CN101440092A - 2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 - Google Patents
2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 Download PDFInfo
- Publication number
- CN101440092A CN101440092A CNA2008101641055A CN200810164105A CN101440092A CN 101440092 A CN101440092 A CN 101440092A CN A2008101641055 A CNA2008101641055 A CN A2008101641055A CN 200810164105 A CN200810164105 A CN 200810164105A CN 101440092 A CN101440092 A CN 101440092A
- Authority
- CN
- China
- Prior art keywords
- compound
- indazole
- pyrroles
- pyridine
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供一类2-吲唑-4-氮杂吲哚-5-氨基衍生物,是在N5位引入不同的取代基,以2-(叔丁氧羰基(甲基)氨基)-5-硝基吡啶为原料,通过烷基化,缩合反应,还原环合,叔丁氧羰基保护,2-位碘代反应得到中间化合物5-位取代的2-碘代4-氮杂吲哚,与吲唑的锡化物通过Stille偶联,再经酸性条件脱保护基,在碱性条件下在N5位引入取代基得到目的化合物。本发明提供的化合物经药理实验证实对多种肿瘤细胞株均有较好的体外抑制增殖作用,具有抑制肿瘤细胞生长的作用,可在制备抗肿瘤药物中的应用。本发明的结构通式如图。
Description
技术领域
本发明属有机化合物的合成,涉及2-吲唑-4-氮杂吲哚-5-氨基衍生物,尤其涉及在N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物和制备方法,以及在抗肿瘤药物中的应用。
背景技术
CDK7作为CDKs家族的重要成员,在细胞周期过程中发挥重要的作用,是一个新型的抗肿瘤靶点。CDK7主要通过2种方式调节细胞周期:a、CDK7-Cyclin H或CDK7-Cyclin H-MAT1复合物被磷酸化后,可使CDK1、2、4和6活性区域的苏氨酸残基被磷酸化,从而激活它们的活性,主导细胞周期的启动、进行和结束;b、磷酸化的CDK7-Cyclin H-MAT1复合物能磷酸化RNA聚合酶II的C端区域的大亚基,从而促使启动子的清除,诱导转录的开始。因此,抑制CDK7活性区域的磷酸化,就能抑制其在调节细胞周期中的双重作用,从而阻断CDK1、2、4和6在细胞周期中的主导作用,影响转录过程,达到抑制肿瘤细胞增殖的目的。
2006年Mark等人首先发现吲哚-吲唑类衍生物具有CDK7的抑制作用,其中3-(5-(吗啉基甲基)-1H-吲哚-2-基)-1H-吲唑-6-腈基的活性较高,其IC50值仅为11nM。该文所提供的吲哚-吲唑衍生物的结构主要是在吲哚环的N5位引入不同的取代基,并且在吲唑环的6-位引入不同的杂环以及酰胺结构。
发明内容
本发明的目的是提供一类结构新颖未见文献报道的2-吲唑-4-氮杂吲哚-5-氨基衍生物,具体是N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物,在其N5位引入不同的取代基,合成了一系列的N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物。
本发明提供的N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物结构通式如下:
其中:
X为氢原子、羰基、砜基、亚砜基;
L为氮原子、氧原子、C0~C3的烷基链;
R1为C1~C3的直链或支链烷基、C4~C7的环烷烃、苯环、芳杂环,其中苯环可为无取代、单取代、二取代或三取代的苯环,芳杂环为噻吩、吡啶、呋喃、吡咯;
单取代苯环上的取代基为氟原子、氯原子、溴原子、甲氧基、甲基、硝基、羟基、三氟甲基、三氟甲氧基、C1~C3的烷基直链或支链、C1~C3的直链或支链烷氧基;
二取代苯环上的取代基为3,4-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、3-硝基-4-甲氧基、3-氨基-4-甲氧基、3,4-二氟;
三取代苯环上的取代基为3,4,5-三甲氧基;
R2为氢、卤素、腈基、含C1~C3的酰基、吡咯、吡唑、咪唑、三氮唑、二甲胺基;
R3为C1~C3的烷基链。
本发明的另一个目的是提供N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物的制备方法,通过以下步骤实现:
(1)化合物2可以由2-(叔丁氧羰基(甲基)氨基)-5-硝基吡啶(化合物1)在碱性条件下与卤代烃经烷基化反应得到,反应一般在极性溶剂如二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜中进行,常用的碱性物质有氢氧化钠、氢氧化钾、氢化钠、氢化钾,反应温度为-10~5℃,反应时间为5~6小时,得到的产品可以通过重结晶纯化。
(2)化合物3由化合物2通过缩合反应得到,反应一般在极性溶剂如二甲基甲酰胺、二甲基乙酰胺、二甲基亚砜中进行,反应温度一般为60~120℃,反应时间为12~14小时,得到的产品可以直接进行下一步反应。
(3)化合物4可由化合物3在还原剂存在下通过还原环合反应得到,反应一般在质子性溶剂如甲醇、乙醇、甲醇/水、乙醇/水中进行,所用还原剂可为氯化亚锡、还原铁粉、钯/碳,通常在室温下反应,反应时间为8~10小时,得到的产品可以通过重结晶纯化。
(4)化合物5可由化合物4通过叔丁氧羰基保护得到,反应一般以四氢呋喃、二氯甲烷为溶剂,通常在室温下反应,反应时间为1~3小时,得到的产品可以通过重结晶纯化。
(5)化合物6(5-位取代的2-碘代4-氮杂吲哚)可由化合物5通过碘代反应得到,该反应一般以四氢呋喃为溶剂,并需要强碱作用,常用的强碱有二异丙胺锂、叔丁基锂、丁基锂,反应在-75~-80℃条件下进行,反应时间为12~14小时,得到的化合物通过柱层析纯化。
(6)化合物8可由化合物6与化合物7在催化剂存在的条件下,通过Stille偶联得到,该反应一般在甲苯、苯、二氧六环中进行,催化剂为钯试剂,反应温度为95~100℃,反应时间为18~24h,得到的化合物可通过柱层析纯化。
(7)化合物9可由化合物8在酸性条件脱掉叔丁氧羰基保护基团得到,该反应一般在质子性混合溶剂中进行,如甲醇/水、乙醇/水等,常用的酸有浓盐酸、三氟乙酸等,反应一般在室温进行,反应时间为1~5h,得到的化合物可通过柱层析纯化。
(8)目的化合物10可由化合物9在碱性条件下通过取代反应可以得到,碱性条件可以由氢氧化钠、氢氧化钾、氢化钠、氢化钾、三乙胺、二乙胺、吡啶提供,反应温度为55~60℃,反应时间为12~14h,得到的化合物可通过柱层析纯化。
化合物1和化合物7可参照文献方法(Kelly,T.A.Tetrahedron Lett.1994,35,9003-9006)合成得到。
本发明的又一个目的是N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物在制备抗肿瘤药物中的应用。初步的药理实验发现它们对HL60,KB,7721,HCT-116,A549等多种肿瘤细胞株均有较好的体外抑制增殖作用,对HL60作用尤为突出,IC50值在0.80~6.80μM之间,这些数据说明该类化合物具有抑制肿瘤细胞生长的作用。
本发明的有益之处在于:以具有活性的吲哚-吲唑类衍生物为先导化合物,采用生物电子等排原理,以氮原子替代碳原子,得到2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物,再通过母核5-位的氨基引入不同的取代基,合成了一类N5位取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物。这是一类结构全新的化合物,初步的药理活性筛选试验表明这些化合物均具有较好的抗肿瘤活性,且部分化合物的选择性较好。
