CN117229259A - 一种8-喹啉磺酰胺苯基咪唑类化合物及其应用 - Google Patents
一种8-喹啉磺酰胺苯基咪唑类化合物及其应用 Download PDFInfo
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- CN117229259A CN117229259A CN202311199989.9A CN202311199989A CN117229259A CN 117229259 A CN117229259 A CN 117229259A CN 202311199989 A CN202311199989 A CN 202311199989A CN 117229259 A CN117229259 A CN 117229259A
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- 206010028594 Myocardial fibrosis Diseases 0.000 claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 150000001875 compounds Chemical class 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002207 metabolite Substances 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 14
- 229940002612 prodrug Drugs 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- 125000001153 fluoro group Chemical group F* 0.000 claims description 9
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
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Abstract
本发明涉及药物化学领域，特别涉及一种8‑喹啉磺酰胺苯基咪唑类化合物及其应用，该类分子能够调节丙酮酸激酶M2（PKM2）的活性，且激动活性优于Mitapivat，同时有较好的药代动力学性质；可以在制备治疗心肌纤维化的药物中使用，具有良好的应用前景。
Description
技术领域
本发明涉及药物化学领域，特别涉及一种8-喹啉磺酰胺苯基咪唑类化合物及其应用。
发明背景
心肌纤维化(myocardial fibrosis，MF)是多种心脏病常见的病理特征，包括心肌梗死、心肌缺血、扩张性和肥厚性心肌病以及心力衰竭。虽然单核/巨噬细胞，淋巴细胞，肥大细胞，血管细胞和心肌细胞可通过分泌关键的纤维化介质来促进纤维化反应，但心肌成纤维细胞(cardiac fibroblasts，CFs仍被认为是心肌纤维化的主要效应细胞。成纤维细胞是一种具有结构和功能的间充质细胞，合成间质胶原和纤维连接蛋白这两种细胞外基质(extracellular matrix，ECM)的主要成分。在促纤维化因子的刺激下，心肌成纤维细胞可增殖、活化、转分化为肌成纤维细胞(myofibroblasts，MFs)，诱导ECM过度沉积，并伴随各型胶原排列紊乱，导致心室壁的顺应性下降，心脏僵硬度增加，心脏正常功能被破坏，引起心律失常。
丙酮酸激酶(PK)是在糖酵解过程中将磷酸烯醇丙酮酸酯转化为丙酮酸酯的一种代谢酶。在哺乳动物中存在四种PK同工型：L和R同工型在肝脏和红细胞中表达，M1同工型在大部分成年组织中表达，并且M2同工型是在胚胎发育过程中表达的M1的剪接变体。所有肿瘤细胞专门地表达胚胎M2同工型。PK的M1与M2同工型之间的熟知的差别是：M2是低活性酶，其通过上游糖酵解中间体果糖-1，6-双磷酸酯(FBP)依赖变构激活，而M1本质上是活性酶。
研究发现心肌肥厚病人以及TAC诱导的心肌纤维化的小鼠心脏组织中PKM2巯基亚硝基化修饰水平明显升高，PK活性下降，这提示PKM2是针对心肌纤维化是潜在靶点。
发明内容
针对现有技术的不足，本发明的目的是提供一类剂8-喹啉磺酰胺苯基咪唑类化合物及其应用，该类化合物可以作为新型的苯基咪唑类PKM2激动剂使用。
本发明解决其技术问题采用的技术方案是：
第一方面，本发明提供了一种式(Ⅰ)所示的PKM2激动剂8-喹啉磺酰胺苯基咪唑类化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其中：
L选自-C＝O-、或-(CRaRa)m-；
R1选自烷基、碳环、芳基、杂芳基以及杂环基；它们被Rc取代0-5次；
每个Ra独立地选自氢、卤素、烷基、烷氧基以及卤代烷氧基，或两个Ra与它们附接到上面的碳原子一起形成一个可任选取代的环烷基；
每个Rc独立地选自卤素、卤烷基、卤代烷氧基、烷基、炔基、硝基、氰基、羟基、羧基、-C(O)Rb、-OC(O)Rb、-C(O)ORb、-SRb、-NRaRd以及-ORb，或两个Rc与它们附接到上面的碳原子一起形成一个可任选取代的杂环基；
每个Rb独立地选自烷基、酰基、羟烷基以及卤烷基；
每个Rd独立地选自氢或烷基；
m选自1-5中的任一个。
在具体的实施方案中，R1选自C1-8烷基、碳环、C6-10芳基、5-10元杂芳基以及3-10元杂环基；它们被Rc取代0-4次；
Ra为氢；
每个Rc独立地选自卤素、C1-8烷基、被一个或多个卤素取代的C1-8烷基、被一个或多个卤素取代的C1-8烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自C1-8烷基、酰基或被一个或多个卤素取代的C1-8烷基；
每个Rd独立地选自氢或C1-8烷基；
m为1、2或3。
在具体的实施方案中，R1选自C1-5烷基、C3-8环烷基、C6-8芳基、5-8元杂芳基以及3-8元杂环烷基；它们被Rc取代0-3次；
Ra为氢；
每个Rc独立地选自卤素、C1-5烷基、被一个或多个卤素取代的C1-5烷基、被一个或多个卤素取代的C1-5烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自C1-5烷基或酰基；
每个Rd独立地选自氢或C1-5烷基。
在具体的实施方案中，R1选自C1-3烷基、C6环烷基、苯基、5-6元杂芳基以及6元杂环烷基；它们被Rc取代0-2次；
每个Rc独立地选自卤素、C1-3烷基、被一个或多个卤素取代的C1-3烷基、被一个或多个卤素取代的C1-3烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自C1-3烷基或酰基；
