HK40010367B - Bicyclic bromodomain inhibitors - Google Patents

Bicyclic bromodomain inhibitors Download PDF

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HK40010367B
HK40010367B HK42019000070.3A HK42019000070A HK40010367B HK 40010367 B HK40010367 B HK 40010367B HK 42019000070 A HK42019000070 A HK 42019000070A HK 40010367 B HK40010367 B HK 40010367B
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dimethylisoxazol
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benzyl
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HK40010367A (en
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John Frederick QUINN
Ruifang WANG
May Xiaowu Jiang
Gregory Scott MARTIN
Gregory Steven WAGNER
Peter Ronald Young
Bryan Cordell DUFFY
Shuang Liu
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恒翼生物医药(上海)股份有限公司
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双环溴结构域抑制剂Bicyclic bromodomain inhibitors

本申请为2014年6月20日提交的申请号为PCT/US2014/043423、发明名称为“新双环溴结构域抑制剂”的国际申请的分案申请,该国际申请于2015年12月18日进入中国国家阶段,申请号为201480034817.9。This application is a divisional application of the international application with application number PCT/US2014/043423 filed on June 20, 2014, and invention name “Novel Bicyclic Bromodomain Inhibitors”, which entered the Chinese national phase on December 18, 2015, with application number 201480034817.9.

本申请要求于2013年6月21日提交的美国临时专利申请号61/837,841的优先权,其据此通过引用整体并入。This application claims priority to U.S. Provisional Patent Application No. 61/837,841, filed June 21, 2013, which is hereby incorporated by reference in its entirety.

技术领域Technical Field

本发明提供新化合物、含有此类化合物的药物组合物、以及它们在预防和治疗与溴结构域和额外末端结构域(BET)蛋白相关的疾病和病状中的用途。The present invention provides novel compounds, pharmaceutical compositions containing such compounds, and their use in preventing and treating diseases and conditions associated with bromodomain and extra-terminal domain (BET) proteins.

背景技术Background Art

组蛋白的翻译后修饰(PTM)参与真核细胞中基因表达和染色质组织化的调控。特异性赖氨酸残基处的组蛋白乙酰化是通过组蛋白乙酰化酶(HAT)和去乙酰化酶(HDAC)调控的PTM。Peserico,A.和C.Simone,“Physical and functional HAT/HDAC interplayregulates protein acetylation balance,”J Biomed Biotechnol,2011:371832(2011)。HDAC和HAT的小分子抑制剂正作为癌症疗法在研究中。Hoshino,I.和H.Matsubara,“Recentadvances in histone deacetylase targeted cancer therapy”Surg Today 40(9):809-15(2010);Vernarecci,S.,F.Tosi和P.Filetici,“Tuning acetylated chromatin withHAT inhibitors:a novel tool for therapy”Epigenetics 5(2):105-11(2010);Bandyopadhyay,K.等人,“Spermidinyl-CoA-based HAT inhibitors block DNA repairand provide cancer-specific chemo-and radiosensitization,”Cell Cycle8(17):2779-88(2009);Arif,M.等人,“Protein lysine acetylation in cellular functionand its role in cancer manifestation,”Biochim Biophys Acta 1799(10-12):702-16(2010)。组蛋白乙酰化通过募集经由溴结构域直接结合乙酰化赖氨酸的蛋白质复合物来控制基因表达。Sanchez,R.和M.M.Zhou,“The role of human bromodomains in chromatinbiology and gene transcription,”Curr Opin Drug Discov Devel 12(5):659-65(2009)。一个这种家族(溴结构域和额外末端结构域(BET)蛋白)包括Brd2、Brd3、Brd4和BrdT,其各自含有可独立地结合乙酰化赖氨酸的两个串联溴结构域,如在Wu,S.Y.和C.M.Chiang,“The double bromodomain-containing chromatin adaptor Brd4andtranscriptional regulation,”J Biol Chem 282(18):13141-5(2007)中所综述。Post-translational modifications (PTMs) of histones are involved in the regulation of gene expression and chromatin organization in eukaryotic cells. Histone acetylation at specific lysine residues is a PTM regulated by histone acetylases (HATs) and deacetylases (HDACs). Peserico, A. and C. Simone, “Physical and functional HAT/HDAC interplay regulates protein acetylation balance,” J Biomed Biotechnol, 2011: 371-832 (2011). Small molecule inhibitors of HDACs and HATs are being investigated as cancer therapies. Hoshino, I. and H. Matsubara, “Recent advances in histone deacetylase targeted cancer therapy” Surg Today 40(9):809-15(2010); Vernarecci, S., F. Tosi and P. Filetici, “Tuning acetylated chromatin with HAT inhibitors: a novel tool for therapy” Epigenetics 5(2):105-11(2010); Bandyopadhyay, K. et al., "Spermidinyl-CoA-based HAT inhibitors block DNA repair and provide cancer-specific chemo-and radiosensitization," Cell Cycle8(17):2779-88(2009); Arif, M. et al., "Protein lysine acetylation in cellular function and its role in cancer manifestation,” Biochim Biophys Acta 1799(10-12):702-16(2010). Histone acetylation controls gene expression by recruiting protein complexes that directly bind acetylated lysine via bromodomains. Sanchez, R. and M.M. Zhou, “The role of human bromodomains in chromatin biology and gene transcription,” Curr Opin Drug Discov Devel 12(5):659-65(2009). One such family (bromodomain and extra-terminal domain (BET) proteins) includes Brd2, Brd3, Brd4, and BrdT, each of which contains two tandem bromodomains that can independently bind acetylated lysine, as reviewed in Wu, S.Y. and C.M. Chiang, “The double bromodomain-containing chromatin adaptor Brd4 and transcriptional regulation,” J Biol Chem 282(18):13141-5(2007).

通过溴结构域抑制干扰BET蛋白质相互作用导致转录程序的调节,转录程序通常与以细胞周期控制、炎症性细胞因子表达、病毒转录、造血分化、胰岛素转录和脂肪生成的调节异常为特征的疾病相关。Belkina,A.C.和G.V.Denis,“BET domain co-regulators inobesity,inflammation and cancer,”Nat Rev Cancer 12(7):465-77(2012)。BET抑制剂被认为可用于治疗与全身性或组织炎症、对感染或缺氧的炎症反应、细胞活化和增殖、脂质代谢、纤维化相关的疾病或病状以及预防和治疗病毒感染。Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”Nat Rev Cancer12(7):465-77(2012);Prinjha,R.K.,J.Witherington和K.Lee,“Place your BETs:thetherapeutic potential of bromodomains,”Trends Pharmacol Sci 33(3):146-53(2012)。Interference with BET protein interactions through bromodomain inhibition results in the regulation of transcriptional programs that are often associated with diseases characterized by dysregulation of cell cycle control, inflammatory cytokine expression, viral transcription, hematopoietic differentiation, insulin transcription, and adipogenesis. Belkina, A.C. and G.V. Denis, “BET domain co-regulators inobesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012). BET inhibitors are believed to be useful in treating diseases or conditions associated with systemic or tissue inflammation, inflammatory responses to infection or hypoxia, cell activation and proliferation, lipid metabolism, fibrosis, and in preventing and treating viral infections. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Prinjha, R.K., J. Witherington, and K. Lee, “Place your BETs: thetherapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53(2012).

自身免疫性疾病(其通常是慢性和衰弱性的)是失调的免疫应答的结果,其导致身体攻击其自身细胞、组织和器官。包括IL-1β、TNF-α、IL-6、MCP-1和IL-17的促炎性细胞因子在自身免疫性疾病中过表达。IL-17表达限定被称为Th17细胞的T细胞亚群,Th17细胞部分地由IL-6分化并且驱动自身免疫性疾病的许多致病性后果。因此,IL-6/Th17轴代表自身免疫性疾病疗法的重要潜在成药靶标。Kimura,A.和T.Kishimoto,“IL-6:regulator ofTreg/Th17 balance,”Eur J Immunol 40(7):1830-5(2010)。BET抑制剂预期具有抗炎和免疫调节特性。Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”Nat Rev Cancer 12(7):465-77(2012);Prinjha,R.K.,J.Witherington和K.Lee,“Place your BETs:the therapeutic potential ofbromodomains,”Trends Pharmacol Sci 33(3):146-53(2012)。BET抑制剂已经显示出具有广谱体外抗炎作用,包括减少活化的免疫细胞中促炎性细胞因子如IL-1β、MCP-1、TNF-α和IL-6的表达的能力。Mirguet,O.,等人,“From ApoA1upregulation to BET familybromodomain inhibition:discovery of I-BET151,”Bioorg Med Chem Lett 22(8):2963-7(2012);Nicodeme,E.,等人,“Suppression of inflammation by a synthetichistone mimic,”Nature 468(7327):1119-23(2010);Seal,J.,等人,“Identification ofa novel series of BET family bromodomain inhibitors:binding mode and profileof I-BET151(GSK1210151A),”Bioorg Med Chem Lett 22(8):2968-72(2012)。这些抗炎作用的机制可能涉及NF-κB调控的促炎性细胞因子的Brd4共活化的BET抑制剂破坏和/或BET蛋白从细胞因子启动子包括IL-6的位移。Nicodeme,E.,等人,“Suppression ofinflammation by a synthetic histone mimic,”Nature 468(7327):1119-23(2010);Zhang,G.,等人,“Down-regulation of NF-kappaB Transcriptional Activity inHIVassociated Kidney Disease by BRD4 Inhibition,”J Biol Chem,287(34):8840-51(2012);Zhou,M.,等人,“Bromodomain protein Brd4 regulates humanimmunodeficiency virus transcription through phosphorylation of CDK9atthreonine 29,”J Virol 83(2):1036-44(2009)。此外,因为Brd4参与T细胞谱系分化,所以BET抑制剂可以适用于以T细胞分化的特定程序为特征的炎症性病症。Zhang,W.S.,等人,“Bromodomain-Containing-Protein 4(BRD4)Regulates RNA Polymerase II Serine 2Phosphorylation in Human CD4+T Cells,”J Biol Chem(2012)。Autoimmune diseases (which are often chronic and debilitating) are the result of a dysregulated immune response that causes the body to attack its own cells, tissues, and organs. Proinflammatory cytokines including IL-1β, TNF-α, IL-6, MCP-1, and IL-17 are overexpressed in autoimmune diseases. IL-17 expression defines a subset of T cells known as Th17 cells, which are differentiated in part by IL-6 and drive many of the pathogenic consequences of autoimmune diseases. Therefore, the IL-6/Th17 axis represents an important potential druggable target for the treatment of autoimmune diseases. Kimura, A. and T. Kishimoto, "IL-6: regulator of Treg/Th17 balance," Eur J Immunol 40(7):1830-5(2010). BET inhibitors are expected to have anti-inflammatory and immunomodulatory properties. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Prinjha, R.K., J. Witherington and K. Lee, “Place your BETs: the therapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012). BET inhibitors have been shown to have broad-spectrum anti-inflammatory effects in vitro, including the ability to reduce the expression of proinflammatory cytokines such as IL-1β, MCP-1, TNF-α, and IL-6 in activated immune cells. Mirguet, O., et al., “From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Nicodeme, E., et al., “Suppression of inflammation by a synthetic histone mimic,” Nature 468(7327):1119-23 (2010); Seal, J., et al., “Identification of a novel series of BET family bromodomain inhibitors: binding mode and profileof I-BET151 (GSK1210151A),” Bioorg Med Chem Lett 22(8):2968-72 (2012). The mechanism of these anti-inflammatory effects may involve BET inhibitors disrupting Brd4 coactivation of NF-κB-regulated proinflammatory cytokines and/or displacement of BET proteins from cytokine promoters, including IL-6. Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic," Nature 468(7327): 1119-23 (2010); Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition," J Biol Chem, 287(34): 8840-51 (2012); Zhou, M., et al., "Bromodomain protein Brd4 regulates human immunodeficiency virus transcription through phosphorylation of CDK9atthreonine 29," J Virol 83(2): 1036-44 (2009). In addition, because Brd4 is involved in T cell lineage differentiation, BET inhibitors may be applicable to inflammatory disorders characterized by specific programs of T cell differentiation. Zhang, W.S., et al., "Bromodomain-Containing-Protein 4(BRD4)Regulates RNA Polymerase II Serine 2Phosphorylation in Human CD4+T Cells," J Biol Chem (2012).

BET抑制的抗炎和免疫调节作用也已在体内证实。BET抑制剂预防小鼠中内毒素或细菌性败血症诱导的死亡和盲肠结扎穿孔诱导的死亡,从而表明BET抑制剂在败血症和急性炎症性病症中的效用。Nicodeme,E.,等人,“Suppression of inflammation by asynthetic histone mimic,”Nature 468(7327):1119-23(2010)。BET抑制剂已被证明部分地通过抑制Brd4与NF-κB的相互作用来改善HIV-1转基因小鼠(HIV相关肾病的动物模型)中的炎症和肾损伤。Zhang,G.,等人,“Down-regulation of NF-kappaB TranscriptionalActivity in HIVassociated Kidney Disease by BRD4Inhibition,”J Biol Chem,287(34):8840-51(2012)。BET抑制在自身免疫性疾病中的效用在多发性硬化症的小鼠模型中证明,其中BET抑制导致部分地通过抑制IL-6和IL-17来消除疾病的临床病征。R.Jahagirdar,S.M.等人,“An Orally Bioavailable Small Molecule RVX-297Significantly Decreases Disease in a Mouse Model of Multiple Sclerosis,”WorldCongress of Inflammation,Paris,France(2011)。这些结果在类似的小鼠模型中得到支持,其中显示用BET抑制剂治疗抑制T细胞体外分化成促自身免疫性Th1和Th17亚群,并且还消除由促炎性Th1细胞诱导的疾病。Bandukwala,H.S.,等人,“Selective inhibition ofCD4+T-cell cytokine production and autoimmunity by BET protein and c-Mycinhibitors,”Proc Natl Acad Sci USA,109(36):14532-7(2012)。The anti-inflammatory and immunomodulatory effects of BET inhibition have also been demonstrated in vivo. BET inhibitors prevented endotoxin- or bacterial sepsis-induced death and cecal ligation and puncture-induced death in mice, demonstrating the utility of BET inhibitors in sepsis and acute inflammatory conditions. Nicodeme, E., et al., “Suppression of inflammation by asynthetic histone mimic,” Nature 468(7327):1119-23 (2010). BET inhibitors have been shown to improve inflammation and renal damage in HIV-1 transgenic mice (an animal model of HIV-associated nephropathy) in part by inhibiting the interaction of Brd4 with NF-κB. Zhang, G., et al., “Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition,” J Biol Chem, 287(34):8840-51 (2012). The utility of BET inhibition in autoimmune diseases was demonstrated in a mouse model of multiple sclerosis, where BET inhibition resulted in abolition of clinical signs of disease, in part by inhibition of IL-6 and IL-17. R. Jahagirdar, S. M. et al., “An Orally Bioavailable Small Molecule RVX-297 Significantly Decreases Disease in a Mouse Model of Multiple Sclerosis,” World Congress of Inflammation, Paris, France (2011). These results were supported in a similar mouse model, where treatment with a BET inhibitor was shown to inhibit T cell differentiation into pro-autoimmune Th1 and Th17 subsets in vitro and also abrogate disease induced by pro-inflammatory Th1 cells. Bandukwala, H. S., et al., “Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Mycinhibitors,” Proc Natl Acad Sci USA, 109(36):14532-7 (2012).

BET抑制剂可用于治疗多种慢性自身免疫性炎症性病状。因此,本发明的一方面提供用于通过施用本发明的一种或多种化合物或包含一种或多种那些化合物的药物组合物来治疗自身免疫性和/或炎症性疾病的化合物、组合物和方法。可使用本发明的化合物和方法治疗的自身免疫性和炎症性疾病、病症和综合征包括但不限于,盆腔炎症性疾病、尿道炎、皮肤晒伤、窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎(Zhang,G.,等人,“Down-regulationof NF-kappaB Transcriptional Activity in HIVassociated Kidney Disease by BRD4Inhibition,”J Biol Chem,287(34):8840-51(2012))、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮炎、龈炎、阑尾炎、胰腺炎、胆囊炎、无丙种球蛋白血症、银屑病、过敏症、克罗恩氏病、肠易激综合症、溃疡性结肠炎(Prinjha,R.K.,J.Witherington和K.Lee,“Place your BETs:thetherapeutic potential of bromodomains,”Trends Pharmacol Sci 33(3):146-53(2012))、斯耶格伦氏病、组织移植物排斥、移植器官的超急性排斥、哮喘、过敏性鼻炎、慢性阻塞性肺病(COPD)、自身免疫性多腺体疾病(也称为自身免疫性多腺体综合征)、自身免疫性脱发、恶性贫血、肾小球性肾炎、皮肤肌炎、多发性硬化症(Bandukwala,H.S.,等人,“Selective inhibition of CD4+T-cell cytokine production and autoimmunity byBET protein and c-Myc inhibitors,”Proc Natl Acad Sci USA,109(36):14532-7(2012))、硬皮病、血管炎、自身免疫性溶血性和血小板减少状态、古德帕斯丘综合征、动脉粥样硬化、阿狄森氏病、帕金森氏病、阿尔茨海默氏病、I型糖尿病(Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”NatRev Cancer12(7):465-77(2012))、败血病休克(Zhang,G.,等人,“Down-regulation ofNF-kappaB Transcriptional Activity in HIVassociated Kidney Disease byBRD4Inhibition,”J Biol Chem,287(34):8840-51(2012))、全身性红斑狼疮(SLE)(Prinjha,R.K.,J.Witherington和K.Lee,“Place your BETs:the therapeuticpotential of bromodomains,”Trends Pharmacol Sci 33(3):146-53(2012))、类风湿性关节炎(Denis,G.V.,“Bromodomain coactivators in cancer,obesity,type 2diabetes,and inflammation,”Discov Med 10(55):489-99(2010))、银屑病性关节炎、幼年型关节炎、骨关节炎、慢性特发性血小板减少性紫癜、瓦尔登斯特伦巨球蛋白血症、重症肌无力、桥本氏甲状腺炎、特应性皮炎、退行性关节病、白癜风、自身免疫性垂体功能减退症、格林-巴利综合征、白塞氏病、葡萄膜炎、干眼疾病、硬皮病、蕈样真菌病以及格雷夫斯氏病。BET inhibitors can be used to treat a variety of chronic autoimmune inflammatory conditions. Accordingly, one aspect of the invention provides compounds, compositions and methods for treating autoimmune and/or inflammatory diseases by administering one or more compounds of the invention or pharmaceutical compositions comprising one or more of those compounds. Autoimmune and inflammatory diseases, conditions and syndromes that can be treated using the compounds and methods of the present invention include, but are not limited to, pelvic inflammatory disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis (Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIV associated Kidney Disease by BRD4 Inhibition," J Biol Chem, 287(34):8840-51 (2012)), osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis (Prinjha, R.K., J. Witherington and K. Lee, "Place your BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci 33(3):146-53 (2012)), Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis (Bandukwala, H.S., et al., "Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors," Proc Natl Acad Sci USA, 109(36):14532-7(2012)), scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, type I diabetes (Belkina, A.C. and G.V. Denis, "BET domain co-regulators in obesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77(2012)), septic shock (Zhang, G., et al., "Down-regulation of NF-kappaB Transcriptional Activity in HIV-associated Kidney Disease by BRD4 Inhibition," J Biol Chem, 287(34):8840-51(2012)), systemic lupus erythematosus (SLE) (Prinjha, R.K., J. Witherington and K. Lee, "Place your BETs: the therapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53(2012)), rheumatoid arthritis (Denis, G.V., “Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99(2010)), psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom’s macroglobulinemia, myasthenia gravis, Hashimoto’s thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet’s disease, uveitis, dry eye disease, scleroderma, mycosis fungoides, and Graves’ disease.

BET抑制剂可用于治疗各种各样的急性炎症性病状,因此,本发明的一方面提供用于治疗炎症性病状的化合物、组合物和方法,包括但不限于、急性痛风、巨细胞动脉炎、肾炎(包括狼疮性肾炎)、具有器官损害的血管炎(诸如肾小球性肾炎)、血管炎(包括巨细胞动脉炎)、韦格纳肉芽肿病、结节性多动脉炎、白塞氏病、川崎病以及高安氏动脉炎。BET inhibitors are useful in treating a wide variety of acute inflammatory conditions, and thus, one aspect of the invention provides compounds, compositions, and methods for treating inflammatory conditions, including, but not limited to, acute gout, giant cell arteritis, nephritis (including lupus nephritis), vasculitis with organ damage (such as glomerulonephritis), vasculitis (including giant cell arteritis), Wegener's granulomatosis, polyarteritis nodosa, Behcet's disease, Kawasaki disease, and Takayasu's arteritis.

BET抑制剂可用于预防和治疗涉及对细菌、病毒、真菌、寄生虫以及其毒素的炎症反应的疾病或病状,诸如但不限于败血症、败血症综合征、败血病休克(Nicodeme,E.,等人,“Suppression of inflammation by a synthetic histone mimic,”Nature 468(7327):1119-23(2010))、全身炎症反应综合征(SIRS)、多器官功能障碍综合征、中毒性休克综合征、急性肺损伤、成人呼吸窘迫综合征(ARDS)、急性肾衰竭、暴发性肝炎、烧伤、术后综合征、结节病、赫氏反应、脑炎、脊髓炎、脑膜炎、疟疾以及与病毒感染如流感、带状疱疹、单纯性疱疹和冠状病毒相关的SIRS。Belkina,A.C.和G.V.Denis,“BET domain co-regulators inobesity,inflammation and cancer,”Nat Rev Cancer 12(7):465-77(2012)。因此,本发明的一方面提供用于治疗对本文所述的细菌、病毒、真菌、寄生虫以及其毒素的炎症反应的疾病或病状的这些炎症性响应的化合物、组合物和方法。BET inhibitors can be used to prevent and treat diseases or conditions involving inflammatory responses to bacteria, viruses, fungi, parasites and their toxins, such as, but not limited to, sepsis, septic syndrome, septic shock (Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic," Nature 468(7327): 1119-23 (2010)), systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, toxic shock syndrome, acute lung injury, adult respiratory distress syndrome (ARDS), acute renal failure, fulminant hepatitis, burns, postoperative syndrome, sarcoidosis, Herxheimer's reaction, encephalitis, myelitis, meningitis, malaria, and SIRS associated with viral infections such as influenza, herpes zoster, herpes simplex, and coronaviruses. Belkina, A.C. and G.V. Denis, "BET domain co-regulators inobesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77 (2012). Thus, one aspect of the present invention provides compounds, compositions and methods for treating diseases or conditions that are inflammatory responses to bacteria, viruses, fungi, parasites and their toxins as described herein.

癌症是由失调的细胞增殖引起的一组疾病。治疗方法目标在于通过抑制细胞复制或通过诱导癌细胞分化或死亡来减少癌细胞的数目,但仍然存在对更有效的治疗剂的显著未满足的医学需要。癌细胞积聚改变细胞生长和代谢的遗传和表观遗传变化,从而促进细胞增殖并且增加对程序性细胞死亡或细胞凋亡的抗性。这些变化中的一些包括肿瘤抑制基因的灭活、致癌基因的活化以及染色质结构的调控的修饰,包括组蛋白PTM的调节异常。Watson,J.D.,“Curing‘incurable’cancer,”Cancer Discov1(6):477-80(2011);Morin,R.D.,等人,“Frequent mutation of histone-modifying genes in non-Hodgkinlymphoma”Nature 476(7360):298-303(2011)。Cancer is a group of diseases caused by dysregulated cell proliferation. Treatment methods aim to reduce the number of cancer cells by inhibiting cell replication or by inducing cancer cell differentiation or death, but there is still a significant unmet medical need for more effective therapeutic agents. Cancer cells accumulate genetic and epigenetic changes that alter cell growth and metabolism, thereby promoting cell proliferation and increasing resistance to programmed cell death or apoptosis. Some of these changes include inactivation of tumor suppressor genes, activation of oncogenes, and modifications of chromatin structure regulation, including dysregulation of histone PTMs. Watson, J.D., "Curing 'incurable' cancer," Cancer Discov1(6):477-80(2011); Morin, R.D., et al., "Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma" Nature 476(7360):298-303(2011).

本发明的一方面提供一种用于治疗人癌症的化合物、组合物和方法,癌症包括但不限于,由BET蛋白的异常易位或过表达造成的癌症(例如,NUT中线癌(NMC)(French,C.A.,“NUT midline carcinoma,”Cancer Genet Cytogenet 203(1):16-20(2010)和B细胞淋巴瘤(Greenwald,R.J.,等人,“E mu-BRD2 transgenic mice develop B-cell lymphoma andleukemia,”Blood 103(4):1475-84(2004))。NMC肿瘤细胞生长由Brd4或Brd3基因至nutlin1基因的易位驱动。Filippakopoulos,P.,等人,“Selective inhibition of BETbromodomains,”Nature 468(7327):1067-73(2010)。BET抑制已证明在NMC(一种罕见但致死形式的癌症)的小鼠异种移植物模型中的有效抗肿瘤活性。本公开也提供用于治疗人癌症的方法,所述癌症包括但不限于,依赖癌蛋白的myc家族的成员(包括c-myc、MYCN和L-myc)的癌症。Vita,M.和M.Henriksson,“The Myc oncoprotein as a therapeutic targetfor human cancer,”Semin Cancer Biol 16(4):318-30(2006)。这些癌症包括伯基特氏淋巴瘤、急性骨髓性白血病、多发性骨髓瘤和侵袭性人成神经管细胞瘤。Vita,M.和M.Henriksson,“The Myc oncoprotein as a therapeutic target for human cancer,”Semin Cancer Biol 16(4):318-30(2006)。其中c-myc过度表达的癌症可能对BET蛋白抑制特别敏感;已经证明用BET抑制剂治疗具有c-myc活化的肿瘤通过c-myc转录的失活导致肿瘤消退。Dawson,M.A.,等人,Inhibition of BET recruitment to chromatin as aneffective treatment for MLL-fusion leukaemia.Nature,2011.478(7370):第529-33页;Delmore,J.E.,等人,“BET bromodomain inhibition as a therapeutic strategy totarget c-Myc,”Cell 146(6):904-17(2010);Mertz,J.A.,等人,“Targeting MYCdependence in cancer by inhibiting BET bromodomains,”Proc Natl Acad Sci USA108(40):16669-74(2011);Ott,C.J.,等人,“BET bromodomain inhibition targets bothc-Myc and IL7R in high risk acute lymphoblastic leukemia,”Blood 120(14):2843-52(2012);Zuber,J.,等人,“RNAi screen identifies Brd4 as a therapeutic targetin acute myeloid leukaemia,”Nature 478(7370):524-8(2011)。One aspect of the present invention provides compounds, compositions and methods for treating human cancers, including but not limited to cancers caused by aberrant translocation or overexpression of BET proteins (e.g., NUT midline carcinoma (NMC) (French, C.A., "NUT midline carcinoma," Cancer Genet Cytogenet 203(1):16-20 (2010) and B cell lymphoma (Greenwald, R.J., et al., "E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia," Blood 103(4):1475-84 (2004)). NMC tumor cell growth is driven by translocation of the Brd4 or Brd3 gene to the nutlin1 gene. Filippakopoulos, P., et al., "Selective inhibition of BET bromodomains," Nature 468(7327):1067-73(2010). BET inhibition has demonstrated potent antitumor activity in a mouse xenograft model of NMC, a rare but lethal form of cancer. The present disclosure also provides methods for treating human cancers, including, but not limited to, cancers that depend on members of the myc family of oncoproteins, including c-myc, MYCN, and L-myc. Vita, M. and M. Henriksson, “The Myc oncoprotein as a therapeutic target for human cancer,” Semin Cancer Biol 16(4):318-30(2006). These cancers include Burkitt's lymphoma, acute myeloid leukemia, multiple myeloma, and aggressive human medulloblastoma. Vita, M. and M. Henriksson, “The Myc oncoprotein as a therapeutic target for human cancer,” Semin Cancer Biol 16(4):318-30(2006). Cancers in which c-myc is overexpressed may be particularly sensitive to BET protein inhibition; treatment of tumors with c-myc activation with BET inhibitors has been shown to result in tumor regression through inactivation of c-myc transcription. Dawson, M.A., et al., Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature, 2011. 478(7370): p. 529-33; Delmore, J.E., et al., “BET bromodomain inhibition as a therapeutic strategy to target c-Myc,” Cell 146(6):904-17(2010); Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA108(40):16669-74(2011); Ott, C.J., et al., “BET bromodomain inhibition targets both c-Myc and IL7R in high risk acute lymphoblastic leukemia,” Blood 120(14):2843-52(2012); Zuber, J., et al., “RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia,” Nature 478(7370):524-8(2011).

本发明的实施方案包括用于治疗以下人癌症的方法:依赖于BET蛋白和pTEFb(Cdk9/CyclinT)来调控致癌基因的癌症(Wang,S.和P.M.Fischer,“Cyclin-dependentkinase9:a key transcriptional regulator and potential drug target inoncology,virology and cardiology,”Trends Pharmacol Sci 29(6):302-13(2008))以及可通过经由抑制Bcl2、细胞周期蛋白依赖性激酶6(CDK6)(Dawson,M.A.,等人,“Inhibition of BET recruitment to chromatin as an effective treatment forMLL-fusion leukaemia,”Nature 478(7370):529-33(2011))、或人端粒酶逆转录酶(hTERT)诱导细胞凋亡或衰老来治疗的癌症。Delmore,J.E.,等人,“BET bromodomaininhibition as a therapeutic strategy to target c-Myc,”Cell 146(6):904-17(2010);Ruden,M.和N.Puri,“Novel anticancer therapeutics targeting telomerase,”Cancer Treat Rev(2012)。Embodiments of the present invention include methods for treating human cancers that rely on BET proteins and pTEFb (Cdk9/CyclinT) for regulation of oncogenes (Wang, S. and P.M. Fischer, "Cyclin-dependent kinase9: a key transcriptional regulator and potential drug target inoncology, virology and cardiology," Trends Pharmacol Sci 29(6):302-13 (2008)) and cancers that can be treated by inducing apoptosis or senescence through inhibition of Bcl2, cyclin-dependent kinase 6 (CDK6) (Dawson, M.A., et al., "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia," Nature 478(7370):529-33 (2011)), or human telomerase reverse transcriptase (hTERT). Delmore, J.E., et al., "BET bromodomaininhibition as a therapeutic strategy to target c-Myc," Cell 146(6):904-17 (2010); Ruden, M. and N. Puri, "Novel anticancer therapeutics targeting telomerase," Cancer Treat Rev (2012).

BET抑制剂可用于治疗癌症,所述癌症包括但不限于,肾上腺癌、腺泡细胞癌、听神经瘤、肢端雀斑样痣黑色素瘤、肢端汗腺瘤、急性嗜酸性粒细胞白血病、急性红白血病、急性成淋巴细胞性白血病、急性成巨核细胞性白血病、急性单核细胞性白血病、急性骨髓性白血病(Dawson,M.A.,等人,“Inhibition of BET recruitment to chromatin as aneffective treatment for MLL-fusion leukaemia,”Nature 478(7370):529-33(2011);Mertz,J.A.,等人,“Targeting MYC dependence in cancer by inhibiting BETbromodomains,”Proc Natl Acad Sci USA 108(40):16669-74(2011);Zuber,J.,等人,“RNAi screen identifies Brd4 as a therapeutic target in acute myeloidleukaemia,”Nature 478(7370):524-8(2011))、腺癌、腺样囊性癌、腺瘤、牙源性腺瘤样肿瘤、腺鳞癌、脂肪组织肿瘤、肾上腺皮质癌、成人T细胞白血病/淋巴瘤、侵袭性NK细胞白血病、AIDS相关淋巴瘤、腺泡状横纹肌肉瘤、腺泡状软组织肉瘤、成釉细胞纤维瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、血管免疫母细胞性T细胞淋巴瘤、血管肌脂瘤、血管肉瘤、星形细胞瘤、非典型畸胎样横纹肌样肿瘤、B细胞急性成淋巴细胞性白血病(Ott,C.J.,等人,“BET bromodomain inhibition targets both c-Myc and IL7R in highrisk acutelymphoblastic leukemia,”Blood 120(14):2843-52(2012))、B细胞慢性淋巴细胞性白血病、B-细胞幼淋巴细胞白血病、B细胞淋巴瘤(Greenwald,R.J.,等人,“E mu-BRD2transgenic mice develop B-cell lymphoma and leukemia,”.Blood 103(4):1475-84(2004))、基底细胞癌、胆道癌、膀胱癌、胚细胞瘤、骨癌、布伦纳瘤、棕色瘤、伯基特氏淋巴瘤(Mertz,J.A.,等人,“Targeting MYC dependence in cancer by inhibiting BETbromodomains,”Proc Natl Acad Sci USA 108(40):16669-74(2011))、乳腺癌、脑癌、癌、原位癌、癌肉瘤、软骨肿瘤、牙骨质瘤、髓样肉瘤、软骨瘤、脊索瘤、绒毛膜癌、脉络丛乳头状瘤、肾透明细胞肉瘤、颅咽管瘤、皮肤T细胞淋巴瘤、宫颈癌、结肠直肠癌、德戈斯病、促结缔组织增生性小圆细胞肿瘤、弥漫性大B细胞淋巴瘤、胚胎发育不良性神经上皮肿瘤、无性细胞瘤、胚胎性癌、内分泌腺肿瘤、内胚窦瘤、肠病相关性T细胞淋巴瘤、食道癌、寄生胎、纤维瘤、纤维肉瘤、滤泡性淋巴瘤、滤泡性甲状腺癌、神经节细胞瘤、胃肠癌、生殖细胞瘤、妊娠性绒癌、巨细胞成纤维细胞瘤、骨巨细胞瘤、胶质肿瘤、多形性成胶质细胞瘤、神经胶质瘤、脑胶质瘤、胰高血糖素瘤、性腺胚细胞瘤、颗粒细胞瘤、两性母细胞瘤、胆囊癌、胃癌、毛细胞白血病、成血管细胞瘤、头颈癌、血管外皮细胞瘤、血液恶性肿瘤、肝母细胞瘤、肝脾T细胞淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、浸润性小叶癌、肠癌、肾癌、喉癌、恶性雀斑样痣、致死性中线癌、白血病、莱迪希(Leydig)细胞瘤、脂肪肉瘤、肺癌、淋巴管瘤、淋巴管肉瘤、淋巴上皮瘤、淋巴瘤、急性淋巴细胞性白血病、急性骨髓性白血病(Mertz,J.A.,等人,“Targeting MYC dependence in cancer by inhibiting BET bromodomains,”Proc NatlAcad Sci USA 108(40):16669-74(2011))、慢性淋巴细胞性白血病、肝癌、小细胞肺癌、非小细胞肺癌、MALT淋巴瘤、恶性纤维组织细胞瘤、恶性外周神经鞘肿瘤、恶性蝾螈瘤、套细胞淋巴瘤、边缘区B细胞淋巴瘤、肥大细胞白血病、纵膈生殖细胞瘤、乳腺髓样癌、髓样甲状腺癌、成神经管细胞瘤、黑色素瘤(Miguel F.Segura,等人,“BRD4 is a novel therapeutictarget in melanoma,”Cancer Research.72(8):增刊1(2012))、脑膜瘤、梅克尔(Merkel)细胞癌、间皮瘤、转移性尿路上皮癌、苗勒型(Mullerian)混合瘤、混合谱系白血病(Dawson,M.A.,等人,“Inhibition of BET recruitment to chromatin as an effectivetreatment for MLL-fusion leukaemia,”Nature 478(7370):529-33(2011))、粘液性肿瘤、多发性骨髓瘤(Delmore,J.E.,等人,“BET bromodomain inhibition as atherapeutic strategy to target c-Myc,”Cell 146(6):904-17(2010))、肌肉组织肿瘤、蕈样真菌病、粘液样脂肪肉瘤、粘液瘤、粘液肉瘤、鼻咽癌、神经鞘瘤、成神经细胞瘤、神经纤维瘤、神经瘤、结节性黑色素瘤、NUT-中线癌(Filippakopoulos,P.,等人,“Selectiveinhibition of BET bromodomains,”Nature 468(7327):1067-73(2010))、眼癌、少突星形细胞瘤、少突神经胶质瘤、嗜酸细胞瘤、视神经鞘脑膜瘤、视神经肿瘤、口腔癌、骨肉瘤、卵巢癌、潘科斯特瘤、乳头状甲状腺癌、副神经节瘤、成松果体细胞瘤、松果体细胞瘤、垂体细胞瘤、垂体腺瘤、垂体瘤、浆细胞瘤、多胚瘤、前体T成淋巴细胞性淋巴瘤、原发性中枢神经系统淋巴瘤、原发性渗出性淋巴瘤、原发性腹膜癌、前列腺癌、胰腺癌、咽癌、腹膜假粘液瘤、肾细胞癌、肾髓质癌、成视网膜细胞瘤、横纹肌瘤、横纹肌肉瘤、里希特氏转化(Richter'stransformation)、直肠癌、肉瘤、神经鞘瘤(Schwannomatosis)、精原细胞瘤、赛尔托立(Sertoli)细胞瘤、性索-性腺间质肿瘤、印戒细胞癌、皮肤癌、小圆蓝细胞肿瘤、小细胞癌、软组织肉瘤、生长抑素瘤、煤烟疣、脊柱肿瘤、脾边缘区淋巴瘤、鳞状细胞癌、滑膜肉瘤、塞扎里氏病(Sezary's disease)、小肠癌、鳞状癌、胃癌、睾丸癌、卵泡膜细胞瘤、甲状腺癌、移行细胞癌、喉癌、脐尿管癌、泌尿生殖器癌、尿路上皮癌、葡萄膜黑色素瘤、子宫癌、疣状癌、视通路胶质瘤、外阴癌、阴道癌、瓦尔登斯特伦巨球蛋白血症、沃辛以及维尔姆斯氏肿瘤。因此,本发明的一方面提供用于治疗此类癌症的化合物、组合物和方法。BET inhibitors can be used to treat cancers including, but not limited to, adrenal carcinoma, acinar cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrohidrosis, acute eosinophilic leukemia, acute erythroleukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, and acute myeloid leukemia (Dawson, M.A., et al., “Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia,” Nature 478(7370):529-33 (2011); Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA 108(40):16669-74 (2011); Zuber, J., et al., “RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukemia” ... myeloidleukaemia,” Nature 478(7370):524-8 (2011)), adenocarcinoma, adenoid cystic carcinoma, adenoma, odontogenic adenomatoid tumor, adenosquamous carcinoma, adipose tissue tumor, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid carcinoma, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell acute lymphoblastic leukemia (Ott, C.J., et al., “BET bromodomain inhibition targets both c-Myc and IL7R in high risk acute lymphoblastic leukemia,” Blood 120(14):2843-52(2012)), B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma (Greenwald, R.J., et al., “E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia,”. Blood 103(4):1475-84(2004)), basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, brown tumor, Burkitt's lymphoma (Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BETbromodomains,” Proc Natl Acad Sci USA 108(40):16669-74(2011)), breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementum tumor, medullary sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos' disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland tumor, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, parasitic fetus, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma , giant cell tumor of bone, glioma, glioblastoma multiforme, neuroglioma, glioma, glioblastoma, glucagonoma, gonadoblastoma, granulosa cell tumor, amphotericinoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancies, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, infiltrative lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline cancer, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia (Mertz, J.A., et al., “Targeting MYC dependence in cancer by inhibiting BET bromodomains,” Proc Natl Acad Sci USA 108(40):16669-74(2011)), chronic lymphocytic leukemia, hepatocellular carcinoma, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant salamander tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary breast carcinoma, medullary thyroid carcinoma, medulloblastoma, melanoma (Miguel F. Segura, et al., “BRD4 is a novel therapeutic target in melanoma,” Cancer Research. 72(8): Suppl 1 (2012)), meningioma, Merkel cell carcinoma, mesothelioma, metastatic urothelial carcinoma, Mullerian mixed tumor, mixed lineage leukemia (Dawson, M.A., et al., “Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia,” Nature 478(7370): 529-33 (2011)), mucinous tumors, multiple myeloma (Delmore, J.E., et al., “BET bromodomain inhibition as atherapeutic strategy to target c-Myc,” Cell 146(6):904-17 (2010)), muscle tissue tumors, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, NUT-midline carcinoma (Filippakopoulos, P., et al., “Selective inhibition of BET bromodomains,” Nature 468(7327):1067-73(2010)), eye cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancrest tumor, papillary thyroid cancer, paraganglioma, pinealocyte tumor, pinealocyte tumor, pituitary cell tumor, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, kidney cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small round blue cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatinoma, sooty warts, spinal tumors, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sézary's disease, small intestinal cancer, squamous cell carcinoma, gastric cancer, testicular cancer, theca cell tumor, thyroid cancer, transitional cell carcinoma, laryngeal cancer, urachal cancer, genitourinary cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, optic pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom's macroglobulinemia, Worthing and Wilms' tumors. Thus, one aspect of the present invention provides compounds, compositions and methods for treating such cancers.

BET抑制剂可用于治疗良性增生和纤维化病症,包括良性软组织肿瘤、骨肿瘤、脑和脊髓肿瘤、眼睑和眼眶肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌腺瘤形成、鼻息肉、垂体肿瘤、泌乳素瘤、假性脑瘤、脂溢性角化症、胃息肉、甲状腺结节、胰腺囊性肿瘤、血管瘤、声带小结、息肉和囊肿、卡斯特莱曼(Castleman)病,慢性藏毛病、皮肤纤维瘤、毛发囊肿、化脓性肉芽肿、幼年性息肉病综合征、特发性肺纤维化、肾纤维化、手术后狭窄、瘢痕疙瘩形成、硬皮病以及心脏纤维化。参见例如,Tang,X等人,“Assessment of Brd4 Inhibition inIdiopathic Pulmonary Fibrosis Lung Fibroblasts and in Vivo Models of LungFibrosis,”.Am J Pathology in press(2013)。因此,本发明的一方面提供用于治疗此类良性增生和纤维化病症的化合物、组合物和方法。BET inhibitors may be used to treat benign proliferative and fibrotic disorders, including benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic tumors, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic pilonidal disease, dermatofibromas, pilaris cysts, pyogenic granulomas, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, scleroderma, and cardiac fibrosis. See, e.g., Tang, X et al., “Assessment of Brd4 Inhibition in Idiopathic Pulmonary Fibrosis Lung Fibroblasts and in Vivo Models of Lung Fibrosis,” Am J Pathology in press (2013). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating such benign proliferative and fibrotic disorders.

心血管疾病(CVD)是美国死亡率和发病率的主要原因。Roger,V.L.,等人,“Heartdisease and stroke statistics--2012update:a report from the American HeartAssociation,”Circulation 125(1):e2-e220(2012)。动脉粥样硬化(CVD的潜在病因)是以血脂异常和炎症为特征的多因素疾病。BET抑制剂由于前述抗炎作用以及增加ApoA-I(HDL的主要成分)的转录的能力而预期在动脉粥样硬化和相关病状中有效。Mirguet,O.,等人,“From ApoA1 upregulation to BET family bromodomain inhibition:discovery of I-BET151,”Bioorg Med Chem Lett 22(8):2963-7(2012);Chung,C.W.,等人,“Discoveryand characterization of small molecule inhibitors of the BET familybromodomains,”J Med Chem54(11):3827-38(2011)。因此,本发明的一方面提供用于治疗心血管疾病(包括但不限于动脉粥样硬化)的化合物、组合物和方法。Cardiovascular disease (CVD) is a leading cause of mortality and morbidity in the United States. Roger, V.L., et al., "Heart disease and stroke statistics--2012 update: a report from the American Heart Association," Circulation 125(1):e2-e220 (2012). Atherosclerosis, a potential cause of CVD, is a multifactorial disease characterized by dyslipidemia and inflammation. BET inhibitors are expected to be effective in atherosclerosis and related conditions due to their aforementioned anti-inflammatory effects and ability to increase the transcription of ApoA-I (the main component of HDL). Mirguet, O., et al., "From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151," Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C.W., et al., "Discovery and characterization of small molecule inhibitors of the BET family bromodomains," J Med Chem 54(11):3827-38 (2011). Accordingly, one aspect of the present invention provides compounds, compositions, and methods for treating cardiovascular diseases, including but not limited to atherosclerosis.

ApoA-I的上调被认为是治疗动脉粥样硬化和CVD的有用策略。Degoma,E.M.和D.J.Rader,“Novel HDL-directed pharmacotherapeutic strategies,”Nat Rev Cardiol8(5):266-77(2011)。BET抑制剂已经显示增加ApoA-I转录和蛋白质表达。Mirguet,O.,等人,“From ApoA1upregulation to BET family bromodomain inhibition:discovery ofI-BET151,”Bioorg Med Chem Lett22(8):2963-7(2012);Chung,C.W.,等人,“Discoveryand characterization of small molecule inhibitors of the BET familybromodomains,”J Med Chem 54(11):3827-38(2011)。还已经显示,BET抑制剂直接结合BET蛋白并且抑制其在ApoA-1启动子处结合乙酰化组蛋白,从而表明在ApoA-1启动子上存在BET蛋白抑制复合物,所述复合物可被BET抑制剂功能性破坏。由此断定,BET抑制剂可适用于通过调控ApoA-I和HDL来治疗脂质代谢紊病症,如高胆固醇血症、血脂异常、动脉粥样硬化(Degoma,E.M.和D.J.Rader,“Novel HDL-directed pharmacotherapeuticstrategies,”Nat Rev Cardiol 8(5):266-77(2011))和阿尔茨海默氏病以及其它神经病症。Elliott,D.A.,等人,“Apolipoproteins in the brain:implications forneurological and psychiatric disorders,”Clin Lipidol 51(4):555-573(2010)。因此,本发明的一方面提供用于通过上调ApoA-1来治疗心血管病症的化合物、组合物和方法。Upregulation of ApoA-I is considered a useful strategy for treating atherosclerosis and CVD. Degoma, E.M. and D.J. Rader, “Novel HDL-directed pharmacotherapeutic strategies,” Nat Rev Cardiol 8(5):266-77 (2011). BET inhibitors have been shown to increase ApoA-I transcription and protein expression. Mirguet, O., et al., “From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C.W., et al., “Discovery and characterization of small molecule inhibitors of the BET family bromodomains,” J Med Chem 54(11):3827-38 (2011). It has also been shown that BET inhibitors directly bind to BET proteins and inhibit their binding to acetylated histones at the ApoA-1 promoter, indicating the presence of a BET protein inhibitory complex on the ApoA-1 promoter that can be functionally disrupted by BET inhibitors. It has been concluded that BET inhibitors may be useful for treating lipid metabolism disorders such as hypercholesterolemia, dyslipidemia, atherosclerosis (Degoma, E.M. and D.J. Rader, "Novel HDL-directed pharmacotherapeutic strategies," Nat Rev Cardiol 8(5):266-77 (2011)) and Alzheimer's disease and other neurological disorders by regulating ApoA-1 and HDL. Elliott, D.A., et al., "Apolipoproteins in the brain: implications for neurological and psychiatric disorders," Clin Lipidol 51(4):555-573 (2010). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating cardiovascular disorders by upregulating ApoA-1.

BET抑制剂可用于预防和治疗与缺血-再灌注损伤相关的病状,如但不限于心肌梗死、中风、急性冠状动脉综合征(Prinjha,R.K.,J.Witherington和K.Lee,“Place yourBETs:the therapeutic potential of bromodomains,”Trends Pharmacol Sci 33(3):146-53(2012))、肾再灌注损伤、器官移植、冠状动脉旁路移植术、心肺旁路手术、高血压、肺、肾、肝、胃肠或肢外周栓塞。因此,本发明的一方面提供用于预防和治疗本文所述的与缺血-再灌注损伤相关的病状的化合物、组合物和方法。BET inhibitors can be used to prevent and treat conditions associated with ischemia-reperfusion injury, such as, but not limited to, myocardial infarction, stroke, acute coronary syndrome (Prinjha, R.K., J. Witherington, and K. Lee, "Place your BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci 33(3):146-53 (2012)), renal reperfusion injury, organ transplantation, coronary artery bypass grafting, cardiopulmonary bypass surgery, hypertension, pulmonary, renal, hepatic, gastrointestinal or limb peripheral embolism. Thus, one aspect of the present invention provides compounds, compositions, and methods for preventing and treating conditions associated with ischemia-reperfusion injury as described herein.

肥胖相关炎症是II型糖尿病、胰岛素抗性和其它代谢病症的标志。Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”NatRev Cancer12(7):465-77(2012);Denis,G.V.,“Bromodomain coactivators in cancer,obesity,type2diabetes,and inflammation,”Discov Med 10(55):489-99(2010)。与BET抑制剂抑制炎症的能力一致,在小鼠中Brd2的基因破坏消除炎症并且保护动物免受肥胖诱导的胰岛素抗性。Wang,F.,等人,“Brd2 disruption in mice causes severe obesitywithout Type 2diabetes,”Biochem J 425(1):71-83(2010)。已经显示,Brd2与PPARγ相互作用并且反对它的转录功能。体外敲低Brd2促进PPARγ调控网络(包括控制脂肪生成的那些)的转录。Denis,G.V.,等人,“An emerging role for bromodomain-containingproteins in chromatin regulation and transcriptional control ofadipogenesis,”FEBS Lett 584(15):3260-8(2010)。此外,Brd2在胰腺β细胞中高度表达并且调控增殖和胰岛素转录。Wang,F.,等人,“Brd2 disruption in mice causes severeobesity without Type 2diabetes,”Biochem J 425(1):71-83(2010)。总之,BET抑制剂对炎症和代谢的组合作用降低胰岛素抗性并且可适用于治疗前驱糖尿病和II型糖尿病个体以及具有其它代谢并发症的患者。Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”Nat Rev Cancer 12(7):465-77(2012)。因此,本发明的一方面提供用于治疗和预防代谢性病症的化合物、组合物和方法,所述代谢性病症包括但不限于肥胖相关炎症、II型糖尿病和胰岛素抗性。Obesity-associated inflammation is a hallmark of type 2 diabetes, insulin resistance, and other metabolic disorders. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G.V., “Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99 (2010). Consistent with the ability of BET inhibitors to inhibit inflammation, genetic disruption of Brd2 in mice abolished inflammation and protected animals from obesity-induced insulin resistance. Wang, F., et al., “Brd2 disruption in mice causes severe obesity without Type 2 diabetes,” Biochem J 425(1):71-83 (2010). Brd2 has been shown to interact with PPARγ and oppose its transcriptional function. Knockdown of Brd2 in vitro promotes transcription of the PPARγ regulatory network, including those that control adipogenesis. Denis, G.V., et al., “An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis,” FEBS Lett 584(15):3260-8 (2010). In addition, Brd2 is highly expressed in pancreatic beta cells and regulates proliferation and insulin transcription. Wang, F., et al., “Brd2 disruption in mice causes severe obesity without Type 2 diabetes,” Biochem J 425(1):71-83 (2010). In summary, the combined effects of BET inhibitors on inflammation and metabolism reduce insulin resistance and may be useful in treating individuals with prediabetes and type 2 diabetes, as well as patients with other metabolic complications. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating and preventing metabolic disorders including, but not limited to, obesity-related inflammation, type II diabetes, and insulin resistance.

宿主编码的BET蛋白已经显示对于转录活化和病毒启动子的抑制是重要的。Brd4与人乳头状瘤病毒(HPV)的E2蛋白相互作用,以实现E2-靶基因的E2介导的转录。Gagnon,D.,等人,“Proteasomal degradation of the papillomavirus E2 protein isinhibited by overexpression of bromodomain-containing protein4,”J Virol 83(9):4127-39(2009)。类似地,Brd2、Brd3和Brd4全部结合由卡波济氏肉瘤相关的疱疹病毒(KSHV)编码的潜伏期核抗原1(LANA1),从而促进感染KSHV的细胞的LANA1依赖性增殖。You,J.,等人,“Kaposi’s sarcoma-associated herpesvirus latency-associated nuclearantigen interacts with bromodomain protein Brd4 on host mitotic chromosomes,”J Virol 80(18):8909-19(2006)。BET抑制剂已经显示抑制转录延伸复合物pTEFb至埃-巴二氏病毒(Epstein-Barr virus)(EBV)病毒C启动子的Brd4介导的募集,从而表明针对EBV相关恶性肿瘤的治疗价值。Palermo,R.D.,等人,“RNA polymerase II stalling promotesnucleosome occlusion and pTEFb recruitment to drive immortalization byEpstein-Barr virus,”PLoS Pathog 7(10):e1002334(2011)。此外,BET抑制剂在潜伏性T细胞感染和潜伏性单核细胞感染的模型中再活化HIV,从而潜在允许通过互补抗逆转录病毒疗法根除病毒。Zhu,J.,等人,“Reactivation of Latent HIV-1by Inhibition ofBRD4,”Cell Rep(2012);Banerjee,C.,等人,“BET bromodomain inhibition as a novelstrategy for reactivation of HIV-1,”J Leukoc Biol(2012);Bartholomeeusen,K.,等人,“BET bromodomain inhibition activates transcription via a transientrelease of P-TEFb from7SK snRNP,”J Biol Chem(2012);Li,Z.,等人,“The BETbromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4inhibition of Tat-transactivation,”Nucleic Acids Res(2012)。Host-encoded BET proteins have been shown to be important for transcriptional activation and repression of viral promoters. Brd4 interacts with the E2 protein of human papillomavirus (HPV) to enable E2-mediated transcription of E2-target genes. Gagnon, D., et al., “Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein4,” J Virol 83(9):4127-39 (2009). Similarly, Brd2, Brd3, and Brd4 all bind to the latent nuclear antigen 1 (LANA1) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV), thereby promoting LANA1-dependent proliferation of KSHV-infected cells. You, J., et al., “Kaposi’s sarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes,” J Virol 80(18):8909-19 (2006). BET inhibitors have been shown to inhibit Brd4-mediated recruitment of the transcription elongation complex pTEFb to the Epstein-Barr virus (EBV) viral C promoter, suggesting therapeutic value against EBV-associated malignancies. Palermo, R.D., et al., “RNA polymerase II stalling promotes nucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus,” PLoS Pathog 7(10):e1002334 (2011). In addition, BET inhibitors reactivate HIV in models of latent T cell infection and latent mononuclear cell infection, potentially allowing viral eradication by complementary antiretroviral therapy. Zhu, J., et al., "Reactivation of Latent HIV-1 by Inhibition of BRD4," Cell Rep (2012); Banerjee, C., et al., "BET bromodomain inhibition as a novel strategy for reactivation of HIV-1," J Leukoc Biol (2012); Bartholomeeusen, K., et al., "BET bromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP," J Biol Chem (2012); Li, Z., et al., "The BETbromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4inhibition of Tat-transactivation," Nucleic Acids Res (2012).

BET抑制剂可用于预防和治疗基于游离基因的DNA病毒,包括但不限于,人乳头状瘤病毒、疱疹病毒、埃-巴二氏病毒、人免疫缺陷病毒(Belkina,A.C.和G.V.Denis,“BETdomain co-regulators in obesity,inflammation and cancer,”Nat Rev Cancer 12(7):465-77(2012))、腺病毒、痘病毒、乙型肝炎病毒和丙型肝炎病毒。因此,本发明也提供用于治疗和预防本文所述的基于游离基因的DNA病毒感染的化合物、组合物和方法。BET inhibitors can be used to prevent and treat episomal DNA viruses, including but not limited to human papillomavirus, herpes virus, Epstein-Barr virus, human immunodeficiency virus (Belkina, A.C. and G.V. Denis, "BETdomain co-regulators in obesity, inflammation and cancer," Nat Rev Cancer 12(7):465-77 (2012)), adenovirus, poxvirus, hepatitis B virus and hepatitis C virus. Therefore, the present invention also provides compounds, compositions and methods for treating and preventing episomal DNA virus infections as described herein.

一些中枢神经系统(CNS)疾病的特征在于表观遗传过程的病症。Brd2单倍体不足已经与神经元不足和癫痫相联系。Velisek,L.,等人,“GABAergic neuron deficit as anidiopathic generalized epilepsy mechanism:the role of BRD2 haploinsufficiencyin juvenile myoclonic epilepsy,”PLoS One6(8):e23656(2011)。各种含溴结构域蛋白中的SNP也已经与精神病症包括精神分裂症和双相性精神病症相联系。Prinjha,R.K.,J.Witherington和K.Lee,“Place your BETs:the therapeutic potential ofbromodomains,”Trends Pharmacol Sci 33(3):146-53(2012)。此外,BET抑制剂增加ApoA-I转录的能力可使BET抑制剂适用于阿尔茨海默氏病疗法,从而考虑增加的ApoA-I与阿尔茨海默氏病和其它神经病症之间的所建议的关系。Elliott,D.A.,等人,“Apolipoproteinsin the brain:implications for neurological and psychiatric disorders,”ClinLipidol 51(4):555-573(2010)。因此,本发明的一方面提供用于治疗此类CNS疾病和病症的化合物、组合物和方法。Some central nervous system (CNS) diseases are characterized by disorders of epigenetic processes. Brd2 haploinsufficiency has been linked to neuronal insufficiency and epilepsy. Velisek, L., et al., “GABAergic neuron deficit as anidiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy,” PLoS One 6(8):e23656 (2011). SNPs in various bromodomain-containing proteins have also been linked to psychiatric disorders, including schizophrenia and bipolar disorder. Prinjha, R.K., J. Witherington, and K. Lee, “Place your BETs: the therapeutic potential of bromodomains,” Trends Pharmacol Sci 33(3):146-53 (2012). Furthermore, the ability of BET inhibitors to increase ApoA-I transcription may make BET inhibitors suitable for Alzheimer's disease therapy, taking into account the proposed relationship between increased ApoA-I and Alzheimer's disease and other neurological disorders. Elliott, D.A., et al., "Apolipoproteins in the brain: implications for neurological and psychiatric disorders," Clin Lipidol 51(4):555-573 (2010). Thus, one aspect of the present invention provides compounds, compositions, and methods for treating such CNS diseases and disorders.

BRDT是BET蛋白家族的睾丸特异性成员,其对于精子发生期间的染色质重塑是必不可少的。Gaucher,J.,等人,“Bromodomain-dependent stage-specific male genomeprogramming by Brdt,”EMBO J31(19):3809-20(2012);Shang,E.,等人,“The firstbromodomain of Brdt,a testis-specific member of the BET sub-family of double-bromodomain-containing proteins,is essential for male germ celldifferentiation,”Development 134(19):3507-15(2007)。BRDT的遗传缺失或通过BET抑制剂抑制BRDT与乙酰化组蛋白相互作用在小鼠中导致避孕作用,当使用小分子BET抑制剂时这是可逆的。Matzuk,M.M.,等人,“Small-Molecule Inhibition of BRDT for MaleContraception,”Cell 150(4):673-684(2012);Berkovits,B.D.,等人,“The testis-specific double bromodomain-containing protein BRDT forms a complex withmultiple spliceosome components and is required for mRNA splicing and3’-UTRtruncation in round spermatids,”Nucleic Acids Res 40(15):7162-75(2012)。这些数据表明BET抑制剂作为新型和有效的男性避孕方法的潜在效用。因此,本发明的另一方面提供用于男性避孕的化合物、组合物和方法。BRDT is a testis-specific member of the BET protein family that is essential for chromatin remodeling during spermatogenesis. Gaucher, J., et al., "Bromodomain-dependent stage-specific male genome programming by Brdt," EMBO J 31(19): 3809-20 (2012); Shang, E., et al., "The first bromodomain of Brdt, a testis-specific member of the BET sub-family of double-bromodomain-containing proteins, is essential for male germ cell differentiation," Development 134(19): 3507-15 (2007). Genetic deletion of BRDT or inhibition of BRDT interaction with acetylated histones by BET inhibitors results in a contraceptive effect in mice, which is reversible when a small molecule BET inhibitor is used. Matzuk, M.M., et al., "Small-Molecule Inhibition of BRDT for Male Contraception," Cell 150(4):673-684 (2012); Berkovits, B.D., et al., "The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTRtruncation in round spermatids," Nucleic Acids Res 40(15):7162-75 (2012). These data suggest the potential utility of BET inhibitors as novel and effective male contraceptive methods. Therefore, another aspect of the present invention provides compounds, compositions, and methods for male contraception.

单核细胞趋化蛋白-1(MCP-1,CCL2)在心血管疾病中起重要作用。Niu,J.和P.E.Kolattukudy,“Role of MCP-1in cardiovascular disease:molecular mechanismsand clinical implications,”Clin Sci(Lond)117(3):95-109(2009)。MCP-1通过其趋化活性调控单核细胞从动脉管腔至内皮下间隙的募集,其中它们发育成巨噬细胞泡沫细胞并且起始脂纹的形成,脂纹可发展成动脉粥样硬化斑块。Dawson,J.,等人,“Targetingmonocyte chemoattractant protein-1signalling in disease,”Expert Opin TherTargets 7(1):35-48(2003)。MCP-1(及其同源受体CCR2)在动脉粥样硬化发展中的重要作用已经在高脂血症背景的不同转基因和敲除小鼠模型中进行了检查。Boring,L.,等人,“Decreased lesion formation in CCR2-/-mice reveals a role for chemokines inthe initiation of atherosclerosis,”Nature 394(6696):894-7(1998);Gosling,J.,等人,“MCP-1deficiency reduces susceptibility to atherosclerosis in mice thatoverexpress human apolipoprotein B,”J Clin Invest 103(6):773-8(1999);Gu,L.,等人,“Absence of monocyte chemoattractant protein-1reduces atherosclerosis inlow density lipoprotein receptor-deficient mice,”Mol Cell 2(2):275-81(1998);Aiello,R.J.,等人,“Monocyte chemoattractant protein-1acceleratesatherosclerosis in apolipoprotein E-deficient mice,”Arterioscler Thromb VascBiol 19(6):1518-25(1999)。这些报道证明MCP-1信号传导的消除导致对动脉壁的巨噬细胞浸润减少和减少的动脉粥样硬化病变发展。Monocyte chemoattractant protein-1 (MCP-1, CCL2) plays an important role in cardiovascular disease. Niu, J. and P.E. Kolattukudy, “Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications,” Clin Sci (Lond) 117(3):95-109 (2009). MCP-1 regulates the recruitment of monocytes from the arterial lumen to the subendothelial space through its chemotactic activity, where they develop into macrophage foam cells and initiate the formation of fatty streaks that can develop into atherosclerotic plaques. Dawson, J., et al., “Targeting monocyte chemoattractant protein-1 signaling in disease,” Expert Opin Ther Targets 7(1):35-48 (2003). The important role of MCP-1 (and its cognate receptor CCR2) in the development of atherosclerosis has been examined in different transgenic and knockout mouse models in a hyperlipidemic background. Boring, L., et al., “Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis,” Nature 394(6696):894-7(1998); Gosling, J., et al., “MCP-1deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B,” J Clin Invest 103(6):773-8(1999); Gu, L., et al., "Absence of monocyte chemoattractant protein-1reduces atherosclerosis in low density lipoprotein receptor-deficient mice," Mol Cell 2(2):275-81(1998); Aiello, R.J., et al., "Monocyte chemoattractant protein-1accelerates atherosclerosis in apolipoprotein E-deficient mice,” Arterioscler Thromb VascBiol 19(6):1518-25(1999). These reports demonstrated that ablation of MCP-1 signaling resulted in reduced macrophage infiltration of the arterial wall and reduced atherosclerotic lesion development.

在人中MCP-1与心血管疾病之间的关联是已经确立的。Niu,J.和P.E.Kolattukudy,“Role of MCP-1in cardiovascular disease:molecular mechanismsand clinical implications,”Clin Sci(Lond)117(3):95-109(2009)。MCP-1及其受体在人动脉粥样硬化斑块中由内皮细胞、平滑肌细胞和浸润单核细胞/巨噬细胞过度表达。Nelken,N.A.,等人,“Monocyte chemoattractant protein-1in human atheromatousplaques,”J Clin Invest 88(4):1121-7(1991)。此外,MCP-1的升高的循环水平与大多数心血管危险因素、冠状动脉粥样硬化负担的测量以及冠状动脉性心脏病(CHD)的发病率正相关。Deo,R.,等人,“Association among plasma levels of monocyte chemoattractantprotein-1,traditional cardiovascular risk factors,and subclinicalatherosclerosis,”J Am Coll Cardiol 44(9):1812-8(2004)。具有最高MCP-1水平的CHD患者是具有急性冠状动脉综合征(ACS)的那些。de Lemos,J.A.,等人,“Associationbetween plasma levels of monocyte chemoattractant protein-1and long-termclinical outcomes in patients with acute coronary syndromes,”Circulation 107(5):690-5(2003)。除了在与CHD相关的潜在炎症中起作用之外,MCP-1已经显示参与斑块破裂、缺血/再灌注损伤、再狭窄以及心脏移植排斥。Niu,J.和P.E.Kolattukudy,“Role ofMCP-1in cardiovascular disease:molecular mechanisms and clinicalimplications,”Clin Sci(Lond)117(3):95-109(2009)。The association between MCP-1 and cardiovascular disease in humans is well established. Niu, J. and P.E. Kolattukudy, “Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications,” Clin Sci (Lond) 117(3):95-109 (2009). MCP-1 and its receptors are overexpressed by endothelial cells, smooth muscle cells, and infiltrating monocytes/macrophages in human atherosclerotic plaques. Nelken, N.A., et al., “Monocyte chemoattractant protein-1 in human atheromatousplaques,” J Clin Invest 88(4):1121-7 (1991). In addition, elevated circulating levels of MCP-1 are positively correlated with most cardiovascular risk factors, measures of coronary atherosclerosis burden, and the incidence of coronary heart disease (CHD). Deo, R., et al., “Association among plasma levels of monocyte chemoattractant protein-1, traditional cardiovascular risk factors, and subclinicalatherosclerosis,” J Am Coll Cardiol 44(9):1812-8 (2004). CHD patients with the highest MCP-1 levels are those with acute coronary syndrome (ACS). de Lemos, J.A., et al., “Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute coronary syndromes,” Circulation 107(5):690-5 (2003). In addition to playing a role in the underlying inflammation associated with CHD, MCP-1 has been shown to be involved in plaque rupture, ischemia/reperfusion injury, restenosis, and cardiac transplant rejection. Niu, J. and P.E. Kolattukudy, "Role of MCP-1 in cardiovascular disease: molecular mechanisms and clinical implications," Clin Sci (Lond) 117(3):95-109 (2009).

