TW202317105A - 作為egfr抑制劑之含六員雜芳基之胺基吡啶化合物 - Google Patents
作為egfr抑制劑之含六員雜芳基之胺基吡啶化合物 Download PDFInfo
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- TW202317105A TW202317105A TW111131848A TW111131848A TW202317105A TW 202317105 A TW202317105 A TW 202317105A TW 111131848 A TW111131848 A TW 111131848A TW 111131848 A TW111131848 A TW 111131848A TW 202317105 A TW202317105 A TW 202317105A
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- Taiwan
- Prior art keywords
- amino
- pyrimidin
- pyrazol
- bipyridyl
- cyclopropylsulfonyl
- Prior art date
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- -1 aminopyridine compounds Chemical class 0.000 title claims abstract description 667
- 125000001072 heteroaryl group Chemical group 0.000 title claims abstract description 29
- 229940121647 egfr inhibitor Drugs 0.000 title description 5
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims abstract 21
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims abstract 21
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims abstract 21
- VEKIYFGCEAJDDT-UHFFFAOYSA-N 2-pyridin-3-ylpyridine Chemical group N1=CC=CC=C1C1=CC=CN=C1 VEKIYFGCEAJDDT-UHFFFAOYSA-N 0.000 claims description 952
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 613
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- 150000001875 compounds Chemical class 0.000 claims description 506
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- 102200048955 rs121434569 Human genes 0.000 claims description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 35
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Abstract
本發明提供新穎含六員雜芳基之胺基吡啶化合物及其藥學上可接受之組成物,以針對特定之EGFR突變形式展現抑制活性。
Description
本發明係關於新穎性胺基吡啶化合物及其藥學上可接受之組成物,其可針對特定之EGFR突變形式展現抑制活性。
表皮生長因子受體(EGFR)突變陽性非小細胞肺癌(NSCLC)為肺癌之一種獨特的亞型。人類EGFR為屬於ErbB家族之膜結合受體酪胺酸激酶。其活化經由例如RAS/RAF/MEK/ERK/MAPK及PI3K/PTEN/Akt/mTOR等若干傳訊路徑導致下游效應(參見「Chen et al., 2020」)。EGFR傳訊路徑調節包含增殖、遷移、分化、凋亡在內之重要事件以及負責管理發育過程中細胞間通訊之事件(參見「Wee et al., 2017」、「Huang et al., 2015」、「Yewale et al., 2013」)。
約10%至50%之NSCLC患者具有EGFR活化性突變,例如外顯子19缺失(Del19)中之剪接缺失突變或外顯子21(L858R)中之錯義突變。(參見「Yang et al., 2018」、「Shigematsu et al., 2005」、「Shu et al., 2017」、「Zhang et al., 2010」)。此類患者對於例如吉非替尼(IRESSA
TM)、厄洛替尼(TARCEVA
TM)及阿法替尼(GIOTRIF
TM)等第一代及第二代EGFR酪胺酸激酶抑制劑(TKI)反應良好,因而目前對於出現一般EGFR突變之晚期NSCLC患者常以此等藥物作為初始治療方式(參見「Kashima et al., 2020」、「Mok et al., 2009」、「Zhou et al., 2011」、「Sequist et al., 2013」)。但以吉非替尼或厄洛替尼治療常因守門殘基T790M之突變而終至出現續發抗藥性問題,約半數臨床上產生抗藥性之患者屬於此類,此突變導致雙突變體L858R/T790M及Del19/T790M之產生。
為克服上述抗藥性,多種第三代EGFR-TKI已在開發之中。目前在第三代EGFR-TKI方面,奧希替尼已為多國主管當局核准而可用於治療在第一代或第二代EGFR-TKI作用下有所進展之T790M陽性患者(參見「Leonetti et al., 2019」、「Soria et al., 2018」)。
奧希替尼可有效抑制EGFR突變及T790M抵抗性突變,但在NSCLC患者身上卻會出現無效結合及C797S後續抗藥性等問題(參見「Arulananda et al., 2017」)。關於以第三代EGFR-TKI治療肺癌患者後出現續發抗藥性突變已有相關報導。10%至30%上述患者使用第三代EGFR TKI後常出現C797S突變。(參見「Ramalingam et al., 2018」、「Thress et al., 2015」、「Oxnard et al., 2018」、「Starrett et al., 2020」、「Mehlman et al., 2019」、「Rangachari et al., 2019」、「Zhou et al., 2019」)。由EGFR三突變(Del19/T790M/C797S及L858R/T790M/C797S)所引發之奧希替尼抗藥性已有所聞,故需尋求新一代EGFR-TKI克服抗奧希替尼之EGFR三突變(參見「Kashima et al., 2020」)。
於使用第三代TKI之前線療法中,C797S會在缺乏T790M之情況下發展(參見「Chen et al., 2020」)。奧希替尼亦於2018年獲准為局部晚期或轉移性EGFR突變NSCLC之第一線療法,不受T790M突變狀態影響(參見「Leonetti et al., 2019」)。當以奧希替尼為前線療法時, C797S突變頻率為7%,為在此設定下僅次於MET擴增之次高頻率抗藥機制(參見「Leonetti et al., 2019」、「Ramalingam et al., 2018」)。
當以奧希替尼為前線療法時,最普遍之抗藥機制為C797S突變(7%)及MET 擴增(15%)。其他機制包括HER2擴增、PIK3CA及RAS突變(參見「Ramalingam et al., 2018」)。並且,由於野生型(WT) EGFR抑制會造成例如皮疹、腹瀉等不良反應,且此等WT EGFR衍生毒性會導致劑量限制效應,因此對野生型(WT)EGFR之選擇性亦為EGFR-TKI之重要考量 (參見「Kashima et al., 2020」、「Fakih et al., 2010」、「Takeda et al., 2015」)。
新一代EGFR化合物應具備抑制Del19/T790M/C797S、L858R/T790M/C797S、Del19/C797S及L858R/C797S之能力,且應對照於WT EGFR具有高度選擇性以避免不良反應。近年來已有將突變體選擇性抑制劑BI-4020及BLU-945用為應對EGFR Del19/T790M/C797S突變之可能治療策略(參見「Engelhardt et al., 2019」、「Schalm et al., 2020」)。
然對於此等化合物能否抑制Del19/C797S及L858R/C797S尚未有相關報導。因此,能夠有效應對EGFR三/雙突變之新穎EGFR-TKI實為所冀。
為滿足此一需求,本案發明人特別針對C797S三突變體及雙突變體研發新一代TKI,目的在為繼使用第三代EGFR TKI為第二線或直接療法後發生Del19/T790M/C797S、L858R/T790M/C797S、Del19/C797S及L858R/C797S突變之晚期或轉移性疾病NSCLC患者提供新穎之選擇性(新一代)抑制劑。
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本發明係關於下式(I)所示新穎性胺基吡啶化合物或其藥學上可接受之鹽:
X
1與X
2係各自獨立為-CH=或-N=,附帶條件為X
1與X
2不可同時為-N=,
X
3與X
4係各自獨立為-CH=或-N=,附帶條件為X
3與X
4不可同時為-CH=,
R
1是-A-(R
1A)
m,
A是六至十員雜芳基,
R
1A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
氰基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素、C
1-3烷氧基、C
3-6環烷基、-NHC
1-6烷基、-N(C
1-6烷基)
2及隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C
1-6烷基;
C
3-6環烷基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-3烷氧基:OH、鹵素、-N(C
1-6烷基)
2及隨選或獨立由選自下列群組中之一或多個取代基所取代之三至七員雜環基:鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
1-6烷基:OH、鹵素、-N(C
1-6烷基)
2及隨選由選自下列群組中之一或多個取代基所取代之三至七員雜環基:OH、鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
3-6環烷基:OH、鹵素及隨選由OH所取代之C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NH 三至七員雜環基:OH、鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-N(C
1-6烷基)
2:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-NHC(O)C
1-6烷基:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-NHC(O)C
3-6環烷基:OH及鹵素;
隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至七員雜環基:C
1-6烷基及C
1-6鹵烷基;
隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素、C
1-6烷基、C
1-3烷氧基、C
1-6羥烷基及C
1-6鹵烷基;
隨選由一或多個鹵素所取代之-S(O)
2C
1-6烷基;
隨選由一或多個鹵素所取代之-S(O)
2C
3-6環烷基;
隨選由一或多個鹵素所取代之-S(O)
2N(C
1-6烷基)
2;
隨選由選自下列群組中之一或多個取代基所取代之-S(O)
2-三至七員雜環基:OH、鹵素及C
1-6烷基;
-C(O)OC
1-6烷基;
-C(O)C
1-6烷基;及
隨選由選自下列群組中之一或多個取代基所取代之-C(O)-三至七員雜環基:OH、鹵素及C
1-6烷基,
m為一0至2之整數,
R
2是隨選由選自下列群組中之一或多個取代基所取代之-XC
1-6烷基:OH、鹵素及-N(C
1-6烷基)
2;或-X(CH
2)
n-B-(R
2A)
o,
X是-NH-、-O-、鍵或-C≡C-,
n為一0至2之整數,
o為一0至3之整數,
B係選自包含下列項目之群組:C
3-8環烷基、C
6-10芳基;四至十一員雜環基;及五至六員雜芳基,
R
2A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
NH
2;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、NH
2、鹵素、C
3-6環烷基、C
1-3烷氧基、-NHC
1-6烷基、-NHC
1-6羥烷基、-NHC
1-6鹵烷基、-NHC
3-6環烷基、-N(C
1-6烷基)
2、-N(C
1-6鹵烷基)
2、-NHC(O)C
1-6烷基、-C(O)NHC
1-6烷基、-C(O)N(C
1-6烷基)
2、三至七員雜環基及五至六員雜芳基;
C
3-6環烷基;
隨選由一或多個鹵素所取代之C
1-3烷氧基;
隨選由選自下列群組中之一或多個取代基所取代之-C(O)NHC
1-6烷基:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-C(O)N(C
1-6烷基)
2:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
1-6烷基:OH、鹵素、-NHC
1-6烷基、-N(C
1-6烷基)
2、及隨選由鹵素或-N(C
1-6烷基)
2所取代之三至七員雜環基;
-N(C
1-6烷基)
2,其中C
1-6烷基係隨選由一或多個鹵素所取代;
隨選由C
1-6烷基所取代之-NH-四至七員雜環基;及
四至七員雜環基,
R
3是Y-Q-(R
3A)
p,
Y是-NH-或鍵,
Q係選自包含下列項目之群組:乙炔;四至七員雜環基;C
6-10芳基;及五至十員雜芳基,
p為一0至2之整數,
R
3A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
C
1-3烷氧基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素、C
3-6環烷基、S(O)
2C
1-6烷基及C
1-3烷氧基;
C
2-6烯基;
C
3-6環烷基;
四至七員雜環基;
-C(O)C
1-6烷基;
-C(O)N(C
1-6烷基)
2;
隨選由一或多個鹵素所取代之-S(O)
2C
1-6烷基;
-S(O)
2C
2-6烯基;
隨選由一或多個鹵素所取代之-S(O)
2C
3-6環烷基;
-S(O)
2N(C1
-6烷基)
2;及
隨選由選自下列群組中之一或多個取代基所取代之-S(O)
2-四至七員雜環基:OH及鹵素,且
R
4係選自包含下列項目之群組:H、鹵素及C
1-6烷基。
本發明亦關於用於治療蛋白激酶介導疾病之方法,特別是需治療對象之突變體EGFR介導疾病,所述方法包含向該對象施用治療上有效量之所述式(I)化合物或其藥學上可接受之鹽。
本發明亦關於藥學上可接受之組成物,其係包含所述式(I)化合物或其藥學上可接受之鹽,且可針對對照於野生型EGFR之至少一種突變體EGFR選擇性展現抑制活性。
以下將就本發明詳細說明。
除非另有定義,否則在此使用之所有技術術語均具有熟悉本發明相關技藝人士所通常理解之相同意義。並且,雖然本發明是配合特定方法及樣本進行說明,其類似物或等效物亦應屬於本發明範疇。再者,除非另有聲明,否則本文中所設定之數值應視同包括「大約」之意涵。在此提及之所有公開文件及其他參考文獻均經引用而以其整體併入本文。
在此對本文所用殘基之定義加以說明。除非另有指明,否則各殘基應具有以下定義且其用法與熟悉此技藝人士通常所知者相同。
在此所用之術語「鹵」、「鹵素」或「鹵化物」包括氟、氯、溴及碘。
在此所稱之「烷基」意指脂肪族烴基,線性及分枝烴基均包含在內。例如,C
1-6烷基為具有1至6個碳原子之脂肪族烴,包括甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、叔丁基、戊基、異戊基、新戊基、1-乙丙基、己基、異己基、1,1-二甲丁基、2,2-二甲丁基、3,3-二甲丁基及2-乙丁基。除非另有定義,否則烷基意指C
1-6烷基,較佳者為C
1-4烷基,更佳者為C
1-3烷基。
在此所稱之「烯基」意指包含至少一碳碳雙鍵之脂肪族烴基,線性及分支烴基均包含在內。「烯基」之非限制範例為乙烯基、丙烯基、丁-1-烯基或丁-2-烯基。
在此所稱之「炔基」意指至少一碳碳三鍵之脂肪族烴基,線性及分枝烴基均包含在內。「炔基」之非限制範例為乙炔基、丙炔基、丁-1-炔基或丁-2-炔基。
在此所稱之「鹵烷基」意指以一或多個鹵素原子取代之烷基基團,烷基基團之定義如上。「鹵」意指F、Cl、Br或I,且此術語可與術語「鹵素」相容使用。除非另有定義,否則鹵烷基意指氟甲基、二氟甲基、氯甲基、三氟甲基或2,2,2-三氟乙基。
在此所用之術語「烷氧基」意指-O-烷基或烷基-O-基團,烷基基團之定義如上。其可例如包括甲氧基、乙氧基、正丙氧基、正丁氧基及叔丁氧基。
在此所用之術語「羥基」或「氫氧基」單獨或配合其他術語意指-OH。
在此所用之術語「羥烷基」意指烷基之任何羥基衍生物。所有其一或多個氫原子受羥基基團取代之烷基均屬於術語「羥烷基」之範圍。
在此所稱之「胺基」意指-NH
2。
在此所用之術語「環烷基」意指可經取代或未經取代之環烷基,且例如,C
3-20環烷基代表具有3至20個碳原子之單價飽和烴環系統。環烷基之範例包括但不限於,環丙基、環丁基、環戊基、環己基、環庚基、環辛基等等。較佳者,除非另有定義,否則環烷基可為C
3-8環烷基或C
3-6環烷基。
在此所用之術語「芳基」意指自母芳環系統之單一碳原子去除一個氫原子而得,具有例如6至20個碳原子(C
6-20)之單價芳香烴。芳基可包括具有飽和或部分不飽和環稠合之芳環之雙環基。範例芳基基團可包括衍生自苯之基(苯基)、取代苯基、二苯基、萘基、甲苯基、亞萘基、蒽基、茚基、二氫茚基等等之基團。除非另有定義,否則芳基意指C
6-12芳基,較佳者為C
6-10芳基。
在此所稱之「雜環」意指包含指定數量環原子之芳族飽和或部分不飽和單、雙或多環系統,且包括一或多個選自N、O及S之雜原子為其環成員,其中雜環環係經由一可為C或N之環原子連接至鹼分子。雙環系統可經由1,1-融合(螺旋)、1,2-融合(稠合)或1,>2-融合(橋頭)連接。
在此所稱之「雜芳基」意指衍生自具有1至10個碳環成員之單雜環或多雜環芳族烴且所述碳環成員包含一或多個,較佳為一至三個,選自N、O及S之雜原子之單價或二價取代基。雜芳基之範例包括但不限於噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、異噻唑基、噁唑基、異噁唑基、吡啶基、吡嗪基、嘧啶基、噠嗪基、1,2,4-噁二唑基、l,1,3,4-噁二唑基、1,2,4-噻二唑基、1,3,4-噻二唑基、三唑基、四唑基、三嗪基、吲哚基等等。雙環雜芳基之範例包括吲哚基、苯并噻吩基,苯并呋喃基,苯并咪唑基,苯并噁唑基、苯并異噁唑基、苯并噻唑基、苯并噻二唑基、喹啉基、異喹啉基、呋喃吡啶基及其類似基團,但不以此為限。除非另有定義,所述雜芳基為四至十二員雜芳基,較佳者為四至十員雜芳基,更佳者為四至七員雜芳基。
在此所稱之「雜環烷基」意指具有3至10個碳環成員且所述碳環成員含有一或多個,例如一至四個,選自N、O及S之雜原子之單環、雙環、三環或更多環烷基。此外,本發明之雜環亦可為稠合或橋接雜環烷基。非芳族環之範例包括吖丁啶基、氧雜環丁烷基、四氫噻吩基、四氫呋喃基、吡咯啉基、吡咯啶基、咪唑啉基、咪唑啶基、噁唑啉基、噁唑啶基、噁哌嗪基、噁哌啶基、吡唑啉基、吡唑啶基、噻唑啉基、噻唑啶基、四氫異噻唑基、四氫噁唑基、四氫異噁唑基、哌啶基、哌嗪基、四氫哌喃基、二氫哌喃基、四氫吡啶基、二氫吡啶基、二氫噻喃基、四氫嘧啶基、四氫噠嗪基、二氫哌喃基、四氫哌喃基、四氫噻喃基、四氫吡唑吡啶基、嗎啉基、吲哚啉基、硫代嗎啉基、氮雜基、二氮雜基、氮雜金剛烷基、二金剛烷基等等,但不以此為限。雜環烷基取代基可經由一碳原子或一雜原子附連。雜環烷基基團可經由上述一或多個基團隨選以一或多個適當基團取代。除非另有定義,否則雜環烷基意指四至十二員雜環烷基,較佳者為四至十員雜環烷基,更佳者為四至七員雜環烷基。
本發明提供能夠抑制表皮生長因子受體(EGFR)之新穎化合物、藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物,用以治療由蛋白激酶所介導之疾病與疾患,例如,癌症等細胞增殖性疾病與疾患,關節炎、風濕性關節炎或自體免疫等免疫疾病,感染、心血管疾病及神經退化性疾病與疾患。
本發明亦提供包含至少一式(I)化合物連同其藥學上可接受之載體、稀釋劑或輔藥之藥物組成物。
本發明提供用以控制表皮生長因子受體(EGFR) 突變體活性之組成物及方法。於一態樣中,本發明提供作為EGFR突變體抑制劑之化合物。
在一實施例中,本發明提供下式(I)之化合物、其藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物:
X
1與X
2係各自獨立為-CH=或-N=,附帶條件為X
1與X
2不可同時為-N=,
X
3與 X
4係各自獨立為-CH=或-N=,附帶條件為X
3與X
4不可同時為-CH=,
R
1是-A-(R
1A)
m,
A是六至十員雜芳基,
R
1A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
氰基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素、C
1-3烷氧基、C
3-6環烷基、-NHC
1-6烷基、-N(C
1-6烷基)
2及隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C
1-6烷基;
C
3-6環烷基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-3烷氧基:OH、鹵素、-N(C
1-6烷基)
2及隨選或獨立由選自下列群組中之一或多個取代基所取代之三至七員雜環基:鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
1-6烷基:OH、鹵素、-N(C
1-6烷基)
2及隨選由選自下列群組中之一或多個取代基所取代之三至七員雜環基:OH、鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
3-6環烷基:OH、鹵素及隨選由OH所取代之C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NH 三至七員雜環基:OH、鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-N(C
1-6烷基)
2:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-NHC(O)C
1-6烷基:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-NHC(O)C
3-6環烷基:OH及鹵素;
隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至七員雜環基:C
1-6烷基及C
1-6鹵烷基;
隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素、C
1-6烷基、C
1-3烷氧基、C
1-6羥烷基及C
1-6鹵烷基;
隨選由一或多個鹵素所取代之-S(O)
2C
1-6烷基;
隨選由一或多個鹵素所取代之-S(O)
2C
3-6環烷基;
隨選由一或多個鹵素所取代之-S(O)
2N(C
1-6烷基)
2;
隨選由選自下列群組中之一或多個取代基所取代之-S(O)
2-三至七員雜環基:OH、鹵素及C
1-6烷基;
-C(O)OC
1-6烷基;
-C(O)C
1-6烷基;及
隨選由選自下列群組中之一或多個取代基所取代之-C(O)-三至七員雜環基:OH、鹵素及C
1-6烷基,
m為一0至2之整數,
R
2是隨選由選自下列群組中之一或多個取代基所取代之-XC
1-6烷基:OH、鹵素及-N(C
1-6烷基)
2;或-X(CH
2)
n-B-(R
2A)
o,
X是-NH-、-O-、鍵或-C≡C-,
n為一0至2之整數,
o為一0至3之整數,
B係選自包含下列項目之群組:C
3-8環烷基、C
6-10芳基;四至十一員雜環基;及五至六員雜芳基,
R
2A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
NH
2;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、NH
2、鹵素、C
3-6環烷基、C
1-3烷氧基、-NHC
1-6烷基、-NHC
1-6羥烷基、-NHC
1-6鹵烷基、-NHC
3-6環烷基、-N(C
1-6烷基)
2、-N(C
1-6鹵烷基)
2、-NHC(O)C
1-6烷基、-C(O)NHC
1-6烷基、-C(O)N(C
1-6烷基)
2、三至七員雜環基及五至六員雜芳基;
C
3-6環烷基;
隨選由一或多個鹵素所取代之C
1-3烷氧基;
隨選由選自下列群組中之一或多個取代基所取代之-C(O)NHC
1-6烷基:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-C(O)N(C
1-6烷基)
2:OH及鹵素;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
1-6烷基:OH、鹵素、-NHC
1-6烷基、-N(C
1-6烷基)
2、及隨選由鹵素或-N(C
1-6烷基)
2所取代之三至七員雜環基;
-N(C
1-6烷基)
2,其中C
1-6烷基係隨選由一或多個鹵素所取代;
隨選由C
1-6烷基所取代之-NH-四至七員雜環基;及
四至七員雜環基,
R
3是Y-Q-(R
3A)
p,
Y是-NH-或鍵,
Q係選自包含下列項目之群組:乙炔;四至七員雜環基;C
6-10芳基;及五至十員雜芳基,
p為一0至2之整數,
R
3A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
C
1-3烷氧基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素、C
3-6環烷基、S(O)
2C
1-6烷基及C
1-3烷氧基;
C
2-6烯基;
C
3-6環烷基;
四至七員雜環基;
-C(O)C
1-6烷基;
-C(O)N(C
1-6烷基)
2;
隨選由一或多個鹵素所取代之-S(O)
2C
1-6烷基;
-S(O)
2C
2-6烯基;
隨選由一或多個鹵素所取代之-S(O)
2C
3-6環烷基;
-S(O)
2N(C
1-6烷基)
2;及
隨選由選自下列群組中之一或多個取代基所取代之-S(O)
2-四至七員雜環基:OH及鹵素,且
R
4係選自包含下列項目之群組:H、鹵素及C
1-6烷基。
於特定實施例中,X
1及X
2是-CH=。
於再一特定實施例中,X
3及X
4是-N=。
於特定實施例中,A是吡啶基、嘧啶基、噠嗪基或吡嗪基。
於特定實施例中,R
1A是H;OH;F;Cl;氰基;隨選由選自下列群組之一至三個取代基所取代之C
1-4烷基:OH、F、Cl、C
1-3烷氧基、C
3-6環烷基、-NHC
1-4烷基、-N(C
1-4烷基)
2及隨選由選自下列群組之一至三個取代基所取代之四至六員雜環基:OH、F、Cl及C
1-3烷基;C
3-6環烷基;隨選由一至三個F或Cl所取代之C
1-2烷氧基;隨選由選自下列群組之一至三個取代基所取代之-NHC
1-4烷基:OH、F、Cl、-N(C
1-6烷基)
2及隨選由選自下列群組之一至三個取代基所取代之三至七員雜環基:OH、F、Cl及C
1-6烷基;隨選由選自下列群組之一至三個取代基所取代之-NHC
3-6環烷基:OH、F、Cl及隨選由OH所取代之C
1-6烷基;隨選由選自下列群組之一至三個取代基所取代之-NH 三至七員雜環基:C
1-6烷基;隨選由選自下列群組之一至三個取代基所取代之-N(C
1-6烷基)
2:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-NHC(O)C
1-6烷基:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-NHC(O)C
3-6環烷基:OH、F及Cl;隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至六員雜環基:C
1-6烷基、C
1-6鹵烷基;隨選或獨立由選自下列群組之一至三個取代基所取代之四至六員雜環基:OH、F、Cl、C
1-6烷基、C
1-3烷氧基、C
1-6羥烷基及C
1-6鹵烷基;-S(O)
2C
1-6烷基;-S(O)
2N(C
1-6烷基)
2;隨選由選自下列群組之一至三個取代基所取代之-S(O)
2-三至七員雜環基:C
1-6烷基;-C(O)OC
1-6烷基;-C(O)C
1-6烷基;或隨選由一至三個C
1-6烷基取代之-C(O)-三至七員雜環基。
於再一特定實施例中,R
1A是隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素、C
1-3烷氧基、C
3-6環烷基、-NHC
1-6烷基、-N(C
1-6烷基)
2及隨選由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C
1-6烷基。
在另一特定實施例中,R
1A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
氰基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素、C
1-3烷氧基、-N(C
1-6烷基)
2及隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之C
1-3烷氧基:OH、鹵素、-N(C
1-6烷基)
2及隨選或獨立由選自下列群組中之一或多個取代基所取代之三至七員雜環基:鹵素及C
1-6烷基;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
1-6烷基:OH、鹵素、-N(C
1-6烷基)
2及隨選由一或多個鹵素所取代之三至七員雜環基;
隨選由選自下列群組中之一或多個取代基所取代之-NHC
3-6環烷基:OH、鹵素及隨選由OH所取代之C
1-6烷基;
隨選由一或多個C
1-6烷基所取代之-NH 三至七員雜環基;
-N(C
1-6烷基)
2;
隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至七員雜環基:C
1-6烷基及C
1-6鹵烷基;
隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素、C
1-6烷基及C
1-3烷氧基;
-S(O)
2C
1-6烷基;
-S(O)
2N(C
1-6烷基)
2;
隨選由一或多個C
1-6烷基所取代之-S(O)
2-三至七員雜環基;
-C(O)C
1-6烷基;及
-C(O)-三至七員雜環基隨選由一或多個C
1-6烷基所取代。
於以上R
1A之實施例中,所述三至七員雜環基或四至七員雜環基可獨立選自包含下列項目之群組:吖丁啶基、哌啶基、哌嗪基、嗎啉基、四氫哌喃基、四氫呋喃基、氧雜環丁烷基、2-氧雜-6-氮螺[3.3]庚烷基及吡咯啶基。
於特定實施例中,R
2是-XC
1-6烷基。
於再一特定實施例中,R
2是-X(CH
2)
n-B-(R
2A)
o。
於特定實施例中,X是-NH-或鍵。
於特定實施例中,B是C
3-6環烷基;苯基;具有一至三個選自包含N、O及S之群組之雜原子之四至十員雜環烷基;或具有一至三個選自包含N、O及S之群組之雜原子之五至六員雜芳基。
於再一特定實施例中,B是C
3-6環烷基。
在另一特定實施例中,B是四至十員雜環烷基或五至六員雜芳基具有一至三個選自包含N及O之群組之雜原子。
在另一特定實施例中,B是C
3-8環烷基,哌啶基或氧雜環丁烷基。
於特定實施例中,R
2A是H;F;Cl;OH;NH
2;隨選由選自下列群組中之一或多個取代基所取代之C
1-4烷基:OH、NH
2、F、Cl、C
3-6環烷基、C
1-3烷氧基、-NHC
1-3烷基、-NHC
1-3羥烷基、-NHC
1-3鹵烷基、-NHC
3-6環烷基、-N(C
1-3烷基)
2、-N(C
1-3鹵烷基)
2、-NHC(O)C
1-3烷基、-C(O)NHC
1-3烷基、-C(O)N(C
1-6烷基)
2、三至七員雜環基及具有一至三個選自包含N、O及S之群組之雜原子之五至六員雜芳基;C
3-6環烷基;隨選由一至三個F或Cl所取代之C
1-3烷氧基;隨選由選自下列群組之一至三個取代基所取代之-C(O)NHC
1-3烷基:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-C(O)N(C
1-3烷基)
2:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-NHC
1-3烷基:OH、F、Cl、-NHC
1-3烷基、-N(C
1-3烷基)
2、及具有一至三個選自包含N、O及S之群組之雜原子且隨選由F、Cl或-N(C
1-3烷基)
2所取代之三至六員雜環基;-N(C
1-3烷基)
2,其中C
1-3烷基係隨選由一至三個F或Cl所取代;具有一至三個選自包含N、O及S之群組之雜原子且隨選由C
1-3烷基所取代之-NH-四至六員雜環基;或四至七員雜環基。
於再一特定實施例中,R
2A是OH;鹵素;隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、NH
2、鹵素、C
3-6環烷基、C
1-3烷氧基、-NHC
1-6烷基、-NHC
1-6羥烷基、-NHC
1-6鹵烷基、-NHC
3-6環烷基、-N(C
1-6烷基)
2、-N(C
1-6鹵烷基)
2、-NHC(O)C
1-6烷基、-C(O)NHC
1-6烷基、-C(O)N(C
1-6烷基)
2、三至七員雜環基及具有一至三個選自包含N、O及S之群組之雜原子之五至六員雜芳基;隨選由選自下列群組之一至三個取代基所取代之-C(O)NHC
1-3烷基:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-C(O)N(C
1-3烷基)
2:OH、F及Cl;或隨選由選自下列群組之一至三個取代基所取代之-NHC
1-3烷基:OH、鹵素、-NHC
1-3烷基、-N(C
1-3烷基)
2、及具有一至三個選自包含N、O及S之群組之雜原子且隨選由鹵素或-N(C
1-3烷基)
2所取代之三至七員雜環基。
在另一特定實施例中,R
2A係獨立選自包含下列項目之群組
OH;
鹵素;
隨選由選自下列群組中之一或多個取代基所取代之C
1-6烷基:OH、鹵素及-N(C
1-6烷基)
2;
-C(O)N(C
1-6烷基)
2;及
隨選由一或多個鹵素所取代之-NHC
1-6烷基。
於特定實施例中,Y為鍵。
於特定實施例中,Q是吡唑基、3,4-二氫哌喃并[2,3-b]吡啶基或哌啶基。
於特定實施例中,R
3A係獨立選自包含下列項目之群組:
H;
OH;
鹵素;
C
1-3烷氧基;
隨選由一或多個鹵素所取代之C
1-6烷基;
-S(O)
2C
3-6環烷基;及
-S(O)
2N(C
1-6烷基)
2。
於特定實施例中,R
4是H或鹵素。
代表性式(I)化合物列示如下:
(1) (1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇;
(2)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(3) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(4) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(5) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(6) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(7) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈;
(8) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(9) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(10) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(11) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇;
(12) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(13) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(14) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(15) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(16) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(17) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(18) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮;
(19) (1
s,4
s) -4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(20) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(21) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇;
(22) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇;
(23) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(24) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(25) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(26) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(27) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(28) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(29) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(30) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(31) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(32) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(33) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(34) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-異丙基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(35) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(36)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(37) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇;
(38) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(39) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(40) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(41) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(42) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(43) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(44) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(45) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(46) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(47) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(48) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(49) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇;
(50) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(51) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(52) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(53) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(54) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(55) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(56) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(57) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(58) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(59) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(60) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(61) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(62) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-甲基哌嗪-1-基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(63) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(64) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(65) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((二甲胺基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(66) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(67) (1
s,4
s)-4-((5-(6-(2-氧雜-6-氮螺[3.3]庚烷-6-基)噠嗪-3-基)-2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(68) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(69) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇;
(70) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(71) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(72) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(73)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺;
(74)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺;
(75) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(76) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(77) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(78) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(79)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(二氟甲基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(80) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(81) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(82) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(83) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(84) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(85) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(86) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(87) 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇;
(88) 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇;
(89) 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇;
(90) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(91) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(92) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(93)
N 6'-(2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1s,4s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4',6'-二胺;
(94) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(95) 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(96) 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(97) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(98) 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇;
(99) 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇;
(100) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(101)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(4,4-二氟哌啶-1-基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(102) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(103) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(104) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(105) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(106) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(107) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇;
(108) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(109) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(110) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(111) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(112) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(113) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(114) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(115) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(116) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(117) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(118) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(119) 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇;
(120) 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇;
(121) 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(異丙基胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇;
(122)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)-
N 4-異丙基吡啶-2,4-二胺;
(123)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺;
(124)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺;
(125)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(126)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(127)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)-
N 4-異丙基吡啶-2,4-二胺;
(128) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(129) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(130) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(131)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺;
(132)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(133)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(134) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(三氟甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(135)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(136)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(137)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺;
(138)
N 4'-(3,3-二氟環戊基)-
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(139)
N 4'-(3,3-二氟環丁基)-
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(140)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3,3-二氟環丁基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(141)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(142) (1
s,4
s)-4-((6'-((2-(3,4-二氫-2
H-哌喃并[2,3-b]吡啶-6-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(143)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3,3-二氟環戊基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(144)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺;
(145) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(146) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(147) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(148) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(149) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(150) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(151)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺;
(152)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-2,4-二胺;
(153) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(154) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(155) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇;
(156) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(157)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺;
(158) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(159)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺;
(160) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(161) (3-(((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)甲基)氧雜環丁-3-基)甲醇;
(162) (4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇;
(163) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(164) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺;
(165) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺;
(166) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺;
(167) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(168) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(169) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(170) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(171) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(172) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)
-N,
N-二甲基環己烷-1-碳醯胺;
(173) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(174) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(175) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(176) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(177) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(178) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(179) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(180) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(181) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(182) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(183) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(184) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(185) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(186) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(187) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌啶-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(188) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(189) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(190) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(191) (1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇;
(192) ((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇;
(193) 2-((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)丙-2-醇;
(194) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(195) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(196) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(197)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(198) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(199) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(200) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮;
(201) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮;
(202) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(203) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(204) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(205) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(206) 2-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇;
(207) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(208) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(209) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(210) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(211) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(212) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(213) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(214) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(215) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(216)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(3,3-二氟環丁基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4',6'-三胺;
(217) 2-((1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(218) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(219) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(220) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(221)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺;
(222) ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(223) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(224) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(225) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(226) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(227) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇;
(228) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇;
(229) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(230) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(231) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(232) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(233) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(234) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(235) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(236) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(237)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺;
(238)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺;
(239)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺;
(240)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4,4-二氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺;
(241) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(242) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(243)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(1,1-二氟乙基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(244) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇;
(245) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇;
(246) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(247) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(248)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺;
(249)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-異丙基-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(250) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(251) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(252) 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(253) ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(254)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(255)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4,4-二氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(256)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2-氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(257)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2-氟乙基)哌啶-3-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(258)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2,2-二氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(259) (4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇;
(260) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(261) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(262)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4',6'-二胺;
(263) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(264) 5-(2-(吖丁啶-1-基)乙氧基)
-N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(265) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(266) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(267)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)
-N 4-(4-氟環己基)吡啶-2,4-二胺;
(268)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(4,4-二氟環己基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-2,4-二胺;
(269) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(270)
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-((1
s,4
s)-4-氟環己基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-2,4-二胺;
(271) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(272) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(273)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-6-氟
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(274)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺;
(275)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2,2-二氟乙基)胺基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺;
(276) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(二甲胺基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(277) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(278) (1
s,4
s)-4-((6'-((2-(1-(Cylo丙基磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((1-甲基哌啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(279) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4((2-嗎啉基乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(280) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(281) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(282) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(283) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(284) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮;
(285) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(286) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(287) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(288) 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-基)甲基)吖丁啶-3-醇;
(289) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(290) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(291) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(292) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(293) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(294) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇;
(295) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(296) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺;
(297) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺;
(298) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺;
(299) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(300) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(301) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)-
N,
N-二甲基-1
H-吡唑-1-磺胺;
(302) (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(303) (1
s,4
s)-1-M乙基-4-((6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇;
(304) (1
s,4
s)-1-M乙基-4-((5-((1-甲基哌啶-4-基)氧基)-6'-((2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇;
(305) 2-((1
r,4
r)-4-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(306) ((1
S,3
S)-3-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(307)
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)
-N 6'-(2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-[2,3'-聯吡啶]-4',6'-二胺;
(308)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(309)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(310) (1
s,4
s)-4-((6-氟-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(311) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(312) (1
s,4
s)-4-((5-(3,3-二氟吖丁啶-1-基)-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(313) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(314) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(315) (1
s,4
s)-4-((2-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(316) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(317) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(318) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基)-3,5-二甲基
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(319) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2,3,3-四氟丙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(320) 3,3-二氟-1-(5-氟-4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)哌啶-4-醇;
(321) (1
s,4
s)-4-((6'-((5-氟-2-((3
R,4
S)-3-氟-4-甲氧基哌啶-1-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(322) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(323)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(324)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(325) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(326) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(327) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(328) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(329) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(330) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(331) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(332) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(333) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2,2-三氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(334) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2-二氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(335) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(336) (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;及
(337) (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇。
更具代表性式(I)化合物列示如下:
(2)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(4) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(5) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(6) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(7) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈;
(8) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(9) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(10) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(12) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(15) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(16) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(17) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(19) (1
s,4
s) -4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(21) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇;
(22) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇;
(23) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(24) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(25) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(26) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(27) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(28) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(29) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(30) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(31) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(32) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(33) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(34) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-異丙基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(35) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(36)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(37) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇;
(38) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(39) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(40) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(42) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(43) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(44) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(45) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(46) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(47) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(49) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇;
(50) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(51) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(52) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(53) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(54) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(55) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(56) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(57) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(59) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(60) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(61) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(62) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-甲基哌嗪-1-基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(63) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(64) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(65) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((二甲胺基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(66) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(68) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(69) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇;
(70) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(76) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(77) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(78) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(79)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(二氟甲基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(80) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(81) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(83) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(84) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(85) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(86) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(87) 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇;
(88) 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇;
(89) 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇;
(90) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(91) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(92) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(93)
N 6'-(2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1s,4s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4',6'-二胺;
(94) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(97) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(98) 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇;
(99) 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇;
(102) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(104) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(105) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(107) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇;
(108) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(109) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(110) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(111) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇;
(112) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(113) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(114) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(115) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(116) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(117) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(118) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(119) 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇;
(120) 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇;
(123)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺;
(125)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(126)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺;
(129) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(132)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(141)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(145) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(146) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(147) 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇;
(148) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(149) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(150) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(153) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(154) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(155) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇;
(156) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(158) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(159)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺;
(160) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(163) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(164) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺;
(165) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺;
(166) 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺;
(168) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(169) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(170) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(171) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(172) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)
-N,
N-二甲基環己烷-1-碳醯胺;
(173) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(174) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(175) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(176) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(177) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(178) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(179) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(182) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(183) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(184) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(185) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(188) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(189) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(190) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(191) (1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇;
(192) ((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇;
(194) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(195) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(196) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(197)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(198) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(199) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(200) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮;
(201) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮;
(202) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(203) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(204) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮;
(205) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(206) 2-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇;
(207) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(208) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(209) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(210) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(211) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(212) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(214) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(215) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(216)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(3,3-二氟環丁基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4',6'-三胺;
(217) 2-((1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(218) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(219) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(220) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(221)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺;
(222) ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(223) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(224) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(225) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(226) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(227) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇;
(228) 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇;
(229) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(230) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(231) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(232) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(233) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(234) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇;
(235) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(236) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(237)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺;
(241) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(242) 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇;
(243)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(1,1-二氟乙基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺;
(244) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇;
(250) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(251) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(252) 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇;
(253) ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(254)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(260) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(261) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(262)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4',6'-二胺;
(263) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(269) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(271) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(272) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(274)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺;
(275)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2,2-二氟乙基)胺基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺;
(277) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(280) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(281) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(284) (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮;
(285) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(287) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(289) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(290) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(291) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(292) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(296) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺;
(297) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺;
(298) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺;
(301) 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)-
N,
N-二甲基-1
H-吡唑-1-磺胺;
(302) (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(303) (1
s,4
s)-1-M乙基-4-((6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇;
(304) (1
s,4
s)-1-M乙基-4-((5-((1-甲基哌啶-4-基)氧基)-6'-((2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇;
(308)
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(310) (1
s,4
s)-4-((6-氟-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(316) (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(322) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(323)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺;
(326) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(327) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(328) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(329) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(330) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(331) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(332) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;及
(337) (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇。
更優選代表性式(I)化合物列示如下:
(9) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(38) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(43) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(47) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(63) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(129) ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇;
(150) (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇;
(156) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(168) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(169) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(173) 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇;
(194) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(195) ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇;
(263) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(271) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;
(274)
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺;
(331) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;及
(332) (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇。
以上例示化合物之單立體異構物、鏡像異構物、非鏡像異構物及藥學上可接受之鹽亦屬本發明之範疇。藥學上可接受之鹽可例如取自適當無機及有機酸及鹼。
在可行之情況下,將自由鹼形式之純化化合物與適當有機或無機酸反應後將鹽分離出而形成酸加成鹽。藥學上可接受之酸加成鹽範例包括但不限於,以無機酸或有機酸所形成胺基基團之鹽,所述無機酸例如為鹽酸、氫溴酸、磷酸、硫酸及過氯酸,有機酸例如為醋酸、草酸、順丁烯二酸、酒石酸、檸檬酸、琥珀酸或丙二酸。
將酸形式之純化化合物與適當有機或無機鹼反應後將鹽分離出而形成鹼加成鹽。此類鹽包括但不限於鹼金屬(例如鈉、鋰及鉀)、鹼土金屬(例如鎂及鈣)、銨及N
+(C
1-4烷基)
4鹽。
其他藥學上可接受之鹽包括己二酸鹽、藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯磺酸鹽、苯甲酸鹽、硫酸氫鹽、硼酸鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、檸檬酸鹽、環戊丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、甘油磷酸鹽、甘醇酸鹽、葡萄糖酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、氫溴酸鹽、碘化氫鹽、2-羥基-乙磺酸鹽、乳糖酸鹽、乳酸鹽、月桂酸鹽、十二烷基硫酸鹽、蘋果酸鹽、順丁烯二酸鹽、丙二酸鹽、甲磺酸鹽、2-萘磺酸鹽、煙酸鹽、硝酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、巴莫酸鹽、果凍酸鹽、過硫酸鹽、3-苯基丙酸鹽、磷酸鹽、苦味酸鹽、戊酸鹽、丙酸鹽、水楊酸鹽、硬脂酸鹽、琥珀酸鹽、硫酸鹽、酒石酸鹽、硫氰酸鹽、對甲苯磺酸鹽、十一酸鹽及戊酸鹽。
本發明化合物可經由此技藝中已知方法合成,或利用以下範例1-337所述之方法合成。
藥物組成物、方法及用途
在一實施例中,本發明係關於用以治療需治療對象之蛋白激酶介導疾病之方法,包含向該對象施用治療上有效量之式(I)化合物或其藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物。於特定實施例中,所述蛋白激酶介導疾病為癌症或免疫疾病。
在此所用之術語「癌症」意指可能以不受控的方式增殖且在某些情況下轉移之細胞異常生長。癌症類型包括但不限於實質固態瘤,例如膀胱癌、大腸直腸癌、腦癌、乳癌、卵巢癌、子宮內膜癌、子宮癌、心臟癌、腎臟癌、肺癌、肝癌、胃癌、淋巴瘤、胰臟癌、頭頸癌或其他內分泌器官(甲狀腺癌)、前列腺癌、皮膚(黑色素瘤)或血液系統腫瘤(例如白血病)之腫瘤。在另一實施例中,所述癌症為非小細胞肺癌(NSCLC)。
在一實施例中,本發明之方法係關於癌症之治療,其中所述癌症產生自至少一EGFR 突變。
在一實施例中,所述癌症治療方法尤其適合對本發明化合物或其藥學上可接受之鹽、溶劑合物、酯或前驅藥以外之激酶抑制劑具有抗藥性之患者。在另一實施例中,所述激酶抑制劑為突變EGFR抑制劑。
本發明亦關於在生物樣本中或於患者體內選擇性抑制至少一種對照於野生型EGFR之EGFR突變體之方法,所述方法包含使生物樣本接觸或對患者施用治療上有效量之本發明化合物或其藥學上可接受之鹽。
在一實施例中,所述至少一突變體是至少一個選自下表1之單突變體。
在一實施例中,所述至少一突變體是至少一個選自下表1之雙突變體。
在一實施例中,所述至少一突變體是至少一個選自下表1之三突變體。
[表1]
編號(#) | 突變類型 |
1 | EGFR Del19 (Del E746-A750) |
2 | EGFR L858R |
3 | EGFR Del19/T790M |
4 | EGFR Del19/C797S |
5 | EGFR Del19/C797X (X=G、N) |
6 | EGFR Del19/L792X (X=F、H、P、R、V、Y) |
7 | EGFR Del19/L718X (X=Q、V) |
8 | EGFR L858R/T790M |
9 | EGFR L858R/C797S |
10 | EGFR L858R/C797X (X=G、N) |
11 | EGFR L858R/L792X (X=F、H、P、R、V、Y) |
12 | EGFR L858R/L718X (X=Q、V) |
13 | EGFR Del19/T790M/C797S |
14 | EGFR Del19/T790M/C797X (X=G、N) |
15 | EGFR Del19/T790M/L792X (X=F、H、P、R、V、Y) |
16 | EGFR Del19/T790M/L718X (X=Q、V) |
17 | EGFR L858R/T790M/C797S |
18 | EGFR L858R/T790M/C797X (X=G、N) |
19 | EGFR L858R/T790M/L792X (X=F、H、P、R、V、Y) |
20 | EGFR L858R/T790M/L718X (X=Q、V) |
本發明並關於治療方法及用途,包含單獨施用本發明化合物或其藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物或配合其他治療劑或緩和劑一同施用。
本發明之又一實施例係關於作為藥劑之本發明化合物,更具體而言係用於治療可因抑制突變EGFR蛋白(如表1所示者)活性而改善之疾病,例如癌症。本發明之再一實施例係關於本發明化合物或其藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物在製造藥物上之用途,所述藥物係具有EGFR抑制活性而可用於治療EGFR介導疾病及/或症狀,特別是上述疾病及/或症狀。
術語「治療上有效量」意指施用之化合物可將欲治療疾患之一或多種症狀緩解至一定程度時之用量。於癌症治療方面,治療上有效量意指藥物具有縮減腫瘤大小、抑制(亦即減緩或停止)腫瘤轉移、抑制(亦即減緩或停止)腫瘤生長或腫瘤侵入及/或將一或多種癌症相關徵兆或症狀緩解至一定程度之效果時之用量。
熟悉此技藝人士,如主治醫師,應可運用習知技術並透過觀察類似情況下所得結果而輕易決定治療上有效量。於判定治療上有效量時,主治診斷者考量之劑量決定因素包括但不限於:哺乳動物種類;體型、年齡及總體健康狀態;所涉具體疾病;疾病涉及程度或嚴重程度;個別患者之反應;施用之具體化合物;給藥方式;所施用藥物之生物利用特性;所選劑量給法;共伴藥物治療;及其他相關情況。
除非另有指明,否則在此所用之術語「治療」意指對於此術語所應用之疾病或症狀或其一或多種症候,將進程逆轉、緩和、抑制或加以預防。術語「治療」亦指上句所定義「治療」之行為。術語「治療」並包括哺乳動物之輔助治療。
在此所稱之「對象」或「患者」包含哺乳動物及非哺乳動物。哺乳動物之範例包括但不限於人、黑猩猩、猿猴、牛、馬、綿羊、山羊、豬、兔、犬、貓、大鼠、小鼠、天竺鼠等等。非哺乳動物之範例包括但不限於鳥、魚等等。
在此所用之術語「生物樣本」包含取自(分離自)人類(例如癌症患者)等哺乳動物或上文例示非哺乳動物之細胞、組織與體液,以及其培養物。
本發明化合物之施用可採任何可將化合物遞送至作用位置之方法。此等方法包括口腔途徑、十二指腸途徑、腸胃外注射(包括靜脈、皮下、肌肉內、血管內或輸注)、局部及直腸給藥。
本發明之其他態樣亦提供以式(I)化合物、其藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物為有效成分及藥學上可接受輔藥之藥物組成物。在一實施例中,所述藥物組成物係用於治療蛋白激酶介導疾病。在另一實施例中,所述藥物組成物係用於選擇性抑制至少一種對照於野生型EGFR之EGFR突變體。
本發明化合物可經口服方式給藥。口服給藥可包括吞嚥,使化合物進入消化道,或可採用口內或舌下給藥,使化合物直接自口腔進入血流。適用於口服給藥之製劑形式包括如藥錠、含顆粒膠囊、液體或粉末等固體製劑、喉片(包括內裝液體者)、嚼錠、多重奈米微粒、凝膠、固溶體、脂質體、薄膜(包括黏膜粘合)、陰道栓劑、噴劑及液體製劑。
液體製劑包括懸浮液、溶液、糖漿及酏劑。此類製劑可填裝入軟膠囊或硬膠囊中,且通常包括載劑,例如水、乙醇、聚乙二醇、丙二醇、甲基纖維素或適當油體及一或多種乳化劑及/或懸浮劑。液態製劑亦可由固體配製而得。
可包含於組成物中之載劑、賦形劑及稀釋劑範例可包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藻糖醇、麥芽糖醇、澱粉、阿拉伯膠、藻酸鹽、明膠、磷酸鈣、矽酸鈣、纖維素、甲基纖維素、微晶纖維素、聚乙烯吡咯烷酮、水、甲基羥基苯甲酸鹽、丙基羥基苯甲酸鹽、滑石、硬脂酸鎂及礦物油,但不以此為限。當配製為製劑時,並可使用如常用填充物、穩定劑、結合劑、崩解劑及界面活性劑等稀釋劑及賦形劑。口服用固體製劑包括藥錠、藥丸、藥粉、藥粒、膠囊等等,且製作此類固體製劑時可將本發明化合物混合至少一賦形劑,例如澱粉、微晶纖維素、蔗糖、乳糖、低取代羥基丙基纖維素、羥丙基甲基纖維素等等。除簡單賦形劑外,亦可使用如硬脂酸鎂及滑石等潤滑劑。口服液體製劑包括懸浮液、內用液、乳膠、糖漿等等。除水及液態石蠟等常用簡單稀釋劑外,亦可加入各種輔藥,例如濕潤劑、增甜劑、芳香劑、防腐劑等等。腸胃外給藥製劑包括穩定水溶液、非水溶液、懸浮液、乳膠、凍乾製劑及栓劑。非水溶液或懸浮液可包含丙二醇、聚乙二醇、如橄欖油等蔬菜油、如乙基油酸鹽等可注射酯等等。栓劑之基料可為Witepsol、Macrogol、Tween 61、可可脂、月桂脂、甘油明膠等等。為配製腸胃外給藥製劑,可將式I化合物或其藥學上可接受之鹽聯同穩定劑混合於水中並/或加入佐藥,例如防腐劑、穩定劑、可濕性粉劑等輔助劑或乳化加速劑、用以控制滲透壓之鹽及/或緩衝劑等等,及其他治療上有用之物質,如此製成以安瓿或小管單位形式施用之溶液或懸浮液。
總體反應方案與合成路徑概述
本發明之範圍包括依據以下方案1製備式(I)化合物或其藥學上可接受之鹽、非鏡像異構物、鏡像異構物、外消旋體、互變異構物、前驅藥、水合物或溶劑合物之程序:
其中,R
1、R
2、R
3、R
4、X
1、X
2、X
3及X
4之定義同上;X為鹵素;M為B(OH)
2或BPin;且Q為氫、B(OH)
2或BPin。
具體而言,式(I)化合物或其藥學上可接受之鹽可利用包含以下步驟之程序製備:將式(IIa)化合物與R
1-M反應以取得式(IIIa)化合物,將式(IIIa)化合物與R
2-Q反應以取得式(IV)化合物,再將式(IV)化合物與式(V)化合物反應以取得式(I)化合物。
於方案1之程序中係經商業管道取得式(IIa)、R
1-M、R
2-Q及(V) 化合物。式(IIa)化合物與R
1-M之反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下執行。並且,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑中配合例如40-120
oC之加熱下進行。
式(IIIa)化合物與R
2-Q之反應可在如氫化鈉、碳酸鉀、碳酸銫、氫氧化鉀、TEA、DIPEA等鹼之存在下進行。並且,反應可在如無水THF、DMF、DMA等有機溶劑中於室溫下或配合例如40-140
oC之加熱下進行。若Q為B(OH)
2或BPin,反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下進行。並且,若Q為B(OH)
2或BPin,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑配合例如40-120
oC之加熱下進行。
可利用Buchwald-Hartwig反應,將式(IV)化合物與式(V)化合物偶聯以取得式(I)化合物。式(IV)與式(V)化合物之反應可在如碳酸鈉、碳酸鉀、碳酸銫等鹼之存在下執行。並且,反應可在如Pd(OAc)
2、Pd
2(dba)
3、Pd(PPh
3)
4、Pd(dppf)Cl
2、BrettPhos Pd G1甲基叔丁基醚加合物等鈀催化劑及如BINAP、SPhos、XPhos、Xantphos、BrettPhos等配體之存在下執行。再者,反應可在如1,4-二氧陸圜或甲苯等無水有機溶劑中配合例如80-120
oC之加熱下進行。
或者,可將式(IIa)化合物與R
2-Q反應以取得式(IIIb)化合物,再將式(IIIb)化合物與R
1-M反應,藉此製成式(IV)化合物。
式(IIa)化合物與 R
2-Q之反應可在如氫化鈉、碳酸鉀、碳酸銫、氫氧化鉀、TEA、DIPEA等鹼之存在下執行。並且,反應可於如無水 THF、DMF、DMA等有機溶劑中在室溫或配合例如40-140
oC之加熱下進行。若Q為B(OH)
2或BPin,反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下執行。並且,若Q為B(OH)
2或BPin,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑中配合例如40-120
oC之加熱下進行。
式(IIIb)化合物與R
1-M之反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下執行。並且,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑中配合例如40-120
oC之加熱下進行。
依據本發明另一態樣,式(I)化合物或其藥學上可接受之鹽可依據以下方案2製備:
其中,R
1、R
2、R
3、R
4、X
1、X
2、X
3及X
4之定義同上;X為鹵素;M為B(OH)
2或BPin;且Q為氫、B(OH)
2或BPin。
具體而言,式(I)化合物或其藥學上可接受之鹽可經由包含以下步驟之程序製備:將式(IIb)化合物與R
1-X反應以取得式(IIIa)化合物,而後將式(IIIa)化合物與R
2-Q反應以取得式(IV)化合物,再將式(IV)化合物與式(V)化合物反應以取得式(I)化合物。
於方案2之程序中係經商業管道取得式(IIb)、R
1-X、R
2-Q及(V)化合物。式(IIb)化合物與R
1-X之反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下執行。並且,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑中配合例如40-120
oC之加熱下進行。
式(IIIb)化合物與R
2-Q之反應可在如氫化鈉、碳酸鉀、碳酸銫、氫氧化鉀、TEA、DIPEA等鹼之存在下進行。並且,反應可在如無水THF、DMF、DMA等有機溶劑中於室溫下或配合例如40-140
oC之加熱下進行。若Q為B(OH)
2或BPin,反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下進行。並且,若Q為B(OH)
2或BPin,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑配合例如40-120
oC之加熱下進行。
可利用Buchwald-Hartwig反應,將式(IV)化合物與式(V)化合物偶聯以取得式(I)化合物。式(IV)與式(V)化合物之反應可在如碳酸鈉、碳酸鉀、碳酸銫等鹼之存在下執行。並且,反應可在如Pd(OAc)
