CN102245610B - 吡咯并三嗪激酶抑制剂 - Google Patents
吡咯并三嗪激酶抑制剂 Download PDFInfo
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- CN102245610B CN102245610B CN200980149134.7A CN200980149134A CN102245610B CN 102245610 B CN102245610 B CN 102245610B CN 200980149134 A CN200980149134 A CN 200980149134A CN 102245610 B CN102245610 B CN 102245610B
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- Prior art keywords
- pyrrolo
- triazine
- piperazine
- pyrazole
- isophthalic acid
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000006459 vascular development Effects 0.000 description 1
- 239000002525 vasculotropin inhibitor Substances 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 229940099039 velcade Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Abstract
本发明提供式I的化合物及其药用盐。所述式I的化合物抑制诸如Jak2和CK2的酪氨酸激酶活性,由此使它们可用作用于治疗癌症和其它疾病的抗增殖药物。
Description
相关申请
本申请要求2008年10月8日提交的美国临时申请60/103,620的优先权,将其公开的全部内容并入本申请作为参考。
技术领域
本发明涉及可用作抗癌药物/抗增殖药物的新颖化合物。本发明还涉及使用所述化合物治疗增殖性疾病(诸如癌症)的方法及含有所述化合物的药物组合物。
背景技术
蛋白激酶在针对一些细胞功能的信号转导中发挥关键作用,所述细胞功能包括细胞增殖、致癌作用、细胞凋亡及细胞分化。这些酶的抑制剂可用于治疗或预防依赖于这些酶的增殖性疾病。流行病学证据有力地表明,导致组成性有丝分裂信号传导的受体蛋白质酪氨酸激酶的过表达或活化在数量持续增加的人类恶性肿瘤中是重要的因素。参与这些过程的蛋白激酶包括Abl、CDK’s、EGF、EMT、FGF、FAK、Flk-1/KDR、Flt-3、GSK-3、GSKβ-3、HER-2、IGF-1R、IR、Jak2、LCK、MET、PDGF、Src、Tie-2、TrkA、TrkB、SRC、CK2和VEGF。因此,一直需要研究出可用于调节或抑制酪氨酸激酶的新颖化合物。蛋白激酶抑制剂可用于治疗以酪氨酸激酶活性过表达或上调为特征的疾病,所述疾病为例如癌症、糖尿病、再狭窄、动脉硬化、牛皮癣、血管形成性疾病及免疫性疾病(Powis,G.;Workman P.Signaling Targets For TheDevelopment of Cancer Drugs.Anti-Cancer Drug Design(1994),9:263-277;Merenmies,J.;Parada,L.F.;Henkemeyer,M.Receptor Tyrosine Kinase Signalingin Vascular Development.Cell Growth Differ(1997)8:3-10;Shawver,L.K.;Lipsosn,K.E.;Fong,T.A.T.;McMahon,G.;Plowman,G.D.;Strawn,L.M.Receptor Tyrosine Kinases As Targets For Inhibition of Angiogenesis.DrugDiscovery Today(1997)2:50-63;将所有这些文献并入本申请作为参考)。
受体酪氨酸激酶(RTK)在生物化学信号传递经过细胞质膜中是重要的。这些跨膜分子特有地由细胞外配体结合域和细胞内酪氨酸激酶域构成,这二者通过质膜中的片段来连接。通常,RTK通过由配体引起的低聚化和特异性细胞内底物(例如PLCγ、PI3激酶、ras和raf/MEK/Erk1)的酪氨酸自磷酸化来活化。就通过该类受体进行的信号转导而言,酪氨酸激酶活性是必不可少的。
Janus激酶(Jak)通过整合由细胞因子受体介导的信号转导来调节多种细胞类型的增殖、存活和分化。Jak家族的酪氨酸激酶包括四个家族成员即Tyk2、Jak1、Jak2和Jak3。该激酶家族共有一些结构特征,包括一些Jak同源(JH)结构域。羧基端JH1结构域含有与伪激酶(pseudokinase)JH2结构域相邻的活性激酶结构域。这些结构域的氨基端为JH3-4和JH5-7,其分别编码与SH2和FERM结构域类似的结构域。SH2样结构域在Jak家族成员中就功能而言没有充分表征,而包含JH5-7的FERM结构域已被证实介导与细胞因子受体的结合。细胞因子受体缺乏内在激酶活性,当结合配体时,Jak家族成员被募集至这些受体且被活化以使受体复合物和下游信号传导分子上的酪氨酸残基发生磷酸化。细胞因子受体信号传导的关键下游介质为信号转导和转录活化(STAT)蛋白。存在7种哺乳动物STAT蛋白(STAT1、2、3、4、5a、5b、6和7),其整合在细胞因子受体活化下游的信号传导。当募集至细胞因子受体-Jak复合物时,STAT通过Jak激酶而在羧基端进行酪氨酸磷酸化。该磷酸化通过磷酸化酪氨酸和SH2结构域的相互作用而导致STAT同或异二聚体的形成。通过二聚化而活化后,STAT蛋白易位至细胞核,其中它们与启动子中的响应元件结合以活化参与增殖和分化的关键基因的转录。除调节STAT外,也已报道Jak的活化作用还调节其它关键的生长/存活途径(包括由IRS-1、Ras-MAPK、PI3K和Src激酶介导的那些途径)。
已在多种疾病中报道了Jak信号转导的变化。就白血病(leukemia)而言,已在非典型性慢性髓细胞性白血病中观察到产生组成性活性Jak激酶的染色体重排(Tel-Jak2)。已在急性成巨核细胞性白血病中观察到Jak3的活化点突变及已在急性骨髓性白血病和骨髓增殖性障碍(诸如红细胞增多症、特发性血小板增多症和髓样化生)中观察到Jak2的活化点突变。最近证实Jak2突变(Jak2V617F)是多种骨髓增殖性疾病(例如红细胞增多症、特发性血小板减少症和骨髓纤维化)的原因。Jak激酶在实体瘤中的作用也被大量有关很多种癌症中具有组成性STAT3活化的报道所支持。已在乳腺、前列腺、头/颈和黑素瘤肿瘤样品和细胞系中观察到增加性或组成性STAT3活性,其中药理学或遗传学证据表明在所观察的STAT3活化中涉及Jak活性。另外,Jak信号传导通过活化其它关键信号传导途径(诸如PI3K、Src、Bcl2和Ras-MAPK)而参与恶性转化。Jak信号传导与这些关键途径的联系潜在地使该激酶家族参与很多种恶性肿瘤。
原肌球蛋白相关激酶(Trk)为包括三个家族成员即TrkA、TrkB和TrkC的受体酪氨酸激酶家族。Trk以高亲合力与神经营养蛋白家族中的配体结合并介导后者所引起的信号转导,所述配体的原型成员为神经生长因子(NGF)、脑源性神经营养因子(BDNF)及神经营养蛋白-3、神经营养蛋白-4和神经营养蛋白-5(NT-3、NT-4和NT-5)。另外,已鉴定了缺乏酶活性的共受体即p75,其以低亲合力与所有神经营养蛋白(NT)结合并调节神经营养蛋白信号传导。Trk及其配体在中枢和外周神经系统发育期间的关键作用已通过在小鼠中进行的基因破坏研究来确认。具体地,证实了TrkA-NGF相互作用就介导疼痛信号传导中涉及的某些外周神经元群落的存活而言是必需的。除Trk信号传导在发育中的这些重要作用外,该受体及其信号传导途径在某些恶性肿瘤中遭到破坏也是有案可查的。应该特别注意以下报道即NGF和TrkA受体激酶的异常表达参与人前列腺癌和胰管肾上腺癌(pancreatic ductaladrenocarcinoma)的发展和进展、参与急性骨髓性白血病(AML)、甲状腺癌和乳腺癌中Trk染色体重排的活化及参与结肠肿瘤中预示组成性活化的受体点突变。除这些活化机制外,还在包括多发性骨髓瘤、黑素瘤、神经母细胞瘤、卵巢癌和胰腺癌的多种肿瘤类型中报道了Trk受体和配体的增加。已证实神经营养蛋白及其相应的Trk受体亚型对恶性细胞施加多种多效应答,包括提高肿瘤侵入性和趋化性、活化凋亡、刺激克隆生长和改变细胞形态。已在前列腺癌、乳腺癌、甲状腺癌、结肠癌、恶性黑素瘤、肺癌、胶质母细胞瘤、胰腺类癌(pancreatic carcinoid)及很多种儿科和神经外胚层源性肿瘤(包括维尔姆斯肿瘤(Wilm’s tumor)、神经母细胞瘤和成神经管细胞瘤)中观察到这些作用。神经营养蛋白及其受体亚型通过涉及癌细胞及周围实质和基质组织的自分泌或旁分泌机制而与这些癌症相关。另外,最近已通过使用抗NGF抗体而极度或显著地减轻了由前列腺癌转移引起的骨疼痛。总的说来,Trk信号传导在多种肿瘤类型中的致癌性使对Trk受体信号传导的调节成为在不同恶性肿瘤中具有潜在吸引力的治疗介入点。
Trk家族的RTK经常表达在肺癌、乳腺癌、胰腺癌和前列腺癌中及表达在某种类型的急性骨髓性白血病和先天性纤维肉瘤中。据信Trk的酪氨酸激酶活性促进细胞增殖机制的无节制活化。据信单独使用或组合使用的TrkA激酶抑制剂、TrkB激酶抑制剂或TrkC激酶抑制剂具有对抗一些最常见癌症的功效,这些癌症为诸如脑部癌症、黑素瘤、多发性骨髓瘤、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头部癌症、颈部癌症、食道癌、前列腺癌、结肠直肠癌、肺癌、肾癌、卵巢癌、妇科癌症、甲状腺癌和某种类型的血液恶性肿瘤。
酪蛋白激酶2(CK2)为参与多种致癌或肿瘤抑制蛋白稳定性调节的丝氨酸/苏氨酸激酶。已被确认为癌细胞中信号传导途径重要组成的蛋白质(诸如β-联蛋白和c-Myc)已被证实通过CK2来磷酸化且已提出这些磷酸化事件是稳定这些蛋白质所需要的。也已证实肿瘤抑制蛋白(诸如PML和PTEN)通过CK2来磷酸化且已表明这些修饰促进这些蛋白质的降解。对CK2酶活性的抑制(诸如通过小分子来抑制)可使致癌基因产物不稳定且使肿瘤抑制蛋白稳定,这引起对肿瘤细胞的抗增殖作用。
另一个重要的激酶家族为Src激酶家族。这些激酶参与癌症、免疫系统功能障碍和骨再造疾病。一般综述请参见Thomas and Brugge,Annu.Rev.CellDev.Biol.(1997)13,513;Lawrence and Niu,Pharmacol.Ther.(1998)77,81;Tatosyan and Mizenina,Biochemistry(Moscow)(2000)65,49;Boschelli et al.,Drugs of the Future 2000,25(7),717,(2000)。Src家族的成员包括哺乳动物中的以下8种激酶:Src、Fyn、Yes、Fgr、Lyn、Hck、Lck和Blk。
美国专利公开文本US20080045496披露了Trk受体激酶。所述公开文本中的实施例74如下所示。该化合物对Jak2的IC50为0.031μM及对Jak3的IC50为0.46μM。
发明内容
本发明提供式I的化合物、使用所述化合物的药物组合物及使用所述化合物的方法。
本发明公开了式I的化合物或其立体异构体、互变异构体、药用盐或溶剂化物:
其中
R1为氢、取代有0-3个Ra的C1-6烷基、取代有0-3个Ra的C3-6环烷基、取代有0-3个Ra的C6-10芳基或-CONR12R13;
R2和R3与它们所连接的氮原子一起形成哌嗪基环或二氮杂二环[2.2.1]庚基环;所述环取代有-COR14、-C(O)-C(O)-R14或-SO2R14中的至少一个,所述环还取代有0-3个Ra;
R7和R8独立为氢、C1-6烷基、C3-6环烷基或-(CH2)r-苯基;可选择地,R7和R8与它们所连接的氮原子一起形成5-10元杂环;
R12和R13独立为氢、任选取代有Ra的C1-6烷基、任选取代有Ra的C3-6环烷基、取代有0-3个Ra的C6-10芳基或含有选自N、O和S的1-4个杂原子的取代有0-3个Ra的5-10元杂环系统;或
可选择地,R12和R13与它们所连接的氮原子一起形成4-8元环,所述环任选含有选自-N-、-S-和-O-的一个或多个额外杂原子;所述环取代有0-1个以下基团:氢、-OH或任选取代有0-5个Ra的C1-6烷基;
R14为氢、取代有0-3个R14a的C1-6烷基、取代有0-3个R14a的C1-6烯基、取代有0-3个R14a的C1-6炔基、C1-6卤代烷基、取代有0-3个R14a的-(CHR)r-C3-6环烷基、取代有0-3个R14a的二环[4.2.0]辛三烯基、取代有0-3个R14a的茚基、取代有0-3个R14a的二氢茚酮基、取代有0-5个R14a的-(CH2)r-C6-10芳基或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-5至10元杂环系统;
R14a为F、Cl、Br、OCF3、CF3、CHF2、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、-(CH2)rNR7R8、-(CH2)rC(O)NR7R8、-(CH2)rNRbC(O)Rb、-(CH2)rNRbC(O)ORc、-NRbC(O)NR7R8、-S(O)pNR7R8、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-1个Ra的C1-6烷基、取代有0-1个Ra的C1-6烯基、取代有0-1个Ra的C1-6炔基、C1-6卤代烷基、任选取代有0-2个Ra的-(CH2)r-3至14元碳环或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环,其中所述杂环取代有0-2个Ra;
Ra为氢、F、Cl、Br、OCF3、CF3、CHF2、CN、NO2、-(CH2)rORW、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、-(CH2)rNR7R8、-(CH2)rC(O)NR7R8、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR7R8、-S(O)pNR7R8、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、C1-6烷基、C1-6卤代烷基、-(CH2)r-3至14元碳环或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环;
Rb为氢、取代有0-2个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或取代有0-2个Rd的-(CH2)r-苯基;
Rc为C1-6烷基、C3-6环烷基或-(CH2)r-苯基;
Rd为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rb、-NReRe、-NReC(O)ORc、C1-6烷基或-(CH2)r-苯基;
