TW202408502A - 雜芳基衍生物化合物及其用途 - Google Patents
雜芳基衍生物化合物及其用途 Download PDFInfo
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- TW202408502A TW202408502A TW112116031A TW112116031A TW202408502A TW 202408502 A TW202408502 A TW 202408502A TW 112116031 A TW112116031 A TW 112116031A TW 112116031 A TW112116031 A TW 112116031A TW 202408502 A TW202408502 A TW 202408502A
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- pyrimidin
- isopropyl
- pyridin
- alkyl
- pyrrolo
- Prior art date
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本發明涉及一種雜芳基衍生物及其用途。本發明的雜芳基衍生物對EGFR表現出優異的抑制活性,因此可以有用地用作上述EGFR相關疾病的治療劑。
Description
本發明涉及一種雜芳基衍生物化合物以及其醫藥用途。具體地,本發明涉及一種具有EGFR抑制活性的雜芳基衍生物化合物。
蛋白激酶作爲分子開關參與信號通路,因此需要靈活調節細胞內激酶引起的靶蛋白的活性與非活性狀態之間的轉換。如果上述活性與非活性狀態之間的轉換調節異常,則細胞內信號傳遞會被過度啟動或失活而導致不可控的細胞分裂以及增值。尤其,由蛋白激酶基因的變異、擴增和/或過表達引起的異常啟動會導致各種腫瘤的産生以及發展,或者在炎症性疾病、腦退行性疾病、自身免疫性疾病等各種疾病的發病中起到決定性作用。
表皮生長因數受體(epidermal growth factor receptor,EGFR)作爲ErbB家族的受體酪氨酸激酶(receptor tyrosine kinase)在包括非小細胞肺癌(NSCLC)、乳腺癌、神經膠質瘤、頭頸部鱗狀細胞癌、大腸癌、直腸腺癌、頭頸部癌、胃癌以及前列腺癌在內的許多上皮細胞腫瘤中異常啟動,並且已知上述EGFR-酪氨酸激酶的啟動導致持續性的細胞增殖、侵襲周圍組織、遠處轉移、血管生成以及增加細胞存活。
另一方面,已知作爲EGFR突變的EGFR Del19或EGFR L858R爲非小細胞肺癌及頭頸部癌的主要原因,並且已開發了易瑞沙、特羅凱作爲針對這些的治療劑,並且目前正在用於臨床實踐中。然而,當將這種藥物用於患者時,觀察到産生基於藥物結構的EGFR二次突變的獲得耐藥性(acquired resistance),還表明這是實際耐藥性的主要原因。當將第一代EGFR抑制劑平均使用10個月左右時,産生位於EGFR激酶的關守(gatekeeper)處的稱爲T790M突變的獲得耐藥性,從而導致第一代EGFR抑制劑無法發揮藥效。即,由於産生EGFR Del19/T790M或EGFR L858R/T790M雙突變導致現有治療劑無法發揮藥效。雖然開發了作爲第三代EGFR-TKI靶向藥物的奧希替尼(Osimertinib),其對由EGFR T790M突變引起的耐藥性表現出高反應性,但報道稱由此也會産生耐藥性(Clin Cancer Res,2015,17:21)。EGFR C797S突變被認爲是導致對奧希替尼的耐藥性的主要機制中之一,據報道,約40%的臨床試驗患者具有EGFR C797S突變(Nature Medicine,2015,21:560-562)。
像這樣,對可以通過調節EGFR活性(尤其是如EGFR Del19/T790M/C797S或EGFR L858R/T790M/C797S等C797S突變)來有用地用於治療EGFR相關疾病的新型化合物的未滿足的需求日益增加。
現有技術文獻
非專利文獻
Clin Cancer Res,2015,17:21
Nature Medicine,2015,21:560-562
發明所欲解決之問題
本發明的目的在於提供一種新型結構的雜芳基衍生物、其立體異構體或其藥學上可接受的鹽。
本發明的又一目的在於提供一種上述雜芳基衍生物化合物的製備方法。
本發明的另一目的在於提供一種上述雜芳基衍生物化合物的醫藥用途,具體地,提供一種包含上述雜芳基衍生物化合物作爲有效成分的用於治療或預防EGFR相關疾病的藥物組合物、利用上述化合物治療或預防EGFR相關疾病的用途或者包括給藥上述化合物的步驟的用於治療或預防EGFR相關疾病的方法。
解決問題之技術手段
爲了實現上述目的,本發明人研究並努力的結果確認,如下述化學式1所示的雜芳基衍生物化合物抑制被啟動EGFR的細胞的增殖,從而完成了本發明。
雜芳基衍生物化合物
本發明提供一種如下述化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽:
化學式1:
在上述化學式1中,
X爲CH或N;
環A爲3-6元雜環烷基或5-6元雜芳基{其中,上述3-6元雜環烷基或5-6元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
2-6烯基、-C
2-6炔基、-C
1-6烷基-C
3-6環烷基、-C
1-6羥烷基、-OH、-O-C
1-6烷基、=O、-C(=O)-C
1-6烷基、-C(=O)-C
3-6環烷基、-S(=O)
2-C
1-6烷基、-S(=O)
2-C
3-6環烷基或-鹵素取代,上述3-6元雜環烷基環的-CH
2-能夠被-S(=O)
2-取代};
環B爲
或
;
Y
1爲CH或N;
Y
2爲CH、C或N;
Y
3爲CH、CH
2、C(=O)、N、NH或N(C
1-6烷基);
Y
4爲C或N;
Y
5以及Y
6分別獨立地爲CH或N;
爲單鍵或雙鍵;
L爲-C≡C-或-CR
L1=CR
L2-;
R
L1以及R
L2分別獨立地爲-H、-C
1-6烷基或-鹵素;
Z
1爲-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-O-C
1-6烷基、-C
1-6烷基-O-C
1-6烷基、3-12元環烷基、3-12元雜環烷基、6-12元芳基、5-12元雜芳基或不存在(null){其中,上述3-12元環烷基、3-12元雜環烷基、6-12元芳基或5-12元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-CN、-NO
2、-NH
2、-NH-C
1-6烷基、-N(C
1-6烷基)(C
1-6烷基)、-OH、-O-C
1-6烷基或-鹵素取代},或者Z
1能夠與環A相連成環{其中,上述環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-CN、-NO
2、-NH
2、-NH-C
1-6烷基、-N(C
1-6烷基)(C
1-6烷基)、-OH、-O-C
1-6烷基或-鹵素取代};
Z
2爲-C
1-6烷基、-C
2-6烯基、-C
2-6炔基、3-12元環烷基、3-12元雜環烷基、6-12元芳基或5-12元雜芳基,
{其中,上述-C
1-6烷基、-C
2-6烯基或-C
2-6炔基的一個以上H能夠被-CN、-NO
2、-NR
1R
2、-OR
3、-C(=O)-C
1-6烷基、-S(=O)
2-C
1-6烷基、-S(=O)(=NH)-C
1-6烷基、-鹵素、3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基取代[在此情況下,上述3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、=O、-S(=O)
2-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基或-鹵素取代,上述3-6元環烷基或3-6元雜環烷基的-CH
2-能夠被-S(=O)
2-取代],
上述3-12元環烷基或3-12元雜環烷基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-CN、-NO
2、-NR
1R
2、-OR
3、-C(=O)-芳基、-S(=O)
2-C
1-6烷基、-S(=O)(=NH)-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基、-C
1-6烷基-S(=O)(=NH)-C
1-6烷基、=O或-鹵素取代,
上述6-12元芳基或5-12元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-CN、-NO
2、-NR
1R
2、-OR
3、-S(=O)
2-C
1-6烷基、-S(=O)
2-C
3-6環烷基、-S(=O)(=NH)-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基或-鹵素取代};
R
1以及R
2分別獨立地爲-H、-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-S(=O)
2-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基;以及
R
3爲-H、-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基。
根據本發明具體例,上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽可以爲下述範圍:
X爲CH或N;
環A爲5-6元雜環烷基或5-6元雜芳基{其中,上述5-6元雜環烷基或5-6元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
2-6烯基、-C
1-6烷基-C
3-6環烷基、-C
1-6羥烷基、-OH、-O-C
1-6烷基、=O、-S(=O)
2-C
1-6烷基、-S(=O)
2-C
3-6環烷基或-鹵素取代,上述5-6元雜環烷基環的-CH
2-能夠被-S(=O)
2-取代};
環B爲
或
;
Y
1爲CH或N;
Y
2爲C或N;
Y
3爲CH、C(=O)、N、NH或N(C
1-6烷基);
Y
4爲C或N;
Y
5以及Y
6分別獨立地爲CH或N;
爲單鍵或雙鍵;
L爲-C≡C-或-CR
L1=CR
L2-;
R
L1以及R
L2分別獨立地爲-H或-鹵素;
Z
1爲-C
1-6烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-O-C
1-6烷基、-C
1-6烷基-O-C
1-6烷基、3-6元環烷基、3-6元雜環烷基或不存在{其中,上述3-6元環烷基或3-6元雜環烷基環的一個以上H能夠被-C
1-6烷基、-OH、-O-C
1-6烷基或-鹵素取代,上述Z
1與Y
2或Y
3中的任一個相連},或者Z
1能夠與環A相連成環{其中,上述環的一個以上H能夠被-C
1-6烷基、-OH、-O-C
1-6烷基或-鹵素取代};
Z
2爲-C
1-6烷基、-C
2-6烯基、3-6元環烷基、3-6元雜環烷基、苯基或5-10元雜芳基,
{其中,上述-C
1-6烷基或-C
2-6烯基的一個以上H能夠被-NR
1R
2、-OR
3、-S(=O)
2-C
1-6烷基、-鹵素、3-6元環烷基、3-6元雜環烷基或苯基取代[在此情況下,上述3-6元環烷基、3-6元雜環烷基或苯基環的一個以上H能夠被-C
1-6烷基、-S(=O)
2-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基取代,上述3-6元環烷基或3-6元雜環烷基的-CH
2-能夠被-S(=O)
2-取代],
上述3-6元環烷基或3-6元雜環烷基環的一個以上H能夠被-C
1-6烷基、-OR
3、-C(=O)-芳基、-S(=O)
2-C
1-6烷基、-S(=O)(=NH)-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基、-C
1-6烷基-S(=O)(=NH)-C
1-6烷基、=O或-鹵素取代,
上述苯基或5-10元雜芳基環的一個以上H能夠被-C
1-6烷基、-NR
1R
2、-OR
3、-S(=O)
2-C
1-6烷基、-S(=O)
2-環烷基、-S(=O)(=NH)-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基或-鹵素取代};
R
1以及R
2分別獨立地爲-H、-C
1-6烷基、-C
1-6鹵代烷基、-S(=O)
2-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基;以及
R
3爲-H、-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基。
根據本發明具體例,上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽可以爲下述範圍:
環A爲選自由
、
、
、
以及
組成的組中的雜環烷基;或選自由
、
、
、
、
以及
組成的組中的雜芳基{其中,上述雜環烷基環的一個以上H能夠被-C
1-6烷基、-OH、-O-C
1-6烷基、=O、-S(=O)
2-C
1-6烷基、-S(=O)
2-環烷基或-鹵素取代,上述雜芳基環的一個以上H能夠被-C
1-6烷基、-C
2-6烯基、-C
1-6羥烷基、-C
1-6烷基-環烷基,-O-C
1-6烷基、-S(=O)
2-C
1-6烷基,或-S(=O)
2-C
3-6環烷基取代}。
根據本發明具體例,上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽可以爲下述範圍:
環B爲
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
或
。
根據本發明具體例,上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽可以爲下述範圍:
上述如化學式1所示的化合物爲如下述化學式1a所示的化合物;
化學式1a:
在上述化學式1a中,
X爲CH或N;
環A爲5-6元雜芳基{其中,上述5-6元雜芳基環的一個以上H能夠被-C
1-3烷基取代};
Y
1爲CH或N;
Y
2爲CH、C或N;
Y
3爲CH、CH
2、C(=O)、N、NH或N(C
1-6烷基);
Y
4爲C或N;
爲單鍵或雙鍵;
Z
1’爲-(CH
2CH
2)-或-(CH
2CH
2CH
2)-{其中,上述-(CH
2CH
2)-或-(CH
2CH
2CH
2)-的一個以上H能夠被-C
1-3烷基取代};
Z
1’’爲-(CH
2)-或-O-;
Z
1’’’爲鍵(null)、-(CH
2)-或-(CH
2CH
2)-,
L爲-C≡C-或-CR
L1=CR
L2-;
R
L1以及R
L2分別獨立地爲-H、-C
1-6烷基或-鹵素;
Z
2爲-C
1-6烷基、-C
2-6烯基、-C
2-6炔基、3-12元環烷基、3-12元雜環烷基、6-12元芳基或5-12元雜芳基,
{其中,上述-C
1-6烷基、-C
2-6烯基或-C
2-6炔基的一個以上H能夠被-CN、-NO
2、-NR
1R
2、-OR
3、-C(=O)-C
1-6烷基、-S(=O)
2-C
1-6烷基、-S(=O)(=NH)-C
1-6烷基、-鹵素、3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基取代[在此情況下,上述3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、=O、-S(=O)
2-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基或-鹵素取代,上述3-6元環烷基或3-6元雜環烷基的-CH
2-能夠被-S(=O)
2-取代],
上述3-12元環烷基或3-12元雜環烷基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-CN、-NO
2、-NR
1R
2、-OR
3、-C(=O)-芳基、-S(=O)
2-C
1-6烷基、-S(=O)(=NH)-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基、-C
1-6烷基-S(=O)(=NH)-C
1-6烷基、=O或-鹵素取代,
上述6-12元芳基或5-12元雜芳基環的一個以上H能夠被-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-CN、-NO
2、-NR
1R
2、-OR
3、-S(=O)
2-C
1-6烷基、-S(=O)
2-C
3-6環烷基、-S(=O)(=NH)-C
1-6烷基、-C
1-6烷基-S(=O)
2-C
1-6烷基或-鹵素取代};
R
1以及R
2分別獨立地爲-H、-C
1-6烷基、-C
1-6氨烷基、-C
1-6羥烷基、-C
1-6鹵代烷基、-S(=O)
2-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基;以及
R
3爲-H、-C
1-6烷基或-C
1-6烷基-S(=O)
2-C
1-6烷基。
根據本發明具體例,上述如化學式1所示的化合物可以選自由下述表2中列出的化合物組成的中。
在本發明中,除非另有說明,否則“烷基”可以是指直鏈或支鏈的非環狀、環狀或它們鍵合的飽和烴。例如,“C
1-6烷基”可以是指包含1至6個碳原子的烷基。作爲一例,非環狀烷基可以包括甲基、乙基、正丙基、正丁基、異丙基、仲丁基(二級丁基)、異丁基或叔丁基(三級丁基)等,但不限於此。環狀烷基可以在本說明書中與“環烷基”互換使用,作爲一例,可以包括環丙基、環丁基、環戊基、環己基、環庚基或環辛基等,但不限於此。
在本發明中,除非另有說明,否則“烯基”可以是指包含一個以上雙鍵的不飽和烴。例如,“C
2-6烯基”可以包含2至6個碳原子並包含一個以上雙鍵。作爲一例,可以包括乙烯基、1-丙烯基、1-丁烯基、1-戊烯基、1-己烯基等,但不限於此。
在本發明中,除非另有說明,否則“炔基”可以是指包含一個以上三鍵的不飽和烴。例如,“C
2-6炔基”可以包含2至6個碳原子並包含一個以上三鍵。作爲一例,可以包括乙炔基、1-丙炔基、1-丁炔基、1-戊烯基、1-己烯基等,但不限於此。
在本發明中,“烷氧基”可以是指-(O-烷基)作爲烷基醚基團,其中烷基與上述中的定義相同。例如,“C
1-6烷氧基”可以是指包含C
1-6烷基的烷氧基,即-(O-C
1-6烷基),作爲一例,烷氧基可以包括甲氧基(methoxy)、乙氧基(ethoxy)、正丙氧基(n-propoxy)、異丙氧基(isopropoxy)、正丁氧基(n-butoxy)、異丁氧基(isobutoxy)、仲丁氧基(sec-butoxy)或叔丁氧基(tert-butoxy)等,但不限於此。
在本發明中,“鹵素”可以爲F、Cl、Br或I。
在本發明中,“鹵代烷基”可以是指具有被一個以上如本發明所定義的鹵素取代的碳原子的直鏈或支鏈烷基(烴)。上述鹵代烷基的例子包括獨立地被一個以上鹵素,例如F、Cl、Br或I取代的甲基、乙基、丙基、異丙基、異丁基或正丁基,但不限於此。
在本發明中,“羥烷基”可以是指具有被-羥基(-OH)取代的碳原子的直鏈或支鏈烷基(烴)。上述羥烷基的例子包括獨立地被一個以上-OH取代的甲基、乙基、丙基、異丙基、異丁基或正丁基,但不限於此。
在本說明書中,“氨烷基”可以是指具有被氨基(NR’R’’)取代的碳原子的直鏈或支鏈烷基(烴)。其中,R’以及R’’可以分別獨立地選自由氫以及C
1-6烷基組成的組中,並且所選的上述R’以及R’’可以分別獨立地被取代或未被取代。
在本發明中,“雜環烷基”可以是指包含選自N、O以及S的1至5個雜原子作爲成環的原子的環,可以飽和或部分不飽和。其中,在不飽和的情況下可以被稱爲雜環烯烴。除非另有說明,否則雜環烷基可以爲單環或者如螺(spiro)環、橋(bridged)環或稠(fused)環等多環。並且,“3至12原子的雜環烷基”可以是指包含3至12個成環的原子的雜環烷基,作爲一例,雜環烷基可以包括吡咯烷、呱啶、咪唑烷、吡唑烷、丁內醯胺、戊內醯胺、咪唑烷酮、乙內醯脲、二氧戊環、鄰苯二甲醯亞胺、呱啶、嘧啶-2,4(1H,3H)-二酮,1,4-二惡烷、嗎啉、硫代嗎啉、硫代嗎啉-S-氧化物、硫代嗎啉-S,S-氧化物、呱嗪、吡喃、吡啶酮、3-吡咯啉、噻喃、吡喃酮、四氫呋喃、四氫噻吩、奎寧環、托品烷、2-氮雜螺[3.3]庚烷、(1R,5S)-3-氮雜雙環[3.2.1]辛烷、(1S,4S)-2-氮雜雙環[2.2.2]辛烷或(1R,4R)-2-氧雜-5-氮雜雙環[2.2.2]辛烷等,但不限於此。
在本發明中,“芳烴”可以是指芳香族烴環。芳烴可以爲單環芳烴或多環芳烴。芳烴的成環碳原子數可以爲5以上30以下、5以上20以下或5以上15以下。芳烴的例子可以包括苯、萘、芴、蒽、菲、聯苯、三苯、四苯、五苯、六苯、苯幷菲、芘、苯幷熒蒽、䓛等,但不限於此。在本說明書中,將從上述“芳烴”中去除一個氫原子的殘基稱爲“芳基”。
在本發明中,“雜芳烴”可以爲包含O、N、P、Si以及S中的一個以上作爲異質元素的環。雜芳烴的成環碳原子數可以爲2以上30以下或2以上20以下。雜芳烴可以爲單環雜芳烴或多環雜芳烴。例如,多環雜芳烴可以具有雙環或三環結構。雜芳烴的例子包括噻吩、嘌呤、吡咯、吡唑、咪唑、噻唑、噁唑、異噻唑、噁二唑、三唑、吡啶、聯吡啶基、三嗪、吖啶基、噠嗪、吡嗪、喹啉、喹唑啉、喹喔啉、吩噁嗪、酞嗪、嘧啶、吡啶幷嘧啶、吡啶幷吡嗪、吡嗪幷吡嗪、異喹啉、吲哚、哢唑、咪唑幷噠嗪、咪唑幷吡啶、咪唑幷嘧啶、吡唑幷嘧啶、咪唑幷吡嗪或吡唑幷吡啶、三唑幷吡啶、三唑幷嘧啶、N-芳基哢唑、N-雜芳基哢唑、N-烷基哢唑、苯幷噁唑、苯幷咪唑、苯幷噻唑、苯幷哢唑、苯幷噻吩、二苯幷噻吩、噻吩幷噻吩、苯幷呋喃、菲咯啉、異噁唑、噁二唑、噻二唑、苯幷噻唑、四唑、吩噻嗪、二苯幷噻咯以及二苯幷呋喃等,但不限於此。在本發明一實施方式中,雜芳烴還可以包括雙環雜環芳烴,其包含稠合到雜環烷基環的芳烴環或稠合到環烷基環的雜芳烴。在本說明書中,將從上述“雜芳烴”中去除一個氫原子的殘基稱爲“雜芳基”。
在本發明中,“環(ring)”可以爲單環或多環,上述多環可以爲如螺環、橋環或稠環等形式。
在本說明書中,“立體異構體(stereoisomer)”是指具有相同的化學式或分子式而立體結構不同的化合物。在本說明書中,立體異構體包括光學異構體(optical isomer)、對映異構體(enantiomer)、非對映異構體(diasteromer)、順(cis)/反(trans)異構體、旋轉異構體(rotamer)以及阻轉異構體(atropisomer),這些分別的異構體、外消旋體以及他們的混合物也包括在本發明的範圍內。例如,由於未特定本發明的化學式1的立體化學結構,因此可以包括化學式1的上述立體異構體。除非另有說明,否則與不對稱碳原子相連的實綫鍵合(
)可以包括表示立體中央的絕對排列的楔形實綫鍵合(
)或楔形虛綫鍵合(
)。
本發明的如化學式1所示的化合物可以以“藥學上可接受的鹽”的形式存在。作爲鹽有用的是由藥學上可接受的遊離酸(free acid)形成的酸加成鹽。本發明的術語“藥學上可接受的鹽”是指上述化合物的任意的所有有機酸或無機酸加成鹽,其在對患者具有相對無毒且無害的有效作用的濃度下由其鹽引起的副作用不降低如化學式1所示的化合物的有益功效。
尤其,上述藥學上可接受的鹽可以爲由遊離酸(free acid)形成的酸加成鹽。其中,酸加成鹽可以從如鹽酸、硝酸、磷酸、硫酸、氫溴酸、氫碘酸、亞硝酸、亞磷酸等無機酸類、如脂肪族單羧酸鹽及脂肪族二羧酸鹽、苯基取代的鏈烷酸酯、羥基鏈烷酸鹽以及羥基鏈烷二酸酯、芳香族酸類、脂肪族磺酸類以及芳香族磺酸類等無毒有機酸、如三氟乙酸、乙酸鹽、苯甲酸、檸檬酸、乳酸、馬來酸、葡糖酸、甲磺酸、4-甲苯磺酸、酒石酸、富馬酸等有機酸中得到。
這種藥學上可接受的鹽的種類可以包括硫酸鹽、亞硫酸鹽、硝酸鹽、磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、氟化物、乙酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸鹽、甲酸鹽、異丁酸鹽、癸酸鹽、庚酸鹽、丙炔酸鹽、草酸鹽、丙二酸鹽、琥珀酸鹽、辛二酸鹽、癸二酸鹽、富馬酸鹽、馬來酸鹽、苯甲酸鹽、鄰苯二甲酸鹽、苯磺酸鹽、甲苯磺酸鹽、苯乙酸鹽、苯丙酸鹽、苯丁酸鹽、檸檬酸鹽、乳酸鹽、乙醇酸鹽、蘋果酸鹽、酒石酸鹽、扁桃酸鹽等。
上述酸加成鹽可以通過常規方法製備,例如,可以將化學式1的衍生物溶於如甲醇、乙醇、丙酮、二氯甲烷、乙腈等有機溶劑中後,通過將添加有機酸或無機酸後生成的沉澱物過濾並乾燥來製備,或者將溶劑及過量的酸減壓蒸餾後乾燥並在有機溶劑的存在下進行晶化來製備。
並且,上述藥學上可接受的鹽可以爲使用堿基得到的鹽或金屬鹽。作爲金屬鹽的例子,鹼金屬鹽或鹼土金屬鹽可以通過將化合物溶於過量的鹼金屬氫氧化物溶液或鹼土金屬氫氧化物溶液中,並過濾未溶解的化合物鹽後蒸發及乾燥濾液來得到。鈉鹽、鉀鹽或鈣鹽可以爲在製藥上合適的鹼金屬鹽。並且,與此相應的鹽可以通過將鹼金屬鹽或鹼土金屬鹽與合適的銀鹽(例如,硝酸銀)反應來得到,並且可以通過本領域已知的鹽的製備方法製備。
雜芳基衍生物化合物的用途
本發明提供一種如下述化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽的用途。
化學式1
上述化學式1如上所定義。
本發明的如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽對各種激酶表現出抑制活性。
根據本發明一具體例,由於上述如化學式1所示的雜芳基衍生物對EGFR激酶表現出優異的抑制活性,因此可以有用地用於治療或預防EGFR相關疾病,特別是癌症。尤其,由於本發明的雜芳基衍生物化合物對EGFR突變(例如,EGFR Del19/C797S、EGFR L858R/C797S、EGFR Del19/T790M/C797S或EGFR L858R/T790M/C797S等)表現出優異的抑制活性,因此可以有用地用於治療或預防由EGFR引起的癌症。
在本發明中,上述癌症包括所有能夠因抑制EGFR激酶活性而表現出治療或預防功效的癌症,可以爲實體癌或血液癌。癌症的種類不受限制,但例如,可以爲選自由假性粘液瘤、肝內膽管癌、肝胚細胞瘤、肝癌、甲狀腺癌、結腸癌、睾丸癌、骨髓增生異常綜合征、膠質母細胞瘤、口腔癌、唇癌、蕈樣真菌病、急性骨髓性白血病、急性淋巴細胞性白血病、基底細胞癌、卵巢上皮癌、卵巢生殖細胞腫瘤、男性乳腺癌、腦癌、垂體腺瘤、多發性骨髓瘤、膽囊癌、膽道癌、大腸癌、慢性髓細胞白血病、慢性淋巴細胞性白血病、視網膜母細胞瘤、脈絡膜黑素瘤、法特壺腹癌、膀胱癌、腹膜癌、甲狀旁腺癌、腎上腺腫瘤、鼻腔副鼻竇癌、非小細胞肺癌、舌癌、星形細胞瘤、小細胞肺癌、小兒腦癌、小兒淋巴瘤、小兒白血病、小腸癌、腦膜瘤、食道癌、神經膠質瘤、腎盂癌、腎癌、心臟癌、十二指腸癌、惡性軟組織癌、惡性骨癌、惡性淋巴瘤、惡性間皮瘤、惡性黑色素瘤、眼癌、外陰癌、輸尿管癌、尿道癌、原發部位不明癌、胃淋巴瘤、胃癌、胃類癌、胃腸道間質瘤、腎母細胞癌、乳腺癌、肉瘤、陰莖癌、咽癌、妊娠絨毛膜癌、宮頸癌、子宮內膜癌、子宮肉瘤、前列腺癌、轉移性骨癌、轉移性腦癌、縱隔腫瘤、直腸癌、直腸類癌、陰道癌、脊髓癌、前庭神經鞘瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃體癌、鱗狀細胞癌、肺腺癌、肺癌、肺鱗狀細胞癌、皮膚癌、肛門癌、橫紋肌肉瘤、喉癌、胸膜癌、血癌以及胸腺癌組成的組中的一種以上。並且,上述癌症不僅包括原發性癌症,還包括轉移性癌症。
