CN112424201A - 促进肝再生或者减少或预防肝细胞死亡的蛋白激酶抑制剂 - Google Patents
促进肝再生或者减少或预防肝细胞死亡的蛋白激酶抑制剂 Download PDFInfo
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- CN112424201A CN112424201A CN201980047654.0A CN201980047654A CN112424201A CN 112424201 A CN112424201 A CN 112424201A CN 201980047654 A CN201980047654 A CN 201980047654A CN 112424201 A CN112424201 A CN 112424201A
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- pyrrolo
- pyridine
- carbonyl
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- sulfonamide
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- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 108010003524 sodium-bile acid cotransporter Proteins 0.000 description 1
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- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- 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
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- 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
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- ZQOMVWOJNNEKDE-UHFFFAOYSA-N thiane Chemical compound C1CCSCC1.C1CCSCC1 ZQOMVWOJNNEKDE-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—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
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- A—HUMAN NECESSITIES
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract
本发明涉及式(I)的化合物,其是MKK4(丝裂原活化蛋白激酶激酶4)的抑制剂,以及它们在促进肝再生或者减少或预防肝细胞死亡的用途。所述化合物相对于蛋白激酶JNK和MKK7选择性抑制蛋白激酶MKK4。(I),其中Rx,Ry,Rz和Rzz选自:a)Rx和Ry为F,且Rz和Rzz为H;b)Rx、Ry和Rzz独立地是卤素,且Rz为H;c)Rx、Rz和Rzz独立地是卤素,且Ry为H;和d)Rx、Ry和Rz独立地是卤素,且Rzz为H。
Description
本发明涉及蛋白激酶抑制剂,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选择性抑制MKK4。
背景技术
肝病可能是由感染、损伤、暴露于毒性化合物如酒精或药物、自身免疫过程、遗传缺陷和其他因素导致的。肝具有显著的再生能力,但是在疾病状态下该能力可能会受损,并因此可能不足以补偿肝细胞和器官功能的丧失。
WO 2007/002433描述了作为蛋白激酶抑制剂的化合物,其可用于治疗与蛋白激酶异常活性有关的疾病和病症。这些化合物是Raf蛋白激酶特别是B-Raf和c-Raf及其突变体的抑制剂,因此可用于癌症治疗。此外,据说它们抑制多种其他蛋白激酶,其中包括c-JunN-末端激酶(JNK),尤其是JNK1。WO 2010/002325具有类似的公开内容,WO 2012/109075和WO 2014/194127公开了具有Raf蛋白激酶抑制活性的经修饰的化合物。H.Vin等将WO 2007/002433的两种化合物称为“B-Raf抑制剂”,其通过脱靶抑制JNK信号传导来抑制细胞凋亡。WO 2010/111527描述了吡唑并[3,4-b]吡啶化合物,其为蛋白激酶抑制剂,可用于治疗Raf蛋白激酶介导的疾病或病症,如癌症。此外,据说它们抑制多种其他蛋白激酶,其中包括c-Jun N-末端激酶(JNK),尤其是JNK1。WO 2012/136859公开了一些化合物,其被描述为丝裂原活化蛋白激酶激酶4(MKK4)的抑制剂,并且被描述为可用于治疗肝衰竭,用于保护肝细胞免于凋亡和肝细胞的再生。Wuestefeld等(Cell 153:389-401,2013)描述了一种功能遗传方法,用于鉴定可用于提高肝细胞再生能力的基因靶标。特别是,Wuestefeld等确认了蛋白激酶MKK4是肝脏再生的关键调节剂,并报告MKK4抑制经由MKK7的代偿性上调以及ATF2和ELK1的JNK1依赖性激活而提高了肝细胞再生。基于现有技术的发现,已经得出结论,MKK4和JNK1抑制剂可用于治疗JNK1介导的疾病。但是,在临床治疗中已经认识到用此类化合物治疗肝病是失败的。
发明内容
本发明的基本问题是提供有用的化合物,其为MKK4抑制剂,特别是相对于MKK7和JNK1选择性地抑制MKK4的MKK4抑制剂。另一个问题是提供作为MKK4抑制剂的化合物,其相对于MKK7和JNK1选择性抑制MKK4,并且可用于治疗肝病,尤其是用于促进肝再生或者减少或预防肝细胞死亡。
通过提供式(I)的化合物解决了该问题。
因此,本发明涉及以下实施例:
1.具有式(I)的化合物
其中
R1是H或烷基;
R2是H或烷基;
R4是H、卤素、CN或烷基;
R6是H、烷氧基或烷基;
Rw为-NR10SO2R12;
R10为H、烷基或苯基烷基;
R12选自
H,
烷基,其中该烷基可选地被1或2个羟基取代或被乙酰基取代,
卤代烷基或
苯基烷基,其中所述苯基可选地被1或2个独立地选自烷基和卤素的基团取代;
Rx、Ry、Rz和Rzz选自:
a)Rx和Ry为F,且Rz和Rzz为H;
b)Rx、Ry和Rzz独立地是卤素,且Rz为H;
c)Rx、Rz和Rzz独立地是卤素,且Ry为H;和
d)Rx、Ry和Rz独立地是卤素,且Rzz为H;
R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
卤素,
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
其中烷基被1、2或3个卤素原子取代的烷氧基,
卤代烷基,
羟基,
-SO2NR10R10,
-CO2R10,
-CN,
-SF5,
-(NR10=)S(=O)-烷基(S-烷基亚磺酰亚胺基(S-alkylsulfonimidoyl)),
1H-或2H-四唑基,
-SO2烷基,其中所述烷基可选地被1、2或3个卤素原子取代,
-SO烷基,
烷硫基(alkylsulfanyl),其中烷基可选地被-NR10R10或1、2或3个卤素原子取代,
-PO二(烷基),
-NO2,
-NR10R10,
R10R10N-CO-,
-NR10CO烷基,
羟烷基-ONH-CO-,
环烷基,
具有1、2或3个独立地选自O、N和S的杂原子的非芳族杂环5元或6元的单环基团,该基团可选地被1或2个独立地选自烷基和C2-C5烷酰基的基团取代,和
烷氧基,其中烷基被具有1、2或3个独立地选自O、N和S的杂原子的非芳族杂环5元或6元的单环基团取代,该单环基团可选地被1或2个独立地选自烷基和卤素的基团取代;
(b)萘基;
(c)具有1或2个独立地选自O、N和S的杂原子的杂芳族5元或6元的单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
羟基,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
-SO2NR10R10,
-SO2烷基,
-(NR10=)S(=O)-烷基,
环烷基-NR10-,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,
和
具有1或2个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环4元、5元或6元单环基团,该杂环基团可选地被烷基、羟烷基或羟基取代;
(d)C2-C5炔烃基;
(e)C2-C5烯烃基;
(f)卤素;
(g)环烷基;
(h)苯基,其与具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团稠合;
i)1,3-二烷基-1-氧代-1I4-苯并[e][1,2]噻嗪;
j)具有1、2或3个独立地选自O、N、S、SO和SO2的杂原子的饱和或不饱和非芳族杂环4元、5元或6元单环基团,所述杂环基团可选地被1或2个独立地选自烷基、C2-C5烷酰基、苯甲酰基、羟基、-CO2R10或羰基(环碳原子之一是>C=O基团)的基团取代;
k)氧杂环丁胺基(oxetanamino);
及其药学上可接受的盐、溶剂化物和光学异构体。
2.根据实施方案1所述的化合物,其中
R1是H或烷基;
R2是H或烷基;
R4是H或烷基;
R6是H或烷基;
Rw为-NR10SO2R12;
R10为H、烷基或苯基烷基;
R12为H、烷基、卤代烷基或苯基烷基,其中苯基可选地被1或2个独立地选自烷基和卤素的基团取代;
Rx、Ry、Rz和Rzz选自:
a)Rx和Ry为F,且Rz和Rzz为H;
b)Rx、Ry和Rzz独立地是卤素,且Rz为H;
c)Rx、Rz和Rzz独立地是卤素,且Ry是H;和
d)Rx、Ry和Rz独立地是卤素,且Rzz是H;
R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
卤素,
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
卤代烷基,
羟基,
-SO2NR10R10,
-CO2R10,
-CN,
-SF5,
-(NR10=)S(=O)-烷基(S-烷基亚磺酰亚胺基),和
1H-四唑基或2H-四唑基;
(b)萘基;
(c)具有1或2个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
羟基,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
烷基-S(=O)(=NR10)-,
环烷基-NR10-,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,
和
具有1或2个独立地选自O和N的杂原子的非芳族杂环4元、5元或6元单环基团,该杂环基团可选地被烷基、羟烷基或羟基取代,
(d)C2-C5炔烃基,
(e)C2-C5-烯烃基,
(f)卤素,和
(g)环烷基,
及其药学上可接受的盐、溶剂化物和光学异构体。
3.根据实施方案2的化合物,其中R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
卤素,
烷基,
烷氧基,
其中烷基被1或2个羟基取代的烷氧基,
羟基,
-SO2NR10R10,
-CO2R10,
-CN,
-SF5,
-(NR10=)S(=O)-烷基(S-烷基亚磺酰亚胺基),和
1H-四唑基或2H-四唑基;
(b)萘基;
(c)具有1或2个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
烷基-S(=O)(=NR10)-,
环烷基-NR10-,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,
和
具有1或2个独立地选自O和N的杂原子的非芳族杂环4元、5元或6元单环基团,该杂环基团可选地被烷基、羟烷基或羟基取代,
(f)卤素;和
(g)环烷基;
及其药学上可接受的盐、溶剂化物和光学异构体。
4.根据实施方案1至3中任一项所述的化合物,其中,如果R5被1、2或3个卤素取代,则该卤素独立地选自F或Cl,
及其药学上可接受的盐、溶剂化物和光学异构体。
5.根据实施方案1至3中任一项所述的化合物,其中,R5是被1、2或3个独立地选自以下的基团取代的苯基
卤素,
烷基,
烷氧基,
其中烷基被1或2个羟基取代的烷氧基,
羟基,
-SO2NR10R10,
-CO2R10,
-CN,
-SF5,
-(NR10=)S(=O)-烷基(S-烷基亚磺酰亚胺基),和
1H-或2H-四唑基。
6.根据实施方案1至3中任一项所述的化合物,其中R5是具有1或2个独立地选自O和N的杂原子的杂芳族5元或6元单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
烷基-S(=O)(=NR10)-,
环烷基-NR10-,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,
和
具有1或2个独立地选自O和N的杂原子的非芳族杂环4元、5元或6元单环基团,该杂环基团可选地被烷基、羟烷基或羟基取代。
7.根据实施方案6所述的化合物,其中所述杂芳族5元或6元单环基团选自吡咯基、吡唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基和吡嗪基,该基团可选地如实施方案1至3或6中任一项、特别是如实施方案6中所定义地那样被取代。
8.根据实施方案7所述的化合物,其中所述杂芳族5元或6元单环基团选自吡啶基、哒嗪基、嘧啶基和吡嗪基,该基团可选地如实施方案6中所定义地那样被取代。
9.根据实施方案8所述的化合物,其中所述杂芳族5元或6元单环基团选自吡啶基和嘧啶基,该基团可选地如实施方案6中所定义地那样被取代。
10.根据实施方案9所述的化合物,其中所述杂芳族5元或6元单环基团是吡啶基,其可选地被1、2或3个独立地选自以下的基团取代:卤素特别是F或Cl,烷基,烷氧基,卤代烷基特别是CF3,环烷基,-NR10R10,环烷基-NR10-,烯烃基特别是乙烯基,以及烷基-S(=O)(=NR10)-。
11.根据实施方案9所述的化合物,其中所述杂芳族5元或6元单环基团是嘧啶基,其可选地被1或2个独立地选自以下的基团取代
烷基,
烷氧基,其可选地被-NR10R10取代,
卤素,特别是F或Cl,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
-NR10R10,
卤代烷基,特别是CF3,
环烷基,
烯烃基,
-CN,
烷硫基,
-NR10R10,
R10R10N-CO-,
环烷基-NR10-,
苯并咪唑基,和
具有1或2个独立地选自O和N的杂原子的非芳族杂环4元、5元或6元单环基团,该杂环基团可选地被烷基、羟烷基或羟基取代。
12.根据实施方案11所述的化合物,其中所述嘧啶基被非芳族杂环4元、5元或6元单环基团取代,该单环基团选自:可选地被羟基取代的氮杂环丁烷基,可选地被羟基取代的吡咯烷基,哌啶基(piperidinyl),吗啉基(morpholidinyl),和哌嗪基,其可选地被烷基、羟基或羟烷基取代。
13.根据实施方案11所述的化合物,其中所述嘧啶基被环烷基、特别是C3-C6环烷基取代。
14.根据实施方案12或13所述的化合物,其中所述嘧啶基在5位结合至1H-吡咯并[2,3-b]吡啶,并在2位被取代。
15.根据实施方案3所述的化合物,其中R5选自C3-C6环烷基。
16.根据前述实施方案中任一项所述的化合物,其中R12为C1-C4烷基,C1-C4卤代烷基,特别是-CH2CH2CF3,或苄基。
17.根据实施方案12所述的化合物,其中R12为C1-C4烷基,并且优选为甲基、乙基或丙基。
18.根据前述实施方案中任一项所述的化合物,其具有式(Ia)
及其药学上可接受的盐、溶剂化物和光学异构体。
19.根据实施方案1至17中任一项所述的化合物,其具有式(Ib)
及其药学上可接受的盐、溶剂化物和光学异构体。
20.根据实施方案1至17中任一项所述的化合物,其具有式(Ic)
及其药学上可接受的盐、溶剂化物和光学异构体。
21.根据实施方案1至17中任一项所述的化合物,其具有式(Id)
及其药学上可接受的盐、溶剂化物和光学异构体。
22.根据前述实施方案中任一项所述的化合物,其中R1、R2、R3、R4和R6是H或烷基,特别是H。
23.根据前述实施方案中任一项所述的化合物,其中R10是H或烷基,特别是H。
其他实施方案是:
24.具有式(I)的化合物
其中
R1是H或烷基;
R2是H或烷基;
R4是H、卤素、CN或烷基;
R6是H、烷氧基或烷基;
Rw是-NR10SO2R12或-N=S(=O)R10NR10R10;
R10为H、烷基或苯基烷基;
R12为H、烷基、羟烷基、烷氧基烷基、卤代烷基或苯基烷基,其中所述苯基可选地被1或2个独立地选自烷基、卤素的基团取代;
Rx是H、卤素、CN或烷基;
Ry是H、卤素、CN或烷基;
Rz是H、卤素、CN或烷基;
R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
烷氧基,其中烷基被具有1、2或3个独立地选自O、N和S的杂原子的非芳族杂环5元或6元单环基团取代,该单环基团可选地被1或2个独立地选自烷基和卤素的基团取代,
卤代烷基,
羟基,
NR10R10,
烷基磺酰基-NR10-,
-SO2NR10R10,
烷硫基,其中烷基可选地被NR10R10或1、2或3个卤素原子取代,
烷基亚磺酰基,
烷基磺酰基,其中烷基可选地被1、2或3个卤素原子取代,
卤代烷氧基,
环烷基,
硫胍基(H2NC(=NH)-S-),
R10R10N-CO-,
R10R11NSO2-
烷基羰基-NR10-
CN,和
具有1、2或3个独立地选自O、N和S的杂原子的非芳族杂环5元或6元单环基团,其可选地被1或2个独立地选自烷基、C2-C5烷酰基和苯甲酰基的基团取代,
(b)苯基,其与具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团稠合,
(c)杂芳族5元或6元单环或杂芳族9元或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,所述杂芳族基团可选地被以下取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
烷氧基,
-CO2R10和
具有1、2或3个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环5元或6元单环基团,该杂环基团可选地被烷硫基或1或2个羟基取代,
(d)具有1、2或3个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环5元或6元单环基团,所述杂环基团可选地被1或2个独立地选自以下的基团取代
烷基,
C2-C5烷酰基,
苯甲酰基,
羟基,
-CO2R10和
羰基(环碳原子之一是>C=O基团),
(e)C2-C5-炔烃基,
(f)C2-C5-烯烃基,
(g)卤素;
(h)环烷基
及其药学上可接受的盐、溶剂化物和光学异构体。
25.根据实施方案24所述的化合物,其中R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
烷氧基,其中烷基被具有1或2个独立地选自O和N的杂原子的非芳族杂环5元或6元单环基团取代,并且该单环基团可选地被1或2个烷基、-SO2NR10R10取代,
烷硫基,其中烷基可选地被NR10R10或1、2或3个卤素原子取代,
烷基亚磺酰基,
烷基磺酰基,其中烷基可选地被1、2或3个卤素原子取代,
环烷基,
硫胍基,
NR10R10,和
具有1或2个独立地选自O和N的杂原子的非芳族杂环5元或6元单环基团,其可选地被1或2个独立地选自烷基和C2-C5烷酰基的基团取代,
(b)苯基,其与具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团稠合,
(c)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元或6元单环基团,所述杂芳族基团可选地被以下取代
烷基,
环烷基,
-NR10R10,
-CO2R10和
具有1、2或3个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环5元或6元单环基团,所述杂环基团可选地被烷硫基或者1或2个羟基取代,
(d)具有1或2个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环5元或6元单环基团,所述杂环基团可选地被1或2个独立地选自以下的基团取代
烷基,
C2-C5烷酰基,
羟基,
-CO2R10和
羰基,
(e)C2-C5-炔烃基,
(f)卤素,及
(g)环烷基。
26.根据实施方案24或25所述的化合物,其中R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
烷氧基,其中烷基被具有1或2个氧杂原子的非芳族杂环5或6元单环基团取代,其中单环基团可选地被1或2个烷基取代,
-SO2NR10R10,
烷硫基,其中烷基可选地被NR10R10或1、2或3个卤素原子取代,
烷基亚磺酰基,
烷基磺酰基,其中烷基可选地被1、2或3个卤素原子取代,
环烷基,
硫胍基,
NR10R10,和
具有1或2个独立地选自O和N的杂原子的非芳族杂环6元单环基团,其可选地被1或2个独立地选自烷基和C2-C5烷酰基的基团取代,
(b)苯基,其与具有1或2个独立地选自N、O和S的杂原子的杂芳族5元单环基团稠合,
(c)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元或6元单环基团,其可选地被以下取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
-CO2R10或
具有1、2或3个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环5元或6元单环基团,所述杂环基团可选地被烷硫基或1或2个羟基取代,
(d)具有1或2个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环5元或6元单环基团,所述杂环基团可选地被1或2个独立地选自烷基、C2-C5-烷酰基和羟基的基团取代,
(e)C2-C5-炔烃基,
(f)卤素,和
(g)环烷基。
27.根据实施方案24至26中任一项所述的化合物,其中R5选自
苯基,其被1、2或3个独立地选自以下的基团取代:烷基;烷氧基;C2-C4烷氧基取代,其中所述烷基被1、2或3个羟基取代;C2-C4烷氧基,其中烷基被具有1或2个氧杂原子的非芳族杂环5元或6元单环基团取代,该单环基团可选地被1或2个烷基取代;-SO2NR10R10;烷基磺酰基;NR10R10;具有1或2个独立地选自O和N的杂原子的非芳族杂环6元单环基团,其可选地被1或2个独立地选自烷基和C2-C5烷酰基的基团取代。
28.根据实施方案24至26中任一项所述的化合物,其中R5选自苯并噻吩和苯并呋喃。
29.根据实施方案24至26中任一项所述的化合物,其中R5选自呋喃基、噻唑基、被烷硫基取代的噻唑基、吡唑基、三唑基、噻二唑基、被烷硫基取代的噻二唑基、嘧啶基、吡啶基和哒嗪基。
30.根据实施方案24至26中任一项所述的化合物,其中R5选自:可选地被1或2个烷基取代的吗啉基,可选地被1或2个烷基取代的哌嗪基,氧杂环烷基,氮杂环烷基,其可选地被1或2个独立地选自烷基、羟基、-COOR10以及氧氮杂环烷基(oxoazacycloalkyl)的基团取代。
31.根据实施方案24至26中任一项所述的化合物,其中R5为乙炔基或环烷基。
32.根据实施方案24至31中任一项所述的化合物,其中Rw是-NR10SO2R12。
33.根据实施方案32所述的化合物,其中R12为烷基、羟烷基或苯基烷基,其中所述苯基可选地被1或2个独立地选自烷基和卤素的基团取代。
34.根据实施方案33的化合物,其中R12为烷基。
35.根据实施方案24至34中任一项所述的化合物,其具有式(Ia)
36.根据实施方案24至34中任一项所述的化合物,其具有式(Ib)
37.根据实施方案24至34中任一项所述的化合物,其具有式(Ic)
38.根据实施方案24至34中任一项所述的化合物,其具有式(Id)
39.根据实施方案24至34中任一项所述的化合物,其具有式(Ie)
40.根据实施方案24至34中任一项所述的化合物,其具有式(If)
41.根据实施方案24至34中任一项所述的化合物,其具有式(Ig)
42.根据实施方案24至34中任一项所述的化合物,其具有式(Ih)
43.根据实施方案35所述的化合物,其中R5是被卤素取代的苯基,并且Rw是-NR10SO2R12,其中R12是烷基。
44.根据实施方案36所述的化合物,其中R5为烯烃基,Rx和Ry为卤素,且Rw为-NR10SO2R12,其中R12为烷基。
45.根据实施方案36所述的化合物,其中
R5是苯基,其被选自以下的基团取代
a)具有1或2个独立地选自O和N的杂原子的非芳族杂环6元单环基团,其可选地被1或2个独立地选自烷基和C2-C5烷酰基的基团取代,
b)C2-C4烷氧基,其中所述烷基被具有1或2个氧杂原子的非芳族杂环5元或6元单环基团取代,所述单环基团可选地被1或2个烷基取代,
c)烷氧基,其中烷基被1、2或3个羟基取代,
并且其中R5可选地被卤素和/或烷基取代,
d)可选地被1、2或3个卤素原子取代的烷基磺酰基,
e)烷硫基,其中烷基可选地被NR10R10或1、2或3个卤素原子取代,
f)硫胍基,和
g)环烷基,
Rx和Ry是卤素,并且Rw是-NR10SO2R12,其中R12是烷基或苄基,其可选地被1或2个独立地选自烷基和卤素的基团取代。
46.根据实施方案36所述的化合物,其中
R5是被烷氧基,-SO2NR10R10,卤素,其中烷基被1、2或3个羟基取代的烷氧基,烷基取代的苯基;具有1或2个独立地选自N和S的杂原子的杂芳族5元或6元单环基团,该单环基团可选地被烷基、环烷基和-NR10R10取代,
Rx和Ry是卤素,并且Rw是-NR10SO2R12,其中R12是苄基,其可选地被1或2个独立地选自烷基和卤素的基团取代。
47.根据实施方案36所述的化合物,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元单环基团,其可选地被以下取代
a)烷硫基,
b)环烷基,
c)氧杂环烷基
d)氮杂环烷基,其可选地被羟基取代,
e)-CO2R10,
f)氧代二氢吡嗪基,
g)氧代哌啶基,和
h)吗啉基,其可选地被1或2个烷基取代,
Rx和Ry是卤素,并且Rw是-NR10SO2R12,其中R12是烷基。
48.根据实施方案36所述的化合物,其中R5选自
a)嘧啶,其可选地被环烷基取代,
b)哒嗪,
c)苯并噻吩
d)苯并呋喃,
e)吡啶基,其被-SO2NR10R10、吗啉基、硫代吗啉基、1,1-二氧硫代吗啉基(1,1-dioxidothiomorpholinyl)、烷基磺酰基取代,
f)呋喃,
g)噻唑,
h)吡唑,
i)三唑,尤其是1,2,4-三唑,
j)噻二唑,
k)被烷硫代(alkythio)取代的噻二唑,和
l)被烷硫代取代的噻唑,
Rx和Ry独立地是卤素或CN,并且Rw是-NR10SO2R12,其中R12是烷基或苄基,其可选地被1、2或3个独立地选自烷基和卤素的基团取代。
49.根据实施方案47所述的化合物,其中R5为吡啶基,其被吗啉基、硫代吗啉基或1,1-二氧硫代吗啉基取代,Rx和Ry为卤素,并且Rw为-NR10SO2R12,其中R12是被1、2或3个卤素原子取代的烷基。
50.根据实施方案36所述的化合物,其中R5是具有1或2个独立地选自O和N的杂原子的非芳族杂环5元或6元单环基团,其可选地被1或2个烷基取代,Rx和Ry是卤素,并且Rw是-NR10SO2R12,其中R12是烷基。
51.根据实施方案37所述的化合物,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6元单环基团,其可选地被以下取代
a)环烷基,
b)烷基,
c)卤代烷基,
d)-COOR10,
e)氧杂环烷烃,其可选地被羟基取代,
Rx和Ry是卤素,并且Rw是-NR10SO2R12,其中R12是烷基、烷氧基烷基或卤代烷基。
52.根据实施方案51所述的化合物,其中杂芳族6元单环基团是吡啶基、嘧啶基或哒嗪基。
53.根据实施方案38所述的化合物,其中R5是被1或2个卤素原子取代的苯基,Rx和Ry是卤素,并且Rw是-NR10SO2R12,其中R12是烷基。
54.根据实施方案39所述的化合物,其中R5是被1或2个卤素原子取代的苯基,Rx、Ry和Rz是卤素,并且Rw是-NR10SO2R12,其中R12是烷基。
55.根据实施方案40所述的化合物,其中R5是被1或2个卤素原子取代的苯基,Rx、Ry和Rz是卤素,并且Rw是-NR10SO2R12,其中R12是烷基。
56.根据实施方案41所述的化合物,其中R5是被1或2个卤素原子取代的苯基,Rx、Ry和Rz是卤素,并且Rw是-NR10SO2R12,其中R12是烷基。