2、Pd
2(dba)
3、Pd(PPh
3)
4、Pd(dppf)Cl
2、BrettPhos Pd G1甲基叔丁基醚加合物等鈀催化劑及如BINAP、SPhos、XPhos、Xantphos、BrettPhos等配體之存在下執行。再者,反應可在如1,4-二氧陸圜或甲苯等無水有機溶劑中配合例如80-120
oC之加熱下進行。
或者,可將式(IIb)化合物與R
2-Q反應以取得式(IIIc)化合物,再將式(IIIc)化合物與R
1-X反應,藉此製成式(IV)化合物。
式(IIb)化合物與 R
2-Q之反應可在如氫化鈉、碳酸鉀、碳酸銫、氫氧化鉀、TEA、DIPEA等鹼之存在下執行。並且,反應可於如無水 THF、DMF、DMA等有機溶劑中在室溫或配合例如40-140
oC之加熱下進行。若Q為B(OH)
2或BPin,反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下執行。而若Q為B(OH)
2或BPin,則反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑中配合例如40-120
oC之加熱下進行。
式(IIIc)化合物與R
1-X之反應可在如碳酸鈉、碳酸鉀等鹼及如Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下執行。並且,反應可在如DME、THF、1,4-二氧陸圜等無水有機溶劑中配合例如40-120
oC之加熱下進行。
依據本發明另一態樣,可依據以下方案3將式(VI)化合物與式R
3-Q之化合物反應以取得式(V)化合物:
其中,R
3、R
4、X
3及X
4之定義同上;X為鹵素;且Q為氫、B(OH)
2或BPin。
式(VI)化合物與R
3-Q之反應可在如氫化鈉、碳酸鉀、碳酸銫、氫氧化鉀、TEA、DIPEA等鹼之存在下進行。並且,反應可在如無水THF、DMF、DMA等有機溶劑中於室溫下或配合例如40-140
oC之加熱下進行。若Q為B(OH)
2或BPin,反應可在如碳酸鈉、碳酸鉀等鹼及如PdCl
2(PPh
3)
2、Pd(dppf)Cl
2、Pd(PPh
3)
4等配體偶聯鈀催化劑之存在下進行。並且,若Q為B(OH)
2或BPin,則反應可在如THF、1,4-二氧陸圜、乙腈等無水有機溶劑配合例如40-120
oC之加熱下進行。
範例
以下以式(I)化合物之製備為例進一步說明本發明。所提供之範例僅屬說明性質,且不應解讀為以任何方式構成對於本發明之限制。熟悉此技藝人士應可於不脫離本發明範圍之情形下為各種變化及修改。
以下範例中所製備之化合物經下述方法分析:使用Bruker 400 MHz 光譜儀及Agilent 600 MHz光譜儀執行核磁共振(NMR)光譜分析,並將其化學位移以ppm解析。繼而使用配備有靜電噴霧界面之Agilent 1260 Infinity系列液相層析/質量選擇檢測器 (MSD)測量指定分子量(使用Single Quadrupole,其指示ESI+ (ESI-MS (陽離子)中m/z數值,以(M + H)
+峰表示)。於矽膠上執行管柱層析(參見「Merck,70-230目」)。(參見「W.C. Still, J. Org. Chem., 43, 2923, 1978」)。並且,各範例中之常溫材料均為可依據文獻合成或自如Sigma-Aldrich等商業管道取得之已知化合物。以下實例中所用縮寫列示如下:
[表2] 縮寫列表
DCM | 二氯甲烷 |
DIPEA | N, N-二異丙乙胺 |
DMA | N, N-二甲基乙醯胺 |
DMF | N, N-二甲基甲醯胺 |
DMSO | 二甲基亞碸 |
EA | 乙酸乙酯 |
HATU | 氮雜苯并三氮唑四甲基脲六氟磷酸鹽 |
K 2CO 3 | 碳酸鉀 |
MeCN | 乙腈 |
MeOH | 甲醇 |
MgSO 4 | 硫酸鎂 |
n-Hex | 正己烷 |
Sat. NaHCO 3soln. | 飽和碳酸氫鈉溶液 |
TFA | 三氟乙酸 |
XPhos | [2-二環己基膦基-2′,4′,6′-三異丙基二苯基] |
參考範例1. (1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶
在2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶(500 mg,1.84 mmol)之1,4-二氧陸圜(4.53 mL)溶液中加入2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(617 mg,2.4 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II),錯合二氯甲烷(151 mg,0.180 mmol)及3M K
2CO
3溶液(1.84 mL,5.53 mmol)。將反應混合物在 90
oC攪拌2小時。將反應混合物冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-30%)純化而產出形態為淺棕色固體之6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(531 mg)。MS (ESI) m/z = 322.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
在 6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(96 mg,0.298 mmol)之DMA (2 mL)溶液中加入DIPEA (0.21 mL,1.19 mmol)及順-4-胺基-1-甲基環己醇(58 mg,0.450 mmol)。將反應混合物在90
oC攪拌4小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-30%)純化而產出形態為淺棕色固體之(1s,4s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(92 mg)。MS (ESI) m/z = 431.2 (M + H)
+
參考範例2. 6'-氯-
N-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為棕色固體(92 mg),程序差異之處在於以4-氟環己-1-胺鹽酸鹽(72 mg,0.466 mmol)代替順-4-胺基-1-甲基環己醇。MS (ESI) m/z = 419.2 (M + H)
+
參考範例3. (1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
在2-氯-4-氟吡啶-5-硼酸頻哪醇酯(1000 mg,3.88 mmol)之DMA (10 mL)溶液中加入順
-4-胺基-1-甲基環己醇(753 mg,5.83 mmol)及DIPEA (1.73 mL,9.71 mmol)。將反應混合物在90
oC攪拌4小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-50%)純化而產出形態為淺黃色固體之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(1313 mg,3.581 mmol)。
1H-NMR (CDCl
3, 400 MHz) δ 8.26 (s, 1H), 6.39 (d, 1H), 6.37 (s, 1H), 3.27-3.20 (m, 1H), 1.90-1.86 (m, 2H), 1.76-1.73 (m, 2H), 1.69-1.49 (m, 4H), 1.33 (s,12H), 1.30 (s, 3H); MS (ESI) m/z = 285.1 (M + H)
+
參考範例4. 6'-氯-4'-氟-[2,3'-聯吡啶]-5-醇
在2-溴基-5-羥基吡啶(84 mg,0.485 mmol)之1,4-二氧陸圜(3 mL)溶液中加入2-氯-4-氟-5-(4,4,5,5,-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(150 mg,0.583 mmol)、 [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II),錯合二氯甲烷(48 mg,0.058 mmol)及3M K
2CO
3溶液(0.49 mL,1.456 mmol)。將反應混合物在90
oC攪拌2小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-40%)純化而產出形態為淺黃色固體之6'-氯-4'-氟-[2,3'-聯吡啶]-5-醇(112 mg)。MS (ESI) m/z = 225.0 (M + H)
+
參考範例5. 2-氯-4-氟-5-(5-甲基磺醯基-2-吡啶基)吡啶
在2-溴基-5-(甲基磺醯基)吡啶(300 mg,1.27 mmol)之1,4-二氧陸圜(4.53 mL)溶液中加入2-氯-4-氟-5-(4,4,5,5,-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(425 mg,1.65 mmol)、 [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)、錯合二氯甲烷(104 mg,0.130 mmol)及3M K
2CO
3溶液(1.27 mL,3.81 mmol)。將反應混合物在90
oC攪拌2小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-30%)純化而產出形態為淺黃色固體之2-氯-4-氟-5-(5-甲基磺醯基-2-吡啶基)吡啶(332 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (s, 1H), 9.15 (d, 1H), 8.34 (d, 1H), 7.99 (d, 1H), 7.27 (d, 1H), 3.18 (s, 3H); MS (ESI) m/z = 287.0 (M + H)
+
參考範例6. 6'-氯-4',6-二氟-2,3'-聯吡啶
在2-氯-4-氟-5-碘吡啶(1000 mg,3.88 mmol)之1,4-二氧陸圜(19.4 mL) 溶液中加入6-氟吡啶-2-硼酸(657 mg,4.66 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II),錯合二氯甲烷(317 mg,0.390 mmol)及3M K
2CO
3溶液(3.88 mL,11.65 mmol)。將反應混合物在90
oC攪拌3小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-50%)純化而產出形態為白色固體之6'-氯-4',6-二氟-2,3'-聯吡啶(790 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 9.07 (d, 1H), 7.92 (q, 1H), 7.69 (d, 1H), 7.22 (d, 1H), 7.00 (dd, 1H)
參考範例7. 2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例4之方式製備標題化合物,其形態為白色固體(545 mg),程序差異之處在於以2-(6-溴基-3-吡啶基)丙-2-醇(700 mg,3.24 mmol)代替2-溴基-5-羥基吡啶。
1H-NMR CDCl
3, 400 MHz) δ 8.99 (d, 1H), 8.85 (d, 1H), 7.93 (dd, 1H), 7.70 (dd, 1H), 7.19 (d, 1H), 2.24 (s, 1H), 1.65 (s, 6H); MS (ESI) m/z = 267.0 (M + H)
+
參考範例8. 6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶
以如同參考範例4之方式製備標題化合物,其形態為白色固體(488 mg),程序差異之處在於以2-溴基-5-(2,2,2-三氟乙基)吡啶(500 mg,2.08 mmol)代替2-溴基-5-羥基吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.06 (d, 1H), 8.68 (s, 1H), 7.78 (s, 2H), 7.22 (d, 1H), 3.47 (q, 2H); MS (ESI) m/z = (M + H)
+
參考範例9. 6'-氯-5-(3,3-二氟吖丁啶-1-基)-4'-氟-2,3'-聯吡啶
以如同參考範例4之方式製備標題化合物,其形態為米白色固體(185 mg),程序差異之處在於以2-溴基-5-(3,3-二氟吖丁啶-1-基)吡啶(500 mg,2.01 mmol)代替2-溴基-5-羥基吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.99 (d, 1H), 8.04 (d, 1H), 7.65 (d, 1H), 7.17 (d, 1H), 6.88 (dd,1H), 4.37 (q, 4H)
參考範例10. 1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同參考範例4之方式製備標題化合物,其形態為米白色固體(185 mg),程序差異之處在於以1-(6-溴基-3-吡啶基)-2,2,2-三氟-乙醇(514 mg,2.01 mmol)代替2-溴基-5-羥基吡啶。MS (ESI) m/z = 307.0 (M + H)
+
參考範例11. 2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例4之方式製備標題化合物,其形態為米白色固體(185 mg),程序差異之處在於以2-(6-溴基-3-吡啶基)-1,1,1-三氟-丙-2-醇(542 mg,2.01 mmol)代替2-溴基-5-羥基吡啶。MS (ESI) m/z = 321.0 (M + H)
+
參考範例12. 6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶
以如同參考範例4之方式製備標題化合物,其形態為米白色固體(402 mg),程序差異之處在於以2-溴基-5-(1-氟-1-甲基-乙基)吡啶(436 mg,2 mmol)代替2-溴基-5-羥基吡啶。MS (ESI) m/z 269.0 = (M + H)
+
參考範例13. 5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-4'-氟-2,3'-聯吡啶
以如同參考範例4之方式製備標題化合物標題化合物,其形態為淺棕色固體(113 mg),程序差異之處在於以5-[2-(吖丁啶-1-基)ethoxy]-2-溴基-吡啶(100 mg,0.390 mmol)代替2-溴基-5-羥基吡啶。MS (ESI) m/z = 308.0 (M + H)
+
參考範例14. (1
s,4
s)-4-((2-氯-5-碘吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(2.12 g),程序差異之處在於以2-氯-4-氟-5-碘吡啶(2.0 g,7.769 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 367.0 (M + H)
+
參考範例15. 6'-氯
-N-(3,3-二氟環丁基)-4'-氟-[2,3'-聯吡啶]-4-胺
步驟1. 2-溴基
-N-(3,3-二氟環丁基)吡啶-4-胺
將2-溴基-4-氟吡啶(500 mg,2.841 mmol)、3,3-二氟環丁-1-胺鹽酸鹽(489 mg,3.409 mmol)與DIPEA (1.24 mL,7.103 mmol)在DMA (5 mL)中之反應混合物於90
oC攪拌4小時。將反應混合物冷卻至室溫,稀釋在DCM中,以水清洗,利用MgSO
4乾燥,而後濃縮。粗產物經管柱層析提純(EA/n-Hex = 0-50%)產出形態為淺黃色固體之2-溴基
-N-(3,3-二氟環丁基)吡啶-4-胺(567 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 7.95 (d, 1H), 6.57 (s, 1H), 6.38 (d, 1H), 4.86 (s, 1H), 3.88 (s, 1H), 3.15-3.05 (m, 2H), 2.55-2.44 (m, 2H)
步驟2. 6'-氯
-N-(3,3-二氟環丁基)-4'-氟-[2,3'-聯吡啶]-4-胺
以如同參考範例1步驟1之方式製備標題化合物,其形態為白色固體(631 mg),程序差異之處在於以步驟1中所製備之2-溴基
-N-(3,3-二氟環丁基)吡啶-4-胺(567 mg,2.16 mmol)代替2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.97 (d, 1H), 8.36 (d, 1H), 7.18 (d, 1H), 6.83 (s, 1H), 6.44 (s, 1H), 4.64 (s, 1H), 3.96 (s, 1H), 3.17-3.07 (m, 2H), 2.58-2.46 (m, 2H)
參考範例16. 2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺
在4-胺基-2-氯-5-氟嘧啶(1500 mg,10.17 mmol)之1,4-二氧陸圜(50.85 mL)溶液中加入1-(cyclopropane磺醯基)-4-(四甲基-1,3,2-二氧雜硼戊環-2-基)
-1
H-吡唑 (3638 mg,12.2 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) 、錯合二氯甲烷(830 mg,1.02 mmol)及3M K
2CO
3溶液(10.17 mL,30.5 mmol)。反應混合物在90
oC攪拌3小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-60%)純化而產出形態為淡黃色固體之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(1494 mg)。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.47 (s, 1H), 8.29 (s, 1H), 8.19 (d, 1H), 7.38 (s, 2H), 3.26-3.19 (m, 1H), 1.33-1.20 (m, 4H); MS (ESI) m/z = 284.0 (M + H)
+
參考範例17. 2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺
在2-溴基-4-嘧啶胺(500 mg,2.874 mmol)之1,4-二氧陸圜(9 mL)溶液中加入1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑 (964 mg,3.736 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) 、錯合二氯甲烷(235 mg,0.290 mmol)及3M K
2CO
3溶液(2.87 mL,8.62 mmol)。反應混合物在90
oC攪拌3小時,冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-50%)純化而產出形態為淡黃色固體之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(325 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.23 (d, 1H), 8.18 (s,1H), 8.12 (s, 1H), 6.27 (d, 1H), 6.13 (tt, 1H), 4.87 (s, 2H), 4.50 (td, 2H); MS (ESI) m/z = 226.0 (M + H)
+
參考範例18. 2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺
以如同參考範例17之方式製備標題化合物,其形態為白色固體(303 mg),程序差異之處在於以4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1-(2,2,2-三氟乙基)
-1
H-吡唑 (619 mg,2.241 mmol)代替1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑。
1H-NMR (MeOD, 400 MHz) δ 8.30 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H), 6.36 (d, 1H), 5.01 (q, 2H); MS (ESI) m/z = 244.0 (M + H)
+
參考範例19. 2-(3-M乙基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺
以如同參考範例17之方式製備標題化合物,其形態為白色固體(325 mg),程序差異之處在於以3-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-1-(2,2,2-三氟乙基)吡唑(650 mg,2.241 mmol)代替1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑。MS (ESI) m/z = 284.0 (M + H)
+
參考範例20. 4-(4-胺基嘧啶-2-基)-
N,
N-二甲基
-1
H-吡唑-1-磺胺
以如同參考範例17之方式製備標題化合物,其形態為白色固體(344 mg),程序差異之處在於以4-胺基-2-氯嘧啶(250 mg,1.93 mmol)及
N,
N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑-1-磺胺(697 mg,2.316 mmol)代替2-溴基-4-嘧啶胺及1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑。
1H-NMR (CDCl
3, 400 MHz) δ 8.59 (s, 1H), 8.33 (s, 1H), 8.25 (sd, 1H), 6.31 (d, 1H), 4.95 (s, 2H), 2.98 (s, 6H)
參考範例21. 2-(1-(2,2-二氟乙基)-3,5-二甲基
-1
H-吡唑-4-基)嘧啶-4-胺
以如同參考範例17之方式製備標題化合物,其形態為白色固體(123 mg),程序差異之處在於以1-(2,2-二氟乙基)-3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)
-1
H-吡唑 (641 mg,2.24 mmol)代替1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑。
1H-NMR (CDCl
3, 400 MHz) δ 8.29 (d, 1H), 6.26 (d, 1H), 6.12 (tt, 1H), 4.78 (s, 2H), 4.39 (td, 2H), 2.62 (s, 3H), 2.52 (s, 3H)
參考範例22. 2-(1-(2,2,3,3-四氟丙基)
-1
H-吡唑-4-基)嘧啶-4-胺
以如同參考範例17之方式製備標題化合物,其形態為白色固體(293 mg),程序差異之處在於以1-(2,2,3,3-四氟丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)
-1
H-吡唑 (691 mg,2.24 mmol)代替1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑。
1H-NMR (CDCl
3, 400 MHz) δ 8.24 (d, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 6.28 (d, 1H), 5.88 (tt, 1H), 4.85 (s, 2H), 4.70 (t, 2H)
參考範例23. 1-(4-Amino-5-氟嘧啶-2-基)-3,3-二氟哌啶-4-醇
在2-氯-5-氟嘧啶-4-胺(150 mg,1.017 mmol)之DMA (2 mL)溶液中加入DIPEA (0.53 mL,3.05 mmol)及3,3-二氟哌啶-4-醇鹽酸鹽(229 mg,1.322 mmol)。反應混合物在90
oC攪拌過夜。將反應混合物冷卻至室溫,及以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/MeOH = 0-20%)純化而產出形態為淺黃色油體之1-(4-胺基-5-氟嘧啶-2-基)-3,3-二氟哌啶-4-醇(122 mg)。MS (ESI) m/z = 249.1 (M + H)
+
參考範例24. 5-氟-2-((3
R,4
S)-3-氟-4-甲氧基哌啶-1-基)嘧啶-4-胺
以如同參考範例23之方式製備標題化合物,其形態為淺黃色油體(202 mg),程序差異之處在於以(3
R,4
S)-3-氟-4-甲氧基哌啶鹽酸鹽(224 mg,1.322 mmol)代替3,3-二氟哌啶-4-醇鹽酸鹽。MS (ESI) m/z = 245.1 (M + H)
+
參考範例25. 4-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)嗎啉
將2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(159 mg,0.620 mmol)、4-(6-溴基-3-吡啶基)嗎啉(150 mg,0.617 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) 、錯合二氯甲烷(50 mg,0.062 mmol)與3M K
2CO
3溶液(0.62 mL,1.851 mmol)在1,4-二氧陸圜(2 mL)中之反應混合物於70
oC攪拌3小時。將反應混合物冷卻至室溫並以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 10-60%)純化而產出形態為淺黃色固體之4-(6’-氯-4’-氟-[2,3’-聯吡啶]-5-基)嗎啉(93 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.42 (d, 1H), 7.65 (dd, 1H), 7.23 (dd, 1H) 7.17 (d, 1H), 3.91 (t, 4H), 3.29 (t, 4H)
參考範例26. ((1
s,4
s)-4-((2-氯-5-碘吡啶-4-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色液體(606 mg),程序差異之處在於以2-氯-4-氟-5-碘吡啶(500 mg,1.942 mmol)及((1
s,4
s)-4-胺基環己基)甲醇(376 mg,2.91 mmol)代替6’-氯-4’-氟-5-((1-甲基哌啶-4-基)氧基)-2,3’-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 367.0 (M + H)
+
參考範例27. (1
s,4
s)
-N 1 -(2-氯-5-碘吡啶-4-基)
-N 4-(2-氟乙基)環己烷-1,4-二胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色液體(635 mg),程序差異之處在於以2-氯-4-氟-5-碘吡啶(500 mg,1.942 mmol)及(1
s,4
s)
-N 1 -(2-氟乙基)環己烷-1,4-二胺(160 mg,2.91 mmol)代替6’-氯-4’-氟-5-((1-甲基哌啶-4-基)氧基)-2,3’-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 398.0 (M + H)
+
參考範例28. 2-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-碘吡啶-4-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色液體(661 mg),程序差異之處在於以2-氯-4-氟-5-碘吡啶(500 mg,1.942 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(668 mg,2.91 mmol)代替6’-氯-4’-氟-5-((1-甲基哌啶-4-基)氧基)-2,3’-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 394.0 (M + H)
+
範例1. (1-(6’-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3’-聯吡啶]-4’-基)-4-甲基哌啶-4-基)甲醇
步驟1. 6’-氯-4’-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3’-聯吡啶
在2-氯-4-氟吡啶-5-硼酸頻哪醇酯(100 mg,0.390 mmol)之1,4-二氧陸圜(2 Ml) 溶液 中加入1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪(115 mg,0.430 mmol)、(1,1’-雙(二苯基膦基)二茂鐵)-二氯鈀(II) 、錯合有二氯甲烷(3 mg,0.040 mmol)及3 M K
2CO
3溶液(0.4 Ml,1.170 mmol)。反應混合物在90
oC攪拌3小時,冷卻至室溫,以水及DCM稀釋,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-10%)純化而產出形態為淺黃色固體之6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶(93 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.65 (s, 1H), 7.76 (d, 1H), 7.67 (d, 1H), 7.18 (d, 1H), 3.56 (s, 2H), 2.45 (brs, 8H), 2.28 (s, 3H); MS (ESI) m/z = 321.1 (M + H)
+
步驟2. (1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇
步驟1中所製備之6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶(45 mg,0.130 mmol)、(4-甲基哌啶-4-基)甲醇(25 mg,0.195 mmol)與DIPEA (0.04 mL,0.27 mmol)在DMA (5 mL)中之反應混合物於90
oC攪拌過夜。反應混合物經冷卻後稀釋於EA,以水清洗,利用MgSO
4乾燥後濃縮。粗產物經管柱層析提純(MeOH/DCM = 10%)產出形態為固體之(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇(36 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.60 (d, 1H), 8.23 (s, 1H), 7.71 (dd, 1H), 7.62 (d, 1H), 6.84 (s, 1H), 3.57 (s, 2H), 3.33 (s, 2H), 2.97-2.03 (m, 2H), 2.89-2.83 (m, 2H), 2.49 (brs, 8H), 2.29 (s, 3H), 1.50-1.43 (m, 2H), 0.93 (s, 3H)
步驟3. (1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇
2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺(10 mg,0.038 mmol)、三(二亞苄基丙酮)二鈀(0) (7 mg,0.01 mmol)、Xphos (7 mg,0.02 mmol,碳酸銫 (31 mg,0.09 mmol)與步驟2中所製備之(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3′-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇(21 mg,0.050 mmol)在1,4-二氧陸圜(5 mL)中之懸浮液於110
oC攪拌過夜。將混合物稀釋在DCM中,經矽藻土過濾,而後濃縮。粗產物經管柱層析提純(EA/n-Hex = 35-50%)產出形態為米白色固體之(1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇(8.5 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.64 (s, 1H), 8.45 (d, 1H), 8.38-8.34 (m, 3H), 8.01 (s, 1H), 7.74 (dd, 1H), 7.63 (d, 1H), 6.99 (d, 1H), 3.68 (s, 2H), 3.41 (s, 2H), 3.27-3.24 (m, 2H), 3.15-3.03 (m, 6H), 2.88-2.79 (m, 5H), 2.69 (s, 3H), 1.62-1.52 (m, 4H), 1.38-1.34 (m, 2H), 1.28-1.24 (m, 2H), 1.00 (s, 3H); MS (ESI) m/z = 659.3 (M + H)
+
範例2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. (1
s,4
s)-
N 1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-
N 4-(2-氟乙基)環己烷-1,4-二胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(48 mg),程序差異之處在於以(1
s,4
s)
-N 1- (2-氟乙基)環己烷-1,4-二胺(31 mg,0.195 mmol)代替(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.77 (d, 1H), 8.50 (d, 1H), 8.40 (s, 1H), 7.77 (dd, 1H), 7.69 (d, 1H), 6.55 (s, 1H), 4.61 (dd, 1H), 4.49 (dd, 1H), 3.65-3.62 (m, 1H), 3.54 (s, 2H), 2.96 (dd, 1H), 2.89 (dd, 1H), 2.68-2.63 (m, 1H), 2.46 (brs, 8H), 2.29 (s, 3H), 1.93-1.88 (m, 2H), 1.81-1.73 (m, 4H), 1.56-1.42 (m, 2H)
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(4.6 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-
N 1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-
N 4-(2-氟乙基)環己烷-1,4-二胺(23 mg,0.050 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.61 (d, 1H), 8.45 (d, 1H), 8.37-8.34 (m, 3H), 8.13 (s, 1H), 7.82-7.72 (m, 3H), 7.06 (d, 1H), 4.78 (brs, 1H), 4.66 (brs, 1H), 4.08 (brs, 1H), 3.71 (s, 2H) 3.26-3.02 (m, 6H), 2.88-2.77 (m, 5H), 2.66 (s, 3H), 2.20-1.94 (m, 6H), 1.74-1.68 (m, 2H), 1.57-1.55 (m, 2H), 1.28-1.25 (m, 2H); MS (ESI) m/z = 659.3 (M + H)
+
範例3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-氯-4-氟-5-(3-甲氧基-2-吡啶基)吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(142 mg),程序差異之處在於以2-溴基-3-甲氧基吡啶(183 mg,0.97 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.51 (d, 1H), 8.29 (s, 1H), 7.31 (m, 2H), 7.13 (d, 1H), 3.82 (s, 3H)
步驟2. (1
s,4
s)-4-((6'-氯-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(135 mg),程序差異之處在於以步驟1中所製備之2-氯-4-氟-5-(3-甲氧基-2-吡啶基)吡啶(142 mg,0.59 mmol)及順
-4-胺基-1-甲基環己醇(115 mg,0.89 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.32 (s, 1H), 8.17 (d, 1H), 7.27 (d, 1H), 7.19 (m, 2H), 6.52 (s, 1H), 3.77 (s, 3H), 3.23 (m, 1H), 1.99 (m, 2H), 1.80 (m, 2H), 1.69-1.46 (m, 4H), 1.21 (s, 3H); MS (ESI) m/z = 348.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(3.4 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(98 mg,0.28 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3’-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.94 (s, 1H), 8.60 (m, 3H), 8.30 (m, 1H), 7.70 (d, 1H), 7.52 (m, 1H), 6.94 (m, 1H), 6.64 (s, 1H), 3.99 (s, 3H), 3.56 (m, 1H), 3.05 (m, 1H), 1.79 (m, 2H), 1.77 (m, 4H), 1.59 (m, 2H), 1.46 (m, 2H), 1.26 (m, 5H); MS (ESI) m/z = 577.2 (M + H)
+
範例4. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-氯-4-氟-5-(3-氟-2-吡啶基)吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(160 mg),程序差異之處在於以2-溴基-3-氟吡啶(171 mg,0.97 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (d, 1H), 8.56 (m, 1H), 7.55 (t, 1H), 7.43 (m, 1H), 7.21 (d, 1H); MS (ESI) m/z = 226.8 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(122 mg),程序差異之處在於以步驟1中所製備之2-氯-4-氟-5-(3-氟-2-吡啶基)吡啶(160 mg,0.70 mmol)及順
-4-胺基-1-甲基環己醇(136 mg,1.06 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.37 (d, 1H), 8.32 (d, 1H), 8.03 (m, 1H), 7.47 (m, 1H), 7.23 (m, 1H), 6.55 (s, 1H), 3.25 (m, 1H), 1.82 (m, 2H), 1.68-1.66 (m, 4H), 1.48 (m, 2H), 1.23 (s, 3H); MS (ESI) m/z = 336.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(3.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(76 mg,0.23 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.84 (s, 1H), 8.52 (s, 2H), 8.47 (m, 1H), 8.42 (m, 1H), 7.80 (m, 1H), 7.48 (m, 1H), 7.20 (m, 1H), 7.03 (m, 1H), 3.56 (m, 1H), 3.04 (m, 1H), 1.92 (m, 2H), 1.76 (m, 4H), 1.58 (m, 2H), 1.50 (m, 2H), 1.25 (m, 5H); MS (ESI) m/z = 565.1 (M + H)
+
範例5. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲醇
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(1600 mg),程序差異之處在於以6-溴基-3-吡啶甲醇(2920 mg,15.6 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.72 (d, 1H), 7.84 (d, 1H), 7.74 (d, 1H), 7.21 (d, 1H), 4.82 (d, 2H), 2.18 (t, 1H); MS (ESI) m/z = 238.8 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(510 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲醇(388 mg,1.625 mmol)及順
-4-胺基-1-甲基環己-1-醇(210 mg,1.625 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.36 (d, 1H), 8.58 (s, 1H), 8.40 (s, 1H), 7.82 (d, 1H), 7.73 (d, 1H), 6.58 (s, 1H), 4.79 (d, 2H), 3.35 (m, 1H), 1.94 (m, 2H), 1.78-1.67 (m, 4H), 1.62-1.55 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 348.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(110 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(110 mg,0.415 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.02 (s, 1H), 9.49 (d, 1H), 8.65 (s, 1H), 8.53 (d, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 7.95 (d, 1H), 7.81 (d, 1H), 7.53 (s, 1H), 7.31 (s, 1H), 5.36 (t, 1H), 4.56 (d, 2H) 3.45 (m, 1H), 3.30-3.22 (m, 1H), 1.84 (m, 2H), 1.68-1.56 (m, 4H), 1.45-1.39 (m, 2H), 1.31 (m, 2H), 1.24 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 577.2 (M + H)
+
範例6. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4',5-二氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(71 mg),程序差異之處在於以2-溴基-5-氟吡啶(137 mg,0.78 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.61 (d, 1H), 7.80-7.76 (m, 1H), 7.55-7.50 (m, 1H), 7.21 (d, 1H); MS (ESI) m/z = 227.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(58 mg),程序差異之處在於以步驟1中所製備之6'-氯-4',5-二氟-2,3'-聯吡啶(53 mg,0.231 mmol)及順
-4-胺基-1-甲基環己-1-醇(30 mg,0.231 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.90 (d, 1H), 8.45 (d, 1H), 8.34 (s, 1H), 7.73 (dd, 1H), 7.54 (m, 1H), 6.58 (s, 1H), 3.39-3.31 (m, 1H), 1.96-1.92 (m, 2H), 1.78-1.66 (m, 4H), 1.61-1.55 (m, 2H), 1.31 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(12.9 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(51 mg,0.151 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.99 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.42-8.45 (m, 2H), 8.36 (brs, 1H), 7.71-7.75 (m, 1H), 7.60 (s, 1H), 7.50-7.55 (m, 1H), 7.33 (d, 1H), 7.00 (s, 1H), 3.51 (m, 1H), 2.85-2.80 (m, 1H), 2.06-1.99 (m, 2H), 1.77-1.51 (m, 8H), 1.32 (s, 3H), 1.23-1.18 (m, 2H); MS (ESI) m/z = 565.2 (M + H)
+
範例7. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈
步驟1. 6'-氯-4'-氟-[2,3'-聯吡啶]-5-甲腈
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(132 mg),程序差異之處在於以2-溴基-5-氰基吡啶(284 mg,1.56 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.97 (d, 1H), 8.09 (dd, 1H), 7.93 (d, 1H), 7.26 (d, 1H); MS (ESI) m/z = 234.0 (M + H)
+
步驟2. 6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(87 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-[2,3'-聯吡啶]-5-甲腈(72 mg,0.308 mmol)及順-4-胺基-1-甲基環己-1-醇(40 mg,0.308 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.26 (d, 1H), 8.85 (d, 1H), 8.48 (s, 1H), 8.15 (dd, 1H), 8.02 (dd, 1H), 7.87 (d, 1H), 6.62 (s, 1H), 3.40-3.34 (m, 1H), 1.97-1.93 (m, 2H), 1.80-1.69 (m, 4H), 1.62-1.54 (m, 2H), 1.32 (s, 3H); MS (ESI) m/z = 343.1 (M + H)
+
步驟3. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(3.4 mg),程序差異之處在於以步驟2中所製備之6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈(52 mg,0.151 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.82 (d, 1H), 8.62 (s, 1H), 8.42 (s, 1H), 8.39 -8.36 (m, 2H), 8.16 (s, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.54 (s, 1H), 7.07 (d, 1H), 3.55 (m, 1H), 2.82-2.78 (m, 1H), 1.91-1.83 (m, 2H), 1.80-1.65 (m, 4H), 1.55-1.45 (m, 4H), 1.24 (s, 3H), 1.23-1.18 (m, 2H); MS (ESI) m/z = 572.1 (M + H)
+
範例8. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-甲基-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(92 mg),程序差異之處在於以2-溴基-5-甲基吡啶(267 mg,1.55 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.57 (s, 1H), 7.65-7.59 (m, 2H), 7.18 (d, 1H), 2.40 (s, 3H); MS (ESI) m/z = 223.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(73 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-甲基-2,3'-聯吡啶(52 mg,0.231 mmol)及順
-4-胺基-1-甲基環己-1-醇(30 mg,0.231 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.33 (d, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.61 (t, 2H), 6.56 (s, 1H), 3.39-3.31 (m, 1H), 2.38 (s, 3H), 1.98-1.93 (m, 2H), 1.78-1.67 (m, 4H), 1.61-1.54 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 332.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(15.9 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.151 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.00 (s, 1H), 9.43 (d, 1H), 8.72 (s, 1H), 8.65-8.44 (m, 4H), 7.87 (d, 1H), 7.70 (dd, 1H), 7.55 (brs, 1H), 7.28 (brs, 1H), 3.45 (m, 1H), 3.27-3.22 (m, 1H), 2.33 (s, 3H), 1.84 (m, 2H), 1.67-1.56 (m, 4H), 1.45-1.39 (m, 2H), 1.33 (m, 2H), 1.26 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 561.2 (M + H)
+
範例9. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(84 mg),程序差異之處在於以
順 -4-胺基-1-甲基環己-1-醇(58 mg,0.446 mmol)代替(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.44 (d, 1H), 8.49 (d, 1H), 8.38 (s, 1H), 7.76 (dd, 1H), 7.67 (d, 1H), 6.56 (s, 1H), 3.54 (s, 2H), 3.35-3.24 (m, 1H), 2.50 (m, 8H), 2.29 (s, 3H), 1.93 (m, 2H), 1.77-1.67 (m, 4H), 1.60-1.52 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 430.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(5 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(32 mg,0.075 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.57 (s, 1H), 8.53 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 8.21 (s, 1H), 7.92 (s, 1H), 7.81 (d, 2H), 7.68 (d, 1H), 7.10 (d, 1H), 3.68 (m, 1H), 3.60 (s, 2H), 2.82 (m, 1H), 2.63 (m, 8H), 2.44 (s, 3H), 2.02 (m, 2H), 1.81 (m, 4H), 1.62 (m, 2H), 1.54 (m, 2H), 1.33 (s, 3H), 1.23 (m, 2H); MS (ESI) m/z = 659.2 (M + H)
+
範例10. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. (1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(94 mg),程序差異之處在於以((1
s,4
s)-4-胺基環己基)甲醇(58 mg,0.446 mmol)代替(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.50 (d, 1H), 8.49 (d, 1H), 8.37 (s, 1H), 7.76 (dd, 1H), 7.67 (d, 1H), 6.56 (s, 1H), 3.54 (s, 2H), 3.49 (s, 2H), 3.35 (m, 1H), 3.26 (brs, 1H), 2.50 (m, 8H), 2.29 (s, 3H), 2.19 (brs, 1H), 1.98 (m, 2H), 1.85-1.69 (m, 4H), 1.50-1.42 (m, 2H); MS (ESI) m/z = 430.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(7 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(32 mg,0.075 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.64 (s, 1H), 8.59 (s, 1H), 8.53 (s, 1H), 8.45 (s, 1H), 8.44 (s, 1H), 8.23 (s, 1H), 8.03 (brs, 1H), 7.84 (dd, 1H), 7.72 (d, 1H), 7.07 (d, 1H), 4.10 (m, 1H), 3.64 (s, 2H), 3.56 (d, 2H), 2.83 (m, 1H), 2.68 (m, 8H), 2.50 (s, 3H), 1.95 (m, 2H), 1.79 (m, 4H), 1.55 (m, 2H), 1.39 (m, 2H), 1.24 (m, 2H); MS (ESI) m/z = 659.3 (M + H)
+
範例11. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(94 mg),程序差異之處在於以(1
s,4
s)-4-胺基-1-(羥甲基)環己-1-醇(64 mg,0.446 mmol)代替(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.89 (d, 1H), 8.49 (d, 1H), 8.43 (s, 1H), 7.79-7.73 (m, 2H), 6.58 (s, 1H), 3.80 (m, 1H), 3.79-3.52 (m, 4H), 2.50 (m, 8H), 2.30 (s, 3H), 1.95-1.91 (m, 2H), 1.73-1.62 (m, 4H), 1.40-1.34 (m, 2H); MS (ESI) m/z = 446.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇(34 mg,0.075 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.70 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.42-8.30 (m, 3H), 7.84-7.76 (m, 1H), 7.15 (m, 1H), 3.55 (s, 2H), 3.50 (m, 1H), 2.78 (m, 8H), 2.30 (s, 3H), 1.98 (m, 2H), 1.79-1.71 (m, 4H), 1.62-1.49 (m, 4H), 1.30 (s, 3H), 1.23-1.17 (m, 2H); MS (ESI) m/z = 675.3 (M + H)
+
範例12. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-4-甲基-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(114 mg),程序差異之處在於以2-溴基-4-甲基吡啶(145 mg,0.776 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.61 (d, 1H), 7.56 (s, 1H), 7.22-7.16 (m, 1H), 2.45 (s, 3H); MS (ESI) m/z = 223.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(88 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-4-甲基-2,3'-聯吡啶(103 mg,0.464 mmol)及順
-4-胺基-1-甲基環己-1-醇(60 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.32 (s, 1H), 7.71 (t, 1H), 7.60 (d, 1H), 7.14 (d, 1H), 3.41-3.36 (m, 1H), 2.54 (s, 3H), 1.89-1.85 (m, 2H), 1.74-1.65 (m, 4H), 1.59-1.52 (m, 2H), 1.24 (s, 3H); MS (ESI) m/z = 332.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(19.6 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(56 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.77 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.40 (d, 1H), 7.67 (t, 1H), 7.54 (d, 1H), 7.28 (m, 1H), 7.06 (d, 1H), 7.01 (s, 1H), 3.53 (m, 1H), 2.84-2.81 (m, 1H), 2.60 (s, 3H), 2.04-2.01 (m, 2H), 1.78-1.51 (m, 8H), 1.31 (s, 3H), 1.22-1.19 (m, 2H); MS (ESI) m/z = 561.2 (M + H)
+
範例13. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (6'-氯-3,4'-二氟-[2,3'-聯吡啶]-4-基)甲醇
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(148 mg),程序差異之處在於以(2-溴基-3-氟吡啶-4-基)甲醇(320 mg,3.100 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.65 (d, 1H), 8.58 (d, 1H), 7.63 (t, 1H), 7.24 (d, 1H), 4.93 (d, 2H), 2.12 (t, 1H); MS (ESI) m/z = 257.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-3-氟-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(104 mg),程序差異之處在於以步驟1中所製備之(6'-氯-3,4'-二氟-[2,3'-聯吡啶]-4-基)甲醇(119 mg,0.464 mmol)及順
-4-胺基-1-甲基環己-1-醇(60 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.47 (d, 1H), 8.15 (d, 1H), 7.58 (t, 1H), 6.76 (s, 1H), 4.80 (s, 2H), 3.44-3.40 (m, 1H), 1.83-1.80 (m, 2H), 1.71-1.52 (m, 6H), 1.23 (s, 3H); MS (ESI) m/z = 366.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(21.1 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-3-氟-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(56 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3’-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.75 (s, 1H), 8.49 (s, 1H), 8.47 (d, 1H), 8.38 (d, 1H), 8.24 (d, 1H), 7.55 (t, 1H), 7.41 (d, 1H), 7.32 (s, 1H), 4.75 (s, 2H), 4.62 (s, 1H), 3.54 (m, 1H), 3.05-3.00 (m, 1H), 1.94-1.90 (m, 2H), 1.72-1.64 (m, 4H), 1.59-1.53 (m, 2H), 1.47-1.43 (m, 2H), 1.29-1.25 (m, 2H), 1.24 (s, 3H); MS (ESI) m/z = 595.2 (M + H)
+
範例14. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-6-(三氟甲基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(176 mg),程序差異之處在於以2-溴基-6-(三氟甲基)吡啶(183 mg,0.776 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.12 (d, 1H), 8.04-7.96 (m, 2H), 7.73 (d, 1H), 7.24 (d, 1H); MS (ESI) m/z = 276.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(93 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-6-(三氟甲基)-2,3'-聯吡啶(128 mg,0.464 mmol)及順
-4-胺基-1-甲基環己-1-醇(60 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 9.46 (s, 1H), 8.50 (s, 1H), 8.13 (m, 2H), 7.73 (s, 1H), 3.42 (m, 1H), 1.87 (m, 2H), 1.73 (m, 4H), 1.59 (m, 2H), 1.24 (s, 3H); MS (ESI) m/z = 386.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(7.5 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(65 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.30 (d, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H), 7.94 (d, 1H), 7.80 (brs, 1H), 7.56 (t, 1H), 7.32 (d, 1H), 7.03 (brs, 1H), 3.49 (m, 1H), 2.85-2.80 (m, 1H), 2.05-2.00 (m, 2H), 1.80-1.73 (m, 4H), 1.63-1.51 (m, 4H), 1.29 (s, 3H), 1.23-1.19 (m, 2H); MS (ESI) m/z = 615.1 (M + H)
+
範例15. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-6-甲基-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(134 mg),程序差異之處在於以2-溴基-6-甲基吡啶(183 mg,0.776 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 7.69 (t, 1H), 7.54 (d, 1H), 7.22-7.18 (m, 2H), 2.65 (s, 3H); MS (ESI) m/z = 223.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(134 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-6-甲基-2,3'-聯吡啶(103 mg,0.464 mmol)及順
-4-胺基-1-甲基環己-1-醇(60 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.43 (d, 1H), 8.30 (s, 1H), 7.66 (s, 1H), 7.16 (d, 1H), 6.68 (s, 1H), 3.44-3.39 (m, 1H), 2.42 (s, 3H), 1.87-1.83 (m, 2H), 1.67-1.63 (m, 4H), 1.60-1.52 (m, 2H), 1.24 (s, 3H); MS (ESI) m/z = 332.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(15 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(56 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.42 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.44-8.40 (m, 3H), 7.52 (s, 1H), 7.29 (m, 1H), 7.03 (m, 2H), 3.50 (m, 1H), 2.85-2.79 (m, 1H), 2.43 (s, 3H), 2.04-1.97 (m, 2H), 1.81-1.51 (m, 8H), 1.31 (s, 3H), 1.22-1.18 (m, 2H); MS (ESI) m/z = 561.2 (M + H)
+
範例16. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)甲醇
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(147 mg),程序差異之處在於以(2-溴基吡啶-4-基)甲醇(219 mg,1.16 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.02 (d, 1H), 8.72 (d, 1H), 7.75 (s, 1H), 7.35 (d, 1H), 7.22 (d, 1H), 4.84 (d, 2H), 2.09 (t, 1H); MS (ESI) m/z = 239.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(88 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)甲醇(111 mg,0.464 mmol)及順
-4-胺基-1-甲基環己-1-醇(60 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.53 (d, 1H), 8.33 (s, 1H), 7.80 (s, 1H), 7.30 (d, 1H), 6.69 (s, 1H), 4.71 (S, 2H), 3.45-3.39 (m, 1H), 1.87-1.83 (m, 2H), 1.74-1.64 (m, 4H), 1.59-1.52 (m, 2H), 1.24 (s, 3H); MS (ESI) m/z = 348.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(15 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(62 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.74 (s, 1H), 8.54 (d, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.36 (d, 1H), 7.82 (s, 1H), 7.37 (d, 1H), 7.27 (d, 2H), 4.62 (s, 2H), 3.57 (m, 1H), 3.07-3.01 (m, 1H), 1.98-1.94 (m, 2H), 1.79-1.71 (m, 4H), 1.61-1.55 (m, 2H), 1.47-1.43 (m, 2H), 1.26 (m, 2H), 1.24 (s, 3H); MS (ESI) m/z = 577.2 (M + H)
+
範例17. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(三氟甲基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(131 mg),程序差異之處在於以2-溴基-5-(三氟甲基)吡啶(210 mg,0.932 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.12 (d, 1H), 9.02 (s, 1H), 8.06 (d, 1H), 7.92 (d, 1H), 7.27 (m, 1H)
步驟2. (1
s,4
s)-4-((6'-氯-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(80 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(三氟甲基)-2,3'-聯吡啶(107 mg,0.387 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.33 (d, 1H), 8.83 (s, 1H), 8.44 (s, 1H), 7.99 (dd, 1H), 7.85 (d, 1H), 6.60 (s, 1H), 3.37-3.32 (m, 1H), 1.95-1.91 (m, 2H), 1.78-1.69 (m, 4H), 1.60-1.53 (m, 2H), 1.30 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(37 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(44 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (d, 1H), 8.84 (s, 1H), 8.67 (s, 1H), 8.50 (d, 2H), 8.44 (d, 1H), 7.98 (dd 1H), 7.86 (d, 1H), 7.78 (brs, 1H), 7.29 (m, 1H), 7.09 (s, 1H), 3.53 (m, 1H), 2.84-2.81 (m, 1H), 2.03-1.99 (m, 2H), 1.83-1.52 (m, 8H), 1.32 (s, 3H), 1.25-1.21 (m, 2H); MS (ESI) m/z = 615.2 (M + H)
+
範例18. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮
步驟1. 1-(6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)乙-1-酮
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(115 mg),程序差異之處在於以2-乙醯基-6-溴基吡啶(186 mg,0.932 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.17 (d, 1H), 8.10-7.96 (m, 3H), 7.24 (d, 1H), 2.79 (s, 3H)
步驟2. 1-(6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(85 mg),程序差異之處在於以步驟1中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)乙-1-酮(97 mg,0.387 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.83 (d, 1H), 8.37 (s, 1H), 8.02-7.86 (m, 3H), 6.61 (s, 1H), 3.39-3.35 (m, 1H), 2.72 (s, 3H), 1.97-1.93 (m, 2H), 1.79-1.66 (m, 4H), 1.60-1.53 (m, 2H), 1.29 (s, 3H)
步驟3. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(31 mg),程序差異之處在於以步驟2中所製備之1-(6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮(35 mg,0.098 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.89 (d, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.42 (t, 1H), 8.18 (s, 1H), 7.97-7.88 (m, 3H), 7.31 (d, 1H), 7.12 (s, 1H), 3.53 (m, 1H), 2.84-2.80 (m, 1H), 2.04 (m, 2H), 1.76 (m, 4H), 1.63-1.50 (m, 4H), 1.30 (S, 3H), 1.26 (m, 2H); MS (ESI) m/z = 589.2 (M + H)
+
範例19. (1
s,4
s) -4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4',6-二氟-4-甲基-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(102 mg),程序差異之處在於以2-溴基-6-氟-4-甲基吡啶(616 mg,3.26 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 7.50 (s, 1H), 7.22 (d, 1H), 6.81 (s, 1H), 2.49 (s, 3H); MS (ESI) m/z = 241.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(39 mg),程序差異之處在於以步驟1中所製備之6'-氯-4',6-二氟-4-甲基-2,3'-聯吡啶(93 mg,0.387 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.73 (d, 1H), 8.37 (s, 1H), 7.38 (s, 1H), 6.69 (s, 1H), 6.56 (s, 1H), 3.38-3.31 (m, 1H), 2.46 (s, 3H), 1.93 (m, 2H), 1.78-1.68 (m, 4H), 1.61-1.53 (m, 2H), 1.27 (s, 3H)
步驟3. (1
s,4
s) -4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(8.8 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(34 mg,0.098 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.88 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.42 (d, 1H), 8.39 (s, 1H), 7.39 (s, 1H), 7.13 (s, 1H), 6.66 (s, 1H), 3.54 (m, 1H), 2.86-2.80 (m, 1H), 2.47 (s, 3H), 2.05-1.98 (m, 2H), 1.84-1.74 (m, 4H), 1.65-1.53 (m, 4H), 1.28 (m, 3H), 1.25 (m, 2H); MS (ESI) m/z = 579.2 (M + H)
+
範例20. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-4-(三氟甲基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(144 mg),程序差異之處在於以2-溴基-4-(三氟甲基)吡啶(210 mg,0.932 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.11 (d, 1H), 8.95 (d, 1H), 7.99 (s, 1H), 7.58 (d, 1H), 7.26 (d, 1H), 4.84 (d, 2H), 2.09 (t, 1H)
步驟2. (1
s,4
s) -4-((6'-氯-4-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(80 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-4-(三氟甲基)-2,3'-聯吡啶(108 mg,0.387 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.20 (d, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 7.90 (s, 1H), 7.43 (d, 1H), 6.59 (s, 1H), 3.37-3.33 (m, 1H), 1.94-1.90 (m, 2H), 1.79-1.68 (m, 4H), 1.60-1.52 (m, 2H), 1.30 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(28.7 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(38 mg,0.098 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.48 (s, 1H), 8.77 (d, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 8.45 (m, 2H), 7.97 (s, 1H), 7.43 (d, 1H), 7.29 (s, 1H), 4.94 (brs, 1H), 3.59 (m, 1H), 2.85 (m, 1H), 1.98 (m, 2H), 1.89-1.76 (m, 4H), 1.66-1.56 (m, 4H), 1.28 (s, 3H), 1.24 (m, 2H); MS (ESI) m/z = 615.1 (M + H)
+
範例21. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇
步驟1. (6'-氯-4'-(((1
s,4
s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(100 mg),程序差異之處在於以範例5步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲醇(82 mg,0.344 mmol)及(1
s,4
s)-
N 1-(2-氟乙基)環己烷-1,4-二胺(55 mg,0.344 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。MS (ESI) m/z = 379.1 (M + H)
+
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(16 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇(100 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.86 (d, 1H), 8.66 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.40 (d, 1H), 7.79 (dd, 1H), 7.73 (d, 1H), 7.25 (m, 1H), 7.12 (d, 1H), 4.77 (s, 2H), 4.63 (t, 1H), 4.51 (t, 1H), 3.87 (m 1H), 2.99 (t, 1H), 2.92 (t, 1H), 2.83 (m, 1H), 2.66 (m, 1H), 2.04 (m, 2H), 1.84-1.46 (m, 8H), 1.27-1.21 (m, 2H); MS (ESI) m/z = 608.2 (M + H)
+
範例22. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇
步驟1. (6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(104 mg),程序差異之處在於以範例5步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲醇(82 mg,0.344 mmol)及((1
s,4
s)-4-胺基環己基)甲醇(43 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。MS (ESI) m/z = 348.1 (M + H)
+
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(37 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇(92 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 9.99 (d, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 8.39 (d, 1H), 7.80-7.73 (m, 2H), 7.30 (s, 1H), 7.09 (d, 1H), 4.77 (s, 2H), 3.98 (m, 1H), 3.54 (d, 2H), 2.86-2.82 (m, 1H), 2.04 (m, 2H), 1.82-1.70 (m, 5H), 1.54 (m, 2H), 1.43-1.34 (m, 3H), 1.26 (m, 2H); MS (ESI) m/z = 577.2 (M + H)
+
範例23. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
於室溫下在範例18中所製備之1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮(20 mg,0.034 mmol)之MeOH (0.5 mL)溶液中加入硼氫化鈉(6 mg,0.17 mmol)。將此混合物在室溫下攪拌30分鐘。以DCM稀釋混合物。有機層以水清洗,利用MgSO
4乾燥後濃縮。粗產物經管柱層析提純(MeOH/DCM=0-10%)產出形態為米白色固體之(1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(20.2 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.78 (d, 1H), 8.66 (d, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.32 (s, 1H), 7.79 (t, 1H), 7.55 (d, 1H), 7.25 (s, 1H), 7.22 (d, 1H), 7.13 (s, 1H), 4.98 (m, 1H), 3.56 (m, 1H), 3.49 (s, 3H), 2.85-2.81 (m, 1H), 1.97 (m, 2H), 1.89 (m, 4H), 1.76-1.50 (m, 7H), 1.29 (s, 3H), 1.26-1.19 (m, 2H); MS (ESI) m/z = 591.2 (M + H)
+
範例24. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(133 mg),程序差異之處在於以範例5步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲醇(150 mg,0.629 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(99 mg,0.629 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.69 (s, 1H), 8.41 (s, 1H), 7.93-7.86 (m, 2H), 6.70 (s, 1H), 4.69 (s, 2H), 3.87 (m, 1H), 1.95 (m, 2H), 1.79-1.62 (m, 4H), 1.43-1.38 (m, 3H), 1.17 (s, 6H); MS (ESI) m/z = 348.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(5 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(78 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.65 (s, 1H), 8.54 (s, 1H), 8.39 (s, 2H), 8.28 (d, 1H), 7.81 (s, 2H), 7.38 (d, 1H), 7.17 (d, 1H), 4.65 (s, 2H), 3.94 (m, 1H), 3.07-3.01 (m, 1H), 2.05 (m, 2H), 1.75 (m, 4H), 1.47-1.37 (m, 4H), 1.30-1.26 (m, 3H), 1.17 (s, 6H); MS (ESI) m/z = 605.2 (M + H)
+
範例25. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛
在範例24中所製備之2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(100 mg,0.166 mmol)之DCM (2.4 mL) 溶液中加入戴斯馬丁氧化劑(Dess−Maroom temperaturein periodinane )(140 mg,0.33 mmol)。將反應混合物在室溫下攪拌一小時,以DCM稀釋,再以10%水性Na
2S
2O
3清洗,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-10%)純化而產出形態為米白色固體之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛(70 mg)。MS (ESI) m/z = 603.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
在步驟1中所製備之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛 (26 mg,0.044 mmol)之DCM (1 mL)溶液中加入嗎啉(8 mg,0.088 mmol)。將此混合物攪拌20分鐘後冷卻至 0℃。於0
oC在混合物中加入三乙醯氧基硼氫鈉(46 mg,0.218 mmol),然後將反應混合物在室溫下攪拌4小時。在反應混合物中加入飽和NaHCO
3並以水及DCM稀釋,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-10%)純化而產出形態為米白色固體之2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(7.5 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.63 (s, 1H), 8.54-8.45 (m, 4H), 8.30 (s, 1H), 8.18 (m, 1H), 7.87 (d, 1H), 7.78 (d, 1H), 7.07 (s, 1H), 4.13 (m, 1H), 3.74 (brs, 4H), 3.59 (s, 2H), 2.85 (m, 1H), 2.52 (brs, 4H), 2.14 (m, 2H), 1.89 (m, 4H), 1.56-1.41 (m, 5H), 1.25 (m, 8H) MS (ESI) m/z = 674.3 (M + H)
+
範例26. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例25步驟2之方式製備標題化合物,其形態為米白色固體(9.6 mg),程序差異之處在於以二甲基胺(4 mg,0.088 mmol)代替嗎啉。
1H-NMR (CDCl
3, 400 MHz) δ 10.10 (d, 1H), 8.66 (s, 1H), 8.46 (s, 3H), 8.39 (d, 1H), 7.76 (s, 2H), 7.36 (s, 1H), 7.07 (d, 1H), 4.00 (m, 1H), 3.47 (s, 2H), 2.84 (m, 1H), 2.28 (s, 6H), 2.12 (m, 2H), 1.79 (m, 4H), 1.54-1.44 (m, 5H), 1.24 (m, 8H); MS (ESI) m/z = 632.3 (M + H)
+
範例27. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)甲醇
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(220 mg),程序差異之處在於以(6-溴基-2-吡啶基)甲醇(261 mg,1.39 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。MS (ESI) m/z = 239.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(226 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)甲醇(184 mg,0.774 mmol)及順
-4-胺基-1-甲基環己-1-醇(100 mg,0.774 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.96 (d, 1H), 8.36 (s, 1H), 7.83 (t, 1H), 7.60 (d, 1H), 6.59 (s, 1H), 4.85 (s, 2H), 3.43 (m, 1H), 1.89 (m, 2H), 1.74 (m, 4H), 1.58 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 348.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(15 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(100 mg,0.287 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.34 (d, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.30 (d, 1H), 7.70 (t, 1H), 7.51 (d, 1H), 7.26 (d, 1H), 7.19 (d, 1H), 7.06 (brs, 1H), 4.78 (s, 2H), 3.60 (m, 1H), 2.82 (m, 1H), 1.89 (m, 2H), 1.74 (m, 4H), 1.56 (m, 2H), 1.49 (m, 2H), 1.26 (s, 3H), 1.19 (m, 2H); MS (ESI) m/z = 577.2 (M + H)
+
範例28. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-6-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(219 mg),程序差異之處在於以1-((6-溴基-2-吡啶基)甲基)-4-甲基-哌嗪(374 mg,1.39 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。MS (ESI) m/z = 321.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(151 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-6-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶(124 mg,0.387 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.70 (d, 1H), 8.40 (s, 1H), 7.75 (t, 1H), 7.61 (d, 1H), 7.35 (d, 1H), 6.56 (s, 1H), 3.66 (s, 2H), 3.34 (m, 1H), 2.53 (m, 8H), 2.29 (m, 3H), 1.94 (m, 2H), 1.75 (m, 4H), 1.56 (m, 2H), 1.29 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(12.9 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(49 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3’-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.76 (d, 1H), 8.66 (s, 1H), 8.44 (m, 3H), 7.75 (s, 1H), 7.62 (s, 1H), 7.30 (m, 2H), 7.07 (s, 1H), 3.68 (s, 2H), 3.49 (m, 1H), 2.82 (m, 1H), 2.55 (m, 8H), 2.30 (s, 3H), 2.01 (m, 2H), 1.76 (m, 4H), 1.53 (m, 4H), 1.29 (s, 3H), 1.22 (m, 2H); MS (ESI) m/z = 659.3 (M + H)
+
範例29. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 4-((6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)甲基)嗎啉
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(127 mg),程序差異之處在於以4-((6-溴基-2-吡啶基)甲基)嗎啉(119 mg,0.462 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。MS (ESI) m/z = 308.0 (M + H)
+
步驟2. (1
s,4
s)- 4-((6'-氯-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(127 mg),程序差異之處在於以步驟1中所製備之4-((6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)甲基)嗎啉(119 mg,0.387 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.66 (d, 1H), 8.37 (s, 1H), 7.73 (t, 1H), 7.58 (d, 1H), 7.33 (d, 1H), 6.54 (s, 1H), 3.71 (brs, 4H), 3.63 (s, 2H), 3.32 (m, 1H), 2.50 (brs, 4H), 1.92 (m, 2H), 1.74 (m, 4H), 1.54 (m, 2H), 1.27 (s, 3H); MS (ESI) m/z = 417.2 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)- 4-((6'-氯-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(47 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.70 (d, 1H), 8.66 (s, 1H), 8.43 (m, 3H), 7.78 (s, 1H), 7.63 (s, 1H), 7.37 (m, 2H), 7.00 (s, 1H), 3.76 (brs, 4H), 3.68 (s, 2H), 3.37 (m, 1H), 2.82 (m, 1H), 2.55 (brs, 4H), 1.97 (m, 2H), 1.74 (m, 8H), 1.31 (s, 3H), 1.25 (m, 2H); MS (ESI) m/z = 646.2 (M + H)
+
範例30. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 1-(6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)-
N,
N-二甲基甲胺
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(103 mg),程序差異之處在於以1-(6-溴基-2-吡啶基)-
N,
N-二甲基甲胺(99 mg,0.462 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。MS (ESI) m/z = 266.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(112 mg),程序差異之處在於以驟1中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-6-基)-
N,
N-二甲基甲胺(103 mg,0.387 mmol) 步及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.387 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.39 (d, 1H), 8.48 (d, 1H), 8.38 (s, 1H), 7.65 (s, 1H), 7.21 (d, 1H), 6.55 (s, 1H), 3.47 (s, 2H), 3.32 (m, 1H), 2.26 (s, 6H), 1.92 (m, 2H), 1.72 (m, 4H), 1.54 (m, 2H), 1.29 (s, 3H); MS (ESI) m/z = 375.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(48.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(42 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.52 (d, 1H), 8.66 (s, 1H), 8.43 (m, 4H), 7.69 (s, 1H), 7.17 (m, 3H), 3.48 (m, 3H), 2.82 (m, 1H), 2.28 (s, 6H), 1.97 (m, 2H), 1.74 (m, 4H), 1.53 (m, 4H), 1.30 (s, 3H), 1.21 (m, 2H); MS (ESI) m/z = 604.3 (M + H)
+
範例31. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-5-(1,3-二氧戊環-2-基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為米白色固體(1250 mg),程序差異之處在於以2-溴基-5-(1,3-二氧戊環-2-基)吡啶(2680 mg,11.65 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。MS (ESI) m/z = 280.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(1,3-二氧戊環-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(1367 mg),程序差異之處在於以驟1中所製備之6'-氯-5-(1,3-二氧戊環-2-基)-4'-氟-2,3'-聯吡啶(1076 mg,3.83 mmol) 步及順
-4-胺基-1-甲基環己-1-醇(495 mg,3.83 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3,600 MHz) δ 9.38 (d, 1H), 8.66 (s, 1H), 7.88 (dd, 1H), 7.73 (d, 1H), 6.56 (s, 1H), 5.89 (s, 1H), 4.17-4.07 (m, 4H), 3.35 (m, 1H), 1.93 (m, 2H), 1.72 (m, 4H), 1.57 (m, 2H), 1.30 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,3-二氧戊環-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(600 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(1,3-二氧戊環-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(1175 mg,3.02 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.48 (d, 1H), 8.67 (d, 2H), 8.48 (s, 1H), 8.45 (s, 1H), 8.41 (d, 1H), 7.87 (m, 2H), 7.54 (d, 1H), 7.02 (brs, 1H), 5.89 (s, 1H), 4.19-4.07 (m, 4H), 3.53 (m, 1H), 2.82 (m, 1H), 1.99 (m, 2H), 1.76 (m, 4H), 1.62 (m, 2H), 1.53 (m, 2H), 1.30 (s, 3H), 1.22 (m, 2H); MS (ESI) m/z = 619.2 (M + H)
+
步驟4. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-羰醛
在步驟3中所製備之(1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,3-二氧戊環-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(520 mg,0.84 mmol)之1,4-二氧陸圜(8 mL) 溶液中加入4N鹽酸溶液(2 mL)。將此混合物在室溫下攪拌10小時。再將反應混合物以飽和NaHCO
3溶液鹽基化,以DCM及水稀釋,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-10%))純化而產出形態為白色固體之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-羰醛(450 mg)。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.13 (s, 1H), 10.07 (s, 1H), 9.67 (d, 1H), 9.10 (s, 1H), 8.67 (m, 2H), 8.45 (m, 1H), 8.23 (s, 2H), 7.50 (s, 1H), 7.40 (s, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H), 1.59 (m, 2H), 1.44 (m, 2H), 1.33 (m, 2H), 1.23 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 575.2 (M + H)
+
步驟5. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例25步驟2之方式製備標題化合物,其形態為米白色固體(10 mg),程序差異之處在於以6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-羰醛 (25 mg,0.044 mmol)及二甲胺(8 mg,0.174 mmol)代替6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛及嗎啉。
1H-NMR (CDCl
3, 400 MHz) δ 10.73 (d, 1H), 8.65 (s, 1H), 8.59 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.45 (d, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.10 (d, 1H), 7.07 (d, 1H), 3.66 (m, 1H), 3.57 (s, 2H), 2.84 (m, 1H), 2.34 (s, 6H), 2.02 (m, 2H), 1.86 (m, 2H), 1.74 (m, 2H), 1.65 (m, 2H), 1.54 (m, 2H), 1.32 (s, 3H), 1.24 (m, 2H); MS (ESI) m/z = 604.2 (M + H)
+
範例32. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例25步驟2之方式製備標題化合物,其形態為米白色固體(11.2 mg),程序差異之處在於以範例31步驟4中之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-羰醛 (30 mg,0.052 mmol)代替6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛。
1H-NMR (CDCl
3, 400 MHz) δ 10.97 (d, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.49 (d, 2H), 8.41 (s, 1H), 8.26 (m, 3H), 8.07 (s, 1H), 7.88 (d, 1H), 7.07 (d, 1H), 3.77 (m, 4H), 3.70 (m, 1H), 3.65 (s, 2H), 2.83 (m, 1H), 2.58 (m, 4H), 2.03 (m, 2H), 1.88 (m, 2H), 1.75 (m, 2H), 1.65 (m, 2H), 1.55 (m, 2H), 1.33 (s, 3H), 1.24 (m, 2H); MS (ESI) m/z = 646.2 (M + H)
+
範例33. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例25步驟2之方式製備標題化合物,其形態為米白色固體(11.1 mg),程序差異之處在於以範例31步驟4中之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-羰醛 (30 mg,0.052 mmol)及4,4-二氟哌啶(19 mg,0.156 mmol)代替6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛及嗎啉。
1H-NMR (CDCl
3, 400 MHz) δ 10.99 (d, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.47 (m, 4H), 8.32 (s, 1H), 8.07 (s, 1H), 7.85 (d, 1H), 7.75 (d, 1H), 7.07 (d, 1H), 3.69 (m, 1H), 3.63 (s, 2H), 2.84 (m, 1H), 2.62 (brs, 4H), 2.10-2.02 (m, 6H), 1.87 (m, 2H), 1.75 (m, 2H), 1.62 (m, 2H), 1.55 (m, 2H), 1.33 (s, 3H), 1.23 (m, 2H); MS (ESI) m/z = 680.2 (M + H)
+
範例34. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-異丙基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例25步驟2之方式製備標題化合物,其形態為米白色固體(10.5 mg),程序差異之處在於以範例31步驟4之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-羰醛 (25 mg,0.044 mmol)及1-異丙基哌嗪(17 mg,0.131 mmol)代替6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-羰醛及嗎啉。
1H-NMR (MeOD, 400 MHz) δ 8.79 (s, 1H), 8.59 (s, 1H), 8.50 (d, 2H), 8.43 (d, 1H), 8.38 (s, 2H), 7.90 (s, 2H), 7.23 (d, 1H), 7.14 (s, 1H), 3.72 (s, 2H), 3.60 (m, 1H), 3.47 (m, 1H), 3.28 (m, 8H), 3.03 (m, 1H), 1.97 (m, 2H), 1.78 (m, 4H), 1.59 (m, 2H), 1.46 (m, 2H), 1.37 (s, 6H), 1.25 (m, 5H); MS (ESI) m/z = 687.3 (M + H)
+
範例35. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(364 mg),程序差異之處在於以2-溴基吡啶(307 mg,1.942 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.03 (d, 1H), 8.77 (d, 1H), 7.83-7.79 (m, 1H) 7.76-7.74 (m, 1H), 7.36-7.33 (m, 1H), 7.21 (d, 1H); MS (ESI) m/z = 208.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(220 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-2,3'-聯吡啶(150 mg,0.719 mmol)及順
-4-胺基-1-甲基環己-1-醇(111 mg,0.863 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.38 (s,1H), 8.58-8.57 (m, 1H), 8.40 (s, 1H), 7.82-7.77 (m, 1H), 7.73-7.71 (m, 1H), 7.26-7.23 (m, 1H), 6.58 (s, 1H), 3.39-3.33 (m, 1H), 1.96-1.94 (m, 2H), 1.78-1.63 (m, 4H), 1.58-1.55 (m, 2H), 1.31 (s, 3H), 1.20 (s, 1H); MS (ESI) m/z = 319.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(50 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(173 mg,0.543 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.61 (s, 1H), 8.47-8.45 (m, 4H), 8.26 (s, 1H), 8.11 (s, 1H), 7.84 (t, 1H), 7.75 (d, 1H), 7.27 (t, 1H), 7.06 (d, 1H), 4.71 (t, 1H), 4.59 (t, 1H), 4.04 (s, 1H), 3.13 (t, 1H), 3.06 (t, 1H), 2.88-2.83 (m, 2H), 2.15-2.11 (m, 2H), 2.00-1.90 (m, 4H), 1.63-1.54 (m, 2H), 1.27-1.25 (m,3H); MS (ESI) m/z = 547.1 (M + H)
+
範例36.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. (1
s,4
s)-
N 1-(6'-氯-[2,3'-聯吡啶]-4'-基)-
N 4-(2-氟乙基)環己烷-1,4-二胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(195 mg),程序差異之處在於以範例35步驟1中所製備之6'-氯-4'-氟-2,3'-聯吡啶(150 mg,0.719 mmol)及(1
s,4
s)-
N 1- (2-氟乙基)環己烷-1,4-二胺(138 mg,0.863 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.69 (s, 1H), 8.78 (d, 1H), 8.42 (s, 1H), 7.81-7.78 (m, 1H), 7.74 (d, 1H), 7.25-7.23 (m, 1H), 6.58 (s, 1H), 4.62 (t,1 H), 4.50 (t, 1H), 3.66 (s, 1H), 2.97 (t, 1H), 2.90 (t, 1H), 2.78-2.58 (m, 1H), 1.93-1.90 (m, 2H), 1.82-1.70 (m, 4H), 1.55-1.49 (m, 3H); MS (ESI) m/z = 349.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(5 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-
N 1-(6'-氯-[2,3'-聯吡啶]-4'-基)-
N 4-(2-氟乙基)環己烷-1,4-二胺(189 mg,0.543 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (s, 1H), 8.67 (s, 1H), 8.58 (d,1H), 8.49 (s, 1H), 8.44-8.42 (m, 2H), 7.80-7.72 (m, 2H), 7.53 (s, 1H), 7.36 (d, 1H), 7.20 (t, 1H), 6.97 (s, 1H), 3.50 (br, 1H), 2.85-2.81 (m, 1H), 2.03-1.99 (m, 2H), 1.82-1.74 (m, 4H), 1.59-1.58 (m, 1H), 1.55-1.53 (m, 3H), 1.32 (s, 3H), 1.23-1.21 (m, 3H); MS (ESI) m/z = 578.2 (M + H)
+
範例37. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(220 mg),程序差異之處在於以範例35步驟1中所製備之6'-氯-4'-氟-2,3'-聯吡啶(150 mg,0.719 mmol)及(1
s,4
s)-4-胺基-1-(羥甲基)環己-1-醇(125 mg,0.863 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.32 (d, 1H), 8.47 (d, 1H), 8.28-8.26 (m, 1H), 7.72-7.60 (m, 2H), 7.16-7.13 (d, 1H), 6.49-6.47 (m, 1H), 4.16-4.14 (m, 1H), 3.41 (s, 1H), 3.26 (s, 2H), 1.86 (s, 2H), 1.75-1.67 (m, 4H), 1.40-1.37 (m, 2H); MS (ESI) m/z = 334.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇
以如同範例1步驟3之方式製備標題化合物(53 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇(194 mg,0.58 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.53 (d, 1H), 8.66 (s, 1H), 8.64-8.54 (m,1H) 8.49 (s, 1H), 8.43-8.37 (m, 2H), 7.80-7.61 (m, 2H), 7.53 (s, 1H), 7.21-7.18 (m, 3H), 2.87-2.83 (m, 1H), 2.08-2.05 (m, 2H), 1.81-1.62 (m, 5H), 1.56-1.50 (m, 4H), 1.26-1.23 (m, 3H); MS (ESI) m/z = 563.0 (M + H)
+
範例38. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(111 mg),程序差異之處在於以參考範例25中所製備之4-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)嗎啉(93 mg,0.316 mmol)及順
-4-胺基-1-甲基環己-1-醇(49 mg,0.379 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.21 (d, 1H), 8.29 (s, 1H), 8.22 (d, 1H), 7.60 (d, 1H), 7.29 (d, 1H), 6.53 (s, 1H) 3.89 (t, 4H), 3.33-3.32 (m, 1H), 3.23 (t, 4H), 1.94-1.91 (m, 3H), 1.77-1.66 (m, 4H), 1.56-1.53 (m, 2H), 1.45 (s, 1H), 1.25 (s。3H); MS (ESI) m/z = 403.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(3.6 mg),其形態為淺黃色固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(105 mg,0.261 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.33 (s, 1H), 8.66 (s, 1H), 8.45 (d, 1H), 8.40 (s, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 7.84 (br, 1H), 7.63 (d, 1H), 7.31 (d, 2H), 7.01 (s, 1H), 3.91 (t, 4H), 3.50 (s, 1H), 3.25 (t, 4H), 2.85-2.80 (m, 1H), 1.99-1.81 (m, 3H), 1.76-1.52 (m, 6H), 1.31 (s, 3H), 1.28-1.19 (m, 3H); MS (ESI) m/z = 632.3 (M + H)
+
範例39. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-
N,
N-二甲基嘧啶-5-胺
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(59 mg),程序差異之處在於以2-溴基-
N,
N-二甲基嘧啶-5-胺(88 mg,0.436 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.07 (d, 1H), 8.33 (s, 2H), 7.19 (d, 1H), 3.09 (s, 6H); MS (ESI) m/z = 252.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(80 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-
N,
N-二甲基嘧啶-5-胺(59 mg,0.233 mmol)及順
-4-胺基-1-甲基環己-1-醇(56 mg,0.436 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.51 (d, 1H), 9.13 (s, 1H), 8.25 (s, 2H), 6.55 (s, 1H), 3.39-3.36 (m, 1H), 3.02 (s, 6H), 1.99-1.94 (m, 2H), 1.79-1.70 (m, 4H), 1.29 (s, 3H), 1.26-1.19 (m, 3H); MS (ESI) m/z = 362.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(10 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(85 mg,0.235 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.61 (s, 1H), 9.13 (s, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.40 (d, 1H), 8.26 (s, 2H), 7.13 (s, 1H), 7.08 (s, 1H) 7.06-6.99 (m, 1H), 3.57-3.50 (m, 1H), 3.50 (s, 5H), 2.86-2.80 (m, 1H), 2.08-2.02 (m,2H), 1.85-1.76 (m, 4H), 1.54-1.53 (m, 4H), 1.33 (s, 3H), 1.29-2.27 (m, 6H); MS (ESI) m/z = 591.2 (M + H)
+
範例40. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-
N,
N-二甲基-[2,3'-聯吡啶]-5-胺
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(46 mg),程序差異之處在於以6-溴基-
N,
N-二甲基吡啶-3-胺(88 mg,0.436 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d,1H), 8.26 (d, 1H), 7.61 (t, 1H), 7.15 (d, 1H), 7.03 (dd, 1H), 3.07 (s, 6H); MS (ESI) m/z = 251.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(65 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-
N,
N-二甲基-[2,3'-聯吡啶]-5-胺(46 mg,0.183 mmol)及順
-4-胺基-1-甲基環己-1-醇(56 mg,0.436 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.24 (d, 1H), 8.27 (s, 1H), 8.07 (d, 1H), 7.50 (d, 1H), 7.10 (dd,1H), 6.52 (s, 1H), 3.35-3.32 (m, 1H), 2.95 (s, 6H), 1.96-1.93 (m, 2H), 1.78-1.70 (m, 4H), 1.65-1.55 (m,3H), 1.26-1.22 (m, 2H); MS (ESI) m/z = 361.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(4.4 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(70 mg,0.194 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.85 (s, 1H), 8.54 (s, 1H), 8.48-8.46 (m, 3H), 8.37 (s, 1H), 7.73 (d, 1H), 7.27 (dd, 1H), 7.10 (d, 1H), 6.88 (s, 1H), 4.50 (s, 1H), 3.57 (s, 1H), 3.06 (s, 6H), 1.98-1.94 (m, 3H), 1.83-1.78 (m, 5H), 1.63-1.56 (m, 3H), 1.49-1.44 (m, 3H), 1.39-1.33 (m, 2H); MS (ESI) m/z = 590.2 (M + H)
+
範例41. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-
N,
N-二甲基嘧啶-4-胺
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(152 mg),程序差異之處在於以2-溴基-
N,
N-二甲基-嘧啶-4-胺(157 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.11 (d, 1H), 8.32 (d, 1H), 7.95 (d, 1H), 7.19 (d, 1H), 6.42 (d, 1H), 6.34 (d, 1H), 3.18 (s, 6H); MS (ESI) m/z = 252.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(4-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(108 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-
N,
N-二甲基嘧啶-4-胺(150 mg,0.594 mmol)及順
-4-胺基-1-甲基環己-1-醇(115 mg,0.89 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.88 (d, 1H), 9.22 (s, 1H), 8.18 (d, 1H), 6.54 (s, 1H), 6.33 (d, 1H), 3.37-3.32 (m, 1H), 3.17 (s, 6H), 2.06-1.94 (m, 2H), 1.78-1.60 (m, 5H), 1.31 (s, 3H), 1.16 (s, 1H); MS (ESI) m/z = 362.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(13 mg),其形態為為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(4-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(105 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 9.67 (d, 1H), 9.09 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.22 (d, 1H), 7.49 (s, 1H), 7.28 (s, 1H), 6.54 (d, 1H), 3.23-3.12 (m, 2H), 3.02 (s, 6H), 1.85-1.82 (m, 2H), 1.64-1.56 (m, 4H), 1.44-1.38 (m, 2H), 1.33-1.31 (m, 2H) 1.31-1.25 (m, 3H), 1.24 (s, 3H); MS (ESI) m/z = 591.3 (M + H)
+
範例42. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟-3-吡啶基)噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(34 mg),程序差異之處在於以3-溴基噠嗪(123 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 9.24 (dd, 1H), 7.94 (d, 1H), 7.63 (dd, 1H), 7.30 (s, 1H); MS (ESI) m/z = 209.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(38 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟-3-吡啶基)噠嗪(35 mg,0.167 mmol)及順
-4-胺基-1-甲基環己-1-醇(32 mg,0.25 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.53 (s, 1H), 9.11 (t, 1H), 7.94 (d,1H), 7.60 (dd, 1H), 6.66 (s, 1H), 3.42-3.40 (m, 1H), 1.98-1.94 (m, 2H), 1.80-1.76 (m,4h),1.59-1.55 (m, 2H), 1.31 (s, 3H), 1.26 (s, 1H); MS (ESI) m/z = 319.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(10 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(59 mg,0.185 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.62 (d, 1H), 9.07 (t, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 7.94 (d, 1H), 7.58-7.50 (m, 2H), 7.35 (d, 1H), 7.08 (s, 1H), 3.58-3.57 (m, 1H), 2.86-2.82 (m, 1H), 2.06-2.00 (m, 2H), 1.88-1.62 (m, 5H), 1.58-1.52 (m, 4H), 1.26-1.20 (m, 4H), 1.15-1.13 (m, 1H); MS (ESI) m/z = 548.2 (M + H)
