CN111788195B - 用于促进肝脏再生或减少或预防肝细胞死亡的蛋白激酶mkk4抑制剂 - Google Patents
用于促进肝脏再生或减少或预防肝细胞死亡的蛋白激酶mkk4抑制剂 Download PDFInfo
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- CN111788195B CN111788195B CN201980011310.4A CN201980011310A CN111788195B CN 111788195 B CN111788195 B CN 111788195B CN 201980011310 A CN201980011310 A CN 201980011310A CN 111788195 B CN111788195 B CN 111788195B
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- pyridine
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- 239000002511 suppository base Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000006068 taste-masking agent Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- WGTODYJZXSJIAG-UHFFFAOYSA-N tetramethylrhodamine chloride Chemical compound [Cl-].C=12C=CC(N(C)C)=CC2=[O+]C2=CC(N(C)C)=CC=C2C=1C1=CC=CC=C1C(O)=O WGTODYJZXSJIAG-UHFFFAOYSA-N 0.000 description 1
- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- ZQOMVWOJNNEKDE-UHFFFAOYSA-N thiane Chemical compound C1CCSCC1.C1CCSCC1 ZQOMVWOJNNEKDE-UHFFFAOYSA-N 0.000 description 1
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 1
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 108091008762 thyroid hormone receptors ß Proteins 0.000 description 1
- 229950004996 tipelukast Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003628 tricarboxylic acids Chemical class 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 1
- 229940070126 tropifexor Drugs 0.000 description 1
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- 239000011534 wash buffer Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- C07D405/02—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 two hetero rings
- C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
本发明涉及吡唑并吡啶化合物,其抑制丝裂原活化蛋白激酶激酶4(MKK4),特别是相对于蛋白激酶JNK1和MKK7选择性抑制MKK4。所述化合物可用于促进肝脏再生或减少或预防肝细胞死亡。它们还可用于治疗骨关节炎或类风湿性关节炎或CNS相关疾病。
Description
技术领域
本发明涉及吡唑并吡啶蛋白激酶抑制剂,其抑制丝裂原活化蛋白激酶激酶4(MKK4),特别是相对于蛋白激酶JNK1和MKK7选择性地抑制MKK4。
背景技术
肝病可由感染、损伤、暴露于有毒化合物(如酒精或药物)、自身免疫过程、遗传缺陷和其它因素引起。肝脏具有显著的再生能力,然而,其在疾病状态下可能受损,并且可能因此不足以补偿肝细胞和器官功能的丧失。
WO2007/002433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,特别是B-Raf和C-Raf及其突变的抑制剂,并且因此可用于癌症治疗。此外,据说它们抑制多种其它蛋白激酶,其中包括c-Jun N-末端激酶(JNK),特别是JNK1。WO2007/002325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的化合物。H.Vin等人提及作为B-Raf抑制剂的WO2007/002433的两种化合物,其通过JNK信号传导的脱靶抑制来抑制细胞凋亡。WO2010/111527描述了吡唑并[3,4-b]吡啶化合物,其是用于治疗Raf蛋白激酶介导的疾病或病症(如癌症)的蛋白激酶抑制剂。此外,据说它们抑制多种其它蛋白激酶,其中包括c-Jun N-末端激酶(JNK),特别是JNK1。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以及用于肝细胞再生。Wuestefeld等人(细胞(Cell)153:389-401,2013)描述了用于鉴定可用于增加肝细胞的再生能力的基因靶标的功能性遗传方法。特别地,Wuestefeld等人鉴定蛋白激酶MKK4作为肝再生的关键调节剂,并报告MKK4抑制通过MKK7的代偿性上调和ATF2和ELK1的JNK1依赖性活化增加肝细胞再生。基于现有技术的发现,已经得出MKK4和JNK1抑制剂可用于治疗JNK1介导的疾病的结论。然而,尽管认识到JNK1的抑制可有益于治疗肝病,但尚未进行临床研究。WO2018/134254公开了吡咯并吡啶化合物,其是用于促进肝脏再生或减少或预防肝细胞死亡的蛋白激酶抑制剂。
发明内容
本发明所要解决的问题是提供可用作MKK4抑制剂的化合物,特别是相对于MKK7和JNK1选择性抑制MKK4。另一个问题是提供作为MKK4抑制剂的化合物,其相对于MKK7和JNK1选择性地抑制MKK4,其可用于治疗肝脏疾病,尤其用于促进肝脏再生或减少或预防肝细胞死亡。
该问题通过提供式(I)化合物解决。
因此,本发明涉及以下实施方案:
1.一种具有式(I)的化合物
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(I)中的变量具有如下含义:
R1是H、烷基、或具有4至5个环碳原子和1或2个独立地选自O、NH或N-烷基的杂原子的杂环烷基;
A是键或选自以下的连接基团
-CO-,
-S-,
-SO-,
-SO2-,
-O-,
-C(=N-NHR10)-,
-CH<,
-NR10-,
亚烷基,其任选地被OH或烷氧基取代,
亚烷基-NR10-亚烷基,
亚烷基-NR10SO2-亚烷基,
亚烷基-NR10CONR10-亚烷基,
亚烷基-NR10CSNR10-亚烷基,
-CONR10-,
-NR10CO-,
-NR10-SO2-,
-O2S-NR10-,
-CO-亚烷基,
亚烷基-CO-,
亚烷基-NR10CO-,
-OCNR10-亚烷基,
亚烷基-NR10,
NR10-亚烷基,
亚烷基-NR10SO2-,
-SO2NR10-亚烷基,
亚烷基-CONR10-亚烷基,
亚烷基-NR10CO-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-,和
-O-亚烷基-CO-;
Q是芳族或杂芳族的5-或6-元单环基团或芳族或杂芳族的9-或10-元双环基团,其中所述杂芳族基团具有1、2或3个独立地选自O、N和S的杂原子,
其中Q被-NR10SO2R12或-N=S(=O)R10NR10R10取代;
且任选地被1、2或3个独立地选自以下的基团取代
烷基,其任选地被1或2个独立地选自以下的取代基取代:苯基、卤素取代的苯基、卤素、OH、CN、-NR10R10、环烷基和具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团;
卤素;
羟基;
烷氧基;
卤代烷氧基;
苯基,其任选地被1或2个独立地选自烷基、羟烷基、烷氧基、卤素、烷硫基和NR10R10的基团取代;
-NR10R10;
-NR10SO2R12;
-NR10SO2R13;
-NR10SO2NHR10;
-NR10CONR10R17;
-NR10COR18;
-NR10COOR10;
-CO-NR10R19;
-亚烷基-NR10SO2R20;
-SO2R21;和
-亚烷基-NR10COR23;
R4是
H,
卤素,
CN,
NO2,
烷基,
苯基,任选地被1、2或3个独立地选自烷基、烷氧基、卤代烷基、羟烷基、烷基磺酰基、CN和NO2的基团取代,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族或非芳族杂环的5-或6-元单环或杂芳族9-或10-元双环的基团,所述基团任选地被1或2个独立选自烷基、烷氧基、卤素、环烷基和NR10R10的基团取代;
R5是
卤素,
烷基,其任选地被1或2个独立地选自烷氧基、NR10R10、-COOR10、和噁二唑基的基团取代,
烷氧基,
烯基,
炔基(alkinyl),
苯基或萘基,其中苯基或萘基任选地被1、2或3个独立地选自以下的基团取代:烷基、卤素、卤代烷基、羟基、羟烷基、烷硫基、烷基亚磺酰基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、苄氧基、卤代烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、NO2、-COOR10、-COOR14、R10R10N(C=O)-、CN、烷基羰基-NR10-、四唑基、烯基、-CONR10-O-亚烷基-OH、-CONR10-O-亚烷基-O-烷基,和羧基取代的烯基、苯基烯基,其中苯基任选被1、2或3个独立地选自以下的基团取代:OH、烷氧基和-CONR10R19,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族或非芳族杂环的5-或6-元单环或杂芳族9-或10-元双环的基团,所述基团任选地被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH、-CONR10-O-亚烷基-O-烷基、-COOR10、吗啉基、哌嗪基、噁二唑基和苯基羰基;
R6是H、烷氧基、NR10R10,或-NR10-苯基,其中所述苯基任选地被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是H、烷基、任选地被羟基或烷氧基取代的苯基,或是苯基烷基,其中所述苯基任选地被卤素取代;
R11是被1、2或3个羟基取代的烷基;
R12是H、烷基、苯基烷基、苯基-NR10-、-NR10R10、具有1、2或3个独立地选自O、N和S的杂原子的杂烷基,或是任选地被1、2或3个独立地选自以下的基团取代的苯基: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、噁唑基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),和-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
R13是具有1、2或3个独立地选自O、N和S的杂原子的杂芳香族或非芳香族杂环5-或6-元基团,所述基团任选地被1或2个独立地选自以下的基团取代:烷基、吡啶基、烷氧基羰基、噁唑基和被烷基或烷氧基-羰基取代的噁唑基;
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基;
R17是H,
烷基,
卤代烷基,
烷氧基烷基,
环烷基,
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族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,或
苯基烷基,其中所述苯基任选地被烷基、卤代烷基或卤素取代,或
R17和R10一起形成任选地被乙酰氨基取代的环烷基环,
R18是烷基、卤代烷基、苯基、
吗啉基或吡咯烷基,其任选地被-NR10R10取代;
R19是H、烷基、苯基烷基、苯基、被烷氧基取代的苯基,或是亚烷基-SO2-烷基或
R20是任选地被以下取代的苯基:烷基、苯基或被烷基或羟烷基取代的苯基;
R21是NR10R10、烷基、或任选被卤素取代的苯基;
R23是苯基或被烷基取代的苯基,其任选地被哌嗪基或烷基取代的哌嗪基取代;
2.如实施方案1所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R1是H、烷基或具有4至5个环碳原子和1或2个独立地选自O、NH或N-烷基的杂原子的杂环烷基;
A是键或选自以下的连接基团
-CO-,
-CO-CO-,
-S-,
-SO-,
-SO2-,
-O-,
-NR10-,
亚烷基,其任选地被1或2个独立地选自OH和烷氧基的基团取代,
-CONR10-,
-NR10CO-,
-NR10-SO2-,和
-O2S-NR10-;
Q是芳族或杂芳族的5-或6-元单环或9-或10-元双环基团
其中Q被-NR10SO2R12或-N=S(=O)R10NR10R10取代且任选地被1、2或3个独立地选自以下的基团取代
烷基,其任选地被1或2个独立地选自苯基、卤素取代的苯基和卤素的取代基取代;和
卤素;
R4是H、卤素或烷基;
R5是
卤素,
烷基,其任选地被1或2个独立地选自烷氧基、NR10R10、-COOR10和噁二唑基的基团取代,
烯基,
炔基,
苯基或萘基,其任选地被1、2或3个独立地选自以下的基团取代
烷基,
卤素,
卤代烷基,
羟基,
羟烷基,
烷硫基,
烷基亚磺酰基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
苄氧基,
卤代烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
CN,
烷基羰基-NR10-,
四唑基,
烯基,
-CONR10-O-亚烷基-OH,
-CONR10-O-亚烷基-O-烷基,和
羧基取代的烯基,
苯基烯基,其中所述苯基任选地被1、2或3个独立地选自OH、烷氧基和-CONR10R19的基团取代,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族或非芳族杂环的5-或6-元单环或杂芳族9-或10-元双环的基团,所述基团任选地被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,
-CONR10-O-亚烷基-O-烷基,
吗啉基,
哌嗪基,
噁二唑基和
苯基羰基;
R6是H,或烷基;
R10在每次出现时独立地是H、烷基、任选地被羟基或烷氧基取代的苯基,或是苯基烷基,其中所述苯基任选地被卤素取代;
R11是被1、2或3个羟基取代的烷基;
R12是H、烷基、苯基烷基,或-NR10R10;
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基;
R19是H、烷基、苯基烷基、苯基、被烷氧基取代的苯基,或是亚烷基-SO2-烷基或
3.如实施方案1或2所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R1是H或具有4至5个环碳原子和1个氧杂原子的杂环烷基。
4.如实施方案1或2所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R1是H。
5.如实施方案1或2所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R1是具有4至5个环碳原子和1个氧杂原子的杂环烷基。
6.如前述实施方案中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中A是选自以下的连接基团
-CO-,
-S-,
-SO-,
-SO2-,
亚烷基,其任选地被1或2个独立地选自OH和烷氧基的基团取代,
-CONR10-,和
-NR10CO-。
7.如前述实施方案中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Q是苯基或萘基,并且如权利要求2中所定义被取代和任选地被取代。
8.如实施方案7所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Q是苯基且如权利要求2中所定义被取代和任选地被取代。
9.如实施方案7或8所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Q是这样的苯基,其被-NR10SO2R12取代且进一步被1、2或3个独立地选自卤素和烷基的基团取代,所述烷基任选地被1或2个独立地选自苯基和卤素取代的苯基的取代基取代。
10.如实施方案9所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Q是被-NR10SO2R12取代且进一步被1、2或3个卤素原子取代的苯基。
11.如实施方案10所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中所述苯基被-NR10SO2R12取代且进一步被2或3个卤素原子取代。
12.如实施方案9、10或11中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中卤素原子或多个卤素原子是F或Cl,特别是F。
13.如前述实施方案中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R4和R6是H或烷基。
14.如实施方案1至13中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中排除丙烷-1-磺酸[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]酰胺。
15.如实施方案2至13中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
烷基,其任选地被1或2个独立地选自烷氧基、NR10R10、-COOR10和噁二唑基的基团取代,
烯基,
炔基,
苯基或萘基,其任选地被1、2或3个独立地选自以下的基团取代
烷基,
卤素,
卤代烷基,
羟基,
羟烷基,
烷硫基,
烷基亚磺酰基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
苄氧基,
卤代烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
CN,
烷基羰基-NR10-,
四唑基,
烯基,
-CONR10-O-亚烷基-OH,
-CONR10-O-亚烷基-O-烷基,和
羧基取代的烯基,
苯基烯基,其中所述苯基任选地被1、2或3个独立地选自OH、烷氧基和-CONR10R19的基团取代,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族或非芳族杂环的5-或6-元单环或杂芳族9-或10-元双环的基团,所述基团任选地被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
吗啉基,
哌嗪基,
噁二唑基,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-O-烷基,和
苯基羰基。
16.如前述实施方案中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
苯基或萘基,其任选地被1、2或3个独立地选自以下的基团取代
烷基,
卤素,
卤代烷基,
羟基,
羟烷基,
烷硫基,
烷基亚磺酰基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
苄氧基,
卤代烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
CN,
烷基羰基-NR10-,
四唑基,
烯基,
-CONR10-O-亚烷基-OH,
-CONR10-O-亚烷基-O-烷基,和
羧基取代的烯基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族或非芳族杂环的5-或6-元单环或杂芳族9-或10-元双环基团,所述基团任选地被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
吗啉基,
哌嗪基,
噁二唑基,
烷基SO(=NR10)-,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,
-CONR10-O-亚烷基-O-烷基,和
苯基羰基。
17.如实施方案16所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是苯基或萘基,其中苯基或萘基被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-、四唑基、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基。
18.如实施方案2至16中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环或杂芳族9-或10-元双环基团,所述基团任选地被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、-COOR10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基。
19.如实施方案18所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团任选地被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、-COOR10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基。
20.如实施方案19所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团未被取代或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10,和-COOR10。
21.如实施方案20所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中杂芳族基团未被取代或被1或2个独立地选自烷基、卤代烷基或-COOR10的基团取代。
22.如实施方案20所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中所述杂芳族基团为吡啶基、被-COOR10取代的吡啶基、嘧啶基或被选自以下的基团取代的嘧啶基:CF3、卤代烷基、烷氧基、-NR10R10、卤素,-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN,和-CONR10R10。
23.如实施方案22所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中所述杂芳族基团是嘧啶基或在2-位取代的嘧啶基。
24.如实施方案22所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中所述杂芳族基团是吡啶基或被-COOR10取代的吡啶基。
25.如前述实施方案中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R10是H或烷基。
26.如前述实施方案中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R12是烷基或苯基烷基。
27.如实施方案26所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R12是C1-C3-烷基或苄基。
28.如实施方案2至24中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Ia)
其中
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是H、卤素或烷基;
Ry是H、卤素或烷基;
Rz是H、卤素或烷基;
其中Rx、Ry或Rz中的一个或两个是卤素,且Rx、Ry和Rz中的其他是H、卤素或烷基;
R1、R4、R5、R6、R10和R12如实施方案2至27中任一项所定义。
29.如实施方案28所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R1是H或烷基;
R4是H或烷基;
R6是H或烷基;
R10是H、烷基或苯基烷基;
R12是H、烷基或苯基烷基;
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是H、卤素或烷基;
Ry是H、卤素或烷基;
Rz是H、卤素或烷基;
其中Rx、Ry或Rz中的一个或两个是卤素,且Rx、Ry和Rz中的其他是H、卤素或烷基;
R5是
苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
羟基,
卤素,
卤代烷基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
-NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
四唑基,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基;
R11是被1、2或3个羟基取代的烷基;且
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基。
30.如实施方案29所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-、四唑基、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自烷基、卤代烷基和-COOR10的基团取代。
31.如实施方案28至30中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Iaa)
32.如实施方案2至27中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Ib)
其中
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是卤素;
Ry是卤素;且
R1、R4、R5、R6、R10和R12如实施方案2至30中任一项所定义。
33.如实施方案32所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
Rw是-NR10SO2R12;
Rx是卤素;
Ry是卤素;
R5是
苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
羟基,
卤素,
卤代烷基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
-NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
四唑基,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
-COOR10,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基;
R11是被1、2或3个羟基取代的烷基;且
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基。
34.如实施方案33所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是苯基,其被1、2或3个独立地选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-NO2、-COOR10、R10R10N(C=O)-,和四唑基。
35.如实施方案33所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自烷基、卤代烷基、-COOR10的基团取代。
36.如实施方案2至31中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Ic)
其中
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是卤素;
Ry是卤素;且
R1、R4、R5、R6、R10和R12如实施方案2至30中任一项所定义。
37.如实施方案36所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
Rw是-NR10SO2R12;
Rx是卤素;
Ry是卤素;
R5是
卤素,
苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
羟基,
卤素,
卤代烷基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
-NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,
-CONR10-O-亚烷基-O-烷基,和
四唑基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基;
R11是被1、2或3个羟基取代的烷基;且
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基。
38.如实施方案37所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
羟基,
卤素,
卤代烷基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
-NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
四唑基,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基。
39.如实施方案37所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是苯基,其被1、2或3个独立地选自以下的基团取代:烷基、羟基、卤素、烷基SO(=NR10)-、R10R10NSO2-、-COOR10、-COOR14、R10R10N(C=O)-,和四唑基。
40.如实施方案37所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是吡啶基、被-COOR10取代的吡啶基、嘧啶基或被CF3取代的嘧啶基。
41.如实施方案2至31中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Id)
其中
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是卤素;且
R1、R4、R5、R6、R10和R12如实施方案2至30中任一项所定义。
42.如实施方案41所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
Rw是-NR10SO2R12;
Rx是卤素;
R5是
卤素,
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-,和四唑基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10,和-COOR10;
R11是被1、2或3个羟基取代的烷基;且
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基。
43.如实施方案42所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基-SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10,和-COOR14,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、卤素、-NR10-环烷基和-COOR10。
44.如实施方案42所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是苯基,其被1、2或3个独立选自以下的基团取代:烷基、卤素、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)。
45.如实施方案42所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是吡啶基、被-COOR10取代的吡啶基、嘧啶基或被CF3取代的嘧啶基。
46.如实施方案2至31中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Ie)
其中
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是卤素;
Ry是卤素;
Rz是卤素;且
R1、R4、R5、R6、R10和R12如实施方案2至30中任一项所定义。
47.如实施方案46所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
Rw是-NR10SO2R12;
Rx是卤素;
Ry是卤素;
R5是
卤素,
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-、四唑基、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、-COOR10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH和-CONR10-O-亚烷基-O-烷基;
R11是被1、2或3个羟基取代的烷基;且
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基。
48.如实施方案47所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-、四唑基、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、-COOR10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH和-CONR10-O-亚烷基-O-烷基。
49.如实施方案43所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是苯基,其被1、2或3个独立地选自以下的基团取代:烷基、羟基、卤素、烷基SO(=NR10)-、R10R10NSO2-、-COOR10、-COOR14、R10R10N(C=O)-,和四唑基。
50.如实施方案47或48所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是吡啶基、被-COOR10取代的吡啶基、嘧啶基或被CF3取代的嘧啶基。
51.如实施方案28至25至41中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Rx、Ry和Rz是F或Cl,特别是F。
52.一种化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其具有式(Ic)
R1是H或烷基;
R4是H或烷基;
R5是
卤素,
苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
羟基,
卤素,
卤代烷基,
烷基磺酰基,
烷基SO(=NR10)-,
烷基磺酰基-NR10-,
-NR10R10,
R10R10NSO2-,
R10R11NSO2-,
烷基-C(=O)-NR10SO2-,
R10R11N(C=O)-,
烷氧基,
-OCH2O-(在相邻位置连接到苯环的亚甲二氧基),
-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基),
-NO2,
-COOR10,
-COOR14,
R10R10N(C=O)-,
四唑基,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代
烷基,
卤代烷基,
烷氧基,
-NR10R10,
卤素,
-NR10-环烷基,
四唑基,
-O-亚烷基-NR10R10,
-NR10-亚烷基-O-烷基,
-CN,
-CONR10R10,
-COOR10,
烷基SO(=NR10)-,
-CONR10-O-亚烷基-OH,和
-CONR10-O-亚烷基-O-烷基;
R6是H或烷基;
R10是H、烷基或苯基烷基;
R11是被1、2或3个羟基取代的烷基;
R12是H、烷基或苯基烷基;
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基。
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
Rx是卤素;且
Ry是卤素。
53.如实施方案52所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R1、R4和R6是H。
54.如实施方案52或53所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Rw是-NR10SO2R12。
55.如实施方案52至54中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R12是C1-C4-烷基,特别是C1-C3-烷基或苄基。
