CN111423422A - 芳基酰胺类抑制剂及其制备方法和应用 - Google Patents
芳基酰胺类抑制剂及其制备方法和应用 Download PDFInfo
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- CN111423422A CN111423422A CN201910020117.9A CN201910020117A CN111423422A CN 111423422 A CN111423422 A CN 111423422A CN 201910020117 A CN201910020117 A CN 201910020117A CN 111423422 A CN111423422 A CN 111423422A
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- XKPKPGCRSHFTKM-UHFFFAOYSA-L magnesium;diacetate;tetrahydrate Chemical compound O.O.O.O.[Mg+2].CC([O-])=O.CC([O-])=O XKPKPGCRSHFTKM-UHFFFAOYSA-L 0.000 description 1
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- ULDKTZNEIVWCNY-UHFFFAOYSA-N methyl 6-fluoro-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxine-7-carboxylate Chemical compound COC(=O)C1=CC2=C(C=C1F)OCC(O2)CO ULDKTZNEIVWCNY-UHFFFAOYSA-N 0.000 description 1
- ZKEBLWCAZCFJLA-UHFFFAOYSA-N methyl 6-fluoro-2-(methylsulfonyloxymethyl)-2,3-dihydro-1,4-benzodioxine-7-carboxylate Chemical compound COC(=O)C1=CC2=C(C=C1F)OCC(O2)COS(=O)(=O)C ZKEBLWCAZCFJLA-UHFFFAOYSA-N 0.000 description 1
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- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
芳基酰胺类抑制剂及其制备方法和应用。本发明公开了一种凋亡信号调节激酶1(ASK1)抑制剂,提供具有式(I)结构的芳基酰胺类化合物,其立体异构体、互变异构体或药学上可以接受的盐、水合物、溶剂合物及前药,还提供该类化合物在药学上可接受的盐的药物组合物。所述芳基酰胺类化合物可用于治疗和预防非酒精性脂肪肝炎以及相关的疾病。
Description
技术领域
本发明属于药物合成领域,具体涉及一种芳基酰胺类抑制剂及其制备方法和应用。
背景技术
有丝分裂激活蛋白激酶信号(MAPK)通路介导是细胞有丝分裂和凋亡的关键信号通路。 MAPK主要有三种类型,包括有丝分裂激活蛋白激酶激酶激酶(MAP3K)、有丝分裂激活蛋白激酶激酶(MAP2K)以及有丝分裂激活蛋白激酶激酶激酶(MAPK)。在相应环境信号刺激下,MAP3K、MAP2K和MAPK被依次顺序激活,最后MAPK通过磷酸化下游底物产生相应细胞效应,如细胞生长、分化、生存和凋亡等。
细胞存活和凋亡之间的平衡是人体正常发育的关键,如果这些平衡失调会导致各种疾病 (如癌症、自身免疫性疾病、心脏疾病及代谢性疾病等)。肝细胞凋亡目前被认为是肝病进展的重要诱因之一。尽管这是一个普遍的过程,但是它在肝纤维化中起到的作用与病毒性肝炎、酒精性和非酒精性肝病(炎)等息息相关。在动物实验中发现,通过调节肝细胞凋亡可以降低肝纤维化水平(Alexander J.Kovalic,Sanjaya K.Satapathy,NagaChalasani;Hepatology International 2018,12:97–106)。
非酒精性脂肪性肝病影响到约10%~30%的普通成人以及60-80%的II型糖尿病患者。在美国,NAFLD的发病率约占总人口的10-46%,其中约10-30%的患者会发展成为非酒精性脂肪性肝炎(NASH,nonalcoholic steatohepatitis)。非酒精性脂肪性肝炎(NASH)表现为炎症及肝细胞损伤的脂肪变性现象的出现,会导致晚期肝脏纤维化、肝硬化、肝衰竭及肝脏肿瘤等重大疾病。到2025年,预计其用药将超过350-400亿美元。早期在研的靶点包括PPAR、FXR、 GLP、ACC及THR等等,但到目前为止,NASH临床上还没有被批准的治疗药物。
凋亡信号激酶1(apoptosis signal-regulating kinase 1,ASK1)是有丝分裂原激活的蛋白激酶激酶家族成员之一,在细胞因子和应激诱导凋亡中起着关键作用(PaulYosuke Kawarazaki,Hidenori Ichijo,Isao Naguro,Expert Opin.Ther.Targets 201418(6):651-664)。众多的动物和人体实验表明,ASK1通路在肥胖和非酒精性脂肪肝病人的肝细胞中过度表达,并且与脂肪变性、胰岛素耐受性和炎症具有密切联系。因此凋亡信号激酶1特异性抑制剂有望成为新一代的治疗炎症和代谢性疾病(如非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化及肝硬化等)的药物。因此,ASK1抑制剂作为药物在医药行业具有非常良好的开发和应用前景。
综上所述,本领域迫切需要开发一种新的具有优异效果的ASK1抑制剂。
发明内容
本发明的目的就是提供一类具有新颖结构的化合物,其能够作为选择性ASK1抑制剂,对凋亡信号激酶1具有选择性抑制作用、优异的药效学性能等的。
在本发明的第一方面,提供了一种具有通式(I)结构的芳基酰胺类化合物,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可以接受的盐、水合物、溶剂合物,或前药;
式中:
M1、M2各自独立地选自:N或CR7;
环A选自下组:取代或未取代的C3-C20碳环(较佳地,C3-C10碳环)、取代或未取代的 3-20元杂环(较佳地,3-12元杂环)、取代或未取代的C6-C20芳环(较佳地,C6-C12芳环)或取代或未取代的5-20元杂芳环(较佳地,5到12元杂芳环);环A中,所述取代指环A被氧代、硫代、或-(CH2)n-所取代(即基团上连接于同一碳原子的两个氢原子被所述基团取代),或者环A 上的H被选自下组的一个或多个(较佳地1~3个)取代基所取代:氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nO(CH2)oR10、 -(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12 (包括-(CH2)nC(O)NHR11)、-(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;
各个R1是相同的或不同的,且各自独立地为选自下组的基团:取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nR10、-(CH2)nOR10、 -(CH2)nCH(R10)(CH2)oNR11R12(包括:-(CH2)n CH(OH)(CH2)o NHR11)、-(CH2)nO(CH2)oR10、 -(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12、 -(CH2)nNR11C(O)R10或-(CH2)nNR11S(O)mR10、-(CH2)nN(R11)(CH2)oR10(包括-(CH2)nNH(CH2)oR10);
R2、各个R3和R5各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、 -(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(较佳地-(CH2)nC(O)NHR11)、 -(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;
R4选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、羟基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;或者,R4与M3以及与其相连的N原子共同构成选自下组的环:取代或未取代的杂环、取代或未取代的杂芳环;
M3、M4各自独立地选自:N或CR7;或M3与M4以及其相邻的化学键共同构成选自下组的基团:取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
M5选自下组:N或CR7;
或者,X和/或Y与M1、M2或M5及其相连的化学键共同构成选自下组的环:取代或未取代的碳环、取代或未取代的杂环、取代或未取代的芳环、取代或未取代的杂芳环;
R7、R8和R9各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(包括-(CH2)nC(O)NHR11)、 -(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;
除非特别说明,以上所述的取代指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH2)nR10、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、 -(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(包括-(CH2)nC(O)NHR11)、 -(CH2)nNR11C(O)R10、或-(CH2)nNR11S(O)mR10;
R10各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、氨基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基;
R11和R12各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、氨基、羟基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;或者,R11和R12以及与其相连的N原子共同构成选自下组的环:取代或未取代的杂环,或取代或未取代的杂芳环;
其中,所述的R10、R11和R12中,取代指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH2)nR13、-(CH2)nOR13、-(CH2)nSR13、-(CH2)nCOR13、 -(CH2)nC(O)OR13、-(CH2)nS(O)mR13、-(CH2)nNR13R14、-(CH2)nC(O)NR13R14、(包括-(CH2)nC(O)NHR14)、 -(CH2)nNR14C(O)R13和-(CH2)nNR14S(O)mR13;
R13和R14各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、氨基、羟基、酯基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;其中,所述的R13和R14中,取代指基团上的一个或多个(较佳地 1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、烷氧基、卤素、氨基、硝基、羟基、氰基、酯基;
x为0、1、2、3或4;y为0、1或2;m为0、1或2;且n为0、1、2、3、4或5;
o为0、1、2、3、4或5;
除非特别说明,上述各式中,“(CH2)n”或“(CH2)o”中0-3个氢被C1-C6烷基取代;各个所述的环烷基为C3-C20环烷基(较佳地C3-C10环烷基);各个所述的杂环基为3-20元杂环基(较佳地3-10元杂环基);各个所述的芳基为C6-C20芳基(较佳地C6-C12芳基);各个所述的杂芳基为5-20元杂芳基(较佳地5到12元杂芳基)各个所述的烷基为C1-C18烷基(较佳地C1-C6 烷基);各个所述的烷氧基为C1-C18烷氧基(较佳地C1-C6烷氧基);各个所述的酯基为C2-C10 酯基(较佳地C2-C6酯基);各个所述的碳环为C3-C20碳环(较佳地C3-C10碳环);各个所述的杂环为3-20元杂环(较佳地3-10元杂环);各个所述的芳环为C6-C20芳环(较佳地C6-C12 芳环);各个所述的杂芳环为5-20元杂芳环(较佳地5到12元杂芳环)。
在另一优选例中,R2、各个R3和R5各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;较佳地,各自独立地选自下组:氢原子、氘原子、烷基、烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基;更佳地,各自独立地选自下组:氢原子、氘原子。
在另一优选例中,R2为氢原子或氘原子。
在另一优选例中,R5为氢原子或氘原子。
在另一优选例中,各个R1各自独立地选自下组:取代或未取代的烷基、取代或未取代的环烷基、取代或未取代的杂环基、-(CH2)nR10、-(CH2)nOR10、-(CH2)nCH(R10)(CH2)oNR11R12(包括:-(CH2)n CH(OH)(CH2)o NHR11)、-(CH2)nO(CH2)oR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、 -(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12、-(CH2)nNR11C(O)R10或-(CH2)nNR11S(O)mR10、 -(CH2)nN(R11)(CH2)oR10(包括-(CH2)nNH(CH2)oR10)。
在另一优选例中,各个R1各自独立地为取代或未取代的选自下组的基团:
-C1-C6烷基、-C1-C6烷基-O-C1-C6烷基、
其中,所述取代是指基团上一个或多个(较佳地1-3个)氢被选自下组的取代基取代:氘原子、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6氘代烷基。
在另一优选例中,各个R1各自独立地为具体化合物中对应的基团。
在另一优选例中,M5为CR7时,M5中的R7选自下组:氢原子、氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素(较佳地F或Cl)、氨基、硝基、羟基、氰基(更佳地, R7为卤素)。
在另一优选例中,M5为CR7时,M5中的R7为氟或氯。
在另一优选例中,M5为N。
X或Y为-NR8-。
在另一优选例中,X为-NR8-时,(i)R8选自氢原子或氘原子;或者,(ii)X、Y与M5及其相连的化学键共同构成选自下组的环:取代或未取代的杂环、取代或未取代的杂芳基。
在另一优选例中,M1为CR7、M2为N,或者M2为CR7、M1为N。
在另一优选例中,当M1为CR7、M2为N,或者M2为CR7、M1为N时,M1或M2基团中的 R7选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基;较佳地,M1或M2基团中的R7为氢原子或氘原子。
在另一优选例中,M3为CR7。