+
範例43. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 4-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)嗎啉
以如同範例1步驟1之方式製備標題化合物,其形態為米灰色固體(67 mg),程序不同之處在於以4-(6-溴基-3-噠嗪基)嗎啉(142 mg,0.583 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.17 (d, 1H), 7.70 (dd, 1H), 7.21 (d, 1H), 6.84 (d, 1H), 3.89 (t, 4H), 3.73 (t, 4H)
步驟2. (1
s,4
s)-4-((2-氯-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(74 mg),程序差異之處在於以步驟1中所製備之4-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)嗎啉(58 mg,0.197 mmol)及順
-4-胺基-1-甲基環己-1-醇(38 mg,0.295 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.27 (s, 1H), 7.69 (d, 1H), 7.04 (d, 1H), 6.61 (s, 1H), 4.13 (t, 4H), 3.89 (t, 4H), 3.38-3.36 (m, 1H), 1.96-1.94 (m, 2H), 1.82-1.73 (m, 4H), 1.61-1.60 (m, 1H), 1.54 (s, 1H), 1.20 (s, 3H); MS (ESI) m/z = 404.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(14.9 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(70 mg,0.173 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.30 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H), 8.29 (s, 1H), 7.72 (d, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 7.05 (d, 1H), 6.69 (s ,1H), 3.89 (t, 4H), 3.67 (t, 4H), 3.53-3.51 (m, 1H), 2.85-2.81 (m, 1H), 2.06-1.99 (m, 2H), 1.85-1.74 (m, 5H), 1.56-1.52 (m, 3H), 1.31 (s,H) 1.29-1.19 (m.3H); MS (ESI) m/z = 633.3 (M + H)
+
範例44. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 4-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)嗎啉
將2-氯-4-氟-5-碘吡啶(133 mg,0.515 mmol)、4-(5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡嗪-2-基)嗎啉(150 mg,0.515 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II) 、錯合有二氯甲烷(42 mg,0.05 mmol)與3 M K
2CO
3溶液(0.77 mL,2.32 mmol)在1,4-二氧陸圜(4 mL)中之反應混合物於70 °C攪拌3小時。將反應混合物冷卻至室溫並以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 10-60%)純化而產出形態為淺黃色固體之4-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)嗎啉(130 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.98 (d, 1H), 8.56 (s, 1H), 8.24 (s, 1H), 7.19 (d, 1H), 3.87 (t, 4H), 3.67 (t, 4H); MS (ESI) m/z = 294.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(103 mg),程序差異之處在於以步驟1中所製備之4-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)嗎啉(130 mg,0.441 mmol)及順
-4-胺基-1-甲基環己-1-醇(85 mg,0.662 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.50 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 6.55 (s, 1H), 3.87 (t, 4H), 3.61 (t, 4H), 3.35-3.33 (t, 1H), 1.95-1.91 (m, 2H), 1.77-1.70 (m, 3H), 1.67-1.54 (m, 3H), 1.31 (s, 3H); MS (ESI) m/z = 404.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(11 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(89 mg,0.22 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.42 (d, 1H), 8.39 (d, 1H), 8.31 (s, 1H), 8.07 (s, 1H), 7.53 (s, 1H), 7.35 (d, 1H), 6.97 (s, 1H), 3.88 (t, 4H), 3.65 (t, 4H), 3.50 (s, 1H), 2.84-2.81 (m, 1H), 2.00-1.98 (m, 2H), 1.75-1.70 (m, 5H), 1.56-1.51 (m, 3H), 1.32 (s, 3H), 1.29-1.27 (m, 3H); MS (ESI) m/z = 633.2 (M + H)
+
範例45. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為淺黃色固體(94 mg),程序差異之處在於以參考範例25中所製備之4-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)嗎啉(85 mg,0.289 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(59 mg,0.376 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.79 (d, 1H), 8.36 (s, 1H), 8.20 (d, 1H), 7.67 (d, 1H), 7.32 (dd, 1H), 6.56 (s, 1H), 3.91 (t, 1H), 3.84-3.82 (m, 1H), 3.23 (t, 4H), 2.03-2.00 (m, 2H), 1.78-1.65 (m, 2H), 1.43-1.33 (m, 4H), 1.26 (s, 2H), 1.22 (s, 6H); MS (ESI) m/z = 403.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(6.6 mg),其形態為淺黃色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(85 mg,0.197 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.90 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.39 (d, 1H), 8.36 (s, 1H), 7.69 (d, 1H), 7.34-7.29 (m, 1H), 7.10 (d, 1H), 3.98 (s, 1H), 3.91 (t, 4H), 3.23 (t, 4H), 2.87-2.83 (m, 1H), 2.12-2.10 (m, 2H), 1.80-1.75 (m, 4H), 1.56-1.53 (m, 5H), 1.23 (s, 7H), 1.14 (d, 2H); MS (ESI) m/z = 660.3 (M + H)
+
範例46. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-(4-甲基哌嗪-1-基)噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(102 mg),程序差異之處在於以3-溴基-6-(4-甲基哌嗪-1-基)噠嗪(149 mg,0.583 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.99 (d, 1H), 8.43 (d, 1H), 7.63 (t, 1H), 7.16 (d, 1H), 4.23 (t, 1H), 3.34 (t, 4H), 2.61 (t, 4H), 2.38 (s, 3H); MS (ESI) m/z = 307.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米灰色固體(47 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4-甲基哌嗪-1-基)噠嗪(93 mg,0.303 mmol)及順
-4-胺基-1-甲基環己-1-醇(59 mg,0.455 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.29 (d, 1H), 8.25 (s, 1H), 7.66 (d, 1H), 7.05 (d, 1H), 6.60 (s, 1H), 3.73 (t, 4H), 3.58 (t, 4H), 3.38-3.36 (m, 1H), 2.38 (s, 3H), 1.96-1.94 (m, 2H), 1.81-1.73 (m, 5H), 1.57-.1.54 (m, 2H), 1.26 (s, 3H); MS (ESI) m/z = 417.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(6.1 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(45 mg,0.108 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.30 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H) 8.28 (s, 1H), 7.68 (d, 1H), 7.34 (d, 1H), 7.06 (d, 1H), 7.00 (s, 1H), 3.71 (t, 4H), 3.50 (s, 1H), 2.85-2.81 (m, 1H), 2.58 (t, 4H), 2.38 (s, 3H), 2.01-1.97 (m, 2H), 1.85-1.82 (m, 3H), 1.75-1.51 (m。6H), 1.30 (s, 3H), 1.24-1.19 (m, 2H); MS (ESI) m/z = 646.2 (M + H)
+
範例47. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-5-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(97 mg),程序差異之處在於以2-溴基-5-(4,4-二氟哌啶-1-基)吡啶(161 mg,0.583 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.45 (d, 1H), 7.65 (d, 1H), 7.17 (d, 1H), 3.50 (t, 4H), 2.20-2.01 (m, 5H); MS (ESI) m/z = 327.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(102 mg),程序差異之處在於以步驟1中所製備之6'-氯-5-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶(92 mg,0.28 mmol)及順
-4-胺基-1-甲基環己-1-醇(54 mg,0.42 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.20 (d, 1H), 8.31 (s, 1H), 8.27 (d, 1H), 7.62 (d, 1H), 7.34 (dd, 1H), 6.55 (s, 1H), 3.45 (t, 4H), 3.38-3.31 (m, 1H), 2.19-2.10 (m, 4H), 1.98-1.93 (m, 2H), 1.78-1.66 (m, 5H), 1.31 (s, 3H), 1.29-1.25 (m, 2H), 1.17-1.15 (m, 1H); MS (ESI) m/z = 437.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(21 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(97 mg,0.223 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 8.27 (s, 1H), 7.63 (d, 1H), 7.37-7.32 (m, 2H), 7.00 (s, 1H), 3.50 (s, 1H), 3.45 (t, 4H), 2.85-2.81 (m, 1H), 2.20-2.11 (m, 4H), 2.02-2.00 (m, 2H), 1.81-1.74 (m, 4H), 1.64-1.54 (m, 4H), 1.32 (s, 3H), 1.26-1.19 (m。3H); MS (ESI) m/z = 666.3 (M + H)
+
範例48. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 4-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)嗎啉
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(77 mg),程序差異之處在於以4-(2-溴基吡啶-4-基)嗎啉(142 mg,0.583 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.95 (d, 1H), 8.43 (d, 1H), 7.19 (d, 1H), 7.09 (s, 1H), 6.71 (dd, 1H), 3.88 (t, 4H), 3.36 (t, 4H); MS (ESI) m/z = 294.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(98 mg),程序差異之處在於以步驟1中所製備之4-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)嗎啉(74 mg,0.252 mmol)及順
-4-胺基-1-甲基環己-1-醇(49 mg,0.378 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.02 (d, 1H), 8.28 (d, 1H), 8.25 (s, 1H), 6.96 (d, 1H), 6.65 (dd, 1H), 6.53 (s, 1H), 3.87 (t, 4H), 3.36 (t, 4H), 3.31 (s, 1H), 1.94-1.90 (m, 2H), 1.76-1.67 (m, 4H), 1.56-1.53 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 403.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(34 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(95 mg,0.236 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.14 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.42 (d, 1H), 8.29 (d, 1H), 7.53 (s, 1H), 7.36 (d, 1H), 7.23 (s, 1H), 7.00 (t, 1H), 6.93 (s,1H), 6.64 (dd, 1H), 3.88 (t, 4H), 3.46 (s, 1H), 3.37 (t, 4H), 2.85-2.81 (m, 1H), 1.99-1.97 (m, 2H), 1.79-1.73 (m, 5H), 1.56-1.52 (m, 3H), 1.31 (m, 3H), 1.30-1.27 (m, 3H); MS (ESI) m/z = 632.3 (M + H)
+
範例49. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇
步驟1. 1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)哌啶-4-醇
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(143 mg),不同之處在於以1-(6-溴基-3-吡啶基)哌啶-4-醇(150 mg,0.583 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.44 (s, 1H), 7.62 (d, 1H), 7.29 (d, 1H), 7.25 (d, 1H), 7.16 (d, 1H), 3.97-3.92 (m, 2H), 3.71-3.67 (m, 2H), 3.66-3.52 (m, 1H), 3.14-3.13 (m, 2H), 3.11-3.08 (m, 1H), 2.08-2.03 (m, 3H), 1.74-1.62 (m, 3H); MS (ESI) m/z = 307.9 (M + H)
+
步驟2. 1-(6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(95 mg),程序差異之處在於以步驟1中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)哌啶-4-醇(86 mg,0.28 mmol)及順
-4-胺基-1-甲基環己-1-醇(54 mg,0.839 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.24 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.58 (d, 1H), 7.32 (dd, 1H), 6.53 (s, 1H), 3.96-3.93 (m, 1H), 3.67-3.62 (m, 2H), 3.35-3.33 (m, 1H), 3.10-3.03 (m, 2H), 2.07-2.03 (m, 2H), 1.95-1.93 (m, 2H), 1.78-1.69 (m, 6H), 1.29 (s, 3H), 1.27-1.26 (m, 1H), 1.18 (s, 1H); MS (ESI) m/z = 417.1 (M + H)
+
步驟3. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇
以如同範例1步驟3之方式製備標題化合物(7 mg),其形態為固體,程序差異之處在於以步驟2中所製備之1-(6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇(93 mg,0.223 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.36 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.31 (s, 1H), 8.26 (d, 1H), 7.59 (d, 1H), 7.35-7.32 (m, 2H), 7.01 (s, 1H), 3.94-3.93 (m, 1H), 3.67-3.63 (m, 2H), 3.62 (s, 1H), 3.09-3.03 (m, 2H), 2.83-2.82 (m, 1H), 2.08-2.01 (m, 5H), 1.99-1.71 (m, 6H), 1.56-1.51 (m, 3H), 1.26 (s, 3H), 1.22-1.21 (m, 3H); MS (ESI) m/z = 646.3 (M + H)
+
範例50. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 6-(6-氯-4-氟吡啶-3-基)-3,4-二甲基噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(95 mg),程序不同之處在於以6-溴基-3,4-二甲基-噠嗪(145 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.17 (d, 1H), 7.62 (s, 1H), 7.25 (d, 1H), 2.75 (s, 3H), 2.40 (s, 3H); MS (ESI) m/z = 237.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(81 mg),程序差異之處在於以步驟1中所製備之6-(6-氯-4-氟吡啶-3-基)-3,4-二甲基噠嗪(90 mg,0.379 mmol)及順-4-胺基-1-甲基環己-1-醇(73 mg,0.568 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.54 (d, 1H), 8.37 (s, 1H), 7.63 (s, 1H), 6.63 (s, 1H), 3.40-3.36 (m, 1H), 2.70 (s, 3H), 2.40 (s, 3H), 1.95-1.92 (m, 2H), 1.82-1.72 (m, 4H), 1.54-1.53 (m, 2H), 1.26 (s, 3H); MS (ESI) m/z = 347.0 (M + H)
+
步驟3. 1 (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(22.5 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(80 mg,0.231 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.59 (d。1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H), 8.40 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.33 (d, 1H), 7.05 (s, 1H), 3.57-3.55 (m, 1H), 2.85-2.80 (m, 1H), 2.70 (s 3H), 2.40 (s, 3H), 2.02-1.98 (m, 2H), 1.86-1.68 (m, 5H), 1.60-1.49 (m, 5H), 1.30 (s, 3H), 1.27-1.20 (m, 1H); MS (ESI) m/z = 576.2 (M + H)
+
範例51. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-(三氟甲基)噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(177 mg),程序差異之處在於以3-溴基-6-(三氟甲基)噠嗪(176 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.31 (d, 1H), 8.14 (d, 1H), 7.96 (d, 1H), 7.33 (d, 1H); MS (ESI) m/z = 278.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(135 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(三氟甲基)噠嗪(105 mg,0.379 mmol)及順
-4-胺基-1-甲基環己-1-醇(73 mg,0.568 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.46 (d, 1H), 8.47 (s, 1H), 8.14 (d, 1H), 7.91 (d, 1H), 6.70 (s, 1H), 3.45-3.41 (m, 1H), 1.97-1.94 (m, 2H), 1.85-1.76 (m, 4H), 1.55 (s, 2H), 1.31 (s, 3H), 1.26-1.20 (m, 1H); MS (ESI) m/z = 387.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(19 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(89 mg,0.231 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.55 (d, 1H), 8.68 (s, 1H), 8.49 (s, 2H), 8.47 (d, 1H), 8.12 (d, 1H), 7.86 (d, 1H), 7.52 (d, 1H), 7.33 (d, 1H),7.14 (s, 1H), 3.60-3.58 (m, 1H), 2.86-2.81 (m, 1H), 2.06-2.01 (m, 2H), 1.89-1.75 (m, 5H), 1.56-1.50 (m, 3H), 1.32 (s, 3H), 1.26-1.20 (m, 3H); MS (ESI) m/z = 616.2 (M + H)
+
範例52. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-甲基噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(76 mg),程序差異之處在於以3-溴基-6-甲基-噠嗪(134.38 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.20 (d, 1H), 7.81 (dd, 1H), 7.46 (d, 1H), 7.25 (s, 1H), 2.81 (s, 3H); MS (ESI) m/z = 223.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(103 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-甲基噠嗪(75 mg,0.335 mmol)及順
-4-胺基-1-甲基環己-1-醇(65 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.56 (d,1H), 8.38 (s, 1H), 7.84 (d, 1H), 7.45 (d, 1H), 6.64 (s, 1H), 3.42-3.39 (m, 1H), 2.95 (s, 3H), 1.97-1.93 (m, 2H), 1.83-1.71 (m, 4H), 1.61-1.58 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 333.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(24.6 mg),其形態為米灰色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(100 mg,0.3 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.62 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H), 8.41 (s, 2H), 7.85 (d, 1H), 7.68 (s, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.06 (s, 1H), 3.56-3.55 (m, 1H), 2.86-2.80 (m, 1H), 2.75 (s, 3H), 2.03-1.99 (m, 2H), 1.87-1.78 (m, 3H), 1.64-1.53 (m, 5H), 1.30 (s, 3H); MS (ESI) m/z = 562.2 (M + H)
+
範例53. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-甲氧基噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(84 mg),程序差異之處在於以3-溴基-6-甲氧基-噠嗪(147 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.14 (d, 1H), 7.81 (dd, 1H), 7.25 (d, 1H), 7.11 (d, 1H), 4.22 (s, 3H); MS (ESI) m/z = 239.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(105 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-甲氧基噠嗪(80 mg,0.335 mmol)及順
-4-胺基-1-甲基環己-1-醇(65 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.32 (s, 1H), 7.82 (d, 1H), 7.10 (d, 1H), 6.63 (s, 1H), 4.18 (s, 3H), 3.40-3.37 (m, 1H), 1.99-1.94 (m, 2H), 1.80-1.77 (m, 5H), 1.58-1.55 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 333.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(71 mg),其形態為米白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(105 mg,0.3 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.30 (d, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.44 (d, 1H), 8.34 (s, 1H), 7.84 (d, 1H), 7.47 (s, 1H), 7.38 (d, 1H), 7.30 (s, 1H), 7.09 (d, 1H), 7.01 (s, 1H), 4.18 (s, 3H), 3.60-3.54 (m, 1H), 2.86-2.80 (m, 1H), 2.05-1.95 (m, 2H), 1.87-1.75 (m, 4H), 1.56-1.40 (m, 3H), 1.32 (s, 3H), 1.26-1.10 (m, 4H); MS (ESI) m/z = 578.2 (M + H)
+
範例54. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(哌啶-1-基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(130 mg),程序 不同之處在於以2-溴基-5-(1-哌啶基)吡啶(187 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.42 (d, 1H), 7.61 (dd, 1H), 7.23 (d, 1H), 7.16 (d, 1H), 3.31 (t, 4H), 1.77-1.71 (m, 4H), 1.67-1.65 (m, 2H); MS (ESI) m/z = 291.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(130 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(哌啶-1-基)-2,3'-聯吡啶(98 mg,0.335 mmol)及順
-4-胺基-1-甲基環己-1-醇(65 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.30 (s, 1H), 8.23 (d, 1H), 7.57 (d, 1H), 7.30 (dd, 1H), 6.53 (s, 1H) 3.35-3.33 (m, 1H), 3.26 (t, 4H), 1.95-1.93 (m, 2H), 1.78-1.69 (m, 8H), 1.66-1.62 (m, 3H), 1.31 (s, 3H), 1.17 (s, 1H); MS (ESI) m/z = 401.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(10.5 mg),其形態為米灰色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(120 mg,0.3 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.32 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H), 8.24 (d, 1H), 7.58 (d, 1H), 7.33-7.30 (m, 2H), 6.95 (s, 3H), 3.50-3.49 (m, 2H), 3.26 (t, 4H), 2.85-2.81 (m, 1H), 2.01-1.99 (m, 2H), 1.74-1.64 (m, 8H), 1.60-1.52 (m, 3H), 1.31 (s。3H), 1.26-1.19 (m。3H); MS (ESI) m/z = 630.3 (M + H)
+
範例55. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)甲醇
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(480 mg),程序差異之處在於以2-溴基-4-(羥甲基)吡啶(500 mg,2.659 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.71 (d, 1H), 7.74 (s, 1H), 7.35 (d, 1H), 7.21 (d, 1H), 4.83 (d, 2H), 2.31 (t, 1H); MS (ESI) m/z = 238.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(449 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)甲醇(475 mg,1.99 mmol)及順
-4-胺基-1-甲基環己-1-醇(386 mg,2.986 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.37 (d, 1H), 8.54 (d, 1H), 8.41 (s, 1H), 7.72 (s, 1H), 7.01 (s, 1H), 6.57 (s, 1H), 3.36-3.34 (m, 1H), 1.96-1.93 (m, 2H), 1.78-1.68 (m, 4H), 1.31-1.26 (m, 6H); MS (ESI) m/z = 348.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(273 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(445 mg,1.279 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.49 (d。1H), 8.67 (s, 1H), 8.54 (d, 1H), 8.48 (s, 1H), 8.44-8.42 (m, 2H), 7.74 (s, 1H), 7.30 (s, 1H), 7.20 (d, 1H), 7.03 (d, 1H), 4.83 (s, 2H), 3.53 (s, 1H), 3.50 (s, 2H), 2.85-2.82 (m, 2H), 2.02-1.74 (m, 5H), 1.61-1.42 (m, 3H), 1.32-1.23 (m, 8H); MS (ESI) m/z = 577.2 (M + H)
+
步驟4. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-羰醛
將(1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(235 mg,0.410 mmol)與戴斯馬丁氧化劑(346 mg,0.820 mmol)在DCM (4 mL)中之反應混合物攪拌20分鐘。而後以飽和NaHCO
3溶液將反應混合物淬火。將有機層濃縮。粗反應混合物以矽膠管柱層析(MeOH/DCM = 0-20%)純化而產出形態為黃色固體之6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-羰醛 (247 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 10.15 (s, 1H), 9.55 (d, 1H), 8.81 (d, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.47 (d, 1H), 8.16 (s, 1H), 7.61 (d, 1H), 7.23 (s, 2H), 3.57-3.50 (m, 1H), 2.85-2.80 (m, 1H), 2.06-2.01 (m, 2H), 1.84-1.74 (m, 7H), 1.66-1.62 (m, 3H), 1.59-1.48 (m, 2H), 1.33 (s, 3H), 1.29-1.20 (m, 1H); MS (ESI) m/z = 575.1 (M + H)
+
步驟5. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
將6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-羰醛(30 mg,0.050 mmol)、三乙醯氧基硼氫鈉 (55 mg,0.260 mmol)與1-甲基哌嗪(0.02 mL,0.160 mmol)之反應混合物攪拌4小時。而後以飽和NaHCO
3溶液將反應混合物淬火。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-20%)純化而產出形態為米白色固體之(1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(7.9 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (d, 1H), 8.67 (s, 1H), 8.50-8.48 (m, 2H), 8.44 (s, 1H), 8.42 (d, 1H), 7.72 (s, 1H), 7.33 (d, 1H), 7.18 (d, 1H), 7.00 (s, 1H), 3.57 (s, 2H), 3.51-3.50 (m, 1H), 2.86-2.80 (m, 1H), 2.53 (br, 6H), 2.31 (s, 3H), 2.02-1.98 (m, 2H), 1.81-1.74 (m, 6H), 1.63-1.51 (m, 5H), 1.31 (s, 3H), 1.29-1.19 (m, 2H); MS (ESI) m/z = 659.3 (M + H)
+
範例56. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-5-甲氧基吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(127 mg),程序差異之處在於以2-溴基-5-甲氧基-吡嗪(147 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.58 (s, 1H), 8.36 (s, 1H), 7.23 (d, 1H), 4.05 (s, 3H); MS (ESI) m/z = 239.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(141 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-甲氧基吡嗪(125 mg,0.522 mmol)及順
-4-胺基-1-甲基環己-1-醇(81 mg,0.626 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.49 (d, 1H), 8.30 (s, 1H), 8.20 (d, 1H), 8.15 (d, 1H), 6.57 (s, 1H), 4.02 (s, 3H), 3.35-3.31 (m, 1H), 1.95-1.91 (m, 2H), 1.77-1.67 (m, 4H), 1.63-1.54 (m, 2H), 1.31 (s, 3H), 1.29-1.26 (m, 1H); MS (ESI) m/z = 349.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(12 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(92 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.01 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.43-8.39 (m, 2H), 8.35 (s, 1H), 8.10 (d, 1H), 7.55 (s, 1H), 7.25 (s, 1H), 3.94 (s, 3H), 1.97-1.78 (m, 2H), 1.60-1.42 (m, 4H), 1.40-1.36 (m, 2H), 1.33-1.26 (m, 2H), 1.25-1.24 (m, 3H), 1.11 (s, 3H); MS (ESI) m/z = 578.2 (M + H)
+
範例57. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(113 mg),程序差異之處在於以參考範例25中所製備之4-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)嗎啉(100 mg,0.34 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(73 mg,0.443 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.69 (d, 1H), 8.33 (s, 1H), 8.21 (d, 1H), 7.64 (d, 1H), 7.29 (dd, 1H), 6.52 (s, 1H), 3.89 (t, 1H), 3.74-3.72 (m, 1H), 3.24 (t, 1H), 2.37 (br, 1H), 2.14 (d, 2H), 1.89-1.86 (m, 2H), 1.71-1.58 (m, 5H), 1.31-1.28 (m, 2H); MS (ESI) m/z = 403.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(4.8 mg),其形態為固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(105 mg,0.261 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.62 (d, 1H), 8.46-8.44 (m, 2H), 8.21 (s, 1H), 8.12 (d, 1H), 7.63 (d, 1H), 7.32 (dd, 1H), 7.06 (d, 1H), 4.11 (s, 1H), 3.90 (t, 4H), 3.58 (d, 2H), 3.27 (t, 4H), 2.87-2.83 (m, 1H), 2.11-2.05 (m, 2H), 1.95-1.81 (m, 2H), 1.78-1.72 (m, 2H), 1.57-1.54 (m, 1H), 1.53-1.40 (m, 2H), 1.26-1.22 (m, 3H); MS (ESI) m/z = 632.3 (M + H)
+
範例58. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-4-(4-甲基哌嗪-1-基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為固體(156 mg),程序差異之處在於以1-(2-溴基-4-吡啶基)-4-甲基-哌嗪(199 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.91 (d, 1H), 8.37 (d, 1H), 7.17 (d, 1H), 7.06 (s, 1H), 6.69 (dd, 1H), 3.40 (t, 1H), 2.55 (t, 4H), 2.35 (s, 3H); MS (ESI) m/z = 307.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(110 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-4-(4-甲基哌嗪-1-基)-2,3'-聯吡啶(160 mg,0.522 mmol)及順
-4-胺基-1-甲基環己-1-醇(81 mg,0.626 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.24-8.23 (m, 2H), 6.94 (d, 1H), 6.64 (dd, 1H), 6.52 (s, 1H), 3.41 (t, 4H), 3.33-3.26 (m, 1H), 2.56 (t, 4H), 2.36 (s, 3H), 2.05-1.89 (m, 3H), 1.78-1.63 (m,5H), 1.58-1.52 (m, 2H), 1.29 (s, 3H); MS (ESI) m/z = 416.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(21 mg),其形態為米白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(110 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.11 (d, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 8.26 (d, 1H), 7.34 (d, 1H), 6.99 (d, 1H), 6.95 (s, 1H), 6.63 (dd, 1H), 3.49-3.41 (m, 5H), 2.82-2.81 (m, 1H), 2.56 (t, 4H), 2.37 (s, 3H), 1.99-1.95 (m, 3H), 1.84 (br, 4H), 1.78-1.71 (m ,2H), 1.61-1.50 (m, 3H), 1.30 (s, 3H), 1.27-1.19 (m, 2H); MS (ESI) m/z = 645.3 (M + H)
+
範例59. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-5-甲基吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(100 mg),程序差異之處在於以2-溴基-5-甲基-吡嗪(134 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 8.93 (s, 1H), 8.60 (s, 1H), 7.25 (d, 1H), 2.66 (s, 3H); MS (ESI) m/z = 224.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(117 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-甲基吡嗪(107 mg,0.522 mmol)及順
-4-胺基-1-甲基環己-1-醇(81 mg,0.626 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.88 (s, 1H), 8.72 (d, 1H), 8.41 (s, 1H), 8.37 (s, 1H), 6.57 (s, 1H), 3.36-3.32 (m, 1H), 2.59 (s, 3H), 1.96-1.90 (m, 2H), 1.88-1.76 (m, 4H), 1.74-1.68 (m, 2H), 1.28 (s, 3H); MS (ESI) m/z = 333.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(39.7 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(88 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 9.09 (s, 1H), 8.74 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 3.22-3.15 (m, 1H), 1.80 (s, 2H), 1.63-1.54 (m, 4H), 1.43-1.38 (m, 2H), 1.32-1.31 (m, 2H), 1.24-1.21 (m, 4H), 1.12 (s, 3H); MS (ESI) m/z = 562.2 (M + H)
+
範例60. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. (5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)甲醇
以如同範例1步驟1之方式製備標題化合物,其形態為固體(480 mg),程序差異之處在於以(5-溴基吡嗪-2-基)甲醇(503 mg,2.659 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.07 (d, 1H), 9.00 (s, 1H), 8.78 (s, 1H), 4.93 (d, 2H), 3.26 (t, 1H); MS (ESI) m/z = 239.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(464 mg),程序差異之處在於以步驟1中所製備之(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)甲醇(475 mg,1.982 mmol)及順
-4-胺基-1-甲基環己-1-醇(384 mg,2.973 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.99 (s, 1H), 8.80 (d, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 6.62 (s, 1H), 4.89 (s 2H), 3.50-3.36 (m, 1H), 2.09-1.92 (m, 2H), 1.78-1.61 (m, 4H), 1.57-1.43 (m, 4H), 1.26 (s, 3H); MS (ESI) m/z = 349.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(85 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(316 mg,0.906 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.05 (s, 1H), 9.15 (d, 1H), 8.85 (s, 1H), 8.66-8.63 (m, 2H), 8.46 (s, 1H), 8.42 (d, 1H), 7.50 (s, 1H), 7.34 (s, 1H), 5.70-5.67 (s, 1H), 4.64 (d, 2H), 4.29 (s, 1H), 3.22-3.18 (m, 1H), 1.80 (s, 2H), 1.65-1.55 (m, 5H), 1.44-.1.38 (m, 2H), 1.33-1.28 (m, 2H), 1.26-1.24 (m, 3H), 1.23 (s, 3H); MS (ESI) m/z = 578.2 (M + H)
+
範例61. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例55步驟5之方式製備標題化合物(7.2 mg),其形態為固體,程序差異之處在於以嗎啉(0.01 mL,0.157 mmol)代替1-甲基哌嗪。
1H-NMR (CDCl
3,600 MHz) δ 9.63 (s, 1H), 8.65 (s, 1H), 8.49 (d, 1H), 8.47 (s, 1H), 8.41-8.39 (m, 2H), 7.71 (s, 1H), 7.20 (s, 1H), 7.18 (d, 1H), 3.74 (t, 4H), 3.55 (s, 2H), 3.52 (s, 1H), 2.82-2.80 (m, 1H), 2.49 (s, 4H), 2.04-1.98 (m, 5H), 1.78-1.72 (m, 5H), 1.61-1.59 (m, 2H), 1.59-1.51 (m, 2H), 1.30 (s, 3H), 1.25-1.20 (m, 5H); MS (ESI) m/z = 646.3 (M + H)
+
範例62. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-甲基哌嗪-1-基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)吡嗪-2-羰醛
以如同範例55步驟4之方式製備標題化合物(50 mg),其形態為黃色固體,程序差異之處在於以範例60中所製備之(1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(50 mg,0.087 mmol)代替(1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.19 (s, 1H), 10.03 (s, 1H), 9.50 (d, 1H), 9.29 (d,1H), 9.06 (d, 1H), 8.89 (s, 1H), 8.67 (s, 1H), 8.47-8.45 (m, 2H) 7.47 (s, 1H), 7.43 (s, 1H), 1.84-1.82 (m, 2H), 1.71-1.69 (m, 2H), 1.66-1.56 (m, 2H), 1.44-1.42 (m, 2H), 1.39-1.31 (m, 2H), 1.28-1.25 (m, 4H), 1.12 (s, 3H); MS (ESI) m/z = 576.2 (M + H)
+
步驟2. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-甲基哌嗪-1-基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例55步驟5之方式製備標題化合物(5.8 mg),其形態為固體,程序差異之處在於以步驟1中所製備之5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)吡嗪-2-羰醛 (15 mg,0.026 mmol)代替6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-羰醛。
1H-NMR (CDCl
3,600 MHz) δ 9.01 (d, 2H), 8.66 (s, 1H), 8.53 (d, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 8.42 (s, 1H), 7.71 (s, 1H), 7.30 (s, 1H), 7.07 (s, 1H), 3.73 (s, 2H), 3.48 (s, 1H), 2.83-2.82 (m, 1H), 2.80-2.61 (m, 6H), 2.30 (s, 4H), 2.00-1.97 (m, 3H), 1.77-1.72 (m, 3H), 1.62-1.57 (m, 3H), 1.53-1.51 (m, 3H), 1.31 (s, 4H), 1.30-1.19 (m, 6H); MS (ESI) m/z = 660.3 (M + H)
+
範例63. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-5-(二氟甲基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為固體(130 mg),程序差異之處在於以2-溴基-5-(二氟甲基)吡啶(162 mg,0.777 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.10 (d, 1H), 8.89 (s, 1H), 7.97 (d, 1H), 7.87 (d, 1H), 7.24 (d, 1H), 6.79 (t, 1H); MS (ESI) m/z = 258.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(125 mg),程序差異之處在於以步驟1中所製備之6'-氯-5-(二氟甲基)-4'-氟-2,3'-聯吡啶(85 mg,0.329 mmol)及順
-4-胺基-1-甲基環己-1-醇(64 mg,0.494 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.33 (d, 1H), 8.72 (d, 1H), 8.44 (s, 1H), 7.94 (dd, 1H), 7.83 (d, 1H), 6.76 (t, 1H), 6.60 (s, 1H), 3.38-3.35 (m, 1H), 1.96-1.93 (m, 2H), 1.78-1.63 (m, 4H), 1.58-1.54 (m, 1H), 1.26 (s, 3H), 1.20 (s, 1H); MS (ESI) m/z = 368.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(25 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(120 mg,0.326 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 600 MHz) δ 9.47 (d, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.47 (s, 2H), 8.43 (d, 1H), 7.91 (d, 1H), 7.83 (d, 1H), 7.30 (s, 1H), 7.26 (s, 1H), 7.05 (s, 1H), 6.75 (t, 1H), 3.53 (s, 1H), 2.83-2.81 (m, 1H), 2.04-1.99 (m, 3H), 1.80-1.76 (m, 6H), 1.74-1.51 (m, 3H), 1.31 (s, 4H); MS (ESI) m/z = 597.3 (M + H)
+
範例64. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例55步驟5之方式製備標題化合物(1 mg),其形態為固體,程序差異之處在於以二甲胺(0.01 mL,0.157 mmol)代替1-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.66 (d, 1H), 8.66 (s, 1H), 8.51 (d, 1H), 8.49 (s, 1H), 8.42-8.41 (m, 2H), 7.70 (s, 1H), 7.01 (s, 2H), 3.55 (s, 1H), 3.50 (s, 2H), 2.85-2.80 (m, 1H), 2.30 (s, 4H), 2.04-1.99 (m, 3H), 1.80-1.77 (m, 2H), 1.64-1.61 (m, 4H), 1.54-1.51 (m, 3H), 1.34 (s, 3H), 1.23-1.20 (m, 2H); MS (ESI) m/z = 604.3 (M + H)
+
範例65. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((二甲胺基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例55步驟5之方式製備標題化合物(1.9 mg),其形態為固體,程序差異之處在於以範例62步驟1中所製備之5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)吡嗪-2-羰醛 (15 mg,0.026 mmol)及二甲胺(4 mg,0.078 mmol)代替6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-羰醛及1-甲基哌嗪。
1H-NMR (MeOD, 400 MHz) δ 9.12 (s, 1H), 8.74 (s, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.38 (d, 1H), 7.43 (d, 1H), 7.34 (s, 1H), 3.72 (s, 2H), 3.61 (s, 1H), 3.03 (s, 1H), 2.36 (s, 5H), 2.04-1.90 (m, 4H), 1.81-1.72 (m, 4H), 1.61-1.55 (m, 4H), 1.44 (s, 2H), 1.29-1.26 (m, 4H); MS (ESI) m/z = 605.2 (M + H)
+
範例66. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-溴基-6-(3,3-二氟吖丁啶-1-基)噠嗪
將3-溴基-6-氟-噠嗪(100 mg,0.570 mmol)、3,3-二氟吖丁啶鹽酸鹽(110 mg,0.848 mmol)與DIPEA (0.49 mL,2.825 mmol)在DMA (3 mL)中之反應混合物於100 °C攪拌4小時。反應混合物經冷卻後稀釋於EA,以水清洗,利用 MgSO
4乾燥後濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-10%)純化而產出3-溴基-6-(3,3-二氟吖丁啶-1-基)噠嗪(123 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 7.41 (d, 1H), 6.56 (d, 1H), 4.49 (t, 4H); MS (ESI) m/z = 231.9 (M + H)
+
步驟2. 3-(6-氯-4-氟吡啶-3-基)-6-(3,3-二氟吖丁啶-1-基)噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(53 mg),程序差異之處在於以步驟1中所製備之3-溴基-6-(3,3-二氟吖丁啶-1-基)噠嗪(87 mg,0.349 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.14 (d, 1H), 7.73 (d, 1H), 7.22 (d, 1H), 6.75 (d, 1H), 4.58 (t, 4H); MS (ESI) m/z = 301.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-氯-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(68 mg),程序差異之處在於以步驟2中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(3,3-二氟吖丁啶-1-基)噠嗪(54 mg,0.179 mmol)及順
-4-胺基-1-甲基環己-1-醇(35 mg,0.269 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.16 (d, 1H), 8.26 (s,1H), 7.74 (d, 1H), 6.79 (d, 1H), 6.61 (s, 1H), 4.59-4.52 (m, 4H), 3.38-3.35 (m, 1H), 1.95-1.81 (m, 1H), 1.77-1.60 (m, 4H), 1.59-1.53 (m, 3H), 1.29 (s, 3H); MS (ESI) m/z = 410.0 (M + H)
+
步驟4. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(8 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((2-氯-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(50 mg,0.122 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.22 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.43 (d, 1H), 8.28 (s, 1H), 7.76 (d, 1H), 7.61 (s, 1H), 7.36 (d, 1H), 7.01 (d, 1H), 6.81 (d, 1H), 4.59-4.53 (m, 4H), 3.52-3.50 (m, 1H), 2.85-2.81 (m, 1H), 2.05-1.99 (m, 3H), 1.86-1.74 (m, 5H), 1.55-1.52 (m, 3H), 1.31 (s, 3H), 1.30-1.29 (m, 3H); MS (ESI) m/z = 639.2 (M + H)
+
範例67. (1
s,4
s)-4-((5-(6-(2-氧雜-6-氮螺[3.3]庚烷-6-基)噠嗪-3-基)-2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 6-(6-溴基噠嗪-3-基)-2-氧雜-6-氮螺[3.3]庚烷
以如同範例66步驟1之方式製備標題化合物(40 mg),其形態為固體,程序差異之處在於以2-氧雜-6-氮螺[3.3]庚烷(84 mg,0848 mmol)代替3,3-二氟吖丁啶。
1H-NMR (CDCl
3, 400 MHz) δ 7.31 (d, 1H), 6.44 (d, 1H), 4.87 (s, 4H), 4.29 (s, 4H); MS (ESI) m/z = 257.9 (M + H)
+
步驟2. 6-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)-2-氧雜-6-氮螺[3.3]庚烷
以如同範例1步驟1之方式製備標題化合物,其形態為固體(59 mg),程序差異之處在於以步驟1中所製備之6-(6-溴基噠嗪-3-基)-2-氧雜-6-氮螺[3.3]庚烷(89 mg,0.348 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.13 (d, 1H), 7.65 (d, 1H), 7.20 (d, 1H), 6.62 (d, 1H), 4.90 (s, 4H), 4.39 (s, 4H), 4.37 (s, 4H); MS (ESI) m/z = 307.0 (M + H)
+
步驟3. (1
s,4
s)-4-((5-(6-(2-氧雜-6-氮螺[3.3]庚烷-6-基)噠嗪-3-基)-2-氯吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(67 mg),程序差異之處在於以步驟2中所製備之6-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)-2-氧雜-6-氮螺[3.3]庚烷(55 mg,0.179 mmol)及順
-4-胺基-1-甲基環己-1-醇(35 mg,0.269 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.98 (d, 1H), 8.24 (s, 1H), 7.66 (d, 1H), 6.69 (d, 1H), 6.60 (s,1H), 4.90 (s, 4H), 3.38-3.35 (m, 1H), 1.94-1.92 (m, 2H), 1.77-1.71 (m, 4H), 1.57-1.44 (m, 2H), 1.29 (s, 3H); MS (ESI) m/z = 416.1 (M + H)
+
步驟4. (1
s,4
s)-4-((5-(6-(2-氧雜-6-氮螺[3.3]庚烷-6-基)噠嗪-3-基)-2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(3 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((5-(6-(2-氧雜-6-氮螺[3.3]庚烷-6-基)噠嗪-3-基)-2-氯吡啶-4-基)胺基)-1-甲基環己-1-醇(51 mg,0.122 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.26 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.42 (d, 1H), 8.25 (s, 1H), 7.80 (br, 1H), 7.67 (d, 1H), 7.33 (d, 1H), 7.03 (s, 1H), 6.70 (d, 1H), 4.90 (s, 4H), 4.37 (s, 4H), 3.52 (s, 1H), 2.85-2.83 (s, 1H), 2.05-1.97 (m, 2H), 1.84-1.77 (m, 2H), 1.63-1.53 (m, 3H), 1.30 (s, 3H), 1.26-1.25 (m, 3H); MS (ESI) m/z = 645.3 (M + H)
+
範例68. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(327 mg),程序差異之處在於以3-溴基-6-(4,4-二氟哌啶-1-基)噠嗪(652 mg,2.343 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.16 (d, 1H), 7.70 (dd, 1H), 7.22 (d, 1H), 7.06 (d, 1H), 3.93 (t, 4H), 2.17-2.07 (m, 4H); MS (ESI) m/z = 329.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(90 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪(75 mg,0.228 mmol)及順
-4-胺基-1-甲基環己-1-醇(44 mg,0.342 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.24 (d, 1H), 8.26 (s, 1H), 7.19 (d, 1H), 7.10 (d, 1H), 6.61 (s, 1H), 3.88 (t, 4H), 3.38-3.37 (m, 1H), 2.16-2.06 (m, 4H), 1.96-1.94 (m, 2H), 1.82-1.60 (m, 4H), 1.55-1.54 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 438.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(17.7 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(85 mg,0.194 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.43 (d, 1H), 8.29 (s, 1H), 7.72 (d, 1H), 7.50 (s, 1H), 7.37 (d, 1H), 7.06 (d, 1H), 6.99 (s, 1H), 3.88 (t, 4H), 3.53 (s, 1H), 2.84-2.80 (m, 1H), 2.16-2.07 (m, 4H), 2.03-2.00 (m, 2H), 1.86-1.75 (m, 4H), 1.31 (s, 3H), 1.27 (s, 3H); MS (ESI) m/z = 667.3 (M + H)
+
範例69. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(100 mg),程序差異之處在於以範例68步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪(75 mg,0.228 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(54 mg,0.342 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.82 (d, 1H), 8.30 (d, 1H), 7.74 (d, 1H), 7.12 (d, 1H), 6.62 (s, 1H), 3.87 (t, 4H), 3.82 (s, 1H), 3.58 (d, 1H), 2.17-2.07 (m, 4H), 1.92-1.89 (m, 2H), 1.74-1.68 (m, 5H), 1.53-1.46 (m, 2H); MS (ESI) m/z = 438.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(16.3 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇(85 mg,0.194 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.89 (d, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.32 (s, 1H), 7.76 (d, 1H), 7.53 (s, 1H), 7.17 (d, 1H), 7.12 (d, 1H), 4.00 (s, 1H), 3.87 (t, 4H), 3.58 (d, 1H), 2.88-2.84 (m, 1H), 2.16-2.02 (m, 6H), 1.85-1.78 (m, 5H), 1.55-1.52 (m, 4H), 1.48-1.27 (m, 3H); MS (ESI) m/z = 667.3 (M + H)
+
範例70. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-5-(4,4-二氟哌啶-1-基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(423 mg),程序差異之處在於以2-溴基-5-(4,4-二氟哌啶-1-基)吡嗪(652 mg,2.343 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.98 (d, 1H), 8.56 (t, 1H), 8.32 (d, 1H), 7.19 (d, 1H), 3.87 (t, 4H), 2.13-2.06 (m, 4H); MS (ESI) m/z = 329.0 (M + H)
+
步驟2. ((1
s,4
s)-4-((2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(98 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(4,4-二氟哌啶-1-基)吡嗪(84 mg,0.259 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(64 mg,0.388 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.82 (d, 1H), 8.55 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 6.56 (s, 1H), 3.83 (t, 4H), 3.78-3.77 (m, 1H), 3.54 (d, 2H), 2.14-2.06 (m, 4H), 1.92-1.89 (m, 2H), 1.72-1.68 (m, 3H), 1.65 (s, 2H), 1.50 (s, 1H), 1.37-1.28 (m, 2H); MS (ESI) m/z = 438.0 (M + H)
+
步驟3. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(10.5 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之((1
s,4
s)-4-((2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇(84 mg,0.191 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.92 (d 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.41 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.15 (d, 1H), 3.96 (s, 1H), 3.83 (t, 4H), 3.55 (d, 2H), 2.84 (s, 1H), 2.14-2.01 (m, 6H), 1.83-1.71 (m, 5H), 1.55-1.49 (m, 3H), 1.39-1.26 (m, 4H), 1.24-2.20 (m, 5H); MS (ESI) m/z = 667.2 (M + H)
+
範例71. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(86 mg),程序差異之處在於以範例68步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪(75 mg,0.228 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(54 mg,0.342 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.45 (d, 1H), 8.33 (s, 1H), 7.76 (d, 1H), 7.11 (d, 1H), 6.63 (s, 1H), 3.90 (s, 1H), 3.87-3.85 (m, 4H), 2.12-2.06 (m, 4H), 2.02-1.98 (m, 2H), 1.75 (m, 2H), 1.49-1.44 (m, 3H), 1.22 (m, 6H); MS (ESI) m/z = 466.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(7.5 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)丙-2-醇(79 mg,0.169 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 8.34 (s, 1H), 7.78 (d, 1H), 7.55 (s, 1H), 7.34 (s, 1H), 7.12 (d, 2H), 4.08-4.06 (m, 1H), 3.85 (t, 2H), 2.86-2.82 (m, 1H), 2.23-2.06 (m, 6H), 1.79-1.73 (m, 4H), 1.56-1.39 (m, 4H), 1.13 (s, 7H); MS (ESI) m/z = 695.3 (M + H)
+
範例72. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(98 mg),程序差異之處在於以範例70步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(4,4-二氟哌啶-1-基)吡嗪(85 mg,0.259 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(61 mg,0.388 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.87 (d, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 6.57 (s, 1H), 3.81 (t, 5H), 2.13-1.99 (m, 6H), 1.78-1.75 (m, 2H), 1.41-1.25 (m, 4H), 1.22 (s, 6H); MS (ESI) m/z = 466.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(13 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇(79 mg,0.169 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.92 (d, 1H), 8.66 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 8.35 (s, 1H), 8.11 (s, 1H), 7.53 (s, 1H), 7.13 (d, 1H), 3.98 (s, 1H), 3.81 (t, 4H), 2.85-2.83 (m, 1H), 2.12-2.06 (m, 6H), 1.80-1.72 (m, 4H), 1.55-1.54 (m, 3H), 1.46-1.33 (m, 4H), 1.23 (s, 6H); MS (ESI) m/z = 695.2 (M + H)
+
範例73.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺
步驟1. 2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(85 mg),程序差異之處在於以範例68步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪(75 mg,0.228 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(78 mg,0.342 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.65 (d, 1H), 8.29 (d, 1H), 7.27 (d, 1H), 7.11 (d, 1H), 6.61 (s, 1H), 3.88 (t, 4H), 3.73 (s, 1H), 2.24 (s, 6H), 2.20-2.07 (m, 6H), 1.86-1.83 (m, 2H), 1.74-1.63 (m, 5H), 1.43-1.34 (m, 2H); MS (ESI) m/z = 465.1 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(5 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-4-胺(79 mg,0.17 mmol)代替(1-(6’-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3’-聯吡啶]-4’-基)-4-甲基哌啶-4-基)甲醇(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.74 (d, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.31 (s, 1H), 7.75 (d, 1H), 7.60 (s, 1H), 7.30-7.18 (m, 2H), 7.12 (d, 1H), 3.92 (s, 1H), 3.87 (t, 4H), 2.85-2.83 (m, 1H), 2.23 (s, 6H), 2.18-2.09 (m, 6H), 1.99-1.96 (m, 2H), 1.83-1.77 (m, 2H), 1.61-1.55 (m, 2H), 1.42-1.39 (m, 3H); MS (ESI) m/z = 694.3 (M + H)
+
範例74.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺
步驟1. 2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為淺黃色固體(83 mg),程序差異之處在於以範例70步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(4,4-二氟哌啶-1-基)吡嗪(85 mg,0.259 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(89 mg,0.388 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.79 (d, 1H), 8.56 (s, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 6.55 (s, 1H), 3.84 (t, 4H), 3.34 (s, 1H), 2.53 (s, 6H), 2.18-2.05 (m, 6H), 1.89-1.86 (m, 2H), 1.73-1.62 (m, 3H), 1.29-1.23 (m, 2H); MS (ESI) m/z = 465.1 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(16 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-4-胺(79 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.88 (d, 1H), 8.66 (s, 1H), 8.63 (s, 1H), 8.58 (s, 1H), 8.41 (d, 1H), 8.35 (s, 1H), 8.14 (s, 1H), 7.69 (s, 1H), 7.19 (s, 2H), 3.92 (s, 2H), 3.83 (t, 4H), 2.85-2.83 (m, 1H), 2.16 (s, 6H), 2.14-2.06 (m, 6H), 2.02-1.98 (m, 2H), 1.81-1.66 (m, 4H), 1.54-1.53 (m, 3H), 1.29-1.26 (m, 4H); MS (ESI) m/z = 694.3 (M + H)
+
範例75. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為淺黃色固體(112 mg),程序差異之處在於以範例70步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(4,4-二氟哌啶-1-基)吡嗪(85 mg,0.259 mmol)及順
-4-胺基-1-甲基環己-1-醇(50 mg,0.388 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.50 (s, 1H), 8.33 (d, 1H), 8.29 (s, 1H), 8.13 (s, 1H), 6.55 (s, 1H), 3.82 (t, 4H), 3.35-3.33 (m, 1H), 2.13-2.04 (m, 4H), 1.94-1.91 (m, 2H), 1.77-1.54 (m, 5H), 1.31 (s, 3H); MS (ESI) m/z = 438.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(12 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((2-氯-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(84 mg,0.191 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.70 (d, 1H), 8.68 (s, 1H), 8.63 (s, 1H), 8.54 (s, 1H), 8.45-8.43 (m, 2H), 8.14 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.08 (d, 1H), 4.06 (s, 1H), 3.83 (t, 4H), 2.86-2.84 (m, 1H), 2.13-2.06 (m, 6H), 1.85 (s, 4H), 1.54 (s, 2H), 1.49-1.34 (m, 3H); MS (ESI) m/z = 667.3 (M + H)
+
範例76. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(376 mg),程序差異之處在於以2-溴基-4-(二氟甲基)吡啶(500 mg,2.404 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.09 (d, 1H), 8.89 (d, 1H), 7.88 (s, 1H), 7.48 (d, 1H), 7.25 (d, 1H), 6.72 (t, 1H); MS (ESI) m/z = 259.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(108 mg),程序差異之處在於以步驟1中所製備之6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶(80 mg,0.309 mmol)及順
-4-胺基-1-甲基環己-1-醇(60 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.26 (d, 1H), 8.70 (d, 1H), 8.43 (s, 1H), 7.81 (s, 1H), 7.37 (d, 1H), 6.70 (t, 1H), 6.60 (s, 1H), 3.35 (s, 1H), 1.96-1.93 (d, 2H), 1.78-1.65 (m, 4H), 1.61-1.54 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 368.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(35 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(80 mg,0.217 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.39 (d, 1H), 8.70 (d, 1H), 8.67 (s, 1H), 8.48 (d, 2H), 8.44 (d, 1H), 7.84 (s, 1H), 7.55 (s, 1H), 7.32 (d, 2H), 7.05 (s, 1H), 6.70 (t, 1H), 3.53 (s, 1H), 2.84-2.82 (m, 1H), 2.02-2.00 (m, 2H), 1.80-1.74 (m, 4H), 1.54-1.53 (m, 3H), 1.32 (s, 3H), 1.26-1.19 (m, 3H); MS (ESI) m/z = 597.2 (M + H)
+
範例77. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(109 mg),程序差異之處在於以範例76步驟1中所製備之6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶(80 mg,0.309 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(79 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.76 (d, 1H), 8.70 (d, 1H), 8.44 (s, 1H), 7.84 (s, 1H), 7.36 (d, 1H), 6.70 (t, 1H), 6.60 (s, 1H), 3.80 (s, 1H), 3.53 (d, 2H), 1.91-1.89 (m, 2H), 1.73-1.65 (m, 4H), 1.38-1.29 (m,2H); MS (ESI) m/z = (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(12 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(80 mg,0.217 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.89 (d, 1H), 8.70 (d, 1H), 8.67 (s, 1H), 8.49 (d, 1H), 8.42 (d, 1H), 7.88 (s, 1H), 7.63 (s, 1H), 7.32 (d, 1H), 7.11 (d, 1H), 6.71 (t, 1H), 4.01 (s, 1H), 3.54 (d, 2H), 2.85-2.84 (m, 1H), 2.06-2.04 (d, 2H), 1.85-1.73 (m, 3H), 1.55-1.42 (m, 2H), 1.39-1.26 (m, 2H), 1.24-1.22 (m, 4H); MS (ESI) m/z = 597.2 (M + H)
+
範例78. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(117 mg),程序差異之處在於以範例76步驟1中所製備之6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶(80 mg,0.309 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(73 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.81 (d, 1H), 8.70 (d, 1H), 8.46 (s, 1H), 7.86 (s, 1H), 7.36 (d, 1H), 6.71 (t, 1H), 6.61 (s, 1H), 3.84 (s, 1H), 2.05-1.98 (m, 2H), 1.80-1.77 (m, 3H), 1.66-1.60 (m, 2H), 1.43-1.34 (m, 6H); MS (ESI) m/z = 396.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(13 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(86 mg,0.217 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.91 (d, 1H), 8.69 (d, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.89 (s, 1H), 7.61 (s, 1H), 7.37 (s, 1H), 7.31 (d, 1H), 7.09 (d, 1H), 6.71 (t, 1H), 4.02 (s, 1H), 2.86-2.84 (d, 1H), 2.13-2.06 (m, 2H), 1.81-1.75 (m, 4H), 1.57-1.54 (m, 2H), 1.46-1.41 (m, 3H), 1.26 (s, 8H); MS (ESI) m/z = 625.2 (M + H)
+
範例79.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(二氟甲基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-4-(二氟甲基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(103 mg),程序差異之處在於以範例76步驟1中所製備之6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶(80 mg,0.309 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(106 mg,0.464 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.70 (d, 1H), 8.71 (d, 1H), 8.46 (s, 1H), 7.86 (s, 1H), 7.38 (d, 1H), 6.71 (t, 1H), 6.60 (s, 1H), 3.78 (s, 1H), 2.24 (s, 6H), 2.15-2.01 (m, 2H), 1.94-1.87 (m, 2H), 1.75-1.65 (m, 5H), 1.31-1.22 (m, 2H); MS (ESI) m/z = 395.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(二氟甲基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(35 mg),其形態為固體,程序差異之處在於以步驟1中所製備之6'-氯-4-(二氟甲基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4'-胺(86 mg,0.217 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.84 (d, 1H), 8.70 (d, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.88 (s, 1H), 7.60 (s, 1H), 7.32 (d, 1H), 7.13 (d, 1H), 6.71 (t, 1H), 3.98 (s, 1H), 2.86-2.84 (m, 1H), 2.25 (s, 6H), 2.17-2.15 (m, 2H), 2.03-2.00 (m, 2H), 1.83-1.68 (m, 4H), 1.55-1.54 (m, 2H), 1.32-1.24 (m, 4H); MS (ESI) m/z = 624.2 (M + H)
+
範例80. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(吡咯啶-1-基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(339 mg),程序差異之處在於以2-溴基-5-(吡咯啶-1-基)吡啶(546 mg,2.404 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.11 (s, 1H), 7.60 (d, 1H), 7.14 (d, 1H), 6.87 (d, 1H), 3.38 (s, 4H), 2.08 (s, 4H); MS (ESI) m/z = 278.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(107 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(吡咯啶-1-基)-2,3'-聯吡啶(80 mg,0.288 mmol)及順
-4-胺基-1-甲基環己-1-醇(56 mg,0.432 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.21 (d, 1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.54 (d, 1H), 6.94 (d, 1H), 6.52 (s, 1H), 3.35 (s, 4H), 2.07 (s, 4H), 1.96-1.93 (m, 2H), 1.78-1.67 (m, 5H), 1.27 (s, 3H), 1.27-1.18 (m, 2H); MS (ESI) m/z = 387.2 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(20 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(85 mg,0.22 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.31 (s, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.40 (d, 1H), 8.27 (s, 1H), 7.94 (s, 2H), 7.55 (d, 1H), 7.34 (s, 1H), 6.97-6.95 (m, 2H), 3.50 (s, 1H), 3.36 (s, 4H), 2.83-2.82 (m, 1H), 2.08 (s, 4H), 2.03-2.00 (m, 2H), 1.82-1.74 (m, 4H), 1.54-1.48 (m, 2H), 1.32 (s, 4H), 1.27 (s, 2H), 1.24 (s, 2H), 1.22-1.20 (m, 2H); MS (ESI) m/z = 616.3 (M + H)
+
範例81. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(100 mg),程序差異之處在於以範例80步驟1中所製備之6'-氯-4'-氟-5-(吡咯啶-1-基)-2,3'-聯吡啶(80 mg,0.288 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(68 mg,0.432 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.73 (d, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.58 (d, 1H), 6.95 (d, 1H), 6.53 (s, 1H), 3.78 (s, 1H), 3.54 (d, 1H), 3.36 (t, 4H), 2.07 (s, 4H), 1.94-1.91 (m, 2H), 1.61 (s, 5H), 1.42-1.27 (m, 2H); MS (ESI) m/z = 387.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(14.5 mg) ,其形態為淺黃色固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(85 mg,0.220 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.81 (d, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.38 (d, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.60 (d, 1H), 7.17 (d, 2H), 6.97 (d, 1H), 3.96 (s, 1H), 3.55 (d, 1H), 3.37 (s, 4H), 2.84 (s, 1H), 2.08 (s, 4H), 2.03 (s, 1H), 1.82-1.71 (m, 4H), 1.56-1.48 (m, 4H), 1.44-1.29 (m, 3H), 1.27-1.25 (m, 3H); MS (ESI) m/z = 616.3 (M + H)
+
範例82. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(92 mg),程序差異之處在於以範例80步驟1中所製備之6'-氯-4'-氟-5-(吡咯啶-1-基)-2,3'-聯吡啶(80 mg,0.288 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(68 mg,0.432 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.83 (d, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.59 (d, 1H), 6.68 (d, 1H), 6.53 (s, 1H), 3.82-3.81 (m,H), 3.35 (s, 4H), 2.06 (s, 4H), 2.03-1.99 (m, 2H), 1.74 (s, 3H), 1.63-1.57 (m, 2H), 1.40-1.67 (m, 1H), 1.22 (s, 6H); MS (ESI) m/z = 415.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(23 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(70 mg,0.169 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.93 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.30 (s, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.13 (d, 1H), 6.98 (dd, 1H), 3.98 (s, 1H), 3.35 (t, 4H), 2.85-2.83 (m, 1H), 2.13 (s, 1H), 2.09-2.05 (m, 4H), 1.75-1.71 (m, 4H), 1.56-1.54 (m, 3H), 1.52-1.43 (m, 3H), 1.32-1.26 (m, 2H), 1.25-1.23 (m, 8H); MS (ESI) m/z = 644.3 (M + H)
+
範例83. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(4-甲基哌嗪-1-基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為固體(392 mg),程序差異之處在於以1-(6-溴基吡啶-3-基)-4-甲基哌嗪(500 mg,1.952 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.43 (s, 1H), 7.63 (d, 1H), 7.24 (d, 1H), 7.16 (d, 1H), 3.34 (t, 4H), 2.61 (t, 4H), 2.38 (s, 3H); MS (ESI) m/z = 307.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為淺棕色固體(80 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(4-甲基哌嗪-1-基)-2,3'-聯吡啶(80 mg,0.261 mmol)及順
-4-胺基-1-甲基環己-1-醇(51 mg,0.391 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.23 (d, 1H), 8.30 (s, 1H), 8.23 (d, 1H), 7.59 (d, 1H), 7.31 (dd, 1H), 6.53 (s, 1H), 3.35-3.33 (m, 1H), 3.30 (t, 4H), 2.61 (t, 4H), 2.38 (s, 3H), 1.95-1.92 (m, 2H), 1.77-1.72 (m, 4H), 1.69-1.57 (m, 2H), 1.40 (s, 3H); MS (ESI) m/z = 416.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(14 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(64 mg,0.153 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.28 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.33 (s, 1H), 8.25 (d, 1H), 7.61 (d, 1H), 7.47 (s, 1H), 7.35-7.30 (m, 2H), 6.93 (s, 1H), 3.50-3.48 (m, 1H), 3.30 (t, 4H), 2.85-2.81 (m, 1H), 2.62 (t, 4H), 2.39 (s, 3H), 2.02-1.98 (m, 2H), 1.81-1.74 (m, 4H), 1.54-1.51 (m, 3H), 1.32 (s, 3H), 1.28-1.24 (m, 4H); MS (ESI) m/z = 645.3 (M + H)
+
範例84. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為淺棕色固體(80 mg),程序差異之處在於以範例83步驟1中所製備之6'-氯-4'-氟-5-(4-甲基哌嗪-1-基)-2,3'-聯吡啶(80 mg,0.261 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(62 mg,0.391 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.80 (d, 1H), 8.34 (s, 1H), 8.21 (d, 1H), 7.64 (d, 1H), 7.32 (dd, 1H), 6.55 (s, 1H), 3.83-3.81 (m, 1H), 3.28 (t, 4H), 2.61 (t, 4H), 2.05 (s, 3H), 2.05-1.99 (m, 2H), 1.77-1.74 (m, 2H), 1.64-1.58 (m, 3H), 1.40-1.32 (m, 3H), 1.21 (s, 6H); MS (ESI) m/z = 444.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(21 mg),其形態為淺黃色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(68 mg,0.153 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.90 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.39 (d, 1H), 8.35 (s, 1H), 8.22 (d, 1H), 7.81 (s, 1H), 7.65 (d, 1H), 7.33 (dd, 1H), 7.12 (d, 1H), 3.99 (s, 1H), 3.28 (t, 4H), 2.85-2.82 (m, 1H), 2.61 (t, 4H), 2.38 (s, 3H), 2.14-2.09 (m, 2H), 1.79-1.75 (m, 6H), 1.55 (d, 1H), 1.54-1.52 (m, 3H), 1.29-1.22 (m, 2H), 1.21 (s, 7H); MS (ESI) m/z = 673.3 (M + H)
+
範例85. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為淺棕色固體(64 mg),程序差異之處在於以範例83步驟1中所製備之6'-氯-4'-氟-5-(4-甲基哌嗪-1-基)-2,3'-聯吡啶(80 mg,0.261 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(62 mg,0.391 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.74 (d, 1H), 8.33 (s, 1H), 8.22 (d, 1H), 7.63 (d, 1H), 7.31 (dd, 1H), 6.54 (s, 1H), 3.80-3.76 (m, 1H), 3.54 (d, 2H), 3.31 (t, 4H), 2.62 (t, 4H), 2.38 (s, 3H), 1.94-1.90 (m, 2H), 1.73-1.61 (m, 4H), 1.41-1.32 (m, 2H); MS (ESI) m/z = 416.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(10 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(55 mg,0.132 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.81 (d, 1H), 8.66 (S, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.36 (s, 1H), 8.23 (d, 1H), 7.66 (d, 1H), 7.35 (s, 1H), 7.32 (d, 1H), 7.19 (s, 1H), 7.16 (d, 1H), 3.97 (s, 1H), 3.55 (d, 2H), 3.30 (t, 4H), 2.85-2.82 (m, 1H), 2.62 (t, 4H), 2.39 (s, 3H), 2.06-2.03 (m, 2H), 1.82-1.53 (m, 4H), 1.44-1.38 (m, 3H), 1.26-1.21 (m, 5H); MS (ESI) m/z = 645.1 (M + H)
+
範例86. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(450 mg),程序差異之處在於以2-(6-溴基噠嗪-3-基)丙-2-醇(500 mg,2.304 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.21 (d, 1H), 7.92 (d, 1H), 7.82 (d, 1H), 7.29 (s, 1H), 1.72 (s, 6H); MS (ESI) m/z = 267.9 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(65 mg),程序差異之處在於以步驟1中所製備之2-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)丙-2-醇(100 mg,0.374 mmol)及順
-4-胺基-1-甲基環己-1-醇(72 mg,0.56 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.40 (d, 1H), 8.39 (s, 1H), 7.92 (d, 1H), 7.77 (d, 1H), 6.65 (s, 1H), 4.07 (s, 1H), 3.42-3.38 (m, 1H), 2.08-1.94 (m, 2H), 1.84-1.71 (m, 5H), 1.62 (s, 6H), 1.62-1.55 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 377.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(16 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(52 mg,0.138 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (d, 1H), 8.68 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 8.43 (s, 1H), 7.93 (d, 1H), 7.72 (d, 1H), 7.53 (s, 1H), 7.36 (d, 1H), 7.06 (s, 1H), 3.57-3.55 (m, 1H), 2.87-2.80 (m, 1H), 2.03-2.01 (m, 1H), 1.86-1.80 (m, 4H), 1.69 (s, 6H), 1.57-1.52 (m, 3H), 1.29 (s, 3H), 1.27-1.23 (m, 3H); MS (ESI) m/z = 606.2 (M + H)
+
範例87. 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
步驟1. 2-(6-(6-氯-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(68 mg),程序差異之處在於以範例86步驟1中所製備之2-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)丙-2-醇(100 mg,0.374 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(93 mg,0.56 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.93 (d, 1H), 8.44 (s, 1H), 7.97 (d,1H), 7.75 (d, 1H), 6.67 (s, 1H), 4.21 (s, 1H), 3.86-3.83 (m, 1H), 3.56 (d, 2H), 1.95-1.91 (m, 2H), 1.77-1.70 (m, 4H), 1.69 (s, 6H), 1.49-1.46 (m, 2H); MS (ESI) m/z = 377.0 (M + H)
+
步驟2. 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(28.7 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6-(6-氯-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇(52 mg,0.138 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.05 (d, 1H), 8.67 (s, 1H), 8.46 (d, 2H), 8.44 (d, 1H), 7.98 (d, 1H), 7.71 (d, 1H), 7.64 (s, 1H), 7.36 (s, 1H), 7.15 (d, 1H), 4.04-4.03 (m, 1H), 3.57 (d, 1H), 2.87-2.83 (m, 1H), 2.07-2.04 (m, 2H), 1.87-1.81 (m, 2H), 1.76-1.73 (m, 2H), 1.70 (s, 6H), 1.61-1.41 (m, 6H), 1.26-1.22 (m, 3H); MS (ESI) m/z = 606.2 (M + H)
+
範例88. 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
步驟1. 2-(6-(6-氯-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(86 mg),程序差異之處在於以範例86步驟1中所製備之2-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)丙-2-醇(100 mg,0.374 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.56 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.19 (d, 1H), 8.47 (s, 1H), 7.98 (d, 1H), 7.75 (d, 1H), 6.69 (s, 1H), 3.95-3.91 (m, 1H), 2.04-2.01 (m, 2H), 1.79-1.76 (m, 2H), 1.66 (s, 7H), 1.62 (s, 3H), 1.45-1.43 (m, 2H), 1.37-1.25 (m, 2H), 1.21 (s, 6H); MS (ESI) m/z = 405.0 (M + H)
+
步驟2. 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(35 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-(6-(6-氯-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇(76 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.23 (d, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 8.00 (d, 1H), 7.71 (d, 1H), 7.60 (s, 1H), 7.42 (s, 1H), 7.10 (d, 1H), 4.25 (br, 1H), 4.12-4.08 (m, 1H), 2.88-2.82 (br, 1H), 2.14-2.11 (m, 2H), 1.78 (s, 4H), 1.62 (s, 6H), 1.57-1.48 (m, 5H), 1.26-1.24 (m, 2H), 1.22 (s, 6H); MS (ESI) m/z = 634.3 (M + H)
+
範例89. 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
步驟1. 2-(6-(6-氯-4-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(55 mg),程序差異之處在於以範例86步驟1中所製備之2-(6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)丙-2-醇(100 mg,0.374 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(128 mg,0.56 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.84 (d, 1H), 8.43 (s, 1H), 7.96 (d, 1H), 7.74 (d, 1H), 6.66 (s, 1H), 3.78 (s, 1H), 2.24 (s, 6H), 2.21-2.20 (m, 2H), 1.88-1.85 (m, 2H), 1.75-1.70 (m, 4H), 1.68 (s, 6H), 1.42-1.37 (m, 2H); MS (ESI) m/z = 404.0 (M + H)
+
步驟2. 2-(6-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(15.5 mg) ,其形態為淺黃色固體,程序差異之處在於以步驟1中所製備之2-(6-(6-氯-4-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇(41 mg,0.101 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.94 (d, 1H), 8.67 (s, 1H), 8.46 (d, 2H), 8.41 (d, 1H), 7.96 (d, 1H), 7.90 (s, 1H), 7.69 (d, 1H), 7.31 (s, 1H), 7.16 (d, 1H), 3.97 (s, 1H), 2.86-2.82 (m, 1H), 2.21 (s, 6H), 2.17-2.15 (m, 2H), 2.05-1.97 (m, 2H), 1.84-1.56 (m, 5H), 1.54 (s, 6H), 1.53-1.52 (m, 2H), 1.40-1.28 (m, 2H), 1.26-1.21 (m, 3H), 1.13 (d, 1H); MS (ESI) m/z = 633.3 (M + H)
+
範例90. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(3-甲氧基吖丁啶-1-基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為固體(455 mg),程序差異之處在於以2-溴基-5-(3-甲氧基吖丁啶-1-基)吡啶(550 mg,2.626 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.97 (d, 1H), 7.98 (d, 1H), 7.59 (dd, 1H), 7.15 (d, 1H), 6.80 (dd, 1H), 4.43-4.39 (m, 1H), 4.23 (t, 2H), 3.86 (t, 2H), 3.37 (s, 3H); MS (ESI) m/z = 294.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(90 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(3-甲氧基吖丁啶-1-基)-2,3'-聯吡啶(109 mg,0.371 mmol)及順
-4-胺基-1-甲基環己-1-醇(72 mg, 0.557 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.12 (d, 1H), 8.26 (s, 1H), 7.82 (d, 2H), 7.53 (d, 1H), 6.87 (dd, 1H), 6.52 (s, 1H), 4.42-4.39 (m, 1H), 4.20 (t, 2H), 3.83 (t, 4H), 3.37 (s, 3H), 3.35-3.31 (m, 1H), 1.95-1.92 (m, 2H), 1.77-1.66 (m, 4H), 1.61-1.57 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 403.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(19.3 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(115 mg,0.285 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.23 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.40 (d, 1H), 8.27 (s, 1H), 7.85 (s, 1H), 7.55 (d, 1H), 7.34 (d, 1H), 6.90 (s, 1H), 6.88 (d, 1H), 4.41-4.40 (m, 1H), 4.21 (t, 2H), 3.83 (t, 2H), 3.48 (s, 1H), 3.37 (s, 3H), 2.84-2.82 (m, 1H), 2.05-1.98 (m, 2H), 1.77-1.61 (m, 5H), 1.54-1.51 (m, 3H), 1.31 (s, 3H), 1.29-1.20 (m, 4H); MS (ESI) m/z = 632.3 (M + H)
+
範例91. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(82 mg),程序差異之處在於以範例90步驟1中所製備之6'-氯-4'-氟-5-(3-甲氧基吖丁啶-1-基)-2,3'-聯吡啶(109 mg,0.371 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(92 mg,0.557 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.61 (d, 1H), 8.29 (s, 1H), 7.80 (d, 1H), 7.58 (d, 1H), 6.87 (dd, 1H), 6.53 (s, 1H), 4.43-4.38 (m, 1H), 4.21 (t, 2H), 3.83 (t, 2H), 3.81-3.76 (m, 1H), 3.54 (d, 2H), 3.37 (s, 3H), 1.94-1.90 (m, 2H), 1.72-1.64 (m, 3H), 1.43-1.30 (m, 2H); MS (ESI) m/z = 403.0 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(15 mg),其形態為固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(70 mg,0.174 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.72 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 7.82 (d, 1H), 7.60 (d, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 6.89 (d, 1H), 4.42-4.40 (m, 1H), 4.22 (t, 2H), 3.96 (s, 1H), 3.84 (t, 2H), 3.54 (d, 2H), 3.37 (s, 3H), 2.84-2.82 (m, 1H), 2.05-2.03 (m, 2H), 1.82-1.71 (m, 4H), 1.54-1.51 (m, 3H), 1.41-1.32 (m, 3H), 1.29-1.21 (m, 4H); MS (ESI) m/z = 632.3 (M + H)
+
範例92. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(126 mg),程序差異之處在於以範例90步驟1中所製備之6'-氯-4'-氟-5-(3-甲氧基吖丁啶-1-基)-2,3'-聯吡啶(109 mg,0.371 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.557 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.69 (d, 1H), 8.30 (s, 1H), 7.78 (d, 1H), 7.59 (d, 1H), 6.88 (dd, 1H), 6.54 (s, 1H), 4.43-4.38 (m, 1H), 4.19 (t, 2H), 3.82-3.79 (m, 3H), 3.37 (s, 3H), 2.02-1.99 (m, 2H), 1.76-1.73 (m, 2H), 1.60-1.57 (m, 2H), 1.42-1.30 (m, 4H), 1.21 (s, 6H); MS (ESI) m/z = 431.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(20 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(75 mg,0.174 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.75 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.31 (s, 1H), 7.81 (s, 1H), 7.60 (d, 1H), 7.24 (s, 1H), 7.12 (d, 1H), 6.90 (dd, 1H), 4.41-4.40 (m, 1H), 4.20 (t, 2H), 3.96 (s, 1H), 3.82 (t, 2H), 3.37 (s, 3H), 2.85-2.83 (m, 1H), 2.12-2.05 (m, 2H), 1.78-1.63 (m, 4H), 1.55-1.52 (m, 3H), 1.44-1.40 (m, 3H), 1.28-1.23 (m, 2H), 1.20 (s, 6H); MS (ESI) m/z = 660.3 (M + H)
+
範例93.