57.根据实施方案42所述的化合物,其中R5是被1或2个卤素原子取代的苯基,并且Rw是-NR10SO2R12,其中R12是烷基。
58.根据实施方案24至57中任一项所述的化合物,其中R1、R2、R3、R4和R6为H或烷基,特别是H。
59.根据前述实施方案中任一项所述的化合物,其中R10是H或烷基,特别是H。
36.根据实施方案24至59中任一项所述的化合物,其中R12为烷基,特别是C1-C4烷基,最优选为甲基、乙基或丙基。
发明的详细说明
在一个实施方案中,本发明涉及选择性MKK4抑制剂化合物及其药学上可接受的盐、溶剂化物和光学异构体,其中所述化合物具有式I,其中R1至R6、R10、A和Q在任意组合中如上述实施方案中所定义。
在一个实施方案中,本发明的化合物及其药学上可接受的盐、溶剂化物和光学异构体相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4。
此外,本发明还涉及所述化合物在促进肝再生或者减少或预防肝细胞死亡并同时提高肝细胞增殖方面的用途。
本发明还包括上述化合物的药学上可接受的盐。药学上可接受的盐特别是与药学上可接受的酸或碱的酸加成盐或碱加成盐。合适的药学上可接受的有机酸和无机酸的实例是盐酸,氢溴酸,磷酸,硫酸,氨基磺酸,C1-C4烷基磺酸如甲磺酸,脂环族磺酸如S-(+)-10-樟脑磺酸,芳族磺酸诸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,诸如草酸、丙二酸、马来酸、富马酸、乳酸、酒石酸、柠檬酸、乙醇酸、己二酸和苯甲酸。其他可利用的酸,例如在Fortschritte der Arzneimittelforschung[药物研究进展],第10卷,第224页及以后的页数,Basel和Stuttgart,1966年中进行了描述。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,有机氮碱诸如二甲胺、三甲胺、乙醇胺、二乙醇胺、三乙醇胺、胆碱、2-氨基-2-羟甲基丙烷-1,3-二醇、葡甲胺、普鲁卡因等、L-精氨酸,L-赖氨酸、乙二胺或羟乙基吡咯烷。
本发明还包括本发明的化合物和盐的任何互变异构的、晶体的和多态性的形式及其混合物。
本发明还包括溶剂化物,如水合物。
本发明的化合物可以包含一个或更多个手性中心,并且可以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试剂。前药的一个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特性。例如,前药可以比最终药物(ultimate drug)更易溶于水,从而有利于药物的静脉内给药。前药还可以具有比最终药物高的口服生物利用度。给药后,在血液或组织中前药被酶解或化学裂解从而递送最终药物。示例性前药包括但不限于具有羧酸取代基的化合物,其中游离氢被以下取代:(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(alkoxycarbonyloxymethyl),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,3-2-苯并[c]呋喃酮基(3-phthalidyl),4-巴豆酰基-内酯基(4-crotono-lactonyl),γ-丁内酯-4-基,二-N,N-(C1-C2)烷基氨基(C2-C3)烷基(如β-二甲基氨基乙基),氨基甲酰基-(C1-C2)烷基,N,N-二(C1-C2)-烷基氨基甲酰基-(C1-C2)烷基以及哌啶基-、吡咯烷基-或吗啉基(C2-C3)烷基。其他示例性前药释放式(I)的醇,其中羟基取代基(例如,R基团包含羟基)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(carbonyloxy)-甲基,N-(C1-C6)-烷氧基-羰基氨基甲基,琥珀酰基,(C1-C6)烷酰基,α-氨基(C1-C4)烷酰基,芳基酰基(arylactyl)和α-氨基酰基,或α-氨基酰基-α-氨基酰基,其中所述α-氨基酰基部分独立地是任何在蛋白质中发现的天然存在的L-氨基酸,P(O)(OH)2,-P(O)(O(C1-C6)烷基)2或糖基(由碳水化合物的半缩醛的羟基脱离产生的基团)。
MKK4抑制剂的表述是指给药时,MKK4的激酶活性被抑制,其IC50<10μmol/l,优选<1μmol/l,特别是<0.5μmol/l。如本文所用,表述“相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4”是指如用KINOMEscanTM测量的,以对照的百分数或Kd表示,MKK7抑制活性与MKK4抑制活性之比或JNK1抑制活性与MKK4抑制活性之比≥10。
如本文所用,表述“促进肝再生或者减少或预防肝细胞死亡”是指与治疗开始时的增殖细胞数相比,增殖肝细胞的相对数量增加至少30%,优选至少50%。特别是,该表述表示与治疗开始时的增殖细胞数量相比,增加≥100%。在这种情况下,将使用标准方法进行实验确定和量化,例如蛋白Ki67的定量分析,其与细胞增殖严格相关。为了量化组织玻片中增殖的肝细胞,有数种免疫组织化学标准方法可用,这些方法使用抗Ki67一级抗体,然后通过使用例如缀合有辣根过氧化物酶的二级抗体进行抗Ki67的结合的可视化。过氧化物酶活性的量可通过生色底物的酶促转化的方式可视化,并且与Ki67蛋白的量和增殖细胞的数量相关。
在下面描述的实验中,通过使用来自Abcam的多克隆兔抗Ki67一级抗体(商品编号ab15580,Abcam,Cambridge,美国)以及来自Invitrogen的含荧光团四甲基罗丹明的山羊多克隆二级抗体(商品编号16101,Invitrogen/ThermoFisher)对Ki67进行染色来对肝细胞增殖进行定量。基于从数个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抑制使肝细胞增殖从13%增至27%(与对照shRNA相比)并与肝损伤(转氨酶)减少和肝纤维化减少有关。根据上一章的定义,增殖细胞的相对增长为108%。在酒精诱导的脂肪性肝炎(ASH)模型中,相比于使用对照shRNA时的肝细胞增殖率2%,shRNA介导的MKK4沉默得到4%的肝细胞增殖率(相对增长:100%)。肝细胞增殖的翻倍(duplication)与脂肪变性(脂肪沉积)的减少和肝损伤的减少(如通过转氨酶测定)有关。同样,在部分肝切除模型(手术切除三分之二的肝脏后48小时)中,shRNA介导的MKK4沉默使肝细胞增殖从16%(对照shRNA)增加到33%(相对增长:106%)。同样,肝细胞增殖增加与肝再生的改善和肝脏肿块(liver mass)的更快恢复有关。
在上述变量的定义中提到的有机部分-如术语卤素-是各个基团成员的各个列表的总称。前缀Cn-Cm在每种情况下表示基团中可能存在的碳原子数。
术语卤素在每种情况下表示氟、溴、氯或碘,尤其是氟或氯。
烷基是直链或支链烷基基团,其优选为C1-C6烷基,即具有1至6个碳原子的烷基,更优选为C1-C4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-甲基丙基以及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。
卤代烷基是如上所定义的卤代烷基基团,其中至少一个(例如,1、2、3、4个)或全部氢原子被1、2、3、4或相应数目的相同或不同的卤素原子取代,诸如三氟甲基、氯甲基、溴甲基、二氟甲基、氟甲基、二氟乙基等。具体的实例包括如所定义的氟代C1-C4烷基基团,诸如三氟甲基、二氟甲基、氟甲基、二氟乙基、2,2,2-三氟乙基或3,3,3-三氟丙基。
环烷基是脂环族基团,其优选为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,诸如环丙基、环丁基、环戊基和环己基。该环状结构可以是未取代的或可以带有1、2、3或4个C1-C4烷基,优选一个或更多个甲基。
羰基为>C=O。
氨基羰基为NH2C(O)-。
烯烃基为单不饱和烃基,其优选为C2-C6烯烃基,即具有2、3、4、5或6个碳原子的烯基基团,例如乙烯基,烯丙基(2-丙烯-1-基),1-丙烯-1-基,2-丙烯-2-基,以及甲代烯丙基(2-甲基丙-2-烯-1-基)等。特别地,C3-C5-烯烃基为烯丙基,1-甲基丙-2-烯-1-基,2-丁烯-1-基,3-丁烯-1-基,甲代烯丙基,2-戊烯-1-基,3-戊烯-1-基,4-戊烯-1-基,1-甲基丁-2-烯-1-基或2-乙基丙-2-烯-1-基,2-己烯-1-基。
炔烃基为单不饱和烃基,其优选为C2-C6炔烃基,即具有2、3、4、5或6个碳原子的炔基基团,例如乙炔基,2-丙炔-1-基,1-丙炔-1-基,以及2-丙炔-2-基等。特别地,C3-C5-炔基为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。
杂芳族(或杂芳基)基团是具有1、2或3个选自O、N和S的杂原子的5元或6元单环基团或9元或10元双环芳族基团。该杂芳基或杂芳族基团可以经由碳原子(C-键合)或经由氮杂原子(N-键合)键合至相邻基团。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并可选地包含1或2个其他杂原子作为环成员,所述杂原子彼此独立地选自O、S和N。实例为:
C键合的5元杂芳环:
2-呋喃基,3-呋喃基,5-呋喃基,2-噻吩基,3-噻吩基,5-噻吩基,吡咯-2-基,吡咯-3-基,吡咯-5-基,吡唑-3-基,吡唑-4-基,吡唑-5-基,异恶唑-3-基,异恶唑-4-基,异恶唑-5-基,异噻唑-3-基,异噻唑-4-基,异噻唑-5-基,咪唑-2-基,咪唑-4-基,咪唑-5-基,恶唑-2-基,恶唑-4-基,恶唑-5-基,噻唑-2-基,噻唑-4-基,噻唑-5-基,1,2,3-恶二唑-咪唑-4-基,4-基,1,2,3-恶二唑-5-基,1,2,4-恶二唑-3-基,1,2,4,-恶二唑-5-基,1,3,4-恶二唑-2-基,1,2,3-噻二唑-4-基,1,2,3-噻二唑-5-基,1,2,4-噻二唑-3-基,1,2,4-噻二唑-5-基,1,3,4-噻二唑基-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元杂芳环:
吡啶-2-基,吡啶-3-基(3-吡啶基),吡啶-4-基(4-吡啶基),吡啶-5-基,哒嗪-3-基,哒嗪-4-基,哒嗪6-基,嘧啶-2-基,嘧啶-4-基,嘧啶-5-基,吡嗪-2-基,吡嗪-5-基,1,3,5-三嗪-2-基,1,2,4-三嗪-3-基,1,2,4-三嗪-5-基,1,2,4-三嗪-6基,1,2,4,5-四嗪-3-基;
N键合的5元杂芳环:
吡咯-1-基,吡唑-1-基,咪唑-1-基,1,2,3-三唑-1-基,1,2,4-三唑-1-基。
双环杂芳族基团包括所描述的5元或6元杂芳环之一和另外的稠合的(anellated)、饱和的或不饱和的或芳族的碳环,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,吲哚嗪基,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,苯并恶唑基,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,以及吡咯并[d]嘧啶基。包含稠合的环烯基环的5元或6元杂芳族化合物的实例包括二氢吲哚基,二氢吲哚嗪基,二氢异吲哚基,二氢喹啉基,二氢异喹啉基,二氢苯并呋喃基,苯并吡喃基(chromenyl),苯并二氢吡喃基(chromanyl),二氢吡咯并[a]咪唑基,以及四氢苯并噻唑基。
非芳族5元或6元基团(杂环基团)可以是饱和或部分不饱和的,并且包括1、2或3个选自O、N和S的杂原子。该杂环基团可以经由碳原子(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可选地包括1或2个其他杂原子作为环成员,所述杂原子彼此独立地选自O、S和N。实例为:
C键合的4元饱和环,诸如
氮杂环丁烷-2-基(azetidin-2-yl),氮杂环丁烷-3-基,氧杂环丁烷-2-基(oxetan-2-yl),氧杂环丁烷-3-基;
C键合的5元饱和环,诸如
四氢呋喃-2-基,四氢呋喃-3-基,四氢噻吩(tetrahydrothien)-2-基,四氢噻吩-3-基,四氢吡咯-2-基,四氢吡咯-3-基,四氢吡唑-3-基,四氢吡唑-4-基,四氢异恶唑-3-基,四氢异恶唑-4-基,四氢异恶唑-5-基,1,2-氧硫杂环戊烷(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,四氢恶唑-2-基,四氢恶唑-4-基,四氢恶唑-5-基,四氢噻唑-2-基,四氢噻唑-4-基,四氢噻唑-5-基,1,3-二氧杂环戊烷(dioxolan)-2-基,1,3-二氧杂环戊烷-4-基,1,3-氧硫杂环戊烷-2-基,1,3-氧硫杂环戊烷-4-基,1,3-氧硫杂环戊烷-5-基,1,3-二硫杂环戊烷-2-基,1,3-二硫杂环戊烷-4-基,1,3,2-二氧硫杂环戊烷(dioxathiolan)-4-基;
C键合的6元饱和环,诸如
四氢吡喃-2-基,四氢吡喃-3-基,四氢吡喃-4-基,哌啶-2-基,哌啶-3-基,哌啶-4-基,四氢噻喃(tetrahydrothiopyran)-2-基,四氢噻喃-3-基,四氢噻喃-4-基,1,3-二氧六环-2-基,1,3-二氧六环-4-基,1,3-二氧六环-5-基,1,4-二氧六环-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-恶嗪(oxazin)-2-基,四氢-1,3-恶嗪-4-基,四氢-1,3-恶嗪-5-基,四氢-1,3-恶嗪-6基,四氢-1,3-噻嗪-2-基,四氢-1,3-噻嗪-4-基,四氢-1,3-噻嗪-5-基,四氢-1,3-噻嗪-6基,四氢-1,4-噻嗪-2-基,四氢-1,4-噻嗪-3-基,四氢-1,4-恶嗪-2-基,四氢-1,4-恶嗪-3-基,四氢-1,2-恶嗪-3-基,四氢-1,2-恶嗪-4-基,四氢-1,2-恶嗪-5-基,四氢-1,2-恶嗪-6-基;
N键合的4元饱和环,如
氮杂环丁烷-1-基;
N键合的5元饱和环,诸如
四氢吡咯-1-基(吡咯烷-1-基),四氢吡唑-1-基,四氢异恶唑-2-基,四氢异噻唑-2-基,四氢咪唑-1-基,四氢恶唑-3-基,四氢噻唑-3-基;
N键合的6元饱和环,诸如
哌啶-1-基,六氢嘧啶-1-基,六氢吡嗪-1-基(哌嗪-1-基),六氢哒嗪-1-基,四氢-1,3-恶嗪-3-基,四氢-1,3-噻嗪-3-基,四氢-1,4-噻嗪-4-基,四氢-1,4-恶嗪-4-基(吗啉-1-基),四氢1,2-恶嗪-2-基;
C键合的5元部分不饱和环,诸如
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(thien)-2-基,2,3-二氢噻吩-3-基,2,5-二氢噻吩-2-基,2,5-二氢噻吩-3-基,4,5-二氢噻吩-2-基,4,5-二氢噻吩-3-基,2,3-二氢-1H-吡咯-2-基,2,3-二氢-1H-吡咯-3-基,2,5-二氢-1H-吡咯-2-基,2,5-二氢-1H-吡咯-3-基,4,5-二氢-1H-吡咯-2-基,4,5-二氢-1H-吡咯-3-基,3,4-二氢-2H-吡咯-2-基,3,4-二氢-2H-吡咯-3-基,3,4-二氢-5H-吡咯-2-基,3,4-二氢-5H-吡咯-3-基,4,5-二氢-1H-吡唑-3-基,4,5-二氢-1H-吡唑-4-基,4,5-二氢-1H-吡唑-5-基,2,5-二氢-1H-吡唑-3-基,2,5-二氢-1H-吡唑-4-基,2,5-二氢-1H-吡唑-5-基,4,5-二氢异恶唑-3-基,4,5-二氢异恶唑-4-基,4,5-二氢异恶唑-5-基,2,5-二氢异恶唑-3-基,2,5-二氢异恶唑-4-基,2,5-二氢异恶唑-5-基,2,3-二氢异恶唑-3-基,2,3-二氢异恶唑-4-基,2,3-二氢异恶唑-5-基,4,5-二氢异噻唑-3-基,4,5-二氢异噻唑-4-基,4,5-二氢异噻唑-5-基,2,5-二氢异噻唑-3-基,2,5-二氢异噻唑-4-基,2,5-二氢异噻唑-5-基,2,3-二氢异噻唑-3-基,2,3-二氢异噻唑-4-基,2,3-二氢异噻唑-5-基,4,5-二氢-1H-咪唑-2-基,4,5-二氢-1H-咪唑-4-基,4,5-二氢-1H-咪唑-5-基,2,5-二氢-1H-咪唑-2-基,2,5-二氢-1H-咪唑-4-基,2,5-二氢-1H-咪唑-5-基,2,3-二氢-1H-咪唑-2-基,2,3-二氢-1H-咪唑-4-基,4,5-二氢-恶唑-2-基,4,5-二氢恶唑-4-基,4,5-二氢恶唑-5-基,2,5-二氢恶唑-2-基,2,5-二氢恶唑-4-基,2,5-二氢恶唑-5-基,2,3-二氢恶唑-2-基,2,3-二氢恶唑-4-基,2,3-二氢恶唑-5-基,4,5-二氢噻唑-2-基,4,5-二氢噻唑-4-基,4,5-二氢噻唑-5-基,2,5-二氢噻唑-2-基,2,5-二氢噻唑-4-基,2,5-二氢噻唑-5-基,2,3-二氢噻唑-2-基,2,3-二氢噻唑-4-基,2,3-二氢噻唑-5-基,1,3-二氧杂环戊烯(dioxol)-2-基,1,3-二氧杂环戊烯-4-基,1,3-二硫杂环戊烯(dithiol)-2-基,1,3-二硫杂环戊烯-4-基,1,3-氧硫杂环戊烯(oxathiol)-2-基,1,3-氧硫杂环戊烯-4-基,1,3-氧硫杂环戊烯-5-基;
C结合的6元部分不饱和环,诸如
2H-3,4-二氢吡喃-6-基,2H-3,4-二氢吡喃-5-基,2H-3,4-二氢吡喃-4-基,2H-3,4-二氢吡喃-3-基,2H-3,4-二氢吡喃-2-基,2H-3,4-二氢噻喃-6基,2H-3,4-二氢噻喃-5-基,2H-3,4-二氢噻喃-4-基,2H-3,4-二氢噻喃-3-基,2H-3,4-二氢噻喃-2-基,1,2,3,4-四氢吡啶-6-基,1,2,3,4-四氢吡啶-5-基,1,2,3,4-四氢吡啶-4-基,1,2,3,4-四氢吡啶-3-基,1,2,3,4-四氢吡啶-2-基,2H-5,6-二氢吡喃-2-基,2H-5,6-二氢吡喃-3-基,2H-5,6-二氢吡喃-4-基,2H-5,6-二氢吡喃-5-基,2H-5,6-二氢吡喃-6-基,2H-5,6-二氢噻喃-2-基,2H-5,6-二氢噻喃-3-基,2H-5,6-二氢噻喃-4-基,2H-5,6-二氢噻喃-5-基,2H-5,6-二氢噻喃-6-基,1,2,5,6-四氢吡啶-2-基,1,2,5,6-四氢吡啶-3-基,1,2,5,6-四氢吡啶-4-基,1,2,5,6-四氢吡啶-5-基,1,2,5,6-四氢吡啶-6-基,2,3,4,5-四氢吡啶-2-基,2,3,4,5-四氢吡啶-3-基,2,3,4,5-四氢吡啶-4-基,2,3,4,5-四氢吡啶-5-基,2,3,4,5-四氢吡啶-6-基,4H-吡喃-2-基,4H-吡喃-3-基,4H-吡喃-4-基,4H-噻喃-2-基,4H-噻喃-3-基,4H-噻喃-4-基,1,4-二氢吡啶-2-基,1,4-二氢吡啶-3-基,1,4-二氢吡啶-4-基,2H-吡喃-2-基,2H-吡喃-3-基,2H-吡喃-4-基,2H-吡喃-5-基,2H-吡喃-6-基,2H-噻喃-2-基,2H-噻喃-3-基,2H-噻喃-4-基,2H-噻喃-5-基,2H-噻喃-6-基,1,2-二氢吡啶-2-基,1,2-二氢吡啶-3-基,1,2-二氢吡啶-4-基,1,2-二氢吡啶-5-基,1,2-二氢吡啶-6基,3,4-二氢吡啶-2-基,3,4-二氢吡啶-3-基,3,4-二氢吡啶-4-基,3,4-二氢吡啶-5-基,3,4-二氢吡啶-6-基,2,5-二氢吡啶-2-基,2,5-二氢吡啶-3-基,2,5-二氢吡啶-4-基,2,5-二氢吡啶-5-基,2,5-二氢吡啶-6-基,2,3-二氢吡啶-2-基,2,3-二氢吡啶-3-基,2,3-二氢吡啶-4-基,2,3-二氢吡啶-5-基,2,3-二氢吡啶-6-基,2H-5,6-二氢-1,2-恶嗪-3-基,2H-5,6-二氢-1,2-恶嗪-4-基,2H-5,6-二氢-1,2-恶嗪-5-基,2H-5,6-二氢-1,2-恶嗪-6基,2H-5,6-二氢-1,2-噻嗪-3-基,2H-5,6-二氢-1,2-噻嗪-4-基,2H-5,6-二氢-1,2-噻嗪-5-基,2H-5,6-二氢-1,2-噻嗪-6-基,4H-5,6-二氢-1,2-恶嗪-3-基,4H-5,6-二氢-1,2-恶嗪-4-基,4H-5,6-二氢-1,2-恶嗪-5-基,4H-5,6-二氢-1,2-恶嗪-6-基,4H-5,6-二氢-1,2-噻嗪-3-基,4H-5,6-二氢-1,2-噻嗪-4-基,4H-5,6-二氢-1,2-噻嗪-5-基,4H-5,6-二氢-1,2-噻嗪-6-基,2H-3,6-二氢-1,2-恶嗪-3-基,2H-3,6-二氢-1,2-恶嗪-4-基,2H-3,6-二氢-1,2-恶嗪-5-基,2H-3,6-二氢-1,2-恶嗪-6-基,2H-3,6-二氢-1,2-噻嗪-3-基,2H-3,6-二氢-1,2-噻嗪-4-基,2H-3,6-二氢-1,2-噻嗪-5-基,2H-3,6-二氢-1,2-噻嗪-6基,2H-3,4-二氢-1,2-恶嗪-3-基,2H-3,4-二氢-1,2-恶嗪-4-基,2H-3,4-二氢-1,2-恶嗪-5-基,2H-3,4-二氢-1,2-恶嗪-6-基,2H-3,4-二氢-1,2-噻嗪-3-基,2H-3,4-二氢-1,2-噻嗪-4-基,2H-3,4-二氢-1,2-噻嗪-5-基,2H-3,4-二氢-1,2-噻嗪-6基,2,3,4,5-四氢哒嗪-3-基,2,3,4,5-四氢哒嗪-4-基,2,3,4,5-四氢哒嗪-5-基,2,3,4,5-四氢哒嗪-6-基,3,4,5,6-四氢哒嗪-3-基,3,4,5,6-四氢哒嗪-4-基,1,2,5,6-四氢哒嗪-3-基,1,2,5,6-四氢哒嗪-4-基,1,2,5,6-四氢哒嗪-5-基,1,2,5,6-四氢哒嗪-6-基,1,2,3,6-四氢哒嗪-3-基,1,2,3,6-四氢哒嗪-4-基,4H-5,6-二氢-1,3-恶嗪-2-基,4H-5,6-二氢-1,3-恶嗪-4-基,4H-5,6-二氢-1,3-恶嗪-5-基,4H-5,6-二氢-1,3-恶嗪-6-基,4H-5,6-二氢-1,3-噻嗪-2-基,4H-5,6-二氢-1,3-噻嗪-4-基,4H-5,6-二氢-1,3-噻嗪-5-基,4H-5,6-二氢-1,3-噻嗪-6-基,3,4,5-6-四氢嘧啶-2-基,3,4,5,6-四氢嘧啶-4-基,3,4,5,6-四氢嘧啶-5-基,3,4,5,6-四氢嘧啶-6-基,1,2,3,4-四氢吡嗪-2-基,1,2,3,4-四氢吡嗪-5-基,1,2,3,4-四氢嘧啶-2-基,1,2,3,4-四氢嘧啶-4-基,1,2,3,4-四氢嘧啶-5-基,1,2,3,4-四氢嘧啶-6基,2,3-二氢-1,4-噻嗪-2-基,2,3-二氢.1,4-噻嗪-3-基,2,3-二氢-1,4-噻嗪-5-基,2,3-二氢-1,4-噻嗪-6-基,2H-1,3-恶嗪-2-基,2H-1,3-恶嗪-4-基,2H-1,3-恶嗪-5-基,2H-1,3-恶嗪-6-基,2H-1,3-噻嗪-2-基,2H-1,3-噻嗪-4-基,2H-1,3-噻嗪-5-基,2H-1,3-噻嗪-6-基,4H-1,3-恶嗪-2-基,4H-1,3-恶嗪-4-基,4H-1,3-恶嗪-5-基,4H-1,3-恶嗪-6-基,4H-1,3-噻嗪-2-基,4H-1,3-噻嗪-4-基,4H-1,3-噻嗪-5-基,4H-1,3-噻嗪-6-基,6H-1,3-恶嗪-2-基,6H-1,3-恶嗪-4-基,6H-1,3-恶嗪-5-基,6H-1,3-恶嗪-6-基,6H-1,3-噻嗪-2-基,6H-1,3-恶嗪-4-基,6H-1,3-恶嗪-5-基,6H-1,3-噻嗪-6-基,2H-1,4-恶嗪-2-基,2H-1,4-恶嗪-3-基,2H-1,4-恶嗪-5-基,2H-1,4-恶嗪-6-基,2H-1,4-噻嗪-2-基,2H-1,4-噻嗪-3-基,2H-1,4-噻嗪-5-基,2H-1,4-噻嗪-6-基,4H-1,4-恶嗪-2-基,4H-1,4-恶嗪-3-基,4H-1,4-噻嗪-2-基,4H-1,4-噻嗪-3-基,1,4-二氢哒嗪-3-基,1,4-二氢哒嗪-4-基,1,4-二氢哒嗪-5-基,1,4-二氢哒嗪-6-基,1,4-二氢吡嗪-2-基,1,2-二氢吡嗪-2-基,1,2-二氢吡嗪-3-基,1,2-二氢吡嗪-5-基,1,2-二氢吡嗪-6-基,1,4-二氢嘧啶-2-基,1,4-二氢嘧啶-4-基,1,4-二氢嘧啶-5-基,1,4-二氢嘧啶-6基,3,4-二氢嘧啶-2-基,3,4-二氢嘧啶-4-基,3,4-二氢嘧啶-5-基或3,4-二氢嘧啶-6-基;
N键合的5元部分不饱和环,诸如
2,3-二氢-1H-吡咯-1-基,2,5-二氢-1H-吡咯-1-基,4,5-二氢-1H-吡唑-1-基,2,5-二氢-1H-吡唑-1-基,2,3-二氢-1H-吡唑-1-基,2,5-二氢异恶唑-2-基,2,3-二氢异恶唑-2-基,2,5-二氢异噻唑-2-基,2,3-二氢异恶唑-2-基,4,5-二氢-1H-咪唑-1-基,2,5-二氢-1H-咪唑-1-基,2,3-二氢-1H-咪唑-1-基,2,3-二氢恶唑-3-基,2,3-二氢噻唑-3-基;
N键合的6元部分不饱和环,例如
1,2,3,4-四氢吡啶-1-基,1,2,5,6-四氢吡啶-1-基,1,4-二氢吡啶-1-基,1,2-二氢吡啶-1-基,2H-5,6-二氢-1,2-恶嗪-2-基,2H-5,6-二氢-1,2-噻嗪-2-基,2H-3,6-二氢-1,2-恶嗪-2-基,2H-3,6-二氢-1,2-噻嗪-2-基,2H-3,4-二氢-1,2-恶嗪-2-基,2H-3,4-二氢-1,2-噻嗪-2-基,2,3,4,5-四氢哒嗪-2-基,1,2,5,6-四氢哒嗪-1-基,1,2,5,6-四氢哒嗪-2-基,1,2,3,6-四氢哒嗪-1-基,3,4,5,6-四氢嘧啶-3-基,1,2,3,4-四氢吡嗪-1-基,1,2,3,4-四氢嘧啶-1-基,1,2,3,4-四氢嘧啶-3-基,2,3-二氢-1,4-噻嗪-4-基,2H-1,2-恶嗪-2-基,2H-1,2-噻嗪-2-基,4H-1,4-恶嗪-4-基,4H-1,4-噻嗪-4-基,1,4-二氢哒嗪-1-基,1,4-二氢吡嗪-1-基,1,2-二氢吡嗪-1-基,1,4-二氢嘧啶-1-基或3,4-二氢嘧啶-3-基。
任何包含杂原子的基团可以包含1、2或3个相同或不同的杂原子。
本发明的化合物,包括其药学上可接受的盐、前药、生物活性代谢物、溶剂化物和立体异构体,可以按照WO 2007/002433中公开的方法(该文献通过引用全文并入本文)或类似的程序制备。通过将游离碱与相应的酸混合或通过将游离酸与所需的碱混合,以常规方式制备酸加成盐或碱加成盐。可选地,该反应在有机溶剂的溶液中进行,有机溶剂例如低级醇诸如甲醇、乙醇或丙醇,醚诸如甲基叔丁基醚或二异丙基醚,酮诸如丙酮或甲基乙基酮,或酯如EtOAc。
本发明的化合物可用于促进肝再生或者减少或预防肝细胞死亡,同时使肝细胞增殖增加。因此,这些化合物可用于治疗、调节、改善或预防与肝脏的急性或慢性损伤有关的疾病,这些损伤可能是由感染、创伤、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导致的。
这样的肝病包括其中增加肝再生和减少或预防肝细胞死亡可以有助于实现有效力的治疗效果(即,肝功能部分或完全恢复)的所有疾病。这些疾病包括急性和慢性或慢加急性肝病,诸如急性和慢性病毒性肝炎如乙型、丙型、戊型肝炎,由爱泼斯坦-巴尔病毒(Epstein-Barr virus)、巨细胞病毒、单纯疱疹病毒和其他病毒引起的肝炎,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,诸如代谢综合征,脂肪肝如非酒精性脂肪肝(NAFL),非酒精性脂肪性肝炎(NASH),酒精性脂肪性肝炎(ASH),Morbus Wilson病,血色素沉着症,α1-抗胰蛋白酶缺乏症,糖原贮积病;
所有类型的肝硬化,诸如原发性胆汁性肝硬化,酒精中毒性(ethyl toxic)肝硬化,隐源性肝硬化;
急性(暴发性)或慢性肝衰竭,诸如中毒性肝衰竭如对乙酰氨基酚(扑热息痛)引发的肝衰竭,α-鹅膏蕈碱引发的肝衰竭,药物诱发的例如由抗生素、非甾体抗炎药和抗惊厥药导致的肝毒性、肝衰竭,草药补充剂(卡瓦、麻黄、黄芩(skullcap)、薄荷(pennyroyal)等)诱发的急性肝衰竭,由于血管疾病如布加综合征导致的肝病和肝衰竭,起因不明的急性肝衰竭,由于右心衰竭导致的慢性肝病;
半乳糖血症,囊性纤维化,卟啉症,肝缺血灌注损伤,肝移植后小肝综合征,原发性硬化性胆管炎或肝性脑病。
为了促进肝再生或者减少或预防肝细胞死亡,将本发明的化合物以治疗有效量给药至有需要的患者。各种诊断方法可以用于检测是否存在肝病。已知丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)的血液水平高于临床上可接受的正常范围可指示进行性(on-going)肝损伤。血液胆红素水平或其他肝酶可以用作检测或诊断标准。对肝病患者的ALT和AST血液水平进行常规监测被用于测量医治期间肝病的进展。将升高的ALT和AST水平降低到可接受的正常范围之内被视为反映患者肝损伤严重程度降低的临床证据。商业化检测,诸如FibroTest/FibroSURE,FibroMeter或Cirrhometer评估了用于检测肝脂肪变性、肝纤维化和肝硬化的五个或更多个生化参数的组合结果。此外,无创、创新的物理成像技术,例如磁共振成像、超声检查以及特别是弹性成像技术,可用于检测和监测肝病的状况和进展。
