CN115715287A - 作为IL-12、IL-23和/或IFNα调节剂的经取代的N-(甲基-d3)哒嗪-3-甲酰胺或N-(甲基-d3)-烟酰胺化合物 - Google Patents
作为IL-12、IL-23和/或IFNα调节剂的经取代的N-(甲基-d3)哒嗪-3-甲酰胺或N-(甲基-d3)-烟酰胺化合物 Download PDFInfo
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- CN115715287A CN115715287A CN202180043740.1A CN202180043740A CN115715287A CN 115715287 A CN115715287 A CN 115715287A CN 202180043740 A CN202180043740 A CN 202180043740A CN 115715287 A CN115715287 A CN 115715287A
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- amino
- methyl
- carboxamide
- pyridazine
- methoxyphenyl
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- ZYVXHFWBYUDDBM-FIBGUPNXSA-N N-(trideuteriomethyl)pyridine-3-carboxamide Chemical class [2H]C(NC(C1=CN=CC=C1)=O)([2H])[2H] ZYVXHFWBYUDDBM-FIBGUPNXSA-N 0.000 title description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
公开了可用于通过作用于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,其中所有取代基都是如本文所定义的。本发明的化合物可用于治疗炎性和自身免疫性疾病或障碍。
Description
相关申请的交叉引用
本申请要求2020年4月28日提交的美国临时申请号63/016,539的权益,将其公开内容通过引用以其整体并入本文。
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。本文提供了经取代的杂环化合物、包含此类化合物的组合物以及它们的使用方法。本发明进一步涉及含有至少一种根据本发明的化合物的药物组合物,所述药物组合物可用于治疗哺乳动物的与IL-12、IL-23和/或IFNα的调节相关的病症。
背景技术
共有共同的p40亚基的异二聚体细胞因子白介素(IL)-12和IL-23由激活的抗原呈递细胞产生,并且在Th1和Th17细胞(在自身免疫中起着关键作用的两个效应T细胞谱系)的分化和增殖中至关重要。IL-23由p40亚基以及独特的p19亚基构成。IL-23通过由IL-23R和IL-12Rβ1构成的异二聚体受体起作用,对于产生促炎细胞因子(如IL-17A、IL-17F、IL-6和TNF-α)的Th17细胞的存活和扩增而言是必不可少的(McGeachy,M.J.等人,"The linkbetween IL-23and Th17 cell-mediated immune pathologies",Semin.Immunol.,19:372-376(2007))。这些细胞因子在介导许多自身免疫性疾病的病理生物学中至关重要,所述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。除了与IL-23共有的p40亚基之外,IL-12还含有p35亚基并且通过由IL-12Rβ1和IL-12Rβ2构成的异二聚体受体起作用。IL-12对于Th1细胞发育和IFNγ分泌而言是必不可少的,IFNγ是一种通过刺激MHC的表达、B细胞向IgG亚类的类别转换以及巨噬细胞的激活而在免疫中发挥至关重要的作用的细胞因子(Gracie,J.A.等人,"Interleukin-12induces interferon-gamma-dependent switching of IgG alloantibody subclass",Eur.J.Immunol.,26:1217-1221(1996);Schroder,K.等人,"Interferon-gamma:an overview of signals,mechanismsand functions",J.Leukoc.Biol.,75(2):163-189(2004))。
含有p40的细胞因子在自身免疫中的重要性通过如下发现得以证明:缺乏p40、p19或IL-23R的小鼠被保护尤其免于多发性硬化、类风湿性关节炎、炎性肠病、狼疮和银屑病的模式的疾病(Kyttaris,V.C.等人,"Cutting edge:IL-23receptor deficiency preventsthe 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 crucialrole in the pathogenesis of a murine psoriasis like skin disorder",J.Immunol.,162:7480-7491(1999);Hue,S.等人,"Interleukin-23drives innate and Tcell-mediated intestinal inflammation",J.Exp.Med.,203:2473-2483(2006);Cua,D.J.等人,"Interleukin-23rather than interleukin-12is the critical cytokinefor 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-12injoint autoimmune inflammation",J.Exp.Med.,198:1951-1957(2003))。
在人类疾病中,已经在银屑病病变中测量到p40和p19的高表达,并且已经在来自MS患者的大脑中的活动性病变中和在患有活动性克罗恩病的患者的肠粘膜中鉴定出Th17细胞(Lee,E.等人,"Increased expression of interleukin 23p19 and p40 inlesional skin of patients with psoriasis vulgaris",J.Exp.Med.,199:125-130(2004);Tzartos,J.S.等人,"Interleukin-17production in central nervous systeminfiltrating T cells and glial cells is associated with active disease inmultiple sclerosis",Am.J.Pathol.,172:146-155(2008))。也显示活动性SLE患者中p19、p40和p35的mRNA水平与非活动性SLE患者中的水平相比显著更高(Huang,X.等人,"Dysregulated expression of interleukin-23and interleukin-12subunits insystemic lupus erythematosus patients",Mod.Rheumatol.,17:220-223(2007)),并且来自狼疮患者的T细胞具有占主导地位的Th1表型(Tucci,M.等人,"Overexpression ofinterleukin-12and T helper 1predominance in lupus nephritis",Clin.Exp.Immunol.,154:247-254(2008))。
此外,全基因组关联研究已经鉴定出许多与慢性炎性疾病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,"NewIBD genetics: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))。
事实上,已经证明抗p40治疗(其抑制IL-12和IL-23两者)和IL-23特异性抗p19疗法在包括银屑病、克罗恩病和银屑病关节炎在内的疾病中的自身免疫的治疗中是有效的(Leonardi,C.L.等人,"PHOENIX 1study investigators.Efficacy and safety ofustekinumab,a human interleukin-12/23monoclonal antibody,in patients withpsoriasis:76-week results from a randomized,double-blind,placebo-controlledtrial(PHOENIX 1)",Lancet,371:1665-1674(2008);Sandborn,W.J.等人,"UstekinumabCrohn's Disease Study Group.A randomized trial of Ustekinumab,a humaninterleukin-12/23monoclonal antibody,in patients with moderate-to-severeCrohn's disease",Gastroenterology,135:1130-1141(2008);Gottlieb,A.等人,"Ustekinumab,a human interleukin 12/23monoclonal antibody,for psoriaticarthritis:randomized,double-blind,placebo-controlled,crossover trial",Lancet,373:633-640(2009))。因此,可以预期抑制IL-12和IL-23作用的药剂在人类自身免疫性障碍中具有治疗益处。
干扰素(IFN)的I型分组(其包括IFNα成员以及IFNβ、IFNε、IFNκ和IFNω)通过异二聚体IFNα/β受体(IFNAR)起作用。I型IFN在先天性和适应性两种免疫系统中都具有多种作用,包括激活细胞和体液两种免疫反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 inautoimmunity",Nat.Rev.Rheumatol.,6:40-49(2010))。
在患有系统性红斑狼疮(SLE,一种具有潜在致命性的自身免疫性疾病)的患者中,干扰素(IFN)α(一种I型干扰素)血清水平增加或I型IFN调节的基因(所谓的IFNα签名)在外周血单个核细胞和受影响器官中的表达增加已经在大多数患者中得到证明(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)),并且几项研究已经证明,血清IFNα水平与疾病活动度和严重程度两者都相关(Bengtsson,A.A.等人,"Activation of type I interferon system in systemiclupus erythematosus correlates with disease activity but not withantiretroviral antibodies",Lupus,9:664-671(2000))。IFNα在狼疮的病理生物学中的直接作用通过如下观察结果得以证实:向患有恶性或病毒性疾病的患者施用IFNα可能诱导狼疮样综合征。此外,狼疮易感小鼠中IFNAR的缺失提供了对自身免疫、疾病严重程度和致死性的高度保护(Santiago-Raber,M.L.等人,"Type-I interferon receptor deficiencyreduces lupus-like disease in NZB mice",J.Exp.Med.,197:777-788(2003)),并且全基因组关联研究已经鉴定出与狼疮相关的基因座,所述基因座编码在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 tosystemic lupus erythematosus in the genomic era",Nat.Rev.Rheumatol.,6:683-692(2010);Sandling,J.K.等人,"A candidate gene study of the type I interferonpathway implicates IKBKE and IL8 as risk loci for SLE",Eur.J.Hum.Genet.,19:479-484(2011))。除了狼疮之外,还有证据表明I型干扰素介导的途径的异常激活在其他自身免疫性疾病(如舍格伦综合征和硬皮病)的病理生物学中是十分重要的(U.等人,"Activation of the type I interferon system in primarysyndrome:apossible etiopathogenic mechanism",Arthritis Rheum.,52:1185-1195(2005);Kim,D.等人,"Induction of interferon-alpha by scleroderma sera containingautoantibodies to topoisomerase I:association of higher interferon-alphaactivity with lung fibrosis",Arthritis Rheum.,58:2163-2173(2008))。因此,可以预期抑制I型干扰素反应的作用的药剂在人类自身免疫性障碍中具有治疗益处。
酪氨酸激酶2(Tyk2)是非受体酪氨酸激酶的Janus激酶(JAK)家族的成员,并且已经证明在小鼠(Ishizaki,M.等人,"Involvement of Tyrosine Kinase-2in Both the IL-12/Th1 and IL-23/Th17 Axes In vivo",J.Immunol.,187:181-189(2011);Prchal-Murphy,M.等人,"TYK2kinase activity is required for functional type Iinterferon responses in vivo",PLoS One,7:e39141(2012))和人类(Minegishi,Y.等人,"Human tyrosine kinase 2deficiency reveals its requisite roles in multiplecytokine signals involved in innate and acquired immunity",Immunity,25:745-755(2006))两者中在调节IL-12、IL-23和I型干扰素的受体下游的信号转导级联中都至关重要。Tyk2介导受体诱导的转录因子STAT家族成员的磷酸化,磷酸化是导致STAT蛋白的二聚化和STAT依赖性促炎基因的转录的必需信号。Tyk2缺陷小鼠对结肠炎、银屑病和多发性硬化的实验模型具有抗性,这证明了Tyk2介导的信号传导在自身免疫和相关障碍中的重要性(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);Oyamada,A.等人,"Tyrosine kinase 2plays critical roles in the pathogenic CD4 T cell responsesfor the development of experimental autoimmune encephalomyelitis",J.Immunol.,183:7539-7546(2009))。
在人类中,表达Tyk2的非活性变体的个体被保护免于多发性硬化和可能的其他自身免疫性障碍(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经证明,Tyk2的其他变体与自身免疫性障碍(如克罗恩病、银屑病、系统性红斑狼疮和类风湿性关节炎)相关,这进一步证明了Tyk2在自身免疫中的重要性(Ellinghaus,D.等人,"Combined Analysis of Genome-wide AssociationStudies for Crohn Disease and Psoriasis Identifies Seven SharedSusceptibility Loci",Am.J.Hum.Genet.,90:636-647(2012);Graham,D.等人,"Association of polymorphisms across the tyrosine kinase gene,TYK2 in UK SLEfamilies",Rheumatology(Oxford),46:927-930(2007);Eyre,S.等人,"High-densitygenetic mapping identifies new susceptibility loci for rheumatoid arthritis",Nat.Genet.,44:1336-1340(2012))。
鉴于可能通过涉及细胞因子和/或干扰素调节的治疗而受益的病症,能够调节细胞因子和/或干扰素(如IL-12、IL-23和/或IFNα)的新化合物以及使用这些化合物的方法可能为有需要的各种各样的患者提供实质性的治疗益处。
发明内容
本发明涉及下式I的化合物,所述化合物可通过抑制Tyk2介导的信号转导而用作IL-12、IL-23和/或IFNα的调节剂。
本发明还提供了用于制备本发明的化合物的方法和中间体。
本发明还提供了药物组合物,所述药物组合物包含药学上可接受的载体和至少一种本发明的化合物。
本发明还提供了一种用于通过抑制Tyk-2介导的信号转导来调节IL-12、IL-23和/或IFNα的方法,所述方法包括向需要这种治疗的宿主施用治疗有效量的至少一种本发明的化合物。
本发明还提供了一种用于治疗增生性、代谢性、过敏性、自身免疫性和炎性疾病的方法,所述方法包括向需要这种治疗的宿主施用治疗有效量的至少一种本发明的化合物。
一个优选实施方案是一种用于治疗炎性和自身免疫性疾病或疾病的方法。出于本发明的目的,炎性和自身免疫性疾病或障碍包括具有炎性或自身免疫性组分的任何疾病。
一个替代性优选实施方案是一种用于治疗代谢性疾病(包括2型糖尿病和动脉粥样硬化)的方法。
本发明还提供了本发明的化合物用于制造用以治疗癌症的药剂的用途。
本发明还提供了用于在疗法中使用的本发明的化合物。
本发明的这些和其他特征将随本公开文本的继续以扩展的形式加以阐述。
本发明实施方案的详细描述
在本发明的第一方面,提供了一种式I的化合物
其中
Y是N或CH;
R1是H、CD3或C1-3烷基;
R2是-C(O)R2a;C1-6烷基;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是氢、卤基或C1-4烷基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
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,提供了一种式II的化合物
其中
Y是N或CH;
R2是-C(O)R2a;C1-6烷基;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是氢、卤基或C1-4烷基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
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,提供了一种式II的化合物
其中
Y是N或CH;
R2是-C(O)R2a;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是氢、卤基或C1-4烷基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
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,提供了一种式II的化合物
其中
Y是N或CH;
