CN111936486B - 用作IL-12、IL-23和/或IFNα响应的调节剂的包含吡啶的杂环化合物 - Google Patents
用作IL-12、IL-23和/或IFNα响应的调节剂的包含吡啶的杂环化合物 Download PDFInfo
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- CN111936486B CN111936486B CN201980020946.5A CN201980020946A CN111936486B CN 111936486 B CN111936486 B CN 111936486B CN 201980020946 A CN201980020946 A CN 201980020946A CN 111936486 B CN111936486 B CN 111936486B
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
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- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- MHSMAFNXVWZVOC-UHFFFAOYSA-N tributyl-(5-chloropyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=C(Cl)C=N1 MHSMAFNXVWZVOC-UHFFFAOYSA-N 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
具有下式(I)的化合物或其立体异构体或药学上可接受的盐,其中R1、R2、R3、R4和R5如本申请定义,其通过作用于Tyk‑2以引起信号转导抑制,可用于调节IL‑12、IL‑23和/或IFNα。
Description
相关申请的交叉引用
本申请要求2018年3月22日提交的第62/646432号美国临时申请的权益,其公开内容以全文引用的方式并入本文中。
技术领域
本发明涉及可用于通过作用于Tyk-2以引起信号转导抑制来调节IL-12、IL-23和/或IFNα的化合物。本文提供酰胺取代的杂环化合物、包含此类化合物的组合物及其使用方法。本发明进一步涉及含有至少一种本发明化合物的药物组合物,其可用于治疗哺乳动物中与调节IL-12、IL-23和/或IFNα相关的病状。
背景技术
共用常见p40亚基的杂二聚体细胞因子白介素(IL)-12和IL-23通过活化抗原递呈细胞制得且在Th1和Th17细胞的分化和增殖中十分关键,所述Th1和Th17细胞为在自身免疫中起关键作用的两种效应子T细胞谱系。IL-23由p40亚基以及特有p19亚基构成。通过由IL-23R和IL-12Rβ1构成的杂二聚体受体起作用的IL-23为Th17细胞存活和扩增所必需,所述Th17细胞会产生促炎性细胞因子,诸如IL-17A、IL-17F、IL-6和TNF-α(McGeachy,M.J.等人,“The link between IL-23and Th17 cell-mediated immune pathologies”,Semin.Immunol.,19:372-376(2007))。这些细胞因子在介导多种自身免疫性疾病,包括类风湿性关节炎、多发性硬化、炎性肠病和狼疮的病理学中十分关键。与IL-23相同,IL-12除p40亚基以外还含有p35亚基且通过由IL-12Rβ1和IL-12Rβ2构成的杂二聚体受体起作用。IL-12为Th1细胞发育和分泌IFNγ所必需,IFNγ为通过刺激MHC表达、将B细胞类别转换至IgG亚类和活化巨噬细胞而在免疫中关键起作用的细胞因子(Gracie,J.A.等人,“Interleukin-12induces interferon-gamma-dependent switching of IgGalloantibody subclass”,Eur.J.Immunol.,26:1217-1221(1996);Schroder,K.等人,“Interferon-gamma:an overview of signals,mechanisms and functions”,J.Leukoc.Biol.,75(2):163-189(2004))。
自身免疫中含p40的细胞因子的重要性通过以下发现来证明:保护缺乏p40、p19、或IL-23R的小鼠免受多发性硬化、类风湿性关节炎、炎性肠病、狼疮和牛皮癣以及其它疾病的模型中的疾病(Kyttaris,V.C.等人,“Cutting edge:IL-23receptor deficiencyprevents the development of lupus nephritis in C57BL/6-lpr/lpr mice”,J.Immunol.,184:4605-4609(2010);Hong,K.等人,“IL-12,independently of IFN-gamma,plays a crucial role in the pathogenesis of a murine psoriasis like skindisorder”,J.Immunol.,162:7480-7491(1999);Hue,S.等人,“Interleukin-23drivesinnate and T cell-mediated intestinal inflammation”,J.Exp.Med.,203:2473-2483(2006);Cua,D.J.等人,“Interleukin-23rather than interleukin-12is the criticalcytokine for autoimmune inflammation of the brain”,Nature,421:744-748(2003);Murphy,C.A.等人,“Divergent pro-and anti-inflammatory roles for IL-23and IL-12in joint autoimmune inflammation”,J.Exp.Med.,198:1951-1957(2003))。
在人类疾病中,在牛皮癣性病变中已测量到p40和p19的高表达,且在来自MS患者的大脑的活性病变中和在患有活性克罗恩病患者的肠粘膜中已鉴别出Th17细胞(Lee,E.等人,“Increased expression of interleukin 23p19 and p40 in lesional skin ofpatients with psoriasis vulgaris”,J.Exp.Med.,199:125-130(2004);Tzartos,J.S.等人,“Interleukin-17production in central nervous system infiltrating T cellsand glial cells is associated with active disease in multiple sclerosis”,Am.J.Pathol.,172:146-155(2008))。还展示活性SLE患者中p19、p40和p35的mRNA水平明显比非活性SLE患者中那些mRNA水平更高(Huang,X.等人,“Dysregulated expression ofinterleukin-23and interleukin-12subunits in systemic lupus erythematosuspatients”,Mod.Rheumatol.,17:220-223(2007)),且来自狼疮患者的T细胞具有主要Th1表型(Tucci,M.等人,“Overexpression of interleukin-12and T helper 1predominancein lupus nephritis”,Clin.Exp.Immunol.,154:247-254(2008))。
此外,全基因组关联研究已鉴别多个与慢性炎性和自身免疫性疾病相关的基因座,所述基因座编码在IL-23和IL-12途径中起作用的因子。这些基因包括IL23A、IL12A、IL12B、IL12RB1、IL12RB2、IL23R、JAK2、TYK2、STAT3和STAT4(Lees,C.W.等人,“New IBDgenetics:common pathways with other diseases”,Gut,60:1739-1753(2011);Tao,J.H.等人,“Meta-analysis of TYK2 gene polymorphisms association withsusceptibility to autoimmune and inflammatory diseases”,Mol.Biol.Rep.,38:4663-4672(2011);Cho,J.H.等人,“Recent insights into the genetics ofinflammatory bowel disease”,Gastroenterology,140:1704-1712(2011))。
实际上,已展示在包括牛皮癣、克罗恩病和牛皮癣性关节炎的疾病中抑制IL-12和IL-23的抗p40治疗以及IL-23特异性抗p19疗法在自身免疫的治疗中有效(Leonardi,C.L.等人,“PHOENIX 1study investigators.Efficacy and safety of ustekinumab,a humaninterleukin-12/23monoclonal antibody,in patients with psoriasis:76-weekresults from a randomized,double-blind,placebo-controlled trial(PHOENIX 1)”,Lancet,371:1665-1674(2008);Sandborn,W.J.等人,“Ustekinumab Crohn's DiseaseStudy Group.Arandomized trial of Ustekinumab,a human interleukin-12/23monoclonal antibody,in patients with moderate-to-severe Crohn's disease”,Gastroenterology,135:1130-1141(2008);Gottlieb,A.等人,“Ustekinumab,a humaninterleukin 12/23monoclonal antibody,for psoriatic arthritis:randomized,double-blind,placebo-controlled,crossover trial”,Lancet,373:633-640(2009))。因此,可预期抑制IL-12和IL-23的作用的药剂在人类自身免疫病症中具有治疗益处。
包括IFNα成员以及IFNβ、IFNε、IFNκ和IFNω的I型干扰素(IFN)群组经由杂二聚体IFNα/β受体(IFNAR)起作用。I型IFN在先天与后天免疫系统中具有多种作用,包括活化细胞与体液免疫响应以及增强自身抗原的表达和释放(Hall,J.C.等人,“Type I interferons:crucial participants in disease amplification in autoimmunity”,Nat.Rev.Rheumatol.,6:40-49(2010))。
在患有系统性红斑性狼疮(SLE)(一种可能致命的自身免疫性疾病)的患者中,已证明在大多数患者中在末梢血液单核细胞中和在受影响的器官中血清干扰素(IFN)α(I型干扰素)水平增加或I型IFN调节的基因(所谓IFNα特征)的表达增加(Bennett,L.等人,“Interferon and granulopoiesis signatures in systemic lupus erythematosusblood”,J.Exp.Med.,197:711-723(2003);Peterson,K.S.等人,“Characterization ofheterogeneity in the molecular pathogenesis of lupus nephritis fromtranscriptional profiles of laser-captured glomeruli”,J.Clin.Invest.,113:1722-1733(2004)),且若干研究已展示血清IFNα水平与疾病活性和严重程度相关(Bengtsson,A.A.等人,“Activation of type I interferon system in systemic lupuserythematosus correlates with disease activity but not with antiretroviralantibodies”,Lupus,9:664-671(2000))。IFNα在狼疮的病理学中的直接作用通过向患有恶性或病毒性疾病的患者给药IFNα可诱导狼疮样综合征的观察结果来证明。此外,易感狼疮的小鼠中缺失IFNAR提供高度保护以免于自身免疫、疾病严重程度和死亡(Santiago-Raber,M.L.等人,“Type-Iinterferon receptor deficiency reduces lupus-likedisease in NZB mice”,J.Exp.Med.,197:777-788(2003)),且全基因组关联研究已鉴别出与狼疮相关的基因座,其编码在I型干扰素途径中起作用的因子,包括IRF5、IKBKE、TYK2和STAT4(Deng,Y.等人,“Genetic susceptibility to systemic lupus erythematosus inthe genomic era”,Nat.Rev.Rheumatol.,6:683-692(2010);Sandling,J.K.等人,“Acandidate gene study of the type I interferon pathway implicates IKBKE andIL8 as risk loci for SLE”,Eur.J.Hum.Genet.,19:479-484(2011))。除狼疮以外,有证据表明I型干扰素介导的途径的异常活化在诸如干燥综合征(syndrome)和硬皮病的其它自身免疫性疾病的病理学中十分重要(U.等人,“Activation of the typeI interferon system in primarysyndrome:apossible etiopathogenicmechanism”,Arthritis Rheum.,52:1185-1195(2005);Kim,D.等人,“Induction ofinterferon-alpha by scleroderma sera containing autoantibodies totopoisomerase I:association of higher interferon-alpha activity with lungfibrosis”,Arthritis Rheum.,58:2163-2173(2008))。因此,可预期抑制I型干扰素响应的作用的药剂在人类自身免疫病症中具有治疗益处。
酪氨酸激酶2(Tyk2)为非受体酪氨酸激酶的Janus激酶(JAK)家族的成员,且已展示在调节以下两者中IL-12、IL-23和I型干扰素的受体的信号转导级联下游中十分关键:小鼠(Ishizaki,M.等人,“Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 andIL-23/Th17 Axes In vivo”,J.Immunol.,187:181-189(2011);Prchal-Murphy,M.等人,“TYK2 kinase activity is required for functional type I interferon responsesin vivo”,PLoS One,7:e39141(2012))和人类(Minegishi,Y.等人,“Human tyrosinekinase 2deficiency reveals its requisite roles in multiple cytokine signalsinvolved in innate and acquired immunity”,Immunity,25:745-755(2006))。Tyk2介导转录因子的STAT家族成员的受体诱导的磷酸化,其为一种导致STAT蛋白质二聚和STAT依赖型促炎性基因转录的必要信号。缺乏Tyk2的小鼠对结肠炎、牛皮癣和多发性硬化的实验模型具有抗性,表明Tyk2介导的信号传导在自身免疫和相关病症中的重要性(Ishizaki,M.等人,“Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 and IL-23/Th17 AxesIn vivo”,J.Immunol.,187:181-189(2011);Oyamada,A.等人,“Tyrosine kinase 2playscritical roles in the pathogenic CD4 T cell responses for the development ofexperimental autoimmune encephalomyelitis”,J.Immunol.,183:7539-7546(2009))。
在人类中,表达Tyk2的无活性变体的个体经保护以免发生多发性硬化和可能的其它自身免疫病症(Couturier,N.等人,“Tyrosine kinase 2variant influences Tlymphocyte polarization and multiple sclerosis susceptibility”,Brain,134:693-703(2011))。全基因组关联研究已展示Tyk2的其它变体与诸如克罗恩病、牛皮癣、系统性红斑性狼疮和类风湿性关节炎的自身免疫病症有关,进一步表明Tyk2在自身免疫中的重要性(Ellinghaus,D.等人,“Combined Analysis of Genome-wide Association Studies forCrohn Disease and Psoriasis Identifies Seven Shared Susceptibility Loci”,Am.J.Hum.Genet.,90:636-647(2012);Graham,D.等人,“Association of polymorphismsacross the tyrosine kinase gene,TYK2 in UK SLE families”,Rheumatology(Oxford),46:927-930(2007);Eyre,S.等人,“High-density genetic mappingidentifies new susceptibility loci for rheumatoid arthritis”,Nat.Genet.,44:1336-1340(2012))。