56.如实施方案52至55中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-、四唑基、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基,或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5-或6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、-COOR10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH和-CONR10-O-亚烷基-O-烷基。
57.如实施方案56所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是
苯基,其被1、2或3个独立选自以下的基团取代:烷基、羟基、卤素、卤代烷基、烷基磺酰基、烷基SO(=NR10)-、烷基磺酰基-NR10-、-NR10R10、R10R10NSO2-、R10R11NSO2-、烷基-C(=O)-NR10SO2-、R10R11N(C=O)-、烷氧基、-OCH2O-(在相邻位置连接到苯环的亚甲二氧基)、-OCH2CH2O-(在相邻位置连接到苯环的亚乙二氧基)、-NO2、-COOR10、-COOR14、R10R10N(C=O)-、四唑基、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基或
具有1、2或3个独立地选自O、N和S的杂原子的杂芳族6-元单环基团,所述基团是未取代的或被1或2个独立地选自以下的基团取代:烷基、卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10、-COOR10、烷基SO(=NR10)-、-CONR10-O-亚烷基-OH,和-CONR10-O-亚烷基-O-烷基。
58.如实施方案52至57中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中
R5是苯基,其被1、2或3个独立地选自以下的基团取代:烷基、羟基、卤素、烷基SO(=NR10)-、R10R10NSO2-、-COOR10、-COOR14、R10R10N(C=O)-,和四唑基。
59.如实施方案52至58中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是吡啶基、被-COOR10取代的吡啶基、嘧啶基或被以下取代的嘧啶基:卤代烷基、烷氧基、-NR10R10、卤素、-NR10-环烷基、四唑基、-O-亚烷基-NR10R10、-NR10-亚烷基-O-烷基、-CN、-CONR10R10,和-COOR10。
60.如实施方案59所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是吡啶基、被-COOR10取代的吡啶基、嘧啶基或被卤代烷基(特别是CF3)取代的嘧啶基。
61.如实施方案59或60所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中R5是在2-位(即在两个氮原子之间的碳原子处)取代的嘧啶基。
62.如实施方案52至61中任一项所述的化合物及其药学上可接受的盐、前药、溶剂化物和光学异构体,其中Rx和Ry是F或Cl,特别是F。
具体实施方式
在一个实施方案中,R5不是卤素。在进一步的实施方案中,R1、R4和R6彼此独立地为H或烷基,并且特别是H。
在更进一步的实施方案中,R10是H、烷基或苯基烷基,其中苯基基团任选地被卤素取代,并且特别地R10是H或烷基。
在更进一步的实施方案中,A是-CO-。
在更进一步的实施方案中,Q是苯基,其如上所述被取代。
在更进一步的实施方案中,本发明涉及式I的化合物及其药学上可接受的盐、前药、酯、溶剂化物和光学异构体,其中R1、R4至R6、R10、A和Q以任何组合如上定义。
在更进一步的实施方案中,本发明涉及式(Ia)、(Ib)、(Ic)和(Id)的化合物及其药学上可接受的盐、前药、酯、溶剂化物和光学异构体,其中变量如上述实施方案中所定义。
在进一步的实施方案中,Rx、Ry或Rz中的至少一个或至少两个是卤素,并且Rx、Ry和Rz中的其他是H、卤素或烷基,特别是烷基或卤素。卤素优选是F或Cl。
在进一步的实施方案中,R1、R4和R6是H。
在进一步的实施方案中,R12是甲基、乙基或丙基。
在一个实施方案中,本发明涉及式(I)和(Ia)至(Id)的MKK4抑制剂及其药学上可接受的盐、前药、溶剂化物和光学异构体,并且特别涉及这样的MKK4抑制剂,其相对于蛋白激酶JNK1和MKK7选择性地抑制蛋白激酶MKK4。
此外,本发明还涉及本发明的化合物,其用于抑制蛋白激酶MKK4,特别是用于相对于蛋白激酶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,其用于促进肝再生或者减少或预防肝细胞死亡,并且同时增加肝细胞增殖。
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与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和无机酸的实例是盐酸、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)、芳族磺酸(例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(例如草酸、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)。其它可用的酸描述于例如Fortschritte der Arzneimittelforschung[药物研究进展(Advances in drug research)],第10卷,第224页及其后,Verlag,Basel和Stuttgart,1966。合适的药学上可接受的有机碱和无机碱的实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(procaine)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、晶体和多晶型形式及其混合物。
本发明还包括溶剂化物如水合物。
本发明的化合物可以含有一个或多个手性中心,并且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成母体药物的药剂。前药的非限制性实例是酯形式的本发明化合物。
前药具有许多有用的性质。例如,前药可以比最终药物更易溶于水,从而促进药物的静脉内施用。前药还可以具有比最终药物更高水平的口服生物利用度。施用后,前药被酶促或化学裂解以在血液或组织中递送最终的药物。示例性前药包括但不限于具有羧酸取代基的化合物,其中游离氢被以下取代:(C1-C4)烷基、(C1-C12)烷酰氧基-甲基、(C4-C9)1-(烷酰氧基)乙基、具有5至10个碳原子的1-甲基-1-(烷酰氧基)-乙基、具有3至6个碳原子的烷氧基羰基氧基甲基、具有4至7个碳原子的1-(烷氧基羰基-氧基)乙基、具有5至8个碳原子的1-甲基-1-(烷氧基羰基氧基)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-酞基(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-或吗啉代(C2-C3)烷基。其它示例性前药释放式(I)的醇,其中羟基取代基(例如R基团含有羟基)的游离氢被以下取代:(C1-C6)烷酰氧基-甲基、1-((C1-C6)烷酰氧基)-乙基、1-甲基-1-((C1-C6)烷酰氧基)乙基、(C1-C12)烷氧基-羰基氧基-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、芳酰基(arylactyl)和α-氨酰基或α-氨酰基-α-氨酰基(其中所述α-氨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(由碳水化合物半缩醛的羟基脱离产生的基团)。
表述MKK4抑制剂意味着MKK4的激酶活性以<10μmol/l,优选<1μmol/l,并且特别是<0.5μmol/l的IC50被抑制。如本文所用的表述“相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4”意指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,如使用KINOMEscanTM所测量。
本文所用的表述“促进肝脏再生或减少或预防肝细胞死亡”意指与治疗开始时增殖细胞的数量相比,增殖肝细胞的相对数量增加至少30%,优选至少50%。特别地,当与治疗开始时增殖细胞的数量相比时,该表述意指增加≥100%。在本文中,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,其与细胞增殖密切相关。对于组织载玻片中增殖肝细胞的定量,几种免疫组织化学标准方法是可用的,其使用第一抗-Ki67抗体,随后通过使用例如辣根过氧化物酶缀合的第二抗体可视化抗-Ki67-结合。通过发色底物的酶促转化可视化的过氧化物酶活性的量与Ki67蛋白的量和增殖细胞的数目相关。
在以下描述的实验中,肝细胞增殖通过使用来自Abcam的第一多克隆兔抗-Ki67抗体(产品编号(article no.)ab15580,Abcam,Cambridge,USA)和来自Invitrogen的含有荧光基团四甲基罗丹明的第二山羊多克隆抗体(产品编号16101,Invitrogen/ThermoFisher)的Ki67染色来定量。
基于从几种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抑制将肝细胞增殖从13%增加至27%(与对照shRNA相比),并且与降低的肝损伤(转氨酶)和降低的肝纤维化相关。根据上一章的定义,增殖细胞的相对增加是108%。在酒精诱导的脂肪性肝炎(ASH)模型中,与使用对照shRNA时的2%相比,shRNA介导的MKK4沉默导致肝细胞增殖率为4%(相对增加:100%)。肝细胞增殖的重复与降低的脂肪变性(脂肪沉积)和降低的肝损伤有关,如转氨酶所测。同样,在部分肝切除模型中(手术切除三分之二的肝脏后48小时),shRNA介导的MKK4沉默将肝细胞增殖从16%(对照shRNA)增加至33%(相对增加:106%)。肝细胞增殖增加与肝再生改善和肝量恢复加快有关。总之,这些研究证实MKK4作为治疗急性和慢性肝病的治疗靶标。此外,WO2018/134254公开了新的化合物,其相对于MKK7和JNK1选择性地抑制MKK4。在肝再生的体外和体内实验模型中,这些化合物在预防由施用Jo2抗体诱导的急性肝衰竭中是有效的并且诱导分离的原代小鼠肝细胞增殖。
本申请公开的新化合物是对MKK7和JNK1具有选择性的有效MKK4抑制剂,因此,与WO2018/134254中公开的化合物类似,可以用于治疗肝病和用于促进肝脏再生或减少或预防肝细胞死亡。
在变量的上述定义中提及的有机部分-如术语卤素-为各个基团成员的单独列表的集合性术语。前缀Cn-Cm在每种情况下表示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,并且优选氟。
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,特别是C1-C3-烷基。烷基的实例是甲基、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的烷基,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卤素原子替换,例如三氟甲基、氯甲基、溴甲基、二氟甲基、氟甲基、二氟乙基等。具体实例包括所定义的氟化C1-C4烷基,例如三氟甲基、二氟甲基、氟甲基,或二氟乙基。
环烷基是脂环族基团,其优选是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,优选一个或多个甲基。
羰基是>C=O。
氨基羰基是NH2C(O)-。
烯基是单不饱和烃基,其优选是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、甲基烯丙基(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、甲基烯丙基、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,其优选是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,其优选是C1-C5-亚烷基,即具有1至5个碳原子的亚烷基。特别优选具有2至4个,特别是2至3个碳原子的亚烷基。实例包括亚甲基、亚乙基和1-甲基亚乙基。另一个实例是亚丙基。另一个进一步的实例是亚丁基。亚烷基的定义同样适用于包括亚烷基的任何基团。
杂亚烷基是具有1、2或3个选自氧、氮和硫的杂原子的直链或支链烷基。杂亚烷基的实例是烷氧基烷基、烷基氨基烷基、二烷基氨基烷基或烷硫基烷基。任何烷基或亚烷基如上所定义。优选烷氧基烷基。
亚烯基是直链或支链亚烯基,其优选是C2-C4-亚烯基,即具有2至4个碳原子的亚烯基。实例包括乙烯基和丙烯基。
亚炔基是直链或支链亚炔基,其优选是C2-C4-亚炔基,即具有2至4个碳原子的亚炔基。实例包括亚丙炔基。
芳基(或芳族基团)是6-至12-元,特别是6-至10-元芳族环状基团,其可以是单环芳族环,例如苯基等,或包含第一单环芳族环和一个或多个饱和、部分不饱和或芳族碳环的稠合多环芳族环,例如萘基、茚基、四氢萘基、茚满基。
杂芳族(或杂芳基)基团是具有1、2或3个选自O、N或S的杂原子的5-或6-元单环或9-或10-元双环芳族基团。杂芳基或杂芳族基团可经由碳原子(C-键合)或经由氮杂原子(N-键合)与相邻基团键合。杂环基可以经由碳原子(C-键合)或氮原子(N-键合)键合。优选的杂芳族基团包含1个氮原子作为环成员原子和任选1或2个另外的杂原子作为环成员,所述杂原子彼此独立地选自O、S和N。实例是:
C-键合的5元杂芳族环:
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、异噁唑-3-基、异噁唑-4-基、异噁唑-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、噁唑-2-基、噁唑-4-基、噁唑-5-基、噻唑-2-基、噻唑-4-基、噻唑-5-基、1,2,3-噁二唑-咪唑-4-基,4-基、1,2,3-噁二唑-5-基、1,2,4-噁二唑-3-基、1,2,4,-噁二唑-5-基、1,3,4-噁二唑-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-噻二唑基-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元杂芳族环:
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元杂芳族环:
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5-或6-元杂芳族环之一和另外的环状的(anellated)、饱和或不饱和或芳族碳环,如苯、环己烷、环己烯或环己二烯环。实例是喹啉基、异喹啉基、吲哚基、吲嗪基、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、苯并噁唑基、苯并噻唑基、苯并咪唑基、咪唑并[b]噻唑基、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。包含环状的环烯基环的5-或6-元杂芳族化合物的实例包括二氢吲哚基、二氢吲嗪基、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)、色烷基(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1、2或3个选自O、N和S的杂原子。杂环基可以经由碳原子(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个另外的杂原子作为环成员,所述杂原子彼此独立地选自O、S和N。实例是:
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、四氢异噁唑-3-基、四氢异噁唑-4-基、四氢异噁唑-5-基、1,2-氧硫杂环戊烷(oxathiolan)-3-基、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(dithiolan)-3-基、1,2-二硫杂环戊烷-4-基、四氢咪唑-2-基、四氢咪唑-4-基、四氢噁唑-2-基、四氢噁唑-4-基、四氢噁唑-5-基、四氢噻唑-2-基、四氢噻唑-4-基、四氢噻唑-5-基、1,3-二氧戊环-2-基、1,3-二氧戊环-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、四氢硫代吡喃(tetrahydrothiopyran)-2-基、四氢硫代吡喃-3-基、四氢硫代吡喃-4-基、1,3-二噁烷-2-基、1,3-二噁烷-4-基、1,3-二噁烷-5-基、1,4-二噁烷-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(oxathian)-2-基、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-噁嗪-2-基、四氢-1,3-噁嗪-4-基、四氢-1,3-噁嗪-5-基、四氢-1,3-噁嗪-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-噁嗪-2-基、四氢-1,4-噁嗪-3-基、四氢-1,2-噁嗪-3-基、四氢-1,2-噁嗪-4-基、四氢-1,2-噁嗪-5-基、四氢-1,2-噁嗪-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、四氢异噁唑-2-基、四氢异噻唑-2-基、四氢咪唑-1-基、四氢噁唑-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-噁嗪-3-基、四氢-1,3-噻嗪-3-基、四氢-1,4-噻嗪-4-基、四氢-1,4-噁嗪-4-基(吗啉-1-基)、四氢-1,2-噁嗪-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、4,5-二氢异噁唑-3-基、4,5-二氢异噁唑-4-基、4,5-二氢异噁唑-5-基、2,5-二氢异噁唑-3-基、2,5-二氢异噁唑-4-基、2,5-二氢异噁唑-5-基、2,3-二氢异噁唑-3-基、2,3-二氢异噁唑-4-基、2,3-二氢异噁唑-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-噁唑-2-基、4,5-二氢噁唑-4-基、4,5-二氢噁唑-5-基、2,5-二氢噁唑-2-基、2,5-二氢噁唑-4-基、2,5-二氢噁唑-5-基、2,3-二氢噁唑-2-基、2,3-二氢噁唑-4-基、2,3-二氢噁唑-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(dioxol)-2-基、1,3-二氧杂环戊-4-基、1,3-二巯基(dithiol)-2-基、1,3-二巯基-4-基、1,3-氧杂硫醇(oxathiol)-2-基、1,3-氧杂硫醇-4-基、1,3-氧杂硫醇-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-3,4-二氢硫代吡喃-6-基、2H-3,4-二氢硫代吡喃-5-基、2H-3,4-二氢硫代吡喃-4-基、2H-3,4-二氢硫代吡喃-3-基、2H-3,4-二氢硫代吡喃-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-5,6-二氢硫代吡喃-2-基、2H-5,6-二氢硫代吡喃-3-基、2H-5,6-二氢硫代吡喃-4-基、2H-5,6-二氢硫代吡喃-5-基、2H-5,6-二氢硫代吡喃-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-硫代吡喃-2-基、4H-硫代吡喃-3-基、4H-硫代吡喃-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-硫代吡喃-2-基、2H-硫代吡喃-3-基、2H-硫代吡喃-4-基、2H-硫代吡喃-5-基、2H-硫代吡喃-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-噁嗪-3-基、2H-5,6-二氢-1,2-噁嗪-4-基、2H-5,6-二氢-1,2-噁嗪-5-基、2H-5,6-二氢-1,2-噁嗪-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-噁嗪-3-基、4H-5,6-二氢-1,2-噁嗪-4-基、4H-5,6-二氢-1,2-噁嗪-5-基、4H-5,6-二氢-1,2-噁嗪-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-噁嗪-3-基、2H-3,6-二氢-1,2-噁嗪-4-基、2H-3,6-二氢-1,2-噁嗪-5-基、2H-3,6-二氢-1,2-噁嗪-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-噁嗪-3-基、2H-3,4-二氢-1,2-噁嗪-4-基、2H-3,4-二氢-1,2-噁嗪-5-基、2H-3,4-二氢-1,2-噁嗪-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-噁嗪-2-基、4H-5,6-二氢-1,3-噁嗪-4-基、4H-5,6-二氢-1,3-噁嗪-5-基、4H-5,6-二氢-1,3-噁嗪-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-噁嗪-2-基、2H-1,3-噁嗪-4-基、2H-1,3-噁嗪-5-基、2H-1,3-噁嗪-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-噁嗪-2-基、4H-1,3-噁嗪-4-基、4H-1,3-噁嗪-5-基、4H-1,3-噁嗪-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-噁嗪-2-基、6H-1,3-噁嗪-4-基、6H-1,3-噁嗪-5-基、6H-1,3-噁嗪-6-基、6H-1,3-噻嗪-2-基、6H-1,3-噁嗪-4-基、6H-1,3-噁嗪-5-基、6H-1,3-噻嗪-6-基、2H-1,4-噁嗪-2-基、2H-1,4-噁嗪-3-基、2H-1,4-噁嗪-5-基、2H-1,4-噁嗪-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-噁嗪-2-基、4H-1,4-噁嗪-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、2,5-二氢异噁唑-2-基、2,3-二氢异噁唑-2-基、2,5-二氢异噻唑-2-基、2,3-二氢异噁唑-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、2,3-二氢噁唑-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-噁嗪-2-基、2H-5,6-二氢-1,2-噻嗪-2-基、2H-3,6-二氢-1,2-噁嗪-2-基、2H-3,6-二氢-1,2-噻嗪-2-基、2H-3,4-二氢-1,2-噁嗪-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-dihdro-1,4-噻嗪-4-基、2H-1,2-噁嗪-2-基、2H-1,2-噻嗪-2-基、4H-1,4-噁嗪-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。
包含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。
本发明的化合物可以如WO2010/111527中公开的制备,其通过引用或根据类似程序以其整体并入本文。酸或碱加成盐以常规方式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来制备。任选地,反应在有机溶剂例如低级醇(如MeOH、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EtOAc)的溶液中进行。
本发明的化合物可用于促进肝脏再生或减少或预防肝细胞死亡,并且同时增加肝细胞增殖。因此,所述化合物可用于治疗、调节、改善或预防涉及可能由感染、损伤、暴露于毒性化合物、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引起的急性或慢性肝脏损伤的疾病。
这类肝脏疾病包含其中增加的肝脏再生和减少或预防肝细胞死亡可有助于实现潜在治疗效果(即部分或完全恢复肝功能)的所有疾病。所述疾病包含
急慢性或慢加急性肝病,如急慢性病毒性肝炎如乙型肝炎,丙型肝炎,戊型肝炎,由EB病毒(Epstein-Barr virus)、巨细胞病毒、单纯疱疹病毒等病毒引起的肝炎,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,如代谢性综合征、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))、Morbus Wilson、血色素沉着病、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、乙基毒性肝硬化、隐源性肝硬化;
急性(暴发性)或慢性肝衰竭,例如毒性肝衰竭如扑热息痛(对乙酰氨基酚)诱导的肝衰竭、α-鹅膏蕈碱诱导的肝衰竭,药物诱导的肝中毒、肝衰竭(例如由抗生素、非甾体抗炎药和抗惊厥药引起)、由草药补充剂(卡瓦、麻黄、黄芩、普列薄荷(pennyroyal)等)诱导的急性肝衰竭,由血管疾病引起的肝病和衰竭(例如Budd-Chiari综合征)、原因不明的急性肝衰竭、右心衰引起的慢性肝病;
半乳糖血症、囊性纤维化、卟啉症、肝脏缺血灌注损伤、肝移植后小体积综合征、原发性硬化性胆管炎或肝性脑病。
为了促进肝脏再生或减少或预防肝细胞死亡,将治疗有效量的本发明化合物施用给有需要的患者。各种诊断方法可用于检测肝病的存在。已知丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的血液水平高于临床上可接受的正常范围,表明正在发生的肝损伤。血胆红素水平或其它肝酶可用作检测或诊断标准。常规监测肝病患者的ALT和AST血液水平用于测量在医疗时肝病的进展。将升高的ALT和AST水平降低至可接受的正常范围内作为反映患者肝损伤严重程度降低的临床证据。商业测定法例如FibroTest/FibroSURE、FibroMeter或Cirrhometer评价用于检测肝脂肪变性、纤维化和肝硬化的五个和更多个生化参数的组合结果。此外,可利用非侵入性、创新的物理成像技术(例如磁共振成像、超声波扫描,尤其是弹性成像技术)来检测和监测肝病的状态和进展。
进一步发现shRNA介导的MKK4抑制减弱了骨关节炎中TNF-α-驱动的软骨基质降解(细胞死亡和疾病(Cell Death and Disease)(2017)8,e3140)。因此,使用本发明的化合物抑制MKK4的活性进一步可用于治疗骨关节炎和类风湿性关节炎。
此外,MKK4抑制剂还可用于治疗神经变性疾病,例如阿尔茨海默病和帕金森病。Grueninger等人发现在人神经母细胞瘤细胞中,MKK4在丝氨酸422位的Tau蛋白磷酸化中起关键作用,其中Tau蛋白磷酸化促进Tau聚集(分子细胞生物化学(Mol Cell Biochem)(2011)357:199–207)。预防Tau聚集的Tau磷酸化抑制剂被认为可用于预防或治疗阿尔茨海默病。
最近,已经描述了MKK4抑制剂在体外和体内具有有效的神经保护作用。在海马培养物中,与MKK4抑制剂的孵育防止谷氨酸诱导的细胞死亡和半胱天冬酶-3活化,还抑制在SH-SY5Y细胞中N-甲基-4-苯基吡啶鎓(phenylpyridinium)碘化物和淀粉样蛋白β1-42诱导的细胞死亡。相同化合物还减轻小鼠中1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的黑质纹状体多巴胺能神经元的退化(生物化学药理学(生化药理学(Biochemical Pharmacology)(2018),doi:https://doi.org/10.1016/j.bcp.2018.10.008)。
本发明的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赋形剂)以及适当时的其它药物。这些组合物可以例如口服、直肠、经皮、皮下、腹膜内、静脉内、肌内或鼻内施用。
合适的药物组合物的实例是固体药物形式,例如粉末、颗粒剂、片剂(特别是薄膜片剂)、锭剂、囊剂(sachet)、扁囊剂(cachet)、糖衣片剂、胶囊剂(例如硬明胶胶囊剂和软明胶胶囊剂),或栓剂、半固体药物形式(例如软膏剂、乳膏剂、水凝胶剂、糊剂或硬膏剂),以及液体药物形式(例如溶液剂、乳剂(特别是水包油乳剂)、混悬剂(例如洗剂、注射制剂和输液制剂))。此外,还可以使用脂质体或微球体。
当制备组合物时,根据本发明的化合物任选地与一种或多种载体(赋形剂)混合或稀释。载体(赋形剂)可以是用于活性化合物的用作媒介物、载体或介质的固体、半固体或液体材料。
合适的载体(赋形剂)在专家医学专著中列出。另外,制剂中可以含有药学上可接受的辅助物质,如润湿剂;乳化剂和助悬剂;防腐剂;抗氧化剂;抗刺激剂;螯合剂;涂布助剂;乳化稳定剂;成膜剂;凝胶形成剂;掩味剂;矫味剂;树脂;水胶体;溶剂;增溶剂;中和剂;扩散促进剂;颜料;季铵化合物;加脂剂(refatting agent)和过脂剂(overfattingagent);软膏剂、乳膏剂或油剂的原料;硅酮衍生物;铺展(spreading)助剂;稳定剂;杀菌剂;栓剂基质;片剂助剂,例如粘合剂、填充剂、助流剂、崩解剂或包衣;推进剂;干燥剂;遮光剂;增稠剂;蜡;增塑剂和白色矿物油。在这方面,制剂基于专家的知识,例如Fiedler,H.P.,Lexikon der Hilfsstoffe für Pharmazie,Kosmetik und angrenzende Gebiete[用于制药、化妆品及相关领域的辅助物质百科全书(Encyclopedia of auxiliary substancesfor pharmacy,cosmetics and related fields)],第4版,Aulendorf:ECV-Editio-Cantor-Verlag,1996。
本发明的化合物还可适于与其它治疗剂组合。因此,本发明还涉及包含本发明化合物与一种或多种其它治疗剂的组合,特别是用于促进肝再生或减少或预防肝细胞死亡。本发明的组合疗法可以辅助施用。辅助施用(adjunctive administration)是指以分开的药物组合物或设备的形式连续(coterminous)或重叠施用每种组分。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参考,并且在本文中称为辅助治疗性施用;也称为附加治疗性施用。其中患者接受本发明的化合物和至少一种另外的治疗剂的分开但连续或重叠的治疗性施用的任何和所有治疗方案在本发明的范围内。在本文所述的辅助治疗性施用的一个实施方案中,患者通常稳定在一种或多种组分的治疗性施用一段时间,然后接受另一组分的施用。
本发明的组合疗法也可以同时施用。同时施用是指,以包含或含有两种组分的单一药物组合物或设备的形式,或者以作为各自包含一种组分的分开的组合物或设备同时施用的形式,一起施用各组分的治疗方案。用于同时组合的分开的单独组分的这样的组合可以以成套试剂盒的形式提供。
与本发明的化合物组合使用的合适的试剂包括例如:
ACC抑制剂,例如TOFA(5-(十四烷氧基)-2-糠酸)、PF-05221304,
GS 0976和ACC抑制剂,如WO2016/112305中公开,
血管紧张素II受体拮抗剂,
血管紧张素转化酶(ACE)抑制剂,例如依那普利(enalapril),
半胱天冬酶抑制剂,例如恩利卡生(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cenicriviroc;
CCR5趋化因子拮抗剂,
氯化物通道刺激剂,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,
二酰基甘油O-酰基转移酶2(DGAT2)抑制剂,例如PF-06865571,己酮糖激酶(KHK)抑制剂,例如PF-06835919,
二肽基肽酶IV(DPPIV)抑制剂,例如利格列汀(linagliptin),
法尼酯X受体(FXR)激动剂,例如Tully等人(药物化学杂志(J.Med.Chem.),201760(24),9960-9973)中公开的INT-747(奥贝胆酸)、LJN452(tropifexor)和类似物或GS-9674(PX-102),
FXR/TGR5双重激动剂,例如INT-767,
半乳凝素-3抑制剂,例如GR-MD-02,
胰高血糖素样肽1(GLP1)激动剂,例如利拉鲁肽或艾塞那肽,
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peg-ilodecakin,
IL-17拮抗剂,例如KD-025,
回肠钠胆汁酸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基因刺激剂,例如阿利泼金(alipogene tiparvovec),
赖氨酰氧化酶同系物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,
钠葡萄糖转运体-2(SGLT2)抑制剂,例如依碳酸瑞格列净(remogliflozinetabonate),
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抑制剂如GS4977。
在一些实施方案中,所述一种或多种另外的治疗剂选自乙酰水杨酸、阿利泼金、aramchol、阿托伐他汀、BLX-1002、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(ethyleicosapentaenoic acid)、IMM-124E、KD-025、利格列汀、利拉鲁肽、巯乙胺、MGL-3196、奥贝胆酸、奥利索西(olesoxime)、peg-ilodecakin、吡格列酮、GS-9674、依碳酸瑞格列净、SHP-626、索利霉素(solithromycin)、tipelukast、TRX-318,熊脱氧胆酸(ursodeoxycholicacid)和VBY-376。
在一些实施方案中,一种或多种另外的治疗剂中的一种选自以下:乙酰水杨酸、阿利泼金(alipogene tiparvovec)、aramchol、阿托伐他汀(atorvastatin)、BLX-1 002和cenicriviroc。
在一个实施方案中,本发明涉及一种方法
抑制蛋白激酶MKK4,
相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4,促进肝脏再生或预防肝细胞死亡,
治疗急性、慢加急性或慢性肝病,
治疗急慢性或慢加急性肝病,如急慢性病毒性肝炎如乙型肝炎,丙型肝炎,戊型肝炎,由EB病毒(Epstein-Barr virus)、巨细胞病毒、单纯疱疹病毒等病毒引起的肝炎,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;
治疗代谢性肝病,如代谢性综合征、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))、Morbus Wilson、血色素沉着病、α1-抗胰蛋白酶缺乏症、糖原贮积病;
治疗所有类型的肝硬化,如原发性胆汁性肝硬化、乙基毒性肝硬化、隐源性肝硬化;
治疗急性(暴发性)或慢性肝衰竭,例如毒性肝衰竭如扑热息痛(对乙酰氨基酚)诱导的肝衰竭、α-鹅膏蕈碱诱导的肝衰竭,药物诱导的肝中毒和肝衰竭(例如由抗生素、非甾体抗炎药、抗惊厥药引起)、由草药补充剂(卡瓦、麻黄、黄芩、普列薄荷等)诱导的急性肝衰竭、血管疾病引起的肝病和衰竭(例如Budd-Chiari综合征)、原因不明的急性肝衰竭、右心衰引起的慢性肝病;
治疗半乳糖血症、囊性纤维化、卟啉症、肝脏缺血灌注损伤、肝移植后小体积综合征、原发性硬化性胆管炎或肝性脑病,
治疗骨关节炎、类风湿性关节炎,或CNS相关疾病如阿尔茨海默病和帕金森病,
其包括向有需要的受试者施用有效量的如上定义的化合物或组合物。
在一个实施方案中,本发明的化合物以0.2至15mg/kg或0.5至12mg/kg被治疗的受试者的剂量施用。所述化合物可以每天施用一次或数次。所述化合物施用4至12周。
以下实施例说明本发明而不对其进行限制。
实施例
缩写:
Boc2O二-叔丁氧基碳酸酯
CPME 环戊基甲基醚
DCM 二氯甲烷
4-DMAP 4-二甲氨基吡啶
DME 二甲醚
DMF 二甲基甲酰胺
DMSO 二甲亚砜
EtOAc 乙酸乙酯
HPLC 高效液相色谱法
LDA 二异丙基氨基锂
MeCN 乙腈
MeOH 甲醇
NaHCO3 碳酸氢钠
NH4Cl 氯化铵
Na2SO4硫酸钠
Pd2(dba3)三(二亚苄基丙酮)二钯(0)
PE 石油醚
RT 室温
Sol.溶液
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(xanthene)
实施例1:N-(3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(VI)的合成
步骤1:5-溴-3-碘-1H-吡唑并[3,4-b]吡啶(II)的合成
在室温下向5-溴-1H-吡唑并[3,4-b]吡啶((I),6.81g,34.4mmol)和KOH(6.75g,120.4mmol)在DMF(45mL)中的搅拌混合物中一次性加入碘(9.60g,37.8mmol)。在短的诱导期之后,放热反应开始。1小时后,加入另外1g部分的碘,并将混合物在45℃下搅拌1小时。将混合物倒入300mL的Na2SO3稀释溶液中,并将混合物用2N HCl酸化。通过抽滤(suctionfiltration)收集固体,用水洗涤并在110℃的烘箱中干燥。产率:10.92g,HPLC纯度:95%,1H NMR(200MHz,DMSO)δ14.29(s,1H),8.62(s,1H),8.17(s,1H);13C NMR(50MHz,DMSO)δ150.53,150.17,131.86,120.58,112.43,91.95;[M-H]-=322.0/324.0.