R2是-C(O)R2a;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、C1-3烷基、OCH3、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是卤基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
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,提供了一种式II的化合物
其中
Y是N或CH;
R2是-C(O)R2a;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、C1-3烷基、OCH3、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是F;
R5和R6在每次出现时独立地是氢或C1-4烷基,
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,提供了一种化合物II,其中
R3是含有1-4个选自N、O和S的杂原子的6元杂环,每个基团被0-4个R3a取代。
在另一个方面,提供了一种选自第一方面的范围内的所例示的例子的化合物或其药学上可接受的盐。
在另一个方面,提供了一种选自任何以上方面的范围内的化合物的任何子集列表的化合物。
在另一个方面,提供了一种化合物(IUPAC命名惯例)或其药学上可接受的盐。
选自
4-((3-(5-氰基嘧啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(4-氰基嘧啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丁烷甲酰胺基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(4-甲氧基嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲氧基嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲氧基吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丁-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(1-羟基乙基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1-氟-2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1-羟基环丁基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(1-羟基环丁基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1,3-二氟-2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(1,1,1-三氟-2-羟基丙-2-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(3-羟基四氢呋喃-3-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(1-氟-2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(3-羟基氧杂环丁烷-3-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(3-羟基四氢呋喃-3-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1-氟-2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
(R)-6-(环丙烷甲酰胺基)-4-((3-(5-(3-氟吡咯烷-1-羰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(吗啉-4-羰基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(甲基氨基甲酰基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(氮杂环丁烷-1-羰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(二甲基氨基甲酰基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(二甲基氨基甲酰基)哒嗪-3-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡啶-2-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(吡咯烷-1-羰基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(氮杂环丁烷-1-羰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(4-(二甲基氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二乙基氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(环丙基(甲基)氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)嘧啶-2-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(4-甲基哌嗪-1-基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(4-乙酰基哌嗪-1-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(1H-1,2,4-三唑-1-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)烟酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1,5-二甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-5-(三氟甲基)-1H-吡唑-3-基)氨基)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-吡唑-3-基)氨基)烟酰胺,
6-((5-氯-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1-乙基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1-环丙基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1-环丙基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(吡啶-2-基氨基)烟酰胺,
6-((5-氰基吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基吡嗪-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((6-甲氧基哒嗪-3-基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)烟酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-6-氧代-1,6-二氢嘧啶-4-基)氨基)烟酰胺,
6-((1-环丙基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((5-(二甲基氨基甲酰基)-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((2-乙基-2H-1,2,3-三唑-4-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((2-乙基-2H-1,2,3-三唑-4-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((1-乙基-1H-1,2,3-三唑-4-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((1-乙基-1H-1,2,3-三唑-4-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((2-甲基-2H-1,2,3-三唑-4-基)氨基)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-1,2,3-三唑-4-基)氨基)哒嗪-3-甲酰胺
6-((1-乙基-1H-1,2,3-三唑-4-基)氨基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-1,2,3-三唑-4-基)氨基)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((6-甲基哒嗪-3-基)氨基)哒嗪-3-甲酰胺,
6-((6-氰基哒嗪-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((6-甲氧基哒嗪-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((6-甲氧基哒嗪-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)哒嗪-3-甲酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)哒嗪-3-甲酰胺,
6-((6-环丙基哒嗪-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(噌啉-3-基氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)吡嗪-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((4-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((4-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-6-氧代-1,6-二氢嘧啶-4-基)氨基)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺,或
6-((5-环丙基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺。
在另一个实施方案中,提供了一种药物组合物,所述药物组合物包含一种或多种式I的化合物以及药学上可接受的载体或稀释剂。
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IL-12、IL-23和/或IFNα的调节相关的疾病的药物组合物,所述药物组合物包含式I的化合物或其药学上可接受的盐以及药学上可接受的载体或稀释剂。
本发明进一步涉及治疗与IL-12、IL-23和/或IFNα的调节相关的疾病的方法,所述方法包括向需要这种治疗的患者施用治疗有效量的根据式I的化合物。
本发明还提供了用于制备本发明的化合物的方法和中间体。
本发明还提供了一种用于治疗增生性、代谢性、过敏性、自身免疫性和炎性疾病的方法(或本发明的化合物用于制造用以治疗这些疾病的药剂的用途),所述方法(或用途)包括向需要这种治疗的宿主施用治疗有效量的至少一种本发明的化合物。
本发明还提供了一种治疗炎性或自身免疫性疾病的方法(或本发明的化合物用于制造用以治疗这些疾病的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物。
本发明还提供了一种用于治疗疾病的方法(或本发明的化合物用于制造用以治疗这些疾病的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述疾病是类风湿性关节炎、多发性硬化、系统性红斑狼疮(SLE)、狼疮性肾炎、皮肤狼疮、炎性肠病、银屑病、克罗恩病、银屑病关节炎、舍格伦综合征、系统性硬皮病、溃疡性结肠炎、格雷夫斯病、盘状红斑狼疮、成人斯蒂尔病、全身型幼年特发性关节炎、痛风、痛风性关节炎、1型糖尿病、胰岛素依赖型糖尿病、败血症、感染性休克、志贺氏菌病、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、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、重症肌无力、胰腺炎(急性或慢性)、强直性脊柱炎、寻常型天疱疮、古德帕斯丘病、抗磷脂综合征、特发性血小板减少症、ANCA相关性血管炎、天疱疮、川崎病、慢性炎性脱髓鞘性多发性神经病(CIDP)、皮肌炎、多肌炎、葡萄膜炎、吉兰-巴雷综合征、自身免疫性肺部炎症、自身免疫性甲状腺炎、自身免疫性炎性眼病和慢性脱髓鞘性多发性神经病。
本发明还提供了一种治疗炎性或自身免疫性疾病的方法(或本发明的化合物用于制造用以治疗所述疾病的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述疾病选自系统性红斑狼疮(SLE)、狼疮性肾炎、皮肤狼疮、克罗恩病、溃疡性结肠炎、1型糖尿病、银屑病、类风湿性关节炎、全身型幼年特发性关节炎、强直性脊柱炎和多发性硬化。
本发明还提供了一种用于治疗类风湿性关节炎的方法(或本发明的化合物用于制造用以治疗类风湿性关节炎的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物。
另外,本发明还提供了一种治疗病症的方法(或本发明的化合物用于制造用以治疗这些病症的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述病症选自急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、实体瘤、眼部新生血管、和婴儿血管瘤、B细胞淋巴瘤、系统性红斑狼疮(SLE)、类风湿性关节炎、银屑病关节炎、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、冷和温凝集素病、伊文思综合征、溶血性尿毒症综合征/血栓性血小板减少性紫癜(HUS/TTP)、结节病、舍格伦综合征、周围神经病、寻常型天疱疮和哮喘。
本发明还提供了一种治疗IL-12、IL-23和/或IFNα介导的疾病的方法(或本发明的化合物用于制造用以治疗这些疾病的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物。
本发明还提供了一种治疗IL-12、IL-23和/或IFNα介导的疾病的方法(或本发明的化合物用于制造用以治疗这些疾病的药剂的用途),所述方法(或用途)包括向需要这种治疗的患者施用治疗有效量的式I的化合物,其中所述IL-12、IL-23和/或IFNα介导的疾病是由IL-12、IL-23和/或IFNα调节的疾病。
本发明还提供了一种治疗疾病的方法,所述方法包括向需要这种治疗的患者施用与其他治疗剂组合的治疗有效量的式I的化合物。
本发明还提供了用于在疗法中使用的本发明的化合物。
在另一个实施方案中,式I的化合物选自所例示的化合物或所例示的化合物的组合或者本文的其他实施方案。
在另一个实施方案中,提供了在至少一种下述测定中IC50<1000nM的化合物。
本发明可以在不背离其精神或本质属性的情况下体现为其他具体形式。本发明涵盖本文所述的本发明的优选方面和/或实施方案的所有组合。应理解,可以将本发明的任何和所有实施方案与任何其他一个或多个实施方案结合来描述另外的更优选的实施方案。还应理解,优选实施方案的每个单独要素是其自己独立的优选实施方案。此外,实施方案的任何要素意在与来自任何实施方案的任何和所有其他要素组合来描述另外的实施方案。
具体实施方式
以下是本说明书和所附权利要求中使用的术语的定义。除非另有指示,否则本文提供的对于基团或术语的初始定义适用于整个说明书和权利要求中的该基团或术语(单独地或作为另一个基团的一部分)。
本发明的化合物可以具有一个或多个不对称中心。除非另有指示,否则本发明的化合物的所有手性(对映异构和非对映异构)和外消旋形式都包括在本发明中。化合物中也可以存在烯烃、C=N双键等的许多几何异构体,并且所有此类稳定的异构体都考虑在本发明中。描述了本发明的化合物的顺式和反式几何异构体,并且其可以作为异构体的混合物或作为分开的异构形式分离。本发明化合物可以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,如通过拆分外消旋形式或通过从光学活性起始材料合成。除非明确指示具体的立体化学或异构体形式,否则意指结构的所有手性(对映异构和非对映异构)和外消旋形式以及所有几何异构形式。
当任何变量(例如,R3)在化合物的任何成分或式中出现多于一次时,其在每次出现时的定义独立于其在其他每次出现时的定义。因此,例如,如果显示基团被0-2个R3取代,则所述基团可以任选地被最多两个R3基团取代,并且R3在每次出现时独立地选自R3的定义。此外,只有当取代基和/或变量的组合产生稳定的化合物时,此类组合才可被允许。
当显示到取代基的键与连接环中两个原子的键交叉时,则这个取代基可以与环上的任何原子键合。当列出取代基而没有指示这个取代基是经由哪个原子与给定式的化合物的其余部分键合时,则这个取代基可以经由这个取代基中的任何原子键合。只有当取代基和/或变量的组合产生稳定的化合物时,此类组合才可被允许。
在本发明的化合物上存在氮原子(例如,胺)的情况下,可以通过用氧化剂(例如,MCPBA和/或过氧化氢)处理将这些氮原子转化为N-氧化物,以提供本发明的其他化合物。因此,所显示和要求保护的所有氮原子都被认为包括所显示的氮及其N-氧化物(N→O)衍生物两者。
不在两个字母或符号之间的短划线“-”用于指示取代基的附接点。例如,-CONH2通过碳原子附接。
关于式I的化合物的特定部分(例如,任选经取代的杂芳基)的术语“任选经取代的”是指具有0、1、2个或更多个取代基的部分。例如,“任选经取代的烷基”涵盖如下定义的“烷基”和“经取代的烷基”两者。本领域技术人员将理解,对于含有一个或多个取代基的任何基团,此类基团不旨在引入在空间上不实用、在合成上不可行和/或内在地不稳定的任何取代或取代模式。
如本文所用,术语“至少一种化学实体”可与术语“化合物”互换。
如本文所用,术语“烷基”或“亚烷基”旨在包括具有指定碳原子数的支链和直链饱和脂族烃基两者。例如,“C1-10烷基”(或亚烷基)旨在包括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。烷基可以是未经取代的或经取代的,使得其一个或多个氢被另一个化学基团替代。示例性烷基包括但不限于甲基(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)等。
“烯基”或“亚烯基”旨在包括直链或支链构型并且具有一个或多个碳-碳双键(其可以出现在沿着链的任何稳定的点)的烃链。例如,“C2-6烯基”(或亚烯基)旨在包括C2、C3、C4、C5和C6烯基。烯基的例子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”旨在包括直链或支链构型并且具有一个或多个碳-碳三键(其可以出现在沿着链的任何稳定的点)的烃链。例如,“C2-6炔基”(或亚炔基)旨在包括C2、C3、C4、C5和C6炔基;如乙炔基、丙炔基、丁炔基、戊炔基、己炔基等。
O
本领域技术人员将理解,当在本文中使用名称“CO2”时,这旨在指代基团CO。
当术语“烷基”与另一个基团一起使用时,如在“芳基烷基”中,这种结合以更高的专一性定义了经取代的烷基将含有的取代基中的至少一个。例如,“芳基烷基”是指如上定义的经取代的烷基,其中至少一个取代基是芳基,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级烷基,并且还包括与另一个基团直接键合的芳基,即芳基(C0)烷基。术语“杂芳基烷基”是指如上定义的经取代的烷基,其中至少一个取代基是杂芳基。