鉴于所述病状可受益于涉及细胞因子和/或干扰素调节的治疗,能够调节诸如IL-12、IL-23和/或IFNα的细胞因子和/或干扰素的新型化合物和使用这些化合物的方法可对多个有需要患者提供实质性治疗益处。
发明内容
本发明涉及下文的式I化合物,其通过抑制Tyk2-介导的信号转导可用作IL-12、IL-23和/或IFNα的调节剂。
本发明还提供制备本发明化合物的方法和中间体。
本发明还提供包含药学上可接受的载体和至少一种本发明化合物的药物组合物。
本发明还提供一种通过抑制Tyk-2介导的信号转导调节IL-12、IL-23和/或IFNα的方法,其包括向需要此类治疗的宿主给药治疗有效量的至少一种本发明化合物。
本发明还提供一种治疗增殖性疾病、代谢性疾病、过敏性疾病、自身免疫性疾病和炎性疾病的方法,其包括向需要此类治疗的宿主给药治疗有效量的至少一种本发明化合物。
一个优选的实施方案为一种治疗一种或多种炎性疾病和自身免疫性疾病的方法。出于本发明的目的,炎性和自身免疫性疾病或病症包括具有炎性或自身免疫性组分的任何疾病。
本发明还提供本发明化合物用于制备用以治疗癌症的药物的用途。
本发明还提供本发明化合物,其用于疗法中。
随着公开的继续,将以扩展形式阐述本发明的这些和其它特征。
具体实施方式
在本发明的第一方面,提供式(I)化合物:
其中
X为N或CH;
R1选自H、CD3、C1-3烷基或C3-6环烷基;
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R3为H、C1-3烷基或C3-6环烷基;R4为H、C1-3烷基或C3-6环烷基;
R5为取代有0-1个R5a的C1-4烷基、取代有0-1个R5a的C1-4烷氧基、取代有0-3个R5a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)-5-7元杂环;
R5a在每次出现时独立地为H、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R7为H、C1-3烷基或C3-6环烷基;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第二方面,提供下式化合物:
其中
X为N或CH;
R1选自H、CD3、C1-3烷基或C3-6环烷基;
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R3为H、C1-3烷基或C3-6环烷基;R4为H、C1-3烷基或C3-6环烷基;
R5为取代有0-1个R5a的C1-4烷基、取代有0-1个R5a的C1-4烷氧基、取代有0-3个R5a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)-5-7元杂环;
R5a在每次出现时独立地为H、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第三方面,提供下式化合物:
其中
X为N或CH;
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R3为H、C1-3烷基或C3-6环烷基;R4为H、C1-3烷基或C3-6环烷基;
R5为取代有0-1个R5a的C1-4烷基、取代有0-1个R5a的C1-4烷氧基、取代有0-3个R5a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)-5-7元杂环;
R5a在每次出现时独立地为H、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第四方面,提供下式化合物:
其中
X为N或CH;
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R3为H、C1-3烷基或C3-6环烷基;R5为取代有0-1个R5a的C1-4烷基、取代有0-1个R5a的C1-4烷氧基、取代有0-3个R5a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)-5-7元杂环;
R5a在每次出现时独立地为H、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自的杂原子N、O和S(O)p的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第五方面,提供下式化合物:
其中
X为N或CH;
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R5为取代有0-1个R5a的C1-4烷基、取代有0-1个R5a的C1-4烷氧基、取代有0-3个R5a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)-5-7元杂环;
R5a在每次出现时独立地为H、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第六方面,提供下式化合物:
其中
X为N或CH;
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子、取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第七方面,提供下式化合物:
其中
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子、取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2、3或4;
或其立体异构体或药学上可接受的盐。
在本发明的第八方面,提供下式化合物:
其中
R2为-C(O)R2a;C1-6烷基、取代有0-1个R2a的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2或3;
或其立体异构体或药学上可接受的盐。
在本发明的第九方面,提供下式化合物:
其中
R2为-C(O)R2a或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R6为取代有0-1个R6a的C1-4烷基、取代有0-3个R6a的(CH2)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2或3;
或其立体异构体或药学上可接受的盐。
在本发明的第十方面,提供下式化合物
其中
R2为-C(O)R2a或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R6为包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3,R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2或3;
或其立体异构体或药学上可接受的盐。
在本发明的第十一方面,提供下式化合物
其中
R2为-C(O)R2a或包含1-4个选自N、O和S的杂原子且取代有0-4个R2a的5-12元杂环;
R2a在每次出现时独立地为H、OCF3、CN、NO2、-(CH2)rORb、-(CH2)rSRb、-(CH2)rC(O)Rb、-(CH2)rC(O)ORb、-(CH2)rOC(O)Rb、CH2)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)pRc、取代有0-3个Ra的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-1个Ra的-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子且取代有0-2个Ra的-(CH2)r-5-7元杂环;
R6为包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个R6a的-(CH2)-5-7元杂环;
R6a为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
R11在每次出现时独立地为H、取代有0-3个Rf的C1-4烷基、CF3、取代有0-1个Rf的C3-10环烷基、取代有0-3个Rd的(CH)r-苯基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rd的-(CH2)r-5-7元杂环;
Ra在每次出现时独立地为H、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)rNR11R11、-(CH2)rC(O)NR11R11、-(CH2)rNRbC(O)Rc、-(CH2)rNRbC(O)ORc、-NRbC(O)NR11R11、-S(O)pNR11R11、-NRbS(O)pRc、-S(O)Rc、-S(O)2Rc、取代有0-3个Rf的C1-6烷基、C1-6卤代烷基、取代有0-3个Ra的C2-6烯基、取代有0-3个Ra的C2-6炔基、-(CH2)r-3-14元碳环或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环,其取代有0-3个Rf;
Rb为H、取代有0-3个Rd的C1-6烷基、C1-6卤代烷基、取代有0-2个Rd的C3-6环烷基或包含1-4个选自N、O和S(O)p的杂原子且取代有0-3个Rf的-(CH2)r-5-7元杂环或取代有0-3个Rd的(CH2)r-苯基;
Rc为取代有0-3个Rf的C1-6烷基、取代有0-3个Rf的(CH2)r-C3-6环烷基或取代有0-3个Rf的(CH2)r-苯基;
Rd在每次出现时独立地为氢、F、Cl、Br、OCF3、CF3、CN、NO2、-ORe、-(CH2)rC(O)Rc、-NReRe、-NReC(O)ORc、C1-6烷基或(CH2)r-苯基,其取代有0-3个Rf;
Re在每次出现时独立地为氢、C1-6烷基、C3-6环烷基或(CH2)r-苯基,其取代有0-3个Rf;
Rf在每次出现时独立地为氢、卤素、CN、NH2、OH、C3-6环烷基、CF3、O(C1-6烷基)或包含1-4个选自N、O和S(O)p的杂原子的-(CH2)r-5-7元杂环;
p为0、1或2;
r为0、1、2或3;
或其立体异构体或药学上可接受的盐。
在另一方面,提供一种选自第一方面范围内的例示性实施例的化合物,或其药学上可接受的盐或立体异构体。
在另一方面,提供一种选自任何上述方面的范围内的化合物的任何子集清单的化合物。
在另一方面,提供一种化合物(IUPAC命名规范),其选自:
6-环丙酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(吡啶-2-基)氨基]哒嗪-3-甲酰胺,
6-环丁酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[2-(吗啉-4-基)乙酰氨基]哒嗪-3-甲酰胺,
6-乙酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-丁酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
N-(5-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基)氨基甲酸甲酯,
6-(2-环丙基乙酰氨基)-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-6-[(4-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-氰基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4,5-二甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氟-4-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-乙基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[5-(2-氧基吡咯烷-1-基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-[(4-氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(5-甲基-1,3,4-噻二唑-2-基)氨基]哒嗪-3-甲酰胺,
6-[(4-氯吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氯-4-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-氯-5-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-({2-氧代-2H-[1,3'-联吡啶]-6'-基}氨基)哒嗪-3-甲酰胺,
6-{[4-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[2-氧代-3-(三氟甲基)-2H-[1,3'-联吡啶]-6'-基]氨基}哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-6-[(6-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-(苯基氨基)哒嗪-3-甲酰胺,
6-[(4-乙酰基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-({5-氯-2-氧代-2H-[1,3'-联吡啶]-6'-基}氨基)-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-({[1,3]噻唑并[5,4-b]吡啶-5-基}氨基)哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[4-(三氟甲基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-{[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-氟苯基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(吡啶-4-基)氨基]哒嗪-3-甲酰胺,
6-[(6-乙氧基哒嗪-3-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-{[5-(3-叔丁基-2-氧基咪唑啉-1-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[5-(吗啉-4-基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-[(4,5-二氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(6-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
6-环丙酰氨基-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基吡啶-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({4-[5-(乙氧基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(丙烷-2-基氧基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基吡啶-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,
4-({4-[5-(乙氧基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
4-[(4-氰基-3-甲氧基吡啶-2-基)氨基]-6-环丙酰氨基-N-(2H3)甲基哒嗪-3-甲酰胺,
N-{5-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基}氨基甲酸甲酯,
N-{5-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基}氨基甲酸甲酯,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
N-(5-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基)氨基甲酸甲酯,
6-环丙酰氨基-4-[(4-{5-[(1S)-1-羟基乙基]-1,2,4-噁二唑-3-基}-3-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(4-{5-[(二甲基氨基)甲基]-1,2,4-噁二唑-3-基}-3-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(甲基氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({4-[5-(氰基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-6-环丙酰氨基-N-(2H3)甲基哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-((3-甲氧基-4-(5-(吗啉代甲基)-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺,
N-{5-[(4-{5-[(1,1-二氧基-1λ6,2-噻嗪烷-2-基)甲基]-1,2,4-噁二唑-3-基}-3-甲氧基吡啶-2-基)氨基]-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基}氨基甲酸甲酯,
4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(2-氧代-1,3-噁唑烷-3-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-({4-[5-(羟基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-[2-(氧杂环丁烷-3-基)乙酰氨基]哒嗪-3-甲酰胺,