MCP-1还促进与自身免疫性疾病包括类风湿性关节炎(RA)和多发性硬化症(MS)相关的组织炎症。MCP-1在RA中巨噬细胞和淋巴细胞至关节中的浸润中起作用并且在RA患者的滑液中过度表达。Koch,A.E.,等人,“Enhanced production of monocytechemoattractant protein-1in rheumatoid arthritis,”J Clin Invest 90(3):772-9(1992)。在RA动物模型中MCP-1和MCP-1信号传导的阻断也已经显示MCP-1对于与RA相关的巨噬细胞积聚和促炎细胞因子表达的重要性。Brodmerkel,C.M.,等人,“Discovery andpharmacological characterization of a novel rodent-active CCR2 antagonist,INCB3344,”J Immunol 175(8):5370-8(2005);Bruhl,H.,等人,“Dual role ofCCR2during initiation and progression of collagen-induced arthritis:evidencefor regulatory activity of CCR2+T cells,”J Immunol 172(2):890-8(2004);Gong,J.H.,等人,“An antagonist of monocyte chemoattractant protein 1(MCP-1)inhibitsarthritis in the MRL-lpr mouse model,”J Exp Med 186(1):131-7(1997);65.Gong,J.H.,等人,“Post-onset inhibition of murine arthritis using combined chemokineantagonist therapy,”Rheumatology(Oxford 43(1):39-42(2004).MCP-1 also promotes tissue inflammation associated with autoimmune diseases including rheumatoid arthritis (RA) and multiple sclerosis (MS). MCP-1 plays a role in the infiltration of macrophages and lymphocytes into the joints in RA and is overexpressed in the synovial fluid of RA patients. Koch, A.E., et al., "Enhanced production of monocytechemoattractant protein-1 in rheumatoid arthritis," J Clin Invest 90(3):772-9 (1992). Blockade of MCP-1 and MCP-1 signaling in animal models of RA has also shown the importance of MCP-1 for macrophage accumulation and proinflammatory cytokine expression associated with RA. Brodmerkel, C.M., et al., "Discovery and pharmacological characterization of a novel rodent-active CCR2 antagonist, INCB3344," J Immunol 175(8):5370-8(2005); Bruhl, H., et al., "Dual role of CCR2 during initiation and progression of collagen-induced arthritis: evidence for regulatory activity of CCR2+T cells," J Immunol 172(2):890-8(2004); Gong, J.H., et al., "An antagonist of monocyte chemoattractant protein 1(MCP-1) inhibitsarthritis in the MRL-lpr mouse model," J Exp Med 186(1):131-7(1997); 65. Gong, J.H., et al., "Post-onset inhibition of murine arthritis using combined chemokineantagonist therapy,” Rheumatology (Oxford 43(1):39-42(2004).

脑、脑脊髓液(CSF)和血液中MCP-1的过表达也已经与人中的慢性和急性MS相关联。Mahad,D.J.和R.M.Ransohoff,“The role of MCP-1(CCL2)and CCR2 in multiplesclerosis and experimental autoimmune encephalomyelitis(EAE),”Semin Immunol15(1):23-32(2003)。在疾病进展期间MCP-1由脑中的多种细胞类型过度表达并且促成巨噬细胞和淋巴细胞浸润,浸润介导与MS相关的组织损伤。在实验性自身免疫性脑脊髓炎(EAE)小鼠模型(一种类似人MS的模型)中MCP-1或CCR2的遗传缺失导致对疾病的抵抗性,这主要是由于减少的巨噬细胞浸润至CNS。Fife,B.T.,等人,“CC chemokine receptor 2iscritical for induction of experimental autoimmune encephalomyelitis,”J ExpMed 192(6):899-905(2000);Huang,D.R.,等人,“Absence of monocyte chemoattractantprotein 1in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1immune response in experimental autoimmuneencephalomyelitis,”J Exp Med 193(6):713-26(2001)。Overexpression of MCP-1 in the brain, cerebrospinal fluid (CSF) and blood has also been associated with chronic and acute MS in humans. Mahad, DJ and RM Ransohoff, "The role of MCP-1 (CCL2) and CCR2 in multiplesclerosis and experimental autoimmune encephalomyelitis (EAE)," Semin Immunol 15 (1): 23-32 (2003). During disease progression, MCP-1 is overexpressed by multiple cell types in the brain and contributes to the infiltration of macrophages and lymphocytes, which mediate the tissue damage associated with MS. Genetic deletion of MCP-1 or CCR2 in the experimental autoimmune encephalomyelitis (EAE) mouse model (a model similar to human MS) leads to resistance to the disease, mainly due to reduced macrophage infiltration into the CNS. Fife, B.T., et al., "CC chemokine receptor 2iscritical for induction of experimental autoimmune encephalomyelitis," J ExpMed 192(6):899-905(2000); Huang, D.R., et al., "Absence of monocyte chemoattractantprotein 1in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1immune response in experimental autoimmuneencephalomyelitis,” J Exp Med 193(6):713-26(2001).

临床前数据已经表明,MCP-1和CCR2的小分子和大分子抑制剂具有作为炎症和自身免疫性适应症的治疗剂的潜力。因此,本发明的一方面提供用于治疗与MCP-1和CCR2相关的心血管、炎症性和自身免疫性病状的化合物、组合物和方法。Preclinical data have shown that small and macromolecular inhibitors of MCP-1 and CCR2 have potential as therapeutic agents for inflammatory and autoimmune indications. Accordingly, one aspect of the present invention provides compounds, compositions and methods for treating cardiovascular, inflammatory and autoimmune conditions associated with MCP-1 and CCR2.

发明内容Summary of the Invention

因此,本发明提供可用于通过结合于溴结构域来抑制BET蛋白功能的化合物、包含那些化合物中的一种或多种的药物组合物、以及这些化合物或组合物在治疗和预防疾病和病状(包括但不限于癌症、自身免疫和心血管疾病)中的用途。本发明的化合物由式Ia或式IIa定义:Thus, the present invention provides compounds useful for inhibiting BET protein function by binding to bromodomains, pharmaceutical compositions comprising one or more of those compounds, and the use of these compounds or compositions in treating and preventing diseases and conditions, including but not limited to cancer, autoimmunity, and cardiovascular disease. The compounds of the present invention are defined by Formula Ia or Formula IIa:

或其立体异构体、互变异构体、药学上可接受的盐、或水合物,or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof,

其中:in:

A选自5-或6-元单环杂环稠合于环B;A is selected from a 5- or 6-membered monocyclic heterocyclic ring fused to ring B;

条件是A不能为取代的或未取代的Provided that A cannot be substituted or unsubstituted

B为六元芳族碳环或杂环;B is a six-membered aromatic carbocyclic ring or heterocyclic ring;

Y选自N、C和CH;Y is selected from N, C and CH;

W1选自N和CR1W 1 is selected from N and CR 1 ;

W2选自N和CR2W 2 is selected from N and CR 2 ;

W3选自N和CR3W 3 is selected from N and CR 3 ;

W4和W5独立地选自N、CH和C或可选地,W4和W5均为C(参见,例如,下面式Ib和式IIb);W 4 and W 5 are independently selected from N, CH and C or alternatively, W 4 and W 5 are both C (see, e.g., Formula Ib and Formula IIb below);

W1、W2和W3可以彼此相同或不同;W 1 , W 2 and W 3 may be the same as or different from each other;

R1和R2独立地选自氢、氘、烷基、-OH、-NH2、-硫代烷基、烷氧基、酮、酯、羧酸、脲、氨基甲酸酯、氨基、酰胺、卤素、碳环、杂环、砜、亚砜、硫化物、磺酰胺和–CN;R 1 and R 2 are independently selected from hydrogen, deuterium, alkyl, —OH, —NH 2 , -alkylthio, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN;

R3选自氢、-NH2、-CN、-N3、卤素和氘;或可选地,R3选自-NO2、-OMe、-OEt、-NHC(O)Me、NHSO2Me、环氨基、环酰胺基、-OH、-SO2Me、-SO2Et、-CH2NH2、-C(O)NH2和-C(O)OMe;R 3 is selected from hydrogen, -NH 2 , -CN, -N 3 , halogen, and deuterium; or alternatively, R 3 is selected from -NO 2 , -OMe, -OEt, -NHC(O)Me, NHSO 2 Me, cyclic amino, cyclic amido, -OH, -SO 2 Me, -SO 2 Et, -CH 2 NH 2 , -C(O)NH 2 , and -C(O)OMe;

X选自–CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2O-、-CH2CH2NH-、-CH2CH2S-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-、-CH2C(O)-、-CH2CH2C(O)-、-C(O)NH-、-C(O)O-、-C(O)S-、-C(O)NHCH2-、-C(O)OCH2-、-C(O)SCH2-,其中一个或多个氢可独立地被氘、卤素、-CF3、酮替代,且其中S可被氧化成亚砜或砜;或可选地,X可选自–NH-、-CH(OH)-、-CH(CH3)-和羟基甲基,其中一个或多个氢可独立地被氘、卤素、-CF3、酮替代,且其中S可被氧化成亚砜或砜;X is selected from -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH2CH2O- , -CH2CH2NH-, -CH2CH2S-, -C (O ) - , -C( O) CH2- , -C (O )CH2- , -C(O) CH2CH2- , -CH2C(O)-, -CH2CH2C(O) - , -C (O) NH- , -C(O) O- , -C(O)S-, -C(O)NHCH2-, -C(O) OCH2- , -C(O) SCH2- , wherein one or more hydrogens may be independently replaced by deuterium, halogen, -CF3 , ketone, and wherein S may be oxidized to sulfoxide or sulfone; or alternatively, X may be selected from -NH-, -CH (OH)-, -CH( CH3 )- and hydroxymethyl, wherein one or more hydrogens may be independently replaced by deuterium, halogen, -CF 3 , ketone, and wherein S may be oxidized to form a sulfoxide or sulfone;

R4选自4-7元碳环和杂环;或可选地,R4为3元碳环或杂环;R 4 is selected from 4-7 membered carbocyclic and heterocyclic rings; or alternatively, R 4 is a 3 membered carbocyclic or heterocyclic ring;

D1选自5-元单环碳环和杂环;或可选地,D1为单环杂环,其中D1经由为双键的部分的碳原子连接至B环;D 1 is selected from 5-membered monocyclic carbocycles and heterocycles; or alternatively, D 1 is a monocyclic heterocycle, wherein D 1 is connected to the B ring via a carbon atom that is part of a double bond;

条件是如果R3为氢且A为5-元环,则D1不能为Provided that if R 3 is hydrogen and A is a 5-membered ring, then D 1 cannot be

并且条件是如果D1为且R2和R3为氢且R1为–OMe,则A-B双环不为and provided that if D 1 is and R 2 and R 3 are hydrogen and R 1 is –OMe, then the AB bicyclic ring is not

并且条件是如果D1为且R1、R2、R3中的每一个为氢,则A-B双环不为and provided that if D 1 is and each of R 1 , R 2 , and R 3 is hydrogen, then the AB bicyclic ring is not

除非B环是被取代的;Unless the B ring is substituted;

并且条件是如果R1、R2、R3中的每一个为氢,则A-B双环不为and provided that if each of R 1 , R 2 , and R 3 is hydrogen, then the AB bicyclic ring is not

并且条件是如果R1、R2、R3中的每一个为氢,则A-B双环不为and provided that if each of R 1 , R 2 , and R 3 is hydrogen, then the AB bicyclic ring is not

在某些实施方案中A为五元环。在一些实施方案中Y为N或C。在一些实施方案中,R1和R2独立地选自氢、氘、烷基、-OH、-NH2、-硫代烷基、烷氧基、酮、酯、羧酸、脲、氨基甲酸酯、氨基、酰胺、卤素、砜、亚砜、硫化物、磺酰胺和–CN。在一些实施方案中,式Ia化合物为式Ib化合物,即,其中式I的W4和W5均为C。In certain embodiments, A is a five-membered ring. In certain embodiments, Y is N or C. In certain embodiments, R 1 and R 2 are independently selected from hydrogen, deuterium, alkyl, -OH, -NH 2 , -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide, sulfonamide, and -CN. In certain embodiments, the compound of Formula Ia is a compound of Formula Ib, i.e., wherein W 4 and W 5 of Formula I are both C.

在一些实施方案中,式IIa化合物为式IIb化合物,即,其中式I的W4和W5均为C。In some embodiments, the compound of Formula IIa is a compound of Formula IIb, ie, wherein W 4 and W 5 of Formula I are both C.

在本发明的另一方面,提供了包含式Ia、式Ib、式IIa和/或式IIb的化合物、或其立体异构体、互变异构体、药学上可接受的盐或水合物和一种或多种药学可接受的载体、稀释剂或赋形剂的药物组合物。In another aspect of the present invention, a pharmaceutical composition comprising a compound of Formula Ia, Formula Ib, Formula IIa and/or Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable carriers, diluents or excipients is provided.

在本发明的又一方面,提供了式Ia、式Ib、式IIa和/或式IIb的化合物、或其立体异构体、互变异构体、药学上可接受的盐或水合物、或包含此类化合物的药物组合物、用于在治疗、特别是在治疗针对其指示溴结构域抑制剂的疾病或病状中使用。In another aspect of the present invention, provided are compounds of Formula Ia, Formula Ib, Formula IIa and/or Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, or pharmaceutical compositions comprising such compounds, for use in treatment, particularly in the treatment of diseases or conditions for which bromodomain inhibitors are indicated.

在本发明的又一方面,提供了在制造用于治疗针对其指示溴结构域抑制剂的疾病或病状的药剂中的式Ia、式Ib、式IIa和/或式IIb的化合物、或其立体异构体、互变异构体、药学上可接受的盐或水合物。In yet another aspect of the present invention, provided are compounds of Formula Ia, Ib, IIa, and/or IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, in the manufacture of a medicament for treating a disease or condition for which a bromodomain inhibitor is indicated.

定义definition

当用于本说明书中时,以下词语、短语和符号通常旨在具有如下所述的含义,除了到使用它们的上下文中另有说明的程度。以下缩写和术语在全文中具有所指示的含义。When used in this specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, except to the extent otherwise indicated by the context in which they are used. The following abbreviations and terms have the indicated meanings throughout.

如本文所用,“心血管疾病”是指心脏和循环系统的由BET抑制介导的疾病、病症和病状。示例性心血管疾病(包括胆固醇或脂质相关的病症)包括但不限于,急性冠状动脉综合征、心绞痛、动脉硬化、动脉粥样硬化、颈动脉粥样硬化、脑血管疾病、脑梗死、充血性心力衰竭、先天性心脏疾病、冠状动脉性心脏病、冠状动脉疾病、冠状动脉斑块稳定、血脂异常、异常脂蛋白血症、内皮功能障碍、家族性高胆固醇血症、家族性混合型高脂血症、低α脂蛋白血症、高甘油三酯血症、高β脂蛋白血症、高胆固醇血症、高血压症、高血脂症、间歇性跛行、局部缺血、局部缺血再灌注损伤、局部缺血性心脏病、心肌缺血、代谢综合征、多梗塞性痴呆、心肌梗死、肥胖症、周围血管疾病、再灌注损伤、再狭窄、肾动脉粥样硬化、风湿性心脏病、中风、血栓形成性病症、短暂性脑缺血发作、以及与阿尔茨海默氏病、肥胖症、糖尿病、X综合征、阳痿、多发性硬化症、帕金森氏病和炎症性疾病相关的脂蛋白异常。As used herein, "cardiovascular disease" refers to diseases, disorders, and conditions of the heart and circulatory system that are mediated by BET inhibition. Exemplary cardiovascular diseases (including cholesterol or lipid-related disorders) include, but are not limited to, acute coronary syndrome, angina pectoris, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemia, dyslipoproteinemia, endothelial dysfunction, familial hypercholesterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, Hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia-reperfusion injury, ischemic heart disease, myocardial ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal atherosclerosis, rheumatic heart disease, stroke, thrombotic disorders, transient ischemic attack, and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes, syndrome X, impotence, multiple sclerosis, Parkinson's disease, and inflammatory diseases.

如本文所用,“炎症性疾病”是指通过BET抑制介导的疾病、病症和病状。示例性炎症性疾病包括但不限于,关节炎、哮喘、皮炎、银屑病、囊肿性纤维化、移植后晚期和慢性实体器官排斥、多发性硬化症、系统性红斑狼疮、炎性肠疾病、自身免疫性糖尿病、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性血管病变、眼部炎症、葡萄膜炎、鼻炎、局部缺血再灌注损伤、血管成形术后再狭窄、慢性阻塞性肺疾病(COPD)、肾小球性肾炎、格雷夫斯病、胃肠过敏症、结膜炎、动脉粥样硬化、冠状动脉疾病、心绞痛以及小动脉疾病。As used herein, "inflammatory diseases" refers to diseases, disorders, and conditions mediated by BET inhibition. Exemplary inflammatory diseases include, but are not limited to, arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, late and chronic solid organ rejection after transplantation, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, autoimmune diabetes, diabetic retinopathy, diabetic nephropathy, diabetic vasculopathy, ocular inflammation, uveitis, rhinitis, ischemia-reperfusion injury, restenosis after angioplasty, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves' disease, gastrointestinal irritability, conjunctivitis, atherosclerosis, coronary artery disease, angina, and arteriole disease.

如本文所用,“癌症”是指通过BET抑制介导的疾病、病症和病状。示例性癌症包括但不限于,慢性淋巴细胞性白血病和多发性骨髓瘤、滤泡性淋巴瘤、具有生发中心表型的弥漫性大B细胞淋巴瘤、伯基特氏淋巴瘤、霍奇金氏淋巴瘤、滤泡性淋巴瘤和活化间变性大细胞淋巴瘤、成神经细胞瘤和原发性神经外胚层肿瘤、横纹肌肉瘤、前列腺癌、乳腺癌、NMC(NUT-中线癌)、急性骨髓性白血病(AML)、急性B成淋巴细胞性白血病(B-ALL)、伯基特淋巴瘤、B细胞淋巴瘤、黑色素瘤、混合谱系白血病、多发性骨髓瘤、早幼粒细胞性白血病(PML)、非霍奇金氏淋巴瘤、成神经细胞瘤、成神经管细胞瘤、肺癌(NSCLC、SCLC)以及结肠癌。As used herein, "cancer" refers to diseases, disorders, and conditions mediated by BET inhibition. Exemplary cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma, follicular lymphoma, diffuse large B-cell lymphoma with a germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphoma, and activated anaplastic large cell lymphoma, neuroblastoma and primary neuroectodermal tumors, rhabdomyosarcoma, prostate cancer, breast cancer, NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute B-lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, B-cell lymphoma, melanoma, mixed lineage leukemia, multiple myeloma, promyelocytic leukemia (PML), non-Hodgkin's lymphoma, neuroblastoma, medulloblastoma, lung cancer (NSCLC, SCLC), and colon cancer.

“受试者”是指已经是或将是治疗、观察或实验的对象的动物,如哺乳动物。本文所述的方法可用于人疗法和兽医应用两者。在一个实施方案中,受试者是人。"Subject" refers to an animal, such as a mammal, that has been or will be the object of treatment, observation, or experiment. The methods described herein can be used in both human therapy and veterinary applications. In one embodiment, the subject is a human.

如本文所用,“治疗(treatment)”或“治疗(treating)”是指疾病或病症或其至少一种可觉察的症状的改善。在另一实施方案中,“治疗(treatment)”或“治疗(treating)”是指不一定可由患者察觉的至少一种可测量的物理参数的改善。在另一个实施方案中,“治疗(treatment)”或“治疗(treating)”是指在身体上(例如,可觉察的症状的稳定化)、生理学上(例如,物理参数的稳定化)或两者抑制疾病或病症的进展。在另一个实施方案中,“治疗(treatment)”或“治疗(treating)”是指延迟疾病或病症的发作。例如,治疗胆固醇病症可包括降低血液胆固醇水平。As used herein, "treatment" or "treating" refers to the improvement of a disease or disorder or at least one of its perceptible symptoms. In another embodiment, "treatment" or "treating" refers to the improvement of at least one measurable physical parameter that is not necessarily perceptible by the patient. In another embodiment, "treatment" or "treating" refers to inhibiting the progression of a disease or disorder physically (e.g., stabilization of perceptible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In another embodiment, "treatment" or "treating" refers to delaying the onset of a disease or disorder. For example, treating a cholesterol disorder may comprise lowering blood cholesterol levels.

如本文所用,“预防(prevention)”或“预防(preventing)”是指降低获得给定疾病或病症的风险。As used herein, "prevention" or "preventing" refers to reducing the risk of acquiring a given disease or condition.

未在两个字母或符号之间的连接号(“-”)用于指示取代基的连接点。例如,-CONH2通过碳原子连接。A hyphen ("-") not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached through a carbon atom.

“任选的”或“任选地”意指随后描述的事件或情况可发生或可未发生,并且描述包括其中事件或情况发生的情况和其中它未发生的情况。例如,“任选取代的芳基”涵盖如以下所定义的“芳基”和“取代的芳基”两者。本领域的技术人员将会理解,关于含有一个或多个取代基的任何基团,基团不意图引入任何立体不切实际的、合成不可行的和/或固有不稳定的取代或取代型式。"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined below. One skilled in the art will understand that, with respect to any group containing one or more substituents, the group is not intended to introduce any sterically impractical, synthetically unfeasible, and/or inherently unstable substitution or substitution pattern.

如本文所用,术语“水合物”是指化学计量或非化学计量量的水并入晶体结构的一种晶体形式。As used herein, the term "hydrate" refers to a crystal form in which a stoichiometric or non-stoichiometric amount of water is incorporated into the crystal structure.

如本文所用的术语“烯基”是指具有至少一个碳-碳双键的不饱和直链或支链烃,如2-8个碳原子的直链或支链基团,在本文中被称为(C2-C8)烯基。示例性烯基包括但不限于,乙烯基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二烯基、己二烯基、2-乙基己烯基、2-丙基-2-丁烯基和4-(2-甲基-3-丁烯)-戊烯基。As used herein, the term "alkenyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2 to 8 carbon atoms, referred to herein as a ( C2 - C8 ) alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butene)-pentenyl.

如本文所用的术语“烷氧基”是指连接至氧的烷基(-O-烷基-)。“烷氧基”还包括连接至氧的烯基(“烯氧基”)或连接至氧的炔基(“炔氧基”)。示例性烷氧基包括但不限于,具有1-8个碳原子的烷基、烯基或炔基的基团,在本文中被称为(C1-C8)烷氧基。示例性烷氧基包括但不限于甲氧基和乙氧基。As used herein, the term "alkoxy" refers to an alkyl group attached to an oxygen group (-O-alkyl-). "Alkoxy" also includes an alkenyl group attached to an oxygen group ("alkenyloxy") or an alkynyl group attached to an oxygen group ("alkynyloxy"). Exemplary alkoxy groups include, but are not limited to, groups of alkyl, alkenyl, or alkynyl groups having 1-8 carbon atoms, referred to herein as (C1 - C8 )alkoxy groups. Exemplary alkoxy groups include, but are not limited to, methoxy and ethoxy groups.

如本文所用的术语“烷基”是指饱和直链或支链烃,如1-8个碳原子的直链或支链基团,在本文中被称为(C1-C8)烷基。示例性烷基包括但不限于,甲基、乙基、丙基、异丙基、2-甲基-1-丙基、2-甲基-2-丙基、2-甲基-1-丁基、3-甲基-1-丁基、2-甲基-3-丁基、2,2-二甲基-1-丙基、2-甲基-1-戊基、3-甲基-1-戊基、4-甲基-1-戊基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲基-1-丁基、2-乙基-1-丁基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、庚基和辛基。As used herein, the term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1 to 8 carbon atoms, referred to herein as a (Ci - Cg) alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2 -methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl.

如本文所用的术语“炔基”是指具有至少一个碳-碳三键的不饱和直链或支链烃,如2-8个碳原子的直链或支链基团,在本文中被称为(C2-C8)炔基。示例性炔基包括但不限于,乙炔基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙炔基、4-甲基-1-丁炔基、4-丙基-2-戊炔基和4-丁基2-己炔基。As used herein, the term "alkynyl" refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2 to 8 carbon atoms, referred to herein as a (C2 - C8 ) alkynyl. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and 4-butyl-2-hexynyl.

如本文所用的术语“酰胺”是指形式-NRaC(O)(Rb)-或-C(O)NRbRc,其中Ra、Rb和Rc各自独立地选自烷基、烯基、炔基、芳基、芳基烷基、环烷基、卤代烷基、杂芳基、杂环基和氢。酰胺可通过碳、氮、Rb或Rc连接至另一基团。酰胺也可以是环状的,例如Rb和Rc可连接以形成3至8元环,如5或6元环。术语“酰胺”涵盖基团如磺酰胺、脲、脲基、氨基甲酸酯、氨基甲酸及其环状型式。术语“酰胺”还涵盖连接至羧基的酰胺基团,例如-酰胺-COOH或盐如-酰胺-COONa;连接至羧基的氨基(例如,-氨基-COOH或盐如-氨基-COONa)。As used herein, the term "amide" refers to the form -NRaC (O)( Rb )- or -C (O) NRbRc , wherein Ra , Rb and Rc are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. Amides can be connected to another group through carbon, nitrogen, Rb or Rc . Amides can also be cyclic, for example, Rb and Rc can be connected to form a 3 to 8-membered ring, such as a 5 or 6-membered ring. The term "amide" encompasses groups such as sulfonamide, urea, urea radicals, carbamates, carbamic acid and cyclic versions thereof. The term "amide" also encompasses amide groups connected to a carboxyl group, for example -amide-COOH or salts such as -amide-COONa; amino groups connected to a carboxyl group (for example, -amino-COOH or salts such as -amino-COONa).

如本文所用的术语“胺”或“氨基”是指形式-NRdRe或-N(Rd)Re-,其中Rd和Re独立地选自烷基、烯基、炔基、芳基、芳基烷基、氨基甲酸酯、环烷基、卤代烷基、杂芳基、杂环基和氢。氨基可通过氮连接至母体分子基团。氨基也可以是环状的,例如Rd和Re中的任何两个可连接在一起或与N连接以形成3至12元环(例如,吗啉代或哌啶基)。术语氨基还包括任何氨基的相应季铵盐。示例性氨基包括烷基氨基,其中Rd或Re中的至少一个是烷基。在一些实施方案中,Rd和Re各自可任选地被羟基、卤素、烷氧基、酯或氨基取代。As used herein, the term "amine" or "amino" refers to the form -NRdRe or -N( Rd ) Re- , wherein Rd and Re are independently selected from alkyl, alkenyl , alkynyl, aryl, arylalkyl, carbamate, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl and hydrogen. The amino group can be connected to the parent molecular group through nitrogen. The amino group can also be cyclic, for example, any two of Rd and Re can be connected together or connected to N to form a 3 to 12-membered ring (for example, morpholino or piperidinyl). The term amino also includes the corresponding quaternary ammonium salt of any amino group. Exemplary amino groups include alkylamino groups, wherein at least one of Rd or Re is an alkyl group. In some embodiments, Rd and Re can each be optionally substituted by hydroxyl, halogen, alkoxy, ester or amino.

如本文所用的术语“芳基”是指单-、双-或其它多碳环、芳香族环系统。芳基可任选地稠合至选自芳基、环烷基和杂环基中的一种或多个环。本公开的芳基可被选自烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺和硫酮的基团取代。示例性芳基包括但不限于,苯基、甲苯基、蒽基、芴基、茚基、薁基和萘基,以及苯并稠合碳环部分如5,6,7,8-四氢萘基。示例性芳基还包括但不限于单环芳香族环系统,其中环包含6个碳原子,在本文中被称为“(C6)芳基”。As used herein, the term "aryl" refers to a mono-, bi- or other polycyclic, aromatic ring system. The aryl group may optionally be fused to one or more rings selected from aryl, cycloalkyl and heterocyclyl. The aryl groups of the present disclosure may be substituted with groups selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thione. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Exemplary aryl groups also include, but are not limited to, monocyclic aromatic ring systems wherein the ring contains 6 carbon atoms, referred to herein as "(C 6 )aryl".

如本文所用的术语“芳基烷基”是指具有至少一个芳基取代基的烷基(例如,-芳基-烷基-)。示例性芳基烷基包括但不限于,具有单环芳香族环系统的芳基烷基,其中环包含6个碳原子,在本文中被称为“(C6)芳基烷基”。As used herein, the term "arylalkyl" refers to an alkyl group having at least one aryl substituent (e.g., -aryl-alkyl-). Exemplary arylalkyl groups include, but are not limited to, arylalkyl groups having a monocyclic aromatic ring system, wherein the ring contains 6 carbon atoms, referred to herein as "(C 6 )arylalkyl".

如本文所用的术语“氨基甲酸酯”是指形式-RgOC(O)N(Rh)-、-RgOC(O)N(Rh)Ri-或-OC(O)NRhRi,其中Rg、Rh和Ri各自独立地选自烷基、烯基、炔基、芳基、芳基烷基、环烷基、卤代烷基、杂芳基、杂环基和氢。示例性氨基甲酸酯包括但不限于,芳基氨基甲酸酯或杂芳基氨基甲酸酯(例如,其中Rg、Rh和Ri中的至少一个独立地选自芳基或杂芳基,如吡啶、哒嗪、嘧啶和吡嗪)。As used herein, the term "carbamate" refers to a group of the form -RgOC (O)N( Rh )-, -RgOC (O)N( Rh ) Ri- , or -OC(O) NRhRi , wherein Rg , Rh , and Ri are each independently selected from alkyl, alkenyl, alkynyl, aryl, arylalkyl, cycloalkyl, haloalkyl, heteroaryl, heterocyclyl, and hydrogen. Exemplary carbamates include, but are not limited to, arylcarbamates or heteroarylcarbamates (e.g., wherein at least one of Rg , Rh , and Ri is independently selected from aryl or heteroaryl, such as pyridine, pyridazine, pyrimidine, and pyrazine).

如本文所用的术语“碳环”是指芳基或环烷基。The term "carbocycle" as used herein refers to an aryl group or a cycloalkyl group.

如本文所用的术语“羧基”是指-COOH或其相应羧酸盐(例如,-COONa)。术语羧基还包括“羧基羰基”,例如连接至羰基的羧基,例如,-C(O)-COOH或盐,如-C(O)-COONa。As used herein, the term "carboxyl" refers to -COOH or its corresponding carboxylate (e.g., -COONa). The term carboxyl also includes "carboxycarbonyl," such as a carboxyl group attached to a carbonyl, e.g., -C(O)-COOH or a salt such as -C(O)-COONa.

术语“氰基”如本文所用是指-CN.The term "cyano" as used herein refers to -CN.

如本文所用的术语“环烷氧基”是指连接至氧的环烷基。The term "cycloalkoxy" as used herein refers to a cycloalkyl group attached to an oxygen.

如本文所用的术语“环烷基”是指衍生自环烷烃的3-12个碳或3-8个碳的饱和或不饱和环、双环或桥联双环烃基,在本文中被称为“(C3-C8)环烷基”。示例性环烷基包括但不限于,环己烷、环己烯、环戊烷和环戊烯。环烷基可被烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺和硫酮取代。环烷基可稠合至其它环烷基、饱和或不饱和的芳基或杂环基。As used herein, the term "cycloalkyl" refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon radical of 3-12 carbon atoms or 3-8 carbon atoms derived from a cycloalkane, referred to herein as a "( C3 - C8 )cycloalkyl". Exemplary cycloalkyl radicals include, but are not limited to, cyclohexane, cyclohexene, cyclopentane, and cyclopentene. Cycloalkyl radicals may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione. Cycloalkyl radicals may be fused to other cycloalkyl radicals, saturated or unsaturated aryl radicals, or heterocyclyl radicals.

如本文所用的术语“二羧酸”是指含有至少两个羧酸基团的基团,如饱和和不饱和烃二羧酸及其盐。示例性二羧酸包括烷基二羧酸。二羧酸可被烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、氢、羟基、酮、硝基、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺和硫酮取代。二羧酸包括但不限于琥珀酸、戊二酸、己二酸、辛二酸、癸二酸、壬二酸、马来酸、邻苯二甲酸、天冬氨酸、谷氨酸、丙二酸、富马酸,(+)/(-)-苹果酸、(+)/(-)酒石酸、间苯二甲酸和对苯二甲酸。二羧酸还包括其羧酸衍生物,如酸酐、酰亚胺、酰肼(例如,琥珀酸酐和琥珀酰亚胺)。As used herein, term " dicarboxylic acid " refers to the group containing at least two carboxylic acid groups, such as saturated and unsaturated hydrocarbon dicarboxylic acids and salts thereof. Exemplary dicarboxylic acids include alkyl dicarboxylic acids. Dicarboxylic acids can be replaced by alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclic radical, hydrogen, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Dicarboxylic acids include but are not limited to succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, toxilic acid, phthalic acid, aspartic acid, glutamic acid, malonic acid, fumaric acid, (+)/(-)-malic acid, (+)/(-) tartaric acid, isophthalic acid and terephthalic acid. The dicarboxylic acid also includes its carboxylic acid derivatives such as anhydrides, imides, and hydrazides (eg, succinic anhydride and succinimide).

术语“酯”是指结构-C(O)O-、-C(O)O-Rj-、-RkC(O)O-Rj-或-RkC(O)O-,其中O未结合至氢,并且Rj和Rk可独立地选自烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、环烷基、醚、卤代烷基、杂芳基和杂环基。Rk可以是氢,但Rj不可能是氢。酯可以是环状的,例如碳原子和Rj、氧原子和Rk或Rj和Rk可连接以形成3至12元环。示例性酯包括但不限于烷基酯,其中Rj或Rk中的至少一个是烷基,如-O-C(O)-烷基、-C(O)-O-烷基-和-烷基-C(O)-O-烷基。示例性酯还包括芳基或杂芳基酯,例如其中Rj或Rk中的至少一个是杂芳基,如吡啶、哒嗪、嘧啶和吡嗪,如烟酸酯。示例性酯还包括具有结构-RkC(O)O-的反酯,其中氧结合至母体分子。示例性反酯包括琥珀酸酯、D-精氨酸酯、L-精氨酸酯、L-赖氨酸酯和D-赖氨酸酯。酯还包括羧酸酐和酰基卤。The term "ester" refers to the structure -C(O)O-, -C(O)O- Rj- , -RkC (O)O-Rj- , or -RkC (O)O-, wherein O is not bonded to a hydrogen, and Rj and Rk can be independently selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, cycloalkyl, ether, haloalkyl, heteroaryl, and heterocyclyl. Rk can be hydrogen, but Rj cannot be hydrogen. Esters can be cyclic, for example, a carbon atom and Rj, an oxygen atom and Rk , or Rj and Rk can be linked to form a 3- to 12-membered ring. Exemplary esters include, but are not limited to, alkyl esters in which at least one of Rj or Rk is an alkyl group, such as -OC(O)-alkyl, -C(O)-O-alkyl-, and -alkyl-C(O)-O-alkyl. Exemplary esters also include aryl or heteroaryl esters, for example, where at least one of Rj or Rk is a heteroaryl group, such as pyridine, pyridazine, pyrimidine, and pyrazine, such as nicotinate. Exemplary esters also include reverse esters having the structure -RkC (O)O-, where the oxygen is bound to the parent molecule. Exemplary reverse esters include succinate, D-arginine ester, L-arginine ester, L-lysine ester, and D-lysine ester. Esters also include carboxylic anhydrides and acyl halides.

如本文所用的术语“卤代”或“卤素”是指F、Cl、Br或I。As used herein, the term "halo" or "halogen" refers to F, Cl, Br, or I.

如本文所用的术语“卤代烷基”是指被一个或多个卤素原子取代的烷基。“卤代烷基”还涵盖被一个或多个卤素原子取代的烯基或炔基。As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms."Haloalkyl" also encompasses alkenyl or alkynyl groups substituted with one or more halogen atoms.

如本文所用的术语“杂芳基”是指含有一个或多个杂原子例如1-3个杂原子如氮、氧和硫的单环、双环或其他多环芳香族环系统。杂芳基可被包括烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺和硫酮的一个或多个取代基取代。杂芳基也可稠合至非芳香族环。杂芳基的说明性实例包括但不限于,吡啶基、哒嗪基、嘧啶基、吡嗪基(pyrazyl)、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-和(1,2,4)-三唑基、吡嗪基、嘧啶基(pyrimidilyl)、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、呋喃基、苯基、异噁唑基和噁唑基。示例性杂芳基包括但不限于单环芳香族环,其中环包含2-5个碳原子和1-3个杂原子,在本文中被称为“(C2-C5)杂芳基”。As used herein, the term "heteroaryl" refers to a monocyclic, bicyclic or other polycyclic aromatic ring system containing one or more heteroatoms, for example 1-3 heteroatoms such as nitrogen, oxygen and sulfur. Heteroaryl can be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide and thioketone. Heteroaryl can also be fused to a non-aromatic ring. Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, pyrimidilyl, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, furanyl, phenyl, isoxazolyl, and oxazolyl. Exemplary heteroaryl groups include, but are not limited to, monocyclic aromatic rings wherein the ring contains 2-5 carbon atoms and 1-3 heteroatoms, referred to herein as "(C 2 -C 5 )heteroaryl".

如本文所用的术语“杂环”、“杂环基”或“杂环的”是指含有一个、两个或三个独立地选自氮、氧和硫的杂原子的饱和或不饱和的3、4、5、6或7元环。杂环可以是芳香族的(杂芳基)或非芳香族的。杂环可被包括烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、硝基、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺和硫酮的一个或多个取代基取代。杂环还包括双环、三环和四环基团,其中任何上述杂环稠合至一个或两个独立地选自芳基、环烷基和杂环的环。示例性杂环包括吖啶基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、生物素基、噌啉基、二氢呋喃基、二氢吲哚基、二氢吡喃基、二氢噻吩基、二噻唑基、呋喃基、高哌啶基、咪唑烷基、咪唑啉基、咪唑基、吲哚基、异喹啉基、异噻唑烷基、异噻唑基、异噁唑烷基、异噁唑基、吗啉基、噁二唑基、噁唑烷基、噁唑基、哌嗪基、哌啶基、吡喃基、吡唑烷基、吡嗪基、吡唑基、吡唑啉基、哒嗪基、吡啶基、嘧啶基(pyrimidinyl)、嘧啶基(pyrimidyl)、吡咯烷基、吡咯烷-2-酮基、吡咯啉基、吡咯基、喹啉基、喹喔啉基(quinoxaloyl)、四氢呋喃基、四氢异喹啉基、四氢吡喃基、四氢喹啉基、四唑基、噻二唑基、噻唑烷基、噻唑基、噻吩基、硫代吗啉基、噻喃基(thiopyranyl)和三唑基。As used herein, the terms "heterocycle," "heterocyclyl," or "heterocyclic" refer to saturated or unsaturated 3-, 4-, 5-, 6-, or 7-membered rings containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocycle may be aromatic (heteroaryl) or non-aromatic. The heterocycle may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thione. Heterocycles also include bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles are fused to one or two rings independently selected from aryl, cycloalkyl, and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, biotinyl, cinnolinyl, dihydrofuranyl, dihydroindolinyl, dihydropyranyl, dihydrothiophenyl, dithiazolyl, furanyl, homopiperidinyl, imidazolidinyl, imidazolinyl, imidazolyl, indolyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, isoxazolidinyl, isoxazolidinyl, morpholinyl, oxadiazolyl, oxazolidinyl, oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazine 1-Hydroxy, ...

如本文所用的术语“羟基(hydroxy)”和“羟基(hydroxyl)”是指-OH。As used herein, the terms "hydroxy" and "hydroxyl" refer to -OH.

如本文所用的术语“羟基烷基”是指连接至烷基的羟基。The term "hydroxyalkyl" as used herein refers to a hydroxy group attached to an alkyl group.

如本文所用的术语“羟基芳基”是指连接至芳基的羟基。The term "hydroxyaryl" as used herein refers to a hydroxy group attached to an aryl group.

如本文所用的术语“酮”是指结构-C(O)-Rn(如乙酰基、-C(O)CH3)或-Rn-C(O)-Ro-。酮可通过Rn或Ro连接至另一基团。Rn或Ro可以是烷基、烯基、炔基、环烷基、杂环基或芳基,或Rn或Ro可连接以形成3至12元环。As used herein, the term "ketone" refers to the structure -C(O)-Rn (e.g., acetyl, -C(O) CH3 ) or -Rn- C(O) -R0- . The ketone can be attached to another group through Rn or R0 . Rn or R0 can be an alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or aryl, or Rn or R0 can be attached to form a 3- to 12-membered ring.

如本文所用的术语“单酯”是指二羧酸的类似物,其中一个羧酸被官能为酯并且另一个羧酸是游离羧酸或羧酸的盐。单酯的实例包括但不限于,琥珀酸、戊二酸、己二酸、辛二酸、癸二酸、壬二酸、草酸和马来酸的单酯。As used herein, the term "monoester" refers to an analog of a dicarboxylic acid in which one carboxylic acid is functionalized as an ester and the other carboxylic acid is a free carboxylic acid or a salt of a carboxylic acid. Examples of monoesters include, but are not limited to, monoesters of succinic acid, glutaric acid, adipic acid, suberic acid, sebacic acid, azelaic acid, oxalic acid, and maleic acid.

如本文所用的术语“苯基”是指6元碳环芳香族环。苯基也可稠合至环己烷或环戊烷环。苯基可被包括烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺和硫酮的一个或多个取代基取代。As used herein, the term "phenyl" refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be fused to a cyclohexane or cyclopentane ring. The phenyl group may be substituted with one or more substituents including alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone.

如本文所用的术语“硫代烷基”是指连接至硫的烷基(-S-烷基-)。The term "thioalkyl" as used herein refers to an alkyl group attached to a sulfur (-S-alkyl-).

“烷基”、“烯基”、“炔基”、“烷氧基”、“氨基”和“酰胺”基团可任选地被至少一个选自烷氧基、芳氧基、烷基、烯基、炔基、酰胺、氨基、芳基、芳基烷基、氨基甲酸酯、羰基、羧基、氰基、环烷基、酯、醚、甲酰基、卤素、卤代烷基、杂芳基、杂环基、羟基、酮、磷酸酯、硫化物、亚磺酰基、磺酰基、磺酸、磺酰胺、硫酮、脲基和N的基团取代、间断或分支。取代基可分支以形成取代的或未取代的杂环或环烷基。"Alkyl," "alkenyl," "alkynyl," "alkoxy," "amino," and "amide" groups may be optionally substituted, interrupted, or branched with at least one group selected from alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carbonyl, carboxyl, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxy, ketone, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, thione, urea, and N. The substituents may be branched to form substituted or unsubstituted heterocyclic or cycloalkyl groups.

如本文所用,任选取代的取代基上的适合的取代是指不抵消本公开的化合物或用于制备化合物的中间体的合成或药物效用的基团。适合的取代的实例包括但不限于:C1-8烷基、烯基或炔基;C1-6芳基、C2-5杂芳基;C37环烷基;C1-8烷氧基;C6芳氧基;-CN;-OH;氧代;卤代、羧基;氨基,如-NH(C1-8烷基)、-N(C1-8烷基)2、-NH((C6)芳基)或-N((C6)芳基)2;甲酰基;酮,如-CO(C1-8烷基)、-CO((C6芳基)酯,如-CO2(C1-8烷基)和-CO2(C6芳基)。本领域的技术人员可基于本公开的化合物的稳定性和药理学活性以及合成活性容易地选择适合的取代。As used herein, suitable substitutions on optionally substituted substituents refer to groups that do not counteract the synthetic or pharmaceutical utility of the compounds of the present disclosure or the intermediates used to prepare the compounds. Examples of suitable substitutions include, but are not limited to, C 1-8 alkyl, alkenyl, or alkynyl; C 1-6 aryl, C 2-5 heteroaryl; C 37 cycloalkyl; C 1-8 alkoxy; C 6 aryloxy; -CN; -OH; oxo; halo, carboxyl; amino, such as -NH(C 1-8 alkyl), -N(C 1-8 alkyl) 2 , -NH((C 6 ) aryl) or -N((C 6 ) aryl) 2 ; formyl; ketone, such as -CO(C 1-8 alkyl), -CO((C 6 aryl) ester, such as -CO 2 (C 1-8 alkyl) and -CO 2 (C 6 aryl). Those skilled in the art can readily select suitable substitutions based on the stability and pharmacological activity of the compounds of the present disclosure and the synthetic activity.

如本文所用的术语“药学上可接受的载体”是指与药物施用相容的任何和所有溶剂、分散介质、包衣剂、等渗剂和吸收延迟剂等。使用此类介质和试剂用于药物活性物质是本领域中熟知的。组合物还可包含提供补足、另外或增强的治疗功能的其它活性化合物。As used herein, the term "pharmaceutically acceptable carrier" refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The composition may also contain other active compounds that provide complementary, additional, or enhanced therapeutic functions.

如本文所用的术语“药学上可接受的组合物”是指包含与一种或多种药学上可接受的载体一起配制的至少一种如本文所公开的化合物的组合物。As used herein, the term "pharmaceutically acceptable composition" refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

如本文所用的术语“药学上可接受的前药”表示在合理医学判断范围内适合用于与人和低等动物的组织相接触,而无不当毒性、刺激、过敏反应、与合理的益处/风险比相称并且对于其意图用途来说有效的本公开的化合物的那些前药以及本公开的化合物的(在可能的情况下)两性离子形式。论述提供于Higuchi等人,“Prodrugs as Novel DeliverySystems,”ACS Symposium Series,第14卷,和Roche,E.B.,编辑Bioreversible Carriersin Drug Design,American Pharmaceutical Association and Pergamon Press,1987中,这两个文献均以引用的方式并入本文。As used herein, the term "pharmaceutically acceptable prodrugs" refers to those prodrugs of the compounds of the present disclosure, and where possible, zwitterionic forms of the compounds of the present disclosure, that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. A discussion is provided in Higuchi et al., "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, and Roche, E.B., ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

术语“药学上可接受的盐”是指可存在于本发明组合物中使用的化合物中的酸性或碱性基团的盐。本发明组合物中包含的本质上为碱性的化合物能够与各种无机酸和有机酸形成各种各样的盐。可用于制备这类碱性化合物的药学上可接受的酸加成盐的酸是形成无毒酸加成盐的那些,即含有药理学上可接受的阴离子的盐,包括但不限于硫酸盐、柠檬酸盐、苹果酸盐、乙酸盐、草酸盐、氯化物盐、溴化物盐、碘化物盐、硝酸盐、硫酸盐、硫酸氢盐、磷酸盐、酸式磷酸盐、异烟酸盐、乙酸盐、乳酸盐、水杨酸盐、柠檬酸盐、酒石酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐和双羟萘酸盐(即,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))。除以上提到的酸之外,包含氨基部分的包括于本组合物中的化合物可与多种氨基酸形成药学上可接受的盐。本发明组合物中包含的本质上为酸性的化合物能够与各种药学上可接受的阳离子形成碱式盐。这类盐的实例包括碱金属盐和碱土金属盐并且,具体地,钙盐、镁盐、钠盐、锂盐、锌盐、钾盐以及铁盐。The term "pharmaceutically acceptable salts" refers to salts of acidic or basic groups that may be present in the compounds used in the compositions of the present invention. Compounds included in the compositions of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, sulfate, citrate, malate, acetate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)). In addition to the acids mentioned above, compounds included in the present compositions that contain an amino moiety can form pharmaceutically acceptable salts with a variety of amino acids. The compounds that are acidic in nature and included in the compositions of the present invention are capable of forming basic salts with various pharmaceutically acceptable cations. Examples of such salts include alkali metal salts and alkaline earth metal salts and, in particular, calcium salts, magnesium salts, sodium salts, lithium salts, zinc salts, potassium salts and iron salts.

本公开的化合物可含有一个或多个手性中心和/或双键,并且因此作为立体异构体,如几何异构体、对映体或非对映体而存在。本文所用术语“立体异构体”由所有的几何异构体、对映体和非对映体组成。这些化合物可取决于在立体异构碳原子周围的取代基构型,由符号“R”或“S”来指定。本公开涵盖这些化合物的多种立体异构体及其混合物。立体异构体包括对映体和非对映体。对映体或非对映体的混合物在命名法中可被指定为“(±)”,但是熟练技术人员将认识到,一个结构可隐含地表示一个手性中心。The compounds of the present disclosure may contain one or more chiral centers and/or double bonds and therefore exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. As used herein, the term "stereoisomer" is comprised of all geometric isomers, enantiomers and diastereomers. These compounds may be designated by the symbols "R" or "S" depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses a variety of stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. A mixture of enantiomers or diastereomers may be designated as "(±)" in nomenclature, but a skilled artisan will recognize that a structure may implicitly represent a chiral center.

可从含有不对称或立构中心的可商购起始材料合成地制备、或通过制备外消旋混合物随后进行本领域普通技术人员熟知的拆分方法来制备本公开的化合物的单个立体异构体。这些拆分方法由以下来例示:(1)将对映体混合物连接至手性助剂,通过再结晶或色谱法来分离所得非对映体混合物,并且从助剂释放光学纯产物,(2)采用光学活性拆分剂来形成盐,或(3)在手性液相色谱柱上直接分离光学对映体的混合物。立体异构混合物还可通过熟知的方法,如手性相气相色谱法、手性相高效液相色谱法、使化合物结晶为手性盐复合物或在手性溶剂中结晶化合物来拆分成其组分立体异构体。还可通过熟知的不对称合成方法从立体异构纯中间体、试剂和催化剂中获得立体异构体。Individual stereoisomers of the compounds of the present disclosure can be prepared synthetically from commercially available starting materials containing asymmetric or stereogenic centers, or by preparing racemic mixtures followed by resolution methods well known to those skilled in the art. These resolution methods are exemplified by (1) coupling the enantiomeric mixture to a chiral auxiliary, separating the resulting diastereomeric mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary, (2) employing an optically active resolving agent to form a salt, or (3) directly separating the mixture of optical enantiomers on a chiral liquid chromatography column. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods such as chiral gas chromatography, chiral high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Stereoisomers can also be obtained from stereoisomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

几何异构体也可存在于本公开的化合物中。本公开涵盖由碳-碳双键周围的取代基布置或在碳环周围的取代基布置所得到的各种几何异构体及其混合物。在碳-碳双键周围的取代基被指定为处于“Z”或“E”构型,其中术语“Z”和“E”根据IUPAC标准来使用。除非另有规定,描绘双键的结构涵盖E和Z异构体二者。Geometric isomers may also exist in the compounds of the present disclosure. The present disclosure encompasses various geometric isomers and mixtures thereof resulting from the arrangement of substituents around carbon-carbon double bonds or around carbocyclic rings. Substituents around carbon-carbon double bonds are designated as being in "Z" or "E" configurations, where the terms "Z" and "E" are used according to IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both E and Z isomers.

在碳-碳双键周围的取代基可替代地可被称为“顺式”或“反式”,其中“顺式”表示在双键的同侧上的取代基,而“反式”表示在双键的相对侧上的取代基。在碳环周围的取代基布置被指定为“顺式”或“反式”。术语“顺式”表示在环的平面的同侧上的取代基,而术语“反式”表示在环的平面的相对侧上的取代基。其中取代基被布置在环的平面的同侧和相对侧上的化合物的混合物被指定为“顺式/反式”。Substituents around a carbon-carbon double bond may alternatively be referred to as "cis" or "trans," where "cis" refers to substituents on the same side of the double bond, and "trans" refers to substituents on opposite sides of the double bond. The arrangement of substituents around a carbon ring is designated as "cis" or "trans." The term "cis" refers to substituents on the same side of the plane of the ring, while the term "trans" refers to substituents on opposite sides of the plane of the ring. A mixture of compounds in which substituents are arranged on both the same and opposite sides of the plane of the ring is designated "cis/trans."

本文公开的化合物可作为互变异构体存在并且两种互变异构形式均意图由本公开的范围所涵盖,虽然仅描绘一种互变异构结构。The compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the present disclosure, even though only one tautomeric structure is depicted.

本发明的示例性实施方案Exemplary embodiments of the present invention

本发明提供化合物和包含那些化合物中的一种或多种的药物组合物,其中所述化合物的结构由式Ia、式Ib、式IIa和/或式IIb定义:The present invention provides compounds and pharmaceutical compositions comprising one or more of those compounds, wherein the structure of the compound is defined by Formula Ia, Formula Ib, Formula IIa and/or Formula IIb:

或其立体异构体、互变异构体、药学上可接受的盐或水合物,or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof,

其中:in:

A选自任选取代的稠合于环B的5-或-6元单环杂环,A is selected from an optionally substituted 5- or 6-membered monocyclic heterocycle fused to ring B,

条件是A不能为取代的或未取代的Provided that A cannot be substituted or unsubstituted

B为六元芳族碳环或杂环;B is a six-membered aromatic carbocyclic ring or heterocyclic ring;

Y选自N和C;Y is selected from N and C;

W1选自N和CR1W 1 is selected from N and CR 1 ;

W2选自N和CR2W 2 is selected from N and CR 2 ;

W3选自N和CR3W 3 is selected from N and CR 3 ;

W4和W5,如果存在的话,独立地选自N、CH和C; W4 and W5 , if present, are independently selected from N, CH and C;

W1、W2和W3可以彼此相同或不同;W 1 , W 2 and W 3 may be the same as or different from each other;

X选自-NH-、–CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2O-、-CH2CH2NH-、-CH2CH2S-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-、-CH2C(O)-、-CH2CH2C(O)-、-C(O)NH-、-C(O)O-、-C(O)S-、-C(O)NHCH2-、-C(O)OCH2-、-C(O)SCH2-、-CH(OH)-和–CH(CH3)-,其中一个或多个氢可独立地被氘、羟甲基、卤素、-CF3、酮替代,且其中S可被氧化成亚砜或砜;X is selected from -NH-, -CH2- , -CH2CH2- , -CH2CH2CH2- , -CH2CH2O- , -CH2CH2NH- , -CH2CH2S-, -C ( O ) -, -C( O) CH2- , -C(O)CH2CH2-, -CH2C(O)-, -CH2CH2C (O ) -, -C(O) NH-, -C ( O) O- , -C (O)S- , -C(O)NHCH2-, -C(O)OCH2-, -C(O) SCH2- , -CH(OH)-, and -CH( CH3 )-, wherein one or more hydrogens can be independently replaced by deuterium, hydroxymethyl, halogen, -CF3 , ketone, and wherein S can be oxidized to form a sulfoxide or sulfone ;

R4选自3-7元碳环和杂环; R4 is selected from 3-7 membered carbocyclic and heterocyclic rings;

D1选自5-元单环杂环,其中D1经由为D1环内双键的部分的碳原子连接至B环。D 1 is selected from a 5-membered monocyclic heterocycle, wherein D 1 is connected to the B ring via a carbon atom that is part of the double bond within the D 1 ring.

R1和R2独立地选自氢、氘、烷基、-OH、-NH2、-硫代烷基、烷氧基、酮、酯、羧酸、脲、氨基甲酸酯、氨基、酰胺、卤素、砜、亚砜、硫化物、磺酰胺和–CN;R 1 and R 2 are independently selected from hydrogen, deuterium, alkyl, —OH, —NH 2 , -alkylthio, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, sulfone, sulfoxide, sulfide, sulfonamide, and —CN;

R3选自氢、-NH2、-CN、-N3、卤素、氘、-NO2、-OMe、-OEt、-NHC(O)Me、NHSO2Me、环氨基、环酰胺基、-OH、-SO2Me、-SO2Et、-CH2NH2、-C(O)NH2和-C(O)OMe;R 3 is selected from hydrogen, -NH 2 , -CN, -N 3 , halogen, deuterium, -NO 2 , -OMe, -OEt, -NHC(O)Me, NHSO 2 Me, cyclic amino, cyclic amido, -OH, -SO 2 Me, -SO 2 Et, -CH 2 NH 2 , -C(O)NH 2 , and -C(O)OMe;

条件是如果R3为氢且A为5-元环,则D1不能为Provided that if R 3 is hydrogen and A is a 5-membered ring, then D 1 cannot be

并且条件是如果D1为且R2和R3为氢且R1为–OMe,则A-B双环不为and provided that if D 1 is and R 2 and R 3 are hydrogen and R 1 is –OMe, then the AB bicyclic ring is not

并且条件是如果D1为且R1、R2、R3中的每一个为氢,则A-B双环不为and provided that if D 1 is and each of R 1 , R 2 , and R 3 is hydrogen, then the AB bicyclic ring is not

除非B环是被取代的;Unless the B ring is substituted;

并且条件是如果R1、R2、R3中的每一个为氢,则A-B双环不为and provided that if each of R 1 , R 2 , and R 3 is hydrogen, then the AB bicyclic ring is not

并且条件是如果R1、R2、R3中的每一个为氢,则A-B双环不为and provided that if each of R 1 , R 2 , and R 3 is hydrogen, then the AB bicyclic ring is not

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物的A环任选地被Z取代,其中Z选自氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6)。在一些实施方案中,Z选自In some embodiments, the A ring of the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is optionally substituted with Z, wherein Z is selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NH pyridinyl, -NH heterocycle(C 4 -C 6 ), -NH carbocycle(C 4 -C 6 )), alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ), and alkoxy(C 1 -C 6 ). In some embodiments, Z is selected from

-Me、-CF3、-Et、CH3CH2O-、CF3CH2-、SMe、-SOMe、-SO2Me、-CN、-Me, -CF 3 , -Et, CH 3 CH 2 O-, CF 3 CH 2 -, SMe, -SOMe, -SO 2 Me, -CN,

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物选自In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如NH(C1-C5)、碳环(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、杂环(C4-C6)、碳环(C4-C6)、卤素、-CN、-OH、-CF3、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6);其中X、R4和D1如对于本文公开的任何实施方案所定义。It may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH2 , amino (such as NH( C1 - C5 ), carbocycle( C1 - C5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle( C4 - C6 ), -NHcarbocycle(C4-C6)), heterocycle( C4 - C6 ), carbocycle( C4 - C6 ), halogen, -CN, -OH, -CF3 , alkyl( C1 - C6 ), thioalkyl( C1 - C6 ), alkenyl( C1 - C6 ), and alkoxy( C1 - C6 ); wherein X, R4 , and D1 are as defined for any embodiment disclosed herein.

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物选自In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6)、杂环(C4-C6)、碳环(C4-C6)、卤素、-CN、-OH、-CF3、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6);其中X、R4和D1如对于本文公开的任何实施方案所定义。Which may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 6 ), -NHcarbocycle(C 4 -C 6 ), heterocycle(C 4 -C 6 ), carbocycle(C 4 -C 6 ), halogen, -CN, -OH, -CF 3 , alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ); wherein X, R 4 and D 1 are as defined for any embodiment disclosed herein.

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物选自In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、杂环(C4-C6)、碳环(C4-C6)、卤素、-CN、-OH、-CF3、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6);其中X、R4和D1如对于本文公开的任何实施方案所定义。It may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 6 ), -NHcarbocycle(C 4 -C 6 )), heterocycle(C 4 -C 6 ), carbocycle(C 4 -C 6 ), halogen, -CN, -OH, -CF 3 , alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ); wherein X, R 4 and D 1 are as defined for any embodiment disclosed herein.

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物选自In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、杂环(C4-C6)、碳环(C4-C6)、卤素、-CN、-OH、-CF3、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6);其中X、R4和D1的定义如对于本文公开的任何实施方案所定义。It may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 6 ), -NHcarbocycle(C 4 -C 6 )), heterocycle(C 4 -C 6 ), carbocycle(C 4 -C 6 ), halogen, -CN, -OH, -CF 3 , alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ); wherein X, R 4 and D 1 are as defined for any embodiment disclosed herein.

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物选自In some embodiments, the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

其中Z选自氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6);羧基;wherein Z is selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 6 ), -NHcarbocycle(C 4 -C 6 )), alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ); carboxyl;

D1 D1 is

X选自–CH2-和–CH(CH3)-;以及X is selected from -CH 2 - and -CH(CH 3 )-; and

R4为苯基环,其任选地被独立地选自一个或多个独立地选自氘、烷基(C1-C4)、烷氧基(C1-C4)、卤素、-CF3、CN和-硫代烷基(C1-C4)的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。R 4 is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C 1 -C 4 ), alkoxy (C 1 -C 4 ), halogen, -CF 3 , CN and -thioalkyl (C 1 -C 4 ), wherein each alkyl, alkoxy and thioalkyl may be optionally substituted with F, Cl or Br.

在某些实施方案中,R4为苯基环,其任选地被一个或多个选自甲基、乙基、丙基、异丙基和丁基的烷基(C1-C4);选自甲氧基、乙氧基和异丙氧基的烷氧基(C1-C4);选自F和Cl的卤素;和选自–SMe、-SEt、-SPr和–Sbu的硫代烷基(C1-C4)取代。In certain embodiments, R 4 is a phenyl ring optionally substituted with one or more alkyl (C 1 -C 4 ) selected from methyl, ethyl, propyl, isopropyl, and butyl; alkoxy (C 1 -C 4 ) selected from methoxy, ethoxy, and isopropoxy; halogen selected from F and Cl; and thioalkyl (C 1 -C 4 ) selected from —SMe, —SEt , —SPr , and —Sbu.

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的A-B双环选自In some embodiments, the A-B bicyclic ring in the compound of any of Formulas Ia, Ib, IIa, or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

其中Z选自氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6)。wherein Z is selected from hydrogen, deuterium, -NH 2 , amino (such as —NH(C 1 -C 5 ), —N(C 1 -C 5 ) 2 , —NHPh, —NHBn, —NHpyridyl, —NHheterocycle(C 4 -C 6 ), —NHcarbocycle(C 4 -C 6 )), alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ).

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的A-B双环选自In some embodiments, the A-B bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的A-B双环选自但不限于In some embodiments, the A-B bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from but not limited to

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代。It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 7 ), -NHcarbocycle(C 4 -C 7 )), heterocycle(C 4 -C 7 ), carbocycle(C 4 -C 7 ), halogen, -CN, -OH, -CF 3 , sulfone, sulfoxide, alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ), alkoxy(C 1 -C 6 ), ketone(C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide(C 1 -C 6 ), oxo, and thio-oxo.

在式Ia、式Ib、式IIa和式IIb中的任一式、或其立体异构体、互变异构体、药学上可接受的盐或水合物的一些实施方案中,A-B双环选自In some embodiments of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, the A-B bicyclic ring is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代。It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 7 ), -NHcarbocycle(C 4 -C 7 )), heterocycle(C 4 -C 7 ), carbocycle(C 4 -C 7 ), halogen, -CN, -OH, -CF 3 , sulfone, sulfoxide, alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ), alkoxy(C 1 -C 6 ), ketone(C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide(C 1 -C 6 ), oxo, and thio-oxo.

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的A-B双环选自In some embodiments, the A-B bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代。It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 7 ), -NHcarbocycle(C 4 -C 7 )), heterocycle(C 4 -C 7 ), carbocycle(C 4 -C 7 ), halogen, -CN, -OH, -CF 3 , sulfone, sulfoxide, alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ), alkoxy(C 1 -C 6 ), ketone(C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide(C 1 -C 6 ), oxo, and thio-oxo.

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物的A-B双环选自In some embodiments, the A-B bicyclic ring of the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、磺酰胺、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代。It may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 7 ), -NHcarbocycle(C 4 -C 7 )), heterocycle(C 4 -C 7 ), carbocycle(C 4 -C 7 ), halogen, -CN, -OH, -CF 3 , sulfone, sulfoxide, sulfonamide, alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ), alkoxy(C 1 -C 6 ), ketone(C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide(C 1 -C 6 ), oxo, and thio-oxo.

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的A-B双环选自其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、磺酰胺、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代。In some embodiments, the AB bicyclic ring in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from the group which may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH2 , amino (such as -NH( C1 - C5 ), -N( C1 - C5 ) 2 , -NHPh, -NHBn, -NHpyridinyl, -NHheterocycle( C4 - C7 ), -NHcarbocycle( C4 - C7 )), heterocycle( C4 -C7), carbocycle( C4 - C7 ), halogen, -CN, -OH, -CF3 , sulfone, sulfoxide, sulfonamide, alkyl( C1 - C6 ), thioalkyl( C1 - C6 ), alkenyl( C1 - C6 ), alkoxy( C1 - C6 ) , ketone(C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide (C 1 -C 6 ), oxo, and thio-oxo.

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的A环选自稠合于B环的5-元杂环。In some embodiments, the A ring in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-membered heterocyclic ring fused to the B ring.

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的Y为氮。In some embodiments, Y in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

在一些实施方案中,式I、式Ia或式II中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1选自5-元单环杂环,诸如但不限于:In some embodiments, D1 in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-membered monocyclic heterocycle, such as, but not limited to:

其任选地被氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、-COOH和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。It is optionally replaced by hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl (C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl (C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,式Ia、Ib、IIa或IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1为单环杂环,其任选地被氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、-COOH和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, D1 in the compound of any of Formulas Ia, Ib, IIa or IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is a monocyclic heterocycle, which is optionally substituted by hydrogen, deuterium, alkyl ( C1 - C4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( C1 - C4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH2 , -NHMe, -NHEt, -NHiPr, -NHBu- NMe2 , NMeEt, -NEt2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O) NEt2 , -C(O)NiPr), -CF3 , CN, -N3 , ketone ( C1 -C4), -C (O)Pr), -S(O)alkyl(C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl(C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl(C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1选自含有一个氧和一个或两个氮的5-元单环杂环,其中所述杂环经由碳-碳键连接于所述分子的剩余部分,且其任选地被氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、-COOH和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, D1 in the compound of any of Formula Ia, Ib, IIa and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from a 5-membered monocyclic heterocycle containing one oxygen and one or two nitrogens, wherein the heterocycle is attached to the remainder of the molecule via a carbon-carbon bond and is optionally substituted by hydrogen, deuterium, alkyl ( C1 - C4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( C1 - C4 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH2 , -NHMe, -NHEt, -NHiPr, -NHBu- NMe2 , NMeEt, -NEt2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt2 , , -C(O)NiPr), -CF3 , CN, -N3 , ketone ( C1 - C4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl ( C1 - C4 ) (such as -S(O)Me, -S(O)Et), -SO2alkyl ( C1 - C4 ) (such as -SO2Me , -SO2Et , -SO2Pr ), -thioalkyl ( C1 - C4 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1为任选地被以下取代的异噁唑:氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、-COOH和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu),所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, D1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is isoxazole optionally substituted with hydrogen, deuterium, alkyl (C1-C4) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( C1 - C4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH2, -NHMe, -NHEt, -NHiPr, -NHBu-NMe2, NMeEt, -NEt2, -NEtBu , -NHC(O ) NHalkyl), halogen (such as F , Cl), amide (such as -NHC( O) Me, -NHC(O ) Et, -C(O)NHMe, -C(O)NEt2, -C(O)NiPr), -CF3, CN, -N3, ketone (C1-C4), or a ketone (such as -NH2, -NHMe, -NHEt, -NHiPr , -NHBu-NMe2, NMeEt, -NEt2 , -NEtBu , -NHC(O)NHalkyl). -C 1 -C 4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl(C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl(C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl(C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), -COOH and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1选自5-元单环杂环,其任选地被氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基)取代,所述基团各自可任选地被氢、-OH、-F和–NH2取代。In some embodiments, D1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from a 5-membered monocyclic heterocycle, which is optionally substituted with hydrogen, deuterium, alkyl (C1-C4) (such as methyl, ethyl, propyl), each of which may be optionally substituted with hydrogen, -OH, -F and -NH2 .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1选自含有一个氧和一个或两个氮的5-元单环杂环,其中所述杂环经由碳-碳键连接于所述分子的剩余部分,且其任选地被氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基)取代,所述基团各自可任选地被以下取代:氢、-OH、-F和–NH2In some embodiments, D1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from a 5-membered monocyclic heterocycle containing one oxygen and one or two nitrogens, wherein the heterocycle is linked to the remainder of the molecule via a carbon-carbon bond and is optionally substituted with hydrogen, deuterium, alkyl ( C1 - C4 ) such as methyl, ethyl, propyl, each of which may be optionally substituted with hydrogen, -OH, -F and -NH2 .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1为异噁唑或吡唑,其任选地被氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基)取代,所述基团各自可任选地被以下取代:氢、-OH、-F和–NH2In some embodiments, D 1 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is isoxazole or pyrazole, optionally substituted with hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl), each of which may be optionally substituted with hydrogen, -OH, -F, and -NH 2 .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1为在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的D1为在一些实施方案中,式Ia、式Ib、式IIa和式IIb的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物的D1为In some embodiments, D1 in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is In some embodiments, D1 in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is In some embodiments, D1 in the compound of any of Formula Ia , Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W1为CR1In some embodiments, W 1 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CR 1 .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W2为CR2In some embodiments, W 2 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CR 2 .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W1和W2中的至少一个为氮。In some embodiments, at least one of W 1 and W 2 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W1为CH。In some embodiments, W 1 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CH.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W2为CR2,其中R2选自氢、氘、-OH、-NH2、甲基、卤素和-CN。In some embodiments, W2 in the compound of any of Formula Ia, Ib, IIa, and IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is CR2 , wherein R2 is selected from hydrogen, deuterium, -OH, -NH2 , methyl, halogen, and -CN.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W2为CH。In some embodiments, W 2 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CH.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W4和W5为碳。In some embodiments, W 4 and W 5 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, are carbon.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W4和W5中的至少一个为氮。In some embodiments, at least one of W 4 and W 5 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W3为氮。In some embodiments, W 3 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is nitrogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的W3为CR3,其中R3选自氢、-NH2和卤素。In some embodiments, W 3 in the compound of any of Formula Ia, Ib, IIa, and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is CR 3 , wherein R 3 is selected from hydrogen, —NH 2 , and halogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R3选自氢和-NH2In some embodiments, R 3 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from hydrogen and -NH 2 .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R3为–NH2In some embodiments, R 3 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is —NH 2 .