当提及经取代的烯基、炔基、亚烷基、亚烯基或亚炔基时,这些基团被如上针对经取代的烷基所定义的一个至三个取代基取代。
术语“烷氧基”是指被如本文定义的烷基或经取代的烷基取代的氧原子。例如,术语“烷氧基”包括基团-O-C1-6烷基,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-甲基戊氧基等。“低级烷氧基”是指具有一个至四个碳的烷氧基。
应当理解,本领域技术人员将对所有基团(包括例如烷氧基、硫代烷基和氨基烷基)进行选择,以提供稳定的化合物。
如本文所用,术语“经取代的”意指在指定的原子或基团上的任何一个或多个氢被所指示的基团替代,条件是不超过指定原子的正常化合价。当取代基是氧代或酮基(即,=O)时,则原子上的2个氢被替代。酮基取代基不存在于芳族部分上。除非另有说明,否则取代基被命名在核心结构中。例如,应理解,当(环烷基)烷基被列为可能的取代基时,此取代基与核心结构的附接点在烷基部分中。如本文所用,环双键是在两个相邻环原子之间形成的双键(例如,C=C、C=N或N=N)。
只有当取代基和/或变量的组合产生稳定的化合物或有用的合成中间体时,此类组合才可被允许。稳定的化合物或稳定的结构意在暗示化合物足够稳健以经受住从反应混合物中分离至有用程度的纯度并且随后被配制成有效的治疗剂。优选的是,本发明列举的化合物不含N-卤基、S(O)2H或S(O)H基团。
术语“环烷基”是指经环化的烷基,包括单环、二环或多环的环系。C3-7环烷基旨在包括C3、C4、C5、C6和C7环烷基。示例性环烷基包括但不限于环丙基、环丁基、环戊基、环己基、降冰片基等。如本文所用,“碳环”或“碳环的残基”旨在意指任何稳定的3、4、5、6或7元单环或二环或者7、8、9、10、11、12或13元二环或三环的环,其中的任何一个都可以是饱和的、部分不饱和的、不饱和的或芳族的。此类碳环的例子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(四氢化萘)。如上所示,桥接环也包括在碳环的定义中(例如,[2.2.2]二环辛烷)。除非另有说明,否则优选的碳环是环丙基、环丁基、环戊基、环己基和苯基。当使用术语“碳环”时,它旨在包括“芳基”。当一个或多个碳原子连接两个非相邻碳原子时,出现桥接环。优选的桥是一个或两个碳原子。应注意,桥总是将单环的环转化为二环的环。当环桥接时,针对环所列举的取代基也可以存在于桥上。
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,如苯基和萘基,其中的每一个都可以是经取代的。
因此,在式I的化合物中,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:
等,其任选地可以在一个或多个环的任何可用的原子处被取代。
优选的环烷基包括环丙基、环丁基、环戊基和环己基。
术语“卤基(halo)”或“卤素”是指氯、溴、氟和碘。
术语“卤代烷基”意指具有一个或多个卤基取代基的经取代的烷基。例如,“卤代烷基”包括单氟甲基、二氟甲基和三氟甲基。
术语“卤代烷氧基”意指具有一个或多个卤基取代基的烷氧基。例如,“卤代烷氧基”包括OCF3。
术语“杂环”、“杂环烷基”、“杂环基(heterocyclo)”、“杂环的”或“杂环基(heterocyclyl)”可以可互换地使用,并且是指经取代的和未经取代的3至7元单环基团、7至11元二环基团以及10至15元三环基团,其中至少一个环具有至少一个杂原子(O、S或N),所述含有杂原子的环优选地具有1、2或3个选自O、S和N的杂原子。这种含有杂原子的基团的每个环都可以含有一个或两个氧或硫原子和/或一个至四个氮原子,条件是每个环中的杂原子总数是四个或更少,并且进一步的条件是环含有至少一个碳原子。氮和硫原子可以任选地被氧化,并且氮原子可以任选地被季铵化。完成二环和三环基团的稠环可以仅含有碳原子,并且可以是饱和的、部分饱和的或完全不饱和的。杂环基可以附接在任何可用的氮或碳原子上。如本文所用,术语“杂环”、“杂环烷基”、“杂环基(heterocyclo)”、“杂环的”和“杂环基(heterocyclyl)”包括“杂芳基”基团,如下所定义。
除了下述杂芳基之外,示例性单环杂环基包括氮杂环丁烷基、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-氧代氮杂卓基、氮杂卓基、1-吡啶酮基、4-哌啶酮基、四氢吡喃基、吗啉基、硫杂吗啉基、硫杂吗啉基亚砜、硫杂吗啉基砜、1,3-二氧戊环和四氢-1,1-二氧代噻吩基等。示例性二环杂环基包括奎宁环基。另外的单环杂环基包括
术语“杂芳基”是指经取代的和未经取代的芳族5或6元单环基团、9或10元二环基团以及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),所述含有杂原子的环优选地具有1、2或3个选自O、S和N的杂原子。含有杂原子的杂芳基的每个环都可以含有一个或两个氧或硫原子和/或一个至四个氮原子,条件是每个环中的杂原子总数是四个或更少,并且每个环都具有至少一个碳原子。完成二环和三环基团的稠环可以仅含有碳原子,并且可以是饱和的、部分饱和的或不饱和的。氮和硫原子可以任选地被氧化,并且氮原子可以任选地被季铵化。二环或三环的杂芳基必须包括至少一个完全芳族的环,但是其他一个或多个稠环可以是芳族的或非芳族的。杂芳基可以附接在任何环的任何可用的氮或碳原子上。当化合价允许时,如果所述另一环是环烷基或杂环基,则它另外任选地被=O(氧代)取代。
示例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、三嗪基等。
示例性二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、四氢喹啉基等。
示例性三环杂芳基包括咔唑基、苯并吲哚基、菲咯啉基、吖啶基、菲啶基、呫吨基等。在式I的化合物中,优选的杂芳基包括:
除非另有指示,否则当提及明确命名的芳基(例如,苯基)、环烷基(例如,环己基)、杂环基(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,所述提及旨在包括视情况具有0至3个、优选0至2个取代基的环,所述取代基选自上文针对芳基、环烷基、杂环基和/或杂芳基所列举的取代基。
术语“碳环基”或“碳环的”是指饱和的或不饱和的单环或二环的环,其中所有环的所有原子都是碳。因此,所述术语包括环烷基和芳基环。单环碳环具有3至6个环原子、仍更通常5或6个环原子。二环碳环具有7至12个环原子,例如排列为二环[4,5]、[5,5]、[5,6]或[6,6]体系;或者9或10个环原子,排列为二环[5,6]或[6,6]体系。单环和二环碳环的例子包括环丙基、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。碳环的环可以是经取代的,在这种情况下,取代基选自上文针对环烷基和芳基所列举的取代基。
术语“杂原子”应当包括氧、硫和氮。
当术语“不饱和的”在本文中用于指代环或基团时,所述环或基团可以是完全不饱和的或部分不饱和的。
在整个说明书中,本领域技术人员可以选择基团及其取代基以提供稳定的部分和化合物以及可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的化合物可以以游离形式(未电离)存在或者可以形成盐,所述盐也在本发明的范围内。除非另有指示,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“一种或多种盐”表示与无机和/或有机酸和碱形成的酸式和/或碱式盐。另外,术语“一种或多种盐”可以包括两性离子(内盐),例如,当式I的化合物含有碱性部分(如胺或吡啶或咪唑环)和酸性部分(如羧酸)两者时。药学上可接受的(即,无毒的生理学上可接受的)盐是优选的,例如像阳离子对盐的毒性或生物活性没有显著贡献的可接受的金属盐和胺盐。然而,其他盐可以例如可用于可以在制备期间采用的分离或纯化步骤中,因此考虑在本发明的范围内。式I的化合物的盐可以例如通过如下方式来形成:使式I的化合物与一定量(如当量量)的酸或碱在介质(如盐在其中沉淀的介质)中或在水性介质中反应,然后冻干。
示例性酸加成盐包括乙酸盐(如与乙酸或三卤乙酸(例如,三氟乙酸)形成的盐)、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、乙磺酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐(与盐酸形成)、氢溴酸盐(与溴化氢形成)、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐(与马来酸形成)、甲磺酸盐(与甲磺酸形成)、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐(如与硫酸形成的盐)、磺酸盐(如在本文中提到的盐)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(toluenesulfonate)(如甲苯磺酸盐(tosylate))、十一烷酸盐等。
示例性碱式盐包括铵盐;碱金属盐,如钠盐、锂盐和钾盐;碱土金属盐,如钙盐和镁盐;钡盐、锌盐和铝盐;与有机碱(例如,有机胺)的盐,所述有机碱如三烷基胺(如三乙胺)、普鲁卡因、二苄胺、N-苄基-β-苯乙胺、1-二苯羟甲胺(ephenamine)、N,N′-二苄乙烯-二胺、脱氢枞胺、N-乙基哌啶、苄胺、二环己胺或类似的药学上可接受的胺;以及与氨基酸的盐,所述氨基酸如精氨酸、赖氨酸等。碱性含氮基团可以用诸如低级烷基卤化物(例如,甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物)、二烷基硫酸酯(例如,二甲基、二乙基、二丁基和二戊基的硫酸酯)、长链卤化物(例如,癸基、月桂基、肉豆蔻基和硬脂酰基的氯化物、溴化物和碘化物)、芳烷基卤化物(例如,苄基和苯乙基的溴化物)等的试剂季铵化。优选的盐包括单盐酸盐、硫酸氢盐、甲磺酸盐、磷酸盐或硝酸盐。
短语“药学上可接受的”在本文中用于指代在合理的医学判断范围内适用于与人和动物的组织接触而没有过度的毒性、刺激、过敏反应或其他问题或并发症,与合理的效益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用,“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物通过制备其酸式或碱式盐而被修饰。药学上可接受的盐的例子包括但不限于碱性基团(如胺)的矿物酸或有机酸盐;以及酸性基团(如羧酸)的碱盐或有机盐。药学上可接受的盐包括常规无毒盐或例如从无毒无机酸或有机酸形成的母体化合物的季铵盐。例如,此类常规无毒盐包括从如下无机酸衍生的盐:如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸和硝酸;以及由如下有机酸制备的盐: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、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、磺胺酸、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸和羟乙基磺酸等。
本发明的药学上可接受的盐可以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。通常,此类盐可以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的碱或酸在水中或在有机溶剂中或者在这两者的混合物中反应来制备;通常,非水性介质(如醚、乙酸乙酯、乙醇、异丙醇或乙腈)是优选的。合适的盐的列表可见于Remington'sPharmaceutical Sciences,第18版,Mack Publishing Company,Easton,PA(1990),将其公开内容通过引用特此并入。
考虑了本发明的化合物的所有立体异构体,呈混合物或呈纯的或基本上纯的形式。立体异构体可以包括通过具有一个或多个手性原子作为光学异构体的化合物以及由于围绕一个或多个键的有限旋转作为光学异构体的化合物(阻转异构体)。根据本发明的化合物的定义包括所有可能的立体异构体及其混合物。它非常特别地包括具有指定活性的外消旋形式和分离的光学异构体。外消旋形式可以通过物理方法拆分,所述物理方法例如像非对映异构衍生物的分级结晶、分离或结晶或者通过手性柱色谱分离。单独的光学异构体可以由常规方法从外消旋体获得,所述方法例如像用光学活性酸形成盐,然后结晶。
本发明旨在包括本发明化合物中存在的原子的所有同位素。同位素包括具有相同原子序数但质量数不同的那些原子。通过一般举例而非限制的方式,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的化合物通常可以通过本领域技术人员已知的常规技术或通过与本文所述的方法类似的方法使用适当的同位素标记的试剂代替原本采用的未标记的试剂来制备。
还考虑了本发明化合物的前药和溶剂化物。术语“前药”表示如下化合物,其在被施用于受试者后通过代谢或化学过程进行化学转化以产生式I的化合物和/或其盐和/或溶剂化物。将在体内转化以提供生物活性剂(即,式I的化合物)的任何化合物是在本发明的范围和精神内的前药。例如,含有羧基的化合物可以形成生理学上可水解的酯,其通过在体内水解产生式I化合物本身而充当前药。优选地口服施用此类前药,因为在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在血液中的那些情况下,可以使用肠胃外施用。式I的化合物的生理学上可水解的酯的例子包括C1-6烷基苄基、4-甲氧基苄基、茚满基、邻苯二甲酰基、甲氧基甲基、C1-6烷酰基氧基-C1-6烷基(例如,乙酰氧基甲基、新戊酰氧基甲基或丙酰氧基甲基)、C1-6烷氧基羰基氧基-C1-6烷基(例如,甲氧基羰基-氧基甲基或乙氧基羰基氧基甲基)、甘氨酰氧基甲基、苯基甘氨酰氧基甲基、(5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)-甲基以及例如在青霉素和头孢菌素领域中使用的其他熟知的生理学上可水解的酯。此类酯可以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例子,参见:
a)Bundgaard,H.编辑,Design of Prodrugs,Elsevier(1985)和Widder,K.等人编辑,Methods in Enzymology,112:309-396,Academic Press(1985);
b)Bundgaard,H.,第5章,"Design and Application of Prodrugs",Krosgaard-Larsen,P.等人编辑,A Textbook of Drug Design and Development,第113-191页,Harwood Academic Publishers(1991);以及
c)Bundgaard,H.,Adv.Drug Deliv.Rev.,8:1-38(1992),
将其中的每一个通过引用并入本文。
式I的化合物及其盐可以以其互变异构形式存在,其中氢原子转置到分子的其他部分,因此分子的原子之间的化学键得以重排。应当理解,所有互变异构形式(只要它们可以存在)都包括在本发明内。另外,本发明化合物可以具有反式和顺式异构体。
应当进一步理解,式I的化合物的溶剂化物(例如,水合物)也在本发明的范围内。溶剂化方法是本领域众所周知的。
实用性
本发明的化合物调节IL-23刺激的细胞功能和IFNα刺激的细胞功能,包括基因转录。可以由本发明的化合物调节的其他类型的细胞功能包括但不限于IL-12刺激的反应。
因此,式I的化合物通过作用于Tyk2以介导信号转导而在治疗与IL-23或IFNα的功能的调节相关,特别是与IL-23、IL-12和/或IFNα的功能的选择性抑制相关的病症中具有效用。此类病症包括IL-23、IL-12或IFNα相关的疾病,其中发病机制通过这些细胞因子介导。
如本文所用,术语“治疗(treating)”或“治疗(treatment)”涵盖对哺乳动物、特别是人的疾病状态的治疗,并且包括:(a)防止或延迟疾病状态在哺乳动物中发生,特别是当这个哺乳动物易患疾病状态,但尚未被诊断为患有所述疾病状态时;(b)抑制疾病状态,即阻止其发展;和/或(c)实现症状或疾病状态的完全或部分减少,和/或缓解、改善、减轻或治愈疾病或障碍和/或其症状。
鉴于它们作为IL-23、IL-12和IFNα刺激的细胞反应的调节剂的活性,式I的化合物可用于治疗IL-23、IL-12或IFNα相关的疾病,包括但不限于炎性疾病,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,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、银屑病;自身炎性疾病,包括CAPS、TRAPS、FMF、成人斯蒂尔病、全身型幼年特发性关节炎、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、心肌梗死;破坏性骨障碍,如骨吸收疾病、骨关节炎、骨质疏松症、多发性骨髓瘤相关骨障碍;增生性障碍,如急性骨髓性白血病、慢性骨髓性白血病;血管生成障碍,如包括实体瘤、眼部新生血管和婴儿血管瘤的血管生成障碍;感染性疾病,如败血症、感染性休克和志贺氏菌病;神经退行性疾病,如阿尔茨海默病、帕金森病、脑缺血或由创伤性损伤引起的神经退行性疾病;肿瘤以及病毒性疾病,分别如转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤,以及HIV感染和CMV视网膜炎、AIDS。
更特别地,可以用本发明化合物治疗的特定病症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、自身免疫性中性粒细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠病、溃疡性结肠炎、克罗恩病、银屑病、移植物抗宿主病、由内毒素诱导的炎性反应、结核病、动脉粥样硬化、肌肉退化、恶病质、银屑病关节炎、莱特尔综合征、痛风、创伤性关节炎、风疹关节炎、急性滑膜炎、胰腺β细胞病;以大量嗜中性粒细胞浸润为特征的疾病;类风湿性脊椎炎、痛风性关节炎和其他关节炎病症、脑型疟疾、慢性肺部炎性疾病、矽肺病、肺结节病、骨吸收疾病、同种异体移植物排斥、感染引起的发热和肌痛、继发于感染的恶病质、瘢痕疙瘩形成、瘢痕组织形成、溃疡性结肠炎、热病、流感、骨质疏松症、骨关节炎、急性骨髓性白血病、慢性骨髓性白血病、转移性黑色素瘤、卡波西肉瘤、多发性骨髓瘤、败血症、感染性休克和志贺氏菌病;阿尔茨海默病、帕金森病、脑缺血或由创伤性损伤引起的神经退行性疾病;血管生成障碍,包括实体瘤、眼部新生血管和婴儿血管瘤;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或恶性肿瘤和疱疹;中风、心肌缺血、中风心脏病发作中的缺血、器官缺氧[这应该是低氧症]、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聚集、内毒素血症和/或中毒性休克综合征、与前列腺素内过氧化酶合酶-2相关的病症和寻常型天疱疮。优选的治疗方法是病症选自克罗恩病、溃疡性结肠炎、同种异体移植物排斥、类风湿性关节炎、银屑病、强直性脊柱炎、银屑病关节炎和寻常型天疱疮的治疗方法。可替代地,优选的治疗方法是病症选自缺血再灌注损伤的治疗方法,所述缺血再灌注损伤包括由中风引起的脑缺血再灌注损伤和由心肌梗死引起的心肌缺血再灌注损伤。另一种优选的治疗方法是病症为多发性骨髓瘤的治疗方法。
当在本文中使用术语“IL-23、IL-12和/或IFNα相关的病症”或“IL-23、IL-12和/或IFNα相关的疾病或障碍”时,每一个都旨在涵盖以上鉴定的所有病症(如同在长度上重复)以及受IL-23、IL-12和/或IFNα影响的任何其他病症。
因此,本发明提供了用于治疗此类病症的方法,所述方法包括向有需要的受试者施用治疗有效量的至少一种式I的化合物或其盐。“治疗有效量”旨在包括本发明的化合物在单独或组合施用时有效抑制IL-23、IL-12和/或IFNα功能和/或治疗疾病的量。
