CN110291089B - 用于促进肝再生或者减少或预防肝细胞死亡的蛋白激酶抑制剂 - Google Patents
用于促进肝再生或者减少或预防肝细胞死亡的蛋白激酶抑制剂 Download PDFInfo
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Abstract
本发明涉及MKK4(丝裂原活化蛋白激酶4)及其在促进肝再生或者减少或预防肝细胞死亡中的用途。MKK4抑制剂相对于蛋白激酶JNK和MKK7选择性地抑制蛋白激酶MKK4。
Description
技术领域
本发明涉及蛋白激酶抑制剂,其抑制丝裂原活化蛋白激酶4(MKK4),特别是相对于蛋白激酶JNK1和MKK7选择性抑制MKK4。
背景技术
肝脏疾病可能由感染、损伤、暴露于有毒化合物如酒精或药物、自身免疫过程、遗传缺陷和其他因素引起。肝脏具有显著的再生能力,然而,这种再生能力可能在疾病状态中受损,因此可能不足以补偿肝细胞和器官功能的丧失。
WO 2007/002433描述了作为蛋白激酶抑制剂的化合物,其可用于治疗与蛋白激酶的异常活性相关的疾病和病症。这些化合物是Raf蛋白激酶的抑制剂,特别是B-Raf和 c-Raf及其突变的抑制剂,因此可用于癌症治疗。此外,据说它们抑制多种其他蛋白激酶,其中包括c-Jun N-末端激酶(JNK),特别是JNK1。WO 2010/002325具有类似的公开内容,WO2012/109075和WO2014/194127公开了具有Raf蛋白激酶抑制活性的修饰化合物。H.Vin等人将WO2007/002433的两种化合物称为B-Raf抑制剂,其通过非靶标抑制JNK信号传导来抑制细胞凋亡。WO2012/136859公开了一些化合物,其被描述为丝裂原活化蛋白激酶4(MKK4)的抑制剂,并且可用于治疗肝衰竭,用于保护肝细胞免于凋亡并用于肝细胞的再生。Wuestefeld等人(Cell 153:389-401,2013)描述了用于鉴定可用于增加肝细胞再生能力的基因靶标的功能性遗传学方法。具体地,Wuestefeld等人鉴定出蛋白激酶MKK4是肝再生的关键调节因子,并报道MKK4抑制是通过MKK7的补偿性上调以及JNK1依赖性的ATF2和ELK1活化来增加肝细胞再生。基于现有技术的发现,已经得出结论,MKK4和JNK1抑制剂可用于治疗JNK1介导的疾病。然而,在临床治疗中已经认识到用这些化合物治疗肝病失败了。
发明内容
本发明的基本问题是提供有用的MKK4抑制剂,特别是相对于MKK7和JNK1选择性地抑制MKK4的MKK4抑制剂。另一个问题是提供MKK4抑制剂,特别是相对于 MKK7和JNK1选择性地抑制MKK4的MKK4抑制剂,其可用于治疗肝脏疾病,特别是用于促进肝脏再生或者减少或预防肝细胞死亡。
通过提供式(I)的MKK4抑制剂和式(Ia)的化合物解决了该问题。
因此,本发明涉及具有式(I)的MKK4抑制剂及其药学上可接受的盐、前药、生物活性代谢物、溶剂化物和立体异构体,
其中式(1)中的变量具有以下含义:
R1为H或烷基;
R2为H、烷基、-CF3、-CH2-X-(CH2)n-Y或CH2X1;
X为–N(R10)-、-S-、或–O-;
Y为以下:
H,
苯基,其任选地被一个或两个基团取代,所述基团独立地选自烷基、卤素、烷氧基、羟基和SO2烷基,
烷氧基,
呋喃基,
噻吩基,或
吡啶基,和
其中基团-(CH2)n-任选地被OH取代;
n为1、2或3;
X1为NR10SO2-苯基,其中所述苯基基团任选地被独立地选自以下基团的一个或两个基团取代:卤素、-OCF3和烷氧基,或杂环基团,所述杂环基团选自哌啶基、哌嗪基、吗啉基和硫代吗啉基,所述杂环基团能够被烷基、羟烷基、烷氧基烷基、羟基或羧基取代;
A为键或选自以下的连接基团:
-CO-,
-CO-CO-,
-S-,
-SO-,
-SO2-,
-O-,
-C(=N-NHR10)-,
-CH=,-CONR10-,
-NR10CO-,
-NR10-SO2-,
-O2S-NR10-,
-CO-亚烷基-,
-亚烷基-CO-,
-亚烷基-NR10CO-,
-OCNR10-亚烷基-,
任选地被一个或两个独立地选自OH和烷氧基的基团取代的亚烷基,
亚烯基,
亚炔基(alkinylene),
-NR10-,
-亚烷基-NR10-亚烷基-,
-亚烷基-NR10-,
-NR10-亚烷基-,
-亚烷基-NR10SO2-,
-SO2NR10-亚烷基-,
-亚烷基-NR10SO2-亚烷基-,
-亚烷基-CONR10-亚烷基-,
-亚烷基-NR10CO-亚烷基-,
-亚烷基-NR10CONR10-亚烷基-,
-亚烷基-NR10CSNR10-亚烷基-,
-亚烷基-NR10CONR10-,
-NR10CONR10-亚烷基-,
-亚烷基-NR10CSNR10-,
-NR10CSNR10-亚烷基-,
-亚烷基-NR10-亚烷基-NR10-,
-NR10-亚烷基-NR10-亚烷基-,
-CO-亚烷基-O-,
-O-亚烷基-CO-;
Q为芳族或杂芳族5-或6-元单环或者芳族或杂芳族9-或10-元双环基团,其中所述杂芳族基团具有独立地选自O、N和S的1、2或3个杂原子,所述单环或双环基团任选被独立地选自以下基团的一个、二个或三个基团取代:
任选地被一个或两个取代基取代的烷基,所述取代基独立地选自苯基、卤素取代的苯基、卤素、OH、CN、-NR10R10、环烷基和具有独立地选自O、N和S的1、2或 3个杂原子的杂芳族5-或6-元单环基团;
任选地被–NO2取代的烯基;
卤素;
羟基;
-CHO;
-COOR22;
-NO2;
烷氧基;
卤代烷氧基;
环烷氧基;
烷基羰基氧基;
烷基硫(alkylthio);
噻吩基硫(thienylthio);
苯基,其任选地被一个或两个基团取代,所述基团独立地选自烷基、羟基烷基、烷氧基、卤素、烷基硫和NR10R10;
任选地被卤素取代的苯氧基;
任选地被苯氧基取代的-CO-烷基;
任选地被卤素或烷氧基取代的-CO-苯基;
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环5-或 6-元单环基团,所述单环基团任选地被独立地选自烷基、卤代烷基、卤素、硫代烷基和苯基中的一个或两个基团取代;
-NR10R11;
-NR10SO2R12;
-NR10SO2R13;
-NR10SO2NHR10;
-N=S(=O)R10NR10R10;
-O-亚烷基-苯基,其中所述苯基基团任选被选自烷基、卤代烷基、卤素、-SO2烷基、咪唑基,恶二唑基(oxadiazolyl)和CH2-哌嗪基的基团取代;
-O-亚烷基-R14;
-OCH2O-(连接在Q的相邻位置);
-OCF2O-(连接在Q的相邻位置);
-OCH2CH2O-(连接在Q的相邻位置);
-O-亚烷基-R15;
-O-亚烷基-苯基,其中所述苯基任选地被一个、二个或三个取代基取代,所述取代基独立地选自烷基、卤素、卤代烷基和任选地在第二个氮上被烷基取代的–CH2哌嗪基;
吲哚基,在氮原子上任选地被烷基、烯基、炔基、-CH2-O-亚烷基-苯基、-SO2- 苯基、-CONR10R16或-SO2NR10R10取代;
-NR10CONR10R17;
-NR10COR18;
-NR10COOR10;
-CO-NR10R19;
-亚烷基-NR10SO2R20;
-SO2R21;和
-亚烷基-NR10COR23;
R4为 H,
卤素,
CN,
NO2,
烷基,
任选地被一个、二个或三个基团取代的苯基,所述基团独立地选自NR26R26、 -COR24、烷基、烷氧基、卤代烷基、羟烷基、烷基磺酰基、CN、NO2、烯基和羧基取代的烯基,
-亚烷基-NR10SO2-R27,
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环5-或 6-元单环或杂芳族9-或10-元双环基团,所述单环或双环基团任选地被独立地选自以下的一个或两个基团取代:
烷基,
烷氧基,
卤素,
环烷基,
-CHO,
苯基羰基,
苯基羰基,其中所述苯基基团被卤素或羟基取代,
卤代烷基羰基,
NR10R10,
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环 5-或6-元单环基团,所述单环基团又能被烷基取代,
亚烷基氧基苯基(alkylenoxyphenyl),
亚烷基硫代苯基,
苯基烷基,其中所述苯基基团任选被烷基或烷氧基取代,
-亚烷基-COOR10,或
烯基,其任选地被苯基或卤素取代的苯基取代;
R5为
H,
卤素,
烷基,其任选地被一个或两个基团取代,所述基团独立地选自烷氧基、NR10R10、 -COOR10和恶二唑基,
烷氧基,
烯基,
炔基(alkinyl),
苯基或萘基,其中所述苯基或萘基任选地被独立地选自以下基团的一个、两个或三个基团取代:烷基、卤素、卤代烷基、羟基、羟烷基、烷基硫、烷基磺酰基、烷基磺酰基-NR10-、NR10R10、R10R10NSO2-、烷氧基、苄氧基、卤代烷氧基、-OCH2O-(连接到苯基环的相邻位置的亚甲二氧基)、-OCH2CH2O-(连接到苯基环的相邻位置的亚乙二氧基)、NO2、-COOR10、-CONR10R10、CN、烷基羰基-NR10-、烯基和羧基-取代的烯基,
苯基烯基,其中所述苯基任选地被一个、二个或三个基团取代,所述基团独立地选自OH、烷氧基和–CONR10R19;
NR10R28,
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环5-或 6-元单环或杂芳族9-或10-元双环基团,所述单环或双环基团任选地被独立地选自以下基团的一个或两个基团取代:烷基,烷氧基,吗啉基,哌嗪基,恶二唑基和其中苯基任选地被烷基、卤素或烷氧基取代的苯基羰基;
R6为H、烷氧基、NR10R10或-NR10-苯基,其中所述苯基基团任选地被NR10R10、烷氧基、吗啉基、卤素或-SO2吗啉基取代;
R10在每次出现时独立地为H、烷基、任选地被羟基或烷氧基取代的苯基,或者为其中苯基基团任选地被卤素取代的苯基烷基;
R11为H,
烷基,其任选地被一个或两个基团取代,所述基团独立地选自苯基、吡啶基和环烷基,
苯基烷基,其中所述苯基基团任选被卤素、烷氧基或卤代烷基取代,
苯基,其任选地被苄氧基、呋喃基、环烷基烷基、噻吩基、-CO2烷基、-CO2烷基苯基或-CO烷基取代;
R12为烷基,具有独立地选自O、N和S的1、2或3个杂原子的杂烷基,或苯基,其中所述杂烷基任选地被独立地选自以下基团的一个或两个基团取代:烷基、烷氧基、烷氧基羰基、卤代烷氧基、卤素、卤代烷基、CN、NO2、烷基羰基氨基、恶唑基(oxazolyl)、 -OCH2O-(连接到苯基环的相邻位置的亚甲二氧基)和-OCH2CH2O-(连接到苯基环的相邻位置的亚乙二氧基),
R13为具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环5-或 6-元基团,所述基团任选地被独立地选自烷基、吡啶基、烷氧基羰基、恶唑基和被烷基或烷氧基羰基取代的恶唑基中的一个或两个基团取代;
R14为具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环5-或6-元单环或杂芳族9-或10-元双环基团,所述单环或双环基团任选地被独立地选自烷基、卤代烷基、-NR10R10、吗啉基和2-吡咯烷酮中的一个或两个基团取代;
R15为羟基、烷氧基、卤代烷氧基、烷氧基烷氧基、苯基烷氧基、吡喃氧基(pyranyloxy)、NR10R10、吗啉基、环烷基、-CONR10R10、-COOR10、-CH2F、-CHF2、 -CF3、或-CN,
R16为任选地被苯基或吡啶基取代的烷基,
R17为H,
烷基,
卤代烷基,
烷氧基烷基,
环烷基,
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族5-或6-元基团,所述基团任选地被烷基或烷氧基取代,
吗啉代烷基,
环烷基烷基,
N-苄基吡咯烷基,
苯基,其任选地被烷基、烷氧基、卤代烷基、-NR10R10或卤素取代,
苯基烷基,其中所述苯基基团任选地被烷基、卤代烷基或卤素取代,或者
R17和R10一起形成任选地被乙酰氨基取代的环烷基环,
R20为苯基,其任选地被烷基、苯基或者被烷基或羟烷基取代的苯基所取代;
R21为NR10R10、烷基或者任选地被卤素取代的苯基;
R22为H、烷基或苯基;
R23为苯基或者被烷基取代的苯基,其任选地被哌嗪基或烷基取代的哌嗪基取代;
R24为烷基,噻吩基,被烷基取代的噻吩基或NR25R25;
R25在每次出现时独立地为H或烷基,或者两个R25基团与其所连接的氮原子一起形成亚烷基或氧杂亚烷基(oxaalkylene)基团;
R26在每次出现时都独立地为:
H,
烷基,
苯基烷基,
烷基羰基,
烷基磺酰基,或者
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族5-或6-元单环基团,所述基团任选地被烷基或卤素取代,
任选地被以下基团取代的苯基:NR10R10,卤素,烷氧基,具有选自O、N和S 的1、2或3个杂原子的非芳族杂环5-或6-元单环基团,烷基磺酰基和杂烷基磺酰基;
R27为苯基或萘基,其中所述苯基或萘基任选地被独立地选自卤素、烷氧基、卤代烷氧基、烷基和卤代烷基、苯基烷基中的一个或两个基团取代,
噻吩基,其任选地被独立地选自以下基团的一个或两个基团取代:卤素,烷基,卤代烷基和具有独立地选自O、N和S的1、2或3个杂原子的芳族杂环5-或6-元单环基团,或
NR10R10,
R28为苯基,喹啉基,烷基磺酰基,或者被卤素、烷基、NR10R10、吗啉基或吗啉代磺酰基取代的苯基。
附图说明
图1是与相比,本发明化合物存活率的Kaplan-Meier图。
图2是示出根据实施例1和2的化合物在培养的原代小鼠肝细胞中共孵育后BrdU阳性细胞的百分比的图。
具体实施方式
在一个实施方案中,R5为:
H,
卤素,
烷基,其任选地被独立地选自以下基团中的1或2个基团取代:烷氧基、NR10R10、 -COOR10和恶二唑基,
烷氧基,
烯基,
炔基,
苯基,其任选地被独立地选自以下基团中的1、2或3个基团取代:烷基、卤素、卤代烷基、羟烷基、烷基磺酰基、烷基磺酰基-NR10-、NR10R10、烷氧基、苄氧基、卤代烷氧基、NO2、-COOR10、-CONR10R10、CN、烷基羰基-NR10-、烯基和羧基取代的烯基,
NR10R28,
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族或非芳族杂环5-或6-元单环或者杂芳族9-或10-元双环基团,所述单环或双环基团任选地被独立地选自以下基团中的1或2个基团取代:烷基、烷氧基、吗啉基、哌嗪基、恶二唑基和任选地被烷基、卤素和烷氧基取代的苯基羰基。
在另一个实施方案中,R5为:
卤素,
苯基,其任选地被独立地选自以下基团中的1、2或3个基团取代:烷基、卤素、卤代烷基、烷基磺酰基、烷基磺酰基-NR10-、NO2、-COOR10和-CONR10R10,或者
具有独立地选自O、N和S的1、2或3个杂原子的杂芳族5-或6-元单环基团,所述基团任选地被独立地选自以下基团中的1或2个基团取代:烷基、烷氧基、吗啉基、哌嗪基、恶二唑基和其中苯基任选地被烷基、卤素或烷氧基取代的苯基羰基。
在又一个实施方案中,R5为卤素,具有独立地选自O、N和S的1、2或3个杂原子的杂芳族5-或6-元单环基团,或者任选地被独立地选自以下基团中的1或2个基团取代的苯基:卤素、烷基、NR10R10、-OCH2O-、-OCH2CH2O-和烷氧基。
在又一个实施方案中,R5为被独立地选自以下基团中的1、2或3个基团取代的苯基:烷基、卤素、卤代烷基、羟基、羟烷基、烷基硫、NH2、烷氧基、卤代烷氧基、-OCH2O-(连接到苯基环的相邻位置的亚甲二氧基)、-OCH2CH2O-(连接到苯基环的相邻位置的亚乙二氧基)和CN,或者R5为萘基、噻吩基、呋喃基或喹啉基,其任选地被烷基、卤素或烷氧基取代。
在又一个实施方案中,R1、R2、R4和R6彼此独立地为H或烷基,特别是H。
在又一个实施方案中,R10在每次出现时独立地为H、烷基或苯基烷基,其中所述苯基基团任选地被卤素取代,特别地R10在每次出现时独立地为H或烷基。
在又一个实施方案中,A为-CO-、-CO-CO-、-CH(OH)-CH(OH)-或–CH=CH-。
在又一个实施方案中,A为-CO-。
在又一个实施方案中,Q为如上所定义的取代的苯基。
在又一个实施方案中,本发明涉及MKK4抑制剂及其药学上可接受的盐、溶剂化物和光学异构体,其中MKK4抑制剂具有式I,其中R1至R6、R10、A和Q如上文以任何组合定义。
在又一个实施方案中,本发明涉及MKK4抑制剂及其药学上可接受的盐、溶剂化物和光学异构体,其中MKK4抑制剂具有式Ia
其中
R1为H或烷基;
R2为H或烷基;
R4为H或烷基;
R6为H或烷基;
R10为H、烷基或苯基烷基;
R12为H、烷基或苯基烷基;
Rw为-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx为H、卤素或烷基;
Ry为H、卤素或烷基;
R5为被独立地选自以下中的1、2或3个基团取代的苯基:烷基,卤素,卤代烷基,羟基,羟烷基,烷基硫,NH2,烷氧基,卤代烷氧基,-OCH2O-(连接到苯基环的相邻位置的亚甲二氧基),-OCH2CH2O-(连接到苯基环的相邻位置的亚乙二氧基)和CN,或者
R5为萘基、噻吩基、呋喃基或喹啉基,其任选地被烷基、卤素或烷氧基取代。
在式Ia的实施方案中,Rx或Ry之一为烷基或卤素,Rx与Ry中的另一个是H、卤素或烷基,特别是烷基或卤素。卤素优选为F或Cl。特别地,Rx和Ry都是氟,最优选在羰基的邻位。在另一个实施方案中,Rw相对于羰基处于3-位。优选地,Rw为 -NR10SO2R12。
在式Ia的另一个实施方案中,R10是H或烷基。
在式Ia的另一个实施方案中,R12是烷基。
此外,本发明涉及式(Ia)的化合物,其中变量如上所定义。
在一个实施方案中,式(Ia)及其药学上可接受的盐、溶剂化物和光学异构体不包括以下化合物:
在一个实施方案中,式(I)和(Ia)的MKK4抑制剂以及式(Ia)化合物以及它们的药学上可接受的盐、溶剂化物和光学异构体相对于蛋白激酶JNK1和MKK7选择性地抑制蛋白激酶MKK4。
此外,本发明还涉及所述化合物在促进肝再生或者减少或预防肝细胞死亡,同时增加肝细胞增殖中的用途。
在一个实施方案中,本发明涉及MKK4抑制剂及其药学上可接受的盐、溶剂化物和光学异构体,其选自:
丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}酰胺;
丙烷-1-磺酸[3-(5-氯-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基}酰胺;
丙烷-1-磺酸[3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基}酰胺;
丙烷-1-磺酸[3-(1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基}酰胺;和
丙烷-1-磺酸[3-(5-氯-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基}-N-甲基酰胺。
本发明还包括上述化合物的药学上可接受的盐。所述药学上可接受的盐尤其是采用药学上可接受的酸或碱的酸或碱加成盐。合适的药学上可接受的有机酸和无机酸的示例是盐酸,氢溴酸,磷酸,硫酸,氨基磺酸,C1-C4-烷基磺酸例如甲磺酸,脂环族磺酸例如S-(+)-10-樟脑磺酸,芳香磺酸如苯磺酸和甲苯磺酸,具有2至10个碳原子的二羧酸和三羧酸以及羟基羧酸如草酸、丙二酸、马来酸、富马酸、乳酸、酒石酸、柠檬酸、乙醇酸、己二酸和苯甲酸。其他可利用的酸描述于例如Fortschritte der Arzneimittelforschung [Advances indrug research(药物研究进展)],Volume 10,pages 224ff., Verlag, Baseland Stuttgart,1966。合适的药学上可接受的有机碱和无机碱的示例是碱金属氢氧化物如氢氧化钠或氢氧化钾,碱土金属氢氧化物如氢氧化钙或氢氧化镁,氢氧化铵,有机氮碱如二甲胺、三甲胺,乙醇胺,二乙醇胺,三乙醇胺,胆碱,2-氨基-2-羟甲基丙烷 -1,3-二醇,葡甲胺,普鲁卡因等,L-精氨酸,L-赖氨酸,乙二胺或羟乙基吡咯烷。
本发明还包括本发明的化合物和盐的任何互变异构体、晶体和多晶型形式及其混合物。
本发明还包括溶剂化物,例如水合物。
本发明的化合物可含有一个或多个手性中心,并以不同的光学活性形式存在,例如对映异构体和非对映异构体。
如本文所用,术语“前药”是指通过一些生理化学过程在体内转化为母体药物的药剂。前药的一个非限制性示例是作为酯形式的本发明化合物。
前药具有许多有用的特性。例如,前药可能比最终药物更易溶于水,从而有利于药物的静脉内施用。前药还可以比最终药物具有更高水平的口服生物利用度。在施用后,前药经酶促或化学裂解以在血液或组织中递送最终药物。示例性前药包括但不限于:具有羧酸取代基的化合物,其中游离氢被以下基团替代:(C1-C4)烷基,(C1-C12)烷酰基氧- 甲基,(C4-C9)1-(烷酰基氧)乙基,具有5至10个碳原子的1-甲基-1-(烷酰基氧)-乙基,具有3至6个碳原子的烷氧基羰基氧甲基,具有4至7个碳原子的1-(烷氧基羰基-氧)乙基,具有5至8个碳原子的1-甲基-1-(烷氧基羰基氧)-乙基,具有3至9个碳原子的N-(烷氧基羰基)氨基甲基,具有4至10个碳原子的1-(N-(烷氧基羰基)氨基)乙基,3-邻苯二甲酰基(3-phthalidyl),4-巴豆酰基-内酯基(4-crotono-lactonyl),γ-丁内酯-4-基,二-N,N-(C1-C2) 烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基),氨基甲酰基-(C1-C2)烷基,N,N-二(C1-C2)- 烷基氨基甲酰基-(C1-C2)烷基和哌啶基-、吡咯烷基-或吗啉基(C2-C3)烷基。其他示例性前药释放式(I)的醇,其中羟基取代基的游离氢(例如,R基团含有羟基)被以下基团替代: (C1-C6)烷酰基氧-甲基,1-((C1-C6)烷酰基氧)-乙基,1-甲基-1-((C1-C6)烷酰基氧)乙基, (C1-C12)烷氧基-羰基氧-甲基,N-(C1-C6)-烷氧基-羰基氨基甲基,琥珀酰基,(C1-C6)烷酰基,α-氨基(C1-C4)烷酰基,芳基酰基(arylactyl)和α-氨基酰基,或α-氨基酰基-α-氨基酰基,其中所述α-氨基酰基部分独立地是蛋白质中发现的任何天然存在的L-氨基酸, P(O)(OH)2,-P(O)(O(C1-C6)烷基)2或糖基(由碳水化合物的半缩醛的羟基分离产生的自由基)。