N 6'-(2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1s,4s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(88 mg),程序差異之處在於以範例90步驟1中所製備之6'-氯-4'-氟-5-(3-甲氧基吖丁啶-1-基)-2,3'-聯吡啶(109 mg,0.371 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(128 mg,0.557 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.60 (d, 1H), 8.30 (s, 1H), 7.82 (d, 1H), 7.58 (d, 1H), 6.88 (dd, 1H), 6.52 (s, 1H), 4.43-4.39 (m, 1H), 4.21 (t, 2H), 3.82 (t, 2H), 3.74-3.72 (m, 1H), 3.37 (s, 3H), 2.24 (s, 6H), 2.17-2.05 (m, 2H), 1.90-1.86 (m, 2H), 1.75-1.62 (m, 4H), 1.29-1.24 (m, 2H);MS (ESI) m/z = 430.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1s,4s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(7 mg),其形態為固體,程序差異之處在於以步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-胺(75 mg,0.174 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.73 (d, 1H), 8.66 (s, 1H), 8.46 (s 1H), 8.38 (d, 1H), 8.31 (s, 1H), 7.83 (d, 1H), 7.59 (d, 1H), 7.17-7.15 (m, 2H), 6.90 (d, 1H), 4.43-4.40 (m, 1H), 4.21 (t, 2H), 3.92 (s, 1H), 3.83 (t, 2H), 3.37 (s, 3H), 2.85-2.81 (m, 1H), 2.24 (s, 6H), 2.15 (d, 1H), 2.02-1.99 (m, 2H), 1.66-1.64 (m, 2H), 1.55-1.51 (m, 2H), 1.34-1.19 (m, 6H); MS (ESI) m/z = 659.3 (M + H)
+
範例94. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(128 mg),程序差異之處在於以範例63步驟1中所製備之6'-氯-5-(二氟甲基)-4'-氟-2,3'-聯吡啶(100 mg,0.387 mmol)及2-((1
s,4
s)-4-胺基環己基)乙-1-醇( 72 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.77 (d, 1H), 8.71 (s, 1H), 8.48 (s, 1H), 7.95 (d, 1H), 7.88 (d, 1H), 6.77 (t, 1H), 6.61 (s, 1H), 3.79-3.72 (m, 3H), 1.90-1.86 (m, 2H), 1.72-1.65 (m, 3H), 1.61-1.55 (m, 3H), 1.35-1.31 (m, 3H); MS (ESI) m/z = 382.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物(47.9 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(111 mg,0.291 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.91 (d, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.94-7.88 (m, 2H), 7.53 (s, 1H), 7.12 (d, 1H), 6.77 (t, 1H), 3.97-3.96 (m, 2H), 2.88-2.81 (m, 1H), 2.02-1.99 (m, 2H), 1.84-1.71 (m, 4H), 1.55-1.52 (m, 2H), 1.48-1.32 (m, 3H), 1.29-1.20 (m, 5H); MS (ESI) m/z = 611.2 (M + H)
+
範例95. 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
步驟1. 2-((1
r,4
r)-4-((6'-氯-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(118 mg),程序差異之處在於以範例63步驟1中所製備之6'-氯-5-(二氟甲基)-4'-氟-2,3'-聯吡啶(100 mg,0.987 mmol)及2-((1
r,4
r)-4-胺基環己基)乙-1-醇鹽酸鹽(90 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.21 (d, 1H), 8.71 (s, 1H), 8.43 (s, 1H), 7.93 (d, 1H), 7.83 (d, 1H), 6.76 (t, 1H), 6.60 (s, 1H), 3.73 (t, 2H), 3.36-3.28 (m, 1H), 2.17 (d, 2H), 1.90 (d, 2H), 1.56-1.51 (m, 3H), 1.36-1.26 (m, 3H), 1.25-1.11 (m, 2H); MS (ESI) m/z = 382.0 (M + H)
+
步驟2. 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物(61.7 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
r,4
r)-4-((6'-氯-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(111 mg,0.291 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.29 (d, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.48 (d, 2H), 8.44 (d, 1H), 7.91 (d, 1H), 7.83 (d, 1H), 7.49 (s, 1H), 7.37 (d, 1H), 6.96 (s, 1H), 6.76 (t, 1H), 3.73 (t, 1H), 3.46-3.42 (m, 1H), 2.87-2.83 (d, 1H), 2.23 (d, 2H), 1.88 (d, 2H), 1.56-1.52 (m, 3H), 1.37-1.29 (m, 3H), 1.26 (s, 3H), 1.24-1.18 (m, 3H); MS (ESI) m/z = 611.2 (M + H)
+
範例96. 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
步驟1. 2-((1
r,4
r)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(121 mg),程序差異之處在於以範例76步驟1中所製備之6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶(100 mg,0.387 mmol)及2-((1
r,4
r)-4-胺基環己基)乙-1-醇鹽酸鹽(90 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.14 (d, 1H), 8.70 (d, 1H), 8.42 (d, 1H), 7.81 (s, 1H), 7.37 (d, 1H), 6.70 (t, 1H), 6.60 (s, 1H), 3.73 (t, 2H), 3.35-3.28 (m, 1H), 2.17 (d, 2H), 1.90 (d, 2H), 1.58-1.49 (m, 3H), 1.36-1.33 (m, 4H), 1.32-1.19 (m, 2H); MS (ESI) m/z = 382.0 (M + H)
+
步驟2. 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物(19 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-((1
r,4
r)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(110 mg,0.288 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.23 (d, 1H), 8.69 (d, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 7.53 (s, 1H), 7.37 (d, 1H), 7.31 (d, 1H), 7.01 (s, 1H), 6.70 (t, 1H), 3.72 (t, 2H), 3.45-3.42 (m, 1H), 2.87-2.83 (m, 1H), 2.23 (d, 2H), 1.88 (d, 2H), 1.56-1.42 (m, 3H), 1.39-1.26 (m, 3H), 1.24-1.13 (m, 4H); MS (ESI) m/z = 611.2 (M + H)
+
範例97. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(125 mg),程序差異之處在於以範例76步驟1中所製備之6'-氯-4-(二氟甲基)-4'-氟-2,3'-聯吡啶(100 mg,0.387 mmol)及2-((1
s,4
s)-4-胺基環己基)乙-1-醇(72 mg,0.503 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.70 (d, 1H), 8.71 (d, 1H), 8.46 (s, 1H), 7.86 (d, 1H), 7.38 (d, 1H), 6.71 (t, 1H), 6.60 (s, 1H), 3.78-3.77 (m, 1H), 3.73 (t, 1H), 1.89-1.86 (m, 2H), 1.72-1.65 (m, 4H), 1.57-1.54 (m, 2H), 1.34-1.25 (m, 4H); MS (ESI) m/z = 381.9 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物(5.5 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(110 mg,0.288 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.86 (d, 1H), 8.70 (d, 1H), 8.66 (s, 1H), 8.49 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.88 (s, 1H), 7.53 (s, 1H), 7.34-7.31 (m, 2H), 7.13 (d, 1H), 6.71 (t, 1H), 4.16-4.14 (m, 1H), 4.12-3.98 (m, 1H), 3.74 (t, 2H), 2.87-2.83 (m, 1H), 2.02-1.98 (m, 2H), 1.84-1.69 (m, 4H), 1.45-1.29 (m, 4H), 1.28-1.22 (m, 6H); MS (ESI) m/z = 611.3 (M + H)
+
範例98. 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
步驟1. 1-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
以如同範例1步驟1之方式製備標題化合物,其形態為固體(506 mg),程序差異之處在於以1-[(6-溴基-3-吡啶基)甲基]哌啶-4-醇(580 mg,2.139 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.03 (d, 1H), 8.67 (s, 1H), 7.79 (dd, 1H), 7.71 (d, 1H), 7.20 (d, 1H), 3.77-3.73 (m, 1H), 3.57 (s, 2H), 2.79-2.76 (m, 2H), 2.23 (t, 2H), 1.93-1.89 (m, 2H), 1.66-1.62 (m, 1H), 1.27 (br, 1H); MS (ESI) m/z = 322.0 (M + H)
+
步驟2. 1-((6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米灰色固體(78 mg),程序差異之處在於以步驟1中所製備之1-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇(120 mg,0.373 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.559 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.00 (d, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.80-7.73 (m, 2H), 6.58 (s, 1H), 3.85 (s, 1H), 3.81 (s, 1H), 3.54 (s, 2H), 2.77-2.74 (m, 2H), 2.19 (t, 2H), 2.02 (d, 2H), 1.92-1.89 (m, 2H), 1.78-1.75 (m, 2H), 1.65-1.62 (m, 4H), 1.40-1.33 (m, 3H), 1.21 (s, 6H); MS (ESI) m/z = 459.1 (M + H)
+
步驟3. 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
以如同範例1步驟3之方式製備標題化合物(27.1 mg),其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之1-((6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇(72 mg,0.157 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.09 (d, 1H), 8.66 (s, 1H), 8.47-8.46 (m, 3H), 8.41 (d, 1H), 7.76 (s, 2H), 7.61 (s, 1H), 7.31 (s, 1H), 7.11 (d, 1H), 4.14-4.12 (m, 1H), 4.01 (s, 1H), 3.75-3.74 (m, 1H), 3.54 (s, 2H), 2.85-2.83 (m, 1H), 2.78-2.75 (m, 2H), 2.21 (t, 2H), 2.12 (d, 2H), 1.92-1.90 (m, 2H), 1.80-1.74 (m, 4H), 1.61-1.52 (m, 4H), 1.25 (s, 3H), 1.32 (s, 6H); MS (ESI) m/z = 688.3 (M + H)
+
範例99. 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
步驟1. 1-((6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米灰色固體(55 mg),程序差異之處在於以範例98步驟1中所製備之1-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇(120 mg,0.373 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(93 mg,0.559 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.95 (d, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 7.80-7.73 (m, 2H), 6.58 (s, 1H), 3.82-3.76 (m, 2H), 3.55-3.54 (m, 4H), 2.79-2.76 (m, 2H), 2.23-2.21 (m, 2H), 1.94-1.91 (m, 4H), 1.74-1.61 (m, 4H), 1.38-1.35 (m, 3H), 1.26 (s, 1H); MS (ESI) m/z = 431.0 (M + H)
+
步驟2. 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇
以如同範例1步驟3之方式製備標題化合物(3 mg),其形態為淺黃色固體,程序差異之處在於以步驟1中所製備之1-((6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇(50 mg,0.116 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.08 (d, 1H), 8.66 (s, 1H), 8.49-8.46 (m, 3H), 8.41 (d, 1H), 7.75-7.73 (m, 3H), 7.13 (d, 1H), 4.14-4.12 (m, 1H), 3.99 (s, 1H), 3.76 (s, 1H), 3.55 (s, 4H), 2.86-2.82 (m, 1H), 2.81-2.77 (m, 2H), 2.23-2.20 (m, 2H), 2.05-1.93 (m, 2H), 1.93-1.91 (m, 2H), 1.83-1.62 (m, 5H), 1.53-1.41 (m, 3H), 1.38-1.32 (m, 3H), 1.29-1.20 (m, 5H); MS (ESI) m/z = 660.3 (M + H)
+
範例100. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. 6'-氯-4-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(396 mg),程序差異之處在於以2-溴基-4-(4,4-二氟哌啶-1-基)吡啶(592 mg,2.136 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.96 (d, 1H), 8.43 (d, 1H), 7.19 (d, 1H), 7.11 (s, 1H), 6.74 (dd, 1H), 3.59 (t, 4H), 2.14-2.06 (m, 4H); MS (ESI) m/z = 328.0 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-氯-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(85 mg),程序差異之處在於以步驟1中所製備之6'-氯-4-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶(90 mg,0.275 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(68 mg,0.412 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.27 (d, 1H), 8.25 (s, 1H), 6.98 (s, 1H), 6.68 (d, 1H), 6.54 (s, 1H), 3.59 (t, 4H), 3.33-3.31 (m, 1H), 2.14-2.04 (m, 4H), 1.92 (d, 1H), 1.77-1.65 (m, 4H), 1.60 (s, 1H), 1.54 (s, 1H), 1.30 (s, 3H); MS (ESI) m/z = 437.0 (M + H)
+
步驟3. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(16.5 mg),其形態為固體,程序差異之處在於以步驟2中所製備之((1
s,4
s)-4-((6'-氯-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(77 mg,0.176 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.69 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.39 (d, 1H), 8.34 (s, 1H), 8.29 (d, 1H), 7.60 (br, 1H), 7.21 (s, 1H), 7.15 (d, 1H), 7.06 (s, 1H), 6.66 (d 1H), 4.14-4.10 (m, 1H), 3.94 (s, 1H), 3.60 (t, 4H), 3.53 (d, 2H), 2.85-2.82 (m, 1H), 2.14-2.08 (m, 3H), 2.05-2.00 (m, 2H), 1.80-1.69 (m, 5H), 1.55-1.51 (m, 2H), 1.41-1.32 (m, 2H), 1.28-1.19 (m, 4H); MS (ESI) m/z = 666.2 (M + H)
+
範例101.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(4,4-二氟哌啶-1-基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-4-(4,4-二氟哌啶-1-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(89 mg),程序差異之處在於以範例100步驟1中所製備之6'-氯-4-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶(90 mg,0.275 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(94 mg,0.412 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.55 (d, 1H), 8.29-8.28 (m, 2H), 7.03 (s, 1H), 6.68 (d, 1H), 6.54 (s, 1H), 3.72 (s, 1H), 3.60 (t, 4H), 2.24 (s, 6H), 2.17-2.05 (m, 6H), 1.87-1.84 (m, 2H), 1.71-1.68 (m, 2H), 1.65-1.62 (m, 2H), 1.32-1.27 (m, 3H); MS (ESI) m/z = 464.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-4-(4,4-二氟哌啶-1-基)-
N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(26.5 mg),其形態為固體,程序差異之處在於以步驟1中所製備之6'-氯-4-(4,4-二氟哌啶-1-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4'-胺(82 mg,0.176 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 9.97 (s, 1H), 9.88 (d, 1H), 8.62 (d, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.41 (d, 1H), 8.20 (d, 1H), 7.48 (s, 1H), 7.34 (s, 2H), 6.88 (d, 1H), 4.05-4.00 (m, 1H), 3.84 (s, 1H), 3.64 (s, 3H), 3.31 (s, 1H), 2.07 (s, 6H), 2.05-1.98 (m, 4H), 1.89 (s, 2H), 1.84-1.81 (m, 2H), 1.71-1.62 (m, 3H), 1.46-1.45 (m, 2H), 1.34-1.23 (m, 4H), 1.18-1.15 (m, 3H); MS (ESI) m/z = 693.3 (M + H)
+
範例102. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(95 mg),程序差異之處在於以範例100步驟1中所製備之6'-氯-4-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶(90 mg,0.275 mmol)及順
-4-胺基-1-甲基環己-1-醇(53 mg,0.412 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.28 (d, 1H), 8.25 (s, 1H), 6.99 (s, 1H), 6.67 (d, 1H), 6.54 (s, 1H), 3.59 (t, 4H), 3.33-3.31 (d, 1H), 2.14-2.04 (m, 4H), 1.94-1.91 (m, 1H), 1.77-1.65 (m, 4H), 1.60-1.57 (m, 1H), 1.54 (s, 1H), 1.27 (s, 3H),; MS (ESI) m/z = 437.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(21.3 mg),其形態為固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(90 mg,0.206 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 9.94 (s, 1H), 9.38 (d, 1H), 8.64 (s, 1H), 8.47 (d, 2H), 8.43 (d, 1H), 8.22 (d, 1H), 7.60 (s, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 6.87 (d, 1H), 4.14 (s, 1H), 4.05-4.00 (m, 1H), 3.63 (s, 4H), 3.37 (s, 1H), 3.24-3.23 (m, 1H), 2.05-2.01 (m, 3H), 1.82-2.80 (m, 2H), 1.64-1.55 (m, 4H), 1.47-1.44 (m, 2H), 1.41 (s, 2H), 1.38-1.34 (m, 3H), 1.13 (s, 3H); MS (ESI) m/z = 666.3 (M + H)
+
範例103. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(111 mg),程序差異之處在於以範例100步驟1中所製備之6'-氯-4-(4,4-二氟哌啶-1-基)-4'-氟-2,3'-聯吡啶(90 mg,0.275 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(65 mg,0.412 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.65 (d, 1H), 8.30 (s, 1H), 8.27 (d, 1H), 7.04 (s, 1H), 6.67 (d, 1H), 6.56 (s, 1H), 3.81 (s, 1H), 3.60 (t, 4H), 2.14-2.06 (m, 4H), 2.01-1.98 (m, 2H), 1.76-1.73 (m, 2H), 1.63-1.60 (m, 2H), 1.41-1.34 (m, 3H), 1.22 (s, 6H); MS (ESI) m/z = 465.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(37.9 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(96 mg,0.206 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.72 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 8.33 (s, 1H), 8.28 (d, 1H), 7.53 (s, 1H), 7.21 (s, 1H), 7.16 (d, 1H), 7.07 (s, 1H), 6.65 (d, 1H), 3.96 (s, 1H), 3.61 (t, 4H), 2.85-2.83 (m, 1H), 2.13-2.07 (m, 6H), 1.76-1.71 (m, 4H), 1.62 (s, 3H), 1.56-1.54 (m, 3H), 1.43-1.41 (m, 3H), 1.20 (s, 6H); MS (ESI) m/z = 694.3 (M + H)
+
範例104. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6'-氯-4',5-二氟-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟1之方式製備標題化合物,其形態為固體(365 mg),程序差異之處在於以2-(2-溴基-5-氟吡啶-4-基)丙-2-醇(500 mg,2.136 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.97 (d, 1H), 8.50 (d, 1H), 8.03 (d, 1H), 7.21 (d, 1H), 1.99 (s, 1H), 1.70 (s, 6H); MS (ESI) m/z = 294.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(99 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4',5-二氟-[2,3'-聯吡啶]-4-基)丙-2-醇(89 mg,0.313 mmol)及順
-4-胺基-1-甲基環己-1-醇(61 mg,0.469 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.87 (d, 1H), 8.39 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 6.57 (s, 1H), 3.35-3.33 (m, 1H), 2.35 (s, 1H), 1.95-1.92 (m, 2H), 1.77-1.72 (m, 3H), 1.70 (s, 6H), 1.58 (s, 1H), 1.54 (s, 1H), 1.26 (s, 3H); MS (ESI) m/z = 394.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(50.5 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(89 mg,0.225 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.05 (s, 1H), 8.87 (s, 1H), 8.65 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.40 (s,1H), 8.01 (d, 1H), 7.50 (s, 1H), 7.35 (s, 1H) 5.61 (s, 1H), 4.14 (s, 1H), 3.44 (s, 1H), 3.24 (t, 1H), 1.84-1.81 (m, 2H), 1.64-1.58 (m, 3H), 1.53 (s, 6H), 1.44-1.39 (m, 2H), 1.34 (s, 2H), 1.25-1.23 (d, 2H), 1.13 (s, 3H); MS (ESI) m/z = 623.3 (M + H)
+
範例105. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
步驟1. 2-(6'-氯-5-氟-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(106 mg),程序差異之處在於以範例104步驟1中所製備之2-(6'-氯-4',5-二氟-[2,3'-聯吡啶]-4-基)丙-2-醇(89 mg,0.313 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(78 mg,0.469 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.35 (d, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 8.06 (d, 1H), 6.58 (s, 1H), 3.80-3.78 (m, 1H), 3.55 (d, 1H), 3.50 (s, 1H), 2.28 (s, 1H), 1.92-1.89 (m, 1H), 1.70-1.65 (m, 10H),1.39-1.26 (m, 3H); MS (ESI) m/z = 394.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(20 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6'-氯-5-氟-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇(89 mg,0.225 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.10 (s, 1H), 9.41 (d, 1H), 8.63 (s, 1H), 8.48 (s, 1H), 8.45 (s, 2H), 8.41 (d, 1H), 8.07 (d, 1H), 7.54 (s, 1H), 7.36 (s, 1H), 5.63 (s, 1H), 4.41 (t, 1H), 4.04-3.99 (m, 1H), 3.91 (s, 1H), 3.27-3.26 (m, 3H), 1.98 (s, 2H), 1.87-1.85 (m, 2H), 1.73-7.67 (m, 2H), 1.62-1.59 (m, 6H), 1.54 (s, 6H), 1.48 (s, 1H), 1.34 (s, 2H), 1.33-1.19 (m, 5H); MS (ESI) m/z = 623.3 (M + H)
+
範例106. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
步驟1. 2-(6'-氯-5-氟-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(115 mg),程序差異之處在於以範例104步驟1中所製備之2-(6'-氯-4',5-二氟-[2,3'-聯吡啶]-4-基)丙-2-醇(89 mg,0.313 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(74 mg,0.469 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.40 (d, 1H), 8.43 (s, 1H), 8.32 (s, 1H), 8.08 (d, 1H), 6.58 (s, 1H), 3.83-3.82 (m, 1H), 3.50 (s, 1H), 2.51 (s, 1H), 2.01-1.98 (m, 2H), 1.78-1.76 (m, 2H), 1.71 (s, 6H), 1.64-1.58 (m, 1H), 1.42-1.33 (m, 3H), 1.23 (s, 6H); MS (ESI) m/z = 422.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(51.6 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6'-氯-5-氟-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇(95 mg,0.225 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.11 (s, 1H), 9.49 (d, 1H), 8.62 (s, 1H), 8.46-8.40 (d, 4H) 8.08 (d, 1H), 7.60 (s, 1H), 7.31 (s, 1H), 5.63 (s, 1H), 4.06 (s, 1H), 4.05-4.01 (m, 1H), 3.96 (s, 1H), 3.28-3.27 (m, 1H), 1.98-1.94 (m, 3H), 1.69-1.63 (m, 4H), 1.54 (s, 6H), 1.34-1.33 (m, 2H), 1.30-1.22 (m, 6H), 1.18-1.15 (m, 1H), 1.04 (s, 6H); MS (ESI) m/z = 651.3 (M + H)
+
範例107. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(66 mg),程序差異之處在於以範例104步驟1中所製備之2-(6'-氯-4',5-二氟-[2,3'-聯吡啶]-4-基)丙-2-醇(89 mg,0.313 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(107 mg,0.469 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.35 (d, 1H), 8.43 (s, 1H), 8.34 (d, 1H), 8.06 (d, 1H), 6.57 (s,1H), 3.75-3.74 (m, 1H), 2.23 (s, 6H), 2.16-2.15 (m, 2H), 1.87-1.84 (m, 3H), 1.74-1.64 (m, 10H), 1.30-1.24 (m, 2H); MS (ESI) m/z = 421.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(28 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇(77 mg,0.183 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.09 (s, 1H), 9.29 (d, 1H), 8.63 (s, 1H), 8.49 (s, 2H), 8.44 (s, 1H), 8.41 (d, 1H), 8.06 (d, 1H), 7.49 (s, 1H), 7.40 (s, 1H), 3.88 (s, 1H), 3.27-3.26 (m, 1H), 2.07 (s, 6H), 2.07-2.05 (m, 2H), 1.85-1.82 (m, 2H), 1.73-1.63 (m, 4H), 1.54 (s, 6H), 1.34-1.33 (m, 2H), 1.26-1.17 (m, 5H); MS (ESI) m/z = 650.2 (M + H)
+
範例108. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟1之方式製備標題化合物,其形態為固體(471 mg),程序差異之處在於以2-(2-溴基吡啶-4-基)丙-2-醇(462 mg,2.136 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.97 (d, 1H), 8.69 (d, 1H), 7.84 (s, 1H), 7.42 (d, 1H), 7.20 (d, 1H), 1.24 (s, 6H); MS (ESI) m/z = 266.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(113 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)丙-2-醇(100 mg,0.375 mmol)及順
-4-胺基-1-甲基環己-1-醇(73 mg,0.562 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.26 (d, 1H), 8.53 (d, 1H), 8.41 (s, 1H), 7.33 (d, 1H), 6.57 (s, 1H), 3.36-3.34 (m, 1H), 1.96-1.90 (m, 3H), 1.78-1.67 (m, 4H), 1.62 (s, 6H), 1.31 (s, 3H), 1.29-1.25 (m, 2H); MS (ESI) m/z = 375.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(72 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(99 mg,0.262 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.02 (s, 1H), 9.39 (d, 1H), 8.65 (s, 1H), 8.53-8.51 (m, 2H), 8.47 (s, 1H), 8.62 (d, 1H), 7.94 (s, 1H), 7.54 (s, 1H), 7.38 (d, 1H), 7.32 (s, 1H), 5.30 (s, 1H), 4.16 (s, 1H), 3.43 (s, 1H), 3.25-3.23 (m, 1H), 1.85-1.82 (m, 2H), 1.65-1.56 (m, 4H), 1.47 (s, 6H), 1.42 (s, 2H), 1.34-1.33 (m, 2H), 1.25-1.24 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 605.2 (M + H)
+
範例109. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(106 mg),程序差異之處在於以範例108步驟1中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)丙-2-醇(100 mg,0.375 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.562 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.85 (d, 1H), 8.52 (d, 1H), 8.46 (s, 1H), 7.89 (s, 1H), 7.32 (d, 1H), 6.59 (s, 1H), 3.83 (d, 1H), 2.05-1.99 (m, 3H), 1.78-1.75 (m, 2H), 1.65 (s, 6H), 1.41-1.36 (m, 3H), 1.26-1.25 (m, 1H), 1.22 (s, 6H); MS (ESI) m/z = 404.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(37.1 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇(106 mg,0.262 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.07 (s, 1H), 10.02 (d, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.48 (d, 1H), 8.45 (s, 1H), 8.41 (d, 1H), 8.00 (s, 1H), 7.56 (s, 1H), 7.39 (d, 1H), 7。35 (s, 1H), 5.31 (s, 1H), 4.07 (s, 1H), 3.95 (d, 1H), 3.31-3.28 (m, 2H), 1.97-1.94 (m, 2H), 1.70-1.66 (m, 4H), 1.48 (s, 5H), 1.34-1.26 (m, 7H), 1.05 (s, 6H); MS (ESI) m/z = 633.3 (M + H)
+
範例110. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(101 mg),程序差異之處在於以範例108步驟1中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)丙-2-醇(100 mg,0.375 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(129 mg,0.562 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.77 (d, 1H), 8.53 (d, 1H), 8.45 (s, 1H), 7.87 (s, 1H), 7.33 (d, 1H), 6.57 (s, 1H), 3.76 (s, 1H), 2.24 (s, 6H), 2.16 (d, 2H), 1.89-1.86 (m, 2H), 1.73-1.67 (m, 3H), 1.63 (s, 7H), 1.33-1.24 (m, 3H); MS (ESI) m/z = 403.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(22.7 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇(106 mg,0.262 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.06 (s, 1H), 9.87 (d, 1H), 8.63 (s, 1H), 8.56 (s, 1H), 8.50 (d, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 7.99 (s, 1H), 7.45-7.44 (m, 1H), 7.41-7.39 (m, 1H), 5.32 (s, 1H), 3.89 (s, 1H), 3.27-3.24 (m, 1H), 2.11 (s, 6H), 2.05 (d, 2H), 1.87-1.84 (m, 2H), 1.74-1.64 (m, 4H), 1.56 (m, 1H), 1.48 (s, 6H), 1.34-1.33 (m, 2H), 1.26-1.23 (m, 5H); MS (ESI) m/z = 632.3 (M + H)
範例111. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(61 mg),程序差異之處在於以範例108步驟1中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)丙-2-醇(100 mg,0.375 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(93 mg,0.562 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.26 (d, 1H), 8.53 (d, 1H) 8.41 (s, 1H), 7.82 (s, 1H), 7.33 (d, 1H), 6.57 (s, 1H), 3.36-3.34 (m, 1H), 1.96-1.90 (m, 3H), 1.78-1.67 (m, 4H), 1.62 (s, 6H), 1.31 (s, 3H), 1.29-1.25 (m, 2H); MS (ESI) m/z = 375.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(36.1 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇(61 mg,0.162 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.06 (s, 1H), 9.95 (d, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.50 (d, 1H), 8.45 (s, 1H), 8.41 (d, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.39 (d, 2H), 5.31 (s, 1H), 4.42 (t, 1H), 3.91 (s, 1H), 3.27-3.24 (m, 2H), 1.89-1.83 (m, 2H), 1.73-1.61 (m, 4H), 1.48 (s, 7H), 1.34-1.33 (m, 2H), 1.27-1.21 (m, 4H); MS (ESI) m/z = 605.3 (M + H)
+
範例112. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為固體(498 mg),程序差異之處在於以2-溴基-4-[(4,4-二氟-1-哌啶基)甲基]吡啶(622 mg,2.136 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.02 (d, 1H), 8.68 (d, 1H), 7.73 (s, 1H), 7.32 (d, 1H), 7.21 (d, 1H), 3.64 (s, 2H), 2.60 (t, 4H), 2.08-1.99 (m, 4H); MS (ESI) m/z = 342.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(150 mg),程序差異之處在於以步驟1中所製備之6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-4'-氟-2,3'-聯吡啶(120 mg,0.351 mmol)及順
-4-胺基-1-甲基環己-1-醇(68 mg,0.527 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.36 (d, 1H), 8.51 (d, 1H), 8.39 (s, 1H), 7.69 (s, 1H), 7.23 (d, 1H), 6.57 (s, 1H), 3.62 (s, 2H), 3.34 (s, 1H), 2.60-2.59 (m, 4H), 2.08-1.93 (m, 8H), 1.78-1.61 (m, 4H), 1.31 (s, 3H); MS (ESI) m/z = 451.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(39 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(12 mg,0.284 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.46 (d, 1H), 8.67 (s, 1H), 8.51 (d, 1H), 8.48 (s, 1H), 8.44-8.42 (m, 2H), 7.72 (s, 1H), 7.45 (s, 1H), 7.36 (d, 1H), 7.19 (d, 1H), 6.96 (s, 1H), 3.62 (s, 2H), 3.51-3.50 (m, 1H), 2.86-2.80 (m, 1H), 2.61 (s, 4H), 2.09-2.00 (m, 6H), 1.82-1.74 (m, 4H), 1.64-1.63 (m, 1H), 1.54-1.53 (m, 2H), 1.32 (s, 3H), 1.26-1.19 (m, 2H); MS (ESI) m/z = 680.3 (M + H)
範例113. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(136 mg),程序差異之處在於以範例112步驟1中所製備之6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-4'-氟-2,3'-聯吡啶(120 mg,0.351 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(87 mg,0.527 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.21 (d, 1H), 8.52 (d, 1H), 8.44 (s, 1H), 7.74 (s, 1H), 7.24 (d, 1H), 6.59 (s, 1H), 3.81 (s, 1H), 3.63 (s, 2H), 3.54 (d, 2H), 2.61 (s, 4H), 2.08-2.00 (m, 5H), 1.94-1.91 (m, 2H), 1.70-1.65 (m, 5H), 1.41-1.29 (m, 5H); MS (ESI) m/z = 451.2 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(59 mg),其形態為固體,程序差異之處在於以步驟2中所製備之((1
s,4
s)-4-((6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(128 mg,0.284 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.02 (d, 1H), 8.66 (s, 1H), 8.51 (d, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 7.76 (s, 1H), 7.70 (s, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 3.99 (s, 1H), 3.63 (s, 2H), 3.54 (d, 2H), 2.85-2.83 (m, 2H), 2.61 (s, 4H), 2.09-2.03 (m, 4H), 2.01-1.99 (m, 2H), 1.83-1.76 (m, 4H), 1.65-1.53 (m, 2H), 1.43-1.41 (m, 2H), 1.37-1.27 (m, 2H); MS (ESI) m/z = 680.3 (M + H)
+
範例114. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(136 mg),程序差異之處在於以範例112步驟1中所製備之6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-4'-氟-2,3'-聯吡啶(120 mg,0.351 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(83 mg,0.527 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.95 (d, 1H), 8.51 (d, 1H), 8.44 (s, 1H), 7.74 (s, 1H), 7.23 (d, 2H), 6.59 (s, 1H), 3.85-3.84 (m, 1H), 3.63 (s, 2H), 2.60 (s, 4H), 2.07-2.00 (m, 4H), 1.78-1.76 (m, 2H), 1.66-1.63 (m, 2H), 1.41-1.33 (m, 5H), 1.29 (s, 6H); MS (ESI) m/z = 479.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(59 mg),其形態為固體,程序差異之處在於以步驟2中所製備之2-((1
s,4
s)-4-((6'-氯-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(136 mg,0.284 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.05 (d, 1H), 8.66 (s, 1H), 8.51 (d, 1H), 8.47 (s, 2H), 8.41 (d, 1H), 7.76 (s, 1H), 7.62 (s, 1H), 7.30 (s, 1H), 7.18 (d, 1H), 7.13 (d, 1H), 4.00 (s, 1H), 3.63 (s, 2H), 2.86-2.83 (m, 1H), 2.61 (s, 4H), 2.12-2.00 (m, 4H), 1.79-1.73 (m, 4H) 1.57-1.54 (m, 2H), 1.45 (s, 3H), 1.23 (s, 6H); MS (ESI) m/z = 708.3 (M + H)
+
範例115. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)-
N,
N-二甲基乙-1-胺
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(227 mg),程序差異之處在於以2-((5-溴基吡嗪-2-基)氧基)-
N,
N-二甲基乙-1-胺(478 mg,1.942 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 7.22 (d, 1H), 4.51 (t, 2H), 2.77 (t, 2H), 2.36 (s, 6H); MS (ESI) m/z = 297.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(53 mg),程序差異之處在於以步驟1中所製備之2-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)-
N,
N-二甲基乙-1-胺(55 mg,0.185 mmol)及順
-4-胺基-1-甲基環己-1-醇(36 mg,0.278 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.47 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 8.13 (d, 1H), 6.57 (s, 1H), 4.49 (t, 2H), 3.32 (s, 1H), 2.77 (t, 2H), 2.36 (s, 6H), 1.94-1.91 (m, 2H), 1.77-1.70 (m, 4H), 1.64-1.57 (m, 3H), 1.30 (s, 3H); MS (ESI) m/z = 406.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(15.7 mg),其形態為固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(40 mg,0.099 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.48 (s, 2H), 8.43 (d, 1H), 8.31 (s, 2H), 8.24 (s, 1H), 8.18 (d, 1H), 7.48 (s, 1H), 7.37 (d, 1H), 6.96 (s, 1H), 4.49 (t, 1H), 3.48 (s, 1H), 2.83 (s, 1H), 2.77 (t, 2H), 2.37 (s, 6H), 2.00-1.97 (m, 2H), 1.75-1.69 (m, 4H), 1.56-1.53 (m, 2H), 1.31 (s, 3H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 635.3 (M + H)
+
範例116. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(44 mg),程序差異之處在於以範例115步驟1中所製備之2-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)-
N,
N-二甲基乙-1-胺(55 mg,0.185 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(46 mg,0.278 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.70 (d, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 6.59 (s, 1H), 4.50 (t, 2H), 3.82 (s, 1H), 2.77 (t, 2H), 2.37 (s, 6H), 2.01-2.00 (m, 2H), 1.78-1.74 (m, 3H), 1.69-1.65 (m, 2H), 1.41-1.29 (m, 4H), 1.26 (s, 6H); MS (ESI) m/z = 406.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(13.6 mg),其形態為固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇(40 mg,0.099 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.68 (d, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 8.35 (s, 1H), 8.24 (s, 1H), 7.68 (s, 1H), 7.23 (s, 1H), 7.16 (d, 1H), 4.49 (t, 2H), 3.95 (s, 1H), 3.52 (d, 2H), 2.85-2.82 (m, 1H), 2.77 (t, 2H), 2.36 (s, 6H), 2.02-1.99 (m, 6H), 1.81-1.69 (m, 5H), 1.54-1.53 (m, 2H), 1.34-1.25 (m, 5H); MS (ESI) m/z = 635.3 (M + H)
+
範例117. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(40 mg),程序差異之處在於以範例115步驟1中所製備之2-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)-
N,
N-二甲基乙-1-胺(55 mg,0.185 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(44 mg,0.278 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.62 (d, 1H), 8.52 (s, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 6.58 (s, 1H), 4.50 (t, 2H), 3.78 (s, 1H), 3.52 (d, 2H), 2.77 (t, 2H), 2.32 (s, 6H), 1.90-1.87 (m, 2H), 1.68 (s, 3H), 1.33-1.26 (m, 3H); MS (ESI) m/z = 434.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(15 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇(43 mg,0.099 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.72 (d, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.49 (s, 1H), 7.14 (d, 1H), 4.48 (t, 2H), 3.96 (s, 1H), 2.85-2.83 (m, 1H), 2.76 (t, 2H), 2.36 (s, 6H), 2.09-2.06 (m, 2H), 1.79-1.65 (m, 4H), 1.54-1.53 (m, 2H), 1.46-1.35 (m, 3H), 1.22 (s, 7H); MS (ESI) m/z = 663.3 (M + H)
+
範例118. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟1之方式製備標題化合物,其形態為固體(348 mg),程序差異之處在於以2-(5-溴基吡嗪-2-基)丙-2-醇(422 mg,1.942 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.07 (d, 1H), 8.94 (d, 2H), 7.26 (d, 1H), 3.72 (d, 1H), 1.67 (s, 6H); MS (ESI) m/z = 268.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(97 mg),程序差異之處在於以步驟1中所製備之2-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)丙-2-醇(82 mg,0.306 mmol)及順
-4-胺基-1-甲基環己-1-醇(59 mg,0.459 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.96 (s, 1H), 8.85 (d, 1H), 8.73 (s, 1H), 8.50 (s, 1H), 6.62 (s, 1H), 3.37 (s, 1H), 1.96-1.93 (m, 2H), 1.79-1.68 (m, 3H), 1.66 (s, 6H), 1.32 (s, 3H), 1.28-1.26 (m, 3H); MS (ESI) m/z = 377.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(53.2 mg),其形態為白色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(93 mg,0.247 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.98-8.96 (m, 2H), 8.70 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 7.45 (s, 1H), 7.34 (d, 1H), 7.05 (s, 1H), 3.73 (S, 1H), 3.68 (s, 1H), 2.83-2.82 (m, 1H), 2.02-2.00 (m, 2H), 1.82-1.74 (m, 4H), 1.66 (s, 6H), 1.58-1.55 (m, 2H), 1.33 (s, 3H), 1.25-1.23 (m, 2H); MS (ESI) m/z = 606.2 (M + H)
+
範例119. 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
步驟1. 2-(5-(6-氯-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(95 mg),程序差異之處在於以範例118步驟1中所製備之2-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)丙-2-醇(82 mg,0.306 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(76 mg,0.459 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.32 (d, 1H), 9.01 (s, 1H), 8.72 (s, 1H), 8.55 (s, 1H), 6.63 (s, 1H), 3.81 (s, 1H), 3.56 (s, 2H), 1.93-1.91 (m, 2H), 1.74-1.72 (m, 3H), 1.66 (s, 6H), 1.39-1.25 (m, 6H); MS (ESI) m/z = 377.1 (M + H)
+
步驟2. 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(41.3 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(5-(6-氯-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇(93 mg,0.247 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.43 (d, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 7.54 (s, 1H), 7.32 (s, 1H), 7.13 (d, 1H), 4.00 (s, 1H), 3.63 (s, 1H), 3.56 (d, 1H), 2.86-2.84 (m, 1H), 2.06-2.03 (m, 2H), 1.85-1.74 (m, 4H), 1.67 (s, 6H), 1.55-1.54 (m, 2H), 1.41-1.35 (m, 2H), 1.26-1.22 (m, 2H); MS (ESI) m/z = 606.2 (M + H)
+
範例120. 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
步驟1. 2-(5-(6-氯-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(102 mg),程序差異之處在於以範例118步驟1中所製備之2-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)丙-2-醇(82 mg,0.306 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(72 mg,0.459 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.37 (d, 1H), 9.01 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 6.64 (s, 1H), 3.86 (s, 1H), 2.03-2.00 (m, 2H), 1.81-1.77 (m, 2H), 1.68 (s, 7H) 1.43-1.27 (m, 5H), 1.22 (s, 7H); MS (ESI) m/z = 405.2 (M + H)
+
步驟2. 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(56.9 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-(5-(6-氯-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇(100 mg,0.247 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.45 (d, 1H), 9.02 (s, 1H), 8.67 (d, 2H), 8.57 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 7.55 (s, 1H), 7.37 (s, 1H), 7.10 (d, 1H), 4.02 (s, 1H), 3.62 (s, 1H), 2.88-2.81 (m, 1H), 2.13-2.09 (m, 2H), 1.81-1.75 (m, 4H), 1.66 (s, 6H), 1.59-1.54 (m, 2H), 1.48-1.37 (m, 3H), 1.23 (s, 6H); MS (ESI) m/z = 634.3 (M + H)
+
範例121. 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(異丙基胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
步驟1. 2-(5-(6-氯-4-(異丙基胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(68 mg),程序差異之處在於以範例118步驟1中所製備之2-(5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)丙-2-醇(76 mg,0.284 mmol)及異丙胺鹽酸鹽(41 mg,0.426 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.96 (d, 1H), 8.74 (d, 1H), 8.71 (d, 1H), 8.50 (s, 1H), 6.63 (s, 1H), 1.66 (s, 6H), 1.33 (s, 3H), 1.31 (s, 3H); MS (ESI) m/z = 306.9 (M + H)
+
步驟2. 2-(5-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(異丙基胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(30 mg),程序差異之處在於以步驟1中所製備之2-(5-(6-氯-4-(異丙基胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇(35 mg,0.116 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.97 (d, 1H), 8.82 (d, 1H), 8.72 (d, 1H), 8.68 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.44 (d, 1H), 7.39 (s, 1H), 7.18 (d, 1H), 3.92-3.87 (m, 1H), 3.69 (s, 1H), 2.87-2.83 (m, 1H), 1.67 (s, 6H), 1.41 (s, 3H), 1.40 (s, 3H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 536.2 (M + H)
+
範例122.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)-
N 4-異丙基吡啶-2,4-二胺
步驟1. 2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)-
N-異丙基吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(43 mg),程序差異之處在於以範例115步驟1中所製備之2-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)-
N,
N-二甲基乙-1-胺(84 mg,0.284 mmol)及異丙胺鹽酸鹽(41 mg,0.426 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.46 (d, 1H), 8.29 (s, 1H), 8.24 (d, 1H), 7.96 (d, 1H), 7.01 (s, 1H), 4.49 (t, 2H), 3.72-3.65 (m, 1H), 2.77 (t, 2H), 2.36 (s, 6H), 1.29 (s, 3H), 1.28 (s, 3H); MS (ESI) m/z = 336.0 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)-
N 4-異丙基吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(13 mg),程序差異之處在於以步驟1中所製備之2-氯-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)-
N-異丙基吡啶-4-胺(39 mg,0.118 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.47 (d, 2H), 8.43 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 8.00 (d, 1H), 7.40 (s, 1H), 7.22 (d, 1H), 7.17 (s, 1H), 4.49 (t, 2H), 3.87-3.82 (m, 1H), 2.87-2.81 (m, 1H), 2.77 (t, 2H), 2.37 (s, 6H), 1.38 (s, 3H), 1.36 (s, 3H), 1.27-1.23 (m, 4H); MS (ESI) m/z = 565.3 (M + H)
+
範例123.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(76 mg),程序差異之處在於以參考範例25中所製備之4-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)嗎啉(83 mg,0.283 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(65 mg,0.424 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.40 (d, 1H), 8.34 (s, 1H), 8.24 (d, 1H), 7.64 (d, 1H), 7.31 (dd, 1H), 6.55 (s, 1H), 4.87-4.74 (m, 1H), 3.91 (t, 4H), 3.48-3.47 (m, 1H), 3.26 (t, 4H), 2.06-2.03 (m, 2H), 1.93-1.89 (m,2H), 1.83-1.71 (m, 4H); MS (ESI) m/z = 391.0 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(10 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4'-胺(76 mg,0.194 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.48 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 8.37 (s, 1H), 8.25 (d, 1H), 7.66 (d, 1H), 7.34-7.31 (m, 2H), 7.01 (s, 1H), 4.85-4.73 (m, 1H), 3.92 (t, 4H), 3.65 (s, 1H), 3.26 (t, 4H), 2.86-2.81 (m, 1H), 1.02-1.81 (m, 8H), 1.79-1.76 (m, 2H), 1.25-1.19 (m, 2H); MS (ESI) m/z = 620.3 (M + H)
+
範例124.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-異丙基-5-嗎啉基-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(59 mg),程序差異之處在於以參考範例25中所製備之4-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)嗎啉(80 mg,0.271 mmol)及異丙胺鹽酸鹽(39 mg,0.406 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.02 (d, 1H), 8.30 (s, 1H), 8.25 (d, 1H), 7.61 (d, 1H), 7.31 (dd, 1H), 6.55 (s, 1H), 3.91 (t, 4H), 3.70-3.69 (m, 1H), 3.25 (t, 4H), 1.31 (s, 3H), 1.29 (s, 3H); MS (ESI) m/z = 333.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(5 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-異丙基-5-嗎啉基-[2,3'-聯吡啶]-4'-胺(73 mg,0.218 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.06 (d, 1H), 8.67 (s, 1H), 8.47 (s, 1H), 8.40 (d, 1H), 8.33 (s, 1H), 8.26 (d, 1H), 7.63 (d, 1H), 7.49 (s, 1H), 7.32 (dd, 1H), 7.20 (d, 1H), 7.15 (s, 1H), 3.92 (t, 4H), 3.87-3.82 (m, 1H), 3.25 (t, 4H), 2.86-2.82 (m, 1H), 1.56-1.52 (m, 2H), 1.40 (s, 3H), 1.38 (s, 3H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 562.2 (M + H)
+
範例125.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 4-((6-溴基吡啶-3-基)甲基)嗎啉
在嗎啉(0.26 mL,2.957 mmol)之DCM (5 mL)溶液中加入6-溴基-3-吡啶羧醛(500 mg,2.688 mmol)及三乙醯氧基硼氫鈉(1709 mg,8.06 mmol)。將反應混合物於45
oC 攪拌3小時。反應混合物冷卻後加入飽和NaHCO
3溶液,經DCM萃取,以水清洗,利用 MgSO
4乾燥而後濃縮。粗產物經管柱層析提純(MeOH/DCM = 0-100%)產出形態為米灰色固體之4-((6-溴基吡啶-3-基)甲基)嗎啉(493 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.31 (d, 1H), 7.57 (dd, 1H), 7.45 (d, 1H), 3.71 (t, 4H), 3.47 (s, 2H), 2.44 (t, 4H); MS (ESI) m/z = 257.0 (M + H)
+
步驟2. 4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲基)嗎啉
以如同範例1步驟1之方式製備標題化合物,其形態為固體(355 mg),程序差異之處在於以步驟1中所製備之4-((6-溴基吡啶-3-基)甲基)嗎啉(466 mg,1.814 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 8.69 (s, 1H), 7.80 (dd, 1H), 7.72 (dd, 1H), 7.21 (d, 1H), 3.74 (t, 4H), 3.58 (s, 2H), 2.50 (t, 4H); MS (ESI) m/z = 307.9 (M + H)
+
步驟3. 6'-氯-
N-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(58 mg),程序差異之處在於以步驟2中所製備之4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲基)嗎啉(83 mg,0.271 mmol)及異丙胺鹽酸鹽(39 mg,0.406 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.28 (d, 1H), 8.53 (s, 1H), 8.40 (s, 1H), 7.78 (dd, 1H), 7.70 (d, 1H), 6.58 (s, 1H), 3.74 (t, 4H), 3.55 (s, 2H), 2.49 (t, 4H), 1.32 (s, 3H), 1.30 (s, 3H); MS (ESI) m/z = 347.0 (M + H)
+
步驟4.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為固體(5.5 mg),程序差異之處在於以步驟3中所製備之6'-氯-
N-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-胺(55 mg,0.159 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.38 (d, 1H), 8.67 (s, 1H), 8.52 (s, 1H), 8.48 (s, 1H), 8.42 (d, 2H), 7.77 (d, 1H), 7.71 (d, 1H), 7.56 (s, 1H), 7.22-7.18 (m, 2H), 4.00-3.85 (m, 1H), 3.74 (t, 4H), 3.55 (s, 2H), 2.86-2.81 (m, 1H), 2.50 (s, 4H), 2.25-2.21 (m, 1H), 2.06 (s, 1H), 1.56-1.52 (m, 2H), 1.41 (s, 3H), 1.39 (s, 3H), 1.41-1.39 (m, 2H), 1.27-1.22 (m, 2H); MS (ESI) m/z = 576.2 (M + H)
+
範例126.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(85 mg),程序差異之處在於以範例125步驟2中所製備之4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)甲基)嗎啉(83 mg,0.27 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(39 mg,0.406 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.62 (d, 1H), 8.52 (s, 1H), 8.43 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 6.58 (s, 1H), 4.81 (d, 1H), 3.74 (t, 4H), 3.55 (s, 2H), 2.49 (t, 4H), 2.09-2.05 (m, 3H), 1.92-1.89 (m, 2H), 1.81-1.75 (m, 2H), 1.71-1.63 (m, 4H), 1.32-1.26 (m, 1H); MS (ESI) m/z = 405.0 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為固體(3 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-胺(52 mg,0.129 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.75 (d, 1H), 8.66 (s, 1H), 8.52 (s, 1H), 8.47 (s, 2H), 8.43 (d, 1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.32-7.30 (m, 2H), 7.04-7.01 (m, 1H), 4.86-4.85 (m, 1H), 3.75 (t, 4H), 3.67 (s, 1H), 3.55 (s, 2H), 2.88-2.80 (m, 1H), 2.50 (s, 4H), 2.05-1.79 (m, 8H), 1.27-1.21 (m, 2H); MS (ESI) m/z = 634.3 (M + H)
+
範例127.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)-
N 4-異丙基吡啶-2,4-二胺
步驟1. 2-(6-氯-4-氟吡啶-3-基)-5-(二氟甲氧基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(470 mg),程序差異之處在於以2-溴基-5-(二氟甲氧基)吡嗪(500 mg,2.222 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.05 (d, 1H), 8.64 (s, 1H), 8.52 (s, 1H), 7.47 (t, 1H), 7.25 (s, 1H); MS (ESI) m/z = 276.0 (M + H)
+
步驟2. 2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)-
N-異丙基吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(100 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(二氟甲氧基)吡嗪(90 mg,0.327 mmol)及異丙胺鹽酸鹽(47 mg,0.49 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.58 (s, 1H), 8.37 (s, 2H), 8.10-8.08 (m, 1H), 7.45 (t, 1H), 6.62 (s, 1H), 3.75-3.70 (m, 1H), 1.31 (s, 3H), 1.29 (s, 3H); MS (ESI) m/z = 314.9 (M + H)
+
步驟3.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)-
N 4-異丙基吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(5mg),其形態為固體,程序差異之處在於以步驟2中所製備之2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)-
N-異丙基吡啶-4-胺(85 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.18 (d, 1H), 7.44 (t, 1H), 7.38 (s, 1H), 7.26 (s, 1H), 7.19 (d, 1H), 3.90-3.85 (m, 1H), 2.86-2.82 (m, 1H), 1.55-1.52 (m, 2H), 1.40 (s, 3H), 1.38 (s, 3H), 1.30-1.20 (m, 3H); MS (ESI) m/z = 544.2 (M + H)
+
範例128. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(111 mg),程序差異之處在於以範例127步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(二氟甲氧基)吡嗪(90 mg,0.327 mmol)及順
-4-胺基-1-甲基環己-1-醇(63 mg,0.49 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。1H-NMR (CDCl
3, 400 MHz) δ 8.59 (s, 1H), 8.38 (s, 1H), 8.36 (s, 1H), 8.24 (d, 1H), 7.44 (t, 1H), 6.62 (s, 1H), 4.16-4.11 (m, 1H), 3.37-3.34 (m, 1H), 1.94-1.92 (m, 2H), 1.78-1.69 (m, 4H), 1.61-1.57 (m, 1H), 1.31 (s, 3H), 1.28-1.25 (m, 1H); MS (ESI) m/z = 385.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(30 mg),其形態為固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(104 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.60 (s, 1H), 8.48 (s, 1H), 8.45 (d, 1H), 8.40 (s, 1H), 8.35-8.32 (m, 2H), 7.44 (t, 1H), 7.37-7.35 (m, 2H), 7.00 (s, 1H), 3.50 (s, 1H), 2.85-2.81 (m, 1H), 2.01-2.00 (m, 2H), 1.76-1.74 (m, 4H), 1.63-1.52 (m, 2H), 1.32 (s, 3H), 1.27-1.22 (m, 3H), 1.13 (s, 1H); MS (ESI) m/z = 614.1 (M + H)
+
範例129. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(104 mg),程序差異之處在於以範例127步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(二氟甲氧基)吡嗪(90 mg,0.327 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(81 mg,0.49 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.70 (d, 1H), 8.64 (s, 1H), 8.42 (s, 1H), 8.36 (d, 1H), 7.45 (t, 1H), 6.63 (s, 1H), 3.81-3.79 (m, 1H), 3.55 (t, 2H), 1.92-1.88 (m, 2H), 1.75-1.66 (m, 5H), 1.33-1.30 (m, 2H); MS (ESI) m/z = 385.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(23 mg),其形態為固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇(104 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.81 (d, 1H), 8.66 (d, 2H), 8.47 (s, 1H), 8.44 (t, 2H), 8.35 (s ,1H), 7.44 (t, 1H), 7.28 (s, 1H), 7.15 (d, 1H), 3.98-3.97 (m, 1H), 3.55 (m, 2H), 2.87-2.83 (m, 1H), 2.06-2.00 (m, 2H), 1.85-1.66 (m, 6H), 1.38-1.29 (m, 6H); MS (ESI) m/z = 614.2 (M + H)
+
範例130. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(114 mg),程序差異之處在於以範例127步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(二氟甲氧基)吡嗪(90 mg,mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇鹽酸鹽(95 mg,0.49 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.78 (d, 1H), 8.65 (s, 1H), 8.42 (s, 1H), 8.33 (s, 1H), 7.45 (t, 1H), 6.63 (s, 1H), 3.85-3.84 (m, 1H), 2.01-1.97 (m, 2H), 1.80-1.78 (m, 2H), 1.64 (t, 2H), 1.42-1.27 (m, 3H), 1.23 (s, 6H); MS (ESI) m/z = 413.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(9 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇(112 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.87 (d, 1H), 8.66 (s, 2H), 8.47 (s, 1H), 8.44 (t, 2H), 8.33 (s, 1H), 7.44 (t, 1H), 7.40 (s, 1H), 7.34 (s, 1H), 7.12 (d, 1H), 4.01 (s, 1H), 2.87-2.83 (m, 1H), 2.10-2.06 (m, 2H), 1.81-1.74 (m, 4H), 1.56-1.30 (m, 4H), 1.24 (s, 6H); MS (ESI) m/z = 642.2 (M + H)
+
範例131.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺
步驟1. 2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(76 mg),程序差異之處在於以範例127步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(二氟甲氧基)吡嗪(90 mg,0.327 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(112 mg,0.49 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66-8.63 (m, 2H), 8.41 (s, 1H), 8.35 (s, 1H), 7.45 (t, 1H), 6.62 (s, 1H), 3.77-3.75 (m, 1H), 2.23 (s, 6H), 2.14-2.12 (m, 1H), 1.86-1.83 (m, 2H), 1.75-1.66 (m, 5H), 1.26-1.20 (m, 3H); MS (ESI) m/z = 412.0 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)-
N 4-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(25 mg),其形態為固體,程序差異之處在於以步驟1中所製備之2-氯-5-(5-(二氟甲氧基)吡嗪-2-基)-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)吡啶-4-胺(111 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.78 (d, 1H), 8.66 (s, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.44-8.43 (m, 2H), 8.34 (d, 1H), 7.45 (t, 1H), 7.44 (s, 1H), 7.25 (s, 1H), 7.18 (d, 1H), 3.95-3.94 (m, 1H), 2.86-2.82 (m, 1H), 2.23 (s, 6H), 2.14-2.12 (m, 2H), 1.99-1.96 (m, 2H), 1.83-1.73 (m, 4H), 1.55-1.53 (m, 2H), 1.29-1.20 (m, 6H); MS (ESI) m/z = 641.3 (M + H)
+
範例132.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(114 mg),程序差異之處在於參考範例1步驟1中所製備之6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(100 mg,0.311 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(57 mg,0.373 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.24 (d, 1H), 8.33 (s, 1H), 8.27 (d, 1H), 7.65 (d, 1H), 7.34 (dd, 1H), 6.56 (s, 1H), 4.87-4.75 (m, 1H), 4.42-4.41 (m, 1H), 3.48 (s, 1H), 2.72 (s, 2H), 2.33 (s, 6H), 2.06-2.05 (m, 5H), 1.91-1.89 (m, 4H), 1.80-1.70 (m, 3H); MS (ESI) m/z = 419.0 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(6.4 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(52 mg,0.124 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.55 (d, 1H), 8.63 (s, 1H), 8.50-8.45 (m, 2H), 8.30 (d, 1H), 8.18 (s, 1H), 8.06 (s, 1H), 7.71 (d, 1H), 7.41 (d, 1H), 7.05 (d, 1H), 4.85-4.69 (m, 1H), 3.81 (s, 1H), 3.11-3.04 (m, 4H), 2.84 (s, 1H), 2.66 (s, 3H), 2.35-2.32 (m, 2H), 2.15-2.12 (m, 3H), 2.05-2.19 (m, 5H), 1.55-1.54 (m, 2H), 1.25-1.23 (m, 2H); MS (ESI) m/z = 648.2 (M + H)
+
範例133.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(2.8 mg),其形態為白色固體,程序差異之處在於以範例132步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(52 mg,0.124 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(34 mg,0.149 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.39 (d, 1H), 8.36 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.18 (d, 1H), 7.67 (d, 1H), 7.34 (d, 1H), 6.97 (s, 1H), 6.15 (tt, 1H), 4.86-4.74 (m, 1H), 4.52 (td, 2H), 4.44-4.41 (m ,1H), 3.64 (s, 1H), 2.73 (s, 2H), 2.34 (s, 5H), 1.94-1.90 (m, 4H), 1.87-1.75 (m, 8H); MS (ESI) m/z = 608.2 (M + H)
+
範例134. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(三氟甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-5-(三氟甲基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為棕色固體(97 mg),程序差異之處在於以2-溴基-5-(三氟甲基)吡嗪(190 mg,0.837 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.18 (s, 1H), 9.14 (d, 1H), 9.09 (s, 1H), 7.32 (d, 1H)
步驟2. (1
s,4
s)-4-((2-氯-5-(5-(三氟甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為固體(60 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(三氟甲基)吡嗪(47 mg,0.169 mmol)及順
-4-胺基-1-甲基環己-1-醇(33 mg,0.254 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.18 (s, 1H), 8.95 (d, 1H), 8.88 (s, 1H), 8.62 (s, 1H), 6.67 (s, 1H), 3.41-3.39 (m, 1H), 1.96-1.93 (m, 2H), 1.80-1.70 (m, 4H), 1.62-1.57 (m, 1H), 1.32 (s, 3H), 1.27-1.25 (m, 1H); MS (ESI) m/z = 387.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(三氟甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(5 mg) ,其形態為淺黃色固體,程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-(三氟甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(30 mg,0.087 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 10.19 (s, 1H), 9.50 (s, 1H), 9.14 (s, 1H), 9.02 (d, 1H), 8.86 (s, 1H), 8.67 (s, 1H), 8.48-8.46 (d, 2H) 7.53 (s, 1H), 7.43 (s, 1H), 2.00-1.98 (m, 1H), 1.82 (s, 2H), 1.71-1.57 (m, 5H), 1.45-1.31 (m, 5H), 1.25 (s, 3H); MS (ESI) m/z = 616.2 (M + H)
+
範例135.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(151 mg),程序差異之處在於以範例1步驟1中所製備之6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶(173 mg,0.539 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(99 mg,0.647 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.63 (d, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.78 (d, 1H), 7.71 (d, 1H), 6.58 (s, 1H), 4.87-4.75 (m, 1H), 3.56 (s, 2H), 3.74 (S, 1H), 2.51 (s, 7H), 2.31-2.05 (m, 2H), 1.91-1.89 (m, 2H),1.81-1.71 (m, 6H); MS (ESI) m/z = 418.2 (M + H)
+
步驟2.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(9 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-胺(46 mg,0.11 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(30 mg,0.132 mmol) 代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.71 (d, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.39 (d, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.78-7.71 (m, 2H), 7.39 (s, 1H), 7.25 (s, 1H), 7.03 (s, 1H), 6.15 (tt, 1H), 4.86-4.74 (m, 1H), 4.52 (td, 2H), 3.67-3.65 (m, 1H), 3.56 (s, 2H), 2.53 (s, 7H), 2.31 (s, 3H), 2.05-1.94 (m, 2H), 1.92-1.83 (m, 5H), 1.78-1.72 (m, 1H), 1.27 (s, 1H); MS (ESI) m/z = 608.3 (M + H)
+
範例136.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(8 mg),其形態為白色固體,程序差異之處在於以範例126步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-胺(45 mg,0.11 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(30 mg,0.132 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.69 (d, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.79-7.72 (m, 2H), 7.35 (s, 1H), 7.24 (s, 1H), 7.03-7.01 (m, 1H), 6.15 (tt, 1H), 4.86-4.74 (m, 1H), 4.53 (td, 2H), 3.74 (s, 4H), 3.67 (s, 1H), 3.55 (s, 2H), 2.50 (s, 4H), 2.07-2.06 (m, 2H), 1.98-1.86 (m, 5H), 1.79-1.75 (m, 2H); MS (ESI) m/z = 594.3 (M + H)
+
範例137.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(9 mg),其形態為白色固體,程序差異之處在於以範例123步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4'-胺(43 mg,0.11 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(30 mg,0.132 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.42 (d, 1H), 8.39-8.37 (m, 2H), 8.24 (s, 2H), 8.17 (s, 1H), 7.65 (d, 1H), 7.34-7.32 (m, 3H), 6.97 (s, 1H), 6.15 (tt, 1H), 4.85-4.74 (m, 1H), 4.52 (td, 2H), 3.92 (t, 4H), 3.65 (s, 1H), 3.26 (t, 4H), 2.06-2.03 (m, 2H), 1.97-1.84 (m, 5H), 1.76-1.57 (m, 1H); MS (ESI) m/z = 580.3 (M + H)
+
範例138.
N 4'-(3,3-二氟環戊基)-
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-(3,3-二氟環戊基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(70 mg),程序差異之處在於以參考範例1步驟1中所製備之6'-氯-4'- 氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(79 mg,0.246 mmol)及3,3-二氟環戊胺鹽酸鹽(50 mg,0.319 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (d, 1H), 8.36 (s, 1H), 8.26 (d, 1H), 7.67 (d, 1H), 7.34 (dd, 1H), 6.52 (s, 1H), 4.41 (s, 1H), 4.07-4.06 (m, 1H), 2.72-2.63 (m, 3H), 2.36-1.30 (m, 8H), 2.07-2.05 (m, 3H), 1.93-1.89 (m, 4H); MS (ESI) m/z = 423.0 (M + H)
+
步驟2.
N 4'-(3,3-二氟環戊基)-
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(12.2 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-(3,3-二氟環戊基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(66 mg,0.155 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(42 mg,0.186 mmol) 代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 8.53 (s, 1H), 8.40 (d, 1H), 8.38 (s, 1H), 8.25-8.17 (m, 3H), 7.94 (s, 1H), 7.66 (d, 1H), 7.38 (d, 1H), 7.37 (dd, 1H), 7.27 (s, 1H), 7.97 (d, 1H), 6.15 (tt, 1H), 4.63 (s, 1H), 4.55 (td, 2H), 4.33-4.31 (m, 1H), 2.97 (s, 3H), 2.73-2.63 (m, 1H), 2.59 (s, 3H), 2.44-2.23 (m, 5H), 2.10-2.02 (m, 1H), 1.98-1.97 (m, 1H); MS (ESI) m/z = 612.2 (M + H)
+
範例139.
N 4'-(3,3-二氟環丁基)-
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-(3,3-二氟環丁基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(71 mg),程序差異之處在於以參考範例1步驟1中所製備之6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(79 mg,0.246 mmol)及3,3-二氟環丁胺鹽酸鹽(46 mg,0.319 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.43 (s, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 7.68 (d, 1H), 7.36 (d, 1H), 6.39 (s, 1H), 4.43-4.42 (m, 1H), 3.91 (s, 1H), 3.20-3.12 (m, 2H), 2.63-2.54 (m, 4H), 2.33 (s, 4H), 2.09-2.05 (m, 3H), 1.91-1.89 (m, 2H); MS (ESI) m/z = 409.0 (M + H)
+
步驟2.
