CN116655636A - 一类五元并六元杂环化合物及其作为蛋白激酶抑制剂的用途 - Google Patents
一类五元并六元杂环化合物及其作为蛋白激酶抑制剂的用途 Download PDFInfo
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
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- 229960004891 lapatinib Drugs 0.000 description 1
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- 229960001691 leucovorin Drugs 0.000 description 1
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- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
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- 102000006240 membrane receptors Human genes 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 201000005737 orchitis Diseases 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
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- 239000000312 peanut oil Substances 0.000 description 1
- 108010006260 pegylated granulocyte colony-stimulating factor Proteins 0.000 description 1
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- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 201000006292 polyarteritis nodosa Diseases 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 238000012284 sample analysis method Methods 0.000 description 1
- 108010011655 saratin Proteins 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000009131 signaling function Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000004759 spandex Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
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- 208000011580 syndromic disease Diseases 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229940061353 temodar Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- GZCRRIHWUXGPOV-UHFFFAOYSA-N terbium atom Chemical compound [Tb] GZCRRIHWUXGPOV-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
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- 229940100411 torisel Drugs 0.000 description 1
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- 125000004306 triazinyl group Chemical group 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229950001212 volociximab Drugs 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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- 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
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本发明提供了一类五元并六元杂环化合物的制备和应用,具体地,本发明提供了一类如下式I所示的化合物,其中,各基团的定义如说明书中所述。所述的化合物具有TYK2激酶抑制或调控活性,可以作为治疗TYK2相关病症的药物组合物。
Description
技术领域
本发明涉及小分子药物领域,具体地,本发明涉及一类TYK2激酶抑制剂及其制 备和用途。
背景技术
JAK激酶(Janus kinase)隶属于细胞内非受体酪氨酸激酶家族,介导由细胞因子引 起的JAK-STAT通路激活并将信号传导入细胞核,启动相关基因的转录表达。JAK激 酶家族包含JAK1激酶、JAK2激酶、JAK3激酶和TYK2激酶,它们通过形成同源二聚 体、异源二聚体或多聚体来发挥其信号传导功能。JAK激酶通过JAK-STAT信号通路 的激活实现对细胞增殖、分化、凋亡及免疫反应等重要事件的调控。其中TYK2激酶 对I型干扰素以及白介素IL-6、IL-10、IL-12、IL-13、IL-23等细胞因子的信号转导至关 重要。JAK激酶是由N端FERM结构域,SH2样结构域,所谓的假激酶结构域(JAK同 源性2,JH2)和具有催化活性的信号PTK结构域(JH1)等多结构域组成的蛋白。其 中,JH2结构域的功能和调节作用被广泛研究,JH2结构域非常类似于真核蛋白激酶, 但显示出与活性激酶不同的模式,包括缺乏催化天冬氨酸,在所有JAK激酶的JH2结 构域中均被天冬酰胺取代,从而将其归类为“假激酶”结构域。JH2结构域对JAK激酶功 能具有关键的调控功能,在未激活状态下,JH2结构域表现出对JH1激酶催化活性的抑 制作用;当细胞因子与其受体结合激活JAK-STAT信号通路时,JH2表现出对JH1催化 活性的促进效应。
此外JAK-STAT通路在许多癌症中都被持续性激活,这导致了在血液学和实体瘤中使用JAK抑制剂的多项试验的启动,包括多种激酶抑制剂联合使用的试验。
近年来,在炎症与自身免疫药物研发方面,靶向细胞因子的抗体或生物制剂不断涌现,且表现出了优异的临床表现。Tofacitinib是第一个开发用于治疗自身免疫性疾 病的JAK抑制剂,于2012年批准用于类风湿性关节炎的治疗,其表现出对JAK3、JAK1 的高度抑制以及较小程度的JAK2抑制。由于包括促红细胞生成素在内的造血生长因 子通过JAK2来传导信号,因此,在接受第一代泛JAK激酶抑制剂治疗的患者中,常见 到中性粒细胞减少和贫血等不良反应,尤其是在较高剂量的Tofatinib时,因此限制了 其在类风湿性关节炎及其他免疫疾病的临床试验剂量选择。因此,在开发新一代JAK 抑制剂的时候,人们更加关注JAK家族成员之间的特异性、高选择性。依据JAK家族 各成员在细胞因子相关通路中的生物学作用,选择性抑制某一成员可进一步提高治疗 安全窗,避免泛JAK激酶抑制剂所带来的不良反应。然而,由于JAK激酶JH1催化活性 区的高度保守性,使得开发高选择性的JAK1、JAK3或TYK2抑制剂是非常具有挑战的。 研究发现TYK2与多种炎症性疾病的发生如炎症性肠炎,银屑病,皮炎和类风湿关节 炎等密切相关,TYK2缺失突变可抑制IL-12和IL-23通路相关的自身免疫性疾病和炎症 的发生。因此高选择性地抑制TYK2激酶活性有望成为更安全、更有效的治疗手段。 综上所述,本领域尚缺乏新型的TYK2激酶抑制剂。
发明内容
本发明的目的是提供一类新型TYK2激酶抑制剂。本发明通过靶向TYK2假性激酶区JH2实现了针对于其他JAK成员更高的选择性,使得其作用疗效更加精准,极大地 改善了药物相关的副反应。
本发明的第一方面,提供了一类如下式I所示的化合物:
其中,
A环选自下组:苯环,具有1-3个选自N、S和O的杂原子的5-10元杂芳基,具有1-3 个选自N、S和O的杂原子的4-15元杂环基(包括单环、并环、螺环或桥环);所述苯环、 杂芳基、杂环基可被独立地选自下组的一个或多个取代基团取代:卤素、H、C1-C3烷 基、C1-C3烷氧基、卤代的C1-C3烷基、卤代的C1-C3烷氧基、氧代(=O)、硫代(=S)、-CN、 NHR6、NR6R7、酰胺基、SO2R8、SOR8;
B环选自下组:
R1选自下组:NHR5,R5为C1-C3的烷基,或氘代C1-C3的烷基;
R2选自下组:H,苯基,C3-C8环烷基,1-3个选自N、S和O的杂原子的3-10元杂环 基,1-3个选自N、S和O的杂原子的5-14元杂芳基;所述苯环、环烷基、杂芳基、杂环 基可被独立地选自下组的一个或多个取代基团取代:卤素,C1-C3烷基,C1-C3烷氧基, (CH2)nOH,卤代的C1-C3烷基,卤代的C1-C3烷氧基,氧代(=O),硫代(=S),-CN,NHR6, NR6R7,酰胺基,C3-C6的环烷基,氟代的C3-C6的环烷基,1-3个选自N、S和O的杂原 子的3-6元杂环基;
R6,R7各自独立地选自C1-C3的烷基,COR8,SO2R8;
R8选自C1-C3的烷基,C3-C6的环烷基,氟代的C3-C6的环烷基;