表述MKK4抑制剂意指在施用后,MKK4的激酶活性被抑制,IC50<10μmol/l,优选<1μmol/l,特别是<0.5μmol/l。如本文所用,表述“选择性地抑制蛋白激酶MKK4而非蛋白激酶JNK1和MKK7”是指用KINOMEscanTM测量时,MKK7抑制活性与MKK4 抑制活性的比率或JNK1抑制活性与MKK4抑制活性的比率(表示为对照的百分比或 Kd)≥10。
本文所用的表述“促进肝再生或者减少或预防肝细胞死亡”是指增殖性肝细胞的相对数量与治疗开始时增殖细胞的数量相比增加至少30%,优选至少50%。特别地,该表述意味着与治疗开始时增殖细胞的数量相比增加≥100%。在这种情况下,实验测定和定量将使用标准方法进行,例如,蛋白质Ki67的定量,其与细胞增殖严格相关。对于组织载玻片中增殖的肝细胞的定量,可以使用几种免疫组织化学标准方法,这些方法使用一级抗-Ki67抗体,然后通过使用例如辣根过氧化物酶缀合的二级抗体进行抗Ki67结合的可视化。通过发色底物的酶促转化而可视的过氧化物酶活性的量与Ki67蛋白的量和增殖细胞的数量相关。
在下述实验中,使用来自Abcam的一级多克隆兔抗Ki67抗体(产品编号ab15580,Abcam,Cambridge,USA)和含有来自Invitrogen的二级山羊多克隆抗体(产品编号 16101,Invitrogen/ThermoFisher)的荧光团四甲基罗丹明,通过Ki67染色定量肝细胞增殖。基于从一些临床前小鼠模型获得的数据,发现在慢性CCl4(四氯化碳)介导的肝损伤小鼠模型中shRNA(小发夹RNA)介导的MKK4的抑制使肝细胞增殖从13%增加至 27%(与对照shRNA相比),并且与肝损伤(转氨酶)减少和肝纤维化减少有关。根据前面章节的定义,增殖细胞的相对增加为108%。在酒精诱导的脂肪性肝炎(ASH)模型中, shRNA介导的MKK4沉默导致肝细胞增殖率为4%,与之比较的是使用对照shRNA时为2%(相对增加:100%)。如通过转氨酶测量的,肝细胞增殖的复制与脂肪变性(脂肪沉积)减少和肝损伤减少有关。同样,在部分肝切除术的模型(手术切除肝脏的三分之二后48小时)中,shRNA介导的MKK4沉默使肝细胞增殖从16%(对照shRNA)增加至 33%(相对增加:106%)。同样,增加的肝细胞增殖与改善的肝再生和更快的肝脏肿块 (liver mass)恢复相关。
上述可变量的定义中提到的有机部分-如术语卤素-是各个基团成员的各个列出的集合术语。前缀Cn-Cm在每种情况下表示该基团中可能的碳原子数。
术语卤素在每种情况下表示氟、溴、氯或碘,特别是氟或氯。
烷基是直链或支链烷基,优选C1-C6烷基,即具有1至6个碳原子的烷基,更优选 C1-C4-烷基。烷基的示例是甲基,乙基,正丙基,异丙基,正丁基,2-丁基,异丁基,叔丁基,戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,2,2-二甲基丙基,1-乙基丙基,己基,1,1-二甲基丙基,1,2-二甲基丙基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1,1-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,2,2-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-乙基丁基,2-乙基丁基,1,1,2-三甲基丙基,1,2,2-三甲基丙基, 1-乙基-1-甲基丙基和1-乙基-2-甲基丙基。
烷基的定义同样适用于包括烷基的任何基团。
卤代烷基是如上定义的卤化烷基,其中至少一个例如1、2、3、4个或所有氢原子被1、2、3、4个或相应数目的相同或不同的卤原子替代,如三氟甲基,氯甲基,溴甲基,二氟甲基,氟甲基,二氟乙基等。具体示例包括如所定义的氟化C1-C4烷基,例如三氟甲基、二氟甲基、氟甲基或二氟乙基。
环烷基是脂环族自由基,优选C3-C8-环烷基,即具有3至8个碳原子的环烷基。特别地,3至6个碳原子形成环状结构,例如环丙基、环丁基、环戊基和环己基。环状结构可以是未取代的或可以带有1、2、3或4个C1-C4烷基,优选带有一个或多个甲基自由基。
羰基是>C=O。
氨基羰基是NH2C(O)-。
烯基是单不饱和烃基自由基,优选C2-C6-烯基,即具有2、3、4、5或6个碳原子的烯基,例如乙烯基,烯丙基(2-丙烯-1-基),1-丙烯-1-基,2-丙烯-2-基,甲代烯丙基(2- 甲基丙-2-烯-1-基)等。C3-C5-烯基特别是烯丙基,1-甲基丙-2-烯-1-基,2-丁烯-1-基,3- 丁烯-1-基,甲代烯丙基,2-戊烯-1-基,3-戊烯-1-基,4-戊烯-1-基,1-甲基丁-2-烯-1-基或 2-乙基丙-2-烯-1-基,2-己烯-1-基。
炔基是单不饱和烃基自由基,优选C2-C6-炔基,即具有2、3、4、5或6个碳原子的炔基,例如乙炔基,2-丙炔-1-基,1-丙炔-1-基,2-丙炔-2-基等。C3-C5-炔基特别是2- 丙炔-1-基,2-丁炔-1-基,3-丁炔-1-基,2-戊炔-1-基,3-戊炔-1-基,4-戊炔-1-基。
亚烷基是直链或支链亚烷基,优选C1-C5亚烷基,即具有1至5个碳原子的亚烷基。示例包括亚甲基,亚乙基和1-甲基亚乙基。另一个例子是亚丙基。另一个例子是亚丁基。亚烷基的定义同样适用于包括亚烷基的任何基团。
杂亚烷基(heteroalkylene)是具有1、2或3个杂原子的直链或支链烷基,所述杂原子选自氧,氮和硫。杂亚烷基的示例是烷氧基烷基,烷基氨基烷基,二烷基氨基烷基或烷基硫烷基。任何烷基或亚烷基如上所定义。烷氧基烷基是优选的。
亚烯基是直链或支链亚烯基,其优选为C2-C4亚烯基,即具有2至4个碳原子的亚烯基。示例包括乙烯基和丙烯基。
亚炔基(alkinylene)是直链或支链亚炔基,优选C2-C4亚炔基,即具有2至4个碳原子的亚炔基。示例包括亚丙炔基。
芳基(或芳族基团)是6至12元、特别是6至10元芳族环状自由基,其可以是单环芳环,例如苯基等,或是稠合多环芳环,其包含第一单环芳环和一个或多个饱和、部分不饱和或芳族的碳环,例如萘基、茚基、四氢萘基、茚满基(indanyl)。
杂芳族(或杂芳基)基团是具有选自O、N和S的1、2或3个杂原子的5-或6-元单环或者9-或10-元双环芳族基团。杂芳基或杂芳族基团可以通过碳原子(C-键合)或通过氮杂原子(N-键合)键合到相邻基团。杂环自由基可以通过碳原子(C-键合)或氮原子(N- 键合)键合。优选的杂芳族自由基包含1个氮原子作为环成员原子和任选地1或2个其他杂原子作为环成员,杂原子彼此独立地选自O、S和N。示例是:
C-键合的5-元杂芳环:
2-呋喃基,3-呋喃基,5-呋喃基,2-噻吩基,3-噻吩基,5-噻吩基,吡咯-2-基,吡咯-3-基,吡咯-5-基,吡唑-3-基,吡唑-4-基,吡唑-5-基,异恶唑-3-基,异恶唑-4-基,异恶唑-5-基,异噻唑-3-基,异噻唑-4-基,异噻唑-5-基,咪唑-2-基,咪唑-4-基,咪唑-5-基,恶唑-2-基,恶唑-4-基,恶唑-5-基,噻唑-2-基,噻唑-4-基,噻唑-5-基,1,2,3-恶二唑-咪唑-4-基,4-基,1,2,3-恶二唑-5-基,1,2,4-恶二唑-3-基,1,2,4-恶二唑-5-基,1,3,4-恶二唑 -2-基,1,2,3-噻二唑-4-基,1,2,3-噻二唑-5-基,1,2,4-噻二唑-3-基,1,2,4-噻二唑-5-基,1,3,4- 噻二唑-2-基,1,2,3-三唑-4-基,1,2,4-三唑-3-基,四唑-5-基;
C-键合的6-元杂芳环:
吡啶-2-基,吡啶-3-基(3-吡啶基),吡啶-4-基(4-吡啶基),吡啶-5-基,哒嗪-3-基,哒嗪-4-基,哒嗪-6-基,嘧啶-2-基,嘧啶-4-基,嘧啶-5-基,吡嗪-2-基,吡嗪-5-基,1,3,5- 三嗪-2-基,1,2,4-三嗪-3-基,1,2,4-三嗪-5-基,1,2,4-三嗪-6-基,1,2,4,5-四嗪-3-基;
N-键合的5-元杂芳环:
吡咯-1-基,吡唑-1-基,咪唑-1-基,1,2,3-三唑-1-基,1,2,4-三唑-1-基。
双环杂芳族基团包括所述的5-或6-元杂芳族环之一和另外的稠合的(anellated)、饱和的或不饱和的或芳族的碳环,例如苯、环己烷、环己烯或环己二烯环。示例是喹啉基,异喹啉基,吲哚基,吲嗪基(indolizinyl),异吲哚基,4-、5-、6-或7-氮杂吲哚,吲唑基,苯并呋喃基,苯并噻吩基,苯并[b]噻唑基,苯并恶唑基,苯并噻唑基,苯并咪唑基,咪唑并[b]噻唑,噻吩并[b]吡啶基,咪唑并[a]吡啶基,吡唑并[a]吡啶基和吡咯并[d] 嘧啶基(pyrimide)。包括稠合环烯基环的5-或6-元杂芳族化合物的示例包括二氢吲哚基,二氢吲嗪基(dihydroindolizinyl),二氢异吲哚基,二氢喹啉基,二氢异喹啉基,二氢苯并呋喃基,色烯基(chromenyl),苯并二氢吡喃基(chromanyl),二氢吡咯并[a]咪唑基和四氢苯并噻唑基。
非芳族5-或6-元基团(杂环基团)可以是饱和的或部分不饱和的并且包括选自O、N和S的1、2或3个杂原子。杂环基团可以通过碳原子(C-键合)或氮原子(N-键合)键合。优选的杂环基团包含1个氮原子作为环成员原子和任选地1或2个其他杂原子作为环成员,所述杂原子彼此独立地选自O、S和N。示例是:
C-键合的5元饱和环,例如
四氢呋喃-2-基,四氢呋喃-3-基,四氢噻吩-2-基,四氢噻吩-3-基,四氢吡咯-2-基,四氢吡咯-3-基,四氢吡唑-3-基,四氢-吡唑-4-基,四氢异恶唑-3-基,四氢异恶唑-4-基,四氢异恶唑-5-基,1,2-氧硫杂环戊烷-3-基(1,2-oxathiolan-3-yl),1,2-氧硫杂环戊烷-4-基, 1,2-氧硫杂环戊烷-5-基,四氢异噻唑-3-基,四氢异噻唑-4-基,四氢异噻唑-5-基,1,2-二硫杂环戊烷-3-基,1,2-二硫杂环戊烷-4-基,四氢咪唑-2-基,四氢咪唑-4-基,四氢恶唑-2- 基,四氢恶唑-4-基,四氢恶唑-5-基,四氢噻唑-2-基,四氢噻唑-4-基,四氢噻唑-5-基, 1,3-二氧杂环戊烷-2-基(1,3-dioxolan-2-yl),1,3-二氧杂环戊烷-4-基,1,3-氧硫杂环戊烷-2- 基,1,3-氧硫杂环戊烷-4-基,1,3-氧硫杂环戊烷-5-基,1,3-二硫杂环戊烷-2-基,1,3-二硫杂环戊烷-4-基,1,3,2-二氧硫杂环戊烷-4-基;
C-键合的6-元饱和环,例如
四氢吡喃-2-基,四氢吡喃-3-基,四氢吡喃-4-基,哌啶-2-基,哌啶-3-基,哌啶-4-基,四氢噻喃-2-基,四氢噻喃-3-基,四氢噻喃-4-基,1,3-二恶烷-2-基,1,3-二恶烷-4-基,1,3- 二恶烷-5-基,1,4-二恶烷-2-基,1,3-二噻烷-2-基,1,3-二噻烷-4-基,1,3-二噻烷-5-基,1,4- 二噻烷-2-基,1,3-氧硫杂环己烷-2-基(1,3-oxathian-2-yl),1,3-氧硫杂环己烷-4-基,1,3- 氧硫杂环己烷-5-基,1,3-氧硫杂环己烷-6-基,1,4-氧硫杂环己烷-2-基,1,4-氧硫杂环己烷 -3-基,1,2-二噻烷-3-基,1,2-二噻烷-4-基,六氢嘧啶-2-基,六氢嘧啶-4-基,六氢嘧啶-5- 基,六氢吡嗪-2-基,六氢哒嗪-3-基,六氢哒嗪-4-基,四氢-1,3-恶嗪-2-基,四氢-1,3-恶嗪 -4-基,四氢-1,3-恶嗪-5-基,四氢-1,3-恶嗪-6-基,四氢-1,3-噻嗪-2-基,四氢-1,3-噻嗪-4- 基,四氢-1,3-噻嗪-5-基,四氢-1,3-噻嗪-6-基,四氢-1,4-噻嗪-2-基,四氢-1,4-噻嗪-3-基,四氢-1,4-恶嗪-2-基,四氢-1,4-恶嗪-3-基,四氢-1,2-恶嗪-3-基,四氢-1,2-恶嗪-4-基,四氢 -1,2-恶嗪-5-基,四氢-1,2-恶嗪-6-基;
N键合的5元饱和环,例如
四氢吡咯-1-基(吡咯烷-1-基),四氢吡唑-1-基,四氢异恶唑-2-基,四氢异噻唑-2-基,四氢咪唑-1-基,四氢恶唑-3-基,四氢噻唑-3-基;
N-键合的6-元饱和环,例如
哌啶-1-基,六氢嘧啶-1-基,六氢吡嗪-1-基(哌嗪-1-基),六氢-哒嗪-1-基,四氢-1,3- 恶嗪-3-基,四氢-1,3-噻嗪-3-基,四氢-1,4-噻嗪-4-基,四氢-1,4-恶嗪-4-基(吗啉-1-基),四氢-1,2-恶嗪-2-基;
C-键合的5-元部分不饱和环,例如
2,3-二氢呋喃-2-基,2,3-二氢呋喃-3-基,2,5-二氢呋喃-2-基,2,5-二氢呋喃-3-基,4,5- 二氢呋喃-2-基,4,5-二氢呋喃-3-基,2,3-二氢-噻吩-2-基,2,3-二氢噻吩-3-基,2,5-二氢噻吩-2-基,2,5-二氢噻吩-3-基,4,5-二氢噻吩-2-基,4,5-二氢噻吩-3-基,2,3-二氢-1H-吡咯 -2-基,2,3-二氢-1H-吡咯-3-基,2,5-二氢-1H-吡咯-2-基,2,5-二氢-1H-吡咯-3-基,4,5-二氢-1H-吡咯-2-基,4,5-二氢-1H-吡咯-3-基,3,4-二氢-2H-吡咯-2-基,3,4-二氢-2H-吡咯-3- 基,3,4-二氢-5H-吡咯-2-基,3,4-二氢-5H-吡咯-3-基,4,5-二氢-1H-吡唑-3-基,4,5-二氢-1H- 吡唑-4-基,4,5-二氢-1H-吡唑-5-基,2,5-二氢-1H-吡唑-3-基,2,5-二氢-1H-吡唑-4-基,2,5- 二氢-1H-吡唑-5-基,4,5-二氢异恶唑-3-基,4,5-二氢异恶唑-4-基,4,5-二氢异恶唑-5-基, 2,5-二氢-异恶唑-3-基,2,5-二氢异恶唑-4-基,2,5-二氢异恶唑-5-基,2,3-二氢异恶唑-3- 基,2,3-二氢异恶唑-4-基,2,3-二氢异恶唑-5-基,4,5-二氢异噻唑-3-基,4,5-二氢异噻唑 -4-基,4,5-二氢异噻唑-5-基,2,5-二氢异噻唑-3-基,2,5-二氢异噻唑-4-基,2,5-二氢异噻唑-5-基,2,3-二氢异噻唑-3-基,2,3-二氢异噻唑-4-基,2,3-二氢异噻唑-5-基,4,5-二氢-1H- 咪唑-2-基,4,5-二氢-1H-咪唑-4-基,4,5-二氢-1H-咪唑-5-基,2,5-二氢-1H-咪唑-2-基,2,5- 二氢-1H-咪唑-4-基,2,5-二氢-1H-咪唑-5-基,2,3-二氢-1H-咪唑-2-基,2,3-二氢-1H-咪唑 -4-基,4,5-二氢-恶唑-2-基,4,5-二氢恶唑-4-基,4,5-二氢恶唑-5-基,2,5-二氢恶唑-2-基, 2,5-二氢恶唑-4-基,2,5-二氢恶唑-5-基,2,3-二氢恶唑-2-基,2,3-二氢恶唑-4-基,2,3-二氢恶唑-5-基,4,5-二氢噻唑-2-基,4,5-二氢-噻唑-4-基,4,5-二氢噻唑-5-基,2,5-二氢噻唑 -2-基,2,5-二氢-噻唑-4-基,2,5-二氢噻唑-5-基,2,3-二氢噻唑-2-基,2,3-二氢噻唑-4-基, 2,3-二氢噻唑-5-基,1,3-二氧杂环戊烯(dioxol)-2-基,1,3-二氧杂环戊烯-4-基,1,3-二硫杂环戊烯-2-基,1,3-二硫杂环戊烯-4-基,1,3-氧硫杂环戊烯(oxathiol)-2-基,1,3-氧硫杂环戊烯-4-基,1,3-氧硫杂环戊烯-5-基;
C-键合的6-元部分不饱和环,例如
2H-3,4-二氢吡喃-6-基,2H-3,4-二氢吡喃-5-基,2H-3,4-二氢吡喃-4-基,2H-3,4-二氢吡喃-3-基,2H-3,4-二氢吡喃-2-基,2H-3,4-二氢噻喃-6-基,2H-3,4-二氢噻喃-5-基,2H-3,4- 二氢噻喃-4-基,2H-3,4-二氢噻喃-3-基,2H-3,4-二氢噻喃-2-基,1,2,3,4-四氢吡啶-6-基, 1,2,3,4-四氢吡啶-5-基,1,2,3,4-四氢吡啶-4-基,1,2,3,4-四氢吡啶-3-基,1,2,3,4-四氢吡啶 -2-基,2H-5,6-二氢吡喃-2-基,2H-5,6-二氢吡喃-3-基,2H-5,6-二氢吡喃-4-基,2H-5,6- 二氢吡喃-5-基,2H-5,6-二氢吡喃-6-基,2H-5,6-二氢噻喃-2-基,2H-5,6-二氢噻喃-3-基, 2H-5,6-二氢噻喃-4-基,2H-5,6-二氢噻喃-5-基,2H-5,6-二氢噻喃-6-基,1,2,5,6-四氢吡啶 -2-基,1,2,5,6-四氢吡啶-3-基,1,2,5,6-四氢吡啶-4-基,1,2,5,6-四氢吡啶-5-基,1,2,5,6-四氢吡啶-6-基,2,3,4,5-四氢吡啶-2-基,2,3,4,5-四氢吡啶-3-基,2,3,4,5-四氢吡啶-4-基, 2,3,4,5-四氢吡啶-5-基,2,3,4,5-四氢吡啶-6-基,4H-吡喃-2-基,4H-吡喃-3-基,4H-吡喃-4- 基,4H-噻喃-2–基,4H-噻喃-3-基,4H-噻喃-4-基,1,4-二氢吡啶-2-基,1,4-二氢吡啶-3- 基,1,4-二氢吡啶-4-基,2H-吡喃-2-基,2H-吡喃-3-基,2H-吡喃-4-基,2H-吡喃-5-基, 2H-吡喃-6-基,2H-噻喃-2-基,2H-噻喃-3-基,2H-噻喃-4-基,2H-噻喃-5-基,2H-噻喃-6- 基,1,2-二氢吡啶-2-基,1,2-二氢-吡啶-3-基,1,2-二氢吡啶-4-基,1,2-二氢吡啶-5-基,1,2- 二氢-吡啶-6-基,3,4-二氢吡啶-2-基,3,4-二氢吡啶-3-基,3,4-二氢-吡啶-4-基,3,4-二氢吡啶-5-基,3,4-二氢吡啶-6-基,2,5-二氢吡啶-2-基,2,5-二氢吡啶-3-基,2,5-二氢吡啶-4- 基,2,5-二氢吡啶-5-基,2,5-二氢吡啶-6-基,2,3-二氢吡啶-2–基,2,3-二氢吡啶-3-基,2,3- 二氢吡啶-4-基,2,3-二氢吡啶-5-基,2,3-二氢吡啶-6-基,2H-5,6-二氢-1,2-恶嗪-3-基, 2H-5,6-二氢-1,2-恶嗪-4-基,2H-5,6-二氢-1,2-恶嗪-5-基,2H-5,6-二氢-1,2-恶嗪-6-基, 2H-5,6-二氢-1,2-噻嗪-3-基,2H-5,6-二氢-1,2-噻嗪-4-基,2H-5,6-二氢-1,2-噻嗪-5-基, 2H-5,6-二氢-1,2-噻嗪-6-基,4H-5,6-二氢-1,2-恶嗪-3-基,4H-5,6-二氢-1,2-恶嗪-4-基, 4H-5,6-二氢-1,2-恶嗪-5-基,4H-5,6-二氢-1,2-恶嗪-6-基,4H-5,6-二氢-1,2-噻嗪-3-基, 4H-5,6-二氢-1,2-噻嗪-4-基,4H-5,6-二氢-1,2-噻嗪-5-基,4H-5,6-二氢-1,2-噻嗪-6-基, 2H-3,6-二氢-1,2-恶嗪-3-基,2H-3,6-二氢-1,2-恶嗪-4-基,2H-3,6-二氢-1,2-恶嗪-5-基, 2H-3,6-二氢-1,2-恶嗪-6-基,2H-3,6-二氢-1,2-噻嗪-3-基,2H-3,6-二氢-1,2-噻嗪-4-基, 2H-3,6-二氢-1,2-噻嗪-5-基,2H-3,6-二氢-1,2-噻嗪-6-基,2H-3,4-二氢-1,2-恶嗪-3-基, 2H-3,4-二氢-1,2-恶嗪-4-基,2H-3,4-二氢-1,2-恶嗪-5-基,2H-3,4-二氢-1,2-恶嗪-6-基, 2H-3,4-二氢-1,2-噻嗪-3-基,2H-3,4-二氢-1,2-噻嗪-4-基,2H-3,4-二氢-1,2-噻嗪-5-基, 2H-3,4-二氢-1,2-噻嗪-6-基,2,3,4,5-四氢哒嗪-3-基,2,3,4,5-四氢哒嗪-4-基,2,3,4,5-四氢哒嗪-5-基,2,3,4,5-四氢哒嗪-6-基,3,4,5,6-四氢哒嗪-3-基,3,4,5,6-四氢哒嗪-4-基,1,2,5,6- 四氢哒嗪-3-基,1,2,5,6-四氢哒嗪-4-基,1,2,5,6-四氢哒嗪-5-基,1,2,5,6-四氢哒嗪-6-基,1,2,3,6-四氢-哒嗪-3-基,1,2,3,6-四氢哒嗪-4-基,4H-5,6-二氢-1,3-恶嗪-2-基,4H-5,6-二氢 -1,3-恶嗪-4-基,4H-5,6-二氢-1,3-恶嗪-5-基,4H-5,6-二氢-1,3-恶嗪-6-基,4H-5,6-二氢-1,3- 噻嗪-2-基,4H-5,6-二氢-1,3-噻嗪-4-基,4H-5,6-二氢-1,3-噻嗪-5-基,4H-5,6-二氢-1,3-噻嗪-6-基,3,4,5-6-四氢嘧啶-2-基,3,4,5,6-四氢嘧啶-4-基,3,4,5,6-四氢嘧啶-5-基,3,4,5,6- 四氢嘧啶-6-基,1,2,3,4-四氢吡嗪-2-基,1,2,3,4-四氢吡嗪-5-基,1,2,3,4-四氢-嘧啶-2-基, 1,2,3,4-四氢嘧啶-4-基,1,2,3,4-四氢嘧啶-5-基,1,2,3,4-四氢嘧啶-6-基,2,3-二氢-1,4-噻嗪 -2-基,2,3-二氢-1,4-噻嗪-3-基,2,3-二氢-1,4-噻嗪-5-基,2,3-二氢-1,4-噻嗪-6-基,2H-1,3- 恶嗪-2-基,2H-1,3-恶嗪-4-基,2H-1,3-恶嗪-5-基,2H-1,3-恶嗪-6-基,2H-1,3-噻嗪-2-基, 2H-1,3-噻嗪-4-基,2H-1,3-噻嗪-5-基,2H-1,3-噻嗪-6-基,4H-1,3-恶嗪-2-基,4H-1,3-恶嗪-4-基,4H-1,3-恶嗪-5-基,4H-1,3-恶嗪-6-基,4H-1,3-噻嗪-2-基,4H-1,3-噻嗪-4-基, 4H-1,3-噻嗪-5-基,4H-1,3-噻嗪-6-基,6H-1,3-恶嗪-2-基,6H-1,3-恶嗪-4-基,6H-1,3-恶嗪-5-基,6H-1,3-恶嗪-6-基,6H-1,3-噻嗪-2-基,6H-1,3-恶嗪-4-基,6H-1,3-恶嗪-5-基, 6H-1,3-噻嗪-6-基,2H-1,4-恶嗪-2-基,2H-1,4-恶嗪-3-基,2H-1,4-恶嗪-5-基,2H-1,4-恶嗪-6-基,2H-1,4-噻嗪-2-基,2H-1,4-噻嗪-3-基,2H-1,4-噻嗪-5-基,2H-1,4-噻嗪-6-基, 4H-1,4-恶嗪-2-基,4H-1,4-恶嗪-3-基,4H-1,4-噻嗪-2-基,4H-1,4-噻嗪-3-基,1,4-二氢哒嗪-3-基,1,4-二氢哒嗪-4-基,1,4-二氢哒嗪-5-基,1,4-二氢哒嗪-6-基,1,4-二氢吡嗪-2- 基,1,2-二氢吡嗪-2-基,1,2-二氢吡嗪-3-基,1,2-二氢吡嗪-5-基,1,2-二氢吡嗪-6-基,1,4-二氢嘧啶-2-基,1,4-二氢嘧啶-4-基,1,4-二氢嘧啶-5-基,1,4-二氢嘧啶-6-基,3,4-二氢嘧啶-2-基,3,4-二氢嘧啶-4-基,3,4-二氢嘧啶-5-基或3,4-二氢嘧啶-6-基;
