CN117402178A - 作为jak抑制剂和phd抑制剂的嘧啶类化合物 - Google Patents
作为jak抑制剂和phd抑制剂的嘧啶类化合物 Download PDFInfo
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
本发明公开了作为JAK抑制剂和PHD抑制剂的嘧啶类化合物。具体地,本发明公开了式(I)所示的化合物或其药学上可接受的盐,其可用于治疗炎症性肠病。
Description
技术领域
本发明属于医药领域,具体涉及作为JAK抑制剂和PHD抑制剂的嘧啶类化合物。
背景技术
细胞蛋白质酪氨酸激酶的JAK家族(JAK1、JAK2、JAK3和TYK2)在细胞因子信号转导中扮演重要的角色。当细胞因子与其受体结合时,细胞因子活化JAK,然后JAK磷酸化细胞因子受体,从而产生信号转导分子的停靠位点,值得注意的是,最终导致基因表达的信号转导子和转录活化子(STAT)家族成员。许多细胞因子已知可活化JAK家族。这些细胞因子包括干扰素IFN家族(IFN-α、IFN-β、IFN-ω、限制素(Limitin)、IFN-γ、IL-10、IL-19、IL-20、IL-22)、gp130家族(IL-6、IL-11、OSM、LIF、CNTF、NNT-1/BSF-3、G-CSF、CT-1、瘦素、IL-12、IL-23)、γC家族(IL-2、IL-7、TSLP、IL-9、IL-15、IL-21、IL-4、IL-13)、IL-3家族(IL-3、IL-5、GM-CSF)、单链家族(EPO、GH、PRL、TPO)、受体酪氨酸激酶(EGF、PDGF、CSF-1、HGF)、及G-蛋白偶联受体(AT1)。JAK1在所有组织中有不同水平的表达。已有动物研究表明,JAK1是免疫系统的发育、发挥作用和体内稳态所必须的。通过抑制JAK1激酶活性来调节免疫活性证实可用于治疗多种免疫病症。
炎症性肠病(IBD)是其中由于过度免疫应答而在肠黏膜中引起炎症和溃疡的慢性疾病。IBD包括例如溃疡性结肠炎和克罗恩病。已知在IBD的病理状况下,与胃肠道上皮的屏障功能相关的基因的表达由低氧诱导因子1α(HIF-1α)诱导。HIF-1α是低氧诱导因子α(HIF-α)的亚型之一。HIF-α在低氧环境(低氧)中变得稳定,然后它对低氧做出响应而激活几个基因的转录。与此相反,在富氧环境(常氧)中HIF-α的脯氨酸残基被脯氨酰羟化酶(PHD)羟化,然后所述HIF-α通过蛋白酶体途径降解。已知PHD有3种亚型,即PHD1、PHD2和PHD3。
发明内容
本发明首次提出了一种结构新颖、能同时抑制JAK1和PHD2的化合物。
在本发明的第一方面, 本发明提出了一种式(I)所示的化合物或其药学上可接受的盐,
式(I),
R1选自或-OC(CH3)3;
L选自-L1-L2-L3-L4-L5-;
L1选自单键或5-6元杂芳基;
L2选自单键、C1-3亚烷基或C3-6环烷基;
L3选自单键或O;
L4选自单键或C1-3亚烷基;
L5选自单键、O或-N(R3)-;
R2、R3分别独立地选自H或C1-6烷基。
在本发明的一些方案中,L1选自单键、或/>,其余变量如本发明所定义。
在本发明的一些方案中,L2选自单键、-CH2-、-CH2CH2-或,其余变量如本发明所定义。
在本发明的一些方案中,L4选自单键、-CH2-或-CH2CH2-,其余变量如本发明所定义。
在本发明的一些方案中,R2、R3分别独立地选自H或C1-3烷基,其余变量如本发明所定义。
在本发明的一些方案中,L选自单键、、/>、或/>,其余变量如本发明所定义。
在本发明的一些方案中,式(I)所示化合物的结构如下之一所示:
、/>、、/>或。
在本发明的另一方面,本发明提出了一种药物组合物,所述药物组合物包括前面所述的化合物或其药学上可接受的盐,以及,药学上可接受的载体。
在本发明的另一方面,本发明提出了前面所述的化合物或其药学上可接受的盐或前面所述的药物组合物在制备治疗PHD2和JAK1介导的疾病药物中的应用。
在本发明的一些方案中,所述PHD2和JAK1介导的疾病为炎症性肠病。
术语“5-6元杂芳基”意味着在环中具有1至4个选自氧原子、氮原子和硫原子的杂原子的5-或6-元芳香族杂环基团。例如,可以示例的是呋喃基、吡咯基、噻吩基、咪唑基、吡唑基、1,2,4-三唑基、异噻唑基、异噁唑基、噁唑基、噻唑基、1,3,4-噁二唑基、1,2,4-噁二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基等。
