2H), 4.18-4.17 (m, 2H), 3.54 - 3.47 (m, 1H), 3.47 - 3.38 (m, 1H), 3.34 (s, 3H), 2.74 (d, J = 12.8 Hz, 1H), 2.35- 2.24 (m, 1H), 2.23 - 2.16 (m, 3H), 2.06 (s, 3H), 1.97 (t, J = 1.2 Hz, 4H), 1.93 - 1.79 (m, 1H), 1.70 (p, J = 6.7 Hz, 2H), 1.58 (d, J = 5.2 Hz, 2H). | 541.35 | |
(S)-N-(4-(5-(4-(2-氧雜-5-氮雜螺[3.4]辛烷-5-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.11 (s, 1H), 7.73-7.70 (m, 1H), 7.63-7.62 (m, 1H), 7.20-7.17 (m, 1H), 6.51 (d, J = 28.6 Hz, 2H), 5.83 (s, 1H), 5.68 (d, J = 10.9 Hz, 1H), 5.55 (t, J = 1.5 Hz, 1H), 5.31-5.26 (m, 2H), 4.18-4.17 (m, 2H), 3.54 - 3.47 (m, 1H), 3.47 - 3.38 (m, 1H), 3.34 (s, 3H), 2.74 (d, J = 12.8 Hz, 1H), 2.35- 2.24 (m, 1H), 2.23 - 2.16 (m, 3H), 2.06 (s, 3H), 1.97 (t, J = 1.2 Hz, 4H), 1.93 - 1.79 (m, 1H), 1.70 (p, J = 6.7 Hz, 2H), 1.58 (d, J = 5.2 Hz, 2H). | 541.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.15 (s, 1H), 8.12 (s, 1H), 7.83 (dd,J = 12.5, 2.0 Hz, 1H), 7.59 (dd,J = 8.5, 2.0 Hz, 1H), 7.37 (t,J = 8.4 Hz, 1H), 6.60 (s, 2H), 5.86 (s, 1H), 5.69 (s, 1H), 5.60 (s, 1H), 3.55 - 3.40 (m, 5H), 3.28 (d,J = 6.5 Hz, 1H), 2.83 - 2.76 (m, 1H), 2.21 (d,J = 16.9 Hz, 2H), 1.98 (t,J = 1.2 Hz, 3H), 1.87 (p,J = 6.8 Hz, 2H), 1.76 (p,J = 6.8 Hz, 2H), 1.63 (s, 2H). | 503.25 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.86 (s, 1H), 8.10 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.61 (t, J = 8.2, 2.3 Hz, 1H), 7.18 (t, J = 8.3, 6.6 Hz, 1H), 6.50 (s, 2H), 5.87 - 5.78 (m, 1H), 5.64 (s, 1H), 5.54 (d, J = 1.8 Hz, 1H), 3.52 - 3.38 (m, 2H), 3.33 - 3.22 (m, 5H), 2.73 (t, J = 6.1 Hz, 1H), 2.25 (t, J = 42.5, 23.2 Hz, 2H), 2.06 (s, 3H), 1.97 (d, J = 1.2 Hz, 4H), 1.93 - 1.80 (m, 3H), 1.75 (p, J = 6.7 Hz, 2H), 1.56 (d, J = 6.1 Hz, 2H). | 499.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.12 (s, 1H), 7.80 - 7.72 (m, 2H), 7.32 - 7.24 (m, 2H), 5.86 - 5.78 (m, 2H), 5.76 (s, 2H), 5.56 - 5.51 (m, 1H), 3.58 (s, 3H), 3.39 (s, 4H), 2.74 (d,J = 16.0 Hz, 1H), 2.05 - 1.82 (m, 7H), 1.77 - 1.55 (m, 5H), 1.16 (s, 3H). | 499.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 8.13 (s, 1H), 7.80 - 7.72 (m, 2H), 7.32 - 7.24 (m, 2H), 6.05 - 5.65 (m, 3H), 5.56 - 5.51 (m, 1H), 3.59 (s, 3H), 3.41 (s, 4H), 2.75 (d,J = 16.7 Hz, 1H), 2.08 - 1.89 (m, 7H), 1.75 (s, 4H), 1.63 (dd,J = 12.6, 6.4 Hz, 1H), 1.16 (s, 3H). | 499.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.08 (s, 1H), 7.84 - 7.76 (m, 2H), 7.45 - 7.37 (m, 2H), 6.53 (s, 2H), 5.83 (s, 1H), 5.78 (d,J = 4.5 Hz, 1H), 5.56 (t,J = 1.5 Hz, 1H), 3.57 (s, 4H), 3.33 (s, 3H), 2.77 (d,J = 14.8 Hz, 1H), 2.11 (d,J = 13.6 Hz, 1H), 1.98 (d,J = 1.2 Hz, 3H), 1.90 (d,J = 17.3 Hz, 1H), 1.77 (s, 6H), 1.44 (s, 1H), 1.21 (s, 3H). | 499.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-甲基-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.08 (s, 1H), 7.84 - 7.77 (m, 2H), 7.45 - 7.37 (m, 2H), 6.52 (s, 2H), 5.83 (t,J = 1.1 Hz, 1H), 5.81 - 5.75 (m, 1H), 5.56 (t,J = 1.5 Hz, 1H), 3.57 (s, 4H), 3.50 (s, 3H), 2.82 - 2.73 (m, 1H), 2.12 (d,J = 13.7 Hz, 1H), 1.97 (t,J = 1.2 Hz, 3H), 1.90 (d,J = 17.1 Hz, 1H), 1.77 (s, 6H), 1.70 - 1.37 (m, 1H), 1.21 (s, 3H). | 499.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氯苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.13 (s, 1H), 8.15 - 8.03 (m, 2H), 7.74 (ddd,J = 8.4, 3.6, 2.2 Hz, 1H), 7.37 (dd,J = 8.4, 6.4 Hz, 1H), 6.55 (d,J = 48.7 Hz, 2H), 5.87 (s, 1H), 5.78 - 5.60 (m, 2H), 3.54 - 3.41 (m, 2H), 3.40 (d,J = 2.0 Hz, 3H), 3.27 (ddt,J = 12.1, 8.4, 4.5 Hz, 2H), 2.75 (tt,J = 9.5, 4.2 Hz, 1H), 2.36 - 2.03 (m, 3H), 1.97 (s, 4H), 1.84 (qd,J = 6.7, 3.3 Hz, 2H), 1.76 (qd,J = 6.8, 2.2 Hz, 2H), 1.70 - 1.44 (m, 2H). | 519.20 | |
(R)-N-(4-(5-(4-(6-氮雜螺[3.4]辛烷-6-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, 甲醇-d4) 8.14 (s, 1H), 7.81 -7.75 (m, 2H), 7.49 - 7.43 (m, 2H), 5.93 (s, 1H), 5.85 (t, J = 0.9 Hz, 1H), 5.57 (d, J = 1.7 Hz, 1H), 3.66 (s, 3H), 3.64 - 3.49 (m, 2H), 3.28 - 3.17 (m, 2H), 2.88 - 2.80 (m, 1H), 2.43 (t, J = 11.5 Hz, 1H), 2.35 (s, 1H), 2.16 - 1.98 (m, 7H), 1.96 - 1.86 (s, 1H), 1.86 - 1.68 (s, 7H), 1.28 (s, 1H). | 525.30 | |
(S)-N-(4-(5-(4-(6-氮雜螺[3.4]辛烷-6-羰基)環己-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, 甲醇-d4) 8.14 (s, 1H), 7.82 - 7.74 (m, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.93 (s, 1H), 5.85 (t, J = 1.0 Hz, 1H), 5.57 (d, J = 1.5 Hz, 1H), 3.66 (s, 3H), 3.64 - 3.50 (m, 2H), 3.28 - 3.17 (m, 2H), 2.84 (t, J = 6.2 Hz, 1H), 2.42 (s, 1H), 2.35 (s, 1H), 2.16 - 1.98 (m, 7H), 1.96 - 1.85 (m, 1H), 1.81 (q, J = 6.6 Hz, 2H), 1.76 (s, 5H), 1.28 (s, 1H). | 525.30 | |
N-(4-(4-胺基-5-(4-(吲哚啉-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.22 (s, 1H), 7.73 (d,J = 8.5 Hz, 2H), 7.55 (d,J = 7.7 Hz, 2H), 7.35 - 7.24 (m, 5H), 7.16 (s, 1H), 7.02 (s, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 4.05 (t,J = 8.3 Hz, 2H), 3.62 (s, 3H), 3.08 (t,J = 8.2 Hz, 2H), 1.95 (d,J = 1.3 Hz, 3H). | 529.25 | |
(S)-N-(4-(4-胺基-5-(4-(吲哚啉-1-羰基)環己-1-烯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.13 (d,J = 8.7 Hz, 2H), 7.82 (d,J = 8.6 Hz, 2H), 7.52 - 7.39 (m, 2H), 7.23 (d,J = 7.4 Hz, 1H), 7.14 (t,J = 7.7 Hz, 1H), 6.99 (t,J = 7.4 Hz, 1H), 6.57 (s, 2H), 5.83 (d,J = 7.2 Hz, 2H), 5.55 (s, 1H), 4.32 - 4.02 (m, 2H), 3.59 (s, 3H), 3.14 (t,J = 8.5 Hz, 2H), 3.01 (s, 1H), 2.37 (s, 2H), 1.98 (t,J = 1.2 Hz, 5H), 1.75 (s, 2H). | 533.25 | |
(R)-N-(4-(4-胺基-5-(4-(吲哚啉-1-羰基)環己-1-烯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.13 (d,J = 8.7 Hz, 2H), 7.82 (d,J = 8.6 Hz, 2H), 7.52 - 7.39 (m, 2H), 7.23 (d,J = 7.4 Hz, 1H), 7.14 (t,J = 7.7 Hz, 1H), 6.99 (t,J = 7.4 Hz, 1H), 6.57 (s, 2H), 5.83 (d,J = 7.2 Hz, 2H), 5.55 (s, 1H), 4.32 - 4.02 (m, 2H), 3.59 (s, 3H), 3.14 (t,J = 8.5 Hz, 2H), 3.01 (s, 1H), 2.37 (s, 2H), 1.98 (t,J = 1.2 Hz, 5H), 1.75 (s, 2H). | 533.30 | |
N-(4-(4-胺基-7-甲基-5-((S)-4-((R)-2-甲基哌啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (s, 1H), 7.81 (d,J = 8.5 Hz, 2H), 7.43 (d,J = 8.3 Hz, 2H), 6.54 (s, 2H), 5.83 (s, 1H), 5.79 - 5.71 (m, 1H), 5.55 (s, 1H), 4.74 (s, 1H), 4.30 (s, 1H), 3.58 (s, 3H), 3.05 (dd,J = 31.8, 9.0 Hz, 2H), 2.36 - 2.11 (m, 2H), 1.97 (s, 3H), 1.87 - 1.70 (m, 2H), 1.72 - 1.34 (m, 7H), 1.35 - 1.12 (m, 2H), 1.05 (d,J = 6.9 Hz, 2H). | 513.30 | |
N-(4-(5-((S)-4-((1S,5R)-2-氮雜雙環[3.1.0]己烷-2-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.96 (d,J = 2.1 Hz, 1H), 8.10 (s, 1H), 7.81 (dt,J = 8.8, 2.2 Hz, 2H), 7.49 - 7.40 (m, 2H), 6.55 (s, 1H), 5.84 (t,J = 1.0 Hz, 1H), 5.78 (d,J = 9.9 Hz, 1H), 5.56 (d,J = 1.7 Hz, 1H), 3.80 - 3.65 (m, 1H), 3.59 (s, 4H), 3.17 (dd,J = 19.5, 9.2 Hz, 1H), 2.96 (dt,J = 12.5, 8.6 Hz, 1H), 2.44 - 2.20 (m, 2H), 2.19 - 1.99 (m, 1H), 1.98 (d,J = 1.2 Hz, 3H), 1.95 - 1.73 (m, 3H), 1.75 - 1.48 (m, 2H), 0.85 - 0.67 (m, 1H), 0.61 - 0.47 (m, 1H). | 497.25 | |
(S)-N-(4-(5-(4-(2-氮雜雙環[2.1.1]己烷-2-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.95 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.7, 2.2 Hz, 2H), 7.43 (dd, J = 8.7, 3.1 Hz, 2H), 6.55 (s, 1H), 5.83 (s, 1H), 5.77 (d, J = 6.0 Hz, 1H), 5.55 (s, 1H), 4.56 (dd, J = 21.1, 7.0 Hz, 1H), 3.58 (s, 3H), 3.51 - 3.41 (m, 1H), 3.24 (d, J = 4.3 Hz, 1H), 2.98 - 2.78 (m, 2H), 2.73 (q, J = 6.1 Hz, 1H), 2.37 - 2.13 (m, 2H), 1.98 (d, J = 1.2 Hz, 4H), 1.90 (s, 3H), 1.66 (d, J = 6.2 Hz, 1H), 1.58 (s, 1H), 1.38 - 1.19 (m, 2H). | 497.25 | |
N-(4-(4-胺基-5-((S)-4-((S)-2-(甲氧基甲基)吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.10 (d, J = 5.0 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.53 - 7.39 (m, 2H), 6.59 (s, 2H), 5.85 - 5.81 (m, 1H), 5.77 (s, 1H), 5.55 (d, J = 1.7 Hz, 1H), 4.08 (dd, J = 7.4, 3.7 Hz, 1H), 3.58 (s, 3H), 3.56 - 3.47 (m, 1H), 3.46 - 3.35 (m, 2H), 3.28 (d, J = 4.0 Hz, 1H), 3.18 (s, 3H), 2.93 - 2.81 (m, 1H), 2.39 - 2.27 (m, 0H), 2.20 (d, J = 18.4 Hz, 1H), 1.98 (t, J = 1.3 Hz, 3H), 1.95 - 1.74 (m, 6H), 1.63 (d, J = 18.3 Hz, 2H). | 529.30 | |
(S)-N-(4-(4-胺基-5-(4-(氮雜環庚烷-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.10 (s, 1H), 7.80 (d,J = 8.7 Hz, 2H), 7.43 (d,J = 8.6 Hz, 2H), 6.52 (s, 2H), 5.83 (s, 1H), 5.76 (s, 1H), 5.55 (s, 1H), 3.58 (s, 3H), 3.55 - 3.33 (m, 4H), 2.96 (s, 1H), 2.24 (t,J = 17.8 Hz, 2H), 1.97 (d,J = 1.3 Hz, 3H), 1.92 (s, 1H), 1.87 (s, 1H), 1.67 (d,J = 6.0 Hz, 2H), 1.61 (d,J = 6.5 Hz, 4H), 1.48 (s, 4H). | 513.35 | |
(R)-N-(4-(5-(4-(2-氮雜雙環[2.1.1]己烷-2-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.95 (d, J = 1.8 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 8.7, 2.2 Hz, 2H), 7.43 (dd, J = 8.7, 3.1 Hz, 2H), 6.55 (s, 1H), 5.83 (s, 1H), 5.77 (d, J = 6.0 Hz, 1H), 5.55 (s, 1H), 4.56 (dd, J = 21.1, 7.0 Hz, 1H), 3.58 (s, 3H), 3.51 - 3.41 (m, 1H), 3.24 (d, J = 4.3 Hz, 1H), 2.98 - 2.78 (m, 2H), 2.73 (q, J = 6.1 Hz, 1H), 2.37 - 2.13 (m, 2H), 1.98 (d, J = 1.2 Hz, 4H), 1.90 (s, 3H), 1.66 (d, J = 6.2 Hz, 1H), 1.58 (s, 1H), 1.38 - 1.19 (m, 2H). | 497.25 | |
N-(4-(4-胺基-5-((R)-4-((S)-2-(甲氧基甲基)吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.10 (d, J = 5.0 Hz, 1H), 7.84 - 7.76 (m, 2H), 7.53 - 7.39 (m, 2H), 6.59 (s, 2H), 5.85 - 5.81 (m, 1H), 5.77 (s, 1H), 5.55 (d, J = 1.7 Hz, 1H), 4.08 (dd, J = 7.4, 3.7 Hz, 1H), 3.58 (s, 3H), 3.56 - 3.47 (m, 1H), 3.46 - 3.35 (m, 2H), 3.28 (d, J = 4.0 Hz, 1H), 3.18 (s, 3H), 2.93 - 2.81 (m, 1H), 2.39 - 2.27 (m, 0H), 2.20 (d, J = 18.4 Hz, 1H), 1.98 (t, J = 1.3 Hz, 3H), 1.95 - 1.74 (m, 6H), 1.63 (d, J = 18.3 Hz, 2H). | 529.30 | |
(R)-N-(4-(4-胺基-5-(4-(氮雜環庚烷-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.93 (s, 1H), 8.11 (s, 1H), 7.80 (d,J = 8.7 Hz, 2H), 7.43 (d,J = 8.6 Hz, 2H), 6.57(s, 2H)5.83 (s, 1H), 5.76 (s, 1H), 5.55 (s, 1H), 3.58 (s, 3H), 3.53 - 3.41 (m, 2H), 3.44 - 3.30 (m, 2H), 2.96 (s, 1H), 2.39 - 2.04 (m, 2H), 1.97 (d,J = 1.3 Hz, 3H), 1.87 (s, 2H), 1.67 (d,J = 5.8 Hz, 2H), 1.60 (d,J = 6.5 H, 4H), 1.49(s, 4H). | 513.30 | |
N-(4-(4-胺基-7-甲基-5-((R)-4-((R)-2-甲基哌啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.09 (s, 1H), 7.87 - 7.75 (m, 2H), 7.51 - 7.29 (m, 2H), 6.57 (s, 2H), 5.83 (t,J = 1.1 Hz, 1H), 5.76 (t,J = 1.9 Hz, 1H), 5.55 (s, 1H), 4.77 (s, 1H), 4.28 - 3.67 (m, 1H), 3.58 (s, 3H), 3.15 - 2.58 (m, 2H), 2.42 - 2.11 (m, 2H), 1.97 (d,J = 1.2 Hz, 3H), 1.80 (d,J = 13.6 Hz, 2H), 1.68 - 1.41 (m, 7H), 1.11 (dd,J = 78.3, 6.8 Hz, 4H). | 513.30 | |
N-(4-(5-((R)-4-((1S,5R)-2-氮雜雙環[3.1.0]己烷-2-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (d,J = 1.0 Hz, 1H), 7.91 - 7.64 (m, 2H), 7.44 (dq,J = 8.7, 2.1, 1.5 Hz, 2H), 6.71 - 6.31 (m, 1H), 5.83 (s, 1H), 5.77 (d,J = 3.6 Hz, 1H), 5.56 (t,J = 1.4 Hz, 1H), 3.72 - 3.61 (m, 1H), 3.59 (d,J = 0.9 Hz, 3H), 3.49 (d,J = 5.9 Hz, 1H), 3.18 - 2.64 (m, 2H), 2.45 - 2.19 (m, 2H), 2.19 - 1.77 (m, 8H), 1.69 (dd,J = 13.2, 6.6 Hz, 2H), 1.55 (dd,J = 28.9, 6.9 Hz, 1H), 0.88 - 0.73 (m, 1H), 0.63 - 0.51 (m, 1H). | 497.25 | |
N-(4-(5-((S)-4-((1R,5S)-2-氮雜雙環[3.1.0]己烷-2-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (d,J = 1.0 Hz, 1H), 7.89 - 7.72 (m, 2H), 7.53 - 7.32 (m, 2H), 6.52 (s, 1H), 5.84 (d,J = 1.3 Hz, 1H), 5.77 (s, 1H), 5.56 (d,J = 1.9 Hz, 1H), 3.75 - 3.63 (m, 1H), 3.59 (d,J = 0.9 Hz, 3H), 3.49 (q,J = 6.5, 5.8 Hz, 1H), 3.22 - 2.63 (m, 2H), 2.41 - 2.14 (m, 2H), 2.13 - 2.01 (m, 1H), 2.00 - 1.97(m, 3H), 1.96 - 1.81 (d,J = 6.3 Hz, 2H), 1.75- 1.63(m, 2H), 1.61- 1.45 (m, 1H), 0.86 - 0.77 (m, 1H), 0.62 - 0.48 (m, 1H). | 497.30 | |
N-(4-(5-((R)-4-((1R,5S)-2-氮雜雙環[3.1.0]己烷-2-羰基)環己-1-烯-1-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (s, 1H), 7.81 (dt,J = 8.8, 2.1 Hz, 2H), 7.44 (d,J = 8.3 Hz, 2H), 6.54 (s, 1H), 5.83 (s, 1H), 5.77 (d,J = 9.8 Hz, 1H), 5.55 (s, 1H), 3.80 - 3.65 (m, 1H), 3.58 (s, 4H), 3.23 - 3.07 (m, 1H), 2.96 - 2.63 (m, 1H), 2.32 (q,J = 18.6, 18.0 Hz, 2H), 1.98 (m, 4H), 1.94 - 1.74 (m, 3H), 1.67 (ddd,J = 21.7, 11.2, 5.8 Hz, 2H), 0.77 (q,J = 7.4, 6.7 Hz, 1H), 0.69 (q,J = 6.7 Hz, 0H), 0.59 - 0.43 (m, 1H). | 497.25 | |
N-(4-(4-胺基-7-甲基-5-((S)-4-((R)-2-甲基吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.09 (d,J = 4.8 Hz, 1H), 7.80 (d,J = 8.3 Hz, 2H), 7.47 - 7.39 (m, 2H), 6.59 (s, 2H), 5.83 (s, 1H), 5.77 (s, 1H), 5.55 (s, 1H), 4.03 (q,J = 9.6, 8.8 Hz, 1H), 3.58 (d,J = 2.2 Hz, 3H), 3.48 (q,J = 7.3, 6.4 Hz, 1H), 3.32 (s, 1H), 2.82 (s, 1H), 2.32 (d,J = 17.2 Hz, 1H), 2.20 (d,J = 17.1 Hz, 1H), 1.97 (s, 3H), 1.96 - 1.73 (m, 5H), 1.61 (s, 2H), 1.47 (s, 1H), 1.14 (d,J = 6.4 Hz, 1H), 1.04 (d,J = 6.3 Hz, 2H). | 499.25 | |
N-(4-(4-胺基-7-甲基-5-((S)-4-((S)-2-甲基吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (d,J = 4.7 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.43 (dd,J = 8.7, 2.1 Hz, 2H), 6.62 (s, 2H), 5.83 (s, 1H), 5.76 (d,J = 3.8 Hz, 1H), 5.55 (d,J = 1.9 Hz, 1H), 4.10 - 3.97 (m, 1H), 3.58 (d,J = 2.2 Hz, 3H), 3.48 (q,J = 6.8, 6.2 Hz, 1H), 2.83 (q,J = 5.4 Hz, 1H), 2.32 (d,J = 16.7 Hz, 1H), 2.20 (d,J = 18.7 Hz, 1H), 2.00 - 1.86 (m, 4H), 1.84 (s, 3H), 1.66 - 1.57 (m, 2H), 1.52 - 1.41 (m, 2H), 1.14 (d,J = 6.3 Hz, 1H), 1.05 (d,J = 6.2 Hz, 3H). | 499.30 | |
N-(4-(4-胺基-5-((S)-4-((R)-2-環丙基吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) 9.93 (s, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.83 -7.77 (m, 2H), 7.43 (dd, J = 8.7, 2.7 Hz, 2H), 6.63-6.45 (m, 2H), 5.83 (t, J = 2.9 Hz, 1H), 5.77 (s, 1H), 5.57-5.52 (m, 1H), 3.80 (t, J=7.5Hz,1H),3.60-3.50(s,3H),3.50-3.40(s,2H),2.86(s,1H),2.40-2.10(m,2H),2.00-1.95(s,3H),1.95-1.65(m,6H), 1.65-1.50(s,2H),1.00-0.75(m,1H), 0.53 -0.41 (m, 1H), 0.32-0.13 (m, 2H), 0.10 (dt, J = 9.8, 4.3 Hz, 1H).(m,2H),2.00-1.95(s,3H),1.95-1.65(m,6H),1.65-1.50(s,2H), 1.00-0.75(m,1H), 0.53 - 0.41 (m, 1H), 0.32 - 0.13 (m, 2H), 0.10 (dt, J = 9.8, 4.3 Hz, 1H). | 525.25 | |
N-(4-(4-胺基-7-甲基-5-((R)-4-((R)-2-甲基吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.10 (d,J = 3.7 Hz, 1H), 7.81 (dd,J = 8.3, 3.9 Hz, 2H), 7.43 (dd,J = 8.7, 2.5 Hz, 2H), 6.46 (s, 2H), 5.83 (s, 1H), 5.75 (s, 1H), 5.55 (s, 1H), 4.05 - 3.96 (m, 1H), 3.58 (d,J = 1.9 Hz, 4H), 3.46 - 3.39 (m, 1H), 2.77 (s, 1H), 2.27 - 2.22 (m, 2H), 1.94 (d,J = 22.2 Hz, 8H), 1.60 (s, 2H), 1.49 (d,J = 7.6 Hz, 1H), 1.09 (dd,J = 8.2, 6.2 Hz, 3H). | 499.30 | |
N-(4-(4-胺基-7-甲基-5-((R)-4-((S)-2-甲基吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (d,J = 2.0 Hz, 1H), 8.11 (d,J = 3.8 Hz, 1H), 7.81 (dq,J = 9.1, 2.1 Hz, 2H), 7.43 (dd,J = 8.8, 2.5 Hz, 2H), 6.46 (s, 2H), 5.83 (s, 1H), 5.79 - 5.72 (m, 1H), 5.55 (d,J = 1.9 Hz, 1H), 4.01 (td,J = 6.6, 2.7 Hz, 1H), 3.58 (d,J = 1.9 Hz, 3H), 3.44 (t,J = 7.9 Hz, 1H), 2.76 (dd,J = 12.2, 6.3 Hz, 1H), 2.25 (s, 2H), 1.97 (t,J = 1.2 Hz, 4H), 1.90 (s, 3H), 1.81 (s, 2H), 1.61 (s, 2H), 1.52 - 1.45 (m, 1H), 1.09 (dd,J = 8.2, 6.3 Hz, 3H). | 499.30 | |
N-(4-(4-胺基-5-((S)-4-((S)-2-環丙基吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) 9.94 (s, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.81 (dd, J = 8.5, 5.9 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 6.44 (s, 1H), 5.83 (s, 1H), 5.79 - 5.73 (m, 1H), 5.55 (t, J = 1.5 Hz, 1H), 3.75 (t, J = 7.0 Hz, 1H), 3.58 (d, J = 1.8 Hz, 3H), 3.55 (s, 1H), 3.55 - 3.42 (m, 1H),2.78 (s, 1H),2.27 (s, 1H), 2.22 (s, 1H), 1.97 (d, J = 1.3 Hz, 9H),1.79(d, J = 1.3 Hz, 3H) 0.91 (d, J = 7.8 Hz, 1H), 0.50 (dd, J = 9.6, 4.9 Hz, 1H), 0.35 (dddt, J = 27.8, 13.4, 9.3, 4.6 Hz, 2H), 0.13 (dt, J = 9.5, 4.8 Hz, 1H). | 525.25 | |
N-(4-(4-胺基-5-((R)-4-((R)-2-環丙基吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.85 - 7.73 (m, 2H), 7.45 - 4.41 (m, 2H), 6.65 (s, 2H), 5.82 (d, J = 4.9 Hz, 1H), 5.77 (s, 1H), 5.55 (d, J = 1.8 Hz, 1H), 3.81 - 3.79 (m, 1H), 3.58 (s, 5H), 2.86 (s, 1H), 2.42 -2.14 (m, 2H), 1.97 (d, J = 1.3 Hz, 2H), 1.88 - 1.67 (m, 4H), 1.67 - 1.55 (m, 2H), 0.87 - 0.85 (m, 1H), 0.47 (d, J = 4.3 Hz, 1H), 0.38 - 0.14 (m, 2H), 0.09 (d, J = 4.8 Hz, 1H). | 525.30 | |
N-(4-(4-胺基-5-((R)-4-((S)-2-環丙基吡咯啶-1-羰基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.10 (d, J = 2.8 Hz, 1H), 7.87 - 7.75 (m, 2H), 7.43 (d, J = 8.3 Hz, 2H), 6.44 (s, 2H), 5.83 (s, 1H), 5.76 (s, 1H), 5.55 (d, J = 1.8 Hz, 1H), 3.74 (t, J = 7.2 Hz, 1H), 3.58 (d, J = 2.1 Hz, 4H), 3.46 - 3.40 (m, 1H), 2.79 (d, J = 7.2 Hz, 1H), 2.24 (d, J = 20.6 Hz, 2H), 2.02 - 1.88 (m, 6H), 1.89 - 1.50 (m, 5H), 0.95 - 0.86 (m, 1H), 0.55 - 0.25 (m, 3H), 0.15 - 0.11 (m, 1H). | 525.30 | |
N-(4-(4-胺基-3-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-1-甲基-1H-吡咯并[3,2-c]吡啶-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 7.78 - 7.69 (m, 3H), 7.37 - 7.27 (m, 3H), 7.24 - 7.16 (m, 2H), 7.16 - 7.09 (m, 1H), 6.88 (d,J = 6.0 Hz, 1H), 5.80 (s, 1H), 5.54 (s, 1H), 5.15 (s, 2H), 3.57 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H). | 509.20 | |
4-(4-胺基-2-(4-甲基丙烯醯胺基苯基)-1-甲基-1H-吡咯并[3,2-c]吡啶-3-基)-N-(環丁基甲基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.89 (s, 1H), 8.10 (t,J = 5.8 Hz, 1H), 7.75 - 7.66 (m, 3H), 7.64 (d,J = 7.8 Hz, 1H), 7.31 - 7.23 (m, 2H), 6.95 (d,J = 1.6 Hz, 1H), 6.91 - 6.84 (m, 2H), 5.80 (t,J = 1.2 Hz, 1H), 5.53 (t,J = 1.6 Hz, 1H), 5.18 (s, 2H), 3.73 (s, 3H), 3.57 (s, 3H), 3.29 (m,J = 12.0 Hz, 2H), 2.54 (d,J = 7.6 Hz, 1H), 2.04 - 1.92 (m, 5H), 1.89 - 1.78 (m, 2H), 1.78 - 1.65 (m, 2H). | 524.25 | |
N-(4-(4-胺基-1-甲基-3-(4-((6-甲基吡啶-2-基)氧基)苯基)-1H-吡咯并[3,2-c]吡啶-2-基)苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.80 - 7.62 (m, 4H), 7.34 - 7.23 (m, 4H), 7.11 - 7.06 (m, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.99 (s, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.48-6.41 (m, 1H), 6.29-6.25 (m, 1H), 5.79-5.76 (m, 1H), 5.52 (s, 2H), 3.62 (s, 3H), 2.35 (s, 4H). | 476.20 | |
(S)-N-(4-(4-胺基-1-甲基-3-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-1H-吡咯并[3,2-c]吡啶-2-基)苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 5.9 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 6.2 Hz, 1H), 6.51-6.44 (m, 1H), 6.32-6.27 (m, 1H), 5.83 - 5.74 (m, 2H), 5.69 (s, 2H), 3.55 (d, J = 1.9 Hz, 3H), 3.52 - 3.41 (m, 1H), 3.30 - 3.22 (m, 2H), 2.79 - 2.64 (m, 1H), 2.38 - 2.16 (m, 2H), 2.04 - 1.82 (m, 4H), 1.76 (p, J = 6.6 Hz, 2H), 1.61 (d, J = 30.7 Hz, 2H). | 470.20 | |
(R)-N-(4-(4-胺基-1-甲基-3-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-1H-吡咯并[3,2-c]吡啶-2-基)苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 5.9 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 6.74 (d, J = 6.2 Hz, 1H), 6.51-6.44 (m, 1H), 6.32-6.27 (m, 1H), 5.83 - 5.74 (m, 2H), 5.69 (s, 2H), 3.55 (d, J = 1.9 Hz, 3H), 3.52 - 3.41 (m, 1H), 3.30 - 3.22 (m, 2H), 2.79 - 2.64 (m, 1H), 2.38 - 2.16 (m, 2H), 2.04 - 1.82 (m, 4H), 1.76 (p, J = 6.6 Hz, 2H), 1.61 (d, J = 30.7 Hz, 2H). | 470.25 | |
(E)-N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-(二甲基胺基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.22 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.72 (d,J = 8.2 Hz, 2H), 7.33 (d,J = 8.4 Hz, 3H), 7.23 - 7.15 (m, 2H), 7.15 - 7.07 (m, 1H), 6.76 (dt,J = 15.1, 5.9 Hz, 1H), 6.29 (d,J = 15.4 Hz, 1H), 5.98 (s, 2H), 3.60 (s, 3H), 3.12 (d,J = 5.9 Hz, 2H), 2.42 (s, 3H), 2.22 (s, 6H). | 553.25 | |
(R,E)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-(二甲基胺基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.10 (d,J = 1.8 Hz, 1H), 7.78 (d,J = 8.2 Hz, 2H), 7.51 - 7.38 (m, 2H), 6.77 (dt,J = 15.3, 5.9 Hz, 1H), 6.53 (s, 2H), 6.32 (d,J = 15.4 Hz, 1H), 5.84 - 5.72 (m, 1H), 3.58 (s, 3H), 3.56 - 3.47 (m, 1H), 3.47 - 3.39 (m, 1H), 3.27 (dd,J = 16.0, 9.3 Hz, 3H), 3.11 (d,J = 5.9 Hz, 2H), 2.84 (q,J = 6.0 Hz, 1H), 2.27 (d,J = 14.7 Hz, 2H), 2.22 (s, 6H), 1.87 (dt,J = 13.3, 6.4 Hz, 4H), 1.76 (p,J = 6.7 Hz, 2H), 1.63 (q,J = 6.4 Hz, 2H). | 528.40 | |
(S,E)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-(二甲基胺基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.10 (d,J = 1.7 Hz, 1H), 7.77 (d,J = 8.2 Hz, 2H), 7.47 - 7.40 (m, 2H), 6.77 (dt,J = 15.4, 5.9 Hz, 1H), 6.53 (s, 2H), 6.31 (d,J = 15.3 Hz, 1H), 5.76 (d,J = 4.5 Hz, 1H), 3.58 (d,J = 1.8 Hz, 3H), 3.56 - 3.48 (m, 1H), 3.47 - 3.38 (m, 1H), 3.32 - 3.21 (m, 1H), 3.10 (d,J = 5.8 Hz, 2H), 2.83 (p,J = 6.0 Hz, 1H), 2.40 - 2.23 (m, 2H), 2.21 (s, 6H), 1.87 (dt,J = 13.2, 6.4 Hz, 4H), 1.76 (p,J = 6.5 Hz, 2H), 1.63 (d,J = 6.3 Hz, 2H). | 528.35 | |
(E)-N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-(二甲基胺基)丁-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.74 - 7.67 (m, 2H), 7.36 - 7.24 (m, 4H), 7.23 - 7.07 (m, 4H), 6.75 (dt,J = 15.4, 5.8 Hz, 1H), 6.28 (dt,J = 15.4, 1.6 Hz, 1H), 5.90 (s, 2H), 3.60 (s, 3H), 3.07 (dd,J = 5.9, 1.6 Hz, 2H), 2.41 (s, 3H), 2.19 (s, 7H). | 535.35 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基磺醯基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.12 (s, 1H), 7.72 (dd,J = 13.0, 2.2 Hz, 1H), 7.63 (ddd,J = 13.1, 8.3, 2.2 Hz, 1H), 7.18 (dd,J = 12.5, 8.3 Hz, 1H), 6.35 (s, 2H), 5.83 (t,J = 1.1 Hz, 1H), 5.62 (s, 1H), 5.59 - 5.50 (m, 1H), 3.54 (d,J = 15.4 Hz, 1H), 3.34 (s, 3H), 3.31 - 3.24 (m, 4H), 2.37 (d,J = 30.0 Hz, 2H), 2.10 - 2.02 (m, 5H), 1.97 (t,J = 1.3 Hz, 3H), 1.95 - 1.79 (m, 5H), 1.56 (p,J = 10.8 Hz, 1H). | 535.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基磺醯基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.92 (s, 1H), 8.40 (s, 1H), 7.78 (d,J = 2.1 Hz, 3H), 7.20 (dd,J = 9.9, 8.3 Hz, 1H), 5.84 (s, 1H), 5.71 (s, 1H), 5.56 (d,J = 1.9 Hz, 1H), 3.43 (d,J = 1.6 Hz, 4H), 3.31 - 3.23 (m, 4H), 2.42 (s, 2H), 2.06 (d,J = 3.6 Hz, 4H), 1.97 (t,J = 1.2 Hz, 4H), 1.94 - 1.82 (m, 5H), 1.60 (s, 1H). | 535.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) 10.24 (d, J = 1.5 Hz, 1H), 8.10 (s, 1H), 7.78 -7.64 (m, 1H), 7.59 (ddd, J = 7.9, 5.5, 2.1 Hz, 1H), 7.20 (dd, J = 8.3, 6.5 Hz, 1H), 6.47 (dd, J = 17.0, 10.1 Hz,2H), 6.29 (dd, J = 16.9, 2.0 Hz, 1H), 5.79 (dd, J = 10.1, 2.1 Hz, 1H), 5.67 (d, J = 15.5 Hz, 1H), 3.53 -3.37 (m, 2H), 3.34 (s, 3H), 3.27 (q, J = 6.9 Hz, 2H), 2.73 (p, J = 6.2 Hz, 1H), 2.21 (q, J = 18.5 Hz, 2H), 1.93 (d, J = 14.5 Hz, 3H), 1.89 -1.80 (m, 4H), 1.80 -1.68 (m, 2H), 1.57 (d, J = 6.3 Hz, 2H). | 485.15 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) 10.24 (d, J = 1.5 Hz, 1H), 8.10 (s, 1H), 7.78 -7.64 (m, 1H), 7.59 (ddd, J = 7.9, 5.5, 2.1 Hz, 1H), 7.20 (dd, J = 8.3, 6.5 Hz, 1H), 6.47 (dd, J = 17.0, 10.1 Hz,2H), 6.29 (dd, J = 16.9, 2.0 Hz, 1H), 5.79 (dd, J = 10.1, 2.1 Hz, 1H), 5.67 (d, J = 15.5 Hz, 1H), 3.53 -3.37 (m, 2H), 3.34 (s, 3H), 3.27 (q, J = 6.9 Hz, 2H), 2.73 (p, J = 6.2 Hz, 1H), 2.21 (q, J = 18.5 Hz, 2H), 1.93 (d, J = 14.5 Hz, 3H), 1.89 -1.80 (m, 4H), 1.80 -1.68 (m, 2H), 1.57 (d, J = 6.3 Hz, 2H). | 485.15 | |
N-(4-(4-胺基-7-甲基-5-(4-(4-甲基-1H-吡唑-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.89 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.79-7.66 (m, 4H), 7.56 (s, 1H), 7.34-7.25 (m, 4H), 5.89 (s, 2H), 5.79 (t, J = 1.0 Hz, 1H), 5.53 (t, J = 1.5 Hz, 1H), 3.62 (s, 3H), 2.10 (s, 3H), 1.94 (t, J = 1.2 Hz, 3H). | 464.10 | |
N-(4-(4-胺基-7-甲基-5-(6-(3-甲基-1H-吡唑-1-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.90 (s, 1H), 8.47 (d,J = 2.5 Hz, 1H), 8.25 - 8.15 (m, 2H), 7.80 (dd,J = 8.4, 0.8 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.33 - 7.25 (m, 2H), 6.37 (d,J = 2.5 Hz, 1H), 6.09 (s, 2H), 5.82 - 5.77 (m, 1H), 5.55 - 5.50 (m, 1H), 3.62 (s, 3H), 2.29 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 465.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(4-(三氟甲基)-1H-吡唑-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.89 (s, 1H), 9.20 - 9.15 (m, 1H), 8.21 (d,J = 1.2 Hz, 2H), 7.91 - 7.83 (m, 2H), 7.75 - 7.68 (m, 2H), 7.41 - 7.34 (m, 2H), 7.33 - 7.25 (m, 2H), 5.95 (s, 2H), 5.81 - 5.76 (m, 1H), 5.56 - 5.50 (m, 1H), 3.62 (s, 3H), 1.95 (t,J = 1.3 Hz, 3H). | 518.30 | |
N-(4-(4-胺基-7-甲基-5-(6-(1-甲基-1H-吡唑-3-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.91 (s, 1H), 8.35 - 8.30 (m, 1H), 8.22 (s, 1H), 7.85 (dd,J = 8.2, 0.9 Hz, 1H), 7.79 - 7.69 (m, 3H), 7.63 (dd,J = 8.2, 2.3 Hz, 1H), 7.29 (d,J = 8.6 Hz, 2H), 6.77 (d,J = 2.2 Hz, 1H), 6.02 (s, 1H), 5.79 (s, 1H), 5.53 (s, 1H), 3.91 (s, 3H), 3.62 (s, 3H), 1.94 (t,J = 1.3 Hz, 3H). | 465.20 | |
N-(4-(4-胺基-7-甲基-5-(6-(1-甲基-1H-吡唑-5-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.92 (s, 1H), 8.44 (dd,J = 2.3, 0.9 Hz, 1H), 8.23 (s, 1H), 7.81 - 7.70 (m, 3H), 7.69 (dd,J = 8.2, 2.3 Hz, 1H), 7.48 (d,J = 2.0 Hz, 1H), 7.35 - 7.28 (m, 2H), 6.80 (d,J = 2.0 Hz, 1H), 6.10 (s, 2H), 5.80 (t,J = 1.1 Hz, 1H), 5.54 (t,J = 1.4 Hz, 1H), 4.14 (s, 3H), 3.62 (s, 3H), 1.95 (t,J = 1.2 Hz, 3H). | 460.30 | |
N-(4-(5-(4-(1H-吡唑-5-基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 12.87 (1H, s), 9.88 (1H, s), 8.21 (1H, s), 7.84-7.62 (5H, m), 7.32-8211;7.23 (4H, m), 6.72 (1H, d, J=2.2 Hz), 5.79 (3H, s), 5.52 (1H, t, J=1.5 Hz), 3.63 (3H, s), 1.95 (3H, d, J=1.2 Hz) | 450.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(5-甲基-1,2,4-噁二唑-3-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.89 (s, 1H), 8.22 (s, 1H), 7.94 (d,J = 7.8 Hz, 2H), 7.71 (d,J = 8.2 Hz, 2H), 7.38 (d,J = 7.9 Hz, 2H), 7.27 (d,J = 8.2 Hz, 2H), 5.96 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 3.31 (s, 1H), 2.66 (s, 3H), 1.95 (s, 3H). | 466.35 | |
N-(4-(4-胺基-7-甲基-5-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.91 (s, 1H), 8.22 (s, 1H), 7.92 (d,J = 7.9 Hz, 2H), 7.71 (d,J = 8.3 Hz, 2H), 7.40 (d,J = 7.9 Hz, 2H), 7.27 (d,J = 8.3 Hz, 2H), 5.99 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 3.32 (s, 1H), 2.57 (s, 3H), 1.95 (s, 3H). | 466.20 | |
N-(4-(4-胺基-7-甲基-5-(2-甲基-2H-吲唑-5-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.85 (s, 1H), 8.29 (s, 1H), 8.19 (s, 1H), 7.65 (d,J = 8.4 Hz, 2H), 7.55 (d,J = 9.2 Hz, 2H), 7.27 (d,J = 8.3 Hz, 2H), 7.07 (dd,J = 8.8, 1.8 Hz, 1H), 5.77 (s, 1H), 5.52 (s, 1H), 4.15 (s, 3H), 3.64 (s, 3H), 1.93 (s, 3H). | 438.15 | |
N-(4-(4-胺基-7-甲基-5-(1,2,3,6-四氫-[1,1'-聯苯]-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.97 (s, 1H), 8.14 (s, 1H), 7.88-7.80 (m, 2H), 7.50- 7.42 (m, 2H), 7.34-7.23 (m, 4H), 7.23-7.14 (m, 1H), 6.29 (s, 1H), 5.89-5.82 (m, 2H), 5.56 (t, J = 1.4 Hz, 1H), 3.58 (s, 3H), 2.82 (dd, J = 10.7, 5.7 Hz, 1H), 2.42 (d, J = 17.3 Hz, 1H), 2.28 (d, J = 16.6 Hz, 1H), 2.14 (s, 1H), 1.98 (t, J = 1.2 Hz, 3H), 1.92 (d, J = 4.8 Hz, 1H), 1.77 (s, 2H). | 464.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(3-甲基-1,2,4-噁二唑-5-基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.95 (s, 1H), 8.12 (s, 1H), 7.80 (d,J = 8.5 Hz, 2H), 7.42 (d,J = 8.3 Hz, 2H), 5.82 (d,J = 8.1 Hz, 2H), 5.55 (s, 1H), 3.58 (s, 3H), 3.45 (s, 1H), 2.69-2.57 (m, 2H), 2.33 (s, 3H), 1.98 (s, 3H), 1.95-1.76 (m, 4H). | 470.25 | |
N-(4-(4-胺基-5-(苯并[b]噻吩-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.90 (s, 1H), 8.23 (s, 1H), 7.85 (dd, J = 18.2, 7.7 Hz, 2H), 7.76-7.69 (m, 2H), 7.42-7.32 (m, 4H), 7.32 (td, J = 7.5, 1.5 Hz, 1H), 6.22 (s, 2H), 5.79 (s, 1H), 5.53 (s, 1H), 3.62 (s, 3H), 1.94 (d, J = 1.2 Hz, 3H). | 440.10 | |
N-(4-(4-胺基-7-甲基-5-(4-苯基噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.92 (s, 1H), 8.22 (s, 1H), 7.82 (d,J = 1.6 Hz, 1H), 7.76 (dd,J = 8.5, 2.5 Hz, 2H), 7.70 (d,J = 7.6 Hz, 2H), 7.53 (d,J = 1.6 Hz, 1H), 7.41 (dt,J = 7.9, 3.3 Hz, 4H), 7.30 (t,J = 7.4 Hz, 1H), 6.13 (s, 2H), 5.80 (s, 1H), 5.53 (s, 1H), 3.61 (s, 3H), 1.95 (s, 3H). | 466.20 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基苯并[b]噻吩-2-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.85 (s, 1H), 8.22 (s, 1H), 7.94-7.86 (m, 1H), 7.79-7.70 (m, 1H), 7.70-7.59 (m, 2H), 7.46-7.35 (m, 2H), 7.35-7.26 (m, 2H), 5.76 (t,J = 1.1 Hz, 1H), 5.55-5.46 (m, 1H), 3.68 (s, 3H), 2.07 (s, 3H), 1.92 (t,J = 1.3 Hz, 3H). | 454.05 | |
N-(4-(4-胺基-7-甲基-5-(4-(3-甲基-1,2,4-噁二唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.91 (s, 1H), 8.23 (s, 1H), 8.07 - 7.99 (m, 2H), 7.76 - 7.68 (m, 2H), 7.46 - 7.38 (m, 2H), 7.32 - 7.24 (m, 2H), 6.02 (s, 2H), 5.80 (t,J = 1.1 Hz, 1H), 5.53 (t,J = 1.5 Hz, 1H), 3.62 (s, 3H), 2.41 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 466.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(2-甲基噁唑-4-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d )δ 8.39 (s, 1H), 7.81 (s, 1H), 7.66 (d,J = 7.8 Hz, 2H), 7.58 (d,J = 8.5 Hz, 3H), 7.33 -7.22 (m, 3H), 5.81 (s, 1H), 5.50 (s, 1H), 5.10 (s, 2H), 3.75 (s, 3H), 2.53 (s, 3H), 2.08 (s, 3H),1.91 (s, 1H). | 465.30 | |
N-(4-(4-胺基-5-(6-(4-乙基-1H-吡唑-1-基)吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d )δ 8.42 (s, 1H), 8.30 (ddd,J = 4.7, 2.1, 0.9 Hz, 2H), 7.92 (dd,J = 8.5, 0.8 Hz, 1H), 7.70 (dd,J = 8.5, 2.3 Hz, 1H), 7.66 -.56 (m, 4H), 7.29 -7.21 (m, 2H), 5.82 (s, 1H), 5.52 (d,J = 1.7 Hz, 1H), 5.01 (s, 2H), 3.76 (s, 3H), 2.59 (q,J = 7.5 Hz, 2H), 2.09 (dd,J = 1.6, 0.9 Hz, 3H), 1.27 (t,J = 7.6 Hz, 3H). | 479.35 | |
N-(4-(4-胺基-7-甲基-5-(1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 12.89 (s, 1H), 10.28 (s, 1H), 8.17 (d, J = 1.3 Hz, 1H), 7.54 (dd, J = 143.2, 8.2 Hz, 6H), 6.46 (dd, J = 16.9, 10.0 Hz, 1H), 6.29 (dt, J = 16.9, 1.7 Hz, 1H), 5.94 (s, 2H), 5.79 (d, J = 10.2 Hz, 1H), 3.58 (s, 3H). | 360.10 | |
N-(4-(4-胺基-7-甲基-5-(1H-吡咯-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.87 (s, 1H), 10.24 (s, 1H), 8.13 (s, 1H), 7.72 - 7.65 (m, 2H), 7.40 - 7.32 (m, 2H), 6.79 (q,J = 2.4 Hz, 1H), 6.65 (q,J = 2.0 Hz, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.0 Hz, 1H), 5.99 (q,J = 2.4 Hz, 1H), 5.78 (dd,J = 10.0, 2.1 Hz, 1H), 3.56 (s, 3H). | 359.15 | |
N-(4-(4-胺基-5-(1H-吲哚-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 11.24-11.19 (m, 1H), 10.19 (s, 1H), 8.17 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.36- 7.27 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.93 (t, J = 7.5 Hz, 1H), 6.41 (dd, J = 16.9, 10.1 Hz, 1H), 6.24 (dd, J = 16.9, 2.1 Hz, 1H), 5.75 (dd, J = 10.0, 2.1 Hz, 2H), 3.66 (s, 3H). | 409.15 | |
N-(4-(4-胺基-5-(異噻唑-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.29 (s, 1H), 8.87 (s, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.75-7.68 (m, 2H), 7.35-7.28 (m, 2H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 6.01 (s, 1H), 5.79 (dd, J = 10.1, 2.1 Hz, 1H), 3.60 (s, 3H). | 377.10 | |
N-(4-(4-胺基-5-(1H-吲哚-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 11.13 (s, 1H), 10.25 (s, 1H), 8.22 (s, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.11-7.03 (m, 1H), 6.99 (t, J = 7.4 Hz, 1H), 6.55-6.21 (m, 3H), 6.10 (s, 2H), 5.77 (dd, J = 10.0, 2.0 Hz, 1H), 3.66 (s, 3H). | 409.10 | |
N-(4-(4-胺基-7-甲基-5-(6-側氧基-1,6-二氫吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 11.52 (s, 1H), 10.28 (s, 1H), 8.17 (s, 1H), 7.77- 7.71 (m, 2H), 7.37-7.25 (m, 2H), 7.21 (dd, J = 9.4, 2.6 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 17.0, 10.1 Hz, 1H), 6.33-6.25 (m, 2H), 6.12 (s, 2H), 5.79 (dd, J = 10.1, 2.0 Hz, 1H), 3.58 (s, 3H). | 387.15 | |
N-(4-(4-胺基-5-(1H-吲哚-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 11.17 (s, 1H), 10.20 (s, 1H), 8.17 (s, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 6.96 (dd, J = 8.3, 1.7 Hz, 1H), 6.47-6.36 (m, 2H), 6.25 (dd, J = 16.9, 2.1 Hz, 1H), 5.76 (dd, J = 10.0, 2.1 Hz, 1H), 3.63 (s, 3H). | 409.15 | |
N-(4-(4-胺基-5-(4-羥基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.24 (s, 1H), 9.49 (s, 1H), 8.16 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.31-7.24 (m, 2H), 7.08-7.00 (m, 2H), 6.78-6.71 (m, 2H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H), 3.60 (s, 3H). | 386.15 | |
N-(4-(4-胺基-7-甲基-5-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.27 (s, 1H), 8.16 (s, 1H), 7.84 -7.59 (m, 3H), 7.39- 7.31 (m, 2H), 7.27 (d, J = 0.9 Hz, 1H), 6.46 (dd, J = 17.0, 10.1 Hz, 1H), 6.28 (dd, J = 17.0, 2.0 Hz, 1H), 6.01 (s, 2H), 5.79 (dd, J = 10.1, 2.1 Hz, 1H), 3.81 (s, 3H), 3.56 (s, 3H). | 374.10 | |
N-(4-(4-胺基-5-(苯并[b]噻吩-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.28 (s, 1H), 8.23 (s, 1H), 7.90-7.79 (m, 2H), 7.75-7.67 (m, 2H), 7.45-7.37 (m, 2H), 7.41-7.32 (m, 2H), 7.32 (ddd, J = 8.5, 7.1, 1.5 Hz, 1H), 6.43 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.0 Hz, 2H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 3.62 (s, 3H). | 426.10 | |
N-(4-(4-胺基-5-(1H-吲哚-6-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 11.07 (t, J = 2.3 Hz, 1H), 10.21 (s, 1H), 8.18 (s, 1H), 7.67-7.60 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.36-7.26 (m, 3H), 7.23 (q, J = 1.0 Hz, 1H), 6.91 (dd, J = 8.1, 1.5 Hz, 1H), 6.47 – 6.36 (m, 2H), 6.25 (dd, J = 17.0, 2.1 Hz, 1H), 5.76 (dd, J = 10.0, 2.1 Hz, 2H), 3.63 (s, 3H). | 409.15 | |
N-(4-(4-胺基-7-甲基-5-(1-苯基-1,2,3,6-四氫吡啶-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.94 (s, 1H), 8.15 (s, 1H), 7.80 (d,J = 7.9 Hz, 2H), 7.43 (d,J = 8.3 Hz, 2H), 7.20 (t,J = 7.7 Hz, 2H), 6.91 (d,J = 8.2 Hz, 2H), 6.73 (t,J = 7.2 Hz, 1H), 6.26 (s, 2H), 5.92 (s, 1H), 5.82 (s, 1H), 5.55 (s, 1H), 3.84 (s, 2H), 3.58 (s, 3H), 2.16-2.05 (m, 4H), 1.97 (s, 3H). | 465.25 | |
4-(4-胺基-6-(4-甲基丙烯醯胺基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-3,6-二氫吡啶-1(2H)-甲酸苯甲酯 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.96 (s, 1H), 8.14 (s, 1H), 7.83 (dd,J = 8.7, 2.3 Hz, 2H), 7.53- 7.27 (m, 7H), 6.33 (s, 2H), 5.80 (d,J = 21.2 Hz, 2H), 5.55 (s, 1H), 5.09 (s, 2H), 4.06 (s, 2H), 3.56 (s, 3H), 3.46 (s, 2H), 1.99 (d,J = 11.6 Hz, 5H). | 523.20 | |
N-(4-(4-胺基-5-(1-苯甲基-1,2,3,6-四氫吡啶-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.98 (s, 1H), 8.14 (s, 1H), 7.87- 7.80 (m, 2H), 7.47- 7.40 (m, 2H), 7.33 (d,J = 5.1 Hz, 4H), 7.27 (s, 1H), 6.26 (s, 2H), 5.81 (d,J = 25.0 Hz, 2H), 5.56 (t,J = 1.5 Hz, 1H), 3.56 (s, 5H), 3.34 (s, 2H), 3.10 (s, 2H), 1.98 (d,J = 1.3 Hz, 5H). | 479.25 | |
N-(4-(4-胺基-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.21 (s, 1H), 7.81 - 7.67 (m, 3H), 7.37 - 7.29 (m, 2H), 7.26 (t,J = 8.4 Hz, 1H), 7.16 (dd,J = 11.5, 2.0 Hz, 1H), 7.07 (dd,J = 8.5, 2.0 Hz, 1H), 7.00 (d,J = 7.3 Hz, 1H), 6.86 (d,J = 8.2 Hz, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.1 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.62 (s, 3H), 2.30 (s, 3H). | 495.20 | |
4-(6-(4-乙醯胺基苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環丁基-2-甲氧基苯甲醯胺 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 8.22 (d,J = 3.3 Hz, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.60 (d,J = 7.8 Hz, 1H), 7.32 (d,J = 8.6 Hz, 2H), 6.95 - 6.81 (m, 2H), 6.45 (dd,J = 17.0, 9.9 Hz, 1H), 6.28 (dd,J = 17.0, 2.2 Hz, 1H), 5.79 (dd,J = 9.9, 2.2 Hz, 1H), 4.39 (q,J = 8.3 Hz, 1H), 3.70 (s, 3H), 3.60 (s, 3H), 2.21 (s, 2H), 1.98 (q,J = 9.7 Hz, 2H), 1.76 - 1.53 (m, 2H). | 497.20 | |
N-(4-(4-胺基-7-甲基-5-(3-甲基-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 8.43 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.81 (dd,J = 12.1, 2.0 Hz, 1H), 7.44 - 7.27 (m, 2H), 7.22 (s, 1H), 7.15 - 7.02 (m, 3H), 6.44 (dd,J = 17.0, 10.0 Hz, 1H), 6.31 (dd,J = 17.0, 2.1 Hz, 1H), 5.82 (dd,J = 10.0, 2.0 Hz, 1H), 3.53 (s, 3H), 2.41 (s, 3H), 2.03 (s, 3H). | 510.15 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氯苯基)丙烯醯胺 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.49 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.07 (d,J = 2.0 Hz, 1H), 7.57 (dd,J = 8.4, 2.1 Hz, 1H), 7.41 (d,J = 8.4 Hz, 1H), 7.27 (d,J = 8.6 Hz, 2H), 7.20 - 7.05 (m, 3H), 6.50 - 6.25 (m, 2H), 5.83 (dd,J = 9.8, 2.3 Hz, 1H), 3.48 (s, 3H), 2.40 (s, 3H). | 512.10 |
步驟 1
:在氮氣氛圍下,在0℃下,將丙烯醯氯(0.63 g,7.006 mmol)分數份逐滴添加至2-(4-溴苯基)丙-2-胺(1.50 g,7.006 mmol)及TEA (2.13 g,21.018 mmol)於DCM (30 mL)中之經攪拌溶液/混合物中。在0℃下攪拌混合物1小時。所得混合物用CH2
Cl2
萃取。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥。過濾之後,在減壓下濃縮濾液,得到呈黃色固體狀的N-(2-(4-溴苯基)丙-2-基)丙烯醯胺(500 mg,27%)。
N-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙-2-基)丙烯醯胺
步驟 2
:N-[2-(4-溴苯基)丙-2-基]丙-2-烯醯胺(470.00 mg,1.753 mmol)、雙(頻哪醇根基)二硼(667.63 mg,2.629 mmol)、AcOK (516.05 mg,5.258 mmol)及Pd(dppf)Cl2 (128.25 mg,0.175 mmol)於DMF (10 mL)中之溶液/混合物在氮氣氛圍下,在80℃下攪拌2小時。所得混合物用EtOAc萃取。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥。過濾之後,在減壓下濃縮濾液。殘餘物用PE/EtOAc=4/1溶離、藉由矽膠管柱層析來純化,得到呈灰白色固體狀之N-(2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)丙-2-基)丙烯醯胺(400 mg,72%)。
N-(2-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙-2-基)丙烯醯胺
步驟 3
:6-碘-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-4-胺(200.00 mg,0.44 mmol)、N-[2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-2-基]丙-2-烯醯胺(165.1 mg,0.52 mmol)、K3
PO4
(277.9 mg,1.31 mmol)及Pd(dppf)Cl2
(31.9 mg,0.04 mmol)於DMF (4 mL)及H2
O (1 mL)中之溶液/混合物在氮氣氛圍下、在90℃下攪拌1小時。所得混合物用EtOAc萃取。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥。過濾之後,在減壓下濃縮濾液。粗產物藉由HPLC純化(管柱:XBridge Shield RP18 OBD管柱,5um,19*150mm;移動相A:水(10 mM NH4
HCO3
),移動相B:ACN;流量:25 mL/min;梯度:25 B至43 B,歷時7分鐘;220/254 nm;RT1:6.25;RT2:;注射體積:ml;操作次數:;)。凍乾產生呈灰白色非晶形固體狀之N-(2-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙-2-基)丙烯醯胺(51 mg,22.3%)。
根據實例13之方法製備的其他化合物描繪於下表12中。表 12 . 其他例示性化合物
實例14流程 12
3-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
7-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,4-二氫吡啶并[1,2-a]嘧啶-2-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.41 (s, 1H), 7.61 (t,J = 7.7 Hz, 1H), 7.53 (dd,J = 9.2, 2.1 Hz, 1H), 7.20 - 7.13 (m, 2H), 7.05 (d,J = 9.2 Hz, 1H), 6.94 - 6.84 (m, 3H), 6.73 (d,J = 8.2 Hz, 1H), 5.20 (s, 2H), 4.20 (t,J = 7.4 Hz, 2H), 3.80 (s, 3H), 3.74 (s, 3H), 2.74 (t,J = 7.4 Hz, 2H), 2.40 (s, 3H). | 508.00 | |
1-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-6-甲基-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.67 (td,J = 7.7, 2.1 Hz, 1H), 7.18 (dd,J = 8.0, 6.2 Hz, 1H), 7.10 - 7.05 (m, 1H), 7.00 - 6.92 (m, 2H), 6.86 - 6.73 (m, 1H), 6.68 (t,J = 7.6 Hz, 1H), 6.09 (dt,J = 34.3, 19.4 Hz, 2H), 5.86 (s, 1H), 5.67 (d,J = 11.0 Hz, 1H), 4.93 - 4.61 (m, 1H), 4.48 (s, 1H), 4.14 - 3.73 (m, 1H), 3.67 (s, 6H), 3.25 - 2.64 (m, 1H), 2.30 (d,J = 3.1 Hz, 3H), 1.96 (dd,J = 67.9, 16.5 Hz, 1H), 1.31 - 0.80 (m, 3H). | 511.40 | |
1-(3-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.67 (td,J = 7.7, 4.7 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.04 - 6.90 (m, 2H), 6.68 (dd,J = 8.2, 3.6 Hz, 1H), 6.58 (dd,J = 16.7, 10.3 Hz, 1H), 6.42 - 6.10 (m, 3H), 6.02(s, 1H), 5.68 (ddd,J = 16.3, 10.2, 2.4 Hz, 1H), 4.56 (p,J = 2.5 Hz, 1H), 4.33 (s, 2H), 4.05 (p,J = 2.2 Hz, 1H), 3.79 (d,J = 2.9 Hz, 3H), 3.69 (s, 3H), 2.30 (d,J = 11.6 Hz, 3H). | 483.20 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 9.83 (s, 1H), 8.12 (s, 1H), 7.77 (t,J = 7.8 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.42 - 7.35 (m, 2H), 7.38 - 7.26 (m, 2H), 7.23 - 7.15 (m, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 5.78 (s, 2H), 5.52 (t,J = 1.5 Hz, 1H), 2.38 (s, 3H), 1.94 (d,J = 1.3 Hz, 3H). | 477.30 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)呋喃并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.03 (s, 1H), 8.27 (s, 1H), 7.93 (d,J = 8.2 Hz, 2H), 7.75 (t,J = 7.8 Hz, 1H), 7.50 (dd,J = 8.4, 5.2 Hz, 4H), 7.11 (d,J = 8.4 Hz, 2H), 7.03 (d,J = 7.4 Hz, 1H), 6.81 (d,J = 8.2 Hz, 1H), 5.84 (s, 1H), 5.56 (s, 1H), 2.33 (s, 3H), 1.98 (s, 3H). | 478.30 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-N-甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ12.17 (s, 1H), 8.14 (s, 1H), 7.77 (t,J = 7.7 Hz, 1H), 7.44 (dd,J = 15.1, 8.2 Hz, 4H), 7.23 (dd,J = 8.2, 5.9 Hz, 4H), 7.04 (d,J = 7.3 Hz, 1H), 6.86 (d,J = 8.2 Hz, 1H), 6.24 - 5.44 (m, 5H), 3.24 (s, 3H), 2.37 (s, 3H). | 477.35 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.12 (s, 1H), 9.82 (s, 1H), 8.13 (s, 1H), 7.59 (d,J = 8.3 Hz, 4H), 7.39 (d,J = 8.1 Hz, 2H), 7.25 (d,J = 8.7 Hz, 2H), 5.79 (s, 1H), 5.52 (s, 1H), 3.48 (dt,J = 11.2, 6.4 Hz, 4H), 1.94 (s, 3H), 1.87 (dq,J = 13.0, 6.8 Hz, 4H). | 467.30 | |
N-(4-(4-胺基-5-(3-乙氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 9.83 (s, 1H), 8.13 (s, 1H), 7.70 (t, J = 7.7 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.39 - 7.30 (m, 2H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 7.01 - 6.90 (m, 2H), 6.74 (d, J = 8.2 Hz, 1H), 5.79 (s, 2H), 5.53 (t, J = 1.5 Hz, 1H), 3.91 (q, J = 6.9 Hz, 2H), 2.34 (s, 3H), 1.95 (d, J = 1.5 Hz, 3H), 1.27 - 1.07 (m, 1H), 1.00 (t, J = 6.9 Hz, 3H). | 521.25 | |
N-(4-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丁-2-炔醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.66 (s, 1H), 8.13 (s, 1H), 7.74 - 7.65 (m, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.38 - 7.29 (m, 2H), 7.21 - 7.06 (m, 2H), 7.02 - 6.88 (m, 2H), 6.72 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 3.62 (s, 2H), 2.34 (s, 3H), 2.05 (s, 2H). | 505.25 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 10.19 (s, 1H), 8.12 (s, 1H), 7.77 (t,J = 7.8 Hz, 1H), 7.60 (d,J = 8.6 Hz, 2H), 7.41 - 7.36 (m, 2H), 7.32 (d,J = 8.6 Hz, 2H), 7.22 - 7.16 (m, 2H), 7.04 (d,J = 7.3 Hz, 1H), 6.85 (d,J = 8.2 Hz, 1H), 6.43 (dd,J = 17.0, 10.1 Hz, 1H), 6.26 (dd,J = 17.0, 2.0 Hz, 1H), 5.76 (dd,J = 10.1, 2.0 Hz,2H), 2.38 (s, 3H). | 463.40 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)異丁醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.05 (s, 1H), 9.87 (s, 1H), 8.12 (s, 1H), 7.76 (t,J = 7.8 Hz, 1H), 7.54 (d,J = 8.7 Hz, 2H), 7.39 - 7.35 (m, 2H), 7.28 (d,J = 8.6 Hz, 2H), 7.19 (d,J = 8.4 Hz, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.84 (d,J = 8.2 Hz, 1H), 5.75 (s, 1H), 2.79 - 2.57 (m, 1H), 2.38 (s, 3H), 1.09 (d,J = 6.8 Hz, 6H). | 479.45 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.12 (s, 1H), 10.20 (s, 1H), 8.13 (s, 1H), 7.62 - 7.54 (m, 4H), 7.45 - 7.36 (m, 2H), 7.31 - 7.23 (m, 2H), 6.42 (dd,J = 17.0, 10.1 Hz, 1H), 6.25 (dd,J = 17.0, 2.1 Hz, 1H), 5.76 (dd,J = 10.0, 2.1 Hz, 2H), 3.54 - 3.43 (m, 4H), 2.08 (s, 1H), 1.88 (dt,J = 12.6, 6.7 Hz, 4H). | 453.30 | |
1-(6-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氧雜-8-氮雜雙環[3.2.1]辛-8-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 3.2 Hz, 1H), 7.77 (t,J = 7.7 Hz, 1H), 7.45 - 7.09 (m, 4H), 7.05 (d,J = 7.4 Hz, 1H), 6.87 (dd,J = 10.3, 8.2 Hz, 1H), 6.65 (ddd,J = 35.0, 16.7, 10.3 Hz, 1H), 6.24 (ddd,J = 16.7, 4.8, 2.4 Hz, 1H), 5.70 (td,J = 10.5, 2.4 Hz, 1H), 4.68 (s, 1H), 4.50 (d,J = 16.1 Hz, 2H), 3.95 (dt,J = 24.1, 7.3 Hz, 1H), 3.77 - 3.67 (m, 5H), 3.67 - 3.52 (m, 2H), 3.44 (dd,J = 10.8, 6.1 Hz, 1H), 2.37 (d,J = 2.4 Hz, 3H), 2.31 - 2.06 (m, 2H). | 497.35 | |
N-(4-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)噻吩并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 8.35 (s, 1H), 7.85 (d,J = 8.3 Hz, 2H), 7.74 (t,J = 7.8 Hz, 1H), 7.39 (d,J = 8.2 Hz, 2H), 7.29 (d,J = 8.5 Hz, 2H), 7.03 (t,J = 7.6 Hz, 3H), 6.79 (d,J = 8.1 Hz, 1H), 5.83 (s, 1H), 5.56 (s, 1H), 2.33 (s, 3H), 1.97 (s, 3H). | 494.30 | |
N-(4-(4-胺基-5-(4-(吡咯啶-1-基磺醯基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 9.85 (s, 1H), 8.14 (s, 1H), 7.88 - 7.81 (m, 2H), 7.62 - 7.52 (m, 4H), 7.16 (d, J = 8.8 Hz, 2H), 5.86 (s, 2H), 5.78 (s, 1H), 5.52 (s, 1H), 3.24 - 3.12 (m, 2H), 1.94 (d, J = 1.2 Hz, 3H), 1.71 - 1.63 (m, 3H), 1.57 (s, 1H), 1.32 (q, J = 7.2 Hz, 1H), 0.94 (t, J = 7.2 Hz, 1H). | 503.2 | |
N-(4-(4-胺基-5-(3-氟-4-((5-氟嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.14 (s, 1H), 9.85 (s, 1H), 8.81 (s, 2H), 8.14 (s, 1H), 7.70 - 7.59 (m, 2H), 7.48 (t,J = 8.4 Hz, 1H), 7.38 - 7.26 (m, 3H), 7.24 (dd,J = 8.3, 2.0 Hz, 1H), 5.80 (s, 3H), 5.53 (d,J = 1.7 Hz, 1H), 1.95 (s, 3H). | 500.35 | |
N-(4-(7-(4-((6-甲基吡啶-2-基)氧基)苯基)-5H-吡咯并[3,2-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.99 (s, 1H), 8.91 (s, 1H), 8.86 (s, 1H), 7.83 - 7.76 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.58 - 7.50 (m, 4H), 7.17 - 7.10 (m, 2H), 7.02 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.83 (s, 1H), 5.56 (s, 1H), 2.36 (s, 3H), 1.97 (d, J = 1.2 Hz, 3H). | 462.3 | |
N-(4-(4-胺基-5-(4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 10.13 (s, 1H), 8.12 (d, J = 13.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.59 - 7.52 (m, 2H), 7.46 - 7.39 (m, 2H), 7.23 - 7.14 (m, 3H), 6.57 - 6.37 (m, 1H), 6.24 (m, J = 17.0, 2.1 Hz, 1H), 5.96 (s, 2H), 5.81 - 5.69 (m, 1H), 3.80 (s, 3H). | 452 | |
N-(6-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.09 (s, 1H), 10.04 (s, 1H), 8.90 (d,J = 2.5 Hz, 1H), 8.13 (s, 1H), 7.91 (dd,J = 8.8, 2.5 Hz, 1H), 7.78 (t,J = 7.8 Hz, 1H), 7.50 - 7.42 (m, 2H), 7.28 - 7.20 (m, 2H), 7.07 (t,J = 7.6 Hz, 2H), 6.88 (d,J = 8.1 Hz, 1H), 5.85 (s, 2H), 5.58 (s, 1H), 2.39 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 478.30 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)氮丙啶-2-甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.55 - 7.49 (m, 2H), 7.43 (d,J = 8.3 Hz, 2H), 7.40 - 7.29 (m, 4H), 4.33 (dd,J = 5.6, 2.6 Hz, 1H), 3.99 (t,J = 5.8 Hz, 1H), 3.69 (s, 3H), 3.61 (t,J = 6.9 Hz, 2H), 3.50 (t,J = 6.6 Hz, 2H), 3.45 (dd,J = 6.0, 2.7 Hz, 1H), 1.97 (dq,J = 25.9, 6.8 Hz, 4H). | 482.20 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)氮丙啶-2-甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.55 - 7.49 (m, 2H), 7.43 (d,J = 8.3 Hz, 2H), 7.40 - 7.29 (m, 4H), 4.33 (dd,J = 5.6, 2.6 Hz, 1H), 3.99 (t,J = 5.8 Hz, 1H), 3.69 (s, 3H), 3.61 (t,J = 6.9 Hz, 2H), 3.50 (t,J = 6.6 Hz, 2H), 3.45 (dd,J = 6.0, 2.7 Hz, 1H), 1.97 (dq,J = 25.9, 6.8 Hz, 4H). | 482.20 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)氮丙啶-2-甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.22 (s, 1H), 7.55 - 7.49 (m, 2H), 7.43 (d,J = 8.3 Hz, 2H), 7.40 - 7.29 (m, 4H), 4.33 (dd,J = 5.6, 2.6 Hz, 1H), 3.99 (t,J = 5.8 Hz, 1H), 3.69 (s, 3H), 3.61 (t,J = 6.9 Hz, 2H), 3.50 (t,J = 6.6 Hz, 2H), 3.45 (dd,J = 6.0, 2.7 Hz, 1H), 1.97 (dq,J = 25.9, 6.8 Hz, 4H). | 482.20 | |
(4-(4-胺基-7-甲基-6-(1-甲基-2-乙烯基-1H-苯并[d]咪唑-6-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.62 (d,J = 1.6 Hz, 1H), 7.57 (d,J = 8.3 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.31 - 7.25 (m, 2H), 7.12 - 7.05 (m, 1H), 7.04 (dd,J = 16.1, 10.0 Hz, 1H), 6.43 (dd,J = 17.1, 2.1 Hz, 1H), 5.94 (s, 1H), 5.73 (dd,J = 11.0, 2.0 Hz, 1H), 3.80 (s, 3H), 3.64 (s, 3H), 3.41 (dt,J = 24.1, 6.5 Hz, 4H), 1.82 (dq,J = 19.1, 6.8 Hz, 4H). | 478.25 | |
(S)-N-(5-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.43 (s, 1H), 8.13 (s, 1H), 7.59 (d,J = 7.9 Hz, 2H), 7.36 (d,J = 7.7 Hz, 2H), 7.05 (s, 1H), 5.89 (s, 1H), 5.53 (d,J = 1.8 Hz, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 3.68 (t,J = 6.9 Hz, 2H), 3.47 (t,J = 6.5 Hz, 2H), 3.25 (s, 3H), 2.09 (s, 3H), 1.97 (dp,J = 24.7, 6.7 Hz, 4H). | 485.20 | |
(4-(4-胺基-7-甲基-6-(1-甲基-2-乙烯基-1H-苯并[d]咪唑-5-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.62 - 7.53 (m, 2H), 7.48 - 7.41 (m, 2H), 7.30 - 7.23 (m, 2H), 7.16 (dd,J = 8.3, 1.5 Hz, 1H), 7.04 (dd,J = 17.1, 11.0 Hz, 1H), 6.41 (dd,J = 17.1, 2.1 Hz, 1H), 5.92 (s, 2H), 5.72 (dd,J = 11.0, 2.1 Hz, 1H), 3.85 (s, 3H), 3.61 (s, 3H), 3.41 (dt,J = 18.5, 6.5 Hz, 4H), 1.81 (dq,J = 20.2, 6.8 Hz, 4H). | 478.25 | |
(S)-N-(4-(4-胺基-7-甲基-5-(2-側氧基-4-(吡咯啶-1-羰基)哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.10 (s, 1H), 7.88 - 7.80 (m, 2H), 7.42 - 7.33 (m, 2H), 6.91 (s, 2H), 5.83 (t,J = 1.1 Hz, 1H), 5.59 - 5.53 (m, 1H), 3.62 (s, 3H), 3.53 (dt,J = 10.2, 6.6 Hz, 1H), 3.45 - 3.33 (m, 2H), 3.32 - 3.29 (m, 1H), 3.15 (s, 1H), 2.95 (dd,J = 11.4, 4.9 Hz, 1H), 2.49 - 2.32 (m, 2H), 1.98 (d,J = 1.2 Hz, 4H), 1.88 (p,J = 6.2 Hz, 2H), 1.79 (p,J = 7.8, 7.1 Hz, 2H), 1.68 (s, 1H), 1.24 (s, 1H). | 502.25 | |
(R)-N-(4-(4-胺基-7-甲基-5-(2-側氧基-4-(吡咯啶-1-羰基)哌啶-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.10 (s, 1H), 7.88 - 7.80 (m, 2H), 7.43 - 7.33 (m, 2H), 6.93 (s, 1H), 5.83 (t,J = 1.0 Hz, 1H), 5.59 - 5.53 (m, 1H), 3.62 (s, 3H), 3.53 (dt,J = 10.3, 6.6 Hz, 1H), 3.45 - 3.33 (m, 2H), 3.32 (s, 1H), 3.15 (s, 1H), 2.99 - 2.91 (m, 1H), 2.47 - 2.33 (m, 2H), 1.98 (d,J = 1.2 Hz, 4H), 1.88 (d,J = 6.6 Hz, 2H), 1.80 (d,J = 6.5 Hz, 2H), 1.73 - 1.61 (m, 1H), 1.24 (s, 1H). | 502.25 | |
N-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-氯乙醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.41 (d,J = 5.1 Hz, 1H), 8.21 (s, 1H), 7.66 (d,J = 8.5 Hz, 2H), 7.35 (t,J = 9.3 Hz, 4H), 7.24 - 7.06 (m, 3H), 4.21 (s, 2H), 3.71 (s, 3H), 2.50 (s, 3H). | 500.30 | |
7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-6-(2-乙烯基嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.66 (s, 2H), 8.44 - 8.36 (m, 2H), 7.40-7.30 (m, 2H), 7.38-7.23 (m, 2H), 6.98 - 6.86 (m, 2H), 6.68 (dd,J = 17.4, 1.7 Hz, 1H), 5.82 (dd,J = 10.6, 1.7 Hz, 1H), 5.16 (s, 2H), 3.81 (s, 3H), 2.53 (s, 3H). | 437.25 | |