根據本發明一具體例,本發明提供一種用於治療或預防EGFR相關疾病的藥物組合物,上述組合物包含上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽作爲有效成分。具體地,上述EGFR相關疾病可以爲癌症。上述癌症的種類如上所述。
本發明的上述藥物組合物除了上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽以外,還可以包含一種以上表現出相同或相似的藥效的有效成分。
本發明的藥物組合物可以在臨床給藥時使用,並且可以製備成能夠以口服及腸胃外的各種劑型給藥。
並且,根據本發明一具體例,本發明提供一種上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽在用於製備用於治療或預防EGFR相關疾病的藥劑(medicament)中的用途(use)。具體地,上述EGFR相關疾病可以爲癌症。上述癌症的種類如上所述。
並且,根據本發明一具體例,本發明提供一種上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽在用於製備用於治療或預防癌症疾病的藥劑中的用途。上述癌症的種類如上所述。
並且,根據本發明一具體例,本發明提供一種用於治療或預防EGFR相關疾病的方法,上述方法包括將治療有效量的上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽給藥到需要其的對象的步驟。上述對象(subject)可以爲包括人類在內的哺乳類。具體地,上述EGFR相關疾病可以爲癌症。上述癌症的種類如上所述。
並且,根據本發明一具體例,本發明提供一種治療或預防癌症的方法,上述方法包括將治療有效量的上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽給藥到需要其的對象的步驟。上述癌症的種類如上所述。
並且,根據本發明一具體例,本發明提供一種抑制EGFR的方法,上述方法包括將治療有效量的上述如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽給藥到需要其的對象的步驟。
本發明中使用的術語“治療有效量”是指有效治療或預防EGFR相關疾病的上述如化學式1所示的化合物的量。具體地,“治療有效量”是指足以以可應用於醫學治療的合理效益/風險比來治療疾病的量,有效量水準可以根據包括個體種類及嚴重程度、年齡、性別、疾病的種類、藥物的活性、對藥物的敏感性、給要時間、給藥途徑及排泄率、治療時間、同時使用的藥物在內的因素以及其他醫學領域已知的因素來確定。本發明的藥物組合物可以以單獨治療劑給藥或與其他治療劑聯合給藥,並且可以與市售治療劑依次或同時給藥。而且,可以單次給藥或多次給藥。考慮到所有上述因素,重要的是能夠以最小的量獲得最大效果而沒有副作用的量給藥,並且這可以由本領域的普通技術人員容易地確定。本發明的藥物組合物的給藥量可以由醫學專家根據患者的狀態、年齡以及併發症等各種因素來決定。由於本發明的藥物組合物的有效成分具有優異的穩定性,因此可以使用所確定的給藥量以上。
本發明中使用的“預防”是指通過給藥上述化合物來抑制或延緩上述疾病的産生、擴散以及復發的所有行爲,“治療”是指通過給藥上述化合物使上述疾病的症狀好轉或有益地改善的所有行爲。
並且,根據本發明一具體例,上述藥物組合物還可以包含藥學上可接受的載體、稀釋劑或賦形劑。在一具體例中,本發明提供一種包含如化學式1所示的化合物、或其藥學上可接受的鹽或立體異構體以及藥學上可接受的添加劑的藥物組合物。
用於上述藥物組合物的添加劑的例子包括甜味劑、粘合劑、溶劑、助溶劑、潤濕劑、乳化劑、等滲劑、吸水劑、崩解劑、抗氧化劑、保存劑、潤滑劑、填充劑、增香劑等。例如,上述添加劑可以包括乳糖、葡萄糖、蔗糖、甘露糖醇、山梨糖醇、纖維素、甘氨酸、二氧化矽、滑石粉、硬脂酸、三硬脂酸甘油酯、硬脂酸鎂、鋁矽酸鎂、澱粉、明膠、黃芪膠、海藻酸、海藻酸鈉、甲基纖維素、羧甲基纖維素鈉、瓊脂、水、乙醇、聚乙二醇、聚乙烯吡咯烷酮、氯化鈉、氯化鈣、柑橙香精、草莓香精、香草味等。
上述藥物組合物可以配合成用於口服給藥(例如,片劑、丸劑、散劑。膠囊劑、糖漿或乳液)或腸胃外給藥(例如,肌肉內、靜脈內或皮下注射)的各種製劑形式。
例如,上述藥物組合物可以配合成用於口服給藥的製劑,在此情況下使用的添加劑可以包括纖維素、矽酸鈣、玉米澱粉、乳糖、蔗糖、葡萄糖、磷酸鈣、硬脂酸、硬脂酸鎂、硬脂酸鈣、明膠、滑石粉、表面活性劑、懸浮劑、乳化劑、稀釋劑等。具體地,用於口服給藥的固體製劑包括片劑、丸劑、散劑、顆粒劑、膠囊劑等,這種固體製劑可以通過在上述組合物中混合一種以上賦形劑,例如,澱粉、碳酸鈣、蔗糖、乳糖、明膠等來配置。並且,除了簡單的賦形劑以外可以使用如硬脂酸鎂、滑石粉等潤滑劑。並且,用於口服給藥的液體製劑可以包括如懸浮劑、乳劑、糖漿劑等,並且除了如水、液體石蠟等常用的簡單稀釋劑以外可以包括如潤濕劑、甜味劑、芳香劑、保存劑等各種賦形劑。
並且,用於腸胃外給藥的製劑包括滅菌的水溶液劑、非水性溶劑、懸浮劑、乳劑、凍幹製劑以及栓劑。可以使用如丙二醇、聚乙二醇、橄欖油等植物油、如油酸乙酯等可注射的酯類等作爲非水性溶劑、懸浮劑。可以使用半合成脂肪酸酯、聚乙二醇、吐溫61、可哥脂、月桂酸甘油酯、甘油明膠作爲栓劑的基質。另一方面,注射劑可以包含如增溶劑、等滲劑、助懸劑、乳化劑、穩定劑、防腐劑等現有的添加劑。
並且,可以與其他活性製劑一起製備成複合製劑,從而具有活性成分的協同作用。
本發明的用途、組合物、治療方法中提及的事項除非相互矛盾,否則均同等適用。
對照先前技術之功效
由於本發明的雜芳基衍生物化合物對EGFR表現出優異的抑制活性,因此可以有用地用於治療或預防上述EGFR相關疾病的。
以下,通過實施例以及實驗例詳細說明本發明。但是,下述實施例以及實驗例僅用於示例本發明,本發明的內容並不限於此。
<分析以及純化條件>
根據下述條件對本發明實施例中合成的化合物進行純化或結構分析。
1.高效液相色譜法(HPLC)以及中壓液相色譜法(MPLC)
用於分析的高效液相色譜(ACQUITY UPLC超高效液相色譜核心系統(ACQUITY UPLC H-Class Core System))
使用在Waters公司的超高效液相色譜系統(ACQUITY UPLC二極管陣列檢測器(ACQUITY UPLC PDA Detector))中裝配有Waters公司的Qda質量檢測器(mass QDa Detector)的設備。使用Waters公司的ACQUITY UPLC
®BEH C18(1.7μm,2.1×50mm)色譜柱,將色譜柱溫度設爲30℃。
流動相A使用包含有0.1%的甲酸的水,流動相B使用包含有0.1%的甲酸的乙腈。
梯度條件(Gradient condition)(10-100%的B進行3分鐘,流速=0.6ml/分鐘)
用於純化的製備高效液相色譜系統(Preparative HPLC System)(製備液相色譜紫外光譜法,Preparative-Liquid chromatography UV spectrometry)
使用Teledyne公司製備的ACCQPrep HP150設備。使用Water公司的XTERRA
®Prep RP18 OBD
TM(10μm,30×300mm)色譜柱,將色譜柱溫度設爲室溫。
梯度條件(10-100%的B進行120分鐘,流速=42ml/分鐘)
用於純化的中壓液相色譜法(Medium pressure liquid chromatography)
使用Teledyne ISCO公司的CombiFlash Rf+UV進行中壓液相色譜。
2.核磁共振波譜法(NMR)
使用Bruker公司的AVANCE III 400或AVANCE III 400 HD進行核磁共振波譜法分析,用百萬分率(parts per milion(δ),ppm)表示數據。
使用未經進一步純化的市售試劑。在本發明中,室溫或常溫是指約5℃至40℃的溫度,作爲一例,10℃至30℃,作爲另一例,20℃至27℃,其並不嚴格限於上述範圍內。使用旋轉蒸發器(rotary evaporator)進行減壓濃縮或溶劑蒸餾。
製備例:製備本發明的中間體化合物
<製備例1>製備2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-胺
步驟1:製備順式-3-氟-4-甲氧基呱啶-1-甲酸叔丁酯
將順式-3-氟-4-羥基呱啶-1-甲酸叔丁酯(1g,1.0eq)溶於四氫呋喃(THF;23mL)中,然後在0℃及氮氣流下添加氫化鈉(NaH;0.22g,60%的純度,1.2eq)。將反應混合物在0℃的溫度下攪拌30分鐘,並在0℃的溫度下滴加碘甲烷(0.31mL,1.1eq)。之後,將反應混合物在常溫下攪拌3小時。LCMS分析結果,所有起始物質均消失且檢測出目標化合物。減壓濃縮反應混合物後,添加乙酸乙酯(EA;100mL)及飽和碳酸氫鈉水溶液(200mL×2)以萃取有機層。用硫酸鈉乾燥後,通過減壓濃縮得到黃色油狀的目標化合物(1.0g,94%的産率)。
MS:m/z 234.3 [M+H]
+步驟2:製備順式-3-氟-4-甲氧基呱啶鹽酸鹽
將從上述步驟1中得到的順式-3-氟-4-甲氧基呱啶-1-甲酸叔丁酯(1.0g,1.0eq)溶於二氯甲烷(DCM;24mL)中,然後在0℃的溫度下添加鹽酸(HCl)/二惡烷(4M,3.7mL,3.0eq)。之後,將反應混合物在常溫下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。減壓濃縮反應混合物後,添加二乙醚(60mL)以得到固體。通過過濾沉澱物並乾燥得到白色固體的目標化合物(0.56g,77%的産率)。
MS:m/z 134.3 [M+H]
+步驟3:製備2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-胺
將從上述步驟2中得到的順式-3-氟-4-甲氧基呱啶鹽酸鹽(0.56g,1.0eq)及2-氯嘧啶-4-胺(0.32g,0.8eq)在常溫下溶於異丙醇(IPA;8mL)中,然後添加N,N-二異丙基乙胺(DIPEA;2.52mL,4.0eq)。將反應混合物在120℃的溫度下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。減壓濃縮反應混合物後,將濃縮的化合物通過中壓液相色譜法(己烷/乙基乙酸鹽)進行純化得到白色固體的目標化合物(0.59g,83%的産率)。
1H NMR(400MHz,CDCl
3)δ7.92(d,J=5.6Hz,1H),5.75(d,J=5.6Hz,1H),4.77(ddtd,J=48.3,6.2,2.6,0.9Hz,1H),4.62(s,2H),4.50(dddd,J=14.0,7.8,6.2,1.4Hz,1H),4.21(dddd,J=13.5,6.5,3.9,1.4Hz,1H),3.67-3.49(m,2H),3.47(s,3H),3.40(dddd,J=13.7,8.8,3.7,1.8Hz,1H),1.99-1.88(m,1H),1.82-1.72(m,1H)。
MS:m/z 227.3 [M+H]
+
<製備例2>製備2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-胺
步驟1:製備4-溴-1-(環丙基磺醯基)-1H-吡唑
將4-溴-1H-吡唑(10g,1eq)溶於二氯甲烷(DCM; 170mL)中,然後添加環丙磺醯氯(7.62mL,1.1eq)及三乙胺(TEA;12.33mL,1.3eq)。將反應混合物在室溫下攪拌19小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。在反應混合物中添加水(100mL)並利用二氯甲烷(DCM; 200mL)進行萃取。減壓濃縮有機層後,通過中壓液相色譜法(己烷/乙基乙酸鹽)進行純化得到目標化合物(10g,59%的産率)。
MS:m/z 250.3 [M+H]
+步驟2:製備1-(環丙基磺醯基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡唑
將從上述步驟1中得到的4-溴-1-(環丙基磺醯基)-1H-吡唑(10g,1eq)溶於1,4-二惡烷(133mL)中,然後添加雙(頻哪醇合)二硼(bis(pinacolato)diboron;12.14g,1.2eq)及乙酸鉀(7.82g,2eq)。將反應混合物脫氣10分鐘後添加[1,1’-雙(二苯基膦基)二茂鐵]二氯化鈀(II)(1.17g,0.04eq)。之後,將反應混合物在110℃及氮氣流下攪拌16小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。通過矽藻土過濾反應混合物。通過減壓濃縮濾液得到目標化合物(11g,93%),在沒有純化的情況下用於下一步反應。
MS:m/z 299.3 [M+H]
+步驟3:製備2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-胺
將從上述步驟2中得到的1-(環丙基磺醯基)-4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡唑(2.3g,1eq)溶於乙腈(ACN;15mL)中,然後添加2-氯嘧啶-4-胺(1g,1eq)及碳酸鈉水溶液(2M,11.57mL,3eq)。將反應混合物脫氣10分鐘後添加雙[二叔丁基(4-二甲基氨基苯基)膦]二氯鈀(0.109g,0.02eq)。將反應混合物在100℃及氮氣流下攪拌2小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。通過矽藻土過濾反應混合物。減壓濃縮濾液後,通過中壓液相色譜法(乙基乙酸鹽/二氯甲烷)進行純化得到目標化合物(1g,49%的産率)。
MS:m/z 266.3 [M+H]
+
<製備例3>至<製備例19>
通過與上述<製備例1>相似的方法製備以下製備例3至製備例11的化合物。並且,通過與上述<製備例2>相似的方法製備以下製備例12至製備例19的化合物。將製備例3至製備例19的化學結構式以及化合物名稱示於表1中。
表1
製備例 | 結構式 | 化合物名稱 |
3 | 2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-胺 | |
4 | 2-嗎啉幷嘧啶-4-胺 | |
5 | 2-(4-甲基呱嗪-1-基)嘧啶-4-胺 | |
6 | 4-(4-氨基嘧啶-2-基)硫代嗎啉1,1-二氧化物 | |
7 | 2-(4-(甲基磺醯基)呱嗪-1-基)嘧啶-4-胺 | |
8 | 4-(4-氨基嘧啶-2-基)呱嗪-2-酮 | |
9 | 2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)吡啶-4-胺 | |
10 | 2-(4-乙烯基-1H-咪唑-1-基)嘧啶-4-胺 | |
11 | 2-(4-(環丙基磺醯基)-1H-咪唑-1-基)嘧啶-4-胺 | |
12 | 2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-胺 | |
13 | (4-(4-氨基嘧啶-2-基)-1H-吡唑-1-基)(環丙基)甲烷酮 | |
14 | 2-(1-(環丙基甲基)-1H-吡唑-4-基)嘧啶-4-胺 | |
15 | 2-(1H-吡唑-4-基)嘧啶-4-胺 | |
16 | 2-(2-(環丙基磺醯基)-1H-咪唑-5-基)嘧啶-4-胺 | |
17 | 2-(4-(4-氨基嘧啶-2-基)-1H-吡唑-1-基)乙烷-1-醇 | |
18 | 4’-甲氧基-[2,3’-聯吡啶]-4-胺 | |
19 | 2-(4-甲氧基吡啶-3-基)嘧啶-4-胺 |
<製備例20>製備4-溴-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮
步驟1:製備2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮
將1-甲基-1H-吡唑-5-醇(6g,1eq)溶於乙腈(ACN; 204mL)中,然後添加碳酸鉀(25.4g,3eq)。將反應混合物在室溫下攪拌30分鐘,然後緩慢添加2-(三甲基甲矽烷基)乙氧基甲基氯(14.1mL,1.3eq)並在室溫下攪拌3小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。通過矽藻土過濾反應混合物。減壓濃縮濾液後,倒入己烷後過濾沉澱的固體並乾燥得到目標化合物(14g,100%的産率)。
MS:m/z 229.3 [M+H]
+步驟2:製備4-溴-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮
將從上述步驟1中得到的2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮(5g,1eq)溶於乙腈(ACN; 110mL)中,然後在0℃的溫度下緩慢添加N-溴代琥珀醯亞胺(NBS;5.07g,1.3eq)。將反應混合物在15℃的溫度下攪拌1小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。在反應混合物中添加飽和硫代硫酸鈉水溶液(100mL)以終止反應。利用乙酸乙酯(EA; 200mL)萃取有機層,然後將有機層用飽和氯化鈉水溶液(100mL×2)清洗數次。之後,用硫酸鎂乾燥有機層後減壓濃縮。將濃縮的化合物通過中壓液相色譜法(乙酸乙酯/己烷)進行純化得到目標化合物(6g,89%的産率)。
MS:m/z 307.3 [M+H]
+
<製備例21>製備4-(4-氨基嘧啶-2-基)-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮
步驟1:製備(叔丁氧基羰基)(2-氯嘧啶-4-基)氨基甲酸叔丁酯
將2-氯嘧啶-4-胺(10g,1eq)溶於四氫呋喃(THF; 77mL)中,然後在0℃的溫度下依次添加二碳酸二叔丁酯(44.8mL,2.5eq)、三乙胺(TEA; 32.3mL,3eq)、4-(二甲氨基)吡啶(0.943g,0.1eq)。將反應混合物在50℃的溫度下攪拌1小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。利用乙酸乙酯(EA; 200mL)及飽和氯化銨水溶液(100mL)萃取有機層,然後將有機層用飽和氯化鈉水溶液(100mL×2)清洗數次。用硫酸鎂乾燥有機層後減壓濃縮。將濃縮的化合物通過中壓液相色譜法(己烷/乙基乙酸鹽)進行純化得到目標化合物(22.5g,88%的産率)。
MS:m/z 330.3 [M+H]
+步驟2:製備(叔丁氧基羰基)(2-(2-甲基-3-氧代-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-2,3-二氫-1H-吡唑-4-基)嘧啶-4-基)氨基甲酸叔丁酯
將從上述步驟1中得到的(叔丁氧基羰基)(2-氯嘧啶-4-基)氨基甲酸叔丁酯(12.88g,6eq)、從上述<製備例20>中得到的4-溴-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮(2g,1eq)、雙(頻哪醇合)二硼(9.92g,6eq)以及碳酸鈉(3.45g,5eq)溶於乙腈(ACN; 100mL)及水(10mL)中,然後脫氣10分鐘。在反應混合物中添加雙(二叔丁基(4-二甲基氨基苯基)膦)二氯鈀(II)(Pd(amphos)Cl
2;0.69g,0.15eq),然後在100℃及氮氣流下攪拌2小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。通過矽藻土過濾反應混合物。減壓蒸幹濾液後,將濃縮的化合物通過中壓液相色譜法(甲醇/二氯甲烷)進行純化得到目標化合物(2.5g,75%的純度,55%的産率)。
MS:m/z 522.3 [M+H]
+步驟3:製備4-(4-氨基嘧啶-2-基)-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮
將從上述步驟2中得到的(叔丁氧基羰基)(2-(2-甲基-3-氧代-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-2,3-二氫-1H-吡唑-4-基)嘧啶-4-基)氨基甲酸叔丁酯(3g,5.75mmol)溶於1,1,1,3,3,3-六氟-2-丙醇(HFIP;30mL)中,然後添加三氟乙酸(TFA;6.65mL,15eq)並在15℃的溫度下攪拌3小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。在反應混合物中緩慢添加飽和碳酸氫鈉水溶液(100mL)後,利用乙酸乙酯(200mL)萃取有機層。將有機層用飽和氯化鈉水溶液(100mL×2)清洗數次。之後,用硫酸鎂乾燥有機層後減壓濃縮。將濃縮的化合物通過中壓液相色譜法(甲醇/二氯甲烷)進行純化得到目標化合物(1.1g,59.5%的産率)。
MS:m/z 322.3 [M+H]
+
<製備例22>製備4-(4-氨基吡啶-2-基)-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮
通過與上述<製備例21>相似的方法製備製備例22的化合物。
MS:m/z 321.3 [M+H]
+實施例:製備本發明的化合物
<實施例1>製備4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇
步驟1:製備6-氯-3-碘-1H-吡咯幷[3,2-c]吡啶
將6-氯-1H-吡咯幷[3,2-c]吡啶(5g,1.0eq)及氫氧化鉀(7.0g,3.8eq)溶於二甲基甲醯胺(DMF;48mL)中,然後添加碘(8.3g,1.0eq)。將反應混合物在常溫下攪拌1小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。爲了得到固體,將通過添加蒸餾水(800mL)形成的沉澱物過濾並乾燥得到黃色固體的目標化合物(8.3g,91%的産率)。
MS:m/z 278.3 [M+H]
+步驟2:製備6-氯-3-碘-1-異丙基-1H-吡咯幷[3,2-c]吡啶
將從上述步驟1中得到的6-氯-3-碘-1H-吡咯幷[3,2-c]吡啶(4g,1.0eq)溶於二甲基甲醯胺(DMF; 48mL)中,然後在0℃及氮氣流下添加氫化鈉(NaH; 2.3g,60%的純度,4.0eq)。將反應混合物在0℃的溫度下攪拌30分鐘後添加2-碘丙烷(4.9g,2.0eq)。之後,將反應混合物在常溫下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。減壓濃縮反應混合物後,添加乙酸乙酯(EA; 200mL)及飽和碳酸氫鈉水溶液(500mL×2)以萃取有機層,然後用硫酸鈉乾燥後減壓濃縮。將濃縮的化合物通過中壓液相色譜法(己烷/乙基乙酸鹽)進行純化得到黃色固體的目標化合物(3.9g,85%的産率)。
MS:m/z 320.3 [M+H]
+步驟3:製備4-(6-氯-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇
將從上述步驟2中得到的6-氯-3-碘-1-異丙基-1H-吡咯幷[3,2-c]吡啶(500mg,1eq)及2-甲基丁-3-炔-2-醇(0.3mL,2.0eq)溶於乙酸乙酯(EA; 0.8mL)中,然後在常溫及氮氣流下添加雙(三苯基膦)二氯化鈀(II)(55mg,0.05eq)、碘化銅(copper(I))(30mg,0.1eq)以及三乙胺(0.55mL,2.5eq)。將反應混合物在40℃的溫度下攪拌3小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。減壓濃縮反應混合物後,添加乙酸乙酯(EA; 100mL)及飽和碳酸氫鈉水溶液(200mL×2)以萃取有機層,然後用硫酸鈉乾燥後減壓濃縮。將濃縮的化合物通過中壓液相色譜法(己烷/乙基乙酸鹽)進行純化得到棕色固體的目標化合物(410mg,95%的産率)。
MS:m/z 277.3 [M+H]
+步驟4:製備4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇
將從上述步驟3中得到的4-(6-氯-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇(90mg,1eq)以及從上述製備例1中得到的2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-胺(88mg,1.2eq)溶於二惡烷(1.6mL)中,然後在常溫及氮氣流下添加三(二亞苄基丙酮)二鈀(0)(Pd
2(dba)
3;30mg,0.1eq)、二環己基(2’,4’,6’-三異丙基-[1,1’-聯苯基]-2-基)膦(31mg,0.2eq)以及碳酸銫(212mg,2.0eq)。將反應混合物在100℃的溫度下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。減壓濃縮反應混合物後,添加乙酸乙酯(EA; 100mL)及飽和碳酸氫鈉水溶液(200mL×2)以萃取有機層。用硫酸鈉乾燥後減壓濃縮。將濃縮的化合物通過用於純化的高效液相製備色譜法(Prep-HPLC)(水/甲醇)進行純化得到淺黃色固體的目標化合物(34mg,22%的産率)。
1H NMR(400MHz,CDCl
3)δ8.59(d,J=0.9Hz,1H),8.29(s,1H),8.03(d,J=5.7Hz,1H),7.63(s,1H),7.34(s,1H),6.07(d,J=5.7Hz,1H),4.87-4.69(m,1H),4.61(p,J=6.7Hz,1H),4.35(dt,J=13.9,7.1Hz,1H),4.10-3.91(m,2H),3.80-3.61(m,2H),3.51(s,3H),2.63(s,1H),2.07-1.99(m,1H),1.83-1.76(m,1H),1.67(s,6H),1.53(d,J=6.6Hz,6H)。
MS:m/z 467.3 [M+H]
+
<實施例16>製備(E)-4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-烯-2-醇
步驟1:製備(E)-4-(6-氯-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-烯-2-醇