Re为氢、C1-6烷基、C3-6环烷基或-(CH2)r-苯基;
R在每次出现时独立选自H、C1-6烷基、-(CH2)rC3-6环烷基或-(CH2)r苯基;
p为0、1或2;
r为0、1、2、3或4。
本发明另一个实施方案为式I的化合物或其立体异构体、互变异构体、药用盐或溶剂化物:
其中
R1为氢、取代有0-3个Ra的C1-6烷基、取代有0-3个Ra的C3-6环烷基、取代有0-3个Ra的C6-10芳基或-CONR12R13;
R2和R3与它们所连接的氮原子一起形成哌嗪基环或二氮杂二环[2.2.1]庚基环;所述环取代有-COR14、-C(O)-C(O)-R14或-SO2R14中的至少一个,所述环还取代有0-3个Ra;
R7和R8独立为氢、C1-6烷基、C3-6环烷基或-(CH2)r-苯基;可选择地,R7和R8与它们所连接的氮原子一起形成5-10元杂环;
R12和R13独立为氢、任选取代有Ra的C1-6烷基、任选取代有Ra的C3-6环烷基、取代有0-3个Ra的C6-10芳基或含有选自N、O和S的1-4个杂原子的取代有0-3个Ra的5-10元杂环系统;或
可选择地,R12和R13与它们所连接的氮原子一起形成4-8元环,所述环任选含有选自-N-、-S-和-O-的一个或多个额外杂原子;所述环取代有氢、-OH或任选取代有0-5个Ra的C1-6烷基中的0-1个;
R14为氢、取代有0-3个R14a的C1-6烷基、取代有0-3个R14a的C1-6烯基、取代有0-3个R14a的C1-6炔基、C1-6卤代烷基、取代有0-3个R14a的-(CHR)r-C3-6环烷基、取代有0-5个R14a的-(CH2)r-C6-10芳基或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-5至10元杂环系统;
R14a为F、Cl、Br、OCF3、CF3、CHF2、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、-(CH2)rNR7R8、-(CH2)rC(O)NR7R8、-(CH2)rNRbC(O)Rb、-(CH2)rNRbC(O)ORc、-NRbC(O)NR7R8、-S(O)pNR7R8、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-1个Ra的C1-6烷基、取代有0-1个Ra的C1-6烯基、取代有0-1个Ra的C1-6炔基、C1-6卤代烷基、任选取代有0-2个Ra的-(CH2)r-3至14元碳环或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环,其中所述杂环取代有0-2个Ra;
Ra为氢、F、Cl、Br、OCF3、CF3、CHF2、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、-(CH2)rNR7R8、-(CH2)rC(O)NR7R8、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR7R8、-S(O)pNR7R8、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、C1-6烷基、C1-6卤代烷基、-(CH2)r-3至14元碳环或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环;
Rb为氢、取代有0-2个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或取代有0-2个Rd的-(CH2)r-苯基;
Rc为C1-6烷基、C3-6环烷基或-(CH2)r-苯基;
Rd为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rb、--NReRe、-NReC(O)ORc、C1-6烷基或-(CH2)r-苯基;
Re为氢、C1-6烷基、C3-6环烷基或-(CH2)r-苯基;
R在每次出现时独立选自H、C1-6烷基、-(CH2)rC3-6环烷基或-(CH2)r苯基;
p为0、1或2;
r为0、1、2、3或4。
另一个实施方案为式(I)的化合物,其中
R2和R3与它们所连接的氮原子一起形成环,所述环为:
所述环还取代有0-2个Ra。
另一个实施方案为式(I)的化合物,其中
R1为氢、C1-4烷基、取代有0-1个Ra的C3-6环烷基或-CONR12R13;
R12和R13为氢、C1-6烷基或C3-6环烷基。
另一个实施方案为式(I)的化合物,其中
R7和R8独立为氢、C1-6烷基、C3-6环烷基或-(CH2)r-苯基。
另一个实施方案为式(I)的化合物,其中
R14为氢;取代有0-3个R14a的C1-6烷基;取代有0-3个R14a的C1-6烯基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基、二环[4.2.0]辛三烯基、茚基或二氢茚酮基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-5至10元杂环系统;
R14a为F;Cl;Br;OCF3;CF3;CHF2;CN;NO2;-(CH2)rORb;-(CH2)rSRb;-(CH2)rC(O)Rb;-(CH2)rC(O)ORb;-(CH2)rOC(O)Rb;-(CH2)rNR7R8;-(CH2)rC(O)NR7R8;-(CH2)rNRbC(O)Rb;-(CH2)rNRbC(O)ORc;-NRbC(O)NR7R8;-S(O)pNR7R8;-NRbS(O)pRc;-S(O)Rc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;取代有0-1个Ra的C1-6炔基;C1-6卤代烷基;任选取代有0-2个Ra的-(CH2)r-3至14元碳环,其中所述碳环残基为环丙基、环戊基、环己基、芴基或苯基;或包含碳原子和选自N、O和S(O)p的1-4个杂原子-(CH2)r-5至7元杂环,其中所述杂环取代有0-2个Ra,其中所述杂环为吡啶基、吡啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基。
另一个实施方案为式(I)的化合物,其中
R14为氢;取代有0-3个R14a的C1-6烷基;取代有0-3个R14a的C1-6烯基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基、二环[4.2.0]辛三烯基、茚基或二氢茚酮基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-5至10元杂环系统;
R14a为F;Cl;Br;OCF3;CF3;CHF2;CN;NO2;-(CH2)rORW;-(CH2)rSRb;-(CH2)rC(O)Rb;-(CH2)rC(O)ORb;-(CH2)rOC(O)Rb;-(CH2)rNR7R8;-(CH2)rC(O)NR7R8;-(CH2)rNRbC(O)Rb;-(CH2)rNRbC(O)ORc;-NRbC(O)NR7R8;-S(O)pNR7R8;-NRbS(O)pRW;-S(O)Rc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;取代有0-1个Ra的C1-6炔基;C1-6卤代烷基;任选取代有0-2个Ra的-(CH2)r-3至14元碳环,其中所述碳环残基为环丙基、环戊基、环己基、芴基或苯基;或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环,其中所述杂环取代有0-2个Ra,其中所述杂环为吡啶基、吡啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基。
另一个实施方案为式(I)的化合物,其中
r为0、1或2。
另一个实施方案为式(I)的化合物,其中
R14为氢;取代有0-3个R14a的C1-6烷基;C1-6烯基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基、二环[4.2.0]辛三烯基、茚基或二氢茚酮基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-杂环系统,其中所述杂环系统为吡啶基、吡啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基;
R14a为F;Cl;Br;OCF3;CF3;CHF2;CN;NO2;-ORb;-C(O)Rb;-C(O)ORb;-OC(O)Rb;-(CH2)rNR7R8;-C(O)NR7R8;-NRbC(O)Rb;-NRbC(O)ORc;-C(O)NR7R8;-S(O)pNR7R8;-NRbS(O)pRc;-S(O)Rc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;-C≡CH,;C1-2卤代烷基;任选取代有0-2个Ra的-(CH2)r-3至7元碳环,其中所述碳环残基为环丙基、环戊基、环己基、芴基或苯基;或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环,其中所述杂环取代有0-2个Ra,其中所述杂环为吡啶基、吡啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基;
另一个实施方案为式(I)的化合物,其中
R14为氢;取代有0-3个R14a的C1-6烷基;C1-6烯基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基、二环[4.2.0]辛三烯基、茚基或二氢茚酮基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-杂环系统,其中所述杂环系统为吡啶基、吡啶基、哌啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基;
R14a为F;Cl;Br;OCF3;CF3;CHF2;CN;NO2;-(CH2)rORb;-C(O)Rb;-C(O)ORb;-OC(O)Rb;-(CH2)rNR7R8;-C(O)NR7R8;-NRbC(O)Rb;-NRbC(O)ORc;-C(O)NR7R8;-S(O)pNR7R8;-NRbS(O)pRc;-S(O)Rc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;-C≡CH;C1-2卤代烷基;任选取代有0-2个Ra的-(CH2)r-3至7元碳环,其中所述碳环残基为环丙基、环戊基、环己基、芴基或苯基;或包含碳原子和选自N、O和S(O)p的1-4个杂原子的-(CH2)r-5至7元杂环,其中所述杂环取代有0-2个Ra,其中所述杂环为吡啶基、吡啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基。
另一个实施方案为药物组合物,其包含一种或多种式(I)的化合物及药用载体。
另一个实施方案为治疗白血病、骨髓增殖性障碍和/或血液障碍的方法,其包括对有此需要的哺乳动物物种给药治疗有效量的一种或多种式(I)的化合物。
另一个实施方案为式(I)的化合物,其中
R2和R3与它们所连接的氮原子一起形成环,所述环为:
所述环还取代有0-2个Ra。
另一个实施方案为式(I)的化合物,其中
R1为氢、C1-4烷基或取代有0-1个Ra的C3-6环烷基;
R12和R13为氢、C1-6烷基或C3-6环烷基。
在另一个实施方案中,R1为C1-4烷基、取代有0-1个Ra的C3-6环烷基或-CONR12R13。
在另一个实施方案中,R1为甲基、取代有0-1个甲基或三氟甲基的环丙基或-CONR12R13。
在另一个实施方案中,R12和R13为氢、甲基、乙基或环丙基。
在另一个实施方案中,R14为取代有0-3个R14a的C1-6烷基;C1-6烯基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基、二环[4.2.0]辛三烯基、茚基或二氢茚酮基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-杂环系统,其中所述杂环系统为吡啶基、吡啶基、异噁唑基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基。
在另一个实施方案中,R14a为F;Cl;Br;OCF3;CF3;CHF2;CN;NO2;-ORb;-C(O)Rb;-C(O)ORb;-OC(O)Rb;-(CH2)rNR7R8;-C(O)NR7R8;-NRbC(O)Rb;-NRbC(O)ORc;-C(O)NR7R8;-S(O)pNR7R8;-NRbS(O)pRc;-S(O)Rc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;-C≡CH;C1-2卤代烷基;任选取代有0-2个Ra的-(CH2)r-3至4元碳环,其中所述碳环残基为环丙基、环戊基、环己基、芴基或苯基;或取代有0-2个Ra的吡唑基。
在另一个实施方案中,R14a为F;Cl;Br;OCF3;CF3;CHF2;CN;NO2;-ORb;-NRbC(O)Rb;-NRbC(O)ORc;-S(O)Rc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;-C≡CH;C1-2卤代烷基;任选取代有0-2个Ra的-(CH2)r-3至7元碳环,其中所述碳环残基为环丙基、环戊基、环己基、芴基或苯基;或取代有0-2个Ra的吡唑基。
在另一个实施方案中,本发明提供药物组合物,其包含药用载体和至少一种本发明化合物或其立体异构体、互变异构体、药用盐、溶剂化物或前药。
在另一个实施方案中,本发明提供药物组合物,其包含药用载体和治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药用盐、溶剂化物或前药。
在另一个实施方案中,本发明提供治疗增殖性障碍和/或癌症的方法,其包括对需要所述治疗的患者给药治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药用盐、溶剂化物或前药及至少一种其它抗癌药物或其立体异构体、互变异构体、药用盐、溶剂化物或前药。
在另一个实施方案中,本发明提供治疗增殖性障碍和/或癌症的方法,其包括对需要所述治疗的患者给药治疗有效量的至少一种本发明化合物或其立体异构体、互变异构体、药用盐、溶剂化物或前药。
在另一个实施方案中,本发明提供对需要治疗增殖性障碍和/或癌症的患者进行治疗的方法,其包括给药有效量的本发明化合物或其立体异构体、互变异构体、药用盐、溶剂化物或前药形式以治疗增殖性障碍和/或癌症。
在另一个实施方案中,本发明提供治疗骨髓增殖性疾病(红细胞增多症、特发性血小板减少症和骨髓纤维化)、实体瘤即胰腺癌、前列腺癌、肺癌、头颈癌、乳腺癌、结肠癌、卵巢癌、胃癌及其它肿瘤类型(包括多发性骨髓瘤、黑素瘤、神经母细胞瘤、胶质母细胞瘤和血液恶性肿瘤(诸如急性骨髓性白血病))的方法。
在另一个实施方案中,本发明提供新颖的方法,其包括给药有效量的本发明化合物或其立体异构体、互变异构体、药用盐、溶剂化物或前药形式以治疗增殖性障碍和/或癌症。
