TW202334096A - 喹唑啉衍生化合物及其用途 - Google Patents
喹唑啉衍生化合物及其用途 Download PDFInfo
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- TW202334096A TW202334096A TW111141253A TW111141253A TW202334096A TW 202334096 A TW202334096 A TW 202334096A TW 111141253 A TW111141253 A TW 111141253A TW 111141253 A TW111141253 A TW 111141253A TW 202334096 A TW202334096 A TW 202334096A
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- Prior art keywords
- phenyl
- methoxy
- acetamide
- trifluoromethyl
- quinazolin
- Prior art date
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- XLRPYZSEQKXZAA-OCAPTIKFSA-N tropane Chemical compound C1CC[C@H]2CC[C@@H]1N2C XLRPYZSEQKXZAA-OCAPTIKFSA-N 0.000 description 1
- 229930004006 tropane Natural products 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Abstract
本發明係關於喹唑啉衍生化合物及其醫學用途。特定言之,本發明提供能夠藉由抑制c-KIT或PDGFR來治療或預防c-KIT或PDGFR相關疾病之化合物。
Description
本發明係關於喹唑啉衍生化合物及其醫學用途。特定言之,本發明係關於能夠藉由抑制c-KIT或PDGFR來治療或預防c-KIT或PDGFR相關疾病之化合物。
c-KIT係編碼人類KIT基因之蛋白質。c-KIT受體之配位體係幹細胞因子(SCF)且當SCF作用於c-KIT配位體結合域時,發生SCF/c-KIT相互作用。因此,c-KIT蛋白質形成二聚體且藉由自體磷酸化變得具有活性。活化之c-KIT隨後經由各種信號轉導過程,諸如細胞內PI3K/Akt系統、Ras/MAP激酶及JAK/STAT調節細胞之存活,諸如生長、分化、增殖及自然死亡。與c-KIT相關聯之各種癌症係與c-KIT之活化相關。當可活化c-KIT時,除了藉由與配位體相互作用之表現之外,其亦可由過度表現或突變引起。c-KIT之過度表現係根據自分泌機制實現,且乳癌、直腸癌、小細胞肺癌及神經母細胞瘤可根據此迴路出現。此外,當發生c-KIT之功能獲得型突變時,不管SCF配位體及其下級信號傳輸系統如何,c-KIT由於過度活化,諸如c-KIT之持續活化而變得抗自然死亡。在各種人類癌症,包括由c-KIT之近膜區中之突變所引起的胃腸道間質瘤(GIST),以及由c-KIT突變所引起之神經母細胞瘤、急性骨髓性白血病(AML)及全身性肥大細胞增多症(SM)中發現編碼c-KIT基因之許多突變。特定言之,其中c-KIT活化迴路之殘基816處之天冬胺酸殘基經纈胺酸取代的c-KIT D816V突變(c-KIT D816V)主要出現在肥大細胞相關疾病中,尤其出現在符合世界衛生組織之全身性肥大細胞增多症診斷準則的超過90%病例中。目前,伊馬替尼(imatinib) (Gleevec)及舒尼替尼(sunitinib) (Sutent)已由FDA批准具有c-KIT抑制作用且用於治療GIST患者。其已知針對c-KIT野生型(c-KIT WT)及c-KIT V560G突變有效,但確認不存在抑制c-KIT D816V之作用。
同時,血小板衍生生長因子受體(PDGFR)為屬於PDGFR家族之酪胺酸激酶受體。PDGFR由PDGF-α及PDGF-β子單元構成,且根據生長因子,諸如PDGF之結合形成均二聚體或雜二聚體,以經由細胞內信號轉導在細胞增殖、細胞分化及細胞生長及發育中起重要作用。歸因於PDGFR過度活性之信號傳導功能異常發現於多種病理性病狀,諸如纖維化、癌症、神經疾病及粥狀硬化症中(文獻[Papadopoulos, Natalia, and Johan Lennartsson. 「The PDGF/PDGFR pathway as a drug target.」 Molecular aspects of medicine 62 (2018): 75-88.])。纖維化疾病之一,全身性硬化症為造成多器官病症之疾病,且其特徵為皮膚及血管之纖維化及諸如胃腸道、肺、心及腎之內臟的纖維化。肺纖維化,全身性硬化症之主要症狀之一,推測係由歸因於肺中存在之纖維母細胞不受控增殖且分化成肌纖維母細胞,細胞間空間中過量沈積細胞外基質(ECM)蛋白質的誘導而引起。
如此,對可有效地用於藉由調節c-KIT或PDGFR活性來治療c-KIT或PDGFR相關疾病之新穎化合物的未滿足需求愈來愈高。
[先前技術文獻]
[非專利文獻]
[Papadopoulos、Natalia及Johan Lennartsson. 「The PDGF/PDGFR pathway as a drug target.」 Molecular aspects of medicine 62 (2018): 75-88。]
[技術難題]
本發明之一個目標為提供喹唑啉衍生化合物、其立體異構體或其醫藥學上可接受之鹽。
本發明之另一目標為提供一種製備該化合物之方法。
本發明之又另一目標係提供一種化合物,尤其包含化合物作為活性成分之醫藥組合物用於治療或預防c-KIT或PDGFR相關疾病之醫藥用途,或提供一種用於治療或預防c-KIT或PDGFR相關疾病之方法,包括投與化合物之方法。
[技術解決方案]
為了達成上述目標,本發明人努力研究,且因此發現以下由式1表示之喹唑啉衍生化合物抑制c-KIT或PDGFR活性,且完成本發明。
喹唑啉衍生化合物本發明之一個實施例為由以下化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽。
[化學式1]
在該化學式1中,
R
1及R
2各自獨立地為-H、-(C1-C6)烷基、-(CH
2)
m-R
X或-(C=O)-R
X{其中,R
1及R
2不能同時為甲基};
R
X為-(C1-C6)烷氧基、-NR
AR
B、-鹵基、環烷基、雜環烷基、芳基、雜芳基或雜氫芳基{其中,該環烷基或該雜環烷基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)羥基烷基、-(C1-C6)烷基-O-(C1-C6)烷基、-(C=O)-(C1-C6)烷基、-(C=O)-O-(C1-C6)烷基、-NR
CR
D、-(=O)-、環烷基或苯甲基取代[其中,該苯甲基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)烷氧基、-(C1-C6)鹵基烷基或鹵基取代];該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基或鹵基取代};
R
A及R
B各自獨立地為-H、-(C1-C6)烷基、環烷基、雜環烷基、芳基或雜芳基{其中,該環烷基、該雜環烷基、該芳基或該雜芳基環中之至少一個H可經-(C1-C6)烷基取代};
R
C及R
D各自獨立地為-H或-(C1-C6)烷基;
m為0、1、2、3或4;
R
3為-H、-(C1-C6)烷基、-(C1-C6)烷氧基或-鹵基;
L為-NH(C=O)-L
1-(CH
2)
n-L
2-、-NH-S(=O)
2-L
1-(CH
2)
n-L
2-、-(C=O)NH-L
1-(CH
2)
n-L
2-、-L
1-(CH
2)
n-L
2-(C=O)NH-或-NH(C=O)NH-;
L
1及L
2各自獨立地為-CR
ER
F-、-C(=O)NH-或為空值;
R
E及R
F各自獨立地為-H、-(C1-C6)烷基、-NH
2、-NH(C=O)O-(C1-C6)烷基、-OH或-鹵基,或R
E及R
F與碳組合形成-(C3-C6)環烷基;
n為0、1、2、3或4;
Z為芳基、雜芳基、雜氫芳基、環烷基、雜環烷基或-(C2-C6)烯基{其中,該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基、-(C1-C6)羥基烷基、-(C1-C6)氰基烷基、-CN、-NR
GR
H、-(C1-C6)烷氧基或-鹵基取代;該環烷基或該雜環烷基環中之至少一個H可經-(C1-C6)烷基取代};
R
G及R
H各自獨立地為H或-(C1-C6)烷基。
根據本發明之一實施例,由以上化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽可包括於以下範疇中:
R
1及R
2各自獨立地為-H、-(C1-C6)烷基、-(CH
2)
m-R
X或-(C=O)-R
X{其中,R
1及R
2不能同時為甲基};
R
X為-(C1-C6)烷氧基、-NR
AR
B、-鹵基、雜環烷基、芳基、雜芳基或雜氫芳基{其中,該雜環烷基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)羥基烷基、-(C1-C6)烷基-O-(C1-C6)烷基、-(C=O)-(C1-C6)烷基、-(C=O)-O-(C1-C6)烷基、-NR
CR
D、-(=O)-、環烷基或苯甲基取代[其中,該苯甲基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)烷氧基、-(C1-C6)鹵基烷基或鹵基取代];該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)鹵基烷基取代};
R
A及R
B各自獨立地為-H、-(C1-C6)烷基、環烷基或雜芳基{其中,該環烷基或該雜芳基環中之至少一個H可經-(C1-C6)烷基取代};
R
C及R
D各自獨立地為-H或-(C1-C6)烷基;
m為0、1、2、3或4;
R
3為-H、-(C1-C6)烷基或-鹵基;
L為-NH(C=O)-L
1-(CH
2)
n-L
2-、-NH-S(=O)
2-L
1-(CH
2)
n-L
2-、-(C=O)NH-L
1-(CH
2)
n-L
2-或-NH(C=O)NH-;
L
1及L
2各自獨立地為-CR
ER
F-或為空值;
R
E及R
F各自獨立地為-H、-(C1-C6)烷基或-NH
2,或R
E及R
F與碳組合形成-(C3-C6)環烷基;
n為0、1、2、3或4;
Z為苯基、5-10員雜芳基、5-10員雜氫芳基、5-10員雜環烷基或-(C2-C6)烯基{其中,該苯基、該5-10員雜芳基或該5-10員雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基、-CN、-(C1-C6)烷氧基或-鹵基取代;該5-10員雜環烷基環中之至少一個H可經-(C1-C6)烷基取代}。
根據本發明之一實施例,由以上化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽可包括於以下範疇中:
R
1及R
2各自獨立地為-H、-(C1-C6)烷基、-(CH
2)
m-R
X或-(C=O)-R
X{其中,R
1及R
2不能同時為甲基};
R
X為-(C1-C6)烷氧基、-NR
AR
B、-鹵基、雜環烷基、芳基、雜芳基或雜氫芳基{其中,該雜環烷基為單環、螺環、橋連環或稠環,該雜環烷基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)羥基烷基、-(C1-C6)烷基-O-(C1-C6)烷基、-(C=O)-(C1-C6)烷基、-(C=O)-O-(C1-C6)烷基、-NR
CR
D、-(=O)-、環烷基或苯甲基取代[其中,該苯甲基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)烷氧基、-(C1-C6)鹵基烷基或鹵基取代];該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)鹵基烷基取代};
R
A及R
B各自獨立地為-H、-(C1-C6)烷基、環烷基或雜芳基{其中,該環烷基或該雜芳基環中之至少一個H可經-(C1-C6)烷基取代};
R
C及R
D各自獨立地為-H或-(C1-C6)烷基;
m為0、1、2或3。
根據本發明之一實施例,由以上化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽可包括於以下範疇中:
由化學式1表示之化合物由以下化學式2表示;
[化學式2]
在該化學式2中,
R
3為-H、-(C1-C6)烷基或-鹵基。
根據本發明之一實施例,由以上化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽可包括於以下範疇中:
L為-NH(C=O)-L
1-(CH
2)
n-L
2-、-NH-S(=O)
2-L
1-(CH
2)
n-L
2-、-(C=O)NH-L
1-(CH
2)
n-L
2-或-NH(C=O)NH-;
L
1及L
2各自獨立地為-CR
ER
F-或為空值;
R
E及R
F各自獨立地為-H、-(C1-C6)烷基或-NH
2,或R
E及R
F與碳組合形成-(C3-C6)環烷基;
n為0、1、2或3。
根據本發明之一實施例,由以上化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽可包括於以下範疇中:
Z為苯基、5-10員雜芳基、5-10員雜氫芳基、5-10員雜環烷基或-(C2-C6)烯基{其中,該苯基、該5-10員雜芳基或該5-10員雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基、-CN、-(C1-C6)烷氧基或-鹵基取代;該5-10員雜環烷基環中之至少一個H可經-(C1-C6)烷基取代}。
另外,根據本發明之一特定實施例,由化學式1表示之化合物可選自由描述如下的表1至5中所列之實例1至169之化合物組成之群。
本發明之一實施例為一種醫藥組合物,其包含由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽作為活性成分。
在本發明中,除非另外規定,否則「烷基」可指係直鏈或分支鏈的非環狀基團、環狀基團或其結合之飽和烴。舉例而言,「C
1 - 6烷基」可指示含有1至6個碳原子之烷基。非環狀烷基可包括(例如)甲基、乙基、正丙基、正丁基、異丙基、二級丁基、異丁基、三級丁基及其類似基團,但不限於此。環狀烷基可與本文中之「環烷基」互換使用,且舉例而言,可包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基及其類似基團,但不限於此。
在本發明中,「烷氧基」可指示-(O-烷基)為烷基醚基,其中烷基與上文所定義相同。舉例而言,「C
1 - 6烷氧基」可意謂含有C
1 - 6烷基之烷氧基,即-(O-C
1 - 6烷基),且舉例而言,烷氧基可包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、二級丁氧基、三級丁氧基及其類似基團,但不限於此。
在本發明中,「鹵基」可為F、Cl、Br或I。
在本發明中,「鹵基烷基」可意謂如本文所定義之具有一或多個鹵代碳原子的直鏈或分支鏈烷基(烴)。鹵基烷基之實例可包括獨立地經一或多個鹵素,諸如F、Cl、Br或I取代之甲基、乙基、丙基、異丙基、異丁基或正丁基,但不限於此。
在本發明中,「羥烷基」可意謂具有經羥基(OH)取代之碳原子的直鏈或分支鏈烷基(烴)。
在本發明中,「胺基烷基」可意謂具有經胺基取代之碳原子之直鏈或分支鏈烷基(烴) (NR'R")。在此,R'及R"可各自獨立地選自由氫及C
1 - 6烷基組成之群,且所選R'及R"可各自獨立地為經取代或未經取代的。
在本發明中,「氰基烷基」可意謂具有經氰基(CN)取代之碳原子之直鏈或分支鏈烷基(烴)。
在本發明中,「雜環烷基」可意謂在環中含有選自N、O、P、P(=O)及S中之至少一者的環,且可為飽和或部分不飽和的。此處,當不飽和時,其可稱為雜環烯烴。除非另外說明,否則雜環烷基可為單環或多環,諸如螺環、橋連環或稠環。另外,「3至12員雜環烷基」可意謂含有形成環之3至12個原子之雜環烷基,且舉例而言,雜環烷基可包括吡咯啶、哌啶、咪唑啶、吡唑啶、丁內醯胺、戊內醯胺、咪唑啶酮、海因(hydantoin)、間二氧雜環戊烷、鄰苯二甲醯亞胺、哌啶、嘧啶-2,4(1
H,3
H)-二酮、1,4-二㗁烷、嗎啉、硫代嗎啉、硫代嗎啉-
S-氧化物、硫代嗎啉-
S,
S-氧化物、哌𠯤、哌喃、吡啶酮、3-吡咯啉、硫代哌喃、比隆(pyron)、四氫呋喃、四氫噻吩、奎寧環、托烷、2-氮雜螺[3.3]庚烷、(1
R,5
S)-3-氮雜雙環[3.2.1]辛烷、(1
s,4
s)-2-氮雜雙環[2.2.2]辛烷、(1
R,4
R)-2-氧雜-5-氮雜雙環[2.2.2]辛烷及其類似基團,但不限於此。
在本發明中,「芳烴」可意謂芳族烴環。芳烴可為單環芳烴或多環芳烴。芳烴之成環碳原子之數目可為5或更大及30或更小、5或更大及20或更小或5或更大及15或更小。芳烴之實例可包括苯、萘、 芴、蒽、菲、聯苯、三聯苯、四聯苯、五聯苯、六聯苯、聯伸三苯、芘、苯并丙二烯合茀、䓛及其類似基團,但不限於此。在本說明書中,藉由自以上「芳烴」移除一個氫原子而獲得的殘基稱為「芳基」。
在本發明中,「雜芳烴」可為包括O、N、P、Si及S中之一或多者作為雜元素之環。雜芳烴之成環碳原子之數目可為2或更大及30或更小,或2或更大及20或更小。雜芳烴可為單環雜芳烴或多環雜芳烴。多環雜芳烴可具有例如雙環或三環結構。雜芳烴之實例可包括噻吩、嘌呤、吡咯、吡唑、咪唑、噻唑、㗁唑、異噻唑、㗁二唑、三唑、吡啶、二吡啶基、三𠯤、吖啶基、嗒𠯤、吡𠯤、喹啉、喹唑啉、喹㗁啉、 吩噁嗪、呔𠯤、嘧啶、吡啶并嘧啶、吡啶并吡𠯤、吡𠯤并吡𠯤、異喹啉、吲哚、咔唑、咪唑并嗒𠯤、咪唑并吡啶、咪唑并嘧啶、吡唑并嘧啶、咪唑并吡𠯤、吡唑并吡啶、
N-芳基咔唑、
N-雜芳基咔唑、
N-烷基咔唑、苯并㗁唑、苯并咪唑、苯并噻唑、苯并咔唑、苯并噻吩、二苯并噻吩、噻吩并噻吩、苯并呋喃、啡啉、異㗁唑、㗁二唑、噻二唑、苯并噻唑、四唑、啡噻𠯤、二苯并矽羅(dibenzosilol)、二苯并呋喃及其類似基團,但不限於此。在本發明之一個實施例中,雜芳烴亦可包括含有稠合至雜環烷基環之芳烴環或稠合至環烷基環之雜芳烴的雙環雜環芳烴。在本說明書中,藉由自「雜芳烴」移除一個氫原子而獲得之殘基稱為「雜芳基」。
在本發明中,「氫芳烴」或「氫芳基」意謂在芳族烴環中一或多個雙鍵飽和。
在本發明中,「雜氫芳烴」或「雜氫芳基」意謂在「雜芳烴」或「雜芳基」環中一或多個雙鍵飽和。在本發明中,「環」可為單環或多環。多環可為螺環、橋連環或稠環。
在本發明中,術語「立體異構體」意謂本發明之化合物或其鹽具有相同化學式或分子式但在空間上不同。此等立體異構體中之各者及其混合物亦包括在本發明之範疇內。除非另外說明,否則連接至不對稱碳原子之實線鍵(
)可包括楔形實線鍵(
)或楔形虛線鍵(
),其表示立體中心之絕對佈置。
本發明之化學式1之化合物可以「醫藥學上可接受之鹽」形式存在。作為鹽,由醫藥學上可接受之游離酸形成之酸加成鹽係有用的。術語「醫藥學上可接受之鹽」係指化合物之任何有機酸或無機酸加成鹽,其副作用在具有有效作用的濃度下不降低由化學式1表示之化合物之有益功效,對於患者而言相對無毒且無害。
酸加成鹽藉由習知方法來製備,例如藉由將化合物溶解於過量水性酸溶液中且使用可與水混溶之有機溶劑,諸如甲醇、乙醇、丙酮或乙腈來沈澱鹽。可加熱等莫耳量之化合物及酸或醇之水溶液,且隨後混合物可蒸發至乾燥,或沈澱鹽可藉由抽吸濾出。
此處,並且有機酸及無機酸可用作游離酸,其中無機酸可為鹽酸、磷酸、硫酸、硝酸或其類似酸,且有機酸可為甲磺酸、對甲苯磺酸、乙酸、三氟乙酸、順丁烯二酸、丁二酸、草酸、苯甲酸、酒石酸、反丁烯二酸、杏仁酸、丙酸、檸檬酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、麩胺酸、戊二酸、葡糖醛酸、天冬胺酸、抗壞血酸、碳酸、香草酸、氫碘酸或其類似酸。然而,其不限於此。
另外,醫藥學上可接受之金屬鹽可使用鹼製備。例如藉由將化合物溶解於過量鹼金屬氫氧化物或鹼土金屬氫氧化物溶液中,過濾未溶解的化合物鹽且隨後蒸發及乾燥濾液獲得鹼金屬鹽或鹼土金屬鹽。此處,作為金屬鹽,尤其適合製備鈉鹽、鉀鹽或鈣鹽,但不限於此。此外,對應銀鹽可藉由使鹼金屬或鹼土金屬鹽與適合銀鹽(例如硝酸銀)反應獲得。
除非另外指明,否則本發明之醫藥學上可接受之鹽包括可存在於化學式1之化合物中的酸性或鹼性基團之鹽。舉例而言,醫藥學上可接受之鹽可包括羥基之鈉鹽、鈣鹽及鉀鹽,且胺基之其他醫藥學上可接受之鹽可包括氫溴酸鹽、硫酸鹽、硫酸氫鹽、磷酸鹽、磷酸氫鹽、磷酸二氫鹽、乙酸鹽、丁二酸鹽、檸檬酸鹽、酒石酸鹽、乳酸鹽、杏仁酸鹽、甲烷磺酸鹽(甲磺酸鹽)及對甲苯磺酸鹽(甲苯磺酸鹽)及其類似鹽;且可經由此項技術中已知的製備鹽之方法製備。
喹唑啉衍生化合物的使用本發明之一個實施例為用於抑制c-KIT或PDGFR之組合物,其包含由以下化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽作為活性成分。本發明之一個實施例亦為包含該化合物之用於治療或預防c-KIT或PDGFR相關疾病之醫藥組合物。
[化學式1]
化學式1如上文所定義。
根據本發明之一個實施例,由化學式1表示之喹唑啉衍生物展現極佳的針對c-KIT或PDGFR之抑制活性,且因此可用於治療或預防c-KIT或PDGFR相關疾病。
在本發明中,c-KIT相關疾病可為選自癌症或肥大細胞相關疾病之任一或多者但不限於此。
在本發明中,在c-KIT相關疾病中,癌症可為選自由以下組成之群中之任一或多者:白血病、皮膚癌、乳癌、直腸癌、肺癌、 神經芽細胞腫、甲狀腺癌、生殖細胞腫瘤、前列腺癌以及胃腸道間質瘤中之任一或多者,但不限於此。
在本發明中,在c-KIT相關疾病中,肥大細胞相關疾病可為肥大細胞增多症、痤瘡、進行性骨化性纖維發育不良及囊胞性纖維症;急性腎病症候群、絲球體腎炎、腎澱粉樣變性、腎間質纖維化及發炎性肌病;HIV、II型糖尿病、大腦缺血、CNS病症、細菌感染、間質膀胱炎及發炎性腸病;腫瘤血管生成;自體免疫疾病及過敏性病症中之任一或多者,但不限於此。
同時,在本發明中,PDGFR相關疾病可為選自纖維化、癌症、神經疾病、粥狀硬化症及肺高血壓中之任一或多者,但不限於此。
在本發明中,在PDGFR相關疾病中,纖維化包括可歸因於抑制PDGFR活性而呈現預防或治療功效之所有纖維化,且特定言之,其可為選自以下之任一或多者:全身性硬化症、肺纖維化、肝纖維化、肝硬化、腎纖維化、骨髓纖維化、心肌纖維化、類肉瘤病、瘢痕瘤、燒傷誘導之肥厚性瘢痕、增生性視網膜病變、青光眼、白內障、後囊膜混濁(posterior capsular opacification)、血管成形術、血管手術或血管損傷後的血管再狹窄、囊腫性纖維化及馬凡氏症候群(Marfan syndrome),但不限於此。
在本發明中,在PDGFR相關疾病中,癌症包括可歸因於抑制PDGFR活性而呈現預防或治療功效之所有癌症,且其可為實體癌症或血癌。舉例而言,癌症可為選自由以下組成之群中之任一或多者:鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、肺腺癌、肺鱗狀細胞癌、腹膜癌、皮膚癌、皮膚或眼黑色素瘤、直腸癌、肛周腺癌、食道癌、小腸癌、內分泌腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、慢性或急性白血病、淋巴球性淋巴瘤、肝細胞癌、胃腸癌、胃癌、胰臟癌、神經膠母細胞瘤、子宮頸癌、卵巢癌、肝癌、膀胱癌、肝腫瘤、乳癌、結腸癌、大腸癌、子宮內膜癌或子宮癌、唾液腺癌、腎癌、前列腺癌、外陰癌、甲狀腺癌、頭頸癌、腦癌、骨肉瘤,但不限於此。癌症不僅包括原發性癌症且亦包括轉移性癌症。
在本發明中,在PDGFR相關疾病中,神經疾病包括可歸因於抑制PDGFR活性而呈現預防或治療作用之所有神經疾病,且特定言之,其可為選自以下之任一或多者:中樞神經系統疾病、神經退化性疾病、阿茲海默氏症(Alzheimer's disease)、帕金森氏症(Parkinson's disease)、多發性硬化、亨廷頓氏病(Huntington's disease)、老年癡呆症、癲癇症、肌肉萎縮性側索硬化、中風及腦或脊髓損傷繼以神經損傷及軸索變性相關病症,但不限於此。
在本發明中,在PDGFR相關疾病中, 粥狀硬化症包括可歸因於抑制PDGFR活性而呈現預防或治療功效之所有 粥狀硬化症。
在本發明中,在PDGFR相關疾病中,肺高血壓包括可歸因於抑制PDGFR活性而呈現預防或治療功效之所有肺高血壓。
本發明之醫藥組合物除了由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽之外可進一步包括一或多種醫藥學上可接受之載劑以供投與。醫藥學上可接受之載劑可為生理食鹽水、無菌水、林格氏溶液(Ringer's solution)、緩衝生理食鹽水、右旋糖溶液、麥芽糊精溶液、甘油、乙醇及此等組分中之一或多者的混合物,且視需要可添加其他習知添加劑,諸如抗氧化劑、緩衝劑及抑細菌劑。另外,可另外添加稀釋劑、分散劑、界面活性劑、黏合劑及潤滑劑以製備用於注射之調配物,諸如水性溶液、懸浮液及乳液、丸劑、膠囊、粒劑或錠劑。因此,本發明之組合物可為貼劑、液體、丸劑、膠囊、粒劑、錠劑、栓劑或其類似者。此等調配物可藉由此項技術中用於調配之習知方法或文獻[Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA]中所揭示之方法來製備,且可調配成視各疾病或成分而定的各種調配物。
本發明之醫藥組合物除了由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽之外可進一步包括一或多種展現相同或類似功效的活性成分。本發明之醫藥組合物可用於臨床投與且可經製備而以各種經口及非經腸劑型投與。
本發明提供一種用於預防或治療c-KIT或PDGFR相關疾病之方法,其包含:向有需要之個體投與治療有效量之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽。個體可為哺乳動物,包括人類。
本發明中所使用之術語「治療有效量」係指可有效地用於預防或治療c-KIT或PDGFR相關疾病之由化學式1表示之化合物的量。特定言之,「治療有效量」意謂足以以適用於醫學治療之合理益處/風險比治療疾病的量,且有效劑量水平可藉由包括個體類型及嚴重程度、年齡、性別、疾病類型、藥物活性、藥物敏感性、投與時間、投與途徑及排出速率、治療時段、包括同時使用之藥物的因素及醫學領域中熟知之其他因素的因素確定。本發明之醫藥組合物可作為個別治療劑或與其他治療劑組合投與,且可與市售治療劑依序或同時投與。另外,本發明之醫藥組合物可為單次投藥或多次投藥。重要的係考慮到所有上述因素投與能夠獲得最大作用而無副作用的最小量,且可容易地由熟習此項技術者確定。本發明之醫藥組合物之劑量可由專家根據各種因素來確定,該等因素諸如患者之狀況、年齡、性別、併發症及其類似因素。因為本發明之醫藥組合物之活性成分具有極佳安全性,所以其可超過所確定的劑量使用。
此外,本發明可藉由向包括人類之哺乳動物投與由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽來抑制c-KIT或PDGFR。
此外,根據本發明之一個實施例,本發明提供由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽的用途,其用於製備供治療c-KIT或PDGFR相關疾病用之藥劑。用於製備藥物之由化學式1表示之化合物可與可接受之佐劑、稀釋劑、載劑及其類似物混合,且可以與其他活性劑製備為組合製劑以得到活性成分之協同作用。
本發明之一個實施例提供一種治療或預防選自由以下組成之群中之任一或多種疾病的方法:癌症、肥大細胞相關疾病、纖維化疾病、神經疾病、 粥狀硬化症及肺高血壓,該方法包含向有需要之個體投與治療有效量之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽。
本發明之一個實施例提供一種用於抑制c-KIT或PDGFR之方法,該方法包含向有需要之個體投與治療有效量之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽。