如本文所用,术语“药学上可接受的盐”是指在制药上可接受的并且具有母体化合物药理学活性的本发明化合物的盐。这类盐包括:与无机酸或与有机酸形成的酸加成的盐,所述的无机酸诸如硝酸,磷酸,碳酸等;所述的有机酸诸如丙酸,己酸,环戊丙酸,乙醇酸,丙酮酸,葡糖酸,硬脂酸,粘康酸等;或在母体化合物上存在的酸性质子被金属离子,例如碱金属离子或碱土金属离子取代时形成的盐;或与有机碱形成的配位化合物,所述的有机碱诸如乙醇胺,二乙醇胺,三乙醇胺,N-甲基葡糖胺等。本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。除了盐的形式,本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外,前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
如本文所用,术语“C1-6烷基”指具有1至6个碳原子的直链或支链一价烷基。具体实例包括甲基、乙基、正丙基和异丙基,及其各种支链异构体等。
如本文所用,术语“C1-3烷基”指具有1至3个碳原子的直链或支链一价烷基。具体实例包括甲基、乙基、正丙基和异丙基,及其各种支链异构体等。
如本文所用,术语“C1-6亚烷基”指具有1至3个碳原子的直链或支链二价烷基。具体实例包括甲基、乙基、正丙基和异丙基,及其各种支链异构体等。
本发明式(I)所示的化合物可使用本领域已知的合成方法或使用本领域已知的方法与本发明记载的方法组合制备得到。本发明给出的溶剂、温度和其它反应条件均为示例性的,可根据本领域熟知的方法而变化。本发明所记载的实施例化合物可根据其具体结构,使用适当的起始原料按照实施例中记载的方法合成,也可以使用与实施例中记载的类似方法合成得到。用于合成本发明实施例化合物的起始原料可通过已知合成方法或文献记载的类似方法制备得到或从商业来源获得。化合物可根据需要,进一步通过本领域熟知的方法,例如结晶、色谱法等拆分得到其立体异构体,其拆分条件是本领域技术人员通过常规手段或有限试验而容易获得的。作为进一步说明,本发明式(I)化合物可利用以下的方法合成,其中每个步骤中的溶剂、温度及其它反应条件可与下述实施例中记载的相同或类似,或使用本领域已知的反应条件。
具体实施方式
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。
以下简写贯穿本发明。
PPh3代表三苯基膦,THF代表四氢呋喃,DEAD代表偶氮二甲酸二乙酯,MeOH代表甲醇,Pd2(dba)3代表三(二亚苄基丙酮)二钯,SPhos代表2-二环己基膦基-2′,6′-二甲氧基联苯基,Cs2CO3代表碳酸铯,NaCl代表氯化钠,Na2SO4代表硫酸钠,TBAF代表四正丁基氟化铵,DMA代表二甲基乙酰胺,Pd(OAc)2代表醋酸钯,BINAP代表1,1'-联萘-2,2'-双二苯膦,TBS代表叔丁基二甲基硅基,Boc代表叔丁氧羰基,Ts代表对甲苯磺酰基,TsCl代表对甲苯磺酰氯,Et3N代表三乙胺,DMAP代表4-二甲氨基吡啶,DCM代表二氯甲烷,K2CO3代表碳酸钾,DMSO代表二甲基亚砜,DIPEA代表N,N-二异丙基乙胺,EtOAc代表乙酸乙酯,TFA代表三氟乙酸,HATU代表2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯,n-BuOH代表正丁醇,XantPhos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽,TBAF代表四正丁基氟化铵。
实施例1
步骤1:
将化合物1-1(2.00g,17.7mmol),2-(2-((叔丁基二甲基硅氧基)乙氧基)乙氧基)乙醇(3.89g,17.7mmol)和PPh3(9.28g,35.4mmol)溶解在THF(25.0mL)中。然后在0℃下滴加DEAD(4.62g,26.5mmol)。将反应混合物在室温下搅拌4小时。反应混合物经减压浓缩以去除溶剂。粗品通过柱层析纯化得到化合物1-2。LCMS:316.4[M+H]+。
步骤2:
将化合物1-2(1.00g,3.17mmol)溶解在MeOH(10.0mL)中,加入10% Pd/C(168mg,1.58mmol),在H2(15psi)氛,室温下搅拌反应12小时。反应混合物经过过滤并在减压下浓缩,得到粗品1-3。不经纯化直接用于下一步。LCMS:286.2[M+H]+。
步骤3:
将化合物1-3(1.03g,3.60mmol)和3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(CAS#:201162-46-1,900mg,2.771mmol)溶解在二氧六环(20.0mL)中,加入Pd2(dba)3(253mg,0.277mmol),SPhos(227mg,0.554mmol)和Cs2CO3(1.81g,5.54mmol)。混合物在N2氛,在120℃条件下搅拌反应12小时。将反应混合物冷却至室温,用100mL水稀释,然后用乙酸乙酯(100mL×2)萃取。有机相用饱和NaCl溶液(100mL)洗涤,Na2SO4干燥,过滤后减压浓缩。粗品通过柱层析纯化得到化合物1-4。LCMS:574.6[M+H]+。
步骤4:
将化合物1-4(1.27g,2.21mmol)溶解在THF(15.0mL)中,加入TBAF溶液(6.64mL,6.64mmol)。在2室温下,反应12小时。反应混合物用100mL水稀释,然后用乙酸乙酯(100mL×2)萃取。有机相用饱和食盐水(100mL×2)洗涤,用Na2SO4干燥,过滤后减压浓缩。粗品通过柱层析纯化得到化合物1-5。LCMS:460.3[M+H]+。
步骤5:
将化合物1-5(50.0mg,0.109mmol)和2-氯-N-((6-氰基吡啶-3-基)甲基)-5-羟基-1,7-萘啶-6-甲酰胺(可通过WO2023072257中的实施例29步骤1的方法制备获得,40.7mg,0.120mmol)溶解在DMA(2.0mL)中,加入Pd(OAc)2(2.44mg,0.011mmol),BINAP(6.77mg,0.011mmol)和Cs2CO3(70.9mg,0.218mmol)。在N2氛,130℃下用微波加热搅拌2小时。粗品通过制备HPLC(0.1% FA)进行纯化。得到化合物1。LCMS:763.6[M+H]+。1H NMR(400MHz,MeOD)δ= 8.78(s,1H),8.63-8.52(m,2H),8.07-8.00(m,2H),7.89-7.83(m,2H),7.79(br d,J =9.1Hz,1H),7.55(s,1H),6.47(d,J = 6.4Hz,1H),4.77(s,2H),4.61(s,1H),4.36(br t,J =5.0Hz,2H),4.29(br s,2H),4.03-3.92(m,1H),3.89(br t,J = 5.2Hz,2H),3.65-3.60(m,2H),3.57-3.52(m,2H),3.12-2.96(m,2H),1.93(br dd,J = 2.4,8.3Hz,2H),1.69(br d,J= 6.9Hz,2H),1.49(s,9H)。
实施例2
步骤1:
在0℃时,将TsCl(458mg,2.40mmol),Et3N(0.514mL,3.69mmol)和DMAP(22.6mg,0.185mmol),加入到化合物1-5(850mg,1.85mmol)的DCM(10.0mL)溶液中。混合物在室温下搅拌12小时。混合物用水(10.0mL)淬灭,并用DCM萃取(50.0mL×3)。有机相用盐水洗涤(20.0mL×3),Na2SO4干燥,过滤,然后减压浓缩。粗品经柱层析纯化后得到2-1。LCMS:614.5[M+H]+。
步骤2:
将化合物2-1(500mg,0.815mmol)溶解在二氧六环(7.00mL)中,加入甲胺盐酸盐(275mg,4.07mmol)和K2CO3(788mg,5.70mmol)。混合物在70℃下搅拌12小时。混合物用水(10mL)淬灭,并用EtOAc萃取(10.0mL×3)。有机相合并后用盐水洗涤(20mL×3),Na2SO4干燥,过滤后减压浓缩。粗品经柱层析纯化后得到2-2。LCMS:473.3[M+H]+。
步骤3:
将化合物2-2(215mg,0.455mmol)溶解在DMSO(4.00mL)中后,加入2-氯-N-((6-氰基吡啶-3-基)甲基)-5-羟基-1,7-萘啶-6-甲酰胺(77.2mg,0.227mmol)和DIPEA(300μL,1.82mmol)。混合物在微波100℃下反应2小时。混合物用水(10.0mL)淬灭,EtOAc萃取(5.00mL×3)。有机相合并后用盐水洗涤(10.0mL×3),Na2SO4干燥,过滤后减压浓缩。粗品用制备TLC纯化后得到化合物2-3。LCMS:776.6[M+H]+。
步骤4:
将化合物2-3(120mg,0.155mmol)溶解在DCM(3.00mL)中,加入TFA(17.6mg,0.155mmol)。混合物在室温下搅拌2小时后,减压浓缩得到化合物2-4。LCMS:676.4[M+H]+。
步骤5:
将化合物2-4(59.0mg,0.0870mmol)溶解在DMF(0.500mL)中,加入(1S)-2,2-二氟环丙烷-1-羧酸(CAS#:1883301-82-3,10.6mg,0.0870mmol),HATU(49.8mg,0.131mmol)和DIPEA(43.2μL,0.262mmol),然后在室温下搅拌12小时。混合物经过制备液相色谱纯化(FA条件),得到化合物2。LCMS:780.4[M+H]+。1H NMR(400 MHz, DMSO-d6)δ = 13.25(br s,1H),9.88-9.58(m,2H),8.76(s,1H),8.33(br s,1H),8.19-7.93(m,3H),7.82(br d,J = 3.4Hz,1H)7.69(br s,1H),7.49(br d,J = 3.1Hz,1H),7.30-7.13(m,1H),6.37(br d,J = 6.9Hz,1H),4.74-4.60(m,4H),4.22(br t,J = 4.8Hz,3H),3.79(br t,J = 4.6Hz,5H),3.67-3.61(m,4H),3.12(s,3H),2.02-1.78(m,4H),1.72-1.50 (m,2H),1.21-1.03(m,1H)。
实施例3:
按实施例2类似的方法制得。
LCMS:720.5[M+H]+。1H NMR(400 MHz,METHANOL-d4)δ = 9.04(d,J = 2.6Hz,2H),8.73(s,1H),8.36(br s,1H),8.26(br d,J = 8.6Hz,1H),8.03-7.94(m,2H),7.84(d,J =8.0Hz,1H),7.13(d,J = 9.0Hz,1H),6.39(d,J = 6.6Hz,1H),4.71(s,3H),4.60(br d,J =5.8Hz,1H),3.21-3.07(m,2H),3.06-2.90(m,1H),2.24-1.64(m,7H),1.37(br dd,J = 3.3,6.8Hz,2H)。
实施例4
步骤1:
将化合物4-1(500mg,3.86mmol)溶解在n-BuOH(5.0mL)中,加入3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(983mg,4.63mmol)。混合物在120℃反应2小时后,冷却到室温,减压浓缩得到化合物4-2。粗品不经纯化直接用于下一步。LCMS:306.2[M+H]+。
步骤2:
将化合物4-2(410mg,1.34mmol)和2-氯-N-((6-氰基吡啶-3-基)甲基)-5-羟基-1,7-萘啶-6-甲酰胺(456mg,1.34mmol)溶解在DMA(5.0mL)中,加入Pd2(dba)3(123mg,0.134mmol),XantPhos(75.0mg,0.134mmol)和Cs2CO3(875mg,2.68mmol)。混合物在N2氛110℃下反应2小时。冷却至室温后,用H2O(50.0mL)淬灭,EtOAc(100mL×2)萃取。有机相用饱和食盐水(100mL)洗,Na2SO4干燥,过滤后减压浓缩。粗品经柱层析纯化后得到化合物4-3。LCMS:609.2[M+H]+。
步骤3:
将化合物4-4(400mg,0.657mmol)溶解在二氧六环(5.0mL)中加入HCl二氧六环溶液(2.0mL)。混合物在室温下搅拌1小时。浓缩后得到粗品4-5,不经纯化直接用于下一步反应。LCMS:509.4[M+H]+。
步骤4:
在化合物(1S)-2,2-二氟环丙烷-1-羧酸(57.6mg,0.472mmol)和DIPEA(0.195mL,1.18mmol)的DMF(10.0mL)溶液中,加入HATU(224mg,0.590mmol)和化合物33-6(200mg,0.393mmol)。混合物在室温下搅拌1小时。粗品由制备HPLC(0.1% FA)纯化得到化合物4。LCMS:613.4[M+H]+。1HNMR(DMSO-d6)δ = 13.51(s,1H),9.87(br t,J = 5.5Hz,1H),8.78(s,1H),8.73-8.64(m,1H),8.59(br d,J = 7.9Hz,1H),8.18-8.13(m,1H),8.02(d,J = 1.3Hz,2H),6.55(br dd,J = 3.0,10.9Hz,1H),4.73(br d,J = 5.6Hz,1H),4.71-4.61(m,4H),3.28-3.18(m,2H),3.02(br d,J = 10.0Hz,2H),2.10-1.96(m,2H),1.96-1.82(m,3H),1.82-1.72(m,2H),1.72-1.61(m,1H)。