N 4'-(3,3-二氟環丁基)-
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(15.5 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-(3,3-二氟環丁基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(63 mg,0.155 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(42 mg,0.186 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 8.51 (s, 2H), 8.39 (d, 1H), 8.27 (d, 1H), 8.20-8.18 (m, 3H), 7.79 (s, 1H), 7.67 (d, 1H), 7.37 (dd, 1H), 6.95 (d, 1H), 6.16 (tt, 1H), 4.64 (s, 1H), 4.56 (td, 2H), 4.16 (s, 1H), 3.48-3.16 (m, 2H), 3.02-3.01 (m, 3H), 2.64-2.57 (m, 5H), 2.35-2.30 (m, 2H), 2.12-2.08 (m, 2H); MS (ESI) m/z = 598.2 (M + H)
+
範例140.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3,3-二氟環丁基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(7 mg),其形態為白色固體,程序差異之處在於以範例139步驟1中所製備之6'-氯-
N-(3,3-二氟環丁基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(58 mg,0.142 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.04 (d, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 8.44 (d, 2H), 8.28-8.25 (m, 2H), 7.66 (d,1H), 7.38-7.36 (m, 2H), 7.18 (d, 1H), 4.53 (s, 1H), 4.12-4.11 (m, 1H), 3.23-3.19 (m, 2H), 2.85-2.83 (m, 3H), 2.66-2.58 (m, 4H), 2.46 (s, 3H), 2.21-2.16 (m, 2H), 2.01 (s, 2H), 1.56-1.55 (m, 2H), 1.26-1.23 (m, 3H); MS (ESI) m/z = 638.2 (M + H)
+
範例141.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(66 mg),程序差異之處在於以參考範例1步驟1中所製備之6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(79 mg,0.246 mmol)及3-氟環己胺鹽酸鹽(49 mg,0.319 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.09 (d, 1H), 8.32 (s, 1H), 8.25 (d, 1H), 7.65 (d, 1H), 7.34 (dd, 1H), 6.61 (s, 1H), 5.04-4.92 (m, 1H), 4.41-4.40 (m, 1H), 3.81-3.79 (m, 1H), 2.72 (m, 2H), 2.09 (s, 7H), 2.33-2.05 (m, 3H), 1.93-1.86 (m, 3H), 1.73-1.68 (m, 3H), 1.47-1.36 (m, 1H); MS (ESI) m/z = 419.0 (M + H)
+
步驟2.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(6.4 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(65 mg,0.155 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(42 mg,0.186 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 10.63-10.17 (m, 1H), 8.59 (s, 1H), 8.42-8.40 (m, 1H), 8.26 (s, 2H), 8.18 (s, 1H), 8.11-8.09 (m, 1H), 8.01-7.92 (m, 1H), 7.66-7.61 (m, 1H), 7.39-7.37 (m, 1H), 7.01-6.99 (m, 1H), 6.15 (t, 1H), 5.15-4.94 (m, 1H), 4.58-4.52 (m, 3H), 4.08-3.98 (m, 1H), 2.90-2.78 (m, 4H), 2.45 (s, 3H), 2.22 (s, 1H), 2.22 (s, 3H), 2.05-2.04 (m, 3H), 1.91-1.80 (m,2H), 1.74-1.45 (m, 4H); MS (ESI) m/z = 608.3 (M + H)
+
範例142. (1
s,4
s)-4-((6'-((2-(3,4-二氫-2
H-哌喃并[2,3-b]吡啶-6-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(3,4-二氫-2
H-哌喃并[2,3-b]吡啶-6-基)嘧啶-4-胺
以如同參考範例17之方式製備標題化合物(93 mg),其形態為固體,程序差異之處在於以6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)-3,4-二氫-2
H-哌喃并[2,3-b]吡啶(225 mg,0.862 mmol)代替1-(2,2-二氟乙基)-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡唑。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (s, 1H), 8.34 (s, 1H), 8.30 (d, 1H), 6.33 (d, 1H), 4.92 (s, 2H), 4.41 (t, 2H), 2.89 (t, 2H), 2.09-2.03 (m, 3H); MS (ESI) m/z = 229.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(3,4-二氫-2
H-哌喃并[2,3-b]吡啶-6-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(9 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(65 mg,0.151 mmol)及步驟1中所製備之2-(3,4-二氫
-2H-哌喃并[2,3-b]吡啶-6-基)嘧啶-4-胺(40 mg,0.173 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.95 (s, 1H), 8.38 (d, 2H), 8.29 (s, 2H), 7.75 (d, 1H), 7.48 (d, 1H), 7.34-7.31 (m, 2H), 4.54 (s, 1H), 4.43 (m, 2H), 3.48 (s, 1H), 2.94 (t, 2H), 2.75 (s, 2H), 2.41 (s, 2H), 2.33 (s, 3H), 2.09-2.06 (m, 4H), 1.93-1.85 (m, 4H), 1.73-1.64 (m, 4H), 1.49-1.46 (s, 2H), 1.20 (s, 3H); MS (ESI) m/z = 623.3 (M + H)
+
範例143.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4'-(3,3-二氟環戊基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物(12 mg),其形態為白色固體,程序差異之處在於以範例138步驟1中所製備之6'-氯-
N-(3,3-二氟環戊基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(65 mg,0.154 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.63 (s, 1H), 8.50 (s, 2H), 8.46-8.43 (m, 2H), 8.26 (s, 1H), 8.20 (s, 1H), 8.01 (s, 1H), 7.70 (d, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 4.68 (s, 1H), 4.35 (s, 1H), 3.49-3.01 (m, 4H), 2.85-2.69 (m, 2H), 2.66 (s, 3H), 2.49-2.44 (m, 1H), 2.38-2.28 (m, 5H), 2.14-2.04 (m, 3H), 1.56-1.55 (m, 2H), 1.25 (d, 2H); MS (ESI) m/z = 652.3 (M + H)
+
範例144.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺
步驟1. 2-溴基-5-((1-甲基哌啶-4-基)氧基)吡嗪
於室溫下在4-羥基-1-甲基哌啶(213 mg,1.85 mmol)之THF (2 mL)溶液中加入氫化鈉 (61 mg,2.522 mmol)。將反應混合物攪拌5分鐘後將2,5-二溴吡嗪(400 mg,1.682 mmol)加入混合物。在50
oC下將反應混合物攪拌4小時後以水淬火。以DCM萃取水相。結合之有機相利用MgSO
4乾燥後,進行過濾及濃縮。粗產物經管柱層析提純(MeOH/EA = 0-15%)產出形態為米白色固體之2-溴基-5-((1-甲基哌啶-4-基)氧基)吡嗪(450 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.16 (s, 1H), 7.99 (s, 1H), 5.00 (s, 1H), 2.71 (s, 2H), 2.32 (s, 5H), 2.05-2.04 (m, 2H), 1.90-1.82 (m, 2H), 1.67-1.66 (m, 1H); MS (ESI) m/z = 273.8 (M + H)
+
步驟2. 2-(6-氯-4-氟吡啶-3-基)-5-((1-甲基哌啶-4-基)氧基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(400 mg),程序差異之處在於以步驟1中所製備之2-溴基-5-((1-甲基哌啶-4-基)氧基)吡嗪(414 mg,1.521 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.21 (d, 1H), 2.75 (s, 2H), 2.34 (s, 6H), 2.09-2.05 (m, 2H), 1.94-1.73 (m, 2H); MS (ESI) m/z = 323.0 (M + H)
+
步驟3. 2-氯-
N-((1
s,4
s)-4-氟環己基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(78 mg),程序差異之處在於以步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((1-甲基哌啶-4-基)氧基)吡嗪(95 mg,0.294 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(68 mg,0.441 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.47 (s, 1H), 8.32 (s, 1H), 8.29 (d, 1H), 8.17 (s, 1H), 6.58 (s, 1H), 5.31 (s, 1H), 4.87-4.75 (m, 1H), 3.46 (s, 1H), 2.76 (s, 2H), 2.34 (s, 1H), 2.09-2.06 (m, 5H), 1.92-1.89 (m, 7H), 1.82-1.68 (m, 5H); MS (ESI) m/z = 420.1 (M + H)
+
步驟4.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(6 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之2-氯-
N-((1
s,4
s)-4-氟環己基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-胺(78 mg,0.185 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.65 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.38 (d, 1H), 8.33 (s, 1H), 8.18 (s, 1H), 7.46 (s, 1H), 7.32 (d, 1H), 7.04 (s, 1H), 5.10 (s, 1H), 4.84-4.72 (m, 1H), 3.62 (s, 1H), 2.85-2.81 (m, 1H), 2.77-2.76 (m, 2H), 2.34 (s, 5H), 2.00-1.97 (m, 3H), 1.95-1.63 (m, 8H), 1.78 (s, 2H), 1.63-1.53 (m, 3H), 1.27-1.22 (m, 2H); MS (ESI) m/z = 649.3 (M + H)
+
範例145. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((2-氯-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(80 mg),程序差異之處在於以範例144步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((1-甲基哌啶-4-基)氧基)吡嗪(95 mg,0.294 mmol)及順
-4-胺基-1-甲基環己-1-醇(57 mg,0.441 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.45 (s, 1H), 8.29 (s, 1H), 8.15 (s, 2H), 6.57 (s, 1H), 3.34-3.32 (m, 1H), 2.75 (s, 2H), 2.34 (s, 6H), 2.09-2.05 (m, 2H), 1.92-1.88 (m, 4H), 1.77-1.56 (m, 9H) 1.31 (s, 3H); MS (ESI) m/z = 432.1 (M + H)
+
步驟2. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(8 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((2-氯-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(80 mg,0.185 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.47 (d, 2H), 8.43 (d, 1H), 8.31 (s, 1H), 8.19-8.16 (m, 2H), 7.41-7.37 (m, 2H), 6.94 (s, 1H), 5.09 (s, 1H), 3.50 (s, 1H), 2.84-1.82 (m, 1H), 2.75 (s, 2H), 2.34 (s, 5H), 2.90 (s, 2H), 2.00-1.89 (m, 4H), 1.75-1.70 (m, 5H), 1.62-1.54 (m, 4H), 1.32 (s, 3H), 1.23-1.21 (m, 2H); MS (ESI) m/z = 661.2 (M + H)
+
範例146. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((2-氯-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(77 mg),程序差異之處在於以範例144步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((1-甲基哌啶-4-基)氧基)吡嗪(95 mg,0.294 mmol)及順
-(4-胺基環己基)甲醇鹽酸鹽(73 mg,0.441 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.68 (d, 1H), 8.51 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 6.58 (s, 1H), 5.11-5.09 (m, 1H), 3.78 (d, 1H), 3.53 (d, 2H), 2.74 (m, 2H), 2.34 (s, 5H), 2.08-2.06 (m, 2H), 2.92-1.88 (m, 4H), 1.72-1.61 (m, 5H), 1.35-1.27 (m, 2H); MS (ESI) m/z = 432.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物(6 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((2-氯-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇(80 mg,0.185 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.74 (d, 1H), 8.66 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.36 (s, 1H), 8.17 (s, 1H), 7.42 (s, 1H), 7.20-7.17 (m, 2H), 5.11 (s, 1H), 3.95 (s, 1H), 3.54-3.50 (m, 2H), 2.85-2.83 (m, 1H), 2.75 (s, 2H), 2.34 (s, 5H), 2.03-2.00 (m, 2H), 1.91-1.89 (m, 2H), 1.82-1.67 (m, 6H), 1.55 (s, 2H), 1.37-1.27 (m, 5H); MS (ESI) m/z = 661.2 (M + H)
+
範例147. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((2-氯-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(76 mg),程序差異之處在於以範例144步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((1-甲基哌啶-4-基)氧基)吡嗪(95 mg,0.294 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇鹽酸鹽(86 mg,0.441 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.72 (d, 1H), 7.51 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 6.59 (s, 1H), 5.11-5.10 (m, 1H), 3.83-3.81 (m, 1H), 2.74 (s, 2H), 2.34 (s, 6H), 2.09-2.05 (m, 2H), 1.97-1.91 (m, 2H), 1.89-1.87 (m, 2H), 1.78-1.75 (m, 3H), 1.65-1.58 (m, 2H), 1.41-1.30 (m, 3H), 1.23 (s, 7H); MS (ESI) m/z = 460.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物(7 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((2-氯-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇(85 mg,0.185 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.74 (d, 1H), 8.73 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 8.35 (s, 1H), 8.15(s, 1H), 7.40 (s, 1H), 7.25 (s, 1H), 7.15 (d, 1H), 5.10 (s, 1H), 3.99 (s, 1H), 2.85-2.84 (m, 1H), 2.75 (s, 2H), 2.34 (s, 5H), 2.10-2.08 (m,4H), 1.92-1.88 (m, 2H), 1.79-1.72 (m, 4H), 1.55 (s, 3H), 1.46-1.36 (m, 3H), 1.24 (s, 9H); MS (ESI) m/z = 689.3 (M + H)
+
範例148. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基-5-((四氫-2
H-哌喃-4-基)氧基)吡嗪
以如同範例144步驟1之方式製備標題化合物(160 mg),其形態為白色固體,程序差異之處在於以四氫-2
H-哌喃-4-醇(86 mg,0.841 mmol)代替4-羥基-1-甲基哌啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.16 (s, 1H), 8.01 (s, 1H), 5.19-5.15 (m, 1H), 4.02-3.96 (m, 2H), 3.64-3.58 (m, 2H), 2.08-2.04 (m, 2H), 1.85-1.78 (m, 2H)
步驟2. 2-(6-氯-4-氟吡啶-3-基)-5-((四氫-2
H-哌喃-4-基)氧基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以步驟1中所製備之2-溴基-5-((四氫-2
H-哌喃-4-基)氧基)吡嗪(156 mg,0.602 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 7.22 (d, 1H), 5.31-5.28 (m, 1H) 4.04-4.01 (m, 2H), 3.67-3.62 (m, 2H), 2.13-1.91 (m, 2H), 1.91-1.82 (m, 2H); MS (ESI) m/z = 310.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-氯-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(55 mg),程序差異之處在於以步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((四氫-2
H-哌喃-4-基)氧基)吡嗪(50 mg,0.161 mmol)及順
-4-胺基-1-甲基環己-1-醇(31 mg,0.242 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.45 (s, 1H), 8.30 (s, 1H), 8.17-8.13 (m, 2H), 6.58 (s, 1H), 5.29-5.25 (m, 1H), 4.04-4.01 (m, 2H), 3.66-3.61 (m, 2H), 3.34-3.33 (m, 1H), 2.12 (s, 1H), 1.91-1.84 (m, 4H), 1.78-1.65 (m, 5H), 1.60 (s, 1H), 1.31 (s, 3H), 1.13 (s, 1H); MS (ESI) m/z = 419.2 (M + H)
+
步驟4. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(16 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((2-氯-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(55 mg,0.131 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.47 (d, 2H), 8.44 (d, 1H), 8.32 (s, 1H), 8.18 (s, 2H), 7.38 (d, 2H), 6.95 (s, 1H), 5.28-5.25 (m, 1H), 4.05-4.02 (m, 2H), 3.67-3.62 (m, 2H), 3.49-3.48 (m, 1H), 2.84-2.82 (m, 2H), 2.13-2.10 (m, 2H), 2.01-1.98 (m, 2H), 1.91-1.85 (m, 4H), 1.75-1.59 (m, 2H), 1.32 (s, 3H), 1.26-1.25 (m, 2H), 1.23 (s, 1H); MS (ESI) m/z = 648.3 (M + H)
+
範例149. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基-5-((四氫呋喃-3-基)氧基)吡嗪
以如同範例144步驟1之方式製備標題化合物(137 mg),其形態為白色固體,程序差異之處在於以四氫呋喃-3-醇(74 mg,0.841 mmol)代替4-羥基-1-甲基哌啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.18 (s, 1H), 8.03 (s, 1H), 5.49 (d, 1H), 4.05-4.00 (m, 2H), 3.98-3.92 (m, 2H), 2.30-2.26 (m ,1H), 2.16-2.14 (m, 1H)
步驟2. 2-(6-氯-4-氟吡啶-3-基)-5-((四氫呋喃-3-基)氧基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(125 mg),程序差異之處在於以步驟1中所製備之2-溴基-5-((四氫呋喃-3-基)氧基)吡嗪(148 mg,0.602 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 7.22 (d, 1H), 5.61 (s, 1H), 4.14-3.92 (m, 5H), 2.36-2.29 (m, 1H), 2.23-2.17 (m, 1H); MS (ESI) m/z = 295.8 (M + H)
+
步驟3. (1
s,4
s)-4-((2-氯-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(54 mg),程序差異之處在於以步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((四氫呋喃-3-基)氧基)吡嗪(48 mg,0.161 mmol)及順
-4-胺基-1-甲基環己-1-醇(31 mg,0.242 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.47 (s, 1H), 8.30 (s, 1H), 8.19 (s, 1H), 8.15 (d, 1H), 6.58 (s, 1H), 5.59 (s, 1H), 4.09-3.93 (m, 4H), 3.33-3.32 (m, 1H), 2.35-2.30 (m, 1H), 2.21 (s, 1H), 1.94-1.91 (m, 2H), 1.77-1.68 (m, 4H), 1.60 (s, 1H), 1.54 (s, 1H), 1.31 (s, 3H), 1.13 (s, 1H); MS (ESI) m/z = 405.1 (M + H)
+
步驟4. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(8 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((2-氯-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(53 mg,0.131 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.48 (s, 2H), 8.43 (d, 1H), 8.32 (s, 1H), 8.20-8.18 (m, 2H), 7.41-7.36 (m, 2H), 6.96 (s, 1H), 5.59 (s, 1H), 4.10-3.92 (m, 4H), 3.50 (s, 1H), 2.85-2.82 (m, 1H), 2.35-2.30 (m, 1H), 2.22-2.18 (m, 1H), 2.02-1.98 (m, 2H), 1.75-1.70 (m, 4H), 1.62 (s, 1H), 1.55-1.54 (m, 2H), 1.32 (s, 3H), 1.26-1.19 (m, 2H), 1.16 (s, 1H); MS (ESI) m/z = 634.3 (M + H)
+
範例150. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基-5-(氧雜環丁-3-基氧基)吡嗪
以如同範例144步驟1之方式製備標題化合物(157 mg),其形態為白色固體,程序差異之處在於氧雜環丁-3-醇(74 mg,0.841 mmol)代替4-羥基-1-甲基哌啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.12 (d, 1H), 5.61-5.55 (m, 1H), 4.99 (t, 2H), 4.74 (t, 2H)
步驟2. 2-(6-氯-4-氟吡啶-3-基)-5-(氧雜環丁-3-基氧基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(81 mg),程序差異之處在於以步驟1中所製備之2-溴基-5-(氧雜環丁-3-基氧基)吡嗪(139 mg,0.602 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.02 (d, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.23 (d, 1H), 5.70-5.67 (m, 1H), 5.04 (t, 2H), 4.80 (t, 2H); MS (ESI) m/z = 281.9 (M + H)
+
步驟3. (1
s,4
s)-4-((2-氯-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(60 mg),程序差異之處在於以步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-(氧雜環丁-3-基氧基)吡嗪(45 mg,0.161 mmol)及順
-4-胺基-1-甲基環己-1-醇(31 mg,0.242 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.43 (s, 1H), 8.29 (s, 1H) 8.26 (s, 1H), 8.15 (d, 1H), 6.58 (s, 1H), 5.67-5.64 (m, 1H), 5.03 (t, 2H), 4.78 (t, 2H), 3.32 (s, 1H), 1.93-1.91 (m, 2H), 1.77-1.71 (m, 3H), 1.65-1.54 (m, 2H), 1.31 (s, 3H), 1.24 (s, 1H); MS (ESI) m/z = 391.1 (M + H)
+
步驟4. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(16 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((2-氯-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(51 mg,0.131 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.48 (s, 1H), 8.44 (s, 2H), 8.31 (s, 1H), 8.27 (s, 1H), 8.21 (d, 1H), 7.36 (d, 2H), 6.98 (s, 1H), 5.67 (s, 1H), 5.04 (t, 2H), 4.80 (t, 2H), 3.50 (s, 1H), 2.84-2.81 (m, 1H), 2.01-1.98 (m, 2H), 1.76-1.73 (m, 4H), 1.63 (s, 2H), 1.32 (s, 3H), 1.27-1.15 (m, 3H); MS (ESI) m/z = 620.2 (M + H)
+
範例151.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺
步驟1. 2-氯-
N-((1
s,4
s)-4-氟環己基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(79 mg),程序差異之處在於以範例148步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((四氫-2
H-哌喃-4-基)氧基)吡嗪(47 mg,0.152 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(35 mg,0.228 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.47 (s, 1H), 8.32 (s, 1H), 8.28 (d, 1H), 8.18 (s, 1H), 6.58 (s, 1H), 5.31-5.27 (m, 1H), 4.88-4.76 (m, 1H), 4.04-4.01 (m, 2H), 3.67-3.61 (m, 2H), 3.46 (s, 1H), 2.12-1.92 (m, 4H), 1.90-1.65 (m, 8H); MS (ESI) m/z = 407.1 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(18 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-氯-
N-((1
s,4
s)-4-氟環己基)-5-(5-((四氫-2
H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-胺(41.89 mg,0.103 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.65 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.38 (d, 1H), 8.33 (s, 1H), 8.19 (s, 1H), 7.51 (s, 1H), 7.31 (d, 1H), 7.06 (s, 1H), 5.29-5.27 (m, 1H), 4.85-4.73 (m, 1H), 4.05-4.01 (m, 2H), 3.68-3.63 (m, 3H), 2.84-2.82 (m, 1H), 2.13-2.10 (m, 2H), 2.01-1.75 (m, 10H), 1.56-1.54 (m,2H), 1.27-1.22 (m, 2H); MS (ESI) m/z = 636.2 (M + H)
+
範例152.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-2,4-二胺
步驟1. 2-氯-
N-((1
s,4
s)-4-氟環己基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-胺
以如同範例1步驟2之方式製備標題化合物,其形態為固體(79 mg),程序差異之處在於以範例149步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((四氫呋喃-3-基)氧基)吡嗪(45 mg,0.152 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(35 mg,0.228 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.49 (s, 1H), 8.33 (s, 1H), 8.28 (d, 1H), 8.20 (s, 1H), 6.59 (S, 1H), 5.61-5.60 (m, 1H), 4.88-4.75 (m, 1H), 4.10-3.94 (m, 5H), 3.46 (s, 1H), 2.34-2.30 (m, 1H), 2.21-2.18 (m, 1H), 2.06-2.04 (m, 2H), 1.93-1.90 (m, 1H), 1.78-1.68 (m, 4H); MS (ESI) m/z = 393.1 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-
N 4-((1
s,4
s)-4-氟環己基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物(17 mg),其形態為白色固體,程序差異之處在於以步驟1中所製備之2-氯-
N-((1
s,4
s)-4-氟環己基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-胺(40 mg,0.103 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.65 (s, 1H), 8.50 (s, 1H), 8.46 (s, 1H), 8.44 (d, 1H), 8.37-8.35 (m, 2H), 8.21 (s, 1H), 7.40 (s, 1H), 7.32 (d, 1H), 7.04 (s, 1H), 6.00 (s, 1H), 4.85-4.73 (m, 1H), 4.11-3.95 (m, 5H), 3.63-3.61 (m, 1H), 2.84-2.82 (m, 1H), 2.34-2.31 (m, 1H), 2.22-2.19 (m, 1H), 2.05-1.96 (m, 4H), 1.84-1.74 (m, 4H), 1.54-1.52 (m, 2H), 1.25-1.20 (m, 2H); MS (ESI) m/z = 622.2 (M + H)
+
範例153. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 叔丁基4-((5-溴基吡嗪-2-基)氧基)哌啶-1-羧酸鹽
以如同範例144步驟1之方式製備標題化合物(548 mg),其形態為米白色固體,程序差異之處在於以1-(叔丁氧羰基)-4-羥基哌啶(372 mg,1.85 mmol)代替4-羥基-1-甲基哌啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.16 (s, 1H), 8.00 (s, 1H), 5.15 (s, 1H), 3.79-3.76 (m, 2H), 3.33-3.26 (m, 2H), 1.97 (s, 2H), 1.76-1.73 (m, 2H), 1.48 (s, 9H)
步驟2. 叔丁基4-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)哌啶-1-羧酸鹽
以如同範例1步驟1之方式製備標題化合物,其形態為固體(431 mg),程序差異之處在於以步驟1中所製備之叔丁基4-((5-溴基吡嗪-2-基)氧基)哌啶-1-羧酸鹽 (545 mg,1.521 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.01 (d, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 7.22 (d, 1H), 5.28-5.27 (m, 1H), 3.83-3.80 (m, 2H), 3.35-3.29 (m, 2H), 2.02 (s, 2H), 1.83-1.76 (m, 2H), 1.49 (s, 9H)
步驟3. 2-(6-氯-4-氟吡啶-3-基)-5-(哌啶-4-基氧基)吡嗪
將TFA (794 uL,10.37 mmol)加入步驟2中所製備之叔丁基4-((5-(6-氯-4-氟吡啶-3-基)吡嗪-2-基)氧基)哌啶-1-羧酸鹽 (424 mg,1.037 mmol)之DCM (4 mL) 溶液。於室溫下將反應混合物攪拌1.5小時。將反應混合物溶解於 DCM並揮發。粗產物經管柱層析提純(MeOH/EA = 0-45%)產出形態為白色固體之2-(6-氯-4-氟吡啶-3-基)-5-(哌啶-4-基氧基)吡嗪(402 mg)。
1H-NMR (MeOD, 400 MHz) δ 8.95 (d, 1H), 8.62 (s, 1H), 8.42 (s, 1H), 7.53 (d, 1H), 5.47-5.46 (m, 1H), 3.49-3.43 (m, 2H), 3.32-3.26 (m, 2H), 2.31-2.26 (m, 2H), 2.17-2.12 (m, 2H); MS (ESI) m/z = 308.9 (M + H)
+
步驟4. 2-(6-氯-4-氟吡啶-3-基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪
將步驟3中所製備之 2-(6-氯-4-氟吡啶-3-基)-5-(哌啶-4-基氧基)吡嗪(130 mg,0.421 mmol)、1-氟-2-碘乙烷(81 mg,0.463 mmol)與碳酸銫 (343 mg,1.053 mmol)在DMF (2 mL)中之反應混合物在60
oC下攪拌19小時。將反應混合物溶解於 EA,以水清洗,利用MgSO
4乾燥後濃縮。粗產物經管柱層析提純(EA/n-Hex = 40-100%)產出形態為黃色固體之2-(6-氯-4-氟吡啶-3-基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪(20 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 8.86 (d, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 7.81 (d, 1H), 5.08-5.05 (m, 1H), 4.59 (t 1H), 4.47 (t, 1H), 2.80 (s, 2H), 2.77-2.72 (m, 1H), 2.67-2.61 (m, 1H), 2.33 (t, 2H), 2.00 (s, 2H), 1.74-1.72 (m, 2H), 1.23 (s, 1H); MS (ESI) m/z = 355.0 (M + H)
+
步驟5. (1
s,4
s)-4-((2-氯-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(20 mg),程序差異之處在於以步驟4中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪(19 mg,0.054 mmol)及順
-4-胺基-1-甲基環己-1-醇(10 mg,0.08 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.44 (s, 1H), 8.28 (S, 1H), 8.15-8.12 (d, 2H), 6.56 (s, 1H), 5.12-5.10 (m, 1H), 4.67 (t, 1H), 4.55 (t, 1H), 3.33 (s, 1H), 2.94 (s, 2H), 2.87 (t, 1H), 2.80 (t, 1H), 2.74 (t, 2H), 2.08-2.05 (m, 2H), 1.98-1.90 (m, 4H), 1.82-1.70 (m, 9H), 1.30 (s, 3H); MS (ESI) m/z = 464.1 (M + H)
+
步驟6. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(3 mg),其形態為白色固體,程序差異之處在於以步驟5中製備之(1
s,4
s)-4-((2-氯-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(19 mg,0.049 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.47 (d, 2H), 8.44 (d, 1H), 8.31 (s, 1H), 8.19 (d, 1H), 8.17 (s, 1H), 7.43 (s, 1H), 7.38 (d, 1H), 6.96 (s, 1H), 5.12 (s, 1H), 4.67 (t, 1H), 4.55 (t, 1H), 3.50 (s, 2H), 2.89-2.79 (m, 3H), 2.73 (t, 1H), 2.48 (t, 2H), 2.10 (s, 2H), 2.00-1.89 (m, 4H), 1.75-1.70 (m, 4H), 1.62 (s, 1H), 1.55-1.53 (m, 3H), 1.32 (s, 3H), 1.23-1.19 (m, 2H); MS (ESI) m/z = 693.3 (M + H)
+
範例154. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基-5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪
以如同範例144步驟1之方式製備標題化合物,其形態為固體(154 mg), 不同之處在於以4-氟-1-甲基-4-哌啶甲醇(93 mg,0.631 mmol)代替4-羥基-1-甲基哌啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.18 (s, 1H), 8.09 (s, 1H), 4.35 (d, 2H), 2.73-2.70 (m, 2H), 2.38-2.33 (m, 5H), 2.05-1.99 (m, 2H), 1.92-1.76 (m, 2H)
步驟2. 2-(6-氯-4-氟吡啶-3-基)-5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為固體(122 mg),程序差異之處在於以步驟1中所製備之2-溴基-5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪(150 mg,0.493 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.55 (s, 1H), 8.41 (s, 1H), 7.22 (d, 1H), 4.45 (d, 2H), 2.75-2.72 (m, 3H), 2.40-2.38 (m, 2H), 1.09-2.03 (m, 3H), 1.92-1.83 (m, 3H)
步驟3. (1
s,4
s)-4-((2-氯-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(60 mg),程序差異之處在於以步驟2中所製備之2-(6-氯-4-氟吡啶-3-基)-5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪(60 mg,0.169 mmol)及順
-4-胺基-1-甲基環己-1-醇(33 mg,0.254 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.47 (s, 1H), 8.30 (s, 1H), 8.25 (s, 1H), 8.12 (d, 1H), 6.58 (s, 1H), 4.45 (s, 1H), 4.41 (s, 1H), 3.32 (s, 1H), 2.74-2.71 (m, 2H), 2.39-2.35 (m, 5H), 2.08-2.02 (m, 3H), 1.94-1.86 (m, 3H), 1.82-1.60 (m, 5H), 1.31-1.25 (m, 4H), 1.11 (s, 1H); MS (ESI) m/z = 464.2 (M + H)
+
步驟4. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(5 mg),其形態為白色固體,程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((2-氯-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(40 mg,0.086 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.48 (s, 2H), 8.44 (d, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.16 (d, 1H), 7.39 (s, 1H), 6.94 (s, 1H), 4.43 (d, 2H), 3.53 (s, 1H), 3.50 (s, 1H), 2.84-2.82 (m, 1H), 2.74-2.71 (m, 2H), 2.40-2.35 (m, 5H), 2.09-1.83 (m, 7H), 1.75-1.72 (m, 3H), 1.69 (s, 1H), 1.58-1.54 (m, 2H), 1.32 (s, 3H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 693.3 (M + H)
+
範例155. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇
步驟1. 6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(60 mg),程序差異之處在於以參考範例4中所製備之6'-氯-4'-氟-[2,3'-聯吡啶]-5-醇(55 mg,0.245 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 334.1 (M + H)
+
步驟2. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(2.2 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇(42 mg,0.124 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3’-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.09 (s, 1H), 9.95 (s, 1H), 9.11 (s, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.36 (s, 1H), 8.15 (d, 1H), 7.79 (d, 1H), 7.29 (dd, 1H), 4.19 (s, 1H), 3.28-3.21 (m, 1H), 1.84-1.81 (m, 2H), 1.63-1.56 (m, 4H), 1.45-1.39 (m, 2H), 1.34-1.32 (m, 2H), 1.25-1.23 (m, 2H), 1.13 (s, 3H)
範例156. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(96 mg),程序差異之處在於以參考範例5中所製備之6'-氯-4'-氟-5-(甲基磺醯基)-2,3'-聯吡啶(70 mg,0.244 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 396.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(25 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(49 mg,0.124 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.15 (s, 1H), 9.52 (s, 1H), 9.07 (s, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.46 (d, 1H), 8.29 (s, 2H), 7.52 (s, 1H), 7.41 (s, 1H), 4.21 (s, 1H), 3.28-3.22 (m, 1H), 1.99-1.97 (m, 2H), 1.84-1.57 (m, 4H), 1.46-1.40 (m, 2H), 1.34-1.32 (m, 2H), 1.26-1.24 (m, 2H), 1.17 (s, 3H); MS (ESI) m/z = 625.2 (M + H)
+
範例157.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. (1
s,4
s)
-N 1-(6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)
-N 4-(2-氟乙基)環己烷-1,4-二胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(89 mg),程序差異之處在於以參考範例5中所製備之6'-氯-4'-氟-5-(甲基磺醯基)-2,3'-聯吡啶(70 mg,0.244 mmol)及(1
s,4
s)
-N 1-(2-氟乙基)環己烷-1,4-二胺(59 mg,0.366 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 427.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(27 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)
-N 1-(6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)
-N 4-(2-氟乙基)環己烷-1,4-二胺(48 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.89 (d, 1H), 9.12 (d, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.24 (dd, 1H), 7.95 (d, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 7.10 (d, 1H), 4.64 (t, 1H), 4.52 (t, 1H), 3.91 (brs, 1H), 3.18 (s, 3H), 3.00 (t, 1H), 2.93 (t, 1H), 2.88-2.82 (m, 1H), 2.71-2.66 (m, 1H), 2.07-2.05 (m, 2H), 1.88-1.82 (m, 4H), 1.57-1.43 (m, 4H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 656.2 (M + H)
+
範例158. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(88 mg),程序差異之處在於以參考範例5中所製備之6'-氯-4'-氟-5-(甲基磺醯基)-2,3'-聯吡啶(70 mg,0.244 mmol)及((1
s,4
s)-4-胺基環己基)甲醇(47 mg,0.366 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.94 (d, 1H), 9.08 (d, 1H), 8.69 (s, 1H), 8.41-8.34 (m, 2H), 6.82 (s, 1H), 4.50 (t, 1H), 3.94-3.91 (m, 1H), 3.29 (t, 2H), 1.76-1.72 (m, 2H), 1.63-1.57 (m, 4H), 1.49-1.46 (m, 1H), 1.28-1.25 (m, 2H)
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(48.6 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(86 mg,0.218 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.02 (d, 1H), 9.08 (d, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 8.23 (dd, 1H), 7.96 (d, 1H), 7.93 (s, 1H), 7.41 (s, 1H), 7.06 (d, 1H), 4.02 (brs, 1H), 3.56 (d, 2H), 3.17 (s, 3H), 2.88-2.82 (m, 1H), 2.05-2.03 (m, 2H), 1.86-1.75 (m, 5H), 1.56-1.52 (m, 2H), 1.41-1.32 (m, 2H), 1.28-1.21 (m, 2H); MS (ESI) m/z=625.1 (M + H)
+
範例159.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(89 mg),程序差異之處在於以參考範例5中所製備之6'-氯-4'-氟-5-(甲基磺醯基)-2,3'-聯吡啶(70 mg,0.244 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(84 mg,0.366 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 423.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(44.2 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-胺(88 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.97 (d, 1H), 9.08 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 8.24 (d, 1H), 7.97 (d, 1H), 7.70 (s, 1H), 7.34 (s, 1H), 7.11 (d, 1H), 4.00 (brs, 1H), 3.17 (s, 3H), 2.88-2.82 (m, 1H), 2.24 (s, 6H), 2.16 (d, 2H), 2.03-2.00 (m, 2H), 1.85-1.73 (m, 5H), 1.57-1.52 (m, 2H), 1.28-1.21 (m, 4H); MS (ESI) m/z = 652.2 (M + H)
+
範例160. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(152 mg),程序差異之處在於以參考範例5中所製備之6'-氯-4'-氟-5-(甲基磺醯基)-2,3'-聯吡啶(100 mg,0.349 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(82 mg,0.523 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.87 (d, 1H), 9.07 (d, 1H), 8.53 (d, 1H), 8.27 (dt, 1H), 7.98 (dd, 1H), 6.64 (d, 1H), 3.86-3.84 (m, 1H), 3.15 (s, 3H), 2.04-1.91 (m, 2H), 1.81-1.78 (m, 2H), 1.68-1.61 (m, 2H), 1.43-1.30 (m, 3H), 1.22 (s, 6H)
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(52 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(141 mg,0.332 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.00 (d, 1H), 9.07 (d, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.24 (dd, 1H), 7.97 (d, 1H), 7.62 (s, 1H), 7.42 (s, 1H), 7.06 (d, 1H), 4.03 (brs, 1H), 3.16 (s, 3H), 2.88-2.82 (m, 1H), 2.13-2.10 (m, 2H), 1.84-1.76 (m, 4H), 1.57-1.53 (m, 2H), 1.48-1.40 (m, 2H), 1.29-1.22 (m, 8H); MS (ESI) m/z = 6532 (M + H)
+
範例161. (3-(((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)甲基)氧雜環丁-3-基)甲醇
步驟1. (3-(((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)甲基)氧雜環丁-3-基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(119 mg),程序差異之處在於以參考範例6中所製備之6'-氯-4',6-二氟-2,3'-聯吡啶(100 mg,0.441 mmol)及(3-(胺基甲基)氧雜環丁-3-基)甲醇(78 mg,0.662 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.68 (t, 1H), 8.47 (s, 1H), 8.11 (q, 1H), 7.89 (dd, 1H), 7.18 (dd, 1H), 6.87 (s, 1H), 5.14 (t, 1H), 4.35 (s, 4H), 3.70 (d, 2H), 3.52 (d, 2H)
步驟2. (3-(((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)甲基)氧雜環丁-3-基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(35.6 mg),程序差異之處在於以步驟1中所製備之(3-(((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)甲基)氧雜環丁-3-基)甲醇(107 mg,0.332 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.15 (s, 1H), 8.74 (t, 1H), 8.68 (s, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.45 (d, 1H), 8.06 (q, 1H), 7.91 (dd, 1H), 7.51 (s, 1H), 7.44 (s, 1H), 7.08 (dd, 1H), 5.13 (t, 1H), 4.42 (brs, 4H), 3.75 (d, 2H), 3.59 (d, 2H), 3.30-3.23 (m, 1H), 1.36-1.32 (m, 2H), 1.27-1.22 (m, 2H); MS (ESI) m/z = 553.2 (M + H)
+
範例162. (4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇
步驟1. (4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(121 mg),程序差異之處在於以參考範例6中所製備之6'-氯-4',6-二氟-2,3'-聯吡啶(100 mg,0.441 mmol)及(4-胺基-1-氟環己基)甲醇(97 mg,0.662 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.48 (d, 1H), 8.46 (d 1H), 8.14-8.08 (m, 1H), 7.90 (d, 1H), 7.18 (d, 1H), 6.86 (s, 1H), 5.00 (t, 1H), 3.59 (brs, 1H), 3.43-3.41 (brs, 1H), 1.90-1.82 (m, 4H), 1.71-1.55 (m, 2H), 1.49-1.41 (m, 2H)
步驟2. (4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(53.7 mg),程序差異之處在於以步驟1中所製備之(4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇(117 mg,0.332 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.08 (s, 1H), 8.66 (s, 1H), 8.63 (d, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.45 (d, 1H), 8.06 (q, 1H), 7.91 (dd, 1H), 7.64 (s, 1H), 7.24 (s, 1H), 7.09 (dd, 1H), 4.97 (t, 1H), 3.50-3.52 (m, 1H), 3.45 (d, 2H), 3.28-3.22 (m, 1H), 2.02-1.98 (m, 2H), 1.90-1.86 (m, 2H), 1.66-1.52 (m, 4H), 1.37-1.28 (m, 4H); MS (ESI) m/z = 583.1 (M + H)
+
範例163. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(171 mg),程序差異之處在於以參考範例6中所製備之6'-氯-4',6-二氟-2,3'-聯吡啶(100 mg,0.441 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(104 mg,0.662 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 364.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(68.4 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(121 mg,0.332 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.34 (d, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 7.87 (q, 1H), 7.72 (s, 1H), 7.65 (dd, 1H), 7.32 (s, 1H), 7.09 (d, 1H), 6.83 (dd, 1H), 4.00 (brs, 1H), 2.88-2.82 (m, 1H), 2.13-2.10 (m, 2H), 1.80-1.74 (m, 4H), 1.57-1.48 (m, 4H), 1.27-1.23 (m, 8H); MS (ESI) m/z = 593.2 (M + H)
+
範例164. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
步驟1. 6'-氯-4'-氟
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同參考範例5之方式製備標題化合物,其形態為固體(221 mg),程序差異之處在於以6-溴基
-N,
N-二甲基吡啶-3-磺胺(300 mg,1.132 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 316.0 (M + H)
+
步驟2. 6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(87 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺(70 mg,0.22 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 425.1 (M + H)
+
步驟3. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11 mg),程序差異之處在於以步驟2中所製備之6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺(79 mg,0.19 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.57 (d, 1H), 8.94 (s, 1H), 8.67 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 8.09 (d, 1H), 7.91 (d, 1H), 7.57 (s, 1H), 7.28 (s, 1H), 7.10 (s, 1H), 3.54 (brs, 1H), 2.82 (s, 7H), 2.03-2.00 (m, 2H), 1.84-1.75 (m, 4H), 1.64-1.54 (m, 4H), 1.33 (s, 3H), 1.26-1.22 (m, 2H)
範例165. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
步驟1. 6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(91 mg),程序差異之處在於以範例164步驟1中所製備之6'-氯-4'-氟
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺(70 mg,0.22 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(52 mg,0.33 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.92 (d, 1H), 8.93 (d, 1H), 8.54 (s, 1H), 8.13 (dd, 1H), 7.96 (d, 1H), 6.64 (s, 1H), 3.88-3.86 (m, 1H), 2.80 (s, 6H), 2.04-2.00 (m, 2H), 1.82-1.70 (m, 2H), 1.68-1.62 (m, 1H), 1.44-1.30 (m, 4H), 1.22 (s, 6H)
步驟2. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(41.3 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺(85 mg,0.19 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.07 (s, 1H), 8.92 (s, 1H), 8.67 (d, 1H), 8.58 (d, 1H), 8.48 (d, 1H), 8.43 (d, 1H), 8.09 (d, 1H), 7.96 (d, 1H), 7.64 (s, 1H), 7.43 (s, 1H), 7.06 (s, 1H), 4.05 (s, 1H), 2.85-2.82 (m, 1H), 2.80 (s, 6H), 2.12-2.05 (m, 2H), 1.84-1.80 (m, 4H), 1.56-1.40 (m, 5H), 1.24-1.13 (m, 8H)
範例166. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
步驟1. 6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(83 mg),程序差異之處在於以範例164步驟1中所製備之6'-氯-4'-氟
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺(70 mg,0.22 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(155 mg,0.33 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.84 (d, 1H), 8.95 (d, 1H), 8.53 (s, 1H), 8.13 (dd, 1H), 7.95 (d, 1H), 6.64 (s, 1H), 3.84-3.82 (m, 1H), 3.55 (d, 2H), 2.81 (s, 6H), 1.94-1.91 (m, 2H), 1.77-1.71 (m, 4H), 1.55 (brs, 1H), 1.40-1.30 (m, 2H)
步驟2. 6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(18.9 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)
-N,
N-二甲基-[2,3'-聯吡啶]-5-磺胺(62 mg,0.15 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.01 (d, 1H), 8.93 (d, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 8.10 (dd, 1H), 7.94 (d,1 H), 7.72 (brs, 1H), 7.39 (s,1 H), 7.08 (d, 1H), 4.02 (brs, 1H), 3.55 (d, 2H), 2.88-2.82 (m, 1H), 2.82 (s, 6H), 2.07-2.04 (m, 2H), 1.86-1.75 (m, 5H), 1.57-1.53 (m, 2H), 1.41-1.33 (m, 2H), 1.29-1.21 (m, 2H); MS (ESI) m/z = 654.2 (M + H)
+
範例167. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟
-N,
N-二甲基-[2,3'-聯吡啶]-4-胺
以如同參考範例5之方式製備標題化合物,其形態為白色固體(74 mg),程序差異之處在於以2-溴基
-N,
N-二甲基-吡啶-4-胺(200 mg,0.995 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 252.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(92 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟
-N,
N-二甲基-[2,3'-聯吡啶]-4-胺(70 mg,0.278 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 361.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(25.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(82 mg,0.23 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.17 (s,1 H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.32 (s, 1H), 8.22 (d, 1H), 7.40 (d, 1H), 6.88 (s, 1H), 6.80 (d, 1H), 6.48 (dd, 1H), 3.45 (brs, 1H), 3.08 (s, 6H), 2.86-2.80 (m, 1H), 1.99-1.96 (m, 2H), 1.76-1.70 (m, 4H), 1.58-1.52 (m, 4H), 1.31 (s, 3H), 1.24-1.21 (m, 2H); MS (ESI) m/z = 590.2 (M + H)
+
範例168. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(120 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(100 mg,0.37 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 376.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(40 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(85 mg,0.23 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.01 (s, 1H), 9.57 (s, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.83 (d, 2H), 7.55 (brs, 1H), 7.29 (brs, 1H), 4.20 (s, 1H), 3.27-3.21 (m, 1H), 1.85-1.83 (m, 2H), 1.66-1.57 (m, 4H), 1.49 (s, 6H), 1.46-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.27-1.23 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 605.2 (M + H)
+
範例169. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(133 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(100 mg,0.37 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 404.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(47.8 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(91 mg,0.23 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.12 (d, 1H), 10.06 (s, 1H), 8.66 (d, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.45 (s, 1H), 8.41 (d, 1H), 7.98-7.91 (m, 2H), 7.52 (brs, 1H), 7.37 (brs, 1H), 4.12 (s, 1H), 3.95 (brs, 1H), 3.31-3.25 (m, 1H), 1.98-1.95 (m, 2H), 1.81-1.63 (m, 4H), 1.47 (s, 6H), 1.35-1.26 (m, 7H), 1.07 (s, 6H); MS (ESI) m/z = 633.3 (M + H)
+
範例170. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(140 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(100 mg,0.37 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(93 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 376.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(28.7 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(132 mg,0.35 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.11 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.45 (d, 1H), 8.38 (d, 1H), 7.87 (d, 1H), 7.72 (d, 1H), 7.32 (s, 1H), 7.09 (s, 1H), 3.98 (brs, 1H), 3.55 (d, 2H), 2.86-2.81 (m, 1H), 2.05-2.03 (m, 2H), 1.82-1.67 (m, 4H), 1.53-1.38 (m, 4H), 1.26-1.22 (m, 3H); MS (ESI) m/z = 605.2 (M + H)
+
範例171. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(100 mg,0.37 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(129 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 403.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(21.7 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(106 mg,0.26 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.06 (s, 1H), 8.69 (d, 2H), 8.45-8.37 (m, 3H), 7.88 (s, 1H), 7.72 (s, 1H), 7.30 (d, 2H), 7.08 (s, 1H), 3.95 (brs, 1H), 2.84 (brs, 1H), 2.23 (s, 6H), 2.17 (d, 2H), 2.01-1.98 (m, 2H), 1.74-1.53 (m, 7H), 1.30-1.23 (m, 4H); MS (ESI) m/z = 632.3 (M + H)
+
範例172. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)
-N,
N-二甲基環己烷-1-碳醯胺
步驟1. (1
s,4
s)-4-((6'-氯-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)
-N,
N-二甲基環己烷-1-碳醯胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(125 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(100 mg,0.37 mmol)及(1
s,4
s)-4-胺基
-N,
N-二甲基環己烷-1-碳醯胺(116 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 417.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)
-N,
N-二甲基環己烷-1-碳醯胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(33.1 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)
-N,
N-二甲基環己烷-1-碳醯胺(110 mg,0.26 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.24 (d, 1H), 8.85 (d, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.46 (d, 1H), 8.39 (d, 1H), 7.78 (dd, 1H), 7.71 (d, 1H), 7.38 (s, 1H), 7.04 (d, 1H), 4.00 (brs, 1H), 3.09 (s, 3H), 2.94 (s, 3H), 2.89-2.82 (m, 1H), 2.69-2.64 (m, 1H), 2.12-2.10 (m, 2H), 1.95-1.82 (m, 4H), 1.64 (s, 6H), 1.56-1.51 (m, 2H), 1.30-1.20 (m, 4H); MS (ESI) m/z = 646.3 (M + H)
+
範例173. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(98 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(74 mg,0.28 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(64 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 364.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(9 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(45 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.03 (s, 1H), 9.80 (br, 1H), 8.69 (s, 1H), 8.65 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 7.97-7.91 (m, 2H), 7.58 (br, 1H), 7.26 (br, 1H), 4.77 (d, 1H), 3.64-3.58 (m, 1H), 3.28-3.23 (m, 1H), 2.01-1.84 (m, 5H), 1.75-1.69 (m, 3H), 1.49 (s, 6H), 1.35-1.33 (m, 2H), 1.26-1.22 (m, 2H); MS (ESI) m/z = 593.2 (M + H)
+
範例174. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(98 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(74 mg,0.28 mmol)及4-氟環己-1-胺鹽酸鹽(64 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 364.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11.5 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(45 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 9.75 (d, 1H), 8.68 (d, 1H), 8.65 (s, 1H), 8.55 (d, 1H), 8.46 (d, 1H), 8.44 (d, 1H), 7.97-7.90 (m ,2H), 7.59 (br, 1H), 7.25 (d, 1H), 4.82-4.68 (m, 1H), 3.64-3.60 (m, 1H), 3.29-3.23 (m, 1H), 2.11-2.02 (m, 1H), 1.97-1.84 (m, 4H), 1.76-1.65 (m, 2H), 1.54-1.52 (m, 7H), 1.49-1.36 (m, 4H); MS (ESI) m/z = 593.2 (M + H)
+
範例175. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(100 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(74 mg,0.28 mmol)及4,4-二氟環己-1-胺鹽酸鹽(72 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 382.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(6.5 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(48 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 9.75 (d, 1H), 8.68 (d, 1H), 8.65 (s, 1H), 8.55 (d, 1H), 8.46 (d, 1H), 8.44 (d, 1H), 7.97-7.90 (m ,2H), 7.59 (br, 1H), 7.25 (d, 1H), 4.82-4.68 (m, 1H), 3.64-3.60 (m, 1H), 3.29-3.23 (m, 1H), 2.11-2.02 (m, 1H), 1.97-1.84 (m, 4H), 1.76-1.65 (m, 2H), 1.54-1.52 (m, 7H), 1.49-1.36 (m, 4H); MS (ESI) m/z = 611.2 (M + H)
+
範例176. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(93 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(70 mg,0.26 mmol)及1-(2-氟乙基)哌啶-4-胺鹽酸鹽(62 mg,0.34 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.63 (d, 1H), 8.69 (s, 1H), 8.37 (s, 1H), 7.90 (dd, 1H), 7.69 (d, 1H), 6.57 (s, 1H), 4.65 (t, 1H), 4.53 (t, 1H), 3.49-3.46 (m, 1H), 2.90-2.88 (m, 2H), 2.78 (t, 1H), 2.71 (t, 1H), 2.39 (t, 2H), 2.08-2.06 (m, 2H), 1.74-1.69 (m, 2H), 1.65 (s, 6H)
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(23.4 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(89 mg,0.23 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 8.74 (s, 1H), 8.69 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.45 (d, 1H), 7.95 (s, 2H), 7.64 (brs, 1H), 7.20 (brs, 1H), 4.74-4.66 (m, 2H), 3.62 (brs, 1H), 3.27-3.23 (m, 1H), 2.81 (brs, 4H), 2.15 (brs, 2H), 1.70 (brs, 2H), 1.49 (s, 6H), 1.35-1.23 (m, 4H); MS (ESI) m/z = 622.3 (M + H)
+
範例177. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(96 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(70 mg,0.26 mmol) 及1-(2-氟乙基)哌啶-3-二氫氯化胺(75 mg,0.34 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.64 (d, 1H), 8.72 (d, 1H), 8.31 (s, 1H), 7.89 (dd, 1H), 7.64 (d, 1H), 6.58 (s, 1H), 4.61 (t, 1H), 4.49 (t, 1H), 3.66-3.64 (m, 1H), 2.84-2.81 (m, 1H), 2.75-2.71 (m, 2H), 2.69-2.66 (m, 1H), 2.55-2.52 (m, 2H), 2.43-2.40 (m, 1H), 1.81-1.79 (m, 2H), 1.63 (s, 6H), 1.63-1.60 (m, 2H)
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(29.4 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(89 mg,0.23 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.13 (s, 1H), 9.87 (brs, 1H), 8.68 (d, 2H), 8.55 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 7.95-7.90 (m, 2H), 7.55 (brs, 1H), 7.20 (brs, 1H), 4.65-4.53 (m, 2H), 3.79 (brs, 1H), 3.28-3.23 (m, 1H), 2.94-2.58 (brs, 6H), 1.73-1.61 (m, 4H), 1.49 (s, 6H), 1.35-1.17 (m, 4H); MS (ESI) m/z = 622.2 (M + H)
+
範例178. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
步驟1. 2-(6'-氯-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(99 mg),程序差異之處在於以參考範例7中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)丙-2-醇(70 mg,0.26 mmol)及1-(2,2-二氟乙基)哌啶-4-胺(56 mg,0.34 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.63 (d, 1H), 8.69 (d, 1H), 8.35 (s, 1H), 7.90 (dd, 1H), 7.67 (d, 1H), 6.55 (s, 1H), 5.88 (tt, 1H), 3.47-3.44 (m, 1H), 2.93-2.90 (m, 2H), 2.89-2.73 (m, 3H), 2.48 (t, 2H), 2.07-2.03 (m, 2H), 1.71-1.66 (m, 2H), 1.64 (s, 6H)
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(19.8 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(93 mg,0.23 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.03 (s, 1H), 9.88 (brs, 1H), 8.77 (s, 2H), 8.63 (s, 1H), 8.52 (s, 1H), 8.49 (d, 1H), 8.07-7.95 (m, 2H), 7.43 (brs, 1H), 7.09 (brs, 1H), 6.18 (tt, 1H), 3.61 (brs, 1H), 3.28-3.23 (m, 1H), 2.85 (brs, 4H), 2.04-1.93 (m, 2H), 1.65 (brs, 2H), 1.50 (s, 6H), 1.36-1.24 (m, 4H); MS (ESI) m/z = 640.2 (M + H)
+
範例179. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4',6-二氟-5-甲基-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(302 mg),程序差異之處在於以6-溴基-2-氟-3-甲基吡啶(300 mg,1.579 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 7.72 (t, 1H), 7.59 (d, 1H), 7.20 (d, 1H), 2.36 (s, 3H)
步驟2. (1
s,4
s)-4-((6'-氯-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(50 mg),程序差異之處在於以步驟1中所製備之6'-氯-4',6-二氟-5-甲基-2,3'-聯吡啶(100 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (DMSO
-d
6 ), 400 MHz) δ 8.52 (d, 1H), 8.44 (s, 1H), 7.95 (t, 1H), 7.82 (dd, 1H), 6.75 (s, 1H), 4.17 (s, 1H), 3.43 (s, 1H), 2.28 (s, 3H), 1.73-1.71 (m, 2H), 1.61-1.55 (m, 4H), 1.49-1.41 (m, 2H), 1.12 (s, 3H); MS (ESI) m/z = 350.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(47.4 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(102 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.05 (s, 1H), 8.65 (s, 1H), 8.60 (d, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 7.91 (t, 1H), 7.80 (t, 1H), 7.53 (brs, 1H), 7.30 (brs, 1H), 4.20 (s, 1H), 3.27-3.21 (m, 1H), 2.27 (s, 3H), 1.85-1.83 (m, 2H), 1.67-1.57 (m, 4H), 1.44-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.27-1.22 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 579.2 (M + H)
+
範例180. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(111 mg),程序差異之處在於以範例179步驟1中所製備之6'-氯-4',6-二氟-5-甲基-2,3'-聯吡啶(100 mg,0.42 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(98 mg,0.62 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.12 (d, 1H), 8.53 (s, 1H), 7.96 (t, 1H), 7.89 (dd, 1H), 6.72 (s, 1H), 4.10 (s, 1H), 3.90-3.88 (m, 1H), 2.27 (s, 3H), 1.82 (d, 2H), 1.68 (d, 2H), 1.53 (t, 2H), 1.28-1.15 (m,3),1.02 (s, 6H); MS (ESI) m/z = 378.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(53.8 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(110 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.09 (s, 1H), 9.11 (d, 1H), 8.62 (d, 1H), 8.57 (d, 1H), 8.45 (d, 1H), 8.42 (t, 1H), 7.92-7.85 (m, 2H), 7.53 (brs, 1H), 7.36 (brs, 1H), 4.10 (s, 1H), 3.94 (brs, 1H), 3.31-3.25 (m, 1H), 2.26 (s, 3H), 1.99-1.96 (m, 2H), 1.72-1.64 (m, 4H), 1.35-1.26 (m, 7H), 1.03 (s, 6H); MS (ESI) m/z = 607.2 (M + H)
+
範例181. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4',6-二氟-5-(三氟甲基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(319 mg),程序差異之處在於以6-溴基-2-氟-3-(三氟甲基)吡啶(300 mg,1.23 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 295.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-氟-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(121 mg),程序差異之處在於以步驟1中所製備之6'-氯-4',6-二氟-5-(三氟甲基)-2,3'-聯吡啶(100 mg,0.34 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 404.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.6 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-氟-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(117 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.18 (s, 1H), 8.67 (s, 2H), 8.53 (d, 1H), 8.48 (s, 1H), 8.46 (d, 1H), 8.37 (t, 1H), 8.12 (d, 1H), 7.51 (brs, 1H), 7.39 (s, 1H), 4.21 (s, 1H), 3.27-3.21 (m, 1H), 1.87-1.83 (m, 2H), 1.70-1.57 (m, 4H), 1.45-1.36 (m, 2H), 1.32-1.22 (m, 4H), 1.13 (s, 3H); MS (ESI) m/z = 633.2 (M + H)
+
範例182. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)磺醯基)嗎啉
以如同參考範例5之方式製備標題化合物,其形態為固體(195 mg),程序差異之處在於以4-((6-溴基吡啶-3-基)磺醯基)嗎啉(300 mg,0.977 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 358.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(80 mg),程序差異之處在於以步驟1中所製備之4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)磺醯基)嗎啉(60 mg,0.17 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 467.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(16.1 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(68 mg,0.15 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.57 (d, 1H), 8.91 (d, 1H), 8.67 (s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 8.06 (dd, 1H), 7.92 (d, 1H), 7.71 (brs, 1H), 7.12 (s, 1H), 3.80 (t, 4H), 3.55 (brs, 1H), 3.11 (t, 4H), 2.87-2.80 (m, 1H), 2.03-2.00 (m, 2H), 1.84-1.57 (m, 6H), 1.56-1.52 (m, 2H), 1.33 (s, 3H), 1.26-1.20 (m, 2H); MS (ESI) m/z = 696.2 (M + H)
+
範例183. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(87 mg),程序差異之處在於以範例182步驟1中所製備之4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)磺醯基)嗎啉(60 mg,0.17 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(42 mg,0.25 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 399.0 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(68 mg,0.25 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.03 (d, 1H), 8.91 (d, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.07 (dd, 1H), 7.95 (d, 1H), 7.44 (s, 1H), 7.08 (d, 1H), 4.03 (brs, 1H), 3.80 (t, 4H), 3.55 (d, 2H), 3.11 (t, 4H), 2.88-2.82 (m, 1H), 2.07-2.04 (m, 2H), 1.87-1.73 (m, 5H), 1.57-1.53 (m, 2H), 1.42-1.32 (m, 2H), 1.29-1.22 (m, 2H); MS (ESI) m/z = 969.2 (M + H)
+
範例184. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(76 mg),程序差異之處在於以範例182步驟1中所製備之4-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)磺醯基)嗎啉(60 mg,0.17 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(40 mg,0.25 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 495.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(23.6 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(72 mg,0.15 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.04 (d, 1H), 8.89 (d, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 8.06 (d, 1H), 7.95 (d, 1H), 7.47 (s, 1H), 7.03 (d, 1H), 4.04 (brs, 1H), 3.79 (t, 4H), 3.08 (t, 4H), 2.88-2.82 (m, 1H), 2.13-2.10 (m, 2H), 1.84-1.73 (m, 5H), 1.54-1.39 (m, 4H), 1.25-1.22 (m, 8H); MS (ESI) m/z = 724.2 (M + H)
+
範例185. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-5-氟吡嗪
以如同參考範例5之方式製備標題化合物,其形態為固體(322 mg),程序差異之處在於以2-溴基-5-氟吡嗪(300 mg,1.695 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 228.0 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(33 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-氟吡嗪(100 mg,0.44 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 337.1 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(32 mg,0.09 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.09 (s, 1H), 8.91 (s, 1H), 8.73 (d, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.45 (d, 1H), 8.25 (d, 1H), 7.56 (brs, 1H), 7.34 (brs, 1H), 4.17 (s, 1H), 3.27-3.21 (m, 1H), 1.83-1.81 (m, 2H), 1.64-1.55 (m, 4H), 1.44-1.33 (m, 4H), 1.27-1.25 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 566.2 (M + H)
+
範例186. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((2-氯-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(51 mg),程序差異之處在於以範例185步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-5-氟吡嗪(100 mg,0.44 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(104 mg,0.66 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 365.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(7.7 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((2-氯-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇(37 mg,0.10 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。MS (ESI) m/z = 594.2 (M + H)
+
範例187. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌啶-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 6'-氯-4'-氟-5-((4-甲基哌啶-1-基)磺醯基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(162 mg),程序差異之處在於以2-溴基-5-((4-甲基哌啶-1-基)磺醯基)吡啶(300 mg,0.94 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 370.0 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-氯-5-((4-甲基哌啶-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(66 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-((4-甲基哌啶-1-基)磺醯基)-2,3'-聯吡啶(50 mg,0.14 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(32 mg,0.20 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 507.2 (M)
+
步驟3. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌啶-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(4.1 mg),程序差異之處在於以步驟2中所製備之2-((1
s,4
s)-4-((6'-氯-5-((4-甲基哌啶-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(63 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 10.08 (d, 1H), 8.89 (d, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.06 (dd, 1H), 7.93 (d, 1H), 7.74 (brs, 1H), 7.44 (s, 1H), 7.05 (d, 1H), 4.03 (brs, 1H), 3.81 (d, 2H), 2.88-2.82 (m, 1H), 2.35 (t, 2H), 2.13-2.09 (m, 2H), 1.83-1.70 (m, 5H), 1.57-1.53 (m, 2H), 1.48-1.25 (m, 9H), 1.22 (s, 6H), 0.94 (d, 3H); MS (ESI) m/z = 736.2 (M + H)
+
範例188. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)磺醯基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(310 mg),程序差異之處在於以1-((6-溴基吡啶-3-基)磺醯基)-4-甲基哌嗪(301 mg,0.94 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 371.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(101 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)磺醯基)-2,3'-聯吡啶(80 mg,0.216 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 480.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(25.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(54 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.50 (d, 1H), 8.91 (s, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 8.49 (s, 1H), 8.45 (d, 1H), 8.06 (d, 1H), 7.88 (d, 1H), 7.67 (brs, 1H), 7.30 (s, 1H), 7.09 (s, 1H), 3.54 (brs, 1H), 3.14 (brs, 4H), 2.85-2.83 (m, 1H), 2.54 (brs, 4H), 2.30 (s, 3H), 2.03-2.00 (m, 2H), 1.84-1.54 (m, 8H), 1.32 (s, 3H), 1.29-1.22 (m, 2H); MS (ESI) m/z = 709.2 (M + H)
+
範例189. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(105 mg),程序差異之處在於以範例188步驟1中所製備之6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)磺醯基)-2,3'-聯吡啶(80 mg,0.216 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(54 mg,0.324 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 480.2 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(28.1 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(54 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.76 (d, 1H), 8.90 (s, 1H), 8.66 (d, 1H), 8.51 (s, 1H), 8.46 (d, 1H), 8.42 (dd, 1H), 8.07 (d, 1H), 7.90 (t, 2H), 7.39 (s, 1H), 7.08 (s, 1H), 4.02 (brs, 1H), 3.50 (d, 2H), 3.13 (brs, 4H), 2.86-2.83 (m, 1H), 2.54 (brs, 4H), 2.30 (s, 3H), 2.09-2.04 (m, 2H), 1.82-1.67 (m, 5H), 1.57-1.53 (m, 2H), 1.39-1.22 (m, 4H); MS (ESI) m/z = 709.2 (M + H)
+
範例190. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(105 mg),程序差異之處在於以範例188步驟1中所製備之6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)磺醯基)-2,3'-聯吡啶(80 mg,0.216 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(51 mg,0.324 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 508.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.1 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(57 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.89 (d, 1H), 8.89 (d, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 8.07 (dd, 1H), 7.91 (d, 1H), 7.44 (s, 1H), 7.05 (d, 1H), 4.03 (brs, 1H), 3.11 (brs, 4H), 2.88-2.82 (m, 1H), 2.52 (brs, 4H), 2.29 (s, 3H), 2.13-2.10 (m, 2H), 1.83-1.70 (m, 4H), 1.57-1.53 (m, 2H), 1.40-1.36 (m, 3H), 1.26-1.22 (m, 2H), 1.20 (s, 6H)
範例191. (1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇
步驟1. 4-(6-氯-4-氟吡啶-3-基)-2-氟嘧啶
以如同參考範例5之方式製備標題化合物,其形態為固體(227 mg),程序差異之處在於以4-溴基-2-氟-嘧啶(300 mg,1.695 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 227.9 (M)
+
步驟2. (1
s,4
s)-4-((4-(6-氯-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(87 mg),程序差異之處在於以步驟1中所製備之4-(6-氯-4-氟吡啶-3-基)-2-氟嘧啶(70 mg,0.308 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 446.2 (M)
+
步驟3. (1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(28.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((4-(6-氯-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇(84 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.07 (s, 1H), 9.13 (brs, 1H), 8.66 (s, 1H), 8.48 (d, 2H), 8.44 (d, 1H), 8.23 (d, 1H), 7.55 (brs, 1H), 7.26 (brs, 1H), 7.10 (brs, 1H), 7.01 (d, 1H), 4.14-4.03 (m, 2H), 3.27-3.20 (m, 1H), 1.84-1.82 (m, 2H), 1.70-1.55 (m, 10H), 1.44-1.40 (m, 4H), 1.36-1.32 (m, 2H), 1.27-1.21 (m, 2H), 1.13 (s, 6H); MS (ESI) m/z = 675.3 (M + H)
+
範例192. ((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((4-(6-氯-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(97 mg),程序差異之處在於以範例191步驟1中所製備之4-(6-氯-4-氟吡啶-3-基)-2-氟嘧啶(70 mg,0.308 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(109 mg,0.659 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 446.2 (M)
+
步驟2. ((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(48.1 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((4-(6-氯-4-(((1
s,4
s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇(84 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.10 (s, 1H), 8.63 (s, 1H), 8.48-8.42 (m, 3H), 8.28 (d, 1H), 7.43 (brs, 2H), 7.05 (d, 1H), 4.56 (brs, 1H), 4.39 (t, 1H), 3.94 (brs, 1H), 3.82 (brs, 1H), 3.27-3.24 (m, 1H), 1.88 (brs, 2H), 1.71-1.68 (m, 4H), 1.57-1.43 (m,12H), 1.40-1.33 (m, 2H), 1.30-1.26 (m, 2H); MS (ESI) m/z = 675.3 (M + H)
+
範例193. 2-((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((4-(6-氯-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(90 mg),程序差異之處在於以範例191步驟1中所製備之4-(6-氯-4-氟吡啶-3-基)-2-氟嘧啶(70 mg,0.308 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(104 mg,0.659 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 503.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((4-(6-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(30.3 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((4-(6-氯-4-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)丙-2-醇(95 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.13 (s, 1H), 8.62 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.43 (d, 1H), 8.29 (d, 1H), 7.52 (brs, 1H), 7.36 (brs, 1H), 7.08 (d, 1H), 4.11 (brs, 2H), 4.02 (s, 1H), 3.92 (brs, 1H), 3.28-3.25 (m, 1H), 2.11-2.08 (m, 2H), 1.96-1.93 (m, 2H), 1.64-1.57 (m, 6H), 1.52-1.45 (m, 2H), 1.36-1.30 (m, 4H), 1.29-1.25 (m, 6H), 1.03 (s, 6H), 1.00 (s, 6H); MS (ESI) m/z = 731.3 (M + H)
+
範例194. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(三氟甲氧基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(386 mg),程序差異之處在於以2-溴基-5-(三氟甲氧基)吡啶(410 mg,1.695 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 293.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(150 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(三氟甲氧基)-2,3'-聯吡啶(100 mg,0.342 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 402.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(53 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(125 mg,0.311 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.07 (s, 1H), 9.10 (d, 1H), 8.72 (d, 1H), 8.66 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.13 (d, 1H), 7.96 (t, 1H), 7.55 (brs, 1H), 7.32 (brs, 1H), 4.19 (s, 1H), 3.30-3.21 (m, 1H), 1.85-1.82 (m, 2H), 1.66-1.56 (m, 4H), 1.45-1.42 (m, 2H), 1.34-1.25 (m, 4H), 1.13 (s, 3H); MS (ESI) m/z = 631.2 (M + H)
+
範例195. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(144 mg),程序差異之處在於以範例194步驟1中所製備之6'-氯-4'-氟-5-(三氟甲氧基)-2,3'-聯吡啶(100 mg,0.342 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(85 mg,0.513 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 402.1(M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(56.1 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(125 mg,0.311 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d
6 , 400 MHz) δ 10.11 (s, 1H), 9.61 (d, 1H), 8.68 (d, 1H), 8.63 (s, 1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.43 (d, 1H), 8.19 (d, 1H), 7.98 (dd, 1H), 7.51 (brs, 1H), 7.40 (brs, 1H), 4.46 (t, 1H), 3.92 (brs, 1H), 3.30-3.25 (m, 3H), 1.88-1.86 (m, 2H), 1.74-1.67 (m, 2H), 1.63-1.59 (m, 2H), 1.48-1.45 (m, 1H), 1.36-1.23 (m, 4H); MS (ESI) m/z = 631.2 (M + H)
+
範例196. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(152 mg),程序差異之處在於以範例194步驟1中所製備之6'-氯-4'-氟-5-(三氟甲氧基)-2,3'-聯吡啶(100 mg,0.342 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(81 mg,0.513 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 430.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(47 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(134 mg,0.311 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.12 (s, 1H), 9.69 (d, 1H), 8.64 (d, 1H), 8.62 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.42 (d, 1H), 8.20 (d, 1H), 7.98 (dd, 1H), 7.58 (brs, 1H), 7.35 (brs, 1H), 4.10 (s, 1H), 3.98 (brs, 1H), 3.31-3.25 (m, 1H), 1.98-1.95 (m, 2H), 1.69-1.63 (m, 4H), 1.37-1.22 (m, 7H), 1.02 (s, 6H); MS (ESI) m/z = 659.2 (M + H)
+
範例197.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(176 mg),程序差異之處在於以範例194步驟1中所製備之6'-氯-4'-氟-5-(三氟甲氧基)-2,3'-聯吡啶(150 mg,0.513 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(176 mg,0.769 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 429.1 (M + H)
+
步驟2. 2
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(57.8 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-胺(170 mg,0.396 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.61 (d, 1H), 8.66 (s, 1H), 8.51 (s, 1H), 8.46 (d, 2H), 8.41 (d, 1H), 7.84 (brs, 1H), 7.83 (d, 1H), 7.66 (d, 1H), 7.30 (s, 1H), 7.11 (d, 1H), 3.96 (brs, 1H), 2.85-2.83 (m, 1H), 2.24 (s, 6H), 2.15 (d, 2H), 2.05-1.99 (m, 2H), 1.85-1.70 (m, 4H), 1.65 (brs, 1H), 1.56-1.52 (m, 2H), 1.31-1.21 (m, 4H); MS (ESI) m/z = 658.2 (M + H)
+
範例198. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-4-(甲基磺醯基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(297 mg),程序差異之處在於以2-溴基-4-(甲基磺醯基)吡啶(295 mg,1.251 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 287.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(136 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-4-(甲基磺醯基)-2,3'-聯吡啶(100 mg,0.349 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 396.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(53 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(115 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.15 (s, 1H), 9.27 (s, 1H), 8.93 (s, 1H), 8.68 (d, 2H), 8.47-8.42 (m, 3H), 7.75 (s, 1H), 7.46 (d, 2H), 4.21 (brs, 1H), 3.28-3.25 (m, 1H), 1.86-1.84 (m, 2H), 1.66-1.58 (m, 4H), 1.44-1.25 (m, 6H), 1.14 (s, 3H); MS (ESI) m/z = 625.2 (M + H)
+
範例199. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
步驟1. (6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同參考範例5之方式製備標題化合物,其形態為固體(255 mg),程序差異之處在於以(6-溴基-3-吡啶基)-(4-甲基哌嗪-1-基)甲酮(355 mg,1.251 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 335.1 (M + H)
+
步驟2. (6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(126 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(117 mg,0.349 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 444.2 (M + H)
+
步驟3. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(51.9 mg),程序差異之處在於以步驟2中所製備之(6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(117 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.45 (s, 1H), 8.65 (s, 2H), 8.47 (s, 2H), 8.42 (d, 1H), 8.21 (brs, 1H), 7.80 (t, 2H), 7.12 (d, 1H), 3.83-3.54 (m, 5H), 2.84-2.80 (m, 1H), 2.48 (brs, 4H), 2.36 (s, 3H), 2.00-1.97 (m, 2H), 1.74-1.54 (m, 8H), 1.29 (s, 3H), 1.25-1.21 (m, 2H); MS (ESI) m/z = 673.2 (M + H)
+
範例200. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
步驟1. (6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同參考範例5之方式製備標題化合物,其形態為固體(110 mg),程序差異之處在於以(6-溴基吡啶-3-基)(嗎啉基)甲酮(100 mg,0.369 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 399.0 (M + H)
+
步驟2. (6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(121 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮(100 mg,0.311 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(77 mg,0.466 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 431.1 (M + H)
+
步驟3. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.4 mg),程序差異之處在於以步驟2中所製備之(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮(114 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.95 (d, 1H), 8.66 (s, 2H), 8.49 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 7.83 (s, 3H), 7.35 (s, 1H), 7.09 (d, 1H), 4.00 (brs, 1H), 3.75-3.54 (m, 8H), 3.53 (d, 2H), 2.85-2.82 (m, 1H), 2.05-2.02 (m, 2H), 1.83-1.72 (m, 5H), 1.53-1.22 (m, 6H); MS (ESI) m/z = 660.3 (M + H)
+
範例201. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
步驟1. (6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(131 mg),程序差異之處在於以範例200步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮(100 mg,0.311 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(73 mg,0.466 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 459.1 (M + H)
+
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(25.6 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮(121 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.96 (d, 1H), 8.65 (s, 2H), 8.50 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 7.83 (s, 3H), 7.38 (s, 1H), 7.06 (d, 1H), 4.01 (brs, 1H), 3.75-3.60 (m, 8H), 2.85-2.82 (m, 1H), 2.11-2.08 (m, 2H), 1.83-1.75 (m, 5H), 1.53-1.26 (m, 6H), 1.23 (s, 6H); MS (ESI) m/z = 688.3 (M + H)
+
範例202. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