將從上述<實施例1>的步驟2中得到的6-氯-3-碘-1-異丙基-1H-吡咯幷[3,2-c]吡啶(200mg,1eq)、2-甲基丁-3-烯-2-醇(72µl,1.1eq)以及碳酸銫(610mg,3.0eq)溶於二惡烷(2mL)中,然後進行脫氣。之後,在60℃及氮氣流下添加[(2-二環己基膦-3,6-二甲氧基-2’,4’,6’-三異丙基-1,1’-聯苯基)-2-(2'-氨基-1,1’-聯苯基)]鈀(II)甲烷磺酸甲烷磺酸(Brettphos Pd(II) G3;62.5mg,0.1eq)。將反應混合物在110℃的溫度下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。減壓濃縮反應混合物後,添加乙酸乙酯(EA; 100mL)及飽和氯化鈉水溶液(200mL×2)以萃取有機層。用硫酸鈉乾燥後減壓濃縮。將濃縮的化合物通過中壓液相色譜法(己烷/乙基乙酸鹽)進行純化得到棕色固體的目標化合物(50mg,28.7%的産率)。
MS:m/z 279.3 [M+H]
+步驟2:製備(E)-4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-烯-2-醇
將從上述步驟1中得到的(E)-4-(6-氯-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-烯-2-醇(50mg,1eq)、從上述製備例2中得到的2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-胺(52.3mg,1.1eq)以及碳酸銫(175mg,3.0eq)溶於二惡烷(600µL)中,然後用超聲波進行脫氣。之後,在60℃及氮氣流下添加[(2-二環己基膦-3,6-二甲氧基-2’,4’,6’-三異丙基-1,1’-聯苯基)-2-(2'-氨基-1,1’-聯苯基)]鈀(II)甲烷磺酸甲烷磺酸 (Brettphos Pd(II) G3;18mg,0.1eq)。將反應混合物在110℃的溫度下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標物質。在反應結束後用矽藻土過濾並用二氯甲烷清洗。將得到的濾液濃縮後,通過高效液相製備色譜法進行純化得到目標化合物(20mg,22%)。
1H NMR(400MHz,MeOD)δ8.81(s,1H),8.73(s,1H),8.44(s,1H),8.30(d,J=6.1Hz,1H),8.24(s,1H),7.48(s,1H),7.08(d,J=5.9Hz,1H),6.75(dd,J=16.3,3.3Hz,1H),6.39(d,J=16.3Hz,1H),4.74(dt,J=13.4,6.7Hz,1H),3.05(dq,J=7.9,4.6Hz,1H),1.60(d,J=6.7Hz,6H),1.47-1.44(m,8H),1.28(dd,J=7.9,2.4Hz,2H)。
MS:m/z 508.2 [M+H]
+
<實施例68>製備(S)-1
1,5-二甲基-4
3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1
1H,4
1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷
步驟1:製備(S)-4-(4-((1-(4-羥基丁烷-2-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)-1-甲基-1H-吡唑-5-醇
將通過與上述實施例1相似的方法得到的(S)-4-(4-((1-(4-((叔丁基二甲基甲矽烷基)氧基)丁基-2-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)-2-甲基-1-((2-(三甲基甲矽烷基)乙氧基)甲基)-1,2-二氫-3H-吡唑-3-酮(74mg,1eq)溶於四氫呋喃(THF; 5mL)中,然後在0℃的溫度下添加四丁基氟化銨(TBAF;1M,0.383mL,4eq)。之後,將反應混合物在80℃的溫度下攪拌1小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。減壓濃縮反應混合物後,通過高效液相製備色譜法(0.035%的三氟乙酸、甲醇/水)進行純化得到目標化合物(25mg,50%的産率)。
MS:m/z 524.3 [M+H]
+步驟2:製備(S)-1
1,5-二甲基-4
3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1
1H,4
1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷
將從上述步驟1中得到的(S)-4-(4-((1-(4-羥基丁烷-2-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)-1-甲基-1H-吡唑-5-醇(25mg,1eq)溶於甲苯(1.6mL)中,然後添加氰基亞甲基三正丁基膦(CMBP;65µL,5eq)。將反應混合物脫氣10分鐘後在70℃及氮氣流下攪拌12小時。LCMS分析結果,所有起始物質均消失並檢測出目標化合物。減壓濃縮反應混合物後,通過高效液相製備色譜法(0.035%的三氟乙酸,甲醇/水)進行純化得到目標化合物(5mg,21%的産率)。
1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),9.06(d,J=1.0Hz,1H),8.53(d,J=0.8Hz,1H),8.25(d,J=5.8Hz,1H),7.97(s,1H),7.91(s,1H),6.71(d,J=5.8Hz,1H),4.96(q,J=7.9,7.2Hz,1H),4.42(t,J=11.1Hz,1H),4.00-3.95(m,1H),3.75(s,3H),3.19(s,3H),1.74(s,1H),1.72(s,1H),1.69(d,J=1.2Hz,6H),1.67(s,3H)。
MS:m/z 506.3 [M+H]
+
<實施例1>至<實施例15>、<實施例17>至<實施例67>、<實施例69>至<實施例155>
通過與上述實施例1、實施例16或實施例68相似的方法製備本發明的其他所有實施例化合物(實施例1至實施例155化合物),並將每個實施例化合物的化學結構式、化合物名稱、核磁共振波譜法以及LCMS分析結果始示於下述表2中。
表2
實施例化合物 | 結構 | 化合物名稱 | 1H NMR;MS[M+H] + |
1 | 4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ8.59(d,J=0.9Hz,1H),8.29(s,1H),8.03(d,J=5.7Hz,1H),7.63(s,1H),7.34(s,1H),6.07(d,J=5.7Hz,1H),4.87–4.69(m,1H),4.61(p,J=6.7Hz,1H),4.35(dt,J=13.9,7.1Hz,1H),4.10–3.91(m,2H),3.80-3.61(m,2H),3.51(s,3H),2.63(s,1H),2.07–1.99(m,1H),1.83–1.76(m,1H),1.67(s,6H),1.53(d,J=6.6Hz,6H)。;467.3[M+H] + | |
2 | 4-(2-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-5-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ9.00(s,1H),8.85(s,1H),8.25(d,J=5.7Hz,1H),7.74(d,J=5.7Hz,1H),7.30(s,1H),5.00(hept,J=6.7Hz,1H),4.82(ddt,J=48.2,5.6,2.5Hz,1H),4.59(dt,J=14.1,7.3Hz,1H),4.31(dt,J=13.6,5.0Hz,1H),3.64–3.50(m,2H),3.48(s,3H),3.43–3.32(m,1H),2.77(s,1H),2.03–1.94(m,1H),1.86–1.78(m,1H),1.65(s,6H),1.54(d,J=6.8Hz,6H)。;468.3[M+H] + | |
3 | 4-(2-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-基)氨基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-5-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.52(s,1H),8.45(d,J=5.7Hz,1H),8.32(s,1H),8.21(d,J=2.1Hz,1H),8.15(s,1H),7.43(dd,J=5.8,2.1Hz,1H),7.31(s,1H),5.01(hept,J=6.7Hz,1H),2.99(s,1H),2.83(tt,J=7.9,4.7Hz,1H),1.67(s,6H),1.59(d,J=6.8Hz,6H),1.30–1.14(m,4H)。;506.3[M+H] + | |
4 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基丁-3-烯-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.63(d,J=1.0Hz,1H),8.31–8.26(m,1H),8.03(d,J=5.7Hz,1H),7.61(s,1H),7.37(s,1H),6.07(d,J=5.7Hz,1H),5.39(dd,J=2.0,1.0Hz,1H),5.28(t,J=1.8Hz,1H),4.78(ddt,J=48.0,6.8,2.9Hz,1H),4.62(hept,J=6.7Hz,1H),4.36(dt,J=13.7,7.0Hz,1H),4.11–3.92(m,2H),3.80–3.60(m,2H),3.51(s,3H),2.03(t,J=1.3Hz,3H),2.04–1.97(m,1H),1.85–1.75(m,1H),1.54(dd,J=6.7,1.3Hz,6H)。;449.4[M+H] + | |
5 | 4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ8.72(d,J=1.1Hz,1H),8.33–8.28(m,1H),8.07(d,J=5.6Hz,1H),7.78(s,1H),6.07(d,J=5.6Hz,1H),4.90–4.68(m,2H),4.40(dt,J=14.3,7.1Hz,1H),4.08(s,1H),3.93(dd,J=21.3,13.7Hz,1H),3.76–3.60(m,2H),3.52(s,3H),2.84(s,1H),2.08–2.00(m,1H),1.86–1.77(m,1H),1.70(s,6H),1.60(d,J=6.7Hz,6H)。;468.3[M+H] + | |
6 | 3-((6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)苯酚 | 1H NMR(400MHz,CDCl 3)δ9.87(s,1H),9.65(s,1H),8.64(d,J=0.9Hz,1H),8.37(s,1H),8.00–7.92(m,2H),7.22(t,J=7.9Hz,1H),7.00(dt,J=7.7,1.2Hz,1H),6.93(t,J=2.0Hz,1H),6.80(ddd,J=8.2,2.5,1.0Hz,1H),6.43–6.37(m,1H),5.04–4.85(m,1H),4.72–4.57(m,2H),4.44–4.35(m,1H),3.64–3.42(m,2H),3.37(s,3H),3.31–3.25(m,1H),1.85–1.69(m,2H),1.52(dd,J=6.7,4.6Hz,6H)。;501.3[M+H] + | |
7 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-3-((3-氟苯基)乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.70(d,J=1.0Hz,1H),8.35–8.30(m,1H),8.04(d,J=5.6Hz,1H),7.74(s,1H),7.46(s,1H),7.35–7.29(m,2H),7.24(ddd,J=9.9,2.9,1.1Hz,1H),7.08–6.98(m,1H),6.08(d,J=5.7Hz,1H),4.79(ddt,J=47.9,6.7,3.0Hz,1H),4.65(hept,J=6.8Hz,1H),4.37(dt,J=13.9,7.0Hz,1H),4.11–3.92(m,2H),3.76(d,J=14.0Hz,1H),3.67(ddt,J=17.8,7.7,3.1Hz,1H),3.52(s,3H),2.04(dtd,J=17.2,7.5,3.7Hz,1H),1.86–1.74(m,1H),1.57(dd,J=6.7,1.4Hz,6H)。;503.3[M+H] + | |
8 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(吡啶-4-基乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.70(d,J=1.0Hz,1H),8.63–8.57(m,2H),8.36(d,J=1.0Hz,1H),8.05(d,J=5.6Hz,1H),7.79(s,1H),7.51(s,1H),7.42–7.36(m,2H),6.09(d,J=5.6Hz,1H),4.79(ddt,J=48.0,6.9,3.1Hz,1H),4.66(hept,J=6.5Hz,1H),4.36(dt,J=13.6,7.0Hz,1H),4.11–3.91(m,2H),3.83–3.72(m,1H),3.67(ddt,J=17.7,7.6,3.0Hz,1H),3.52(s,3H),2.04(ddt,J=14.8,7.4,3.7Hz,1H),1.80(ddt,J=11.8,7.5,3.7Hz,1H),1.58(dd,J=6.7,1.5Hz,6H)。;486.2[M+H] + | |
9 | 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ8.80(s,1H),8.68(s,1H),8.64(d,J=0.9Hz,1H),8.47(s,1H),8.42(s,1H),8.34(d,J=5.9Hz,1H),7.39(s,1H),6.77(d,J=5.9Hz,1H),4.67(hept,J=6.7Hz,1H),3.73(s,1H),2.84(tt,J=8.0,4.7Hz,1H),1.68(s,6H),1.60(d,J=6.7Hz,6H),1.19(s,4H)。;506.2[M+H] + | |
10 | 4-(6-((2-(1-(環丙基甲基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ9.25(s,1H),8.79(s,1H),8.32(d,J=5.8Hz,1H),8.27(s,1H),8.26(s,1H),8.19(s,1H),7.37(s,1H),6.78(d,J=5.9Hz,1H),4.65(hept,J=6.7Hz,1H),4.05(d,J=7.1Hz,2H),3.83(s,1H),1.67(s,6H),1.58(d,J=6.7Hz,6H),1.38–1.29(m,1H),0.74–0.63(m,2H),0.42(dt,J=6.1,4.8Hz,2H)。;456.2[M+H] + | |
11 | 1-((6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)環己烷-1-醇 | 1H NMR(400MHz,CDCl 3)δ8.61(d,J=0.9Hz,1H),8.30(s,1H),8.01(d,J=5.6Hz,1H),7.97(s,1H),7.33(s,1H),6.08(d,J=5.7Hz,1H),4.79(ddt,J=48.0,6.9,3.0Hz,1H),4.60(hept,J=6.7Hz,1H),4.37(dt,J=13.5,7.1Hz,1H),4.11–3.89(m,2H),3.80–3.60(m,2H),3.51(s,3H),2.92(s,1H),2.11–1.96(m,3H),1.85–1.56(m,9H),1.53(dd,J=6.7,1.4Hz,6H)。;507.3[M+H] + | |
12 | 5-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)戊-4-炔-1-醇 | 1H NMR(400MHz,CDCl 3)δ8.60(d,J=1.0Hz,1H),8.28(s,1H),8.02(d,J=5.6Hz,1H),7.90(s,1H),7.30(s,1H),6.08(d,J=5.6Hz,1H),4.79(ddt,J=48.1,7.2,3.0Hz,1H),4.60(hept,J=6.6Hz,1H),4.37(dt,J=13.8,7.0Hz,1H),4.11–4.02(m,1H),3.96(dd,J=20.4,13.9Hz,1H),3.87(t,J=6.1Hz,2H),3.78–3.71(m,1H),3.70–3.60(m,2H),3.51(s,3H),2.62(t,J=6.9Hz,2H),2.03(ddt,J=13.5,7.6,3.8Hz,1H),1.91(p,J=6.6Hz,2H),1.80(ddt,J=13.4,7.5,3.7Hz,1H),1.53(dd,J=6.7,1.3Hz,6H)。;467.2[M+H] + | |
13 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(4-甲基呱嗪-1-基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.60(s,1H),8.28(s,1H),8.02(d,J=5.7Hz,1H),7.89(s,1H),7.32(s,1H),6.09(d,J=5.7Hz,1H),4.79(ddt,J=47.9,7.0,3.0Hz,1H),4.60(hept,J=6.7Hz,1H),4.38(dt,J=13.6,6.9Hz,1H),4.12–3.91(m,2H),3.80–3.60(m,2H),3.52(s,3H),2.96–2.72(m,4H),2.71–2.38(m,4H),2.31(s,3H),2.04(ddt,J=15.1,7.7,3.9Hz,1H),1.80(ddt,J=12.0,7.4,3.7Hz,1H),1.56–1.49(m,12H)。;549.4[M+H] + | |
14 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-((甲基磺醯基)甲氧基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.63(s,1H),8.62(s,1H),8.46(s,1H),8.45(s,1H),8.37(d,J=5.9Hz,1H),7.45(s,1H),6.81(d,J=5.9Hz,1H),4.72(s,2H),4.71–4.66(m,1H),2.95(s,3H),2.84(tt,J=8.1,4.7Hz,1H),1.70(s,6H),1.63(d,J=6.7Hz,6H),1.53(dt,J=7.6,3.7Hz,2H),1.25–1.21(m,2H)。;598.2[M+H] + | |
15 | 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-苯基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ8.73(s,1H),8.67(s,1H),8.59(s,1H),8.45(s,1H),8.38(s,1H),8.28(d,J=5.9Hz,1H),7.81(s,1H),7.79(s,1H),7.41–7.36(m,3H),7.31(d,J=7.4Hz,1H),6.69(d,J=5.9Hz,1H),4.72(s,1H),4.64(hept,J=7.3Hz,1H),2.82(tt,J=8.3,4.6Hz,1H),1.93(s,3H),1.61–1.55(m,6H),1.52(dt,J=7.8,5.0Hz,2H),1.23–1.17(m,2H)。;568.3[M+H] + | |
16 | (E)-4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-烯-2-醇 | 1H NMR(400MHz,MeOD)δ8.81(s,1H),8.73(s,1H),8.44(s,1H),8.30(d,J=6.1Hz,1H),8.24(s,1H),7.48(s,1H),7.08(d,J=5.9Hz,1H),6.75(dd,J=16.3,3.3Hz,1H),6.39(d,J=16.3Hz,1H),4.74(dt,J=13.4,6.7Hz,1H),3.05(dq,J=7.9,4.6Hz,1H),1.60(d,J=6.7Hz,6H),1.47–1.44(m,8H),1.28(dd,J=7.9,2.4Hz,2H)。;508.2[M+H] + | |
17 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.87(s,1H),8.84(s,1H),8.70(s,1H),8.55(s,1H),8.45(d, J=6.1Hz,1H),8.37(s,1H),8.10(s,1H),7.19(s,1H),4.81(p, J=6.6Hz,1H),3.29(tt, J=7.8,4.7Hz,1H),3.20(s,3H),1.70(s,6H),1.53(d, J=6.6Hz,6H),1.36(ddt, J=6.1,4.6,2.5Hz,2H),1.28(ddd, J=7.5,5.4,1.8Hz,2H)。;568.2[M+H] + | |
18 | N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ11.14(s,1H),8.66(s,1H),8.27(s,1H),8.09(s,1H),7.97(d, J=6.9Hz,1H),6.60(s,1H),5.07(d, J=48.9Hz,1H),4.68(p, J=6.7Hz,1H),4.57(s,1H),4.27(s,1H),3.36(s,3H),3.19(s,2H),1.92(d, J=8.7Hz,1H),1.80(t, J=11.0Hz,1H),1.69(s,4H),1.49(dd, J=6.6,5.5Hz,6H)。;529.2[M+H] + | |
19 | (E)-N-(3-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)烯丙基)-N-甲基甲磺醯胺 | 1H NMR(400MHz,CDCl 3)δ8.82(s,1H),8.68(s,1H),8.47(s,1H),8.38(d,J=5.9Hz,1H),8.31(s,1H),7.84(s,1H),7.26–7.25(m,1H),6.82(d,J=5.8Hz,1H),6.75(d,J=15.8Hz,1H),6.16(dt,J=15.9,6.7Hz,1H),4.74–4.63(m,1H),3.98(d,J=6.6Hz,2H),2.92(s,3H),2.87(s,3H),1.62(d,J=6.7Hz,6H),1.55–1.52(m,2H),1.24–1.21(m,2H)。;571.2[M+H] + | |
20 | (E)-N-(3-(2-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-基)氨基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-5-基)烯丙基)-N-甲基甲磺醯胺 | 1H NMR(400MHz,CDCl 3)δ8.92(s,1H),8.52(d,J=0.4Hz,1H),8.45(d,J=5.7Hz,1H),8.33(d,J=0.5Hz,2H),7.46(s,1H),7.33(dd,J=5.7,2.1Hz,1H),7.16(s,1H),6.67(d,J=15.9Hz,1H),6.13(dt,J=15.9,6.6Hz,1H),5.02(dt,J=13.5,6.8Hz,1H),3.97(d,J=6.5Hz,2H),2.91(s,3H),2.87(s,3H),1.60(d,J=6.8Hz,6H),1.53(dd,J=5.2,2.5Hz,2H),1.21(dd,J=8.0,1.8Hz,2H)。;571.2[M+H] + | |
21 | 1,1,1-三氟-4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 1H NMR(400MHz,CDCl 3)δ8.54–8.49(m,1H),8.25(s,1H),8.23(s,1H),7.98(d,J=5.7Hz,1H),7.34(s,1H),6.04(dd,J=5.7,2.6Hz,1H),4.72(ddt,J=45.3,5.4,3.0Hz,1H),4.49(hept,J=6.6Hz,1H),4.26–4.16(m,1H),4.02–3.89(m,2H),3.88(s,1H),3.75(s,1H),3.72–3.61(m,1H),3.50(s,3H),2.09–1.96(m,1H),1.84–1.78(m,1H),1.77(s,3H),1.48(d,J=4.2Hz,3H),1.46(d,J=4.1Hz,3H)。;521.2[M+H] + | |
22 | N-(4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)甲磺醯胺 | 1H NMR(400MHz,CDCl 3)δ8.61(s,1H),8.40(s,1H),8.03(d,J=5.6Hz,1H),8.01(s,1H),7.39(s,1H),6.14(d,J=5.7Hz,1H),5.86(s,1H),4.84–4.72(m,1H),4.63(hept,J=6.7Hz,1H),4.34(dt,J=13.6,6.8Hz,1H),4.10–3.91(m,2H),3.80–3.74(m,1H),3.73–3.61(m,1H),3.51(s,3H),3.23(s,3H),2.08–1.98(m,1H),1.83–1.79(m,1H),1.77(s,6H),1.56(d,J=1.4Hz,3H),1.54(d,J=1.4Hz,3H)。;544.3[M+H] + | |
23 | N-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)甲磺醯胺 | 1H NMR(400MHz,CDCl 3)δ8.80(s,1H),8.71(d,J=1.0Hz,1H),8.70–8.63(m,2H),8.47(d,J=0.6Hz,1H),8.36(d,J=5.9Hz,1H),7.48(s,1H),6.93(s,1H),6.81(d,J=5.9Hz,1H),4.72(hept,J=6.6Hz,1H),3.27(s,3H),2.84(tt,J=8.0,4.7Hz,1H),1.80(s,6H),1.65(s,3H),1.64(s,3H),1.56–1.51(m,2H),1.25–1.22(m,2H)。;583.3[M+H] + | |