在一些实施方案中,在式I、式Ia或式II中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的X选自–CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2O-、-CH2CH2NH-、-CH2CH2S-、-C(O)-、-C(O)NH-、-C(O)O-、-C(O)S-,其中一个或多个氢可独立地被氘、卤素替代,且其中S可被氧化成亚砜或砜。In some embodiments, X in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer , pharmaceutically acceptable salt, or hydrate thereof , is selected from -CH2- , -CH2CH2-, -CH2CH2CH2- , -CH2CH2O-, -CH2CH2NH-, -CH2CH2S-, -C (O ) -, -C(O) NH- , -C(O ) O-, -C(O)S-, wherein one or more hydrogens can be independently replaced by deuterium, halogen, and wherein S can be oxidized to a sulfoxide or sulfone.

在一些实施方案中,式I、式Ia或式II中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的X选自–CH2-和–C(O)-。In some embodiments, X in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from —CH 2 — and —C(O)—.

在一些实施方案中,X选自–CH2-、-CH(CH3)-、-CH(OH)-、-NH-、CH2CH2-,其中一个或多个氢可独立地被氘或卤素替代。In some embodiments, X is selected from -CH2- , -CH(CH3)-, -CH(OH)-, -NH-, CH2CH2- , wherein one or more hydrogens may be independently replaced by deuterium or halogen.

在一些实施方案中,X选自–CH2-、CH(CH3)-和–NH-,其中一个或多个氢可独立地被氘或卤素替代。In some embodiments, X is selected from -CH2- , CH( CH3 )-, and -NH-, wherein one or more hydrogens may be independently replaced by deuterium or halogen.

在一些实施方案中,X选自–CH2-、-CH(CH3)-,其中一个或多个氢可独立地被氘或卤素替代。In some embodiments, X is selected from -CH2- , -CH( CH3 )-, wherein one or more hydrogens may be independently replaced by deuterium or halogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的X为–CH2-。In some embodiments, X in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is -CH2- .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R1选自氢、氘、烷基、-OH、-NH2、-硫代烷基、烷氧基、酮、酯、羧酸、脲、氨基甲酸酯、氨基、酰胺、卤素、碳环、杂环、砜、亚砜、硫化物、磺酰胺和–CN。In some embodiments, R 1 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from hydrogen, deuterium, alkyl, —OH, —NH 2 , -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and —CN.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R2选自氢、氘、烷基、-OH、-NH2、-硫代烷基、烷氧基、酮、酯、羧酸、脲、氨基甲酸酯、氨基、酰胺、卤素、碳环、杂环、砜、亚砜、硫化物、磺酰胺和–CN。In some embodiments, R2 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from hydrogen, deuterium, alkyl, -OH, -NH2 , -thioalkyl, alkoxy, ketone, ester, carboxylic acid, urea, carbamate, amino, amide, halogen, carbocycle, heterocycle, sulfone, sulfoxide, sulfide, sulfonamide, and -CN.

在一些实施方案中,式I、式Ia中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R1和R2独立地选自氢、氘、烷基、-NH2、-硫代烷基、烷氧基、氨基、酰胺、卤素、碳环、杂环和–CN。In some embodiments, R 1 and R 2 in the compound of any of Formula I, Formula Ia, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof are independently selected from hydrogen, deuterium, alkyl, -NH 2 , -thioalkyl, alkoxy, amino, amide, halogen, carbocycle, heterocycle, and -CN.

在一些实施方案中,式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R1和R2独立地选自氢、氘、烷基(C1-C6)、-NH2、-硫代烷基(C1-C6)、烷氧基(C1-C6)、氨基和酰胺。In some embodiments, R 1 and R 2 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, are independently selected from hydrogen, deuterium, alkyl (C 1 -C 6 ), -NH 2 , -thioalkyl (C 1 -C 6 ), alkoxy (C 1 -C 6 ), amino and amide.

在一些实施方案中,R1和R2为氢。In some embodiments, R 1 and R 2 are hydrogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R1、R2和R3中的至少一个不为氢。In some embodiments, at least one of R 1 , R 2 , and R 3 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb , or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is not hydrogen.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自5-6元碳环和杂环。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-6 membered carbocyclic ring and a heterocyclic ring.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自5-6元杂环。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-6 membered heterocycle.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自含有1或2个氮的5-6元杂环,诸如未取代的和取代的嘧啶基环,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from a 5-6 membered heterocyclic ring containing 1 or 2 nitrogen atoms, such as unsubstituted and substituted pyrimidinyl rings, which are optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl (C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl (C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自含有至少一个氮的6-元杂环,诸如未取代的和取代的吡啶基环,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from a 6-membered heterocyclic ring containing at least one nitrogen, such as unsubstituted and substituted pyridyl rings, which are optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl (C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl (C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式I、式Ia或式II中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自In some embodiments, R 4 in the compound of any of Formula I, Formula Ia, or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4为异噁唑或吡唑,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is isoxazole or pyrazole, which is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 -C(O)OEt, -C(O) OBu ) , each of which may be optionally substituted with hydrogen, F , Cl , Br , -OH , -NH 2 , -NHMe, -OMe, -SMe , oxo and/or thio-oxo .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自含有一个或两个氮的5-元杂环。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-membered heterocyclic ring containing one or two nitrogens.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自5-6元碳环,诸如苯基环,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from a 5-6 membered carbocyclic ring, such as a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropoxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 -C(O) OBu ) , each of which may be optionally substituted with hydrogen , F , Cl , Br , -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio -oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4为苯基环,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O )Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr , -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), -C (O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen , F , Cl, Br, -OH, -NH 2 , -NHMe , -OMe, -SMe, oxo and/or thio - oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自芳基,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from aryl, which is optionally independently selected from hydrogen, deuterium, alkyl ( C1 - C4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy ( C1 - C4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH2 , -NHMe, -NHEt, -NHiPr, -NHBu- NMe2 , NMeEt, -NEt2, -NEtBu , -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O) NEt2 , -C(O)NiPr), -CF3 , CN, -N3 , ketone (C1-C4), ... -C (O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen , F , Cl, Br, -OH, -NH 2 , -NHMe , -OMe, -SMe, oxo and/or thio - oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中,-X-R4选自–CH2芳基。In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, -XR 4 is selected from -CH 2 aryl.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自吡啶基,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is selected from pyridinyl, which is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 -C(O)OEt, -C(O) OBu ) , each of which may be optionally substituted with hydrogen, F , Cl , Br , -OH , -NH 2 , -NHMe, -OMe, -SMe , oxo and/or thio-oxo .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) -C(O)OEt, -C( O ) OBu ) , each of which may be optionally substituted with hydrogen , F , Cl , Br , -OH, -NH2, -NHMe, -OMe, -SMe, oxo and/or thio-oxo .

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自5-6元碳环。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is selected from a 5-6 membered carbocyclic ring.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4选自低级环烷基(C3-C6)和苯基环,其任选地任选地被一个或多个独立地选自氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基和丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基和异丙氧基)、卤素(诸如F和Cl)、-CF3、CN和-硫代烷基(C1-C4)(诸如,例如,–SMe、-SEt、-SPr和–Sbu)的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。In some embodiments, R4 in the compound of any of Formula Ia, Formula Ib, Formula IIa and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts or hydrates thereof, is selected from lower cycloalkyl ( C3 - C6 ) and phenyl rings, which are optionally optionally substituted with one or more groups independently selected from deuterium, alkyl ( C1 - C4 ) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C1- C4 ) (such as methoxy, ethoxy and isopropoxy), halogen (such as F and Cl), -CF3 , CN and -thioalkyl ( C1 - C4 ) (such as, for example, -SMe, -SEt, -SPr and -Sbu), wherein each of the alkyl, alkoxy and thioalkyl groups may be optionally substituted with F, Cl or Br.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4为苯基环,其任选地被一个或多个独立地选自氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基和丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基和异丙氧基)、卤素(诸如F和Cl)、-CF3、CN和-硫代烷基(C1-C4)(诸如,例如,–SMe、-SEt、-SPr和–Sbu)的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, and butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, and isopropoxy), halogen (such as F and Cl), —CF 3 , CN, and -thioalkyl (C 1 -C 4 ) (such as, for example, —SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl, or Br.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的R4为芳基,其任选地被一个或多个独立地选自氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基和丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基和异丙氧基)、卤素(诸如F和Cl)、-CF3、CN和-硫代烷基(C1-C4)(诸如,例如,–SMe、-SEt、-SPr和–Sbu)的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。In some embodiments, R 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, is aryl, which is optionally substituted with one or more groups independently selected from deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, and butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, and isopropoxy), halogen (such as F and Cl), —CF 3 , CN, and -thioalkyl (C 1 -C 4 ) (such as, for example, —SMe, —SEt, —SPr, and —Sbu), wherein each alkyl, alkoxy, and thioalkyl may be optionally substituted with F, Cl, or Br.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中,A-B双环选自In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclic ring is selected from

其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代;which may be optionally substituted with groups independently selected from the group consisting of hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 7 ), -NHcarbocycle(C 4 -C 7 )), heterocycle(C 4 -C 7 ), carbocycle(C 4 -C 7 ), halogen, -CN, -OH, -CF 3 , sulfone, sulfoxide, alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ), alkoxy(C 1 -C 6 ), ketone(C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide(C 1 -C 6 ), oxo, and thio-oxo;

D1 D1 is

X选自–CH2-和–C(O)-;X is selected from -CH 2 - and -C(O)-;

R4为苯基环,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。R 4 is a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl (C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl (C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中,A-B双环选自其可任选地被独立地选自以下的基团取代:氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C7)、-NH碳环(C4-C7))、杂环(C4-C7)、碳环(C4-C7)、卤素、-CN、-OH、-CF3、砜、亚砜、磺酰胺、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)、烷氧基(C1-C6)、酮(C1-C6)、酯、脲、羧酸、氨基甲酸酯、酰胺(C1-C6)、氧代和硫代-氧代。In some embodiments, in the compound of any of Formula Ia, Ib, IIa and IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt or hydrate thereof, the AB bicyclic ring is selected from the group which may be optionally substituted with groups independently selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NH pyridyl, -NH heterocycle (C 4 -C 7 ), -NH carbocycle (C 4 -C 7 )), heterocycle (C 4 -C 7 ), carbocycle (C 4 -C 7 ), halogen, -CN, -OH, -CF 3 , sulfone, sulfoxide, sulfonamide, alkyl (C 1 -C 6 ), thioalkyl (C 1 -C 6 ), alkenyl (C 1 -C 6 ), alkoxy (C 1 -C 6 ), ), ketone (C 1 -C 6 ), ester, urea, carboxylic acid, carbamate, amide (C 1 -C 6 ), oxo, and thio-oxo.

D1 D1 is

X选自–CH2-、–CH(CH3)-、–CH(OH)-和–NH-;X is selected from -CH 2 -, -CH(CH 3 )-, -CH(OH)-, and -NH-;

R4为苯基环,其任选地被独立地选自氢、氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基、丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基、异丙氧基)、氨基(诸如–NH2、-NHMe、-NHEt、-NHiPr、-NHBu-NMe2、NMeEt、-NEt2、-NEtBu、-NHC(O)NH烷基)、卤素(诸如F、Cl)、酰胺(诸如-NHC(O)Me、-NHC(O)Et、-C(O)NHMe、-C(O)NEt2、-C(O)NiPr)、-CF3、CN、-N3、酮(C1-C4)(诸如乙酰基、-C(O)Et、-C(O)Pr)、-S(O)烷基(C1-C4)(诸如-S(O)Me、-S(O)Et)、-SO2烷基(C1-C4)(诸如–SO2Me、-SO2Et、-SO2Pr)、-硫代烷基(C1-C4)(诸如–SMe、-SEt、-SPr、-SBu)、羧基(诸如-COOH)和/或酯(诸如–C(O)OMe、-C(O)OEt、-C(O)OBu)的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。R 4 is a phenyl ring, which is optionally independently selected from hydrogen, deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl, butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy, isopropyloxy), amino (such as -NH 2 , -NHMe, -NHEt, -NHiPr, -NHBu-NMe 2 , NMeEt, -NEt 2 , -NEtBu, -NHC(O)NHalkyl), halogen (such as F, Cl), amide (such as -NHC(O)Me, -NHC(O)Et, -C(O)NHMe, -C(O)NEt 2 , -C(O)NiPr), -CF 3 , CN, -N 3 , ketone (C 1 -C 4 ) (such as acetyl, -C(O)Et, -C(O)Pr), -S(O)alkyl (C 1 -C 4 ) (such as -S(O)Me, -S(O)Et), -SO 2 alkyl (C 1 -C 4 ) (such as -SO 2 Me, -SO 2 Et, -SO 2 Pr), -thioalkyl (C 1 -C 4 ) (such as -SMe, -SEt, -SPr, -SBu), carboxyl (such as -COOH) and/or ester (such as -C(O)OMe, -C(O)OEt, -C(O)OBu), each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中的-X-R4为–CH2芳基。In some embodiments, -XR 4 in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, is -CH 2 aryl.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中,A-B双环选自In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclic ring is selected from

其中Z选自氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6)、羧基;wherein Z is selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 6 ), -NHcarbocycle(C 4 -C 6 )), alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ), carboxyl;

D1为并且D 1 is and

X选自–CH2-和–CH(CH3)-;以及X is selected from -CH 2 - and -CH(CH 3 )-; and

R4为苯基环,其任选地被独立地选自一个或多个独立地选自氘、烷基(C1-C4)、烷氧基(C1-C4)、卤素、-CF3、CN和-硫代烷基(C1-C4)的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。R 4 is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C 1 -C 4 ), alkoxy (C 1 -C 4 ), halogen, -CF 3 , CN and -thioalkyl (C 1 -C 4 ), wherein each alkyl, alkoxy and thioalkyl may be optionally substituted with F, Cl or Br.

在一些实施方案中,在式Ia、式Ib、式IIa和式IIb中的任一式的化合物或其立体异构体、互变异构体、药学上可接受的盐或水合物中,A-B双环选自In some embodiments, in the compound of any of Formula Ia, Formula Ib, Formula IIa, and Formula IIb, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, the A-B bicyclic ring is selected from

其中Z选自氢、氘、-NH2、氨基(诸如–NH(C1-C5)、-N(C1-C5)2、-NHPh、-NHBn、-NH吡啶基、-NH杂环(C4-C6)、-NH碳环(C4-C6))、烷基(C1-C6)、硫代烷基(C1-C6)、烯基(C1-C6)和烷氧基(C1-C6);羧基;wherein Z is selected from hydrogen, deuterium, -NH 2 , amino (such as -NH(C 1 -C 5 ), -N(C 1 -C 5 ) 2 , -NHPh, -NHBn, -NHpyridyl, -NHheterocycle(C 4 -C 6 ), -NHcarbocycle(C 4 -C 6 )), alkyl(C 1 -C 6 ), thioalkyl(C 1 -C 6 ), alkenyl(C 1 -C 6 ) and alkoxy(C 1 -C 6 ); carboxyl;

D1 D1 is

X选自–CH2-和–CH(CH3)-;以及X is selected from -CH 2 - and -CH(CH 3 )-; and

R4为苯基环,其任选地被一个或多个独立地选自氘、烷基(C1-C4)(诸如甲基、乙基、丙基、异丙基和丁基)、烷氧基(C1-C4)(诸如甲氧基、乙氧基和异丙氧基)、卤素(诸如F和Cl)、-CF3、CN和-硫代烷基(C1-C4)(诸如,例如,–SMe、-SEt、-SPr和–Sbu)的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。R 4 is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, alkyl (C 1 -C 4 ) (such as methyl, ethyl, propyl, isopropyl and butyl), alkoxy (C 1 -C 4 ) (such as methoxy, ethoxy and isopropyloxy), halogen (such as F and Cl), —CF 3 , CN and -thioalkyl (C 1 -C 4 ) (such as, for example, —SMe, —SEt, —SPr and —Sbu), wherein each alkyl, alkoxy and thioalkyl may be optionally substituted with F, Cl or Br.

在本发明的某些实施方案中,式I、式Ia或式II的化合物选自:In certain embodiments of the present invention, the compound of Formula I, Formula Ia, or Formula II is selected from:

9-苄基-2-(3,5-二甲基异噁唑-4-基)-9H-嘌呤-6-胺;9-Benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine;

3-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

4-(3-苄基-3H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

4-(1-苄基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

3-苄基-5-(3,5-二甲基异噁唑-4-基)苯并[d]噁唑-2(3H)-酮;3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-7-胺;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine;

N,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺;N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-苄基-7-(3,5-二甲基异噁唑-4-基)喹喔啉-2(1H)-酮;和1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one; and

1-苄基-7-(3,5-二甲基异噁唑-4-基)-3,4-二氢喹唑啉-2(1H)-酮.1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one.

在本发明的某些实施方案中,式I、式Ia或式II的化合物选自:In certain embodiments of the present invention, the compound of Formula I, Formula Ia, or Formula II is selected from:

9-苄基-2-(3,5-二甲基异噁唑-4-基)-9H-嘌呤-6-胺;9-Benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine;

3-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

4-(3-苄基-3H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

4-(1-苄基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

3-苄基-5-(3,5-二甲基异噁唑-4-基)苯并[d]噁唑-2(3H)-酮;3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-7-胺;1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine;

N,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺;N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-苄基-7-(3,5-二甲基异噁唑-4-基)喹喔啉-2(1H)-酮;1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one;

1-苄基-7-(3,5-二甲基异噁唑-4-基)-3,4-二氢喹唑啉-2(1H)-酮;1-Benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one;

4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

4-(1-(环丙基甲基)-2-甲基-4-硝基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑;4-(1-(cyclopropylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one;

4-氨基-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮;4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-乙氧基-1H-苯并[d]咪唑-4-胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-乙基-4-硝基-1H-苯并[d]咪唑-2-胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N2-乙基-1H-苯并[d]咪唑-2,4-二胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1H-benzo[d]imidazole-2,4-diamine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-羧酸甲酯;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid methyl ester;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-甲酰胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide

4-(氨基甲基)-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮4-(Aminomethyl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

5-(3,5-二甲基异噁唑-4-基)-N-苯基-1H-吡咯并[3,2-b]吡啶-3-胺5-(3,5-Dimethylisoxazol-4-yl)-N-phenyl-1H-pyrrolo[3,2-b]pyridin-3-amine

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-3-甲基-1H-吡唑并[4,3-b]吡啶4-氧化物6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine 4-oxide

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-3-甲基-1H-吡唑并[4,3-b]吡啶-5(4H)-酮6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5(4H)-one

4-(3-苄基-3H-咪唑并[4,5-b]吡啶-5-基)-3,5-二甲基异噁唑4-(3-Benzyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,5-dimethylisoxazole

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-1H-苯并[d]咪唑-4-胺6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-N-甲基-1H-苯并[d]咪唑-4-胺6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-benzo[d]imidazol-4-amine

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-N,N-二甲基-1H-苯并[d]咪唑-4-胺6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N,N-dimethyl-1H-benzo[d]imidazol-4-amine

3,5-二甲基-4-(1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(1-苄基-1H-咪唑并[4,5-c]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-c]吡啶5-氧化物1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridine 5-oxide

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-c]吡啶-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine

4-(1-苄基-3-溴-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-3-bromo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醛1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde

1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)乙酮1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-5-基甲酸酯1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-ylcarboxylate

4-((6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲酰胺4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzamide

4-(1-苄基-3-硝基-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-3-nitro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

3,5-二甲基-4-(3-(4-(三氟甲基)苄基)-3H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(3-(4-(trifluoromethyl)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)isoxazole

3,5-二甲基-4-(1-(4-(三氟甲基)苄基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(1-(4-(trifluoromethyl)benzyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(3-(4-氯苄基)-3H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(3-(4-chlorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-氯苄基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-chlorobenzyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(3-(4-氟苄基)-3H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(3-(4-fluorobenzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-氟苄基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

3,5-二甲基-4-(3-(吡啶-2-基甲基)-3H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridin-6-yl)isoxazole

3,5-二甲基-4-(1-(吡啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(1-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(1-(4-氟苄基)-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-Fluorobenzyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-氟苄基)-1H-吡咯并[2,3-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-Fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(5-(4-氟苄基)-5H-吡咯并[2,3-b]吡嗪-3-基)-3,5-二甲基异噁唑4-(5-(4-Fluorobenzyl)-5H-pyrrolo[2,3-b]pyrazin-3-yl)-3,5-dimethylisoxazole

4-(1-(4-氟苄基)-1H-吡唑并[4,3-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-Fluorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-1H-吡咯并[2,3-b]吡啶-4-胺6-(3,5-Dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridin-4-amine

4-(1-(4-氟苄基)-3-甲基-1H-吡唑并[4,3-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-Fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吲唑-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-indazol-4-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-5(4H)-酮1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5(4H)-one

3-((5-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)氨基)苄腈3-((5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)amino)benzonitrile

4-(1-(4-氟苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-苄基-2-乙氧基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-ethoxy-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-((6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)-3,5-二甲基异噁唑4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)-3,5-dimethylisoxazole

4-(1-(2,4-二氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-甲氧基苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(环丙基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(cyclopropylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-基)乙酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)acetamide

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-基)乙磺酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)ethanesulfonamide

4-(1-苄基-4-甲氧基-2-甲基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-4-methoxy-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

7-氨基-3-苄基-5-(3,5-二甲基异噁唑-4-基)苯并[d]噁唑-2(3H)-酮7-amino-3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one

3,5-二甲基-4-(2-甲基-1-(吡啶-3-基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(2-methyl-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

3,5-二甲基-4-(2-甲基-1-(噻吩-2-基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(2-methyl-1-(thien-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-((6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苄腈4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile

4-(1-苄基-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)-N,N-二甲基甲胺1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[2,3-b]吡啶-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-4-amine

3,5-二甲基-4-(2-甲基-1-(吡啶-4-基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(2-methyl-1-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-胺1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

3,5-二甲基-4-(2-甲基-1-((5-甲基噻吩-2-基)甲基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(2-methyl-1-((5-methylthien-2-yl)methyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

4-(1-((5-氯噻吩-2-基)甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-((5-chlorothien-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

5-((6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)噻吩-2-甲腈5-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)thiophene-2-carbonitrile

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-1H-咪唑并[4,5-b]吡啶4-氧化物6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridine 4-oxide

乙酸6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-1H-咪唑并[4,5-b]吡啶-5-基酯6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-5-yl acetate

1-苄基-6-(1,4-二甲基-1H-吡唑-5-基)-2-甲基-4-硝基-1H-苯并[d]咪唑1-Benzyl-6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-4-nitro-1H-benzo[d]imidazole

1-苄基-6-(1,4-二甲基-1H-吡唑-5-基)-2-甲基-1H-苯并[d]咪唑-4-胺1-Benzyl-6-(1,4-dimethyl-1H-pyrazol-5-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

4-(1-(4-氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-((6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯酚4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)phenol

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-甲腈1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carbonitrile

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-甲腈1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-吗啉代-1H-苯并[d]咪唑-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-morpholino-1H-benzo[d]imidazol-4-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲腈1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile

4-(1-苄基-3-氯-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-3-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-氨基-1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮4-Amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮1-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

4-(1-苄基-1H-吡唑并[4,3-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(4-氯苄基)-1H-吡唑并[4,3-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(4-chlorobenzyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-2-甲基-6-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-4-胺1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-4-amine

4-(1-(3,4-二氯苄基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(3,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

6-(3,5-二甲基异噁唑-4-基)-2-甲基-1-(1-苯乙基)-1H-苯并[d]咪唑-4-胺6-(3,5-Dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine

2-(氮杂环丁烷-1-基)-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺2-(azetidin-1-yl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine

3,5-二甲基-4-(1-(噻吩-3-基甲基)-1H-吡唑并[4,3-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(1-(thien-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)isoxazole

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)乙酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine

1-(3,4-二氯苄基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-(3,4-Dichlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-1H-吲唑-4-胺1-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-indazol-4-amine

6-(3,5-二甲基异噁唑-4-基)-1-(4-甲氧基苄基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(4-甲氧基苄基)-1H-苯并[d]咪唑-2(3H)-酮4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-2(3H)-one

1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-(4-Chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

6-(3,5-二甲基异噁唑-4-基)-1-(噻吩-2-基甲基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮6-(3,5-dimethylisoxazol-4-yl)-1-(thien-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-乙基-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine

3,5-二甲基-4-(2-甲基-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑3,5-Dimethyl-4-(2-methyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N2-(四氢-2H-吡喃-4-基)-1H-苯并[d]咪唑-2,4-二胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(tetrahydro-2H-pyran-4-yl)-1H-benzo[d]imidazole-2,4-diamine

6-(3,5-二甲基异噁唑-4-基)-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮6-(3,5-Dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)乙酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide

6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

6-(3,5-二甲基异噁唑-4-基)-N-乙基-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2-胺6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉4-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

4-(1-(环丁基甲基)-2-甲基-4-硝基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-(cyclobutylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(1-(环戊基甲基)-2-甲基-4-硝基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-(cyclopentylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-(乙氨基)-1H-苯并[d]咪唑-4-基)乙酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(ethylamino)-1H-benzo[d]imidazol-4-yl)acetamide

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-乙氧基-1H-苯并[d]咪唑-4-基)乙酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)acetamide

4-(1-苄基-4-溴-2-甲基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

3-苄基-5-(3,5-二甲基异噁唑-4-基)-1-乙基-1H-苯并[d]咪唑-2(3H)-酮3-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-1H-benzo[d]imidazol-2(3H)-one

4-(2-(氮杂环丁烷-1-基)-1-苄基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(2-(azetidin-1-yl)-1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-((5-氯噻吩-2-基)甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-((5-chlorothien-2-yl)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

(S)-3,5-二甲基-4-(2-甲基-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-6-基)异噁唑(S)-3,5-Dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole

(R)-3,5-二甲基-4-(2-甲基-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-6-基)异噁唑(R)-3,5-Dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole

6-(3,5-二甲基异噁唑-4-基)-N-乙基-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-2-胺6-(3,5-Dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine

4-(1-苄基-2-乙基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-ethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(4-羟基苄基)-1H-苯并[d]咪唑-2(3H)-酮4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2(3H)-one

N-(2-(氮杂环丁烷-1-基)-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-基)乙酰胺N-(2-(azetidin-1-yl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-yl)acetamide

1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-乙基-1H-咪唑并[4,5-b]吡啶-2-胺1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine

1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-胺1-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-胺1-(Cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine

6-(3,5-二甲基异噁唑-4-基)-N2-乙基-1-(1-苯乙基)-1H-苯并[d]咪唑-2,4-二胺6-(3,5-Dimethylisoxazol-4-yl)-N2-ethyl-1-(1-phenylethyl)-1H-benzo[d]imidazole-2,4-diamine

4-(1-苄基-4-硝基-2-(吡咯烷-1-基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-4-nitro-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(1-苄基-2-(4-甲基哌嗪-1-基)-4-硝基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-(4-methylpiperazin-1-yl)-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(2-甲氧基乙基)-4-硝基-1H-苯并[d]咪唑-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxyethyl)-4-nitro-1H-benzo[d]imidazol-2-amine

4-(1-苄基-2-环丙基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-cyclopropyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N2-(2-甲氧基乙基)-1H-苯并[d]咪唑-2,4-二胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(2-methoxyethyl)-1H-benzo[d]imidazole-2,4-diamine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-(吡咯烷-1-基)-1H-苯并[d]咪唑-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(pyrrolidin-1-yl)-1H-benzo[d]imidazol-4-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-4-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-4-amine

1-苄基-N6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4,6-二胺1-Benzyl-N6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4,6-diamine

(S)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1-(1-苯乙基)-1H-苯并[d]咪唑-4-胺(S)-6-(3,5-Dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine

(R)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1-(1-苯乙基)-1H-苯并[d]咪唑-4-胺(R)-6-(3,5-Dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine

1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine

N,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2-胺N,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-4-硝基-N-(吡啶-3-基甲基)-1H-苯并[d]咪唑-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-N-(pyridin-3-ylmethyl)-1H-benzo[d]imidazol-2-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-甲基-4-硝基-1H-苯并[d]咪唑-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-4-nitro-1H-benzo[d]imidazol-2-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-4-硝基-1H-苯并[d]咪唑-2(3H)-酮1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N2-甲基-1H-苯并[d]咪唑-2,4-二胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-methyl-1H-benzo[d]imidazole-2,4-diamine

N2,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2,4-二胺N2,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2,4-diamine

N,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺N,1-Dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine

1-苄基-2-甲基-6-(1-甲基-1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine

N-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑-4-胺N-(1-Benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol-4-amine

4-苄基-6-(3,5-二甲基异噁唑-4-基)-3,4-二氢喹喔啉-2(1H)-酮4-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinoxalin-2(1H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N2-(吡啶-3-基甲基)-1H-苯并[d]咪唑-2,4-二胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N2-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole-2,4-diamine

4-(1-苄基-4-氟-2-甲基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-4-fluoro-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-乙基-4-硝基-1H-苯并[d]咪唑-2-胺1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine

1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-N2-乙基-1H-苯并[d]咪唑-2,4-二胺1-(Cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N2-ethyl-1H-benzo[d]imidazole-2,4-diamine

4-氨基-1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮4-Amino-1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one

4-氨基-1-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-1H-苯并[d]咪唑-2(3H)-酮4-Amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-4-氟-1H-苯并[d]咪唑-2(3H)-酮1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-fluoro-1H-benzo[d]imidazol-2(3H)-one

N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)乙酰胺N-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide

4-(1-苄基-2-(4-甲基哌嗪-1-基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-(4-methylpiperazin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-苄基-6-(1-甲基-1H-吡唑-5-基)-3,4-二氢喹喔啉-2(1H)-酮4-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(2-甲氧基乙基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-methoxyethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(1-苄基-2-甲基-4-(甲磺酰基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-methyl-4-(methylsulfonyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(吡啶-4-基甲基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-4-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine

1-苄基-6-(1-甲基-1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

(S)-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮(S)-6-(3,5-Dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-醇1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-ol

(R)-4-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-3,4-二氢喹喔啉-2(1H)-酮(R)-4-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one

4-(1-苄基-6-(1-甲基-1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉4-(1-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

1-苄基-6-(1-甲基-1H-吡唑-5-基)-N-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(1-methyl-1H-pyrazol-5-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine

4-氨基-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-硫酮4-Amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione

(S)-4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮(S)-4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

(R)-4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮(R)-4-Amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one

1-苄基-6-(3,5-二甲基异噁唑-4-基)-7-甲基-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one

4-(1-苄基-2,7-二甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-基)吗啉4-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)morpholine

1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-基)氮杂环丁烷-2-酮1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-2-one

1-苄基-2-甲基-6-(1,3,5-三甲基-1H-吡唑-4-基)-1H-苯并[d]咪唑-4-胺1-Benzyl-2-methyl-6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1H-benzo[d]imidazol-4-amine

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(吡啶-3-基甲基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(4-溴-2-甲基-1-苯乙基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(4-Bromo-2-methyl-1-phenethyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(4-溴-2-甲基-1-(3-苯基丙基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(4-Bromo-2-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(7-溴-2-甲基-1-(3-苯基丙基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异噁唑4-(7-Bromo-2-methyl-1-(3-phenylpropyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole

4-(4-溴-2-甲基-1-(2-苯氧基乙基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑4-(4-Bromo-2-methyl-1-(2-phenoxyethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole

4-(7-溴-2-甲基-1-(2-苯氧基乙基)-1H-苯并[d]咪唑-5-基)-3,5-二甲基异噁唑4-(7-Bromo-2-methyl-1-(2-phenoxyethyl)-1H-benzo[d]imidazol-5-yl)-3,5-dimethylisoxazole

4-(1-(环己基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(cyclohexylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(环戊基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(cyclopentylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(环丁基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-(cyclobutylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(吡啶-2-基甲基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine

4-(1-苄基-2-(吡咯烷-1-基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-(pyrrolidin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

2-((1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)氨基)乙醇2-((1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)ethanol

1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-基)氮杂环丁烷-3-醇1-(1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-yl)azetidin-3-ol

1-苄基-3-甲基-6-(1-甲基-1H-吡唑-5-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮1-Benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one

4-氨基-1-苄基-3-甲基-6-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2(3H)-酮4-amino-1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one

(4-溴-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-1-基)(苯基)甲酮(4-Bromo-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-1-yl)(phenyl)methanone

1-苄基-2-甲基-6-(5-甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺1-Benzyl-2-methyl-6-(5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine

1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-(Cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮1-(Cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one

N-(1-苄基-3-甲基-6-(1-甲基-1H-吡唑-5-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)乙酰胺N-(1-Benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(4-甲氧基苄基)-1H-咪唑并[4,5-b]吡啶-2-胺1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridin-2-amine

1-苄基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-5-基)-1H-咪唑并[4,5-b]吡啶1-Benzyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazo[4,5-b]pyridine

4-((1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)氨基)环己醇4-((1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)cyclohexanol

4-(1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉4-(1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

4-(2-(氮杂环丁烷-1-基)-1-(环戊基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(2-(azetidin-1-yl)-1-(cyclopentylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

4-(1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉4-(1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine

4-(2-(氮杂环丁烷-1-基)-1-(环丁基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(2-(azetidin-1-yl)-1-(cyclobutylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

N1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)-N2,N2-二甲基乙烷-1,2-二胺N1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)-N2,N2-dimethylethane-1,2-diamine

4-(1-苄基-2-(哌嗪-1-基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑4-(1-Benzyl-2-(piperazin-1-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole

1-苄基-N-环戊基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-Benzyl-N-cyclopentyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(2-吗啉代乙基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-morpholinoethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

3-(((1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)氨基)甲基)苄腈;3-(((1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)methyl)benzonitrile;

(R)-6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;(R)-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

(S)-6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;(S)-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

4-(1-苄基-2-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-甲酰胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-carboxamide;

1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-(Cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

N1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)环己烷-1,4-二胺;N1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)cyclohexane-1,4-diamine;

1-苄基-N-(环己基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-Benzyl-N-(cyclohexylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(3-甲氧基丙基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(3-methoxypropyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(氧杂环丁烷-3-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(oxetan-3-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮;6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(吡嗪-2-基甲基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyrazin-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-((四氢-2H-吡喃-4-基)甲基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(2-(4-甲基哌嗪-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺;6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine;

1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-胺;1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-N-环己基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-Benzyl-N-cyclohexyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(1-甲基哌啶-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(1-methylpiperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine;

4-(1-苄基-2-(吡啶-3-基氧基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-2-(pyridin-3-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

1-((1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)氨基)-2-甲基丙-2-醇;1-((1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)amino)-2-methylpropan-2-ol;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(2-(吡咯烷-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(pyrrolidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(2-(哌啶-1-基)乙基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(2-(piperidin-1-yl)ethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

(R)-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮;(R)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one;

4-(1-苄基-7-甲氧基-2-(三氟甲基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(噻唑-2-基甲基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(thiazol-2-ylmethyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-甲脒;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboximidazole;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-甲酰胺;1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamide;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-((1-甲基哌啶-4-基)甲基)-1H-咪唑并[4,5-b]吡啶-2-胺;1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-((1-methylpiperidin-4-yl)methyl)-1H-imidazo[4,5-b]pyridin-2-amine;

1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)氮杂环丁烷-3-醇;1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)azetidin-3-ol;

4-(1-苄基-2-(吡啶-4-基氧基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑;4-(1-benzyl-2-(pyridin-4-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole;

1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(吡啶-3-基)-1H-苯并[d]咪唑-2-胺;和1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine; and

3-(1-苄基-1H-苯并[d]咪唑-6-基)-4-乙基-1H-1,2,4-三唑-5(4H)-酮;3-(1-Benzyl-1H-benzo[d]imidazol-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one;

或其立体异构体、互变异构体、盐或水合物。or a stereoisomer, tautomer, salt or hydrate thereof.

本发明的另一方面提供用于通过结合于溴结构域来抑制BET蛋白功能的方法,以及其在治疗和预防哺乳动物(例如,人)的疾病和病状中的用途,包括施用治疗有效量的式I、式Ia和/或式II的化合物。Another aspect of the present invention provides methods for inhibiting the function of BET proteins by binding to bromodomains, and their use in treating and preventing diseases and conditions in mammals (e.g., humans), comprising administering a therapeutically effective amount of a compound of Formula I, Formula Ia, and/or Formula II.

在一个实施方案中,由于BET抑制剂在体外对IL-6和IL-17转录的强效作用,式I、式Ia和/或式II的BET抑制剂化合物可用作IL-6和/或IL-17牵连在疾病中的炎症性病症的治疗剂。下列自身免疫性疾病由于IL-6和/或IL-17的显著作用而适于通过施用式I、式Ia和/或式II的化合物或式I、式Ia和/或式II的立体异构体、互变异构体、药学上可接受的盐或水合物抑制BET的治疗性作用:急性散播性脑脊髓炎(Ishizu,T.,等人,“CSF cytokineand chemokine profiles in acute disseminated encephalomyelitis,”JNeuroimmunol 175(1-2):52-8(2006))、无丙种球蛋白血症(Gonzalez-Serrano,M.E.,等人,”Increased Pro-inflammatory Cytokine Production After LipopolysaccharideStimulation in Patients with X-linked Agammaglobulinemia,”J Clin Immunol 32(5):967-74(2012))、变应性疾病(McKinley,L.,等人,“TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,”JImmunol 181(6):4089-97(2008))、强直性脊柱炎(Taylan,A.,等人,“Evaluation of theT helper 17axis in ankylosing spondylitis,”Rheumatol Int 32(8):2511-5(2012))、抗GBM/抗TBM肾炎(Ito,Y.,等人,“Pathogenic significance of interleukin-6in apatient with antiglomerular basement membrane antibody-inducedglomerulonephritis with multinucleated giant cells,”Am J Kidney Dis26(1):72-9(1995))、抗磷脂综合征(Soltesz,P.,等人,“Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction,”Rheumatology(Oxford)47(11):1628-34(2008))、自身免疫性再生障碍性贫血(Gu,Y.,等人,“Interleukin(IL)-17promotes macrophages to produce IL-8,IL-6and tumournecrosis factor-alpha in aplastic anaemia,”Br J Haematol 142(1):109-14(2008))、自身免疫性肝炎(Zhao,L.,等人,“Interleukin-17contributes to thepathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6expression,”PLoS One6(4):e18909(2011))、自身免疫性内耳疾病(Gloddek,B.,等人,“Pharmacological influence on inner ear endothelial cells in relation to thepathogenesis of sensorineural hearing loss,”Adv Otorhinolaryngol59:75-83(2002))、自身免疫性心肌炎(Yamashita,T.,等人,“IL-6-mediated Th17differentiation through RORgammat is essential for the initiation ofexperimental autoimmune myocarditis,”Cardiovasc Res 91(4):640-8(2011))、自身免疫性胰腺炎(Ni,J.,等人,”Involvement of Interleukin-17A in Pancreatic Damage inRat Experimental Acute Necrotizing Pancreatitis,”Inflammation(2012))、自身免疫性视网膜病变(Hohki,S.,等人,“Blockade of interleukin-6signaling suppressesexperimental autoimmune uveoretinitis by the inhibition of inflammatory Th17responses,”Exp Eye Res 91(2):162-70(2010))、自身免疫性血小板减少性紫癜(Ma,D.,等人,“Profile of Th17 cytokines(IL-17,TGF-beta,IL-6)and Th1 cytokine(IFN-gamma)in patients with immune thrombocytopenic purpura,”Ann Hematol 87(11):899-904(2008))、白塞氏病(Yoshimura,T.,等人,“Involvement of Th17 cells and theeffect of anti-IL-6therapy in autoimmune uveitis,”Rheumatology(Oxford)48(4):347-54(2009))、大疱性类天疱疮(D'Auria,L.,P.等人,“Cytokines and bullouspemphigoid,”Eur Cytokine Netw 10(2):123-34(1999))、卡斯特曼氏病(El-Osta,H.E.和R.Kurzrock,“Castleman's disease:from basic mechanisms to moleculartherapeutics,”Oncologist 16(4):497-511(2011))、乳糜泻(Lahdenpera,A.I.,等人,“Up-regulation of small intestinal interleukin-17immunity in untreatedcoeliac disease but not in potential coeliac disease or in type 1diabetes,”Clin Exp Immunol 167(2):226-34(2012))、丘-斯综合征(Fujioka,A.,等人,“Theanalysis of mRNA expression of cytokines from skin lesions in Churg-Strausssyndrome,”J Dermatol 25(3):171-7(1998))、克罗恩氏病(Holtta,V.,等人,“IL-23/IL-17immunity as a hallmark of Crohn's disease,”Inflamm Bowel Dis 14(9):1175-84(2008))、科根综合征(Shibuya,M.,等人,“Successful treatment with tocilizumab ina case of Cogan's syndrome complicated with aortitis,”Mod Rheumatol(2012))、干眼综合征(De Paiva,C.S.,等人,“IL-17disrupts corneal barrier followingdesiccating stress,”Mucosal Immunol 2(3):243-53(2009))、自发性混合冷球蛋白血症(Antonelli,A.,等人,“Serum levels of proinflammatory cytokines interleukin-1beta,interleukin-6,and tumor necrosis factor alpha in mixedcryoglobulinemia,”Arthritis Rheum 60(12):3841-7(2009))、皮肌炎(Chevrel,G.,等人,“Interleukin-17increases the effects of IL-1beta on muscle cells:argumentsfor the role of T cells in the pathogenesis of myositis,”J Neuroimmunol 137(1-2):125-33(2003))、德维克氏病(Linhares,U.C.,等人,“The Ex Vivo Production ofIL-6and IL-21by CD4(+)T Cells is Directly Associated with NeurologicalDisability in Neuromyelitis Optica Patients,”J Clin Immunol(2012))、脑炎(Kyburz,D.和M.Corr,“Th17 cells generated in the absence of TGF-beta induceexperimental allergic encephalitis upon adoptive transfer,”Expert Rev ClinImmunol7(3):283-5(2011))、嗜酸细胞性食管炎(Dias,P.M.和G.Banerjee,“The Role ofTh17/IL-17on Eosinophilic Inflammation,”J Autoimmun(2012))、嗜酸细胞性筋膜炎(Dias,P.M.和G.Banerjee,“The Role of Th17/IL-17on Eosinophilic Inflammation,”JAutoimmun(2012))、结节性红斑(Kahawita,I.P.和D.N.Lockwood,“Towardsunderstanding the pathology of erythema nodosum leprosum,”Trans R Soc TropMed Hyg102(4):329-37(2008))、巨细胞动脉炎(Deng,J.,等人,“Th17 and Th1 T-cellresponses in giant cell arteritis,”Circulation 121(7):906-15(2010))、肾小球性肾炎(Ooi,J.D.,等人,“Review:T helper 17cells:their role inglomerulonephritis,”Nephrology(Carlton)15(5):513-21(2010))、古德帕斯丘综合征(Ito,Y.,等人,“Pathogenic significance of interleukin-6in a patient withantiglomerular basement membrane antibody-induced glomerulonephritis withmultinucleated giant cells,”Am J Kidney Dis 26(1):72-9(1995))、具有多血管炎的肉芽肿病(韦格纳氏)(Nakahama,H.,等人,“Distinct responses of interleukin-6andother laboratory parameters to treatment in a patient with Wegener'sgranulomatosis,”Intern Med 32(2):189-92(1993))、格雷夫斯氏病(Kim,S.E.,等人,“Increased serum interleukin-17in Graves'ophthalmopathy,”Graefes Arch ClinExp Ophthalmol 250(10):1521-6(2012))、格林-巴利综合征(Lu,M.O.和J.Zhu,“The roleof cytokines in Guillain-Barre syndrome,”J Neurol 258(4):533-48(2011))、桥本氏甲状腺炎(Figueroa-Vega,N.,等人,“Increased circulating pro-inflammatorycytokines and Th17 lymphocytes in Hashimoto’s thyroiditis,”J Clin EndocrinolMetab 95(2):953-62(2009))、溶血性贫血(Xu,L.,等人,“Critical role of Th17 cellsin development of autoimmune hemolytic anemia,”Exp Hematol(2012))、亨-舍二氏紫癜(Jen,H.Y.,等人,“Increased seruminterleukin-17and peripheral Th17 cells inchildren with acute Henoch-Schonlein purpura,”Pediatr Allergy Immunol 22(8):862-8(2011))、IgA肾病(Lin,F.J.,等人,“Imbalance of regulatory T cells to Th17cells in IgA nephropathy,”Scand J Clin Lab Invest 72(3):221-9(2012))、包涵体肌炎(Baron,P.,等人,“Production of IL-6by human myoblasts stimulated with Abeta:relevance in the pathogenesis of IBM,”Neurology 57(9):1561-5(2001))、I型糖尿病(Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammationand cancer,”Nat Rev Cancer12(7):465-77(2012))、间质性膀胱炎(Lamale,L.M.,等人,“Interleukin-6,histamine,and methylhistamine as diagnostic markers for间质性膀胱炎,”Urology68(4):702-6(2006))、川崎病(Jia,S.,等人,“The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease,”Clin ExpImmunol 162(1):131-7(2010))、白细胞破碎性血管炎(Min,C.K.,等人,“Cutaneousleucoclastic vasculitis(LV)following bortezomib therapy in a myeloma patient;association with pro-inflammatory cytokines,”Eur J Haematol 76(3):265-8(2006))、扁平苔癣(Rhodus,N.L.,等人,“Proinflammatory cytokine levels in salivabefore and after treatment of(erosive)oral lichen planus with dexamethasone,”Oral Dis12(2):112-6(2006))、狼疮(SLE)(Mok,M.Y.,等人,“The relation ofinterleukin 17(IL-17)and IL-23to Th1/Th2 cytokines and disease activity insystemic lupus erythematosus,”J Rheumatol 37(10):2046-52(2010))、显微镜下多血管炎(Muller Kobold,A.C.,等人,“In vitro up-regulation of E-selectin andinduction of interleukin-6in endothelial cells by autoantibodies in Wegener'sgranulomatosis and microscopic polyangiitis,”Clin Exp Rheumatol 17(4):433-40(1999))、多发性硬化(Jadidi-Niaragh,F.和Mirshafiey A.,“Th17 cell,the new playerof neuroinflammatory process in multiple sclerosis,”Scand J Immunol 74(1):1-13(2011))、重症肌无力(Aricha,R.,等人,“Blocking of IL-6suppresses experimentalautoimmune myasthenia gravis,”J Autoimmun 36(2):135-41(2011))、肌炎(Chevrel,G.,等人,“Interleukin-17increases the effects of IL-1beta on muscle cells:arguments for the role of T cells in the pathogenesis of myositis,”JNeuroimmunol 137(1-2):125-33(2003))、视神经炎(Icoz,S.,等人,“Enhanced IL-6production in aquaporin-4antibody positive neuromyelitis optica patients,”Int J Neurosci 120(1):71-5(2010))、天疱疮(Lopez-Robles,E.,等人,“TNFalpha andIL-6are mediators in the blistering process of pemphigus,”Int J Dermatol 40(3):185-8(2001))、POEMS综合征(Kallen,K.J.,等人,“New developments in IL-6dependent biology and therapy:where do we stand and what are the options?”Expert Opin Investig Drugs 8(9):1327-49(1999))、结节性多动脉炎(Kawakami,T.,等人,“Serum levels of interleukin-6in patients with cutaneous polyarteritisnodosa,”Acta Derm Venereol 92(3):322-3(2012))、原发性胆汁性肝硬化(Harada,K.,等人,“Periductal interleukin-17production in association with biliary innateimmunity contributes to the pathogenesis of cholangiopathy in primary biliarycirrhosis,”Clin Exp Immunol 157(2):261-70(2009))、银屑病(Fujishima,S.,等人,“Involvement of IL-17F via the induction of IL-6in psoriasis,”Arch DermatolRes 302(7):499-505(2010))、银屑病性关节炎(Raychaudhuri,S.P.,等人,IL-17receptorand its functional significance in psoriatic arthritis,”Mol Cell Biochem 359(1-2):419-29(2012))、坏疽性脓皮病(Kawakami,T.,等人,“Reduction of interleukin-6,interleukin-8,and anti-phosphatidylserine-prothrombin complex antibody bygranulocyte and monocyte adsorption apheresis in a patient with pyodermagangrenosum and ulcerative colitis,”Am J Gastroenterol 104(9):2363-4(2009))、复发性多软骨炎(Kawai,M.,等人,“Sustained response to tocilizumab,anti-interleukin-6receptor antibody,in two patients with refractory relapsingpolychondritis,”Rheumatology(Oxford)48(3):318-9(2009))、类风湿性关节炎(Ash,Z.和P.Emery,“The role of tocilizumab in the management of rheumatoidarthritis,”Expert Opin Biol Ther,12(9):1277-89(2012))、结节病(Belli,F.,等人,“Cytokines assay in peripheral blood and bronchoalveolar lavage in thediagnosis and staging of pulmonary granulomatous diseases,”Int J ImmunopatholPharmacol13(2):61-67(2000))、硬皮病(Radstake,T.R.,等人,“The pronouncedTh17profile in systemic sclerosis(SSc)together with intracellular expressionof TGFbeta and IFNgamma distinguishes SSc phenotypes,”PLoS One,4(6):e5903(2009))、舍格伦综合征(Katsifis,G.E.,等人,“Systemic and local interleukin-17andlinked cytokines associated with Sjogren's syndrome immunopathogenesis,”Am JPathol 175(3):1167-77(2009))、高安动脉炎(Sun,Y.,等人,“MMP-9and IL-6arepotential biomarkers for disease activity in Takayasu's arteritis,”Int JCardiol 156(2):236-8(2012))、横贯性脊髓炎(Graber,J.J.,等人,“Interleukin-17intransverse myelitis and multiple sclerosis,”J Neuroimmunol 196(1-2):124-32(2008))、溃疡性结肠炎(Mudter,J.和M.F.Neurath,“Il-6signaling in inflammatorybowel disease:pathophysiological role and clinical relevance,”Inflamm BowelDis 13(8):1016-23(2007))、葡萄膜炎(Haruta,H.,等人,“Blockade of interleukin-6signaling suppresses not only th17 but also interphotoreceptor retinoidbinding protein-specific Th1 by promoting regulatory T cells in experimentalautoimmune uveoretinitis,”Invest Ophthalmol Vis Sci52(6):3264-71(2011))、以及白癜风(Bassiouny,D.A.和O.Shaker,“Role of interleukin-17in the pathogenesis ofvitiligo,”Clin Exp Dermatol36(3):292-7115.(2011))。因此,本发明包括式I、式Ia和/或式II的化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物;包含一种或多种那些化合物的药物组合物;以及使用用于治疗这些疾病的那些化合物或组合物的方法。In one embodiment, due to the potent effects of BET inhibitors on IL-6 and IL-17 transcription in vitro, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II are useful as therapeutic agents for inflammatory disorders in which IL-6 and/or IL-17 are implicated in the disease. The following autoimmune diseases are suitable for therapeutic inhibition of BET by administering a compound of Formula I, Formula Ia, and/or Formula II, or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate of Formula I, Formula Ia, and/or Formula II, due to the significant effects of IL-6 and/or IL-17: acute disseminated encephalomyelitis (Ishizu, T., et al., "CSF cytokine and chemokine profiles in acute disseminated encephalomyelitis," J Neuroimmunol 175(1-2):52-8 (2006)), agammaglobulinemia (Gonzalez-Serrano, M.E., et al., "Increased Pro-inflammatory Cytokine Production After Lipopolysaccharide Stimulation in Patients with X-linked Agammaglobulinemia," J Clin Immunol 32(5):967-74(2012)), allergic diseases (McKinley, L., et al., “TH17 cells mediate steroid-resistant airway inflammation and airway hyperresponsiveness in mice,” J Immunol 181(6):4089-97(2008)), ankylosing spondylitis (Taylan, A., et al., “Evaluation of the T helper 17 axis in ankylosing spondylitis,” Rheumatol Int 32(8):2511-5(2012)), anti-GBM/anti-TBM nephritis (Ito, Y., et al., “Pathogenic significance of interleukin-6 in a patient with antiglomerular basement membrane antibody-induced glomerulonephritis with multinucleated giant cells,” Am J Kidney Dis 26(1):72-9(1995)), antiphospholipid syndrome (Soltesz, P., et al., “Immunological features of primary anti-phospholipid syndrome in connection with endothelial dysfunction,” Rheumatology (Oxford) 47(11):1628-34(2008)), autoimmune aplastic anemia (Gu, Y., et al., “Interleukin (IL)-17 promotes macrophages to produce IL-8, IL-6 and tumornecrosis factor-alpha in aplastic anaemia,” Br J Haematol 142(1):109-14(2008)), autoimmune hepatitis (Zhao, L., et al., “Interleukin-17 contributes to the pathogenesis of autoimmune hepatitis through inducing hepatic interleukin-6 expression,” PLoS One6(4):e18909(2011)), autoimmune inner ear diseases (Gloddek, B., et al., “Pharmacological influence on inner ear endothelial cells in relation to thepathogenesis of sensorineural hearing loss,” Adv Otorhinolaryngol 59:75-83(2002)), autoimmune myocarditis (Yamashita, T., et al., “IL-6-mediated Th17 differentiation through RORgammat is essential for the initiation ofexperimental autoimmune myocarditis,” Cardiovasc Res 91(4):640-8(2011)), autoimmune pancreatitis (Ni, J., et al., “Involvement of Interleukin-17A in Pancreatic Damage in Rat Experimental Acute Necrotizing Pancreatitis,” Inflammation(2012)), autoimmune retinopathy (Hohki, S., et al., “Blockade of interleukin-6 signaling suppresses experimental autoimmune uveoretinitis by the inhibition of inflammatory Th17 responses,” Exp Eye Res 91(2):162-70(2010)), autoimmune thrombocytopenic purpura (Ma, D., et al., “Profile of Th17 cytokines (IL-17, TGF-beta, IL-6) and Th1 cytokine (IFN-gamma) in patients with immune thrombocytopenic purpura,” Ann Hematol 87(11):899-904(2008)), Behçet’s disease (Yoshimura, T., et al., “Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis,” Rheumatology (Oxford) 48(4):347-54 (2009)), bullous pemphigoid (D'Auria, L., P. et al., “Cytokines and bullous pemphigoid,” Eur Cytokine Netw 10(2):123-34 (1999)), Castleman's disease (El-Osta, H.E. and R. Kurzrock, “Castleman's disease:from basic mechanisms to molecular therapeutics,” Oncologist 16(4):497-511 (2011)), celiac disease (Lahdenpera, A.I., et al., “Up-regulation of small intestinal interleukin-17 immunity in untreated coeliac disease but not in potential coeliac disease or in type 1 diabetes,” Clin Exp Immunol 167(2):226-34(2012)), Churg-Strauss syndrome (Fujioka, A., et al., “The analysis of mRNA expression of cytokines from skin lesions in Churg-Strauss syndrome,” J Dermatol 25(3):171-7(1998)), Crohn's disease (Holtta, V., et al., “IL-23/IL-17 immunity as a hallmark of Crohn's disease,” Inflamm Bowel Dis 14(9):1175-84(2008)), Cogan's syndrome (Shibuya, M., et al., “Successful treatment with tocilizumab in a case of Cogan's syndrome complicated with aortitis,” Mod Rheumatol(2012)), dry eye syndrome (De Paiva, C.S., et al., “IL-17 disrupts corneal barrier following desiccating stress,” Mucosal Immunol 2(3):243-53(2009)), spontaneous mixed cryoglobulinemia (Antonelli, A., et al., “Serum levels of proinflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor alpha in mixed cryoglobulinemia,” Arthritis Rheum 60(12):3841-7(2009)), dermatomyositis (Chevrel, G., et al., “Interleukin-17 increases the effects of IL-1beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis,” J Neuroimmunol 137(1-2):125-33(2003)), Devic's disease (Linhares, U.C., et al., “The Ex Vivo Production of IL-6and IL-21by CD4(+)T Cells is Directly Associated with Neurological Disability in Neuromyelitis Optica Patients,” J Clin Immunol (2012)), encephalitis (Kyburz, D. and M. Corr, “Th17 cells generated in the absence of TGF-beta induce experimental allergic encephalitis upon adoptive transfer,” Expert Rev Clin Immunol 7(3):283-5(2011)), eosinophilic esophagitis (Dias, P.M. and G. Banerjee, “The Role of Th17/IL-17 on Eosinophilic Inflammation,” J Autoimmun (2012)), eosinophilic fasciitis (Dias, P.M. and G. Banerjee, “The Role of Th17/IL-17 on Eosinophilic Inflammation,” J Autoimmun (2012)), erythema nodosum (Kahawita, I.P. and D.N. Lockwood, “Towards understanding the pathology of erythema nodosum leprosum,”Trans R Soc Trop Med Hyg 102(4):329-37(2008)), giant cell arteritis (Deng, J., et al., “Th17 and Th1 T-cell responses in giant cell arteritis,” Circulation 121(7):906-15(2010)), glomerulonephritis (Ooi, J.D., et al., “Review: T helper 17 cells: their role in glomerulonephritis,” Nephrology (Carlton) 15(5):513-21(2010)), Goodpasture's syndrome (Ito, Y., et al., “Pathogenic significance of interleukin-6 in a patient with antiglomerular basement membrane antibody-induced glomerulonephritis with multinucleated giant cells,” Am J Kidney Dis 26(1):72-9 (1995)), granulomatosis with polyangiitis (Wegener's) (Nakahama, H., et al., “Distinct responses of interleukin-6 and other laboratory parameters to treatment in a patient with Wegener's granulomatosis,” Intern Med 32(2):189-92 (1993)), Graves' disease (Kim, S.E., et al., “Increased serum interleukin-17 in Graves' ophthalmopathy,” Graefes Arch Clin Exp Ophthalmol 250(10):1521-6 (2012)), Guillain-Barré syndrome (Lu, M.O. and J. Zhu, “The role of cytokines in Guillain-Barré syndrome,” J Neurol 258(4):533-48(2011)), Hashimoto’s thyroiditis (Figueroa-Vega, N., et al., “Increased circulating pro-inflammatory cytokines and Th17 lymphocytes in Hashimoto’s thyroiditis,” J Clin Endocrinol Metab 95(2):953-62(2009)), hemolytic anemia (Xu, L., et al., “Critical role of Th17 cells in development of autoimmune hemolytic anemia,” Exp Hematol (2012)), Henoch-Schonlein purpura (Jen, H.Y., et al., “Increased serum interleukin-17 and peripheral Th17 cells in children with acute Henoch-Schonlein purpura,” Pediatr Allergy Immunol 22(8):862-8(2011)), IgA nephropathy (Lin, F.J., et al., “Imbalance of regulatory T cells to Th17 cells in IgA nephropathy,” Scand J Clin Lab Invest 72(3):221-9(2012)), inclusion body myositis (Baron, P., et al., “Production of IL-6 by human myoblasts stimulated with Abeta: relevance in the pathogenesis of IBM,” Neurology 57(9):1561-5(2001)), type I diabetes (Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012)), interstitial cystitis (Lamale, L.M., et al., “Interleukin-6, histamine, and methylhistamine as diagnostic markers for interstitial cystitis,” Urology 68(4):702-6(2006)), Kawasaki disease (Jia, S., et al., “The T helper type 17/regulatory T cell imbalance in patients with acute Kawasaki disease,” Clin Exp Immunol 162(1):131-7(2010)), leukocytoclastic vasculitis (Min, C.K., et al., “Cutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma patient;association with pro-inflammatory cytokines,” Eur J Haematol 76(3):265-8(2006)), lichen planus (Rhodus, N.L., et al., “Proinflammatory cytokine levels in saliva before and after treatment of (erosive) oral lichen planus with dexamethasone,” Oral Dis 12(2):112-6(2006)), lupus erythematosus (SLE) (Mok, M.Y., et al., “The relation of interleukin 17 (IL-17) and IL-23 to Th1/Th2 cytokines and disease activity insystemic lupus erythematosus,” J Rheumatol 37(10):2046-52(2010)), microscopic polyangiitis (Muller Kobold, A.C., et al., “In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener's granulomatosis and microscopic polyangiitis,” Clin Exp Rheumatol 17(4):433-40(1999)), multiple sclerosis (Jadidi-Niaragh, F. and Mirshafiey A., “Th17 cell, the new player of neuroinflammatory process in multiple sclerosis,” Scand J Immunol 74(1):1-13(2011)), myasthenia gravis (Aricha, R., et al., “Blocking of IL-6suppresses experimental autoimmune myasthenia gravis,” J Autoimmun 36(2):135-41(2011)), myositis (Chevrel, G., et al., “Interleukin-17increases the effects of IL-1beta on muscle cells: arguments for the role of T cells in the pathogenesis of myositis,” J Neuroimmunol 137(1-2):125-33(2003)), optic neuritis (Icoz, S., et al., “Enhanced IL-6production in aquaporin-4antibody positive neuromyelitis optica patients,” Int J Neurosci 120(1):71-5(2010)), pemphigus (Lopez-Robles, E., et al., “TNFalpha and IL-6are mediators in the blistering process of pemphigus,” Int J Dermatol 40(3):185-8(2001)), POEMS syndrome (Kallen, K.J., et al., “New developments in IL-6dependent biology and therapy: where do we stand and what are the options?” Expert Opin Investig Drugs 8(9):1327-49(1999)), polyarteritis nodosa (Kawakami, T., et al., “Serum levels of interleukin-6 in patients with cutaneous polyarteritis nodosa,” Acta Derm Venereol 92(3):322-3(2012)), primary biliary cirrhosis (Harada, K., et al., “Periductal interleukin-17 production in association with biliary innate immunity contributes to the pathogenesis of cholangiopathy in primary biliary cirrhosis,” Clin Exp Immunol 157(2):261-70(2009)), psoriasis (Fujishima, S., et al., “Involvement of IL-17F via the induction of IL-6 in psoriasis,” Arch Dermatol Res 302(7):499-505(2010)), psoriatic arthritis (Raychaudhuri, S.P., et al., IL-17 receptor and its functional significance in psoriatic arthritis,” Mol Cell Biochem 359(1-2):419-29(2012)), pyoderma gangrenosum (Kawakami, T., et al., “Reduction of interleukin-6, interleukin-8, and anti-phosphatidylserine-prothrombin complex antibody by granulocyte and monocyte adsorption apheresis in a patient with pyodermagangrenosum and ulcerative colitis,” Am J Gastroenterol 104(9):2363-4(2009)), relapsing polychondritis (Kawai, M., et al., “Sustained response to tocilizumab, anti-interleukin-6 receptor antibody, in two patients with refractory relapsingpolychondritis,” Rheumatology(Oxford)48(3):318-9(2009)), rheumatoid arthritis (Ash, Z. and P. Emery, “The role of tocilizumab in the management of rheumatoidarthritis,” Expert Opin Biol Ther,12(9):1277-89(2012)), sarcoidosis (Belli, F., et al., “Cytokines assay in peripheral blood and bronchoalveolar lavage in the diagnosis and staging of pulmonary granulomatous diseases,” Int J Immunopathol Pharmacol 13(2):61-67(2000)), scleroderma (Radstake, T.R., et al., “The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFbeta and IFNgamma distinguishes SSc phenotypes,” PLoS One, 4(6):e5903(2009)), Sjögren's syndrome (Katsifis, G.E., et al., “Systemic and local interleukin-17 and linked cytokines associated with Sjogren's syndrome immunopathogenesis,” Am J Pathol 175(3):1167-77(2009)), Takayasu's arteritis (Sun, Y., et al., “MMP-9 and IL-6 are potential biomarkers for disease activity in Takayasu's arteritis,” Int J Cardiol 156(2):236-8(2012)), transverse myelitis (Graber, J.J., et al., “Interleukin-17 in transverse myelitis and multiple sclerosis,” J Neuroimmunol 196(1-2):124-32(2008)), ulcerative colitis (Mudter, J. and M.F. Neurath, “Il-6 signaling in inflammatory bowel disease: pathophysiological role and clinical relevance,” Inflamm Bowel Dis 13(8):1016-23(2007)), uveitis (Haruta, H., et al., “Blockade of interleukin-6 signaling suppresses not only th17 but also interphotoreceptor retinoid binding protein-specific Th1 by promoting regulatory T cells in experimental autoimmune uveoretinitis,” Invest Ophthalmol Vis Sci 52(6):3264-71(2011)), and vitiligo (Bassiouny, D.A. and O. Shaker, "Role of interleukin-17 in the pathogenesis of vitiligo," Clin Exp Dermatol 36(3):292-7115.(2011)). Therefore, the present invention includes compounds of Formula I, Formula Ia and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; pharmaceutical compositions comprising one or more of those compounds; and methods of using those compounds or compositions for treating these diseases.