本發明之一個實施例提供一種由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽的用途,其用於製備供治療或預防選自由以下組成之群的任一或多種疾病用之藥劑:癌症、肥大細胞相關疾病、纖維化疾病、神經疾病、 粥狀硬化症及肺高血壓。
本發明之一個實施例提供一種由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽的用途,其用於製備供治療或預防c-KIT或PDGFR相關疾病用之藥劑。
除非彼此矛盾,否則本發明之用途、組合物、治療方法及其類似者中所提及的內容同樣適用。
此研究由科學技術信息通信部、通商產業能源部及保健福祉部資助的韓國藥物開發資金支持(RS-2022-00165937,大韓民國)。
[有利作用]
本發明之新穎化合物展現抑制c-KIT或PDGFR活性之作用效應。因此,本發明之化合物可有效地用於治療或預防c-KIT或PDGFR相關疾病。
在下文中,將經由實例更詳細地描述本發明之組分及作用。然而,呈現以下實例僅為說明本發明,且本發明之範疇不限於此。
因為不需進一步純化即可購得,使用市售試劑。在本發明中,室溫係指20℃至25℃之溫度,且使用旋轉式蒸發器進行在減壓下濃縮或溶劑蒸餾移除。
< 用於分析及純化之方法及條件 >在本發明中,合成由實例合成之一系列化合物,藉由以下方法純化,且分析其結構。
1. 化合物之分析條件用於分析之高效液相層析(HPLC)條件
使用Waters之UPLC系統中配備有質量QDa偵測器之設備(ACQUITY UPLC PDA偵測器)分析化合物。用於化合物純化之管柱為Waters之ACQUITY UPLC BEH C18 (1.7 μm,2.1×50 mm),且管柱溫度設定在30℃下。含有0.1%甲酸之水用作移動相A,且含有0.1%甲酸之乙腈用作移動相B。梯度條件為3分鐘內10-100% B,且流動速率為0.6 mL/min。
在本說明書中,HPLC及UPLC用作可互換的術語。
2. 化合物之純化條件(1)用於純化之中壓液相層析(MPLC)
使用TELEDYNE ISCO之CombiFlash Rf+UV (使用時間60分鐘)進行中壓液相層析。
(2)製備型HPLC
1)用於純化之製備型液相層析質譜分析(製備型LCMS)
使用Waters之自動純化HPLC系統中配備有質量QDa偵測器之設備(2767樣品管理器,2545二元梯度模組,2998光二極體陣列偵測器)純化化合物。所用管柱為Waters之SunFire製備型C18 OBDTM (5 μm,19×50 mm),且管柱溫度維持在室溫下。含有0.035%三氟乙酸之水用作移動相A,且含有0.035%三氟乙酸之甲醇用作移動相B。梯度條件為10分鐘內15-100% B,且流動速率為25 mL/min。
2)用於純化之製備型150 LC系統(製備型液相層析UV光譜測定法)
使用Waters之製備型150 LC系統(2545四級梯度模組,2998光二極體陣列偵測器,溶離份收集器III)純化化合物。所用管柱為Waters之XTerra製備型RP18 OBDTM (10 μm,30×300 mm),且管柱溫度維持在室溫下。
3)用於純化之ACCQ製備型HP150系統
化合物使用Teledyne Isco之ACCQ製備型HP150系統純化。所用管柱為Waters之XTerra製備型RP18 OBDTM (10 μm,30×300 mm),且管柱溫度維持在室溫下。
3. NMR 分析記錄NMR光譜且使用Bruker之AVANCE III 400或AVANCE III 400 HD分析,且獲取之資料以百萬分率(ppm,δ)表示。
製備實例展示如下。儘管鹽(例如,TFA,HCl)用於實際製備方法中,但其可不包括於各製備實例之反應流程中。
< 實例 1> N -( 4 -( 7 -( 2 -( 二乙基胺基 ) 乙氧基 )- 6 - 甲氧基喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:在氮氣下將4-胺基苯基硼酸(boronic acid)頻哪醇酯鹽酸鹽(0.50 g,2.88 mmol)、7-(苯甲基氧基)-4-氯-6-甲氧基喹唑啉(0.87 g,2.88 mmol)、肆(三苯基膦)鈀(0) (0.30 g,0.87 mmol)及碳酸鈉(0.61 g,5.77 mmol)溶解於1,4-二㗁烷(11.1 ml)及蒸餾水(3.3 ml)中之後,進行氧氣移除10分鐘。在反應混合物在80℃下反應3小時之後,將蒸餾水添加至反應混合物中,且隨後用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。經濃縮之有機層使用二氯甲烷結晶,且隨後過濾,得到所要化合物4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯胺(0.80 g,78%)。
MS(m/z): 358.3 [M+H]
+; UPLC r.t. (min): 1.37
步驟2:將2-(4-(三氟甲基)苯基)乙酸(1.62 g,7.93 mmol)、1-[雙(二甲基胺基)亞甲基]-1H-1,2,3-三唑并[4,5,-b]吡錠3-氧化物六氟磷酸鹽(HATU) (4.02 g,10.58 mmol)溶解於二甲基甲醯胺(13.2 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(2.73 g,21.15 mmol)。將在步驟1中獲得之4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯胺(2.70 g,5.29 mmol)逐滴添加至反應混合物中,且隨後在室溫下攪拌3小時。在將蒸餾水添加至反應物中之後,用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。經濃縮之混合物經由MPLC (EtOAc:Hex= 10-100%)純化,得到固體所要化合物
N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(2.30 g,80%)。
MS(m/z): 544.3 [M+H]
+; UPLC r.t.(min): 1.83
步驟3:將步驟2中獲得之
N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(1.20 g,2.21 mmol)溶解於甲醇(11.0 ml)中之後,添加Pd/C (0.20 g,0.44 mmol)。在25℃下,在氫氣下,攪拌反應混合物1小時。反應物藉由矽藻土過濾器過濾,用甲醇洗滌,且隨後在減壓下濃縮。在濃縮之後,其經由MPLC (DCM:MeOH= 0-10%)純化,得到所要化合物
N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.78 g,78%)。
MS(m/z): 454.1 [M+H]
+UPLC r.t.(min): 1.47
步驟4:將步驟3中獲得之
N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.09 g,0.20 mmol)、2-氯-
N,
N-二乙基乙烷-1-胺鹽酸鹽(0.04 g,0.24 mmol)及碳酸鉀(0.05 g,0.40 mmol)溶解於二甲基甲醯胺(2.0 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(0.05 g,0.40 mmol),隨後在90℃下攪拌6小時。在確認反應完成且添加蒸餾水之後,用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。在濃縮之後,其經由MPLC (DCM:MeOH=0-10%)純化,得到所要化合物
N-(4-(7-(2-(二乙基胺基)乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.05 g,45.6 %)。
MS(m/z): 553.4 [M+H]
+UPLC r.t.(min): 1.35
< 實例 2> N -( 4 -( 6 - 甲氧基 - 7 -(( 1 - 甲基哌啶 - 4 - 基 ) 氧基 ) 喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:將實例1之步驟3中獲得之
N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.05 g,0.11 mmol)、1-甲基哌啶-4-醇(0.02 g,0.17 mmol)及三苯基膦(0.09 g,0.33 mmol)溶解於二氯甲烷(1.1 ml)中之後,逐滴添加偶氮二甲酸二異丙酯(0.07 g,0.33 mmol)。在室溫下攪拌隔夜之後,當反應完成時,將其減壓濃縮且經由MPLC (DCM:MeOH=0-10%)純化,得到所要化合物
N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.02 g,33 %)。
MS(m/z): 551.3 [M+H]
+UPLC r.t.(min): 1.32
< 實例 3> N -( 4 -( 6 - 甲氧基 - 7 -( 2 -( 4 - 甲基哌 𠯤 - 1 - 基 ) 乙氧基 ) 喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:將實例1之步驟3中獲得之
N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(80.0 mg,0.18 mmol)、2-溴乙醇(35.3 mg,0.28 mmol)及三苯基膦(64.8 mg,0.25 mmol)溶解於二氯甲烷(1.7 ml)中之後,逐滴添加偶氮二甲酸二異丙酯(42.8 mg,0.21 mmol),隨後在室溫下攪拌隔夜。當反應完成時,將其在減壓下濃縮且經由MPLC (EtOAc:Hex=30-100%)純化,得到所要化合物
N-(4-(7-(2-溴乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(80.0 mg,81 %)。
MS(m/z): 562.1 [M+H]
+UPLC r.t.(min): 1.71
步驟2:將步驟1中獲得之
N-(4-(7-(2-溴乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.05 g,0.09 mmol)及1-甲基哌𠯤(0.04 g,0.36 mmol)溶解於二甲基甲醯胺(0.9 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(0.02 g,0.18 mmol)且隨後在室溫下攪拌隔夜。在反應完成之後,添加蒸餾水,且用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。經濃縮之混合物經由MPLC (EtOAc:Hex=30-100%)純化且得到所要化合物
N-(4-(6-甲氧基-7-(2-(4-甲基哌𠯤-1-基)乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(11.0 mg,65.5 %)。
MS(m/z): 580.4 [M+H]
+UPLC r.t.(min): 1.26
< 實例 4> N -( 4 -( 7 -(( 1 - 乙基哌啶 - 4 - 基 ) 甲氧基 )- 6 - 甲氧基喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:將實例1之步驟3中得到之
N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.10 g,0.22 mmol)及4-((甲苯磺醯基氧基)甲基)哌啶-1-甲酸三級丁酯(0.12 g,0.33 mmol)溶解於二甲基甲醯胺(1.1 ml)中之後,逐滴添加碳酸鉀(0.06 g,0.44 mmol)。在70℃下攪拌反應混合物隔夜之後,當反應完成時,藉由經由MPLC (DMC:MeOH= 0-10%)純化得到所要化合物4-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯(0.08 g,55.7 %)。
MS(m/z): 651.4 [M+H]
+UPLC r.t.(min): 1.99
步驟2:將步驟1中獲得之4-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯(0.08 g,0.12 mmol)溶解於二氯甲烷(1.2 ml)中之後,在0℃下緩慢逐滴添加三氟乙酸(0.14 g,1.229 mmol)。在室溫下攪拌反應混合物隔夜之後,將其濃縮且使用製備型HPLC純化,得到所要化合物N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺2,2,2-三氟乙酸鹽(7.5 mg,92 %)。
MS(m/z): 551.3 [M+H]
+UPLC r.t.(min): 1.40
步驟3:將步驟2中獲得之N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺2,2,2-三氟乙酸鹽(0.03 g,0.05 mmol)、三乙醯氧基硼氫化鈉(0.02 g,0.09 mmol)、乙醛(2.98 mg,0.07 mmol)溶解於1,4-二㗁烷(0.5 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(0.03 g,0.23 mmol)。在室溫下攪拌反應混合物隔夜之後,當反應完成時,其經由製備型HPLC純化,得到所要化合物
N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.01 g,38 %)。
MS(m/z): 595.4 [M+H]
+UPLC r.t.(min): 1.50
實例 1 至 54實例5至54以類似於實例1至4之方式製備,且實例1至54之化合物名稱、NMR、質量及UPLC分析結果概述於下表1中。
在上述製備實例中,即使化合物係呈鹽形式製備,但其在表中以游離形式列出。因此,可將實際上用於製備方法之鹽添加至未添加鹽之化合物中,或可添加其他鹽。
[表1]
實例 | 結構 | 化合物名稱 | 1H NMR; MS(m/z) | UPLC r.t. (min) |
1 | N-(4-(7-(2-(二乙基胺基)乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.02 (s, 1H), 7.86 (d, J= 8.5 Hz, 2H), 7.77 (d, J= 8.7 Hz, 2H), 7.66 (d, J= 8.1 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.40 - 7.35 (m, 2H), 4.36 (t, J= 5.5 Hz, 2H), 3.93 - 3.82 (m, 5H), 3.12 (t, J= 5.4 Hz, 2H), 2.79 (q, J= 7.2 Hz, 4H), 1.15 (t, J= 7.1 Hz, 6H) 553.3 [M+H] + | 1.35 | |
2 | N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 551.3 [M+H] + | 1.32 | |
3 | N-(4-(6-甲氧基-7-(2-(4-甲基哌𠯤-1-基)乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 580.4 [M+H] + | 1.26 | |
4 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 579.3 [M+H] + | 1.51 | |
5 | N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 544.2 [M+H] + | 1.81 | |
6 | N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 454.1 [M+H] + | 1.45 | |
7 | 2-胺基- N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)丙醯胺 | 523.3 [M+H] + | 1.33 | |
8 | 2-胺基-2-(4-氟苯基)- N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)丙醯胺 | 433.2 [M+H] + | 0.96 | |
9 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.15 (s, 1H), 7.75 (d, J= 8.8 Hz, 2 H), 7.67 (d, J= 8.8 Hz, 4 H), 7.51 (d, J= 8 Hz, 2 H), 7.35 (s, 1H), 7.30-7.29 (m, 2H), 4.35 (t, J= 6, 6.4 Hz, 2H), 3.86-3.84 (m, 5H), 2.96 (t, J= 6 Hz, 2H), 2.67 (brs, 4H), 2.48 (brs, 4H), 2.30 (s, 1H) 594.4 [M+H] + | 1.22 | |
10 | 2-胺基-2-(4-氟苯基)- N-(4-(7-異丁氧基-6-甲氧基喹唑啉-4-基)苯基)丙醯胺 | 498.2 [M+H] + | 1.34 | |
11 | N-(4-(7-(3-(二乙基胺基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ δ 9.00 (s, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.76 (d, J= 8.4 Hz, 2H), 7.66 (d, J= 8.1 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.39 - 7.31 (m, 2H), 4.26 (t, J= 6.0 Hz, 2H), 3.90 - 3.81 (m, 5H), 2.86 - 2.78 (m, 2H), 2.69 (q, J= 7.2 Hz, 4H), 2.10 (dd, J= 9.5, 5.8 Hz, 2H), 1.12 (t, J= 7.2 Hz, 6H) 567.3 [M+H] + | 1.36 | |
12 | N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-甲基-2-(4-(三氟甲基)苯基)丙醯胺 | 572.4 [M+H] + | 1.99 | |
13 | N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-甲基-2-(4-(三氟甲基)苯基)丙醯胺 | 482.2 [M+H] + | 1.63 | |
14 | 3-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯 | 651.4 [M+H] + | 2.00 | |
15 | 4-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯 | 651.4 [M+H] + | 2.00 | |
16 | N-(4-(6-甲氧基-7-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 551.3 [M+H] + | 1.41 | |
17 | N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 551.2 [M+H] + | 1.40 | |
18 | N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 8.99 (s, 1H), 7.86 (d, J= 8.5 Hz, 2H), 7.75 (d, J= 8.3 Hz, 2H), 7.66 (d, J= 8.1 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.35 - 7.28 (m, 2H), 4.20 (dd, J= 9.7, 5.0 Hz, 1H), 4.11 (dd, J= 9.7, 6.7 Hz, 1H), 3.90 - 3.82 (m, 5H), 3.71 - 3.63 (m, 1H), 3.56 - 3.46 (m, 1H), 3.14 (qd, J= 7.3, 2.4 Hz, 2H), 2.87 - 2.76 (m, 2H), 2.54 - 2.41 (m, 1H), 2.08 - 1.98 (m, 2H), 1.92 - 1.85 (m, 1H), 1.56 - 1.44 (m, 1H), 1.34 (t, J= 7.3 Hz, 3H) 579.3 [M+H] + | 1.51 | |
19 | 6-(3-((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)丙氧基)-2,6-二氮雜螺[3.3]庚烷-2-甲酸三級丁酯 | 692.5 [M+H] + | 1.58 | |
20 | N-(4-(7-(3-(2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 592.3 [M+H] + | 1.23 | |
21 | N-(4-(7-(3-(6-乙基-2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 620.4 [M+H] + | 1.33 | |
22 | N-(4-(7-(3-(3-(二甲基胺基)氮雜環丁烷-1-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 594.3 [M+H] + | 1.27 | |
23 | N-(4-(7-(3-氯丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 530.2 [M+H] + | 1.77 | |
24 | N-(4-(7-(氮雜環丁烷-3-基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 509.3 [M+H] + | 1.63 | |
25 | N-(4-(7-(3-(環丙基胺基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 551.3 [M+H] + | 1.68 | |
26 | N-(4-(6-甲氧基-7-(3-((1-甲基-1 H-吡唑-4-基)胺基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 591.3 [M+H] + | 1.68 | |
27 | N-(4-(6-甲氧基-7-((1-(4-甲氧基苯甲基)氮雜環丁-3-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 629.4 [M+H] + | 1.45 | |
28 | N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)氮雜環丁-3-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 571.3 [M+H] + | 1.36 | |
29 | N-(4-(6-甲氧基-7-(吡啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 545.3 [M+H] + | 1.45 | |
30 | N-(4-(7-(2-(1 H-吡唑-1-基)乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 8.99 (s, 1H), 7.84 (d, J= 8.7 Hz, 2H), 7.79 (d, J= 2.3 Hz, 1H), 7.77 - 7.72 (m, 2H), 7.66 (d, J= 8.2 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.51 (d, J= 1.9 Hz, 1H), 7.36 - 7.30 (m, 2H), 6.29 (t, J= 2.1 Hz, 1H), 4.67 (t, J= 5.0 Hz, 2H), 4.55 (t, J= 5.0 Hz, 2H), 3.90 - 3.78 (m, 5H) 548.3 [M+H] + | 1.60 | |
31 | N-(4-(6-甲氧基-7-(3-((1 R,4 R)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 606.3 [M+H] + | 1.21 | |
32 | N-(4-(6-甲氧基-7-(3-((1 S,4 S)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 606.4 [M+H] + | 1.29 | |
33 | N-(4-(7-(3-(六氫吡咯并[1,2- a]吡𠯤-2(1 H)-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 620.4 [M+H] + | 1.29 | |
34 | N-(4-(6-甲氧基-7-(3-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑[4,3-a]吡𠯤-7(8 H)-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 686.3 [M+H] + | 1.60 | |
35 | ( R)-3-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)吡咯啶-1-甲酸三級丁酯 | 637.4 [M+H] + | 1.86 | |
36 | ( S)-3-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)吡咯啶-1-甲酸三級丁酯 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.01 (s, 1H), 7.86 (d, J= 8.0 Hz, 2H), 7.77 (d, J= 8.0 Hz, 2H), 7.66 (d, J= 8.1 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.36 (s, 2H), 4.29 - 4.22 (m, 1H), 4.21 - 4.14 (m, 1H), 3.92 - 3.84 (m, 5H), 3.67 - 3.60 (m, 1H), 3.57 - 3.48 (m, 1H), 3.43 - 3.35 (m, 1H), 3.29 - 3.24 (m, 1H), 2.86 - 2.76 (m, 1H), 2.21 - 2.11 (m, 1H), 1.97 - 1.82 (m, 1H), 1.47 (s, 9H) 637.4 [M+H] + | 1.86 | |
37 | N-(4-(6-甲氧基-7-(3-(3-甲基-3,6-二氮雜雙環[3.1.1]庚烷-6-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 606.3 [M+H] + | 1.23 | |
38 | ( R)- N-(4-(6-甲氧基-7-(吡咯啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 537.3 [M+H] + | 1.30 | |
39 | ( S)- N-(4-(6-甲氧基-7-(吡咯啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 537.3 [M+H] + | 1.30 | |