进一步发现,shRNA介导的MKK4抑制作用减弱了骨关节炎中TNF-α驱动的软骨基质降解(Cell Death and Disease(2017)8,e3140)。因此,使用本发明的化合物抑制MKK4的活性还用于治疗骨关节炎和类风湿性关节炎。
本发明的化合物通常以药物组合物的形式给药,所述药物组合物包含至少一种根据本发明的化合物,可选地连同惰性载体(例如药学上可接受的赋形剂)以及在合适的情况下的其他药物。这些组合物可以例如通过口服、直肠、透皮、皮下、腹膜内、静脉内、肌肉内或鼻内给药。
适用的药物组合物的实例是固体药物形式诸如粉末、颗粒剂、片剂特别是薄膜片剂、锭剂(lozenges)、小袋(sachets)、扁囊剂(cachets)、糖衣片剂、胶囊剂比如硬明胶胶囊和软明胶胶囊、或栓剂,半固体药用形式诸如软膏、乳膏、水凝胶、糊剂或贴膏(plasters),以及液体药用形式诸如溶液、乳剂特别是水包油乳剂、混悬液例如洗剂、注射剂和输注剂。另外,也可以使用脂质体或微球。
在制备组合物时,本发明的化合物可选地与一种或更多种载体(赋形剂)混合或用其稀释。载体(赋形剂)可以是固体、半固体或液体物质,它们用作活性化合物的媒介物、载体或介质。
合适的载体(赋形剂)在专业药学专著中列出。另外,制剂可以包含药学上可接受的辅助物质,诸如润湿剂;乳化和助悬剂;防腐剂;抗氧化剂;抗刺激剂;螯合剂;包衣助剂;乳液稳定剂;成膜剂;凝胶形成剂;掩味剂;矫味剂;树脂类;亲水胶体;溶剂;增溶剂;中和剂;扩散促进剂;色素;季铵化合物;再脂化剂和超脂化剂(refatting and overfattingagents);软膏、乳膏或油的原料(raw materials);有机硅衍生物;铺展助剂(spreadingauxiliaries);稳定剂;灭菌剂;栓剂基质;片剂助剂,如粘合剂、填充剂、助流剂、崩解剂或包衣;抛射剂(propellants);干燥剂;遮光剂(opacifiers);增稠剂;蜡类;增塑剂以及液体石蜡(white mineral oils)。这方面的制剂是基于专业知识,例如,如在,1996年的Fiedler,H.P.,Lexikon der Hilfsstoffe für Pharmazie,Kosmetik und angrenzendeGebiete[用于制药、化妆品和相关领域的辅助物质百科全书],第4版,Aulendorf:ECV-Editio-Cantor-Verlag中描述的。
本发明的化合物还可以适用于与其他治疗剂组合。因此,本发明还涉及包含本发明化合物与一种或更多种其他治疗剂的组合,所述其他治疗剂特别用于促进肝再生或者减少或预防肝细胞死亡。本发明的联合治疗可以辅助的给药。辅助的给药(adjunctiveadministration)是指每种组分以单独的药物组合物或装置的形式相连(coterminous)或叠加(overlapping)地给药。本领域技术人员和本文中通常将这种两种或更多种治疗剂的治疗性给药方案称为辅助的治疗给药;它也被称为加合(add-on)治疗给药。其中患者接受本发明的化合物与至少一种其他治疗剂的单独的但相连或叠加的治疗给药的任意和全部治疗方案都在本发明的范围内。在本文所述的一个辅助性治疗给药的实施方案中,通常使患者在一段时间内稳定于一种或更多种组分的治疗给药,然后接受另一种组分的给药。
本发明的联合治疗也可以同时给药。同时给药是指其中一起施用各个组分的治疗方案,各个组分以包含或含有两种组分的单一药物组合物或装置的形式,或者作为各自包含一种组分的单独的组合物或装置同时给药的形式。这种用于同时联合单独的各个组分的联合形式可以以成套试剂盒(kit-of-parts)的形式提供。
与本发明的化合物联合使用的合适试剂包括例如:
ACC抑制剂,诸如TOFA(5-(十四烷基氧基)-2-呋喃甲酸),GS 0976和WO 2016/112305中公开的ACC抑制剂,
血管紧张素II受体拮抗剂,
血管紧张素转换酶(ACE)抑制剂,如依那普利,
半胱天冬酶(caspase)抑制剂,如恩利卡生(emricasan),
组织蛋白酶B抑制剂,例如混合的组织蛋白酶B/丙型肝炎病毒NS3蛋白酶抑制剂,如VBY-376,
CCR2趋化因子拮抗剂,例如混合的CCR2/CCR5趋化因子拮抗剂,如cenicriviroc,CCR5趋化因子拮抗剂,
氯离子通道刺激剂,如cobiprostone,
胆固醇增溶剂,
二酰基甘油O-酰基转移酶1(DGAT1)抑制剂,如LCQ908,
二肽基肽酶IV(DPPIV)抑制剂,如利格列汀(linagliptin),
法尼醇X受体(farnesoid X receptor,FXR)激动剂,如INT-747(奥贝胆酸(obeticholic acid))或GS-9674
(PX-102),
FXR/TGR5双重激动剂,如INT-767,
半乳糖凝集素3(galectin-3)抑制剂,如GR-MD-02,
胰高血糖素样肽1(GLP1)激动剂,如利拉鲁肽(liraglutide)或艾塞那肽(exenatide),谷胱甘肽前体,
丙型肝炎病毒NS3蛋白酶抑制剂,例如混合的组织蛋白酶B/丙型肝炎病毒NS3蛋白酶抑制剂,如VBY-376,
HMG CoA还原酶抑制剂,如他汀类(如阿托伐他汀(atorvastatin)),
11β-羟基类固醇脱氢酶(11β-HSD1)抑制剂,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,如聚乙二醇化白细胞介素10(peg-ilodecakin)
IL-17拮抗剂,如KD-025,
回肠钠胆汁酸共转运体蛋白抑制剂(ileal sodium bile acid cotransporterinhibitors),如SHP-626,
瘦素类似物,例如美曲普汀(metreleptin),
5-脂氧合酶抑制剂,例如混合的5-脂氧合酶/PDE3/PDE4/PLC抑制剂,如tipelukast,LPL基因刺激物,如alipogene tiparvovec,
赖氨酰氧化酶样蛋白2(lysyl oxidase homolog 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PPAR α/δ激动剂,如GFT505(elafibranor),
PPARγ激动剂,如吡格列酮,
PPARδ激动剂,
Rho关联蛋白激酶2(ROCK2)抑制剂,如KD-025,
钠-葡萄糖转运蛋白2(SGLT2)抑制剂,如依碳酸瑞格列净(remogliflozinetabonate)硬脂酰CoA去饱和酶1抑制剂,诸如aramchol或CVT-12805,
甲状腺激素受体β激动剂,如MGL-3196,
肿瘤坏死因子α(TNF α)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,如巯基乙胺,
PTPlb抑制剂,诸如A119505,A220435,A321842,CPT633,ISIS-404173,JTT-551,MX-7014,MX-7091,MX-7102,NNC-521246,OTX-001,OTX-002或TTP814,以及
ASK1抑制剂,如GS4977(selonsertib)。
在一些实施方案中,一种或更多种其他治疗剂选自乙酰水杨酸,alipogenetiparvovec,aramchol,阿托伐他汀,BLX-1002,cenicriviroc,cobiprostone,colesevelam,恩利卡生,依那普利,GFT-505,GR-MD-02,氢氯噻嗪,二十碳五烯酸乙酯(icosapent ethyl ester)(乙基二十碳五烯酸),IMM-124E,KD-025,利格列汀,利拉鲁肽,巯基乙胺,MGL-3196,奥贝胆酸,奥利索西(olesoxime),聚乙二醇化白细胞介素(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,熊去氧胆酸和VBY-376。
在一些实施方案中,所述一种或更多种其他治疗剂中的一种选自乙酰水杨酸,alipogene tiparvovec,aramchol,阿托伐他汀,BLX-1002和cenicriviroc。
在一个实施方案中,本发明涉及一种方法,其
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,促进肝再生或防止肝细胞死亡,
治疗急性、慢加急性或慢性肝病,
治疗或慢加急性肝病,诸如急性和慢性病毒性肝炎如乙型、丙型、戊型肝炎,由爱泼斯坦-巴尔病毒、巨细胞病毒、单纯疱疹病毒和其他病毒引起的肝炎,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,诸如代谢综合征,脂肪肝如非酒精性脂肪肝(NAFL),非酒精性脂肪性肝炎(NASH),酒精性脂肪性肝炎(ASH),Morbus Wilson病,血色素沉着症,α1-抗胰蛋白酶缺乏症,糖原贮积病;
治疗所有类型的肝硬化,诸如原发性胆汁性肝硬化,酒精中毒性(ethyl toxic)肝硬化,隐源性肝硬化;
治疗急性(暴发性)或慢性肝衰竭,诸如中毒性肝衰竭如对乙酰氨基酚(扑热息痛)引发的肝衰竭,α-鹅膏蕈碱引发的肝衰竭,药物诱发的例如由抗生素、非甾体抗炎药、抗惊厥药导致的肝毒性和肝衰竭,草药补充剂(卡瓦、麻黄、黄芩(skullcap)、薄荷(pennyroyal)等)诱发的急性肝衰竭,由于血管疾病如布加综合征导致的肝病和肝衰竭,起因不明的急性肝衰竭,由于右心衰竭导致的慢性肝病;
治疗半乳糖血症,囊性纤维化,卟啉症,肝缺血灌注损伤,肝移植后小肝综合征,原发性硬化性胆管炎或肝性脑病,或
治疗骨关节炎或类风湿性关节炎,
其包括将有效量的如上述定义的化合物或组合物给药至有此需要的受试对象。
在一个实施方案中,本发明的化合物以对于被治疗受试对象0.2至15mg/kg或0.5至12mg/kg的剂量施用。化合物可以一天给药一次或数次。化合物给药4至12周。
下列示例说明本发明而不是限制本发明。
实施例
缩略语:
AcOH 醋酸
ATP 三磷酸腺苷
Boc2O 二叔丁氧基碳酸酯
CDE 1,2-二甲基丙胺
CPME 环戊基甲基醚
DCE 二氯乙烷
DCM 二氯甲烷
DEA 二乙醚
DIPEA 二异丙基乙胺
4-DMAP (4-)二甲基氨基吡啶
DMA 二甲基乙酰胺
DME 二甲醚
DMF 二甲基甲酰胺
DMSO 二甲基亚砜
DPPA 二苯基磷酰基叠氮化物
DTT 二硫苏糖醇
EtOH 乙醇
EtOAC 乙酸乙酯
HOBt 羟基苯并三唑
HPLC 高效液相色谱
IPA 异丙醇(或iPrOH)
KOAc 醋酸钾
LAH 氢化铝锂
LCMS 液相色谱质谱联用
LDA 二异丙基氨基锂
LiHDMS 双(三甲基甲硅烷基)氨基锂
mCPBA 间氯过氧苯甲酸
MeCN 乙腈
MeOH 甲醇
Nhex 正己烷
NIS N-碘代琥珀酰亚胺
NMP N-甲基吡咯烷酮
Pd2(dba3) 三(二亚苄基丙酮)二钯(0)
Pd(dppf)Cl2 [1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)
PE 石油醚
pMBCl 对甲氧基苄基氯
rt或RT 室温
Ruphos 2-环己基膦基-2′,6′-二异丙氧基联苯(diisopropoxybiphenyl)
SFC 超临界流体色谱
Sol. 溶液
TEA 三乙胺
TfOH 三氟甲磺酸
THF 四氢呋喃
TLC 薄层色谱
Xantphos 4,5-双(二苯基膦基)-9,9-二甲基氧杂蒽
实施例
实施例1:被取代的苯甲酸磺酰胺衍生物的合成(通用方法)
实施例1a
步骤1a-1:
将草酰氯(1.1当量)加入到1当量的苯甲酸衍生物(1)在干燥的DCM(0.5M)中的混悬液中。加入几滴DMF,并将所得混合物在室温(RT)下搅拌直至气体形成完全。将过量的MeOH加入溶液中,并在减压下蒸发溶剂。残余物真空干燥,产物无需进一步纯化即可使用。(X为H或如示例、说明书和权利要求书所定义的取代基)。
步骤1a-2:
将Pd/C(0.1当量)加入到3-硝基苯甲酸甲酯衍生物(2,1.0当量)在EtOH(0.2M)中的溶液中。混悬液用H2吹扫并在室温下搅拌,直到起始物料完全消耗。然后,使混合物通过硅藻土垫,并将滤液真空浓缩。该产物无需进一步纯化即可使用。
步骤1a-3:
将3-氨基苯甲酸甲酯衍生物(3,1.0当量)和Et3N(2.2当量)在干燥的DCM(0.25M)中的溶液冷却至0℃,然后逐滴加入相应的磺酰氯(1.1当量,2.2当量的二磺酰胺,分别地)。完成后,移去冰浴,并将溶液在室温搅拌约1小时。然后将溶液用水稀释,用EtOAc萃取,并将合并的有机层用Na2SO4干燥。减压除去溶剂,并经由快速色谱法(SiO2,nHex/EtOAc 9/1)纯化产物。
将酯/单-/二磺酰胺溶解在THF/MeOH(1M,4:1)中,冷却至0℃,并用NaOH水溶液(2M,2-3当量)处理。10分钟后。除去冰浴,在室温搅拌反应物直至完全水解。真空除去THF/MeOH,用HCl水溶液(2M)处理残余物,沉淀出产物。过滤出沉淀物,干燥,无需进一步纯化即可使用。
实施例1b
步骤1b-1:(被取代的)3-硝基苯甲酸(2)
将1当量的硝酸钾在15分钟内分批添加到被搅拌并在冰浴中冷却的1当量的苯甲酸衍生物(1)的浓硫酸(20mL)溶液中。将反应混合物在0℃搅拌1小时,然后倒入50mL冰水中,并用EtOAc(15mL×3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤并减压浓缩,以>80%的收率获得相应的3-硝基苯甲酸衍生物(2)。
步骤1b-2和1b-3:2,6-二溴-3-(N-(丙基磺酰基)丙基磺酰胺基)苯甲酸(4)
在室温下将3当量的氯化亚锡加入到被搅拌的1当量的3-硝基苯甲酸(2)在THF(20mL)中的溶液中。在80℃搅拌该混合物3小时。通过TLC(30%EtOAc的己烷溶液)监测反应进程。完成后,反应混合物用氨水溶液(10mL)淬灭,产物用EtOAc(20mL×3)萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,过滤,并减压浓缩,得到3-氨基-苯甲酸衍生物(3),其为粗物质,其无需进一步纯化即可用于下一步。
将4当量TEA加入被搅拌的3-氨基-苯甲酸(3)在二氯甲烷(DCM,20mL)中的溶液中,并将混合物冷却至0℃。加入2当量的1-烷基磺酰氯,并通过TLC监测反应。完成后(约12小时),反应用2N HCl(10mL)淬灭,产物用DCM(10mL×2)萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,得到粗制的3-(N-(烷基磺酰基)-丙基磺酰胺基)苯甲酸衍生物(4),其无需进一步纯化即可用于下一步。(X为H或如示例、说明书和权利要求书所定义的取代基)。
实施例2
实施例2a:(通用方法)
将根据实施例1a(1)制备的苯甲酸衍生物(1.1当量)悬浮在干燥的DCM中(0.5M),相继加入草酰氯(1.05当量)和几滴DMF。在气体的形成停止之后,将所得溶液逐滴加入到1当量氮杂吲哚(2)和AlCl3(5当量)在干燥的DCM(0.5M)中的悬浮液中。在室温搅拌该混合物0.5-3小时。加入饱和的NH4Cl水溶液以淬灭反应。水相用EtOAc(3×)萃取,合并的有机层经Na2SO4干燥并减压蒸发溶剂。产物(3)通过快速色谱法纯化(SiO2,nHex/EtOAc 1∶1或DCM/MeOH 1-3%),得到标题化合物。
按照此方法制备下列化合物:
实施例13步骤2,实施例14步骤2,实施例15步骤2,实施例16步骤2,实施例17步骤2
实施例2b:N-(2,4-二溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
向0℃的被搅拌的2,6-二溴-3-(N-(丙基磺酰基)丙基磺酰胺基)苯甲酸(1)(1当量,900mg,粗品)在DCM(10mL)中的溶液中加入草酰氯(2当量,450.6mg,3.55mmol),随后加入催化量的DMF。在室温搅拌反应混合物4小时。反应完成(TLC)后,减压除去溶剂,并将获得的残余物溶于DCM(10mL)。在下文中,该反应物被称为溶液A。
将AlCl3(1.18g,8.87mmol)加入到DCM(40mL)中,并将混合物在室温搅拌10分钟,然后冷却至0℃。加入5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶(2)(1当量,405.92mg,1.77mmol),并将混合物搅拌30min,然后温热至RT持续3小时。在0℃将溶液A缓慢加入上述悬浮液中,并在室温搅拌反应混合物2天。完全转化后,反应用甲醇(MeOH,10mL)淬灭并浓缩,得到深棕色残余物。向残余物中加入冷水(50mL),并用氨水溶液将溶液的pH调节至7(中性)。加入EtOAc(50mL),并将混合物搅拌30分钟。然后将其通过硅藻土过滤,滤液用EtOAc(20mL×3)萃取,并将合并的有机层用盐水洗涤,经无水Na2SO4干燥,并在减压下浓缩,得到粗制的N-(2,4-二溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺(900mg,粗品),其无需进一步纯化即可用于下一步。
将粗制的N-(2,4-二溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺(900mg)溶解于THF(5mL)中,并向其中加入NaOH(2当量,238.9mg,7.09mmol)在水(5mL)中的水溶液,反应混合物在室温搅拌4小时。反应完成后,用5N HCl将pH调至pH-6,混合物用EtOAc(20mL×3)萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,得到粗物质,将其通过FCC(快速色谱)纯化,得到N-(2,4-二溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺(5)(400mg,0.65mmol,36%收率)。
根据实施例2b,制备表1中给出的下列化合物:
表1
实施例3:卤素取代的(=X)N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺的合成(烷基=R2)
将3-氨基苯基衍生物(1,1当量)溶解于吡啶(1M),并分批加入磺酰氯(1.5当量)。将混合物加热至60℃并搅拌1-6h。起始物料完全消耗完后,将粗产物用1N HCl水溶液稀释,并用EtOAc萃取3次。有机层经硫酸钠干燥,并蒸发溶剂。通过快速色谱法使用以下溶剂梯度DCM/EtOAc/MeOH(95/5/0-92/5/3)进行产物的纯化。
实施例4:卤素取代的(=X)N-(3-(1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺的合成(烷基=R2)
步骤4-1:
向1当量的根据实施例3制备的1H-吡咯并[2,3-b]吡啶衍生物(1)在THF(0.1M)中的溶液加入三乙胺(1.05当量)。将所得溶液冷却至0℃,逐滴添加2,6-二氯苯甲酰氯(1.01当量),然后添加0.1当量的4-DMAP。除去冰浴,并在室温搅拌反应物直到TLC显示起始物料完全消耗(约30分钟)。将粗物质倾倒在水上,并用EtOAc萃取三次。合并的有机层经硫酸钠干燥,真空除去溶剂,经由快速色谱法(SiO2,PE/EtOAc 15-25%)纯化产物。
步骤4-2:
将1当量的中间体2、B2Pin2(双(频哪醇合)二硼)(1.05当量)和KOAc(3.0当量)悬浮于干燥的1,4-二氧六环(0.5M)中,并用氩气脱气5分钟。加入Pd(PPh3)2Cl2(0.05当量),并将混合物在80℃搅拌5小时。使粗物质通过硅藻土垫,并用EtOAc冲洗该垫。依次用盐水和水洗涤有机相。有机相用硫酸钠干燥后,除去溶剂。应用快速色谱法(SiO2,PE/EtOAc 25%)得到纯产物。
步骤4-3:
将频哪醇酯(B2Pin2)(1当量)、芳基溴化物(1.5当量)和碳酸钾(2当量)溶解于1,4-二氧六环/水(2∶1,1M),并将该混合物用氩气脱气。加入Pd(dppf)C12(0.06当量),并将混合物加热至60℃持续2小时。使粗混合物通过硅藻土垫,用MeOH和EtOAc冲洗,并真空除去溶剂。将残余物重新溶解于MeOH中,加入碳酸钾(1g),并在室温搅拌该悬浮液3h。添加水,用1MHCl水溶液将pH调节至6-8,用EtOAc萃取水相,分离各层,合并有机层,经硫酸钠干燥,并在减压下除去溶剂。经由快速色谱法使用DCM/EtOAc/丙酮(70/25/5)作为洗脱剂进行产物预纯化。将预纯化的产物重新溶解于DCM/iPrOH(9∶1)中,并用正戊烷使其析出,过滤并真空干燥。
根据实施例4,制备实施例20、21、22、23、24、25、29、35、36、39、45,46、47、48、49、50和51的化合物。
实施例5:5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶的合成
程序:将5-溴-1H-吡咯并[2,3-b]吡啶(1,2g,10.2mmol,1.0当量)、K2CO3(2.8g,20.3mmol,2当量)和(4-氯苯基)硼酸(1.8g,11.2mmol,1.1当量)悬浮于DME/H2O(30ml,4∶1)中,并用氩气脱气。加入Pd(PPh3)4(587mg,508μmol,0.05当量),并将反应混合物在回流下加热直至起始物料完全消耗。使所得溶液通过硅藻土垫,用EtOAc稀释并用水洗涤。合并的有机层经Na2SO4干燥,并在减压下蒸发溶剂。经由快速色谱法(SiO2,nHex/EtOAc 6∶4)对粗产物进行纯化。
收率:2.23g,9.4mmol,92%(白色固体)。
TLC:PE/EtOAc 1∶1
1H NMR(DMSO-d6,200MHz,ppm):δ11.76(s,1H),8.51(d,J=2.1Hz,1H),8.20(d,J=1.9Hz,1H),7.72(d,J=8.5Hz,2H),7.57-7.43(m,3H),6.50(dd,J=3.2,1.7Hz,1H);13C NMR(DMSO-d6,50Hz,ppm):δ148.2,141.4,138.0,131.7,128.9,128.6,127.1,126.9,126.1,119.7,100.2。
实施例6
根据实施例5制备起始物料1。
以类似于Zhang等人公开的方法(Nature,256,583-586,Supplementarymaterial;doi:10.1038/nature14982)来进行步骤6-1和步骤6-2。
步骤6-3:
将一当量(1当量)的3-氨基苯基-1H-吡咯并[2,3-b]吡啶衍生物(3)溶解在吡啶(1M)中,并分批加入磺酰氯(1.5当量)。将混合物加热至60℃并搅拌1-6小时。起始物料完全消耗后,将粗产物用1N HCl水溶液稀释,并用EtOAc萃取3次。合并有机层,并用硫酸钠干燥。溶剂蒸发后,通过快速色谱法使用以下溶剂梯度:DCM/EtOAc/MeOH(95/5/0-92/5/3)对产物进行纯化。
根据实施例6,制备实施例37、38、42、43和44的化合物。
实施例7:
将1当量的5-溴-1H-吡咯并[2,3-b]吡啶、K2CO3(2当量)和硼酸/频哪醇酯(1.5当量)悬浮于DME/H2O(0.15M,4∶1)或1,4-二氧六环/H2O(0.15M,2∶1)中并用氩气脱气10分钟。加入Pd(PPh3)4(0.1当量),然后将悬浮液在130℃的微波炉中辐照30分钟(μw)。使所得混合物通过硅藻土垫,并在减压下除去溶剂。粗混合物经快速色谱纯化(SiO2,DCM/EtOAc/MeOH95/5/0至92/5/3),得到标题化合物。
根据实施例7,制备实施例21、26、27、32、33和34的化合物。
实施例8:(3-氨基)(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)甲酮衍生物的合成
步骤8-1:(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)(3-硝基苯基)甲酮(2)
在室温和氩气气氛下,将5当量的AlCl3在300ml无水DCM中搅拌。1小时后,加入1当量的5-溴-1H-吡咯并[2,3-b]吡啶(1)。将反应混合物进一步在室温下搅拌1小时,然后冷却至0℃。将新制备的3-硝基苯甲酰氯衍生物溶解在150mL DCM中,并逐滴加入到反应混合物中。完成后,将混合物在室温搅拌3天。通过TLC(40%EtOAc的己烷溶液)监测反应进程。然后将所得混合物在0℃下用乙腈:H2O(1∶1,300mL)小心地淬灭。将析出的固体滤出,用MeOH洗涤并干燥,得到(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)(3-硝基苯基)甲酮衍生物2(20.0g,粗品),其无需进一步纯化即用于下一步反应。
步骤8-2:(3-氨基苯基)(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)甲酮衍生物(3)
在室温下将氯化亚锡(3当量,29.77g,157.02mmol)加入到被搅拌的1当量的(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)(3-硝基苯基)-甲酮衍生物(2)在2-甲基THF中的溶液中。将反应混合物在60℃搅拌16小时。通过TLC(30%EtOAc的己烷溶液)监测反应进程。完成后,将反应混合物用20%的K2CO3水溶液(100mL)淬灭并搅拌10分钟,通过硅藻土垫过滤,并将硅藻土床用THF(250mL)洗涤。所得有机层用盐水洗涤,经Na2SO4干燥,过滤,并减压浓缩,得到粗化合物。向粗化合物中加入MeOH,获得固体,将其过滤并干燥,得到(3-氨基苯基)(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)甲酮衍生物3,其为灰白色(off-white)固体,无需进一步纯化即用于下一步反应。
实施例9:卤素取代的(=X)N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺的合成(烷基=R2)
将根据实施例8制备的(3-氨基苯基)(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)甲酮衍生物(1)(1当量)溶于吡啶(1M)并分批加入对应的磺酰氯(1.5当量)。将混合物加热至60℃并搅拌1-6小时。起始物料完全消耗完后,将粗产物用1N HCl水溶液稀释,并用EtOAc萃取3次。有机层经硫酸钠干燥,并蒸发溶剂。通过快速色谱法使用以下溶剂梯度:DCM/EtOAc/MeOH(95/5/0-92/5/3)进行(2)的纯化。
实施例10:
将对甲苯磺酸一水合物(0.6当量)加入到乙缩醛(1当量)在乙醇(EtOH,0.05M)和水(0.21M)中的溶液中。将混合物加热至50℃保持6小时,然后浓缩至干,将残余物引入(taken up)EtOAc,并将有机物用碳酸氢钠水溶液(5%)洗涤两次。有机相经硫酸钠干燥,并减压浓缩。将残余物重新溶解在EtOAc中,并用正戊烷进行沉淀,将固体滤出并真空干燥以获得所需产物。
根据实施例10,制备实施例30、31、40和41的化合物。
实施例11:
将相应的苯酚(1.0当量)和K2CO3或Cs2CO3(1.5当量)在DMF(0.4M)中的溶液在室温搅拌30分钟。将特定的卤代烷(1.5当量)和KI(1.0当量)加入到该悬浮液中,并将混合物在80℃搅拌2小时。将混合物冷却至室温,并用饱和NH4Cl水溶液稀释。水相用Et2O萃取,有机萃取物经硫酸钠干燥,并在减压下除去溶剂。经由快速色谱法(SiO2,PE/EtOAc 0-5%)对粗产物进行纯化。
根据实施例11,制备实施例25(步骤1)和29(步骤1)的化合物。
实施例12
根据实施例8制备起始反应物(1)。
步骤12-1:(3-(3-氨基-2,4-二氟苯甲酰基)-5-溴-1H-吡咯并[2,3-b]吡啶-1-基)(2,6-二氯苯基)甲酮(2)
在0℃向被搅拌的(3-氨基-2,4-二氟苯基)(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(1,1当量,11.0g,31.24mmol)在2-甲基-THF(200mL)中的溶液中,加入Et3N(1.1当量,3.47g,34.36mmol),然后加入4-DMAP(0.1当量,0.38g,3.12mmol),并将反应混合物搅拌5分钟。在0℃下历时2小时向该混合物中逐滴加入2,6-二氯苯甲酰氯(1当量,6.54g,31.24mmol)。将反应混合物在室温搅拌1h。通过TLC(20%EtOAc的己烷溶液)监测反应进程。反应完成后,将反应混合物用水(100mL)淬灭,并用EtOAc(500mL×2)萃取。有机层用盐水洗涤,经Na2SO4干燥,过滤并在减压下浓缩。将粗残余物用MeOH研磨,然后过滤,得到(3-(3-氨基-2,4-二氟苯甲酰基)-5-溴-1H-吡咯并[2,3-b]吡啶-1-基)(2,6-二氯苯基)甲酮(2,14.0g,85%),其为灰白色固体。
分析数据:1H NMR(400MHz,DMSO-d6)δ8.69(d,J=1.96Hz,1H),8.53(br s,1H),8.31(br s,1H),7.67(m,3H),7.11(t,J=9.29Hz,1H),6.88-6.96(m,1H),5.59(s,2H)。
步骤12-2:(3-(3-氨基-2,4-二氟苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(dioxaborolan)-2-基)-1H-吡咯并[2,3-b]吡啶-1-基)(2,6-二氯苯基)甲酮衍生物(3)