在另一个实施方案中,本发明提供本发明化合物,其用于治疗。
在另一个实施方案中,本发明提供本发明化合物,其在用于治疗增殖性障碍和/或癌症的疗法中使用。
在另一个实施方案中,本发明提供本发明式I的化合物在制备用于治疗增殖性障碍和/或癌症的药物中的用途。
本发明可按其它具体的形式实施而不偏离其主旨或本质属性。本发明包括本申请中描述的本发明优选方面的所有组合。应该理解的是,本发明任何及所有实施方案可与任何其它一个或多个实施方案组合以描述其它更优选的实施方案。还应该理解的是,优选实施方案中的每个单独要素其本身就是独立的优选实施方案。另外,实施方案中的任何要素可与来自任何实施方案的任何及所有其它要素组合以描述其它实施方案。
定义
以下是可在本说明书中使用的术语的定义。除非另有说明,本申请就基团或术语所提供的初始定义适用于在说明书通篇中出现的所述基团或术语,不论是单独使用还是作为另一个基团的部分使用。
本发明化合物可具有一个或多个不对称中心。除非另有说明,本发明化合物的所有手性(对映异构和非对映异构)及外消旋形式包括在本发明中。烯烃、C=N双键等的多种几何异构体也可存在于所述化合物中且所有稳定的上述异构体包括在本发明中。描述了本发明化合物的顺式和反式几何异构体且可将其分离为异构体的混合物或单独的异构形式。可将本发明化合物分离为光学活性形式或外消旋形式。如何制备光学活性形式是本领域公知的,诸如通过对外消旋形式进行拆分或由光学活性起始物质合成。本发明包括结构的所有手性(对映异构和非对映异构)及外消旋形式及所有几何异构形式,除非具体指出特定的立体化学或异构形式。
本申请使用的术语“取代”是指所指定的原子上的任意一个或多个氢被选自所示组群的基团代替,条件是没有超过所指定的原子的正常化合价且所述取代得到稳定的化合物。当取代基为酮基(即=O)时,所述原子上的2个氢被代替。酮基取代基不存在于芳族部分上。本申请使用的环双键为这样的双键,其形成在两个相邻环原子之间(例如C=C、C=N或N=N)。
当任意变量(例如R3)就化合物而言在任意组成部分或结构式中出现不止一次时,其在每次出现时的定义独立于其在其它每次出现时的定义。因此,例如如果显示基团取代有0-2个R3,则所述基团可任选被至多2个R3基团取代且R3在每次出现时独立选自R3的定义。另外,仅当取代基和/或变量的组合得到稳定的化合物时,所述组合才是允许的。
当将连接取代基的键显示成与连接环中两个原子的键交叉时,所述取代基可与环上的任意原子连接。当列出取代基而没有指明所述取代基通过哪个原子来与给定结构式的化合物的其余部分连接时,所述取代基可通过所述取代基中的任意原子来连接。仅当取代基和/或变量的组合得到稳定的化合物时,所述组合才是允许的。
当在本发明化合物上存在氮原子(例如胺)时,可通过用氧化剂(例如MCPBA(间氯过氧苯甲酸)和/或过氧化氢)处理这些氮原子来将这些氮原子转化为N-氧化物以得到本发明其它化合物。因此,所有显示和要求保护的氮原子都被视为包括所显示的氮及其N-氧化物(N→O)衍生物。
本申请使用的术语“烷基”或“亚烷基”意在包括具有指定数目碳原子的支链和直链饱和脂族烃基。例如,“C1-10烷基”(或亚烷基)意在包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外,例如“C1-C6烷基”表示具有1至6个碳原子的烷基。烷基可以是未取代或取代的且就取代而言,烷基中的一个或多个氢被另一个化学基团代替。烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(例如正丙基和异丙基)、丁基(例如正丁基、异丁基和叔丁基)、戊基(例如正戊基、异戊基和新戊基)等。
“烯基”或“亚烯基”意在包括构型为直链或支链且具有一个或多个碳-碳双键的烃链,所述碳-碳双键可位于链中的任何稳定点处。例如,“C2-6烯基”(或亚烯基)意在包括C2、C3、C4、C5和C6烯基。烯基的实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基、4-甲基-3-戊烯基等。
“炔基”或“亚炔基”意在包括构型为直链或支链且具有一个或多个碳-碳叁键的烃链,所述碳-碳叁键可位于链中的任何稳定点处。例如,“C2-6炔基”(或亚炔基)意在包括C2、C3、C4、C5和C6炔基;诸如乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。
术语“取代的烷基”是指被例如一个至四个取代基取代的烷基,所述取代基为诸如卤素、羟基、烷氧基、氧代、烷酰基、芳基氧基、烷酰基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二取代的氨基(其中氨基上的2个取代基选自烷基、芳基或芳基烷基)、烷酰基氨基、芳酰基氨基、芳烷酰基氨基、取代的烷酰基氨基、取代的芳基氨基、取代的芳烷酰基氨基、巯基(thiol)、烷基硫基、芳基硫基、芳基烷基硫基、烷基硫羰基、芳基硫羰基、芳基烷基硫羰基、烷基磺酰基、芳基磺酰基、芳基烷基磺酰基、氨磺酰基(例如-SO2NH2)、取代的氨磺酰基、硝基、氰基、羧基、氨甲酰基(例如-CONH2)、取代的氨甲酰基(例如烷基NHCO-、芳基NHCO-或芳基烷基NHCO-,或当氮上存在两个取代基时,所述取代基选自烷基、芳基或芳基烷基)、烷氧基羰基、芳基、取代的芳基、胍基、杂环基(例如吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基、吡咯烷基、哌啶基、吗啉基、哌嗪基、高哌嗪基等)和取代的杂环基。当在上文指出取代基被进一步取代时,其将取代有烷基、烷氧基、芳基或芳基烷基。
“卤代”或“卤素”包括氟、氯、溴和碘。“卤代烷基”意在包括取代有一个或多个卤素的具有指定数目碳原子的支链和直链饱和脂肪族烃基。卤代烷基的实例包括但不限于氟甲基、二氟甲基、三氟甲基、三氯甲基、五氟乙基、五氯乙基、2,2,2-三氟乙基、七氟丙基和七氯丙基。卤代烷基的实例也包括“氟代烷基”,所述“氟代烷基”意在包括取代有一个或多个氟原子的具有指定数目碳原子的支链和直链饱和脂肪族烃基。
术语“环烷基”是指环化的烷基,包括单环、二环或多环环系。C3-7环烷基意在包括C3、C4、C5、C6和C7环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基等。本申请使用的“碳环”或“碳环残基”意在表示任何稳定的3、4、5、6或7元单环或二环或7、8、9、10、11、12或13元二环或三环,其中任何一个环可以是饱和、部分不饱和、不饱和或芳族的。所述碳环的实例包括但不限于环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环己烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、二环[3.3.0]辛烷、二环[4.3.0]壬烷、二环[4.4.0]癸烷、二环[2.2.2]辛烷、芴基、苯基、萘基、茚满基、金刚烷基、蒽基及四氢萘基。如上所述,桥环也包括在碳环的定义中(例如二环[2.2.2]辛烷)。除非另有说明,优选的碳环为环丙基、环丁基、环戊基、环己基、苯基及茚满基。当使用术语“碳环”时,其意在包括“芳基”。当一个或多个碳原子连接两个不相邻的碳原子时,形成桥环。优选的桥为一个或两个碳原子。应该注意的是,桥总是将单环转化为三环。当环被桥接时,就环所述的取代基也可存在于桥上。
术语“芳基”是指在环部分中具有6至12个碳原子的单环或二环芳族烃基,诸如苯基、萘基、联苯基及二苯基,所述基团各自可被取代。
术语“取代的芳基”是指被例如1个至4个取代基取代的芳基,所述取代基为诸如烷基、取代的烷基、烯基、取代的烯基、炔基、取代的炔基、芳基、取代的芳基、芳基烷基、卤素、三氟甲氧基、三氟甲基、羟基、烷氧基、烷酰基、烷酰基氧基、芳基氧基、芳基烷基氧基、氨基、烷基氨基、芳基氨基、芳基烷基氨基、二烷基氨基、烷酰基氨基、巯基、烷基硫基、脲基、硝基、氰基、羧基、羧基烷基、氨甲酰基、烷氧基羰基、烷基硫羰基、芳基硫羰基、芳基磺酰基氨基、磺基、烷基磺酰基、氨磺酰基、芳基氧基等。所述取代基可进一步被羟基、卤素、烷基、烷氧基、烯基、炔基、芳基或芳基烷基取代。
术语“杂芳基”是指任选取代的芳基,例如其为4至7元单环环系、7至11元二环环系或10至15元三环环系,其具有的环含有至少一个杂原子和至少一个碳原子,例如吡啶、四唑或吲唑。
本申请使用的术语“杂环”、“杂环基”、“杂环系统”或“杂环基团”意在表示稳定的5、6或7元单环或二环杂环或稳定的7、8、9、10、11、12、13或14元二环杂环,其是饱和、部分不饱和或完全不饱和的且由碳原子及独立选自N、O及S的1、2、3或4个杂原子构成;且包括任何以下二环基团,其中如上定义的任何一种杂环与苯环稠合。氮杂原子及硫杂原子可任选被氧化(即N→O及S(O)p)。氮原子可以是取代或未取代的(即N或NR[其中R为H或另一种取代基(如果定义)])。杂环可在得到稳定结构的任何杂原子或碳原子处与其侧基连接。本申请描述的杂环可在碳原子或氮原子上被取代,只要所得化合物是稳定的。杂环中的氮可任选被季铵化。优选的是,当杂环中S原子和O原子的总数超过1时,这些杂原子不彼此相邻。优选的是,杂环中S原子和O原子的总数不超过1。当使用术语“杂环”时,其意在包括杂芳基。
杂环的实例包括但不限于吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并噁唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、苯并吡喃基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、3H-吲哚基(indolenyl)、二氢吲哚基、吲嗪基、吲哚基、3H-吲哚基、靛红酰基(isatinoyl)、异苯并呋喃基、异苯并二氢吡喃基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异噻唑并吡啶基、异噁唑基、异噁唑并吡啶基、亚甲二氧基苯基、吗啉基、二氮杂萘基、八氢异喹啉基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑烷基、噁唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、酚黄素基(phenoxathinyl)、吩噁嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡咯烷基、吡咯啉基、2-吡咯烷酮基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基及呫吨基。本发明也包括含有例如上述杂环的稠环及螺环化合物。
优选的5至10元杂环包括但不限于吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、哌嗪基、哌啶基、咪唑基、咪唑烷基、吲哚基、四唑基、异噁唑基、吗啉基、噁唑基、噁二唑基、噁唑烷基、四氢呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基、三唑基、苯并咪唑基、1H-吲唑基、苯并呋喃基、苯并噻吩基、苯并四唑基、苯并三唑基、苯并异噁唑基、苯并噁唑基、羟吲哚基、苯并噁唑啉基、苯并噻唑基、苯并异噻唑基、靛红酰基、异喹啉基、八氢异喹啉基、四氢异喹啉基、四氢喹啉基、异噁唑并吡啶基、喹唑啉基、喹啉基、异噻唑并吡啶基、噻唑并吡啶基、噁唑并吡啶基、咪唑并吡啶基及吡唑并吡啶基。
优选的5至6元杂环包括但不限于吡啶基、呋喃基、噻吩基、吡咯基、吡唑基、吡嗪基、哌嗪基、哌啶基、咪唑基、咪唑烷基、吲哚基、四唑基、异噁唑基、吗啉基、噁唑基、噁二唑基、噁唑烷基、四氢呋喃基、噻二嗪基、噻二唑基、噻唑基、三嗪基及三唑基。本发明也包括含有例如上述杂环的稠环及螺环化合物。
在另一个实施方案中,杂环包括但不限于吡啶基、吡啶基、异噁唑基、异喹啉基、噻吩基、吡唑基、呋喃基、吡咯基、噻唑基、咪唑基、吡嗪基、噻二唑基、嘧啶基、哒嗪基、噁唑基、异噻唑基、噁二唑基、二氢茚酮基、哌嗪基、吡喃基或吡咯基。
本发明也包括较小的杂环,诸如环氧乙烷和氮丙啶。
本申请使用的术语“芳族杂环基团”或“杂芳基”意在表示稳定的单环和多环芳族烃基,其包含至少一个杂原子环成员(诸如硫、氧或氮)。杂芳基包括但不限于吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、呋喃基、喹啉基、异喹啉基、噻吩基、咪唑基、噻唑基、吲哚基、吡咯基、噁唑基、苯并呋喃基、苯并噻吩基、苯并噻唑基、异噁唑基、吡唑基、三唑基、四唑基、吲唑基、1,2,4-噻二唑基、异噻唑基、嘌呤基、咔唑基、苯并咪唑基、二氢吲哚基、苯并二氧杂环戊基、苯并二氧杂环己基等。杂芳基可以是取代或未取代的。氮原子可以是取代或未取代的(即N或NR[其中R为H或另一种取代基(如果定义)])。氮杂原子及硫杂原子可任选被氧化(即N→O及S(O)p)。应该注意的是,芳族杂环中S原子和O原子的总数不超过1。桥环也包括在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时,形成桥环。优选的桥包括但不限于一个碳原子、两个碳原子、一个氮原子、两个氮原子及碳-氮基团。应该注意的是,桥总是将单环转化为三环。当环被桥接时,就环所述的取代基也可存在于桥上。
术语“取代的烯基”是指被例如一个至两个取代基取代的烯基,所述取代基为诸如卤素、羟基、烷氧基、烷酰基、烷酰基氧基、氨基、烷基氨基、二烷基氨基、烷酰基氨基、巯基、烷基硫基、烷基硫羰基、烷基磺酰基、氨磺酰基、硝基、氰基、羧基、氨甲酰基、取代的氨甲酰基、胍基、吲哚基、咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基等。
术语“取代的炔基”是指被例如取代基取代的炔基,所述取代基为诸如卤素、羟基、烷氧基、烷酰基、烷酰基氧基、氨基、烷基氨基、二烷基氨基、烷酰基氨基、巯基、烷基硫基、烷基硫羰基、烷基磺酰基、氨磺酰基、硝基、氰基、羧基、氨甲酰基、取代的氨甲酰基、胍基和杂环基(例如咪唑基、呋喃基、噻吩基、噻唑基、吡咯烷基、吡啶基、嘧啶基等)。
术语“碳环”或“碳环基”是指稳定的饱和、部分饱和或不饱和的含有3-12个原子的单环烃环或二环烃环。具体地,其包括含有5或6个原子的单环或包含9或10个原子的二环。合适的基团包括环丙基、环丁基、环戊基、环已基、环庚基、二氢茚基和四氢萘基。本申请中涉及“碳环”或“碳环基”的术语“任选取代”表示所述碳环可在一个或多个可取代的环位置处被独立选自以下的一个或多个基团取代:烷基(优选为低级烷基)、烷氧基(优选为低级烷氧基)、硝基、单烷基氨基(优选为低级烷基氨基)、二烷基氨基(优选为二[低级]烷基氨基)、氰基、卤素、卤代烷基(优选为三氟甲基)、烷酰基、氨基羰基、单烷基氨基羰基、二烷基氨基羰基、烷基酰氨基(优选为低级烷基酰氨基)、烷氧基烷基(优选为低级烷氧基[低级]烷基)、烷氧基羰基(优选为低级烷氧基羰基)、烷基羰基氧基(优选为低级烷基羰基氧基)和芳基(优选为苯基),所述芳基任选被卤素、低级烷基和低级烷氧基取代。
术语“杂原子”将包括氧、硫及氮。
式I的化合物可按游离形式存在或可形成也在本发明范围内的盐。尽管其它盐也可在例如本发明化合物的分离或纯化中使用,但药学上可接受的(即无毒的生理学上可接受的)盐是优选的。