40 | ( R)- N-(4-(7-((1-乙基吡咯啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 565.4 [M+H] + | 1.34 | |
41 | ( S)- N-(4-(7-((1-乙基吡咯啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 565.4 [M+H] + | 1.34 | |
42 | N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-3-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 609.3 [M+H] + | 1.36 | |
43 | N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 609.3 [M+H] + | 1.35 | |
44 | N-(4-(6-甲氧基-7-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 593.3 [M+H] + | 1.39 | |
45 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-1-苯基甲磺醯胺 | 561.2 [M+H] + | ||
46 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-1-(4-(三氟甲基)苯基)甲磺醯胺 | 629.2 [M+H] + | ||
47 | 1-(4-溴苯基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)甲磺醯胺 | 639.1 [M+H] + | ||
48 | 2-(呋喃-2-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)丙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.34 (d, J= 4.4 Hz, 1H), 9.08 (s, 1H), 8.45 (d, J= 4.5 Hz, 1H), 8.27 (d, J= 8.4 Hz, 1H), 7.83 (q, J= 8.6 Hz, 4H), 7.60 (d, J= 3.1 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.27 (dd, J= 8.3, 4.3 Hz, 1H), 4.26 (t, J= 6.4 Hz, 2H), 3.85 (s, 3H), 3.78 (q, J= 7.0 Hz, 2H), 2.62-2.53 (m, 8H), 2.30 (s, 3H), 1.98 (t, J= 6.8 Hz, 2H), 1.41 (d, J= 7.0 Hz, 3H). 530.1 [M+H] + | 1.28 | |
49 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)-2-甲基苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.16 (s, 1H), 7.95 (d, J= 8.2 Hz, 1H), 7.83 (s, 1H), 7.65 (d, J= 7.9 Hz, 2H), 7.57-7.48 (m, 4H), 7.37 (s, 1H), 7.28 (s, 1H), 4.28 (t, J= 6.6 Hz, 2H), 3.88 (s, 2H), 3.86 (s, 3H), 2.88-2.33 (m, 10H), 2.30 (s, 3H), 2.14 (d, J= 6.7 Hz, 5H) . 608.2 [M+H] + | 1.36 | |
50 | N-(2-氟-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.15 (s, 1H), 8.51 (t, J= 8.3 Hz, 1H), 7.82 (d, J= 3.3 Hz, 1H), 7.67 (d, J= 8.0 Hz, 2H), 7.60-7.49 (m, 4H), 7.39 (s, 1H), 7.28 (s, 1H), 4.29 (t, J= 6.6 Hz, 2H), 3.89 (s, 2H), 3.88 (s, 3H), 2.86-2.32 (m, 10H), 2.31 (s, 3H), 2.13 (p, J= 6.8 Hz, 2H) . 612.2 [M+H] + | 1.44 | |
51 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(噻唑-4-基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.57 (s, 1H), 9.09 (s, 1H), 9.07 (d, J= 2.0 Hz, 1H), 7.87 (d, J= 8.8 Hz, 2H), 7.82 (d, J= 8.7 Hz, 2H), 7.58 (d, J= 2.0 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 4.25 (t, J= 6.4 Hz, 2H), 3.94 (s, 2H), 3.85 (s, 3H), 2.47 (t, J= 7.0 Hz, 2H), 2.44-2.37 (m, 8H), 2.20 (s, 3H), 1.98 (q, J= 6.7 Hz, 2H). 533.1 [M+H] + | 1.10 | |
52 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(2-氟-4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3): δ 9.15 (s, 1H), 8.56 (t, J= 8.2 Hz, 1H), 7.63 - 7.51 (m, 3H), 7.27 (d, J= 5.5 Hz, 2H), 6.90 - 6.79 (m, 3H), 6.01 (s, 2H), 4.07 (d, J= 6.5 Hz, 2H), 3.88 (s, 3H), 3.74 (s, 2H), 3.57 (s, 2H), 3.36 (s, 3H), 3.10 (s, 1H), 2.66 (s, 2H), 2.09 (d, J= 40.1 Hz, 4H), 1.92 (d, J= 13.1 Hz, 2H), 1.59 (d, J= 10.8 Hz, 2H) 603.2 [M+H] + | ||
53 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)-2-甲基苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3): δ 9.14 (s, 1H), 8.24 (d, J= 8.7 Hz, 1H), 7.61 (d, J= 6.9 Hz, 2H), 7.32 (s, 2H), 7.20 (s, 1H), 6.93 - 6.82 (m, 3H), 6.02 (s, 2H), 4.06 (d, J= 6.6 Hz, 2H), 3.87 (s, 3H), 3.75 (s, 2H), 3.53 (t, J= 5.6 Hz, 2H), 3.36 (s, 3H), 3.03 (d, J= 11.1 Hz, 2H), 2.60 (d, J= 7.0 Hz, 2H), 2.07 (s, 3H), 2.03 (d, J= 11.7 Hz, 2H), 1.90 (d, J= 13.0 Hz, 2H), 1.58 - 1.45 (m, 3H) 599.2 [M+H] + | ||
54 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.40 (s, 1H), 9.09 (s, 1H), 7.83 (d, J= 1.8 Hz, 3H), 7.40 (s, 1H), 7.36 (s, 1H), 6.95 (d, J= 1.6 Hz, 1H), 6.89 (d, J= 7.9 Hz, 1H), 6.82 (dd, J= 8.0, 1.7 Hz, 1H), 6.00 (s, 1H), 4.25 (t, J= 6.4 Hz, 2H), 3.85 (s, 3H), 3.61 (s, 2H), 2.53 (d, J= 1.8 Hz, 4H), 2.45 (t, J= 7.1 Hz, 4H), 2.15 (s, 4H), 1.97 (t, J= 6.9 Hz, 2H), 1.24 (s, 3H). 570.2 [M+H] + | 1.30 |
< 實例 55> N -( 4 -( 6 - 甲氧基 - 7 -( 3 -( 4 - 甲基哌 𠯤 - 1 - 基 ) 丙氧基 ) 喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 3 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:將7-(苯甲基氧基)-4-氯-6-甲氧基喹唑啉(1.0 g,3.33 mmol)、(4-硝基苯基)硼酸(0.83 g,4.99 mmol)溶解於1,4-二㗁烷(12.4 ml)、2 M碳酸鈉(4.2 ml)中之後,逐滴添加肆(三苯基膦)鈀(0) (1.15 g,0.99 mmol),在用氮氣鼓泡之後,且隨後其在80℃下攪拌隔夜。在確認反應完成且添加蒸餾水之後,用二氯甲烷(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。經濃縮之混合物經由二氯甲烷固化,且獲得所要化合物7-(苯甲基氧基)-6-甲氧基-4-(4-硝基苯基)喹唑啉(1.25 g,97 %)而無需進一步純化,且進行以下反應。
MS(m/z): 388.2 [M+H]
+UPLC r.t.(min): 1.76
步驟2:將步驟1中獲得之7-(苯甲基氧基)-6-甲氧基-4-(4-硝基苯基)喹唑啉(1.27 g,3.28 mmol)溶解於三氟乙酸(5.0 ml)中之後,且在75℃下攪拌2小時。反應完成時,在減壓濃縮之後,獲得固體所要化合物6-甲氧基-4-(4-硝基苯基)喹唑啉-7-醇2,2,2-三氟乙酸(0.95 g,70%)且以下反應不經進一步純化即進行。
MS(m/z): 298.1 [M+H]
+UPLC r.t.(min): 1.28
步驟3:將步驟2中獲得之 2,2,2-三氟乙酸6-甲氧基-4-(4-硝基苯基)喹唑啉-7-醇(2.0 g,4.86 mmol)、三苯基膦(2.55 g,9.73 mmol)溶解於二氯甲烷(48.6 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(1.25 g,9.73 mmol)。在逐滴添加偶氮二甲酸二異丙酯(1.97 g,9.73 mmol)至反應混合物之後,將其在室溫下攪拌隔夜。當反應完成時,將其減壓濃縮且經由MPLC (EA:HEX=30-100%)純化,得到所要化合物7-(3-氯丙氧基)-6-甲氧基-4-(4-硝基苯基)喹唑啉(1.82 g,80%純度,及100%產率)。
MS(m/z): 374.1 [M+H]
+UPLC r.t.(min): 1.66
步驟4:將步驟3中獲得之7-(3-氯丙氧基)-6-甲氧基-4-(4-硝基苯基)喹唑啉(1.5 g,4.01 mmol)及1-甲基哌𠯤(2.0 g,20.06 mmol)溶解於二甲基乙醯胺(20.0 ml)中之後,且將其在80℃下攪拌隔夜。在確認反應完成且添加蒸餾水之後,用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。將濃縮混合物溶解於丙酮(10.0 ml)中,用4 M HCl/乙醚酸化,且過濾固體濾液,得到所要化合物6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)-4-(4-硝基苯基)喹唑啉二鹽酸鹽(1.77 g,86%)。
MS(m/z): 438.3 [M+H]
+UPLC r.t.(min): 1.04
步驟5:將步驟4中獲得之6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)-4-(4-硝基苯基)喹唑啉二鹽酸鹽(1.77 g,3.47 mmol)溶解於甲醇(34 ml)中之後,添加Pd/C (0.19 g,1.734 mmol)。在40℃下,在氫氣下,攪拌反應混合物1小時。反應物經由矽藻土過濾器過濾,用甲醇洗滌,且減壓濃縮,得到所要化合物4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯胺二鹽酸鹽(1.6 g,50 %)。
MS(m/z): 410.3 [M+H]
+UPLC r.t.(min): 0.26
步驟6:將2-(3-(三氟甲基)苯基)乙酸(6.0 mg,0.31 mmol)及HATU (0.16 g. 0.42 mmol)溶解於二氯甲烷(0.7 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(0.11 g,0.83 mmol),且逐滴添加步驟5中獲得之4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯胺二鹽酸鹽(0.1 g,0.21 mmol)。在室溫下攪拌混合物隔夜,在反應完成之後添加蒸餾水,且用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。經濃縮之混合物經由MPLC (DCM:MeOH=0-10%)純化,得到所要化合物
N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺(3.0 mg,24 %)。
MS(m/z): 594.4 [M+H]
+UPLC r.t.(min): 1.25
< 實例 56> N -( 4 -( 6 - 甲氧基 - 7 -(( 1 - 甲基哌啶 - 4 - 基 ) 甲氧基 ) 喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:將實例55之步驟2中獲得之2,2,2-三氟乙酸6-甲氧基-4-(4-硝基苯基)喹唑啉-7-醇(5.0 g,12.16 mmol)及4-((甲苯磺醯基氧基)甲基)哌啶-1-甲酸三級丁酯(5.84 g,15.80 mmol)溶解於二甲基甲醯胺(40.0 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(7.86 g,60.80 mmol)及碳酸鉀(3.36 g,24.31 mmol)。在70℃下攪拌反應混合物隔夜,且當反應完成時,用水過濾固體濾液,得到所要化合物4-(((6-甲氧基-4-(4-硝基苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯(6.20 g,粗物質,103 %)。其未經進一步純化即用於以下反應中。
MS(m/z): 495.3 [M+H]
+UPLC r.t.(min): 1.86
步驟2:將4-(((6-甲氧基-4-(4-硝基苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯(6.20 g,12.54 mmol)溶解於二氯甲烷(62.0 ml)中之後,逐滴添加4 M HCl (31.3 ml,125.00 mmol)/二㗁烷。在室溫下攪拌隔夜之後,當反應完成時,過濾固體化合物,得到所要化合物6-甲氧基-4-(4-硝基苯基)-7-(哌啶-4-基甲氧基)喹唑啉鹽酸鹽(5.0 g,93%),且不經進一步純化即用於以下反應中。
MS(m/z): 395.2 [M+H]
+UPLC r.t.(min): 1.17
步驟3:將步驟2中獲得之6-甲氧基-4-(4-硝基苯基)-7-(哌啶-4-基甲氧基)喹唑啉鹽酸鹽(0.50 g,1.16 mmol)及三乙醯氧基硼氫化鈉(0.37 g,1.74 mmol)溶解於1,4-二㗁烷(5.8 ml)中之後,逐滴添加甲醛(0.94 g,11.60 mmol)及
N,
N-二異丙基乙基胺(0.30 g,2.32 mmol),且隨後在室溫下攪拌混合物隔夜。反應完成後,添加蒸餾水,且用二氯甲烷(×3)萃取有機物。在用鹽水洗滌所收集之有機層後,使用硫酸鈉移除剩餘水且在減壓下濃縮,得到所要化合物6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)-4-(4-硝基苯基)喹唑啉。經濃縮之混合物(0.45 g,95%)未經進一步純化即用於以下反應中。
MS(m/z): 409.2 [M+H]
+UPLCr.t. (min): 1.14
步驟4:將步驟3中獲得之6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)-4-(4-硝基苯基)喹唑啉(0.45 g,1.10 mmol)溶解於甲醇(10.9 ml)中之後,添加Pd/C (0.05 g,0.55 mmol)。在室溫下,在氫氣下,攪拌反應混合物1小時。反應物經由矽藻土過濾器過濾,用甲醇洗滌,且隨後在減壓下濃縮,得到所要化合物2,2,2-三氟乙酸4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯胺(0.30 g,72.3%)。
MS(m/z): 397.3 [M+H]
+UPLCr.t. (min): 0.84
步驟5:將2-(4-(三氟甲基)苯基)乙酸(22.0 mg,0.11 mmol)及HATU (54.0 mg,0.14 mmol)溶解於二氯甲烷(0.7 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(3.7 mg,0.28 mmol)。將步驟4中獲得之 2,2,2-三氟乙酸4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯胺(35.0 mg,0.07 mmol)加入反應混合物,且在室溫下攪拌混合物隔夜。在反應完成之後,添加蒸餾水,且隨後用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。在分離及MPLC (DCM:MeOH=0-20%)純化濃縮混合物之後,得到所要化合物
N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(20.0 mg,49.8%)。
MS(m/z): 565.4 [M+H]
+UPLC r.t.(min): 1.34
實例 55 至 121實例57至121以類似於實例55及56之方式製備,且實例55至121之化合物名稱、NMR、質量及UPLC分析結果概述於下表2中。
[表2]
實例 | 結構 | 化合物名稱 | 1H NMR; MS(m/z) | UPLC r.t. (min) |
55 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺 | 594.3 [M+H] + | 1.25 | |
56 | N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 8.98 (s, 1H), 7.85 (d, J= 8.4 Hz, 2H), 7.76 - 7.71 (m, 2H), 7.66 (d, J= 8.0 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.33 - 7.27 (m, 2H), 4.14 - 4.06 (m, 2H), 3.88 - 3.81 (m, 5H), 3.53 - 3.45 (m, 2H), 3.03 - 2.92 (m, 2H), 2.79 (s, 3H), 2.26 - 2.08 (m, 3H), 1.83 - 1.69 (m, 2H) 565.4 [M+H] + | 1.34 | |
57 | N-(4-(6,7-雙(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 556.3 [M+H] + | 1.59 | |
58 | 2-胺基- N-(4-(6,7-雙(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(4-氟苯基)丙醯胺 | 535.3 [M+H] + | 1.14 | |
59 | N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.61 (s, 1H), 9.08 (s, 1H), 8.75 (s, 1H), 8.07 (d, J= 8.3 Hz, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.83 (s, 4H), 7.38 (d, J= 24.9 Hz, 2H), 4.07 (d, J= 6.4 Hz, 2H), 3.94 (s, 2H), 3.85 (s, 3H), 2.61 (s, 2H), 1.99 (s, 1H), 1.79 (d, J= 10.9 Hz, 2H), 1.26 (d, J= 14.7 Hz, 2H). 552.3 [M+H] + | 1.17 | |
60 | N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.10 (s, 1H), 8.58 (s, 1H), 8.28 (s, 1H), 7.84 (s, 4H), 7.74 (s, 1H), 7.63 (dq, J= 15.0, 7.9 Hz, 3H), 7.52-7.41 (m, 1H), 7.37 (s, 1H), 4.15 (d, J= 6.3 Hz, 2H), 3.85 (d, J= 3.6 Hz, 5H), 2.96 (s, 2H), 2.20 (s, 1H), 1.98 (d, J = 13.8 Hz, 2H), 1.52 (d, J= 12.9 Hz, 2H). 551.3 [M+H] + | 1.30 | |
61 | 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.78 (s, 1H), 9.11 (s, 1H), 8.60 (d, J= 11.1 Hz, 1H), 8.29 (d, J= 12.0 Hz, 1H), 7.90 (s, 1H), 7.85 (s, 4H), 7.47 (s, 1H), 7.37 (s, 1H), 4.15 (d, J= 6.3 Hz, 2H), 3.86 (s, 3H), 3.34 (d, J= 12.4 Hz, 2H), 3.00 (ddd, J= 21.2, 13.9, 8.6 Hz, 3H), 2.20 (t, J= 8.6 Hz, 1H), 1.98 (d, J= 14.0 Hz, 2H), 1.59-1.46 (m, 2H), 1.26 (d, J= 6.9 Hz, 6H). 516.4 [M+H] + | 1.06 | |
62 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.75 (s, 1H), 9.11 (d, J= 2.8 Hz, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 7.87 (d, J= 21.5 Hz, 5H), 7.42 (d, J= 39.1 Hz, 2H), 5.33 (s, 2H), 4.15 (d, J= 6.4 Hz, 2H), 3.86 (s, 3H), 2.94 (d, J= 14.0 Hz, 2H), 2.21 (s, 1H), 1.98 (d, J= 13.9 Hz, 2H), 1.91 (d, J= 3.1 Hz, 1H), 1.58-1.46 (m, 2H), 1.34-1.27 (m, 9H). 530.4 [M+H] + | 1.12 | |
63 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.58 (s, 1H), 9.08 (s, 1H), 8.75 (d, J= 2.0 Hz, 1H), 8.07 (dd, J= 8.0, 2.1 Hz, 1H), 7.91 (dd, J= 8.0, 0.9 Hz, 1H), 7.83 (s, 4H), 7.40 (s, 1H), 7.35 (s, 1H), 4.08 (d, J= 6.1 Hz, 2H), 3.94 (s, 2H), 3.85 (s, 3H), 2.99-2.85 (m, 2H), 1.88 (s, 2H), 1.79 (d, J= 13.3 Hz, 2H), 1.35 (q, J= 12.0 Hz, 2H), 1.24 (d, J= 4.0 Hz, 1H), 1.01 (t, J= 7.2 Hz, 3H). 580.3 [M+H] + | 1.19 | |
64 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺 | 579.3 [M+H] + | 1.30 | |
65 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-異丙基-1 H-1,2,3-三唑-1-基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.75 (s, 1H), 9.09 (s, 1H), 7.94-7.76 (m, 5H), 7.38 (d, J= 22.6 Hz, 2H), 5.33 (s, 2H), 4.08 (d, J= 6.1 Hz, 2H), 3.85 (s, 3H), 2.90 (d, J= 10.7 Hz, 2H), 2.32 (q, J= 7.0 Hz, 2H), 2.09 (d, J= 2.8 Hz, 2H), 1.26-1.23 (m, 6H), 1.00 (t, J= 7.0 Hz, 4H), 0.91-0.82 (m, 4H). 544.4 [M+H] + | 1.07 | |
66 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.75 (s, 1H), 9.08 (s, 1H), 7.96-7.73 (m, 5H), 7.38 (d, J= 21.8 Hz, 2H), 5.32 (s, 2H), 4.08 (d, J= 7.1 Hz, 2H), 3.84 (d, J= 10.5 Hz, 3H), 2.89 (s, 2H), 2.31 (s, 4H), 1.89 (d, J= 9.6 Hz, 4H), 1.30 (d, J= 6.4 Hz, 9H), 1.00 (t, J= 7.6 Hz, 4H). 558.4 [M+H] + | 1.13 | |
67 | 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 559.3 [M+H] + | 1.02 | |
68 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 573.4 [M+H] + | 1.08 | |
69 | 2-(6-氯吡啶-3-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.19 (s, 1H), 9.07 (s, 1H), 7.80 (d, J= 7.5 Hz, 4H), 7.44-7.03 (m, 9H), 3.99 (s, 2H), 3.85 (s, 3H), 2.71 (d, J= 7.2 Hz, 2H), 1.24 (s, 2H), 0.85 (d, J= 7.7 Hz, 2H). 518.3 [M+H] + | 1.10 | |