在另一优选例中,M4为N。
在另一优选例中,x为0、1或2;更佳地,x为0或1。
在另一优选例中,R3为氢原子或氘原子。
在另一优选例中,所述化合物为通式(II)所示的化合物:
式中,R6选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、 -(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12、-(CH2)nNR11C(O)R10和 -(CH2)nNR11S(O)mR10;其中,所述取代是指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH2)nOR13、-(CH2)nSR13、-(CH2)nCOR13、 -(CH2)nC(O)OR13、-(CH2)nS(O)mR13、-(CH2)nNR13R14、-(CH2)nC(O)NR13R14(包括 -(CH2)nC(O)NHR14)、-(CH2)nNR14C(O)R13和-(CH2)nNR14S(O)mR13;或者,R4以及与其相连的N 原子,与R6以及与其相连的C原子共同构成:取代或未取代的杂环,或者取代或未取代的杂芳环;
除非特别说明,取代、环A、M1、M2、M5、X、Y、R1、R2、R3、R4、R5、R10、R11、R12、 R13、R14、x和y的定义如前所述。
在另一优选例中,R4和R6各自独立地选自下组:氢原子、氘原子、卤素、烷基、氘代烷基、卤代烷基;或者
R4以及与其相连的N原子,与R6以及与其相连的C原子共同构成取代或未取代的杂环(较佳地,所述杂环环上仅有1个N杂原子);其中,取代是指基团上的一个或多个(较佳地1-3个) 氢原子被选自下组的取代基取代:氘原子、卤素、烷基、氘代烷基、卤代烷基。
在另一优选例中,
或者,环A选自下组:
其中,R1的定义如前所述。
在另一优选例中,所述化合物为通式(III)所示的化合物;
其中,环A、M1、M2、R1、R2、R3、R4、R5、R6、x和y的定义如前所述。
在另一优选例中,所述化合物为通式(X)所示的化合物;
其中,M6和M7各自独立地选自下组:CH、CH2、N、NH、O;环A、M1、M2、R1、R2、R3、 R4、R5、R6、x和y的定义如前所述。
在另一优选例中,所述化合物为通式(XII)所示的化合物;
其中,M8选自下组:CH2、NH、O;环A、M1、M2、R1、R2、R3、R4、R5、R6、x和y的定义如前所述。
在另一优选例中,所述化合物为通式(IV)所示的化合物;
其中,环A、R1、R4、R6和x的定义如前所述。
在另一优选例中,所述化合物为通式(V)所示的化合物;
其中,环A、R1、R4、R6和x的定义如前所述。
在另一优选例中,所述化合物为通式(VI)所示的化合物;
其中,V1和V2各自独立地选自:键、O、-NR8-、CR8R9或-S(O)m-;R1、R4、R8、R9、R6、 m和x的定义如前所述。
在另一优选例中,所述化合物为通式(VII)所示的化合物;
其中,V1和V2各自独立地选自:键、O、-NR8-、CR8R9或-S(O)m-;R1、R4、R8、R9、R6、m 和x的定义如前所述。
在另一优选例中,V1和V2不同时为键。
在另一优选例中,V1和V2各自独立地选自:O、-NH-、-S(O)m-、CH2。
在另一优选例中,所述化合物为通式(VIII)所示的化合物;
在另一优选例中,所述化合物为通式(IX)所示的化合物;
在另一优选例中,所述化合物为通式(XI)所示的化合物;
其中,环A、M6、M7、R1、R4、R6和x的定义如前所述。
在另一优选例中,所述化合物为通式(XIII)所示的化合物;
其中,环A、M8、R1、R4、R6和x的定义如前所述。
在另一优选例中,所述的化合物选自下组:
在本发明的第二方面,提供了一种如第一方面所述的化合物的制备方法,所述化合物为通式 (III)所示化合物,所述制备方法包括如下步骤:
使通式(X-A)化合物和通式(X-B)化合物偶联后得到通式(III)化合物。
在本发明的第三方面,提供了一种药物组合物,所述组合物包括(i)药学上可接受的载体,和(ii)如第一方面所述的化合物,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可接受的盐、或其水合物,或其溶剂合物,或前药。
在另一优选例中,所述的药物组合物还包括另外的治疗药物;所述的另外治疗药物为用于治疗或预防选自下组疾病的药物:心血管疾病、代谢性疾病、免疫性疾病、炎症、癌症,或其组合。
在另一优选例中,所述药物组合物的剂型包括但不限于:注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、外用擦剂,或控释型或缓释型或纳米制剂。
在另一优选例中,所述的另外的治疗药物包括:胆汁酸受体(FXR)激动剂(如Obeticholic acid、Tropifexor、GS-9674)、过氧化物酶体增殖物激活受体(PPAR)激动剂(如Elafibranor, Saroglitazar、Remogliflozin Etabonate)、甲状腺激素受体β(THRβ)激动剂(如MGL-3196)、二酰甘油-O-酰基转移酶(DGAT)抑制剂(如Pradigastat、PF-06865571)、乙酰辅酶A羧化酶(ACC)抑制剂(如GS-0976、PF-05221304)、半胱天冬酶抑制剂(如Emricasan)、平滑受体(SMO)抑制剂(如Vismodegib)、半乳糖凝结素抑制剂(如GR-MD-02)、C-C趋化因子受体2型和5型(CCR2和CCR5)的双重拮抗剂(如Cenicriviroc)、已酮糖激酶(KHK)抑制剂(PF-06835919)、胰高血糖素样肽-1(GLP-1)受体激动剂(如利拉鲁肽、semaglutide)、抗赖氨酰氧化酶样蛋白-2(LOXL2)单抗(如simtuzumab)、胆酸和花生四烯酸的复合物 Aramchol,或其组合。
在本发明的第四方面,提供了一种制备如第三方面所述药物组合物的方法,包括步骤:将药学上可接受的载体,与如第一方面所述的化合物、或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可接受的盐、或其水合物,或其溶剂合物,或前药进行混合,进行混合,从而形成药物组合物。
在本发明的第五方面,提供了一种如第一方面所述化合物,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可接受的盐、或其水合物,或其溶剂合物,或前药的用途,用于制备对ASK1具有选择性抑制作用的药物组合物。
在本发明的第六方面,提供了一种如第一方面所述化合物,或如第三方面所述的药物组合物的用途,
(i)用于制备ASK1抑制剂药物;
(ii)用于制备治疗和/或预防ASK1介导的疾病的药物;和/或
(iii)用于治疗和/或预防ASK1介导的疾病;
其中,所述ASK1介导的疾病包括:炎症、心血管疾病、感染、免疫性疾病、代谢性疾病,或其组合。
在另一优选例中,所述的炎症或代谢性疾病包括但并不限于:非酒精性脂肪肝炎、非酒精性脂肪肝病、肝纤维化、胆结石、原发性胆汁性肝硬化、原发性硬化性胆管炎、肝硬化、糖尿病、动脉粥样硬化、肥胖,或其组合。
在另一优选例中,所述炎症选自下组:非酒精性脂肪肝炎(NASH)、非酒精性脂肪肝病、原发性胆汁性肝硬化、原发性硬化性胆管炎,或其组合。
在本发明的第七方面,提供了一种预防和/或治疗ASK1介导的疾病的方法,包括步骤:
给需要治疗的对象施用如第一方面所述的化合物,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可接受的盐、或其水合物,或其溶剂合物,或前药;或者给需要治疗的对象施用如第三方面所述的药物组合物。
在另一优选例中,ASK1介导的疾病包括:炎症、心血管疾病、感染、免疫性疾病,代谢性疾病,或其组合。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
发明人经过广泛而深入地研究。首次开发了一种具有新颖结构的芳基酰胺类化合物。所述芳基酰胺类化合物具有优异的对凋亡信号调节激酶1(ASK1)选择性抑制活性,基于此完成了本发明。
术语
术语“烷基”是指直链或支链烷烃基,包含1-18个碳原子,尤其指1-6个碳原子。典型的“烷基”包括甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基、戊基、异戊基、庚基、4,4–二甲基戊基,辛基,2,2,4-三甲基戊基,壬基,癸基、十一烷基,十二烷基等等。术语“(C1-C6) 烷基”指的是直链或支链烷基,包括从1-6个碳原子,如甲基、乙基、丙基、异丙基、正丁基、叔丁基、异丁基。“取代烷基”是指烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、 S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、 S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、 NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或 NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说 Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“烯基”是指直链或支链烃基含有2-18个碳原子,至少一个碳碳双键的取代基。典型的基团包括乙烯基或烯丙基。术语“(C2-C6)烯基”是指直链或支链的含有2-6个碳原子,至少有一个碳碳双键的基团,如乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(Z)-1-己烯基、(E)-2- 戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3-己烯基和(E)-1,3-己二烯基。“取代烯基”是指烯基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、 P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、 C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、 NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基,如烷基、环烷基、烯基、环烯基、炔基、杂环或芳环可以任选取代。
术语“炔基”是指直链或支链烃基含有2-18个碳原子,至少一个碳碳三键的取代基。典型的基团包括乙炔基。术语“(C2-C6)炔基”是指直链或支链的含有2-6个碳原子,至少有一个碳碳双键的基团,如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、 2-己炔基、3-己炔基。“取代炔基”是指炔基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、 P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、 C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、 NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。典型的取代基可以任选取代。
术语“碳环”是指饱和或不饱和的环状烃类化合物基团,例如环烷基、环烯基等,包括1-4个环,每个环中含有3-8个碳原子。术语“环烷基”是指完全饱和的环状烃类化合物基团,包括1-4 个环,每个环中含有3-8个碳原子。“取代环烷基”或“取代碳环”是指环烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、 NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、 OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环、桥环或稠环取代基,尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、桥环烷基、桥环烯基、桥环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基,上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“环烯基”是指部分不饱和的环状烃类化合物基团,包括1-4个环,每个环中含有3-8个碳原子。典型的环烯基如环丁烯基、环戊烯基、环己烯基等等。“取代环烯基”是指环烷基中的一个或多个位置被取代,尤其是1-4个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、 NRbS(=O)2Re、NRbP(=O)2Re、S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、 OC(=O)Ra、OC(=O)NRbRc、NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、 NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括螺环或稠环取代基,尤其是螺环烷基、螺环烯基、螺环杂环(不包括杂芳环)、稠环烷基、稠环烯基、稠环杂环基或稠环芳环基,上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂环基”或“杂环”是指完全饱和的或部分不饱和的的环状基团(包含但不限于如4-7元单环,7-11元双环,或8-16元三环系统),其中至少有一个杂原子存在于至少有一个碳原子的环中。每个含有杂原子的杂环可以带有1,2,3或4个杂原子,这些杂原子选自氮原子、氧原子或硫原子,其中氮原子或硫原子可以被氧化,氮原子也可以被季铵化。杂环基团可以连接到环或环系分子的任何杂原子或碳原子的残基上。典型的单环杂环包括但不限于氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、吡唑啉基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、六氢吖庚因基、4-哌啶酮基、四氢吡喃基、吗啡啉基、硫代吗啡啉基、硫代吗啡啉亚砜基、硫代吗啡啉砜基、1,3-二噁烷基和四氢-1,1-二氧噻吩等。多环杂环基包括螺环、稠环和桥环的杂环基;其中涉及到的螺环、稠环和桥环的杂环基任选与其他基团通过单键相连接,或者通过环上的任意两个或两个以上的原子与其他环烷基、杂环基、芳基和杂芳基进一步并环连接;杂环基团可以是取代的或者非取代的,当被取代时,取代基优选为一个或多个一下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“芳基”或“芳环”是指芳香环状烃类化合物基团,具有1-5个环,尤其指单环和双环基团,如苯基、联苯基或萘基。凡含有两个或两个以上芳香环(双环等),芳基基团的芳香环可由单键联接(如联苯),或稠合(如萘、蒽等等)。“取代芳基”是指芳基中的一个或多个位置被取代,尤其是1-3个取代基,可在任何位置上取代。典型的取代包括但不限于一个或多个以下基团:如氢,氘,卤素(例如,单卤素取代基或多卤素取代基,后者如三氟甲基或包含Cl3的烷基)、腈基、硝基、氧(如=O)、三氟甲基、三氟甲氧基、环烷基、烯基、环烯基、炔基、杂环、芳环、 ORa、SRa、S(=O)Re、S(=O)2Re、P(=O)2Re、S(=O)2ORe,P(=O)2ORe、NRbRc、NRbS(=O)2Re、NRbP(=O)2Re、 S(=O)2NRbRc、P(=O)2NRbRc、C(=O)ORd、C(=O)Ra、C(=O)NRbRc、OC(=O)Ra、OC(=O)NRbRc、 NRbC(=O)ORe,NRdC(=O)NRbRc、NRdS(=O)2NRbRc、NRdP(=O)2NRbRc、NRbC(=O)Ra、或NRbP(=O)2Re,其中在此出现的Ra可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环,Rb、Rc和Rd可以独立表示氢、氘、烷基、环烷基、杂环或芳环,或者说Rb和Rc与N原子一起可以形成杂环;Re可以独立表示氢、氘、烷基、环烷基、烯基、环烯基、炔基、杂环或芳环。上述典型的取代基可以任选取代。典型的取代还包括稠环取代基,尤其是稠环烷基、稠环烯基、稠环杂环基或稠环芳环基,上述环烷基、环烯基、杂环基和杂环芳基可以任选取代。