24 | N-((E)-3-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)烯丙基)-N-甲基甲磺醯胺 | 1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.30(s,1H),8.05(d,J=5.6Hz,1H),7.24(s,1H),6.73(d,J=15.9Hz,1H),6.21–6.08(m,2H),4.88–4.71(m,1H),4.62(dt,J=13.3,6.7Hz,1H),4.36(dd,J=13.6,6.8Hz,1H),4.10–3.93(m,4H),3.77–3.62(m,2H),3.51(s,3H),2.91(s,3H),2.87(s,3H),2.04(dd,J=9.6,3.9Hz,1H),1.81(dd,J=10.7,6.4Hz,1H),1.56–1.53(m,6H)。;532.3[M+H] + | |
25 | N-(4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)-N-甲基甲磺醯胺 | 1H NMR(400MHz,CDCl 3)δ8.57(s,1H),8.32(s,1H),8.04(d,J=5.6Hz,1H),7.78(s,1H),7.35(s,1H),6.10(d,J=5.7Hz,1H),4.78(ddt,J=47.9,6.8,2.9Hz,1H),4.62(hept,J=6.5Hz,1H),4.36(dt,J=13.5,7.0Hz,1H),4.09–3.93(m,2H),3.80–3.61(m,2H),3.51(s,3H),3.09(s,3H),3.03(s,3H),2.09–1.98(m,1H),1.84(s,6H),1.82–1.76(m,1H),1.56(d,J=1.3Hz,3H),1.55–1.52(m,3H)。;558.3[M+H] + | |
26 | 3-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ9.79(s,1H),8.55(d, J=0.9Hz,1H),8.31(s,1H),7.95(d, J=5.7Hz,1H),7.76(s,1H),6.39(d, J=5.7Hz,1H),4.93(d, J=48.0Hz,2H),4.60(td, J=13.4,12.9,6.1Hz,3H),4.38(d, J=13.7Hz,1H),3.50(s,2H),3.35(s,5H),3.12(s,3H),1.59(s,3H),1.51(s,6H),1.48(dd, J=6.7,4.5Hz,6H)。;543.3[M+H] + | |
27 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.52(s,1H),8.75(s,1H),8.67(s,1H),8.50(s,1H),8.42(d, J=6.0Hz,1H),8.37(s,1H),7.89(s,1H),7.15(s,1H),4.78(p, J=6.6Hz,2H),3.52(s,2H),3.12(s,3H),1.95(d, J=14.1Hz,2H),1.53(s,3H),1.52(s,6H),1.51(s,3H),1.35(dd, J=4.8,2.6Hz,3H),1.28–1.25(m,3H)。;582.3[M+H] + | |
28 | 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 557.3[M+H] + | |
29 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.28(s,1H),8.69(s,1H),8.55(s,1H),8.47(s,1H),8.38(d, J=5.9Hz,1H),7.81(s,1H),7.13(s,1H),4.80–4.74(m,1H),3.05(s,3H),1.96–1.90(m,2H),1.68(s,3H),1.53(s,3H),1.52(s,3H),1.37–1.35(m,6H),1.26(dd, J=11.2,5.2Hz,4H)。;596.3[M+H] + | |
30 | N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((1-((甲基磺醯基)甲基)環丙基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 541.3[M+H] + | |
31 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-((甲基磺醯基)甲基)環丙基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.66(s,1H),8.77(s,1H),8.71(s,1H),8.51(s,1H),8.44(d, J=6.0Hz,1H),8.33(s,1H),7.90(s,1H),7.15(s,1H),4.78(p, J=6.7Hz,1H),3.27(td, J=7.8,4.0Hz,3H),3.13(s,3H),1.52(s,3H),1.50(s,3H),1.35(dd, J=4.8,2.6Hz,2H),1.26(dd, J=7.6,2.5Hz,2H),1.23(s,1H),1.20–1.17(m,4H)。;580.3[M+H] + | |
32 | N-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)-N-甲基甲磺醯胺 | 597.3[M+H] + | |
33 | N-(3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)-4-氟苯基)甲磺醯胺 | 635.3[M+H] + | |
34 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.77(s,1H),8.69(s,1H),8.46(d,J=11.6Hz,2H),8.38(d,J=5.7Hz,2H),8.13(s,1H),7.88(d,J=7.8Hz,1H),7.80(d,J=7.8Hz,1H),7.58(d,J=7.8Hz,1H),7.55(d,J=3.4Hz,1H),6.80(d,J=5.9Hz,1H),4.73(p,J=6.7Hz,1H),3.11(s,3H),2.85(tt,J=8.2,4.7Hz,1H),1.66(d,J=6.6Hz,6H),1.54(dt,J=7.8,5.3Hz,2H),1.25–1.19(m,2H)。;602.3[M+H] + | |
35 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(咪唑幷[1,2-b]噠嗪-3-基乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.81(s,1H),8.72(s,1H),8.69(s,1H),8.53–8.45(m,3H),8.37(d,J=5.8Hz,1H),8.07(s,1H),8.01(dd,J=9.2,1.6Hz,1H),7.62(s,1H),7.13(dd,J=9.2,4.4Hz,1H),6.80(d,J=5.9Hz,1H),4.74(p,J=6.7Hz,1H),2.85(tt,J=8.2,4.6Hz,1H),1.67(s,3H),1.65(s,3H),1.57–1.51(m,2H),1.26–1.21(m,2H)。;565.3[M+H] + | |
36 | (E)-4-(3-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)烯丙基)硫代嗎啉1,1-二氧化物 | 597.3[M+H] + | |
37 | (E)-5-(2-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙烯基)吡咯烷-2-酮 | 533.3[M+H] + | |
38 | (E)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(2-(1-(甲基磺醯基)呱啶-3-基)乙烯基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 611.3[M+H] + | |
39 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.28(s,1H),8.70–8.68(m,1H),8.57(d, J=0.9Hz,1H),8.47(d, J=0.6Hz,2H),8.38(d, J=5.9Hz,1H),7.81(s,1H),7.12(s,1H),4.76(p, J=6.7Hz,1H),3.57(dd, J=11.4,3.7Hz,1H),3.36(s,1H),3.30–3.24(m,2H),3.03(dd, J=11.5,8.9Hz,1H),2.99–2.94(m,1H),2.92(s,3H),2.03–1.97(m,1H),1.83(s,1H),1.60(t, J=9.3Hz,2H),1.53(s,3H),1.52(s,3H),1.34(q, J=4.0,3.5Hz,2H),1.26(dd, J=7.6,2.5Hz,2H)。;609.3[M+H] + | |
40 | 8-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 | 554.3[M+H] + | |
41 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-5-異丙基異喹啉-3-胺 | 593.3[M+H] + | |
42 | 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 | 568.3[M+H] + | |
43 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.39(s,1H),8.76–8.70(m,2H),8.52(s,1H),8.43(d,J=5.8Hz,1H),8.23(s,1H),7.56–7.47(m,2H),6.99(d,J=5.9Hz,1H),3.70(h,J=6.9Hz,1H),3.39–3.31(m,2H),2.98(s,3H),2.86(tt,J=8.2,4.7Hz,1H),2.16–2.10(m,2H),1.54(dt,J=7.7,3.7Hz,2H),1.46(s,12H),1.25–1.21(m,2H)。;607.3[M+H] + | |
44 | 4-(1-環戊基-6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 532.3[M+H] + | |
45 | 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-(四氫呋喃-3-基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 534.3[M+H] + | |
46 | 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-(吡咯烷-3-基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 533.3[M+H] + | |
47 | 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-(1,1,1-三氟丙烷-2-基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 560.3[M+H] + | |
48 | 6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-3-(3-羥基-3-甲基丁-1-炔-1-基)-1-異丙基-1,3-二氫-2H-咪唑幷[4,5-c]吡啶-2-酮 | 523.3[M+H] + | |
49 | 4-(5-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-3-異丙氧基-1H-吡唑幷[3,4-c]吡啶-1-基)-2-甲基丁-3-炔-2-醇 | 523.3[M+H] + | |
50 | (S)-4-(1 1,5-二甲基-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷-4 3-基)-2-甲基丁-3-炔-2-醇 | 444.3[M+H] + | |
51 | (S)-N-(4-(1 1,5-二甲基-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷-4 3-基)-2-甲基丁-3-炔-2-基)甲磺醯胺 | 521.3[M+H] + | |
52 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-((2,2,2-三氟乙基)氨基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 587.3[M+H] + | |
53 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-((2-(甲基磺醯基)乙基)氨基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 611.3[M+H] + | |
54 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(3-((甲基磺醯基)甲基)氮雜環丁烷-1-基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 637.3[M+H] + | |
55 | N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(3-((甲基磺醯基)甲基)氮雜環丁烷-1-基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 598.3[M+H] + | |
56 | 4-(1-異丙基-6-((2-嗎啉幷嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 421.3[M+H] + | |
57 | 4-(1-異丙基-6-((2-(4-甲基呱嗪-1-基)嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 434.3[M+H] + | |
58 | 4-(4-((3-(3-羥基-3-甲基丁-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)硫代嗎啉1,1-二氧化物 | 469.3[M+H] + | |
59 | 4-(1-異丙基-6-((2-(4-(甲基磺醯基)呱嗪-1-基)嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 498.3[M+H] + | |
60 | 4-(4-((3-(3-羥基-3-甲基丁-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)呱嗪-2-酮 | 434.3[M+H] + | |
61 | 4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)吡啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 466.3[M+H] + | |
62 | 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-2,7-萘啶-3-胺 | 569.3[M+H] + | |
63 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基-2,7-萘啶-3-胺 | 608.3[M+H] + | |
64 | 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-2,6-萘啶-3-胺 | 569.3[M+H] + | |
65 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基-2,6-萘啶-3-胺 | 608.3[M+H] + | |
66 | 4-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基吡啶幷[3,4-d]噠嗪-7-胺 | 570.3[M+H] + | |
67 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-4-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基吡啶幷[3,4-d]噠嗪-7-胺 | 609.3[M+H] + | |
68 | (S)-1 1,5-二甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷 | 1H NMR(400MHz,DMSO- d 6)δ10.14(s,1H),9.06(d, J=1.0Hz,1H),8.53(d, J=0.8Hz,1H),8.25(d, J=5.8Hz,1H),7.97(s,1H),7.91(s,1H),6.71(d, J=5.8Hz,1H),4.96(q, J=7.9,7.2Hz,1H),4.42(t, J=11.1Hz,1H),4.00–3.95(m,1H),3.75(s,3H),3.19(s,3H),1.74(s,1H),1.72(s,1H),1.69(d, J=1.2Hz,6H),1.67(s,3H)。;506.3[M+H] + | |
69 | (S)-1 1,5-二甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-吡啶-1(4,5)-吡唑環八烷 | 505.2[M+H] + | |
70 | (S)-1 1,5-二甲基-4 5-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1 1H,4 7H-8-氧雜-3-氮雜-4(2,7)-吡咯幷[2,3-d]嘧啶-2(2,4)-吡啶-1(4,5)-吡唑環八烷 | 506.3[M+H] + | |
71 | N-(2-(4-(環丙基磺醯基)-1H-咪唑-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 568.2[M+H] + | |
72 | N-(2-(2-(環丙基磺醯基)-1H-咪唑-5-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 568.3[M+H] + | |
73 | N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-3-(咪唑幷[1,2-b]噠嗪-3-基乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.73(s,1H),8.49(dd,J=4.5,1.6Hz,1H),8.40(s,1H),8.06(d,J=3.5Hz,1H),8.04(s,1H),8.01(dd,J=9.1,1.6Hz,1H),7.98(s,1H),7.56(s,1H),7.12(dd,J=9.2,4.4Hz,1H),6.11(d,J=5.7Hz,1H),4.89–4.71(m,1H),4.67(p,J=6.7Hz,1H),4.36(dt,J=13.7,7.1Hz,1H),4.09–3.96(m,2H),3.83–3.74(m,1H),3.68(dd,J=17.7,6.9Hz,1H),3.52(s,3H),2.09–2.00(m,1H),1.80(td,J=8.4,4.0Hz,1H),1.59(d,J=1.4Hz,3H),1.57(d,J=1.4Hz,3H)。;526.3[M+H] + | |
74 | 1-環戊基-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.57(s,1H),8.46(s,1H),8.43–8.34(m,2H),8.28(s,1H),7.42(s,1H),6.83(d,J=5.9Hz,1H),4.88–4.79(m,1H),3.11(s,3H),2.87–2.79(m,1H),2.34(dt,J=13.3,7.0Hz,2H),1.99–1.93(m,2H),1.92–1.86(m,4H),1.80(s,6H),1.55–1.51(m,2H),1.24–1.21(m,2H)。;594[M+H] + | |
75 | 1-環己基-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.66(s,1H),8.56(s,1H),8.46(s,1H),8.38(d, J=5.9Hz,1H),8.28(s,1H),7.47(s,1H),6.89(d, J=5.8Hz,1H),4.27–4.19(m,1H),3.11(s,3H),2.87–2.79(m,1H),2.19(d, J=12.7Hz,2H),1.99(d, J=13.6Hz,2H),1.85(d, J=13.1Hz,2H),1.80(s,6H),1.72–1.59(m,4H),1.56–1.51(m,2H),1.23–1.19(m,2H)。;608[M+H] + | |
76 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.36(s,1H),8.12(t,J=1.8Hz,1H),8.04(d,J=5.6Hz,2H),7.87(ddd,J=7.9,1.9,1.2Hz,1H),7.79(dt,J=7.8,1.4Hz,1H),7.56(t,J=7.8Hz,1H),7.49(s,1H),6.10(d,J=5.7Hz,1H),4.80(ddt,J=48.0,6.8,3.0Hz,1H),4.66(p,J=6.7Hz,1H),4.38(dt,J=13.6,7.0Hz,1H),4.12(q,J=7.1Hz,1H),3.77(d,J=6.9Hz,1H),3.67(ddt,J=18.0,6.1,2.9Hz,1H),3.51(s,3H),3.10(s,3H),2.11–1.97(m,2H),1.85–1.76(m,1H),1.58(dd,J=6.7,1.5Hz,6H)。;563.3[M+H] + | |
77 | 4-(6-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 | 467.3[M+H] + | |
78 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 595.3[M+H] + | |
79 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.67(m,2H),8.51(s,1H),8.46(s,1H),8.40(d, J=5.8Hz,1H),7.40(s,1H),6.86(d, J=5.9Hz,1H),4.70(p, J=6.7Hz,1H),3.67(d, J=10.0Hz,1H),3.64–3.58(m,2H),3.35(d, J=10.0Hz,1H),2.91(s,3H),2.84(tt, J=8.0,4.7Hz,1H),2.33(dt, J=11.7,5.6Hz,1H),2.03(dt, J=12.4,8.1Hz,1H),1.63(d, J=6.7Hz,6H),1.58–1.46(m,5H),1.25–1.20(m,2H)。;609.3[M+H] + | |
80 | 3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)-1-(甲基磺醯基)吡咯烷-3-醇 | 611.3[M+H] + | |
81 | (R)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.70–8.62(m,3H),8.46(s,1H),8.42–8.32(m,2H),7.37(s,1H),6.81(d,J=5.9Hz,1H),4.68(hept,J=6.8Hz,1H),2.98–2.85(m,4H),2.84(s,3H),2.83(d,J=5.0Hz,1H),2.17–2.11(m,1H),2.05(s,1H),1.95–1.89(m,1H),1.74–1.65(m,2H),1.61(d,J=6.7Hz,6H),1.53–1.51(m,2H),1.24–1.20(m,2H)。;609.3[M+H] + | |
82 | (S)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.67(d,J=7.7Hz,2H),8.59(s,1H),8.46(s,2H),8.38(d,J=5.9Hz,1H),7.38(s,1H),6.82(d,J=5.9Hz,1H),4.56(hept,J=6.7Hz,1H),3.88(d,J=10.3Hz,2H),3.64(d,J=12.1Hz,2H),2.84(s,3H),1.71(dddd,J=17.5,12.3,7.3,3.8Hz,6H),1.61(d,J=6.7Hz,6H),1.25 – 1.21(m,4H)。;609.3[M+H] + | |
83 | 3-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)噻唑烷1,1-二氧化物 | 609.3[M+H] + | |
84 | 3-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 | 1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.65(s,1H),8.47(s,1H),8.40(s,1H),8.38(d, J=5.9Hz,1H),8.10(s,1H),7.44(s,1H),6.81(d, J=5.9Hz,1H),4.69(p, J=6.8Hz,1H),4.41–4.30(m,2H),4.16–4.05(m,2H),2.84(tt, J=8.0,4.7Hz,1H),2.58(p, J=9.1Hz,1H),1.62(d, J=6.7Hz,6H),1.54(m,2H),1.37(s,6H),1.27–1.19(m,2H)。;594.3[M+H] + | |