70 | 2-(6-氯吡啶-3-基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.18-8.96 (m, 2H), 8.39 (s, 1H), 7.89-7.78 (m, 5H), 7.56-7.44 (m, 2H), 7.38 (s, 1H), 4.16 (d, J= 6.0 Hz, 2H), 3.83 (d, J= 19.5 Hz, 5H), 3.55 (d, J= 11.8 Hz, 2H), 3.14-3.06 (m, 2H), 2.95 (d, J= 11.6 Hz, 2H), 2.05 (d, J= 14.0 Hz, 2H), 1.57 (d, J= 13.6 Hz, 2H), 1.24 (d, J= 6.6 Hz, 3H), 0.86 (t, J= 6.7 Hz, 1H). 546.3 [M+H] + | 1.13 | |
71 | N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-3-苯基丙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.19 (s, 1H), 9.07 (s, 1H), 7.80 (d, J= 7.5 Hz, 4H), 7.46-7.03 (m, 9H), 3.99 (s, 2H), 3.85 (s, 3H), 2.71 (d, J= 7.2 Hz, 2H), 2.08 (d, J= 6.8 Hz, 4H), 1.24 (s, 2H), 0.85 (d, J= 7.7 Hz, 2H). 497.3 [M+H] + | 1.22 | |
72 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-3-苯基丙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.20 (s, 1H), 9.09 (s, 1H), 7.82 (s, 4H), 7.51-7.15 (m, 7H), 4.14 (d, J= 6.2 Hz, 2H), 3.86 (s, 3H), 2.96 (t, J= 7.4 Hz, 2H), 2.82-2.65 (m, 4H), 2.14-1.88 (m, 5H), 1.60-1.44 (m, 2H), 1.27 (d, J= 17.5 Hz, 1H), 1.14 (t, J= 7.2 Hz, 3H), 0.90 - 0.78 (m, 1H). 525.4 [M+H] + | 1.25 | |
73 | ( R)- N-(4-(6-甲氧基-7-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.55 (s, 1H), 9.09 (d, J= 1.5 Hz, 1H), 7.84 (d, J= 1.9 Hz, 3H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.42 (s, 1H), 7.36 (s, 1H), 4.11 (d, J= 8.3 Hz, 2H), 3.85 (d, J= 2.4 Hz, 3H), 2.09 (s, 4H), 1.90 (s, 4H), 1.70 (s, 1H), 1.50 (s, 1H), 1.27 (d, J= 19.0 Hz, 2H). 551.3 [M+H] + | 1.32 | |
74 | ( R)- N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.08 (s, 1H), 7.83 (d, J= 1.4 Hz, 4H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.41 (s, 1H), 7.36 (s, 1H), 4.11 (d, J= 6.5 Hz, 2H), 3.85 (d, J= 2.7 Hz, 5H), 2.98 (s, 1H), 2.81 (s, 1H), 2.41 (s, 1H), 2.01 (d, J= 81.3 Hz, 3H), 1.87-1.78 (m, 1H), 1.70 (d, J= 12.9 Hz, 1H), 1.52 (d, J= 12.8 Hz, 1H), 1.29-1.11 (m, 2H), 1.02 (t, J= 7.1 Hz, 3H). 579.3 [M+H] + | 1.34 | |
75 | ( S)- N-(4-(6-甲氧基-7-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.58 (s, 1H), 9.11 (s, 1H), 8.70 (d, J= 11.4 Hz, 1H), 8.45 (d, J= 11.3 Hz, 1H), 7.84 (d, J= 3.2 Hz, 3H), 7.73 (d, J= 8.1 Hz, 2H), 7.67-7.53 (m, 5H), 7.46 (s, 1H), 7.38 (s, 1H), 4.28-4.12 (m, 2H), 3.86 (s, 3H), 2.89-2.79 (m, 2H), 2.41-2.28 (m, 1H), 1.96-1.82 (m, 2H), 1.67 (dt, J= 13.3, 3.6 Hz, 1H), 1.40 (dd, J= 12.1, 3.3 Hz, 1H). 551.3 [M+H] + | 1.31 | |
76 | ( S)- N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.08 (d, J= 2.8 Hz, 1H), 7.83 (t, J= 2.3 Hz, 4H), 7.72 (d, J= 8.3 Hz, 2H), 7.60 (d, J= 7.9 Hz, 2H), 7.41 (s, 1H), 7.36 (s, 1H), 4.11 (d, J= 6.4 Hz, 2H), 3.85 (d, J= 2.8 Hz, 5H), 2.97 (s, 1H), 2.79 (s, 1H), 2.39 (s, 1H), 2.01 (d, J= 80.5 Hz, 3H), 1.81 (d, J= 12.1 Hz, 1H), 1.69 (s, 1H), 1.51 (s, 1H), 1.28-1.05 (m, 2H), 1.02 (t, J= 7.2 Hz, 3H). 579.3 [M+H] + | 1.32 | |
77 | 2-(4-氯-3-(三氟甲基)苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.51 (s, 1H), 9.08 (s, 1H), 7.85 (d, J= 17.2 Hz, 5H), 7.69 (q, J= 8.2 Hz, 2H), 7.43 (s, 1H), 7.36 (s, 1H), 4.10 (d, J= 6.2 Hz, 2H), 3.86 (d, J= 7.2 Hz, 4H), 2.71 (t, J= 12.3 Hz, 2H), 2.07 (d, J= 11.2 Hz, 2H), 1.89 (s, 4H), 1.36 (d, J= 12.5 Hz, 2H), 1.26 (d, J= 13.5 Hz, 1H). 585.3 [M+H] + | 1.37 | |
78 | 2-(4-氯-3-(三氟甲基)苯基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.06 (d, J= 31.8 Hz, 2H), 7.85 (d, J= 14.6 Hz, 5H), 7.70 (q, J= 7.5 Hz, 2H), 7.47 (d, J= 6.4 Hz, 1H), 7.38 (s, 1H), 4.16 (d, J= 6.2 Hz, 2H), 3.86 (d, J= 5.9 Hz, 5H), 3.10 (s, 2H), 2.95 (d, J= 12.0 Hz, 2H), 2.13-2.03 (m, 2H), 1.92 (d, J= 5.5 Hz, 2H), 1.57 (d, J= 11.8 Hz, 2H), 1.23 (t, J= 6.3 Hz, 3H). 613.3 [M+H] + | 1.41 | |
79 | 2-(3-氟-4-(三氟甲基)苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.09 (s, 1H), 7.89-7.75 (m, 5H), 7.51 (d, J= 12.1 Hz, 1H), 7.47-7.35 (m, 3H), 4.12 (d, J= 6.2 Hz, 2H), 3.87 (d, J= 13.2 Hz, 5H), 2.82 (d, J= 12.7 Hz, 2H), 2.21-2.03 (m, 2H), 1.95-1.87 (m, 4H), 1.54-1.39 (m, 2H). 569.3 [M+H] + | 1.34 | |
80 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(3-氟-4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.55 (s, 1H), 9.09 (s, 1H), 7.84 (s, 4H), 7.78 (t, J= 8.0 Hz, 1H), 7.52 (d, J= 11.9 Hz, 1H), 7.42 (d, J= 6.0 Hz, 2H), 7.36 (s, 1H), 4.10 (d, J= 6.2 Hz, 2H), 3.89 (s, 2H), 3.85 (s, 3H), 3.05-2.92 (m, 2H), 2.43 (s, 2H), 2.03 (s, 2H), 1.92-1.77 (m, 3H), 1.39 (q, J= 11.1 Hz, 2H), 1.03 (t, J= 7.1 Hz, 3H). 597.3 [M+H] + | 1.37 | |
81 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺 | 557.3 [M+H] + | 1.02 | |
82 | 2-(4-氯-3-(三氟甲基)苯基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.00 (s, 1H), 7.87 - 7.79 (m, 3H), 7.77 - 7.72 (m, 2H), 7.64 - 7.57 (m, 2H), 7.34 (s, 2H), 4.29 (t, J= 6.0 Hz, 2H), 3.90 - 3.78 (m, 5H), 3.04 - 2.89 (m, 4H), 2.87 - 2.68 (m, 6H), 2.65 - 2.57 (m, 3H), 2.20 - 2.08 (m, 2H). 628.4 [M+H] + | 1.34 | |
83 | 2-(4-氰基苯基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.14 (s, 1H), 7.75-7.73 (m, 2H), 7.69-7.66 (m, 5H), 7.49-7.47 (m, 2H), 7.37 (s, 1H), 7.27 (d, J= 10Hz, 1H), 4.29-4.26 (m, 2H), 3.85-3.81 (m, 5H), 2.58-2.47 (m, 10H), 2.28 (s, 3H), 2.15-2.10 (m, 2H). 551.3 [M+H] + | 1.07 | |
84 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(噻吩-3-基)乙醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.15 (s, 1H), 7.78-7.72 (m, 2H), 7.69-7.63 (m, 2H), 7.46-7.42 (m, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.30-7.28 (m, 1H), 7.12 (dd, J = 4.9, 1.4 Hz, 1H), 4.29 (t, J= 6.6 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 2H), 2.84-2.37 (m, 10H), 2.31 (s, 3H), 2.19-2.07 (m, 2H). 532.3 [M+H] + | 1.08 | |
85 | 2-(2,3-二氫苯并呋喃-5-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.15 (s, 1H), 7.74 (d, J= 8.7 Hz, 2H), 7.66 (d, J= 8.6 Hz, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.20 (s, 1H), 7.09 (dd, J= 8.1, 2.0 Hz, 1H), 6.83 (d, J= 8.1 Hz, 1H), 4.62 (t, J= 8.7 Hz, 2H), 4.29 (t, J= 6.6 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 2H), 3.25 (t, J= 8.7 Hz, 2H), 2.81-2.44 (m, 10H), 2.38 (s, 3H), 2.13 (p, J= 6.6 Hz, 2H). 568.4 [M+H] + | 1.11 | |
86 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(哌啶-4-基)乙醯胺 | 533.4 [M+H] + | 0.80 | |
87 | N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)丁-3-烯醯胺 | 476.3 [M+H] + | 0.98 | |
88 | 2-(4-氟苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-甲基丙醯胺 | 529.4 [M+H] + | 1.34 | |
89 | 2-(4-氟苯基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-甲基丙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 9.37 (s, 1H), 9.07 (s, 1H), 7.90-7.75 (m, 4H), 7.46-7.39 (m, 3H), 7.36 (s, 1H), 7.24-7.14 (m, 2H), 4.08 (d, J= 6.1 Hz, 2H), 3.85 (s, 3H), 3.43 (t, J= 5.9 Hz, 2H), 3.23 (s, 3H), 2.91 (d, J= 10.9 Hz, 2H), 2.46 (s, 2H), 1.98 (s, 1H), 1.80 (dd, J= 28.1, 11.3 Hz, 3H), 1.60 (s, 6H), 1.37 (t, J= 11.2 Hz, 2H). 587.4 [M+H] + | 1.35 | |
90 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)-2-甲基丙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 9.37 (s, 1H), 9.07 (s, 1H), 7.90-7.75 (m, 4H), 7.46-7.39 (m, 3H), 7.36 (s, 1H), 7.24-7.14 (m, 2H), 4.08 (d, J= 6.1 Hz, 2H), 3.85 (s, 3H), 3.43 (t, J= 5.9 Hz, 2H), 3.23 (s, 3H), 2.91 (d, J= 10.9 Hz, 2H), 2.46 (s, 2H), 1.98 (s, 1H), 1.80 (dd, J= 28.1, 11.3 Hz, 3H), 1.60 (s, 6H), 1.37 (t, J= 11.2 Hz, 2H). 557.4 [M+H] + | 1.36 | |
91 | 1-(4-氟苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 9.27 (s, 1H), 9.07 (s, 1H), 7.78 (d, J= 8.5 Hz, 4H), 7.56-7.46 (m, 2H), 7.37 (d, J= 26.0 Hz, 2H), 7.20 (t, J= 8.7 Hz, 2H), 4.07 (d, J= 6.6 Hz, 2H), 3.84 (s, 3H), 3.06 (s, 2H), 2.60 (s, 2H), 2.08 (s, 1H), 1.78 (d, J= 12.4 Hz, 2H), 1.52-1.47 (m, 2H), 1.32-1.22 (m, 3H), 1.14 (dt, J= 8.9, 4.3 Hz, 2H). 527.3 [M+H] + | 1.32 | |
92 | 1-(4-氟苯基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 9.29 (s, 1H), 9.07 (s, 1H), 7.83-7.76 (m, 4H), 7.52-7.45 (m, 2H), 7.39 (s, 1H), 7.34 (s, 1H), 7.24-7.17 (m, 2H), 4.08 (d, J= 6.1 Hz, 2H), 3.84 (s, 3H), 3.43 (t, J= 5.9 Hz, 2H), 3.23 (s, 3H), 2.91 (d, J= 10.9 Hz, 2H), 2.46 (s, 2H), 1.97 (d, J= 13.6 Hz, 2H), 1.78 (t, J= 16.1 Hz, 3H), 1.50 (q, J= 4.1 Hz, 2H), 1.35 (q, J= 11.7 Hz, 2H), 1.18-1.10 (m, 2H). 585.4 [M+H] + | 1.36 | |
93 | N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-1-(4-氟苯基)環丙烷-1-甲醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 9.28 (s, 1H), 9.07 (s, 1H), 7.79 (s, 4H), 7.54-7.44 (m, 2H), 7.40 (s, 1H), 7.34 (s, 1H), 7.20 (t, J= 8.3 Hz, 2H), 4.09 (d, J= 6.2 Hz, 2H), 3.84 (s, 3H), 2.95 (d, J= 10.9 Hz, 2H), 2.38 (s, 2H), 1.98 (s, 2H), 1.80 (d, J= 13.4 Hz, 2H), 1.49 (d, J= 5.6 Hz, 2H), 1.37 (d, J= 12.4 Hz, 2H), 1.25 (s, 1H), 1.14 (d, J= 5.9 Hz, 2H), 1.02 (t, J= 6.9 Hz, 3H). 555.4 [M+H] + | 1.35 | |
94 | 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.74 (s, 1H), 9.09 (s, 1H), 7.90 (d, J= 0.7 Hz, 1H), 7.87-7.82 (m, 4H), 7.41 (s, 1H), 7.35 (s, 1H), 5.33 (s, 2H), 4.09 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.45 (d, J= 5.8 Hz, 2H), 3.24 (s, 3H), 3.05-2.89 (m, 3H), 2.05 (d, J= 28.9 Hz, 2H), 1.78 (d, J= 13.4 Hz, 3H), 1.43-1.33 (m, 2H), 1.26 (d, J= 6.9 Hz, 6H). 574.4 [M+H] + | 1.11 | |
95 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.75 (s, 1H), 9.09 (s, 1H), 7.90 (s, 1H), 7.89-7.81 (m, 4H), 7.41 (s, 1H), 7.35 (s, 1H), 5.33 (s, 2H), 4.08 (d, J= 6.1 Hz, 2H), 3.85 (s, 3H), 3.43 (t, J= 5.9 Hz, 2H), 3.23 (s, 3H), 2.92 (d, J= 10.9 Hz, 2H), 2.00 (s, 2H), 1.87-1.72 (m, 3H), 1.38 (t, J= 11.7 Hz, 2H), 1.31 (s, 9H). 588.4 [M+H] + | 1.16 | |
96 | N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.60 (s, 1H), 9.08 (s, 1H), 8.75 (d, J= 2.1 Hz, 1H), 8.07 (dd, J= 8.1, 2.1 Hz, 1H), 7.91 (d, J= 8.0 Hz, 1H), 7.83 (s, 4H), 7.41 (s, 1H), 7.35 (s, 1H), 4.09 (d, J= 6.2 Hz, 2H), 3.94 (s, 2H), 3.85 (s, 3H), 3.46 (d, J= 5.8 Hz, 2H), 3.24 (s, 3H), 2.98 (d, J= 11.0 Hz, 2H), 2.61-2.53 (m, 2H), 2.10 (d, J= 12.8 Hz, 2H), 1.84 (dd, J= 37.3, 15.6 Hz, 3H), 1.48-1.31 (m, 2H). 610.4 [M+H] + | 1.23 | |
97 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.51 (s, 1H), 9.08 (s, 1H), 7.83 (s, 4H), 7.72 (d, J= 7.7 Hz, 2H), 7.60 (d, J= 7.7 Hz, 2H), 7.39 (d, J= 21.8 Hz, 2H), 4.11 (s, 2H), 3.85 (s, 3H), 2.08 (s, 2H), 1.90 (s, 4H), 1.69 (s, 1H), 1.55-1.45 (m, 1H), 1.28 (d, J= 26.4 Hz, 3H), 0.86 (s, 1H). 527.4 [M+H] + | 1.17 | |
98 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.41 (s, 1H), 9.08 (s, 1H), 7.87-7.80 (m, 4H), 7.37 (d, J= 17.2 Hz, 2H), 6.95 (d, J= 1.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.00 (s, 2H), 4.08 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.61 (s, 2H), 2.95 (dt, J= 11.9, 3.4 Hz, 2H), 2.39 (q, J= 7.2 Hz, 2H), 2.02-1.95 (m, 2H), 1.84-1.78 (m, 2H), 1.38 (qd, J= 12.0, 3.6 Hz, 2H), 1.02 (t, J= 7.1 Hz, 3H). 585.4 [M+H] + | 1.21 | |
99 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.41 (s, 1H), 9.08 (s, 1H), 7.87-7.80 (m, 4H), 7.37 (d, J= 17.2 Hz, 2H), 6.95 (d, J= 1.7 Hz, 1H), 6.91-6.81 (m, 2H), 6.00 (s, 2H), 4.08 (d, J= 6.2 Hz, 2H), 3.85 (s, 3H), 3.61 (s, 2H), 2.95 (dt, J= 11.9, 3.4 Hz, 2H), 2.39 (q, J= 7.2 Hz, 2H), 2.02-1.95 (m, 2H), 1.84-1.78 (m, 2H), 1.38 (qd, J= 12.0, 3.6 Hz, 2H), 1.02 (t, J= 7.1 Hz, 3H). 555.4 [M+H] + | 1.21 | |
100 | N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺 | 528.4 [M+H] + | 1.09 | |
101 | N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 566.4 [M+H] + | 1.20 | |
102 | N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 593.4 [M+H] + | 1.57 | |
103 | N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺 | 556.3 [M+H] + | 1.29 | |
104 | N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 594.3 [M+H] + | 1.42 | |
105 | 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 530.3 [M+H] + | 1.09 | |
106 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 544.3 [M+H] + | 1.13 | |
107 | N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-異丙基-1 H-1,2,3-三唑-1-基)乙醯胺 | 558.3 [M+H] + | 1.28 | |
108 | N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)乙醯胺 | 572.4 [M+H] + | 1.34 | |
109 | N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺 | 542.3 [M+H] + | 1.12 | |
110 | N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 580.3 [M+H] + | 1.22 | |
111 | N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-異丙基-1 H-1,2,3-三唑-1-基)乙醯胺 | 544.4 [M+H] + | 1.12 | |
112 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 8.97 (s, 1H), 7.88 - 7.82 (m, 3H), 7.78 - 7.71 (m, 2H), 7.29 - 7.23 (m, 2H), 5.37 (s, 2H), 4.23 - 4.15 (m, 1H), 4.12 - 4.06 (m, 1H), 3.85 (s, 3H), 3.72 - 3.63 (m, 1H), 3.58 - 3.50 (m, 1H), 3.22 - 3.12 (m, 2H), 2.91 - 2.78 (m, 2H), 2.55 - 2.40 (m, 1H), 2.08 - 1.98 (m, 2H), 1.93 - 1.84 (m, 1H), 1.58 - 1.44 (m, 1H), 1.39 - 1.33 (m, 12H). 558.4 [M+H] + | 1.16 | |