特征在于促炎性细胞因子(包括IL-6、MCP-1和IL-17)的表达增加的急性和慢性(非自身免疫性)炎症性疾病也将适合于治疗性BET抑制。这些包括但不限于,窦炎(Bradley,D.T.和S.E.Kountakis,“Role of interleukins and transforming growthfactor-beta in chronic rhinosinusitis and nasal polyposis,”Laryngoscope 115(4):684-6(2005))、肺炎(Besnard,A.G.,等人,“Inflammasome-IL-1-Th17 response inallergic lung inflammation”J Mol Cell Biol4(1):3-10(2012))、骨髓炎(Yoshii,T.,等人,“Local levels of interleukin-1beta,-4,-6and tumor necrosis factor alphain an experimental model of murine osteomyelitis due to staphylococcusaureus,”Cytokine19(2):59-652002)、胃炎(Bayraktaroglu,T.,等人,“Serum levels oftumor necrosis factor-alpha,interleukin-6and interleukin-8are not increasedin dyspeptic patients with Helicobacter pylori-associated gastritis,”Mediators Inflamm13(1):25-8(2004))、肠炎(Mitsuyama,K.,等人,“STAT3 activationvia interleukin6trans-signalling contributes to ileitis in SAMP1/Yit mice,”Gut55(9):1263-9.(2006))、龈炎(Johnson,R.B.,等人,“Interleukin-11and IL-17andthe pathogenesis of periodontal disease,”J Periodontol75(1):37-43(2004))、阑尾炎(Latifi,S.Q.,等人,“Persistent elevation of seruminterleukin-6inintraabdominal sepsis identifies those with prolonged length of stay,”JPediatr Surg39(10):1548-52(2004))、肠易激综合症(Ortiz-Lucas,M.,等人,“Irritablebowel syndrome immune hypothesis.Part two:the role of cytokines,”Rev EspEnferm Dig 102(12):711-7(2010))、组织移植物排斥(Kappel,L.W.,等人,“IL-17contributes to CD4-mediated graft-versus-host disease,”Blood 113(4):945-52(2009))、慢性阻塞性肺病(COPD)(Traves,S.L.和L.E.Donnelly,“Th17 cells in airwaydiseases,”Curr Mol Med8(5):416-26(2008))、败血病休克(中毒性休克综合征、SIRS、细菌性败血症等)(Nicodeme,E.,等人,“Suppression of inflammation by a synthetichistone mimic,”Nature 468(7327):1119-23(2010))、骨关节炎(Chen,L.,等人,“IL-17RAaptamer-mediated repression of IL-6inhibits synovium inflammation in a murinemodel of osteoarthritis,”Osteoarthritis Cartilage 19(6):711-8(2011))、急性痛风(Urano,W.,等人,“The inflammatory process in the mechanism of decreased serumuric acid concentrations during acute gouty arthritis,”J Rheumatol29(9):1950-3(2002))、急性肺损伤(Traves,S.L.和L.E.Donnelly,“Th17 cells in airwaydiseases,”Curr Mol Med8(5):416-26(2008))、急性肾衰竭(Simmons,E.M.,等人,“Plasmacytokine levels predict mortality in patients with acute renal failure,”Kidney Int65(4):1357-65(2004))、烧伤(Paquet,P.和G.E.Pierard,“Interleukin-6andthe skin,”Int Arch Allergy Immunol 109(4):308-17(1996))、赫氏反应(Kaplanski,G.,等人,“Jarisch-Herxheimer reaction complicating the treatment of chronic Qfever endocarditis:elevated TNFalpha and IL-6serum levels,”J Infect37(1):83-4(1998))、以及与病毒感染相关的SIRS(Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”Nat Rev Cancer12(7):465-77(2012))。因此,本发明包括式I、式Ia和/或式II的化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物;包含一种或多种那些化合物的药物组合物;以及使用用于治疗这些疾病的那些化合物或组合物的方法。Acute and chronic (non-autoimmune) inflammatory diseases characterized by increased expression of proinflammatory cytokines, including IL-6, MCP-1, and IL-17, would also be amenable to therapeutic BET inhibition. These include, but are not limited to, sinusitis (Bradley, D.T. and S.E. Kountakis, “Role of interleukins and transforming growth factor-beta in chronic rhinosinusitis and nasal polyposis,” Laryngoscope 115(4):684-6 (2005)), pneumonia (Besnard, A.G., et al., “Inflammasome-IL-1-Th17 response in allergic lung inflammation,” J Mol Cell Biol 4(1):3-10 (2012)), osteomyelitis (Yoshii, T., et al., “Local levels of interleukin-1beta, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to staphylococcus aureus,” Cytokine 19(2):59-65 (2002)), gastritis (Bayraktaroglu, T., et al., “Serum levels of tumor "Necrosis factor-alpha, interleukin-6 and interleukin-8 are not increased in dyspeptic patients with Helicobacter pylori-associated gastritis," Mediators Inflamm13(1):25-8 (2004)), "STAT3 activation via interleukin6trans-signalling contributes to ileitis in SAMP1/Yit" mice," Gut55(9):1263-9.(2006)), gingivitis (Johnson, R.B., et al., "Interleukin-11and IL-17and the pathogenesis of periodontal disease," J Periodontol75(1):37-43(2004)), appendicitis (Latifi, S.Q., et al., "Persistent elevation of seruminterleukin-6inintraabdominal sepsis identifies those with prolonged length of stay,” JPediatr Surg 39(10):1548-52(2004)), irritable bowel syndrome (Ortiz-Lucas, M., et al., “Irritable bowel syndrome immune hypothesis. Part two: the role of cytokines,” Rev Esp Enferm Dig 102(12):711-7(2010)), tissue transplant rejection (Kappel, L.W., et al., “IL-17 contributes to CD4-mediated graft-versus-host disease,” Blood 113(4):945-52(2009)), chronic obstructive pulmonary disease (COPD) (Traves, S.L. and L.E. Donnelly, “Th17 cells in airway diseases,” Curr Mol Med 8(5):416-26(2008)), septic shock (toxic shock syndrome, SIRS, bacterial sepsis, etc.) (Nicodeme, E., et al., “Suppression of inflammation by a synthetic histone mimic,” Nature 468(7327):1119-23(2010)), osteoarthritis (Chen, L., et al., “IL-17RAaptamer-mediated repression of IL-6inhibits synovium inflammation in a murine model of osteoarthritis,” Osteoarthritis Cartilage 19(6):711-8(2011)), acute gout (Urano, W., et al., “The inflammatory process in the mechanism of decreased serumuric acid concentrations during acute gouty arthritis,” J Rheumatol 29(9):1950-3(2002)), acute lung injury (Traves, S.L. and L.E.Donnelly, “Th17 cells in airway diseases,” Curr Mol Med8(5):416-26(2008)), acute renal failure (Simmons, E.M., et al., “Plasmacytokine levels predict mortality in patients with acute renal failure,” Kidney Int65(4):1357-65(2004)), burns (Paquet, P. and G.E. Pierard, “Interleukin-6 and the skin,” Int Arch Allergy Immunol 109(4):308-17(1996)), Herxheimer reaction (Kaplanski, G., et al., “Jarisch-Herxheimer reaction complicating the treatment of chronic Qfever endocarditis: elevated TNFalpha and IL-6 serum levels,” J Infect37(1):83-4(1998)), and SIRS associated with viral infection (Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77(2012)). Therefore, the present invention includes compounds of Formula I, Formula Ia and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof; pharmaceutical compositions comprising one or more of those compounds; and methods of using those compounds or compositions for treating these diseases.

在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗类风湿性关节炎(RA)和多发性硬化(MS)。存在针对BET抑制剂在RA和MS的临床前模型的中的效用的强力专有数据。R.Jahagirdar,S.M.等人,“An Orally Bioavailable SmallMolecule RVX-297 Significantly Decreases Disease in a Mouse Model of MultipleSclerosis,”World Congress of Inflammation,Paris,France(2011)。RA和MS两者的特征在于IL-6和IL-17炎性途径的调节异常(Kimura,A.和T.Kishimoto,“IL-6:regulator ofTreg/Th17 balance,”Eur J Immunol 40(7):1830-5(2010))并且因此将对BET比抑制尤其敏感。在另一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物可用于治疗败血症和相关痛苦。BET比抑制已被证明在公开(Nicodeme,E.,等人,“Suppression ofinflammation by a synthetic histone mimic,”Nature 468(7327):1119-23(2010))和专有数据两者中的临床前模型中部分地通过抑制IL-6表达来抑制败血症的发展。In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used to treat rheumatoid arthritis (RA) and multiple sclerosis (MS). There is strong proprietary data for the efficacy of BET inhibitors in preclinical models of RA and MS. R. Jahagirdar, S.M. et al., "An Orally Bioavailable Small Molecule RVX-297 Significantly Decreases Disease in a Mouse Model of Multiple Sclerosis," World Congress of Inflammation, Paris, France (2011). Both RA and MS are characterized by dysregulation of the IL-6 and IL-17 inflammatory pathways (Kimura, A. and T. Kishimoto, "IL-6: regulator of Treg/Th17 balance," Eur J Immunol 40(7):1830-5 (2010)) and are therefore particularly sensitive to BET ratio inhibition. In another embodiment, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II can be used to treat sepsis and related afflictions. BET ratio inhibition has been shown to inhibit the development of sepsis in preclinical models in both published (Nicodeme, E., et al., "Suppression of inflammation by a synthetic histone mimic," Nature 468(7327):1119-23 (2010)) and proprietary data, in part by inhibiting IL-6 expression.

在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗癌症。具有过度表达、易位、扩增或重排c-myc或其它myc家族癌蛋白(MYCN,L-myc)的癌症是对BET抑制特别敏感的。Delmore,J.E.,等人,“BET bromodomain inhibition as atherapeutic strategy to target c-Myc,”Cell 146(6):904-17(2010);Mertz,J.A.,等人,“Targeting MYC dependence in cancer by inhibiting BET bromodomains,”ProcNatl Acad Sci USA 108(40):16669-74(2011)。这些癌症包括但不限于,B急性淋巴细胞白血病、伯基特氏淋巴瘤、弥漫性大细胞淋巴瘤、多发性骨髓瘤、原发性浆细胞白血病、非典型类癌肺癌、膀胱癌、乳腺癌、宫颈癌、结肠癌、胃癌、成胶质细胞瘤、肝细胞癌、大细胞神经内分泌癌、成神经管细胞瘤、黑色素瘤、结节性黑色素瘤、浅表扩散性黑色素瘤、成神经细胞瘤、食管鳞状细胞癌、骨肉瘤、卵巢癌、前列腺癌、肾透明细胞癌、视网膜母细胞瘤、横纹肌肉瘤以及小细胞肺癌。Vita,M.和M.Henriksson,“The Myc oncoprotein as a therapeutictarget for human cancer,”Semin Cancer Biol16(4):318-30(2006)。In one embodiment, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds, can be used to treat cancer. Cancers that overexpress, translocate, amplify, or rearrange c-myc or other myc family oncoproteins (MYCN, L-myc) are particularly sensitive to BET inhibition. Delmore, J.E., et al., "BET bromodomain inhibition as an atherapeutic strategy to target c-Myc," Cell 146(6):904-17 (2010); Mertz, J.A., et al., "Targeting MYC dependence in cancer by inhibiting BET bromodomains," Proc Natl Acad Sci USA 108(40):16669-74 (2011). These cancers include, but are not limited to, B acute lymphoblastic leukemia, Burkitt's lymphoma, diffuse large cell lymphoma, multiple myeloma, primary plasma cell leukemia, atypical carcinoid lung cancer, bladder cancer, breast cancer, cervical cancer, colon cancer, gastric cancer, glioblastoma, hepatocellular carcinoma, large cell neuroendocrine carcinoma, medulloblastoma, melanoma, nodular melanoma, superficial spreading melanoma, neuroblastoma, esophageal squamous cell carcinoma, osteosarcoma, ovarian cancer, prostate cancer, renal clear cell carcinoma, retinoblastoma, rhabdomyosarcoma, and small cell lung cancer. Vita, M. and M. Henriksson, "The Myc oncoprotein as a therapeutic target for human cancer," Semin Cancer Biol 16(4):318-30 (2006).

在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗由BET蛋白的异常调控(过度表达、易位等)引起的癌症。这些包括但不限于,NUT中线癌(Brd3或Brd4易位至nutlin1基因)(French,C.A.,“NUT midline carcinoma,”CancerGenet Cytogenet 203(1):16-20(2010))、B细胞淋巴瘤(Brd2过表达)(Greenwald,R.J.,等人,“E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia,”.Blood103(4):1475-84(2004))、非小细胞肺癌(BrdT过表达)(Grunwald,C.,等人,“Expressionof multiple epigenetically regulated cancer/germline genes in nonsmall celllung cancer,”Int J Cancer 118(10):2522-8(2006))、食道癌和头颈部鳞状细胞癌(BrdT过表达)(Scanlan,M.J.,等人,“Expression of cancer-testis antigens in lungcancer:definition of bromodomain testis-specific gene(BRDT)as a new CT gene,CT9,”Cancer Lett 150(2):55-64(2000))、以及结肠癌(Brd4)(Rodriguez,R.M.,等人,“Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer,”JMol Med(Berl)90(5):587-95(2012))。In one embodiment, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds can be used to treat cancers caused by abnormal regulation (overexpression, translocation, etc.) of BET proteins. These include, but are not limited to, NUT midline carcinoma (Brd3 or Brd4 translocation to the nutlin1 gene) (French, C.A., “NUT midline carcinoma,” Cancer Genet Cytogenet 203(1):16-20 (2010)), B cell lymphoma (Brd2 overexpression) (Greenwald, R.J., et al., “E mu-BRD2 transgenic mice develop B-cell lymphoma and leukemia,” Blood 103(4):1475-84 (2004)), non-small cell lung cancer (BrdT overexpression) (Grunwald, C., et al., “Expression of multiple epigenetically regulated cancer/germline genes in nonsmall cell lung cancer,” Int J Cancer 118(10):2522-8 (2006)), esophageal cancer and head and neck squamous cell carcinoma (BrdT overexpression) (Scanlan, M.J., et al., “Expression of cancer-testis antigens in lung cancer: definition of bromodomain testis-specific gene (BRDT) as a new CT gene, CT9," Cancer Lett 150(2):55-64(2000)), and colon cancer (Brd4) (Rodriguez, R.M., et al., "Aberrant epigenetic regulation of bromodomain BRD4 in human colon cancer," JMol Med(Berl)90(5):587-95(2012)).

在一个实施方案中,因为BET抑制剂降低pTEFb至参与细胞增殖的基因的Brd依赖性募集,所以式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗依赖于pTEFb(Cdk9/细胞周期蛋白T)和BET蛋白来调控致癌基因的癌症。这些癌症包括但不限于,慢性淋巴细胞性白血病和多发性骨髓瘤(Tong,W.G.,等人,“Phase I and pharmacologic studyof SNS-032,a potent and selective Cdk2,7,and9inhibitor,in patients withadvanced chronic lymphocytic leukemia and multiple myeloma,”J Clin Oncol28(18):3015-22(2010))、滤泡性淋巴瘤、具有生发中心表型的弥漫性大B细胞淋巴瘤、伯基特氏淋巴瘤、霍奇金氏淋巴瘤、滤泡性淋巴瘤和活化间变性大细胞淋巴瘤(Bellan,C.,等人,“CDK9/CYCLIN T1 expression during normal lymphoid differentiation andmalignant transformation,”J Pathol 203(4):946-52(2004))、成神经细胞瘤和原发性神经外胚层肿瘤(De Falco,G.,等人,“Cdk9 regulates neural differentiation andits expression correlates with the differentiation grade of neuroblastoma andPNET tumors,”Cancer Biol Ther4(3):277-81(2005))、横纹肌肉瘤(Simone,C.和A.Giordano,“Abrogation of signal-dependent activation of the cdk9/cyclin T2acomplex in human RD rhabdomyosarcoma cells,”Cell Death Differ14(1):192-5(2007))、前列腺癌(Lee,D.K.,等人,“Androgen receptor interacts with the positiveelongation factor P-TEFb and enhances the efficiency of transcriptionalelongation,”J Biol Chem 276(13):9978-84(2001))、以及乳腺癌(Bartholomeeusen,K.,等人,“BET bromodomain inhibition activates transcription via a transientrelease of P-TEFb from7SK snRNP,”J Biol Chem(2012))。In one embodiment, because BET inhibitors reduce the Brd-dependent recruitment of pTEFb to genes involved in cell proliferation, BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be used to treat cancers that rely on pTEFb (Cdk9/cyclin T) and BET proteins to regulate oncogenes. These cancers include, but are not limited to, chronic lymphocytic leukemia and multiple myeloma (Tong, W.G., et al., “Phase I and pharmacologic study of SNS-032, a potent and selective Cdk2,7,and9 inhibitor, in patients with advanced chronic lymphocytic leukemia and multiple myeloma,” J Clin Oncol 28(18):3015-22 (2010)), follicular lymphoma, diffuse large B-cell lymphoma with germinal center phenotype, Burkitt's lymphoma, Hodgkin's lymphoma, follicular lymphoma, and activated anaplastic large cell lymphoma (Bellan, C., et al., “CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation,” J Pathol 203(4):946-52 (2004)), neuroblastoma, and primary neuroectodermal tumor (De Falco, G., et al., “Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors,” Cancer Biol Ther 4(3):277-81(2005)), rhabdomyosarcoma (Simone, C. and A. Giordano, “Abrogation of signal-dependent activation of the cdk9/cyclin T2a complex in human RD rhabdomyosarcoma cells,” Cell Death Differ 14(1):192-5(2007)), prostate cancer (Lee, D.K., et al., “Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptionalelongation,” J Biol Chem 276(13):9978-84(2001)), and breast cancer (Bartholomeeusen, K., et al., “BET bromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP,” J Biol Chem (2012)).

在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗其中BET应答基因如CDK6、Bcl2、TYRO3、MYB和hTERT上调的癌症。Dawson,M.A.,等人,“Inhibition of BET recruitment to chromatin as an effective treatment forMLL-fusion leukaemia,”Nature 478(7370):529-33(2011);Delmore,J.E.,等人,“BETbromodomain inhibition as a therapeutic strategy to target c-Myc,”Cell 146(6):904-17(2010)。这些癌症包括但不限于,胰腺癌、乳腺癌、结肠癌、成胶质细胞瘤、腺样囊性癌、T细胞幼淋巴细胞白血病、恶性胶质瘤、膀胱癌、成神经管细胞瘤、甲状腺癌、黑色素瘤、多发性骨髓瘤、巴雷特氏腺癌、肝细胞瘤、前列腺癌、早幼粒细胞性白血病,慢性淋巴细胞性白血病,套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、小细胞肺癌以及肾癌。Ruden,M.和N.Puri,“Novel anticancer therapeutics targeting telomerase,”Cancer Treat Rev(2012);Kelly,P.N.和A.Strasser,“The role of Bcl-2and its pro-survivalrelatives in tumourigenesis and cancer therapy”Cell Death Differ18(9):1414-24(2011);Uchida,T.,等人,“Antitumor effect of bcl-2antisense phosphorothioateoligodeoxynucleotides on human renal-cell carcinoma cells in vitro and inmice,”Mol Urol5(2):71-8(2001)。In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used to treat cancers in which BET-responsive genes such as CDK6, Bcl2, TYRO3, MYB, and hTERT are upregulated. Dawson, M.A., et al., "Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia," Nature 478(7370):529-33 (2011); Delmore, J.E., et al., "BET bromodomain inhibition as a therapeutic strategy to target c-Myc," Cell 146(6):904-17 (2010). These cancers include, but are not limited to, pancreatic cancer, breast cancer, colon cancer, glioblastoma, adenoid cystic carcinoma, T-cell prolymphocytic leukemia, glioblastoma, bladder cancer, medulloblastoma, thyroid cancer, melanoma, multiple myeloma, Barrett's adenocarcinoma, hepatoma, prostate cancer, promyelocytic leukemia, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, small cell lung cancer, and renal cancer. Ruden, M. and N. Puri, "Novel anticancer therapeutics targeting telomerase," Cancer Treat Rev (2012); Kelly, P.N. and A. Strasser, "The role of Bcl-2 and its pro-survivalrelatives in tumorigenesis and cancer therapy" Cell Death Differ 18(9):1414-24 (2011); Uchida, T., et al., "Antitumor Effect of bcl-2antisense phosphorothioateoligodeoxynucleotides on human renal-cell carcinoma cells in vitro and inmice,” Mol Urol 5(2):71-8 (2001).

公开和专有数据已经显示BET抑制对各种癌症中的细胞增殖的直接作用。在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗针对其存在显示BET抑制对细胞增殖的直接作用的公开和(对于一些癌症)专有体内和/或体外数据的癌症。这些癌症包括NMC(NUT-中线癌)、急性骨髓性白血病(AML)、急性B成淋巴细胞性白血病(B-ALL)、伯基特氏淋巴瘤、B细胞淋巴瘤、黑色素瘤、混合谱系白血病、多发性骨髓瘤、早幼粒细胞性白血病(PML)、以及非霍奇金氏淋巴瘤。Filippakopoulos,P.,等人,“Selectiveinhibition of BET bromodomains,”Nature 468(7327):1067-73(2010);Dawson,M.A.,等人,“Inhibition of BET recruitment to chromatin as an effective treatment forMLL-fusion leukaemia,”Nature 478(7370):529-33(2011);Zuber,J.,等人,“RNAiscreen identifies Brd4 as a therapeutic target in acute myeloid leukaemia,”Nature 478(7370):524-8(2011);Miguel F.Segura,等人,“BRD4 is a noveltherapeutic target in melanoma,”Cancer Research.72(8):增刊1(2012)。本发明化合物已表明BET抑制对以下癌症的体外细胞增殖的直接作用:成神经细胞瘤、成神经管细胞瘤、肺癌(NSCLC、SCLC)以及结肠癌。Public and proprietary data have shown a direct effect of BET inhibition on cell proliferation in various cancers. In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used to treat cancers for which there is public and (for some cancers) proprietary in vivo and/or in vitro data showing a direct effect of BET inhibition on cell proliferation. These cancers include NMC (NUT-midline carcinoma), acute myeloid leukemia (AML), acute B-lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, B-cell lymphoma, melanoma, mixed lineage leukemia, multiple myeloma, promyelocytic leukemia (PML), and non-Hodgkin's lymphoma. Filippakopoulos, P., et al., “Selective inhibition of BET bromodomains,” Nature 468(7327):1067-73(2010); Dawson, M.A., et al., “Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia,” Nature 478(7370):529-33(2011); Zuber, J., et al., “RNAiscreen identifies Brd4 as a therapeutic target in acute myeloid leukaemia,” Nature 478(7370):524-8(2011); Miguel F. Segura, et al., “BRD4 is a novel therapeutic target in melanoma,” Cancer Research.72(8):Supplement 1(2012). Compounds of the present invention have demonstrated direct effects of BET inhibition on cell proliferation in vitro of the following cancers: neuroblastoma, medulloblastoma, lung cancer (NSCLC, SCLC) and colon cancer.

在一个实施方案中,由于BET抑制剂与其它癌症疗法之间的潜在协同作用或累加作用,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可与其它疗法、化学治疗剂或抗增殖剂组合以治疗人癌症和其它增生性病症。可在癌症治疗中与BET抑制剂组合的治疗剂的列表包括但不限于,ABT-737、阿扎胞苷(维达扎)、AZD1152(Barasertib)、AZD2281(奥拉帕尼)、AZD6244(司美替尼)、BEZ235、硫酸博莱霉素、硼替佐米(万珂)、白消安(马利兰)、喜树碱、顺铂、环磷酰胺(Clafen)、CYT387、阿糖胞苷(Ara-C)、达卡巴嗪、DAPT(GSI-IX)、地西他滨、地塞米松、多柔比星(阿霉素)、依托泊苷、依维莫司(RAD001)、夫拉平度(Alvocidib)、Ganetespib(STA-9090)、吉非替尼(易瑞沙)、伊达比星、异环磷酰胺(Mitoxana)、IFNa2a(罗扰素A)、美法仑(爱克兰)、Methazolastone(替莫唑胺)、二甲双胍、米托蒽醌(Novantrone)、紫杉醇、苯乙双胍、PKC412(米哚妥林)、PLX4032(威罗菲尼)、泊马度胺(CC-4047)、泼尼松(Deltasone)、雷帕霉素、雷利米得(来那度胺)、卢佐替尼(INCB018424)、索拉非尼(蕾莎瓦)、SU11248(舒尼替尼)、SU11274、长春碱、长春新喊(安可平)、长春瑞滨(诺维本)、伏立诺他(SAHA)和WP1130(Degrasyn)。In one embodiment, due to potential synergistic or additive effects between BET inhibitors and other cancer therapies, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be combined with other therapies, chemotherapeutic agents, or anti-proliferative agents to treat human cancer and other proliferative disorders. The list of therapeutic agents that can be combined with BET inhibitors in cancer treatment includes, but is not limited to, ABT-737, azacitidine (Vidaza), AZD1152 (Barasertib), AZD2281 (Olaparib), AZD6244 (Selumetinib), BEZ235, Bleomycin sulfate, Bortezomib (Velcade), Busulfan (Mileland), Camptothecin, Cisplatin, Cyclophosphamide (Clafen), CYT387, Cytarabine (Ara-C), Dacarbazine, DAPT (GSI-IX), Decitabine, Dexamethasone, Doxorubicin (Adriamycin), Etoposide, Everolimus (RAD001), Flavopiridol (Alvocidib), Ganetespib (STA-9090), Gefitinib (Iressa) , Idarubicin, Ifosfamide (Mitoxana), IFNa2a (interferon A), Melphalan (Aikran), Methazolastone (temozolomide), Metformin, Mitoxantrone (Novantrone), Paclitaxel, Phenformin, PKC412 (midostaurin), PLX4032 (vemurafenib), Pomalidomide (CC-4047), Prednisone (Deltasone), Rapamycin, Lenalidomide (lenalidomide), Ruxolitinib (INCB018424), Sorafenib (Resalva), SU11248 (sunitinib), SU11274, Vinblastine, Vincristine (Ancoping), Vinorelbine (Navelbine), Vorinostat (SAHA) and WP1130 (Degrasyn).

在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗良性增生和纤维化病症,包括但不限于,良性软组织肿瘤、骨肿瘤、脑及脊髓肿瘤、眼睑及眼眶肿瘤、肉芽瘤、脂肪瘤、脑脊髓膜瘤、多发性内分泌瘤、鼻息肉、垂体肿瘤、泌乳素瘤、假脑瘤、皮脂溢角化病、胃息肉、甲状腺结节、胰腺囊性赘瘤、血管瘤、声带结节、息肉及囊肿、卡斯尔曼病、慢性藏毛病、皮肤纤维瘤、毛发囊肿、化脓性肉芽肿、青少年多发性息肉综合征、特发性肺纤维化、肾纤维化、术后狭窄、瘢痕疙瘩形成、硬皮病、以及心肌纤维化。Tang,X等人,“Assessment of Brd4 Inhibition in Idiopathic Pulmonary Fibrosis LungFibroblasts and in Vivo Models of Lung Fibrosis,”.Am J Pathology in press(2013)。In one embodiment, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be used to treat benign proliferative and fibrotic disorders, including, but not limited to, benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulomas, lipomas, meningiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinomas, pseudotumor cerebri, seborrheic keratoses, gastric polyps, thyroid nodules, pancreatic cystic neoplasms, hemangiomas, vocal cord nodules, polyps and cysts, Castleman's disease, chronic pilonidal disease, dermatofibromas, pilaris cysts, pyogenic granulomas, juvenile polyposis syndrome, idiopathic pulmonary fibrosis, renal fibrosis, postoperative stenosis, keloid formation, scleroderma, and myocardial fibrosis. Tang,

在一个实施方案中,由于式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物上调ApoA-1转录和蛋白质表达的能力(Mirguet,O.,等人,“From ApoA1 upregulation to BETfamily bromodomain inhibition:discovery of I-BET151,”Bioorg Med Chem Lett 22(8):2963-7(2012);Chung,C.W.,等人,“Discovery and characterization of smallmolecule inhibitors of the BET family bromodomains,”J Med Chem 54(11):3827-38(2011)),它们可用于治疗通常与包括血脂异常、动脉粥样硬化、高胆固醇血症和代谢综合征相关的心血管疾病。(Belkina,A.C.和G.V.Denis,“BET domain co-regulators inobesity,inflammation and cancer,”Nat Rev Cancer12(7):465-77(2012);Denis,G.V.,“Bromodomain coactivators in cancer,obesity,type2diabetes,and inflammation,”Discov Med10(55):489-99(2010))。在另一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物可用于治疗特征在于ApoA-1的缺陷的非心血管疾病,包括阿尔茨海默氏病。Elliott,D.A.,等人,“Apolipoproteins in the brain:implications for neurologicaland psychiatric disorders,”Clin Lipidol 51(4):555-573(2010)。In one embodiment, due to the ability of the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds to upregulate ApoA-1 transcription and protein expression (Mirguet, O., et al., “From ApoA1 upregulation to BET family bromodomain inhibition: discovery of I-BET151,” Bioorg Med Chem Lett 22(8):2963-7 (2012); Chung, C.W., et al., “Discovery and characterization of smallmolecule inhibitors of the BET family bromodomains,” J Med Chem 54(11):3827-38 (2011)), they are useful in treating cardiovascular diseases commonly associated with conditions including dyslipidemia, atherosclerosis, hypercholesterolemia, and metabolic syndrome. (Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G.V., “Bromodomain coactivators in cancer, obesity, type 2 diabetes, and inflammation,” Discov Med 10(55):489-99 (2010)). In another embodiment, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II can be used to treat non-cardiovascular diseases characterized by defects in ApoA-1, including Alzheimer's disease. Elliott, D.A., et al., “Apolipoproteins in the brain: implications for neurological and psychiatric disorders,” Clin Lipidol 51(4):555-573 (2010).

在一个实施方案中,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于患有胰岛素抗性和II型糖尿病的患者。Belkina,A.C.和G.V.Denis,“BET domain co-regulators in obesity,inflammation and cancer,”Nat Rev Cancer12(7):465-77(2012);Denis,G.V.,“Bromodomain coactivators in cancer,obesity,type2diabetes,and inflammation,”Discov Med10(55):489-99(2010);Wang,F.,等人,“Brd2disruptionin mice causes severe obesity without Type2diabetes,”Biochem J 425(1):71-83(2010);Denis,G.V.,等人,“An emerging role for bromodomain-containing proteinsin chromatin regulation and transcriptional control of adipogenesis,”FEBSLett 584(15):3260-8(2010)。BET抑制的抗炎作用将具有在减少与糖尿病和代谢性疾病相关的炎症方面的另外价值。Alexandraki,K.,等人,“Inflammatory process intype2diabetes:The role of cytokines,”Ann N Y Acad Sci 1084:89-117(2006)。In one embodiment, a BET inhibitor compound of Formula I, Formula Ia, and/or Formula II, a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof, or a composition comprising one or more of those compounds, can be used in patients with insulin resistance and type II diabetes. Belkina, A.C. and G.V. Denis, “BET domain co-regulators in obesity, inflammation and cancer,” Nat Rev Cancer 12(7):465-77 (2012); Denis, G.V., “Bromodomain coactivators in cancer, obesity, type2diabetes, and inflammation,” Discov Med10(55):489-99(2010); Wang, F., et al., "Brd2disruption in mice causes severe obesity without Type2diabetes," Biochem J 425(1):71-83(2010); Denis, G.V., et al., "An emerging role for bromodomain-containing proteins in chromatin regulation and transcriptional control of adipogenesis," FEBS Lett 584(15):3260-8(2010). The anti-inflammatory effects of BET inhibition would have additional value in reducing inflammation associated with diabetes and metabolic diseases. Alexandraki, K., et al., "Inflammatory process in type 2 diabetes: The role of cytokines," Ann N Y Acad Sci 1084:89-117 (2006).

在一个实施方案中,由于式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物下调病毒启动子的能力,它们可用作与包括埃-巴二氏病毒(EBV)、肝炎病毒(HBV、HCV)、卡波西肉瘤相关病毒(KSHV)、人乳头状瘤病毒(HPV)、梅克尔细胞多瘤病毒以及人巨细胞病毒(CMV)的病毒相关的癌症的治疗剂。Gagnon,D.,等人,“Proteasomal degradation of thepapillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein4,”J Virol83(9):4127-39(2009);You,J.,等人,“Kaposi’ssarcoma-associated herpesvirus latency-associated nuclear antigen interactswith bromodomain protein Brd4 on host mitotic chromosomes,”J Virol80(18):8909-19(2006);Palermo,R.D.,等人,“RNA polymerase II stalling promotesnucleosome occlusion and pTEFb recruitment to drive immortalization byEpstein-Barr virus,”PLoS Pathog 7(10):e1002334(2011);Poreba,E.,等人,“Epigenetic mechanisms in virus-induced tumorigenesis,”Clin Epigenetics2(2):233-47.2011。在另一个实施方案中,由于BET抑制剂在潜伏性T细胞感染和潜伏性单核细胞感染的模型中再活化HIV-1的能力,BET抑制剂可与抗逆转录病毒治疗剂组合用于治疗HIV。Zhu,J.,等人,“Reactivation of Latent HIV-1by Inhibition of BRD4,”Cell Rep(2012);Banerjee,C.,等人,“BET bromodomain inhibition as a novel strategy forreactivation of HIV-1,”J Leukoc Biol(2012);Bartholomeeusen,K.,等人,“BETbromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP,”J Biol Chem(2012);Li,Z.,等人,“The BET bromodomaininhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition ofTat-transactivation,”Nucleic Acids Res(2012.)In one embodiment, due to the ability of the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds to downregulate viral promoters, they can be used as therapeutic agents for cancers associated with viruses including Epstein-Barr virus (EBV), hepatitis viruses (HBV, HCV), Kaposi's sarcoma-associated virus (KSHV), human papilloma virus (HPV), Merkel cell polyomavirus, and human cytomegalovirus (CMV). Gagnon, D., et al., “Proteasomal degradation of the papillomavirus E2 protein is inhibited by overexpression of bromodomain-containing protein4,” J Virol83(9):4127-39(2009); You, J., et al., “Kaposi’ssarcoma-associated herpesvirus latency-associated nuclear antigen interacts with bromodomain protein Brd4 on host mitotic chromosomes,” J Virol80(18):8909-19(2006); Palermo, R.D., et al., "RNA polymerase II stalling promotesnucleosome occlusion and pTEFb recruitment to drive immortalization by Epstein-Barr virus," PLoS Pathog 7(10):e1002334(2011); Poreba, E., et al., "Epigenetic mechanisms in virus-induced mechanisms" tumorigenesis,” Clin Epigenetics 2(2):233-47. 2011. In another embodiment, BET inhibitors can be used in combination with antiretroviral therapeutics to treat HIV due to their ability to reactivate HIV-1 in models of latent T cell infection and latent monocyte infection. Zhu, J., et al., "Reactivation of Latent HIV-1 by Inhibition of BRD4," Cell Rep (2012); Banerjee, C., et al., "BET bromodomain inhibition as a novel strategy for reactivation of HIV-1," J Leukoc Biol (2012); Bartholomeeusen, K., et al., "BET bromodomain inhibition activates transcription via a transient release of P-TEFb from7SK snRNP," J Biol Chem (2012); Li, Z., et al., "The BET bromodomaininhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition ofTat-transactivation," Nucleic Acids Res (2012.)

在一个实施方案中,由于表观遗传过程和含溴结构域蛋白在神经病症中的作用,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用于治疗疾病,包括但不限于,阿尔茨海默氏病、帕金森氏病、亨廷顿病、双相性精神病症、精神分裂症、鲁-泰二氏综合征(Rubinstein-Taybi syndrome)以及癫痫。Prinjha,R.K.,J.Witherington和K.Lee,“Placeyour BETs:the therapeutic potential of bromodomains,”Trends Pharmacol Sci33(3):146-53(2012);Muller,S.,等人,“Bromodomains as therapeutic targets,”ExpertRev Mol Med13:e29(2011)。In one embodiment, due to the role of epigenetic processes and bromodomain-containing proteins in neurological disorders, BET inhibitor compounds of Formula I, Formula Ia, and/or Formula II, stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates thereof, or compositions comprising one or more of those compounds, can be used to treat diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, Rubinstein-Taybi syndrome, and epilepsy. Prinjha, R.K., J. Witherington, and K. Lee, "Place your BETs: the therapeutic potential of bromodomains," Trends Pharmacol Sci 33(3):146-53 (2012); Muller, S., et al., "Bromodomains as therapeutic targets," Expert Rev Mol Med 13:e29 (2011).

在一个实施方案中,由于BRDT缺失或抑制对精子细胞发育的作用,式I、式Ia和/或式II的BET抑制剂化合物、其立体异构体、互变异构体、药学上可接受的盐、或水合物、或包含一种或多种那些化合物的组合物可用作可逆的男性避孕药。Matzuk,M.M.,等人,“Small-Molecule Inhibition of BRDT for Male Contraception,”Cell 150(4):第673-684页(2012);Berkovits,B.D.,等人,“The testis-specific double bromodomain-containingprotein BRDT forms a complex with multiple spliceosome components and isrequired for mRNA splicing and3’-UTR truncation in round spermatid,”NucleicAcids Res 40(15):7162-75(2012)。In one embodiment, due to the effects of BRDT deletion or inhibition on spermatocyte development, the BET inhibitor compounds of Formula I, Formula Ia and/or Formula II, their stereoisomers, tautomers, pharmaceutically acceptable salts, or hydrates, or compositions comprising one or more of those compounds can be used as reversible male contraceptives. Matzuk, M.M., et al., "Small-Molecule Inhibition of BRDT for Male Contraception," Cell 150(4): 673-684 (2012); Berkovits, B.D., et al., "The testis-specific double bromodomain-containing protein BRDT forms a complex with multiple spliceosome components and is required for mRNA splicing and 3'-UTR truncation in round spermatid," Nucleic Acids Res 40(15): 7162-75 (2012).

药物组合物Pharmaceutical composition

本公开的药物组合物包含与一种或多种药学上可接受的载体一起配制的至少一种式I-II的化合物或其互变异构体、立体异构体、药学上可接受的盐或水合物。这些制剂包括适合用于口服、直肠、局部、经颊和胃肠外(例如,皮下、肌内、皮内或静脉内)施用的那些。在任何给定情况下,最适合的施用形式将取决于所治疗的病状的程度和严重性并且取决于所使用的具体化合物的性质。The pharmaceutical composition of the present disclosure comprises a compound of at least one Formula I-II or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate prepared together with one or more pharmaceutically acceptable carriers. These preparations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. In any given case, the most suitable form of administration will depend on the degree and severity of the condition being treated and on the properties of the specific compound used.

适合用于口服施用的制剂可以呈现为离散单元,如各自含有预定量的本公开的化合物的胶囊剂、扁囊剂、锭剂或片剂;粉剂或颗粒剂;含水液体或非水液体中的溶液剂或混悬剂;或水包油液体乳剂或油包水乳剂。如所指示,这类制剂可通过任何适合的制药学方法来制备,方法包括以下步骤:使作为活性化合物的本公开的至少一种化合物与载体或赋形剂(其可构成一种或多种辅助成分)缔合。载体在与制剂的其它成分可相容的意义上必须是可接受的并且对接受者必须是无害的。载体可以是固体或液体或两者,并且可与作为活性化合物的本文所述的至少一种化合物一起配制在单位剂量制剂(例如,片剂)中,单位剂量制剂可含有约0.05重量%至约95重量%的至少一种活性化合物。其它药理活性物质也可存在,包括其它化合物。本公开的制剂可通过主要由混合组分组成的任何熟知制药学技术来制备。Formulations suitable for oral administration can be presented as discrete units such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of a compound of the present disclosure; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; or oil-in-water liquid emulsions or water-in-oil emulsions. As indicated, such formulations can be prepared by any suitable pharmaceutical method comprising the steps of bringing into association at least one compound of the present disclosure as the active compound with a carrier or excipient (which may constitute one or more auxiliary ingredients). The carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and must be innocuous to the recipient. The carrier can be a solid or liquid, or both, and can be formulated with at least one compound described herein as the active compound in a unit dose formulation (e.g., a tablet) containing from about 0.05% to about 95% by weight of at least one active compound. Other pharmacologically active substances may also be present, including other compounds. The formulations of the present disclosure can be prepared by any well-known pharmaceutical technique consisting essentially of mixing the components.

对于固体组合物来说,常规无毒固体载体包括例如,药用等级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、葡萄糖、蔗糖、碳酸镁等。液体药学上可施用的组合物可例如通过以下方式来制备,例如使如本文所述的本公开的至少一种活性化合物和任选的药物佐剂溶解或分散于赋形剂(例如像水、盐水、葡萄糖水溶液、甘油、乙醇等)中以由此形成溶液或悬浮液。一般来说,适合的制剂可通过以下方式来制备:将本公开的至少一种活性化合物与液体或细碎固体载体或两者均匀地和密切地混合,并且然后(如果必要)使产物成形。例如,片剂可通过以下方式来制备:压制或模制可任选地与一种或多种辅助成分组合的本公开的至少一种化合物的粉末或颗粒。压制片剂可通过在适合的机器中压制可任选地与粘合剂、润滑剂、惰性稀释剂和/或表面活性剂/分散剂混合的呈自由流动形式(如粉末或颗粒)的本公开的至少一种化合物来制备。模制片剂可通过在适合的机器中模制来制备,在机器中本公开的至少一种化合物的粉末状形式用惰性液体稀释剂润湿。For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Liquid pharmaceutically administrable compositions can be prepared, for example, by dissolving or dispersing at least one active compound of the present disclosure as described herein and optional pharmaceutical adjuvants in an excipient (e.g., such as water, saline, aqueous glucose solution, glycerol, ethanol, etc.) to thereby form a solution or suspension. In general, suitable formulations can be prepared by uniformly and intimately mixing at least one active compound of the present disclosure with a liquid or finely divided solid carrier or both, and then (if necessary) shaping the product. For example, tablets can be prepared by pressing or molding a powder or granules of at least one compound of the present disclosure optionally in combination with one or more auxiliary ingredients. Compressed tablets can be prepared by compressing at least one compound of the present disclosure in a free-flowing form (e.g., powder or granules) optionally mixed with a binder, lubricant, inert diluent, and/or surfactant/dispersant in a suitable machine. Molded tablets may be made by molding in a suitable machine wherein the powdered form of at least one compound of the present disclosure is moistened with an inert liquid diluent.

适合用于经颊(舌下)施用的制剂包括锭剂,锭剂包含在调味的基剂(通常是蔗糖和阿拉伯胶或黄芪胶)中的本公开的至少一种化合物;和香锭剂,香锭剂包含在惰性基剂(如明胶和甘油或蔗糖和阿拉伯胶)中的至少一种化合物。Suitable formulations for buccal (sublingual) administration include lozenges comprising at least one compound of the present disclosure in a flavored base, usually sucrose and acacia or tragacanth, and pastilles comprising at least one compound of the present disclosure in an inert base such as gelatin and glycerin or sucrose and acacia.

适合用于胃肠外施用的本公开的制剂包含式I-II的至少一种化合物的无菌水性制剂或其互变异构体、立体异构体、药学上可接受的盐和水合物,制剂与预期接受者的血液大约等渗。这些制剂是经静脉内施用,但是还可通过皮下、肌内或皮内注射实现施用。这类制剂可方便地通过将本文所述的至少一种化合物与水混合并且使所得溶液无菌并与血液等渗来制备。根据本公开的可注射组合物可含有约0.1%w/w至约5%w/w的活性化合物。The formulations of the present disclosure suitable for parenteral administration comprise a sterile aqueous formulation of at least one compound of Formula I-II or its tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates, which is approximately isotonic with the blood of the intended recipient. These formulations are administered intravenously, but administration can also be achieved by subcutaneous, intramuscular or intradermal injection. Such formulations can be conveniently prepared by mixing at least one compound described herein with water and making the resulting solution sterile and isotonic with the blood. Injectable compositions according to the present disclosure may contain from about 0.1% w/w to about 5% w/w of active compound.

适合用于直肠施用的制剂被呈现为单位剂量栓剂。这些可通过使如本文所述的至少一种化合物与一种或多种常规固体载体(例如,可可脂)混合并且然后使所得混合物成形来制备。Formulations suitable for rectal administration are presented as unit dose suppositories. These can be prepared by mixing at least one compound as described herein with one or more conventional solid carriers (eg, cocoa butter) and then shaping the resulting mixture.

适合用于局部涂覆至皮肤的制剂可采取软膏剂、乳膏剂、洗剂、糊剂、凝胶、喷雾剂、气雾剂或油的形式。可使用的载体和赋形剂包括凡士林、羊毛脂、聚乙二醇、醇以及其两种或更多种的组合。活性化合物(即,式I-IV的至少一种化合物或其互变异构体、立体异构体、药学上可接受的盐以及其水合物)通常以约0.1%w/w至约15%w/w(例如约0.5%至约2%)的组合物的浓度存在。Preparations suitable for topical application to the skin can take the form of ointments, creams, lotions, pastes, gels, sprays, aerosols or oils. Operable carriers and excipients include vaseline, lanolin, polyethylene glycol, alcohol and two or more combinations thereof. The active compound (i.e., at least one compound of Formulas I-IV or its tautomers, stereoisomers, pharmaceutically acceptable salts and hydrates thereof) is typically present in a concentration of about 0.1% w/w to about 15% w/w (e.g., about 0.5% to about 2%) of the composition.

所施用的活性化合物的量可取决于所治疗的受试者、受试者的体重、施用方式以及处方医师的判断。例如,给药时间表可涉及在约1μg至约1000mg的感知剂量下每日或每半日施用包封化合物。在另一个实施方案中,可采用间歇施用(如基于每月或每年)包封化合物的剂量。包封有助于可及作用部位并允许同时施用活性成分,从而在理论上产生协同作用。根据标准给药方案,医师将容易地确定最佳剂量,并且将能够容易地修改施用以实现这类剂量。The amount of the active compound administered may depend on the subject being treated, the subject's weight, the mode of administration, and the judgment of the prescribing physician. For example, a dosing schedule may involve administering the encapsulated compound daily or half a day at a perceived dose of about 1 μg to about 1000 mg. In another embodiment, intermittent administration (such as on a monthly or annual basis) of the encapsulated compound may be employed. Encapsulation helps to achieve accessible sites of action and allows the active ingredient to be administered simultaneously, thereby theoretically producing a synergistic effect. According to the standard dosing regimen, the physician will easily determine the optimal dose and will be able to easily modify administration to achieve such doses.

本文公开的化合物或组合物的治疗有效量可通过化合物的治疗效力来测量。然而,剂量可根据患者的需要、所治疗的病状的严重性以及所使用的化合物而变化。在一个实施方案中,所公开的化合物的治疗有效量足以产生最大血浆浓度。初步剂量(如例如,根据动物测试所确定)和用于人施用的剂量的缩放是根据本领域公认实践来进行。The therapeutically effective amount of the compound or composition disclosed herein can be measured by the therapeutic efficacy of the compound. However, the dosage can vary according to the needs of the patient, the severity of the condition being treated, and the compound used. In one embodiment, the therapeutically effective amount of the disclosed compound is sufficient to produce a maximum plasma concentration. The scaling of the preliminary dose (such as, for example, determined according to animal testing) and the dosage for human administration is carried out according to recognized practices in the art.

在细胞培养物或实验动物中,可通过标准药学程序确定毒性和治疗功效,例如,用于测定LD50(群体的50%致死剂量)和ED50(群体的50%治疗有效剂量)。毒性作用与治疗作用之间的剂量比率是治疗指数,并且它可被表示为比率LD50/ED50。优选表现出较大治疗指数的组合物。Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD50 / ED50 . Compositions that exhibit large therapeutic indices are preferred.

可在配制用于在人中使用的剂量范围中使用由细胞培养测定或动物研究获得的数据。在一种动物模型中实现的治疗有效剂量可使用本领域中已知的转换因子被转换用于在另一种动物(包括人)中使用(参见,例如,Freireich等人,Cancer Chemother.Reports50(4):219-244(1966)和等效表面积剂量因子的表I)。Data obtained from cell culture assays or animal studies can be used in formulating a dosage range for use in humans. A therapeutically effective dose achieved in one animal model can be converted for use in another animal (including humans) using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports 50(4):219-244 (1966) and Table 1 of equivalent surface area dose factors).

表I:等效表面积剂量因子:Table I: Equivalent surface area dose factors:

化合物的剂量优选地在包括ED50的具有极小毒性或没有毒性的循环浓度范围内。剂量可取决于所采用的剂型和所利用的施用途径而在这个范围内变化。一般来说,治疗有效量可随受试者的年龄、状况和性别以及受试者的医学病状的严重性变化。剂量可由医师确定并且根据需要进行调整,以适应所观察到的治疗作用。The dosage of the compound is preferably within a circulating concentration range that includes the ED50 with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. In general, the therapeutically effective amount may vary with the age, condition, and sex of the subject, as well as the severity of the subject's medical condition. The dosage may be determined by the physician and adjusted as needed to suit the observed therapeutic effect.

在一个实施方案中,式I-II的化合物或其互变异构体、立体异构体、药学上可接受的盐或水合物与另一种治疗剂组合施用。其它治疗剂可提供相对于本公开化合物的单独施用的累加或协同值。治疗剂可以是例如,抑制素;PPAR激动剂,例如噻唑烷二酮或贝特类;烟酸、RVX、FXR或LXR激动剂;胆汁酸再摄取抑制剂;胆固醇吸收抑制剂;胆固醇合成抑制剂;胆固醇酯转运蛋白(CETP)、离子交换树脂;抗氧化剂;AcylCoA胆固醇酰基转移酶的抑制剂(ACAT抑制剂);酪氨酸磷酸激酶抑制剂(tyrophostine);基于磺酰脲类的药物;双胍;α-葡萄糖苷酶抑制剂;载脂蛋白E调节剂;HMG-CoA还原酶抑制剂、微粒体甘油三酯转运蛋白;LDL-降低药物;HDL-升高药物;HDL增强剂;载脂蛋白A-IV和/或载脂蛋白基因的调节剂;或任何心血管药物。In one embodiment, the compound of Formula I-II or its tautomer, stereoisomer, pharmaceutically acceptable salt or hydrate is administered in combination with another therapeutic agent. Other therapeutic agents can provide cumulative or synergistic value relative to the separate administration of the disclosed compounds. The therapeutic agent can be, for example, a statin; a PPAR agonist, such as a thiazolidinedione or fibrate; nicotinic acid, RVX, FXR or LXR agonist; a bile acid reuptake inhibitor; a cholesterol absorption inhibitor; a cholesterol synthesis inhibitor; a cholesterol ester transfer protein (CETP), an ion exchange resin; an antioxidant; an inhibitor of AcylCoA cholesterol acyltransferase (ACAT inhibitor); a tyrosine phosphokinase inhibitor (tyrophostine); a sulfonylurea-based drug; a biguanide; an alpha-glucosidase inhibitor; an apolipoprotein E regulator; an HMG-CoA reductase inhibitor, a microsomal triglyceride transfer protein; an LDL-lowering drug; an HDL-raising drug; an HDL enhancer; a regulator of apolipoprotein A-IV and/or apolipoprotein genes; or any cardiovascular drug.

在另一个实施方案中,式I和/或式II的化合物或其互变异构体、立体异构体、药学上可接受的盐或水合物与一种或多种抗炎剂组合施用。抗炎剂可包括免疫抑制剂、TNF抑制剂、皮质类固醇类、非类固醇抗炎药(NSAID)、改善疾病的抗风湿药物(DMARDS)等。示例性抗炎剂包括例如,强的松、甲基强的松龙曲安西龙、甲氨蝶呤羟氯喹柳氮磺吡啶来氟米特依那西普英夫利昔单抗阿达木单抗利妥昔单抗阿巴西普白细胞介素-1、阿那白滞素(KineretTM)、布洛芬、酮洛芬、非诺洛芬、萘普生、阿司匹林、对乙酰氨基酚、吲哚美辛、舒林酸、美洛昔康、吡罗昔康、替诺昔康、氯诺昔康、酮咯酸、依托度酸、甲芬那酸、甲氯芬那酸、氟芬那酸、托芬那酸、双氯芬酸、奥沙普秦、阿扎丙宗、尼美舒利、萘丁美酮、替尼达普、依那西普、托美汀、保泰松、羟布宗、二氟尼柳、双水杨酯、奥沙拉秦或柳氮磺吡啶。In another embodiment, the compound of Formula I and/or Formula II, or a tautomer, stereoisomer, pharmaceutically acceptable salt, or hydrate thereof, is administered in combination with one or more anti-inflammatory agents. Anti-inflammatory agents may include immunosuppressants, TNF inhibitors, corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDS), and the like. Exemplary anti-inflammatory agents include, for example, prednisone, methylprednisolone, triamcinolone, methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, etanercept, infliximab, adalimumab, rituximab, abatacept, interleukin-1, anakinra (Kineret ), ibuprofen, ketoprofen, fenoprofen, naproxen, aspirin, acetaminophen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, azapropazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, hydroxybutazone, diflunisal, salsalate, olsalazine, or sulfasalazine.

实施例Example

一般方法。除非另有说明,否则试剂和溶剂按从商业供应商的原样使用。质子核磁共振光谱在Bruker AVANCE 300光谱仪上以300MHz或在Bruker AVANCE 500光谱仪中以500MHz或在Bruker AVANCE 300光谱仪上以300MHz获得。光谱以ppm(δ)单位给出并且耦合常数、J值均以赫兹(Hz)报道。四甲基硅烷用作1H核磁共振的内标。质谱分析在WatersAquity UPLC质谱仪上以ESI或APCI模式(适当时)、在Agilent 6130A质谱仪以ESI、APCI或MultiMode模式(适当时)或在Applied Biosystems API-150EX光谱仪上以ESI或APCI模式(适当时)进行。硅胶色谱通常在Teledyne IscoRf 200系统或Teledyne IscoCompanion系统上进行。General method. Unless otherwise stated, reagents and solvents are used as received from commercial suppliers. Proton nuclear magnetic resonance spectra are obtained on a Bruker AVANCE 300 spectrometer at 300 MHz or in a Bruker AVANCE 500 spectrometer at 500 MHz or on a Bruker AVANCE 300 spectrometer at 300 MHz. Spectra are given in ppm (δ) units and coupling constants and J values are reported in Hertz (Hz). Tetramethylsilane is used as an internal standard for 1 H nuclear magnetic resonance. Mass spectrometry is performed on a Waters Aquity UPLC mass spectrometer in ESI or APCI mode (when appropriate), on an Agilent 6130A mass spectrometer in ESI, APCI or MultiMode mode (when appropriate), or on an Applied Biosystems API-150EX spectrometer in ESI or APCI mode (when appropriate). Silica gel chromatography is typically performed on a Teledyne Isco Rf 200 system or a Teledyne Isco Companion system.

缩写:CDI:1,1'-羰基二咪唑;DMAP:N,N-二甲氨基丙基胺;EDC:1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐;m-CPBA:3-氯过氧苯甲酸;NBS:N-溴琥珀酰亚胺。Abbreviations: CDI: 1,1'-carbonyldiimidazole; DMAP: N,N-dimethylaminopropylamine; EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; m-CPBA: 3-chloroperoxybenzoic acid; NBS: N-bromosuccinimide.

一般程序A:General Procedure A:

制备9-苄基-2-(3,5-二甲基异噁唑-4-基)-9H-嘌呤-6-胺(实施例化合物1)Preparation of 9-benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine (Example Compound 1)

步骤1:向1(1.50g,8.84mmol)于DMF(50mL)的浆料加入碳酸钾(3.64g,26.4mmol)和苄基氯(1.01mL,8.84mmol)。将反应在室温搅拌16小时。过滤反应混合物,将滤液倾入水(100mL)中并搅拌5分钟。收获并干燥固体以得到为黄色固体的2(1.60g,70%):1zH NMR(300MHz,DMSO–d6)δ8.26(s,1H),7.80(br s,2H),7.38–7.26(m,5H),5.34(s,2H);ESI m/z260[M+H]+Step 1: To a slurry of 1 (1.50 g, 8.84 mmol) in DMF (50 mL) was added potassium carbonate (3.64 g, 26.4 mmol) and benzyl chloride (1.01 mL, 8.84 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was filtered, and the filtrate was poured into water (100 mL) and stirred for 5 min. The solid was harvested and dried to give 2 (1.60 g, 70%) as a yellow solid: 1z H NMR (300 MHz, DMSO-d 6 ) δ 8.26 (s, 1H), 7.80 (br s, 2H), 7.38–7.26 (m, 5H), 5.34 (s, 2H); ESI m/z 260 [M+H] + .

步骤2:向2(260mg,1.0mmol)于1,4-二噁烷(10mL)和DMF(4mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(335mg,1.5mmol)、碳酸钠(2.0M于H2O中,1.0mL,2.0mmol)和四(三苯基膦)钯(0)(116mg,0.1mmol)。反应混合物用氮气吹扫并在80℃加热16小时。混合物用二氯甲烷(20mL)稀释并过滤。将滤液浓缩并通过色谱(硅胶,0–5%二氯甲烷/甲醇)纯化,之后用EtOAc/己烷研磨以提供为白色固体的9-苄基-2-(3,5-二甲基异噁唑-4-基)-9H-嘌呤-6-胺(实施例化合物1)(110mg,34%):1H NMR(300MHz,DMSO–d6)δ8.29(s,1H),7.36–7.28(m,7H),5.38(s,2H),2.73(s,3H),2.51(s,3H);ESI m/z 321[M+H]+Step 2: To a solution of 2 (260 mg, 1.0 mmol) in 1,4-dioxane (10 mL) and DMF (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (335 mg, 1.5 mmol), sodium carbonate (2.0 M in H 2 O, 1.0 mL, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 h. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-5% dichloromethane/methanol) followed by trituration with EtOAc/hexanes to provide 9-benzyl-2-(3,5-dimethylisoxazol-4-yl)-9H-purin-6-amine (Example Compound 1) (110 mg, 34%) as a white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.29 (s, 1H), 7.36-7.28 (m, 7H), 5.38 (s, 2H), 2.73 (s, 3H), 2.51 (s, 3H); ESI m/z 321 [M+H] + .

制备3-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物2)Preparation of 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 2)

步骤1:向4(500mg,2.66mmol)于1,4-二噁烷(15mL)中的溶液加入CDI(517mg,3.19mmol)。将反应在60℃加热16小时。收获并干燥固体以得到为浅紫色固体的5(340mg,60%):1H NMR(300MHz,DMSO–d6)δ11.58(br s,1H),11.02(br s,1H),7.19(d,J=8.1Hz,1H),7.13(d,J=8.1Hz,1H)。Step 1: To a solution of 4 (500 mg, 2.66 mmol) in 1,4-dioxane (15 mL) was added CDI (517 mg, 3.19 mmol). The reaction was heated at 60° C. for 16 hours. The solid was harvested and dried to afford 5 (340 mg, 60%) as a light purple solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.58 (br s, 1H), 11.02 (br s, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H).

步骤2:向5(170mg,0.79mmol)于1,4-二噁烷(12mL)和DMF(6mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(352mg,1.58mmol)、碳酸钠(2.0M于H2O中,1.19mL,2.37mmol)和四(三苯基膦)钯(0)(92mg,0.08mmol)。反应混合物用氮气吹扫并在80℃加热16小时。混合物用二氯甲烷(20mL)稀释并过滤。将滤液浓缩并通过色谱(硅胶,0–5%二氯甲烷/甲醇)纯化以提供为白色固体的6(130mg,71%):1H NMR(300MHz,DMSO–d6)δ11.38(br s,1H),10.90(br s,1H),7.30(d,J=7.8Hz,1H),7.07(d,J=8.1Hz,1H),2.49(s,3H),2.33(s,3H)。Step 2: To a solution of 5 (170 mg, 0.79 mmol) in 1,4-dioxane (12 mL) and DMF (6 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (352 mg, 1.58 mmol), sodium carbonate (2.0 M in H 2 O, 1.19 mL, 2.37 mmol) and tetrakis(triphenylphosphine)palladium(0) (92 mg, 0.08 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-5% dichloromethane/methanol) to provide 6 (130 mg, 71%) as a white solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 11.38 (br s, 1H), 10.90 (br s, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.07 (d, J=8.1 Hz, 1H), 2.49 (s, 3H), 2.33 (s, 3H).

步骤3:向6(100mg,0.43mmol)于DMF(10mL)中的溶液加入碳酸钾(72mg,0.52mmol)和二碳酸二叔丁酯(104mg,0.48mmol)。将反应在室温搅拌16小时。向反应混合物加入碳酸钾(72mg,0.52mmol)和苄基氯(0.14mL,0.48mmol)。将反应在室温搅拌16小时。混合物用EtOAc(100mL)稀释并用盐水(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化得到为无色胶的6(130mg,71%):1H NMR(300MHz,DMSO–d6)δ7.97(d,J=8.1Hz,1H),7.38–7.27(m,6H),5.05(s,2H),2.49(s,3H),2.29(s,3H),1.61(s,9H)。Step 3: To a solution of 6 (100 mg, 0.43 mmol) in DMF (10 mL) was added potassium carbonate (72 mg, 0.52 mmol) and di-tert-butyl dicarbonate (104 mg, 0.48 mmol). The reaction was stirred at room temperature for 16 hours. Potassium carbonate (72 mg, 0.52 mmol) and benzyl chloride (0.14 mL, 0.48 mmol) were added to the reaction mixture. The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate/hexanes) gave 6 (130 mg, 71%) as a colorless gum: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.97 (d, J=8.1 Hz, 1H), 7.38-7.27 (m, 6H), 5.05 (s, 2H), 2.49 (s, 3H), 2.29 (s, 3H), 1.61 (s, 9H).

步骤4:将7(130mg,0.31mmol)于二氯甲烷(4mL)和TFA(2mL)中的溶液在室温搅拌2小时。浓缩混合物,将残余物溶解于二氯甲烷(100mL)中,用饱和NaHCO3(50mL×2)和盐水(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩以提供为灰白色固体的3-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物2)(81mg,81%):1HNMR(300MHz,DMSO–d6)δ11.31(s,1H),7.40(d,J=7.8Hz,1H),7.34–7.25(m,5H),7.15(d,J=7.8Hz,1H),5.03(s,2H),2.47(s,3H),2.28(s,3H);ESI m/z 321[M+H]+Step 4: A solution of 7 (130 mg, 0.31 mmol) in dichloromethane (4 mL) and TFA (2 mL) was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was dissolved in dichloromethane (100 mL), washed with saturated NaHCO 3 (50 mL×2) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to provide 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 2) (81 mg, 81%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.31 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.34-7.25 (m, 5H), 7.15 (d, J=7.8 Hz, 1H), 5.03 (s, 2H), 2.47 (s, 3H), 2.28 (s, 3H); ESI m/z 321 [M+H] + .

制备1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物3)Preparation of 1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 3)

步骤1:向4(500mg,2.66mmol)和苯甲醛(282mg,2.66mmol)于二氯甲烷(15mL)中的溶液加入乙酸(319mg,5.32mmol)。将反应在室温搅拌30分钟,然后加入NaBH(OAc)3(1.69g,7.98mmol)。将反应混合物在室温搅拌16小时。混合物用二氯甲烷(100mL)稀释并缓慢加入饱和NaHCO3水溶液(50mL)。将有机层分离,经硫酸钠干燥,过滤并浓缩。将残余物用二氯甲烷/EtOAc研磨以得到为浅褐色固体的8(401mg,54%):1H NMR(300MHz,DMSO–d6)δ7.34–7.22(m,5H),6.48(d,J=7.8Hz,1H),6.40(d,J=7.8Hz,1H),6.02(br s,2H),5.54(t,J=5.7Hz,1H),4.27(d,J=5.4Hz,2H)。Step 1: To a solution of 4 (500 mg, 2.66 mmol) and benzaldehyde (282 mg, 2.66 mmol) in dichloromethane (15 mL) was added acetic acid (319 mg, 5.32 mmol). The reaction was stirred at room temperature for 30 minutes, and then NaBH (OAc) 3 (1.69 g, 7.98 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with dichloromethane (100 mL) and saturated NaHCO 3 aqueous solution (50 mL) was slowly added. The organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was triturated with dichloromethane/EtOAc to give 8 (401 mg, 54%) as a light brown solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.34-7.22 (m, 5H), 6.48 (d, J=7.8 Hz, 1H), 6.40 (d, J=7.8 Hz, 1H), 6.02 (br s, 2H), 5.54 (t, J=5.7 Hz, 1H), 4.27 (d, J=5.4 Hz, 2H).

步骤2:向8(400mg,1.44mmol)于1,4-二噁烷(10mL)中的溶液加入CDI(514mg,3.17mmol)。将反应在110℃加热16小时。浓缩反应混合物。通过色谱(硅胶,0–40%乙酸乙酯/己烷)纯化得到为白色固体的9(310mg,71%):1H NMR(300MHz,DMSO–d6)δ11.96(s,1H),7.35–7.27(m,6H),7.19(d,J=7.8Hz,1H),5.02(s,2H)。Step 2: To a solution of 8 (400 mg, 1.44 mmol) in 1,4-dioxane (10 mL) was added CDI (514 mg, 3.17 mmol). The reaction was heated at 110° C. for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0–40% ethyl acetate/hexanes) afforded 9 (310 mg, 71%) as a white solid: 1 H NMR (300 MHz, DMSO–d 6 ) δ 11.96 (s, 1H), 7.35–7.27 (m, 6H), 7.19 (d, J=7.8 Hz, 1H), 5.02 (s, 2H).

步骤3:向9(310mg,1.02mmol)于1,4-二噁烷(10mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(341mg,1.53mmol)、碳酸钠(2.0M于H2O中,1.02mL,2.04mmol)和四(三苯基膦)钯(0)(59mg,0.05mmol)。反应混合物用氮气吹扫并在80℃加热16小时。混合物用二氯甲烷(20mL)稀释并过滤。浓缩滤液且残余物通过色谱(硅胶,0–80%EtOAc/己烷)纯化且用EtOAc研磨以提供为白色固体的1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物3)(202mg,62%):1HNMR(300MHz,DMSO–d6)δ11.76(s,1H),7.44(d,J=7.8Hz,1H),7.36–7.28(m,5H),7.11(d,J=7.8Hz,1H),5.05(s,2H),2.49(s,3H),2.32(s,3H);ESI m/z 321[M+H]+Step 3: To a solution of 9 (310 mg, 1.02 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (341 mg, 1.53 mmol), sodium carbonate (2.0 M in H 2 O, 1.02 mL, 2.04 mmol) and tetrakis(triphenylphosphine)palladium(0) (59 mg, 0.05 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and the residue was purified by chromatography (silica gel, 0-80% EtOAc/hexanes) and triturated with EtOAc to provide 1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 3) (202 mg, 62%) as a white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 11.76 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.36-7.28 (m, 5H), 7.11 (d, J=7.8 Hz, 1H), 5.05 (s, 2H), 2.49 (s, 3H), 2.32 (s, 3H); ESI m/z 321 [M+H] + .

一般程序BGeneral Procedure B

制备4-(3-苄基-3H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物4)和4-(1-苄基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物5).Preparation of 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 4) and 4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 5).

步骤1:向10(400mg,2.0mmol)于1,4-二噁烷(10mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(669mg,1.5mmol)、碳酸钠(2.0M于H2O中,2.0mL,4.0mmol)和四(三苯基膦)钯(0)(116mg,0.1mmol)。反应混合物用氮气吹扫并在80℃加热16小时。将混合物浓缩并通过色谱(硅胶,0–8%二氯甲烷/甲醇)纯化,之后用EtOAc/己烷研磨以提供为浅黄色固体的11(228mg,53%):ESI m/z 215[M+H]+Step 1: To a solution of 10 (400 mg, 2.0 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (669 mg, 1.5 mmol), sodium carbonate (2.0 M in H 2 O, 2.0 mL, 4.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-8% dichloromethane/methanol) followed by trituration with EtOAc/hexanes to provide 11 (228 mg, 53%) as a light yellow solid: ESI m/z 215 [M+H] + .