向被搅拌的(3-(3-氨基苯甲酰基)-5-溴-1H-吡咯并[2,3-b]吡啶-1-基)(2,6-二氯苯基)甲酮衍生物(2,1当量,7.0g,13.33mmol)在干燥1,4-二氧六环(100mL)中的溶液,加入双(频哪醇合)二硼(1.20当量,4.06g,16.00mmol),然后加入乙酸钾(熔融,2.50当量,3.28g,33.33mmol)。加入PdCl2(dppf)Cl2(0.05当量,0.54g,0.67mmol),并将反应混合物在80℃搅拌3小时。通过TLC(20%EtOAc的己烷溶液)和LCMS监测反应进程。完成后,将反应混合物冷却至室温,并通过硅藻土垫过滤。将得到的有机层减压浓缩。将获得的粗产物溶解在Et2O(200mL)中,过滤,并将有机层在减压下浓缩。用乙腈研磨粗残余物,然后过滤,得到(3-(3-氨基-2,4-二氟苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡咯并[2,3-b]吡啶-1-基)(2,6-二氯苯基)甲酮(3,7.0g),其为浅棕色固体。
分析数据:LCMS(ESI)m/z=572.20[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.81(d,J=1.47Hz,1H),8.49(br s,1H),8.29(br s,1H),7.66(s,3H),7.11(t,J=9.54Hz,1H),6.95-6.88(m,1H),5.58(s,2H),1.31(s,12H)。
步骤12-3:类似于实施例4的步骤3进行该反应。
步骤12-4:类似于实施例6的步骤3进行该反应。
步骤12-5:通过将中间体5溶解在MeOH中,然后加入碳酸钾,并将混合物在室温搅拌3小时,实现2,6-二氯苯基甲酮保护基的去除。
类似于示例12,制备实施例75和76的化合物。
各个化合物的合成
实施例13:N-(3-溴-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺的合成
步骤13-1:根据实施例1a制备化合物1。
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ8.06(d,J=2.3Hz,1H),7.66(dd,J=8.8,2.5Hz,1H),7.49(d,J=8.8Hz,1H),3.23-3.09(m,2H),1.75-1.52(m,2H),0.91(t,J=7.4Hz,3H)。
13C NMR(DMSO-d6,50MHz,ppm):δ168.4,140.5,135.5,133.6,121.3,119.4,113.5,52.7,16.8,12.4。
TLC-MS:C10H12BrNO4S([M-H]-)的m/z计算值:320.0,实测值:320.0。
步骤13-2:N-(3-溴-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺的合成(2)
根据实施例2a制备标题化合物。
收率:71mg,133μmol,38%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.88(s,1H),9.48(s,1H),8.69(d,J=2.2Hz,1H),8.67(d,J=2.2Hz,1H),8.10(s,1H),7.81(d,J=2.3Hz,1H),7.77(d,J=8.5Hz,3H),7.57(d,J=8.5Hz,2H),7.50(d,J=8.7Hz,1H),3.13-3.07(m,2H),1.58(dq,J=14.9,7.4Hz,2H),0.80(t,J=7.4Hz,3H);
13C NMR(DMSO-d6,101MHz,ppm):188.5,148.9,143.5,138.3,137.1,135.1,134.2,133.9,132.4,132.2,129.8,129.1,128.8,127.4,125.7,118.5,116.9,114.6,53.6,16.8,12.3。TLC-MS:C23H19BrClN3O3S([M-H]-)的m/z计算值:530.0,实测值:529.9。
纯度:95%
实施例14:3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-N-丙基苯磺酰胺的合成
步骤14-1
步骤14-1:根据实施例1(步骤3)制备3-(N-丙基氨磺酰)苯甲酸(1),其具有以下差异:将磺酰氯溶解在DCM中,然后加入丙胺和三甲胺。将混合物在室温搅拌过夜。分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ8.32(s,1H),8.16(d,J=7.6Hz,1H),8.01(d,J=7.8Hz,1H),7.82-7.64(m,1H),2.69(dd,J=13.0,6.8Hz,1H),1.48-1.23(m,1H),0.76(t,J=7.3Hz,1H)。
13C NMR(DMSO-d6,50MHz,ppm):δ166.3,141.3,133.0,131.9,130.7,130.0,127.2,44.5,22.5,11.2。
步骤14-2:3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-N-丙基苯磺酰胺
方法:根据实施例2a制备标题化合物。
收率:317mg,750μmol,73%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),8.65(d,J=2.3Hz,1H),8.48(d,J=2.3Hz,1H),8.22(s,1H),8.16(t,J=1.4Hz,1H),8.07(m,2H),7.84-7.71(m,2H),2.74(dd,J=13.0,6.7Hz,2H),1.39(h,J=7.0Hz,2H),0.80(t,J=7.3Hz,3H);
13C NMR(DMSO-d6,101MHz,ppm):188.2,147.6,145.0,141.1,139.8,137.7,132.3,131.6,129.8,129.4,126.2,120.3,113.8,112.8,44.4,22.5,11.2。
TLC-MS:C17H16BrN3O3S([M-H]-)的m/z计算值:420.0,实测值:419.7。
实施例15:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-丙烷-1-磺酰胺的合成
步骤1:3-(丙基磺酰胺基)苯甲酸
步骤15-1:根据实施例1a制备3-(丙基磺酰胺基)苯甲酸(1)。
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ13.05(s,1H),10.01(s,1H),7.81(s,1H),7.65(t,J=4.1Hz,1H),7.44(d,J=4.8Hz,2H),3.08(dd,J=8.6,6.7Hz,2H),1.79-1.55(m,2H),0.92(t,J=7.3Hz,3H)。
13C NMR(DMSO-d6,50MHz,ppm):δ166.9,138.8,131.9,129.7,124.4,123.4,119.8,52.5,16.8,12.5。
TLC-MS:C10H13NO4S([M-H]-)的m/z计算值:242.1,实测值:241.8。
步骤15-2:根据通用方法2a制备N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-丙烷-1-磺酰胺(2)
收率:62mg,137μmol,52%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ11.40(s,1H),8.73(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H),8.16(s,1H),7.77(d,J=8.5Hz,2H),7.68(s,1H),7.52(m,5H),3.17-3.08(m,2H),1.77-1.63(m,2H),0.95(t,J=7.4Hz,3H);13C NMR(DMSO-d6,101MHz,ppm):189.0,148.7,143.4,140.4,138.8,137.3,136.6,132.3,129.6,129.6,129.0,128.8,127.6,123.5,122.2,119.3,118.7,113.7,52.7,16.8,12.5。TLC-MS:C23H20ClN3O3S([M-H]-)的m/z计算值:452.1,实测值:451.9。
纯度:96%
实施例16:N-(3-氯-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
步骤16-1:与实施例1a类似地制备3-氯-5-(丙基磺酰胺基)苯甲酸(1)。硝基的还原不是根据实施例1a(步骤2)进行的,而是如下进行的:将3-氯-5-硝基苯甲酸甲酯(1.0当量)悬浮在EtOH/H2O(4∶1,0.5M)中,加入细粉状的Fe0(1.5当量)和固体NH4Cl(3当量)。将混合物加热至回流3小时。倾注粗产物使其流过硅藻土垫,并将溶剂浓缩至最少。残余物用EtOAc稀释并用盐水洗涤,合并的有机萃取物经硫酸钠干燥,并减压除去溶剂。该产物无需任何进一步纯化而被用于步骤3。
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ10.86(s,1H),7.94(d,J=2.1Hz,1H),7.72-7.52(m,2H),3.34-3.18(m,2H),1.78-1.51(m,2H),0.92(t,J=7.4Hz,3H)。
13C NMR(DMSO-d6,50MHz,ppm):δ168.7,139.5,134.1,130.8,126.4,119.6,118.3,53.0,16.8,12.4。
TLC-MS:C10H12CINO4S([M-H]-)的m/z计算值:276.0,实测值:275.9。
步骤16-2:类似于实施例2a制备N-(3-氯-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺(2)。
收率:78mg,160μmol,61%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.89(s,1H),9.49(s,1H),8.68(dd,J=5.4,2.2Hz,2H),8.12(d,J=3.0Hz,1H),7.77(d,J=8.5Hz,2H),7.71(d,J=2.5Hz,1H),7.65(dd,J=8.7,2.5Hz,1H),7.57(dd,J=8.7,3.0Hz,3H),3.14-3.06(m,2H),1.64-1.52(m,2H),0.80(t,J=7.4Hz,3H):
13C NMR(DMSO-d6,101MHz,ppm):188.5,148.8,143.5,138.3,137.1,134.5,133.7,132.4,131.2,129.8,129.4,129.0,128.9,128.7,127.4,125.5,118.5,114.6,53.6,16.7,12.3。
TLC-MS:C23H19Cl2N3O3S([M-H]-)的m/z计算值:486.1,实测值:486.1。
纯度:>99%
实施例17:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-5-氟苯基)丙烷-1-磺酰胺的合成
步骤17-1:根据实施例1a制备3-氟-5-(丙基磺酰胺基)苯甲酸。
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ13.47(br.s.,1H),10.47(s,1H),7.85-7.36(m,2H),3.41-3.05(m,2H),1.83-1.46(m,2H),0.92(t,J=7.3Hz,3H)。
13C NMR(DMSO-d6,50MHz,ppm):δ168.72(d,J=2.3Hz),157.12(d,J=241.1Hz),136.86(d,J=2.5Hz),121.74(d,J=22.8Hz),120.50(d,J=7.7Hz),118.23(d,J=6.9Hz),117.42(d,J=23.9Hz),53.0,16.8,12.4。
TLC-MS:C10H12FNO4s([M-H]-)的m/z计算值:260.1,实测值:260.0。
步骤17-2:根据实施例2a制备N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-5-氟苯基)丙烷-1-磺酰胺(2)。
收率:113mg,239μmol,55%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.88(s,1H),9.33(s,1H),8.69(s,2H),8.10(s,1H),7.77(d,J=8.5Hz,2H),7.60-7.50(m,4H),7.44(td,J=8.5,3.0Hz,1H),3.08-2.98(m,2H),1.62-1.49(m,2H),0.76(t,J=7.4Hz,3H);
13C NMR(DMSO-d6,101MHz,ppm):188.6,158.8(d,J=244.5Hz),148.9,143.5,138.4,137.1,135.1(d,J=6.2Hz),132.4,131.5(d,J=2.4Hz),129.8,129.1,128.8,127.4,127.2(d,J=8.4Hz),118.4,118.0(d,J=22.5Hz),116.4(d,J=24.0Hz),114.6,53.5,16.7,12.3。
TLC-MS:C23H19ClFN3O3S([M-H]-)的m/z计算值:470.1,实测值:470.1。
纯度:91%
实施例18:N-(3-(5-乙炔基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
方法:将N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(100mg,218μmol,1.0当量)、CuI(8mg,44μmol,0.2当量)和Pd(PPh3)2Cl2(31mg,44μmol,0.2当量)悬浮在MeCN中。加入三乙胺(76μL,546μmol2.5当量)和乙炔基三甲基硅烷(93μL,655μmol,3.0当量),并将混合物在微波炉中于130℃加热2小时。将粗产物倾倒在硅藻土垫上,将其用EtOAc冲洗,有机相用盐水洗涤并经硫酸钠干燥。除去溶剂后,将剩余物溶解在MeOH中,并加入0.5g K2CO3。在室温下搅拌该混合物直至TMS完全裂解,并在减压下除去溶剂。随后进行快速色谱分离(SiO2,DCM/MeOH 0-2%),得到了所需的足够纯度的产物。
收率:45mg,112μmol,51%(米色(beige)固体)。
TLC:nHex/EE(1∶1)
PKL440:1H NMR(DMSO-d6,400MHz,ppm):δ13.15(s,1H),9.79(s,1H),8.52(d,J=1.6Hz,1H),8.50(s,1H),8.30(d,J=2.2Hz,1H),7.59(td,J=9.0,6.0Hz,1H),7.28(t,J=8.4Hz,1H),4.34(s,1H),3.16-3.06(m,2H),1.79-1.67(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C19H15F2N3O3S([M-H]-)的m/z计算值:402.1,实测值:402.0。
纯度:97%
实施例19:N-(2,4-二氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丁烷-1-磺酰胺的合成
步骤19-1:根据实施例2a制备N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-1-磺酰胺(2)。
收率:1.4g,3mmol,84%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.99(s,1H),9.80(s,1H),8.59(d,J=1.4Hz,1H),8.47(d,J=1.6Hz,1H),8.08(s,1H),7.60(t,J=7.2Hz,1H),7.37(m,2H),3.23-3.09(m,2H),1.81-1.59(m,2H),1.38(dq,J=14.0,7.0Hz,2H),0.85(t,J=7.1Hz,3H)。
TLC-MS:C18H17BrFN3O3S([M-H]-)的m/z计算值:452.0,实测值:452.4。
步骤19-2:根据实施例7制备N-(2,4-二氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丁烷-1-磺酰胺(3)。
收率:37mg,73μmol,49%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),9.78(s,1H),8.37(d,J=2.0Hz,1H),8.34(s,1H),8.26(s,1H),7.58(td,J=8.9,6.0Hz,1H),7.36(dd,J=8.3,6.1Hz,1H),7.28(t,J=8.7Hz,1H),7.23(dd,J=10.1,2.5Hz,1H),7.14(td,J=8.5,2.6Hz,1H),3.18-3.07(m,2H),2.26(s,3H),1.69(dt,J=15.2,7.6Hz,2H),1.43-1.32(m,2H),0.85(t,J=7.4Hz,3H)。TLC-MS:C25H22F3N3O3S([M-H]-)的m/z计算值:500.1,实测值:500.0。
纯度:97%
实施例20:N-(3-(5-(4-(叔丁氧基)-2-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤:根据实施例4,步骤3制备标题化合物。
收率:52mg,93μmol,63%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(d,J=1.7Hz,1H),9.78(s,1H),8.47(s,1H),8.45(d,J=2.1Hz,1H),8.27(d,J=1.9Hz,1H),7.59(td,J=9.0,6.0Hz,1H),7.47(d,J=8.4Hz,1H),7.28(t,J=8.3Hz,1H),7.22(d,J=2.3Hz,1H),7.12(dd,J=8.4,2.4Hz,1H),3.15-3.09(m,2H),1.80-1.67(m,2H),1.37(s,9H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C27H26ClF2N3O4S([M-H]-)的m/z计算值:560.1,实测值:559.9。
纯度:>99%
实施例21:N-(3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丁烷-1-磺酰胺的合成
方法:根据实施例7制备标题化合物。
收率:37mg,69μmol,47%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.78(s,1H),8.44(s,1H),8.41(d,J=2.1Hz,1H),8.26(d,J=0.7Hz,1H),7.58(td,J=9.0,6.0Hz,1H),7.47(d,J=8.5Hz,1H),7.31-7.25(m,1H),7.22(d,J=2.6Hz,1H),7.07(dd,J=8.6,2.6Hz,1H),3.85(s,3H),3.18-3.08(m,2H),1.69(dt,J=15.2,7.6Hz,2H),1.43-1.30(m,2H),0.85(t,J=7.4Hz,3H)。
TLC-MS:C25H22ClF2N3O4S([M-H]-)的m/z计算值:532.1,实测值:531.9。
纯度:97%
实施例22:N-(2,4-二氟-3-(5-(4-吗啉代苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
方法:根据实施例4,步骤3制备标题化合物。
收率:18mg,32μmol,22%(米色固体)。
TLC:nHex/EE(1∶1)
PKL503:1H NMR(DMSO-d6,400MHz,ppm):δ12.91(s,1H),9.77(s,1H),8.66(d,J=1.8Hz,1H),8.55(s,1H),8.19(s,1H),7.66-7.54(m,3H),7.28(t,J=8.6Hz,1H),7.09(d,J=8.6Hz,2H),3.82-3.72(m,4H),3.21-3.15(m,4H),3.14-3.09(m,2H),1.79-1.67(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C27H26F2N4O4S([M-H]-)的m/z计算值:539.2,实测值:539.0。
纯度:97%
实施例23:N-(2,4-二氟-3-(5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]-吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
方法:根据实施例4,步骤3制备标题化合物。
收率:38mg,68μmol,46%(米色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.96(s,1H),9.92(s,1H),8.66(d,J=1.8Hz,1H),8.55(s,1H),8.19(s,1H),7.66-7.53(m,3H),7.28(t,J=8.6Hz,1H),7.09(d,J=8.6Hz,2H),3.31(s,4H),3.17-3.07(m,2H),2.74(s,4H),2.42(s,3H),1.74(dq,J=14.8,7.4Hz,2H),0.96(t,J=7.4Hz,3H)。TLC-MS:C28H29F2N5O3S([M-H]-)的m/z计算值:552.2,实测值:551.9。
纯度:96%
实施例24:N-(3-(5-(4-(4-乙酰基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤1:N-(3-(5-溴-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
步骤24-1:根据实施例4,步骤1制备N-(3-(5-溴-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(2)。
收率:5.1g,8.1mmol,74%(浅米色固体)。
TLC:nHex/EE 25%
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ9.84(s,1H),8.90(s,1H),8.72(d,J=2.0Hz,1H),8.31(s,1H),7.72-7.62(m,4H),7.33(t,J=8.9Hz,1H),3.21-3.10(m,2H),1.83-1.68(m,2H),0.97(t,J=7.4Hz,3H)。TLC-MS:C24H16BrCl2F2N3O4S([M-H]-)的m/z计算值:627.9,实测值:628.0。
步骤24-2:根据实施例4,步骤2制备N-(3-(1-(2,6-二氯苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(3)。收率:2.8g,4.1mmol,88%(米色固体)。
TLC:nHex/EE 25%
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ9.06(d,J=1.6Hz,1H),8.48(s,1H),8.37(s,1H),7.77(td,J=8.9,5.6Hz,1H),7.45-7.32(m,3H),7.09(t,J=8.5Hz,1H),6.74(s,1H),3.18-3.05(m,2H),1.90(dp,J=10.3,7.5Hz,2H),1.33(s,12H),1.07(t,J=7.4Hz,3H)。
TLC-MS:C30H28BCl2F2N3O6S([M-H]-)的m/z计算值:676.1,实测值:676.5。
步骤24-3:根据实施例4,步骤3制备N-(3-(5-(4-(4-乙酰基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(4)。
收率:29mg,49μmol,33%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:
1H NMR(DMSO-d6,400MHz,ppm):δ12.73(s,1H),9.52(s,1H),8.66(d,J=1.9Hz,1H),8.56(s,1H),8.19(s,1H),7.68-7.53(m,3H),7.28(t,J=8.6Hz,1H),7.10(d,J=8.6Hz,2H),3.61(s,4H),3.28-3.22(m,2H),3.22-3.15(m,2H),3.15-3.08(m,2H),2.06(s,3H),1.80-1.67(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C29H29F2N5O4S([M-H]-)的m/z计算值:580.2,实测值:579.8。
纯度:>99%
实施例25:N-(3-(5-(2-氯-4-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤25-1:根据实施例11制备4-((4-溴-3-氯苯氧基)甲基)-2,2-二甲基-1,3-二氧杂环戊烷(1)。
收率:447mg,1.4μmol,96%(白色固体)。
TLC:nHex/EE 25%
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ7.63(d,J=8.9Hz,1H),7.27(d,J=2.9Hz,1H),6.91(dd,J=8.9,2.9Hz,1H),4.46-4.31(m,1H),4.13-3.92(m,3H),3.73(dd,J=8.3,6.3Hz,1H),1.34(s,3H),1.29(s,3H)。
13C NMR(DMSO-d6,50MHz,ppm):δ158.5,134.1,133.6,116.4,115.9,112.0,108.9,73.5,69.4,65.5,26.5,25.3。
步骤25-2:根据实施例4,步骤3制备N-(3-(5-(2-氯-4-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(2)。
收率:97mg,156μmol,70%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.99(s,1H),9.76(s,1H),8.44(s,1H),8.41(d,J=1.9Hz,1H),8.26(s,1H),7.58(td,J=9.0,6.0Hz,1H),7.47(d,J=8.5Hz,1H),7.32-7.23(m,J=14.0,5.6Hz,2H),7.09(dd,J=8.6,2.5Hz,1H),4.50-4.38(m,1H),4.19-4.03(m,3H),3.78(dd,J=8.3,6.4Hz,1H),3.17-3.08(m,2H),1.82-1.67(m,2H),1.38(s,3H),1.32(s,3H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C29H28ClF2N3O6S([M-H])的m/z计算值:618.1,实测值:617.8。
纯度:95%
实施例26:N-(2,4-二氟-3-(5-(4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺的合成
方法:根据实施例7制备标题化合物。
收率:11mg,21μmol,15%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.97(s,1H),9.83(s,1H),8.67(s,1H),8.59(s,1H),8.19(s,1H),7.69(d,J=8.2Hz,2H),7.51(dd,J=14.7,8.7Hz,1H),7.43-7.30(m,J=9.6Hz,5H),7.24(t,J=8.7Hz,1H),7.09(d,J=8.4Hz,2H),4.53(s,2H),3.82(s,3H)。
TLC-MS:C28H21F2N3O4S([M-H])的m/z计算值:532.1,实测值:531.8。
纯度:99%
实施例27:4-(3-(2,6-二氟-3-((苯甲基)磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯磺酰胺的合成
方法:根据实施例7制备标题化合物。
收率:75mg,129μmol,65%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.10(s,1H),9.85(s,1H),8.80(s,1H),8.75(s,1H),8.27(d,J=1.8Hz,1H),7.98(q,J=8.5Hz,4H),7.52(dd,J=14.9,9.0Hz,1H),7.46(s,2H),7.43-7.32(m,5H),7.25(t,J=8.7Hz,1H),4.55(s,2H)。