每个Rd独立地选自氢或C1-3烷基。
在具体的实施方案中，R1选自C1-3烷基、C6环烷基、苯基、含N的5-6元杂芳基以及含O的6元杂环烷基；
每个Rc独立地选自氟、氯、溴、C1-3烷基、1个或多个氟取代C1-3烷基、1个或多个氟取代C1-3烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb。
在具体的实施方案中，L选自或-(CRaRa)m-；
R1选自C1-3烷基、C6环烷基、苯基、含N的5-6元杂芳基以及含O的6元杂环烷基；它们被Rc取代0-2次；
每个Rc独立地选自氟、C1-3烷基、1、2或3个氟取代的C1-3烷基、1、2或3个氟取代C1-3烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb。
在具体的实施方案中，R1选自C1-3烷基、C6环烷基、苯基、含1个或2个N的5-6元杂芳基以及含O的6元杂环烷基；它们被Rc取代0-2次；
每个Rc独立地选自氟、甲基、1、2或3个氟取代的甲基、1、2或3个氟取代甲氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自甲基；
每个Rd独立地选自氢或甲基。
第二方面，本发明还提供如下所示的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药：
本发明所述的药学上可接受的盐为通式(Ⅰ)化合物的酸加成盐，其中用于成盐的酸包括无机酸及有机酸,所述无机酸包括:盐酸、硫酸、磷酸和甲磺酸,有机酸包括乙酸、三氟乙酸、丙酸、丁酸、马来酸、对甲苯磺酸、苹果酸、丙二酸、肉桂酸、柠檬酸、富马酸、樟脑酸、二葡糖酸、天冬氨酸和酒石酸。
第三方面，本发明保护一种药物组合物，包括根据前文所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，以及药学上可接受的载体。
药学上可接受的载体指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的赋形剂或稀释剂。所述赋形剂包括黏合剂、填充剂、崩解剂、润滑剂、防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等，所述稀释剂包括生理盐水、淀粉、糊精、蔗糖、乳糖等。
第四方面，本发明保护前文所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药、权利要求9所述的药物组合物，在制备治疗心肌纤维化的药物中的应用。
本发明中的术语除特别说明外，一般具有如下的含义。
术语“烷基”表示具有所述数目之碳原子的直链或支链饱和烃基。
术语“Cm-n烷基”是指具有m-n个碳原子的支链或支链饱和烃基。例如“C1-8烷基”是指具有1-8个碳原子的支链或支链饱和烃基。
术语“卤素或卤”是指氟、氯、溴、碘。
术语“羟基”指-OH基团。
术语“氰基”指-CN基团。
术语“硝基”指-NO2基团。
术语“烷氧基”指-O-烷基。
有益效果：本发明与现有技术相比，具有如下优势：
本发明提供一类具有治疗心肌纤维化的新型PKM2激动剂，与PKM2激动剂Mitapivat相比，本化合物的最高激动活性要优于Mitapivat，同时有较好的药代动力学性质。
附图说明
图1.化合物2，4，18，23及24细胞水平抗纤维化作用；其中图1A-1E分别对应化合物2，4，18，23及24。
具体实施方式
以下结合实施例对本发明做进一步详细说明，但并不限定本发明。所用试剂或者仪器设备未注明生产厂商的，均视为可以通过市场购买的常规产品。下述实施例中的试验方法，如无特殊说明，均为常规方法。下面结合具体实施例对本发明作出详细说明。
实施例1【化合物1】N-(4-(1-(4-甲氧基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
将对硝基苯甲腈(4.44g,29.98mmol)溶解在甲醇(30mL)中。向该溶液中加入1.14mL 5mol/L的甲醇钠溶液。将混合物在室温下搅拌4小时。继续向溶液中加入氨基乙醛缩二乙醇(4g,30.03mmol),3.6mL冰醋酸，将混合物在50℃下搅拌1小时。继续向该溶液中加入15mL6mol/L HCl水溶液,60mL甲醇，回流反应过夜。然后将溶液倒入大量水中，产物析出，抽滤并在红外灯下烘干得到纯中间体1(5g,88％)。
将中间体1(350mg,1.85mmol)溶解在无水THF中，于N2和冰浴下加入NaH(54mg,2.25mmol)。在一小时后加入4-甲氧基溴苄(446mg,2.22mmo)。将混合物在50℃搅拌3小时，然后冷却至室温。将混合物用饱和氯化铵溶液淬灭，用乙酸乙酯萃取，用无水硫酸钠干燥，过滤，蒸发得到粗产物，将其通过柱色谱纯化(EA/PE 1:2,v/v)得到纯中间体2(407mg,71％)，为白色固体。
将中间体2(407mg,1.32mmol)溶解在15mL NH4Cl/EtOH(1:1)中。向该溶液中加入还原铁粉(293mg,5.25mmol)。将混合物在65℃搅拌1小时，然后冷却至室温。将混合物加入大量水，用硅藻土过滤，用乙酸乙酯萃取，用无水硫酸钠干燥，蒸发得到纯中间体3(300mg,81.6％)。
将中间体3(400mg,1.43mmol)溶解在15mL DCM中。向该溶液中加入三乙胺(595μL，2.86mmol)和喹啉-8-磺酰氯(489mg,2.19mmol)。将混合物在室温搅拌12小时。将混合物用水淬灭，用二氯甲烷萃取，用无水硫酸钠干燥，过滤，蒸发得到粗产物，将其通过柱色谱纯化(MeOH/CH2Cl2 1:120,v/v)得到得到化合物1(203mg,30％)，为白色固体。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.24(dt,J＝7.9,1.6Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.37-7.32(m,2H),7.30-7.22(m,3H),7.19(d,J＝7.5Hz,1H),6.86-6.80(m,2H),5.45(t,J＝1.0Hz,2H),3.78(s,2H).13C NMR(125MHz,Chloroform-d)δ159.29,146.60,146.24,142.42,137.32,135.08,134.93,131.27,129.60,129.26,129.22,128.88,128.24,128.06,127.30,125.37,123.16,122.43,120.61,114.36,55.29,50.40.HR-MS(ESI)m/z:calcd for C26H22N4O3S[M+H]+470.1413,found 470.1419.