113 | 2-(6-氯吡啶-3-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.07 (s, 1H), 8.38 (d, J= 2.4 Hz, 1H), 7.87-7.77 (m, 5H), 7.50 (d, J= 8.2 Hz, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 4.07 (d, J= 6.2 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 2H), 3.44 (s, 2H), 3.23 (s, 3H), 2.95 (d, J= 10.6 Hz, 2H), 2.53 (s, 2H), 1.89-1.74 (m, 3H), 1.39 (t, J= 12.5 Hz, 2H). 576.3 [M+H] + | 1.17 | |
114 | N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-4-苯基丁醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.18 (s, 1H), 9.08 (s, 1H), 7.82 (s, 4H), 7.46-7.14 (m, 12H), 4.09 (d, J= 6.2 Hz, 2H), 3.86 (s, 3H), 3.02-2.91 (m, 4H), 2.82 (t, J= 7.5 Hz, 2H), 2.70 (t, J= 7.7 Hz, 2H), 2.09 (s, 2H), 1.79 (d, J= 12.6 Hz, 2H), 1.40 (s, 2H), 1.25 (s, 1H), 0.95-0.79 (m, 1H). 555.4 [M+H] + | 1.30 | |
115 | N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.08 (s, 1H), 7.88-7.77 (m, 4H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.37 (d, J= 17.4 Hz, 2H), 4.07 (d, J= 6.0 Hz, 2H), 3.85 (s, 5H), 2.88-2.80 (m, 2H), 2.74-2.65 (m, 1H), 2.22-2.11 (m, 2H), 1.85-1.75 (m, 3H), 1.39-1.26 (m, 2H), 0.98 (d, J= 6.5 Hz, 6H). 593 [M+H] + | 1.38 | |
116 | N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.49 (s, 1H), 9.08 (s, 1H), 8.23-8.03 (m, 1H), 7.89-7.78 (m, 3H), 7.70 (dd, J= 8.5, 2.5 Hz, 1H), 7.38 (d, J= 18.5 Hz, 2H), 6.81 (dd, J= 8.5, 0.7 Hz, 1H), 4.08 (d, J= 6.0 Hz, 2H), 3.94-3.76 (m, 6H), 3.68 (s, 2H), 3.08-2.61 (m, 3H), 2.46-2.01 (m, 2H), 1.82 (d, J= 12.8 Hz, 3H), 1.53-1.27 (m, 2H), 1.01 (d, J= 6.6 Hz, 6H). 556.4 [M+H] + | 1.14 | |
117 | N-(4-(6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3- d 3): δ 9.17 (s, 1H), 7.79-7.73 (m, 2H), 7.71-7.65 (m, 5H), 7.51 (d, J= 8.0 Hz, 2H), 7.41-7.35 (m, 2H), 7.31 (s, 1H), 4.08 (s, 3H), 3.90 (s, 3H), 3.85 (s, 2H), 3.53-3.45 (m, 4H). 512.3 [M+H] + | 1.61 | |
118 | N-(4-(6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 1H NMR (400 MHz, CDCl 3- d 3) δ 9.18 (s, 1H), 8.72 (s, 1H), 7.98 (d, J= 7.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.75-7.68 (m, 3H), 7.48 (s, 1H), 7.41-7.36 (m, 1H), 7.32 (s, 1H), 4.08 (s, 3H), 3.90 (s, 3H), 3.86 (s, 2H), 3.59-3.40 (m, 4H). 513.3 [M+H] + | 1.45 | |
119 | 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3- d 3): δ 9.15 (s, 1H), 8.57-8.41 (m, 1H), 7.82-7.75 (m, 2H), 7.72 (d, J= 8.6 Hz, 2H), 7.50 (s, 1H), 7.33 (s, 1H), 5.20 (s, 2H), 4.12-3.99 (m, 2H), 3.87 (s, 3H), 3.04-2.88 (m, 2H), 2.82-2.66 (m, 1H), 2.32-2.11 (m, 2H), 2.07-1.84 (m, 4H), 1.43-1.38 (m, 9H), 1.14-1.00 (m, 6H). 572.4 [M+H] + | 1.20 | |
120 | 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3- d 3): δ 9.14 (s, 1H), 8.54-8.31 (m, 1H), 7.81-7.74 (m, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.50 (s, 1H), 7.33 (s, 1H), 5.21 (s, 2H), 4.13-3.96 (m, 2H), 3.86 (s, 3H), 3.23-3.09 (m, 1H), 3.05-2.87 (m, 2H), 2.84-2.63 (m, 1H), 2.31-2.10 (m, 2H), 2.05-1.86 (m, 3H), 1.36 (d, J= 6.9 Hz, 6H), 1.16-0.98 (m, 6H). 558.4 [M+H] + | 1.15 | |
121 | N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺 | 1H NMR (400 MHz, CDCl 3- d 3): δ 9.15 (s, 1H), 8.75-8.68 (m, 1H), 8.01-7.94 (m, 1H), 7.78 (d, J= 8.6 Hz, 2H), 7.74-7.68 (m, 3H), 7.59-7.49 (m, 1H), 7.34 (s, 1H), 7.29 (s, 1H), 4.06 (d, J= 6.5 Hz, 2H), 3.87 (s, 3H), 3.86 (s, 2H), 3.10-2.87 (m, 2H), 2.82-2.66 (m, 1H), 2.33-2.13 (m, 2H), 2.08-1.87 (m, 4H), 1.55-1.38 (m, 2H), 1.18-0.97 (m, 6H). 594.4 [M+H] + | 1.26 |
< 實例 122> N -( 4 -( 6 -( 2 -( 二乙基胺基 ) 乙氧基 )- 7 - 甲氧基喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 - 氟苯基 ) 乙醯胺之製備 步驟1:將乙酸4-氯-7-甲氧基喹唑啉-6-基酯(0.10 g,0.40 mmol)及(4-(2-(4-氟苯基)乙醯胺基)苯基)硼酸(0.11 g,0.40 mmol)溶解於1,4-二㗁烷(1.0 ml)及1 M碳酸鈉(0.3 ml)中之後,逐滴添加肆(三苯基膦)鈀(0) (0.14 g,0.12 mmol)。在用氮氣鼓泡之後,其在80℃下攪拌隔夜。反應完成後,其經由矽藻土過濾器過濾,用甲醇洗滌,且隨後在減壓下濃縮,得到所要化合物乙酸4-(4-(2-(4-氟苯基)乙醯胺基)苯基)-7-甲氧基喹唑啉-6-基酯(250.0 mg,70%純度,99%產率)。其未經進一步純化即用於以下反應中。
MS(m/z): 446.2 [M+H]
+UPLC r.t.(min): 1.55
步驟2:將步驟1中獲得之乙酸4-(4-(2-(4-氟苯基)乙醯胺基)苯基)-7-甲氧基喹唑啉-6-基酯(0.25 g,0.56 mmol)溶解於7 N (4.0 ml)氨之甲醇溶液中之後,隨後在室溫下攪拌30分鐘。反應完成後,其經由矽藻土過濾器過濾,用二氯甲烷洗滌且在減壓下濃縮。使用二氯甲烷及乙醚獲得固體所要化合物2-(4-氟苯基)-
N-(4-(6-羥基-7-甲氧基喹唑啉-4-基)苯基)乙醯胺(0.23 g,80%純度,81%產率)。其未經進一步純化即用於以下反應中。
MS(m/z): 404.1 [M+H]
+UPLC r.t.(min): 1.33
步驟3:將步驟2中獲得之2-(4-氟苯基)-
N-(4-(6-羥基-7-甲氧基喹唑啉-4-基)苯基)乙醯胺(0.04 g,0.10 mmol)、2-氯-N,N-二乙基乙烷-1-胺鹽酸鹽(1.9 mg,0.1 mmol)及碳酸鉀(3.0 mg,0.22 mmol)溶解於乙腈(0.3 ml)及蒸餾水(0.3 ml)中之後,且將其在80℃下攪拌2小時。在反應完成之後,添加蒸餾水,且用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。在分離及藉由MPLC (DCM:MeOH=0-10%)純化濃縮混合物之後,得到所要化合物
N-(4-(6-(2-(二乙基胺基)乙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)乙醯胺(17.0 mg,34.1%)。
MS(m/z): 503.3 [M+H]
+UPLC r.t.(min): 1.46
< 實例 123> N -( 4 -( 6 -(( 1 - 乙基哌啶 - 4 - 基 ) 氧基 )- 7 - 甲氧基喹唑啉 - 4 - 基 ) 苯基 )- 2 -( 4 -( 三氟甲基 ) 苯基 ) 乙醯胺之製備 步驟1:將4-((4-氯-7-甲氧基喹唑啉-6-基)氧基)哌啶-1-甲酸三級丁酯(0.30 g,0.75 mmol)及(4-(2-(4-三氟甲基苯基)乙醯胺基)苯基)硼酸(0.36 g,1.12 mmol)溶解於1,4-二㗁烷(2.1 ml)及2 M碳酸鈉(0.9 ml)中之後,逐滴添加肆(三苯基膦)鈀(0) (0.26 g,0.23 mmol)。在用氮氣鼓泡之後,其在80℃下攪拌隔夜。反應完成後,將其經由矽藻土過濾器過濾且減壓濃縮,得到所要化合物4-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)哌啶-1-甲酸三級丁酯(0.26 g,54.5 %)。其未經進一步純化即用於以下反應中。
MS(m/z): 637.4 [M+H]
+UPLC r.t.(min): 1.87
步驟2:將步驟1中獲得之4-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)哌啶-1-甲酸三級丁酯(0.26 g,0.41 mmol)溶解於二氯甲烷(4.1 ml)中之後,逐滴添加三氟乙酸(0.47 g,4.08 mmol)且在室溫下攪拌隔夜。反應完成後,將其在減壓下濃縮,且隨後將所要化合物2,2,2-三氟乙酸
N-(4-(7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.2 g,75%)分離且藉由製備型HPLC純化。
MS(m/z): 537.3 [M+H]
+UPLC r.t.(min): 1.25
步驟3:將步驟2中獲得之2,2,2-三氟乙酸
N-(4-(7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(0.03 g,0.05 mmol)及三乙醯氧基硼氫化鈉(0.02 g,0.09 mmol)溶解於1,4-二㗁烷(0.5 ml)中之後,逐滴添加乙醛(3.05 mg,0.07 mmol)及
N,
N-二異丙基乙基胺(0.03 g,0.23 mmol),隨後在室溫下攪拌隔夜。反應完成後,將其減壓濃縮且經由製備型HPLC純化,得到所要化合物
N-(4-(6-((1-乙基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺(15.0mg,57.6%)。
MS(m/z): 565.3 [M+H]
+UPLC r.t.(min): 1.29
實例 122 至 164實例124至164以類似於實例122及123之方式製備,且實例122至164之化合物名稱、NMR、質量及UPLC分析結果概述於下表3中。
[表3]
實例 | 結構 | 化合物名稱 | 1H NMR; MS(m/z) | UPLC r.t. (min) |
122 | N-(4-(6-(2-(二乙基胺基)乙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3- d 3): δ 9.15 (s, 1H), 7.75-7.63 (m, 4H), 7.39-7.33 (m, 3H), 7.31 (s, 1H), 7.20 (s, 1H), 7.13 (t, J= 8.6 Hz, 2H), 4.10-4.05 (m, 2H), 4.04 (s, 3H), 3.78 (s, 2H), 2.93 (t, J= 6.6 Hz, 2H), 2.62 (q, J= 7.1 Hz, 4H), 1.04 (t, J= 7.1 Hz, 6H). 503.3 [M+H] + | 1.46 | |
123 | N-(4-(6-((1-乙基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 565.3 [M+H] + | 1.30 | |
124 | 2-(4-氟苯基)- N-(4-(6-羥基-7-甲氧基喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.44 (s, 1H), 9.03 (s, 1H), 7.81 (d, J= 8.6 Hz, 2H), 7.71 (d, J= 8.6 Hz, 2H), 7.64-7.60 (m, 2H), 7.58-7.54 (m, 2H), 7.41-7.39 (m, 1H), 7.17 (t, J= 8.8 Hz, 2H), 4.00 (s, 3H), 3.71 (s, 2H). 404.3 [M+H] + | 1.43 | |
125 | ( R)- N-(4-(7-甲氧基-6-((四氫呋喃-3-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.56 (s, 1H), 9.10 (s, 1H), 7.87-7.78 (m, 4H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.44 (s, 1H), 7.28 (s, 1H), 5.08-4.99 (m, 1H), 4.00 (s, 3H), 3.92 (d, J= 10.5 Hz, 1H), 3.89-3.79 (m, 4H), 3.73 (td, J= 8.3, 5.0 Hz, 1H), 2.22-2.03 (m, 2H). 524.3 [M+H] + | 1.62 | |
126 | N-(4-(7-甲氧基-6-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.09 (s, 1H), 7.82 (q, J= 8.8 Hz, 4H), 7.72 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.42 (s, 1H), 7.33 (s, 1H), 4.05 (t, J= 6.4 Hz, 2H), 4.00 (s, 3H), 3.84 (s, 2H), 2.40 (t, J= 7.0 Hz, 8H), 2.12 (s, 3H), 1.92-1.86 (m, 2H). 594.3 [M+H] + | 1.22 | |
127 | N-(4-(6-(3-(4-環丙基哌𠯤-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.29 (s, 1H), 8.85 (s, 1H), 7.58 (q, J= 8.7 Hz, 4H), 7.48 (d, J= 8.0 Hz, 2H), 7.36 (d, J= 8.0 Hz, 2H), 7.18 (s, 1H), 7.10 (s, 1H), 3.81 (t, J= 6.4 Hz, 2H), 3.76 (s, 3H), 3.60 (s, 2H), 3.16 (s, 2H), 2.23 (s, 8H), 2.14 (t, J= 7.1 Hz, 2H), 1.66 (q, J= 6.6 Hz, 2H), 1.31 (tt, J= 6.7, 3.6 Hz, 1H), 0.12 (td, J= 6.4, 4.1 Hz, 2H). 620.4 [M+H] + | 1.34 | |
128 | N-(4-(6-(3-(4-乙醯基哌𠯤-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.09 (s, 1H), 7.82 (q, J= 8.5 Hz, 4H), 7.72 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 7.9 Hz, 2H), 7.42 (s, 1H), 7.35 (s, 1H), 4.08 (t, J= 6.4 Hz, 2H), 4.01 (s, 3H), 3.84 (s, 2H), 3.39 (s, 2H), 2.43 (t, J= 7.1 Hz, 2H), 2.34 (t, J= 5.0 Hz, 2H), 2.28 (t, J= 5.1 Hz, 2H), 1.96 (s, 3H), 1.92 (t, J= 6.9 Hz, 2H). 622.4 [M+H] + | 1.28 | |
129 | N-(4-(7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.09 (d, J= 0.9 Hz, 1H), 7.82 (q, J= 8.7 Hz, 4H), 7.72 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.42 (s, 1H), 7.33 (s, 1H), 4.06 (t, J= 6.3 Hz, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 3.53 (t, J= 4.6 Hz, 4H), 2.40 (t, J= 7.2 Hz, 2H), 2.33 (t, J= 4.5 Hz, 4H), 1.91 (p, J= 6.7 Hz, 2H). 581.3 [M+H] + | 1.30 | |
130 | 3-(((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)甲基)哌啶-1-甲酸三級丁酯 | 651.4 [M+H] + | 1.92 | |
131 | N-(4-(7-甲氧基-6-(2-(4-甲基哌𠯤-1-基)乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.55 (s, 1H), 9.10 (s, 1H), 7.88-7.79 (m, 4H), 7.75-7.69 (m, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.43 (s, 1H), 7.38 (s, 1H), 4.16 (t, J= 5.5 Hz, 2H), 4.01 (s, 3H), 3.85 (s, 2H), 2.94 (s, 1H), 2.82 (d, J= 30.3 Hz, 4H), 1.91 (s, 3H), 1.31-1.21 (m, 2H), 0.98-0.79 (m, 2H). 580.3 [M+H] + | 1.34 | |
132 | 4-甲基哌𠯤-1-甲酸7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基酯 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.55 (s, 1H), 9.21 (s, 1H), 7.87-7.82 (m, 2H), 7.76-7.70 (m, 5H), 7.62-7.56 (m, 3H), 4.01 (s, 3H), 3.85 (s, 2H), 3.59 (s, 2H), 3.43-3.38 (m, 2H), 2.35 (s, 4H), 2.22 (s, 3H). 580.3 [M+H] + | 1.29 | |
133 | N-(4-(7-甲氧基-6-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.67 (s, 1H), 9.08 (s, 1H), 7.82 (q, J= 8.8 Hz, 4H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.41 (s, 1H), 7.32 (s, 1H), 4.01 (s, 3H), 3.87 (d, J= 9.6 Hz, 4H), 1.91 (s, 2H), 1.55 (s, 2H), 1.46-1.13 (m, 4H), 0.89-0.81 (m, 1H). 551.3 [M+H] + | 1.31 | |
134 | N-(4-(6-((1-乙基哌啶-3-基)甲氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.09 (s, 1H), 7.87-7.76 (m, 4H), 7.72 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.43 (s, 1H), 7.33 (s, 1H), 4.01 (s, 3H), 3.92 (d, J= 6.0 Hz, 2H), 3.84 (s, 2H), 1.74 (s, 2H), 1.48 (s, 2H), 1.24 (s, 3H), 1.06-0.93 (m, 3H), 0.90-0.79 (m, 1H). 579.3 [M+H] + | 1.34 | |
135 | 3-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)氮雜環丁-1-甲酸三級丁酯 | 609.3 [M+H] + | 1.80 | |
136 | 3-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)吡咯啶-1-甲酸三級丁酯 | 623.3 [M+H] + | 1.82 | |
137 | 4-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)哌啶-1-甲酸三級丁酯 | 637.4 [M+H] + | 1.88 | |
138 | N-(4-(6-(氮雜環丁-3-基氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 509.3 [M+H] + | 1.25 | |
139 | N-(4-(7-甲氧基-6-(吡咯啶-3-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 523.3 [M+H] + | 1.25 | |
140 | N-(4-(7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 537.3 [M+H] + | 1.25 | |
141 | N-(4-(7-(3-(4-乙醯基哌𠯤-1-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 622.4 [M+H] + | 1.30 | |
142 | N-(4-(7-(3-(4-環丙基哌𠯤-1-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 620.4 [M+H] + | 1.35 | |
143 | N-(4-(6-甲氧基-7-(3-(4-甲基-3-側氧基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 608.3 [M+H] + | 1.32 | |
144 | N-(4-(6-((1-乙基氮雜環丁-3-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 537.3 [M+H] + | 1.30 | |
145 | N-(4-(6-((1-乙基吡咯啶-3-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.03 (s, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.74 (d, J= 8.1 Hz, 2H), 7.66 (d, J= 8.2 Hz, 2H), 7.58 (d, J= 8.1 Hz, 2H), 7.41 (s, 1H), 7.32 (s, 1H), 4.06 (s, 3H), 3.86 (s, 2H), 3.50 - 3.40 (m, 1H), 3.38 - 3.31 (m, 2H), 3.16 - 2.96 (m, 3H), 2.46 - 2.33 (m, 1H), 2.30 - 2.18 (m, 1H), 1.27 (t, J= 7.2 Hz, 3H). 551.3 [M+H] + | 1.30 | |
146 | N-(4-(7-甲氧基-6-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.05 (s, 1H), 7.89-7.85 (m, 2H), 7.80-7.75 (m, 2H), 7.68 (d, J= 8.2 Hz, 2H), 7.61 (d, J= 8.1 Hz, 2H), 7.41 (d, J= 14.1 Hz, 2H), 4.08 (s, 3H), 3.98 (d, J= 5.7 Hz, 2H), 3.88 (s, 2H), 3.48-3.39 (m, 2H), 3.04 (td, J= 12.8, 3.1 Hz, 2H), 2.11-2.04 (m, 2H), 1.73-1.60 (m, 2H). 551.3 [M+H] + | 1.32 | |
147 | N-(4-(6-((1-乙基哌啶-4-基)甲氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.08 (s, 1H), 7.86-7.78 (m, 4H), 7.73 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.42 (s, 1H), 7.33 (s, 1H), 4.01 (s, 3H), 3.92-3.80 (m, 4H), 2.90 (d, J= 10.9 Hz, 2H), 2.33 (q, J= 7.3 Hz, 2H), 1.90 (q, J= 11.2, 8.1 Hz, 2H), 1.73 (d, J= 12.9 Hz, 2H), 1.30 (ddd, J= 23.4, 16.7, 9.5 Hz, 3H), 1.00 (t, J= 7.1 Hz, 3H). 579.3 [M+H] + | 1.33 | |
148 | N-(4-(6-(3-(2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.63 (s, 1H), 9.08 (s, 1H), 7.87-7.76 (m, 4H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.41 (s, 1H), 7.30 (s, 1H), 4.00 (s, 5H), 3.85 (s, 2H), 3.53 (s, 4H), 2.41 (t, J= 6.9 Hz, 2H), 1.85 (s, 5H), 1.74-1.66 (m, 2H). 592.3 [M+H] + | 1.26 | |