R3,R3’各自独立选自下组:H、C1-C3烷基、卤代的C1-C3烷基、环丙基、卤代的环 丙基、氘代C1-C3烷基;
n为0,1,2,3;
为基团的连接位点;
附加条件是,式I化合物为化学上稳定的结构。
在另一优选例中,所述的R1为NHCH3。
在另一优选例中,所述的化合物具有如下式II、式III、式IV所示的结构:
在另一优选例中,所述的式I化合物具有式II-a、III-a或式IV-a所示的结构:
在另一优选例中,所述的A环选自取代或未取代的选自下组的基团:苯环、吡啶环、其中,所述 取代的定义如本发明第一方面中所述。
在另一优选例中,所述的具有如下式所示的结构:
其中,R2选自下组:取代或未取代的C3-C8环烷基、取代或未取代的3- 8元杂环基、取代或未取代的5-6元杂芳基;所述取代的定义如本发明第一方面中所述。
在另一优选例中,所述的化合物具有选自下组的结构:
本发明的第二方面,提供了一种药物组合物,所述的药物组合物包含(1)如本发明第 一方面所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶 剂化物;(2)药学上可接受的载体。
在另一优选例中,所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒 剂。
在另一优选例中,所述的疾病选自下组:所述的疾病选自下组:自身免疫性疾病、炎性疾病、代谢性疾病、癌症、心血管疾病、骨髓增殖性疾病、病毒性疾病、代谢性疾病、 或器官移植。
本发明的第三方面,提供了一种如本发明第一方面所述的化合物或其立体异构体或 互变异构体,或其药学上可接受的盐、水合物或溶剂化物,或如本发明第二方面所述的药 物组合物的用途,其用于制备预防和/或治疗疾病或疾病状况的药物组合物。所述疾病状况包括但不限于TYK2激酶功能障碍有关的状况。
在另一优选例中,所述的疾病选自下组:自身免疫性疾病、炎性疾病、代谢性疾病、癌症、心血管疾病、骨髓增殖性疾病、病毒性疾病、代谢性疾病、或器官移植。所述自身 免疫性疾病或炎性疾病包括但不限于炎症性肠炎病、类风湿关节炎、骨关节炎、类风 湿性脊柱炎、痛风、哮喘、支气管炎、鼻炎、慢性阻塞性肺病、肺纤维化、囊性纤维 化病、桥本氏甲状腺炎、自身免疫性溶血性贫血、恶性贫血的自身免疫性萎缩性胃炎、 自身免疫性脑脊髓炎、自身免疫性睾丸炎、古德帕斯丘病、自身免疫性血小板减少症、 交感性眼炎、重症肌无力、格雷夫斯病、原发性胆汁性肝硬化、肝炎、原发性胆汁性 胆管炎(PBC)、慢性侵袭性肝炎、非酒精性脂肪肝病、非酒精性脂肪性肝炎、膜性 肾小球病、系统性红斑狼疮、牛皮鲜性关节炎、干燥综合征、莱特综合征、孟德尔疾 病、结节性多动脉炎、多发性硬化症、大疱性类天疱疮、炎症类皮肤疾病(包括但不 限于银屑病、特应性皮炎等)、基于0-细胞或T-细胞的自身免疫性疾病(包括但不限 于科根综合征、强直性脊柱炎、韦格纳肉芽肿病、自身免疫性脱发)、过敏反应、、 移植排斥等。所述肠炎病包括但不限于炎症性肠病(IBD)、克罗恩氏病、溃疡性结肠炎、炎性肠病、乳糜泻、嗜酸性粒细胞胃肠炎。所述的代谢性疾病包括(但并不限 于):2型糖尿病、1型糖尿病、糖尿病并发症(如糖尿病肾病、糖尿病视网膜病变、肝 纤维化、胰岛素抵抗、肥胖)。所述的骨髓增殖性疾病包括(但并不限于):自发性血小 板增多(ET)、特发性骨髓纤维化(IMF)、慢性髓性白血病(CML)、原发性骨髓纤维化、 慢性嗜中性粒细胞白血病(CNL)或真心红细胞增多症(PV)。所述的癌症疾病包括但不 限于TYK2及其信号通路异常引起的癌症的治疗,包括急性淋巴细胞白血病(ALL)、 (T细胞急性淋巴细胞白血病(T-ALL)、B细胞急性淋巴细胞白血病(B-ALL))、 急性髓细胞性白血病(AML)、非典型慢性粒细胞性白血病(CML)、骨髓增生性肿 瘤(MPN)、霍奇金淋巴瘤、肝癌、肺癌、卵槽癌、前列腺癌、乳腺癌、骨肉瘤、鳞 状宫颈癌、子宫癌、直肠癌、结肠癌、脑癌、膀胱癌、肾癌、胃癌、甲状腺癌、鼻咽癌和胰腺癌等。本发明中的化合物可单独使用,或者与化疗药物、靶向药物及免疫疗 法联合使用。
在另一优选例中,所述的药物组合物与第二治疗组分联合使用,且所述的第二治疗 组分包括(但并不限于):5-氟尿嘧啶、阿瓦斯丁TM(avastin,bevacizumab)、贝沙罗汀(bexarotene)、硼替佐米(bortezomib)、骨化三醇(calcitriol)、卡奈替尼(canertinib)、卡 培他滨(capecitabine)、碳铂(carboplatin)、塞来考昔(celecoxib)、西妥昔单抗(cetuximab)、顺铂(cisplatin)、达沙替尼(dasatinib)、地高辛(digoxin)、enzastaurin、埃罗替尼(Erlotinib)、依托泊甙(etoposide)、依维莫司(everolimus)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、2,2-二氟脱氧胞嘧啶核苷(gemcitabine)、金雀异黄素 (genistein)、伊马替尼(imatinib)、依立替康(irinotecan)、拉帕替尼(lapatinib)、来那度 胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、马妥珠单抗(matuzumab)、 奥沙利铂(oxaliplatin)、紫杉醇(paclitaxel)、帕尼单抗(panitumumab)、PEG化的粒细胞 集落刺激因子(pegfilgrastin)、PEG化的a-干扰素(peglated alfa-interferon)、培美曲塞 (pemetrexed)、E、沙铂(satraplatin)、西罗莫司(sirolimus)、舒尼替尼(sutent, sunitinib)、舒林酸(sulindac)、泰索帝(taxotere)、替莫唑胺(temodar、temozomolomide)、 驮瑞塞尔(Torisel)、替西罗莫司(temsirolimus)、替吡法尼(tipifarnib)、曲妥单抗 (trastuzumab)、丙戊酸(valproic acid)、长春氟宁(vinflunine)、Volociximab、Vorinostat、 索拉非尼(Sorafenib)、安贝生坦(ambrisentan)、CD40和/或CD154特异性抗体、融合 蛋白、NF-kB抑制剂、非甾体抗炎药、β-激动剂如沙美特罗等、凝血因子FXa抑制剂(如 利伐沙班等)、抗-TNF抗体、前列腺素药物或孟鲁司特(montelukast)。
本发明的第四方面,提供了一类TYK2抑制剂,所述抑制剂包含本发明第一方面所述 的化合物、或其立体异构体或互变异构体、或其药学上可接受的盐、水合物或溶剂化物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇 幅,在此不再一一累述。
具体实施方式
术语
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于5%。例如,表述“约100”包括95和105之间的全部值(例如,95.1、95.2、 95.3、95.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
定义
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子(优选地,可以具有1、2、3、4、5、6、7或8个)的直链或支链的烷基,例如 甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C6烯基指具有2-6个碳原子(优选地,可以具有2、3、4、5或6个)的直链或支链的烯基,例如乙烯基、烯丙 基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环, 例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环 或螺环形式,术语“C3-C12环烷基”具有类似的含义,指具有3-12个碳原子的环烷基(优选地,可以具有3、4、5、6、7、8、9、10、11、或12个)。
如本文所用,术语“C1-C8烷氧基”是指具有1-8个碳原子的直链或支链的烷氧基;例如,甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“具有1-3个选自N、S和O的杂原子的3-12元杂环基”或“3-12元杂环基”是指具有3-12个环原子(优选地,可以具有3、4、5、6、7、8、9、10、11、 或12个)的且其中1-3个原子为选自N、S和O的杂原子的饱和或部分饱和的环状基团。 其可以是单环,也可以是双环形式,例如桥环、并环或螺环形式。具体的实例可以为 氧杂环丁烷、氮杂环丁烷、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷 基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。如本文所用,术语“具有1-3个选自N、S和O的杂原子的5-14元杂芳基”指 具有5-14个原子(优选地,可以具有5、6、7、8、9、10、11、12、13或14个)的且其 中1-3个原子(优选地,可以具有1、2或3个)为选自N、S和O的杂原子的环状芳香基 团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、 吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑 基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