6-[(5-氯-4-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(6-甲基嘧啶-4-基)氨基]哒嗪-3-甲酰胺,
6-{[4-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
6-{[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺
6-环丙酰氨基-4-({3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-({3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({5-环丙酰氨基-3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
4-({5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-6-环丙酰氨基-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(4-{5-[乙基(甲基)氨基甲酰基]吡嗪-2-基}-3-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基-6-[(1-甲基-1H-吡唑-3-基)氨基]哒嗪-3-甲酰胺,
6-[(1,5-二甲基-1H-吡唑-3-基)氨基]-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氯-1-甲基-1H-吡唑-3-基)氨基]-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-6-{[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-{[5-(2-氨基丙烷-2-基)吡啶-2-基]氨基}-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-[(5-甲基吡嗪-2-基)氨基]哒嗪-3-甲酰胺,
6-[(6-乙氧基哒嗪-3-基)氨基]-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-{[5-(吗啉-4-基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-[(4-氟吡啶-2-基)氨基]-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-6-[(6-甲氧基哒嗪-3-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-[(吡啶-2-基)氨基]哒嗪-3-甲酰胺,
6-环丙酰氨基-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]吡啶-3-甲酰胺,
N-(4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-5-[(2H3)甲基氨基甲酰基]吡啶-2-基)氨基甲酸甲酯,
4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,或
6-[(4-氰基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-N-(2H3)甲基吡啶-3-甲酰胺
或其立体异构体或药学上可接受的盐。
在另一实施方案中,提供一种包含一或多种式I化合物和药学上可接受的载体或稀释剂的药物组合物。
本发明还涉及可用于通过作用于Tyk-2以引起信号转导抑制来治疗与调节IL-12、IL-23和/或IFNα相关的疾病的药物组合物,其包含式I化合物或其药学上可接受的盐和药学上可接受的载体或稀释剂。
本发明进一步涉及治疗与调节IL-12、IL-23和/或IFNα相关的疾病的方法,其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
本发明还提供制备本发明化合物的方法和中间体。
本发明还提供一种治疗增殖性疾病、代谢性疾病、过敏性疾病、自身免疫性疾病和炎性疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的宿主给药治疗有效量的至少一种本发明化合物。
本发明还提供一种治疗炎性疾病或自身免疫性疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
本发明还提供一种治疗疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中该疾病为类风湿性关节炎、多发性硬化、系统性红斑性狼疮(SLE)、狼疮性肾炎、皮肤狼疮、炎性肠病、牛皮癣、克罗恩病、牛皮癣性关节炎、干燥综合征、系统性硬皮病、溃疡性结肠炎、格雷夫斯病、盘状红斑狼疮、成年发作型斯蒂尔病、全身发作型青少年特发性关节炎、痛风、痛风性关节炎、I型糖尿病、胰岛素依赖性糖尿病、败血症、败血性休克、志贺杆菌病、胰腺炎(急性或慢性)、肾小球肾炎、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性嗜中性白细胞减少症、血小板减少、特应性皮炎、重症肌无力、胰腺炎(急性或慢性)、强直性脊柱炎、寻常天疱疮、古德帕斯彻病、抗磷脂综合征、特发性血小板减少、ANCA相关的血管炎、天疱疮、川崎病、慢性炎性脱髓鞘多发性神经病(CIDP)、皮肌炎、多发性肌炎、葡萄膜炎、格林-巴利综合征、自身免疫性肺炎、自身免疫性甲状腺炎、自身免疫性炎性眼病和慢性脱髓鞘多发性神经病。
本发明还提供一种治疗炎性疾病或自身免疫性疾病的方法(或本发明化合物用于制备用以治疗所述疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中该疾病选自系统性红斑性狼疮(SLE)、狼疮性肾炎、皮肤狼疮、克罗恩病、溃疡性结肠炎、I型糖尿病、牛皮癣、类风湿性关节炎、全身发作型青少年特发性关节炎、强直性脊柱炎和多发性硬化。
本发明还提供一种治疗类风湿性关节炎的方法(或本发明化合物用于制备用以治疗类风湿性关节炎的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
另外,本发明还提供一种治疗病状的方法(或本发明化合物用于制备用以治疗这些病状的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中该病状选自急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤、实体肿瘤、眼部血管再生和婴儿血管瘤、B细胞淋巴瘤、系统性红斑性狼疮(SLE)、类风湿性关节炎、牛皮癣性关节炎、多发性血管炎、特发性血小板减少性紫癜(ITP)、重症肌无力、过敏性鼻炎、多发性硬化(MS)、移植排斥、I型糖尿病、膜性肾炎、炎性肠病、自身免疫性溶血性贫血、自身免疫性甲状腺炎、冷和温凝集素疾病、伊文氏综合征、溶血尿毒综合征/血栓性血小板减少性紫癫(HUS/TTP)、类肉瘤病、干燥综合征、周围神经病、寻常天疱疮和哮喘。
本发明还提供一种治疗IL-12、IL-23和/或IFNα介导的疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物。
本发明还提供一种治疗IL-12、IL-23和/或IFNα介导的疾病的方法(或本发明化合物用于制备用以治疗这些疾病的药物的用途),其包括向需要此类治疗的患者给药治疗有效量的式I化合物,其中IL-12、IL-23和/或IFNα介导的疾病为通过IL-12、IL-23和/或IFNα调节的疾病。
本发明还提供一种治疗疾病的方法,其包括向需要此类治疗的患者给药治疗有效量的式I化合物以及其它治疗剂。
本发明还提供用于疗法中的本发明化合物。
在另一实施方案中,式I化合物选自例示化合物或例示化合物的组合或本文中其它实施方案。
在另一实施方案中,化合物在下面描述的至少一种测定中具有IC50<1000nM。
本发明可在不背离其精神或基本属性的情况下以其它特定形式来实施。本发明涵盖本文中所提及的本发明的优选方面和/或实施方案的所有组合。应了解,本发明的任何和所有实施方案均可结合任何一或多种其它实施方案来描述本发明的额外更优选实施方案。还应了解,优选实施方案的各个别元素为其自身独立的优选实施方案。此外,一实施方案的任何要素意欲与任何实施方案的任何和所有其它要素组合以描述另一实施方案。
具体实施方式
以下为本说明书和随附权利要求书中所用的术语的定义。除非另外指明,否则对于本文的基团或术语提供的初始定义适用于本说明书和权利要求书通篇中的个别或作为另一基团的一部分的基团或术语。
本发明化合物可具有一或多个不对称中心。除非另外指明,否则在本发明中包括本发明化合物的所有手性(对映异构和非对映异构)和外消旋形式。烯烃的许多几何异构体、C=N双键及其类似物也可存在于化合物中,且本发明中涵盖所有此类稳定异构体。描述本发明化合物的顺式和反式几何异构体且可以异构体混合物或以分开的异构形式分离。本发明化合物可以光学活性或外消旋形式分离。本领域熟知如何制备光学活性形式,诸如通过拆分外消旋形式或通过自光学活性起始物质合成。除非特别指定特定立体化学或异构形式,否则欲为结构的所有手性、(对映异构和非对映异构)和外消旋形式及全部几何异构形式。
当任何变量(例如R3)在化合物的任何组成部分或式中出现一次以上时,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,举例而言,若展示基团经0至2个R3取代,则所述基团可任选经多达两个R3基团取代且R3在每次出现时独立地选自R3的定义。此外,取代基和/或变量的组合仅在此类组合产生稳定化合物时是容许的。
当展示连至取代基的键与连接环中的两个原子的键交叉时,则此类取代基可键合至该环上的任何原子。若所列取代基未指示此类取代基键合至指定化学式的化合物的其余部分的原子,则此类取代基可经此类取代基中的任何原子键合。取代基和/或变量的组合仅在此类组合产生稳定化合物时是容许的。
在本发明化合物上存在氮原子(例如胺)的情况下,这些氮原子可通过用氧化剂(例如MCPBA和/或过氧化氢)处理而转化成N-氧化物,得到本发明的其它化合物。因此,认为所展示和所要求保护的所有氮原子涵盖所示氮及其N-氧化物(N→O)衍生物。
根据本领域所使用的惯例,用于本文的结构式中以描绘部分或取代基与核心或骨架结构的连接点的键。
不在两个字母或符号之间的虚线“-”用于指示取代基的连接点。举例而言,-CONH2经由碳原子连接。
关于式I化合物的特定部分的术语“任选经取代的”(例如任选经取代的杂芳基)是指具有0、1、2或更多个取代基的部分。举例而言,如下文所定义的“任选经取代的烷基”涵盖“烷基”与“经取代的烷基”。本领域技术人员应了解,对于含有一或多个取代基的任何基团,此类基团不意欲引入空间上不切实际、合成上不可行和/或本身不稳定的任何取代或取代模式。
如本文所使用,术语“至少一个化学实体”可与术语“化合物”互换。
如本文中所使用,术语“烷基”或“亚烷基”意欲包括具有指定数目的碳原子的支链与直链饱和脂族烃基。举例而言,“C1-10烷基”(或亚烷基)意欲包括C1、C2、C3、C4、C5、C6、C7、C8、C9和C10烷基。另外,举例而言,“C1-C6烷基”表示具有1至6个碳原子的烷基。烷基可未经取代或经取代以使得其氢中的一或多者经另一化学基团替换。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、叔丁基)、戊基(例如正戊基、异戊基、新戊基)及其类似基团。
“烯基”或“亚烯基”意欲包括呈直链或支链构型且具有一或多个可存在于沿链的任何稳定点的碳-碳双键的烃链。举例而言,“C2-6烯基”(或亚烯基)意欲包括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-戊烯基及其类似基团。
“炔基”或“亚炔基”意欲包括呈直链或支链构型且具有一或多个可存在于沿链的任何稳定点的碳-碳三键的烃链。举例而言,“C2-6炔基”(或亚炔基)意欲包括C2、C3、C4、C5和C6炔基;诸如乙炔基、丙炔基、丁炔基、戊炔基、己炔基及其类似基团。
本领域技术人员应了解,当本文中使用命名“CO2”时,此意指基团O
-C-O-。
当术语“烷基”与另一基团一起使用,诸如用于“芳基烷基”中时,此组合更明确定义经取代的烷基所含有的至少一个取代基。举例而言,“芳基烷基”是指如上所定义的经取代的烷基,其中至少一个取代基为芳基,诸如苄基。因此,术语芳基(C0-4)烷基包括具有至少一个芳基取代基的经取代的低碳烷基,且还包括直接键合至另一基团的芳基,即芳基(C0)烷基。术语“杂芳基烷基”是指如上所定义的经取代的烷基,其中至少一个取代基为杂芳基。
当提及经取代的烯基、炔基、亚烷基、亚烯基或亚炔基时,这些基团经一至三个如上针对经取代的烷基所定义的取代基取代。
术语“烷氧基”是指经如本文所定义的烷基或经取代的烷基取代的氧原子。举例而言,术语“烷氧基”包括基团-O-C1-6烷基,诸如甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、戊氧基、2-戊氧基、异戊氧基、新戊氧基、己氧基、2-己氧基、3-己氧基、3-甲基戊氧基及其类似基团。”低碳烷氧基”是指具有一至四个碳的烷氧基。
应了解,通过本领域技术人员选择所有基团,包括例如烷氧基、硫代烷基和氨基烷基以提供稳定化合物。
如本文所用,“经取代的”意谓指定原子或基团上的任何一或多个氢经选自指定基团替换,其限制条件为不超出指定原子的正常价数。若取代基为氧代(oxo)或酮基(即=O),则替换原子上的2个氢。酮基取代基不存在于芳族部分上。除非另外规定,否则取代基依核心结构命名。举例而言,应了解,当列出(环烷基)烷基为可能的取代基时,此取代基与核心结构的连接点位于烷基部分中。如本文所使用,环双键是在两个相邻环原子之间所形成的双键(例如C=C、C=N或N=N)。
取代基和/或变量的组合仅在此类组合可以产生稳定化合物或有用的合成中间体时才容许。稳定化合物或稳定结构意谓化合物足够稳固以承受自反应混合物中分离得到可用纯度且随后配制成为有效治疗剂。目前所述的化合物优选不含有N-卤素、S(O)2H或S(O)H基团。
术语“环烷基”是指环化烷基,包括单环状、二环状或多环状环系统。C3-7环烷基意欲包括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、降冰片烷基及其类似基团。如本文所用,“碳环”或“碳环基团”欲意意谓任何稳定3、4、5、6或7元单环状或双环状、或7、8、9、10、11、12或13元双环状或三环状环,其中任一者可为饱和、部分不饱和、不饱和或芳族环。此类碳环的实例包括(但不限于)环丙基、环丁基、环丁烯基、环戊基、环戊烯基、环己基、环庚烯基、环庚基、环庚烯基、金刚烷基、环辛基、环辛烯基、环辛二烯基、[3.3.0]二环辛烷、[4.3.0]二环壬烷、[4.4.0]二环癸烷、[2.2.2]二环辛烷、芴基、苯基、萘基、茚满基、金刚烷基、蒽基和四氢萘基(萘满)。如上文所示,桥接环也包括于碳环定义中(例如[2.2.2]二环辛烷)。除非另外规定,否则优选的碳环为环丙基、环丁基、环戊基、环己基和苯基。当使用术语“碳环”时,意欲包括“芳基”。当一或多个碳原子键联两个非相邻碳原子时,产生桥接环。优选的桥键为一或两个碳原子。应注意,一个桥键总是将单环转变成三环。当环桥接时,该环中所述取代基还可存在于桥键上。
术语“芳基”是指环部分中具有6至12个碳原子的单环或双环芳族烃基,诸如苯基和萘基,其各可经取代。
因此,在式I化合物中,术语“环烷基”包括环丙基、环丁基、环戊基、环己基、环庚基、二环辛基等,以及以下环系统:
及其类似基团,其任选可在环的任何可用原子处经取代。优选环烷基包括环丙基、环戊基、环己基和
术语“卤基”或“卤素”是指氯、溴、氟和碘。
术语“卤烷基”意谓具有一或多个卤素取代基的经取代的烷基。举例而言,“卤烷基”包括单、二和三氟甲基。
术语“卤代烷氧基”意谓具有一或多个卤素取代基的烷氧基。举例而言,“卤代烷氧基”包括OCF3。
因此,芳基的实例包括:
(芴基)及其类似基团,其任选可在任何可用碳或氮原子处经取代。优选芳基为任选经取代的苯基。
术语“杂环(heterocycle)”、“杂环烷基”、“杂环(heterocyclo)”、“杂环的(heterocyclic)”或“杂环基(heterocyclyl)”可互换使用且是指经取代和未经取代的3至7元单环基团、7至11元二环基团和10至15元三环基团,其中该等环中的至少一者具有至少一个杂原子(O、S或N),所述含杂原子的环优选具有1、2或3个选自O、S和N的杂原子。此类含有杂原子的基团的各环可含有一或两个氧或硫原子和/或一至四个氮原子,其限制条件为各环中杂原子的总数为四或更小,且其它限制条件为环含有至少一个碳原子。氮和硫原子可任选经氧化且氮原子可任选经季铵化。包括二环和三环基团的稠合环可仅含有碳原子,且可为饱和、部分饱和或完全不饱和的。杂环基可在任何可用氮或碳原子处连接。如本文所用,术语“杂环(heterocycle)”、“杂环烷基”、“杂环(heterocyclo)”、“杂环的(heterocyclic)”和“杂环基(heterocyclyl)”包括如下所定义的“杂芳基”。
除下文所述杂芳基之外,例示性单环杂环基团包括氮杂环丁烷基、吡咯烷基、氧杂环丁烷基、咪唑啉基、噁唑烷基、异噁唑啉基、噻唑烷基、异噻唑烷基、四氢呋喃基、哌啶基、哌嗪基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、2-氧代氮杂基、氮杂基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、硫吗啉基、硫吗啉基亚砜、硫吗啉基砜、1,3-二氧杂环戊烷和四氢-1,1-二氧代噻吩基及其类似基团。例示性二环杂环基包括奎宁环基。其它单环杂环基包括
术语“杂芳基”是指经取代和未经取代的芳族5或6元单环基团、9或10元二环基团和11至14元三环基团,其在至少一个环中具有至少一个杂原子(O、S或N),所述含杂原子环优选具有1、2或3个选自O、S和N的杂原子。含杂原子的杂芳基的各环可含有一或两个氧或硫原子和/或一至四个氮原子,其限制条件为各环中杂原子的总数为四个或更小且各环具有至少一个碳原子。包括二环和三环基团的稠合环可仅含有碳原子,且可为饱和、部分饱和或不饱和的。氮和硫原子可任选经氧化且氮原子可任选经季铵化。二环或三环杂芳基必须包括至少一个完全芳族环,但其它稠合环可为芳族或非芳族环。杂芳基可在任何环的任何可用的氮或碳原子处进行连接。价数允许时,若所述其它环为环烷基或杂环,则其另外任选经=O(氧代)取代。