式I的化合物可与碱金属诸如钠、钾和锂、碱土金属诸如钙和镁、有机碱诸如二环己胺、三丁胺和吡啶及氨基酸诸如精氨酸和赖氨酸等形成盐。所述盐可如本领域技术人员已知的那样来形成。
式I的化合物可与各种有机酸和无机酸形成盐。所述盐包括与以下酸形成的那些盐:氯化氢、溴化氢、甲磺酸、硫酸、乙酸、三氟乙酸、草酸、马来酸、苯磺酸、甲苯磺酸等(例如硝酸盐、磷酸盐、硼酸盐、酒石酸盐、枸橼酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、水杨酸盐等)。所述盐可如本领域技术人员已知的那样来形成。
另外,可形成两性离子(“内盐”)。
本发明包括呈混合物形式或呈纯或基本纯形式的本发明化合物的所有立体异构体。本发明化合物的定义包括所有可能的立体异构体及其混合物。其非常具体地包括外消旋形式和分离的具有特定活性的光学异构体。外消旋形式可通过物理方法来拆分,所述物理方法为诸如对非对映异构体衍生物进行分级结晶、分离或结晶或通过手性柱色谱来分离。可通过常规方法例如与光学活性酸形成盐接着进行结晶由外消旋体得到单独的光学异构体。
本发明意在包括本发明化合物中出现的原子的所有同位素。同位素包括原子数相同但质量数不同的那些原子。例如但不限于此,氢的同位素包括氘和氚。碳的同位素包括13C和14C。经同位素标记的本发明化合物通常可通过本领域技术人员已知的常规技术或通过与本申请所述类似的方法使用经同位素标记的合适试剂代替未经标记的所用相应试剂来制备。
式I的化合物也可具有前药形式。因为已知前药可提高药物的多种所需性质(例如溶解度、生物利用度、制备等),所以本发明化合物可按前药形式来给药。因此,本发明意在包括本发明化合物的前药、递送所述前药的方法及含有所述前药的组合物。“前药”意在包括任何共价结合的载体,当将所述前药给药于哺乳动物受试者时,所述共价结合的载体在体内释放具有活性的本发明母体药物。本发明前药通过对化合物中存在的官能团进行修饰来制备,从而使修饰物以常规处理方法裂解或使修饰物在体内裂解以得到母体化合物。前药包括这样的本发明化合物,其中羟基、氨基或巯基与任何以下基团连接,当将本发明前药给药于哺乳动物受试者时,所述基团裂解以分别形成游离的羟基、游离的氨基或游离巯基。前药的实例包括但不限于本发明化合物中醇官能团和胺官能团的乙酸化衍生物、甲酸化衍生物和苯甲酸化衍生物。
各种形式的前药是本领域公知的。所述前药衍生物的实例参见:
a)Design of Prodrugs,edited by H.Bundgaard,(Elsevier,1985)和Methods inEnzymology,Vol.112,pp.309-396,edited by K.Widder,et al.(Academic Press,1985);
b)A Textbook of Drug Design and Development,edited by Krosgaard-Larsenand H.Bundgaard,Chapter 5,“Design and Application of Prodrugs,”by H.Bundgaard,pp.113-191(1991);和
c)H.Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992)。
还应该理解的是,式I的化合物的溶剂化物(例如水合物)也在本发明范围内。溶剂化的方法是本领域公知的。
“稳定的化合物”和“稳定的结构”意在表明这样的化合物,其足够稳定以耐受得住由反应混合物分离为有用的纯度并配制成有效的治疗药物。优选的是,本申请化合物不含有N-卤素、-S(O)2H或-S(O)H基团。
本申请使用的“治疗”包括在哺乳动物特别是人类中对病症进行治疗并包括:(a)在哺乳动物中预防所述病症发生,特别是当所述哺乳动物易患所述病症但尚未确诊患上所述病症时;(b)抑制所述病症,即阻止其发展;和/或(c)减轻所述病症,即令所述病症消退。
“治疗有效量”意在包括本发明化合物的以下量,所述量当单独给药或组合给药时是有效的。“治疗有效量”还意在包括化合物的组合量。
本发明还包括组合物,其包含一种或多种本发明化合物和药用载体。
“药用载体”是指本领域通常接受的用于将生物活性药物递送至动物特别是哺乳动物的媒介物。药用载体根据本领域技术人员知识范围内所公知的多种因素来配制。这些因素包括但不限于:所配制的活性药物的类型和性质;含有药物的组合物所待给药的受试者;给药组合物的预期途径;和所靶向的治疗适应症。药用载体包括水性和非水性液体媒介物及多种固体和半固体剂型。除活性药物外,所述载体还可包括多种不同的成分和添加剂,这些额外的成分出于本领域技术人员公知的各种原因(例如使活性药物、粘合剂等稳定)而包含在制剂中。有关合适的药用载体和当选择它们时涉及的因素的描述参见各种容易得到的来源,例如Remington’s Pharmaceutical Sciences,17th ed.,Mack Publishing Company,Easton,PA,1985,将其全部内容并入本申请作为参考。
用途
本发明基于以下发现即某些吡咯并三嗪类化合物为蛋白激酶抑制剂。更具体地,吡咯并三嗪类化合物诸如本发明描述的那些吡咯并三嗪类化合物抑制Jak受体家族成员即TRK及Src的蛋白质酪氨酸激酶活性。吡咯并三嗪类化合物诸如本发明描述的那些吡咯并三嗪类化合物也抑制CK2受体家族成员的蛋白质丝氨酸/苏氨酸激酶活性。这些抑制剂将可用于治疗依赖于通过这些受体中的一种或多种进行信号传导的增殖性疾病。上述疾病包括骨髓增殖性疾病、实体瘤即胰腺癌、前列腺癌、肺癌、头颈癌、乳腺癌、结肠癌、卵巢癌及其它肿瘤类型(包括多发性骨髓瘤、黑素瘤、神经母细胞瘤、胶质母细胞瘤和血液恶性肿瘤(诸如急性骨髓性白血病)。
本发明还涉及包含式I的化合物或其药用盐及药用载体的药物组合物,其用于在哺乳动物中治疗过度增殖性障碍。具体地,预期所述药物组合物抑制以下那些原发性和复发性实体瘤的生长和/或转移,所述实体瘤与TrkA、TrkB、TrkC、Flt-3(Fms样激酶-3)、Jak2、Jak3、Src和CK2相关,尤其是其生长和扩散显著依赖于Jak2、TrkA、TrkB、TrkC和CK2的那些肿瘤,包括例如血液癌症、甲状腺癌、乳腺癌、结肠癌、胰腺癌或多种肿瘤类型(包括多发性骨髓瘤、黑素瘤、神经母细胞瘤和胶质母细胞瘤)。
因此,本发明另一个方面提供式I的化合物或其药用盐在制备用于在温血动物诸如人类中产生抗增殖作用的药物中的用途。
本发明另一个方面提供用于在需要所述治疗的温血动物诸如人类中产生抗增殖作用的方法,所述方法包括给药所述动物有效量的本申请在上文定义的式I的化合物或其药用盐。
由于本发明化合物能够抑制TrkA、TrkB、TrkC、Flt-3、Jak2、Jak3、Src、CK2和Tie-2激酶,因此本发明化合物可用于治疗增殖性疾病(包括癌症)。已证实TrkA、TkB和TrkC受体激酶在肿瘤(包括甲状腺癌、乳腺癌、结肠癌和急性骨髓性白血病)中表达并活化且也已在多种肿瘤类型(包括多发性骨髓瘤、黑素瘤、胰腺癌、神经母细胞瘤和胶质母细胞瘤)中报道Trk受体和相应的配体是提高的。因此,预期TrkA、TrkB和TrkC激酶抑制剂将在治疗依赖于通过上述两种受体中的一种或两种进行信号传导的肿瘤中具有功效。预期这些化合物作为单一药物或当与其它化学治疗药物诸如阿霉素和顺铂联用(同时或先后)时具有功效。
因此,本发明提供用于治疗多种癌症的方法,所述癌症包括但不限于以下:
癌瘤,其包括膀胱癌(包括加速性和转移性膀胱癌)、乳腺癌、结肠癌(包括结肠直肠癌)、肾癌、肝癌、肺癌(包括小细胞和非小细胞肺癌及肺腺癌)、卵巢癌、前列腺癌、睾丸癌、生殖泌尿道癌、淋巴系统癌、直肠癌、喉癌、胰腺癌(包括外分泌腺胰腺癌)、食管癌、胃癌、胆囊癌、宫颈癌、甲状腺癌和皮肤癌(包括鳞状细胞癌);
淋巴系造血肿瘤,其包括白血病、急性淋巴细胞性白血病、急性淋巴母细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤、组织细胞淋巴瘤及伯克特淋巴瘤;
骨髓系造血肿瘤,其包括急性和慢性骨髓性白血病、骨髓发育不良综合征、髓细胞性白血病及前髓细胞性白血病;
中枢及外周神经系统肿瘤,其包括星形细胞瘤、神经母细胞瘤、神经胶质瘤及神经鞘瘤;
间充质细胞源性肿瘤,其包括纤维肉瘤、横纹肌肉瘤及骨肉瘤;及
其它肿瘤,其包括黑素瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌及畸胎癌。
本发明提供治疗白血病、骨髓增殖性疾病(红细胞增多症、特发性血小板减少症和骨髓纤维化)、多发性骨髓瘤、结肠癌、乳腺癌和胃癌的方法。
本申请在上文定义的抗增殖治疗可用作单一疗法或除本发明化合物外还可涉及一种或多种其它物质和/或治疗。所述治疗可通过同时、先后或分开给药治疗中的各个组分来实现。本发明化合物也可与已知的抗癌药和细胞毒性药物和治疗(包括放射)联用。若配制成固定剂量,则所述组合产品在如下所述的剂量范围内使用本发明化合物且在批准的剂量范围内使用其它药物活性物质。当组合制剂不合适时,式I的化合物可与已知的抗癌药或细胞毒性药物和治疗(包括放射)先后使用。
术语“抗癌药”包括可用于治疗癌症的任何已知药物,其包括以下药物:17α-炔雌醇、己烯雌酚、睾酮、泼尼松、氟甲睾酮、丙酸屈他雄酮、睾内酯、醋酸甲地孕酮、甲泼尼龙、甲基睾酮、泼尼松龙、曲安西龙、氯烯雌醚、羟孕酮、氨鲁米特、雌莫司汀、醋酸甲羟孕酮、亮丙瑞林、氟他胺、托瑞米芬和Zoladex;基质金属蛋白酶抑制剂;VEGF抑制剂,诸如抗VEGF抗体和小分子化合物诸如ZD6474和SU6668;Vatalanib、BAY-43-9006、SU11248、CP-547632和CEP-7055;HER1和HER2抑制剂,包括抗HER2抗体(Herceptin);EGFR抑制剂,包括吉非替尼、厄洛替尼、ABX-EGF、EMD72000、11F8和西妥昔单抗;Eg5抑制剂,诸如SB-715992、SB-743921和MKI-833;胰腺Her抑制剂(pan Her inhibitor),诸如卡奈替尼、EKB-569、CI-1033、AEE-788、XL-647、mAb 2C4和GW-572016;激酶抑制剂,例如和达沙替尼 (比卡鲁胺,Astra Zeneca)和他莫昔芬;MEK-1激酶抑制剂、MAPK激酶抑制剂和PI3激酶抑制剂;PDGF抑制剂,诸如伊马替尼;抗血管形成药和抗血管药,其通过中断流向实体瘤的血液来使癌细胞不能得到营养而使癌细胞静止;去势药,其使雄激素依赖性癌瘤不再增殖;非受体酪氨酸激酶抑制剂和受体酪氨酸激酶抑制剂;整联蛋白信号传导抑制剂;作用于微管蛋白的药物,诸如长春碱、长春新碱、长春瑞滨、长春氟宁、紫杉醇、多西紫杉醇、7-O-甲基硫基甲基紫杉醇、4-去乙酰基-4-甲基碳酸酯紫杉醇、3’-叔丁基-3’-N-叔丁基氧基羰基-4-去乙酰基-3’-去苯基-3’-N-去苯甲酰基-4-O-甲氧基羰基-紫杉醇、C-4甲基碳酸酯紫杉醇、埃坡霉素A、埃坡霉素B、埃坡霉素C、埃坡霉素D、去氧埃坡霉素A、去氧埃坡霉素B、[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-二羟基-8,8,10,12,16-五甲基-3-[1-甲基-2-(2-甲基噻唑-4-基)乙烯基]-4-氮杂-17-氧杂二环[14.1.0]十七烷-5,9-二酮(伊沙匹隆)、
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(氨基甲基)噻唑-4-基]-1-甲基乙烯基]-7,11-二羟基-8,8,10,12,16-五甲基-4,17-二氧杂二环[14.1.0]十七烷-5,9-二酮和它们的衍生物;CDK抑制剂、抗增殖细胞周期抑制剂、表鬼臼毒素、依托泊苷和VM-26;抗肿瘤酶,例如拓扑异构酶I抑制剂、喜树碱、托泊替康和SN-38;丙卡巴肼;米托蒽醌;铂配位复合物,诸如顺铂、卡铂和奥沙利铂;生物应答调节剂;生长抑制剂;抗激素治疗药;亚叶酸;替加氟;抗代谢药,诸如嘌呤拮抗剂(例如6-硫代鸟嘌呤和6-巯基嘌呤);谷氨酰胺拮抗剂,例如DON(AT-125;d-氧代-正亮氨酸);核苷酸还原酶抑制剂;mTOR抑制剂;和造血生长因子。
其它细胞毒性药物包括环磷酰胺、多柔比星、柔红霉素、米托蒽醌、美法仑、六甲密胺、塞替派、阿糖胞苷、依达曲沙、三甲曲沙、达卡巴嗪、L-天冬酰胺酶、比卡鲁胺、亮丙瑞林、吡啶并苯并吲哚衍生物、干扰素和白介素。
在医用肿瘤学领域中,使用不同治疗形式的组合来治疗患有癌症的每位患者是常见的实践。在医用肿瘤学中,除本申请定义的抗增殖治疗外,所述治疗中的其它组分还可以是外科手术、放射疗法或化学疗法。所述化学疗法可包括三种主要类别的治疗药:
(i)通过与本申请在上文所定义不同的机制来发挥作用的抗血管形成药(例如利诺胺、整联蛋白αvβ3功能抑制剂、制管张素和雷佐生);
(ii)细胞抑制药,诸如抗雌激素药(例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬和艾多昔芬)、孕激素(例如醋酸甲地孕酮)、芳香酶抑制剂(例如阿那曲唑、来曲唑、硼嗪和依西美坦)、抗激素药、抗孕激素药、抗雄激素药(例如氟他胺、尼鲁米特、比卡鲁胺和醋酸环丙孕酮)、LHRH激动剂和拮抗剂(例如醋酸戈舍瑞林和亮丙瑞林)、睾酮5α-二氢还原酶抑制剂(例如非那雄胺)、法尼基转移酶抑制剂、抗浸润药(例如金属蛋白酶抑制剂诸如马力马司他和尿激酶纤溶酶原活化剂受体功能抑制剂)和生长因子功能抑制剂(所述生长因子包括例如EGF、FGF、血小板源性生长因子和肝细胞生长因子,所述抑制剂包括生长因子抗体、生长因子受体抗体(诸如(贝伐单抗)和(西妥昔单抗))、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂);及
(iii)在医用肿瘤学中使用的抗增殖/抗肿瘤药及其组合,诸如抗代谢药(例如抗叶酸药诸如甲氨喋呤、氟嘧啶类化合物诸如5-氟尿嘧啶及嘌呤和腺苷类似物诸如阿糖胞苷);插入性抗肿瘤抗生素(例如蒽环类抗生素诸如多柔比星、柔红霉素、表柔比星和伊达比星、丝裂霉素C、放线菌素D和光辉霉素);铂衍生物(例如顺铂和卡铂);烷化剂(例如氮芥、美法仑、苯丁酸氮芥、白消安、环磷酰胺、异环磷酰胺、亚硝基脲和塞替派);抗有丝分裂药(例如长春花生物碱如长春新碱、长春瑞滨、长春碱和长春氟宁)和紫杉烷类化合物诸如(紫杉醇)、(多西紫杉醇)和更新颖的微管药诸如埃坡霉素类似物(伊沙匹隆)、discodermolide类似物和eleutherobin类似物;拓扑异构酶抑制剂(例如表鬼臼毒素类化合物诸如依托泊苷和替尼泊苷、安吖啶、托泊替康和伊立替康);细胞周期抑制剂(例如flavopyridol类化合物);生物应答调节剂和蛋白酶体抑制剂,诸如(硼替佐米)。
如上所述,本发明式I的化合物由于其抗增殖作用而是重要的。预期本发明这些化合物可用于很多种病症,包括癌症、牛皮癣和类风湿性关节炎。
更具体地,式I的化合物可用于治疗多种癌症,包括但不限于以下癌症:
-癌瘤,包括前列腺癌、胰管肾上腺癌(pancreatic ductal adreno-carcinoma)、乳腺癌、结肠癌、肺癌、卵巢癌、胰腺癌和甲状腺癌;
-中枢神经系统肿瘤和外周神经系统肿瘤,包括神经母细胞瘤、胶质母细胞瘤和髓母细胞瘤(medullobalstoma);
-血液恶性肿瘤,诸如急性骨髓性白血病(AML);和
-其它肿瘤,包括黑色素瘤和多发性骨髓瘤。
通常,由于激酶在调节细胞增殖中的关键作用,抑制剂可作为可逆性细胞抑制药,其可用于治疗以异常细胞增殖为特征的任何疾病过程,例如良性前列腺增生、家族性腺瘤性息肉病、神经纤维瘤病、肺纤维化、关节炎、牛皮癣、肾小球肾炎、血管成形术或血管外科手术后的再狭窄、肥厚性瘢痕形成和炎性肠病。