N-键合的5元部分不饱和环,例如
2,3-二氢-1H-吡咯-1-基,2,5-二氢-1H-吡咯-1-基,4,5-二氢-1H-吡唑-1-基,2,5-二氢 -1H-吡唑-1-基,2,3-二氢-1H-吡唑-1-基,2,5-二氢异恶唑-2-基,2,3-二氢异恶唑-2-基,2,5- 二氢异噻唑-2-基,2,3-二氢异恶唑-2-基,4,5-二氢-1H-咪唑-1-基,2,5-二氢-1H-咪唑-1- 基,2,3-二氢-1H-咪唑-1-基,2,3-二氢恶唑-3-基,2,3-二氢噻唑-3-基;
N-键合的6-元部分不饱和环,例如
1,2,3,4-四氢吡啶-1-基,1,2,5,6-四氢吡啶-1-基,1,4-二氢-吡啶-1-基,1,2-二氢吡啶-1- 基,2H-5,6-二氢-1,2-恶嗪-2-基,2H-5,6-二氢-1,2-噻嗪-2-基,2H-3,6-二氢-1,2-恶嗪-2-基, 2H-3,6-二氢-1,2-噻嗪-2-基,2H-3,4-二氢-1,2-恶嗪-2-基,2H-3,4-二氢-1,2-噻嗪-2-基, 2,3,4,5-四氢哒嗪-2-基,1,2,5,6-四氢哒嗪-1-基,1,2,5,6-四氢哒嗪-2-基,1,2,3,6-四氢哒嗪 -1-基,3,4,5,6-四氢嘧啶-3-基,1,2,3,4-四氢吡嗪-1-基,1,2,3,4-四氢嘧啶-1-基,1,2,3,4-四氢嘧啶-3-基,2,3-二氢-1,4-噻嗪-4-基,2H-1,2-恶嗪-2-基,2H-1,2-噻嗪-2-基,4H-1,4-恶嗪-4-基,4H-1,4-噻嗪-4-基,1,4-二氢哒嗪-1-基,1,4-二氢吡嗪-1-基,1,2-二氢-吡嗪-1-基, 1,4-二氢嘧啶-1-基或3,4-二氢嘧啶-3-基。
含有杂原子的任何基团可以含有1、2或3个可以相同或不同的杂原子。
本发明的化合物,其在此处和下文中是指MKK4抑制剂,以及包括其药学上可接受的盐、前药、生物活性代谢物、溶剂化物和立体异构体的本发明的化合物,可以如通过引用而整体并入本文的WO 2007/002433中所公开的那样或根据类似过程制备。通过将游离碱与相应的酸混合或通过将游离酸与所需碱混合,以常规方式制备酸或碱加成盐。任选地,反应在有机溶剂的溶液中进行,所述有机溶剂例如低级醇如甲醇、乙醇或丙醇,醚如甲基叔丁基醚或二异丙基醚,酮如丙酮或甲基乙基酮,或酯如乙酸乙酯。
本发明化合物可用于促进肝再生或者减少或预防肝细胞死亡,同时增加肝细胞增殖。因此,该化合物可用于治疗、调节、改善或预防可能由感染、损伤、暴露于有毒化合物、血液中正常物质的异常积聚、自身免疫过程、遗传缺陷或未知原因导致的涉及对肝脏的急性或慢性损害的疾病。
这些肝脏疾病包括其中增加肝再生和减少或预防肝细胞死亡可能有助于实现潜在的治疗效果,即肝功能的部分或完全恢复的所有疾病。这些疾病包括:
急性和慢性或慢加急性(acute on chronic)肝病,诸如急性和慢性病毒性肝炎,如乙型肝炎、丙型肝炎、戊型肝炎,由艾普斯登-巴尔病毒(Epstein-Barr virus)、巨细胞病毒、单纯疱疹病毒和其他病毒导致的肝炎,所有类型的自身免疫性肝炎、原发性硬化性肝炎(primary sclerosing hepatitis)、酒精性肝炎;
代谢性肝病,诸如代谢综合征,脂肪肝如非酒精性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、威尔森氏症(Morbus Wilson)、血色素沉着症、α1-抗胰蛋白酶缺乏症,糖原贮积病(glycogen storage diseases);
所有类型的肝硬化,如原发性胆汁性肝硬化、乙醇中毒性肝硬化(ethyl toxicliver cirrhosis)、隐源性肝硬化;
急性(暴发性)或慢性肝衰竭,诸如中毒性肝衰竭,如对乙酰氨基酚(扑热息痛)诱导的肝衰竭,α-鹅膏蕈碱诱导的肝衰竭,例如由抗生素、非甾体类抗炎药、抗痉挛药导致的药物诱导性肝毒性、肝衰竭,由草药补充剂(卡瓦、麻黄、黄芩(skullcap)、薄荷等)诱导的急性肝衰竭,由诸如布-加综合征(Budd-Chiari syndrom)的血管疾病引起的肝病和肝衰竭,不明原因的急性肝衰竭,由右心衰竭引起的慢性肝病;
半乳糖血症,囊性纤维化,卟啉症,肝脏缺血灌注损伤,肝移植术后小肝综合征,原发性硬化性胆管炎或肝性脑病。
为了促进肝再生或者减少或预防肝细胞死亡,本发明化合物以治疗有效量施用于有需要的患者。肝脏疾病的存在可以通过血液中存在升高的酶水平来检测。已知丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)的血液水平高于临床上可接受的正常范围,表明进行性(on-going)肝损伤。血液胆红素水平或其他肝酶可以用作检测或诊断标准。常规监测肝病患者的血液ALT和AST水平用于测量治疗期间肝病的进展。将升高的ALT 和AST水平降低至可接受的正常范围内被视为反映患者肝损伤严重程度降低的临床证据。
本发明化合物通常以药物组合物的形式施用,所述药物组合物包含至少一种根据本发明的化合物,任选地连同惰性载体(例如药学上可接受的辅料)以及适当时连同其他药物。这些组合物可以,例如,口服、直肠、透皮、皮下、腹膜内、静脉内、肌肉内或鼻内施用。
合适的药物组合物的示例是固体药物形式,例如粉末、颗粒、片剂,特别是薄膜片剂、锭剂、袋剂(sachet)、扁囊剂、糖衣片剂,胶囊,例如硬明胶胶囊和软明胶胶囊,或栓剂,半固体药物形式,例如软膏、乳膏、水凝胶、糊剂或膏药(plaster),以及液体药物形式,例如溶液、乳液,特别是水包油乳液,悬浮液,例如洗剂、注射制剂和输注制剂。此外,还可以使用脂质体或微球。
当制备该组合物时,任选地将根据本发明的化合物与一种或多种载体(辅料)混合或稀释。所述载体(辅料)可以是固体、半固体或液体材料,其用作活性化合物的(vehicle)、载体或介质。
合适的载体(辅料)列在专业医学专论中。此外,制剂可包含药学上可接受的辅助物质,例如润湿剂;乳化剂和助悬剂;防腐剂;抗氧化剂;抗刺激剂(antiirritant);螯合剂;包衣助剂;乳液稳定剂;成膜剂;凝胶形成剂;气味掩蔽剂;味道矫正剂;树脂;亲水胶体(hydrocolloid);溶剂;增溶剂;中和剂;扩散加速剂;色素;季铵化合物;加脂剂(refattingagent)和超脂剂(overfatting agent);软膏、乳膏或油剂的原料;硅酮衍生物;分散助剂;稳定剂;杀菌剂;栓剂基质;片剂助剂,如粘合剂、填充剂、助流剂、崩解剂或涂料;推进剂;干燥剂;遮光剂;增稠剂;蜡;增塑剂和白色矿物油。这方面的制剂基于专业知识,例如,在Fiedler,H.P.,Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzendeGebiete[Encyclopedia of auxiliary substances for pharmacy, cosmetics andrelated fields(药学、化妆品及相关领域的辅助物质百科全书)],4th edition (第4版),Aulendorf:ECV-Editio-Cantor-Verlag,1996所述。
本发明化合物也适合与其他治疗剂组合。因此,本发明还涉及包含本发明化合物与一种或多种其他治疗剂的组合,特别是用于促进肝再生或者减少或预防肝细胞死亡。本发明的联合疗法可以辅助施用。辅助施用(adjunctive administration)是指以单独的药物组合物或装置形式连续或叠加施用每种组分。这种两种或更多种治疗剂的治疗性施用方案通常被本领域技术人员并在本文中称为辅助治疗性施用;它也被称为附加(add-on) 治疗施用。其中患者接受单独的但连续或叠加的治疗性施用本发明的化合物和至少一种其他治疗剂的任何和所有治疗方案都在本发明的范围内。在如本文所述的辅助治疗性施用的一个实施方案中,通常使患者在一段时间内稳定于一种或多种组分的治疗性施用,然后接受另一种组分的施用。本发明的组合疗法也可以同时施用。同时施用是指这样的治疗方案,即其中各个组分一起施用,或者以包含或含有两种组分的单一药物组合物或装置的形式,或作为单独的组合物或装置,各自包含组分之一,同时施用。用于同时组合的单独的各个组分的这种组合可以以试剂盒的形式提供。
与本发明的化合物组合使用的合适试剂包括例如:
ACC抑制剂如TOFA(5-(十四烷氧基)-2-糠酸),GS 0976和如WO 2016/112305中公开的ACC抑制剂,
血管紧张素II受体拮抗剂,
血管紧张素转换酶(ACE)抑制剂,如依那普利(enalapril),
半胱天冬酶抑制剂,如恩利卡生(emricasan),
组织蛋白酶B抑制剂,例如混合的组织蛋白酶B/丙型肝炎病毒NS3蛋白酶抑制剂,如VBY-376,
CCR2趋化因子拮抗剂,例如混合的CCR2/CCR5趋化因子拮抗剂,如赛尼克韦罗(cenicriviroc),
CCR5趋化因子拮抗剂,
氯通道刺激剂,如cobiprostone,
胆固醇增溶剂,
二酰基甘油O-酰基转移酶1(DGAT1)抑制剂,例如LCQ908,
二肽基肽酶IV(DPPIV)抑制剂,例如利格列汀(linagliptin),
法呢醇X受体(FXR)激动剂,例如INT-747(奥贝胆酸)或GS-9674
(PX-102),
FXR/TGR5双重激动剂,例如INT-767,
半乳糖凝集素-3抑制剂,例如GR-MD-02,
胰高血糖素样肽1(GLP1)激动剂,例如利拉鲁肽(liraglutide)或艾塞那肽(exenatide),
谷胱甘肽前体,
丙型肝炎病毒NS3蛋白酶抑制剂,例如混合的组织蛋白酶B/丙型肝炎病毒NS3蛋白酶抑制剂如VBY-376,
HMG CoA还原酶抑制剂,例如他汀类,如阿托伐他汀,
11β-羟基类固醇脱氢酶(11β-HSD1)抑制剂,例如R05093151,
IL-1β拮抗剂,
IL-6拮抗剂,例如混合的IL-6/IL-1β/TNFα配体抑制剂,如BLX-1002,
IL-10激动剂,例如聚乙二醇-伊洛白介素(peg-ilodecakin),
IL-17拮抗剂,例如KD-025,
回肠钠胆汁酸(ileal sodium bile acid)协同转运蛋白抑制剂,例如SHP-626,
瘦素类似物,例如美曲普汀(metreleptin),
5-脂氧合酶抑制剂,例如混合的5-脂氧合酶/PDE3/PDE4/PLC抑制剂如tipelukast,
LPL基因刺激物,例如阿利泼金(alipogene tiparvovec),
赖氨酰氧化酶同源物2(LOXL2)抑制剂,例如抗LOXL2抗体,如GS-6624,
PDE3抑制剂,例如混合的5-脂氧合酶/PDE3/PDE4/PLC抑制剂,如tipelukast,
PDE4抑制剂,例如ASP-9831或混合的5-脂氧合酶/PDE3/PDE4/PLC抑制剂如tipelukast,
磷脂酶C(PLC)抑制剂,例如混合的5-脂氧合酶/PDE3/PDE4/PLC抑制剂如tipelukast,
PPARα激动剂,例如混合的PPARα/δ激动剂如GFT505,
PPARγ激动剂,例如吡格列酮,
PPARδ激动剂,
Rho相关蛋白激酶2(ROCK2)抑制剂,例如KD-025,
钠葡萄糖转运蛋白(transporter)-2(SGLT2)抑制剂,例如依碳酸瑞格列净(remogliflozin etabonate),
硬脂酰CoA去饱和酶-1抑制剂,例如aramchol或CVT-12805,
甲状腺激素受体β激动剂,例如MGL-3196,
肿瘤坏死因子α(TNFα)配体抑制剂,
转谷氨酰胺酶抑制剂和转谷氨酰胺酶抑制剂前体,例如巯基乙胺,
PTPlb抑制剂,例如A119505,A220435,A321842,CPT633,ISIS-404173,JTT-551,MX-7014,MX-7091,MX-7102,NNC-521246,OTX-001,OTX-002或TTP814,和
ASK1抑制剂例如GS4977。
在一些实施方案中,一种或多种其他治疗剂选自乙酰水杨酸,阿利泼金(alipogene tiparvovec),aramchol,阿托伐他汀,BLX-1002,赛尼克韦罗(cenicriviroc),cobiprostone,考来维仑(colesevelam),emncasan,依那普利,GFT-505,GR-MD-02,氢氯噻嗪,二十碳五烯酸乙酯(乙基二十碳五烯酸),IMM-124E,KD-025,利格列汀(linagliptin),利拉鲁肽,巯基乙胺,MGL-3196,奥贝胆酸(obeticholic acid),奥利索西(olesoxime),聚乙二醇-伊洛白介素,吡格列酮,GS-9674,依碳酸瑞格列净(remogliflozin etabonate),SHP-626,索利霉素(solithromycin),tipelukast,TRX-318,熊去氧胆酸和VBY-376。
在一些实施方案中,所述一种或多种其他治疗剂中的一种选自乙酰水杨酸,阿利泼金,aramchol,阿托伐他汀,BLX-1002和赛尼克韦罗。
本发明还涉及相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4,促进肝再生或者预防肝细胞死亡,治疗急性、慢加急性或慢性肝病,或用于治疗以下的方法:急性和慢性或慢加急性肝病,诸如急性和慢性病毒性肝炎,如乙型肝炎、丙型肝炎、戊型肝炎,由艾普斯登-巴尔病毒、巨细胞病毒、单纯疱疹病毒和其他病毒导致的肝炎,所有类型的自身免疫性肝炎、原发性硬化性肝炎、酒精性肝炎;
代谢性肝病,诸如代谢综合征,脂肪肝如非酒精性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、威尔森氏症、血色素沉着症、α1-抗胰蛋白酶缺乏症,糖原贮积病;
所有类型的肝硬化,如原发性胆汁性肝硬化、乙醇中毒性肝硬化、隐源性肝硬化;
急性(暴发性)或慢性肝衰竭,诸如中毒性肝衰竭,如对乙酰氨基酚(扑热息痛)诱导的肝衰竭,α-鹅膏蕈碱诱导的肝衰竭,例如由抗生素、非甾体类抗炎药、抗惊厥药导致的药物诱导性肝毒性和肝衰竭,由草药补充剂(卡瓦、麻黄、黄芩、薄荷等)诱导的急性肝衰竭,由诸如布-加综合征的血管疾病引起的肝病和肝衰竭,不明原因的急性肝衰竭,由右心衰竭引起的慢性肝病;
半乳糖血症,囊性纤维化,卟啉症,肝脏缺血灌注损伤,肝移植术后小肝综合征,原发性硬化性胆管炎或肝性脑病,
所述方法包括将有效量的如上定义的MKK4抑制剂或者化合物或组合物施用于有需要的受试者。
在一个实施方案中,本发明的化合物以关于要治疗的受试者0.2至15mg/kg或0.5至12mg/kg的剂量施用。该化合物可以一天施用一次或数次。该化合物施用4至12周。
以下实施例说明本发明而不是限制本发明。
实施例
缩写:
ATP 三磷酸腺苷
Boc2O 二叔丁氧基碳酸酯
CDE 1,2-二甲基丙胺
CPME 环戊基甲基醚
DCE 二氯乙烷
DCM 二氯甲烷
DIPEA 二异丙基乙胺
(4-)DMAP (4-)二甲基氨基吡啶
DME 二甲醚
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
DPPA 叠氮磷酸二苯酯
DTT 二硫苏糖醇
EtOAc 乙酸乙酯
HEPES 2-(4-(2-羟乙基)-1-哌嗪基)-乙磺酸
HOBt 羟基苯并三唑
HPLC 高效液相色谱
IPA 异丙醇
LAH 氢化铝锂
LDA 二异丙基氨基锂
mCPBA 间氯过氧苯甲酸
MeCN 乙腈
MeOH 甲醇
NIS N-碘代琥珀酰亚胺
Pd2(dba3) 三(二亚苄基丙酮)二钯(0)
Pd(dppf)Cl2 [1,1'-双(二苯基膦基)二茂铁]钯(II)二氯化物
PE 石油醚
PMBCl 对甲氧基苄基氯
Rt或RT 室温
Sol. 溶液
TEA 三乙醇胺
TfOH 三氟甲磺酸
THF 四氢呋喃
TLC 薄层色谱
Xantphos 4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽 (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)
实施例1:丙烷-1-磺酸[3-(5-氯-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基}酰胺,如WO 2007/002433中公开进行制备:
实施例2:丙烷-1-磺酸{3-[5-(4-氯-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟-苯基}-酰胺,如WO 2007/002433中公开进行制备:
对于本发明化合物的制备,使用一般过程(GP)aa至ae:
一般过程aa:
将乙二酰氯(1.1当量)加入到羧酸(1.0当量)在无水DCM(0.5m)中的悬浮液中。加入几滴DMF,将所得混合物在室温下搅拌直至气体形成完成。向溶液中加入过量的 MeOH,减压蒸发溶剂。将残余物真空干燥,产物无需进一步纯化即使用。
一般过程ab:
将Pd/C(0.1当量)加入到硝基苯(1.0当量)在EtOH(0.2m)中的溶液中。将悬浮液用H2脱气,并在室温下搅拌反应物,完全消耗起始物料。然后,使混合物通过硅藻土垫,并将滤液真空浓缩。产物无需进一步纯化即使用。
一般过程ac:
将苯胺(1.0当量)和Et3N(2.2当量)在无水DCM(0.25m)中的溶液冷却至0℃并逐滴加入相应的磺酰氯。加完后,移去冰浴,将溶液在室温下搅拌约1小时。然后将溶液用水稀释,用EtOAc萃取,并将合并的有机层用Na2SO4干燥。减压下除去溶剂,通过快速色谱(SiO2,nHex/EtOAc 9/1)纯化产物。
将酯/二磺酰胺溶于THF/MeOH(1m,4:1)中,冷却至0℃并用NaOH水溶液(2M, 2-3当量)处理。10分钟后,移去冰浴,将反应物在室温下搅拌直至完全水解。真空除去 THF/MeOH,残余物用HCl水溶液(2m)处理,沉淀产物,将沉淀物过滤、干燥,无需任何进一步纯化即使用。
一般过程ad:
将芳基溴(1当量)、K2CO3(2当量)和硼酸/频哪醇酯(1.2当量)悬浮在DME/H2O(0.15m,4:1)中并用氩气脱气10分钟。向悬浮液中加入Pd(PPh3)4(0.05当量),然后在130℃下照射30分钟(μw)。使所得混合物通过硅藻土垫,减压下除去溶剂。粗混合物经由快速色谱(SiO2,DCM/MeOH(MeOH的含量以0.5%的步长从0%(v/v)增加至 5%(v/v))纯化,得到标题化合物。
一般过程ae:
将羧酸(1.1当量)悬浮在无水DCM(0.5m)中,依次加入乙二酰氯(1.05当量)和几滴DMF。在气体形成停止后,将所得溶液滴加到氮杂吲哚(1当量)和AlCl3(5当量) 在无水DCM(0.5m)中的悬浮液中。将混合物在室温下搅拌0.5至3小时。加入饱和的 NH4Cl水溶液以淬灭反应。水相用EtOAc(3x)萃取,合并的有机层用Na2SO4干燥,减压蒸发溶剂。通过快速色谱法(SiO2,nHex/EtOAc 1:1或DCM/MeOH(MeOH的含量以0.5%的步长从0%(v/v)增大至3%(v/v))纯化产物,得到标题化合物。
2,6-二氟-3-硝基苯甲酸甲酯
过程:按照GP aa获得标题化合物。
产量:2.1g,9.4mmol,96%(白色固体)
TLC:PE/EtOAc 3/1
1H NMR(DMSO-d6,200MHz,ppm):δ8.45(td,J=9.0,5.6Hz,1H),7.52(td,J=9.4,1.8Hz,1H),3.95(s,3H);13C NMR(DMSO-d6,50Hz,ppm):δ162.1(dd,J=263.5,5.7 Hz),159.7,153.6(dd,J=271.1,7.6Hz),134.4(dd,J=7.5,4.1Hz),130.6(dd,J=12.0,1.5Hz),113.4(dd,J=23.8,4.4Hz),112.2(dd,J=20.3,18.0Hz),53.6。
3-氨基2,6-二氟苯甲酸甲酯
过程:按照GP ab获得标题化合物。
产量:1.8g,9.7mmol,98%
TLC:PE/EtOAc 3:1
2,6-二氟-3-(N-(丙基磺酰基)丙基磺酰氨基)苯甲酸甲酯
过程:按照GP ac的第一部分获得标题化合物。
产量:8.86g,22.2mmol,90%
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ7.95(td,J=8.8,5.8Hz,1H),7.40(t,J=8.9 Hz,1H),3.92(s,3H),3.67(td,J=7.3,4.2Hz,4H),1.92–1.70(m,4H),1.01(t,J=7.4Hz, 6H);13C NMR(DMSO-d6,50Hz,ppm):δ161.42(dd,J=143.7,6.7Hz),160.25(t,J=1.3 Hz),156.25(dd,J=145.2,6.7Hz),137.45(d,J=11.1Hz),118.81(dd,J=14.0,4.1Hz),113.20(dd,J=23.1,4.0Hz),111.17(dd,J=19.8,17.9Hz),57.0,53.3,16.4,12.4.TLC-MS: C14H19F2NO6S2([M-H]-)的m/z的计算值:398.4,实测值:398.3。
2,6-二氟-3-(丙基磺酰氨基)苯甲酸
过程:按照GP ac的第二部分获得标题化合物。
产量:1.2g,4.2mmol,55%
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ14.01(s,1H),9.74(s,1H),7.54(dd,J=14.8,8.7Hz,1H),7.20(t,J=9.2Hz,1H),3.15–3.02(m,2H),1.85–1.63(m,2H),0.97(t,J=7.4Hz,3H);13C NMR(DMSO-d6,50Hz,ppm):δ161.8,157.3(dd,J=174.8,6.9Hz), 152.3(dd,J=178.1,6.9Hz),129.8(dd,J=10.2,2.2Hz),122.0(dd,J=13.5,3.8Hz), 112.8(dd,J=21.3,19.3Hz),112.3(dd,J=22.6,4.1Hz),53.8,16.9,12.6.TLC-MS: C10H11F2NO4S([M-H]-)的m/z的计算值:278.0,实测值:278.0。