例示性单环杂芳基包括吡咯基、吡唑基、吡唑啉基、咪唑基、噁唑基、异噁唑基、噻唑基、噻二唑基、异噻唑基、呋喃基、噻吩基、噁二唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基及其类似基团。
例示性双环杂芳基包括吲哚基、苯并噻唑基、苯并二氧杂环戊烯基、苯并噁唑基、苯并噻吩基、喹啉基、四氢异喹啉基、异喹啉基、苯并咪唑基、苯并吡喃基、吲嗪基、苯并呋喃基、色酮基、香豆素基、苯并吡喃基、噌啉基、喹喔啉基、吲唑基、吡咯并吡啶基、呋喃并吡啶基、二氢异吲哚基、四氢喹啉基及其类似基团。
例示性三环杂芳基包括咔唑基、苯并吲哚基、菲啉基、吖啶基、菲啶基、呫吨基及其类似基团。
在式I化合物中,优选的杂芳基包括:
及其类似基团,其任选可在任何可用碳或氮原子处经取代。
除非另外指明,否则当提及特定命名的芳基(例如苯基)、环烷基(例如环己基)、杂环(例如吡咯烷基、哌啶基和吗啉基)或杂芳基(例如四唑基、咪唑基、吡唑基、三唑基、噻唑基和呋喃基)时,如果适用,该提及意欲包括具有0至3个、优选0至2个选自以上针对芳基、环烷基、杂环和/或杂芳基所述取代基的取代基的环。
术语“碳环基”或“碳环状”是指饱和或不饱和单环或二环,其中所有环的所有原子均为碳。因此,该术语包括环烷基和芳基环。单环碳环具有3至6个环原子,更通常具有5或6个环原子。二环碳环具有7至12个环原子,例如配置为二环[4,5]、[5,5]、[5,6]或[6,6]系统,或9或10个环原子,配置为二环[5,6]或[6,6]系统。单和二环碳环的实例包括环丙基、环丁基、环戊基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、环己基、1-环己-1-烯基、1-环己-2-烯基、1-环己-3-烯基、苯基和萘基。碳环可经取代,在此情况下所述取代基选自上文针对环烷基和芳基所述的那些基团。
术语“杂原子”应包括氧、硫和氮。
当术语“不饱和”在本文中用以指环或基团时,该环或基团可为完全不饱和或部分不饱和的。
在整个本说明书中,其基团和取代基可由本领域技术人员选择,以提供稳定部分和化合物和适用作药学上可接受的化合物的化合物和/或可用于制备药学上可接受的化合物的中间体化合物。
式I化合物可以游离形式存在(在无电离的情况下)或可形成还在本发明范围内的盐。除非另外指明,否则提及本发明化合物应理解为包括提及游离形式及其盐。术语“盐”表示与无机和/或有机酸和碱形成的酸式和/或碱式盐。另外,例如当式I化合物含有碱性部分(诸如胺或吡啶或咪唑环)与酸性部分(诸如甲酸)时,术语“盐”可包括两性离子(内盐)。药学上可接受的(即无毒的生理学上可接受的)盐优选为诸如可接受的金属和胺盐,其中阳离子并不明显促进盐的毒性或生物活性。然而,其它盐可用于例如可在制备期间所用的分离或纯化步骤中,且因此涵盖在本发明的范围内。式I化合物的盐例如可由使式I化合物与一定量(诸如等量)的酸或碱在介质(诸如使盐析出的介质)中或在水性介质中反应,继而冻干来形成。
例示性酸加成盐包括乙酸盐(诸如由乙酸或三卤乙酸(例如三氟乙酸)形成的那些盐)、己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、富马酸盐、葡糖庚酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(由盐酸形成)、氢溴酸盐(由溴化氢形成)、氢碘酸盐、2-羟基乙烷磺酸盐、乳酸盐、马来酸盐(由马来酸形成)、甲烷磺酸盐(由甲烷磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(诸如由硫酸形成的那些盐)、磺酸盐(诸如本文中提及的那些盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(诸如甲苯磺酸盐(tosylate))、十一烷酸盐及其类似盐。
例示性碱性盐包括铵盐,碱金属盐,诸如钠盐、锂盐和钾盐;碱土金属盐,诸如钙盐和镁盐;钡盐、锌盐和铝盐;由有机碱(例如有机胺)形成的盐,诸如三烷基胺(诸如三乙胺)、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺、N,N'-二苄基乙二胺、去氢松香胺、N-乙基哌啶、苄胺、二环己胺或类似药学上可接受的胺,和由氨基酸(诸如精氨酸、赖氨酸和类似物)形成的盐。碱性含氮基团可由试剂季铵化,诸如低碳烷基卤化物(例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物)、二烷基硫酸盐(例如二甲基、二乙基、二丁基和二戊基硫酸盐)、长链卤化物(例如癸基、十二烷基、十四烷基和十八烷基氯化物、溴化物和碘化物)、芳基烷基卤化物(例如苄基和苯乙基溴化物)及其它试剂。优选的盐包括单盐酸盐、硫酸氢盐、甲烷磺酸盐、磷酸盐或硝酸盐。
短语“药学上可接受的”在本文中用于指在合理医学判断范围内,适用于与人类和动物的组织接触而无过度毒性、刺激、过敏响应或其它问题或并发症、与合理益处/风险比相匹配的化合物、物质、组合物和/或剂型。
如本文所使用,“药学上可接受的盐”是指本发明化合物的衍生物,其中母体化合物通过制备其酸盐或碱盐而经修饰。药学上可接受的盐的实例包括(但不限于)碱性基团(诸如胺)的无机酸盐或有机酸盐;以及酸性基团(诸如羧酸)的碱盐或有机盐。药学上可接受的盐包括由例如无毒的无机酸或有机酸形成的母体化合物的常规无毒盐或季铵盐。举例而言,此类常规无毒盐包括那些衍生自无机酸的盐,所述无机酸为诸如盐酸、氢溴酸、硫酸、氨磺酸、磷酸和硝酸;和自有机酸制备的盐,所述有机酸为诸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲烷磺酸、乙烷二磺酸、草酸和羟乙基磺酸及其类似物。
本发明的药学上可接受的盐可通过常规化学方法由含有碱性或酸性部分的母体化合物合成。一般而言,这些盐可通过使这些化合物的游离酸或碱形式与化学计量量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中反应来制备;一般而言,优选非水性介质(如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈)。适合的盐的清单见于Remington'sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA(1990)中,其公开内容特此以引用的方式并入。
涵盖呈掺合物或纯或大体上纯形式的本发明化合物的所有立体异构体。立体异构体可包括经由拥有一或多个手性原子而成为光学异构体的化合物,以及借助于一或多个键周围的受限旋转而成光学异构体的化合物(阻转异构体)。本发明化合物的定义涵盖所有可能的立体异构体及其混合物。具体涵盖外消旋形式和具有指定活性的分离的光学异构体。外消旋形式可通过物理方法拆分,诸如非对映异构体衍生物的分步结晶、分离或结晶,或通过手性柱色谱分离。单个光学异构体可由常规方法(诸如与光活性酸形成盐接着通过结晶)自外消旋体获得。
本发明意欲包括存在于本发明化合物中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。作为一般实例且非限制性地,氢的同位素包括氘和氚。碳的同位素包括13C和14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过类似于本文所述的方法,使用适当同位素标记试剂代替另外使用的非标记试剂来制备。
还涵盖本发明化合物的前药和溶剂合物。术语“前药”表示向受试者给药时通过代谢或化学方法经历化学转化产生式I化合物和/或其盐和/或溶剂合物的化合物。将在体内转化以提供生物活性药剂(即式I化合物)的任何化合物为本发明的范围和精神内的前药。举例而言,含有羧基的化合物可形成生理学上可水解的酯,其充当前药通过在体内水解产生式I化合物本身。此类前药优选经口给药,因为许多情况下水解主要在消化酶的影响下发生。在酯本身具有活性的情况下或在水解发生于血液中的那些情况下,可使用肠胃外给药。式I化合物的生理学上可水解的酯的实例包括C1-6烷基苄基、4-甲氧基苄基、茚满基、苯二甲酰基、甲氧基甲基、C1-6烷酰氧基-C1-6烷基(例如乙酰氧基甲基、特戊酰氧基甲基或丙酰氧基甲基)、C1-6烷氧基羰氧基-C1-6烷基(例如甲氧基羰氧基甲基或乙氧基羰氧基甲基、甘氨酰基氧基甲基、苯基甘氨酰基氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基),和用于例如青霉素和头孢菌素领域中的其它熟知的生理学上可水解的酯。此类酯可通过本领域已知的常规技术来制备。
各种形式的前药是本领域熟知的。关于此类前药衍生物的实例,参见:
a)Bundgaard,H.编,Design of Prodrugs,Elsevier(1985),和Widder,K.等人编,Methods in Enzymology,112:309-396,Academic Press(1985);
b)Bundgaard,H.,第5章,“Design and Application of Prodrugs”,Krosgaard-Larsen,P.等人编,A Textbook of Drug Design and Development,第113-191页,HarwoodAcademic Publishers(1991);和
c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992),各文献以引用的方式并入本文中。
式I化合物及其盐可以互变异构形式存在,其中氢原子转置至分子的其它部分且分子的原子之间的化学键因此发生重排。应了解,所有互变异构体形式,只要其可存在,均包括于本发明内。另外,本发明化合物可具有反式和顺式异构体。
进一步应了解,式I化合物的溶剂合物(例如水合物)也在本发明的范围内。溶剂化方法一般为本领域已知的。
效用
本发明化合物调节IL-23刺激和IFNα刺激的细胞功能,包括基因转录。可通过本发明化合物调节的其它类型的细胞功能包括(但不限于)IL-12刺激的响应。
因此,式I化合物通过对Tyk2起作用来介导信号转导而在治疗与调节IL-23或IFNα的功能,且尤其选择性抑制IL-23、IL-12和/或IFNα的功能相关的病状中具有效用。此类病状包括IL-23、IL-12或IFNα相关疾病,其中致病机制通过这些细胞因子介导。
如本文所使用,术语“治疗(treating/treatment)”涵盖治疗哺乳动物,尤其人类中的疾病状态,且包括:(a)预防或延迟哺乳动物疾病状态的出现,当此类哺乳动物易患该疾病状态但又尚未诊断患有该疾病状态时尤其如此;(b)抑制疾病状态,即遏制其显现;和/或(c)实现症状或疾病状态的全部或部分减少,和/或缓解、改善、减轻或治愈疾病或病症和/或其症状。
鉴于其作为IL-23、IL-12和IFNα刺激的细胞响应的调节剂的活性,式I化合物适用于治疗IL-23、IL-12或IFNα相关疾病,分别包括(但不限于)炎性疾病,诸如克罗恩病、溃疡性结肠炎、哮喘、移植物抗宿主病、同种异体移植物排斥、慢性阻塞性肺病;自身免疫性疾病,诸如格雷夫斯病、类风湿性关节炎、系统性红斑狼疮、皮肤狼疮、狼疮性肾炎、盘状红斑狼疮、牛皮癣;自身炎性疾病,包括CAPS、TRAPS、FMF、成年发作型斯蒂尔病、全身发作型青少年特发性关节炎、痛风、痛风性关节炎;代谢性疾病,包括2型糖尿病、动脉粥样硬化、心肌梗塞;破坏性骨骼病症,诸如骨骼再吸收疾病、骨关节炎、骨质疏松、多发性骨髓瘤相关的骨骼病症;增殖性病症,诸如急性骨髓性白血病、慢性骨髓性白血病;血管生成病症,诸如包括实体肿瘤、眼部血管再生和婴儿血管瘤的血管生成病症;传染病,诸如败血症、败血性休克和志贺杆菌病;神经变性疾病,诸如阿尔兹海默病、帕金森病、大脑缺血或由创伤性损伤所产生的神经变性疾病、致癌性和病毒性疾病,诸如转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤和HIV感染和CMV视网膜炎、AIDS。
更具体地,可用本发明化合物处理的具体病状或疾病包括(但不限于)胰腺炎(急性或慢性)、哮喘、过敏、成人呼吸窘迫综合征、慢性阻塞性肺病、肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、皮肤狼疮、狼疮性肾炎、盘状红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫性胃炎、糖尿病、自身免疫性溶血性贫血、自身免疫性嗜中性白细胞减少症、血小板减少、特应性皮炎、慢性活性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、牛皮癣、移植物抗宿主疾病、通过内毒素诱导的炎性反应、肺结核、动脉粥样硬化、肌肉变性、恶病质、牛皮癣性关节炎、莱特综合征、痛风、创伤性关节炎、风疹性关节炎、急性关节膜炎、胰腺β细胞疾病;以大规模嗜中性白细胞浸润为特征的疾病;类风湿性脊柱炎、痛风性关节炎及其它关节炎病状、大脑疟疾、慢性肺部炎性疾病、硅肺、肺部类肉瘤病、骨骼再吸收疾病、同种异体移植物排斥、归因于感染的发热和肌痛、继发于感染的恶病质、瘢痕瘤形成、疤组织形成、溃疡性结肠炎、发热、流感、骨质疏松、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、败血性休克和志贺杆菌病;阿尔兹海默病、帕金森病、大脑缺血或由创伤性损伤所产生的神经变性疾病;血管生成病症,包括实体肿瘤、眼部血管再生和婴儿血管瘤;病毒性疾病,包括急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎、AIDS、ARC或恶性病、和疱疹;中风、心肌缺血、中风性心脏病发作中的缺血、器官缺氧[此应视为低氧]、血管增生、心脏和肾脏再灌注损伤、血栓形成、心脏肥大、凝血酶诱导的血小板凝集、内毒素血症和/或毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病状和寻常天疱疮。优选的治疗方法为其中病状选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、牛皮癣、强直性脊柱炎、牛皮癣性关节炎和寻常天疱疮的那些方法。或者优选的治疗方法为其中病状选自缺血再灌注损伤的那些方法,所述缺血再灌注损伤包括由中风产生的脑缺血再灌注损伤和由心肌梗塞产生的心脏缺血再灌注损伤。另一优选的治疗方法为其中病状为多发性骨髓瘤的治疗方法。
当本文使用术语“IL-23、IL-12和/或IFNα相关的病状”或“IL-23、IL-12和/或IFNα相关的疾病或病症”时,各自意欲涵盖所有上文所鉴别的病状,如同其详细重复一般,以及受IL-23、IL-12和/或IFNα影响的任何其它病状。
本发明因此提供用于治疗此类病状的方法,其包括向有需要的受试者给药治疗有效量的至少一种式I化合物或其盐。“治疗有效量”意欲包括当单独或组合给药以抑制IL-23、IL-12和/或IFNα功能和/或治疗疾病时有效的本发明化合物的量。
治疗IL-23、IL-12和/或IFNα相关病状的方法可包含单独给药或彼此和/或与可用于治疗此类病状的其它适合的治疗剂组合给药式I化合物。因此,“治疗有效量”还意欲包括有效抑制IL-23、IL-12和/或IFNα功能和/或治疗与IL-23、IL-12和/或IFNα相关的疾病所要求的化合物的组合的量。
例示性此类其它治疗剂包括皮质类固醇、咯利普兰(rolipram)、钙磷酸蛋白、抑制细胞因子的消炎药(CSAID)、白介素-10、糖皮质激素、水杨酸盐、氧化氮及其它免疫抑制剂;核易位抑制剂,诸如去氧斯匹胍素(deoxyspergualin,DSG);非甾体抗炎药(NSAID),诸如布洛芬(ibuprofen)、塞来昔布(celecoxib)和罗非昔布(rofecoxib);类固醇,诸如泼尼松(prednisone)或地塞米松(dexamethasone);抗病毒剂,诸如阿巴卡韦(abacavir);抗增殖剂,诸如甲氨蝶呤(methotrexate)、来氟米特(leflunomide)、FK506(他克莫司(tacrolimus)、);抗疟疾药,诸如羟氯喹(hydroxychloroquine);细胞毒性药物,诸如硫唑嘌呤(azathiprine)和环磷酰胺(cyclophosphamide);TNF-α抑制剂,诸如替尼达普(tenidap)、抗TNF抗体或可溶性TNF受体和雷帕霉素(rapamycin)(西罗莫司(sirolimus)或)或其衍生物。
以上其它治疗剂在与本发明化合物组合使用时可例如以Physicians'DeskReference(PDR)中所示或如原本通过本领域普通技术人员确定的那些量使用。在本发明方法中,此类其它治疗剂可在给药本发明化合物之前、同时或之后给药。本发明还提供能够通过抑制Tyk2介导的信号转导治疗IL-23、IL-12或IFNα相关病状(包括如上文所述IL-23、IL-12和/或IFNα介导的疾病)的药物组合物。
本发明组合物可含有如上文所述的其它治疗剂且可根据技术,诸如药物制剂领域中熟知的那些技术,例如通过采用常规固体或液体媒介物或稀释剂以及类型适于所需给药模式的药物添加剂(例如赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)来配制。
因此,本发明进一步包括包含一或多种式I化合物和药学上可接受的载体的组合物。
“药学上可接受的载体”是指用于将生物活性剂递送至动物,尤其哺乳动物的领域中普遍接受的介质。药学上可接受的载体根据本领域普通技术人员范围内的多个因素配制。这些因素包括(但不限于)所配制的活性剂的类型和性质;给药含该药剂的组合物的受试者;组合物的预期给药途径;和所靶向的治疗适应症。药学上可接受的载体包括水性和非水性液体介质,以及多种固体和半固体剂型。除活性剂以外,此类载体可包括多种不同成分和添加剂,此类额外成分出于本领域普通技术人员熟知的多种原因(例如使活性剂、粘合剂稳定等)包括于制剂中。适合的药学上可接受的载体的描述和涉及其选择的因素见于多种容易获得的来源中,诸如Remington's Pharmaceutical Sciences,第17版(1985),其以全文引用的方式并入本文中。
式I化合物可通过适用于待治疗的病状的任何手段给药,其可取决于位点特异性治疗需要或待递送药物的量。对于皮肤相关疾病而言,通常优选局部给药,且对于癌或癌前病状而言,优选全身治疗,但还涵盖其它递送模式。举例而言,化合物可经口递送,诸如呈片剂、胶囊、颗粒、粉末或液体制剂(包括糖浆)形式;局部递送,诸如呈溶液、悬浮液、凝胶或软膏形式;舌下、颊内、肠胃外递送,诸如通过皮下、静脉内、肌肉内或胸骨内注射或输注技术(例如呈无菌可注射水性或非水性溶液或悬浮液形式);经鼻递送,诸如通过吸入喷雾;局部递送,诸如呈乳膏或软膏形式;经直肠递送,诸如呈栓剂形式;或经脂质体递送。可给药含有无毒的药学上可接受的媒介物或稀释剂的剂量单位制剂。化合物可以适用于立即释放或延长释放的形式给药。立即释放或延长释放可由适合的药物组合物实现,或尤其在延长释放的情况下用诸如皮下植入物或渗透泵的装置实现。