除非特别说明,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧 基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄 基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基 -羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自 F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双 键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、 非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互 变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
式I化合物
本发明提供了一类如下式I所示的化合物:
其中,
A环选自下组:苯环,具有1-3个选自N、S和O的杂原子的5-10元杂芳基,具有1-3 个选自N、S和O的杂原子的4-15元杂环基(包括单环、并环、螺环或桥环);所述苯环、 杂芳基、杂环基可被独立地选自下组的一个或多个取代基团取代:卤素、H、C1-C3烷 基、C1-C3烷氧基、卤代的C1-C3烷基、卤代的C1-C3烷氧基、氧代(=O)、硫代(=S)、-CN、 NHR6、NR6R7、酰胺基、SO2R8、SOR8;
B环选自下组:
R1选自下组:NHR5,R5为C1-C3的烷基,或氘代C1-C3的烷基;
R2选自下组:H,苯基,C3-C8环烷基,1-3个选自N、S和O的杂原子的3-10元杂环 基,1-3个选自N、S和O的杂原子的5-14元杂芳基;所述苯环、环烷基、杂芳基、杂环 基可被独立地选自下组的一个或多个取代基团取代:卤素,C1-C3烷基,C1-C3烷氧基, (CH2)nOH,卤代的C1-C3烷基,卤代的C1-C3烷氧基,氧代(=O),硫代(=S),-CN,NHR6, NR6R7,酰胺基,C3-C6的环烷基,氟代的C3-C6的环烷基,1-3个选自N、S和O的杂原 子的3-6元杂环基;
R6,R7各自独立地选自C1-C3的烷基,COR8,SO2R8;
R8选自C1-C3的烷基,C3-C6的环烷基,氟代的C3-C6的环烷基;
R3,R3’各自独立选自下组:H、C1-C3烷基、卤代的C1-C3烷基、环丙基、卤代的环 丙基、氘代C1-C3烷基;
n为0,1,2,3;
为基团的连接位点;
附加条件是,式I化合物为化学上稳定的结构。
在优选的实施方式下,本发明的化合物优选具有如实施例中所示的各个化合物的结 构。
式I化合物的制备
本发明的式I化合物可以通过以下方法制备:
药物组合物和施用方法
由于本发明化合物具有优异的TYK2激酶的抑制活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物 为主要活性成分的药物组合物可用于预防和/或治疗疾病,所述疾病状况包括但不限 于TYK2激酶功能障碍的状况。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至 于产生严重的副作用。通常,药物组合物含有1-2000毫克本发明化合物/剂,更佳地, 含有10-200毫克本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组 合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。 药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维 素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、 植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山 梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、 抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体 剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二 钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘 露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、 蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃 薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f) 吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸 附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二 醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣 和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或 化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实 例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形 成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶 剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁 二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和 芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜 味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙 烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含 水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
联合给药时,所述药物组合物还包括与一种或多种其他药学上可接受的化合物。该其他药学上可接受的化合物中的一种或多种可与本发明的化合物同时、分开或顺序 地给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60千克体重的人而言, 日给药剂量通常为1~2000毫克,优选20~500毫克。当然,具体剂量还应考虑给药途 径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常 规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计 算。
中间体A的合成:
6,8-二氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯和8-溴-6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯
向4-溴-6-氯哒嗪-3-胺(8.63克,41.7毫摩尔)的乙醇(100毫升)溶液中加入2-氯-3-羰基丙酸乙酯(10.0克,66.7毫摩尔),80度反应16小时。旋蒸除去溶剂后,加 入二氯甲烷和水。有机相分离后用水洗、饱和食盐水洗、无水硫酸钠干燥。过滤后旋 蒸浓缩,粗产品通过正相柱层析(乙酸乙酯:石油醚=1:5)纯化,得到6,8-二氯咪唑并 [1,2-b]哒嗪-3-羧酸乙酯和8-溴-6-氯咪唑并[1,2-b]哒嗪-3-羧酸乙酯的混合物(比例约 11:14),此混合物直接用于下一步反应。
MS(ESI):m/z=260.0[M+H]+;MS(ESI):m/z=304.0[M+H]+.
6-氯-8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸乙酯
上一步得到的混合中间体溶于1,4-二氧六环(5毫升)中,然后加入l-(4-甲氧苯基)- N-甲基甲胺(785毫克,5.20毫摩尔)和N,N-二异丙基乙胺(1.03克,8.00毫摩尔),90度反应3小时,减压旋蒸除去溶剂。残留物溶于乙酸乙酯(20毫升),有机相用水洗、 饱和食盐水洗、无水硫酸钠干燥。过滤后旋蒸浓缩,粗产品通过正相柱层析(乙酸乙 酯:石油醚=1:3)纯化,得到乙基6-氯-8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪 -3-羧酸乙酯(1.30克,收率87%),为浅黄色固体。
MS(ESI):m/z=375.1[M+H]+.
中间体B的合成:
6-氯-8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸
向6-氯-8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸乙酯(1.80克,4.81 毫摩尔)的甲醇(15毫升)和四氢呋喃(15毫升)溶液中加入氢氧化锂水溶液(2M, 15毫升,30毫摩尔)。室温反应2小时,旋蒸除去有机溶剂,残留物用1mol/L的稀盐 酸调节pH约等于3,生成的沉淀经过滤、减压干燥得到6-氯-8-((4-甲氧苄基)(甲基)氨基) 咪唑并[1,2-b]哒嗪-3-羧酸(1.35克,收率81%),为白色固体。
MS(ESI):m/z=347.1[M+H]+.
(R)-(3-羰基异噁唑烷-4-基)氨基甲酸叔丁酯
室温下向(R)-4-氨基异噁唑烷-3-酮(15.0克,147毫摩尔)和N,N-二异丙基乙胺(22.7克,147毫摩尔)的四氢呋喃(120毫升)和水(120毫升)的混合物中滴加入 二碳酸二叔丁酯(35.0克,162毫摩尔),混合物室温搅拌16个小时后用乙酸乙酯(150 毫升)萃取两次。有机相用水洗、饱和食盐水洗、无水硫酸钠干燥。过滤后旋蒸浓缩, 粗产品通过正相柱层析(甲醇:二氯甲烷=1:15)纯化,得到(R)-(3-羰基异噁唑烷-4- 基)氨基甲酸叔丁酯(13.0克,收率43.8%),为淡黄色浆状物。
MS(ESI):m/z=147.0[M-56+H]+.