步骤2:向11(220mg,1.03mmol)于CH3CN(10mL)中的溶液加入碳酸钾(426mg,3.09mmol)和苄基氯(0.12mL,1.03mmol)。将反应在室温搅拌16小时。将混合物浓缩并通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为灰白色固体的4-(3-苄基-3H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物4)(34mg,11%):1H NMR(300MHz,CDCl3)δ8.34(d,J=1.8Hz,1H),8.14(s,1H),7.99(d,J=1.8Hz,1H),7.40–7.31(m,5H),5.52(s,2H),2.44(s,3H),2.30(s,3H);ESI m/z 305[M+H]+;为灰白色固体的4-(1-苄基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物5)(39mg,12%):1H NMR(300MHz,CDCl3)δ8.46(d,J=1.8Hz,1H),8.29(s,1H),7.40–7.37(m,3H),7.34(d,J=2.1Hz,1H),7.24–7.21(m,2H),5.41(s,2H),2.33(s,3H),2.16(s,3H);ESI m/z 305[M+H]+Step 2: To a solution of 11 (220 mg, 1.03 mmol) in CH 3 CN (10 mL) were added potassium carbonate (426 mg, 3.09 mmol) and benzyl chloride (0.12 mL, 1.03 mmol).The reaction was stirred at room temperature for 16 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 4) (34 mg, 11%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.34 (d, J=1.8 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J=1.8 Hz, 1H), 7.40-7.31 (m, 5H), 5.52 (s, 2H), 2.44 (s, 3H), 2.30 (s, 3H); ESI m/z 305 [M+H] + 4-(1-Benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 5) (39 mg, 12%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.46 (d, J=1.8 Hz, 1H), 8.29 (s, 1H), 7.40–7.37 (m, 3H), 7.34 (d, J=2.1 Hz, 1H), 7.24–7.21 (m, 2H), 5.41 (s, 2H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 305 [M+H] + .

制备3-苄基-5-(3,5-二甲基异噁唑-4-基)苯并[d]噁唑-2(3H)-酮(实施例化合物6)Preparation of 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (Example Compound 6)

步骤1:向13(5.00g,22.9mmol)于乙酸(50mL)、乙醇(100mL)和水(5mL)中的溶液加入铁粉(6.42g,115mmol)。将反应在80℃在氮气下加热2小时。将反应混合物冷却至室温,浓缩并通过色谱(硅胶,0–100%己烷/乙酸乙酯)纯化以得到为褐色固体的14(3.27g,76%):1H NMR(300MHz,CDCl3)δ6.88(d,J=2.2Hz,1H),6.77(dd,J=8.3,2.3Hz,1H),6.60(d,J=8.3Hz,1H),6.00–5.20(br s,3H)。Step 1: To a solution of 13 (5.00 g, 22.9 mmol) in acetic acid (50 mL), ethanol (100 mL) and water (5 mL) was added iron powder (6.42 g, 115 mmol). The reaction was heated at 80° C. under nitrogen for 2 h. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% hexanes/ethyl acetate) to afford 14 (3.27 g, 76%) as a brown solid: 1 H NMR (300 MHz, CDCl 3 ) δ 6.88 (d, J=2.2 Hz, 1H), 6.77 (dd, J=8.3, 2.3 Hz, 1H), 6.60 (d, J=8.3 Hz, 1H), 6.00–5.20 (br s, 3H).

步骤2:向14(1.50g,7.98mmol)于1,4-二噁烷(100mL)中的溶液加入1,1'-羰基二咪唑(1.55g,9.58mmol)。将反应在80℃在氮气下加热17小时。将混合物冷却至室温并加入2N HCl水溶液(40mL)。溶液用乙酸乙酯(200mL)稀释并用盐水洗涤(2×50mL)。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–50%乙酸乙酯/己烷)纯化得到为橙色固体的15(1.08g,63%):1H NMR(500MHz,DMSO–d6)δ11.81(s,1H),7.27–7.25(m,3H)。Step 2: To a solution of 14 (1.50 g, 7.98 mmol) in 1,4-dioxane (100 mL) was added 1,1'-carbonyldiimidazole (1.55 g, 9.58 mmol). The reaction was heated at 80 °C under nitrogen for 17 hours. The mixture was cooled to room temperature and 2N aqueous HCl (40 mL) was added. The solution was diluted with ethyl acetate (200 mL) and washed with brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexane) gave 15 (1.08 g, 63%) as an orange solid: 1H NMR (500 MHz, DMSO- d6 ) δ 11.81 (s, 1H), 7.27-7.25 (m, 3H).

步骤3:向15(150mg,0.701mmol)于乙腈(10mL)中的溶液加入苄基溴(180mg,1.05mmol)和碳酸钾(193mg,1.40mmol)。将反应在80℃加热3小时。将反应混合物冷却至室温,浓缩并通过色谱(硅胶,0–50%乙酸乙酯/己烷)纯化以提供为灰白色固体的16(195mg,92%):1H NMR(500MHz,CDCl3)δ7.41–7.30(m,5H),7.22(dd,J=8.5,1.7Hz,1H),7.08(d,J=8.5Hz,1H),6.97(d,J=1.6Hz,1H),4.97(s,2H)。Step 3: To a solution of 15 (150 mg, 0.701 mmol) in acetonitrile (10 mL) was added benzyl bromide (180 mg, 1.05 mmol) and potassium carbonate (193 mg, 1.40 mmol). The reaction was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0–50% ethyl acetate/hexanes) to afford 16 (195 mg, 92%) as an off-white solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.41–7.30 (m, 5H), 7.22 (dd, J=8.5, 1.7 Hz, 1H), 7.08 (d, J=8.5 Hz, 1H), 6.97 (d, J=1.6 Hz, 1H), 4.97 (s, 2H).

步骤4:向16(195mg,0.641mmol)于1,4-二噁烷(10mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(172mg,0.769mmol)、碳酸钾(177mg,1.28mmol)和四(三苯基膦)钯(0)(37mg,0.032mmol)。反应混合物用氮气吹扫并在100℃加热4小时。将反应混合物冷却至室温,浓缩并通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC进一步纯化以得到为灰白色固体的3-苄基-5-(3,5-二甲基异噁唑-4-基)苯并[d]噁唑-2(3H)-酮(实施例化合物6)(115mg,56%):1H NMR(500MHz,DMSO–d6)δ7.47–7.42(m,3H),7.40–7.34(m,2H),7.34–7.28(m,1H),7.23(d,J=1.6Hz,1H),7.12(dd,J=8.2Hz,7.7Hz,1H),5.07(s,2H),2.33(s,3H),2.15(s,3H);ESI m/z 321[M+H]+Step 4: To a solution of 16 (195 mg, 0.641 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (172 mg, 0.769 mmol), potassium carbonate (177 mg, 1.28 mmol) and tetrakis(triphenylphosphine)palladium(0) (37 mg, 0.032 mmol). The reaction mixture was purged with nitrogen and heated at 100 ° C for 4 hours. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexane). This was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O to give 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)benzo[d]oxazol-2(3H)-one (Example Compound 6) (115 mg, 56%) as an off-white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.47-7.42 (m, 3H), 7.40-7.34 (m, 2H), 7.34-7.28 (m, 1H), 7.23 (d, J=1.6 Hz, 1H), 7.12 (dd, J=8.2 Hz, 7.7 Hz, 1H), 5.07 (s, 2H), 2.33 (s, 3H), 2.15 (s, 3H); ESI m/z 321 [M+H] + .

一般程序C:General Procedure C:

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺(实施例化合物7)、1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-7-胺(实施例化合物8)和N,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺(实施例化合物9)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 7), 1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine (Example Compound 8), and N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 9)

向6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺17(290mg,1.27mmol)于CH3CN(15mL)中的溶液加入碳酸钾(350mg,2.54mmol)和苄基氯(200mg,1.59mmol)。将反应混合物在60℃搅拌16小时。混合物用二氯甲烷(20mL)稀释并通过硅藻土层过滤。浓缩滤液并通过色谱(硅胶,0–10%CH3OH/CH2Cl2)纯化以提供为灰白色固体的1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺(实施例化合物7)(109mg,27%):1H NMR(300MHz,CDCl3)δ7.95(s,1H),7.37–7.34(m,3H),7.23–7.20(m,2H),6.46(d,J=1.2Hz,1H),6.40(d,J=1.2Hz,1H),5.34(s,2H),2.31(s,3H),2.16(s,3H);ESIMS m/z 319[M+H]+;为灰白色固体的1-苄基-5-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-7-胺(实施例化合物8)(19mg,4.7%):1H NMR(300MHz,CDCl3)δ8.15(s,1H),7.43–7.40(m,3H),7.23(d,J=1.2Hz,1H),7.20–7.17(m,2H),6.39(d,J=1.2Hz,1H),5.69(s,2H),2.40(s,3H),2.27(s,3H);ESIMS m/z 319[M+H]+;为灰白色固体的N,1-二苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺(实施例化合物9)(40mg,8%):1H NMR(300MHz,DMSO–d6)δ8.27(s,1H),7.40–7.18(m,10H),6.62(d,J=1.2Hz,1H),6.57(t,J=6.0Hz,1H),5.97(d,J=1.2Hz,1H),5.41(s,2H),4.48(d,J=6.0Hz,2H),2.12(s,3H),1.94(s,3H);ESIMS m/z 409[M+H]+To a solution of 6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine 17 (290 mg, 1.27 mmol) in CH 3 CN (15 mL) was added potassium carbonate (350 mg, 2.54 mmol) and benzyl chloride (200 mg, 1.59 mmol). The reaction mixture was stirred at 60° C. for 16 hours. The mixture was diluted with dichloromethane (20 mL) and filtered through a pad of celite. The filtrate was concentrated and purified by chromatography (silica gel, 0-10% CH3OH / CH2Cl2 ) to provide 1 -benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 7) (109 mg, 27%) as an off-white solid: 1H NMR (300 MHz, CDCl3 ) δ 7.95 (s, 1H), 7.37-7.34 (m, 3H), 7.23-7.20 (m, 2H), 6.46 (d, J = 1.2 Hz, 1H), 6.40 (d, J = 1.2 Hz, 1H), 5.34 (s, 2H), 2.31 (s, 3H), 2.16 (s, 3H); ESIMS m/z 319 [M+H] + 1-Benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-7-amine (Example Compound 8) (19 mg, 4.7%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.15 (s, 1H), 7.43–7.40 (m, 3H), 7.23 (d, J=1.2 Hz, 1H), 7.20–7.17 (m, 2H), 6.39 (d, J=1.2 Hz, 1H), 5.69 (s, 2H), 2.40 (s, 3H), 2.27 (s, 3H); ESIMS m/z 319 [M+H] + N,1-dibenzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 9) (40 mg, 8%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.27 (s, 1H), 7.40–7.18 (m, 10H), 6.62 (d, J=1.2 Hz, 1H), 6.57 (t, J=6.0 Hz, 1H), 5.97 (d, J=1.2 Hz, 1H), 5.41 (s, 2H), 4.48 (d, J=6.0 Hz, 2H), 2.12 (s, 3H), 1.94 (s, 3H); ESIMS m/z 409 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物10)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 10)

1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物10)通过按照用于制备实施例3的方法来制备,得到为白色固体的产物(158mg,47%):1H NMR(300MHz,DMSO–d6)δ11.81(s,1H),7.90(d,J=2.1Hz,1H),7.44–7.25(m,6H),5.05(s,2H),2.34(s,3H),2.16(s,3H);MM m/z 321[M+H]+1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 10) was prepared by following the method used to prepare Example 3 to give the product as a white solid (158 mg, 47%): 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.81 (s, 1H), 7.90 (d, J=2.1 Hz, 1H), 7.44-7.25 (m, 6H), 5.05 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); MM m/z 321 [M+H] + .

制备1-苄基-7-(3,5-二甲基异噁唑-4-基)喹喔啉-2(1H)-酮(实施例化合物11)Preparation of 1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one (Example Compound 11)

步骤1:将18(500mg,2.3mmol)、苄基胺(1.2g,11.4mmmol)和吡啶(5.0mL)的溶液在室温搅拌18小时。真空除去溶剂并且产物通过色谱(硅胶,0–10%乙酸乙酯/己烷)纯化以提供为黄色固体的19(630mg,91%):1H NMR(500MHz,CDCl3)δ8.38(s,1H),8.05(d,J=9.1Hz,1H),7.40–7.32(m,5H),7.01(d,J=1.9Hz,1H),6.79(dd,J=9.1,1.9Hz,1H),4.51(d,J=5.5Hz,2H)。Step 1: A solution of 18 (500 mg, 2.3 mmol), benzylamine (1.2 g, 11.4 mmmol) and pyridine (5.0 mL) was stirred at room temperature for 18 h. The solvent was removed in vacuo and the product was purified by chromatography (silica gel, 0-10% ethyl acetate/hexanes) to afford 19 (630 mg, 91%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 8.38 (s, 1 H), 8.05 (d, J=9.1 Hz, 1 H), 7.40-7.32 (m, 5 H), 7.01 (d, J=1.9 Hz, 1 H), 6.79 (dd, J=9.1, 1.9 Hz, 1 H), 4.51 (d, J=5.5 Hz, 2 H).

步骤2:将19(100mg,0.33mmol)、铁粉(127mg,2.28mmol)、氯化铵(27mg,0.5mmol)、水(0.5mL)和乙醇(3mL)的混合物在回流加热0.5小时。冷却反应混合物并过滤。除去溶剂以提供为灰白色固体的20(90mg,100%):1H NMR(300MHz,CDCl3)δ7.40–7.29(m,5H),6.81–6.77(m,2H),6.61–6.58(m,1H),4.27(s,2H),3.41(s,1H);ESI m/z 278[M+H]+Step 2: A mixture of 19 (100 mg, 0.33 mmol), iron powder (127 mg, 2.28 mmol), ammonium chloride (27 mg, 0.5 mmol), water (0.5 mL), and ethanol (3 mL) was heated at reflux for 0.5 h. The reaction mixture was cooled and filtered. The solvent was removed to afford 20 (90 mg, 100%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.40–7.29 (m, 5H), 6.81–6.77 (m, 2H), 6.61–6.58 (m, 1H), 4.27 (s, 2H), 3.41 (s, 1H); ESI m/z 278 [M+H] + .

步骤3:在室温向20(100mg,0.36mmol)、三乙胺(48mg,0.47mmol)、CH2Cl2(0.5mL)和THF(1.0mL)的混合物加入溴乙酸乙酯(78mg,0.47mmol)于THF(1.0mL)中的溶液。将反应混合物搅拌18小时,然后加热至75℃持续1小时。将反应混合物浓缩并且产物通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化以提供为棕褐色固体的21(44mg,39%):1H NMR(500MHz,CDCl3)δ7.38–7.29(m,4H),7.24–7.22(m,2H),6.98–6.93(m,2H),6.55(d,J=8.3Hz,1H),5.13(s,2H),4.05(s,2H);ESI m/z 318[M+H]+Step 3: To a mixture of 20 (100 mg, 0.36 mmol), triethylamine (48 mg, 0.47 mmol), CH2Cl2 (0.5 mL ) and THF (1.0 mL) was added a solution of ethyl bromoacetate (78 mg, 0.47 mmol) in THF (1.0 mL) at room temperature. The reaction mixture was stirred for 18 h and then heated to 75 °C for 1 h. The reaction mixture was concentrated and the product was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 21 (44 mg, 39%) as a tan solid: 1 H NMR (500 MHz, CDCI 3 ) δ 7.38-7.29 (m, 4H), 7.24-7.22 (m, 2H), 6.98-6.93 (m, 2H), 6.55 (d, J=8.3 Hz, 1H), 5.13 (s, 2H), 4.05 (s, 2H); ESI m/z 318 [M+H] + .

步骤4:将21(44mg,0.14mmol)、3(47mg,0.21mmol)、K2CO3(39mg,0.28mmol)、四(三苯基膦)钯(0)(8mg,0.01mmol)、1,4-二噁烷(3mL)和水(0.5mL)的混合物在90℃加热16小时。将反应混合物浓缩于硅胶上并且产物通过色谱(硅胶,0–50%乙酸乙酯/己烷)纯化以提供为灰白色固体的1-苄基-7-(3,5-二甲基异噁唑-4-基)喹喔啉-2(1H)-酮(实施例化合物11)(16mg,34%):1H NMR(300MHz,CDCl3)δ8.43(s,1H),7.94(d,J=8.2Hz,1H),7.35–7.32(m,2H),7.29–7.27(m,1H),7.21–7.18(m,3H),7.04(s,1H),5.51(s,1H),2.16(s,3H),2.02(s,3H);ESI m/z 332[M+H]+Step 4: A mixture of 21 (44 mg, 0.14 mmol), 3 (47 mg, 0.21 mmol), K2CO3 (39 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium(0) (8 mg, 0.01 mmol), 1,4-dioxane (3 mL) and water (0.5 mL) was heated at 90 °C for 16 h. The reaction mixture was concentrated onto silica gel and the product was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to provide 1-benzyl-7-(3,5-dimethylisoxazol-4-yl)quinoxalin-2(1H)-one (Example Compound 11) (16 mg, 34%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (s, 1H), 7.94 (d, J=8.2 Hz, 1H), 7.35-7.32 (m, 2H), 7.29-7.27 (m, 1H), 7.21-7.18 (m, 3H), 7.04 (s, 1H), 5.51 (s, 1H), 2.16 (s, 3H), 2.02 (s, 3H); ESI m/z 332 [M+H] + .

制备1-苄基-7-(3,5-二甲基异噁唑-4-基)-3,4-二氢喹唑啉-2(1H)-酮(实施例化合物12)Preparation of 1-benzyl-7-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinazolin-2(1H)-one (Example Compound 12)

步骤1:向22(1.19g,5.53mmol)和苯甲醛(594mg,5.60mmol)于CH2Cl2(50mL)和CH3CN(50mL)中的溶液加入乙酸(0.2mL)。将混合物在室温搅拌1小时。加入NaBH(OAc)3(3.52g,16.59mmol)。将混合物在室温搅拌8小时。反应用饱和NaHCO3水溶液(50mL)淬灭并浓缩,将残余物悬浮于EtOAc(300mL)中,用盐水(100mL)洗涤。将有机层分离,经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–50%EtOAc/庚烷)纯化以提供为灰白色固体的23(201mg,12%):1H NMR(300MHz,DMSO–d6)δ8.75(d,J=5.7Hz,1H),7.93(br.s,1H),7.55(d,J=8.4Hz,1H),7.38–7.31(m,6H),6.76(d,J=1.8Hz,1H),6.69(dd,J=8.4,1.8Hz,1H),4.39(d,J=6.0Hz,2H)。Step 1: To a solution of 22 (1.19 g, 5.53 mmol) and benzaldehyde (594 mg, 5.60 mmol) in CH 2 Cl 2 (50 mL) and CH 3 CN (50 mL) was added acetic acid (0.2 mL). The mixture was stirred at room temperature for 1 hour. NaBH(OAc) 3 (3.52 g, 16.59 mmol) was added. The mixture was stirred at room temperature for 8 hours. The reaction was quenched with saturated aqueous NaHCO 3 (50 mL) and concentrated. The residue was suspended in EtOAc (300 mL) and washed with brine (100 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-50% EtOAc/heptane) to afford 23 (201 mg, 12%) as an off-white solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 8.75 (d, J=5.7 Hz, 1H), 7.93 (br. s, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.38-7.31 (m, 6H), 6.76 (d, J=1.8 Hz, 1H), 6.69 (dd, J=8.4, 1.8 Hz, 1H), 4.39 (d, J=6.0 Hz, 2H).

步骤2:向23(518mg,1.70mmol)于THF(20mL)中的溶液加入BH3·THF(1.0M于THF中,8.50mL,8.50mmol)。将混合物加热至回流16小时。缓慢加入MeOH(40mL),之后加入2NHCl(40mL)。将混合物加热至回流3小时。加入NH4OH(60mL),混合物用EtOAc萃取(200mL×3)。将有机层分离,经硫酸钠干燥,过滤并浓缩。将残余物通过色谱(硅胶,0–10%MeOH/二氯甲烷)纯化以提供为无色胶的24(372mg,75%):1H NMR(300MHz,DMSO–d6)δ7.32–7.21(m,5H),6.98(d,J=7.8Hz,1H),6.87(t,J=6.0Hz,1H),6.65(dd,J=8.1,2.1Hz,1H),6.53(d,J=2.1Hz,1H),4.33(d,J=5.7Hz,2H),3.71(s,2H),1.92(br.s,2H)。Step 2: To a solution of 23 (518 mg, 1.70 mmol) in THF (20 mL) was added BH 3 ·THF (1.0 M in THF, 8.50 mL, 8.50 mmol). The mixture was heated to reflux for 16 h. MeOH (40 mL) was slowly added, followed by 2N HCl (40 mL). The mixture was heated to reflux for 3 h. NH 4 OH (60 mL) was added, and the mixture was extracted with EtOAc (200 mL x 3). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/dichloromethane) to afford 24 (372 mg, 75%) as a colorless gum: 1H NMR (300 MHz, DMSO-d 6 ) δ 7.32-7.21 (m, 5H), 6.98 (d, J=7.8 Hz, 1H), 6.87 (t, J=6.0 Hz, 1H), 6.65 (dd, J=8.1, 2.1 Hz, 1H), 6.53 (d, J=2.1 Hz, 1H), 4.33 (d, J=5.7 Hz, 2H), 3.71 (s, 2H), 1.92 (br. s, 2H).

步骤3:使用用于实施例化合物3步骤2的程序,以化合物24(362mg,1.24mmol)开始,得到为黄色固体的25(325mg,85%):1H NMR(300MHz,DMSO-d6)δ7.33–7.31(m,3H),7.25–7.23(m,3H),7.09(d,J=1.8Hz,2H),6.86(s,1H),5.05(s,2H),4.35(d,J=1.5Hz,2H)。Step 3: Using the procedure used for Example 3, Step 2, starting with compound 24 (362 mg, 1.24 mmol), 25 (325 mg, 85%) was obtained as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.33-7.31 (m, 3H), 7.25-7.23 (m, 3H), 7.09 (d, J=1.8 Hz, 2H), 6.86 (s, 1H), 5.05 (s, 2H), 4.35 (d, J=1.5 Hz, 2H).

步骤4:使用用于实施例化合物3步骤3的程序,以化合物25(317mg,1.00mmol)开始,得到为白色固体的实施例化合物12(199mg,60%):1H NMR(500MHz,DMSO–d6)δ7.34–7.21(m,7H),6.90(dd,J=7.5,1.0Hz,1H),6.58(d,J=1.0Hz,1H),5.09(s,2H),4.43(s,2H),2.06(s,3H),1,89(s,3H);MM m/z 334[M+H]+Step 4: Using the procedure used for Example Compound 3, Step 3, starting with Compound 25 (317 mg, 1.00 mmol), Example Compound 12 (199 mg, 60%) was obtained as a white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.34-7.21 (m, 7H), 6.90 (dd, J=7.5, 1.0 Hz, 1H), 6.58 (d, J=1.0 Hz, 1H), 5.09 (s, 2H), 4.43 (s, 2H), 2.06 (s, 3H), 1.89 (s, 3H); MM m/z 334 [M+H] + .

一般程序D:General Procedure D:

制备4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物13)Preparation of 4-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 13)

步骤1:向26(1.00g,5.32mmol)和3(1.78g,7.98mmol)于1,4-二噁烷(35mL)和水(7.5mL)中的混合物加入碳酸钾(1.47g,10.6mmol)和四(三苯基膦)钯(0)(307mg,0.27mmol)。将反应搅拌并在90℃加热16小时。反应混合物用甲醇(20mL)稀释并加入硅胶(15g)。将浆料浓缩至干并将所得粉末负载于硅胶上且用0–90%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为黄绿色固体的27(939mg,70%):1H NMR(500MHz,CDCl3)δ7.45(t,J=2.0Hz,1H),6.78(t,J=2.0Hz,1H),2.37(s,3H),2.22(s,3H)。Step 1: To a mixture of 26 (1.00 g, 5.32 mmol) and 3 (1.78 g, 7.98 mmol) in 1,4-dioxane (35 mL) and water (7.5 mL) was added potassium carbonate (1.47 g, 10.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (307 mg, 0.27 mmol). The reaction was stirred and heated at 90 ° C for 16 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The slurry was concentrated to dryness and the resulting powder was loaded on silica gel and eluted with 0-90% ethyl acetate in hexane. The clean product was concentrated to give 27 (939 mg, 70%) as a yellow-green solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.45 (t, J=2.0 Hz, 1H), 6.78 (t, J=2.0 Hz, 1H), 2.37 (s, 3H), 2.22 (s, 3H).

步骤2:在室温向27(300mg,1.47mmol)于1,2-二氯乙烷(15mL)中的溶液加入苯甲醛(156mg,1.47mmol)和冰乙酸(200μL)。在搅拌17小时后,加入CH2Cl2(20mL),然后加入饱和NaHCO3水溶液(20mL,缓慢地)。将有机层分离且经Na2SO4干燥。将悬浮液过滤并浓缩。材料通过色谱(硅胶,0–60%于己烷中的乙酸乙酯)纯化以提供黄色固体,将其溶解于甲醇(10mL)中,在室温加入硼氢化钠(52mg,1.35mmol)。搅拌1小时后,加入另外的硼氢化钠(156mg,3.40mmol)并将反应搅拌1小时。将2N HCl水溶液加入至混合物直至pH4(2mL),然后加入饱和NaHCO3溶液碱化至pH8(2mL)。加入水(10mL)并将溶液用乙酸乙酯萃取(3×100mL)。将乙酸乙酯萃取液合并,经Na2SO4干燥,过滤并浓缩以提供为白色固体的28(401mg,93%):1HNMR(500MHz,CDCl3)δ7.48(s,1H),7.37–7.26(m,5H),6.58(s,1H),4.38(s,2H),4.33(br s,2H),3.77(br s,1H),2.24(s,3H),2.08(s,3H)。Step 2: To a solution of 27 (300 mg, 1.47 mmol) in 1,2-dichloroethane (15 mL) was added benzaldehyde (156 mg, 1.47 mmol) and glacial acetic acid (200 μL) at room temperature. After stirring for 17 hours, CH 2 Cl 2 (20 mL) was added, followed by a saturated aqueous NaHCO 3 solution (20 mL, slowly). The organic layer was separated and dried over Na 2 SO 4. The suspension was filtered and concentrated. The material was purified by chromatography (silica gel, 0–60% ethyl acetate in hexane) to provide a yellow solid, which was dissolved in methanol (10 mL) and sodium borohydride (52 mg, 1.35 mmol) was added at room temperature. After stirring for 1 hour, additional sodium borohydride (156 mg, 3.40 mmol) was added and the reaction was stirred for 1 hour. A 2N aqueous HCl solution was added to the mixture until pH 4 (2 mL), and then a saturated NaHCO 3 solution was added to alkalize to pH 8 (2 mL). Water (10 mL) was added and the solution was extracted with ethyl acetate (3×100 mL). The ethyl acetate extracts were combined, dried over Na 2 SO 4 , filtered and concentrated to afford 28 (401 mg, 93%) as a white solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.48 (s, 1H), 7.37–7.26 (m, 5H), 6.58 (s, 1H), 4.38 (s, 2H), 4.33 (br s, 2H), 3.77 (br s, 1H), 2.24 (s, 3H), 2.08 (s, 3H).

步骤3:向28(350mg,1.19mmol)加入原乙酸三乙酯(3.0mL,16.4mmol)和氨基磺酸(1mg)。将混合物加热至100℃持续1小时。混合物用甲醇(20mL)稀释并吸附于硅胶(10g)上。材料通过色谱(硅胶,0–60%于己烷中的乙酸乙酯,然后0–5%于CH2Cl2中的甲醇)纯化以提供为白色固体的4-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物13,169mg,45%):1H NMR(500MHz,CD3OD)δ8.32(d,J=1.0Hz,1H),7.78(d,J=1.0Hz,1H),7.36–7.29(m,3H),7.20–7.17(m,2H),5.56(s,2H),2.69(s,3H),2.36(s,3H),2.18(s,3H);ESI m/z 319[M+H]+Step 3: To 28 (350 mg, 1.19 mmol) was added triethyl orthoacetate (3.0 mL, 16.4 mmol) and sulfamic acid (1 mg). The mixture was heated to 100° C. for 1 hour. The mixture was diluted with methanol (20 mL) and adsorbed onto silica gel (10 g). The material was purified by chromatography (silica gel, 0-60% ethyl acetate in hexanes, then 0-5% methanol in CH2Cl2 ) to provide 4- (1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 13, 169 mg, 45%) as a white solid: 1H NMR (500 MHz, CD3OD ) δ 8.32 (d, J=1.0 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.36-7.29 (m, 3H), 7.20-7.17 (m, 2H), 5.56 (s, 2H), 2.69 (s, 3H), 2.36 (s, 3H), 2.18 (s, 3H); ESI m/z 319 [M+H] + .

一般程序E:General Procedure E:

制备1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物91)和4-氨基-1-(4-氯苄基)-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物90)Preparation of 1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 91) and 4-amino-1-(4-chlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 90)

步骤1:向29(1.00g,4.61mmol)于1,4-二噁烷(40mL)和水(4mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(1.23g,5.53mmol)、碳酸钾(1.27g,9.22mmol)和四(三苯基膦)钯(0)(266mg,0.231mmol)。反应混合物用氮气吹扫且在90℃加热过夜。将反应混合物冷却至室温,浓缩并通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化以得到黄色固体,其溶解于乙酸(15mL)中,在0℃加入N-溴琥珀酰亚胺(753mg,4.23mmol)。将反应升温至室温并搅拌过夜。真空浓缩混合物。将残余物悬浮于热MeOH中,冷却至室温并用10%NaHCO3水溶液碱化。混合物用水稀释且过滤。滤饼用水洗涤并真空干燥以提供为黄色固体的30(1.10g,87%):1H NMR(500MHz,CDCl3)δ8.04(d,J=2.1Hz,1H),7.61(d,J=2.1Hz,1H),6.69(bs,2H),2.40(s,3H),2.26(s,3H);ESI m/z 312[M+H]+Step 1: To a solution of 29 (1.00 g, 4.61 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.23 g, 5.53 mmol), potassium carbonate (1.27 g, 9.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (266 mg, 0.231 mmol). The reaction mixture was purged with nitrogen and heated at 90 ° C overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate/hexane) to give a yellow solid, which was dissolved in acetic acid (15 mL) and N-bromosuccinimide (753 mg, 4.23 mmol) was added at 0 ° C. The reaction was warmed to room temperature and stirred overnight. The mixture was concentrated in vacuo. The residue was suspended in hot MeOH, cooled to room temperature and basified with 10% aqueous NaHCO 3 solution. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to afford 30 (1.10 g, 87%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 8.04 (d, J = 2.1 Hz, 1H), 7.61 (d, J = 2.1 Hz, 1H), 6.69 (bs, 2H), 2.40 (s, 3H), 2.26 (s, 3H); ESI m/z 312 [M+H] + .

步骤2:在氮气气氛下向30(500mg,1.60mmol)于甲苯(50mL)中的溶液加入4-氯苄基胺(1.36g,9.62mmol)、碳酸铯(1.04g,3.02mmol)、2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基(114mg,0.240mmol)和三(二亚苄基丙酮)二钯(0)(146mg,0.160mmol)。将反应混合物在90℃加热过夜,冷却至室温,并通过色谱(硅胶,0–50%于己烷中的乙酸乙酯)纯化以提供为红色固体的31(290mg,49%):ESI m/z 373[M+H]+Step 2: To a solution of 30 (500 mg, 1.60 mmol) in toluene (50 mL) was added 4-chlorobenzylamine (1.36 g, 9.62 mmol), cesium carbonate (1.04 g, 3.02 mmol), 2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (114 mg, 0.240 mmol) and tris(dibenzylideneacetone)dipalladium(0) (146 mg, 0.160 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 90° C. overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 31 (290 mg, 49%) as a red solid: ESI m/z 373 [M+H] + .

步骤3:向31(290mg,0.779mmol)于1,4-二噁烷(10mL)中的混合物加入1,1'-羰基二咪唑(630mg,3.89mmol)和DMAP(晶体)。将反应在密封管中于130℃加热4天。将混合物浓缩并通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为橙色固体的实施例化合物91(144mg,46%):1H NMR(500MHz,CD3OD)δ7.80(d,J=1.4Hz,1H),7.40–7.35(m,4H),7.24(d,J=1.4Hz,1H),5.15(s,2H),2.32(s,3H),2.15(s,3H);ESI m/z 399[M+H]+Step 3: To a mixture of 31 (290 mg, 0.779 mmol) in 1,4-dioxane (10 mL) was added 1,1'-carbonyldiimidazole (630 mg, 3.89 mmol) and DMAP (crystals). The reaction was heated in a sealed tube at 130°C for 4 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford Example Compound 91 (144 mg, 46%) as an orange solid: 1H NMR (500 MHz, CD3OD ) δ 7.80 (d, J = 1.4 Hz, 1H), 7.40-7.35 (m, 4H), 7.24 (d, J = 1.4 Hz, 1H), 5.15 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 399 [M+H] + .

步骤4:向实施例化合物91(70mg,0.18mmol)于四氢呋喃(10mL)中的溶液加入于水(10mL)中的连二亚硫酸钠(183mg,1.05mmol)。将反应混合物在室温搅拌过夜且在真空下浓缩。向残余物加入2N HCl并加热至回流,冷却至室温,并真空浓缩。将残余物溶解于MeOH中并用浓NH4OH碱化,浓缩,并通过色谱(硅胶,0–100%己烷/乙酸乙酯)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC进一步纯化以得到为灰白色固体的实施例化合物90(34mg,51%):1H NMR(500MHz,CD3OD)δ7.36–7.28(m,4H),6.40(d,J=1.4Hz,1H),6.25(d,J=1.4Hz,1H),5.03(s,2H),2.28(s,3H),2.12(s,3H);ESI m/z 369[M+H]+Step 4: To a solution of Example Compound 91 (70 mg, 0.18 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (183 mg, 1.05 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. 2N HCl was added to the residue and heated to reflux, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in MeOH and basified with concentrated NH4OH , concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to give Example Compound 90 (34 mg, 51%) as an off-white solid: 1H NMR (500 MHz, CD3OD ) δ 7.36-7.28 (m, 4H), 6.40 (d, J=1.4 Hz, 1H), 6.25 (d, J=1.4 Hz, 1H), 5.03 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); ESI m/z 369 [M+H] + .

一般程序F:General Procedure F:

制备4-(1-(环丙基甲基)-2-甲基-4-硝基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑(实施例化合物14)和1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-胺(实施例化合物75)Preparation of 4-(1-(cyclopropylmethyl)-2-methyl-4-nitro-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 14) and 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine (Example Compound 75)

步骤1:将32(488mg,2.10mmol)和2,4-戊二酮(421mg,4.21mmol)于无水乙醇(28mL)和5N HCl水溶液(7.8mL)中的溶液加热至回流3小时。将混合物浓缩至干且加入乙酸乙酯(200mL)。将溶液用饱和NaHCO3水溶液(250mL)和饱和NaCl水溶液(250mL)洗涤,经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,0–40%己烷/乙酸乙酯)纯化以提供为橙色固体的33(495mg,92%):1H NMR(500MHz,CDCl3)δ10.38(br s,1H),8.24(d,J=2.0Hz,1H),8.12(d,J=1.0Hz,1H),2.73(s,3H)。Step 1: A solution of 32 (488 mg, 2.10 mmol) and 2,4-pentanedione (421 mg, 4.21 mmol) in anhydrous ethanol (28 mL) and 5N aqueous HCl (7.8 mL) was heated to reflux for 3 h. The mixture was concentrated to dryness and ethyl acetate (200 mL) was added. The solution was washed with saturated aqueous NaHCO 3 solution (250 mL) and saturated aqueous NaCl solution (250 mL), dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-40% hexane/ethyl acetate) to provide 33 (495 mg, 92%) as an orange solid: 1 H NMR (500 MHz, CDCl 3 ) δ 10.38 (br s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 1.0 Hz, 1H), 2.73 (s, 3H).

步骤2:向33(200mg,0.78mmol)和3(262mg,1.17mmol)于1,4-二噁烷(6mL)和水(1.5mL)中的混合物加入碳酸钾(216mg,1.56mmol)和四(三苯基膦)钯(0)(45mg,0.04mmol)。将反应搅拌并在90℃加热17小时。反应混合物用甲醇(20mL)稀释且加入硅胶(15g)。将悬浮液浓缩至干且所得粉末通过色谱(硅胶,0–90%己烷/乙酸乙酯)纯化以得到为黄色固体的34(187mg,88%):1H NMR(500MHz,CDCl3)δ8.00(d,J=1.5Hz,1H),7.89(s,1H),2.76(s,3H),2.45(s,3H),2.30(s,3H)。Step 2: To a mixture of 33 (200 mg, 0.78 mmol) and 3 (262 mg, 1.17 mmol) in 1,4-dioxane (6 mL) and water (1.5 mL) was added potassium carbonate (216 mg, 1.56 mmol) and tetrakis(triphenylphosphine)palladium(0) (45 mg, 0.04 mmol). The reaction was stirred and heated at 90° C. for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The suspension was concentrated to dryness and the resulting powder was purified by chromatography (silica gel, 0-90% hexane/ethyl acetate) to give 34 (187 mg, 88%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 8.00 (d, J=1.5 Hz, 1H), 7.89 (s, 1H), 2.76 (s, 3H), 2.45 (s, 3H), 2.30 (s, 3H).

步骤3:向34(217mg,0.797mmol)、碳酸钾(220mg,1.59mmol)、乙腈(5mL)和DMF(1mL)的溶液加入溴甲基环丙烷(129mg,0.956mmol)且将反应在60℃加热17小时。将材料冷却至室温且倾入饱和NaCl水溶液(30mL)。加入乙酸乙酯(100mL)且将层分离。乙酸乙酯层用饱和NaCl水溶液洗涤(2×20mL),经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,0–90%己烷/乙酸乙酯)纯化以得到为黄色固体的实施例14(178mg,68%):1H NMR(500MHz,CD3OD)δ8.03(d,J=1.5Hz,1H),7.93(d,J=1.5Hz,1H),4.27(d,J=7.0Hz,2H),2.75(s,3H),2.46(s,3H),2.30(s,3H),1.38–1.28(m,1H),0.65-0.60(m,2H),0.51–0.46(m,2H).ESI m/z 327[M+H]+ Step 3: To a solution of 34 (217 mg, 0.797 mmol), potassium carbonate (220 mg, 1.59 mmol), acetonitrile (5 mL) and DMF (1 mL) was added bromomethylcyclopropane (129 mg, 0.956 mmol) and the reaction was heated at 60°C for 17 hours. The material was cooled to room temperature and poured into saturated aqueous NaCl solution (30 mL). Ethyl acetate (100 mL) was added and the layers were separated. The ethyl acetate layer was washed with saturated aqueous NaCl solution (2 x 20 mL ), dried over Na2SO4 , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-90% hexanes/ethyl acetate) to give Example 14 (178 mg, 68%) as a yellow solid: 1H NMR (500 MHz, CD 3 OD) δ 8.03 (d, J = 1.5 Hz, 1H), 7.93 (d, J = 1.5 Hz, 1H), 4.27 (d, J = 7.0 Hz, 2H), 2.75 (s, 3H), 2.46 (s, 3H), 2.30 (s, 3H), 1.38-1.28 (m, 1H), 0.65-0.60 (m, 2H), 0.51-0.46 (m, 2H). ESI m/z 327 [M+H] +

步骤4:在5分钟内向实施例化合物14(160mg,0.51mmol)于THF(10mL)中的溶液逐滴加入连二亚硫酸钠(446mg,2.56mmol)于水(10mL)中的溶液。将溶液在室温搅拌16小时并真空除去溶剂。加入甲醇(20mL)且将悬浮液在室温搅拌3小时。过滤混合物并浓缩滤液至干。将2N HCl水溶液(10mL)加入至残余物并加热至回流5分钟。浓缩至干后,加入甲醇(20mL)且使用饱和NaHCO3水溶液(10mL)将溶液调节至pH8。加入硅胶(10g)并将悬浮液浓缩至干。所得粉末通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化,产物然后通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC纯化以得到为白色固体的实施例化合物75(131mg,99%):1H NMR(500MHz,CD3OD)δ6.70(s,1H),6.44(d,J=1.0Hz,1H),4.08(d,J=6.5Hz,2H),2.61(s,3H),2.40(s,3H),2.25(s,3H),1.30–1.19(m,1H),0.62–0.53(m,2H),0.45–0.40(m,2H).ESI m/z 297[M+H]+Step 4: To a solution of embodiment compound 14 (160 mg, 0.51 mmol) in THF (10 mL) was added dropwise a solution of sodium dithionite (446 mg, 2.56 mmol) in water (10 mL) within 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. 2N HCl aqueous solution (10 mL) was added to the residue and heated to reflux for 5 minutes. After being concentrated to dryness, methanol (20 mL) was added and the solution was adjusted to pH 8 using saturated NaHCO 3 aqueous solution (10 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) and the product was then purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to give Example Compound 75 (131 mg, 99%) as a white solid: 1H NMR (500 MHz, CD3OD ) δ 6.70 (s, 1H), 6.44 (d, J=1.0 Hz, 1H), 4.08 (d, J=6.5 Hz, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.25 (s, 3H), 1.30-1.19 (m, 1H), 0.62-0.53 (m, 2H), 0.45-0.40 (m, 2H). ESI m/z 297 [M+H] + .

一般程序G:General Procedure G:

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物15)和4-氨基-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物16)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 15) and 4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 16)

步骤1:向32(232mg,1.0mmol)于1,4-二噁烷(5mL)中的溶液加入CDI(194mg,1.2mmol)。将反应在60℃加热16小时。收获并干燥固体以得到为褐黄色固体的35(202mg,78%):1H NMR(300MHz,DMSO–d6)δ11.83(br s,1H),11.53(br s,1H),7.86(d,J=1.8Hz,1H),7.43(d,J=1.8Hz,1H)。Step 1: To a solution of 32 (232 mg, 1.0 mmol) in 1,4-dioxane (5 mL) was added CDI (194 mg, 1.2 mmol). The reaction was heated at 60° C. for 16 h. The solid was harvested and dried to afford 35 (202 mg, 78%) as a tan solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.83 (br s, 1H), 11.53 (br s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.43 (d, J=1.8 Hz, 1H).

步骤2:向35(200mg,0.78mmol)于DMF(7mL)中的溶液加入碳酸钾(118mg,0.85mmol)和苄基氯(98mg,0.78mmol)。将反应在室温搅拌16小时。混合物用EtOAc(100mL)稀释并用盐水(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–100%乙酸乙酯/己烷)纯化得到为黄色固体的36(101mg,37%):1H NMR(300MHz,DMSO–d6)δ12.15(s,1H),7.90(d,J=0.9Hz,1H),7.75(d,J=1.2Hz,1H),7.36–7.28(m,5H),5.10(s,2H)。Step 2: To a solution of 35 (200 mg, 0.78 mmol) in DMF (7 mL) was added potassium carbonate (118 mg, 0.85 mmol) and benzyl chloride (98 mg, 0.78 mmol). The reaction was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexane) gave 36 (101 mg, 37%) as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.15 (s, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.36-7.28 (m, 5H), 5.10 (s, 2H).

步骤3:向36(100mg,0.29mmol)于1,4-二噁烷(7mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(128mg,0.57mmol)、碳酸钠(2.0M于H2O中,0.43mL,0.86mmol)和四(三苯基膦)钯(0)(34mg,0.03mmol)。反应混合物用氮气吹扫并在80℃加热16小时。混合物用二氯甲烷(20mL)稀释并过滤。浓缩滤液且通过色谱(硅胶,10–50%乙酸乙酯/己烷)纯化,之后用乙酸乙酯研磨以提供为黄色固体的实施例化合物15(70mg,66%):1H NMR(300MHz,DMSO–d6)δ12.11(s,1H),7.72(d,J=1.5Hz,1H),7.50(d,J=1.5Hz,1H),7.42–7.28(m,5H),5.13(s,2H),2.35(s,3H),2.15(s,3H);ESI m/z 365[M+H]+Step 3: To a solution of 36 (100 mg, 0.29 mmol) in 1,4-dioxane (7 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (128 mg, 0.57 mmol), sodium carbonate (2.0 M in H 2 O, 0.43 mL, 0.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 h. The mixture was diluted with dichloromethane (20 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 10-50% ethyl acetate/hexanes) followed by trituration with ethyl acetate to provide Example Compound 15 (70 mg, 66%) as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.11 (s, 1H), 7.72 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 7.42-7.28 (m, 5H), 5.13 (s, 2H), 2.35 (s, 3H), 2.15 (s, 3H); ESI m/z 365 [M+H] + .

步骤4:向实施例化合物15(52mg,0.14mmol)于THF(5mL)和水(4mL)中的溶液加入Na2S2O4(149mg,0.86mmol)。将混合物在室温搅拌4小时,加入2N HCl(1mL),将混合物加热至回流15分钟,然后冷却至室温。缓慢地加入Na2CO3以调节至pH9。混合物用CH2Cl2(100mL)萃取,有机层用盐水(50mL)洗涤,过滤,浓缩且通过色谱(硅胶,70–100%乙酸乙酯/己烷)纯化以提供为灰白色固体的实施例化合物16(30mg,63%):1H NMR(500MHz,DMSO–d6)δ10.44(s,1H),7.36–7.25(m,5H),6.28(s,2H),5.04(s,2H),4.95(s,2H),2.28(s,3H),2.10(s,3H);ESI m/z 335[M+H]+Step 4: To a solution of Example Compound 15 (52 mg, 0.14 mmol) in THF (5 mL) and water (4 mL) was added Na 2 S 2 O 4 (149 mg, 0.86 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na 2 CO 3 was slowly added to adjust the pH to 9. The mixture was extracted with CH2Cl2 (100 mL ), and the organic layer was washed with brine (50 mL), filtered, concentrated, and purified by chromatography (silica gel, 70-100% ethyl acetate/hexanes) to provide Example Compound 16 (30 mg, 63%) as an off-white solid: 1H NMR (500 MHz, DMSO- d6 ) δ 10.44 (s, 1H), 7.36-7.25 (m, 5H), 6.28 (s, 2H), 5.04 (s, 2H), 4.95 (s, 2H), 2.28 (s, 3H), 2.10 (s, 3H); ESI m/z 335 [M+H] + .

一般程序H:General Procedure H:

制备4-(1-苄基-4-溴-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑(实施例化合物121)Preparation of 4-(1-benzyl-4-bromo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 121)

步骤1:向30(1.09g,3.49mmol)于四氢呋喃(30mL)中的溶液加入于水(15mL)中的连二亚硫酸钠(4.86g,28.0mmol)。将反应混合物在室温搅拌过夜且在真空下浓缩。将残余物溶解于MeOH/水(1:1,150mL)中且固体通过在真空下除去一些MeOH而沉淀。过滤固体,用水洗涤并在真空下干燥以提供为黄色固体的37(440mg,34%):1H NMR(500MHz,CDCl3)δ6.85(d,J=1.8Hz,1H),6.51(d,J=1.8Hz,1H),4.00–3.60(bs,2H),3.60–3.30(bs,2H),2.36(s,3H),2.23(s,3H);ESI m/z 282[M+H]+Step 1: To a solution of 30 (1.09 g, 3.49 mmol) in tetrahydrofuran (30 mL) was added sodium dithionite (4.86 g, 28.0 mmol) in water (15 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was dissolved in MeOH/water (1:1, 150 mL) and a solid was precipitated by removing some of the MeOH under vacuum. The solid was filtered, washed with water and dried under vacuum to afford 37 (440 mg, 34%) as a yellow solid: 1 H NMR (500 MHz, CDCI 3 ) δ 6.85 (d, J=1.8 Hz, 1H), 6.51 (d, J=1.8 Hz, 1H), 4.00-3.60 (bs, 2H), 3.60-3.30 (bs, 2H), 2.36 (s, 3H), 2.23 (s, 3H); ESI m/z 282 [M+H] + .

步骤2:向37(4.01g,14.2mmol)于甲醇(87mL)中的溶液加入原乙酸三乙酯(3.45g,21.3mmol)和氨基磺酸(69mg,0.71mmol)。将反应在室温搅拌5小时。反应混合物用水(50mL)稀释,用NaHCO3碱化且过滤。将固体干燥以提供为褐色固体的38(4.2g,96%):1H NMR(300MHz,DMSO–d6)δ12.82(br.s,1H),7.42(d,J=1.5Hz,1H),7.31(d,J=1.5Hz,1H),2.52(s,3H),2.40(s,3H),2.24(s,3H)。Step 2: To a solution of 37 (4.01 g, 14.2 mmol) in methanol (87 mL) was added triethyl orthoacetate (3.45 g, 21.3 mmol) and sulfamic acid (69 mg, 0.71 mmol). The reaction was stirred at room temperature for 5 hours. The reaction mixture was diluted with water (50 mL), basified with NaHCO 3 and filtered. The solid was dried to provide 38 (4.2 g, 96%) as a brown solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.82 (br. s, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 1.5 Hz, 1H), 2.52 (s, 3H), 2.40 (s, 3H), 2.24 (s, 3H).

步骤3:将38(300mg,0.980mmol)、苄基溴(503mg,2.94mmol)和碳酸钾(676mg,4.90mmol)于乙腈(50mL)中的混合物在密封管中于75℃加热过夜。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为灰白色固体的实施例化合物121(276mg,71%):1H NMR(500MHz,CD3OD)δ7.40–7.25(m,5H),7.15(d,J=7.7Hz,2H),5.51(s,2H),2.64(s,3H),2.32(s,3H),2.15(s,3H);ESI m/z 396[M+H]+Step 3: A mixture of 38 (300 mg, 0.980 mmol), benzyl bromide (503 mg, 2.94 mmol) and potassium carbonate (676 mg, 4.90 mmol) in acetonitrile (50 mL) was heated in a sealed tube at 75° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 121 (276 mg, 71%) as an off-white solid: 1H NMR (500 MHz, CD 3 OD) δ 7.40-7.25 (m, 5H), 7.15 (d, J=7.7 Hz, 2H), 5.51 (s, 2H), 2.64 (s, 3H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 396 [M+H] + .

制备4-(1-苄基-4-甲氧基-2-甲基-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑(实施例化合物66)Preparation of 4-(1-benzyl-4-methoxy-2-methyl-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 66)

将实施例121(80mg,0.20mmol)、NaOCH3(108mg,2.0mmol)和CuI(57mg,0.30mmol)于MeOH(1mL)和DMF(3mL)中的混合物用氮气吹扫并在100℃加热6小时。混合物用乙酸乙酯(100mL)稀释并用盐水(50mL)洗涤。有机层经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,40–100%EtOAc/己烷)纯化以提供为灰白色固体的实施例化合物66(386mg,55%):1HNMR(300MHz,CDCl3)δ7.35–7.30(m,3H),7.09–7.06(m,2H),6.64(d,J=1.2Hz,1H),6.53(s,1H),5.32(s,2H),4.03(s,3H),2.66(s,3H),2.33(s,3H),2.19(s,3H);ESI m/z 348[M+H]+A mixture of Example 121 (80 mg, 0.20 mmol), NaOCH 3 (108 mg, 2.0 mmol) and CuI (57 mg, 0.30 mmol) in MeOH (1 mL) and DMF (3 mL) was purged with nitrogen and heated at 100° C. for 6 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL). The organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (silica gel, 40-100% EtOAc/hexanes) to provide Example Compound 66 (386 mg, 55%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.35-7.30 (m, 3H), 7.09-7.06 (m, 2H), 6.64 (d, J=1.2 Hz, 1H), 6.53 (s, 1H), 5.32 (s, 2H), 4.03 (s, 3H), 2.66 (s, 3H), 2.33 (s, 3H), 2.19 (s, 3H); ESI m/z 348 [M+H] + .

一般程序I:General Procedure I:

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-乙基-4-硝基-1H-苯并[d]咪唑-2-胺(实施例化合物18)和1-苄基-6-(3,5-二甲基异噁唑-4-基)-N2-乙基-1H-苯并[d]咪唑-2,4-二胺(实施例化合物19)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine (Example Compound 18) and 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N 2 -ethyl-1H-benzo[d]imidazol-2,4-diamine (Example Compound 19)

步骤1:将实施例化合物15(73mg,0.668mmol)于POCl3(3mL)中的混合物在110℃加热持续16小时。浓缩反应混合物,将残余物溶解于CH2Cl2(100mL)中,用饱和NaHCO3(2×50mL)和盐水(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。将残余物溶解于乙基胺于THF(2.0M,10mL)中的溶液且将混合物在70℃加热3小时。浓缩反应混合物,残余物通过色谱(硅胶,20–60%EtOAc/己烷)纯化以提供为橙色固体的实施例化合物18(113mg,43%):1HNMR(300MHz,CDCl3)δ7.84(d,J=1.5Hz,1H),7.42–7.35(m,3H),7.16–7.13(m,2H),7.03(d,J=1.5Hz,1H),5.15(s,2H),4.29(t,J=5.4Hz,1H),3.78–3.69(m,2H),2.36(s,3H),2.21(s,3H),1.27(t,J=7.5Hz,3H);ESI m/z 392[M+H]+Step 1: A mixture of Example Compound 15 (73 mg, 0.668 mmol) in POCl₃ (3 mL) was heated at 110°C for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in CH₂Cl₂ (100 mL ) and washed with saturated NaHCO₃ (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in a solution of ethylamine in THF (2.0 M, 10 mL) and the mixture was heated at 70°C for 3 hours. The reaction mixture was concentrated and the residue was purified by chromatography (silica gel, 20-60% EtOAc/hexanes) to provide Example Compound 18 (113 mg, 43%) as an orange solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.84 (d, J=1.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.16-7.13 (m, 2H), 7.03 (d, J=1.5 Hz, 1H), 5.15 (s, 2H), 4.29 (t, J=5.4 Hz, 1H), 3.78-3.69 (m, 2H), 2.36 (s, 3H), 2.21 (s, 3H), 1.27 (t, J=7.5 Hz, 3H); ESI m/z 392 [M+H] + .

步骤2:向实施例化合物18(90mg,0.23mmol)于THF(5mL)和水(4mL)中的溶液加入Na2S2O4(240mg,1.38mmol)。将混合物在室温搅拌4小时,加入2N HCl(1mL),将混合物加热至回流15分钟,然后冷却至室温。缓慢地加入Na2CO3以调节至pH9。混合物用CH2Cl2(100mL)萃取,有机层用盐水(50mL)洗涤,经Na2SO4干燥,过滤,浓缩且通过色谱(硅胶,0–10%甲醇/乙酸乙酯)纯化以提供为灰白色固体的实施例化合物19(60mg,72%):1H NMR(300MHz,DMSO–d6)δ7.34–7.20(m,5H),6.62(t,J=5.4Hz,1H),6.30(d,J=1.5Hz,1H),6.21(d,J=1.5Hz,1H),5.19(s,2H),4.83(s,2H),3.47–3.38(m,2H),2.28(s,3H),2.11(s,3H),1.22(t,J=7.2Hz,3H);ESI m/z 362[M+H]+Step 2: To a solution of Example Compound 18 (90 mg, 0.23 mmol) in THF (5 mL) and water (4 mL) was added Na 2 S 2 O 4 (240 mg, 1.38 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na 2 CO 3 was slowly added to adjust the pH to 9. The mixture was extracted with CH2Cl2 (100 mL ), and the organic layer was washed with brine (50 mL), dried over Na2SO4 , filtered, concentrated, and purified by chromatography (silica gel , 0-10% methanol/ethyl acetate) to provide Example Compound 19 (60 mg, 72%) as an off-white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 7.34-7.20 (m, 5H), 6.62 (t, J=5.4 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.19 (s, 2H), 4.83 (s, 2H), 3.47-3.38 (m, 2H), 2.28 (s, 3H), 2.11 (s, 3H), 1.22 (t, J=7.2 Hz, 3H); ESI m/z 362[M+H] + .

一般程序J:General Procedure J:

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-羧酸甲酯(实施例化合物20)、1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-甲酰胺(实施例化合物21)和4-(氨基甲基)-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物22)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid methyl ester (Example Compound 20), 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carboxamide (Example Compound 21), and 4-(aminomethyl)-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-one (Example Compound 22)

步骤1:向39(2.00g,8.70mmol)于1,4-二噁烷(80mL)和水(8mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(2.13g,9.57mmol)、碳酸钾(2.40g,17.4mmol)和四(三苯基膦)钯(0)(502mg,0.435mmol)。反应混合物用氮气吹扫且在90℃加热过夜。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–50%于己烷中的乙酸乙酯)纯化以提供为灰白色固体的40(1.43g,63%):1H NMR(500MHz,CDCl3)δ7.74(d,J=2.1Hz,1H),7.15(dd,J=2.1,8.4Hz,1H),6.73(d,J=8.4Hz,1H),5.81(s,2H),3.88(s,3H),2.37(s,3H),2.23(s,3H);ESI m/z 247[M+H]+Step 1: To a solution of 39 (2.00 g, 8.70 mmol) in 1,4-dioxane (80 mL) and water (8 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.13 g, 9.57 mmol), potassium carbonate (2.40 g, 17.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (502 mg, 0.435 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to provide 40 (1.43 g, 63%) as an off-white solid: 1 H NMR (500 MHz, CDCI 3 ) δ 7.74 (d, J=2.1 Hz, 1 H), 7.15 (dd, J=2.1, 8.4 Hz, 1 H), 6.73 (d, J=8.4 Hz, 1 H), 5.81 (s, 2H), 3.88 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H); ESI m/z 247 [M+H] + .

步骤2:向40(1.34g,5.45mmol)于乙酸(40mL)中的混合物加入N-溴琥珀酰亚胺(1.07g,5.99mmol)。将混合物在室温搅拌30分钟并浓缩。将残余物溶解于MeOH中且用10%碳酸氢钠中和至pH7。混合物用水稀释,过滤。滤饼用水洗涤,并在真空下干燥以提供为黄色固体的41(1.65g,93%):1H NMR(500MHz,CDCl3)δ7.74(d,J=2.1Hz,1H),7.47(d,J=2.1Hz,1H),6.43(bs,2H),3.90(s,3H),2.37(s,3H),2.23(s,3H)。Step 2: To a mixture of 40 (1.34 g, 5.45 mmol) in acetic acid (40 mL) was added N-bromosuccinimide (1.07 g, 5.99 mmol). The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in MeOH and neutralized to pH 7 with 10% sodium bicarbonate. The mixture was diluted with water and filtered. The filter cake was washed with water and dried under vacuum to provide 41 (1.65 g, 93%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.74 (d, J = 2.1 Hz, 1H), 7.47 (d, J = 2.1 Hz, 1H), 6.43 (bs, 2H), 3.90 (s, 3H), 2.37 (s, 3H), 2.23 (s, 3H).

步骤3:向41(500mg,1.54mmol)于甲苯(40mL)中的溶液在氮气气氛下加入苄基胺(823mg,7.69mmol)、碳酸铯(1.00g,2.08mmol)、2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基(110mg,0.231mmol)和三(二亚苄基丙酮)二钯(0)(141mg,0.154mmol)。将反应混合物在90℃加热过夜,冷却至室温且通过色谱(硅胶,0–20%于己烷中的乙酸乙酯)纯化以为浅褐色固体的提供42(310mg,57%):1H NMR(500MHz,CDCl3)δ7.40–7.25(m,6H),6.56(d,J=1.8Hz,1H),5.68(s,2H),4.36(d,J=4.4Hz,2H),3.88(s,3H),3.68(s,1H),2.22(s,3H),2.09(s,3H);ESI m/z 352[M+H]+Step 3: To a solution of 41 (500 mg, 1.54 mmol) in toluene (40 mL) under nitrogen atmosphere were added benzylamine (823 mg, 7.69 mmol), cesium carbonate (1.00 g, 2.08 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (110 mg, 0.231 mmol) and tris(dibenzylideneacetone)dipalladium(0) (141 mg, 0.154 mmol). The reaction mixture was heated at 90° C. overnight, cooled to room temperature and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to provide 42 (310 mg, 57%) as a light brown solid: 1H NMR (500 MHz, CDCI 3 ) δ 7.40-7.25 (m, 6H), 6.56 (d, J=1.8 Hz, 1H), 5.68 (s, 2H), 4.36 (d, J=4.4 Hz, 2H), 3.88 (s, 3H), 3.68 (s, 1H), 2.22 (s, 3H), 2.09 (s, 3H); ESI m/z 352 [M+H] + .

步骤4:向42(310mg,0.883mmol)于1,4-二噁烷(10mL)中的混合物加入1,1'-羰基二咪唑(244mg,2.12mmol)和DMAP(一种晶体)。将反应在密封管中于80℃加热5天。将混合物浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为灰白色固体的实施例化合物20(160mg,48%):1H NMR(500MHz,CD3OD)δ7.54(d,J=1.5Hz,1H),7.37–7.24(m,5H),7.07(d,J=1.5Hz,1H),5.14(s,2H),3.97(s,3H),2.27(s,3H),2.09(s,3H);HPLC>99%,tR=15.0分钟;ESI m/z 378[M+H]+Step 4: To a mixture of 42 (310 mg, 0.883 mmol) in 1,4-dioxane (10 mL) was added 1,1'-carbonyldiimidazole (244 mg, 2.12 mmol) and DMAP (a crystal).The reaction was heated at 80°C in a sealed tube for 5 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 20 (160 mg, 48%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.54 (d, J=1.5 Hz, 1 H), 7.37-7.24 (m, 5 H), 7.07 (d, J=1.5 Hz, 1 H), 5.14 (s, 2 H), 3.97 (s, 3 H), 2.27 (s, 3 H), 2.09 (s, 3 H); HPLC >99%, t R =15.0 min; ESI m/z 378 [M+H] + .

步骤5:向实施例化合物20(50mg,0.13mmol)于甲酰胺(4mL)中的混合物加入叔丁醇钾(30mg,0.26mmol)。将混合物在微波中于100℃加热3小时,浓缩,且通过色谱(硅胶,0–20%于乙酸乙酯中的甲醇)纯化以提供为灰白色固体的实施例化合物21(13mg,26%):1HNMR(500MHz,CD3OD)δ7.41(d,J=1.3Hz,1H),7.37–7.24(m,5H),7.00(d,J=1.4Hz,1H),5.13(s,2H),2.28(s,3H),2.11(s,3H);HPLC98.3%,tR=12.3分钟;ESI m/z 363[M+H]+Step 5: To a mixture of Example Compound 20 (50 mg, 0.13 mmol) in formamide (4 mL) was added potassium tert-butoxide (30 mg, 0.26 mmol). The mixture was heated in a microwave at 100° C. for 3 h, concentrated, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford Example Compound 21 (13 mg, 26%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.41 (d, J=1.3 Hz, 1H), 7.37-7.24 (m, 5H), 7.00 (d, J=1.4 Hz, 1H), 5.13 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H); HPLC 98.3%, t R =12.3 min; ESI m/z 363 [M+H] + .

步骤6:向实施例化合物21(40mg,0.11mmol)于THF(10mL)中的溶液在氮气气氛下加入硼氢化钠(38mg,0.99mmol)。将混合物加热至65℃且加入三氟化硼二乙基醚合物(0.2mL)。将混合物在65℃加热2小时。冷却至室温后,加入盐酸(2N,5mL)且将混合物搅拌2小时。混合物用NaOH(2N,5mL)碱化,浓缩,且通过色谱(硅胶,0–100%于二氯甲烷中的CMA)(CMA=氯仿:甲醇:浓氢氧化铵=80:18:2)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC进一步纯化以得到为灰白色固体的实施例化合物22(16mg,42%):1HNMR(500MHz,CD3OD)δ7.37–7.23(m,5H),6.99(d,J=1.4Hz,1H),6.77(d,J=1.4Hz,1H),5.10(s,2H),3.93(s,2H),2.27(s,3H),2.10(s,3H);ESI m/z 340[M+H]+Step 6: To a solution of Example Compound 21 (40 mg, 0.11 mmol) in THF (10 mL) was added sodium borohydride (38 mg, 0.99 mmol) under a nitrogen atmosphere. The mixture was heated to 65 ° C and boron trifluoride diethyl etherate (0.2 mL) was added. The mixture was heated at 65 ° C for 2 hours. After cooling to room temperature, hydrochloric acid (2N, 5 mL) was added and the mixture was stirred for 2 hours. The mixture was basified with NaOH (2N, 5 mL), concentrated, and purified by chromatography (silica gel, 0-100% CMA in dichloromethane) (CMA = chloroform: methanol: concentrated ammonium hydroxide = 80: 18: 2). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O to give Example Compound 22 (16 mg, 42%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.37-7.23 (m, 5H), 6.99 (d, J=1.4 Hz, 1H), 6.77 (d, J=1.4 Hz, 1H), 5.10 (s, 2H), 3.93 (s, 2H), 2.27 (s, 3H), 2.10 (s, 3H); ESI m/z 340 [M+H] + .

一般程序K:General Procedure K:

1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-胺(实施例化合物55)1-Benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-amine (Example Compound 55)

将实施例121(250mg,0.63mmol)、BocNH2(221mg,1.89mmol)、Xantphos(73mg,0.126mmol)、Pd2(dba)3(58mg,0.063mmol)和Cs2CO3(720mg,2.21mmol)于1,4-二噁烷(13mL)中的混合物用氮气吹扫并在100℃加热18小时。混合物用二氯甲烷(200mL)稀释并过滤。浓缩滤液且通过色谱(硅胶,0–50%EtOAc/己烷)纯化以提供浅褐色泡沫,将其溶解于CH2Cl2(4mL)中,加入TFA(2mL)。将混合物在室温搅拌2小时,浓缩,将残余物溶解于乙酸乙酯(100mL)中并用饱和NaHCO3洗涤(50mL×2)。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–10%MeOH/EtOAc)纯化得到为灰白色固体的实施例化合物55(146mg,88%):1HNMR(500MHz,CDCl3)δ7.34–7.28(m,3H),7.09–7.08(m,2H),6.42(d,J=1.5Hz,1H),6.36(d,J=1.5Hz,1H),5.28(s,2H),4.42(br.s,2H),2.60(s,3H),2.31(s,3H),2.17(s,3H);ESI m/z 333[M+H]+A mixture of Example 121 (250 mg, 0.63 mmol), BocNH 2 (221 mg, 1.89 mmol), Xantphos (73 mg, 0.126 mmol), Pd 2 (dba) 3 (58 mg, 0.063 mmol) and Cs 2 CO 3 (720 mg, 2.21 mmol) in 1,4-dioxane (13 mL) was purged with nitrogen and heated at 100 ° C for 18 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-50% EtOAc/hexane) to provide a light brown foam, which was dissolved in CH 2 Cl 2 (4 mL) and TFA (2 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated, and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO 3 (50 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-10% MeOH/EtOAc) gave Example Compound 55 (146 mg, 88%) as an off-white solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.34-7.28 (m, 3H), 7.09-7.08 (m, 2H), 6.42 (d, J=1.5 Hz, 1H), 6.36 (d, J=1.5 Hz, 1H), 5.28 (s, 2H), 4.42 (br. s, 2H), 2.60 (s, 3H), 2.31 (s, 3H), 2.17 (s, 3H); ESI m/z 333 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲腈(实施例化合物88)和4-(1-苄基-3-氯-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物89)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile (Example Compound 88) and 4-(1-benzyl-3-chloro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 89)

步骤1:向43(200mg,1.0mmol)于CH3CN(6mL)中的悬浮液加入ClSO2NCO(360mg,2.5mmol)。将反应混合物在60℃搅拌4小时。将混合物冷却至室温后,加入DMF(1mL)。将混合物在室温搅拌1小时。混合物用30%于CHCl3中的i-PrOH(50mL)稀释并用盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。将粗品溶解于CH3CN(4mL)中,加入碳酸钾(280mg,2.0mmol)和苄基氯(128mg,1.0mmol)。将反应在70℃搅拌16小时。将反应混合物滤过硅藻土层,浓缩。残余物通过色谱(硅胶,0–50%乙酸乙酯/己烷)纯化以提供为黄色油的44(16mg,5%)和为灰白色固体的45(12mg,4%);44:ESIMS m/z 312[M+H]+;45:ESI MS m/z 321[M+H]+Step 1: To a suspension of 43 (200 mg, 1.0 mmol) in CH₃CN (6 mL) was added ClSO₂NCO (360 mg, 2.5 mmol). The reaction mixture was stirred at 60°C for 4 h. After the mixture was cooled to room temperature, DMF (1 mL) was added. The mixture was stirred at room temperature for 1 h. The mixture was diluted with 30% i-PrOH in CHCl₃ (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was dissolved in CH₃CN (4 mL), and potassium carbonate (280 mg, 2.0 mmol) and benzyl chloride (128 mg, 1.0 mmol) were added. The reaction was stirred at 70°C for 16 h. The reaction mixture was filtered through a pad of celite and concentrated. The residue was purified by chromatography (silica gel, 0-50% ethyl acetate/hexanes) to afford 44 (16 mg, 5%) as a yellow oil and 45 (12 mg, 4%) as an off-white solid; 44: ESIMS m/z 312 [M+H] + ; 45: ESI MS m/z 321 [M+H] + .