(R)-(3-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)(環氧乙烷-2-基)甲酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.44 (dd,J = 5.1, 3.5 Hz, 1H), 8.19 (d,J = 2.8 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.38 - 7.27 (m, 2H), 7.16 (dd,J = 5.1, 2.3 Hz, 1H), 6.25 (dt,J = 23.2, 2.0 Hz, 1H), 4.82 - 4.61 (m, 1H), 4.49 - 4.29 (m, 2H), 4.20 (d,J = 3.9 Hz, 1H), 3.87 (d,J = 13.1 Hz, 3H), 3.60 (ddd,J = 90.2, 4.3, 2.4 Hz, 1H), 2.94 (ddd,J = 36.6, 6.4, 4.3 Hz, 1H), 2.81 (ddd,J = 28.6, 6.4, 2.4 Hz, 1H), 2.52 (d,J = 2.1 Hz, 3H). | 470.20 | |
(S)-(3-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)(環氧乙烷-2-基)甲酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.44 (dd,J = 5.1, 3.5 Hz, 1H), 8.19 (d,J = 2.8 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.38 - 7.27 (m, 2H), 7.16 (dd,J = 5.1, 2.3 Hz, 1H), 6.25 (dt,J = 23.2, 2.0 Hz, 1H), 4.82 - 4.61 (m, 1H), 4.49 - 4.29 (m, 2H), 4.20 (d,J = 3.9 Hz, 1H), 3.87 (d,J = 13.1 Hz, 3H), 3.60 (ddd,J = 90.2, 4.3, 2.4 Hz, 1H), 2.94 (ddd,J = 36.6, 6.4, 4.3 Hz, 1H), 2.81 (ddd,J = 28.6, 6.4, 2.4 Hz, 1H), 2.52 (d,J = 2.1 Hz, 3H). | 470.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-氰基乙醯胺 | 1H NMR (400 MHz, DMSO-d6) δ10.42 (s, 1H), 8.21 (s, 1H), 7.57 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.33 - 7.22 (m, 4H), 6.00 (s, 2H), 3.92 (s, 2H), 3.61 (s, 3H), 3.44 (dt, J = 19.1, 6.5 Hz, 4H), 1.84 (dq, J = 18.4, 6.8 Hz, 4H). | 480.20 | |
N-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4,5-二氫呋喃-3-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.47 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.75 - 7.64 (m, 2H), 7.51 (d,J = 1.9 Hz, 1H), 7.29 (d,J = 8.4 Hz, 4H), 7.21 - 7.14 (m, 3H), 5.90 (s, 1H), 4.52 (t,J = 9.7 Hz, 2H), 3.61 (s, 3H), 3.06 - 2.75 (m, 2H), 2.41 (s, 3H). | 520.25 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2,5-二氫呋喃-3-甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.75 - 7.68 (m, 2H), 7.37 - 7.25 (m, 4H), 7.22 - 7.12 (m, 3H), 6.97 - 6.92 (m, 1H), 5.93 (s, 2H), 4.77 (h,J = 2.9 Hz, 4H), 3.61 (s, 3H), 2.41 (s, 3H). | 520.20 | |
5-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)噻唑-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.86 (d,J = 8.3 Hz, 2H), 7.53 (d,J = 8.3 Hz, 2H), 7.33 (d,J = 8.5 Hz, 2H), 7.24 - 7.19 (m, 2H), 7.16 (d,J = 5.0 Hz, 1H), 3.67 (s, 3H), 2.41 (s, 3H). | 517.20 | |
5-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)噁唑-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H), 7.88 (d,J = 8.2 Hz, 2H), 7.55 (d,J = 8.1 Hz, 2H), 7.31 (d,J = 8.2 Hz, 2H), 7.23 - 7.13 (m, 3H), 5.98 (s, 1H), 3.67 (s, 3H), 2.41 (s, 3H). | 501.15 | |
7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(4-(2-乙烯基噻唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.42 - 8.36 (m, 2H), 7.99 (s, 1H), 7.63 - 7.55 (m, 2H), 7.38 - 7.30 (m, 4H), 7.26 - 7.16 (m, 2H), 6.99 - 6.88 (m, 2H), 6.09 (d,J = 17.5 Hz, 1H), 5.61 (d,J = 10.9 Hz, 1H), 5.27 (s, 2H), 3.80 (s, 3H), 2.52 (s, 3H). | 518.25 | |
6-(4-(2-氯噁唑-5-基)苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.86 (s, 1H), 7.76 - 7.69 (m, 2H), 7.53 - 7.46 (m, 2H), 7.34 - 7.27 (m, 2H), 7.23 - 7.13 (m, 3H), 3.66 (s, 3H), 2.41 (s, 3H), 1.24 (s, 1H). | 510.15 | |
6-(4-(2-乙炔基噁唑-5-基)苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6)8.46 (s, 1H), 8.23 (s, 1H), 7.89 (s, 1H), 7.80-7.75 (m, 2H), 7.50 (s, 2H), 7.31 (m, 2H), 7.19 (s, 3H), 5.95 (s, 1H), 4.97 (s, 1H), 3.66 (s, 3H), 2.41 (s, 3H). | 500.15 | |
6-(2-氟嘧啶-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, J = 1.5 Hz, 2H), 8.48 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.44 - 7.31 (m, 2H), 7.26 - 7.21 (m, 2H), 5.81 (s, 1H), 7.17 (d, J = 5.0 Hz, 1H), 3.70 (s, 3H), 2.42 (s, 3H). | 429.10 | |
(S)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(4-(環氧乙烷-2-基甲氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.39 - 7.23 (m, 4H), 7.22 - 7.09 (m, 3H), 7.07 - 6.92 (m, 2H), 5.82 (d,J = 52.7 Hz, 2H), 4.36 (dd,J = 11.3, 2.8 Hz, 1H), 3.86 (dd,J = 11.4, 6.6 Hz, 1H), 3.58 (s, 3H), 3.17 (d,J = 5.3 Hz, 1H), 2.85 (t,J = 4.7 Hz, 1H), 2.76 - 2.61 (m, 1H), 2.42 (s, 3H). | 481.20 | |
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)氮雜環丁-2-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.37 (s, 4H), 7.31 - 7.25 (m, 2H), 7.21 - 7.14 (m, 3H), 5.84 (d, J = 60.6 Hz, 1H), 3.65 (t, J = 4.5 Hz, 2H), 3.60 (s, 3H), 3.09 (t, J = 4.5 Hz, 2H), 2.41 (s, 3H). | 478.15 | |
7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(4-((環氧乙烷-2-基甲基)胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.0 Hz,1H), 8.17 (s, 1H), 7.33 - 7.24 (m, 2H), 7.21 - 7.12 (m, 3H), 7.11 - 7.00 (m, 2H), 6.64 (d, J = 8.5 Hz, 2H), 6.14 (t, J = 5.6 Hz, 1H), 5.81 (s, 1H), 3.58 (s, 3H), 3.40 - 3.33 (m, 1H), 3.09 (td, J = 7.6, 6.2, 3.5 Hz, 2H), 2.75 (dd, J = 5.1, 3.9 Hz, 1H), 2.60 (dd, J = 5.1, 2.3 Hz, 1H), 2.42 (s, 3H), | 480.15 | |
(R)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(4-(環氧乙烷-2-基甲氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.38 - 7.22 (m, 4H), 7.22 - 7.11 (m, 3H), 7.07 - 6.97 (m, 2H), 4.36 (dd,J = 11.4, 2.8 Hz, 1H), 3.86 (dd,J = 11.3, 6.6 Hz, 1H), 3.58 (s, 3H), 3.31 (s, 1H), 2.85 (dd,J = 5.1, 4.2 Hz, 1H), 2.72 (dd,J = 5.1, 2.7 Hz, 1H), 2.41 (s, 3H). | 481.25 | |
7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(4-(2-乙烯基噁唑-5-基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.84 - 7.76 (m, 3H), 7.51 - 7.45 (m, 2H), 7.35 - 7.27 (m, 2H), 7.23 - 7.12 (m, 3H), 6.70 (dd,J = 17.6, 11.2 Hz, 1H), 6.26 (dd,J = 17.6, 1.1 Hz, 1H), 6.03 (s, 1H), 5.91 (s, 1H), 5.79 - 5.72 (m, 1H), 3.66 (s, 3H), 2.40 (s, 3H). | 502.15 | |
(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)胺基甲酸甲酯 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.80 (s, 1H), 8.20 (s, 1H), 7.48 (dd,J = 8.7, 7.1 Hz, 4H), 7.32 - 7.18 (m, 4H), 3.67 (s, 3H), 3.60 (s, 3H), 3.43 (dt,J = 16.5, 6.5 Hz, 4H), 1.83 (dq,J = 18.3, 6.7 Hz, 4H). | 471.25 | |
1-(7-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,4-二氫異喹啉-2(1H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.36 - 7.26 (m, 2H), 7.25 - 7.09 (m, 6H), 6.89 (dd,J = 16.6, 10.6 Hz, 1H), 6.15 (dd,J = 16.7, 2.4 Hz, 1H), 5.72 (dd,J = 10.4, 2.4 Hz, 1H), 4.76 (d,J = 41.4 Hz, 2H), 3.78 (dt,J = 24.4, 5.9 Hz, 2H), 3.61 (s, 3H), 2.94 - 2.71 (m, 2H), 2.41 (s, 3H). | 518.20 | |
(R)-N-(7-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,2,3,4-四氫萘-2-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.23 - 8.14 (m, 2H), 7.38 - 7.29 (m, 2H), 7.24 - 7.07 (m, 6H), 6.26 (dd,J = 17.1, 10.0 Hz, 1H), 6.10 (dd,J = 17.1, 2.4 Hz, 1H), 5.97 - 5.69 (m, 1H), 5.59 (dd,J = 10.1, 2.4 Hz, 1H), 4.03 (s, 1H), 3.61 (s, 3H), 2.97 (dd,J = 16.6, 5.3 Hz, 1H), 2.85 (d,J = 11.2 Hz, 2H), 2.71 - 2.57 (m, 2H), 2.41 (s, 3H), 1.97 (d,J = 12.0 Hz, 1H), 1.76 - 1.62 (m, 1H). | 532.25 | |
(S)-N-(7-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,2,3,4-四氫萘-2-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.19 (d,J = 4.2 Hz, 2H), 7.35 - 7.27 (m, 2H), 7.26 - 7.08 (m, 6H), 6.33 - 6.23 (m, 1H), 6.12 (d,J = 2.3 Hz, 1H), 6.08 (d,J = 2.4 Hz, 1H), 5.59 (dd,J = 10.1, 2.4 Hz, 1H), 4.03 (s, 1H), 3.61 (s, 3H), 2.97 (dd,J = 16.5, 5.3 Hz, 1H), 2.85 (d,J = 11.2 Hz, 2H), 2.84 - 2.57 (m, 2H), 2.41 (s, 3H), 1.98 (d,J = 11.9 Hz, 1H), 1.67 (p,J = 9.8 Hz, 1H). | 532.25 | |
(S)-N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,3-二氫-1H-茚-1-基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 8.3 Hz, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.35 - 7.26 (m, 3H), 7.25 - 7.14 (m, 5H), 6.32 - 6.12 (m, 2H), 5.81 (s, 1H), 5.63 (dd, J = 9.9, 2.5 Hz, 1H), 5.39 (q, J = 8.0 Hz, 1H), 3.59 (s, 3H), 2.99 - 2.88 (m, 1H), 2.83 (dt, J = 16.2, 8.3 Hz, 1H), 2.45 (dt, J = 8.0, 3.8 Hz, 1H), 2.41 (s, 3H), 1.82 (dq, J = 12.5, 8.7 Hz, 1H). | 518.25 | |
(R)-N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,3-二氫-1H-茚-1-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.73 (t,J = 7.7 Hz, 1H), 7.30 - 7.15 (m, 5H), 7.13 - 7.06 (m, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.89 (dd,J = 16.7, 10.5 Hz, 1H), 6.77 (d,J = 8.2 Hz, 1H), 6.15 (dd,J = 16.7, 2.4 Hz, 1H), 5.88 (s, 2H), 5.72 (dd,J = 10.4, 2.4 Hz, 1H), 4.81 (s, 1H), 4.71 (s, 1H), 3.80 (d,J = 6.3 Hz, 2H), 3.62 (s, 3H), 2.83 (s, 2H), 2.33 (s, 3H). | 517.25 | |
(R)-N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,3-二氫-1H-茚-2-基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.41 (m, 2H), 8.20 (s, 1H), 7.34 - 7.23 (m, 4H), 7.21 - 7.13 (m, 4H), 6.26 - 6.06 (m, 2H), 5.88 (s, 1H), 5.58 (dd, J = 9.9, 2.5 Hz, 1H), 4.56 (q, J = 6.6 Hz, 1H), 3.59 (s, 3H), 3.23 (ddd, J = 16.2, 12.9, 7.6 Hz, 2H), 2.81 (ddd, J = 16.8, 11.8, 5.6 Hz, 2H), 2.41 (s, 3H). | 518.20 | |
(S)-N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,3-二氫-1H-茚-2-基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.49 - 8.41 (m, 2H), 8.20 (s, 1H), 7.34 - 7.23 (m, 4H), 7.21 - 7.13 (m, 4H), 6.26 - 6.06 (m, 2H), 5.88 (s, 1H), 5.58 (dd, J = 9.9, 2.5 Hz, 1H), 4.56 (q, J = 6.6 Hz, 1H), 3.59 (s, 3H), 3.23 (ddd, J = 16.2, 12.9, 7.6 Hz, 2H), 2.81 (ddd, J = 16.8, 11.8, 5.6 Hz, 2H), 2.41 (s, 3H). | 518.25 | |
1-(2-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1,5,6,7-四氫-4H-咪唑并[4,5-b]吡啶-4-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.74 (dd,J = 28.0 Hz, 1H), 7.31 (d,J = 8.2 Hz, 2H), 7.25 (d,J = 8.4 Hz, 2H), 7.16 (d,J = 5.2 Hz, 1H), 6.25 (d,J = 16.0 Hz, 1H), 5.77 - 5.69 (m, 1H), 3.83 (s, 2H), 3.66 (s, 3H), 2.99 (s, 3H), 2.58 (t,J = 6.4 Hz, 2H), 2.40 (s, 3H), 1.94 (s, 2H). | 522.25 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯甲基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.65 (t, J = 6.1 Hz, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.36 (d, J = 8.2 Hz, 2H), 7.33 - 7.27 (m, 4H), 7.21 - 7.13 (m, 3H), 6.30 (dd, J = 17.1, 10.1 Hz, 1H), 6.14 (dd, J = 17.1, 2.2 Hz, 1H), 5.89 (s, 1H), 5.64 (dd, J = 10.1, 2.3 Hz, 1H), 4.40 (d, J = 6.0 Hz, 2H), 3.59 (s, 3H), 2.41 (s, 3H). | 492.20 | |
N-(2-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙-2-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.48 (s, 1H), 8.20 (s, 1H), 7.73 (t,J = 7.7 Hz, 1H), 7.62 (d,J = 8.2 Hz, 1H), 7.32 - 7.25 (m, 2H), 7.23 (d,J = 2.0 Hz, 1H), 7.17 (dd,J = 8.3, 2.1 Hz, 1H), 7.15 - 7.07 (m, 2H), 7.01 (d,J = 7.3 Hz, 1H), 6.77 (d,J = 8.1 Hz, 1H), 6.57 (dd,J = 17.0, 10.2 Hz, 1H), 6.26 (dd,J = 17.0, 2.1 Hz, 1H), 6.14 - 5.86 (m, 1H), 5.77 (dd,J = 10.2, 2.0 Hz, 1H), 3.63 (s, 3H), 2.34 (s, 3H), 2.20 (s, 3H). | 491.35 | |
7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(2-乙烯基-1H-苯并[d]咪唑-6-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.74 (d,J = 14.7 Hz, 1H), 8.44 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.62 (s, 1H), 7.55 - 7.34 (m, 1H), 7.34 - 7.24 (m, 2H), 7.21 - 7.04 (m, 4H), 6.77 (dd,J = 17.8, 11.2 Hz, 1H), 6.28 (d,J = 17.8 Hz, 1H), 5.88 (s, 1H), 5.69 (d,J = 11.4 Hz, 1H), 3.61 (s, 3H), 2.39 (s, 3H). | 475.20 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-(己-5-炔-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.76 (d,J = 8.7 Hz, 2H), 7.37 - 7.28 (m, 3H), 7.24 - 7.15 (m, 2H), 7.11 (d,J = 8.1 Hz, 1H), 6.01 (s, 2H), 5.81 (s, 1H), 5.54 (s, 1H), 4.11 (t,J = 7.2 Hz, 2H), 2.70 (t,J = 2.7 Hz, 1H), 2.42 (s, 3H), 2.04 (td,J = 7.0, 2.6 Hz, 2H), 1.96 (t,J = 1.2 Hz, 3H), 1.60 (q,J = 7.4 Hz, 2H), 1.26 (q,J = 7.3 Hz, 2H). | 576.25 | |
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4-羥基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.04 (d,J = 3.8 Hz, 1H), 9.95 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.00 (d,J = 3.7 Hz, 1H), 7.82 - 7.70 (m, 2H), 7.38 - 7.23 (m, 3H), 7.20 - 7.11 (m, 2H), 7.06 - 6.99 (m, 1H), 5.81 (d,J = 1.4 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.57 (s, 3H), 2.42 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 511.20 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-5-氯-2-氟苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) 9.78 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.93 (d, J = 7.0 Hz, 1H), 7.52 (d, J = 10.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.23 -7.12 (m, 3H), 6.38-5.88(s,1H),5.88 (s, 1H), 5.60 (s, 1H), 3.51 (s, 3H), 2.40 (s, 3H), 1.95 (d, J = 1.3 Hz, 3H). | 544.15 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氯-2-氟苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.21 (s, 1H), 7.42 (s, 4H), 7.30 (d,J = 8.5 Hz, 2H), 7.22 - 7.12 (m, 3H), 5.82 (d,J = 1.6 Hz, 1H), 4.27 (s, 2H), 3.61 (s, 3H), 2.41 (s, 3H). | 544.30 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-5-氯-2-甲基苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) 9.38 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.68 (s, 1H), 7.34 (s, 1H), 7.32-7.25 (m, 2H), 7.22-7.11 (m, 3H), 5.95 (s, 2H), 5.55 (t, J = 1.5 Hz, 1H), 3.48 (s, 3H), 2.40 (s, 3H), 2.18 (s, 3H), 1.97 (t, J = 1.3 Hz, 3H). | 540.15 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氟-5-甲基苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6)9.88 (s, 1H), 8.57-8.39 (m, 2H), 7.85-7.59 (m, 1H), 7.35 (dd, J = 8.4, 1.5 Hz, 1H), 7.31-7.25 (m, 2H), 7.24-7.19 (m, 2H), 7.16 (d, J = 5.0 Hz, 1H), 5.90 (s, 1H), 5.62 (d, J = 1.8 Hz, 1H), 3.58 (s, 3H), 2.41 (s, 3H), 1.96 (d, J = 1.2 Hz, 3H). | 524.35 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.39 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.61 (d,J = 8.1 Hz, 1H), 7.38 (d,J = 8.3 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.19 - 7.11 (m, 3H), 5.92 (s, 2H), 5.56 (t,J = 1.5 Hz, 1H), 3.45 (s, 3H), 2.40 (s, 3H), 2.06 (s, 3H), 1.97 (t,J = 1.2 Hz, 3H). | 540.20 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氯-2-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.63 (s, 1H), 8.44 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.38 - 7.24 (m, 4H), 7.20 - 7.11 (m, 3H), 5.88 (s, 1H), 5.55 (t,J = 1.5 Hz, 1H), 3.46 (s, 3H), 2.40 (s, 3H), 2.27 (s, 3H), 1.96 (t,J = 1.2 Hz, 3H). | 540.20 | |
N-(3-氯-4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.77 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.72 (dd, J = 8.5, 2.1 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.31 (t, J = 6.0 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 5.84 (s, 1H), 5.59 (s, 1H), 3.58 (s, 3H), 2.41 (d, J = 8.0 Hz, 6H), 1.96 (d, J = 1.3 Hz, 3H). | 543.20 | |
N-(3-氯-4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 8.77 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.08 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.5, 2.0 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38 - 7.25 (m, 2H), 7.16 (dd, J = 16.1, 6.7 Hz, 2H), 6.43 (dd, J = 16.9, 10.0 Hz, 1H), 6.31 (dd, J = 17.0, 2.1 Hz, 1H), 5.84 (dd, J = 9.9, 2.1 Hz, 1H), 3.58 (s, 3H), 2.41 (d, J = 8.9 Hz, 6H). | 529.20 | |
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基氮雜環丁-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d,J = 11.7 Hz, 1H), 8.13 (s, 1H), 7.63 (d,J = 2.7 Hz, 1H), 6.59 (s, 2H), 5.69 (d,J = 30.0 Hz, 2H), 4.42 (d,J = 1.1 Hz, 1H), 3.51 - 3.38 (m, 2H), 3.37 (d,J = 1.4 Hz, 3H), 3.28 (s, 0H), 2.75 (s, 0H), 2.68 (p,J = 1.8 Hz, 1H), 2.34 (p,J = 1.9 Hz, 1H), 2.20 (d,J = 7.1 Hz, 2H), 1.93 (d,J = 9.1 Hz, 2H), 1.85 (q,J = 6.1 Hz, 1H), 1.82 - 1.69 (m, 2H), 1.60 (d,J = 7.0 Hz, 2H). | 490.15 | |
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-甲基-1,5-二氫-2H-吡咯-2-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.41 (d,J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.90 - 7.80 (m, 2H), 7.42 - 7.34 (m, 4H), 7.22 - 7.12 (m, 3H), 7.03 (q,J = 1.8 Hz, 1H), 4.45 (p,J = 2.0 Hz, 2H), 3.72 (s, 3H), 2.50 (s, 3H), 1.94 (q,J = 1.9 Hz, 3H). | 504.20 | |
N-(6-(4-胺基-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-5-甲基吡啶-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.10 (s, 1H), 8.90 (d,J = 2.4 Hz, 1H), 8.24 (s, 1H), 8.03 (d,J = 2.4 Hz, 1H), 7.78 - 7.71 (m, 1H), 7.24 (t,J = 8.4 Hz, 1H), 7.07 - 6.95 (m, 3H), 6.86 (d,J = 8.2 Hz, 1H), 6.21 (s, 1H), 5.87 (s, 1H), 5.60 (s, 1H), 3.51 (s, 3H), 2.30 (s, 3H), 1.97 (t,J = 1.2 Hz, 3H), 1.83 (s, 3H). | 524.35 | |
N-(6-(4-胺基-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-5-氟吡啶-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 (s, 1H), 8.89 - 8.84 (m, 1H), 8.25 (s, 1H), 8.13 (dd,J = 11.9, 2.0 Hz, 1H), 7.75 (dd,J = 8.2, 7.3 Hz, 1H), 7.27 (t,J = 8.4 Hz, 1H), 7.14 (dd,J = 11.5, 2.1 Hz, 1H), 7.07 - 6.98 (m, 2H), 6.86 (d,J = 8.2 Hz, 1H), 6.22 (s, 1H), 5.90 (s, 1H), 5.68 - 5.63 (m, 1H), 3.65 (s, 3H), 2.31 (s, 3H), 1.97 (t,J = 1.2 Hz, 3H). | 528.35 | |
N-(5-(4-胺基-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-6-甲基吡啶-2-基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.32 (d, J = 13.1 Hz, 1H), 8.23 (s, 1H), 8.11 - 8.00 (m, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.73 (dd, J = 8.2, 7.4 Hz, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.13 (dd, J = 11.6, 2.0 Hz, 1H), 7.07 - 6.97 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.13 (s, 1H), 5.94 (s, 1H), 5.58 - 5.53 (m, 1H), 3.50 (s, 3H), 2.28 (s, 3H), 2.10 (s, 3H), 1.96 (t, J = 1.2 Hz, 3H). | 524.21 | |
N-(5-(4-胺基-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-甲基吡啶-2-基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.23 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.25 (t, J = 8.4 Hz, 1H), 7.13 (dd, J = 11.5, 2.1 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.85 (d, J = 8.2 Hz, 1H), 5.94 (s, 1H), 5.58 - 5.53 (m, 1H), 3.50 (s, 3H), 2.28 (s, 3H), 2.09 (s, 3H), 1.96 (t, J = 1.2 Hz, 3H). | 524.21 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟-5-甲基苯基)甲基丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.66 (dd, J = 11.6, 2.0 Hz, 1H), 7.44 - 7.42 (m, 1H), 7.26 - 7.22 (m, 2H), 7.21 - 7.13 (m, 3H), 6.01 (s, 1H), 5.82 (s, 1H), 5.57 (s, 1H), 3.45 (s, 3H), 2.40 (s, 3H), 1.96 - 1.89 (m, 6H). | 524.25 | |
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 9.23 (s, 1H), 8.94 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 7.76 -7.67 (m, 2H), 7.42 (d,J = 8.3 Hz, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.26 -7.15 (m, 3H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.30 (dd,J = 17.0, 2.1 Hz, 1H), 5.80 (dd,J = 10.1, 2.1 Hz, 1H), 3.55 (s, 3H), 2.42 (s, 3H), 2.00 (s, 3H). | 495.20 | |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) 10.22 (s, 1H), 8.45 (d, J = 4.3 Hz, 1H), 8.21 (d, J = 3.0 Hz, 1H), 7.60 (d, J = 13.2 Hz, 2H), 7.35 -7.28 (m, 1H), 7.28 -7.22 (m, 2H), 7.15 (d, J = 7.4 Hz, 3H), 6.45 (dd, J = 17.9, 9.9 Hz, 1H), 6.27 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.2 Hz, 1H),5.56 (s, 1H), 3.39 (s, 3H), 2.40 (d, J = 3.0 Hz, 3H), 1.97 (d, J = 3.0 Hz, 3H). | 492.20 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6)10.24 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.66 -7.57 (m, 2H), 7.32 (t, J = 8.4 Hz, 2H), 7.17 (d, J = 5.0 Hz, 1H), 7.12 (dd, J = 11.6, 2.1 Hz, 1H), 7.06 (dd, J = 8.4, 2.0 Hz, 1H), 6.45 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J = 17.0, 2.1 Hz, 1H), 6.08 -6.01 (m, 1H), 5.78 (dd, J = 10.0, 2.1 Hz, 1H), 3.43 (s, 3H), 2.41 (s, 3H), 1.96 (s, 3H). | 510.10 | |
6-(2,6-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ8.47 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.72 (d,J = 7.8 Hz, 1H), 7.33 (t,J = 8.4 Hz, 1H), 7.24-7.11 (m, 3H), 7.08-7.01 (m, 1H), 3.44 (s, 3H), 2.48 (s, 3H), 2.41 (s, 3H), 2.12 (s, 3H). | 456.20 | |
(2E)-3-[4-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基]-2-氰基-N-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.41 (d,J = 4.6 Hz, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.94 - 7.89 (m, 1H), 7.86 (d,J = 1.8 Hz, 1H), 7.62 (s, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.06 (ddd,J = 8.3, 2.1, 0.8 Hz, 1H), 6.09 (s, 1H), 3.46 (s, 3H), 2.77 (d,J = 4.5 Hz, 3H), 2.40 (s, 3H), 2.04 (s, 3H). | 549.35 | |
(E)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(6-(3-甲氧基丙-1-烯-1-基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.01 (s, 3H), 2.40 (s, 3H), 3.46 (s, 3H), 4.11 (d,J = 5.1 Hz, 2H), 6.68 (s, 1H), 6.79 - 6.88 (m, 1H), 7.05 (d,J = 8.3 Hz, 1H), 7.12 - 7.21 (m, 2H), 7.32 (t,J = 8.4 Hz, 1H), 7.43 (s, 1H), 8.23 (s, 1H), 8.46 (d,J = 4.9 Hz, 2H). | 512.4 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環己-3-烯-1-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (d,J = 5.0 Hz, 1H), 8.17 (s, 1H), 8.08 (d,J = 7.5 Hz, 1H), 7.43 (t,J = 8.4 Hz, 1H), 7.32 (dd,J = 11.5, 2.1 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.22 (dd,J = 17.0, 10.0 Hz, 1H), 6.07 (dd,J = 17.1, 2.3 Hz, 2H), 5.84 (d,J = 4.4 Hz, 1H), 5.57 (dd,J = 10.0, 2.4 Hz, 1H), 3.91 (s, 1H), 3.66 (s, 3H), 2.42 (m, 4H), 2.21 (s, 1H), 2.08 (d,J = 15.5 Hz, 2H), 1.78 (d,J = 25.3 Hz, 1H), 1.53 (dd,J = 11.5, 5.2 Hz, 1H). | 500.10 | |
(R)-N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環己-3-烯-1-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (d,J = 5.0 Hz, 1H), 8.16 (s, 1H), 8.07 (d,J = 7.5 Hz, 1H), 7.43 (t,J = 8.4 Hz, 1H), 7.32 (dd,J = 11.4, 2.1 Hz, 1H), 7.26 - 7.17 (m, 2H), 6.22 (dd,J = 17.1, 10.1 Hz, 1H), 6.07 (dd,J = 17.1, 2.4 Hz, 1H), 6.00 (s, 1H), 5.83 (d,J = 4.6 Hz, 1H), 5.56 (dd,J = 10.1, 2.3 Hz, 1H), 3.91 (s, 1H), 3.65 (s, 3H), 2.42 (s, 3H), 2.27 (d,J = 45.4 Hz, 1H), 2.08 (d,J = 15.3 Hz, 2H), 1.89 - 1.73 (m, 1H), 1.54 (dd,J = 11.3, 5.2 Hz, 1H). | 500.25 | |
(S)-N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環己-3-烯-1-基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (d,J = 5.0 Hz, 1H), 8.16 (s, 1H), 8.06 (d,J = 7.5 Hz, 1H), 7.43 (t,J = 8.3 Hz, 1H), 7.33 (d,J = 2.0 Hz, 1H), 7.21 (dd,J = 13.1, 6.7 Hz, 2H), 6.22 (dd,J = 17.1, 10.1 Hz, 1H), 6.07 (dd,J = 17.1, 2.3 Hz, 1H), 5.98 (s, 1H), 5.84 (s, 1H), 5.56 (dd,J = 10.0, 2.4 Hz, 1H), 3.91 (s, 1H), 3.65 (s, 3H), 2.42 (s, 4H), 2.21 (s, 1H), 2.15 - 1.97 (m, 2H), 1.83 (d,J = 11.9 Hz, 1H), 1.54 (dd,J = 11.5, 5.2 Hz, 1H). | 500.25 | |
7-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-亞甲基-3,4-二氫萘-1(2H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 )δ 8.46 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.91 (d,J = 1.9 Hz, 1H), 7.60 (dd,J = 7.9, 2.0 Hz, 1H), 7.44 (d,J = 8.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 7.22 - 7.10 (m, 3H), 6.05 (d,J = 2.1 Hz, 1H), 5.93 (s, 2H), 5.56 (d,J = 1.9 Hz, 1H), 3.61 (s, 3H), 3.02 (t,J = 6.4 Hz, 2H), 2.90 - 2.82 (m, 2H), 2.40 (s, 3H). | 489.30 | |
6-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-亞甲基-3,4-二氫萘-1(2H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 )δ 8.46 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.93 (d,J = 8.1 Hz, 1H), 7.42 (d,J = 1.7 Hz, 1H), 7.36 (dd,J = 8.0, 1.7 Hz, 1H), 7.35 -7.27 (m, 2H), 7.24- 7.13 (m, 3H), 6.06 (d,J = 2.1 Hz, 1H), 5.99 (s, 2H), 5.56 (d,J = 2.0 Hz, 1H), 3.68 (s, 3H), 2.96 (t,J = 6.3 Hz, 2H), 2.84 (t,J = 6.1 Hz, 2H), 2.41 (s, 3H). | 489.35 |
步驟 1
:向可再密封之反應瓶中裝入3-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(1.2 g,3.07 mmol)、Pd-C (120 mg,1.2 mol)及攪拌棒,隨後抽真空且用氫氣淨化三次。添加MeOH (20 mL),且在50℃下攪拌混合物隔夜。反應混合物經由Celite®墊過濾,該墊用水洗滌,且真空濃縮濾液,產生呈灰白色固體狀之3-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-甲酸第三丁酯(0.9 g,91.8%)。
3-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲酸第三丁酯
步驟 2
:向圓底燒瓶中裝入3-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-甲酸第三丁酯(300 mg,945 µmol)、NBS (168 mg,945 µmol)及攪拌棒。添加二氯甲烷(5 mL),且在室溫下攪拌溶液30分鐘。反應混合物用水(10 mL)稀釋,且水相用二氯甲烷(10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮,產生呈淺黃色固體狀之3-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-吡咯啶-1-甲酸第三丁酯(230 mg,61.4%)。
3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲酸第三丁酯
步驟 3
:向可再密封之反應瓶中裝入3-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-甲酸第三丁酯(200 mg,504 µmol)、2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]嘧啶(165 mg,554 µmol)、Pd(dtbpf)Cl2 (32.8 mg,50.4 µmol)、K3PO4 (320 mg,1.51 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF/水(2 mL),且在90℃下攪拌混合物2小時。反應混合物用水(10 mL)稀釋,且水相用二氯甲烷(10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(5 g管柱;用二氯甲烷/甲醇/0.1%三乙胺溶離;比率)。真空濃縮,產生呈淡棕色固體狀之3-{4-胺基-7-甲基-5-[4-(嘧啶-2-基氧基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-甲酸第三丁酯(100 mg,40.7%)。
7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-6-(吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入3-{4-胺基-7-甲基-5-[4-(嘧啶-2-基氧基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-甲酸第三丁酯(200 mg,410 µmol)及攪拌棒。添加TFA/DCM (1/4 mL),且在室溫下攪拌溶液30分鐘。真空濃縮反應混合物。接著溶解於飽和NaHCO3中,用DCM萃取三次。合併之有機層經無水Na2
SO4
脫水。過濾且蒸發,得到呈灰白色固體狀之7-甲基-5-[4-(嘧啶-2-基氧基)苯基]-6-(吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(150 mg,94.4%)。
1-(3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮
步驟 5
:向圓底燒瓶中裝入7-甲基-5-[4-(嘧啶-2-基氧基)苯基]-6-(吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(50 mg,129 µmol)、TEA (39.0 mg,387 µmol)、二氯甲烷(4 mL)及攪拌棒。在-30℃下添加丙-2-烯醯氯(10.4 mg,116 µmol),且在-30℃下攪拌溶液30分鐘。反應混合物經由Celite®
墊過濾,該墊用DCM洗滌且真空濃縮濾液。所得粗物質藉由HPLC純化(乙腈/水/0.1%甲酸)。凍乾產生呈白色非晶形固體狀之1-(3-{4-胺基-7-甲基-5-[4-(嘧啶-2-基氧基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮(5.92 mg,11.6%)。
根據實例14之方法製備的其他化合物描繪於下表13中。表 13 . 其他例示性化合物
實例15
(2S)-4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基-2-甲基吡咯啶-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-[4-(4-胺基-5-{3-甲氧基-4-[(6-甲基吡啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.68 (t,J = 7.7 Hz, 1H), 7.17 (d,J = 8.0 Hz, 1H), 7.10 - 7.05 (m, 1H), 6.94 (d,J = 7.3 Hz, 2H), 6.76 (dd,J = 16.7, 10.5 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.04 (dd,J = 16.7, 2.4 Hz, 1H), 5.61 (dd,J = 10.4, 2.5 Hz, 2H), 4.47 (s, 1H), 4.13 - 4.06 (m, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 3.09 (s, 2H), 2.64 (s, 2H), 2.31 (s, 3H), 1.83 (s, 2H), 1.57 (s, 2H). | 498.587 | |
1-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.30 (s, 1H), 7.66 (t,J = 7.7 Hz, 1H), 7.35 (d,J = 8.5 Hz, 2H), 7.21 (d,J = 8.3 Hz, 2H), 6.97 (d,J = 7.4 Hz, 1H), 6.76 (d,J = 8.1 Hz, 1H), 6.58 (dd,J = 16.8, 10.6 Hz, 1H), 6.28 (dd,J = 16.8, 2.0 Hz, 1H), 5.70 (dd,J = 10.5, 2.0 Hz, 1H), 4.87 - 4.83 (m, 2H), 4.79 (s, 1H), 4.08 (d,J = 13.6 Hz, 1H), 3.88 (s, 3H), 3.18 - 3.03 (m, 2H), 2.64 (s, 1H), 2.50 (s, 3H), 1.83 (s, 2H), 1.75 (s, 2H). | 469.25 | |
1-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.77 (t,J = 7.7 Hz, 1H), 7.44 (d,J = 7.3 Hz, 2H), 7.23 (d,J = 8.1 Hz, 2H), 7.05 (d,J = 7.3 Hz, 1H), 6.87 (d,J = 9.1 Hz, 1H), 6.84 - 6.75 (m, 1H), 6.08 (t,J = 17.7 Hz, 1H), 5.67 (t,J = 9.9 Hz, 1H), 4.51- 4.45 (d,J = 12.5 Hz, 1H), 4.15 - 4.07 (d,J = 13.4 Hz, 1H), 3.84 (s, 3H), 3.17 - 3.07 (m, 1H), 2.97 (s, 1H), 2.87 - 2.61 (t,J = 12.2 Hz, 1H), 2.42 - 2.35 (s, 3H), 1.90 (d,J = 12.6 Hz, 1H), 1.67 (s, 2H), 1.41 (d,J = 13.9 Hz, 2H), 1.18 (t,J = 7.3 Hz, 1H). | 469.35 | |
1-[5-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-1,2,3,6-四氫吡啶-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.34 (s, 1H), 7.64 (t,J = 7.8 Hz, 1H), 7.41 (d,J = 8.1 Hz, 2H), 7.22 (d,J = 8.6 Hz, 2H), 6.95 (d,J = 7.4 Hz, 1H), 6.75 (d,J = 8.1 Hz, 1H), 6.67 - 6.56 (m, 1H), 6.33 - 6.20 (d,J = 16.6 Hz, 1H), 6.03 (s, 1H), 5.75 (d,J = 10.6 Hz, 1H), 5.61 (d,J = 10.4 Hz, 1H), 5.44 (s, 1H) , 4.14 (s, 1H), 3.91 (s, 1H), 3.79 (s, 3H), 3.77 (s, 1H), 3.64 (s, 1H), 2.48 (s, 3H), 2.43 (s, 1H), 2.39 (s, 1H). | 467.35 | |
1-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.36 (d,J = 3.2 Hz, 1H), 7.70 - 7.59 (m, 1H), 7.40 (dd,J = 11.3, 8.3 Hz, 2H), 7.23 (dd,J = 11.3, 8.2 Hz, 2H), 6.96 (d,J = 7.3 Hz, 1H), 6.79 - 6.70 (m, 1H), 6.47- 6.37 (m, 1H), 6.24 - 6.11 (m, 1H), 5.96 (s, 1H), 5.79 - 5.64 (m, 1H), 5.02 (s, 2H), 4.52 (s, 2H), 4.32 (s, 1H), 4.22 (s, 1H), 3.88 (d,J = 10.2 Hz, 3H), 2.49 (d,J = 9.9 Hz, 3H). | 453.30 | |
1-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 7.3 Hz, 1H), 6.88 - 6.70 (m, 2H), 6.12 (d, J = 16.7 Hz, 1H), 5.97 (s, 1H), 5.92 (s, 1H), 5.69 (t, J = 9.4 Hz, 1H), 4.23 (s, 1H), 4.14 (s, 1H), 3.66 (m, 5H), 2.36 (s, 3H), 2.13 (s, 2H). | 467.2 | |
1-(3-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d,J = 1.6 Hz, 1H), 7.67 (t,J = 7.8 Hz, 1H), 7.26 - 7.07 (m, 2H), 6.96 (dd,J = 15.4, 7.5 Hz, 3H), 6.70 (dd,J = 8.2, 5.8 Hz, 1H), 6.58 - 6.39 (m, 1H), 6.10 (dd,J = 16.9, 2.6 Hz, 1H), 5.69 - 5.57 (m, 1H), 3.97 (t,J = 9.2 Hz, 1H), 3.79 (d,J = 6.4 Hz, 4H), 3.73 - 3.63 (m, 4H), 3.55 (dq,J = 17.8, 9.8, 9.2 Hz, 2H), 2.30 (d,J = 5.6 Hz, 3H), 2.21 - 1.89 (m, 2H). | 485.15 | |
1-(3-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.69 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.95 (d, J = 7.3 Hz, 1H), 6.88 - 6.71 (m, 2H), 6.09 (t, J = 17.2 Hz, 1H), 5.68 (d, J = 10.9 Hz, 1H), 4.57 - 4.47 (d, 1H), 4.19 - 4.09 (d, 1H), 3.81 (s, 3H), 3.71 (s, 3H), 3.17 - 2.98 (d, 2H), 2.72 - 2.43 (d, 1H), 2.28 (s, 3H), 1.94 (d, J = 12.6 Hz, 1H), 1.71 (s, 2H), 1.41 (s, 1H). | 499.2 | |
1-(4-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.21 (s, 1H), 7.33 - 7.25 (m, 2H), 7.06 - 6.99 (m, 2H), 6.79 (ddd, J = 21.6, 16.7, 10.4 Hz, 1H), 6.13 (dt, J = 16.7, 3.6 Hz, 1H), 5.92 (d, 1H), 5.75 - 5.64 (m, 1H), 4.22 (s, 1H), 4.13 (s, 1H), 3.80 (s, 3H), 3.66 (m, 5H), 2.08 (s, 2H). | 390.2 | |
1-(5-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.66 (dt, J = 11.8, 7.8 Hz, 1H), 7.17 (m, 1H), 7.11 (d, J = 1.9 Hz, 1H), 7.02 - 6.91 (m, 2H), 6.85 (dd, J = 16.6, 10.4 Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.31 (dd, J = 16.6, 10.4 Hz, 1H), 6.20 -5.95 (m, J = 16.1 Hz, 3H), 5.75 -5.52 (d, J = 10.5 Hz, 1H), 4.01 (s, 2H), 3.71 - 3.62 (m, 8H), 2.30 (d, J = 2.6 Hz, 5H). | 497.3 | |
1-(3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 4.5 Hz, 2H), 8.13 (d, J = 1.8 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.36 - 7.28 (m, 3H), 6.51 (ddd, J = 34.2, 16.8, 10.4 Hz, 1H), 6.11 (ddd, J = 16.8, 5.6, 2.4 Hz, 1H), 5.70 - 5.59 (m, 1H), 3.95 (t, J = 9.2 Hz, 1H), 3.80 (d, J = 6.8 Hz, 3H), 3.77 - 3.45 (m, 1H), 2.27 - 1.97 (m, 2H). | 442.25 | |
1-(4-(4-胺基-7-甲基-5-(4-(吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.23 - 8.10 (m, 2H), 7.92 - 7.82 (m, 1H), 7.39 (d, J = 7.9 Hz, 2H), 7.25 - 7.10 (m, 3H), 7.06 (d, J = 8.3 Hz, 1H), 6.78 (ddd, J = 25.5, 16.6, 10.4 Hz, 1H), 6.12 (dt, J = 16.4, 3.7 Hz, 1H), 5.94 (d, J = 24.1 Hz, 2H), 5.69 (t, J = 9.0 Hz, 1H), 4.26 - 4.08 (m, 2H), 3.63 (d, J = 12.5 Hz, 4H), 2.13 (s, 2H). | 453.1 | |
1-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.7 Hz, 2H), 8.17 (s, 1H), 7.43 (d, J = 8.0 Hz, 2H), 7.30 (q, J = 4.0, 3.2 Hz, 3H), 6.80 (ddd, J = 26.5, 16.7, 10.5 Hz, 1H), 6.12 (d, J = 16.8 Hz, 1H), 5.99 (s, 1H), 5.93 (s, 1H), 5.69 (t, J = 9.7 Hz, 1H), 4.23 (s, 1H), 4.14 (s, 1H), 3.66 (s, 3H), 3.62 (s, 0H), 3.07 (s, 1H), 2.15 (s, 2H), 1.17 (t, J = 7.3 Hz, 1H). | 454.3 | |
1-(4-(4-胺基-5-(3-甲氧基-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.20 - 8.06 (m, 2H), 7.88 - 7.75 (m, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 7.0, 4.8 Hz, 2H), 6.97 (d, J = 8.2 Hz, 2H), 6.80 (ddd, J = 27.3, 16.6, 10.3 Hz, 1H), 6.05 (dd, J = 56.4, 20.5 Hz, 3H), 5.68 (d, J = 9.0 Hz, 1H), 4.20 (d, J = 31.9 Hz, 2H), 3.66 (d, J = 3.0 Hz, 8H), 2.18 (s, 2H). | 483.35 | |
1-(4-(4-胺基-5-(3-甲氧基-4-((4-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,6-二氫吡啶-1(2H)-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 1H), 7.97 (d, J = 5.1 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 7.01 - 6.88 (m, 2H), 6.86 - 6.76 (m, 2H), 6.05 (dd, J = 56.6, 19.7 Hz, 3H), 5.68 (d, J = 9.2 Hz, 1H), 4.20 (d, J = 33.4 Hz, 2H), 2.33 (s, 3H), 2.18 (s, 2H). | 497.4 | |
1-(3-(4-胺基-7-甲基-5-(4-(吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.31 - 8.14 (m, 2H), 7.90 (ddd, J = 9.0, 7.2, 2.0 Hz, 1H), 7.56 - 7.38 (m, 2H), 7.26 - 7.21 (m, 2H), 7.19 (s, 1H), 7.10 (dd, J = 8.3, 2.7 Hz, 1H), 6.50 (ddd, J = 36.0, 16.8, 10.3 Hz, 1H), 6.11 (dt, J = 16.8, 2.7 Hz, 1H), 5.64 (td, J = 9.9, 2.4 Hz, 1H), 4.03 - 3.66 (m, 5H), 3.64 - 3.23 (m, 5H), 2.35 - 1.94 (m, 2H). | 441 | |
1-(3-(4-胺基-5-(3-甲氧基-4-(吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 2H), 7.82 (t, J = 8.1 Hz, 1H), 7.27 - 6.94 (m, 5H), 6.64 - 6.37 (m, 1H), 6.11 (d, J = 16.6 Hz, 1H), 5.64 (t, J = 10.5 Hz, 2H), 3.99 - 3.75 (m, 5H), 3.69 (s, 4H), 3.66 - 3.48 (m, 2H), 2.37 - 1.96 (m, 2H). | 471.20 | |
1-(3-(4-胺基-5-(3-甲氧基-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.64 (t, J = 4.8 Hz, 2H), 8.14 (s, 1H), 7.37 - 7.19 (m, 2H), 7.12 (s, 1H), 7.01 (dd, J = 7.9, 1.9 Hz, 1H), 4.00 - 3.82 (m, 1H), 3.80 (d, J = 6.4 Hz, 3H), 3.69 (s, 4H), 3.63 (t, J = 10.3 Hz, 1H), 3.33 (s, 1H), 2.35 - 1.95 (m, 2H). | 472 | |
1-(3-(4-胺基-5-(3-甲氧基-4-((6-甲基吡啶-3-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.20 (dd, J = 12.7, 2.9 Hz, 1H), 8.12 (d, J = 2.1 Hz, 1H), 7.32 - 7.17 (m, 2H), 7.17 - 7.04 (m, 2H), 6.96 (d, J = 8.1 Hz, 1H), 6.60 - 6.38 (m, 1H), 6.10 (dd, J = 16.8, 2.5 Hz, 1H), 5.76 - 5.54 (m, 2H), 3.92 (t, J = 9.1 Hz, 1H), 3.56 (s, 1H), 2.44 (s, 3H), 2.31 - 2.22 (m, 1H), 2.08 (s, 2H). | 485.35 | |
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丁-2-炔-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d,J = 2.1 Hz, 1H), 7.76 (td,J = 7.7, 2.9 Hz, 1H), 7.40 (dd,J = 8.6, 3.3 Hz, 2H), 7.21 (dd,J = 8.1, 5.6 Hz, 2H), 7.04 (d,J = 7.3 Hz, 1H), 6.85 (dd,J = 8.2, 2.9 Hz, 1H), 5.78 (s, 1H), 3.92 - 3.65 (m, 5H), 3.50 (dt,J = 18.9, 9.8 Hz, 2H), 3.28 - 3.14 (m, 1H), 2.36 (s, 3H), 2.19 (d,J = 6.9 Hz, 1H), 1.97 (d,J = 19.3 Hz, 4H). | 467.25 | |
(E)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丁-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J = 2.7 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.41 (dd, J = 8.6, 3.8 Hz, 2H), 7.19 (dd, J = 8.2, 5.7 Hz, 2H), 7.04 (d, J = 7.3 Hz, 1H), 6.84 (dd, J = 8.2, 2.6 Hz, 1H), 6.65 (ddt, J = 13.7, 10.7, 6.7 Hz, 1H), 6.17 (ddd, J = 31.7, 14.9, 1.9 Hz, 1H), 5.78 (s, 1H), 3.98 - 3.85 (m, 1H), 3.79 (d, J = 8.4 Hz, 4H), 3.63 (d, J = 9.9 Hz, 1H), 3.53 (d, J = 10.2 Hz, 1H), 3.48 - 3.39 (m, 1H), 2.36 (d, J = 4.2 Hz, 3H), 2.26 - 1.91 (m, 2H), 1.80 (td, J = 6.9, 1.6 Hz, 3H). | 469 | |
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)-2-甲基丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.76 (q, J = 7.5 Hz, 1H), 7.62 - 7.33 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 7.4 Hz, 1H), 6.84 (s, 1H), 5.61(s, 1H), 5.22 (d, J = 18.1 Hz, 1H), 5.05 (d, J = 52.4 Hz, 1H), 3.78 (s, 3H), 3.71 (d, J = 9.5 Hz, 2H), 3.34 (s, 2H), 3.34 (s, 1H), 2.36 (s, 3H), 2.19 (s, 1H), 1.99 (dt, J = 21.1, 10.0 Hz, 1H), 1.81 (d, J = 14.3 Hz, 3H). | 469.30 | |
1-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)-2-甲基丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 7.4 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 5.08 (s, 1H), 4.80 (s, 1H), 4.36 (s, 1H), 3.78 (s, 3H), 3.20 (t, J = 12.4 Hz, 1H), 3.06 (s, 1H), 2.37 (s, 3H), 1.78 (s, 4H), 1.50 (d, J = 10.0 Hz, 2H). | 483.35 | |
(E)-1-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)丁-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.43 - 7.32 (m, 2H), 7.24 - 7.13 (m, 2H), 7.04 (d, J = 7.4 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.63 (dq, J = 13.4, 6.7 Hz, 1H), 6.46 (dd, J = 14.8, 1.9 Hz, 1H), 4.48 (s, 1H), 4.09 (d, J = 13.1 Hz, 1H), 3.77 (s, 3H), 3.16 (t, J = 12.3 Hz, 1H), 3.03 (s, 1H), 2.58 (s, 1H), 2.36 (s, 3H), 1.87 - 1.72 (m, 5H), 1.52 (d, J = 16.1 Hz, 2H). | 483.25 | |
1-(4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)丁-2-炔-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.31 - 7.15 (m, 2H), 7.04 (d, J = 7.3 Hz, 1H), 6.82 (d, J = 8.1 Hz, 1H), 4.39 - 4.20 (m, 2H), 3.78 (s, 3H), 3.23 - 3.07 (m, 2H), 2.66 (dd, J = 13.5, 10.8 Hz, 1H), 2.36 (s, 3H), 2.00 (s, 3H), 1.90 - 1.73 (m, 2H), 1.50 (dtd, J = 37.5, 12.7, 4.2 Hz, 2H). | 481.35 | |
1-(4-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 2H), 8.14 (s, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.35 - 7.21 (m, 3H), 6.76 (dd, J = 16.7, 10.3 Hz, 1H), 6.17 - 5.90 (m, 1H), 5.63 (d, J = 10.7 Hz, 1H), 4.49 (s, 1H), 4.10 (s, 1H), 3.79 (s, 3H), 2.65 (d, J = 19.5 Hz, 3H), 1.81 (s, 2H), 1.54 (s, 2H). | 456 | |
1-(3-(4-胺基-7-甲基-5-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 1.9 Hz, 1H), 7.53 - 7.36 (m, 5H), 6.46 (ddd,J = 40.1, 16.8, 10.3 Hz, 1H), 6.08 (ddd,J = 16.8, 4.7, 2.4 Hz, 1H), 5.63 (ddd,J = 12.9, 10.3, 2.5 Hz, 1H), 3.78 (d,J = 6.5 Hz, 4H), 3.66 (s, 1H), 3.50 (s, 2H), 3.25 (s, 1H), 2.31 - 1.71 (m, 2H). | 348.15 | |
1-(4-(4-胺基-7-甲基-5-(4-(吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (ddd,J = 4.9, 2.1, 0.8 Hz, 1H), 8.11 (s, 1H), 7.90 (ddd,J = 8.3, 7.2, 2.1 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.25 - 7.15 (m, 3H), 7.07 (dt,J = 8.2, 0.9 Hz, 1H), 6.77 (dd,J = 16.7, 10.5 Hz, 1H), 6.05 (dd,J = 16.7, 2.5 Hz, 1H), 5.63 (dd,J = 10.5, 2.5 Hz, 2H), 4.48 (d,J = 12.7 Hz, 1H), 4.08 (d,J = 13.5 Hz, 1H), 3.78 (s, 3H), 3.23 - 3.12 (m, 1H), 3.06 (t,J = 12.8 Hz, 1H), 2.62 (t,J = 12.6 Hz, 1H), 1.81 (d,J = 12.9 Hz, 2H), 1.58 - 1.48 (m, 2H). | 455.25 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 4.5 Hz, 2H), 8.15 (d, J = 1.1 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.32 (dd, J = 7.6, 2.9 Hz, 3H), 6.51 (ddd, J = 34.7, 16.8, 10.3 Hz, 1H), 6.11 (ddd, J = 16.8, 5.7, 2.4 Hz, 1H), 5.65 (ddd, J = 12.4, 10.4, 2.5 Hz, 1H), 4.00 - 3.91 (m, 0H), 3.81 (d, J = 6.5 Hz, 3H), 3.78 - 3.45 (m, 3H), 3.34 - 3.24 (m, 0H), 2.22 (tt, J = 10.7, 5.9 Hz, 0H), 2.13 (d, J = 8.3 Hz, 1H), 2.04 (dt, J = 21.0, 11.0 Hz, 0H), 1.24 (s, 1H), 1.18 (t, J = 7.2 Hz, 0H), 0.89 (s, 1H). | 442.25 | |
(S)-1-(3-(4-胺基-7-甲基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 4.5 Hz, 2H), 8.13 (d, J = 1.8 Hz, 1H), 7.49 - 7.42 (m, 2H), 7.32 (dd, J = 6.5, 3.5 Hz, 3H), 6.51 (ddd, J = 34.2, 16.8, 10.3 Hz, 1H), 6.11 (ddd, J = 16.8, 5.7, 2.4 Hz, 1H), 5.87 (s, 2H), 5.64 (ddd, J = 12.4, 10.4, 2.5 Hz, 1H), 3.80 (d, J = 6.7 Hz, 3H), 3.78 - 3.61 (m, 1H), 3.54 (dtd, J = 24.3, 10.1, 9.6, 6.2 Hz, 1H), 3.34 - 3.24 (m, 0H), 2.28 - 1.94 (m, 2H). | 442.25 | |
1-(3-(4-胺基-5-(4-甲氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d,J = 1.7 Hz, 1H), 7.30 (d,J = 8.2 Hz, 2H), 7.03 (d,J = 8.3 Hz, 2H), 6.47 (ddd,J = 40.7, 16.8, 10.3 Hz, 1H), 6.09 (ddd,J = 16.8, 5.6, 2.4 Hz, 1H), 5.63 (ddd,J = 14.6, 10.3, 2.5 Hz, 2H), 3.81 (d,J = 1.1 Hz, 3H), 3.77 (d,J = 6.0 Hz, 4H), 3.66 (q,J = 8.7, 7.2 Hz, 1H), 3.52 (d,J = 9.7 Hz, 2H), 2.35 - 1.70 (m, 2H). | 378.15 | |
1-(3-(4-胺基-7-乙基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.0 Hz, 2H), 8.13 (d, J = 1.6 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.31 (dd, J = 6.0, 3.6 Hz, 3H), 6.49 (ddd, J = 30.9, 16.8, 10.3 Hz, 1H), 6.10 (ddd, J = 16.8, 5.9, 2.5 Hz, 1H), 5.64 (td, J = 10.0, 2.4 Hz, 1H), 4.31 (t, J = 3.2 Hz, 1H), 4.29 (s, 2H), 3.76 (s, 1H), 3.66 (t, J = 9.2 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.49 (t, J = 9.8 Hz, 1H), 3.32 - 3.24 (m, 1H), 2.27 - 2.11 (m, 1H), 2.11 - 1.90 (m, 1H), 1.35 (td, J = 7.0, 3.7 Hz, 3H). | 456.3 | |
1-(3-(4-胺基-7-(3-羥基環丁基)-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, 氯仿-d) δ 8.63 (t, J = 3.9 Hz, 2H), 8.26 (d, J = 6.1 Hz, 1H), 7.39 (q, J = 8.9, 8.3 Hz, 4H), 7.14 (t, J = 4.8 Hz, 1H), 6.60 - 6.15 (m, 2H), 5.88 - 5.54 (m, 1H), 4.72 - 4.46 (m, 1H), 4.27 (dd, J = 13.0, 6.6 Hz, 1H), 4.11 - 3.88 (m, 1H), 3.80 (d, J = 8.2 Hz, 1H), 3.59 (tt, J = 19.8, 9.5 Hz, 3H), 3.37 - 2.99 (m, 2H), 2.20 (q, J = 10.3, 9.6 Hz, 2H), 2.05 (d, J = 9.7 Hz, 1H), 1.28 (s, 1H). | 498 | |
1-(3-(4-胺基-7-(2-(4-甲基哌嗪-1-基)乙基)-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.62 (t,J = 4.8 Hz, 2H), 8.31 (d,J = 3.2 Hz, 1H), 7.44 (d,J = 8.2 Hz, 2H), 7.37 - 7.29 (m, 2H), 7.12 (q,J = 4.4 Hz, 1H), 6.43 - 6.33 (m, 1H), 6.28 (dd,J = 16.8, 9.8 Hz, 1H), 5.75 - 5.64 (m, 1H), 4.73 (s, 2H), 4.42 (dd,J = 14.1, 7.2 Hz, 2H), 3.97 - 3.72 (m, 1H), 3.68 - 3.32 (m, 4H), 2.96 - 2.78 (m, 2H), 2.71 (d,J = 24.7 Hz, 8H), 2.41 (d,J = 27.9 Hz, 3H), 2.32 - 2.19 (m, 2H), 1.28 (s, 1H). | 554.30 | |
1-(3-(4-胺基-5-(4-(嘧啶-2-基氧基)苯基)-7-(四氫-2H-哌喃-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 4.5 Hz, 2H), 8.11 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.31 (td, J = 6.1, 5.0, 2.0 Hz, 3H), 6.60 (dd, J = 16.8, 10.3 Hz, 1H), 6.13 (ddd, J = 16.7, 8.6, 2.4 Hz, 1H), 5.66 (ddd, J = 19.8, 10.2, 2.4 Hz, 1H), 4.43 (s, 1H), 4.00 (d, J = 11.1 Hz, 2H), 3.80 (s, 2H), 3.72 (s, 0H), 3.57 - 3.48 (m, 2H), 3.51 - 3.38 (m, 1H), 3.38 - 3.25 (m, 1H), 3.04 (d, J = 14.2 Hz, 2H), 2.21 (dd, J = 12.7, 6.6 Hz, 0H), 1.93 (t, J = 10.5 Hz, 0H), 1.74 (d, J = 13.8 Hz, 2H). | 512.4 | |
1-(3-(4-胺基-7-(2-N-嗎啉基乙基)-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (t,J = 5.0 Hz, 2H), 8.12 (s, 1H), 7.46 (d,J = 8.1 Hz, 2H), 7.32 (d,J = 7.8 Hz, 3H), 6.48 (ddd,J = 30.4, 16.8, 10.3 Hz, 1H), 6.16 - 6.05 (m, 1H), 5.88 - 5.31 (m, 2H), 4.35 (q,J = 5.9, 4.8 Hz, 2H), 4.13 - 3.84 (m, 1H), 3.68 (dd,J = 23.6, 9.2 Hz, 2H), 3.64 - 3.44 (m, 6H), 3.34 (s, 2H), 2.72 - 2.50 (m, 4H), 2.40 - 1.47 (m, 2H). | 541.45 | |
1-(3-(4-胺基-7-(2-(二甲基胺基)乙基)-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.61 (t,J = 4.6 Hz, 2H), 8.32 (d,J = 2.1 Hz, 1H), 7.50 - 7.40 (m, 2H), 7.36 - 7.30 (m, 2H), 7.12 (td,J = 4.8, 2.4 Hz, 1H), 6.47 - 6.36 (m, 1H), 6.36 - 6.19 (m, 1H), 5.68 (ddd,J = 15.8, 8.6, 3.7 Hz, 1H), 4.70 (s, 2H), 4.41 (dp,J = 21.2, 6.9 Hz, 2H), 4.15 - 3.73 (m, 2H), 3.57 (dtd,J = 39.7, 19.1, 17.7, 8.6 Hz, 3H), 2.77 (t,J = 7.2 Hz, 2H), 2.37 (d,J = 10.1 Hz, 6H), 2.31 - 1.98 (m, 2H). | 499.25 | |
1-(3-(4-胺基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (d,J = 2.0 Hz, 1H), 8.69 (d,J = 4.8 Hz, 2H), 8.10 (s, 1H), 7.47 (dd,J = 8.5, 3.5 Hz, 2H), 7.41 - 7.23 (m, 3H), 6.59 (ddd,J = 16.8, 10.3, 2.4 Hz, 1H), 6.15 (dd,J = 16.8, 2.5 Hz, 1H), 5.67 (ddd,J = 10.7, 8.7, 2.5 Hz, 2H), 4.01 (t,J = 8.9 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.78 - 3.50 (m, 2H), 3.42 (dd,J = 10.7, 6.2 Hz, 1H), 2.42 - 2.03 (m, 2H). | 428.25 | |
rel-(R)-1-(3-(4-胺基-7-乙基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.0 Hz, 2H), 8.14 (d, J = 1.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.31 (dd, J = 6.3, 3.9 Hz, 3H), 6.49 (ddd, J = 31.1, 16.8, 10.3 Hz, 1H), 6.10 (ddd, J = 16.9, 5.9, 2.4 Hz, 1H), 5.64 (td, J = 10.0, 2.5 Hz, 1H), 4.30 (d, J = 6.8 Hz, 2H), 3.85 (dd, J = 11.8, 8.0 Hz, 1H), 3.61 - 3.51 (m, 1H), 3.49 (t, J = 9.7 Hz, 1H), 3.27 (d, J = 11.4 Hz, 1H), 2.18 (ddt, J = 26.2, 14.2, 7.0 Hz, 1H), 1.99 - 1.90 (m, 1H), 1.35 (td, J = 7.2, 3.8 Hz, 3H). | 456.3 | |
rel-(S)-1-(3-(4-胺基-7-乙基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (t, J = 5.1 Hz, 2H), 8.15 (s, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.31 (td, J = 5.7, 4.9, 2.0 Hz, 3H), 6.49 (ddd, J = 31.5, 16.8, 10.3 Hz, 1H), 6.10 (ddd, J = 16.8, 5.9, 2.4 Hz, 1H), 5.64 (td, J = 10.0, 2.5 Hz, 1H), 4.31 (d, J = 7.5 Hz, 2H), 3.66 (t, J = 9.1 Hz, 2H), 3.51 (dt, J = 19.2, 9.5 Hz, 1H), 2.29 - 2.13 (m, 1H), 2.07 (d, J = 9.5 Hz, 1H), 1.96 (q, J = 10.4 Hz, 1H), 1.35 (td, J = 7.1, 3.5 Hz, 3H). | 456.3 | |
(R)-1-(3-(4-胺基-7-(2-N-嗎啉基乙基)-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (t,J = 5.0 Hz, 2H), 8.12 (d,J = 1.9 Hz, 1H), 7.46 (d,J = 8.2 Hz, 2H), 7.31 (dq,J = 7.0, 2.5, 1.9 Hz, 3H), 6.48 (ddd,J = 31.7, 16.8, 10.3 Hz, 1H), 6.10 (ddd,J = 16.8, 5.5, 2.4 Hz, 1H), 5.64 (ddd,J = 10.3, 6.4, 2.4 Hz, 1H), 4.36 (s, 2H), 4.02 - 3.83 (m, 1H), 3.82 - 3.62 (m, 2H), 3.60 - 3.45 (m, 6H), 3.32 (s, 1H), 2.71 - 2.66 (m, 2H), 2.48 (s, 3H), 2.22 (ddt,J = 35.7, 12.7, 6.6 Hz, 1H), 1.99 (dq,J = 44.7, 10.4 Hz, 1H). | 541.45 | |
(S)-1-(3-(4-胺基-7-(2-N-嗎啉基乙基)-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.69 (t,J = 5.0 Hz, 2H), 8.12 (d,J = 1.9 Hz, 1H), 7.46 (d,J = 8.0 Hz, 2H), 7.31 (dd,J = 6.1, 3.7 Hz, 3H), 6.48 (ddd,J = 31.6, 16.7, 10.2 Hz, 1H), 6.10 (ddd,J = 16.9, 5.6, 2.5 Hz, 1H), 5.64 (ddd,J = 10.0, 6.6, 2.4 Hz, 1H), 4.37 (d,J = 8.7 Hz, 2H), 4.03 - 3.84 (m, 1H), 3.83 - 3.63 (m, 2H), 3.60 - 3.45 (m, 6H), 3.30 (d,J = 13.6 Hz, 1H), 2.68 (q,J = 6.0, 5.5 Hz, 2H), 2.56 - 2.43 (m, 3H), 2.33 - 2.11 (m, 1H), 1.99 (dq,J = 44.8, 10.6 Hz, 1H). | 541.45 | |
(R)-1-(3-(4-胺基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 8.69 (d,J = 4.8 Hz, 2H), 8.10 (s, 1H), 7.47 (dd,J = 8.5, 3.5 Hz, 2H), 7.39 - 7.19 (m, 3H), 6.59 (ddd,J = 16.8, 10.3, 2.5 Hz, 1H), 6.15 (dd,J = 16.7, 2.5 Hz, 1H), 5.97 - 5.53 (m, 2H), 4.14 - 3.39 (m, 5H), 2.44 - 1.99 (m, 2H). | 428.15 | |
(S)-1-(3-(4-胺基-5-(4-(嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.87 (s, 1H), 8.69 (d,J = 4.8 Hz, 2H), 8.11 (s, 1H), 7.47 (dd,J = 8.5, 3.5 Hz, 2H), 7.43 - 7.24 (m, 3H), 6.59 (ddd,J = 16.8, 10.3, 2.5 Hz, 1H), 6.15 (dd,J = 16.8, 2.5 Hz, 1H), 5.67 (ddd,J = 10.7, 8.7, 2.5 Hz, 2H), 4.16 - 3.37 (m, 5H), 2.42 - 2.00 (m, 2H). | 428.15 | |
1-(3-(4-胺基-5-(4-(環丙基甲氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d,J = 1.7 Hz, 1H), 7.27 (d,J = 8.1 Hz, 2H), 7.01 (d,J = 8.1 Hz, 2H), 6.47 (ddd,J = 39.8, 16.8, 10.2 Hz, 1H), 6.09 (ddd,J = 16.8, 5.4, 2.5 Hz, 1H), 5.63 (ddd,J = 15.4, 10.3, 2.5 Hz, 1H), 3.89 (dd,J = 17.8, 8.0 Hz, 2H), 3.77 (d,J = 5.8 Hz, 4H), 3.77 - 3.58 (m, 1H), 3.55 - 3.44 (m, 2H), 3.26 (d,J = 10.8 Hz, 1H), 2.00 (dt,J = 45.8, 9.7 Hz, 2H), 1.25 (m, 1H), 0.64 - 0.55 (m, 2H), 0.35 (dd,J = 4.7, 2.3 Hz, 2H). | 418.20 | |
1-(3-(5-(1-((1-乙醯基哌啶-4-基)甲基)-1H-吡唑-4-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.09 (d,J = 1.3 Hz, 1H), 7.88 - 7.82 (m, 1H), 7.51 (d,J = 6.1 Hz, 1H), 6.62 - 6.40 (m, 1H), 6.13 (dd,J = 16.7, 2.4 Hz, 1H), 5.71 - 5.61 (m, 2H), 4.34 (d,J = 13.1 Hz, 1H), 4.06 (d,J = 7.4 Hz, 2H), 3.93 (q,J = 9.4 Hz, 0H), 3.76 (d,J = 5.6 Hz, 3H), 3.68 (s, 2H), 3.53 (q,J = 8.1 Hz, 1H), 3.32 (s, 2H), 3.30 (s, 1H), 2.95 (t,J = 13.0 Hz, 1H), 2.47 (d,J = 12.2 Hz, 1H), 2.16 (s, 3H), 1.97 (t,J = 2.2 Hz, 3H), 1.45 (s, 2H), 1.16 - 0.98 (m, 2H). | 477.50 | |
1-(3-(4-胺基-7-甲基-5-(1-(哌啶-4-基甲基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d,J = 2.6 Hz, 1H), 7.89 - 7.81 (m, 1H), 7.49 (q,J = 3.8 Hz, 1H), 6.47 (ddd,J = 39.8, 16.8, 10.2 Hz, 1H), 6.09 (ddd,J = 16.8, 5.4, 2.5 Hz, 1H), 5.90 (bar, 1H), 5.62 (s, 1H), 4.00 (d,J = 7.6 Hz, 2H), 3.82 - 3.62 (m, 5H), 3.55 - 3.40 (m, 2H), 3.20 (m, 1H), 2.89 (d,J = 11.3 Hz, 1H), 2.79 (s, 1H), 2.36 (d,J = 16.4 Hz, 2H), 2.21 (s, 1H), 2.07 (s, 1H), 1.92 (s, 1H), 1.82 (s, 1H), 1.36 (s, 2H), 1.15 (s, 1H), 1.04 (d,J = 12.9 Hz, 1H). | 435.20 | |
1-(3-(4-胺基-5-(4-(環丙烷羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.17 - 8.10 (m, 3H), 7.55 (d,J = 7.9 Hz, 2H), 6.46 (ddd,J = 38.7, 16.7, 10.3 Hz, 1H), 6.08 (ddd,J = 16.7, 6.1, 2.5 Hz, 1H), 5.61 (ddd,J = 20.0, 10.2, 2.5 Hz, 2H), 4.03 - 3.74 (m, 5H), 3.69 (t,J = 9.0 Hz, 2H), 3.57 (t,J = 9.9 Hz, 1H), 3.00 - 2.92 (m, 1H), 2.28 - 1.84 (m, 2H), 1.07 (d,J = 6.3 Hz, 4H). | 416.20 | |
1-(3-(4-胺基-5-(4-(2-甲氧基乙氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d,J = 1.6 Hz, 1H), 7.29 (d,J = 8.1 Hz, 2H), 7.03 (d,J = 8.2 Hz, 2H), 6.51 -6.42 (dd,J = 16.8, 10.3 Hz, 1H), 6.09 (ddd,J = 16.7, 5.3, 2.4 Hz, 1H), 5.63 (ddd,J = 14.2, 10.3, 2.5 Hz, 2H), 4.18 - 4.11 (m, 2H), 3.97 - 3.88 (m, 4H), 3.77 -3.70 (d,J = 4.6 Hz, 5H), 3.70 - 3.58 (m, 3H), 3.57 - 3.41 (m, 1H), 2.19 (s, 1H), 2.00 (dt,J = 46.6, 9.6 Hz, 1H). | 422.20 | |
1-(3-(4-胺基-5-(4-環丙氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) 8.10 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 6.46 (ddd, J = 45.8, 16.7, 10.2 Hz, 1H), 6.09 (ddd, J = 16.8, 7.0, 2.5 Hz, 1H), 5.79 - 5.51 (m, 2H), 3.89 (dt, J = 6.1, 2.6 Hz, 1H), 3.82 - 3.53 (m, 4H), 3.32 (s, 3H), 3.27 - 3.15 (m, 1H), 2.34 - 1.81 (m, 2H), 1.24 (s, 1H), 0.80 (t, J = 5.7 Hz, 2H), 0.70 (d, J = 3.5 Hz, 2H). | 404.20 | |
1-(3-(4-胺基-7-甲基-5-(1-(四氫呋喃-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d,J = 1.5 Hz, 1H), 7.88 (s, 1H), 7.52 (d,J = 7.5 Hz, 1H), 6.50 (ddd,J = 43.5, 16.8, 10.3 Hz, 1H), 6.11 (dt,J = 16.8, 2.6 Hz, 1H), 5.85 - 5.40 (bar, 2H), 5.64 (td,J = 10.8, 2.5 Hz, 1H), 5.05 (t,J = 5.3 Hz, 1H), 3.98 (ddd,J = 19.1, 10.3, 6.6 Hz, 3H), 3.95 - 3.78 (m, 2H), 3.76 (s, 3H), 3.76 - 3.62 (m, 1H), 3.62 - 3.46 (m, 2H), 3.38 (t,J = 10.1 Hz, 1H), 2.36 (dtd,J = 17.9, 9.2, 8.5, 3.1 Hz, 2H), 2.22 (s, 1H), 2.16 - 1.94 (m, 1H). | 408.20 | |