步骤2:5-溴-1H-吡唑并[3,4-b]吡啶-3-羧酸(III)的合成
将5-溴-3-碘-1H-吡唑并[3,4-b]吡啶((II),10.44g,32.2mmol)与DMF、MeOH和三乙胺(每个75mL)合并。将容器抽真空并用氩气(4x)吹扫。加入XantPhos(1.12g,1.93mmol)和Pd(OAc)2(217mg,0.97mmol),并将一氧化碳(由甲酸和硫酸产生)鼓泡通过溶液,同时加热至60℃。将混合物在一氧化碳气氛(气球)下搅拌8h。每1.5小时将一氧化碳鼓泡通过该溶液5分钟。将混合物在减压下浓缩,并将残余物用2N HCl研碎。将固体在95℃在约100mL 1NNaOH中加热过夜。冷却至室温后,混合物用浓HCl酸化,通过抽滤收集沉淀物并用水洗涤。将固体在110℃的烘箱中干燥至恒重。将固体在100mL甲苯中超声处理5分钟并搅拌30分钟。将产物过滤,用另外20mL甲苯洗涤并在110℃下干燥。产率:7.92g HPLC纯度:>99%,1H NMR(200MHz,DMSO)δ8.64(d,J=7.9Hz,2H),5.69(bs,1H);13C NMR(50MHz,DMSO)δ163.27,150.97,149.67,136.69,132.65,115.73,113.6;[M-H]-=239.9/241.9.
步骤3:5-溴-N-甲氧基-N-甲基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(IV)的合成
将5-溴-1H-吡唑并[3,4-b]吡啶-3-甲酸((III),7.91g,32.7mmol)和1,1’-羰基二咪唑(5.83g,35.9mmol)在200mL DMF中在60℃下搅拌45分钟。向所得悬浮液中加入N,O-二甲基羟胺盐酸盐(3.51g,35.9mmol)并将混合物在65℃下搅拌4h。在真空下除去大部分溶剂并向残余物中加入半饱和NaHCO3-溶液。通过抽滤收集固体,用水洗涤并在110℃下干燥。产率:7.94g,HPLC纯度:96%,1H NMR(200MHz,DMSO)δ14.46(s,1H),8.62(d,J=20.4Hz,2H),3.76(s,3H),3.44(s,3H),[M-H]-=283.0/285.0.
步骤4:(3-氨基-2,6-二氟苯基)(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(V)的
合成
在氩气气氛下,将2,4-二氟苯胺(6.25g,48.4mmol)溶于50mL无水THF中并冷却至-78℃。滴加2.5M正丁基锂的己烷溶液(19.4mL,48.4mmol)。15分钟后,滴加1,2-双(氯二甲基甲硅烷基)乙烷(10.9g,49.5mmol)的15mL无水THF溶液,并将混合物搅拌30分钟。滴加2.5M正丁基锂的己烷溶液(19.4mL,48.4mmol),并使混合物在1h内达到室温。冷却至-78℃后,滴加2.5M正丁基锂的己烷溶液(19.4mL,48.4mmol)并在-78℃下搅拌1h。(将其称为溶液A)。
在氩气气氛下,将5-溴-N-甲氧基-N-甲基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺((IV),6.00g,21.1mmol)悬浮于50mL无水THF中并冷却至0℃。分批加入NaH(60%,在矿物油中,0.88g,22.1mmol),并将溶液在室温下搅拌1小时。(将其称为溶液B)。
在-78℃下将溶液B滴加至溶液A。加入完成后,将混合物在30分钟内升温至室温。小心加入12mL浓HCl,并将混合物搅拌30分钟。加入固体NaHCO3以中和溶液,滤出固体并用THF洗涤。蒸发滤液,残余物用MeOH和水研碎并在110℃下干燥。产率:4.03g;HPLC纯度:97%,1H NMR(200MHz,DMSO)δ14.91(s,1H),8.77(dd,J=5.4,2.1Hz,2H),7.18–6.59(m,2H),5.25(s,2H);13C NMR(50MHz,DMSO)δ183.95,151.04,150.79,150.27(dd,J=161.0,6.8Hz),145.50(dd,J=167.3,6.8Hz),141.34,133.35(dd,J=12.8,2.6Hz),132.28,117.45(dd,J=8.4,6.5Hz),116.24(dd,J=22.7,19.1Hz),115.55,114.81,111.26(dd,J=21.7,3.5Hz);[M-H]-=351.1/353.1.
步骤5:N-(3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺
酰胺(VI)的合成
将(3-氨基-2,6-二氟苯基)(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮((V),2.00g,5.66mmol)和4-DMAP(35mg,0.28mmol)在9mL吡啶中加热至65℃并加入1-丙烷磺酰氯(1.21g,0.96mL,8.50mmol)。2小时后,再加入0.19mL 1-丙烷磺酰氯。将温热的溶液加入到约80mL 2N HCl中,收集固体并用水洗涤。将固体置于EtOAc,用2N HCl和盐水洗涤,用Na2SO4干燥。将溶剂蒸发并将产物通过快速色谱法(SiO2,DCM/EtOAc梯度,0%至20%EtOAc)纯化并用正己烷研碎。产率:1.68g,HPLC纯度:97%,1H NMR(200MHz,DMSO)δ9.86(s,1H),8.79(dd,J=5.3,2.0Hz,3H),7.64(td,J=9.0,6.0Hz,1H),7.30(t,J=8.9Hz,1H),3.17–2.96(m,3H),1.87–1.62(m,2H),0.96(t,J=7.4Hz,4H);13C NMR(50MHz,DMSO)δ182.75,157.39(dd,J=177.1,7.4Hz),152.42(dd,J=180.3,7.3Hz),151.56,151.34,141.39,132.59,130.78–130.05(m),122.20(dd,J=13.5,3.6Hz),117.19(dd,J=23.0,20.9Hz),116.14,115.18,112.59(dd,J=22.2,3.8Hz),54.14,17.22 12.97;[M-H]-=457.1/459.1.
实施例2:N-(2,4-二氟-3-(5-苯基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
向微波容器中装入磁力搅拌棒、N-(3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺((VI),50mg,0.11mmol)、苯基硼酸(15mg,0.12mmol)、Pd(PPh3)4(6mg,5mol%)并用氩气吹扫。加入脱气的1,4-二噁烷(0.3mL)和脱气的1.5M K2CO3水溶液(0.25mL,0.38mmol)并将混合物在微波辐射下加热至120℃持续30分钟。冷却后,将混合物用EtOAc稀释并用饱和NH4Cl溶液中和。除去溶剂,通过快速色谱法分离产物,并在100℃下在真空烘箱中干燥。产率:27mg,HPLC纯度:97,1H NMR(200MHz,DMSO)δ7.84(d,J=7.2Hz,2H),7.71–7.40(m,4H),7.31(t,J=8.7Hz,1H),3.18–3.04(m,2H),1.87–1.63(m,2H),0.97(t,J=7.4Hz,3H).[M-H]-=455.1。
Suzuki偶联的一般程序:向微波容器中装入磁力搅拌棒、N-(3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺、适当的硼酸或硼酸频哪醇(pinacole)酯(1.1当量)和Pd(PPh3)4[(tBu)3P Pd G4和/或XPhos Pd G4(G4:第4代;可商购),对于硝基苯基硼酸、4-羟基苯基硼酸和4-二甲基氨基苯基硼酸频哪醇酯](0.05当量)并用氩气吹扫。加入脱气的1,4-二噁烷(0.4M)和脱气的1.5M K2CO3水溶液(3.5当量)并将混合物在微波辐射下加热至120℃直至完全转化(通常30分钟)。冷却后,将混合物用EtOAc稀释并用饱和NH4Cl溶液中和。除去溶剂,通过快速色谱法分离产物,并在100℃下在真空烘箱中干燥。
类似地,制备下表1中给出的化合物。
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实施例44:N-(5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,6-二氟-3-(丙基磺酰胺基)苯甲酰胺的合成
2,6-二氟-3-(丙基磺酰胺基)苯甲酸(中间体E)的合成
N-(5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)-2,6-二氟-3-(丙基磺酰胺基)苯甲酰胺的合成:
实施例45:5-(4-氯苯基)-N-(2,6-二氟-3-(丙基磺酰胺基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺的合成
N-(3-氨基-2,4-二氟苯基)丙烷-1-磺酰胺(中间体F)的合成
5-(4-氯苯基)-N-(2,6-二氟-3-(丙基磺酰胺基)苯基)-1H-吡唑并[3,4-b]吡啶-3-甲酰胺的合成:
实施例46:N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)硫代)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
N-(2,4-二氟-3-巯基苯基)丙烷-1-磺酰胺(中间体C)的合成
N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)硫代)-2,4-二氟苯基)丙烷-1-磺酰胺的合成:
实施例47和48:N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)亚磺酰基)-2,4-二氟苯基)丙烷-1-磺酰胺(实施例47)和N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)磺酰基)-2,4-二氟苯基)丙烷-1-磺酰胺(实施例48)的合成
实施例49:N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)(羟基)甲基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
N-(2,4-二氟-3-甲酰基苯基)丙烷-1-磺酰胺(中间体A)的合成:
N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-基)(羟基)甲基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成:
实施例50:N-(3-((5-(4-氯苯基)-1H-吡唑并[3,4-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51:
根据方案1中所示的程序制备实施例51a-51m的化合物。
方案1:
如实施例1(步骤1-4)中所述制备(3-氨基-2,6-二氟苯基)(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(1)。
与实施例1步骤5类似地进行随后的用磺酰氯的转化,得到中间体2。
如下进行(一般程序)至最终产物51a-51m的Suzuki偶联反应:向微波容器中装入磁力搅拌棒、5-溴-1H-吡唑并吡啶衍生物、适当的硼酸或硼酸频哪醇酯(1.1当量)和XPhosPd G3或Pd G4(0.05当量)并用氩气吹扫。加入脱气的1,4-二噁烷(0.4M)和脱气的1.5MK2CO3水溶液(3.5当量,对于每个酸性官能团,+1当量)并将混合物在微波辐射下加热至120℃(对于酰胺为100℃)直至完全转化(30至60分钟)。冷却后,将混合物用EtOAc稀释并用饱和NH4Cl溶液中和(或用2N HCl酸化用于酸性官能团)。除去溶剂并通过快速色谱法(使用DCM、EtOAc和/或MeOH的混合物)分离产物,必要时研碎并在100℃下在真空烘箱中干燥。
实施例51a:4-(3-(2,6-二氟-3-(苯基甲基)磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺
步骤1:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]-1-苯基甲
磺酰胺:
将(3-氨基-2,6-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(350mg,0.991mmol)和N,N-二甲基吡啶-4-胺(6.05mg,0.0496mmol)溶解于吡啶(1.98mL)中并加热至65℃。加入苯基甲磺酰氯(283mg,1.49mmol)并将混合物搅拌2h。将混合物倒入2N HCl水溶液中,用EtOAc萃取。有机相用2N HCl和盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂。将残余物通过快速色谱法(正己烷+EtOAc)0%至50%纯化并用正己烷研碎。N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]-1-苯基甲磺酰胺(315mg,0.6210mmol,63%产率)。
1H NMR(200MHz,CDCl3)δ14.22(s,1H),8.96(s,1H),8.79(d,J=2.2Hz,1H),8.59(d,J=2.1Hz,1H),7.52–7.25(m,6H),6.87(td,J=9.1,1.6Hz,1H),4.32(s,2H);
13C NMR(101MHz,CDCl3)δ182.7,156.6(dd,J=251,6.8Hz),153.03(d,J=7.7Hz),151.2,150.6,150.5,141.6,132.9,130.8,127.75(dd,J=151.3,7.9Hz),126.9,121.87(dd,J=13.1,3.9Hz),117.12(dd,J=22.8,20.7Hz),115.7,115.5,111.61(dd,J=22.5,3.8Hz),58.8.
MS:[M-1]-=504.7
步骤2:根据一般程序的Suzuki偶联(参见以上实施例2)
分析数据:
1H NMR(200MHz,DMSO)δ15.01(s,1H),9.89(s,1H),9.11(d,J=1.7Hz,1H),8.87(d,J=1.7Hz,1H),8.17–7.81(m,4H),7.70–7.14(m,9H),4.54(s,2H);
13C NMR(101MHz,DMSO)δ182.6,155.95(dd,J=248.0,6.2Hz),152.4,152.14(dd,J=251.0,7.4Hz),149.8,143.5,142.0,140.4,132.0,131.9,131.5,131.5,131.4,130.9,129.2,128.7,128.6,128.3,128.3,127.9,127.5,126.4,126.3,122.10(dd,J=13.1,3.5Hz),117.2,117.0,113.4,111.90(dd,J=22.0,3.9Hz)58.5;
MS:[M-1]-=581.8.
实施例51b:4-(3-(2,6-二氟-3-(甲基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺
步骤1:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]甲烷磺酰
胺:
将(3-氨基-2,6-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(350mg,0.991mmol)和N,N-二甲基吡啶-4-胺(6.05mg,0.0496mmol)溶解于吡啶(1.98mL)中并加热至65℃。加入甲磺酰氯(0.357mL,1.49mmol)并将混合物搅拌2h。将混合物倒入2N HCl水溶液中,用EtOAc萃取。有机相用2N HCl和盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂。将残余物通过快速色谱法(DCM+EtOAc)0%至30%纯化并用正己烷研碎。N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]甲磺酰胺(164mg,0,3800mmol,38%产率)
分析数据:
1H NMR(200MHz,DMSO)δ15.07(s,1H),9.82(s,1H),8.80(dd,J=4.8,2.1Hz,2H),7.65(td,J=9.0,5.9Hz,1H),7.32(td,J=8.9,1.5Hz,1H),3.07(s,3H);
13C NMR(101MHz,DMSO)δ182.3,156.4(dd,J=248.8,6.6Hz),152.92(dd,J=251.8,8.1Hz),151.0,150.9,141.0,132.2,130.1,130.0,121.80(dd,J=13.2,3.7Hz),116.84(dd,J=23.0,20.9Hz),115.7,114.7,112.16(dd,J=22.4,3.7Hz),40.4;
MS:[M-1]-=428.7.
步骤2:根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ14.99(s,1H),9.85(s,1H),9.10(d,J=2.1Hz,1H),8.86(d,J=2.1Hz,1H),8.03(dd,J=20.8,8.4Hz,4H),7.65(td,J=9.1,6.1Hz,1H),7.48(s,2H),7.33(t,J=8.8Hz,1H),3.08(s,3H);
13C NMR(101MHz,DMSO)δ182.5,156.40(dd,J=248.5,6.7Hz),153.0(dd,J=251.5,8.0Hz),152.4,149.8,143.5,142.0,140.3,131.5,130.0,129.9,128.2,127.9,126.4,121.8(dd,J=13.3,3.5Hz),117.13(dd,J=23.0,21.5Hz),113.4,112.15(dd,J=22.1,3.1Hz),40.4;
MS:[M-1]-=505.9.
实施例51c:4-(3-(3-(丁基磺酰胺基)-2,6-二氟苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺
步骤1:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]丁烷-1-磺
酰胺:
将(3-氨基-2,6-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(350mg,0.991mmol)和N,N-二甲基吡啶-4-胺(6.05mg,0.0496mmol)溶解于吡啶(1.98mL)中并加热至65℃。加入丁烷-1-磺酰氯(0.357mL,1.49mmol)并将混合物搅拌过夜。加入0,25当量丁烷-1-磺酰氯并在65℃继续搅拌2h。将混合物倒入2N HCl水溶液中并用EtOAc萃取。有机相用2N HCl和盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂。将残余物通过快速色谱法(己烷+EtOAc)10%至50%纯化并用正己烷研碎。N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]丁烷-1-磺酰胺(180mg,0,3800mmol,38%产率)
分析数据:
1H NMR(200MHz,DMSO)δ15.03(s,1H),9.83(s,1H),9.02–8.62(m,2H),3.21–3.03(m,2H),1.70(dt,J=15.0,7.5Hz,2H),1.37(dq,J=14.5,7.3Hz,2H),0.84(t,J=7.2Hz,3H);
13C NMR(50MHz,DMSO)δ182.4,151.1,151.0,141.1,132.3,115.8,114.8,51.8,25.1,20.7,13.4;
MS:[M-1]-=470.8.
步骤2:根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ15.00(s,1H),9.82(s,1H),9.10(d,J=2.1Hz,1H),8.86(d,J=2.0Hz,1H),8.13–7.93(m,4H),7.64(td,J=9.0,6.2Hz,1H),7.48(s,2H),7.32(td,J=8.9,1.2Hz,1H),3.21–3.07(m,2H),1.82–1.61(m,2H),1.50–1.27(m,2H),0.85(t,J=7.2Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,156.3(dd,J=248.2,6.3Hz),152.7(dd,J=251.1,8.8Hz),152.4,149.8,143.5,142.0,140.3,131.5,129.9,129.8,128.2,127.9,127.5,126.4,126.3,121.8(dd,J=13.0,3.7Hz),117.08(dd,J=23.1,21.2Hz),113.4,112.2,112.2,112.0,51.8,25.1,20.7,13.4;
MS:[M-1]-=547.9.
实施例51d:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯甲酸
根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ14.99(s,1H),13.14(bs,1H),9.83(s,1H),9.10(d,J=2.1Hz,1H),8.84(d,J=2.2Hz,1H),8.04(dd,J=22.3,8.5Hz,4H),7.64(td,J=9.0,5.9Hz,1H),7.31(td,J=8.9,1.5Hz,1H),3.21–3.03(m,2H),1.86–1.61(m,2H),0.97(t,J=7.4Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,167.0,152.4,149.8,142.0,141.3,131.8,130.2,130.1,128.1,127.6,113.5,53.8,16.8,12.5;
MS:[M-1]-=499.6.
实施例51e:N-[2,4-二氟-3-[5-[4-(1H-四唑-5-基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺
根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ14.99(s,1H),9.83(s,1H),9.14(d,J=2.1Hz,1H),8.88(d,J=2.2Hz,1H),8.17(dd,J=19.9,8.4Hz,4H),7.65(td,J=9.0,6.1Hz,1H),7.32(td,J=9.0,1.4Hz,1H),3.20–3.05(m,2H),1.90–1.59(m,2H),0.97(t,J=7.4Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,156.29(dd,J=248.3,6.4Hz),152.8(dd,J=251.2,8.2Hz),152.4,149.8,142.0,139.7,131.7,129.9,129.8,128.3,127.9,127.7,127.6,123.8,121.79(dd,J=13.4,3.4Hz),117.1,113.5,112.12(dd,J=22.6,4.3Hz),53.8,16.8,12.5;
MS:[M-1]-=522.9.