(R)-(2-甲基-3-羰基异噁唑烷-4-基)氨基甲酸叔丁酯
在0度下,向(R)-(3-羰基异噁唑烷-4-基)氨基甲酸叔丁酯(6.50克,32.毫摩尔)的N,N-二甲基甲酰胺(50毫升)混合物中缓慢加入叔丁醇钾(3.79克,33.8毫摩尔), 反应30分钟。将碘甲烷(1.90毫升,30.5毫摩尔)的N,N-二甲基甲酰胺(10毫升)溶 液缓慢滴加到上述混合物中,并在0度反应1个小时,然后室温反应3小时。混合物用 乙酸乙酯(150毫升)萃取两次,合并有机相用水洗、饱和食盐水洗、无水硫酸钠干 燥。过滤后旋蒸浓缩,粗产品通过正相柱层析(甲醇:二氯甲烷=1:15)纯化,得到5.6 克粗产品,粗产品用二氯甲烷(10毫升)/石油醚(90毫升)打浆,得到(R)-(2-甲基 -3-羰基异噁唑烷-4-基)氨基甲酸叔丁酯(4.0克,收率57.6%),为白色固体。
MS(ESI):m/z=161.0[M-56+H]+.
(R)-4-氨基-2-甲基异噁唑烷-3-酮
向(R)-(2-甲基-3-羰基异噁唑烷-4-基)氨基甲酸叔丁酯(4.0克,18.5毫摩尔)的二 氯甲烷(5毫升)混合物中加入HCl的1,4-二氧六环溶液(4M,20毫升),在20度反应 3个小时,旋蒸浓缩,粗产品用二氯甲烷(20毫升)打浆,得到(R)-4-氨基-2-甲基异噁 唑烷-3-酮(3.2克,粗收率>100%),为白色固体。
MS(ESI):m/z=117.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.02(brs,3H),4.65-4.58(m,1H),4.47(t,J=8.4 Hz,1H),4.28-4.20(m,1H),3.12(s,3H).
(R)-6-氯-8-((4-甲氧苄基)(甲基)氨基)-N-(2-甲基-3-羰基异噁唑烷-4-基)咪唑并[1, 2-b]哒嗪-3-甲酰胺
向6-((2-甲氧苯基)氨基)-8-(甲基氨基)咪唑并[1,2-b]哒嗪-3-羧酸(1.0克,2.88毫 摩尔),2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(1.6克,4.32毫摩尔) 和N,N-二异丙基乙胺(1.43毫升,8.65毫摩尔)的N,N-二甲基甲酰胺(6毫升)溶液中 加入(R)-4-氨基-2-甲基异噁唑烷-3-酮盐酸盐(0.4克,2.88毫摩尔),室温搅拌2小时。 有固体析出,加入水(20毫升),析出的固体过滤干燥得到标题产品(1.1克,收率 85.7%),为白色固体。
MS(ESI):m/z=445.2[M+H]+.
中间体C的合成:
二苯甲基-D-丝氨酸甲酯
向化合物C-1(3.1克,20毫摩尔)的四氢呋喃(50毫升)和二甲基亚砜(12毫升) 溶液中加入溴化苄(10.2克,60毫摩尔)和碳酸氢钠(6.72克,80毫摩尔),混合物在 80度反应过夜,然后冷却至室温。向反应液中加入水(20毫升)和乙酸乙酯(50毫升), 分出有机相,用饱和食盐水洗涤(20毫升)两次,无水硫酸钠干燥,过滤并浓缩。残 余物用硅胶柱层析分离纯化(乙酸乙酯:石油醚=1:5),得标题化合物(4.73克,收 率79%),为黄色固体。
MS(ESI):m/z=300.2[M+H]+.
二苯甲基-D-丝氨酸
向化合物C-2(1.50克,5毫摩尔)的甲醇(10毫升)溶液中加入氢氧化钠溶液(5 毫升,5毫摩尔),室温反应2小时。反应混合物经旋蒸除去有机溶剂,加入1M的稀 盐酸溶液调节至pH=3,生成的沉淀经过滤、真空干燥得标题化合物(910毫克,收率 64%),黄色固体。
MS(ESI):m/z=286.1[M+H]+.
(R)-2-(二苯甲基氨基)-N-乙基-3-羟基丙酰胺
将化合物C-3(20克,70.1毫摩尔)溶于N,N-二甲基甲酰胺(200毫升)后加入N,N-二异丙基乙胺(24.3毫升,140毫摩尔)和乙胺(8.57克,105毫摩尔),然后缓慢分批 加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(40克,105毫摩尔),将 混合物20度下搅拌16小时,LC-MS检测反应完成。将反应物倒入水(800毫升)中, 用乙酸乙酯(300毫升)萃取两次。合并有机相用饱和食盐水(500毫升)洗涤,然后 用无水硫酸钠干燥,过滤浓缩得到粗品。粗品用快速硅胶柱(乙酸乙酯:石油醚=1: 2)纯化得到黄色油状产物(19.1克,收率87.2%)。
MS(ESI):m/z=313.1[M+H]+.
(R)-3-(二苯甲基氨基)-1-乙基吖丁啶-2-酮
将化合物C-4(12.3克,39.3毫摩尔)溶于N,N-二甲基甲酰胺(100毫升)后在冰 浴下冷却至0度,然后加入化合物1,1'-磺酰二(1H-咪唑)(11.7克,59.0毫摩尔)。将反 应液在氮气保护下0度搅拌1小时后,加入氢化钠(2.36克,59.0毫摩尔),继续搅拌1 小时,LCMS检测反应完成。将反应物缓慢倒入水(700毫升)中,用乙酸乙酯(300 毫升)萃取三次,合并有机相用饱和食盐水(500毫升)洗涤,然后用无水硫酸钠干 燥,过滤浓缩得到粗品。粗品用快速硅胶柱(乙酸乙酯:石油醚=1:2)纯化得到白 色固体产物(6.4克,收率55.3%)。
MS(ESI):m/z=295.1[M+H]+.
(R)-3-氨基-1-乙基吖丁啶-2-酮
将化合物C-5(14.4克,48.9毫摩尔)溶于甲醇(100毫升)后加入钯碳(1.5克,5wt%),脱氧后在20度将混合物于氢气(15psi)氛围下搅拌16小时,LCMS检测反应 完成.将反应液过滤,滤液浓缩得到黄色油状产物(5.71克,收率100%)。
1H NMR(400MHz,CDCl3)δ4.11(dd,J=2.1,5.0Hz,1H),3.49(t,J=5.3Hz,1H),3.22(dq,J=1.4,7.3Hz,2H),2.95(dd,J=2.2,5.6Hz,1H),1.77(br s,2H),1.11(t,J=7.3Hz,3H).
(R)-6-氯-N-(1-乙基-2-羰基吖丁啶-3-基)-8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2- b]哒嗪-3-甲酰胺
采用中间体B类似合成方法,得到标题化合物。
MS(ESI):m/z=443.2[M+H]+.
实施例1:(R)-N-(2-甲基-3-羰基异噁唑烷-4-基)-8-(甲基氨基)-6-((2-羰基-2H-[1, 2'-联吡啶]-3-基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
3-氨基-2H-[1,2'-联吡啶]-2-酮
在氮气保护下将3-氨基吡啶-2-酚(2.0克,18.18毫摩尔),2-溴吡啶(7.2克,45.45毫摩尔),N1,N2-二甲基乙烷-1,2-二胺(0.64克,7.27毫摩尔),碳酸钾(7.5克,54.54 毫摩尔)和碘化亚铜(0.69克,3.63毫摩尔)混合均匀后加入1,4-二氧六环(40毫升), 混合物在氮气保护下加热到110度,反应16小时。等反应液冷却到室温,加入水和乙 酸乙酯.分离的有机相用水洗、饱和食盐水洗、无水硫酸钠干燥。过滤后旋蒸浓缩,粗 产品通过正相柱层析(乙酸乙酯:石油醚=4:1)纯化,得到3-氨基-2H-[1,2'-联吡啶]- 2-酮(980毫克,产率28%),为棕色固体。
MS(ESI):m/z=188.4[M+H]+.