85 | N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)異喹啉-3-胺 | 540.3[M+H] + | |
86 | 1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-N-(2-(4-乙烯基-1H-咪唑-1-基)嘧啶-4-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.58(s,1H),8.55(s,1H),8.30(d, J=5.8Hz,1H),8.20(s,1H),7.81(s,1H),7.48(s,1H),6.87(d, J=5.9Hz,1H),6.65(dd, J=17.4,10.9Hz,1H),5.96(d, J=17.5Hz,2H),5.26(d, J=10.9Hz,1H),4.68(p, J=6.7Hz,1H),3.11(s,3H),1.80(s,6H),1.62(d, J=6.7Hz,6H)。;490.3[M+H] + | |
87 | (S)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 609.3[M+H] + | |
88 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(((S)-3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 570.3[M+H] + | |
89 | 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ9.81(s,1H),8.50(s,1H),8.32(s,1H),7.95(d, J=5.6Hz,1H),7.76(s,1H),6.38(d, J=5.7Hz,1H),5.00–4.85(m,1H),4.61(dp, J=19.9,7.6,6.7Hz,2H),4.38(d, J=13.4Hz,1H),3.61(d, J=7.7Hz,1H),3.57–3.52(m,1H),3.36(s,3H),3.04(s,3H),1.95–1.90(m,2H),1.82–1.70(m,4H),1.48(dd, J=6.7,4.5Hz,6H),1.35(s,6H)。;557.3[M+H] + | |
90 | 8-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 | 554.3[M+H] + | |
91 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-((甲基磺醯基)甲基)氮雜環丁烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 609.3[M+H] + | |
92 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-((甲基磺醯基)甲基)氮雜環丁烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 570.3[M+H] + | |
93 | (S)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-((甲基磺醯基)甲基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 623.3[M+H] + | |
94 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(((S)-3-甲基-1-((甲基磺醯基)甲基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 584.3[M+H] + | |
95 | ((3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)吡咯烷-1-基)甲基)(亞氨基)(甲基)-λ 6-磺酮 | 608.3[M+H] + | |
96 | 2-(4-(4-((1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)乙烷-1-醇 | 1H NMR(400MHz,CDCl 3)δ8.63(s,1H),8.50(s,1H),8.33(d, J=5.8Hz,1H),8.18(s,2H),7.47(s,1H),6.75(d, J=5.9Hz,1H),4.71(p, J=6.7Hz,1H),4.35–4.30(m,2H),4.10–4.04(m,2H),3.11(s,3H),1.80(s,6H),1.63(d, J=6.7Hz,6H)。;508.3[M+H] + | |
97 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ9.76(s,1H),8.51(s,1H),8.44(s,1H),8.03(d,J=5.6Hz,1H),7.34(s,1H),6.19(d,J=5.7Hz,1H),4.78(ddt,J=47.8,6.9,3.0Hz,1H),4.62(p,J=6.8Hz,1H),4.33(dt,J=14.1,6.9Hz,1H),3.99(t,J=16.5Hz,2H),3.81–3.63(m,3H),3.57(dd,J=9.7,6.8Hz,1H),3.51(s,3H),3.43(dd,J=9.9,6.4Hz,1H),3.34(p,J=6.7Hz,1H),2.90(s,3H),2.34(dq,J=13.1,6.7Hz,1H),2.21–2.15(m,2H),2.03(dtd,J=15.3,7.8,4.0Hz,1H),1.79(ddd,J=17.1,7.7,3.8Hz,1H),1.55(s,3H),1.53(s,3H)。;556.3[M+H] + | |
98 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-((甲基磺醯基)甲基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 616.3[M+H] + | |
99 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-((甲基磺醯基)甲基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 577.3[M+H] + | |
100 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲氧基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.32(s,1H),8.69(s,1H),8.62(d, J=0.9Hz,1H),8.52(s,1H),8.47(s,1H),8.38(d, J=5.9Hz,1H),7.96(s,1H),7.13(s,1H),4.79(p, J=6.6Hz,1H),3.57(s,1H),3.42(s,4H),3.28(ddt, J=9.3,7.9,4.0Hz,2H),2.94(s,3H),1.73(s,3H),1.55(s,3H),1.53(s,3H),1.35(p, J=4.8,4.4Hz,2H),1.26(tt, J=8.7,3.4Hz,3H)。;625.4[M+H] + | |
101 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.68(d, J=0.6Hz,1H),8.62(d, J=1.0Hz,1H),8.46(d, J=0.6Hz,1H),8.39(s,0H),8.37(s,1H),7.73(s,1H),7.38(s,1H),6.77(d, J=5.9Hz,1H),4.68(p, J=6.8Hz,1H),3.80(d, J=9.2Hz,1H),3.62(d, J=9.5Hz,1H),3.55–3.45(m,2H),2.88(s,3H),2.86–2.77(m,1H),1.99(dt, J=8.3,4.4Hz,1H),1.61(d, J=6.7Hz,6H),1.57–1.50(m,2H),1.34–1.15(m,4H)。;607.3 [M+H] + | |
102 | 1-環丁基-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ9.35(s,1H),8.70(s,1H),8.51(s,1H),8.48(s,1H),8.43(s,1H),8.38(d, J=5.9Hz,1H),7.54(s,1H),6.83(d, J=5.9Hz,1H),4.89(p, J=8.3Hz,1H),3.11(s,3H),2.84(td, J=8.0,4.1Hz,1H),2.74–2.62(m,2H),2.46(dq, J=12.1,9.5Hz,2H),2.14(m,1H),2.00(q, J=9.5,9.1Hz,1H),1.80(s,6H),1.54(td, J=4.8,2.9Hz,2H),1.23(m,2H)。;580.3 [M+H] + | |
103 | N-(3-((6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)苯基)甲磺醯胺 | 1H NMR(400MHz,DMSO- d 6)δ9.90(s,1H),8.66(s,1H),8.35(s,1H),8.03(s,1H),7.97(d, J=5.8Hz,1H),7.40(d, J=7.9Hz,1H),7.37–7.36(m,1H),7.31(dt, J=7.6,1.4Hz,1H),7.22(dt, J=8.1,1.6Hz,1H),6.42(s,1H),4.64(q, J=6.8Hz,2H),4.38(d, J=13.4Hz,1H),3.36(s,3H),3.05(s,4H),1.81(s,2H),1.74(d, J=11.1Hz,1H),1.52(dd, J=6.7,4.9Hz,6H),1.47(d, J=6.6Hz,1H),1.23(s,4H)。;578.3[M+H] + | |
104 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((2-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.87(s,1H),8.69(s,1H),8.47(m,2H),8.39(d, J=5.8Hz,1H),8.15(dd, J=8.0,1.3Hz,1H),8.09(s,1H),7.74(dd, J=7.8,1.3Hz,1H),7.63(td, J=7.6,1.4Hz,1H),7.59(s,1H),7.50(td, J=7.7,1.4Hz,1H),6.83(d, J=5.9Hz,1H),4.74(p, J=6.7Hz,1H),3.36(s,3H),2.84(td, J=8.1,4.0Hz,1H),1.67(d, J=6.7Hz,6H),1.54(td, J=5.0,3.1Hz,2H),1.24(dd, J=9.0,3.2Hz,2H)。;602.3 [M+H] + | |
105 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.67(s,1H),8.64(s,1H),8.48(s,1H),8.39(d, J=5.9Hz,1H),7.97–7.90(m,2H),7.74–7.68(m,2H),7.58(s,1H),6.81(d, J=5.9Hz,1H),3.47(s,3H),3.09(s,3H),2.84(td, J=8.0,4.1Hz,1H),1.67(d, J=6.7Hz,6H),1.54(m,2H),1.29–1.22(m,2H)。;602.3 [M+H] + | |
106 | N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((1-((甲基磺醯基)甲基)環丙基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.39(s,1H),8.68(s,1H),8.24(s,1H),8.09(d,J=5.9Hz,1H),7.50–7.45(m,2H),6.34(d,J=5.6Hz,1H),4.96–4.73(m,1H),4.59(dt,J=14.2,7.0Hz,1H),4.33(dt,J=12.0,5.0Hz,1H),3.85(dd,J=23.9,13.5Hz,1H),3.73–3.57(m,3H),3.51(s,3H),3.26(s,2H),3.17(s,3H),2.13–2.00(m,1H),1.88(ddt,J=13.7,6.9,3.7Hz,1H),1.45–1.41(m,2H),1.39(d,J=3.4Hz,3H),1.37(d,J=3.3Hz,3H),1.31–1.27(m,2H)。;552.3[M+H] + | |
107 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((1-((甲基磺醯基)甲基)環丙基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.47(s,1H),9.05(s,1H),8.77(s,1H),8.72(s,1H),8.54(s,1H),8.41(d,J=5.7Hz,1H),7.51(d,J=7.6Hz,1H),7.48(d,J=7.6Hz,1H),7.12(d,J=5.8Hz,1H),3.67(p,J=6.8Hz,1H),3.30(s,2H),3.19(s,3H),2.87(tt,J=8.2,4.6Hz,1H),1.54(dt,J=7.5,3.7Hz,2H),1.44(d,J=6.6Hz,6H),1.31–1.28(m,2H),1.27–1.21(m,4H)。;591.2[M+H] + | |
108 | (R)-(3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)呱啶-1-基)(苯基)甲烷酮 | 1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.46(s,1H),8.40(s,1H),8.35(d,J=5.8Hz,1H),7.72–7.63(m,1H),7.58–7.32(m,7H),6.80(d,J=5.9Hz,1H),4.68(hept,J=6.7Hz,1H),4.12(q,J=7.2Hz,1H),2.83(td,J=8.0,4.0Hz,1H),2.13(s,1H),2.05(s,1H),1.86(d,J=13.5Hz,1H),1.61(d,J=6.7Hz,6H),1.56–1.50(m,2H),1.28–1.19(m,7H)。;635.4[M+H] + | |
109 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 595.3 [M+H] + | |
110 | (Z)-3-(1-氯-2-(3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙烯基)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 631.3 [M+H] + | |
111 | 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.35(s,1H),8.70(s,1H),8.09(d,J=5.7Hz,1H),7.66(s,1H),7.49–7.45(m,2H),6.21(d,J=5.7Hz,1H),4.84(ddt,J=48.1,6.0,2.7Hz,1H),4.58(dt,J=14.0,7.2Hz,1H),4.29(dd,J=13.5,6.8Hz,1H),3.92–3.78(m,1H),3.75–3.57(m,3H),3.52(s,3H),3.37–3.28(m,2H),2.96(s,3H),2.15–2.09(m,2H),2.08–1.99(m,1H),1.86(ddt,J=13.7,7.2,3.7Hz,1H),1.46(s,6H),1.40(d,J=2.9Hz,3H),1.39(d,J=2.9Hz,3H)。;568.3[M+H] + | |
112 | N-(2-(1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.39(s,1H),8.80(s,1H),8.44– 8.37(m,2H),8.34(d,J=6.1Hz,1H),7.56–7.50(m,2H),7.06(s,1H),3.77(p,J=6.9Hz,1H),3.38–3.32(m,2H),2.99(s,3H),2.17–2.09(m,2H),1.50–1.45(m,12H)。;503.3[M+H] + | |
113 | 順式-3-氟-1-(4-((5-異丙基-8-((1-((甲基磺醯基)甲基)環丙基)乙炔基)異喹啉-3-基)氨基)嘧啶-2-基)呱啶-4-醇 | 1H NMR(400MHz,CDCl 3)δ9.37(s,1H),8.71(s,1H),8.09(s,1H),8.06(d,J=5.7Hz,1H),7.47–7.43(m,2H),6.21(d,J=5.7Hz,1H),4.77(ddt,J=48.1,6.4,2.9Hz,1H),4.47(dt,J=14.1,7.3Hz,1H),4.22(ddd,J=13.4,7.3,3.8Hz,1H),4.10(ddt,J=19.3,7.3,3.3Hz,1H),3.96(ddd,J=22.6,13.7,3.1Hz,1H),3.79–3.69(m,1H),3.64(h,J=6.8Hz,1H),3.25(s,2H),3.17(s,3H),2.85(s,1H),2.07–1.96(m,1H),1.91(ddt,J=9.5,7.3,3.8Hz,1H),1.44–1.40(m,2H),1.37(d,J=2.1Hz,3H),1.36(d,J=2.1Hz,3H),1.30–1.26(m,2H)。;538.3[M+H] + | |
114 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.41(s,1H),8.76–8.71(m,2H),8.53(s,1H),8.44(d,J=5.9Hz,1H),8.01(s,1H),7.57–7.53(m,2H),6.99(d,J=5.9Hz,1H),4.31–4.22(m,2H),3.97–3.89(m,2H),3.74(h,J=6.8Hz,1H),2.96(s,3H),2.86(tt,J=7.9,4.7Hz,1H),1.80(s,3H),1.60–1.51(m,2H),1.48(d,J=6.8Hz,6H),1.24–1.20(m,2H)。;606.3[M+H] + | |
115 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.39–9.34(m,1H),8.71(s,1H),8.09(d,J=5.6Hz,1H),7.63(s,1H),7.54–7.46(m,2H),6.20(d,J=5.7Hz,1H),4.84(ddt,J=48.2,6.1,2.7Hz,1H),4.58(dt,J=14.1,7.2Hz,1H),4.33–4.27(m,1H),4.25(d,J=7.5Hz,2H),3.93(d,J=7.5Hz,2H),3.91–3.78(m,1H),3.76–3.57(m,3H),3.52(s,3H),2.95(s,3H),2.11–1.99(m,1H),1.86(ddt,J=13.7,7.3,3.8Hz,1H),1.78(s,3H),1.41(d,J=2.9Hz,3H),1.39(d,J=2.9Hz,3H)。;567.4[M+H] + | |
116 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.97(s,1H),8.70(s,1H),8.68(s,1H),8.60(s,1H),8.47(s,1H),8.43(d, J=5.9Hz,1H),6.82(d, J=5.9Hz,1H),4.84(p, J=6.7Hz,1H),3.75(d, J=10.3,1H),3.63(dd, J=8.1,5.5Hz,2H),3.39(d, J=10.2Hz,1H),2.94(s,3H),2.84(td, J=8.1,4.0Hz,1H),2.41(dt, J=11.7,5.6Hz,1H),2.07(dt, J=12.4,8.1Hz,1H),1.67(d, J=6.7Hz,6H),1.57(s,3H),1.56–1.51(m,2H),1.29–1.19(m,2H)。;610.3 [M+H] + | |
117 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-2-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-2H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.86(m,1H),8.70(s,1H),8.55(s,1H),8.39(d, J=5.9Hz,1H),8.17(s,1H),7.97(s,1H),6.96(d, J=5.9Hz,1H),5.05(p, J=6.7Hz,1H),3.81–3.73(d, J=9.9Hz,1H),3.72–3.57(m,2H),3.40(d, J=9.9Hz,1H),2.93(s,3H),2.84(tt, J=8.0,4.7Hz,1H),2.41(m,1H),2.17–2.06(m,1H),1.67(d, J=6.6Hz,6H),1.61(s,3H),1.55(m,2H),1.24–1.18(m,2H)。;610.3 [M+H] + | |
118 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-((甲基磺醯基)甲基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.33(s,1H),8.71(d, J=4.4Hz,2H),8.54(s,1H),8.48(s,1H),8.39(d, J=5.9Hz,1H),8.03(s,1H),7.54(d, J=7.6Hz,1H),7.47(s,1H),7.45(s,1H),7.14(s,1H),4.82(p, J=6.6Hz,1H),4.54(s,2H),2.93(s,2H),1.59(s,2H),1.58(s,3H),1.56(s,3H),1.36(dd, J=7.8,4.9Hz,3H),1.29–1.24(m,3H)。;616.2[M+H] + | |
119 | (S)-(3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)呱啶-1-基)(苯基)甲烷酮 | 1H NMR(400MHz,CDCl 3)δ9.00–8.84(m,1H),8.68(s,1H),8.67–8.53(m,1H),8.47(s,1H),8.40(s,1H),8.33(d,J=5.9Hz,1H),7.44(d,J=6.6Hz,2H),7.38(d,J=6.3Hz,4H),6.81(d,J=5.9Hz,1H),4.68(p,J=6.7Hz,1H),4.12(q,J=7.1Hz,2H),3.99–2.90(m,5H),2.86–2.81(m,1H),1.61(d,J=6.7Hz,6H),1.52(tt,J=6.0,3.3Hz,3H),1.21(td,J=7.2,6.4,1.9Hz,3H)。;635.3[M+H] + | |
120 | (R)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(呱啶-3-基乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.92(d,J=0.9Hz,1H),8.78(s,1H),8.69(s,1H),8.47(s,1H),8.33(d,J=3.7Hz,1H),7.47(s,1H),6.85(d,J=5.9Hz,1H),6.12(d,J=3.0Hz,1H),4.68(p,J=6.7Hz,1H),3.10–2.92(m,3H),2.84(tt,J=8.0,4.7Hz,1H),2.63(q,J=3.3Hz,1H),2.09–1.94(m,2H),1.61(t,J=7.1Hz,6H),1.56–1.49(m,3H),1.41(dq,J=10.5,5.8,5.0Hz,1H),1.31–1.15(m,4H)。;531.3[M+H] + | |
121 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-基)-5-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-2-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.15(s,1H),8.79(s,1H),8.58(s,1H),8.47(d, J=2.1Hz,1H),8.39(s,1H),8.37(d, J=5.7Hz,1H),7.80(s,1H),7.58(dd, J=5.8,2.1Hz,1H),4.98(p, J=6.7Hz,1H),3.23(tt, J=7.9,4.7Hz,1H),3.05(s,3H),1.95–1.90(m,2H),1.53(s,3H),1.52(s,3H),1.38(d, J=4.6Hz,1H),1.35(s,6H),1.32(d, J=4.5Hz,2H),1.24(ddd, J=8.7,5.3,3.2Hz,4H)。;596.3[M+H] + | |
122 | 3-((1-(環丙基磺醯基)-1H-吡唑-4-基)乙炔基)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.98(s,1H),8.69(s,1H),8.64(s,1H),8.60(s,1H),8.47(s,1H),8.38(d, J=5.8Hz,1H),8.16(s,1H),7.94(s,1H),7.50(s,1H),6.80(d, J=5.9Hz,1H),4.73(p, J=6.7Hz,1H),2.89–2.75(m,2H),1.65(d, J=6.6Hz,6H),1.60–1.46(m,4H),1.28–1.19(m,4H)。;618.3 [M+H] + | |