实施例51f:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯甲酰胺
根据一般程序的Suzuki偶联
分析数据:
1H NMR(400MHz,DMSO)δ14.97(s,1H),9.83(s,1H),9.10(d,J=1.3Hz,1H),8.83(d,J=1.3Hz,1H),8.13–7.92(m,5H),7.64(td,J=8.9,6.2Hz,1H),7.46(s,1H),7.32(t,J=8.7Hz,1H),3.18–3.06(m,2H),1.83–1.68(m,2H),0.97(t,J=7.5Hz,3H);
13C NMR(101MHz,DMSO)δ182.6,167.4,152.4,149.8,142.0,139.8,133.7,132.0,128.4,127.9,127.2,113.5,53.8,16.8,12.6;
MS:[M-1]-=498.0.
实施例51g:N-(2,4-二氟-3-(5-(4-(甲基磺酰胺基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺
步骤1:N-(4-溴苯基)甲磺酰胺(2)
将4-溴苯胺(1,2.08g,12.1mmol)和4-二甲基氨基吡啶(0.0739g,0.605mmol)溶解在吡啶(12.1mL)中并在室温下加入甲磺酰氯(1.03mL,13.3mmol),导致放热反应。再次达到室温(30min)后,将混合物倒入2N HCl中。将产物用EtOAc萃取,将萃取物用2N HCl和盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,将残余物用正己烷研碎,得到N-(4-溴苯基)甲磺酰胺(2.40g,9.6mmol,79%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ9.91(s,1H),7.60–7.42(m,2H),7.22–7.09(m,2H),3.00(s,3H);
13C NMR(50MHz,DMSO)δ137.9,132.2,121.5,115.9,39.3;[M-1]-=247.7.
步骤2:N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(dioxaborolan)-2-基)
苯基]甲磺酰胺(3)
向容器中装入N-(4-溴苯基)甲磺酰胺(2,252mg,1.01mmol)、双(频哪醇合(pinacolato))二硼(281mg,1.11mmol)、乙酸钾(297mg,3.02mmol)和脱气的无水1,4-二噁烷(5.04mL)。将容器抽真空并用氩气(3x)回填,加入XPhos Pd G4(8.67mg,0.0101mmol),并将混合物在85℃下搅拌4h。冷却至室温后,将混合物用EtOAc和乙酸(0.173mL,3.02mmol)稀释,搅拌30分钟并经硅藻土过滤。在减压下除去溶剂。将残余物溶解于最小量的EtOAc中,用正庚烷沉淀,并且通过抽滤收集固体,以产生N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]甲磺酰胺(281mg,0,9460mmol,94%产率),其无需进一步纯化即使用。
分析数据:
1H NMR(200MHz,DMSO)δ7.60(d,J=8.5Hz,2H),7.17(d,J=8.5Hz,2H),2.99(s,3H),1.27(s,12H);
13C NMR(50MHz,DMSO)δ142.4,135.8,117.9,83.5,24.7.
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ14.93(s,1H),9.98(s,1H),9.83(s,1H),9.02(d,J=2.2Hz,1H),8.73(d,J=2.1Hz,1H),7.84(d,J=8.6Hz,2H),7.64(td,J=9.0,6.1Hz,1H),7.43–7.26(m,3H),3.19–3.03(m,5H),1.86–1.63(m,2H),0.97(t,J=7.4Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,152.1,149.6,141.8,138.5,132.4,128.3,127.0,120.0,113.5,53.8,16.8,12.5;
[M-1]-=547.8.
实施例51h:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-N-甲基苯磺酰胺
步骤1:4-溴-N-甲基苯磺酰胺(2)
向4-溴苯磺酰氯(1,2.52g,9.86mmol)的四氢呋喃(49.3mL)溶液中加入甲胺(14.8mL,29.6mmol)2M的THF溶液。将反应混合物在室温下搅拌15分钟,倒入NH4Cl溶液中并用EtOAc萃取。将有机层经Na2SO4干燥,浓缩并用正己烷研碎,得到4-溴-N-甲基苯磺酰胺(2.15g,8,6mmol,87%产率)。
分析数据:
1H NMR(200MHz,CDCl3)δ7.77–7.59(m,1H),5.03(dd,J=10.0,4.9Hz,1H),2.62(d,J=5.2Hz,1H);
13C NMR(50MHz,CDCl3)δ137.8,132.5,128.9,127.8,29.3;[M-1]-=247.8.
步骤2:[4-(甲基氨磺酰基)苯基]硼酸(3)
在-70℃下向4-溴-N-甲基苯磺酰胺(2,1.05g,4.20mmol)和硼酸三异丙酯(1.45mL,6.30mmol)的四氢呋喃(8.40mL)溶液中加入正丁基锂(4.20mL,10.5mmol)。将混合物缓慢升温至0℃,然后加入10%HCl溶液直至pH 3-4。将所得混合物用EtOAc萃取。有机层用NaOH(2M)萃取,且水相用乙醚洗涤。将水相酸化至pH 3,用EtOAc萃取(杂质和未消耗的反应物仍然存在),经Na2SO4干燥,并在减压下蒸发。将残余物用乙醚研碎,得到[4-(甲基氨磺酰基)苯基]硼酸(187mg,0,8700mmol,21%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ7.96(d,J=8.1Hz,2H),7.72(d,J=8.0Hz,2H),7.42(q,J=4.9Hz,1H),2.39(d,J=5.0Hz,3H);
13C NMR(50MHz,DMSO)δ140.6,134.8,125.7,28.8.
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(400MHz,DMSO)δ15.01(s,1H),9.83(s,1H),9.11(d,J=2.1Hz,1H),8.87(d,J=2.0Hz,1H),8.11(d,J=8.3Hz,2H),7.93(d,J=8.3Hz,2H),7.64(td,J=9.0,5.9Hz,1H),7.58(q,J=5.0Hz,1H),7.32(t,J=8.7Hz,1H),3.19–3.02(m,2H),1.80–1.70(m,2H),0.97(t,J=7.5Hz,3H);
13C NMR(101MHz,DMSO)δ182.6,152.5,149.9,142.0,141.0,138.8,131.4,128.4,128.2,127.5,113.4,53.8,28.6,16.8,12.5;
MS:[M-1]-=547.9.
实施例51i:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-N-乙基苯磺酰胺
步骤1:4-溴-N-乙基苯磺酰胺(2)
将4-溴苯磺酰氯(1,2.57g,10.1mmol)溶解在DCM(25.1mL)中。加入三乙胺(3.50mL,25.1mmol)和乙胺盐酸盐(1.07g,13.1mmol),并将混合物在室温下搅拌1h。将混合物用半饱和NH4Cl溶液稀释并用EtOAc萃取。将有机相用盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂。将残余物用正己烷研碎,得到4-溴-N-乙基苯磺酰胺(2.40g,9,09mmol,90%产率)。
分析数据:
1H NMR(200MHz,CDCl3)δ7.92–7.47(m,4H),5.17(s,1H),3.08–2.81(m,2H),1.08(t,J=7.2Hz,3H);
13C NMR(50MHz,CDCl3)δ139.1,132.4,128.7,127.6,38.3,15.1;[M-1]-=261.7.
步骤2:[4-(乙基氨磺酰基)苯基]硼酸(3)
在-70℃下向4-溴-N-乙基苯磺酰胺(2,1.06g,4.01mmol)和硼酸三异丙酯(1.39mL,6.02mmol)的四氢呋喃(20.1mL)溶液中加入正丁基锂(4.01mL,10.0mmol)。将混合物缓慢升温至0℃,然后加入10%HCl溶液直至pH 3-4。将所得混合物用EtOAc萃取,萃取物用盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂。将残余物用乙醚研碎,得到[4-(乙基氨磺酰基)苯基]硼酸(368mg,1,61mmol,40%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ8.41(s,2H),7.94(d,J=8.1Hz,2H),7.74(d,J=8.1Hz,2H),7.52(t,J=5.7Hz,1H),2.87–2.67(m,2H),0.93(t,J=7.2Hz,3H);
13C NMR(50MHz,DMSO)δ142.1,135.0,125.7,37.9,15.0.
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(400MHz,DMSO)δ14.97(s,1H),9.82(s,1H),9.10(d,J=2.1Hz,1H),8.86(d,J=2.1Hz,1H),8.09(d,J=8.3Hz,2H),7.94(d,J=8.5Hz,2H),7.73–7.58(m,2H),7.31(t,J=8.7Hz,1H),3.16–3.06(m,2H),2.89–2.80(m,2H),1.81–1.69(m,2H),1.05–0.94(m,6H);
13C NMR(101MHz,DMSO)δ182.5,152.5,149.8,142.0,140.8,140.0,131.4,128.3,128.2,127.3,113.4,53.8,37.6,16.8,14.8,12.5;
MS:[M-1]-=561.9.
实施例51j:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-N-(2,3-二羟基丙基)苯磺酰胺
步骤1:4-溴-N-(2,3-二羟基丙基)苯磺酰胺(2)
将4-溴苯磺酰氯(1,2.10g,8.22mmol)和三乙胺(2.29mL,16.4mmol)在DCM(41.1mL)中合并。加入3-氨基丙烷-1,2-二醇(0.952mL,12.3mmol),并将混合物在室温下搅拌1h。蒸发溶剂后,将残余物溶于EtOAc,用1N HCl、水和盐水洗涤。萃取物经Na2SO4干燥,过滤并在减压下除去溶剂。将产物用水和乙醚洗涤并干燥,得到4-溴-N-(2,3-二羟基丙基)苯磺酰胺(0.980g,3,16mmol,38%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ7.77(dd,J=17.1,8.5Hz,5H),4.79(s,1H),4.56(s,1H),3.46(s,1H)在水峰值下,3.27(s,2H),2.89(dd,J=12.6,4.2Hz,1H),2.61(dd,J=12.5,7.1Hz,1H);
13C NMR(50MHz,DMSO)δ139.9,132.3,128.7,126.1,70.3,63.5,46.1;[M-1]-=307.8.
步骤2:N-(2,3-二羟基丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-
基)苯磺酰胺(3)
向容器中装入4-溴-N-(2,3-二羟基丙基)苯磺酰胺(2,205mg,0.661mmol)、乙酸钾(195mg,1.98mmol)、双(频哪醇合)二硼(185mg,0.727mmol)和脱气的无水1,4-二噁烷(6.61mL)。将容器抽真空并用氩气(3x)回填,加入XPhos Pd G4(5.69mg,0.00661mmol),并将混合物在85℃下搅拌过夜。冷却至室温后,将混合物用EtOAc稀释并搅拌30分钟,经硅藻土过滤并在减压下除去溶剂。将残余物溶于最小量的EtOAc中,用正庚烷沉淀,并通过抽滤收集固体,得到N-(2,3-二羟基丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯磺酰胺(202mg,0,5650mmol,86%产率),其未经进一步纯化即使用。
分析数据:
1H NMR(200MHz,DMSO)δ7.80(q,J=8.0Hz,3H),7.44(s,2H),3.52–2.56(m,5H),1.35–1.22(m,7H),1.15(s,5H),1.07(s,2H).
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(400MHz,DMSO)δ15.00(s,1H),9.82(s,1H),9.11(d,J=2.1Hz,1H),8.87(d,J=2.1Hz,1H),8.09(d,J=8.5Hz,2H),7.95(d,J=8.5Hz,2H),7.68–7.60(m,2H),7.32(t,J=8.3Hz,1H),4.82(d,J=5.2Hz,1H),4.58(t,J=5.7Hz,1H),3.50(dq,J=10.6,5.3Hz,1H),3.32–3.22(m,2H),3.14–3.08(m,2H),2.94(ddd,J=11.7,6.6,4.9Hz,1H),2.66(ddd,J=12.8,7.0,5.8Hz,1H),1.83–1.69(m,2H),0.97(t,J=7.5Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,152.5,149.8,142.0,140.8,140.0,131.4,128.3,128.1,127.3,113.4,70.3,63.5,53.8,46.1,16.8,12.5;
MS:[M-1]-=607.8.
实施例51k:N-((4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯基)磺酰基)乙酰胺
步骤1:N-(4-溴苯基)磺酰基乙酰胺(2)
将4-溴苯磺酰氯(1,2.32g,9.08mmol)和乙酰胺(1.34g,22.7mmol)(使用前用乙醚洗涤)溶于四氢呋喃(30.3mL)。在0℃下分批加入氢化钠(0.908g,22.7mmol)(60%)并将混合物搅拌2h。将混合物用浓HCl酸化并加入水直至发生相分离。分离各相,用EtOAc萃取水相。将有机相用水和盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂。将残余物用水研碎并真空干燥,得到N-(4-溴苯基)磺酰基乙酰胺(1.33g,4,78mmol,53%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ12.22(s,1H),7.84(s,4H),1.93(s,3H);
13C NMR(50MHz,DMSO)δ169.0,138.6,132.3,129.6,127.7,23.3;[M-1]-=275.8.
步骤2:N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基乙
酰胺(3)
向容器中装入N-(4-溴苯基)磺酰基乙酰胺(2,206mg,0.741mmol)、乙酸钾(218mg,2.22mmol)、双(频哪醇合)二硼(207mg,0.815mmol)和脱气的无水1,4-二噁烷(7.41mL)。将容器抽真空并用氩气(3x)回填,加入XPhos Pd G4(6.37mg,0.00741mmol),并将混合物在85℃下搅拌过夜。加入另外的XPhos Pd G4和双(频哪醇合)二硼并将混合物再搅拌2h。冷却至室温后,将混合物用EtOAc稀释并搅拌30分钟,并经硅藻土过滤。弃去滤液,用2N HCl和EtOAc洗涤过滤器。在减压下除去溶剂,并将残余物用正庚烷研碎,得到N-[4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯基]磺酰基乙酰胺(163mg,0,5010mmol,68%产率),其未经进一步纯化即使用。
分析数据:
1H NMR(200MHz,DMSO)δ12.14(s,1H),8.02–7.81(m,4H),1.92(s,3H),1.30(s,12H);
13C NMR(50MHz,DMSO)δ168.8,141.8,134.9,126.8,84.3,24.6,23.2.
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(400MHz,DMSO)δ15.01(s,1H),12.21(s,1H),9.83(s,1H),9.11(d,J=2.1Hz,1H),8.87(d,J=2.1Hz,1H),8.12(d,J=8.5Hz,2H),8.05(d,J=8.5Hz,2H),7.64(td,J=9.0,5.9Hz,1H),7.32(t,J=8.5Hz,1H),3.11(dd,J=5.7,3.8Hz,2H),1.96(s,3H),1.83–1.69(m,2H),0.97(t,J=7.5Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,168.9,152.5,149.9,142.1,138.8,131.2,128.6,128.3,128.1,113.4,53.8,23.2,16.8,12.5;
MS:[M-1]-=575.7.
实施例51l:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-N-(2,3-二羟基丙基)苯甲酰胺
步骤1:4-溴-N-(2,3-二羟基丙基)苯甲酰胺(2)
将4-溴苯甲酸甲酯(2.41g,11.2mmol)和3-氨基丙烷-1,2-二醇(1.12g,12.3mmol)加热至125℃持续4h。将混合物用MeOH稀释,经硅藻土蒸发并经短柱(DCM+MeOH+甲酸(99+0+1至90+9+1)纯化。蒸发溶剂后,将油状残余物在0.05mbar下干燥直至发生结晶。然后将其用乙醚研碎,得到4-溴-N-(2,3-二羟基丙基)苯甲酰胺(1.90g,6,93mmol,62%产率),其为白色固体。1H NMR(200MHz,DMSO)δ8.49(s,1H),7.73(d,J=22.1Hz,4H),4.72(d,J=48.1Hz,2H),3.83–2.99(m,5H);13C NMR(50MHz,DMSO)δ165.8,133.7,131.3,129.5,124.9,70.4,64.0,43.2;[M-1]-=271.7.
步骤2:N-(2,3-二羟基丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-
基)苯甲酰胺(3)
向容器中装入4-溴-N-(2,3-二羟基丙基)苯甲酰胺(656mg,2.39mmol)、双(频哪醇合)二硼(669mg,2.63mmol)、乙酸钾(705mg,7.18mmol)和脱气的无水1,4-二噁烷(12.0mL)。将容器抽真空并用氩气(3x)回填,加入XPhos Pd G3(10.3mg,0.0120mmol),并将混合物在85℃下搅拌2h。冷却至室温后,将混合物用EtOAc稀释,搅拌30分钟,并经硅藻土过滤。在减压下除去溶剂。将残余物溶解在最小量的EtOAc中,在搅拌下滴加到正庚烷中,并且通过抽滤收集固体,以产生N-(2,3-二羟基丙基)-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酰胺(410mg,1,28mmol,53%产率),其未经进一步纯化即使用。
分析数据:
1H NMR(200MHz,DMSO)δ7.91–7.65(m,4H),1.30(s,12H),1.15(s,4H),1.07(s,2H);
13C NMR(101MHz,DMSO)δ134.2,126.5,83.8,81.3,73.5,70.3,64.0,39.5,24.9,24.6,24.4.
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ9.10(d,J=2.1Hz,1H),8.83(d,J=2.2Hz,1H),8.54(t,J=5.7Hz,1H),8.00(q,J=8.5Hz,4H),7.64(td,J=9.0,5.8Hz,1H),7.32(td,J=9.1,1.3Hz,1H),4.87(d,J=5.1Hz,1H),4.62(t,J=5.7Hz,1H),3.80–3.58(m,1H),3.26–3.02(m,3H),1.75(dq,J=14.9,7.4Hz,2H),0.97(t,J=7.4Hz,3H);
13C NMR(50MHz,CDCl3)δ182.6,166.1,152.5,142.0,139.7,133.9,132.0,128.2,127.3,113.6,70.4,64.0,53.8,43.1,16.9,12.6;
MS:[M-1]-=571.7.
实施例51m:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-氟苯磺酰胺
步骤1:4-溴-3-氟苯磺酰胺(2)
向4-溴-3-氟苯磺酰氯(1,1.03g,3.77mmol)的乙腈(1.88mL)的冰冷溶液中滴加25%氨溶液(1.46mL,9.41mmol)。将混合物在室温下搅拌10分钟,用水稀释并用乙醚萃取。萃取物用盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,得到4-溴-3-氟苯磺酰胺(0.780g,3,07mmol,82%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ7.95(dd,J=8.2,6.9Hz,1H),7.75(dd,J=8.4,2.1Hz,1H),7.64–7.57(m,3H);
13C NMR(50MHz,DMSO)δ157.9(d,J=249.0Hz),145.5(d,J=6.1Hz),134.6,123.2(d,J=3.8Hz),114.1(d,J=25.3Hz),112.3(d,J=20.8Hz).
步骤2:3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯磺酰胺(3)
向容器中装入4-溴-3-氟苯磺酰胺(2,255mg,1.00mmol)、双(频哪醇合)二硼(280mg,1.10mmol)、乙酸钾(295mg,3.01mmol)和脱气的无水1,4-二噁烷(5.02mL)。将容器抽真空并用氩气(3x)回填,加入XPhos Pd G4(4.32mg,0.00502mmol),并将混合物在85℃下搅拌过夜。冷却至室温后,将混合物用EtOAc和乙酸(0.172mL,3.01mmol)稀释,搅拌30分钟并经硅藻土过滤。在减压下除去溶剂。将残余物溶于最小量的EtOAc中,用正庚烷沉淀,并通过抽滤收集固体,得到3-氟-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯磺酰胺(220mg,0,7310mmol,73%产率),其未经进一步纯化即使用。
分析数据:
1H NMR(200MHz,DMSO)δ7.91–7.09(m,5H),1.42–0.95(m,12H);
13C NMR(50MHz,DMSO)δ148.6(d,J=8.2Hz),137.5(d,J=8.3Hz),121.05(d,J=2.1Hz),112.48(d,J=27.6Hz),83.9,73.6,25.0,24.7.
步骤3:根据一般程序的Suzuki偶联
分析数据:
1H NMR(200MHz,DMSO)δ15.06(s,1H),9.83(s,1H),8.95(s,1H),8.81(s,1H),7.99(t,J=8.0Hz,1H),7.88–7.74(m,2H),7.73–7.55(m,3H),7.40–7.23(m,1H),3.22–2.98(m,2H),1.88–1.59(m,2H),0.97(t,J=7.4Hz,3H).
MS:[M-1]-=551.7.
实施例52
根据方案2中所示的程序制备实施例52a-52c的化合物。
方案2:
步骤1:N-[3-[5-溴-1-(噁烷(oxan)-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4-二
氟苯基]丙烷-1-磺酰胺(2)
向N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,4-二氟苯基]丙烷-1-磺酰胺(1,0.333g,0.725mmol)的DCM(2.90mL)悬浮液中加入二氢吡喃(0.132mL,1.45mmol)和对甲苯磺酸一水合物(0.0276g,0.145mmol)并将混合物加热至回流温度持续45分钟。冷却后,将混合物用饱和NaHCO3-溶液洗涤,经Na2SO4干燥,过滤并减压除去溶剂。将残余物溶于最小量的DCM中,并在搅拌下滴加至正己烷中。5分钟后,通过抽滤收集固体并干燥,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4-二氟苯基]丙烷-1-磺酰胺(0.297g,0,5470mmol,75%产率),其不经进一步纯化即使用。
分析数据:
1H NMR(200MHz,CDCl3)δ8.83(s,1H),8.65(s,1H),7.70(dd,J=13.6,8.1Hz,1H),7.02(d,J=9.6Hz,2H),6.14(d,J=9.2Hz,1H),4.14–3.64(m,2H),3.22–2.90(m,2H),2.61–2.31(m,1H),2.15–1.16(m,10H);
13C NMR(50MHz,CDCl3)δ182.4,151.0,149.7,140.7,133.7,127.33(d,J=8.6Hz),121.36(dd,J=13.1,3.8Hz),116.8,116.6,112.44(dd,J=22.6,3.7Hz),83.3,77.2,68.2,54.1,28.9,24.8,22.4,17.3,12.9;
MS:[M-1]-=540.7.
步骤2:N-[2,4-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂
环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(3)
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4-二氟苯基]丙烷-1-磺酰胺(2,271mg,0.499mmol)、双(频哪醇合)二硼(139mg,0.549mmol)和无水乙酸钾(147mg,1.50mmol)。加入脱气的干燥1,4-二噁烷(4.99mL)并且将容器抽真空并用氩气(3x)回填。加入1,1'-双(二苯基膦基)二茂铁-二氯化钯(1:1)(9.12mg,0.0125mmol),并将混合物在85℃下搅拌过夜。冷却至室温后,将混合物用EtOAc稀释,经硅藻土过滤并除去溶剂。将残余物溶于DCM,加入石油醚(60/90),并在减压下除去DCM。在4℃下冷却1h后,通过抽滤收集固体并干燥,得到N-[2,4-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(267mg,0,4520mmol,91%产率),其未经进一步纯化即使用。
分析数据:
1H NMR(200MHz,CDCl3)δ9.11(s,1H),8.94(s,1H),7.68(d,J=5.9Hz,1H),7.12–6.83(m,2H),6.22(d,J=9.0Hz,1H),4.19–3.60(m,2H),3.07(s,2H),2.57–1.11(m,23H);
13C NMR(50MHz,CDCl3)δ182.5,155.5,152.4,141.9,139.3,127.3(d,J=9.0Hz),121.23(dd,J=13.1,4.0Hz),114.9,112.33(dd,J=23.2,2.9Hz),84.4,82.8,77.2,68.1,54.1,29.0,24.9,22.5,17.2,12.9;
MS:[M-1]-=588.9.
实施例52a:3-氯-4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺
步骤1:4-溴-3-氯苯磺酰胺(2)
向4-溴-3-氯苯磺酰氯(1,0.450g,1.55mmol)的乙腈(7.76mL)的冰冷溶液中滴加25%氨溶液(0.602mL,3.88mmol)。将混合物在室温下搅拌10分钟,用水稀释并用EtOAc萃取。萃取物用盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,得到4-溴-3-氯苯磺酰胺(0.370g,1,37mmol,88%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ8.01(d,J=8.1Hz,2H),7.89–7.47(m,3H);
13C NMR(50MHz,DMSO)δ144.9,134.8,133.8,127.3,125.8,125.5;
MS:[M-1]-=267.7.