1-(3-{4-胺基-5-[4-(環戊基硫基)苯基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.11 (d, J = 1.8 Hz, 1H), 7.43-7.37 (m, 2H), 7.32 (d, J = 7.2 Hz, 2H), 6.52-6.39 (dd, J = 16.8, 10.3 Hz, 1H), 6.09 (ddd, J = 16.8, 6.4, 2.4 Hz, 1H), 5.62 (ddd, J = 18.5, 10.3, 2.5 Hz, 3H), 3.90 (t, J = 9.1 Hz, 1H), 3.81-3.73 (m, 5H), 3.66 (q, J = 10.1, 9.4 Hz, 1H), 3.59-3.52 (m, 1H), 3.48-3.24 (m, 1H), 2.10-1.88 (m, 4H), 1.76-1.52 (m, 6H). | 448.19 | |
N-(4-{4-胺基-7-甲基-6-[1-(丙-2-烯醯基)吡咯啶-3-基]-7H-吡咯并[2,3-d]嘧啶-5-基}苯基)-N-甲基乙醯胺 | 1H NMR (400 MHz, DMSO-d6 ) 8.12 (d, J=2.7 Hz, 1H), 7.42 (t, J=6.4 Hz, 4H), 6.45 (ddd, J=49.5, 16.8, 10.3 Hz, 1H), 6.08 (dd, J=16.8, 2.4 Hz, 1H), 5.62 (ddd, J=14.9, 10.3, 2.5 Hz, 3H), 4.17-3.40 (m, 7H), 3.22 (s, 3H), 1.95 (s, 3H), 1.85 (s, 2H). | 419.25 | |
1-(3-{4-胺基-7-甲基-5-[1-(哌啶-4-基)-1H-吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 -8.06 (m, 1H), 7.87 (d,J = 3.0 Hz, 1H), 7.58 -7.46 (m, 1H), 6.65 -6.33 (m, 1H), 6.11 (d,J = 16.8 Hz, 1H) , 5.83 - 5.49 (m, 2H), 4.50 (s, 1H), 4.21 (s, 1H), 3.87 (dt,J = 18.6, 8.5 Hz, 1H), 3.75 (d,J = 7.0 Hz, 5H), 3.64 (dt,J = 17.7, 9.1 Hz, 1H), 3.04 (t,J = 8.0 Hz, 1H), 2.79 (d,J = 13.0 Hz, 2H), 2.38 - 2.06 (m, 3H), 1.97 (d,J = 11.8 Hz, 2H), 1.83 (d,J = 12.1 Hz, 2H). | 421.25 | |
1-(3-{4-胺基-5-[1-(氮雜環丁-3-基)-1H-吡唑-4-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮;三氟乙酸鹽 | 1H NMR (400 MHz, DMSO-d6) 9.10-8.95 (s, 2H), 8.45-8.39 (m,1H), 7.99 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 10.1 Hz, 1H), 6.53-6.41 (dd, J = 16.8, 10.3 Hz, 1H), 6.11 (dd, J = 16.8, 2.4 Hz, 1H), 5.66 (ddd, J = 12.8, 10.2, 2.5 Hz, 1H), 5.41 (td, J = 7.5, 3.7 Hz, 1H), 4.41(m,4H), 3.86 (d, J = 6.2 Hz, 4H), 3.81-3.58 (m, 2H), 3.58-3.33 (dt, J = 12.0, 7.7 Hz, 2H), 2.31-1.93 (m, 2H), 1.08 (s, 1H). | 3293.25 | |
1-(3-(4-胺基-5-(4-(環戊基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.10 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 6.97 (d, J = 8.1 Hz, 2H), 6.45 (ddd, J = 49.5, 16.8, 10.3 Hz, 1H), 6.08 (ddd, J = 16.8, 7.7, 2.5 Hz, 1H), 5.62 (ddd, J = 19.2, 10.3, 2.5 Hz, 1H), 4.86 (q, J = 4.6, 3.2 Hz, 1H), 3.95 - 3.73 (m, 4H), 3.65 (d, J = 9.8 Hz, 1H), 3.54 - 3.45 (m, 1H), 3.32 (s, 4H), 2.24 - 1.88 (m, 4H), 1.76 (d, J = 12.6 Hz, 4H), 1.60 (d, J = 9.0 Hz, 2H). | 432.35 | |
1-(3-(4-胺基-5-(4-(3,3-二氟吡咯啶-1-羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.14 (d,J = 2.0 Hz, 1H), 7.68 (s, 2H), 7.55 (d,J = 7.9 Hz, 2H), 6.53 (t,J = 13.7 Hz,1H), 6.25 - 6.16 (m, 1H), 5.70 (dd,J = 17.9, 10.5 Hz, 1H), 4.04 (s, 2H), 4.02 - 3.91 (m, 6H), 3.88 (d,J = 4.8 Hz, 4H), 2.50 (s, 2H), 2.28 (s, 1H), 2.23 - 2.04 (m, 1H). | 481.35 | |
(R)-1-(3-(4-胺基-5-(4-(甲氧基甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d,J = 1.9 Hz, 2H), 7.39 (q,J = 7.8 Hz, 8H), 6.51 (dd,J = 16.8, 10.3 Hz, 1H), 6.40 (dd,J = 16.8, 10.3 Hz, 1H), 6.08 (ddd,J = 16.8, 5.7, 2.5 Hz, 2H), 5.62 (ddd,J = 15.9, 10.3, 2.5 Hz, 2H), 4.48 (s, 4H), 3.92 (t,J = 9.1 Hz, 1H), 3.78 (s, 4H), 3.75 - 3.64 (m, 1H), 3.67 - 3.57 (m, 1H), 3.53 (s, 1H), 3.51 (s, 1H), 3.49 - 3.41 (m, 1H), 3.36 - 3.25 (m, 9H), 3.28 - 3.20 (m, 1H), 2.20 (dt,J = 12.5, 6.7 Hz, 1H), 2.15 - 1.89 (m, 2H). | 392.10 | |
1-(3-{4-胺基-7-甲基-5-[1-(1-甲基哌啶-4-基)-1H-吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.11 (s, 1H), 7.84 (d,J = 3.3 Hz, 1H), 7.57 (d,J = 6.3 Hz, 1H), 6.56 - 6.43 (ddd,J = 16.7, 10.4 Hz, 1H), 6.30 - 6.19 (m, 1H), 5.78 - 5.67 (m, 1H), 4.26 (s, 1H), 3.99 - 3.86 (m, 1H), 3.84 (d,J = 2.7 Hz, 4H), 3.75 (d,J = 7.5 Hz, 1H), 3.69 - 3.57 (m, 2H), 3.02 (d,J = 11.4 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 3H), 2.34 - 2.25 (m, 3H), 2.12 (d,J = 12.1 Hz, 2H), 2.05 (s, 1H). | 435.20 | |
1-(3-{4-胺基-7-甲基-5-[1-(2,2,2-三氟乙基)-1H-吡唑-4-基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 7.99 (s, 1H), 7.67 (d,J = 4.6 Hz, 1H), 6.62- 6.36 (m, 1H), 6.12 (ddd,J = 16.7, 4.7, 2.4 Hz, 1H), 5.76 (s, 1), 0 (d, J = 44.9 Hz, 1H), 5.17 (q,J = 9.0 Hz, 2H), 3.93 (t,J = 9.0 Hz, 1H), 3.87 - 3.74 (m, 4H), 3.68 (t,J = 9.1 Hz, 1H), 3.61 - 3.45 (m, 3H), 2.29 - 1.89 (m, 2H). | 420.15 | |
1-(3-(4-胺基-7-甲基-5-(4-(嗎啉-4-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d,J = 3.0 Hz, 1H), 7.50 (d,J = 7.8 Hz, 2H), 7.46 (d,J = 4.8 Hz, 2H), 6.51- 6.42 (dd,J = 16.7, 10.3 Hz, 1H), 6.07 (ddd,J = 16.9, 7.1, 2.4 Hz, 1H), 5.68 - 5.57 (m, 3H), 3.91 (t,J = 9.2 Hz, 4H), 3.79 - 3.31 (d,J = 16.0 Hz, 11H), 3.27 (s, 1H), 2.23 (s, 1H), 2.10 (s, 1H). | 461.20 | |
1-(3-(4-胺基-5-(4-(羥基甲基)環己-1-烯-1-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.06 (d,J = 1.3 Hz, 1H), 6.62 (dd,J = 16.8, 10.3 Hz, 1H), 6.01 (s, 3H), 5.76 (s, 2H), 4.52 (t,J = 4.9 Hz, 1H), 4.01 (s, 2H), 3.69 (d,J = 6.0 Hz, 5H), 3.36 (d,J = 5.7 Hz, 2H), 2.21 (s, 5H), 1.87 (s, 3H), 1.40 (s, 1H). | 382.40 | |
1-(3-(4-胺基-7-甲基-5-(1-(吡啶-3-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 9.15 (t,J = 2.5 Hz, 1H), 8.69 (d,J = 11.2 Hz, 1H), 8.54 (dt,J = 4.6, 1.5 Hz, 1H), 8.27 (d,J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.86 (d,J = 4.0 Hz, 1H), 7.57 (dd,J = 8.4, 4.8 Hz, 1H), 6.48 (ddd,J = 29.3, 16.7, 10.3 Hz, 1H), 6.01 (ddd,J = 16.7, 6.1, 2.5 Hz, 1H), 5.87 (s, 1H), 5.56 (ddd,J = 16.3, 10.3, 2.5 Hz, 1H), 3.94 (t,J = 9.0 Hz, 2H), 3.88 - 3.63 (m, 5H), 3.52 (ddt,J = 29.1, 19.5, 8.3 Hz, 1H), 2.25 (s, 1H), 2.12 (dt,J = 36.2, 10.9 Hz, 1H). | 415.40 | |
1-[3-(4-胺基-5-{4-[(3,3-二甲基吡咯啶-1-基)甲基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基]丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.11 (d, J = 2.0 Hz, 1H), 7.36 (ddd, J = 26.6, 8.1, 2.7 Hz, 4H), 6.51-6.37 (dd, J = 16.8, 10.3 Hz, 1H), 6.08 (ddd, J = 16.8, 6.5, 2.5 Hz, 1H), 5.64-5.58 (dd, J = 10.3, 2.5 Hz, 2H), 3.94-3.85 (m, 1H), 3.81-3.69 (m, 4H), 3.69-3.62 (s, 3H), 3.58-3.21 (m, 3H), 3.18 (s, 1H), 2.58 (td, J = 7.0, 3.2 Hz, 2H), 2.29 (d, J = 2.2 Hz, 2H), 2.21-1.88 (m, 2H), 1.54 (t, J = 7.0 Hz, 2H), 1.24 (s, 1H), 1.06 (d, J = 1.4 Hz, 5H). | 459.25 | |
1-(3-(4-胺基-5-(4-(氮雜環丁烷-1-羰基)-3-氟苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d,J = 2.6 Hz, 1H), 7.56 (q,J = 7.1 Hz, 1H), 7.30 (ddd,J = 17.0, 10.0, 1.7 Hz, 2H), 6.49 (ddd,J = 29.8, 16.8, 10.4 Hz, 1H), 6.09 (dt,J = 16.8, 3.0 Hz, 1H), 5.64 (td,J = 10.5, 2.4 Hz, 2H), 4.11 - 4.03 (m, 4H), 3.94 (t,J = 9.3 Hz, 1H), 3.82 - 3.66 (m,5H), 3.62 - 3.47 (m, 1H), 2.27 (p,J = 7.6 Hz, 2H), 2.07 (dd,J = 19.2, 9.6 Hz, 1H), 2.03 - 1.91 (m, 1H). | 449.25 | |
1-(3-(4-胺基-5-(4-苯甲醯基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d,J = 2.4 Hz, 1H), 7.83 (ddd,J = 12.3, 8.9, 6.7 Hz, 4H), 7.71 (t,J = 7.4 Hz, 1H), 7.64 - 7.53 (m, 4H), 6.47 (ddd,J = 38.4, 16.7, 10.3 Hz, 1H), 6.07 (dt,J = 16.8, 2.8 Hz, 1H), 5.90 - 5.33 (bar, 1H), 5.61 (ddd,J = 16.5, 10.3, 2.5 Hz, 1H), 4.00 - 3.68 (m, 6H), 3.65 - 3.54 (m, 1H), 3.54 - 3.37 (m, 1H), 2.24 (s, 1H), 2.18 - 1.97 (m, 1H). | 452.15 | |
1-(3-(4-胺基-7-甲基-5-(5-(N-嗎啉基甲基)噻吩-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) 8.10 (d, J = 1.7 Hz, 1H), 7.44 (dd, J = 4.5, 1.5 Hz, 1H), 7.00 (d, J = 5.3 Hz, 1H), 6.48 (ddd, J = 50.3, 16.8, 10.3 Hz, 1H), 6.10 (dd, J = 16.7, 2.5 Hz, 2H), 5.80 - 5.50 (m, 2H), 3.92 (t, J = 9.0 Hz, 1H), 3.76 (d, J = 5.7 Hz, 4H), 3.71 (d, J = 4.0 Hz, 3H), 3.58 (t, J = 4.6 Hz, 4H), 3.51 (d, J = 10.1 Hz, 1H), 3.32 (s, 1H), 2.41 (d, J = 5.8 Hz, 4H), 2.32 - 2.11 (m, 1H), 2.10 - 1.89 (m, 1H). | 453.20 | |
1-(3-(4-胺基-7-甲基-5-(1-(吡啶-2-基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.65 (d,J = 4.4 Hz, 1H), 8.49 (d,J = 4.9 Hz, 1H), 8.12 (d,J = 1.6 Hz, 1H), 8.07 - 7.95 (m, 2H), 7.88 (d,J = 3.3 Hz, 1H), 7.38 (td,J = 5.5, 4.8, 2.9 Hz, 1H), 6.49 (td,J = 17.4, 10.2 Hz, 1H), 6.04 (dt,J = 16.7, 2.2 Hz, 1H), 5.57 (ddd,J = 15.5, 10.2, 2.5 Hz, 1H), 3.97 (s, 1H), 4.07 - 3.72 (m, 5H), 3.72 - 3.37 (m, 2H), 2.20 - 2.02 (m, 2H). | 415.40 | |
1-(3-(4-胺基-5-(1-異丙基-1H-吡唑-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.09 (s, 1H), 7.87 (s, 1H), 7.48 (d,J = 6.5 Hz, 1H), 6.50 (ddd,J = 46.6, 16.8, 10.3 Hz, 1H), 6.11 (ddd,J = 16.8, 4.3, 2.5 Hz, 1H), 5.64 (ddd,J = 12.5, 10.2, 2.5 Hz, 1H), 4.53 (p,J = 6.6 Hz, 1H), 3.89 (t,J = 9.1 Hz, 1H), 3.82 - 3.66 (m, 5H), 3.56 (tq,J = 17.0, 8.9 Hz, 2H), 3.37 (d,J = 10.8 Hz, 0H), 2.26 - 1.93 (m, 2H), 1.44 (d,J = 6.7 Hz, 6H), . | 380.25 | |
1-(3-(4-胺基-7-甲基-5-(1-(鄰甲苯基)-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.24 - 8.01 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.54 - 7.27 (m, 3H), 6.51 (ddd, J = 31.5, 16.7, 10.3 Hz, 1H), 6.10 (dt, J = 16.8, 2.2 Hz, 1H), 5.63 (ddd, J = 10.3, 5.7, 2.5 Hz, 2H), 4.00 - 3.67 (m, 4H), 3.65 - 3.39 (m, 3H), 3.33 - 3.17 (m, 2H), 2.34 - 2.00 (m, 5H). | 428.35 | |
1-{3-[4-胺基-5-(4-{[(3R)-3-羥基吡咯啶-1-基]甲基}苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基]吡咯啶-1-基}丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.11 (d, J=2.0 Hz, 1H), 7.39 (d, J=7.9 Hz, 4H), 6.38 (dd, J=16.8, 10.0 Hz, 1H), 6.08 (ddd, J=16.7, 7.3, 2.5 Hz, 1H), 5.68-5.56 (m, 3H), 4.69 (s, 1H), 4.21 (s, 1H), 3.90-3.42 (t, J=9.0 Hz, 9H), 3.32-3.23 (m, 1H), 2.72 (s, 1H), 2.58 (s, 1H), 2.44 (s, 1H), 2.06-1.89 (m, 3H), 1.56 (s, 1H). | 447.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.13 (d,J = 2.6 Hz, 1H), 7.60 (t,J = 7.3 Hz, 2H), 7.44 (dd,J = 8.3, 3.3 Hz, 2H), 6.46 (ddd,J = 40.8, 16.8, 10.3 Hz, 1H), 6.07 (dt,J = 16.8, 2.2 Hz, 1H), 5.62 (ddd,J = 14.8, 10.3, 2.5 Hz, 1H), 3.92 (t,J = 9.2 Hz, 1H), 3.79 (d,J = 7.2 Hz, 4H), 3.76 - 3.64 (m, 2H), 3.60 - 3.47 (m, 2H), 3.48 (s, 5H), 3.45 (s, 0H), 2.21 (s, 1H), 2.08 (dd,J = 19.3, 9.4 Hz, 1H), 2.01 - 1.80 (m, 4H). | 445.25 | |
4-{4-胺基-7-甲基-6-[1-(丙-2-烯醯基)吡咯啶-3-基]-7H-吡咯并[2,3-d]嘧啶-5-基}-N-(吡啶-2-基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H), 8.41 (d,J = 4.9 Hz, 1H), 8.21 (d,J = 8.4 Hz, 1H), 8.17 -8.08 (m, 3H), 7.91 -7.82 (m, 1H), 7.53 (d,J = 7.8 Hz, 2H), 7.22 -7.15 (m, 1H), 6.59 -6.40 (m, 1H), 6.15 -6.05 (m, 1H), 5.63 (t,J = 11.4 Hz, 2H), 3.81 (d,J = 7.0 Hz, 6H), 3.57 (t,J = 9.6 Hz, 2H), 2.21 (s, 1H), 2.10 (d,J = 12.5 Hz, 1H). | 468.20 | |
1-(3-(4-胺基-5-(1-環戊基-1H-吡唑-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.09 (d,J = 1.4 Hz, 1H), 7.87 (s, 1H), 7.48 (d,J = 6.2 Hz, 1H), 6.50 (ddd,J = 46.7, 16.8, 10.3 Hz, 1H), 6.11 (ddd,J = 16.8, 4.0, 2.5 Hz, 1H), 5.64 (ddd,J = 12.5, 10.2, 2.5 Hz, 1H), 4.73 (p,J = 6.7 Hz, 2H), 3.93 - 3.46 (m, 8H), 2.28 - 1.50 (m, 10H). | 406.30 | |
1-[3-(4-胺基-7-甲基-5-{4-[4-(丙-2-基)哌嗪-1-基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.11 (s, 1H), 7.29 (d,J = 8.6 Hz, 2H), 7.08 (s, 2H), 6.36 - 6.23 (m, 1H), 6.23- 6.14 (m, 1H), 5.76- 5.61 (m, 1H), 3.84 (s, 5H), 3.68 (s, 2H), 3.61 (s, 2H), 3.59- 3.39 (m, 2H), 3.32 (d, J = 1.7 Hz, 1H), 2.80 (s, 5H), 2.34 - 1.97 (m, 2H), 1.18 (d,J = 6.5 Hz, 6H). | 474.45 | |
1-(3-(4-胺基-5-(4-(氮雜環丁-3-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.12 (d,J = 7.3 Hz, 1H), 7.57 (dd,J = 8.1, 2.3 Hz, 1H), 7.50 (dd,J = 8.2, 2.4 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.04 (ddd,J = 8.0, 5.5, 2.6 Hz, 1H), 4.99 (dt,J = 21.0, 6.5 Hz, 1H), 4.12 - 4.00 (m, 1H), 3.84 (d,J = 1.1 Hz, 3H), 3.68 (dd,J = 9.6, 6.4 Hz, 1H), 3.64 - 3.57 (m, 1H), 3.51 (t,J = 6.9 Hz, 3H), 3.43 (q,J = 7.2 Hz,2H), 3.24 - 3.05 (m, 1H), 2.56 - 2.38 (m, 2H), 2.17 - 1.84 (m, 3H). | 419.30 | |
1-(3-{4-胺基-7-甲基-5-[4-(吡咯啶-1-基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.21 (s, 1H), 8.11 (d,J = 1.4 Hz, 1H), 7.23 - 7.14 (m, 2H), 6.71 - 6.63 (m, 2H), 6.52 (dd,J = 16.8, 10.4 Hz, 1H), 6.36 - 6.10 (m, 1H), 5.66 (ddd, J = 37.9, 10.4, 2.1 Hz, 1H), 3.85 (s, 5H), 3.82 - 3.62 (m, 2H), 3.66 -3.45 (dd,J = 12.3, 7.8 Hz, 4H), 3.36 (s, 1H), 2.28 (s, 2H), 2.07 (td,J = 7.5, 6.3, 4.2 Hz, 5H). | 417.20 | |
(R)-1-(3-(4-胺基-5-(1-(2-(二甲基胺基)乙基)-1H-吡唑-4-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d,J = 1.6 Hz, 1H), 7.82 (s, 1H), 7.48 (d,J = 8.2 Hz, 1H), 6.52 (ddd,J = 35.3, 16.7, 10.3 Hz, 1H), 6.12 (dt,J = 16.8, 2.1 Hz, 1H), 5.65 (td,J = 10.2, 2.5 Hz, 1H), 4.23 (t,J = 6.1 Hz, 2H), 3.93 (t,J = 8.9 Hz, 1H), 3.84 - 3.61 (m, 5H), 3.61 - 3.45 (m, 1H), 3.40 - 3.29 (m, 0H), 2.61 (t,J = 6.2 Hz, 2H), 2.14 (d,J = 1.7 Hz, 8H). | 409.25 | |
1-(3-(5-(1-乙醯基-3,3-二甲基-1,2,3,6-四氫吡啶-4-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.08 (s, 1H), 7.35 - 7.26 (m, 1H), 6.61 (ddd,J = 15.4, 7.8, 3.3 Hz, 1H), 6.44 (d,J = 12.0 Hz, 1H), 6.12 (dt,J = 15.7, 3.6 Hz, 1H), 4.23 - 4.07 (dd,J = 11.4, 6.4 Hz, 3H), 3.92 - 3.79 (m, 1H), 3.78 (d,J = 3.7 Hz, 4H), 3.73 (s, 1H), 3.71 - 3.60 (m, 1H), 3.44 (dd,J = 19.4, 4.4 Hz, 2H), 2.59 - 2.40 (dd,J = 12.0, 6.0 Hz, 1H), 2.28 - 2.06 (m, 1H), 2.16 (dd,J = 6.0, 4.1 Hz, 3H), 1.16 (dd,J = 19.4, 4.7 Hz, 6H). | 423.20 | |
1-(3-(4-胺基-5-(6-環丙氧基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) 8.20 (dd, J = 5.9, 2.4 Hz, 1H), 8.13 (s, 1H), 7.71 (dt, J = 8.4, 2.3 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.47 (ddd, J = 38.4, 16.7, 10.2 Hz, 1H), 6.09 (dt, J = 16.8, 2.8 Hz, 1H), 5.63 (ddd, J = 13.1, 10.2, 2.5 Hz, 3H), 4.25 (td, J = 6.1, 3.4 Hz, 1H), 3.81 - 3.59 (m, 5H), 3.51 (m, 2H), 3.26 (s, 1H), 2.28 - 1.59 (m, 2H), 0.90 - 0.57 (m, 4H). | 405.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基)-3-(三氟甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 1.5 Hz, 1H), 7.58 - 7.30 (m, 2H), 7.11 (d,J = 8.6 Hz, 1H), 6.73 - 6.25 (m, 1H), 6.08 (ddd,J = 16.8, 9.1, 2.5 Hz, 1H), 5.62 (ddd,J = 20.0, 10.3, 2.3 Hz, 3H), 3.77 (d,J = 5.8 Hz, 4H), 3.65 (q,J = 8.8 Hz, 1H), 3.51 (dt,J = 21.3, 9.3 Hz, 1H), 3.36 (s, 4H), 2.39 - 1.96 (m, 2H), 1.92 (d,J = 6.0 Hz, 5H). | 485.35 | |
1-(4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-3-環丙基脲 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (s, 1H), 8.10 (d,J = 1.7 Hz, 1H), 7.57 - 7.44 (m, 2H), 7.23 (d,J = 8.2 Hz, 2H), 6.59 - 6.37 (m, 2H), 6.09 (ddd,J = 16.8, 4.2, 2.5 Hz, 1H), 5.63 (ddd,J = 13.1, 10.3, 2.5 Hz, 1H), 3.96 - 3.38 (m, 8H), 2.56 (dt,J = 7.1, 3.5 Hz, 1H), 2.31 - 1.94 (m, 2H), 0.65 (td,J = 6.9, 4.7 Hz, 2H), 0.47 - 0.38 (m, 2H). | 446.35 | |
5-(4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (t,J = 2.9 Hz, 2H), 7.39 (d,J = 2.5 Hz, 4H), 6.62 - 6.28 (m, 1H), 6.14 - 6.04 (m, 1H), 5.63 (ddd,J = 14.3, 10.2, 2.4 Hz, 2H), 4.75 (t,J = 7.0 Hz, 1H), 3.91 (t,J = 9.2 Hz, 1H), 3.79 (d,J = 6.8 Hz, 3H), 3.74 (s, 2H), 3.66 (d,J = 9.8 Hz, 1H), 3.54 (s, 1H), 2.30 - 2.20 (m, 2H), 2.20 (s, 1H), 2.09 (d,J = 8.3 Hz, 1H), 2.03 - 1.69 (m, 3H). | 431.25 | |
4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-1-苯甲基吡啶-2(1H)-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.16 (d,J = 1.0 Hz, 1H), 7.78 (dd,J = 11.1, 6.8 Hz, 1H), 7.45 - 7.35 (m, 4H), 7.39 - 7.29 (m, 1H), 6.65 - 6.42 (m, 3H), 6.31 - 6.20 (m, 1H), 5.72 (ddd,J = 22.8, 10.4, 2.0 Hz, 1H), 5.25 (s, 2H), 4.08 - 3.43 (m, 8H), 2.44 - 2.18 (m, 2H). | 455.35 | |
1-(4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)咪唑啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 1.8 Hz, 1H), 7.66 (d,J = 8.1 Hz, 2H), 7.31 (d,J = 8.2 Hz, 2H), 7.02 (s, 1H), 6.48 (ddd,J = 33.0, 16.7, 10.3 Hz, 1H), 6.14 - 6.04 (m, 1H), 5.68 - 5.57 (m, 2H), 3.92 (dt,J = 15.5, 8.6 Hz, 2H), 3.78 (d,J = 6.3 Hz, 4H), 3.50 (s, 3H), 3.43 (t,J = 8.1 Hz, 2H), 3.27 (s, 1H), 2.20 (d,J = 12.5 Hz, 1H), 2.06 (s, 1H). | 432.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-基甲基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 2.1 Hz, 1H), 7.36 (ddd,J = 28.1, 7.8, 4.0 Hz, 4H), 6.66 - 6.22 (m, 1H), 6.08 (ddd,J = 16.9, 6.5, 2.4 Hz, 1H), 5.61 (ddd,J = 20.5, 10.3, 2.5 Hz, 1H), 3.81 - 3.71 (m, 4H), 3.68 - 3.63 (m, 1H), 3.63 (s, 2H), 3.59 - 3.42 (m, 1H), 3.26 (dd,J = 19.8, 9.4 Hz, 1H), 2.46 (s, 5H), 2.21 (s, 1H), 2.16 - 1.97 (m, 1H), 1.72 (d,J = 6.0 Hz, 4H). | 431.50 | |
(R)-1-(3-(4-胺基-5-(4-(苯甲氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 1.6 Hz, 1H), 7.54 - 7.28 (m, 7H), 7.11 (d,J = 8.0 Hz, 2H), 6.52 (dd,J = 16.8, 10.3 Hz, 1H), 6.10 (ddd,J = 16.8, 5.7, 2.4 Hz, 1H), 5.63 (ddd,J = 15.0, 10.3, 2.5 Hz, 1H), 5.14 (s, 2H), 3.97 - 3.88 (m, 0H), 3.77 (d,J = 5.9 Hz, 4H), 3.70 - 3.58 (m, 1H), 3.57 - 3.40 (m, 1H), 3.27 (s, 1H), 2.26 - 1.87 (m, 2H). | 454.35 | |
2-(4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-N,N-二甲基乙醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 2.0 Hz, 1H), 7.32 (d,J = 2.5 Hz, 4H), 6.45 (dd,J = 41.8, 10.3 Hz, 1H), 6.09 (ddd,J = 16.7, 6.1, 2.4 Hz, 1H), 5.63 (ddd,J = 13.5, 10.3, 2.5 Hz, 1H), 3.92 (t,J = 9.2 Hz, 1H), 3.81 - 3.74 (m, 6H), 3.72 - 3.63 (m, 1H), 3.51 (dd,J = 20.4, 10.0 Hz, 1H), 3.03 (s, 3H), 2.99 (s, 1H), 2.86 (s, 3H), 2.20 (d,J = 7.3 Hz, 1H), 2.09 (t,J = 10.3 Hz, 1H). | 433.25 | |
1-(3-(4-胺基-7-甲基-5-(6-(2,2,2-三氟乙氧基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (t,J = 2.9 Hz, 1H), 8.12 (d,J = 1.5 Hz, 1H), 7.80 (dd,J = 8.3, 2.9 Hz, 1H), 7.06 (d,J = 8.4 Hz, 1H), 6.51 - 6.41 (dd,J = 16.7, 10.2 Hz, 1H), 6.09 (dt,J = 16.9, 3.1 Hz, 1H), 5.80 - 5.50 (bar, 2H), 5.63 (ddd,J = 15.3, 10.2, 2.5 Hz, 1H), 5.01 (q,J = 9.1 Hz, 2H), 3.93 (t,J = 9.1 Hz, 1H), 3.79 (d,J = 6.8 Hz, 4H), 3.67 (s, 1H), 3.56 - 3.43 (m, 1H), 3.31 - 3.22 (m, 1H), 2.25 - 1.89 (m, 2H). | 447.10 | |
1-(4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)-3-甲基咪唑啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 1.8 Hz, 1H), 7.68 (d,J = 8.3 Hz, 2H), 7.32 (d,J = 8.1 Hz, 2H), 6.48 (ddd,J = 33.2, 16.8, 10.3 Hz, 1H), 6.09 (ddd,J = 16.8, 5.4, 2.5 Hz, 1H), 5.62 (ddd,J = 14.2, 10.3, 2.5 Hz, 1H), 3.94 (t,J = 9.0 Hz, 1H), 3.80 (dd,J = 21.6, 7.2 Hz, 5H), 3.65 (tt,J = 18.0, 8.7 Hz, 1H), 3.57 - 3.42 (m, 2H), 3.30 - 3.15 (m, 1H), 2.79 (s, 3H), 2.24 - 2.17 (m, 1H), 2.12 - 1.91 (m, 1H). | 446.30 | |
1-(3-(4-胺基-5-(4-(2-羥基-1-苯基乙基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d,J = 2.7 Hz, 1H), 7.41 - 7.35 (m, 2H), 7.34 - 7.26 (m, 6H), 7.20 (tt,J = 5.6, 2.8 Hz, 1H), 6.51 - 6.37 (ddd,J = 16.9, 10.3, 3.9 Hz, 1H), 6.08 (ddd,J = 16.8, 13.8, 2.3 Hz, 1H), 5.69 - 5.52 (ddd,J = 10.3, 4.6, 2.4 Hz, 1H), 4.81 (t,J = 5.3 Hz, 1H), 4.16 (t,J = 7.2 Hz, 1H), 4.08 - 3.94 (m, 2H), 3.80 - 3.68 (m, 4H), 3.66 - 3.41 (m, 3H), 3.24 (dd,J = 11.9, 8.0 Hz, 1H), 2.18 - 1.91 (t,J = 10.7 Hz, 2H). | 468.20 | |
1-(3-(4-胺基-5-(4-(環丙基磺醯基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (d,J = 2.1 Hz, 1H), 7.96 (dd,J = 8.4, 2.9 Hz, 2H), 7.65 (d,J = 7.9 Hz, 2H), 6.59 - 6.40 (dd,J = 16.8, 10.3 Hz, 1H), 6.10 (ddd,J = 16.8, 4.0, 2.5 Hz, 1H), 5.64 (ddd,J = 14.4, 10.2, 2.4 Hz, 1H), 3.94 - 3.72 (m, 3H), 3.71 - 3.55 (m, 3H), 3.55 - 3.44 (m, 1H), 3.27 (s, 1H), 2.96 - 2.87 (m, 1H), 2.21 (d,J = 6.7 Hz, 1H), 2.12 (t,J = 10.3 Hz, 1H), 1.27 - 1.15 (m, 2H), 1.09 (dt,J = 8.2, 2.7 Hz, 2H). | 452.15 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-(四氫-2H-哌喃-4-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 2.0 Hz, 1H), 7.35 (q,J = 7.3, 6.7 Hz, 4H), 6.51 (dd,J = 16.8, 10.3 Hz, 1H), 6.38 (dd,J = 16.8, 10.3 Hz, 0H), 6.08 (ddd,J = 16.8, 10.2, 2.5 Hz, 1H), 5.62 (ddd,J = 20.1, 10.2, 2.5 Hz, 1H), 4.01 - 3.93 (m, 2H), 3.93 - 3.84 (m, 1H), 3.79 (s, 2H), 3.77 (s, 2H), 3.76 - 3.59 (m, 1H), 3.58 - 3.44 (m, 2H), 3.43 (d,J = 2.8 Hz, 1H), 3.36 - 3.21 (m, 1H), 2.89 - 2.79 (m, 1H), 2.10 (s, 1H), 2.08 (s, 1H), 1.97 (p,J = 10.9, 10.3 Hz, 1H), 1.72 (dq,J = 16.5, 12.6 Hz, 4H). | 432.35 | |
1-(3-{4-胺基-7-甲基-5-[4-(苯氧基甲基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d,J = 1.7 Hz, 1H), 7.56 (d,J = 7.8 Hz, 2H), 7.43 (d,J = 7.7 Hz, 2H), 7.32 (t,J = 7.7 Hz, 2H), 7.06 (d,J = 8.0 Hz, 2H), 6.97 (t,J = 7.3 Hz, 1H), 6.47 (ddd,J = 37.4, 16.8, 10.3 Hz, 1H), 6.09 (ddd,J = 16.6, 7.2, 2.4 Hz, 1H), 5.63 (ddd,J = 15.7, 10.1, 2.5 Hz, 1H), 5.17 (s, 2H), 3.94 (t,J = 9.2 Hz, 1H), 3.79 (d,J = 6.2 Hz, 4H), 3.66 (q,J = 9.3 Hz, 1H), 3.60 - 3.42 (m, 2H), 3.28 (d,J = 11.6 Hz, 1H), 2.08 (s, 4H), 1.16 (dt,J = 26.1, 13.1 Hz, 1H). | 454.20 | |
1-(3-(4-胺基-5-(4-環丁氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.10 (d, J = 1.7 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 6.46 (ddd, J = 46.5, 16.8, 10.3 Hz, 1H), 6.09 (ddd, J = 16.8, 7.0, 2.5 Hz, 1H), 5.83 - 4.98 (m, 2H), 4.72 (q, J = 7.1 Hz, 1H), 3.93 - 3.60 (m, 5H), 3.32 (s, 3H), 3.31 - 3.23 (m, 1H), 2.48 - 2.00 (m, 5H), 1.87 - 1.60 (m, 2H). | 418.25 | |
1-(3-(4-胺基-5-(4-(環戊基胺基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.08 (d,J = 1.8 Hz, 1H), 7.05 (d,J = 7.7 Hz, 2H), 6.63 (d,J = 8.0 Hz, 2H), 6.48 (ddd,J = 41.0, 16.7, 10.3 Hz, 1H), 6.09 (ddd,J = 16.8, 7.6, 2.4 Hz, 1H), 5.83 - 5.76 (m, 1H), 5.62 (ddd,J = 17.7, 10.2, 2.5 Hz, 1H), 3.95 - 3.70 (m, 6H), 3.70 - 3.42 (m, 1H), 3.28 (d,J = 10.9 Hz, 1H), 2.25 - 1.85 (m, 4H), 1.72 - 1.67 (m, 2H), 1.60 - 1.44 (m, 4H), 1.29 - 0.99 (m, 1H). | 431.35 | |
1-(3-(5-(4-(1H-咪唑-2-基)苯基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.58 (s, 1H), 8.13 (d,J = 1.8 Hz, 1H), 8.02 (d,J = 8.2 Hz, 2H), 7.45 (d,J = 7.9 Hz, 2H), 7.29 (d,J = 2.0 Hz, 1H), 7.07 (s, 1H), 6.47 (ddd,J = 27.8, 16.8, 10.3 Hz, 1H), 6.07 (ddd,J = 16.8, 5.9, 2.5 Hz, 1H), 5.60 (ddd,J = 19.1, 10.3, 2.5 Hz, 2H), 3.97 (t,J = 9.3 Hz, 0H), 3.80 (d,J = 6.6 Hz, 4H), 3.68 (d,J = 9.0 Hz, 1H), 3.60 - 3.49 (m, 2H), 2.04 (dq,J = 33.4, 11.2 Hz, 2H). | 414.15 | |
1-[3-(4-胺基-7-甲基-5-{4-[(1H-吡唑-1-基)甲基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基]丙-2-烯-1-酮 | 1H NMR (400 MHz, 甲醇-d4) 8.14 (d, J = 0.8 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.46-7.38 (m, 2H), 7.32 (d, J = 8.1 Hz, 2H), 6.50 (dd, J = 16.8, 10.4 Hz, 1H), 6.39 (t, J = 2.2 Hz, 1H), 6.32-6.21 (td, J = 16.4, 2.1 Hz, 2H), 5.73-5.66 (dd, J = 10.3, 2.2 Hz, 1H), 5.51 (s, 1H), 5.45 (d, J = 2.6 Hz, 2H), 3.98-3.75 (m, 5H), 3.78-3.35 (m, 3H), 2.35-2.05 (s, 2H). | 428.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(1-甲基-1H-吡唑-4-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 8.12 (d,J = 1.8 Hz, 1H), 7.92 (s, 1H), 7.66 (d,J = 7.8 Hz, 2H), 7.36 (d,J = 7.8 Hz, 2H), 6.51- 6.43 (dd,J = 16.8, 10.3 Hz, 1H), 6.07 (ddd,J = 16.7, 8.1, 2.5 Hz, 1H), 5.61 (ddd,J = 20.9, 10.3, 2.4 Hz, 2H), 3.95 (t,J = 9.2 Hz, 0H), 3.89 (s, 3H), 3.79 (d,J = 6.2 Hz,4H), 3.67 (q,J = 12.0, 10.8 Hz, 1H), 3.56 (t,J = 10.1 Hz, 2H), 3.54 - 3.27 (d,J = 8.1 Hz, 1H), 2.25- 1.95 (m, 1H). | 428.15 | |
1-(3-(4-胺基-7-甲基-5-(4-(5-甲基-1,2,4-噁二唑-3-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d,J = 1.7 Hz, 1H), 8.07 (d,J = 8.2 Hz, 2H), 7.57 (d,J = 8.2 Hz, 2H), 6.51 -6.42 (dd,J = 16.7, 10.3 Hz, 1H), 6.06 (ddd,J = 16.8, 7.1, 2.4 Hz, 1H), 5.63 (dd,J = 10.3, 2.5 Hz, 1H), 5.57 (dd,J = 10.2, 2.5 Hz, 1H), 3.99 - 3.90 (m, 1H), 3.81 (d,J = 6.6 Hz, 5H), 3.69 (d,J = 8.6 Hz, 1H), 3.58 (d,J = 9.8 Hz, 1H), 3.50 -3.28 (d,J = 10.1 Hz, 1H), 2.70 (s, 3H), 2.26 - 2.19 (m, 1H), 2.11 - 1.94 (m, 1H). | 430.15 | |
1-(3-(4-胺基-5-(4-((1,1-二氧離子基異噻唑啶-2-基)甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) 8.12 (d, J = 2.2 Hz, 1H), 7.53 - 7.30 (m, 4H), 6.45 (ddd, J = 46.4, 16.7, 10.3 Hz, 1H), 6.08 (dt, J = 16.7, 2.4 Hz, 1H), 5.62 (ddd, J = 15.1, 10.2, 2.4 Hz, 1H), 5.58 - 4.92 (s, 1H),4.23 - 4.09 (m, 2H), 4.00 - 3.72 (m, 4H), 3.70 - 3.35 (m, 2H), 3.33 (s, 1H), 3.28 (t, J = 7.7 Hz, 3H), 3.14 (td, J = 6.8, 2.3 Hz, 2H), 2.24 (p, J = 7.0 Hz, 3H), 2.09 (dt, J = 14.1, 8.2 Hz, 1H), 1.96 (dq, J = 21.2, 10.5 Hz, 1H). | 481.25 | |
1-(3-(4-胺基-5-(4-(環戊基甲基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (d,J = 2.2 Hz, 1H), 7.28 (d,J = 2.6 Hz, 4H), 6.44 (ddd,J = 55.7, 16.7, 10.3 Hz, 1H), 6.08 (ddd,J = 16.7, 7.0, 2.4 Hz, 1H), 5.61 (ddd,J = 20.9, 10.2, 2.5 Hz, 2H), 3.92 - 3.73 (m, 4H), 3.64 (t,J = 9.1 Hz, 1H), 3.58 - 3.38 (m, 2H), 3.29 - 3.22 (m, 1H), 2.64 (d,J = 7.5 Hz, 2H), 2.28 - 1.85 (m, 3H), 1.76 - 1.44 (m, 6H), 1.20 (q,J = 10.2, 9.3 Hz, 2H). | 430.35 | |
1-(3-(4-胺基-7-甲基-5-(4-((四氫-2H-哌喃-4-基)胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 2.0 Hz, 1H), 7.35 (q,J = 7.3, 6.7 Hz, 4H), 6.51 (dd,J = 16.8, 10.3 Hz, 1H), 6.38 (dd,J = 16.8, 10.3 Hz, 1H), 6.08 (ddd,J = 16.8, 10.2, 2.5 Hz, 1H), 5.71 (ddd,J = 18.2, 10.2, 2.5 Hz, 1H), 5.62 (ddd,J = 20.1, 10.2, 2.5 Hz, 1H), 4.01 - 3.93 (m, 2H), 3.93 - 3.84 (m, 1H), 3.79 (s, 2H), 3.77 (s, 2H), 3.76 - 3.59 (m, 1H), 3.58 - 3.44 (m, 2H), 3.43 (d,J = 2.8 Hz, 1H), 3.36 - 3.21 (m, 1H), 2.89 - 2.79 (m, 1H), 2.10 (s, 1H), 2.08 (s, 1H), 1.97 (p,J = 10.9, 10.3 Hz, 1H), 1.72 (dq,J = 16.5, 12.6 Hz, 4H). | 447.35 | |
1-(4-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲基)吡啶-2(1H)-酮 | 1 H NMR (400 MHz, DMSO-d6) 8.11 (d, J = 2.0 Hz, 1H), 7.83 (dd, J = 6.9, 2.0 Hz, 1H), 7.46 (ddt, J = 8.7, 6.6, 1.9 Hz, 1H), 7.36 (d, J = 5.3 Hz, 4H), 6.56 - 6.34 (m, 2H), 6.31 - 6.23 (m, 1H), 6.08 (ddd, J = 16.8, 11.7, 2.4 Hz, 1H), 5.62 (ddd, J = 19.2, 10.3, 2.5 Hz, 1H), 5.18 (d, J = 1.7 Hz, 2H), 3.92 - 3.75 (m, 4H), 3.75 - 3.40 (m, 4H), 3.30 - 3.18 (m, 2H), 2.27 - 1.87 (m, 2H). | 455.30 | |
1-[3-(4-胺基-5-{4-[環丙基(羥基)甲基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基]丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.12 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 7.7 Hz, 2H), 7.38 - 7.31 (m, 2H), 6.53- 6.43 (ddd, J = 16.9, 10.4, 3.3 Hz, 1H), 6.09 (ddd, J = 16.9, 8.8, 2.5 Hz, 1H), 5.76-5.63 (ddd, J = 16.5, 10.3, 2.4 Hz, 2H), 5.25 (dd, J = 4.5, 2.3 Hz, 1H), 4.06 (dd, J = 7.4, 4.4 Hz, 1H), 3.92 (t, J = 9.2 Hz, 1H), 3.79 (d, J = 6.5 Hz, 4H), 3.73-3.51 (dd, J = 21.7, 11.0 Hz, 3H), 3.31 - 3.21 (m, 1H), 2.20 -1.93 (m, 2H), 1.13-1.06 (m, 1H), 0.44 (td, J = 12.9, 6.6 Hz, 4H). | 418.30 | |
1-[3-(4-胺基-7-甲基-5-{4-[(3-甲基-1H-吡唑-1-基)甲基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基]丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.11 (t, J = 2.1 Hz, 1H), 7.73 (t, J = 2.6 Hz, 1H), 7.41-7.32 (m, 2H), 7.25 (dd, J = 8.3, 3.4 Hz, 1H), 7.14 (dd, J = 8.1, 3.7 Hz, 1H), 6.57-6.32 (m, 1H), 6.15-6.07 (m, 1H), 6.11-6.03 (m, 1H), 5.62 (ddt, J = 15.8, 10.3, 2.6 Hz, 1H), 5.38 (s, 1H), 5.32 (d, J = 2.7 Hz, 1H), 3.81-3.75 (m, 3H), 3.79-3.56 (m, 2H), 3.58-3.41 (m, 2H), 3.32-3.15 (m, 1H), 2.20 (dd, J = 21.3, 2.3 Hz, 3H), 2.10-1.89 (m, 2H). | 442.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(4-甲基-1H-吡唑-1-基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 8.12 (d,J = 1.7 Hz, 1H), 7.87 (d,J = 8.1 Hz, 2H), 7.60 (s, 1H), 7.47 (d,J = 8.2 Hz, 2H), 6.47 (ddd,J = 31.9, 16.7, 10.2 Hz, 1H), 6.06 (ddd,J = 16.8, 7.5, 2.5 Hz, 1H), 5.60 (ddd,J = 21.7, 10.2, 2.5 Hz, 2H), 3.94 (d,J = 9.1 Hz, 1H), 3.79 (d,J = 6.3 Hz, 3H), 3.67 (q,J = 9.1 Hz, 1H), 3.60 - 3.45 (m, 1H), 3.29 (d,J = 10.7 Hz, 1H), 2.33 (d,J = 2.2 Hz, 1H), 2.13 (s, 5H). | 428.25 | |
1-(3-(4-胺基-7-甲基-5-(4-((5-(三氟甲基)吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) 8.68 - 8.58 (m, 1H), 8.27 (dt, J = 8.7, 2.8 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 2H), 7.32 (dd, J = 9.1, 4.1 Hz, 3H), 6.51 (ddd, J = 32.6, 16.8, 10.3 Hz, 1H), 6.13 (t, J = 1.9 Hz, 1H), 6.09 - 5.57 (m, 2H), 4.00 - 3.76 (m, 4H), 3.75 - 3.34 (m, 3H), 3.31 (s, 1H), 2.40 - 1.94 (m, 2H). | 509.20 | |
1-(3-(4-胺基-5-(4-(環戊烷羰基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d,J = 1.8 Hz, 1H), 8.06 (d,J = 7.9 Hz, 2H), 7.53 (d,J = 7.9 Hz, 2H), 6.55 - 6.35 (dd,J = 16.7, 10.3 Hz, 1H), 6.07 (ddd,J = 16.8, 7.0, 2.4 Hz, 1H), 5.63 - 5.58 (dd,J = 10.2, 2.5 Hz, 1H), 3.96 - 3.87 (m, 1H), 3.80 (d,J = 6.6 Hz, 4H), 3.77 (s, 1H), 3.68 (d,J = 8.9 Hz, 1H), 3.48 (t,J = 9.8 Hz, 1H), 3.27 (s, 1H), 2.21 (d,J = 7.3 Hz, 1H), 2.11 (s, 1H), 1.95 (s, 1H), 1.92 (d,J = 8.1 Hz, 1H), 1.80 (s, 2H), 1.64 (td,J = 8.4, 7.0, 4.9 Hz, 4H). | 444.20 | |
1-(5-(6-(1-丙烯醯基吡咯啶-3-基)-4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)吡啶-2-基)吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (t,J = 6.8 Hz, 2H), 8.13 (d,J = 1.7 Hz, 1H), 7.86 - 7.78 (m, 1H), 6.47 (ddd,J = 32.7, 16.8, 10.3 Hz, 1H), 6.13 - 6.04 (m, 1H), 5.68 - 5.57 (m, 3H), 4.05 - 3.95 (t,J = 9.2 Hz, 3H), 3.79 (d,J = 6.8 Hz,3 H), 3.76 - 3.60 (m, 2H), 3.52 (dt,J = 16.6, 9.1 Hz, 2H), 3.27 (s, 1H), 2.61 (t,J = 8.0 Hz, 2H), 2.13 - 1.90 (m, 4H). | 432.35 | |
1-(3-(4-胺基-5-(4-(異噁唑-5-基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.70 (d,J = 1.9 Hz, 1H), 8.14 (d,J = 1.8 Hz, 1H), 7.97 (d,J = 8.1 Hz, 2H), 7.55 (d,J = 8.0 Hz, 2H), 7.10 (d,J = 2.0 Hz, 1H), 6.51 - 6.42 (dd,J = 16.8, 10.2 Hz, 1H), 6.11 - 6.01 (m, 1H), 5.63 - 5.53 (m, 1H), 3.95 (t,J = 9.1 Hz, 1H), 3.80 (d,J = 6.7 Hz, 4H), 3.69 (s, 1H), 3.57 (t,J = 9.6 Hz, 1H), 3.53 (s, 1H), 3.52 - 3.43 (m, 1H), 3.28 (d,J = 9.7 Hz, 1H), 2.21 -1.97 (m, 2H). | 415.15 | |
4-[(4-{4-胺基-7-甲基-6-[1-(丙-2-烯醯基)吡咯啶-3-基]-7H-吡咯并[2,3-d]嘧啶-5-基}苯基)甲基]嗎啉-3-酮 | 1H NMR (400 MHz, DMSO-d6) 8.12 (d, J = 2.2 Hz, 1H), 7.36 (qd, J = 8.2, 3.7 Hz, 4H), 6.51-6.39 (dd, J = 16.8, 10.3 Hz, 1H), 6.08 (dt, J = 16.8, 2.9 Hz, 1H), 5.84-5.47 (s, 2H), 4.63 (s, 2H), 4.15 (s, 2H), 3.94-3.83 (m, 2H), 3.84 -3.62 (m, 5H), 3.54 (dt, J = 8.0, 5.6 Hz, 2H), 3.52-3.21 (m, 3H), 2.21-1.91 (m, 3H). | 461.30 | |
1-(3-(4-胺基-5-(4-((5-氯嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (d,J = 3.5 Hz, 2H), 8.13 (d,J = 1.7 Hz, 1H), 7.50 - 7.44 (m, 2H), 7.35 (d,J = 8.6 Hz, 2H), 6.51 (ddd,J = 33.8, 16.7, 10.3 Hz, 2H), 6.11 (ddd,J = 16.8, 5.5, 2.4 Hz, 1H), 5.74 - 5.44 (m, 3H), 4.01 - 3.91 (m, 1H), 3.80 (d,J = 6.8 Hz, 3H), 3.74 - 3.52 (m, 3H), 3.35 (d,J = 11.1 Hz, 1H), 2.20 - 2.04 (m, 2H). | 476.20 | |
1-(3-(4-胺基-5-(4-((5-氯吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.28 (dd, J = 7.5, 2.7 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 8.00 (dt, J = 8.8, 2.5 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.25 (dd, J = 8.6, 3.1 Hz, 2H), 7.22 - 7.15 (m, 1H), 6.50 (ddd, J = 33.1, 16.8, 10.3 Hz, 1H), 6.11 (dt, J = 16.8, 2.3 Hz, 1H), 5.64 (td, J = 10.2, 2.5 Hz, 1H), 3.95 (t, J = 9.2 Hz, 1H), 3.84 - 3.68 (m, 5H), 3.62 - 3.47 (m, 2H), 2.28 - 1.91 (m, 2H). | 475.1 | |
1-(3-(4-胺基-5-(4-((5-氯-6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, 氯仿-d) δ 8.32 (d, J = 2.5 Hz, 1H), 7.68 (dd, J = 8.6, 1.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 7.2 Hz, 2H), 6.80 (t, J = 8.6 Hz, 1H), 6.48 - 6.22 (m, 2H), 5.69 (ddd, J = 15.2, 9.2, 3.0 Hz, 1H), 4.87 (s, 1H), 4.02 (dd, J = 11.4, 7.2 Hz, 0H), 3.92 - 3.80 (m, 3H), 3.80 - 3.47 (m, 2H), 2.53 (d, J = 4.4 Hz, 3H), 2.25 (q, J = 7.2 Hz, 1H), 2.03 (s, 1H). | 490.2 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d,J = 1.1 Hz, 1H), 7.79 - 7.72 (m, 1H), 7.45 - 7.39 (m, 2H), 7.20 (dd,J = 8.5, 3.7 Hz, 2H), 7.04 (d,J = 7.3 Hz, 1H), 6.84 (dd,J = 8.1, 4.2 Hz, 1H), 6.49 (ddd,J = 33.6, 16.8, 10.3 Hz, 1H), 6.10 (dt,J = 16.6, 2.0 Hz, 1H), 5.69 - 5.51 (m, 2H), 3.95 (t,J = 9.2 Hz, 1H), 3.80 (d,J = 6.5 Hz, 4H), 3.70 - 3.47 (m, 3H), 2.36 (d,J = 3.8 Hz, 3H), 2.27 - 1.93 (m, 2H). | 455.20 | |
(S)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d,J = 2.0 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.46 - 7.36 (m, 2H), 7.19 (dd,J = 8.6, 3.9 Hz, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.84 (dd,J = 8.1, 4.1 Hz, 1H), 6.49 (ddd,J = 33.2, 16.7, 10.2 Hz, 1H), 6.10 (dd,J = 16.7, 2.3 Hz, 1H), 5.63 (ddd,J = 10.8, 9.0, 2.4 Hz, 1H), 3.95 (t,J = 9.0 Hz, 1H), 3.79 (d,J = 6.8 Hz, 4H), 3.53 (dq,J = 18.8, 9.7 Hz, 2H), 2.36 (d,J = 3.8 Hz, 3H), 2.27 - 1.94 (m, 2H). | 455.20 | |
1-(3-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.82 (d,J = 2.6 Hz, 1H), 8.09 (s, 1H), 7.76 (t,J = 7.8 Hz, 1H), 7.49 - 7.36 (m, 2H), 7.22 (dd,J = 8.5, 2.1 Hz, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 6.58 (ddd,J = 16.7, 10.3, 3.8 Hz, 1H), 6.15 (dd,J = 16.7, 2.5 Hz, 1H), 5.67 (ddd,J = 10.6, 8.5, 2.5 Hz, 2H), 3.99 (t,J = 8.8 Hz, 1H), 3.89 - 3.77 (m, 1H), 3.77 - 3.60 (m, 1H), 3.54 (dt,J = 11.0, 5.4 Hz, 1H), 3.42 (d,J = 6.8 Hz, 1H), 2.37 (s, 3H), 2.36 - 2.07 (m, 2H). | 441.30 | |
(S)-1-(3-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.82 (s, 1H), 8.09 (s, 1H), 7.76 (t,J = 7.8 Hz, 1H), 7.43 (dd,J = 8.5, 3.5 Hz, 2H), 7.27 - 7.19 (m, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 6.59 (ddd,J = 16.8, 10.3, 3.9 Hz, 1H), 6.15 (dd,J = 16.8, 2.5 Hz, 1H), 5.76 (s, 1H), 5.67 (ddd,J = 10.7, 8.5, 2.5 Hz, 1H), 4.06 - 3.78 (m, 1H), 3.77 - 3.60 (m, 1H), 3.54 (dt,J = 11.2, 5.4 Hz, 1H), 3.42 (d,J = 6.9 Hz, 1H), 2.37 (s, 3H), 2.37 - 2.10 (m, 2H). | 441.30 | |
(R)-1-(3-(4-胺基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.92 - 11.73 (m, 1H), 8.09 (s, 1H), 7.76 (t,J = 7.8 Hz, 1H), 7.43 (dd,J = 8.4, 3.5 Hz, 2H), 7.27 - 7.16 (m, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 6.58 (ddd,J = 16.8, 10.3, 3.8 Hz, 1H), 6.15 (dd,J = 16.7, 2.5 Hz, 1H), 5.90 - 5.75 (m, 2H), 5.67 (ddd,J = 10.6, 8.5, 2.5 Hz, 1H), 4.08 - 3.78 (m, 1H), 3.68 (dt,J = 28.8, 11.1 Hz, 1H), 3.55 (td,J = 10.7, 6.7 Hz, 1H), 3.50 - 3.39 (m, 1H), 2.37 (s, 3H), 2.30 (q,J = 8.9, 7.8 Hz, 0H), 2.23 - 2.08 (m, 1H). | 441.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 2.8 Hz, 1H), 7.45 (d, J = 6.8 Hz, 4H), 6.46 (ddd, J = 40.4, 16.8, 10.4 Hz, 1H), 6.08 (dt, J = 16.8, 2.4 Hz, 1H), 5.62 (ddd, J = 12.9, 10.4, 2.4 Hz, 1H), 3.96 - 3.87 (m, 0H), 3.79 (d, J = 7.6 Hz, 3H), 3.69 (q, J = 8.2 Hz, 1H), 3.61 - 3.44 (m, 1H), 2.23 (s, 1H), 2.03 (ddt, J = 50.6, 20.8, 10.4 Hz, 2H), 1.67 - 1.61 (m, 2H), 1.54 (s, 5H). | 459.3 | |
1-(3-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 8.10 (d,J = 1.0 Hz, 1H), 7.72 - 7.60 (m, 2H), 7.45 (dd,J = 8.1, 3.6 Hz, 2H), 6.58 (ddd,J = 16.7, 10.3, 4.3 Hz, 1H), 6.14 (dd,J = 16.7, 2.5 Hz, 1H), 5.67 (ddd,J = 10.8, 8.8, 2.5 Hz, 3H), 3.83 (q,J = 9.2 Hz, 1H), 3.76 - 3.59 (m, 1H), 3.59 - 3.38 (m, 6H), 2.39 - 2.05 (m, 2H), 1.86 (dq,J = 19.0, 6.8 Hz, 4H). | 431.15 | |
1-(3-(4-胺基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丁-2-炔-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.02 - 11.71 (m, 1H), 8.10 (d,J = 2.2 Hz, 1H), 7.64 (dd,J = 7.9, 4.8 Hz, 2H), 7.44 (dd,J = 7.9, 5.7 Hz, 2H), 5.68 (d,J = 65.3 Hz, 2H), 3.98 - 3.80 (m, 1H), 3.77 - 3.58 (m, 2H), 3.50 (t,J = 6.7 Hz, 4H), 3.38 (d,J = 11.0 Hz, 1H), 3.28 - 3.20 (m, 1H), 2.35 - 2.11 (m, 2H), 2.02 (s, 1H), 1.98 (s, 2H), 1.87 (dq,J = 19.0, 6.7 Hz, 4H). | 443.25 | |
1-(3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丁-2-炔-1-酮 | 1 H NMR (400 MHz, 氯仿-d) δ 8.32 (d, J = 3.3 Hz, 1H), 7.68 (t, J = 9.1 Hz, 2H), 7.43 (d, J = 8.1 Hz, 2H), 4.86 (s, 2H), 3.99 - 3.82 (m, 5H), 3.69 (dt, J = 21.4, 8.0 Hz, 5H), 3.65 - 3.47 (m, 4H), 2.24 - 2.10 (m, 2H), 2.07 - 1.93 (m, 6H), 1.86 (s, 6H). | 457.35 | |
1-(3-(4-胺基-5-(4-((5-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.82 (d,J = 2.5 Hz, 1H), 8.07 (dd,J = 19.5, 1.7 Hz, 2H), 7.71 (dd,J = 8.3, 2.5 Hz, 1H), 7.41 (dd,J = 8.5, 3.7 Hz, 2H), 7.24 - 7.16 (m, 2H), 7.02 (d,J = 8.3 Hz, 1H), 6.58 (ddd,J = 16.8, 10.3, 2.8 Hz, 1H), 6.15 (dd,J = 16.8, 2.5 Hz, 1H), 5.75 (s, 1H), 5.67 (ddd,J = 10.8, 8.7, 2.5 Hz, 2H), 3.99 (dd,J = 9.9, 7.9 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.75 - 3.59 (m, 1H), 3.54 (tt,J = 12.8, 6.9 Hz, 1H), 3.41 (dd,J = 9.5, 6.1 Hz, 1H), 2.27 (s, 4H), 2.22 - 2.05 (m, 2H). | 441.15 | |
1-(3-{4-胺基-5-[4-(氮雜環丁-3-基氧基)苯基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡咯啶-1-基)丙-2-烯-1-酮;三氟乙酸鹽 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.27 (d,J = 52.2 Hz, 2H), 8.58 - 8.34 (m, 1H), 7.35 (d,J = 8.3 Hz, 2H), 6.97 (d,J = 8.0 Hz, 2H), 6.44 (ddd,J = 53.6, 16.7, 10.3 Hz, 1H), 6.09 (ddd,J = 16.8, 4.6, 2.4 Hz, 1H), 5.64 (ddd,J = 13.9, 10.3, 2.4 Hz, 1H), 5.15 (t,J = 6.1 Hz, 1H), 4.50 (s, 2H), 4.07 (d,J = 10.2 Hz, 2H), 3.97 - 3.43 (m, 7H), 3.28 (dt,J = 12.0, 9.1 Hz, 1H), 2.31 - 1.85 (m, 2H). | 419.30 | |
N-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環戊基)丙烯醯胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 12.7 Hz, 2H), 7.77 (td, J = 7.7, 1.6 Hz, 1H), 7.39 (d, J = 8.3 Hz, 2H), 7.26 - 7.19 (m, 2H), 7.05 (d, J = 7.3 Hz, 1H), 6.85 (dd, J = 8.2, 4.6 Hz, 1H), 6.24 - 6.15 (m, 1H), 6.06 (dd, J = 17.1, 2.4 Hz, 1H), 5.56 (ddd, J = 10.0, 3.7, 2.4 Hz, 1H), 4.27 - 4.03 (m, 1H), 3.81 (d, J = 10.3 Hz, 3H), 3.65 (d, J = 43.2 Hz, 1H), 2.37 (s, 3H), 2.18 (s, 1H), 2.12 - 1.77 (m, 3H), 1.68 (q, J = 12.0 Hz, 1H), 1.62 - 1.48 (m, 1H). | 469 | |
N-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環戊基)-N-甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.77 (t,J = 7.7 Hz, 1H), 7.43 (d,J = 7.9 Hz, 2H), 7.22 (d,J = 8.0 Hz, 2H), 7.04 (d,J = 7.4 Hz, 1H), 6.84 (d,J = 8.1 Hz, 1H), 6.06 (t,J = 15.7 Hz, 1H), 5.63 (s, 2H), 4.69 (d,J = 173.3 Hz, 1H), 3.78 (s, 3H), 3.43 (d,J = 10.4 Hz, 1H), 2.67 (d,J = 54.3 Hz, 3H), 2.35 (s, 3H), 2.11 - 1.50 (m, 6H). | 483.20 | |
1-((2R)-4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-(羥基甲基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.75 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.88 - 6.80 (m, 1H), 6.53 (dd, J = 16.4, 10.4 Hz, 1H), 6.11 (d, J = 17.0 Hz, 1H), 5.64 (dd, J = 10.4, 2.4 Hz, 1H), 4.07 (s, 1H), 3.98 (s, 1H), 3.82 (d, J = 7.4 Hz, 3H), 3.58 - 3.46 (m, 2H), 2.35 (s, 3H). | 485.22 | |
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-(羥基甲基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 1.2 Hz, 1H), 7.75 (td,J = 7.8, 3.3 Hz, 1H), 7.49 - 7.28 (m, 2H), 7.16 (ddd,J = 19.5, 8.4, 3.9 Hz, 2H), 7.04 (d,J = 7.3 Hz, 1H), 6.82 (dd,J = 8.1, 1.9 Hz, 1H), 6.42 (dd,J = 16.7, 10.3 Hz, 1H), 6.20 (dd,J = 16.8, 10.1 Hz, 1H), 6.04 - 5.58 (ddd,J = 10.2, 3.9, 2.5 Hz, 2H), 4.62 (dt,J = 15.6, 5.0 Hz, 1H), 3.95 (dq,J = 37.7, 8.1 Hz, 1H), 3.79 (s, 3H), 3.62 (ddd,J = 17.2, 11.4, 7.4 Hz, 1H), 3.52 - 3.35 (m, 1H), 3.18 (dq,J = 10.2, 5.1 Hz, 1H), 3.12 - 3.00 (m, 1H), 2.84 - 2.65 (m, 1H), 2.36 (d,J = 7.9 Hz, 3H), 2.08 (s, 2H). | 485.40 | |
1-(3-(4-胺基-7-甲基-5-(4-(甲基(四氫-2H-哌喃-4-基)胺基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 2.0 Hz, 1H), 7.35 (q,J = 7.3, 6.7 Hz, 4H), 6.51 (dd,J = 16.8, 10.3 Hz, 1H), 6.38 (dd,J = 16.8, 10.3 Hz, 0H), 6.08 (ddd,J = 16.8, 10.2, 2.5 Hz, 1H), 5.71 (ddd,J = 18.2, 10.2, 2.5 Hz, 1H), 5.62 (ddd,J = 20.1, 10.2, 2.5 Hz, 1H), 4.01 - 3.93 (m, 2H), 3.93 - 3.84 (m, 1H), 3.79 (s, 2H), 3.77 (s, 2H), 3.76 - 3.59 (m, 1H), 3.58 - 3.44 (m, 2H), 3.43 (d,J = 2.8 Hz, 1H), 3.36 - 3.21 (m, 1H), 2.89 - 2.79 (m, 1H), 2.78 (d,J = 7.0 Hz, 3H), 2.10 (s, 1H), 2.08 (s, 1H), 1.97 (p,J = 10.9, 10.3 Hz, 1H), 1.72 (dq,J = 16.5, 12.6 Hz, 4H). | 461.35 | |
3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.67 - 7.60 (m, 2H), 7.48 - 7.41 (m, 2H), 5.59 (s, 2H), 3.79 (s, 3H), 3.73 (td,J = 9.2, 8.7, 6.9 Hz, 1H), 3.66 (t,J = 8.8 Hz, 1H), 3.55 - 3.42 (m, 5H), 3.46 - 3.33 (m, 2H), 2.15 (ddd,J = 14.4, 7.3, 4.8 Hz, 1H), 2.06 - 1.80 (m, 5H). | 416.20 | |
(S)-3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.67 - 7.60 (m, 2H), 7.48 - 7.41 (m, 2H), 5.59 (s, 2H), 3.79 (s, 3H), 3.73 (td,J = 9.2, 8.7, 6.9 Hz, 1H), 3.66 (t,J = 8.8 Hz, 1H), 3.55 - 3.42 (m, 5H), 3.46 - 3.33 (m, 2H), 2.15 (ddd,J = 14.4, 7.3, 4.8 Hz, 1H), 2.06 - 1.80 (m, 5H). | 416.20 | |
(R)-3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.67 - 7.60 (m, 2H), 7.48 - 7.41 (m, 2H), 5.59 (s, 2H), 3.79 (s, 3H), 3.73 (td,J = 9.2, 8.7, 6.9 Hz, 1H), 3.66 (t,J = 8.8 Hz, 1H), 3.55 - 3.42 (m, 5H), 3.46 - 3.33 (m, 2H), 2.15 (ddd,J = 14.4, 7.3, 4.8 Hz, 1H), 2.06 - 1.80 (m, 5H). | 416.20 | |
(4-(4-胺基-7-甲基-6-(1-(乙烯基磺醯基)吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.66 - 7.59 (m, 2H), 7.46 - 7.40 (m, 2H), 6.74 (dd,J = 16.5, 10.0 Hz, 1H), 6.12 (d,J = 10.0 Hz, 1H), 6.04 (d,J = 16.5 Hz, 1H), 5.58 (s, 1H), 3.78 (s, 3H), 3.67 (q,J = 9.4, 8.9 Hz, 1H), 3.49 (ddd,J = 13.2, 8.5, 6.2 Hz, 5H), 3.32 - 3.25 (m, 1H), 3.18 (td,J = 10.0, 6.6 Hz, 1H), 3.10 (t,J = 10.1 Hz, 1H), 2.17 (dq,J = 12.8, 7.0, 6.2 Hz, 1H), 2.01 - 1.81 (m, 5H). | 481.20 | |
(R)-(4-(4-胺基-7-甲基-6-(1-(乙烯基磺醯基)吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.66 - 7.59 (m, 2H), 7.46 - 7.40 (m, 2H), 6.74 (dd,J = 16.5, 10.0 Hz, 1H), 6.12 (d,J = 10.0 Hz, 1H), 6.04 (d,J = 16.5 Hz, 1H), 5.58 (s, 1H), 3.78 (s, 3H), 3.67 (q,J = 9.4, 8.9 Hz, 1H), 3.49 (ddd,J = 13.2, 8.5, 6.2 Hz, 5H), 3.32 - 3.25 (m, 1H), 3.18 (td,J = 10.0, 6.6 Hz, 1H), 3.10 (t,J = 10.1 Hz, 1H), 2.17 (dq,J = 12.8, 7.0, 6.2 Hz, 1H), 2.01 - 1.81 (m, 5H). | 481.20 | |
(S)-(4-(4-胺基-7-甲基-6-(1-(乙烯基磺醯基)吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.66 - 7.59 (m, 2H), 7.46 - 7.40 (m, 2H), 6.74 (dd,J = 16.5, 10.1 Hz, 1H), 6.12 (d,J = 10.0 Hz, 1H), 6.04 (d,J = 16.6 Hz, 1H), 5.60 (s, 1H), 3.78 (s, 3H), 3.67 (q,J = 9.9, 9.5 Hz, 1H), 3.49 (ddd,J = 13.2, 8.5, 6.3 Hz, 5H), 3.32 - 3.25 (m, 1H), 3.18 (td,J = 10.1, 6.7 Hz, 1H), 3.10 (t,J = 10.1 Hz, 1H), 2.17 (dt,J = 12.9, 7.1 Hz, 1H), 2.01 - 1.81 (m, 5H). | 481.20 | |
1-((R)-3-(4-胺基-7-甲基-5-((R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 6.62 (dt, J = 16.7, 11.2 Hz, 1H), 6.46 (s, 1H), 6.17 (dt, J = 16.8, 2.5 Hz, 1H), 5.69 (td, J = 10.0, 2.6 Hz, 1H), 4.05 - 3.80 (m, 2H), 3.68 (d, J = 5.9 Hz, 5H), 3.61 - 3.44 (m, 3H), 3.43 - 3.36 (m, 1H), 3.30 (d, J = 6.9 Hz, 2H), 2.91 (s, 1H), 2.23 (q, J = 36.2, 32.0 Hz, 6H), 1.90 (p, J = 6.7 Hz, 3H), 1.79 (p, J = 6.8 Hz, 3H). | 449.25 | |
(S)-1-(3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 6.62 (dt, J = 17.4, 9.1 Hz, 3H), 6.21 (d, J = 16.1 Hz, 2H), 5.75 (d, J = 9.3 Hz, 2H), 4.53 (dd, J = 88.7, 39.5 Hz, 4H), 3.73 (s, 3H), 3.63 - 3.47 (m, 2H), 3.31 (s, 2H), 2.96 (d, J = 9.2 Hz, 1H), 2.30 (s, 2H), 2.17 (d, J = 7.2 Hz, 2H), 1.85 (dq, J = 36.4, 6.8 Hz, 6H). | 447.25 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)-2-氯乙-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (dd,J = 4.9, 3.1 Hz, 1H), 8.13 (d,J = 2.8 Hz, 1H), 7.44 (d,J = 8.0 Hz, 2H), 7.30 (d,J = 8.0 Hz, 2H), 7.18 (d,J = 5.0 Hz, 1H), 4.37 - 4.08 (m, 2H), 3.93 - 3.41 (m, 7H), 3.25 (s, 1H), 2.43 (s, 3H), 2.36 - 1.92 (m, 2H). | 478.25 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1H), 6.62 (dt, J = 17.4, 9.1 Hz, 3H), 6.21 (d, J = 16.1 Hz, 2H), 5.75 (d, J = 9.3 Hz, 2H), 4.53 (dd, J = 88.7, 39.5 Hz, 4H), 3.73 (s, 3H), 3.63 - 3.47 (m, 2H), 3.31 (s, 2H), 2.96 (d, J = 9.2 Hz, 1H), 2.30 (s, 2H), 2.17 (d, J = 7.2 Hz, 2H), 1.85 (dq, J = 36.4, 6.8 Hz, 6H). | 447.25 | |
(S)-1-(3-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)-2-氯乙-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (dd,J = 5.0, 3.0 Hz, 1H), 8.13 (d,J = 2.8 Hz, 1H), 7.44 (d,J = 8.0 Hz, 2H), 7.30 (d,J = 7.8 Hz, 2H), 7.18 (d,J = 5.0 Hz, 1H), 5.60 (s, 1H), 4.37 - 4.09 (m, 2H), 3.66 (dd,J = 105.6, 8.9 Hz, 7H), 3.28 (d,J = 23.2 Hz, 1H), 2.43 (s, 3H), 2.31 - 1.96 (m, 2H). | 478.25 | |
1-((R)-3-(4-胺基-7-甲基-5-((S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 6.62 (dt, J = 16.7, 11.2 Hz, 1H), 6.46 (s, 1H), 6.17 (dt, J = 16.8, 2.5 Hz, 1H), 5.69 (td, J = 10.0, 2.6 Hz, 1H), 4.05 - 3.80 (m, 2H), 3.68 (d, J = 5.9 Hz, 5H), 3.61 - 3.44 (m, 3H), 3.43 - 3.36 (m, 1H), 3.30 (d, J = 6.9 Hz, 2H), 2.91 (s, 1H), 2.23 (q, J = 36.2, 32.0 Hz, 6H), 1.90 (p, J = 6.7 Hz, 3H), 1.79 (p, J = 6.8 Hz, 3H). | 449.25 | |
1-((S)-3-(4-胺基-7-甲基-5-((S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.01 (s, 1H), 6.63 (dd,J = 16.7, 10.3 Hz, 1H), 6.43 (s, 1H), 6.24 - 6.05 (m, 1H), 5.69 (dt,J = 8.9, 2.9 Hz, 2H), 3.99 (s, 1H), 3.68 (d,J = 7.9 Hz, 6H), 3.61 - 3.45 (m, 2H), 3.41 (d,J = 9.5 Hz, 1H), 3.31 (d,J = 9.9 Hz, 2H), 2.90 (s, 1H), 2.44 - 2.31 (m, 1H), 2.24 (d,J = 19.4 Hz, 3H), 2.11 (d,J = 18.0 Hz, 2H), 1.89 (q,J = 6.7, 6.2 Hz, 3H), 1.79 (p,J = 6.7 Hz, 2H). | 449.25 | |
1-((S)-3-(4-胺基-7-甲基-5-((R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (s, 1H), 6.62 (dt,J = 16.6, 11.1 Hz, 1H), 6.45 (s, 1H), 6.17 (dt,J = 16.8, 2.6 Hz, 1H), 5.69 (td,J = 11.1, 10.0, 3.6 Hz, 2H), 4.12 - 3.36 (m, 10H), 3.30 (s, 1H), 2.91 (s, 1H), 2.47 - 1.95 (m, 6H), 1.85 (dq,J = 36.9, 6.8 Hz, 6H). | 449.30 | |
1-[4-(4-胺基-5-{3-甲氧基-4-[(6-甲基吡啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)哌啶-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 7.68 (t,J = 7.7 Hz, 1H), 7.17 (d,J = 8.0 Hz, 1H), 7.10 - 7.05 (m, 1H), 6.94 (d,J = 7.3 Hz, 2H), 6.76 (dd,J = 16.7, 10.5 Hz, 1H), 6.64 (d,J = 8.2 Hz, 1H), 6.04 (dd,J = 16.7, 2.4 Hz, 1H), 5.61 (dd,J = 10.4, 2.5 Hz, 2H), 4.47 (s, 1H), 4.13 - 4.06 (m, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 3.09 (s, 2H), 2.64 (s, 2H), 2.31 (s, 3H), 1.83 (s, 2H), 1.57 (s, 2H). | 498.587 | |
N-((1r,4r)-4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環己基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.11 (s, 1H), 7.71 (t,J = 7.8 Hz, 1H), 7.24 (d,J = 8.0 Hz, 1H), 7.13 (d,J = 2.0 Hz, 1H), 7.05 (dd,J = 8.0, 1.9 Hz, 1H), 6.97 (d,J = 7.3 Hz, 1H), 6.71 (d,J = 8.3 Hz, 1H), 6.22 (d,J = 6.0 Hz, 2H), 5.65 (t,J = 6.0 Hz, 1H), 4.60 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.70 (s, 1H), 2.98 (t,J = 12.5 Hz, 1H), 2.42 (s, 3H), 2.01 (d,J = 14.2 Hz, 2H), 1.94 (s, 2H), 1.81 (d,J = 12.7 Hz, 1H), 1.75 (d,J = 12.6 Hz, 1H), 1.45 - 1.29 (m, 2H). | 512.614 | |
N-((1s,4s)-4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環己基)丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.11 (s, 1H), 7.71 (t,J = 7.8 Hz, 1H), 7.24 (d,J = 8.0 Hz, 1H), 7.13 (d,J = 2.0 Hz, 1H), 7.05 (dd,J = 8.0, 1.9 Hz, 1H), 6.97 (d,J = 7.3 Hz, 1H), 6.71 (d,J = 8.3 Hz, 1H), 6.22 (d,J = 6.0 Hz, 2H), 5.65 (t,J = 6.0 Hz, 1H), 4.60 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H), 3.70 (s, 1H), 2.98 (t,J = 12.5 Hz, 1H), 2.42 (s, 3H), 2.01 (d,J = 14.2 Hz, 2H), 1.94 (s, 2H), 1.81 (d,J = 12.7 Hz, 1H), 1.75 (d,J = 12.6 Hz, 1H), 1.45 - 1.29 (m, 2H). | 512.614 | |
1-[4-(4-胺基-5-{3-甲氧基-4-[(6-甲基吡啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1,2,3,6-四氫吡啶-1-基]丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.68 (t,J = 7.7 Hz, 1H), 7.17 (d,J = 8.0 Hz, 1H), 7.09 (d,J = 2.6 Hz, 1H), 6.95 (dd,J = 9.6, 7.6 Hz, 2H), 6.79 (ddd,J = 26.2, 16.7, 10.4 Hz, 1H), 6.67 (d,J = 8.2 Hz, 1H), 6.12 (dq,J = 16.7, 2.5 Hz, 1H), 6.05 (s, 2H), 5.73 - 5.64 (m, 1H), 4.25 (s, 1H), 4.16 (d,J = 3.3 Hz, 1H), 3.69 - 3.60 (m, 8H), 2.31 (s, 3H), 2.17 (d,J = 11.8 Hz, 2H). | 496.571 | |
N-(4-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環己-3-烯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 8.08 (d,J = 7.6 Hz, 1H), 7.72 - 7.64 (m, 1H), 7.18 (d,J = 8.0 Hz, 1H), 7.11 (d,J = 1.9 Hz, 1H), 7.01 - 6.91 (m, 2H), 6.68 (d,J = 8.2 Hz, 1H), 6.22 (dd,J = 17.1, 10.0 Hz, 1H), 6.09 (dd,J = 17.1, 2.4 Hz, 2H), 5.86 (dt,J = 4.9, 2.4 Hz, 1H), 5.58 (dd,J = 10.0, 2.4 Hz, 1H), 3.93 (q,J = 8.9 Hz, 1H), 3.72 (s, 3H), 3.67 (s, 3H), 2.48 - 2.38 (m, 1H), 2.30 (s, 3H), 2.21 (d,J = 10.1 Hz, 1H), 2.13 - 2.01 (m, 2H), 1.87 - 1.79 (m, 1H), 1.52 (qd,J = 11.2, 5.2 Hz, 1H). | 510.598 | |
1-(3-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (d,J = 2.1 Hz, 1H), 7.80 - 7.71 (m, 1H), 7.45 - 7.38 (m, 2H), 7.19 (dd,J = 8.6, 3.9 Hz, 2H), 7.04 (d,J = 7.3 Hz, 1H), 6.84 (dd,J = 8.2, 4.1 Hz, 1H), 6.49 (ddd,J = 33.0, 16.8, 10.3 Hz, 1H), 6.10 (dt,J = 16.8, 1.9 Hz, 1H), 5.63 (ddd,J = 10.8, 8.9, 2.5 Hz, 2H), 4.00 - 3.91 (m, 1H), 3.79 (d,J = 6.8 Hz, 4H), 3.68 (t,J = 9.3 Hz, 1H), 3.53 (dq,J = 18.9, 9.5 Hz, 2H), 2.36 (d,J = 3.8 Hz, 3H), 2.28 - 2.20 (m, 1H), 2.17 - 1.93 (m, 1H). | 454.534 | |
N-(4-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環己基)丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.25 (s, 1H), 7.67 (t,J = 7.7 Hz, 1H), 7.47 - 7.39 (m, 2H), 7.30 - 7.23 (m, 2H), 6.97 (d,J = 7.4 Hz, 1H), 6.81 (d,J = 8.1 Hz, 1H), 6.21 (dd,J = 16.9, 1.4 Hz, 1H), 5.97 (dd,J = 16.9, 10.3 Hz, 1H), 5.80 - 5.72 (m, 1H), 5.56 (dd,J = 10.3, 1.4 Hz, 1H), 5.36 (d,J = 7.2 Hz, 1H), 4.26 - 4.19 (m, 1H), 3.87 (s, 3H), 2.92 (dd,J = 16.9, 10.3 Hz, 1H), 2.44 (s, 3H), 1.94 (d,J = 11.5 Hz, 2H), 1.74 (d,J = 11.2 Hz, 2H). | 482.588 |
步驟 1
:向圓底燒瓶中裝入4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(1.7 g,10.18 mmol)、THF (30 mL)及攪拌棒。在-78℃下,向上述溶液中逐滴添加LDA (7.63 mL,15.26 mmol,2 M),在相同溫度下攪拌1小時之後,在-78℃下添加含有(S)-2-甲基-4-側氧基吡咯啶-1-甲酸第三丁酯(4.05 g,20.35 mmol)的THF (10 mL),且使混合物升溫至室溫維持1小時。混合物用飽和NH4Cl (10 mL)淬滅,且用EtOAc (40 mL)萃取3次,合併的有機相用鹽水洗滌,經Na2
SO4
乾燥且在減壓下合併。所得粗產物藉由矽膠層析純化(用PE/EtOAc=2:1溶離),得到呈灰白色固體狀的(2S)-4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基-2-甲基吡咯啶-1-甲酸第三丁酯(550 mg,1.50 mmol,15%)。
(2S)-4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基-2-甲基吡咯啶-1-甲酸第三丁酯
步驟 2