用于局部给药的例示性组合物包括局部载体,诸如(用聚乙烯胶化的矿物油)。
用于经口给药的例示性组合物包括悬浮液,其可含有例如用于增量的微晶纤维素,作为悬浮剂的海藻酸或海藻酸钠、作为粘度增强剂的甲基纤维素和甜味剂或调味剂(诸如本领域已知的那些);和立即释放片剂,其可含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其它赋形剂、粘合剂、增量剂、崩解剂、稀释剂和润滑剂(诸如本领域已知的那些)。本发明化合物还可例如以模制、压缩或冻干片剂的形式通过舌下和/或经颊给药来经口递送。例示性组合物可包括快速溶解稀释剂,诸如甘露糖醇、乳糖、蔗糖和/或环糊精。此类制剂中还可包括高分子量赋形剂,诸如纤维素()或聚乙二醇(PEG);用以辅助粘膜粘附的赋形剂,诸如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)和/或马来酸酐共聚物(例如);和用以控制释放的试剂,诸如聚丙烯酸共聚物(例如)。还可添加润滑剂、助流剂、调味剂、着色剂和稳定剂以便易于制备和使用。
用于经鼻气雾剂或吸入给药的例示性组合物包括溶液,其可含有例如苯甲醇或其它适合的防腐剂、用以增强吸收和/或生物利用度的吸收促进剂和/或其它增溶剂或分散剂,诸如本领域已知的那些。
用于肠胃外给药的例示性组合物包括可注射溶液或悬浮液,其可含有例如适合的无毒肠胃外可接受的稀释剂或溶剂,诸如甘露糖醇、1,3-丁二醇、水、林格氏溶液、等张氯化钠溶液或其它适合的分散剂或润湿剂和悬浮剂(包括合成的单甘油酯或二甘油酯)和脂肪酸(包括油酸)。
用于经直肠给药的例示性组合物包括栓剂,其可含有例如适合的无刺激性赋形剂,诸如可可脂、合成的甘油酯或聚乙二醇,其在常温为固体但在直肠腔内液化和/或溶解以释放药物。
本发明化合物的治疗有效量可由本领域普通技术人员确定,且包括用于哺乳动物的例示性剂量每天每kg体重约0.05至1000mg;1-1000mg;1-50mg;5-250mg;250-1000mg的活性化合物,其可以单次剂量或以个别分次剂量形式给药,诸如每天1至4次。应了解,任何特定受试者的特定剂量水平和剂量频率可以是变化的且其将取决于多种因素,所述因素包括所采用的特定化合物的活性;该化合物的代谢稳定性和作用时长;受试者的物种、年龄、体重、一般健康状况、性别和饮食;给药模式和时间;排泄速率;药物联用;和特定病状的严重程度。治疗的优选受试者包括动物,最优选哺乳动物物种,诸如人类和家养动物,诸如狗、猫、马及其类似动物。因此,当本文使用“患者”时,该术语意欲包括由调节IL-23、IL-12和/或IFNα介导的功能影响的所有受试者,最优选哺乳动物物种。
制备方法
本发明化合物可通过有机化学领域技术人员可得的多种方法合成。下文描述用于制备本发明化合物的一般合成方案。这些方案为说明性的且不意欲限制本领域技术人员可用于制备本文所披露化合物的可能技术。制备本发明化合物的不同方法对于本领域技术人员显而易见。另外,合成中的多个步骤可以替代次序进行以得到一或多种期望化合物。下文所述的制备和实施例部分中给出通过一般方案中所述的方法制备的本发明化合物的实施例。
实施例
式(I)化合物和用于制备式(I)化合物的中间体可使用以下实施例中所示的操作及相关操作制备。用于这些实施例中的方法和条件及这些实施例中制备的实际化合物并不意欲为限制性的,但意欲表明可如何制备式(I)化合物。当未通过本文所描述的操作制备时,用于这些实施例中的起始物质和试剂通常为市售的或在化学文献中报道或可通过使用化学文献中所描述的操作来制备。
在给定实施例中,短语“干燥且浓缩”通常是指经硫酸钠或硫酸镁对于有机溶剂中的溶液进行干燥,之后自滤液过滤且移除溶剂(通常在减压下且在适合于所制备物质的稳定性的温度)。使用Isco中压色谱设备(Teledyne Corporation),利用预装填的硅胶管柱,用所指示的溶剂或溶剂混合物洗脱进行柱色谱。使用以下缩写:
缩写
制备
以下列出的制备用于合成不是从商业来源获得的试剂,而是以及用于制备本发明的式I化合物。除非另有说明,否则表和方案中的所有手性化合物都是外消旋的。
反相制备型高效液相色谱("HPLC")通过Shimadzu 8A液相色谱仪使用YMC S5 ODS柱(20x 100,20x 250,或30x 250毫米("mm"))来进行。梯度洗脱用甲醇("MeOH")/水混合物在0.1%三氟乙酸("TFA")的存在下进行。
HPLC方法
方法A:(分析型)
柱:Waters Acquity BEH C18,2.0x 50mm,1.7μm;流动相A:含0.1%TFA的水;流动相B:含0.1% TFA的MeCN;温度:40℃;流速:1mL/min;梯度:在1.5min内0-100% B,然后在100% B等度0.5min。
方法B:(分析型)
柱:AcquityBEH C18,2.1x 50mm,1.7μm(Waters Corp.);流动相A:含0.05% TFA的水;流动相B:含0.05% TFA的MeCN;温度:50℃;流速:0.8mL/min;梯度:在1.8min内0-100% B。
方法C:(分析型)
柱:AcquityBEH C18,2.1x 50mm,1.7μm(Waters Corp.);流动相A:含0.1% TFA的水;流动相B:含0.1% TFA的MeCN;温度:50℃;流速:1mL/min;梯度:在3min内0-100% B,然后在100% B等度0.5min。
方法D:(QC-ACN-AA-XB)Waters Acquity UPLC BEH C18,2.1x 50mm,1.7-μm颗粒;流动相A:含10mM乙酸铵的5:95乙腈:水;流动相B:含10mM乙酸铵的95:5乙腈:水;温度:50℃;梯度:在3min内0-100% B,然后在100% B保持0.75分钟;流量:1.0mL/min;检测:在220nm处的UV。
实施例1
6-(环丙烷甲酰氨基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1:
在冰冷却下加入溶解在浓硫酸(3mL)、硝酸(0.378ml,8.45mmol)(发烟)中的4-溴吡啶-3-醇(0.98g,5.63mmol),将混合物搅拌20小时。在搅拌下将反应混合物缓慢地倒入冰水(40mL)中。将混合物用AcOEt(50mL)萃取,将其用盐水(30mL)洗涤,经Na2SO4干燥,并且在真空下浓缩,得到4-溴-2-硝基吡啶-3-醇(0.45g),将其原样使用。LCMS m/z 219.1(M+H)+;HPLC tR 1.04min(分析型HPLC方法A);1H NMR(400MHz,甲醇-d4)δ8.01(d,J=4.6Hz,1H),7.95(d,J=4.6Hz,1H)。
步骤2:
将4-溴-2-硝基吡啶-3-醇(400mg,1.827mmol)溶解在DMF(5mL)中。加入K2CO3(505mg,3.65mmol),将混合物在室温搅拌10min,然后加入MeI(228μl,3.65mmol),将混合物在室温搅拌过夜(o/n)。将反应混合物用AcOEt(40mL)和水(20mL)稀释,分离有机层,用饱和NaHCO3(2x 20mL)、盐水(20mL)洗涤,经Na2SO4干燥,并且在真空下浓缩。将粗制产物用ISCO柱(12g,AcOEt/己烷=0-60%,梯度时间=16min)纯化,得到4-溴-3-甲氧基-2-硝基吡啶(260mg)。LCMS m/z 233.1(M+H)+;HPLC tR 1.17min(分析型HPLC方法A);1H NMR(400MHz,氯仿-d)δ8.10(d,J=5.1Hz,1H),7.79(d,J=5.1Hz,1H),4.06(s,3H)。
步骤3:
将4-溴-3-甲氧基-2-硝基吡啶(350mg,1.502mmol)溶解在AcOH(1mL)、EtOH(1mL)和水(0.5mL)中,加入铁(419mg,7.51mmol)。1h后,LC-MS指示完全消耗了原料,将混合物过滤,滤液用AcOEt(50mL)稀释,将其与饱和NaHCO3混合,有机层用盐水(30mL)洗涤,经Na2SO4干燥,并且在真空下浓缩,得到期望产物,将其原样使用(300mg)。LCMS m/z 205.1(M+H)+;HPLC tR 0.66min(分析型HPLC方法A);1H NMR(400MHz,甲醇-d4)δ7.51(d,J=5.7Hz,1H),6.81(d,J=5.5Hz,1H),3.89-3.78(m,3H)。
步骤4:
将4-溴-3-甲氧基吡啶-2-胺(100mg,0.493mmol)与二氰基锌(57.8mg,0.493mmol)、Pd2(dba)3(18.04mg,0.020mmol)、DPPF(21.84mg,0.039mmol)、锌(3.86mg,0.059mmol)在乙酰胺(2mL)中混合。将混合物用N2吹扫几分钟,在135℃加热过夜。LC-MS指示完全消耗了原料,将混合物过滤,滤液用AcOEt(40mL)稀释,将其用饱和NaHCO3(2x 20mL)和盐水(20mL)洗涤,经Na2SO4干燥,并且在真空下浓缩,得到2-氨基-3-甲氧基异烟腈,将其用ISCO柱(12g,MeOH/DCM=0-15%,12min梯度)纯化(45mg期望产物)。LCMS m/z 150.3(M+H)+;HPLC tR 0.34min(分析型HPLC方法A);1H NMR(400MHz,甲醇-d4)δ7.80-7.67(m,1H),6.79-6.71(m,1H),4.06(s,3H)。
步骤5:
向在5mL THF(55-60℃)中的2-氨基-3-甲氧基异烟腈(100mg,0.670mmol)和N-甲基甲酰肼(174mg,2.347mmol)中加入叔丁醇钾(2682μl,2.68mmol)。将混合物在60℃搅拌1h。将混合物与1mL MeOH混合,浓缩,用ISCO柱(12g,MeOH/DCM=0-10%,梯度时间=12min)纯化,得到3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-胺(62mg)。LCMS m/z 206.3(M+H)+;HPLC tR 0.36min(分析型HPLC方法A);1H NMR(400MHz,甲醇-d4)δ8.50(s,1H),7.74(d,J=5.5Hz,1H),7.10(d,J=5.3Hz,1H),4.03(s,3H),3.75(s,3H)。
步骤6:
向4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(61.1mg,0.292mmol)和3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-胺(60mg,0.292mmol)在四氢呋喃(10mL)中的澄清溶液中逐滴加入双(三甲基甲硅烷基)氨基锂(877μl,0.877mmol),使颜色变成深琥珀色,将混合物在室温搅拌过夜。通过加入水(2mL)淬灭反应,用AcOEt(40mL)萃取,用盐水(20mL)洗涤,有机层经Na2SO4干燥,并且在真空下浓缩,残留物用ISCO柱(12g,AcOEt/己烷=0-100%,梯度时间=12min)纯化,得到6-氯-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(50mg)。LCMS m/z 378.4(M+H)+;HPLC tR 1.01min(分析型HPLC方法A);1H NMR(400MHz,氯仿-d)δ9.41-9.36(m,1H),8.22-8.16(m,2H),7.67-7.61(m,1H),4.05(d,J=13.4Hz,6H)。
步骤7:
将6-氯-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(15mg,0.040mmol)、环丙烷甲酰胺(6.76mg,0.079mmol)、Xanthpos(4.59mg,7.94μmol)、Cs2CO3(25.9mg,0.079mmol)和Pd2(dba)3(3.64mg,3.97μmol)在二噁烷(1mL)中的混合物用氮气吹扫2min,然后将其在130℃搅拌3h。冷却后,将混合物用DMSO稀释,粗制物质经制备型LC/MS利用以下条件进行纯化:柱:XBridge C18,19x 200mm,5-μm颗粒;流动相A:含10-mM乙酸铵的5:95乙腈:水;流动相B:含10-mM乙酸铵的95:5乙腈:水;梯度:在20分钟内5-55% B,然后在100% B保持5分钟;流量:20mL/min。将包含期望产物的级分合并,通过离心蒸发干燥。6-(环丙烷甲酰氨基)-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺的为8.6mg,通过LCMS分析估计其纯度为99%。LCMS m/z 427.5(M+H)+;HPLC tR 0.89min(分析型HPLC方法A);1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),11.46-11.25(m,1H),9.88(s,1H),9.24(br s,1H),8.75-8.60(m,1H),8.14(d,J=5.1Hz,1H),7.50(d,J=5.2Hz,1H),3.99(s,3H),3.94-3.81(m,3H),2.18-2.04(m,1H),0.96-0.80(m,4H)。
表1中的实施例使用与用于制备实施例1类似的操作来制备。
表1
实施例41
6-(环丙烷甲酰氨基)-4-((3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺
步骤1:
将4,6-二氯-N-(甲基-d3)烟酰胺(430mg,2.065mmol)和2-氨基-3-甲氧基异烟腈(280mg,1.877mmol)在DMF(20ml)中的溶液冷却至0℃,一次性地加入NaH(300mg,7.51mmol)。将反应混合物搅拌过夜,使得反应温热至室温。LCMS表明反应不完全。再顺序地加入4,6-二氯-N-(甲基-d3)烟酰胺(430mg,2.065mmol)和NaH(300mg,7.51mmol)。再搅拌4小时后,用少量水淬灭。将反应混合物在真空中浓缩。将所得固体在DCM中研磨。通过过滤收集固体,干燥,得到6-氯-4-((3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(370mg,1.154mmol,61.4%收率)。MS(m+1)=321.0。HPLC峰RT=0.86分钟。(方法I)
步骤2:
将6-氯-4-((4-氰基-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺(40mg,0.125mmol)、环丙烷甲酰胺(21.23mg,0.249mmol)、Xanthpos(14.43mg,0.025mmol)、Cs2CO3(81mg,0.249mmol)和Pd2(dba)3(11.42mg,0.012mmol)在二噁烷(0.60mL)中的混合物用氮气吹扫2min,然后密封,在130℃搅拌1h。将反应混合物用乙酸乙酯稀释,用饱和NaCl洗涤。将有机层用MgSO4干燥,过滤,浓缩。MS(m+1)=370.0。HPLC峰RT=0.67分钟。将粗制残留物转移至小瓶中,加入乙醇(5mL),随后加入1M的在EtOH中的NH2OH(0.624mL,0.624mmol)。将反应混合物在85℃在密封小瓶中加热过夜。冷却,过滤掉任何固体。将滤液浓缩,无需进一步纯化即可用于下一步。MS(m+1)=403.1。HPLC峰RT=0.50分钟。(方法I)。
步骤3:
向(E)-6-(环丙烷甲酰氨基)-4-((4-(N'-羟基氨基甲酰氨基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺(50mg,0.124mmol)和乙酸(0.014mL,0.248mmol)在DMF(2mL)中的混合物中加入DIC(0.039mL,0.248mmol)。1小时后,LCMS显示偶联完全。加入在THF中的TBAF(0.373mL,0.373mmol)。在80℃加热过夜。将反应混合物用二氯甲烷稀释,用H2O和1mL饱和NaHCO3洗涤。再用水洗涤4次以除去TBAF。将有机层用MgSO4干燥,过滤,浓缩。将粗制物质通过制备型LC/MS利用以下条件进行纯化:柱:XBridge C18,19x 200mm,5-μm颗粒;流动相A:含10-mM乙酸铵的5:95乙腈:水;流动相B:含10-mM乙酸铵的95:5乙腈:水;梯度:在20分钟内15-55% B,然后在100% B保持5分钟;流量:20mL/min。将包含期望产物的级分合并,通过离心蒸发干燥,得到6-(环丙烷甲酰氨基)-4-((3-甲氧基-4(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺(6.2mg,0.014mmol,11.23%收率)。1H NMR(500MHz,DMSO-d6)δ12.12(s,1H),10.81(s,1H),9.59(s,1H),8.71(s,1H),8.62(s,1H),8.21(d,J=5.1Hz,1H),7.39(d,J=5.1Hz,1H),3.88(s,3H),2.72(s,3H),2.03(d,J=4.6Hz,1H),0.97-0.69(m,4H);MS(m+1)=427.3;HPLC峰RT=1.14分钟。(方法qc-acn-tfa-xb-02);HPLC纯度=96%
实施例42
4-((3-甲氧基-4-(5-(吗啉代甲基)-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-三氘代甲基-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺
步骤1:
将4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺(0.420g,2.01mmol)和2-氨基-3-甲氧基异烟腈(0.300g,2.01mmol)在DMF(13.4mL)中的溶液冷却至0℃,一次性地加入NaH(0.257g,6.44mmol)。5分钟后,使得反应温热至室温。2.5小时后,再加入NaH(0.050g,1.25mmol)。再搅拌21.5小时后,加入NaH(0.050g,1.25mmol),30分钟后,再次加入NaH(0.050g,1.25mmol),此时认为反应完全。用饱和含水氯化铵、水和DCM淬灭反应,析出固体。加入饱和含水KH2PO4,使混合物至pH为约5。将淬灭的反应混合物用CHCl3/iPrOH的4/1混合物萃取三次,将合并的有机物用水洗涤,浓缩,由于悬浮的固体而无需过滤。浓缩有机层后,将得到的橙色固体吸收为DCM中的浆料,通过中号垂熔漏斗过滤。将固体用DCM研磨,干燥,得到6-氯-4-((4-氰基-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(0.273g,0.849mmol,42%收率),其为灰白色固体。LCMS RT=0.89分钟(TS)。MS(m+1)=322.0。该物质无需另外纯化即可继续进行。