术语“杂芳基”或“杂芳环”指包含1-4个杂原子、5-14个环原子的杂芳族体系,其中杂原子选自氧、氮和硫。杂芳基优选5至10元环,更优选为5元或6元,例如吡咯基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三氮嗪基、三氮唑基及四氮唑基等。“杂芳基”可以是取代的或者非取代的,当被取代时,取代基优选为一个或多个一下基团,其独立地选自烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、烷硫基、烷基氨基、卤素、氨基、硝基、羟基、巯基、氰基、环烷基、杂环基、芳基、杂芳基、环烷硫基、氧代基、羧基和羧酸酯基。
术语“卤素”或“卤”是指氯、溴、氟、碘。
除非另外说明,假定任何不满价态的杂原子有足够的氢原子补充其价态。
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。在此使用的术语“盐”,指用无机或有机酸和碱形成酸式或碱式的盐。此外,当本发明中的化合物含一个碱性片段时,它包括但不限于吡啶或咪唑,含一个酸性片段时,包括但不限于羧酸,可能形成的两性离子(“内盐”)包含在术语“盐”的范围内。药学上可接受的(即无毒,生理可接受的)盐是首选,虽然其他盐类也有用,例如可以用在制备过程中的分离或纯化步骤。本发明的化合物可能形成盐,例如,化合物I与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。
本发明中的化合物含有的碱性片段,包括但不限于胺或吡啶或咪唑环,可能会和有机或无机酸形成盐。可以成盐的典型的酸包括醋酸盐(如用醋酸或三卤代醋酸,如三氟乙酸)、己二酸盐、藻朊酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑盐、樟脑磺酸盐、环戊烷丙酸盐、二甘醇酸盐、十二烷基硫酸盐、乙烷磺酸盐、延胡索酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、羟基乙磺酸盐(如,2-羟基乙磺酸盐)、乳酸盐、马来酸盐、甲磺酸盐、萘磺酸盐(如,2-萘磺酸盐)、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、苯丙酸盐(如3-苯丙酸盐)、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐,水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的)、磺酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐如对甲苯磺酸盐、十二烷酸盐等等。
本发明的某些化合物可能含有的酸性片段,包括但不限于羧酸,可能会和各种有机或无机碱形成盐。典型的碱形成的盐包括铵盐、碱金属盐如钠、锂、钾盐,碱土金属盐如钙、镁盐,和有机碱形成的盐(如有机胺),如苄星、二环已基胺、海巴胺(与N,N-二(去氢枞基)乙二胺形成的盐)、N-甲基-D-葡糖胺、N-甲基-D-葡糖酰胺、叔丁基胺,以及和氨基酸如精氨酸、赖氨酸等等形成的盐。碱性含氮基团可以与卤化物季铵盐,如小分子烷基卤化物(如甲基、乙基、丙基和丁基的氯化物、溴化物及碘化物),二烷基硫酸盐(如,硫酸二甲酯、二乙酯,二丁酯和二戊酯),长链卤化物(如癸基、十二烷基、十四烷基和十四烷基的氯化物、溴化物及碘化物),芳烷基卤化物(如苄基和苯基溴化物)等等。
本发明中化合物的前药及溶剂化物也在涵盖的范围之内。此处术语“前药”是指一种化合物,在治疗相关疾病时,经过代谢或化学过程的化学转化而产生本发明中的化合物、盐、或溶剂化物。本发明的化合物包括溶剂化物,如水合物。
本发明中的化合物、盐或溶剂化物,可能存在的互变异构形式(例如酰胺和亚胺醚)。所有这些互变异构体都是本发明的一部分。
所有化合物的立体异构体(例如,那些由于对各种取代可能存在的不对称碳原子),包括其对映体形式和非对映形式,都属于本发明的设想范围。本发明中的化合物独立的立体异构体可能不与其他异构体同时存在(例如,作为一个纯的或者实质上是纯的光学异构体具有特殊的活性),或者也可能是混合物,如消旋体,或与所有其他立体异构体或其中的一部分形成的混合物。本发明的手性中心有S或R两种构型,由理论与应用化学国际联合会(IUPAC)1974年建议定义。外消旋形式可通过物理方法解决,例如分步结晶,或通过衍生为非对映异构体分离结晶,或通过手性柱色谱法分离。单个的光学异构体可通过合适的方法由外消旋体得到,包括但不限于传统的方法,例如与光学活性酸成盐后再结晶。
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本发明的化合物所有的构型异构体都在涵盖的范围之内,无论是混合物、纯的或非常纯的形式。在本发明化合物的定义包含顺式(Z)和返式(E)两种烯烃异构体,以及碳环和杂环的顺式和反式异构体。
在整个说明书中,基团和取代基可以被选择以提供稳定的片段和化合物。
特定官能团和化学术语定义都详细介绍如下。对本发明来说,化学元素与Periodic Table of the Elements,CAS version,Handbook of Chemistry and Physics,75th Ed.中定义的一致。特定官能团的定义也在其中描述。此外,有机化学的基本原则以及特定官能团和反应性在“Organic Chemistry”, Thomas Sorrell,University ScienceBooks,Sausalito:1999,也有说明,其全部内容纳入参考文献之列。
本发明的某些化合物可能存在于特定的几何或立体异构体形式。本发明涵盖所有的化合物,包括其顺式和反式异构体、R和S对映异构体、非对映体、(D)型异构体、(L)型异构体、外消旋混合物和其它混合物。另外不对称碳原子可表示取代基,如烷基。所有异构体以及它们的混合物,都包涵在本发明中。
按照本发明,同分异构体的混合物含有异构体的比率可以是多样的。例如,在只有两个异构体的混合物可以有以下组合:50:50,60:40,70:30,80:20,90:10,95:5,96:4,97:3,98:2,99:1,或100:0,异构体的所有比率都在本发明范围之内。本专业内一般技术人员容易理解的类似的比率,及为更复杂的异构体的混合物的比率也在本发明范围之内。
本发明还包括同位素标记的化合物,等同于原始化合物在此公开。不过实际上对一个或更多的原子被与其原子量或质量序数不同的原子取代通常会出现。可以列为本发明的化合物同位素的例子包括氢,碳,氮,氧,磷,硫,氟和氯同位素,分别如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。本发明中的化合物,或对映体,非对映体,异构体,或药学上可接受的盐或溶剂化物,其中含有上述化合物的同位素或其他其他同位素原子都在本发明的范围之内。本发明中某些同位素标记化合物,例如3H和14C的放射性同位素也在其中,在药物和底物的组织分布实验中是有用的。氚,即3H和碳-14,即14C,它们的制备和检测比较容易。是同位素中的首选。此外,较重同位素取代如氘,即2H,由于其很好的代谢稳定性在某些疗法中有优势,例如在体内增加半衰期或减少用量,因此,在某些情况下可以优先考虑。同位素标记的化合物可以用一般的方法,通过用易得的同位素标记试剂替换为非同位素的试剂,用批露在示例中的方案可以制备。
如果要设计一个本发明的化合物特定的对映体的合成,它可以不对称合成制备,或用手性辅剂衍生化,将所产生的非对映混合物分离,再除去手性辅剂而得到纯的对映体。另外,如果分子中含有一个碱性官能团,如氨基酸,或酸性官能团,如羧基,可以用合适的光学活性的酸或碱的与之形成非对映异构体盐,再通过分离结晶或色谱等常规手段分离,然后就得到了纯的对映体。
如本文所述,本发明中的化合物可与任何数量取代基或官能团取而扩大其包涵范围。通常,术语“取代”不论在术语“可选”前面或后面出现,在本发明配方中包括取代基的通式,是指用指定结构取代基,代替氢自由基。当特定结构中的多个在位置被多个特定的取代基取代时,取代基每一个位置可以是相同或不同。本文中所使用的术语“取代”包括所有允许有机化合物取代。从广义上讲,允许的取代基包括非环状的、环状的、支链的非支链的、碳环的和杂环的,芳环的和非芳环的有机化合物。在本发明中,如杂原子氮可以有氢取代基或任何允许的上文所述的有机化合物来补充其价态。此外,本发明是无意以任何方式限制允许取代有机化合物。本发明认为取代基和可变基团的组合在以稳定化合物形式在疾病的治疗上是很好的,例如传染病或增生性疾病。此处术语“稳定”是指具有稳定的化合物,在足够长的时间内检测足以维持化合物结构的完整性,最好是在足够长的时间内都在效,本文在此用于上述目的。
本申请所涉及的化合物及其药学可接受的盐的代谢产物,以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药,也包含在本申请的权利要求中。
药物组合物和施用方法
由于本发明化合物具有优异的凋亡信号调节激酶1(ASK1)选择性抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由凋亡信号调节激酶1 (ASK1)介导的疾病。根据现有技术,本发明化合物可用于治疗以下疾病:炎症、心血管疾病、感染、免疫性疾病或代谢性疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-500mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时,式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与本发明的化合物进行药物联用的药物或活性成分包括但不局限为:胆汁酸受体 (FXR)激动剂(如Obeticholic acid、Tropifexor、GS-9674)、过氧化物酶体增殖物激活受体(PPAR)激动剂(如Elafibranor,Saroglitazar、Remogliflozin Etabonate)、甲状腺激素受体β(THRβ)激动剂(如MGL-3196)、二酰甘油-O-酰基转移酶(DGAT)抑制剂(如Pradigastat、 PF-06865571)、乙酰辅酶A羧化酶(ACC)抑制剂(如GS-0976、PF-05221304)、半胱天冬酶抑制剂(如Emricasan)、平滑受体(SMO)抑制剂(如Vismodegib)、半乳糖凝结素抑制剂(如GR-MD-02)、C-C趋化因子受体2型和5型(CCR2和CCR5)的双重拮抗剂(如Cenicriviroc)、已酮糖激酶(KHK)抑制剂(PF-06835919)、胰高血糖素样肽-1(GLP-1)受体激动剂(如利拉鲁肽、semaglutide)、抗赖氨酰氧化酶样蛋白-2(LOXL2)单抗(如simtuzumab)、胆酸和花生四烯酸的复合物Aramchol等。
本申请所涉及的炎症、心血管疾病、感染、免疫性疾病、代谢性疾病或癌症包括(但并不限于):原发性胆汁淤积性肝硬化(PBC)、原发性硬化性胆囊炎(PSC)、胆汁淤积症、自身免疫肝炎、病毒性肝炎(如乙肝)、酒精性肝病、非酒精性脂肪肝病(NAFLD)、非酒精性脂肪肝炎(NASH)或肝纤维化;动脉硬化症、血脂障碍、高胆固醇血症或高甘油三酯血症;I型糖尿病、II型糖尿病或肥胖;肺癌、乳腺癌、前列腺癌、食道癌、结直肠癌、血癌、骨癌、肾癌、胃癌、肝癌或大肠癌。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为 1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
芳基酰胺类化合物
本发明的目的就是提供一类新型的对凋亡信号调节激酶1(ASK1)有选择性抑制作用、或更好药效学性能的化合物及其用途。
具体地,本发明的化合物具有式(I)所示的结构
其中,各个基团或环的定义如上所述。
本发明的主要优点包括:
(a)本发明的化合物对于凋亡信号调节激酶1(ASK1)具有优异的选择性抑制活性。
(b)本发明化合物表现出优异的代谢性能。
(c)本发明化合物在体内表现出优异的活性。
(d)本发明化合物对CYP3A4等CYP酶抑制活性低,从而避免药物-药物可能相互作用,增加药物安全性。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
本发明的化合物结构是通过核磁共振(NMR)和液质联用色谱(LC-MS)来确定的。
NMR是使用Bruker AVANCE-400核磁仪检测的,测定溶剂包含氘代二甲亚砜(DMSO-d6)、氘代丙酮(CD3COCD3)、氘代氯仿(CDCl3)及氘代甲醇(CD3OD)等,内标采用四甲基硅烷(TMS),化学位移以百万分之一(ppm)的单位计量。
液质联用色谱(LC-MS)是使用Waters SQD2质谱仪检测的。HPLC的测定使用Agilent 1100高压色谱仪(Microsorb 5 micron C18 100x 3.0mm色谱柱)。
薄层层析硅胶板使用青岛GF254硅胶板,TLC采用的是0.15-0.20mm,制备薄层色谱采用的是0.4mm-0.5mm。柱层析一般使用青岛硅胶200-300目硅胶作为载体。
本发明实施例中的起始原料都是已知并有市售的,或者可以采用或按照本领域已报道的文献资料合成的。
除特殊说明外,本发明所有反应均在干燥的惰性气体(如氮气或氩气)保护下通过连续磁力搅拌进行,反应温度均为摄氏度。
实施例1
7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-(2-甲氧基乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺的制备
第一步:2,4-二氟-5-硝基苯甲酸甲酯的制备
在室温下将氯化亚砜(18mL,242mmol)滴加到2,4-二氟-5-硝基苯甲酸(10g,49mmol)的甲醇(150mL)溶液中。滴加完毕反应液在室温搅拌4h,随后在40℃以下减压浓缩反应液。在残留物中加入乙酸乙酯(200mL)和水(200mL)分层,有机相收集后依次用碳酸氢钠水溶液(5%wt,2x100mL)、水(100mL)和饱和食盐水(100mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃以下减压浓缩得到目标产品(粗产品9.5g,粗产率92%),无需纯化直接用于下一步反应。
第二步:2-氟-4-苄氧基-5-硝基苯甲酸甲酯的制备
在0~5℃下将氢化钠(~60%wt,950mg,24mmol)分批加入到苄醇(2.4g,22mmol)的 N,N-二甲基甲酰胺(30mL)溶液中。滴加完毕后反应液在0~5℃搅拌30min,随后滴加2,4- 二氟-5-硝基苯甲酸甲酯(4.0g,18mmol)的N,N-二甲基甲酰胺(10mL)溶液。滴加完毕后反应液自然升至室温,并在室温搅拌12h。得到的反应液用乙酸乙酯(150mL)和水(150mL)分层。水相分离后用乙酸乙酯萃取(2x50mL)。有机相合并后依次用水(2x100mL)和饱和食盐水(2x100mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃减压浓缩干得到目标产品(粗产品4.2g),无需纯化直接用于下一步反应。