N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:1.8g,3.9mmol,77%
TLC:PE/EtOAc 50%
1H NMR(DMSO-d6,200MHz,ppm):δ13.14(s,1H),9.78(s,1H),8.59(d,J=1.8Hz,1H),8.51(d,J=2.0Hz,1H),8.28(s,1H),7.59(td,J=9.0,6.4Hz,1H),7.28(t,J=8.8Hz,1H),3.19–3.06(m,2H),1.86–1.62(m,2H),0.96(t,J=7.3Hz,3H).;13C NMR (DMSO-d6,50Hz,ppm):δ180.6,156.6(dd,J=184.1,7.6Hz),151.7(dd,J=187.1,7.7 Hz),147.8,145.3,139.3,131.1,128.9(dd,J=10.1,2.1Hz),122.0(dd,J=13.6,3.8Hz), 119.0,117.8(dd,J=24.3,22.1Hz),114.9,114.3,112.4(dd,J=22.8,3.8Hz),53.5,16.8,12.6.TLC-MS:C17H14BrF2N3O3S([M-H]-)的m/z的计算值:456.0,实测值:456.1。
5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶
过程:将5-溴-1H-吡咯并[2,3-b]吡啶(2g,10.2mmol,1.0当量)、K2CO3(2.8g,20.3mmol,2当量)和(4-氯苯基)硼酸(1.8g,11.2mmol,1.1当量)悬浮在DME/H2O(30ml, 4:1)中并用氩气脱气。加入Pd(PPh3)4(587mg,508μmol,0.05当量),并将反应混合物在回流下加热直至起始物料完全消耗。使所得溶液通过硅藻土垫,用EtOAc稀释并用水洗涤。将合并的有机层用Na2SO4干燥,减压蒸发溶剂。通过快速色谱(SiO2,nHex/EtOAc 6:4)纯化粗产物。
产量:2.23g,9.4mmol,92%(白色固体)。
TLC:PE/EtOAc 1:1
1H NMR(DMSO-d6,200MHz,ppm):δ11.76(s,1H),8.51(d,J=2.1Hz,1H),8.20(d, J=1.9Hz,1H),7.72(d,J=8.5Hz,2H),7.57–7.43(m,3H),6.50(dd,J=3.2,1.7Hz, 1H).;13CNMR(DMSO-d6,50Hz,ppm):δ148.2,141.4,138.0,131.7,128.9,128.6,127.1, 126.9,126.1,119.7,100.2。
实施例3:上述N-(2,4-二氟-3-(5-(4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰
基)苯基)丙烷-1-磺酰胺)
过程:按照GP ad获得标题化合物。
产量:22.7mg,47μmol,36%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.96(s,1H),9.78(s,1H),8.67(d,J=1.7Hz,1H),8.57(s,1H),8.21(s,1H),7.68(d,J=8.5Hz,2H),7.59(dd,J=14.8,8.9Hz,1H),7.28(t,J=8.5Hz,1H),7.08(d,J=8.6Hz,2H),3.82(s,3H),3.19–3.06(m,2H),1.74(dq, J=14.7,7.2Hz,2H),0.96(t,J=7.4Hz,3H);13C NMR(DMSO-d6,101Hz,ppm):δ180.5, 159.0,156.0(dd,J=246.6,6.9Hz),152.4(dd,J=258.5,8.9Hz),148.5,143.7,138.4,131.3,130.4,128.7(d,J=8.7Hz),128.2,126.4,121.9(dd,J=13.1,3.6Hz),118.2(dd,J=25.0,23.0Hz),117.5,115.6,114.6,112.2(dd,J=22.5,3.3Hz),55.2,53.5,16.74,12.5.TLC-MS: C24H21F2N3O4S([M-H]-)的m/z的计算值:484.1,实测值:484.2。
实施例4:N-(3-(5-(4-氰基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:31mg,65μmol,49%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.10(s,1H),9.79(s,1H),8.80(d,J=2.1Hz,1H),8.73(s,1H),8.29(s,1H),8.00(d,J=8.6Hz,2H),7.97(d,J=8.5Hz,2H),7.60(dd,J=14.8,8.9Hz,1H),7.29(t,J=8.5Hz,1H),3.17–3.09(m,2H),1.81–1.68(m,2H),0.97 (t,J=7.4Hz,3H);13C NMR(DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.8,6.7 Hz),152.4(dd,J=249.8,8.7Hz),149.4,144.2,142.8,139.0,132.9,131.4(d,J=9.6Hz), 129.7,128.7(t,J=11.5Hz),128.0,127.6,121.9(dd,J=13.2,2.7Hz),118.8,118.1(dd,J=24.9,22.1Hz),117.5,115.8,112.3(dd,J=22.7,3.6Hz),110.1,53.6,16.8,12.5.TLC-MS:C24H18F2N4O3S([M-H]-)的m/z的计算值:479.1,实测值:479.2。
实施例5:N-(2,4-二氟-3-(5-(噻吩-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:48mg,104μmol,79%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.79(s,1H),8.78(d,J=2.2Hz,1H),8.60(s,1H),8.24(s,1H),7.65–7.53(m,3H),7.29(t,J=8.7Hz,1H),7.20(dd,J=5.0,3.7Hz,1H),3.16–3.08(m,2H),1.80–1.68(m,2H),0.96(t,J=7.4Hz,3H).;13C NMR (DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.4,7.1Hz),152.3(dd,J=249.6,8.4 Hz),148.7,142.7,140.7,138.7,128.8(d,J=10.2Hz),128.7,126.0,125.5,124.1,121.9(dd,J=13.8,4.0Hz),117.5,115.5,112.3(dd,J=22.6,3.0Hz),53.5,16.8,12.5.TLC-MS:C21H17F2N3O3S2([M-H]-)的m/z的计算值:461.1,实测值:461.2。
实施例6:N-(2,4-二氟-3-(5-(喹啉-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:42mg,84μmol,64%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.10(s,1H),9.80(s,1H),9.34(d,J=2.2Hz,1H),8.93(d,J=2.2Hz,1H),8.86(s,1H),8.79(d,J=1.9Hz,1H),8.31(s,1H),8.11(dd,J=13.0,8.1Hz,2H),7.84–7.77(m,1H),7.68(t,J=7.5Hz,1H),7.60(td,J=9.0,6.0Hz,1H),7.30(t,J=8.7Hz,1H),3.17–3.09(m,2H),1.81–1.68(m,2H),0.96(t,J=7.4Hz, 3H);13C NMR(DMSO-d6,101Hz,ppm):δ180.7,156.1(dd,J=247.4,6.2Hz),152.4(dd, J=249.7,8.4Hz),149.6,149.2,146.8,144.4,139.1,133.5,131.1,129.7,128.8(d,J=9.7Hz),128.7,128.5,128.4,127.7,127.1,122.0(dd,J=13.8,3.8Hz),118.2(dd,J=25.6,20.8 Hz),117.6,115.8,112.4(dd,J=22.8,3.4Hz),53.5,16.8,12.6.TLC-MS:C26H20F2N4O3S ([M-H]-)的m/z的计算值:505.1,实测值:505.1。
实施例7:N-(2,4-二氟-3-(5-(4-异丙基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)
苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:39mg,78μmol,60%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.99(s,1H),9.79(s,1H),8.69(d,J=2.1Hz,1H),8.60(s,1H),8.23(s,1H),7.66(d,J=8.1Hz,2H),7.59(td,J=9.0,6.0Hz,1H),7.39(d,J=8.2Hz,2H),7.29(t,J=8.4Hz,1H),3.16–3.08(m,2H),2.95(sept,1H),1.80– 1.68(m,2H),1.25(d,J=6.9Hz,6H),0.96(t,J=7.4Hz,3H);13C NMR(DMSO-d6,101 Hz,ppm):δ180.6,156.0(dd,J=246.7,6.9Hz),152.3(dd,J=250.0,8.0Hz),148.7,147.8, 143.9,138.5,135.6,131.5,128.73(d,J=9.5Hz),127.1,127.0,126.7,121.9(dd,J=13.7,3.3Hz),118.2(dd,J=24.5,22.9Hz),117.5,115.6,112.3(dd,J=22.5,3.1Hz),53.5,33.1, 23.8,16.8,12.6.TLC-MS:C26H25F2N3O3S([M-H]-)的m/z的计算值:496.2,实测值:496.1。
实施例8:N-(2,4-二氟-3-(5-(4-(甲基硫)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰
基)苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:47mg,93μmol,71%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.00(s,1H),9.78(s,1H),8.70(d,J=2.1Hz,1H),8.62(s,1H),8.23(s,1H),7.71(d,J=8.3Hz,2H),7.63–7.56(m,1H),7.40(d,J=8.3Hz,2H),7.29(t,J=8.7Hz,1H),3.16–3.09(m,2H),2.53(s,3H),1.80–1.69(m,2H), 0.96(t,J=7.4Hz,3H);13C NMR(DMSO-d6,101MHz,ppm):δ180.6,156.0(dd,J=246.7, 7.0Hz),152.3(dd,J=249.8,8.8Hz),148.8,143.8,138.6,137.7,134.6,131.4(d,J=9.8 Hz),130.9,128.7(dd,J=10.9,4.2Hz),127.5,126.6,121.92(dd,J=13.4,3.2Hz),118.2 (dd,J=24.5,22.8Hz),117.5,115.7,112.3(dd,J=22.5,3.2Hz),53.5,16.8,14.7,12.6. TLC-MS:C24H21F2N3O3S2([M-H]-)的m/z的计算值:500.1,实测值:500.0。
实施例9:N-(2,4-二氟-3-(5-(2-羟基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:30mg,64μmol,49%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.91(s,1H),9.77(s,1H),9.69(s,1H),8.62(s,1H),8.54(d,J=2.1Hz,1H),8.18(s,1H),7.58(td,J=9.0,5.9Hz,1H),7.36(dd,J=7.5,1.2Hz,1H),7.28(t,J=8.4Hz,1H),7.25–7.20(m,1H),7.00(d,J=7.7Hz,1H),6.94(t,J =7.4Hz,1H),3.15–3.09(m,2H),1.80–1.68(m,2H),0.96(t,J=7.4Hz,3H).;13C NMR (DMSO-d6,101Hz,ppm):δ180.5,156.0(dd,J=246.5,6.9Hz),154.4,152.27(dd, J=249.5,8.8Hz),148.1,145.7,138.1,130.6,129.5,129.5,128.8,128.69–128.44(m),125.3,121.9(dd,J=13.2,3.5Hz),119.6,118.2(t,J=23.8Hz),116.9,116.0,115.6,112.2(dd,J= 23.1,3.9Hz),53.5,16.7,12.5.TLC-MS:C23H19F2N3O4S([M-H]-)的m/z的计算值:470.1,实测值:470.4。
实施例10:N-(3-(5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡
啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:59mg,119μmol,91%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.96(s,1H),9.77(s,1H),8.64(d,J=2.0Hz,1H),8.56(s,1H),8.20(s,1H),7.67–7.50(m,1H),7.33(s,1H),7.28(t,J=8.7Hz,1H),7.20(dd,J=8.1,1.1Hz,1H),7.05(d,J=8.0Hz,1H),6.09(s,2H),3.17–3.08(m,2H),1.82–1.69(m,2H),0.97(t,J=7.4Hz,3H);13C NMR(DMSO-d6,101Hz,ppm):δ180.5, 156.0(dd,J=246.7,7.3Hz),152.3(dd,J=249.7,8.6Hz),148.6,148.1,147.0,143.9,138.4,132.4,131.5,128.6(d,J=11.8Hz),126.8,122.0(dd,J=13.8,3.4Hz),120.8,118.2(dd,J=24.5,22.7Hz),117.4,115.7,112.2(dd,J=22.8,3.4Hz),108.8,107.5,101.2,53.6,16.8, 12.5.TLC-MS:C24H19F2N3O5S([M-H]-)的m/z的计算值:498.1,实测值:498.3。
实施例11:N-(2,4-二氟-3-(5-(4-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:55mg,115μmol,88%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.99(s,1H),9.78(s,1H),8.69(d,J=2.2Hz,1H),8.62(s,1H),8.25(s,1H),7.80(dd,J=8.6,5.4Hz,2H),7.59(td,J=9.0,5.9Hz,1H),7.35(t,J=8.8Hz,2H),7.29(t,J=8.7Hz,1H),3.15–3.10(m,2H),1.80–1.69(m,2H), 0.96(t,J=7.4Hz,3H);13C NMR(DMSO-d6,101Hz,ppm):δ180.6,161.9(d,J=244.6 Hz),156.0(dd,J=246.4,6.9Hz),152.3(dd,J=249.6,8.6Hz),148.8,143.9,138.6,134.6 (d,J=3.0Hz),130.6,129.1(d,J=8.2Hz),128.7(dd,J=10.8,4.2Hz),127.0,121.9(dd,J =13.6,3.6Hz),118.1(dd,J=24.4,22.6Hz),117.4,115.9(d,J=21.4Hz),115.6,112.2(dd,J=22.9,3.2Hz),53.5,16.8,12.5.TLC-MS:C23H18F3N3O3S([M-H]-)的m/z的计算值: 472.1,实测值:472.3。
实施例12:N-(2,4-二氟-3-(5-(4-氟-2-甲基苯基(-1H-吡咯并[2,3-b]吡啶-3-羰
基)苯基)丙烷-1-磺酰胺)
过程:按照GP ad获得标题化合物。
产量:47mg,96μmol,73%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),9.78(s,1H),8.37(d,J=1.6Hz,1H),8.34(s,1H),8.26(s,1H),7.58(td,J=8.9,6.1Hz,1H),7.35(dd,J=8.3,6.2Hz,1H),7.28(t,J=8.7Hz,1H),7.23(dd,J=10.1,2.4Hz,1H),7.14(td,J=8.5,2.5Hz,1H),3.16 –3.09(m,2H),2.26(s,3H),1.80–1.69(m,2H),0.96(t,J=7.4Hz,3H);13C NMR (DMSO-d6,101Hz,ppm):δ180.6,161.6(d,J=244.0Hz),156.0(dd,J=246.4,6.9Hz), 152.3(dd,J=249.5,8.5Hz),148.4,145.4,138.5,138.2(d,J=8.1Hz),134.9(d,J=2.9 Hz),132.0(d,J=8.5Hz),131.2,129.3,128.7(d,J=9.8Hz),121.9(dd,J=13.6,3.5Hz), 118.1(dd,J=24.6,22.3Hz),117.0,116.73(d,J=21.1Hz),115.5,112.7(d,J=20.9Hz), 112.2(dd,J=22.7,3.5Hz),53.5,20.2,16.8,12.5.TLC-MS:C24H20F3N3O3S([M-H]-)的m/z 的计算值:486.1,实测值:486.3。
实施例13:N-(3-(5-(2-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:42mg,86μmol,66%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.07(s,1H),9.78(s,1H),8.49(s,1H),8.46 (d,J=2.1Hz,1H),8.28(s,1H),7.66–7.54(m,3H),7.52–7.43(m,2H),7.28(t,J=8.7 Hz,1H),3.16–3.08(m,2H),1.80–1.68(m,2H),0.96(t,J=7.4Hz,3H);13C NMR (DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.6,7.1Hz),152.3(dd,J=249.6,8.5 Hz),148.6,145.4,138.7,137.3,132.0,131.8,129.8,129.8,129.7,129.6,128.7(d,J=8.4 Hz),127.6,121.9(dd,J=13.6,3.6Hz),118.1(dd,J=24.3,22.6Hz),116.8,115.6,112.27 (dd,J=22.7,3.6Hz),53.5,16.8,12.5.TLC-MS:C23H18ClF2N3O3S([M-H]-)的m/z的计算值: 488.1,实测值:488.3。
实施例14:N-(3-(5-(3-氰基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:42mg,87μmol,67%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.06(br.s.,1H),9.79(br.s,1H),8.78(d,J=2.2Hz,1H),8.73(s,1H),8.28(d,J=7.3Hz,2H),8.12(d,J=8.0Hz,1H),7.88(d,J=7.7Hz,1H),7.72(t,J=7.8Hz,1H),7.59(td,J=9.0,6.0Hz,1H),7.29(t,J=8.7Hz,1H),3.17–3.09(m,2H),1.80–1.67(m,2H),0.96(t,J=7.4Hz,3H).13C NMR(DMSO-d6,101 MHz,ppm):δ180.6,156.0(dd,J=246.6,6.9Hz),152.4(dd,J=249.6,8.2Hz),149.2, 144.2,139.4,138.9,132.0,131.1,130.7,130.2,129.5,128.8(d,J=8.7Hz),127.6,121.9(dd, J=13.6,3.4Hz),118.7,118.1(dd,J=24.6,22.6Hz),117.4,115.8,112.3(dd,J=22.7,3.7Hz),112.2,53.6,16.8,12.6.TLC-MS:C24H18F2N4O3S([M-H]-)的m/z的计算值:479.1,实测值:479.4。