具体实施方式
本发明结合实施例作进一步的说明。以下的实施例是说明本发明的,而不是以任何方式限制本发明。
实施例1、2-(叔丁氧羰基(甲基)氨基)-6-甲基-5-硝基吡啶2a(R3=-CH3):
将化合物1(14.3g,56.5mmol)溶于二甲基甲酰胺(170ml)中,降温至-5℃左右,依次加入氢化钠(3.1g,130.0mmol)和碘甲烷(4.2ml),TLC跟踪反应。反应结束,乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,减压回收溶剂,重结晶得到淡黄色固体9.5g,收率:58%;熔点:89-91℃。
1H NMR(δ,DMSO-d6):8.39(d,1H,J=9.2Hz),7.84(d,1H,J=9.2Hz),3.39(s,3H),2.73(s,3H),1.50(s,9H)
实施例2、(E)-叔丁基-6-(2-(二甲氨基)乙烯基)-5-硝基吡啶-2-基(甲基)氨基甲酸酯3a(R3=-CH3):
化合物2a(21.9g,81.8mmol)溶于二甲基甲酰胺(278.0ml),加入N,N-二甲基甲酰胺二甲基缩醛(20.4g,171.4mmol),TLC跟踪反应。反应结束,减压回收二甲基甲酰胺,得到红色液体29.0g,收率:95%。
1H NMR(δ,DMSO-d6):8.61(d,1H,J=1.6Hz),8.12(d,1H,J=1.6Hz),7.02(d,1H,J=2.0Hz),5.58(d,1H,J=2.0Hz),2.74(s,3H),2.47(s,6H),1.40(s,9H)
实施例3、5-(叔丁氧羰基(甲基)氨基)-1H-吡咯[3,2-b]吡啶4a(R3=-CH3):
将化合物3a(29g,87.3mmol)溶于甲醇(150.0ml)中,加入钯碳(13.0g),氢气环境下反应,TLC跟踪反应。反应结束,抽滤,滤液减压回收溶剂,重结晶得白色固体21.9g,收率:40%;熔点:151-153℃。
1H NMR(δ,DMSO-d6):11.30(s,1H),7.73(d,1H,J=8.8Hz),7.60(t,1H,J=3.2Hz,J=5.6Hz),7.17(d,1H,J=8.8Hz),3,27(s,3H),1.42(s,9H)
实施例4、N1-叔丁氧羰基-5-(叔丁氧羰基(甲基)氨基)-1H-吡咯[3,2-b]吡啶5a(R3=-CH3):
化合物4a(21.91g,88.7mmol)溶于THF(427.2ml),加入4-二甲氨基吡啶(1.08g,9.6mmol)和叔丁氧羰基碳酸酐(23.88g,109mmol),室温反应30分钟。减压回收THF,重结晶得到白色固体22.19g,收率:77%;熔点:256-258℃
1H NMR(δ,CDCl3):8.26(s,1H),7.77(s,1H),7.44(d,1H,J=8.8Hz),6.67(d,1H,J=3.6Hz),3.41(s,3H),1.65(s,9H),1.48(s,9H)
实施例5、N1-叔丁氧羰基-5-(叔丁氧羰基(甲基)氨基)-2-碘-1H-吡咯[3,2-b]吡啶6a(R3=-CH3):
化合物5a(6.6g,19.0mmol)溶于四氢呋喃(60.0ml),氮气保护,-78℃反应,缓缓滴加丁基锂(9.2ml,2.5mol/L),反应1~2小时,滴加碘的四氢呋喃溶液(碘5.3g,20.9mmol溶于四氢呋喃40.0ml)反应1~2小时,TLC跟踪反应。反应结束,加饱和亚硫酸钠溶液,乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,减压回收溶剂,用洗脱剂(石油醚:丙酮=15:1)进行柱层析,得到淡黄色液体5.42g,收率:61%。
1H NMR(δ,DMSO-d6):8.19(d,1H,J=8.8Hz),7.42(d,1H,J=8.8Hz),3.28(s,3H),1.66(s,9H),1.43(s,9H)
实施例6、N1-叔丁氧羰基-5-(叔丁氧羰基(甲基)氨基)-2-(1-(叔丁氧羰基)-1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶8a(R2=H;R3=-CH3):
化合物6a(3.1g,6.2mmol),化合物7a(R2=H)(2.8g,5.8mmol),钯试剂(0.7g,0.5mmol),甲苯(118.0ml)加入反应器,氮气保护,85℃反应,TLC跟踪反应。反应结束,乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,减压回收溶剂,用洗脱剂(石油醚:丙酮=15:1)进行柱层析,得到淡黄色液体3.35g,收率:62%。
1H NMR(δ,DMSO-d6):8.42(d,1H,J=7.2Hz),8.18(d,1H,J=6.4Hz),7.78(d,1H,J=6.4Hz),7.67(t,1H,J=6.4Hz,J=12.4Hz),7.64(d,1H,J=7.2Hz),7.43(t,1H,J=6.4Hz,J=12.4Hz),7.20(s,1H),3.35(s,1H),1.66(s,9H),1.47(s,9H),1.14(s,9H)
实施例7、2-(1H-吲唑-3-基)-N-甲基-1H-吡咯[3,2-b]吡啶-5-氨基9a(R2=H;R3=-CH3):
化合物8a(1.6g,2.8mmol)溶于乙醇(37.0ml),加入浓盐酸(37.0ml),室温反应,TLC跟踪反应。反应结束,氢氧化钠溶液调节谱H至中性,乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,减压回收溶剂,用洗脱剂(石油醚:乙醇=4:1)进行柱层析,得到黄绿色固体0.3g,收率:42%;熔点:270℃(dec)。
1H NMR(δ,DMSO-d6):13.27(s,1H),11.25(s,1H),8.18(d,1H,J=8.4Hz),7.59(d,1H,J=8.0Hz),7.46(d,1H,J=8.0Hz),7.42(t,1H,J=7.2Hz,J=15.2Hz),7.23(t,1H,J=7.2Hz,J=15.2Hz),6.92(s,1H),6.35(d,1H,J=8.4Hz),6.04(d,1H,4.8Hz),2.81(s,3H)
实施例8、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基苯甲酰胺10a:
化合物9a(26.3mg,0.1mmol),苯甲酰氯(13.5μl,0.1mmol),吡啶(2.0ml)加入反应器,55~60℃反应,TLC跟踪反应。反应结束,减压回收吡啶,1N氢氧化钠调PH值至碱性,二氯甲烷萃取,饱和氯化钠洗涤,无水硫酸钠干燥,减压回收溶剂,用洗脱剂(石油醚:乙醇=8:1)进行柱层析,得到淡黄色固体36.0mg,收率:67%;熔点:177-180℃。
1H NMR(δ,DMSO-d6):13.51(s,1H),11.90(s,1H),8.22(d,1H,J=8.0Hz),7.62(d,1H,J=8.4Hz),7.57(d,1H,J=8.8Hz),7.44(t,1H,J=7.2Hz),7.23~7.29(m,4H),7.17~7.21(m,3H),6.75(d,1H,J=8.4Hz),3.48(s,3H)
实施例9、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-4-溴-N-甲基苯甲酰胺10b:
操作过程同实例8,只是用对溴苯甲酰氯代替苯甲酰氯,得到淡黄色固体,收率:38%;熔点:272℃(dec)。
1H NMR(δ,DMSO-d6):13.61(s,1H),11.94(s,1H),8.22(d,1H,J=8.0Hz),7.63(d,2H,J=8.5Hz),7.46(t,1H,J=7.0Hz),7.41(dd,2H,J=1.5Hz,J=6.5Hz),7.26(t,1H,J=7.0Hz),7.21(dd,2H,J=2.0Hz,J=7.0Hz),7.19(s,1H),6.80(d,1H,J=10.5Hz),3.47(s,1H)
实施例10、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基乙酰胺10c
操作过程同实例8,只是用乙酰氯代替苯甲酰氯,得到淡黄色固体,收率:43%;熔点:275℃(dec)。