步骤2:
将6-氯-4-((4-氰基-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(0.100g,0.311mmol)、Xanthpos(0.036g,0.062mmol)、Pd2(dba)3(0.028g,0.031mmol)、4-甲基吡啶-2-胺(0.067g,0.622mmol)和Cs2CO3(0.253g,0.777mmol)在二噁烷(3.11mL)中的混合物通过将氮气鼓泡通过混合物10分钟进行脱气。将反应容器密封并且加热至130℃持续1小时。将反应冷却至室温,用EtOAc稀释,通过硅藻土垫过滤。滤液用水洗涤两次,经硫酸钠干燥,过滤,浓缩,得到粗制黄色固体。该粗制黄色固体包含一些期望物质以及剩余的胺和催化剂。其余产物析出并且保留在具有硅藻土垫的垂熔漏斗中。将来自垂熔漏斗的固体混合物悬浮在20mL的DMF中,然后将其过滤。将DMF滤液用EtOAc(120mL)稀释,用水洗涤。将有机层浓缩,悬浮于DCM/Et2O中,在垂熔漏斗中真空干燥。将收集的固体用水和Et2O研磨,得到30mg棕色固体。将来自初始反应过滤和后处理中的粗制黄色固体用Et2O研磨,得到98mg固体。总共得到128mg固体,这比定量回收率高。认为该物质定量转化为4-((4-氰基-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺(0.122g,0.311mmol,100%收率)LCMS RT=0.71分钟(TS)。MS(m+1)=394.1,无需另外纯化即可继续进行。将盐酸羟胺(0.216g,3.11mmol)和KOH(0.174g,3.11mmol)在乙醇(6.22mL)中的溶液在室温搅拌1小时,然后过滤。将滤液加入至来自上述4-((4-氰基-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺(0.122g,0.311mmol)的物质中,将所得混合物密封,加热至85℃。5小时15min后,反应已结束。将反应冷却至室温,浓缩,无需纯化即可继续进行。认为定量获取(Z)-4-((4-(N'-羟基氨基甲酰氨基)-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺(0.133g,3.11mmol,100%收率)。LCMS RT=0.55分钟(TS)。MS(m+1)=427.1。
步骤3:
向(Z)-4-((4-(N'-羟基氨基甲酰氨基)-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺(44.4mg,0.104mmol)和2-吗啉代乙酸(45.3mg,0.312mmol)在DMF(1mL)中的溶液中加入DIC(0.065mL,0.416mmol)。30分钟后,一次性地加入TBAF(0.624mL,0.624mmol)。30分钟后,加入另一等份的TBAF(0.624mL,0.624mmol)。再过10分钟后,将反应用DCM、水稀释,加入约1.5mL NaHCO3以保持溶液为碱性。有机层用水洗涤五次,经硫酸钠干燥,过滤,浓缩,得到粗制棕色物质。该物质溶于DMF中,并且通过制备型LC/MS利用以下条件进行纯化:柱:XBridge C18,19x 200mm,5-μm颗粒;流动相A:含0.1%三氟乙酸的5:95乙腈:水;流动相B:含0.1%三氟乙酸的95:5乙腈:水;梯度:在20分钟内5-45%B,然后在100% B保持5分钟;流量:20mL/min。将包含期望产物的级分合并,通过离心蒸发干燥,得到4-((3-甲氧基-4-(5-(吗啉代甲基)-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-三氘代甲基-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺,TFA(11.1mg,0.017mmol,16.19%收率),通过LCMS分析估计其纯度为98%。使用两次分析型LC/MS进样来确定最终纯度。进样1条件:柱:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7-μm颗粒;流动相A:含10mM乙酸铵的5:95乙腈:水;流动相B:含10mM乙酸铵的95:5乙腈:水;温度:50℃;梯度:在3min内0-100% B,然后在100% B保持0.75分钟;流量:1.0mL/min;检测:在220nm处的UV。进样2条件:柱:Waters Acquity UPLC BEH C18,2.1x 50mm,1.7-μm颗粒;流动相A:含0.1%三氟乙酸的5:95乙腈:水;流动相B:含0.1%三氟乙酸的95:5乙腈:水;温度:50℃;梯度:在3min内0-100% B,然后在100% B保持0.75分钟;流量:1.0mL/min;检测:在220nm处的UV。LCMS RT=1.73分钟(QC-ACN-AA-XB)。MS(m+1)=536.3。1H NMR(500MHz,DMSO-d6)δ12.64(s,1H),9.32(s,1H),9.22(s,1H),8.33(d,J=5.1Hz,1H),8.29(d,J=5.6Hz,1H),7.94(s,1H),7.55(d,J=5.1Hz,1H),7.37(s,1H),7.07(br d,J=5.4Hz,1H),4.25(s,2H),3.92(s,3H),3.67(br s,4H),2.79(br s,4H),2.41(s,3H)
表2中的实施例使用与用于制备实施例41和实施例42类似的操作来制备。
表2
实施例83
6-(环丙烷甲酰氨基)-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1.合成3'-甲氧基-[2,4'-联吡啶]-2'-胺
将4-溴-3-甲氧基吡啶-2-胺(90mg,0.443mmol)、2-(三丁基甲锡烷基)吡啶(245mg,0.665mmol)和双(三苯基膦)氯化钯(II)(46.7mg,0.066mmol)在1,4-二噁烷(3.5mL)中的混合物在115℃加热16h。一旦冷却至室温,将混合物用乙酸乙酯(15mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。将残留物经历快速色谱(24g硅胶,固体负载,100%乙酸乙酯),得到期望产物3'-甲氧基-[2,4'-联吡啶]-2'-胺(64.0mg,0.318mmol,71.8%收率),其为白色固体。LCMS m/z=202.1(M+H)+。
步骤2.合成6-氯-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和3'-甲氧基-[2,4'-联吡啶]-2'-胺(63.7mg,0.316mmol)在四氢呋喃(4mL)中的溶液中经2min加入在THF中的双(三甲基甲硅烷基)氨基锂(0.753mL,0.753mmol)。在室温将所得混合物搅拌1h。将反应用水(2mL)淬灭。将混合物用1N HCl溶液调节至pH为9-10,用乙酸乙酯(80mL)稀释,用水(20mL)和盐水(20mL)洗涤。有机层经无水MgSO4干燥,在真空下浓缩。将残留物经历快速色谱(24g硅胶,固体负载,35-80%乙酸乙酯/二氯甲烷),得到期望产物6-氯-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(47.6mg,0.127mmol,42.3%收率),其为白色固体。LCMS m/z=373.9(M+H)+。
步骤3.合成6-(环丙烷甲酰氨基)-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
6-氯-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(47.6mg,0.127mmol)、环丙烷甲酰胺(27.1mg,0.318mmol)、三(二亚苄基丙酮)二钯(0)(17.49mg,0.019mmol)、Xanthpos(11.05mg,0.019mmol)和碳酸铯(104mg,0.318mmol)在1,4-二噁烷(2.2mL)和NMP(0.3mL)中的混合物在微波下在145℃加热1h。将混合物用乙酸乙酯(8mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。向残留物中加入DMSO(1.5mL),随后加入水(20mL)。通过抽滤收集不溶物为米色固体,在50℃在真空下干燥。将该物质通过快速色谱(24g硅胶,固体负载,0-6% MeOH/CH2Cl2)进一步纯化,得到期望产物6-(环丙烷甲酰氨基)-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(21.9mg,0.050mmol,39.5%收率),其为浅黄色固体。LCMS m/z=423.0(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),11.34(s,1H),9.88(s,1H),9.24(s,1H),8.85-8.72(m,1H),8.19(d,J=5.3Hz,1H),8.03-7.95(m,2H),7.53-7.48(m,1H),7.37(d,J=5.3Hz,1H),3.63(s,3H),2.19-2.10(m,1H),0.96-0.84(m,4H)。
实施例84
6-(环丙烷甲酰氨基)-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺
步骤1.合成6-氯-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺
在室温向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和3'-甲氧基-[2,4'-联吡啶]-2'-胺(62.6mg,0.311mmol)在四氢呋喃(4mL)中的溶液中经2min加入在THF中的双(三甲基甲硅烷基)氨基锂(0.740mL,0.740mmol)。在室温将所得混合物搅拌2.5h。将反应用水(2mL)淬灭。将混合物用1N HCl溶液调节至pH为9-10,用乙酸乙酯(80mL)稀释,用水(20mL)和盐水(20mL)洗涤。有机层经无水MgSO4干燥,在真空下浓缩。将残留物经历快速色谱(24g硅胶,固体负载,50-100%乙酸乙酯/二氯甲烷),得到期望产物(37.0mg,0.099mmol,33.5%收率),其为白色固体。LCMS m/z=372.9(M+H)+。
步骤2.合成6-(环丙烷甲酰氨基)-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺
将6-氯-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-三氘代甲基烟酰胺(37mg,0.099mmol)、环丙烷甲酰胺(21.11mg,0.248mmol)、三(二亚苄基丙酮)二钯(0)(13.63mg,0.015mmol)、Xanthpos(8.61mg,0.015mmol)和碳酸铯(81mg,0.248mmol)在1,4-二噁烷(2.2mL)和NMP(0.3mL)中的混合物在微波下在145℃加热1h。将混合物用乙酸乙酯(8mL)稀释,通过硅藻土过滤。滤液用DMSO和MeOH稀释,进样至制备型HPLC。将正确的级分合并,在真空下浓缩,用1.5M K2HPO4溶液碱化至pH为9-10,用二氯甲烷(3x 30mL)萃取。合并的萃取物经无水NaSO4干燥,在真空下浓缩。将残留物通过快速色谱(12g硅胶,固体负载,1-8%甲醇/二氯甲烷)进一步纯化,得到期望产物6-(环丙烷甲酰氨基)-4-((3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-三氘代甲基烟酰胺(13.2mg,0.031mmol,30.9%收率)为浅色固体。LCMS m/z=422.0(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.01(s,1H),10.77(br s,1H),9.57(s,1H),8.80–8.74(m,1H),8.67(s,1H),8.60(s,1H),8.14(d,J=5.1Hz,1H),8.04–7.94(m,2H),7.49(ddd,J=6.7,4.7,2.1Hz,1H),7.31(d,J=5.3Hz,1H),3.60(s,3H),2.10–1.99(m,1H),0.90–0.78(m,4H)。
实施例85
6-(环丙烷甲酰氨基)-4-((5-(环丙烷甲酰氨基)-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺
步骤1.合成5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-胺
在115℃将4-溴-3-甲氧基吡啶-2-胺(180mg,0.887mmol),5-氯-2-(三丁基甲锡烷基)吡啶(535mg,1.330mmol)和双(三苯基膦)氯化钯(II)(93mg,0.133mmol)在1,4-二噁烷(8mL)中的混合物加热16h。将混合物用乙酸乙酯(15mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。将残留物经历快速色谱(24g硅胶,固体负载,100%乙酸乙酯),得到期望产物5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-胺(177mg,0.751mmol,85%收率),其为白色固体。LCMSm/z=236.0(M+H)+。
步骤2.合成6-氯-4-((5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺
在室温向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-胺(88mg,0.373mmol)在四氢呋喃(5mL)中的溶液中经2min加入在THF中的双(三甲基甲硅烷基)氨基锂(0.889mL,0.889mmol)。在室温将所得混合物搅拌90min。将反应用水(2mL)淬灭。将混合物用1N HCl溶液调节至pH为9-10,用乙酸乙酯(80mL)稀释,用水(20mL)和盐水(20mL)洗涤。有机层经无水MgSO4干燥,在真空下浓缩。将残留物经历快速色谱(24g硅胶,固体负载,50-100%乙酸乙酯/二氯甲烷),得到期望产物(68mg,0.167mmol,46.9%收率),其为白色固体。
步骤3.合成6-(环丙烷甲酰氨基)-4-((5-(环丙烷甲酰氨基)-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺
将6-氯-4-((5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-(甲基-d3)烟酰胺(40mg,0.098mmol)、环丙烷甲酰胺(20.90mg,0.246mmol)、三(二亚苄基丙酮)二钯(0)(13.49mg,0.015mmol)、Xanthpos(8.52mg,0.015mmol)和碳酸铯(80mg,0.246mmol)在1,4-二噁烷(2.2mL)和NMP(0.3mL)中的混合物在微波下在140℃加热1h。将混合物用乙酸乙酯(8mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。残留物溶解在DMSO(2mL)中并且提交给SCP组用于纯化,得到期望产物(20mg,37%收率)。LCMS m/z=505.2(M+H)+;1H NMR(500MHz,DMSO-d6)δ11.98(br s,1H),10.76(s,1H),10.67(s,1H),9.58(s,1H),8.90(s,1H),8.68(s,1H),8.58(s,1H),8.22(br d,J=8.2Hz,1H),8.11(d,J=5.1Hz,1H),8.01(br d,J=8.6Hz,1H),7.34(d,J=5.1Hz,1H),3.60(s,3H),2.03(br s,1H),1.88-1.81(m,1H),0.93-0.76(m,8H)。
实施例86
4-((5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-6-(环丙烷甲酰氨基)-N-(甲基-d3)烟酰胺
将6-氯-4-((5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-N-三氘代甲基烟酰胺(53mg,0.130mmol)、环丙烷甲酰胺(11.30mg,0.133mmol)、三(二亚苄基丙酮)二钯(0)(17.88mg,0.020mmol)、Xanthpos(11.29mg,0.020mmol)和碳酸铯(106mg,0.325mmol)在1,4-二噁烷(2.5mL)和NMP(0.3mL)中的混合物在微波下在135℃加热1h。将混合物用乙酸乙酯(8mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。残留物溶解在DMSO和MeOH中,进样至制备型HPLC。将正确的级分合并,在真空下浓缩,用1.5M K2HPO4溶液碱化至pH为9-10,用二氯甲烷(3x 35mL)萃取。合并的萃取物经无水MgSO4干燥。在真空下除去溶剂,得到期望产物4-((5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基)氨基)-6-(环丙烷甲酰氨基)-N-三氘代甲基烟酰胺(4.6mg,9.38μmol,7.21%收率),其为黄色固体。LCMS m/z=455.9(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.05(s,1H),10.93-10.72(m,1H),9.55(s,1H),8.82(dd,J=2.5,0.7Hz,1H),8.72-8.67(m,1H),8.60(s,1H),8.18-8.09(m,2H),8.07-8.02(m,1H),7.31(d,J=5.3Hz,1H),3.61(s,3H),2.09-1.99(m,1H),0.90-0.81(m,4H)
实施例87
6-(环丙烷甲酰氨基)-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1.合成5-氯-N,N-二甲基吡嗪-2-甲酰胺