8-((4-甲氧苄基)(甲基)氨基)-6-((2-羰基-2H-[1,2'-联吡啶]-3-基)氨基)咪唑并[1,2- b]哒嗪-3-羧酸乙酯
在氩气保护下将6-氯-8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸乙酯 (1.5克,4.0毫摩尔),3-氨基-2H-[1,2'-联吡啶]-2-酮(899毫克,4.8毫摩尔),三(二亚苄基丙酮)二钯(360毫克,0.40毫摩尔),4,5-双二苯基膦-9,9-二甲基氧杂蒽(462 毫克,0.80毫摩尔),碘化亚铜(300毫克,1.60毫摩尔)和碳酸铯(2.6克,12毫摩尔) 混合均匀后加入无水的1,4-二氧六环(12毫升),反应混合物在氩气保护下100度封 管反应16小时。加入水和乙酸乙酯,有机相用水洗、饱和食盐水洗、无水硫酸钠干燥。 过滤后旋蒸浓缩,粗产品通过正相柱层析得到标题产物(2.21克,收率78.7%),为棕 色固体。
MS(ESI):m/z=526.2[M+H]+.
8-((4-甲氧苄基)(甲基)氨基)-6-((2-羰基-2H-[1,2'-联吡啶]-3-基)氨基)咪唑并[1,2- b]哒嗪-3-羧酸
向化合物1-4(2.2克,4.19毫摩尔)的甲醇(36毫升)和四氢呋喃(60毫升)溶液 中加入氢氧化锂(1.22克,29.3毫摩尔)和水(24毫升),室温反应4小时,用2mol/L 的稀盐酸调节pH约等于6。加入二氯甲烷(500毫升)萃取,有机相用水洗、饱和食盐 水洗、无水硫酸钠干燥。过滤后旋蒸浓缩得到标题化合物(1.94克,收率93%),为 黄色固体。
MS(ESI):m/z=498.2[M+H]+.
(R)-8-((4-甲氧苄基)(甲基)氨基)-N-(2-甲基-3-羰基异噁唑烷-4-基)-6-((2-羰基-2H- [1,2'-联吡啶]-3-基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
室温状态下向化合物1-5(150毫克,0.30毫摩尔)和(R)-4-氨基-2-甲基异恶唑烷-3-酮盐酸盐(57毫克,0.30毫摩尔)的N,N-二甲基甲酰胺(1毫升)溶液中加入N,N-二 异丙基乙胺(0.25毫升,1.51毫摩尔)和2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六 氟磷酸酯(172毫克,0.45毫摩尔)。反应液室温搅拌20分钟。反应液经Prep-HPLC分 离(乙腈/0.1%碳酸氢铵水溶液梯度冲洗)纯化,得到标题化合物(122毫克,收率68.2%), 为黄色固体。
MS(ESI):m/z=596.2[M+H]+.
(R)-N-(2-甲基-3-羰基异噁唑烷-4-基)-8-(甲基氨基)-6-((2-羰基-2H-[1,2'-联吡啶]- 3-基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
在0度下,向1-6(122毫克,0.20毫摩尔)的二氯甲烷(4毫升)溶液中加入三氟 乙酸(2毫升)。反应液0度搅拌20分钟后浓缩,用氨甲醇溶液碱化,浓缩残渣经Prep- HPLC分离(乙腈/0.1%碳酸氢铵水溶液梯度冲洗)得到标题化合物(60毫克,收率 61.6%),为白色固体。
MS(ESI):m/z=476.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.91(d,J=8.0Hz,1H),8.66–8.58(m,2H),8.07 –7.95(m,2H),7.92(s,1H),7.83(d,J=8.1Hz,1H),7.53-7.47(m,3H),6.40(s,1H),6.36 (t,J=7.2Hz,1H),5.18(dd,J=18.0,8.9Hz,1H),4.69(t,J=8.6Hz,1H),4.12-4.05(m, 1H),3.14(s,3H),2.86(d,J=4.8Hz,3H).
实施例2:(R)-N-(2-甲基-3-羰基异噁唑烷-4-基)-8-(甲基氨基)-6-((6-(2-羰基哌啶- 1-基)吡啶-2-基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
1-(6-硝基吡啶-2-基)哌啶-2-酮
在氩气保护下将2-1(506毫克,3.19毫摩尔),2-哌啶酮(411.3毫克,4.15毫摩尔),三(二亚苄基丙酮)二钯(292.0毫克,0.32毫摩尔),4,5-双二苯基膦-9,9-二甲基 氧杂蒽(369.0毫克,0.64毫摩尔)和碳酸钾(882.2毫克,6.38毫摩尔)混合均匀后加 入无水的1,4-二氧六环(8毫升)。反应混合物在氩气保护下100度封管反应2小时。 加入水和乙酸乙酯,有机相分离后用水洗、饱和食盐水洗、无水硫酸钠干燥。过滤后 旋蒸浓缩,粗产品通过正相柱层析(乙酸乙酯:石油醚=1:1),得标题产物(670毫克, 收率94.9%),为黄色固体。
MS(ESI):m/z=222.1[M+H]+.
1-(6-氨基吡啶-2-基)哌啶-2-酮
向化合物2-2(663毫克,2.99毫摩尔)的甲醇(15毫升)溶液中,加入钯碳(66 毫克,5wt%),在氢气保护下室温反应3小时。反应混合物过滤,滤液经旋蒸浓缩得 到产品(570毫克,收率99.4%),为棕色固体,直接用于下一步。
MS(ESI):m/z=192.1[M+H]+.
(R)-8-((4-甲氧苄基)(甲基)氨基)-N-(2-甲基-3-羰基异噁唑烷-4-基)-6-((6-(2-羰基哌 啶-1-基)吡啶-2-基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
在氩气保护下将中间体B(100毫克,0.22毫摩尔)和2-3(55.9毫克,0.29毫摩尔),甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯- 2-基)钯(II)(20.4毫克,0.022毫摩尔),2-(二叔丁基膦)-3,6-二甲氧基-2'-4'-6'三-1-丙基 -1,1'-双苯基(21.8毫克,0.045毫摩尔)和乙酸钾(44.1毫克,0.450毫摩尔)加入烧瓶 中,混合均匀后加入无水的1,4-二氧六环(1.5毫升)。反应混合物在氩气保护下100度 封管反应3小时,反应液冷却至室温后加入乙酸乙酯和水,有机相分离后用饱和食盐水洗涤(10毫升)两次,无水硫酸钠干燥,过滤并浓缩。残余物用硅胶柱层析分离纯 化(甲醇:二氯甲烷=1:15),得标题化合物(120毫克,收率89%),为黄色固体。
MS(ESI):m/z=600.2[M+H]+.
(R)-N-(2-甲基-3-羰基异噁唑烷-4-基)-8-(甲基氨基)-6-((6-(2-羰基哌啶-1-基)吡啶- 2-基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
向化合物2-4(120毫克,0.2毫摩尔)的二氯甲烷(2毫升)溶液中,加入三氟乙 酸(0.5毫升),室温反应1小时。反应混合物减压浓缩,残余物溶于N-甲基吡咯烷酮 (2毫升),用氨甲醇溶液(7摩尔)调节pH至8,然后用Prep-HPLC纯化(乙腈/0.08%碳 酸氢铵溶液梯度冲洗)得到目标化合物(79毫克,收率82.3%),为白色固体。
MS(ESI):m/z=480.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),9.15(d,J=8.2Hz,1H),7.92(s,1H), 7.66(t,J=8.0Hz,2H),7.27(d,J=7.9Hz,1H),7.18(d,J=8.0Hz,1H),6.67(s,1H), 5.13(dd,J=18.4,9.1Hz,1H),4.64(t,J=8.7Hz,1H),4.22-4.10(m,1H),3.88(t,J=5.7 Hz,2H),3.12(s,3H),2.88(d,J=4.8Hz,3H),2.47-2.41(m,2H),1.90-1.75(m,4H).