:向50 mL未密封試管中裝入(2S)-4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基-2-甲基吡咯啶-1-甲酸第三丁酯(550 mg,1.50 mmol)、NH3/H2O (10 mL,25%~30%)及1,4-二噁烷(10 mL),密封該試管,且在100℃下攪拌混合物溶液12小時。將試管冷卻至室溫且倒出混合物,濃縮溶劑,粗產物用DCM (100 mL)洗滌3次,濃縮且得到呈灰白色固體狀之(2S)-4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基-2-甲基吡咯啶-1-甲酸第三丁酯(400 mg,77%)。
(S)-7-甲基-6-(5-甲基-2,5-二氫-1H-吡咯-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向圓底燒瓶中裝入(2S)-4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基-2-甲基吡咯啶-1-甲酸第三丁酯(380 mg,1.09 mmol)、HCl (5 mL)及攪拌棒。在100℃下攪拌混合物2小時。冷卻至室溫後,將所得混合物濃縮且用水(10 mL)稀釋,將pH調整至7-8,且用DCM (20 mL)萃取3次。合併有機相且在減壓下濃縮,得到呈棕色固體狀之粗產物(S)-7-甲基-6-(5-甲基-2,5-二氫-1H-吡咯-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(330 mg)。
7-甲基-6-((5S)-5-甲基吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向可再密封之反應瓶中裝入(S)-7-甲基-6-(5-甲基-2,5-二氫-1H-吡咯-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(330 mg,粗物質)、Pd/C (30 mg)及MeOH (10 mL)及攪拌棒。將混合物抽真空且用氮氣淨化三次,接著抽真空且用氫氣淨化五次。在50℃下攪拌混合物隔夜。隨後過濾混合物,用MeOH洗滌濾餅5次,濃縮有機相,得到呈棕色固體狀之7-甲基-6-((5S)-5-甲基吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(220 mg,63% (兩個步驟))。
(2S)-4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-甲酸第三丁酯
步驟 5
:向圓底燒瓶中裝入7-甲基-6-((5S)-5-甲基吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺(220 mg,0.95 mmol)、TEA (288 mg,2.85 mmol)、MeOH (5 mL)及攪拌棒。添加Boc2O (308 mg,1.42 mmol),且在室溫下攪拌溶液12小時。混合物用水(10 mL)稀釋,用DCM (50 mL)萃取3次。合併有機相且用鹽水洗滌,經Na2
SO4
乾燥,真空濃縮,藉由使用DCM/MeOH (20:1)製備型TLC純化粗產物,得到呈棕色固體狀之(2S)-4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-甲酸第三丁酯(190 mg,60%)。
(2S)-4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-甲酸第三丁酯
步驟 6
:向圓底燒瓶中裝入(2S)-4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2-甲基吡咯啶-1-甲酸第三丁酯(180 mg,543 µmol)、二甲基甲醯胺(15 mL)及攪拌棒。添加NBS (101 mg,570 µmol µmol),且在0℃下攪拌溶液1小時。混合物用DCM (50 mL)稀釋,用水及鹽水洗滌,經無水Na2
SO4
乾燥,在減壓下濃縮,藉由使用DCM:MeOH (12:1)的製備型TLC純化粗產物,得到呈棕色固體狀之(2S)-4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2-甲基吡咯啶-1-甲酸第三丁酯(200 mg,85%)。
(2S)-4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-甲酸第三丁酯
步驟 7
:向可再密封之反應瓶中裝入(2S)-4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2-甲基吡咯啶-1-甲酸第三丁酯(200 mg,487 µmol)、2-甲基-6-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(181 mg,584 µmol)、K3PO4 (309 mg,1.46 mmol)、Pd(DtBPF)Cl2 (47.5 mg,73.0 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF:水=16:1 (10 mL),且在90℃下攪拌溶液1小時。混合物用EtOAc (50 mL)稀釋,用水及鹽水分別洗滌3次。有機相經無水Na2
SO4
乾燥,在減壓下濃縮。藉由C18急驟層析純化粗產物,得到呈淺棕色油狀之(2S)-4-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-甲酸第三丁酯(140 mg,56%)。
7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-6-((5S)-5-甲基吡咯啶-3-基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 8
:向圓底燒瓶中裝入(2S)-4-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-甲酸第三丁酯(140 mg,272 µmol)、TFA/DCM (1:4 V/V,15 mL)及攪拌棒。在室溫下攪拌溶液3小時。移除溶劑且粗產物用DCM稀釋且用Na2CO3水溶液調整至pH 7。濃縮有機相,得到7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-6-[(5S)-5-甲基吡咯啶-3-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(90.0 mg,100%),其不經純化即用於下一步驟。
1-((2S)-4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮
步驟 9
:向圓底燒瓶中裝入TEA (65.7 mg,651 µmol)、丙-2-烯醯氯(15.6 mg,173 µmol)、7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-6-[(5S)-5-甲基吡咯啶-3-基]-7H吡咯并[2,3-d]嘧啶-4-胺(90.0 mg,217 µmol)及攪拌棒。添加二氯甲烷(5 mL),且在-65℃下攪拌溶液0.5小時。用MeOH淬滅混合物且濃縮。粗產物藉由製備型HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm,5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:60 mL/min;梯度:25 B至50 B,歷時8分鐘;220 nm; RT1:7.23),得到呈白色固體狀的1-[(2S)-4-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基]丙-2-烯-1-酮(38.3 mg,38%)。
根據實例15之方法製備的其他化合物描繪於下表14中。表 14 . 其他例示性化合物
實例16流程 13
3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-氟吡咯啶-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-((2R)-4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 7.75 (t,J = 7.8 Hz, 1H), 7.43 (d,J = 8.0 Hz, 2H), 7.22 (d,J = 8.1 Hz, 2H), 7.02 (d,J = 7.4 Hz, 1H), 6.83 (d,J = 8.2 Hz, 1H), 6.50 (dd,J = 16.7, 10.4 Hz, 1H), 6.11 (t,J = 15.2 Hz, 1H), 5.62 (d,J = 10.7 Hz, 1H), 4.00 (s, 2H), 3.79 (s, 3H), 3.47 - 3.34 (m,J = 2.8 Hz, 1H), 2.32 (s, 4H), 1.65 (d,J = 9.8 Hz, 1H), 1.24 (s, 1H), 1.12 (d,J = 6.6 Hz, 3H). | 469.40 | |
1-((2S)-4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.75 (t,J = 7.8 Hz, 1H), 7.44 (d,J = 8.1 Hz, 2H), 7.27 - 7.18 (m, 2H), 7.03 (d = 7.3 Hz, 1H), 6.83 (d,J = 8.2 Hz, 1H), 6.64 - 6.43 (m, 1H), 6.17 - 6.07 (m, 1H), 5.75 - 5.38 (m, 2H), 4.24 - 3.94 (m, 2H), 3.79 (d,J = 3.8 Hz, 3H), 3.68 - 3.36 (m, 2H), 2.34 - 2.32 (m, 4H), 1.81 - 1.60 (m, 1H), 1.22 - 1.06 (m, 3H). | 469.20 | |
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,2-二甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 7.76 (t,J = 7.7 Hz, 1H), 7.43 (d,J = 8.0 Hz, 1H), 7.38 (d,J = 8.2 Hz, 1H), 7.17 (t,J = 8.8 Hz, 2H), 7.03 (d,J = 7.4 Hz, 1H), 6.85 (d,J = 8.2 Hz, 1H), 6.42 (dd,J = 16.5, 10.4 Hz, 1H), 6.03 (d,J = 16.6 Hz, 1H), 5.52 (d,J = 10.3 Hz, 1H), 3.80 (s, 3H), 3.61 (t,J = 8.6 Hz, 1H), 3.59(s, 1H), 2.33 (s, 3H), 2.15 (s, 2H), 1.46 (s, 3H), 1.16 (s, 4H). | 483.40 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基-2,5-二氫-1H-吡咯-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (s, 1H), 7.76 (dt,J = 12.1, 7.7 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.23 (t,J = 5.3 Hz, 2H), 7.04 (t,J = 8.5 Hz, 1H), 6.82 (t,J = 9.7 Hz, 1H), 6.25 (d,J = 57.7 Hz, 1H), 5.94 (s, 2H), 5.33 - 4.74 (m, 2H), 4.57 - 4.19 (m, 3H), 3.75 (d,J = 4.7 Hz, 3H), 2.37 (s, 3H), 1.84 (s, 2H), 1.73 (s, 1H), 1.21 (d,J = 27.1 Hz, 1H), 0.96 (dd,J = 25.8, 6.3 Hz, 3H). | 481.25 | |
(S)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基-2,5-二氫-1H-吡咯-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.76 (dt,J = 12.1, 7.8 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.23 (dd,J = 8.8, 3.0 Hz, 2H), 7.04 (t,J = 8.5 Hz, 1H), 6.82 (t,J = 9.7 Hz, 1H), 6.24 (d,J = 57.7 Hz, 1H), 5.94 (s, 2H), 5.31 - 4.75 (m, 2H), 4.60 - 4.17 (m, 3H), 3.75 (d,J = 5.0 Hz, 3H), 2.37 (s, 3H), 1.79 (d,J = 45.3 Hz, 3H), 0.96 (dd,J = 26.0, 6.3 Hz, 3H). | 481.25 | |
(R)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基-2,5-二氫-1H-吡咯-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (d,J = 2.0 Hz, 1H), 7.75 (t,J = 7.7 Hz, 1H), 7.41 (t,J = 8.0 Hz, 2H), 7.22 (dd,J = 8.8, 2.3 Hz, 2H), 7.03 (d,J = 7.4 Hz, 1H), 6.80 (d,J = 8.1 Hz, 1H), 6.60 - 6.22 (m, 2H), 6.15 (ddd,J = 16.8, 5.1, 2.5 Hz, 1H), 5.97 (s, 2H), 5.66 (ddd,J = 22.4, 10.1, 2.5 Hz, 1H), 4.60 - 4.15 (m, 3H), 3.75 (d,J = 4.6 Hz, 3H), 2.36 (d,J = 8.8 Hz, 3H), 1.01 (dd,J = 6.2, 4.3 Hz, 3H). | 467.25 | |
(S)-1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基-2,5-二氫-1H-吡咯-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.19 (d,J = 2.0 Hz, 1H), 7.75 (t,J = 7.7 Hz, 1H), 7.41 (t,J = 8.0 Hz, 2H), 7.22 (dd,J = 8.8, 2.3 Hz, 2H), 7.03 (d,J = 7.3 Hz, 1H), 6.80 (d,J = 8.1 Hz, 1H), 6.55 (dd,J = 16.7, 10.3 Hz, 1H), 6.35 - 5.84 (m, 3H), 5.66 (ddd,J = 22.4, 10.2, 2.5 Hz, 1H), 4.60 - 4.14 (m, 3H), 3.75 (d,J = 4.6 Hz, 3H), 2.36 (d,J = 8.8 Hz, 3H), 1.01 (dd,J = 6.2, 4.4 Hz, 3H). | 467.15 | |
1-((2R,3R)-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (d,J = 0.9 Hz, 1H), 7.77 (t,J = 7.7 Hz, 1H), 7.40 (td,J = 5.7, 2.7 Hz, 2H), 7.19 (tt,J = 8.2, 2.2 Hz, 2H), 7.04 (dd,J = 7.4, 2.1 Hz, 1H), 6.85 (d,J = 8.1 Hz, 1H), 6.71 (dd,J = 16.6, 10.3 Hz, 1H), 6.51 (dd,J = 16.7, 10.3 Hz, 1H), 6.15-5.43 (ddd,J = 16.8, 12.1, 2.5 Hz, 2H), 4.55 (dp,J = 31.3, 6.6 Hz, 1H), 3.89 - 3.62 (m, 5H), 3.42 - 3.33 (m, 1H), 2.35 (d,J = 3.6 Hz,3H), 1.85 (dtd,J = 22.6, 12.4, 6.1 Hz, 2H), 0.83 (d,J = 6.5 Hz, 3H). | 469.20 | |
1-((2S,3S)-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.65 (t,J = 7.8 Hz, 1H), 7.43 (t,J = 3.9 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.07 (dd,J = 8.1, 1.0 Hz, 1H), 7.00 (d,J = 2.0 Hz, 1H), 6.92 (d,J = 7.3 Hz, 1H), 6.81 (dd,J = 8.0, 1.6 Hz, 1H), 6.67 (ddt,J = 21.6, 8.0, 4.6 Hz, 2H), 6.23 (dt,J = 16.8, 2.2 Hz, 1H), 6.05 (s, 1H), 5.76 (ddd,J = 10.3, 3.7, 2.3 Hz, 1H), 5.00 (s, 1H), 4.95 (s, 1H), 4.73 (d,J = 17.7 Hz, 2H), 3.62 (d,J = 1.7 Hz, 3H), 3.56 (s, 3H), 2.29 (d,J = 3.6 Hz, 3H). | 533.40 | |
(S)-1-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基-2,5-二氫-1H-吡咯-1-基)-2-甲基丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.18 (s, 1H), 7.61 (d,J = 8.0 Hz, 2H), 7.43 (d,J = 7.7 Hz, 2H), 6.27 - 6.18 (m, 1H), 6.10 (s, 1H), 5.21 (d,J = 10.5 Hz, 1H), 5.07 (s, 1H), 4.89 (s, 1H), 4.17 - 4.03 (m, 1H), 3.98 (d,J = 14.4 Hz, 1H), 3.77 (s, 3H), 3.50 (t,J = 6.7 Hz, 2H), 3.44 (t,J = 6.4 Hz, 2H), 1.87 (dq,J = 17.8, 6.5 Hz, 5H), 1.70 (s, 2H), 1.26 (d,J = 6.4 Hz, 2H), 1.19 (d,J = 6.3 Hz, 1H). | 471.30 | |
1-((2S,4R)-4-(4-胺基-7-甲基-5-(4-(哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.48 (s, 4H), 6.52 (ddd,J = 27.6, 16.6, 10.2 Hz, 1H), 6.20 - 5.95 (m, 1H), 5.85 - 5.13 (m, 3H), 4.22 - 3.90 (m, 2H), 3.80 (s, 3H), 3.71 - 3.51 (m, 3H), 3.44 (t,J = 10.9 Hz, 1H), 3.14 (t,J = 11.7 Hz, 1H), 2.39 - 2.23 (m, 1H), 1.84 - 1.62 (m, 3H), 1.55 (t,J = 10.8 Hz, 5H), 1.06 (d,J = 6.3 Hz, 3H). | 473.30 | |
1-((2S,4R)-4-(4-胺基-5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 - 8.43 (m, 1H), 8.14 (s, 1H), 7.50 (td,J = 8.5, 3.8 Hz, 1H), 7.36 (ddt,J = 10.0, 4.8, 2.4 Hz, 1H), 7.27 - 7.13 (m, 2H), 6.75 - 6.41 (m, 1H), 6.19 - 5.98 (m, 1H), 5.80 - 5.33 (m, 3H), 4.36 - 3.91 (m, 2H), 3.80 (d,J = 4.0 Hz, 3H), 3.69 - 3.53 (m, 1H), 3.42 (dd,J = 20.4, 10.2 Hz, 1H), 2.42 (d,J = 8.0 Hz, 4H), 2.04 - 1.38 (m, 1H), 1.24 - 1.00 (m, 3H). | 488.25 | |
1-((2S,4S)-4-(4-胺基-7-甲基-5-(4-(哌啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d,J = 1.5 Hz, 1H), 7.45 (dd,J = 5.9, 3.0 Hz, 4H), 6.49 (ddd,J = 69.2, 16.7, 10.3 Hz, 1H), 6.11 (ddd,J = 16.4, 13.1, 2.5 Hz, 1H), 5.63 (ddd,J = 21.8, 10.2, 2.5 Hz, 3H), 4.22 (dt,J = 39.9, 7.0 Hz, 1H), 3.92 (dd,J = 15.7, 7.8 Hz, 2H), 3.79 (d,J = 11.1 Hz, 3H), 3.70 (dd,J = 12.5, 9.0 Hz, 1H), 3.56 (d,J = 17.7 Hz, 3H), 3.42 (d,J = 12.6 Hz, 1H), 2.37 - 2.06 (m, 1H), 1.95 (dd,J = 12.4, 6.8 Hz, 1H), 1.58 (d,J = 41.4 Hz, 6H), 1.24 (s, 1H), 1.14 (dd,J = 10.0, 6.4 Hz, 3H). | 473.30 | |
1-((2S)-4-(4-胺基-7-甲基-5-((R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (d,J = 16.1 Hz, 1H), 6.63 (ddd,J = 26.2, 16.6, 10.2 Hz, 1H), 6.46 (s, 1H), 6.16 (td,J = 16.7, 2.6 Hz, 1H), 5.88 - 5.49 (m, 2H), 4.44 - 3.96 (m, 2H), 3.67 (d,J = 5.2 Hz, 4H), 3.52 (q,J = 8.8, 7.4 Hz, 3H), 3.32 (d,J = 5.6 Hz, 2H), 2.94 (s, 1H), 2.43 (d,J = 6.3 Hz, 1H), 2.37 - 2.19 (m, 3H), 2.18 - 1.99 (m, 2H), 1.89 (q,J = 6.6 Hz, 3H), 1.80 (h,J = 8.1, 7.0 Hz, 3H), 1.27 (dt,J = 18.0, 6.3 Hz, 3H). | 463.30 | |
1-((2S)-4-(4-胺基-7-甲基-5-((S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-甲基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.02 (d,J = 16.7 Hz, 1H), 6.64 (td,J = 16.7, 10.5 Hz, 1H), 6.49 (s, 1H), 6.28 - 6.03 (m, 1H), 5.87 - 5.58 (m, 2H), 4.16 (d,J = 74.3 Hz, 2H), 3.67 (d,J = 4.2 Hz, 4H), 3.53 (s, 3H), 3.31 (s, 2H), 2.94 (s, 1H), 2.33 (s, 1H), 2.27 (s, 4H), 1.89 (q,J = 6.7 Hz, 4H), 1.80 (q,J = 6.7 Hz, 3H), 1.27 (dd,J = 21.1, 7.7 Hz, 3H). | 463.35 |
步驟 1
:向圓底燒瓶中裝入3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-甲酸第三丁酯(200 mg,0.39 mmol)、DCM (10 mL)及攪拌棒。添加DAST (74.8 mg,0.46 mmol),且在0℃下攪拌溶液3小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色固體狀之3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-氟吡咯啶-1-甲酸第三丁酯(127 mg,63%)。
6-(4-氟吡咯啶-3-基)-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 2
:向可再密封之反應瓶中裝入3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-氟吡咯啶-1-甲酸第三丁酯(127 mg,0.24 mmol)、DCM (5 mL)及攪拌棒。添加TFA (2 mL),且在25℃下攪拌溶液1小時。濃縮反應混合物,用水稀釋,用飽和Na2CO3將pH值調整至7,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由製備型TLC純化。真空濃縮,產生呈棕色固體狀之6-(4-氟吡咯啶-3-基)-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(77 mg,77%)。
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-氟吡咯啶-1-基)丙-2-烯-1-酮
步驟 3
:向圓底燒瓶中裝入6-(4-氟吡咯啶-3-基)-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(77 mg,180 µmol)、TEA (55.8 mg,0.55 mmol)、DCM (5 mL)及攪拌棒,添加丙烯醯氯(13.2 mg,147 µmol),且在-35℃下攪拌溶液0.5小時。反應混合物用MeOH淬滅,濃縮所得混合物,藉由製備型HPLC純化粗物質。凍乾得到呈白色非晶形固體狀之1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-氟吡咯啶-1-基)丙-2-烯-1-酮(5.2 mg,6%)。
根據實例16之方法製備的其他化合物描繪於下表15中。表 15 . 其他例示性化合物
實例17流程 14
3-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-氟吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (s, 1H), 7.76 (td,J = 7.8, 4.4 Hz, 1H), 7.42 (s, 3H), 7.18 (s, 2H), 7.06 (dd,J = 7.3, 2.7 Hz, 1H), 6.87 (t,J = 8.1 Hz, 1H), 6.38 (ddd,J = 50.2, 16.7, 10.3 Hz, 1H), 6.07 (dt,J = 16.7, 2.8 Hz, 1H), 5.62 (td,J = 10.1, 2.4 Hz, 1H), 5.46 (ddd,J = 52.8, 19.4, 4.3 Hz, 1H), 4.58 - 3.27 (m, 8H), 2.39 (d,J = 1.4 Hz, 3H). | 473.20 |
步驟 1
:向可再密封之反應瓶中裝入4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(5 g,29.9 mmol)、四氫呋喃(200 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在-78℃下逐滴添加LDA (30 mL,59.9 mmol),且在-78℃下攪拌混合物30分鐘。逐滴添加存在於100 mL THF中的3-側氧基吡咯啶-1-甲酸第三丁酯(17 g,89.8 mmol),在-78℃下攪拌混合物1小時。使混合物升溫至室溫且反應混合物用H2
O (300 mL)稀釋,且水相用EA (300 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用PE/EA=10/1溶離)純化。真空濃縮,產生呈淡黃色固體狀之3-(4-氯-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(2.20 g,20.9%)。
3-(4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯
步驟 2
:向圓底燒瓶中裝入3-{4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3-羥基吡咯啶-1-甲酸第三丁酯(976 mg,2.76 mmol)、NIS (621 mg,2.76 mmol)、TFA (943 mg,8.28 mmol)及攪拌棒。添加DCM (20 mL),且在室溫下、在氮氣保護下攪拌溶液3小時。混合物用飽和Na2
S2
O3
水溶液(10 mL)淬滅,且用DCM (3*40 mL)萃取,合併有機相且經無水Na2
SO4
乾燥,在減壓下濃縮,藉由C18 Flash純化粗產物,得到呈白色固體狀的3-{4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3-羥基吡咯啶-1-甲酸第三丁酯(980 mg,73.9%)。
3-(4-氯-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯
步驟 3
:向可再密封之反應瓶中裝入3-{4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3-羥基吡咯啶-1-甲酸第三丁酯(800 mg,1.67 mmol)、2-甲基-6-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(519 mg,1.67 mmol)、Pd(PPh3)2Cl2 (175 mg,250 µmol)、K3PO4 (1.06 g,5.01 mmol)及攪拌棒。添加DMF/H2O (25 mL),且在50℃下攪拌溶液1小時。混合物用EtOAc (100 mL)稀釋且用水(3*50 mL)洗滌,濃縮有機相且粗產物藉由C18 flash純化且藉由使用EA:PE=2:1的製備型TLC進一步純化,得到呈淡黃色固體狀之3-(4-氯-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(140 mg,15.6%)。
3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯
步驟 4
:向可再密封之反應瓶中裝入3-(4-氯-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(120 mg,223 µmol)、NH3H2O (1.82 g,52.0 mmol)及攪拌棒。添加二噁烷(1.5 mL),將管密封且在100℃下攪拌溶液10小時。濃縮混合物且藉由C18 flash純化粗產物,得到呈淺黃色油狀之3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(62.4 mg,54.2%)。
3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-醇
步驟 5
:向圓底燒瓶中裝入3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(80.0 mg,154 µmol)、TFA (52.6 mg,462 µmol)及攪拌棒。添加DCM (25 mL),且在室溫下攪拌溶液5小時。混合物用水稀釋,且用Na2
CO3
調節pH至7,混合物用DCM (8*40 mL)萃取,濃縮有機相且粗產物3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-醇(60.0 mg,93.6%)不經純化即用於下一步驟。
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-基)丙-2-烯-1-酮
步驟 6
:向圓底燒瓶中裝入3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-醇(40 mg,96.0 µmol)、TEA (29.0 mg,288 µmol)、DCM (15 mL)及攪拌棒。添加丙-2-烯醯氯(6.95 mg,76.8 µmol,3.4 mL),且在-45℃下攪拌溶液0.5小時。混合物用MeOH淬滅,且移除溶劑,粗產物藉由HPLC純化(管柱:XBridge Prep OBD C18管柱,19*250 mm,5um),得到呈白色固體狀的1-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-基]丙-2-烯-1-酮(10.5 mg, 23.2%)。
根據實例17之方法製備之化合物的特徵資料提供於下表16中。表 16 . 例示性化合物
實例18流程 15
3-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.76 (t,J = 7.6 Hz, 1H), 7.52 - 7.43(m, 2H), 7.24 - 7.21(m, 2H), 7.04 (dd,J = 7.4, 1.9 Hz, 1H), 6.84 (d,J = 8.2 Hz, 1H), 6.61 - 6.25 (m, 1H), 6.15 - 6.05(m, 1H), 5.88 - 5.83 (m, 1H), 5.65 - 5.59 (m, 1H), 3.96 (d,J = 4.9 Hz, 3H), 3.89 - 3.81 (m, 1H), 3.69 - 3.53 (m, 1H), 3.47 - 3.41 (m, 1H), 3.29 - 3.22 (m, 1H), 2.36 - 2.30 (m, 3H), 2.21 - 2.10 (m, 1H), 2.16 - 1.88 (m, 1H). | 471.20 |
步驟 1
:向圓底燒瓶中裝入5-溴-6-碘-7-甲基吡咯并[2,3-d]嘧啶-4-胺(3 g,8.50 mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2,5-二氫吡咯-1-甲酸第三丁酯(3.01 g,10.20 mmol)、Pd(PPh3)4 (982 mg,850 µmol)、K3PO4 (5.41 g,25.5 mmol)及攪拌棒。添加二甲基甲醯胺/水(40 mL,v/v=16:1),且在50℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色固體狀的3-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(2 g,60%)。
3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯
步驟 2
:向可再密封之反應瓶中裝入3-[4-胺基-5-溴-7-甲基吡咯并[2,3-d]嘧啶-6-基]-2,5-二氫吡咯-1-甲酸第三丁酯(600 mg,1.52 mmol)、2-甲基-6-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(568 mg,1.83 mmol)、Pd(DtBPF)Cl2 (99 mg,152 µmol)、K3PO4 (0.97 g,4.56 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF:水=16:1 (10 mL),且在90℃下攪拌溶液3小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色固體狀的3-(4-胺基-7-甲基-5-[4-[(6-甲基吡啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫吡咯-1-甲第三丁酸酯(510 mg,67%)。
3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-甲酸第三丁酯
步驟 3
:向圓底燒瓶中裝入3-(4-胺基-7-甲基-5-[4-[(6-甲基吡啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-2,5-二氫吡咯-1-甲酸第三丁酯(450 mg,0.90 mmol)、THF (10 mL)及攪拌棒。在0℃下添加BH3-THF (9.03 mL,9.03 mmol,1 M於THF中),且在室溫下攪拌溶液2小時。接著添加NaOH (9.03 mL,9.03 mmol,1M於H2O中)及H2O2 (0.21 mL,30%於水中)且再攪拌2小時。反應混合物用水淬滅,且用HCl (2 M)調節pH值至7,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈棕色非晶形固體狀之3-(4-胺基-7-甲基-5-[4-[(6-甲基吡啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-甲酸第三丁酯(160 mg,34%)。
4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-醇
步驟 4
:向可再密封之反應瓶中裝入3-(4-胺基-7-甲基-5-[4-[(6-甲基吡啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-甲酸第三丁酯(160 mg,0.31 mmol)、DCM (5 mL)及攪拌棒。添加TFA (2 mL),且在25℃下攪拌溶液1小時。濃縮反應混合物,用水稀釋,用飽和Na2CO3將pH值調整至7,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由製備型TLC純化。真空濃縮,產生呈棕色固體狀之4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-醇(100 mg,78%)。
1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-基)丙-2-烯-1-酮
步驟 5
:向圓底燒瓶中裝入4-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-醇(82 mg,170 µmol)、TEA (52.8 mg,0.52 mmol)、DCM (5 mL)及攪拌棒。添加丙烯醯氯(12.8 mg,142 µmol),且在-35℃下攪拌溶液0.5小時。反應混合物用MeOH淬滅,濃縮所得混合物,粗物質藉由製備型HPLC純化(管柱:Xselect CSH OBD管柱30*150mm 5um, n;移動相A:水(0.1% FA),移動相B:ACN;流量:60 mL/min;梯度:5 B至27 B,歷時7分鐘;220 nm;RT1:6.10,6.80;RT2)。凍乾得到1-(3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-基)丙-2-烯-1-酮(47.4 mg,57%),包括:呈白色非晶形固體狀的1
(19.1 mg),及呈白色固體狀的2
(28.3 mg)。
根據實例18之方法製備的其他化合物描繪於下表17中。表 17 . 其他例示性化合物
實例19流程 16
3-(4-氯-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-((3R,4S)-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.42 (s, 1H), 7.76 (td,J = 7.8, 3.2 Hz, 1H), 7.44 (d,J = 8.4 Hz, 2H), 7.21 (d,J = 7.8 Hz, 2H), 7.05 (d,J = 7.4 Hz, 1H), 6.85 (t,J = 7.1 Hz, 1H), 6.41 (ddd,J = 59.1, 16.7, 10.2 Hz, 1H), 6.18 - 5.98 (m, 1H), 5.62 (t,J = 11.2 Hz, 1H), 4.42 (dd,J = 18.5, 7.3 Hz, 1H), 4.05 - 3.89 (m, 3H), 3.76 (s, 3H), 3.42 - 3.08 (m, 2H), 2.38 (s, 3H). | 471.30 | |
1-((3R,4R)-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-4-羥基吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d,J = 2.1 Hz, 1H), 7.77 (td,J = 7.8, 3.7 Hz, 1H), 7.49 (ddd,J = 9.4, 6.7, 2.9 Hz, 2H), 7.34 - 7.18 (m, 2H), 7.06 (dd,J = 7.3, 2.4 Hz, 1H), 6.86 (d,J = 8.1 Hz, 1H), 6.43 (ddd,J = 104.5, 16.8, 10.3 Hz, 1H), 6.18 - 5.90 (m, 2H), 5.63 (ddd,J = 26.1, 10.2, 2.4 Hz, 1H), 4.05 (d,J = 4.3 Hz, 3H), 3.93 - 3.78 (m, 1H), 3.71 - 3.22 (m, 3H), 2.38 (d,J = 11.5 Hz, 3H), 2.34 - 2.10 (m, 1H), 2.00 (dt,J = 38.0, 10.5 Hz, 1H). | 471.30 |
步驟 1
:向可再密封之反應瓶中裝入3-(4-氯-5-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(700 mg,1.46 mmol)、2-甲基-6-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(546 mg,1.75 mmol)、Pd(PPh3)2Cl2 (102 mg,146 µmol)、K3PO4 (929 mg,4.38 mmol)及攪拌棒。添加DMF/H2O (25 mL),且在50℃下攪拌溶液1小時。混合物用EtOAc (100 mL)稀釋,且用水(3*50 mL)洗滌,濃縮有機相且粗產物藉由C18 flash純化且藉由使用EA:PE=2:1的製備型TLC進一步純化,得到呈淡黃色固體狀之3-(4-氯-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(100 mg,18.7%)。
3-(4-氯-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟吡咯啶-1-甲酸第三丁酯
步驟 2
:向圓底燒瓶中裝入3-(4-氯-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-羥基吡咯啶-1-甲酸第三丁酯(90.0 mg,167 µmol)、DAST (4.00 mg,24.8 µmol)及攪拌棒。添加二氯甲烷(10 mL),且在室溫下攪拌溶液2小時。混合物用NaHCO3水溶液(10 mL)淬滅且用DCM (30 mL)萃取3次,濃縮有機相,藉由製備型TLC (PE:EA=1:1)純化粗產物,得到呈棕色固體狀之3-(4-氯-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟吡咯啶-1-甲酸第三丁酯(40.0 mg,44%)。
3-胺基-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲酸第三丁酯
步驟 3
:向密封管中裝入3-(4-氯-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟吡咯啶-1-甲酸第三丁酯(40.0 mg,74.3 µmol)、NH3H2O/1,4-二噁烷(46 mL,v/v=1:1)及攪拌棒,將管密封且在100℃下攪拌混合物18小時。濃縮混合物且藉由C18 FLASH純化粗產物,得到呈黃色油狀的3-胺基-3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲酸第三丁酯(26.0 mg,68%)。
6-(3-胺基吡咯啶-3-基)-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向可再密封之反應瓶中裝入、向圓底燒瓶中裝入3-胺基-3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-甲酸第三丁酯(26.0 mg,50.4 µmol)、TFA/DCM (5 mL,v/v=1:2)及攪拌棒,在室溫下攪拌溶液2小時。濃縮混合物且藉由C18 FLASH純化粗產物,得到呈黃色油狀的3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-胺(15.0 mg,72%)。
1-(3-胺基-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮
步驟 5
:向圓底燒瓶中裝入3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-3-胺(15.0 mg,36.1 µmol)、丙-2-烯醯氯(2.60 mg,28.8 µmol)、TEA (10.9 mg,108 µmol)及攪拌棒。添加二氯甲烷(1 mL),且在-65℃下攪拌溶液0.5小時。混合物用MeOH淬滅,且在減壓下濃縮,粗產物藉由HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm,5um;移動相A:未定義;移動相B:未定義;流量:60 mL/min;梯度:2 B至22 B,歷時8分鐘;220 nm),得到呈白色固體狀的1-[3-胺基-3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基]丙-2-烯-1-酮(3.00 mg,18%)。
根據實例19之方法製備之化合物的特徵資料提供於下表18中。表 18 . 例示性化合物
實例20流程 17
5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-甲酸乙酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-(3-胺基-3-(4-胺基-7-甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡咯啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 (s, 1H), 7.80 - 7.74 (m, 1H), 7.58 - 7.46 (m, 2H), 7.26 - 7.15 (m, 2H), 7.04 (dd,J = 7.4, 3.6 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.58 - 6.51 (m, 1H), 6.28 - 6.17 (m, 1H), 6.14 - 6.03 (m, 1H), 5.66 - 5.54 (m, 1H), 4.00 (d,J = 4.5 Hz, 3H), 3.80 - 3.57 (m, 2H), 3.53 - 3.37 (m, 2H), 2.44 - 2.24 (m, 4H), 2.17 - 1.95 (m, 2H). | 470.25 |
步驟 1
:向圓底燒瓶中裝入4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼雜環戊烷)(610 mg,2.4 mmol)、5-溴-1-甲基-1H-吡唑-3-甲酸乙酯(464 mg,2 mmol)、6-碘-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(916 mg,2 mmol)、K3PO4 (1.27 g,6 mmol)、DMF/H2O (8:1,10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物4小時。冷卻後,混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由C18管柱層析來純化(移動相A:水(0.05% TFA),移動相B:ACN;流量:30 mL/min;梯度:0 B%至45 B%,歷時25分鐘;254 nm;),得到呈灰白色固體狀的5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-甲酸乙酯(100 mg,10%)。
5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-甲酸
步驟 2
:向圓底燒瓶中裝入5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-甲酸乙酯(550 mg,1.14 mmol)、NaOH (136 mg,3.40 mmol)、MeOH (10 mL)、H2O (5 mL)及攪拌棒。在室溫下攪拌混合物1小時。混合物在減壓下濃縮,且用HCl (1 N)調節pH至3,過濾且在減壓下乾燥,得到呈灰白色固體狀之5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-甲酸(350 mg,67%)。
(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)胺基甲酸第三丁酯
步驟 3
:向圓底燒瓶中裝入5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-甲酸(310 mg,0.68 mmol)、DPPA (280 mg,1.02 mmol)、TEA (138 mg,1.36 mmol)、DMSO/ t
BuOH (1:2,24 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物4小時。冷卻後,混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由C18管柱層析純化(移動相A:水(0.05% TFA),移動相B:ACN;流量:30 mL/min;梯度:0 B%至60 B%,歷時35分鐘;254 nm;),得到呈灰白色固體狀的(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)胺基甲酸酯(60 mg,8.3%)。
6-(3-胺基-1-甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入2-氯-4-甲基嘧啶(60 mg,0.11 mmol)、TFA (0.4 mL)、DCM (4 mL)及攪拌棒。在室溫下攪拌反應混合物1小時。濃縮混合物且用DCM (20 mL)溶解,用飽和NaHCO3水溶液及鹽水洗滌,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由C18管柱層析純化(移動相A:水(0.05% TFA),移動相B:ACN;流量:30 mL/min;梯度:0 B%至60 B%,歷時35分鐘;254 nm;),得到呈黃色固體狀的6-(3-胺基-1-甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(35 mg,74%)。
N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)甲基丙烯醯胺
步驟 5
:向圓底燒瓶中裝入6-(3-胺基-1-甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(70 mg,0.16 mmol)、Na2CO3 (34 mg,0.32 mmol)、ACN (20 mL)及攪拌棒。在-30℃下逐滴添加甲基丙烯醯氯(14.6 mg,0.14 mmol),且攪拌混合物1小時。混合物接著在-30℃下用MeOH淬滅,且用水(10 mL)稀釋,用DCM (20 mL*3)萃取,合併有機相且用鹽水洗滌兩次,經Na2
SO4
乾燥,真空濃縮,藉由HPLC純化殘餘物且凍乾,得到呈白色固體狀的N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)甲基丙烯醯胺(12.5 mg,15%)。
根據實例20之方法製備的其他化合物描繪於下表19中。表 19 . 其他例示性化合物
實例21流程 18
4-氯-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.48(d, J = 4.2 Hz, 1H), 8.25 (s, 1H), 7.31 (d, J = 8.4 Hz, 2H),7.24 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 4.2 Hz, 1H), 6.84 (s, 1H), 5.87(s,1H), 5.49 (s, 1H), 3.59(s, 3H), 3.27(s, 3H),2.41(s, 3H), 1.93(s, 3H). | 496.10 | |
N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-4-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.53 (s, 1H), 8.47(d, J = 4.8 Hz, 1H), 8.24 (s, 1H), 7.72(s, 1H), 7.37 (d, J = 8.4 Hz, 2H),7.22 - 7.15 (m, 3H), 5.60(s,1H), 5.41 (s, 1H), 3.51(s, 3H), 3.27(s, 3H),2.41(s, 3H), 1.92(s, 3H). | 496.15 | |
N-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-1-甲基-1H-吡唑-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.41 (t,J = 8.4 Hz, 1H), 7.23 - 7.18 (m, 2H), 7.11 (m, 1H), 6.87 (s, 1H), 6.25 (s, 1H), 5.88 (s, 1H), 5.54 - 5.46 (s, 1H), 3.59 (s, 3H), 3.30 (s, 3H), 2.42 (s, 3H), 1.94 (s, 3H). | 514.20 |
步驟 1
:向三頸燒瓶中裝入4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(3 g,17.96 mmol)、THF (50 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在約-78℃下逐滴添加LDA (13.5 mL,26.9 mmol)。在約-78℃下攪拌反應混合物1小時。接著添加I2
(5.9 g,23.3 mmol),在-78℃下攪拌反應混合物1小時。混合物用水淬滅,用EA萃取,經Na2
SO4
乾燥,真空蒸發,藉由矽膠管柱層析(用DCM/MeOH (50:1至10:1)溶離)來純化殘餘物,得到呈黃色固體狀的4-氯-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶(4 g,76%)。
N-(4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
步驟 2
:向圓底燒瓶中裝入4-氯-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶(1 g,3.4 mmol)、N-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)甲基丙烯醯胺(1.2 g,4.1 mmol)、Pd(PPh3)2Cl2
(4.5 g,6.2 mmol)、K3PO4 (2.16 g,10.2 mmol)、DMF/H2O (16:1,20 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在50℃下攪拌混合物1小時。冷卻後,混合物用水稀釋,用EA萃取,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由矽膠管柱層析(用DCM/MeOH (100:1至10:1)溶離)來純化,得到呈黃色固體狀之N-(4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(700 mg,70%)。
N-(4-(4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
步驟 3
:向圓底燒瓶中裝入N-(4-(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(0.7 g,2.3 mmol)、Pd(PPh3)4 (0.26 g,0.23 mmol)、DMF (10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加Zn(CH3)2 (1 M,3.45 mL,3.45 mmol)。在90℃下攪拌混合物2小時。冷卻後,混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,藉由矽膠管柱層析(用DCM/MeOH (100:1至10:1)溶離)純化殘餘物,得到呈棕色固體狀之N-(4-(4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(400 mg,57%)。
6-碘-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入N-(4-(4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺(0.4 g,1.3 mmol)、DCM (10 mL)及攪拌棒。添加NBS (7.43 g,1.3 mmol)。攪拌混合物1小時。反應物用飽和NaHSO3
水溶液淬滅直至pH至8-9,用DCM (100 mL*3)萃取,合併有機相且用鹽水洗滌兩次,經Na2
SO4
乾燥,真空蒸發,殘餘物用ACN (25 mL)溶解且過濾,濾餅用ACN洗滌,在減壓下乾燥,得到呈灰白色固體狀之6-碘-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(340 mg,67%)。
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺
步驟 5
:向圓底燒瓶中裝入6-碘-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(340 mg,0.88 mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)-4-甲基嘧啶(330 mg,1 mmol)、Pd(dppf)Cl2
(66 mg,0.09 mmol)、K3PO4 (560 mg,2.64 mmol)、DMF/H2O (16:1,10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。冷卻後,混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,藉由製備型HPLC純化殘餘物,得到呈白色固體狀的6-(4-胺基苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(46.6 mg,10.4%)。
根據實例21之方法製備的其他化合物描繪於下表20中。表 20 . 其他例示性化合物
實例22流程 19
5-[2-(第三丁基二甲基矽烷基)乙炔基]-2-氯-3-甲基吡嗪
化合物 | 結構 | 質子 NMR | MS [M+1] | ||
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.95 (s, 1H), 8.74 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 7.80 - 7.74 (m, 2H), 7.41 - 7.26 (m, 4H), 7.22 - 7.11 (m, 2H), 5.80 (s, 1H), 5.54 (t,J = 1.5 Hz, 1H), 3.70 (s, 3H), 2.40 (d,J = 11.0 Hz, 6H), 1.95 (d,J = 1.2 Hz, 3H). | 509.20 | |||
N-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )10.24 (s, 1H), 8.74 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 7.66-7.57 (m, 1H), 7.35 (d,J = 8.3 Hz, 1H), 7.33-7.24 (m, 2H), 7.17 (d,J = 5.1 Hz, 1H), 7.16-7.10 (m, 1H), 6.45 (dd,J = 17.0, 10.1 Hz, 1H), 6.28 (dd,J = 17.0, 2.1 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.52 (s, 3H), 2.41 (d,J = 8.1 Hz, 6H), 2.00 (s, 3H). | 509.35 | |||
(S)-N-(4-(4,7-二甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )10.27 (s, 1H), 8.65 (s, 1H), 7.71 (dd,J = 4.9, 2.1 Hz, 1H), 7.66-7.58 (m, 1H), 7.24 (dd,J = 10.7, 8.3 Hz, 1H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.29 (dd,J = 17.0, 2.1 Hz, 1H), 5.80 (dd,J = 10.1, 2.1 Hz, 1H), 5.66 (d,J = 14.9 Hz, 1H), 3.47-3.39 (m, 5H), 3.32 (s, 3H), 3.26 (t,J = 6.8 Hz, 2H), 2.65 (s, 3H), 2.27-2.16 (m, 1H), 2.07 (t,J = 3.8 Hz, 4H), 1.85 (p,J = 6.6 Hz, 2H), 1.74 (p,J = 6.5 Hz, 3H), 1.49-1.41 (m, 1H). | 484.45 | |||
(R)-N-(4-(4,7-二甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )10.28 (s, 1H), 8.64 (s, 1H), 7.71 (dd,J = 5.1, 2.0 Hz, 1H), 7.62 (dt,J = 5.9, 3.2 Hz, 1H), 7.23 (dd,J = 10.6, 8.3 Hz, 1H), 6.47 (dd,J = 17.0, 10.1 Hz, 1H), 6.29 (dd,J = 17.0, 2.1 Hz, 1H), 5.79 (dd,J = 10.0, 2.0 Hz, 1H), 5.70-5.61 (m, 1H), 3.42 (s, 4H), 3.26 (t,J = 6.9 Hz, 2H), 2.65 (s, 3H), 2.18 (d,J = 10.3 Hz, 0H), 2.06 (d,J = 4.0 Hz, 4H), 1.85 (p,J = 6.7 Hz, 2H), 1.74 (p,J = 6.7 Hz, 3H), 1.45 (d,J = 12.9 Hz, 1H). | 484.45 | |||
N-[4-(3-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-1,4-二甲基-1H-吡咯并[3,2-c]吡啶-2-基)-3-甲基苯基]丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.23 (s, 1H), 8.47 (d,J = 5.1 Hz, 1H), 8.29 (s, 1H), 7.64 (s, 1H), 7.61 (s, 1H), 7.59 (s, 1H), 7.30 (dd,J = 12.2, 8.6 Hz, 3H), 7.15 (dd,J = 17.4, 6.6 Hz, 2H), 6.45 (dd,J = 16.9, 10.1 Hz, 1H), 6.36 - 6.09 (m, 1H), 5.78 (d,J = 11.8 Hz, 1H), 3.56 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H), 2.01 (s, 3H). | 508.25 | |||
N-(4-(4,7-二甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6)10.22 (s, 1H), 8.73 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.64-7.55 (m, 2H), 7.36-7.26 (m, 3H), 7.17-7.08 (m, 3H), 6.44 (dd, J = 17.0, 10.1 Hz, 1H), 6.27 (dd, J =17.0, 2.1 Hz, 1H), 5.78 (dd, J = 10.1, 2.1 Hz, 1H), 3.52 (s, 3H), 2.39 (d, J = 4.4 Hz, 6H), 1.99 (s, 3H). | 491.35 | |||
N-[4-(5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基]-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.87 (s, 1H), 8.74 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 7.68 (d,J = 2.1 Hz, 1H), 7.65-7.61 (m, 1H), 7.34 (d,J = 8.3 Hz, 1H), 7.32- 7.26 (m, 2H), 7.18 (d,J = 5.1 Hz, 1H), 7.16- 7.10 (m, 1H), 5.81 (t,J = 1.1 Hz, 1H), 5.54 (s, 1H), 3.52 (s, 3H), 2.41 (d,J = 7.5 Hz, 6H), 1.99 (s, 3H), 1.97 -1.91 (m, 3H). | 523.35 | |||
N-[4-(4,7-二甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基]-2-甲基丙-2-烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.73 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 7.65 (d,J = 2.1 Hz, 1H), 7.63 - 7.59 (m, 1H), 7.50 - 7.27 (m, 3H), 7.18 - 6.92 (m, 3H), 5.80 (t,J = 1.0 Hz, 1H), 5.53 (d,J = 1.9 Hz, 1H), 3.52 (s, 3H), 2.39 (d,J = 4.6 Hz, 6H), 1.98 (s, 3H), 1.95 (d,J = 1.3 Hz, 3H). | 505.35 | |||
N-(4-(4,7-二甲基-5-(4-苯氧基苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.28 (s, 1H), 8.72 (s, 1H), 7.71 (d,J = 8.6 Hz, 2H), 7.46-7.32 (m, 2H), 7.30 (s, 2H), 7.29 (d,J = 8.7 Hz, 2H), 7.16 (t,J = 7.4 Hz, 1H), 7.07-7.00 (m, 2H), 6.96 (d,J = 8.6 Hz, 2H), 6.45 (dd,J = 16.9, 10.1 Hz, 1H), 6.28 (dd,J = 17.1, 2.0 Hz, 0H), 5.79 (dd,J = 10.1, 2.0 Hz, 1H), 3.70 (s, 3H), 2.34 (s, 3H). | 461.30 | |||
N-(4-(4-甲基-5-(4-苯氧基苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 9.46 (s, 1H), 8.52 (t, J = 6.1 Hz, 1H), 8.22-7.98 (m, 4H), 7.96-7.76 (m, 4H), 7.42 (t, J = 7.8 Hz, 1H), 7.37-7.26 (m, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 6.29 (dd, J = 17.1, 10.1 Hz, 1H), 6.14 (dd, J = 17.1, 2.3 Hz, 1H), 5.62 (dd, J = 10.0, 2.4 Hz, 1H), 4.28 (d, J = 5.9 Hz, 2H), 3.50 (s, 3H), 3.18 (s, 4H), 3.05 (s, 2H). | 447.30 | |||
N-(4-(4,7-二甲基-5-苯基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.27 (s, 1H), 8.71 (s, 1H), 7.72-7.64 (m, 2H), 7.38-7.25 (m, 7H), 6.43 (dd,J = 17.0, 10.1 Hz, 1H), 6.27 (dd,J = 17.0, 2.1 Hz, 1H), 5.78 (dd,J = 10.0, 2.1 Hz, 1H), 3.70 (s, 3H), 2.28 (s, 3H). | 369.20 | |||
N-(4-(4,7-二甲基-5-(6-(4-甲基-1H-吡唑-1-基)吡啶-3-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.29 (s, 1H), 8.75 (s, 1H), 8.37 (t,J = 1.0 Hz, 1H), 8.29 (dd,J = 2.3, 0.8 Hz, 1H), 7.90 (dd,J = 8.4, 2.3 Hz, 1H), 7.84 (dd,J = 8.4, 0.8 Hz, 1H), 7.76-7.69 (m, 2H), 7.65 (s, 1H), 7.42-7.34 (m, 2H), 6.43 (dd,J = 16.9, 10.0 Hz, 1H), 6.27 (dd,J = 17.0, 2.1 Hz, 1H), 5.78 (dd,J = 10.1, 2.1 Hz, 1H), 3.72 (s, 3H), 2.39 (s, 3H), 2.11 (d,J = 1.0 Hz, 3H). | 450.30 | |||
N-(4-(4,7-二甲基-5-(4-((6-甲基吡啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.29 (s, 1H), 8.72 (s, 1H), 7.78-7.69 (m, 3H), 7.36 (d,J = 8.2 Hz, 2H), 7.30 (d,J = 8.0 Hz, 2H), 7.06 (d,J = 8.0 Hz, 2H), 7.01 (d,J = 7.4 Hz, 1H), 6.75 (d,J = 8.2 Hz, 1H), 6.44 (dd,J = 17.0, 10.1 Hz, 1H), 6.33-6.23 (m, 1H), 5.78 (d,J = 10.1 Hz, 1H), 3.71 (s, 3H), 2.34 (s, 6H). | 476.15 | |||
N-(4-(7-異丙基-4-甲基-5-(4-苯氧基苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.29 (s, 1H), 8.69 (s, 1H), 7.72 (d,J = 8.2 Hz, 2H), 7.41 (t,J = 7.8 Hz, 2H), 7.29 (dd,J = 16.6, 8.3 Hz, 4H), 7.16 (t,J = 7.3 Hz, 1H), 7.02 (d,J = 8.0 Hz, 2H), 6.90 (d,J = 8.2 Hz, 2H), 6.45 (dd,J = 16.9, 10.0 Hz, 1H), 6.29 (dd,J = 16.8, 1.9 Hz, 1H), 5.79 (dd,J = 10.2, 2.0 Hz, 1H), 4.43 (p,J = 6.8 Hz, 1H), 2.30 (s, 3H), 1.63 (d,J = 6.8 Hz, 6H). | 489.15 | |||
N-(4-(5-(苯并[b]噻吩-2-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 10.28 (s, 1H), 8.77 (s, 1H), 7.89 (d,J = 7.9 Hz, 1H), 7.86-7.79 (m, 1H), 7.75-7.68 (m, 2H), 7.52-7.43 (m, 3H), 7.42-7.29 (m, 2H), 6.42 (dd,J = 17.0, 10.1 Hz, 1H), 6.26 (dd,J = 16.9, 2.1 Hz, 1H), 5.77 (dd,J = 10.0, 2.1 Hz, 1H), 3.72 (s, 3H), 2.44 (s, 3H). | 425.25 | |||
N-(4-(5-(苯并[b]噻吩-2-基)-4-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 )δ 12.74 (s, 1H), 10.25 (s, 1H), 8.68 (s, 1H), 8.05-7.95 (m, 1H), 7.89 (dd, J = 6.8, 1.8 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.57-7.49 (m, 3H), 7.45-7.35 (m, 2H), 6.41 (dd, J = 17.0, 10.1 Hz, 1H), 6.25 (dd, J = 17.0, 2.1 Hz, 1H), 5.77 (dd, J = 10.1, 2.1 Hz, 1H), 2.36 (s, 3H). | 411.15 | |||
步驟1:向圓底燒瓶中裝入5-溴-2-氯-3-甲基吡嗪(1 g,4.82 mmol)、第三丁基(乙炔基)二甲基矽烷(810 mg,5.78 mmol)、Pd(PPh3)2Cl2 (675 mg,964 µmol)、CuI (364 mg,1.92 mmol)、TEA (2.43 g,24.1 mmol)及攪拌棒。添加二甲基甲醯胺(20 mL),且在50℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色油狀之5-[2-(第三丁基二甲基矽烷基)乙炔基]-2-氯-3-甲基吡嗪(1 g,77%)。
6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 2
:向可再密封之反應瓶中裝入5-[2-(第三丁基二甲基矽烷基)乙炔基]-2-氯-3-甲基吡嗪(600 mg,2.24 mmol)、(4-{[(第三丁氧基)羰基]胺基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)酸(1.30 g,4.48 mmol)、G3-X-phos (189 mg,224 µmol)、Xphos (213 mg,448 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷:水=16:1 (20 mL),且在90℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色非晶形固體狀之6-{5-[2-(第三丁基二甲基矽烷基)乙炔基] -3-甲基吡嗪-2-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(600 mg,70%)。
5-溴-6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向圓底燒瓶中裝入6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,1.32 mmol)、二甲基甲醯胺(5 mL)及攪拌棒。添加NBS (234 mg,1.32 mmol),且在室溫下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色非晶形固體狀之5-溴-6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,82%)。
6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟4:向可再密封之反應瓶中裝入4-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]嘧啶(374 mg,1.20 mmol)、5-溴-6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(460 mg,1.00 mmol)、Pd(dppf)Cl2 (73.1 mg,100 µmol)、Cs2CO3 (975 mg,3.00 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷:水=16:1 (10 mL),且在90℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由製備型TLC純化。真空濃縮,產生呈灰白色非晶形固體狀之6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,73%)。
6-(5-乙炔基-3-甲基吡嗪-2-基)-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 5
:向圓底燒瓶中裝入6-{5-[2-(第三丁基二甲基矽烷基)乙炔基]-3-甲基吡嗪-2-基}-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(480 mg,852 µmol)、CsF (387 mg,2.55 mmol)及攪拌棒。添加THF (10 mL),且在50℃下攪拌溶液2小時。過濾反應混合物,用DCM洗滌,真空濃縮。所得粗物質藉由製備型HPLC純化。凍乾產生呈灰白色非晶形固體狀之6-(5-乙炔基-3-甲基吡嗪-2-基)-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(260 mg,68%)。
根據實例22之方法製備的其他化合物描繪於下表21中。表 21. 其他例示性化合物
實例23流程 20
化合物 | 結構 | 質子 NMR | MS [M+1] |
6-(5-乙炔基吡嗪-2-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.92 (d,J = 1.5 Hz, 1H), 8.50 (d,J = 5.0 Hz, 1H), 8.29 - 8.20 (m, 2H), 7.43 - 7.33 (m, 2H), 7.33 - 7.23 (m, 2H), 7.18 (d,J = 5.0 Hz, 1H), 6.10 (s, 2H), 4.75 (s, 1H), 3.85 (s, 3H), 2.43 (s, 3H). | 435.30 | |
6-(5-乙炔基-3-甲基吡嗪-2-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.81 (d,J = 0.8 Hz, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.20 -7.12 (m, 5H), 4.73 (s, 1H), 3.57 (s, 3H), 2.38 (s, 3H), 1.98 -1.94 (m, 3H). | 449.20 | |
6-(5-乙炔基-3-甲基吡嗪-2-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.85 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.35 (s, 1H), 7.35 (t,J = 8.4 Hz, 2H), 7.20 (d,J = 5.0 Hz,2H), 7.08 (s, 1H), 6.92 (d,J = 7.9 Hz, 1H), 4.78 (s, 1H), 3.62 (s, 3H), 2.42 (s, 3H), 2.02 (s, 3H). | 467.15 | |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 - 8.59 (m, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.43 (s, 1H), 8.21 (s, 1H), 7.52 (dd,J = 8.8, 2.8 Hz, 1H), 7.19 (d,J = 5.1 Hz, 1H), 6.88 - 6.81 (m, 1H), 4.86 (d,J = 0.8 Hz, 1H), 3.47 (s, 3H), 2.41 (s, 3H), 2.02 (d,J = 2.1 Hz, 3H). | 467.30 | |
5-(3-氟-4-(4-甲基嘧啶-2-基氧基)苯基)-7-甲基-6-(3-甲基-5-(丙-1-炔基)吡嗪-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) 8.72 (d, J = 0.8 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.11 (d, J = 11.2 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 3.58 (s, 3H), 2.42 (s, 3H), 2.16 (s, 3H), 2.00 (d, J = 0.6 Hz, 3H). | 481.15 | |
(S)-(4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.29 (d,J = 7.0 Hz, 1H), 8.18 (s, 1H), 5.93 (s, 1H), 4.21 (dd,J = 1.9, 0.9 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.51 (s, 3H), 3.49 - 3.37 (m, 2H), 2.85 (q,J = 6.1 Hz, 1H), 2.45 - 2.28 (m, 2H), 2.21 (dd,J = 3.7, 2.2 Hz, 3H), 2.18 - 2.01 (m, 2H), 2.03 - 1.95 (m, 2H), 1.92 - 1.85 (m, 2H), 1.77 (dt,J = 12.1, 6.1 Hz, 2H). | 459.30 | |
(R)-(4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.29 (d,J = 7.0 Hz, 1H), 8.18 (s, 1H), 5.83 (dd,J = 3.8, 1.9 Hz, 1H), 4.21 (dd,J = 1.9, 0.8 Hz, 1H), 3.55 (dtd,J = 10.2, 6.6, 3.6 Hz, 2H), 3.51 (s, 3H), 3.43 (ddt,J = 9.3, 6.5, 3.7 Hz, 2H), 2.86 (p,J = 6.2 Hz, 1H), 2.44 - 2.31 (m, 1H), 2.28 (s, 1H), 2.21 (dd,J = 3.7, 2.2 Hz, 3H), 2.12 (d,J = 14.2 Hz, 2H), 2.04 - 1.96 (m, 2H), 1.94 - 1.86 (m, 2H), 1.79 (p,J = 6.9, 6.4 Hz, 2H). | 459.30 | |
6-(4-(二甲基胺基)-6-乙炔基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (d,J = 5.1 Hz, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.36 (t,J = 8.4 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.09 (d,J = 8.6 Hz, 1H), 6.91 (s, 1H), 6.14(s,1H), 4.25 (s, 1H), 3.54 (s, 3H), 2.63 (s, 6H), 2.42 (s, 3H). | 495.20 |
根據實例23之方法製備的其他化合物描繪於下表22中。表 22. 其他例示性化合物
實例24流程 21
(1R)-4-{4-胺基-6-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}環己-3-烯-1-甲酸
化合物 | 結構 | 質子 NMR | MS [M+1] |
7-甲基-6-(4-甲基-2-乙烯基嘧啶-5-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.46 (d,J = 5.1 Hz, 1H), 8.25 (s, 1H), 7.28 (d,J = 8.6 Hz, 2H), 7.19 (d,J = 8.7 Hz, 2H), 7.15 (d,J = 5.0 Hz, 1H), 6.81 (d,J = 10.7 Hz, 1H),6.65 (d,J = 10.8 Hz, 1H), 5.82 (s, 1H), 3.54 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H). | 451.10 | |
7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(2-(丙-1-炔-1-基)嘧啶-5-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 2H), 8.48 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.38 - 7.31 (m, 2H), 7.29 - 7.18 (m, 2H), 7.17 (s, 1H), 5.89 (d,J = 103.6 Hz, 1H), 3.71 (s, 3H), 2.43 (s, 3H), 2.12 (s, 3H). | 449.15 | |
5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基菸腈 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.63 (d,J = 2.2 Hz, 1H), 8.50 (d,J = 2.1 Hz, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.34-7.27 (m, 2H), 7.25-7.18 (m, 2H), 7.14 (d,J = 5.0 Hz, 1H), 5.03 (s, 1H), 3.68 (s, 3H), 2.40 (s, 3H). | 459.10 | |
7-甲基-6-(4-甲基-2-(丙-1-炔-1-基)嘧啶-5-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.25 (d,J = 8.6 Hz, 2H), 7.26 - 7.13 (m, 3H), 3.53 (s, 3H), 2.41 (s, 3H), 2.12 (d,J = 3.2 Hz, 6H). | 463.35 | |
6-(2-(3-甲氧基丙-1-炔-1-基)-4-甲基嘧啶-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.29 - 7.17 (m, 5H), 4.40 (s, 2H), 3.55 (s, 3H), 3.36 (d, J = 1.4 Hz, 3H), 2.41 (s, 3H), 2.14 (s, 3H). | 493.15 | |
6-(6-乙炔基-2-氟吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d 6 ) 8.49 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 8.08 (dd,J = 9.6, 7.6 Hz, 1H), 7.65 (dd,J = 7.5, 1.7 Hz, 1H), 7.37 (t,J = 8.4 Hz, 1H), 7.27 - 7.17 (m, 2H), 7.07 (d,J = 8.3 Hz, 1H), 4.64 (s, 1H), 3.60 (s, 3H), 2.42 (s, 3H), 2.08 (s, 1H). | 470.25 | |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR(300 MHz, DMSO-d6) 8.47 (d, J = 5.0 Hz, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.24 - 7.12 (m, 2H), 7.03 (d, J = 9.4 Hz, 1H), 4.79 (s, 1H), 3.51 (s, 3H), 2.40 (s, 3H), 1.97 (d, J = 2.2 Hz, 3H). | 484.35 | |
6-(6-乙炔基-5-甲氧基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 5.1 Hz, 1H), 8.32 (s, 1H), 8.24 (s, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.04 - 6.98 (m, 1H), 6.18 (s, 2H), 4.63 (s, 1H), 3.83 (s, 3H), 3.51 (s, 3H), 2.40 (s, 3H), 1.91 (s, 3H). | 496.30 | |
4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-異丁基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.35 (s, 1H), 8.25 (s, 1H), 7.83 - 7.76 (m, 2H), 7.29 - 7.22 (m, 2H), 6.12 (s, 2H), 4.80 (s, 1H), 3.51 (s, 3H), 3.06 (t,J = 6.4 Hz, 2H), 1.94 (d,J = 2.1 Hz, 3H), 1.82 (dq,J = 13.3, 6.7 Hz, 1H), 0.88 (d,J = 6.7 Hz, 6H). | 457.20 | |
4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-異丁基-N-甲基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.37 (s, 1H), 8.25 (s, 1H), 7.41 - 7.26 (m, 2H), 7.22 (d,J = 7.6 Hz, 2H), 6.16 (s, 2H), 4.78 (s, 1H), 3.53 (d,J = 7.5 Hz, 3H), 3.29 (d,J = 11.4 Hz, 1H), 3.05 - 2.80 (m, 4H), 1.89 (d,J = 26.0 Hz, 4H), 0.93 (dd,J = 17.7, 7.0 Hz, 3H), 0.63 (s, 3H). | 471.25 | |
4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-甲氧基-N-(2,2,2-三氟乙基)苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.62 (t,J = 6.4 Hz, 1H), 8.39 (s, 1H), 8.26 (s, 1H), 7.70 (d,J = 7.9 Hz, 1H), 6.92 (d,J = 1.5 Hz, 1H), 6.83 (dd,J = 7.9, 1.5 Hz, 1H), 6.21 (s, 1H), 4.81 (d,J = 0.8 Hz, 1H), 4.08 (td,J = 9.7, 6.6 Hz, 2H), 3.75 (s, 3H), 3.52 (s, 3H), 1.97 (d,J = 2.1 Hz, 3H). | 513.35 | |
((S)-4-(4-胺基-6-(6-(3-甲氧基丙-1-炔-1-基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.42 - 8.35 (m, 1H), 8.17 - 8.06 (m, 1H), 7.61 (d, J = 2.3 Hz, 1H), 6.67 (s, 2H), 5.69 (d, J = 36.7 Hz, 1H), 4.39 (s, 2H), 4.01 (t, J = 4.6 Hz, 1H), 3.45 (d, J = 6.6 Hz, 1H), 3.37 (s, 7H), 2.71 (d, J = 33.3 Hz, 1H), 2.24 (s, 1H), 2.18 - 2.03 (m, 4H), 2.00 - 1.42 (m, 8H), 1.13 - 1.01 (m, 3H). | 499.30 | |
((R)-4-(4-胺基-6-(6-(3-甲氧基丙-1-炔-1-基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.47 - 8.34 (m, 1H), 8.13 (s, 1H), 7.61 (d, J = 2.2 Hz, 1H), 6.54 (s, 2H), 5.66 (d, J = 26.0 Hz, 1H), 4.39 (s, 2H), 4.04 (d, J = 37.4 Hz, 1H), 3.57 - 3.40 (m, 1H), 3.37 (s, 7H), 2.69 (s, 1H), 2.13 (d, J = 4.4 Hz, 5H), 2.05 - 1.42 (m, 8H), 1.08 (dd, J = 12.8, 6.5 Hz, 3H). | 499.30 | |
6-(6-(3-甲氧基丙-1-炔-1-基)-4-甲基吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.53 (s, 1H), 7.27 - 7.20 (m, 2H), 7.20 - 7.11 (m, 3H), 6.03 (s, 2H), 4.37 (s, 2H), 3.47 (s, 3H), 3.35 (s, 3H), 2.40 (s, 3H), 2.01 (s, 3H). | 492.40 | |
5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(6-(3-甲氧基丙-1-炔-1-基)-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.54 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 7.57 (s, 1H), 7.36 - 7.27 (m, 2H), 7.18 (d,J = 5.0 Hz, 1H), 7.17 - 7.09 (m, 1H), 4.38 (s, 2H), 3.57 (s, 3H), 3.35 (s, 3H), 2.41 (d,J = 9.6 Hz, 6H), 2.06 (s, 3H). | 509.25 | |
5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(2-(3-甲氧基丙-1-炔-1-基)喹啉-6-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.40 (d,J = 8.5 Hz, 1H), 8.26 (s, 1H), 8.09 (d,J = 1.9 Hz, 1H), 8.00 (d,J = 8.7 Hz, 1H), 7.74 (dd,J = 8.7, 2.0 Hz, 1H), 7.68 (d,J = 8.5 Hz, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.25 (dd,J = 11.3, 2.0 Hz, 1H), 7.20 - 7.11 (m, 2H), 6.09 (s, 2H), 4.45 (s, 2H), 3.69 (s, 3H), 3.40 (s, 3H), 2.39 (s, 3H). | 546.25 | |
5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(4-甲氧基-6-(3-甲氧基丙-1-炔-1-基)吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.29 (s, 1H), 7.40 (s, 1H), 7.34 - 7.28 (m, 2H), 7.19 (d,J = 5.1 Hz, 1H), 7.10 (d,J = 8.3 Hz, 1H), 4.39 (s, 2H), 3.87 (s, 3H), 3.61 (s, 3H), 3.37 (s, 3H), 2.41 (d,J = 1.9 Hz, 7H). | 525.25 |
步驟 1
:向圓底燒瓶中裝入(1R)-4-{4-胺基-6-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}環己-3-烯-1-甲酸(1 g,3.25 mmol)、二甲基甲醯胺(15 mL)、吡咯啶(462 mg,6.50 mmol)、HATU (2.47 g,6.50 mmol)、NaHCO3 (546 mg,6.50 mmol)及攪拌棒,且在25℃下攪拌溶液1小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇40:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之(1R)-4-{4-胺基-6-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}環己-3-烯-1-甲酸(1 g,85%)。
6-{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟2:向可再密封之反應瓶中裝入6-氯-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,1.38 mmol)、2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶(541 mg,1.51 mmol)、Na2CO3 (438 mg,4.14 mmol)、X-phos (131 mg,276 µmol)、X-phos G3 (116 mg,138 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷/H2O (10 mL),且在90℃下攪拌混合物1小時。反應混合物用水(30 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇40:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之6-{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,59%)。
6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟3:向圓底燒瓶中裝入6-{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(600 mg,1.07 mmol)、TBAF (1.28 mL,1.28 mmol)及攪拌棒。添加四氫呋喃(10 mL),且在25℃下攪拌溶液1小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化。凍乾產生呈灰白色非晶形固體狀之6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(109 mg,23%)。
根據實例24之方法製備的其他化合物描繪於下表23中。表 23. 其他例示性化合物
實例25流程 22
6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
(R)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.68 (d,J = 13.6 Hz, 1H), 8.14 (s, 1H), 6.65 (s, 2H), 5.67 (s, 1H), 4.51 (d,J = 0.8 Hz, 1H), 3.54 - 3.39 (m, 5H), 3.27 (tt,J = 8.3, 4.3 Hz, 2H), 2.82 - 2.73 (m, 1H), 2.33 (d,J = 1.0 Hz, 3H), 2.19 (s, 2H), 1.96 (s, 2H), 1.80 (dp,J = 27.0, 7.0 Hz, 4H), 1.63 (d,J = 6.5 Hz, 2H). | 442.35 | |
(S)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.68 (d,J = 13.8 Hz, 1H), 8.14 (s, 1H), 6.66 (s, 2H), 5.70 (d,J = 19.4 Hz, 1H), 4.51 (d,J = 0.8 Hz, 1H), 3.58 - 3.39 (m, 5H), 3.26 (dd,J = 6.8, 3.2 Hz, 2H), 2.78 (t,J = 5.9 Hz, 1H), 2.33 (d,J = 1.0 Hz, 3H), 2.20 (s, 2H), 1.97 (s, 2H), 1.85 (q,J = 6.5 Hz, 2H), 1.77 (q,J = 6.6 Hz, 2H), 1.63 (d,J = 6.4 Hz, 2H). | 442.15 | |
(R)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(2-氧雜-5-氮雜螺[3.4]辛-5-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.38 (d,J = 7.1 Hz, 1H), 8.12 (d,J = 1.1 Hz, 1H), 7.61 (s, 1H), 6.52 (s, 2H), 5.68 (d,J = 24.1 Hz, 1H), 5.26 (dt,J = 15.3, 4.2 Hz, 2H), 4.41 (d,J = 1.2 Hz, 1H), 4.15 (d,J = 4.9 Hz, 2H), 3.53-3.34 (m, 3H), 3.30-3.25(m, 3H),2.32-2.07 (m, 7H), 1.74-1.49 (m, 5H), 1.22 (s, 1H). | 483.15 | |
(R)-(4-(4-胺基-6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(2-氧雜-5-氮雜螺[3.4]辛-5-基)甲酮 | H NMR (400 MHz, 甲醇-d 4 ) 8.16 (s, 1H), 7.78 (dd,J = 9.0, 7.9 Hz, 1H), 7.55 (dd,J = 7.9, 4.8 Hz, 1H), 5.88 (d,J = 14.9 Hz, 1H), 5.52-5.44 (m, 2H), 4.41 (dd,J = 5.3, 2.1 Hz, 2H), 3.89 (d,J = 0.9 Hz, 1H), 3.58 (f,J = 14.1, 7.1, 6.6, 3.0 Hz, 2H), 3.48 (s, 3H), 2.90 (d,J = 5.9 Hz, 1H), 2.43 (d,J = 18.4 Hz, 1H), 2.37 (s, 3H), 2.43-2.23 (m, 3H), 2.22 (dd,J = 45.1, 24.5 Hz, 2H), 1.94-1.67 (m, 4H). | 483.20 | |