步骤2:3-氯-4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]
吡啶-5-基]苯磺酰胺(3)
向容器中装入N-[2,4-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(71.0mg,0.120mmol)、Tetrakis Pd(6.95mg,0.00601mmol)和4-溴-3-氯苯磺酰胺(2,39.0mg,0.144mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.401mL)和脱气的1.5M碳酸钾水溶液(0.240mL,0.361mmol),并将容器抽真空并用氩气(3x)回填。将混合物加热至55℃持续1h。将混合物冷却至室温,用iPrOH稀释,加入浓HCl直至混合物呈强酸性,并在70℃下继续搅拌过夜。冷却至室温后,加入固体NaHCO3中和混合物,除去溶剂,残余物经快速色谱纯化(DCM+EtOAc 20%-60%),得到3-氯-4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(23.0mg,0,0378mmol,产率31%)。
分析数据:
1H NMR(200MHz,DMSO)δ8.82(d,J=2.0Hz,1H),8.69(d,J=1.8Hz,1H),7.96–7.81(m,2H),7.74–7.55(m,3H),7.31(t,J=8.7Hz,1H),3.19–3.05(m,3H),1.87–1.62(m,2H),0.97(t,J=7.5Hz,3H);
13C NMR(101MHz,DMSO)δ183.1,152.7,151.3,145.9,142.5,140.2,133.4,132.9,131.2,130.6,127.3,125.2,122.4,113.3,54.4,17.3,13.1;
MS:[M-1]-=567.9.
实施例52b:4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]-2-氟苯磺酰胺
步骤1:4-溴-2-氟苯磺酰胺(2)
向4-溴-2-氟苯磺酰氯(1,0.450g,1.55mmol)的乙腈(10.6mL)的冰冷溶液中滴加25%氨溶液(0.823mL,5.30mmol)。将混合物在室温下搅拌10分钟,用水稀释并用EtOAc萃取。萃取物用盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,得到4-溴-2-氟苯磺酰胺(0.520g,2,05mmol,97%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ7.87–7.67(m,4H),7.60(dd,J=8.6,1.5Hz,1H);
13C NMR(50MHz,DMSO)δ158(d,J=258Hz),131.1(d,J=15Hz),129.9,127.9(d,J=4Hz),126.4(d,J=9Hz),120.5(d,J=25Hz);
MS:[M-1]-=251.8.
步骤2:4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-
5-基]-2-氟苯磺酰胺(3)
向容器中装入N-[2,4-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(74.0mg,0.125mmol)、4-溴-2-氟苯磺酰胺(35.0mg,0.138mmol)和XPhos Pd G3(1.06mg,0.00125mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.418mL)和脱气的1.5M碳酸钾水溶液(0.251mL,0.376mmol),将容器抽真空并用氩气(3x)回填。将混合物加热至55℃持续2h。将混合物冷却至室温,用iPrOH(3mL)稀释,加入浓HCl直至混合物呈强酸性,并在70℃下继续搅拌过夜。冷却至室温后,加入固体NaHCO3中和混合物,除去溶剂,残余物经快速色谱纯化(DCM+EtOAc 20%-60%),得到4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]-2-氟苯磺酰胺(26.0mg,0,0460mmol,37%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ15.01(s,1H),9.81(s,1H),9.13(s,1H),8.91(s,1H),8.14–7.53(m,6H),7.43–7.21(m,1H),3.21–3.06(m,2H),1.90–1.63(m,2H),0.97(t,J=7.5Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,159.6,157.1,155.0,155.0,154.0,153.9,152.5,149.8,143.2,143.2,142.0,130.8,130.7,130.3,130.2,129.9,129.8,129.0,128.6,123.3,123.3,121.8,121.8,121.7,121.7,116.0,115.7,113.3,112.2,112.2,112.0,53.8,16.7,12.5,所有报告的峰;
MS:[M-1]-=551.9.
实施例52c:4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]-3-甲基苯磺酰胺
步骤1:4-溴-3-甲基苯磺酰胺(2):
向4-溴-3-甲基苯磺酰氯(1,0.690g,2,76mmol)的乙腈(1.48mL)的冰冷溶液中滴加25%氨溶液(1.15mL,7.42mmol)。将混合物在室温下搅拌10分钟,用水稀释并用乙醚萃取。萃取物用盐水洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,得到4-溴-3-甲基苯磺酰胺(0.690g,2,76mmol,93%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ7.86–7.72(m,2H),7.56(ddd,J=8.4,2.3,0.5Hz,1H),7.43(s,2H),2.41(s,3H);
13C NMR(50MHz,DMSO)δ143.5,138.5,132.8,127.9,125.0,22.6;
MS:[M-1]-=247.7.
步骤2:4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-
5-基]-3-甲基-苯磺酰胺(3)
向容器中装入N-[2,4-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(75.0mg,0.127mmol)、4-溴-3-甲基苯磺酰胺(34.9mg,0.140mmol)和XPhos Pd G3(2.69mg,0.00318mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.423mL)和脱气的1.5M碳酸钾水溶液(0.254mL,0.381mmol),将容器抽真空并用氩气(3x)回填。将混合物加热至55℃持续1.5h。在减压下去除溶剂,将残余物置于THF 2mL和1.25M HCl的iPrOH溶液中且在70℃下搅拌过夜。除去溶剂,残余物用NaHCO3中和并用EtOAc萃取。除去溶剂,残余物通过快速色谱法纯化(DCM+EtOAc 10%-50%)并用DCM研碎,得到4-[3-[2,6-二氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]-3-甲基苯磺酰胺(41.0mg,0,0739mmol,58%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ15.00(s,1H),9.82(s,1H),8.76(d,J=2.0Hz,1H),8.55(d,J=1.9Hz,1H),7.84(s,1H),7.78(dd,J=8.0,1.3Hz,1H),7.67–7.56(m,2H),7.44(s,2H),7.31(t,J=8.7Hz,1H),3.16–3.07(m,2H),1.80–1.69(m,2H),0.97(t,J=7.4Hz,3H);
13C NMR(101MHz,DMSO)δ182.5,152.0,150.7,143.7,141.8,141.0,136.6,132.4,130.9,129.9,127.3,123.3,113.0,53.8,20.1,16.8,12.5;
MS:[M-1]-=547.9.
实施例53
根据方案3中所示的程序制备实施例53a-53c的化合物。
方案3:
步骤1:5-溴-N-甲氧基-N-甲基-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-甲酰胺
向5-溴-N-甲氧基-N-甲基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(4.43g,15.5mmol)的DCM(62.2mL)悬浮液中加入二氢吡喃(2.84mL,31.1mmol)和对甲苯磺酸一水合物(0.591g,3.11mmol)并将混合物加热至回流温度持续30分钟。冷却后,将混合物用饱和NaHCO3-溶液和盐水洗涤,经Na2SO4干燥,过滤并减压除去溶剂。将残余物通过快速色谱法(己烷+EtOAc 10%至50%)纯化,得到呈油状物的5-溴-N-甲氧基-N-甲基-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-甲酰胺(5.05g,13,7mmol,88%产率),将其在高真空中干燥并静置后固化。
分析数据:
1H NMR(200MHz,CDCl3)δ8.69(d,J=2.0Hz,1H),8.58(d,J=2.2Hz,1H),6.12(dd,J=10.0,2.4Hz,1H),4.15–4.01(m,1H),3.93–3.71(m,4H),3.54(s,3H),2.71–2.48(m,1H),2.22–1.65(m,5H);
13C NMR(50MHz,CDCl3)δ150.5,149.0,136.5,134.2,118.3,115.1,83.0,68.2,61.9,29.2,25.0,22.8;
MS:[M+H]+=390.8.
步骤2a:(3-氨基-2,6-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-
基]甲酮:
向冷却至-78℃的2,4-二氟苯胺(0.815g,6.32mmol)和三甲基氯硅烷(1.60mL,12.6mmol)的四氢呋喃(5.74mL)溶液中滴加2M二异丙基氨基锂(6.32mL,12.6mmol)的THF/庚烷/乙苯溶液。将混合物升温至室温并搅拌30分钟。加入5-溴-N-甲氧基-N-甲基-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-甲酰胺(1.06g,2.87mmol),并将混合物冷却至-30℃。滴加二异丙基氨基锂(3.16mL,6.32mmol)的THF/庚烷/乙苯溶液,并将混合物在-15℃下搅拌10分钟。加入2N HCl(20mL)并在室温下继续搅拌20分钟。将混合物用2N NaOH调节至pH~9并用EtOAc萃取。将萃取物用盐水洗涤,经Na2SO4干燥,过滤并除去溶剂。将残余物通过快速色谱法(己烷+EtOAc,10%至40%)纯化,得到为黄色固体的(3-氨基-2,6-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(0.732g,1,67mmol,58%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ8.86(d,J=2.2Hz,1H),8.79(d,J=2.2Hz,1H),7.31–6.69(m,2H),6.14(dd,J=9.8,2.0Hz,1H),5.28(s,2H),4.02–3.85(m,1H),3.81–3.62(m,1H),2.42–2.14(m,1H),2.04–1.46(m,5H);
13C NMR(50MHz,DMSO)δ183.7,151.0,149.1,140.3,132.8,116.3,115.5,82.9,67.1,28.4,24.4,21.6;
MS:[M+Na]+=458.9.
步骤2b:(3-氨基-2,4,6-三氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-
3-基]甲酮:
向冷却至-78℃的2,4,6-三氟苯胺(0.789g,5.36mmol)和三甲基氯硅烷(1.36mL,10.7mmol)的四氢呋喃(4.88mL)溶液中滴加2M二异丙基氨基锂(5.36mL,10.7mmol)的THF/庚烷/乙苯溶液。将混合物升温至室温并搅拌30分钟。加入5-溴-N-甲氧基-N-甲基-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-甲酰胺(0.900g,2.44mmol),并将混合物冷却至-30℃。滴加二异丙基氨基锂(2.68mL,5.36mmol)的THF/庚烷/乙苯溶液,并将混合物在-15℃下搅拌20分钟。加入2N HCl(20mL)并在室温下继续搅拌10分钟。将混合物用2N NaOH调节至pH 9并用EtOAc萃取。萃取物用盐水洗涤,经Na2SO4干燥并除去溶剂。TLC-MS显示TMS-基团几乎没有去保护。将残余物溶解于10mL THF,加入1mL浓HCl。立即完成去保护。在用EtOAc稀释后,加入固体K2CO3,过滤悬浮液并除去溶剂。残留物通过快速色谱法纯化(己烷+EtOAc 5%至25%)。产率:715mg,64%。
分析数据:
1H NMR(200MHz,DMSO)δ8.85(d,J=2.1Hz,1H),8.79(d,J=2.2Hz,1H),7.34–7.16(m,1H),6.14(d,J=8.4Hz,1H),5.36(s,2H),4.03–3.82(m,1H),3.84–3.58(m,1H),2.44–2.17(m,1H),2.05–1.51(m,5H);
13C NMR(50MHz,DMSO)δ182.7,151.0,149.2,140.2,132.8,116.3,115.5,82.9,67.0,28.4,24.4,21.6;
MS:[M+Na]+=476.9.
实施例53a:4-[3-[2,6-二氟-3-(苯基氨磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺
步骤1:N-苯基氨基磺酸钠(2)的制备
将苯胺(1,3.95g,42.4mmol)和三乙胺(59.1mL,424mmol)溶解于DCM(106mL)中。在-5℃滴加氯磺酸(2.82mL,42.4mmol)并将混合物搅拌10分钟。将混合物真空浓缩并将固体溶解在1N氢氧化钠(84.8mL,84.8mmol)中。将混合物真空浓缩至干燥。将产物悬浮在约500mL沸腾EtOH中,趁热过滤并减少至约150mL。冷却至7℃过夜后,过滤收集产物,真空干燥,得到N-苯基氨基磺酸钠(3.94g,20,2mmol,48%产率),为白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ7.90(s,1H),7.15–7.01(m,4H),6.74–6.63(m,1H);
13C NMR(50MHz,DMSO)δ143.7,128.2,118.5,116.3.
步骤2:苯基氨磺酰氯(3)的制备
将N-苯基氨基磺酸钠(2,1.12g,5.74mmol)和五氯化磷(1.20g,5.74mmol)在80℃下在甲苯(19.1mL)中在油浴中加热6h。将反应物过滤并真空浓缩,得到N-苯基氨磺酰氯(0.990g,5,17mmol,90%产率),为油状物,其在静置后固化。产物无需进一步纯化和表征即可使用。
步骤3:[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]-[2,6-二氟-3-(苯基氨
磺酰胺基)苯基]甲酮(4)
在0℃向(3-氨基-2,6-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(0.127g,0.290mmol)和三乙胺(0.0607mL,0.436mmol)的DCM(1.45mL)溶液中加入N-苯基氨磺酰氯(0.0724g,0.378mmol)的DCM(1.45mL)溶液。在室温下搅拌10分钟后,用DCM稀释混合物,用水和NH4Cl溶液洗涤,经Na2SO4干燥,过滤并减压除去溶剂,得到[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]-[2,6-二氟-3-(苯基氨磺酰胺基)苯基]甲酮(0.170g,0,2870mmol,99%收率),其不经进一步纯化即使用。向粘性油中添加2mL Et2O并在真空中快速去除溶剂以获得呈发泡固体状的产物。
分析数据:
1H NMR(200MHz,CDCl3)δ8.89(d,J=2.1Hz,1H),8.71(d,J=2.1Hz,1H),7.73(td,J=8.9,5.4Hz,1H),7.47–6.97(m,8H),6.21(dd,J=9.7,2.1Hz,1H),3.97(dd,J=46.6,10.1Hz,2H),2.66–2.39(m,1H),2.22–1.56(m,5H);
13C NMR(50MHz,CDCl3)δ182.4,151.0,149.6,140.7,136.0,133.7,129.5,125.8,121.6,116.8,116.6,83.4,68.2,29.0,24.8,22.4;
MS:[M-1]-=589.8.
步骤4:4-[3-[2,6-二氟-3-(苯基氨磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡
啶-5-基]苯磺酰胺(5)
向容器中装入[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]-[2,6-二氟-3-(苯基氨磺酰胺基)苯基]甲酮(4,0.0880g,0.149mmol)、(4-氨磺酰基苯基)硼酸(32.8mg,0.163mmol)和XPhos Pd G3(3.77mg,0.00446mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.495mL)和脱气的1.5M碳酸钾水溶液(0.297mL,0.446mmol),并将混合物在65℃下搅拌1.5h。加入饱和NH4Cl溶液和EtOAc,分离各相。有机相经Na2SO4干燥并蒸发。将残余物置于THF(3mL)中并在室温下添加TFA(300μL)。搅拌过夜后,再加入300μL TFA,并继续搅拌2h(10-12h)。(仍未转化)将混合物浓缩并置于DCM(3mL)中并超声处理。加入另外300μL TFA并在室温下继续搅拌。3h后,在室温下加入3mL TFA,将混合物搅拌过夜并在NaHCO3溶液中淬灭。水相用EtOAc萃取,萃取物经Na2SO4干燥并除去溶剂。产物经快速色谱法(DCM+MeOH 3%至13%)纯化,得到4-[3-[2,6-二氟-3-(苯基氨磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(34.0mg,0,0547mmol,37%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ14.96(s,1H),10.20(s,1H),10.09(s,1H),9.09(d,J=1.9Hz,1H),8.84(d,J=1.9Hz,1H),8.14–7.89(m,4H),7.60–7.41(m,3H),7.37–7.15(m,5H),7.02(t,J=6.9Hz,1H);
MS:[M-1]-=583.0.
实施例53b:4-([3-[2,6-二氟-3-(氨磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺
步骤1:N-氯磺酰基氨基甲酸叔丁酯(2)的制备
向氯磺酰基异氰酸酯(1,1.78mL,20.4mmol)的甲苯(8.17mL)溶液中缓慢加入2-甲基丙-2-醇(1.66g,22.5mmol)的甲苯(1.16mL)溶液。将混合物在室温下搅拌1h。加入己烷(23.1mL)并将溶液搅拌30分钟。将形成的沉淀过滤并用己烷洗涤,得到N-氯磺酰基氨基甲酸叔丁酯(3.33g,15,4mmol,76%产率),为白色固体,将其在氮气下在-20℃储存。
分析数据:
1H NMR(200MHz,CDCl3)δ8.86(s,1H),1.56(s,9H);
13C NMR(50MHz,CDCl3)δ148.0,87.3,27.9.
步骤2:N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4-二氟苯基]
氨磺酰基]氨基甲酸叔丁酯(3)
在0℃下℃,向(3-氨基-2,6-二氟苯基)[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(3,0.126g,0.288mmol)和三乙胺(0.0602mL,0.432mmol)的DCM(1.15mL)溶液中加入N-氯磺酰基氨基甲酸叔丁酯(0.0808g,0.375mmol)的DCM(1mL)溶液。在室温下搅拌10分钟后,将混合物用DCM稀释,用水和NH4Cl溶液洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4-二氟苯基]氨磺酰基]氨基甲酸叔丁酯(0.176g,0,2860mmol,99%产率),为黄色泡沫,其不经进一步纯化即使用。
分析数据:
1H NMR(200MHz,CDCl3)δ8.89(d,J=1.8Hz,1H),8.70(d,J=1.8Hz,1H),7.74(td,J=8.9,5.8Hz,1H),7.06(t,J=8.4Hz,1H),6.19(d,J=7.6Hz,1H),4.08(d,J=11.1Hz,1H),3.91–3.72(m,1H),2.66–2.39(m,1H),2.22–1.90(m,2H),1.88–1.57(m,3H),1.45(s,9H);
13C NMR(50MHz,CDCl3)δ182.4,151.0,150.4,149.7,140.7,133.7,116.8,116.6,84.2,83.5,77.2,68.2,46.0,27.9,24.8,22.4.
MS:[M-1]-=613.9.
步骤3:4-[3-[2,6-二氟-3-(氨磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-
基]苯磺酰胺(4)
向容器中装入N-[[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4-二氟苯基]氨磺酰基]氨基甲酸叔丁酯(3,129mg,0.209mmol)、(4-氨磺酰基苯基)硼酸(46.3mg,0.230mmol)和XPhos Pd G3(5.31mg,0.00628mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.698mL)和脱气的1.5M碳酸钾水溶液(0.419mL,0.628mmol),并将混合物在65℃下搅拌1.5h。加入饱和NH4Cl溶液和EtOAc,分离各相。有机相经Na2SO4干燥并蒸发。将残余物置于DCM(3mL)中并在室温下添加TFA(300μL)。搅拌过夜后,将混合物在NaHCO3溶液中淬灭并用EtOAc萃取。将萃取物经Na2SO4干燥并除去溶剂。产物经快速色谱法(DCM+MeOH 1%至11%)纯化,得到4-[3-[2,6-二氟-3-(氨磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(37.0mg,0.0728mmol,35%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ14.96(s,1H),9.32(s,1H),9.10(d,J=2.0Hz,1H),8.86(d,J=2.0Hz,1H),8.02(dd,J=20.7,8.4Hz,4H),7.68(td,J=8.9,5.9Hz,1H),7.47(s,2H),7.36–7.13(m,3H);
MS:[M-1]-=507.0.
实施例53c:4-[3-[2,4,6-三氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺
步骤1:N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4,6-三氟苯
基]-N-丙基磺酰基丙烷-1-磺酰胺(2)
在0℃下,向(3-氨基-2,4,6-三氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(1,0.289g,0.635mmol)和三乙胺(0.133mL,0.952mmol)的DCM(2.54mL)溶液中缓慢加入1-丙烷磺酰氯(0.0715mL,0.635mmol)。在室温下搅拌15分钟后,将混合物用DCM稀释,用NH4Cl溶液洗涤,经Na2SO4干燥并除去溶剂。残余物通过快速色谱法(己烷+EtOAc,0至25%)纯化,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4,6-三氟苯基]-N-丙基磺酰基丙烷-1-磺酰胺(0.233g,0,3490mmol,55%产率)。将得到的油状物溶解于DCM,加入己烷,并除去溶剂。灰白色固体。
分析数据:
1H NMR(200MHz,CDCl3)δ8.81(d,J=2.0Hz,1H),8.65(d,J=2.0Hz,1H),6.97(td,J=9.1,1.8Hz,1H),6.15(dd,J=9.9,2.2Hz,1H),4.03(d,J=11.1Hz,1H),3.88–3.48(m,5H),2.53(dd,J=20.4,11.9Hz,1H),2.15–1.51(m,9H),1.07(td,J=7.4,3.9Hz,6H);
13C NMR(50MHz,CDCl3)δ180.6,151.1,149.7,140.4,133.5,116.8,116.5,83.2,68.1,58.3,28.7,24.8,22.4,16.7,12.9;
MS:[M+Na]+=688.8.
步骤2:N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4,6-三氟苯
基]丙烷-1-磺酰胺(3)
向N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4,6-三氟苯基]-N-丙基磺酰基丙烷-1-磺酰胺(2,0.227g,0.340mmol)的四氢呋喃(1.2mL)和MeOH(0.40mL)溶液中加入1M NaOH水溶液(1.02mL,1.02mmol)。搅拌1h后,加入水(3mL)并蒸发有机溶剂。加入2N HCl中和混合物。通过抽滤收集固体并干燥,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4,6-三氟苯基]丙烷-1-磺酰胺(0.159g,0,2830mmol,83%产率),为灰白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ9.70(s,1H),8.84(d,J=10.9Hz,2H),7.62(t,J=9.3Hz,1H),6.15(d,J=8.6Hz,1H),4.08–3.59(m,2H),3.25–3.06(m,2H),2.40–2.16(m,1H),2.08–0.76(m,10H);
13C NMR(50MHz,DMSO)δ151.2,149.2,139.8,132.7,116.6,115.5,82.9,67.1,54.8,28.4,24.4,21.7,16.9,12.6;
MS:[M-1]-=559.0.
步骤3:4-[3-[2,4,6-三氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡
啶-5-基]苯磺酰胺(4)
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,4,6-三氟苯基]丙烷-1-磺酰胺(3,0.113g,0.201mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯磺酰胺(62.7mg,0.221mmol)和XPhos Pd G3(4.26mg,0.00503mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.671mL)和脱气的1.5M碳酸钾(0.403mL,0.604mmol),并将混合物加热至65℃持续1h。加入NH4Cl溶液,混合物用EtOAc萃取。萃取物用盐水洗涤,经Na2SO4干燥并除去溶剂。将残余物置于DCM(3mL),加入TFA(300μL),将混合物在室温下搅拌过夜。加入3mL TFA并继续搅拌1h。将反应在NaHCO3溶液中淬灭,用EtOAc萃取,用Na2SO4干燥并除去溶剂。将残余物通过快速色谱法(DCM+MeOH 1%至11%)纯化,得到4-[3-[2,4,6-三氟-3-(丙基磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(60.0mg,0,1070mmol,53%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ15.02(s,1H),9.66(s,1H),9.10(d,J=2.1Hz,1H),8.85(d,J=2.1Hz,1H),8.02(dd,J=37.6,8.5Hz,4H),7.59(t,J=9.4Hz,1H),7.47(s,2H),3.14(dd,J=8.7,6.6Hz,2H),1.88–1.73(m,2H),0.99(t,J=7.4Hz,3H);
13C NMR(101MHz,DMSO)δ181.5,152.4,149.9,143.5,141.8,140.3,131.5,128.2,127.9,126.4,113.4,54.7,16.8,12.5;
MS:[M-1]-=552.0.
实施例53d:4-[3-[3-(乙基氨磺酰胺基)-2,6-二氟苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(5)
步骤1:N-乙基氨磺酰氯(2)
类似于文献程序:将乙胺盐酸盐(2.00g,24.5mmol)和磺酰氯(7.93mL,98.1mmol)的乙腈(4.91mL)混合物加热至75℃过夜。将混合物蒸发,用乙醚处理并过滤。除去溶剂,得到N-乙基氨磺酰氯(3.28g,22,8mmol,93%产率),其不经进一步表征即使用。
步骤2:[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]-[3-(乙基氨磺酰胺基)-
2,6-二氟苯基]甲酮(4)
在0℃下,向(3-氨基-2,6-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(90.0mg,0.206mmol)和三乙胺(0.0373mL,0.268mmol)的DCM(0.823mL)溶液中加入N-乙基氨磺酰氯(35.5mg,0.247mmol)的DCM(0.823mL)溶液。在室温下搅拌10分钟后,将混合物用DCM稀释,用水和NH4Cl溶液洗涤,经Na2SO4干燥,过滤并在减压下除去溶剂,得到[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]-[3-(乙基氨磺酰胺基)-2,6-二氟苯基]甲酮(4,0.110g,0,202mmol,98%产率),为黄色泡沫状物,其不经进一步纯化即使用。
分析数据:
1H NMR(200MHz,CDCl3)δ8.85(s,1H),8.67(s,1H),7.69(td,J=8.9,5.6Hz,1H),7.01(t,J=8.9Hz,1H),6.73(s,1H),6.15(d,J=7.5Hz,1H),4.75(t,J=5.9Hz,1H),4.13–3.97(m,1H),3.90–3.67(m,1H),3.24–3.04(m,2H),2.63–2.31(m,1H),2.21–1.51(m,5H),1.16(t,J=7.2Hz,3H).