实施例2【化合物2】N-(4-(1-(3-甲氧基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-甲氧基溴苄。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.24(dt,J＝7.6,1.6Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.91–7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.37–7.32(m,2H),7.27(d,J＝7.5Hz,1H),7.23(t,J＝7.5Hz,1H),7.14(d,J＝7.5Hz,1H),7.02–6.96(m,1H),6.86(dt,J＝7.5,1.5Hz,1H),6.69(p,J＝1.3Hz,1H),5.46(t,J＝1.0Hz,2H),3.79(s,2H).13CNMR(125MHz,Chloroform-d)δ158.72,146.60,146.24,142.42,137.32,136.97,135.08,134.93,131.27,129.57,129.26,128.88,128.24,128.06,127.30,125.37,123.16,122.43,121.76,120.61,112.94,112.80,55.18,50.15.HR-MS(ESI)m/z:calcdforC26H22N4O3S[M+H]+470.1413,found 470.1407.
实施例3【化合物3】N-(4-(1-(3-羟基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-羟基溴苄。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.5Hz,1H),8.86(s,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.7Hz,1H),8.00(dt,J＝7.7,1.7Hz,1H),7.91–7.85(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39–7.33(m,2H),7.27(d,J＝7.5Hz,1H),7.17–7.10(m,2H),6.97–6.91(m,1H),6.76(dt,J＝7.5,1.6Hz,1H),6.65(p,J＝1.2Hz,1H),5.45(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ155.81,146.60,146.24,141.93,137.83,137.32,135.08,134.89,131.23,129.90,129.26,128.88,128.24,128.08,127.51,125.37,123.16,122.43,120.88,120.65,115.53,113.96,50.26.HR-MS(ESI)m/z:calcdfor C25H20N4O3S[M+H]+456.1526,found 456.1521.
实施例4【化合物4】N-(4-(1-(3-氨基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-氨基溴苄。1HNMR(500MHz,Chloroform-d)δ9.01(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.7Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.27(d,J＝7.5Hz,1H),7.19-7.08(m,3H),6.52(dq,J＝5.8,1.5Hz,2H),5.41(t,J＝1.0Hz,2H),4.68(d,J＝5.5Hz,1H),4.62(d,J＝5.5Hz,1H).13CNMR(125MHz,Chloroform-d)δ148.07,146.69,146.24,141.93,137.32,136.29,135.08,134.89,131.23,129.26,128.91,128.88,128.24,128.08,127.51,125.37,123.16,122.43,120.65,118.98,115.57,114.87,50.20.HR-MS(ESI)m/z:calcdfor C25H21N5O2S[M+H]+455.1416,found 455.1423.
实施例5【化合物5】N-(4-(1-(4-氨基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为4-氨基溴苄。1HNMR(500MHz,Chloroform-d)δ9.01(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.7Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.28(d,J＝7.5Hz,1H),7.18-7.10(m,3H),6.60-6.54(m,2H),5.40(t,J＝1.0Hz,2H),5.07(d,J＝5.7Hz,1H),4.94(d,J＝5.7Hz,1H).13C NMR(125MHz,Chloroform-d)δ147.17,146.69,146.24,141.93,137.32,135.08,134.89,134.33,131.23,129.26,128.88,128.24,128.08,127.51,125.37,123.16,122.43,120.65,111.11,50.29.HR-MS(ESI)m/z:calcd for C25H21N5O2S[M+H]+455.1416,found 455.1410.
实施例6【化合物6】N-(4-(1-(4-氟苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为4-氟溴苄。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.7Hz,1H),8.00(dt,J＝7.8,1.7Hz,1H),7.91-7.85(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.27(d,J＝7.5Hz,1H),7.21-7.13(m,3H),7.06-6.98(m,2H),5.45(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.60,146.24,141.93,137.32,135.08,134.89,131.23,130.35,130.29,129.26,128.88,128.24,128.08,127.51,125.37,123.16,122.43,120.65,115.56,115.40,50.29.HR-MS(ESI)m/z:calcd for C25H19FN4O2S[M+H]+458.1213,found 458.1206.