((R)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(甲氧基甲基)吡咯啶-1-基)甲酮 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.44 - 8.32 (m, 1H), 8.10 (d,J = 3.4 Hz, 1H), 7.60 (s, 1H), 6.63 (s, 2H), 5.72 (s, 1H), 4.40 (s, 1H), 4.04 (s, 1H), 3.51 - 3.32 (m, 5H), 3.24 - 3.14 (m, 5H), 2.76 (s, 1H), 2.21 (s, 1H), 2.12 (d,J = 4.3 Hz, 3H), 1.82 (d,J = 28.6 Hz, 6H), 1.57 (s, 2H). | 485.40 | |
((S)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(甲氧基甲基)吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.40 (s, 1H), 8.14 (d,J = 3.8 Hz, 1H), 7.63 (s, 1H), 6.52 (s, 1H), 5.65 (d,J = 7.1 Hz, 1H), 4.43 (s, 1H), 4.10 (d,J = 37.6 Hz, 1H), 3.45 (m,J = 11.4, 4.6 Hz, 2H),3.44- 3.35 (m, 3H), 3.23 (d,J = 4.3 Hz, 5H), 2.70 (d,J = 15.0 Hz, 1H), 2.15 (d,J = 13.9 Hz, 5H), 1.93 (d,J = 23.9 Hz, 2H), 1.80 (s, 4H), 1.58 (s, 2H), | 485.25 | |
((R)-4-(4-胺基-6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(甲氧基甲基)吡咯啶-1-基)甲酮 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.14 - 8.06 (m, 1H), 7.78 - 7.63 (m, 1H), 7.49 (dd,J = 8.0, 3.8 Hz, 1H), 6.58 (d,J = 30.8 Hz, 1H), 5.67 (d,J = 14.1 Hz, 1H), 4.43 - 4.37 (m, 1H), 4.03 (s, 1H), 3.35 (d,J = 1.2 Hz, 5H), 3.24 - 3.12 (m, 5H), 2.76 (s, 1H), 2.25 (d,J = 2.5 Hz, 3H), 2.11 (s, 1H), 1.81 (d,J = 21.3 Hz, 6H), 1.57 (s, 2H). | 485.40 | |
((S)-4-(4-胺基-6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(甲氧基甲基)吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.14 (d,J = 3.7 Hz, 1H), 7.73 (d,J = 7.9 Hz, 1H), 7.52 (d,J = 7.9 Hz, 1H), 6.51 (s, 2H), 5.66 (d,J = 12.7 Hz, 1H), 4.43 (s, 1H), 4.08 (d,J = 37.6 Hz, 1H), 3.44 (m,J = 11.4, 4.6 Hz, 2H), 3.38 (d,J = 3.2 Hz, 3H), 3.23 (d,J = 4.9 Hz, 5H), 2.71 (t,J = 10.2 Hz, 1H), 2.28 (d,J = 3.2 Hz, 3H), 2.17 (s, 2H), 1.91 (d,J = 22.3 Hz, 3H), 1.80 (s,J = 7.7, 6.8 Hz,3H), 1.58 (s, 2H). | 485.20 | |
(S)-1-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d,J = 11.4 Hz, 1H), 8.14 (s, 1H), 7.63 (d,J = 2.4 Hz, 1H), 6.46 (s, 2H), 5.72 (d,J = 24.8 Hz, 1H), 4.43 (s, 1H), 3.65 (m,J = 33.4 Hz, 3H), 3.37 (d,J = 2.7 Hz, 3H), 2.60 - 2.53 (m, 1H), 2.39 - 2.19 (m, 2H), 2.14 (s, 3H), 1.99 - 1.86 (m, 4H), 1.81 - 1.57 (m, 3H). | 455.30 | |
(R)-1-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-酮 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.37 (d,J = 8.3 Hz, 1H), 8.12 (s, 1H), 7.64 - 7.57 (m, 1H), 6.43 (s, 2H), 5.70 (d,J = 18.3 Hz, 1H), 4.39 (s, 1H), 3.73 - 3.55 (m, 3H), 3.35 (d,J = 1.9 Hz, 3H), 2.57 - 2.48 (m, 1H), 2.28 (d,J = 23.1 Hz, 2H), 2.11 (s, 3H), 1.89 (p,J = 7.6 Hz, 4H), 1.79 - 1.42 (m, 3H). | 455.20 | |
((S)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 - 8.31 (m, 1H), 8.14 (d,J = 3.3 Hz, 1H), 7.63 (s, 1H), 6.54 (s, 2H), 5.67 (d,J = 26.6 Hz, 1H), 4.43 (s, 1H), 4.00 (s, 1H), 3.51 (s, 1H), 3.38 (d,J = 2.7 Hz, 1H), 3.37 (s, 3H), 2.68 (t,J = 1.9 Hz, 1H), 2.53 (s, 1H), 2.14 (d,J = 4.4 Hz, 4H), 2.07 - 1.44 (m, 8H), 1.07 (d,J = 6.2 Hz, 3H). | 455.25 | |
((S)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(羥基甲基)吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 - 8.36 (m, 1H), 8.14 (d,J = 2.7 Hz, 1H), 7.63 (s, 1H), 6.51 (s, 2H), 5.67 (d,J = 25.9 Hz, 1H), 4.95 - 4.67 (m, 1H), 4.42 (s, 1H), 3.95 (d,J = 15.4 Hz, 1H), 3.47 (dt,J = 10.0, 4.4 Hz, 2H), 3.37 (s, 3H), 3.29 - 3.19 (m, 1H), 2.70 (s, 1H), 2.14 (d,J = 5.2 Hz, 5H), 1.97 - 1.78 (m, 6H), 1.58 (s, 2H). | 471.35 | |
(S)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(2-氧雜-5-氮雜螺[3.4]辛-5-基)甲酮 | 1H NMR: 1H NMR (400 MHz, DMSO-d6) 8.41 (d, J = 8.2 Hz, 1H), 8.15 (s, 1H), 7.71 - 7.56 (m, 1H), 6.59 (s, 1H), 5.71 (d, J = 24.5 Hz, 1H), 5.36 - 5.21 (m, 2H), 4.43 (s, 1H), 4.18 (d, J = 4.9 Hz, 2H), 3.53 - 3.41 (m, 2H), 3.38 (s, 3H), 2.77 (s, 1H), 2.39 - 2.18 (m, 4H), 2.14 (d, J = 2.8 Hz, 3H), 1.94 (d, J = 18.5 Hz, 2H), 1.71 (t, J = 6.8 Hz, 2H), 1.61 (s, 2H). | 483.20 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-[(4S)-4-[(2S)-2-甲基吡咯啶-1-羰基]環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43 - 8.24 (m, 1H), 8.10 (d, J = 3.2 Hz, 1H), 7.60 (s, 1H), 5.67 (d, J = 27.0 Hz, 1H), 4.40 (s, 1H), 3.99 (s, 1H),3.44 (s, 2H), 3.35(s, 3H), 2.48 (s, 2H), 2.11 (d, J = 3.6 Hz, 2H), 1.88 (s, 5H), 1.77 -1.57(m, 4H), 1.19-0.81 (m, 4H). | 455.20 | |
((R)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.45-8.37 (m, 1H), 8.13 (d,J = 4.3 Hz, 1H), 7.63 (s, 1H), 6.55 (s, 1H), 5.70 (d,J = 37.1 Hz, 1H), 4.42 (d,J = 2.0 Hz, 1H), 4.01 (s, 1H), 3.47 (t,J = 6.4 Hz, 1H), 3.40-3.35 (m, 4H), 2.72 (d,J = 33.0 Hz, 1H), 2.24 (s, 1H), 2.19-2.13 (m, 4H), 1.85 (d,J = 44.5 Hz, 5H), 1.57 (s, 2H), 1.47 (s, 1H), 1.13-1.03 (m, 3H). | 455.20 | |
((R)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d6) 8.42-8.37 (m, 1H), 8.14 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.54 (s, 1H), 5.67 (d, J = 26.1 Hz, 1H), 4.42 (s, 1H), 4.05 (d, J = 39.4 Hz, 1H), 3.57 (d, J = 42.9 Hz, 1H), 3.35-3.48 (m, 4H), 2.69 (d, J = 6.9 Hz, 1H), 2.14 (d, J = 4.3 Hz, 5H), 1.94 (d, J = 18.5 Hz, 3H), 1.82 (s, 2H), 1.57 (s, 2H), 1.49 (d, J = 5.7 Hz, 1H), 1.09 (dd, J = 12.6, 6.6 Hz, 3H). | 455.15 | |
((S)-4-(4-胺基-6-(2-乙炔基-1H-苯并[d]咪唑-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(甲氧基甲基)吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 13.32 (s, 1H), 8.12 (d, J = 3.9 Hz, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.38 (s, 1H), 6.3(s,2H), 5.79 (s, 1H), 4.71 (s, 1H), 4.02 (s, 1H), 3.59 (s, 3H), 3.53 - 3.37 (m, 3H), 3.24 (s, 4H), 2.72 (s, J = 32.8 Hz, 1H), 2.29 (d, J = 36.4 Hz, 2H), 1.90 (d, J = 13.4 Hz, 3H), 1.80 (d, J = 5.1 Hz, 3H), 1.54 (s, 2H). | 510.30 | |
((R)-4-(4-胺基-6-(2-乙炔基-1H-苯并[d]咪唑-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((S)-2-(甲氧基甲基)吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 13.33 (d, J = 10.2 Hz, 1H), 8.13 - 8.08 (m, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 14.6, 8.7 Hz, 1H), 6.59 (s, 2H), 5.80 (s, 1H), 4.72 (d, J = 1.1 Hz, 1H), 4.05 (s,1H), 3.59 (d, J = 6.7 Hz, 3H), 3.49 (d, J = 8.1 Hz, 1H), 3.27 - 3.22 (m, 1H), 3.17 (d, J = 1.3 Hz, 2H), 2.83 (s, 3H), 2.4(s,1H), 2.20 (s, 1H), 1.87 - 1.83 (m, 1H), 1.78 (s, 6H), 1.54 (s, 2H). | 510.30 | |
((S)-4-(4-胺基-6-(6-乙炔基-4-甲氧基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ8.28-8.25 (m, 1H), 8.16-8.10 (m, 1H), 7.41 (d,J = 4.3 Hz, 1H), 6.54 (s, 2H), 5.66 (d,J = 33.7 Hz, 1H),4.46 (s, 1H), 4.15-3.96 (m, 1H), 3.91 (d,J = 3.4 Hz, 3H), 3.42 (d,J = 3.4 Hz, 4H), 3.34 (s, 1H), 2.72(s, 1H), 2.17 (s, 2H), 2.04-1.72 (m, 5H), 1.66 (d,J = 30.2 Hz, 2H), 1.50 (d,J = 6.2 Hz, 1H), 1.13- 1.04 (m, 3H). | 471.35 | |
((R)-4-(4-胺基-6-(6-乙炔基-4-甲氧基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ8.26 (s, 1H), 8.16-8.06 (m, 1H), 7.41 (s, 1H), 6.59 (d,J = 95.2 Hz, 2H), 5.83-5.57 (m, 1H), 4.45 (d,J = 2.5 Hz, 1H), 4.03 (d,J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.48 (s, 1H), 3.42 (d,J = 3.1 Hz, 3H), 2.84-2.65 (m, 1H), 2.36-2.04 (m, 2H), 2.02-1.72 (m,5H), 1.56 (d,J = 60.9 Hz, 3H), 1.17-1.01 (m, 3H). | 471.35 | |
(R)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(4-氮雜螺[2.4]庚-4-基)甲酮 | 1 H NMR (400 MHz, DMSO-d6) 8.39 (d, J = 6.1 Hz, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 6.53 (s, 1H), 5.66 (d, J = 28.0 Hz, 1H), 4.42 (s, 1H), 3.77 -3.52 (m, 2H),3.32(m,3H), 2.70 (s, 1H), 2.36 -2.03 (m, 5H), 1.97 -1.51 (m, 8H), 1.36(s,2H),0.39 (s, 2H). | 467.25 | |
(S)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(4-氮雜螺[2.4]庚-4-基)甲酮 | 1 H NMR (400 MHz, DMSO-d6) 8.39 (d, J = 6.1 Hz, 1H), 8.13 (s, 1H), 7.62 (s, 1H), 6.53 (s, 1H), 5.66 (d, J = 28.0 Hz, 1H), 4.42 (s, 1H), 3.77 -3.52 (m, 2H),3.32(m,3H), 2.70 (s, 1H), 2.36 -2.04 (m, 5H), 1.98 -1.50 (m, 8H), 1.35(s,2H),0.39 (s, 2H). | 467.25 | |
(S)-(4-(4-胺基-6-(2-乙炔基-1-甲基-1H-苯并[d]咪唑-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d6) 8.11 (s, 1H), 7.76 (d, J = 1.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 8.5, 1.6 Hz, 1H), 6.56 (s, 1H), 5.80 (s, 1H), 5.00 (s, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 3.49 (dt, J = 10.1, 6.6 Hz, 1H), 3.43 -3.37 (m, 1H), 3.28 (d, J = 6.4 Hz, 0H), 3.23 (dd, J = 11.9, 6.6 Hz, 1H), 2.80 (t, J = 5.9 Hz, 1H), 2.26 (q, J = 20.5, 18.0 Hz, 2H), 1.84 (q, J = 6.6 Hz, 4H), 1.55 (s, 2H). | 480.25 |
步驟 1
:向可再密封之反應瓶中裝入4-氯-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶(1.2 g,4.1 mmol)、N6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(1.82 g,4.91 mmol)、PAd2nBu Pd-G2 (0.27 g,0.41 mmol)、PAd2nBu (0.29 g,0.82 mmol)、K3PO4 (2.61 g,12.3 mmol)、二噁烷(30 mL)、H2O (3 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在70℃下攪拌混合物15小時。真空濃縮反應混合物。所得粗物質藉由矽膠層析(用MeOH/DCM = 1/100~1/20溶離)純化。真空濃縮,產生呈棕色固體狀之6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(0.7 g,42%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 2
:向可再密封之反應瓶中裝入6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶(0.7 g,1.7 mmol)、Pd(PPh3)4 (0.2 g,0.17 mmol)、THF (20 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加Zn(CH3)2 (1M, 2.04 mL, 2.04 mmol)。在70℃下攪拌混合物2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析(用MeOH/DCM = 1/100~1/30)溶離)純化。真空濃縮,產生呈棕色固體狀之6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(0.4 g,60%)。
5-溴-6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 3
:向圓底燒瓶中裝入6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(0.4 g,1 mmol)、DMF (10 mL)及攪拌棒。添加NBS (0.18 g,1 mmol)。攪拌混合物1小時。反應物用飽和NaHSO3
水溶液淬滅,用DCM (50 mL*3)萃取,合併有機相且用鹽水洗滌兩次,經Na2
SO4
乾燥,真空蒸發,殘餘物用ACN (25 mL)溶解且過濾,濾餅用ACN洗滌,在減壓下乾燥,得到呈黃色固體狀之5-溴-6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(440 mg,94%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 4
:向圓底燒瓶中裝入5-溴-6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(440 mg,0.94 mmol)、2-(2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)-4-甲基嘧啶(371.5 mg,1.1 mmol)、Pd(PPh3)4 (104 mg,0.09 mmol)、K3PO4 (598 mg,2.82 mmol)、DME/H2O (10:1,10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。冷卻後,混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由矽膠層析(用MeOH/DCM=1/100~1/10溶離)純化,得到呈棕色固體狀之6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(300 mg,54%)。
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 5
:向圓底燒瓶中裝入6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(300 mg,0.51 mmol)、THF (10 mL)及攪拌棒。逐滴添加TBAF (0.61 mL,0.61 mmol)。在室溫下攪拌混合物0.5小時。混合物用水稀釋,用DCM萃取,用鹽水洗滌,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由製備型HPLC純化,得到白色固體(100 mg,41%)。將100 mg標靶送交對掌性分離(管柱:CHIRALPAK IF, 2*25cm, 5um;移動相A:Hex (0.5% 2M NH3-MeOH),移動相B:EtOH:DCM=1:1--HPLC;流量:20 mL/min;梯度:20 B至20 B,歷時15.5分鐘;220/254 nm;RT1:10.826;RT2:12.649;注射體積:0.8 ml;操作次數:5)。凍乾得到前峰(43.4 mg)及後峰(40.2 mg)。
根據實例25之方法製備的其他化合物描繪於下表24中。表 24. 其他例示性化合物
實例26流程 23
4-(4-胺基-6-(2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸甲酯
化合物 | 結構 | 質子 NMR | MS [M+1] | |||
6-(2-乙炔基嘧啶-5-基)-4,7-二甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.87 (s, 2H), 8.79 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.43-7.35 (m, 2H), 7.25-7.14 (m, 3H), 4.55 (s, 1H), 3.81 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H). | 434.15 | ||||
6-(2-乙炔基-4-甲基嘧啶-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.83 (d,J = 17.9 Hz, 2H), 8.49 (d,J = 5.0 Hz, 1H), 7.46 - 7.29 (m, 2H), 7.17 (dd,J = 18.9, 6.7 Hz, 2H), 4.52 (s, 1H), 3.64 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H). | 466.25 | ||||
5-{4,7-二甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-6-基}-2-乙炔基-4-甲基嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d,J = 11.1 Hz, 2H), 5.85 - 5.20 (m, 1H), 4.53 (s, 1H), 3.53 (d,J = 1.3 Hz, 3H), 3.45 (td,J = 6.8, 2.9 Hz, 2H), 3.26 (d,J = 6.8 Hz, 2H), 2.67 (s, 3H), 2.33 (d,J = 3.2 Hz, 4H), 2.22 - 2.00 (m, 4H), 1.99 - 1.81 (m, 2H), 1.77 (q,J = 6.7 Hz, 3H), 1.49 (t,J = 11.9 Hz, 1H). | 441.35 | ||||
5-{4,7-二甲基-5-[(4S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-6-基}-2-乙炔基-4-甲基嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (d,J = 11.0 Hz, 2H), 5.91 - 5.36 (m, 1H), 4.53 (s, 1H), 3.52 (d,J = 1.3 Hz, 3H), 3.45 (td,J = 6.7, 3.0 Hz, 2H), 3.26 (d,J = 6.9 Hz, 2H), 2.67 (s, 3H), 2.33 (t,J = 2.8 Hz, 4H), 2.15 (d,J = 30.9 Hz, 4H), 1.95 - 1.70 (m, 5H), 1.50 (s, 1H). | 441.35 | ||||
((R)-4-(6-(6-乙炔基-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯基)(吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) 8.69 (s, 1H), 8.44 (d, J = 11.8 Hz, 1H), 7.66 (s, 1H), 5.67 (d, J = 24.4 Hz, 1H), 4.45 (s, 1H), 3.45 (d, J = 11.5 Hz, 5H), 3.26 (t, J = 6.9 Hz, 2H), 2.67 (s, 3H), 2.47 (s, 1H), 2.26-2.02 (m, 7H), 1.92-1.81 (m, 2H), 1.77-1.75 (m, J = 6.7 Hz, 3H), 1.46-1.44 (m, 1H). | 440.30 | ||||
((S)-4-(6-(6-乙炔基-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯基)(吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) 8.69 (s, 1H), 8.44 (d, J = 11.9 Hz, 1H), 7.66 (s, 1H), 5.67 (d, J = 24.4 Hz, 1H), 4.45 (s, 1H), 3.45 (d, J = 11.4 Hz, 5H), 3.26 (t, J = 7.0 Hz, 2H), 2.67 (s, 3H), 2.50 (s, 1H), 2.26-1.99 (m, 7H), 1.94-1.80 (m, 2H), 1.80-1.69 (m, 3H), 1.46-1.44 (m, 1H). | 440.25 | ||||
2-{4-[6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]-2-氟苯氧基}-4-甲基嘧啶 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.49-8.40 (m, 2H), 7.39-7.24 (m, 2H), 7.20-7.06 (m, 2H), 4.80 (d,J = 0.9 Hz, 1H), 3.59 (s, 3H), 2.39 (d,J = 13.1 Hz, 6H), 2.00 (d,J = 2.2 Hz, 3H). | 483.30 | ||||
4-氯-6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶 | 1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.58 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.60 (s, 1H), 7.34 - 7.26 (m, 2H), 7.18 (d, J = 5.0 Hz, 1H), 7.10 (dt, J = 8.4, 1.4 Hz, 1H), 4.47 (s, 1H), 3.61 (s, 3H), 2.40 (s, 3H), 2.05 (s, 3H). | 485.10 | ||||
6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 7.62 (s, 1H), 7.37 - 7.29 (m, 2H), 7.19 (d, J = 5.0 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 4.61 (s, 1H), 3.61 (s, 3H), 2.45 (s, 3H), 2.41 (s, 3H), 2.09 (s, 3H). | 483.20 | ||||
6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.62 (s, 1H), 7.37 - 7.29 (m, 2H), 7.19 (d,J = 5.1 Hz, 1H), 7.11 - 7.06 (m, 1H), 4.62 (s, 1H), 3.61 (s, 3H), 2.45 (s, 3H), 2.40 (d,J = 5.3 Hz, 3H), 2.09 (s, 3H). | 483.25 | |||
6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.62 (s, 1H), 7.37 - 7.30 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.11 - 7.06 (m, 1H), 4.62 (s, 1H), 3.61 (s, 3H), 2.46 (s, 3H), 2.41 (s, 3H), 2.09 (s, 3H). | 483.25 | |||
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 7.45 (s, 1H), 7.34-7.25 (m, 2H), 7.18 (d,J = 5.0 Hz, 1H), 7.07 (d,J = 8.9 Hz, 1H), 4.39 (s, 1H), 3.51 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H). | 479.35 | ||||
4-氯-6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶 | 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.48 (d, J = 5.1 Hz, 1H), 7.63 (s, 1H), 7.31 (t, J = 8.5 Hz, 2H), 7.19 (d, J = 5.0 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 4.62 (s, 1H), 3.66 (s, 3H), 2.40 (s, 3H), 2.09 (s, 3H). | 503.15 | ||||
4-氯-6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.63 (s, 1H), 7.36 - 7.29 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.07 - 7.04 (m, 1H), 4.64 (s, 1H), 3.66 (s, 3H), 2.41 (s, 3H), 2.09 (s, 3H) | 503.25 | |||
4-氯-6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.81 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.63 (s, 1H), 7.34 - 7.29 (m, 2H), 7.19 (d,J = 5.1 Hz, 1H), 7.08 - 7.04 (m, 1H), 4.64 (s, 1H), 3.66 (s, 3H), 2.41 (s, 3H), 2.09 (s, 3H). | 503.25 | |||
2-{4-[4-氯-6-(6-乙炔基-4-甲氧基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]-2-氟苯氧基}-4-甲基嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.31 (s, 1H), 7.44 (s, 1H), 7.34 - 7.25 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.11 - 7.03 (m, 1H), 4.50 (s, 1H), 3.87 (s, 3H), 3.67 (s, 3H), 2.41 (s, 3H). | 501.15 | ||||
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.83 (s, 1H), 8.48 (d,J = 5.1 Hz, 1H), 7.46 (s, 1H), 7.36 - 7.24 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.11 - 7.04 (m, 1H), 4.40 (s, 1H), 3.53 (s, 3H), 2.46 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 2.05 (s, 3H). | 479.25 | |||
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 7.46 (s, 1H), 7.35 - 7.24 (m, 2H), 7.18 (d,J = 5.1 Hz, 1H), 7.11 - 7.04 (m, 1H), 4.39 (s, 1H), 3.51 (s, 3H), 2.45 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H), 2.06 (d,J = 14.0 Hz, 3H). | 479.25 | |||
步驟 1
:向圓底燒瓶中裝入4-(4-胺基-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸甲酯(3 g,7.35 mmol)、2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶(3.26 g,8.82 mmol)、Pd(dppf)Cl2
(538 mg,735 µmol)、Cs2
CO3
(4.79 g,14.7 mmol)、DME:水=10:1 (4 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取。有機相經Na2
SO4
乾燥,過濾且真空蒸發。所得粗物質藉由矽膠管柱層析來純化。真空濃縮,產生呈黃色非晶形固體狀之4-(4-胺基-6-(2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸甲酯(1.5 g,39%)。
4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸
步驟2:向圓底燒瓶中裝入4-(4-胺基-6-(2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸甲酯(500 mg,977 μmol)、THF (10 mL)及攪拌棒。添加NaOH (2M,1 mL,1.95 mmol),且在60℃下攪拌溶液1小時。移除溶劑。將混合物溶解於水中且用1 M HCl調整至PH=2,且接著用乙酸乙酯萃取。合併有機層且在真空下移除溶劑。由此產生呈黃色非晶形固體狀之4-(4-胺基--6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯甲酸(230 mg,63%)。
(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮
步驟 3
:向圓底燒瓶中裝入(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮(210 mg,0.55 mmol)、2-乙炔基吡咯啶(95 mg,0.82 mmol)、HATU (312 mg,0.82 mmol)、DIEA (211 mg,1.64 mmol)、二甲基甲醯胺(5 mL)。在室溫下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,過濾且真空蒸發。所得粗物質藉由製備型HPLC純化(管柱:YMC-Actus Triart C18,30*250,5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:50 mL/min;梯度:35 B至53 B,歷時8分鐘;220 nm;RT1:7.03)。真空濃縮,產生呈灰白色非晶形固體狀之(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮(60 mg,24%)。
(S)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮及(R)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮
步驟 4
:外消旋(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮(60 mg,0.13 mmol)藉由對掌性HPLC來純化(管柱:CHIRAL ART纖維素-SB,4.6*100mm,3.0um;移動相:Hex (0.2% IPAmine):(EtOH:DCM=1:1)=50:50)。凍乾產生呈灰白色非晶形固體狀之(S)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮(3.9 mg,13%)及(R)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮(13.5 mg,45%)。
根據實例26之方法製備的其他化合物描繪於下表25中。表 25. 其他例示性化合物
實例27流程 24
5-溴-2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
(S)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (s, 1H), 8.24 (s, 1H), 7.53 - 7.42 (m, 3H), 7.22 (d,J = 7.8 Hz, 2H), 6.10 - 6.08 (m, 1H), 4.71 - 4.60 (m, 1H), 4.40 (s, 1H), 3.53 - 3.35 (m, 5H), 3.17 (s, 1H), 2.18 - 2.09 (m, 1H), 2.01 - 1.83 (m, 6H). | 461.35 | |
(R)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (s, 1H), 8.24 (s, 1H), 7.59 - 7.46 (m, 3H), 7.22 (d,J = 7.8 Hz, 2H), 6.09 - 6.07 (m, 1H), 4.72 - 4.60 (m, 1H), 4.39 (s, 1H), 3.53 - 3.48 (m, 5H), 3.17 (s, 1H), 2.19 - 2.11 (m, 1H), 2.01 - 1.81 (m, 6H). | 461.35 | |
(S)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 4.66 (d, J = 50.5 Hz, 1H), 4.48 (d, J = 1.1 Hz, 1H), 3.55 (s, 5H), 3.17 (d, J = 2.0 Hz, 1H), 2.09 (s, 4H), 2.03 - 1.76 (m, 3H). | 462.15 | |
(R)-(4-(4-胺基-6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 4.8 Hz, 1H), 8.26 (s, 1H), 7.53 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 7.7 Hz, 2H), 4.66 (d, J = 50.5 Hz, 1H), 4.48 (d, J = 1.1 Hz, 1H), 3.55 (s, 5H), 3.17 (d, J = 2.0 Hz, 1H), 2.09 (s, 4H), 2.03 - 1.76 (m, 3H). | 462.20 | |
(S)-(4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36 (s, 1H), 8.25 (s, 1H), 7.51 (d,J = 10.3 Hz, 2H), 7.23 (d,J = 7.7 Hz, 2H), 6.13 (s, 2H), 4.80 (s, 1H), 4.65 (d,J = 49.4 Hz, 1H), 3.51 (s, 5H), 3.17 (s, 1H), 2.43 - 1.67 (m, 7H). | 479.35 | |
(R)-(4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(2-乙炔基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.36 (s, 1H), 8.25 (s, 1H), 7.51 (d,J = 7.1 Hz, 2H), 7.23 (d,J = 7.8 Hz, 2H), 6.12 (s, 2H), 4.80 (s, 1H), 4.66 (d,J = 46.9 Hz, 1H), 3.52 (s, 5H), 3.17 (s, 1H), 2.36-1.72 (m, 7H). | 479.30 | |
4-(6-(6-乙炔基-4-甲氧基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-((1-氟環丁基) 甲基)-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.76 (s, 1H), 8.28 (t,J = 6.1 Hz, 1H), 8.20 (s, 1H), 7.69 (d,J = 7.9 Hz, 1H), 7.41 (s, 1H), 7.02 (s, 1H), 6.91 (d,J = 7.9 Hz, 1H), 4.45 (s, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.67 (d,J = 6.1 Hz, 1H), 3.62 (s, 1H), 3.60 (s, 3H), 2.40 (s, 3H), 2.23 - 2.14 (m, 4H), 1.76 (dd,J = 11.2, 7.1 Hz, 1H), 1.58 - 1.49 (m, 1H). | 514.25 |
步驟1:向可再密封之反應瓶中裝入2,5-二溴-4-甲基吡啶(3 g,11.9 mmol)、第三丁基(乙炔基)二甲基矽烷(1.82 g,13.0 mmol)、TEA (3.60 g,35.7 mmol)、CuI (452 mg,2.38 mmol)、二甲基甲醯胺(40 mL)及攪拌棒,添加Pd(PPh3)2Cl2 (834 mg,1.19 mmol),隨後抽真空且用氮氣淨化三次。在50℃下攪拌混合物2小時。反應混合物用H2O (20 mL)稀釋,且用EA (120 mL)萃取水相三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(300 g管柱;用PE/EA 50/1-20/1溶離)。真空濃縮,產生呈黃色非晶形固體狀之5-溴-2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶(3.10 g,83.9%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶
步驟 2
:向可再密封之反應瓶中裝入5-溴-2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶(3 g,9.66 mmol)、{4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}酸(2.43 g,11.5 mmol)、K3PO4 (6.12 g,28.9 mmol)、Pd(dppf)Cl2 (706 mg,966 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷/H2O (50 mL),且在70℃攪拌混合物2小時。水相用二甲基甲醯胺(100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(300 g管柱;用PE/EA 10/1溶離)。真空濃縮,產生呈橙色非晶形固體狀之2-[2-(第三丁基二甲基矽烷基)乙炔基]-5-{4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-4-甲基吡啶(1.60 g,41.7%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 3
:向可再密封之反應瓶中裝入2-[2-(第三丁基二甲基矽烷基)乙炔基]-5-{4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-4-甲基吡啶(1.5 g,3.77 mmol)、二甲基鋅(359 mg,3.77 mmol)、Pd(PPh3)4 (435 mg,377 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二甲基甲醯胺(20 mL),且在90℃下攪拌混合物1小時。反應混合物用H2O (10 mL)稀釋,且水相用EA (100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(300 g管柱;用二氯甲烷/甲醇40/1溶離)。真空濃縮,產生呈灰白色非晶形固體狀之2-[2-(第三丁基二甲基矽烷基)乙炔基]-5-{4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-4-甲基吡啶(1.2 g,84.4%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-5-碘-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 4
:向圓底燒瓶中裝入2-[2-(第三丁基二甲基矽烷基)乙炔基]-5-{4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-4-甲基吡啶(1.1 g,2.92 mmol)、TFA (849 mg,8.76 mmol)、DCM (15 mL)及攪拌棒。在0℃下添加NIS (722 mg,3.21 mmol),升溫至室溫。混合物用飽和NaHSO3
水溶液淬滅直至pH至8-9,用DCM (100 mL*3)萃取,合併有機相且經Na2
SO4
乾燥,真空濃縮,產生呈黃色非晶形固體狀之2-[2-(第三丁基二甲基矽烷基)乙炔基]-5-{5-碘-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-4-甲基吡啶(1.20 g,81.5%)。
(R)-4-(6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯
步驟 5
:向可再密封之反應瓶中裝入(1R)-6'-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯(40 mg,122 µmol)、2-[2-(第三丁基二甲基矽烷基)乙炔基]-5-{5-碘-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-4-甲基吡啶(73.3 mg,146 µmol)、K3
PO4
(25.8 mg,122 µmol)、Pd(dppf)Cl2
(89.2 mg,122 µmol)及攪拌棒,隨後抽真空且用氮氣淨化。添加DME/H2
O (2 mL),且在90℃下攪拌混合物1小時。反應混合物用H2
O (1 mL)稀釋,且水相用EA (10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(10 g管柱;用二氯甲烷/甲醇15/1溶離)。真空濃縮,產生呈黑色非晶形固體狀之(1R)-4-(6-{6-[2-(第三丁基-二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯(35 mg,49.8%)。
(R)-4-(6-(6-乙炔基-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯
步驟 6
:向圓底燒瓶中裝入(1R)-4-(6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯(30 mg,52.0 µmol)、氟化銫(23.6 mg,156 µmol)及攪拌棒。添加THF (2 mL),且在50℃下攪拌溶液2小時。過濾且蒸發。所得粗物質藉由HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm,5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:ACN;流量:60 mL/min;梯度:30 B至55 B,歷時7分鐘;220 nm;RT1:5.97;RT2)。凍乾產生呈灰白色非晶形固體狀之(1R)-4-[6-(6-乙炔基-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯(3.90 mg,16.9%)。
根據實例27之方法製備的其他化合物描繪於下表26中。表 26 . 其他例示性化合物
實例28流程 25
5-溴-2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(6-(5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-5-甲基吡啶-3-基)甲基丙烯醯胺;部分甲酸鹽 | 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.90 (d, J = 2.4 Hz, 1H), 8.78 (s, 1H), 8.23 (d, J = 4.8 Hz, 1H), 8.06 (d, J = 2.4 Hz, 1H), 7.75 (ddd, J = 8.3, 7.3, 1.5 Hz, 1H), 7.68 - 7.63 (m, 1H), 7.27 - 7.16 (m, 2H), 7.02 (dd, J = 12.6, 8.1 Hz, 2H), 6.86 (t, J = 7.4 Hz, 1H), 5.87 (t, J = 1.0 Hz, 1H), 5.60 (d, J = 1.9 Hz, 1H), 3.61 (s, 3H), 3.33 (s, 3H), 2.28 (s, 3H), 1.97 (t, J = 1.2 Hz, 3H), 1.89 (s, 3H). | 523.25 | |
(1R)-4-[6-(6-乙炔基-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.72 (s, 1H), 8.49 (d,J = 6.4 Hz, 1H), 7.69 (d,J = 4.4 Hz, 1H), 7.41 (dd,J = 7.3, 3.3 Hz, 1H), 6.68 (d,J = 7.3 Hz, 1H), 5.60 (d,J = 37.3 Hz, 1H), 4.47 (d,J = 2.1 Hz, 1H), 3.49 (s, 3H), 2.99-2.83 (m, 1H), 2.72 (s, 3H), 2.68 (p,J = 2.2 Hz, 1H), 2.47 - 2.31 (m, 2H), 2.30 (s, 3H), 2.25 (d,J = 18.4 Hz, 1H), 2.17 (d,J = 1.5 Hz, 3H), 2.12 - 1.94 (m, 1H), 1.89 (dd,J = 12.7, 6.2 Hz, 1H), 1.74 (dq,J = 14.0, 6.4 Hz, 1H). | 462.30 | |
(S)-4-(6-(6-乙炔基-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯 | 1H NMR (400 MHz, DMSO-d6) δ8.71 (s, 1H), 8.49 (d, J = 6.4 Hz, 1H), 7.69 (d, J = 4.3 Hz, 1H), 7.41 (dd, J = 7.2, 3.4 Hz, 1H), 6.68 (d, J = 7.3 Hz, 1H), 5.65 (s, 1H), 4.47 (d, J = 2.1 Hz, 1H), 3.52 - 3.47 (m, 3H), 2.91 (dd, J = 29.8, 16.2 Hz, 1H), 2.72 (s, 3H), 2.38 (d, J = 16.3 Hz, 3H), 2.30 (s, 3H), 2.27 (s, 1H), 2.19 - 2.14 (m, 3H), 2.06 (s, 1H), 1.89 (dd, J = 12.5, 6.1 Hz, 1H), 1.74 (dq, J = 14.1, 6.4 Hz, 1H). | 462.20 |
步驟 1
:向可再密封之反應瓶中裝入5-溴-2-碘-4-甲基嘧啶(600 mg,2.00 mmol)、CuI (152 mg,800 µmol)、Et3
N (606 mg,6.00 mmol)、Pd(PPh3
)2
Cl2
(280 mg,400 µmol)、DMF (15 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,添加第三丁基(乙炔基)二甲基矽烷(280 mg,2.00 mmol),且在50℃下攪拌混合物2小時。反應混合物用水(20 mL)稀釋,且水相用乙酸乙酯(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由TLC (PE:EA=8:1)來純化。真空濃縮,產生呈灰白色非晶形固體狀之5-溴-2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶(500 mg,80%)。
(2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基嘧啶-5-基)酸
步驟 2
:向可再密封之反應瓶中裝入5-溴-2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶(480 mg,1.54 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(467 mg,1.84 mmol)、AcOK (452 mg,4.62 mmol)、Pd(dppf)Cl2
(112 mg,154 µmol),添加二噁烷(10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在80℃下攪拌混合物2小時。反應混合物用水(15 mL)稀釋,且水相用EA (15 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水0%~60%,30分鐘)。凍乾產生呈灰白色非晶形固體狀之{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}酸(400 mg,94%)。
6-(2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基嘧啶-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向可再密封之反應瓶中裝入6-碘-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(520 mg,1.13 mmol)、{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}酸(380 mg,1.37 mmol)、Na2
CO3
(358 mg,3.38 mmol)、Pd(dppf)Cl2
(82.6 mg,113 µmol),添加DMF/H2O=16/1 (15 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在90℃下攪拌混合物1小時。反應混合物用水(15 mL)稀釋,且水相用DCM (15 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(DCM/MeOH=15/1)。凍乾產生呈黃色非晶形固體狀之6-{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(200 mg,34%)。
6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入6-{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(180 mg,319 µmol)、TBAF (638 µg,638 µmol)及攪拌棒。添加四氫呋喃(5 mL),且在25℃下攪拌溶液1小時。反應混合物用水(10 mL)稀釋,且水相用二氯甲烷(10 mL)萃取三次。合併之有機層用鹽水洗滌十次,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(管柱:SunFire Prep C18 OBD管柱,19×150mm 5um 10nm;移動相:水(0.05% FA),移動相B:CAN (0.1% DEA)--HPLC--;流量:25 mL/min;梯度:15 B至38 B,歷時8分鐘;220 nm;RT1:6.36)。凍乾產生呈黃色非晶形固體狀之6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(31.1 mg,21%)。
根據實例28之方法製備的其他化合物描繪於下表27中。表 27. 其他例示性化合物
實例29流程 26
6-(4-胺基苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
(4-(4-胺基-6-(2-乙炔基嘧啶-5-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 2H), 8.25 (s, 1H), 7.60 - 7.43 (m, 2H), 7.38 - 7.21 (m, 2H), 5.81 (s, 1H), 4.52 (s, 1H), 3.72 (s, 3H), 3.45 (dt, J = 17.5, 6.5 Hz, 4H), 1.85 (dq, J = 18.0, 6.8 Hz, 4H). | 424.10 | |
6-(2-乙炔基嘧啶-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (s, 2H), 8.48 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.38 - 7.31 (m, 2H), 7.28 - 7.21 (m, 2H), 7.17 (d,J = 5.0 Hz, 1H), 6.08 (s, 1H), 4.52 (s, 1H), 3.72 (s, 3H), 2.42 (s, 3H). | 435.20 | |
(4-(4-胺基-2-(6-乙炔基吡啶-3-基)-1-甲基-1H-吡咯并[2,3-b]吡啶-3-基)苯基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 - 8.41 (m, 1H), 8.24 (s, 1H), 7.84 (dd,J = 8.0, 2.3 Hz, 1H), 7.61 (dd,J = 8.1, 0.8 Hz, 1H), 7.52 (d,J = 8.1 Hz, 2H), 7.28 (d,J = 8.1 Hz, 2H), 4.44 (s, 1H), 3.66 (s, 3H), 3.44 (dt,J = 17.6, 6.4 Hz, 4H), 1.90 - 1.79 (m, 4H). | 423.10 | |
6-(6-乙炔基吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 - 8.45 (m, 2H), 8.23 (s, 1H), 7.89 (dd,J = 8.1, 2.3 Hz, 1H), 7.63 (dd,J = 8.1, 0.9 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.25 - 7.18 (m, 2H), 7.16 (d,J = 5.1 Hz, 1H), 4.44 (s, 1H), 3.66 (s, 3H), 2.42 (s, 3H). | 434.10 | |
6-(2-乙炔基-4-甲基嘧啶-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.30 - 7.23 (m, 2H), 7.23 - 7.13 (m, 3H), 6.06 (s, 2H), 4.49 (s, 1H), 3.55 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H). | 449.20 | |
6-(6-乙炔基-5-氟吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (d,J = 5.0 Hz, 1H), 8.31 (t,J = 1.6 Hz, 1H), 8.25 (s, 1H), 8.02 (dd,J = 10.0, 1.8 Hz, 1H), 7.37 - 7.29 (m, 2H), 7.28 - 7.20 (m, 2H), 7.17 (d,J = 5.0 Hz, 1H), 4.84 (d,J = 0.8 Hz, 1H), 3.71 (s, 3H), 2.42 (s, 3H). | 452.15 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.46 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.86 (d,J = 7.9 Hz, 1H), 7.50 (d,J = 7.8 Hz, 1H), 7.28 -7.21 (m, 2H), 7.21 -7.12 (m, 3H), 6.01 (s, 1H), 4.41 (s, 1H), 3.48 (s, 3H), 2.41 (s, 3H), 2.14 (s, 3H). | 448.20 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 - 8.44 (m, 2H), 8.24 (s, 1H), 7.56 (s, 1H), 7.28 - 7.21 (m, 2H), 7.21 - 7.12 (m, 3H), 4.41 (s, 1H), 3.48 (s, 3H), 2.41 (s, 3H), 2.02 (s, 3H). | 448.20 | |
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-1H-吡咯-2,5-二酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d, J = 5.2 Hz, 1H), 8.25 (s, 1H), 7.55 - 7.51 (m, 2H), 7.50 - 7.40 (m, 2H), 7.33(dd, J = 2.0 Hz, 2H), 7.31 - 7.20(m, 4H), 7.16 (d, J = 4.8 Hz, 1H), 3.65(s, 3H), 2.40(s, 3H). | 504.15 | |
6-(2-乙炔基-4-甲基嘧啶-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) 8.81 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.26 -7.16 (m, 2H), 7.08 -7.01 (m, 1H), 6.19 (s, 2H), 4.49 (s, 1H), 3.54 (s, 3H), 2.41 (s, 3H), 2.15 (s, 3H). | 467.20 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51(s, 1H), 8.47 (S, 1H), 8.24 (s, 1H), 7.58(s,1H), 7.36 - 7.30(m, 1H), 7.19 - 7.16 (m, 2H), 7.06 - 7.03 (m, 1H), 4.42 (s, 1H), 3.47 (s, 3H), 2.41 (s, 3H), 2.02 (s, 3H). | 466.20 | |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.47 (d,J = 5.0 Hz, 1H), 8.40 (s, 1H), 8.25 (s, 1H), 7.28 -7.22 (m, 2H), 7.22-7.12 (m, 3H), 4.80 (d,J = 0.8 Hz, 1H), 3.52 (s, 3H), 2.40 (s, 3H), 1.96 (d,J = 2.2 Hz, 3H). | 466.25 | |
6-(6-乙炔基-5-氟-2-甲基吡啶-3-基)-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6)8.47(d, J=5.0Hz,1H), 8.25(s,1H), 8.04(d, J = 9.3 Hz,1H), 7.30-7.23 (m,2H), 7.23-7.16 (m,2H), 7.15(d, J = 5.0Hz, 1H), 4.80(d, J=0.8Hz, 1H), 3.52 (s, 3H), 2.41(s,3H), 2.08(d, J =1.1Hz, 3H). | 466.20 | |
6-(6-乙炔基-4-甲基噠嗪-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.27 (s, 1H), 7.39 - 7.29 (m, 3H), 7.28 - 7.20 (m, 2H), 7.17 (d,J = 5.0 Hz, 1H), 6.08 (s, 2H), 4.97 (s, 1H), 3.83 (s, 3H), 2.42 (s, 3H), 2.28 (d,J = 0.9 Hz, 3H). | 449.20 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-(1-甲基-1H-吡唑-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6)8.43 (s, 1H),8.19(s, 1H),7.62(d, J = 0.7 Hz,1H), 7.57(s,1H), 7.17(d, J = 0.8 Hz,1H),6.16(s, 1H),4.41(s,1H),3.79(s,3H),3.43(s,3H),2.02(s,3H). | 344.15 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-[4-(三氟甲氧基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR: 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.24 (s, 1H), 7.55 (s, 1H), 7.31 (q, J = 8.7 Hz, 4H), 6.05 (s, 1H), 4.41 (s, 1H), 3.47 (s, 3H), 1.97 (s, 3H). | 424.10 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(4-異丙氧基苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.44 (s, 1H), 8.21 (s, 1H), 7.53 (s, 1H), 7.12-7.04 (m, 2H), 6.91-6.84 (m, 2H), 5.95 (s, 2H), 4.58 (hept,J = 6.0 Hz, 1H), 4.39 (s, 1H), 3.46 (s, 3H), 1.98 (s, 3H), 1.25 (d,J = 6.0 Hz, 6H). | 398.30 | |
6-(4-乙炔基-3-氟苯基)-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.40 (d,J = 5.6 Hz, 2H), 7.32 (s, 1H), 7.29 (s, 2H), 7.25 - 7.20 (m, 2H), 7.05 (d,J = 1.6 Hz, 1H), 7.04 - 7.02 (m, 1H), 6.95 (d,J = 5.0 Hz, 1H), 5.13 (s, 2H), 3.77 (s, 3H), 3.39 (s, 1H), 2.53 (s, 3H). | 451.05 | |
6-(6-乙炔基-5-甲氧基吡啶-3-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.45 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.09 (d,J = 1.7 Hz, 1H), 7.45 (d,J = 1.7 Hz, 1H), 7.35 - 7.26 (m, 2H), 7.25 - 7.17 (m, 2H), 7.14 (d,J = 5.0 Hz, 1H), 4.50 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 2.40 (s, 3H). | 464.05 | |
6-(4-乙炔基-3,5-二氟苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d6) 8.48 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.36-7.30(m,2H), 7.28-7.21(m,4H),7.19-7.13 (m, 1H), 4.91 (s, 1H), 3.69 (s, 3H), 2.41 (s, 3H). | 469.15 | |
6-(3-乙炔基-1-甲基-1H-吡唑-5-基)-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.34-7.20 (m, 4H), 7.16 (d, J = 5.0 Hz, 1H), 6.91 (s, 1H), 4.23 (s, 1H), 3.57 (s, 3H), 3.33 (s, 3H), 2.42 (s, 3H). | 437.25 | |
6-(2-乙炔基苯并[d]噁唑-6-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.88-7.80 (m, 2H), 7.44 (dd,J = 8.3, 1.6 Hz, 1H), 7.35-7.27 (m, 2H), 7.20-7.12 (m, 3H), 5.75 (s, 1H), 5.16 (s, 1H), 3.64 (s, 3H), 2.40 (s, 3H). | 474.30 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.55 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 7.59 (t, J = 0.9 Hz, 1H), 7.38 - 7.26 (m, 2H), 7.18 (d, J = 5.0 Hz, 1H), 7.16 - 7.09 (m, 1H), 4.44 (s, 1H), 3.56 (s, 3H), 2.41 (d, J = 8.9 Hz, 6H), 2.06 (s, 3H). | 465.15 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d,J = 5.0 Hz, 1H), 8.40 (s, 1H), 8.24 (s, 1H), 7.56 (d,J = 7.9 Hz, 1H), 7.45 - 7.24 (m, 1H), 7.23 - 7.14 (m, 2H), 7.07 (dd,J = 8.4, 2.3 Hz, 1H), 6.01 (m, 2H), 4.40 (s, 1H), 3.49 (s, 3H), 2.42 (s, 3H), 2.06 (d,J = 19.2 Hz, 3H). | 466.20 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d = 4.8 Hz, 1H), 8.24 (s, 1H), 7.75 (d,J = 7.6 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.31 (m, 1H), 7.18 (m, 2H), 7.12 - 7.01 (m, 1H), 6.01 (m, 2H), 4.40 (s, 1H), 3.49 (s, 3H), 2.42 (s, 3H), 2.18 (m, 3H). | 466.15 | |
6-(6-乙炔基-4-氟吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (d,J = 10.1 Hz, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.76 (d,J = 10.0 Hz, 1H), 7.35 (d,J = 8.4 Hz, 1H), 7.27 - 7.23 (m, 1H), 7.23 - 7.17 (m, 1H), 7.10 - 6.99 (m, 1H), 6.17 (s, 1H), 4.63 (s, 1H), 3.63 - 3.56 (m, 3H), 2.42 (s, 3H). | 470.10 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.20 - 7.11 (m, 2H), 7.06 - 6.99 (m, 1H), 6.13 (s, 1H), 4.42 (s, 1H), 4.42 (s, 5H), 3.47 (s, 1H), 2.41 (s, 1H), 2.14 (s, 1H), | 466.15 | |
2-{4-[6-(6-乙炔基-2-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]-2-氟苯氧基}-4-甲基嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.78 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 7.91 (d,J = 7.8 Hz, 1H), 7.54 (d,J = 7.9 Hz, 1H), 7.37 - 7.27 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.12 (d,J = 8.2 Hz, 1H), 4.44 (s, 1H), 3.57 (s, 3H), 2.44 (s, 3H), 2.41 (s, 3H), 2.19 (s, 3H). | 465.25 | |
(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)甲醇 | 1H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J = 0.8 Hz, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.67 (s, 1H), 7.34 (t, J = 8.4 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.06 (dd, J = 9.3, 1.6 Hz, 1H), 5.48 (t, J = 5.7 Hz, 1H), 4.46 (s, 1H), 4.25 (dd, J = 15.7, 5.8 Hz, 1H), 4.03 (dd, J = 15.6, 5.9 Hz, 1H), 3.46 (s, 3H), 2.41 (s, 3H). | 482.15 | |
6-(4-((二甲基胺基)甲基)-6-乙炔基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 0.8 Hz, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.66 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.19 - 7.13 (m, 2H), 4.46 (s, 1H), 3.46 (s, 3H), 3.23 (d, J = 15.1 Hz, 1H), 2.85 (d, J = 15.2 Hz, 1H), 2.40 (s, 3H), 1.97 (s, 6H). | 509.40 | |
6-(4-(二氟甲基)-6-乙炔基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d6) 8.81 (d, J = 0.9 Hz, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.82 (s, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.24 -7.11 (m, 2H), 7.03 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 6.73 (s, 1H), 6.12 (s, 1H), 4.62 (s, 1H), 3.46 (s, 3H), 2.37 (s, 3H). | 502.15 | |
6-(2-乙基-6-乙炔基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.20 - 7.05 (m, 2H), 6.99 (d, J = 8.2 Hz, 1H), 6.11 (s, 1H), 4.38 (s, 1H), 3.35 (s, 3H), 2.42 - 2.21 (m, 4H), 0.90 (t, J = 7.5 Hz, 3H). | 480.15 | |
6-(4-乙基-6-乙炔基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.58 (s, 1H), 7.33 (t,J = 8.4 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.04 (d,J = 8.3 Hz, 1H), 6.13 (s, 1H), 4.44 (s, 1H), 3.46 (s, 3H), 2.39 (d,J = 10.2 Hz, 4H), 2.22 (dt,J = 14.9, 7.6 Hz, 1H), 0.91 (t,J = 7.5 Hz, 3H). | 480.30 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.56 (s, 1H), 7.31 (t, J = 8.4 Hz, 1H), 7.22 - 7.11 (m, 2H), 7.03 (d, J = 8.6 Hz, 1H), 6.08 (s, 2H), 4.43 (s, 1H), 4.11 - 4.00 (m, 1H), 2.41 (s, 3H), 2.06 (d, J = 14.2 Hz, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.50 (d, J = 6.7 Hz, 3H). | 494.20 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.56 (s, 1H), 7.31 (t,J = 8.4 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.04 (dd,J = 8.2, 2.1 Hz, 1H), 6.10 (s, 1H), 4.42 (s, 1H), 4.07 (p,J = 6.8 Hz, 1H), 2.41 (s, 3H), 2.04 (s, 3H), 1.62 (d,J = 6.8 Hz, 3H), 1.50 (d,J = 6.8 Hz, 3H). | 494.35 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.56 (s, 1H), 7.31 (t,J = 8.4 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.04 (dt,J = 8.3, 1.4 Hz, 1H), 6.09 (s, 1H), 4.42 (s, 1H), 4.07 (p,J = 6.8 Hz, 1H), 2.41 (s, 3H), 2.04 (s, 3H), 1.62 (d,J = 6.8 Hz, 3H), 1.50 (d,J = 6.8 Hz, 3H). | 494.35 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.22 - 7.10 (m, 2H), 7.02 (d, J = 8.6 Hz, 1H), 6.10 (s, 1H),4.43 (s, 1H), 4.13 - 4.02 (m, 1H), 2.41 (s, 3H), 2.16 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H), 1.50 (d, J = 6.8 Hz, 3H). | 494.20 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.89 (d,J = 7.9 Hz, 1H), 7.52 (dd,J = 7.9, 0.7 Hz, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.21 - 7.11 (m, 2H), 7.02 (ddd,J = 8.3, 2.1, 0.9 Hz, 1H), 6.04 (s, 2H), 4.42 (s, 1H), 4.08 (p,J = 6.7 Hz, 1H), 2.41 (s, 3H), 2.16 (s, 3H), 1.62 (d,J = 6.8 Hz, 3H), 1.50 (d,J = 6.8 Hz, 3H). | 494.35 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.89 (d,J = 7.8 Hz, 1H), 7.53 (d,J = 7.9 Hz, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.21 - 7.12 (m, 2H), 7.02 (d,J = 8.1 Hz, 1H), 6.04 (s, 1H) 4.42 (s, 1H), 4.08 (t,J = 6.8 Hz, 1H), 2.41 (s, 3H), 2.16 (s, 3H), 1.62 (d,J = 6.8 Hz, 3H), 1.50 (d,J = 6.8 Hz, 3H) | 494.35 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-(嘧啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 4.8 Hz, 2H), 8.52 (s, 1H), 8.27 (d, J = 2.7 Hz, 1H), 7.59 (s, 1H), 7.41 -7.29 (m, 2H), 7.19 -7.06 (m, J = 8.3 Hz, 2H), 6.15 (s, 1H),4.43 (s, 1H), 3.47 (s, 3H), 2.04 (s, 3H). | 452.15 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((6-甲基吡啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.22 (s, 1H), 7.71 (dd, J = 8.2, 7.3 Hz, 1H), 7.53 (d, J = 0.8 Hz, 1H), 7.22 (t, J = 8.4 Hz, 1H), 7.10 (dd, J = 11.5, 2.0 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.97 (d, J = 3.4 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.15 (s, 2H), 4.39 (s, 1H), 3.46 (s, 3H), 2.26 (s, 3H), 1.97 (s, 3H). | 465.35 | |
6-(2-乙炔基吡啶-4-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (300 MHz, DMSO-d6) δ 8.60 (dd, J = 5.2, 0.9 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.53 (t, J = 1.3 Hz, 1H), 7.46 - 6.99 (m, 5H), 4.39 (s, 1H), 3.68 (s, 3H), 2.43 (s, 3H). | 452.15 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((1-甲基-1H-吡唑-3-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.20 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 0.9 Hz, 1H), 7.17 - 7.04 (m, 2H), 6.92 (dt, J = 8.4, 1.5 Hz, 1H), 6.10 (s, 1H), 5.82 (d, J = 2.3 Hz, 1H), 4.39 (s, 1H), 3.70 (s, 3H), 3.43 (s, 3H), 1.97 (s, 3H). | 454.10 | |
6-(1-乙炔基異喹啉-4-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.61 (s, 1H), 8.48 - 8.37 (m, 2H), 8.29 (s, 1H), 7.87 - 7.80 (m, 2H), 7.63 - 7.56 (m, 1H), 7.26 - 7.17 (m, 2H), 7.14 (d,J = 5.1 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.15 (s, 1H), 4.97 (s, 1H), 3.43 (s, 3H), 2.36 (s, 3H). | 502.20 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.58 (d,J = 2.7 Hz, 1H), 8.50 (s, 1H), 8.43 (d,J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.70 (s, 1H), 7.46 (dd,J = 8.8, 2.8 Hz, 1H), 7.15 (d,J = 5.1 Hz, 1H), 6.92 (d,J = 8.7 Hz, 1H), 4.58 (s, 1H), 3.55 (s, 3H), 2.48 (s, 3H), 2.17 (s, 3H). | 449.30 | |
6-(4-氯-6-乙炔基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 7.35 (s, 1H), 7.23 - 7.15 (m, 2H), 7.09 - 6.99 (m, 1H), 6.18 (s, 1H), 4.63 (s, 1H), 3.53 (s, 3H), 2.42 (s, 3H). | 486.25 | |
6-(6-乙炔基-5-氟-4-甲氧基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ8.48 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 7.38-7.34 (m, 1H), 7.23-7.18 (m, 2H), 7.08-7.05 (m, 1H), 6.13 (s, 1H), 4.84 (d,J = 1.0 Hz, 1H), 3.91 (d,J = 4.5 Hz, 3H), 3.56 (s, 3H), 2.51 (s, 3H). | 500.15 | |
4-(4-胺基-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟-N-異丁基苯甲醯胺 | 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 8.23 (s, 2H), 7.51 (t,J = 7.9 Hz, 1H), 7.10-6.98 (m, 2H), 6.16 (s, 1H), 4.79 (d,J = 0.8 Hz, 1H), 3.48 (s, 3H), 3.09-2.98 (m, 2H), 1.95 (d,J = 2.1 Hz, 3H), 1.79 (dp,J = 13.4, 6.7 Hz, 1H), 0.86 (d,J = 6.7 Hz, 6H). | 475.30 | |
5-(3-氯-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J = 5.0 Hz, 1H), 8.44 (s, 1H), 8.26 (s, 1H), 7.38 (s, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.22 - 7.13 (m, 2H), 6.18 (s, 2H), 4.81 (d, J = 0.8 Hz, 1H), 3.52 (s, 3H), 2.41 (s, 3H), 1.96 (d, J = 2.1 Hz, 3H). | 500.15 | |
2-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)乙-1-醇 | 1 H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.54 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.22 - 7.09 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.14 (s, 1H), 4.79 (t, J = 5.6 Hz, 1H), 4.42 (s, 1H), 4.09 (dd, J = 13.3, 6.5 Hz, 1H), 3.85 (dt, J = 13.5, 6.2 Hz, 1H), 3.52 (q, J = 6.0 Hz, 2H), 2.41 (s, 3H), 1.97 (s, 3H). | 496.30 | |
(1S,3r)-3-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-7-基)環丁-1-醇 | 1H NMR (400 MHz, 氯仿-d) δ 8.44 (s, 1H), 8.41 - 8.33 (m, 2H), 7.42 (s, 1H), 7.28 (s, 2H), 7.23 (t, J = 8.2 Hz, 1H), 7.04 - 6.92 (m, 3H), 6.19 (s, 1H), 5.22 (s, 2H), 4.23 - 4.14 (m, 1H), 4.10 (p, J = 7.4 Hz, 1H), 3.24 (s, 1H), 3.03 (dt, J = 10.6, 6.5 Hz, 4H), 2.51 (s, 3H), 2.04 (s, 3H). | 522.20 | |
5-(3-氯-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.58 (s, 1H), 7.41 -7.27 (m, 2H), 7.25 - 7.13 (m, 2H),6.14-6.11(m,1H), 4.43 (s, 1H), 3.47 (s, 3H), 2.42 (s, 3H), 2.02 (s, 3H). | 482.15 | |
5-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-((4-甲基嘧啶-2-基)氧基)苯甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (d,J = 5.1 Hz, 2H), 8.25 (s, 1H), 7.70 (d,J = 2.2 Hz, 1H), 7.58 (d,J = 0.8 Hz, 1H), 7.49 (dd,J = 8.6, 2.3 Hz, 1H), 7.40 (d,J = 8.6 Hz, 1H), 7.25 (d,J = 5.1 Hz, 1H), 6.21 (s, 2H), 4.43 (s, 1H), 3.47 (s, 3H), 2.44 (s, 3H), 2.01 (s, 3H). | 473.20 | |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-5-{2-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d,J = 5.0 Hz, 1H), 8.32 (d,J = 6.6 Hz, 1H), 8.25 (s, 1H), 7.35 (t,J = 8.6 Hz, 1H), 7.26 - 7.16 (m, 2H), 7.12 - 7.02 (m, 1H), 6.08 (s, 1H), 4.79 (d,J = 0.8 Hz, 1H), 3.54 (s, 3H), 2.41 (s, 3H), 2.00 (d,J = 24.8 Hz, 3H). | 484.30 | |
6-(6-乙炔基-4-氟吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.80 (s, 1H), 8.65 (d,J = 10.0 Hz, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.79 (d,J = 10.0 Hz, 1H), 7.43 - 7.30 (m, 2H), 7.17 (dd,J = 12.6, 6.7 Hz, 2H), 4.64 (s, 1H), 3.70 (s, 3H), 2.41 (d,J = 2.9 Hz, 6H). | 469.30 | |
5-{4-[(4,6-二甲基嘧啶-2-基)氧基]-3-氟苯基}-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (d,J = 0.7 Hz, 1H), 8.24 (s, 1H), 7.56 (t,J = 0.8 Hz, 1H), 7.30 (t,J = 8.4 Hz, 1H), 7.14 (dd,J = 11.4, 2.0 Hz, 1H), 7.07 - 6.99 (m, 2H), 6.16 (s, 1H), 4.42 (s, 1H), 3.49 (s, 3H), 2.33 (s, 6H), 2.00 (s, 3H). | 480.35 | |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.42 (s, 1H), 8.22 (s, 1H), 7.31 (t,J = 8.4 Hz, 1H), 7.22 - 7.14 (m, 2H), 7.02 (ddd,J = 8.4, 2.3, 0.9 Hz, 1H), 6.09 (s, 2H), 4.82 (d,J = 0.7 Hz, 1H), 4.13 (p,J = 6.7 Hz, 1H), 2.39 (s, 3H), 1.99 (d,J = 2.1 Hz, 3H), 1.61 (d,J = 6.8 Hz, 3H), 1.51 (d,J = 6.7 Hz, 3H). | 512.35 | |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體1 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.42 (d,J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.23 (s, 1H), 7.29 (t,J = 8.2 Hz, 1H), 7.19 - 7.05 (m, 3H), 4.29 (p,J = 6.9 Hz, 1H), 4.19 (d,J = 0.8 Hz, 1H), 2.49 (s, 3H), 2.10 (d,J = 2.2 Hz, 3H), 1.72 (s, 3H), 1.60 (d,J = 6.8 Hz, 3H). | 512.35 |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-異丙基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (d,J = 5.0 Hz, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.22 - 7.13 (m, 2H), 7.02 (dd,J = 8.3, 2.1 Hz, 1H), 5.93 (d,J = 130.2 Hz, 1H), 4.82 (s, 1H), 4.14 (p,J = 6.7 Hz, 1H), 2.40 (s, 3H), 2.00 (d,J = 2.1 Hz, 3H), 1.62 (d,J = 6.8 Hz, 3H), 1.51 (d,J = 6.8 Hz, 3H). | 512.40 |
6-(6-乙炔基-4,5-二甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.33 (s, 1H), 8.24 (s, 1H), 7.32 (t,J = 8.4 Hz, 1H), 7.21 - 7.13 (m, 2H), 7.07 - 6.99 (m, 1H), 6.14 (s, 1H), 4.58 (s, 1H), 3.44 (s, 3H), 2.40 (d,J = 3.2 Hz, 6H), 2.00 (s, 3H). | 480.30 | |
6-(6-乙炔基-5-甲氧基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d6) δ8.79 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.18 (d, J = 1.7 Hz, 1H), 7.57 (d, J = 1.7 Hz, 1H), 7.41- 7.36 (m, 2H), 7.22 -7.14 (m, 2H), 4.56 (s, 1H), 3.80 (s, 6H), 2.41 (d, J = 6.3 Hz, 6H). | 481.20 | |
6-(2-乙炔基喹喏啉-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ9.04 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.16 (d,J = 1.8 Hz, 1H), 8.08 (d,J = 8.7 Hz, 1H), 7.85 (dd,J = 8.6, 2.0 Hz, 1H), 7.38-7.24 (m, 2H), 7.20-7.11 (m, 2H), 4.90 (s, 1H), 3.71 (s, 3H), 2.38 (s, 3H), 1.15 (s, 1H). | 503.15 | |
6-(2-乙炔基喹唑啉-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 2H), 8.05 - 7.91 (m, 2H), 7.35 - 7.21 (m, 2H), 7.20 - 7.09 (m, 2H), 6.12 (s, 2H), 4.51 (s, 1H), 3.70 (s, 3H), 2.38 (s, 3H). | 503.15 | |
6-(3-乙炔基喹喏啉-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.15 - 8.08 (m, 2H), 7.83 (dd, J = 8.6, 1.9 Hz, 1H), 7.33 (t, J = 8.3 Hz, 1H), 7.28 (dd, J = 11.4, 2.0 Hz, 1H), 7.18 - 7.12 (m, 2H), 6.10 (s, 2H), 4.88 (s, 1H), 3.71 (s, 3H), 2.38 (s, 3H). | 503.15 | |
6-(2-乙炔基喹唑啉-7-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.62 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.20 (d,J = 8.4 Hz, 1H), 8.04 (s, 1H), 7.74 (dd,J = 8.4, 1.7 Hz, 1H), 7.38 - 7.24 (m, 2H), 7.20 - 7.10 (m, 2H), 6.12 (s, 1H), 4.49 (s, 1H), 3.71 (s, 3H), 2.38 (s, 3H). | 503.35 | |
2'-乙炔基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7,7'-二甲基-7H,7'H-[6,6'-聯吡咯并[2,3-d]嘧啶]-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 )9.07 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.29 (s, 1H), 7.34 (t,J = 8.2 Hz, 1H), 7.25 (d,J = 11.2 Hz, 1H), 7.18 (d,J = 5.1 Hz, 1H), 7.10 (d,J = 11.7 Hz, 2H), 4.25 (s, 1H), 3.62 (s, 3H), 3.31 (s, 3H), 2.41 (s, 3H). | 506.20 | |
6-(2-乙炔基-5-甲基-5H-吡咯并[3,2-d]嘧啶-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.30 (s, 1H), 7.34 (t,J = 8.4 Hz, 1H), 7.26 (dd,J = 11.3, 2.1 Hz, 1H), 7.18 (d,J = 5.0 Hz, 1H), 7.11 (dd,J = 7.9, 1.9 Hz, 1H), 7.07 (s, 1H), 4.11 (s, 1H), 3.63 (s, 3H), 3.46 (s, 3H), 2.40 (s, 3H). | 506.25 | |
6-(2-乙炔基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ13.36 (d,J = 16.4 Hz, 1H), 8.75 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 7.77-7.67 (m, 1H), 7.53 (d,J = 9.6 Hz, 1H), 7.38 -7.23 (m, 3H), 7.17 (d,J = 5.0 Hz, 2H), 4.72 (s, 1H), 3.69 (d,J = 3.6 Hz, 3H), 2.38 (q,J = 2.0 Hz, 6H). | 490.30 | |