13C NMR(50MHz,CDCl3)δ182.6,156.8(dd,J=252.0,6.7Hz),151.5(dd,J=250.7,7.5Hz),151.1,149.7,140.8,133.8,125.8(dd,J=9.8,2.0Hz),122.0(dd,J=12.7,3.5Hz),116.8,116.6,112.29(dd,J=22.2,3.8Hz),83.4,68.3,38.6,29.0,24.8,22.5,15.1.
步骤3:4-[3-[3-(乙基氨磺酰胺基)-2,6-二氟苯甲酰基]-1H-吡唑并[3,4-b]吡
啶-5-基]苯磺酰胺(5)
向容器中装入[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]-[3-(乙基氨磺酰胺基)-2,6-二氟苯基]甲酮(4,94.0mg,0.173mmol)、(4-氨磺酰基苯基)硼酸(38.2mg,0.190mmol)和XPhos Pd G3(4.38mg,0.00518mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.576mL)和脱气的1.5M碳酸钾水溶液(0.345mL,0.518mmol),并将混合物在65℃下搅拌1.5h。加入饱和NH4Cl溶液和EtOAc,分离各相。有机相经Na2SO4干燥并蒸发。将残余物置于DCM(3mL)中并在室温下添加TFA(300μL)。4h后,将混合物在NaHCO3溶液中淬灭并用EtOAc萃取。将萃取物经Na2SO4干燥并除去溶剂。产物经快速色谱法(DCM+MeOH 1%至11%)纯化,得到4-[3-[3-(乙基氨磺酰胺基)-2,6-二氟苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(5,35.0mg,0,0652mmol,38%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ14.97(s,1H),9.54(s,1H),9.10(d,J=2.0Hz,1H),8.86(d,J=1.9Hz,1H),8.02(dd,J=38.5,8.3Hz,4H),7.64(td,J=9.0,5.9Hz,1H),7.51–7.41(m,3H),7.30(t,J=8.7Hz,1H),3.04–2.88(m,2H),1.04(t,J=7.2Hz,3H);
13C NMR(101MHz,DMSO)δ182.8,162.8,152.4,149.8,143.5,142.0,140.3,131.4,128.2,127.9,126.4,113.4,37.2,14.6;
MS:[M-1]-=535.0.
实施例54:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲磺酰胺(6)的合成
步骤1:N-(2,6-二氟苯基)乙酰胺
将2,6-二氟苯胺(1,3.34g,25.9mmol)和乙酸酐(2.56mL,27.2mmol)在DCM(34.5mL)中合并并在室温下搅拌过夜。将反应混合物用DCM(50mL)稀释,用水和饱和碳酸氢钠洗涤,经Na2SO4干燥并蒸发,得到N-(2,6-二氟苯基)乙酰胺(2,3.88g,22,7mmol,88%产率),为白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ9.69(s,1H),7.43–7.23(m,1H),7.13(t,J=7.9Hz,2H),2.08(s,3H);
13C NMR(50MHz,DMSO)δ168.5,160.4,160.3,155.5,155.4,128.0,127.8,127.6,115.1,114.7,114.4,112.1,112.0,111.9,111.8,111.6,111.6,22.4,所有报告的峰;
MS:[M+H]+=171.9.
步骤2:3-溴-2,6-二氟苯胺(3)
将N-(2,6-二氟苯基)乙酰胺(2,8.77g,51.2mmol)溶解于硫酸(41.0mL,769mmol)中并且在室温下分批添加N-溴代琥珀酰亚胺(9.12g,51.2mmol)。将反应物在室温下搅拌过夜并在搅拌下在冰水(400mL)中缓慢淬灭。通过抽滤收集固体,并用水、己烷、己烷+EtOAc(8+2)和己烷再次洗涤。将固体置于乙醇(30.0mL)和浓HCl(30mL)并加热至回流持续3h。将混合物倒入冰(400g),然后用固体NaOH中和,并通过抽滤收集固体,用水洗涤并真空干燥,得到3-溴-2,6-二氟苯胺(3,7.83g,37,6mmol,73%产率)。
分析数据:
1H NMR(200MHz,CDCl3)δ6.95–6.59(m,2H),3.84(s,2H);
13C NMR(50MHz,CDCl3)δ152.2(dd,J=133.8,6.5Hz),147.5(dd,J=132.7,6.9Hz),125.4(t,J=16.9Hz),122,119.6(d,J=8.4Hz),111.7(dd,J=19.9,3.1Hz),103.8(dd,J=19.2,3.8Hz).
步骤3:(3-氨基-2,4-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(5)
在0℃下,向3-溴-2,6-二氟苯胺(3,12.9g,61.9mmol)的四氢呋喃(76.9mL)溶液中滴加2M异丙基氯化镁的THF(30.9mL,61.9mmol)溶液,并在室温下搅拌15分钟。冷却至0℃后,加入三甲基氯硅烷(7.85mL,61.9mmol),将混合物升温至25℃并搅拌20分钟。将悬浮液冷却至0℃,滴加2M异丙基氯化镁的THF(30.9mL,61.9mmol)溶液,并在室温下搅拌15分钟。冷却至0℃后,加入三甲基氯硅烷(7.85mL,61.9mmol),在25℃下继续搅拌20分钟。将悬浮液再次冷却至0℃,滴加2M异丙基氯化镁的THF(30.9mL,61.9mmol)溶液,并将混合物在0℃下搅拌10分钟(溶液A)。同时,在0℃下,将2M异丙基氯化镁的THF(13.5mL,26.9mmol)溶液滴加到5-溴-N-甲氧基-N-甲基-1H-吡唑并[3,4-b]吡啶-3-甲酰胺(4,7.67g,26.9mmol)的四氢呋喃(76.9mL)悬浮液中。将所得悬浮液搅拌5分钟并转移至溶液A中。将反应物在室温下搅拌过夜,加入浓HCl(26.9mL,323mmol)并搅拌10分钟。加入水直至各相变得澄清。将混合物用2N NaOH中和,用NaCl饱和并用THF萃取。将萃取物用盐水洗涤,经Na2SO4干燥并过滤。蒸发溶剂后,将固体在100mL DCM中搅拌,通过抽滤收集并干燥,得到6.35g第一批产物,为浅黄色固体。蒸发滤液,用乙醚和DCM研碎,得到第二批产物(0.41g)。总共产生(3-氨基-2,4-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(5,6.76g,19.1mmol,71%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ14.55(s,1H),8.65(dd,J=5.2,2.1Hz,2H),7.13–6.86(m,2H),5.44(s,2H);
13C NMR(50MHz,DMSO)δ186.1,153.5(dd,J=188,9Hz),150.8,150.3,148.6(dd,J=191,9Hz),141.1,132.5,126.1(t,J=17Hz),122.8(dd,J=12,3Hz),116.2(dd,J=9,3Hz),115.4,115,110.6(dd,J=19,3Hz);
MS:[M-1]-=351.2.
步骤4:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲磺酰胺
(6)
向(3-氨基-2,4-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(5,0.620g,1.76mmol)的吡啶(2.83mL,35.1mmol)悬浮液中加入甲磺酰氯(0.544mL,7.02mmol),在RT 50℃持续2h。将反应物浓缩,置于2M氢氧化钠溶液(13.2mL,26.3mmol),并搅拌15分钟。将该溶液倒入冷冻的3N HCl 20mL中,用EtOAc萃取,萃取物用2N HCl洗涤,经Na2SO4干燥并蒸发。产物通过快速色谱法(DCM+EtOAc 0%至40%)纯化,得到N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲烷-磺酰胺(0.390g,0,9040mmol,52%产率),为红色固体。
分析数据:
1H NMR(400MHz,DMSO)δ14.87(s,1H),9.75(s,1H),8.71(d,J=13.9Hz,2H),7.85(d,J=6.6Hz,1H),7.39(t,J=8.5Hz,1H),3.12(s,3H);
13C NMR(101MHz,DMSO)δ184.7,160.8(dd,J=255,3Hz),157.06(dd,J=257.4,4.2Hz),150.8,150.5,140.9,132.4,130.6(dd,J=10,3Hz),123.3(dd,J=13,3Hz),115.4,115.1,114.3(t,J=17Hz),111.9(dd,J=21,3Hz),41.5;
MS:[M-1]-=429.1.
实施例54a:N-[2,6-二氟-3-[5-[4-(1H-四唑-5-基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺
向微波容器中装入N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲磺酰胺(60.0mg,0.139mmol)、XPhos Pd G3(3.53mg,0.00417mmol)和[4-(1H-四唑-5-基)苯基]硼酸(31.7mg,0.167mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.464mL)和脱气的1.5M碳酸钾水溶液(0.325mL,0.487mmol)并且将混合物在微波辐射下加热至110℃持续60分钟。冷却后,将混合物用EtOAc稀释并用饱和NH4Cl溶液中和。将有机相减压浓缩,并将产物通过快速色谱法(DCM+MeOH(+1%甲酸)5%至15%)分离,用MeOH研碎,并在真空烘箱中在100℃下干燥,得到N-[2,6-二氟-3-[5-[4-(1H-四唑-5-基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(21.0mg,0,0423mmol,30%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ14.85(s,1H),9.75(s,1H),9.10(d,J=2.1Hz,1H),8.86(d,J=2.2Hz,1H),8.25–8.00(m,4H),7.97–7.81(m,1H),7.41(td,J=8.9,1.3Hz,1H),3.12(s,3H);
MS:[M-1]-=495.2.
实施例54b:4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酰胺
向微波容器中装入N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲磺酰胺(60.0mg,0.139mmol)、XPhos Pd G3(5.89mg,0.00696mmol)和(4-氨基甲酰基苯基)硼酸(27.5mg,0.167mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.464mL)和脱气的1.5M碳酸钾水溶液(0.325mL,0.487mmol)并且将混合物在微波辐射下加热至110℃持续60分钟。冷却后,将混合物用EtOAc稀释并用饱和NH4Cl溶液中和。在减压下除去溶剂,并将产物通过快速色谱法(DCM+MeOH,5%至15%)分离,在真空烘箱中于100℃下干燥,得到4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酰胺(40.0mg,0,0789mmol,57%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ9.06(d,J=1.9Hz,1H),8.82(d,J=2.0Hz,1H),8.14–7.80(m,6H),7.49–7.33(m,2H),3.11(s,3H);
MS:[M-1]-=470.3
实施例54c:4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺
向微波容器中装入N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲磺酰胺(60.0mg,0.139mmol)、XPhos Pd G3(5.89mg,0.00696mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯磺酰胺(47.3mg,0.167mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.464mL)和脱气的1.5M碳酸钾水溶液(0.325mL,0.487mmol)并且将混合物在微波辐射下加热至110℃持续60分钟。冷却后,将混合物用EtOAc稀释并用饱和NH4Cl溶液中和。在减压下除去溶剂,并将产物通过快速色谱法(DCM+EtOAc,50%至100%)分离,在真空烘箱中于100℃下干燥,得到4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺(31.0mg,0,0574mmol,41%产率)。1H NMR(200MHz,DMSO)δ9.07(d,J=2.1Hz,1H),8.84(d,J=2.1Hz,1H),8.12–7.78(m,4H),7.50–7.32(m,2H),3.11(s,3H);[M-1]-=506.2.
实施例55:4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸(4)和4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸乙酯(5)的合成
步骤1:N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]
甲磺酰胺(2)
向N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]甲磺酰胺(380mg,0.881mmol)和对甲苯磺酸一水合物(33.5mg,0.176mmol)的DCM(2.94mL)悬浮液中加入二氢吡喃(0.161mL,1.76mmol)并将反应物加热至回流温度持续1h。将反应物用DCM稀释,用饱和NaHCO3溶液洗涤,经Na2SO4干燥并浓缩。将残余物用正己烷研碎,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]甲烷-磺酰胺(370mg,0,7180mmol,81%产率),为米色固体。
分析数据:
1H NMR(200MHz,DMSO)δ9.78(s,1H),8.80(dd,J=13.4,1.6Hz,2H),7.88(dd,J=14.6,7.8Hz,1H),7.43(t,J=9.0Hz,1H),6.14(d,J=8.6Hz,1H),3.94(d,J=11.6Hz,1H),3.72(dd,J=14.6,9.1Hz,1H),3.13(s,3H),2.46–2.19(m,1H),2.00–1.18(m,5H);
13C NMR(50MHz,DMSO)δ184.4,150.8,149.0,139.9,133.0,116.1,116.0,82.7,67.2,41.5,28.5,24.5,21.8;
MS:[M-1]-=513.2.
步骤2:4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-
b]吡啶-5-基]苯甲酸(3)
N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]甲磺酰胺(355mg,0.689mmol)和4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苯甲酸(188mg,0.758mmol)和XPhos Pd G3(17.5mg,0.0207mmol)在脱气的1,4-二噁烷(2.30mL)和1.5M碳酸钾(2.07mL,3.10mmol)中合并。将反应抽真空并用氩气(3x)吹扫。加入XPhos PdG3(17.5mg,0.0207mmol)并将反应在60℃油浴温度下搅拌3h。冷却后,将混合物用2N HCl酸化并用EtOAc萃取。将萃取物用盐水洗涤,经Na2SO4干燥并浓缩。将残余物通过快速色谱法(DCM+MeOH 3%至25%)纯化并用正己烷研碎,得到4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸(276mg,0,4960mmol,72%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ9.77(s,1H),9.10(d,J=2.1Hz,1H),8.83(d,J=2.1Hz,1H),8.09(d,J=8.3Hz,2H),7.96(d,J=8.3Hz,2H),7.90(dd,J=14.8,7.6Hz,1H),7.44(t,J=8.8Hz,1H),6.21(dd,J=9.9,2.0Hz,1H),4.01–3.91(m,1H),3.80–3.68(m,1H),3.59(t,J=6.6Hz,2H),3.13(s,3H),2.46–2.33(m,1H),2.06–1.93(m,2H),1.84–1.68(m,2H);
MS:[M-1]-=555.4.
步骤3:4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-
基]苯甲酸(4)
将4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸(203mg,0.365mmol)悬浮于3N HCl中并在搅拌下加热至70℃过夜。将反应物浓缩,通过抽滤收集固体,用水洗涤并在100℃下干燥,得到4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸(133mg,0.2820mmol,77%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ9.06(d,J=2.1Hz,1H),8.83(d,J=2.1Hz,1H),8.10(d,J=8.3Hz,2H),8.00–7.80(m,3H),7.40(td,J=9.0,1.3Hz,1H),3.12(s,3H);
MS:[M-1]-=471.2.
步骤4:4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-
基]苯甲酸乙酯(5)
将4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸(50.0mg,0.0898mmol)在1.25M HCl的乙醇(0.719mL,0.898mmol)溶液中在密封容器中在75℃下搅拌。3h后加入200μL H2SO4并继续在75℃下搅拌过夜。将反应物在NaHCO3溶液中淬灭,通过离心收集固体,用水和乙醚洗涤,真空干燥,得到4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸乙酯(22.0mg,0,0440mmol,49%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ14.86(s,1H),9.74(s,1H),9.06(d,J=2.1Hz,1H),8.83(d,J=2.1Hz,1H),8.18–7.80(m,5H),7.41(t,J=8.9Hz,1H),4.36(q,J=7.0Hz,2H),3.12(s,3H),1.35(t,J=7.0Hz,3H);
MS:[M-1]-=499.4.
实施例56:[(2S)-2-氨基-3-甲氧基-3-氧代丙基-4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸酯盐酸盐的合成
步骤1:[(2S)-3-甲氧基-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代丙基]4-溴
苯甲酸酯
将4-溴苯甲酰氯(1.13g,5.15mmol)溶于25.7mL THF中并冷却至0℃。加入三乙胺(0.861mL,6.18mmol)并向所得悬浮液中加入(2S)-3-羟基-2-[(2-甲基丙-2-基)氧基羰基氨基]-丙酸甲酯(1.35g,6.18mmol)和4-DMAP(31.5-mg,0.257mmol)。将混合物在室温下搅拌60分钟,然后用EtOAc稀释并用水、饱和NaHCO3和饱和NH4Cl溶液洗涤。在经Na2SO4干燥后,真空除去溶剂。将残余物溶于少量MeOH中并在搅拌下加入水中。通过抽滤收集固体并干燥,得到[(2S)-3-甲氧基-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代丙基]4-溴苯甲酸酯(1.70g,4,23mmol,82%产率)。
分析数据:
1H NMR(200MHz,CDCl3)δ7.89–7.78(m,2H),7.61–7.50(m,2H),5.38(d,J=8.0Hz,1H),4.70(dd,J=8.2,4.0Hz,1H),4.59(d,J=4.0Hz,2H),3.76(d,J=4.3Hz,3H),1.42(d,J=4.2Hz,9H).
13C NMR(50MHz,CDCl3)δ170.4,165.4,155.2,132.0,131.3,128.7,128.5,80.6,65.3,53.1,52.9,28.4.
MS(ESI+):m/z 424.04[M+1]+.
步骤2:N-(2,6-二氟-3-(1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二
氧杂硼杂环戊烷-2-基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)甲磺酰胺
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]甲磺酰胺(0.630g,1.22mmol)、双(频哪醇合)二硼(341mg,1.34mmol)、无水乙酸钾(360mg,3.67mmol)和干燥1,4-二噁烷(4.08mL)。将容器抽真空并充入氩气(3x)。加入1,1'-双(二苯基膦基)二茂铁-二氯钯(1:1)(17.9mg,0.0245mmol)并将反应在80℃搅拌过夜。冷却后,加入EtOAc,将悬浮液搅拌30分钟并经硅藻土过滤。浓缩溶剂,加入正庚烷且通过抽滤收集固体,用己烷洗涤且干燥,得到N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(0.690g,1.23mmol,定量)。
分析数据:
1H NMR(200MHz,DMSO)δ8.94–8.71(m,2H),7.19–6.88(m,2H),6.18(d,J=9.1Hz,1H),4.05–3.61(m,2H),2.64(s,3H),2.44–1.10(m,18H).
步骤3:[(2S)-3-甲氧基-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代丙基]4-[3-
[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸
酯
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(101mg,0.180mmol)、[(2S)-3-甲氧基-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代丙基]4-溴苯甲酸酯(79.5mg,0.198mmol)、氟化钾(31.3mg,0.539mmol)、Pd(dppf)Cl2·DCM(7.33mg,0.00898mmol)和脱气的1,4-二噁烷/水(4+1)(0.6mL),然后抽真空并充入氩气(3x)。将反应混合物在搅拌下加热至65℃过夜。将混合物用EtOAc稀释,用盐水洗涤并除去溶剂。通过快速色谱法(DCM/EtOAc梯度,0%至20%EtOAc)分离产物,得到[(2S)-3-甲氧基-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代丙基]4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸酯(68.0mg,0,0897mmol,50%产率),为白色固体。
分析数据:
1H NMR(400MHz,丙酮)δ9.00(d,J=2.0Hz,1H),8.85(d,J=2.1Hz,1H),8.47(s,1H),8.17(d,J=8.3Hz,2H),7.97–7.89(m,3H),7.33(t,J=8.5Hz,1H),6.65(d,J=7.6Hz,1H),6.26(dd,J=9.9,2.3Hz,1H),4.79–4.58(m,3H),4.02(d,J=11.4Hz,1H),3.85–3.69(m,4H),3.21(s,3H),2.60–2.46(m,1H),2.17–2.06(m,1H),2.04–1.96(m,1H),1.92–1.78(m,1H),1.74–1.57(m,2H),1.42(s,9H).
13C NMR(101MHz,丙酮)δ185.7,171.1,166.2,162.2(dd,J=256,3Hz),158.7(dd,J=258,5Hz),156.4,151.9,150.3,143.3,142.2,133.6,131.6(dd,J=11,4Hz),131.3,130.3,130.2,128.6,124.7(dd,J=14,4Hz),116.2,115.8(t,J=17Hz),112.7(dd,J=21,4Hz),83.9,79.8,68.3,65.4,54.0,52.8,42.1,29.8,29.8,28.6,25.7,23.1.
TLC-MS(ESI-):m/z 756.5[M-1]-.
步骤4:[(2S)-2-氨基-3-甲氧基-3-氧代丙基]4-[3-[2,4-二氟-3-(甲磺酰胺基)
苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸酯盐酸盐
将[(2S)-3-甲氧基-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代丙基]4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸酯(63.0mg,0.0831mmol)在三氟乙酸(1mL)中在室温下搅拌3h。将混合物加热至50℃持续40分钟。在冰上冷却后,向该溶液中加入4N HCl(1.04mL,4.16mmol)的1,4-二噁烷溶液,继续搅拌5分钟,加入乙醚(3mL)。通过抽滤收集产物,用乙醚洗涤并真空干燥,得到[(2S)-2-氨基-3-甲氧基-3-氧代丙基]4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸酯盐酸盐(44.0mg,0,0721mmol,87%产率),为灰白色固体。
分析数据:
1H NMR(400MHz,DMSO)δ14.92(s,1H),9.76(s,1H),9.10(d,J=2.0Hz,1H),8.97(s,2H),8.86(d,J=2.1Hz,1H),8.20(d,J=8.5Hz,2H),8.03(d,J=8.3Hz,2H),7.88(dd,J=14.7,7.6Hz,1H),7.41(t,J=8.7Hz,1H),4.73(d,J=3.3Hz,2H),4.67(s,1H),3.81(s,3H),3.12(s,3H).
13C NMR(101MHz,DMSO)δ185.1,167.4,164.8,152.2,149.5,142.3,141.8,131.1,130.5,128.5,128.0,127.5,114.0,62.2,53.1,51.3,41.5,40.1.
TLC-MS(ESI-):m/z 572.4[M-1].
实施例57:(2S)-2-氨基-3-[4-[3-[2,4-二氟-3-(甲磺酰胺基)-苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酰基]氧基丙酸盐酸盐的合成
步骤1:(2S)-3-羟基-2-[(2-甲基丙-2-基)氧基羰基氨基]丙酸苄酯
将二碳酸二叔丁酯(7.06mL,30.7mmol)的1,4-二噁烷(14.5mL)溶液加入到(2S)-2-氨基-3-羟基丙酸(2.69g,25.6mmol)和碳酸钾(3.54g,25.6mmol)的水(14.5mL)溶液中。将溶液在室温下搅拌16h。蒸发1,4-二噁烷,水溶液用3×乙醚(10mL)洗涤。将水在真空中蒸发并用EtOH共沸除去残留的痕量物质。将得到的白色粉末悬浮在DMF(28.9mL)中并加入苄基溴(3.44mL,28.9mmol)。将混合物在室温下搅拌16h。真空蒸发DMF,残余物与甲苯(28.9mL)一起搅拌并过滤。将该相用水和盐水洗涤两次并经Na2SO4干燥。过滤后,在90℃真空下蒸发溶剂。将油状(2S)-3-羟基-2-[(2-甲基丙-2-基)氧基羰基氨基]丙酸苄酯(4.77g,16.2mmol,63%产率)未经进一步纯化用于下一步骤。
分析数据:
1H NMR(200MHz,CDCl3)δ7.34(s,5H),5.56(s,1H),5.20(s,2H),4.40(s,1H),3.92(qd,J=11.2,3.7Hz,2H),2.46(s,1H),1.43(s,9H).