实施例7【化合物7】N-(4-(1-(3-氟苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-氟溴苄。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.7Hz,1H),8.00(dt,J＝7.7,1.7Hz,1H),7.91-7.85(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.36-7.29(m,1H),7.32-7.25(m,1H),7.22(d,J＝7.5Hz,1H),7.11-7.06(m,1H),7.02(ddt,J＝17.0,7.7,1.4Hz,2H),5.47(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.60,146.24,141.93,137.32,135.08,134.89,131.23,130.41,130.35,129.26,128.88,128.24,128.08,127.51,125.37,124.15,124.12,123.16,122.43,120.65,115.26,115.10,114.98,114.82,50.27,50.24.HR-MS(ESI)m/z:calcd for C25H19FN4O2S[M+H]+458.1213,found 458.1222.
实施例8【化合物8】N-(4-(1-(2-氰基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为2-氰基溴苄。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.24(dt,J＝7.8,1.7Hz,1H),8.01(dt,J＝7.9,1.6Hz,1H),7.92-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.61-7.53(m,2H),7.47-7.38(m,2H),7.37-7.32(m,2H),7.30-7.22(m,2H),7.16(d,J＝7.5Hz,1H),5.52(d,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.60,146.12,142.42,137.32,136.89,135.08,134.90,133.71,131.30,129.26,128.88,128.43,128.42,128.24,128.07,127.64,127.30,125.37,123.21,122.43,120.61,116.93,111.69,49.05.HR-MS(ESI)m/z:calcd for C26H19N5O2S[M+H]+465.1259,found 465.1250.
实施例9【化合物9】N-(4-(1-(3-氰基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-氰基溴苄。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.24(dt,J＝7.9,1.6Hz,1H),8.01(dt,J＝7.9,1.7Hz,1H),7.91-7.86(m,2H),7.73(p,J＝1.2Hz,1H),7.69-7.59(m,2H),7.56(t,J＝7.5Hz,1H),7.49(t,J＝7.5Hz,1H),7.37-7.30(m,3H),7.27(d,J＝7.5Hz,1H),7.18(d,J＝7.5Hz,1H),5.46(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.60,146.24,142.42,137.32,137.00,135.08,134.90,131.30,131.19,129.98,129.49,129.44,129.26,128.88,128.24,128.07,127.30,125.37,123.16,122.43,120.61,118.49,111.62,50.26.HR-MS(ESI)m/z:calcd for C26H19N5O2S[M+H]+465.1259,found 465.1263.
实施例10【化合物10】N-(4-(1-(4-氰基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为4-氰基溴苄。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.24(dt,J＝7.8,1.6Hz,1H),8.01(dt,J＝7.8,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.59-7.52(m,3H),7.37-7.32(m,2H),7.30-7.24(m,3H),7.15(d,J＝7.5Hz,1H),5.45(t,J＝0.9Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.60,146.24,142.42,137.89,137.32,135.08,134.90,132.33,131.30,129.26,128.88,128.40,128.24,128.07,127.30,125.37,123.16,122.43,120.61,118.48,111.73,50.40.HR-MS(ESI)m/z:calcdfor C26H19N5O2S[M+H]+465.1259,found465.1271.
实施例11【化合物11】N-(4-(1-(3-(三氟甲氧基)苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-(三氟甲氧基)溴苄。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.6Hz,1H),8.34(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.6,1.7Hz,1H),8.01(dt,J＝7.9,1.6Hz,1H),7.91-7.86(m,2H),7.66(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.27(d,J＝7.5Hz,1H),7.23(t,J＝7.5Hz,1H),7.14(d,J＝7.5Hz,1H),7.05(dt,J＝7.5,1.5Hz,1H),7.03-6.95(m,2H),5.46(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.72,146.69,142.09,137.46,137.15,135.17,134.90,131.02,129.65,129.26,128.27,128.13,128.06,127.92,125.21,123.16,122.42,121.99,120.48,119.17,119.16,117.71,50.31.HR-MS(ESI)m/z:calcd for C26H19F3N4O3S[M+H]+
524.1130,found 524.1134.
实施例12【化合物12】N-(4-(1-(3-(三氟甲基)苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-(三氟甲基)溴苄。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.6Hz,1H),8.34(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.6Hz,1H),8.01(dt,J＝7.7,1.7Hz,1H),7.91-7.86(m,2H),7.66(t,J＝7.5Hz,1H),7.59-7.47(m,4H),7.39-7.33(m,2H),7.30-7.24(m,2H),7.19(d,J＝7.5Hz,1H),5.40(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.72,146.69,142.09,137.15,136.50,136.48,135.17,134.91,131.52,131.27,131.15,129.37,129.03,129.02,128.86,128.28,128.24,
128.06,128.03,126.80,126.77,125.37,125.00,123.88,123.85,123.16,122.85,122.42,120.48,50.59.HR-MS(ESI)m/z:calcd for C26H19F3N4O2S[M+H]+508.1181,found 508.1175.