TLC-MS:C27H20F2N4O5S2([M-H])的m/z计算值:581.1,实测值:580.7。
纯度:93%
实施例28:N-(2,4-二氟-3-(5-(4-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺的合成
步骤28-1:根据实施例6,步骤1制备(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)(2,6-二氟-3-硝基苯基)甲酮(1)。(Lit.:Zhang等人[doi:10.1038/nature14982])。
收率:17.3g,45.3mmol,59%(米色固体)。
TLC:PE/EtOAc 1∶1
分析数据:1H NMR(DMsO-d6,200MHz,ppm):δ13.16(s,1H),8.64(d,J=2.3Hz,1H),8.51(d,J=2.3Hz,1H),8.49-8.37(m,2H),7.54(ddd,J=9.5,8.3,1.6Hz,1H)。13C NMR(DMSO-d6,50Hz,ppm):δ178.9,161.5(dd,J=257.6,7.5Hz),152.8(dd,J=264.4,9.3Hz),147.9,145.5,140.3,134.4(dd,J=7.9,3.8Hz),131.2,129.1(dd,J=11.4,1.2Hz),119.2(dd,J=25.1,23.0Hz),119.0,114.7,114.5,113.3(dd,J=24.0,4.2Hz)。
TLC-MS:C14H6BrF2N3O3([M-H]-)的m/z计算值:380.0,实测值:380.1。
步骤28-2:根据实施例6,步骤2制备(3-氨基-2,6-二氟苯基)(5-溴-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(2)。(Lit.:Zhang等人[doi:10.1038/nature14982])。
收率:16.8g,44.4mmol,98%(米色固体)。
TLC:PE/EtOAc 1∶1
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ13.04(s,1H),8.56(d,J=2.2Hz,1H),8.49(d,J=2.3Hz,1H),8.15(s,1H),7.03-6.81(m,2H),5.22(s,2H)。
13C NMR(DMSO-d6,50Hz,ppm):δ182.27(s),150.0(dd,J=157.3,7.2Hz),147.7,145.2(dd,J=163.6,7.1Hz),145.1,138.7,133.48(dd,J=13.1,2.4Hz),131.1,119.1,117.88-116.41(m),115.2,114.1,111.44(dd,J=22.0,3.3Hz)。
TLC-MS:C14H8BrF2N3O([M-H]-)的m/z计算值:350.0,实测值:349.9。
步骤28-3:根据实施例6,步骤3制备N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺(3)。
收率:1.7g,3.4mmol,79%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.15(s,1H),9.86(s,1H),8.61(s,1H),8.50(d,J=2.0Hz,1H),8.24(d,J=2.0Hz,1H),7.51(td,J=8.9,6.3Hz,1H),7.43-7.30(m,5H),7.23(t,J=8.7Hz,1H),4.53(s,2H)。
TLC-MS:C21H14BrF2N3O3S([M-H]-)的m/z计算值:504.0,实测值:503.8。
步骤28-4:根据实施例7制备N-(2,4-二氟-3-(5-(4-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺(4)。
收率:27mg,51μmol,37%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),9.84(s,1H),8.70(s,1H),8.64(s,1H),8.22(d,J=2.3Hz,1H),7.81(dd,J=8.1,5.6Hz,2H),7.51(dd,J=14.7,8.9Hz,1H),7.41-7.31(m,7H),7.24(t,J=8.7Hz,1H),4.54(s,2H)。
TLC-MS:C27H18F3N3O3S([M-H])的m/z计算值:520.1,实测值:519.8。
纯度:93%
实施例29:N-(3-(5-(4-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤29-1:根据实施例11制备4-((4-溴苯氧基)甲基)-2,2-二甲基-1,3-二氧杂环戊烷(1)。
收率:474mg,1.7μmol,95%(无色的油)。
TLC:nHex/EE 25%
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ7.43(d,J=9.1Hz,2H),6.92(d,J=9.1Hz,2H),4.46-4.31(m,1H),4.13-3.92(m,3H),3.73(dd,J=8.3,6.3Hz,1H),1.34(s,3H),1.29(s,3H)。
13C NMR(DMSO-d6,50MHz,ppm):δ157.8,132.2,116.9,112.3,109.0,73.7,69.0,65.7,26.7,25.4。
步骤29-2:根据实施例4,步骤3制备N-(3-(5-(4-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(2)。
收率:67mg,114μmol,52%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.96(s,1H),9.77(s,1H),8.67(d,J=2.2Hz,1H),8.57(s,1H),8.21(s,1H),7.68(d,J=8.7Hz,2H),7.59(td,J=9.0,6.0Hz,1H),7.28(t,J=8.4Hz,1H),7.11(d,J=8.8Hz,2H),4.51-4.39(m,1H),4.16-4.00(m,3H),3.79(dd,J=8.3,6.4Hz,1H),3.18-3.03(m,2H),1.80-1.66(m,2H),1.38(s,3H),1.32(s,3H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C29H29F2N3O6S([M-H])的m/z计算值:584.2,实测值:583.7。
纯度:95%
实施例30:N-(3-(5-(2-氯-4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
方法:根据实施例10制备标题化合物。
收率:18mg,31μmol,38%(灰白色固体)。
TLC:DCM/MeOH 5%
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.03(s,1H),9.78(s,1H),8.44(s,1H),8.41(d,J=2.0Hz,1H),8.26(s,1H),7.58(td,J=9.0,6.0Hz,1H),7.46(d,J=8.5Hz,1H),7.28(t,J=8.7Hz,1H),7.21(d,J=2.5Hz,1H),7.07(dd,J=8.6,2.5Hz,1H),5.03(d,J=5.1Hz,1H),4.72(t,J=5.6Hz,1H),4.11(dd,J=10.1,4.0Hz,1H),3.97(dd,J=10.0,6.2Hz,1H),3.87-3.79(m,1H),3.47(t,J=5.6Hz,2H),3.17-3.06(m,2H),1.81-1.65(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C26H24ClF2N3O6S([M-H])的m/z计算值:578.1,实测值:577.7。
纯度:>99%
实施例31:N-(3-(5-(4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
方法:根据实施例10制备标题化合物。
收率:25mg,45μmol,66%(灰白色固体)。
TLC:DCM/MeOH5%
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.92(s,1H),9.81(s,1H),8.67(d,J=2.1Hz,1H),8.57(s,1H),8.21(s,1H),7.67(d,J=8.6Hz,2H),7.58(td,J=9.0,6.1Hz,1H),7.27(t,J=8.4Hz,1H),7.09(d,J=8.7Hz,2H),5.00(d,J=4.5Hz,1H),4.71(s,1H),4.07(dd,J=9.8,4.1Hz,1H),3.93(dd,J=9.8,6.2Hz,1H),3.83(td,J=10.7,5.7Hz,1H),3.48(s,2H),3.17-3.06(m,2H),1.74(dq,J=14.9,7.4Hz,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C26H25F2N3O6S([M-H])的m/z计算值:544.1,实测值:543.8。
纯度:95%
实施例32:N-(3-(5-(3-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
方法:根据实施例7制备标题化合物。
收率:50mg,102μmol,47%(米色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.78(s,1H),8.74(d,J=1.9Hz,1H),8.66(s,1H),8.27(s,1H),7.83(s,1H),7.73(d,J=7.6Hz,1H),7.64-7.52(m,2H),7.48(d,J=7.9Hz,1H),7.29(t,J=8.6Hz,1H),3.18-3.07(m,2H),1.74(dq,J=14.8,7.4Hz,2H),0.96(t,J=7.4Hz,3H)。TLC-MS:C23H18ClF2N3O3S([M-H]-)的m/z计算值:488.1,实测值:487.8。
纯度:92%
实施例33:N-(3-(5-(2,4-二氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
方法:根据实施例7制备标题化合物。
收率:50mg,101μmol,46%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.07(s,1H),9.78(s,1H),8.57(s,1H),8.55(s,1H),8.28(d,J=1.6Hz,1H),7.73(dd,J=15.5,8.7Hz,1H),7.59(td,J=8.9,6.1Hz,1H),7.48-7.39(m,1H),7.32-7.21(m,2H),3.17-3.06(m,2H),1.80-1.67(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C23H17F4N3O3S([M-H]-)的m/z计算值:490.1,实测值:489.9。
纯度:99%
实施例34:N-(2,4-二氟-3-(5-(2-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
方法:根据实施例7制备标题化合物。
收率:31mg,66μmol,30%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.06(s,1H),9.78(s,1H),8.59(s,2H),8.27(s,1H),7.67(t,J=7.7Hz,1H),7.59(dd,J=14.7,8.8Hz,1H),7.49(dd,J=12.3,6.3Hz,1H),7.38(dd,J=16.4,8.7Hz,2H),7.29(t,J=8.5Hz,1H),3.18-3.07(m,2H),1.74(dq,J=14.1,7.0Hz,2H),0.96(t,J=7.3Hz,3H)。
TLC-MS:C23H18F3N3O3S([M-H]-)的m/z计算值:472.1,实测值:471.9。
纯度:99%
实施例35:N-(2,4-二氟-3-(5-(4-羟基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
方法:根据实施例4,步骤3制备标题化合物。
收率:54mg,115μmol,52%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.93(s,1H),9.77(s,1H),9.63(s,1H),8.63(d,J=1.7Hz,1H),8.53(s,1H),8.19(s,1H),7.64-7.50(m,3H),7.28(t,J=8.7Hz,1H),6.91(d,J=8.4Hz,2H),3.19-3.05(m,2H),1.81-1.65(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C23H19F2N3O4S([M-H]-)的m/z计算值:470.1,实测值:469.9。
纯度:97%
实施例36:N-(2,4-二氟-3-(5-(2-氟-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
方法:根据实施例4,步骤3制备标题化合物。
收率:54mg,107μmol,48%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.02(s,1H),9.78(s,1H),8.53(s,2H),8.25(s,1H),7.64-7.54(m,2H),7.28(t,J=8.7Hz,1H),7.02(dd,J=12.8,2.1Hz,1H),6.95(dd,J=8.6,2.1Hz,1H),3.84(s,3H),3.19-3.06(m,2H),1.74(dq,J=14.9,7.4Hz,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C24H20F3N3O4S([M-H]-)的m/z计算值:502.1,实测值:502.0。
纯度:>99%
实施例37:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(间甲苯基)甲磺酰胺的合成
方法:根据实施例6,步骤3制备标题化合物。
收率:31mg,57μmol,27%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.82(s,1H),8.72(s,1H),8.66(s,1H),8.24(s,1H),7.80(d,J=8.3Hz,2H),7.61-7.50(m,3H),7.28-7.12(m,5H),4.49(s,2H),2.24(s,3H)。TLC-MS:C28H20ClF2N3O3S([M-H]-)的m/z计算值:550.1,实测值:549.6。
纯度:93%
实施例38:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(对甲苯基)甲磺酰胺
方法:根据实施例6,步骤3制备标题化合物。
收率:31mg,56μmol,27%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.78(s,1H),8.72(d,J=2.2Hz,1H),8.66(s,1H),8.24(s,1H),7.80(d,J=8.5Hz,2H),7.57(d,J=8.5Hz,2H),7.52(td,J=9.0,6.0Hz,1H),7.29-7.21(m,3H),7.16(d,J=7.9Hz,2H),4.48(s,2H),2.28(s,3H)。TLC-MS:C28H20ClF2N3O3S([M-H]-)的m/z计算值:550.1,实测值:549.9。
纯度:94%
实施例39:N-(2,4-二氟-3-(5-(4-甲氧基-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
方法:根据实施例4,步骤3制备标题化合物。
收率:61mg,122μmol,55%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,200MHz,ppm):δ12.97(s,1H),9.76(s,1H),8.35(d,J=1.9Hz,1H),8.31(s,1H),8.22(s,1H),7.58(td,J=9.0,6.0Hz,1H),7.27(t,J=8.8Hz,1H),7.23(d,J=8.4Hz,1H),6.94(d,J=2.4Hz,1H),6.88(dd,J=8.4,2.5Hz,1H),3.80(s,3H),3.15-3.08(m,2H),2.24(s,3H),1.81-1.67(m,2H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C25H23F2N3O4S[M-H]-的m/z计算值:498.1,实测值:498.0。
纯度:>99%
实施例40:N-(3-(5-(4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺的合成
方法:根据实施例10制备标题化合物。
收率:54mg,92μmol,80%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ12.96(s,1H),9.83(s,1H),8.67(d,J=1.8Hz,1H),8.60(s,1H),8.18(s,1H),7.68(d,J=8.5Hz,2H),7.51(dd,J=15.0,9.0Hz,1H),7.43-7.30(m,5H),7.23(t,J=8.7Hz,1H),7.09(d,J=8.7Hz,2H),5.01(d,J=4.9Hz,1H),4.72(s,1H),4.53(s,2H),4.08(dd,J=9.8,4.1Hz,1H),3.94(dd,J=9.8,6.2Hz,1H),3.84(dq,J=10.6,5.3Hz,1H),3.49(t,J=5.2Hz,2H)。
TLC-MS:C30H25F2N3O6S([M-H]-)的m/z计算值:592.1,实测值:592.0。
纯度:94%
实施例41:N-(3-(5-(2-氯-4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺的合成
方法:根据实施例10制备标题化合物。
收率:76mg,121μmol,77%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.83(s,1H),8.47(s,1H),8.43(d,J=2.0Hz,1H),8.23(s,1H),7.55-7.44(m,2H),7.43-7.30(m,5H),7.27-7.17(m,2H),7.08(dd,J=8.6,2.4Hz,1H),5.04(d,J=4.9Hz,1H),4.73(s,1H),4.53(s,2H),4.12(dd,J=10.1,3.9Hz,1H),3.98(dd,J=10.0,6.2Hz,1H),3.84(dq,J=10.7,5.3Hz,1H),3.48(t,J=5.2Hz,2H)。
TLC-MS:C30H24ClF2N3O6S([M-H]-)的m/z计算值:626.1,实测值:625.9。
纯度:>99%
实施例42:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(4-氟苯基)甲磺酰胺的合成
方法:根据实施例6,步骤3制备标题化合物。
收率:36mg,66μmol,31%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.83(s,1H),8.72(s,1H),8.67(s,1H),8.24(s,1H),7.80(d,J=7.8Hz,2H),7.61-7.48(m,3H),7.46-7.39(m,2H),7.25(t,J=8.8Hz,1H),7.19(t,J=8.4Hz,2H),4.55(s,2H)。
TLC-MS:C27H17ClF3N3O3S([M-H]-)的m/z计算值:554.1,实测值:553.8。
纯度:96%
实施例43:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(3-氟苯基)甲磺酰胺的合成
方法:根据实施例6,步骤3制备标题化合物。
收率:53mg,66μmol,45%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),9.83(s,1H),8.72(s,1H),8.67(s,1H),8.24(s,1H),7.80(d,J=7.8Hz,2H),7.61-7.48(m,3H),7.46-7.39(m,2H),7.25(t,J=8.8Hz,1H),7.19(t,J=8.4Hz,2H),4.55(s,2H)。
TLC-MS:C27H17ClF3N3O3S([M-H]-)的m/z计算值:554.1,实测值:553.9。
纯度:97%
实施例44:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(2-氟苯基)甲磺酰胺的合成
方法:根据实施例6,步骤3制备标题化合物。
收率:52mg,93μmol,44%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.04(s,1H),10.02(s,1H),8.72(d,J=2.1Hz,1H),8.67(s,1H),8.21(s,1H),7.80(d,J=8.5Hz,2H),7.61-7.52(m,3H),7.51-7.38(m,2H),7.31-7.15(m,3H),4.60(s,2H)。TLC-MS:C27H17ClF3N3O3S([M-H]-)的m/z计算值:554.1,实测值:553.9。
纯度:95%
实施例45:N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤1:5-溴-2-环丙基嘧啶
方法:根据Gabos等人[WO 2006004532 A1]的方法制备标题化合物。
收率:403mg,2.2mmol,13%(两步的)(无色的油)。
TLC:nHex/EE 10%
分析数据:1H NMR(CDCl3,200MHz,ppm):δ8.58(s,2H),2.31-2.12(m,1H),1.13-1.05(m,4H)。13C NMR(CDCl3,50MHz,ppm):δ170.7,157.5,116.7,18.0,11.4。
步骤2:N-(3-(5-(2-(环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺
方法:根据实施例4,步骤3制备标题化合物。
收率:51mg,103μmol,47%(白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.08(s,1H),9.77(s,1H),9.03(s,2H),8.75(d,J=1.9Hz,1H),8.70(s,1H),8.28(s,1H),7.59(td,J=8.9,6.2Hz,1H),7.28(t,J=8.6Hz,1H),3.17-3.09(m,2H),2.28(ddd,J=12.6,7.9,5.0Hz,1H),1.80-1.68(m,2H),1.14-1.02(m,4H),0.96(t,J=7.4Hz,3H)。
TLC-MS:C24H21F2N5O3S([M-H]-)的m/z计算值:496.1,实测值:496.1。
纯度:97%
实施例46:N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺的合成
步骤46-1:根据实施例4,步骤1制备N-(3-(5-溴-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺。
收率:2.1g,3.12mmol,93%(白色固体)。
TLC:nHex/EE 25%
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ9.93(s,1H),8.88(s,1H),8.75(d,J=1.8Hz,1H),8.34(s,1H),7.66(s,3H),7.60(dd,J=14.6,8.6Hz,1H),7.41(d,J=3.7Hz,2H),7.36-7.33(m,3H),7.28(t,J=9.0Hz,1H),4.57(s,2H)。
TLC-MS:C28H16BrCl2F2N3O4S([M-H]-)的m/z计算值:675.9,实测值:675.4。
步骤46-2:根据实施例4,步骤2制备N-(3-(1-(2,6-二氯苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺。收率:1.2g,1.7mmol,75%(灰白色固体)。
TLC:nHex/EE 25%
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ9.91(s,1H),8.86(d,J=1.6Hz,1H),8.83(s,1H),8.33(s,1H),7.65(s,3H),7.63-7.55(m,1H),7.43-7.32(m,5H),7.28(t,J=8.9Hz,1H),4.57(s,2H),1.30(s,12H)。
TLC-MS:C34H28BCl2F2N3O6S([M-H]-)的m/z计算值:724.1,实测值:723.6。
步骤46-3:根据实施例4,步骤3制备N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺。
收率:53mg,97μmol,47%(灰白色固体)。
TLC:nHex/EE(1∶1)
分析数据:1H NMR(DMSO-d6,400MHz,ppm):δ13.10(s,1H),9.83(s,1H),9.04(s,2H),8.76(s,1H),8.72(s,1H),8.25(s,1H),7.51(dd,J=14.8,8.8Hz,1H),7.43-7.31(m,5H),7.24(t,J=8.6Hz,1H),4.54(s,2H),2.33-2.24(m,1H),1.14-1.03(m,4H)。
TLC-MS:C28H21F2N5O3S([M-H]-)的m/z计算值:544.1,实测值:544.0。
纯度:97%
根据通过以下反应方案示出的实施例4,步骤2和3,制备表2中给出的化合物。
表2:以类似于实施例4,步骤2和3的方式制备的实施例47-57。
以类似于实施例7的方式制备化合物58和化合物59。
实施例60:N-(4-溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-1-磺酰胺的合成
步骤60-1:6-溴-2-氟-3-硝基苯甲酸(2)的合成
将4-溴-2-氟-1-硝基苯(1,1当量,4g,18.18mmol)溶解在无水四氢呋喃(THF,100mL)中并冷却至-78℃。逐滴加入二异丙基氨基锂(2M的THF溶液,2当量,18.18mL,36.36mmol),并在-78℃搅拌反应物1小时,然后用气态二氧化碳淬灭。将反应混合物加热至室温,并在真空下除去溶剂。得到的残余物用0.5M氢氧化钠水溶液(20mL×3)萃取。合并的水层用乙酸乙酯(EtOAc,30mL×2)洗涤,用浓盐酸酸化至约pH 1,然后用乙醚(30mL×2)萃取。合并的有机层经硫酸镁干燥,并减压浓缩,得到期望的产物6-溴-2-氟-3-硝基苯甲酸(1.3g,4.92mmol,27%收率),为白色固体,其无需进一步纯化即用于下一步。
步骤60-2:6-溴-2-氟-3-硝基苯甲酰氯(3)的合成
在0℃向6-溴-2-氟-3-硝基苯甲酸(1当量,1.3g,4.92mmol)在DCM(25mL)中的溶液中加入草酰氯(2.5当量,1.55g,12.3mmol),随后加入二甲基甲酰胺(0.5mL)。将所得的反应混合物在环境温度下搅拌约3小时。减压蒸发溶剂,得到酰氯(acid chloride)(3,1.3g,粗品),其无需进一步纯化即可使用。
步骤60-3:(6-溴-2-氟-3-硝基苯基)(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(4)的合成
在室温和氩气下,将5当量的AlCl3(4.39g,32.94mmol)在30ml无水DCM中进行搅拌。1小时后,加入5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶2(1当量,1.5g,6.588mmol)。将混合物在室温再搅拌一小时,然后冷却至0℃。将新制备的6-溴-2-氟-3-硝基苯甲酰氯(3,1.3g,粗品)溶解在15mL DCM中,并将其逐滴加入到所述反应混合物中。将反应混合物在室温搅拌3天。通过TLC(40%EtOAc的己烷溶液)监测反应进程。然后将所得混合物在0℃用冷乙腈:H2O(1∶1,30mL)小心地淬灭。过滤出析出的固体,并用DCM(25mL)萃取滤液。合并滤出的沉淀物和DCM萃取物,并使用20%EtOAc/己烷通过FCC进行纯化,得到(3-硝基-6-溴-2-氟苯基)(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(4,610mg,1.29mmol,19.50%收率),为灰白色固体。