实施例3:N-((R)-1-乙基-2-氧代氮杂丁烷-3-基)-6-((1-((1r,4R)-4-甲 氧基环己基)-2-氧代-1,2-二氢吡啶-3-基)氨基)-8-(甲氨基)咪唑[1,2-b]哒嗪-3- 甲酰胺)
乙基8-((4-甲氧苄基)(甲基)氨基)-6-((1-((1r,4r)-4-甲氧基环己基)-2-羰基-1,2-二氢 吡啶-3-基)氨基)咪唑并[1,2-b]哒嗪-3-羧酸酯
在氩气保护下将6-氯-8-((4-甲氧基苄基)(甲基)氨基)咪唑[1,2-b]哒嗪-3-羧酸乙酯 (300毫克,0.80毫摩尔),3-氨基-1-((1r,4r)-4-甲氧基环己基)吡啶-2(1H)-酮一盐酸盐 (311毫克,1.20毫摩尔),三(二亚苄-BASE丙酮)二钯(0)(147毫克,0.16毫摩尔), 2-二环己基膦-2',4',6'-三异丙基联苯(76毫克,0.16毫摩尔),碳酸钠(255毫克,2.40 毫摩尔)混合均匀,加入二氧六环(5毫升)。反应液封管100度搅拌过夜。反应液加 水(100毫升)稀释,用乙酸乙酯萃取(100毫升)两次。有机相浓缩,残渣通过正相柱 层析(石油醚:乙酸乙酯=5:2)纯化,得到标题化合物(400毫克,收率89.2%)为 绿色液体。
MS(ESI):m/z=561.4[M+H]+.
8-((4-甲氧基苄基)(甲基)氨基)-6-((1-((1r,4r)-4-甲氧基环己基)-2-氧基-1,2-二氢吡 啶-3-基)氨基)咪唑[1,2-b]哒嗪-3-羧酸
采用中间体1-5类似合成方法,得到标题化合物。
MS(ESI):m/z=533.2[M+H]+.
N-((R)-1-乙基-2-氧代氮杂丁烷-3-基)-8-((4-甲氧基苄基)(甲基)氨基)-6-((1-((r, 4R)-4-甲氧基环己基)-2-氧代-1,2-二氢吡啶-3-基)氨基)咪唑[1,2-b]哒嗪-3-甲酰胺
采用中间体1-6类似合成方法,得到标题化合物。
MS(ESI):m/z=476.2[M+H]+.
N-((R)-1-乙基-2-氧代氮杂丁烷-3-基)-6-((1-((1r,4R)-4-甲氧基环己基)-2-氧代-1,2- 二氢吡啶-3-基)氨基)-8-(甲氨基)咪唑[1,2-b]哒嗪-3-甲酰胺)
MS(ESI):m/z=509.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.95(d,J=8.7Hz,1H),8.48(s,1H),7.90–7.85 (m,2H),7.48–7.41(m,1H),7.34(dd,J=7.0,1.5Hz,1H),6.38–6.30(m,2H),5.20– 5.12(m,1H),4.83–4.72(m,1H),3.59(t,J=5.3Hz,1H),3.28-3.26(m,1H),3.26(s,3H), 3.24-3.15(m,3H),2.85(d,J=4.9Hz,3H),2.18-2.08(m,2H),1.84-1.70(m,4H),1.36– 1.23(m,2H),1.07(t,J=7.3Hz,3H).
实施例4:(R)-N-(1-乙基-2-氧杂氮-3-基)-6-(3'-氟-2-氧-2H-[1,2'-联吡啶]-3-基)氨基)-8-(甲氨基)咪唑[1,2-b]哒嗪-3-甲酰胺
向2,3-二氟吡啶(780毫克,7.56毫摩尔)的N-甲基吡咯烷酮(15毫升)溶液中 加入3-氨基吡啶-2-酚(1.82克,9.83毫摩尔)和磷酸钾(4.02克,18.9毫摩尔)。反应 液加热至90度搅拌过夜。反应液加水(200毫升)稀释,用乙酸乙酯萃取(200毫升) 两次。合并有机相浓缩。残渣通过正相柱层析(二氯甲烷:甲醇=10:1)纯化,得到 标题化合(700毫克,收率32.9%),为黄色固体。
MS(ESI):m/z=206.1[M+H]+.
(R)-N-(1-乙基-2-羰基吖丁啶-3-基)-6-((3'-氟-2-羰基-2H-[1,2'-联吡啶]-3-基)氨基)- 8-((4-甲氧苄基)(甲基)氨基)咪唑并[1,2-b]哒嗪-3-甲酰胺
采用实施例1-6类似合成方法,得到标题化合物。
MS(ESI):m/z=612.4[M+H]+.
(R)-N-(1-乙基-2-氧杂氮-3-基)-6-(3'-氟-2-氧-2H-[1,2'-联吡啶]-3-基)氨基)-8-(甲氨 基)咪唑[1,2-b]哒嗪-3-甲酰胺
采用实施例2类似合成方法,得到标题化合物。
MS(ESI):m/z=492.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ8.99(d,J=8.7Hz,1H),8.68(s,1H),8.51(d,J=4.6Hz,1H),8.12(dd,J=7.4,1.5Hz,1H),8.09-8.03(m,1H),7.93(s,1H),7.77-7.70(m,1H),7.55-7.48(m,1H),7.37(dd,J=6.9,1.6Hz,1H),6.51(t,J=7.2Hz,1H),6.42(s, 1H),5.26–5.16(m,1H),3.63(t,J=5.3Hz,1H),3.36-3.33(m,1H),3.28-3.18(m,2H), 2.87(d,J=4.8Hz,3H),1.11(t,J=7.3Hz,3H).