1H NMR(δ,DMSO-d6):13.66(s,1H),12.02(s,1H),8.23(d,1H,J=8.4Hz),7.84(d,1H,J=8.4Hz),7.63(d,1H,J=8.4Hz),7.44(t,1H,J=7.2Hz),7.26(t,1H,J=7.2Hz),7.24(s,1H),7.13(d,1H,J=8.0Hz),3.25(s,3H),1.89(s,3H)
实施例11、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基特戊酰胺10d
操作过程同实例8,只是用特戊酰氯代替苯甲酰氯,得到黄绿色固体,收率:77%;熔点:260℃(dec)。
1H NMR(δ,DMSO-d6):13.67(s,1H),12.03(s,1H),8.23(d,1H,J=8.4Hz),7.84(d,1H,J=8.0Hz),7.63(d,1H,J=8.4Hz),7.44(t,1H,J=7.6Hz),7.25(t,1H,J=7.6Hz),7.23(s,1H),7.11(d,1H,J=8.0Hz),3.16(s,3H),0.96(s,3H)
实施例12、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-4-甲氧基-N-甲基苯甲酰胺10e
操作过程同实例8,只是用4-甲氧基苯甲酰氯代替苯甲酰氯,得到淡黄色固体,收率:44%;熔点:265℃(dec)。
1H NMR(δ,DMSO-d6):13.60(s,1H),11.92(s,1H),8.22(d,1H,J=8.4Hz),7.63(d,1H,J=8.4Hz),7.60(d,1H,J=8.8Hz),7.43(t,1H,J=7.2Hz),7.25(t,1H,J=7.2Hz),7.24(s,1H),7.21(d,2H,J=2.8Hz),6.71~6.75(m,3H),3.66(s,3H),3.45(s,3H)
实施例13、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基-4-硝基苯甲酰胺10f
操作过程同实例8,只是用4-硝基苯甲酰氯代替苯甲酰氯,得到淡黄色固体,收率:26%;熔点:231℃(dec)。
1H NMR(δ,DMSO-d6):13.59(s,1H),11,94(s,1H),8.20(d,1H,J=8.5Hz),8.05(d,1H,J=8.5Hz),7.63(t,2H,J=8.0Hz),7.52(d,2H,J=9.0Hz),7.44(t,1H,J=7.0Hz),7.16(s,1H),6.91(d,1H,J=8.0Hz),3.51(s,3H)
实施例14、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-4-氯-N-甲基苯甲酰胺10g
操作过程同实例8,只是用4-氯苯甲酰氯代替苯甲酰氯,得到淡黄色固体,收率:27%;熔点:260-262℃。
1H NMR(δ,DMSO-d6):13.60(s,1H),11.94(s,1H),8.22(d,1H,J=7.6Hz),7.62(dd,2H,J=2.8Hz,J=8.0Hz),7.43(t,1H,J=7.2Hz),7.25~7.28(m,5H),7.19(s,1H),6.79(d,1H,J=8.4Hz),3.47(s,3H)
实施例15、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-2,5-二甲氧基-N-甲基苯磺酰胺10h
操作过程同实例8,只是用2,5-二甲氧基苯磺酰氯代替苯甲酰氯,得到黄绿色固体,收率:30%;熔点:90-92℃。
1H NMR(δ,DMSO-d6):13.47(s,1H),11.86(s,1H),8.22(d,1H,J=8.0Hz),7.73(d,1H,J=8.4),7.61(d,1H,J=8.0Hz),7.42(t,1H,J=7.2Hz),7.32(d,1H,J=2.8Hz),7.23(t,1H,J=7.2Hz),7.22(d,1H,J=8.8Hz),7.17(s,1H),7.15(d,1H,J=2.8Hz),7.07(d,1H,J=9.2Hz),3.74(s,3H),3.48(s,3H),3.37(s,3H)
实施例16、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-2,4-二甲氧基-N-甲基苯磺酰胺10i
操作过程同实例8,只是用2,4-二甲氧基苯磺酰氯代替苯甲酰氯,得到黄绿色固体,收率:60%;熔点:81-83℃。
1H NMR(δ,DMSO-d6):13.46(s,1H),11.82(s,1H),8.22(d,1H,J=8.4Hz),7.69(t,2H,J=8.4Hz),7.61(d,1H,J=8.4Hz),7.42(t,1H,J=7.2Hz),7.23~7.26(m,2H),7.17(d,1H,J=1.2Hz),6.58~6.63(m,2H),3.80(s,3H),3.47(s,3H),3.32(s,3H)
实施例17、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-4-溴-N-甲基苯磺酰胺10j
操作过程同实例8,只是用4-溴苯磺酰氯代替苯甲酰氯,得到黄绿色固体,收率:42%;熔点:80-82℃。
1H NMR(δ,DMSO-d6):13.58(s,1H),12.03(s,1H),8.22(d,1H,J=8.0Hz),7.84(d,1H,J=8.8Hz),7.76(d,2H,J=8.8Hz),7.62(d,1H,J=8.4Hz),7.48(d,2H,J=8.8Hz),7.43(t,1H,J=8.0Hz),7.28(d,1H,J=8.4Hz),7.23(t,1H,J=8.0Hz),7.19(s,1H)
实施例18、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-3-甲氧基-N-甲基苯甲酰胺10k
操作过程同实例8,只是用3-甲氧基苯磺酰氯代替苯甲酰氯,得到淡黄色固体,收率:45%;熔点:152-154℃。
1H NMR(δ,DMSO-d6):13.57(s,1H),11.90(s,1H),7.23(d,1H,J=8.0Hz),7.63(d,1H,J=8.5Hz),7.60(d,1H,J=8.5Hz),7.45(t,1H,J=7.5Hz),7.26(t,1H,J=7.5Hz),7.21(s,1H),7.09(t,1H,J=8.0Hz),6.85(t,1H,J=2.0Hz),6.81~6.84(m,2H),6.79(d,1H,J=8.5Hz),3.58(s,3H),3.47(s,3H)
实施例19、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-4-甲氧基-N-甲基苯磺酰胺10l
操作过程同实例8,只是用4-甲氧基苯磺酰氯代替苯甲酰氯,得到黄绿色固体,收率:43%;熔点:125-127℃。
1H NMR(δ,DMSO-d6):13.49(s,1H),11.94(s,1H),8.21(d,1H,J=8.8Hz),7.81(d,1H,J=8.0Hz),7.61(d,1H,J=8.4Hz),7.46(d,2H,J=8.4Hz),7.42(t,1H,J=8.0Hz),7.32(d,1H,J=8.4Hz),7.22(t,1H,J=8.0Hz),7.17(d,1H,J=1.2Hz),7.03(d,1H,J=9.2),3.80(s,3H),3.20(s,3H)
实施例20、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-4-氯-N-甲基苯磺酰胺10m
操作过程同实例8,只是用4-氯苯磺酰氯代替苯甲酰氯,得到黄色固体,收率:40%;熔点:90-92℃。
1H NMR(δ,DMSO-d6):13.50(s,1H),11.98(s,1H),8.22(d,1H,J=8.4Hz),7.83(d,1H,J=8.8Hz),7.61~7.64(m,3H),7.58(s,1H),7.56(d,1H,J=8.4Hz),7.43(t,1H,J=8.0Hz),7.29(d,1H,J=8.8Hz),7.23(t,1H,J=8.0Hz),7.18(d,1H,J=1.2Hz),3.23(s,3H)