149 | N-(4-(6-(3-(6-乙基-2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.53 (s, 1H), 9.08 (s, 1H), 7.87-7.77 (m, 4H), 7.72 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.41 (s, 1H), 7.31 (s, 1H), 4.00 (s, 5H), 3.85 (s, 2H), 2.44 (t, J= 6.9 Hz, 2H), 2.37-2.30 (m, 2H), 1.91 (s, 5H), 1.72 (q, J= 6.7, 5.4 Hz, 2H), 1.43-1.08 (m, 2H), 0.89-0.79 (m, 4H). 620.4 [M+H] + | 1.23 | |
150 | N-(4-(6-(3-(3,3-雙(羥基甲基)氮雜環丁-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.15-9.00 (m, 1H), 7.88-7.67 (m, 6H), 7.60 (d, J= 7.8 Hz, 2H), 7.44 (s, 1H), 7.32 (s, 1H), 4.03 (d, J= 12.2 Hz, 5H), 3.85 (s, 2H), 2.88 (s, 2H), 2.09 (d, J= 2.8 Hz, 4H), 1.89 (d, J= 12.4 Hz, 6H). 611.4 [M+H] + | 1.38 | |
151 | N-(4-(6-(3-(7-氧雜-2-氮雜螺[3.5]壬烷-2-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.10 (s, 1H), 7.82 (q, J= 8.1 Hz, 4H), 7.73 (d, J= 7.8 Hz, 2H), 7.60 (d, J= 7.9 Hz, 2H), 7.44 (s, 1H), 7.32 (s, 1H), 4.03 (d, J= 17.4 Hz, 5H), 3.85 (s, 2H), 2.09 (s, 4H), 1.88 (d, J= 25.3 Hz, 6H), 1.65 (s, 4H), 1.25 (s, 1H), 0.85 (dt, J= 10.7, 6.3 Hz, 1H). 621.3 [M+H] + | 1.37 | |
152 | N-(4-(6-(3-(3-(二甲基胺基)氮雜環丁-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.55 (s, 1H), 9.11 (s, 1H), 7.89-7.67 (m, 6H), 7.60 (d, J= 7.8 Hz, 2H), 7.46 (s, 1H), 7.33 (s, 1H), 4.05 (d, J= 22.0 Hz, 6H), 3.85 (s, 2H), 2.10-2.08 (m, 8H), 1.98-1.90 (m, 4H), 1.25 (s, 1H), 0.85 (d, J= 10.0 Hz, 1H). 594.3 [M+H] + | 1.24 | |
153 | N-(4-(7-甲氧基-6-(氧雜環丁-3-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.59 (s, 1H), 9.11 (s, 1H), 7.85 (d, J= 8.2 Hz, 2H), 7.79-7.68 (m, 4H), 7.60 (d, J= 7.9 Hz, 2H), 7.48 (s, 1H), 6.93 (s, 1H), 5.42-5.31 (m, 1H), 4.82 (t, J= 7.0 Hz, 2H), 4.75-4.58 (m, 2H), 4.04 (s, 3H), 3.86 (s, 2H). 510.2 [M+H] + | 1.71 | |
154 | N-(4-(6-(3-(環丙基胺基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.52 (d, J= 2.6 Hz, 1H), 9.09 (d, J= 2.6 Hz, 1H), 7.82 (qd, J= 8.8, 2.5 Hz, 4H), 7.72 (dd, J= 8.4, 2.5 Hz, 2H), 7.60 (dd, J= 8.4, 2.5 Hz, 2H), 7.42 (d, J= 2.7 Hz, 1H), 7.34 (d, J= 2.6 Hz, 1H), 4.07 (td, J= 6.5, 2.6 Hz, 2H), 4.01 (d, J= 2.6 Hz, 3H), 3.85 (s, 1H), 2.71 (dt, J= 9.0, 4.6 Hz, 2H), 2.03 (dq, J= 6.6, 3.3 Hz, 1H), 1.90 (d, J= 2.6 Hz, 4H), 0.32 (tq, J= 6.3, 3.7, 3.2 Hz, 2H), 0.19-0.11 (m, 2H). 551.3 [M+H] + | 1.41 | |
155 | N-(4-(7-甲氧基-6-(3-((1-甲基-1 H-吡唑-4-基)胺基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.57 (s, 1H), 9.09 (s, 1H), 7.81 (t, J= 9.1 Hz, 4H), 7.72 (d, J= 8.0 Hz, 2H), 7.60 (d, J= 7.8 Hz, 2H), 7.43 (s, 1H), 7.34 (s, 1H), 7.03 (s, 1H), 6.91 (s, 1H), 4.10 (d, J= 6.4 Hz, 2H), 4.02 (s, 3H), 3.85 (s, 2H), 3.65 (s, 3H), 2.97 (s, 2H), 1.98 (s, 2H). 591.3 [M+H] + | 1.44 | |
156 | ( S)- N-(4-(7-甲氧基-6-((四氫呋喃-2-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.58 (s, 1H), 9.09 (d, J= 7.2 Hz, 1H), 7.93-7.65 (m, 6H), 7.60 (d, J= 7.9 Hz, 2H), 7.44 (s, 1H), 7.28 (s, 1H), 5.04 (s, 1H), 4.00 (s, 3H), 3.91-3.80 (m, 4H), 2.18 (q, J= 6.7 Hz, 1H), 1.76 (s, 1H), 1.27 (d, J= 18.1 Hz, 1H), 0.86 (t, J= 7.7 Hz, 1H). 524.3 [M+H] + | 1.61 | |
157 | N-(4-(7-甲氧基-6-(吡啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.55 (s, 1H), 9.10 (s, 1H), 8.67 (dd, J= 2.3, 0.8 Hz, 1H), 8.58 (dd, J= 4.8, 1.7 Hz, 1H), 7.89-7.82 (m, 3H), 7.72 (td, J= 7.3, 1.4 Hz, 4H), 7.63-7.57 (m, 2H), 7.49-7.42 (m, 3H), 5.27 (s, 2H), 4.02 (s, 3H), 3.85 (s, 2H). 561.3 [M+H] + | 1.45 | |
158 | N-(4-(7-甲氧基-6-(3-((1 S,4 S)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.10 (s, 1H), 7.87 (d, J= 8.2 Hz, 2H), 7.77 (d, J= 8.3 Hz, 2H), 7.68 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 9.6 Hz, 2H), 4.13 (t, J= 6.0 Hz, 2H), 4.09 (d, J= 4.9 Hz, 3H), 3.89 (d, J= 5.0 Hz, 2H), 3.87-3.82 (m, 1H), 3.74-3.68 (m, 1H), 3.03-2.92 (m, 3H), 2.87-2.80 (m, 1H), 2.71 (s, 2H), 2.26 (s, 3H), 2.03 (q, J= 4.9, 3.3 Hz, 4H), 1.35-1.29 (m, 1H). 606.4 [M+H] + | 1.16 | |
159 | N-(4-(7-甲氧基-6-(3-((1 R,4 R)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, MeOD- d 4 ): δ 9.03 (s, 1H), 7.87 (d, J= 8.4 Hz, 2H), 7.78-7.73 (m, 2H), 7.68 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 7.37 (d, J= 10.2 Hz, 2H), 4.12 (t, J= 6.0 Hz, 2H), 4.07 (d, J= 1.3 Hz, 3H), 3.89 (d, J= 10.3 Hz, 3H), 3.73 (d, J= 2.3 Hz, 1H), 3.06 (d, J= 11.8 Hz, 1H), 2.97 (ddd, J= 11.6, 8.9, 2.4 Hz, 3H), 2.82 (dt, J= 11.9, 7.0 Hz, 1H), 2.05 (d, J= 3.7 Hz, 3H), 1.96 (s, 4H), 1.33-1.28 (m, 1H). 606.4 [M+H] + | 1.16 | |
160 | N-(4-(7-甲氧基-6-(3-(吡咯啶-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.52 (s, 1H), 9.08 (s, 1H), 7.87-7.77 (m, 4H), 7.72 (d, J= 8.1 Hz, 2H), 7.60 (d, J= 8.0 Hz, 2H), 7.42 (s, 1H), 7.33 (s, 1H), 4.07 (t, J= 6.4 Hz, 2H), 4.01 (s, 3H), 3.84 (s, 2H), 2.56 (s, 2H), 1.90 (s, 6H), 1.69-1.61 (m, 4H). 565.3 [M+H] + | 1.31 | |
161 | N-(4-(6-(3-(六氫吡咯并[1,2-a]吡𠯤-2(1H)-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.57 (s, 1H), 9.11 (s, 1H), 7.83 (q, J= 8.1, 7.7 Hz, 4H), 7.73 (d, J= 7.9 Hz, 2H), 7.60 (d, J= 7.9 Hz, 2H), 7.45 (s, 1H), 7.35 (s, 1H), 4.09 (t, J= 6.0 Hz, 2H), 4.02 (s, 3H), 3.85 (s, 3H), 2.86 (s, 5H), 2.00 (d, J= 70.5 Hz, 9H), 1.25 (s, 1H), 0.86 (s, 1H). 620.4 [M+H] + | 1.24 | |
162 | N-(4-(6-(3-(2-氧雜-6-氮雜螺[3.3]庚烷-6-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺 | 1H NMR (400 MHz, DMSO- d 6 ): δ 10.54 (s, 1H), 9.08 (s, 1H), 7.88-7.76 (m, 4H), 7.75-7.68 (m, 2H), 7.63-7.56 (m, 2H), 7.41 (s, 1H), 7.30 (s, 1H), 4.55 (s, 4H), 4.05-3.93 (m, 5H), 3.85 (s, 2H), 3.20 (s, 4H), 2.41 (t, J= 6.9 Hz, 2H), 1.77-1.66 (m, 2H). 593.4 [M+H] + | 1.30 | |
163 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(2-氟-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3): δ 9.15 (s, 1H), 8.56 (t, J= 8.2 Hz, 1H), 7.70 - 7.65 (m, 2H), 7.48 (dd, J= 7.7, 2.8 Hz, 2H), 7.38 (s, 1H), 6.91 - 6.79 (m, 3H), 6.01 (s, 2H), 4.29 (t, J= 6.6 Hz, 2H), 3.89 (s, 3H), 3.74 (s, 2H), 2.59 (t, J= 7.1 Hz, 10H), 2.33 (s, 3H), 2.15 - 2.10 (m, 2H). 588.2 [M+H]+ | 1.38 | |
164 | 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)-2-甲基苯基)乙醯胺 | 1H NMR (400 MHz, CDCl 3): δ 9.14 (s, 1H), 8.24 (d, J= 8.7 Hz, 1H), 7.61 (d, J= 7.1 Hz, 2H), 7.35 (d, J= 16.8 Hz, 2H), 7.20 (s, 1H), 6.92 - 6.83 (m, 3H), 6.02 (s, 2H), 4.29 (t, J= 6.6 Hz, 2H), 3.87 (s, 3H), 3.75 (s, 2H), 2.62 - 2.36 (m, 10H), 2.30 (s, 3H), 2.13 (t, J= 7.0 Hz, 2H), 2.07 (s, 3H). 584.2 [M+H] + | 1.33 |
< 實例 165> 4 -( 6 - 甲氧基 - 7 -( 3 -( 4 - 甲基哌 𠯤 - 1 - 基 ) 丙氧基 ) 喹唑啉 - 4 - 基 )- N -( 4 -( 三氟甲基 ) 苯甲基 ) 苯甲醯胺之製備 步驟1:將7-(苯甲基氧基)-4-氯-6-甲氧基喹唑啉(1 g,3.33 mmol)及(4-(乙氧基羰基)苯基)硼酸(0.774 g,3.99 mmol)溶解於1,4-二㗁烷(11.08 ml)及1 M碳酸鈉(7.32 ml)中之後,逐滴添加肆(三苯基膦)鈀(0) (0.19 g,0.17 mmol)。在用氮氣鼓泡之後,將其在80℃下攪拌2.5小時。反應完成後,其經矽藻土過濾器過濾,用甲醇洗滌,減壓濃縮,且隨後分離且藉由MPLC (EA:HEX=0-80%)純化,且得到所要化合物4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯甲酸乙酯(850.0 mg,產率61.7%)。
MS(m/z): 414.9 [M+H]
+UPLC r.t.(min): 2.07
步驟2:將步驟1中獲得之4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯甲酸乙酯(1.34 g,3.23 mmol)溶解於三氟乙酸(4.74 ml)中之後,將其在80℃下攪拌隔夜。當反應完成時,在減壓濃縮之後,獲得固體所要化合物2,2,2-三氟乙酸4-(7-羥基-6-甲氧基喹唑啉-4-基)苯甲酸乙酯(0.9 g,90 %)。以下反應不經進一步純化即進行。
MS(m/z): 325.0 [M+H]
+UPLC r.t.(min): 1.57
步驟3:將步驟2中獲得之2,2,2-三氟乙酸4-(7-羥基-6-甲氧基喹唑啉-4-基)苯甲酸乙酯(0.56 g,1.33 mmol)及碳酸鉀(0.733 g,5.30 mmol)溶解於乙腈(3.79 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(0.857 g,6.63 mmol)。在向反應混合物中逐滴添加1-(3-氯丙基)-4-甲基哌𠯤二鹽酸鹽(0.993 g,3.98 mmol)之後,將其在70℃下攪拌隔夜。反應完成時,將其減壓濃縮且經由MPLC (DCM:MeOH=0-20%)純化,得到所要化合物4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲酸乙酯(0.29 g,產率47.1%)。
MS(m/z): 465.3 [M+H]
+UPLC r.t.(min): 1.32
步驟4:將步驟3中獲得之4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲酸乙酯(0.29 g,0.624 mmol)及水合氫氧化鋰(52.4 mg,1.248 mmol)溶解於甲醇(1.24 ml)及蒸餾水(1.24 ml)中之後,將其在室溫下攪拌隔夜。在反應完成之後,添加1 N鹽酸及蒸餾水,且用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。在濃縮之後,獲得所要化合物4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲酸(180 mg,66%)。
MS(m/z): 437.2 [M+H]
+UPLC r.t.(min): 1.09
步驟5:將(4-(三氟甲基)苯基)甲胺(108 mg,0.61 mmol)及HATU (235.0 mg,0.61 mmol)溶解於二氯甲烷(0.8 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(133 mg,1.03 mmol)。將在步驟4中獲得之4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲酸(108 mg,0.619 mmol)添加至反應混合物中,且隨後在室溫下攪拌2小時。在反應完成之後,添加蒸餾水,且隨後用乙酸乙酯(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘水,且在減壓下濃縮。在分離及藉由MPLC (DCM:MeOH=0-20%)純化濃縮混合物之後,得到所要化合物4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)-
N-(4-(三氟甲基)苯甲基)苯甲醯胺(21 mg,17.1 %)。
MS(m/z): 594.3 [M+H]
+UPLC r.t.(min): 1.52
實例 165 至 167實例166至167以類似於實例165之方式製備,且實例165至167之化合物名稱、NMR、質量及UPLC分析結果概述於下表4中。
[表4]
實例 | 結構 | 化合物名稱 | 1H NMR; MS(m/z) | UPLC r.t. (min) |
165 | 4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)- N-(4-(三氟甲基)苯甲基)苯甲醯胺 | 1H NMR (400 MHz, DMSO-d 6) δ 9.39 (t, J= 6.0 Hz, 1H), 9.16 (s, 1H), 8.13 (d, J= 8.1 Hz, 2H), 7.95 (d, J= 8.1 Hz, 2H), 7.73 (d, J= 8.0 Hz, 2H), 7.59 (d, J= 8.0 Hz, 2H), 7.46 (s, 1H), 7.31 (s, 1H), 4.61 (d, J= 5.9 Hz, 2H), 4.28 (t, J= 6.4 Hz, 2H), 3.85 (s, 3H), 2.94 (d, J= 19.4 Hz, 2H), 2.88-2.72 (m, 8H), 2.61-2.55 (m, 3H), 2.02 (p, J= 6.4, 5.9 Hz, 2H). 594.3[M+H] + | 1.52 | |
166 | N-(苯并[ d][1,3]間二氧雜環戊烯-5-基甲基)-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.20 (s, 1H), 7.99 (d, J= 8.2 Hz, 2H), 7.85 (d, J= 8.2 Hz, 2H), 7.41 (s, 1H), 7.21 (s, 1H), 6.92-6.78 (m, 3H), 6.43 (t, J= 5.7 Hz, 1H), 5.98 (s, 2H), 4.61 (d, J= 5.6 Hz, 2H), 4.30 (t, J= 6.6 Hz, 2H), 3.87 (s, 3H), 2.59 (t, J= 7.2 Hz, 4H), 2.32 (s, 3H), 2.14 (t, J= 6.9 Hz, 2H), 1.25 (s, 3H), 0.92-0.80 (m, 2H). 570.1[M+H] + | 1.25 | |
167 | N-(3,4-二氟苯甲基)-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲醯胺 | 1H NMR (400 MHz, CDCl 3) δ 9.19 (s, 1H), 8.03-7.97 (m, 2H), 7.88-7.82 (m, 2H), 7.41 (s, 1H), 7.24-7.07 (m, 3H), 6.63 (t, J= 5.9 Hz, 1H), 4.67 (d, J= 5.9 Hz, 2H), 4.30 (t, J= 6.6 Hz, 2H), 3.87 (s, 3H), 2.61 (t, J= 7.2 Hz, 4H), 2.38 (s, 3H), 2.14 (p, J= 6.8 Hz, 2H), 1.25 (s, 6H), 0.87 (dt, J= 8.2, 4.2 Hz, 2H). 562.2[M+H] + | 1.39 |
< 實例 168> 1 -( 4 - 氯 - 3 -( 三氟甲基 ) 苯基 )- 3 -( 4 -( 6 - 甲氧基 - 7 -( 3 -( 4 - 甲基哌 𠯤 - 1 - 基 ) 丙氧基 ) 喹唑啉 - 4 - 基 ) 苯基 ) 脲之製備 步驟1:將4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯胺(128 mg,0.314 mmol)及1,1'-羰基二咪唑(CDI) (102 mg,0.628 mmol)溶解於二氯甲烷(0.8 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(60.9 mg,0.471 mmol)。在室溫下攪拌1小時且反應結束之後,添加蒸餾水且用二氯甲烷(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,用硫酸鈉移除剩餘水且在減壓下濃縮,獲得所要化合物
N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-1
H-咪唑-1-甲醯胺(136 mg,86%)。其未經單獨純化即用於以下反應中。
MS(m/z): 466.0 [M+H]
+UPLC r.t.(min): 1.12
步驟2:將步驟1中獲得之
N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-1
H-咪唑-1-甲醯胺(136 mg,0.271 mmol)溶解於二氯甲烷(0.8 ml)中之後,逐滴添加
N,
N-二異丙基乙基胺(60.9 mg,0.471 mmol)及4-氯-3-(三氟甲基)苯胺(80 mg,0.407 mmol)。在50℃下攪拌1小時且反應完成後,添加蒸餾水且用二氯甲烷(×3)萃取有機物。所收集之有機層在用鹽水洗滌後,使用硫酸鈉移除剩餘的水,在減壓下濃縮,且分離並使用製備型HPLC純化所要化合物1-(4-氯-3-(三氟甲基)苯基)-3-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)脲(38.7 mg,22.6 %)。
MS(m/z): 629.2 [M+H]
+UPLC r.t.(min): 1.60
實例 168 至 169實例169以與實例168類似之方式製備,且實例168至169之化合物名稱、NMR、質量及UPLC分析結果概述於下表5中。
[表5]
實例 | 結構 | 化合物名稱 | 1H NMR; MS(m/z) | UPLC r.t. (min) |
168 | 1-(4-氯-3-(三氟甲基)苯基)-3-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)脲 | 1H NMR (400 MHz, DMSO- d 6 ) δ 9.39 (s, 1H), 9.28 (s, 1H), 9.09 (s, 1H), 8.17 (d, J= 2.4 Hz, 1H), 7.84 (d, J= 8.5 Hz, 2H), 7.76-7.62 (m, 4H), 7.41 (d, J= 1.5 Hz, 2H), 4.26 (t, J= 6.4 Hz, 2H), 3.88 (s, 3H), 2.65-2.52 (m, 6H), 2.25 (s, 4H), 1.99 (p, J= 6.7 Hz, 2H), 1.25 (q, J= 4.9, 3.8 Hz, 3H). 629.2[M+H] + | 1.60 | |
169 | 1-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-3-(3-(三氟甲基)苯基)脲 | 1H NMR (400 MHz, DMSO- d 6 ) δ 9.21 (s, 1H), 9.17 (s, 1H), 9.09 (s, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.76-7.69 (m, 2H), 7.62 (d, J= 8.4 Hz, 1H), 7.55 (t, J= 7.9 Hz, 1H), 7.41 (s, 2H), 7.35 (d, J= 7.7 Hz, 1H), 4.26 (t, J= 6.4 Hz, 2H), 3.88 (s, 3H), 2.53 (d, J= 1.9 Hz, 6H), 2.21 (s, 4H), 1.98 (t, J=6.9 Hz, 2H), 1.24 (s, 3H). 595.2[M+H] + | 1.50 |
實驗實例 1 : 評價針對 PDGFR - α 、 PDGFR - β 、 c - KIT 激酶之酶抑制活性為了評價根據以上實例合成之化合物對PDGFR-α(wt)、PDGFR-β(wt)、c-KIT(wt)及c-KIT(D816V)激酶之抑制活性,進行以下方法。使實例之化合物與經純化人類PDGFR-α(wt)(Signalchem #P12-18G)酶、人類PDGFR-β(wt)(Signalchem #P13-11G)酶、人類c-KIT(wt)(Signalchem #K06-11BG)酶、人類c-KIT(D816V)(Signalchem #C06-12LG)酶反應,且藉由以下方法評價酶抑制能力。
反應緩衝液作為40 mM Tris-HCl pH 7.4、20 mM MgCl
2、0.5 mg/ml BSA、50 μM DTT之組合物使用,且所有測試之反應均在反應緩衝液上進行。化合物使用連續稀釋方法由10 mM DMSO儲備液以12個步驟稀釋,且以10至0.00005645 μM之最終化合物濃度量測酶活性。在測試期間,在恰當濃度之人類PDGFR-α(wt)酶、人類PDGFR-β(wt)、人類c-KIT(wt)酶及人類c-KIT(D816V)酶在25℃下與純化ATP及酶受質反應1至2小時之後,使用活體外ADP-Glo
TM激酶分析(Promega)確認酶活性。使酶活性反應溶液、ADP-Glo反應溶液及酶活性偵測溶液在2:2:1之比率下反應以用發光(luminoscence)量測酶活性之抑制。基於未用化合物處理的溶劑對照組的酶活性螢光,根據各化合物的處理濃度計算酶活性抑制程度,且抑制50%酶活性的各化合物的濃度確定為IC