式I的化合物尤其可用于治疗具有酪氨酸激酶活性高发生率的肿瘤,诸如前列腺肿瘤、结肠肿瘤、脑肿瘤、甲状腺肿瘤和胰腺肿瘤。通过给药包含本发明化合物的组合物(或组合)来降低哺乳动物宿主中的肿瘤发展。
式I的化合物也可用于治疗与以下信号转导途径有关的其它癌性疾病(诸如急性骨髓性白血病),所述信号转导途径通过激酶诸如Flt-3(Fme样激酶-3)、Tie-2、CDK2、VEGFR、FGFR及IGFR激酶来运转。
含有活性成分的本发明药物组合物可呈适于口服的形式,例如片剂、含片、锭剂、水性或油性混悬剂、可分散的粉末剂或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、糖浆剂或酏剂。
当将本发明化合物给药于人类受试者时,每日剂量通常将由开具处方的医师来确定且剂量通常根据个体患者的年龄、体重、性别和应答及患者症状的严重程度而变化。
若配制为固定剂量,则所述组合产品使用在上述剂量范围内的本发明化合物及在所批准的剂量范围内的其它药物活性物质或治疗。当组合制剂不合适时,式I的化合物还可与已知的抗癌药或细胞毒性药物先后给药。本发明不受给药顺序的限制;式I的化合物可在给药已知的抗癌药或细胞毒性药物之前或之后来给药。
本发明化合物的给药剂量范围可为约0.05至200毫克/千克/日,优选小于100毫克/千克/日,其为单一剂量或2至4个分份剂量。
剂量和制剂
本发明化合物可所述口服剂型给药,所述剂型诸如片剂、胶囊剂(其各自包括持续释放或即时释放制剂)、丸剂、粉末剂、颗粒剂、酏剂、酊剂、混悬剂、糖浆剂和乳剂。它们也可静脉内(推注或输注)、腹膜内、皮下或肌内形式给药,使用药学领域技术人员熟知的剂型。它们可单独给药,但一般地与药物载体给药,对所述药物载体基于给药所选的途径及标准药学实践进行选择。
对于本发明化合物的给药方案当然依照多种已知因素来改变,所述因素诸如具体药物的药效学特征及其给药方式和途径;受试者的种类、年龄、性别、健康、医疗条件和体重;症状的性质和程度;共同治疗的种类;治疗频率;给药途径、患者的肾和肝功能,及预期的作用。医师或兽医可对用于治疗癌症的有效量的药物进行确定并开具处方。
通过一般指导,当用于指明功效时,每个活性成分的每日剂量将在每千克体重约0.001至1000mg之间的范围内,优选地在每日每千克体重约0.001至100mg之间且最优选地在每日每千克体重约0.001至20mg之间。静脉内给药最优选的剂量将在约0.1至约10mg/kg之间的范围内。本发明化合物可单一每日剂量进行给药,或总体每日剂量可每日二、三或四次的分开剂量进行给药。
本发明化合物可鼻内形式通过局部使用合适的鼻内媒介物或通过经皮途径使用透皮贴剂来进行给药。当以经皮递送系统给药时,所述剂量给药在整个给药方案中当然应当为连续的而不是间歇的。
化合物典型地以与合适的药物稀释剂、赋形剂或载体(本申请共同指作药物载体)的混合物给药,对所述药物稀释剂、赋形剂或载体根据给药的预期形式(即口服片剂、胶囊剂、酏剂、糖浆剂等)且与常规药学实践一致进行合适选择。
例如,对于片剂或胶囊剂形式的口服给药,活性药物成分可与口服、无毒、药用惰性载体(诸如乳糖、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等)组合;对于液体形式的口服给药,所述口服药物成分可与任意可口服、无毒、药用惰性载体(诸如乙醇、甘油、水等)组合。另外,需要或必要时,也可将合适的粘合剂、润滑剂、崩解剂和着色剂掺入至混合物中。合适的粘合剂包括淀粉、明胶、天然糖(诸如右旋糖或β-乳糖)、玉米增甜剂、天然和合成树胶(诸如阿拉伯胶、西黄蓍胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。在这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄胞胶等。
本发明化合物也可脂质体递送系统(诸如小单层脂质体、大单层脂质体和多层脂质体)给药。脂质体可由各种磷脂(诸如胆固醇、硬脂酰胺或磷酸卵磷酯)形成。
本发明化合物也可与合适高分子材料如靶标药物载体偶联。所述高分子材料可包括聚乙烯吡咯烷酮、吡喃复聚物、多羟基丙基异丁烯酰胺-苯酚、多羟基乙基天冬酰胺苯酚或取代有棕榈酰残基的聚环氧乙烷-多聚赖氨酸。另外,本发明化合物可与用于实现药物控制释放的一类生物可降解聚合物偶联,所述生物可降解聚合物例如,聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε己内酯、多羟基丁酸、多正酯类、聚缩醛、聚二氢吡喃、聚氰基酰化物和水凝胶的交联或两亲嵌段共聚物。
适于给药的剂型(药物组合物)可含有每剂量单位约1毫克至约1000毫克的活性成分。在这些药物组合物中,基于组合物的总重,活性成分通常以按重量计约0.1-95%的量存在。
明胶胶囊可含有活性成分和粉末化载体,诸如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。类似的稀释剂可用于制备压制片剂。片剂和胶囊剂均可配制为持续释放产物以提供历时几小时的药物连续释放。压制片剂可为糖包衣的或薄膜包衣的以遮掩任意不适宜味道且防止片剂与大气接触,或压制片剂可为肠溶包衣以在胃肠道中进行选择性崩解。
用于口服给药的液体剂型可含有增加患者接受度的颜色和香味。
一般而言,水、合适的油、盐水、右旋糖(葡萄糖)水溶液和相关糖溶液及乙二醇诸如丙二醇或聚乙二醇为用于肠胃外溶液的合适载体。用于肠胃外给药的溶液优选地含有活性成分的水溶性盐、合适的稳定剂且如果必要含有缓冲物质。单独或组合使用的抗氧化剂(诸如亚硫酸氢钠、亚硫酸钠或抗坏血酸)为合适的稳定剂。也使用枸橼酸及其盐和EDTA钠盐。另外,肠胃外溶液可含有防腐剂诸如苯扎氯铵、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯及三氯叔丁醇。
合适的药物载体在Remington’s Pharmaceutical Sciences,Mack PublishingCompany中所述,其在该领域中为标准参考文献。
生物学测定
Jak2酪氨酸激酶测定
测定在V形底384孔板中进行。最终测定体积为30μl,其通过加入酶和底物(荧光肽和ATP)在测定缓冲液(100mM HEPES pH 7.4、10mM MgCl2、25mM β-磷酸甘油酯、0.015%Brij35和4mM DTT)中的15μl溶液及测试化合物在测定缓冲液(100mM HEPES pH 7.4、10mM MgCl2、25mM β-磷酸甘油酯、0.015%Brij35和4mM DTT)中的15μl溶液来制备。反应通过将Jak2与底物和测试化合物混合来启动。将反应混合物在室温孵育60分钟,然后通过向每个样品中加入45μl浓度为35mM的EDTA来终止。反应混合物在Caliper LabChip3000上通过对荧光底物和磷酸化产物进行电泳分离来分析。抑制数据通过与作为100%抑制的不含有酶的对照反应混合物和作为0%抑制的仅含有媒介物的反应混合物进行比较来计算。试剂在测定中的最终浓度:ATP为30μM;Jak2荧光肽为1.5μM;Jak2为1nM;及DMSO为1.6%。得到剂量-响应曲线以确定抑制50%激酶活性所需要的浓度(IC50)。将化合物以10mM溶于二甲基亚砜(DMSO)中且以11个浓度来评价(一式两份)。IC50值通过非线性回归分析来得到。
Jak3酪氨酸激酶测定
测定在V形底384孔板中进行。最终测定体积为30μl,其通过加入酶和底物(荧光肽和ATP)在测定缓冲液(100mM HEPES pH 7.4、10mM MgCl2、25mM β-磷酸甘油酯、0.015%Brij35和4mM DTT)中的15μl溶液及测试化合物在测定缓冲液(100mM HEPES pH 7.4、10mM MgCl2、25mM β-磷酸甘油酯、0.015%Brij35和4mM DTT)中的15μl溶液来制备。反应通过将Jak3与底物和测试化合物混合来启动。将反应混合物在室温孵育60分钟,然后通过向每个样品中加入45μl浓度为35mM的EDTA来终止。反应混合物在Caliper LabChip3000上通过对荧光底物和磷酸化产物进行电泳分离来分析。抑制数据通过与作为100%抑制的不含有酶的对照反应混合物和作为0%抑制的仅含有媒介物的反应混合物进行比较来计算。试剂在测定中的最终浓度:ATP为8μM;Jak3荧光肽为1.5μM;Jak3为2.5nM;及DMSO为1.6%。得到剂量-响应曲线以确定抑制50%激酶活性所需要的浓度(IC50)。将化合物以10mM溶于二甲基亚砜(DMSO)中且以11个浓度来评价(一式两份)。IC50值通过非线性回归分析来得到。
本申请描述的化合物在上述Jak2测定中测试。得到以下结果。
实施例编号 | Jak2(IC50,μM) | Jak3(IC50,μM) |
7 | 0.32 | 2.06 |
10 | 6.04E-04 | 9.84E-03 |
20 | 8.14E-03 | 0.05 |
24 | 1.14E-03 | 5.98E-03 |
32 | 7.16E-03 | 0.12 |
37 | 7.73E-03 | 0.16 |
38 | 1.12E-03 | 0.03 |
43 | 2.66 | 50.00 |
45 | 8.91E-04 | 0.01 |
48 | 9.03E-04 | 0.02 |
49 | 7.90E-03 | 0.17 |
66 | 8.98E-04 | 0.01 |
90 | 8.15E-03 | 0.07 |
91 | 6.97E-04 | 0.02 |
95 | 6.65E-03 | 0.09 |
106 | 7.14E-03 | 0.04 |
110 | 1.00E-03 | 0.02 |
126 | 0.15 | 1.41 |
132 | 9.71E-04 | 0.03 |
134 | 8.87E-04 | 8.41E-03 |
139 | 1.04E-03 | 0.07 |
150 | 0.70 | 13.65 |
152 | 0.30 | 2.36 |
158 | 0.30 | 1.74 |
164 | 0.24 | 1.49 |
168 | 7.07E-03 | 0.21 |
187 | 6.83E-03 | 0.20 |
193 | 0.13 | 3.05 |
200 | 7.25E-03 | 0.12 |
211 | 0.59 | 9.48 |
222 | 0.17 | 0.76 |
230 | 0.19 | 0.42 |
A.CK2激酶测定
CK2酶测定在384孔板中进行且反应混合物含有10μM肽底物(RRRADDSDDDDD-NH2)、25μM[γ-33P]ATP(10μCi)(CK2A1)或5μM[γ-33P]ATP(10μCi)(CK2A2)、20mM Hepes(pH 7.4)、100mM NaCl、10mMMgCl2、0.25mM二硫苏糖醇、0.015%Brij-35和重组CK2A1(10nM,Invitrogen)或CK2A2(5nM,Upstate Biotechnology)。将反应混合物在30℃孵育1小时且反应产物通过与磷酸纤维素(P81)滤板结合来捕获。向肽底物中引入的放射性磷酸酯基通过液体闪烁计数来确定。将化合物抑制CK2的效力表达为IC50,其被定义为抑制50%酶活性所需要的化合物浓度。本申请描述的化合物及落入式I(包括式I(a))范围内的其它化合物由于其CK2酶抑制活性和/或其它可药物性例如具有理想的稳定性、生物利用度、治疗指数和毒性值而是极其有利的,这些性质对于所述化合物用作药物是重要的。
B.细胞增殖抑制测定
化合物抑制细胞增殖的能力使用对线粒体代谢活性进行测量的测定来评价,所述线粒体代谢活性与细胞数目直接相关。将细胞以2000个细胞/孔铺于96孔板中,在补充有2%胎牛血清的RPMI-1640中培养24小时,然后加入测试化合物。将化合物在培养基中稀释以使二甲基亚砜的最终浓度从不超过1%。加入化合物后,将细胞再培养72小时,然后细胞存活力如下确定:使用CellTiter96试剂盒(Promega)来测量3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物(MTT)染料的转化。
本申请描述的化合物已在上述一种或多种鉴定测定中被测试且已被发现是具有活性的。
本发明另一个实施方案为在上述Jak2测定中IC50为5nM或更小的化合物且选自以下化合物或其盐:
N-(5-甲基-1H-吡唑-3-基)-2-(4-(苯基乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-戊酰基哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2-(三氟甲基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-苯基环丙基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(环己基乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-甲基环丙基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((6-甲基吡啶-3-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(呋喃-3-甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-甲基-1H-吡咯-2-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(4-甲氧基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(4-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1H-吡唑-3-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((4-甲基噻吩-2-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2,5-二甲基呋喃-3-甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯甲腈;
2-(4-((2,6-二氯苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(二环[4.2.0]辛-1,3,5-三烯-7-基羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-甲氧基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-甲基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((3-(三氟甲基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-氯苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2-氯苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氟-6-(三氟甲基)苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-甲基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(3-(三氟甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-氯苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-甲氧基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