实施例21、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-3,4-二甲氧基-N-甲基苯磺酰胺10n
操作过程同实例8,只是用3,4-二甲氧基苯磺酰氯代替苯甲酰氯,得到淡黄色固体,收率:40%;熔点:88-90℃。
1H NMR(δ,DMSO-d6):13.50(s,1H),11.96(s,1H),8.21(d,1H,J=8.0Hz),7.83(d,1H,J=8.4Hz),7.61(d,1H,J=8.4Hz),7.43(t,1H,J=7.6Hz),7.33(d,1H,J=8.0Hz),7.23(t,1H,J=7.6Hz),7.19(dd,1H,J=2.4Hz,J=8.8),7.18(d,1H,J=1.2Hz),7.07(d,1H,J=8.8Hz),6.85(d,1H,J=1.2Hz),3.81(s,3H),3.55(s,3H),3.19(s,3H)
实施例22、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-2-甲氧基-N-甲基萘-1-磺酰胺10o
操作过程同实例8,只是用2-甲氧-1-萘磺酰氯代替苯甲酰氯,得到淡黄色固体,收率:35%;熔点:259-261℃。
1H NMR(δ,DMSO-d6):13.48(s,1H),11.95(s,1H),8.29(s,1H),8.17(d,1H,J=8.0Hz),8.03(d,1H,J=9.6Hz),7.86(d,1H,J=8.8Hz),7.83(d,1H,J=8.4Hz),7.60(d,1H,J=8.4Hz),7.41~7.45(m,2H),7.33~7.37(m,2H),7.26(dd,1H,J=2.0Hz,J=9.2Hz),7.19(t,1H,J=7.6Hz),7.11(s,1H),3.89(s,3H),3.26(s,3H)
实施例23、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基-3-硝基苯磺酰胺10p
操作过程同实例8,只是用3-硝基苯磺酰氯代替苯甲酰氯,得到黄褐色固体,收率:37%;熔点:92-94℃。
1H NMR(δ,DMSO-d6):13.52(s,1H),12.03(s,1H),8.51(dd,1H,J=2.4Hz,J=8.4Hz),8.34(s,1H),8.18(d,1H,J=8.0Hz),8.01(d,1H,J=7.2Hz),7.86(t,2H,J=8.0Hz),7.62(d,1H,J=8.4Hz),7.43(t,1H,J=8.4Hz),7.28(d,1H,J=8.8Hz),7.24(t,1H,J=8.4Hz),7.13(s,1H),3.26(s,3H)
实施例24、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基苯磺酰胺10q
操作过程同实例8,只是用苯磺酰氯代替苯甲酰氯,得到黄绿色固体,收率:40%;熔点:78-80℃。
1H NMR(δ,DMSO-d6):13.46(s,1H),11.93(s,1H),8.18(d,1H,J=8.4Hz),7.79(d,1H,J=8.4Hz),7.61~7.63(m,1H),7.58(d,1H,J=8.4Hz),7.49~7.54(m,4H),7.39(t,1H,J=8.0Hz),7.29(d,1H,J=8.8Hz),7.19(t,1H,J=8.0Hz),7.13(d,1H,J=1.6Hz),3.20(s,3H)
实施例25、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N,4-二甲基苯磺酰胺10r
操作过程同实例8,只是用4-甲基苯磺酰氯代替苯甲酰氯,得到淡黄色固体,收率:25%;熔点:91-93℃。
1H NMR(δ,DMSO-d6):13.46(s,1H),11.92(s,1H),8.18(d,1H,J=8.0Hz),7.78(d,1H,J=8.4Hz),7.58(d,1H,J=8.4Hz),7.39~7.43(m,3H),7.29(d,3H,J=8.0Hz),7.19(t,1H,J=7.6Hz),7.14(d,1H,J=0.8Hz),3.18(s,3H)
实施例26、N-(2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基-4-(三氟甲氧基)苯磺酰胺10s
操作过程同实例8,只是用4-(三氟甲氧基)苯磺酰氯代替苯甲酰氯,得到淡黄色固体,收率:45%;熔点:107-109℃。
1H NMR(δ,DMSO-d6):10.73(s,1H),9.54(s,1H),8.05(d,1H,J=8.5Hz),7.67~7.72(m,3H),7.53(d,1H,J=8.5Hz),7.46(t,1H,J=7.0Hz),7.44(d,1H,J=8.5Hz),7.29(t,1H,J=7.0Hz),7.25(d,2H,J=8.5Hz),7.16(d,1H,J=1.0Hz),3.36(s,3H)
实施例27、N-(2-(6-氯-1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基苯甲酰胺10t
操作过程同实例8,只是用2-(6-氯-1H-吲唑-3-基)-N-甲基-1H-吡咯[3,2-b]吡啶-5-氨基代替2-(1H-吲唑-3-基)-N-甲基-1H-吡咯[3,2-b]吡啶-5-氨基得到淡黄色固体,收率:27%;熔点:275℃(dec)。
1H NMR(δ,DMSO-d6):9.24(s,1H),8.62(d,1H,J=4.0Hz),7.99(d,1H,J=8.5Hz),7.53(d,1H,J=1.0Hz),7.42(d,1H,J=8.5Hz),7.83(d,2H,J=7.5Hz),7.29(dd,2H,J=1.5Hz,J=9.0Hz),7.22(d,2H,J=7.5Hz),7.14(t,2H,J=8.0Hz),6.64(d,1H,J=8.5Hz),3.67(s,3H)
实施例28、N-(2-(1H-咪唑-3-基)-1H-吡咯[3,2-b]吡啶-5-基)-N-甲基呋喃-2-甲酰胺10u
操作过程同实例8,只是用呋喃-2酰氯代替苯甲酰氯,得到淡黄色固体,收率:45%;熔点:110-113℃。
1H NMR(δ,DMSO-d6):13.59(s,1H),12.00(s,1H),8.22(d,1H,J=8.0Hz),7.79(d,1H,J=8.5Hz),7.63(d,1H,J=8.5Hz),7.57(d,1H,J=1.0Hz),7.44(t,1H,J=7.5Hz),7.25(t,1H,J=7.5Hz),7.23(s,1H),7.00(d,1H,J=8.0Hz),6.33(dd,1H,J=1.5Hz,J=3.5Hz),6.01(d,1H,J=3.5Hz),3.39(s,3H)
实施例29、抗肿瘤生物活性测试方法:
肿瘤细胞离体培养:
选取肿瘤细胞HL60、KB、7721、HCT-116、A549,于37℃、5% CO2细胞培养箱中孵育,待细胞密度长到70~90%时传代(贴壁细胞用Puck’s EDTA消化后传代),用于以后实验所需。
MTT法测定N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物对不同瘤株的体外抑制作用:
将化合物用二甲基亚砜(DMSO)溶解,稀释,肿瘤细胞HL60、KB、7721、HCT-116、A549在96孔板上种入4000个/200μl/孔,每孔加入化合物2μl,终浓度为12.0μM,6.0μM,3.0μM,1.5μM,共同于37℃、5% CO2细胞培养箱中孵育72小时,以DMSO(1%)为空白对照。72小时后,加入终浓度为0.25mg/ml的MTT,置于37℃、5% CO2细胞培养箱中4小时,之后吸干溶剂,每孔加入100μl DMSO,用酶联免疫仪于570nm处测定吸光度(OD值),所得数据用于计算IC50。部分化合物的实验结果见表1:
表1 部分化合物对不同肿瘤细胞株的IC50值(μM)
从上表可以看出,1)所有的10个化合物对5种不同的肿瘤细胞株均有一定的抑制活性。2)R基团与5-N-2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶之间为酰胺键连接的化合物10f和10g对5种肿瘤细胞株均有较高的抑制率。3)R基团与5-N-2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶之间为磺酰胺键连接的化合物的活性一般比10f和10g要低,但其中的一个化合物10h对HL60的抑制率仅次于化合物10g,其IC50值达到0.84μM。总而言之,该类化合物有较好的抗肿瘤应用前景,因而具良好的商业价值。