步驟1. (6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色黏性油體(85 mg),程序差異之處在於以範例199步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(100 mg,0.299 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(74 mg,0.448 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 444.2 (M + H)
+
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(28.9 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(75 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.94 (d, 1H), 8.66 (s, 2H), 8.49 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 7.91 (brs, 1H), 7.81 (s, 2H), 7.34 (s, 1H), 7.09 (d, 1H), 3.99 (brs, 1H), 3.84 (brs, 2H), 3.54 (brs, 2H), 3.53 (d, 2H), 2.87-2.81 (m, 1H), 2.52-2.44 (m, 4H), 2.35 (s, 3H), 2.05-2.02 (m, 2H), 1.83-1.67 (m, 5H), 1.56-1.51 (m, 2H), 1.41-1.31 (m, 2H), 1.26-1.20 (m, 2H); MS (ESI) m/z = 673.3 (M + H)
+
範例203. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
步驟1. (6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色黏性油體(98 mg),程序差異之處在於以範例199步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(100 mg,0.299 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(70 mg,0.448 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 472.2 (M + H)
+
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(38.8 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(80 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.97 (d, 1H), 8.66 (s, 2H), 8.65 (d, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 7.92 (brs, 1H), 7.82 (s, 2H), 7.38 (s, 1H), 7.06 (d, 1H), 4.00 (brs, 1H), 3.82 (brs, 2H), 3.54 (brs, 2H), 3.53 (d, 2H), 2.87-2.81 (m, 1H), 2.51-2.43 (m, 4H), 2.35 (s, 3H), 2.11-2.08 (m, 2H), 1.80-1.74 (m, 5H), 1.56-1.52 (m, 2H), 1.45-1.41 (m, 2H), 1.24-1.20 (m, 8H); MS (ESI) m/z = 701.3 (M + H)
+
範例204. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
步驟1. (6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色黏性油體(85 mg),程序差異之處在於以範例199步驟1中所製備之(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(100 mg,0.299 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(103 mg,0.448 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 471.2 (M + H)
+
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(16.1 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮(80 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.91 (d, 1H), 8.66 (d, 2H), 8.50 (s, 1H), 8.47 (d, 1H), 8.41 (d, 1H), 7.83 (q, 2H), 7.76 (brs, 1H), 7.28 (s, 1H), 7.12 (d, 1H), 3.96 (brs, 1H), 3.83 (brs, 2H), 3.57 (brs, 2H), 2.87-2.81 (m, 1H), 2.52-2.46 (m, 4H), 2.36 (s, 3H), 2.22 (s, 6H), 2.13 (d, 2H), 2.04-1.99 (m, 2H), 1.82-1.72 (m, 4H), 1.65-1.61 (m, 1H), 1.56-1.52 (m, 2H), 1.32-1.20 (m, 4H); MS (ESI) m/z = 700.3 (M + H)
+
範例205. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇
以如同參考範例5之方式製備標題化合物,其形態為固體(396 mg),程序差異之處在於以2-((6-溴基吡啶-3-基)氧基)乙-1-醇(500 mg,2.293 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.47 (d, 1H), 7.71 (dd, 1H), 7.33 (dd, 1H), 7.18 (d, 1H), 4.21 (t, 2H), 4.05 (s, 2H), 2.17 (s, 1H)
步驟2. (1
s,4
s)-4-((6'-氯-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(86 mg),程序差異之處在於以步驟1中所製備之2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇(100 mg,0.372 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 378.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(22.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(71 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.96 (s, 1H), 9.12 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.40 (s, 1H), 8.34 (d, 1H), 7.89 (d, 1H), 7.56 (brs, 1H), 7.51 (dd, 1H), 7.25 (brs, 1H), 4.18 (brs, 1H), 4.12 (t, 2H), 3.74 (t, 2H), 3.26-3.20 (m, 1H), 1.84-1.82 (m, 2H), 1.67-1.56 (m, 4H), 1.45-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.27-1.22 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 607.2 (M + H)
+
範例206. 2-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇
步驟1. 2-((6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(84 mg),程序差異之處在於以範例205步驟1中所製備之2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇(100 mg,0.372 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(92 mg,0.558 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 378.1 (M + H)
+
步驟2. 2-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(10.1 mg),程序差異之處在於以步驟1中所製備之2-((6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇(71 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.00 (s, 1H), 9.67 (d, 1H), 8.62 (s, 1H), 8.46 (s, 1H), 8.45 (s, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 7.94 (d, 1H), 7.53 (dd, 1H), 7.42 (brs, 2H), 4.95 (t, 1H), 4.46 (t, 1H), 4.13 (t, 2H), 3.89 (brs, 1H), 3.75 (q, 2H), 3.30-3.23 (m, 3H), 1.87-1.85 (m, 2H), 1.72-1.60 (m, 4H), 1.47 (brs, 1H), 1.36-1.32 (m, 2H), 1.30-1.22 (m, 4H); MS (ESI) m/z = 607.2 (M + H)
+
範例207. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(92 mg),程序差異之處在於以範例205步驟1中所製備之2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇(100 mg,0.372 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.558 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 406.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(13.6 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(69 mg,0.17 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.01 (s, 1H), 9.72 (d, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.44 (s, 1H), 8.40 (d, 1H), 8.26 (d, 1H), 7.95 (d, 1H), 7.53 (dd, 1H), 7.49 (brs, 1H), 7.37 (brs, 1H), 4.11 (t, 2H), 3.93 (brs, 1H), 3.74 (t, 2H), 3.30-3.25 (m, 1H), 1.96-1.93 (m, 2H), 1.69-1.62 (m, 4H), 1.34-1.21 (m, 7H), 1.05 (s, 6H); MS (ESI) m/z = 635.2 (M + H)
+
範例208. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)
-N,
N-二甲基乙-1-胺
以如同參考範例5之方式製備標題化合物,其形態為固體(390 mg),程序差異之處在於以2-((6-溴基吡啶-3-基)氧基)
-N,
N-二甲基乙-1-胺(562 mg,2.293 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 296.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(92 mg),程序差異之處在於以步驟1中所製備之2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)
-N,
N-二甲基乙-1-胺(100 mg,0.338 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 405.2 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(19.5 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(92 mg,0.226 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.12 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.73 (brs, 1H), 7.64 (d, 1H), 7.35 (d, 1H), 7.32 (d, 1H), 6.98 (s, 1H), 4.17 (t, 2H), 3.50 (brs, 1H), 2.86-2.77 (m, 3H), 2.37 (s, 6H), 2.01-1.98 (m, 2H), 1.80-1.73 (m, 4H), 1.63-1.52 (m, 4H), 1.31 (s, 3H), 1.26-1.20 (m, 2H); MS (ESI) m/z = 634.2 (M + H)
+
範例209. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(102 mg),程序差異之處在於以範例208步驟1中所製備之2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)
-N,
N-二甲基乙-1-胺(100 mg,0.338 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(84 mg,0.507 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 405.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(30 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(92 mg,0.226 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.64 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.35 (d, 1H), 8.29 (d, 1H), 7.68 (d, 1H), 7.36 (dd, 1H), 7.26 (s, 1H), 7.11 (d, 1H), 4.17 (t, 2H), 3.96 (brs, 1H), 3.53 (d, 2H), 2.86-2.82 (m, 1H), 2.78 (t, 2H), 2.37 (s, 6H), 2.05-2.01 (m, 2H), 1.80-1.70 (m, 5H), 1.55-1.52 (m, 2H), 1.41-1.32 (m, 2H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 634.3 (M + H)
+
範例210. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(106 mg),程序差異之處在於以範例208步驟1中所製備之2-((6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)氧基)
-N,
N-二甲基乙-1-胺(100 mg,0.338 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(80 mg,0.507 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 433.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(42.7 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(98 mg,0.226 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.66 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.36 (s, 1H), 8.29 (d, 1H), 7.69 (d, 1H), 7.36 (dd, 1H), 7.29 (s, 1H), 7.09 (d, 1H), 4.15 (t, 2H), 3.98 (brs, 1H), 2.86-2.82 (m, 1H), 2.78 (t, 2H), 2.37 (s, 6H), 2.11-2.03 (m, 3H), 1.80-1.70 (m, 4H), 1.56-1.51 (m, 2H), 1.44-1.40 (m, 2H), 1.26-1.20 (m, 8H); MS (ESI) m/z = 662.3 (M + H)
+
範例211. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 4-(2-((6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)氧基)乙基)嗎啉
以如同參考範例5之方式製備標題化合物,其形態為固體(661 mg),程序差異之處在於以4-(2-((2-溴基吡啶-4-基)氧基)乙基)嗎啉(1000 mg,3.483 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 338.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(133 mg),程序差異之處在於以步驟1中所製備之4-(2-((6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)氧基)乙基)嗎啉(100 mg,0.296 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 447.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(35 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(126 mg,0.283 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.36 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (t, 2H), 8.36 (s, 1H), 7.62 (br, 1H), 7.32 (d, 1H), 7.20 (s, 1H), 6.98 (s, 1H), 6.76 (d, 1H), 4.23 (t, 2H), 3.76 (t, 4H), 3.49 (br, 1H), 2.87-2.80 (m, 3H), 2.60 (t, 4H), 2.00-1.98 (m, 2H), 1.81-1.73 (m, 4H), 1.63-1.51 (m, 4H), 1.31 (s, 3H), 1.26-1.22 (m, 2H); MS (ESI) m/z = 676.2 (M + H)
+
範例212. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(138 mg),程序差異之處在於以範例211步驟1中所製備之4-(2-((6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)氧基)乙基)嗎啉(100 mg,0.296 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(74 mg,0.444 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 447.2 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(46.9 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(126 mg,0.283 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.88 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.39 (t, 2H), 7.29 (s, 1H), 7.23 (s, 1H), 7.09 (d, 1H), 6.76 (d, 1H), 4.23 (t, 2H), 3.96 (br, 1H), 3.75 (t, 4H), 3.53 (d, 2H), 2.85 (t, 3H), 2.60 (br, 4H), 2.04-2.01 (m, 2H), 1.84-1.69 (m, 5H), 1.55-1.52 (m, 2H), 1.41-1.35 (m, 2H), 1.24-1.19 (m, 2H); MS (ESI) m/z = 676.2 (M + H)
+
範例213. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(146 mg),程序差異之處在於以範例211步驟1中所製備之4-(2-((6'-氯-4'-氟-[2,3'-聯吡啶]-4-基)氧基)乙基)嗎啉(100 mg,0.296 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(70 mg,0.444 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 475.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(55.5 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(134 mg,0.283 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.92 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.38 (s, 2H), 7.87 (d, 1H), 7.35 (s, 1H), 7.23 (s, 1H), 7.05 (d, 1H), 6.75 (d, 1H), 4.22 (t, 2H), 3.98 (br, 1H), 3.75 (t, 4H), 2.85 (t, 3H), 2.61-2.59 (m, 4H), 2.10-2.07 (m, 2H), 1.78-1.71 (m, 4H), 1.55-1.52 (m, 2H), 1.43-1.40 (m, 3H), 1.26-1.22 (m, 8H); MS (ESI) m/z = 704.3 (M + H)
+
範例214. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(126 mg),程序差異之處在於以參考範例15中所製備之6'-氯
-N-(3,3-二氟環丁基)-4'-氟-[2,3'-聯吡啶]-4-胺(100 mg,0.319 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(79 mg,0.478 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 423.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(43.3 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(114 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.78 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.37 (d, 1H), 8.32 (s, 1H), 8.22 (d, 1H), 7.23 (s, 1H), 7.10 (d, 1H), 6.76 (s, 1H), 6.32 (d, 1H), 4.62 (d, 1H), 3.94 (br, 2H), 3.52 (d, 2H), 3.14-3.07 (m, 2H), 2.87-2.81 (m, 1H), 2.58-2.46 (m, 2H), 2.02-1.99 (m, 2H), 1.78-1.68 (m, 5H), 1.54-1.52 (m, 2H), 1.40-1.35 (m, 2H), 1.27-1.24 (m, 2H); MS (ESI) m/z = 652.2 (M + H)
+
範例215. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(123 mg),程序差異之處在於以參考範例15中所製備之6'-氯
-N-(3,3-二氟環丁基)-4'-氟-[2,3'-聯吡啶]-4-胺(100 mg,0.319 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(75 mg,0.478 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 451.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(55 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(122 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.81 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.36 (d, 1H), 8.32 (s, 1H), 8.21 (d, 1H), 7.29 (s, 1H), 7.06 (d, 1H), 6.77 (s, 1H), 6.34 (d, 1H), 4.66 (d, 1H), 3.95 (br, 2H), 3.16-3.06 (m, 2H), 2.83 (br, 1H), 2.58-2.46 (m, 2H), 2.06-2.05 (m, 2H), 1.90 (br, 1H), 1.74-1.69 (m, 4H), 1.54-1.52 (m, 2H), 1.42-1.40 (m, 2H), 1.25-1.20 (m, 8H); MS (ESI) m/z = 680.2 (M + H)
+
範例216.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(3,3-二氟環丁基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4',6'-三胺
步驟1. 6'-氯
-N 4-(3,3-二氟環丁基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4'-二胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(144 mg),程序差異之處在於以參考範例15中所製備之6'-氯
-N-(3,3-二氟環丁基)-4'-氟-[2,3'-聯吡啶]-4-胺(100 mg,0.319 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(110 mg,0.478 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 450.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(3,3-二氟環丁基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4',6'-三胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(24.6 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N 4-(3,3-二氟環丁基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4'-二胺(110 mg,0.245 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.83 (d, 1H), 8.66 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.32 (s, 1H), 8.23 (d, 1H), 7.17 (d, 2H), 6.77 (s, 1H), 6.36 (d, 1H), 4.57 (d, 1H), 3.94 (d, 2H), 3.18-3.11 (m, 2H), 2.84-2.81 (m, 1H), 2.58-2.47 (m, 2H), 2.22 (s, 6H), 2.13 (d, 2H), 1.99-1.95 (m, 2H), 1.78-1.72 (m, 4H), 1.61 (br, 1H), 1.54-1.52 (m, 2H), 1.30-1.24 (m, 4H); MS (ESI) m/z = 679.3 (M + H)
+
範例217. 2-((1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(57 mg),程序差異之處在於以參考範例13中所製備之5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-4'-氟-2,3'-聯吡啶(100 mg,0.325 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(81 mg,0.487 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 445.2 (M)
+
步驟2. 2-((1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(17.7 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(50 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.74 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.34 (s, 1H), 8.26 (d, 1H), 7.68 (d, 1H), 7.34 (dd, 1H), 7.31 (s, 1H), 7.11 (d, 1H), 4.05 (t, 2H), 3.97 (br, 1H), 3.38 (t, 4H), 2.89 (t, 2H), 2.86-2.82 (m, 1H), 2.16 (quin, 2H), 2.11-2.08 (m, 2H), 1.79-1.71 (m, 4H), 1.56-1.52 (m, 2H), 1.44-1.40 (m, 3H), 1.25-1.21 (m, 8H); MS (ESI) m/z = 674.3 (M + H)
+
範例218. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(120 mg),程序差異之處在於以參考範例8中所製備之6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.344 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 400.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(44.1 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(116 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.46 (d, 1H), 8.66 (s, 1H), 8.48 (t, 3H), 8.42 (d, 1H), 7.83 (br, 1H), 7.77-7.74 (m, 2H), 7.28 (d, 1H), 7.05 (s, 1H), 3.53-3.51 (m, 1H), 3.42 (q, 2H), 2.85-2.81 (m, 1H), 2.04-1.99 (m, 2H), 1.82-1.74 (m, 4H), 1.63-1.60 (m, 2H), 1.57-1.51 (m, 2H), 1.31 (s, 3H), 1.24-1.19 (m, 2H); MS (ESI) m/z = 629.2 (M + H)
+
範例219. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(131 mg),程序差異之處在於以參考範例8中所製備之6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.344 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(86 mg,0.516 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 400.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(36.1 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(116 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.68 (s, 1H), 8.56 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.33 (d, 1H), 7.91-7.83 (m, 2H), 7.42 (s, 1H), 7.23 (d, 1H), 3.98 (s, 1H), 3.60 (q, 2H), 3.43 (d, 2H), 3.08-3.01 (m, 1H), 2.01-1.99 (m, 2H), 1.83-1.71 (m, 4H), 1.64-1.59 (m, 1H), 1.47-1.43 (m, 2H), 1.39-1.25 (m, 4H); MS (ESI) m/z = 629.2 (M + H)
+
範例220. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(119 mg),程序差異之處在於以參考範例8中所製備之6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.344 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(81 mg,0.516 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 428.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(43.6 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(124 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.71 (s, 1H), 8.58 (s, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.35 (d, 1H), 7.90 (dd, 2H), 7.48 (s, 1H), 7.23 (d, 1H), 4.03 (s, 1H), 3.62 (q, 2H), 3.08-3.01 (m, 1H), 2.11-2.02 (m, 4H), 1.81-1.75 (m, 4H), 1.47-1.40 (m, 3H), 1.34-1.24 (m, 2H), 1.17 (s, 6H); MS (ESI) m/z = 657.2 (M + H)
+
範例221.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(120 mg),程序差異之處在於以參考範例8中所製備之6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.344 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(118 mg,0.516 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 427.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(35.4 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-胺(113 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.67 (s, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.41 (s, 1H), 8.31 (d, 1H), 7.89 (dd, 2H), 7.40 (s, 1H), 7.23 (d, 1H), 3.96 (s, 1H), 3.61 (q, 2H), 3.08-3.01 (m, 1H), 2.26 (s, 6H), 2.23 (d, 2H), 2.01-1.97 (m, 2H), 1.83-1.71 (m, 5H), 1.46-1.43 (m, 2H), 1.30-1.24 (m, 4H); MS (ESI) m/z = 656.2 (M + H)
+
範例222. ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
S,3
S)-3-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(110 mg),程序差異之處在於以參考範例8中所製備之6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.344 mmol)及((1
S,3
S)-3-胺基環己基)甲醇鹽酸鹽(86 mg,0.516 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 400.1 (M + H)
+
步驟2. ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(21 mg),程序差異之處在於以步驟1中所製備之((1
S,3
S)-3-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(75 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.06 (s, 1H), 9.98 (d, 1H), 8.63 (s, 1H), 8.59 (d, 2H), 8.45 (s, 1H), 8.41 (d, 1H), 8.07 (d, 1H), 7.88 (d, 1H), 7.47 (s, 1H), 7.42 (s, 1H), 4.46 (t, 1H), 4.04-4.00 (m, 1H), 3.77 (q, 2H), 3.25-3.21 (m, 2H), 1.97-1.85 (m, 2H), 1.76-1.73 (m, 1H), 1.65-1.50 (m, 4H), 1.38-1.28 (m, 5H), 1.04-1.00 (m, 1H); MS (ESI) m/z = 629.2 (M + H)
+
範例223. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(96 mg),程序差異之處在於以參考範例8中所製備之6'-氯-4'-氟-5-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.344 mmol)及2-((1
s,4
s)-4-胺基環己基)乙-1-醇(74 mg,0.516 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 414.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(31.4 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(77 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.67 (s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.31 (d, 1H), 7.86 (dd, 2H), 7.39 (s, 1H), 7.21 (d, 1H), 3.94 (s, 1H), 3.65-3.56 (m, 4H), 3.07-3.01 (m, 1H), 2.03-1.94 (m, 3H), 1.82-1.68 (m, 4H), 1.60-1.57 (m, 1H), 1.53-1.43 (m, 4H), 1.33-1.25 (m, 3H); MS (ESI) m/z = 643.2 (M + H)
+
範例224. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(103 mg),程序差異之處在於以參考範例9中所製備之6'-氯-5-(3,3-二氟吖丁啶-1-基)-4'-氟-2,3'-聯吡啶(90 mg,0.3 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 409.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(25.1 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(76 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.93 (s, 1H), 9.21 (d, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.40 (d, 1H), 8.39 (s, 1H), 7.99 (d, 1H), 7.84 (d, 1H), 7.53 (br, 1H), 7.23 (br, 1H), 7.14 (dd, 1H), 4.39 (t, 4H), 4.19 (s, 1H), 3.28-3.23 (m, 1H), 1.83-1.81 (m, 2H), 1.62-1.56 (m, 4H), 1.44-1.39 (m, 2H), 1.33-1.31 (m, 2H), 1.25-1.22 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 638.2 (M + H)
+
範例225. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(85 mg),程序差異之處在於以參考範例9中所製備之6'-氯-5-(3,3-二氟吖丁啶-1-基)-4'-氟-2,3'-聯吡啶(90 mg,0.3 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(71 mg,0.45 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 437.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(20.3 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(82 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.63 (s, 1H), 8.38 (s, 1H), 8.28 (d, 1H), 8.25 (s, 1H), 7.88 (d, 1H), 7.67 (d, 1H), 7.32 (s, 1H), 7.11 (d, 1H), 7.05 (dd, 1H), 4.31 (t, 4H), 3.92 (s, 1H), 3.06-3.00 (m, 1H), 2.05-2.02 (m, 2H), 1.75-1.69 (m, 4H), 1.44-1.34 (m, 3H), 1.30-1.23 (m, 2H), 1.16 (s, 6H); MS (ESI) m/z = 603.2 (M + H)
+
範例226. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(108 mg),程序差異之處在於以參考範例10中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(80 mg,0.261 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 416.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(12.2 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(103 mg,0.249 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.63 (s, 1H), 8.38 (s, 1H), 8.28 (d, 1H), 8.25 (s, 1H), 7.88 (d, 1H), 7.67 (d, 1H), 7.32 (s, 1H), 7.11 (d, 1H), 7.05 (dd, 1H), 4.31 (t, 4H), 3.92 (s, 1H), 3.06-3.00 (m, 1H), 2.05-2.02 (m, 2H), 1.75-1.69 (m, 4H), 1.44-1.34 (m, 3H), 1.30-1.23 (m, 2H), 1.16 (s, 6H); MS (ESI) m/z = 645.2 (M + H)
+
範例227. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
步驟1. 1-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(107 mg),程序差異之處在於以參考範例10中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(80 mg,0.261 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(65 mg,0.391 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 416.1 (M + H)
+
步驟2. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(9.9 mg),程序差異之處在於以步驟1中所製備之1-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(103 mg,0.249 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.08 (s, 1H), 9.99 (d, 1H), 8.67 (s, 1H), 8.62 (d, 2H), 8.45 (s, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.97 (d, 1H), 7.52 (br, 1H), 7.40 (br, 1H), 7.07 (d, 1H), 5.37 (quin, 1H), 4.44 (t, 1H), 3.94 (br, 1H), 3.28-3.24 (m, 3H), 1.97-1.88 (m, 2H), 1.74-1.64 (m, 4H), 1.49 (br, 1H), 1.34-1.30 (m, 2H), 1.29-1.22 (m, 4H); MS (ESI) m/z = 645.2 (M + H)
+
範例228. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
步驟1. 1-(6'-氯-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以參考範例10中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(80 mg,0.261 mmol)及((1
S,3
S)-3-胺基環己基)甲醇鹽酸鹽(65 mg,0.391 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 416.1 (M + H)
+
步驟2. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.5 mg),程序差異之處在於以步驟1中所製備之1-(6'-氯-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(103 mg,0.249 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.08 (s, 1H), 9.99 (d, 1H), 8.67 (s, 1H), 8.62 (d, 2H), 8.45 (s, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.97 (d, 1H), 7.52 (br, 1H), 7.40 (br, 1H), 7.07 (d, 1H), 5.37 (quin, 1H), 4.44 (t, 1H), 3.94 (br, 1H), 3.28-3.24 (m, 3H), 1.97-1.88 (m, 2H), 1.74-1.64 (m, 4H), 1.49 (br, 1H), 1.34-1.30 (m, 2H), 1.29-1.22 (m, 4H); MS (ESI) m/z = 645.2 (M + H)
+
範例229. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以參考範例10中所製備之1-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(80 mg,0.261 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(62 mg,0.391 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 444.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(17.3 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(110 mg,0.249 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.08 (s, 1H), 10.05 (d, 1H), 8.66 (s, 1H), 8.62 (d, 2H), 8.45 (s, 1H), 8.42 (d, 1H), 8.11 (d, 1H), 7.97 (d, 1H), 7.56 (br, 1H), 7.36 (br, 1H), 7.07 (d, 1H), 5.37 (quin, 1H), 4.08 (s, 1H), 3.97 (br, 1H), 3.28-3.24 (m, 1H), 1.99-1.93 (m, 2H), 1.72-1.63 (m, 4H), 1.34-1.24 (m, 7H), 1.02 (s, 6H); MS (ESI) m/z = 673.2 (M + H)
+
範例230. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(107 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(85 mg,0.265 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 430.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(37.7 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(89 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.81 (s, 1H), 8.73 (s, 1H), 8.46 (d, 2H), 8.35 (d, 1H), 8.07 (d, 1H), 7.88 (d, 1H), 7.37 (d, 1H), 7.28 (s, 1H), 3.60-3.58 (m, 1H), 3.05-3.00 (m, 1H), 1.99-1.95 (m, 2H), 1.81 (s, 3H), 1.78-1.72 (m, 4H), 1.62-1.55 (m, 2H), 1.47-1.43 (m, 2H), 1.30-1.28 (m, 5H); MS (ESI) m/z = 659.2 (M + H)
+
範例231. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(108 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(85 mg,0.265 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(66 mg,0.398 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 430.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(40 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(89 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.80 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 8.32 (d, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.42 (s, 1H), 7.23 (d, 1H), 3.98 (s, 1H), 3.43 (d, 2H), 3.07-3.01 (m, 1H), 2.02-1.99 (m, 2H), 1.83 (s, 3H), 1.81-1.72 (m, 4H), 1.64-1.61 (m, 1H), 1.47-1.43 (m, 2H), 1.39-1.33 (m, 2H), 1.30-1.28 (m, 2H); MS (ESI) m/z = 659.2 (M + H)
+
範例232. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(107 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(85 mg,0.265 mmol)及((1
S,3
S)-3-胺基環己基)甲醇鹽酸鹽(66 mg,0.398 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 430.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(39.8 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
S,3
S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(89 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.81 (s, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 8.41 (s, 1H), 8.30 (d, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 7.39 (s, 1H), 7.23 (d, 1H), 4.06 (s, 1H), 3.40 (d, 2H), 3.08-3.02 (m, 1H), 2.10-2.07 (m, 1H), 1.97-1.94 (m, 1H), 1.89-1.86 (m, 1H), 1.81 (s, 3H), 1.75-1.65 (m, 4H), 1.49-1.40 (m, 3H), 1.31-1.27 (m, 2H), 1.14-1.10 (m, 1H); MS (ESI) m/z = 659.2.2 (M + H)
+
範例233. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(85 mg,0.265 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(63 mg,0.398 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 458.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(43.1 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(95 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.82 (s, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 8.44 (s, 1H), 8.35 (d, 1H), 8.07 (d, 1H), 7.93 (d, 1H), 7.48 (s, 1H), 7.23 (d, 1H), 4.03 (s, 1H), 3.08-3.02 (m, 1H), 2.11-2.08 (m, 2H), 1.80 (s, 3H), 1.78-1.75 (m, 4H), 1.47-1.40 (m, 4H), 1.30-1.25 (m, 2H), 1.17 (s, 6H); MS (ESI) m/z = 687.2 (M + H)
+
範例234. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(85 mg,0.265 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(91 mg,0.398 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 457.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(27.5 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(86 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.80 (s, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 8.32 (d, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.42 (s, 1H), 7.23 (d, 1H), 3.98 (s, 1H), 3.08-3.02 (m, 1H), 2.25 (s, 6H), 2.22 (d, 2H), 2.01-1.98 (m, 2H), 1.83-1.67 (m, 8H), 1.47-1.43 (m, 2H), 1.31-1.24 (m, 4H); MS (ESI) m/z = 686.2 (M + H)
+
範例235. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(119 mg),程序差異之處在於以參考範例12中所製備之6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶(100 mg,0.37 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(92 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 378.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(38.8 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(118 mg,0.28 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.67 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 8.31 (d, 1H), 7.86 (s, 2H), 7.39 (s, 1H), 7.22 (d, 1H), 3.97 (s, 1H), 3.43 (d, 2H), 3.06-3.03 (m, 1H), 2.01-1.98 (m, 2H), 1.83-1.71 (m, 10H), 1.61-1.58 (m, 1H), 1.45-1.40 (m, 2H), 1.38-1.35 (m, 2H), 1.29-1.26 (m, 2H); MS (ESI) m/z = 607.2 (M + H)
+
範例236. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(122 mg),程序差異之處在於以參考範例12中所製備之6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶(100 mg,0.37 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(88 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 406.2 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(43 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(126 mg,0.28 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.62 (s, 1H), 8.60 (s, 1H), 8.41-8.24 (m, 3H), 7.81 (d, 1H), 7.79 (s, 1H), 7.40 (d, 1H), 7.11 (d, 1H), 3.96-3.92 (m, 1H), 3.03 (br, 1H), 2.04-2.01 (m, 2H), 1.75-1.68 (m, 9H), 1.44-1.33 (m, 5H) 1.27-1.25 (m, 2H), 1.14 (s, 6H); MS (ESI) m/z = 635.3 (M + H)
+
範例237.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(129 mg),程序差異之處在於以參考範例12中所製備之6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶(100 mg,0.37 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(128 mg,0.56 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 405.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(32.1 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺(114 mg,0.28 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.70 (s, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.44 (s, 1H), 8.34 (d, 1H), 7.89 (s, 2H), 7.42 (s, 1H), 7.26 (d, 1H), 3.98 (s, 1H), 3.27-3.23 (m, 1H), 2.27 (s, 6H), 2.25 (d, 2H), 2.02-1.99 (m, 2H), 1.85-1.63 (m,11H), 1.44-1.25 (m, 6H); MS (ESI) m/z = 635.3 (M + H)
+
範例238.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(88 mg),程序差異之處在於以參考範例12中所製備之6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶(75 mg,0.28 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(64 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 366.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(9 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺(46 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.65 (s, 1H), 8.45 (d, 2H), 8.36 (d, 1H), 7.92-7.86 (m, 2H), 7.39 (d, 1H), 7.25 (s, 1H), 4.73 (d, 1H), 3.74-3.68 (m, 1H), 3.07-3.00 (m, 1H), 1.97-1.95 (m, 2H), 1.88-1.73 (m, 10H), 1.44-1.42 (m, 2H), 1.29-1.26 (m, 4H); MS (ESI) m/z = 595.2 (M + H)
+
範例239.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-(4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(93 mg),程序差異之處在於以參考範例12中所製備之6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶(75 mg,0.28 mmol)及4-氟環己-1-胺鹽酸鹽(64 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 366.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(7.1 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-(4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺(46 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.65 (s, 1H), 8.46 (d, 2H), 8.36 (d, 1H), 7.93-7.87 (m, 2H), 7.41 (dd, 1H), 7.23 (d, 1H), 4.80-4.62 (m, 1H), 3.76 (br, 1H), 3.06-2.98 (m, 1H), 2.22-1.95 (m, 4H), 1.88-1.80 (m, 1H), 1.78 (s, 3H), 1.72 (s, 3H), 1.65-1.57 (m, 1H), 1.45-1.40 (m, 2H), 1.33-1.21 (m, 3H); MS (ESI) m/z = 595.2 (M + H)
+
範例240.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4,4-二氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-(4,4-二氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(95 mg),程序差異之處在於以參考範例12中所製備之6'-氯-4'-氟-5-(2-氟丙-2-基)-2,3'-聯吡啶(75 mg,0.28 mmol)及4,4-二氟環己-1-胺鹽酸鹽(72 mg,0.42 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 382.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4,4-二氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.3 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-(4,4-二氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-胺(48 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.73 (s, 1H), 8.65 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.37 (d, 1H), 7.93-7.88 (m, 2H), 7.43 (d, 1H), 7.24 (s, 1H), 3.81 (br, 1H), 3.06-2.97 (m, 1H), 2.24-1.97 (m, 6H), 1.86-1.81 (m, 2H), 1.78 (s, 3H), 1.73 (s, 3H), 1.47-1.43 (m, 2H), 1.33-1.24 (m, 2H); MS (ESI) m/z = 613.2 (M + H)
+
範例241. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. 6'-氯-5-(1,1-二氟乙基)-4'-氟-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(431 mg),程序差異之處在於以2-溴基-5-(1,1-二氟乙基)吡啶(444 mg,2.0 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 273.0 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-氯-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(123 mg),程序差異之處在於以步驟1中所製備之6'-氯-5-(1,1-二氟乙基)-4'-氟-2,3'-聯吡啶(100 mg,0.37 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(91 mg,0.55 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 382.1 (M + H)
+
步驟3. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(44 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(119 mg,0.31 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.29 (d, 1H), 7.96-7.91 (m, 2H), 7.40 (s, 1H), 7.21 (d, 1H), 3.96 (s, 1H), 3.43 (d, 2H), 3.07-3.01 (m, 1H), 2.05-1.96 (m, 5H), 1.82-1.69 (m, 4H), 1.60 (br, 1H), 1.45-1.40 (m, 2H), 1.36-1.28 (m, 4H); MS (ESI) m/z = 611.2 (M + H)
+
範例242. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(134 mg),程序差異之處在於以範例241步驟1中所製備之6'-氯-5-(1,1-二氟乙基)-4'-氟-2,3'-聯吡啶(100 mg,0.37 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(87 mg,0.55 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 410.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(46.2 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(127 mg,0.31 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.74 (s, 1H), 8.67 (s, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.32 (d, 1H), 7.97 (s, 2H), 7.47 (s, 1H), 7.21 (d, 1H), 4.00 (s, 1H), 3.06-3.03 (m, 1H), 2.09-1.96 (m, 5H), 1.80-1.74 (m, 4H), 1.44-1.38 (m, 5H), 1.28-1.25 (m, 2H), 1.17 (s, 6H); MS (ESI) m/z = 639.2 (M + H)
+
範例243.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(1,1-二氟乙基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-5-(1,1-二氟乙基)
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(133 mg),程序差異之處在於以範例241步驟1中所製備之6'-氯-5-(1,1-二氟乙基)-4'-氟-2,3'-聯吡啶(100 mg,0.37 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(126 mg,0.55 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 409.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(1,1-二氟乙基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(41.4 mg),程序差異之處在於以步驟1中所製備之6'-氯-5-(1,1-二氟乙基)
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4'-胺(116 mg,0.31 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.71 (s, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.39 (s, 1H), 8.29 (d, 1H), 7.97-7.92 (m, 2H), 7.38 (s, 1H), 7.22 (d, 1H), 3.94 (s, 1H), 3.05-3.01 (m, 1H), 2.24 (s, 6H), 2.21 (d, 2H), 2.06-1.97 (m, 5H), 1.82-1.67 (m, 5H), 1.44-1.26 (m, 6H); MS (ESI) m/z = 634.3 (M + H)
+
範例244. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
步驟1. 2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
以如同參考範例5之方式製備標題化合物,其形態為固體(365 mg),程序差異之處在於以2-(6-溴基吡啶-3-基)-2,2-二氟乙-1-醇(476 mg,2.0 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 289.0 (M + H)
+
步驟2. 2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(113 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇(100 mg,0.35 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(86 mg,0.52 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 398.1 (M + H)
+
步驟3. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(17.8 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇(107 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.73 (s, 1H), 8.69 (s, 1H), 8.51 (s, 1H), 8.42 (s, 1H), 8.33 (d, 1H), 7.99 (s, 2H), 7.43 (s, 1H), 7.24 (d, 1H), 4.00 (t, 3H), 3.44 (d, 2H), 3.08-3.02 (m, 1H), 2.02-1.95 (m, 2H), 1.85-1.71 (m, 4H), 1.62 (br, 1H), 1.45-1.42 (m, 6H); MS (ESI) m/z = 627.2 (M + H)
+
範例245. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(105 mg),程序差異之處在於以範例244步驟1中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇(100 mg,0.35 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(119 mg,0.52 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 425.2 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(13.1 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇(104 mg,0.25 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.74 (s, 1H), 8.64 (s, 1H), 8.48 (s, 1H), 8.38 (s, 1H), 8.29 (d, 1H), 7.98 (s, 2H), 7.38 (d, 1H), 7.21 (d, 1H), 4.77 (t, 2H), 3.94 (br, 1H), 3.07-3.01 (m, 1H), 2.30 (s, 6H), 2.28 (d, 2H), 2.06-1.97 (m, 2H), 1.83-1.70 (m, 5H), 1.44-1.26 (m, 4H), 1.16-1.12 (m, 2H); MS (ESI) m/z = 758.2 (M + H)
+
範例246. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. 6'-氯-4'-氟-6-(2,2,2-三氟乙基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(501 mg),程序差異之處在於以2-溴基-6-(2,2,2-三氟乙基)吡啶(480 mg,2 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 291.0 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-氯-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(116 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-6-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.34 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(86 mg,0.52 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 400.1 (M + H)
+
步驟3. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(36.1 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(108 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.46 (s, 2H), 8.36 (d, 1H), 7.91-7.86 (m, 2H), 7.40 (s, 1H), 7.36 (d, 1H), 7.32 (d, 1H), 3.95 (s, 1H), 3.78 (q, 2H), 3.44 (d, 2H), 3.08-3.02 (m, 1H), 2.04-1.98 (m, 2H), 1.88-1.82 (m, 2H), 1.75-1.65 (m, 3H), 1.45-1.34 (m, 4H), 1.32-1.28 (m, 2H); MS (ESI) m/z = 629.2 (M + H)
+
範例247. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
步驟1. 2-((1
s,4
s)-4-((6'-氯-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(116 mg),程序差異之處在於以範例247步驟1中所製備之6'-氯-4'-氟-6-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.34 mmol)及2-((1
s,4
s)-4-胺基環己基)丙-2-醇(81 mg,0.52 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 428.1 (M + H)
+
步驟2. 2-((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(38.3 mg),程序差異之處在於以步驟1中所製備之2-((1
s,4
s)-4-((6'-氯-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇(115 mg,0.27 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.45 (s, 2H), 8.35 (d, 1H), 7.89-7.86 (m, 2H), 7.45 (s, 1H), 7.37 (d, 1H), 7.27 (d, 1H), 3.98 (s, 1H), 3.81 (q, 2H), 3.08-3.02 (m, 1H), 2.18-2.15 (m, 2H), 1.81-1.79 (m, 4H), 1.45-1.32 (m, 5H), 1.29-1.26 (m, 2H), 1.14 (s, 6H); MS (ESI) m/z = 657.2 (M + H)
+
範例248.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(106 mg),程序差異之處在於以範例247步驟1中所製備之6'-氯-4'-氟-6-(2,2,2-三氟乙基)-2,3'-聯吡啶(100 mg,0.34 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(118 mg,0.52 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 427.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(27 mg),程序差異之處在於以步驟1中所製備之6'-氯-
N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-胺(105 mg,0.25 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.71 (s, 1H), 8.44 (s, 2H), 8.34 (d, 1H), 7.89-7.86 (m, 2H), 7.38-7.30 (m, 3H), 3.93 (s, 1H), 3.77 (q, 2H), 3.06-3.04 (m, 1H), 2.24 (s, 8H), 1.98-1.94 (m, 2H), 1.88-1.82 (m, 2H), 1.77-1.73 (m, 3H), 1.45-1.40 (m, 2H), 1.39-1.33 (m, 2H), 1.28-1.24 (m, 2H); MS (ESI) m/z = 656.2 (M + H)
+
範例249.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-異丙基-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-異丙基-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(95 mg),程序差異之處在於以參考範例1步驟1中所製備之6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶(100 mg,0.311 mmol)及異丙胺(28 mg,0.466 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 361.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-異丙基-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(45.1 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-異丙基-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(75 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.98 (d, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.31 (s, 1H), 8.28 (d, 1H), 7.63 (d, 1H), 7.33 (dd, 1H), 7.25 (s, 1H), 7.14 (d, 1H), 4.41 (brs, 1H), 3.87-3.82 (m, 1H), 2.85-2.82 (m, 1H), 2.73 (brs, 2H), 2.33 (s, 5H), 2.09-2.04 (m, 2H), 1.93-1.88 (m, 2H), 1.54-1.51 (m, 2H), 1.38 (d, 6H), 1.24-1.20 (m, 2H); MS (ESI) m/z = 590.2 (M + H)
+
範例250. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(23.2 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(89 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.73 (s, 1H), 8.47 (s, 1H), 8.36-8.30 (m, 3H), 7.76 (d, 1H), 7.49 (dd, 1H), 7.35 (d, 1H), 7.24 (s, 1H), 4.58-4.56 (m, 1H), 3.56 (brs, 1H), 3.05-3.01 (m, 1H), 2.78 (brs, 2H), 2.46 (brs, 2H), 2.35 (s, 3H), 2.11-2.07 (m, 2H), 1.97-1.87 (m, 4H), 1.78-1.71 (m, 4H), 1.61-1.54 (m, 2H), 1.44-1.40 (m, 2H), 1.29-1.23 (m, 5H); MS (ESI) m/z = 660.2 (M + H)
+
範例251. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(95 mg),程序差異之處在於以((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(77 mg,0.466 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 431.2 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.7 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(89 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.71 (s, 1H), 8.45 (s, 1H), 8.35-8.30 (m, 3H), 7.81 (d, 1H), 7.51 (dd, 1H), 7.38 (s, 1H), 7.26 (d, 1H), 4.59 (brs, 1H), 3.98 (brs, 1H), 3.44 (d, 2H), 3.08-3.02 (m, 1H), 2.80 (brs, 2H), 2.49 (brs, 2H), 2.37 (s, 3H), 2.11-2.06 (m, 2H), 2.02-1.98 (m, 2H), 1.91-1.69 (m, 6H), 1.61 (brs, 1H), 1.47-1.43 (m, 2H), 1.42-1.32 (m, 2H), 1.30-1.25 (m, 2H); MS (ESI) m/z = 660.3 (M + H)
+
範例252. 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
步驟1. 2-((1
r,4
r)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(132 mg),程序差異之處在於以2-((1
r,4
r)-4-胺基環己基)乙-1-醇鹽酸鹽(84 mg,0.466 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 445.2 (M+H)
+
步驟2. 2-((1
r,4
r)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(14.3 mg),程序差異之處在於以步驟1中所製備之2-((1
r,4
r)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(50 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.95 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.32 (s, 1H), 8.26 (d, 1H), 7.63 (d, 1H), 7.38-7.31 (m, 2H), 6.90 (s, 1H), 4.40 (brs, 1H), 3.71 (t, 2H), 3.39 (brs, 1H), 2.87-2.80 (m, 1H), 2.72 (brs, 2H), 2.33 (brs, 5H), 2.23-2.20 (m, 2H), 2.05-1.84 (m, 8H), 1.58-1.51 (m, 4H), 1.37-1.12 (m, 5H); MS (ESI) m/z = 675.3 (M + H)
+
範例253. ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
S,3
S)-3-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(132 mg),程序差異之處在於以((1
S,3
S)-3-胺基環己基)甲醇鹽酸鹽(77 mg,0.466 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 431.2 (M + H)
+
步驟2. ((1
S,3
S)-3-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.1 mg),程序差異之處在於以步驟1中所製備之((1
S,3
S)-3-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(49 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.63 (d, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.38 (d, 1H), 8.35 (s, 1H), 8.27 (d, 1H), 7.67 (d, 1H), 7.34 (d, 1H), 7.13 (s, 1H), 7.12 (s, 1H), 4.42 (brs, 1H), 4.04 (brs, 1H), 3.52 (d, 2H), 2.87-2.79 (m, 1H), 2.72 (brs, 2H), 2.34 (s, 5H), 2.08-2.05 (m, 4H), 1.97-1.85 (m, 4H), 1.74-1.45 (m, 5H), 1.26-1.11 (m, 4H); MS (ESI) m/z = 661.3 (M + H)
+
範例254.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11.3 mg),程序差異之處在於以參考範例2中所製備之6'-氯
-N-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(30 mg,0.072 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.91 (s, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 8.54 (d, 1H), 8.43 (s, 1H), 7.97 (d, 1H), 7.67 (d, 1H), 7.02 (s, 1H), 6.71 (s, 1H), 4.78-4.63 (m, 1H), 3.73 (brs, 1H), 3.08 (brs, 1H), 2.95 (s, 3H), 2.27-2.02 (m, 8H), 1.82-1.55 (m, 6H), 1.47-1.27 (m, 6H); MS (ESI) m/z = 648.3 (M + H)
+
範例255.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4,4-二氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-(4,4-二氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(106 mg),程序差異之處在於以4,4-二氟環己-1-胺鹽酸鹽(80 mg,0.466 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 437.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4,4-二氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(12.4 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-(4,4-二氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(35 mg,0.08 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.46 (s, 1H), 8.36-8.28 (m, 3H), 7.80 (d, 1H), 7.51 (dd, 1H), 7.41 (d, 1H), 7.21 (s, 1H), 4.58 (brs, 1H), 3.78-3.74 (m, 1H), 3.06-3.00 (m, 1H), 2.81 (brs, 2H), 2.50 (brs, 2H), 2.38 (s, 3H), 2.16-2.00 (m, 8H), 1.90-1.79 (m, 4H), 1.46-1.43 (m, 2H), 1.29-1.27 (m, 2H); MS (ESI) m/z = 666.2 (M + H)
+
範例256.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2-氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-(1-(2-氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(81 mg),程序差異之處在於以1-(2-氟乙基)哌啶-4-胺鹽酸鹽(74 mg,0.404 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 448.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2-氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(6.6 mg),程序差異之處在於以步驟2中所製備之6'-氯
-N-(1-(2-氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(51 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.96 (s, 1H), 9.28 (d, 1H), 8.64 (s, 1H), 8.45-8.41 (m, 3H), 8.32 (d, 1H), 7.90 (d, 1H), 7.60 (brs, 1H), 7.54 (dd, 1H), 7.21 (brs, 1H), 4.59 (t, 1H), 4.53 (brs, 1H), 4.47 (t, 1H), 2.72 (brs, 2H), 2.67 (t, 1H), 2.60 (t, 1H), 2.36-2.24 (m, 4H), 2.00-1.93 (m, 4H), 1.84-1.54 (m, 5H), 1.35-1.23 (m, 5H); MS (ESI) m/z = 677.3 (M + H)
+
範例257.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2-氟乙基)哌啶-3-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-(1-(2-氟乙基)哌啶-3-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(98 mg),程序差異之處在於以1-(2-氟乙基)哌啶-3-二氫氯化胺(89 mg,0.404 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 448.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2-氟乙基)哌啶-3-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.6 mg),程序差異之處在於以步驟2中所製備之6'-氯
-N-(1-(2-氟乙基)哌啶-3-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(51 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.98 (s, 1H), 9.40 (d,1 H), 8.85 (s, 1H), 8.45 (s, 1H), 8.41 (d, 2H), 8.28 (d, 1H), 7.85 (dd, 1H), 7.53 (d, 2H), 4.59-4.46 (m, 3H), 3.73 (brs, 1H), 2.76 (brs, 2H), 2.69-2.57 (m, 2H), 2.34 (brs, 2H), 2.30 (s, 3H), 1.98-1.93 (m, 2H), 1.70-1.54 (m, 7H), 1.34-1.19 (m, 5H), ; MS (ESI) m/z = 677.3 (M + H)
+
範例258.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2,2-二氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-(1-(2,2-二氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(86 mg),程序差異之處在於以1-(2,2-二氟乙基)哌啶-4-胺(66 mg,0.404 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 466.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(1-(2,2-二氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(16 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-(1-(2,2-二氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(53 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.67 (s, 1H), 9.20 (dd, 1H), 8.75 (d, 1H), 8.46-8.34(m, 3H), 7.79 (dd, 1H), 7.61 (brs, 1H), 7.56 (d, 1H), 7.21 (brs, 1H), 6.12 (tt, 1H), 4.58 (brs, 1H), 2.78-2.67 (m, 4H), 2.44-2.33 (m, 5H), 2.00-1.87 (m, 4H), 1.84-1.76 (m, 3H), 1.56-1.44 (m, 3H), 1.34-1.23 (m, 5H); MS (ESI) m/z = 695.3 (M + H)
+
範例259. (4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇
步驟1. (4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(87 mg),程序差異之處在於以(4-胺基-1-氟環己基)甲醇(59 mg,0.404 mmol)代替順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 449.2 (M + H)
+
步驟2. (4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(9.5 mg),程序差異之處在於以步驟1中所製備之(4-((6’-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3’-聯吡啶]-4’-基)胺基)-1-氟環己基)甲醇(40 mg,0.089 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.95 (s, 1H), 9.16 (d, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.43 (s, 1H), 8.35 (s, 1H), 7.89 (d, 1H), 7.67 (brs, 1H), 7.53 (d, 1H), 7.16 (brs, 1H), 4.95 (t, 1H), 4.54 (brs, 1H), 4.33 (d, 2H), 2.71 (brs, 2H), 2.32-2.29 (m, 2H), 2.25 (s, 3H), 1.97-1.97 (m, 6H), 1.71-1.61 (3H), 1.53-1.50 (m, 3H), 1.34-1.26 (m, 2H), 1.24-1.16 (m, 2H); MS (ESI) m/z = 678.3 (M + H)
+
範例260. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(2,2,2-三氟-1-甲氧基乙基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(508 mg),程序差異之處在於以2-溴基-5-(2,2,2-三氟-1-甲氧基乙基)吡啶(1000 mg,3.703 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (MeOD, 400 MHz) δ 8.96 (d, 1H), 8.80 (d, 1H), 8.05 (dd, 1H), 7.93 (dd, 1H), 7.53 (d, 1H), 5.02 (q, 1H), 3.52 (s, 3H)
步驟2. (1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(121 mg),程序差異之處在於以步驟1中所製備之6’-氯-4’-氟-5-(2,2,2-三氟-1-甲氧基乙基)-2,3’-聯吡啶(100 mg,0.312 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 430.1 (M + H)
+
步驟3. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(47.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(98 mg,0.228 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.64 (s, 1H), 8.47 (d, 2H), 8.35 (d, 1H), 7.94 (s, 2H), 7.37 (s, 1H), 7.28 (s, 1H), 4.93 (q, 1H), 3.57 (brs, 1H), 3.50 (s, 3H), 3.03 (brs, 1H), 1.97-1.95 (m, 2H), 1.75-1.72 (m, 4H), 1.60-1.53 (m, 2H), 1.45-1.43 (m, 2H), 1.25 (s, 5H); MS (ESI) m/z = 659.2 (M + H)
+
範例261. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)- 4-((6'-氯-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(135 mg),程序差異之處在於以範例260步驟1中所製備之6’-氯-4’-氟-5-(2,2,2-三氟-1-甲氧基乙基)-2,3’-聯吡啶(100 mg,0.312 mmol)及((1
s,4
s)-4-胺基環己基)甲醇鹽酸鹽(77 mg,0.468 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 430.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(57 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)- 4-((6'-氯-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(98 mg,0.228 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.69 (s, 1H), 8.64 (d, 1H), 8.50 (s, 1H), 8.43 (s, 1H), 8.33 (d, 1H), 7.99-7.92 (m, 2H), 7.44 (s, 1H), 7.25 (d, 1H), 4.93 (q, 1H), 4.00 (brs, 1H), 3.50 (s, 3H), 3.43 (d, 2H), 3.08-3.02 (m, 1H), 2.03-1.99 (m, 2H), 1.84-1.71 (m, 4H), 1.66-1.59 (m, 1H), 1.47-1.43 (m, 2H), 1.40-1.32 (m, 2H), 1.30-1.24 (m, 2H); MS (ESI) m/z = 659.1 (M + H)
+
範例262.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(100 mg),程序差異之處在於以範例260步驟1中所製備之6’-氯-4’-氟-5-(2,2,2-三氟-1-甲氧基乙基)-2,3’-聯吡啶(100 mg,0.312 mmol)及(1
s,4
s)-4-((二甲胺基)甲基)環己-1-二氫氯化胺(107 mg,0.516 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 457.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(27.5 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-胺(95 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.67 (s, 1H), 8.64 (d, 1H), 8.49 (s, 1H), 8.41 (s, 1H), 8.31 (d,1 H), 7.98-7.94 (m, 2H), 7.42 (s, 1H), 7.23 (d, 1H), 7.95 (q, 1H), 3.97 (brs, 1H), 3.51 (s, 3H), 3.08-3.01 (m, 1H), 2.28 (s, 6H), 2.25 (d, 2H), 2.01-1.98 (m, 2H), 1.84-1.67 (m, 5H), 1.47-1.43 (m, 2H), 1.33-1.24 (m, 4H); MS (ESI) m/z = 686.3 (M + H)
+
範例263. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-5-(3,3,3-三氟丙基)-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為固體(525 mg),程序差異之處在於以2-溴基-5-(3,3,3-三氟丙基)吡啶(500 mg,1.968 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 8.63 (d, 1H), 7.73 (d, 1H), 7.65 (dd, 1H), 7.21 (d, 1H), 2.97 (dd, 2H), 2.53-2.41 (m, 2H)
步驟2. (1
s,4
s)-4-((6'-氯-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-5-(3,3,3-三氟丙基)-2,3'-聯吡啶(100 mg,0.328 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.52 (d, 1H), 8.59 (d, 1H), 8.49 (s, 1H), 7.96 (d, 1H), 7.88 (dd, 1H), 6.73 (s, 1H), 4.15 (s, 1H), 3.46-3.44 (m, 1H), 2.92-2.88 (m, 2H), 2.74-2.62 (m, 1H), 1.74-1.72 (m, 2H), 1.67-1.42 (m, 6H), 1.13 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(33.6 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(86 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (s, 1H), 8.66 (s, 1H), 8.48-8.38 (m, 3H), 7.85 (brs, 1H), 7.66 (dd, 2H), 7.30 (s, 1H), 7.04 (s, 1H), 3.52 (brs, 1H), 2.96-2.92 (m, 2H), 2.86-2.82 (m, 1H), 2.49-2.42 (m, 2H), 2.03-1.99 (m, 2H), 1.77-1.73 (m, 4H), 1.63-1.53 (m, 4H), 1.32 (s, 3H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 643.2 (M + H)
+
範例264. 5-(2-(吖丁啶-1-基)乙氧基)
-N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 5-(2-(吖丁啶-1-基)乙氧基)-6'-氯
-N-((1
s,4
s)-4-氟環己基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(27 mg),程序差異之處在於以參考範例13中所製備之5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-4'-氟-2,3'-聯吡啶(46 mg,0.151 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(30 mg,0.196 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 405.2 (M + H)
+
步驟2. 5-(2-(吖丁啶-1-基)乙氧基)
-N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(6.1 mg),程序差異之處在於以步驟1中所製備之5-(2-(吖丁啶-1-基)乙氧基)-6'-氯
-N-((1
s,4
s)-4-氟環己基)-[2,3'-聯吡啶]-4'-胺(23 mg,0.057 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.71 (s, 1H), 8.44 (s, 1H), 8.34 (d, 1H), 8.30 (s, 1H), 7.78 (d, 1H), 7.47 (d, 1H), 7.37 (d, 1H), 7.21 (s, 1H), 7.01 (s, 1H), 4.72 (d, 1H), 4.14 (t, 2H), 3.67 (brs, 1H), 3.50 (t。4H), 3.04-3.02 (m, 1H), 2.98 (t, 2H), 2.21 (quin, 2H), 2.04-1.78 (m, 8H), 1.52-1.26 (m, 4H); MS (ESI) m/z = 635.3 (M + H)
+
範例265. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(141 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(120 mg,0.375 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(86 mg,0.562 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 418.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(8.5 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(52 mg,0.124 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.82 (s, 1H), 8.72 (s, 1H), 8.68 (s, 1H), 8.50 (d, 2H), 8.08 (s, 2H), 7.44 (brs, 1H), 7.16 (brs, 1H), 6.93 (s, 1H), 4.79 (d, 1H), 3.65 (brs, 1H), 3.26-3.24 (m, 1H), 1.96-1.82 (m, 5H), 1.77 (s, 3H), 1.74-1.72 (m, 2H), 1.35-1.22 (m, 5H); MS (ESI) m/z = 647.2 (M + H)
+
範例266. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(136 mg),程序差異之處在於以參考範例11中所製備之2-(6'-氯-4'-氟-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(120 mg,0.375 mmol)及4-氟環己-1-胺鹽酸鹽(86 mg,0.562 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 418.1 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(52 mg,0.124 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.84 (d, 1H), 8.75 (s, 1H), 8.57 (s, 2H), 8.14-8.07 (m, 2H), 7.30 (brs, 1H), 7.02 (brs, 1H), 6.97 (s, 1H), 4.88-4.67 (m, 1H), 3.66 (brs, 1H), 3.26-3.24 (m, 1H), 2.09-1.82 (m, 4H), 1.78 (s, 3H), 1.75-1.55 (m, 3H), 1.35-1.26 (m, 5H); MS (ESI) m/z = 647.2 (M + H)
+
範例267.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)
-N 4-(4-氟環己基)吡啶-2,4-二胺
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪
以如同參考範例5之方式製備標題化合物,其形態為固體(888 mg),程序差異之處在於以3-溴基-6-(4,4-二氟哌啶-1-基)噠嗪(1287 mg,4.628 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.88 (d, 1H), 7.78 (t, 2H), 7.51 (d, 1H), 3.86 (t, 4H), 2.11-2.01 (m, 4H)
步驟2. 2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N-(4-氟環己基)吡啶-4-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(76 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪(100 mg,0.304 mmol)及4-氟環己-1-胺鹽酸鹽(70 mg,0.456 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.41-9.35 (m, 1H), 8.29 (s, 1H) 7.71 (dd, 1H), 7.11 (d, 1H), 6.61 (s, 1H), 4.89-4.59 (m, 1H), 3.88 (brs, 4H), 3.54-3.47 (m, 1H), 2.18-2.08 (m, 7H), 1.97-1.94 (m, 1H), 1.87-1.66 (m, 4H), 1.58-1.52 (m, 1H)
步驟3.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)
-N 4-(4-氟環己基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(24.4 mg),程序差異之處在於以步驟2中所製備之2-氯-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)-
N-(4-氟環己基)吡啶-4-胺(71 mg,0.166 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.70 (brs, 1H), 8.68 (d, 1H), 8.44 (dd, 2H), 8.32 (s, 1H), 7.74 (dd, 1H), 7.33 (brs, 1H), 7.13 (d, 1H), 7.01 (brs, 1H), 4.92-4.63 (m, 1H), 3.88 (brs, 4H), 3.68-3.64 (m, 1H), 2.86-2.81 (m, 1H), 2.23-1.61 (m,12H), 1.54-1.51 (m, 2H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 655.3 (M + H)
+
範例268.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(4,4-二氟環己基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-2,4-二胺
步驟1. 2-氯
-N-(4,4-二氟環己基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(109 mg),程序差異之處在於以範例267步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-(4,4-二氟哌啶-1-基)噠嗪(100 mg,0.304 mmol)及4,4-二氟環己-1-胺鹽酸鹽(78 mg,0.456 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.52 (d, 1H), 8.31 (s, 1H), 7.72 (d, 1H), 7.12 (d, 1H), 6.61 (s, 1H), 3.89 (t, 4H), 3.61-3.59 (m, 1H), 2.16-2.07 (m, 8H), 2.03-1.78 (m, 4H)
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-(4,4-二氟環己基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(26.5 mg),程序差異之處在於以步驟1中所製備之2-氯
-N-(4,4-二氟環己基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-胺(74 mg,0.166 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.73 (brs, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 8.42 (d, 1H), 8.34 (s, 1H), 7.76 (d, 1H), 7.13 (d, 2H), 3.88 (t, 4H), 3.74 (brs, 1H), 2.86-2.82 (m, 1H), 2.16-2.09 (m, 4H), 2.05-1.84 (m, 6H), 1.57-1.54 (m, 2H), 1.26-1.21 (m, 4H); MS (ESI) m/z = 673.2 (M + H)
+
範例269. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 3-(6-氯-4-氟吡啶-3-基)-6-((1-甲基哌啶-4-基)氧基)噠嗪
以如同參考範例5之方式製備標題化合物,其形態為固體(246 mg),程序差異之處在於以3-溴基-6-((1-甲基哌啶-4-基)氧基)噠嗪(250 mg,0.919 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。MS (ESI) m/z = 323.1 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(105 mg),程序差異之處在於以步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-((1-甲基哌啶-4-基)氧基)噠嗪(100 mg,0.31 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 432.2 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(13 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(50 mg,0.116 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.79 (s, 1H), 8.52 (d, 2H), 8.44 (d, 1H), 8.19 (d, 1H), 7.32 (d, 1H), 7.27 (d, 1H), 7.09 (s, 1H), 5.58 (brs, 1H), 3.60-3.34 (m, 4H), 3.06-3.02 (m, 1H), 2.94 (s, 3H), 2.30 (brs, 2H), 2.05-1.96 (m, 4H), 1.83-1.73 (m, 4H), 1.62-1.56 (m, 2H), 1.56-1.29 (m, 4H), 1.29 (s, 3H); MS (ESI) m/z = 661.3 (M + H)
+
範例270.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-((1
s,4
s)-4-氟環己基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-2,4-二胺
步驟1. 2-氯
-N-((1
s,4
s)-4-氟環己基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為固體(105 mg),程序差異之處在於以範例269步驟1中所製備之3-(6-氯-4-氟吡啶-3-基)-6-((1-甲基哌啶-4-基)氧基)噠嗪(100 mg,0.31 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(71 mg,0.465 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 420.2 (M + H)
+
步驟2.
N 2-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4-((1
s,4
s)-4-氟環己基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-2,4-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(19 mg),程序差異之處在於以步驟1中所製備之2-氯
-N-((1
s,4
s)-4-氟環己基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-胺(50 mg,0.119 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.45 (s, 2H), 8.37 (d, 1H), 8.17 (d, 1H), 7.42 (s, 1H), 7.28 (s, 1H), 7.26 (s, 1H), 5.51 (brs, 1H), 4.75 (d, 1H), 3.74-3.68 (m, 1H), 3.19-3.14 (m, 2H), 3.06-3.02 (m, 1H), 2.81 (s, 3H), 2.33-1.20 (m, 4H), 2.04-1.97 (m, 4H), 1.80-1.73 (m, 4H), 1.45-1.28 (m, 6H); MS (ESI) m/z = 649.3 (M + H)
+
範例271. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例6之方式製備標題化合物,其形態為固體(120 mg),程序差異之處在於以參考範例14中所製備之(1
s,4
s)-4-((2-氯-5-碘吡啶-4-基)胺基)-1-甲基環己-1-醇(150 mg,0.409 mmol)及2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(119 mg,0.532 mmol)代替2-氯-4-氟-5-碘吡啶及6-氟吡啶-2-硼酸。MS (ESI) m/z = 336.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(55.1 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(118 mg,0.352 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.08 (s, 1H), 8.66 (s, 2H), 8.57 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.06 (q, 1H), 7.92 (dd, 1H), 7.54 (brs, 1H), 7.32 (brs, 1H), 7.08 (dd, 1H), 4.19 (s, 1H), 3.28-3.21 (m, 1H), 1.86-1.84 (m, 2H), 1.68-1.57 (m, 4H), 1.45-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.27-1.22 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 565.1 (M + H)
+
範例272. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
步驟1. ((1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同參考範例6之方式製備標題化合物,其形態為固體(121 mg),程序差異之處在於以參考範例26中所製備之((1
s,4
s)-4-((2-氯-5-碘吡啶-4-基)胺基)環己基)甲醇(150 mg,0.409 mmol)及2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(119 mg,0.532 mmol)代替2-氯-4-氟-5-碘吡啶及6-氟吡啶-2-硼酸。MS (ESI) m/z = 336.1 (M + H)
+
步驟2. ((1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(30.2 mg),程序差異之處在於以步驟1中所製備之((1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(111 mg,0.332 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.31 (d, 1H), 8.66 (s, 1H), 8.49 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.88 (q, 1H), 7.65 (d, 1H), 7.60 (brs, 1H), 7.29 (s, 1H), 7.12 (dd, 1H), 6.83 (dd, 1H), 4.01 (brs, 1H), 3.58 (d, 2H), 2.88-2.82 (m, 1H), 2.06-2.03 (m, 2H), 1.84-1.75 (m, 4H), 1.57-1.52 (m, 2H), 1.48-1.38 (m, 3H), 1.26-1.23 (m, 2H); MS (ESI) m/z = 565.2 (M + H)
+
範例273.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-6-氟
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. (1
s,4
s)
-N 1-(6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)
-N 4-(2-氟乙基)環己烷-1,4-二胺
以如同參考範例6之方式製備標題化合物,其形態為固體(126 mg),程序差異之處在於以參考範例27中所製備之(1
s,4
s)
-N 1-(2-氯-5-碘吡啶-4-基)
-N 4-(2-氟乙基)環己烷-1,4-二胺(150 mg,0.377 mmol)及2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(109 mg,0.532 mmol)代替2-氯-4-氟-5-碘吡啶及6-氟吡啶-2-硼酸。MS (ESI) m/z = 367.1 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)-6-氟
-N 4'-((1
s,4
s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(72 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)
-N 1-(6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)
-N 4-(2-氟乙基)環己烷-1,4-二胺(111 mg,0.302 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.22 (d, 1H), 8.66 (s, 1H), 8.47 (s, 2H), 8.41 (d, 1H), 7.87 (q, 2H), 7.62 (dd, 1H), 7.12 (d, 1H), 6.84 (dd, 1H), 4.57 (dt, 2H), 3.89 (brs, 1H), 2.97 (dt, 2H), 2.87-2.81 (m, 1H), 2.69-2.64 (m, 1H), 2.07-2.04 (m, 2H), 1.90-1.79 (m, 5H), 1.56-1.51 (m, 4H), 1.26-1.21 (m, 2H); MS (ESI) m/z = 596.2 (M + H)
+
範例274.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4'-胺
以如同參考範例6之方式製備標題化合物,其形態為固體(56 mg),程序差異之處在於以參考範例28中所製備之2-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-5-碘吡啶-4-胺(100 mg,0.254 mmol)及2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(74 mg,0.33 mmol)代替2-氯-4-氟-5-碘吡啶及6-氟吡啶-2-硼酸。
1H-NMR (CDCl
3, 400 MHz) δ 9.18 (d, 1H), 8.44 (s, 1H), 7.90 (q, 1H), 7.64 (d, 1H), 6.88 (d, 1H), 6.59 (s, 1H), 3.80 (brs, 1H), 2.22 (s, 6H), 2.17 (d, 2H), 1.89-1.86 (m, 2H), 1.75-1.63 (m, 5H), 1.37-1.28 (m, 2H)
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(23.3 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4'-胺(55 mg,0.151 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.28 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.47 (s, 1H), 8.41 (d, 1H), 7.87 (q, 1H), 7.64 (d, 2H), 7.14 (d, 1H), 6.83 (d, 1H), 3.99 (brs, 1H), 2.85 (brs, 1H), 2.24 (s, 6H), 2.19 (d, 2H), 2.01-1.98 (m, 2H), 1.81-1.70 (m, 5H), 1.54-1.52 (m, 2H), 1.42-1.32 (m, 2H), 1.26-1.22 (m, 2H); MS (ESI) m/z = 592.1 (M + H)
+
範例275.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2,2-二氟乙基)胺基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺
步驟1. (1
s,4
s)
-N 1-(2-氯-5-碘吡啶-4-基)
-N 4-(2,2-二氟乙基)環己烷-1,4-二胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色液體(753 mg),程序差異之處在於以2-氯-4-氟-5-碘吡啶(500 mg,1.942 mmol)及(1
s,4
s)
-N 1-(2,2-二氟乙基)環己烷-1,4-二胺(519 mg,2.913 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 416.0 (M + H)
+
步驟2. (1
s,4
s)
-N 1-(6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)
-N 4-(2,2-二氟乙基)環己烷-1,4-二胺
以如同參考範例6之方式製備標題化合物,其形態為固體(127 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)
-N 1-(2-氯-5-碘吡啶-4-基)
-N 4-(2,2-二氟乙基)環己烷-1,4-二胺(150 mg,0.361 mmol)及2-氟-6-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶(105 mg,0.469 mmol)代替2-氯-4-氟-5-碘吡啶及6-氟吡啶-2-硼酸。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.91 (d, 1H), 8.54 (s, 1H), 8.12 (q, 1H), 7.96 (dd, 1H), 7.19 (dd, 1H), 6.76 (s, 1H), 5.94 (tt, 1H), 3.73 (s, 1H), 2.87 (td, 2H), 2.58 (brs, 1H), 1.83 (s, 1H), 1.70-1.59 (m, 6H), 1.41-1.35 (m, 2H)
步驟3.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-((2,2-二氟乙基)胺基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(66 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)
-N 1-(6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)
-N 4-(2,2-二氟乙基)環己烷-1,4-二胺(126 mg,0.329 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 8.99 (d, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 8.45 (s, 1H), 8.43 (d, 1H), 8.06 (q, 1H), 7.95 (dd, 1H), 7.44 (d, 2H), 7.09 (dd, 1H), 5.94 (tt, 1H), 3.78 (brs, 1H), 3.30-3.23 (m,1 H), 2.89 (td, 2H), 2.57 (brs, 1H), 1.88-1.85 (m, 3H), 1.75-1.71 (m, 4H), 1.44-1.32 (m, 4H), 1.28-1.23 (m, 2H); MS (ESI) m/z = 614.2 (M + H)
+
範例276. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(二甲胺基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1.