50(nM)值且該值藉由使用GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego)軟體獲得。結果展示於下表6中。(A:IC
50≤
50nM;B:50nM < IC
50≤ 100nM;C:100nM < IC
50≤ 500nM;D:IC
50> 500nM)。
[表6]
實例 | PDGFR-α | PDGFR-β | c-KIT (WT) | c-KIT (D816V) | 實例 | PDGFR-α | PDGFR-β | c-KIT (WT) | c-KIT (D816V) |
1 | A | A | A | A | 2 | A | A | A | A |
3 | A | A | A | A | 4 | - | A | - | - |
9 | A | A | A | A | 10 | A | C | - | - |
11 | A | A | A | A | 30 | - | A | - | - |
31 | - | A | - | - | 32 | - | A | - | - |
37 | - | A | - | - | 40 | - | A | - | - |
43 | - | A | - | - | 48 | - | A | - | - |
49 | - | A | - | - | 50 | - | A | - | - |
51 | - | A | - | - | 54 | - | A | - | - |
56 | - | A | - | - | 57 | A | A | A | A |
58 | A | A | - | - | 59 | - | A | - | - |
63 | - | A | - | - | 64 | - | A | - | - |
69 | - | A | - | - | 70 | - | A | - | - |
72 | A | A | - | - | 74 | - | A | - | - |
75 | - | A | - | - | 76 | - | A | - | - |
81 | - | A | - | - | 82 | - | A | - | - |
83 | A | A | - | - | 84 | A | A | - | - |
85 | A | A | - | - | 89 | A | A | - | - |
90 | A | A | - | - | 96 | - | A | - | - |
97 | - | A | - | - | 98 | - | A | - | - |
99 | - | A | - | - | 100 | - | A | - | - |
101 | - | A | - | - | 109 | - | A | - | - |
110 | - | A | - | - | 113 | - | A | - | - |
115 | - | A | - | - | 116 | - | A | - | - |
121 | - | A | - | - | 122 | A | B | A | A |
124 | A | C | - | - | 129 | - | A | - | - |
130 | - | A | - | - | 131 | - | A | - | - |
137 | - | A | - | - | 140 | A | A | - | - |
142 | - | A | - | - | 147 | A | A | - | - |
149 | A | A | - | - | 150 | - | A | - | - |
151 | A | A | - | - | 158 | - | A | - | - |
161 | - | A | - | - | 163 | - | A | - | - |
164 | - | A | - | - | 165 | - | A | - | - |
166 | - | A | - | - | 167 | - | A | - | - |
168 | - | B | - | - |
如表6中所展示,證實本發明之化合物具有抑制PDGFR-α、PDGFR-β、c-KIT(wt)及c-KIT(D816V)激酶之活性的作用。此等表明,本發明之化合物可有效地用於預防或治療與PDGFR-α、PDGFR-β、c-KIT(wt)或c-KIT(D816V)相關之疾病。
實驗實例 2 : 評價對 Ba / F3 細胞之增殖抑制活性將Ba/F3-TEL-PDGFRα(WT)、Ba/F3-TEL-PDGFRβ(WT)、Ba/F3-c-KIT(D816V)(Kyinno,#KC-0138)、c-KIT V560G/D816V、c-KIT D814Y以3×10
3/100 μl/孔接種於透明底白色96孔盤中。將含有連續稀釋3倍之12種濃度(0.00001-2 mM)之化合物之培養溶液及DMSO對照物以各自0.5 μl/孔添加至0.00005-10 μM之最終濃度,且隨後在CO
2培育箱中在37℃下培育72小時。72小時後,取出用化合物處理之盤,用100 μl/孔CellTiter-Glo®分析(Promega)溶液處理,隨後充分混合。在室溫下充分混合約10分鐘之後,使用微量盤讀取器量測螢光。資料以基於媒劑之與經處理細胞成比例之百分比呈現,使用GraphPad Prism 8.3.0(GraphPad software Inc., San Diego)計算GI
50(nM)值。
量測如上文所描述量測之表現PDGFR-α、PDGFR-β、c-KIT(D816V)、c-KIT V560G/D816V及c-KIT D814Y之Ba/F3之抑制活性且展示於下表7中(A:GI
50≤
200nM;B:200nM < GI
50≤ 500nM;C:GI
50> 500nM)。
[表7]
實例 | Ba/F3(nM) | 細胞(nM) | 實例 | Ba/F3(nM) | 細胞(nM) | ||||||
Tel-PDGFRα | Tel-PDGFRβ | c-KIT (D816V) | c-KIT V560G/D816V | c-KIT D814Y | Tel-PDGFRα | Tel-PDGFRβ | c-KIT (D816V) | c-KIT V560G/D816V | c-KIT D814Y | ||
1 | A | A | A | A | 2 | A | A | A | B | ||
3 | A | A | A | A | A | 4 | A | A | A | A | |
9 | A | A | A | A | A | 10 | A | B | A | C | |
11 | A | A | A | A | A | 14 | C | ||||
15 | C | 16 | A | ||||||||
17 | A | 18 | A | A | A | A | |||||
19 | A | 20 | C | ||||||||
21 | A | 22 | A | A | A | ||||||
23 | A | B | 24 | A | C | ||||||
25 | A | A | 26 | A | |||||||
27 | A | C | 28 | A | C | ||||||
29 | A | A | 30 | A | A | A | |||||
31 | A | A | A | 32 | A | A | |||||
33 | A | A | 34 | A | A | ||||||
35 | A | C | 36 | A | C | ||||||
37 | A | A | 38 | A | |||||||
39 | A | B | 40 | A | A | A | |||||
41 | A | A | 42 | A | A | ||||||
43 | A | A | A | 44 | A | A | |||||
45 | 48 | A | |||||||||
49 | A | 50 | A | ||||||||
51 | A | 52 | A | ||||||||
53 | A | 54 | A | ||||||||
55 | A | A | 56 | A | |||||||
57 | A | A | A | 58 | A | A | A | C | |||
59 | B | 60 | A | B | |||||||
61 | C | 62 | C | ||||||||
63 | A | A | 64 | A | A | ||||||
65 | A | 66 | A | ||||||||
67 | A | 68 | A | ||||||||
69 | A | 70 | A | A | |||||||
71 | A | B | 72 | A | A | A | A | ||||
73 | A | A | 74 | A | A | ||||||
75 | A | A | 76 | A | A | ||||||
77 | A | B | 78 | A | A | ||||||
79 | A | 80 | A | A | |||||||
81 | A | A | 82 | A | A | ||||||
83 | A | A | A | A | 84 | A | A | A | A | ||
85 | A | A | A | B | 86 | C | |||||
87 | A | 88 | B | ||||||||
89 | A | A | A | 90 | A | A | A | ||||
91 | B | 92 | B | ||||||||
93 | B | 94 | C | ||||||||
95 | C | 96 | A | ||||||||
97 | A | C | 98 | A | A | ||||||
99 | A | A | 100 | A | A | ||||||
101 | A | 102 | A | ||||||||
103 | B | 104 | B | ||||||||
105 | C | 106 | C | ||||||||
107 | C | 108 | C | ||||||||
109 | A | A | 110 | A | A | ||||||
111 | C | 112 | C | ||||||||
113 | A | A | 114 | B | |||||||
115 | A | A | 116 | A | A | ||||||
117 | A | 118 | A | A | |||||||
119 | C | 120 | C | ||||||||
121 | A | A | 122 | A | A | ||||||
123 | A | A | 124 | A | A | ||||||
125 | A | C | C | 126 | A | A | A | ||||
127 | A | B | 128 | A | |||||||
129 | A | B | 130 | B | |||||||
131 | A | B | B | 132 | A | A | C | ||||
133 | A | B | C | 134 | A | A | A | ||||
135 | B | 136 | A | ||||||||
137 | B | 138 | A | B | A | ||||||
139 | A | C | 140 | A | A | A | C | C | |||
141 | A | A | 142 | A | A | A | |||||
143 | A | A | 144 | A | B | A | |||||
145 | A | B | A | 146 | C | ||||||
147 | A | A | A | 148 | C | ||||||
149 | A | A | C | 150 | C | ||||||
151 | A | A | A | 152 | A | ||||||
153 | A | 154 | A | ||||||||
155 | A | 156 | A | B | |||||||
157 | A | C | 158 | A | A | B | |||||
159 | A | B | 160 | A | A | ||||||
161 | A | A | A | 163 | A | ||||||
164 | A | 165 | A | ||||||||
166 | A | 167 | A | ||||||||
169 | A |
如表7中所展示,本發明化合物展示抑制PDGFR-α、PDGFR-β、c-KIT(D816V)、c-KIT V560G/D816V及c-KIT D814Y之過度活化細胞株之增殖的活性。
實驗實例 3 : 評價針對各種激酶之抑制活性評價根據本發明之化合物針對各種酶之活性。特定言之,委託DiscoverX量測以上實例3、9及83之化合物的酶選擇性,且使用scanMAX™激酶分析小組進行實驗。在本文中,將藉由以1 μM的濃度溶解於DMSO中製備的溶液用作酶處理的藥物,且藉由以下方程式1的方法確定對照百分比(對照%),且結果展示於下表8中。
[方程式1]
在該方程式中,陽性對照組及陰性對照組分別意謂展現0%之對照百分比之化合物及展現100%之對照百分比的DMSO。本文中,當所計算之各酶之百分比值小於35%時,確定對酶具有抑制活性。因此,在所測試之一系列酶中,展示本發明化合物之抑制活性的酶以及其對照百分比概述且示於下表8中。(◎:小於10%;○:10%或更大至小於35%)。
[表8]
激酶 | 實例 | 激酶 | 實例 | ||||
3 | 9 | 83 | 3 | 9 | 83 | ||
KIT | ◎ | ◎ | ◎ | KIT(A829P) | ◎ | ◎ | ◎ |
KIT(D816H) | ◎ | ◎ | ◎ | KIT(D816V) | ◎ | ◎ | ◎ |
KIT(L576P) | ◎ | ○ | ◎ | KIT(V559D) | ◎ | ○ | ◎ |
KIT(V559D,T670I) | ○ | ○ | KIT(V559D,V654A) | ◎ | ○ | ||
KIT-自抑制 | ○ | PDGFRA | ◎ | ◎ | |||
PDGFRB | ◎ | ◎ |
由於上文已詳細描述本發明的具體部分,因此熟習此項技術者將清楚,具體技術僅為較佳實施例,且本發明的範疇不受此限制。因此,本發明之實質範疇將由隨附申請專利範圍及其等效物定義。
Claims (17)
- 一種由以下化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽: [化學式1] 在化學式1中, R 1及R 2各自獨立地為-H、-(C1-C6)烷基、-(CH 2) m-R X或-(C=O)-R X{其中,R 1及R 2不能同時為甲基}; R X為-(C1-C6)烷氧基、-NR AR B、-鹵基、環烷基、雜環烷基、芳基、雜芳基或雜氫芳基{其中該環烷基或該雜環烷基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)羥基烷基、-(C1-C6)烷基-O-(C1-C6)烷基、-(C=O)-(C1-C6)烷基、-(C=O)-O-(C1-C6)烷基、-NR CR D、-(=O)-、環烷基或苯甲基取代,[其中,該苯甲基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)烷氧基、-(C1-C6)鹵基烷基或鹵基取代];該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基或鹵基取代}; R A及R B各自獨立地為-H、-(C1-C6)烷基、環烷基、雜環烷基、芳基或雜芳基{其中,該環烷基、該雜環烷基、該芳基或該雜芳基環中之至少一個H可經-(C1-C6)烷基取代}; R C及R D各自獨立地為-H或-(C1-C6)烷基; m為0、1、2、3或4; R 3為-H、-(C1-C6)烷基、-(C1-C6)烷氧基或-鹵基; L為-NH(C=O)-L 1-(CH 2) n-L 2-、-NH-S(=O) 2-L 1-(CH 2) n-L 2-、-(C=O)NH-L 1-(CH 2) n-L 2-、-L 1-(CH 2) n-L 2-(C=O)NH-或-NH(C=O)NH-; L 1及L 2各自獨立地為-CR ER F-、-C(=O)NH-或為空值; R E及R F各自獨立地為-H、-(C1-C6)烷基、-NH 2、-NH(C=O)O-(C1-C6)烷基、-OH或-鹵基,或R E及R F與碳組合形成-(C3-C6)環烷基; n為0、1、2、3或4; Z為芳基、雜芳基、雜氫芳基、環烷基、雜環烷基或-(C2-C6)烯基{其中,該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基、-(C1-C6)羥基烷基、-(C1-C6)氰基烷基、-CN、-NR GR H、-(C1-C6)烷氧基或-鹵基取代;該環烷基或該雜環烷基環中之至少一個H可經-(C1-C6)烷基取代}; R G及R H各自獨立地為H或-(C1-C6)烷基。
- 如請求項1之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽,其中 R 1及R 2各自獨立地為-H、-(C1-C6)烷基、-(CH 2) m-R X或-(C=O)-R X{其中,R 1及R 2不能同時為甲基}; R X為-(C1-C6)烷氧基、-NR AR B、-鹵基、雜環烷基、芳基、雜芳基或雜氫芳基{其中,該雜環烷基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)羥基烷基、-(C1-C6)烷基-O-(C1-C6)烷基、-(C=O)-(C1-C6)烷基、-(C=O)-O-(C1-C6)烷基、-NR CR D、-(=O)-、環烷基或苯甲基取代[其中,該苯甲基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)烷氧基、-(C1-C6)鹵基烷基或鹵基取代];該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)鹵基烷基取代}; R A及R B各自獨立地為-H、-(C1-C6)烷基、環烷基或雜芳基{其中,該環烷基或該雜芳基環中之至少一個H可經-(C1-C6)烷基取代}; R C及R D各自獨立地為-H或-(C1-C6)烷基; m為0、1、2、3或4; R 3為-H、-(C1-C6)烷基或-鹵基; L為-NH(C=O)-L 1-(CH 2) n-L 2-、-NH-S(=O) 2-L 1-(CH 2) n-L 2-、-(C=O)NH-L 1-(CH 2) n-L 2-或-NH(C=O)NH-; L 1及L 2各自獨立地為-CR ER F-或為空值; R E及R F各自獨立地為-H、-(C1-C6)烷基或-NH 2,或R E及R F與碳組合形成-(C3-C6)環烷基; n為0、1、2、3或4; Z為苯基、5-10員雜芳基、5-10員雜氫芳基、5-10員雜環烷基或-(C2-C6)烯基{其中,該苯基、該5-10員雜芳基或該5-10員雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基、-CN、-(C1-C6)烷氧基或-鹵基取代;該5-10員雜環烷基環中之至少一個H可經-(C1-C6)烷基取代}。
- 如請求項1之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽,其中 R 1及R 2各自獨立地為-H、-(C1-C6)烷基、-(CH 2) m-R X或-(C=O)-R X{其中,R 1及R 2不能同時為甲基}; R X為-(C1-C6)烷氧基、-NR AR B、-鹵基、雜環烷基、芳基、雜芳基或雜氫芳基{其中,該雜環烷基為單環、螺環、橋連環或稠環,該雜環烷基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)羥基烷基、-(C1-C6)烷基-O-(C1-C6)烷基、-(C=O)-(C1-C6)烷基、-(C=O)-O-(C1-C6)烷基、-NR CR D、-(=O)-、環烷基或苯甲基取代[其中,該苯甲基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)烷氧基、-(C1-C6)鹵基烷基或鹵基取代];該芳基、該雜芳基或該雜氫芳基環中之至少一個H可經-(C1-C6)鹵基烷基取代}; R A及R B各自獨立地為-H、-(C1-C6)烷基、環烷基或雜芳基{其中,該環烷基或該雜芳基環中之至少一個H可經-(C1-C6)烷基取代}; R C及R D各自獨立地為-H或-(C1-C6)烷基; m為0、1、2或3。
- 如請求項1之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽,其中該由化學式1表示之化合物由以下化學式2表示: [化學式2] 在化學式2中, R 3為-H、-(C1-C6)烷基或-鹵基。
- 如請求項1之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽,其中 L為-NH(C=O)-L 1-(CH 2) n-L 2-、-NH-S(=O) 2-L 1-(CH 2) n-L 2-、-(C=O)NH-L 1-(CH 2) n-L 2-或-NH(C=O)NH-; L 1及L 2各自獨立地為-CR ER F-或為空值; R E及R F各自獨立地為-H、-(C1-C6)烷基或-NH 2,或R E及R F與碳組合形成-(C3-C6)環烷基; n為0、1、2或3。
- 如請求項1之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽,其中 Z為苯基、5-10員雜芳基、5-10員雜氫芳基、5-10員雜環烷基或-(C2-C6)烯基{其中,該苯基、該5-10員雜芳基或該5-10員雜氫芳基環中之至少一個H可經-(C1-C6)烷基、-(C1-C6)鹵基烷基、-CN、-(C1-C6)烷氧基或-鹵基取代;該5-10員雜環烷基環中之至少一個H可經-(C1-C6)烷基取代}。
- 如請求項1之由化學式1表示之化合物、其立體異構體或其醫藥學上可接受之鹽,其中該由化學式1表示之化合物選自由下列化合物組成之群: (1) N-(4-(7-(2-(二乙基胺基)乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (2) N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (3) N-(4-(6-甲氧基-7-(2-(4-甲基哌𠯤-1-基)乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (4) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (5) N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (6) N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (7) 2-胺基- N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)丙醯胺; (8) 2-胺基-2-(4-氟苯基)- N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)丙醯胺; (9) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (10) 2-胺基-2-(4-氟苯基)- N-(4-(7-異丁氧基-6-甲氧基喹唑啉-4-基)苯基)丙醯胺; (11) N-(4-(7-(3-(二乙基胺基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (12) N-(4-(7-(苯甲基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-甲基-2-(4-(三氟甲基)苯基)丙醯胺; (13) N-(4-(7-羥基-6-甲氧基喹唑啉-4-基)苯基)-2-甲基-2-(4-(三氟甲基)苯基)丙醯胺; (14) 3-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯; (15) 4-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)哌啶-1-甲酸三級丁酯; (16) N-(4-(6-甲氧基-7-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (17) N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (18) N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (19) 6-(3-((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)丙氧基)-2,6-二氮雜螺[3.3]庚烷-2-甲酸三級丁酯; (20) N-(4-(7-(3-(2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (21) N-(4-(7-(3-(6-乙基-2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (22) N-(4-(7-(3-(3-(二甲基胺基)氮雜環丁烷-1-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (23) N-(4-(7-(3-氯丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (24) N-(4-(7-(氮雜環丁烷-3-基氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (25) N-(4-(7-(3-(環丙基胺基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (26) N-(4-(6-甲氧基-7-(3-((1-甲基-1 H-吡唑-4-基)胺基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (27) N-(4-(6-甲氧基-7-((1-(4-甲氧基苯甲基)氮雜環丁-3-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (28) N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)氮雜環丁-3-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (29) N-(4-(6-甲氧基-7-(吡啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (30) N-(4-(7-(2-(1 H-吡唑-1-基)乙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (31) N-(4-(6-甲氧基-7-(3-((1 R,4 R)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (32) N-(4-(6-甲氧基-7-(3-((1 S,4 S)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (33) N-(4-(7-(3-(六氫吡咯并[1,2- a]吡𠯤-2(1 H)-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (34) N-(4-(6-甲氧基-7-(3-(3-(三氟甲基)-5,6-二氫-[1,2,4]三唑[4,3-a]吡𠯤-7(8 