实施例13【化合物13】3-((2-(4-(喹啉-8-磺酰胺基)苯基)-1H-咪唑-1-基)甲基)苯甲酸甲酯
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-溴甲基苯甲酸甲酯。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.5Hz,1H),8.34(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.6Hz,1H),8.01(dt,J＝7.7,1.7Hz,1H),7.98(p,J＝1.2Hz,1H),7.88(ddt,J＝7.7,4.8,1.7Hz,3H),7.66(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.49(t,J＝7.5Hz,1H),7.39-7.33(m,3H),7.28(d,J＝7.3Hz,1H),7.19(d,J＝7.5Hz,1H),5.44(t,J＝1.0Hz,2H),3.93(s,2H).13C NMR(125MHz,Chloroform-d)δ166.51,146.72,146.69,142.09,137.15,136.46,135.17,134.91,131.06,130.25,130.22,129.37,128.91,128.86,128.69,128.24,128.10,128.06,128.03,125.37,123.16,122.42,120.48,52.13,50.46.HR-MS(ESI)m/z:calcd for C27H22N4O4S[M+H]+
498.1362,found 498.1366.
实施例14【化合物14】N-(4-(1-苄基-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
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参照实施例1中化合物1的合成方法，中间体2的合成原料更换为溴苄。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.6Hz,1H),8.37(dd,J＝7.5,1.6Hz,1H),8.25(dt,J＝7.7,1.7Hz,1H),8.02(dt,J＝7.1,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.23(m,6H),7.17-7.09(m,3H),5.44(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.69,146.24,142.03,137.22,136.73,135.08,134.89,131.23,129.23,129.09,128.24,128.17,128.07,127.96,127.71,127.62,125.37,123.16,122.43,120.52,
50.56.HR-MS(ESI)m/z:calcd for C25H20N4O2S[M+H]+440.1307,found 440.1312.
实施例15【化合物15】3-((2-(4-(喹啉-8-磺酰胺基)苯基)-1H-咪唑-1-基)甲基)苯甲酸
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-溴甲基苯甲酸。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.6Hz,1H),8.34(dd,J＝7.5,1.7Hz,1H),8.25(dt,J＝7.7,1.7Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.93-7.84(m,4H),7.66(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.48(t,J＝7.5Hz,1H),7.43-7.37(m,1H),7.39-7.33(m,2H),7.28(d,J＝7.3Hz,1H),7.19(d,J＝7.5Hz,1H),5.44(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ168.26,146.72,146.69,142.09,137.23,135.99,135.08,134.92,131.00,130.20,129.47,129.37,129.30,128.88,128.75,128.24,128.06,127.89,127.60,125.37,123.16,122.42,120.61,50.45.HR-MS(ESI)m/z:calcd for C26H20N4O4S[M+H]+484.1205,found 484.1209.
实施例16【化合物16】N-(4-(1-(3-硝基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-硝基溴苄。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.6Hz,1H),8.34(dd,J＝7.5,1.7Hz,1H),8.25(dt,J＝7.4,1.6Hz,1H),8.17-8.11(m,2H),8.01(dt,J＝7.5,1.6Hz,1H),7.92-7.86(m,2H),7.66(t,J＝7.5Hz,1H),7.57(dt,J＝12.4,7.6Hz,2H),7.45(dt,J＝7.5,1.5Hz,1H),7.39-7.33(m,2H),7.26(d,J＝7.5Hz,1H),7.15(d,J＝7.5Hz,1H),5.53(t,J＝1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ148.02,146.72,146.69,142.09,137.23,136.84,135.08,134.92,132.10,131.00,129.37,129.07,128.88,128.24,128.06,127.60,125.37,123.16,122.79,122.62,122.42,120.61,50.36.HR-MS(ESI)m/z:calcd for C25H19N5O4S[M+H]+485.1158,found 485.1154.
实施例17【化合物17】N-(4-(1-(3-甲基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3-甲基溴苄。1HNMR(500MHz,Chloroform-d)δ9.01(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.6Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.28(d,J＝7.5Hz,1H),7.22-7.13(m,2H),7.13-7.07(m,1H),7.06-7.00(m,2H),5.45(t,J＝1.0Hz,2H),2.34-2.30(m,2H).13CNMR(125MHz,Chloroform-d)δ146.69,146.24,141.93,137.51,137.32,136.24,135.08,134.89,131.23,129.26,128.97,128.88,128.42,128.24,128.08,128.00,127.51,125.88,125.37,123.16,122.43,120.65,50.34,21.19.HR-MS(ESI)m/z:calcd for C26H22N4O2S[M+H]+454.1463,found 454.1460.
实施例18【化合物18】N-(4-(1-(3,4-二甲氧基苄基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为3，4-二甲氧基溴苄。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.5Hz,1H),8.34(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.7,1.7Hz,1H),8.01(dt,J＝7.7,1.7Hz,1H),7.91-7.86(m,2H),7.66(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.27(d,J＝7.5Hz,1H),7.14(d,J＝7.5Hz,1H),6.88(dq,J＝7.5,1.1Hz,1H),6.84-6.79(m,2H),5.46(t,J＝1.0Hz,2H),3.80(d,J＝2.0Hz,6H).13C NMR(125MHz,Chloroform-d)δ149.36,149.08,146.72,146.69,142.09,137.15,135.17,134.91,131.66,131.06,129.37,128.86,128.24,128.06,128.03,125.37,123.16,122.42,122.29,120.48,112.20,112.16,55.92,55.86,50.29.HR-MS(ESI)m/z:calcd for C27H24N4O4S
[M+H]+500.1518,found 500.1522.