N 1-(2-溴基吡啶-4-基)
-N 2,
N 2-二甲基乙-1,2-二胺
將2-溴基-4-氟吡啶(200 mg,1.14 mmol)、
N 1,
N 1-二甲基乙-1,2-二胺(130 mg,1.477 mmol)與DIPEA (594 uL,3.41 mmol)在在yDMA (4 mL)中之反應混合物於90
oC攪拌 3小時。將反應混合物冷卻至室溫,稀釋在DCM中,以水清洗,利用MgSO
4乾燥後濃縮。粗產物經管柱層析提純(EA/n-Hex = 0-80%)產出形態為淺黃色固體之
N 1-(2-溴基吡啶-4-基)
-N 2,
N 2-二甲基乙-1,2-二胺(235 mg)。MS (ESI) m/z = 246.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((2-(二甲胺基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(90 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(99 mg,0.27 mmol)及步驟1中所製備之
N 1-(2-溴基吡啶-4-基)
-N 2,
N 2-二甲基乙-1,2-二胺(60 mg,0.246 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 404.2 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(二甲胺基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(6.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((2-(二甲胺基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(61 mg,0.151 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.28 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.29 (s, 1H), 6.94 (d, 1H), 6.78 (s, 1H), 6.41 (s, 1H), 3.47 (brs, 1H), 3.23 (t, 2H), 2.84-2.80 (m, 1H), 2.59 (t, 2H), 2.28 (s, 6H), 2.04-2.01 (m, 2H), 1.84-1.74 (m, 4H), 1.52-1.50 (m, 2H), 1.33-1.30 (m, 2H), 1.28 (s, 3H), 1.27-1.24 (m, 2H); MS (ESI) m/z = 633.3 (M + H)
+
範例277. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基
-N-(3,3,3-三氟丙基)吡啶-4-胺
以如同範例276步驟1之方式製備標題化合物,其形態為淺黃色固體(265 mg),程序差異之處在於3,3,3-三氟丙-1-胺鹽酸鹽(221 mg,1.477 mmol)代替
N 1,
N 1-二甲基乙-1,2-二胺。MS (ESI) m/z = 270.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(87 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(99 mg,0.27 mmol)及步驟1中所製備之2-溴基
-N-(3,3,3-三氟丙基)吡啶-4-胺(66 mg,0.246 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 429.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(22.6 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(71 mg,0.166 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.67 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.30 (d, 1H), 8.23 (s, 1H), 7.94 (brs, 1H), 7.29 (s, 1H), 6.97 (d, 1H), 6.79 (d, 1H), 6.42 (s, 1H), 4.49 (brs, 1H), 3.56 (t, 2H), 2.47 (brs, 1H), 2.84-2.80 (m, 1H), 2.47 (t, 2H), 2.00-1.98 (m, 2H), 1.75-1.56 (m, 4H), 1.53-1.51 (m, 2H), 1.29-1.24 (m, 4H); MS (ESI) m/z = 658.2 (M + H)
+
範例278. (1
s,4
s)-4-((6'-((2-(1-(Cylo丙基磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((1-甲基哌啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基
-N-(1-甲基哌啶-4-基)吡啶-4-胺
以如同範例276步驟1之方式製備標題化合物,其形態為淺黃色固體(239 mg),程序差異之處在於以1-甲基哌啶-4-胺(169 mg,1.477 mmol)代替
N 1,
N 1-二甲基乙-1,2-二胺。MS (ESI) m/z = 272.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((1-甲基哌啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(91 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(99 mg,0.27 mmol)及步驟1中所製備之2-溴基
-N-(1-甲基哌啶-4-基)吡啶-4-胺(66 mg,0.246 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 430.2 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(Cylo丙基磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((1-甲基哌啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(21 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((1-甲基哌啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(65 mg,0.151 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.22 (d, 1H), 8.66 (s, 1H), 8.48 (s, 1H), 8.41 (d, 1H), 8.29 (d, 1H), 8.16 (s, 1H), 7.67 (dd, 1H), 7.35 (d, 1H), 6.91 (s, 1H), 6.74 (d,1 H), 6.38 (s, 1H), 4.91 (brs, 1H), 4.20 (brs, 1H), 3.44 (brs, 2H), 2.87-2.80 (m, 3H), 2.33 (s, 3H), 2.33-2.08 (m, 4H), 1.98-1.75 (m, 6H), 1.56-1.25 (m, 6H); MS (ESI) m/z = 660.3 (M + H)
+
範例279. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4((2-嗎啉基乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基
-N-(2-嗎啉基乙基)吡啶-4-胺
以如同範例276步驟1之方式製備標題化合物,其形態為淺黃色固體(265 mg),程序差異之處在於以2-嗎啉基乙-1-胺(192 mg,1.477 mmol)代替
N 1,
N 1-二甲基乙-1,2-二胺。
1H-NMR (CDCl
3, 400 MHz) δ 7.91 (d, 1H), 6.62 (d, 1H), 6.40 (dd, 1H), 5.02 (s, 1H), 3.72 (t, 4H), 3.17 (dd, 2H), 2.62 (t, 2H), 2.47 (t, 4H)
步驟2. (1
s,4
s)-4-((6'-氯-4-((2-嗎啉基乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(95 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(99 mg,0.27 mmol)及步驟1中所製備之2-溴基
-N-(2-嗎啉基乙基)吡啶-4-胺(70 mg,0.246 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 446.2 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4((2-嗎啉基乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(18.4 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((2-嗎啉基乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。MS (ESI) m/z = 675.3 (M + H)
+
範例280. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(94 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(100 mg,0.273 mmol)及參考範例15步驟1中所製備之2-溴基
-N-(3,3-二氟環丁基)吡啶-4-胺(105 mg,0.469 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.52 (d, 1H), 8.32 (s, 1H), 8.12 (d, 1H), 7.21 (d, 1H), 6.86 (d, 1H), 6.65 (s, 1H), 6.50 (dd, 1H), 4.15 (s, 1H), 4.00 (brs, 1H), 3.16-3.06 (m, 2H), 2.54-2.44 (m, 2H), 1.70-1.68 (m, 2H), 1.55-1.49 (m, 4H), 1.46-1.41 (m, 2H), 1.11 (s, 3H)
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(30.1 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(70 mg,0.166 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.27 (d, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.28 (s, 1H), 8.21 (d, 1H), 7.28 (d, 1H), 6.97 (s, 1H), 6.72 (s, 1H), 6.35 (d, 1H), 4.60 (d, 1H), 3.96 (brs, 1H), 3.46 (brs, 1H), 3.17-3.07 (m, 2H), 2.83-2.81 (m, 1H), 2.58-2.46 (m, 2H), 2.05-1.96 (m, 2H), 1.79-1.71 (m, 4H), 1.61-1.52 (m, 4H), 1.30 (s, 3H), 1.23-1.18 (m, 2H); MS (ESI) m/z = 652.2 (M + H)
+
範例281. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基
-N-(2-(3-氟吖丁啶-1-基)乙基)吡啶-4-胺
以如同範例276步驟1之方式製備標題化合物,其形態為固體(262 mg),程序差異之處在於以2-(3-氟吖丁啶-1-基)乙-1-胺(215 mg,1.847 mmol)代替
N 1,
N 1-二甲基乙-1,2-二胺。MS (ESI) m/z =274.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(64 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(100 mg,0.273 mmol)及步驟1中所製備之2-溴基
-N-(2-(3-氟吖丁啶-1-基)乙基)吡啶-4-胺(105 mg,0.469 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.58 (d, 1H), 8.28 (s, 1H), 8.06 (d, 1H), 6.90 (d, 1H), 6.64 (s, 1H), 6.61 (t,1 H), 6.51 (dd, 1H), 5.14 (dt, 1H), 4.15 (s, 1H), 3.61-3.53 (m, 2H), 3.17-3.08 (m, 4H), 2.61 (t, 2H), 1.70-1.68 (m, 2H), 1.55-1.49 (m, 4H), 1.48-1.40 (m, 2H), 1.11 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(12.2 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(49 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.93 (s, 1H), 9.47 (brs, 1H), 8.63 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.32 (s, 1H), 8.05 (d, 1H), 7.55 (brs, 1H), 7.20 (brs, 1H), 6.90 (d, 1H), 6.54 (s, 1H), 6.47 (dd, 1H), 5.23-5.07 (m, 1H), 4.17 (s, 1H), 3.63-3.56 (m, 2H), 3.26-3.20 (m, 1H), 3.20-3.10 (m, 4H), 2.65 (t, 2H), 1.81-1.78 (m, 2H), 1.63-1.51 (m, 4H), 1.44-1.36 (m, 4H), 1.30-1.27 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 663.3(M + H)
+
範例282. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 3-((2-溴基吡啶-4-基)胺基)丙-1-醇
以如同範例276步驟1之方式製備標題化合物,其形態為固體(220 mg),程序差異之處在於以3-胺基丙-1-醇(139 mg,1.847 mmol)代替
N 1,
N 1-二甲基乙-1,2-二胺。MS (ESI) m/z = 231.0 (M)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((3-羥基丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(64 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(100 mg,0.273 mmol)及步驟1中所製備之3-((2-溴基吡啶-4-基)胺基)丙-1-醇(81 mg,0.351 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.56 (s, 1H), 8.26 (s, 1H), 8.06 (d, 1H), 6.88 (s, 1H), 6.70 (s, 1H), 6.64 (s, 1H), 6.58 (dd, 1H), 4.55 (t, 1H), 4.15 (s,1 H), 3.50 (q, 2H), 3.19 (q, 2H), 1.71-1.67 (m, 4H), 1.55-1.39 (m, 6H), 1.11 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(10.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((3-羥基丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(44 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.73 (s, 1H), 8.47 (s, 1H), 8.35 (d, 1H), 8.15 (s, 1H), 8.08 (d, 1H), 7.35 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 6.52 (dd, 1H), 3.70 (t, 1H), 3.49 (brs, 1H), 3.06-3.00 (m, 1H), 1.94-1.84 (m, 4H), 1.71-1.65 (m,4H), 1.58-1.51 (m, 2H), 1.46-1.42 (m, 2H), 1.27-1.25 (m, 4H), 1.23 (s, 3H); MS (ESI) m/z = 620.2 (M + H)
+
範例283. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 3-((2-溴基吡啶-4-基)胺基)環丁-1-醇
以如同範例276步驟1之方式製備標題化合物,其形態為固體(183 mg),程序差異之處在於以3-胺基環丁-1-醇(161 mg,1.847 mmol)代替
N 1,
N 1-二甲基乙-1,2-二胺。MS (ESI) m/z = 244.0 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-((3-羥基環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為固體(48 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(100 mg,0.273 mmol)及步驟1中所製備之3-((2-溴基吡啶-4-基)胺基)環丁-1-醇(85 mg,0.351 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.53 (d, 1H), 8.24 (s, 1H), 8.07 (d, 1H), 6.95 (d, 1H), 6.79 (s, 1H), 6.63 (s, 1H), 6.43 (d, 1H), 5.14 (t, 1H), 4.15 (s, 1H), 3.90-3.84 (m, 1H), 3.45-3.40 (m, 2H), 2.72-2.67 (m, 2H), 2.22-2.14 (m, 1H), 1.73-1.68 (m, 4H), 1.56-1.46 (m, 6H), 1.11 (s, 3H)
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(7.9 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-((3-羥基環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(46 mg,0.113 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.73 (s, 1H), 8.47 (s, 1H), 8.35 (d, 1H), 8.13 (s, 1H), 8.08 (d, 1H), 7.36 (d, 1H), 7.19 (s, 1H), 6.73 (d, 1H), 6.45 (dd, 1H), 4.11-4.06 (m, 1H), 3.59-3.49 (m, 2H), 3.06-3.00 (m, 1H), 2.89-2.83 (m, 1H), 2.38-2.32 (m, 1H), 1.94-1.84 (m, 4H), 1.71-1.65 (m, 4H), 1.58-1.51 (m, 2H), 1.46-1.42 (m, 2H), 1.27-1.25 (m, 2H), 1.23 (s, 3H); MS (ESI) m/z = 632.2 (M + H)
+
範例284. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
步驟1. (6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(127 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(163 mg,0.44 mmol)及(6-溴基吡啶-3-基)(嗎啉基)甲酮(100 mg,0.37 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.29 (d, 1H), 8.66 (d, 1H), 8.42 (s, 1H), 7.86 (dd, 1H), 7.79 (d, 1H), 6.60 (s, 1H), 3.76-3.59 (m, 8H), 3.40-3.33 (m, 1H), 1.95-1.93 (m, 2H), 1.79-1.68 (m, 4H), 1.61-1.31 (m, 2H), 1.31 (s, 3H)
步驟2. (6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(50.7 mg),程序差異之處在於以步驟1中所製備之(6'-氯-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮(122 mg,0.283 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.46 (d, 1H), 8.66 (s, 1H), 8.64 (d, 1H), 8.47 (d, 1H), 8.42 (d, 1H), 7.99 (brs, 1H), 7.85-7.77 (m, 2H), 7.26 (s, 1H), 7.09 (s, 1H), 3.76-3.51 (m, 9H), 2.85-2.79 (m, 1H), 2.01-1.97 (m, 2H), 1.81-1.73 (m, 4H), 1.62-1.50 (m, 4H), 1.31 (s, 3H), 1.24-1.18 (m, 2H); MS (ESI) m/z = 660.2 (M + H)
+
範例285. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(121 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(318 mg,1.01 mmol)及2-((6-溴基吡啶-2-基)胺基)乙-1-醇(200 mg,0.92 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 377.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(23.7 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(86 mg,0.228 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.88 (brs, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.30 (s, 1H), 7.53 (dd, 1H), 7.20 (brs, 1H), 7.13 (brs, 1H), 6.94 (d, 1H), 6.35 (d, 1H), 5.03 (brs, 1H), 3.87 (t, 2H), 3.63 (brs, 1H), 3.52 (q, 2H), 2.86-2.80 (m, 1H), 1.97-1.94 (m, 2H), 1.95-1.59 (m, 6H), 1.55-1.51 (m, 2H), 1.33 (s, 3H), 1.24-1.19 (m, 2H); MS (ESI) m/z = 606.2 (M + H)
+
範例286. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-6-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(96 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(318 mg,1.01 mmol)及2-溴基-6-((1-甲基哌啶-4-基)氧基)吡啶(250 mg,0.92 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 431.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(33.3 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-6-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(89 mg,0.207 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.48 (s,1 H), 8.41 (d, 1H), 8.30 (s, 1H), 8.22 (d, 1H), 7.68 (t, 1H), 7.34 (d, 1H), 7.20 (d, 1H), 6.97 (s, 1H), 6.67 (d,1 H), 5.04-5.02 (m, 1H), 3.51-3.45 (m, 1H), 2.86-2.79 (m, 1H), 2.73 (brs, 2H), 2.41 (brs, 2H), 2.34 (s, 3H), 2.15-2.10 (m, 2H), 2.03-2.00 (m, 2H), 1.92-1.68 (m, 6H), 1.61-1.51 (m, 4H), 1.30 (s, 3H), 1.24-1.19 (m, 2H); MS (ESI) m/z = 660.3 (M + H)
+
範例287. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(77 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(180 mg,0.49 mmol)及2-((2-溴基吡啶-4-基)氧基)
-N,
N-二甲基乙-1-胺(100 mg,0.408 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 405.2 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(31.8 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(76 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.99 (s, 1H), 9.47 (d, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 8.46 (s, 1H), 8.41 (dd, 2H), 7.55 (brs, 1H), 7.44 (d, 1H), 7.27 (brs, 1H), 6.89 (dd, 1H), 4.24 (t, 1H), 4.19 (s, 1H), 3.28-3.24 (m, 1H), 2.65 (t, 2H), 2.22 (s, 6H), 1.84-1.81 (m, 2H), 1.63-1.56 (m, 4H), 1.44-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.27-1.22 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 634.2 (M + H)
+
範例288. 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-基)甲基)吖丁啶-3-醇
步驟1. 1-((6'-氯-4'-(((1s,4s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-基)甲基)吖丁啶-3-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(79 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(180 mg,0.49 mmol)及1-((2-溴基吡啶-4-基)甲基)吖丁啶-3-醇(99 mg,0.408 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 403.1 (M + H)
+
步驟2. 1-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-基)甲基)吖丁啶-3-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(20.3 mg),程序差異之處在於以步驟1中所製備之1-((6'-氯-4'-(((1s,4s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-基)甲基)吖丁啶-3-醇(76 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 9.44 (d, 1H), 8.65 (s, 1H), 8.51 (d, 1H), 8.49 (s, 1H), 8.47 (s, 1H), 8.42 (d, 1H), 7.79 (s, 1H), 7.53 (brs, 1H), 7.31 (brs, 1H), 7.19 (d, 1H), 6.37 (d, 1H), 4.25-4.21 (m, 1H), 4.19 (s, 1H), 3.65 (s, 2H), 3.56 (t, 2H), 3.26-3.20 (m, 1H), 2.83 (t, 2H), 1.84-1.82 (m, 2H), 1.67-1.56 (m, 4H), 1.45-1.39 (m, 2H), 1.36-1.32 (m, 2H), 1.27-1.24 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 632.3 (M + H)
+
範例289. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(82 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(180 mg,0.49 mmol)及2-溴基-5-((1-甲基吖丁啶-3-基)氧基)吡啶(99 mg,0.408 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 403.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.8 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(76 mg,0.188 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.95 (s, 1H), 9.05 (d, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.40 (s, 1H), 8.22 (d, 1H), 7.88 (d, 1H), 7.57 (brs, 1H), 7.39 (dd, 1H), 7.24 (s, 1H), 4.92-4.86 (m, 1H), 4.18 (s, 1H), 3.76 (q, 2H), 3.26-3.20 (m, 1H), 3.02 (t, 2H), 2.29 (s, 3H), 1.84-1.81 (m, 2H), 1.63-1.56 (m, 4H), 1.44-1.39 (m, 2H), 1.34-1.32 (m, 2H), 1.27-1.24 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 632.2 (M + H)
+
範例290. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺棕色固體(113 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(171 mg,0.467 mmol)及5-(2-(吖丁啶-1-基)乙氧基)-2-溴基吡啶(100 mg,0.89 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 417.2 (M + H)
+
步驟2. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(40.4 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(110 mg,0.264 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.10 (d, 1H), 8.65 (s, 1H), 8.47 (s, 1H), 8.39 (d, 1H), 8.33 (s, 1H), 8.25 (d, 1H), 7.95 (brs, 1H), 7.62 (d, 1H), 7.32 (dd, 2H), 6.99 (s, 1H), 4.04 (t, 2H), 3.47 (brs, 1H), 3.34 (t, 4H), 2.87-2.78 (m, 3H), 2.14 (quin, 2H), 2.00-1.96 (m, 2H), 1.79-1.72 (m, 4H), 1.61-1.51 (m, 4H), 1.30 (s, 3H), 1.27-1.24 (m, 2H); MS (ESI) m/z = 646.2 (M + H)
+
範例291. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1s,4s)-4-((6'-氯-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(110 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(219 mg,0.596 mmol)及2-溴基-5-(2-氟丙-2-基)吡啶(100 mg,0.459 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 378.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(39.1 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(110 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.49 (d, 1H), 8.67 (s, 1H), 8.61 (s, 1H), 8.48 (s, 1H), 8.45 (s, 1H), 8.42 (d, 1H), 7.77 (dd, 2H), 7.59 (brs, 1H), 7.34 (d, 1H), 6.99 (s, 1H), 3.51 (brs, 1H), 2.84-2.80 (m, 1H), 2.03-2.00 (m, 2H), 1.79-1.74 (m, 9H), 1.65-1.53 (m, 5H), 1.32 (s, 3H), 1.26-1.19 (m, 2H); MS (ESI) m/z = 607.2 (M + H)
+
範例292. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(141 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(219 mg,0.596 mmol)及2-溴基-5-(1,1-二氟乙基)吡啶(102 mg,0.459 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 382.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(40.2 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(111 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 9.47 (d, 1H), 8.72 (s, 1H), 8.67 (s, 1H), 8.48 (s, 2H), 8.41 (d, 1H), 7.97 (brs, 1H), 7.89 (d, 1H), 7.79 (d, 1H), 7.29 (s, 1H), 7.07 (s, 1H), 3.52 (brs, 1H), 2.85-2.79 (m, 1H), 2.05-1.96 (m, 5H), 1.82-1.74 (m, 4H), 1.63-1.51 (m, 4H), 1.31 (s, 3H), 1.24-1.18 (m, 2H); MS (ESI) m/z = 611.2 (M + H)
+
範例293. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. (1
s,4
s)-4-((6'-氯-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(145 mg),程序差異之處在於以參考範例3中所製備之(1
s,4
s)-4-((2-氯-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(219 mg,0.596 mmol)及2-溴基-6-(2,2,2-三氟乙基)吡啶(110 mg,0.459 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 400.1 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(28.8 mg),程序差異之處在於以步驟1中所製備之(1
s,4
s)-4-((6'-氯-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(116 mg,0.29 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.72 (s, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.34 (d, 1H), 7.88-7.80 (m, 2H), 7.40 (d, 1H), 7.32 (d, 1H), 7.21 (s, 1H), 3.74 (q, 2H), 3.51-3.49 (m, 1H), 3.06-3.00 (m, 1H), 1.96-1.94 (m, 2H), 1.80-1.71 (m, 4H), 1.60-1.53 (m, 2H), 1.47-1.44 (m, 2H), 1.26-1.24 (m, 5H); MS (ESI) m/z = 629.2 (M + H)
+
範例294. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
步驟1. 1-(6'-氯-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(67 mg),程序差異之處在於以2-氯-
N-異丙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-胺(136 mg,0.457 mmol)及1-(6-溴基吡啶-3-基)-2,2,2-三氟乙-1-醇(90 mg,0.352 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 346.0 (M + H)
+
步驟2. 1-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(7.3 mg),程序差異之處在於以步驟1中所製備之1-(6'-氯-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇(62 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.74 (s, 1H), 8.67 (d, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 8.37 (d, 1H), 8.00 (dd, 1H), 7.91 (d, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 5.19 (q, 1H), 3.95-3.87 (m, 1H), 3.06-3.02 (m, 1H), 1.47-1.43 (m, 2H), 1.39 (d, 6H), 1.30-1.25 (m, 2H); MS (ESI) m/z = 575.2 (M + H)
+
範例295. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
步驟1. 2-(6'-氯-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同參考範例1步驟1之方式製備標題化合物,其形態為淺黃色固體(82 mg),程序差異之處在於以2-氯-
N-異丙基-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶-4-胺(136 mg,0.457 mmol)及2-(6-溴基吡啶-3-基)-1,1,1-三氟丙-2-醇(95 mg,0.352 mmol)代替2-氯-4-氟-5-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)吡啶及2-溴基-5-((1-甲基-4-哌啶基)氧基)吡啶。MS (ESI) m/z = 360.0 (M + H)
+
步驟2. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(35.8 mg),程序差異之處在於以步驟1中所製備之2-(6'-氯-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇(67 mg,0.187 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 9.41 (d, 1H), 8.79 (d, 1H), 8.68 (s, 1H), 8.48 (s, 1H), 8.41 (d, 2H), 7.98 (dd, 1H), 7.76 (d, 2H), 7.31 (s, 1H), 7.11 (d, 1H), 3.92-3.84 (m, 1H), 2.87-2.81 (m, 1H), 1.87 (s, 3H), 1.56-1.52 (m, 2H), 1.40 (d, 6H), 1.26-1.20 (m, 2H); MS (ESI) m/z = 589.2 (M + H)
+
範例296. 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(13.2 mg),程序差異之處在於以範例218步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(45 mg,0.11 mmol)及參考範例20中所製備之4-(4-胺基嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺(30 mg,0.11 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.01 (s, 1H), 9.46 (d, 1H), 8.59 (s, 2H), 8.56 (s, 1H), 8.42 (d, 1H), 8.41 (s, 1H), 8.02 (d, 1H), 7.87 (dd, 1H), 7.51 (d, 2H), 7.32 (s, 1H), 4.20 (s, 1H), 3.76 (q, 2H), 3.43 (brs, 1H), 2.91 (s, 6H), 1.86-1.83 (m, 2H), 1.70-1.58 (m, 4H), 1.46-1.41 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 632.2 (M + H)
+
範例297. 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(13 mg),程序差異之處在於以範例226步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(47 mg,0.11 mmol)及參考範例20中所製備之4-(4-胺基嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺(30 mg,0.11 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 9.50 (d, 1H), 8.69 (d, 1H), 8.59 (s, 1H), 8.57 (s, 1H), 8.42 (d, 1H), 8.41 (s, 1H), 8.06 (d, 1H), 7.96 (dd, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 7.07 (d, 1H), 5.37-5.30 (m, 1H), 4.20 (s, 1H), 3.45-3.42 (m, 1H), 2.91 (s, 6H), 1.87-1.83 (m, 2H), 1.78-1.58 (m, 4H), 1.46-1.44 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 648.2 (M + H)
+
範例298. 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(10.8 mg),程序差異之處在於以範例230步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(48 mg,0.11 mmol)及參考範例20中所製備之4-(4-胺基嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺(30 mg,0.11 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.02 (s, 1H), 9.55 (d, 1H), 8.79 (d, 1H), 8.58 (d, 1H), 8.42 (d, 1H), 8.41 (s, 1H), 8.04 (d, 1H), 7.52 (s, 1H), 7.33 (s, 1H), 6.87 (s, 1H), 4.20 (s, 1H), 3.44 (brs, 1H), 2.91 (s, 6H), 1.86-1.84 (m, 2H), 1.77 (s, 3H), 1.70-1.58 (m, 4H), 1.46-1.41 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 662.2 (M + H)
+
範例299. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.5 mg),程序差異之處在於以範例218步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(47 mg,0.12 mmol)及參考範例16中所製備之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(30 mg,0.11 mmol) 代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.65 (s, 1H), 9.59 (d, 1H), 8.62 (s, 1H), 8.60 (d, 1H), 8.59 (s, 1H), 8.51 (d, 1H), 8.45 (s, 1H), 8.07 (d, 1H), 7.89 (d, 1H), 7.66 (s, 1H), 4.17 (s, 1H), 3.78 (q, 2H), 3.53 (brs, 1H), 3.25-3.19 (m, 1H), 1.84-1.82 (m, 2H), 1.70-1.62 (m, 2H), 1.55-1.52 (m, 2H), 1.40-1.33 (m, 4H), 1.29-1.23 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 647.2 (M + H)
+
範例300. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(21 mg),程序差異之處在於以參考範例1 中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.12 mmol) 及參考範例16中所製備之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(36 mg,0.13 mmol) 代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.31 (d, 1H), 8.61 (s, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.27 (dd, 2H), 7.84 (s, 1H), 7.68 (s, 1H), 7.65 (s, 1H), 7.34 (dd, 1H), 4.42 (s, 1H), 3.65 (s, 1H), 2.84-2.74 (m, 1H), 2.74 (brs, 2H), 2.35 (brs, 5H), 2.10-2.03 (m, 4H), 1.94-1.70 (m, 2H), 1.84-1.72 (m, 4H), 1.67-1.60 (m, 2H), 1.56-1.52 (m, 2H), 1.32 (s, 3H), 1.30-1.22 (m, 2H); MS (ESI) m/z = 678.3 (M + H)
+
範例301. 4-(4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)-
N,
N-二甲基-1
H-吡唑-1-磺胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(19.1 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.12 mmol)及參考範例20中所製備之4-(4-胺基嘧啶-2-基)
-N,
N-二甲基
-1
H-吡唑-1-磺胺(34 mg,0.13 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.18 (d, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.40 (d, 1H), 8.32 (s, 1H), 8.27 (d, 1H), 7.64 (d, 2H), 7.33 (dd, 2H), 7.02 (s, 1H), 4.41 (brs, 1H), 3.50 (brs, 1H), 3.00 (s, 6H), 2.76-2.73 (m, 2H), 2.34 (brs, 5H), 2.09-2.00 (m, 4H), 1.94-1.89 (m, 2H), 1.81-1.74 (m, 4H), 1.65-1.58 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 663.3 (M + H)
+
範例302. (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(2.7 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.12 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(29 mg,0.13 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.09 (d, 1H), 8.39 (d, 1H), 8.33 (s, 1H), 8.27 (d, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.64 (d, 1H), 7.50 (brs, 1H), 7.34 (d, 1H), 7.31 (dd, 1H), 6.95 (s, 1H), 6.15 (tt, 1H), 4.52 (td, 2H), 4.39 (brs, 1H), 3.50 (brs, 1H), 2.73 (brs, 2H), 2.34 (brs, 3H), 2.30 (brs, 2H), 2.09-1.93 (m, 4H), 1.92-1.86 (m, 2H), 1.77-1.56 (m, 6H), 1.31 (s, 3H); MS (ESI) m/z = 620.3 (M + H)
+
範例303. (1
s,4
s)-1-M乙基-4-((6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(17 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(59 mg,0.14 mmol)及參考範例19中所製備之2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(35 mg,0.14 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (s, 1H), 8.43 (d, 1H), 8.34 (s, 1H), 8.26 (d, 1H), 8.16 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.38 (brs, 1H), 7.33 (dd, 1H), 6.47 (s, 1H), 4.67 (q, 2H), 4.40 (brs, 1H), 3.40-3.38 (m, 1H), 2.73 (brs, 2H), 2.67 (s, 3H), 2.34 (s, 5H), 2.05 (brs, 2H), 1.97-1.89 (m, 4H), 1.77-1.70 (m, 4H), 1.57-1.50 (m, 2H), 1.30 (s, 3H); MS (ESI) m/z = 652.2 (M + H)
+
範例304. (1
s,4
s)-1-M乙基-4-((5-((1-甲基哌啶-4-基)氧基)-6'-((2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(22.4 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(53 mg,0.12 mmol)及參考範例18中所製備之2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(30 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.37 (s, 1H), 8.30 (d, 1H), 8.29 (s, 2H), 8.25 (s, 1H), 7.74 (d, 1H), 7.47 (dd, 1H), 7.32 (d, 1H), 7.19 (s, 1H), 5.04 (q, 2H), 4.53 (brs, 1H), 3.53 (brs, 1H), 2.75 (brs, 2H), 2.42 (brs, 2H), 2.33 (s, 3H), 2.05 (brs, 2H), 1.94-1.1.85 (m, 4H), 1.76-1.71 (m, 4H), 1.59-1.52 (m, 2H), 1.23 (s, 3H); MS (ESI) m/z = 638.3 (M + H)
+
範例305. 2-((1
r,4
r)-4-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(12.2 mg),程序差異之處在於以範例252步驟1中所製備之2-((1
r,4
r)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇(49 mg,0.113 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(25 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.32 (s, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 7.74 (d, 1H), 7.49 (dd, 1H), 7.33 (d, 1H), 7.14 (s, 1H), 6.25 (tt, 1H), 4.66 (td, 2H), 4.55 (brs, 1H), 3.61 (t, 2H), 3.47 (brs, 1H), 2.72 (brs, 2H), 2.42 (brs, 2H), 2.33 (s, 3H), 2.22-2.19 (m, 2H), 2.07-2.02 (m, 3H), 1.90-1.84 (m, 4H), 1.51-1.48 (m, 2H), 1.36-1.28 (m, 3H), 1.21-1.14 (m, 1H); MS (ESI) m/z = 634.3 (M + H)
+
範例306. ((1
S,3
S)-3-((6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(12.6 mg),程序差異之處在於以範例253步驟1中所製備之((1
S,3
S)-3-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇(48 mg,0.113 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(25 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.45-8.29 (m, 4H), 8.20 (s, 1H), 7.81 (d, 1H), 7.51 (dd, 1H), 7.29 (s, 1H), 7.26 (d, 1H), 6.27 (tt, 1H), 4.66 (td, 2H), 4.57 (brs, 1H), 4.06 (s, 1H), 3.41 (d, 2H), 2.75 (brs, 2H), 2.43 (brs, 2H), 2.33 (s, 3H), 2.07-1.95 (m, 4H), 1.88-1.85 (m, 4H), 1.74-1.1.64 (m, 3H), 1.45-1.40 (m, 1H), 1.13-1.00 (m, 1H); MS (ESI) m/z = 621.3 (M + H)
+
範例307.
N 4'-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)
-N 6'-(2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(17.7 mg),程序差異之處在於以範例132步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(30 mg,0.07 mmol)及參考範例18中所製備之2-(1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(21 mg,0.09 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.37 (s, 1H), 8.32 (d, 3H), 8.24 (s, 1H), 7.79 (d, 1H), 7.51 (dd, 1H), 7.35 (d, 1H), 7.20 (s, 1H), 5.05 (q, 2H), 4.74 (d, 1H), 4.57 (brs, 1H), 3.67 (brs, 1H), 2.77 (brs, 2H), 2.45 (brs, 2H), 2.35 (s, 3H), 2.08-1.90 (m, 6H), 1.86-1.73 (m, 6H); MS (ESI) m/z = 626.3 (M + H)
+
範例308.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11.5 mg),程序差異之處在於以參考範例2中所製備之6'-氯
-N-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(30 mg,0.07 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(19 mg,0.09 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.32-8.21 (m, 4H), 8.17 (s, 1H), 7.78 (d, 1H), 7.51 (dd, 1H), 7.34 (dd, 1H), 7.19 (d, 1H), 6.25 (tt, 1H), 4.70-4.56 (m, 3H), 3.71-3.68 (m, 1H), 2.76 (brs, 2H), 2.43 (brs, 2H), 2.34 (s, 3H), 2.18-2.17 (m, 1H), 2.05-1.93 (m, 5H), 1.88-1.69 (m, 4H), 1.58-1.52 (m, 2H); MS (ESI) m/z = 608.3 (M + H)
+
範例309.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)
-N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(24.6 mg),程序差異之處在於以參考範例2中所製備之6'-氯
-N-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(35 mg,0.08 mmol)及參考範例16中所製備之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(28 mg,0.10 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.61 (d, 1H), 8.39 (d, 1H), 8.35-8.24 (m, 3H), 7.77 (dd, 1H), 7.70 (d, 1H), 7.48 (d, 1H), 4.68 (d, 1H), 4.56 (brs, 1H), 3.71-3.68 (m, 1H), 3.05-2.98 (m, 1H), 2.78 (brs, 2H), 2.46 (brs, 2H), 2.36 (s, 3H), 2.19-2.16 (m, 1H), 2.07-2.02 (m, 3H), 1.95-1.71 (m, 7H), 1.60 (brs, 1H), 1.44-1.40 (m, 2H), 1.27-1.23 (m, 2H); MS (ESI) m/z = 666.3 (M + H)
+
範例310. (1
s,4
s)-4-((6-氟-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(28.8 mg),程序差異之處在於以範例271步驟1中所製備之(1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(39 mg,0.12 mmol)及參考範例19中所製備之2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(27 mg,0.10 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.77 (s, 1H), 8.55 (s, 1H), 8.52 (d, 1H), 8.42 (d, 1H), 8.31 (s, 1H), 8.05 (q, 1H), 7.90 (d, 1H), 7.81 (d, 1H), 7.08 (d, 1H), 6.86 (s, 1H), 5.13 (q, 2H), 4.18 (s, 1H), 2.55 (s, 3H), 1.83-1.81 (m, 2H), 1.65-1.57 (m, 4H), 1.39-1.33 (m, 2H), 1.12 (s, 3H); MS (ESI) m/z = 557.2 (M + H)
+
範例311. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(14.4 mg),程序差異之處在於以範例271步驟1中所製備之(1
s,4
s)-4-((6'-氯-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(39 mg,0.12 mmol)及參考範例16中所製備之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(30 mg,0.11 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.70 (s, 1H), 8.76 (d, 1H), 8.63 (s, 1H), 8.59 (s, 1H), 8.52 (d, 1H), 8.45 (s, 1H), 8.07 (q, 1H), 7.95 (d, 1H), 7.66 (s, 1H), 7.11 (dd, 1H), 4.16 (s, 1H), 3.51 (brs, 1H), 3.25-3.19 (m, 1H), 1.85-1.82 (m, 2H), 1.69-1.61 (m, 2H), 1.55-1.52 (m, 2H), 1.39-1.33 (m, 4H), 1.24-1.21 (m, 2H), 1.09 (s, 3H); MS (ESI) m/z = 583.1 (M + H)
+
範例312. (1
s,4
s)-4-((5-(3,3-二氟吖丁啶-1-基)-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(16 mg),程序差異之處在於以範例224步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(47 mg,0.12 mmol)及參考範例19中所製備之2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(27 mg,0.10 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.64 (s, 1H), 9.09 (d, 1H), 8.38 (s, 1H), 8.37 (d, 1H), 8.30 (s, 1H), 7.99 (d, 1H), 7.84 (s, 1H), 7.82 (s, 1H), 7.14 (dd, 1H), 6.79 (s, 1H), 5.13 (q, 2H), 4.39 (t, 4H), 4.15 (s, 1H), 2.55 (s, 3H), 1.81-1.79 (m, 2H), 1.63-1.57 (m, 4H), 1.39-1.33 (m, 2H), 1.13 (s, 3H); MS (ESI) m/z = 630.2 (M + H)
+
範例313. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11.9 mg),程序差異之處在於以範例224步驟1中所製備之(1
s,4
s)-4-((6'-氯-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(48 mg,0.12 mmol)及參考範例16中所製備之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(30 mg,0.11 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.54 (s, 1H), 9.37 (d, 1H), 8.61 (s, 1H), 8.49 (s, 1H), 8.43 (d, 2H), 8.01 (d, 1H), 7.88 (d, 1H), 7.60 (s, 1H), 7.15 (dd, 1H), 4.41 (t, 4H), 4.13 (s, 1H), 3.49 (brs, 1H), 3.25-3.21 (m, 1H), 1.83-1.81 (m, 2H), 1.67-1.51 (m, 4H), 1.40-1.33 (m, 4H), 1.24-1.22 (m, 2H), 1.09 (s, 3H); MS (ESI) m/z = 656.2 (M + H)
+
範例314. 2-(6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.5 mg),程序差異之處在於以範例173步驟1中所製備之2-(6'-氯-4'-(((1
s,4
s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇(50 mg,0.14 mmol)及參考範例16中所製備之2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)-5-氟嘧啶-4-胺(35 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 8.74 (s, 1H), 8.69 (s, 1H), 8.68 (s, 1H), 8.60 (s, 1H), 8.49 (s, 1H), 8.01 (s, 2H), 7.46 (s, 1H), 5.33 (s, 1H), 4.76 (d, 1H), 3.71 (brs, 1H), 3.23-3.21 (m, 1H), 1.96-1.71 (m, 8H), 1.50 (s, 6H), 1.34-1.24 (m, 4H); MS (ESI) m/z = 611.2 (M + H)
+
範例315. (1
s,4
s)-4-((2-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(11 mg),程序差異之處在於以範例269步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(50 mg,0.116 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(31 mg,0.12 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.62 (s, 1H), 8.44 (s, 1H), 8.42 (d,1 H), 8.29 (s, 1H), 8.23 (d, 1H), 7.33 (d, 1H), 7.14 (brs, 1H), 7.01 (brs, 1H), 6.28 (tt, 1H), 5.62-5.58 (m, 1H), 4.69 (td, 2H), 3.60-3.43 (m, 4H), 2.94 (s, 3H), 2.30 (brs, 4H), 2.02-1.96 (m,2H), 1.81-1.75 (m, 4H), 1.62-1.57 (m, 2H), 1.26 (s, 3H); MS (ESI) m/z = 621.3 (M + H)
+
範例316. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.6 mg),程序差異之處在於以範例290步驟1中所製備之(1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.12 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(32 mg,0.144 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.06 (d, 1H), 8.38 (d, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 8.17 (s, 1H), 7.63 (d, 1H), 7.46 (brs, 1H), 7.33-7.29 (m, 2H), 6.92 (s, 1H), 6.14 (tt, 1H), 4.52 (td, 2H), 4.05 (t, 2H), 3.49 (brs, 1H), 3.35 (t, 4H), 2.87 (t, 2H), 2.15 (quin, 2H), 2.00-1.97 (m, 2H), 1.77-1.70 (m, 4H), 1.62-1.55 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 606.3 (M + H)
+
範例317. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(16.6 mg),程序差異之處在於以範例290步驟1中所製備之(1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.12 mmol)及參考範例19中所製備之2-(3-甲基-1-(2,2,2-三氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(35 mg,0.136 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.43 (d, 1H), 8.34 (s, 1H), 8.26 (d, 1H), 8.15 (s, 1H), 7.63 (d, 1H), 7.60 (d, 1H), 7.34 (s, 1H), 7.33 (dd, 1H), 6.46 (s, 1H), 4.67 (q, 2H), 4.05 (t, 2H), 3.34 (t, 5H), 2.86 (t, 2H), 2.66 (s, 3H), 2.15 (quin, 2H), 1.98-1.93 (m, 2H), 1.77-1.69 (m, 4H), 1.56-1.49 (m, 2H), 1.29 (s, 3H); MS (ESI) m/z = 639.3 (M + H)
+
範例318. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基)-3,5-二甲基
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(15.9 mg),程序差異之處在於以範例290步驟1中所製備之(1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(30 mg,0.072 mmol)及參考範例21中所製備之2-(1-(2,2-二氟乙基)-3,5-二甲基
-1
H-吡唑-4-基)嘧啶-4-胺(22 mg,0.086 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.00 (d, 1H), 8.47 (d, 1H), 8.33 (s, 1H), 8.25 (d, 1H), 7.63 (d,1 H), 7.45 (d, 2H), 7.33 (dd, 1H), 6.64 (s, 1H), 6.14 (tt, 1H), 4.40 (td, 2H), 4.05 (t, 2H), 3.35 (t, 5H), 2.87 (t, 2H), 2.63 (s, 3H), 2.55 (s, 3H), 2.15 (quin, 2H), 1.95-1.93 (m, 2H), 1.72-1.66 (m, 4H), 1.52-1.46 (m, 2H), 1.28 (s, 3H); MS (ESI) m/z = 634.3 (M + H)
+
範例319. (1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2,3,3-四氟丙基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(12.5 mg),程序差異之處在於以範例290步驟1中所製備之(1
s,4
s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-氯-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(30 mg,0.072 mmol)及參考範例22中所製備之2-(1-(2,2,3,3-四氟丙基)
-1
H-吡唑-4-基)嘧啶-4-胺(24 mg,0.086 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (CDCl
3, 400 MHz) δ 9.05 (d, 1H), 8.41 (d, 1H), 8.39 (d, 1H), 8.34 (d, 1H), 8.26 (t, 1H), 8.20 (s, 1H), 7.64 (d, 1H), 7.43 (brs 1H), 7.32 (d, 2H), 6.91 (s, 1H), 6.90 (tt, 1H), 4.72 (td, 1H), 4.05 (t, 2H), 3.48 (brs, 1H), 3.35 (t, 4H), 2.87 (t, 2H), 2.15 (quin, 2H), 2.05-1.98 (m, 2H), 1.77-1.71 (m, 4H), 1.63-1.57 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 656.3 (M + H)
+
範例320. 3,3-二氟-1-(5-氟-4-((4'-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)哌啶-4-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(23 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.116 mmol)及參考範例23中所製備之1-(4-胺基-5-氟嘧啶-2-基)-3,3-二氟哌啶-4-醇(35 mg,0.139 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.27 (d, 1H), 9.01 (s, 1H), 8.42 (s, 2H), 8.10 (d, 1H), 7.93 (d, 1H), 7.59 (d, 1H), 7.29 (s, 1H), 5.78 (d, 1H), 4.77 (s, 1H), 4.22 (s, 1H), 4.16 (dd, 1H), 3.95-3.87 (m, 3H), 3.68-3.66 (m, 2H), 3.25-3.09 (m, 3H), 2.70 (s, 3H), 2.16 (brs, 2H), 1.98-1.93 (m, 2H), 1.83-1.76 (m, 3H), 1.66-1.57 (m, 5H), 1.43-1.38 (m, 2H), 1.14 (s, 3H); MS (ESI) m/z = 643.3 (M + H)
+
範例321. (1
s,4
s)-4-((6'-((5-氟-2-((3
R,4
S)-3-氟-4-甲氧基哌啶-1-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(32 mg),程序差異之處在於以參考範例1中所製備之(1
s,4
s)-4-((6'-氯-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(50 mg,0.116 mmol)及參考範例24中所製備之5-氟-2-((3
R,4
S)-3-氟-4-甲氧基哌啶-1-基)嘧啶-4-胺(34 mg,0.139 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.23 (d, 1H), 8.92 (brs, 1H), 8.40 (s, 1H), 8.39 (d, 1H), 8.07 (d, 1H), 7.91 (d, 1H), 7.56 (dd, 1H), 7.31 (s, 1H), 4.89 (d, 1H), 4.67 (brs, 1H), 4.55-4.50 (m, 1H), 4.26 (d, 1H), 4.22 (s, 1H), 3.61-3.57 (m, 2H), 3.32-3.22 (m, 2H), 3.02 (brs, 2H), 2.76 (brs, 1H), 2.08 (brs, 2H), 1.86-1.76 (m, 6H), 1.67-1.58 (m, 4H), 1.43-1.36 (m, 2H), 1.27-1.22 (m, 1H), 1.15 (s, 3H); MS (ESI) m/z = 639.3 (M + H)
+
範例322. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 叔丁基4-(甲苯磺醯氧基)哌啶-1-羧酸鹽
在1-(叔丁氧羰基)-4-羥基哌啶(500 mg,2.484 mmol)之知之DCM (10 mL)溶液中加入三乙胺(0.87 mL,6.211 mmol)及對甲苯磺醯氯(710 mg,3.727 mmol)。將反應混合物在室溫下攪拌3小時。傾注於冰水上,攪拌後以DCM萃取。有機層先後以飽和NaHCO
3溶液及鹽水清洗,利用 MgSO
4乾燥後過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-30%)純化而產出 叔丁基4-(對甲苯磺醯基氧基)哌啶-1-羧酸鹽(777 mg),其形態為白色固體。
1H-NMR (CDCl
3, 400 MHz) δ 7.79 (d, 1H), 7.34 (d, 1H), 4.69-4.66 (m, 1H), 3.62-3.3.56 (m, 2H), 3.28-3.22 (m, 2H), 2.45 (s, 3H), 1.79-1.64 (m, 4H), 1.43 (s, 9H)
步驟2. 叔丁基4-((6-溴基吡啶-3-基)氧基)哌啶-1-羧酸鹽
在步驟1中所製備之叔丁基4-(甲苯磺醯氧基)哌啶-1-羧酸鹽 (770 mg,2.166 mmol)之DMF (15.4 mL)溶液中加入2-溴基-5-羥基吡啶(377 mg,2.166 mmol)及K
2CO
3(599 mg,4.333 mmol)。在90
oC下將反應混合物攪拌3小時。將反應混合物冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-30%)純化而產出形態為白色固體之叔丁基4-[(6-溴基-3-吡啶基)oxy]哌啶-1-羧酸鹽 (523 mg)。MS (ESI) m/z = 358.1 (M + H)
+
步驟3. 6'-氯-4'-氟-5-(哌啶-4-基氧基)-2,3'-聯吡啶
在2-氯-4-氟吡啶-5-硼酸頻哪醇酯 (412 mg,1.6 mmol)之1,4-二氧陸圜(4.52 mL)溶液中加入步驟2中所製備之叔丁基4-((6-溴基吡啶-3-基)氧基)哌啶-1-羧酸鹽 (520 mg,1.46 mmol)、[1,1' -雙(二苯基膦基)二茂鐵]二氯鈀(II),錯合有二氯甲烷(119 mg,0.150 mmol)及3M K
2CO
3溶液(1.46 mL,4.37 mmol)。在80
oC下將反應混合物攪拌1小時後冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物稀釋在DCM中,經矽藻土過濾後濃縮。將粗產物及TFA (0.5 mL)在DCM (5 mL)中於室溫下攪拌 3小時,而後濃縮。將殘餘物稀釋在DCM中,加入1 N NaOH溶液(>pH 8),以水清洗,利用MgSO
4乾燥後濃縮。粗殘餘物以EA調製成漿,1小時後過濾,產出形態為白色固體之6'-氯-4'-氟-5-(哌啶-4-基氧基)-2,3'-聯吡啶(202 mg)。MS (ESI) m/z = 308.2 (M + H)
+
步驟4. 6'-氯-4'-氟-5-((1-(2-氟乙基)哌啶-4-基)氧基)-2,3'-聯吡啶
在步驟3中所製備之6'-氯-4'-氟-5-(哌啶-4-基氧基)-2,3'-聯吡啶(200 mg,0.6500 mmol)之DMF (4 mL)溶液中加入1-氟-2-碘乙烷(170 mg,0.970 mmol)及K
2CO
3(225 mg,1.625 mmol)。於90
oC下將反應混合物攪拌3小時。將反應混合物冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(EA/n-Hex = 0-30%)純化而產出6'-氯-4'-氟-5-((1-(2-氟乙基)哌啶-4-基)氧基)-2,3'-聯吡啶(155 mg),其形態為白色固體。MS (ESI) m/z = 354.2 (M + H)
+
步驟5. (1
s,4
s)-4-((6'-氯-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色固體(57 mg),程序差異之處在於以步驟4中所製備之6'-氯-4'-氟-5-((1-(2-氟乙基)哌啶-4-基)氧基)-2,3'-聯吡啶(50 mg,0.141 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 463.2 (M + H)
+
步驟6. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(17.7 mg),程序差異之處在於以步驟5中製備之(1
s,4
s)-4-((6'-氯-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(55 mg,0.119 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.97 (s, 1H), 9.14 (s, 1H), 8.65 (s, 1H), 8.46-8.36 (m, 4H), 7.90 (d, 1H), 7.55 (d, 2H), 7.24 (brs, 1H), 4.77-4.57 (m, 3H), 4.15 (s, 1H), 3.41 (brs, 1H), 3.28-3.21 (m, 1H), 2.72 (brs, 2H), 2.02-1.93 (m, 4H), 1.84-1.82 (m, 2H), 1.73-1.56 (m, 6H), 1.45-1.33 (m, 4H), 1.24-1.21 (m, 4H), 1.14 (s, 3H); MS (ESI) m/z = 692.3 (M + H)
+
範例323.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
步驟1. 6'-氯
-N-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色固體(42 mg),程序差異之處在於以範例322步驟4中所製備之6'-氯-4'-氟-5-((1-(2-氟乙基)哌啶-4-基)氧基)-2,3'-聯吡啶(50 mg,0.141 mmol)及(1
s,4
s)-4-氟環己-1-胺鹽酸鹽(33 mg,0.212 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及順
-4-胺基-1-甲基環己醇。MS (ESI) m/z = 451.2 (M + H)
+
步驟2.
N 6'-(2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(4.3 mg),程序差異之處在於以步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(20 mg,0.044 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 9.99 (s, 1H), 9.32 (d, 1H), 8.64 (s, 1H), 8.45 (s, 2H), 8.43 (d, 1H), 8.35 (s, 1H), 7.92 (d, 1H), 7.60 (s, 1H), 7.56 (d, 1H), 7.23 (brs, 1H), 4.78 (d, 1H), 4.66-4.57 (m, 4H), 3.59 (brs, 1H), 3.28-3.23 (m, 1H), 2.85 (brs, 4H), 2.03-1.65 (m,13H), 1.34-1.25 (m, 5H); MS (ESI) m/z = 680.2 (M + H)
+
範例324.
N 6'-(2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-基)
-N 4'-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.2 mg),程序差異之處在於以範例323步驟1中所製備之6'-氯
-N-((1
s,4
s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-胺(20 mg,0.044 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(10.99 mg,0.049 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 11.21 (s, 1H), 9.69 (d, 1H), 9.44 (s, 1H), 8.67-8.36 (m, 3H), 7.78 (s, 1H), 7.71 (d, 2H), 6.78 (d, 1H), 6.63 (s, 1H), 6.33 (tt, 1H), 5.02 (td, 2H), 4.91-4.61 (m, 4H), 3.58-3.49 (m, 3H), 2.73 (brs, 4H), 2.12-1.64 (m,12H); MS (ESI) m/z = 640.3 (M + H)
+
範例325. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 叔丁基4-((6-溴基噠嗪-3-基)氧基)哌啶-1-羧酸鹽
在1-(叔丁氧羰基)-4-羥基哌啶(423 mg,2.1 mmol)之DMF (5 mL)溶液中加入氫化鈉(101 mg,2.52 mmol),在室溫下將反應混合物攪拌30分鐘。在反應混合物中加入3,6-二溴-噠嗪(500 mg,2.1 mmol),於室溫下攪拌3小時。將水緩慢加入反應混合物進行淬火,直到觀察不到沉澱為止。過濾收集產生之固體,先後以水及正己烷清洗,再於真空下乾燥以產出形態為白色固體之叔丁基4-(6-溴基噠嗪-3-基)氧基哌啶-1-羧酸鹽 (344 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 7.50 (d, 1H), 6.84 (d, 1H), 5.45-5.41 (m, 1H), 3.82-3.79 (m, 2H), 3.29-3.23 (m, 2H), 2.09-2.05 (m, 3H), 1.77-1.75 (m, 4H), 1.48 (s, 9H)
步驟2. 叔丁基4-((6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)氧基)哌啶-1-羧酸鹽
在步驟1中所製備之叔丁基4-((6-溴基噠嗪-3-基)氧基)哌啶-1-羧酸鹽 (340 mg,0.949 mmol)之1,4-二氧陸圜(5 mL)溶液中加入2-氯-4-氟吡啶-5-硼酸頻哪醇酯 (244 mg,0.949 mmol)、[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II),錯合有二氯甲烷(78 mg,0.090 mmol)及3M K
2CO
3溶液(0.95 mL,2.85 mmol)。將反應混合物在80
oC 下攪拌1小時後冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析(MeOH/DCM = 0-20%)純化而產出形態為白色固體之叔丁基4-[6-(6-氯-4-氟-3-吡啶基)噠嗪-3-基]氧基哌啶-1-羧酸鹽(194 mg)。
1H-NMR (CDCl
3, 400 MHz) δ 9.14 (d, 1H), 7.83 (d, 1H), 7.25 (d, 1H), 7.08 (d, 1H), 5.60-5.56 (m, 1H), 3.85 (brs, 2H), 3.32-3.26 (m, 2H), 2.15-2.13 (m, 2H), 1.84-1.81 (m, 2H), 1.49 (s, 9H)
步驟3. 叔丁基4-((6-(6-氯-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)噠嗪-3-基)氧基)哌啶-1-羧酸鹽
以如同參考範例1步驟2之方式製備標題化合物,其形態為淺黃色固體(99 mg),程序差異之處在於以步驟2中所製備之叔丁基4-((6-(6-氯-4-氟吡啶-3-基)噠嗪-3-基)氧基)哌啶-1-羧酸鹽 (97 mg,0.237 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。MS (ESI) m/z = 518.2 (M + H)
+
步驟4. (1
s,4
s)-4-((2-氯-5-(6-(哌啶-4-基氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
在步驟3中所製備之叔丁基4-((6-(6-氯-4-(((1
s,4
s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)噠嗪-3-基)氧基)哌啶-1-羧酸鹽 (80 mg,0.1500 mmol)之DCM (2 mL)溶液中加入三氟乙酸(118.17 uL,1.54 mmol),並將反應混合物在室溫下攪拌3小時。反應混合物經減壓濃縮後,將DCM加入殘餘物中。接著加入1N NaOH溶液(>pH8)於殘餘物中,以水清洗,利用MgSO
4乾燥,及減壓濃縮。粗殘餘物以EA漿化1小時後過濾產出(1
s,4
s)-4-((2-氯-5-(6-(哌啶-4-基氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(59 mg),其形態為白色固體。MS (ESI) m/z = 418.2 (M + H)
+
步驟5. (1
s,4
s)-4-((2-氯-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
在步驟4中所製備之 (1
s,4
s)-4-((2-氯-5-(6-(哌啶-4-基氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(57 mg,0.136 mmol)之DMF (1 mL)溶液中加入1-氟-2-碘乙烷(35.59 mg,0.205 mmol)及K
2CO
3(47.12 mg,0.341 mmol)。反應混合物在90
oC下攪拌3小時。將反應混合物冷卻至室溫,以水淬火,而後以DCM萃取。有機層先利用MgSO
4乾燥後,再經過濾及濃縮。粗殘餘物以矽膠管柱層析 (MeOH/DCM = 0-10 %) 純化而產出(1
s,4
s)-4-((2-氯-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(36 mg),其形態為白色固體。MS (ESI) m/z = 464.2 (M + H)
+
步驟6. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(5.1 mg),程序差異之處在於以步驟5中製備之以(1
s,4
s)-4-((2-氯-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(30 mg,0.065 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO
-d
6 , 400 MHz) δ 10.06 (s, 1H), 9.24 (d, 1H), 8.66 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.44 (d, 1H), 8.29 (d, 1H), 7.55 (brs, 1H), 7.36 (brs, 1H), 7.30 (d, 1H), 5.37 (brs, 1H), 4.72-4.61 (m, 2H), 4.18 (t, 2H), 3.46 (brs, 1H), 3.26-3.22 (m, 1H), 2.16 (brs, 2H), 1.93-1.84 (m, 4H), 1.67-1.55 (m, 6H), 1.46-1.40 (m, 2H), 1.34-1.24 (m, 6H), 1.14 (s, 3H); MS (ESI) m/z = 693.3 (M + H)
+
範例326. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-3-甲氧基吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(242.8 mg),程序差異之處在於以2-溴基-3-甲氧基吡嗪(257 mg,1.359 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.51 (d, 1H), 8.24 (s, 1H), 8.16 (s, 1H), 7.16 (d, 1H), 3.96 (s, 3H); MS (ESI) m/z = 239.8 (M + H)
+
步驟2. (1
s,4
s)-4-((2-氯-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為白色固體(285.4 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-3-甲氧基吡嗪(243 mg,1.013 mmol)及順
-4-胺基-1-甲基環己醇(196 mg,1.52 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.71 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 8.05-8.03 (m, 1H), 4.02 (s, 3H), 3.34-3.33 (m, 1H), 1.93-1.90 (m, 1H), 1.76-1.58 (m, 7H), 1.30 (s, 3H); MS (ESI) m/z = 349.9 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(127.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(285 mg,0.818 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d
6 , 400 MHz) δ 10.00 (s, 1H), 8.65 (s, 1H), 8.46 (s, 1H), 8.43 (d, 1H), 8.38 (s, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 7.61 (brs, 1H), 7.39 (d, 1H), 7.24 (brs, 1H), 4.11 (s, 1H), 3.95 (s, 3H), 3.30 (m, 1H), 3.24 (m, 1H), 1.75 (d, 2H), 1.57-1.54 (m, 4H), 1.39-1.34 (m, 4H), 1.25-1.24 (m, 2H), 1.12 (s, 3H); MS (ESI) m/z = 578.2 (M + H)
+
範例327. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
步驟1. 2-(6-氯-4-氟吡啶-3-基)-3-氟吡嗪
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(146.4 mg),程序差異之處在於以2-溴基-3-氟吡嗪(172 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.67-8.63 (m, 2H), 8.30 (s, 1H), 7.24 (d, 1H)
步驟2. (1
s,4
s)-4-((2-氯-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米白色固體(87.6 mg),程序差異之處在於以步驟1中所製備之2-(6-氯-4-氟吡啶-3-基)-3-氟吡嗪(93 mg,0.409 mmol)及順
-4-胺基-1-甲基環己醇(79 mg,0.613 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.53 (s, 1H), 8.46 (s, 1H), 8.31 (d, 1H), 8.11 (s, 1H), 6.60 (s, 1H), 3.32 (m, 1H), 1.89-1.86 (m, 2H), 1.75-1.70 (m, 4H), 1.67-1.52 (m, 2H), 1.27 (s, 3H); MS (ESI) m/z = 337.0 (M + H)
+
步驟3. (1
s,4
s)-4-((2-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(4.5 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((2-氯-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇(87 mg,0.259 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.75 (s, 1H), 8.59 (s, 1H), 8.50 (s, 2H), 8.40 (d, 1H), 7.45-7.43 (m, 1H), 7.38 (s, 1H), 3.60 (m, 1H), 3.03 (m, 1H), 1.94 (m, 2H), 1.72-1.69 (m, 2H), 1.57 (t, 2H), 1.45 (m, 2H), 1.25 (m, 5H), 1.13 (d, 2H); MS (ESI) m/z = 566.2 (M + H)
+
範例328. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-氯-4-氟-5-(5-氟-3-甲氧基-2-吡啶基)吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(148.2 mg),程序差異之處在於以2-溴基-5-氟-3-甲氧基吡啶(200 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.47 (d, 1H), 8.18 (s, 1H), 7.13 (d, 1H), 7.08 (d, 1H), 3.83 (s, 3H); MS (ESI) m/z = 256.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米白色固體(200 mg),程序差異之處在於以步驟1中所製備之2-氯-4-氟-5-(5-氟-3-甲氧基-2-吡啶基)吡啶(148 mg,0.577 mmol)及順
-4-胺基-1-甲基環己醇(112 mg,0.866 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.18 (s, 1H), 8.03 (s, 1H), 7.04 (d, 1H), 6.79-6.77 (m, 1H), 6.49 (s, 1H), 3.74 (s, 3H), 3.20-3.19 (m, 1H), 2.54 (m, 1H), 1.79-1.76 (m, 2H), 1.66-1.54 (m, 4H), 1.45-1.42 (m, 2H), 1.18 (s, 3H); MS (ESI) m/z = 366.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(6.7 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(90 mg,0.245 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.48 (s, 1H), 8.42 (d, 1H), 8.34 (s, 1H), 8.16 (s, 1H), 7.39 (s, 1H), 7.13 (d, 1H), 7.01-6.96 (m, 2H), 3.87 (s, 3H), 3.44 (m, 1H), 2.84-2.82 (m, 1H), 1.98-1.95 (m, 2H), 1.70-1.54 (m, 8H), 1.30 (s, 3H), 1.23-1.21 (m, 2H); MS (ESI) m/z = 595.2 (M + H)
+
範例329. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-氯-4-氟-5-(6-氟-3-甲氧基-2-吡啶基)吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(118.5 mg),程序差異之處在於以2-溴基-6-氟-3-甲氧基吡啶(200 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.50 (d, 1H), 7.45 (t, 1H), 7.14 (d, 1H), 6.96 (d, 1H), 3.82 (s, 3H); MS (ESI) m/z = 256.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米白色固體(197.9 mg),程序差異之處在於以步驟1中所製備之2-氯-4-氟-5-(6-氟-3-甲氧基-2-吡啶基)吡啶(119 mg,0.462 mmol)及順
-4-胺基-1-甲基環己醇(89 mg,0.693 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.33 (s, 1H), 7.42-7.40 (m, 1H), 6.90-6.81 (m, 2H), 6.51 (s, 1H), 3.77 (s, 3H), 3.25-3.24 (m, 1H), 1.99 (m, 2H), 1.83-1.62 (m, 4H), 1.59-1.47 (m, 2H), 1.22 (s, 3H); MS (ESI) m/z = 366.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(3.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(90 mg,0.245 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.66 (s, 1H), 8.48 (s, 1H), 8.42 (d, 1H), 7.49-5.46 (m, 1H), 7.36 (m, 1H), 7.20 (m, 1H), 7.01-6.98 (m, 1H), 6.88-6.86 (m, 1H), 3.88 (s, 3H), 3.49 (m, 1H), 2.83 (m, 1H), 2.03-1.96 (m, 2H), 1.72-1.53 (m, 8H), 1.30 (s, 3H), 1.23-1.21 (m, 2H); MS (ESI) m/z = 595.2 (M + H)
+
範例330. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-3-(二氟甲氧基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(153.9 mg),程序差異之處在於以2-溴基-3-(二氟甲氧基)吡啶(217 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.57-8.52 (m, 2H), 7.64 (d, 1H), 7.40 (t, 1H), 7.18 (d, 1H), 6.49 (t, 1H); MS (ESI) m/z = 275.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟2之方式製備標題化合物,其形態為米白色固體(213.7 mg),程序差異之處在於以步驟1中所製備之6'-氯-3-(二氟甲氧基)-4'-氟-2,3'-聯吡啶(154 mg,0.560 mmol)及順
-4-胺基-1-甲基環己醇(109 mg,0.841 mmol)代替6'-氯-4'-氟-5-((4-甲基哌嗪-1-基)甲基)-2,3'-聯吡啶及(4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.44 (d, 1H), 8.15 (s, 1H), 7.63-7.61 (m, 1H), 7.27-7.26 (m, 1H), 6.79-6.78 (m, 1H), 6.53 (s, 1H), 6.41 (t, 1H), 3.24-3.22 (m, 1H), 2.32-2.28 (m, 1H), 1.97 (m, 2H), 1.78-1.44 (m, 6H), 1.97 (s, 3H); MS (ESI) m/z = 384.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為白色固體(9.9 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(94 mg,0.245 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (CDCl
3, 400 MHz) δ 8.67 (s, 1H), 8.55-8.54 (m, 1H), 8.48 (s, 1H), 8.44 (d, 1H), 8.31 (s, 1H), 7.69 (d, 1H), 7.48 (s, 1H), 7.34-7.29 (m, 2H), 7.08-7.03 (m, 2H), 6.44 (t, 1H), 3.46 (m, 1H), 2.83-2.82 (m, 1H), 2.05-1.96 (m, 2H), 1.74-1.54 (m, 8H), 1.30 (s, 3H), 1.23-1.21 (m, 2H); MS (ESI) m/z = 613.2 (M + H)
+
範例331. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4-(二氟甲氧基)-4'-氟-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為白色固體(183 mg),程序差異之處在於以2-溴基-4-(二氟甲氧基)吡啶(200 mg,0.893 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.08 (d, 1H), 8.72 (d, 1H), 7.51 (s, 1H), 7.23 (d, 1H), 7.10 (d, 1H), 6.70 (t, 1H)。
步驟2. (1
s,4
s)-4-((6'-氯-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(105 mg),程序差異之處在於以步驟1中所製備之6'-氯-4-(二氟甲氧基)-4'-氟-2,3'-聯吡啶(90 mg,0.328 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.22 (d, 1H), 8.54 (d, 1H), 8.35 (s, 1H), 7.40 (s, 1H), 7.01 (d, 1H), 6.70 (t, 1H), 6.58 (s, 1H), 3.34 (brs, 1H), 1.94 (d, 2H), 1.78-1.68 (m, 4H), 1.61-1.55 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 384.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(36 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(95.5 mg,0.249 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 9.39 (d, 1H), 8.66 (s, 1H), 8.60 (d, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 8.43 (d, 1H), 7.72 (s, 1H), 7.60 (t, 1H), 7.52 (brs, 1H), 7.32 (brs, 1H), 7.13 (d, 1H), 4.22 (s, 1H), 3.23 (brs, 1H), 1.88-1.81 (m, 2H), 1.64-1.56 (m, 4H), 1.46-1.42 (m, 2H), 1.33-1.23 (m, 4H), 1.13 (s, 3H); MS (ESI) m/z= 613.2 (M + H)+
範例332. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-5-(二氟甲氧基)-4'-氟-2,3'-聯吡啶
以如同參考範例5之方式製備標題化合物,其形態為白色固體(467 mg),程序差異之處在於以2-溴基-5-(二氟甲氧基)吡啶(500 mg,2.232 mmol)代替2-溴基-5-(甲基磺醯基)吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 8.63 (s, 1H), 7.80 (d, 1H), 7.61 (d, 1H), 7.22 (d, 1H), 6.63 (t, 1H)
步驟2. (1
s,4
s)-4-((6'-氯-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(111 mg),程序差異之處在於以步驟1中所製備之6'-氯-5-(二氟甲氧基)-4'-氟-2,3'-聯吡啶(90 mg,0.328 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 9.04 (d, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 7.74 (d, 1H), 7.61 (d, 1H), 6.60 (t, 1H), 6.59 (s, 1H), 3.36-3.34 (m, 1H), 1.95 (d, 2H), 1.79-1.67 (m, 4H), 1.61-1.55 (m, 2H), 1.31 (s, 3H); MS (ESI) m/z = 384.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為淺黃色固體(41 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(95.5 mg,0.249 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (DMSO-
d 6, 400 MHz) δ 9.23 (brs, 1H), 8.69 (s, 1H), 8.54 (d, 2H), 8.49 (s, 1H), 8.46 (d, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 7.45 (brs, 1H), 7.34 (t, 1H), 7.21 (brs, 1H), 4.23 (s, 1H), 3.23 (brs, 1H), 1.88-1.81 (m, 2H), 1.66-1.57 (m, 4H), 1.45-1.39 (m, 2H), 1.34-1.24 (m, 4H), 1.13 (s, 3H); MS (ESI) m/z= 613.2 (M + H)
+
範例333. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2,2-三氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4'-氟-3-(2,2,2-三氟乙氧基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(196.5 mg),程序差異之處在於以2-溴基-3-(2,2,2-三氟乙氧基)吡啶(249 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.49 (d, 1H), 8.37 (d, 1H), 7.33-7.32 (m, 2H), 7.13 (d, 1H), 4.38 (q, 2H); ; MS (ESI) m/z= 306.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-3-(2,2,2-三氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(245.2 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-3-(2,2,2-三氟乙氧基)-2,3'-聯吡啶(196.5 mg,0.641 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.30-8.28 (m, 2H), 7.34 (d, 1H), 7.24-1.21 (m, 1H), 7.16 (d, 1H), 6.53 (s, 1H), 4.29 (q, 2H), 3.25-3.22 (m, 1H), 2.09 (s, 1H), 1.80 (m, 2H), 1.69-1.46 (m, 6H), 1.21 (s, 3H); MS (ESI) m/z = 416.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2,2-三氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(16.3 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-3-(2,2,2-三氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(108 mg,0.259 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.75 (s, 1H), 8.49 (s, 1H), 8.38-8.35 (m, 2H), 8.18 (s, 1H), 7.68 (d, 1H), 7.44-7.42 (m, 1H), 7.35 (d, 1H), 7.29 (s, 1H), 4.64 (q, 2H), 3.52-3.48 (m, 1H), 3.05-3.01 (m, 1H), 1.91-1.87 (m, 2H), 1.69-1.44 (m, 8H), 1.27-2.25 (m, 2H), 1.22 (s, 3H); MS (ESI) m/z= 645.2 (M + H)
+
範例334. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2-二氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-3-(2,2-二氟乙氧基)-4'-氟-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(170.7 mg),程序差異之處在於以2-溴基-3-(2,2-二氟乙氧基)吡啶(231 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.50 (d, 1H), 8.34 (d, 1H), 7.32-7.30 (m, 2H), 7.12 (d, 1H), 5.95 (t, 1H), 4.19 (td, 2H); MS (ESI) m/z= 288.9 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-3-(2,2-二氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(217.3 mg),程序差異之處在於以步驟1中所製備之6'-氯-3-(2,2-二氟乙氧基)-4'-氟-2,3'-聯吡啶(170.7 mg,0.591 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.29 (s, 1H), 8,25 (d, 1H), 7.30 (d, 1H), 7.23-7.20 (m, 2H), 6.53 (s, 1H), 6.01 (t, 1H), 4.13 (t, 2H), 3.25-3.22 (m, 1H), 1.84-1.80 (m, 2H), 1.66-1.46 (m, 6H), 1.22 (s, 3H); MS (ESI) m/z = 398.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2-二氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(9.1 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-3-(2,2-二氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(103 mg,0.259 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.75 (s, 1H), 8.49 (s, 1H), 8.34 (d, 1H), 8.31 (d, 1H), 8.20 (s, 1H), 7.60 (d, 1H), 7.43-7.41 (m, 1H), 7.36-7.35 (m, 1H), 7.25 (s, 1H), 6.17 (t, 1H), 4.34 (t, 2H), 3.51-3.48 (m, 1H), 3.05-3.01 (m, 1H), 1.91-1.88 (m, 2H), 1.70-1.44 (m, 8H), 1.45-1.44 (m, 2H), 1.25 (s, 3H); MS (ESI) m/z= 627.2 (M + H)
+
範例335. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 6'-氯-4,4'-二氟-3-甲氧基-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(180 mg),程序差異之處在於以2-溴基-4-氟-3-甲氧基吡啶(200 mg,0.971 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.48 (d, 1H), 8.30 (t, 1H), 7.16-7.09 (m, 2H), 3.91 (s, 3H); MS (ESI) m/z= 256.8 (M + H)
+
步驟2. (1
s,4
s)-4-((6'-氯-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(226.2 mg),程序差異之處在於以步驟1中所製備之6'-氯-4,4'-二氟-3-甲氧基-2,3'-聯吡啶(180 mg,0.700 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.29 (s, 1H), 8.22 (t, 1H), 7.21 (d, 1H), 7.03-6.99 (m, 1H), 6.52 (s, 1H), 3.75 (s, 3H), 3.24-3.22 (m, 1H), 1.82-1.79 (m, 2H), 1.69-1.54 (m, 4H), 1.48-1.42 (m, 2H), 1.20 (s, 3H); MS (ESI) m/z = 366.0 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-((2-(1-(環丙磺醯基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(15.7 mg),程序差異之處在於以步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(95 mg,0.259 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇。
1H-NMR (MeOD, 400 MHz) δ 8.75 (s, 1H), 8.49 (s, 1H), 8.39-8.35 (m, 2H), 8.22 (s, 1H), 7.40 (d, 1H), 7.29-7.25 (m, 2H), 3.84 (s, 3H), 3.52 (m, 1H), 3.05-3.01 (m, 1H), 1.93-1.90 (m, 2H), 1.70-1.1.44 (m, 8H), 1.30-1.29 (m, 2H), 1.27 (s, 3H); MS (ESI) m/z= 595.2 (M + H)
+
範例336. (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物(1.1 mg),其形態為白色固體,程序差異之處在於以範例335步驟2中所製備之(1
s,4
s)-4-((6'-氯-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(81 mg,0.222 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(40 mg,0.178 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。
1H-NMR (MeOD, 400 MHz) δ 8.37-8.36 (m, 3H), 8.25 (s, 2H), 7.31-7.26 (m, 2H), 7.15 (m, 1H), 6.26 (t, 1H), 4.66 (t, 2H), 3.87 (s, 3H), 3.52-3.51 (m, 1H), 1.91-1.88 (m, 2H), 1.72-1.67 (m, 4H), 1.57-1.54 (m, 2H), 1.23 (s, 3H); MS (ESI) m/z= 555.2 (M + H)
+
範例337. (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
步驟1. 2-溴基-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)吡啶
以如同範例322步驟2之方式製備標題化合物,其形態為白色固體(382 mg),程序差異之處在於以6-溴基-5-甲氧基吡啶-3-醇(499 mg,2.445 mmol)及1-(2,2,2-三氟乙基)哌啶-4-基4-甲基苯磺酸鹽(750 mg,2.223 mmol)代替2-溴基-5-羥基吡啶及叔丁基4-(對甲苯氧基)哌啶-1-羧酸鹽。
1H-NMR (CDCl
3, 400 MHz) δ 7.68 (s, 1H), 6.74 (s, 1H), 4.39 (s, 1H), 3.90 (s, 3H), 3.05-2.98 (q, 2H), 2.91-2.90 (m, 2H), 2.67-2.62 (m, 2H), 2.05-1.86 (m, 4H); MS (ESI) m/z= 369.6 (M + H)
+
步驟2. 6'-氯-4'-氟-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-2,3'-聯吡啶
以如同範例1步驟1之方式製備標題化合物,其形態為白色固體(301 mg),程序差異之處在於以2-溴基-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)吡啶(380 mg,1.029 mmol)代替1-((6-溴基吡啶-3-基)甲基)-4-甲基哌嗪。
1H-NMR (CDCl
3, 400 MHz) δ 8.50 (d, 1H), 8.02 (s, 1H), 7.15 (d, 1H), 6.87 (s, 1H), 4.49 (m, 1H), 3.83 (s, 3H), 3.07-2.93 (m, 4H), 2.69-2.65 (m, 2H), 2.09-2.05 (m, 2H), 1.94-1.91 (m, 2H); MS (ESI) m/z= 420.1 (M + H)
+
步驟3. (1
s,4
s)-4-((6'-氯-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同參考範例1步驟2之方式製備標題化合物,其形態為白色固體(94 mg),程序差異之處在於以步驟1中所製備之6'-氯-4'-氟-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-2,3'-聯吡啶(87 mg,0.217 mmol)代替6'-氯-4'-氟-5-((1-甲基哌啶-4-基)氧基)-2,3'-聯吡啶。
1H-NMR (CDCl
3, 400 MHz) δ 8.25 (s, 1H), 7.90 (s, 1H), 7.01-6.99 (m, 1H), 6.86 (s, 1H), 6.52 (s, 1H), 4.43 (m, 1H), 3.77 (s, 3H), 3.25-3.24 (m, 1H), 3.01 (q, 2H), 2.96-2.91 (m, 2H), 2.65-2.61 (m, 2H), 2.02-1.83 (m, 8H), 1.57-1.48 (m, 4H), 1.24 (s, 3H); MS (ESI) m/z= 529.2 (M + H)
+
步驟4. (1
s,4
s)-4-((6'-((2-(1-(2,2-二氟乙基)-1
H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇
以如同範例1步驟3之方式製備標題化合物,其形態為米白色固體(1.4 mg),程序差異之處在於以步驟3中所製備之(1
s,4
s)-4-((6'-氯-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇(94 mg,0.178 mmol)及參考範例17中所製備之2-(1-(2,2-二氟乙基)
-1
H-吡唑-4-基)嘧啶-4-胺(40 mg,0.178 mmol)代替(1-(6'-氯-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇及2-(1-(環丙磺醯基)
-1
H-吡唑-4-基)嘧啶-4-胺。MS (ESI) m/z= 718.3 (M + H)
+
生物檢驗
1.