123 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.70(s,1H),8.48(s,1H),8.47(s,1H),8.43(d,J=5.8Hz,1H),8.30(s,1H),6.82(d,J=5.8Hz,1H),4.84(hept,J=6.7Hz,1H),3.39–3.30(m,2H),2.98(s,3H),2.85(tt,J=7.9,4.7Hz,1H),2.15–2.07(m,2H),1.68(d,J=6.6Hz,6H),1.54(td,J=4.7,2.9Hz,2H),1.46(s,6H),1.25–1.21(m,2H)。;597.3[M+H] + | |
124 | 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.34(s,1H),8.14(s,1H),8.07(d,J=5.6Hz,1H),6.12(d,J=5.7Hz,1H),4.91–4.70(m,2H),4.44(dt,J=14.1,7.0Hz,1H),4.13(t,J=10.5Hz,1H),3.92(dd,J=21.4,14.1Hz,1H),3.78–3.60(m,2H),3.52(s,3H),3.38–3.30(m,2H),2.97(s,3H),2.14–2.07(m,2H),2.06–1.97(m,1H),1.88–1.77(m,1H),1.61(d,J=6.7Hz,6H),1.45(s,6H)。;558.4[M+H] + | |
125 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((1-((甲基磺醯基)甲基)環丙基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.71(d,J=1.1Hz,1H),8.33(d,J=1.1Hz,1H),8.07(d,J=5.6Hz,1H),7.84(s,1H),6.09(d,J=5.6Hz,1H),4.90–4.69(m,2H),4.42(dt,J=13.9,7.1Hz,1H),4.16–4.04(m,1H),4.00–3.86(m,1H),3.75–3.60(m,2H),3.52(s,3H),3.23(s,2H),3.20(s,3H),2.10–1.97(m,1H),1.81(ddt,J=13.7,7.6,3.8Hz,1H),1.59(d,J=6.7Hz,6H),1.49–1.41(m,2H),1.31–1.26(m,2H)。;542.3[M+H] + | |
126 | 5-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-7-異丙基-N-(4’-甲氧基-[2,3’-聯吡啶]-4-基)-7H-吡咯幷[2,3-d]嘧啶-2-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.14(s,1H),8.77(s,1H),8.74(s,1H),8.48(d, J=5.7Hz,1H),8.45(d, J=5.7Hz,1H),8.35(d, J=2.1Hz,1H),7.86(dd, J=5.8,2.2Hz,1H),7.78(s,1H),7.20(d, J=5.8Hz,1H),4.90(p, J=6.8Hz,1H),3.92(s,3H),3.33(s,6H),3.05(s,4H),1.47(s,2H),1.46(s,2H),1.34(s,6H)。;533.3[M+H] + | |
127 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((2-甲氧基-5-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.74(s,1H),8.69(s,1H),8.48(m,2H),8.39(d, J=5.8Hz,1H),8.08(d, J=2.4Hz,1H),7.88(dd, J=8.8,2.4Hz,1H),7.55(s,1H),7.05(d, J=8.8Hz,1H),6.81(d, J=5.9Hz,1H),4.73(p, J=6.6Hz,1H),4.04(s,3H),3.08(s,3H),2.84(dq, J=8.1,4.7,4.1Hz,1H),1.66(d, J=6.7Hz,6H),1.54(m,2H),1.28–1.19(m,2H)。;632.3 [M+H] + | |
128 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-((4-氟-3-(甲基磺醯基)苯基)乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.69(s,1H),8.61(s,1H),8.48(s,1H),8.45(s,1H),8.39(m,2H),8.25(d, J=5.8Hz,1H),8.15(dd, J=6.6,2.2Hz,1H),7.94(s,1H),7.79(ddd, J=8.5,4.7,2.2Hz,1H),7.53(s,1H),6.79(d, J=5.8Hz,1H),6.32(d, J=5.8Hz,1H),4.88(s,1H),4.73(p, J=6.8Hz,1H),3.26(s,3H),2.82(m,1H),1.66(d, J=6.7Hz,6H),1.53(m,2H),1.29–1.21(m,2H)。;620.3 [M+H] + | |
129 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基-3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.73–8.67(m,2H),8.48(m,2H),8.38(d, J=5.8Hz,1H),8.19(d, J=2.2Hz,1H),7.76(dd, J=8.5,2.2Hz,1H),7.50(s,1H),7.06(d, J=8.7Hz,1H),6.81(d, J=5.9Hz,1H),4.73(p, J=6.7Hz,1H),4.05(s,3H),3.25(s,3H),2.90–2.79(m,1H),1.65(d, J=6.7Hz,6H),1.53(m,2H),1.28–1.19(m,2H)。;632.3 [M+H] + | |
130 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 555.3 [M+H] + | |
131 | 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-N-(2-(4-甲氧基吡啶-3-基)嘧啶-4-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.23(s,1H),8.68(s,1H),8.55–8.52(m,2H),8.44(d, J=5.9Hz,1H),8.32(s,1H),7.75(s,1H),7.28(s,1H),7.24(d, J=5.9Hz,1H),4.52(p, J=6.7Hz,1H),3.89(s,3H),3.35(d, J=4.7Hz,1H),3.31(s,1H),3.04(s,3H),1.95–1.90(m,2H),1.44(s,3H),1.42(s,3H),1.35(s,6H)。;533.4[M+H] + | |
132 | 3-((3-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-5-異丙基異喹啉-8-基)乙炔基)-1-(甲基磺醯基)吡咯烷-3-醇 | 1H NMR(400MHz,CDCl 3)δ9.17(s,1H),8.54(s,1H),8.00(d,J=5.7Hz,1H),7.94(s,1H),7.45(d,J=7.5Hz,1H),7.42(d,J=7.6Hz,1H),6.08(s,1H),4.76(d,J=48.3Hz,1H),4.46–4.32(m,1H),4.12(d,J=12.0Hz,1H),3.84–3.72(m,3H),3.70–3.51(m,6H),3.50(s,3H),2.95(s,3H),2.43(dd,J=7.1,2.8Hz,2H),2.00(qd,J=8.6,4.0Hz,1H),1.79(dd,J=13.1,6.2Hz,1H),1.31(d,J=3.2Hz,3H),1.30(d,J=3.3Hz,3H)。;583.3[M+H] + | |
133 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.43–9.38(m,1H),8.73(s,1H),8.72(s,1H),8.52(s,1H),8.44(d,J=5.8Hz,1H),7.79(s,1H),7.54(d,J=7.6Hz,1H),7.51(d,J=7.5Hz,1H),6.96(d,J=5.9Hz,1H),3.80(dd,J=10.0,6.8Hz,1H),3.73(p,J=6.8Hz,1H),3.66–3.51(m,3H),3.45(p,J=6.6Hz,1H),2.92(s,3H),2.86(tt,J=8.0,4.7Hz,1H),2.48–2.35(m,1H),2.27(ddd,J=14.0,12.7,6.7Hz,1H),1.58–1.52(m,2H),1.48(d,J=6.8Hz,6H),1.25–1.20(m,2H)。;606.3[M+H] + | |
134 | N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.36(s,1H),8.71(s,1H),8.09(d,J=5.7Hz,1H),7.71(s,1H),7.50–7.45(m,2H),6.20(d,J=5.7Hz,1H),4.84(ddt,J=48.2,6.0,2.7Hz,1H),4.58(dt,J=14.0,7.1Hz,1H),4.29(dd,J=13.0,6.7Hz,1H),3.92–3.76(m,2H),3.74–3.53(m,6H),3.52(s,3H),3.44(p,J=6.5Hz,1H),2.91(s,3H),2.46–2.34(m,1H),2.25(ddd,J=14.0,12.7,6.7Hz,1H),2.12–1.98(m,1H),1.87(ddd,J=13.3,7.1,3.7Hz,1H),1.40(d,J=2.9Hz,3H),1.39(d,J=2.8Hz,3H)。;567.3[M+H] + | |
135 | 3-(4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 | 1H NMR(400MHz,CDCl 3)δ8.59(s,1H),8.31(s,1H),8.04(d, J=5.7Hz,1H),7.93(d, J=5.6Hz,1H),7.39(s,1H),6.10(d, J=5.7Hz,1H),5.76(d, J=5.6Hz,1H),4.84–4.72(m,1H),4.62(p, J=6.8Hz,1H),4.40–4.30(m,2H),4.14–4.05(m,2H),3.51(s,3H),2.58(p, J=8.9Hz,1H),2.03(m,1H),1.79(m,1H),1.55(dd, J=6.7,1.3Hz,6H),1.36(s,6H)。;555.3 [M+H] + | |
136 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基-3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.34(s,1H),8.18(d, J=2.2Hz,1H),8.04(d, J=5.6Hz,1H),7.75(dd, J=8.6,2.2Hz,1H),7.68(s,1H),7.45(s,1H),7.05(d, J=8.7Hz,1H),6.09(d, J=5.7Hz,1H),4.88–4.70(m,1H),4.65(p, J=6.7Hz,1H),4.36(dt, J=13.7,6.9Hz,1H),4.04(m,5H),3.77(m,1H),3.72–3.62(m,1H),3.52(s,3H),3.24(s,3H),2.04(m,1H),1.85–1.75(m,1H),1.57(dd, J=6.7,1.4Hz,6H)。;593.3 [M+H] + | |
137 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.63(s,1H),8.43(d, J=5.8Hz,1H),8.32(s,1H),8.04(d, J=5.7Hz,1H),7.48(s,1H),6.84(d, J=5.8Hz,1H),6.08(d, J=5.7Hz,1H),4.88-4.71(m,1H),4.65(p, J=6.7Hz,1H),4.36(dt, J=13.7,6.8Hz,1H),3.99(m,5H),3.78(m,1H),3.73–3.62(m,1H),3.52(s,3H),2.04(m,1H),1.86–1.75(m,1H),1.57(d, J=6.7,6H)。;516.3 [M+H] + | |
138 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.56(s,1H),8.31(s,1H),8.04(d, J=5.7Hz,1H),7.34(s,1H),6.09(d, J=5.7Hz,1H),4.84–4.72(m,1H),4.61(p, J=6.7Hz,1H),4.41–4.29(m,1H),4.00(m,2H),3.78(m,3H),3.62(m,3H),3.51(s,3H),2.88(s,3H),2.06–1.95(m,2H),1.85–1.71(m,1H),1.53(dd, J=6.7,1.2Hz,6H),1.33–1.16(m,4H)。;568.3 [M+H] + | |
139 | 4-(3-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-5-異丙基異喹啉-8-基)丁-3-炔-1-醇 | 1H NMR(400MHz,CDCl 3)δ9.41(s,1H),8.68(s,1H),8.07(d,J=5.6Hz,1H),7.60(s,1H),7.49(d,J=7.5Hz,1H),7.46(d,J=7.5Hz,1H),6.16(d,J=5.6Hz,1H),4.83(ddt,J=48.1,6.1,2.7Hz,1H),4.54(dt,J=14.0,7.2Hz,1H),4.26(d,J=14.3Hz,1H),3.93(t,J=6.3Hz,2H),3.89–3.76(m,1H),3.74–3.56(m,3H),3.52(s,3H),2.85(t,J=6.3Hz,2H),2.18(s,1H),2.05(dtt,J=12.1,8.0,3.6Hz,1H),1.85(ddt,J=13.6,7.1,3.7Hz,1H),1.39(d,J=2.6Hz,3H),1.38(d,J=2.6Hz,3H)。;464.3[M+H] + | |
140 | 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-N-(2-(4-甲氧基吡啶-3-基)嘧啶-4-基)-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.97(s,1H),8.72(d,J=1.1Hz,1H),8.60(d,J=5.8Hz,1H),8.56(d,J=5.8Hz,1H),8.31(s,1H),8.15(s,1H),6.99(s,1H),6.98(s,1H),4.71(hept,J=6.7Hz,1H),3.96(s,3H),3.38–3.30(m,2H),2.97(s,3H),2.15–2.07(m,2H),1.58(s,3H),1.57(s,3H),1.45(s,6H)。;534.3[M+H] + | |
141 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.40(s,1H),8.78(s,1H),8.73(s,1H),8.53(s,1H),8.44(d,J=5.9Hz,1H),8.07(s,1H),7.56(d,J=1.3Hz,2H),6.96(d,J=5.8Hz,1H),4.28(dd,J=8.5,7.6Hz,2H),4.19–4.14(m,2H),3.83–3.70(m,2H),2.95(s,3H),2.86(tt,J=7.9,4.7Hz,1H),1.56–1.54(m,2H),1.49(d,J=6.8Hz,6H),1.24–1.22(m,2H)。;592.3[M+H] + | |
142 | N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 | 1H NMR(400MHz,CDCl 3)δ9.37(s,1H),8.73(s,1H),8.08(d,J=5.6Hz,1H),7.79(s,1H),7.52(d,J=7.5Hz,1H),7.49(d,J=7.6Hz,1H),6.19(d,J=5.6Hz,1H),4.84(ddt,J=48.2,6.0,2.7Hz,1H),4.58(dt,J=14.0,7.1Hz,1H),4.33–4.29(m,1H),4.27(t,J=8.0Hz,2H),4.14(t,J=7.3Hz,2H),3.92–3.74(m,2H),3.72–3.58(m,3H),3.52(s,3H),2.94(s,3H),2.10–2.04(m,1H),1.86(ddt,J=13.8,7.2,3.8Hz,1H),1.41(d,J=2.8Hz,3H),1.39(d,J=2.8Hz,3H)。;553.3[M+H] + | |
143 | 3-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 | 1H NMR(400MHz,CDCl 3)δ8.88(d,J=1.1Hz,1H),8.70(s,1H),8.47(s,1H),8.45–8.40(m,2H),7.89(s,1H),6.80(d,J=5.8Hz,1H),4.85(hept,J=6.6Hz,1H),4.43–4.32(m,2H),4.20–4.09(m,2H),2.85(tt,J=7.9,4.6Hz,1H),2.64(p,J=9.1Hz,1H),1.68(d,J=6.7Hz,6H),1.59–1.50(m,2H),1.42(s,6H),1.27–1.21(m,2H)。;595.3[M+H] + | |
144 | 3-(4-(6-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 | 1H NMR(400MHz,CDCl 3)δ8.81(d,J=1.1Hz,1H),8.33(d,J=1.2Hz,1H),8.07(d,J=5.6Hz,1H),7.77(s,1H),6.09(d,J=5.6Hz,1H),4.90–4.71(m,2H),4.47–4.31(m,3H),4.18–4.08(m,3H),3.95(dd,J=21.6,13.6Hz,1H),3.76–3.60(m,2H),3.52(s,3H),2.63(p,J=9.1Hz,1H),2.11–1.97(m,1H),1.86–1.78(m,1H),1.61(d,J=6.7Hz,6H),1.41(s,6H)。;556.4[M+H] + | |
145 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.77(d,J=1.1Hz,1H),8.70(s,1H),8.47(s,1H),8.45–8.41(m,2H),7.73(s,1H),6.77(d,J=5.9Hz,1H),4.83(hept,J=6.4Hz,1H),3.84(d,J=9.3Hz,1H),3.65(d,J=9.6Hz,1H),3.54(d,J=9.3Hz,1H),3.49(dd,J=9.6,3.8Hz,1H),2.89(s,3H),2.88–2.80(m,1H),2.14–2.05(m,1H),1.67(d,J=6.7Hz,6H),1.55(qd,J=5.5,4.7,2.4Hz,2H),1.40(dd,J=8.1,5.3Hz,1H),1.27–1.22(m,3H)。;608.3[M+H] + | |
146 | N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.72(d,J=1.1Hz,1H),8.33(d,J=1.2Hz,1H),8.08(d,J=5.6Hz,1H),7.62(s,1H),6.07(d,J=5.6Hz,1H),4.90–4.70(m,2H),4.42(dt,J=13.6,6.9Hz,1H),4.14–4.06(m,1H),3.94(dd,J=21.3,13.3Hz,1H),3.83(d,J=9.3Hz,1H),3.77–3.65(m,2H),3.64(d,J=9.6Hz,1H),3.55–3.52(m,1H),3.51(s,3H),3.48(dd,J=9.6,3.8Hz,1H),2.88(s,3H),2.13–2.05(m,1H),2.04–1.98(m,1H),1.81(ddt,J=16.5,8.5,4.2Hz,1H),1.60(d,J=6.7Hz,6H),1.39(dd,J=8.1,5.3Hz,1H),1.25(d,J=5.0Hz,1H)。;569.3[M+H] + | |
147 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((5-((甲基磺醯基)甲基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ10.35(s,1H),8.79(d, J=2.1Hz,1H),8.76(s,1H),8.71(s,1H),8.56(d, J=2.1Hz,2H),8.48(s,1H),8.40(d, J=5.9Hz,1H),8.10(s,1H),8.01(t, J=2.2Hz,1H),4.62(s,2H),2.68–2.65(m,2H),2.34–2.32(m,2H),1.58(s,3H),1.56(s,6H),1.23(s,4H)。;617.3[M+H] + | |
148 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((5-((甲基磺醯基)甲基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,DMSO- d 6)δ9.89(s,1H),8.78(d, J=2.0Hz,1H),8.70(s,1H),8.56(d, J=2.1Hz,1H),8.39(s,1H),8.05(s,1H),8.00(t, J=2.1Hz,1H),7.97(d, J=5.7Hz,1H),6.39(d, J=5.7Hz,1H),4.94(d, J=49.0Hz,1H),4.66(q, J=6.8Hz,2H),4.62(s,2H),4.40(d, J=13.4Hz,1H),3.54(ddd, J=46.3,27.8,11.8Hz,4H),3.01(s,3H),1.85–1.77(m,2H),1.74(d, J=10.9Hz,1H),1.62(s,1H),1.53(dd, J=6.7,4.8Hz,7H)。;578.3[M+H] + | |
149 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((5-(甲基磺醯基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ9.04(m,1H),9.00(m,1H),8.73(s,1H),8.69(s,1H),8.51(s,1H),8.48(s,1H),8.40(d, J=5.9Hz,1H),8.34(m,1H),7.59(s,1H),6.80(d, J=5.9Hz,1H),4.80–4.68(m,1H),3.16(s,3H),2.84(td, J=8.2,4.2Hz,1H),1.67(d, J=6.7Hz,6H),1.56–1.52(m,2H),1.25(s,2H)。;603.3 [M+H] + | |
150 | N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-2-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.57(s,1H),8.47(s,1H),8.39(d, J=5.9Hz,1H),8.29(s,1H),7.40(s,1H),6.82(d, J=5.9Hz,1H),5.10(s,1H),4.70(p, J=6.7Hz,1H),3.71(d, J=11.7Hz,1H),3.20–3.11(m,1H),2.97(s,3H),2.89–2.78(m,1H),2.07–1.66(m,4H),1.63(d, J=6.7Hz,6H),1.53(m,2H),1.29–1.19(m,2H)。;609.3 [M+H] + | |
151 | N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((5-(甲基磺醯基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 | 1H NMR(400MHz,CDCl 3)δ9.03(s,1H),8.99(s,1H),8.67(s,1H),8.40(s,1H),8.33(s,1H),8.05(d, J=5.7Hz,1H),7.78(s,1H),7.53(s,1H),6.10(d, J=5.7Hz,1H),4.85(m,1H),4.73(m,1H),4.67(p, J=6.7Hz,1H),4.40–4.30(m,1H),4.04(m,2H),3.79(m,1H),3.73–3.63(m,1H),3.52(s,3H),3.16(s,3H),2.10–1.96(m,1H),1.86–1.74(m,1H),1.59(dd, J=6.6,1.5Hz,6H)。;564.3 [M+H] + | |
152 | (S)-5-甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(3,4)-吡啶環八烷 | 503.3 [M+H] + | |
153 | (S)-5-甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-1(3,4),2(2,4)-聯吡啶環八烷 | 502.3 [M+H] + | |
154 | (S)-5-甲基-4 5-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 7H-8-氧雜-3-氮雜-4(2,7)-吡咯幷[2,3-d]嘧啶-1(3,4),2(2,4)-聯吡啶環八烷 | 503.3 [M+H] + | |
155 | (S)-5-甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 1H-8-氧雜-3-氮雜-4(6,1)-吡唑幷[4,3-c]吡啶-2(2,4)-嘧啶-1(3,4)-吡啶環八烷 | 504.3 [M+H] + |
<實驗例1>評價EGFR C797S酶抑制活性
將本發明的化合物與純化的人EGFR(d746-750/T790M/C797S)(668-end,SignalChem)酶以及特異性底物一起反應幷通過如下方法評價酶抑制能力。反應緩衝液的組成使用pH7.4的40mM的Tris鹽酸鹽(Tris-HCl)、20mM的MgCl