采用上述类似方法,替换相应的起始原料,得到如下表中所示的化合物:
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生物测试例1 TYK2 JH2 domain结合亲和力测定
TYK2 JH2均相时间分辨荧光(HTRF)测定待测物与JH2结构域亲和力水平
实验材料包括0.5纳摩尔TYK2(His-TVMV-TYK2-JH2(575-869)),0.2纳摩尔terbium-anti-His抗体,荧光素标记的激酶示踪剂,以及由20毫摩尔Hepes PH7.5,10 毫摩尔MgCl2,0.015%Brij-35,2毫摩尔DTT和50微克/毫升BSA组成的试验缓冲液。 实验是在黑色平底的384孔板中进行的。用DMSO(Sigma,D8418)溶解化合物配成 10毫摩尔原液,然后将化合物3倍稀释11个浓度点。反应在室温下孵育90分钟,然后 用酶标仪测量荧光素受体(520纳米)和铽供体(495纳米)产生的HTRF信号,根据 无蛋白质对照反应产生的520/495比值计算出100%抑制,溶剂对照组计算出0%抑 制。生成的剂量-效应曲线,以确定抑制50%的HTRF信号的化合物浓度(IC50)。
生物测试例2 TYK2/JAK1活性抑制测试
HEK 293T/ISRE细胞中荧光素酶报告基因表达的测定
通过荧光素酶检测(luciferase)方法评估本发明的化合物对TYK2/JAK1活性抑制情况。实验原理:HEK 293T/ISRE/luc细胞系包含稳定整合的荧光素酶报告基因,该 报告基因受干扰素刺激反应元件(ISRE)的控制。IFNa可激活TYK2/JAK1信号通路,活 化的转录因子STAT1/STAT2二聚体可以结合干扰素刺激反应元件(ISRE),启动荧光素 酶报告基因的表达。
实验方法:
化合物配制:用DMSO(Sigma,D8418)500倍溶解稀释10毫摩尔化合物原液配 成200x(20微摩尔),然后将最高浓度点20微摩尔用DMSO 3倍稀释10个浓度点至 最低浓度1.02纳摩尔,每个浓度点再用细胞培养基DMEM(Gibco,11965092) +10%FBS(Gibco,10099141)+1%PS(Gibco,15140122)1:33.3稀释成6x。
293T/ISRE细胞在细胞培养基中培养,当细胞在细胞培养瓶中覆盖率到80%-90%密度时,将细胞吹散种植于384孔板(PerkinElmer,6007660),每孔40000个细胞, 20微升,加入5微升稀释的6x化合物,对照孔加5微升同样浓度的DMSO,然后将384 孔板置于37℃、5%CO2的培养箱中培养半小时。用培养基稀释IFNa(106单位/毫 升)(pbl assay science,11100-1)333倍,配制6xIFNa(3000单位/毫升)溶液。除 阴性对照孔外,每孔加5微升6xIFNa,阴性对照孔加5微升培养基,37℃、5%CO2的 培养箱中孵育。6小时后,将One-Glo(Promega,E6120)试剂和细胞培养板平衡到 室温,每孔加25微升One-Glo试剂,室温孵育5分钟,用酶标仪检测荧光素酶报告基 因的表达。
化合物对HEK 293T细胞中IFNa诱导的荧光素酶报告基因表达抑制率计算公式:抑制率=【(信号值刺激对照-信号值化合物)/(信号值刺激对照-信号值无刺激对照)】*100,Z因子 =1-3*【(标准差刺激对照+标准差无刺激对照)/(平均值刺激对照-平均值无刺激对照)】。将浓度转换 成对数(浓度),化合物IC50值由每个浓度点的抑制率和对数(浓度)用GraphPad Prism 软件计算得出,具体见表1(第一栏)。
生物测试例3 TYK2/JAK2活性抑制测试
HEK Blue IL-23细胞中IL-23诱导分泌的胚胎碱性磷酸酶(SEAP)报告基因量抑制的测定
通过检测SEAP报告基因的量评估本发明的化合物对TYK2/JAK2活性抑制情况。 实验原理:白细胞介素23(IL-23)是IL-12家族成员之一,由IL-12p40和IL-23p19亚 基组成的异二聚体细胞因子,通过与HEK-Blue IL-23细胞表面的IL-12受体β1(IL- 12Rβ1)和IL-23受体(IL-23R)组成的受体复合体结合,触发信号级联,导致STAT3的 激活和随后的SEAP的产生。最后可使用QUANTI-BlueTM溶液(一种SEAP检测试剂)进 行定量评估。
实验方法:
准备细胞培养基DMEM(Gibco,11965092)+10%FBS(Gibco,10099141)+1%PS(Gibco,15140122)和实验培养基DMEM(Gibco,11965092)+10%灭活的FBS(56 摄氏度,30分钟灭活)(Gibco,10099141)+1%PS(Gibco,15140122)。
用DMSO(Sigma,D8418)10倍溶解稀释10毫摩尔化合物原液配成1000x(1毫 摩尔),然后将最高浓度点(1毫摩尔)用DMSO3倍稀释10个浓度点至最低浓度17纳 摩尔,每个浓度点再用实验培养基1:90.9稀释成11x。
HEK Blue IL-23(InvivoGen,HKB-IL23)细胞在细胞培养基中培养,当细胞在75cm2细胞培养瓶中覆盖率到80%-90%密度时,用37摄氏度预温的磷酸盐缓冲盐(PBS)(Biological industries,02-023-1ACS)轻轻冲洗细胞两次,然后加入0.02%EDTA消 化细胞,用新鲜的、预热的试验培养基重悬细胞,将细胞吹散种植于384孔板 (PerkinElmer,6007480),每孔12500个细胞,45微升,加入5微升稀释的11x化合物, 对照孔加5微升同样浓度的DMSO,然后将384孔板置于37摄氏度、5%CO2的培养箱中 培养半小时。用实验培养基稀释IL-23(1微克/毫升)(R&D,1290IL)227倍,配制 11xIL-23(4.4纳克/毫升)溶液。除阴性对照孔外,每孔加5微升11xIL-23,阴性对照 孔加5微升实验培养基,37摄氏度、5%CO2的培养箱中孵育。21小时后,配制QUANTI- Blue溶液(InvivoGen,rep-qbs):加1毫升QB试剂和1毫升QB缓冲液到98毫升无菌水中, 涡旋均匀,室温孵育10分钟后使用。每孔加45微升QUANTI-Blue溶液和5微升细胞上 清液到白色透底的384孔平板(PerkinElmer,6007480)中,37摄氏度孵育半小时,用 酶标仪在650纳米处测定SEAP表达水平。
化合物对HEK Blue IL-23细胞中IL-23诱导的SEAP报告基因表达抑制率计算公式: 抑制率=【(信号值刺激对照-信号值化合物)/(信号值刺激对照-信号值无刺激对照)】*100,Z因子 =1-3*【(标准差刺激对照+标准差无刺激对照)/(平均值刺激对照-平均值无刺激对照)】。将浓度转换 成对数(浓度),化合物IC50值由每个浓度点的抑制率和对数(浓度)用GraphPad Prism 软件计算得出。
生物测试例4 JAK2活性抑制测试
红细胞生成素(EPO)诱导TF-1细胞测定P-STAT5的含量
通过检测P-STAT5的含量评估本发明的化合物对JAK2活性抑制情况。实验原理:EPO通过与TF-1细胞的同型二聚体细胞表面受体结合,激活JAK2/STAT5通路。
实验方法:
准备细胞培养基RPMI1640(Gibco,22400089)+10%FBS(Gibco,10099141) +1%PS(Gibco,15140122)+2纳克/毫升human GM-CSF(粒细胞-巨噬细胞集落刺激 因子)(Peprotech,300035)和实验培养基RPMI1640(Gibco,22400089)+0.5%FBS (Gibco,10099141)。