治疗IL-23、IL-12和/或IFNα相关的病症的方法可以包括将式I的化合物单独施用或与彼此组合和/或与可用于治疗此类病症的其他合适的治疗剂组合施用。因此,“治疗有效量”还旨在包括所要求保护的化合物的组合有效抑制IL-23、IL-12和/或IFNα功能和/或治疗与IL-23、IL-12和/或IFNα相关的疾病的量。
此类其他治疗剂的例子包括皮质类固醇、咯利普兰、卡弗他丁、细胞因子抑制性抗炎药(CSAID)、白介素-10、糖皮质激素、水杨酸盐、一氧化氮和其他免疫抑制剂;核转位抑制剂,如脱氧精胍菌素(DSG);非甾体抗炎药(NSAID),如布洛芬、塞来昔布和罗非昔布;类固醇,如泼尼松或地塞米松;抗病毒剂,如阿巴卡韦;抗增殖剂,如甲氨蝶呤、来氟米特、FK506(他克莫司,);抗疟药,如羟氯喹;细胞毒性药物,如硫唑嘌呤和环磷酰胺;TNF-α抑制剂,如替尼达普、抗TNF抗体或可溶性TNF受体和雷帕霉素(西罗莫司或)或其衍生物。
当与本发明的化合物组合采用时,以上其他治疗剂可以例如以Physicians'DeskReference(PDR)中所指示的或者如本领域普通技术人员以其他方式确定的那些量来使用。在本发明的方法中,此类一种或多种其他治疗剂可以在施用本发明的化合物之前、同时或之后施用。本发明还提供了能够通过抑制Tyk2介导的信号转导来治疗IL-23、IL-12或IFNα相关的病症(包括如上所述的IL-23、IL-12和/或IFNα介导的疾病)的药物组合物。
本发明组合物可以含有如上所述的其他治疗剂,并且可以例如通过采用常规的固体或液体媒介物或稀释剂以及适合于所需的施用方式的类型的药物添加剂(例如,赋形剂、粘合剂、防腐剂、稳定剂、调味剂等)根据诸如药物配制领域熟知的技术的技术来配制。
因此,本发明进一步包括包含一种或多种式I的化合物以及药学上可接受的载体的组合物。
“药学上可接受的载体”是指本领域通常接受的用于将生物活性剂递送至动物、特别是哺乳动物的介质。根据完全在本领域普通技术人员的范围内的许多因素来配制药学上可接受的载体。这些因素包括但不限于所配制的活性剂的类型和性质;待被施用含有药剂的组合物的受试者;组合物的预期施用途径;以及所靶向的治疗适应证。药学上可接受的载体包括水性和非水性两种液体介质以及多种固体和半固体剂型。此类载体还可以包括除了活性剂之外的许多不同的成分和添加剂,此类另外的成分出于本领域普通技术人员熟知的多种原因(例如,活性剂、粘合剂等的稳定化)被包括在配制品中。合适的药学上可接受的载体及其选择中涉及的因素的描述可见于多种可容易获得的来源,例如像Remington'sPharmaceutical Sciences,第17版(1985),将其通过引用以其整体并入本文。
式I的化合物可以通过适合于待治疗病症的任何手段施用,这可以取决于对位点特异性治疗的需要或待递送的药物的量。局部施用对于皮肤相关疾病通常是优选的,并且全身性治疗对于癌性或癌变前病症是优选的,但是也考虑了其他递送方式。例如,化合物可以口服递送,如以片剂、胶囊剂、颗粒剂、散剂或包括糖浆剂在内的液体配制品的形式;局部递送,如以溶液剂、混悬剂、凝胶剂或软膏剂的形式;舌下递送;经颊递送;肠胃外递送,如通过皮下、静脉内、肌内或胸骨内注射或输注技术(例如,作为无菌可注射水溶液或非水溶液或悬浮液);鼻腔递送,如通过吸入喷雾;局部递送,如以乳膏剂或软膏剂的形式;直肠递送,如以栓剂的形式;或脂质体递送。可以施用含有无毒的药学上可接受的媒介物或稀释剂的剂量单位配制品。化合物可以以适合于立即释放或延长释放的形式施用。立即释放或延长释放可以用合适的药物组合物来实现,或者特别是在延长释放的情况下,用诸如皮下植入器或渗透泵的装置来实现。
用于口服施用的示例性组合物包括混悬剂,其可以含有例如用于赋予体积的微晶纤维素、作为助悬剂的海藻酸或海藻酸钠、作为粘度增强剂的甲基纤维素以及甜味剂或调味剂,如本领域已知的那些;以及立即释放片剂,其可以含有例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁和/或乳糖和/或其他赋形剂、粘合剂、增量剂、崩解剂、稀释剂和润滑剂,如本领域已知的那些。本发明化合物还可以通过舌下和/或经颊施用来口服递送,例如采用模制、压缩或冷冻干燥的片剂。示例性组合物可以包括快速溶解的稀释剂,如甘露糖醇、乳糖、蔗糖和/或环糊精。此类配制品中还可以包括高分子量赋形剂,如纤维素或聚乙二醇(PEG);帮助粘膜粘附的赋形剂,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,);以及控制释放的试剂,如聚丙烯酸共聚物(例如,CARBOPOL )。还可以添加润滑剂、助流剂、调味剂、着色剂和稳定剂以便于制造和使用。
用于鼻用气雾剂或吸入施用的示例性组合物包括溶液,其可以含有例如苯甲醇或其他合适的防腐剂、用于增强吸收和/或生物利用度的吸收促进剂和/或其他增溶剂或分散剂,如本领域已知的那些。
用于肠胃外施用的示例性组合物包括可注射溶液或悬浮液,其可以含有例如合适的无毒的肠胃外可接受的稀释剂或溶剂,如甘露糖醇、1,3-丁二醇、水、林格氏溶液、等渗氯化钠溶液或其他合适的分散剂或润湿剂和悬浮剂,包括合成的甘油单酯或甘油二酯和脂肪酸(包括油酸)。
用于直肠施用的示例性组合物包括栓剂,其可以含有例如合适的无刺激性赋形剂,如可可脂、合成甘油酯或聚乙二醇,它们在常温下为固体但在直肠腔中液化和/或溶解以释放药物。
本发明的化合物的治疗有效量可以由本领域普通技术人员确定,并且对于哺乳动物,包括每天约0.05至1000mg/kg、1-1000mg/kg、1-50mg/kg、5-250mg/kg、250-1000mg/kg体重的活性化合物的示例性剂量,其可以以单剂量或以单独的分剂量的形式(如每天1至4次)施用。将理解,用于任何特定受试者的具体剂量水平和剂量频率可以变化并且将取决于多种因素,包括所采用具体化合物的活性、该化合物的代谢稳定性和作用长度、受试者的物种、年龄、体重、一般健康状况、性别和饮食、施用方式和时间、排泄速率、药物组合和特定病症的严重程度。用于治疗的优选受试者包括动物,最优选哺乳动物物种,如人以及家畜(如狗、猫、马等)。因此,当在本文中使用术语“患者”时,此术语旨在包括通过调节IL-23、IL-12和/或IFNα介导的功能而受影响的所有受试者,最优选哺乳动物物种。
制备
除非另有说明,否则所有从商业来源购买的试剂都不经进一步纯化即使用。所有涉及空气或水分敏感试剂的反应都在惰性气氛下进行。在Bruker Avance 400或JEOLEclipse500光谱仪上记录质子和碳磁共振(1H和13C NMR)光谱,并且相对于它们在其中运行的样品的参考溶剂报告(以ppm计)。使用Shimadzu LC-10AS液相色谱仪和SPDUV-vis检测器在220或254nm处进行HPLC和LCMS分析,用Micromass Platform LC光谱仪进行MS检测。
HPLC方法A:采用二元溶剂系统的Ballistic YMC S5 ODS 4.6mm x 50mm柱,其中溶剂A=10%甲醇和90%水(含0.2%磷酸),溶剂B=90%甲醇和10%水(含0.2%磷酸),流速=4mL/min,线性梯度时间=4min。
HPLC方法B:采用二元溶剂系统的PHENOMENEX Luna C18(2),4.6x50mm柱,其中溶剂A=10%甲醇和90%水(含0.1%三氟乙酸),并且溶剂B=90%甲醇和10%水(含0.1%三氟乙酸),流速=4mL/min,线性梯度时间=4min。
HPLC方法C:采用二元溶剂系统的Waters SunFire C18,4.6x50mm柱,其中溶剂A=10%甲醇和90%水(含0.1%三氟乙酸),溶剂B=90%甲醇和10%水(含0.1%三氟乙酸),流速=4mL/min,线性梯度时间=4min。
LCMS方法A:采用二元溶剂系统的Phenomenex 5μm C18,4.6mm x 50mm柱,其中溶剂A=10%甲醇和90%水(含0.1%三氟乙酸),溶剂B=90%甲醇和10%水(含0.1%三氟乙酸),流速=4mL/min,线性梯度时间=4min。
LCMS方法B:采用二元溶剂系统的Ascentis Express C18,4.6x50mm柱,其中溶剂A=5%乙腈和95%水(含10mM乙酸铵),溶剂B=95%乙腈和5%水(含10mM乙酸铵),流速=4mL/min,线性梯度时间=4min。
LCMS方法C:采用二元溶剂系统的Waters Acquity UPLC BEH C18,2.1x50mm柱,其中溶剂A=5%乙腈和95%水(含10mM乙酸铵),溶剂B=95%乙腈和5%水(含10mM乙酸铵),流速=1mL/min,线性梯度时间=3min。
LCMS方法D:采用二元溶剂系统的Waters Acquity UPLC BEH C18,2.1x50mm柱,其中溶剂A=5%乙腈和95%水(含0.1%三氟乙酸),并且溶剂B=95%乙腈和5%水(含0.1%三氟乙酸),流速=1mL/min,线性梯度时间=3min。
制备型HPLC方法A:采用二元溶剂系统的Ballistic YMC S5 ODS 20mm x 100mm柱,其中溶剂A=10%甲醇和90%水(含0.1%三氟乙酸),溶剂B=90%甲醇和10%水(含0.1%三氟乙酸);流速=20mL/min,线性梯度时间=10min。
制备型HPLC方法B:采用二元溶剂系统的Waters XBridge C18,19x200mm柱,其中溶剂A=5%乙腈和95%水(含0.1%三氟乙酸),溶剂B=95%乙腈和5%水(含0.1%三氟乙酸);流速=20mL/min,线性梯度时间=20min。
制备型HPLC方法C:采用二元溶剂系统的Waters XBridge C18,19x200mm柱,其中溶剂A=5%乙腈和95%水(含10mM乙酸铵),溶剂B=95%乙腈和5%水(含10mM乙酸铵);流速=20mL/min,线性梯度时间=20min。
实施例1
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺
将3-溴-2-甲氧基苯胺(3.00g,14.85mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂环戊硼烷)(5.66g,22.27mmol)、PdCl2(dppf)-CH2Cl2加合物(0.728g,0.891mmol)和乙酸钾(4.37g,44.5mmol)在1,4-二噁烷(60ml)中的混合物在压力瓶中在110℃下加热20h。在冷却至室温后,将混合物用乙酸乙酯(60mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩,并且使残余物经受ISCO色谱(330g硅胶,0-40%乙酸乙酯/己烷),以提供呈白色固体的2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(2.31g,9.27mmol,62.5%产率)。LCMS m/z=250.3(M+H)+。1H NMR(400MHz,DMSO-d6)δ6.79-6.77(m,2H),6.76-6.72(m,1H),4.77(s,2H),3.63(s,3H),1.27(s,12H)
步骤2. 2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯胺
将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(250mg,1.004mmol)、2-氯-9-甲基-9H-嘌呤(178mg,1.054mmol)、PdCl2(dppf)-CH2Cl2加合物(49.2mg,0.060mmol)和2M水性三磷酸钾(1.505mL,3.01mmol)在1,4-二噁烷(8mL)中的混合物在100℃下加热16h。在冷却至室温后,将混合物用乙酸乙酯(8mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至接近干燥。向残余物中添加水(10mL),并且将所得混合物用二氯甲烷(3x30mL)萃取。将合并的萃取物经无水Na2SO4干燥。通过ISCO色谱(40g硅胶,固体负载,0-5% MeOH/二氯甲烷)分离到呈白色固体的所需产物2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯胺(208mg,0.815mmol,81%产率)。LCMS m/z=256.3(M+H)+。
步骤3. 6-氯-4-((2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯胺(Moslin,R.等人J.Med.Chem.2019,62,8953-8972)(208mg,0.816mmol)在THF(6mL)中的溶液中经1min添加在THF中的双(三甲基甲硅烷基)氨基锂(1.854mL,1.854mmol)。将混合物在室温下搅拌40min,之后将它用水(1mL)淬灭。将所得混合物用1NHCl溶液调节至pH 9-10,用乙酸乙酯(70mL)稀释,用水(20mL)和盐水(20mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(40g硅胶,固体负载,0-5% MeOH/二氯甲烷)分离到呈白色固体的所需产物6-氯-4-((2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(118mg,0.276mmol,37.2%产率)。LCMS m/z=428.2(M+H)+。
步骤4. 6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(50mg,0.117mmol)、环丙烷甲酰胺(19.89mg,0.234mmol)、三(二亚苄基丙酮)二钯(0)(12.84mg,0.014mmol)、XantPhos(8.11mg,0.014mmol)和碳酸铯(84mg,0.257mmol)在1,4-二噁烷(2.5mL)中的混合物在微波下在135℃下加热1h。将混合物用乙酸乙酯(8mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。使残余物经受制备型HPLC。将正确的级分合并,在真空下浓缩,用饱和NaHCO3溶液碱化至pH 9-10,并且用二氯甲烷(3x30mL)萃取。将合并的萃取物经无水Na2SO4干燥并且在真空下浓缩至干,以提供呈苍白色固体的6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(9-甲基-9H-嘌呤-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(22.9mg,0.047mmol,40.3%产率)。LCMS m/z=477.4(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.97(s,1H),9.26(s,1H),9.14(s,1H),8.61(s,1H),8.18(s,1H),7.60(ddd,J=17.0,7.9,1.5Hz,2H),7.32(t,J=7.8Hz,1H),3.89(s,3H),3.75(s,3H),2.15-2.03(m,1H),0.83(d,J=6.0Hz,4H)。
以与实施例1相同的方式制备表1中的实施例2-13。
表1
实施例14
6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
步骤1. 5-氟-2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺
将3-溴-5-氟-2-甲氧基苯胺(0.304g,1.382mmol)、4,4,4',4',5,5,5',5'-八甲基-2,2'-二(1,3,2-二氧杂环戊硼烷)(0.526g,2.072mmol)、PdCl2(dppf)-CH2Cl2加合物(0.068g,0.083mmol)和乙酸钾(0.407g,4.14mmol)在1,4-二噁烷(7ml)中的混合物在压力瓶中在105℃下加热18h。将混合物用乙酸乙酯(10mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩,并且使残余物经受ISCO色谱(40g硅胶,固体负载,0-60%乙醚/己烷),以提供呈白色固体的5-氟-2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(0.225g,0.842mmol,61.0%产率)。LCMS m/z=268.2(M+H)+。
步骤2. 5-氟-2-甲氧基-3-(嘧啶-2-基)苯胺
将5-氟-2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(225mg,0.842mmol)、2-氯嘧啶(104mg,0.910mmol)、PdCl2(dppf)-CH2Cl2加合物(41.3mg,0.051mmol)和2M水性三磷酸钾(1.264mL,2.53mmol)在1,4-二噁烷(6mL)中的混合物在105℃下加热16h。将混合物用乙酸乙酯(6mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至干。将残余物用水(10mL)稀释并且用二氯甲烷(3x30mL)萃取。将合并的萃取物经无水MgSO4干燥并且在真空下浓缩。使残余物经受ISCO色谱(24g硅胶,40%-85%乙酸乙酯/己烷),以提供呈淡黄色油状物的5-氟-2-甲氧基-3-(嘧啶-2-基)苯胺(126mg,0.575mmol,68.2%产率)。LCMS m/z=220.1(M+H)+。
步骤3. 6-氯-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和5-氟-2-甲氧基-3-(嘧啶-2-基)苯胺(Moslin,R.等人J.Med.Chem.2019,62,8953-8972)(84mg,0.384mmol)在THF(4mL)中的溶液中经1min添加在THF中的双(三甲基甲硅烷基)氨基锂(0.913mL,0.913mmol)。将所得混合物在室温下搅拌1h,之后将它用水(1mL)淬灭。将混合物用1N HCl溶液调节至pH 9-10,用乙酸乙酯(60mL)稀释,相继用水(20mL)和盐水(20mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(40g硅胶,固体负载,70%-100%乙酸乙酯/二氯甲烷)分离到呈白色固体的所需产物6-氯-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-三氘代甲基烟酰胺(73mg,0.187mmol,51.1%产率)。LCMS m/z=391.1(M+H)+。
步骤4. 6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
将6-氯-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-三氘代甲基烟酰胺(73mg,0.187mmol)、环丙烷甲酰胺(31.8mg,0.374mmol)、三(二亚苄基丙酮)二钯(0)(25.7mg,0.028mmol)、XantPhos(16.21mg,0.028mmol)和碳酸铯(134mg,0.411mmol)在1,4-二噁烷(2.2mL)和1-甲基吡咯烷-2-酮(NMP)(0.3mL)中的混合物在微波下在140℃下加热1h。将混合物用乙酸乙酯(8mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物用MeOH稀释并且注射到制备型HPLC中。将正确的级分合并,在真空下浓缩,并且用饱和NaHCO3溶液碱化至pH 9-10。收集到呈白色固体的沉淀产物6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-三氘代甲基烟酰胺(43mg,0.097mmol,51.9%产率)并且将其在真空下在50℃下干燥。LCMS m/z=440.3(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.86(d,J=6.0Hz,2H),8.97(d,J=4.9Hz,2H),8.63(s,1H),8.56(s,1H),8.17(s,1H),7.55(t,J=4.9Hz,1H),7.43(dd,J=10.0,3.1Hz,1H),7.22(dd,J=9.1,3.1Hz,1H),3.69(s,3H),2.07-1.97(m,1H),0.87-0.77(m,4H)。
以与实施例14相同的方式制备表2中的实施例15-18。