3-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯甲腈;
2-(4-(3-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(三氟甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(3-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)乙酰胺;
N-(4-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)乙酰胺;
2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1,2,3-噻二唑-4-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2-甲基吡啶-3-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-苯基环戊基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1,3-噁唑-2-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-苯基环丁基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
3-(2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)苯甲腈;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((4-(三氟甲氧基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氟-6-甲氧基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2-溴苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2,6-二氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氯-6-甲基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(三氟甲氧基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(4-(三氟甲氧基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((3-(三氟甲氧基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-氯-2-氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2R)-2-甲氧基-2-苯基乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1,3-噁唑-5-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((苄基氧基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2S)-3,3,3-三氟-2-甲氧基-2-苯基丙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)苯甲腈;
N-(2-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)乙酰胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1,2,5-噁二唑-3-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
1-(2,6-二氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
1-(4-氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
1-(4-氯苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
((1S)-1-(4-氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)氨基甲酸叔丁酯;
2-(4-(2-(4-氯苯基)-3-甲基丁酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2,6-二氟-4-甲氧基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-乙氧基-2,6-二氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2,2-二甲基丁酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-(三氟甲基)环丁基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)环丙烷甲腈;
2-(4-(2-(4-氯苯基)丙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-(4-氯苯基)-2-甲基丙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙基)乙酰胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2S)-2-苯基丁酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(4-甲基苯基)环己基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(1-(4-氯苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)氨基甲酸叔丁酯;
2-(4-(2-氯-4,5-二氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(2-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)氨基甲酸叔丁酯;
2-(4-(2-(3,5-二甲基-1H-吡唑-4-基)苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-溴苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2,4-二氯苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2,5-二氯苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-苯氧基苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2-氯吡啶-3-基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-硝基苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-氯-1-苯并噻吩-2-基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(苯氧基甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(2-氯-6-氟苯基)环己基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(2R)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-4-苯基丁-2-醇;
(2R)-2-(4-氟苯基)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-丙-2-醇;
(2S)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-3-苯基-丙-2-醇;
(1S)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙醇;
(1R)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙醇;
3-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)二氢茚-1-酮;
1-(2-氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-苯基丁酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;和
(1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)-2,3-二氢-1H-茚-1-基)氨基甲酸叔丁酯。
除对Jak2具有活性外,相对于Jak3对Jak2具有选择性可有益于降低过度免疫抑制的风险。
本发明另一个实施方案为相对于Jak3活性对Jak2活性的选择性为15或更好的化合物且选自以下化合物或其盐:
2-(4-(2-氯苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(苯基乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-戊酰基哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2-(三氟甲基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-苯基环丙基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(环己基乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-甲基环丙基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-甲基-1H-吡咯-2-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((4-甲基噻吩-2-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((5-甲基吡嗪-2-基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(4-氯-2-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2,4-二氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2,6-二氯苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-异丁酰基哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((4-(三氟甲基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(二环[4.2.0]辛-1,3,5-三烯-7-基羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-甲氧基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-甲基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((3-(三氟甲基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-甲氧基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-氯苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((3-氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2-氯苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(3-苯基丙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(4-(三氟甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-氯苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-甲氧基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(三氟甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(3-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)乙酰胺;
N-(4-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)乙酰胺;
2-(4-(2-氯-6-氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2-甲基吡啶-3-基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(吡啶-3-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-苯基环戊基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1,3-噁唑-2-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-苯基环丁基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