第三步:2-氟-4-羟基-5-氨基苯甲酸甲酯的制备
将钯碳(钯含量10%,含水50%,1.0g)在氮气氛围下加入到2-氟-4-苄氧基-5-硝基苯甲酸甲酯(4.2g)的甲醇(50mL)溶液中。随后反应液在氢气氛围下于室温搅拌12h。得到的反应液用硅藻土过滤,滤液在40℃以下减压浓缩得到粗产品。粗品用硅胶柱层析纯化得到目标产物(1.35g)。
LC-MS:m/z 184(M-H)-
第四步:7-氟-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯的制备
2-氟-4-羟基-5-氨基苯甲酸甲酯(1.35g,7.3mmol)、二溴乙烷(1.5g,8.1mmol)、碳酸钾(3.0g,21.7mmol)的N,N-二甲基甲酰胺(30mL)的混合溶液在60~65℃搅拌12h。得到的反应液冷却后用乙酸乙酯(100mL)和水(100mL)分层。水相分离后用乙酸乙酯(2x50 mL)萃取。有机相合并后依次用水(3x70mL)和饱和食盐水(70mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃以下减压浓缩干得到目标产物(粗产品880mg),无需纯化直接用于下一步。
LC-MS:m/z 212(M+H)+
第五步:7-氟-4-(2-甲氧基乙基)3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸的制备
7-氟-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酸甲酯(440mg,2.1mmol)、溴乙基甲醚(440mg, 3.2mmol)和碳酸钾(440mg,3.2mmol)的N,N-二甲基甲酰胺(10mL)混合溶液在80~90 ℃搅拌12h。得到的反应液冷却后用乙酸乙酯(50mL)和水(50mL)分层。水相用稀盐酸(2N)调节pH到3~4后,用乙酸乙酯(50mL)萃取。有机相合并后用水(3x50mL)洗涤后,用无水硫酸钠干燥后过滤。滤液在40℃以下减压浓缩。得到的残留物中加入甲醇(20mL) 和氢氧化钠溶液水溶液(2N,10mL)。反应物在室温搅拌4h后用稀盐酸(2N)调节pH到3~4 后,加入乙酸乙酯(50mL)和水(50mL)分层。有机相分离后依次用水(2x50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃以下减压浓缩干得到粗品。粗品用硅胶柱层析纯化得到目标产物(220mg)。
LC-MS:m/z 254(M-H)-。
第六步7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-4-(2-甲氧基乙基)-3,4-二氢-2H-苯并[b][1,4]噁嗪-6-甲酰胺的制备
在室温下将草酰氯(200mg,1.6mmol)滴加到7-氟-4-(2-甲氧基乙基)3,4-二氢-2H-苯并 [b][1,4]噁嗪-6-甲酸(200mg,0.78mmol)的二氯甲烷(5mL)溶液中。反应液在室温反应1h,然后在40℃减压浓缩。得到的残留物溶于二氯甲烷(10mL),随后加入二异丙基乙基胺(300 mg,2.3mmol)和6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(160mg,0.79mmol)。所得混合液在室温下搅拌3h,随后用乙酸乙酯(50mL)和水(50mL)分层。有机相收集后依次用水(30 mL)和饱和食盐水(30mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压浓缩得粗产品。粗产品经柱层析纯化得到目标产物(90mg,产率26%)。
LC-MS:m/z 439.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.17(d,1H),8.43(d,2H),8.04(d,1H),7.89(t,1H),7.41(d,1H),6.64(d,1H),5.53(m,1H),4.30(t,2H),3.63(t,2H),3.54(t, 2H),3.44(t,2H),3.36(s,3H),1.61(d,6H)。
实施例2
7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(甲氧基甲基)-2,3-二氢苯并 [b][1,4]二恶英-6-甲酰胺的制备
第一步:1-溴-2-氟-4,5-二甲氧基苯的制备
在0℃下将溴素(9.3g,1.1eq)滴加到4-氟-1,2-二甲氧基苯(7g)和铁粉(0.15g,0.05eq)的二氯甲烷(160mL)混合溶液中。反应液在反应0℃反应过夜,然后用水洗涤后干燥浓缩得到目标产物(粗产品9.5g),无需纯化直接用于下一步反应。
第二步:2-氟-4,5-二甲氧基苯甲酸甲酯的制备
1-溴-2-氟-4,5-二甲氧基苯(5g)、1,1’-双(三苯基膦)二茂铁(5g)和乙酸钯(5g)在甲醇 (20mL)、DMF(20mL)和三乙胺(10mL)的混合溶液中在CO氛围下(2Mpa)在100℃反应24h。得到的混合物减压浓缩,残留物用水和乙酸乙酯分层。有机相分离后用无水硫酸镁干燥,然后过滤。滤液减压浓缩,残留物用硅胶准层析分离得到目标产物(2.9g)。
LC-MS:m/z 215(M+H)+。
第三步:2-氟-4,5-二羟基苯甲酸的制备
在0℃下将三溴化硼(12.8g)缓慢滴加到2-氟-4,5-二甲氧基苯甲酸甲酯(2.9g)的DCM(15mL)溶液中。滴加完毕反应液在室温反应过夜。得到的混合物用冰水小心淬灭后减压浓缩,残留物用乙酸乙酯萃取。有机相合并后用无水硫酸镁干燥,然后过滤。滤液减压浓缩得到目标产物(粗产品2.2g),无需纯化直接用于下一步反应。
LC-MS:m/z 173(M+H)+。
第四步:2-氟-4,5-二羟基苯甲酸甲酯的制备
2-氟-4,5-二羟基苯甲酸(0.56g)在氯化氢的甲醇溶液(4N,20mL)中在80℃回流反应过夜,冷却到室温后减压浓缩得到目标产物(粗产品0.75g),无需纯化直接用于下一步反应。
LC-MS:m/z 187(M+H)+。
第五步:7-氟-3-(羟甲基)-2,3-二氢苯并[b][1,4]二恶英-6-甲酸甲酯的制备
2-氟-4,5-二羟基苯甲酸甲酯(2g)和碳酸钾(1.49g)的丙酮(20mL)混合溶液在室温搅拌30min,随后滴加环氧溴丙烷(1.5g)。得到的混合物在80℃反应过夜,然后过滤。滤液减压浓缩,残留物用硅胶柱层析纯化得到目标产物(0.94g)。
LC-MS:m/z 243(M+H)+。
第六步:7-氟-3-(甲磺酰氧甲基)-2,3-二氢苯并[b][1,4]二恶英-6-甲酸甲酯的制备
在室温下将甲磺酰氯(445mg,3.87mmol)滴加到7-氟-3-(羟甲基)-2-3-二氢苯并[b][1,4] 二恶英-6-羧酸甲酯(780mg,3.2mmol)和二异丙基乙基胺(623mg,4.8mmol)的THF(5 mL)溶液中。得到的混合溶液在室温搅拌2~3h,随后加入二氯甲烷(50mL)和水(50mL)分液。有机相收集后依次用水(50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃以下减压浓缩得到目标产物(粗产品920mg),无需纯化直接用于下一步反应。
第七步:7-氟-3-(甲氧基甲基)-2,3-二氢苯并[b][1,4]二恶英-6-甲酸的制备
在室温下将甲醇钠(465mg,8.61mmol)加入到7-氟-3-(甲磺酰基羟甲基)-2-3-二氢苯并 [b][1,4]二恶英-6-羧酸甲酯(920mg,2.87mmol)的甲醇(10mL)溶液中。反应液搅拌回流2 h,然后冷却至室温,随后加入水(10mL)和NaOH(20%wt,10mL)。得到的混合液液在50℃反应1h后降至室温,用稀盐酸(1N)调节pH到6~7后减压浓缩。残余物用酸性水溶液 (pH=2~3,50mL)和二氯甲烷(50mL)分层。水相分离后用二氯甲烷(2x50mL)萃取。有机相合并后用饱和食盐水(2x50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压浓缩得到粗品,粗品经柱层析纯化得到目标产物(400mg)。
LC-MS:m/z 241(M-H)-。
第八步:7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(甲氧基甲基)-2,3-二氢苯并[b][1,4]二恶英-6-甲酰胺的制备
在氮气氛围下于室温下将(氯亚甲基)二甲基氯化铵(400mg,4.34mmol)加入到7-氟 -3-(甲氧基甲基)-2-3-二氢苯并[b][1,4]二恶英-6-羧酸(400mg,1.58mmol)的二氯甲烷(10 mL)溶液中。反应混合物在室温搅拌1h,随后加入6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺 (400mg,1.97mmol)和二乙基异丙基胺(600mg,5.21mmol)。得到的混合物在室温搅拌3h,然后用乙酸乙酯(50mL)和水(50mL)分层。有机相收集后依次用水(2x50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃下减压浓缩得粗产品,然后经制备色谱纯化得到目标产物(180mg,产率26%)。
LC-MS:m/z 426.31(M-H)-。1H NMR(400MHz,CDCl3)δ9.05(d,1H),8.46(s,1H),8.43(d,1H),8.05(d,1H),7.90(t,1H),7.76(d,1H),6.77(d,1H),5.54(m,1H),4.43(dd,1H), 4.34(m,1H),4.18(dd,1H),3.66(m,2H),3.46(s,3H),1.61(d,6H).
实施例2A
(S)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(甲氧基甲基)-2,3-二氢苯并 [b][1,4]二氧-6-甲酰胺的制备
第一步:7-氟-3(S)-羟甲基-2,3-二氢苯并[b][1,4]二氧-6-羧酸甲酯的制备
将2-氟-4,5-二羟基苯甲酸甲酯(8.0g,43mmol)溶解于N,N-二甲基甲酰胺(150mL),随后加入R-脱水甘油对价苯磺酸酯(9.8g,43mmol)和碳酸钾(7.2g,52mmol)。混合物加热至70-75℃反应8h,然后加入乙酸乙酯(400mL)和水(400mL)分层。有机层收集后依次用水(2x300mL)和饱和氯化钠洗涤(2x200mL),然后经无水硫酸钠干燥后过滤。滤液减压浓缩,所得粗品经柱层析纯化得目标产物(6.1g,产率58%)。
LC-MS:m/z 241.49(M-H)-。
第二步:7-氟-3(S)-甲磺酰基羟甲基-2,3-二氢苯并[b][1,4]二氧-6-羧酸甲酯的制备
在室温下,将7-氟-3(S)-羟甲基-2,3-二氢苯并[b][1,4]二氧-6-羧酸甲酯(2.0g,8.26mmol) 和二异丙基乙基胺(1.6g,12.3mmol)溶于二氯甲烷(20mL)中,随后滴加甲磺酰氯(1.14g, 9.91mmol)。得到的反应液在室温搅拌2~3h,然后加入二氯甲烷(20mL)和水(50mL) 分层。有机相后依次用水(50mL)和饱和食盐水(50mL)洗涤,然后经硫酸钠干燥后过滤。滤液减压浓缩得到目标产物(2.4g,粗产率90%),无需纯化直接用于下一步反应。
第三步:7-氟-3(S)-甲氧基甲基-2,3-二氢苯并[b][1,4]二氧-6-羧酸的制备
将7-氟-3(S)-甲磺酰基羟甲基-2,3-二氢苯并[b][1,4]二氧-6-羧酸甲酯(900mg,2.8mmol) 溶于甲醇(10mL),随后加入甲醇钠(400mg,7.4mmol)。反应液在回流反应2h,然后冷却反应液至室温,随后加入水(10mL)和NaOH水溶液(20%,10mL)后。得到的混合液加热至50℃反应1h后降至室温后,然后用稀盐酸(1N)调节反应体系pH至5~6。得到的混合物减压浓缩,随后加入稀盐酸(50mL,pH=2~3)和二氯甲烷(50mL)分层。水相分离后用二氯甲烷(2x50mL)萃取。所有有机相合并后用饱和食盐水(2x50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压浓缩,所得粗品经柱层析纯化得到目标产物(450mg,产率66%)。
LC-MS:m/z 241.41(M-H)-。
第四步:7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3(S)-甲氧基甲基-2,3-二氢苯并[B][1,4]二氧-6-甲酰胺的制备
在氮气氛围下将7-氟-3(S)-甲氧基甲基-2,3-二苯并[b][1,4]二氧-6-羧酸(400mg,1.58 mmol)溶解于二氯甲烷(10mL),随后加入(氯亚甲基)二甲基氯化铵(400mg,4.34mmol)。反应液在室温搅拌1h,随后加入6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(400mg,1.97 mmol)和二乙基异丙基胺(600mg,5.21mmol)。得到的混合物在室温搅拌3h,然后加入乙酸乙酯(50mL)和水(50mL)分层。有机相手机后依次用水(2x50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压,所得粗产品经制备色谱纯化得到目标产物(220mg,产率31%)。
LC-MS:m/z 426.21(M-H)-。1H NMR(400MHz,CDCl3)δ9.09(d,1H),8.90(s,1H),8.47(d,1H),8.07(d,1H),7.93(t,1H),7.76(d,1H),6.75(d,1H),5.58(m,1H),4.41(dd,1H),4.33(m, 1H),4.18(m,1H),3.66(m,2H),3.45(s,3H),1.65(d,6H)。
按以上实施例的方法以不同起始原料合成一下化合物:
实施例2B
(R)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(甲氧基甲基)-2,3-二氢苯并 [b][1,4]二氧-6-甲酰胺
LC-MS:m/z 426.21(M-H)-。1H NMR(400MHz,CDCl3)δ9.09(d,1H),8.90(s,1H),8.47(d,1H),8.07(d,1H),7.93(t,1H),7.76(d,1H),6.75(d,1H),5.58(m,1H),4.41(dd,1H),4.33(m, 1H),4.18(m,1H),3.66(m,2H),3.45(s,3H),1.65(d,6H)。
实施例3A
(S)-3-((苄氧)甲基)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2,3-二氢苯并 [b][1,4]二氧-6-甲酰胺
LC-MS:m/z 504(M+H)+。1H NMR(400MHz,CDCl3)δ9.07(d,J=17.1Hz,1H),8.67(s,1H),8.43(d,J=8.3Hz,1H),8.03(d,J=7.6Hz,1H),7.90(dd,J=13.6,5.6Hz,1H),7.73(d,J =7.7Hz,1H),7.42–7.30(m,5H),6.72(dd,J=14.4,4.9Hz,1H),5.63–5.46(m,1H),4.61(s, 2H),4.47–4.27(m,2H),4.18(m,1H),3.88–3.62(m,2H),1.63(t,J=7.2Hz,6H.