生化
EGFR
抑制檢驗
採用Perkin-Elmer 推出之Lance Ultra 時差性螢光共振能量轉移(TR-FRET)技術進行生化EGFR激酶檢驗。本發明化合物先於100 % DMSO 中稀釋至20 mM以利存放,再製成激酶緩衝液,使化合物濃度在0.003 μM至10 μM之範圍內。
簡言之,EGFR酵素野生型、雙突變體[del19/C797S及L858R/C797S]、三突變體[del19/T790M/C797S及L858R/T790M/C797S]、連續稀釋 EGFR抑制劑、ULight-多GT胜肽基質(PerkinElmer; TRF0100-M)及不同濃度之ATP (Km及100 µM 最終檢驗濃度)分別與激酶檢驗緩衝液(50 mM HEPES pH 7.4、10 mM MgCl
2、1 mM EGTA、2 mM DTT與0.01% Tween-20)混合後置入一384孔盤 (Optiplate
TM384,白色,PerkinEImer;6007290)。
各激酶反應物均在室溫下培養1小時,之後加入4 µL之終止液(10 mM EDTA)終止反應。而後加入稀釋於LANCE偵測緩衝液中之特定銪標記抗磷酸肽抗體(PerkinElmer,AD0069),達2 nM之最終濃度。經於室溫下培養60分鐘後,使用EnVision Multilabel Reader (Perkin-Elmer)測量LANCE訊號。激發波長設定為320 nm,並於615 nm(施體)及665 nm(受體)監控放射。利用GraphPad Prism軟體(美國加州聖地牙哥GraphPad Software, Inc.)判定IC
50值。
如上所評估式(I)化合物於各EGFR激酶活性上之IC
50值列示下表3至表14。
[表3]
[表4]
[表5]
[表6]
[表7]
[表8]
[表9]
[表10]
[表11]
[表12]
[表13]
[表14]
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
1 | 1.2 | 0.8 | 0.4 | 1.3 | 37.5 | 52.3 | 10.5 | 222.7 | 211.8 | >10000 |
2 | 0.2 | 0.1 | 0.2 | 0.3 | 0.2 | 0.1 | 1.8 | 1.4 | 541.0 | |
3 | 0.4 | 0.3 | 23.7 | 15.3 | 99.6 | |||||
4 | 0.1 | 0.1 | 2.1 | 2.2 | 19.9 | |||||
5 | 0.2 | 0.1 | 0.1 | 0.1 | 0.2 | 0.4 | 0.3 | 2.0 | 0.5 | >10000 |
6 | 0.2 | 0.1 | 0.1 | 0.1 | 0.2 | 0.4 | 0.3 | 6.5 | 1.1 | >10000 |
7 | 0.4 | 0.2 | 0.1 | 0.2 | 0.5 | 1.3 | 0.6 | 12.4 | 3.0 | >10000 |
8 | 0.4 | 0.2 | 0.1 | 0.2 | 0.4 | 0.7 | 0.4 | 6.3 | 1.0 | 8893.0 |
9 | 0.1 | 0.1 | 0.3 | 0.2 | 0.7 | 0.2 | 1.9 | 1.0 | 166.7 | |
10 | 0.1 | 0.1 | 0.2 | 0.1 | 0.3 | 0.2 | 1.2 | 0.6 | 46.6 | |
11 | 0.1 | 0.1 | 0.2 | 0.2 | 0.4 | 0.4 | 2.1 | 1.4 | 586.5 | |
12 | 0.4 | 0.2 | 0.6 | 0.4 | 1.0 | 1.1 | 11.5 | 3.6 | 2691.0 | |
13 | 0.1 | 0.1 | 0.6 | 0.5 | 1.4 | 3.4 | 66.8 | 13.3 | >10000 | |
14 | 0.2 | 0.4 | 10.9 | 1.1 | 6.4 | 13.7 | 686.9 | 154.2 | >10000 | |
15 | 0.1 | 0.1 | 1.5 | 0.3 | 0.6 | 1.8 | 22.1 | 5.7 | 889.5 | |
16 | 0.04 | 0.1 | 0.4 | 0.2 | 0.3 | 0.5 | 8.7 | 2.1 | 1899.0 | |
17 | 2.9 | 2.6 | 5.6 | 305.3 | >10000 | |||||
18 | 0.7 | 3.1 | 8.7 | 113.0 | >10000 | |||||
19 | 1.4 | 1.6 | 1.7 | 11.1 | >10000 | |||||
20 | 2.1 | 3.6 | 5.5 | 69.3 | >10000 | |||||
21 | 0.3 | 0.3 | 0.3 | 0.6 | 0.5 | 1.2 | 1.0 | 11.6 | 6.3 | 5572.0 |
22 | 0.3 | 0.3 | 0.2 | 0.2 | 0.1 | 0.2 | 0.2 | 1.1 | 0.3 | 164.8 |
23 | 1.6 | 1.1 | 1.0 | 1.8 | 5.0 | 0.6 | 6.2 | 13.7 | >10000 | |
24 | 1.0 | 8.4 | 0.9 | 1.0 | 2.2 | 0.7 | 3.5 | 2.8 | >10000 | |
25 | 1.0 | 1.1 | 0.8 | 1.2 | 0.5 | 0.5 | 0.3 | 2.0 | 1.9 | 1829.0 |
26 | 0.4 | 0.4 | 0.2 | 0.4 | 0.2 | 0.2 | 0.1 | 0.7 | 0.9 | 107.4 |
27 | 0.3 | 0.3 | 0.2 | 0.4 | 0.1 | 0.3 | 0.1 | 1.6 | 1.7 | 370.3 |
28 | 0.1 | 0.1 | 0.6 | 1.6 | 1526.0 | |||||
29 | 0.2 | 0.4 | 1.8 | 26.2 | >10000 | |||||
30 | 0.1 | 0.1 | 0.4 | 2.0 | 2915.0 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
31 | 0.2 | 0.2 | 0.1 | 0.1 | 0.1 | 0.1 | 0.1 | 0.8 | 0.3 | 52.6 |
32 | 0.2 | 0.4 | 0.2 | 0.3 | 0.2 | 0.1 | 0.1 | 1.9 | 0.3 | 119.9 |
33 | 2.6 | 3.9 | 1.7 | 3.1 | 2.1 | 1.3 | 1.7 | 29.3 | 7.9 | 812.7 |
34 | 0.6 | 0.6 | 0.1 | 0.3 | 0.2 | 0.4 | 0.1 | 0.2 | 0.5 | 61.1 |
35 | 0.6 | 0.3 | 0.2 | 0.3 | 0.3 | 0.2 | 0.3 | 1.2 | 1.3 | 810.9 |
36 | 0.1 | 0.2 | 0.1 | 0.1 | 0.5 | 0.9 | 1.0 | 15.7 | 5.8 | 3084.0 |
37 | 0.2 | 0.2 | 0.1 | 0.3 | 0.7 | 1.1 | 0.7 | 21.3 | 6.6 | >10000 |
38 | 0.4 | 0.2 | 0.7 | 0.3 | 0.6 | 0.9 | 4.3 | 1.5 | 1434.0 | |
39 | 1.0 | 2.1 | 0.4 | 0.7 | 2.5 | 3.3 | 8.7 | 74.8 | 26.0 | >10000 |
40 | 0.7 | 2.1 | 0.5 | 1.7 | 2.3 | 3.2 | 1.7 | 7.7 | 5.0 | 1445.0 |
41 | 0.3 | 0.8 | 0.2 | 0.9 | 4.5 | 5.1 | 4.0 | 523.3 | 43.6 | >10000 |
42 | 0.1 | 0.1 | 0.03 | 0.1 | 0.3 | 0.2 | 0.4 | 2.3 | 2.6 | 1360.0 |
43 | 0.1 | 2.5 | 0.1 | 2.7 | 0.4 | 0.5 | 0.6 | 1.6 | 2.0 | 1557.0 |
44 | 0.6 | 0.6 | 0.8 | 7.1 | >10000 | |||||
45 | 1.7 | 2.6 | 1.7 | 4.2 | 602.0 | |||||
46 | 0.2 | 0.3 | 0.1 | 0.2 | 0.2 | 0.4 | 0.2 | 0.9 | 0.9 | >10000 |
47 | 2.0 | 1.2 | 1.0 | 3.0 | 3.2 | 4.2 | 7.9 | 17.7 | 7.1 | >10000 |
48 | 0.5 | 0.6 | 0.3 | 2.1 | 2.6 | 5.8 | 14.1 | 83.3 | 24.7 | >10000 |
49 | 0.3 | 0.3 | 0.1 | 0.3 | 0.5 | 0.8 | 0.3 | 2.4 | 0.5 | 294.1 |
50 | 0.3 | 0.2 | 0.1 | 0.1 | 0.5 | 1.1 | 0.4 | 2.2 | >10000 | |
51 | 0.8 | 0.6 | 0.3 | 0.6 | 3.1 | 10.6 | 1.0 | 16.7 | >10000 | |
52 | 0.3 | 0.5 | 0.1 | 0.3 | 0.5 | 0.6 | 0.6 | 1.1 | 3.0 | >10000 |
53 | 0.4 | 0.4 | 0.1 | 0.5 | 1.3 | 1.2 | 1.0 | 1.0 | 6.9 | >10000 |
54 | 12.5 | 11.4 | 5.1 | 5.6 | 9.7 | 1.4 | 7.3 | 9.2 | 5836.0 | |
55 | 0.7 | 1.7 | 0.4 | 0.5 | 1.1 | 0.3 | 1.0 | 1.9 | 753.5 | |
56 | 1.4 | 2.4 | 5.9 | 8.8 | 2.6 | 122.3 | 168.8 | >10000 | ||
57 | 1.7 | 1.0 | 2.0 | 1.7 | 0.7 | 4.5 | 4.8 | 635.8 | ||
58 | 1.1 | 1.1 | 8.0 | 7.2 | 1.7 | 56.4 | 97.7 | >10000 | ||
59 | 0.3 | 0.4 | 0.5 | 0.7 | 0.6 | 0.9 | 1.0 | 7.4 | 14.8 | >10000 |
60 | 0.2 | 0.2 | 0.2 | 0.4 | 0.4 | 0.5 | 0.4 | 4.2 | 6.8 | >10000 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
61 | 0.2 | 0.2 | 0.4 | 1.8 | 3941.0 | |||||
62 | 0.1 | 0.1 | 0.2 | 0.9 | 744.7 | |||||
63 | 0.2 | 0.2 | 0.8 | 5.4 | >10000 | |||||
64 | 0.1 | 0.1 | 0.1 | 0.3 | 0.2 | 0.2 | 0.9 | 2.4 | 1168.0 | |
65 | 0.1 | 0.1 | 0.1 | 0.3 | 0.3 | 0.2 | 0.1 | 0.9 | 2.4 | 1136.0 |
66 | 0.3 | 0.5 | 0.1 | 0.5 | 0.4 | 0.9 | 0.5 | 12.2 | 11.5 | >10000 |
67 | 0.3 | 0.3 | 0.1 | 0.3 | 0.5 | 0.5 | 0.8 | 4.5 | 3.7 | >10000 |
68 | 0.9 | 1.5 | 0.8 | 0.8 | 2.8 | 4.9 | 1.1 | 123.6 | 23.2 | >10000 |
69 | 1.9 | 1.6 | 0.8 | 1.4 | 2.4 | 5.3 | 1.4 | 52.7 | 14.5 | 4782.0 |
70 | 3.9 | 4.9 | 13.1 | 81.1 | >10000 | |||||
71 | 4.5 | 4.1 | 44.2 | 354.7 | >10000 | |||||
72 | 10.7 | 12.7 | 1.7 | 12.2 | 22.4 | 21.7 | 61.4 | 2432.0 | 84.2 | >10000 |
73 | 0.4 | 0.7 | 0.2 | 0.5 | 0.4 | 0.5 | 1.5 | 16.3 | 2.2 | 561.5 |
74 | 1.6 | 2.2 | 0.6 | 2.8 | 0.7 | 2.4 | 3.2 | 43.9 | 9.1 | 1608.0 |
75 | 8.7 | 15.2 | 6.6 | 15.2 | 34.0 | 33.2 | 68.9 | 313.2 | 143.0 | >10000 |
76 | 2.0 | 1.0 | 0.9 | 0.8 | 1.6 | 2.0 | 2.1 | 14.5 | 8.1 | >10000 |
77 | 2.1 | 1.7 | 1.1 | 1.4 | 2.2 | 2.3 | 4.1 | 13.0 | 4.0 | 1556.0 |
78 | 6.8 | 5.5 | 2.7 | 5.4 | 8.8 | 15.8 | 16.6 | 85.5 | 23.6 | >10000 |
79 | 0.8 | 0.5 | 0.3 | 0.5 | 0.4 | 0.6 | 0.7 | 4.7 | 1.4 | 450.1 |
80 | 3.8 | 6.2 | 2.8 | 6.3 | 2.5 | 8.4 | 2.3 | 11.1 | 11.4 | 4407.0 |
81 | 2.4 | 3.1 | 2.0 | 6.0 | 4.0 | 19.0 | 3.3 | 13.0 | 11.7 | 3652.0 |
82 | 6.5 | 10.5 | 2.8 | 15.4 | 7.9 | 13.3 | 7.8 | 73.3 | 29.6 | >10000 |
83 | 0.7 | 0.6 | 0.2 | 0.3 | 0.2 | 0.2 | 0.1 | 0.4 | 0.2 | 24.9 |
84 | 0.9 | 0.7 | 0.3 | 0.5 | 0.4 | 0.6 | 0.2 | 0.5 | 0.6 | 181.0 |
85 | 0.4 | 0.4 | 0.1 | 0.3 | 0.1 | 0.3 | 0.1 | 0.2 | 0.2 | 31.7 |
86 | 0.2 | 1.6 | 0.1 | 0.2 | 0.3 | 0.4 | 0.4 | 11.4 | 3.6 | 1478.0 |
87 | 0.1 | 5.9 | 0.1 | 0.1 | 0.4 | 0.5 | 0.6 | 4.7 | 2.2 | 991.7 |
88 | 0.4 | 4.9 | 0.1 | 0.4 | 1.5 | 2.2 | 2.1 | 31.1 | 15.3 | >10000 |
89 | 0.1 | 0.1 | 0.1 | 0.1 | 0.3 | 0.1 | 0.2 | 3.9 | 2.7 | 1641.0 |
90 | 0.6 | 0.4 | 0.3 | 0.4 | 0.4 | 0.9 | 0.4 | 15.1 | 0.4 | 406.0 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
91 | 0.5 | 1.3 | 0.9 | 1.1 | 0.9 | 2.8 | 0.8 | 9.7 | 2.5 | >10000 |
92 | 1.0 | 1.6 | 1.4 | 2.3 | 4.4 | 7.2 | 4.7 | 78.8 | 0.1 | 171.8 |
93 | 0.3 | 0.4 | 0.1 | 0.3 | 0.2 | 0.5 | 0.3 | 2.2 | 0.1 | 171.8 |
94 | 2.7 | 4.4 | 0.9 | 1.5 | 3.9 | 13.3 | 6.0 | 170.1 | 7.2 | >10000 |
95 | 2.5 | 5.6 | 0.9 | 2.0 | 66.9 | 1542.0 | 8479.0 | 9156.0 | 222.3 | >10000 |
96 | 1.5 | 2.0 | 0.7 | 0.8 | 68.0 | 224.2 | 27.4 | 2216.0 | 84.7 | >10000 |
97 | 2.1 | 2.2 | 0.5 | 1.0 | 2.3 | 6.0 | 2.0 | 52.6 | 7.4 | >10000 |
98 | 0.4 | 0.5 | 0.1 | 0.2 | 0.3 | 1.9 | 152.5 | |||
99 | 0.1 | 0.1 | 0.04 | 0.1 | 0.3 | 0.3 | 0.1 | 0.7 | 0.3 | 61.5 |
100 | 6.4 | 8.1 | 1.3 | 5.3 | 6.5 | 10.8 | 12.9 | 24.9 | 12.7 | 7220.0 |
101 | 1.7 | 0.9 | 0.4 | 0.7 | 2.1 | 2.4 | 2.1 | 14.4 | 2.2 | 574.5 |
102 | 2.8 | 1.5 | 0.7 | 1.0 | 4.6 | 9.1 | 8.2 | 29.9 | 21.3 | >10000 |
103 | 6.6 | 3.9 | 66.5 | 653.7 | >10000 | |||||
104 | 1.1 | 1.8 | 0.6 | 0.8 | 2.2 | 3.1 | 0.9 | 21.6 | 21.9 | >10000 |
105 | 2.1 | 3.2 | 1.5 | 1.2 | 3.0 | 3.9 | 0.6 | 5.4 | 5.3 | 787.1 |
106 | 6.2 | 8.6 | 2.6 | 4.1 | 11.7 | 11.2 | 4.1 | 9.6 | 37.8 | 3712.0 |
107 | 0.3 | 0.4 | 0.2 | 0.2 | 0.1 | 0.5 | 0.1 | 1.8 | 0.4 | 327.3 |
108 | 0.4 | 0.4 | 0.2 | 0.2 | 0.4 | 0.9 | 0.4 | 3.6 | 6.9 | 1859.0 |
109 | 2.0 | 1.5 | 0.6 | 0.5 | 0.8 | 6.4 | 0.1 | 11.1 | 5.2 | 1365.0 |
110 | 0.1 | 0.2 | 0.1 | 0.1 | 0.3 | 0.3 | 0.04 | 0.5 | 0.9 | 178.0 |
111 | 0.3 | 0.5 | 0.2 | 0.2 | 0.2 | 0.7 | 0.03 | 0.4 | 0.7 | 198.1 |
112 | 4.5 | 5.7 | 2.0 | 3.6 | 5.1 | 23.2 | 6.8 | 6.9 | 11.7 | >10000 |
113 | 7.5 | 5.3 | 2.3 | 3.2 | 11.0 | 19.9 | 8.8 | 20.8 | 15.0 | >10000 |
114 | 8.5 | 11.2 | 2.8 | 4.5 | 27.1 | 29.9 | 15.7 | 33.7 | 46.8 | 652.9 |
115 | 0.1 | 0.4 | 0.1 | 0.1 | 0.4 | 0.8 | 0.1 | 0.5 | 1.8 | >10000 |
116 | 0.1 | 0.1 | 0.04 | 0.04 | 0.1 | 0.1 | 0.1 | 0.3 | 0.4 | 384.0 |
117 | 0.2 | 0.4 | 0.1 | 0.1 | 0.3 | 0.5 | 0.2 | 0.5 | 1.9 | 6504.0 |
118 | 0.1 | 0.04 | 0.1 | 0.2 | 0.1 | 0.3 | 0.05 | 0.7 | 1.3 | 399.5 |
119 | 0.1 | 0.1 | 0.1 | 0.2 | 0.1 | 0.2 | 0.03 | 0.3 | 1.0 | 108.5 |
120 | 0.2 | 0.2 | 0.1 | 0.4 | 0.5 | 0.7 | 0.1 | 2.1 | 4.3 | 967.8 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
121 | 0.5 | 0.2 | 4.6 | 2.9 | 22.6 | |||||
122 | 0.3 | 0.1 | 9.7 | 4.3 | 7.4 | |||||
123 | 2.6 | 0.7 | 28.6 | 2.3 | 22.0 | |||||
124 | 0.3 | 0.4 | 3.3 | 0.4 | 12.7 | |||||
125 | 0.7 | 0.3 | 8.9 | 12.1 | 44.8 | |||||
126 | 2.7 | 1.2 | 12.1 | 12.6 | 45.7 | |||||
127 | 17.5 | 6.6 | >10000 | >10000 | >10000 | |||||
128 | 1.2 | 0.5 | 41.2 | 95.8 | >10000 | |||||
129 | 1.4 | 0.5 | 12.6 | 12.9 | 116.1 | |||||
130 | 3.9 | 1.7 | 281.5 | 239.0 | >10000 | |||||
131 | 0.2 | 0.1 | 2.1 | 2.2 | 8.1 | |||||
132 | 0.4 | 0.4 | 0.4 | 0.3 | 0.8 | |||||
133 | 0.5 | 0.3 | 1.7 | 1.4 | 9.3 | |||||
134 | 0.9 | 0.6 | 32.1 | 15.6 | 34.2 | |||||
135 | 0.3 | 0.2 | 2.9 | 0.6 | 10.8 | |||||
136 | 0.5 | 0.2 | 19.1 | 6.4 | 69.8 | |||||
137 | 1.1 | 0.2 | 74.4 | 6.4 | 271.9 | |||||
138 | 0.1 | 0.2 | 4.9 | 1.6 | 32.0 | |||||
139 | 0.3 | 0.3 | 19.4 | 5.0 | 208.2 | |||||
140 | 0.2 | 0.2 | 8.3 | 15.1 | 67.6 | |||||
141 | 0.03 | 0.1 | 1.2 | 0.8 | 12.4 | |||||
142 | 0.01 | 0.03 | 2.0 | 0.8 | 17.1 | |||||
143 | 0.1 | 0.2 | 1.0 | 1.1 | 7.9 | |||||
144 | 0.3 | 0.1 | 2.2 | 1.2 | 26.3 | |||||
145 | 0.1 | 0.03 | 0.3 | 0.1 | 1.2 | |||||
146 | 0.1 | 0.02 | 0.3 | 0.1 | 0.8 | |||||
147 | 0.3 | 0.1 | 0.4 | 0.1 | 2.3 | |||||
148 | 0.3 | 0.3 | 2.0 | 1.0 | 15.1 | |||||
149 | 0.4 | 0.3 | 1.0 | 0.4 | 11.2 | |||||
150 | 0.2 | 0.1 | 0.5 | 0.4 | 6.2 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
151 | 0.8 | 0.1 | 34.0 | 17.2 | 1908.0 | |||||
152 | 0.5 | 0.1 | 214.4 | 13.1 | >10000 | |||||
153 | 0.4 | 0.1 | 0.2 | 0.2 | 3.2 | |||||
154 | 0.2 | 0.1 | 0.3 | 0.2 | 2.7 | |||||
155 | 0.3 | 0.7 | 0.1 | 0.5 | 0.7 | 0.7 | 1.1 | 3.7 | 2.5 | 3278.0 |
156 | 0.1 | 0.2 | 0.1 | 0.2 | 0.3 | 0.3 | 0.4 | 2.6 | 1.3 | >10000 |
157 | 0.1 | 0.1 | 0.1 | 0.1 | 0.8 | 0.6 | 0.8 | 11.2 | 6.9 | 2927.0 |
158 | 0.3 | 0.4 | 0.4 | 2.4 | 541.3 | |||||
159 | 0.1 | 0.1 | 0.2 | 1.2 | 322.8 | |||||
160 | 0.5 | 0.8 | 0.2 | 0.7 | 0.5 | 1.3 | 3.0 | 15.0 | 5.1 | >10000 |
161 | 0.1 | 0.1 | 0.1 | 0.5 | 0.9 | 1.2 | 1.9 | 12.4 | 11.6 | >10000 |
162 | 0.5 | 1.3 | 0.4 | 3.0 | 13.1 | 21.0 | 19.9 | 1532.0 | 2966.0 | >10000 |
163 | 1.4 | 2.6 | 0.7 | 2.3 | 2.6 | 3.1 | 13.0 | 49.4 | 18.7 | >10000 |
164 | 0.8 | 0.4 | 0.3 | 0.4 | 0.5 | 1.1 | 0.6 | 1.8 | >10000 | |
165 | 3.5 | 1.2 | 1.0 | 1.7 | 1.8 | 7.6 | 1.6 | 18.5 | >10000 | |
166 | 1.9 | 5.1 | 0.6 | 1.2 | 2.4 | 1.1 | 2.4 | 2.0 | >10000 | |
167 | 2.7 | 3.5 | 45.8 | 52.2 | >10000 | |||||
168 | 0.4 | 0.3 | 0.2 | 0.2 | 0.2 | 0.4 | 0.2 | 0.5 | 92.2 | |
169 | 1.3 | 0.9 | 0.7 | 0.5 | 1.3 | 0.4 | 2.1 | 416.3 | ||
170 | 0.8 | 1.3 | 0.2 | 0.9 | 0.7 | 2.0 | 0.6 | 2.1 | 1.5 | 140.7 |
171 | 0.3 | 0.5 | 0.1 | 0.2 | 0.1 | 0.3 | 0.2 | 0.3 | 0.2 | 67.9 |
172 | 0.7 | 0.6 | 0.2 | 0.2 | 0.3 | 0.8 | 1.3 | 4.8 | 0.4 | 93.2 |
173 | 1.8 | 0.9 | 7.9 | 1.6 | 23.2 | |||||
174 | 2.5 | 1.1 | 7.7 | 1.8 | 23.4 | |||||
175 | 2.4 | 1.1 | 20.4 | 3.9 | 90.3 | |||||
176 | 0.2 | 0.4 | 5.5 | 1.5 | 43.4 | |||||
177 | 0.9 | 1.9 | 3.7 | 9.0 | 40.5 | |||||
178 | 0.7 | 1.0 | 2.6 | 4.7 | 96.5 | |||||
179 | 0.9 | 1.3 | 0.4 | 1.3 | 0.6 | 2.8 | 1.5 | 3.6 | 4.1 | >10000 |
180 | 5.8 | 8.5 | 2.5 | 9.1 | 6.0 | 30.7 | 12.0 | 67.7 | 47.5 | >10000 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
181 | 5.5 | 10.0 | 2.2 | 20.3 | 16.2 | 41.5 | 19.7 | 157.0 | 129.3 | >10000 |
182 | 2.9 | 6.4 | 1.1 | 1.5 | 3.7 | 0.9 | 3.5 | 4.5 | >10000 | |
183 | 2.7 | 10.0 | 1.0 | 1.6 | 3.4 | 0.6 | 3.0 | 3.1 | 678.0 | |
184 | 9.1 | 2.8 | 0.8 | 2.7 | 12.2 | 2.2 | 12.9 | 15.2 | >10000 | |
185 | 2.0 | 8.3 | 1.9 | 6.7 | 20.3 | 3.0 | 32.1 | 111.2 | >10000 | |
186 | 3.8 | 29.0 | 4.8 | 11.5 | 56.8 | 5.8 | 165.2 | 744.2 | >10000 | |
187 | 239.2 | 96.9 | 178.0 | 1952.0 | >10000 | |||||
188 | 1.1 | 1.0 | 2.3 | 1.8 | 0.8 | 11.3 | 9.5 | >10000 | ||
189 | 1.4 | 0.8 | 2.2 | 1.7 | 0.9 | 7.9 | 6.9 | 1774.0 | ||
190 | 3.3 | 4.0 | 0.7 | 3.0 | 6.8 | 20.3 | 3.1 | 31.1 | 32.0 | >10000 |
191 | 1.0 | 1.7 | 0.3 | 1.2 | 2.3 | 6.5 | 1.6 | 26.4 | 27.4 | >10000 |
192 | 0.6 | 0.5 | 2.0 | 7.8 | 6508.0 | |||||
193 | 3.0 | 3.8 | 23.5 | 186.8 | >10000 | |||||
194 | 2.5 | 3.4 | 0.6 | 2.2 | 5.5 | 16.9 | 3.9 | 43.7 | 36.7 | >10000 |
195 | 3.3 | 3.6 | 1.0 | 2.5 | 6.6 | 16.3 | 3.6 | 36.9 | 25.0 | >10000 |
196 | 14.7 | 9.5 | 134.8 | >10000 | >10000 | |||||
197 | 0.6 | 0.5 | 0.3 | 0.5 | 1.0 | 1.1 | 0.3 | 5.3 | 3.0 | 1237.0 |
198 | 0.5 | 0.8 | 0.2 | 0.4 | 0.7 | 2.9 | 0.8 | 2.9 | 3.7 | >10000 |
199 | 0.4 | 0.7 | 0.1 | 0.3 | 0.1 | 0.3 | 0.04 | 0.4 | 0.3 | 137.2 |
200 | 0.1 | 0.2 | 0.1 | 0.2 | 0.3 | 0.3 | 0.2 | 0.6 | 0.6 | 133.9 |
201 | 0.3 | 0.4 | 0.1 | 0.4 | 0.5 | 0.6 | 0.5 | 1.8 | 2.2 | 1039.0 |
202 | 0.2 | 0.3 | 0.1 | 0.1 | 0.1 | 0.2 | 0.03 | 0.3 | 0.2 | 94.2 |
203 | 0.4 | 0.7 | 0.2 | 0.3 | 0.1 | 0.3 | 0.1 | 0.8 | 0.3 | 394.6 |
204 | 0.1 | 0.1 | 0.1 | 0.1 | 0.2 | 0.2 | 0.1 | 1.0 | 0.4 | 124.1 |
205 | 0.3 | 0.7 | 0.2 | 0.2 | 0.7 | 0.6 | 0.4 | 3.5 | 2.0 | 1443.0 |
206 | 0.6 | 0.9 | 0.3 | 0.4 | 0.7 | 0.6 | 0.4 | 2.4 | 1.2 | 348.2 |
207 | 1.3 | 1.6 | 0.3 | 0.8 | 1.4 | 1.5 | 1.0 | 14.0 | 3.8 | 1793.0 |
208 | 0.1 | 0.2 | 0.1 | 0.2 | 0.2 | 0.3 | 0.1 | 0.6 | 0.3 | 242.5 |
209 | 0.1 | 0.2 | 0.1 | 0.2 | 0.1 | 0.3 | 0.1 | 0.6 | 0.2 | 99.2 |
210 | 0.3 | 0.4 | 0.2 | 0.3 | 0.3 | 0.5 | 0.1 | 1.8 | 0.6 | 425.9 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
211 | 0.3 | 0.5 | 0.1 | 0.4 | 1.2 | 2.4 | 0.5 | 30.1 | 6.9 | 9480.0 |
212 | 0.5 | 1.0 | 0.4 | 0.6 | 1.2 | 2.7 | 0.5 | 18.7 | 3.4 | 7861.0 |
213 | 1.2 | 1.5 | 0.8 | 1.3 | 3.8 | 7.7 | 1.4 | 85.4 | 0.6 | >10000 |
214 | 3.0 | 5.6 | 3.5 | 4.5 | 1.8 | 8.0 | 2.2 | 6.9 | 4.5 | 711.4 |
215 | 9.1 | 25.4 | 7.6 | 17.5 | 7.8 | 36.4 | 13.6 | 46.4 | 21.4 | 6108.0 |
216 | 1.2 | 1.2 | 0.8 | 0.7 | 0.8 | 1.3 | 0.3 | 1.4 | 0.8 | 136.0 |
217 | 0.8 | 0.7 | 0.3 | 0.3 | 0.2 | 0.3 | 0.2 | 0.4 | 0.8 | 118.2 |
218 | 2.1 | 0.6 | 0.7 | 1.8 | 3.3 | 7.1 | 3.6 | 59.4 | 10.3 | >10000 |
219 | 3.2 | 1.8 | 1.5 | 2.9 | 4.9 | 8.7 | 2.9 | 27.4 | 12.1 | 2672.0 |
220 | 8.5 | 2.3 | 5.4 | 9.3 | 27.8 | 30.5 | 25.9 | 289.0 | 115.0 | >10000 |
221 | 1.1 | 1.4 | 0.3 | 0.5 | 1.1 | 1.5 | 1.0 | 5.7 | 2.1 | 767.0 |
222 | 3.9 | 3.4 | 1.7 | 2.0 | 8.9 | 16.8 | 11.7 | 296.2 | 37.4 | >10000 |
223 | 6.4 | 3.5 | 2.4 | 5.0 | 10.2 | 14.6 | 4.4 | 115.8 | 11.5 | >10000 |
224 | 2.0 | 1.6 | 0.4 | 1.4 | 2.1 | 3.5 | 1.5 | 171.4 | 5.2 | >10000 |
225 | 6.9 | 6.0 | 2.5 | 4.4 | 16.1 | 19.8 | 10.2 | 799.0 | 33.8 | >10000 |
226 | 0.8 | 0.8 | 0.3 | 0.5 | 1.5 | 4.7 | 2.0 | 8.4 | 4.9 | 5122.0 |
227 | 0.9 | 1.5 | 0.4 | 0.8 | 1.9 | 7.0 | 2.5 | 10.0 | 5.2 | 834.8 |
228 | 1.9 | 2.9 | 0.5 | 1.0 | 5.6 | 14.3 | 12.2 | 64.9 | 19.3 | >10000 |
229 | 3.3 | 4.4 | 0.9 | 1.9 | 4.8 | 20.8 | 11.5 | 96.1 | 17.4 | 9479.0 |
230 | 1.1 | 1.3 | 0.4 | 0.6 | 1.7 | 6.0 | 2.4 | 7.8 | 5.0 | 1660.0 |
231 | 1.4 | 2.0 | 0.4 | 0.9 | 1.7 | 6.4 | 1.2 | 4.6 | 4.1 | 502.3 |
232 | 3.9 | 2.1 | 0.8 | 0.8 | 3.3 | 9.5 | 6.7 | 60.2 | 19.0 | 8760.0 |
233 | 4.7 | 6.3 | 0.9 | 2.7 | 7.1 | 19.2 | 4.7 | 36.0 | 18.3 | 6746.0 |
234 | 0.5 | 0.3 | 0.2 | 0.2 | 0.2 | 0.5 | 0.3 | 0.7 | 0.7 | 121.7 |
235 | 1.0 | 1.5 | 0.8 | 2.7 | 3.1 | 1.5 | 1.0 | 8.1 | 4.9 | 691.7 |
236 | 2.5 | 9.1 | 1.9 | 6.4 | 9.1 | 24.4 | 3.0 | 176.5 | 41.8 | >10000 |
237 | 0.2 | 0.3 | 0.2 | 0.6 | 0.2 | 0.7 | 0.3 | 1.1 | 0.9 | 216.2 |
238 | 28.4 | 9.2 | 95.1 | 18.7 | 317.4 | |||||
239 | 15.1 | 3.9 | 72.7 | 31.6 | 216.2 | |||||
240 | 19.8 | 5.9 | 134.3 | 15.4 | 733.2 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
241 | 2.3 | 4.4 | 1.8 | 6.9 | 6.3 | 12.9 | 2.9 | 22.0 | 20.3 | 2642.0 |
242 | 4.8 | 9.7 | 2.5 | 11.3 | 15.2 | 18.7 | 10.7 | 178.8 | 53.5 | >10000 |
243 | 0.4 | 0.8 | 0.4 | 1.3 | 1.9 | 2.4 | 0.2 | 5.3 | 4.2 | 2557.0 |
244 | 0.9 | 1.7 | 0.2 | 0.3 | 0.6 | 0.9 | 0.4 | 0.9 | 1.8 | 1422.0 |
245 | 1.2 | 2.6 | 0.3 | 0.4 | 1.1 | 2.3 | 0.9 | 3.0 | 3.1 | 2202.0 |
246 | 3.0 | 7.2 | 0.4 | 1.1 | 6.9 | 21.1 | 12.4 | 45.2 | 42.0 | >10000 |
247 | 14.7 | 2.6 | 80.6 | 51.1 | 110.9 | >10000 | ||||
248 | 0.4 | 0.4 | 0.1 | 0.3 | 2.0 | 5.0 | 1.8 | 9.7 | 4.6 | 7625.0 |
249 | 0.5 | 0.2 | 0.4 | 0.2 | 2.8 | |||||
250 | 0.4 | 0.2 | 0.4 | 0.4 | 0.3 | |||||
251 | 0.5 | 0.1 | 0.2 | 0.3 | 0.2 | |||||
252 | 0.3 | 0.2 | 0.6 | 0.4 | 1.3 | |||||
253 | 0.7 | 0.4 | 0.4 | 0.2 | 1.0 | |||||
254 | 0.04 | 0.02 | 0.1 | 0.4 | 0.7 | |||||
255 | 0.1 | 0.03 | 0.5 | 0.02 | 1.9 | |||||
256 | 0.1 | 0.1 | 3.8 | 0.6 | 61.6 | |||||
257 | 0.4 | 0.2 | 1.0 | 0.4 | 7.4 | |||||
258 | 0.2 | 0.1 | 0.7 | 0.1 | 14.1 | |||||
259 | 1.0 | 0.4 | 1.9 | 0.2 | 9.0 | |||||
260 | 6.9 | 4.1 | 10.7 | 8.8 | 7.8 | |||||
261 | 9.6 | 4.1 | 10.3 | 7.5 | 9.2 | |||||
262 | 1.9 | 0.5 | 1.9 | 0.9 | 2.0 | |||||
263 | 8.0 | 3.4 | 23.1 | 0.9 | 14.1 | |||||
264 | 1.1 | 0.3 | 1.2 | 1.6 | 17.7 | |||||
265 | 31.0 | 22.0 | 16.9 | 85.3 | 364.5 | |||||
266 | 33.0 | 18.6 | 12.5 | 39.6 | 168.2 | |||||
267 | 15.4 | 21.7 | 82.1 | 356.8 | 2915.0 | |||||
268 | 28.9 | 22.4 | 761.8 | 1217.0 | 4769.0 | |||||
269 | 0.1 | 0.1 | 0.4 | 0.1 | 2.6 | |||||
270 | 0.3 | 0.1 | 3.2 | 1.1 | 36.0 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
271 | 0.5 | 0.6 | 0.2 | 0.4 | 0.9 | 0.7 | 0.6 | 7.9 | 3.8 | >10000 |
272 | 0.3 | 0.5 | 0.1 | 0.3 | 0.6 | 0.7 | 1.0 | 2.5 | 1.4 | 494.9 |
273 | 0.2 | 0.3 | 1.0 | 8.6 | 2230.0 | |||||
274 | 0.02 | 0.1 | 0.03 | 0.1 | 0.1 | 0.1 | 0.1 | 0.4 | 0.5 | 108.5 |
275 | 0.9 | 1.1 | 0.7 | 1.2 | 2.5 | 2.6 | 4.1 | 11.4 | 18.5 | >10000 |
276 | 0.8 | 1.1 | 0.2 | 0.5 | 0.3 | 0.7 | 0.7 | 2.3 | 2.9 | 2527.0 |
277 | 4.4 | 4.7 | 1.6 | 3.3 | 0.9 | 3.9 | 2.2 | 11.2 | 9.8 | >10000 |
278 | 0.6 | 0.9 | 0.2 | 0.3 | 0.2 | 0.7 | 0.5 | 0.4 | 1.0 | 769.6 |
279 | 2.0 | 2.9 | 0.6 | 1.2 | 1.7 | 5.0 | 0.9 | 6.6 | 11.9 | >10000 |
280 | 1.0 | 0.5 | 2.7 | 20.3 | >10000 | |||||
281 | 0.2 | 0.2 | 0.6 | 2.1 | 6337.0 | |||||
282 | 0.2 | 0.4 | 1.4 | 7.0 | 3973.0 | |||||
283 | 0.1 | 0.4 | 0.6 | 2.3 | 1971.0 | |||||
284 | 0.1 | 0.2 | 0.2 | 0.4 | 176.0 | |||||
285 | 0.1 | 0.2 | 0.2 | 0.4 | 0.9 | 0.5 | 14.1 | 7.8 | 6307.0 | |
286 | 0.2 | 0.3 | 0.1 | 0.3 | 0.3 | 0.3 | 0.1 | 2.5 | 1.5 | 734.9 |
287 | 0.2 | 0.3 | 0.1 | 0.1 | 0.4 | 1.0 | 0.8 | 44.0 | 3.0 | 5138.0 |
288 | 0.2 | 0.3 | 0.1 | 0.2 | 0.2 | 0.5 | 0.3 | 6.8 | 0.7 | 1995.0 |
289 | 0.2 | 0.2 | 0.1 | 0.1 | 0.1 | 0.2 | 0.1 | 0.8 | 0.3 | 205.8 |
290 | 0.4 | 0.4 | 0.1 | 0.2 | 0.2 | 0.3 | 0.1 | 0.6 | 0.5 | 117.7 |
291 | 0.5 | 1.5 | 0.5 | 1.0 | 1.1 | 4.9 | 2.3 | 2.8 | 3.7 | >10000 |
292 | 0.6 | 2.6 | 0.6 | 1.1 | 1.4 | 9.8 | 4.4 | 19.1 | 8.9 | 5169.0 |
293 | 0.7 | 3.4 | 0.7 | 1.3 | 9.6 | 16.2 | 15.4 | 63.0 | 137.5 | 1544.0 |
294 | 9.8 | 2.3 | 60.8 | 38.5 | 28.0 | |||||
295 | 10.4 | 1.5 | 49.2 | 26.5 | 44.7 | |||||
296 | 4.5 | 3.7 | 17.6 | 10.1 | 89.8 | |||||
297 | 1.6 | 1.4 | 4.0 | 3.0 | 39.9 | |||||
298 | 1.8 | 1.1 | 2.9 | 1.7 | 15.4 | |||||
299 | 5.7 | 3.2 | 28.6 | 8.5 | 245.1 | |||||
300 | 0.3 | 0.1 | 0.4 | 0.2 | 1.5 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
301 | 0.3 | 0.1 | 0.8 | 0.3 | 1.1 | |||||
302 | 0.04 | 0.04 | 0.9 | 0.2 | 4.7 | |||||
303 | 0.5 | 0.2 | 0.4 | 0.2 | 5.5 | |||||
304 | 0.4 | 0.2 | 1.4 | 0.3 | 10.9 | |||||
305 | 0.1 | 0.1 | 1.2 | 0.8 | 11.2 | |||||
306 | 0.2 | 0.1 | 0.5 | 0.4 | 14.5 | |||||
307 | 0.02 | 0.04 | 0.7 | 0.6 | 8.1 | |||||
308 | 0.01 | 0.02 | 0.8 | 0.1 | 3.0 | |||||
309 | 0.4 | 0.4 | 1.9 | 1.4 | 45.3 | |||||
310 | 0.7 | 0.4 | 7.5 | 5.5 | 22.1 | |||||
311 | 2.5 | 1.6 | 37.6 | 3.6 | 541.1 | |||||
312 | 2.1 | 1.4 | 13.7 | 14.3 | 53.3 | |||||
313 | 2.7 | 2.1 | 21.3 | 4.8 | 187.2 | |||||
314 | 19.2 | 33.4 | 600.0 | 970.4 | 6551.0 | |||||
315 | 0.3 | 0.1 | 7.0 | 2.7 | 165.6 | |||||
316 | 0.1 | 0.1 | 1.7 | 0.7 | 15.8 | |||||
317 | 0.5 | 0.2 | 0.9 | 0.4 | 12.4 | |||||
318 | 1.9 | 1.2 | 12.6 | 7.8 | 14.3 | |||||
319 | 0.3 | 0.1 | 23.1 | 7.3 | 41.3 | |||||
320 | 3.6 | 1.0 | 306.5 | 28.3 | 526.2 | |||||
321 | 7.4 | 0.7 | 1025.0 | 53.1 | 470.4 | |||||
322 | 0.8 | 0.4 | 0.7 | 0.3 | 0.9 | |||||
323 | 2.4 | 0.9 | 3.4 | 2.1 | 19.1 | |||||
324 | 5.6 | 1.2 | 8.5 | 6.6 | 166.7 | |||||
325 | 2.4 | 1.0 | 1.7 | 0.7 | 9.6 | |||||
326 | 0.1 | 0.1 | 7.5 | 9.6 | 58.5 | |||||
327 | 0.1 | 0.0 | 10.9 | 10.9 | 88.3 | |||||
328 | 3.0 | 1.8 | 98.0 | 98.8 | 178.0 | |||||
329 | 2.0 | 1.9 | 17.7 | 15.0 | 93.7 | |||||
330 | 1.4 | 1.3 | 71.1 | 94.5 | 128.5 |
範例 編號 | del19/T790M/C797S (nM) | L858R/T790M/C797S (nM) | del19/C797S (nM) | L858R/C797S (nM) | WT (nM) | |||||
Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | Km ATP | 100µM ATP | |
331 | 1.9 | 0.7 | 3.5 | 2.4 | 17.4 | |||||
332 | 1.6 | 0.7 | 2.4 | 1.8 | 21.0 | |||||
333 | 4.1 | 2.6 | 460.1 | 795.2 | 116.7 | |||||
334 | 2.1 | 1.4 | 169.7 | 191.4 | 188.8 | |||||
335 | 5.8 | 2.6 | 1838.0 | 1784.0 | 248.1 | |||||
336 | 344.7 | 43.9 | 3818.0 | 1675.0 | 235.5 |
Claims (38)
- 一種式(I)所示之化合物或其藥學上可接受之鹽, , 其中, X 1及X 2各自獨立為-CH=或-N=,附帶條件為X 1與X 2不可同時為-N=, X 3及X 4各自獨立為-CH=或-N=,附帶條件為X 3與X 4不可同時為-CH=, R 1為-A-(R 1A) m, A為六至十員雜芳基, R 1A為獨立選自包含下列項目之群組: H; OH; 鹵素; 氰基; 隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、鹵素、C 1-3烷氧基、C 3-6環烷基、-NHC 1-6烷基、-N(C 1-6烷基) 2、及隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C 1-6烷基; C 3-6環烷基; 隨選由選自下列群組中之一或多個取代基所取代之C 1-3烷氧基:OH、鹵素、-N(C 1-6烷基) 2、及隨選或獨立由選自下列群組中之一或多個取代基所取代之三至七員雜環基:鹵素及C 1-6烷基; 隨選由選自下列群組中之一或多個取代基所取代之-NHC 1-6烷基:OH、鹵素、-N(C 1-6烷基) 2、及隨選由選自下列群組中之一或多個取代基所取代之三至七員雜環基:OH、鹵素及C 1-6烷基; 隨選由選自下列群組中之一或多個取代基所取代之-NHC 3-6環烷基:OH、鹵素、及隨選由OH所取代之C 1-6烷基; 隨選由選自下列群組中之一或多個取代基所取代之-NH 三至七員雜環基:OH、鹵素、及C 1-6烷基; 隨選由選自下列群組中之一或多個取代基所取代之-N(C 1-6烷基) 2:OH及鹵素; 隨選由選自下列群組中之一或多個取代基所取代之-NHC(O)C 1-6烷基:OH及鹵素; 隨選由選自下列群組中之一或多個取代基所取代之-NHC(O)C 3-6環烷基:OH及鹵素; 隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至七員雜環基:C 1-6烷基及C 1-6鹵烷基; 隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素、C 1-6烷基、C 1-3烷氧基、C 1-6羥烷基、及C 1-6鹵烷基; 隨選由一或多個鹵素所取代之-S(O) 2C 1-6烷基; 隨選由一或多個鹵素所取代之-S(O) 2C 3-6環烷基; 隨選由一或多個鹵素所取代之-S(O) 2N(C 1-6烷基) 2; 隨選由選自下列群組中之一或多個取代基所取代之-S(O) 2-三至七員雜環基:OH、鹵素、及C 1-6烷基; -C(O)OC 1-6烷基; -C(O)C 1-6烷基;及 隨選由選自下列群組中之一或多個取代基所取代之-C(O)-三至七員雜環基:OH、鹵素、及C 1-6烷基, m為一0至2之整數, R 2為隨選由選自下列群組中之一或多個取代基所取代之-XC 1-6烷基:OH、鹵素、及-N(C 1-6烷基) 2;或-X(CH 2) n-B-(R 2A) o, X為-NH-、-O-、鍵或-C≡C-, n為一0至2之整數, o為一0至3之整數, B為選自包含下列項目之群組:C 3-8環烷基、C 6-10芳基;四至十一員雜環基;及五至六員雜芳基, R 2A為獨立選自包含下列項目之群組: H; OH; 鹵素; NH 2; 隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、NH 2、鹵素、C 3-6環烷基、C 1-3烷氧基、-NHC 1-6烷基、-NHC 1-6羥烷基、-NHC 1-6鹵烷基、-NHC 3-6環烷基、-N(C 1-6烷基) 2、-N(C 1-6鹵烷基) 2、-NHC(O)C 1-6烷基、-C(O)NHC 1-6烷基、-C(O)N(C 1-6烷基) 2、三至七員雜環基、及五至六員雜芳基; C 3-6環烷基; 隨選由一或多個鹵素所取代之C 1-3烷氧基; 隨選由選自下列群組中之一或多個取代基所取代之-C(O)NHC 1-6烷基:OH及鹵素; 隨選由選自下列群組中之一或多個取代基所取代之-C(O)N(C 1-6烷基) 2:OH及鹵素; 隨選由選自下列群組中之一或多個取代基所取代之-NHC 1-6烷基:OH、鹵素、-NHC 1-6烷基、-N(C 1-6烷基) 2、及隨選由鹵素或-N(C 1-6烷基) 2所取代之三至七員雜環基; -N(C 1-6烷基) 2,其中C 1-6烷基係隨選由一或多個鹵素所取代; 隨選由C 1-6烷基所取代之-NH-四至七員雜環基;及 四至七員雜環基, R 3為Y-Q-(R 3A) p, Y為-NH-或鍵, Q為選自包含下列項目之群組:乙炔;四至七員雜環基;C 6-10芳基;及五至十員雜芳基, p為一0至2之整數, R 3A為獨立選自包含下列項目之群組: H; OH; 鹵素; C 1-3烷氧基; 隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、鹵素、C 3-6環烷基、S(O) 2C 1-6烷基、及C 1-3烷氧基; C 2-6烯基; C 3-6環烷基; 四至七員雜環基; -C(O)C 1-6烷基; -C(O)N(C 1-6烷基) 2; 隨選由一或多個鹵素所取代之-S(O) 2C 1-6烷基; -S(O) 2C 2-6烯基; 隨選由一或多個鹵素所取代之-S(O) 2C 3-6環烷基; -S(O) 2N(C1 -6烷基) 2;及 隨選由選自下列群組中之一或多個取代基所取代之-S(O) 2-四至七員雜環基:OH及鹵素,且 R 4為選自包含下列項目之群組:H、鹵素、及C 1-6烷基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,X 1及X 2為-CH=。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,X 3及X 4為-N=。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,A為吡啶基、嘧啶基、噠嗪基、或吡嗪基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 1A為H;OH;F;Cl;氰基;隨選由選自下列群組之一至三個取代基所取代之C 1-4烷基:OH、F、Cl、C 1-3烷氧基、C 3-6環烷基、-NHC 1-4烷基、-N(C 1-4烷基) 2、及隨選由選自下列群組之一至三個取代基所取代之四至六員雜環基:OH、F、Cl及C 1-3烷基;C 3-6環烷基;隨選由一至三個F或Cl所取代之C 1-2烷氧基;隨選由選自下列群組之一至三個取代基所取代之-NHC 1-4烷基:OH、F、Cl、-N(C 1-6烷基) 2、及隨選由選自下列群組之一至三個取代基所取代之三至七員雜環基:OH、F、Cl、及C 1-6烷基;隨選由選自下列群組之一至三個取代基所取代之-NHC 3-6環烷基:OH、F、Cl、及隨選由OH所取代之C 1-6烷基;隨選由選自下列群組之一至三個取代基所取代之-NH 三至七員雜環基:C 1-6烷基;隨選由選自下列群組之一至三個取代基所取代之-N(C 1-6烷基) 2:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-NHC(O)C 1-6烷基:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-NHC(O)C 3-6環烷基:OH、F及Cl;隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至六員雜環基:C 1-6烷基、C 1-6鹵烷基;隨選或獨立由選自下列群組之一至三個取代基所取代之四至六員雜環基:OH、F、Cl、C 1-6烷基、C 1-3烷氧基、C 1-6羥烷基、及C 1-6鹵烷基;-S(O) 2C 1-6烷基;-S(O) 2N(C 1-6烷基) 2; 隨選由選自下列群組之一至三個取代基所取代之-S(O) 2-三至七員雜環基:C 1-6烷基;-C(O)OC 1-6烷基;-C(O)C 1-6烷基;或隨選由一至三個C 1-6烷基取代之-C(O)-三至七員雜環基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 1A為隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、鹵素、C 1-3烷氧基、C 3-6環烷基、-NHC 1-6烷基、-N(C 1-6烷基) 2、及隨選由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C 1-6烷基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 1A為獨立選自包含下列項目之群組: H; OH; 鹵素; 氰基; 隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、鹵素、C 1-3烷氧基、-N(C 1-6烷基) 2、及隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素及C 1-6烷基; 隨選由選自下列群組中之一或多個取代基所取代之C 1-3烷氧基:OH、鹵素、-N(C 1-6烷基) 2、及隨選或獨立由選自下列群組中之一或多個取代基所取代之三至七員雜環基:鹵素及C 1-6烷基; 隨選由選自下列群組中之一或多個取代基所取代之-NHC 1-6烷基:OH、鹵素、-N(C 1-6烷基) 2、及隨選由一或多個鹵素所取代之三至七員雜環基; 隨選由選自下列群組中之一或多個取代基所取代之-NHC 3-6環烷基:OH、鹵素、及隨選由OH所取代之C 1-6烷基; 隨選由一或多個C 1-6烷基所取代之-NH 三至七員雜環基; -N(C 1-6烷基) 2; 隨選或獨立由選自下列群組中之一或多個取代基所取代之-O-四至七員雜環基:C 1-6烷基及C 1-6鹵烷基; 隨選或獨立由選自下列群組中之一或多個取代基所取代之四至七員雜環基:OH、鹵素、C 1-6烷基、及C 1-3烷氧基; -S(O) 2C 1-6烷基; -S(O) 2N(C 1-6烷基) 2; 隨選由一或多個C 1-6烷基所取代之-S(O) 2-三至七員雜環基; -C(O)C 1-6烷基;及 隨選由一或多個C 1-6烷基所取代之-C(O)-三至七員雜環基。
- 如請求項7所述之化合物或其藥學上可接受之鹽,其中,該三至七員雜環基或四至七員雜環基係獨立選自包含下列項目之群組:吖丁啶基、哌啶基、哌嗪基、嗎啉基、四氫哌喃基、四氫呋喃基、氧雜環丁烷基、2-氧雜-6-氮螺[3.3]庚烷基、及吡咯啶基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 2為-XC 1-6烷基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 2為-X(CH 2) n-B-(R 2A) o。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,X為-NH-或鍵。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,B為C 3-6環烷基;苯基;具有一至三個選自包含N、O及S之群組之雜原子之四至十員雜環烷基;或具有一至三個選自包含N、O及S之群組之雜原子之五至六員雜芳基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,B為C 3-6環烷基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,B為具有一至三個選自包含N及O之群組之雜原子之四至十員雜環烷基或五至六員雜芳基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,B為C 3-8環烷基、哌啶基、或氧雜環丁烷基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 2A為H;F;Cl;OH;NH 2;隨選由選自下列群組中之一或多個取代基所取代之C 1-4烷基:OH、NH 2、F、Cl、C 3-6環烷基、C 1-3烷氧基、-NHC 1-3烷基、-NHC 1-3羥烷基、-NHC 1-3鹵烷基、-NHC 3-6環烷基、-N(C 1-3烷基) 2、-N(C 1-3鹵烷基) 2、-NHC(O)C 1-3烷基、-C(O)NHC 1-3烷基、-C(O)N(C 1-6烷基) 2、三至七員雜環基、及具有一至三個選自包含N、O及S之群組之雜原子之五至六員雜芳基;C 3-6環烷基;隨選由一至三個F或Cl所取代之C 1-3烷氧基;隨選由選自下列群組之一至三個取代基所取代之-C(O)NHC 1-3烷基:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-C(O)N(C 1-3烷基) 2:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-NHC 1-3烷基:OH、F、Cl、-NHC 1-3烷基、-N(C 1-3烷基) 2、及具有一至三個選自包含N、O及S之群組之雜原子且隨選由F、Cl或-N(C 1-3烷基) 2所取代之三至六員雜環基;-N(C 1-3烷基) 2,其中C 1-3烷基係隨選由一至三個F或Cl所取代;具有一至三個選自包含N、O及S之群組之雜原子且隨選由C 1-3烷基所取代之-NH-四至六員雜環基;或四至七員雜環基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 2A為OH;鹵素;隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、NH 2、鹵素、C 3-6環烷基、C 1-3烷氧基、-NHC 1-6烷基、-NHC 1-6羥烷基、-NHC 1-6鹵烷基、-NHC 3-6環烷基、-N(C 1-6烷基) 2、-N(C 1-6鹵烷基) 2、-NHC(O)C 1-6烷基、-C(O)NHC 1-6烷基、-C(O)N(C 1-6烷基) 2、三至七員雜環基、及具有一至三個選自包含N、O及S之群組之雜原子之五至六員雜芳基;隨選由選自下列群組之一至三個取代基所取代之-C(O)NHC 1-3烷基:OH、F及Cl;隨選由選自下列群組之一至三個取代基所取代之-C(O)N(C 1-3烷基) 2:OH、F及Cl;或隨選由選自下列群組之一至三個取代基所取代之-NHC 1-3烷基:OH、鹵素、-NHC 1-3烷基、-N(C 1-3烷基) 2、及具有一至三個選自包含N、O及S之群組之雜原子且隨選由鹵素或-N(C 1-3烷基) 2所取代之三至七員雜環基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 2A為獨立選自包含下列項目之群組: OH; 鹵素; 隨選由選自下列群組中之一或多個取代基所取代之C 1-6烷基:OH、鹵素、及-N(C 1-6烷基) 2; -C(O)N(C 1-6烷基) 2;及 隨選由一或多個鹵素所取代之-NHC 1-6烷基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,Y為鍵。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,Q為吡唑基、3,4-二氫哌喃并[2,3-b]吡啶基、或哌啶基。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 3A為獨立選自包含下列項目之群組: H; OH; 鹵素; C 1-3烷氧基; 隨選由一或多個鹵素所取代之C 1-6烷基; -S(O) 2C 3-6環烷基;及 -S(O) 2N(C1 -6烷基) 2。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,R 4為H或鹵素。
- 如請求項1所述之化合物或其藥學上可接受之鹽,其中,所述化合物為選自下列任一化合物: (1) (1-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)-4-甲基哌啶-4-基)甲醇; (2) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((2-氟乙基)胺基)環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺; (3) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (4) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (5) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (6) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (7) 6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-甲腈; (8) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (9) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (10) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (11) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇; (12) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (13) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-氟-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (14) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (15) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (16) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (17) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (18) 1-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-6-基)乙-1-酮; (19) (1 s,4 s) -4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-4-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (20) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (21) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((2-氟乙基)胺基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇; (22) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲醇; (23) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (24) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (25) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (26) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (27) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(羥甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (28) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (29) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (30) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (31) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (32) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (33) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (34) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-異丙基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (35) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (36) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺; (37) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-(羥甲基)環己-1-醇; (38) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (39) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (40) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (41) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-(二甲胺基)嘧啶-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (42) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (43) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-嗎啉基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (44) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-嗎啉基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (45) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (46) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4-甲基哌嗪-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (47) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (48) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (49) 1-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)哌啶-4-醇; (50) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5,6-二甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (51) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(三氟甲基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (52) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (53) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-甲氧基噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (54) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (55) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (56) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (57) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-嗎啉基-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (58) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (59) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-甲基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (60) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(羥甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (61) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(嗎啉甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (62) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-甲基哌嗪-1-基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (63) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (64) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((二甲胺基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (65) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((二甲胺基)甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (66) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(3,3-二氟吖丁啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (67) (1 s,4 s)-4-((5-(6-(2-氧雜-6-氮螺[3.3]庚烷-6-基)噠嗪-3-基)-2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (68) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (69) ((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)甲醇; (70) ((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇; (71) 2-((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-4-基)胺基)環己基)丙-2-醇; (72) 2-((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇; (73) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)- N 4-((1 s,4 s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺; (74) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)- N 4-((1 s,4 s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺; (75) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(4,4-二氟哌啶-1-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (76) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (77) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (78) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (79) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-4-(二氟甲基)- N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺; (80) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (81) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (82) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(吡咯啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (83) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (84) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (85) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(4-甲基哌嗪-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (86) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-(2-羥基丙-2-基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (87) 2-(6-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-(羥甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇; (88) 2-(6-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇; (89) 2-(6-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)吡啶-3-基)噠嗪-3-基)丙-2-醇; (90) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (91) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (92) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (93) N 6'-(2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1s,4s)-4-((二甲胺基)甲基)環己基)-5-(3-甲氧基吖丁啶-1-基)-[2,3'-聯吡啶]-4',6'-二胺; (94) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (95) 2-((1 r,4 r)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (96) 2-((1 r,4 r)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (97) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (98) 1-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇; (99) 1-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)甲基)哌啶-4-醇; (100) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (101) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-4-(4,4-二氟哌啶-1-基)- N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺; (102) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (103) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(4,4-二氟哌啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (104) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (105) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇; (106) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇; (107) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)-5-氟-[2,3'-聯吡啶]-4-基)丙-2-醇; (108) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (109) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇; (110) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇; (111) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-4-基)丙-2-醇; (112) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (113) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (114) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((4,4-二氟哌啶-1-基)甲基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (115) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (116) ((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇; (117) 2-((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇; (118) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(2-羥基丙-2-基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (119) 2-(5-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-(羥甲基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇; (120) 2-(5-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇; (121) 2-(5-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(異丙基胺基)吡啶-3-基)吡嗪-2-基)丙-2-醇; (122) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(5-(2-(二甲胺基)乙氧基)吡嗪-2-基)- N 4-異丙基吡啶-2,4-二胺; (123) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺; (124) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-異丙基-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺; (125) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-異丙基-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺; (126) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺; (127) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)- N 4-異丙基吡啶-2,4-二胺; (128) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (129) ((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇; (130) 2-((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(二氟甲氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇; (131) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(5-(二氟甲氧基)吡嗪-2-基)- N 4-((1 s,4 s)-4-((二甲胺基)甲基)環己基)吡啶-2,4-二胺; (132) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (133) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (134) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(三氟甲基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (135) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-((4-甲基哌嗪-1-基)甲基)-[2,3'-聯吡啶]-4',6'-二胺; (136) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-(嗎啉甲基)-[2,3'-聯吡啶]-4',6'-二胺; (137) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-((1 s,4 s)-4-氟環己基)-5-嗎啉基-[2,3'-聯吡啶]-4',6'-二胺; (138) N 4'-(3,3-二氟環戊基)- N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (139) N 4'-(3,3-二氟環丁基)- N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (140) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-(3,3-二氟環丁基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (141) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-(3-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (142) (1 s,4 s)-4-((6'-((2-(3,4-二氫-2 H-哌喃并[2,3-b]吡啶-6-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (143) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4'-(3,3-二氟環戊基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (144) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4-((1 s,4 s)-4-氟環己基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺; (145) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (146) ((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)甲醇; (147) 2-((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-甲基哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇; (148) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫-2 H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (149) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (150) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-(氧雜環丁-3-基氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (151) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4-((1 s,4 s)-4-氟環己基)-5-(5-((四氫-2 H-哌喃-4-基)氧基)吡嗪-2-基)吡啶-2,4-二胺; (152) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)- N 4-((1 s,4 s)-4-氟環己基)-5-(5-((四氫呋喃-3-基)氧基)吡嗪-2-基)吡啶-2,4-二胺; (153) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((1-(2-氟乙基)哌啶-4-基)氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (154) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-((4-氟-1-甲基哌啶-4-基)甲氧基)吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (155) 6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-醇; (156) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (157) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((2-氟乙基)胺基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺; (158) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (159) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4',6'-二胺; (160) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (161) (3-(((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)甲基)氧雜環丁-3-基)甲醇; (162) (4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇; (163) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (164) 6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基) -N, N-二甲基-[2,3'-聯吡啶]-5-磺胺; (165) 6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基) -N, N-二甲基-[2,3'-聯吡啶]-5-磺胺; (166) 6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基) -N, N-二甲基-[2,3'-聯吡啶]-5-磺胺; (167) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二甲胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (168) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (169) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (170) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (171) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (172) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基) -N, N-二甲基環己烷-1-碳醯胺; (173) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (174) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (175) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4,4-二氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (176) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (177) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2-氟乙基)哌啶-3-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (178) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((1-(2,2-二氟乙基)哌啶-4-基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (179) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (180) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-甲基-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (181) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-5-(三氟甲基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (182) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (183) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (184) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(嗎啉基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (185) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (186) 2-((1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(5-氟吡嗪-2-基)吡啶-4-基)胺基)環己基)丙-2-醇; (187) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌啶-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (188) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (189) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (190) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((4-甲基哌嗪-1-基)磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (191) (1 s,4 s)-4-((4-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)-1-甲基環己-1-醇; (192) ((1 s,4 s)-4-((4-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-(羥甲基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)甲醇; (193) 2-((1 s,4 s)-4-((4-(6-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)吡啶-3-基)嘧啶-2-基)胺基)環己基)丙-2-醇; (194) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (195) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (196) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (197) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-5-(三氟甲氧基)-[2,3'-聯吡啶]-4',6'-二胺; (198) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(甲基磺醯基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (199) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮; (200) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮; (201) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮; (202) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮; (203) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮; (204) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)(4-甲基哌嗪-1-基)甲酮; (205) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (206) 2-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)氧基)乙-1-醇; (207) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-羥基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (208) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (209) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (210) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (211) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (212) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (213) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-嗎啉基乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (214) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (215) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (216) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4-(3,3-二氟環丁基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4,4',6'-三胺; (217) 2-((1 s,4 s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (218) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (219) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (220) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (221) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺; (222) ((1 S,3 S)-3-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (223) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (224) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (225) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (226) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (227) 1-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇; (228) 1-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 S,3 S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇; (229) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (230) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (231) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (232) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 S,3 S)-3-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (233) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(2-羥基丙-2-基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (234) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (235) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (236) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (237) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺; (238) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺; (239) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(4-氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺; (240) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(4,4-二氟環己基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4',6'-二胺; (241) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (242) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (243) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(1,1-二氟乙基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-[2,3'-聯吡啶]-4',6'-二胺; (244) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-(羥甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇; (245) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-((二甲胺基)甲基)環己基)胺基)-[2,3'-聯吡啶]-5-基)-2,2-二氟乙-1-醇; (246) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (247) 2-((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)丙-2-醇; (248) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4',6'-二胺; (249) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-異丙基-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (250) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (251) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (252) 2-((1 r,4 r)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (253) ((1 S,3 S)-3-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (254) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (255) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(4,4-二氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (256) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(1-(2-氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (257) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(1-(2-氟乙基)哌啶-3-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (258) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(1-(2,2-二氟乙基)哌啶-4-基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (259) (4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-氟環己基)甲醇; (260) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (261) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (262) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-5-(2,2,2-三氟-1-甲氧基乙基)-[2,3'-聯吡啶]-4',6'-二胺; (263) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3,3,3-三氟丙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (264) 5-(2-(吖丁啶-1-基)乙氧基) -N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-氟環己基)-[2,3'-聯吡啶]-4',6'-二胺; (265) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (266) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-((4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (267) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基) -N 4-(4-氟環己基)吡啶-2,4-二胺; (268) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4-(4,4-二氟環己基)-5-(6-(4,4-二氟哌啶-1-基)噠嗪-3-基)吡啶-2,4-二胺; (269) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (270) N 2-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4-((1 s,4 s)-4-氟環己基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-2,4-二胺; (271) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (272) ((1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (273) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)-6-氟 -N 4'-((1 s,4 s)-4-((2-氟乙基)胺基)環己基)-[2,3'-聯吡啶]-4',6'-二胺; (274) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((二甲胺基)甲基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺; (275) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-((2,2-二氟乙基)胺基)環己基)-6-氟-[2,3'-聯吡啶]-4',6'-二胺; (276) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(二甲胺基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (277) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3,3-三氟丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (278) (1 s,4 s)-4-((6'-((2-(1-(Cylo丙基磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((1-甲基哌啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (279) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4((2-嗎啉基乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (280) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3,3-二氟環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (281) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((2-(3-氟吖丁啶-1-基)乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (282) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基丙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (283) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-((3-羥基環丁基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (284) (6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-5-基)(嗎啉基)甲酮; (285) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-((2-羥乙基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (286) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (287) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(2-(二甲胺基)乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (288) 1-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-[2,3'-聯吡啶]-4-基)甲基)吖丁啶-3-醇; (289) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基吖丁啶-3-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (290) (1 s,4 s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (291) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(2-氟丙-2-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (292) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(1,1-二氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (293) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (294) 1-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-2,2,2-三氟乙-1-醇; (295) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-4'-(異丙基胺基)-[2,3'-聯吡啶]-5-基)-1,1,1-三氟丙-2-醇; (296) 4-(4-((4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基) -N, N-二甲基 -1 H-吡唑-1-磺胺; (297) 4-(4-((4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-5-(2,2,2-三氟-1-羥乙基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基) -N, N-二甲基 -1 H-吡唑-1-磺胺; (298) 4-(4-((4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-5-(1,1,1-三氟-2-羥基丙-2-基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基) -N, N-二甲基 -1 H-吡唑-1-磺胺; (299) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-(2,2,2-三氟乙基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (300) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (301) 4-(4-((4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)- N, N-二甲基-1 H-吡唑-1-磺胺; (302) (1 s,4 s)-4-((6'-((2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (303) (1 s,4 s)-1-M乙基-4-((6'-((2-(3-甲基-1-(2,2,2-三氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇; (304) (1 s,4 s)-1-M乙基-4-((5-((1-甲基哌啶-4-基)氧基)-6'-((2-(1-(2,2,2-三氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)環己-1-醇; (305) 2-((1 r,4 r)-4-((6'-((2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)乙-1-醇; (306) ((1 S,3 S)-3-((6'-((2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)環己基)甲醇; (307) N 4'-((1 s,4 s)-4-氟環己基)-5-((1-甲基哌啶-4-基)氧基) -N 6'-(2-(1-(2,2,2-三氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)-[2,3'-聯吡啶]-4',6'-二胺; (308) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (309) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)-5-氟嘧啶-4-基) -N 4'-(4-氟環己基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (310) (1 s,4 s)-4-((6-氟-6'-((2-(3-甲基-1-(2,2,2-三氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (311) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-6-氟-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (312) (1 s,4 s)-4-((5-(3,3-二氟吖丁啶-1-基)-6'-((2-(3-甲基-1-(2,2,2-三氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (313) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-5-(3,3-二氟吖丁啶-1-基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (314) 2-(6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)-5-氟嘧啶-4-基)胺基)-4'-(((1 s,4 s)-4-氟環己基)胺基)-[2,3'-聯吡啶]-5-基)丙-2-醇; (315) (1 s,4 s)-4-((2-((2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-甲基哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (316) (1 s,4 s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (317) (1 s,4 s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(3-甲基-1-(2,2,2-三氟乙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (318) (1 s,4 s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2-二氟乙基)-3,5-二甲基 -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (319) (1 s,4 s)-4-((5-(2-(吖丁啶-1-基)乙氧基)-6'-((2-(1-(2,2,3,3-四氟丙基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (320) 3,3-二氟-1-(5-氟-4-((4'-(((1 s,4 s)-4-羥基-4-甲基環己基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-6'-基)胺基)嘧啶-2-基)哌啶-4-醇; (321) (1 s,4 s)-4-((6'-((5-氟-2-((3 R,4 S)-3-氟-4-甲氧基哌啶-1-基)嘧啶-4-基)胺基)-5-((1-甲基哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (322) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (323) N 6'-(2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (324) N 6'-(2-(1-(2,2-二氟乙基) -1 H-吡唑-4-基)嘧啶-4-基) -N 4'-((1 s,4 s)-4-氟環己基)-5-((1-(2-氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4',6'-二胺; (325) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基) -1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(6-((1-(2-氟乙基)哌啶-4-基)氧基)噠嗪-3-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (326) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-甲氧基吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (327) (1 s,4 s)-4-((2-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(3-氟吡嗪-2-基)吡啶-4-基)胺基)-1-甲基環己-1-醇; (328) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (329) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-6-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (330) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (331) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (332) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-5-(二氟甲氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (333) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2,2-三氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (334) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-(2,2-二氟乙氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (335) (1 s,4 s)-4-((6'-((2-(1-(環丙磺醯基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇; (336) (1 s,4 s)-4-((6'-((2-(1-(2,2-二氟乙基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-4-氟-3-甲氧基-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇;及 (337) (1 s,4 s)-4-((6'-((2-(1-(2,2-二氟乙基)-1 H-吡唑-4-基)嘧啶-4-基)胺基)-3-甲氧基-5-((1-(2,2,2-三氟乙基)哌啶-4-基)氧基)-[2,3'-聯吡啶]-4'-基)胺基)-1-甲基環己-1-醇。
- 一種用以治療一需治療對象體內之蛋白激酶介導疾病之方法,該方法包含向該對象施用治療上有效量之如請求項1至23中任一項所述之化合物或其藥學上可接受之鹽。
- 如請求項24所述之方法,其中,該蛋白激酶介導疾病為癌症或免疫疾病。
- 如請求項25所述之方法,其中,該癌症為膀胱癌、大腸直腸癌、腦癌、乳癌、卵巢癌、子宮內膜癌、子宮癌、心臟癌、腎臟癌、肺癌、肝癌、胃癌、淋巴瘤、胰臟癌、頭頸癌、甲狀腺癌、前列腺癌、皮膚癌、或血液系統腫瘤。
- 如請求項25所述之方法,其中,該癌症為肺癌。
- 如請求項25所述之方法,其中,該癌症為非小細胞肺癌。
- 一種用於選擇性在生物樣本中或於患者體內抑制至少一EGFR突變體之方法,該方法包含使該生物樣本接觸或對該患者施用如請求項1至23中任一項所述之化合物或其藥學上可接受之鹽。
- 如請求項29所述之方法,其中,該至少一EGFR突變體是選自包含下列項目群組中之至少一種單突變體:EGFR Del19 (Del E746-A750)及EGFR L858R。
- 如請求項29所述之方法,其中,該至少一EGFR突變體是選自包含下列項目群組中之至少一種雙突變體:EGFR Del19/T790M、EGFR Del19/C797S、EGFR Del19/C797X (X=G、N)、EGFR Del19/L792X (X=F、H、P、R、V、Y) 、EGFR Del19/L718X (X=Q、V)、EGFR L858R/T790M、EGFR L858R/C797S、EGFR L858R/C797X (X=G、N)、EGFR L858R/L792X (X=F、H、P、R、V、Y) 、及EGFR L858R/L718X (X=Q、V)。
- 如請求項29所述之方法,其中,該至少一EGFR突變體是選自包含下列項目群組中之至少一種雙突變體:EGFR Del19/C797S及EGFR L858R/C797S。
- 如請求項29所述之方法,其中該至少一EGFR突變體是選自包含下列項目群組中之至少一種三突變體:EGFR Del19/T790M/C797S、EGFR Del19/T790M/C797X (X=G、N)、EGFR Del19/T790M/L792X (X=F、H、P、R、V、Y)、EGFR Del19/T790M/L718X (X=Q、V)、EGFR L858R/T790M/C797S、EGFR L858R/T790M/C797X (X=G、N)、EGFR L858R/T790M/L792X (X=F、H、P、R、V、Y) 、及EGFR L858R/T790M/L718X (X=Q、V)。
- 如請求項29所述之方法,其中,該至少一EGFR突變體是選自包含下列項目群組中之至少一種三突變體:EGFR Del19/T790M/C797S及EGFR L858R/T790M/C797S。
- 一種用於治療蛋白激酶介導疾病之藥物組成物,其包含作為有效成分之如請求項1至23中任一項所述之化合物或其藥學上可接受之鹽。
- 如請求項35所述之藥物組成物,其中,該蛋白激酶介導疾病為癌症或免疫疾病。
- 如請求項36所述之藥物組成物,其中,該癌症為膀胱癌、大腸直腸癌、腦癌、乳癌、卵巢癌、子宮內膜癌、子宮癌、心臟癌、腎臟癌、肺癌、肝癌、胃癌、淋巴瘤、胰臟癌、頭頸癌、甲狀腺癌、前列腺癌、皮膚癌、或血液系統腫瘤。
- 一種藥物組成物,用以選擇性抑制至少一種對照於野生型EGFR之EGFR突變體,該藥物組成物包含作為有效成分之如請求項1至23中任一項所述之化合物或其藥學上可接受之鹽。
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