实施例15:N-(3-(5-(2,3-二氢苯并[b][1,4]二氧杂环己烯(dioxin)-6-基)-1H-
吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:60mg,117μmol,89%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.97(s,1H),9.79(s,1H),8.64(d,J=2.0Hz,1H),8.55(s,1H),8.21(s,1H),7.65–7.51(m,2H),7.28(t,J=8.5Hz,1H),7.24–7.16(m,2H),6.99(d,J=8.3Hz,1H),4.29(s,4H),3.17–3.07(m,2H),1.74(dq,J=14.9,7.4Hz,2H),0.96(t,J=7.4Hz,3H).13C NMR(DMSO-d6,101MHz,ppm):δ180.6,156.0(dd,J= 246.4,7.1Hz),152.4(dd,J=249.6,8.3Hz),148.6,143.9,143.8,143.3,138.5,131.4,131.2,128.7(d,J=11.8Hz),126.6,122.0(dd,J=13.7,3.4Hz),120.0,118.24(dd,J=24.2,22.1Hz),117.8,117.5,115.7,115.6,112.3(dd,J=23.0,3.6Hz),64.2,64.2,53.6,16.8,12.6.TLC-MS:C25H21F2N3O5S([M-H]-)的m/z的计算值:512.1,实测值:512.4。
实施例16:N-(3-(5-(3,4-二氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟
苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:51mg,104μmol,80%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.79(s,1H),8.72(d,J=2.1Hz,1H),8.65(s,1H),8.26(s,1H),7.89(ddd,J=9.7,7.7,1.5Hz,1H),7.65–7.50(m,3H),7.29(t,J=8.4Hz,1H),3.16–3.09(m,2H),1.74(dq,J=14.9,7.4Hz,2H),0.96(t,J=7.4Hz,3H).TLC-MS:C23H17F4N3O3S([M-H]-)的m/z的计算值:490.1,实测值:490.1。
实施例17:N-(3-(5-(3,4-二氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟
苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:35mg,79μmol,60%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),9.79(s,1H),8.83(d,J=2.1Hz,1H),8.70(s,1H),8.23(d,J=1.2Hz,1H),7.82(d,J=1.1Hz,1H),7.59(td,J=8.9,6.0Hz,1H),7.29(t,J=8.4Hz,1H),7.10(d,J=3.2Hz,1H),6.65(dd,J=3.3,1.8Hz,1H),3.17–3.07(m,2H),1.74(dq,J=14.9,7.4Hz,2H),0.96(t,J=7.4Hz,3H).13CNMR(DMSO-d6,101MHz,ppm):δ180.6,156.0(dd,J=246.6,6.7Hz),152.3(dd,J=249.4,8.1Hz),151.3,148.5,143.2,141.5,138.6,128.8(d,J=9.8Hz),123.5,122.3,121.9(dd,J=13.3,3.8Hz), 118.5–117.8(m),117.3,115.7,112.5–112.2(m),112.2,105.9,53.5,16.8,12.6.TLC-MS: C21H17F2N3O4S([M-H]-)的m/z的计算值:444.1,实测值:444.1。
实施例18:N-(2,4-二氟-3-(5-(萘-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)
丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:50mg,98μmol,75%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.11(s,1H),9.80(s,1H),8.52(s,1H),8.51(s,1H),8.30(s,1H),8.03(t,J=8.5Hz,2H),7.80(d,J=8.1Hz,1H),7.66–7.50(m,5H), 7.28(t,J=8.7Hz,1H),3.15–3.08(m,2H),1.79–1.67(m,2H),0.96(t,J=7.4Hz,3H). 13C NMR(DMSO-d6,101MHz,ppm):δ180.7,156.1(dd,J=246.4,6.8Hz),152.4(dd,J= 249.5,8.5Hz),148.8,145.9,138.8,136.6,133.5,131.3,131.0,130.1,128.8(d,J=8.6Hz),128.5,128.1,127.9,126.8,126.1,125.7,125.0,122.0(dd,J=13.7,3.4Hz),118.6–117.7(m),117.2,115.7,112.35(dd,J=23.1,3.3Hz),53.6,16.8,12.6.TLC-MS:C27H21F2N3O3S([M-H]-)的m/z的计算值:504.1,实测值:504.2。
实施例19:N-(3-(5-(3-氨基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:33mg,69μmol,53%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.97(s,1H),9.79(s,1H),8.62(d,J=1.7Hz,1H),8.59(s,1H),8.21(s,1H),7.59(td,J=8.9,6.1Hz,1H),7.29(t,J=8.6Hz,1H),7.16(t, J=7.8Hz,1H),6.94(s,1H),6.86(d,J=7.5Hz,1H),6.62(dd,J=8.0,1.0Hz,1H),5.26(s, 2H),3.16–3.06(m,2H),1.81–1.66(m,2H),0.96(t,J=7.4Hz,3H).13C NMR(DMSO-d6,101MHz,ppm):δ180.6,156.0(dd,J=246.5,7.2Hz),152.4(dd,J=250.2,8.1Hz),149.3,148.8,143.8,138.7,138.5,132.3,129.7,129.0–128.5(m),126.7,122.0(dd,J=13.6,3.5Hz),118.7–117.8(m),117.5,115.7,114.6,113.3,112.4,112.2(d,J=3.8Hz),53.6,16.8,12.6.TLC-MS:C23H20F2N4O3S([M-H]-)的m/z的计算值:469.1,实测值:469.2。
实施例20:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)乙烷磺酰胺
过程:按照GP ae获得标题化合物。
产量:40mg,85μmol,29%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,200MHz,ppm):δ13.03(s,1H),9.79(s,1H),8.71(d,J=2.0Hz,1H),8.64(s,1H),8.26(s,1H),7.80(d,J=8.5Hz,2H),7.60(m,3H),7.28(t,J=8.5Hz,1H),3.15(q,7.4Hz,2H),1.26(t,J=7.2Hz,3H).TLC-MS:C22H16ClF2N3O3S([M-H]-)的 m/z的计算值:474.1,实测值:474.1。
实施例21:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)甲烷磺酰胺
过程:按照GP ae获得标题化合物。
产量:41mg,89μmol,30%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.76(s,1H),8.71(d,J=2.1Hz,1H),8.66(s,1H),8.27(s,1H),7.80(d,J=8.5Hz,2H),7.63–7.54(m,3H),7.30(t, J=8.6Hz,1H),3.08(s,3H).13C NMR(DMSO-d6,101Hz,ppm):δ180.6,156.1(dd,J= 247.3,6.8Hz),152.6(dd,J=249.8,8.7Hz),149.0,144.0,138.9,137.0,132.5,130.2,129.0,128.9,127.5(dd,J=35.1,2.0Hz),127.1,121.9(dd,J=13.4,3.8Hz),118.2(dd,J=24.9,22.5Hz),117.5,115.7,112.3(dd,J=23.3,4.0Hz).TLC-MS:C21H14ClF2N3O3S([M-H]-)的 m/z的计算值:460.0,实测值:460.0。
实施例22:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)丁烷-1-磺酰胺
步骤1
步骤2
步骤1:3-(丁基磺酰氨基)-2,6-二氟苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,211mg,720μmol,72%(灰白色固体)
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ14.05(s,1H),9.75(s,1H),7.54(td,J=9.1,6.3Hz,1H),7.20(t,J=9.2Hz,1H),3.16–3.04(m,2H),1.80–1.58(m,2H),1.51–1.26 (m,2H),0.86(t,J=7.2Hz,3H).13C NMR(DMSO-d6,50Hz,ppm):δ161.8,157.3(dd,J= 175.0,6.8Hz),152.3(dd,J=178.3,6.9Hz),129.8(dd,J=10.1,2.2Hz),122.0(dd,J= 13.5,3.8Hz),112.8(dd,J=21.3,19.3Hz),112.3(dd,J=22.6,4.1Hz),51.8,25.2,20.8,13.5.TLC-MS:C11H13F2NO4S([M-H]-)的m/z的计算值:292.1,实测值:292.1。
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丁
烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:49mg,97μmol,37%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.78(s,1H),8.71(d,J=2.1Hz,1H),8.64(s,1H),8.26(s,1H),7.79(d,J=8.5Hz,2H),7.64–7.51(m,3H),7.29(t,J=8.6Hz,1H),3.17–3.07(m,2H),1.70(dt,J=15.2,7.6Hz,2H),1.43–1.30(m,2H),0.85(t,J =7.3Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.6,7.1Hz), 152.3(dd,J=249.7,8.5Hz),149.0,143.9,138.8,137.0,132.5,130.2,129.0,128.9,128.7(m),127.0,121.9(dd,J=13.8,3.4Hz),118.51–117.74(m),117.4,115.7,112.3(dd,J=23.1,3.5Hz),51.6,25.0,20.7,13.4).TLC-MS:C24H20ClF2N3O3S([M-H]-)的m/z的计算值:502.1,实测值:502.0。
实施例23:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)-2-甲基丙烷-1-磺酰胺
步骤1
步骤2
步骤1:3-(丁基磺酰胺基)-2,6-二氟苯甲酸
过程:按照GP ac获得题述化合物。
产量:经2步后,192mg,655μmol,66%(灰白色)
TLC;PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ14.10(s,1H),9.76(s,1H),7.54(td,J=9.0,5.9Hz,1H),7.20(td,J=9.1,1.5Hz,1H),3.01(d,J=6.5Hz,2H),2.28–2.04(m,1H), 1.02(d,J=6.7Hz,6H).13C NMR(DMSO-d6,50Hz,ppm):δ161.8,157.3(dd,J=177.4, 6.9Hz),152.2(dd,J=180.7,6.9Hz),129.7(dd,J=10.1,2.1Hz),122.0(dd,J=13.4,3.8 Hz),112.8(dd,J=21.3,19.2Hz),112.3(dd,J=22.6,4.1Hz),59.6,24.4,22.1.TLC-MS:C11H13F2NO4S([M-H]-)的m/z的计算值:292.1,实测值:292.0
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-
2-甲基丙烷-1-磺酰胺
过程:按照GP ae获得题述化合物。
产量:77mg,153μmol,58%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.79(s,1H),8.71(d,J=2.2Hz,1H),8.65(s,1H),8.26(d,J=1.6Hz,1H),7.79(d,J=8.5Hz,1H),7.64–7.53(m,1H), 7.29(t,J=8.6Hz,1H),3.05(d,J=6.4Hz,1H),2.26–2.09(m,1H),1.02(d,J=6.7Hz, 1H).13CNMR(DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.7,6.9Hz),152.2(dd, J=249.5,8.8Hz),149.0,143.9,138.7,137.0,132.5,130.2,129.0,128.9,128.6(d,J=8.8 Hz),127.0,121.9(dd,J=13.5,2.9Hz),118.1(dd,J=24.3,22.0Hz),117.4,115.7,112.3 (dd,J=23.2,3.1Hz),59.4,24.3,22.0.TLC-MS:C24H20ClF2N3O3S([M-H]-)的m/z的计算值:502.1,实测值:501.9。
实施例24:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-5-甲基苯基)
丙烷-1-磺酰胺
步骤1:3-甲基-5-硝基苯甲酸甲酯
过程:按照GP aa获得标题化合物。
产量:535mg,2.7mmol,99%(米黄色固体)
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ8.40–8.36(m,1H),8.30(m,1H),8.17–8.13 (m,1H),3.90(s,3H),2.49(s,3H).13C NMR(DMSO-d6,50Hz,ppm):δ164.6,147.8,141.1, 135.6,130.9127.8,120.8,52.7,20.4。
步骤2:3-氨基-5-甲基苯甲酸甲酯
过程:按照GP ab获得标题化合物。
产量:446mg,2.7mmol,99%(深黄色油)
TLC:PE/EtOAc 25%
步骤3:3-甲基-5-(丙基磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。不同的是,在第一步中将反应混合物加热以回流至少8小时,然后进行常规后处理。
产量:461mg,1.8mmol,65%(灰白色固体)
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ12.99(s,1H),9.93(s,1H),7.62(s,1H),7.48(s,1H),7.25(s,1H),3.14–2.99(m,2H),2.33(s,3H),1.81–1.52(m,2H),0.93(t,J=7.5Hz,3H).13C NMR(DMSO-d6,50Hz,ppm):δ167.02,139.20,138.69,131.80,125.10,123.82,117.14,52.42,21.00,16.86,12.54.TLC-MS:C11H15NO4S([M-H]-)的m/z的计算值:256.1,实测值:256.0。
步骤4:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-5-甲基苯基)丙
烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:61mg,131μmol,50%(白色固体)
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.82(s,1H),9.96(s,1H),8.72(d,J=1.9Hz,1H),8.68(d,J=2.0Hz,1H),8.16(d,J=2.8Hz,1H),7.77(d,J=8.5Hz,2H),7.56(d,J=8.4Hz,2H),7.49(s,1H),7.37(s,1H),7.27(s,1H),3.20–3.04(m,2H),2.39(s,3H),1.71(dq,J=14.9,7.4Hz,2H),0.95(t,J=7.4Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ 189.2,148.7,143.4,140.4,139.2,138.5,137.3,136.5,132.3,129.6,129.0,128.8,127.6,124.2,122.6,118.7,116.7,113.8,52.6,21.1,16.8,12.5.TLC-MS:C24H22ClN3O3S([M-H]-)的m/z的计算值:466.1,实测值:466.0。
实施例25:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-甲基苯基)丙烷-1- 磺酰胺
步骤1:2-甲基-3-硝基苯甲酸甲酯
过程:按照GP aa获得标题化合物。
产量:1.1g,5.5mmol,99%(浅黄色固体)
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ8.03(t,J=8.0Hz,2H),7.56(t,J=7.9Hz, 1H),3.89(s,3H),2.49(s,3H).13C NMR(DMSO-d6,50Hz,ppm):δ166.5,151.5,133.3, 133.1,131.2,127.3,126.7,52.7,15.5。
步骤2:3-氨基-2-甲基苯甲酸甲酯
过程:按照GP ab获得标题化合物。
产量:0.9g,5.3mmol,99%(棕色油)
TLC:PE/EtOAc 25%
步骤3:2-甲基-3-(丙基磺酰氨基)苯甲酸甲酯
过程:将3-氨基-2-甲基苯甲酸甲酯(914mg,5.5mmol,1当量)溶解在DCM(0.25m)中,加入吡啶(980μl,12.2mmol,2.2当量)并用丙烷-1-磺酰氯(1.4ml,12.2mmol, 2.2当量)处理该溶液。将所得溶液回流过夜,然后冷却至室温。加入水以淬灭反应;将混合物用EtOAc萃取,并将合并的有机层用Na2SO4干燥。减压除去溶剂,粗产物通过快速色谱(SiO2,nHex/EtOAc 20%)纯化。
产量:1.4g,5.2mmol,94%(浅黄色油)。
TLC:PE/EtOAc 25%
1H NMR(CDCl3,200MHz,ppm):δ7.66(dd,J=7.9,2.4Hz,2H),7.26(t,J=7.9Hz,1H),6.50(s,1H),3.90(s,3H),3.13–3.00(m,2H),2.51(s,3H),1.97–1.75(m,2H),1.03(t,J=7.4Hz,3H).13C NMR(CDCl3,50Hz,ppm):δ168.2,136.1,132.4,131.5,127.8,126.7,126.4,54.4,52.4,17.4,15.0,13.1.TLC-MS:C12H17NO4S([M-H]-)的m/z的计算值:270.1,实测值:269.9。
步骤4:2-甲基-3-(丙基磺酰氨基)苯甲酸
过程:用2当量的NaOH按照GP ac的第二部分生产该产物。
产量:1.2g,4.5mmol,86%(白色固体)。
TLC:PE/EtOAc 50%