步骤2:对化合物44(16mg,0.051mmol)使用与用于一般程序C步骤1类似的程序得到为灰白色固体的实施例化合物88(6mg,36%):1H NMR(300MHz,CDCl3)δ8.55(s,1H),7.98(s,1H),7.50(s,1H),7.41–7.40(m,3H),7.20–7.15(m,2H),5.42(s,2H),2.34(s,3H),2.16(s,3H);ESI MS m/z 329[M+H]+Step 2: Compound 44 (16 mg, 0.051 mmol) was subjected to a procedure analogous to that used for General Procedure C, Step 1 to afford Example Compound 88 (6 mg, 36%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.55 (s, 1H), 7.98 (s, 1H), 7.50 (s, 1H), 7.41-7.40 (m, 3H), 7.20-7.15 (m, 2H), 5.42 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); ESI MS m/z 329 [M+H] + .

对化合物45(12mg,0.037mmol)使用与用于一般程序C步骤1类似的程序得到为黄色固体的实施例化合物89(8mg,64%):1H NMR(300MHz,CDCl3)δ8.49(s,1H),7.55(s,1H),7.50(s,1H),7.38–7.36(m,3H),7.18–7.16(m,2H),5.36(s,2H),2.34(s,3H),2.16(s,3H);ESIMS m/z 338[M+H]+Compound 45 (12 mg, 0.037 mmol) was subjected to a procedure analogous to that used for General Procedure C, Step 1 to afford Example Compound 89 (8 mg, 64%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.49 (s, 1H), 7.55 (s, 1H), 7.50 (s, 1H), 7.38-7.36 (m, 3H), 7.18-7.16 (m, 2H), 5.36 (s, 2H), 2.34 (s, 3H), 2.16 (s, 3H); ESIMS m/z 338 [M+H] + .

一般程序M:General Procedure M:

制备5-(3,5-二甲基异噁唑-4-基)-N-苯基-1H-吡咯并[3,2-b]吡啶-3-胺(实施例化合物23)Preparation of 5-(3,5-dimethylisoxazol-4-yl)-N-phenyl-1H-pyrrolo[3,2-b]pyridin-3-amine (Example Compound 23)

步骤1:向46(500mg,2.54mmol)于1,4-二噁烷(10mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(792mg,3.56mmol)、碳酸钠(538mg于2mL H2O中,5.08mmol)和四(三苯基膦)钯(0)(294mg,0.25mmol)。反应混合物用氮气吹扫且在90℃加热16小时。将混合物滤过硅藻土层。浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为黄色油的47(700mg,>100%):1H NMR(300MHz,DMSO–d6)δ11.4(s,1H),7.85(dd,J=8.1,0.9Hz,1H),7.68(t,J=3.0Hz,1H),7.23(d,J=8.1Hz,1H),6.58(d,J=2.1Hz,1H),2.49(s,3H),2.37(s,3H)。Step 1: To a solution of 46 (500 mg, 2.54 mmol) in 1,4-dioxane (10 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (792 mg, 3.56 mmol), sodium carbonate (538 mg in 2 mL H 2 O, 5.08 mmol) and tetrakis(triphenylphosphine)palladium(0) (294 mg, 0.25 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was filtered through a pad of celite. The filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded 47 (700 mg, >100%) as a yellow oil: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.4 (s, 1H), 7.85 (dd, J=8.1, 0.9 Hz, 1H), 7.68 (t, J=3.0 Hz, 1H), 7.23 (d, J=8.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 2.49 (s, 3H), 2.37 (s, 3H).

步骤2:向47(700mg,2.54mmol)于DMF(8mL)中的溶液在0℃加入NBS(497mg,2.79mmol)。将反应混合物在0℃搅拌2小时。混合物用二氯甲烷(50mL)稀释并用盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为褐色固体的48(660mg,89%):1H NMR(300MHz,DMSO–d6)δ11.8(s,1H),7.92(d,J=6.0Hz,1H),7.90(s,1H),7.36(d,J=8.4Hz,1H),2.49(s,3H),2.37(s,3H);ESI m/z 292[M+H]+Step 2: To a solution of 47 (700 mg, 2.54 mmol) in DMF (8 mL) was added NBS (497 mg, 2.79 mmol) at 0 ° C. The reaction mixture was stirred at 0 ° C for 2 hours. The mixture was diluted with dichloromethane (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) gave 48 (660 mg, 89%) as a brown solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.8 (s, 1H), 7.92 (d, J = 6.0 Hz, 1H), 7.90 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 2.49 (s, 3H), 2.37 (s, 3H); ESI m/z 292 [M+H] + .

步骤3:向48(250mg,0.86mmol)于CH2Cl2(5mL)中的溶液加入NEt3(130mg,1.28mmol)、DMAP(12mg,0.1mmol)和二碳酸二叔丁酯(224mg,1.03mmol)。将反应在室温搅拌16小时。浓缩反应混合物。通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化得到为灰白色固体的49(210mg,70%):1H NMR(300MHz,CDCl3)δ8.43(d,J=5.4Hz,1H),7.93(s,1H),7.34(d,J=5.1Hz,1H),2.64(s,3H),2.50(s,3H),1.69(s,9H)。Step 3: To a solution of 48 (250 mg, 0.86 mmol) in CH 2 Cl 2 (5 mL) was added NEt 3 (130 mg, 1.28 mmol), DMAP (12 mg, 0.1 mmol), and di-tert-butyl dicarbonate (224 mg, 1.03 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-30% ethyl acetate/hexanes) gave 49 (210 mg, 70%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.43 (d, J=5.4 Hz, 1H), 7.93 (s, 1H), 7.34 (d, J=5.1 Hz, 1H), 2.64 (s, 3H), 2.50 (s, 3H), 1.69 (s, 9H).

步骤4:向49(100mg,0.26mmol)于1,4-二噁烷(5mL)中的溶液在氮气气氛下加入苯胺(71mg,0.76mmol)、碳酸铯(250mg,0.76mmol)、X-phos(24mg,0.05mmol)和三(二亚苄基丙酮)二钯(0)(23mg,0.03mmol)。将反应混合物在90℃加热16小时。混合物用二氯甲烷(10mL)稀释并通过硅藻土层过滤。浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/己烷)纯化得到红色油,将其溶解于二氯甲烷(5mL)中,加入TFA(2mL),将混合物在室温搅拌2小时。浓缩混合物,将残余物溶解于二氯甲烷(100mL)中,用饱和NaHCO3(50mL×2)和盐水(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为黄色固体的实施例化合物23(47mg,64%):1H NMR(300MHz,DMSO–d6)δ11.1(d,J=1.8Hz,1H),7.82(d,J=8.4Hz,1H),7.61(d,J=2.7Hz,1H),7.43(s,1H),7.25(d,J=8.4Hz,1H),7.09(d,J=8.4Hz,1H),7.07(d,J=7.2Hz,1H),6.85(d,J=7.5Hz,2H),6.60(t,J=7.2Hz,1H),2.48(s,3H),2.29(s,3H);ESIMS m/z 305[M+H]+Step 4: To a solution of 49 (100 mg, 0.26 mmol) in 1,4-dioxane (5 mL) was added aniline (71 mg, 0.76 mmol), cesium carbonate (250 mg, 0.76 mmol), X-phos (24 mg, 0.05 mmol) and tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.03 mmol) under a nitrogen atmosphere. The reaction mixture was heated at 90°C for 16 hours. The mixture was diluted with dichloromethane (10 mL) and filtered through a pad of celite. The filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/hexane) gave a red oil, which was dissolved in dichloromethane (5 mL). TFA (2 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was dissolved in dichloromethane (100 mL) and washed with saturated NaHCO 3 (50 mL×2) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 23 (47 mg, 64%) as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.1 (d, J=1.8 Hz, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.61 (d, J=2.7 Hz, 1H), 7.43 (s, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 7.07 (d, J=7.2 Hz, 1H), 6.85 (d, J=7.5 Hz, 2H), 6.60 (t, J=7.2 Hz, 1H), 2.48 (s, 3H), 2.29 (s, 3H); ESIMS m/z 305 [M+H] + .

一般程序N:General Procedure N:

制备6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-3-甲基-1H-吡唑并[4,3-b]吡啶-4-氧化物(实施例化合物24)和6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-3-甲基-1H-吡唑并[4,3-b]吡啶-5(4H)-酮(实施例化合物25)Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine-4-oxide (Example Compound 24) and 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-3-methyl-1H-pyrazolo[4,3-b]pyridin-5(4H)-one (Example Compound 25)

步骤1:向实施例化合物53(85mg,0.25mmol)于CH2Cl2(3mL)中的溶液加入m-CPBA(160mg,0.5mmol)。将反应混合物在室温搅拌7小时。混合物用二氯甲烷(50mL)稀释并用10%Na2S2O3溶液(10mL)、2N NaOH溶液(10mL)和盐水(10mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–70%乙酸乙酯/二氯甲烷)纯化得到为灰白色固体的实施例化合物24(60mg,67%):1H NMR(300MHz,DMSO–d6)δ8.21(d,J=0.9Hz,1H),7.83(d,J=0.9Hz,1H),7.40–7.35(m,2H),7.20–7.14(m,2H),5.59(s,2H),2.69(s,3H),2.45(s,3H),2.27(s,3H);ESIMS m/z 353[M+H]+Step 1: To a solution of Example Compound 53 (85 mg, 0.25 mmol) in CH 2 Cl 2 (3 mL) was added m-CPBA (160 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 7 hours. The mixture was diluted with dichloromethane (50 mL) and washed with 10% Na 2 S 2 O 3 solution (10 mL), 2N NaOH solution (10 mL), and brine (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-70% ethyl acetate/dichloromethane) provided Example Compound 24 (60 mg, 67%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.21 (d, J=0.9 Hz, 1H), 7.83 (d, J=0.9 Hz, 1H), 7.40-7.35 (m, 2H), 7.20-7.14 (m, 2H), 5.59 (s, 2H), 2.69 (s, 3H), 2.45 (s, 3H), 2.27 (s, 3H); ESIMS m/z 353 [M+H] + .

步骤2:将实施例化合物24(32mg,0.091mmol)于Ac2O(3mL)中的溶液在130℃加热2小时。将混合物浓缩。残余物用1:1 CH3OH/H2O(10mL)稀释且在80℃搅拌10小时。浓缩反应混合物。通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化得到为灰白色固体的实施例化合物25(20mg,63%):1H NMR(300MHz,DMSO–d6)δ2.0(s,1H),8.07(s,1H),7.36–7.31(m,2H),7.19–7.13(m,2H),5.45(s,2H),2.30(s,6H),2.14(s,3H);ESIMS m/z 353[M+H]+Step 2: A solution of Example Compound 24 (32 mg, 0.091 mmol) in Ac 2 O (3 mL) was heated at 130 ° C for 2 hours. The mixture was concentrated. The residue was diluted with 1:1 CH 3 OH/H 2 O (10 mL) and stirred at 80 ° C for 10 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) gave Example Compound 25 (20 mg, 63%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 2.0 (s, 1H), 8.07 (s, 1H), 7.36-7.31 (m, 2H), 7.19-7.13 (m, 2H), 5.45 (s, 2H), 2.30 (s, 6H), 2.14 (s, 3H); ESIMS m/z 353 [M+H] + .

制备4-(3-苄基-3H-咪唑并[4,5-b]吡啶-5-基)-3,5-二甲基异噁唑(实施例化合物26)Preparation of 4-(3-benzyl-3H-imidazo[4,5-b]pyridin-5-yl)-3,5-dimethylisoxazole (Example Compound 26)

步骤1:向50(560mg,2.57mmol)于CH3CN(15mL)中的溶液加入K2CO3(887mg,6.43mmol)和苄基氯(484mg,2.83mmol)。将反应在60℃加热16小时。混合物用乙酸乙酯(100mL)稀释、过滤并浓缩以得到为黄色固体的51(790mg,100%):1H NMR(300MHz,CDCl3)δ8.58(br s,1H),8.24(d,J=8.4Hz,1H),7.46–7.35(m,5H),6.82(d,J=8.7Hz,1H),4.82(d,J=5.7Hz,2H)。[0114] Step 1: To a solution of 50 (560 mg, 2.57 mmol) in CH3CN (15 mL) was added K2CO3 ( 887 mg, 6.43 mmol) and benzyl chloride (484 mg, 2.83 mmol). The reaction was heated at 60°C for 16 hours. The mixture was diluted with ethyl acetate (100 mL), filtered, and concentrated to afford 51 (790 mg, 100%) as a yellow solid: 1H NMR (300 MHz, CDCl3 ) δ 8.58 (br s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.46-7.35 (m, 5H), 6.82 (d, J = 8.7 Hz, 1H), 4.82 (d, J = 5.7 Hz, 2H).

步骤2:向51(790mg,2.56mmol)于1,4-二噁烷(25mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(1.14g,5.12mmol)、碳酸钠(2.0M于H2O中,3.84mL,7.68mmol)和四(三苯基膦)钯(0)(300mg,0.26mmol)。反应混合物用氮气吹扫且在90℃加热8小时。混合物用二氯甲烷(200mL)稀释并过滤。浓缩滤液且通过色谱(硅胶,0–20%EtOAc/己烷)纯化以提供为黄色油的52(500mg,60%):1H NMR(300MHz,DMSO–d6)δ9.09(t,J=6.0Hz,1H),8.51(d,J=8.4Hz,1H),7.32–7.20(m,5H),6.96(d,J=8.7Hz,1H),4.85(d,J=6.3Hz,2H),2.47(s,3H),2.25(s,3H);ESI m/z 325[M+H]+Step 2: To a solution of 51 (790 mg, 2.56 mmol) in 1,4-dioxane (25 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.14 g, 5.12 mmol), sodium carbonate (2.0 M in H 2 O, 3.84 mL, 7.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.26 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 8 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-20% EtOAc/hexanes) to give 52 (500 mg, 60%) as a yellow oil: 1H NMR (300 MHz, DMSO-d 6 ) δ 9.09 (t, J=6.0 Hz, 1H), 8.51 (d, J=8.4 Hz, 1H), 7.32-7.20 (m, 5H), 6.96 (d, J=8.7 Hz, 1H), 4.85 (d, J=6.3 Hz, 2H), 2.47 (s, 3H), 2.25 (s, 3H); ESI m/z 325 [M+H] + .

步骤3:向52(500mg,1.54mmol)于THF(15mL)和水(12mL)中的溶液加入Na2S2O4(1.61g,9.24mmol)。将混合物在室温搅拌5小时;2N HCl(10mL)加入,且将混合物加热至回流15分钟,然后冷却至室温。缓慢地加入Na2CO3以调节至pH9。混合物用乙酸乙酯(100mL)萃取,有机层用盐水(50mL)洗涤、过滤并浓缩以得到为褐色油的53(460mg,100%):1H NMR(300MHz,DMSO–d6)δ7.33–7.18(m,5H),6.78(d,J=7.5Hz,1H),6.52(d,J=7.5Hz,1H),6.29(t,J=5.7Hz,1H),4.94(s,2H),4.60(d,J=5.7Hz,2H),2.36(s,3H),2.17(s,3H);ESI m/z295[M+H]+Step 3: To a solution of 52 (500 mg, 1.54 mmol) in THF (15 mL) and water (12 mL) was added Na 2 S 2 O 4 (1.61 g, 9.24 mmol). The mixture was stirred at room temperature for 5 hours; 2N HCl (10 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na 2 CO 3 was slowly added to adjust to pH 9. The mixture was extracted with ethyl acetate (100 mL), and the organic layer was washed with brine (50 mL), filtered, and concentrated to give 53 (460 mg, 100%) as a brown oil: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.33-7.18 (m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.52 (d, J=7.5 Hz, 1H), 6.29 (t, J=5.7 Hz, 1H), 4.94 (s, 2H), 4.60 (d, J=5.7 Hz, 2H), 2.36 (s, 3H), 2.17 (s, 3H); ESI m/z 295 [M+H] + .

步骤4:将53(150mg,0.51mmol)、原甲酸三甲酯(81mg,0.765mmol)和氨基磺酸(3mg)于MeOH(5mL)中的溶液加热至回流4小时。浓缩混合物,残余物通过色谱(硅胶,30–100%乙酸乙酯/己烷)纯化以提供为灰白色固体的实施例化合物26(100mg,65%):1H NMR(300MHz,DMSO–d6)δ8.67(s,1H),8.17(d,J=8.1Hz,1H),7.44(d,J=8.1Hz,1H),7.36–7.27(m,5H),5.52(s,2H),2.54(s,3H),2.34(s,3H);ESI m/z 305[M+H]+Step 4: A solution of 53 (150 mg, 0.51 mmol), trimethyl orthoformate (81 mg, 0.765 mmol) and sulfamic acid (3 mg) in MeOH (5 mL) was heated to reflux for 4 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 30-100% ethyl acetate/hexanes) to afford Example Compound 26 (100 mg, 65%) as an off-white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 8.67 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.1 Hz, 1H), 7.36-7.27 (m, 5H), 5.52 (s, 2H), 2.54 (s, 3H), 2.34 (s, 3H); ESI m/z 305 [M+H] + .

制备6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-1H-苯并[d]咪唑-4-胺(实施例化合物27),6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-N-甲基-1H-苯并[d]咪唑-4-胺(实施例化合物28)和6-(3,5-二甲基异噁唑-4-基)-1-(4-氟苄基)-N,N-二甲基-1H-苯并[d]咪唑-4-胺(实施例化合物29)Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-1H-benzo[d]imidazol-4-amine (Example Compound 27), 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N-methyl-1H-benzo[d]imidazol-4-amine (Example Compound 28), and 6-(3,5-dimethylisoxazol-4-yl)-1-(4-fluorobenzyl)-N,N-dimethyl-1H-benzo[d]imidazol-4-amine (Example Compound 29)

实施例化合物27通过与对于实施例7所述的类似的程序来制备:1H NMR(300MHz,DMSO–d6)δ8.23(s,1H),7.42(dd,J=8.0,6.0Hz,2H),7.17(dd,J=9.0,9.0Hz,2H),6.62(s,1H),6.32(s,1H),5.40(s,4H),2.33(s,3H),2.16(s,3H);ESI m/z 337[M+H]+Example Compound 27 was prepared by a procedure analogous to that described for Example 7: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 7.42 (dd, J=8.0, 6.0 Hz, 2H), 7.17 (dd, J=9.0, 9.0 Hz, 2H), 6.62 (s, 1H), 6.32 (s, 1H), 5.40 (s, 4H), 2.33 (s, 3H), 2.16 (s, 3H); ESI m/z 337 [M+H] + .

向实施例化合物27(35mg,0.10mmol)于二氯甲烷(5mL)中的溶液加入37%甲醛于水(8.5μL)和乙酸(1滴)中的溶液。将溶液搅拌45分钟,加入三乙酰氧基硼氢化钠(66mg,0.31mmol)且将混合物搅拌16小时。混合物用二氯甲烷(20mL)稀释并用饱和碳酸氢钠(5mL)中和。有机层经无水硫酸钠干燥且真空浓缩。残余物通过色谱(硅胶,0–75%乙酸乙酯/二氯甲烷)纯化以提供为白色固体的实施例化合物28(8mg,22%)和为透明固体的实施例化合物29(7mg,18%)。实施例化合物28:1H NMR(500MHz,DMSO–d6)δ8.22(s,1H),7.43(dd,J=8.8,5.5Hz,2H),7.16(dd,J=8.8,5.5Hz,2H),6.65(d,J=1.0Hz,1H),6.09(d,J=1.0Hz,1H),5.85(q,J=5.0Hz,1H),5.41(s,2H),2.83(d,J=5.5Hz,3H),2.35(s,3H),2.17(s,3H);ESIm/z 351[M+H]+;实施例29:1H NMR(500MHz,DMSO–d6)δ8.28(s,1H),7.41(dd,J=8.5,5.5Hz,2H),7.17(dd,J=9.0,9.0Hz,2H),6.85(d,J=1.0Hz,1H),6.25(d,J=1.0Hz,1H),5.43(s,2H),3.18(s,6H),2.35(s,3H),2.18(s,3H);ESI m/z 365[M+H]+To a solution of Example Compound 27 (35 mg, 0.10 mmol) in dichloromethane (5 mL) was added a solution of 37% formaldehyde in water (8.5 μL) and acetic acid (1 drop). The solution was stirred for 45 minutes, sodium triacetoxyborohydride (66 mg, 0.31 mmol) was added and the mixture was stirred for 16 hours. The mixture was diluted with dichloromethane (20 mL) and neutralized with saturated sodium bicarbonate (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0–75% ethyl acetate/dichloromethane) to provide Example Compound 28 (8 mg, 22%) as a white solid and Example Compound 29 (7 mg, 18%) as a transparent solid. Example Compound 28: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 7.43 (dd, J = 8.8, 5.5 Hz, 2H), 7.16 (dd, J = 8.8, 5.5 Hz, 2H), 6.65 (d, J = 1.0 Hz, 1H), 6.09 (d, J = 1.0 Hz, 1H), 5.85 (q, J = 5.0 Hz, 1H), 5.41 (s, 2H), 2.83 (d, J = 5.5 Hz, 3H), 2.35 (s, 3H), 2.17 (s, 3H); ESI m/z 351 [M+H] + ; Example 29: 1 H NMR (500 MHz, DMSO-d 6 )δ8.28(s,1H),7.41(dd,J=8.5,5.5Hz,2H),7.17(dd,J=9.0,9.0Hz,2H),6.85(d,J=1.0 Hz,1H),6.25(d,J=1.0Hz,1H),5.43(s,2H),3.18(s,6H),2.35(s,3H),2.18(s,3H); ESI m/z 365[M+H] + .

制备4-(1-苄基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物30)Preparation of 4-(1-benzyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 30)

步骤1:向3-氨基-5-溴-2-硝基吡啶(54,780mg,3.58mmol)和碳酸钾(2.28g,16.5mmol)于干燥乙腈(50mL)中的悬浮液加入1-(溴乙基)苯(1.22g,6.60mmol)。将混合物加热至80℃持续48小时,然后加入水(20mL)和乙酸乙酯(20mL)。将层分离且水层用乙酸乙酯萃取(2×20mL)。合并的乙酸乙酯级分经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,0–40%于己烷中的乙酸乙酯)纯化以提供为黄色固体的55(219mg,19%):1H NMR(500MHz,CDCl3)δ8.14(d,J=5.0Hz,1H),7.84(d,J=2.0Hz,1H),7.40–7.29(m,6H),4.64(quint,J=6.5Hz,1H),1.67(d,J=7.0Hz,3H)。Step 1: To a suspension of 3-amino-5-bromo-2-nitropyridine (54, 780 mg, 3.58 mmol) and potassium carbonate (2.28 g, 16.5 mmol) in dry acetonitrile (50 mL) was added 1-(bromoethyl)benzene (1.22 g, 6.60 mmol). The mixture was heated to 80 ° C for 48 hours, then water (20 mL) and ethyl acetate (20 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined ethyl acetate fractions were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-40% ethyl acetate in hexanes) to provide 55 (219 mg, 19%) as a yellow solid: 1H NMR (500 MHz, CDCI 3 ) δ 8.14 (d, J=5.0 Hz, 1H), 7.84 (d, J=2.0 Hz, 1H), 7.40-7.29 (m, 6H), 4.64 (quint, J=6.5 Hz, 1H), 1.67 (d, J=7.0 Hz, 3H).

步骤2:向55(261mg,0.81mmol)和3(217mg,0.97mmol)于1,4-二噁烷(7mL)和水(1.5mL)中的混合物加入碳酸钾(224mg,1.62mmol)和四(三苯基膦)钯(0)(47mg,0.04mmol)。将反应搅拌并在90℃加热17小时。反应混合物用甲醇(20mL)稀释且加入硅胶(15g)。将悬浮液浓缩至干并将所得粉末负载于硅胶上并用0–50%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为黄色固体的56(226mg,82%):1H NMR(500MHz,CDCl3)δ8.19(d,J=4.5Hz,1H),7.77(d,J=2.0Hz,1H),7.40–7.28(m,5H),6.89(d,J=2.0Hz,1H),4.66(quint,J=5.0Hz,1H),2.10(s,3H),1.94(s,3H),1.71(d,J=7.0Hz,3H)。Step 2: To a mixture of 55 (261 mg, 0.81 mmol) and 3 (217 mg, 0.97 mmol) in 1,4-dioxane (7 mL) and water (1.5 mL) was added potassium carbonate (224 mg, 1.62 mmol) and tetrakis(triphenylphosphine)palladium(0) (47 mg, 0.04 mmol). The reaction was stirred and heated at 90 ° C for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (15 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded on silica gel and eluted with 0-50% ethyl acetate in hexane. The clean product was concentrated to give 56 (226 mg, 82%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 8.19 (d, J=4.5 Hz, 1H), 7.77 (d, J=2.0 Hz, 1H), 7.40-7.28 (m, 5H), 6.89 (d, J=2.0 Hz, 1H), 4.66 (quint, J=5.0 Hz, 1H), 2.10 (s, 3H), 1.94 (s, 3H), 1.71 (d, J=7.0 Hz, 3H).

步骤3:在5分钟内向56(226mg,0.67mmol)于THF(20ml)中的溶液逐滴加入连二亚硫酸钠(698mg,4.01mmol)于水(20mL)中的溶液。将溶液在室温搅拌16小时并真空除去溶剂。加入甲醇(20mL)且将悬浮液在室温搅拌3小时。过滤混合物并浓缩滤液至干。将2N HCl水溶液加入至残余物并加热至回流5分钟。浓缩至干后,加入甲醇(10mL)并使用饱和NaHCO3水溶液(20mL)将溶液调节至pH8。加入硅胶(10g)并将悬浮液浓缩至干。将所得粉末负载于硅胶上并用0–70%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为米色固体的57(96mg,47%):1H NMR(500MHz,CDCl3)δ7.42(d,J=2.0Hz,1H),7.33–7.30(m,4H),7.25–7.22(m,1H),6.34(d,J=1.5Hz,1H),4.44(quint,J=5.0Hz,1H),4.36(br s,2H),3.70(br s,1H),2.07(s,3H),1.89(s,3H),1.58(d,J=6.5Hz,3H)。Step 3: To a solution of 56 (226 mg, 0.67 mmol) in THF (20 ml) was added dropwise a solution of sodium dithionite (698 mg, 4.01 mmol) in water (20 mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. A 2N HCl aqueous solution was added to the residue and heated to reflux for 5 minutes. After being concentrated to dryness, methanol (10 mL) was added and the solution was adjusted to pH 8 using a saturated NaHCO 3 aqueous solution (20 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was loaded on silica gel and eluted with 0–70% ethyl acetate in hexane. The clean product was concentrated to give 57 (96 mg, 47%) as a beige solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.42 (d, J = 2.0 Hz, 1H), 7.33-7.30 (m, 4H), 7.25-7.22 (m, 1H), 6.34 (d, J = 1.5 Hz, 1H), 4.44 (quint, J = 5.0 Hz, 1H), 4.36 (br s, 2H), 3.70 (br s, 1H), 2.07 (s, 3H), 1.89 (s, 3H), 1.58 (d, J = 6.5 Hz, 3H).

步骤4:将57(47mg,0.15mmol)、原甲酸三甲酯(2mL,18.3mmol)和氨基磺酸(1mg)的混合物在密封管中于100℃加热30分钟。冷却混合物,浓缩且负载于硅胶上并用0–20%于己烷中的乙酸乙酯洗脱。所得材料通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化以提供为白色固体的(实施例化合物30)(19mg,39%):1H NMR(500MHz,CD3OD)δ8.76(s,1H),8.36(d,J=2.0Hz,1H),7.65(d,J=2.5Hz,1H),7.40–7.30(m,5H),4.44(q,J=7.0Hz,1H),2.29(s,3H),2.10(s,3H),2.06(d,J=7.0Hz,3H).ESI m/z 319[M+H]+Step 4: A mixture of 57 (47 mg, 0.15 mmol), trimethyl orthoformate (2 mL, 18.3 mmol) and sulfamic acid (1 mg) was heated in a sealed tube at 100° C. for 30 min. The mixture was cooled, concentrated and loaded onto silica gel and eluted with 0-20% ethyl acetate in hexanes. The resulting material was purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O to provide (Example Compound 30) (19 mg, 39%) as a white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.76 (s, 1 H), 8.36 (d, J=2.0 Hz, 1 H), 7.65 (d, J=2.5 Hz, 1 H), 7.40-7.30 (m, 5 H), 4.44 (q, J=7.0 Hz, 1 H), 2.29 (s, 3 H), 2.10 (s, 3 H), 2.06 (d, J=7.0 Hz, 3 H). ESI m/z 319 [M+H] + .

制备4-(1-苄基-1H-咪唑并[4,5-c]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物31)、1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-c]吡啶5-氧化物(实施例32)和1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-c]吡啶-4-胺(实施例化合物33)Preparation of 4-(1-benzyl-1H-imidazo[4,5-c]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 31), 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridine 5-oxide (Example 32), and 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-c]pyridin-4-amine (Example Compound 33)

步骤1:向58(1.00g,5.76mmol)于1,4-二噁烷(40mL)和水(4mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(1.93g,8.64mmol)、碳酸钾(1.59g,11.5mmol)和四(三苯基膦)钯(0)(333mg,0.288mmol)。反应混合物用氮气吹扫且在90℃加热过夜。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以提供为黄色固体的59(1.42g,>99%):1H NMR(300MHz,CDCl3)δ9.26(s,1H),6.67(s,1H),6.90–6.00(bs,2H),2.61(s,3H),2.44(s,3H);ESI m/z 235[M+H]+Step 1: To a solution of 58 (1.00 g, 5.76 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.93 g, 8.64 mmol), potassium carbonate (1.59 g, 11.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (333 mg, 0.288 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to provide 59 (1.42 g, >99%) as a yellow solid: 1 H NMR (300 MHz, CDCI 3 ) δ 9.26 (s, 1H), 6.67 (s, 1H), 6.90-6.00 (bs, 2H), 2.61 (s, 3H), 2.44 (s, 3H); ESI m/z 235 [M+H] + .

步骤2:将59(710mg,3.03mmol)、苄基溴(778mg,4.55mmol)和碳酸钾(836mg,6.06mmol)于乙腈(30mL)中的混合物在密封管中于90℃加热过夜。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–30%于己烷中的乙酸乙酯)纯化以提供为褐色固体的60(303mg,30%):1H NMR(500MHz,CDCl3)δ9.26(s,1H),8.68(s,1H),7.50–7.10(m,5H),6.50(s,1H),4.65(d,J=4.1Hz,2H),2.39(s,3H),2.19(s,3H);ESI m/z 325[M+H]+[0114] Step 2: A mixture of 59 (710 mg, 3.03 mmol), benzyl bromide (778 mg, 4.55 mmol) and potassium carbonate (836 mg, 6.06 mmol) in acetonitrile (30 mL) was heated in a sealed tube at 90° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford 60 (303 mg, 30%) as a brown solid: 1H NMR (500 MHz, CDCl 3 ) δ 9.26 (s, 1H), 8.68 (s, 1H), 7.50-7.10 (m, 5H), 6.50 (s, 1H), 4.65 (d, J=4.1 Hz, 2H), 2.39 (s, 3H), 2.19 (s, 3H); ESI m/z 325 [M+H] + .

步骤3:向60(300mg,0.926mmol)于四氢呋喃(10mL)中的溶液加入于水(10mL)中的连二亚硫酸钠(967mg,5.56mmol)。将反应混合物在室温搅拌过夜且在真空下浓缩。将残余物悬浮于MeOH中且过滤固体,用MeOH洗涤,且将滤液在真空下浓缩。向残余物加入2N HCl并加热至刚好沸腾,冷却至室温且在真空下浓缩。将残余物溶解于MeOH中且用10%NaHCO3碱化,浓缩且通过色谱(硅胶,0–20%于乙酸乙酯中的甲醇)纯化以提供为灰色固体的61(150mg,55%):1H NMR(500MHz,CDCl3)δ7.99(s,1H),7.40–7.28(m,5H),6.39(s,1H),4.64(s,1H),4.43(d,J=5.4Hz,2H),3.15(s,2H),2.33(s,3H),2.21(s,3H);ESI m/z 295[M+H]+Step 3: To a solution of 60 (300 mg, 0.926 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (967 mg, 5.56 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was suspended in MeOH and the solid was filtered, washed with MeOH, and the filtrate was concentrated under vacuum. 2N HCl was added to the residue and heated to just boiling, cooled to room temperature and concentrated under vacuum. The residue was dissolved in MeOH and basified with 10% NaHCO 3 , concentrated and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to provide 61 (150 mg, 55%) as a grey solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.40-7.28 (m, 5H), 6.39 (s, 1H), 4.64 (s, 1H), 4.43 (d, J=5.4 Hz, 2H), 3.15 (s, 2H), 2.33 (s, 3H), 2.21 (s, 3H); ESI m/z 295 [M+H] + .

步骤4:向61(150mg,0.51mmol)于乙醇(5mL)中的溶液加入原甲酸三甲酯(81mg,0.77mmol)和氨基磺酸(1mg,0.01mmol)。将反应在密封管中于90℃加热过夜。将混合物浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为黄色固体的实施例化合物31(143mg,92%):1H NMR(500MHz,CD3OD)δ9.00(d,J=1.0Hz,1H),8.05(s,1H),7.48(d,J=1.0Hz,1H),7.40–7.30(m,5H),5.58(s,2H),2.40(s,3H),2.25(s,3H);ESI m/z 305[M+H]+Step 4: To a solution of 61 (150 mg, 0.51 mmol) in ethanol (5 mL) was added trimethyl orthoformate (81 mg, 0.77 mmol) and sulfamic acid (1 mg, 0.01 mmol). The reaction was heated in a sealed tube at 90 ° C. overnight. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 31 (143 mg, 92%) as a yellow solid: 1H NMR (500 MHz, CD 3 OD) δ 9.00 (d, J = 1.0 Hz, 1H), 8.05 (s, 1H), 7.48 (d, J = 1.0 Hz, 1H), 7.40-7.30 (m, 5H), 5.58 (s, 2H), 2.40 (s, 3H), 2.25 (s, 3H); ESI m / z 305 [M + H] + .

步骤5:向实施例化合物31(100mg,0.329mmol)于二氯甲烷(5mL)中的混合物加入3-氯过氧苯甲酸(264mg,77%水溶液,1.18mmol)。将混合物在室温搅拌过夜,浓缩且通过色谱(硅胶,0–20%于乙酸乙酯中的甲醇)纯化以提供为灰白色固体的实施例化合物32(127mg,>99%):1H NMR(500MHz,CD3OD)δ8.92(s,1H),8.61(s,1H),7.67(s,1H),7.45–7.25(m,5H),6.57(s,2H),2.28(s,3H),2.17(s,3H);ESI m/z 321[M+H]+Step 5: To a mixture of Example Compound 31 (100 mg, 0.329 mmol) in dichloromethane (5 mL) was added 3-chloroperoxybenzoic acid (264 mg, 77% aqueous solution, 1.18 mmol). The mixture was stirred at room temperature overnight, concentrated, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate) to afford Example Compound 32 (127 mg, >99%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.92 (s, 1H), 8.61 (s, 1H), 7.67 (s, 1H), 7.45-7.25 (m, 5H), 6.57 (s, 2H), 2.28 (s, 3H), 2.17 (s, 3H); ESI m/z 321 [M+H] + .

步骤6:向氧溴化磷(268mg,0.938mmol)于DMF(2mL)中的混合物加入于DMF(6mL)中的实施例32(100mg,0.313mmol)。将混合物在室温搅拌10分钟并在100℃加热1小时。冷却至室温后,加入水和MeOH。通过添加10%碳酸氢钠将混合物中和至pH7并浓缩。残余物通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以提供为灰白色固体的62(30mg,25%):1HNMR(500MHz,CDCl3)δ8.09(s,1H),7.43–7.35(m,3H),7.23–7.19(m,2H),7.03(s,1H),5.38(s,2H),2.47(s,3H),2.31(s,3H);ESI m/z 383[M+H]+Step 6: To a mixture of phosphorus oxybromide (268 mg, 0.938 mmol) in DMF (2 mL) was added Example 32 (100 mg, 0.313 mmol) in DMF (6 mL). The mixture was stirred at room temperature for 10 minutes and heated at 100°C for 1 hour. After cooling to room temperature, water and MeOH were added. The mixture was neutralized to pH 7 by adding 10% sodium bicarbonate and concentrated. The residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to provide 62 (30 mg, 25%) as an off-white solid: 1 H NMR (500 MHz, CDCI 3 ) δ 8.09 (s, 1H), 7.43-7.35 (m, 3H), 7.23-7.19 (m, 2H), 7.03 (s, 1H), 5.38 (s, 2H), 2.47 (s, 3H), 2.31 (s, 3H); ESI m/z 383 [M+H] + .

步骤7:向62(30mg,0.078mmol)于甲苯(10mL)中的溶液在氮气气氛下加入氨基甲酸叔丁酯(27mg,0.23mmol)、碳酸铯(51mg,0.16mmol)、2-二环己基膦基-2',4',6'-三异丙基-1,1'-联苯基(6mg,0.01mmol)和三(二亚苄基丙酮)二钯(0)(7mg,0.008mmol)。将反应混合物在90℃加热过夜,冷却至室温,且通过色谱(硅胶,0–20%于乙酸乙酯中的甲醇)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC进一步纯化以得到为灰白色固体的实施例化合物33(10mg,40%):1H NMR(500MHz,CD3OD)δ8.21(s,1H),7.42–7.25(m,5H),6.70(s,1H),5.46(s,2H),2.39(s,3H),2.24(s,3H);HPLC 96.9%,tR=10.1分钟;ESI m/z320[M+H]+Step 7: To a solution of 62 (30 mg, 0.078 mmol) in toluene (10 mL) was added tert-butyl carbamate (27 mg, 0.23 mmol), cesium carbonate (51 mg, 0.16 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (6 mg, 0.01 mmol) and tris(dibenzylideneacetone)dipalladium(0) (7 mg, 0.008 mmol) under nitrogen atmosphere. The reaction mixture was heated at 90 ° C. overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It was further purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O to give Example Compound 33 (10 mg, 40%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.21 (s, 1H), 7.42-7.25 (m, 5H), 6.70 (s, 1H), 5.46 (s, 2H), 2.39 (s, 3H), 2.24 (s, 3H); HPLC 96.9%, t R =10.1 min; ESI m/z 320 [M+H] + .

制备4-(1-苄基-3-溴-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑。(实施例化合物化合物34)Preparation of 4-(1-benzyl-3-bromo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole. (Example Compound 34)

步骤1:向46(1.0g,5.08mmol)于1,4-二噁烷(50mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(1.47g,6.6mmol)、碳酸钠(1.10g于8mL H2O中,10.2mmol)和四(三苯基膦)钯(0)(587mg,0.51mmol)。反应混合物用氮气吹扫且在90℃加热16小时。将混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为黄色固体的63(850mg,79%):1H NMR(300MHz,DMSO–d6)δ11.4(s,1H),8.30(t,J=2.1Hz,1H),7.75(dd,J=1.8,0.9Hz,1H),7.70(t,J=3.0Hz,1H),6.61–6.59(m,1H),2.42(s,3H),2.24(s,3H)。Step 1: To a solution of 46 (1.0 g, 5.08 mmol) in 1,4-dioxane (50 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (1.47 g, 6.6 mmol), sodium carbonate (1.10 g in 8 mL H 2 O, 10.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (587 mg, 0.51 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded 63 (850 mg, 79%) as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 11.4 (s, 1H), 8.30 (t, J=2.1 Hz, 1H), 7.75 (dd, J=1.8, 0.9 Hz, 1H), 7.70 (t, J=3.0 Hz, 1H), 6.61-6.59 (m, 1H), 2.42 (s, 3H), 2.24 (s, 3H).

步骤2/3:向63(500mg,2.35mmol)于DMF(10mL)中的溶液在0℃加入NBS(500mg,2.82mmol)。将反应混合物在0℃搅拌2小时。混合物用二氯甲烷(50mL)稀释并用盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。粗品64继续用于反应。向64(300mg,1.03mmol)于DMF(1mL)和CH3CN(10mL)中的溶液加入碳酸钾(283mg,2.06mmol)和苄基氯(130mg,1.03mmol)。将反应在70℃搅拌16小时。将混合物滤过硅藻土层并浓缩滤液。通过色谱硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为灰白色固体的实施例化合物34(200mg,51%):1HNMR(500MHz,CD3OD)δ8.33(d,J=1.5Hz,1H),7.86(s,1H),7.80(d,J=2.0Hz,1H),7.34–7.24(m,5H),5.48(s,2H),2.35(s,3H),2.17(s,3H);ESI MS m/z 382[M+H]+Step 2/3: To a solution of 63 (500 mg, 2.35 mmol) in DMF (10 mL) at 0°C was added NBS (500 mg, 2.82 mmol). The reaction mixture was stirred at 0°C for 2 hours. The mixture was diluted with dichloromethane (50 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product 64 was used further in the reaction. To a solution of 64 (300 mg, 1.03 mmol) in DMF (1 mL) and CH 3 CN (10 mL) were added potassium carbonate (283 mg, 2.06 mmol) and benzyl chloride (130 mg, 1.03 mmol). The reaction was stirred at 70°C for 16 hours. The mixture was filtered through a pad of celite, and the filtrate was concentrated. Purification by chromatography on silica gel, 0-50% ethyl acetate/dichloromethane (500 MHz, CD 3 OD) afforded Example Compound 34 (200 mg, 51%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.33 (d, J=1.5 Hz, 1H), 7.86 (s, 1H), 7.80 (d, J=2.0 Hz, 1H), 7.34-7.24 (m, 5H), 5.48 (s, 2H), 2.35 (s, 3H), 2.17 (s, 3H); ESI MS m/z 382 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-甲醛(实施例化合物35)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carbaldehyde (Example Compound 35)

步骤1:向46(300mg,1.5mmol)和六亚甲基四胺(0.32g,2.25mmol)的混合物加入AcOH(2mL)。将反应混合物在120℃搅拌6小时且用H2O(5mL)淬灭。沉淀通过过滤收获以提供为黄色固体的65(190mg,56%):1H NMR(300MHz,DMSO–d6)δ12.4(s,1H),10.1(s,1H),8.58(d,J=2.1Hz,1H),8.47(s,1H),8.18(d,J=2.1Hz,1H)。Step 1: To a mixture of 46 (300 mg, 1.5 mmol) and hexamethylenetetramine (0.32 g, 2.25 mmol) was added AcOH (2 mL). The reaction mixture was stirred at 120 ° C for 6 hours and quenched with H 2 O (5 mL). The precipitate was harvested by filtration to afford 65 (190 mg, 56%) as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.4 (s, 1H), 10.1 (s, 1H), 8.58 (d, J = 2.1 Hz, 1H), 8.47 (s, 1H), 8.18 (d, J = 2.1 Hz, 1H).

步骤2:向65(190mg,0.84mmol)于1,4-二噁烷(5mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(245mg,1.09mmol)、碳酸钠(178mg于1mL H2O中,1.68mmol)和四(三苯基膦)钯(0)(97mg,0.08mmol)。反应混合物用氮气吹扫且在90℃加热16小时。将混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为灰白色固体的66(135mg,67%):1H NMR(300MHz,DMSO–d6)δ12.5(s,1H),10.2(s,1H),8.51(d,J=1.8Hz,1H),8.49(d,J=3.0Hz,1H),7.92(d,J=1.8Hz,1H),2.44(s,3H),2.26(s,3H);ESIMS m/z 242[M+H]+Step 2: To a solution of 65 (190 mg, 0.84 mmol) in 1,4-dioxane (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (245 mg, 1.09 mmol), sodium carbonate (178 mg in 1 mL H 2 O, 1.68 mmol) and tetrakis(triphenylphosphine)palladium(0) (97 mg, 0.08 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) afforded 66 (135 mg, 67%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.5 (s, 1H), 10.2 (s, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.49 (d, J=3.0 Hz, 1H), 7.92 (d, J=1.8 Hz, 1H), 2.44 (s, 3H), 2.26 (s, 3H); ESIMS m/z 242 [M+H] + .

步骤3:向66(92mg,0.38mmol)于DMF(0.5mL)和CH3CN(5mL)中的溶液加入碳酸钾(105mg,0.76mmol)和苄基氯(58mg,0.46mmol)。将反应在70℃搅拌16小时。将反应混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为灰白色固体的实施例化合物35(72mg,57%):1H NMR(300MHz,DMSO–d6)δ10.2(s,1H),8.73(s,1H),8.53(d,J=1.8Hz,1H),8.11(d,J=1.8Hz,1H),7.44–7.30(m,5H),5.59(s,2H),2.40(s,3H),2.21(s,3H);ESI MS m/z 332[M+H]+Step 3: To a solution of 66 (92 mg, 0.38 mmol) in DMF (0.5 mL) and CH 3 CN (5 mL) were added potassium carbonate (105 mg, 0.76 mmol) and benzyl chloride (58 mg, 0.46 mmol). The reaction was stirred at 70° C. for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 35 (72 mg, 57%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.2 (s, 1H), 8.73 (s, 1H), 8.53 (d, J=1.8 Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.44-7.30 (m, 5H), 5.59 (s, 2H), 2.40 (s, 3H), 2.21 (s, 3H); ESI MS m/z 332 [M+H] + .

制备1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)-N,N-二甲基甲胺(实施例化合物72)Preparation of 1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylmethanamine (Example Compound 72)

将实施例化合物35(54mg,0.16mmol)、二甲胺(0.25mL,2M于THF中,0.49mmol)和NaBH(OAc)3(104mg,0.49mmol)于CH2Cl2(3mL)中的溶液在室温搅拌16小时。将反应混合物在减压下浓缩。粗反应混合物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为灰白色固体的实施例化合物72(42mg,71%):1H NMR(300MHz,CDCl3)δ8.34(d,J=1.8Hz,1H),8.30(s,1H),7.36–7.32(m,4H),7.21–7.18(m,2H),5.39(s,2H),4.50(s,2H),2.86(s,6H),2.32(s,3H),2.16(s,3H);ESIMS m/z 361[M+H]+A solution of Example Compound 35 (54 mg, 0.16 mmol), dimethylamine (0.25 mL, 2 M in THF, 0.49 mmol) and NaBH(OAc) 3 (104 mg, 0.49 mmol) in CH 2 Cl 2 (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude reaction mixture was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 72 (42 mg, 71%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.34 (d, J=1.8 Hz, 1H), 8.30 (s, 1H), 7.36-7.32 (m, 4H), 7.21-7.18 (m, 2H), 5.39 (s, 2H), 4.50 (s, 2H), 2.86 (s, 6H), 2.32 (s, 3H), 2.16 (s, 3H); ESIMS m/z 361 [M+H] + .

制备1-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)乙酮(实施例化合物36)Preparation of 1-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)ethanone (Example Compound 36)

步骤1:向AlCl3(313mg,2.35mmol)于CH2Cl2(20mL)中的悬浮液加入63(100mg,0.47mmol)和AcCl(184mg,2.35mmol)。将反应混合物在室温搅拌6小时。将反应小心地用甲醇(10mL)淬灭且调节pH以用固体Na2CO3中和。将混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化得到为灰白色固体的67(82mg,68%):1H NMR(300MHz,DMSO–d6)δ12.8(s,1H),8.67(s,1H),8.57(s,1H),8.21(s,1H),2.71(s,3H),2.45(s,3H),2.26(s,3H);ESIMS m/z 256[M+H]+Step 1: To a suspension of AlCl 3 (313 mg, 2.35 mmol) in CH 2 Cl 2 (20 mL) was added 63 (100 mg, 0.47 mmol) and AcCl (184 mg, 2.35 mmol). The reaction mixture was stirred at room temperature for 6 hours. The reaction was carefully quenched with methanol (10 mL) and the pH was adjusted to neutralize with solid Na 2 CO 3. The mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-10% methanol/dichloromethane) provided 67 (82 mg, 68%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.8 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 2.71 (s, 3H), 2.45 (s, 3H), 2.26 (s, 3H); ESIMS m/z 256 [M+H] + .

步骤2:向67(62mg,0.24mmol)于DMF(0.5mL)和CH3CN(5mL)中的溶液加入碳酸钾(67mg,0.48mmol)和苄基氯(37mg,0.29mmol)。将反应在70℃搅拌16小时。将反应混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为灰白色固体的实施例化合物36(30mg,36%):1H NMR(300MHz,CDCl3)δ8.59(d,J=1.5Hz,1H),8.22(s,1H),7.45(d,J=1.8Hz,1H),7.40–7.36(m,3H),7.21–7.18(m,2H),5.40(s,2H),2.89(s,3H),2.34(s,3H),2.17(s,3H);ESI MS m/z 346[M+H]+Step 2: To a solution of 67 (62 mg, 0.24 mmol) in DMF (0.5 mL) and CH 3 CN (5 mL) were added potassium carbonate (67 mg, 0.48 mmol) and benzyl chloride (37 mg, 0.29 mmol). The reaction was stirred at 70° C. for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 36 (30 mg, 36%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.59 (d, J=1.5 Hz, 1H), 8.22 (s, 1H), 7.45 (d, J=1.8 Hz, 1H), 7.40-7.36 (m, 3H), 7.21-7.18 (m, 2H), 5.40 (s, 2H), 2.89 (s, 3H), 2.34 (s, 3H), 2.17 (s, 3H); ESI MS m/z 346 [M+H] + .

制备甲酸1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-5-基酯(实施例化合物37)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-5-yl formate (Example Compound 37)

步骤1:将实施例化合物56(165mg,0.52mmol)于DMF(2mL)中的溶液加入POCl3(159mg,1.03mmol)。将反应混合物在100℃加热2小时并浓缩。将残余物溶解于CH2Cl2(100mL)中,用饱和NaHCO3(2×20mL)和盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为黄色固体的实施例化合物37(81mg,45%):1H NMR(300MHz,CDCl3)δ9.90(s,1H),7.62(s,1H),7.43–7.41(m,3H),7.28(s,1H),7.22–7.18(m,3H),5.31(s,2H),2.22(s,3H),2.10(s,3H);ESIMS m/z 348[M+H]+Step 1: A solution of Example Compound 56 (165 mg, 0.52 mmol) in DMF (2 mL) was added to POCl 3 (159 mg, 1.03 mmol). The reaction mixture was heated at 100° C. for 2 hours and concentrated. The residue was dissolved in CH 2 Cl 2 (100 mL) and washed with saturated NaHCO 3 (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 37 (81 mg, 45%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3 ) δ 9.90 (s, 1H), 7.62 (s, 1H), 7.43-7.41 (m, 3H), 7.28 (s, 1H), 7.22-7.18 (m, 3H), 5.31 (s, 2H), 2.22 (s, 3H), 2.10 (s, 3H); ESIMS m/z 348 [M+H] + .

制备4-((6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲酰胺(实施例化合物38)Preparation of 4-((6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzamide (Example Compound 38)

向实施例化合物70(100mg,0.29mmol)于乙醇(3mL)中的溶液加入2N于水中的氢氧化钠(1.46mL,2.9mmol)。将混合物加热至85℃持续20分钟,然后冷却至室温,且用2mL乙酸中和。用固体碳酸钠将混合物碱化(pH8),于二氯甲烷(100mL)中稀释,用盐水(20mL)洗涤且经无水硫酸钠干燥。过滤后,将滤液真空浓缩且通过色谱(硅胶,0–20%甲醇/二氯甲烷)纯化以提供为白色固体的实施例化合物38(71mg,68%):1H NMR(300MHz,DMSO–d6)δ8.35(d,J=1.8Hz,1H),7.99(d,J=2.1Hz,1H),7.94(brs,1H),7.83(d,J=8.4Hz,2H),7.37(br s,1H),7.27(d,J=8.4Hz,2H),5.61(s,2H),2.60(s,3H),2.39(s,3H),2.21(s,3H);ESI m/z362[M+H]+To a solution of Example Compound 70 (100 mg, 0.29 mmol) in ethanol (3 mL) was added 2N sodium hydroxide in water (1.46 mL, 2.9 mmol). The mixture was heated to 85°C for 20 minutes, then cooled to room temperature and neutralized with 2 mL of acetic acid. The mixture was basified (pH 8) with solid sodium carbonate, diluted in dichloromethane (100 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo and purified by chromatography (silica gel, 0-20% methanol/dichloromethane) to provide Example Compound 38 (71 mg, 68%) as a white solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 8.35 (d, J=1.8 Hz, 1H), 7.99 (d, J=2.1 Hz, 1H), 7.94 (br s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.37 (br s, 1H), 7.27 (d, J=8.4 Hz, 2H), 5.61 (s, 2H), 2.60 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H); ESI m/z 362 [M+H] + .

制备4-(1-苄基-3-硝基-1H-吡咯并[3,2-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物39)Preparation of 4-(1-benzyl-3-nitro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 39)

步骤1:向63(100mg,0.47mmol)于H2SO4(0.5mL)中的溶液在0℃加入HNO3(35mg,0.47mmol)。将反应混合物在0℃搅拌1小时。反应混合物用H2O(10mL)稀释且用6N NaOH溶液调节以中和pH。溶液用CH2Cl2萃取(30mL)。将有机层干燥,过滤并浓缩。通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化得到为黄色固体的68(82mg,68%):1H NMR(300MHz,DMSO–d6)δ12.9(s,1H),8.85(s,1H),8.58(d,J=2.1Hz,1H),7.95(d,J=1.8Hz,1H),2.45(s,3H),2.26(s,3H);ESIMS m/z 259[M+H]+Step 1: To a solution of 63 (100 mg, 0.47 mmol) in H2SO4 (0.5 mL ) was added HNO3 (35 mg, 0.47 mmol) at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with H2O (10 mL) and adjusted with 6N NaOH solution to neutralize the pH. The solution was extracted with CH2Cl2 (30 mL). The organic layer was dried, filtered and concentrated. Purification by chromatography (silica gel, 0-10% methanol/dichloromethane) afforded 68 (82 mg, 68%) as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.9 (s, 1H), 8.85 (s, 1H), 8.58 (d, J=2.1 Hz, 1H), 7.95 (d, J=1.8 Hz, 1H), 2.45 (s, 3H), 2.26 (s, 3H); ESIMS m/z 259 [M+H] + .

步骤2:向68(82mg,0.32mmol)于DMF(0.5mL)和CH3CN(5mL)中的溶液加入碳酸钾(88mg,0.64mmol)和苄基氯(44mg,0.35mmol)。将反应在70℃搅拌16小时。将反应混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–50%乙酸乙酯/二氯甲烷)纯化得到为灰白色固体的实施例化合物39(68mg,61%):1H NMR(300MHz,CDCl3)δ8.74(s,1H),8.47(s,1H),7.56(s,1H),7.45–7.42(m,3H),7.27–7.26(m,2H),5.47(s,2H),2.35(s,3H),2.17(s,3H);ESIMSm/z 349[M+H]+Step 2: To a solution of 68 (82 mg, 0.32 mmol) in DMF (0.5 mL) and CH 3 CN (5 mL) were added potassium carbonate (88 mg, 0.64 mmol) and benzyl chloride (44 mg, 0.35 mmol). The reaction was stirred at 70° C. for 16 hours. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated. Purification by chromatography (silica gel, 0-50% ethyl acetate/dichloromethane) provided Example Compound 39 (68 mg, 61%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.74 (s, 1H), 8.47 (s, 1H), 7.56 (s, 1H), 7.45-7.42 (m, 3H), 7.27-7.26 (m, 2H), 5.47 (s, 2H), 2.35 (s, 3H), 2.17 (s, 3H); ESIMS m/z 349 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-乙氧基-1H-苯并[d]咪唑-4-胺(实施例化合物17)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-amine (Example Compound 17)

步骤1:将37(200mg,0.709mmol)于四乙氧基甲烷(340mg,1.77mmol)中的混合物在100℃加热4小时。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–50%于己烷中的乙酸乙酯)纯化以提供为黄色固体的69(177mg,74%):1H NMR(500MHz,CD3OD)δ7.30–7.15(m,2H),4.57(q,J=7.0Hz,2H),2.39(s,3H),2.23(s,3H),1.47(t,J=7.0Hz,3H);ESI m/z 336[M+H]+Step 1: A mixture of 37 (200 mg, 0.709 mmol) in tetraethoxymethane (340 mg, 1.77 mmol) was heated at 100° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to afford 69 (177 mg, 74%) as a yellow solid: 1H NMR (500 MHz, CD 3 OD) δ 7.30-7.15 (m, 2H), 4.57 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 2.23 (s, 3H), 1.47 (t, J=7.0 Hz, 3H); ESI m/z 336 [M+H] + .

步骤2:向69(250mg,0.74mmol)于CH3CN(8mL)和DMF(2mL)中的溶液加入K2CO3(155mg,0.82mmol)和苄基氯(104mg,0.82mmol)。将反应在60℃加热16小时。混合物用乙酸乙酯(100mL)稀释、过滤并浓缩。残余物通过色谱(硅胶,0–30%EtOAc/己烷)纯化以提供为灰白色固体的70(200mg,63%)和为无色油的71(87mg,27%):70:1H NMR(300MHz,CDCl3)δ7.34–7.29(m,3H),7.21–7.18(m,3H),6.77(d,J=1.5Hz,1H),5.16(s,2H),4.75(q,J=7.5Hz,2H),2.29(s,3H),2.14(s,3H),1.50(t,J=7.0Hz,3H);71:1H NMR(300MHz,CDCl3)δ7.37(d,J=1.5Hz,1H),7.34–7.28(m,3H),7.18(d,J=7.5Hz,2H),7.12(d,J=1.5Hz,1H),5.60(s,2H),4.63(q,J=7.0Hz,2H),2.41(s,3H),2.28(s,3H),1.45(t,J=7.0Hz,3H)。Step 2: To a solution of 69 (250 mg, 0.74 mmol) in CH 3 CN (8 mL) and DMF (2 mL) was added K 2 CO 3 (155 mg, 0.82 mmol) and benzyl chloride (104 mg, 0.82 mmol). The reaction was heated at 60° C. for 16 h. The mixture was diluted with ethyl acetate (100 mL), filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to afford 70 (200 mg, 63%) as an off-white solid and 71 (87 mg, 27%) as a colorless oil: 70: 1H NMR (300 MHz, CDCl 3 ) δ 7.34-7.29 (m, 3H), 7.21-7.18 (m, 3H), 6.77 (d, J=1.5 Hz, 1H), 5.16 (s, 2H), 4.75 (q, J=7.5 Hz, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 1.50 (t, J=7.0 Hz, 3H); 71: 1H NMR (300 MHz, CDCl 3 ) δ 7.34-7.29 (m, 3H), 7.21-7.18 (m, 3H), 6.77 (d, J=1.5 Hz, 1H), 5.16 (s, 2H), 4.75 (q, J=7.5 Hz, 2H), 2.29 (s, 3H), 2.14 (s, 3H), 1.50 (t, J=7.0 Hz, 3H ); )δ7.37(d,J=1.5Hz,1H),7.34–7.28(m,3H),7.18(d,J=7.5Hz,2H),7.12(d,J=1.5Hz,1H ), 5.60 (s, 2H), 4.63 (q, J = 7.0Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.45 (t, J = 7.0Hz, 3H).

步骤3:将70(100mg,0.235mmol)、BocNH2(82mg,0.705mmol)、Xantphos(28mg,0.048mmol)、Pd2(dba)3(22mg,0.024mmol)和Cs2CO3(268mg,0.823mmol)于1,4-二噁烷(8mL)中的混合物用氮气吹扫并在100℃加热18小时。混合物用二氯甲烷(200mL)稀释并过滤。浓缩滤液且通过色谱(硅胶,0–30%EtOAc/己烷)纯化以提供为灰白色固体的72(90mg,83%):1HNMR(300MHz,CDCl3)δ7.74(br s,1H),7.41(s,1H),7.32–7.29(m,3H),7.22–7.19(m,2H),6.51(d,J=1.5Hz,1H),5.14(s,2H),4.64(q,J=7.2Hz,2H),2.32(s,3H),2.17(s,3H),1.49(t,J=7.2Hz,3H),1.46(s,9H)。Step 3: A mixture of 70 (100 mg, 0.235 mmol), BocNH2 (82 mg, 0.705 mmol), Xantphos (28 mg, 0.048 mmol), Pd2 (dba) 3 (22 mg, 0.024 mmol) and Cs2CO3 (268 mg, 0.823 mmol) in 1,4- dioxane (8 mL) was purged with nitrogen and heated at 100°C for 18 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-30% EtOAc/hexanes) to afford 72 (90 mg, 83%) as an off-white solid: 1H NMR (300 MHz, CDCI 3 ) δ 7.74 (br s, 1H), 7.41 (s, 1H), 7.32-7.29 (m, 3H), 7.22-7.19 (m, 2H), 6.51 (d, J=1.5 Hz, 1H), 5.14 (s, 2H), 4.64 (q, J=7.2 Hz, 2H), 2.32 (s, 3H), 2.17 (s, 3H), 1.49 (t, J=7.2 Hz, 3H), 1.46 (s, 9H).

步骤4:将72(90mg,0.195mmol)于TFA(1mL)和CH2Cl2(2mL)中的溶液在室温搅拌1小时。浓缩混合物,将残余物溶解于乙酸乙酯(100mL)中并用饱和NaHCO3洗涤(50mL×2)。将有机层经硫酸钠干燥,过滤并浓缩。通过色谱(硅胶,40–100%EtOAc/己烷)纯化得到为灰白色固体的实施例化合物17(51mg,72%):1H NMR(300MHz,CDCl3)δ7.35–7.20(m,5H),6.33(d,J=1.5Hz,1H),6.30(d,J=1.5Hz,1H),5.13(s,2H),4.68(q,J=6.9Hz,2H),4.30(br s,2H),2.30(s,3H),2.16(s,3H),1.49(t,J=7.2Hz,3H);ESI m/z 363[M+H]+Step 4: A solution of 72 (90 mg, 0.195 mmol) in TFA (1 mL) and CH 2 Cl 2 (2 mL) was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was dissolved in ethyl acetate (100 mL) and washed with saturated NaHCO 3 (50 mL×2). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by chromatography (silica gel, 40-100% EtOAc/hexanes) provided Example Compound 17 (51 mg, 72%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.35-7.20 (m, 5H), 6.33 (d, J=1.5 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 5.13 (s, 2H), 4.68 (q, J=6.9 Hz, 2H), 4.30 (br s, 2H), 2.30 (s, 3H), 2.16 (s, 3H), 1.49 (t, J=7.2 Hz, 3H); ESI m/z 363 [M+H] + .

制备4-(1-苄基-2-乙氧基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物59)Preparation of 4-(1-benzyl-2-ethoxy-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 59)

向28(50mg,0.17mmol)和原碳酸四乙酯(131mg,0.68mmol)中的混合物加入氨基磺酸(3mg,0.034mmol)。然后将混合物加热至100℃持续8小时,然后用乙酸乙酯(30mL)稀释,用盐水(15mL)洗涤,经无水硫酸钠干燥,且真空浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为灰白色固体的实施例化合物59(24mg,41%):1H NMR(300MHz,DMSO–d6)δ7.75(d,J=1.2Hz,1H),7.38–7.22(m,5H),7.18(d,J=1.5Hz,1H),4.99(s,2H),4.34(q,J=7.2Hz,2H),2.37(s,3H),2.18(s,3H),1.42(t,J=7.2Hz,3H);ESI m/z 349[M+H]+To a mixture of 28 (50 mg, 0.17 mmol) and tetraethyl orthocarbonate (131 mg, 0.68 mmol) was added sulfamic acid (3 mg, 0.034 mmol). The mixture was then heated to 100 °C for 8 hours, then diluted with ethyl acetate (30 mL), washed with brine (15 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 59 (24 mg, 41%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.75 (d, J=1.2 Hz, 1 H), 7.38-7.22 (m, 5 H), 7.18 (d, J=1.5 Hz, 1 H), 4.99 (s, 2 H), 4.34 (q, J=7.2 Hz, 2 H), 2.37 (s, 3 H), 2.18 (s, 3 H), 1.42 (t, J=7.2 Hz, 3 H); ESI m/z 349 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-甲腈(实施例化合物85)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4-carbonitrile (Example Compound 85)

化合物73通过按照一般程序J步骤1至3的方法,以2-氨基-5-溴苄腈开始来制备。对化合物73(30mg,0.09mmol)使用用于一般程序D步骤3的程序得到为灰白色固体的实施例化合物85(10mg,31%):1H NMR(500MHz,CD3OD)δ7.63(d,J=1.5Hz,1H),7.60(d,J=1.5Hz,1H),7.38–7.27(m,3H),7.19–7.14(m,2H),5.57(s,2H),2.69(s,3H),2.32(s,3H),2.16(s,3H);ESI m/z 343[M+H]+Compound 73 was prepared by following the method of General Procedure J, Steps 1 to 3, starting with 2-amino-5-bromobenzonitrile. Compound 73 (30 mg, 0.09 mmol) was subjected to the procedure of General Procedure D, Step 3 to afford Example Compound 85 (10 mg, 31%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.63 (d, J=1.5 Hz, 1 H), 7.60 (d, J=1.5 Hz, 1 H), 7.38-7.27 (m, 3 H), 7.19-7.14 (m, 2 H), 5.57 (s, 2 H), 2.69 (s, 3 H), 2.32 (s, 3 H), 2.16 (s, 3 H); ESI m/z 343 [M+H] + .