实施例3B
(R)-3-((苄氧)甲基)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2,3-二氢苯并 [b][1,4]二氧-6-甲酰胺
LC-MS:m/z 504(M+H)+。1H NMR(400MHz,CDCl3)δ9.07(d,J=17.3Hz,1H),8.77(s,1H),8.45(d,J=8.3Hz,1H),8.05(d,J=7.6Hz,1H),7.92(t,J=8.0Hz,1H),7.74(d,J=7.7Hz, 1H),7.42–7.29(m,5H),6.73(d,J=12.8Hz,1H),5.68–5.50(m,1H),4.60(s,2H),4.47–4.27 (m,2H),4.18(m,1H),3.86–3.62(m,2H),1.64(t,J=7.2Hz,6H).
实施例4A
(R)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(吗啡啉甲基)-2,3-二氢苯并 [b][1,4]二氧-6-甲酰胺
第一步:7-氟-3(R)-(N-吗啡啉基甲基)-2,3-二氢苯并[b][1,4]二氧-6-羧酸的制备
将7-氟-3(R)-甲磺酰基羟甲基-2,3-二氢苯并[b][1,4]二氧-6-羧酸甲酯(500mg,1.6mmol) 溶于N,N-二甲基甲酰胺(5mL),随后加入吗啡啉(180mg,2.1mmol)和二异丙基乙基胺(250mg,1.9mmol)。反应液在75-80℃搅拌8h后冷却至室温,随后加入甲醇(10mL) 和NaOH水溶液(20%,10mL)。混合液加热至40-50℃反应1h后降至室温后,然后用稀盐酸(1N)调节反应体系pH至5~6。所得混合液减压浓缩,得到的残余物用柱层析纯化得到目标产品(350mg,产率75%)
LC-MS:m/z 296.41(M-H)-。
第二步:(R)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(吗啡啉甲基)-2,3- 二氢苯并[b][1,4]二氧-6-甲酰胺的制备
在氮气氛围下将7-氟-3(R)-(N-吗啡啉基甲基)-2,3-二氢苯并[b][1,4]二氧-6-羧酸(350mg, 1.18mmol)溶解于二氯甲烷(10mL),随后加入(氯亚甲基)二甲基氯化铵(300mg,3.25 mmol)。反应液在室温搅拌1h,随后加入6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(300mg, 1.47mmol)和二异丙基乙基胺(400mg,3.47mmol)。得到的混合物在室温搅拌3h后加入乙酸乙酯(50mL)和水(50mL)分层。有机相收集后依次用水(2x50mL)和饱和食盐水 (50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压浓缩。所得粗产品经制备色谱纯化得到目标产物(180mg,产率32%)。
LC-MS:m/z 481.21(M-H)-。1H NMR(400MHz,CDCl3)δ9.08(d,1H),8.39(m,2H),8.04(d,1H),7.91(t,1H),7.72(d,1H),6.77(d,1H),5.50(m,1H),4.45(d,1H),4.13(m,1H),3.92(m, 5H),2.89(m,6H),1.60(m,6H).
按以上实施例的方法以不同起始原料合成一下化合物:
实施例4B
(S)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(吗啡啉甲基)-2,3-二氢苯并 [b][1,4]二氧-6-甲酰胺
LC-MS:m/z 481.21(M-H)-。1H NMR(400MHz,CDCl3)δ9.09(d,1H),8.40(m,2H),8.03(d,1H),7.91(t,1H),7.74(d,1H),6.76(d,1H),5.50(m,1H),4.44(d,1H),4.11(m,1H),3.84 (m,5H),2.83(m,6H),1.60(m,6H).
实施例5A
(R)-3-((二甲基氨基)甲基)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2,3-二氢苯并[b][1,4]二氧-6-甲酰胺
LCMS m/z 439.45(M-H)-。1H NMR(400MHz,CDCl3)δ9.07(d,1H),8.42(d,1H),8.37(s, 1H),8.03(d,1H),7.90(t,1H),7.76(d,1H),6.75(d,1H),5.51(m,1H),4.41(dd,1H,),4.33(m, 1H),4.08(m,1H),2.65(m,2H),2.38(s,6H),1.60(d,6H).
实施例5B
(S)-3-((二甲基氨基)甲基)-7-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2,3-二氢苯并[b][1,4]二氧-6-甲酰胺
LCMS m/z 439.45(M-H)-。1H NMR(400MHz,CDCl3)δ9.07(d,1H),8.42(d,1H),8.37(s, 1H),8.05(d,1H),7.90(t,1H),7.76(d,1H),6.75(d,1H),5.51(m,1H),4.41(dd,1H),4.32(m,1H), 4.08(m,1H),2.65(m,2H),2.38(s,6H),1.60(d,6H).
实施例6
13-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2,3,5,6,8,9-六氢苯并[b][1,4,7,10] 四氧环十二烷-12-甲酰胺
第一步:13-氟-2,3,5,6,8,9-六氢苯并[b][1,4,7,10]四氧环十二烷-12-羧酸的制备
将三乙二醇二(对甲苯磺酸酯)(2.5g,5.5mmol)和碳酸钾(1.5g,11mmol)加入到2-氟-4,5-二羟基苯甲酸甲酯(1.0g,5.4mmol)的N,N-二甲基甲酰胺(50mL)溶液中。混合物加热在70-75℃搅拌8h后冷却至室温,随后加入乙酸乙酯(200mL)和水(200mL)分层。有机层收集后依次用水(2x200mL)和饱和氯化钠(2x100mL)洗涤,再经无水硫酸钠干燥后过滤。滤液减压浓缩,所得残余物溶于甲醇(10mL)和NaOH水溶液(4N,10mL)。混合物在室温搅拌2-3h后用稀盐酸(2N)调节pH至4-5后减压浓缩。所得残余物用乙酸乙酯(20 mL)和水(20mL)分层。有机相收集后用饱和氯化钠洗涤(2x20mL),然后减压浓缩。夺得残余物用硅胶柱层析纯化得到目标产物(800mg,产率52%)。
LC-MS:m/z 285.31(M-H)-。
第二步:13-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2,3,5,6,8,9-六氢苯并[b] [1,4,7,10]四氧环十二烷-12-甲酰胺的制备
在氮气氛围下,将(氯亚甲基)二甲基氯化铵(400mg,4.34mmol)加入到13-氟
-2,3,5,6,8,9-六氢苯并[b][1,4,7,10]四氧环十二烷-12-羧酸(600mg,2.1mmol)的二氯甲烷(10 mL)溶液中。反应液室温搅拌1h,随后加入6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(400 mg,1.97mmol)和二乙基异丙基胺(800mg,6.2mmol)。所得混合物继续在室温搅拌3h 后加入乙酸乙酯(50mL)和水(50mL)分层。有机相收集后依次用水(2x50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压浓缩,残余物经制备色谱纯化得到目标产物(210mg,产率21%)。
LC-MS:m/z 470.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.10(d,1H,J=16Hz),8.60(s,1H),8.44(d,J=8Hz,1H),8.06(d,J=8Hz,1H),7.90(m,1H),7.84(d,J=8Hz,1H),6.77(d,J= 12Hz,1H),5.53(m,1H),4.25(m,4H),3.94(m,2H),3.78(m,6H),1.63(d,6H)。
实施例7
5-氟-N-(6-(4-异丙基-4H-1,2,4-三氮唑-3-基)吡啶-2-基)-1-(2-甲氧基乙基)-3a,7a-二氢 -1H-吲哚-6-酰胺的制备
第一步:6-溴-5-氟-1-(2-甲氧基乙基)-3a,7a-二氢-1H-吲哚
在室温下将氯乙基甲醚(1.06g,0.01mol)和碳酸铯(6g)加入到5-氟-6-溴吲哚(2.0g, 0.009mol)的N,N-二甲基甲酰胺(16mL)溶液中。反应混合物在80℃反应24h,然后冷却到室温后用水(10mL)稀释后用乙酸乙酯(2x 20mL)萃取。合并的有机相依次用水(10mL)和饱和食盐水(10mL)洗涤,然后用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标化合物(粗产品2.4g),无需纯化直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ:7.89(d,1H),7.48(d,1H),7.45(d,1H),6.45(s,1H),4.34(m,2H),3.62(m,2H),3.20(s,3H)。
第二步:5-氟-1-(2-甲氧基乙基)-3a,7a-二氢-1H-吲哚-6-甲酸甲酯的制备
在室温下,将6-溴-5-氟-1-(2-甲氧基乙基)-3a,7a-二氢-1H-吲哚(1.4g,0.005mol)、N,N- 二甲基甲酰胺(10mL)、甲醇(10mL)、三乙胺(10mL)和PdCl2(dppf)(1g)依次加入到高压釜。反应液在CO氛围下(2.5MPa)在100℃反应过夜,得到的混合物用水(20mL)淬灭后用乙酸乙酯(2x 20mL)萃取。合并的有机相用无水硫酸镁干燥后减压浓缩,残留物用硅胶柱层析得到目标化合物(1.1g)。
1HNMR(400MHz,DMSO-d6)δ:7.98(d,1H),7.40(s,1H),7.35(s,1H),6.45(s,1H),4.31 (s,2H),3.95(s,3H),3.69(m,2H),3.30(s,3H)。
第三步:5-氟-1-(2-甲氧基乙基)-3a,7a-二氢-1H-吲哚-6-甲酸的制备
5-氟-1-(2-甲氧基乙基)-3a,7a-二氢-1H-吲哚-6-甲酸甲酯(1.0g,0.004mol)和氢氧化钠 (0.5g,0.012mol)的甲醇(15mL)和水(6mL)的混合溶液在室温反应过夜。得到的混合物浓缩后用稀HCl(1N,10mL)调节pH到2,然后用乙酸乙酯(3x 10mL)萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标化合物(粗产品0.75g),无需纯化直接用于下一步反应。
LC-MS:m/z 238(M+H)+。
第四步:5-氟-N-(6-(4-异丙基-4H-1,2,4-三氮唑-3-基)吡啶-2-基)-1-(2-甲氧基乙基)-3a,7a- 二氢-1H-吲哚-6-酰胺的制备
在室温下将氯化亚砜(0.1g,0.0014mol)滴加到5-氟-1-(2-甲氧基乙基)-3a,7a-二氢 -1H-吲哚-6-甲酸(0.1g,0.0004mol)的二氯甲烷(1mL)溶液中。反应液在室温反应1h,随后滴加6-4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(0.08g,0.00045mol)和三乙胺(0.2g, 0.225mol)的二氯甲烷(1mL)溶液。得到的混合物在室温反应过夜然后减压浓缩,残留物用硅胶柱层析分离纯化得到目标化合物(0.023g)。
LC-MS:m/z 423(M+H)+。1HNMR(400MHz,CDCl3)δ:9.38(d,1H),8.48(d,1H),8.40(s,1H),8.28(d,1H),8.06(d,1H),7.95(d,1H),7.41(s,1H),7.40(s,1H),5.55(m,1H),4.39(m,2H),3.76(m,2H),3.32(s,3H),1.64(d,6H)。
按以上实施例的方法以不同起始原料合成一下化合物:
实施例8
1-苄基-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 455(M+H)+。1H NMR(400MHz,DMSO)δ10.62(d,J=3.2Hz,1H),8.87(s,1H),8.24(d,J=8.3Hz,1H),8.02(t,J=8.0Hz,1H),7.89(dd,J=9.1,6.8Hz,2H),7.79(d,J= 3.1Hz,1H),7.51(d,J=11.6Hz,1H),7.44–7.13(m,5H),6.59(d,J=3.0Hz,1H),5.65(m,1H), 5.53(s,2H),1.42(d,J=6.7Hz,6H).