Claims (3)
1.一种2-吲唑-4-氮杂吲哚-5-氨基衍生物,具体是N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物,其特征是有以下结构通式:
其中:
X为氢原子、羰基、砜基或亚砜基;
L为氮原子、氧原子或C0~C3的烷基链;
R1为C1~C3的直链或支链烷基、C4~C7的环烷烃、芳环、芳杂环,其中芳环为无取代、单取代、二取代或三取代的苯环,芳杂环为噻吩、吡啶、呋喃或吡咯;
单取代苯环上的取代基为氟原子、氯原子、溴原子、甲氧基、甲基、硝基、羟基、三氟甲基、三氟甲氧基、C1~C3的直链或支链烷基、C1~C3的直链或支链烷氧基;
二取代苯环上的取代基为3,4-二甲氧基、2,4-二甲氧基、2,5-二甲氧基、3-硝基-4-甲氧基、3-氨基-4-甲氧基、3,4-二氟;
三取代苯环上的取代基为3,4,5-三甲氧基;
R2为氢、卤素、腈基、含C1~C3的酰基、吡咯、吡唑、咪唑、三氮唑、二甲胺基;
R3为C1~C3的烷基链。
2.根据权利要求1所述的N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物的制备方法,其特征是:以化合物1:2-(叔丁氧羰基(甲基)氨基)-5-硝基吡啶为原料,通过烷基化得到化合物2,通过缩合反应得到化合物3,通过还原环合反应得到化合物4,通过叔丁氧羰基保护得到化合物5,通过2-位碘代反应得到中间体化合物6:5-位取代的2-碘代4-氮杂吲哚;以5-溴-2-甲基苯胺为原料,通过重氮化环合,碘代反应,氧化还原得到中间体吲唑的锡化物7,将中间体化合物6和化合物7通过Stille偶联得到化合物8,再经酸性条件脱保护基得到化合物9,在碱性条件下在N5位引入取代基得到目的化合物10,反应式:
3.根据权利要求1所述的N5取代的2-(1H-吲唑-3-基)-1H-吡咯[3,2-b]吡啶-5-氨基衍生物在制备抗肿瘤药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008101641055A CN101440092B (zh) | 2008-12-25 | 2008-12-25 | 2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2008101641055A CN101440092B (zh) | 2008-12-25 | 2008-12-25 | 2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN101440092A true CN101440092A (zh) | 2009-05-27 |
CN101440092B CN101440092B (zh) | 2010-11-17 |
Family
ID=40724718
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2008101641055A Expired - Fee Related CN101440092B (zh) | 2008-12-25 | 2008-12-25 | 2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101440092B (zh) |
Cited By (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8252812B2 (en) | 2009-08-10 | 2012-08-28 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US8450340B2 (en) | 2009-12-21 | 2013-05-28 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US8618128B1 (en) | 2012-05-04 | 2013-12-31 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US8664241B2 (en) | 2012-04-04 | 2014-03-04 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8697887B2 (en) | 2011-09-14 | 2014-04-15 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US9657016B2 (en) | 2014-09-08 | 2017-05-23 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US9738638B2 (en) | 2014-09-08 | 2017-08-22 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-B]pyridine and therapeutic uses thereof |
US9758531B2 (en) | 2014-09-08 | 2017-09-12 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US9763951B2 (en) | 2014-09-08 | 2017-09-19 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9844536B2 (en) | 2014-09-08 | 2017-12-19 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9889140B2 (en) | 2014-09-08 | 2018-02-13 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US9908867B2 (en) | 2013-01-08 | 2018-03-06 | Samumed, Llc | 3-(benzoimidazol-2-yl)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US10072004B2 (en) | 2016-06-01 | 2018-09-11 | Samumed, Llc | Process for preparing N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo [4,5-C]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
US10081631B2 (en) | 2014-09-08 | 2018-09-25 | Samumed, Llc | 2-(1H-indazol-3-yl)-1H-imidazo[4,5-C]pyridine and therapeutic uses thereof |
US10166218B2 (en) | 2015-08-03 | 2019-01-01 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10188634B2 (en) | 2015-08-03 | 2019-01-29 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10195185B2 (en) | 2015-08-03 | 2019-02-05 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10226453B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10226448B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US10231956B2 (en) | 2015-08-03 | 2019-03-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10350199B2 (en) | 2015-08-03 | 2019-07-16 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10463651B2 (en) | 2015-08-03 | 2019-11-05 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof |
US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10533020B2 (en) | 2014-09-08 | 2020-01-14 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1 H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10544139B2 (en) | 2015-11-06 | 2020-01-28 | Samumed, Llc | Treatment of osteoarthritis |
US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
US10758523B2 (en) | 2016-11-07 | 2020-09-01 | Samumed, Llc | Single-dose, ready-to-use injectable formulations |
US10806726B2 (en) | 2016-10-21 | 2020-10-20 | Samumed, Llc | Methods of using indazole-3-carb oxamides and their use as Wnt/B-catenin signaling pathway inhibitors |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2864084B1 (fr) * | 2003-12-17 | 2006-02-10 | Aventis Pharma Sa | Nouveaux derives organophosphores des indazoles et leur utilisation comme medicaments |
-
2008
- 2008-12-25 CN CN2008101641055A patent/CN101440092B/zh not_active Expired - Fee Related
Cited By (72)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9763927B2 (en) | 2009-08-10 | 2017-09-19 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8604052B2 (en) | 2009-08-10 | 2013-12-10 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US10016406B2 (en) | 2009-08-10 | 2018-07-10 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US8252812B2 (en) | 2009-08-10 | 2012-08-28 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US8703794B2 (en) | 2009-08-10 | 2014-04-22 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8822478B2 (en) | 2009-08-10 | 2014-09-02 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US8450340B2 (en) | 2009-12-21 | 2013-05-28 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US9855272B2 (en) | 2009-12-21 | 2018-01-02 | Samumed, Llc | 1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US10105370B2 (en) | 2009-12-21 | 2018-10-23 | Samumed, Llc | 1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US8697887B2 (en) | 2011-09-14 | 2014-04-15 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US10464924B2 (en) | 2011-09-14 | 2019-11-05 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US11780823B2 (en) | 2011-09-14 | 2023-10-10 | Biosplice Therapeutics, Inc. | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US11066388B2 (en) | 2011-09-14 | 2021-07-20 | Biosplice Therapeutics, Inc. | Indazole-3-carboxamides and their use as WNT/B-catenin signaling pathway inhibitors |
US9802916B2 (en) | 2011-09-14 | 2017-10-31 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/beta-catenin signaling pathway inhibitors |
US9221793B2 (en) | 2011-09-14 | 2015-12-29 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US10947228B2 (en) | 2012-04-04 | 2021-03-16 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8673936B2 (en) | 2012-04-04 | 2014-03-18 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8664241B2 (en) | 2012-04-04 | 2014-03-04 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US9994563B2 (en) | 2012-04-04 | 2018-06-12 | Samumed, Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