6-(6-乙炔基-5-甲氧基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 )8.79 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.35 (s, 1H), 7.38-7.27 (m, 2H), 7.18 (d,J = 5.0 Hz, 1H), 7.11 (dd,J = 8.4, 2.0 Hz, 1H), 4.64 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H), 2.44 (s, 3H), 2.40 (s, 3H), 1.97 (s, 3H). | 495.20 | |
6-(6-乙炔基-4-甲氧基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.77 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.29 (s, 1H), 7.42 (s, 1H), 7.36 - 7.27 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.14 - 7.07 (m, 1H), 4.48 (s, 1H), 3.87 (s, 3H), 3.61 (s, 3H), 2.41 (s, 6H). | 481.15 | |
6-(2-乙炔基喹啉-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 5.0 Hz, 1H), 8.40 (d,J = 8.5 Hz, 1H), 8.26 (s, 1H), 8.09 (d,J = 2.0 Hz, 1H), 8.00 (d,J = 8.7 Hz, 1H), 7.74 (dd,J = 8.8, 2.0 Hz, 1H), 7.69 (d,J = 8.4 Hz, 1H), 7.32 (t,J = 8.3 Hz, 1H), 7.24 (dd,J = 11.3, 2.0 Hz, 1H), 7.17 (d,J = 5.1 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.08 (s, 1H), 4.56 (s, 1H), 3.69 (s, 3H), 2.39 (s, 3H). | 502.20 | |
6-(2-乙炔基喹啉-7-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) 8.48 -8.41 (m, 2H), 8.26 (s, 1H), 8.04 (dd, J = 5.1, 3.3 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.60 (dd, J = 8.5, 1.6 Hz, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.26 (dd, J = 11.3, 2.0 Hz, 1H), 7.19 -7.11 (m, 2H), 6.08 (s, 1H), 4.54 (s, 1H), 3.69 (s, 3H), 2.38 (s, 3H). | 502.20 | |
6-(3-乙炔基異喹啉-7-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.45 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 8.5, 1.7 Hz, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.24 (dd, J = 11.4, 2.1 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.12 (dd, J = 8.4, 2.0 Hz, 1H), 4.39 (s, 1H), 3.69 (s, 3H), 2.39 (s, 3H) | 502.35 | |
6-(3-乙炔基異喹啉-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 15.7 Hz, 2H), 7.69 (dd, J = 8.7, 1.5 Hz, 1H), 7.32 (t, J = 8.3 Hz, 1H), 7.24 (d, J = 11.0 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 7.14 - 7.08 (m, 1H),6.2-5.4(s,1H), 4.37 (s, 1H), 3.69 (s, 3H), 2.39 (s, 3H). | 502.25 | |
2-乙炔基-6-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)喹喏啉 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.06 (s, 1H), 8.81 (s, 1H), 8.46 (d,J = 5.0 Hz, 1H), 8.24 (d,J = 1.9 Hz, 1H), 8.13 (d,J = 8.7 Hz, 1H), 7.92 (dd,J = 8.7, 2.0 Hz, 1H), 7.43 (dd,J = 11.3, 2.0 Hz, 1H), 7.31 (t,J = 8.3 Hz, 1H), 7.24 - 7.14 (m, 2H), 4.91 (s, 1H), 3.81 (s, 3H), 2.42 (s, 3H), 2.38 (s, 3H). | 502.35 | |
6-(3-乙炔基喹啉-7-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.93 (d,J = 2.1 Hz, 1H), 8.61 (d,J = 2.1 Hz, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.09 - 8.00 (m, 2H), 7.63 (dd,J = 8.5, 1.7 Hz, 1H), 7.36-7.24 (m, 2H), 7.21-7.11 (m, 2H), 6.07 (s, 2H), 4.58 (s, 1H), 3.69 (s, 3H), 2.38 (s, 3H). | 502.20 | |
6-(7-乙炔基-1,8-㖠啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) 8.96 (d, J = 2.5 Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 5.1 Hz, 1H), 8.30 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.39 - 7.27 (m, 2H), 7.21 - 7.11 (m, 2H), 6.00-6.72(s,1H), 4.70 (s, 1H), 3.75 (s, 3H), 2.40 (s, 3H). | 503.25 | |
6-(6-(乙炔基-d)-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (s, 1H), 8.47 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.58 (d,J = 0.8 Hz, 1H), 7.33 (t,J = 8.4 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.07 - 7.01 (m, 1H), 6.14 (s, 1H), 3.47 (s, 3H), 2.41 (s, 3H), 2.02 (s, 3H). | 467.20 | |
6-(2-乙炔基-7-甲基喹喏啉-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.00 (s, 1H), 8.42 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 7.30 - 7.20 (m, 2H), 7.15 (d,J = 5.1 Hz, 1H), 7.10 (dd,J = 8.4, 2.0 Hz, 1H), 6.12 (s, 1H), 4.88 (s, 1H), 3.48 (s, 3H), 2.35 (s, 3H), 2.23 (s, 3H). | 517.20 | |
4-(二氟甲基)-6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶 | 1H NMR (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.44 (s, 1H), 7.56 (dd, J = 11.2, 2.0 Hz, 1H), 7.50 -7.41 (m, 2H), 7.28 (ddd, J = 8.3, 2.1, 0.9 Hz, 1H), 7.21 (d, J = 5.1 Hz, 1H), 6.73 (s, 1H), 4.34 (s, 1H), 3.84 (s, 3H), 2.42 (s, 3H), 1.96 (s, 3H). | 501.15 | |
6-(6-乙炔基-4-甲氧基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.22 (d, J = 1.6 Hz, 2H), 7.39 (s, 1H), 7.33 (t, J = 8.4 Hz, 1H), 7.22 - 7.12 (m, 2H), 7.03 (d, J = 7.9 Hz, 1H), 6.07 (s, 2H), 4.45 (s, 1H), 3.85 (s, 3H), 3.51 (s, 3H), 2.42 (s, 3H). | 482.15 |
步驟 1
:向圓底燒瓶中裝入6-碘-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(5 g,10.9 mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯胺(3.1 g,14.2 mmol)、Pd(dppf)Cl2 (804 mg,1.1 mmol)、K3PO4 (6.9 g,32.7 mmol)、DMF/H2O (16:1,50 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。冷卻後,混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,殘餘物用ACN (50 mL)溶解且過濾,濾餅用ACN洗滌,在減壓下乾燥,得到呈灰白色固體狀之6-(4-胺基苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(3 g,65%)。
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-側氧基吡咯啶-3-甲酸
步驟 2
:向圓底燒瓶中裝入6-(4-胺基苯基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(3 g,7 mmol)、6,6-二甲基-5,7-二氧雜螺[2.5]辛烷-4,8-二酮(2.38 g,14 mmol)、EtOH (50 mL)及攪拌棒。在90℃下攪拌混合物隔夜。真空蒸發溶劑,殘餘物用EA (50 mL)洗滌且過濾,濾餅用ACN洗滌,在減壓下乾燥,得到呈灰白色固體狀之1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-側氧基吡咯啶-3-甲酸(2 g,53%)。
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮
步驟 3
:向圓底燒瓶中裝入1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-2-側氧基吡咯啶-3-甲酸(2 g,3.73 mmol)、HCHO水溶液(0.46 g,5.6 mmol)、二乙胺(0.54 g,7.46 mmol)及DMF (30 mL)、攪拌棒。在90℃下攪拌混合物2小時。冷卻後,混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空蒸發,殘餘物藉由矽膠管柱層析(用DCM/MeOH (50:1~10:1)溶離)來純化。藉由製備型HPLC純化粗產物,得到呈灰白色固體狀的1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮(150 mg)。
根據實例29之方法製備的其他化合物描繪於下表28中。表 28. 其他例示性化合物
實例30流程 27
(S)-1-(4-氯苯基)-5-甲基吡咯啶-2-酮
化合物 | 結構 | 質子 NMR | MS [M+1] | |
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.41 (d,J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.84 (t,J = 8.0 Hz, 2H), 7.44 - 7.34 (m, 4H), 7.20 - 7.11 (m, 3H), 6.06 (s, 1H), 5.53 (d,J = 2.7 Hz, 1H), 4.45 (d,J = 2.8 Hz, 1H), 3.97 (t,J = 6.9 Hz, 1H), 3.72 (s, 3H), 2.97 (s, 1H), 2.50 (s, 3H), 1.94 (d,J = 2.1 Hz, 1H), 1.32 (t,J = 7.3 Hz, 1H). | 504.20 | ||
(R)-1-(3-氯-4-(4,7-二甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.23 (dd, J = 4.9, 2.2 Hz, 1H), 7.86 (ddd, J = 8.6, 2.3, 1.4 Hz, 1H), 7.54 (dd, J = 9.6, 8.5 Hz, 1H), 5.98 (td, J = 2.8, 1.0 Hz, 1H), 5.69 (dd, J = 9.5, 4.3 Hz, 1H), 5.55 (dt, J = 3.0, 1.5 Hz, 1H), 3.96 (qt, J = 9.7, 4.9 Hz, 2H), 3.50 (d, J = 6.3 Hz, 3H), 3.43 (td, J = 6.7, 5.1 Hz, 2H), 3.26 (t, J = 6.8 Hz, 2H), 2.91 (tt, J = 5.9, 2.6 Hz, 2H), 2.67 (d, J = 1.5 Hz, 3H), 2.36 - 1.69 (m, 10H), 1.48 (ddt, J = 29.8, 12.3, 6.6 Hz, 1H). | 530.25 | ||
(S)-1-(3-氯-4-(4,7-二甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.23 (dd, J = 4.9, 2.2 Hz, 1H), 7.86 (ddd, J = 8.5, 2.3, 1.4 Hz, 1H), 7.54 (dd, J = 9.6, 8.5 Hz, 1H), 5.98 (td, J = 2.8, 1.0 Hz, 1H), 5.69 (dd, J = 10.6, 4.1 Hz, 1H), 5.55 (td, J = 2.6, 1.0 Hz, 1H), 3.96 (qt, J = 9.7, 4.9 Hz, 2H), 3.50 (d, J = 6.3 Hz, 3H), 3.47 - 3.39 (m, 2H), 3.26 (t, J = 6.9 Hz, 2H), 2.96 - 2.86 (m, 2H), 2.67 (d, J = 1.6 Hz, 3H), 2.29 - 1.69 (m, 10H), 1.46 (dtt, J = 29.5, 12.2, 6.7 Hz, 1H). | 530.25 | ||
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (s, 1H), 8.22 (s, 1H), 7.76 - 7.72 (m, 2H), 7.40(d, J = 8.4Hz, 1H), 7.26 (t, J= 8.4Hz, 2H), 7.16 - 7.13(m, 3H), 5.92 (s, 1H), 5.77 (s, 1H), 3.90 (t, J = 13.6 Hz, 2H), 3.43 (s, 3H), 2.87 (t, J = 13.6 Hz, 2H), 2.40 (s, 3H), 2.01 (s, 3H). | 518.20 | ||
1-(4-(5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)-3-亞甲基吡咯啶-2-酮 | 1H NMR: 1H NMR (400 MHz, DMSO-d6) 8.75 (s, 1H), 8.47 (d, J = 5.0 Hz, 1H), 7.82-7.73 (m, 2H), 7.45 (d, J = 8.4 Hz, 1H), 7.35-7.25 (m, 2H), 7.20-7.11 (m, 2H), 5.96-5.90 (m, 1H), 5.52-5.47 (m, 1H), 3.90 (t, J = 6.8 Hz, 2H), 3.52 (s, 3H), 2.88 (d, J = 14.1 Hz, 0H), 2.88 (s, 2H), 2.41 (d, J = 6.4 Hz, 6H), 2.05 (s, 3H). | 535.40 | ||
1-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.89 - 7.84 (m, 2H), 7.48 - 7.40 (m, 2H), 7.35 (t,J = 8.4 Hz, 1H), 7.24 - 7.07 (m, 3H), 5.93 (dt,J = 2.8, 1.7 Hz, 1H), 5.49 (dt,J = 3.0, 1.5 Hz, 1H), 3.90 (t,J = 6.9 Hz, 2H), 3.61 (s, 3H), 2.88 (dt,J = 7.1, 3.6 Hz, 2H), 2.42 (s, 3H). | 522.20 | ||
(R)-1-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (d,J = 16.6 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.60 - 7.50 (m, 2H), 6.55 (s, 1H), 5.94 (q,J = 2.4 Hz, 1H), 5.78 (d,J = 3.7 Hz, 1H), 5.50 (q,J = 1.9 Hz, 1H), 3.94 (t,J = 6.9 Hz, 2H), 3.59 (s, 3H), 3.51 (dt,J = 10.1, 6.7 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.32 - 3.26 (m, 1H), 3.25 (d,J = 5.6 Hz, 1H), 2.91 (d,J = 6.8 Hz, 2H), 2.84 (t,J = 5.8 Hz, 1H), 2.36 - 2.17 (m, 2H), 1.88 (dd,J = 13.4, 6.7 Hz, 4H), 1.76 (p,J = 6.8 Hz, 2H), 1.64 (d,J = 6.0 Hz, 2H). | 497.20 | ||
(S)-1-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (d,J = 14.7 Hz, 1H), 7.98 - 7.87 (m, 2H), 7.61 - 7.53 (m, 2H), 7.05 (d,J = 26.7 Hz, 1H), 5.94 (td,J = 2.8, 1.1 Hz, 1H), 5.86 - 5.73 (m, 1H), 5.51 (td,J = 2.5, 1.0 Hz, 1H), 3.94 (t,J = 6.9 Hz, 2H), 3.62 (s, 3H), 3.52 (dt,J = 10.1, 6.6 Hz, 1H), 3.43 (dt,J = 10.0, 6.8 Hz, 1H), 3.30 (d,J = 7.0 Hz, 1H), 3.28 - 3.21 (m, 1H), 2.95 - 2.80 (m, 3H), 2.38 - 2.15 (m, 2H), 1.88 (h,J = 6.5, 5.6 Hz, 4H), 1.81 - 1.55 (m, 4H). | 497.15 | ||
步驟 1
:向可再密封之反應瓶中裝入(5S)-5-甲基吡咯啶-2-酮(1 g,10.0 mmol)、1-氯-4-碘苯(3.57 g,15.0 mmol)、N1,N2-二甲基乙烷-1,2-二胺(196 mg,2.00 mmol)、CuI (191 mg,1.00 mmol)、CsF (9.78 g,30.00 mmol)、THF (10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在25℃下攪拌混合物隔夜。反應混合物用H2
O (10 mL)稀釋,且水相用EtOAc (10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。藉由矽膠管柱層析來純化殘餘物。由此產生(S)-1-(4-氯苯基)-5-甲基吡咯啶-2-酮(1.91 g,91%)。
2-((5S)-1-(4-氯苯基)-5-甲基-2-側氧基吡咯啶-3-基)-2-側氧基乙酸乙酯
步驟 2
:向可再密封之反應瓶中裝入(5S)-1-(4-氯苯基)-5-甲基吡咯啶-2-酮(1 g,4.76 mmol)、乙二酸二乙酯(764 mg,5.23 mmol)、NaH (228 mg,9.52 mmol)、THF (10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在80℃下攪拌混合物2小時。反應混合物用H2O (10 mL)淬滅,且水相用EtOAc (20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。藉由矽膠管柱層析來純化殘餘物。由此產生2-((5S)-1-(4-氯苯基)-5-甲基-2-側氧基吡咯啶-3-基)-2-側氧基乙酸乙酯(1.1 g,74.8%)。
(S)-1-(4-氯苯基)-5-甲基-3-亞甲基吡咯啶-2-酮
步驟 3
:向可再密封之反應瓶中裝入2-[(5S)-1-(4-氯苯基)-5-甲基-2-側氧基吡咯啶-3-基]-2-側氧基乙酸乙酯(1.1 g,3.55 mmol)、(CH2O)n (513 mg,17.7 mmol)、Et2NH (657 mg,10.6 mmol)、DMF (10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在100℃下攪拌混合物1小時。反應混合物用H2
O (10 mL)稀釋,且水相用EtOAc (10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。藉由矽膠管柱層析來純化殘餘物。由此產生(S)-1-(4-氯苯基)-5-甲基-3-亞甲基吡咯啶-2-酮(300 mg,38%)。
(S)-5-甲基-3-亞甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)吡咯啶-2-酮
步驟 4
:向可再密封之反應瓶中裝入(5S)-1-(4-氯苯基)-5-甲基-3-亞甲基吡咯啶-2-酮(300 mg,1.35 mmol)、AcOK (396 mg,4.05 mmol)、Xphos-2G (155 mg,135 µmol)、Xphos (212 mg,270 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷(8 mL),且在90℃下攪拌混合物2小時。反應混合物用H2
O (8 mL)稀釋,且水相用EtOAc (10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。藉由矽膠管柱層析來純化殘餘物。由此產生(S)-5-甲基-3-亞甲基-1-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基)吡咯啶-2-酮(300 mg,71%)。
(S)-1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-5-甲基-3-亞甲基吡咯啶-2-酮及(S)-1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3,5-二甲基-1,5-二氫-2H-吡咯-2-酮
步驟 5
:向可再密封之反應瓶中裝入(5S)-5-甲基-3-亞甲基-1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]吡咯啶-2-酮(200 mg,638 µmol)、6-碘-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(350 mg,765 µmol)、K3PO4 (337 mg,1.59 mmol)、Pd(dppf)Cl2 (46.6 mg,63.8 µmol)及攪拌棒,隨後抽真空及用氮氣淨化三次。添加DME (5 mL)及H2O (1 mL),且在90℃下攪拌混合物2小時。反應混合物用H2
O (2 mL)稀釋,且水相用EtOAc (5 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型HPLC純化(Hex(0.2% IPAmine):(EtOH:DCM=1:1)=50:50)。凍乾產生呈白色非晶形固體狀之(5S)-1-[4-(4-胺基-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)苯基]-5-甲基-3-亞甲基吡咯啶-2-酮(2.5 mg,0.7%)及呈白色非晶形固體狀之(5S)-1-[4-(4-胺基-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)苯基]-3,5-二甲基-2,5-二氫-1H-吡咯-2-酮(120.7 mg,36.5%)。
根據實例30之方法製備的其他化合物描繪於下表29中。表 29. 其他例示性化合物
實例31流程 28
2,5-二氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-2-基)-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d6) δ 8.54 - 8.44 (m, 2H), 8.40 - 8.39 (m, 1H), 8.23 (s, 1H), 7.94 - 7.92 (m, 1H), 7.37 - 7.29 (m, 2H), 7.25 - 7.18 (m, 2H), 7.16 (d, J = 5.0 Hz, 1H), 6.02 - 5.96 (m, 2H), 5.57 - 5.52 (m, 1H), 4.05 - 3.97 (m, 2H), 3.65 (s, 3H), 2.86 (s, 2H), 2.41 (s, 3H). | 505.25 | |
1-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-2-基)-3-甲基-1,5-二氫-2H-吡咯-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.42-8.40 (m, 1H), 8.35-8.34 (m, 1H), 8.23 (s, 1H), 7.92-7.90 (m, 1H), 7.41 - 7.30 (m, 2H), 7.26 - 7.19 (m, 2H), 7.18 -7.09 (m, 2H), 5.99 (s, 1H), 4.54 (q,J = 2.1 Hz, 2H), 3.64 (s, 3H), 2.41 (s, 3H), 1.86 (q,J = 1.9 Hz, 3H). | 505.25 | |
(S)-1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-5-甲基-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, 氯仿-d ) δ 8.40 - 8.38 (m, 2H), 7.60 (d,J = 8.0 Hz, 2H), 7.34-7.17(m, 3H), 6.94 (d,J = 5.2 Hz, 2H), 6.81 (s, 2H), 5.12 (s, 2H), 4.65 (s, 1H), 3.78 (s, 3H), 2.53 (s, 3H), 2.06 - 1.91 (m, 2H), 1.29 (d, J = 6.7 Hz, 3H). | 518.22 | |
(S)-1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3,5-二甲基-1,5-二氫-2H-吡咯-2-酮 | 1H NMR (400 MHz, 甲醇-d4) δ 8.41 (d, J = 5.1 Hz, 1H), 8.22 (s, 1H), 7.62 - 7.59 (m, 2H), 7.47 - 7.36 (m, 4H), 7.18 - 7.02 (m, 3H), 7.03 (t, J = 1.8 Hz, 1H), 4.85-4.83(m, 1H), 3.73 (s, 3H), 2.50 (s, 3H), 1.94 (3, 3H), 1.25 (d, J = 6.7 Hz, 3H). | 518.22 | |
(R)-1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-5-甲基-3-亞甲基吡咯啶-2-酮 | 1H NMR (400 MHz, 氯仿-d) δ 8.42 - 8.36 (m, 2H), 7.64 - 7.56 (m, 2H), 7.37 - 7.29 (m, 4H), 7.23 - 7.15 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.17 (s, 1H), 5.48 (s, 2H), 4.42-4.38 (m, 1H), 3.77 (s, 3H), 3.17-3.11 (m, 1H), 2.55-2.49 (m, 4H), 1.28 (d, J = 6.7 Hz, 3H). | 518.22 | |
(R)-1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3,5-二甲基-1,5-二氫-2H-吡咯-2-酮 | 1H NMR (400 MHz, 氯仿-d) δ 8.42 - 8.36 (m, 2H), 7.65 - 7.57 (m, 2H), 7.37 - 7.28 (m, 4H), 7.23 - 7.15 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 5.48 (t, J = 2.1 Hz, 1H), 5.13 (s, 1H), 4.47 - 4.35 (m, 1H), 3.77 (s, 3H), 3.14 (s, 1H), 2.58 - 2.47 (m, 3H), 1.29 (d, J = 6.2 Hz, 3H). | 518.22 | |
(R)-1-(4-(4-胺基-7-甲基-5-(4-((5-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-甲基-3-亞甲基吡咯啶-2-酮 | 1H NMR (400 MHz, 氯仿-d) δ 8.39 (d, J = 5.0 Hz, 2H), 7.83 -7.76 (m, 2H), 7.36 - 7.28 (m, 4H), 7.23 -7.16 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.19 (d, J = 2.8 Hz, 1H), 5.45 (d, J = 2.5 Hz, 1H), 5.13 (s, 2H), 4.03 (dd, J = 9.4, 8.6 Hz, 1H), 3.75 (s, 3H), 3.44 (dd, J = 9.5, 5.6 Hz, 1H), 3.13 (s, 1H), 2.53 (s, 3H), 1.37 (d, J = 6.9 Hz, 3H). | 518.35 | |
1-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-亞甲基哌啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 )8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.40 (s, 4H), 7.36-7.29 (m, 2H), 7.23-7.13 (m, 3H), 6.18-5.74 (m, 2H), 5.41 (d,J = 2.2 Hz, 1H), 3.75 (t,J = 5.7 Hz, 2H), 3.63 (s, 3H), 2.74-2.61 (m, 2H), 2.41 (s, 3H), 1.95-1.93 (m, 2H). | 518.25 | |
1-(4-(4-胺基-7-甲基-5-(4-(4-甲基嘧啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-3-甲基-5,6-二氫吡啶-2(1H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 )8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.38 (s, 4H), 7.36-7.29 (m, 2H), 7.23-7.17 (m, 2H), 7.16 (d,J = 5.0 Hz, 1H), 6.69-6.46 (m, 1H), 5.89 (s, 1H), 3.82 (t,J = 6.8 Hz, 2H), 3.63 (s, 3H), 2.42-2.36 (m, 5H), 1.82-1.80 (m, 3H). | 518.35 | |
(S)-1-(4-(4-胺基-7-甲基-5-(4-((5-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4-甲基-3-亞甲基吡咯啶-2-酮 | 1H NMR (400 MHz, 氯仿-d) δ8.39 (d, J = 5.3 Hz, 2H), 7.82 - 7.62 (m, 2H), 7.36 -7.28 (m, 4H), 7.23 - 7.15 (m, 2H), 6.94 (d, J = 5.0 Hz, 1H), 6.18 (d, J = 2.9 Hz, 1H), 5.45 (d, J = 2.5 Hz, 1H), 5.11 (s, 2H), 4.03 (t, J = 9.0 Hz, 1H), 3.75 (s, 3H), 3.44 (dd, J = 9.4, 5.5 Hz, 1H), 3.12 (s, 1H), 2.52 (s, 3H), 1.36 (d, J = 6.9 Hz, 3H). | 518.35 | |
1-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)苯基)-4,4-二甲基-3-亞甲基吡咯啶-2-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.86 - 7.80 (m, 2H), 7.46 - 7.39 (m, 2H), 7.35 - 7.25 (m, 2H), 7.23 - 7.12 (m, 3H), 5.90 (s, 1H), 5.50 (s, 1H), 3.67 (s, 2H), 3.62 (s, 3H), 2.41 (s, 3H), 1.27 (s, 6H). | 532.20 | |
7-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-亞甲基-3,4-二氫萘-1(2H)-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.46 (1H, d), 8.22 (1H, s), 7.91 (1H, d), 7.60 (1H, dd), 7.44 (1H, d), 7.35-7.27 (2H, m), 7.22-7.10 (3H, m), 5.81 (3H, dd), 3.61 (3H, s), 3.02 (2H, t), 2.90-2.82 (2H, m), 2.40 (3H, s) | 489.30 | |
6-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-亞甲基-3,4-二氫萘-1(2H)-酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 1.7 Hz, 1H), 7.36 (dd, J = 8.0, 1.7 Hz, 1H), 7.35 -7.27 (m, 2H), 7.24- 7.13 (m, 3H), 6.06 (d, J = 2.1 Hz, 1H), 5.99 (s, 2H), 5.56 (d, J = 2.0 Hz, 1H), 3.68 (s, 3H), 2.96 (t, J = 6.3 Hz, 2H), 2.84 (t, J = 6.1 Hz, 2H), 2.41 (s, 3H). | 489.35 |
步驟 1
:向圓底燒瓶中裝入2,5-二氯-1H-苯并[d]咪唑(1 g,5.4 mmol)、二甲基甲醯胺(5 mL)及攪拌棒,添加NaH (60%,259 mg,6.48),且在0℃下攪拌溶液10分鐘。添加SEMCl (896 mg,5.4 mmol),且在0℃下攪拌溶液10小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得混合物經由C18管柱純化。真空濃縮,產生呈黃色油狀之2,5-二氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑(820 mg,48%)。
2-((第三丁基二甲基矽烷基)乙炔基)-5-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑
步驟 2
:向圓底燒瓶中裝入2,5-二氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑(800 mg,1.30 mmol)、第三丁基(乙炔基)二甲基矽烷(274 mg,1.96 mmol)、Pd(PPh3
)2
Cl2
(183 mg,261 µmol)、CuI (99 mg,0.52 mmol)、TEA (395 mg,3.09 mmol)及攪拌棒。添加二甲基甲醯胺(20 mL),且在50℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得混合物經由C18管柱純化。真空濃縮,產生呈黃色油狀之2-((第三丁基二甲基矽烷基)乙炔基)-5-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑(500 mg,47%)。
2-((第三丁基二甲基矽烷基)乙炔基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑
步驟 3
:向圓底燒瓶中裝入2-((第三丁基二甲基矽烷基)乙炔基)-5-氯-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑(480 mg,1.14 mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-雙(1,3,2-二氧雜硼雜環戊烷)(579 mg,2.28 mmol)、Pd(dppf)Cl2
(83 mg,114 µmol)、AcOK (335 mg,3.42 mmol)及攪拌棒。添加二噁烷(10 mL),且在90℃下攪拌溶液2小時。所得混合物經由C18管柱純化。真空濃縮,產生呈白色油狀之2-((第三丁基二甲基矽烷基)乙炔基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑(550 mg,94%)。
6-(2-((第三丁基二甲基矽烷基)乙炔基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向可再密封之反應瓶中裝入2-((第三丁基二甲基矽烷基)乙炔基)-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑(480 mg,0.86 mmol)、5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(273 mg,0.57 mmol)、Pd(dppf)Cl2
(42 mg,57 µmol)、K3
PO4
(363 mg,1.71 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME:水=10:1 (10 mL),且在90℃下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由製備型TLC純化。真空濃縮,產生呈黃色非晶形固體狀之6-(2-((第三丁基二甲基矽烷基)乙炔基)-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(260 mg,62%)。
6-(2-乙炔基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 5
:向圓底燒瓶中裝入6-(2-乙炔基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(240 mg,0.33 mmol)、THF (4 mL)及攪拌棒。添加TBAF (1 M,0.7 mL,0.66 mmol),且在室溫下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。藉由矽膠管柱層析(用二氯甲烷/甲醇(8:1)溶離)來純化殘餘物。真空濃縮,產生呈黃色油狀之6-(2-乙炔基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(100 mg,49%)。
6-(2-乙炔基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 6
:向圓底燒瓶中裝入6-(2-乙炔基-1-((2-(三甲基矽烷基)乙氧基)甲基)-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(80 mg,852 µmol)、DCM (4 mL)及攪拌棒。添加TFA (44 mg,0.39 mmol),且在室溫下攪拌溶液1小時。使反應混合物處於真空中。所得粗物質藉由製備型HPLC純化(管柱:YMC-Actus Triart C18,30*250,5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:CAN;流量:50 mL/min;梯度:30 B至65 B,歷時8分鐘;220 nm;RT1:7.22)。凍乾產生呈灰白色非晶形固體狀之6-(2-乙炔基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(22.1 mg,35%)。
根據實例31之方法製備的其他化合物描繪於下表30中。表 30. 其他例示性化合物
實例32流程 29
3-溴-6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
6-(2-乙炔基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (300 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.44 (s, 1H), 8.20 (s, 1H), 7.67 - 7.18 (m, 4H), 7.15 (d, J = 5.0 Hz, 3H), 4.67 (s, 1H), 3.61 (s, 3H), 2.38 (s, 3H). | 491.20 | |
6-(2-乙炔基-1,6-二甲基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 5.1 Hz, 1H), 8.23 (s, 1H), 7.70 (s, 1H), 7.56 (s, 1H), 7.28 (t, J = 8.4 Hz,1H), 7.21 - 7.13 (m, 2H), 7.12 - 7.05 (m, 1H), 6.03 (s, 2H), 4.95 (s, 1H), 3.87 (s,3H), 2.38 (s, 3H), 2.12 (s, 3H). | 519.25 | |
6-(2-乙炔基-1-甲基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 5.2 Hz, 1H), 8.22 (s, 1H), 7.70 (d,J = 1.5 Hz, 1H), 7.65 (d,J = 8.4 Hz, 1H), 7.40 - 7.26 (m, 2H), 7.24 - 7.06 (m, 3H), 5.99 (s, 2H), 4.98 (s, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 2.40 (s, 3H). | 505.20 | |
6-(2-乙炔基-6-氟-1-甲基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 )8.44 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.72 (dd,J = 9.8, 8.1 Hz, 2H), 7.30 (t,J = 8.4 Hz, 1H), 7.21 (dd,J = 11.3, 2.0 Hz, 1H), 7.16 (d,J = 5.1 Hz, 1H), 7.13-7.07 (m, 1H), 6.04 (s, 2H), 5.00 (s, 1H), 3.87 (s, 3H), 3.52 (s, 3H), 2.38 (s, 3H). | 523.20 | |
6-(2-乙炔基-1-甲基-1H-苯并[d]咪唑-6-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.65 (s, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.26 -7.14 (m, 3H), 7.14 -7.08 (m, 1H), 6.02 (s, 2H), 4.99 (s, 1H), 3.85 (s, 3H), 3.62 (s, 3H), 2.39 (s, 3H). | 505.20 | |
6-(2-乙炔基-6-甲氧基-1-甲基-1H-苯并[d]咪唑-5-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) 8.44 (d, J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.48 (s, 1H), 7.34 (s, 1H), 7.28 (t, J = 8.4 Hz, 1H), 7.18 -7.10 (m, 2H), 7.05 (dd, J = 8.4, 2.0 Hz, 1H), 5.99 (s, 2H), 4.91 (s, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.44 (s, 3H), 2.38 (s, 3H). | 535.20 |
步驟 1
:向可再密封之反應瓶中裝入3-溴-6-氯-2,4-二甲基吡啶(8 g,36.2 mmol)、第三丁基(乙炔基)二甲基矽烷(5.58 g,39.8 mmol)、CuI (1.37 g,7.24 mmol)、Pd(PPh3
)2
Cl2
(2.54 g,3.62 mmol)、TEA (10.9 g,108 mmol)、二甲基甲醯胺(100 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在80℃下攪拌混合物2小時。反應混合物用水淬滅,用DCM萃取。合併有機相且用鹽水洗滌三次,經Na2
SO4
乾燥,真空蒸發。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色油狀之3-溴-6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶(10.0 g,85%)。
6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶
步驟 2
:向可再密封之反應瓶中裝入3-溴-6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶(9.6 g,29.52 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(14.88 g,59.04 mmol)、Pd(dppf)Cl2
(2.15 mg,2.95 µmol)、AcOK (8.66 g,88.44 mmol)、二甲基甲醯胺(150 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物12小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,真空蒸發。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈灰白色非晶形固體狀之6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(2.5 g,27%)。
6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向可再密封之反應瓶中裝入6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(1.3 g,3.49 mmol)、6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(952 mg,3.49 mmol)、雙(金剛烷-1-基)(丁基)膦(125 mg,349 µmol)、2'-胺基-1,1'-聯苯-2-基雙(金剛烷-1-基)(丁基)膦氯化鈀(1+)(233 mg,349 µmol)、K3
PO4
(2.2 g,1.05 mmol)、二噁烷/H2
O (15 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物6小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,真空蒸發。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色非晶形固體狀之6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,37%)。
5-溴-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,1.27 mmol)、NBS (272 mg,1.53 mmol)、二甲基甲醯胺(20 mL)及攪拌棒。在室溫下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,真空蒸發。所得粗物質藉由矽膠層析純化(20 g管柱;用二氯甲烷/甲醇12:1溶離)。真空濃縮,產生呈紅色非晶形固體狀之5-溴-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,88.3%)。
6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 5
:向可再密封之反應瓶中裝入5-溴-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(460 mg,977 µmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(643 mg,1.95 mmol)、Pd(PPh3
)4
(112 mg,97.7 µmol)、K3
PO4
(621 mg,2.93 mmol)、DME/H2
O (10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。反應混合物用水淬滅,用DCM萃取。有機相用鹽水洗滌三次,經Na2
SO4
乾燥,真空蒸發。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈橙色非晶形固體狀之6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(250 mg,43%)。
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 6
:向圓底燒瓶中裝入6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(230 mg,387 µmol)、CsF (176 mg,1.16 mmol)及攪拌棒。添加四氫呋喃(8 mL),且在50℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm,5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:CAN;流量:60 mL/min;梯度:20 B至45 B,歷時8 min;220 nm;RT1:7.12;)。凍乾產生呈灰白色非晶形固體狀之6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(100 mg,208 µmol)。
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 7
:所得粗物質藉由製備型對掌性HPLC來純化(管柱:DZ-CHIRALPAK IF-3,4.6*50mm,3 um;移動相A:Hex (0.2% IPAmine):(EtOH:DCM=1:1)=75:25)。凍乾產生呈灰白色非晶形固體狀之6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(峰1)(33.7 mg,70.2 µmol,33.7%);呈灰白色非晶形固體狀之6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(峰2)(25 mg,52.1 µmol,25%)。
根據實例32之方法製備的其他化合物描繪於下表31中。表 31. 其他例示性化合物
實例33流程 30
(S)-4-(4-胺基-6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸
化合物 | 結構 | 質子 NMR | MS [M+1] |
6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.59 (s, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.13 (dd, J = 11.3, 2.1 Hz, 1H), 7.01 - 6.96 (m, 1H), 6.21 (s, 1H), 4.59 (s, 1H), 3.49 (s, 3H), 2.41 (s, 3H), 2.02 (s, 3H). | 484.15 | |
6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體1 | 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.59 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.14 (dd, J = 11.3, 2.1 Hz, 1H), 7.04 - 6.93 (m, 1H), 6.21 (s, 2H), 4.59 (s, 1H), 3.50 (s, 4H), 2.41 (s, 3H), 2.03 (s, 3H). | 484.15 |
6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體2 | 1H NMR (400 MHz, DMSO-d6) δ 8.48 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.59 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.14 (dd, J = 11.3, 2.1 Hz, 1H), 7.04 - 6.93 (m, 1H), 6.21 (s, 2H), 4.59 (s, 1H), 3.50 (s, 4H), 2.41 (s, 3H), 2.03 (s, 3H). | 484.15 |
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1H NMR (300 MHz, DMSO-d6) 8.45 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.42 (s, 1H), 7.30 (t, J = 8.4 Hz, 1H), 7.16 (d, J = 5.0 Hz, 1H), 7.05 (dd, J = 11.5, 2.0 Hz, 1H), 6.94 (dt, J = 8.3, 1.4 Hz, 1H), 6.16 (s, 1H), 4.35 (s, 1H),3.32(s,3H), 2.38 (s, 3H), 2.14 (s, 3H), 2.00 (s, 3H). | 480.15 | |
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體1 | 1H NMR (400 MHz, DMSO-d6) 8.47 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.44 (s, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.18 (d, J = 5.1 Hz, 1H), 7.07 (dd, J = 11.4, 2.1 Hz, 1H), 7.00 -6.93 (m, 1H), 6.15 (s, 2H), 4.36 (s, 1H), 3.34 (s, 3H), 2.41 (s, 3H), 2.16 (s, 3H), 2.02 (s, 3H). | 480.15 |
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體2 | 1H NMR (400 MHz, DMSO-d6) 8.47 (d, J = 5.0 Hz, 1H), 8.24 (s, 1H), 7.44 (s, 1H), 7.32 (t, J = 8.4 Hz, 1H), 7.18 (d, J = 5.0 Hz, 1H), 7.07 (dd, J = 11.4, 2.0 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.15 (s, 2H), 4.37 (s, 1H), 3.41 (s, 3H), 2.41 (s, 3H), 2.16 (s, 3H), 2.02 (s, 3H). | 480.15 |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.50 (s, 2H), 7.28 - 7.10 (m, 5H), 5.80 (m, 2H), 5.52 (s, 1H), 3.37 (s, 3H), 2.40 (s, 3H), 1.96 (m, 9H). | 520.40 | |
((S)-4-(4-胺基-6-(6-乙炔基-2-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) δ 8.14 (t, J = 2.8 Hz, 1H), 7.65 (s, 1H), 6.61 (s, 2H), 5.61 (s, 1H), 4.60 (d, J = 1.1 Hz, 1H), 4.01(s,1H), 3.51 (d, J = 8.6 Hz, 2H), 3.46 - 3.36 (m, 3H), 2.71 (s, 1H), 2.17 (s, 5H), 1.91-1.80 (s, 5H), 1.62 (s, 1H), 1.49 (d, J = 5.0 Hz, 1H), 1.17 - 1.03 (m, 3H). | 473.30 |
步驟 1
:向圓底燒瓶中裝入(1S)-4-{4-胺基-6-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基}環己-3-烯-1-甲酸(6 g,19.5 mmol)、{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}酸(10.7 g,39.0 mmol)、Na2CO3 (6.19 g,58.4 mmol)、Xphos Pd.G3. (1.65 g,1.95 mmol)、Xphos (928 mg,1.95 mmol)、二噁烷/H2O (120 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。過濾反應混合物,用DCM洗滌,真空濃縮濾液,且所得粗物質接著藉由combiflash (A:0.1% TFA/水,B:乙腈)來純化。真空濃縮,產生呈黃色固體狀的(1S)-4-(4-胺基-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸(6.20 g,63%)。
(S)-1-((S)-4-(4-胺基-6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈
步驟 2
:向圓底燒瓶中裝入(1S)-4-(4-胺基-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸(5 g,9.96 mmol)、(2S)-吡咯啶-2-甲腈(2.86 g,29.8 mmol)、HATU (7.56 g,19.9 mmol)、DMF (100 mL)及攪拌棒。添加DIEA (15.0 g,116 mmol),且在室溫下攪拌溶液2小時。反應混合物用水(150 mL)稀釋,且水相用EA (300 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(200 g管柱;用二氯甲烷/甲醇溶離;比率=30:1)。真空濃縮,產生呈深色油狀之(2S)-1-[(1S)-4-(4-胺基-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基]吡咯啶-2-甲腈(2.80 g,48%)。
(S)-1-((S)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈
步驟 3
:向圓底燒瓶中裝入(2S)-1-[(1S)-4-(4-胺基-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基]吡咯啶-2-甲腈(2.7 g,4.65 mmol)、THF (10 mL)及攪拌棒。添加TBAF (1.21 g,4.65 mmol),且在室溫下攪拌溶液30分鐘。反應混合物用水(150 mL)稀釋,且水相用DCM (100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由flash (移動相A:水,移動相B:ACN)來純化。所得粗物質藉由HPLC純化(管柱:Xselect CSH OBD管柱30*150mm 5um,n;移動相A:水(0.1% FA),移動相B:MeOH--HPLC;流量:60 mL/min;梯度:20 B至45 B,歷時7分鐘;220 nm:RT1:7.13;RT2)。凍乾產生呈灰白色非晶形固體狀之(2S)-1-[(1S)-4-[4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基]吡咯啶-2-甲腈(520 mg,24%)。
根據實例33之方法製備的其他化合物描繪於下表32中。表 32 . 其他例示性化合物
實例34流程 31
5-溴-2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
(2S)-1-[(1S)-4-[4-胺基-6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基]吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H), 7.88 - 7.64 (m, 1H), 7.53 (d,J = 7.9 Hz, 1H), 6.57 (s, 1H), 5.70 (d,J = 11.1 Hz, 1H), 4.92 - 4.54 (m, 1H), 4.43 (s, 1H), 3.68 (d,J = 8.0 Hz, 1H), 3.53 - 3.43 (m, 1H), 3.38 (s, 3H), 2.81 (d,J = 6.4 Hz, 1H), 2.28 (d,J = 2.3 Hz, 3H), 2.23 (s, 2H), 2.13 (d,J = 6.5 Hz, 2H), 2.09 - 1.73 (m, 4H), 1.61 (s, 2H). | 466.30 | |
(2S)-1-[(1R)-4-[4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基]吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.41 (d,J = 25.1 Hz, 1H), 8.17 (s, 1H), 7.64 (d,J = 3.9 Hz, 1H), 6.73 (s, 1H), 5.71 (d,J = 28.0 Hz, 1H), 4.71 (dd,J = 7.9, 3.8 Hz, 1H), 4.43 (s, 1H), 3.70 - 3.48 (m, 2H), 3.39 (d,J = 1.5 Hz, 3H), 2.86 - 2.74 (m, 1H), 2.28 - 2.20 (m, 2H), 2.14 (d,J = 7.2 Hz, 5H), 2.06 - 1.83 (m, 4H), 1.72 - 1.58 (m, 2H). | 466.20 | |
(2S)-1-[(1S)-4-[4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基]吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d,J = 5.1 Hz, 1H), 8.14 (s, 1H), 7.64 (d,J = 1.9 Hz, 1H), 6.53 (s, 1H), 5.76 (s, 1H), 4.70 (dt,J = 7.3, 3.2 Hz, 1H), 4.43 (d,J = 1.2 Hz, 1H), 3.69 (s, 1H), 3.65 - 3.42 (m, 1H), 3.38 (d,J = 0.9 Hz, 3H), 2.80 (s, 1H), 2.24 (s, 2H), 2.14 (s, 5H), 2.07 - 1.81 (m, 4H), 1.60 (s, 2H). | 466.35 |
步驟 1
:向可再密封之反應瓶中裝入5-溴-2-碘-4-甲基吡啶(5.00 g,16.8 mmol)、二甲基甲醯胺(50 mL)、CuI (1.28 g,6.72 mmol)、Et3
N (8.48 g,84 mmol)、Pd(PPh3
)2
Cl2
(2.36 g,3.36 mmol)、第三丁基(乙炔基)二甲基矽烷(2.35 g,16.8 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。在50℃下攪拌混合物2小時。反應混合物用水(200 mL)稀釋,且水相用EA (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用庚烷/乙酸乙酯10:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之5-溴-2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶(4 g,77%)。
2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶
步驟 2
:向可再密封之反應瓶中裝入5-溴-2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶(3.5 g,11.3 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(3.07 g,12.1 mmol)、AcOK (2.37 g,24.2 mmol)、Pd(dppf)Cl2
(589 mg,807 µmol)、二噁烷(40 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在80℃下攪拌混合物1小時。反應混合物用水(100 mL)稀釋,且水相用EA (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水0~50%)。凍乾產生呈灰白色非晶形固體狀之2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(3.90 g,90%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向可再密封之反應瓶中裝入2-((第三丁基二甲基矽烷基)乙炔基)-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(2.6 g 7.26 mmol)、6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(1.67 g,6.05 mmol)、Pd(dppf)Cl2
(442 mg,605 µmol)、K3
PO4
(3.83 g,18.1 mmol)、DME:H2
O (10:1,25 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在90℃下攪拌混合物3小時。反應混合物用水(40 mL)稀釋,且水相用DCM (40 mL)萃取三次。合併之有機層用飽和鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水=0~50%)。凍乾產生呈黃色非晶形固體狀之6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-7-甲基-7H吡咯并[2,3-d]嘧啶-4-胺(1.6 g,70%)。
5-溴-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(1.6 g,4.24 mmol)、DCM (20 mL)及攪拌棒。添加NBS (754.7 mg,4.24 mmol)。在室溫下攪拌混合物1小時。反應混合物用飽和NaHSO3
水溶液淬滅直至pH至8-9,用DCM (100 mL*3)萃取,合併有機相且用鹽水洗滌,經Na2
SO4
乾燥,真空蒸發,用ACN (25 mL)溶解殘餘物,且過濾,用ACN洗滌濾餅,在減壓下乾燥,得到呈灰白色固體狀的5-溴-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(1.6 g,83%)。
(S)-(4-(4-胺基-6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮
步驟 5
:向可再密封之反應瓶中裝入5-溴-6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(500 mg,1.09 mmol)、DME:H2
O (10:1,8 mL)、[(4S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]酸(290 mg,1.30 mmol)、Pd(dppf)Cl2
(79.6 mg,109 µmol)、K3
PO4
(693 mg,3.27 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物2小時。反應混合物用水(50 mL)稀釋,且水相用EA (30 mL)萃取三次。合併之有機層用飽和鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(1 g管柱;用EA溶離)。真空濃縮,產生呈棕色固體狀之6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-5-[(4S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(110 mg,18%)。
(S)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮
步驟 6
:向可再密封之反應瓶中裝入6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-7-甲基-5-[(4S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(100 mg,180 µmol)、THF (6 mL)及攪拌棒。添加TBAF (2.2 mL,216 µmol),且在室溫下攪拌混合物30分鐘。反應混合物用水(20 mL)稀釋,且水相用DCM (20 mL)萃取三次。合併之有機層用鹽水洗滌五次,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型HPLC純化(乙腈/水/10 mmol NH4
HCO3
,流量:60 mL/min;梯度:40 B至65 B,歷時8分鐘)。凍乾產生呈灰白色非晶形固體狀之6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-[(4S)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(27.6 mg,35%)。
根據實例34之方法製備的其他化合物描繪於下表33中。表 33. 其他例示性化合物
實例35流程 32
5-碘-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
(R)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) 8.40 (d, J = 11.7 Hz, 1H), 8.13 (s, 1H), 7.63 (d, J = 2.7 Hz, 1H), 6.59 (s, 1H), 5.69 (d, J = 30.0 Hz, 1H), 4.42 (d, J = 1.1 Hz, 1H), 3.51-3.38 (m, 2H), 3.37 (d, J = 1.4 Hz, 3H), 3.28 (s, 2H), 2.75 (s, 1H), 2.68 (p, J = 1.8 Hz, 2H), 2.34 (p, J = 1.9 Hz, 5H), 2.20 (d, J = 7.1 Hz, 1H), 1.93 (d, J = 9.1 Hz, 2H), 1.85 (q, J = 6.1 Hz, 2H), 1.60 (d, J = 7.0 Hz, 2H). | 441.35 | |
(S)-(4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.39 (d,J = 6.7 Hz, 1H), 8.17 (s, 1H), 7.65 (d,J = 3.2 Hz, 1H), 5.99 - 5.76 (m, 1H), 3.89 (d,J = 1.8 Hz, 1H), 3.62 - 3.50 (m, 2H), 3.49 (s, 3H), 3.43 (ddt,J = 9.3, 6.4, 3.7 Hz, 2H), 2.90 - 2.78 (m, 1H), 2.44 - 2.30 (m, 1H), 2.24 (d,J = 3.1 Hz,4H), 2.11 (s, 2H), 1.98 (qd,J = 6.4, 2.1 Hz, 2H), 1.90 (td,J = 6.5, 1.4 Hz, 2H), 1.76 (dq,J = 14.4, 6.3 Hz, 2H). | 441.35 | |
4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-N-環丁基-2-甲氧基苯甲醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 8.45 (s, 1H), 8.27 (s, 1H), 7.77 (d,J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.00 - 6.89 (m, 2H), 4.48 (p,J = 8.3 Hz, 1H), 3.86 (s, 1H), 3.81 (s, 3H), 3.60 (s, 3H), 2.38 (d,J = 8.2 Hz, 2H), 2.13 - 1.99 (m, 5H), 1.85 - 1.75 (m, 2H). | 467.15 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO) 9.22 (s, 1H), 8.95 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 7.99 (d,J = 7.9 Hz, 1H), 7.60 (d,J = 7.9 Hz, 1H), 7.38 -7.23 (m, 2H), 7.17 (d,J = 5.1 Hz, 1H), 7.07 (ddd,J = 8.4, 2.2, 0.8 Hz, 1H), 4.47 (s, 1H), 3.57 (s, 3H), 2.40 (s, 3H), 2.14 (s, 3H). | 451.15 | |
(R)-(4-(6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) 9.14 (s, 1H), 8.86 (s, 1H), 7.86 (dd,J = 20.9, 7.9 Hz, 1H), 7.58 (d,J = 7.9 Hz, 1H), 5.81 (s, 1H), 4.47 (d,J = 1.7 Hz, 1H), 3.51 - 3.42 (m, 5H), 3.27 (t,J = 6.8 Hz, 2H), 2.61 (d,J = 12.8 Hz, 1H), 2.26 (t,J = 14.0 Hz, 7H), 1.87 (p,J = 6.7 Hz, 2H), 1.78 - 1.73 (m, 3H), 1.50 (td,J = 12.1, 5.7 Hz, 1H). | 426.30 | |
(S)-(4-(6-(6-乙炔基-2-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-基)(吡咯啶-1-基)甲酮 | 1H NMR (400 MHz, DMSO-d6) 9.14 (s, 1H), 8.86 (s, 1H), 7.86 (dd, J = 20.9, 7.9 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 5.81 (s, 1H), 4.46 (d, J = 1.7 Hz, 1H), 3.47 (dd, J = 6.8, 4.7 Hz, 5H), 3.30 (s, 2H), 2.61 (d, J = 11.0 Hz, 1H), 2.28 (d, J = 7.5 Hz, 3H), 2.23 (s, 2H), 2.18 (s, 1H), 1.91 - 1.83 (m, 2H), 1.85 -1.72 (m, 4H), 1.50 (td, J = 11.9, 5.5 Hz, 1H). | 426.30 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-[(4S)-4-(2-乙炔基吡咯啶-1-羰基)環己-1-烯-1-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (d,J = 2.6 Hz, 1H), 7.73 (td,J = 6.7, 5.6, 2.4 Hz, 1H), 7.51 (s, 1H), 6.53 (s, 2H), 5.74 - 5.64 (m, 1H), 4.83 (d,J = 7.3 Hz, 1H), 4.43 (s, 1H), 3.61 (s, 1H), 3.38 (s, 3H), 3.26 (d,J = 11.8 Hz, 1H), 3.08 (d,J = 2.0 Hz, 1H), 2.96 - 2.63 (m, 1H), 2.32 - 2.15 (m, 3H), 2.15 - 2.06 (m, 2H), 2.04 - 1.80 (m, 6H), 1.75 - 1.53 (m, 2H). | 465.30 | |
6-(6-乙炔基-2-甲基吡啶-3-基)-5-[(4S)-4-[(2R)-2-乙炔基吡咯啶-1-羰基]環己-1-烯-1-基]-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J = 3.1 Hz, 1H), 7.80 - 7.66 (m, 1H), 7.52 (d, J = 7.8 Hz, 1H), 6.56 (s, 2H), 5.71 (dd, J = 24.3, 13.7 Hz, 1H), 4.87 - 4.52 (m, 1H), 4.43 (s, 1H), 3.57 - 3.48 (m, 1H), 3.38 (s, 3H), 3.30 - 3.19 (m, 1H), 3.11 - 2.99 (m, 1H), 2.97 - 2.60 (m, 1H), 2.38 - 2.31 (m, 3H), 2.18 (d, J = 46.6 Hz, 3H), 1.92 (dd, J = 39.2, 17.7 Hz, 6H), 1.61 (s, 2H). | 465.30 | |
((S)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (s, 1H), 7.86 - 7.81 (m, 2H), 7.53 (d,J = 2.2 Hz, 1H), 6.88 (s, 1H), 5.83 (s, 1H), 4.32 (s, 1H), 4.00 (t,J = 6.5 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.40 (s, 1H), 2.82 (t,J = 5.7 Hz, 1H), 2.27 (s, 5H), 1.99 - 1.72 (m, 5H), 1.66 - 1.38 (m, 3H), 1.09 (dd,J = 6.4, 2.0 Hz, 3H). | 441.30 | |
((R)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)吡咯并[2,1-f][1,2,4]三嗪-5-基)環己-3-烯-1-基)((R)-2-甲基吡咯啶-1-基)甲酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.34 (d,J = 1.9 Hz, 1H), 7.83 (d,J = 3.2 Hz, 2H), 7.52 (s, 1H), 7.20 (s, 1H), 5.86 (s, 1H), 4.32 (s, 1H), 4.08 - 3.93 (m, 1H), 3.50 (d,J = 7.6 Hz, 1H), 3.46 - 3.39 (m, 1H), 2.88 (s, 1H), 2.27 (s, 5H), 2.07 - 1.26 (m, 8H), 1.08 (dd,J = 38.2, 6.3 Hz, 3H). | 441.30 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)吡咯并[2,1-f][1,2,4]三嗪-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.49 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.99 (d,J = 12.0 Hz, 2H), 7.45 (s, 1H), 7.37 (t,J = 8.3 Hz, 1H), 7.27 - 7.18 (m, 2H), 7.12 - 7.05 (m, 1H), 5.76 (s, 1H), 4.30 (s, 1H), 2.42 (s, 3H), 2.07 (s, 3H). | 452.20 | |
(R)-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-(6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 16.1 Hz, 1H), 8.17 (s, 1H), 7.66 (d,J = 5.6 Hz, 1H), 7.42 (dd,J = 7.3, 4.0 Hz, 1H), 6.68 (d,J = 7.3 Hz, 1H), 6.48 (d,J = 45.8 Hz, 2H), 5.64 (d,J = 52.5 Hz, 1H), 4.45 (d,J = 2.1 Hz, 1H), 3.49 - 3.37 (m, 3H), 2.98 - 2.62 (m, 2H), 2.30 (s, 6H), 2.17 (d,J = 4.3 Hz, 3H), 2.14 - 1.81 (m, 2H), 1.71 (ddd,J = 19.5, 12.6, 6.6 Hz, 1H). | 463.20 | |
(S)-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-5-(6'-甲基-3'H-螺[環己烷-1,2'-呋喃并[2,3-b]吡啶]-3-烯-4-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 16.2 Hz, 1H), 8.18 (s, 1H), 7.66 (d,J = 5.6 Hz, 1H), 7.41 (dd,J = 7.3, 4.0 Hz, 1H), 6.68 (d,J = 7.3 Hz, 1H), 6.51 (s, 1H), 5.64 (d,J = 52.2 Hz, 1H), 4.44 (d,J = 2.0 Hz, 1H), 3.40 (s, 3H), 2.92 - 2.63 (m, 2H), 2.49 - 2.32 (m, 1H), 2.30 (s, 6H), 2.17 (d,J = 4.4 Hz, 3H), 2.13 - 1.81 (m, 2H), 1.70 (td,J = 12.5, 6.8 Hz, 1H). | 463.25 | |
(S)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2'-甲基螺[環己烷-1,6'-環戊并[b]吡啶]-3-烯-7'(5'H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 5.7 Hz, 1H), 8.16 (s, 1H), 7.85 (t,J = 8.6 Hz, 1H), 7.66 (d,J = 4.8 Hz, 1H), 7.49 (d,J = 7.9 Hz, 1H), 6.63 (s, 1H), 5.73 (d,J = 62.3 Hz, 1H), 4.45 (d,J = 2.7 Hz, 1H), 3.40 (d,J = 1.7 Hz, 3H), 2.89 - 2.58 (m, 2H), 2.55 (s, 3H), 2.44 - 2.28 (m, 1H), 2.17 (d,J = 2.3 Hz, 4H), 2.12 - 1.65 (m, 3H), 1.49 (dd,J = 17.5, 6.5 Hz, 1H). | 475.25 | |
(R)-4-(4-胺基-6-(6-乙炔基-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2'-甲基螺[環己烷-1,6'-環戊并[b]吡啶]-3-烯-7'(5'H)-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.45 (d,J = 5.4 Hz, 1H), 8.16 (s, 1H), 7.85 (t,J = 8.6 Hz, 1H), 7.67 (d,J = 4.8 Hz, 1H), 7.49 (dd,J = 8.1, 1.5 Hz, 1H), 6.58 (d,J = 31.4 Hz, 2H), 5.74 (d,J = 62.1 Hz, 1H), 4.45 (d,J = 2.7 Hz, 1H), 3.41 (d,J = 1.7 Hz, 3H), 2.93 - 2.58 (m, 2H), 2.55 (s, 3H), 2.43 - 2.31 (m, 1H), 2.17 (d,J = 2.3 Hz, 4H), 2.16 - 1.63 (m, 3H), 1.49 (dt,J = 11.4, 6.8 Hz, 1H). | 475.30 |
步驟 1
:向圓底燒瓶中裝入5-碘-7H-吡咯并[2,3-d]嘧啶-4-胺(2 g,7.69 mmol)、Cs2
CO3
(7.49 g,23.0 mmol)及攪拌棒。添加二甲基甲醯胺(40 mL),且在0℃下攪拌溶液30分鐘。接著添加[2-(氯甲氧基)乙基]三甲基矽烷(1.53 g,9.22 mmol)。反應混合物用H2
O (20 mL)稀釋,且水相用EA (100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用二氯甲烷/甲醇溶離;40/1-30/1)。真空濃縮,產生呈灰白色非晶形固體狀之5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(1.60 g,53.2%)。
5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 2
:向可再密封之反應瓶中裝入5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(1.6 g,4.09 mmol)、4-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]嘧啶雙(甲烷)(1.54 g,4.49 mmol)、K3
PO4
(2.58 g,12.2 mmol)、DME/H2
O (16 mL/2 mL)、Pd(dppf)Cl2
(298 mg,409 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌混合物1小時。反應混合物用H2
O (10 mL)稀釋,且水相用二氯甲烷(80 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用二氯甲烷/甲醇溶離;20/1)。真空濃縮,產生呈橙色非晶形固體狀之5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(1.60 g,87.0%)。
6-碘-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]-甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向圓底燒瓶中裝入5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(1.6 g,3.56 mmol)、碘(硫基)胺(680 mg,3.91 mmol)、二氯甲烷(20 mL)及攪拌棒,接著在0℃添加TFA (1.02 g,10.6 mmol)。在室溫下攪拌混合物1小時。混合物用飽和NaHSO3
水溶液淬滅直至pH至8-9,用DCM (100 mL)萃取三次,合併有機相且經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用二氯甲烷/甲醇溶離;15/1)。真空濃縮,產生呈黃色非晶形固體狀之6-碘-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(1.40 g,68.5%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:向可再密封之反應瓶中裝入6-碘-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(400 mg,696 µmol)、2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)嘧啶(274 mg,765 µmol)、K3
PO4
(440 mg,2.08 mmol)、Pd(dppf)Cl2
(50.8 mg,69.6 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (8 mL/2 mL),且在90℃下攪拌混合物1小時。反應混合物用H2
O (3 mL)稀釋,且水相用二氯甲烷(50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(10 g管柱;用二氯甲烷/甲醇=15/1溶離)。真空濃縮,產生呈黃色非晶形固體狀之6-{2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基嘧啶-5-基}-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(310 mg,65.5%)。
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 5
:向圓底燒瓶中裝入6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(290 mg,427 µmol)、TBAF (133 mg,512 µmol)、THF (3 mL)及攪拌棒,且在室溫下攪拌溶液1小時。所得粗物質藉由矽膠層析純化(20 g管柱;用二氯甲烷/甲醇15:1溶離)。真空濃縮,產生呈黑色非晶形固體狀之6-(2-乙炔基-4-甲基嘧啶-5-基)-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(230 mg,95.3%)。
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 6
:向圓底燒瓶中裝入6-(6-乙炔基-4-甲基吡啶-3-基)-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(210 mg,372 µmol),及攪拌棒。添加TFA/DCM (40 ml),且在室溫下攪拌溶液30分鐘。真空濃縮。添加MeOH/EDA (20 ml),且在室溫下攪拌溶液10分鐘。真空濃縮。所得粗物質藉由矽膠層析純化(5 g管柱;用二氯甲烷/甲醇溶離;比率=20:1)。所得粗物質藉由HPLC純化(管柱:YMC-Actus Triart C18,30*250,5 um)。凍乾產生呈灰白色非晶形固體狀之6-(6-乙炔基-4-甲基吡啶-3-基)-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(37.0 mg,22.9%)。
根據實例35之方法製備的其他化合物描繪於下表34中。表 34 . 其他例示性化合物
實例36流程 33
N-[(1r,3r)-3-[2-(4,6-二胺基嘧啶-5-基)乙炔基]環丁基]胺基甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.12 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 7.51 (s, 1H), 7.31 - 7.24 (m, 2H), 7.24 - 7.18 (m, 2H), 7.16 (d,J = 5.0 Hz, 1H), 5.97 (s, 1H), 4.37 (s, 1H), 2.42 (s,3H), 2.08 (s, 3H). | 434.25 | ||
6-(2-乙炔基-4-甲基嘧啶-5-基)-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (s, 1H), 8.48 (d,J = 5.2 Hz, 1H), 8.20 (s, 1H), 7.31 (d,J = 8.2 Hz, 3H), 7.23 (d,J = 8.3 Hz, 4H), 7.16 (d,J = 5.1 Hz, 1H), 4.44 (s, 1H), 2.42 (s, 3H), 2.21 (s, 3H). | 435.25 | ||
步驟 1
:向5-碘嘧啶-4,6-二胺(1.00 g,4.237 mmol)及N-[(1r,3r)-3-乙炔基環丁基]胺基甲酸第三丁酯(0.99 g,5.084 mmol)於DMF (10 mL)中之攪拌溶液中添加Pd(PPh3)2Cl2 (297.40 mg,0.424 mmol)、CuI (161.39 mg,0.847 mmol)及TEA (1.29 g,12.711 mmol)。所得混合物在50℃下在氮氣氛圍下攪拌2小時。LCMS顯示完成。殘餘物用CH2
Cl2
/MeOH (20:1)溶離、藉由矽膠管柱層析來純化,得到呈棕色固體狀之N-[(1r,3r)-3-[2-(4,6-二胺基嘧啶-5-基)乙炔基]環丁基]胺基甲酸第三丁酯(600 mg,46.7%)。
6-((1r,3r)-3-胺基環丁基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 2
:向N-[(1r,3r)-3-[2-(4,6-二胺基嘧啶-5-基)乙炔基]環丁基]胺基甲酸第三丁酯(600.00 mg,1.978 mmol)於NMP (10 mL)中之攪拌溶液中添加第三丁醇鉀(665.81 mg,5.933 mmol)。所得混合物在100℃下攪拌3小時。LCMS顯示完成。殘餘物用CH2
Cl2
/MeOH (1:1)溶離、藉由矽膠管柱層析來純化,得到呈棕色固體狀之6-[(1r,3r)-3-胺基環丁基]-7H-吡咯并[2,3-d]嘧啶-4-胺(300 mg,74.6%)。
5-溴-6-[(1r,3r)-3-胺基環丁基]-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:向6-[(1r,3r)-3-胺基環丁基]-7H-吡咯并[2,3-d]嘧啶-4-胺(300.00 mg,1.476 mmol)於DMF (5 mL)中之攪拌溶液中添加NBS (262.71 mg,1.476 mmol)。所得混合物在0℃下攪拌1小時。LCMS顯示完成。殘餘物用CH2
Cl2
/MeOH (1:1)溶離、藉由矽膠管柱層析來純化,得到呈棕色固體狀之5-溴-6-[(1r,3r)-3-胺基環丁基]-7H-吡咯并[2,3-d]嘧啶-4-胺(200 mg,48%)。
N-((1r,3r)-3-(4-胺基-5-溴-7H-吡咯并[2,3-d]嘧啶-6-基)環丁基)甲基丙烯醯胺
步驟 4
:向5-溴-6-[(1r,3r)-3-胺基環丁基]-7H-吡咯并[2,3-d]嘧啶-4-胺(10.00 mg,0.035 mmol)及TEA (10.76 mg,0.106 mmol)於DCM (1 mL)中之攪拌溶液中添加甲基丙烯醯氯(3.70 mg,0.035 mmol)。所得混合物在-30℃下攪拌1小時。反應混合物經由Celite®
墊過濾,用DCM洗滌墊,且真空濃縮濾液。所得粗物質藉由HPLC純化(乙腈/水/0.1%甲酸)。凍乾產生呈白色非晶形固體狀之N-((1r,3r)-3-(4-胺基-5-溴-7H-吡咯并[2,3-d]嘧啶-6-基)環丁基)甲基丙烯醯胺(3.00 mg,24.5%)。
N-((1r,3r)-3-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)環丁基)甲基丙烯醯胺
步驟 5
:向2-甲基-N-[(1r,3r)-3-[4-胺基-5-溴-7H-吡咯并[2,3-d]嘧啶-6-基]環丁基]丙-2-烯醯胺(60 mg,0.171 mmol)及Cs2CO3 (167.46 mg,0.514 mmol)於DMF (2 mL)中之攪拌溶液中添加CH3I (24.32 mg,0.171 mmol)。所得混合物在0℃下攪拌1小時。過濾所得混合物,用DMF洗滌濾餅。粗物質不經進一步純化即直接用於下一步驟中。
N-((1r,3r)-3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丁基)甲基丙烯醯胺
步驟 6
:向2-甲基-N-[(1r,3r)-3-[4-胺基-5-溴-7-甲基吡咯并[2,3-d]嘧啶-6-基]環丁基]丙-2-烯醯胺(10.00 mg,0.027 mmol)及4-(吡咯啶-1-羰基)苯基酸(7.22 mg,0.033 mmol)於DMF (1 mL)及水(0.1 mL)中之溶液中添加CsF (12.51 mg,0.082 mmol)及Pd(DtBPF)Cl2 (1.79 mg,0.003 mmol)。在90℃下在氮氣氛圍下攪拌殘餘物2小時。反應混合物用水(10 mL)稀釋,且水相用二氯甲烷(10 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(5 g管柱;用二氯甲烷/甲醇/0.1%三乙胺溶離;比率)。真空濃縮,產生呈白色非晶形固體狀之N-((1r,3r)-3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丁基)甲基丙烯醯胺(3.0 mg,24.2%)。
根據實例36之方法製備的其他化合物描繪於下表35中。表 35 . 其他例示性化合物
實例37流程 34
(4-(4-胺基-7-甲基-6-乙烯基-7H-吡咯并[2,3-d]嘧啶-5基)苯基)(吡咯啶-1-基)甲酮
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-(4-(3-(4-胺基-7-甲基-5-(4-(6-甲基吡啶-2-基氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)氮雜環丁-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 7.75 (t,J = 7.7 Hz, 1H), 7.42 - 7.36 (m, 2H), 7.23 - 7.17 (m, 2H), 7.03 (d,J = 7.4 Hz, 1H), 6.82 (d,J = 8.1 Hz, 1H), 6.75 (dd,J = 16.7, 10.5 Hz, 1H), 6.05 (dd,J = 16.7, 2.4 Hz, 1H), 5.73 (s, 1H), 5.63 (dd,J = 10.5, 2.4 Hz, 1H), 3.99 (p,J = 8.0 Hz, 1H), 3.88 (d,J = 13.2 Hz, 1H), 3.75 (d,J = 13.4 Hz, 1H), 3.67 (s, 3H), 3.54 (t,J = 6.9 Hz, 2H), 3.15 (t,J = 11.5 Hz, 1H), 2.99 (t,J = 11.2 Hz, 1H), 2.77 (s, 2H), 2.35 (s, 3H), 2.07 (s, 1H), 1.48 (s, 2H), 1.03 (s, 2H). | 523.64 | |
1-(4-(3-(4-胺基-5-(3-甲氧基-4-(6-甲基吡啶-2-基氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)氮雜環丁-1-基)哌啶-1-基)丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.11 (s, 1H), 7.68 (t,J = 7.7 Hz, 1H), 7.20 (d,J = 8.0 Hz, 1H), 7.10 (d,J = 1.9 Hz, 1H), 7.00 - 6.92 (m, 2H), 6.76 (dd,J = 16.7, 10.5 Hz, 1H), 6.69 (d,J = 8.2 Hz, 1H), 6.05 (dd,J = 16.7, 2.4 Hz, 2H), 5.63 (dd,J = 10.5, 2.5 Hz, 1H), 4.03 (p,J = 8.1 Hz, 1H), 3.90 (d,J = 12.9 Hz, 1H), 3.69 (d,J = 14.5 Hz, 5H), 3.59 (s, 2H), 3.15 (s, 1H), 2.97 (d,J = 11.5 Hz, 1H), 2.81 (s, 2H), 2.30 (s, 3H), 2.09 (s, 1H), 1.50 (s, 2H), 1.04 (s, 2H). | 553.66 | |
N-((1r,3r)-3-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丁基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (d,J = 6.4 Hz, 1H), 8.11 (s, 1H), 7.62 (d,J = 7.7 Hz, 2H), 7.44 (d,J = 7.8 Hz, 2H), 5.64 (s, 2H), 5.36 - 5.31 (m, 1H), 4.08 - 4.00 (m, 2H), 3.70 (s, 3H), 3.54 - 3.44 (m, 4H), 2.29 (t,J = 7.5 Hz, 4H), 1.88 (dt,J = 11.3, 5.7 Hz, 3H), 1.84 (s, 4H). | 459.20 |