步骤2:(2S)-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代-3-苯基甲氧基丙基]4-
溴苯甲酸酯
向4-溴苯甲酰氯(0.500g,2.28mmol)的THF(11.4mL)溶液中加入三乙胺(0.381mL,2.73mmol)和4-DMAP(0.0139g,0.114mmol)。向所得悬浮液中加入(2S)-3-羟基-2-[(2-甲基丙-2-基)氧基羰基氨基]丙酸苄酯(0.807g,2.73mmol)的2mL THF溶液,将反应物在室温下搅拌60分钟。用EtOAc稀释反应物,用水、饱和NaHCO3和饱和NH4Cl溶液洗涤。在经Na2SO4干燥后,真空除去溶剂。产物经快速色谱法(正己烷/EtOAc梯度,0%-20%EtOAc)纯化,得到[(2S)-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代-3-苯基甲氧基丙基]4-溴苯甲酸酯(0.501g,1,05mmol,46%产率),为白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ7.84(d,J=8.5Hz,2H),7.75–7.64(m,3H),7.38–7.23(m,5H),5.26–5.03(m,2H),4.55(dd,J=16.6,7.0Hz,3H),1.38(s,J=14.3Hz,9H).
13C NMR(50MHz,DMSO)δ169.6,164.7,155.4,135.7,131.7,131.3,128.5,128.3,128.0,127.7,127.5,78.6,66.3,52.7,28.1.
MS:[M+Na]+=500.3.
步骤3:[(2S)-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代-3-苯基甲氧基丙基]
4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯
甲酸酯
向容器中装入[(2S)-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代-3-苯基甲氧基丙基]4-溴苯甲酸酯(124mg,0.260mmol)、N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(146mg,0.260mmol)、Pd(dppf)Cl2·DCM(10.6mg,0.0130mmol)、氟化钾(45.2mg,0.779mmol)和脱气的1,4-二噁烷/水(4+1)(0.8mL),并将容器抽真空并充入氩气(3x)。将反应物在搅拌下加热至50℃持续6h。将混合物用EtOAc稀释,用盐水洗涤并除去溶剂。通过快速色谱法(3倍柱体积的己烷/EtOAc(80/20v/v,然后是DCM/EtOAc 80/20v/v以洗脱产物)分离产物,得到[(2S)-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代-3-苯基甲氧基-丙基]4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]-吡啶-5-基]苯甲酸酯(147mg,0,1760mmol,68%产率),为白色固体。
分析数据:
1H NMR(200MHz,丙酮)δ9.06(s,1H),8.90(s,1H),8.55(s,1H),8.22–7.89(m,5H),7.59–7.31(m,5H),6.82(d,J=7.6Hz,1H),6.34(d,J=9.2Hz,1H),5.44–5.23(m,2H),4.99–4.72(m,3H),4.20–3.76(m,2H),3.30(s,3H),2.62(dd,J=20.1,9.7Hz,1H),2.25–1.61(m,5H),1.60–1.32(m,10H).
13C NMR(50MHz,丙酮)δ185.7,170.6,166.1,156.4,151.7,150.3,143.1,142.1,136.8,133.5,131.3,130.1,129.3,129.0,128.9,128.4,116.1,83.8,79.8,68.3,67.6,65.4,54.2,42.0,29.7,28.5,25.7,23.1.
TLC-MS(ESI-):m/z 833.0[M-1]-.
步骤4:(2S)-2-氨基-3-[4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并
[3,4-b]吡啶-5-基]苯甲酰基]氧基丙酸盐酸盐
[(2S)-2-[(2-甲基丙-2-基)氧基羰基氨基]-3-氧代-3-苯基甲氧基丙基]4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]苯甲酸酯(142mg,0.170mmol)溶于EtOAc(1.70mL)并加入14mg钯/活性炭(10%)。将反应物在H2气氛(3巴)下搅拌过夜。将反应脱气,加入5mg钯/活性炭(10%)并将反应物在5巴H2气氛下搅拌(6h)。将反应物经硅藻土过滤并除去溶剂。将残余物置于2mL TFA并在室温下搅拌2h。在冰冷却下加入4N HCl的二噁烷(2mL)溶液。5分钟后,加入5ml THF,通过抽滤收集固体,用THF洗涤并真空干燥,得到(2S)-2-氨基-3-[4-[3-[2,4-二氟-3-(甲磺酰-胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酰基]氧基丙酸盐酸盐(50.0mg,0,0814mmol,48%产率),为灰白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ14.92(s,1H),9.76(s,1H),9.10(d,J=2.1Hz,1H),8.86(d,J=2.1Hz,1H),8.78(s,3H),8.22(d,J=8.5Hz,2H),8.03(d,J=8.5Hz,2H),7.88(dd,J=15.0,7.6Hz,1H),7.41(td,J=8.9,1.2Hz,1H),4.71(s,2H),4.53(s,1H),3.12(s,3H).
13C NMR(50MHz,DMSO)δ185.2,168.4,164.9,152.3,149.6,142.4,141.9,131.1,130.5,128.6,128.2,127.6,114.1,66.3,51.4,41.5.
TLC-MS(ESI-):m/z 558.2[M-1]-.
实施例58:5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸盐酸盐的合成
步骤1:5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-
b]吡啶-5-基]吡啶-2-羧酸甲酯
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(132mg,0.235mmol)、5-溴吡啶-2-羧酸甲酯(55.8mg,0.258mmol)、氟化钾(40.9mg,0.704mmol)、Pd(dppf)Cl2·DCM(9.58mg,0.0117mmol)和脱气的1,4-二噁烷/水(4+1)(0.6mL)并将容器抽真空并充入氩气(3x)。将反应在搅拌下加热至50℃过夜。将混合物用EtOAc稀释,用盐水洗涤并除去溶剂。通过快速色谱法(DCM/EtOAc梯度,20%至60%EtOAc)分离产物,得到5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸甲酯(97.0mg,0,1700mmol,72%产率),为白色固体。
分析数据:
1H NMR(400MHz,丙酮)δ9.14(d,J=1.9Hz,1H),9.06(d,J=2.1Hz,1H),8.91(d,J=2.1Hz,1H),8.40(dd,J=8.1,2.3Hz,1H),8.22(d,J=8.1Hz,1H),7.95(dd,J=14.9,7.5Hz,1H),7.34(dd,J=8.8,8.0Hz,1H),6.27(dd,J=9.9,2.4Hz,1H),4.09–3.91(m,4H),3.80(td,J=11.2,3.5Hz,1H),3.21(s,3H),2.54(ddd,J=16.4,13.3,4.0Hz,1H),2.19–2.06(m,1H),2.05–1.97(m,1H),1.94–1.77(m,1H),1.76–1.56(m,2H).
13C NMR(101MHz,丙酮)δ185.7,166.1,162.3(dd,J=256,3Hz),158.7(dd,J=258,5Hz),152.0,150.3,149.3,148.5,142.3,137.3,136.7,131.63(dd,J=10.9,3.2Hz),130.7,125.9,124.7(dd,J=14,4Hz),116.2,115.8(t,J=17Hz),112.8(dd,J=21,4Hz),83.9,68.4,52.8,42.1,29.8,25.8,23.1.
TLC-MS(ESI-):m/z 570.4[M-1]-.
步骤2:5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-
基]吡啶-2-羧酸甲酯
向5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸甲酯(60.0mg,0.105mmol)的MeOH(0.525mL)溶液中加入甲磺酸(0.0273mL,0.420mmol)并在65℃下搅拌混合物1.5h。将混合物冷却至室温并缓慢加入到15mL乙醚中,通过抽滤收集固体,用乙醚洗涤并真空干燥,得到5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸甲酯(36.0mg,0,0739mmol,70%产率),为白色固体。
分析数据:
1H NMR(200MHz,CDCl3)δ14.90(s,1H),9.74(s,1H),9.16(dd,J=12.4,1.9Hz,2H),8.93(d,J=2.0Hz,1H),8.47(dd,J=8.2,2.3Hz,1H),8.19(d,J=8.3Hz,1H),7.88(dd,J=14.8,7.7Hz,1H),7.41(t,J=8.7Hz,1H),3.93(s,3H),3.12(s,3H).
13C NMR(50MHz,CDCl3)δ185.1,165.0,152.4,149.6,148.3,146.5,141.9,136.1,136.0,129.2,128.4,125.0,114.0,52.5,41.5.
MS:[M+Na]+=510.4.
步骤3:5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-
基]吡啶-2-羧酸盐酸盐
将5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸甲酯(46.0mg,0.0805mmol)在3N HCl(2.68mL,8.05mmol)在70℃下在开放容器中搅拌过夜。除去溶剂,残余的水与甲苯共沸除去。将残余物溶于MeOH(1mL)中并滴加至乙醚中。抽滤收集固体,用乙醚洗涤并真空干燥,得到5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸盐酸盐(33.0mg,0.0647mmol,80%产率)。
分析数据:
1H NMR(200MHz,CDCl3)δ14.96(s,1H),9.77(s,1H),9.18(s,1H),9.13(d,J=1.9Hz,1H),8.93(d,J=1.9Hz,1H),8.48(d,J=8.1Hz,1H),8.19(d,J=7.8Hz,1H),7.88(dd,J=14.7,7.8Hz,1H),7.41(t,J=8.6Hz,1H),3.12(s,3H).
13C NMR(101MHz,DMSO)δ185.0,152.3,149.5,141.9,136.1,114.2,114.0,48.5,41.5,15.1.
TLC-MS(ESI-):m/z 472.3[M-1]-.
实施例59:N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]甲磺酰胺盐酸盐的合成
步骤1:N-[2,6-二氟-3-[1-(噁烷-2-基)-5-吡啶-4-基吡唑并[3,4-b]吡啶-3-羰
基]-苯基]甲磺酰胺
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(86.0mg,0.153mmol)、4-溴吡啶盐酸盐(29.7mg,0.153mmol)、Pd(dppf)Cl2·DCM(3.75mg,0.00459mmol)、脱气的1,4-二噁烷(0.382mL)和脱气的1.5M碳酸钾水溶液(0.408mL,0.612mmol)。将容器抽真空,充入氩气(3x)并加热至60℃持续2h。冷却后,反应物用EtOAc稀释,用NH4Cl溶液中和,弃去水相,浓缩有机物。通过快速色谱法(DCM/MeOH梯度,从2%至12%MeOH)分离产物。N-[2,6-二氟-3-[1-(噁烷-2-基)-5-吡啶-4-基吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(63.0mg,0,1230mmol,产率80%)。
分析数据:
1H NMR(200MHz,丙酮)δ9.03(d,J=2.3Hz,1H),8.89(d,J=2.1Hz,1H),8.72(d,J=5.9Hz,3H),7.94(ddd,J=8.8,7.5,6.2Hz,1H),7.80(dd,J=4.5,1.6Hz,2H),7.34(td,J=9.0,1.7Hz,1H),6.25(dd,J=9.9,2.3Hz,1H),4.12–3.95(m,1H),3.90–3.68(m,1H),3.21(s,3H),2.51(dt,J=10.1,7.1Hz,1H),2.16–1.57(m,5H).
13C NMR(50MHz,丙酮)δ185.7,152.1,151.4,150.1,145.8,142.2,131.9,131.6(dd,J=10,4Hz),130.3,124.6(dd,J=13,4Hz),122.8,116.1,115.8,112.8(dd,J=21,4Hz),83.8,68.3,42.0,29.7,25.7,25.3,23.1.
TLC-MS(ESI-):m/z 512.6[M-1]-.
步骤2:N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]-甲
磺酰胺盐酸盐
将N-[2,6-二氟-3-[1-(噁烷-2-基)-5-吡啶-4-基吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(60.0mg,0.117mmol)在MeOH(2mL)和4N HCl的二噁烷(0.5mL)溶液中加热至回流1h。除去溶剂,残余物用THF研碎,得到N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]甲磺酰胺盐酸盐(37.0mg,0,0794mmol,68%产率),为白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ15.09(s,1H),9.77(s,1H),9.28(d,J=2.3Hz,1H),9.13(d,J=2.3Hz,1H),8.99(d,J=6.7Hz,2H),8.52(d,J=6.7Hz,2H),7.90(dd,J=15.0,7.6Hz,1H),7.42(td,J=8.9,1.2Hz,1H),3.12(s,3H).
13C NMR(101MHz,DMSO)δ184.9,160.7(dd,J=255,3Hz),157.1(dd,J=257,4Hz),153.0,151.8,149.7,143.6,142.3,130.5,127.3,124.1,123.4(dd,J=13,4Hz),114.3(t,J=17Hz),112.0(dd,J=21.3Hz),41.5.
TLC-MS(ESI-):m/z 428.6[M-1]-.
实施例60:N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基(methylsulfonimidoyl))苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺的合成
步骤1:(4-溴苯基)-亚氨基-甲基-氧代-λ^{6}-硫烷
在室温下将1-溴-4-甲基硫烷基(sulfanyl)苯(0.970g,4.78mmol)、乙酸铵(1.47g,19.1mmol)和(二乙酰氧基碘)苯(3.85g,11.9mmol)在9.55mL MeOH中合并。将反应物搅拌1h,用水(20mL)稀释并用EtOAc萃取。萃取物用水洗涤,经Na2SO4干燥并真空除去溶剂。通过快速色谱法(DCM/MeOH,97/3%v/v)分离产物(4-溴苯基)-亚氨基-甲基-氧代-λ^{6}-硫烷(0.570g,2,43mmol,51%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ7.91–7.76(m,4H),4.24(s,1H),3.08(s,1H).
13C NMR(50MHz,DMSO)δ143.5,132.0,129.4,126.4,45.6.
MS:[M+H]+=234.1.
步骤2:N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基)苯基]-1-(噁烷-2-基)吡唑并
[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(93.0mg,0.165mmol)、(4-溴苯基)-亚氨基-甲基-氧代-λ^{6}-硫烷(38.7mg,0.165mmol)、Pd(dppf)Cl2·DCM(4.05mg,0.00496mmol)、氟化钾(28.8mg,0.496mmol)和脱气的1,4-二噁烷/水(4:1,0.5mL)。将容器抽真空,充入氩气(3x)并加热至50℃持续3h。冷却后,将反应用EtOAc稀释,用盐水洗涤并除去溶剂。通过快速色谱法(DCM/MeOH梯度,从1%至8%MeOH)分离产物。N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基)苯基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(63.0mg,0,1070mmol,65%产率)。
分析数据:
1H NMR(200MHz,丙酮)δ8.97(d,J=1.9Hz,1H),8.82(d,J=2.0Hz,1H),8.63(s,1H),8.13(d,J=8.3Hz,2H),8.03–7.87(m,3H),7.33(td,J=8.9,1.3Hz,1H),6.24(dd,J=9.7,1.9Hz,1H),4.11–3.93(m,1H),3.87–3.70(m,1H),3.18(d,J=13.0Hz,7H),2.66–2.37(m,1H),2.18–1.52(m,5H).
13C NMR(50MHz,丙酮)δ151.8,150.4,142.7,142.1,130.3,129.4,129.0,116.1,83.8,68.4,46.6,42.0,35.2,32.3,29.8,25.7,23.1,14.3.
TLC-MS(ESI-):m/z 588.4[M-1]-.
步骤3:N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基)苯基]-1H-吡唑并[3,4-b]吡啶-
3-羰基]苯基]甲磺酰胺
向N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基)苯基]-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(63.0mg,0.107mmol)的2mL MeOH溶液中加入4N HCl的1,4-二噁烷(2mL)溶液且反应在回流温度下搅拌1h。冷却后,将混合物浓缩,用无水THF/乙醚(1+1)处理,通过抽滤收集固体,用乙醚洗涤。将固体置于水中并用NaHCO3溶液中和。通过抽滤收集产物,用水洗涤并真空干燥,得到N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺(24.0mg,0,0451mmol,42%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ9.08(s,1H),8.85(s,1H),8.07(s,4H),7.87(dd,J=14.8,8.0Hz,1H),7.41(t,J=8.5Hz,1H),4.31(s,1H),3.13(d,J=3.4Hz,6H).
13C NMR(101MHz,DMSO)δ185.1,152.3,149.5,143.5,141.8,141.1,131.0,128.6,128.1,127.9,114.0,45.8,41.5.
MS:[M+H]+=506.4.
实施例61:N-(3-(5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺的合成
步骤1:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]丙烷-1-磺
酰胺
在-10℃下,向(3-氨基-2,4-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(805mg,2.28mmol)和三乙胺(3.50mL,25.1mmol)的DCM(11.4mL)悬浮液中缓慢加入1-丙烷磺酰氯(898μL,7.98mmol)的DCM(11.4mL)溶液,并将反应在-10℃下搅拌15分钟。将反应用DCM稀释,用2N HCl和盐水洗涤,经Na2SO4干燥并蒸发。将残余物溶解于THF(2mL)中并加入2N KOH(2mL)。10分钟后,用水稀释反应物,并蒸发THF。在搅拌下将该溶液加入到2N HCl(10mL)中,继续搅拌30分钟并通过抽滤收集固体,用2N HCl和水洗涤并在100℃下干燥,得到N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]丙烷-1-磺酰胺(801mg,1.69mmol,74%产率)。
分析数据:
1H NMR(200MHz,丙酮)δ13.77(s,1H),8.72(d,J=12.1Hz,2H),8.38(s,1H),7.91(dd,J=14.8,7.6Hz,1H),7.30(t,J=8.7Hz,1H),3.40–3.14(m,2H),2.03–1.81(m,2H),1.07(t,J=7.4Hz,3H).
13C NMR(50MHz,丙酮)δ185.7,162.1(dd,J=255,4Hz),153.7(dd,J=222,4Hz),152.0,151.6,142.5,133.7,131.5(dd,J=11,4Hz),124.5(dd,J=14,4Hz),116.6,116.2,115.7(t,J=17Hz),112.8,112.7,112.4,112.3,56.2,18.1,13.1.
MS:[M-1]-=457.3.
步骤2:N-[3-[5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]-
丙烷-1-磺酰胺
向微波容器中装入N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]丙烷-1-磺酰胺(60.0mg,0.131mmol)、(4-氯苯基)硼酸(21.4mg,0.137mmol)和Pd(dppf)Cl2·DCM(5.33mg,0.00653mmol)反应并用氩气吹扫。加入脱气的1,4-二噁烷(0.435mL)和脱气的1.5M K2CO3水溶液(0.261mL,0.392mmol),并将混合物在微波辐射下在110℃搅拌30分钟。加入一刮铲(spatula)Pd(dppf)Cl2并继续加热30分钟。冷却后,将混合物用饱和NH4Cl溶液中和并用EtOAc稀释。弃去水相,在减压下除去溶剂。将残余物通过快速色谱法(DCM/EtOAc梯度,0至35%EtOAc)纯化并用DCM研碎,得到N-[3-[5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(30.0mg,0,0605mmol,46%产率),为白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ14.81(s,1H),9.66(s,1H),9.01(d,J=2.1Hz,1H),8.77(d,J=2.1Hz,1H),7.98–7.78(m,3H),7.60(d,J=8.4Hz,2H),7.40(t,J=8.7Hz,1H),3.22–3.09(m,2H),1.92–1.70(m,2H),1.00(t,J=7.5Hz,3H).
13C NMR(101MHz,DMSO)δ185.2,152.1,149.4,141.8,136.2,133.1,131.3,129.2,128.1,114.1,55.0,39.5,16.9,12.7.
MS:[M-1]-=489.5.
实施例62-67:
类似于实施例61步骤2的程序,制备下列化合物:
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实施例68:N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]-1-苯基甲磺酰胺的合成
步骤1:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]-1-苯基甲
磺酰胺
在-10℃下,向(3-氨基-2,4-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(830mg,2.35mmol)和4-DMAP(0.574g,4.70mmol)的吡啶(4.74mL,58.8mmol)溶液加入苯基甲磺酰氯(583mg,3.06mmol)并将混合物在-10℃搅拌10分钟直至形成均匀悬浮液。在室温下继续搅拌10分钟并且将反应加热至50℃持续30分钟。将反应物在减压下浓缩并置于2NNaOH(3.53mL,7.05mmol)中并在室温下搅拌10分钟。将混合物用水稀释并在搅拌下缓慢加入到25mL 2N HCl中。10分钟后,通过抽滤收集固体,用水洗涤并在100℃下干燥,得到N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]-1-苯基甲磺酰胺(1.02g,2,01mmol,86%产率),为灰白色固体。
分析数据:
1H NMR(200MHz,DMSO)δ14.98(s,1H),9.81(s,1H),8.73(dd,J=6.1,2.2Hz,2H),7.88(dd,J=14.9,7.6Hz,1H),7.50–7.30(m,6H),4.53(s,2H).
13C NMR(50MHz,DMSO)δ184.8,150.9,150.6,140.9,132.5,131.0,129.4,128.4,128.3,115.5,115.2,59.4.
MS:[M-1]-=505.2.
步骤2:N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]-1-
苯基甲磺酰胺
向微波容器中装入N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]-1-苯基甲磺酰胺(75.0mg,0.148mmol)、4-吡啶基硼酸(21.8mg,0.177mmol)和Pd(dppf)Cl2·DCM(6.04mg,0.00739mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.493mL)和脱气的1.5M KCO3水溶液(0.345mL,0.517mmol),并将混合物在微波辐射下加热至110℃持续60分钟。冷却后,将反应物用EtOAc稀释并用NH4Cl溶液中和。切割水相并蒸发溶剂。将残余物通过快速色谱发(DCM+MeOH 2%至10%)纯化并用DCM研碎,得到N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]-1-苯基甲磺酰胺(40.0mg,0,0783mmol,53%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ14.91(s,1H),9.77(s,1H),9.13(d,J=2.3Hz,1H),8.92(d,J=2.3Hz,1H),8.72(dd,J=4.7,1.4Hz,2H),8.07–7.68(m,3H),7.53–7.26(m,6H),4.53(s,2H).[M-1]-=504.4.
实施例69:N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]乙磺酰胺的合成
步骤1:(3-氨基-2,4-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-
基]甲酮
在0℃下,向3-溴-2,6-二氟苯胺(4.69g,22.6mmol)的四氢呋喃(19.6mL)溶液中滴加2M异丙基氯化镁的THF(11.3mL,22.6mmol)溶液,并在不进一步冷却的情况下搅拌15分钟。再次冷却至0℃后,加入三甲基氯硅烷(2.86mL,22.6mmol),将混合物升温至25℃并搅拌20分钟。将溶液冷却至0℃并加入三甲基氯硅烷(2.86mL,22.6mmol),在25℃下继续搅拌20分钟。将溶液再次冷却至0℃,滴加2M异丙基氯化镁的THF(11.3mL,22.6mmol)溶液,并将混合物在0℃搅拌10分钟。将5-溴-N-甲氧基-N-甲基-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-甲酰胺(3.62g,9.80mmol)溶解于10mL THF中并添加至混合物中,并在室温下继续搅拌1h。将反应用饱和NH4Cl溶液淬灭,加入水溶液,直到水相变得澄清并分离各相。水相用EtOAc萃取,萃取物用盐水洗涤,经Na2SO4干燥并除去溶剂。将油状残余物溶解于25mL THF中,在搅拌下加入2mL浓HCl。5分钟后,将混合物用固体K2CO3小心地中和,用EtOAc稀释并过滤。去除溶剂并且将残余物通过快速色谱法(正己烷/EtOAc梯度,从0%至40%EtOAc)纯化,得到(3-氨基-2,4-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(2.35g,5,37mmol,产率55%)。
分析数据:
1H NMR(200MHz,DMSO)δ8.76(dd,J=13.9,2.1Hz,2H),7.15–6.89(m,2H),6.12(d,J=7.8Hz,1H),5.51(s,2H),4.08–3.56(m,2H),2.46–2.20(m,1H),2.06–1.46(m,5H).
13C NMR(50MHz,DMSO)δ185.6,153.6(dd,J=190,9Hz),150.6,149.0,146.8(d,J=9Hz),140.2,133.0,126.3(t,J=17Hz),122.3(dd,J=11,3Hz),116.4(d,J=3Hz),116.2,116.2,115.7,110.7(dd,J=19,3Hz),82.7,67.0,28.5,24.4,21.8.
MS:[M+Na+MeOH]+=491.05.