1H NMR(DMSO-d6,200MHz,ppm):δ12.99(s,1H),9.20(s,1H),7.61(d,J=7.4Hz,1H),7.43(d,J=7.9Hz,1H),7.27(t,J=7.7Hz,1H),3.14–3.00(m,2H),2.46(s,3H), 1.87–1.62(m,2H),0.98(t,J=7.4Hz,3H).13C NMR(DMSO-d6,50Hz,ppm):δ169.0, 136.5,134.82(s),133.4,129.6,127.5,126.0,53.8,16.9,15.6,12.7.TLC-MS:C11H15NO4S ([M-H]-)的m/z的计算值:256.1,实测值:225.9。
步骤5:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-甲基苯基)丙
烷-1-磺酰胺
过程:根据GP ae获得标题化合物。
产量:65mg,140μmol,53%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.81(s,1H),9.25(s,1H),8.67(d,J=2.1Hz,1H),8.54(s,1H),7.85(d,J=2.2Hz,1H),7.75(d,J=8.5Hz,2H),7.55(d,J=8.4Hz,2H),7.44(t,J=7.4Hz,1H),7.38–7.24(m,2H),3.15–3.09(m,2H),2.25(s,3H),1.76(dq, J=15.4,7.7Hz,2H),0.99(t,J=7.4Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ191.6, 168.9,148.8,143.4,141.9,137.2,136.4,132.4,131.2,129.7,129.0,128.8,127.2,127.2,126.0,124.9,118.0,115.4,53.8,16.9,15.1,12.6.TLC-MS:C24H22ClN3O3S([M-H]-)的m/z的计算值:466.1,实测值:466.1。
实施例26:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-甲基苯基)
丙烷-1-磺酰胺
步骤1:2-甲基-5-硝基苯甲酸甲酯
过程:按照GP aa获得标题化合物。
产量:1.0g,5.4mmol,97%(白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ8.52(d,J=2.4Hz,1H),8.29(dd,J=8.5, 2.6Hz,1H),7.62(d,J=8.5Hz,1H),3.88(s,3H),2.62(s,3H).13C NMR(DMSO-d6,50Hz, ppm):δ165.5,147.2,145.5,133.2,130.3,126.3,124.7,52.5,21.1。
步骤2:5-氨基-2-甲基苯甲酸甲酯
过程:按照GP ab获得标题化合物。
产量:0.9g,5.3mmol,99%(米黄色油)。
TLC:PE/EtOAc 25%
步骤3:2-甲基-5-(丙基磺酰氨基)苯甲酸甲酯
过程:将5-氨基-2-甲基苯甲酸甲酯(914mg,5.5mmol,1当量)溶解在DCM(0.25 m)中,加入吡啶(980μl,12.2mmol,2.2当量)并用丙烷-1-磺酰氯(1.4ml,12.2mmol, 2.2当量)处理该溶液。将所得溶液回流过夜,然后冷却至室温。加入水以淬灭反应,将混合物用EtOAc萃取,并将合并的有机层用Na2SO4干燥。减压除去溶剂,粗产物通过快速色谱(SiO2,nHex/EtOAc 20%)纯化。
产量:1.4g,5.1mmol,93%(无色油)。
TLC:PE/EtOAc 25%
1H NMR(CDCl3,200MHz,ppm):δ7.74(d,J=2.5Hz,1H),7.35(dd,J=8.2,2.5Hz,1H),7.23(t,J=6.7Hz,1H),7.09(s,1H),3.89(s,3H),3.11–3.00(m,2H),2.55(s,3H),1.96–1.74(m,2H),1.00(t,J=7.4Hz,3H).13C NMR(CDCl3,50Hz,ppm):δ167.5,137.2,134.8,133.1,130.7,124.5,122.9,53.4,52.3,21.2,17.3,13.0.TLC-MS:C12H17NO4S ([M-H]-)的m/z的计算值:270.1,实测值:269.8。
步骤4:2-甲基-5-(丙基磺酰氨基)苯甲酸
过程:用2当量的NaOH按照GP ac的第二部分获得该产物。
产量:1.0g,4.0mmol,79%(白色固体)。
TLC:PE/EtOAc 50%
1H NMR(DMSO-d6,200MHz,ppm):δ12.92(s,1H),9.82(s,1H),7.69(d,J=2.0Hz,1H),7.36–7.12(m,2H),3.09–2.94(m,2H),2.45(s,3H),1.78–1.54(m,2H),0.92(t, J=7.4Hz,3H).13C NMR(DMSO-d6,50Hz,ppm):δ168.2,136.2,134.3,132.5,131.2,122.9,121.3,52.3,20.6,16.8,12.5.TLC-MS:C11H15NO4S([M-H]-)的m/z的计算值:256.1,实测值:225.9。
步骤5:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-甲基苯基)丙
烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:99mg,211μmol,80%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.83(s,1H),9.83(s,1H),8.68(d,J=1.9Hz,1H),8.63(s,1H),7.91(d,J=2.6Hz,1H),7.77(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),7.36–7.24(m,3H),3.11–3.03(m,2H),2.25(s,3H),1.74–1.62(m,2H),0.93(t,J=7.4 Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ191.2,148.8,143.5,140.4,137.2,135.7, 132.4,131.7,130.6,129.8,129.0,128.8,127.4,121.0,119.1,118.1,115.1,52.4,18.46,16.8,12.5.TLC-MS:C24H22ClN3O3S([M-H]-)的m/z的计算值:466.1,实测值:466.1。
实施例27:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙
烷-1-磺酰胺
步骤1:2-氟-3-硝基苯甲酸甲酯
过程:根据GP aa获得标题化合物。
产量:1.1g,5.4mmol,99%(浅黄色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ8.37(ddd,J=8.7,7.0,1.8Hz,1H),8.22(ddd, J=8.2,6.4,1.8Hz,1H),7.55(td,J=8.2,1.2Hz,1H),3.90(s,3H).13C NMR(DMSO-d6, 50Hz,ppm):δ162.6(d,J=3.2Hz),153.7(d,J=274.1Hz),138.3(d,J=8.9Hz),137.1(d, J=1.8Hz),130.4(d,J=2.0Hz),125.0(d,J=5.4Hz),120.7(d,J=9.7Hz),52.9。
步骤2:3-氨基-2-氟苯甲酸甲酯
过程:按照GP ab获得标题化合物。
产量:0.9g,5.3mmol,99%(棕色油)。
TLC:PE/EtOAc 25%
步骤3:2-氟-3-(丙基磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,754mg,2.9mmol,55%(白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ13.39(s,1H),9.78(s,1H),7.72–7.56(m,2H),7.26(t,J=8.0Hz,1H),3.16–3.04(m,2H),1.86–1.62(m,2H),0.96(t,J=7.4Hz,3H). 13CNMR(DMSO-d6,50Hz,ppm):δ164.8(d,J=2.9Hz),154.5(d,J=258.9Hz),130.3 (d,J=1.8Hz),128.3,126.3(d,J=13.4Hz),124.3(d,J=4.9Hz),120.3(d,J=9.6Hz), 53.8,16.9,12.6.TLC-MS:C10H12FNO4S([M-H]-)的m/z的计算值:260.5,实测值:260.5。
步骤4:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-
1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:84mg,178μmol,68%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.88(s,1H),9.79(s,1H),8.69(d,J=2.2Hz,1H),8.66(d,J=2.1Hz,1H),8.05(s,1H),7.77(d,J=8.5Hz,2H),7.60(td,J=7.9,1.5Hz,1H),7.56(d,J=8.5Hz,2H),7.47–7.41(m,1H),7.33(t,J=7.8Hz,1H),3.15(dd,J=8.6,6.7Hz,2H),1.83–1.69(m,2H),0.97(t,J=7.4Hz,3H).13C NMR(DMSO-d6,101Hz, ppm):δ185.5,152.0(d,J=249.8Hz),148.8,143.6,137.8,137.1,132.4,129.9,129.0,128.9,128.8,127.8,127.2,126.1(d,J=2.0Hz),125.8(d,J=13.1Hz),124.6(d,J=4.0Hz),117.9, 114.9,53.8,16.8,12.5.TLC-MS:C23H19ClFN3O3S([M-H]-)的m/z的计算值:470.1,实测值: 470.1。
实施例28:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-氟苯基)丙
烷-1-磺酰胺
步骤1:3-丁酰胺基(butyramido)-2,6-二氟苯甲酸
过程:使用丁酸(1.1当量)、乙二酰氯(1.05当量)和DMF(催化剂)原位合成丁酰氯,按照GP ac得到标题化合物。
产量:经2步后,646mg,2.7mmol,85%(米黄色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ13.87(s,1H),9.75(s,1H),7.87(td,J=8.9,6.1Hz,1H),7.15(td,J=9.2,1.6Hz,1H),2.33(t,J=7.2Hz,2H),1.72–1.49(m,2H), 0.91(t,J=7.4Hz,3H).13C NMR(DMSO-d6,50Hz,ppm):δ172.1,162.4,156.0(dd,J= 203.4,6.6Hz),151.0(dd,J=207.5,6.6Hz),127.7(dd,J=10.2,3.2Hz),123.5(dd,J= 12.4,3.8Hz),112.7(dd,J=21.3,18.9Hz),111.9(dd,J=22.3,3.9Hz),37.9,18.9,13.9。
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丁
酰胺
过程:按照GP ae获得标题化合物。
产量:46mg,100μmol,38%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.01(s,1H),9.80(s,1H),8.71(d,J=1.7Hz,1H),8.65(s,1H),8.21(s,1H),7.99(dd,J=14.8,8.6Hz,1H),7.79(d,J=8.4Hz,2H),7.56(d,J=8.4Hz,2H),7.23(t,J=8.7Hz,1H),2.36(t,J=7.2Hz,2H),1.67–1.55(m,2H), 0.91(t,J=7.3Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ180.9,171.6,154.61(dd,J= 244.8,5.5Hz),150.4(dd,J=249.4,6.5Hz),148.9,143.8,138.6,137.0,132.5,130.2,129.0,128.9,127.1,126.1(dd,J=6.4,2.6Hz),123.2(dd,J=12.4,3.4Hz),117.7(dd,J=19.8,17.6Hz),117.5,115.7,111.5(dd,J=22.1,2.6Hz),37.5,18.5,13.5.TLC-MS:C24H18ClF2N3O2([M-H]-)的m/z的计算值:452.1,实测值:452.1。
实施例29:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-氟苯基)丙
烷-1-磺酰胺
步骤1:2-氟-5-硝基苯甲酸甲酯
过程:按照GP aa获得标题化合物。
产量:1.1g,5.4mmol,99%(浅黄色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ8.63–8.57(m,1H),8.57–8.47(m,1H),7.73 –7.59(m,1H),3.91(s,3H).13C NMR(DMSO-d6,50Hz,ppm):δ164.2(d,J=267.8Hz), 162.2(d,J=4.0Hz),143.7(d,J=3.3Hz),130.3(d,J=11.6Hz),127.4(d,J=3.2Hz), 119.2(d,J=12.5Hz),119.1(d,J=25.0Hz),53.0。
步骤2:5-氨基-2-氟苯甲酸甲酯
过程:按照GP ab获得标题化合物。
产量:0.9g,5.3mmol,99%(棕色油)。
TLC:PE/EtOAc 25%
步骤3:2-氟-5-(丙基磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,777mg,3.4mmol,55%(白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ13.38(s,1H),9.94(s,1H),7.70(dd,J=6.2,2.5Hz,1H),7.49–7.37(m,1H),7.28(t,J=9.5Hz,1H),3.12–2.96(m,2H),1.78–1.54 (m,2H),0.92(t,J=7.3Hz,3H).13C NMR(DMSO-d6,50Hz,ppm):δ164.7(d,J=3.4Hz), 157.7(d,J=253.8Hz),134.5(d,J=3.1Hz),125.9(d,J=9.0Hz),122.6,119.8(d,J=11.6 Hz),118.0(d,J=24.1Hz),52.4,16.8,12.5.TLC-MS:C10H12FNO4S([M-H]-)的m/z的计算值:260.1,实测值:260.1。
步骤4:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-氟苯基)丙烷- 1-磺酰胺过程:按照GP ae获得标题化合物。
产量:88mg,186μmol,71%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.92(d,J=1.5Hz,1H),9.96(s,1H),8.69(s,1H),8.68(s,1H),8.12(s,1H),7.78(d,J=8.5Hz,2H),7.57(d,J=8.4Hz,2H),7.46–7.33(m,3H),3.15–3.07(m,2H),1.76–1.63(m,2H),0.95(t,J=7.4Hz,3H).13C NMR (DMSO-d6,101Hz,ppm):δ185.5,155.3(d,J=245.2Hz),148.8,143.6,137.9,137.1,134.6, 132.4,130.0,129.0,128.8,128.5(d,J=17.4Hz),127.3,123.7(d,J=8.1Hz),121.0(d,J=3.1Hz),118.0,117.3(d,J=23.4Hz),114.8,52.5,16.8,12.5.TLC-MS:C23H19ClFN3O3S ([M-H]-)的m/z的计算值:470.1,实测值:470.0。
实施例30:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)己烷-1-磺酰胺
步骤1:2,6-二氟-3-(己基磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,237mg,738μmol,70%(灰白色固体)。
TLC:PE/EtOAc 25%
TLC-MS:C12H16F2NO2S·([M-CHO2]·-)的m/z的计算值:276.1,实测值:275.9。
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)己
烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:88mg,165μmol,63%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.78(s,1H),8.71(d,J=2.1Hz,1H),8.63(s,1H),8.25(d,J=1.8Hz,1H),7.79(d,J=8.4Hz,2H),7.66–7.50(m,3H), 7.29(t,J=8.7Hz,1H),3.18–3.07(m,2H),1.76–1.63(m,2H),1.40–1.27(m,2H),1.26 –1.15(m,4H),0.79(t,J=6.7Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ180.6,156.0 (dd,J=247.0,6.9Hz),152.3(dd,J=249.9,8.3Hz),149.0,143.9,138.7,137.0,132.5,130.2, 129.1,128.9,128.7(m),127.0,121.9(dd,J=13.8,3.5Hz),118.1(dd,J=36.3,12.7Hz), 117.5,115.7,112.3(dd,J=22.8,3.5Hz),51.9,30.6,27.0,23.0,21.7,13.7.TLC-MS:C26H24ClF2N3O3S([M-H]-)的m/z的计算值:530.1,实测值:530.0。
实施例31:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)-3-甲基丁烷-1-磺酰胺
步骤1:2,6-二氟-3–((3-甲基丁基)磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,171mg,556μmol,53%(灰白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,400MHz,ppm):δ9.76(s,1H),7.54(td,J=8.9,5.9Hz,1H), 7.20(td,J=9.0,0.9Hz,1H),3.12–3.05(m,2H),1.70–1.56(m,3H),0.86(d,J=6.2Hz, 6H).13CNMR(DMSO-d6,101Hz,ppm):δ161.7,156.5(dd,J=250.9,6.1Hz),153.0(dd, J=254.2,7.5Hz),129.7(d,J=10.1Hz),121.9(dd,J=13.4,3.6Hz),113.0–112.5(m), 112.2(dd,J=22.7,3.8Hz),50.4,31.7,26.4,21.9.TLC-MS:C12H15F2NO4S([M-H]-)的m/z 的计算值:306.1,实测值:306.0。
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-
3-甲基丁烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:77mg,149μmol,57%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.79(s,1H),8.71(d,J=1.9Hz,1H),8.64(s,1H),8.26(s,1H),7.79(d,J=8.4Hz,2H),7.67–7.47(m,3H),7.29(t,J=8.6Hz,1H),3.23–3.02(m,2H),1.69–1.51(m,3H),0.83(d,J=5.7Hz,6H).13C NMR (DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.6,6.9Hz),152.3(dd,J=249.2,8.6 Hz),149.0,143.9,138.8,137.0,132.5,130.2,129.0,128.9,128.7(d,J=11.9Hz),127.0, 121.9(dd,J=12.9,3.1Hz),118.1(dd,J=24.8,23.0Hz),117.4,115.7,112.3(dd,J=23.0, 3.1Hz),50.2,31.6,26.4,21.9.TLC-MS:C25H22ClF2N3O3S([M-H]-)的m/z的计算值:516.1,实测值:516.0。