实施例19【化合物19】N-(4-(1-苯乙基-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为(2-溴乙基)苯。1HNMR(500MHz,Chloroform-d)δ9.01(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.5,1.7Hz,1H),8.01(dt,J＝7.5,1.6Hz,1H),7.92-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.38-7.32(m,2H),7.32-7.13(m,8H),4.23(t,J＝7.1Hz,2H),3.01(tt,J＝7.1,1.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.69,145.06,141.93,137.93,137.32,135.08,134.89,131.23,128.93,128.87,128.82,128.75,128.24,128.08,127.51,127.01,125.37,122.43,122.12,120.65,48.33,36.04.HR-MS(ESI)m/z:calcd for C26H22N4O2S[M+H]+454.1463,found 454.1466.
实施例20【化合物20】N-(4-(1-(3-苯基丙基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为1-溴-3-苯基丙烷。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.6Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.24(dt,J＝7.8,1.7Hz,1H),8.01(dt,J＝7.8,1.6Hz,1H),7.92-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.37-7.31(m,2H),7.29-7.14(m,7H),4.14(t,J＝7.1Hz,2H),2.63(tt,J＝7.1,0.9Hz,2H),2.02(p,J＝7.1Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.60,144.90,142.42,140.61,137.32,135.08,134.91,131.27,128.87,128.82,128.62,128.61,128.24,128.07,127.30,126.42,125.37,122.43,121.77,120.61,45.60,32.59,29.40.HR-MS(ESI)m/z:calcd for C27H24N4O2S[M+H]+468.1620,found468.1615.
实施例21【化合物21】N-(4-(1-乙基-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为溴乙烷。1H NMR(500MHz,Chloroform-d)δ9.00(dd,J＝7.5,1.5Hz,1H),8.38(dd,J＝7.5,1.5Hz,1H),8.25(dt,J＝7.1,1.6Hz,1H),8.03(dt,J＝7.5,1.7Hz,1H),7.94-7.88(m,2H),7.65(t,J＝7.5Hz,1H),7.57(t,J＝7.5Hz,1H),7.38-7.33(m,2H),7.25(d,J＝7.5Hz,1H),7.21(d,J＝7.5Hz,1H),4.08(q,J＝8.0Hz,2H),1.42(t,J＝8.0Hz,3H).13C NMR(125MHz,Chloroform-d)δ147.12,145.25,141.48,137.48,135.12,134.86,131.06,128.35,128.09,128.03,127.91,127.59,125.36,122.42,121.53,120.60,42.86,15.96.HR-MS(ESI)m/z:calcd forC20H18N4O2S[M+H]+378.1150,found 378.1144.
实施例22【化合物22】N-(4-(1-(环己基甲基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为溴甲基环己烷。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.6Hz,1H),8.37(dd,J＝7.5,1.6Hz,1H),8.25(dt,J＝7.7,1.7Hz,1H),8.02(dt,J＝7.3,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.38-7.32(m,2H),7.25-7.18(m,2H),4.06(d,J＝7.0Hz,2H),1.87(dt,J＝13.8,6.9Hz,1H),1.61-1.53(m,4H),1.55-1.48(m,1H),1.51-1.40(m,5H),1.43-1.33(m,1H).13C NMR(125MHz,Chloroform-d)δ146.69,145.01,142.09,137.22,135.08,134.89,131.23,128.70,128.24,128.06,127.92,127.51,125.37,122.43,121.98,120.65,51.06,36.83,29.68,26.54,25.34.HR-MS(ESI)m/z:calcd for C25H26N4O2S[M+H]+446.1776,found 446.1779.
实施例23【化合物23】N-(4-(1-((四氢-2H-吡喃-4-基)甲基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为4-溴甲基四氢吡喃。1H NMR(500MHz,Chloroform-d)δ9.01(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.6Hz,1H),8.25(dt,J＝7.7,1.7Hz,1H),8.02(dt,J＝7.3,1.6Hz,1H),7.92-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.38-7.30(m,3H),7.22(d,J＝7.3Hz,1H),4.08(d,J＝7.0Hz,2H),3.78-3.64(m,4H),2.02(h,J＝7.0Hz,1H),1.86(dq,J＝12.4,7.1Hz,2H),1.76(dq,J＝12.3,7.0Hz,2H).13C NMR(125MHz,Chloroform-d)δ146.69,145.01,141.93,137.22,135.08,134.89,131.23,128.70,128.24,128.06,127.92,127.51,125.37,122.43,121.98,120.65,67.36,50.67,34.76,29.69.HR-MS(ESI)m/z:calcd for C24H24N4O3S[M+H]+448.1569,found 448.1575.