实施例9
1-(2-(苄氧)乙基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 499(M+H)+。1H NMR(400MHz,DMSO)δ10.63(s,1H),8.87(s,1H),8.27(d,J=8.3Hz,1H),8.14–7.99(m,2H),7.88(d,J=7.6Hz,1H),7.64(d,J=3.1Hz,1H),7.49(d,J=11.7Hz,1H),7.23(dt,J=12.5,7.5Hz,5H),6.54(t,J=7.4Hz,1H),5.73–5.59(m,1H),4.65 –4.35(m,4H),3.78(t,J=5.0Hz,2H),1.43(d,J=6.7Hz,6H).
实施例10
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-甲基-1H-吲哚-6-甲酰胺
LC-MS:m/z 379(M+H)+。1H NMR(400MHz,CD3OD)δ8.84(s,1H),8.43(d,J=8.4Hz,1H),8.03(dd,J=10.1,6.5Hz,2H),7.87(d,J=7.6Hz,1H),7.42(m,2H),6.51(d,J=3.0Hz,1H),5.73–5.59(m,1H),3.89(s,3H),1.57(d,J=6.7Hz,6H).
实施例11
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-乙基-1H-吲哚-6-甲酰胺
LC-MS:m/z 393(M+H)+。1H NMR(400MHz,CD3OD)δ8.85(s,1H),8.43(d,J=8.3Hz,1H),8.03(t,J=7.1Hz,2H),7.87(d,J=7.6Hz,1H),7.52(d,J=3.0Hz,1H),7.40(d,J=12.9 Hz,1H),6.52(d,J=3.0Hz,1H),5.79–5.55(m,1H),4.30(q,J=7.2Hz,2H),1.57(d,J=6.7 Hz,6H),1.46(t,J=7.5Hz,3H).
实施例12
5-氟-1-异丙基-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 407(M+H)+。1H NMR(400MHz,CD3OD)δ8.84(s,1H),8.40(d,J=8.3Hz,1H),8.11–7.95(m,2H),7.85(d,J=7.6Hz,1H),7.61(d,J=3.1Hz,1H),7.36(d,J=12.9Hz,1H),6.52(d,J=3.1Hz,1H),5.74–5.49(m,1H),4.89–4.70(m,1H),1.55(dd,J=10.5,6.7Hz, 12H).
实施例13
1-环丙甲基-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 419(M+H)+。1H NMR(400MHz,CD3OD)δ8.84(s,1H),8.43(d,J=8.3Hz,1H),8.18–7.97(m,2H),7.87(d,J=7.6Hz,1H),7.58(d,J=3.0Hz,1H),7.41(d,J=12.9Hz,1H),6.53(d,J=2.9Hz,1H),5.75–5.55(m,1H),4.12(d,J=6.9Hz,2H),1.57(d,J=6.7Hz,6H),1.32(m,1H),0.62(m,2H),0.44(m,2H).
实施例14
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(吡啶-2-基甲基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 456(M+H)+。1H NMR(400MHz,CDCl3)δ9.35(d,J=19.2Hz,1H),8.64(d,J=4.8Hz,1H),8.50(s,1H),8.46(d,J=8.4Hz,1H),8.24(d,J=6.0Hz,1H),8.06(d,J=7.6Hz,1H), 7.92(t,J=8.0Hz,1H),7.70(t,J=7.6Hz,1H),7.51(d,J=3.2Hz,1H),7.43(d,J=13.6Hz,1H),7.31(t, J=5.6Hz,1H),6.89(d,J=8.0Hz,1H),6.63(d,J=2.8Hz,1H),5.64(s,2H),5.57(m,1H),1.63(d, J=6.4Hz,6H)。
实施例15
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(吡啶-3-基甲基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 456(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.65(d,J=2.4Hz,1H),8.86(s, 1H),8.53(s,1H),8.47(d,J=4.8Hz,1H),8.25(d,J=8.4Hz,1H),8.02(t,J=8.0Hz,1H),7.98(t, J=6.0Hz,1H),7.88(d,J=7.6Hz,1H),7.82(d,J=3.2Hz,1H),7.60(d,J=7.6Hz,1H),7.51(d, J=11.6Hz,1H),7.34(dd,J=4.8Hz,J=8.0Hz,1H),6.60(d,J=3.2Hz,1H),5.62-5.69(m,1H),5.59(s, 2H),1.42(d,J=6.8Hz,6H)。
实施例16
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(吡啶-4-基甲基)-1H-吲哚-6-甲酰胺
LC-MS:m/z 456(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.62(d,J=2.8Hz,1H),8.86(s, 1H),8.49(d,J=6.0Hz,2H),8.23(d,J=8.4Hz,1H),8.01(t,J=8.0Hz,1H),7.86-7.88(m,2H),7.80(d, J=3.2Hz,1H),7.54(d,J=11.6Hz,1H),7.08(d,J=5.6Hz,2H),6.64(d,J=3.2Hz,1H),5.62-5.67(m, 3H),1.42(d,J=6.8Hz,6H)。
实施例17
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-苯乙基-1H-吲哚-6-甲酰胺
LC-MS:m/z 469(M+H)+。1H NMR(400MHz,CDCl3)δ9.97(s,1H),9.45(d,J=20Hz,1H), 8.68(d,J=8.4Hz,1H),8.26(d,J=4.0Hz,1H),8.18(d,J=7.6Hz,1H),8.05(d,J=8.0Hz,1H), 7.39(d,J=14.4Hz,1H),7.23-7.29(m,2H),7.09(d,J=2.8Hz,1H),7.04(d,J=7.2Hz,2H), 6.45(d,J=2.8Hz,1H),5.81(m,1H),4.46(t,J=7.2Hz,2H),3.15(t,J=7.2Hz,2H),1.81(d,J= 6.8Hz,6H)。
实施例18
N-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(2-甲氧基乙基)-3a,7a-二氢-1H-吡咯 [3,4-c]吡啶-6-酰胺的制备
第一步:1-(2-甲氧基乙基)-1H-吡咯[3,2-c]吡啶-6-甲酸-(2-甲氧基乙基)酯的制备
1H-吡咯[3,2-c]吡啶-6-甲酸(0.25g,0.0015mol)、碳酸铯(1.0g,0.0030mol)和氯乙基甲醚(0.5g,0.0045mol)的N,N-二甲基甲酰胺(3mL)溶液在85℃反应过夜。得到的反应液冷却到室温后用水(10mL)淬灭,然后用乙酸乙酯萃取(3x10mL)。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标化合物(粗产品0.4g),无需纯化直接用于下一步反应。
LC-MS:m/z 279(M+H)+。
第二步:1-(2-甲氧基乙基)-3a,7a-二氢-1H-吡咯[3,2-c]吡啶-6-甲酸的制备
1-(2-甲氧基乙基)-1H-吡咯[3,2-c]吡啶-6-甲酸-(2-甲氧基乙基)酯(0.4g,0.0014mol)和氢氧化钠(0.17g,0.0042mol)的甲醇(6mL)和水(2mL)的混合溶液在室温下反应过夜。得到的混合物减压浓缩后残留物用稀HCl(1N,10mL)调pH到2,然后用乙酸乙酯(3x10mL) 萃取。合并的有机相用无水硫酸镁干燥后过滤。滤液减压浓缩得到目标化合物(粗产品0.3g),无需纯化直接用于下一步反应。
LC-MS:m/z 221(M+H)+。
第三步:N-6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1–(2-甲氧基乙基)-3a,7a-二氢 -1H-吡咯[3,4-c]吡啶-6-酰胺的制备
在室温下将氯化亚砜(0.1g,0.0014mol)滴加到1-(2-甲氧基乙基)-3a,7a-二氢-1H-吡咯[3,2-c]吡啶-6-羧酸甲酯(0.1g,0.00045mol)的二氯甲烷(1mL)溶液中。反应液在室温反应 1h,随后滴加6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺(0.05g,0.00045mol)和三乙胺(0.2 g,0.225mol)的二氯甲烷(1mL)溶液。得到的混合物在室温反应过夜,然后减压浓缩,残留物用硅胶柱层析分离纯化得到目标化合物(0.005g)。
LC-MS:m/z 406(M+H)+。1HNMR(400MHz,DMSO-d6)δ:12.31(brs,1H),8.96(s,1H),8.52(m,3H),8.11(m,1H),7.95(m,1H),7.52(s,1H),6.8(s,1H),5.36(m,1H),4.42(s,2H),3.76(m,2H),3.37(s,3H),1.25(d,6H)。
实施例19
1-(2-(苄氧)乙基)-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吡咯[3,2-c]吡啶-6- 甲酰胺
LC-MS:m/z 482(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.83(s,1H),9.00(s,1H),8.94(s,1H),8.54(s,1H),8.42(d,J=8.4Hz,1H),8.10(d,J=8.0Hz,1H),7.87(d,J=7.6Hz,1H), 7.78(d,J=2.4Hz,1H),7.18-7.26(m,3H),7.14(d,J=8.0Hz,2H),6.83(d,J=2.0Hz,1H),5.48 (m,2H),4.62(t,J=4.8Hz,2H),4.46(s,2H),3.81(t,J=5.2Hz,1H),1.53(d,J=6.4Hz,6H)。
实施例20
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(2-甲氧基乙基)1H-吲唑-6-甲酰胺和5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-(2-甲氧基乙基)1H-吲唑-6-甲酰胺
第一步:5-氟-1H-吲唑-6-羧酸甲酯的制备
5-氟-6-溴-1H-吲唑(750mg,3.5mmol)、Pd(dppf)Cl2(150mg,0.02mmol)和碳酸钾(1.0g, 7.2mmol)的N,N-二甲基甲酰胺(15mL)和甲醇(30mL)的混合溶液在一氧化碳氛围下(2 MPa)在90~100℃反应8~12h。得到的混合物冷却至室温,然后在40℃以下减压浓缩。残留物用乙酸乙酯(100mL)和水(100mL)分层。有机相收集,依次用水(3x50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃以下减压浓缩得到粗产品(700mg),无需纯化直接用于下一步反应。
LC-MS:m/z 193(M-H)-。
第二步:5-氟-1-(甲氧基乙基)-吲唑-6-羧酸和5-氟-2-(甲氧基乙基)-吲唑-6-羧酸的制备
在室温下将氢化钠(420mg,7.0mmol)加入到5-氟-1H-吲唑-6-羧酸甲酯(700mg,约3.5mmol)的N,N-二甲基甲酰胺(10mL)溶液中。反应混合物在室温搅拌30min后加入溴乙基甲醚(650mg,4.7mmol),然后在50℃搅拌8~10h。得到的混合物冷却到室温后,加入乙酸乙酯(50mL)和水(50mL)分层。有机相收集后用水(2x50mL)洗涤,然后减压浓缩。所得残留物中加入甲醇(20mL)和NaOH水溶液(10%wt,20mL),然后在室温下搅拌2h。得到的混合物用稀盐酸(1N)调节反应pH到2~3后,加入乙酸乙酯(100mL)和水(100mL) 分层。水层分离后用乙酸乙酯(2x30mL)萃取。有机相合并后,依次用水(50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液减压浓缩,残留物经柱层析纯化得5-氟-1-(甲氧基乙基)-吲唑-6-羧酸和5-氟-2-(甲氧基乙基)-吲唑-6-羧酸的混合物(350mg)。
LC-MS:m/z 237.25(M-H)-
第三步:5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(2-甲氧基乙基)1H-吲唑 -6-甲酰胺和5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-(2-甲氧基乙基)1H-吲唑 -6-甲酰胺的制备
在氮气氛围下将(氯亚甲基)二甲基氯化铵(270mg,2.92mmol)加入到上步所得5-氟 -1-(甲氧基乙基)-吲唑-6-羧酸和5-氟-2-(甲氧基乙基)-吲唑-6-羧酸的混合物(350mg,1.46 mmol)的二氯甲烷(10mL)溶液中。反应液在室温搅拌1h,随后加入6-(4-异丙基 -4H-1,2,4-三唑-3-基)吡啶-2-胺(350mg,1.52mmol)和二乙基异丙基胺(335mg,2.92mmol)。得到的混合物在室温搅拌3h,然后用乙酸乙酯(50mL)和水(50mL)分层。有机相收集后依次用水(2x50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在 40℃下减压浓缩,残余物经制备色谱纯化,得到两种异构体5-氟-N-(6-(4-异丙基-4H-1,2,4- 三唑-3-基)吡啶-2-基)-1-(2-甲氧基乙基)1H-吲唑-6-甲酰胺和5-氟-N-(6-(4-异丙基-4H-1,2,4- 三唑-3-基)吡啶-2-基)-2-(2-甲氧基乙基)1H-吲唑-6-甲酰胺。
异构体20A(110mg,产率18%)。LC-MS:m/z 422.37(M-H)-。1H NMR(400MHz,CDCl3)δ9.32(d,1H),8.49(t,2H),8.43(d,1H),8.07(m,2H),7.94(t,1H),7.50(d,1H),5.54(m,1H), 4.65(t,2H),3.88(t,2H),3.31(s,3H),1.63(d,6H)。
异构体20B(100mg,产率16%)。LC-MS:m/z 422.39(M-H)-。1H NMR(400MHz,CDCl3)δ9.21(d,1H),8.67(d,1H),8.50(d,1H),8.40(s,1H),8.05(t,2H),7.93(t,1H),7.41(d,1H), 5.54(m,1H),4.64(t,2H),3.90(t,2H),3.36(s,3H),1.60(d,6H)。
以实施例5做为通用方法,用不同起始原料合成了以下化合物。
实施例21