实施例32:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)-2-甲氧基乙烷-1-磺酰胺
步骤1:2,6-二氟-3-((2-甲氧基乙基)磺酰氨基)苯甲酸
过程:根据GP ac获得标题化合物。
产量:经2步后,79mg,268μmol,25%(白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,400MHz,ppm):δ9.78(s,1H),7.55(td,J=8.8,6.0Hz,1H), 7.20(t,J=9.0Hz,1H),3.68(t,J=6.0Hz,2H),3.40(t,J=6.0Hz,2H),3.19(s,3H).13C NMR(DMSO-d6,101Hz,ppm):δ161.8,156.4(dd,J=251.0,6.2Hz),152.9(dd,J=254.4,7.5Hz),129.3(dd,J=10.1,1.8Hz),121.9(dd,J=13.3,3.7Hz),112.7(dd,J=21.3,19.4Hz),112.1(dd,J=22.5,3.9Hz),65.7,57.9,52.1.TLC-MS:C10H11F2NO5S([M-H]-)的m/z 的计算值:295.0,实测值:295.0。
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-
2-甲氧基乙烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:59mg,117μmol,67%(白色固体)。
TLC::DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.83(s,1H),8.71(d,J=2.2Hz,1H),8.65(s,1H),8.24(s,1H),7.79(d,J=8.5Hz,2H),7.65–7.52(m,3H),7.28(t,J=8.7Hz,1H),3.70(t,J=6.1Hz,2H),3.45(t,J=6.1Hz,2H),3.20(s,3H).13C NMR (DMSO-d6,101Hz,ppm):δ180.6,155.9(dd,J=246.3,7.1Hz),152.2(dd,J=249.0,7.7 Hz),149.0,144.0,138.7,137.0,132.5,130.2,129.0,128.9,128.3(d,J=8.7Hz),127.0, 121.9(dd,J=13.5,3.5Hz),118.1(dd,J=24.2,22.3Hz),117.5,115.7,112.2(dd,J=22.6, 3.5Hz),65.7,57.9,51.8.TLC-MS:C23H18ClF2N3O4S([M-H]-)的m/z的计算值:504.1,实测值:503.9。
实施例33:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯
基)戊烷-1-磺酰胺
步骤1:2,6-二氟-3-(戊基磺酰胺基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,236mg,768μmol,73%(白色固体)。
TLC:PE/EtOAc 25%
TLC-MS:C12H15F2NO4S([M-H]-)的m/z的计算值:306.1,实测值:306.0。
步骤2:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)戊
烷-1-磺酰胺
过程:按照GP ae获得标题化合物。
产量:73mg,141μmol,54%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.78(s,1H),8.71(d,J=1.8Hz,1H),8.63(s,1H),8.25(s,1H),7.79(d,J=8.4Hz,2H),7.62-7.55(m,3H),7.29(t,J=8.7Hz,1H),3.17–3.09(m,2H),1.71(dt,J=15.1,7.5Hz,2H),1.40–1.20(m,4H),0.81(t,J =7.1Hz,3H).13C NMR(DMSO-d6,101Hz,ppm):δ180.6,156.0(dd,J=246.6,6.8Hz), 152.3(dd,J=249.6,8.4Hz),149.0,143.9,138.7,137.0,132.5,130.2,129.0,128.9,128.9–128.5(m),127.0,121.9(dd,J=13.6,3.4Hz),118.5–117.8(m),117.5,115.7,112.3(dd,J= 22.9,3.5Hz),51.8,29.5,22.7,21.5,13.5.TLC-MS:C25H22ClF2N3O3S([M-H]-)的m/z的计算值:516.1,实测值:516.2。
实施例34:N-(3-(5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡
啶-3-羰基)-2,4-二氟苯基)甲烷磺酰胺
步骤1:2-氟-3-(甲基磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,1.82g,7.8mmol,72%(白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ13.36(s,1H),9.76(s,1H),7.65(ddd,J=15.0,8.2,1.2Hz,2H),7.27(t,J=8.0Hz,1H),3.05(s,3H).13C NMR(DMSO-d6,50Hz,ppm):δ 164.8(d,J=2.8Hz),154.7(d,J=259.4Hz),130.5,128.6,126.3(d,J=13.4Hz),124.4(d, J=4.8Hz),120.4(d,J=9.5Hz),40.5(d,J=1.0Hz).TLC-MS:C8H8FNO4S([M-H]-)的m/z的计算值:232.0,实测值:231.9。
步骤2:N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)甲烷磺酰胺
过程:按照GP ae获得标题化合物。
产量:1.19g,2.9mmol,82%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,200MHz,ppm):δ12.98(s,1H),9.77(s,1H),8.61(d,J=2.1Hz,1H),8.47(d,J=2.1Hz,1H),8.09(s,1H),7.60(dd,J=7.9,6.4Hz,1H),7.51–7.25(m, 2H),3.10(s,3H).13C NMR(DMSO-d6,50Hz,ppm):δ185.5,152.2(d,J=250.5Hz), 147.6,145.0,138.5(d,J=1.5Hz),131.3,128.7(d,J=15.1Hz),128.1,126.4(d,J=2.7 Hz),125.8(d,J=13.4Hz),124.7(d,J=4.3Hz),119.6,114.2,114.0.TLC-MS: C15H11BrFN3O3S([M-H]-)的m/z的计算值:410.0,实测值:409.9。
步骤3:N-(3-(5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡啶-3-
羰基)-2-氟苯基)甲烷磺酰胺
过程:按照GP ad获得标题化合物。
产量:42mg,93μmol,45%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.81(s,1H),9.79(s,1H),8.61(d,J=2.0Hz,1H),8.58(d,J=1.9Hz,1H),8.02(s,1H),7.59(t,J=7.2Hz,1H),7.44(t,J=6.1Hz,1H),7.34(t,J=7.8Hz,1H),7.30(d,J=1.3Hz,1H),7.18(dd,J=8.0,1.5Hz,1H),7.04(d, J=8.0Hz,1H),6.08(s,2H),3.09(s,3H).TLC-MS:C22H16FN3O5S([M-H]-)的m/z的计算值:452.1,实测值:452.1。
实施例35:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)甲
烷磺酰胺
过程:按照GP ad获得标题化合物。
产量:27mg,61μmol,31%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.88(s,1H),9.79(s,1H),8.68(dd,J=7.3,2.2Hz,2H),8.06(d,J=1.6Hz,1H),7.77(d,J=8.6Hz,2H),7.63–7.53(m,3H),7.49– 7.41(m,1H),7.34(t,J=7.8Hz,1H),3.10(s,3H).TLC-MS:C21H15ClFN3O3S([M-H]-)的 m/z的计算值:442.1,实测值:442.0。
实施例36:N-(3-(5-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吡咯并[2,
3-b]吡啶-3-羰基)-2-氟苯基)甲烷磺酰胺
过程:按照GP ad获得标题化合物。
产量:39mg,83μmol,43%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.80(s,1H),9.79(s,1H),8.60(d,J=2.2Hz,1H),8.56(d,J=2.2Hz,1H),8.01(s,1H),7.59(td,J=7.8,1.5Hz,1H),7.46–7.41(m, 1H),7.34(t,J=7.8Hz,1H),7.22–7.13(m,2H),6.98(d,J=8.2Hz,1H),4.29(s,4H), 3.09(s,3H).TLC-MS:C23H18FN3O5S([M-H]-)的m/z的计算值:466.1,实测值:466.1。
实施例37:N-(2-氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)
苯基)甲烷磺酰胺
过程:按照GP ad获得标题化合物。
产量:41mg,93μmol,48%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.87(s,1H),9.78(s,1H),8.36(d,J=2.1Hz,1H),8.34(d,J=2.1Hz,1H),8.06(d,J=1.4Hz,1H),7.59(td,J=7.8,1.6Hz,1H),7.47–7.41(m,1H),7.34(dd,J=8.3,6.1Hz,2H),7.22(dd,J=10.1,2.5Hz,1H),7.13(td,J=8.5,2.6Hz,1H),3.09(s,3H),2.26(s,3H).TLC-MS:C22H17F2N3O3S([M-H]-)的m/z的计算值:440.1,实测值:440.1。
实施例38:N-(3-(5-(2-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)甲
烷磺酰胺
过程:按照GP ad获得标题化合物。
产量:32mg,72μmol,46%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ12.93(s,1H),9.79(s,1H),8.52(d,J=2.0Hz,1H),8.44(d,J=2.1Hz,1H),8.10(s,1H),7.66–7.42(m,6H),7.34(t,J=7.8Hz,1H), 3.09(s,3H).TLC-MS:C21H15ClFN3O3S([M-H]-)m/z的计算值:442.1,实测值:442.1。
实施例39:N-(3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,
4-二氟苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:53mg,102μmol,59%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,300MHz,ppm):δ13.03(d,J=1.7Hz,1H),9.77(s,1H),8.44(s,1H),8.41(d,J=2.0Hz,1H),8.25(d,J=2.1Hz,1H),7.58(td,J=9.0,6.0Hz,1H),7.47(d,J=8.5Hz,1H),7.28(t,J=8.4Hz,1H),7.21(d,J=2.5Hz,1H),7.06(dd,J=8.6,2.5Hz,1H),3.85(s,3H),3.18–3.06(m,2H),1.82–1.66(m,2H),0.96(t,J=7.4Hz,3H). TLC-MS:C24H20ClF2N3O4S([M-H]-)的m/z的计算值:518.1,实测值:518.1。
实施例40:N-(3-(5-(2-氯-4-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二
氟苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:36mg,71μmol,41%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,300MHz,ppm):δ13.07(s,1H),9.77(s,1H),8.47(s,1H),8.43 (d,J=2.1Hz,1H),8.27(s,1H),7.67–7.52(m,3H),7.37(td,J=8.5,2.6Hz,1H),7.28(td, J=8.9,1.3Hz,1H),3.18–2.93(m,2H),1.83–1.64(m,2H),0.96(t,J=7.4Hz,3H). TLC-MS:C23H17ClF3N3O3S([M-H]-)的m/z的计算值:506.1,实测值:505.9。
实施例41:N-(3-(5-(2,4-二氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟
苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:25mg,48μmol,27%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,300MHz,ppm):δ13.08(s,1H),9.77(s,1H),8.48(s,1H),8.45 (d,J=1.9Hz,1H),8.28(s,1H),7.80(d,J=1.2Hz,1H),7.59(m,3H),7.28(t,J=8.4Hz, 1H),3.18–3.04(m,2H),1.81–1.65(m,2H),0.96(t,J=7.4Hz,3H).TLC-MS: C23H17Cl2F2N3O3S([M-H]-)的m/z的计算值:522.0,实测值:521.9。
实施例42:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-甲基苯基)
丙烷-1-磺酰胺
步骤1:2-氯-3-硝基苯甲酸甲酯
过程:按照GP aa获得标题化合物。
产量:1.06g,4.9mmol,定量的(浅黄色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ8.21(dd,J=8.0,1.5Hz,1H),8.06(dd,J=7.8,1.5Hz,1H),7.71(t,J=7.9Hz,1H),3.91(s,3H).13C NMR(DMSO-d6,50Hz,ppm):δ 164.4,149.4,133.7,132.7,128.9,127.6,123.0,53.1。
步骤2:3-氨基-2-氯苯甲酸甲酯
过程:将上述酯(1.06g,4.9mmol,1当量)和HCl溶液(1m,4.9mL,1当量) 溶解在EtOH(0.25m)中并加热回流。将细铁粉(302mg,5.4mmol,1.1当量)分批加入到热溶液中,并将所得混合物回流直至起始物料完全消耗。使粗混合物通过硅藻土垫,用EtOAc稀释,并将有机层用水和盐水洗涤。将合并的有机层用Na2SO4干燥,减压除去溶剂,产物无需进一步纯化即可使用。
产量:1.06g,4.8mmol,98%(棕色油)。
TLC:PE/EtOAc 25%
步骤3:2-氯-3-(丙基磺酰氨基)苯甲酸
过程:按照GP ac获得标题化合物。
产量:经2步后,402mg,1.5mmol,61%(灰白色固体)。
TLC:PE/EtOAc 25%
1H NMR(DMSO-d6,200MHz,ppm):δ13.50(s,1H),9.58(s,1H),7.64–7.52(m,2H),7.40(t,J=7.8Hz,1H),3.20–3.03(m,2H),1.87–1.63(m,2H),0.97(t,J=7.4Hz,3H). 13CNMR(DMSO-d6,50Hz,ppm):δ166.9,135.3,133.7,129.3,127.5,127.2,126.5,54.7, 16.9,12.7.TLC-MS:C10H12ClNO4S([M-H]-)的m/z的计算值:276.0,实测值:275.9。
步骤4:N-(2-氯-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷- 1-磺酰胺过程:按照GP ae获得标题化合物。
产量:59mg,121μmol,46%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,300MHz,ppm):δ12.88(s,1H),9.61(s,1H),8.69(d,J=2.2Hz,1H),8.53(s,1H),7.95(s,1H),7.76(d,J=8.5Hz,2H),7.63(dd,J=8.0,1.6Hz,1H),7.55(d,J=8.5Hz,2H),7.49(t,J=7.8Hz,1H),7.40(dd,J=7.5,1.5Hz,1H),3.16(dd,J=8.7,6.6Hz,2H),1.85–1.68(m,2H),0.97(t,J=7.4Hz,3H).TLC-MS:C23H19Cl2N3O3S ([M-H]-)的m/z的计算值:486.1,实测值:486.1。
实施例43:N-(3-(5-(6-氯苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]
吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
步骤1:6-氯苯并[d][1,3]二氧杂环戊烯-5-醇
过程:向-78℃冷却的N-氯代琥珀酰亚胺(967mg,7.2mmol,1当量)在DCM(0.125m)中的溶液中依次加入ZrCl4(337mg,1.5mmol,0.2当量)和芝麻酚(1.0g,7.2mmol,1 当量)。将反应混合物在室温下搅拌130分钟,并用饱和NaHCO3水溶液淬灭。将粗产物用DCM萃取,将合并的有机层用盐水洗涤并经Na2SO4干燥。然后,在减压下除去溶剂,并通过快速色谱法(SiO2,nHex/EtOAc 10%)纯化产物。
产量:998mg,5.8mmol,80%(白色固体)。
TLC:PE/EtOAc 25%
1H NMR(CDCl3,200MHz,ppm):δ6.77(s,1H),6.57(s,1H),5.92(s,2H),5.22(s,1H).13C NMR(CDCl3,50Hz,ppm):δ147.6,146.5,141.7,110.3,108.4,101.8,98.3. TLC-MS:C7H5ClO3([M-H]-)的m/z的计算值:171.0,实测值:171.0。
步骤2:6-氯苯并[d][1,3]二氧杂环戊烯-5-基三氟甲烷磺酸酯
过程:将6-氯苯并[d][1,3]二氧杂环戊烯-5-醇(960mg,5.6mmol,1当量)在DCM(0.57m)中的溶液冷却至0℃,然后加入iPr2NH(782μl,5.6mmol,1当量)和Tf2O (1.0ml,6.1mmol,1.1当量)。将混合物在室温下搅拌直至观察到起始物料完全消耗。使用NaHCO3水溶液(5%)淬灭反应,分离所得的相,并用DCM萃取水相。将合并的有机层用Na2SO4干燥,并将溶剂真空蒸发。快速色谱(SiO2,nHex/EtOAc 5%)得到纯化的产物。
产量:1.1g,3.7mmol,67%(浅黄色油)。
TLC:PE/EtOAc 10%
1H NMR(CDCl3,200MHz,ppm):δ6.92(s,1H),6.82(s,1H),6.07(s,2H)。
步骤3:2-(6-氯苯并[d][1,3]二氧杂环戊烯-5-基)-4,4,5,5-四甲基-1,3,2-二氧
杂环戊硼烷(dioxaborolane)
过程:将Pd(PPh3)2Cl2(127mg,181μmol,0.05当量)、B2Pin2(1.4g,5.42mmol, 1.5当量)、KOAc(1.1g,10.8mmol,3当量)和6-氯苯并[d][1,3]二氧杂环戊烯-5-基三氟甲烷磺酸酯(1.1g,3.6mmol,1当量)在氩气氛围下置于烘箱干燥的烧瓶中。加入无水1,4-二恶烷(0.5m)并将混合物用氩气脱气。将反应混合物加热至100℃过夜,然后通过硅藻土垫,用EtOAc洗涤。快速色谱(SiO2,nHex/EtOAc 5%)得到纯化的产物。
产量:887mg。3.1mmol。87%(白色固体)。
TLC:PE/EtOAc 10%
1H NMR(CDCl3,200MHz,ppm):δ7.11(s,1H),6.81(s,1H),5.95(s,2H),1.33(s,12H).13C(CDCl3,50Hz,ppm):δ150.5,146.3,133.1,114.9,110.6,101.8,84.1,83.6,24.9。
步骤4:N-(3-(5-(6-氯苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡
啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:58mg,109μmol,50%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,300MHz,ppm):δ13.03(s,1H),9.77(s,1H),8.43(s,1H),8.39 (d,J=2.1Hz,1H),8.25(d,J=1.5Hz,1H),7.59(td,J=9.0,5.9Hz,1H),7.31–7.24(m, 1H),7.24(s,1H),7.14(s,1H),6.15(s,2H),3.18–3.06(m,2H),1.82–1.65(m,2H),0.96(t, J=7.4Hz,3H).TLC-MS:C24H18ClF2N3O5S([M-H]-)的m/z的计算值:532.1,实测值: 532.2。
实施例44:N-(3-(5-(7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吡咯 并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
步骤1:2,3-二氢苯并[b][1,4]二氧杂环己烯-6-醇
过程:将2,3-二氢苯并[b][1,4]二氧杂环己烯-6-甲醛(2g,12.2mmol,1当量)置于研钵中,加入mCPBA(4.5g,18.3mmol,1.5当量),用研杵将固体混合。将得到的糊状物在室温下放置5分钟,然后用NaOH(在H2O中10%)稀释。将溶液用Et2O洗涤,用HCl(2m)调节至pH 7并用DCM萃取。将合并的有机层用Na2SO4干燥后,蒸发溶剂,通过快速色谱法(SiO2,nHex/EtOAc/AcoH 79/20/1)纯化产物。
产量:1.7g,11.2mmol,92%(灰白色固体)。
TLC:PE/EtOAc/AcOH 74/25/1
1H NMR(CDCl3,200MHz,ppm):δ6.72(dd,J=8.6,0.4Hz,1H),6.40(dd,J=2.9,0.4Hz,1H),6.33(dd,J=8.6,2.9Hz,1H),4.32–4.14(m,4H),4.00(s,1H).13C NMR (CDCl3,50Hz,ppm):δ150.1,144.0,137.7,117.7,108.5,104.4,64.7,64.2。
步骤2:7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-醇
过程:向-78℃冷却的N-氯代琥珀酰亚胺(1.9g,14.0mmol,1.05当量)在DCM(0.125m)中的溶液中依次加入ZrCl4(619mg,2.7mmol,0.2当量)和2,3-二氢苯并[b][1,4]二氧杂环己烯-6-醇(2.0g,13.3mmol,1当量)。将反应混合物在室温下搅拌180分钟,并用饱和NaHCO3水溶液淬灭。将粗产物用DCM萃取,将合并的有机层用盐水洗涤并经Na2SO4干燥。然后,在减压下除去溶剂,并通过快速色谱法(SiO2,nHex/EtOAc 10%) 纯化产物。
产量:1.4g,7.3mmol,55%(浅绿色油)。
TLC:PE/EtOAc 25%
1H NMR(CDCl3,200MHz,ppm):δ6.83(s,1H),6.55(s,1H),5.21(s,1H),4.27–4.14(m,4H).13CNMR(CDCl3,50Hz,ppm):δ145.9,143.4,137.8,116.8,111.5,104.8,64.6, 64.2。
步骤3:7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基三氟甲烷磺酸酯
过程:将7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-醇(1.3mg,7.1mmol,1当量) 在DCM(0.57m)中的溶液冷却至0℃,然后加入iPr2NH(994μl,7.1mmol,1当量) 和Tf2O(1.3ml,7.8mmol,1.1当量)。将混合物在室温下搅拌直至观察到起始物料完全消耗。使用NaHCO3水溶液(5%)淬灭反应,分离所得的相,并用DCM萃取水相。将合并的有机层用Na2SO4干燥,并将溶剂真空蒸发。快速色谱法(SiO2,nHex/EtOAc 5%) 得到纯化的产物。
产量:1.5g,4.6mmol,64%(无色油)。
TLC:PE/EtOAc 10%
1H NMR(CDCl3,200MHz,ppm):δ7.00(s,1H),6.89(s,1H),4.27(s,4H)。
步骤4:2-(7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-4,4,5,5-四甲基-
1,3,2-二氧杂环戊硼烷
过程:在氩气气氛下将Pd(PPh3)2Cl2(156mg,223μmol,0.05当量)、B2Pin2(1.7g,6.7mmol,1.5当量)、KOAc(1.3g,13.4mmol,3当量)和7-氯-2,3-二氢苯并[b][1,4]二氧杂环 己烯-6-基三氟甲烷磺酸酯(1.4g,4.5mmol,1当量)置于用烘箱干燥的烧瓶中。加入无水1,4-二恶烷(0.5m)并将混合物用氩气脱气。将反应混合物加热至100℃过夜,然后通过硅藻土垫,用EtOAc洗涤。快速色谱法(SiO2,nHex/EtOAc 5%)得到纯化的产物。
产量:1.2mg,4.2mmol,94%(白色固体)。
TLC:PE/EtOAc 10%
1H NMR(CDCl3,200MHz,ppm):δ7.21(s,1H),6.86(s,1H),4.22(s,4H),1.33(s,12H)。13C NMR(CDCl3,50Hz,ppm):δ146.2,142.0,131.8,125.2,118.3,84.0,64.7,64.2,24.9。
步骤5:N-(3-(5-(7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吡咯并
[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
过程:按照GP ad获得标题化合物。
产量:36mg,71μmol,41%(白色固体)。
TLC:DCM/MeOH 5%
1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),9.77(s,1H),8.43(s,1H),8.39 (d,J=2.2Hz,1H),8.24(s,1H),7.58(td,J=9.0,5.9Hz,1H),7.27(td,J=9.0,1.3Hz,1H),7.14(s,1H),7.05(s,1H),4.31(s,4H),3.16–3.07(m,2H),1.80–1.67(m,2H),0.96(t, J=7.4Hz,3H).TLC-MS:C25H20ClF2N3O5S([M-H]-)的m/z的计算值:546.1,实测值: 546.6。
根据上述一般过程,制备表2和表3中给出的化合物:
表2:
表3:
使用常规方法根据下面给出的反应顺序制备以下化合物:
实施例104:N-(3-(2-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-1,3-二氧杂
环戊烷-2-基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
实施例105:N-(3-((5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲基)-2,4-二
氟苯基)丙烷-1-磺酰胺的合成
实施例106:N-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)-2,6-二氟-3-)丙基
磺酰氨基)苯甲酰胺的合成
中间体E(用于实施例106)和F(用于实施例107)的合成
实施例107:5-(4-氯苯基)-N-(2,6-二氟-3-(丙基磺酰氨基)苯基)-1H-吡咯并[2,
3-b]吡啶-3-甲酰胺的合成
实施例108至110
中间体C的合成:
实施例111:N-(4-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)噻唑-2-基)丙烷-1-磺酰胺的合成
中间体G的合成
实施例112:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1- 磺酰亚胺(sulfonimidamide)的合成
实施例113:生物活性
实施例113-1:结合测定
使用DiscoveRx Corporation,42501Albrae St.Fremont,CA 94538,USA的KINOMEscanTM Profiling Service测量本发明化合物的激酶活性,其基于定量测量一种化合物与固定化的、活性位点定向配体竞争的能力的竞争结合测定。该测定通过组合三种组分进行:DNA标记的激酶;固定化配体;和测试化合物。通过DNA标签的定量PCR 测量测试化合物与固定化配体竞争的能力。该技术在Fabian,M.A.et al.A small molecule-kinaseinteraction map for clinical kinase inhibitors(临床激酶抑制剂的小分子激酶相互作用图谱).Nat.Biotechnol.,23,329-336(2005)和Karaman,M.W.et al.A quantitativeanalysis of kinase inhibitor selectivity(激酶抑制剂选择性的定量分析).Nat.Biotechnol.,26,127-132(2008)中有详细描述。
为了研究对MKK4、MKK7和JNK1的亲和力,在HEK-293细胞中产生激酶,随后用DNA标记用于qPCR检测。在室温下用生物素化的小分子配体处理链霉亲和素包被的磁珠30分钟,以产生用于激酶测定的亲和树脂。配体珠用过量的生物素封闭并用封闭缓冲液(SEABLOCKTM(Pierce),1%BSA,0.05%20,1mM DTT)洗涤以除去未结合的配体并减少非特异性结合。通过将激酶、配体亲和珠和测试化合物在1x结合缓冲液(20%SEABLOCKTM,0.17xPBS,0.05%20,6mM DTT)中组合来组装结合反应物。所有反应均在聚苯乙烯96孔板中进行,终体积为0.135mL。将测定板在室温下振荡孵育1小时,并用洗涤缓冲液(lx PBS,0.05%20)洗涤亲和珠。然后将珠子重新悬浮在洗脱缓冲液(lx PBS,0.05%20,0.5 11M非生物素化亲和配体)中,并在室温下振荡孵育30分钟。通过qPCR测量洗脱液中的激酶浓度。
在跨越16个月、超过135个的独立实验中,每个实验基于14个对照孔计算每种激酶的平均Z'值和标准偏差。平均Z'=0.71。
测试化合物的效力:
以指定的浓度筛选化合物,结合相互作用的结果报告为[%对照],其中较低的数字表示较强的结合,即较高的效力。
关于被测试的激酶的细节在下表4中给出。
测试化合物以10mM储备溶液提供。在DiscoverX制备在指定的最终浓度的测试溶液。结果在下表5至7中给出。
表4:
表5:MKK4效力
*:根据以下分类规则从[%对照]值(PoC)得出的效力:
表6:相比于JNK1的选择性
N/E*:JNK1的PoC=100
由于JNK1的PoC的值=100,显然对比JNK1,本发明的化合物20至43以高选择性抑制MKK4。
表7:相比于MKK7的MKK4效力和选择性
N/E*:JNK1的PoC=100
表8:相对于BRaf的MKK4效力和选择性
N/E*:JNK1的PoC=100
实施例113-2:功能性酶测定
(a)材料
重组激酶蛋白(市售)
MEKK2,重组,活性:ProQinase产品#0583-0000-1
MKK4,重组,活化:ProQinase产品#0948-0000-1
MKK4,重组,未活化:ProQinase产品#0948-0000-2
底物蛋白质
酪蛋白(Sigma C-4765)
JNK1 K55R/K56R,重组,无活性:ProQinase产品#0524-0000-1
(b)方法
(b-1)MEKK2依赖性MKK4活化
将MKK4(未活化的)与MEKK2(活性)以10:1(w/w)的比例,对应于摩尔比为20:1,在化合物或媒介物和20μM ATP存在下在30℃下孵育30分钟。活化步骤在50mM HEPES pH 7.5、50mM NaCl、3.8mM MgCl2、2.5mM DTT,10%(v/v)甘油中进行。最终的DMSO浓度为1%。按以下顺序移液活化混合物:
·在4%DMSO中的2.5μl化合物
·2.5μl ATP/MgCl2混合物
·5μl预混激酶溶液MKK4:MEKK2 10:1(w/w)
活化混合物中的蛋白质浓度为1μM MKK4和50nM MEKK2。
(b-2)蛋白激酶测定
放射性蛋白激酶测定法用于测量各蛋白激酶的激酶活性。所有激酶测定均在96孔聚丙烯板中进行。停止反应后,将测定混合物转移到96孔MSFC滤板(Millipore)中。通过抽吸使反应混合物通过滤膜,用150mM H3PO4洗涤膜3次,用乙醇洗涤一次,干燥并加入液体闪烁混合物。通过在Microbeta多孔闪烁计数器(Wallac)中计数样品来确定放射性。按以下顺序移液反应物:
a)MEKK2-MKK4活化混合物
·20μl标准测定缓冲液
·10μl MEKK2-MKK4活化混合物
·5μl放射性33P-γ-ATP溶液(通常为106cpm/孔)
·10μl底物溶液
b)单一激酶
·20μl标准测定缓冲液
·在10%DMSO中的5μl化合物
·20μl酶-底物混合物
·10μl底物溶液
该测定含有70mM HEPES-NaOH pH 7.5、3mM MgCl2、3mM MnCl2、3μM Na-原钒酸盐、1.2mM DTT、ATP(可变的量,对应于相应激酶的表观ATP-Km,参见表1), [33P-γ-ATP(每孔约8×1005cpm)、蛋白激酶(可变量,参见表1)和底物(可变量,参见下表)。
表1 :酶、底物和测定条件(量/孔)
将反应混合物在30℃下孵育30分钟。
测试化合物的效力:
*:根据以下分类规则从IC50值(PoC)得出的效力:
实施例113-3:体内研究
动物
从Charles River Laboratories,Research Models and Services,GermanyGmbH (Sulzfeld)购买的C57BL/6N雌性小鼠,6至9周龄,根据德国蒂宾根大学的制度指南饲养。所有动物实验均经德国法定机构批准。
动物实验和生存研究。
进行每组n=3、n=4、n=6只动物的三次实验。在时间点(t=-1h),通过口服管饲法给予小鼠以2%羟甲基纤维素混合的30mg/kg化合物(pH4.0)或仅给予。1小时后 (t=0小时),所有动物腹膜内(i.p.)注射0.8μg/g小鼠体重的以0.9%NaCl稀释的Jo2 抗体(BDPharmingen,San Diego,CA)。
连续监测小鼠并在15分钟内监测存活。24小时后,处死所有存活的动物。
结果:
Kaplan-Meier图说明了在i.p.注射0.8μg/g Jo2抗体后动物的存活率,所述动物接受 30mg/kg的根据实施例2的化合物或仅。施用实施例2的化合物后动物的存活率显著高于仅用的存活率。结果如图1所示。
实施例113-4:细胞表型分析
肝细胞分离和培养
麻醉小鼠,通过肝内腔静脉灌注肝脏,首先用肝脏灌注培养基(Invitrogen,Darmstadt,德国)灌注肝脏15分钟,然后用含有胶原酶400-480mg/L Serva胶原酶NB 4G验证级别(Serva Electrophoresis GmbH,Heidelberg,德国)的Ca2+补充的培养基 WilliamsE Medium(PAN Biotech,Aidenbach Germany)和胶原酶(Serva)灌注肝脏约15分钟。切除肝脏,将50g肝细胞悬浮液离心5分钟。弃去上清液,收集含有实质细胞的沉淀,用不含胶原酶的Williams'E培养基(PAN Biotech)洗涤一次。使用两步Percoll 梯度(24%+50%)进一步离心肝实质细胞悬浮液,从沉淀中收集98%纯的活肝细胞,洗涤一次并在胶原(Roche)涂覆的12孔板上接种,浓度为在补充有5%FCS、谷氨酰胺和抗生素的HCM培养基(Lonza;德国)中2×106个细胞/孔。
将分离的原代肝细胞与化合物补充培养基一起孵育。24小时后更新培养基。将化合物以1μM的浓度加入培养基中,并将DMSO以等体积加入。
过夜即实现用BrdU 10μg/ml标记(5-溴-2'-脱氧尿苷Sigma B9285-250mg)
BrdU抗体(Abcam目录号AB6326)
用学生t检验评估统计学显著性*P<0.05,**P<0.005和***P<0.0005。
使用ImageJ软件10hpf/孔(高功率场)进行计数。
结果:
图2显示了根据实施例1和2的化合物在培养的原代小鼠肝细胞中共孵育后BrdU阳性细胞的百分比。
Claims (12)
1.一种化合物及其药学上可接受的盐,所述化合物选自:
N-(3-(5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)甲烷磺酰胺;
N-(2-氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)甲烷磺酰胺;
N-(3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)苄基磺酰胺;
N-(3-(5-(2-氯-4-羟基-苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)甲烷-1-磺酰胺;
N-(3-(5-(5-氯-苯并[d][1,3]二氧杂环戊烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)甲烷-1-磺酰胺;
N-(2-氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丁烷磺酰胺;
N-(2-氟-3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丁烷磺酰胺;
N-(3-(5-(苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丁烷-1-磺酰胺;
N-(3-(5-(2,3-二氢苯并[d][1,3]二氧杂环己烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丁烷-1-磺酰胺;
N-(3-(5-(5-氯-苯并[d][1,3]二氧杂环戊烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丁烷-1-磺酰胺;
N-(3-(5-(7-氯-2,3-二氢苯并[b][1,4]二氧杂环己烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丁烷-1-磺酰胺;和
N-(3-(5-(2-氯-4-(甲氧基甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺。
2.一种药物组合物,其包含权利要求1所述的化合物或其药学上可接受的盐。
3.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4的药物中的用途。
4.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于促进肝再生或预防肝细胞死亡的药物中的用途。
5.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于治疗急性、慢加急性或慢性肝病的药物中的用途。
6.根据权利要求1所述的化合物或其药学上可接受的盐在制备用于治疗以下疾病的药物中的用途:
急性和慢性或慢加急性肝病。
7.根据权利要求6所述的用途,其中所述急性和慢性或慢加急性肝病为急性和慢性病毒性肝炎,乙型肝炎,丙型肝炎,戊型肝炎,由艾普斯登-巴尔病毒、巨细胞病毒、单纯疱疹病毒导致的肝炎,所有类型的自身免疫性肝炎,原发性硬化性肝炎,酒精性肝炎。
8.根据权利要求6所述的用途,其中所述急性和慢性或慢加急性肝病为代谢性肝病;所有类型的肝硬化;急性或慢性肝衰竭;半乳糖血症,囊性纤维化,卟啉症,肝脏缺血灌注损伤,肝移植术后小肝综合征,原发性硬化性胆管炎或肝性脑病,由右心衰竭引起的慢性肝病。
9.根据权利要求8所述的用途,其中所述代谢性肝病为脂肪肝、非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)、威尔森氏症、血色素沉着症、α1-抗胰蛋白酶缺乏症、糖原贮积病。
10.根据权利要求9所述的用途,其中所述脂肪肝为非酒精性脂肪肝(NAFL)。
11.根据权利要求8所述的用途,其中所述肝硬化为原发性胆汁性肝硬化、乙醇中毒性肝硬化、隐源性肝硬化。
12.根据权利要求8所述的用途,其中所述急性或慢性肝衰竭为对乙酰氨基酚诱导的肝衰竭,α-鹅膏蕈碱诱导的肝衰竭,由抗生素、非甾体类抗炎药、抗惊厥药导致的药物诱导性肝毒性和肝衰竭,由草药补充剂诱导的急性肝衰竭,由布-加综合征血管疾病引起的肝病和肝衰竭,不明原因的急性肝衰竭。
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US20190365723A1 (en) | 2019-12-05 |
JP2020505452A (ja) | 2020-02-20 |
EP3571200A1 (en) | 2019-11-27 |
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CA3049926A1 (en) | 2018-07-26 |
ZA201905078B (en) | 2023-04-26 |
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AU2018209164A1 (en) | 2019-08-15 |
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