步骤60-4:(3-氨基-6-溴-2-氟苯基)(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(5)的合成
在室温向被搅拌的3-硝基-6-溴-2-氟苯基)(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮(4,1当量,610mg,1.285mmol)在THF(15mL)中的溶液加入氯化亚锡(3eq,731mg,3.85mmol)。将反应混合物在60℃搅拌16h。通过TLC(30%EtOAc的己烷溶液)监测反应进程。完成后,将反应混合物用20%的K2CO3水溶液(10mL)淬灭,并搅拌10分钟。将其通过硅藻土垫过滤,并将硅藻土床用THF(25mL)洗涤。真空蒸发得到的有机层,并将获得的残余物溶于EtOAc(20mL)。将其用盐水洗涤,经Na2SO4干燥,过滤,并减压浓缩,得到(3-氨基-6-溴-2-氟苯基)(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮3(560mg,粗品),其无需进一步纯化即用于下一反应。
步骤60-5:N-(4-溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-1-磺酰胺(6)的合成
向被搅拌的化合物(3-氨基-6-溴-2-氟苯基)(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-基)甲酮5(1当量,400mg,0.90mmol)的溶液加入吡啶(5mL)和DMAP(0.05当量,5.48mg,0.045mmol)。在室温搅拌下向其逐滴加入丙磺酰氯(1.5当量,202mg,1.35mmol)。将反应混合物在室温搅拌16小时。通过TLC监测反应进程。反应完成后,真空除去溶剂,加入水(5mL),并用DCM(10mL×2)萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,得到粗化合物,将其通过FCC纯化,得到所需产物N-(4-溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-1-磺酰胺(6,120mg,0.22mmol,24.4%)。
实施例61:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-氰基-2-氟苯基)丙烷-1-磺酰胺的合成
向微波小瓶(microwave vial)中加入N-(4-溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-1-磺酰胺(1当量,50mg,0.09mmol),将其溶于NMP(2mL)。将混合物用氩气脱气10分钟,并向其中加入CuCN(5当量,40.64mg,0.045mmol)、CuI(0.1当量,1.73mg,0.009mmol)。将反应混合物在微波下于120℃加热2小时。将反应混合物通过硅藻土过滤并在真空下浓缩以提供粗产物,将其通过SFC纯化,以获得N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-氰基-2-氟苯基)丙烷-1-磺酰胺(17mg,0.03mmol,37.69%),为灰白色固体。
分析数据:1H NMR(400MHz,DMSO)δ13.12(s,1H),10.51(s,1H),8.74(s,1H),8.68(s,1H),8.34(s,1H),7.80(dt,J=16.0,10.1Hz,4H),7.58(d,J=8.3Hz,2H),1.74(dd,J=15.1,7.2Hz,2H),0.98(t,J=7.3Hz,3H)。
C24H18ClFN4O3S的精确分子量(exact mass)计算值:496.08。MS(ESI+):497.05[M+H]+。
实施例62:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氰基苯基)丙烷-1-磺酰胺的合成
向被搅拌的N-(2,4-二溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺(5)(1当量,100mg,0.16mmol)在DMF(2mL)中的溶液中加入氰化铜(4当量,58.48mg,0.65mmol),并将反应物在密闭管中于120℃加热5小时。反应完成后,将反应混合物倒入冰冷的水(20mL)中,并将得到的沉淀物过滤,用水(10mL×3)然后用稀氨水(5mL×2)洗涤。将其在真空下干燥并将粗产物通过制备型HPLC进行纯化,以获得N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氰基苯基)丙烷-1-磺酰胺(15mg,0.03mmol,18%收率),为白色固体。
分析数据:1H NMR(400MHz,DMSO)δ13.14(s,1H),8.71(d,J=47.9Hz,2H),8.29(s,1H),7.95(s,1H),7.82(d,J=8.1Hz,2H),7.67(s,1H),7.57(d,J=8.3Hz,2H),3.12(s,2H),1.76(d,J=7.1Hz,2H),0.98(t,J=7.3Hz,3H)。
C25H18ClN5O3S的精确分子量计算值:503.08。
MS(ESI+):504.10[M+H]+。
实施例63:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氰基苯基)丙烷-1-磺酰胺的合成
如以下图式中所示的方案进行合成。单独的步骤类似于实施例60和61中所述的那些来进行。
实施例64:N-(3-(4-氯-5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤64-1:5-(4-氯苯基)-3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶7-氧化物(2)
在0℃,向1(1当量,500mg,1.02mmol)在THF(10mL)中的溶液中分批加入m-CPBA(211.31mg,1.22mmol)。使所得的悬浮液达到室温,并在同一温度下搅拌16小时。通过减压旋转蒸发将反应混合物浓缩至干。向得到的粗产物中加入饱和NaHCO3水溶液(20mL),用DCM(3×60mL)萃取。将合并的有机层干燥并在真空下浓缩以提供5-(4-氯苯基)-3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶7-氧化物(500mg粗品),其为白色固体,无需纯化即用于下一步。
步骤64-2:N-(3-(4-氯-5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(3)
在0℃向被搅拌的5-(4-氯苯基)-3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶7-氧化物(2)(1当量,250mg,0.49mmol)在THF(10mL)中的溶液中逐滴加入甲磺酰氯(1.5当量,84.9mg,0.74mmol)。添加完成后,将反应物加热至70℃并搅拌12h。通过LCMS监测反应。反应完成后,减压除去挥发物得到残余物。用水(20mL)稀释残余物,并用DCM(50mL×3)萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥并减压浓缩,得到粗产物,将其通过制备型HPLC进行纯化,得到N-(3-(4-氯-5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(70mg,0.13mmol,26.5%收率)。
分析数据:1H NMR(400MHz,DMSO)δ13.45-12.72(m,1H),10.09-9.49(m,1H),8.40(s,1H),8.32(s,1H),7.64-7.51(m,5H),7.28(t,J=8.7Hz,1H),3.17-3.06(m,2H),1.81-1.66(m,2H),0.96(t,J=7.4Hz,3H)。
实施例65:N-(3-(5-(4-氯苯基)-4-氰基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
将N-(3-(4-氯-5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(实施例50)(1当量,300mg,0.57mmol)溶解在DMA(3mL)中。加入锌(0.1当量,3.74mg,0.057mmol)、氰化锌(2当量,134.38mg,1.14mmol),Pd(dppf)Cl2(0.035当量,16.74mg,0.02mmol)和Pd2(dba)3(0.0175当量,10.48mg,0.01mmol),将反应混合物用氩气脱气20min,并在微波加热下于120℃搅拌1.5h。反应完成后,将反应混合物通过硅藻土垫过滤。将硅藻土垫用EtOAc(20mL)洗涤,并将滤液在真空下浓缩,获得残余物,将其溶于EtOAc(50mL),用水洗涤,经Na2SO4干燥,在减压下浓缩,得到粗化合物。通过反相制备型HPLC对该粗化合物进行纯化,得到N-(3-(5-(4-氯苯基)-4-氰基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(100mg,0.19mmol,34%收率)。
分析数据:1H NMR(400MHz,DMSO)δ13.19(s,1H),9.78(s,1H),8.41(s,1H),8.33(s,1H),7.64-7.52(m,5H),7.28(t,J=8.4Hz,1H),3.18-3.06(m,2H),1.74(dq,J=15.1,7.5Hz,2H),0.96(t,J=7.4Hz,3H)。
C24H17ClF2N4O3S的精确分子量计算值:514.07。MS(ESI+):515.0[M+H]+。
实施例66:N-(3-(5-(4-氯苯基)-6-甲氧基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
步骤66-1:5-(4-氯苯基)-3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶7-氧化物(2)
在0℃,向1(1当量,1g,2.04mmol)在THF(20mL)中的溶液中加入m-CPBA(1.2当量,422.61mg,2.45mmol)。使所得悬浮液达到室温,并搅拌过夜。使用旋转蒸发仪在减压下将反应混合物浓缩至干。将如此获得的粗产物用DCM研磨从而得到固体,将其过滤并干燥以获得5-(4-氯苯基)-3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶7-氧化物2(700mg,1.38mmol,收率68%),其为白色固体。
步骤66-2:N-(3-(5-(4-氯苯基)-6-甲氧基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(3)
将N-氧化物2(1当量,500mg,0.988mmol)和硫酸二甲酯(1.1当量,137.11mg,1.08mmol)在无水乙腈(15mL)中的悬浮液在氮气下于60℃至65℃搅拌过夜。冷却至RT后,加入NaOMe的MeOH溶液(25wt%,4mL),并将混浊的混合物在60℃至65℃搅拌过夜。用AcOH中和并用MeOH(5mL)稀释后,将混合物蒸发至干。将获得的残余物溶解在EtOAc(40mL)中,并用NaHCO3水溶液(5mL×2)洗涤。用EtOAc(10mL)萃取水层。将合并的有机相干燥(Na2SO4)并蒸发至干。通过制备型HPLC进行纯化,得到22(30mg,0.0576mmol,5.85%),为白色固体。
分析数据:1H NMR(400MHz,DMSO)δ12.80(s,1H),9.75(s,1H),8.30(s,1H),7.94(s,1H),7.60(d,J=8.5Hz,2H),7.55(dd,J=8.9,3.0Hz,1H),7.51(d,J=8.5Hz,2H),7.24(t,J=8.6Hz,1H),3.94(s,3H),3.15-3.04(m,2H),1.73(dq,J=15.0,7.5Hz,2H),0.96(t,J=7.4Hz,3H)。
实施例67:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-3-羟基丙烷-1-磺酰胺的合成
步骤67-1:3-(氯磺酰基)丙基乙酸酯(2)
步骤67-1i:向被搅拌的3-溴丙烷-1-醇1(1当量,3.0g,21.6mmol)在DCM(50mL)中的溶液中加入TEA(3当量,6.5g,64.8mmol)和4-DMAP(0.1当量,0.264g,2.15mmol),并将反应混合物冷却至0℃。在相同温度下在15分钟内将乙酰氯(1.5当量,2.54g,32.4mmol)逐滴加入到该溶液中。通过TLC监测反应进程。反应完成后(TLC),加入水(100mL),并将反应混合物用DCM(20mL×2)萃取。分离有机层,用2N HCl(10mL)溶液和盐水洗涤。有机层经无水Na2SO4干燥并减压浓缩,得到步骤1产物(4g,粗品),其未经进一步纯化即用于下一步。
步骤67-1ii:向被搅拌的步骤1的产物(1当量,4.0g,粗品)在DMF(50mL)中的溶液中加入硫代乙酸钾(1.2当量,3.02g,26.51mmol),并在室温搅拌反应混合物4小时。通过TLC监测反应进程。反应完成后,加入冰冷的水(150mL),并用乙醚(20mL×3)萃取反应混合物。将合并的有机层用盐水溶液洗涤,经无水Na2SO4干燥并且在减压下浓缩以得到步骤2的产物(3g,粗品),其无需进一步纯化即用于下一步。
步骤67-1iii:在0℃向被搅拌的步骤2产物(1当量,3.0g,17.023mmol)在乙腈(30mL)中的溶液加入2N HCl(4mL)。在30分钟内分批加入NCS(4当量,9g,68.09mmol)。将反应混合物在RT搅拌3小时。通过TLC监测反应进程。反应完成后,将乙腈真空蒸发,并加入水(100mL),并用乙醚(50mL×3)萃取反应混合物。合并的有机层用盐水溶液洗涤,经无水Na2SO4干燥并减压浓缩,得到3-(氯磺酰基)丙基乙酸酯2(2g,粗品),其无需进一步纯化即用于下一步。
步骤67-2:3-(N-(3-(5-(4-氯苯基)-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)氨磺酰基)丙基乙酸酯(4)
向被搅拌的(3-(3-氨基-2,6-二氟苯甲酰基)-5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-1-基)(2,6-二氯苯基)甲酮3(1当量,199.8mg,0.359mmol)在DCM(10mL)中的溶液加入TEA(10当量,362.59mg,3.59mmol)和DMAP(0.1当量,4.38mg,0.0359mmol),并将反应混合物冷却至0℃。向其中加入3-(氯磺酰基)丙基乙酸酯2(4当量,287.2mg,1.436mmol)。通过TLC监测反应进程。反应完成(16小时)后,将用1N HCl(2mL)将反应淬灭,并用DCM(10mL×2)萃取反应混合物。合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,得到粗残余物,将其通过FCC进行纯化,以提供作为步骤4的产物的二磺酰胺中间体(150mg)。
向被搅拌的步骤4的产物(1当量,150mg,0.169mmol)在THF(2.5mL)中的溶液加入NaOH(4当量,27.08mg,0.677mmol)水溶液,并将反应混合物在室温搅拌2小时。通过TLC监测反应进程。反应完成后,真空除去THF,加入水(5mL),并用5N HCl中和反应。混合物用EtOAc(10mL×3)萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,得到4(100mg,粗品),其无需进一步纯化即用于下一步。
步骤67-3:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-3-羟基丙烷-1-磺酰胺
向被搅拌的3-(N-(3-(5-(4-氯苯基)-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)氨磺酰基)丙基乙酸酯4(100mg,0.147mmol,粗品)在THF(2mL)中的溶液加入氨水(2mL),并将反应混合物在室温搅拌12小时。在真空下蒸发溶剂以提供残余物,将其通过制备型HPLC进一步纯化以获得白色固体状产物(25mg,0.05mmol,34%收率)。
分析数据:1H NMR(400MHz,DMSO)δ13.12-12.92(m,1H),9.87-9.70(m,1H),8.71(d,J=2.2Hz,1H),8.65(s,1H),8.22(s,1H),7.80(d,J=8.5Hz,2H),7.59(t,J=10.0Hz,3H),7.28(t,J=8.8Hz,1H),4.64(s,1H),3.47(t,J=5.9Hz,2H),3.17(dd,J=10.3,5.2Hz,2H),1.87(dd,J=15.5,6.2Hz,2H)。
C23H18ClF2N3O4S的精确分子量计算值:505.07。
MS(ESI+):506.0[M+H]+。
实施例68:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-羟基丙烷-1-磺酰胺的合成
步骤68-1:2-氧丙烷(oxopropane)-1-磺酰氯(2)
将氯丙酮(1当量,3g,32.425mmol)、Na2SO3(1当量,4.085g,32.425mmol)和水(30mL)在装有回流冷凝器的烧瓶中混合。将混合物在搅拌下回流20小时,然后将混合物蒸发至干。所获得的白色固体(步骤1产物)无需进一步纯化即用于下一步骤。
向被搅拌的步骤1产物(3g,粗品)在甲苯(15mL)中的溶液中加入POCl3(15mL),并将反应混合物在110℃搅拌4h。通过旋转蒸发除去溶剂,加入乙醚(50mL),并将混合物进一步搅拌10分钟。将其过滤,并将滤液减压浓缩,得到标题化合物(2),其为深棕色液体(3g,粗品),其无需进一步纯化即用于下一步。
步骤68-2:N-(3-(5-(4-氯苯基)-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-氧丙烷-1-磺酰胺(4)
向被搅拌的化合物3(1当量,200mg,0.359mmol)在二氧六环(4mL)中的溶液加入吡啶(1mL)和4-DMAP(0.1当量,4.38mg,0.0359mmol)。在室温搅拌下逐滴加入2-氧丙烷磺酰氯2(4当量,224.32mg,1.438mmol)。将反应混合物在室温搅拌8小时。通过TLC监测反应进程。反应完成后,真空除去溶剂,加入水(5mL),并用EtOAc(3×10mL)萃取。合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,得到粗化合物,通过FCC对其进行纯化,得到4(199.75mg,0.295mmol,82%收率)。
步骤68-3:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-羟基丙烷-1-磺酰胺
步骤68-3i:在0℃,向被搅拌的N-(3-(5-(4-氯苯基)-1-(2,6-二氯苯甲酰基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-氧丙烷-1-磺酰胺4(1当量,200mg,0.295mmol)在MeOH(2mL)中的溶液逐滴加入硼氢化钠的甲醇溶液(1当量,11.22mg,0.295mmol,1mL),并将反应混合物搅拌1小时。通过TLC监测反应进程。完成后,将反应混合物加入水(20mL)中,并用EtOAc(3×5mL)萃取。合并的有机层经无水Na2SO4干燥并在减压下浓缩而得到粗产物,其通过FCC使用25%EtOAc/己烷进行纯化,得到步骤4的产物(70mg,0.1mmol,33.89%)。
步骤68-3ii:向被搅拌的步骤71-4i的产物(70mg,0.103mmol)在THF∶MeOH(2mL,1∶1)中的溶液加入氨水(1mL),并将反应混合物在室温搅拌4小时。在真空下蒸发溶剂,并加入水(10mL)。用5N HCl将混合物中和至pH 7,并用EtOAc(3×5mL)萃取。合并的有机层经无水Na2SO4干燥并减压浓缩,得到粗产物,将其通过SFC进行纯化,得到所需产物N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-羟基丙烷-1-磺酰胺(15.99mg,0.0316mmol,21.50%)。
分析数据:1H NMR(400MHz,DMSO)δ13.02(s,1H),9.66(s,1H),8.71(d,J=2.1Hz,1H),8.64(s,1H),8.22(s,1H),7.80(d,J=8.5Hz,2H),7.66-7.53(m,3H),7.28(t,J=8.7Hz,1H),5.01(d,J=4.7Hz,1H),4.12(d,J=5.7Hz,1H),3.23(dd,J=10.2,6.0Hz,2H),1.20(d,J=6.3Hz,3H)。
C23H18ClF2N3O4S的精确分子量计算值:505.07。
MS(ESI+):506.0[M+H]+。
实施例69:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-氧丙烷-1-磺酰胺的合成
分析数据:1H NMR(400MHz,DMSO)δ13.03(s,1H),10.06(s,1H),8.72(d,J=2.1Hz,1H),8.66(s,1H),8.25(s,1H),7.80(d,J=8.4Hz,2H),7.59(t,J=10.2Hz,3H),7.29(t,J=8.6Hz,1H),4.45(s,2H),2.27(s,3H)。
C23H16ClF2N3O4S的精确分子量计算值:503.05。MS(ESI+):504.05[M+H]+。
实施例70:N-(2,4-二氟-3-(5-吗啉基-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
向脱气的被搅拌的RuPhos(0.1当量,20.36mg,0.04mmol)在二氧六环(2mL)中的溶液加入乙酸钯(0.05当量,4.89mg,0.02mmol),并将反应物再次用氩气脱气15分钟。向该混合物中加入N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺(1)(1当量,200mg,0.44mmol)和吗啉(2当量,76.04mg,0.87mmol),然后加入1M的LiHMDS(4当量,1.7mL,1.7mmol)的THF溶液。将反应混合物进一步用氩气脱气10分钟,然后在密闭管中于100℃加热12小时。用水(10mL)稀释反应混合物,并用5N HCl将pH调节至6。反应混合物用EtOAc(10mL×3)萃取。合并的有机层经Na2SO4干燥并在减压下浓缩以获得粗残余物,将其通过SFC进一步纯化以得到N-(2,4-二氟-3-(5-吗啉基-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺(35mg,0.08mmol,17%),其为白色固体。
分析数据:1H NMR(400MHz,DMSO)δ12.69(s,1H),9.74(s,1H),8.28(d,J=2.7Hz,1H),8.02(d,J=3.0Hz,1H),7.92(s,1H),7.61-7.50(m,1H),7.26(t,J=8.6Hz,1H),3.99-3.62(m,19H),3.21-3.06(m,5H),1.73(dt,J=15.0,7.5Hz,2H),0.96(t,J=7.4Hz,3H)。
实施例71:N-(2,4-二氟-3-(5-(哌嗪-1-基)-1H-吡咯并12,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
步骤71-1:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)哌嗪-1-甲酸叔丁酯(2)
向脱气的被搅拌的Ruphos(0.1当量,20.36mg,0.04mmol)在NMP(2mL)中的溶液加入Pd2dba3(0.05当量,19.97mg,0.02mmol),并将反应物再次用氩气脱气15分钟。向该混合物中加入N-(3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺1(1当量,200mg,0.436mmol)和1-Boc-哌嗪(1.5当量,121.81mg,0.65mmol),然后加入叔丁醇钠(3当量,125.66mg,1.31mmol)。将反应混合物进一步用氩气脱气10分钟,然后在微波中于100℃加热1小时。用水(10mL)稀释反应混合物,并用EtOAc(10mL×3)萃取。合并的有机层经硫酸钠干燥,并减压浓缩,得到粗产物,将其通过FCC使用30%EtOAc/己烷进一步纯化,得到4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)哌嗪-1-甲酸叔丁酯(2)(70mg,0.12mmol,28%收率),为白色固体。
步骤71-2:N-(2,4-二氟-3-(5-(哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺HCl盐
在0℃向4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)哌嗪-1-甲酸叔丁酯(2)(70mg,0.12mmol)加入HCl的二氧六环溶液(4M,3mL),并在室温下进一步搅拌反应混合物1小时。反应完成后,真空除去二氧六环,得到粗残余物。将该残余物用乙醚研磨,得到HCl盐形式的N-(2,4-二氟-3-(5-(哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺(25mg,0.05mmol,43%),为白色固体。
分析数据:1H NMR(400MHz,DMSO)δ8.29(d,J=2.4Hz,1H),8.00(s,2H),7.55(dd,J=14.8,8.9Hz,1H),7.25(t,J=8.7Hz,1H),3.37(m,4H),3.30(m,4H),3.14-3.06(m,2H),1.72(dd,J=15.0,7.4Hz,2H),0.94(t,J=7.4Hz,3H)。
5-取代的N-(2,x-二氟-3-(1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺衍生物的合成
根据以下实施例制备下式的5-取代的N-(2,4-二氟-3-(1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺衍生物。
实施例72:N-(2,4-二氟-3-(5-(2-甲氧基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺
将N-[3-[1-(2,6-二氯苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡咯并[2,3-b]吡啶-3-羰基]-2,4-二氟苯基]丙烷-1-磺酰胺(150mg,0.221mmol,类似于实施例4,步骤4-1和4-2进行制备)、5-溴-2-氯嘧啶(64.2mg,0.332mmol)和碳酸钾(62.0mg,0.442mmol)悬浮于1,4-二氧六环(0.600mL)和水(0.300mL)中,并用氩气脱气5分钟。加入[1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)(Pd(dppf)Cl2,8.09mg,0.0111mmol),并将混合物加热至60℃保持2h。通过蒸发除去溶剂,并将残余物溶于10mLMeOH中。加入碳酸钾(1g),并将混合物在50℃搅拌。2小时后,加入水,并用HCl水溶液(1N)将pH调节至~7。将水相用EtOAc萃取3次,将合并的有机物经硫酸钠干燥,并真空除去溶剂。经由快速色谱法使用DCM/EtOAc/MeOH(92/8/0-88/8/4)作为洗脱剂对产物进行纯化。伴随碳酸钾催化的二氯苯甲酰基保护基的去除,5-溴-2-氯嘧啶的氯被甲氧基取代。
分析数据:
1H NMR(600MHz,DMSO-d6):δ13.05(s,1H),9.77(s,1H),9.00(s,2H),8.72(d,J=1.4Hz,1H),8.67(s,1H),8.24(s,1H),7.59(dd,J=14.7,8.8Hz,1H),7.28(t,J=8.6Hz,1H),3.99(s,3H),3.15-3.07(m,2H),1.74(dq,J=14.8,7.3Hz,2H),0.96(t,J=7.4Hz,3H)。