1-(2-异丙氧基乙基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲唑-6-甲酰胺和2-(2-异丙氧基乙基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2H-吲唑-6- 甲酰胺
异构体21A
LCMS m/z 448.48(M-H)-。1H NMR(400MHz,CDCl3)δ9.33(d,J=16Hz,1H),8.49(d,J=8Hz,1H),8.43-8.41(m,2H),8.07(t,J=8Hz,1H),8.05(s,1H),7.95(t,J=8Hz,1H),7.52(d, J=12Hz,1H),5.54(m,1H),4.62(t,J=4Hz,2H),3.99(t,J=4Hz,2H),3.25(m,1H),1.61(d, J=4Hz,6H),0.40(m,4H)。
异构体21B
LCMS m/z 448.47(M-H)-。1H NMR(400MHz,CDCl3)δ9.21(d,J=16Hz,1H),8.50(d,J=8Hz,1H),8.42(d,J=8Hz,1H),8.06(m,2H),7.95(m,1H),7.52(d,J=8Hz,1H),7.44(d, J=8Hz,1H),5.57(m,1H),4.62(t,J=4Hz,2H),3.99(t,J=4Hz,2H),3.25(m,1H),1.61(d, J=8Hz,6H),0.40(m,4H)。
实施例22
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(3-甲氧基丙基)-1H-吲唑-6-甲酰胺和5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-(3-甲氧基丙基)-2H-吲唑-6-甲酰胺
异构体22A
LCMS m/z 436.50(M-H)-。1H NMR(400MHz,CDCl3)δ9.42(d,J=16Hz,1H),8.49(d,J=8Hz,1H),8.41(s,1H),8.40(d,J=8Hz,1H),8.08-8.06(m,2H),7.94(t,J=8Hz,1H),7.53(d, J=12Hz,1H),5.56(m,1H),4.58(t,J=4Hz,2H),3.33(m,5H),2.28(m,2H),1.61(d,J=4Hz, 6H)。
异构体22B
LCMS m/z 436.49(M-H)-。1H NMR(400MHz,CDCl3)δ9.27(d,J=16Hz,1H),8.63(d,J= 8Hz,1H),8.47(d,J=8Hz,1H),8.38(s,1H),8.02(m,2H),7.91(t,J=8Hz,1H),7.42(d,J=12Hz,1H),5.57(m,1H),4.58(t,J=4Hz,2H),3.33(s,3H),3.30(t,J=4Hz,2H),2.22(m,2H), 1.59(d,J=8Hz,6H)。
实施例23
1-(环丙基甲基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲唑-6-甲酰胺和2-(环丙基甲基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2H-吲唑-6-甲酰胺
异构体23A
LCMS m/z 418.48(M-H)-。1H NMR(400MHz,CDCl3)δ9.37(d,J=16Hz,1H),8.49(d,J=8Hz,1H),8.40-8.39(m,2H),8.10(d,J=8Hz,1H),8.03(s,1H),7.95(t,J=8Hz,1H),7.55 (d,J=12Hz,1H),5.54(m,1H),4.37(d,J=8Hz,2H),1.61(d,J=8Hz,6H),1.39(m,1H), 0.62(m,2H),0.45(m,2H)。
异构体23B
LCMS m/z 418.48(M-H)-。1H NMR(400MHz,CDCl3)δ9.19(d,J=16Hz,1H),8.68(d,J=8Hz,1H),8.53-8.49(m,2H),8.11(s,1H),8.08(t,J=8Hz,1H),7.93(t,J=8Hz,1H),7.45(d,J =16Hz,1H),5.58(m,1H),4.35(d,J=8Hz,2H),1.61(d,J=8Hz,6H),1.45(m,1H),0.77(d,J =8Hz,2H),0.51(m,J=8Hz,2H)。
实施例24
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-甲基-1H-吲唑-6-甲酰胺和5-氟 -N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-甲基-2H-吲唑-6-甲酰胺
异构体24A
LCMS m/z 378.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.34(d,J=20Hz,1H), 8.51-8.36(m,3H),8.04(s,1H),7.95(t,J=8Hz,1H),7.61-7.40(m,2H),5.56(m,1H),4.19(s,3H),1.62(d,J=8Hz,6H)。
异构体24B
LCMS m/z 378.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.20(d,J=20Hz,1H),8.67(d,J=8Hz,1H),8.50(d,J=8Hz,1H),8.38(s,1H),8.05(s,1H),7.93(s,1H),7.56-7.40(m,2H), 5.54(m,1H),4.29(s,3H),1.61(d,J=8Hz,6H)。
实施例25
1-(2-(苄氧)乙基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1H-吲唑-6-甲酰胺和2-(2-(苄氧)乙基)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2H-吲唑-6-甲酰胺的混合物(1:1)
LC-MS:m/z 500.8(M+H)+。1H NMR(400MHz,CDCl3)δ9.30-9.17(m,1H),8.67-8.46(m, 2H),8.39(s,1H),8.10-8.04(m,2H),7.97-7.91(m,1H),7.53-7.41(m,1H),7.31-7.30(m,1H), 7.29-7.14(m,4H),5.58-5.51(m,1H),4.69-4.65(m,2H),4.50-4.45(m,2H),4.00-3.91(m, 2H),1.62-1.60(m,6H)。
实施例26
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-((4-甲基吗啡啉-2-基)甲基)-1H- 吲唑-6-甲酰胺和5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-((4-甲基吗啡啉-2- 基)甲基)-2H-吲唑-6-甲酰胺的混合物(1:1)
LC-MS:m/z 479.5[M+H]+。1H NMR(400MHz,CDCl3)δ9.33-9.16(m,1H),8.66-8.44(m,2H),8.38(d,1H),8.09-8.05(m,2H),7.97-7.91(m,1H),7.53-7.41(m,1H),5.57-5.50(m,1H), 4.60-4.48(m,2H),4.08-3.99(m,1H),3.91-3.84(m,1H),3.68-3.56(m,1H),2.81-2.73(m,1H), 2.65-2.59(m,1H),2.28-2.27(d,3H),2.13-2.07(m,1H),1.94-1.81(m,1H),1.62-1.59(m,6H)。
实施例27
(S)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(1-甲氧基丙烷-2-基)-1H-吲唑-6-甲酰胺和(S)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-(1-甲氧基丙烷-2- 基)-2H-吲唑-6-甲酰胺的混合物(1:1)
LCMS m/z 436.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.33(d,J=16Hz,0.6H),9.21(d,J=16Hz,0.4H),8.68-8.39(m,3H),8.09-7.92(m,3H),7.53(d,J=12Hz,0.6H),7.43(d,J=12 Hz,0.4H),5.54(m,1H),5.02-4.80(m,1H),3.90-3.84(m,1H),3.78-3.71(m,1H),3.31-3.27(m, 3H)1.71-1.59(m,9H)。
实施例28
(R)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(1-甲氧基丙烷-2-基)-1H-吲唑-6-甲酰胺和(R)-5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-(1-甲氧基丙烷-2- 基)-2H-吲唑-6-甲酰胺的混合物(1:1)
LCMS m/z 436.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.33(d,J=16Hz,0.6H),9.20(d, J=16Hz,0.4H),8.68-8.40(m,3H),8.09-7.90(m,3H),7.53(d,J=12Hz,0.6H),7.43(d,J=12 Hz,0.4H),5.54(m,1H),5.02-4.80(m,1H),3.89-3.83(m,1H),3.77-3.71(m,1H),3.31-3.26(m, 3H)1.70-1.59(m,9H)。
实施例29
5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-1-(2-甲氧基丙基)-1H-吲唑-6-甲酰胺和5-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-2-(2-甲氧基丙基)-2H-吲唑-6-甲酰胺的混合物(1:1)
LCMS m/z 436.46(M-H)-。1H NMR(400MHz,CDCl3)δ9.26(d,J=16Hz,1H),8.41(d,J=8Hz,1H),8.36(d,J=8Hz,1H),8.31(s,1H),7.98(m,2H),7.86(t,J=8Hz,1H),7.44(d,J=12Hz,1H),5.46(m,1H),4.38(m,2H),3.79(m,1H),3.15(s,3H),1.52(d,J=4Hz,6H),1.13(d,J=4Hz,3H)。
实施例30
6-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(2-甲氧基乙基)-1-甲基-2-氧代 -2,3-二氢-1H-苯并[D]咪唑-5-甲酰胺的制备
第一步:2-氟-4-甲胺基-5-硝基苯甲酸的制备
在冰浴下将甲胺水溶液(30%wt,5g,48.4mmol)滴加到2-氟-4-甲胺基-5-硝基苯甲酸 (5.0g,24.6mmol)的四氢呋喃(50mL)溶液中。滴加完毕反应液自然升至室温,并在室温搅拌12h。得到的混合物物用水(50mL)淬灭,然后在30~35℃减压浓缩。得到的残留物过滤,滤饼用少量水淋洗得后在40~50℃空气干燥至得到目标产物(粗产品2.3g),无需提纯直接用于下一步反应。
LC-MS:m/z 213(M-H)-
第二步:2-氟-4-甲胺基-5-胺基苯甲酸的制备的制备
在氮气氛围下将Pd/C(10%Pd,50%水,0.3g)加入到2-氟-4-甲胺基-5-硝基苯甲酸(2.3g, 10.7mmol)的甲醇(30mL)溶液中。反应物在氢气氛围下搅拌4hr,然后通过硅藻土过滤,滤饼用甲醇淋洗。滤液合并收集后在40℃以下减压浓缩得到目标产品(粗产品1.9g),无需提纯直接用于下一步反应。
LC-MS:m/z 183(M-H)-
第三步:6-氟-1-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-羧酸的制备
在室温下将三光气(0.5g,1.7mmol)加入到2-氟-4-甲胺基-5-胺基苯甲酸(0.5g,2.7 mmol)的乙酸(10mL)溶液中。反应液在室温搅拌3h,然后在40℃以下减压浓缩,得到的残留物经硅胶柱层析纯化得到目标产品(170mg)。
LC-MS:m/z 211(M+H)+
第四步:6-氟-3-(2-甲氧乙基)-1-甲基-2-氧代-2-3-二氢-1H-苯并[d]咪唑-5-羧酸的制备
在室温下将碳酸钠(276mg,2mmol)和氯乙基甲醚(150mg,1.6mmol)加入到6-氟-1-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-羧酸(170mg,0.81mmol)的N,N-二甲基甲酰胺(5 mL)中。反应液在80~85℃搅拌12h后冷却至室温,随后加入乙酸乙酯(30mL)和稀盐酸(0.5N,30mL)分层。水相分离以后用乙酸乙酯(20mL)萃取。有机相合并后依次用水(30 mL)和饱和食盐水(30mL)洗涤,然后在40℃下减压浓缩。所得浓缩残余物中加入四氢呋喃(10mL)和氢氧化钠水溶液(4N,10mL),然后在室温搅拌12h。得到的混合物用稀盐酸(2N)调节pH到3~4,然后用乙酸乙酯(3x20mL)萃取。有机相合并后依次用水(30mL) 和饱和食盐水(30mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃下真空浓缩得到目标产品(110mg),无需提纯直接用于下一步反应。
LC-MS:m/z 267(M-H)-
第五步:6-氟-N-(6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-基)-3-(2-甲氧基乙基)-1-甲基 -2-氧代-2,3-二氢-1H-苯并[D]咪唑-5-甲酰胺的制备
在氮气氛围下将(氯亚甲基)二甲基氯化铵(100mg,0.78mmol)加入到6-氟-3-(2-甲氧乙基)-1-甲基-2-氧代-2-3-二氢-1H-苯并[d]咪唑-5-羧酸(110mg,0.4mmol)的二氯甲烷(10 mL)溶液中。反应物在室温搅拌1h,随后加入6-(4-异丙基-4H-1,2,4-三唑-3-基)吡啶-2-胺 (82mg,0.4mmol)和二乙基异丙基胺(155mg,1.2mmol)。得到的混合物在室温搅拌3h,随后加入乙酸乙酯(50mL)和水(50mL)分层。有机相收集后依次用水(50mL)和饱和食盐水(50mL)洗涤,然后用无水硫酸钠干燥后过滤。滤液在40℃下真空减压,残留物经制备色谱纯化得到目标产物(80mg)。
LC-MS:m/z 452.35(M-H)-。1H NMR(400MHz,CDCl3)δ9.20(d,1H),8.44(m,1H),8.40(s,1H),8.06(d,1H),7.93(m,2H),6.80(d,1H),5.52(m,1H),4.12(t,2H),4.71(t,2H),3.46(s, 3H),3.35(s,3H),1.62(d,6H)。
生物学测试评价
以下生物学测试例进一步描述解释本发明,但这些实例并非意味着限制本发明的范围
化合物对凋亡信号调节激酶1(ASK1)抑制作用的体外实验
试剂:
hASK1酶:GST-ASK1(654-971)
底物:MKK6;HIS-Avi-MKK6
试剂盒:ADP-GloTMKinase Assay 10,000tests;
培养板:Corning 3573
DTT:Sigma-Aldrich;
ATP:Ultra Pure ATP,100mM。包含在试剂盒中。
Magnesium acetate tetrahydrate:Sigma-Aldrich;
MOPS:Ambion;
NP-40:Thermo Scientific Pierce;
BSA:Equitech-Bio Inc;