2、0.5mg/ml的牛血清白蛋白(BSA)、50μM的二硫蘇糖醇(DTT),所有試驗物的反應均在反應緩衝液中進行。用連續稀釋法從10mM的二甲基亞碸儲液(DMSO stock)中分12步驟稀釋化合物,並測定最終濃度爲10μM、3μM、1μM、0.3μM、0.1μM、0.03μM、0.01μM、0.003μM、0.001μM、0.0003μM、0.0001μM、0μM的化合物的酶活性。試驗時,將人EGFR(d746-750/T790M/C797S)(3ng)酶與純化的腺嘌呤核苷三磷酸(ATP)(5μM)、酶底物(0.2μg)在25℃的溫度下反應1小時,然後利用體外ADP-GloTM激酶檢測試劑盒(ADP-GloTM kinase assay)(Promega)確認酶活性。將酶活性反應液與ADP-Glo反應溶液、酶功能檢測液按2:2:1的比例進行反應,然後通過發光法(Luminescence)測定酶活性的抑制程度。以未處理化合物的溶劑對照組的酶活性的發光度爲標準,算出根據各化合物處理濃度的酶活性抑制程度,在此情況下,將抑制50%的酶活性的各化合物的濃度確定爲IC
50(nM)值並利用GraphPad Prism 8.4.3(GraphPad software Inc.,San Diego)算出其值。將其結果總結於下表3中。
表3
(A:IC
50<50nM;B:50nM≤IC
50<500nM;C:500nM≤IC
50<5000nM;D:5000nM≤IC
50)
實施例 化合物 | EGFR DTC Enzyme | 實施例 化合物 | EGFR DTC Enzyme | 實施例 化合物 | EGFR DTC Enzyme | 實施例 化合物 | EGFR DTC Enzyme |
1 | A | 12 | A | 20 | A | 34 | B |
3 | A | 13 | A | 21 | B | 38 | A |
5 | A | 14 | A | 22 | A | 39 | B |
8 | B | 15 | B | 23 | A | 68 | A |
9 | A | 16 | A | 24 | A | ||
10 | B | 17 | A | 25 | A | ||
11 | B | 19 | A | 31 | A |
<實驗例2>評價EGFR C797S過表達Ba/F3細胞增殖抑制活性
爲了評價本發明的化合物對表達EGFR Del19/T790M/C797S突變的Ba/F3細胞增殖的抑制活性,如下進行實驗。
使用含有10%的胎牛血清(FBS)的培養基(RPMI-1640)培養Ba/F3細胞,在用化合物處理前24小時將細胞以3000個細胞/孔(well)接種至白色透明底96孔板(white clear bottom 96 well plate)(Corning)中。將化合物稀釋於二甲基亞碸中(3倍稀釋,總共12個濃度)並以1µl的量注入以使最終濃度爲0.2nM-5µM。用化合物處理細胞後在37℃、CO
2培養箱中反應72小時,並使用Cell Titer-Glo發光細胞活力試劑(Cell Titer-Glo luminescent cell-viability reagent)(Promega)在常溫下保存10分鐘,然後通過利用讀取器(SynergyNeo2,Biotek)測定發光強度來測定活著的細胞。通過與對照組比較的細胞生長率(%)算出結果值。利用GraphPad Prism 8.4.3(GraphPad software Inc.,San Diego)計算GI
50值。將其結果總結於下表4中。
表4
(A:GI
50<500nM;B:500nM≤GI
50<5000nM;C:5000nM≤GI
50)
如上述表3以及表4所示,可知本發明的實施例化合物對包含EGFR C797S突變的酶或細胞系表現出高抑制能力。
實施例 化合物 | Ba/F3(EGFR DTC) | 實施例 化合物 | Ba/F3(EGFR DTC) | 實施例 化合物 | Ba/F3(EGFR DTC) | 實施例 化合物 | Ba/F3(EGFR DTC) |
1 | A | 31 | A | 102 | A | 128 | A |
3 | A | 34 | A | 103 | B | 129 | A |
4 | B | 35 | A | 104 | A | 130 | A |
5 | B | 38 | A | 105 | A | 131 | A |
6 | B | 39 | A | 107 | A | 132 | A |
7 | A | 43 | A | 108 | A | 133 | A |
9 | A | 68 | A | 109 | A | 134 | A |
10 | B | 69 | B | 110 | A | 135 | A |
12 | B | 73 | B | 111 | B | 136 | A |
13 | B | 74 | A | 112 | A | 137 | A |
14 | A | 75 | A | 113 | A | 138 | A |
15 | A | 76 | A | 114 | A | 139 | B |
16 | A | 79 | A | 115 | A | 140 | A |
17 | A | 80 | A | 116 | A | 141 | A |
18 | B | 81 | A | 117 | A | 142 | A |
19 | A | 82 | A | 118 | A | 143 | A |
20 | A | 84 | A | 119 | A | 144 | A |
21 | A | 86 | B | 120 | A | 145 | A |
22 | A | 89 | A | 121 | A | 146 | A |
23 | A | 96 | B | 122 | A | 148 | A |
24 | A | 97 | A | 123 | A | 149 | A |
25 | A | 98 | A | 124 | A | 150 | A |
26 | B | 99 | B | 125 | A | 151 | A |
27 | A | 100 | A | 126 | A | ||
29 | A | 101 | A | 127 | A |
以上,通過優選製備例、實施例以及實驗例詳細說明本發明,但本發明的範圍不限於特定實施例化合物,應根據所附的發明要求保護範圍對其進行解釋。並且,本領域的普通技術人員應理解,在不脫離本發明的範圍的情況下可以進行許多修飾及變更。
Claims (12)
- 一種如下述化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽,其中, 化學式1: 在上述化學式1中, X爲CH或N; 環A爲3-6元雜環烷基或5-6元雜芳基,其中,上述3-6元雜環烷基或5-6元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、-C 1-6烷基-C 3-6環烷基、-C 1-6羥烷基、-OH、-O-C 1-6烷基、=O、-C(=O)-C 1-6烷基、-C(=O)-C 3-6環烷基、-S(=O) 2-C 1-6烷基、-S(=O) 2-C 3-6環烷基或-鹵素取代,上述3-6元雜環烷基環的-CH 2-能夠被-S(=O) 2-取代; 環B爲 或 ; Y 1爲CH或N; Y 2爲CH、C或N; Y 3爲CH、CH 2、C(=O)、N、NH或N(C 1-6烷基); Y 4爲C或N; Y 5以及Y 6分別獨立地爲CH或N; 爲單鍵或雙鍵; L爲-C≡C-或-CR L1=CR L2-; R L1以及R L2分別獨立地爲-H、-C 1-6烷基或-鹵素; Z 1爲-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-O-C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、3-12元環烷基、3-12元雜環烷基、6-12元芳基、5-12元雜芳基或不存在(null),其中,上述3-12元環烷基、3-12元雜環烷基、6-12元芳基或5-12元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-CN、-NO 2、-NH 2、-NH-C 1-6烷基、-N(C 1-6烷基)(C 1-6烷基)、-OH、-O-C 1-6烷基或-鹵素取代,或者Z 1能夠與環A相連成環,其中,上述環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-CN、-NO 2、-NH 2、-NH-C 1-6烷基、-N(C 1-6烷基)(C 1-6烷基)、-OH、-O-C 1-6烷基或-鹵素取代; Z 2爲-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、3-12元環烷基、3-12元雜環烷基、6-12元芳基或5-12元雜芳基, 其中,上述-C 1-6烷基、-C 2-6烯基或-C 2-6炔基的一個以上H能夠被-CN、-NO 2、-NR 1R 2、-OR 3、-C(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-S(=O)(=NH)-C 1-6烷基、-鹵素、3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基取代,在此情況下,上述3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、=O、-S(=O) 2-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基或-鹵素取代,上述3-6元環烷基或3-6元雜環烷基的-CH 2-能夠被-S(=O) 2-取代, 上述3-12元環烷基或3-12元雜環烷基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-CN、-NO 2、-NR 1R 2、-OR 3、-C(=O)-芳基、-S(=O) 2-C 1-6烷基、-S(=O)(=NH)-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基、-C 1-6烷基-S(=O)(=NH)-C 1-6烷基、=O或-鹵素取代, 上述6-12元芳基或5-12元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-CN、-NO 2、-NR 1R 2、-OR 3、-S(=O) 2-C 1-6烷基、-S(=O) 2-C 3-6環烷基、-S(=O)(=NH)-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基或-鹵素取代; R 1以及R 2分別獨立地爲-H、-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-S(=O) 2-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基;以及 R 3爲-H、-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基。
- 如請求項1之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽,其中, X爲CH或N; 環A爲5-6元雜環烷基或5-6元雜芳基,其中,上述5-6元雜環烷基或5-6元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 2-6烯基、-C 1-6烷基-C 3-6環烷基、-C 1-6羥烷基、-OH、-O-C 1-6烷基、=O、-S(=O) 2-C 1-6烷基、-S(=O) 2-C 3-6環烷基或-鹵素取代,上述5-6元雜環烷基環的-CH 2-能夠被-S(=O) 2-取代; 環B爲 或 ; Y 1爲CH或N; Y 2爲C或N; Y 3爲CH、C(=O)、N、NH或N(C 1-6烷基); Y 4爲C或N; Y 5以及Y 6分別獨立地爲CH或N; 爲單鍵或雙鍵; L爲-C≡C-或-CR L1=CR L2-; R L1以及R L2分別獨立地爲-H或-鹵素; Z 1爲-C 1-6烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-O-C 1-6烷基、-C 1-6烷基-O-C 1-6烷基、3-6元環烷基、3-6元雜環烷基或不存在(null),其中,上述3-6元環烷基或3-6元雜環烷基環的一個以上H能夠被-C 1-6烷基、-OH、-O-C 1-6烷基或-鹵素取代,上述Z 1與Y 2或Y 3中的任一個相連,或者Z 1能夠與環A相連成環,其中,上述環的一個以上H能夠被-C 1-6烷基、-OH、-O-C 1-6烷基或-鹵素取代; Z 2爲-C 1-6烷基、-C 2-6烯基、3-6元環烷基、3-6元雜環烷基、苯基或5-10元雜芳基, 其中,上述-C 1-6烷基或-C 2-6烯基的一個以上H能夠被-NR 1R 2、-OR 3、-S(=O) 2-C 1-6烷基、-鹵素、3-6元環烷基、3-6元雜環烷基或苯基取代,在此情況下,上述3-6元環烷基、3-6元雜環烷基或苯基環的一個以上H能夠被-C 1-6烷基、-S(=O) 2-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基取代,上述3-6元環烷基或3-6元雜環烷基的-CH 2-能夠被-S(=O) 2-取代, 上述3-6元環烷基或3-6元雜環烷基環的一個以上H能夠被-C 1-6烷基、-OR 3、-C(=O)-芳基、-S(=O) 2-C 1-6烷基、-S(=O)(=NH)-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基、-C 1-6烷基-S(=O)(=NH)-C 1-6烷基、=O或-鹵素取代, 上述苯基或5-10元雜芳基環的一個以上H能夠被-C 1-6烷基、-NR 1R 2、-OR 3、-S(=O) 2-C 1-6烷基、-S(=O) 2-環烷基、-S(=O)(=NH)-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基或-鹵素取代; R 1以及R 2分別獨立地爲-H、-C 1-6烷基、-C 1-6鹵代烷基、-S(=O) 2-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基;以及 R 3爲-H、-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基。
- 如請求項1之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽,其中, 環A爲選自由 、 、 、 以及 組成的組中的雜環烷基;或選自由 、 、 、 、 以及 組成的組中的雜芳基,其中,上述雜環烷基環的一個以上H能夠被-C 1-6烷基、-OH、-O-C 1-6烷基、=O、-S(=O) 2-C 1-6烷基、-S(=O) 2-環烷基或-鹵素取代,上述雜芳基環的一個以上H能夠被-C 1-6烷基、-C 2-6烯基、-C 1-6羥烷基、-C 1-6烷基-環烷基,-O-C 1-6烷基、-S(=O) 2-C 1-6烷基,或-S(=O) 2-C 3-6環烷基取代。
- 如請求項1之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽,其中, 環B爲 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 或 。
- 如請求項1之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽,其中, 上述如化學式1所示的化合物爲如下述化學式1a所示的化合物, 化學式1a: 在上述化學式1a中, X爲CH或N; 環A爲5-6元雜芳基,其中,上述5-6元雜芳基環的一個以上H能夠被-C 1-3烷基取代; Y 1爲CH或N; Y 2爲CH、C或N; Y 3爲CH、CH 2、C(=O)、N、NH或N(C 1-6烷基); Y 4爲C或N; 爲單鍵或雙鍵; Z 1’爲-(CH 2CH 2)-或-(CH 2CH 2CH 2)-,其中,上述-(CH 2CH 2)-或-(CH 2CH 2CH 2)-的一個以上H能夠被-C 1-3烷基取代; Z 1’’爲-(CH 2)-或-O-; Z 1’’’爲鍵(null)、-(CH 2)-或-(CH 2CH 2)-, L爲-C≡C-或-CR L1=CR L2-; R L1以及R L2分別獨立地爲-H、-C 1-6烷基或-鹵素; Z 2爲-C 1-6烷基、-C 2-6烯基、-C 2-6炔基、3-12元環烷基、3-12元雜環烷基、6-12元芳基或5-12元雜芳基, 其中,上述-C 1-6烷基、-C 2-6烯基或-C 2-6炔基的一個以上H能夠被-CN、-NO 2、-NR 1R 2、-OR 3、-C(=O)-C 1-6烷基、-S(=O) 2-C 1-6烷基、-S(=O)(=NH)-C 1-6烷基、-鹵素、3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基取代,在此情況下,上述3-6元環烷基、3-6元雜環烷基、6-10元芳基或5-10元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、=O、-S(=O) 2-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基或-鹵素取代,上述3-6元環烷基或3-6元雜環烷基的-CH 2-能夠被-S(=O) 2-取代, 上述3-12元環烷基或3-12元雜環烷基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-CN、-NO 2、-NR 1R 2、-OR 3、-C(=O)-芳基、-S(=O) 2-C 1-6烷基、-S(=O)(=NH)-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基、-C 1-6烷基-S(=O)(=NH)-C 1-6烷基、=O或-鹵素取代, 上述6-12元芳基或5-12元雜芳基環的一個以上H能夠被-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-CN、-NO 2、-NR 1R 2、-OR 3、-S(=O) 2-C 1-6烷基、-S(=O) 2-C 3-6環烷基、-S(=O)(=NH)-C 1-6烷基、-C 1-6烷基-S(=O) 2-C 1-6烷基或-鹵素取代; R 1以及R 2分別獨立地爲-H、-C 1-6烷基、-C 1-6氨烷基、-C 1-6羥烷基、-C 1-6鹵代烷基、-S(=O) 2-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基;以及 R 3爲-H、-C 1-6烷基或-C 1-6烷基-S(=O) 2-C 1-6烷基。
- 如請求項1之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽,其中, 上述如化學式1所示的化合物選自由下述化合物組成的組中:
1 4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 2 4-(2-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-5-基)-2-甲基丁-3-炔-2-醇 3 4-(2-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-基)氨基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-5-基)-2-甲基丁-3-炔-2-醇 4 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基丁-3-烯-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 5 4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 6 3-((6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)苯酚 7 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-3-((3-氟苯基)乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 8 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(吡啶-4-基乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 9 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 10 4-(6-((2-(1-(環丙基甲基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 11 1-((6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)環己烷-1-醇 12 5-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)戊-4-炔-1-醇 13 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(4-甲基呱嗪-1-基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 14 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-((甲基磺醯基)甲氧基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 15 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-苯基丁-3-炔-2-醇 16 (E)-4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-烯-2-醇 17 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 18 N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 19 (E)-N-(3-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)烯丙基)-N-甲基甲磺醯胺 20 (E)-N-(3-(2-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-基)氨基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-5-基)烯丙基)-N-甲基甲磺醯胺 21 1,1,1-三氟-4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 22 N-(4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)甲磺醯胺 23 N-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)甲磺醯胺 24 N-((E)-3-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)烯丙基)-N-甲基甲磺醯胺 25 N-(4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)-N-甲基甲磺醯胺 26 3-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 27 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 28 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 29 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 30 N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((1-((甲基磺醯基)甲基)環丙基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 31 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-((甲基磺醯基)甲基)環丙基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 32 N-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)-N-甲基甲磺醯胺 33 N-(3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)-4-氟苯基)甲磺醯胺 34 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 35 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(咪唑幷[1,2-b]噠嗪-3-基乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 36 (E)-4-(3-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)烯丙基)硫代嗎啉1,1-二氧化物 37 (E)-5-(2-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙烯基)吡咯烷-2-酮 38 (E)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(2-(1-(甲基磺醯基)呱啶-3-基)乙烯基)-1H-吡咯幷[3,2-c]吡啶-6-胺 39 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 40 8-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 41 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-5-異丙基異喹啉-3-胺 42 