精确分子量计算值:487.1;MS(ESI-):486.3[M-H]-。
与实施例72类似,制备了表3中给出的实施例73-95的化合物。
实施例96:4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯磺酰胺的合成
将N-[3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基]丙烷-1-磺酰胺(80.0mg,0.175mmol)、(4-氨磺酰基苯基)硼酸(0.0456g,0.227mmol)和碳酸钾(0.0490g,0.349mmol)悬浮于乙二醇二甲醚(ethylene glycol dimethyl ether)(1.60mL)/水(0.400mL)中,并用氩气脱气5分钟。加入四(三苯基膦)钯(Tetrakis Pd)(0.0121g,0.0105mmol),并将得到的混合物在微波中于130℃加热40min。使粗产物通过硅藻土垫,将其用EtOAc冲洗。有机相用水和盐水洗涤,经Na2SO4干燥,并真空除去溶剂。经由快速色谱法(Si2O,DCM/EtOAc 20%至50%)对产物进行纯化。
分析数据:
1H NMR(400MHz,DMSO-d6)δ13.08(d,J=2.3Hz,1H),9.78(s,1H),8.78(d,J=2.2Hz,1H),8.71(s,1H),8.29(d,J=2.6Hz,1H),7.99(d,J=8.6Hz,2H),7.95(d,J=8.7Hz,2H),7.59(td,J=9.0,6.0Hz,1H),7.45(s,2H),7.32-7.25(m,1H),3.17-3.09(m,2H),1.80-1.67(m,2H),0.96(t,J=7.4Hz,3H)。
C23H20F2N4O5S2的精确分子量计算值:534.1(分子量(molecular weight):534.55)
MS(ESI-):532.7[M-H]-。
实施例97:N-(2,4-二氟-3-(5-(2-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
将N-[3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基]丙烷-1-磺酰胺(0.120g,0.262mmol)、[2-(三氟甲基)苯基]硼酸(0.0547g,0.288mmol)和碳酸钾(0.0734g,0.524mmol)悬浮在1,4-二氧六环(0.900mL)和水(0.450mL)中,并用氩气脱气5分钟。加入XPhos Pd G3(0.0111g,0.0131mmol),并将混合物在微波炉中以50W加热至110℃保持45分钟。粗产物经硅藻土垫过滤,用EtOAc冲洗,滤液用饱和NH4Cl水溶液洗涤。有机相经硫酸钠干燥,减压除去溶剂,经快速色谱法使用DCM/MeOH(100/0v/v至97/3v/v)作为洗脱剂对产物进行纯化。
分析数据:
1H NMR(600MHz,DMSO-d6)δ13.07(s,1H),9.76(s,1H),8.39(s,1H),8.35(d,J=1.7Hz,1H),8.29(d,J=1.5Hz,1H),7.90(d,J=7.9Hz,1H),7.78(t,J=7.5Hz,1H),7.69(t,J=7.7Hz,1H),7.61-7.54(m,2H),7.28(t,J=8.6Hz,1H),3.14-3.10(m,2H),1.78-1.70(m,2H),0.96(t,J=7.4Hz,3H)。
C24H18F5N3O3S的精确分子量计算值:523.1(分子量:523.48)
MS(ESI+):521.9[M-H]-。
实施例98:N-(3-(5-(4-(二甲基氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
将N-[3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基]丙烷-1-磺酰胺(0.120g,0.262mmol)、N,N-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(0.0712g,0.288mmol)和碳酸钾(0.0734g,0.524mmol)悬浮于1,4-二氧六环(0.900mL)和水(0.450mL)并用氩气脱气5分钟。加入XPhos Pd G3(0.0111g,0.0131mmol),并将该混合物在微波炉中以50W加热至110℃保持45分钟。粗产物经硅藻土垫过滤,用EtOAc冲洗,滤液用饱和NH4Cl水溶液洗涤。有机相经硫酸钠干燥,减压除去溶剂,采用快速色谱法使用DCM/MeOH(100/0v/v至95/5v/v)作为洗脱剂对产物进行纯化。
分析数据:
1H NMR(600MHz,DMSO-d6)δ12.89(s,1H),9.76(s,1H),8.64(d,J=2.2Hz,1H),8.52(s,1H),8.17(s,1H),7.62-7.53(m,3H),7.28(t,J=8.4Hz,1H),6.86(d,J=8.8Hz,2H),3.12(dd,J=8.6,6.7Hz,2H),2.96(s,6H),1.74(dq,J=15.0,7.5Hz,2H),0.96(t,J=7.4Hz,3H)。
C25H24F2N4O3S的精确分子量计算值:498.2(分子量:498.55);
MS(ESI-):497.0[M-H]-。
类似于实施例96-98,制备了表4中给出的实施例99-123的化合物。
实施例123:N-(3-(5-环丁基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
根据以下合成路线制备实施例123:
分析数据:
化学纯度(HPLC/UV):99.7%
MS(ESI+):434.20(C21H21F2N3O3S的精确分子量计算值:433.13)
5-取代的N-(2-氟苯基)烷基-1-磺酰胺衍生物的合成
根据下文所述的实施例124制备根据下式的5-取代的N-(2-氟-(1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺衍生物。
实施例124:N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺的合成
向N-[3-(5-溴-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基]-1-苯基甲磺酰胺(0.1000g,0.205mmol,类似于实施例3来制备)在1,4-二氧六环(0.700mL)和水(0.350mL)中的溶液加入(4-氯苯基)硼酸(0.0480g,0.307mmol)和碳酸钾(0.0574g,0.410mmol),并将混合物用氩气脱气5分钟。加入Tetrakis Pd(0.0237g,0.0205mmol),并将反应小瓶在微波炉中于110℃(50W)照射45分钟。冷却至室温后,使混合物通过硅藻土垫,将其用EtOAc(50ml)洗涤。将有机相用饱和的NH4Cl水溶液和水洗涤,并在用硫酸钠洗涤后干燥。采用快速色谱法使用DCM/MeOH(0-3%)作为洗脱剂对产物进行纯化。得到为灰白色固体的N-[3-[5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基]-2-氟苯基]-1-苯基甲磺酰胺(0.0548g,0.0843mmol,41%收率)。
分析数据:
1H NMR(600MHz,DMSO-d6)δ8.70(d,J=2.2Hz,1H),8.68(d,J=2.2Hz,1H),8.03(s,1H),7.85(dd,J=20.1,8.4Hz,1H),7.78(dd,J=8.7,2.4Hz,2H),7.57(d,J=8.5Hz,2H),7.51(td,J=7.9,1.4Hz,1H),7.39-7.31(m,5H),7.24(t,J=7.8Hz,1H),4.51(s,2H)。
C27H19ClFN3O3S的精确分子量计算值:(分子量:519.98)
MS(ESI-):518.2[M-H]-。
实施例134:N-(2,4-二氟-3-(5-(3-羟基氮杂环丁烷-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
实施例134-1:3-(苄氧基)氮杂环丁烷的合成
实施例134-2:N-(2,4-二氟-3-(5-(3-羟基氮杂环丁烷-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.57(s,1H),9.70(s,1H),7.93(s,1H),7.70(d,J=2.6Hz,1H),7.52(td,J=9.0,6.0Hz,1H),7.38(s,1H),7.22(t,J=8.7Hz,1H),4.59(dt,J=11.3,5.6Hz,1H),4.14(t,J=6.9Hz,2H),3.55-3.52(m,3H),3.13-3.03(m,2H),1.70(dq,J=15.0,7.5Hz,2H),0.93(t,J=7.4Hz,3H)。
精确分子量计算值:450.12。MS(ESI+):551.0[M+H]+。
实施例135和实施例136:N-(2,4-二氟-3-(5-(4-氧代哌啶-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺和N-(2,4-二氟-3-(5-(4-羟基哌啶-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
分析数据:
实施例135:
1H NMR(400MHz,CDCl3)δ10.23(s,1H),8.38(s,1H),8.31(s,1H),7.70(dd,J=16.1,10.5Hz,2H),7.07(t,J=8.6Hz,1H),6.60(s,1H),3.67(t,J=5.9Hz,4H),3.17-3.09(m,2H),2.68(t,J=5.9Hz,4H),1.92(dd,J=15.3,7.7Hz,2H),1.08(t,J=7.4Hz,3H)。
C22H22F2N4O4S精确分子量计算值:476.13。MS(ESI+):477.1[M+H]+。
实施例136:
1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),9.74(s,1H),8.24(d,J=2.7Hz,1H),8.00(s,1H),7.90(s,1H),7.56(dd,J=14.9,8.9Hz,1H),7.26(t,J=8.4Hz,1H),4.71(d,J=4.2Hz,1H),3.68-3.60(m,1H),3.52-3.45(m,2H),3.14-3.07(m,2H),2.88(t,J=10.0Hz,2H),1.87(s,2H),1.74(dd,J=15.3,7.6Hz,2H),1.61-1.51(m,2H),0.96(t,J=7.4Hz,3H)。
C22H24F2N4O4S精确分子量计算值:478.15。MS(ESI+):479.1[M+H]+。
实施例137:1-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)氮杂环丁烷-3-甲酸的合成
以类似于134来制备实施例137。
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.63(s,1H),9.73(s,1H),7.98(s,1H),7.76(d,J=2.6Hz,1H),7.55(td,J=9.0,6.0Hz,1H),7.42(s,1H),7.25(t,J=8.6Hz,1H),4.11(t,J=7.8Hz,2H),3.95(t,J=6.5Hz,2H),3.17-3.05(m,2H),1.74(dq,J=15.0,7.5Hz,2H),0.96(t,J=7.4Hz,3H)。
C21H20F2N4O5S的精确分子量计算值:478.11(分子量:478.47)。
MS(ESI+):479.1[M+H]+。
实施例138:N-(3-(5-(2,6-二甲基-吗啉基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺的合成
以类似于134来制备实施例138。
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.67(s,1H),9.75(s,1H),8.28(d,J=2.6Hz,1H),8.01(s,1H),7.88(s,1H),7.554.9,8.9Hz,1H),7.25(t,J=8.7Hz,1H),4.11(s,1H),3.84-3.72(m,2H),3.57(d,J=11.3Hz(dd,J=1,2H),3.15-3.06(m,2H),2.33(t,J=11.0Hz,2H),1.74(dd,J=15.1,7.5Hz,2H),1.26(d,J=6.4Hz,1H),1.18(d,J=6.2Hz,4H),0.96(t,J=7.4Hz,3H)。
C23H26F2N4O4S的精确分子量计算值:492.16;分子量:492.54。
MS(ESI+):493.1[M+H]+。
实施例139:N-(2,4-二氟-3-(5-(氧杂环丁烷-3-基氨基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
以类似于实施例134来制备实施例139。
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.54(s,1H),9.73(s,1H),7.91(s,1H),7.83(d,J=2.4Hz,1H),7.55(dd,J=14.9,9.0Hz,1H),7.40(s,1H),7.25(t,J=8.7Hz,1H),4.88(t,J=6.3Hz,2H),4.57(d,J=5.6Hz,1H),4.44(t,J=5.9Hz,2H),3.12(dd,J=17.4,9.9Hz,2H),1.74(dq,J=15.0,7.5Hz,2H),0.96(t,J=7.4Hz,3H)
C20H20F2N4O4S的精确分子量计算值:450.12(分子量:450.46)
MS(ESI+):451.1[M+H]+。
实施例140:N-(2,4-二氟-3-(5-(氧杂环丁烷-3-基氨基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
以类似于134来制备实施例140。
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.82-12.67(m,1H),9.75(s,1H),8.31(s,1H),8.06(s,1H),7.56(dd,J=14.9,9.0Hz,1H),7.26(t,J=8.7Hz,1H),3.22(s,4H),3.16-3.06(m,2H),1.83-1.64(m,6H),1.63-1.51(m,2H),0.96(t,J=7.4Hz,3H)。
C22H24F2N4O3S的精确分子量计算值:462.15(分子量:462.52)
MS(ESl+):463.1[M+H]+。
5-取代的N-(2,x-二氟-3-(1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺衍生物的合成
根据以下实施例制备根据下式的5-取代的N-(2,x-二氟-3-(1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)烷基-1-磺酰胺衍生物。
实施例141:N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,6-二氟苯基)甲磺酰胺的合成
将N-[3-[1-(2,6-二氯苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡咯并[2,3-b]吡啶-3-羰基]-2,6-二氟苯基]-N-甲基磺酰基甲磺酰胺(150mg,0.206mmol)、5-溴-2-环丙基嘧啶(0.0451g,0.227mmol)和碳酸钾(0.0578g,0.412mmol)溶解于1,4-二氧六环(1.40mL)和水(0.700mL)中,并且该混合物用氩气脱气。加入Pd(dppf)Cl2(0.00753g,0.0103mmol)),并将混合物加热至60℃保持2h。使粗混合物通过硅藻土垫,用MeOH和EtOAc冲洗,并真空除去溶剂。将残余物溶于MeOH中,加入碳酸钾(500mg),并将悬浮液在室温搅拌3h。加入水,用1N HCl水溶液将pH调节至6-8,并将水相用EtOAc萃取。合并有机层,经硫酸钠干燥,并在减压下除去溶剂。经由快速色谱法使用DCM/EtOAc/MeOH(92/8/0-88/8/4)作为洗脱剂对产物进行预纯化。此后,将产物悬浮于EtOAc中,并且在加入正戊烷之后,将产物滤出并真空干燥(收率:59mg(60%),化学纯度(HPLC/UV):98%)
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),9.72(s,1H),9.01(s,2H),8.72(s,2H),8.12(d,J=2.6Hz,1H),7.66(q,J=7.6Hz,1H),7.36(t,J=8.9Hz,1H),3.12(s,3H),2.27(td,J=8.0,4.0Hz,1H),1.13-1.01(m,4H)。
C22H17F2N5O3S的精确分子量计算值:469.1(分子量:469.47)
MS(ESI-):468.3[M-H]-。
实施例144:N-(2,6-二氟-3-(5-(2-(三氟甲基)嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-3,3,3-三氟丙烷-1-磺酰胺的合成
将N-[3-[1-(2,6-二氯苯甲酰基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡咯并[2,3-b]吡啶-3-羰基]-2,6-二氟苯基]-3,3,3-三氟-N-(3,3,3-三氟丙基磺酰基)丙烷-1-磺酰胺(200mg,0.224mmol,类似于实施例4步骤4-1和4-2制备的)、5-溴-2-(三氟甲基)嘧啶(56.0mg,0.247mmol)和碳酸钾(62.8mg,0.448mmol)溶解于1,4-二氧六环(1.50mL)和水(0.750mL),并将该混合物用氩气脱气。加入Pd(dppf)Cl2(8.20mg,0.0112mmol),并将混合物加热至60℃保持2小时。使粗混合物通过硅藻土垫,用MeOH和EtOAc冲洗,并真空除去溶剂。将残余物溶解在MeOH中,加入碳酸钾(500mg),并将该悬浮液在室温搅拌3h。添加水,用1N HCl水溶液将pH调节至6-8,水相用EtOAc萃取,分离各层,有机层经硫酸钠干燥,并减压除去溶剂。经由快速色谱法使用DCM/EtOAc/MeOH(92/8/0-88/8/4)作为洗脱剂对产物进行预纯化。将预纯化的产物悬浮于EtOAc中,并用正戊烷进行沉淀,过滤并真空干燥(收率:52mg(40%),化学纯度(HPLC/UV:99%)。
分析数据:
1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),10.05(s,1H),9.50(s,2H),8.89(dd,J=9.9,2.2Hz,2H),8.21(s,1H),7.76-7.64(m,1H),7.40(t,J=8.9Hz,1H),3.53-3.43(m,2H),2.91-2.76(m,2H)。
实施例143:N-(3-(5-(3-氰基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺的合成
将N-[3-[5-溴-1-(2,6-二氯苯甲酰基)吡咯并[2,3-b]吡啶-3-羰基]-2,6-二氟苯基]丙烷-1-磺酰胺(0.150g,0.2383mmol)、3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯甲腈(0.0599g,0.261mmol)和碳酸钾(0.0666g,0.475mmol)悬浮于1,4-二氧六环(1.20mL)和水(0.600mL)中,并用氩气脱气5分钟。加入Pd(dppf)Cl2(0.0137g,0.0119mmol),并将混合物加热至70℃保持2小时。将粗品通过硅藻土垫过滤,用EtOAc冲洗,并蒸发溶剂。将残余物悬浮在MeOH(5ml)中,并加入碳酸钾(200mg)。将混合物在室温搅拌直至TLC显示2,6-二氯苯甲酰基保护基团完全水解。用水稀释后,加入1N HCl(pH6-7),产物用EtOAc(3×50ml)萃取。有机相经硫酸钠干燥,减压除去溶剂,并且采用快速色谱法使用DCM/MeOH(100/0v/v至95/5v/v)作为洗脱剂对产物进行纯化(收率:52.8g(45%);化学纯度(HPLC/UV):97%)。
分析数据:
1H NMR(600MHz,DMSO-d6)δ12.95(s,1H),9.65(s,1H),8.76(d,J=1.9Hz,1H),8.74(d,J=1.9Hz,1H),8.27(s,1H),8.10(s,2H),7.87(d,J=7.6Hz,1H),7.72(t,J=7.8Hz,1H),7.66(dd,J=14.2,7.6Hz,1H),7.36(t,J=8.8Hz,1H),3.19-3.13(m,2H),1.81(dq,J=15.0,7.4Hz,2H),1.00(t,J=7.4Hz,3H)。
C24H18F2N4O3S的精确分子量计算值:480.1(分子量:480.49);
MS(ESI-):479.0[M-H]-。
类似于实施例141-143,制备了表5中给出的实施例144-238的化合物。
实施例239:N-(3-(5-环丁基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺的合成
分析数据:
1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),9.65(s,1H),8.36(s,1H),8.27(s,1H),7.96(s,1H),7.70-7.56(m,1H),7.33(t,J=8.9Hz,1H),3.80-3.60(m,1H),3.20-3.11(m,2H),2.44-2.29(m,3H),2.25-2.11(m,2H),2.10-1.97(m,1H),1.88(d,J=9.1Hz,1H),1.81(dd,J=15.2,7.6Hz,2H),1.00(t,J=7.4Hz,3H)。
C21H21F2N3O3S的精确分子量计算值:433.13(分子量:433.47)
MS(ESI+):434.2[M+H]+
实施例240:N-(2,6-二氟-3-(5-(吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺的合成
向(3-氨基-2,4-二氟苯基)-[1-(2,6-二氯苯甲酰基)-5-吡啶-4-基吡咯并[2,3-b]吡啶-3-基]甲酮(0.200g,0.382mmol)在1,4-二氧六环(0.637mL)和吡啶(0.637mL)的溶液中相继加入苯基甲磺酰氯(0.109g,0.573mmol)和4-二甲基氨基吡啶(0.00467g,0.0382mmol)。将混合物在60℃搅拌直至TLC显示反应完成。将粗品用EtOAc(50ml)稀释,并用1M HCl(20ml水溶液)洗涤两次。有机相经硫酸钠干燥,并真空除去溶剂。采用快速色谱法使用DCM/MeOH(0-5%)作为洗脱剂对产物进行纯化。获得N-[2,6-二氟-3-(5-吡啶-4-基-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基]-1-苯基甲磺酰胺(0.0840g,0.1550mmol,41%收率),其为灰白色固体(收率:84mg(40%),化学纯度(HPLC/UV):93%)。
分析数据:
1H NMR(600MHz,DMSO-d6)δ13.01(s,1H),9.75(s,1H),8.83(dd,J=5.4,2.2Hz,2H),8.68(dd,J=4.5,1.6Hz,2H),8.14(s,1H),7.82(dd,J=4.5,1.6Hz,2H),7.68(dd,J=14.4,7.7Hz,1H),7.45(dd,J=7.8,1.5Hz,2H),7.41-7.35(m,4H),4.54(s,2H)。
C26H18F2N4O3S的精确分子量计算:504.1(分子量:504.51)
MS(ESI-):503.2[M-H]-。
实施例241和实施例242:N-(2,4-二氟-3-(5-(哌啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺和N-(2,4-二氟-3-(5-(1,2,3,4-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺的合成
分析数据:
实施例241:
1H NMR(400MHz,DMSO-d6)δ8.36-8.32(m,1H),8.32-8.29(m,1H),8.09(s,1H),7.56-7.48(m,1H),7.20-7.13(m,1H),3.06-2.99(m,3H),2.98-2.84(m,4H),1.99-1.89(m,2H),1.89-1.78(m,2H),1.77-1.66(m,2H),0.95(t,J=7.4Hz,3H)。
C22H24F2N4O3S的精确分子量计算值:460.14(分子量:462.52)
MS(ESI+):463.20[M+H]+
实施例242:
1H NMR(400MHz,DMSO-d6)δ8.54(d,J=1.9Hz,1H),8.41(s,1H),8.31(s,1H),8.14(s,1H),7.61-7.49(m,1H),7.22(t,J=8.7Hz,1H),6.28(s,1H),3.61(s,2H),3.18(t,J=5.6Hz,2H),3.12-3.02(m,2H),2.62(s,2H),1.73(dd,J=15.2,7.6Hz,2H),0.95(t,J=7.4Hz,3H)。
C22H22F2N4O3S的精确分子量计算值:460.14(分子量:460.50)
MS(ESI+):461.20[M+H]+。
实施例243:生物活性
实施例243-1:结合的测定
使用DiscoveRx公司(美国加利福尼亚州94538,42501Albrae St.Fremont)的KINOMEscanTM Profiling Service测量本发明化合物的激酶活性,该测量基于竞争性结合测定法,其定量地测量化合物与固定的、活性位点定向的配体竞争的能力。该测定通过组合三个成分来进行:DNA标记的激酶;固定配体;和测试化合物。经由DNA标签的定量PCR来测量测试化合物与固定的配体竞争的能力。该技术在Fabian,M.A.等人的A small molecule-kinase interaction map for clinical kinase inhibitors(临床激酶抑制剂的小分子-激酶相互作用图谱),Nat.Biotechnol.(自然-生物技术),23,329-336(2005)和Karaman,M.W.等人的A quantitative analysis of kinase inhibitor selectivity(激酶抑制剂选择性的定量分析),Nat.Biotechnol.,26,127-132(2008)中有详细描述。
为了研究与MKK4、Braf、MKK7和JNK1的亲和力,在HEK-293细胞中产生了激酶,随后用DNA标记以进行qPCR检测。在室温下,用生物素化的小分子配体将链霉亲和素包被的磁珠处理30分钟,以生成用于激酶测定的亲和树脂。用过量的生物素封闭配体珠,并用封闭缓冲液(SEABLOCKTM(Pierce),1%BSA,0.05%20,1mM DTT)洗涤,以除去未结合的配体并减少非特异性结合。通过在1×结合缓冲液(20%SEABLOCKTM,0.17×PBS,0.05%20、6mM DTT)中组合激酶、配体亲和珠和测试化合物来组建结合反应。所有反应均在聚苯乙烯96孔板中进行,最终体积为0.135mL。将测定板在室温摇动温育1小时,并将亲和珠用洗涤缓冲液(1×PBS,0.05%20)洗涤。然后将珠子重新悬浮于洗脱缓冲液(1×PBS,0.05%20,0.5 11M非生物素化的亲和配体)中,并在室温摇动温育30分钟。通过qPCR测量洗脱液中的激酶浓度。
在持续16个月时间的超过135个独立实验中基于每个实验的14个对照孔,针对每种激酶计算了平均Z′值和标准差。平均Z′=0.71。
测试化合物的效力:
以指定的浓度筛选化合物,结合性相互作用的结果报道为[对照的%],其中较低的数字表示较强的结合,即较高的效力。
在下表6中给出与所测试的激酶有关的详细信息。
测试化合物被提供为10mM储备溶液。指定最终浓度的测试溶液是在DiscoverX制备的。结果在表7中给出。
表6
对MKK4的结合亲和力和相对于Braf、MKK7和JNK1的选择性
在100nM的浓度下,测定代表性实施例针对蛋白激酶MKK4、BRAf、MKK7和JNK1的效力,其表示为对照结合的残留百分比(PoC)。测定的效力分类如下:
代表性实施例针对蛋白激酶BRaf、MKK7和JNK1(总称为“脱靶”)的结合选择性由以下比率确定:PoC(脱靶)/PoC(MKK4)。该比率分类如下:
表7:代表性实施例对MKK4的结合亲和力和相对于BRaf、MKK7和JNK1的选择性,其基于结合亲和力,表示为对照的%。
实施例243-2:酶测定