Glycerol:Sigma-Aldrich;
试验步骤:
1.缓冲液:10mM MOPS pH7.0;10mM Mg-Acetate;1mM DTT(用前添加);0.025%NP-40;0.05%BSA;1.5%glycerol。
2.预制备ASK1+MKK6溶液(2x):用缓冲液稀释hASK1酶和MKK6至终浓度 0.25nMhASK1、300nM MKK6;
3.预制备ATP溶液(2x):用缓冲液稀释ATP至终浓度100uM;
4.将化合物以梯度浓度的的方式加入384孔板中,使用HP D300自动移液器补充DMSO 至总体积5nL/孔。最小控制列:底物+ATP+0.1%DMSO;最大控制列:酶+底物+ATP+0.1%DMSO。
5.加入ASK1-MKK6混合液(2x)至步骤4已添加相应化合物的384孔板中,2.5μL/孔,震动混匀、室温孵育15min。
6.加入ATP溶液(2x)至步骤5 384孔板中,2.5μL/孔,震荡混匀并离心、室温孵育30min。
7.然后按照5μL/孔加入ADP-Glo试剂使ATP失活,室温孵育40min。
8.然后按照10μL/孔加入激酶检测试剂将ADP转变为ATP,室温孵育60min。
9.读取荧光数据
10.使用Graphpad Prism计算四参数抑制剂量反应曲线
本发明中实施例化合物酶学活性见表1。
表1本发明中实施例化合物酶学活性
药代动力学测试评价
雄性SD大鼠,体重200g左右,禁食过夜后,灌胃给予5mg/kg本发明化合物溶液[DMSO/PEG400为载体]。分别在给药后0.5,1.0,2.0,4.0,6.0,8.0,12,24和36h采血,用LC/MS/MS测定血浆中本发明化合物的浓度。
实验结果:本发明化合物在大鼠体内体现出较好的代谢性质,包括较高的血浆暴露量 AUC、最大血药浓度Cmax和半衰期t1/2都表现较好。
体内药效学测试
对高脂饲料(HFD)和四氯化碳(CCl4)诱导的非酒精性脂肪肝炎小鼠模型的药效学评价
实验步骤:C57BL/6小鼠在无特定病原体(SPF)屏障内进行3-7天的适应性饲养以后改换为HFD饲料饲养,饲养周期为8周。在HFD给料第五周开始,根据小鼠体重随机分组。分组后的小鼠一周两次给与口服CCl4诱导,并持续四周。在CCl4建模当日开始每天一次口服给药,并连续给药28天。溶媒对照组给与实验品对应的溶媒,给药体积为10mL/Kg。在最后一次给与CCl448小时以后用CO2将小鼠安乐死。从小鼠心脏处采集非凝静脉血,全血在常温下放置30分钟以上,然后在4摄氏度5000转5分钟的离心条件下离心。得到的血清分离后分装成两份,装入1.5mL的EP管中,保存在-80摄氏度备用。利用谷丙转氨酶试剂盒和谷草转氨酶试剂盒检测小鼠血清中的ALT和AST水平,以及进行肝细胞变性、坏死、气球样变、炎细胞浸润等评分。
实验结果:本发明化合物对高脂饲料(HFD)和CCl4诱导的肝维化具有优异的治疗效果。
CYP抑制性检测
CYP3A4抑制性检测(咪达唑仑,midazolam)
将测试化合物以7个浓度(0.14、0.41、1.23、3.70、11.11、33.33、100uM的DMSO溶液) 与人肝微粒体(0.1mg/mL)和NADPH(1mM)在探针底物咪达唑仑(2.5uM)的存在下在 37℃共同培育5分钟。选择性CYP3A4抑制剂(酮康唑,Ketoconazole)作为阳性参照物与测试化合物一同进行实验。
CYP3A4抑制性检测(睾酮,testosterone)
将测试化合物以7个浓度(0.14、0.41、1.23、3.70、11.11、33.33、100uM的DMSO溶液) 与人肝微粒体(0.1mg/mL)和NADPH(1mM)在探针底物睾酮(50uM)的存在下在37℃共同培育5分钟。选择性CYP3A4抑制剂(酮康唑,Ketoconazole)作为阳性参照物与测试化合物一同进行实验。
对照化合物GS-4997的结构如下:
实验结果如表2所示:
表2
结果显示,本发明的化合物对CYP3A4等CYP酶抑制活性低,从而降低药物-药物相互作用可能性,增加药物安全性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种具有通式(I)结构的芳基酰胺类化合物,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可以接受的盐、水合物、溶剂合物,或前药;
式中:
M1、M2各自独立地选自:N或CR7;
环A选自下组:取代或未取代的C3-C20碳环、取代或未取代的3-20元杂环、取代或未取代的C6-C20芳环或取代或未取代的5-20元杂芳环;环A中,所述取代指环A被氧代、硫代、或-(CH2)n-所取代,或者环A上的H被选自下组的一个或多个(较佳地1~3个)取代基所取代:氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nO(CH2)oR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(包括-(CH2)nC(O)NHR11)、-(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;
各个R1是相同的或不同的,且各自独立地为选自下组的基团:取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nR10、-(CH2)nOR10、-(CH2)nCH(R10)(CH2)oNR11R12(包括:-(CH2)n CH(OH)(CH2)o NHR11)、-(CH2)nO(CH2)oR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12、-(CH2)nNR11C(O)R10或-(CH2)nNR11S(O)mR10、-(CH2)nN(R11)(CH2)oR10(包括-(CH2)nNH(CH2)oR10);
R2、各个R3和R5各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(较佳地-(CH2)nC(O)NHR11)、-(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;
R4选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、羟基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;或者,R4与M3以及与其相连的N原子共同构成选自下组的环:取代或未取代的杂环、取代或未取代的杂芳环;
M3、M4各自独立地选自:N或CR7;或M3与M4以及其相邻的化学键共同构成选自下组的基团:取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;
M5选自下组:N或CR7;
或者,X和/或Y与M1、M2或M5及其相连的化学键共同构成选自下组的环:取代或未取代的碳环、取代或未取代的杂环、取代或未取代的芳环、取代或未取代的杂芳环;
R7、R8和R9各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(包括-(CH2)nC(O)NHR11)、-(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;
除非特别说明,以上所述的取代指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH2)nR10、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12(包括-(CH2)nC(O)NHR11)、-(CH2)nNR11C(O)R10、或-(CH2)nNR11S(O)mR10;
R10各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、氨基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基和取代或未取代的杂芳基;
R11和R12各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、氨基、羟基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;或者,R11和R12以及与其相连的N原子共同构成选自下组的环:取代或未取代的杂环,或取代或未取代的杂芳环;
其中,所述的R10、R11和R12中,取代指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH2)nR13、-(CH2)nOR13、-(CH2)nSR13、-(CH2)nCOR13、-(CH2)nC(O)OR13、-(CH2)nS(O)mR13、-(CH2)nNR13R14、-(CH2)nC(O)NR13R14、(包括-(CH2)nC(O)NHR14)、-(CH2)nNR14C(O)R13和-(CH2)nNR14S(O)mR13;
R13和R14各自独立地选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、氨基、羟基、酯基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基;其中,所述的R13和R14中,取代指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、烷氧基、卤素、氨基、硝基、羟基、氰基、酯基;
x为0、1、2、3或4;
y为0、1或2;
m为0、1或2;且
n为0、1、2、3、4或5;
o为0、1、2、3、4或5;
除非特别说明,上述各式中,“(CH2)n”或“(CH2)o”中0-3个氢被C1-C6烷基取代;
各个所述的环烷基为C3-C20环烷基(较佳地C3-C10环烷基);
各个所述的杂环基为3-20元杂环基(较佳地3-10元杂环基);
各个所述的芳基为C6-C20芳基(较佳地C6-C12芳基);
各个所述的杂芳基为5-20元杂芳基(较佳地5到12元杂芳基)
各个所述的烷基为C1-C18烷基(较佳地C1-C6烷基);
各个所述的烷氧基为C1-C18烷氧基(较佳地C1-C6烷氧基);
各个所述的酯基为C2-C10酯基(较佳地C2-C6酯基);
各个所述的碳环为C3-C20碳环(较佳地C3-C10碳环);
各个所述的杂环为3-20元杂环(较佳地3-10元杂环);
各个所述的芳环为C6-C20芳环(较佳地C6-C12芳环);
各个所述的杂芳环为5-20元杂芳环(较佳地5到12元杂芳环)。
2.如权利要求1所述的化合物,其特征在于,所述化合物为通式(II)所示的化合物:
式中,
R6选自下组:氢原子、氘原子、取代或未取代的烷基、取代或未取代的烷氧基、卤素、氨基、硝基、羟基、氰基、取代或未取代的环烷基、取代或未取代的杂环基、取代或未取代的芳基、取代或未取代的杂芳基、-(CH2)nOR10、-(CH2)nSR10、-(CH2)nCOR10、-(CH2)nC(O)OR10、-(CH2)nS(O)mR10、-(CH2)nNR11R12、-(CH2)nC(O)NR11R12、-(CH2)nNR11C(O)R10和-(CH2)nNR11S(O)mR10;其中,所述取代是指基团上的一个或多个(较佳地1-3个)氢原子被选自下组的取代基取代:氘原子、烷基、氘代烷基、卤代烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-(CH2)nOR13、-(CH2)nSR13、-(CH2)nCOR13、-(CH2)nC(O)OR13、-(CH2)nS(O)mR13、-(CH2)nNR13R14、-(CH2)nC(O)NR13R14(包括-(CH2)nC(O)NHR14)、-(CH2)nNR14C(O)R13和-(CH2)nNR14S(O)mR13;或者,R4以及与其相连的N原子,与R6以及与其相连的C原子共同构成:取代或未取代的杂环,或者取代或未取代的杂芳环;
除非特别说明,取代、环A、M1、M2、M5、X、Y、R1、R2、R3、R4、R5、R10、R11、R12、R13、R14、x和y的定义如权利要求1中所述。
9.一种药物组合物,其特征在于,所述组合物包括(i)药学上可接受的载体,和(ii)如权利要求1所述的化合物,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可接受的盐、或其水合物,或其溶剂合物,或前药。
10.如权利要求1所述的化合物、,或其立体异构体、互变异构体、消旋体、或其多晶型、或其药学上可接受的盐、或其水合物,或其溶剂合物,或前药,或者如权利要求9所述的药物组合的用途,其特征在于,
(i)用于制备ASK1抑制剂;和/或
(ii)用于制备治疗和/或预防ASK1介导的疾病的药物:其中所述ASK1介导的疾病选自下组:炎症、心血管疾病、感染、免疫性疾病、代谢性疾病,或其组合。
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CN109265443A (zh) * | 2017-07-18 | 2019-01-25 | 南京圣和药业股份有限公司 | 作为ask抑制剂的杂环化合物及其应用 |
CN109456308A (zh) * | 2017-09-06 | 2019-03-12 | 南京圣和药业股份有限公司 | 作为ask抑制剂的杂环化合物及其应用 |
CN111655678A (zh) * | 2018-01-05 | 2020-09-11 | 广州市恒诺康医药科技有限公司 | 细胞凋亡信号调节激酶-1抑制剂及其应用 |
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2019
- 2019-01-09 CN CN201910020117.9A patent/CN111423422A/zh active Pending
- 2019-12-11 WO PCT/CN2019/124633 patent/WO2020143385A1/zh active Application Filing
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WO2018218051A1 (en) * | 2017-05-25 | 2018-11-29 | Enanta Pharmaceuticals, Inc. | Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof |
WO2018218044A2 (en) * | 2017-05-25 | 2018-11-29 | Enanta Pharmaceuticals Inc | Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof |
WO2018218042A1 (en) * | 2017-05-25 | 2018-11-29 | Enanta Pharmaceuticals, Inc. | Apoptosis signal-regulating kinase 1 inhibitors and methods of use thereof |
CN109265443A (zh) * | 2017-07-18 | 2019-01-25 | 南京圣和药业股份有限公司 | 作为ask抑制剂的杂环化合物及其应用 |
CN109456308A (zh) * | 2017-09-06 | 2019-03-12 | 南京圣和药业股份有限公司 | 作为ask抑制剂的杂环化合物及其应用 |
CN111655678A (zh) * | 2018-01-05 | 2020-09-11 | 广州市恒诺康医药科技有限公司 | 细胞凋亡信号调节激酶-1抑制剂及其应用 |
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