表2
实施例19
6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 3-氯-6-(1-乙氧基乙烯基)哒嗪
将3,6-二氯哒嗪(1.00g,6.71mmol)、三丁基(1-乙氧基乙烯基)锡烷(2.322mL,7.05mmol)、双(三苯基膦)氯化钯(II)(0.141g,0.201mmol)、三乙胺(1.029mL,7.38mmol)在DMF(25mL)中的混合物在100℃下加热16h。将溶剂在真空下去除。将残余物用乙酸乙酯(150mL)稀释,用水(3x40mL)和盐水(40mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(80g硅胶,固体负载,5%-20%乙酸乙酯/己烷)分离到呈白色固体的所需产物3-氯-6-(1-乙氧基乙烯基)哒嗪(0.514g,2.78mmol,41.5%产率)。LCMS m/z=185.0(M+H)+。
步骤2. 3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯胺
将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(650mg,2.61mmol)、3-氯-6-(1-乙氧基乙烯基)哒嗪(506mg,2.74mmol)、PdCl2(dppf)-CH2Cl2加合物(128mg,0.157mmol)和2M水性三磷酸钾(3.91mL,7.83mmol)在1,4-二噁烷(16mL)中的混合物在105℃下加热16h。将混合物用乙酸乙酯(20mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至干。将残余物用水(20mL)稀释并且用二氯甲烷(4x40mL)萃取。将合并的萃取物经无水MgSO4干燥。通过ISCO色谱(80g硅胶,30%-70%乙酸乙酯/己烷)分离到呈浅黄色油状物的所需产物3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯胺(722mg,2.66mmol,100%产率)。LCMS m/z=272.1(M+H)+。
步骤3. 6-氯-4-((3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯胺(0.722g,2.66mmol)在THF(20mL)中的溶液中经1min添加在THF中的双(三甲基甲硅烷基)氨基锂(6.34mL,6.34mmol)。将所得混合物在室温下搅拌1h,之后将它用水(3mL)淬灭。将混合物用1N HCl溶液调节至pH 9-10,用乙酸乙酯(150mL)稀释,并且用水(2x30mL)和盐水(30mL)洗涤。将有机层经无水MgSO4干燥。通过ISCO色谱(40g硅胶,固体负载,25%-50%乙酸乙酯/二氯甲烷)分离到呈白色固体的所需产物6-氯-4-((3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.580g,1.307mmol,51.5%产率)。LCMS m/z=444.2(M+H)+。
步骤4. 6-(环丙烷甲酰胺基)-4-((3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(0.300g,0.676mmol)、环丙烷甲酰胺(0.115g,1.352mmol)、三(二亚苄基丙酮)二钯(0)(0.093g,0.101mmol)、XantPhos(0.059g,0.101mmol)和碳酸铯(0.484g,1.487mmol)在1,4-二噁烷(6mL)和NMP(0.8mL)中的混合物在微波条件下在150℃下加热1h。将混合物用乙酸乙酯(10mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。使残余物经受ISCO色谱(40g硅胶,固体负载,40%-80%乙酸乙酯/二氯甲烷),以提供呈白色固体的6-(环丙烷甲酰胺基)-4-((3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(0.540g,被NMP污染)。LCMS m/z=493.2(M+H)+。
步骤5. 4-((3-(6-乙酰基哒嗪-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向6-(环丙烷甲酰胺基)-4-((3-(6-(1-乙氧基乙烯基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(0.540g,<0.676mmol,来自上一步骤)在THF(20mL)中的溶液中添加1N盐酸(10mL,10.00mmol)。将所得溶液在室温下搅拌4h,然后在真空下浓缩至大约10mL的体积。将残余物用1N NaOH溶液碱化至pH 10。允许将所得悬浮液在0℃下静置0.5h。通过吸滤收集到呈淡黄色固体的所需产物4-((3-(6-乙酰基哒嗪-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-三氘代甲基哒嗪-3-甲酰胺(0.165g,0.337mmol)(52%产率,经两个步骤)并且将其在真空下在60℃下干燥。LCMS m/z=465.3(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),11.01(s,1H),9.16(s,1H),8.32-8.25(m,1H),8.24-8.15(m,2H),7.67(td,J=7.7,1.5Hz,2H),7.42(t,J=7.9Hz,1H),3.51(s,3H),2.84(s,3H),2.14-2.05(m,1H),0.84(d,J=6.1Hz,4H)。
步骤6. 6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在0℃下向4-((3-(6-乙酰基哒嗪-3-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-三氘代甲基哒嗪-3-甲酰胺(85mg,0.183mmol)在四氢呋喃(10mL)中的溶液中逐滴添加甲基溴化镁(0.366mL,1.098mmol)。将所得混合物在0℃下搅拌45min,之后将它用水(5mL)淬灭。将混合物用乙酸乙酯(120mL)稀释,用水(2x30mL)和盐水(30mL)洗涤,并且经无水MgSO4干燥。在真空下去除溶剂后,使残余物经受制备型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 10,并且用二氯甲烷(3x30mL)萃取。将合并的萃取物经无水Na2SO4干燥。在真空下去除溶剂提供呈白色固体的6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(33.4mg,0.069mmol,37.6%产率)。LCMS m/z=481.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),11.00(s,1H),9.15(s,1H),8.18(s,1H),8.08-8.03(m,1H),8.00-7.95(m,1H),7.59(d,J=7.8Hz,2H),7.41-7.34(m,1H),5.53(s,1H),3.49(s,3H),2.10(quin,J=6.1Hz,1H),1.60(s,6H),0.84(d,J=6.1Hz,4H)。
以与实施例19相同的方式制备表3中的实施例20-24。
表3
实施例25
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 2-(5-氯吡嗪-2-基)丙-2-醇
在-78℃下向2-溴-5-氯吡嗪(2.02g,10.44mmol)在乙醚(30mL)中的悬浮液中经10min添加正丁基锂(4.26mL,10.65mmol)。将所得混合物在-78℃下搅拌15min,之后经2min添加丙-2-酮(1.917mL,26.1mmol)。将混合物在-78℃下搅拌15min,然后在室温下搅拌30min。将反应用饱和NH4Cl溶液(30mL)淬灭,并且将溶液用乙酸乙酯(4x40mL)萃取。将合并的萃取物经无水Na2SO4干燥。通过ISCO色谱(120g硅胶,固体负载,10%-40%乙酸乙酯/己烷)分离到所需产物2-(5-氯吡嗪-2-基)丙-2-醇(0.507g,2.94mmol,28.1%产率)。LCMS m/z=173.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.72-8.69(m,2H),5.56(br s,1H),1.47(s,6H)。
步骤1(替代方案).2-(5-氯吡嗪-2-基)丙-2-醇
在0℃下向5-氯吡嗪-2-甲酸甲酯(2.51g,14.54mmol)在THF(48.5ml)中的溶液中经15min逐滴添加在乙醚中的3M甲基溴化镁(15.0ml,45.0mmol)。将混合物在0℃下搅拌2h,之后将它用水(50mL)淬灭并且用乙酸乙酯(125mL)稀释。将各层分离,并且将有机层相继用水(50mL)和盐水(50mL)洗涤,并且经Na2SO4干燥。通过ISCO色谱(120g硅胶,固体负载,0-40%乙酸乙酯/己烷)分离到呈黄色油状物的所需产物2-(5-氯吡嗪-2-基)丙-2-醇(0.4412g,2.352mmol,16.2%产率)。LCMS m/z=173.2(M+H)+。
步骤2. 2-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)丙-2-醇
将2-(5-氯吡嗪-2-基)丙-2-醇(0.191g,1.105mmol)、2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(0.284g,1.015mmol)、2M水性三磷酸钾(1.5ml,3.05mmol)和PdCl2(dppf)-CH2Cl2加合物(0.050g,0.061mmol)在1,4-二噁烷(6.8ml)中的混合物在密封的压力小瓶中在105℃下加热19h。在冷却至室温后,将混合物用乙酸乙酯(25mL)稀释并且通过硅藻土过滤。将滤液用水(10mL)洗涤。将水层用乙酸乙酯(2x25mL)萃取。将有机层合并并且经Na2SO4干燥。通过ISCO色谱(24g硅胶,0-100%乙酸乙酯/己烷)分离到呈黄色油状物的所需产物2-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)丙-2-醇(0.2208g,0.834mmol,82%产率)。LCMS m/z=260.2(M+H)+。
步骤3. 6-氯-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向2-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)丙-2-醇(0.2187g,0.843mmol)和4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺(0.168g,0.803mmol)在THF(8.03ml)中的溶液中经1min添加1M双(三甲基甲硅烷基)氨基锂/THF(3.21ml,3.21mmol)。将混合物在室温下搅拌1h,之后将它用水(5mL)淬灭。将所得混合物用1N HCl溶液调节至pH 9-10,用乙酸乙酯(125mL)稀释,并且用水(20mL)和盐水(20mL)洗涤。将有机层经无水MgSO4溶液干燥。通过ISCO色谱(24g硅胶,0-100%乙酸乙酯/己烷)分离到呈灰白色固体的所需产物6-氯-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.2082g,0.482mmol,60.0%产率)。LCMS m/z=432.2(M+H)+。
步骤4. 6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.102g,0.236mmol)、环丙烷甲酰胺(0.040g,0.473mmol)、XantPhos(0.021g,0.035mmol)、碳酸铯(0.169g,0.520mmol)和Pd2(dba)3(0.032g,0.035mmol)在1,4-二噁烷(5.4ml)和N-甲基-2-吡咯烷酮(0.54ml)中的混合物在微波条件下在145℃下加热1h。在冷却至室温后,将混合物用乙酸乙酯(10mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩,并且使残余物经受制备型HPLC。将正确的级分合并,用固体NaHCO3碱化,在真空下浓缩,并且用二氯甲烷(3x)萃取。将合并的萃取物经Na2SO4干燥。在真空下去除溶剂提供呈浅黄色固体的6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.0342g,0.071mmol,30.1%产率)。LCMS m/z=481.5(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.32(s,1H),10.97(s,1H),9.14(s,1H),9.01(d,J=1.5Hz,1H),8.96(d,J=1.5Hz,1H),8.16(s,1H),7.60-7.52(m,2H),7.39-7.29(m,1H),5.49(s,1H),3.53(s,3H),2.14-2.03(m,1H),1.52(s,6H),0.86-0.78(m,4H)。
以与实施例25相同的方式制备表4中的实施例26-35。
表4
实施例36
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 5-氯-N,N-二甲基吡嗪-2-甲酰胺
在室温下向5-氯吡嗪-2-甲酸(0.500g,3.15mmol)在二氯甲烷(5mL)和DMF(2滴)中的悬浮液中经10min逐滴添加草酰氯(0.402mL,3.63mmol)。将混合物在室温下搅拌2h,之后将它在真空下浓缩至干。将残余物溶解在二氯甲烷(5mL)中。在室温下经5min添加在THF中的二甲胺(1.892mL,3.78mmol),然后添加三乙胺(0.967mL,6.94mmol)。将混合物在室温下搅拌3h,然后在真空下浓缩至干。向残余物中添加二氯甲烷(50mL),并且将不溶性材料通过经硅藻土吸滤而去除。将滤液在真空下浓缩并且将残余物应用于ISCO色谱(80g硅胶,固体负载,70%-100%乙酸乙酯),以提供呈白色固体的5-氯-N,N-二甲基吡嗪-2-甲酰胺(0.304g,1.638mmol,51.9%产率)。LCMS m/z=186.1(M+H)+。
步骤2. 5-(3-氨基-2-甲氧基苯基)-N,N-二甲基吡嗪-2-甲酰胺
将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(200mg,0.803mmol)、5-氯-N,N-二甲基吡嗪-2-甲酰胺(152mg,0.819mmol)、PdCl2(dppf)-CH2Cl2加合物(39.3mg,0.048mmol)和2M水性三磷酸钾(1.204mL,2.409mmol)在1,4-二噁烷(5.5mL)中的混合物在100℃下加热16h。将混合物用乙酸乙酯(15mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至干。将残余物用水(15mL)稀释并且用二氯甲烷(3x40mL)萃取。将合并的萃取物经无水MgSO4干燥。通过ISCO色谱(40g硅胶,固体负载,60%-95%乙酸乙酯/己烷)分离到呈白色固体的所需产物5-(3-氨基-2-甲氧基苯基)-N,N-二甲基吡嗪-2-甲酰胺(143mg,0.525mmol,65.4%产率)。LCMS m/z=273.1(M+H)+。
步骤3. 6-氯-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和5-(3-氨基-2-甲氧基苯基)-N,N-二甲基吡嗪-2-甲酰胺(70.4mg,0.259mmol)在THF(4mL)中的溶液中经5min添加在THF中的双(三甲基甲硅烷基)氨基锂(0.634mL,0.634mmol)。将混合物在室温下搅拌1h,之后将它用水(5mL)淬灭。将所得混合物用1N HCl溶液调节至pH 9-10,用乙酸乙酯(100mL)稀释,并且用水(2x20mL)和盐水(20mL)洗涤。将有机层经无水MgSO4干燥。通过ISCO色谱(24g硅胶,固体负载,60%-100%乙酸乙酯/己烷)分离到呈浅黄色固体的所需产物6-氯-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(93.1mg,0.209mmol,83%产率)。LCMS m/z=445.1(M+H)+。
步骤4. 6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(50mg,0.112mmol)、环丙烷甲酰胺(23.91mg,0.281mmol)、三(二亚苄基丙酮)二钯(0)(15.44mg,0.017mmol)、XantPhos(9.75mg,0.017mmol)和碳酸铯(92mg,0.281mmol)在1,4-二噁烷(2.2mL)和NMP(0.3mL)中的混合物在微波条件下在135℃下加热1h。将混合物用乙酸乙酯(6mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物注射到制备型HPLC中。将正确的级分合并,在真空下浓缩,并且用1.5M K2HPO4溶液碱化至pH10,用二氯甲烷(3x40mL)萃取。将合并的萃取物经无水Na2SO4干燥。在真空下去除溶剂提供呈苍白色固体的6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(27.4mg,0.055mmol,48.9%产率)。LCMS m/z=494.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.35(s,1H),11.01(s,1H),9.16(s,1H),9.08(d,J=1.6Hz,1H),8.96(d,J=1.5Hz,1H),8.17(s,1H),7.63(ddd,J=7.9,6.4,1.5Hz,2H),7.45-7.35(m,1H),3.56(s,3H),3.07(d,J=4.5Hz,6H),2.15-2.05(m,1H),0.87-0.79(m,4H)。
以与实施例36相同的方式制备表5中的实施例37-49。
表5
实施例50
6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 2-(3-氨基-2-甲氧基苯基)嘧啶-5-甲酸乙酯
将2-氯嘧啶-5-甲酸乙酯(1.2442g,6.67mmol)、2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(1.5085g,6.06mmol)、2M K3PO4溶液(9.0ml,18.00mmol)和PdCl2(dppf)-CH2Cl2加合物(0.2604g,0.319mmol)在1,4-二噁烷(40.0ml)中的溶液在密封的小瓶中在75℃下加热4h。在冷却至室温后,将混合物用乙酸乙酯(200mL)稀释并且通过硅藻土过滤。将滤液用盐水洗涤并且经Na2SO4干燥。通过快速色谱(80g硅胶,0-75%乙酸乙酯/己烷)分离到所需产物2-(3-氨基-2-甲氧基苯基)嘧啶-5-甲酸乙酯(1.2886g,4.48mmol,74.0%产率)。LCMS m/z=274.3(M+H)+。
步骤2. 2-(3-((6-氯-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸乙酯