步骤2:N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯 基]-乙磺酰胺在0℃下,向(3-氨基-2,4-二氟苯基)-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-基]甲酮(286mg,0.654mmol)和三乙胺(0.547mL,3.92mmol)的DCM(3.27mL)溶液中加入乙磺酰氯(143μL,1.50mmol)。将反应在室温下搅拌15分钟并用2N HCl和盐水洗涤。除去溶剂,置于2mL THF和2mL 2N KOH水溶液,并搅拌10分钟。将反应物用2N HCl酸化,用水稀释并用EtOAc萃取。将萃取物用盐水洗涤,经Na2SO4干燥并蒸发。将残余物通过快速色谱法(正己烷/EtOAc梯度,5%至40%EtOAc)纯化,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]乙磺酰胺(0.267g,0,5040mmol,77%产率)。
分析数据:
1H NMR(200MHz,DMSO)δ9.70(s,1H),8.80(dd,J=14.1,2.1Hz,2H),7.87(dd,J=14.8,7.7Hz,1H),7.43(td,J=8.9,1.0Hz,1H),6.14(dd,J=9.6,1.7Hz,1H),4.07–3.87(m,1H),3.83–3.62(m,1H),3.20(q,J=7.2Hz,2H),2.34(dd,J=22.5,11.3Hz,1H),2.07–1.46(m,5H),1.33(t,J=7.3Hz,3H).
13C NMR(50MHz,DMSO)δ184.4,161.8(dd,J=191,4Hz),156.7(dd,J=193,4Hz),150.8,149.0,139.9,133.0,130.8(dd,J=11,4Hz),122.9(dd,J=13,4Hz),116.1,116.0,114.4(t,J=17Hz),112.2(dd,J=21,4Hz),82.7,67.1,47.7,28.5,24.5,21.8,8.0.
MS:[M-1]-=527.1.
步骤3:N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]乙
磺酰胺
向微波容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]乙磺酰胺(76.0mg,0.144mmol)、4-吡啶基硼酸(19.4mg,0.158mmol)和三(叔丁基)膦Pd G3(6.08mg,0.00718mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.479mL)和脱气的1.5M碳酸钾水溶液(0.287mL,0.431mmol),并将反应在微波辐射下在70℃搅拌45分钟。将反应物用2mL 6N HCl酸化,用3mL MeOH稀释并在微波辐射下加热至70℃持续60分钟。将混合物用水稀释,用2N NaOH中和并用THF萃取。将萃取物用盐水洗涤,经Na2SO4干燥并除去溶剂。将残余物通过快速色谱法(DCM/MeOH梯度,2%至10%MeOH)纯化,得到N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]乙磺酰胺(42.0mg,0,0947mmol,66%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ14.89(s,1H),9.66(s,1H),9.12(d,J=2.1Hz,1H),8.91(d,J=2.3Hz,1H),8.72(d,J=5.9Hz,2H),7.91–7.83(m,3H),7.40(t,J=8.8Hz,1H),3.18(q,J=7.3Hz,2H),1.33(t,J=7.3Hz,3H).
13C NMR(101MHz,DMSO)δ185.0,152.6,150.3,149.3,144.4,141.9,129.5,128.7,121.8,114.0,47.7,7.9.
MS:[M-1]-=442.1.
实施例70:4-(3-(2,4-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-甲基苯磺酰胺的合成
步骤1:N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]
丙烷-1-磺酰胺
向N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]丙烷-1-磺酰胺(778mg,1.64mmol)的DCM(8.47mL)悬浮液中加入对甲苯磺酸一水合物(31.3mg,0.164mmol)和二氢吡喃(0.165mL,1.81mmol)并将反应升温至40℃持续1h。将反应用NaHCO3溶液洗涤并除去溶剂。将残余物通过快速色谱法(正己烷+EtOAc,5%至45%)纯化,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(693mg,1.28mmol,78%产率)。
分析数据:
1H NMR(200MHz,丙酮)δ8.73(dt,J=8.0,1.8Hz,2H),8.39(s,1H),7.92(ddd,J=8.8,7.4,6.2Hz,1H),7.32(td,J=8.9,1.7Hz,1H),6.18(dd,J=9.8,2.4Hz,1H),4.03–3.67(m,2H),3.33–3.20(m,2H),2.61–2.38(m,1H),2.01–1.54(m,5H),1.07(t,J=7.5Hz,3H).
13C NMR(50MHz,丙酮)δ361.8,339.4(dd,J=178,4Hz),334.3(dd,J=181,4Hz),327.9,326.8,317.5,310.4,308.0(dd,J=11,4Hz),300.7(dd,J=13,4Hz),293.8,293.2,292.2(t,J=17Hz),289.0(dd,J=22,4Hz),260.2,244.7,232.6,206.3,206.0,202.0,199.4,194.5,189.5.
TLC-MS(ESI-):m/z 541.0/543.0[M-H]-.
步骤2:N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂
环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(875mg,1.61mmol)、双(频哪醇合)二硼(429mg,1.69mmol)、双(三苯基膦)二氯化钯(II)(22.6mg,0.0322mmol)、无水乙酸钾(474mg,4.83mmol)和干燥1,4-二噁烷(8.05mL)。将容器抽真空,充入氩气(3x)并将反应加热至80℃持续3h。冷却后,将反应物用EtOAc稀释,经硅藻土过滤并蒸发。将残留物置于EtOAc(约20mL),加入活性炭,并将混合物加热至回流10分钟。冷却后,混合物经硅藻土过滤,蒸发溶剂,且残余物用正己烷超声处理。通过抽滤和真空收集固体,得到N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(765mg,1.3mmol,80%产率),为无色固体。
步骤3:
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(100mg,0.169mmol)、氟化钾(29.5mg,0.508mmol)、4-溴-3-甲基苯磺酰胺(46.6mg,0.186mmol)、Pd(dppf)Cl2·DCM(6.92mg,0.00847mmol)和0.5mL 1,4-二噁烷/水(4+1)。将容器抽真空,充入氩气(3x)并加热至60℃持续2h。反应物用浓HCl(0.3mL)酸化,用MeOH(0.2mL)稀释并加热至60℃过夜。冷却后,将反应物用EtOAc和水稀释。将有机相蒸发并将产物通过快速色谱法(DCM/EtOAc梯度,10%至50%EtOAc)纯化,4-[3-[2,4-二氟-3-(丙基磺酰-胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]-3-甲基苯磺酰胺(42.0mg,0.0764mmol,45%产率)
分析数据:
TLC-MS(ESI-):m/z=528.2,548.1[M-H]-
实施例71:N-(2,6-二氟-3-(5-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(88.0mg,0.149mmol)、5-溴-2-(三氟甲基)嘧啶(37.2mg,0.164mmol)、氟化钾(26.0mg,0.447mmol)、双(三苯基膦)二氯化钯(II)(5.23mg,0.00745mmol)和0.5mL 1,4-二噁烷/水(4+1)。将容器抽真空,充入氩气(3x)并加热至60℃持续2h。反应用浓HCl(0.3mL)酸化,用MeOH(0.2mL)稀释并加热至60℃过夜。冷却后,将反应用EtOAc和水稀释。将有机相蒸发并将产物通过快速色谱法(DCM/EtOAc梯度,5%至35%EtOAc)纯化,N-[2,6-二氟-3-[5-[2-(三氟甲基)嘧啶-5-基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(42.0mg,0.0798mmol,54%产率)。
分析数据:
TLC-MS(ESI-):m/z=505.1,525.1[M-H]-
实施例72:N-(3-(5-(4-氯-2-甲基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺的合成
向容器中装入N-[2,6-二氟-3-[1-(噁烷-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(80.0mg,0.135mmol)、1-溴-4-氯-2-甲基苯(18.0μL,0.135mmol)、氟化钾(23.6mg,0.406mmol)、双(三苯基膦)二氯化钯(II)(4.76mg,0.00677mmol)和0.5mL 1,4-二噁烷/水(4+1)。将容器抽真空,并充入氩气(3x)并加热至60℃持续1h。反应物用浓HCl(0.2mL)酸化,用MeOH(0.2mL)稀释并加热至60℃过夜。冷却后,将反应用EtOAc和水稀释。蒸发有机相,产物通过快速色谱法(DCM/EtOAc梯度,0%-40%EtOAc)纯化,得到N-[3-[5-(4-氯-2-甲基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(32.0mg,0.0608mmol,45%产率)。
分析数据:
TLC-MS(ESI-):m/z=483.3,503.3[M-H]-
实施例73:N-(3-(5-(4-(1H-四唑-5-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)乙磺酰胺的合成
步骤1:N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]乙磺酰胺
在-10℃下,向(3-氨基-2,4-二氟苯基)-(5-溴-1H-吡唑并[3,4-b]吡啶-3-基)甲酮(823mg,2.33mmol)和三乙胺(3.57mL,25.6mmol)的DCM(11.7mL)悬浮液中缓慢加入乙磺酰氯(0.773mL,8.16mmol)的DCM(11.7mL)溶液,并将反应在-10℃下搅拌20分钟。将反应用2N HCl和盐水洗涤并除去溶剂。将残余的胶状物置于10mL THF中并加入2N NaOH(6.99mL,14.0mmol)。搅拌30分钟后,将溶液用2N HCl酸化。添加水,在真空中去除THF并且通过抽滤收集固体,用水洗涤并且在100℃下干燥,得到N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]乙磺酰胺(761mg,1.71mmol,73%产率)。
步骤2:N-(3-(5-溴-1-(四氢-2H-吡喃-2-基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-
2,6-二氟苯基)乙磺酰胺
向N-[3-(5-溴-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基]乙磺酰胺(529mg,1.19mmol)和对甲苯磺酸一水合物(22.6mg,0.119mmol)的DCM(5.94mL)悬浮液中加入二氢吡喃(0.130mL,1.43mmol)并将反应升温至30℃持续1h。将反应用EtOAc稀释,用饱和NaHCO3溶液和盐水洗涤并除去溶剂。产物经快速色谱法(正己烷/EtOAc梯度,0%-40%EtOAc)纯化,得到N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]乙磺酰胺(534mg,1.01mmol,85%产率)。
步骤3:
分析数据:
TLC-MS(ESI-):m/z=509.3[M-H]-
实施例74:N-(3-(5-(4-(1H-四唑-5-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺的合成
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(80.0mg,0.147mmol)、[4-(1H-四唑-5-基)苯基]硼酸(33.6mg,0.177mmol)和Pd(dppf)Cl2·DCM(6.01mg,0.00736mmol)并用氩气吹扫。加入脱气的1,4-二噁烷(0.491mL)和脱气的1.5M碳酸钾水溶液(0.393mL,0.589mmol),将容器密封并将反应加热至80℃持续2.5。将反应物用MeOH稀释,用浓HCl酸化并在60℃下继续搅拌3h。将反应物倒入水中,用EtOAc萃取。将萃取物用盐水洗涤,除去溶剂并将产物通过快速色谱法(DCM+MeOH(+1%甲酸),5%至10%)纯化,用DCM研碎并在100℃下干燥,得到N-[2,6-二氟-3-[5-[4-(1H-四唑-5-基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(38.0mg,0.0724mmol,49%产率)。
分析数据:
H NMR(200MHz,DMSO)δ14.99(s,1H),9.83(s,1H),9.14(d,J=2.1Hz,1H),8.88(d,J=2.2Hz,1H),8.17(dd,J=19.9,8.4Hz,4H),7.65(td,J=9.0,6.1Hz,1H),7.32(td,J=9.0,1.4Hz,1H),3.20–3.05(m,2H),1.90–1.59(m,2H),0.97(t,J=7.4Hz,3H).
13C NMR(101MHz,DMSO)δ182.5,156.29(dd,J=248.3,6.4Hz),152.8(dd,J=251.2,8.2Hz),152.4,149.8,142.0,139.7,131.7,129.9,129.8,128.3,127.9,127.7,127.6,123.8,121.79(dd,J=13.4,3.4Hz),117.1,113.5,112.12(dd,J=22.6,4.3Hz),53.8,16.8,12.5.
TLC-MS(ESI-):m/z=522.9[M-H]-.
实施例75:N-(3-(5-(4-(1H-四唑-5-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)-1-苯基甲磺酰胺的合成
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]-1-苯基甲磺酰胺(76.0mg,0.129mmol)、[4-(1H-四唑-5-基)苯基]硼酸(26.9mg,0.141mmol)和Pd(dppf)Cl2·DCM(5.25mg,0.00643mmol)并且用氩气吹扫。加入脱气的1,4-二噁烷(0.428mL)和脱气的1.5M碳酸钾水溶液(0.343mL,0.514mmol),密封容器并将反应加热至80℃持续2.5h。将反应物用MeOH(1mL)稀释,用浓HCl(1mL)酸化并在60℃下继续搅拌3h。将反应物倒入水中,用EtOAc萃取。将萃取物用盐水洗涤,除去溶剂并将产物通过快速色谱法(DCM/MeOH(+1%甲酸)梯度,5%至15%MeOH(1%甲酸))纯化,用DCM研碎并在100℃下干燥,得到N-[2,6-二氟-3-[5-[4-(1H-四唑-5-基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]-1-苯基甲磺酰胺(40.0mg,0.0699mmol,54%产率)。
TLC-MS(ESI-):m/z 571.0[M-H]-
实施例76:N-(2,6-二氟-3-(5-(4-羟基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
向容器中装入N-[3-[5-溴-1-(噁烷-2-基)吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(72.0mg,0.133mmol)、(4-羟基苯基)硼酸(20.1mg,0.146mmol)、氟化钾(23.1mg,0.398mmol)和Pd(dppf)Cl2·DCM(5.41mg,0.00663mmol)并用氩气吹扫。加入脱气的1,4-二噁烷/水(4+1)并将混合物在80℃下搅拌20分钟。冷却后,将混合物用1mLMeOH稀释,用0.3mL浓HCl酸化并在60℃下搅拌2h。将反应物置于水和EtOAc中,将有机相用盐水洗涤,经Na2SO4干燥并蒸发。将产物通过快速色谱法(DCM 7EtOAc梯度,20%至60%EtOAc)纯化并用DCM研碎,得到N-[2,6-二氟-3-[5-(4-羟基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]丙烷-1-磺酰胺(39.0mg,0.0817mmol,62%产率)。
分析数据:
1H NMR(400MHz,DMSO)δ14.70(s,1H),9.70(s,2H),8.94(d,J=1.9Hz,1H),8.64(d,J=2.0Hz,1H),7.85(dd,J=14.5,7.8Hz,1H),7.63(d,J=8.5Hz,2H),7.39(t,J=8.8Hz,1H),6.93(d,J=8.5Hz,2H),3.20–3.06(m,2H),1.87–1.75(m,2H),1.00(t,J=7.4Hz,3H).
13C NMR(101MHz,DMSO)δ185.2,160.7(dd,J=254,4Hz),157.6,157.0(dd,J=256,4Hz),151.7,149.2,141.5,132.7,130.3(dd,J=10,5Hz),128.5,127.9,126.6,123.7(dd,J=14,4Hz),116.1,114.2,111.9(dd,J=22,3Hz),54.9,16.9,12.6.
TLC-MS(ESI-):m/z 450.9,471.0[M-H]-.
实施例77:生物活性
实施例77-1:结合测定
本发明化合物的激酶活性使用KINOMEscanTMProfiling Service at DiscoveRxCorporation,42501Albrae St.Fremont,CA 94538,USA测量,其基于竞争结合测定,该测定定量测量化合物与固定的活性位点定向配体竞争的能力。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.等人的用于临床激酶抑制剂的小分子-激酶相互作用图谱(A small molecule-kinase interaction map for clinical kinaseinhibitors,自然生物技术(Nat.Biotechnol.),23,329-336(2005))和Karaman,M.W.等人的激酶抑制剂选择性的定量分析(A quantitative analysis of kinase inhibitorselectivity,自然生物技术(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细胞中产生激酶并且随后用DNA标记以用于qPCR检测。将链霉抗生物素蛋白包被的磁珠用生物素化的小分子配体在室温处理30分钟以产生用于激酶测定的亲和树脂。用过量生物素封闭配体珠且用封闭缓冲液(SEABLOCKTM(Pierce),1%BSA,0.05%20,1mM DTT)洗涤以去除未结合配体且减少非特异性结合。通过在1x结合缓冲液(20%SEABLOCKTM,0.17xPBS,0.05%/>20,6mM DTT)中组合激酶、配体亲和珠和测试化合物来组装结合反应。所有反应均在聚苯乙烯96孔板中以0.135mL的终体积进行。将测定板在室温下振荡孵育1小时,并将亲和珠用洗涤缓冲液(lx PBS,0.05%/>20)洗涤。然后将珠粒再悬浮于洗脱缓冲液(lx PBS,0.05%/>20,0.5 11M非生物素化的亲和配体)中,并在室温下振荡温育30分钟。通过qPCR测量洗脱物中的激酶浓度。
在跨越十六个月的时间段的135个独立实验中,基于每个实验的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。
测试化合物的效价:
在指定浓度筛选化合物并将结合相互作用的结果报告为[对照的%],其中较低的数字表示较强的结合,即较高的效价。
关于测试的激酶的细节在下表2中给出。
测试化合物以10mM储备溶液提供。在DiscoverX制备所示终浓度的测试溶液。结果在下表3至6中给出。
表2:
MKK4效价:
在100nM的浓度下测定实施例2-43针对蛋白激酶MKK4的效价,表示为对照结合的残余百分比(PoC)。结果在下面的表3中给出(N/D表示未测定)。
表3
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PoC<1=“+++”;1≤PoC<10=“++”;10≤PoC<30=“+”;PoC≥30=“O”.
对JNK1的选择性:
在100nM的浓度下测定实施例2-67针对脱靶JNK1的选择性,通过计算与JNK1和MKK4的对照结合的残余百分比(PoC)的比率来测定。结果在下表4中给出。
表4:
/>
PoC(JNK1)/PoC(MKK4)≥30=“+++”;30>PoC(JNK1)/PoC(MKK4)≥10=“++”;
10>PoC(JNK1)/PoC(MKK4)≥3=“+”;PoC(JNK1)/PoC(MKK4)<3=“O”.
MKK4效价和对MKK7的选择性:
在100nM的浓度下测定实施例2-43针对脱靶MKK7的选择性,通过计算与MKK7和MKK4的对照结合的残余百分比(PoC)的比率来测定。结果在下表5中给出。
表5:
/>
PoC(MKK7)/PoC(MKK4)≥30=“+++”;30>PoC(MKK7)/PoC(MKK4)≥10=“++”;
10>PoC(MKK7)/PoC(MKK4)≥3=“+”;PoC(MKK7)/PoC(MKK4)<3=“O”.
MKK4效价和对BRaf的选择性:
在100nM的浓度下测定实施例2-43针对脱靶BRaf的选择性,通过计算与BRaf和MKK4的对照结合的残余百分比(PoC)的比率来测定。结果在下表6中给出。
表6:
/>
PoC(BRaf)/PoC(MKK4)≥30=“+++”;30>PoC(BRaf)/PoC(MKK4)≥10=“++”;
10>PoC(BRaf)/PoC(MKK4)≥3=“+”;PoC(BRaf)/PoC(MKK4)<3=“O”.
实施例77-2:功能性酶测定
(a)材料
重组激酶蛋白(可商购)
MEKK2,重组的,活化的:ProQinase产品#0583-0000-1
MKK4,重组的,活化的:ProQinase产品#0948-0000-1
MKK4,重组的,未活化的:ProQinase产物#0948-0000-2
底物蛋白
酪蛋白(Sigma C-4765)
JNK1 K55R/K56R,重组的,无活性的: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(活化的)以10:1(w/w)的比,对应于20:1的摩尔比在化合物或媒介物和20μM ATP的存在下在30℃下孵育30分钟。活化步骤在50mM HEPES pH7.5,50mM NaCl,3.8mM MgCl2,2.5mM DTT,10%(v/v)甘油中进行。DMSO终浓度为1%。按以下顺序移取活化混合物:
2.5μl化合物的4%DMSO溶液
2.5μl ATP/MgCl2混合物
5μl预混合激酶溶液MKK4:MEKK2 10:1(w/w)
活化混合物中的蛋白浓度为1μM MKK4和50nM MEKK2。
(b-2)蛋白激酶测定
使用放射测定蛋白激酶测定(radiometric protein kinase assay)来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。在反应停止后,将测定混合物转移至96孔MSFC过滤板(Millipore)。将反应混合物通过抽吸通过过滤膜,将膜用150mMH3PO4洗涤3次,用乙醇洗涤一次,干燥并加入液体闪烁混合物(scintillation cocktail)。通过在Microbeta多孔闪烁计数器(Wallac)中计数样品来测量放射性。按以下顺序移取反应物:
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(典型地106cpm/孔)
10μl底物溶液
b)单激酶
20μl标准测定缓冲液
5μl化合物的10%DMSO溶液
20μl酶-底物混合物
10μl底物溶液
该测定含有70mM HEPES-NaOH,pH7.5,3mM MgCl2,3mM MnCl2,3μM原钒酸钠,1.2mMDTT,ATP(可变量,对应于相应激酶的表观ATP-Km,参见表1),[33P-γ-ATP(约8x105 cpm/孔),蛋白激酶(可变量;参见表1),和底物(可变量;参见下表7)。结果在下表8中给出。
表7:酶、底物和测定条件(量/孔)
表8:测试化合物的效价
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*:根据以下分类规则从IC50-值(PoC)导出的效价:
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Claims (7)
1.一种化合物,或其药学上可接受的盐,其具有式(Ic)
其中
Rw是-NR10SO2R12;
Rx是F;
Ry是F;
R1是H;
R4是H或烷基;
R5是苯基,其被1、2或3个独立地选自以下的基团取代:烷基、羟基、卤素、烷基-SO(=NR10)-、R10R10NSO2-、-COOR10、-COOR14、R10R10N(C=O)-,和四唑基,或
R5是吡啶基、被-COOR10取代的吡啶基、嘧啶基或被CF3取代的嘧啶基;
R6是H或烷基;
R10是H或烷基;
R12是烷基或苯基烷基;以及
R14是被1或2个独立地选自-NR10R10、羟基或烷氧基的基团取代的烷基;
其中,以上所述烷基为直链或支链C1-6烷基基团。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中R5是吡啶基或由-COOR10取代的吡啶基。
3.一种化合物及其药学上可接受的盐,其为N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]丙烷-1-磺酰胺。
4.一种化合物,其选自由以下各项组成的组:
N-[2,6-二氟-3-[5-[4-(1H-四唑-5-基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺;
4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酰胺;
4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯磺酰胺;
4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸;
4-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]苯甲酸乙酯;
5-[3-[2,4-二氟-3-(甲磺酰胺基)苯甲酰基]-1H-吡唑并[3,4-b]吡啶-5-基]吡啶-2-羧酸;
N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]甲磺酰胺;
N-[2,6-二氟-3-[5-[4-(甲基磺酰亚胺基)苯基]-1H-吡唑并[3,4-b]吡啶-3-羰基]苯基]甲磺酰胺;
N-[3-[5-(4-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺;
4-(3-(2,4-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯甲酸;
N-(3-(5-(2-氯苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺;
N-(2,6-二氟-3-(5-(4-异丙基-苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,6-二氟-3-(5-(4-氟-2-甲基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
4-(3-(2,4-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)苯磺酰胺;
N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]-1-苯基甲磺酰胺;
N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基]-乙磺酰胺;
4-(3-(2,4-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-甲基苯磺酰胺;
N-(2,6-二氟-3-(5-(2-(三氟甲基)嘧啶-5-基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯-2-甲基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(1H-四唑-5-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)乙磺酰胺;
N-(3-(5-(4-(1H-四唑-5-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(1H-四唑-5-基)苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)-2,6-二氟苯基)-1-苯基甲磺酰胺;
N-(2,6-二氟-3-(5-(4-羟基苯基)-1H-吡唑并[3,4-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
或其药学上可接受的盐。
5.一种药物组合物,其包含如权利要求1至4中任一项所述的化合物或其药学上可接受的盐。
6.如权利要求1至4中任一项所述的化合物及其药学上可接受的盐在制备用于相对于蛋白激酶JNK1和MKK7选择性地抑制蛋白激酶MKK4的药物组合物中的应用。
7.如权利要求1至4中任一项所述的化合物或其药学上可接受的盐在制备用于促进肝脏再生或者减少或预防肝细胞死亡的药物组合物中的应用。
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