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 43 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基異喹啉-3-胺 44 4-(1-環戊基-6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 45 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-(四氫呋喃-3-基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 46 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-(吡咯烷-3-基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 47 4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-(1,1,1-三氟丙烷-2-基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 48 6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-3-(3-羥基-3-甲基丁-1-炔-1-基)-1-異丙基-1,3-二氫-2H-咪唑幷[4,5-c]吡啶-2-酮 49 4-(5-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-3-異丙氧基-1H-吡唑幷[3,4-c]吡啶-1-基)-2-甲基丁-3-炔-2-醇 50 (S)-4-(1 1,5-二甲基-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷-4 3-基)-2-甲基丁-3-炔-2-醇 51 (S)-N-(4-(1 1,5-二甲基-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷-4 3-基)-2-甲基丁-3-炔-2-基)甲磺醯胺 52 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-((2,2,2-三氟乙基)氨基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 53 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-((2-(甲基磺醯基)乙基)氨基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 54 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(3-((甲基磺醯基)甲基)氮雜環丁烷-1-基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 55 N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(3-((甲基磺醯基)甲基)氮雜環丁烷-1-基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 56 4-(1-異丙基-6-((2-嗎啉幷嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 57 4-(1-異丙基-6-((2-(4-甲基呱嗪-1-基)嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 58 4-(4-((3-(3-羥基-3-甲基丁-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)硫代嗎啉1,1-二氧化物 59 4-(1-異丙基-6-((2-(4-(甲基磺醯基)呱嗪-1-基)嘧啶-4-基)氨基)-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 60 4-(4-((3-(3-羥基-3-甲基丁-1-炔-1-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)呱嗪-2-酮 61 4-(6-((2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)吡啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 62 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-2,7-萘啶-3-胺 63 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基-2,7-萘啶-3-胺 64 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-2,6-萘啶-3-胺 65 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基-2,6-萘啶-3-胺 66 4-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基吡啶幷[3,4-d]噠嗪-7-胺 67 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-4-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基吡啶幷[3,4-d]噠嗪-7-胺 68 (S)-1 1,5-二甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(4,5)-吡唑環八烷 69 (S)-1 1,5-二甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1 1H,4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-吡啶-1(4,5)-吡唑環八烷 70 (S)-1 1,5-二甲基-4 5-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1 1H,4 7H-8-氧雜-3-氮雜-4(2,7)-吡咯幷[2,3-d]嘧啶-2(2,4)-吡啶-1(4,5)-吡唑環八烷 71 N-(2-(4-(環丙基磺醯基)-1H-咪唑-1-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 72 N-(2-(2-(環丙基磺醯基)-1H-咪唑-5-基)嘧啶-4-基)-1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 73 N-(2-((3R,4S)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-3-(咪唑幷[1,2-b]噠嗪-3-基乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 74 1-環戊基-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 75 1-環己基-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 76 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 77 4-(6-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-醇 78 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 79 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 80 3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)-1-(甲基磺醯基)吡咯烷-3-醇 81 (R)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 82 (S)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 83 3-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)噻唑烷1,1-二氧化物 84 3-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 85 N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)異喹啉-3-胺 86 1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-N-(2-(4-乙烯基-1H-咪唑-1-基)嘧啶-4-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 87 (S)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 88 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(((S)-3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 89 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 90 8-(3,3-二甲基-4-(甲基磺醯基)丁-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 91 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-((甲基磺醯基)甲基)氮雜環丁烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 92 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-((甲基磺醯基)甲基)氮雜環丁烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 93 (S)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-((甲基磺醯基)甲基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 94 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-(((S)-3-甲基-1-((甲基磺醯基)甲基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 95 ((3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)吡咯烷-1-基)甲基)(亞氨基)(甲基)-λ 6-磺酮 96 2-(4-(4-((1-異丙基-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-基)氨基)嘧啶-2-基)-1H-吡唑-1-基)乙烷-1-醇 97 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 98 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-((甲基磺醯基)甲基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 99 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-((甲基磺醯基)甲基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 100 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲氧基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 101 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 102 1-環丁基-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 103 N-(3-((6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)苯基)甲磺醯胺 104 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((2-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 105 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 106 N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((1-((甲基磺醯基)甲基)環丙基)乙炔基)異喹啉-3-胺 107 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((1-((甲基磺醯基)甲基)環丙基)乙炔基)異喹啉-3-胺 108 (R)-(3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)呱啶-1-基)(苯基)甲烷酮 109 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 110 (Z)-3-(1-氯-2-(3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙烯基)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 111 8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基異喹啉-3-胺 112 N-(2-(1H-吡唑-4-基)嘧啶-4-基)-8-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-5-異丙基異喹啉-3-胺 113 順式-3-氟-1-(4-((5-異丙基-8-((1-((甲基磺醯基)甲基)環丙基)乙炔基)異喹啉-3-基)氨基)嘧啶-2-基)呱啶-4-醇 114 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 115 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((3-甲基-1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 116 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 117 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-2-異丙基-3-((3-甲基-1-(甲基磺醯基)吡咯烷-3-基)乙炔基)-2H-吡唑幷[4,3-c]吡啶-6-胺 118 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-((甲基磺醯基)甲基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 119 (S)-(3-((6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)乙炔基)呱啶-1-基)(苯基)甲烷酮 120 (R)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-(呱啶-3-基乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 121 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)吡啶-4-基)-5-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-7-異丙基-7H-吡咯幷[2,3-d]嘧啶-2-胺 122 3-((1-(環丙基磺醯基)-1H-吡唑-4-基)乙炔基)-N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 123 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-6-胺 124 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-6-胺 125 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((1-((甲基磺醯基)甲基)環丙基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 126 5-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-7-異丙基-N-(4’-甲氧基-[2,3’-聯吡啶]-4-基)-7H-吡咯幷[2,3-d]嘧啶-2-胺 127 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((2-甲氧基-5-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 128 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-3-((4-氟-3-(甲基磺醯基)苯基)乙炔基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-6-胺 129 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基-3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 130 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 131 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-N-(2-(4-甲氧基吡啶-3-基)嘧啶-4-基)-1H-吡咯幷[3,2-c]吡啶-6-胺 132 3-((3-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-5-異丙基異喹啉-8-基)乙炔基)-1-(甲基磺醯基)吡咯烷-3-醇 133 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)異喹啉-3-胺 134 N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)吡咯烷-3-基)乙炔基)異喹啉-3-胺 135 3-(4-(6-((2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡咯幷[3,2-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 136 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基-3-(甲基磺醯基)苯基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 137 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((4-甲氧基吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 138 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 139 4-(3-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-5-異丙基異喹啉-8-基)丁-3-炔-1-醇 140 3-(3,3-二甲基-5-(甲基磺醯基)戊-1-炔-1-基)-1-異丙基-N-(2-(4-甲氧基吡啶-3-基)嘧啶-4-基)-1H-吡唑幷[4,3-c]吡啶-6-胺 141 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 142 N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-5-異丙基-8-((1-(甲基磺醯基)氮雜環丁烷-3-基)乙炔基)異喹啉-3-胺 143 3-(4-(6-((2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 144 3-(4-(6-((2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)氨基)-1-異丙基-1H-吡唑幷[4,3-c]吡啶-3-基)-2-甲基丁-3-炔-2-基)硫乙烷1,1-二氧化物 145 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 146 N-(2-((3S,4R)-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((3-(甲基磺醯基)-3-氮雜雙環[3.1.0]己烷-1-基)乙炔基)-1H-吡唑幷[4,3-c]吡啶-6-胺 147 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((5-((甲基磺醯基)甲基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 148 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((5-((甲基磺醯基)甲基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 149 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((5-(甲基磺醯基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 150 N-(2-(1-(環丙基磺醯基)-1H-吡唑-4-基)嘧啶-4-基)-1-異丙基-3-((1-(甲基磺醯基)呱啶-2-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 151 N-(2-(順式-3-氟-4-甲氧基呱啶-1-基)嘧啶-4-基)-1-異丙基-3-((5-(甲基磺醯基)吡啶-3-基)乙炔基)-1H-吡咯幷[3,2-c]吡啶-6-胺 152 (S)-5-甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-2(2,4)-嘧啶-1(3,4)-吡啶環八烷 153 (S)-5-甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 1H-8-氧雜-3-氮雜-4(6,1)-吡咯幷[3,2-c]吡啶-1(3,4),2(2,4)-聯吡啶環八烷 154 (S)-5-甲基-4 5-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 7H-8-氧雜-3-氮雜-4(2,7)-吡咯幷[2,3-d]嘧啶-1(3,4),2(2,4)-聯吡啶環八烷 155 (S)-5-甲基-4 3-(3-甲基-3-(甲基磺醯基)丁-1-炔-1-基)-4 1H-8-氧雜-3-氮雜-4(6,1)-吡唑幷[4,3-c]吡啶-2(2,4)-嘧啶-1(3,4)-吡啶環八烷 - 一種藥物組合物,其中,包含如請求項1至6中任一項之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽以及藥學上可接受的添加劑。
- 一種用於預防或治療癌症的藥物組合物,其中,包含如請求項1至6中任一項之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽作爲有效成分。
- 如請求項8之藥物組合物,其中,抑制EGFR。
- 如請求項9之藥物組合物,其中,抑制選自由EGFR Del19/C797S、EGFR L858R/C797S、EGFR Del19/T790M/C797S以及EGFR L858R/T790M/C797S組成的組中的一種以上。
- 如請求項8之藥物組合物,其中,上述癌症爲選自由假性粘液瘤、肝內膽管癌、肝胚細胞瘤、肝癌、甲狀腺癌、結腸癌、睾丸癌、骨髓增生異常綜合征、膠質母細胞瘤、口腔癌、唇癌、蕈樣真菌病、急性骨髓性白血病、急性淋巴細胞性白血病、基底細胞癌、卵巢上皮癌、卵巢生殖細胞腫瘤、男性乳腺癌、腦癌、垂體腺瘤、多發性骨髓瘤、膽囊癌、膽道癌、大腸癌、慢性髓細胞白血病、慢性淋巴細胞性白血病、視網膜母細胞瘤、脈絡膜黑素瘤、法特壺腹癌、膀胱癌、腹膜癌、甲狀旁腺癌、腎上腺腫瘤、鼻腔副鼻竇癌、非小細胞肺癌、舌癌、星形細胞瘤、小細胞肺癌、小兒腦癌、小兒淋巴瘤、小兒白血病、小腸癌、腦膜瘤、食道癌、神經膠質瘤、腎盂癌、腎癌、心臟癌、十二指腸癌、惡性軟組織癌、惡性骨癌、惡性淋巴瘤、惡性間皮瘤、惡性黑色素瘤、眼癌、外陰癌、輸尿管癌、尿道癌、原發部位不明癌、胃淋巴瘤、胃癌、胃類癌、胃腸道間質瘤、腎母細胞癌、乳腺癌、肉瘤、陰莖癌、咽癌、妊娠絨毛膜癌、宮頸癌、子宮內膜癌、子宮肉瘤、前列腺癌、轉移性骨癌、轉移性腦癌、縱隔腫瘤、直腸癌、直腸類癌、陰道癌、脊髓癌、前庭神經鞘瘤、胰腺癌、唾液腺癌、卡波西肉瘤、佩吉特病、扁桃體癌、鱗狀細胞癌、肺腺癌、肺癌、肺鱗狀細胞癌、皮膚癌、肛門癌、橫紋肌肉瘤、喉癌、胸膜癌、血癌以及胸腺癌組成的組中的一種以上。
- 一種如請求項1至6中任一項之如化學式1所示的化合物、其立體異構體或其藥學上可接受的鹽在製備用於治療或預防EGFR相關疾病的藥劑中的用途。
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