步驟 1
:向可再密封之反應瓶中裝入6-碘-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-胺(1 g,2.23 mmol)、三丁基(乙烯基)錫烷(846 mg,2.67 mmol)、Pd(PPh3)4 (257 mg,223 μmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二甲基甲醯胺(20 mL),且在110℃下攪拌混合物隔夜。反應混合物用水(50 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色非晶形固體狀之6-乙烯基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-胺(700 mg,90%)。
N-[(第三丁氧基)羰基]-N-{6-乙烯基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基}胺基甲酸第三丁酯
步驟 2
:向圓底燒瓶中裝入6-乙烯基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-胺(700 mg,2.01 mmol)、二碳酸二-第三丁酯(1.75 g,8.04 mmol)、Et3N (813 mg,8.04 mmol)、DMAP (24.5 mg,201 μmol)、二氯甲烷(20 mL)及攪拌棒。在室溫下攪拌混合物隔夜。反應混合物用水(50 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色非晶形固體狀之N-[(第三丁氧基)羰基]-N-{6-乙烯基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基}胺基甲酸第三丁酯(990 mg,89%)。
2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙烷-1-甲酸酯
步驟 3
:向可再密封之反應瓶中裝入N-[(第三丁氧基)羰基]-N-{6-乙烯基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-基}胺基甲酸第三丁酯(800 mg,1.46 mmol)、丙酸乙酯(149 mg,1.46 mmol)、5,10,15,20-四苯基-21H,23H-卟吩(19.6 mg,29.2 μmol)、甲苯(15 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在110℃下攪拌反應混合物2小時。反應混合物經由Celite®
墊過濾,用二氯甲烷洗滌墊,且真空濃縮濾液。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色非晶形固體狀之2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3 d]嘧啶-6-基)環丙烷-1-甲酸乙酯(550 mg,59%)。
2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙烷-1-甲酸
步驟 4
:向圓底燒瓶中裝入2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙烷-1-甲酸乙酯(1.7 g,2.68 mmol)、MeOH (15 mL)及攪拌棒。添加NaOH水溶液(2 M)(15 mL),且在室溫下攪拌溶液2小時。用HCl水溶液(2 M)將pH調整至3~4,收集固體,真空乾燥,產生呈灰白色固體狀的2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙烷-1-甲酸(1.30 g,80%)。
(第三丁氧基羰基)(6-(2-((第三丁氧基羰基)胺基)環丙基)-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-基)胺基甲酸第三丁酯
步驟 5
:向圓底燒瓶中裝入2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙烷-1-甲酸(400 mg,660 µmol)、TEA (73.3 mg,726 µmol)、DPPA (2.18 g,7.92 mmol)及攪拌棒。添加t-BuOH (10 mL),且在80℃下攪拌溶液4小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由製備型HPLC (乙腈/水/0.1%甲酸)純化。凍乾產生呈灰白色非晶形固體狀之N-[2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基]胺基甲酸第三丁酯(200 mg,49%)。
(4-(4-胺基-6-(2-胺基環丙基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)苯基)(吡咯啶-1-基)甲酮
步驟 6
:向圓底燒瓶中裝入N-[2-(4-{雙[(第三丁氧基)羰基]胺基}-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基]胺基甲酸第三丁酯(200 mg,295 µmol)及攪拌棒。添加DCM:TFA=4:1 (11 mL),且在室溫下攪拌溶液1小時。移除溶劑,粗產物(200 mg)不經進一步純化即直接用於下一步驟中。
N-(2-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基)丙烯醯胺
步驟 7
:向圓底燒瓶中裝入6-(2-胺基環丙基)-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-4-胺(200 mg,0.42 mmol)、TEA (213 mg,2.1 mmol)、二氯甲烷(10 mL)及攪拌棒。在0℃下添加丙-2-烯醯氯(38 mg,0.42 mmol)。在0℃下攪拌反應混合物0.5小時。移除溶劑,所得粗物質藉由製備型HPLC純化(管柱:XBridge Prep OBD C18管柱,30×150mm 5um;移動相A:未定義,移動相B:未定義;流量:60 mL/min;梯度:11 B至35 B,歷時7分鐘;254 nm;RT1:6.75;RT2:;注射體積:ml;操作次數:;)。凍乾產生呈灰白色非晶形固體狀之N-(2-{4-胺基-7-甲基-5-[4-(吡咯啶-1-羰基)苯基]-7H-吡咯并[2,3-d]嘧啶-6-基}環丙基)丙-2-烯醯胺(140 mg,77%)。將物質送交對掌性分離(管柱:CHIRALPAK IG,2*25cm,5um;移動相A:Hex:DCM=3:1(10 mM NH3-MEOH)--HPLC,移動相B:EtOH--HPLC;流量:20 mL/min;梯度:30 B至30 B,歷時18分鐘;220/254 nm;RT1:7.758;RT2:10.625;注射體積:0.6 ml;操作次數:10),產生四個峰:峰1 (16.7 mg)、峰2 (28.5 mg)、3 (18.1 mg)、峰4 (28.8 mg)。
根據實例37之方法製備的其他化合物描繪於下表36中。表 36 . 其他例示性化合物
實例38流程 35
1,4-二甲基-5-(三丁基錫烷基)-1H-吡唑
化合物 | 結構 | 質子 NMR | MS [M+1] | |||
N-((1S,2S)-2-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.40 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.70 - 7.56 (m, 2H), 7.51 - 7.37 (m, 2H), 6.50 - 5.89 (m, 3H), 5.61 (dd,J = 9.6, 2.6 Hz, 1H), 3.89 (s, 3H), 3.49 (t,J = 6.9 Hz, 2H), 3.44 (q,J = 6.4 Hz, 2H), 2.70 (dq,J = 8.8, 4.5 Hz, 1H), 2.19 (ddd,J = 9.8, 6.4, 3.8 Hz, 1H), 1.87 (ddq,J = 25.5, 13.0, 6.7, 5.8 Hz, 4H), 1.01 (dt,J = 9.8, 5.1 Hz, 1H), 0.57 (dt,J = 7.6, 5.7 Hz, 1H). | 431.20 | ||||
N-((1R,2S)-2-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.20 (s, 1H), 7.70 (d,J = 6.5 Hz, 1H), 7.69 - 7.61 (m, 2H), 7.47 - 7.40 (m, 2H), 6.19 (s, 2H), 5.99 (d,J = 6.2 Hz, 2H), 5.48 (t,J = 6.2 Hz, 1H), 3.73 (s, 3H), 3.50 (td,J = 6.8, 3.0 Hz, 5H), 3.47 - 3.40 (m, 1H), 2.27 (dt,J = 9.1, 7.1 Hz, 1H), 1.88 (dp,J = 19.1, 6.7 Hz, 4H), 1.29 - 1.04 (m, 1H), 0.41 (q,J = 5.7 Hz, 1H). | 431.20 | ||||
N-((1R,2R)-2-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (d,J = 5.0 Hz, 1H), 8.20 (s, 1H), 7.67 - 7.53 (m, 2H), 7.49 - 7.40 (m, 2H), 6.45 - 5.98 (m, 3H), 5.61 (dd,J = 9.7, 2.7 Hz, 1H), 3.88 (s, 3H), 3.50 (d,J = 6.8 Hz, 2H), 3.49 - 3.40 (m, 2H), 2.70 (ddd,J = 8.7, 6.5, 3.1 Hz, 1H), 2.19 (ddd,J = 9.8, 6.4, 3.8 Hz, 1H), 1.89 (t,J = 6.6 Hz, 2H), 1.82 (q,J = 6.3 Hz, 2H), 1.01 (dt,J = 9.8, 5.2 Hz, 1H), 0.57 (dt,J = 7.6, 5.7 Hz, 1H). | 431.20 | ||||
N-((1S,2R)-2-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)環丙基)丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.17 (s, 1H), 7.69 (d,J = 6.5 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.48 - 7.41 (m, 2H), 5.99 (d,J = 6.2 Hz, 3H), 5.47 (t,J = 6.2 Hz, 1H), 3.72 (s, 3H), 3.50 (td,J = 7.0, 3.5 Hz, 4H), 3.47 - 3.40 (m, 1H), 2.27 (dt,J = 9.1, 7.1 Hz, 1H), 1.88 (dp,J = 18.9, 6.8 Hz, 4H), 1.16 (td,J = 8.5, 5.8 Hz, 1H), 0.41 (dt,J = 7.1, 5.5 Hz, 1H). | 431.20 | ||||
步驟 1
:在-78℃下,在N2氛圍下,向1,4-二甲基吡唑(2.00 g,20.805 mmol)於THF (15 mL)中之溶液中逐滴添加正丁基鋰溶液(2.5 M,於THF中,1.07 mL,16.644 mmol)。在-78℃下攪拌反應混合物30分鐘。接著逐滴添加Bu3SnCl (10.16 g,31.207 mmol)溶液且再攪拌混合物2小時。反應物用飽和NH4Cl (100 mL)淬滅,且接著用EtOAc (3*50mL)萃取混合物。合併之有機萃取物用鹽水(50 mL)洗滌,經無水Na2
SO4
乾燥,且在真空下濃縮,產生粗產物,藉由矽膠管柱層析(PE/EA=4:1)來純化,產生呈無色油狀的1,4-二甲基-5-(三丁基錫烷基)吡唑(5.6 g,69.9%)。
6-(1,4-二甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 2
:6-碘-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-4-胺(1.40 g,3.055 mmol)、1,4-二甲基-5-(三丁基錫烷基)吡唑(2.94 g,7.638 mmol)、肆(三苯膦)鈀(353.03 mg,0.306 mmol)及碘化亞銅(I)(116.37 mg,0.611 mmol)於甲苯中之溶液/混合物在氮氣氛圍下、在110℃下攪拌隔夜。反應混合物用水稀釋,用CH2
Cl2
(3×50 mL)萃取。合併之有機層用鹽水(1x70 mL)洗滌,經無水Na2
SO4
乾燥。過濾之後,在減壓下濃縮濾液。殘餘物用CH2
Cl2
/MeOH (12:1)溶離、藉由矽膠管柱層析來純化,得到呈淺黃色固體狀之6-(2,4-二甲基吡唑-3-基)-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-4-胺(320 mg,24.6%)。
6-(3-碘-1,4-二甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:6-(3-碘-1,4-二甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺(320 mg,0.75 mmol)、NIS (337 mg,1.50 mmol)及三氟乙醛(368 mg,3.75 mmol)於DCM中之溶液/混合物在60℃下攪拌48小時。反應混合物用水稀釋,用CH2
Cl2
(3×30 mL)萃取。合併之有機層用鹽水洗滌,經無水Na2
SO4
乾燥。過濾之後,在減壓下濃縮濾液。殘餘物藉由製備型TLC (CH2
Cl2
/MeOH 10:1)純化,得到呈淡黃色固體狀之6-(3-碘-1,4-二甲基-1H-吡唑-5-基)-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-4-胺(171 mg,41.3%)。
(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基-1H-吡唑-3-基)胺基甲酸第三丁酯
步驟 4
:6-(5-碘-2,4-二甲基吡唑-3-基)-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-4-胺(170 mg,0.31 mmol)、胺基甲酸第三丁酯(72 mg,0.62 mmol)、碘化亞銅(I)(12 mg,0.063 mmol)及甲烷過氧酸鉀(86 mg,0.62 mmol)於二噁烷中之溶液/混合物在氮氣氛圍下、在90℃下攪拌隔夜。反應混合物用水稀釋,用CH2
Cl2
(3×30 mL)萃取。合併之有機層用鹽水(1x30 mL)洗滌,經無水Na2
SO4
乾燥。過濾之後,在減壓下濃縮濾液。藉由製備型TLC (CH2
Cl2
/MeOH 10:1)來純化殘餘物,得到呈無色油狀的N-[5-(4-胺基-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基吡唑-3-基]胺基甲酸第三丁酯(25 mg,15%)。
6-(3-胺基-1,4-二甲基-1H-吡唑-5-基)-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 5
:N-[5-(4-胺基-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基吡唑-3-基]胺基甲酸第三丁酯(25 mg,0.046 mmol)於HCl (氣體)/1,4-二噁烷(1 mL)中之混合物在室溫下攪拌10分鐘。所得混合物在減壓下濃縮。由此產生呈黃色油狀的5-(4-胺基-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基吡唑-3-胺(25 mg,98%)。
N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基-1H-吡唑-3-基)甲基丙烯醯胺
步驟 6
:在0℃下向圓底燒瓶中裝入5-(4-胺基-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基吡唑-3-胺(17 mg,0.039 mmol)、TEA (11.7 mg,0.116 mmol)於DCM (2 mL)中,接著添加甲基丙烯醯氯(3.62 mg,0.035 mmol),攪拌2小時。所得粗物質藉由製備型HPLC純化(管柱:XBridge製備型OBD C18管柱,30×150 mm 5 um;移動相A:水(10 MMOL L NH4
HCO3
),移動相B:ACN;流量:60 mL/min;梯度:20 B至45 B,歷時8分鐘;220nm;RT1:5.78;RT2:;注射體積:ml;操作次數:;)。凍乾產生呈灰白色非晶形固體狀之N-[5-(4-胺基-7-甲基-5-[4-[(4-甲基嘧啶-2-基)氧基]苯基]吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基吡唑-3-基]-2-甲基丙-2-烯醯胺(2.1 mg,10.7%)。表 37 . 例示性化合物
實例39流程 36
N-(4-(4-胺基-3-溴吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(5-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-1,4-二甲基-1H-吡唑-3-基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 氯仿-d) 8.44 (s, 1H), 8.39 (d, J = 5.0 Hz, 1H), 7.54 (s, 1H), 7.26 (q, J = 8.7 Hz, 4H), 6.95 (d, J = 5.0 Hz, 1H), 5.89 (s, 1H), 5.52 (s, 1H), 5.28 (s, 2H), 3.68 (s, 3H), 3.38 (s, 3H), 2.52 (s, 3H), 2.08 (s, 3H), 1.94 (s, 3H). | 510.25 |
向圓底燒瓶中裝入3-溴-2-碘吡唑并[1,5-a]吡嗪-4-胺(1 g,2.95 mmol)、2-甲基-N-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]丙-2-烯醯胺(1.26 g,4.42 mmol)、Pd(dppf)Cl2 (215 mg,295 µmol)、K3PO4 (1.87 g,8.85 mmol)、二噁烷(15 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌反應混合物1小時。反應混合物用水(50 mL)稀釋且用DCM (40 mL*3)萃取,經無水硫酸鈉乾燥,過濾且真空蒸發。藉由矽膠管柱層析來純化殘餘物,得到呈灰白色非晶形固體狀之N-(4-(4-胺基-3-溴吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺(860 mg,78.8%)。
N-(4-(4-胺基-3-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺
向圓底燒瓶中裝入N-(4-{4-胺基-3-溴吡唑并[1,5-a]吡嗪-2-基}苯基)-2-甲基丙-2-烯醯胺(100 mg,268 µmol)、1-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-羰基]吡咯啶(112 mg,402 µmol)、Pd(dtbpf)Cl2 (17.4 mg,26.8 µmol)、CsF (122 mg,804 µmol)、DMF/H2O (10:1,5 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。在90℃下攪拌反應混合物1小時。反應混合物用水(20 mL)稀釋且用DCM (10 mL*3)萃取。合併之有機相經無水硫酸鈉乾燥,過濾且蒸發。藉由製備型HPLC純化殘餘物(管柱:Xselect CSH OBD管柱30*150mm 5um, n;移動相A:水(0.1% FA),移動相B:ACN;流量:60 mL/min;梯度:28 B至60 B,歷時8分鐘;220/254 nm;RT1:6.55;RT2)。凍乾產生呈白色非晶形固體狀之化合物(25 mg,13%)。
根據實例39之方法製備的其他化合物描繪於下表38中。表 38. 其他例示性化合物
實例40流程 37
4-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]嘧啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-3-(4-((4-甲基嘧啶-2-基)氧基)苯基)吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d4) δ 8.46 (d, J = 5.0 Hz, 1H), 7.96 (d, J = 4.9 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.55 - 7.45 (m, 4H), 7.38 - 7.30 (m, 2H), 7.30 (d, J = 4.9 Hz, 1H), 7.17 (d, J = 5.1 Hz, 1H), 5.83 - 5.78 (m, 1H), 5.55 - 5.50 (m, 1H), 2.53 (s, 3H), 2.04 (dd, J = 1.7, 0.9 Hz, 3H). | 478.20 | |
N-(4-(4-胺基-3-(4-(吡咯啶-1-羰基)苯基)吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, 甲醇-d 4 ) δ 7.97 (d,J = 4.8 Hz, 1H), 7.68 (d,J = 7.9 Hz, 2H), 7.55 (dd,J = 11.1, 8.2 Hz, 4H), 7.42 (d,J = 8.7 Hz, 2H), 7.31 (d,J = 4.9 Hz, 1H), 5.80 (s, 1H), 5.53 (s, 1H), 3.65 (t,J = 6.9 Hz, 2H), 3.56 (t,J = 6.5 Hz, 2H), 2.05 (d,J = 6.5 Hz, 1H), 2.03 (s, 4H), 1.97 (p,J = 6.9 Hz, 2H). | 467.20 | |
(S)-N-(4-(4-胺基-3-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 7.90 (d,J = 4.6 Hz, 1H), 7.77 (d,J = 2.7 Hz, 4H), 7.22 (d,J = 4.7 Hz, 1H), 6.74 (s, 2H), 5.95 (s, 1H), 5.83 (s, 1H), 5.54 (s, 1H), 3.63 - 3.53 (m, 1H), 3.49 (q,J = 8.7, 7.8 Hz, 1H), 3.39 (s, 1H), 3.36 (d,J = 5.0 Hz, 1H), 3.32 - 3.24 (m, 1H), 3.00 (s, 1H), 2.39 (s, 2H), 2.20 - 1.70 (m, 11H). | 471.25 | |
(R)-N-(4-(4-胺基-3-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 7.90 (d,J = 4.6 Hz, 1H), 7.77 (d,J = 2.7 Hz, 4H), 7.22 (d,J = 4.7 Hz, 1H), 6.74 (s, 2H), 5.95 (s, 1H), 5.83 (s, 1H), 5.54 (s, 1H), 3.63 - 3.53 (m, 1H), 3.49 (q,J = 8.7, 7.8 Hz, 1H), 3.39 (s, 1H), 3.36 (d,J = 5.0 Hz, 1H), 3.32 - 3.24 (m, 1H), 3.00 (s, 1H), 2.39 (s, 2H), 2.20 - 1.70 (m, 11H). | 471.25 | |
N-(4-(4-胺基-3-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)吡唑并[1,5-a]吡嗪-2-基)苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.91 (s, 1H), 7.90 (d,J = 4.6 Hz, 1H), 7.77 (d,J = 2.7 Hz, 4H), 7.22 (d,J = 4.7 Hz, 1H), 6.74 (s, 2H), 5.95 (s, 1H), 5.83 (s, 1H), 5.54 (s, 1H), 3.63 - 3.53 (m, 1H), 3.49 (q,J = 8.7, 7.8 Hz, 1H), 3.39 (s, 1H), 3.36 (d,J = 5.0 Hz, 1H), 3.32 - 3.24 (m, 1H), 3.00 (s, 1H), 2.39 (s, 2H), 2.20 - 1.70 (m, 11H). | 471.25 | |
2-(6-乙炔基-4-甲基吡啶-3-基)-3-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-4H-吡唑并[5,1-c][1,4]噁嗪 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.47 (d,J = 5.0 Hz, 1H), 8.33 (s, 1H), 7.52 (d,J = 0.9 Hz, 1H), 7.29 (t,J = 8.4 Hz, 1H), 7.18 (d,J = 5.1 Hz, 1H), 7.02 (dd,J = 11.7, 2.1 Hz, 1H), 6.85 - 6.78 (m, 1H), 5.02 (s, 2H), 4.36 (s, 1H), 4.27 (t,J = 5.1 Hz, 2H), 4.17 (t,J = 5.2 Hz, 2H), 2.42 (s, 3H), 2.07 (s, 3H). | 442.15 |
步驟 1
:將t
-BuOK (7.24 g,2.0 eq,77.6 mmol)分數份添加2-氯-4-甲基嘧啶(5.00 g,1.2 eq,38.80 mmol)及4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯酚(7.10 g,32.30 mmol)於DMF (30.0 mL)中之溶液,且在120℃下攪拌溶液12小時。將反應混合物冷卻且用水(50.0 mL)稀釋,接著用EtOAc (30.0 mL×3)萃取,在減壓下濃縮合併之有機層。殘餘物藉由管柱層析純化(石油醚/EtOAc=10/1至4/1)。4-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]嘧啶(2.90 g,22.9%產量)以混合物形式獲得,其不經進一步純化即用於下一步驟。
4-氯-5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶
步驟 2
:向4-氯-5-碘-7H
-吡咯并[2,3-d]嘧啶(5.00 g,17.80 mmol)於DMF (20.0 mL)中之溶液中添加NaH (1.06 g,1.5 eq,26.70 mmol,60%純度),所得混合物在25℃下攪拌0.5小時,接著添加SEMCl (3.85 g,1.3 eq,23.14 mmol)。在25℃下攪拌反應混合物12小時。過濾反應混合物且在減壓下濃縮。殘餘物藉由管柱層析純化(石油醚/EtOAc=10/1至4/1)。獲得呈白色固體狀之4-氯-5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶(3.90 g,53.4%產量)。
5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-4-胺
步驟 3
:4-氯-5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶(3.90 g,9.51 mmol)於二噁烷(15.0 mL)及NH3
·H2
O (15.0 mL,15.8 eq,150.26 mmol,25%純度)中之溶液在高壓釜中、在130℃下攪拌19小時。冷卻反應混合物且在減壓下濃縮。殘餘物藉由管柱層析純化(石油醚/EtOAc = 4/1至2/1)。獲得呈白色固體狀之5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-4-胺(3.50 g,94.3%產量)。
5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺
步驟 4
:5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-4-胺(2.58 g,6.62 mmol)、4-甲基-2-(4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基)嘧啶(2.90 g,1.4 eq,9.27 mmol)、Pd(PPh3
)4
(764.0 mg,0.1 eq,0.66 mmol)、K3
PO4
(3.50 g,2.5 eq,16.55 mmol)於二噁烷(30.0 mL)及H2
O (10.0 mL)中之溶液在80℃下攪拌5小時。冷卻且過濾反應物,濃縮濾液,殘餘物藉由管柱層析純化(石油醚/EtOAc = 1/1至0/1)。獲得呈黃色油狀之5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-4-胺(1.70 g,57.4%產率)。
6-溴-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d
]嘧啶-4-胺
步驟 5
:向5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-4-胺(1.60 g,3.56 mmol)於DMF (30.0 mL)中之溶液中分數份添加NBS (695.0 mg,1.1 eq,3.92 mmol)。在25℃下攪拌反應物0.5小時。接著濃縮反應物且藉由管柱層析純化殘餘物(石油醚/EtOAc = 4/1至2/1)。獲得呈淡黃色固體狀之產物6-溴-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d
]嘧啶-4-胺(1.20 g,64.1%產率)。
5-溴-2-氯吡啶-4-甲酸甲酯
步驟 6
:在0℃下,向5-溴-2-氯吡啶-4-甲酸(15.00 g,63.40 mmol)於MeOH (50.0 mL)中之溶液中緩慢添加SOCl2
(11.30 g,1.5 eq,95.10 mmol)。接著將反應混合物加熱至70℃且在此溫度下保持6小時。在減壓下濃縮反應混合物,殘餘物藉由管柱層析純化(石油醚/EtOAc = 10/1至5/1)。獲得呈無色油狀的5-溴-2-氯吡啶-4-甲酸甲酯(12.00 g,75.9%產率)。
(5-溴-2-氯吡啶-4-基)甲醇
步驟 7
:在0℃下,向5-溴-2-氯吡啶-4-甲酸甲酯(11.5 g,45.90 mmol)於THF (100.0 mL)中之溶液中緩慢添加LiBH4
(1.49 g,1.5 eq,68.85 mmol)。使所得溶液升溫至25℃且在此溫度下攪拌2小時,隨後藉由MeOH淬滅。在減壓下濃縮反應混合物,殘餘物藉由管柱層析(石油醚/EtOAc = 10/1至3/1)純化。獲得呈白色固體狀之(5-溴-2-氯吡啶-4-基)甲醇(6.70 g,65.6%產率)。
5-溴-4-(溴甲基)-2-氯吡啶
步驟 8
:(5-溴-2-氯吡啶-4-基)甲醇(1.00 g,4.49 mmol)、PPh3
(1.76 g,1.5 eq,6.73 mmol)及CBr4
(2.23 g,1.5 eq,6.73 mmol)於DCM (15.0 mL)中之溶液在0℃下攪拌0.5小時。在減壓下濃縮反應混合物,殘餘物藉由管柱層析純化(石油醚/EtOAc = 20/1至10/1)。獲得呈無色油狀的5-溴-4-(溴甲基)-2-氯吡啶(1.20 g,93.7%產率)。
2-[(5-溴-2-氯吡啶-4-基)甲基]丙二酸1,3-二甲酯
步驟 9
:在0℃下,將NaH (1.07 g,1.1 eq,26.95 mmol,60%純度)懸浮於無水THF (70.0 mL)中,且用丙二酸二甲酯(3.23 g,1.0 eq,24.50 mmol)溶液逐滴處理。在25℃下攪拌30分鐘之後,添加5-溴-4-(溴甲基)-2-氯吡啶(7.00 g,24.50 mmol)於無水THF (10.0 mL)中之溶液且再繼續攪拌2小時。反應混合物用水(1.0 mL)淬滅且在減壓下濃縮,殘餘物藉由管柱層析純化(石油醚/EtOAc = 1/0至10/1)。獲得呈白色固體狀之2-[(5-溴-2-氯吡啶-4-基)甲基]丙二酸1,3-二甲酯(5.80 g,70.3%產率)。
3-(5-溴-2-氯吡啶-4-基)丙酸甲酯
步驟 10
:2-[(5-溴-2-氯吡啶-4-基)甲基]丙二酸1,3-二甲酯(5.3 g,15.70 mmol)、NaCl (912.0 mg,1.0 eq,15.70 mmol)及H2
O (563.0 mg,2.0 eq,31.40 mmol)於DMSO (80.0 mL)中之溶液在160℃下攪拌2小時。冷卻至室溫後,將反應混合物傾入EtOAc (70.0 mL)中。所得溶液用H2
O (500.0 mL)、鹽水(300.0 mL)洗滌,經無水MgSO4
乾燥且接著在減壓下濃縮,殘餘物藉由管柱層析純化(石油醚/EtOAc = 20/1至10/1)。獲得呈無色油狀的3-(5-溴-2-氯吡啶-4-基)丙酸甲酯(2.60 g,59.9%產率)。
3-[2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-4-基]丙酸甲酯
步驟 11
:3-(5-溴-2-氯吡啶-4-基)丙酸甲酯(1.00 g,3.59 mmol)、BPD (1.09 g,1.2 eq,4.30 mmol)、KOAc (1.05 g,3.0 eq,10.77 mmol)及Pd(dppf)Cl2
(525.0 mg,0.2 eq,0.72 mmol)於二噁烷(20.0 mL)中之溶液在70℃下、在N2
下攪拌12小時。在減壓下濃縮反應混合物,殘餘物藉由管柱層析純化(石油醚/EtOAc = 20/1至10/1)。獲得呈白色固體狀之3-[2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-4-基]丙酸甲酯(0.90 g,77.5%產率)。
3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙酸甲酯
步驟 12
:6-溴-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-4-胺(550.0 mg,1.04 mmol)、3-[2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-4-基]丙酸甲酯(403.0 mg,1.2 eq,1.24 mmol)、Pd[Pd(t - Bu
)3
]2
(106.0 mg,0.2 eq,0.21 mmol)及CsF (521.0 mg,3.3 eq,3.43 mmol)於THF (20.0 mL)及H2
O (20.0 mL)中之溶液在50℃下、在N2
下攪拌12小時。在減壓下濃縮反應混合物,殘餘物藉由管柱層析純化(MeOH/EtOAc = 0/1至1/10)。獲得呈棕色固體狀之3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d
]嘧啶-6-基)-2-氯吡啶-4-基]丙酸甲酯(420.0 mg,62.4%產率)。
3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d
]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇
步驟 13
:將LiBH4
(20.1 mg,3.0 eq,927.0 mmol)緩慢添加至3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d
]嘧啶-6-基)-2-氯吡啶-4-基]丙酸甲酯(200.0 mg,309.0 µmol)於THF (15.0 mL)及MeOH (24.7 mg,2.0 eq,618.0 mmol)中之溶液中。反應混合物在25℃下攪拌2小時,隨後藉由MeOH (0.2 mL)淬滅,濃縮反應混合物,殘餘物藉由管柱層析純化(DCM/MeOH = 1/0至10/1)。獲得呈白色固體狀之3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(180.0 mg,94.2%產率)。
3-{5-[4-胺基-7-(羥基甲基)-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H
-吡咯并[2,3-d
]嘧啶-6-基]-2-氯吡啶-4-基}丙-1-醇
步驟 14
:3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H
-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(190.0 mg,307.0 µmol)於DCM (15.0 mL)及TFA (6.0 mL)中之溶液在25℃下攪拌2小時。在減壓下濃縮反應混合物。獲得呈無色油狀的3-{5-[4-胺基-7-(羥基甲基)-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H
-吡咯并[2,3-d]嘧啶-6-基]-2-氯吡啶-4-基}丙-1-醇(155.0 mg,97.4%產率),其不經進一步純化即可用於下一步驟。
3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇
步驟 15
:3-{5-[4-胺基-7-(羥基甲基)-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H
-吡咯并[2,3-d
]嘧啶-6-基]-2-氯吡啶-4-基}丙-1-醇(155.0 mg,299.0 µmol)於THF (15.0 mL)及TEA (6.0 mL)中之溶液在25℃下攪拌2小時。濃縮反應物混合物,殘餘物藉由管柱層析純化(DCM/MeOH = 1/0至10/1)。獲得呈白色固體狀之3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H
-吡咯并[2,3-d
]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(120.0 mg,82.7%產率)。3 - 氯 - 13 -( 4 -(( 4 - 甲基嘧啶 - 2 - 基 ) 氧基 ) 苯基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 4 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯 - 12 - 胺
步驟 16
:3-[5-(4-胺基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H
-吡咯并[2,3-d
]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(180.0 mg,368.0 µmol)、PPh3
(193.0 mg,2.0 eq,736.0 µmol)及DIAD (148.0 mg,2.0 eq,736.0 µmol)於THF (5.0 mL)中之溶液在25℃下、在N2
下攪拌12小時。濃縮反應混合物,殘餘物藉由管柱層析純化(DCM/MeOH = 20/1至10/1)。獲得呈白色固體狀之3-氯-13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(90.0 mg,52.3%產率)。13 -( 4 -(( 4 - 甲基嘧啶 - 2 - 基 ) 氧基 ) 苯基 )- 3 -(( 三甲基矽烷基 ) 乙炔基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 4 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯 - 12 - 胺
步驟 17
:3-氯-13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(100.0 mg,212.0 µmol)、三甲基乙炔基矽(171.0 mg,8.2 eq,1.74 mmol)、Pd(PPh3
)2
Cl2
(61.7 mg,0.4 eq,84.8 µmol)、PPh3
(45.9 mg,0.8 eq,169.6 µmol)、CuI (33.5 mg,0.8 eq,169.6 µmol)及Et3
N (443.0 mg,20.0 eq,4.24 mmol)於2-Me-THF (4.0 mL)中之溶液在90℃下、在N2
下攪拌12小時。在減壓下濃縮反應混合物,殘餘物藉由管柱層析純化(DCM/MeOH = 10/0至10/1)。13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三甲基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(120.0 mg,107%粗產率)以棕色混合物形式獲得,其不經進一步純化即可用於下一步驟。
3-乙炔基-13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
步驟 18
:向13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三甲基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(100.0 mg,188.0 µmol)於THF (20.0 mL)中之溶液中添加TBAF於THF中之溶液(376.0 µL,2.0 eq,376.0 mol)。所得混合物在25℃下攪拌2小時。在減壓下濃縮反應混合物,殘餘物藉由製備型HPLC純化(NH3
·H2
O)。獲得呈白色固體狀之3-乙炔基-13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(2.6 mg,3.0%產率)。表 39 . 例示性化合物
實例41流程 38
3-(3-溴苯基)-2,5-二氫-1H
-吡咯-1-甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-乙炔基-13-(4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺 | 1 HNMR (400 MHz, CDCl3 ):δ 8.41-8.36 (m, 2H), 8.21 (s, 1H), 7.48 (s, 1H), 7.41-7.38 (m, 2H), 7.31-7.28 (m, 2H), 6.96 (s, 1H), 5.14 (s, 2H), 4.28 (m, 2H), 3.21 (s, 1H), 2.85-2.81 (m, 2H), 2.54 (s, 3H), 2.40-2.36 (m, 2H). | 460.3 |
步驟 1
:1-溴-3-碘苯(956.0 mg,3.4 mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-2,5-二氫-1H
-吡咯-1-甲酸第三丁酯(500.0 mg,1.7 mmol)、Pd(dppf)Cl2
(123.0 mg,169.0 µmol)及K2
CO3
(466.0 mg,3.4 mmol)於二噁烷(20.00 mL)及H2
O (4.0 mL)中之混合物在80℃下、在N2
保護下攪拌12小時。濃縮混合物,得到殘餘物,將其溶解於乙酸乙酯(50 mL)及H2
O (30 mL)中。分離水層且用乙酸乙酯(30 mL×3)萃取。合併之有機層用鹽水(25 mL)洗滌,經無水Na2
SO4
乾燥,過濾且濃縮,得到殘餘物,藉由矽膠層析純化(乙酸乙酯/石油醚 = 0%至11%),得到呈黃色油狀之產物3-(3-溴苯基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(450.0 mg,82.2%產率)。
3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H
-吡咯-1-甲酸第三丁酯
步驟 2
:3-(3-溴苯基)-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(450.0 mg,1.4 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(700.0 mg,2.8 mmol)、Pd(dppf)Cl2
(101.0 mg,138.0 µmol)及AcOK (202.0 mg,2.1 mmol)於二噁烷(20.00 mL)中之混合物在100℃下、在N2
保護下攪拌12小時。濃縮混合物,得到殘餘物,將其溶解於乙酸乙酯(50 mL)及H2
O (30 mL)中。分離水層且用乙酸乙酯(30 mL×3)萃取。合併之有機層用鹽水(25 mL)洗滌,經無水Na2
SO4
乾燥,過濾且濃縮,得到殘餘物,藉由矽膠層析純化(乙酸乙酯/石油醚 = 0%至12%),得到呈黃色油狀之產物3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(450.0 mg,87.8%產率)。
3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H-吡咯鹽酸鹽
步驟 3
:添加HCl/EtOAc (6.00 mL,4 M)中之3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H-吡咯-1-甲酸第三丁酯(450.0,1.2 mmol)。在25℃下攪拌混合物2小時。濃縮混合物,得到呈黃色油狀之3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H
-吡咯鹽酸鹽(372.0 mg,100%產率)。
1-{3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H
-吡咯-1-基}丙-2-烯-1-酮
步驟4:在0℃下,將DCM (3.00 mL)中之丙-2-烯醯氯(140.0 mg,1.6 mmol)添加於3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H-吡咯鹽酸鹽(372.0 mg,1.2 mmol)及DIEA (1.04 mL,6.0 mmol)於DCM (12.00 mL)中之混合物中。在25℃下攪拌混合物4小時。混合物用DCM (20 mL)稀釋,用飽和NaHCO3
(20 mL)、鹽水(20 mL)洗滌,經無水Na2
SO4
乾燥,過濾且濃縮,得到殘餘物,藉由矽膠層析純化(乙酸乙酯/石油醚 = 0%至45%),得到呈黃色油狀之產物1-{3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H-吡咯-1-基}丙-2-烯-1-酮(210.0 mg,53.8%產率)。
1-[3-(3-{4-胺基-5-溴-7-甲基-7H
-吡咯并[2,3-d
]嘧啶-6-基}苯基)-2,5-二氫-1H
-吡咯-1-基]丙-2-烯-1-酮
步驟 5
:1-{3-[3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2,5-二氫-1H
-吡咯-1-基}丙-2-烯-1-酮(210.0 mg,645.0 µmol)、5-溴-6-碘-7-甲基-7H
-吡咯并[2,3-d
]嘧啶-4-胺(250.0 mg,709.0 µmol)、Pd(PPh3
)4
(74.4 mg,64.5 µmol)及K3
PO4
(271.0 mg,1.28 mmol)於DMF (16.00 mL)及H2
O (4.00 mL)中之混合物在50℃下、在N2
保護下攪拌12小時。混合物用乙酸乙酯(30 mL)稀釋,用H2
O (20 mL×3)、鹽水(15 mL)洗滌,經無水Na2
SO4
乾燥,過濾且濃縮,得到殘餘物,藉由矽膠層析純化(甲醇/二氯甲烷 = 0%至14%),得到呈黃色油狀之產物1-[3-(3-{4-胺基-5-溴-7-甲基-7H
-吡咯并[2,3-d
]嘧啶-6-基}苯基)-2,5-二氫-1H
-吡咯-1-基]丙-2-烯-1-酮(70.0 mg,25.6%產率)。
1-{3-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)苯基]-2,5-二氫-1H-吡咯-1-基}丙-2-烯-1-酮
1-[3-(3-{4-胺基-5-溴-7-甲基-7H
-吡咯并[2,3-d
]嘧啶-6-基}苯基)-2,5-二氫-1H
-吡咯-1-基]丙-2-烯-1-酮(50.0 mg,117.0 µmol)、2-甲基-6-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]吡啶(54.4 mg,175.0 µmol)、Pd2
(dba)3
(10.7 mg,117.0 µmol)、XPhos (11.1 mg,117.0 µmol)、K2
CO3
(48.4 mg,117.0 µmol)於二噁烷(4.00 mL)及H2
O (1.00 mL)中之混合物在95℃下、在N2
保護下攪拌12小時。過濾混合物且濃縮濾液,得到殘餘物,藉由製備型HPLC (HCl)純化,得到呈白色固體狀的產物1-{3-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H
-吡咯并[2,3-d
]嘧啶-6-基)苯基]-2,5-二氫-1H
-吡咯-1-基}丙-2-烯-1-酮(4.9 mg,7.41%產率)。
根據實例41之方法製備的其他化合物描繪於下表40中。表 40 . 例示性化合物
實例42流程 39
6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
1-{3-[3-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]-2,5-二氫-1H -吡咯-1-基}丙-2-烯-1-酮 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (s, 1H), 7.73-7.70 (m, 1H), 7.63-7.60 (d,J = 8.0 Hz, 1H), 7.49-7.45 (m, 2H), 7.35-7.28 (m, 3H), 7.32-7.28 (m, 3H), 7.14-7.10 (m, 2H), 7.02-7.00 (d,J = 7.6 Hz, 1H), 6.79-6.76 (m, 1H), 6.69-6.59 (m, 1H), 6.49 (s, 1H), 6.23-6.15 (m, 1H), 5.75-5.70 (m, 1H), 4.69 (s, 1H), 4.55-4.47 (d,J = 32.4 Hz, 2H), 4.32 (s, 1H), 3.75-3.73 (d,J = 6.8 Hz, 3H), 2.31-2.29 (d,J = 7.2 Hz, 3H). | 529.3 | |
1-{3-[4-(4-胺基-7-甲基-5-{4-[(6-甲基吡啶-2-基)氧基]苯基}-7H -吡咯并[2,3-d ]嘧啶-6-基)苯基]-2,5-二氫-1H -吡咯-1-基}丙-2-烯-1-酮鹽酸鹽 | 1 H NMR (400 MHz, DMSO-d 6 ):δ 8.43 (s, 1H), 8.13-8.07 (m, 1H), 7.6 (d,J = 7.6 Hz, 2H), 7.46 (d,J = 7.6 Hz, 2H), 7.41 (d,J = 8.0 Hz, 2H), 7.32-7.27 (m, 3H), 7.06 (d,J = 8.4 Hz, 1H), 6.81-6.64 (m, 1H), 6.49-6.36 (m, 2H), 5.87-5.82 (m, 1H), 4.79 (s, 1H), 4.67 (s, 2H), 4.49 (s, 1H), 3.83 (s, 3H), 2.61 (d,J = 3.2 Hz, 3H). | 529.1 |
步驟 1
:向可再密封之反應瓶中裝入4-氯-6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶(1.50 g,5.11 mmol)、{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}酸(1.62 g,5.62 mmol)、K3
PO4
(3.24 g,15.3 mmol)、PAd2
nBu (183 mg,511 µmol)、PAd2
nBu Pd-G2 (341 mg,511 µmol)、DME/H2
O (20 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在70℃下攪拌混合物隔夜。反應混合物用水(30 mL)稀釋,且水相用二氯甲烷(30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇30:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之6-[2-(第三丁基二甲基矽烷基)乙炔基]-3-{4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2,4-二甲基吡啶(1.50 g,65%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 2
:向可再密封之反應瓶中裝入6-[2-(第三丁基二甲基矽烷基)乙炔基]-3-{4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2,4-二甲基吡啶(3.50 g,8.51 mmol)、四氫呋喃(40 mL)、K3
PO4
(5.40 g,25.5 mmol)、Pd(dppf)Cl2
(622 mg,851 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加三甲基-1,3,5,2,4,6-三氧雜三硼雜環己烷(50%)(6.4 g,25.5 mmol),且在70℃下攪拌混合物2小時。反應混合物用水(50 mL)稀釋,且水相用DCM (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇80:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之6-[2-(第三丁基二甲基矽烷基)乙炔基]-3-{4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2,4-二甲基吡啶(2.80 g,84%)。
5-溴-6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 3
:向圓底燒瓶中裝入6-[2-(第三丁基二甲基矽烷基)乙炔基]-3-{4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-2,4-二甲基吡啶(2.80 g,7.16 mmol)、二甲基甲醯胺(30 mL)及攪拌棒。接著添加NBS (1.39 g,7.87 mmol),且在25℃下攪拌溶液1小時。反應混合物用Na2
SO3
(水溶液)(30 mL)淬滅,且反應混合物經由矽藻土墊過濾,用水洗滌墊,且真空乾燥濾餅,產生呈黃色非晶形固體狀之3-{5-溴-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶(3.02 g,90%)。
4-(6-(6-((第三丁基二甲基矽烷基)乙炔基)-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸乙酯
步驟 4
:向可再密封之反應瓶中裝入3-{5-溴-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶(3.00 g,6.38 mmol)、DME/H2
O (30 mL)、4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)環己-3-烯-1-甲酸乙酯(1.96 g,7.01 mmol)、K3
PO4
(4.04 g,19.1 mmol)、Pd(dppf)Cl2
(466 mg,638 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次,且在70℃下攪拌混合物1小時。反應混合物用水(30 mL)稀釋,且水相用二氯甲烷(30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇40:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之4-(6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸乙酯(2.50 g,72%)。
4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸
步驟 5
:向圓底燒瓶中裝入4-(6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-2,4-二甲基吡啶-3-基}-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-甲酸乙酯(2.48 g,4.56 mmol)、NaOH (543 mg,13.6 mmol)及攪拌棒。添加MeOH/H2
O (20 mL),且在60℃下攪拌溶液1小時。將反應混合物pH調整至5~6,真空濃縮,產生呈黑色非晶形固體狀之4-[6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-甲酸(2.2 g,粗物質)。
(2S)-1-(4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲醯胺
步驟 6
:向圓底燒瓶中裝入4-[6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-甲酸(1.7 g,4.24 mmol)、二甲基甲醯胺(20 mL)、T3P (5.38 g,8.48 mmol)、TEA (856 mg,8.48 mmol)及攪拌棒。添加(2S)-吡咯啶-2-甲醯胺(967 mg,8.48 mmol),且在25℃下攪拌溶液1小時。反應混合物用水(30 mL)稀釋,且水相用二氯甲烷(30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(乙腈/水/0.1%甲酸)。凍乾,產生呈黑色非晶形固體狀之(2S)-1-{4-[6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基}吡咯啶-2-甲醯胺(1.5 g,71%)。
(2S)-1-(4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈
步驟 7
:向可再密封之反應瓶中裝入(2S)-1-{4-[6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基}吡咯啶-2-甲腈(320 mg,668 µmol)、四氫呋喃(5 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次,添加伯格斯試劑(Burgess reagent)(316 mg,1.34 mmol),且在25℃下攪拌混合物2小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型HPLC純化(管柱:XBridge Prep OBD C18管柱,30×150mm 5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:CAN;流量:60 mL/min;梯度:20 B至45 B,歷時8 min;220 nm;RT1:7.23;RT2:;注射體積:ml;操作次數:;)。凍乾產生呈灰白色非晶形固體狀之(2S)-1-{4-[6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基]環己-3-烯-1-羰基}吡咯啶-2-甲腈(160 mg,50%)。 步驟 8
:將所得物質(160 mg)送交對掌性分離(管柱:CHIRALPAK IF,2*25 cm,5um;移動相A:Hex (0.5% 2M NH3-MeOH)—HPLC,移動相B:EtOH:DCM=1:1—HPLC;流量:20 mL/min;梯度:35 B至35 B,歷時11分鐘;220/254 nm;RT1:6.855;RT2:8.514;注射體積:0.7 ml;操作次數:6;)。凍乾產生峰1 (76 mg)、峰2 (67 mg)。接著再次進行對掌性分離操作:峰1 (管柱:CHIRAL ART Cellulose-SB S-5um, 2*25cm, 5um;移動相A:Hex (0.5% 2M NH3-MeOH)—HPLC,移動相B:EtOH:DCM=1:1—HPLC;流量:20 mL/min;梯度:20 B至20 B,歷時17分鐘;220/254 nm;RT1:13.481;RT2:15.128;注射體積:0.65 ml;操作次數:5);產生呈灰白色非晶形固 體狀的異構體2 (27.2 mg)及異構體4 (25 mg)。峰2 (管柱:CHIRAL ART Cellulose-SB,2*25cm,5um;移動相A:Hex (0.5% 2M NH3-MeOH)—HPLC,移動相B:EtOH:DCM=1:1—HPLC;流量:20 mL/min;梯度:20 B至20 B,歷時18分鐘;220/254 nm;RT1:13.832;RT2:15.921;注射體積:0.7 ml;操作次數:6);產生呈灰白色非晶形固體狀的異構體1 (25.7 mg)及異構體3 (21.4 mg)。表 41. 例示性化合物
實例43流程 40
(5-溴-2-氯吡啶-4-基)甲醇
化合物 | 結構 | 質子 NMR | MS [M+1] |
(S)-1-((S)-4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.50 (s, 1H), 5.68 (s, 1H), 4.70 (dd,J = 7.7, 3.5 Hz, 1H), 4.39 (s, 1H), 3.67 (ddd,J = 9.6, 7.0, 4.5 Hz, 1H), 3.54 - 3.44 (m, 1H), 3.42 (s, 3H), 2.68 (d,J = 3.5 Hz, 3H), 2.60 (d,J = 9.3 Hz, 1H), 2.20 (d,J = 2.8 Hz, 5H), 2.18 - 2.07 (m, 3H), 2.06 - 1.94 (m, 6H), 1.76 (d,J = 13.1 Hz, 1H), 1.53 - 1.37 (m, 1H). | 479.25 | |
(S)-1-((R)-4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.73 (s, 1H), 7.50 (s, 1H), 5.67 (s, 1H), 4.71 (dd,J = 7.6, 3.7 Hz, 1H), 4.39 (s, 1H), 3.63 (ddd,J = 11.3, 7.0, 4.4 Hz, 1H), 3.56 - 3.46 (m, 1H), 3.42 (s, 3H), 2.69 (s, 3H), 2.59 (s, 1H), 2.19 (s, 6H), 2.18 - 2.06 (m, 3H), 2.04 (s, 3H), 2.00 (dd,J = 7.4, 3.4 Hz, 2H), 1.80 (d,J = 13.0 Hz, 1H), 1.57 - 1.45 (m, 1H). | 479.25 | |
(S)-1-((S)-4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.71 (s, 1H), 7.49 (s, 1H), 5.64 (s, 1H), 4.71 (dd,J = 7.6, 3.7 Hz, 1H), 4.39 (s, 1H), 3.64 (ddd,J = 11.4, 7.2, 4.6 Hz, 1H), 3.51 (q,J = 8.0 Hz, 1H), 3.41 (s, 3H), 2.68 (s, 3H), 2.60 (s, 1H), 2.19 (d,J = 2.2 Hz, 5H), 2.12 (tq,J = 13.0, 5.1, 3.3 Hz, 4H), 2.04 (s, 3H), 1.99 (dd,J = 10.0, 6.1 Hz, 2H), 1.81 (d,J = 13.2 Hz, 1H), 1.50 (dd,J = 12.0, 5.2 Hz, 1H). | 479.30 | |
(S)-1-((R)-4-(6-(6-乙炔基-2,4-二甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.74 (s, 1H), 7.50 (s, 1H), 5.68 (s, 1H), 4.70 (dd,J = 7.7, 3.6 Hz, 1H), 4.40 (s, 1H), 3.71 - 3.61 (m, 1H), 3.55 - 3.44 (m, 1H), 3.42 (s, 3H), 2.70 (d,J = 3.5 Hz, 3H), 2.60 (d,J = 8.7 Hz, 1H), 2.19 (s, 5H), 2.17 - 2.07 (m, 4H), 2.04 (s, 3H), 2.01 (dd,J = 9.6, 5.3 Hz, 2H), 1.77 (d,J = 12.9 Hz, 1H), 1.48 (td,J = 11.8, 5.5 Hz, 1H). | 479.25 | |
(S)-1-((S)-4-(6-(6-乙炔基-4-甲氧基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 8.33 (d,J = 8.8 Hz, 1H), 7.44 (d,J = 1.4 Hz, 1H), 5.64 (d,J = 23.1 Hz, 1H), 4.73 (dd,J = 7.6, 3.7 Hz, 1H), 4.47 (s, 1H), 3.91 (d,J = 1.7 Hz, 3H), 3.51 (s, 4H), 2.66 (d,J = 2.8 Hz, 3H), 2.28 - 2.11 (m, 4H), 2.08 (s, 2H), 2.02 (s, 2H), 1.83 (s, 1H), 1.66 - 1.45 (m, 2H), 1.45 - 1.34 (m, 1H), 1.24 (s, 1H). | 481.4 | |
S)-1-((R)-4-(6-(6-乙炔基-4-甲氧基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.67 (s, 1H), 8.34 (d,J = 7.8 Hz, 1H), 7.45 (d,J = 3.4 Hz, 1H), 5.66 (d,J = 14.2 Hz, 1H), 4.72 (dd,J = 7.8, 3.5 Hz, 1H), 4.48 (d,J = 1.3 Hz, 1H), 3.91 (d,J = 2.0 Hz, 3H), 3.68 (s, 1H), 3.52 (s, 4H), 2.66 (s, 4H), 2.20 (s, 3H), 2.14 (d,J = 7.8 Hz, 2H), 2.08 (s, 1H), 2.02 (d,J = 8.5 Hz, 3H), 1.80 (s, 1H), 1.54 (d,J = 8.2 Hz, 1H), 1.45 - 1.39 (m, 1H), 1.24 (s, 1H), 1.16 (d,J = 7.2 Hz, 1H). | 481.25 | |
(S)-1-((S)-4-(4-胺基-6-(6-乙炔基-2,4-二甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.13 (s, 1H), 7.47 (s, 1H), 6.55 (s, 2H), 5.65 (q,J = 2.8, 2.2 Hz, 1H), 4.70 (dd,J = 7.4, 3.4 Hz, 1H), 4.38 (s, 1H), 3.69 (ddd,J = 10.9, 7.4, 3.8 Hz, 1H), 3.47 (td,J = 8.9, 6.7 Hz, 1H), 3.31 (s, 3H), 2.79 (t,J = 6.2 Hz, 1H), 2.24 (s, 2H), 2.19 (s, 3H), 2.13 (ddd,J = 9.8, 6.7, 3.5 Hz, 2H), 2.03 (s, 5H), 1.90 (s, 2H), 1.61 (s, 2H). | 480.25 | |
(S)-1-((S)-4-(4-胺基-6-(6-乙炔基-2,4-二甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.14 (s, 1H), 7.47 (s, 1H), 6.58 (s, 2H), 5.66 (s, 1H), 4.70 (dd,J = 7.4, 3.6 Hz, 1H), 4.38 (s, 1H), 3.74 - 3.65 (m, 1H), 3.47 (q,J = 8.6 Hz, 1H), 3.31 (s, 3H), 2.88 (s, 1H), 2.25 (s, 2H), 2.21 - 2.09 (m, 5H), 2.04 (s, 5H), 1.88 (s, 2H), 1.60 (d,J = 9.4 Hz, 2H). | 480.25 | |
(S)-1-((R)-4-(4-胺基-6-(6-乙炔基-2,4-二甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.48 (s, 1H), 6.72 (s, 2H), 5.66 (s, 1H), 4.71 (dd,J = 7.9, 3.7 Hz, 1H), 4.38 (s, 1H), 3.60 (t,J = 6.1 Hz, 1H), 3.53 (q,J = 8.1 Hz, 1H), 3.32 (s, 3H), 2.84 - 2.77 (m, 1H), 2.25 (s, 2H), 2.18 (s, 4H), 2.05 (s, 3H), 2.04 - 1.96 (m, 2H), 1.89 (s, 2H), 1.63 (d,J = 6.3 Hz, 2H), 1.16 (t,J = 7.3 Hz, 1H). | 480.25 | |
(S)-1-((R)-4-(4-胺基-6-(6-乙炔基-2,4-二甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16 (s, 1H), 7.47 (s, 1H), 6.72 (s, 2H), 5.65 (s, 1H), 4.71 (dd,J = 7.9, 3.7 Hz, 1H), 4.39 (s, 1H), 3.61 (dd,J = 10.4, 4.6 Hz, 1H), 3.53 (q,J = 8.5, 8.0 Hz, 1H), 3.32 (s, 3H), 2.80 (t,J = 6.1 Hz, 1H), 2.24 (s, 1H), 2.20 (s, 5H), 2.05 - 1.95 (m, 5H), 1.91 (s, 2H), 1.64 (s, 2H), 1.16 (t,J = 7.3 Hz, 1H). | 480.25 | |
(S)-1-((R)-4-(6-(6-乙炔基-4-甲氧基-2-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (d,J = 1.4 Hz, 1H), 7.28 (s, 1H), 5.60 (s, 1H), 4.70 (t,J = 7.7, 3.5 Hz, 1H), 4.41 (d,J = 1.1 Hz, 1H), 3.81 (s, 3H), 3.70 - 3.57 (m, 1H), 3.51 (t,J = 8.5 Hz, 1H), 3.41 (s, 3H), 2.68 - 2.56 (m, 4H), 2.27 - 2.08 (m, 6H), 2.04 (d,J = 15.4 Hz, 6H), 1.79 (d,J = 13.1 Hz, 1H). | 495.25 |
(S)-1-((R)-4-(6-(6-乙炔基-4-甲氧基-2-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.28 (s, 1H), 5.58 (s, 1H), 4.71 (dd, J = 7.6, 3.7 Hz, 1H), 4.41 (s, 1H), 3.82 (d, J = 2.3 Hz, 3H), 3.70 - 3.59 (m, 1H), 3.51 (q, J = 8.2 Hz, 1H), 3.42 (s, 3H), 2.66 (d, J = 3.3 Hz, 3H), 2.56 (s, 1H), 2.17 (s, 5H), 2.15 - 2.05 (m, 4H), 2.02 (t, J = 7.0 Hz, 2H), 1.81 (d, J = 13.1 Hz, 1H), 1.56 (d, J = 6.6 Hz, 1H). | 495.30 |
(S)-1-((S)-4-(6-(6-乙炔基-4-甲氧基-2-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.66 (s, 1H), 7.28 (s, 1H), 5.60 (s, 1H), 4.71 (dd,J = 7.7, 3.5 Hz, 1H), 4.42 (s, 1H), 3.82 (s, 3H), 3.67 (ddd,J = 9.5, 7.2, 4.4 Hz, 1H), 3.49 (dd,J = 9.4, 7.3 Hz, 1H), 3.42 (s, 3H), 2.66 (d,J = 2.5 Hz, 3H), 2.62 - 2.56 (m, 1H), 2.17 (d,J = 2.2 Hz, 4H), 2.16 - 1.95 (m, 6H), 1.78 (dd,J = 13.1, 3.3 Hz, 1H), 1.61 - 1.43 (m, 2H). | 495.25 |
(S)-1-((S)-4-(6-(6-乙炔基-4-甲氧基-2-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶-5-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.65 (s, 1H), 7.28 (s, 1H), 5.60 (d,J = 25.9 Hz, 1H), 4.71 (d,J = 6.4 Hz, 1H), 4.42 (s, 1H), 3.82 (s, 3H), 3.66 (s, 1H), 3.59 - 3.50 (m, 1H), 2.91 (s, 1H), 2.65 (s, 3H), 2.17 (s, 5H), 2.10 (d,J = 14.7 Hz, 2H), 2.01 (s, 2H), 1.79 (d,J = 24.2 Hz, 1H), 1.45 (s, 1H), 1.24 (s, 4H), 1.15 (d,J = 9.2 Hz, 1H). | 495.30 |
步驟 1
:將5-溴-2-氯吡啶-4-甲酸甲酯(75.0 g,299 mmol)於THF (1.5 L)中之溶液冷卻至-20℃。歷經1.5小時時間段逐滴添加LiBH4
(179 mL,358 mmol,2 M於THF中),同時維持溫度低於-15℃。使溶液升溫至室溫且在25℃下攪拌2小時,接著藉由逐滴添加飽和NH4
Cl (200 mL)小心地淬滅,且用EtOAc (1.2 L)萃取水相三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(450 g管柱;用石油醚:乙酸乙酯10:1溶離)。真空濃縮,產生呈灰白色非晶形固體狀之(5-溴-2-氯吡啶-4-基)甲醇(40 g,60.1%)。
5-溴-4-(溴甲基)-2-氯吡啶
步驟 2
:在0℃下,向(5-溴-2-氯吡啶-4-基)甲醇(54.0 g,242)及CBr4
(87.2 g,266 mmol)於DCM (1.5 L)中之混合物中逐滴添加含PPh3 (69.6 g,266 mmol)的DCM (300 mL),在0℃下攪拌1小時。用鹽水(500 mL)淬滅反應物。分離所分溶的層。用DCM (1 L×3)萃取水相。合併之有機層用鹽水(1 L)洗滌,經無水Na2
SO4
乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由急驟矽膠層析來純化(石油醚:乙酸乙酯=30:1),得到呈白色固體狀的產物5-溴-4-(溴甲基)-2-氯吡啶(51 g,73.9%)。
2-[(5-溴-2-氯吡啶-4-基)甲基]丙二酸1,3-二甲酯
步驟 3
:在-10℃下,向丙二酸1,3-二甲酯(62.0 g,470 mmol)於THF (900 mL)中之混合物中添加NaH (18.6 g,470 mmol),在-10℃下攪拌30分鐘,接著添加含5-溴-4-(溴甲基)-2-氯吡啶(45.0 g,157 mmol)的300 mL。將THF逐滴添加至上述溶液中且攪拌2小時。用飽和NH4Cl (600 mL)淬滅混合物。用EtOAc (1 L)萃取水相三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(500 g管柱;用石油醚:乙酸乙酯=15:1溶離)。真空濃縮,產生呈灰白色非晶形固體狀之2-[(5-溴-2-氯吡啶-4-基)甲基]丙二酸1,3-二甲酯(40 g,75.7%)。
3-(5-溴-2-氯吡啶-4-基)丙酸甲酯
步驟 4
:向圓底燒瓶中裝入2-[(5-溴-2-氯吡啶-4-基)甲基]丙二酸1,3-二甲酯(39.5 g,117 mmol)、NaCl (20.3 g,351 mmol)、H2O (6.31 g,351 mmol)及攪拌棒。添加DMSO (800 mL),且在160℃下攪拌溶液1小時。反應混合物用EtOAc (1.5 L)稀釋,且水相用鹽水(600 mL)洗滌四次。合併之有機層經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(300 g管柱;用石油醚/乙酸乙酯15:1溶離)。真空濃縮,產生呈白色非晶形固體狀之3-(5-溴-2-氯吡啶-4-基)丙酸甲酯(22.0 g,67%)。
3-(2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-4-基)丙酸甲酯
步驟 5
:向可再密封之反應瓶中裝入3-(5-溴-2-氯吡啶-4-基)丙酸甲酯(10 g,35.9 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(11.8 g,46.6 mmol)、Pd(dppf)Cl2
(2.62,3.59 mmol)、KOAc (10.4 g,107 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷(200 mL),且在70℃下攪拌混合物12小時。藉由矽藻土墊過濾收集催化劑及鹽且用EtOAc (100 mL)洗滌三次。合併之有機層經Na2
SO4
乾燥,過濾且在減壓下蒸發。所得粗物質藉由矽膠層析純化(200 g管柱;用石油醚/乙酸乙酯15:1溶離)。真空濃縮,產生呈白色非晶形固體狀之3-[2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-4-基]丙酸甲酯(6.5 g,56.0%)。
3-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)丙酸甲酯
步驟 6
:向可再密封之反應瓶中裝入6-溴-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(14.5 g,26.5 mmol)、3-[2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-4-基]丙酸甲酯(12.9 g,39.7 mmol)、Pd(DTBPF)Cl2 (1.72 g,2.65 mmol)、CsF (12.0 g,79.5 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加THF/H2O (300 mL),且在70℃下攪拌混合物12小時。反應混合物用水(100 mL)稀釋,且水相用二氯甲烷(500 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(200 g管柱;用二氯甲烷/甲醇20:1溶離)。真空濃縮,產生呈棕色非晶形固體狀之3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙酸甲酯(7.00 g,40%)。
3-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)丙-1-醇
步驟 7
:向圓底燒瓶中裝入3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙酸甲酯(7.00 g,10.5 mmol)、DCM (120 mL)及攪拌棒。在0℃下添加DIBAL (8.39 mL,12.6 mmol),且在0℃下攪拌溶液3小時。反應混合物用MeOH (10 mL)及水(60 mL)稀釋,且水相用二氯甲烷(100 mL)萃取三次。將合併之有機層過濾且用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由C18 flash來純化(乙腈/水/0.1%甲酸)。凍乾產生呈黃色非晶形固體狀之3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(3.00 g,45%)。
3-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)丙-1-醇
步驟 8
:向圓底燒瓶中裝入3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(2.60 g,4.08 mmol)、CH3SO3H/THF (40 mL)及攪拌棒。在70℃下攪拌溶液1小時。反應混合物用水(100 mL)稀釋,且水相用Na2CO3將pH值調整至7,用DCM (150 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用二氯甲烷/甲醇12:1溶離)。真空濃縮產生呈灰白色非晶形固體狀之3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(800 mg,39%)。3 - 氯 - 13 -( 3 - 氟 - 4 -(( 4 - 甲基嘧啶 - 2 - 基 ) 氧基 ) 苯基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 4 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯 - 12 - 胺
步驟 9
:向可再密封之反應瓶中裝入3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(680 mg,1.34 mmol)、DIAD (406 mg,2.01 mmol)、四氫呋喃(8 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加含PPh3 (526 mg,2.01 mmol)的2 mL THF,且在25℃下攪拌混合物1小時。反應混合物用水(5 mL)稀釋,且水相用DCM (25 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC (二氯甲烷/甲醇15:1)來純化。真空濃縮,產生呈黃色非晶形固體狀之3-氯-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(450 mg,69%)。
3-((第三丁基二甲基矽烷基)乙炔基)-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
步驟 10
:向可再密封之反應瓶中裝入3-氯-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(430 mg,881 µmol)、第三丁基(乙炔基)二甲基矽烷(246 mg,1.76 mmol)、Pd(dppf)Cl2 (128 mg,176 µmol)、CuI (66.8 mg,352 µmol)、TEA (266 mg,2.64 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二甲基甲醯胺(1 mL),且在50℃下攪拌混合物2小時。反應混合物用水(5 mL)稀釋,且水相用DCM (25 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC (二氯甲烷/甲醇15:1)來純化。真空濃縮,產生呈灰白色非晶形固體狀之3-((第三丁基二甲基矽烷基)乙炔基)-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(350 mg,67%)。
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
步驟 11
:向圓底燒瓶中裝入3-((第三丁基二甲基矽烷基)乙炔基)-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(340 mg,574 µmol)、四氫呋喃(2 mL)及攪拌棒。添加TBAF (179 mg,688 µmol),且在室溫下攪拌溶液1小時。反應混合物藉由矽膠層析純化(20 g管柱;用二氯甲烷/甲醇10:1溶離)。真空濃縮且粗產物用DMF (3 mL)溶解,過濾且濾餅用ACN (10 mL)及DCM (10 mL)洗滌三次,在減壓下乾燥。凍乾產生呈黃色非晶形固體狀之3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(173.1 mg,362 µmol,63.1%)。表 42 . 例示性化合物
實例44流程 41
3-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-((第三丁基二甲基矽烷基)乙炔基)吡啶-4-基)丙-1-醇
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.67 (s, 1H), 7.50 - 7.34 (m, 2H), 7.24 - 7.20 (m, 2H), 6.36 - 5.89 (m, 1H), 5.76 (s, 1H), 4.40 (s, 1H), 4.15 (s, 2H), 2.79 (t,J = 7.0 Hz, 2H), 2.44 (s, 3H), 2.25 (t,J = 7.1 Hz, 2H). | 478.10 |
步驟 1
:向可再密封之反應瓶中裝入3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]丙-1-醇(90.0 mg,177 µmol)、Pd(dppf)Cl2 (25.9 mg,35.4 µmol)、CuI (13.4 mg,70.8 µmol)、TEA (53.6 mg,531 µmol)、第三丁基(乙炔基)二甲基矽烷(49.6 mg,354 µmol)、攪拌棒,隨後抽真空且用氮氣淨化三次。添加二甲基甲醯胺(5 mL),且在50℃下攪拌混合物2小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(25 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC (二氯甲烷/甲醇15:1)來純化。真空濃縮,產生呈黃色非晶形固體狀之3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-[2-(第三丁基二甲基矽烷基)乙炔基]吡啶-4-基]丙-1-醇(80.0 mg,74%)。
3-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)丙-1-醇
步驟2:向圓底燒瓶中裝入3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-[2-(第三丁基二甲基矽烷基)乙炔基]吡啶-4-基]丙-1-醇(70.0 mg,114 µmol)、四氫呋喃(5 mL)及攪拌棒。添加TBAF (35.3 mg,136 µmol),且在室溫下攪拌溶液1小時。反應物質藉由矽膠層析純化(10 g管柱;用二氯甲烷/甲醇10:1溶離)。真空濃縮且粗產物用水洗滌5次,濃縮有機相且所得粗物質藉由製備型HPLC純化(管柱:XBridge Prep OBD C18管柱,30×150mm 5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:ACN;流量:60 mL/min;梯度:15 B至45 B,歷時8分鐘;220 nm;RT1:7.23)。凍乾產生呈白色非晶形固體狀之3-[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基]丙-1-醇(11.2 mg,19.8%)。
表43.例示性化合物
實例45流程 42
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)呋喃并[2,3-d]嘧啶-4-胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-(5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)丙-1-醇 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.21 (s, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.37 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 7.35 (t,J = 8.4 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.06 (dd,J = 8.0, 2.0 Hz, 1H), 6.10 - 6.00(m, 1H), 4.44 (s, 1H), 4.39 (s, 1H), 3.30 - 3.10 (m, 4H), 2.42 (s, 3H), 1.53 - 1.47 (m, 2H). | 496.25 |
步驟 1
:向可再密封之反應瓶中裝入5-溴呋喃并[2,3-d]嘧啶-4-胺(800 mg,3.73 mmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(1.84 g,5.59 mmol)、Pd(dppf)Cl2
(2.72 g,3.73 mmol)、K3
PO4
(790 mg,3.73 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (15 mL),且在90℃下攪拌混合物2小時。反應混合物用水(100 mL)稀釋,且水相用DCM (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(100 g管柱;用庚烷/乙酸乙酯溶離;比率=1:1)。真空濃縮,產生呈灰白色非晶形固體狀之5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(800 mg,64%)。
6-6-溴-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)呋喃并[2,3-d]嘧啶-4-胺
步驟 2
:向圓底燒瓶中裝入5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(800 mg,2.37 mmol)、DCM (15 mL)及攪拌棒。在0℃下添加Br2
(379 mg,2.37 mmol),且在0℃下攪拌溶液1小時。接著藉由飽和硫代硫酸鈉水溶液淬滅反應。反應混合物用水(100 mL)稀釋,且水相用DCM (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型HPLC (乙腈/水/0.1%甲酸)純化。凍乾產生呈灰白色非晶形固體狀之6-溴-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(700 mg,71%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)呋喃并[2,3-d]嘧啶-4-胺
步驟 3
:向可再密封之反應瓶中裝入6-溴-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(680 mg,1.63 mmol)、2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(872 mg,2.44 mmol)、Pd(dppf)Cl2
(238 mg,0.326 mmol)、K3
PO4
(1.03 g,4.89 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2O (20 mL),且在90℃下攪拌混合物1小時。所得粗物質藉由矽膠層析純化(50 g管柱;用二氯甲烷/甲醇溶離;比率=30:1)。真空濃縮,產生呈黑色非晶形固體狀之6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(530 mg,57%)。
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)呋喃并[2,3-d]嘧啶-4-胺
步驟 4
:向圓底燒瓶中裝入6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(500 mg,0.88 mmol)、四氫呋喃(10 mL)及攪拌棒。添加TBAF (0.88 mL,0.88 mmol),且在室溫下攪拌溶液30分鐘。所得粗物質藉由矽膠層析純化(50 g管柱;用二氯甲烷/甲醇溶離;比率=10:1)。真空濃縮產生粗產物。所得粗物質藉由製備型HPLC純化(管柱:XBridge Prep OBD C18管柱,30×150mm 5um;移動相A:水(10MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:ACN;流量:60 mL/min;梯度:25 B至55 B,歷時8分鐘;220 nm; RT1:7.23)。凍乾產生呈白色非晶形固體狀之6-(6-乙炔基-4-甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺(215 mg,54%)。表 44 . 例示性化合物
實例46
流程43
7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}呋喃并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (d,J = 5.0 Hz, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 7.59 (s, 1H), 7.47 - 7.40 (m, 2H), 7.23 - 7.19 (m, 2H), 4.45 (s, 1H), 2.43 (s, 3H), 2.20 (s, 3H). | 453.15 |
步驟 1
:向壓力槽反應器中裝入4-氯-7H-吡咯并[2,3-d]嘧啶(30 g,195 mmol)、TEA (59.1 g,585 mmol)、[(R)-(+)-2,2'-雙(二苯膦基)-1,1'-聯萘]氯化鈀(II)(1.55 g,1.95 mmol)、MeOH (500 mL)及攪拌棒。在100℃下、在CO氛圍(10 atm)下攪拌混合物12小時。反應混合物經由矽藻土墊過濾,用EA洗滌墊,且真空濃縮濾液,產生呈黃色非晶形固體狀之7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯(25.0 g,72%)。
7-甲基-7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯
步驟 2
:向圓底燒瓶中裝入7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯(20 g,112 mmol)、DMF (100 mL)及攪拌棒。添加NaH (10.7 g,448 mmol),且在0℃下攪拌反應混合物30分鐘。接著添加MeI (15.8 g,112 mmol)且在0℃下攪拌溶液1小時。反應混合物用水(500 mL)稀釋,且水相用EA (100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(100 g管柱;用庚烷/乙酸乙酯溶離;比率=3:1)。真空濃縮,產生呈灰白色非晶形固體狀之7-甲基-7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯(13.0 g,61%)。
5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯
步驟3:向圓底燒瓶中裝入7-甲基-7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯(10 g,52.3 mmol)、DMF (200 mL)及攪拌棒。添加NBS (11.1 g,62.7 mmol),且在室溫下攪拌溶液1小時。反應混合物用水(300 mL)稀釋,且水相用EA (300 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(100 g管柱;用二氯甲烷/甲醇溶離;比率=50:4-17561)。真空濃縮,產生呈灰白色非晶形固體狀之5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯(10.0 g,71%)。
(5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)甲醇
步驟 4
:向圓底燒瓶中裝入5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-甲酸甲酯(3 g,11.1 mmol)、THF (50 mL)及攪拌棒。在-50℃下添加LiBH4
(11.1 mL,11.1 mmol)。在-50℃下攪拌反應混合物1小時。藉由添加2 mL EA來淬滅反應。反應混合物用水(100 mL)稀釋,且水相用DCM (100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用庚烷/乙酸乙酯溶離;比率=1:1)。真空濃縮,產生呈灰白色非晶形固體狀之{5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基}甲醇(850 mg,32%)。
5-溴-4-(((第三丁基二甲基矽烷基)氧基)甲基)-7-甲基-7H-吡咯并[2,3-d]嘧啶
步驟 5
:向圓底燒瓶中裝入{5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基}甲醇(400 mg,1.65 mmol)、1H-咪唑(561 mg,8.25 mmol)、THF (10 mL)及攪拌棒。添加TBSCl (745 mg,4.94 mmol),且在室溫下攪拌溶液12小時。反應混合物用水(100 mL)稀釋,且水相用EA (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(20 g管柱;用庚烷/乙酸乙酯溶離;比率=1:1)。真空濃縮,產生呈黃色非晶形固體狀之5-溴-4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶(330 mg,56%)。
4-(((第三丁基二甲基矽烷基)氧基)甲基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶
步驟 6
:向可再密封之反應瓶中裝入5-溴-4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶(750 mg,2.10 mmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(832 mg,2.52 mmol)、K3
PO4
(1.33 g,6.30 mmol)、Pd(dppf)Cl2
(307 mg,0.42 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (20 mL),且在90℃下攪拌混合物1小時。反應混合物用水(50 mL)稀釋,且水相用DCM (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用PE:EA溶離;比率=1:1)。真空濃縮,產生呈黃色非晶形固體狀之2-[4-(4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯氧基]-4-甲基嘧啶(760 mg,75%)。
6-溴-4-(((第三丁基二甲基矽烷基)氧基)甲基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶
步驟 7
:向圓底燒瓶中裝入2-[4-(4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯氧基]-4-甲基嘧啶(700 mg,1.45 mmol)、二甲基甲醯胺(20 mL)及攪拌棒。添加DBDMH (331 mg,1.16 mmol),且在0℃下攪拌溶液2小時。接著用Na2SO3水溶液淬滅反應。反應混合物用水(100 mL)稀釋,且水相用DCM (100 mL)萃取三次。所得粗物質藉由製備型TLC (用DCM:MeOH;比率=20:1溶離)來純化。真空濃縮,產生呈黑色非晶形固體狀之2-[4-(6-溴-4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯氧基]-4-甲基嘧啶(400 mg,49%)。
6-(6-((第三丁基二甲基矽烷基)乙炔基)-4-甲基吡啶-3-基)-4-(((第三丁基二甲基矽烷基)氧基)甲基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶
步驟 8
:向可再密封之反應瓶中裝入2-[4-(6-溴-4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯氧基]-4-甲基嘧啶(350 mg,0.63 mmol)、2-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶(893 mg,2.50 mmol)、Na2
CO3
(198 mg,1.87 mmol)、Pd(PPh3
)4
(144 mg,0.1253 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷/H2
O (20 mL),且在90℃下攪拌混合物1小時。反應混合物用水(50 mL)稀釋,且水相用DCM (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色油狀之2-[4-(6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯氧基]-4-甲基嘧啶(140 mg,31%)。
(6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)甲醇
步驟 9
:向圓底燒瓶中裝入2-[4-(6-{6-[2-(第三丁基二甲基矽烷基)乙炔基]-4-甲基吡啶-3-基}-4-{[(第三丁基二甲基矽烷基)氧基]甲基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)-2-氟苯氧基]-4-甲基嘧啶(130 mg,0.18 mmol)、THF (10 mL)及攪拌棒。添加TBAF (0.45 mL,0.45 mmol),且在室溫下攪拌溶液30分鐘。所得粗物質藉由製備型HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm, 5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:ACN;流量:60 mL/min;梯度:20 B至50 B,歷時8分鐘;254/220 nm; RT1:7.28)。凍乾產生呈灰白色非晶形固體狀之[6-(6-乙炔基-4-甲基吡啶-3-基)-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基]甲醇(39.4 mg,46%)。