一般程序O:General Procedure O:

制备N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-氧代-2,3-二氢-1H-苯并[d]咪唑-4-基)乙酰胺(实施例化合物111)Preparation of N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)acetamide (Example Compound 111)

将实施例化合物16(34mg,0.10mmol)、乙酸酐(12mg,0.12mmol)和i-Pr2NEt(26mg,0.20mmol)于THF(3mL)中的溶液在室温搅拌16小时。浓缩混合物,且残余物通过色谱(硅胶,0–5%甲醇/EtOAc)纯化以提供为白色固体的实施例化合物111(28mg,74%):1H NMR(300MHz,DMSO–d6)δ10.78(s,1H),9.85(s,1H),7.60–7.46(m,5H),7.28(d,J=1.2Hz,1H),7.06(d,J=1.2Hz,1H),5.22(s,2H),2.51(s,3H),2.33(s,3H),2.27(s,3H);ESI m/z 377[M+H]+A solution of Example Compound 16 (34 mg, 0.10 mmol), acetic anhydride (12 mg, 0.12 mmol) and i-Pr 2 NEt (26 mg, 0.20 mmol) in THF (3 mL) was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/EtOAc) to provide Example Compound 111 (28 mg, 74%) as a white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 9.85 (s, 1H), 7.60-7.46 (m, 5H), 7.28 (d, J=1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 5.22 (s, 2H), 2.51 (s, 3H), 2.33 (s, 3H), 2.27 (s, 3H); ESI m/z 377 [M+H] + .

一般程序P:General Procedure P:

制备6-(3,5-二甲基异噁唑-4-基)-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物110)和4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物115)Preparation of 6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 110) and 4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 115)

步骤1:向30(1.00g,3.21mmol)于甲苯(70mL)中的溶液在氮气气氛下加入苄基胺(1.94g,16.0mmol)、叔丁醇钾(539mg,4.82mmol)、2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基(229mg,0.482mmol)和三(二亚苄基丙酮)二钯(0)(293mg,0.321mmol)。将反应混合物在90℃加热过夜,冷却至室温,且通过色谱(硅胶,0–50%于己烷中的乙酸乙酯)纯化以为红褐色固体的提供74(700mg,62%):1H NMR(500MHz,CDCl3)δ7.50(d,J=1.8Hz,1H),7.70–7.22(m,5H),6.41(d,J=1.6Hz,1H),6.07(s,2H),4.48(q,J=3.5Hz,1H),3.65(s,1H),2.05(s,3H),1.90(s,3H),1.62(d,J=6.6Hz,3H);ESI m/z 353[M+H]+Step 1: To a solution of 30 (1.00 g, 3.21 mmol) in toluene (70 mL) under nitrogen atmosphere were added benzylamine (1.94 g, 16.0 mmol), potassium tert-butoxide (539 mg, 4.82 mmol), 2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl (229 mg, 0.482 mmol) and tris(dibenzylideneacetone)dipalladium(0) (293 mg, 0.321 mmol). The reaction mixture was heated at 90° C. overnight, cooled to room temperature, and purified by chromatography (silica gel, 0-50% ethyl acetate in hexanes) to provide 74 (700 mg, 62%) as a reddish-brown solid: 1H NMR (500 MHz, CDCI 3 ) δ 7.50 (d, J=1.8 Hz, 1H), 7.70-7.22 (m, 5H), 6.41 (d, J=1.6 Hz, 1H), 6.07 (s, 2H), 4.48 (q, J=3.5 Hz, 1H), 3.65 (s, 1H), 2.05 (s, 3H), 1.90 (s, 3H), 1.62 (d, J=6.6 Hz, 3H); ESI m/z 353 [M+H] + .

步骤2:向74(600mg,1.70mmol)于1,4-二噁烷(40mL)中的混合物加入1,1'-羰基二咪唑(2.76mg,17.0mmol)和DMAP(晶体)。将反应在密封管中于120℃加热2天。将混合物浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为橙色固体的实施例化合物110(420mg,65%):1H NMR(500MHz,CD3OD)δ7.75(d,J=1.3Hz,1H),7.44(d,J=7.7Hz,2H),7.38(t,J=7.7Hz,2H),7.31(t,J=7.7Hz,1H),6.88(d,J=1.3Hz,1H),5.88(q,J=7.1Hz,1H),2.20(s,3H),2.02(s,3H),1.91(d,J=7.2Hz,3H);ESI m/z 377[M–H]+Step 2: To a mixture of 74 (600 mg, 1.70 mmol) in 1,4-dioxane (40 mL) was added 1,1'-carbonyldiimidazole (2.76 mg, 17.0 mmol) and DMAP (crystals).The reaction was heated in a sealed tube at 120°C for 2 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 110 (420 mg, 65%) as an orange solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.75 (d, J=1.3 Hz, 1 H), 7.44 (d, J=7.7 Hz, 2H), 7.38 (t, J=7.7 Hz, 2H), 7.31 (t, J=7.7 Hz, 1 H), 6.88 (d, J=1.3 Hz, 1 H), 5.88 (q, J=7.1 Hz, 1 H), 2.20 (s, 3H), 2.02 (s, 3H), 1.91 (d, J=7.2 Hz, 3H); ESI m/z 377 [M-H] + .

步骤3:向实施例化合物110(100mg,0.265mmol)于四氢呋喃(10mL)中的溶液加入于水(10mL)中的连二亚硫酸钠(276mg,1.59mmol)。将反应混合物在室温搅拌过夜且在真空下浓缩。将残余物加入2N HCl并加热至刚好沸腾,冷却至室温,并真空浓缩。将残余物溶解于MeOH中并用浓NH4OH碱化,浓缩,并通过色谱(硅胶,0–100%己烷/乙酸乙酯)纯化。其通过Polaris C18柱反相HPLC用洗脱10–90%于H2O中的CH3CN进一步纯化以得到为灰白色固体的实施例化合物115(49mg,53%):1H NMR(500MHz,CD3OD)δ7.42–7.32(m,4H),7.26(t,J=6.9Hz,1H),6.35(s,1H),5.94(s,1H),5.78(q,J=7.2Hz,1H),2.17(s,3H),2.00(s,3H),1.86(d,J=7.2Hz,3H);ESI m/z 349[M+H]+Step 3: To a solution of Example Compound 110 (100 mg, 0.265 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (276 mg, 1.59 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was added 2N HCl and heated to just boiling, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in MeOH and basified with concentrated NH4OH , concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to give Example Compound 115 (49 mg, 53%) as an off-white solid: 1H NMR (500 MHz, CD3OD ) δ 7.42-7.32 (m, 4H), 7.26 (t, J=6.9 Hz, 1H), 6.35 (s, 1H), 5.94 (s, 1H), 5.78 (q, J=7.2 Hz, 1H), 2.17 (s, 3H), 2.00 (s, 3H), 1.86 (d, J=7.2 Hz, 3H); ESI m/z 349 [M+H] + .

一般程序Q:General Procedure Q:

制备4-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉(实施例化合物114)Preparation of 4-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine (Example Compound 114)

将实施例化合物10(90mg,0.28mmol)和氧氯化磷(V)(1mL)的混合物加热至110℃持续5小时,然后冷却至室温。浓缩混合物,用二氯甲烷(75mL)溶解并用饱和碳酸氢钠溶液(20mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。将残余物溶解于2.0M吗啉于四氢呋喃(5.6mL,11.2mmol)中的溶液并将混合物加热至75℃持续3小时。浓缩反应混合物,且残余物通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化,然后用乙酸乙酯/己烷研磨以提供为白色固体的实施例化合物114(62mg,57%):1H NMR(500MHz,CDCl3)δ8.24(d,J=2.0Hz,1H),7.41–7.34(m,3H),7.15(d,J=6.5Hz,2H),7.06(d,J=1.0Hz,1H),5.26(s,2H),3.83(t,J=4.5Hz,4H),3.50(t,J=4.5Hz,4H),2.29(s,3H),2.11(s,3H);ESI m/z 390[M+H]+A mixture of Example Compound 10 (90 mg, 0.28 mmol) and phosphorus (V) oxychloride (1 mL) was heated to 110 ° C for 5 hours and then cooled to room temperature. The mixture was concentrated, dissolved in dichloromethane (75 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in a solution of 2.0 M morpholine in tetrahydrofuran (5.6 mL, 11.2 mmol) and the mixture was heated to 75 ° C for 3 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with ethyl acetate/hexanes to provide Example Compound 114 (62 mg, 57%) as a white solid: 1 H NMR (500 MHz, CDCI 3 ) δ 8.24 (d, J=2.0 Hz, 1 H), 7.41-7.34 (m, 3 H), 7.15 (d, J=6.5 Hz, 2 H), 7.06 (d, J=1.0 Hz, 1 H), 5.26 (s, 2 H), 3.83 (t, J=4.5 Hz, 4 H), 3.50 (t, J=4.5 Hz, 4 H), 2.29 (s, 3 H), 2.11 (s, 3 H); ESI m/z 390 [M+H] + .

一般程序R:General procedure R:

制备1-(3,4-二氯苄基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物101)Preparation of 1-(3,4-dichlorobenzyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 101)

化合物75根据一般程序D,步骤1-2来制备。Compound 75 was prepared according to general procedure D, steps 1-2.

向75(218mg,0.60mmol)于1,4-二噁烷(5mL)中的溶液加入1,1’-羰基二咪唑(117mg,0.72mmol)并将混合物加热至100℃持续16小时。混合物用二氯甲烷(70mL)稀释并用盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为白色固体的实施例化合物101(155mg,66%):1H NMR(500MHz,DMSO–d6)δ11.83(s,1H),7.92(d,J=1.5Hz,1H),7.73(d,J=2.0Hz,1H),7.61(d,J=8.0Hz,1H),7.53(d,J=2.0Hz,1H),7.35(dd,J=8.5,2.0Hz,1H),5.05(s,2H),2.37(s,3H),2.19(s,3H);ESI m/z 389[M+H]+To a solution of 75 (218 mg, 0.60 mmol) in 1,4-dioxane (5 mL) was added 1,1'-carbonyldiimidazole (117 mg, 0.72 mmol) and the mixture was heated to 100°C for 16 hours. The mixture was diluted with dichloromethane (70 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 101 (155 mg, 66%) as a white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 11.83 (s, 1H), 7.92 (d, J=1.5 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.5, 2.0 Hz, 1H), 5.05 (s, 2H), 2.37 (s, 3H), 2.19 (s, 3H); ESI m/z 389 [M+H] + .

一般程序S:General Procedures:

制备(S)-3,5-二甲基-4-(2-甲基-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-6-基)异噁唑(实施例化合物125)和(S)-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1-(1-苯乙基)-1H-苯并[d]咪唑-4-胺(实施例化合物143)Preparation of (S)-3,5-dimethyl-4-(2-methyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-6-yl)isoxazole (Example Compound 125) and (S)-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-4-amine (Example Compound 143)

化合物76通过按照一般程序P步骤1的方法,以(S)-1-苯基乙胺开始来制备。Compound 76 was prepared by following the method of General Procedure P, Step 1, starting from (S)-1-phenylethylamine.

步骤1:使用一般程序F步骤1中使用的程序,以化合物76(140mg,0.40mmol)开始,得到为黄色固体的实施例化合物125(108mg,72%):1H NMR(300 MHz,DMSO–d6)δ7.87(d,J=1.5Hz,1H),7.42-7.30(m,6H),6.11(q,J=7.2Hz,1H),2.74(s,3H),2.23(s,3H),2.04(s,3H),1.94(d,J=6.9Hz,3H);ESIMS m/z 377[M+H]+Step 1: Using the procedure used in step 1 of General Procedure F, starting from compound 76 (140 mg, 0.40 mmol), Example Compound 125 (108 mg, 72%) was obtained as a yellow solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.87 (d, J = 1.5 Hz, 1H), 7.42-7.30 (m, 6H), 6.11 (q, J = 7.2 Hz, 1H), 2.74 (s, 3H), 2.23 (s, 3H), 2.04 (s, 3H), 1.94 (d, J = 6.9 Hz, 3H); ESIMS m/z 377 [M+H] + .

步骤2:使用一般程序P步骤3中使用的程序,以化合物实施例化合物125(80mg,0.21mmol)开始,得到为灰白色固体的实施例化合物143(53mg,72%):1H NMR(300MHz,DMSO–d6)δ7.39-7.26(m,5H),6.23(d,J=1.5Hz,1H),6.14(d,J=1.2Hz,1H),5.86(q,J=7.2Hz,1H),5.26(s,2H),2.58(s,3H),2.20(s,3H),2.02(s,3H),1.86(d,J=6.9Hz,3H);ESIMS m/z 347[M+H]+Step 2: Using the procedure used in General Procedure P, step 3, starting with Example Compound 125 (80 mg, 0.21 mmol), Example Compound 143 (53 mg, 72%) was obtained as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.39-7.26 (m, 5H), 6.23 (d, J=1.5 Hz, 1H), 6.14 (d, J=1.2 Hz, 1H), 5.86 (q, J=7.2 Hz, 1H), 5.26 (s, 2H), 2.58 (s, 3H), 2.20 (s, 3H), 2.02 (s, 3H), 1.86 (d, J=6.9 Hz, 3H); ESIMS m/z 347 [M+H] + .

一般程序T:General Procedure T:

制备4-(1-苄基-2-(吡啶-3-基氧基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物236)Preparation of 4-(1-benzyl-2-(pyridin-3-yloxy)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 236)

将实施例化合物10(100mg,0.31mmol)和氧氯化磷(V)(1mL)的混合物加热至110℃持续5小时,然后冷却至室温。浓缩混合物,用二氯甲烷(75mL)溶解并用饱和碳酸氢钠溶液(20mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。将残余物溶解于N,N-二甲基甲酰胺(2.5mL)中,加入3-羟基吡啶(109mg,1.15mmol)和碳酸钾(175mg,1.27mmol)。将混合物加热至100℃持续16小时,然后用乙酸乙酯(75mL)稀释,用盐水洗涤(2×25mL),经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为浅褐色固体的实施例化合物236(58mg,47%):1H NMR(300MHz,DMSO–d6)δ8.74(d,J=2.7Hz,1H),8.57(dd,J=4.5,0.9Hz,1H),8.27(d,J=1.8Hz,1H),8.02–7.98(m,2H),7.59(dd,J=8.4,4.5Hz,1H),7.47(d,J=6.9Hz,2H),7.42–7.30(m,3H),5.53(s,2H),2.40(s,3H),2.22(s,3H);ESI m/z398[M+H]+A mixture of Example Compound 10 (100 mg, 0.31 mmol) and phosphorus (V) oxychloride (1 mL) was heated to 110 ° C for 5 hours and then cooled to room temperature. The mixture was concentrated, dissolved with dichloromethane (75 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in N, N-dimethylformamide (2.5 mL), and 3-hydroxypyridine (109 mg, 1.15 mmol) and potassium carbonate (175 mg, 1.27 mmol) were added. The mixture was heated to 100 ° C for 16 hours, then diluted with ethyl acetate (75 mL), washed with brine (2×25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 236 (58 mg, 47%) as a light brown solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 8.74 (d, J=2.7 Hz, 1H), 8.57 (dd, J=4.5, 0.9 Hz, 1H), 8.27 (d, J=1.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.59 (dd, J=8.4, 4.5 Hz, 1H), 7.47 (d, J=6.9 Hz, 2H), 7.42-7.30 (m, 3H), 5.53 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 398 [M+H] + .

制备6-(3,5-二甲基异噁唑-4-基)-N-乙基-4-硝基-1-(1-苯乙基)-1H-苯并[d]咪唑-2-胺(实施例化合物127)和6-(3,5-二甲基异噁唑-4-基)-N2-乙基-1-(1-苯乙基)-1H-苯并[d]咪唑-2,4-二胺(实施例化合物134)Preparation of 6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1-(1-phenylethyl)-1H-benzo[d]imidazol-2-amine (Example Compound 127) and 6-(3,5-dimethylisoxazol-4-yl)-N 2 -ethyl-1-(1-phenylethyl)-1H-benzo[d]imidazol-2,4-diamine (Example Compound 134)

步骤1:向实施例化合物110(200mg,0.529mmol)加入氧氯化磷(V)(2mL,21.5mmol)和N,N-二甲基甲酰胺(一滴)。将反应在90℃加热过夜。浓缩混合物,将残余物溶解于四氢呋喃(5mL)中,加入乙基胺(10mL,1M于四氢呋喃中)。将反应混合物于密封管中在70℃加热2天。将混合物浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为黄色固体的实施例化合物127(40mg,19%):1H NMR(500MHz,CD3OD)δ7.70(d,J=1.5Hz,1H),7.45–7.30(m,5H),6.72(d,J=1.5Hz,1H),5.86(q,J=7.0Hz,1H),3.72(q,J=7.2Hz,2H),2.17(s,3H),1.98(s,3H),1.90(d,J=7.0Hz,3H),1.36(t,J=7.2Hz,3H);ESI m/z 406[M–H]+Step 1: To Example Compound 110 (200 mg, 0.529 mmol) was added phosphorus(V) oxychloride (2 mL, 21.5 mmol) and N,N-dimethylformamide (one drop). The reaction was heated at 90°C overnight. The mixture was concentrated, and the residue was dissolved in tetrahydrofuran (5 mL). Ethylamine (10 mL, 1 M in tetrahydrofuran) was added. The reaction mixture was heated at 70°C in a sealed tube for 2 days. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 127 (40 mg, 19%) as a yellow solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.70 (d, J=1.5 Hz, 1 H), 7.45-7.30 (m, 5 H), 6.72 (d, J=1.5 Hz, 1 H), 5.86 (q, J=7.0 Hz, 1 H), 3.72 (q, J=7.2 Hz, 2 H), 2.17 (s, 3 H), 1.98 (s, 3 H), 1.90 (d, J=7.0 Hz, 3 H), 1.36 (t, J=7.2 Hz, 3 H); ESI m/z 406 [M-H] + .

步骤2:向实施例化合物127(35mg,0.086mmol)于四氢呋喃(10mL)中的溶液加入于水(10mL)中的连二亚硫酸钠(90mg,0.52mmol)。将反应混合物在室温搅拌过夜且在真空下浓缩。将残余物加入2N HCl并加热至刚好沸腾,冷却至室温,并真空浓缩。将残余物溶解于MeOH中并用浓NH4OH碱化,浓缩,并通过色谱(硅胶,0–100%己烷/乙酸乙酯)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC进一步纯化以得到为灰白色固体的实施例化合物134(15mg,47%):1H NMR(500MHz,CD3OD)δ7.40–7.25(m,5H),6.31(d,J=1.5Hz,1H),5.92(d,J=1.5Hz,1H),5.72(q,J=6.9Hz,1H),3.53(q,J=7.2Hz,2H),2.15(s,3H),1.99(s,3H),1.86(d,J=7.0Hz,3H),1.33(t,J=7.2Hz,3H);ESI m/z 376[M+H]+Step 2: To a solution of Example Compound 127 (35 mg, 0.086 mmol) in tetrahydrofuran (10 mL) was added sodium dithionite (90 mg, 0.52 mmol) in water (10 mL). The reaction mixture was stirred at room temperature overnight and concentrated under vacuum. The residue was added with 2N HCl and heated to just boiling, cooled to room temperature, and concentrated under vacuum. The residue was dissolved in MeOH and basified with concentrated NH4OH , concentrated, and purified by chromatography (silica gel, 0-100% hexane/ethyl acetate). It was further purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to give Example Compound 134 (15 mg, 47%) as an off-white solid: 1H NMR (500 MHz, CD3OD ) δ 7.40-7.25 (m, 5H), 6.31 (d, J=1.5 Hz, 1H), 5.92 (d, J=1.5 Hz, 1H), 5.72 (q, J=6.9 Hz, 1H), 3.53 (q, J=7.2 Hz, 2H), 2.15 (s, 3H), 1.99 (s, 3H), 1.86 (d, J=7.0 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H); ESI m/z 376 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-4-硝基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物150)和4-氨基-1-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物162)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 150) and 4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-1H-benzo[d]imidazol-2(3H)-one (Example Compound 162)

步骤1:将实施例化合物15(73mg,0.20mmol)、CH3I(85mg,0.60mmol)和K2CO3(110mg,0.8mmol)于DMF(3mL)中的混合物在室温搅拌16小时。反应混合物用EtOAc(100mL)稀释并用盐水洗涤(3×50mL)。将有机层经硫酸钠干燥,过滤并浓缩。残余物用EtOAc/己烷研磨以提供为黄色固体的实施例化合物150(65mg,86%):1H NMR(300MHz,CDCl3)δ7.48(d,J=1.5Hz,1H),7.35–7.30(m,5H),6.84(d,J=1.5Hz,1H),5.15(s,2H),3.65(s,3H),2.26(s,3H),2.09(s,3H);ESI m/z 379[M+H]+Step 1: A mixture of Example Compound 15 (73 mg, 0.20 mmol), CH 3 I (85 mg, 0.60 mmol) and K 2 CO 3 (110 mg, 0.8 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was triturated with EtOAc/hexanes to provide Example Compound 150 (65 mg, 86%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.48 (d, J=1.5 Hz, 1H), 7.35-7.30 (m, 5H), 6.84 (d, J=1.5 Hz, 1H), 5.15 (s, 2H), 3.65 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H); ESI m/z 379 [M+H] + .

步骤2:向实施例化合物150(57mg,0.15mmol)于THF(5mL)和水(4mL)共的溶液加入Na2S2O4(153mg,0.90mmol)。将混合物在室温搅拌4小时,加入2N HCl(1mL),将混合物加热至回流15分钟。冷却至室温后,缓慢地加入Na2CO3以调节至pH9。混合物用CH2Cl2(100mL)萃取,有机层用盐水(50mL)洗涤,过滤,浓缩并通过色谱(硅胶,0–10%甲醇/乙酸乙酯)纯化以提供为白色固体的实施例化合物162(60mg,72%):1H NMR(300MHz,DMSO–d6)δ7.36–7.24(m,5H),6.40(d,J=1.5Hz,1H),6.39(d,J=1.8Hz,1H),5.08(s,2H),4.99(s,2H),3.62(s,3H),2.29(s,3H),2.12(s,3H);ESI m/z 349[M+H]+.HPLC>99%Step 2: To a solution of Example Compound 150 (57 mg, 0.15 mmol) in THF (5 mL) and water (4 mL) was added Na₂S₂O₄ ( 153 mg , 0.90 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes. After cooling to room temperature, Na₂CO₃ was slowly added to adjust the pH to 9. The mixture was extracted with CH2Cl2 (100 mL ), and the organic layer was washed with brine (50 mL), filtered, concentrated, and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to provide Example Compound 162 (60 mg, 72%) as a white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 7.36-7.24 (m, 5H), 6.40 (d, J=1.5 Hz, 1H), 6.39 (d, J=1.8 Hz, 1H), 5.08 (s, 2H), 4.99 (s, 2H), 3.62 (s, 3H), 2.29 (s, 3H), 2.12 (s, 3H); ESI m/z 349 [M+H] + . HPLC>99%

制备4-(1-苄基-2-甲基-4-(甲磺酰基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑(实施例化合物168)Preparation of 4-(1-benzyl-2-methyl-4-(methylsulfonyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 168)

将实施例化合物121(100mg,0.25mmol)、甲烷亚磺酸钠(39mg,0.38mmol)、CuI(5mg,0.025mmol)、L-脯氨酸(6mg,0.05mmol)和NaOH(2mg,0.05mmol)于DMSO(3mL)中的混合物于微波反应器中在150℃加热2小时。混合物用乙酸乙酯(100mL)稀释并用盐水(50mL)洗涤。有机层经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,50–100%EtOAc/己烷)纯化以提供为灰白色固体的实施例化合物168(13mg,13%):1H NMR(300MHz,CDCl3)δ7.75(d,J=1.5Hz,1H),7.37–7.33(m,3H),7.24(d,J=1.5Hz,1H),7.11–7.08(m,2H),5.39(s,2H),3.54(s,3H),2.73(s,3H),2.31(s,3H),2.16(s,3H);ESI m/z 396[M+H]+.HPLC 92.3%。A mixture of Example Compound 121 (100 mg, 0.25 mmol), sodium methanesulfinate (39 mg, 0.38 mmol), CuI (5 mg, 0.025 mmol), L-proline (6 mg, 0.05 mmol), and NaOH (2 mg, 0.05 mmol) in DMSO (3 mL) was heated in a microwave reactor at 150° C. for 2 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with brine (50 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by chromatography (silica gel, 50-100% EtOAc/hexanes) to provide Example Compound 168 (13 mg, 13%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.75 (d, J=1.5 Hz, 1H), 7.37-7.33 (m, 3H), 7.24 (d, J=1.5 Hz, 1H), 7.11-7.08 (m, 2H), 5.39 (s, 2H), 3.54 (s, 3H), 2.73 (s, 3H), 2.31 (s, 3H), 2.16 (s, 3H); ESI m/z 396 [M+H] + . HPLC 92.3%.

制备4-(1-苄基-2,7-二甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物181)Preparation of 4-(1-benzyl-2,7-dimethyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 181)

步骤1:向77(4.4g,16.5mmol)于1,4-二噁烷(100mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(4.4g,19.8mmol)、Na2CO3(2.0M于H2O中,25mL,50.0mmol)和四(三苯基膦)钯(0)(959mg,0.83mmol)。反应混合物用氮气吹扫并在80℃加热16小时。混合物用EtOAc(100mL)稀释并用盐水(50mL)洗涤。有机层经Na2SO4干燥,并过滤。浓缩滤液,然后通过色谱(硅胶,0–60%乙酸乙酯/己烷)纯化以提供为灰白色固体的78(2.64g,57%):1H NMR(300MHz,DMSO–d6)δ7.71(s,1H),6.32(s,2H),2.22(s,3H),2.08(s,3H),2.02(s,3H)。Step 1: To a solution of 77 (4.4 g, 16.5 mmol) in 1,4-dioxane (100 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (4.4 g, 19.8 mmol), Na 2 CO 3 (2.0 M in H 2 O, 25 mL, 50.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (959 mg, 0.83 mmol). The reaction mixture was purged with nitrogen and heated at 80° C. for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (50 mL). The organic layer was dried over Na 2 SO 4 and filtered. The filtrate was concentrated and then purified by chromatography (silica gel, 0-60% ethyl acetate/hexanes) to afford 78 (2.64 g, 57%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.71 (s, 1H), 6.32 (s, 2H), 2.22 (s, 3H), 2.08 (s, 3H), 2.02 (s, 3H).

步骤2:将78(1.3g,4.61mmol)、苄基胺(2.51mL,23.05mmol)、X-phos(658mg,1.38mmol)、Pd2(dba)3(632mg,0.69mmol)和t-BuOK(774mg,6.92mmol)于甲苯(50mL)中的混合物用氮气吹扫10分钟,然后在90℃加热18小时。混合物用二氯甲烷(200mL)稀释并过滤。浓缩滤液且通过色谱(硅胶,0–100%EtOAc/己烷)纯化以提供为褐色胶的79(125mg,9%):1H NMR(300MHz,DMSO–d6)δ7.38(s,1H),7.31–7.22(m,5H),5.68(s,2H),4.28(t,J=7.5Hz,1H),4.01(d,J=7.0Hz,2H),2.14(s,3H),1.93(s,3H),1.74(s,3H)。Step 2: A mixture of 78 (1.3 g, 4.61 mmol), benzylamine (2.51 mL, 23.05 mmol), X-phos (658 mg, 1.38 mmol), Pd 2 (dba) 3 (632 mg, 0.69 mmol) and t-BuOK (774 mg, 6.92 mmol) in toluene (50 mL) was purged with nitrogen for 10 minutes and then heated at 90° C. for 18 hours. The mixture was diluted with dichloromethane (200 mL) and filtered. The filtrate was concentrated and purified by chromatography (silica gel, 0-100% EtOAc/hexanes) to afford 79 (125 mg, 9%) as a brown gum: 1H NMR (300 MHz, DMSO-d 6 ) δ 7.38 (s, 1H), 7.31-7.22 (m, 5H), 5.68 (s, 2H), 4.28 (t, J=7.5 Hz, 1H), 4.01 (d, J=7.0 Hz, 2H), 2.14 (s, 3H), 1.93 (s, 3H), 1.74 (s, 3H).

步骤3:向79(80mg,0.26mmol)于原乙酸三乙酯(2mL)中的溶液加入AcOH(0.2mL)。将混合物加热至120℃持续2小时。浓缩混合物,将残余物溶解于EtOAc(100mL)中并用饱和NaHCO3洗涤(50mL×2)。有机层经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,0–10%MeOH/乙酸乙酯)纯化以提供为灰白色固体的实施例化合物181(39mg,45%):1H NMR(300MHz,CDCl3)δ8.23(s,1H),7.37–7.31(m,3H),6.95–6.92(m,2H),5.58(s,2H),2.64(s,3H),2.23(s,3H),2.22(s,3H),2.06(s,3H);ESI m/z 333[M+H]+Step 3: To a solution of 79 (80 mg, 0.26 mmol) in triethyl orthoacetate (2 mL) was added AcOH (0.2 mL). The mixture was heated to 120 °C for 2 hours. The mixture was concentrated, and the residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCO₃ (50 mL x 2). The organic layer was dried over Na₂SO₄ , filtered , and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/ethyl acetate) to provide Example Compound 181 (39 mg, 45%) as an off-white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.23 (s, 1H), 7.37-7.31 (m, 3H), 6.95-6.92 (m, 2H), 5.58 (s, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.06 (s, 3H); ESI m/z 333 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-7-甲基-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物180)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-7-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 180)

将79(31mg,0.10mmol)和CDI(33mg,0.2mmol)于二噁烷(3mL)中的混合物加热至120℃持续16小时。浓缩混合物,残余物通过色谱(硅胶,50–100%乙酸乙酯/己烷)纯化以提供为灰白色固体的实施例化合物180(10mg,30%):1H NMR(300MHz,DMSO–d6)δ11.89(s,1H),7.74(s,1H),7.38–7.24(m,3H),7.17–7.14(m,2H),5.26(s,2H),2.16(s,3H),2.01(s,3H),1.99(s,3H);ESI m/z 335[M+H]+A mixture of 79 (31 mg, 0.10 mmol) and CDI (33 mg, 0.2 mmol) in dioxane (3 mL) was heated to 120° C. for 16 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 50-100% ethyl acetate/hexanes) to afford Example Compound 180 (10 mg, 30%) as an off-white solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 11.89 (s, 1H), 7.74 (s, 1H), 7.38-7.24 (m, 3H), 7.17-7.14 (m, 2H), 5.26 (s, 2H), 2.16 (s, 3H), 2.01 (s, 3H), 1.99 (s, 3H); ESI m/z 335 [M+H] + .

制备3,5-二甲基-4-(2-甲基-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-6-基)异噁唑(实施例化合物108)Preparation of 3,5-dimethyl-4-(2-methyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-6-yl)isoxazole (Example Compound 108)

步骤1:向27(660mg,3.23mmol)于乙腈(33mL)中的悬浮液加入(1-溴乙基)苯(658mg,3.55mmol)和碳酸钾(893mg,6.46mmol)。将混合物加热至60℃持续16小时,然后冷却,用二氯甲烷(120mL)稀释并用盐水(40mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为白色固体的57(256mg,26%):1HNMR(500MHz,DMSO–d6)δ7.36(d,J=1.5Hz,2H),7.30(t,J=7.5Hz,2H),7.20–7.17(m,2H),6.15(d,J=2.0Hz,1H),5.82(s,2H),5.40(d,J=5.5Hz,1H),4.51–4.45(m,1H),2.05(s,3H),1.84(s,3H),1.48(d,J=7.0Hz,3H)。Step 1: To a suspension of 27 (660 mg, 3.23 mmol) in acetonitrile (33 mL) was added (1-bromoethyl)benzene (658 mg, 3.55 mmol) and potassium carbonate (893 mg, 6.46 mmol). The mixture was heated to 60 ° C for 16 hours, then cooled, diluted with dichloromethane (120 mL) and washed with brine (40 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford 57 (256 mg, 26%) as a white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 7.36 (d, J=1.5 Hz, 2H), 7.30 (t, J=7.5 Hz, 2H), 7.20-7.17 (m, 2H), 6.15 (d, J=2.0 Hz, 1H), 5.82 (s, 2H), 5.40 (d, J=5.5 Hz, 1H), 4.51-4.45 (m, 1H), 2.05 (s, 3H), 1.84 (s, 3H), 1.48 (d, J=7.0 Hz, 3H).

步骤2:向57(41mg,0.13mmol)于原乙酸三乙酯(0.24mL,1.33mmol)中的溶液加入乙酸(20μL,0.36mmol)。将混合物加热至100℃持续1小时,然后加入一滴浓HCl。将混合物加热至100℃持续10分钟。混合物用饱和碳酸氢钠碱化,用二氯甲烷(45mL)稀释并用盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–3%甲醇/二氯甲烷)纯化,之后用二氯甲烷/己烷研磨以提供为白色固体的实施例化合物108(11mg,28%):1H NMR(500MHz,DMSO–d6)δ8.27(d,J=2.0Hz,1H),7.44(d,J=2.0Hz,1H),7.40–7.36(m,4H),7.33–7.30(m,1H),6.01(q,J=7.0Hz,1H),2.70(s,3H),2.26(s,3H),2.06(s,3H),1.93(d,J=7.0Hz,3H);ESI m/z 333[M+H]+Step 2: To a solution of 57 (41 mg, 0.13 mmol) in triethyl orthoacetate (0.24 mL, 1.33 mmol) was added acetic acid (20 μL, 0.36 mmol). The mixture was heated to 100 ° C for 1 hour, and then one drop of concentrated HCl was added. The mixture was heated to 100 ° C for 10 minutes. The mixture was basified with saturated sodium bicarbonate, diluted with dichloromethane (45 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-3% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 108 (11 mg, 28%) as a white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 8.27 (d, J=2.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.40-7.36 (m, 4H), 7.33-7.30 (m, 1H), 6.01 (q, J=7.0 Hz, 1H), 2.70 (s, 3H), 2.26 (s, 3H), 2.06 (s, 3H), 1.93 (d, J=7.0 Hz, 3H); ESI m/z 333 [M+H] + .

制备6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物112)和6-(3,5-二甲基异噁唑-4-基)-N-乙基-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2-胺(实施例化合物113)Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 112) and 6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2-amine (Example Compound 113)

步骤1:向57(250mg,0.81mmol)于1,4-二噁烷(6mL)中的悬浮液加入1,1'-羰基二咪唑(158mg,0.97mmol)。混合物用氮气吹扫5分钟,然后加热至100℃持续16小时。混合物用二氯甲烷(100mL)稀释,过滤并浓缩。残余物通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化,然后用二氯甲烷/己烷研磨以提供为灰白色固体的实施例化合物112(258mg,95%):1H NMR(500MHz,DMSO–d6)δ11.78(s,1H),7.87(d,J=2.0Hz,1H),7.44(d,J=7.5Hz,2H),7.36(t,J=7.5Hz,2H),7.29(t,J=7.5Hz,1H),7.09(d,J=2.0Hz,1H),5.72(q,J=7.0Hz,1H),2.26(s,3H),2.06(s,3H),1.84(d,J=7.0Hz,3H);ESI m/z 335[M+H]+Step 1: To a suspension of 57 (250 mg, 0.81 mmol) in 1,4-dioxane (6 mL) was added 1,1'-carbonyldiimidazole (158 mg, 0.97 mmol). The mixture was purged with nitrogen for 5 minutes and then heated to 100°C for 16 hours. The mixture was diluted with dichloromethane (100 mL), filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 112 (258 mg, 95%) as an off-white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.0 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.0 Hz, 3H); ESI m/z 335 [M+H] + .

步骤2:将实施例化合物112(100mg,0.30mmol)和氧氯化磷(V)(1mL)的混合物加热至110℃持续5小时,并冷却至室温。浓缩反应混合物,用二氯甲烷(75mL)稀释并用饱和碳酸氢钠溶液(20mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。将残余物溶解于2.0M乙基胺于四氢呋喃中的溶液(6.0mL,12.0mmol)并将混合物加热至75℃持续7小时。浓缩反应混合物,且残余物通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化,然后用乙酸乙酯/己烷研磨以提供为白色固体的实施例化合物113(52mg,49%):1H NMR(500MHz,DMSO–d6)δ7.90(d,J=2.0Hz,1H),7.40–7.28(m,6H),6.81(d,J=2.0Hz,1H),5.84(q,J=7.0Hz,1H),3.54–3.48(m,2H),2.20(s,3H),1.99(s,3H),1.83(d,J=7.0Hz,3H),1.27(t,J=7.0Hz,3H);ESI m/z362[M+H]+Step 2: A mixture of Example Compound 112 (100 mg, 0.30 mmol) and phosphorus (V) oxychloride (1 mL) was heated to 110 ° C for 5 hours and cooled to room temperature. The reaction mixture was concentrated, diluted with dichloromethane (75 mL) and washed with saturated sodium bicarbonate solution (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in a solution of 2.0 M ethylamine in tetrahydrofuran (6.0 mL, 12.0 mmol) and the mixture was heated to 75 ° C for 7 hours. The reaction mixture was concentrated, and the residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with ethyl acetate/hexanes to provide Example Compound 113 (52 mg, 49%) as a white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 7.90 (d, J=2.0 Hz, 1H), 7.40-7.28 (m, 6H), 6.81 (d, J=2.0 Hz, 1H), 5.84 (q, J=7.0 Hz, 1H), 3.54-3.48 (m, 2H), 2.20 (s, 3H), 1.99 (s, 3H), 1.83 (d, J=7.0 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H); ESI m/z 362 [M+H] + .

制备6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(对映异构体A)(实施例化合物218)和6-(3,5-二甲基异噁唑-4-基)-1-(1-苯乙基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(对映异构体B)(实施例化合物219)Preparation of 6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Enantiomer A) (Example Compound 218) and 6-(3,5-dimethylisoxazol-4-yl)-1-(1-phenylethyl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Enantiomer B) (Example Compound 219)

实施例化合物112(87mg)通过SFC手性HPLC(Chiralpak AS-H,30mm×250mm,流动相30%于CO2中的EtOH(0.2%Et2NH),120巴,流速80mL/分钟)分离以提供为灰白色固体的实施例化合物218(对映异构体A)(41mg,46%)和实施例化合物219(对映异构体B)(41mg,46%)。Example compound 112 (87 mg) was separated by SFC chiral HPLC (Chiralpak AS-H, 30 mm×250 mm, mobile phase 30% EtOH (0.2% Et 2 NH) in CO 2 , 120 bar, flow rate 80 mL/min) to provide Example compound 218 (enantiomer A) (41 mg, 46%) and Example compound 219 (enantiomer B) (41 mg, 46%) as off-white solids.

实施例化合物218(对映异构体A):1H NMR(500MHz,DMSO–d6)δ11.77(s,1H),7.87(d,J=2.0Hz,1H),7.44(d,J=7.5Hz,2H),7.37(t,J=7.5Hz,2H),7.29(t,J=7.5Hz,1H),7.09(d,J=2.0Hz,1H),5.72(q,J=7.5Hz,1H),2.26(s,3H),2.06(s,3H),1.84(d,J=7.5Hz,3H);ESI m/z 335[M+H]+;HPLC(Chiralcel OD,4.6mm×250mm,10%于庚烷中的EtOH,1mL/分钟)>99%,tR=9.4分钟。Example Compound 218 (Enantiomer A): 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.77 (s, 1H), 7.87 (d, J=2.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.5 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.5 Hz, 3H); ESI m/z 335 [M+H] + ; HPLC (Chiralcel OD, 4.6 mm×250 mm, 10% EtOH in heptane, 1 mL/min) >99%, t R =9.4 minutes.

实施例化合物219(对映异构体B):1H NMR(500MHz,DMSO–d6)δ11.78(s,1H),7.87(d,J=1.5Hz,1H),7.44(d,J=7.5Hz,2H),7.36(t,J=7.5Hz,2H),7.29(t,J=7.5Hz,1H),7.08(d,J=2.0Hz,1H),5.72(q,J=7.5Hz,1H),2.26(s,3H),2.06(s,3H),1.84(d,J=7.5Hz,3H);ESI m/z 335[M+H]+;HPLC(Chiralcel OD,4.6mm×250mm,10%于庚烷中的EtOH,1mL/分钟)>99%,tR=10.9分钟。Example Compound 219 (Enantiomer B): 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 7.87 (d, J=1.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 2H), 7.36 (t, J=7.5 Hz, 2H), 7.29 (t, J=7.5 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 5.72 (q, J=7.5 Hz, 1H), 2.26 (s, 3H), 2.06 (s, 3H), 1.84 (d, J=7.5 Hz, 3H); ESI m/z 335 [M+H] + ; HPLC (Chiralcel OD, 4.6 mm×250 mm, 10% EtOH in heptane, 1 mL/min) >99%, t R =10.9 minutes.

制备3-苄基-5-(3,5-二甲基异噁唑-4-基)-1-乙基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物122)Preparation of 3-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1-ethyl-1H-benzo[d]imidazol-2(3H)-one (Example Compound 122)

步骤1:向20(214mg,0.77mmol)于1,4-二噁烷(5mL)中的溶液加入1,1'-羰基二咪唑(150mg,0.93mmol)并将混合物加热至100℃持续15小时。将混合物浓缩且通过色谱(硅胶,0–20%乙酸乙酯/己烷)纯化以提供为白色固体的80(142mg,61%);1H NMR(500MHz,DMSO–d6)δ11.13(s,1H),7.35–7.25(m,6H),7.12(dd,J=8.5,2.0Hz,1H),6.94(d,J=8.0Hz,1H),5.01(s,2H)。Step 1: To a solution of 20 (214 mg, 0.77 mmol) in 1,4-dioxane (5 mL) was added 1,1'-carbonyldiimidazole (150 mg, 0.93 mmol) and the mixture was heated to 100°C for 15 hours. The mixture was concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate/hexanes) to afford 80 (142 mg, 61%) as a white solid; 1H NMR (500 MHz, DMSO- d6 ) δ 11.13 (s, 1H), 7.35-7.25 (m, 6H), 7.12 (dd, J = 8.5, 2.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H).

步骤2:向80(100mg,0.33mmol)于1,4-二噁烷(5mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(110mg,0.49mmol)、碳酸钾(91mg,0.66mmol)和水(1mL)。混合物用氮气吹扫10分钟,加入四(三苯基膦)钯(0)(19mg,0.016mmol),并将混合物加热至90℃持续16小时。混合物用二氯甲烷(100mL)稀释并用盐水(30mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化,然后用乙酸乙酯/己烷研磨以提供为白色固体的81(55mg,52%):1H NMR(300MHz,DMSO–d6)δ11.07(s,1H),7.40–7.23(m,5H),7.06(d,J=8.1Hz,1H),7.02(s,1H),6.95(dd,J=7.8,1.5Hz,1H),5.03(s,2H),2.30(s,3H),2.13(s,3H);ESI m/z 320[M+H]+Step 2: To a solution of 80 (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (110 mg, 0.49 mmol), potassium carbonate (91 mg, 0.66 mmol) and water (1 mL). The mixture was purged with nitrogen for 10 minutes, tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) was added, and the mixture was heated to 90 ° C for 16 hours. The mixture was diluted with dichloromethane (100 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with ethyl acetate/hexanes to afford 81 (55 mg, 52%) as a white solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 11.07 (s, 1H), 7.40-7.23 (m, 5H), 7.06 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.95 (dd, J=7.8, 1.5 Hz, 1H), 5.03 (s, 2H), 2.30 (s, 3H), 2.13 (s, 3H); ESI m/z 320 [M+H] + .

步骤3:向81(36mg,0.11mmol)于乙腈(3mL)中的溶液加入碳酸钾(109mg,0.79mmol)和碘乙烷(80mg,0.56mmol),然后将混合物加热至40℃持续48小时。混合物用二氯甲烷(75mL)稀释并用盐水(20mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–20%乙酸乙酯/二氯甲烷)纯化,然后用乙酸乙酯/己烷研磨以提供为黄白色固体的实施例化合物122(14mg,37%):1H NMR(500MHz,DMSO–d6)δ7.37(d,J=7.5Hz,2H),7.33(t,J=7.0Hz,2H),7.29(d,J=8.0Hz,1H),7.26(t,J=7.0Hz,1H),7.09(d,J=1.5Hz,1H),7.03(dd,J=8.0,1.5Hz,1H),5.08(s,2H),3.94(q,J=7.0Hz,2H),2.31(s,3H),2.13(s,3H),1.26(t,J=7.0Hz,3H);ESI m/z 348[M+H]+Step 3: To a solution of 81 (36 mg, 0.11 mmol) in acetonitrile (3 mL) was added potassium carbonate (109 mg, 0.79 mmol) and iodoethane (80 mg, 0.56 mmol), and the mixture was heated to 40 ° C for 48 hours. The mixture was diluted with dichloromethane (75 mL) and washed with brine (20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-20% ethyl acetate/dichloromethane) followed by trituration with ethyl acetate/hexanes to provide Example Compound 122 (14 mg, 37%) as an off-white solid: 1H NMR (500 MHz, DMSO- d6 ) δ 7.37 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.0 Hz, 1H), 7.09 (d, J = 1.5 Hz, 1H), 7.03 (dd, J = 8.0, 1.5 Hz, 1H), 5.08 (s, 2H), 3.94 (q, J = 7.0 Hz, 2H), 2.31 (s, 3H), 2.13 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); ESI m/z 348[M+H] + .

制备1-苄基-N6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4,6-二胺(实施例化合物142)Preparation of 1-benzyl-N 6 -(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazole-4,6-diamine (Example Compound 142)

步骤1:向33(790mg,3.09mmol)于乙腈(15mL)中的悬浮液加入苄基氯(703mg,5.55mmol)和碳酸钾(1.07g,7.71mmol)。将反应混合物加热至60℃持续16小时,然后浓缩,且残余物通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化以提供为黄色固体的82(813mg,76%):1H NMR(300MHz,DMSO–d6)δ8.33(d,J=1.8Hz,1H),8.12(d,J=1.8Hz,1H),7.39–7.27(m,3H),7.13(d,J=6.6Hz,2H),5.62(s,2H),2.60(s,3H)。Step 1: To a suspension of 33 (790 mg, 3.09 mmol) in acetonitrile (15 mL) was added benzyl chloride (703 mg, 5.55 mmol) and potassium carbonate (1.07 g, 7.71 mmol). The reaction mixture was heated to 60° C. for 16 h, then concentrated, and the residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 82 (813 mg, 76%) as a yellow solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 8.33 (d, J=1.8 Hz, 1H), 8.12 (d, J=1.8 Hz, 1H), 7.39-7.27 (m, 3H), 7.13 (d, J=6.6 Hz, 2H), 5.62 (s, 2H), 2.60 (s, 3H).

步骤2:向82(150mg,0.43mmol)于甲苯(5mL)中的溶液加入83(73mg,0.65mmol)、碳酸铯(282mg,0.87mmol)和XPhos(41mg,0.087mmol)。溶液用氮气吹扫5分钟,然后加入三(二亚苄基丙酮)二钯(0)(40mg,0.043mmol)并加热至110℃持续16小时。将混合物滤过硅藻土并浓缩,残余物通过色谱(硅胶,0–7%甲醇/二氯甲烷)纯化以提供为褐色油的84(80mg,49%):1H NMR(500MHz,DMSO–d6)δ7.59(s,1H),7.34–7.28(m,4H),7.06(d,J=7.0Hz,2H),6.76(d,J=2.5Hz,1H),5.44(s,2H),2.54(s,3H),2.13(s,3H),1.91(s,3H)。Step 2: To a solution of 82 (150 mg, 0.43 mmol) in toluene (5 mL) was added 83 (73 mg, 0.65 mmol), cesium carbonate (282 mg, 0.87 mmol) and XPhos (41 mg, 0.087 mmol). The solution was purged with nitrogen for 5 minutes, then tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.043 mmol) was added and heated to 110° C. for 16 hours. The mixture was filtered through celite and concentrated, and the residue was purified by chromatography (silica gel, 0-7% methanol/dichloromethane) to afford 84 (80 mg, 49%) as a brown oil: 1H NMR (500 MHz, DMSO-d 6 ) δ 7.59 (s, 1H), 7.34-7.28 (m, 4H), 7.06 (d, J=7.0 Hz, 2H), 6.76 (d, J=2.5 Hz, 1H), 5.44 (s, 2H), 2.54 (s, 3H), 2.13 (s, 3H), 1.91 (s, 3H).

步骤3:向84(78mg,0.21mmol)于四氢呋喃(5mL)中的溶液加入连二亚硫酸钠(215mg,1.24mmol)于水(4mL)中的溶液。将混合物在室温搅拌2小时,然后加入2N HCl(1mL),将混合物加热至回流15分钟。混合物用碳酸钠碱化,并用二氯甲烷(50mL)萃取。将有机层经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为红褐色固体的实施例化合物142(38mg,53%):1H NMR(500MHz,DMSO–d6)δ7.31(t,J=7.5Hz,2H),7.25(t,J=7.5Hz,1H),7.04(d,J=7.5Hz,2H),6.69(s,1H),5.73(d,J=2.0Hz,1H),5.60(d,J=2.0Hz,1H),5.18(s,2H),5.05(s,2H),2.38(s,3H),2.13(s,3H),1.92(s,3H);ESI m/z 348[M+H]+Step 3: To a solution of 84 (78 mg, 0.21 mmol) in tetrahydrofuran (5 mL) was added a solution of sodium dithionite (215 mg, 1.24 mmol) in water (4 mL). The mixture was stirred at room temperature for 2 hours, then 2N HCl (1 mL) was added and the mixture was heated to reflux for 15 minutes. The mixture was basified with sodium carbonate and extracted with dichloromethane (50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to provide Example Compound 142 (38 mg, 53%) as a reddish-brown solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 7.31 (t, J=7.5 Hz, 2H), 7.25 (t, J=7.5 Hz, 1H), 7.04 (d, J=7.5 Hz, 2H), 6.69 (s, 1H), 5.73 (d, J=2.0 Hz, 1H), 5.60 (d, J=2.0 Hz, 1H), 5.18 (s, 2H), 5.05 (s, 2H), 2.38 (s, 3H), 2.13 (s, 3H), 1.92 (s, 3H); ESI m/z 348 [M+H] + .

一般程序U:General Procedure:

制备1-苄基-2-甲基-6-(5-甲基异噁唑-4-基)-1H-苯并[d]咪唑-4-胺(实施例化合物201)Preparation of 1-benzyl-2-methyl-6-(5-methylisoxazol-4-yl)-1H-benzo[d]imidazol-4-amine (Example Compound 201)

向82(100mg,0.29mmol)于1,4-二噁烷(5mL)中的溶液加入5-甲基异噁唑-4-硼酸频哪醇酯(91mg,0.43mmol)、碳酸钠(80mg,0.58mmol)、水(1mL)和四(三苯基膦)钯(0)(17mg,0.01mmol)。反应混合物用氮气吹扫且在90℃加热5小时。混合物用二氯甲烷(70mL)稀释,用盐水(25mL)洗涤,经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–5%乙酸乙酯/二氯甲烷)纯化至黄色固体,将其溶解于THF(4mL)中,加入连二亚硫酸钠(159mg,0.91mmol)于水(2mL)中的溶液并将混合物在室温搅拌2小时。将2N HCl(1mL)加入至混合物,并将混合物加热至回流15分钟。混合物通过饱和碳酸氢钠水溶液来碱化,并用二氯甲烷萃取(40mL×2)。将有机层经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–8%甲醇/二氯甲烷)纯化和用乙酸乙酯/己烷研磨以提供为灰白色固体的实施例化合物201(12mg,25%):1H NMR(300MHz,DMSO–d6)δ8.69(d,J=0.6Hz,1H),7.36–7.26(m,3H),7.15(d,J=6.9Hz,2H),6.78(d,J=1.5Hz,1H),6.47(d,J=1.5Hz,1H),5.40(s,2H),5.33(s,2H),2.50(s,3H),2.47(s,3H);ESI m/z 319[M+H]+To a solution of 82 (100 mg, 0.29 mmol) in 1,4-dioxane (5 mL) was added 5-methylisoxazole-4-boronic acid pinacol ester (91 mg, 0.43 mmol), sodium carbonate (80 mg, 0.58 mmol), water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.01 mmol). The reaction mixture was purged with nitrogen and heated at 90 ° C for 5 hours. The mixture was diluted with dichloromethane (70 mL), washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% ethyl acetate/dichloromethane) to a yellow solid, which was dissolved in THF (4 mL), a solution of sodium dithionite (159 mg, 0.91 mmol) in water (2 mL) was added and the mixture was stirred at room temperature for 2 hours. 2N HCl (1 mL) was added to the mixture, and the mixture was heated to reflux for 15 minutes. The mixture was basified by saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (40 mL x 2).The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) and triturated with ethyl acetate/hexanes to provide Example Compound 201 (12 mg, 25%) as an off-white solid: 1H NMR (300 MHz, DMSO-d 6 ) δ 8.69 (d, J=0.6 Hz, 1H), 7.36-7.26 (m, 3H), 7.15 (d, J=6.9 Hz, 2H), 6.78 (d, J=1.5 Hz, 1H), 6.47 (d, J=1.5 Hz, 1H), 5.40 (s, 2H), 5.33 (s, 2H), 2.50 (s, 3H), 2.47 (s, 3H); ESI m/z 319 [M+H] + .

制备N-(1-苄基-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑-4-胺(实施例化合物155)Preparation of N-(1-benzyl-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazol-4-amine (Example Compound 155)

步骤1:向2,3-二氨基-5-溴吡啶26(1.5g,7.98mmol)于二氯甲烷(80mL)中的悬浮液加入苯甲醛(931mg,8.78mmol)和乙酸(40滴)。将混合物在室温搅拌16小时,然后用饱和碳酸氢钠溶液(40mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。将残余物溶解于甲醇(50mL)中并缓慢加入硼氢化钠(815mg,21.5mmol)。将混合物在室温搅拌1小时。混合物用二氯甲烷(100mL)稀释,用饱和碳酸氢钠(40mL)洗涤,经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化以提供为灰白色固体的85(1.12g,51%):1H NMR(500MHz,DMSO–d6)δ7.35–7.34(m,4H),7.28–7.23(m,2H),6.54(d,J=2.0Hz,1H),5.78(s,2H),5.73(t,J=5.5Hz,1H),4.30(d,J=5.5Hz,2H)。Step 1: To a suspension of 2,3-diamino-5-bromopyridine 26 (1.5 g, 7.98 mmol) in dichloromethane (80 mL) was added benzaldehyde (931 mg, 8.78 mmol) and acetic acid (40 drops). The mixture was stirred at room temperature for 16 hours and then washed with saturated sodium bicarbonate solution (40 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in methanol (50 mL) and sodium borohydride (815 mg, 21.5 mmol) was slowly added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with dichloromethane (100 mL), washed with saturated sodium bicarbonate (40 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) to afford 85 (1.12 g, 51%) as an off-white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 7.35-7.34 (m, 4H), 7.28-7.23 (m, 2H), 6.54 (d, J=2.0 Hz, 1H), 5.78 (s, 2H), 5.73 (t, J=5.5 Hz, 1H), 4.30 (d, J=5.5 Hz, 2H).

步骤2:向85(970mg,3.49mmol)于原乙酸三乙酯(5.66g,37.9mmol)中的悬浮液加入乙酸(539μL,9.42mmol)。将混合物加热至100℃持续40分钟。反应混合物用饱和碳酸氢钠(8mL)碱化,用二氯甲烷(50mL)稀释并用饱和碳酸氢钠(30mL)洗涤。将有机层经硫酸钠干燥,过滤,并浓缩。残余物通过色谱(硅胶,0–8%甲醇/二氯甲烷)纯化以提供为浅褐色固体的86(305mg,30%):1H NMR(500MHz,DMSO–d6)δ8.41(d,J=2.0Hz,1H),8.29(d,J=2.0Hz,1H),7.35(t,J=7.0Hz,2H),7.30(t,J=7.0Hz,1H),7.15(d,J=7.0Hz,2H),5.52(s,2H),2.55(s,3H)。Step 2: To a suspension of 85 (970 mg, 3.49 mmol) in triethyl orthoacetate (5.66 g, 37.9 mmol) was added acetic acid (539 μL, 9.42 mmol). The mixture was heated to 100 ° C for 40 minutes. The reaction mixture was basified with saturated sodium bicarbonate (8 mL), diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) to afford 86 (305 mg, 30%) as a light brown solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 8.41 (d, J=2.0 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.30 (t, J=7.0 Hz, 1H), 7.15 (d, J=7.0 Hz, 2H), 5.52 (s, 2H), 2.55 (s, 3H).

步骤3:向86(80mg,0.26mmol)于甲苯(5mL)中的溶液加入83(44mg,0.40mmol)、碳酸铯(173mg,0.53mmol)和XPhos(25mg,0.053mmol)。溶液用氮气吹扫5分钟,然后加入三(二亚苄基丙酮)二钯(0)(24mg,0.026mmol)。将混合物加热至110℃持续16小时。反应混合物用二氯甲烷(20mL)稀释,滤过硅藻土,并浓缩。残余物通过色谱(硅胶,0–10%甲醇/二氯甲烷)纯化,然后用二氯甲烷/己烷研磨以提供为浅褐色固体的实施例化合物155(40mg,45%):1HNMR(500MHz,DMSO–d6)δ7.88(d,J=2.5Hz,1H),7.34–7.30(m,3H),7.27(t,J=7.0Hz,1H),7.05(d,J=7.0Hz,2H),6.71(d,J=2.5Hz,1H),5.38(s,2H),2.47(s,3H),2.14(s,3H),1.92(s,3H);ESI m/z 334[M+H]+Step 3: To a solution of 86 (80 mg, 0.26 mmol) in toluene (5 mL) was added 83 (44 mg, 0.40 mmol), cesium carbonate (173 mg, 0.53 mmol) and XPhos (25 mg, 0.053 mmol). The solution was purged with nitrogen for 5 minutes, and then tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.026 mmol) was added. The mixture was heated to 110 ° C for 16 hours. The reaction mixture was diluted with dichloromethane (20 mL), filtered through celite, and concentrated. The residue was purified by chromatography (silica gel, 0-10% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 155 (40 mg, 45%) as a light brown solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 7.88 (d, J=2.5 Hz, 1H), 7.34-7.30 (m, 3H), 7.27 (t, J=7.0 Hz, 1H), 7.05 (d, J=7.0 Hz, 2H), 6.71 (d, J=2.5 Hz, 1H), 5.38 (s, 2H), 2.47 (s, 3H), 2.14 (s, 3H), 1.92 (s, 3H); ESI m/z 334 [M+H] + .

制备1-苄基-2-甲基-6-(1-甲基-1H-1,2,3-三唑-5-基)-1H-咪唑并[4,5-b]吡啶(实施例化合物206)Preparation of 1-benzyl-2-methyl-6-(1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazo[4,5-b]pyridine (Example Compound 206)

向86(100mg,0.33mmol)于1,4-二噁烷(5mL)中的溶液加入1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-1,2,3-三唑(138mg,0.66mmol)、K2CO3(137mg,0.99mmol)、水(1mL)和四(三苯基膦)钯(0)(19mg,0.02mmol)。反应混合物用氮气吹扫且在90℃加热16小时。混合物用乙酸乙酯(70mL)稀释,用盐水(25mL)洗涤,经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–8%甲醇/二氯甲烷)纯化,之后用二氯甲烷/己烷研磨以提供为白色固体的实施例化合物206(14mg,14%);1H NMR(500MHz,DMSO–d6)δ8.54(d,J=2.5Hz,1H),8.27(d,J=2.0Hz,1H),7.96(s,1H),7.35(t,J=7.0Hz,2H),7.29(t,J=7.0Hz,1H),7.21(d,J=7.0Hz,2H),5.58(s,2H),4.07(s,3H),2.60(s,3H);ESI m/z 305[M+H]+To a solution of 86 (100 mg, 0.33 mmol) in 1,4-dioxane (5 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-1,2,3-triazole (138 mg, 0.66 mmol), K 2 CO 3 (137 mg, 0.99 mmol), water (1 mL) and tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.02 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 16 hours. The mixture was diluted with ethyl acetate (70 mL), washed with brine (25 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-8% methanol/dichloromethane) followed by trituration with dichloromethane/hexanes to provide Example Compound 206 (14 mg, 14%) as a white solid; 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.54 (d, J=2.5 Hz, 1 H), 8.27 (d, J=2.0 Hz, 1 H), 7.96 (s, 1 H), 7.35 (t, J=7.0 Hz, 2 H), 7.29 (t, J=7.0 Hz, 1 H), 7.21 (d, J=7.0 Hz, 2 H), 5.58 (s, 2 H), 4.07 (s, 3 H), 2.60 (s, 3 H); ESI m/z 305 [M+H] + .

制备1-苄基-2-甲基-6-(1-甲基-1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶(实施例化合物154)Preparation of 1-benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine (Example Compound 154)

1-苄基-2-甲基-6-(1-甲基-1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶(实施例化合物154)通过按照与用于实施例化合物206类似的方法来制备,为灰白色固体:1H NMR(500MHz,DMSO–d6)δ8.48(d,J=2.0Hz,1H),8.14(d,J=2.0Hz,1H),7.50(d,J=2.0Hz,1H),7.35(t,J=7.0Hz,2H),7.29(t,J=7.0Hz,1H),7.21(d,J=7.0Hz,2H),6.46(d,J=2.0Hz,1H),5.57(s,2H),3.83(s,3H),2.60(s,3H);ESI m/z 304[M+H]+1-Benzyl-2-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridine (Example Compound 154) was prepared by following a procedure analogous to that used for Example Compound 206 as an off-white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.48 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.35 (t, J=7.0 Hz, 2H), 7.29 (t, J=7.0 Hz, 1H), 7.21 (d, J=7.0 Hz, 2H), 6.46 (d, J=2.0 Hz, 1H), 5.57 (s, 2H), 3.83 (s, 3H), 2.60 (s, 3H); ESI m/z 304[M+H] + .

制备4-(1-苄基-2-环丙基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物138)Preparation of 4-(1-benzyl-2-cyclopropyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 138)

向二胺28(100mg,0.340mmol)于1,4-二噁烷(2mL)中的溶液加入环丙烷甲醛(29mg,0.408mmol)和乙酸(0.67mL)。将混合物在110℃加热24小时。混合物然后用二氯甲烷稀释并用饱和碳酸氢钠洗涤。有机层然后用硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化以提供为灰白色固体的实施例化合物138(68mg,58%):1HNMR(500MHz,DMSO–d6)δ8.29(d,J=2.1Hz,1H),7.95(d,J=2.0Hz,1H),7.37–7.33(m,2H),7.30-7.28(m,3H),5.67(s,2H),2.38(s,3H),2.37–2.35(m,1H),2.20(s,3H),1.13–1.11(m,4H);ESI m/z 345[M+H]+.HPLC>99%。制备1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物145)、1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-乙基-4-硝基-1H-苯并[d]咪唑-2-胺(实施例化合物159)、4-氨基-1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物161)和1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-N2-乙基-1H-苯并[d]咪唑-2,4-二胺(实施例化合物160)To a solution of diamine 28 (100 mg, 0.340 mmol) in 1,4-dioxane (2 mL) was added cyclopropanecarboxaldehyde (29 mg, 0.408 mmol) and acetic acid (0.67 mL). The mixture was heated at 110 ° C for 24 hours. The mixture was then diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) to provide Example Compound 138 (68 mg, 58%) as an off-white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 8.29 (d, J=2.1 Hz, 1H), 7.95 (d, J=2.0 Hz, 1H), 7.37-7.33 (m, 2H), 7.30-7.28 (m, 3H), 5.67 (s, 2H), 2.38 (s, 3H), 2.37-2.35 (m, 1H), 2.20 (s, 3H), 1.13-1.11 (m, 4H); ESI m/z 345 [M+H] + . HPLC >99%. Preparation of 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 145), 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-4-nitro-1H-benzo[d]imidazol-2-amine (Example Compound 159), 4-amino-1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 161), and 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N 2 -ethyl-1H-benzo[d]imidazol-2,4-diamine (Example Compound 160)

步骤1:向32(1.50g,6.46mmol)和3(2.16g,9.70mmol)于1,4-二噁烷(40mL)和水(4mL)中的混合物加入碳酸钾(1.79g,12.9mmol)和四(三苯基膦)钯(0)(373mg,0.32mmol)。将反应搅拌并在90℃加热17小时。反应混合物用甲醇(20mL)稀释并加入硅胶(20g)。将悬浮液浓缩至干并将所得粉末负载于硅胶上并用0–50%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为褐色固体的87(585mg,36%):1H NMR(500MHz,CDCl3)δ7.62(d,J=2.0Hz,1H),6.81(d,J=2.0Hz,1H),6.01(br s,2H),3.52(br s,2H),2.39(s,3H),2.25(s,3H)。Step 1: To a mixture of 32 (1.50 g, 6.46 mmol) and 3 (2.16 g, 9.70 mmol) in 1,4-dioxane (40 mL) and water (4 mL) was added potassium carbonate (1.79 g, 12.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (373 mg, 0.32 mmol). The reaction was stirred and heated at 90 ° C for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (20 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded on silica gel and eluted with 0-50% ethyl acetate in hexane. The clean product was concentrated to give 87 (585 mg, 36%) as a brown solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.62 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.01 (br s, 2H), 3.52 (br s, 2H), 2.39 (s, 3H), 2.25 (s, 3H).

步骤2:向87(250mg,1.01mmol)、催化量的DMAP和1,4-二噁烷(4mL)于压力管中的溶液加入1,1'-羰基二咪唑(327mg,2.01mmol)。将管密封且加热至80℃持续17小时。反应混合物用甲醇(20mL)稀释并加入硅胶(10g)。将悬浮液浓缩至干并将所得粉末负载于硅胶(40g)上并用0–70%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为橙色固体的88(167mg,60%):1H NMR(500MHz,CDCl3)δ7.74(d,J=1.5Hz,1H),7.17(d,J=1.5Hz,1H),2.43(s,3H),2.28(s,3H)。Step 2: To a solution of 87 (250 mg, 1.01 mmol), a catalytic amount of DMAP, and 1,4-dioxane (4 mL) in a pressure tube was added 1,1'-carbonyldiimidazole (327 mg, 2.01 mmol). The tube was sealed and heated to 80°C for 17 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded onto silica gel (40 g) and eluted with 0-70% ethyl acetate in hexanes. The clean product was concentrated to give 88 (167 mg, 60%) as an orange solid: 1H NMR (500 MHz, CDCl 3 ) δ 7.74 (d, J=1.5 Hz, 1H), 7.17 (d, J=1.5 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 3H).