使用由德国弗莱堡的ProQinase GmbH提供的33Assay Service(测定服务)来测量本发明化合物的激酶活性。测定条件的细节在ProQinase的网站(https://www.proqinase.com/products-services-biochemical-assay-services/kinase-assays)上公开。简而言之,所有激酶测定都是在PerkinElmer(美国马萨诸塞州波士顿)的96孔FlashPlatesTM中进行的,反应体积为50μl。反应混合物按照以下顺序分四个步骤来移液:
·20μl测定缓冲液(标准缓冲液)
·5μl ATP溶液(在H2O中)
·5μl测试化合物(在10%DMSO中)
·20μl酶/底物混合物
所有蛋白激酶的测定均包含70mM HEPES-NaOH pH7.5,3mM MgCl2,3mM MnCl2,3μM原钒酸钠(Na-orthovanadate),1.2mM DTT,50μg/ml PEG20000,ATP(浓度可变,对应于相应激酶的表观ATP-Km),[γ-33P]-ATP(每孔约8×1005cpm),蛋白激酶和底物。
将反应混合物在30℃温育60分钟。用50μl的2%(v/v)H3PO4终止反应,抽吸板并用200μl的0.9%(w/v)NaCl洗涤两次。用微孔板闪烁计数器(Microbeta,Wallac)测定33pi的掺入。
所有测定均使用BeckmanCoulter/SAGIANTM Core System(核心系统)进行。
在单浓度测定的情况下,测试化合物的效力被表示为%残留活性。为了确定IC50值,测试了最终浓度在100μM至3nM之间的系列稀释液(10个浓度)。用于IC50测定的拟合模型为“Sigmoidal响应(可变斜率)”,参数“顶”固定在100%,“底”固定在0%。使用的拟合方法是最小二乘拟合。
MKK4效力:
对MKK4的抑制效力分类如下:
单浓度(100nM)测定:
通过确定IC50值进行测定:
测试化合物相对于BRaf、JNK1和MKK7(总称为“脱靶”)的选择性通过IC50(脱靶)/IC50(MKK4)的比率计算,并分类如下:
表8:代表性实施例对MKK4的生化效力以及相对于BRaf、MKK7和JNK1的选择性,其基于单一浓度下对酶活性的抑制或IC50值。
Claims (18)
1.具有式(I)的化合物
其中
R1是H或烷基;
R2是H或烷基;
R4是H或烷基;
R6是H或烷基;
Rw为-NR10SO2R12;
R10为H、烷基或苯基烷基;
R12是H;烷基,其中所述烷基可选地被1或2个羟基取代或被乙酰基取代;卤代烷基;或苯基烷基,其中所述苯基可选地被1或2个独立地选自烷基和卤素的基团取代;
Rx、Ry、Rz和Rzz选自:
a)Rx和Ry为F,且Rz和Rzz为H;
b)Rx、Ry和Rzz独立地是卤素,且Rz为H;
c)Rx、Rz和Rzz独立地是卤素,且Ry为H;和
d)Rx、Ry和Rz独立地是卤素,且Rzz为H;
R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
卤素,
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
其中烷基被1、2或3个卤素原子取代的烷氧基,
卤代烷基,
羟基,
-SO2NR10R10,
-CO2R10,
-CN,
-SF5,
-(NR10=)S(=O)-烷基(S-烷基亚磺酰亚胺基),
1H-四唑基或2H-四唑基,
-SO2烷基,其中所述烷基可选地被1、2或3个卤素原子取代,
-SO烷基,
烷硫基,其中烷基可选地被-NR10R10或1、2或3个卤素原子取代,
-PO二(烷基),
-NO2,
-NR10R10,
R10R10N-CO-,
-NR10CO烷基,
羟烷基-ONH-CO-,
环烷基,
具有1、2或3个独立地选自O、N和S的杂原子的非芳族杂环5元或6元单环基团,所述基团可选地被1或2个独立地选自烷基和C2-C5烷酰基的基团取代,和
烷氧基,其中烷基被具有1、2或3个独立地选自O、N和S的杂原子的非芳族杂环5元或6元单环基团取代,所述单环基团可选地被1或2个独立地选自烷基和卤素的基团取代;
(b)萘基;
(c)具有1或2个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
羟基,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
-SO2NR10R10,
-SO2烷基,
-(NR10=)S(=O)-烷基,
环烷基-NR10-,
烷基-NR10-,其中所述烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,和
具有1或2个独立地选自O、N、S、SO和SO2的杂原子的非芳族杂环4元、5元或6元单环基团,所述杂环基团可选地被烷基、羟烷基或羟基取代;
(d)C2-C5炔烃基;
(e)C2-C5烯烃基;
(f)卤素;
(g)环烷基;
(h)苯基,其与具有1、2或3个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团稠合;
i)1,3-二烷基-1-氧代-1l4-苯并[e][1,2]噻嗪;
j)具有1、2或3个独立地选自O、N、S、SO和SO2的杂原子的饱和或不饱和非芳族杂环4元、5元或6元单环基团,所述杂环基团可选地被1或2个独立地选自烷基、C2-C5烷酰基、苯甲酰基、羟基、-CO2R10和羰基(环碳原子之一是>C=O基团)的基团取代;
k)氧杂环丁胺基;
以及其药学上可接受的盐、溶剂化物和光学异构体。
2.根据权利要求1所述的化合物,其中
R1是H或烷基;
R2是H或烷基;
R4是H或烷基;
R6是H或烷基;
Rw为-NR10SO2R12;
R10为H、烷基或苯基烷基;
R12为H、烷基、卤代烷基或苯基烷基,其中苯基可选地被1或2个独立地选自烷基和卤素的基团取代;
Rx、Ry、Rz和Rzz选自:
a)Rx和Ry为F,且Rz和Rzz为H;
b)Rx、Ry和Rzz独立地是卤素,且Rz为H;
c)Rx、Rz和Rzz独立地是卤素,且Ry是H;和
d)Rx、Ry和Rz独立地是卤素,且Rzz是H;
R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
卤素,
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
卤代烷基,
羟基,
-SO2NR10R10,
-CO2R10,
-CN,
-SF5,
-(NR10=)S(=O)-烷基(S-烷基亚磺酰亚胺基),和
1H-四唑基或2H-四唑基;
(b)萘基;
(c)具有1或2个独立地选自O、N和S的杂原子的杂芳族5元或6元单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
羟基,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
烷基-S(=O)(=NR10)-,
环烷基-NR10-,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,
和
具有1或2个独立地选自O和N的杂原子的非芳族杂环4元、5元或6元单环基团,所述杂环基团可选地被烷基、羟烷基或羟基取代,
(d)C2-C5炔烃基,
(e)C2-C5-烯烃基,
(f)卤素,和
(g)环烷基,
及其药学上可接受的盐、溶剂化物和光学异构体。
4.根据权利要求3所述的化合物,其中R5选自
(a)苯基,其被1、2或3个独立地选自以下的基团取代
卤素,
烷基,
烷氧基,
其中烷基被1、2或3个羟基取代的烷氧基,
羟基,
-SO2NR10R10,
-CO2R10,
CN,
-SF5,
烷基-S(=O)(=NR10)-(S-烷基亚磺酰亚胺基),和
1H-四唑基或2H-四唑基,
(b)萘基;
(c)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元或6元单环基团,其中所述杂芳族基团可选地被1、2或3个独立地选自以下的基团取代
烷基,
卤代烷基,
环烷基,
-NR10R10,
卤素,
羟基,
烷氧基,其可选地被-NR10R10取代,
-CN,
烯烃基,
炔烃基,
R10R10N-CO-,
烷基-S(=O)(=NR10)-,
环烷基-NR10-,
烷基-NR10-,其中烷基被羟基或烷氧基取代,
烷硫基,
苯并咪唑基,
和
具有1或2个独立地选自O和N的杂原子的非芳族杂环4元、5元或6元单环基团,所述杂环基团可选地被烷基、羟烷基或羟基取代,
(d)卤素;
(e)环烷基;
及其药学上可接受的盐、溶剂化物和光学异构体。
8.根据前述权利要求中任一项所述的化合物,其中R1、R2、R4和R6为H,
及其药学上可接受的盐、溶剂化物和光学异构体。
9.根据前述权利要求中任一项所述的化合物,其中,如果Rx、Ry、Rz和Rzz代表卤素,则所述卤素为F、Cl或Br,优选为F或Cl,特别是F,
及其药学上可接受的盐、溶剂化物和光学异构体。
11.一种化合物,其选自:
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氰基苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
N-(3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
N-(2-氟-3-(5-(4-氟-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
N-(3-(5-(7-氯-2,3-二氢苯并[b][1,4]二恶烯-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
N-(3-(5-(6-氯苯并[d][1,3]二氧杂环戊烯-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
N-(2-氟-3-(5-(吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
N-(2-氟-3-(5-(2-甲氧基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
N-(2-氟-3-(5-(吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
N-(5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
N-(3-溴-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺;
N-(3-氯-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-溴-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺;
N-(3-氯-5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-5-氟苯基)丙烷-1-磺酰胺;
N-(5-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)-1-苯基甲磺酰胺;
及其药学上可接受的盐、溶剂化物和光学异构体。
12.一种化合物,其选自:
N-(2,4-二溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-乙炔基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(叔丁氧基)-2-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-氯-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丁烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-吗啉基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-(4-甲基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]-吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(4-乙酰基哌嗪-1-基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-氯-4-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
4-(3-(2,6-二氟-3-((苯甲基)磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯磺酰胺;
N-(2,4-二氟-3-(5-(4-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
N-(3-(5-(4-((2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-氯-4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(3-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2,4-二氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(2-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-羟基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(2-氟-4-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(间甲苯基)甲磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(对甲苯基)甲磺酰胺;
N-(2,4-二氟-3-(5-(4-甲氧基-2-甲基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺;
N-(3-(5-(2-氯-4-(2,3-二羟基丙氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(4-氟苯基)甲磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(3-氟苯基)甲磺酰胺的合成;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟-苯基)-1-(2-氟苯基)甲磺酰胺;
N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-1-苯基甲磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氰基苯基)丙烷-1-磺酰胺;
N-(4-溴-3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2-氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-4-氰基-2-氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氰基苯基)丙烷-1-磺酰胺;
N-(3-(4-氯-5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-4-氰基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-6-甲氧基-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-3-羟基丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-羟基丙烷-1-磺酰胺;
N-(3-(5-(4-氯苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-2-氧丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(哌嗪-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-环丙基-嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,6-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-环丙基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,6-二氟苯基)甲磺酰胺;
N-(2,6-二氟-3-(5-(2-甲基嘧啶-5-基)-1H-吡咯并-[2,3-b]吡啶-3-羰基)-苯基)-3,3,3-三氟丙烷-1-磺酰胺;
N-(2,6-二氟-3-(5-(2-(三氟甲基)嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-3,3,3-三氟丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(6-吗啉基吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-3,3,3-三氟丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(6-硫代吗啉基吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-3,3,3-三氟丙烷-1-磺酰胺;
N-(3-(5-(6-(1,1-二氧硫代-吗啉基)吡啶-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-3,3,3-三氟丙烷-1-磺酰胺;
N-(3-(5-(4-环丁基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-丙烷-1-磺酰胺;
N-(3-(5-(1H-咪唑-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(1H-吡唑-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(1H-1,2,4-三唑-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)-丙烷-1-磺酰胺;
N-(3-(5-(1,3,4-噻二唑-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(2-(甲硫代)噻唑-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-环丁基-1H-吡咯并-[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(哌啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(5-氧代-4,5-二氢吡嗪-2-基)-1H-吡咯并-[2,3-b]吡啶-3-羰基)-苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(萘-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(1H-吡咯-3-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(氮杂环丁烷-3-基氨基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(哌啶-1-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(吡嗪-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(2-甲氧基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(2-甲氧基嘧啶-5-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)-1-苯基甲磺酰胺;
N-(2,4-二氟-3-(5-(1,2,3,4-四氢吡啶-4-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯磺酰胺;
N-(2,4-二氟-3-(5-(3-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(二甲基磷酰基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-N-(2-羟基乙氧基)-1H-吡咯并[2,3-b]吡啶-5-甲酰胺;
N-(2,4-二氟-3-(5-(3-羟基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(2-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(3-甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(2,4-二甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(3,4-二甲氧基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-硝基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯甲酸;
4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺;
N-(3-(5-(2-氰基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(4-(三氟甲氧基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(对甲苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(叔丁基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(间甲苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(3-氟苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(4-(3-(2,6-二氟-3-(丙基磺酰胺基)苯甲酰基)-1H-吡咯并[2,3-b]吡啶-5-基)苯基)乙酰胺;
N-(3-(5-(4-氨基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-(二甲基氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-氨基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(2,4-二氟-3-(5-(3-(三氟甲基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)苯基)丙烷-1-磺酰胺;
N-(3-(5-(4-((二甲基(氧代)-l6-亚硫烷基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(2-氰基苯基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(3-氯吡嗪-2-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
N-(3-(5-(1,3-二甲基-1-氧代-1l4-苯并[e][1,2]噻嗪-6-基)-1H-吡咯并[2,3-b]吡啶-3-羰基)-2,4-二氟苯基)丙烷-1-磺酰胺;
及其药学上可接受的盐、溶剂化物和光学异构体。
13.一种药物组合物,其包含如权利要求1至12中任一项所述的化合物。
14.根据权利要求1至12中任一项所述的化合物及其药学上可接受的盐、溶剂化物和光学异构体,用于相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4。
15.根据权利要求1至12中任一项所述的化合物及其药学上可接受的盐、溶剂化物和光学异构体,用于促进肝再生或预防肝细胞死亡。
16.根据权利要求1至12中任一项所述的化合物及其药学上可接受的盐、溶剂化物和光学异构体,用于治疗急性、慢加急性或慢性肝病。
17.根据权利要求1至12中任一项所述的化合物及其药学上可接受的盐、溶剂化物和光学异构体,用于治疗:
急性和慢性或慢加急性肝病,诸如急性和慢性病毒性肝炎如乙型、丙型、戊型肝炎,由爱泼斯坦-巴尔病毒、巨细胞病毒、单纯疱疹病毒和其他病毒引起的肝炎,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,诸如代谢综合征,脂肪肝如非酒精性脂肪肝(NAFL),非酒精性脂肪性肝炎(NASH),酒精性脂肪性肝炎(ASH),Morbus Wilson病,血色素沉着症,α1-抗胰蛋白酶缺乏症,糖原贮积病;
所有类型的肝硬化,诸如原发性胆汁性肝硬化,酒精中毒性肝硬化,隐源性肝硬化;
急性(暴发性)或慢性肝衰竭,诸如中毒性肝衰竭如对乙酰氨基酚(扑热息痛)引发的肝衰竭,α-鹅膏蕈碱引发的肝衰竭,药物诱发的例如由抗生素、非甾体抗炎药、抗惊厥药导致的肝毒性和肝衰竭,草药补充剂(卡瓦、麻黄、黄芩、薄荷等)诱发的急性肝衰竭,由于血管疾病如布加综合征导致的肝病和肝衰竭,起因不明的急性肝衰竭,由于右心衰竭导致的慢性肝病;
半乳糖血症,囊性纤维化,卟啉症,肝缺血灌注损伤,肝移植后小肝综合征,原发性硬化性胆管炎或肝性脑病。
18.一种相对于蛋白激酶JNK1和MKK7选择性抑制蛋白激酶MKK4的方法,促进肝再生或预防肝细胞死亡,治疗急性、慢加急性或慢性肝病,或用于治疗以下疾病的方法:
急性和慢性或慢加急性肝病,诸如急性和慢性病毒性肝炎如乙型、丙型、戊型肝炎,由爱泼斯坦-巴尔病毒、巨细胞病毒、单纯疱疹病毒和其他病毒引起的肝炎,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,诸如代谢综合征,脂肪肝如非酒精性脂肪肝(NAFL),非酒精性脂肪性肝炎(NASH),酒精性脂肪性肝炎(ASH),Morbus Wilson病,血色素沉着症,α1-抗胰蛋白酶缺乏症,糖原贮积病;
所有类型的肝硬化,诸如原发性胆汁性肝硬化,酒精中毒性肝硬化,隐源性肝硬化;
急性(暴发性)或慢性肝衰竭,诸如中毒性肝衰竭如对乙酰氨基酚(扑热息痛)引发的肝衰竭,α-鹅膏蕈碱引发的肝衰竭,药物诱发的例如由抗生素、非甾体抗炎药、抗惊厥药导致的肝毒性和肝衰竭,草药补充剂(卡瓦、麻黄、黄芩、薄荷等)诱发的急性肝功能衰竭,由于血管疾病如布加综合征导致的肝病和肝衰竭,起因不明的急性肝衰竭,由于右心衰竭导致的慢性肝病;
半乳糖血症,囊性纤维化,卟啉症,肝缺血灌注损伤,肝移植后小肝综合征,原发性硬化性胆管炎或肝性脑病,
其中所述方法包括将有效量的如权利要求1至13中任一项所定义的化合物或组合物给药至有此需要的受试对象。
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CA3104246A1 (en) | 2020-01-23 |
IL279641A (en) | 2021-03-01 |
CN112424201B (zh) | 2024-04-02 |
JP7365393B2 (ja) | 2023-10-19 |
EP3823968A1 (en) | 2021-05-26 |
MX2020014102A (es) | 2021-05-27 |
AU2019303986B2 (en) | 2024-02-22 |
KR20210035092A (ko) | 2021-03-31 |
IL279641B1 (en) | 2023-12-01 |
IL279641B2 (en) | 2024-04-01 |
AU2019303986A1 (en) | 2021-01-14 |
JP2021529815A (ja) | 2021-11-04 |
BR112020026003A2 (pt) | 2021-03-23 |
SG11202012732UA (en) | 2021-02-25 |
US11912701B2 (en) | 2024-02-27 |
US20220281864A1 (en) | 2022-09-08 |
WO2020016243A1 (en) | 2020-01-23 |
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