用DMSO(Sigma,D8418)10倍溶解稀释10毫摩尔化合物原液配成200x(2毫摩尔),然后将最高浓度点2毫摩尔用DMSO4倍稀释8个浓度点至最低浓度122纳摩尔,每个浓 度点再用实验培养基1:50稀释成4x。
TF-1细胞在细胞培养基中培养,测定细胞密度和细胞活力,确保细胞活力大于90%,且细胞密度足够使用,用新鲜的、预热的实验培养基将细胞吹散种植于圆底96 孔板(Corning,3799),每孔100000个细胞,100微升实验培养基中饥饿过夜。第二 天加入50微升稀释的4x化合物,对照孔加50微升同样浓度的DMSO,然后将96孔板置 于37摄氏度、5%CO2的培养箱中培养半小时。用实验培养基稀释EPO(500单位/毫升) (R&D,287-TC-500)250倍,配制4xEPO(2单位/毫升)溶液。除阴性对照孔外,每 孔加50微升4x EPO,阴性对照孔加50微升实验培养基,37摄氏度、5%CO2的培养箱中 孵育。配制1x细胞裂解溶液:裂解缓冲液(CST,9803)+蛋白酶抑制剂(SIGMA, 4693124001)+磷酸酶抑制剂(SIGMA,P5726)+双蒸水。半小时后,2000转/分钟, 4摄氏度,5分钟离心,弃去培养基,用预冷的磷酸盐缓冲盐(PBS)(Biologicalindustries, 02-023-1ACS)清洗一次,2000转/分钟,4摄氏度,5分钟离心,弃去PBS,每孔加120 微升1x细胞裂解溶液到ELISA96孔板中,冰上孵育20分钟,根据ELISA试剂盒(Abcam, ab176656)的说明书进行酶联免疫吸附测定。
化合物对TF-1细胞中P-STAT5表达抑制率计算公式:抑制率=【(信号值刺激对照-信号值化合物)/(信号值刺激对照-信号值无刺激对照)】*100,Z因子=1-3*【(标准差刺激对照+标准 差无刺激对照)/(平均值刺激对照-平均值无刺激对照)】。将浓度转换成对数(浓度),化合物IC50 值由每个浓度点的抑制率和对数(浓度)用GraphPad Prism软件计算得出。
生物测试例5:本发明中小分子抑制剂小鼠药代动力学实验
分别单次静脉(IV)和口服(PO)给予ICR小鼠测试化合物,于不同时间点采集血样,LC-MS/MS测定小鼠血浆中受试物的浓度并计算相关参数。具体如下:取所需 量供试品,溶于5%DMSO+10%Solutol+85%注射用水中,配成所需浓度的溶液,用 于静脉或口服。给药实验开始时动物年龄约6-8周。静脉采血时间:给药后0.083小 时,0.25小时,0.5小时,1小时,2小时,4小时,8小时和24小时。口服采血时间: 给药后0.25小时,0.5小时,1小时,2小时,4小时,6小时,8小时和24小时。建立生 物样品分析方法及样品检测方法。过不同时间点的血药浓度数据,运用Phoenix WinNonlin 7.0软件计算药代动力学参数,如AUC(0-t),AUC(0-∞),T1/2,Cmax, Tmax和MRT等。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域 技术人员可以对本发明做各种改动或修改,这些等价形式同样落于本申请所附权利 要求书所限定的范围。
Claims (10)
1.一类如下式I所示的化合物:
其中,
A环选自下组:苯环,具有1-3个选自N、S和O的杂原子的5-10元杂芳基,具有1-3个选自N、S和O的杂原子的4-15元杂环基(包括单环、并环、螺环或桥环);所述苯环、杂芳基、杂环基可被独立地选自下组的一个或多个取代基团取代:卤素、H、C1-C3烷基、C1-C3烷氧基、卤代的C1-C3烷基、卤代的C1-C3烷氧基、氧代(=O)、硫代(=S)、-CN、NHR6、NR6R7、酰胺基、SO2R8、SOR8;
B环选自下组:
R1选自下组:NHR5,R5为C1-C3的烷基,或氘代C1-C3的烷基;
R2选自下组:H,苯基,C3-C8环烷基,具有1-3个选自N、S和O的杂原子的3-10元杂环基,具有1-3个选自N、S和O的杂原子的5-14元杂芳基;所述苯环、环烷基、杂芳基、杂环基可被独立地选自下组的一个或多个取代基团取代:卤素,C1-C3烷基,C1-C3烷氧基,(CH2)nOH,卤代的C1-C3烷基,卤代的C1-C3烷氧基,氧代(=O),硫代(=S),-CN,NHR6,NR6R7,酰胺基,C3-C6的环烷基,氟代的C3-C6的环烷基,具有1-3个选自N、S和O的杂原子的3-6元杂环基;
R6,R7各自独立地选自C1-C3的烷基,COR8,SO2R8;
R8选自C1-C3的烷基,C3-C6的环烷基,氟代的C3-C6的环烷基;
R3,R3’各自独立选自下组:H、C1-C3烷基、卤代的C1-C3烷基、环丙基、卤代的环丙基、氘代C1-C3烷基;
n为0,1,2,3;
为基团的连接位点;
附加条件是,式I化合物为化学上稳定的结构。
2.如权利要求1所述的化合物,其特征在于,所述的R1为NHCH3。
3.如权利要求1所述的化合物,其特征在于,所述的化合物具有如下式II、式III、式IV所示的结构:
4.如权利要求1所述的化合物,其特征在于,所述的式I化合物具有式II-a、III-a或式IV-a所示的结构:
5.如权利要求1所述的化合物,其特征在于,所述的A环选自取代或未取代的下组基团:苯环、吡啶环、其中,所述取代的定义如权利要求1中所述。
6.如权利要求1所述的化合物,其特征在于,所述的具有如下式所示的结构:
其中,R2选自下组:取代或未取代的C3-C8环烷基、取代或未取代的3-8元杂环基、取代或未取代的5-6元杂芳基;所述取代的定义如权利要求1中所述。
7.如权利要求1所述的化合物,其特征在于,所述的化合物具有选自下组的结构:
8.一种药物组合物,其特征在于,包含(1)如权利要求1所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物;(2)药学上可接受的载体。
9.如权利要求1所述的化合物或其立体异构体或互变异构体,或其药学上可接受的盐、水合物或溶剂化物,或如权利要求8所述的药物组合物的用途,其特征在于,用于制备预防和/或治疗疾病的药物组合物,疾病状况包括但不限于TYK2激酶功能障碍有关的状况。
10.如权利要求9所述的用途,其特征在于,所述的疾病选自下组:所述的疾病选自下组:自身免疫性疾病、炎性疾病、代谢性疾病、癌症、心血管疾病、骨髓增殖性疾病、病毒性疾病、或器官移植;较佳地,
所述自身免疫性疾病或炎性疾病包括但不限于炎症性肠病(IBD)、类风湿关节炎、骨关节炎、类风湿性脊柱炎、痛风、哮喘、支气管炎、鼻炎、慢性阻塞性肺病、肺纤维化、囊性纤维化病、肝炎、非酒精性脂肪肝病、非酒精性脂肪性肝炎、炎症类皮肤疾病(包括但不限于银屑病、特应性皮炎等)、过敏反应、原发性胆汁性胆管炎(PBC)、移植排斥等;
所述的代谢性疾病包括(但并不限于):2型糖尿病、1型糖尿病、糖尿病并发症(如糖尿病肾病、糖尿病视网膜病变、肝纤维化、胰岛素抵抗、肥胖);
所述的骨髓增殖性疾病包括(但并不限于):自发性血小板增多(ET)、特发性骨髓纤维化(IMF)、慢性髓性白血病(CML)、原发性骨髓纤维化、慢性嗜中性粒细胞白血病(CNL)或真心红细胞增多症(PV);
所述的癌症疾病包括但不限于TYK2及其信号通路异常引起的癌症的治疗,包括急性淋巴细胞白血病(ALL)、(T细胞急性淋巴细胞白血病(T-ALL)、B细胞急性淋巴细胞白血病(B-ALL))、急性髓细胞性白血病(AML)、非典型慢性粒细胞性白血病(CML)、骨髓增生性肿瘤(MPN)、霍奇金淋巴瘤、肝癌、肺癌、卵槽癌、前列腺癌、乳腺癌、骨肉瘤、鳞状宫颈癌、子宫癌、直肠癌、结肠癌、脑癌、膀胱癌、肾癌、胃癌、甲状腺癌、鼻咽癌和胰腺癌等;
较佳地,本发明中的化合物可单独使用,或者与化疗药物、靶向药物及免疫疗法联合使用。
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