在室温向5-氯吡嗪-2-甲酸(1.00g,6.31mmol)在二氯甲烷(12mL)和DMF(0.015mL)中的悬浮液中经10min逐滴加入草酰氯(0.804mL,7.25mmol)。在室温将混合物搅拌2h,然后在真空下浓缩至干。残留物溶解在二氯甲烷(15mL)中。在室温经10min加入在THF中的二甲基胺(3.94mL,7.88mmol),随后加入三乙胺(1.934mL,13.88mmol)。在室温将混合物搅拌2h。将混合物用乙酸乙酯(50mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩至干,残留物施用于快速色谱(80g硅胶,固体负载,65-100%乙酸乙酯),得到期望产物5-氯-N,N-二甲基吡嗪-2-甲酰胺(1.07g,5.76mmol,91%收率),其为白色固体。LCMS m/z=186.1(M+H)+。
步骤2.合成NN-二甲基-5-(三甲基甲锡烷基)吡嗪-2-甲酰胺
将5-氯-N,N-二甲基吡嗪-2-甲酰胺(300mg,1.616mmol)、碘化四丁基铵(657mg,1.778mmol)、1,1,1,2,2,2-六甲基二锡烷(0.402mL,1.940mmol)和四(三苯基膦)钯(0)(112mg,0.097mmol)在甲苯(8mL)中的混合物进行脱气并且在105℃加热16h。一旦冷却至室温,将混合物用乙酸乙酯(15mL)稀释,通过硅藻土过滤。滤液在真空下浓缩,将残留物经历快速色谱(80g硅胶,固体负载,35-85%乙酸乙酯/己烷),得到期望产物N,N-二甲基-5-(三甲基甲锡烷基)吡嗪-2-甲酰胺(96mg,0.306mmol,18.92%收率)为浅黄色固体。LCMS m/z=315.9(M+H)+。
步骤3.合成5-(2-氨基-3-甲氧基吡啶-4-基)-N,N-二甲基吡嗪-2-甲酰胺
在115℃将4-溴-3-甲氧基吡啶-2-胺(133mg,0.655mmol)、N,N-二甲基-5-(三甲基甲锡烷基)吡嗪-2-甲酰胺(226mg,0.721mmol)和双(三苯基膦)氯化钯(II)(69.0mg,0.098mmol)在1,4-二噁烷(6mL)中的混合物加热16h。将混合物用乙酸乙酯(15mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。将残留物经历快速色谱(24g硅胶,固体负载,0-6%MeOH/CH2Cl2),得到期望产物5-(2-氨基-3-甲氧基吡啶-4-基)-N,N-二甲基吡嗪-2-甲酰胺(88mg,0.322mmol,49.2%收率),其为白色固体。LCMS m/z=274.0(M+H)+。
步骤4.合成6-氯-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和5-(2-氨基-3-甲氧基吡啶-4-基)-N,N-二甲基吡嗪-2-甲酰胺(109mg,0.400mmol)在四氢呋喃(6mL)中的溶液中经2min加入在THF中的双(三甲基甲硅烷基)氨基锂(0.981mL,0.981mmol)。在室温将所得混合物搅拌1h。将反应用水(60mL)淬灭。将混合物用1N HCl溶液调节至pH为9-10。通过抽滤收集不溶产物6-氯-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(91mg,0.204mmol,52.0%收率),其为米色固体,并且在50℃在真空下干燥。LCMS m/z=445.9(M+H)+。
步骤5.合成6-(环丙烷甲酰氨基)-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将反应物1(45mg,0.101mmol)、环丙烷甲酰胺(21.47mg,0.252mmol)、三(二亚苄基丙酮)二钯(0)(13.86mg,0.015mmol)、Xanthpos(8.76mg,0.015mmol)和碳酸铯(82mg,0.252mmol)在1,4-二噁烷(2.6mL)和NMP(0.4mL)中的混合物在微波下在145℃加热1h。将混合物用乙酸乙酯(8mL)稀释,通过硅藻土过滤。将滤液在真空下浓缩。残留物溶解在DMSO和MeOH中,进样至制备型HPLC。将正确的级分合并,在真空下浓缩,用1.5M K2HPO4溶液碱化至pH为9,用二氯甲烷(3x 35mL)萃取。合并的萃取物经无水Na2SO4干燥,在真空下浓缩。将残留物通过快速色谱(24g硅胶,固体负载,0-7% MeOH/二氯甲烷)进一步纯化,得到期望产物6-(环丙烷甲酰氨基)-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(10.4mg,0.021mmol,20.63%收率),其为黄色固体。LCMSm/z=495.0(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.50(s,1H),11.36(s,1H),9.88(s,1H),9.26(s,1H),9.21(d,J=1.5Hz,1H),9.02(d,J=1.5Hz,1H),8.26(d,J=5.3Hz,1H),7.44(d,J=5.3Hz,1H),3.71(s,3H),3.08(s,3H),3.06(s,3H),2.19–2.11(m,1H),0.95–0.86(m,4H)。
实施例88
6-(环丙烷甲酰氨基)-4-((4-(5-(乙基(甲基)氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
该化合物使用与用于制备实施例87类似的操作来制备。LCMS m/z=509.0(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),11.40(s,1H),9.89(d,J=2.4Hz,1H),9.29(s,1H),9.21(dd,J=5.0,1.5Hz,1H),9.02(dd,J=2.9,1.5Hz,1H),8.26(d,J=5.3Hz,1H),7.44(d,J=5.1Hz,1H),3.70(s,3H),3.55(q,J=7.1Hz,1H),3.41-3.35(m,1H),3.04(d,J=8.3Hz,3H),2.20-2.07(m,1H),1.23-1.12(m,3H),0.96-0.82(m,4H)。
实施例89
6-(2-环丙基乙酰氨基)-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
该化合物使用与用于制备实施例87类似的操作来制备。LCMS m/z=509.1(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.51(s,1H),10.95(s,1H),9.93(s,1H),9.26(s,1H),9.22(d,J=1.5Hz,1H),9.03(d,J=1.5Hz,1H),8.30(d,J=5.3Hz,1H),7.46(d,J=5.3Hz,1H),3.72(s,3H),3.09(s,3H),3.06(s,3H),2.40(d,J=7.0Hz,2H),1.17–1.05(m,1H),0.55–0.48(m,2H),0.26–0.20(m,2H)。
实施例90
4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-吡唑-3-基)氨基)哒嗪-3-甲酰胺
将6-氯-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(30mg,0.067mmol)、1-甲基-1H-吡唑-3-胺(13.07mg,0.135mmol)和4-甲基苯磺酸一水合物(19.20mg,0.101mmol)在THF(2.0mL)中的混合物在密闭小瓶中在100℃加热20h。然后将混合物在真空下浓缩至干。残留物溶解在DMSO和MeOH中,进样至制备型HPLC。将正确的级分合并,在真空下浓缩,用1.5M K2HPO4溶液碱化至pH为9-10,用二氯甲烷(3x 35mL)萃取。合并的萃取物经无水Na2SO4干燥。在真空下除去溶剂,得到期望产物4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-三氘代甲基-6-((1-甲基-1H-吡唑-3-基)氨基)哒嗪-3-甲酰胺(14.3mg,0.027mmol,40.7%收率),其为黄色固体。LCMS m/z=507.2(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.91(s,1H),9.28(s,1H),9.22(d,J=1.6Hz,1H),9.15(s,1H),9.02(d,J=1.5Hz,1H),8.28(d,J=5.1Hz,1H),7.60(d,J=2.1Hz,1H),7.42(d,J=5.3Hz,1H),6.30(d,J=2.1Hz,1H),3.82(s,3H),3.71(s,3H),3.09(s,3H),3.06(s,3H)。
实施例91
6-((1,5-二甲基-1H-吡唑-3-基)氨基)-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
该化合物使用与用于制备实施例90类似的操作来制备。LCMS m/z=521.2(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),9.80(s,1H),9.31(s,1H),9.22(d,J=1.5Hz,1H),9.13(s,1H),9.02(d,J=1.6Hz,1H),8.28(d,J=5.3Hz,1H),7.42(d,J=5.1Hz,1H),6.11(s,1H),3.71(s,3H),3.70(s,3H),3.09(s,3H),3.06(s,3H),2.26(s,3H)。
实施例92
6-((5-氯-1-甲基-1H-吡唑-3-基)氨基)-4-((4-(5-(二甲基氨基甲酰基)吡嗪-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
该化合物使用与用于制备实施例90类似的操作来制备。LCMS m/z=541.1(M+H)+;1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),10.06(s,1H),9.24–9.20(m,2H),9.17(s,1H),9.02(d,J=1.5Hz,1H),8.29(d,J=5.1Hz,1H),7.43(d,J=5.1Hz,1H),6.48(s,1H),3.78(s,3H),3.71(s,3H),3.08(s,3H),3.06(s,3H)。
实施例93
4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-6-((5-(2-羟基丙烷-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1:
将4-溴-3-甲氧基吡啶-2-胺(500mg,2.463mmol)、双(频哪醇合)二硼(1376mg,5.42mmol)、1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(201mg,0.246mmol)和乙酸钾(725mg,7.39mmol)在二噁烷(20mL)中混合,用氮气脱气5min,然后在100℃加热过夜。冷却至室温后,将反应混合物过滤,加入1,1'-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷络合物(201mg,0.246mmol)和2-氯-5-氟嘧啶(424mg,3.20mmol),然后加入Na2CO3(3694μl,7.39mmol)(2M)溶液,将混合物用氮气脱气,并且在105℃加热4.5h。LC-MS指示反应完全。将混合物用MeOH(15mL)稀释,通过硅藻土垫过滤,将滤液浓缩,残留物与DCM混合,用ISCO柱(12g,AcOEt/己烷=0-100%,梯度时间=15min)纯化,得到4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-胺。产率260mg(47.9%)。LCMS m/z 221.2(M+H)+;HPLC tR0.726min(分析型HPLC方法A);1H NMR(400MHz,甲醇-d4)δ9.00-8.72(m,2H),7.78(d,J=5.5Hz,1H),7.00(d,J=5.3Hz,1H),3.73(s,3H)。
步骤2:
在0℃向4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(195mg,0.931mmol)和4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-胺(205mg,0.931mmol)在THF(6ml)中的澄清溶液中缓慢逐滴加入双(三甲基甲硅烷基)氨基锂(2327μl,2.327mmol),在0℃至室温将混合物搅拌2.5h。在0℃在搅拌下将混合物加入水(1ml),然后加入1N HCl(3ml),在0℃将混合物搅拌30min,过滤收集固体,用水(2x)洗涤,干燥,得到作为灰白色固体的期望化合物:6-氯-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺。产率170mg(46.5%)。LCMS m/z 221.2(M+H)+;HPLC tR 1.13min(分析型HPLC方法A);1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),9.58-9.45(m,1H),9.26(s,1H),9.13(d,J=0.9Hz,2H),8.30(d,J=5.3Hz,1H),7.45(d,J=5.3Hz,1H),3.82(s,3H)
步骤3:
在0℃向4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(195mg,0.931mmol)和4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-胺(205mg,0.931mmol)在THF(6ml)中的澄清溶液中缓慢逐滴加入双(三甲基甲硅烷基)氨基锂(2327μl,2.327mmol),在0℃至室温将混合物搅拌2.5h。在0℃在搅拌下将混合物加入水(1ml),然后加入1N HCl(3ml),在0℃将混合物搅拌30min,过滤收集固体,用水(2x)洗涤,干燥,得到作为灰白色固体的期望化合物:6-氯-4-((4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺。产率170mg(46.5%)。LCMS m/z 221.2(M+H)+;HPLC tR 1.13min(分析型HPLC方法A);1H NMR(400MHz,DMSO-d6)δ12.60(s,1H),9.58-9.45(m,1H),9.26(s,1H),9.13(d,J=0.9Hz,2H),8.30(d,J=5.3Hz,1H),7.45(d,J=5.3Hz,1H),3.82(s,3H)
表3中的实施例使用与用于制备实施例93类似的操作来制备。
表3
实施例103
4-((3-甲氧基-4-(2-甲基-2H-四唑-5-基)吡啶-2-基)氨基)-N-(甲基-d3)-6-((4-甲基吡啶-2-基)氨基)烟酰胺
步骤1:
向2-氨基-3-甲氧基异烟腈(200mg,1.341mmol)、Boc酐(934μl,4.02mmol)在DCM(10ml)中的混合物中加入TEA(561μl,4.02mmol)和DMAP(164mg,1.341mmol),在室温将混合物搅拌过夜,在0℃将混合物用水(5ml)淬灭,用DCM(50ml)稀释,将其用饱和NaHCO3(40ml)洗涤,干燥(Na2SO4),并且在真空下浓缩,残留物用ISCO柱(25g,AcOEt/己烷=0-100%,梯度时间=12min)纯化,峰1(t11,在35% AcOEt洗脱出)为期望产物。产率320mg(68.3%)。LCMSm/z 350.3(M+H)+;HPLC tR 1.26min(分析型HPLC方法A);1H NMR(400MHz,氯仿-d)δ8.46-8.16(m,1H),7.47(d,J=5.1Hz,1H),4.15(s,3H),1.46(s,18H)
步骤2:
在60℃加入在苯甲醚(2ml)、TEA(511μl,3.66mmol)中的步骤1的产物(320mg,0.916mmol),然后加入AcOH(210μl,3.66mmol)和NaN3(208mg,3.21mmol),在130℃(N2)加热4.5h。将混合物冷却,然后用AcOEt(30ml)和水(15ml)混合,振荡,将水层再用AcOEt(10ml)萃取一次,将水层用1NHCl酸化至pH=4-5,用AcOEt(2x 20ml)萃取,将该有机层用盐水洗涤,干燥(Na2SO4),并且在真空下浓缩,得到期望产物,其无需进一步纯化即可用于下一步。
粗产率150mg(41.7%)。LCMS m/z 393.4(M+H)+;HPLC tR 1.06min(分析型HPLC方法A);1H NMR(400MHz,甲醇-d4)δ8.59-8.30(m,1H),8.04(d,J=5.1Hz,1H),3.85(s,3H),1.45(s,18H)
步骤3和4:
向在DMF(2mL)中的步骤2的产物(150mg,0.382mmol)中加入K2CO3(106mg,0.765mmol)和MeI(47.8μl,0.765mmol),在室温将混合物搅拌过夜。将混合物用AcOEt(50ml)和水(20ml)稀释,有机层用NaHCO3(2x 20ml)、盐水(20ml)洗涤,干燥(Na2SO4),在减压下浓缩,残留物用ISCO柱(12g,AcOEt/己烷=0-100%,30ml/min,梯度15min)纯化,得到2种区域异构体。极性较小的峰(峰1)为期望产物(在50% AcOEt洗脱出)。产物用于下一步。将上述产物与DCM(4ml)混合,加入2ml TFA,在室温将混合物搅拌1.5h,在真空下浓缩,残留物溶解在DCM(30ml)中,将其用饱和NaHCO3(15ml)洗涤,水层用DCM(20ml)萃取,合并有机层,干燥(Na2SO4),并且在真空下浓缩,得到期望产物。产率40mg(50.7%);LCMS m/z 207.3(M+H)+;HPLC tR 0.52min(分析型HPLC方法A);1H NMR(400MHz,氯仿-d)δ7.95(d,J=5.3Hz,1H),7.39-7.16(m,1H),4.97(br.s.,2H),4.47(s,3H),3.86(s,3H)
步骤5:
将3-甲氧基-4-(2-甲基-2H-四唑-5-基)吡啶-2-胺(38mg,0.184mmol)和4,6-二氯-N-(甲基-d3)烟酰胺(38.3mg,0.184mmol)在DMF(3ml)中的溶液冷却至0℃,一次性地加入NaH(29.5mg,0.737mmol),15分钟后,反应升至室温。通过LCMS监测反应。溶液缓慢变深和黄褐色。在0℃通过饱和含水氯化铵(2ml)和水(0.5ml)搅拌过夜后淬灭。形成棕色析出物,将混合物搅拌30min。过滤收集固体,用水洗涤,在真空下干燥,得到期望产物,将其原样使用。产率46mg(66.1%)。LCMS m/z 378.0(M+H)+;HPLC tR 0.83min(分析型HPLC方法A);1HNMR(400MHz,DMSO-d6)δ12.34-12.05(m,1H),9.01(s,1H),8.96-8.84(m,1H),8.67(s,1H),8.30(d,J=5.1Hz,1H),7.55(d,J=5.3Hz,1H),4.51(s,3H),3.90(s,3H)