表45.例示性化合物
實例47流程 44
N-(4-溴-3-甲氧基苯基)-2-甲基丙-2-烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
(6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-基)甲醇 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.92 (s, 1H), 8.55 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 7.59 (s, 1H), 7.37 - 7.27 (m, 2H), 7.19 (d,J = 5.0 Hz, 1H), 7.13 (dd,J = 8.3, 2.2 Hz, 1H), 5.19 (s, 1H), 4.59 - 4.42 (m, 3H), 3.59 (s, 3H), 2.41 (s, 3H), 2.06 (s, 3H). | 481.25 |
步驟 1
:向圓底燒瓶中裝入4-溴-3-甲氧基苯胺(2.9 g,14.3 mmol)、二氯甲烷(30 mL)、TEA (4.33 g,42.9 mmol)及攪拌棒。添加2-甲基丙-2-烯醯氯(1.64 g,15.7 mmol),且在0℃下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色固體狀之N-(4-溴-3-甲氧基苯基)-2-甲基丙-2-烯醯胺(3.1 g,80.3%)。
N-[3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2-甲基丙-2-烯醯胺
步驟 2
:向可再密封之反應瓶中裝入N-(4-溴-3-甲氧基苯基)-2-甲基丙-2-烯醯胺(2.8 g,10.3 mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)-1,3,2-二氧雜硼雜環戊烷(5.23 g,20.6 mmol)、Pd(dppf)2
Cl2
(753 mg,1.03 mmol)、AcOK (3.02 g,30.9 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷(30 mL),且在90℃下攪拌混合物2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色固體狀的N-[3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2-甲基丙-2-烯醯胺(2.2 g,67.4%)。
N-(4-{4-胺基-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-6-基}-3-甲氧基苯基)-2-甲基丙-2-烯醯胺
步驟 3
:向可再密封之反應瓶中裝入N-[3-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2-甲基丙-2-烯醯胺(200 mg,630 µmol)、6-氯-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-4-胺(181 mg,504 µmol)、XPhos Pd G3 (53.3 mg,63.0 µmol)、XPhos (29.9 mg,63.0 µmol)、K3
PO4
(398 mg,1.88 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (6 mL),且在90℃下攪拌混合物2小時。所得粗物質藉由製備型HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm, 5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:ACN;流量:60 mL/min;梯度:25 B至50 B,歷時8分鐘;254/220 nm;RT1:7.2)。凍乾產生呈灰白色非晶形固體狀之N-(4-{4-胺基-7-甲基-5-[(4R)-4-(吡咯啶-1-羰基)環己-1-烯-1-基]-7H-吡咯并[2,3-d]嘧啶-6-基}-3-甲氧基苯基)-2-甲基丙-2-烯醯胺(70.0 mg,27%)。
表46.例示性化合物
實例48流程 45
N-(4-(4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲氧基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.94 (s, 1H), 8.08 (d,J = 7.0 Hz, 1H), 7.64 (dd,J = 7.0, 1.9 Hz, 1H), 7.39 (ddd,J = 8.0, 5.9, 1.9 Hz, 1H), 7.15 (dd,J = 8.2, 3.5 Hz, 1H), 6.54 (s, 1H), 6.35 (s, 1H), 5.85 (t,J = 1.1 Hz, 1H), 5.66 (d,J = 22.8 Hz, 1H), 5.56 (s, 1H), 3.76 (d,J = 2.7 Hz, 3H), 3.46 (ddt,J = 18.3, 11.7, 6.1 Hz, 2H), 3.39 (d,J = 3.0 Hz, 3H), 3.31 (s, 2H), 2.84 -2.64 (m, 1H), 2.42 -2.02 (m, 3H), 1.98 (t,J = 1.3 Hz, 3H), 1.94-1.80(m,3H),1.78-1.68 (m, 3H), 1.64-1.36 (m, 1H). | 515.30 | |
N-(4-(4-胺基-7-甲基-5-((R)-4-((R)-2-甲基吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.85 (s, 1H), 8.16 - 8.01 (m, 1H), 7.71 (d,J = 2.3 Hz, 1H), 7.62 (dt,J = 8.3, 2.0 Hz, 1H), 7.25 - 7.12 (m, 1H), 6.56 (s, 2H), 5.83 (s, 1H), 5.67 (ddt,J = 17.5, 4.3, 2.2 Hz, 1H), 5.54 (t,J = 1.5 Hz, 1H), 4.10 - 3.93 (m, 1H), 3.46 (td,J = 6.9, 2.5 Hz, 2H), 3.34 (d,J = 2.7 Hz, 3H), 2.80 - 2.64 (m, 1H), 2.38 - 1.97 (t,J = 1.2 Hz, 3H), 1.90 (dddt,J = 10.3, 7.0, 5.3, 3.1 Hz, 3H), 1.83 - 1.70 (m, 2H), 1.67 - 1.41 (m, 3H), 1.15 - 1.00 (m, 3H). | 513.35 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟-5-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.05 (s, 1H), 8.13 (d,J = 2.9 Hz, 1H), 7.65 (dt,J = 11.8, 2.1 Hz, 1H), 7.52 (d,J = 2.3 Hz, 1H), 6.68 -6.57 (s, 1H), 5.85 (s, 1H), 5.65 (d,J = 3.9 Hz, 1H), 5.59 (s, 1H), 3.51 - 3.41 (m, 2H), 3.42 (s, 3H), 3.26 (t,J = 6.9 Hz, 2H),2.85-2.78(m,2H) 2.19 (s, 2H), 2.05 (s, 3H), 1.97 (d,J = 1.2 Hz, 5H), 1.86 (p,J = 6.8 Hz, 2H), 1.76 (q,J = 6.7 Hz, 2H), 1.61 (d,J = 4.1 Hz, 2H). | 517.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3-氟-5-甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ10.04 (s, 1H), 8.12 (d,J = 3.4 Hz, 1H), 7.64 (d,J = 11.6 Hz, 1H), 7.51 (s, 1H), 6.62 (s, 1H), 5.85 (s, 1H), 5.65 (s, 1H), 5.59 (d,J = 1.8 Hz, 1H), 2.75 (s, 1H), 2.19 (s, 2H), 2.05 (s, 3H), 2.00-1.94 (m, 5H), 1.85 (q,J = 6.7 Hz, 2H), 1.76 (q,J = 6.8 Hz, 2H), 1.61 (s, 2H). | 517.45 |
步驟 1
:向可再密封之反應瓶中裝入N-[3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯基]-2-甲基丙-2-烯醯胺(300 mg,951 µmol)、6-碘-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺(260 mg,951 µmol)、Pd(AdnBuP)-G2 (63.4 mg,95.1 µmol)、P(AdnBu)HBF4 (34.1 mg,95.1 µmol)、K3
PO4
(604 mg,2.85 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷/H2O (10:1,10 mL),且在70℃下攪拌混合物12小時。用水稀釋混合物,且水相用二氯甲烷(30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型TLC (二氯甲烷/甲醇15:1)來純化。真空濃縮,產生呈黃色固體狀的N-(4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3,5-二甲基苯基)-2-甲基丙-2-烯醯胺(180 mg,59%)。
N-(4-(4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺
步驟 2
:向圓底燒瓶中裝入N-(4-{4-胺基-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3,5-二甲基苯基)-2-甲基丙-2-烯醯胺(180 mg,536 µmol)、二甲基甲醯胺(5 mL)及攪拌棒。添加NBS (95.4 mg,536 µmol),且在室溫下攪拌溶液0.5小時。混合物用NaHSO3
水溶液淬滅且用DCM (3*20 mL)萃取。合併有機相且濃縮。所得粗物質藉由製備型TLC (DCM/MeOH=15:1)來純化,產生呈棕色固體狀之N-(4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3,5-二甲基苯基)-2-甲基丙-2-烯醯胺(160 mg,72%)。
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺
步驟 3
:向可再密封之反應瓶中裝入N-(4-{4-胺基-5-溴-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}-3,5-二甲基苯基)-2-甲基丙-2-烯醯胺(150 mg,362 µmol)、4-甲基-2-[4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]嘧啶(113 mg,362 µmol)、Pd(dppf)Cl2
(26.4 mg,36.2 µmol)、K3
PO4
(228 mg,1.08 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (8 mL),且在90℃下攪拌混合物1小時。反應混合物用水(50 mL)稀釋,且水相用EtOAc (30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(管柱:YMC-Actus Triart C18, 30*250, 5um:移動相A:未定義,移動相B:未定義;流量:50 mL/min;梯度:45 B至70 B,歷時8分鐘;220 nm;RT1:7.23)。凍乾產生呈白色非晶形固體狀之N-[4-(4-胺基-7-甲基-5-{4-[(4-甲基嘧啶-2-基)氧基]苯基}-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基]-2-甲基丙-2-烯醯胺(18.2 mg,10%)。表 47
. 例示性化合物
實例49
流程46
4-氯-6-(6-氯-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶
化合物 | 結構 | 質子 NMR | MS [M+1] |
N-(4-(4-胺基-7-甲基-5-(4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.45 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.50 (s, 2H), 7.28 - 7.10 (m, 5H), 5.80 (m, 2H), 5.52 (s, 1H), 3.37 (s, 3H), 2.40 (s, 3H), 1.96 (m, 9H). | 520.40 | |
N-(4-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 7.5 Hz, 1H), 8.48 (d, J = 5.0 Hz, 1H), 8.25 - 8.09 (m, 1H), 7.57 - 7.41 (m, 2H), 7.36 - 6.94 (m, 4H), 6.02 - 5.62 (m, 1H), 5.43 (s, 1H), 5.34 (t, J = 1.6 Hz, 1H), 3.78 (s, 3H), 2.42 (s, 3H), 2.10 (s, 3H), 1.85 (s, 3H), 1.78 (d, J = 1.2 Hz, 3H). | 538.30 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d,J = 5.8 Hz, 1H), 8.14 (d,J = 1.9 Hz, 1H), 7.74 (dd,J = 18.2, 10.8 Hz, 1H), 7.10 (d,J = 6.0 Hz, 1H), 5.84 - 5.74 (m, 1H), 5.65 (s, 1H), 5.54 - 5.47 (m, 1H), 3.76 (s, 3H), 3.59 - 3.43 (m, 2H), 2.78 - 2.62 (m, 1H), 2.37 - 2.14 (m, 3H), 2.10 - 1.99 (m, 9H), 1.99 - 1.91 (m, 5H), 1.88 (d,J = 14.7 Hz, 2H), 1.79 (p,J = 6.7 Hz, 1H), 1.24 (s, 1H). | 513.40 | |
(S)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (s, 1H), 8.13 (s, 1H), 7.72 (d,J = 9.4 Hz, 1H), 7.08 (d,J = 1.3 Hz, 1H), 5.80 (d,J = 16.7 Hz, 1H), 5.76 (s, 1H), 5.66 (d,J = 23.7 Hz, 1H), 5.53 - 5.49 (m, 1H), 3.76 (s, 3H), 3.48 (dt,J = 24.2, 8.0 Hz, 2H), 3.17 (d,J = 5.2 Hz, 1H), 2.77 - 2.63 (m, 1H), 2.30 (d,J = 26.8 Hz, 3H), 2.08 (s, 2H), 2.01 (d,J = 6.9 Hz, 8H), 1.96 (d,J = 10.0 Hz, 5H), 1.92 - 1.81 (m, 2H), 1.78 (q,J = 6.7 Hz, 1H), 1.29 - 1.15 (m, 1H). | 513.40 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d,J = 6.1 Hz, 1H), 8.13 (d,J = 1.6 Hz, 1H), 7.72 (d,J = 16.7 Hz, 1H), 7.08 (d,J = 6.0 Hz, 1H), 5.78 (t,J = 10.2 Hz, 1H), 5.65 (s, 1H), 5.51 (dt,J = 6.3, 1.5 Hz, 1H), 3.76 (s, 3H), 3.53 - 3.41 (m, 2H), 3.30 - 3.28 (m, 1H), 2.80 - 2.61 (m, 1H), 2.36 - 2.21 (m, 3H), 2.08 (s, 1H), 2.05 - 2.00 (m, 5H), 1.98 - 1.95 (m, 3H), 1.89 (q,J = 7.3, 6.8 Hz, 4H), 1.78 (q,J = 6.7 Hz, 2H), 1.67 (d,J = 8.6 Hz, 1H), 1.28 - 1.15 (m, 1H). | 513.35 | |
(R)-N-(4-(4-胺基-7-甲基-5-(4-(吡咯啶-1-羰基)環己-1-烯-1-基)-7H-吡咯并[2,3-d]嘧啶-6-基)-3,5-二甲基苯基)甲基丙烯醯胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.64 (d,J = 2.4 Hz, 1H), 8.13 (s, 1H), 7.73 (d,J = 7.9 Hz, 1H), 7.07 (d,J = 1.4 Hz, 1H), 5.82 (s, 1H), 5.77 (d,J = 6.7 Hz, 1H), 5.69 (s, 1H), 5.63 (s, 1H), 5.51 (d,J = 7.0 Hz, 1H), 3.76 (s, 3H), 3.57 - 3.38 (m, 3H), 2.76 (s, 1H), 2.67 (d,J = 1.9 Hz,1H), 2.34 - 2.23 (m, 2H), 2.12 (s, 1H), 2.08 (s, 1H), 2.02 (s, 5H), 2.01 - 1.97 (m, 3H), 1.95 (s, 5H), 1.89 (d,J = 14.7 Hz, 2H), 1.79 (p,J = 6.7 Hz, 1H), 1.24 (s, 2H). | 513.35 |
步驟 1
:向可再密封之反應瓶中裝入(4-氯-7-甲基-7H-吡咯并[2,3-d]嘧啶-6-基)酸(2 g,9.48 mmol)、5-溴-2-氯-3-氟-4-甲基吡啶(2.3 g,10.4 mmol)、Pd(dtbpf)Cl2
(617 mg,0.948 µmol)、K3
PO4
(6 g,28.44 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷:水=5:1 (40 mL),且在70℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。真空蒸發,殘餘物藉由矽膠管柱層析(用PE/EA (30:1至1:1)溶離)來純化,得到呈黃色非晶形固體狀之4-氯-6-(6-氯-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶(1.3 g,44%)。
6-(6-氯-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 2
:向可再密封之反應瓶中裝入4-氯-6-(6-氯-5-氟-4-甲基吡啶-3-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶(1.28 g,4.13 mmol)、Pd(PPh3
)4
(478 mg,0.413 mmol)、DMF (20 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加Zn (CH3
)2
(2 M,1.4 mL),且在90℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。殘餘物藉由矽膠管柱層析(用PE/EA (30:1至1:2)溶離)來純化,得到呈黃色非晶形固體狀之6-(6-氯-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(420 mg,68%)。
6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 3
:向可再密封之反應瓶中裝入6-(6-氯-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(1.28 g,4.13 mmol)、Pd(PPh3
)2
Cl2
(580 mg,0.826 mmol)、CuI (313 mg,1.65 mmol)、乙炔基三異丙基矽烷(526 mg,2.89 mmol)、TEA (1.25 g,12.39 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF (20 mL),且在90℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得混合物經由C18管柱純化。真空濃縮,產生呈黃色非晶形固體狀之6-(6-氯-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(720 mg,40%)。
6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-5-碘-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶
步驟 4
:向圓底燒瓶中裝入6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(400 mg,1.60 mmol)、DCM (8 mL),添加TFA (547 mg,4.8 mmol)及攪拌棒。添加NIS (396 mg,1.76 mmol),且在室溫下攪拌溶液1小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由矽膠層析純化。真空濃縮,產生呈黃色非晶形固體狀之46-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-5-碘-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(760 mg,85%)。
6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-4,7-二甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶
步驟 5
:向圓底燒瓶中裝入6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-5-碘-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶(740 mg,1.32 mmol)、4-甲基-2-((6-(三丁基錫烷基)吡啶-3-基)氧基)嘧啶(1.26 g,2.64 mmol)、Pd(PPh3
)4
(153 mg,0.132 mmol)、CuI (50 mg,0.264 μmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF (15 mL),且在90℃下攪拌溶液2小時。使反應混合物處於真空中。所得粗物質藉由製備型TLC純化。真空濃縮,產生呈黃色非晶形固體狀之6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-4,7-二甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶(540 mg,66%)。
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶
步驟 6
:向圓底燒瓶中裝入6-(5-氟-4-甲基-6-((三異丙基矽烷基)乙炔基)吡啶-3-基)-4,7-二甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶(520 mg,0.84 mmol)、THF (8 mL)及攪拌棒。添加TBAF (1 mL,1 mmol),且在室溫下攪拌溶液1小時。反應混合物用水稀釋,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。殘餘物藉由製備型HPLC純化(管柱:XBridge Shield RP18 OBD管柱,30*150mm, 5um;移動相A:水(10 MMOL/L NH4
HCO3
+0.1%NH3
·H2
O),移動相B:ACN;流量:60 mL/min;梯度:20 B至45 B,歷時8分鐘;254/220 nm;RT1:7.77)。凍乾產生呈白色非晶形固體狀之6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶(213.2 mg,55%)。表 48. 例示性化合物
實例50
流程47
(6-(6-氯-4-(2-羥基乙氧基)吡啶-3-基)-5-碘-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)胺基甲酸第三丁酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
6-(6-乙炔基-5-氟-4-甲基吡啶-3-基)-4,7-二甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶 | 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.54 (d, J = 2.7 Hz, 1H), 8.50 (d, J = 5.0 Hz, 1H), 8.43 (s, 1H), 7.61 (dd, J = 8.5, 2.8 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 5.0 Hz, 1H), 4.82 (d, J = 0.8 Hz, 1H), 3.63 (s, 3H), 2.40 (s, 3H), 1.98 (d, J = 2.1 Hz, 3H). | 446.15 | |
6-(6-乙炔基-4-甲氧基吡啶-3-基)-7-甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d,J = 2.8 Hz, 1H), 8.48 (d,J = 5.0 Hz, 1H), 8.26 (s, 1H), 8.19 (s, 1H), 7.56 - 7.49 (m, 1H), 7.51 (s, 1H), 7.19 (d,J = 5.0 Hz, 1H), 6.88 (d,J = 8.7 Hz, 1H), 4.49 (s, 1H), 3.89 (s, 3H), 3.48 (s, 3H), 2.42 (s, 3H). | 465.20 | |
6-(6-乙炔基-5-氟-4-甲氧基吡啶-3-基)-7-甲基-5-(5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d6) δ 8.59 (d, J = 2.9 Hz, 1H), 8.49 (d, J = 5.0 Hz, 1H), 8.16 (s, 1H), 8.07 (s, 1H), 7.61 (dd, J = 8.8, 2.8 Hz, 1H), 7.27 (d, J = 9.0 Hz, 1H), 7.20 (d, J = 5.0 Hz, 1H), 5.60 (d, J = 0.9 Hz, 1H), 3.75 (s, 3H), 3.52 (s, 3H), 2.43 (s, 3H). | 483.15 | |
6-(6-乙炔基-4-甲氧基吡啶-3-基)-5-(2-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.77 (s, 1H), 8.50 (d,J = 5.0 Hz, 1H), 8.23 (d,J = 97.8 Hz, 1H), 7.46 (d,J = 19.1 Hz, 1H), 7.38 (s, 1H), 7.33 - 6.95 (m, 3H), 4.47 (d,J = 3.7 Hz, 1H), 3.91 (s, 3H), 3.64 (d,J = 9.7 Hz, 3H), 2.42 (s, 3H), 2.38 (s, 3H). | 481.15 | |
6-(6-乙炔基-4-甲基吡啶-3-基)-5-(3-氟-5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.62 - 8.56 (m, 1H), 8.52 (d,J = 5.0 Hz, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.77 (dd,J = 11.0, 2.3 Hz, 1H), 7.61 (s, 1H), 7.23 (d,J = 5.1 Hz, 1H), 7.02 (s, 1H), 4.42 (s, 1H), 3.52 (s, 3H), 2.43 (s, 3H), 2.05 (s, 3H). | 467.30 | |
6-(6-乙炔基-4-甲氧基-2-甲基吡啶-3-基)-5-(3-氟-5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.58 (s, 1H), 8.53 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.76 (dd,J = 11.0, 2.3 Hz, 1H), 7.30 (s, 1H), 7.23 (d,J = 5.0 Hz, 1H), 6.87 (s, 1H), 4.41 (s, 1H), 3.84 (s, 3H), 3.46 (s, 3H), 2.43 (s, 3H), 1.92 (s, 3H), 1.24 (s, 1H). | 497.20 | |
6-(6-乙炔基-4-甲氧基吡啶-3-基)-5-(3-氟-5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.59 (d,J = 2.3 Hz, 1H), 8.53 (d,J = 5.1 Hz, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.80 - 7.72 (m, 1H), 7.45 (s, 1H), 7.24 (d,J = 5.0 Hz, 1H), 7.01 - 6.96 (m, 1H), 4.47 (s, 1H), 3.88 (s, 3H), 3.56 (s, 3H), 2.44 (s, 3H). | 483.20 | |
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體1 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (dd,J = 2.3, 0.9 Hz, 1H), 8.52 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.78 (dd,J = 11.0, 2.3 Hz, 1H), 7.43 (s, 1H), 7.23 (d,J = 5.0 Hz, 1H), 6.81 (s, 2H), 4.37 (s, 1H), 3.44 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 1.97 (s, 3H). | 491.20 |
6-(6-乙炔基-2,4-二甲基吡啶-3-基)-5-(3-氟-5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-7-甲基-7H-吡咯并[2,3-d]嘧啶-4-胺 | 滯轉異構體2 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.57 (d,J = 2.2 Hz, 1H), 8.52 (d,J = 5.0 Hz, 1H), 8.25 (s, 1H), 7.78 (dd,J = 11.0, 2.3 Hz, 1H), 7.43 (s, 1H), 7.22 (s, 1H), 6.81 (s, 2H), 4.37 (d,J = 0.8 Hz, 1H), 3.44 (s, 3H), 2.42 (s, 3H), 2.13 (s, 3H), 1.97 (s, 3H). | 481.20 |
6-(6-乙炔基-4-甲氧基吡啶-3-基)-5-(3-氟-5-((4-甲基嘧啶-2-基)氧基)吡啶-2-基)-4,7-二甲基-7H-吡咯并[2,3-d]嘧啶 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.79 (s, 1H), 8.53 (d,J = 5.0 Hz, 1H), 8.49 (d,J = 2.2 Hz, 1H), 8.19 (s, 1H), 7.86 (dd,J = 10.3, 2.3 Hz, 1H), 7.41 (s, 1H), 7.24 (d,J = 5.1 Hz, 1H), 4.47 (s, 1H), 3.84 (s, 3H), 3.68 (s, 3H), 2.42 (d,J = 11.5 Hz, 6H). | 482.10 |
步驟 1
:向圓底燒瓶中裝入N-[(第三丁氧基)羰基]-N-{6-[6-氯-4-(2-羥基乙氧基)吡啶-3-基]-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-基}胺基甲酸第三丁酯(3 g,4.71 mmol)、TFA (2.27 g,23.5 mmol)、二氯甲烷(40 mL)及攪拌棒。添加NIS (1.27 g,5.65 mmol),且在室溫下攪拌溶液1小時。反應混合物用水(40 mL)稀釋,且水相用二氯甲烷(60 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由flash來純化(乙腈/水),真空濃縮,產生呈黃色非晶形固體狀之(6-(6-氯-4-(2-羥基乙氧基)吡啶-3-基)-5-碘-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-4-基)胺基甲酸第三丁酯(600 mg)及N-[(第三丁氧基)羰基]-N-{6-[6-氯-4-(2-羥基乙氧基)吡啶-3-基]-5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-基}胺基甲酸第三丁酯(3.00 g,83%)。
2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)氧基)乙-1-醇
步驟 2
:向可再密封之反應瓶中裝入N-{6-[6-氯-4-(2-羥基乙氧基)吡啶-3-基]-5-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-基}胺基甲酸第三丁酯(500 mg,755 µmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(299 mg,906 µmol)、K3
PO4
(479 mg,2.26 mmol)、Pd(dppf)Cl2
(55.2 mg,75.5 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (10 mL),且在90℃下攪拌混合物1小時。反應混合物用水(20 mL)稀釋,且水相用EA (30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(10 g管柱;用二氯甲烷/甲醇溶離;比率=15:1)。真空濃縮,產生呈黃色非晶形固體狀之2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)氧基)乙-1-醇(320 mg,66%)。
2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-((第三丁基二甲基矽烷基)乙炔基)吡啶-4-基)氧基)乙-1-醇
步驟 3
:向可再密封之反應瓶中裝入2-{[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基]氧基}乙-1-醇(280 mg,438 µmol)、第三丁基(乙炔基)二甲基矽烷(122 mg,876 µmol)、CuI (33.2 mg,175 µmol)、TEA (132 mg,1.31 mmol)、Pd(dppf)Cl2
(64.1 mg,87.6 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DMF (5 mL),且在50℃下攪拌混合物2小時。反應混合物用水(20 mL)稀釋,且水相用EA (30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由flash來純化(乙腈/水)。真空濃縮,產生呈灰白色非晶形固體狀之2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-((第三丁基二甲基矽烷基)乙炔基)吡啶-4-基)氧基)乙-1-醇(110 mg,34%)。
2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)氧基)乙-1-醇
步驟 4
:向圓底燒瓶中裝入2-{[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-[2-(第三丁基二甲基矽烷基)乙炔基]吡啶-4基]氧基}乙-1-醇(100 mg,134 µmol)、THF (5 mL)及攪拌棒。添加TBAF (35.0 mg,134 µmol),且在室溫下攪拌溶液30分鐘。所得粗物質藉由矽膠層析純化(5 g管柱;用二氯甲烷/甲醇溶離;比率=10:1)。真空濃縮,產生呈棕色非晶形固體狀之2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)氧基)乙-1-醇(80.0 mg,95%)。
2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)氧基)乙-1-醇
步驟 5
:向圓底燒瓶中裝入2-{[5-(4-胺基-5-{3-氟-4-[(4-甲基嘧啶-2-基)氧基]苯基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基]氧基}乙-1-醇(70 mg,111 µmol)及攪拌棒。添加CH3
SO3
H/MeOH (1:2,2 mL),且在70℃下攪拌溶液1小時,且接著用TEA將溶液pH值調整至7。所得粗物質藉由矽膠層析(5 g管柱;用二氯甲烷/甲醇溶離;比率=10:1)純化,真空濃縮。所得粗物質藉由HPLC純化(管柱:YMC-Actus Triart C18,30*250, 5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:60 mL/min;梯度:15 B至48 B,歷時7分鐘;254/220 nm;RT1:6.48)。凍乾產生呈灰白色非晶形固體狀之2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)氧基)乙-1-醇(9.20 mg,17%)。表 49 . 例示性化合物
實例51
流程48
2-((5-溴-2-氯吡啶-4-基)氧基)乙-1-醇
化合物 | 結構 | 質子 NMR | MS [M+1] |
2-((5-(4-胺基-5-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7H-吡咯并[2,3-d]嘧啶-6-基)-2-乙炔基吡啶-4-基)氧基)乙-1-醇 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.07 (s, 1H), 8.49 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.40 - 7.30 (m, 2H), 7.27 - 7.17 (m, 2H), 7.10 (dd,J = 8.2, 2.0 Hz, 1H), 6.06 (s, 1H), 4.87 (t,J = 5.4 Hz, 1H), 4.40 (s, 1H), 4.01 (t,J = 4.9 Hz, 2H), 3.56 (q,J = 5.1 Hz, 2H), 2.43 (s, 3H). | 498.30 |
步驟 1
:向圓底燒瓶中裝入乙烷-1,2-二醇(81.9 g,1.32 mol)、DMSO (800 mL)及攪拌棒。添加NaH (7.58 g,316 mmol),且在室溫下攪拌溶液30分鐘,且接著添加5-溴-2,4-二氯吡啶(60 g,264 mmol),且在50℃下攪拌溶液1小時。反應混合物用水(500 mL)稀釋,且水相用EA (500 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(500 g管柱;用DCM/EA溶離;比率=1:1)。真空濃縮,產生呈黃色油狀的2-[(5-溴-2-氯吡啶-4-基)氧基]乙-1-醇(55.0 g,82%)。
5-溴-4-(2-((第三丁基二甲基矽烷基)氧基)乙氧基)-2-氯吡啶
步驟 2
:向圓底燒瓶中裝入2-[(5-溴-2-氯吡啶-4-基)氧基]乙-1-醇(55 g,217 mmol)、咪唑(73.5 g,1.08 mol)、DMF (1000 mL)及攪拌棒。添加TBSCl (65.4 g,434 mmol),且在室溫下攪拌溶液16小時。反應混合物用EA (1000 mL)萃取,合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(600 g管柱;用PE/EA溶離;比率=40:1)。真空濃縮,產生呈灰白色結晶固體狀之5-溴-4-(2-((第三丁基二甲基矽烷基)氧基)乙氧基)-2-氯吡啶(82.4 g,100%)。
N-[(第三丁氧基)羰基]-N-[6-(4-{2-[(第三丁基二甲基矽烷基)氧基]乙氧基}-6-氯吡啶-3-基)-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-基]胺基甲酸第三丁酯
步驟 3
:向可再密封之反應瓶中裝入5-溴-4-{2-[(第三丁基二甲基矽烷基)氧基]乙氧基}-2-氯吡啶(28 g,76.3 mmol)、(4-{雙[(第三丁氧基)羰基]胺基}-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)酸(77.2 g,152 mmol)、CsF (34.6 g,228 mmol)、Pd(dtbpf)Cl2
(4.97 g,7.63 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷/H2
O (600 mL),且在70℃下攪拌混合物2小時。反應混合物用水(400 mL)稀釋,且水相用DCM (500 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由flash來純化(乙腈/水)。真空濃縮,產生呈黃色非晶形固體狀之N-[(第三丁氧基)羰基]-N-[6-(4-{2-[(第三丁基二甲基矽烷基)氧基]乙氧基}-6-氯吡啶-3-基)-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-基]胺基甲酸第三丁酯(30.0 g,52%)。
2-((5-(4-胺基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)氧基)乙-1-醇
步驟 4
:向圓底燒瓶中裝入N-[(第三丁氧基)羰基]-N-[6-(4-{2-[(第三丁基二甲基矽烷基)氧基]乙氧基}-6-氯吡啶-3-基)-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-基]胺基甲酸第三丁酯(29 g,38.6 mmol)及攪拌棒。添加HCl (12 M)/MeOH (1:1,600 mL),且在室溫下攪拌溶液3小時,且接著在0℃下用TEA將溶液pH值調整至8,接著真空濃縮。沈澱的固體藉由過濾收集且用ACN (300 mL)洗滌三次,真空乾燥,產生呈灰白色非晶形固體狀之2-((5-(4-胺基-7H-吡咯并[2,3-d]嘧啶-6-基)-2-氯吡啶-4-基)氧基)乙-1-醇(8.00 g,67%)。
3-氯-6,7-二氫吡啶并[3,4-F]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺
步驟 5
:向可再密封之反應瓶中裝入2-[(5-{4-胺基-7H-吡咯并[2,3-d]嘧啶-6-基}-2-氯吡啶-4-基)氧基]乙-1-醇(7.9 g,25.8 mmol)、DIAD (10.4 g,51.6 mmol)、THF (80 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加含PPh3
(13.5 g,51.6 mmol)的THF (40 ml),且在30℃下攪拌混合物3小時。在真空中移除溶劑。殘餘物用DCM (200 mL)洗滌,真空乾燥,產生呈灰白色非晶形固體狀之3-氯-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(5.00 g,67%)。
3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺
步驟 6
:向可再密封之反應瓶中裝入3-氯-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(4.9 g,17.0 mmol)、DMF (150 mL)、TEA (5.15 g,50.9 mmol)、CuI (1.29 g,6.80 mmol)、Pd(dppf)Cl2
.CH2
Cl2
(2.77 g,3.40 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。接著添加乙炔基參(丙-2-基)矽烷(6.20 g,34.0 mmol),且在70℃下攪拌混合物2小時。反應混合物用水(500 mL)稀釋,且水相用二氯甲烷(400 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(100 g管柱;用二氯甲烷/甲醇溶離;比率=20:1)。真空濃縮,產生呈棕色非晶形固體狀之3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(4.5 g,61.0%)。
13-碘-3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺
步驟 7
:向圓底燒瓶中裝入3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(4.4 g,10.1 mmol)、TFA (3.45 g,30.3 mmol)及攪拌棒。添加二氯甲烷(100 mL),且接著在0℃下添加NIS (3.39 g,15.1 mmol),且在室溫下攪拌溶液1小時。反應物用NaHSO3
水溶液淬滅,接著用碳酸氫鈉將PH調整至6-7。反應混合物用水(30 mL)稀釋,沈澱的固體藉由過濾收集且用ACN (300 mL)洗滌。真空乾燥,產生呈灰白色非晶形固體狀之13-碘-3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(5.50 g,97%)。
13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺
步驟 8
:向可再密封之反應瓶中裝入13-碘-3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(5.4 g,9.65 mmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(4.75 g,14.4 mmol)、K3
PO4
(6.13 g,28.9 mmol)、Pd(dppf)Cl2
.CH2
Cl2
(787 mg,965 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (100 mL),且在90℃下攪拌混合物1小時。反應混合物用水(80 mL)稀釋,且水相用二氯甲烷(100 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(100 g管柱;用二氯甲烷/甲醇溶離;比率=20:1)。真空濃縮,產生呈棕色非晶形固體狀之13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(4.70 g,76%)。
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺
步驟 9
:向圓底燒瓶中裝入13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三異丙基矽烷基)乙炔基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(4.6 g,7.23 mmol)、四氫呋喃(60 mL)及攪拌棒。添加TBAF (1.89 g,7.23 mmol),且在室溫下攪拌溶液30分鐘。所得粗物質藉由矽膠層析純化(100 g管柱;用二氯甲烷/甲醇溶離;比率=20:1)。真空濃縮,且接著用水(50 mL)及ACN (100 ml)洗滌殘餘物,產生呈淺黃色非晶形固體狀之3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]氧氮雜環庚三烯-12-胺(3.00 g,86%)。表 50. 例示性化合物
實例52
流程49
3-(3-(4-胺基-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基)丙酸甲酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]噁氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.54 - 7.41 (m, 2H), 7.34 - 7.27 (m, 1H), 7.25 (s, 1H), 7.22 (d,J = 5.1 Hz, 1H), 6.11 (s, 1H), 4.67 (s, 4H), 4.39 (s, 1H), 2.46 (s, 3H). | 480.15 | |
(R)-3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]噁氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.54 (d,J = 5.0 Hz, 1H), 8.22 (s, 1H), 8.05 (s, 1H), 7.52 (d,J = 8.5 Hz, 2H), 7.36 (s, 1H), 7.29 -7.17 (m, 2H), 5.76 (s, 1H), 5.62 -5.37 (m, 1H), 4.73 (dd,J = 12.8, 4.3 Hz, 1H), 4.60 (d,J = 12.6 Hz, 1H), 4.37 (s, 1H), 2.46 (s, 3H), 1.39 (d,J = 7.1 Hz, 3H). | 494.20 | |
(S)-3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-甲基-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]噁氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) 8.53 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.04 (s, 1H), 7.51-7.41 (m, 2H), 7.30-7.20 (m, 3H), 5.76 (s, 1H), 4.94 (td,J = 6.4, 2.8 Hz, 1H), 4.64 (dd,J = 15.3, 2.8 Hz, 1H), 4.42 (s, 1H), 4.34 (dd,J = 15.3, 6.4 Hz, 1H), 2.46 (s, 3H), 1.32 (d,J = 6.4 Hz, 3H). | 494.20 | |
(S)-3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-7-甲基-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]噁氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 8.05 (s, 1H), 7.52 (d,J = 8.6 Hz, 2H), 7.32 (d,J = 28.4 Hz, 1H), 7.23 - 7.16 (m, 2H), 6.12 (s, 1H), 5.54 - 5.39 (m, 1H), 4.73 (dd,J = 12.8, 4.3 Hz, 1H), 4.60 (d,J = 12.6 Hz, 1H), 4.37 (s, 1H), 2.46 (s, 3H), 1.39 (d,J = 7.2 Hz, 3H). | 494.15 | |
(R)-3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6-甲基-6,7-二氫吡啶并[3,4-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]噁氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (d,J = 5.0 Hz, 1H), 8.24 (s, 1H), 8.04 (s, 1H), 7.57 - 7.35 (m, 2H), 7.34 - 7.17 (m, 3H), 6.21 (s, 1H), 4.94 (td,J = 6.4, 2.8 Hz, 1H), 4.65 (dd,J = 15.3, 2.9 Hz, 1H), 4.42 (s, 1H), 4.34 (dd,J = 15.3, 6.4 Hz, 1H), 2.46 (s, 3H), 1.32 (d,J = 6.4 Hz, 3H). | 494.20 | |
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫吡啶并[3,2-f]嘧啶并[5',4':4,5]吡咯并[1,2-d][1,4]噁氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.52 (d,J = 5.0 Hz, 1H), 8.23 (s, 1H), 7.49 - 7.34 (m, 3H), 7.29 - 7.20 (m, 3H), 6.15 (s, 1H), 4.64 (t,J = 5.1 Hz, 2H), 4.55 (t,J = 5.2 Hz, 2H), 4.44 (s, 1H), 2.45 (s, 3H). | 480.20 |
步驟 1
:向圓底燒瓶中裝入6-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-4-胺(23.8 g,61.0 mmol)、3-[6-氯-3-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)吡啶-2-基]丙酸甲酯(21.8 g,67.1 mmol)、Pd(dtbpf)Cl2
(3.97 g,6.10 mmol)、CsF (27.8 g,183 mmol)及攪拌棒。添加二噁烷/H2
O (500 mL),且在90℃下攪拌溶液2小時。反應混合物用水(500 mL)稀釋,且水相用二氯甲烷(800 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(MeCN/H2
O=0%~50%;30分鐘)。真空濃縮,產生呈黃色非晶形固體狀之3-[3-(4-胺基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基]丙酸甲酯(13 g,46%)。
3-(3-(4-胺基-7-((2-(三甲基矽烷基)乙氧基)甲基)-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基)丙-1-醇
步驟 2
:向圓底燒瓶中裝入3-[3-(4-胺基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基]丙酸甲酯(13.0 g,28.1 mmol),添加四氫呋喃(200 mL)。在-30℃下添加LiAlH4
(1.28 g,33.7 mmol)且在-30℃下攪拌溶液2小時。反應混合物用水(2.44 mL)淬滅,且反應混合物經由矽藻土墊過濾,用DCM洗滌墊,且真空濃縮濾液。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇40:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之3-[3-(4-胺基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基]丙-1-醇(6.30 g,52%)。
3-(3-(4-胺基-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基)丙-1-醇
步驟 3
:向圓底燒瓶中裝入3-[3-(4-胺基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)-6-氯吡啶-2-基]丙-1-醇(5.00 g,11.5 mmol)及攪拌棒。添加HCl/MeOH (50 mL),且在40℃下攪拌溶液1小時。真空濃縮反應混合物。接著用MeCN (20 mL)稀釋,反應混合物經由矽藻土墊過濾,用MeCN洗滌墊,及濾餅,產生呈灰白色非晶形固體狀之3-(3-{4-胺基-7H-吡咯并[2,3-d]嘧啶-6-基}-6-氯吡啶-2-基)丙-1-醇(3.00 g,90%)。
3-氯-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
步驟 4
:向可再密封之反應瓶中裝入3-(3-{4-胺基-7H-吡咯并[2,3-d]嘧啶-6-基}-6-氯吡啶-2-基)丙-1-醇(3.50 g,11.5 mmol)、四氫呋喃(40 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DIAD (3.47 g,17.2 mmol)及PPh3
(4.52 g,17.2 mmol),且在25℃下攪拌混合物2小時。反應混合物用水(40 mL)稀釋,且水相用二氯甲烷(40 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇30:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之3-氯-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(2.00 g,61%)。3 -(( 三異丙基矽烷基 ) 乙炔基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 2 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯 - 12 - 胺
步驟 5
:向可再密封之反應瓶中裝入3-氯-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(1.98 g,6.92 mmol)、二甲基甲醯胺(20 mL)、CuI (524 mg,2.76 mmol)、TEA (2.09 g,20.7 mmol)、Pd(dppf)Cl2
(505 mg,692 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加乙炔基參(丙-2-基)矽烷(2.51 g,13.8 mmol),且在90℃下攪拌混合物2小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇40:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(1.50 g,50%)。13 - 碘 - 3 -(( 三異丙基矽烷基 ) 乙炔基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 2 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯 - 12 - 胺
步驟 6
:向圓底燒瓶中裝入3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(1.88 g,4.35 mmol)、二甲基甲醯胺(2 mL)、NIS (978 mg,4.35 mmol)及攪拌棒,且在25℃下攪拌溶液1小時。反應混合物用Na2
SO3
(水溶液)(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇40:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之13-碘-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(1.50 g,62%)。13 -( 3 - 氟 - 4 -(( 4 - 甲基嘧啶 - 2 - 基 ) 氧基 ) 苯基 )- 3 -(( 三異丙基矽烷基 ) 乙炔基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 2 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯 - 12 - 胺
步驟 7
:向可再密封之反應瓶中裝入13-碘-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(1.48 g,2.65 mmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(960 mg,2.91 mmol)、K3
PO4
(1.68 g,7.95 mmol)、Pd(dppf)Cl2
(193 mg,265 µmol),添加DME/H2
O (20 mL),及攪拌棒,隨後抽真空且用氮氣淨化三次,且在90℃下攪拌混合物1小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析(用二氯甲烷/甲醇30:1溶離)純化。真空濃縮,產生呈黃色非晶形固體狀之13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(1 g,60%)。
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
步驟 8
:向圓底燒瓶中裝入13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(980 mg,1.55 mmol)、四氫呋喃(20 mL)、TBAF (2.07 mL,2.07 mmol)及攪拌棒,且在25℃下攪拌溶液1小時。反應混合物用水(20 mL)稀釋,且水相用二氯甲烷(20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由HPLC純化(管柱:YMC-Actus Triart C18, 30*250, 5um;移動相A:水(10 MMOL/L NH4
HCO3
),移動相B:ACN;流量:60 mL/min;梯度:25 B至60 B,歷時7分鐘;254/220 nm;RT1:6.32)。凍乾產生呈灰白色非晶形固體狀之3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(250 mg,34%)。
表51.例示性化合物
實例53
流程50
3-[2-氯-5-(4-氯-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙酸甲酯
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,2-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.50 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 7.45 - 7.35 (m, 3H), 7.29 - 7.19 (m, 3H), 6.12 (s, 2H), 4.41 (s, 1H), 4.17 (d,J = 7.0 Hz, 2H), 2.92 (t,J = 7.1 Hz, 2H), 2.44 (s, 3H), 2.31 (q,J = 6.8 Hz, 2H). | 478.20 | |
(S)-1-((S)-4-(12-胺基-3-乙炔基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-13-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.15 (s, 1H), 7.66 (s, 1H), 6.80 (s, 1H), 5.89 (s, 1H), 4.74 (dd,J = 7.4, 3.4 Hz, 1H), 4.43 (s, 1H), 4.09 (s, 2H), 3.77 (s, 1H), 3.53 (q,J = 8.4 Hz, 1H), 3.02 - 2.89 (m, 1H), 2.66 (d,J = 7.0 Hz, 2H), 2.34 (d,J = 6.1 Hz, 2H), 2.29 - 1.93 (m, 8H), 1.80 - 1.74 (m, 2H). | 478.25 | |
(S)-1-((R)-4-(12-胺基-3-乙炔基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-13-基)環己-3-烯-1-羰基)吡咯啶-2-甲腈 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.53 (s, 1H), 8.11 (s, 1H), 7.65 (s, 1H), 6.61 (d,J = 46.1 Hz, 1H), 5.87 (s, 1H), 4.75 (dd,J = 7.9, 3.7 Hz, 1H), 4.42 (s, 1H), 4.20 (s, 1H), 3.96 (s, 1H), 3.83 - 3.47 (m, 2H), 2.98 (d,J = 5.9 Hz, 1H), 2.76 - 2.59 (m, 2H), 2.33 (s, 2H), 2.28 - 2.10 (m, 4H), 2.04 (d,J = 6.7 Hz, 4H), 1.80 (d,J = 6.2 Hz, 2H). | 478.25 |
步驟 1
:向可再密封之反應瓶中裝入4-氯-6-碘-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶(5 g,12.2 mmol)、{2-[6-氯-4-(3-甲氧基-3-側氧基丙基)吡啶-3-基]-4,5,5-三甲基-1,3,2-二氧雜硼雜環戊烷-4-基}甲基鎓(4.73 g,14.6 mmol)、CsF (5.54 g,36.5 mmol)、Pd(dtbpf)Cl2
(795 mg,1.22 mmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二噁烷/H2
O (100 mL),且在70℃下攪拌混合物1小時。反應混合物用H2
O (400 mL)稀釋,且水相用二氯甲烷(200 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(300 g管柱;用PE/EA 30/1溶離)。真空濃縮,產生呈黑色非晶形固體狀之3-[2-氯-5-(4-氯-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙酸甲酯(2.00 g,34.0%)。
3-[2-氯-5-(4-甲基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙酸甲酯
步驟 2
:向可再密封之反應瓶中裝入3-[2-氯-5-(4-氯-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙酸甲酯(1.9 g,3.94 mmol)、Pd(PPh3
)4
(455 mg,394 µmol)、二甲基甲醯胺(25 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二甲基鋅(413 mg,4.33 mmol),且在90℃下攪拌混合物2小時。反應混合物用H2
O (100 mL)稀釋,且水相用EA (80 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(300 g管柱;用PE/EA 10/1溶離)。真空濃縮,產生呈黑色非晶形固體狀之3-[2-氯-5-(4-甲基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙酸甲酯(850 mg,46.9%)。
3-[2-氯-5-(4-甲基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙-1-醇
步驟 3
:向圓底燒瓶中裝入3-[2-氯-5-(4-甲基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙酸甲酯(800 mg,1.73 mmol)、四氫呋喃(10 mL)及攪拌棒。添加鋁氧烷氫化鋰(98.2 mg,2.59 mmol),且在-30℃下攪拌溶液。反應混合物用H2
O (50 mL)淬滅,且水相用二氯甲烷(50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮,產生呈灰白色非晶形固體狀之3-[2-氯-5-(4-甲基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙-1-醇(570 mg,76.1%)。
3-(2-氯-5-{4-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡啶-4-基)丙-1-醇
步驟 4
:向圓底燒瓶中裝入3-[2-氯-5-(4-甲基-7-{[2-(三甲基矽烷基)乙氧基]甲基}-7H-吡咯并[2,3-d]嘧啶-6-基)吡啶-4-基]丙-1-醇(550 mg,1.27 mmol)及攪拌棒。添加MeOH/HCl (10 mL),且在40℃下攪拌溶液1小時。真空濃縮溶液。接著添加MeOH (5 mL),添加乙二胺(76.3 mg,1.27 mmol),且在室溫下攪拌溶液30分鐘。反應混合物用H2
O (50 mL)稀釋,且水相用DCM (50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮,產生呈灰白色非晶形固體狀之3-(2-氯-5-{4-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡啶-4-基)丙-1-醇(360 mg,93.7%)。
步驟 5
:向可再密封之反應瓶中裝入3-(2-氯-5-{4-甲基-7H-吡咯并[2,3-d]嘧啶-6-基}吡啶-4-基)丙-1-醇(340 mg,1.12 mmol)、PPh3
(510 mg,1.68 mmol)、四氫呋喃(10 mL)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DIAD (655 mg,1.68 mmol),且在40℃下攪拌混合物1小時。反應混合物用H2
O (50 mL)稀釋,且水相用二氯甲烷(50 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。殘餘物藉由矽膠層析純化(300 g管柱;用PE/EA 1/1溶離)。真空濃縮,產生呈灰白色非晶形固體狀之3-氯-12-甲基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(180 mg,56.6%)。12 - 甲基 - 3 -(( 三異丙基矽烷基 ) 乙炔基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 4 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯
步驟 6
:向可再密封之反應瓶中裝入3-氯-12-甲基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(160 mg,561 µmol)、TEA (169 mg,1.68 mmol)、CuI (42.5 mg,224 µmol)、Pd(pddf)Cl2
(81.9 mg,112 µmol)、參(丙-2-基)矽烷(88.8 mg,561 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加二甲基甲醯胺(10 mL),且在70℃下攪拌混合物2小時。反應混合物用H2
O (50 mL)稀釋,且水相用EA (20 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用己烷/乙酸乙酯15/1溶離)。真空濃縮,產生呈橙色非晶形固體狀之12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(150 mg,62.2%)。
13-碘-12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯
步驟 7
:向圓底燒瓶中裝入12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(150 mg,348 µmol)、二氯甲烷(5 mL)、TFA (118 mg,1.04 mmol)及攪拌棒。在0℃下添加1-碘吡咯啶-2,5-二酮(85.9 mg,382 µmol),且在室溫下攪拌溶液30分鐘。混合物用飽和NaHSO3
水溶液淬滅直至pH至8-9,用DCM (100 mL*3)萃取,合併有機相且經Na2
SO4
乾燥,真空濃縮,產生13-碘-12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(180 mg,93.2%)。13 -( 3 - 氟 - 4 -(( 4 - 甲基嘧啶 - 2 - 基 ) 氧基 ) 苯基 )- 12 - 甲基 - 3 -(( 三異丙基矽烷基 ) 乙炔基 )- 6 , 7 - 二氫 - 5H - 吡啶并 [ 3 , 4 - c ] 嘧啶并 [ 5 ', 4 ': 4 , 5 ] 吡咯并 [ 1 , 2 - a ] 氮呯
步驟 8
:向可再密封之反應瓶中裝入13-碘-12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(160 mg,287 µmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(113 mg,344 µmol)、K3
PO4
(182 mg,861 µmol)、Pd(PPh3
)4
(331 mg,287 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME/H2
O (6 mL),且在90℃下攪拌混合物1小時。反應混合物用H2
O (50 mL)稀釋,且水相用二氯甲烷(30 mL)萃取三次。合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由矽膠層析純化(50 g管柱;用己烷/乙酸乙酯1/1溶離)。真空濃縮,產生呈黑色非晶形固體狀之13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(100 mg,55.2%)。
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-12-甲基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯
步驟 9
:向圓底燒瓶中裝入13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-12-甲基-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(90 mg,142 µmol)、四氫呋喃(1 mL)及攪拌棒。添加TBAF (34.4 mg,142 µmol),且在室溫下攪拌溶液。反應混合物用DCM (100 mL)稀釋,合併之有機層用H2
O (200 ml)洗滌六次,經硫酸鈉乾燥,過濾且真空濃縮。所得粗物質藉由製備型HPLC純化(管柱:YMC-Actus Triart C18,20*250MM, 5um, 12nm;移動相A:未定義;移動相B:未定義;流量:60 mL/min;梯度:40 B至65 B,歷時8分鐘;220/254 nm;RT1:7.07)。凍乾產生呈灰白色非晶形固體狀之3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-12-甲基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯(18.9 mg,27.9%)。表 52 . 例示性化合物
實例54
流程51
13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-乙炔基-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-12-甲基-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.75 (s, 1H), 8.51 (d,J = 5.1 Hz, 1H), 8.12 (s, 1H), 7.71 (s, 1H), 7.50 (d,J = 11.2 Hz, 1H), 7.42 (t,J = 8.3 Hz, 1H), 7.29 (d,J = 8.4 Hz, 1H), 7.21 (d,J = 5.0 Hz, 1H), 4.44 (s, 1H), 4.27 (t,J = 6.4 Hz, 2H), 2.80 (t,J = 7.0 Hz, 2H), 2.43 (d,J = 9.3 Hz, 6H), 2.29 (t,J = 6.9 Hz, 2H). | 477.25 |
向可再密封之反應瓶中裝入13-碘-3-((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(180 mg,322 µmol)、2-[2-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷-2-基)苯氧基]-4-甲基嘧啶(159 mg,482 µmol)、K3
PO4
(204 mg,965 µmol)、Pd(PPh3
)4
(37.1 mg,32.1 µmol)及攪拌棒,隨後抽真空且用氮氣淨化三次。添加DME:H2
O=10:1 (3 mL),且在90℃下攪拌溶液2小時。反應混合物用水淬滅,用DCM萃取,經Na2
SO4
乾燥,真空濃縮。所得粗物質藉由製備型TLC純化(DCM:MeOH=15:1)。真空濃縮,產生呈黃色非晶形固體狀之13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(90.0 mg,44%)。
3-(乙炔基-d)-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺
向可再密封之反應瓶中裝入13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-3((三異丙基矽烷基)乙炔基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(90 mg,141 µmol)、TBAF (14.7 mg,56.4 µmol)、D2
O (310 mg,15.5 mmol)、四氫呋喃(2 mL)及攪拌棒。反應混合物在微波反應器中、在100℃下攪拌30分鐘。冷卻後,移除溶劑,殘餘物藉由製備型TLC來純化(DCM:MeOH=15:1)。接著自ACN中再結晶,產生呈灰白色非晶形固體狀之3-(乙炔基-d)-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺(11.8 mg,17%)。
表53.例示性化合物
實例55
化合物 | 結構 | 質子 NMR | MS [M+1] |
3-(乙炔基-d)-13-(3-氟-4-((4-甲基嘧啶-2-基)氧基)苯基)-6,7-二氫-5H-吡啶并[3,4-c]嘧啶并[5',4':4,5]吡咯并[1,2-a]氮呯-12-胺 | 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.51 (d,J = 5.0 Hz, 1H), 8.21 (s, 1H), 8.04 (s, 1H), 7.68 (s, 1H), 7.49 - 7.33 (m, 2H), 7.28 - 7.18 (m, 2H), 5.76 (s, 1H), 4.15 (t,J = 6.7 Hz, 2H), 2.80 (t,J = 7.2 Hz, 2H), 2.45 (s, 3H), 2.30-2.22 (m, 2H). | 479.15 |
本發明之化合物亦在FGFR2生物化學Caliper分析中測試。化合物在10 mM DMSO溶液中製備且依據3倍稀釋度連續稀釋成11種濃度。向384孔盤中添加200 nL化合物溶液且添加15 uL的1.3x酶溶液(FGFR2蛋白質(0.06 nM)、FLPeptide30 (1.5 uM)、MgCl2
(10 mM))且培養盤在室溫下培育30分鐘。添加5 uL ATP溶液(100 uM)以起始反應且將培養盤培育90分鐘,接著添加70 uL中止緩衝液(0.5 M EDTA)以終止反應。使用EZ讀取器分析各孔。
FGFR2生物化學Caliper分析結果呈現於表1中。IC50小於或等於100 nM的化合物表示為「A」;IC50大於100 nM、但小於或等於250 nM的化合物表示為「B」;IC50大於250 nM、但小於或等於1 μM的化合物表示為「C」;且IC50大於1 μM、但小於或等於100 μM的化合物表示為「D」。
實例56
本發明之化合物亦在SNU16癌細胞株增殖分析中測試。測試化合物製備成10 mM DMSO儲備溶液。將45 uL儲備溶液轉移至384孔盤中,且進行3倍11點稀釋。SNU16細胞接種於384孔細胞培養盤中且在37度下培育24小時。利用Echo550液體操縱器自化合物盤轉移40 nL各種濃度的化合物至細胞培養盤的對應孔中。培養盤培育96小時,接著相對於室溫平衡15分鐘。向各孔中添加20 uL CellTiter Glo試劑,接著在室溫下輕緩地振盪培養盤30分鐘。接著在EnVision讀取器讀取化學發光。
SNU16癌細胞株增殖分析結果呈現於表1中。IC50小於或等於100 nM的化合物表示為「A」;IC50大於100 nM、但小於或等於250 nM的化合物表示為「B」;IC50大於250 nM、但小於或等於1 μM的化合物表示為「C」;且IC50大於1 μM、但小於或等於100 μM的化合物表示為「D」。以引用的方式併入
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Claims (21)
- 一種式I-1化合物, 或其醫藥學上可接受之鹽,其中: CyA 為 , 其中表示連至R5 之鍵結且表示連至Cy6 之鍵結; R5 為-R5A -L5 -R5B ; R5A 為RB 之二價基團,其中除-L5 -R5B 之外,R5A 亦經m個R5C 實例取代; R5B 為氫或RB ,其中R5B 經n個R5D 實例取代; Cy6 為伸苯基;3至14員飽和或部分不飽和二價碳環;具有1至4個獨立地選自氮、氧及硫之雜原子的3至14員飽和或部分不飽和二價雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的5至14員伸雜芳基;其中除-L6 -RW 之外,Cy6 亦經p個R6 實例取代; RW 為鹵素、-CN、 ; R6 之各實例獨立地為RA 或RB ,其中R6 經q個RC 實例取代;或 兩個R6 實例、一個R6 實例及一個RL 實例、一個R6 實例及一個RWA 實例,或一個R6 實例及一個R7a 實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至8員部分不飽和或芳族環;其中該環經r個RC 實例取代; R7 為H或RB ,其中R7 經t個R7A 實例取代; R8 為H、-NR2 、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6 脂族; R9 為H、-NR2 、鹵素,或視情況經1至3個鹵素取代的C1 - 6 脂族; R10 為H或視情況經1至3個鹵素取代的C1 - 6 脂族; L5 及L6 中之每一者獨立地為共價鍵,或C1 - 4 飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈中的一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL )-、-C(RL )2 -、C3 - 6 伸環烷基、3至6員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL )-、-NHC(O)-、-N(RL )C(O)-、-C(O)NH-、-C(O)N(RL )-、-NHS(O)2 -、-N(RL )S(O)2 -、-S(O)2 NH-、-S(O)2 N(RL )-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -;其中該C3 - 6 伸環烷基、3至6員伸雜環烷基及5至6員伸雜芳基中之每一者視情況經一個RA 或C1 - 6 脂族實例取代; RWA 、RWB 及RWC 中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6 脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或 RWA 及RWB 、RWB 及RWC 、RWA 及一個RL 實例,或RWC 及一個RL 實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環;其中該環經w個RC 實例取代; RWD 為鹵素或-OS(O)2 R; R5C 、R5D 、R7A 及RL 之各實例獨立地為RA 或RB ,且經u個RC 實例取代;或 兩個R5C 實例、一個R5C 實例及一個R5D 實例,或兩個R5D 實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的3至7員飽和、部分不飽和或芳族環;其中該環經v個RC 實例取代; RA 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)R、-S(O)NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R; RB 之各實例獨立地為C1 - 6 脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環; RC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)R、-S(O)NR2 、-S(O)2 F、-OS(O)2 F、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R,或選自以下之視情況經取代之基團:C1 - 6 脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環; 各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6 脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或: 同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子; m、n、p、q、r、t、u、v及w中之每一者獨立地為0、1、2、3或4。
- 一種式I化合物, 或其醫藥學上可接受之鹽,其中: R5 為-R5A -L5 -R5B ; R5A 為RB 之二價基團,其中除-L5 -R5B 之外,R5A 亦經m個R5C 實例取代; R5B 為氫或RB ,其中R5B 經n個R5D 實例取代; Cy6 為伸苯基或具有1至3個氮原子之6員伸雜芳基,其中除-L6 -RW 之外,Cy6 亦經p個R6 實例取代; RW 為鹵素、-CN、 ; R6 之各實例獨立地為RA 或RB ,其中R6 經q個RC 實例取代;或 兩個R6 實例,或一個R6 實例及一個RL 實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC 實例取代; R7 為H或RB ,其中R7 經t個R7A 實例取代; L5 及L6 中之每一者獨立地為共價鍵,或C1 - 4 飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL )-、-C(RL )2 -、C3 - 5 伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL )-、-NHC(O)-、-N(RL )C(O)-、-C(O)NH-、-C(O)N(RL )-、-NHS(O)2 -、-N(RL )S(O)2 -、-S(O)2 NH-、-S(O)2 N(RL )-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -; RWA 、RWB 及RWC 中之每一者獨立地為氫、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR,或選自以下之視情況經取代的基團:C1 - 6 脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或 RWA 及RWB 、RWB 及RWC 、RWA 及一個RL 實例,或RWC 及一個RL 實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環; RWD 為鹵素或-OS(O)2 R; R5C 、R5D 、R7A 及RL 之各實例獨立地為RA 或RB ,且經u個RC 實例取代; RA 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)R、-S(O)NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R; RB 之各實例獨立地為C1 - 6 脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環; RC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)R、-S(O)NR2 、-S(O)2 F、-OS(O)2 F、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R,或選自以下之視情況經取代之基團:C1 - 6 脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環; 各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6 脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或: 同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;及 m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。
- 一種式X-1、XI-1、XII-1或XIII-1化合物, 或其醫藥學上可接受之鹽,其中: CyA 為 , 其中CyA 之表示連至以下基團之鍵結: ,且CyA 之表示連至之鍵結; R5B 為氫或RB ,其中R5B 經n個R5D 實例取代; RW 為鹵素、-CN、 ; R6 之各實例獨立地為RA 或RB ,其中R6 經q個RC 實例取代;或 兩個R6 實例,或一個R6 實例及一個RL 實例與其間插原子一起形成具有0至4個獨立地選自氮、氧及硫之雜原子的4至7員部分不飽和或芳族環;其中該環經r個RC 實例取代; R7 為H或RB ,其中R7 經t個R7A 實例取代; R8 為H、-NR2 、鹵素、-OH,或視情況經1至3個鹵素取代的C1 - 6 脂族; R9 為H、-NR2 、鹵素,或視情況經1至3個鹵素取代的C1 - 6 脂族; R10 為H或視情況經1至3個鹵素取代的C1 - 6 脂族; L5 及L6 中之每一者獨立地為共價鍵,或C1 - 4 飽和或不飽和、直鏈或分支鏈二價烴鏈,其中該鏈之一或兩個亞甲基單元視情況且獨立地經以下置換:-CH(RL )-、-C(RL )2 -、C3 - 5 伸環烷基、3至5員伸雜環烷基、5至6員伸雜芳基、-NH-、-N(RL )-、-NHC(O)-、-N(RL )C(O)-、-C(O)NH-、-C(O)N(RL )-、-NHS(O)2 -、-N(RL )S(O)2 -、-S(O)2 NH-、-S(O)2 N(RL )-、-O-、-C(O)-、-OC(O)-、-C(O)O-、-S-、-S(O)-或-S(O)2 -; RWA 、RWB 及RWC 中之每一者獨立地為氫、氘、鹵素、-CN、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR,或選自以下之視情況經取代之基團:C1 - 6 脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環;或 RWA 及RWB 、RWB 及RWC 、RWA 及一個RL 實例,或RWC 及一個RL 實例與其間插原子一起形成具有0至2個獨立地選自氮、氧及硫之雜原子的4至7員飽和或部分不飽和環; RWD 為鹵素或-OS(O)2 R; R5C 、R5D 、R7A 及RL 之各實例獨立地為RA 或RB ,且經u個RC 實例取代; RA 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)R、-S(O)NR2 、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 或-N(R)S(O)2 R; RB 之各實例獨立地為C1 - 6 脂族;苯基;具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員單環雜芳基環;具有1至4個獨立地選自氮、氧及硫之雜原子的8至10員雙環雜芳基環;3至7員飽和或部分不飽和碳環;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和單環雜環;或具有1至4個獨立地選自氮、氧及硫之雜原子的7至12員飽和或部分不飽和雙環雜環; RC 之各實例獨立地為側氧基、鹵素、-CN、-NO2 、-OR、-SR、-NR2 、-S(O)2 R、-S(O)2 NR2 、-S(O)R、-S(O)NR2 、-S(O)2 F、-OS(O)2 F、-C(O)R、-C(O)OR、-C(O)NR2 、-C(O)N(R)OR、-OC(O)R、-OC(O)NR2 、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR2 、-N(R)C(NR)NR2 、-N(R)S(O)2 NR2 、-N(R)S(O)2 R,或選自以下之視情況經取代之基團:C1 - 6 脂族、苯基、具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環,及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環; 各R獨立地為氫或選自以下之視情況經取代的基團:C1 - 6 脂族;苯基;具有1至2個獨立地選自氮、氧及硫之雜原子的3至7員飽和或部分不飽和雜環;及具有1至4個獨立地選自氮、氧及硫之雜原子的5至6員雜芳基環,或: 同一氮上之兩個R基團與其間插原子一起形成4至7員飽和、部分不飽和或雜芳基環,除該氮之外,該環亦具有0至3個獨立地選自氮、氧及硫之雜原子;及 m、n、p、q、r、t及u中之每一者獨立地為0、1、2、3或4。
- 如請求項1至9中任一項之化合物,其中L6 為-NH-。
- 如請求項1至10中任一項之化合物,其中該化合物係選自表1中所示之彼等化合物,或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含如請求項1至11中任一項之化合物及醫藥學上可接受之載劑。
- 一種抑制個體中之FGFR2信號傳導活性的方法,其包含向有需要之個體投與治療有效量之如請求項1至11中任一項之化合物或如請求項12之醫藥組合物。
- 一種治療個體之FGFR2介導性病症的方法,包含向有需要的個體投與治療有效量之如請求項1至11中任一項之化合物或如請求項12之醫藥組合物。
- 一種治療個體之病症的方法,包含向有需要的個體投與治療有效量之如請求項1至11中任一項之化合物或如請求項12之醫藥組合物,其中該病症為膽管癌、肝癌、乳癌、前列腺癌、肺癌、甲狀腺癌、胃癌、卵巢癌、直腸癌、子宮內膜癌或尿道上皮癌。
- 如請求項15之方法,其中該病症為膽管癌。
- 如請求項16之方法,其中該膽管癌為肝內膽管癌。
- 如請求項15之方法,其中該病症為肝癌。
- 如請求項18之方法,其中該肝癌為肝細胞癌。
- 如請求項15之方法,其中該病症為肺癌。
- 如請求項20之方法,其中該肺癌為肺鱗狀細胞癌或非小細胞肺癌。
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AU2020274083A1 (en) | 2019-05-13 | 2021-11-18 | D.E. Shaw Research, Llc | FGFR inhibitors and methods of use thereof |
TW202233625A (zh) * | 2020-11-18 | 2022-09-01 | 美商傳達治療有限公司 | Fgfr抑制劑及其製造及使用方法 |
CN115160319B (zh) * | 2021-04-01 | 2023-12-26 | 西安新通药物研究股份有限公司 | 含1,3-苯并二氧戊环结构的化合物及其制备方法与用途 |
CN117222640A (zh) * | 2021-04-03 | 2023-12-12 | 先声再明医药有限公司 | 作为fgfr抑制剂的杂环化合物及其应用 |
CN117677621A (zh) * | 2021-08-04 | 2024-03-08 | 江苏恒瑞医药股份有限公司 | 含氮杂环化合物、其制备方法及其在医药上的应用 |
CA3231948A1 (en) * | 2021-09-23 | 2023-03-30 | Jingyu Hu | Fgfr inhibitors and methods of use thereof |
WO2023104035A1 (zh) * | 2021-12-06 | 2023-06-15 | 英矽智能科技(上海)有限公司 | 取代的单环或双环杂环化合物,其制法与医药上的用途 |
WO2023151560A1 (en) * | 2022-02-08 | 2023-08-17 | Etern Biopharma (Shanghai) Co., Ltd. | Bicyclic heteroaryl compounds and uses thereof |
WO2023202625A1 (zh) * | 2022-04-20 | 2023-10-26 | 深圳福沃药业有限公司 | Fgfr2抑制剂及使用方法 |
TW202400175A (zh) * | 2022-05-10 | 2024-01-01 | 美商傳達治療有限公司 | PI3Kα抑制劑及其使用方法 |
WO2024002157A1 (en) * | 2022-06-29 | 2024-01-04 | Insilico Medicine Ip Limited | Inhibitors of fgfr2 and fgfr3 and uses thereof |
WO2024002223A1 (zh) * | 2022-06-29 | 2024-01-04 | 上海翰森生物医药科技有限公司 | 杂环类衍生物抑制剂、其制备方法和应用 |
CN117402161A (zh) * | 2022-07-06 | 2024-01-16 | 上海科恩泰生物医药科技有限公司 | 一种具有fgfr抑制作用的亚砜亚胺类化合物、包含其的药物组合物及其用途 |
CN115594682B (zh) * | 2022-10-26 | 2024-03-15 | 苏州浦合医药科技有限公司 | Fgfr2抑制剂 |
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CA2283961A1 (en) * | 1997-03-19 | 1998-09-24 | Basf Aktiengesellschaft | Pyrrolo[2,3d]pyrimidines and their use as tyrosine kinase inhibitors |
AUPQ441499A0 (en) * | 1999-12-02 | 2000-01-06 | Fujisawa Pharmaceutical Co., Ltd. | Novel compound |
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US20190192522A1 (en) * | 2016-09-08 | 2019-06-27 | Blueprint Medicines Corporation | Inhibitors of the fibroblast growth factor receptor 4 in combination with cyclin-dependent kinase inhibitors |
EP3515916B1 (en) | 2016-09-22 | 2023-06-07 | Relay Therapeutics, Inc. | Shp2 phosphatase inhibitors and methods of use thereof |
CN110446709B (zh) | 2017-01-23 | 2023-09-12 | 锐新医药公司 | 作为变构shp2抑制剂的二环化合物 |
EA201992253A1 (ru) | 2017-03-23 | 2020-03-31 | Джакобио Фармасьютикалс Ко., Лтд. | Новые гетероциклические производные, применимые в качестве ингибиторов shp2 |
AU2020274083A1 (en) | 2019-05-13 | 2021-11-18 | D.E. Shaw Research, Llc | FGFR inhibitors and methods of use thereof |
TW202233625A (zh) | 2020-11-18 | 2022-09-01 | 美商傳達治療有限公司 | Fgfr抑制劑及其製造及使用方法 |
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BR112021022457A2 (pt) | 2022-03-22 |
JP2022533570A (ja) | 2022-07-25 |
AU2020274083A1 (en) | 2021-11-18 |
CN114126620A (zh) | 2022-03-01 |
CA3137458A1 (en) | 2020-11-19 |
US11780845B2 (en) | 2023-10-10 |
EP4306529A3 (en) | 2024-04-10 |
SG11202111327XA (en) | 2021-11-29 |
EP3968999B1 (en) | 2023-12-27 |
CL2021002882A1 (es) | 2022-10-07 |
US20230104574A1 (en) | 2023-04-06 |
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EP3968999A1 (en) | 2022-03-23 |
MX2021013146A (es) | 2022-01-24 |
WO2020231990A1 (en) | 2020-11-19 |
IL287940A (en) | 2022-01-01 |
PE20220573A1 (es) | 2022-04-20 |
KR20220007889A (ko) | 2022-01-19 |
EP3968999A4 (en) | 2022-08-03 |
EP4306529A2 (en) | 2024-01-17 |
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