H)-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (35) ( R)-3-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)吡咯啶-1-甲酸三級丁酯; (36) ( S)-3-(((6-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-7-基)氧基)甲基)吡咯啶-1-甲酸三級丁酯; (37) N-(4-(6-甲氧基-7-(3-(3-甲基-3,6-二氮雜雙環[3.1.1]庚烷-6-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (38) ( R)- N-(4-(6-甲氧基-7-(吡咯啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (39) ( S)- N-(4-(6-甲氧基-7-(吡咯啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (40) ( R)- N-(4-(7-((1-乙基吡咯啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (41) ( S)- N-(4-(7-((1-乙基吡咯啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (42) N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-3-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (43) N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (44) N-(4-(6-甲氧基-7-(3-(4-甲基哌啶-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (45) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-1-苯基甲磺醯胺; (46) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-1-(4-(三氟甲基)苯基)甲磺醯胺; (47) 1-(4-溴苯基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)甲磺醯胺; (48) 2-(呋喃-2-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)丙醯胺; (49) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)-2-甲基苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (50) N-(2-氟-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (51) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(噻唑-4-基)乙醯胺; (52) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(2-氟-4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (53) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)-2-甲基苯基)乙醯胺; (54) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (55) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺; (56) N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (57) N-(4-(6,7-雙(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (58) 2-胺基- N-(4-(6,7-雙(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(4-氟苯基)丙醯胺; (59) N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (60) N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺; (61) 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺; (62) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺; (63) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (64) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺; (65) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-異丙基-1 H-1,2,3-三唑-1-基)乙醯胺; (66) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (67) 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (68) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (69) 2-(6-氯吡啶-3-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺; (70) 2-(6-氯吡啶-3-基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (71) N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-3-苯基丙醯胺; (72) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-3-苯基丙醯胺; (73) ( R)- N-(4-(6-甲氧基-7-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (74) ( R)- N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (75) ( S)- N-(4-(6-甲氧基-7-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (76) ( S)- N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (77) 2-(4-氯-3-(三氟甲基)苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺; (78) 2-(4-氯-3-(三氟甲基)苯基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (79) 2-(3-氟-4-(三氟甲基)苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺; (80) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(3-氟-4-(三氟甲基)苯基)乙醯胺; (81) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺; (82) 2-(4-氯-3-(三氟甲基)苯基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (83) 2-(4-氰基苯基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (84) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(噻吩-3-基)乙醯胺; (85) 2-(2,3-二氫苯并呋喃-5-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (86) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(哌啶-4-基)乙醯胺; (87) N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)丁-3-烯醯胺; (88) 2-(4-氟苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-甲基丙醯胺; (89) 2-(4-氟苯基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-甲基丙醯胺; (90) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)-2-甲基丙醯胺; (91) 1-(4-氟苯基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)環丙烷-1-甲醯胺; (92) 1-(4-氟苯基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)環丙烷-1-甲醯胺; (93) N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-1-(4-氟苯基)環丙烷-1-甲醯胺; (94) 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (95) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (96) N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (97) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)乙醯胺; (98) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (99) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(7-((1-乙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (100) N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺; (101) N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (102) N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (103) N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺; (104) N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (105) 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (106) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(6-甲氧基-7-((1-甲基哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (107) N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-異丙基-1 H-1,2,3-三唑-1-基)乙醯胺; (108) N-(4-(7-((1-乙醯基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)乙醯胺; (109) N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺; (110) N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (111) N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-異丙基-1 H-1,2,3-三唑-1-基)乙醯胺; (112) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-乙基哌啶-3-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (113) 2-(6-氯吡啶-3-基)- N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)乙醯胺; (114) N-(4-(6-甲氧基-7-((1-(2-甲氧基乙基)哌啶-4-基)甲氧基)喹唑啉-4-基)苯基)-4-苯基丁醯胺; (115) N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (116) N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-甲氧基吡啶-3-基)乙醯胺; (117) N-(4-(6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (118) N-(4-(6-甲氧基-7-(2-甲氧基乙氧基)喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (119) 2-(4-(三級丁基)-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (120) 2-(4-異丙基-1 H-1,2,3-三唑-1-基)- N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)乙醯胺; (121) N-(4-(7-((1-異丙基哌啶-4-基)甲氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(6-(三氟甲基)吡啶-3-基)乙醯胺; (122) N-(4-(6-(2-(二乙基胺基)乙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-氟苯基)乙醯胺; (123) N-(4-(6-((1-乙基哌啶-4-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (124) 2-(4-氟苯基)- N-(4-(6-羥基-7-甲氧基喹唑啉-4-基)苯基)乙醯胺; (125) ( R)- N-(4-(7-甲氧基-6-((四氫呋喃-3-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (126) N-(4-(7-甲氧基-6-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (127) N-(4-(6-(3-(4-環丙基哌𠯤-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (128) N-(4-(6-(3-(4-乙醯基哌𠯤-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (129) N-(4-(7-甲氧基-6-(3-嗎啉基丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (130) 3-(((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)甲基)哌啶-1-甲酸三級丁酯; (131) N-(4-(7-甲氧基-6-(2-(4-甲基哌𠯤-1-基)乙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (132) 4-甲基哌𠯤-1-甲酸7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基酯; (133) N-(4-(7-甲氧基-6-(哌啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (134) N-(4-(6-((1-乙基哌啶-3-基)甲氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (135) 3-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)氮雜環丁-1-甲酸三級丁酯; (136) 3-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)吡咯啶-1-甲酸三級丁酯; (137) 4-((7-甲氧基-4-(4-(2-(4-(三氟甲基)苯基)乙醯胺基)苯基)喹唑啉-6-基)氧基)哌啶-1-甲酸三級丁酯; (138) N-(4-(6-(氮雜環丁-3-基氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (139) N-(4-(7-甲氧基-6-(吡咯啶-3-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (140) N-(4-(7-甲氧基-6-(哌啶-4-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (141) N-(4-(7-(3-(4-乙醯基哌𠯤-1-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (142) N-(4-(7-(3-(4-環丙基哌𠯤-1-基)丙氧基)-6-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (143) N-(4-(6-甲氧基-7-(3-(4-甲基-3-側氧基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (144) N-(4-(6-((1-乙基氮雜環丁-3-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (145) N-(4-(6-((1-乙基吡咯啶-3-基)氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (146) N-(4-(7-甲氧基-6-(哌啶-4-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (147) N-(4-(6-((1-乙基哌啶-4-基)甲氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (148) N-(4-(6-(3-(2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (149) N-(4-(6-(3-(6-乙基-2,6-二氮雜螺[3.3]庚烷-2-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (150) N-(4-(6-(3-(3,3-雙(羥基甲基)氮雜環丁-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (151) N-(4-(6-(3-(7-氧雜-2-氮雜螺[3.5]壬烷-2-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (152) N-(4-(6-(3-(3-(二甲基胺基)氮雜環丁-1-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (153) N-(4-(7-甲氧基-6-(氧雜環丁-3-基氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (154) N-(4-(6-(3-(環丙基胺基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (155) N-(4-(7-甲氧基-6-(3-((1-甲基-1H-吡唑-4-基)胺基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (156) ( S)-N-(4-(7-甲氧基-6-((四氫呋喃-2-基)氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (157) N-(4-(7-甲氧基-6-(吡啶-3-基甲氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (158) N-(4-(7-甲氧基-6-(3-((1 S,4 S)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (159) N-(4-(7-甲氧基-6-(3-((1 R,4 R)-5-甲基-2,5-二氮雜雙環[2.2.1]庚烷-2-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (160) N-(4-(7-甲氧基-6-(3-(吡咯啶-1-基)丙氧基)喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (161) N-(4-(6-(3-(六氫吡咯并[1,2-a]吡𠯤-2(1 H)-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (162) N-(4-(6-(3-(2-氧雜-6-氮雜螺[3.3]庚烷-6-基)丙氧基)-7-甲氧基喹唑啉-4-基)苯基)-2-(4-(三氟甲基)苯基)乙醯胺; (163) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(2-氟-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)乙醯胺; (164) 2-(苯并[ d][1,3]間二氧雜環戊烯-5-基)- N-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)-2-甲基苯基)乙醯胺; (165) 4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)- N-(4-(三氟甲基)苯甲基)苯甲醯胺; (166) N-(苯并[ d][1,3]間二氧雜環戊烯-5-基甲基)-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲醯胺; (167) N-(3,4-二氟苯甲基)-4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯甲醯胺; (168) 1-(4-氯-3-(三氟甲基)苯基)-3-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)脲;及 (169) 1-(4-(6-甲氧基-7-(3-(4-甲基哌𠯤-1-基)丙氧基)喹唑啉-4-基)苯基)-3-(3-(三氟甲基)苯基)脲。
- 一種醫藥組合物,其包含如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其用於預防或治療一或多種選自由以下組成之群的疾病:癌症、肥大細胞相關疾病、纖維化疾病、神經疾病、粥狀硬化症及肺高血壓,該醫藥組合物包含如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽作為活性成分。
- 如請求項9之醫藥組合物,其中該癌症為選自由以下組成之群中之任一或多者:鱗狀細胞癌、小細胞肺癌、非小細胞肺癌、肺腺癌、肺鱗狀細胞癌、腹膜癌、皮膚癌、皮膚或眼黑色素瘤、直腸癌、肛周腺癌、食道癌、小腸癌、內分泌腺癌、甲狀腺癌、副甲狀腺癌、腎上腺癌、軟組織肉瘤、尿道癌、慢性或急性白血病、淋巴球性淋巴瘤、肝細胞癌、胃腸癌、胃癌、胰臟癌、神經膠母細胞瘤、子宮頸癌、卵巢癌、肝癌、膀胱癌、肝腫瘤、乳癌、結腸癌、大腸癌、子宮內膜癌或子宮癌、唾液腺癌、腎癌、前列腺癌、外陰癌、頭頸癌、腦癌、骨肉瘤、神經芽細胞腫、生殖細胞腫瘤及胃腸道間質瘤。
- 如請求項9之醫藥組合物,其中該纖維化為選自由以下組成之群的任一或多者:全身性硬化症、肺纖維化、肝纖維化、肝硬化、腎纖維化、骨髓纖維化、心肌纖維化、類肉瘤病、瘢痕瘤、燒傷誘導之肥厚性瘢痕、增生性視網膜病變、青光眼、白內障、後囊膜混濁(posterior capsular opacification)、血管成形術、血管手術或血管損傷後的血管再狹窄、囊腫性纖維化及馬凡氏症候群(Marfan syndrome)。
- 一種用於預防或治療c-KIT或PDGFR相關疾病之醫藥組合物,其包含如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽作為活性成分。
- 如請求項12之醫藥組合物,其中該組合物抑制選自由以下組成之群中之任一或多者:PDGFR-α、PDGFR-β、c-KIT(D816V)、c-KIT V560G/D816V及c-KIT D814Y。
- 一種治療或預防選自由以下組成之群之任一或多種疾病的方法:癌症、肥大細胞相關疾病、纖維化疾病、神經疾病、粥狀硬化症及肺高血壓,該方法包含向有需要之個體投與治療有效量之如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽。
- 一種治療或預防c-KIT或PDGFR相關疾病之方法,其包含向有需要之個體投與治療有效量之如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽。
- 一種如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽的用途,其用於製備用以治療或預防選自由以下組成之群之任一或多種疾病的藥劑:癌症、肥大細胞相關疾病、纖維化疾病、神經疾病、粥狀硬化症及肺高血壓。
- 一種如請求項1至7中任一項之化合物、其立體異構體或其醫藥學上可接受之鹽的用途,其用於製備用以治療或預防c-KIT或PDGFR相關疾病之藥劑。
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EP1673346A1 (en) * | 2003-10-06 | 2006-06-28 | GPC Biotech AG | Quinazoline derivatives for the treatment of herpesviral infections |
WO2014039714A2 (en) * | 2012-09-06 | 2014-03-13 | Plexxikon Inc. | Compounds and methods for kinase modulation, and indications therefor |
MX2020002183A (es) * | 2017-08-31 | 2020-10-05 | Abbvie Inc | Inhibidores de la ectonucleótido pirofosfatasa-fosfodiesterasa 1 (enpp-1) y usos de los mismos. |
US20220056052A1 (en) * | 2018-12-28 | 2022-02-24 | Riboscience Llc | Quinazoline derivatives as ectonucleotide pyrophosphatase phosphodiesterase 1 inhibitors |
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