在室温下向2-(3-氨基-2-甲氧基苯基)嘧啶-5-甲酸乙酯(0.7097g,2.60mmol)和4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(0.5515g,2.64mmol)在THF(24ml)中的溶液中经3min添加1M双(三甲基甲硅烷基)氨基锂/THF(8.0ml,8.00mmol)。将混合物在室温下搅拌1.25h,之后将它用乙酸(0.51ml,8.91mmol)淬灭,用乙酸乙酯(150mL)稀释,用盐水(30mL)洗涤,并且经无水MgSO4干燥。通过快速色谱(40g硅胶,0-50%乙酸乙酯/己烷)分离到呈白色固体的所需产物2-(3-((6-氯-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸乙酯(0.3656g,0.820mmol,31.6%产率)。LCMS m/z=446.6(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.13(s,1H),9.38(s,3H),7.79-7.67(m,2H),7.37(t,J=7.9Hz,1H),7.22(s,1H),4.42(q,J=7.1Hz,2H),3.70(s,3H),1.38(t,J=7.1Hz,3H)。
步骤3. 2-(3-((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸乙酯
将2-(3-((6-氯-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸乙酯(0.344g,0.772mmol)和环丙烷甲酰胺(0.131g,1.543mmol)、XantPhos(0.067g,0.116mmol)、碳酸铯(0.553g,1.697mmol)和Pd2(dba)3(0.085g,0.093mmol)在1,4-二噁烷(10ml)中的混合物脱气并且在150℃下加热2.5h。在冷却至室温后,将混合物用乙酸乙酯(20mL)稀释并且通过硅藻土过滤。向滤液中添加硅胶(1.7g),并且将混合物在真空下浓缩。使残余物经受快速色谱(24g硅胶,25%-100%乙酸乙酯/己烷),以提供呈黄色固体的2-(3-((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸乙酯(0.2926g,0.556mmol,72.1%产率)。LCMS m/z=495.6(M+H)+。
步骤4. 2-(3-((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸
在室温下向2-(3-((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸乙酯(0.274g,0.554mmol)在甲醇(2ml)和THF(4ml)中的溶液中添加氢氧化锂单水合物(0.1216g,2.90mmol)在水(1.5mL)中的溶液。将混合物在室温下搅拌2h,在真空下浓缩至大约4mL的体积,并且用1N HCl溶液酸化至pH 4-5。通过吸滤收集到呈灰白色固体的沉淀产物2-(3-((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸(0.1700g,0.321mmol,57.9%产率)并且将其干燥。LCMS m/z=467.5(M+H)+。
步骤5. 6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将2-(3-((6-(环丙烷甲酰胺基)-3-((甲基-d3)氨基甲酰基)哒嗪-4-基)氨基)-2-甲氧基苯基)嘧啶-5-甲酸(0.0349g,0.075mmol)、N-甲基乙胺(14.2mg,0.240mmol)、BOP(0.0544g,0.123mmol)和二异丙基乙胺(0.05ml,0.286mmol)在THF(1.5ml)中的混合物在50℃下加热20h。将混合物用DMSO(1mL)和MeOH(3mL)稀释,并且使其经受制备型HPLC。将正确的级分合并,在真空下浓缩,用饱和NaHCO3溶液碱化,并且用二氯甲烷(3x)萃取。将合并的萃取物经无水Na2SO4干燥。在真空下去除溶剂提供呈白色固体的6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.00892g,0.018mmol,23.49%产率)。LCMS m/z=508.6(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.33(s,1H),10.97(s,1H),9.14(s,1H),9.02(br d,J=11.9Hz,2H),8.15(s,1H),7.66-7.57(m,2H),7.34(t,J=7.9Hz,1H),3.71(s,3H),3.58-3.47(m,2H),3.02(s,3H),2.09(quin,J=6.2Hz,1H),1.17(dt,J=10.9,6.9Hz,3H),0.87-0.79(m,4H)。
以与实施例50相同的方式制备表6中的实施例51-54。
表6
实施例55
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 2-氯-5-(2,5-二氢呋喃-3-基)嘧啶
将5-溴-2-氯嘧啶(0.25g,1.292mmol)、2-(4,5-二氢呋喃-3-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(0.2619g,1.336mmol)、2M水性三磷酸钾(2.0ml,4.00mmol)和PdCl2(dppf)-CH2Cl2加合物(0.053g,0.065mmol)在1,4-二噁烷(12.0ml)中的溶液在密封的压力管中在105℃下加热16h。在冷却至室温后,将混合物用乙酸乙酯稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物通过快速色谱(硅胶24g,0-50%乙酸乙酯/己烷)纯化,以得到呈白色固体的2-氯-5-(2,5-二氢呋喃-3-基)嘧啶(0.0869g,0.476mmol,36.8%产率)。LCMS m/z=183.1(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.88(s,2H),6.87(t,J=2.1Hz,1H),4.92(td,J=5.0,2.2Hz,2H),4.75(td,J=5.0,2.0Hz,2H)。
步骤2. 3-(5-(2,5-二氢呋喃-3-基)嘧啶-2-基)-2-甲氧基苯胺
将2-氯-5-(2,5-二氢呋喃-3-基)嘧啶(0.0869g,0.476mmol)、2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(0.1316g,0.528mmol)、2M K3PO4水溶液(0.72ml,1.440mmol)和PdCl2(dppf)-CH2Cl2加合物(0.019g,0.024mmol)在二噁烷(5.0ml)中的溶液在密封的小瓶中在105℃下加热22h。在冷却至室温后,将混合物用乙酸乙酯(30mL)稀释并且通过硅藻土过滤。将滤液与硅胶(1g)一起混合并且在真空下浓缩。使残余物经受ISCO色谱(12g硅胶,0-100%乙酸乙酯/己烷),以提供呈黄色油状物的3-(5-(2,5-二氢呋喃-3-基)嘧啶-2-基)-2-甲氧基苯胺(0.0432g,0.160mmol,33.7%产率)。LCMS m/z=270.2(M+H)+。
步骤3. 2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯胺
将3-(5-(2,5-二氢呋喃-3-基)嘧啶-2-基)-2-甲氧基苯胺(0.0716g,0.266mmol)和10% Pd/C(0.0351g,0.033mmol)在甲醇和四氢呋喃(2.000ml)中的溶液在H2(用H2气球提供)下在室温下搅拌3h。将催化剂通过经硅藻土吸滤而去除。将滤液在真空下浓缩,以得到呈黄色油状物的2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯胺(0.0698g,0.216mmol,81%产率)。LCMS m/z=272.4(M+H)+。
步骤4. 6-氯-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯胺(0.0311g,0.115mmol)和4,6-二氯-N-(甲基-d3)哒嗪-3-甲酰胺(0.0260g,0.124mmol)在THF(1.5)中的混合物中添加双(三甲基甲硅烷基)氨基锂(0.4ml,0.400mmol)。将所得溶液在室温下搅拌2h,然后用水(1mL)淬灭,然后添加1N水性盐酸,直到通过石蕊试纸测得pH 9-10。将混合物用乙酸乙酯稀释,相继用水(10mL)和盐水(10mL)洗涤,经Na2SO4干燥,并且在真空下浓缩。将残余物通过ISCO色谱(4g硅胶,0-100%乙酸乙酯/己烷)纯化,以得到呈白色固体的6-氯-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.014g,0.030mmol,26.1%产率)。LCMS m/z=444.5(M+H)+。
步骤5. 6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.0250g,0.056mmol)、环丙烷甲酰胺(11.4mg,0.134mmol)、XantPhos(6.8mg,0.012mmol)、碳酸铯(0.0521g,0.160mmol)和Pd2(dba)3(9.5mg,10.37μmol)在1,4-二噁烷(1.2ml)中的混合物脱气并且在微波条件下在150℃下加热2h。在冷却至室温后,将混合物用乙酸乙酯(8mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩,并且使残余物经受制备型HPLC,以得到呈白色固体的6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(3.7mg,13%产率)。LCMS m/z=493.5(M+H)+。1H NMR(500MHz,DMSO-d6)δ11.33(s,1H),10.92(s,1H),9.13(br s,1H),8.88(s,2H),8.14(s,1H),7.62-7.48(m,2H),7.31(br t,J=7.8Hz,1H),4.09(br t,J=7.7Hz,1H),4.05-3.97(m,1H),3.85(q,J=7.7Hz,1H),3.72-3.64(m,3H),3.49(s,2H),2.45-2.36(m,1H),2.13-1.99(m,2H),0.87-0.79(m,4H)。
实施例56
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1.N-(5-氯吡嗪-2-基)乙酰胺
将5-溴吡嗪-2-胺(1.00g,5.75mmol)在乙酸酐(10mL,106mmol)中的溶液在室温下搅拌16h。将沉淀材料通过吸滤收集。将滤饼悬浮在水(20mL)和1.5N K2HPO4溶液(5mL)中,并且将悬浮液在室温下搅拌40min。通过吸滤收集到呈米色固体的不溶性产物N-(5-溴吡嗪-2-基)乙酰胺(0.917g,4.24mmol,73.9%产率)并且将其在真空下在60℃下干燥。LCMS m/z=216.0(M+H)+。
步骤2.N-(5-氯吡嗪-2-基)-N-甲基乙酰胺
在0℃下向N-(5-溴吡嗪-2-基)乙酰胺(0.550g,2.55mmol)和碘甲烷(0.198mL,3.18mmol)在DMF(15mL)中的溶液中一次性添加氢化钠(在矿物油中的60%分散液)(0.224g,5.60mmol)。将混合物在室温下搅拌40min,之后将它用饱和NH4Cl溶液(15mL)淬灭。将混合物用乙酸乙酯(3x50mL)萃取。将合并的萃取物在真空下浓缩至干。将残余物溶解在乙酸乙酯(150mL)中,用水(20mL)和盐水(20mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(80g硅胶,固体负载,30%-45%乙酸乙酯/己烷)分离到呈白色固体的所需产物N-(5-溴吡嗪-2-基)-N-甲基乙酰胺(0.445g,1.934mmol,76%产率)。
步骤3.N-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)-N-甲基乙酰胺
将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(235mg,0.943mmol)、N-(5-溴吡嗪-2-基)-N-甲基乙酰胺(228mg,0.991mmol)、PdCl2(dppf)-CH2Cl2加合物(46.2mg,0.057mmol)和2M水性三磷酸钾(1.415mL,2.83mmol)在1,4-二噁烷(6mL)中的混合物在100℃下加热16h。在冷却至室温后,将混合物用乙酸乙酯(15mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至干。将残余物用水(15mL)稀释并且用二氯甲烷(3x40mL)萃取。将合并的萃取物经无水MgSO4干燥。通过ISCO色谱(40g硅胶,固体负载,60%-95%乙酸乙酯/己烷)分离到呈白色固体的所需产物N-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)-N-甲基乙酰胺(158mg,0.580mmol,61.5%产率)。LCMS m/z=273.1(M+H)+。
步骤4. 6-氯-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和N-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)-N-甲基乙酰胺(74.4mg,0.273mmol)在THF(5mL)中的溶液中经5min添加在THF中的双(三甲基甲硅烷基)氨基锂(0.670mL,0.670mmol)。将所得混合物在室温下搅拌1h,之后将它用水(3mL)淬灭。将混合物用1N HCl溶液调节至pH 9-10,用乙酸乙酯(80mL)稀释,用水(2x25mL)和盐水(25mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(24g硅胶,固体负载,65%-100%乙酸乙酯/己烷)分离到呈米色固体的所需产物6-氯-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(71mg,0.160mmol,59.6%产率)。LCMS m/z=445.1(M+H)+。
步骤5. 6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(71.0mg,0.160mmol)、环丙烷甲酰胺(34.0mg,0.399mmol)、三(二亚苄基丙酮)二钯(0)(21.92mg,0.024mmol)、XantPhos(13.85mg,0.024mmol)和碳酸铯(130mg,0.399mmol)在1,4-二噁烷(2.5mL)中的混合物在微波下在145℃下加热1h。将混合物用乙酸乙酯(6mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物用DMSO和MeOH(1:3体积比)稀释,并且注射到制备型HPLC中。将正确的级分合并,在真空下浓缩,用1.5M K2HPO4溶液碱化至pH 10,并且用二氯甲烷(3x35mL)萃取。将合并的萃取物经无水MgSO4干燥。在真空下去除溶剂提供呈苍白色固体的6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(28.0mg,0.056mmol,35.2%产率)。LCMS m/z=494.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),11.00(s,1H),9.16(s,1H),9.08(d,J=1.3Hz,1H),8.96(d,J=1.5Hz,1H),8.18(s,1H),7.62(dd,J=7.8,1.6Hz,1H),7.58(dd,J=7.9,1.5Hz,1H),7.40-7.34(m,1H),3.56(s,3H),3.43(s,3H),2.25(s,3H),2.15-2.05(m,1H),0.88-0.80(m,4H)。
实施例57
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1. 4-(5-氯吡嗪-2-基)吗啉
将2,5-二氯吡嗪(0.5317g,3.57mmol)、吗啉(0.3443g,3.95mmol)和碳酸钾(0.691g,5.00mmol)在N-甲基-2-吡咯烷酮(25.5ml)中的混合物在100℃下加热17h。在冷却至室温后,将混合物用乙酸乙酯(200mL)稀释并且通过硅藻土过滤。将滤液用水(3x50mL)洗涤,经Ma2SO4干燥,并且在真空下浓缩。使残余物经受ISCO色谱(40g硅胶,10%-100%乙酸乙酯/己烷),以提供呈灰白色固体的4-(5-氯吡嗪-2-基)吗啉(0.538g,2.69mmol,76%产率)。LCMS m/z=200.1(M+H)+。
步骤2. 2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯胺
将4-(5-氯吡嗪-2-基)吗啉(0.1796g,0.900mmol)、2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(0.2003g,0.804mmol)、2M水性三磷酸钾(1.206ml,2.412mmol)和PdCl2(dppf)-CH2Cl2加合物(0.039g,0.048mmol)在1,4-二噁烷(6.19ml)中的混合物在密封的小瓶中在105℃下加热16h。在冷却至室温后,将混合物用乙酸乙酯(20mL)稀释并且通过硅藻土过滤。将滤液经Na2SO4干燥并且在真空下浓缩。使残余物经受ISCO色谱(24g硅胶,0-15%甲醇/二氯甲烷),以得到呈浅黄色油状物的2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯胺(0.096g,0.335mmol,41.5%产率)。LCMS m/z=287.1(M+H)+。
步骤3. 6-氯-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
向2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯胺(0.096g,0.335mmol)以及4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和N-(5-(3-氨基-2-甲氧基苯基)吡嗪-2-基)-N-甲基乙酰胺(0.070g,0.335mmol)在THF(3.35ml)中的溶液中经3min添加1M双(三甲基甲硅烷基)氨基锂/THF(1.006ml,1.006mmol)。将混合物在室温下搅拌1.5h,之后将它用水(0.5mL)淬灭。将溶液用1N水性乙酸调节至pH 9-10,用乙酸乙酯(40mL)稀释,并且用水(10mL)和盐水(10mL)洗涤。将有机溶液经Na2SO4干燥并且在真空下浓缩。将残余物用THF研磨,以得到呈浅黄色固体的6-氯-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(31.5mg,0.069mmol,20.5%产率)。LCMS m/z=459.2(M+H)+。
步骤6. 6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
2014年3月21日9:01:42AM-0400
将6-氯-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.0315g,0.069mmol)、环丙烷甲酰胺(0.012g,0.137mmol)、XantPhos(4.77mg,8.24μmol)、碳酸铯(0.049g,0.151mmol)和Pd2(dba)3(7.54mg,8.24μmol)在1,4-二噁烷(2mL)和N-甲基-2-吡咯烷酮(0.2mL)中的混合物在微波小瓶中在微波条件下在140℃下加热1h。将混合物用乙酸乙酯(10mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩,并且使残余物经受制备型HPLC,以提供6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺(0.0088g,0.017mmol,24.2%产率)。LCMS m/z=508.2(M+H)+。1H NMR(500MHz,DMSO-d6)δ11.32(s,1H),10.95(s,1H),9.14(s,1H),8.62(s,1H),8.44(s,1H),8.17(s,1H),7.55(d,J=7.1Hz,1H),7.45(br d,J=7.7Hz,1H),7.29(t,J=7.9Hz,1H),3.74(br t,J=4.5Hz,4H),3.60(br t,J=4.5Hz,4H),3.52(s,3H),2.13-2.01(m,1H),0.89-0.78(m,4H)。