US11697649B2 (en) | 2012-04-04 | 2023-07-11 | Biosplice Therapeutics, Inc. | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US10407425B2 (en) | 2012-04-04 | 2019-09-10 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8618128B1 (en) | 2012-05-04 | 2013-12-31 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US10342788B2 (en) | 2012-05-04 | 2019-07-09 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US10071086B2 (en) | 2012-05-04 | 2018-09-11 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US10654832B2 (en) | 2013-01-08 | 2020-05-19 | Samumed, Llc | 3-(benzoimidazol-2-YL)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US9908867B2 (en) | 2013-01-08 | 2018-03-06 | Samumed, Llc | 3-(benzoimidazol-2-yl)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US10183929B2 (en) | 2013-01-08 | 2019-01-22 | Samumed, Llc | 3-(benzoimidazol-2-yl)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US10596154B2 (en) | 2014-09-08 | 2020-03-24 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10052331B2 (en) | 2014-09-08 | 2018-08-21 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9657016B2 (en) | 2014-09-08 | 2017-05-23 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US10081631B2 (en) | 2014-09-08 | 2018-09-25 | Samumed, Llc | 2-(1H-indazol-3-yl)-1H-imidazo[4,5-C]pyridine and therapeutic uses thereof |
US9738638B2 (en) | 2014-09-08 | 2017-08-22 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-B]pyridine and therapeutic uses thereof |
US9758531B2 (en) | 2014-09-08 | 2017-09-12 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US10202377B2 (en) | 2014-09-08 | 2019-02-12 | Samumed, Llc | 3-(1H-benzo[D]imidazol-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9763951B2 (en) | 2014-09-08 | 2017-09-19 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10206929B2 (en) | 2014-09-08 | 2019-02-19 | Samumed, Llc | 3-(1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
US9844536B2 (en) | 2014-09-08 | 2017-12-19 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9889140B2 (en) | 2014-09-08 | 2018-02-13 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US10533020B2 (en) | 2014-09-08 | 2020-01-14 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1 H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10526347B2 (en) | 2014-09-08 | 2020-01-07 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US10280166B2 (en) | 2014-09-08 | 2019-05-07 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-B]pyridine and therapeutic uses thereof |
US10131677B2 (en) | 2014-09-08 | 2018-11-20 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US10023572B2 (en) | 2014-09-08 | 2018-07-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof |
US10463651B2 (en) | 2015-08-03 | 2019-11-05 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof |
US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10350199B2 (en) | 2015-08-03 | 2019-07-16 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10231956B2 (en) | 2015-08-03 | 2019-03-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10226448B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US10166218B2 (en) | 2015-08-03 | 2019-01-01 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10226453B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
US10188634B2 (en) | 2015-08-03 | 2019-01-29 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10195185B2 (en) | 2015-08-03 | 2019-02-05 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10882860B2 (en) | 2015-11-06 | 2021-01-05 | Samumed, Llc | Treatment of osteoarthritis |
US10899757B2 (en) | 2015-11-06 | 2021-01-26 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-C]pyridines and their anti-inflammatory uses thereof |
US11560378B2 (en) | 2015-11-06 | 2023-01-24 | Biosplice Therapeutics, Inc. | Treatment of osteoarthritis |
US11667632B2 (en) | 2015-11-06 | 2023-06-06 | Biosplice Therapeutics, Inc. | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-C]pyridines and their anti-inflammatory uses thereof |