3-(2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)苯甲腈;
2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙酮;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((4-(三氟甲氧基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氟-6-甲氧基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2-溴苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2,6-二氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-氯-6-甲基苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(三氟甲氧基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(4-(三氟甲氧基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1H-吡唑-4-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((3-(三氟甲氧基)苯基)乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2R)-2-甲氧基-2-苯基乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(1,3-噁唑-5-基羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2S)-2-苯基丙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)苯甲腈;
N-(2-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)乙酰胺;
2-(4-(异噁唑-5-基羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
4-(4-氯苯基)-4-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)哌啶-1-羧酸叔丁酯;
1-(2,6-二氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
1-(4-氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
2-(4-((4-(4-氟苯基)四氢-2H-吡喃-4-基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
1-(4-氯苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
2-(4-(2-(4-氯苯基)-3-甲基丁酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-氟-2-(三氟甲基)苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-氯-2,6-二氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-氟苯基)(哌啶-1-基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2,6-二氟-4-甲氧基苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(4-氟苯基)-2,2-二甲基环丙基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-甲氧基-2-(三氟甲基)苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((4-乙氧基-2,6-二氟苯基)乙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2,2-二甲基丁酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-甲基环己基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-甲基-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代丁-2-醇;
(1,2-二甲基-1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)丙基)氨基甲酸叔丁酯;
(4-((1,1-二甲基-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)氨甲酰基)环己基)氨基甲酸叔丁酯;
(1,1-二甲基-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)氨基甲酸叔丁酯;
(3-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)四氢呋喃-3-基)氨基甲酸叔丁酯;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-(三氟甲基)环丙基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-甲基-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-丙-2-醇;
4-甲基-4-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)哌啶-1-羧酸叔丁酯;
(1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)环己基)氨基甲酸叔丁酯;
(1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)环丁基)氨基甲酸叔丁酯;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((1-(三氟甲基)环丁基)羰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(2R)-1,1,1-三氟-2-甲基-3-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-3-氧代-丙-2-醇;
2-(4-(2,2-二甲基丙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)环丙烷甲腈;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(三氟乙酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(4-氯苯基)环己基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(3-甲基-2-苯基丁酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-(4-氯苯基)丙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(4-甲基苯基)环戊基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-(4-氯苯基)-2-甲基丙酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙基)乙酰胺;
((1R)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙基)氨基甲酸叔丁酯;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2S)-2-苯基丁酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-((2R)-2-苯基丁酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
乙酸(1S)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙基酯;
2-(4-((1-(4-甲基苯基)环己基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(4-甲基苯基)环丙基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(2-氟苯基)环戊基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(4-氟苯基)环戊基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(1-(4-氯苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙基)氨基甲酸叔丁酯;
2-(4-(2-氯-4,5-二氟苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(2-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)苯基)氨基甲酸叔丁酯;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(甲基磺酰基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-(3,5-二甲基-1H-吡唑-4-基)苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2-溴苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(2,4-二氯苯甲酰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-苯氧基苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-(联苯-2-基羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((2-氯吡啶-3-基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-(苯氧基甲基)苯甲酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
2-(4-((1-(2-氯-6-氟苯基)环己基)羰基)哌嗪-1-基)-N-(5-甲基-1H-吡唑-3-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;
(2R)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-2-苯基-丙-2-醇;
(2S)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-2-苯基-丙-2-醇;
(2R)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-4-苯基丁-2-醇;
(2S)-1-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-1-氧代-3-苯基-丙-2-醇;
(1S)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙醇;
(1R)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代-1-苯基乙醇;
1-(2-氟苯基)-2-(4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-氧代乙醇;
N-(5-甲基-1H-吡唑-3-基)-2-(4-(2-苯基丁酰基)哌嗪-1-基)吡咯并[2,1-f][1,2,4]三嗪-4-胺;和
(1-((4-(4-((5-甲基-1H-吡唑-3-基)氨基)吡咯并[2,1-f][1,2,4]三嗪-2-基)哌嗪-1-基)羰基)-2,3-二氢-1H-茚-1-基)氨基甲酸叔丁酯。
缩写
在制备方法和实施例中可使用以下缩写:
h=小时
DCM=二氯甲烷
THF=四氢呋喃
HPLC=高效液相色谱
DIEA=二异丙基乙基胺
i-PrOH=异丙醇
TFA=三氟乙酸
min=分钟
DMF=二甲基甲酰胺
EDC=N-(3-二甲基氨基丙基)-N’-乙基碳二亚胺
HOBt=羟基苯并三唑
NMP=N-甲基吡咯烷酮
EtOAc=乙酸乙酯
AcOH=乙酸
BOP试剂=苯并三唑-1-基-氧基-三(二甲基氨基)鏻六氟磷酸盐
盐水=饱和氯化钠水溶液
Et3N=三乙胺
tR=保留时间
制备方法
式I的化合物一般可根据以下方案和本领域技术人员的知识来制备。
方案1
氨基吡唑类化合物可根据方案1来制备。合适取代的羧酸可使用酸催化剂并进行加热或使用酯化剂诸如TMSCH2N2来酯化。在碱性条件下与乙腈进行缩合,得到β-氰基酮类化合物,所述β-氰基酮类化合物可使用肼来环化为吡唑类化合物。
方案2
合适的二卤代吡咯并三嗪III可用合适取代的氨基吡唑在合适的溶剂(诸如异丙醇)中在碱(诸如二异丙基乙基胺)存在下处理,得到通式IV的化合物。第二个卤素可在加热条件下或在微波条件下使用胺或二甲基甲酰胺或二甲基乙酰胺作为溶剂在存在或不存在过渡金属(诸如Pd)和磷类配体的情况下被二胺(诸如哌嗪或取代的哌嗪)置换,得到式V的化合物。在其它途径中,化合物V可使用标准偶联条件(EDCI)或通过对酰氯或酸酐进行偶联等其它途径来进一步转化为酰胺衍生物VI。类似地,可使V与氯甲酸酯、异氰酸酯和磺酰氯反应,分别得到氨基甲酸酯、脲和磺酰胺衍生物。
其中RX为芳基或杂芳基或烷基的式XIII的化合物可使用方案4中显示的一般方法学来合成。对中间体VII进行的溴化可得到两种区域异构的溴化物(VIII和IX)。区域异构体IX可用合适取代的吡唑处理,得到X。所述溴化物可与经合适活化的RX进行由过渡金属促进的偶联,得到XI。第二个卤素可在加热条件下或在微波条件下使用胺或二甲基甲酰胺或二甲基乙酰胺作为溶剂在存在或不存在过渡金属(诸如Pd)和磷类配体的情况下被胺置换,得到式XII的化合物,可将所述式XII的化合物转化为酰胺XIII。