步骤6:
将6-氯-4-((3-甲氧基-4-(2-甲基-2H-四唑-5-基)吡啶-2-基)氨基)-N-(甲基-d3)烟酰胺(12mg,0.032mmol)、4-甲基吡啶胺(6.87mg,0.064mmol)、Xanthpos(3.68mg,6.35μmol)、Cs2CO3(20.70mg,0.064mmol)和Pd2(dba)3(2.91mg,3.18μmol)在二噁烷中(0.5mL)的混合物用氮气吹扫2min,然后在130℃将其搅拌3h。冷却后,将混合物浓缩,用DMSO稀释,用制备型HPLC纯化。
产率4.4mg(30.6%)。LCMS m/z 450.4(M+H)+;HPLC tR 0.96min(分析型HPLC方法A);1H NMR(500MHz,DMSO-d6)δ12.12(s,1H),9.77(br s,1H),9.36(s,1H),8.58(s,2H),8.24(d,J=5.1Hz,1H),8.16(d,J=5.0Hz,1H),7.53(s,1H),7.47(d,J=5.1Hz,1H),6.77(br d,J=5.0Hz,1H),4.51(s,3H),3.45-3.42(m,3H),2.29(s,3H)
表4中的实施例使用与用于制备实施例103类似的操作来制备。
表4
表5中的实施例使用与用于制备前述实施例类似的操作来制备。
表5
生物学测定
以下测定用于显示本发明化合物的活性。
人全血中的IFNα诱导的STAT磷酸化
与化合物一起温育一小时后,用1000U/mL重组人IFNαA/D(R&DSystems 11200-2)刺激人全血(用EDTA或ACD-A作为抗凝剂抽取)15分钟。通过加入Fix/Lyse缓冲液(BD558049)停止刺激。细胞用CD3 FITC抗体(BD 555916)染色,洗涤,使用Perm III缓冲液(BD558050)在冰上渗透。然后将细胞用Alexa-Fluor 647pSTAT5(pY694)抗体(BD 612599)染色30分钟,然后在FACS Canto II上进行分析。通过对CD3阳性群进行门控后的中值荧光强度来定量pSTAT5表达的量。
人全血抑制数据中的IFNα诱导的STAT磷酸化
ND–无可用数据。
Claims (4)
1.化合物或其立体异构体或药学上可接受的盐,所述化合物为:
6-环丙酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(吡啶-2-基)氨基]哒嗪-3-甲酰胺,
6-环丁酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[2-(吗啉-4-基)乙酰氨基]哒嗪-3-甲酰胺,
6-乙酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-丁酰氨基-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
N-(5-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基)氨基甲酸甲酯,
6-(2-环丙基乙酰氨基)-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-6-[(4-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-氰基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4,5-二甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氟-4-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-乙基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[5-(2-氧基吡咯烷-1-基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-[(4-氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(5-甲基-1,3,4-噻二唑-2-基)氨基]哒嗪-3-甲酰胺,
6-[(4-氯吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氯-4-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-氯-5-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-({2-氧代-2H-[1,3'-联吡啶]-6'-基}氨基)哒嗪-3-甲酰胺,
6-{[4-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[2-氧代-3-(三氟甲基)-2H-[1,3'-联吡啶]-6'-基]氨基}哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-6-[(6-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-(苯基氨基)哒嗪-3-甲酰胺,
6-[(4-乙酰基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-({5-氯-2-氧代-2H-[1,3'-联吡啶]-6'-基}氨基)-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-({[1,3]噻唑并[5,4-b]吡啶-5-基}氨基)哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[4-(三氟甲基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-{[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(4-氟苯基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(吡啶-4-基)氨基]哒嗪-3-甲酰胺,
6-[(6-乙氧基哒嗪-3-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-{[5-(3-叔丁基-2-氧基咪唑啉-1-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-{[5-(吗啉-4-基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-[(4,5-二氟吡啶-2-基)氨基]-4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(1-甲基-1H-1,2,4-三唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(6-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
6-环丙酰氨基-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基吡啶-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({4-[5-(乙氧基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(丙烷-2-基氧基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基吡啶-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,
4-({4-[5-(乙氧基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
4-[(4-氰基-3-甲氧基吡啶-2-基)氨基]-6-环丙酰氨基-N-(2H3)甲基哒嗪-3-甲酰胺,
N-{5-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基}氨基甲酸甲酯,
N-{5-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基}氨基甲酸甲酯,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
N-(5-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基)氨基甲酸甲酯,
6-环丙酰氨基-4-[(4-{5-[(1S)-1-羟基乙基]-1,2,4-噁二唑-3-基}-3-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(4-{5-[(二甲基氨基)甲基]-1,2,4-噁二唑-3-基}-3-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(3-甲氧基-4-{5-[(甲基氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({4-[5-(氰基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-6-环丙酰氨基-N-(2H3)甲基哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-((3-甲氧基-4-(5-(吗啉代甲基)-1,2,4-噁二唑-3-基)吡啶-2-基)氨基)-N-(甲基-d3)-6-((4-甲基吡啶-2-基)氨基)哒嗪-3-甲酰胺,
N-{5-[(4-{5-[(1,1-二氧基-1λ6,2-噻嗪烷-2-基)甲基]-1,2,4-噁二唑-3-基}-3-甲氧基吡啶-2-基)氨基]-6-[(2H3)甲基氨基甲酰基]哒嗪-3-基}氨基甲酸甲酯,
4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(吗啉-4-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(N-甲基甲磺酰氨基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
4-[(3-甲氧基-4-{5-[(2-氧代-1,3-噁唑烷-3-基)甲基]-1,2,4-噁二唑-3-基}吡啶-2-基)氨基]-N-(2H3)甲基-6-(3-甲基丁酰氨基)哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-({4-[5-(羟基甲基)-1,2,4-噁二唑-3-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({3-甲氧基-4-[5-(甲氧基甲基)-1,2,4-噁二唑-3-基]吡啶-2-基}氨基)-N-(2H3)甲基-6-[2-(氧杂环丁烷-3-基)乙酰氨基]哒嗪-3-甲酰胺,
6-[(5-氯-4-甲基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(6-甲基嘧啶-4-基)氨基]哒嗪-3-甲酰胺,
6-{[4-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基哒嗪-3-甲酰胺,
6-{[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-4-{[3-甲氧基-4-(5-甲基-1,2,4-噁二唑-3-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-({3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-({3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({5-环丙酰氨基-3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-N-(2H3)甲基吡啶-3-甲酰胺,
4-({5-氯-3'-甲氧基-[2,4'-联吡啶]-2'-基}氨基)-6-环丙酰氨基-N-(2H3)甲基吡啶-3-甲酰胺,
6-环丙酰氨基-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-环丙酰氨基-4-[(4-{5-[乙基(甲基)氨基甲酰基]吡嗪-2-基}-3-甲氧基吡啶-2-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
6-(2-环丙基乙酰氨基)-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基-6-[(1-甲基-1H-吡唑-3-基)氨基]哒嗪-3-甲酰胺,
6-[(1,5-二甲基-1H-吡唑-3-基)氨基]-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
6-[(5-氯-1-甲基-1H-吡唑-3-基)氨基]-4-({4-[5-(二甲基氨基甲酰基)吡嗪-2-基]-3-甲氧基吡啶-2-基}氨基)-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-6-{[5-(2-羟基丙烷-2-基)吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
6-{[5-(2-氨基丙烷-2-基)吡啶-2-基]氨基}-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-[(5-甲基吡嗪-2-基)氨基]哒嗪-3-甲酰胺,
6-[(6-乙氧基哒嗪-3-基)氨基]-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-{[5-(吗啉-4-基)吡啶-2-基]氨基}哒嗪-3-甲酰胺,
6-[(4-氟吡啶-2-基)氨基]-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-6-[(6-甲氧基哒嗪-3-基)氨基]-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基-6-[(吡啶-2-基)氨基]哒嗪-3-甲酰胺,
6-环丙酰氨基-4-{[4-(5-氟嘧啶-2-基)-3-甲氧基吡啶-2-基]氨基}-N-(2H3)甲基哒嗪-3-甲酰胺,
4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-[(4-甲基吡啶-2-基)氨基]吡啶-3-甲酰胺,
N-(4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-5-[(2H3)甲基氨基甲酰基]吡啶-2-基)氨基甲酸甲酯,
4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-N-(2H3)甲基-6-丙酰氨基吡啶-3-甲酰胺,或
6-[(4-氰基吡啶-2-基)氨基]-4-{[3-甲氧基-4-(2-甲基-2H-1,2,3,4-四唑-5-基)吡啶-2-基]氨基}-N-(2H3)甲基吡啶-3-甲酰胺。
2.药物组合物,其包含一种或多种根据权利要求1所述的化合物或其立体异构体或药学上可接受的盐和药学上可接受的载体或稀释剂。
3.根据权利要求1所述的化合物或其立体异构体或药学上可接受的盐在制备用于治疗疾病的药物中的用途,其中所述疾病为炎性疾病或自身免疫性疾病。
4.根据权利要求3所述的用途,其中所述炎性疾病或自身免疫性疾病为多发性硬化症、类风湿性关节炎、强直性脊柱炎、炎性肠病、系统性红斑狼疮、牛皮癣、牛皮癣性关节炎、克罗恩病、干燥综合征或硬皮病。
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JP2023524361A (ja) * | 2020-03-11 | 2023-06-12 | ベイジン・イノケア・ファーマ・テク・カンパニー・リミテッド | Tyk2活性を阻害する複素環式化合物 |
WO2021211741A1 (en) | 2020-04-14 | 2021-10-21 | Gossamer Bio Services, Inc. | Substituted pyridines for the treatment of inflammatory diseases |
CN116888125B (zh) * | 2021-04-07 | 2024-04-12 | 上海齐鲁制药研究中心有限公司 | Tyk2抑制剂及其用途 |
CN117136058A (zh) * | 2021-05-04 | 2023-11-28 | 上海喆邺生物科技有限公司 | 一类含氮杂环吡啶类化合物 |
BR112023026964A2 (pt) * | 2021-06-22 | 2024-03-12 | Medshine Discovery Inc | Composto de sulfoximina e uso do mesmo |
WO2023284869A1 (zh) * | 2021-07-15 | 2023-01-19 | 南京明德新药研发有限公司 | 含硫/磷的芳基类化合物及其应用 |
TW202313035A (zh) * | 2021-08-21 | 2023-04-01 | 美商傳達治療有限公司 | Jak2抑制劑及其使用方法 |
WO2023064223A1 (en) | 2021-10-11 | 2023-04-20 | Gossamer Bio Services, Inc. | Tri-substituted pyridines |
CA3236262A1 (en) | 2021-10-25 | 2023-05-04 | Isaac Marx | Tyk2 degraders and uses thereof |
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