以与实施例57相同的方式制备表7中的实施例58-60。
表7
实施例61
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
步骤1. 2-甲氧基-3-(嘧啶-2-基)苯胺
将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(1.19g,4.78mmol)、2-氯嘧啶(0.591g,5.16mmol)、PdCl2(dppf)-CH2Cl2加合物(0.234g,0.287mmol)和2M水性三磷酸钾(7.17mL,14.33mmol)在1,4-二噁烷(35mL)中的混合物在105℃下加热16h。将混合物用乙酸乙酯(35mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至干。将残余物用水(20mL)稀释并且用二氯甲烷(4x40mL)萃取。将合并的萃取物经无水MgSO4干燥并且在真空下浓缩。使残余物经受ISCO色谱(24g硅胶,45%-95%乙酸乙酯/己烷),以提供呈淡黄色油状物的2-甲氧基-3-(嘧啶-2-基)苯胺(0.780g,3.88mmol,81%产率)。LCMS m/z=202.2(M+H)+。
步骤2. 6-氯-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺(285mg,1.363mmol)和2-甲氧基-3-(嘧啶-2-基)苯胺(280mg,1.391mmol)在THF(10mL)中的溶液中经2min添加在THF中的双(三甲基甲硅烷基)氨基锂(3.41mL,3.41mmol)。将所得混合物在室温下搅拌75min,之后将它用水(10mL)淬灭。将混合物用1N HCl溶液调节至pH 9-10,用乙酸乙酯(150mL)稀释,相继用水(2x40mL)和盐水(40mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(80g硅胶,固体负载,60%-100%乙酸乙酯/二氯甲烷)分离到呈白色固体的所需产物6-氯-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(384mg,1.027mmol,75%产率)。LCMS m/z=373.9(M+H)+。
步骤3. 6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺
将6-氯-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-三氘代甲基烟酰胺(27mg,0.072mmol)、3-氨基-1-甲基-1H-吡唑-5-甲腈(17.69mg,0.145mmol)、三(二亚苄基丙酮)二钯(0)(9.95mg,10.86μmol)、XantPhos(6.29mg,10.86μmol)和碳酸铯(51.9mg,0.159mmol)在1,4-二噁烷(1.8mL)中的混合物在微波条件下在150℃下加热1h。将混合物用乙酸乙酯(8mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物用DMSO(0.2mL)和MeOH(1.5mL)稀释,并且使其经受制备型HPLC,以提供6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺(16.5mg,0.035mmol,48.2%产率)。LCMS m/z=459.2(M+H)+。1H NMR(500MHz,DMSO-d6)δ10.84(s,1H),8.96(d,J=4.7Hz,2H),8.74(br s,1H),8.40(s,1H),7.96(s,1H),7.63(d,J=7.7Hz,1H),7.57(brd,J=7.7Hz,1H),7.53(t,J=4.9Hz,1H),7.37(t,J=7.7Hz,1H),7.00(br s,1H),6.96(s,1H),3.93(s,3H),3.69(s,3H)。
以与实施例61相同的方式制备表8中的实施例62-107。
表8
实施例107
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺
步骤1. 1-(2-(((苄氧基)羰基)氨基)乙基)-1H-吡唑-3,5-二甲酸二乙酯
将1H-吡唑-3,5-二甲酸二乙酯(2.00g,9.42mmol)、(2-溴乙基)氨基甲酸苄酯(2.92g,11.31mmol)和碳酸钾(1.563g,11.31mmol)在DMF(20mL)中的混合物在55℃下加热1.5h。在冷却至室温后,将混合物用乙酸乙酯(30mL)稀释并且通过硅藻土过滤。将滤液进一步用乙酸乙酯(170mL)稀释,用水(4x40mL)和盐水(40mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(220g硅胶,20%-60%乙酸乙酯/己烷)分离到呈白色固体的所需产物1-(2-((叔丁氧基羰基)氨基)乙基)-1H-吡唑-3,5-二甲酸二乙酯(1.578g,4.05mmol,43.0%产率)。LCMS m/z=390.3(M+H)+。
步骤2. 4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯
将1-(2-((叔丁氧基羰基)氨基)乙基)-1H-吡唑-3,5-二甲酸二乙酯(1.57g,4.03mmol)和10% Pd/C(0.400g,0.332mmol)在甲醇(36mL)和四氢呋喃(12mL)中的混合物在H2(用H2气球提供)下在室温下搅拌1h。将催化剂通过过滤去除。将滤液在室温下搅拌18h,然后在真空下浓缩。使残余物经受ISCO色谱(120g硅胶,30%-60%乙酸乙酯/己烷),以提供呈白色固体的4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯(0.794g,3.80mmol,94%产率)。LCMS m/z=210.1(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.39(br s,1H),7.09(s,1H),4.40(dd,J=6.8,5.4Hz,2H),4.30(q,J=7.1Hz,2H),3.72-3.58(m,2H),1.30(t,J=7.1Hz,3H)。
步骤3. 5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯
在0℃下向4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯(0.740g,3.54mmol)和碘甲烷(0.440mL,7.07mmol)在DMF(15mL)中的溶液中分两次经5min添加氢化钠(60%油分散液)(0.311g,7.78mmol)。将混合物在室温下搅拌100min,之后将它用饱和NH4Cl溶液(5mL)淬灭。将所得混合物在真空下浓缩至大约5mL的体积。将残余物用乙酸乙酯(150mL)稀释并且用水(3x25mL)洗涤。发现水相含有大量的所需产物,因此将其用乙酸乙酯(3x50mL)萃取。将有机层合并并且经无水Na2SO4干燥。通过ISCO色谱(80g硅胶,1%-4%MeOH/二氯甲烷)分离到呈白色固体的所需产物5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯(0.724g,3.24mmol,92%产率)。LCMS m/z=224.1(M+H)+。
步骤4. 5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸
在室温下向5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸乙酯(0.674g,3.02mmol)在MeOH(35mL)中的溶液中一次性添加1M氢氧化钠溶液(12.68mL,12.68mmol)。将混合物在回流下加热70min,然后在真空下浓缩至大约15mL的体积。将残余物用1N HCl溶液酸化至pH 3并且用二氯甲烷(4x40mL)萃取。将合并的萃取物经无水MgSO4干燥。在真空下去除溶剂提供第一批呈白色固体的所需产物(77mg)。在二氯甲烷萃取后,一些沉淀在水层中形成,将所述沉淀通过吸滤收集并且在真空下在50℃下干燥,以得到第二批所需产物(67mg)。将滤液用乙酸乙酯(4x30mL)萃取。将合并的萃取物经无水MgSO4干燥并且在真空下浓缩以得到第三批所需产物(111mg)。
LCMS m/z=196.2(M+H)+。1H NMR(400MHz,DMSO-d6)δ12.94(br s,1H),7.03(s,1H),4.46(dd,J=6.9,5.6Hz,2H),3.82(dd,J=6.8,5.6Hz,2H),3.02(s,3H)。
步骤5.(5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基甲酸叔丁酯
在室温下向5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-甲酸(0.255g,1.033mmol)在无水t-BuOH(10mL)中的溶液中添加叠氮磷酸二苯酯(0.324mL,1.502mmol),然后添加三乙胺(0.273mL,1.960mmol)。将混合物在回流下加热16h。将挥发物在真空下去除。将残余物用二氯甲烷(60mL)稀释,用饱和NaHCO3溶液洗涤,并且经无水MgSO4干燥。通过ISCO色谱(40g硅胶,40%-80%乙酸乙酯/己烷)分离到呈白色固体的所需产物(5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基甲酸叔丁酯(0.158g,0.593mmol,45.4%产率)。LCMS m/z=267.3(M+H)+。
步骤6. 2-氨基-5-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮
在室温下向(5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基甲酸叔丁酯(0.158g,0.593mmol)在二氯甲烷(5mL)中的溶液中经1min添加TFA(5mL,64.9mmol)。将混合物在室温下搅拌50min。将挥发物在真空下去除。向残余物中添加饱和NaHCO3溶液(5mL)并且将混合物用乙酸乙酯(4x35mL)萃取。将合并的萃取物经无水Na2SO4干燥。在真空下去除溶剂提供呈白色固体的2-氨基-5-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮(89mg,0.536mmol,90%产率)。LCMS m/z=167.2(M+H)+。
步骤7. 3-(5-氟嘧啶-2-基)-2-甲氧基苯胺
将2-甲氧基-3-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯胺(650mg,2.61mmol)、2-氯-5-氟嘧啶(353mg,2.66mmol)、PdCl2(dppf)-CH2Cl2加合物(128mg,0.157mmol)和2M水性三磷酸钾(3.91mL,7.83mmol)在1,4-二噁烷(18mL)中的混合物在105℃下加热16h。在冷却至室温后,将混合物用乙酸乙酯(20mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至干。将残余物用水(20mL)稀释并且用二氯甲烷(4x40mL)萃取。将合并的萃取物经无水MgSO4干燥并且在真空下浓缩。使残余物经受ISCO色谱(80g硅胶,35%-60%乙酸乙酯/己烷),以提供呈浅黄色油状物的(3-(5-氟嘧啶-2-基)-2-甲氧基苯胺(488mg,2.226mmol,85%产率)。LCMS m/z=220.4(M+H)+。1H NMR(400MHz,DMSO-d6)δ8.98(d,J=0.7 Hz,2H),6.97-6.88(m,1H),6.87-6.78(m,2H),5.03(s,2H),3.62(s,3H)。
步骤8. 6-氯-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺在室温下向4,6-二氯-N-三氘代甲基哒嗪-3-甲酰胺和3-(5-氟嘧啶-2-基)-2-甲氧基苯胺(0.745 g,3.40 mmol)在THF(25 mL)中的溶液中经5 min添加在THF中的双(三甲基甲硅烷基)氨基锂(8.10 mL,8.10 mmol)。将所得混合物在室温下搅拌2 h,之后将它用水(5 mL)淬灭。将混合物用1 N HCl溶液调节至pH 9-10并且在真空下浓缩至大约15 mL的体积。向非均相残余物中添加水(60 mL),并且通过吸滤收集到呈苍白色固体的不溶性产物6-氯-4-(3-(5-氟嘧啶-2-基)-2-甲氧基苯基氨基)-N-三氘代甲基哒嗪-3-甲酰胺(0.807 g,2.060 mmol,63.6%产率)并且将其在真空下在50℃下干燥。LCMS m/z=392.0(M+H)+。
步骤9. 4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺
将6-氯-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(52.0mg,0.133 mmol)、2-氨基-5-甲基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮(44.1mg,0.265mmol)、三(二亚苄基丙酮)二钯(0)(14.58 mg,0.016 mmol)、XantPhos(9.22 mg,0.016mmol)和碳酸铯(95 mg,0.292 mmol)在1,4-二噁烷(2.5 mL)中的混合物在微波条件下在155℃下加热70 min。将混合物用乙酸乙酯(8 mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物溶解在DMSO和MeOH(1:3体积比)中并且使其经受制备型HPLC。将正确的级分合并,在真空下浓缩,用饱和NaHCO3溶液碱化至pH 9-10,并且用二氯甲烷(3x30mL)萃取。将合并的萃取物经无水MgSO4干燥并且在真空下浓缩至干,以提供呈白色固体的4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-三氘代甲基-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺(23.5 mg,0.045 mmol,34.0%产率)。LCMS m/z=522.3(M+H)+。1H NMR(400 MHz,DMSO-d6)δ10.92(s,1H),9.97(s,1H),9.08(s,1H),9.05(d,J=0.7 Hz,2H),7.69(dd,J=7.9,1.5 Hz,1H),7.56(br s,1H),7.50(dd,J=7.8,1.6 Hz,1H),7.40-7.32(m,1H),6.75(s,1H),4.23(dd,J=7.0,5.4 Hz,2H),3.82-3.75(m,2H),3.69(s,3H),3.00(s,3H)。
实施例108
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺
以与实施例108相同的方式合成此类似物。LCMS m/z=504.3(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.97(s,1H),9.08(s,1H),8.96(d,J=4.9 Hz,2H),7.68(dd,J=7.9,1.5 Hz,1H),7.56(br s,1H),7.55-7.48(m,2H),7.41-7.32(m,1H),6.75(s,1H),4.23(dd,J=7.1,5.3 Hz,2H),3.81-3.74(m,2H),3.70(s,3H),3.00(s,3H)。
实施例109
6-((5-环丙基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
步骤1.N-环丙基-3-硝基-1H-吡唑-5-甲酰胺
将5-硝基-1H-吡唑-3-甲酸(0.800g,5.09mmol)、BOP(2.93g,6.62mmol)、环丙胺(0.706mL,10.19mmol)和N,N-二异丙基乙胺(3.47mL,19.86mmol)在DMF(12mL)中的混合物在50℃下加热1.5h,然后在真空下浓缩至接近干燥。将残余物用乙酸乙酯(100mL)稀释,用水(3x20mL)和盐水(20mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(120g硅胶,固体负载,1%-5% MeOH/二氯甲烷)分离到呈白色固体的所需产物N-环丙基-5-硝基-1H-吡唑-3-甲酰胺(0.887g,4.52mmol,89%产率)。LCMS m/z=197.1(M+H)+。
步骤2. 5-环丙基-2-硝基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮
将N-环丙基-5-硝基-1H-吡唑-3-甲酰胺(0.780g,3.98mmol)、1,2-二溴乙烷(0.685mL,7.95mmol)和碳酸铯(2.59g,7.95mmol)在DMF(20mL)中的混合物在50℃下加热16h。将混合物用乙酸乙酯(20mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩至接近干燥。将残余物用乙酸乙酯(100mL)稀释,用水(3x25mL)和盐水(25mL)洗涤,并且经无水MgSO4干燥。通过ISCO色谱(80g硅胶,固体负载,20%-90%乙酸乙酯/己烷)分离到呈白色固体的所需产物5-环丙基-2-硝基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮(0.305g,1.373mmol,34.5%产率)。LCMS m/z=223.1(M+H)+。1H NMR(400MHz,DMSO-d6)δ7.42(s,1H),4.57-4.42(m,2H),3.88-3.78(m,2H),2.90-2.75(m,1H),0.87-0.79(m,2H),0.78-0.72(m,2H)。
步骤3. 2-氨基-5-环丙基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮
在室温下向5-环丙基-2-硝基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮(0.275g,1.238mmol)和氯化铵(0.927g,17.33mmol)在MeOH(12mL)和THF(4mL)中的悬浮液中一次性添加锌粉(1.133g,17.33mmol)。将混合物在室温下搅拌45min。将固相通过经硅藻土吸滤而去除。将滤液在真空下浓缩至接近干燥。向残余物中添加水(8mL),并且将混合物用二氯甲烷(4x40mL)萃取。将合并的萃取物经无水MgSO4干燥。在真空下去除溶剂提供呈白色固体的2-氨基-5-环丙基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮(0.213g,1.108mmol,90%产率)。LCMS m/z=193.2(M+H)+。
步骤4. 6-((5-环丙基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺
将6-氯-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(45mg,0.115mmol)、2-氨基-5-环丙基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮(44.2mg,0.230mmol)、三(二亚苄基丙酮)二钯(0)(15.78mg,0.017mmol)、XantPhos(9.97mg,0.017mmol)和碳酸铯(82mg,0.253mmol)在1,4-二噁烷(2.5mL)中的混合物在微波条件下在155℃下加热70min。将混合物用乙酸乙酯(8mL)稀释并且通过硅藻土过滤。将滤液在真空下浓缩。将残余物溶解在DMSO和MeOH(1:3体积比)中并且注射到制备型HPLC中。将正确的级分合并,在真空下浓缩,用饱和NaHCO3溶液碱化至pH 9-10,并且用二氯甲烷(3x30mL)萃取。将合并的萃取物经无水MgSO4干燥并且在真空下浓缩至干,以提供呈白色固体的6-((5-环丙基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-三氘代甲基哒嗪-3-甲酰胺(6.5mg,0.012mmol,10.03%产率)。LCMS m/z=548.3(M+H)+。1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),9.95(s,1H),9.09(s,1H),9.05(d,J=0.6Hz,2H),7.68(dd,J=7.9,1.5Hz,1H),7.55-7.46(m,2H),7.39-7.32(m,1H),6.77(s,1H),4.18(t,J=6.1Hz,2H),3.76-3.71(m,2H),3.69(s,3H),2.78(tt,J=7.2,3.7Hz,1H),0.84-0.77(m,2H),0.73-0.67(m,2H)。
以与实施例1类似的方式制备以下实施例,除了实施例115,其以与实施例14类似的方式制备。
生物测定
使用以下测定来显示本发明的化合物的活性。
在人全血中IFNα诱导的STAT磷酸化
在与化合物一起孵育一小时之久后,将人全血(用EDTA或ACD-A作为抗凝剂抽取)用1000U/mL重组人IFNαA/D(R&D Systems 11200-2)刺激15min。通过添加固定/裂解缓冲液(BD 558049)停止刺激。将细胞用CD3 FITC抗体(BD 555916)染色,洗涤,并且使用Perm III缓冲液(BD 558050)在冰上透化。然后将细胞用Alexa-Fluor 647pSTAT5(pY694)抗体(BD612599)染色30min,然后在FACS Canto II上分析。在对CD3阳性群体门控后,通过中值荧光强度定量pSTAT5表达的量。
在人全血中IFNα诱导的STAT磷酸化的抑制数据
Claims (11)
1.一种具有下式I的化合物
其中
Y是N或CH;
R1是H、CD3或C1-3烷基;
R2是-C(O)R2a;C1-6烷基;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是氢、卤基或C1-4烷基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
或其立体异构体或药学上可接受的盐。
2.根据权利要求1所述的化合物,所述化合物具有式II
其中
Y是N或CH;
R2是-C(O)R2a;C1-6烷基;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是氢、卤基或C1-4烷基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
或其立体异构体或药学上可接受的盐。
3.根据权利要求2所述的化合物,所述化合物具有下式
其中
Y是N或CH;
R2是-C(O)R2a;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、NO2、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是氢、卤基或C1-4烷基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
或其立体异构体或药学上可接受的盐。
4.根据权利要求3所述的化合物,所述化合物具有下式
其中
Y是N或CH;
R2是-C(O)R2a;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、C1-3烷基、OCH3、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是卤基;
R5和R6在每次出现时独立地是氢或C1-4烷基,
或其立体异构体或药学上可接受的盐。
5.根据权利要求4所述的化合物,所述化合物具有下式
其中
Y是N或CH;
R2是-C(O)R2a;被0-1个R2a取代的-(CH2)r-3-14元碳环;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R2a取代;
R2a在每次出现时独立地是氢、OH、卤基、氧代(=O)、CF3、CN、C1-3烷基、OCH3、C1-6卤代烷基、C1-6羟基烷基或C3-6环烷基;
R3是含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-4个R3a取代;
R3a在每次出现时独立地是氢;OH;卤基;氧代(=O);CF3;CN;C1-6烷基;C1-6烷氧基;C1-6卤代烷基;C1-6羟基烷基;C3-6环烷基,每个基团被0-2个R3b取代;CO-N(R5R6);含有1-4个选自N、O和S的杂原子的CO-杂环,每个基团被0-2个R3b取代;或含有1-4个选自N、O和S的杂原子的5-14元单环或二环杂环,每个基团被0-2个R3b取代;
R3b在每次出现时独立地是F、OH或C1-3烷基;
R4是F;
R5和R6在每次出现时独立地是氢或C1-4烷基,
或其立体异构体或药学上可接受的盐。
6.根据权利要求5所述的化合物,所述化合物具有下式
其中
R3是含有1-4个选自N、O和S的杂原子的6元杂环,每个基团被0-4个R3a取代。
7.一种化合物,所述化合物是
4-((3-(5-氰基嘧啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(4-氰基嘧啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丁烷甲酰胺基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(4-甲氧基嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲氧基嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-甲基-6-氧代-1,6-二氢哒嗪-3-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(4-甲基-5-氧代-4,5-二氢吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(1-甲基-6-氧代-1,6-二氢嘧啶-4-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲氧基吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-甲基吡嗪-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(6-(2-羟基丙-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(2-羟基丁-2-基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(1-羟基乙基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1-氟-2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1-羟基环丁基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(1-羟基环丁基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1,3-二氟-2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(1,1,1-三氟-2-羟基丙-2-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(3-羟基四氢呋喃-3-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((5-氟-3-(5-(1-氟-2-羟基丙-2-基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(3-羟基氧杂环丁烷-3-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(3-羟基四氢呋喃-3-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(1-氟-2-羟基丙-2-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
(R)-6-(环丙烷甲酰胺基)-4-((3-(5-(3-氟吡咯烷-1-羰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(吗啉-4-羰基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(甲基氨基甲酰基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(氮杂环丁烷-1-羰基)吡嗪-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(二甲基氨基甲酰基)哒嗪-3-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(6-(二甲基氨基甲酰基)哒嗪-3-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)吡啶-2-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(吡咯烷-1-羰基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(氮杂环丁烷-1-羰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(4-(二甲基氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二乙基氨基甲酰基)嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(环丙基(甲基)氨基甲酰基)
嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(二甲基氨基甲酰基)嘧啶-2-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((3-(5-(乙基(甲基)氨基甲酰基)嘧啶-2-基)-5-氟-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(四氢呋喃-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(N-甲基乙酰胺基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-吗啉代吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(4-甲基哌嗪-1-基)吡嗪-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(4-乙酰基哌嗪-1-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-(1H-1,2,4-三唑-1-基)吡嗪-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)烟酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1,5-二甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-5-(三氟甲基)-1H-吡唑-3-基)氨基)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-吡唑-3-基)氨基)烟酰胺,
6-((5-氯-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1-乙基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1-环丙基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((1-环丙基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-(吡啶-2-基氨基)烟酰胺,
6-((5-氰基吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基吡嗪-2-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((6-甲氧基哒嗪-3-基)氨基)-N-(甲基-d3)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)烟酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)烟酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-6-氧代-1,6-二氢嘧啶-4-基)氨基)烟酰胺,
6-((1-环丙基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)烟酰胺,
6-((5-氰基-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((5-(2-羟基丙-2-基)-1-甲基-1H-吡唑-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((5-(二甲基氨基甲酰基)-1-甲基-1H-吡唑-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((2-乙基-2H-1,2,3-三唑-4-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((2-乙基-2H-1,2,3-三唑-4-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((1-乙基-1H-1,2,3-三唑-4-基)氨基)-4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-((1-乙基-1H-1,2,3-三唑-4-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((2-甲基-2H-1,2,3-三唑-4-基)氨基)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-1,2,3-三唑-4-基)氨基)哒嗪-3-甲酰胺
6-((1-乙基-1H-1,2,3-三唑-4-基)氨基)-4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((1-甲基-1H-1,2,3-三唑-4-基)氨基)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((6-甲基哒嗪-3-基)氨基)哒嗪-3-甲酰胺,
6-((6-氰基哒嗪-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((6-甲氧基哒嗪-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((6-甲氧基哒嗪-3-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)哒嗪-3-甲酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((6-(三氟甲基)哒嗪-3-基)氨基)哒嗪-3-甲酰胺,
6-((6-环丙基哒嗪-3-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(噌啉-3-基氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)吡嗪-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((4-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((5-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((5-氟-2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-6-((4-(2-羟基丙-2-基)吡啶-2-基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((1-甲基-6-氧代-1,6-二氢嘧啶-4-基)氨基)哒嗪-3-甲酰胺,
4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺,
4-((2-甲氧基-3-(嘧啶-2-基)苯基)氨基)-N-(甲基-d3)-6-((5-甲基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)哒嗪-3-甲酰胺,
6-((5-环丙基-4-氧代-4,5,6,7-四氢吡唑并[1,5-a]吡嗪-2-基)氨基)-4-((3-(5-氟嘧啶-2-基)-2-甲氧基苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(甲基磺酰基)吡啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(甲基磺酰基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(2-氧代吡咯烷-1-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(2-氧代噁唑烷-3-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(3-氰基-5-氟吡啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)哒嗪-3-甲酰胺,
4-((3-(3-氰基-5-氟吡啶-2-基)-2-甲氧基苯基)氨基)-6-(环丙烷甲酰胺基)-N-(甲基-d3)烟酰胺,
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(3-甲基-2-氧代咪唑烷-1-基)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺,或
6-(环丙烷甲酰胺基)-4-((2-甲氧基-3-(5-(3-氧代吗啉代)嘧啶-2-基)苯基)氨基)-N-(甲基-d3)哒嗪-3-甲酰胺。
8.一种药物组合物,所述药物组合物包含一种或多种根据权利要求1所述的化合物以及药学上可接受的载体或稀释剂。
9.一种药物组合物,所述药物组合物包含一种或多种根据权利要求7所述的化合物以及药学上可接受的载体或稀释剂。
10.一种治疗疾病的方法,所述方法包括向需要这种治疗的患者施用治疗有效量的根据权利要求1所述的化合物,其中所述疾病是炎性或自身免疫性疾病。
11.根据权利要求10所述的方法,其中所述炎性或自身免疫性疾病是多发性硬化、类风湿性关节炎、炎性肠病、系统性红斑狼疮、银屑病、银屑病关节炎、克罗恩病、舍格伦综合征或硬皮病。
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