方案3
类似地,区域异构体VIII可使用方案4中描述的操作来转化为通式XIV的化合物。
方案4
其中RX为H或芳基或杂芳基或烷基的通式XIX的化合物可使用方案5中显示的一般方法学来合成。中间体IV或X可使用微波或加热条件来与取代的含有羟基的饱和氨基杂环偶联。所得到的XVIII可与苯酚在Mitsunobu反应条件下缩合,得到化合物XIX。
方案5
制备实施例1
3-异丙基-1H-吡唑-5-胺
方法一
1A.4-甲基-3-氧代戊腈的制备
NaH(60%在矿物油中的分散液,1.05g,0.026mol)在1,4-二氧杂环己烷(20mL)中的混悬液用CH3CN(1.5mL,0.028mol)处理。将反应混合物在环境温度搅拌20分钟,然后加入异丁酸乙酯(3mL,0.023mol)。将反应混合物加热至55℃且保持4小时,然后冷却至环境温度并搅拌过夜。在0℃加入水(40mL),且未反应的起始物质用DCM(50mL)萃取。水层用1N HCl酸化至pH~5,然后用DCM(2×50mL)萃取。将合并的有机层干燥(Na2SO4),过滤并浓缩,得到所需产物(1.8g,67%)。1H NMR(400MHz,CD3OD)δ3.52(s,1H),2.72-2.80(m,1H),1.14(d,J=6.8Hz)。
2B.3-异丙基-1H-吡唑-5-胺的制备
向4-甲基-3-氧代戊腈(0.9g,0.008mol)在乙醇(5mL)中的混合物中加入肼(0.25mL,0.008mol)。将反应混合物回流1小时,然后冷却至室温。将反应混合物浓缩并将残留物在MeOH(2mL)中溶解。将粗产物加载至结合有硫酸的树脂(AG 50W-X2,氢型,100-200目筛,BioRad)上,用MeOH(50mL)洗涤,然后用2N NH3/甲醇(10mL)洗涤。将氨洗涤液合并并浓缩,得到所需产物(700mg,68%)。1H NMR(400MHz,MeOD)δ5.44(s,1H),2.84-2.90(m,1H),1.24(d,J=6.4Hz)。
制备实施例2
3-乙基-1H-吡唑-5-胺
方法二
2A.3-氧代戊腈的制备
n-BuLi(正丁基锂)(1.6M在己烷中的溶液,5mL,8mmol)在THF(15mL)中的溶液在-78℃用CH3CN(0.4mL,8mmol)处理。将反应混合物在-78℃搅拌1小时,然后加入丙酸乙酯(0.45mL,4mmol)。将反应混合物在-40℃搅拌2小时,然后缓慢温热至室温。反应混合物用1N HCl淬灭并达到pH~5。溶液用乙醚(20mL)萃取,干燥(Na2SO4),然后在20℃以下小心减压浓缩。粗产物(0.4g)无需纯化即用于下一步。
2B.3-乙基-1H-吡唑-5-胺的制备
向3-氧代戊腈在乙醇(5mL)中的混合物中加入肼(0.2mL,6mmol)。将混合物回流1小时,然后减压浓缩。残留物用甲醇(1mL)稀释并通过制备性反相HPLC(YMC ODS-A 5μm 30×100mm,含有0.1%TFA的10-90%甲醇水溶液,15分钟梯度,在220nm监测)来纯化,得到3-乙基-1H-吡唑-5-胺(0.3g,68%)。1HNMR(MeOD)δ5.54(s,1H),2.60(q,2H,J=7.6Hz),1.25(t,3H,J=7.6Hz)。
如下所述,表1中列出的化合物如就制备实施例1或2所述那样来制备。
表1
HPLC条件:
(a)YMC S5Combiscreen ODS 4.6×50mm,含有0.2%H3PO4的10-90%甲醇水溶液,4分钟梯度,在220或254nm监测。
(b)Chromolith SpeedROD 4.6×50mm,含有0.1%TFA的10-90%甲醇水溶液,4分钟梯度,在220或254nm监测。
实施例1
(4-(4-(3-甲基-1H-吡唑-5-基氨基)吡咯并[1,2-f][1,2,4]三嗪-2-基)哌嗪-1-基)(苯基)甲酮
1A.2-氯-N-(5-甲基-1H-吡唑-3-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺的制备
将3-甲基-1H-吡唑-5-胺(387mg,3.99mmol)加到2,4-二氯吡咯并[1,2-f][1,2,4]三嗪(500mg,2.66mmol)在丙-2-醇和三乙胺的混合物(4∶0.2mL)中的搅拌混悬液中。将反应混合物在45℃搅拌16小时。将反应混合物在室温冷却并真空浓缩。粗物质使用硅胶柱色谱来纯化(二氯甲烷/甲醇(98∶2至94∶6)梯度)。收集馏分,分析,合并并浓缩,得到350mg 2-氯-N-(5-甲基-1H-吡唑-3-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺。MS(ESI)m/z 249.06(M+H)。1HNMR(CDCl3)δppm 8.75(s,1H),7.66(s,1H),6.71(s,1H),6.05(宽单峰,1H),2.27(s,3H)。
1B.N-(3-甲基-1H-吡唑-5-基)-2-(哌嗪-1-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺的制备
向配备有搅拌棒的100mL圆底烧瓶中加入2-氯-N-(5-甲基-1H-吡唑-3-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺(5g,20.11mmol)、哌嗪(8.66g,101mmol)和N-甲基吡咯烷(5mL)。当对粗反应混合物进行的LC MS显示起始物质消失时,将反应混合物在125℃搅拌2小时。将粘稠的反应混合物冷却至室温并加入MeOH-DCM的混合物(20mL,1∶1)。将液体小心滗出以避免转移出过量的哌嗪,所述过量的哌嗪已在烧瓶上壁上固化。历时30分钟将溶液在剧烈搅拌下缓慢加到300mL乙醚中。将白色沉淀物过滤并用乙醚洗涤,得到5g N-(5-甲基-1H-吡唑-3-基)-2-(哌嗪-1-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺。MS(ESI)m/z299.16(M+H)。1H NMR(CD3OD)δppm 7.375(d,1H,J=1.83Hz),6.82(d,1H,J=3.97Hz),6-35-6.57(m,2H),3.60-3.71(m,4H),2.88-3.00(m,4H),2.32(s,3H)。
1C.(4-(4-(3-甲基-1H-吡唑-5-基氨基)吡咯并[1,2-f][1,2,4]三嗪-2-基)哌嗪-1-基)(苯基)甲酮TFA盐的制备
N-(3-甲基-1H-吡唑-5-基)-2-(哌嗪-1-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺(20mg,0.06mmol)在DMF(1mL)中的混合物用苯甲酸(10mg,0.08mmol)、N,N,N’,N’-四甲基-O-(苯并三唑-1-基)脲鎓四氟硼酸盐(20mg,0.06mmol)和DIEA(0.1mL,0.59mmol)处理。将反应混合物在室温搅拌过夜。混合物用甲醇稀释并通过制备性反相HPLC(YMC ODS-A 20×100mm,含有0.1%TFA的10-90%甲醇水溶液,10分钟梯度,在220nm监测)来纯化,得到(4-(4-(3-甲基-1H-吡唑-5-基氨基)吡咯并[1,2-f][1,2,4]三嗪-2-基)哌嗪-1-基)(苯基)甲酮TFA盐(11mg)。m/z=403.1(M+H)。1H NMR(CD3OD)δ10.22(s,1H),8.18(d,1H,J=7.6Hz),7.77(d,2H,J=7.6Hz),7.43(m,5H),7.00(s,1H),6.36(s,1H),6.28(s,1H),4.33(d,2H,J=13.2Hz),4.02(s,1H),3.23(t,2H,J=7.6Hz),1.84(m,3H),1.54(m,2H),0.88(m,2H),0.63(m,2H)。
表1中的以下化合物已使用实施例1中描述的方法来合成。
表1
HPLC条件:
(c)YMC S5Combiscreen ODS 4.6×50mm,含有0.2%H3PO4的10-90%甲醇水溶液,4分钟梯度,在220或254nm监测。
(d)Chromolith SpeedROD 4.6×50mm,含有0.1%TFA的10-90%甲醇水溶液,4分钟梯度,在220或254nm监测。
实施例252
(R)-1-(3-甲基-4-(4-(5-甲基-1H-吡唑-3-基氨基)吡咯并[1,2-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-苯基乙酮
252A(R)-N-(5-甲基-1H-吡唑-3-基)-2-(2-甲基哌嗪-1-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺的制备
在小瓶中向2-氯-N-(5-甲基-1H-吡唑-3-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺(100mg,0.402mmol)和(R)-3-甲基哌嗪-1-羧酸叔丁酯(965mg,4.82mmol)在NMP(1mL)中的溶液中加入DIPEA(0.211mL,1.206mmol)。将反应混合物在160℃加热过夜。将反应混合物冷却,用MeOH稀释并通过制备性HPLC(YMCODS S530×100mm,10%MeOH至90%MeOH/H2O(含有0.1%TFA),15分钟,20ml/min流速)来纯化。浓缩馏分后得到的残留物用TFA/CH2Cl2的1∶1混合物(4ml)处理并在室温搅拌30分钟。将反应混合物浓缩,得到47.3mg(R)-N-(5-甲基-1H-吡唑-3-基)-2-(2-甲基哌嗪-1-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺。
252B(R)-1-(3-甲基-4-(4-(5-甲基-1H-吡唑-3-基氨基)吡咯并[1,2-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-苯基乙酮的制备
将(R)-N-(5-甲基-1H-吡唑-3-基)-2-(2-甲基哌嗪-1-基)吡咯并[1,2-f][1,2,4]三嗪-4-胺在二氯甲烷(2mL)中溶解并冷却至0℃。加入2-苯基乙酰氯(0.022mL,0.166mmol)和DIPEA(0.087mL,0.497mmol),使反应混合物达到室温且搅拌过夜。真空除去溶剂且残留的油状物用MeOH稀释。加入4滴1N NaOH水溶液并将反应混合物搅拌45分钟。反应混合物用1N HCl水溶液酸化并通过制备性HPLC(YMC ODS S530×100mm,10%MeOH至90%MeOH/H2O(含有0.1%TFA),15分钟,20ml/min流速)来纯化。得到20.7g(R)-1-(3-甲基-4-(4-(5-甲基-1H-吡唑-3-基氨基)吡咯并[1,2-f][1,2,4]三嗪-2-基)哌嗪-1-基)-2-苯基乙酮TFA盐。m/z=431.2(M+H)。1H NMR(CD3OD)δppm 7.57-7.61(m,1H),7.15-7.22(m,J=9.07,9.07,5.50Hz,2H),7.01(ddd,J=11.41,8.39,2.75Hz,1H),6.88-6.94(m,1H),6.65-6.67(m,1H),6.21(s,1H),5.12-5.17(m,J=1.65Hz,1H),3.75-3.88(m,4H),2.29-2.41(m,5H)。
Claims (10)
1.式I的化合物或其药用盐:
其中
R1为C1-6烷基;
R2和R3与它们所连接的氮原子一起形成环,所述环为:
R14为取代有0-3个R14a的C1-6烷基、取代有0-3个R14a的-(CHR)r-C3-6环烷基、取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基,或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-5至10元杂环系统,其中所述杂环系统选自吡嗪、嘧啶和异噻唑;
R14a为F、Cl、CF3、CN、-(CH2)rORb、-(CH2)rNRbC(O)ORc、-S(O)2Rc、取代有0-1个Ra的C1-6烷基、任选取代有0-2个Ra的-(CH2)r-3至14元碳环,所述碳环为苯基;
Ra为氢、F、-(CH2)rORb或C1-6烷基;
Rb为氢或取代有0-2个Rd的C1-6烷基;
Rc为C1-6烷基;
Rd为氢;
R在每次出现时独立选自H和C1-6烷基;
r为0、1、2、3或4。
2.权利要求1的化合物,其中
R1为C1-4烷基。
3.权利要求1-2中任一项的化合物,其中
R14为取代有0-3个R14a的C1-6烷基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丙基、环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-5至10元杂环系统,其中所述杂环选自吡嗪、嘧啶和异噻唑;
R14a为F;Cl;CF3;CN;-(CH2)rORb;-(CH2)rNRbC(O)ORc;-S(O)2Rc;取代有0-1个Ra的C1-6烷基;任选取代有0-2个Ra的-(CH2)r-3至14元碳环,其中所述碳环残基为苯基。
4.权利要求1的化合物,其中
r为0、1或2。
5.权利要求1的化合物,其中
R14为取代有0-3个R14a的C1-6烷基;取代有0-3个R14a的-(CHR)r-C3-6环烷基,其中所述环烷基为环丁基、环戊基或环己基;取代有0-5个R14a的-(CH2)r-C6-10芳基,其中所述芳基为苯基;或含有选自N、O和S的1-4个杂原子的取代有0-3个R14a的-(CH2)r-杂环系统,其中所述杂环系统为吡嗪、嘧啶或异噻唑;
R14a为F;Cl;CF3;CN;-(CH2)rORb;-NRbC(O)ORc、-S(O)2Rc;取代有0-1个Ra的C1-6烷基;任选取代有0-2个Ra的-(CH2)r-3至7元碳环,其中所述碳环残基为苯基。
6.权利要求1的化合物,其中R1为甲基。
8.一种药物组合物,其包含一种或多种权利要求1-7中任一项的化合物及药用载体。
9.一种或多种权利要求1至7中任一项的化合物在制备用于治疗骨髓增殖性疾病或多发性骨髓瘤的药物中的用途。
10.权利要求9的用途,其中所述骨髓增殖性疾病为红细胞增多症、特发性血小板减少症或骨髓纤维化。
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US9050345B2 (en) * | 2013-03-11 | 2015-06-09 | Bristol-Myers Squibb Company | Pyrrolotriazines as potassium ion channel inhibitors |
CN104016983B (zh) * | 2013-10-08 | 2018-11-02 | 上海创诺制药有限公司 | 吡咯并三嗪类衍生物及其制法和用途 |
WO2015051500A1 (zh) * | 2013-10-08 | 2015-04-16 | 上海创诺制药有限公司 | 吡咯并三嗪类衍生物及其制法和用途 |
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