US10544139B2 (en) | 2015-11-06 | 2020-01-28 | Samumed, Llc | Treatment of osteoarthritis |
US10072004B2 (en) | 2016-06-01 | 2018-09-11 | Samumed, Llc | Process for preparing N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo [4,5-C]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
US10633380B2 (en) | 2016-06-01 | 2020-04-28 | Samumed, Llc | Process for preparing N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-C]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
US10806726B2 (en) | 2016-10-21 | 2020-10-20 | Samumed, Llc | Methods of using indazole-3-carb oxamides and their use as Wnt/B-catenin signaling pathway inhibitors |
US11684615B2 (en) | 2016-10-21 | 2023-06-27 | Biosplice Therapeutics, Inc. | Methods of using indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US10758523B2 (en) | 2016-11-07 | 2020-09-01 | Samumed, Llc | Single-dose, ready-to-use injectable formulations |
US11446288B2 (en) | 2016-11-07 | 2022-09-20 | Biosplice Therapeutics, Inc. | Single-dose, ready-to-use injectable formulations |
US11819499B2 (en) | 2016-11-07 | 2023-11-21 | Biosplice Therapeutics, Inc. | Single-dose, ready-to-use injectable formulations |
Also Published As
Publication number | Publication date |
---|---|
CN101440092B (zh) | 2010-11-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101440092B (zh) | 2-吲唑-4-氮杂吲哚-5-氨基衍生物及制备和应用 | |
KR102400920B1 (ko) | 리신 특이적 데메틸라제-1의 억제제 | |
CN114605401B (zh) | 一类含氧五元杂环化合物、合成方法、药物组合物及用途 | |
US10662187B2 (en) | Bruton's tyrosine kinase inhibitors | |
JP2010523616A (ja) | ジフェニル−ジヒドロ−イミダゾピリジノン | |
KR20170018100A (ko) | 리신 특이적 데메틸라아제-1의 억제제 | |
EP2440544B1 (en) | Hedgehog pathway antagonists and therapeutic applications thereof | |
CA2610446A1 (en) | Nitrogen-containing heterocyclic compound | |
WO2011082098A1 (en) | Lysine and arginine methyltransferase inhibitors for treating cancer | |
KR20030081173A (ko) | α,β-불포화 하이드록사믹 액시드 유도체와 이 화합물의히스톤 디아세틸라제 억제제로서의 용도 | |
WO2019158025A1 (zh) | 一种三氮唑并嘧啶衍生化合物、包含其的药物组合物及其用途 | |
Xin et al. | Design, synthesis, and evaluation of pyrrolo [2, 1-f][1, 2, 4] triazine derivatives as novel hedgehog signaling pathway inhibitors | |
Wang et al. | Design, synthesis and preliminary bioactivity studies of imidazolidine-2, 4-dione derivatives as Bcl-2 inhibitors | |
JP2010507618A (ja) | c−Metキナーゼ阻害薬としての7−アザインドール誘導体 | |
CA2506799A1 (en) | Mixed lineage kinase modulators | |
Zhu et al. | Design, synthesis and anticancer activity of 4-morpholinothieno [3, 2-d] pyrimidine derivatives bearing arylmethylene hydrazine moiety | |
Xu et al. | Design, synthesis, and evaluation of novel porcupine inhibitors featuring a fused 3-ring system based on the ‘reversed’amide scaffold | |
CN110818609A (zh) | 3-乙酰基吲哚类brpf1抑制剂的制备方法及其用途 | |
KR20080086482A (ko) | 글루코코르티코이드 수용체와의 상호 작용에 의한 약효를갖는 화합물 | |
WO1999032475A1 (en) | Novel sulfonamide substituted chroman derivatives useful as beta-3 adrenoreceptor agonists | |
CA2933026A1 (en) | Novel pyridine pyrazinones as brd4 inhibitors | |
JP2022511287A (ja) | c-MYC標的剤としての置換複素環化合物 | |
Chacun-Lefèvre et al. | Synthesis and reactivity of azepino [3, 4-b] indol-5-yl trifluoromethanesulfonate | |
Toan et al. | Synthesis, cytotoxic activity, ADMET and molecular docking study of quinoline-based hybrid compounds of 1, 5-benzothiazepines | |
KR100820039B1 (ko) | 히스톤 디아세틸라제 저해활성을 갖는 알킬아미노나프탈렌일옥시메틸 프로페닐 하이드록시벤즈아마이드유도체, 이의 제조방법 및 이를 유효성분으로 하는항암제용 약학 조성물 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101117 Termination date: 20141225 |
|
EXPY | Termination of patent right or utility model |