实施例5
步骤1:
将化合物5-1(1.00g,8.84mmol)溶解在THF(25.0mL)中,然后加入顺式-3-((叔丁基二甲基硅烷基)氧基)环丁醇(1.79g,8.84mmol)和PPh3(3.48g,13.2mmol)。在N2氛0℃下加入DIAD(2.63mL,13.2mmol)。混合物在室温下反应12小时。反应用H2O(40.0mL)淬灭,EtOAc萃取(50.0mL×3)。有机相用饱和食盐水洗(100mL×3),Na2SO4干燥,过滤浓缩。粗品经柱层析纯化后得到化合物5-2。LCMS:298.2[M+H]+。
步骤2:
将化合物5-2(2.50g,8.40mmol)溶解在EtOH(30.0mL)中,加入10% Pd/C (0.890g,8.40mmol)。混合物在H2氛下反应2小时。过滤浓缩后得到化合物5-3直接用于下一步反应。LCMS:268.2[M+H]+。
步骤3:
将化合物5-3(2.20g,8.22mmol)溶解在二氧六环(30.0mL)中,然后加入3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-羧酸叔丁酯(2.67g,8.22mmol),Pd2(dba)3(0.750g,0.823mmol),SPhos(0.680g,1.64mmol)和Cs2CO3(5.36g,16.4mmol)。混合物在100℃下反应12小时,浓缩后的粗品用柱层析纯化得到化合物5-4。LCMS:556.4[M+H]+。
步骤4:
将化合物5-4(1.00g,1.79mmol)溶解在THF(8.00mL)中,然后加入TBAF(5.39mL,5.39mmol)。混合物在室温下反应12小时。反应用H2O(20.0mL)淬灭,EtOAc(5.00mL×3)萃取。有机相用饱和食盐水(10.0mL×3)洗,Na2SO4干燥,过滤浓缩得到化合物5-5,直接用于下一步反应。LCMS:442.3[M+H]+。
步骤5:
将化合物5-5(840mg,1.90mmol)溶解在DMA(10.0mL)中,然后加入2-氯-N-((6-氰基吡啶-3-基)甲基)-5-羟基-1,7-萘啶-6-甲酰胺(646mg,1.90mmol),Pd(OAc)2(42.7mg,0.190mmol),BINAP(236mg,0.380mmol)和Cs2CO3(1.23g,3.80mmol)。混合物在130℃微波下反应2小时。反应用H2O(100 mL)淬灭,用EtOAc(30.0mL×3)萃取。有机相用饱和食盐水(100mL×3)洗,Na2SO4干燥过滤浓缩后,经柱层析纯化得到化合物5-6。LCMS:745.4[M+H]+。
步骤6:
将化合物5-6(60.0mg,0.081mmol)溶解在DCM(1.00mL)中,加入TFA(0.246mL,3.240mmol)。混合物在室温下反应2小时。减压浓缩后得到化合物5-7直接用于下一步反应。LCMS:645.3[M+H]+。
步骤7:
将化合物(1S)-2,2-二氟环丙烷-1-羧酸溶解在DMF(1.00mL)中,加入HATU(44.2mg,0.116mmol),DIPEA(0.0380mL,0.233mmol)和5-7(50.0mg,0.0780mmol)。混合物在室温下反应2小时,经制备HPLC(FA条件)纯化得到化合物5。LCMS:749.6 [M+H]+。1H NMR(400MHz,DMSO-d6)δ = 13.55(br s,1H),9.96(br s,1H),8.77(s,1H),8.68(br s,1H),8.60-8.50(m,1H),8.11(dd,J = 4.4,6.4Hz,1H),8.06-7.96(m,3H),7.80(d,J = 9.1 Hz,1H),7.59(br s,1H),6.65(br d,J = 4.0 Hz,1H),5.02-4.91(m,1H),4.66(br d,J = 6.3Hz,2H),4.48-4.41(m,1H),4.14-3.95(m,2H),3.18-3.13(m,2H),2.65(td,J = 6.0,11.9Hz,2H),2.37(dt,J = 4.1,8.5Hz,2H),2.02-1.79(m,4H),1.60-1.53(m,2H),1.36-1.26(m,2H),0.93(t,J = 7.3Hz,2H)。
生物测试例
JAK