实施例24【化合物24】N-(4-(1-(吡嗪-2-基甲基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为2-溴甲基吡嗪。1HNMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.5,1.6Hz,1H),8.71(s,1H),8.48(d,J＝7.5Hz,1H),8.37(dd,J＝7.5,1.6Hz,1H),8.29-8.22(m,2H),8.02(dt,J＝7.2,1.6Hz,1H),7.91-7.86(m,2H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.39-7.33(m,2H),7.21(d,J＝7.5Hz,1H),7.08(d,J＝7.5Hz,1H),5.34(s,2H).13C NMR(125MHz,Chloroform-d)δ147.79,146.69,145.83,143.80(d,J＝15.0Hz),142.36,142.03,137.22,135.08,134.89,131.23,129.26,128.86,128.24,128.07,127.51,125.37,123.56,122.43,120.65,50.32.HR-MS(ESI)m/z:calcd for C23H18N6O2S[M+H]+442.1212,found 442.1224.
实施例25【化合物25】N-(4-(1-(吡啶-3-基磺酰基)-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为吡啶-3-磺酰氯。1H NMR(500MHz,Chloroform-d)δ9.03(dd,J＝7.4,1.6Hz,1H),8.98(d,J＝1.4Hz,1H),8.69(dd,J＝7.5,1.6Hz,1H),8.34(dd,J＝7.5,1.7Hz,1H),8.24(dt,J＝7.6,1.7Hz,1H),8.19(dt,J＝7.5,1.5Hz,1H),8.01(dt,J＝7.6,1.7Hz,1H),7.96-7.89(m,3H),7.66(t,J＝7.5Hz,1H),7.59-7.51(m,2H),7.48(t,J＝7.5Hz,1H),7.40-7.34(m,2H).13C NMR(125MHz,Chloroform-d)δ151.90,148.90,146.60,144.12,142.09,137.33,135.08,134.91,134.55,134.02,131.27,129.97,128.67,128.06,127.73,127.47,125.37,124.94,124.28,122.42,122.02.HR-MS(ESI)m/z:calcd for C23H17N5O4S2[M+H]+491.0722,found 491.0734.
实施例26【化合物26】N-(4-(1-烟酰基-1H-咪唑-2-基)苯基)喹啉-8-磺酰胺
参照实施例1中化合物1的合成方法，中间体2的合成原料更换为吡啶-3-羧酸酰氯。1HNMR(500MHz,Chloroform-d)δ9.14(d,J＝1.5Hz,1H),9.01(dd,J＝7.5,1.5Hz,1H),8.76(dd,J＝7.5,1.5Hz,1H),8.37(dd,J＝7.5,1.5Hz,1H),8.26(ddt,J＝17.2,7.7,1.6Hz,2H),8.01(dt,J＝7.5,1.7Hz,1H),7.99-7.93(m,2H),7.84(d,J＝7.3Hz,1H),7.65(t,J＝7.5Hz,1H),7.56(t,J＝7.5Hz,1H),7.50-7.41(m,2H),7.41-7.35(m,2H).13C NMR(125MHz,Common NMR Solvents)δ166.72,152.44,149.56,146.69,146.24,141.93,137.49,136.70,135.08,134.89,131.23,130.03,129.74,128.68,128.20,128.08,127.51,125.37,124.20,123.10,122.43,121.19.HR-MS(ESI)m/z:calcd for C24H17N5O3S[M+H]+455.1052,found455.1067.
实施例27
将溶于DMSO中的化合物于Buffer(HEPES缓冲液1mL、KCl 74.55mg、MgCl213.33mg、Tween20 2μl、BSA(10mg))中梯度稀释，每孔中加入3μl化合物溶液和3μl PKM2激酶(1mg/mL)25℃共孵育5min。每孔中加入3μl ADP(200μM/mL)和3μl PEP(1mM/mL)25℃共孵育90min。结束后加入12μl发光液终止反应，检测吸光度。设空白组和基础激动组，空白组用等体积的buffer溶液替代化合物和酶溶液，基础激动组用等体积的buffer溶液替代化合物溶液。
AC50为达到最大激动效率一半时所需的浓度。
resp.％(最高激动率)＝(化合物最大激动均值-基础激动)/(FBP最大激动均值-基础激动)
表1.部分化合物对PKM2的激动活性
实施例28
将MgCl2\NADPH\不同种属肝微粒体(人、大鼠、小鼠肝微粒体)/PBS在37℃水浴中预温孵5min后，加入相应的化合物溶液启动反应，孵育时间为0min、5min、15min、30min、60min、120min整个体系中有机溶剂的含量<1％，反应完毕后加入冰甲醇400μL终止反应并立即取出。根据相应的LC-MS/MS的检测方法进行样品检测，检测结果使用Graphpad prism8.3.0进行处理，计算化合物在不同种属肝微粒体中的I相代谢稳定性参数t1/2(min)。。
表2.代表化合物的肝微粒体稳定性
实施例29
针对不同母核结构，我们基于PKM2的激动活性，肝微粒体稳定性实验结果，选取2，4，18，23及24继续进行细胞水平抗纤维化活性的研究。我们提取SD乳大鼠心肌成纤维细胞，给予不同浓度(1,2,5μM)化合物及Mitapivat(10μM)预处理1小时后，给予Ang II刺激构建心肌纤维化细胞模型，提取细胞总蛋白western blot检测纤维化指标collagen I和α-SMA的表达水平，发现化合物均可不同程度减轻Ang II诱导的纤维化(图1)。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下，本领域技术人员能够想到的变化和优点都被包括在本发明中，并且以所附的权利要求为保护范围。
Claims (10)
1.一种式(Ⅰ)所示的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其中：
L选自-C＝O-、或-(CRaRa)m-；
R1选自烷基、碳环、芳基、杂芳基以及杂环基；它们被Rc取代0-5次；
每个Ra独立地选自氢、卤素、烷基、烷氧基以及卤代烷氧基，或两个Ra与它们附接到上面的碳原子一起形成一个可任选取代的环烷基；
每个Rc独立地选自卤素、卤烷基、卤代烷氧基、烷基、炔基、硝基、氰基、羟基、羧基、-C(O)Rb、-OC(O)Rb、-C(O)ORb、-SRb、-NRaRd以及-ORb，或两个Rc与它们附接到上面的碳原子一起形成一个可任选取代的杂环基；
每个Rb独立地选自烷基、酰基、羟烷基以及卤烷基；
每个Rd独立地选自氢或烷基；
m选自1-5中的任一个。
2.根据权利要求1所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其特征在于：
R1选自C1-8烷基、碳环、C6-10芳基、5-10元杂芳基以及3-10元杂环基；它们被Rc取代0-4次；
Ra为氢；
每个Rc独立地选自卤素、C1-8烷基、被一个或多个卤素取代的C1-8烷基、被一个或多个卤素取代的C1-8烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自C1-8烷基、酰基或被一个或多个卤素取代的C1-8烷基；
每个Rd独立地选自氢或C1-8烷基；
m为1、2或3。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其特征在于：
R1选自C1-5烷基、C3-8环烷基、C6-8芳基、5-8元杂芳基以及3-8元杂环烷基；它们被Rc取代0-3次；
Ra为氢；
每个Rc独立地选自卤素、C1-5烷基、被一个或多个卤素取代的C1-5烷基、被一个或多个卤素取代的C1-5烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自C1-5烷基或酰基；
每个Rd独立地选自氢或C1-5烷基。
4.根据权利要求3所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其特征在于：
R1选自C1-3烷基、C6环烷基、苯基、5-6元杂芳基以及6元杂环烷基；它们被Rc取代0-2次；每个Rc独立地选自卤素、C1-3烷基、被一个或多个卤素取代的C1-3烷基、被一个或多个卤素取代的C1-3烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自C1-3烷基或酰基；
每个Rd独立地选自氢或C1-3烷基。
5.根据权利要求4所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其特征在于：
R1选自C1-3烷基、C6环烷基、苯基、含N的5-6元杂芳基以及含O的6元杂环烷基；
每个Rc独立地选自氟、氯、溴、C1-3烷基、1个或多个氟取代C1-3烷基、1个或多个氟取代C1-3烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb。
6.根据权利要求5所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其特征在于：
L选自或-(CRaRa)m-；
R1选自C1-3烷基、C6环烷基、苯基、含N的5-6元杂芳基以及含O的6元杂环烷基；它们被Rc取代0-2次；
每个Rc独立地选自氟、C1-3烷基、1、2或3个氟取代的C1-3烷基、1、2或3个氟取代C1-3烷氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb。
7.根据权利要求6所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，其特征在于：
R1选自C1-3烷基、C6环烷基、苯基、含1个或2个N的5-6元杂芳基以及含O的6元杂环烷基；它们被Rc取代0-2次；
每个Rc独立地选自氟、甲基、1、2或3个氟取代的甲基、1、2或3个氟取代甲氧基、硝基、氰基、羟基、羧基、-C(O)ORb、-NRaRd以及-ORb；
每个Rb独立地选自甲基；
每个Rd独立地选自氢或甲基。
8.如下所示的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药：
9.一种药物组合物，包括根据权利要求1-8任一所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药，以及药学上可接受的载体。
10.权利要求1-8任一所述的化合物或其药学上可接受的盐、水合物、溶剂化合物、代谢物或前药、权利要求9所述的药物组合物，在制备治疗心肌纤维化的药物中的应用。
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| CN102448951A (zh) * | 2009-04-06 | 2012-05-09 | 安吉奥斯医药品有限公司 | 丙酮酸激酶m2调节剂、治疗组合物和相关使用方法 |
| CN102482228A (zh) * | 2009-07-17 | 2012-05-30 | 盐野义制药株式会社 | 含有内酰胺或苯磺酰胺化合物的药物 |
| WO2012160447A1 (en) * | 2011-05-25 | 2012-11-29 | Dynamix Pharmaceuticals Ltd. | 3, 5 -diphenyl- substituted pyrazolines for the treatment of cancer, proliferative, inflammatory or autoimmune diseases |
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| CN102448951A (zh) * | 2009-04-06 | 2012-05-09 | 安吉奥斯医药品有限公司 | 丙酮酸激酶m2调节剂、治疗组合物和相关使用方法 |
| CN102482228A (zh) * | 2009-07-17 | 2012-05-30 | 盐野义制药株式会社 | 含有内酰胺或苯磺酰胺化合物的药物 |
| WO2012160447A1 (en) * | 2011-05-25 | 2012-11-29 | Dynamix Pharmaceuticals Ltd. | 3, 5 -diphenyl- substituted pyrazolines for the treatment of cancer, proliferative, inflammatory or autoimmune diseases |
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