用Echo 655(Beckman,ECHO®655 SYSTEM)转移40 nL化合物到384反应板中(厂家:Greiner,货号:784075)。用1×的激酶反应缓冲液(50mM Hepes,10mM MgCl2,0.01%Brij-35,1mM EGTA,2mM DTT)配制2×的激酶溶液,转移2 μL的JAK1(25 nM,厂家:Carna,货号:08-144)溶液到384反应板中。使用离心机在1000rpm离心1分钟,25℃ 孵育10钟。用激酶反应缓冲液准备2×的底物(IRS1: 0.05 mg/mL)和ATP(20 μM,厂家:Promega,货号:V915B)的混合液,向反应板中加入2 μL的底物和ATP的混合液后开始反应,使用离心机在1000rpm离心1分钟。25℃ 孵育60分钟。转移4μL ADP-Glo到384检测板中,1000rpm离心1分钟,25℃孵育40分钟。转移8μL检测溶液到384检测板中,1000rpm离心1分钟,25℃孵育40分钟,在酶标仪(厂家:BMG,型号:PHERAstar FSX)上以ADP-Glo模式读取各孔luminescence信号。将阴性对照的读值设为0%抑制率,阳性对照的读值设为100%抑制率,计算各测试溶液的抑制率,进而通过GraphPad 8软件进行数据分析,利用非线性拟合公式来得到化合物的IC50(半数抑制浓度),结果见下表1。
PHD2
使用DMSO对待测化合物进行梯度稀释。用ECHO向384孔反应板中加入40nL/孔的化合物。密封实验板,1000rpm离心1分钟。向加有上述化合物的384孔反应板中加入4 μL/孔2×PHD2酶工作溶液。密封实验板,1000 rpm 离心1分钟,25℃孵育30分钟。制备2×底物工作液(CODD肽和α-酮戊二酸),向加有上述化合物的384孔反应板中加入4μL/孔2×底物工作溶液。密封实验板,1000 rpm离心1分钟,25℃孵育30分钟。加入4μL/孔4×已制备好的终止工作液到384实验板中终止反应。密封实验板,1000rpm离心1分钟。加入4μL/孔4×检测工作液(Alphascreen链霉亲和素供体磁珠,AlphaScreenA蛋白受体磁珠和羟基-HIF-1α(Pro564)(D43B5)XP® Rabbit mAb)到384实验板中。密封实验板,1000rpm离心1分钟,25℃孵育30分钟。在Envision 2104 Reader上检测荧光信号,结果见下表1。
表1
尽管本发明的具体实施方式已经得到详细的描述,根据已经公开的所有教导,本领域技术人员可以对本发明技术方案的细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (10)
1.一种式(I)所示的化合物或其药学上可接受的盐,
式(I),
R1选自或-OC(CH3)3;
L选自-L1-L2-L3-L4-L5-;
L1选自单键或5-6元杂芳基;
L2选自单键、C1-3亚烷基或C3-6环烷基;
L3选自单键或O;
L4选自单键或C1-3亚烷基;
L5选自单键、O或-N(R3)-;
R2、R3分别独立地选自H或C1-6烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,L1选自单键、或。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中,L2选自单键、-CH2-、-CH2CH2-或。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其中,L4选自单键、-CH2-或-CH2CH2-。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中,R2、R3分别独立地选自H或C1-3烷基。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其中,L选自单键、、/>、/>或/>。
7.根据权利要求1所述的化合物或其药学上可接受的盐,其中,式(I)所示化合物的结构如下之一所示:
、/>、、/>或。
8.一种药物组合物,其中,所述药物组合物包括权利要求1-7任一项所述的化合物或其药学上可接受的盐,
以及,药学上可接受的载体。
9.权利要求1-7任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备治疗PHD2和JAK1介导的疾病药物中的应用。
10.根据权利要求9所述的应用,其中,所述PHD2和JAK1介导的疾病为炎症性肠病。
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