步骤3:向88(309mg,1.13mmol)、碳酸钾(312mg,2.25mmol)、乙腈(5mL)和DMF(2mL)于压力管中的溶液加入(溴甲基)环丙烷(183mg,1.35mmol)并将反应密封且在80℃加热17小时。将材料冷却至室温且倾入饱和NaCl水溶液(30mL)。加入乙酸乙酯(100mL)并将层分离。乙酸乙酯层用饱和NaCl水溶液洗涤(2×100mL),经Na2SO4干燥,过滤且浓缩滤液。将于CH2Cl2(10mL)中的所得油负载于硅胶(80g)上并用0–40%于己烷中的乙酸乙酯洗脱。洁净产物然后通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为黄色固体的实施例化合物145(88mg,35%):1H NMR(500MHz,CD3OD)δ7.82(d,J=1.5Hz,1H),7.52(d,J=1.0Hz,1H),3.87(d,J=7.0Hz,2H),2.45(s,3H),2.29(s,3H),1.30–1.18(m,1H),0.60–0.52(m,2H),0.47–0.43(m,2H).ESI m/z 329[M+H]+.HPLC>99%。Step 3: To a solution of 88 (309 mg, 1.13 mmol), potassium carbonate (312 mg, 2.25 mmol), acetonitrile (5 mL) and DMF (2 mL) in a pressure tube was added (bromomethyl)cyclopropane (183 mg, 1.35 mmol) and the reaction was sealed and heated at 80 ° C for 17 hours. The material was cooled to room temperature and poured into saturated aqueous NaCl solution (30 mL). Ethyl acetate (100 mL) was added and the layers were separated. The ethyl acetate layer was washed with saturated aqueous NaCl solution (2×100 mL), dried over Na 2 SO 4 , filtered and the filtrate was concentrated. The resulting oil in CH 2 Cl 2 (10 mL) was loaded onto silica gel (80 g) and eluted with 0-40% ethyl acetate in hexanes. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example Compound 145 (88 mg, 35%) as a yellow solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.82 (d, J = 1.5 Hz, 1 H), 7.52 (d, J = 1.0 Hz, 1 H), 3.87 (d, J = 7.0 Hz, 2H), 2.45 (s, 3H), 2.29 (s, 3H), 1.30-1.18 (m, 1H), 0.60-0.52 (m, 2H), 0.47-0.43 (m, 2H). ESI m/z 329 [M+H] + . HPLC >99%.

步骤4:将实施例化合物145(171mg,0.521mmol)于氧氯化磷(V)(4mL)中的溶液置于密封管中且在110℃加热持续8小时。真空除去溶剂且加入饱和NaHCO3水溶液(5mL)。混合物用乙酸乙酯萃取(2×20mL)并将合并的萃取液经Na2SO4干燥,过滤且浓缩滤液。然后加入THF(5mL)和2.0M于THF中的乙基胺溶液,并将反应在70℃加热12小时。将反应浓缩至干且残余物用CH2Cl2(5mL)稀释。将所得溶液负载于硅胶(40g)上并用0–80%于己烷中的乙酸乙酯洗脱。洁净产物然后通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为黄色固体的实施例化合物159(105mg,57%):1H NMR(500MHz,CDCl3)δ7.78(d,J=1.5Hz,1H),7.44(d,J=1.5Hz,1H),4.03(d,J=6.5Hz,2H),3.67(q,J=7.0Hz,2H),2.44(s,3H),2.29(s,3H),1.33(t,J=7.0Hz,3H),1.30–1.18(m,1H),0.60–0.52(m,2H),0.47–0.41(m,2H).ESI m/z 356[M+H]+.HPLC>99%。Step 4: A solution of Example Compound 145 (171 mg, 0.521 mmol) in phosphorus (V) oxychloride (4 mL) was placed in a sealed tube and heated at 110 ° C for 8 hours. The solvent was removed in vacuo and saturated aqueous NaHCO 3 solution (5 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined extracts were dried over Na 2 SO 4 , filtered, and the filtrate was concentrated. THF (5 mL) and a 2.0 M solution of ethylamine in THF were then added, and the reaction was heated at 70 ° C for 12 hours. The reaction was concentrated to dryness and the residue was diluted with CH 2 Cl 2 (5 mL). The resulting solution was loaded on silica gel (40 g) and eluted with 0-80% ethyl acetate in hexane. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example Compound 159 (105 mg, 57%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.78 (d, J=1.5 Hz, 1H), 7.44 (d, J=1.5 Hz, 1H), 4.03 (d, J=6.5 Hz, 2H), 3.67 (q, J=7.0 Hz, 2H), 2.44 (s, 3H), 2.29 (s, 3H), 1.33 (t, J=7.0 Hz, 3H), 1.30-1.18 (m, 1H), 0.60-0.52 (m, 2H), 0.47-0.41 (m, 2H). ESI m/z 356 [M+H] + .HPLC>99%.

步骤5:在5分钟内将实施例化合物145(59mg,0.215mmol)于THF(10ml)中的溶液逐滴加入连二亚硫酸钠(225mg,1.29mmol)于水(10mL)中的溶液。将溶液在室温搅拌16小时并真空除去溶剂。加入甲醇(20mL)并将悬浮液在室温搅拌3小时。过滤混合物并浓缩滤液至干。将2N HCl水溶液(10mL)加入至残余物并加热至回流5分钟。浓缩至干后,加入甲醇(10mL)并使用饱和NaHCO3水溶液(15mL)将溶液调节至pH8。加入硅胶(10g)并将悬浮液浓缩至干。将所得粉末负载于硅胶上并用0–4%于二氯甲烷中的甲醇洗脱。洁净产物然后通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例化合物161(32mg,50%):1H NMR(500MHz,CD3OD)δ6.49(d,J=1.5Hz,1H),6.42(d,J=1.5Hz,1H),3.75(d,J=6.5Hz,2H),2.39(s,3H),2.24(s,3H),1.28–1.18(m,1H),0.56–0.48(m,2H),0.44–0.39(m,2H).ESI m/z 299[M+H]+.HPLC 97.4%。Step 5: A solution of Example Compound 145 (59 mg, 0.215 mmol) in THF (10 ml) was added dropwise to a solution of sodium dithionite (225 mg, 1.29 mmol) in water (10 mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. 2N HCl aqueous solution (10 mL) was added to the residue and heated to reflux for 5 minutes. After being concentrated to dryness, methanol (10 mL) was added and the solution was adjusted to pH 8 using saturated NaHCO 3 aqueous solution (15 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was loaded on silica gel and eluted with 0–4% methanol in dichloromethane. The clean product was then purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O and the clean fractions were frozen and lyophilized to give Example Compound 161 (32 mg, 50%) as a white solid: 1H NMR (500 MHz, CD3OD ) δ 6.49 (d, J = 1.5 Hz, 1H), 6.42 (d, J = 1.5 Hz, 1H), 3.75 (d, J = 6.5 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.28-1.18 (m, 1H), 0.56-0.48 (m, 2H), 0.44-0.39 (m, 2H). ESI m/z 299 [M+H] + . HPLC 97.4%.

步骤6:在5分钟内将实施例化合物159(90mg,0.253mmol)于THF(10ml)中的溶液逐滴加入连二亚硫酸钠(265mg,1.52mmol)于水(10mL)中的溶液。将溶液在室温搅拌16小时并真空除去溶剂。加入甲醇(20mL)并将悬浮液在室温搅拌3小时。过滤混合物并浓缩滤液至干。将2N HCl水溶液(10mL)加入至残余物并加热至回流5分钟。浓缩至干后,加入甲醇(10mL)并使用饱和NaHCO3水溶液(15mL)将溶液调节至pH8。加入硅胶(10g)并将悬浮液浓缩至干。将所得粉末负载于硅胶上并用0–4%于二氯甲烷中的甲醇洗脱。然后洁净产物通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例化合物160(61mg,74%):1H NMR(500MHz,CD3OD)δ6.49(d,J=1.5Hz,1H),6.37(d,J=1.5Hz,1H),3.88(d,J=6.5Hz,2H),3.48(q,J=7.0Hz,2H),2.39(s,3H),2.24(s,3H),1.28–1.18(m,1H),0.53–0.48(m,2H),0.40–0.35(m,2H).ESI m/z 326[M+H]+.HPLC>99%。Step 6: A solution of Example Compound 159 (90 mg, 0.253 mmol) in THF (10 ml) was added dropwise to a solution of sodium dithionite (265 mg, 1.52 mmol) in water (10 mL) over 5 minutes. The solution was stirred at room temperature for 16 hours and the solvent was removed in vacuo. Methanol (20 mL) was added and the suspension was stirred at room temperature for 3 hours. The mixture was filtered and the filtrate was concentrated to dryness. 2N HCl aqueous solution (10 mL) was added to the residue and heated to reflux for 5 minutes. After concentration to dryness, methanol (10 mL) was added and the solution was adjusted to pH 8 using saturated NaHCO 3 aqueous solution (15 mL). Silica gel (10 g) was added and the suspension was concentrated to dryness. The resulting powder was loaded on silica gel and eluted with 0–4% methanol in dichloromethane. The clean product was then purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O and the clean fractions were frozen and lyophilized to give Example Compound 160 (61 mg, 74%) as a white solid: 1H NMR (500 MHz, CD3OD ) δ 6.49 (d, J = 1.5 Hz, 1H), 6.37 (d, J = 1.5 Hz, 1H), 3.88 (d, J = 6.5 Hz, 2H), 3.48 (q, J = 7.0 Hz, 2H), 2.39 (s, 3H), 2.24 (s, 3H), 1.28-1.18 (m, 1H), 0.53-0.48 (m, 2H), 0.40-0.35 (m, 2H). ESI m/z 326 [M+H] + . HPLC >99%.

制备4-氨基-6-(3,5-二甲基异噁唑-4-基)-1-(4-羟基苄基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物129)。Preparation of 4-amino-6-(3,5-dimethylisoxazol-4-yl)-1-(4-hydroxybenzyl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 129).

向实施例化合物104(54mg,0.15mmol)于二氯甲烷(5mL)中的溶液在氮气气氛下加入三溴化硼(0.45mL,1M于二氯甲烷中,0.45mmol)。将反应混合物在室温搅拌过夜,用甲醇处理,并真空浓缩。将残余物溶解于甲醇中,用氢氧化铵碱化,真空浓缩,且通过色谱(硅胶,0–20%于乙酸乙酯中的甲醇)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC进一步纯化以得到为灰白色固体的实施例化合物129(31mg,59%):1H NMR(500MHz,CD3OD)δ7.17(d,J=8.6Hz,2H),6.72(d,J=8.6Hz,2H),6.39(d,J=1.3Hz,1H),6.26(d,J=1.3Hz,1H),4.94(s,2H),2.28(s,3H),2.12(s,3H);HPLC>99%,tR=11.0分钟;ESI m/z 351[M+H]+To a solution of Example Compound 104 (54 mg, 0.15 mmol) in dichloromethane (5 mL) was added boron tribromide (0.45 mL, 1 M in dichloromethane, 0.45 mmol) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight, treated with methanol, and concentrated in vacuo. The residue was dissolved in methanol, basified with ammonium hydroxide, concentrated in vacuo, and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It was further purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to give Example Compound 129 (31 mg, 59%) as an off-white solid: 1H NMR (500 MHz, CD3OD ) δ 7.17 (d, J=8.6 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H), 6.39 (d, J=1.3 Hz, 1H), 6.26 (d, J=1.3 Hz, 1H), 4.94 (s, 2H), 2.28 (s, 3H), 2.12 (s, 3H); HPLC >99%, tR = 11.0 min; ESI m/z 351 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-2-甲基-1H-苯并[d]咪唑-4-醇(实施例化合物173)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-benzo[d]imidazol-4-ol (Example Compound 173)

步骤1:在室温向89(5.00g,32.5mmol)和三乙胺(9.04mL,65.0mmol)于N,N-二甲基甲酰胺(150mL)中的溶液加入叔丁基氯二甲基硅烷(5.86g,39.0mmol)。将反应混合物在室温搅拌1小时并用乙酸乙酯稀释。混合物用水、盐水洗涤,经硫酸钠干燥,并过滤。浓缩滤液以提供为褐色油的90(8.59g,98%):1H NMR(300MHz,CDCl3)δ7.75(dd,J=1.3,8.9Hz,1H),6.89(dd,J=1.2,7.6Hz,1H),6.53(dd,J=8.8,7.6Hz,1H),6.45–6.15(bs,2H),1.03(s,9H),0.28(s,6H)。Step 1: To a solution of 89 (5.00 g, 32.5 mmol) and triethylamine (9.04 mL, 65.0 mmol) in N,N-dimethylformamide (150 mL) was added tert-butylchlorodimethylsilane (5.86 g, 39.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate. The mixture was washed with water and brine, dried over sodium sulfate, and filtered. The filtrate was concentrated to afford 90 (8.59 g, 98%) as a brown oil: 1H NMR (300 MHz, CDCl 3 ) δ 7.75 (dd, J = 1.3, 8.9 Hz, 1H), 6.89 (dd, J = 1.2, 7.6 Hz, 1H), 6.53 (dd, J = 8.8, 7.6 Hz, 1H), 6.45–6.15 (bs, 2H), 1.03 (s, 9H), 0.28 (s, 6H).

步骤2:在室温向90(8.59g,32.1mmol)于乙酸(120mL)中的溶液加入N-溴琥珀酰亚胺(6.28g,35.3mmol)。将反应混合物在室温搅拌30分钟,然后浓缩。将残余物溶解于甲醇中并用5%碳酸氢钠水溶液碱化。将所形成的沉淀过滤,用水洗涤,并在真空下干燥以提供为橙色固体的91(8.56g,76%):1H NMR(500MHz,CDCl3)δ7.91(d,J=2.1Hz,1H),6.96(d,J=2.1Hz,1H),6.50–6.12(bs,2H),1.03(s,9H),0.30(s,6H)。Step 2: To a solution of 90 (8.59 g, 32.1 mmol) in acetic acid (120 mL) was added N-bromosuccinimide (6.28 g, 35.3 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated. The residue was dissolved in methanol and basified with 5% aqueous sodium bicarbonate solution. The resulting precipitate was filtered, washed with water, and dried under vacuum to afford 91 (8.56 g, 76%) as an orange solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.91 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.50–6.12 (bs, 2H), 1.03 (s, 9H), 0.30 (s, 6H).

步骤3:向91(5.00g,14.4mmol)于四氢呋喃(60mL)中的溶液加入铂碳(1.00g,5%Pt碳)。将反应混合物在氢气气氛下于室温搅拌过夜。过滤混合物,用MeOH洗涤,并浓缩滤液以提供为深褐色油的92(5.65g,>99%):1H NMR(500MHz,CDCl3)δ6.51(d,J=2.0Hz,1H),6.46(d,J=2.0Hz,1H),3.50–2.50(bs,4H),1.01(s,9H),0.24(s,6H);ESI m/z 317[M+H]+Step 3: To a solution of 91 (5.00 g, 14.4 mmol) in tetrahydrofuran (60 mL) was added platinum on carbon (1.00 g, 5% Pt on carbon). The reaction mixture was stirred at room temperature overnight under a hydrogen atmosphere. The mixture was filtered, washed with MeOH, and the filtrate was concentrated to afford 92 (5.65 g, >99%) as a dark brown oil: 1 H NMR (500 MHz, CDCl 3 ) δ 6.51 (d, J = 2.0 Hz, 1 H), 6.46 (d, J = 2.0 Hz, 1 H), 3.50-2.50 (bs, 4 H), 1.01 (s, 9 H), 0.24 (s, 6 H); ESI m/z 317 [M+H] + .

步骤4:向92(2.00g,6.31mmol)于乙醇(50mL)中的溶液加入原乙酸三乙酯(3.07g,18.9mmol)和氨基磺酸(1mg,0.01mmol)。将反应在密封管中于80℃加热过夜。将混合物浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以提供为浅红色固体的93(2.07g,96%):1H NMR(500MHz,CDCl3)δ8.75(s,1H),7.45(s,1H),6.78(s,1H),3.61(s,3H),1.03(s,9H),0.28(s,6H);ESI m/z 341[M+H]+Step 4: To a solution of 92 (2.00 g, 6.31 mmol) in ethanol (50 mL) was added triethyl orthoacetate (3.07 g, 18.9 mmol) and sulfamic acid (1 mg, 0.01 mmol). The reaction was heated in a sealed tube at 80° C. overnight. The mixture was concentrated and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to afford 93 (2.07 g, 96%) as a light red solid: 1H NMR (500 MHz, CDCl 3 ) δ 8.75 (s, 1H), 7.45 (s, 1H), 6.78 (s, 1H), 3.61 (s, 3H), 1.03 (s, 9H), 0.28 (s, 6H); ESI m/z 341 [M+H] + .

步骤5:将93(200mg,0.587mmol)、苄基溴(150mg,0.880mmol)和碳酸氢钾(113mg,0.822mmol)于乙腈(20mL)中的混合物在45℃加热2天。将反应混合物冷却至室温,浓缩并通过色谱(硅胶,0–30%于己烷中的乙酸乙酯)纯化以提供为褐色固体的94(303mg,30%):1HNMR(500MHz,CDCl3)δ7.36–7.26(m,3H),7.01(d,J=8.2Hz,2H),6.97(d,J=1.6Hz,1H),6.81(d,J=1.6Hz,1H),5.22(s,2H),2.50(s,3H),1.05(s,9H),0.30(s,6H);ESI m/z 431[M+H]+Step 5: A mixture of 93 (200 mg, 0.587 mmol), benzyl bromide (150 mg, 0.880 mmol) and potassium bicarbonate (113 mg, 0.822 mmol) in acetonitrile (20 mL) was heated at 45 °C for 2 days. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to provide 94 (303 mg, 30%) as a brown solid: 1 H NMR (500 MHz, CDCI 3 ) δ 7.36-7.26 (m, 3H), 7.01 (d, J=8.2 Hz, 2H), 6.97 (d, J=1.6 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H), 5.22 (s, 2H), 2.50 (s, 3H), 1.05 (s, 9H), 0.30 (s, 6H); ESI m/z 431 [M+H] + .

步骤6:向94(75mg,0.17mmol)于1,4-二噁烷(10mL)和水(1mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(58mg,0.26mmol)、碳酸氢钾(70mg,0.70mmol)和四(三苯基膦)钯(0)(10mg,0.0087mmol)。反应混合物用氮气吹扫且在90℃加热2小时。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以得到为灰白色固体的95(53mg,70%):1H NMR(500MHz,CD3OD)δ7.33(t,J=6.3Hz,2H),7.27(t,J=5.1Hz,1H),7.14(d,J=7.1Hz,2H),6.89(d,J=1.3Hz,1H),6.58(d,J=1.3Hz,1H),5.45(s,2H),2.59(s,3H),2.32(s,3H),2.16(s,3H),1.05(s,9H),0.30(s,6H);HPLC>99%,tR=16.4分钟;ESI m/z 448[M+H]+Step 6: To a solution of 94 (75 mg, 0.17 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (58 mg, 0.26 mmol), potassium bicarbonate (70 mg, 0.70 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.0087 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated, and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give 95 (53 mg, 70%) as an off-white solid: 1 H NMR (500 MHz, CD 3 OD) δ 7.33 (t, J = 6.3 Hz, 2H), 7.27 (t, J = 5.1 Hz, 1H), 7.14 (d, J = 7.1 Hz, 2H), 6.89 (d, J = 1.3 Hz, 1H), 6.58 (d, J = 1.3 Hz, 1H), 5.45 (s, 2H), 2.59 (s, 3H), 2.32 (s, 3H), 2.16 (s, 3H), 1.05 (s, 9H), 0.30 (s, 6H); HPLC > 99%, t R = 16.4 min; ESI m/z 448 [M+H] + .

步骤7:将95(48mg,0.11mmol)和碳酸钾(30mg,0.22mmol)于乙腈(10mL)中的混合物在密封管中于80℃加热过夜。将反应混合物冷却至室温,浓缩且通过色谱(硅胶,0–20%于乙酸乙酯中的甲醇)纯化。其通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC进一步纯化以得到为灰白色固体的实施例化合物173(32mg,87%):1H NMR(500MHz,DMSO–d6)δ9.84(s,1H),7.33(t,J=7.6Hz,2H),7.26(t,J=7.3Hz,1H),7.18(d,J=7.1Hz,2H),6.86(d,J=1.3Hz,1H),6.47(d,J=1.3Hz,1H),5.42(s,2H),2.52(s,3H),2.33(s,3H),2.15(s,3H);ESI m/z 334[M+H]+Step 7: A mixture of 95 (48 mg, 0.11 mmol) and potassium carbonate (30 mg, 0.22 mmol) in acetonitrile (10 mL) was heated in a sealed tube at 80° C. overnight. The reaction mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% methanol in ethyl acetate). It was further purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to give Example Compound 173 (32 mg, 87%) as an off-white solid: 1H NMR (500 MHz, DMSO- d6 ) δ 9.84 (s, 1H), 7.33 (t, J = 7.6 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1H), 7.18 (d, J = 7.1 Hz, 2H), 6.86 (d, J = 1.3 Hz, 1H), 6.47 (d, J = 1.3 Hz, 1H), 5.42 (s, 2H), 2.52 (s, 3H), 2.33 (s, 3H), 2.15 (s, 3H); ESI m/z 334 [M+H] + .

制备4-氨基-1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2(3H)-硫酮(实施例化合物177)。Preparation of 4-amino-1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2(3H)-thione (Example Compound 177).

将实施例化合物16(34mg,0.10mmol)和劳森试剂(202mg,0.5mmol)的混合物在微波反应器中加热至180℃持续2小时。浓缩混合物,残余物通过色谱(硅胶,0–40%EtOAc/己烷),之后色谱(C18,10–70%CH3CN/水)纯化以得到为灰白色固体的实施例化合物177(13mg,37%):1H NMR(300MHz,DMSO–d6)δ12.56(s,1H),7.45–7.42(m,2H),7.34–7.25(m,3H),6.44(d,J=1.2Hz,1H),6.39(d,J=1.5Hz,1H),5.44(s,4H),2.29(s,3H),2.11(s,3H);ESI m/z351[M+H]+。HPLC 98.6%A mixture of Example Compound 16 (34 mg, 0.10 mmol) and Lawesson's reagent (202 mg, 0.5 mmol) was heated to 180° C. in a microwave reactor for 2 hours. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-40% EtOAc/hexanes) followed by chromatography ( Ci8 , 10-70% CH3CN /water) to afford Example Compound 177 (13 mg, 37%) as an off-white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 12.56 (s, 1H), 7.45-7.42 (m, 2H), 7.34-7.25 (m, 3H), 6.44 (d, J=1.2 Hz, 1H), 6.39 (d, J=1.5 Hz, 1H), 5.44 (s, 4H), 2.29 (s, 3H), 2.11 (s, 3H); ESI m/z 351 [M+H] + . HPLC 98.6%

制备1-苄基-3-甲基-6-(1-甲基-1H-吡唑-5-基)-4-硝基-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物198)和4-氨基-1-苄基-3-甲基-6-(1-甲基-1H-吡唑-5-基)-1H-苯并[d]咪唑-2(3H)-酮(实施例化合物199)。Prepare 1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-4-nitro-1H-benzo[d]imidazol-2(3H)-one (Example Compound 198) and 4-amino-1-benzyl-3-methyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-2(3H)-one (Example Compound 199).

化合物96通过按照与用于制备实施例化合物15类似的方法使用1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑来制备。Compound 96 was prepared by following a procedure similar to that used to prepare Example Compound 15 using 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.

步骤1:将96(70mg,0.20mmol)、CH3I(85mg,0.60mmol)和K2CO3(110mg,0.8mmol)于DMF(3mL)中的混合物在室温搅拌16小时。反应混合物用EtOAc(100mL)稀释并用盐水洗涤(3×50mL)。将有机层经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,20–70%乙酸乙酯/己烷)纯化以提供为黄色固体的实施例化合物198(50mg,68%):1H NMR(300MHz,CDCl3)δ7.66(d,J=1.5Hz,1H),7.50(d,J=1.8Hz,1H),7.36–7.30(m,5H),7.02(d,J=1.5Hz,1H),6.27(d,J=1.2Hz,1H),5.16(s,2H),3.69(s,3H),3.65(s,3H);ESI m/z 364[M+H]+Step 1: A mixture of 96 (70 mg, 0.20 mmol), CH 3 I (85 mg, 0.60 mmol) and K 2 CO 3 (110 mg, 0.8 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 20-70% ethyl acetate/hexanes) to provide Example Compound 198 (50 mg, 68%) as a yellow solid: 1 H NMR (300 MHz, CDCl 3 ) δ 7.66 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.8 Hz, 1H), 7.36-7.30 (m, 5H), 7.02 (d, J=1.5 Hz, 1H), 6.27 (d, J=1.2 Hz, 1H), 5.16 (s, 2H), 3.69 (s, 3H), 3.65 (s, 3H); ESI m/z 364 [M+H] + .

步骤2:向实施例化合物198(45mg,0.12mmol)于THF(5mL)和水(4mL)中的溶液加入Na2S2O4(129mg,0.74mmol)。将混合物在室温搅拌4小时,加入2N HCl(1mL),将混合物加热至回流15分钟,然后冷却至室温。缓慢地加入Na2CO3以调节至pH9。混合物用CH2Cl2(100mL)萃取,有机层用盐水(50mL)洗涤,过滤,浓缩且通过色谱(硅胶,0–10%甲醇/乙酸乙酯)纯化以提供为白色固体的实施例化合物199(37mg,90%):1H NMR(300MHz,DMSO–d6)δ7.39(d,J=1.8Hz,1H),7.35–7.24(m,5H),6.56(d,J=1.5Hz,1H),6.54(d,J=1.5Hz,1H),6.20(d,J=1.8Hz,1H),5.15(s,2H),5.01(s,2H),3.72(s,3H),3.63(s,3H);ESI m/z 334[M+H]+Step 2: To a solution of Example Compound 198 (45 mg, 0.12 mmol) in THF (5 mL) and water (4 mL) was added Na 2 S 2 O 4 (129 mg, 0.74 mmol). The mixture was stirred at room temperature for 4 hours, 2N HCl (1 mL) was added, and the mixture was heated to reflux for 15 minutes and then cooled to room temperature. Na 2 CO 3 was slowly added to adjust the pH to 9. The mixture was extracted with CH2Cl2 (100 mL ), and the organic layer was washed with brine (50 mL), filtered, concentrated, and purified by chromatography (silica gel, 0-10% methanol/ethyl acetate) to provide Example Compound 199 (37 mg, 90%) as a white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 7.39 (d, J=1.8 Hz, 1H), 7.35-7.24 (m, 5H), 6.56 (d, J=1.5 Hz, 1H), 6.54 (d, J=1.5 Hz, 1H), 6.20 (d, J=1.8 Hz, 1H), 5.15 (s, 2H), 5.01 (s, 2H), 3.72 (s, 3H), 3.63 (s, 3H); ESI m/z 334 [M+H] + .

制备4-(1-苄基-2-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物220)Preparation of 4-(1-benzyl-2-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 220)

向28(100mg,0.34mmol)和四氢-2H-吡喃-4-羧酸(65mg,0.51mmol)于CH2Cl2中的溶液加入EDC(131mg,0.68mmol)、i-Pr2NEt(132mg,1.02mmol)和DMAP(10mg)。将反应混合物在室温搅拌16小时。混合物用EtOAc(100mL)稀释,用盐水(50mL)和饱和NaHCO3(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。将残余物溶解于AcOH(2mL)中并加热至回流5小时。浓缩混合物,将残余物溶解于EtOAc(100mL),用饱和NaHCO3(2×50mL)和盐水(50mL)洗涤。将有机层经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–10%MeOH/EtOAc)纯化以得到为浅褐色固体的实施例化合物220(47mg,36%):1H NMR(300MHz,CDCl3)δ8.41(d,J=1.8Hz,1H),7.38–7.32(m,3H),7.24(d,J=2.1Hz,1H),7.08–7.05(m,2H),5.42(s,2H),4.12(dd,J=11.7,1.8Hz,2H),3.52(td,J=11.7,1.8Hz,2H),3.20–3.12(m,1H),2.36–2.23(m,5H),2.14(s,3H),1.83–1.78(m,2H);ESI m/z 389[M+H]+To a solution of 28 (100 mg, 0.34 mmol) and tetrahydro-2H-pyran-4-carboxylic acid (65 mg, 0.51 mmol) in CH 2 Cl 2 was added EDC (131 mg, 0.68 mmol), i-Pr 2 NEt (132 mg, 1.02 mmol) and DMAP (10 mg). The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (100 mL), washed with brine (50 mL) and saturated NaHCO 3 (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in AcOH (2 mL) and heated to reflux for 5 hours. The mixture was concentrated, and the residue was dissolved in EtOAc (100 mL), washed with saturated NaHCO 3 (2×50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-10% MeOH/EtOAc) to give Example Compound 220 (47 mg, 36%) as a light brown solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.41 (d, J=1.8 Hz, 1H), 7.38-7.32 (m, 3H), 7.24 (d, J=2.1 Hz, 1H), 7.08-7.05 (m, 2H), 5.42 (s, 2H), 4.12 (dd, J=11.7, 1.8 Hz, 2H), 3.52 (td, J=11.7, 1.8 Hz, 2H), 3.20-3.12 (m, 1H), 2.36-2.23 (m, 5H), 2.14 (s, 3H), 1.83-1.78 (m, 2H); ESI m/z 389[M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-甲基-1H-咪唑并[4,5-b]吡啶-2-甲酰胺(实施例化合物221)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-methyl-1H-imidazo[4,5-b]pyridine-2-carboxamide (Example Compound 221)

将28(300mg,1.02mmol)和2,2,2-三甲氧基乙酸甲酯(1.5mL)的混合物加热至120℃持续16小时。混合物通过色谱(硅胶,20–80%EtOAc/己烷)纯化以得到褐色固体。将固体溶解于CH3NH2/THF(2M)(3mL)中并在80℃加热16小时。浓缩混合物,残余物通过色谱(C18,10–70%CH3CN/水)纯化以得到为灰白色固体的实施例化合物221(45mg,12%):1H NMR(300MHz,DMSO–d6)δ8.31(q,J=4.5Hz,1H),8.27(d,J=1.8Hz,1H),7.54(d,J=1.8Hz,1H),7.36–7.24(m,5H),5.54(s,2H),3.00(d,J=4.8Hz,3H),2.21(s,3H),2.00(s,3H);ESI m/z362[M+H]+A mixture of 28 (300 mg, 1.02 mmol) and methyl 2,2,2-trimethoxyacetate (1.5 mL) was heated to 120° C. for 16 hours. The mixture was purified by chromatography (silica gel, 20-80% EtOAc/hexanes) to give a brown solid. The solid was dissolved in CH 3 NH 2 /THF (2M) (3 mL) and heated at 80° C. for 16 hours. The mixture was concentrated and the residue was purified by chromatography ( Ci8 , 10-70% CH3CN /water) to give Example Compound 221 (45 mg, 12%) as an off-white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 8.31 (q, J = 4.5 Hz, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.36-7.24 (m, 5H), 5.54 (s, 2H), 3.00 (d, J = 4.8 Hz, 3H), 2.21 (s, 3H), 2.00 (s, 3H); ESI m/z 362 [M+H] + .

制备1-苄基-6-(1-甲基-1H-吡唑-5-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物171)Preparation of 1-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 171)

步骤1:向85(1.14g,4.09mmol)于1,4-二噁烷(41mL)中的溶液加入1,1'-羰基二咪唑(796mg,4.91mmol)。将反应混合物在110℃加热持续16小时。浓缩反应混合物。通过色谱(硅胶,0–100%乙酸乙酯/己烷)纯化得到为白色固体的97(1.03g,83%):1H NMR(500MHz,DMSO–d6)δ11.89(s,1H),8.00(d,J=2.0Hz,1H),7.68(d,J=2.0Hz,1H),7.37–7.32(m,4H),7.30–7.26(m,1H),5.02(s,2H)。Step 1: To a solution of 85 (1.14 g, 4.09 mmol) in 1,4-dioxane (41 mL) was added 1,1'-carbonyldiimidazole (796 mg, 4.91 mmol). The reaction mixture was heated at 110 °C for 16 hours. The reaction mixture was concentrated. Purification by chromatography (silica gel, 0-100% ethyl acetate/hexanes) gave 97 (1.03 g, 83%) as a white solid: 1H NMR (500 MHz, DMSO- d6 ) δ 11.89 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.37-7.32 (m, 4H), 7.30-7.26 (m, 1H), 5.02 (s, 2H).

步骤2:向97(334mg,1.09mmol)于1,4-二噁烷(11mL)中的溶液加入1-甲基-1H-吡唑-5-硼酸频哪醇酯(457mg,2.20mmol)、碳酸钠(1.0M于H2O中,3.29mL,3.29mmol)和四(三苯基膦)钯(0)(127mg,0.1mmol)。反应混合物用氮气吹扫且在90℃加热32小时。混合物用二氯甲烷(80mL)稀释,用盐水(40mL)洗涤,经硫酸钠干燥,过滤并浓缩。残余物通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化,之后用EtOAc研磨以提供为白色固体的实施例化合物171(173mg,52%):1H NMR(500MHz,DMSO–d6)δ11.87(s,1H),8.04(d,J=1.5Hz,1H),7.57(d,J=1.5,1H),7.46(d,J=2.0Hz,1H),7.38(d,J=7.5Hz,2H),7.34(t,J=7.5Hz,2H),7.27(t,J=7.0Hz,1H),6.37(d,J=1.5Hz,1H),5.06(s,2H),3.77(s,3H);ESI m/z 306[M+H]+Step 2: To a solution of 97 (334 mg, 1.09 mmol) in 1,4-dioxane (11 mL) was added 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (457 mg, 2.20 mmol), sodium carbonate (1.0 M in H 2 O, 3.29 mL, 3.29 mmol) and tetrakis(triphenylphosphine)palladium(0) (127 mg, 0.1 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 32 hours. The mixture was diluted with dichloromethane (80 mL), washed with brine (40 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (silica gel, 0-5% methanol/dichloromethane) followed by trituration with EtOAc to provide Example Compound 171 (173 mg, 52%) as a white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 11.87 (s, 1H), 8.04 (d, J=1.5 Hz, 1H), 7.57 (d, J=1.5, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.38 (d, J=7.5 Hz, 2H), 7.34 (t, J=7.5 Hz, 2H), 7.27 (t, J=7.0 Hz, 1H), 6.37 (d, J=1.5 Hz, 1H), 5.06 (s, 2H), 3.77 (s, 3H); ESI m/z 306 [M+H] + .

制备N-(1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-基)乙酰胺(实施例化合物99)Preparation of N-(1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)acetamide (Example Compound 99)

将实施例化合物39(100mg,0.29mmol)于EtOH(3mL)和AcOH(1mL)中的溶液加入铁粉(162mg,2.9mmol)。将反应混合物在80℃加热1小时。其滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化得到为红色固体的实施例化合物99(28mg,27%):1HNMR(300MHz,DMSO–d6)δ10.2(s,1H),8.32(d,J=1.8Hz,1H),8.23(s,1H),7.97(d,J=1.8Hz,1H),7.32–7.25(m,5H),5.45(s,2H),2.40(s,3H),2.22(s,3H),2.12(s,3H);ESI MSm/z 361[M+H]+To a solution of Example Compound 39 (100 mg, 0.29 mmol) in EtOH (3 mL) and AcOH (1 mL) was added iron powder (162 mg, 2.9 mmol). The reaction mixture was heated at 80° C. for 1 hour, filtered through a pad of Celite, and the filtrate was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) provided Example Compound 99 (28 mg, 27%) as a red solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.2 (s, 1H), 8.32 (d, J=1.8 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J=1.8 Hz, 1H), 7.32-7.25 (m, 5H), 5.45 (s, 2H), 2.40 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H); ESI MS m/z 361 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-吡咯并[3,2-b]吡啶-3-胺(实施例化合物100)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-amine (Example Compound 100)

向实施例化合物39(100mg,0.29mmol)于EtOH(3mL)和H2SO4(0.5mL)中的溶液加入铁粉(162mg,2.9mmol)。将反应混合物在80℃加热1小时。其用EtOH(20mL)稀释,用6N NaOH水溶液调节至pH7。将混合物滤过硅藻土层并浓缩滤液。通过色谱(硅胶,0–5%甲醇/二氯甲烷)纯化得到为红色固体的实施例化合物100(12mg,13%):1H NMR(300MHz,DMSO–d6)δ8.18(d,J=1.8Hz,1H),7.82(d,J=1.8Hz,1H),7.33–7.21(m,5H),7.06(s,1H),5.30(s,2H),4.26(s,2H),2.37(s,3H),2.21(s,3H);ESI MS m/z 319[M+H]+To a solution of Example Compound 39 (100 mg, 0.29 mmol) in EtOH (3 mL) and H 2 SO 4 (0.5 mL) was added iron powder (162 mg, 2.9 mmol). The reaction mixture was heated at 80° C. for 1 hour. It was diluted with EtOH (20 mL) and adjusted to pH 7 with 6N aqueous NaOH. The mixture was filtered through a pad of Celite, and the filtrate was concentrated. Purification by chromatography (silica gel, 0-5% methanol/dichloromethane) provided Example Compound 100 (12 mg, 13%) as a red solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 8.18 (d, J=1.8 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 7.33-7.21 (m, 5H), 7.06 (s, 1H), 5.30 (s, 2H), 4.26 (s, 2H), 2.37 (s, 3H), 2.21 (s, 3H); ESI MS m/z 319 [M+H] + .

制备4-苄基-6-(3,5-二甲基异噁唑-4-基)-3,4-二氢喹喔啉-2(1H)-酮(实施例化合物156)Preparation of 4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (Example Compound 156)

步骤1:将4-溴-2-氟-1-硝基苯(1.00g,4.54mmol)、2-(苄基氨基)乙酸乙酯(0.87g,4.5mmol)和碳酸钾(0.78g,5.7mmol)于乙醇(15mL)和水(11mL)中的溶液在85℃加热10小时,然后在室温搅拌8小时。反应混合物用水和盐水稀释,然后用二氯甲烷洗涤。将所生成的水层过滤以提供为橙色固体的99(1.28g,72%):1H NMR(300MHz,DMSO–d6):δ7.57(d,J=8.6Hz,1H),7.37–7.21(m,6H),6.97(dd,J=8.7,2.0Hz,1H),4.52(s,2H),3.40(s,2H)。Step 1: A solution of 4-bromo-2-fluoro-1-nitrobenzene (1.00 g, 4.54 mmol), ethyl 2-(benzylamino)acetate (0.87 g, 4.5 mmol) and potassium carbonate (0.78 g, 5.7 mmol) in ethanol (15 mL) and water (11 mL) was heated at 85° C. for 10 hours and then stirred at room temperature for 8 hours. The reaction mixture was diluted with water and brine, then washed with dichloromethane. The resulting aqueous layer was filtered to provide 99 (1.28 g, 72%) as an orange solid: 1 H NMR (300 MHz, DMSO-d 6 ): δ 7.57 (d, J=8.6 Hz, 1H), 7.37–7.21 (m, 6H), 6.97 (dd, J=8.7, 2.0 Hz, 1H), 4.52 (s, 2H), 3.40 (s, 2H).

步骤2:向99(1.28g,3.51mmol)于乙酸(14mL)中的溶液在室温加入铁(470mg,8.4mmol)并将所生成的浆料加热至90℃持续2.25小时。将混合物冷却至室温并滤过硅藻土,用二氯甲烷冲洗。将滤液真空浓缩并将所生成的油在二氯甲烷与饱和碳酸氢钠水溶液之间分配。水层用二氯甲烷萃取并将合并的有机层用硫酸钠干燥,真空浓缩,且通过快速柱色谱(硅胶,0–100%乙酸乙酯/二氯甲烷)纯化以提供为白色固体的100(430mg,39%收率):1HNMR(300MHz,CDCl3)δ8.74(br s,1H),7.39–7.26(m,5H),6.89–6.85(m,2H),6.62(d,J=8.0Hz,2H),4.39(s,2H),3.80(s,2H)。Step 2: To a solution of 99 (1.28 g, 3.51 mmol) in acetic acid (14 mL) was added iron (470 mg, 8.4 mmol) at room temperature and the resulting slurry was heated to 90 ° C for 2.25 hours. The mixture was cooled to room temperature and filtered through celite, rinsing with dichloromethane. The filtrate was concentrated in vacuo and the resulting oil was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane and the combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by flash column chromatography (silica gel, 0-100% ethyl acetate/dichloromethane) to afford 100 (430 mg, 39% yield) as a white solid: 1 H NMR (300 MHz, CDCl 3 ) δ 8.74 (br s, 1H), 7.39-7.26 (m, 5H), 6.89-6.85 (m, 2H), 6.62 (d, J=8.0 Hz, 2H), 4.39 (s, 2H), 3.80 (s, 2H).

步骤3:对化合物100使用与实施例化合物7步骤1所用的程序类似的程序得到为白色固体的实施例化合物156:1H NMR(500MHz,DMSO–d6)δ10.58(s,1H),7.38–7.34(m,4H),7.30–7.23(m,1H),6.87(d,J=7.9Hz,1H),6.65(d,J=7.9Hz,1H),6.51(s,1H),4.46(s,2H),3.86(s,2H),2.15(s,3H),1.97(s,3H);ESI m/z 334[M+H]+Step 3: Compound 100 was subjected to a procedure analogous to that used in Step 1 of Example 7 to give Example 156 as a white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.58 (s, 1H), 7.38-7.34 (m, 4H), 7.30-7.23 (m, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.65 (d, J=7.9 Hz, 1H), 6.51 (s, 1H), 4.46 (s, 2H), 3.86 (s, 2H), 2.15 (s, 3H), 1.97 (s, 3H); ESI m/z 334 [M+H] + .

制备4-苄基-6-(1-甲基-1H-吡唑-5-基)-3,4-二氢喹喔啉-2(1H)-酮(实施例化合物166)Preparation of 4-benzyl-6-(1-methyl-1H-pyrazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one (Example Compound 166)

对化合物100使用与实施例化合物7步骤1所用的程序类似的程序得到为白色固体的实施例化合物166:1H NMR(500MHz,DMSO–d6)δ10.62(s,1H),7.37–7.33(m,5H),7.29–7.25(m,1H),6.90(d,J=7.9Hz,1H),6.80(dd,J=7.9,1.8Hz,1H),6.70(d,J=1.6Hz,1H),6.18(d,J=1.8Hz,1H),4.49(s,2H),3.83(s,2H),3.58(s,3H);ESI m/z 319[M+H]+Using a procedure analogous to that used for Example 7, Step 1, on Compound 100, Example 166 was obtained as a white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 7.37-7.33 (m, 5H), 7.29-7.25 (m, 1H), 6.90 (d, J=7.9 Hz, 1H), 6.80 (dd, J=7.9, 1.8 Hz, 1H), 6.70 (d, J=1.6 Hz, 1H), 6.18 (d, J=1.8 Hz, 1H), 4.49 (s, 2H), 3.83 (s, 2H), 3.58 (s, 3H); ESI m/z 319 [M+H] + .

制备(R)-4-苄基-6-(3,5-二甲基异噁唑-4-基)-3-甲基-3,4-二氢喹喔啉-2(1H)-酮(实施例化合物174)Preparation of (R)-4-benzyl-6-(3,5-dimethylisoxazol-4-yl)-3-methyl-3,4-dihydroquinoxalin-2(1H)-one (Example Compound 174)

步骤1:将4-溴-2-氟-1-硝基苯(0.50g,2.3mmol)、(R)-2-(苄基氨基)丙酸甲酯(0.55g,2.3mmol)和碳酸钾(0.47g,3.4mmol)于乙醇(8mL)和水(6mL)中的溶液在85℃加热10小时,然后在室温搅拌8小时。反应混合物用水稀释且过滤。用6N HCl水溶液将滤液的pH调节至~4且将所生成的浆料重新过滤以提供为粘性橙色固体的101(不称重;直接用于下一步骤)。Step 1: A solution of 4-bromo-2-fluoro-1-nitrobenzene (0.50 g, 2.3 mmol), (R)-methyl 2-(benzylamino)propanoate (0.55 g, 2.3 mmol) and potassium carbonate (0.47 g, 3.4 mmol) in ethanol (8 mL) and water (6 mL) was heated at 85 ° C for 10 hours and then stirred at room temperature for 8 hours. The reaction mixture was diluted with water and filtered. The pH of the filtrate was adjusted to ~4 with 6N aqueous HCl and the resulting slurry was re-filtered to provide 101 as a sticky orange solid (not weighed; used directly in the next step).

步骤2:对化合物101使用与实施例化合物156步骤2所用的程序类似的程序得到为白色固体的化合物102(430mg,39%收率):1H NMR(500MHz,DMSO–d6)δ10.57(br s,1H),7.39–7.25(m,5H),6.87–6.66(m,3H),4.60(d,J=15.5Hz,1H),4.29(d,J=15.2Hz,1H),3.85(q,J=6.9Hz,1H),1.08(d,J=6.7Hz,3H)。Step 2: Compound 101 was subjected to a procedure analogous to that used in Step 2 of Example 156 to give compound 102 (430 mg, 39% yield) as a white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.57 (br s, 1H), 7.39–7.25 (m, 5H), 6.87–6.66 (m, 3H), 4.60 (d, J=15.5 Hz, 1H), 4.29 (d, J=15.2 Hz, 1H), 3.85 (q, J=6.9 Hz, 1H), 1.08 (d, J=6.7 Hz, 3H).

步骤3:对化合物102使用与实施例化合物156步骤3所用的程序类似的程序得到为灰白色固体的实施例化合物174:1H NMR(500MHz,DMSO-d6)δ10.53(s,1H),7.37–7.32(m,4H),7.26–7.23(m,1H),6.88(d,J=7.9Hz,1H),6.66(dd,J=7.9,1.7Hz,1H),6.42(d,J=1.5Hz,1H),4.54(d,J=15.6Hz,1H),4.37(d,J=15.7Hz,1H),3.98(q,J=6.7Hz,1H),2.11(s,3H),1.93(s,3H),1.12(d,J=6.7Hz,3H);ESI m/z 348[M+H]+Step 3: Compound 102 was subjected to a procedure analogous to that used in Step 3 of Example 156 to provide Example 174 as an off-white solid: 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 7.37–7.32 (m, 4H), 7.26–7.23 (m, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.66 (dd, J=7.9, 1.7 Hz, 1H), 6.42 (d, J=1.5 Hz, 1H), 4.54 (d, J=15.6 Hz, 1H), 4.37 (d, J=15.7 Hz, 1H), 3.98 (q, J=6.7 Hz, 1H), 2.11 (s, 3H), 1.93 (s, 3H), 1.12 (d, J=6.7 Hz, 3H); ESI m/z 348[M+H] + .

制备1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物118)和1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-乙基-1H-咪唑并[4,5-b]吡啶-2-胺(实施例化合物131)Preparation of 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 118) and 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-ethyl-1H-imidazo[4,5-b]pyridin-2-amine (Example Compound 131)

步骤1:向26(2.00g,10.6mmol)于干燥CH2Cl2(50mL)中的搅拌溶液加入冰乙酸(0.61mL,10.8mmol)和环丙烷甲醛(0.81mL,12.3mmol)。将溶液在室温搅拌1小时且冷却至0℃。小心加入硼氢化钠(1.21g,31.8mmol)且将反应升温至室温。在室温搅拌15小时后,加入饱和NaHCO3水溶液(20mL)碱化,然后混合物用CH2Cl2萃取(2×100mL)。合并的二氯甲烷层经Na2SO4干燥,过滤且将滤液浓缩至褐色残余物。将残余物用CH2Cl2(20mL)稀释,将溶液负载硅胶(120g)上并用0–70%于己烷中的乙酸乙酯洗脱以提供为黄色固体的103(330mg,13%):1H NMR(500MHz,CDCl3)δ7.62(d,J=2.0Hz,1H),6.83(d,J=1.5Hz,1H),4.17(br s,2H),3.39(br s,1H),2.90(d,J=5.0Hz,1H),2.89(d,J=5.0Hz,1H),1.19–1.07(m,1H),0.63–0.56(m,2H),0.27–0.22(m,2H)。Step 1: To a stirred solution of 26 (2.00 g, 10.6 mmol) in dry CH2Cl2 (50 mL) was added glacial acetic acid (0.61 mL, 10.8 mmol) and cyclopropanecarboxaldehyde (0.81 mL, 12.3 mmol). The solution was stirred at room temperature for 1 hour and cooled to 0°C. Sodium borohydride (1.21 g, 31.8 mmol) was carefully added and the reaction was warmed to room temperature. After stirring at room temperature for 15 hours, saturated aqueous NaHCO3 (20 mL) was added to basify the mixture, and then the mixture was extracted with CH2Cl2 ( 2 x 100 mL ). The combined dichloromethane layers were dried over Na2SO4 , filtered, and the filtrate was concentrated to a brown residue. The residue was diluted with CH2Cl2 (20 mL ), the solution was loaded onto silica gel (120 g) and eluted with 0-70% ethyl acetate in hexanes to provide 103 (330 mg, 13%) as a yellow solid: 1H NMR (500 MHz, CDCl3 ) δ 7.62 (d, J = 2.0 Hz, 1H), 6.83 (d, J = 1.5 Hz, 1H), 4.17 (br s, 2H), 3.39 (br s, 1H), 2.90 (d, J = 5.0 Hz, 1H), 2.89 (d, J = 5.0 Hz, 1H), 1.19-1.07 (m, 1H), 0.63-0.56 (m, 2H), 0.27-0.22 (m, 2H).

步骤2:向103(300mg,1.24mmol)和3(415mg,1.86mmol)于1,4-二噁烷(10mL)和水(2.5mL)中的混合物加入碳酸钾(343mg,2.48mmol)和四(三苯基膦)钯(0)(76mg,0.062mmol)。将反应搅拌并在90℃加热17小时。混合物用甲醇(20mL)稀释并加入硅胶(10g)。将悬浮液浓缩至干并将所得粉末负载于硅胶(80g)上并用0–80%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为黄色固体的104(312mg,97%):1H NMR(500MHz,CDCl3)δ7.48(d,J=1.5Hz,1H),6.61(d,J=1.5Hz,1H),4.27(br s,2H),3.39(br s,1H),2.92(t,J=6.0Hz,2H),2.38(s,3H),2.24(s,3H),1.18–1.09(m,1H),0.63–0.56(m,2H),0.28–0.22(m,2H)。Step 2: To a mixture of 103 (300 mg, 1.24 mmol) and 3 (415 mg, 1.86 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was added potassium carbonate (343 mg, 2.48 mmol) and tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.062 mmol). The reaction was stirred and heated at 90 ° C for 17 hours. The mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded on silica gel (80 g) and eluted with 0-80% ethyl acetate in hexane. The clean product was concentrated to give 104 (312 mg, 97%) as a yellow solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.48 (d, J=1.5 Hz, 1H), 6.61 (d, J=1.5 Hz, 1H), 4.27 (br s, 2H), 3.39 (br s, 1H), 2.92 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.24 (s, 3H), 1.18-1.09 (m, 1H), 0.63-0.56 (m, 2H), 0.28-0.22 (m, 2H).

步骤3:向104(310mg,1.20mmol)、催化量的DMAP和1,4-二噁烷(4mL)于压力管中的溶液加入1,1'-羰基二咪唑(390mg,2.40mmol)。将管密封且加热至80℃持续2小时。反应混合物用甲醇(20mL)稀释并加入硅胶(10g)。将悬浮液浓缩至干并将所得粉末负载于硅胶(40g)上并用0–80%于己烷中的乙酸乙酯洗脱。将洁净产物浓缩以得到为黄色固体的1-(环丙基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(275mg,81%)。然后将50mg样品通过用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例化合物118(37mg):1H NMR(500MHz,CD3OD)δ7.90(d,J=1.5Hz,1H),7.50(d,J=1.5Hz,1H),3.81(d,J=7.0Hz,2H),2.42(s,3H),2.26(s,3H),1.31–1.20(m,1H),0.60–0.53(m,2H),0.44–0.38(m,2H);ESI m/z 285[M+H]+Step 3: To a solution of 104 (310 mg, 1.20 mmol), a catalytic amount of DMAP, and 1,4-dioxane (4 mL) in a pressure tube was added 1,1'-carbonyldiimidazole (390 mg, 2.40 mmol). The tube was sealed and heated to 80°C for 2 hours. The reaction mixture was diluted with methanol (20 mL) and silica gel (10 g) was added. The suspension was concentrated to dryness and the resulting powder was loaded onto silica gel (40 g) and eluted with 0-80% ethyl acetate in hexanes. The clean product was concentrated to give 1-(cyclopropylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (275 mg, 81%) as a yellow solid. A 50 mg sample was then purified by reverse phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O , and the clean fractions were frozen and lyophilized to give Example Compound 118 (37 mg) as a white solid: 1H NMR (500 MHz, CD3OD ) δ 7.90 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 3.81 (d, J=7.0 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.31-1.20 (m, 1H), 0.60-0.53 (m, 2H), 0.44-0.38 (m, 2H); ESI m/z 285 [M+H] + .

步骤4:将实施例化合物118(220mg,0.774mmol)于氧氯化磷(V)(3mL)中的溶液置于密封管中且在110℃加热持续6小时。真空除去溶剂且加入饱和NaHCO3水溶液(5mL)。混合物用乙酸乙酯萃取(2×20mL)并将合并的萃取液经Na2SO4干燥,过滤且浓缩滤液。然后加入THF(5mL)和2.0M于THF中的乙基胺溶液(6mL,12.0mmol)并将反应在70℃加热17小时。将反应浓缩至干且残余物用CH2Cl2(5mL)稀释。将所得溶液负载于硅胶(40g)上并用0–80%于己烷中的乙酸乙酯洗脱。然后洁净产物通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例化合物131(91mg,38%):1HNMR(500MHz,CDCl3)δ7.93(d,J=2.0Hz,1H),7.48(d,J=1.5Hz,1H),3.98(d,J=6.5Hz,2H),3.57(q,J=7.0Hz,2H),2.42(s,3H),2.26(s,3H),1.30(t,J=7.0Hz,3H),1.29–1.19(m,1H),0.59–0.52(m,2H),0.45–0.39(m,2H);ESI m/z 312[M+H]+Step 4: A solution of Example Compound 118 (220 mg, 0.774 mmol) in phosphorus (V) oxychloride (3 mL) was placed in a sealed tube and heated at 110 ° C for 6 hours. The solvent was removed in vacuo and saturated aqueous NaHCO 3 solution (5 mL) was added. The mixture was extracted with ethyl acetate (2×20 mL) and the combined extracts were dried over Na 2 SO 4 , filtered, and the filtrate was concentrated. THF (5 mL) and a 2.0 M solution of ethylamine in THF (6 mL, 12.0 mmol) were then added and the reaction was heated at 70 ° C for 17 hours. The reaction was concentrated to dryness and the residue was diluted with CH 2 Cl 2 (5 mL). The resulting solution was loaded onto silica gel (40 g) and eluted with 0-80% ethyl acetate in hexane. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example Compound 131 (91 mg, 38%) as a white solid: 1 H NMR (500 MHz, CDCl 3 ) δ 7.93 (d, J=2.0 Hz, 1H), 7.48 (d, J=1.5 Hz, 1H), 3.98 (d, J=6.5 Hz, 2H), 3.57 (q, J=7.0 Hz, 2H), 2.42 (s, 3H), 2.26 (s, 3H), 1.30 (t, J=7.0 Hz, 3H), 1.29-1.19 (m, 1H), 0.59-0.52 (m, 2H), 0.45-0.39 (m, 2H); ESI m/z 312 [M+H] + .

制备4-(1-(环己基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物191)、4-(1-(环戊基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物192)和4-(1-(环丁基甲基)-2-甲基-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物193)Preparation of 4-(1-(cyclohexylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 191), 4-(1-(cyclopentylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 192), and 4-(1-(cyclobutylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 193)

步骤1:将2,3-二氨基-5-溴吡啶(10.0g,0.053mol)、环己烷甲醛(6.08g,0.054mol)和冰乙酸(3.05mL)于干燥CH2Cl2(250mL)中的混合物在室温搅拌1.5小时。在20分钟内分批加入硼氢化钠(6.06g,0.159mol)并将混合物在室温搅拌17小时。加入饱和NaHCO3水溶液直至混合物达到pH8(70mL)并将水层用CH2Cl2(100mL)萃取。将合并的CH2Cl2层合并,用水(500mL)洗涤,经Na2SO4干燥,过滤并浓缩。将褐色固体溶于甲醇(100mL)中并加入硅胶(40g)。将悬浮液浓缩至干且材料通过色谱(硅胶,0–50%EtOAc/己烷,然后0–10%EtOAc/CH2Cl2)纯化以提供为褐灰色固体的105a(1.30g,9%):1H NMR(500MHz,CDCl3)δ7.60(d,J=2.0Hz,1H),6.85(d,J=2.0Hz,1H),4.11(br s,2H),3.28(br s,1H),2.88(d,J=5.0Hz,2H),1.88–1.64(m,4H),1.70–1.52(m,1H),1.38–1.15(m,4H),1.10–0.96(m,2H)。Step 1: A mixture of 2,3-diamino-5-bromopyridine (10.0 g, 0.053 mol), cyclohexanecarboxaldehyde (6.08 g, 0.054 mol), and glacial acetic acid (3.05 mL) in dry CH₂Cl₂ (250 mL) was stirred at room temperature for 1.5 hours. Sodium borohydride (6.06 g, 0.159 mol) was added portionwise over 20 minutes, and the mixture was stirred at room temperature for 17 hours. Saturated aqueous NaHCO₃ was added until the mixture reached pH 8 (70 mL), and the aqueous layer was extracted with CH₂Cl₂ (100 mL ). The combined CH₂Cl₂ layers were combined, washed with water (500 mL ), dried over Na₂SO₄ , filtered, and concentrated. The brown solid was dissolved in methanol (100 mL) and silica gel (40 g) was added. The suspension was concentrated to dryness and the material was purified by chromatography (silica gel, 0-50% EtOAc/hexanes, then 0-10% EtOAc/ CH2Cl2 ) to afford 105a (1.30 g, 9%) as a brown-grey solid: 1H NMR (500 MHz, CDCl3 ) δ 7.60 (d, J=2.0 Hz, 1H), 6.85 (d, J=2.0 Hz, 1H), 4.11 (br s, 2H), 3.28 (br s, 1H), 2.88 (d, J=5.0 Hz, 2H), 1.88-1.64 (m, 4H), 1.70-1.52 (m, 1H), 1.38-1.15 (m, 4H), 1.10-0.96 (m, 2H).

以环戊烷甲醛开始,制备105b(14%收率;褐灰色固体):1H NMR(500MHz,CDCl3)δ7.60(d,J=2.0Hz,1H),6.86(d,J=2.0Hz,1H),4.14(br s,2H),3.28(br s,1H),2.99–2.93(m,2H),2.23–2.11(m,1H),1.88–1.71(m,2H),1.70–1.53(m,4H),1.32–1.23(m,2H)。Starting from cyclopentanecarboxaldehyde, 105b was prepared (14% yield; brown-grey solid): 1 H NMR (500 MHz, CDCl 3 ) δ 7.60 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 4.14 (br s, 2H), 3.28 (br s, 1H), 2.99-2.93 (m, 2H), 2.23-2.11 (m, 1H), 1.88-1.71 (m, 2H), 1.70-1.53 (m, 4H), 1.32-1.23 (m, 2H).

以环丁烷甲醛开始,制备105c(15%收率;褐灰色固体):1H NMR(500MHz,CDCl3)δ7.61(d,J=2.0Hz,1H),6.86(d,J=2.0Hz,1H),4.12(br s,2H),3.14(br s,1H),3.09–3.02(m,2H),2.67–2.52(m,1H),2.18–2.11(m,2H),2.07–1.86(m,2H),1.80–1.71(m,2H)。Starting from cyclobutanecarbaldehyde, 105c was prepared (15% yield; brown-grey solid): 1 H NMR (500 MHz, CDCl 3 ) δ 7.61 (d, J=2.0 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 4.12 (br s, 2H), 3.14 (br s, 1H), 3.09-3.02 (m, 2H), 2.67-2.52 (m, 1H), 2.18-2.11 (m, 2H), 2.07-1.86 (m, 2H), 1.80-1.71 (m, 2H).

步骤2:向105a(500mg,1.76mmol)、3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(589mg,2.64mmol)、碳酸钾(487mg,3.52mmol)、水(4mL)和1,4-二噁烷(16mL)中的混合物加入四(三苯基膦)钯(0)并将混合物加热至90℃持续17小时。两相混合物用甲醇(20mL)稀释并加入硅胶。浓缩至干后,材料通过色谱(硅胶,0–80%EtOAc/己烷)纯化以提供为褐色固体的106a(551mg,99%):1H NMR(500MHz,CDCl3)δ7.47(d,J=2.0Hz,1H),6.62(d,J=2.0Hz,1H),4.25(br s,2H),3.34(br s,1H),2.92(t,J=6.0Hz,2H),2.38(s,3H),2.25(s,3H),1.88–1.67(m,4H),1.67–1.56(m,1H),1.33–1.19(m,4H),1.10–0.96(m,2H)。Step 2: To a mixture of 105a (500 mg, 1.76 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (589 mg, 2.64 mmol), potassium carbonate (487 mg, 3.52 mmol), water (4 mL) and 1,4-dioxane (16 mL) was added tetrakis(triphenylphosphine)palladium(0) and the mixture was heated to 90° C. for 17 hours. The biphasic mixture was diluted with methanol (20 mL) and silica gel was added. After concentration to dryness, the material was purified by chromatography (silica gel, 0-80% EtOAc/hexanes) to afford 106a (551 mg, 99%) as a brown solid: 1H NMR (500 MHz, CDCl 3 ) δ 7.47 (d, J=2.0 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 4.25 (br s, 2H), 3.34 (br s, 1H), 2.92 (t, J=6.0 Hz, 2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.88-1.67 (m, 4H), 1.67-1.56 (m, 1H), 1.33-1.19 (m, 4H), 1.10-0.96 (m, 2H).

以105b开始,制备106b(96%收率;褐灰色固体):1H NMR(500MHz,CDCl3)δ7.47(d,J=1.5Hz,1H),6.64(d,J=1.5Hz,1H),4.25(br s,2H),3.28(br s,1H),2.99(t,J=6.0Hz,1H),2.38(s,3H),2.24(s,3H),2.24–2.17(m,1H),1.90–1.81(m,2H),1.72–1.55(m,4H),1.38–1.22(m,2H)。Starting from 105b, 106b was prepared (96% yield; brown-grey solid): 1 H NMR (500 MHz, CDCl 3 ) δ 7.47 (d, J=1.5 Hz, 1H), 6.64 (d, J=1.5 Hz, 1H), 4.25 (br s, 2H), 3.28 (br s, 1H), 2.99 (t, J=6.0 Hz, 1H), 2.38 (s, 3H), 2.24 (s, 3H), 2.24-2.17 (m, 1H), 1.90-1.81 (m, 2H), 1.72-1.55 (m, 4H), 1.38-1.22 (m, 2H).

以105c开始,制备106c(95%收率;褐灰色固体):1H NMR(500MHz,CDCl3)δ7.65(d,J=1.5Hz,1H),6.64(d,J=2.0Hz,1H),4.26(br s,2H),3.18(br s,1H),3.09(t,J=6.0Hz,1H),2.67–2.58(m,1H),2.20–2.12(m,2H),2.02–1.86(m,2H),1.82–1.72(m,2H)。Starting from 105c, 106c was prepared (95% yield; brown-grey solid): 1 H NMR (500 MHz, CDCl 3 ) δ 7.65 (d, J=1.5 Hz, 1H), 6.64 (d, J=2.0 Hz, 1H), 4.26 (br s, 2H), 3.18 (br s, 1H), 3.09 (t, J=6.0 Hz, 1H), 2.67-2.58 (m, 1H), 2.20-2.12 (m, 2H), 2.02-1.86 (m, 2H), 1.82-1.72 (m, 2H).

步骤3:将106a(100mg,0.33mmol)、原乙酸三乙酯(5mL)和冰乙酸(0.10mL)的溶液于密封管中在80℃加热24小时。将混合物蒸发至干并加入甲醇(10mL)、饱和NaHCO3水溶液(5ml)和硅胶(10g)。浓缩至干后将所得粉末负载于硅胶上并用0–5%于二氯甲烷中的甲醇洗脱。洁净产物然后通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例化合物191(56mg,52%):1H NMR(500MHz,CD3OD)δ8.30(d,J=1.5Hz,1H),7.96(d,J=2.0Hz,1H),4.14(d,J=7.5Hz,2H),2.69(s,3H),2.44(s,3H),2.28(s,3H),1.95–1.82(m,1H),1.76–1.50(m,5H),1.29–1.07(m,5H);ESIm/z 325[M+H]+Step 3: A solution of 106a (100 mg, 0.33 mmol), triethyl orthoacetate (5 mL), and glacial acetic acid (0.10 mL) was heated in a sealed tube at 80°C for 24 h. The mixture was evaporated to dryness and methanol (10 mL), saturated aqueous NaHCO₃ (5 mL), and silica gel (10 g) were added. After concentration to dryness, the resulting powder was loaded onto silica gel and eluted with 0–5% methanol in dichloromethane. The clean product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example Compound 191 (56 mg, 52%) as a white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.30 (d, J=1.5 Hz, 1 H), 7.96 (d, J=2.0 Hz, 1 H), 4.14 (d, J=7.5 Hz, 2 H), 2.69 (s, 3 H), 2.44 (s, 3 H), 2.28 (s, 3 H), 1.95-1.82 (m, 1 H), 1.76-1.50 (m, 5 H), 1.29-1.07 (m, 5 H); ESI m/z 325 [M+H] + .

以106b开始,制备为白色固体的实施例化合物192(31mg,29%):1H NMR(500MHz,CD3OD)δ8.30(d,J=2.0Hz,1H),7.98(d,J=2.0Hz,1H),4.26(d,J=8.0Hz,2H),2.71(s,3H),2.49–2.38(m,1H),2.44(s,3H),2.28(s,3H),1.80–1.68(m,4H),1.66–1.57(m,2H),1.40–1.27(m,2H);ESI m/z 311[M+H]+Starting from 106b, Example Compound 192 (31 mg, 29%) was prepared as a white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.30 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 4.26 (d, J = 8.0 Hz, 2H), 2.71 (s, 3H), 2.49-2.38 (m, 1H), 2.44 (s, 3H), 2.28 (s, 3H), 1.80-1.68 (m, 4H), 1.66-1.57 (m, 2H), 1.40-1.27 (m, 2H); ESI m/z 311 [M+H] + .

以106c开始,制备为白色固体的实施例化合物193(33mg,30%):1H NMR(500MHz,CD3OD)δ8.30(d,J=1.5Hz,1H),8.00(d,J=1.5Hz,1H),4.33(d,J=7.0Hz,2H),2.92–2.80(m,1H),2.70(s,3H),2.45(s,3H),2.28(s,3H),2.10–1.98(m,2H),1.96–1.81(m,4H);ESIm/z 297[M+H]+Starting from 106c, Example Compound 193 (33 mg, 30%) was prepared as a white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.30 (d, J=1.5 Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 4.33 (d, J=7.0 Hz, 2H), 2.92-2.80 (m, 1H), 2.70 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H), 2.10-1.98 (m, 2H), 1.96-1.81 (m, 4H); ESI m/z 297 [M+H] + .

制备1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物202)和1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2(3H)-酮(实施例化合物203)Preparation of 1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 202) and 1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (Example Compound 203)

将106b(1.30g,4.54mmol)、1,1'-羰基二咪唑(1.47g)和N,N-二甲基氨基吡啶(5mg)于1,4-二噁烷(16mL)中的溶液在80℃加热2小时并冷却至室温。向混合物加入硅胶(10g)和甲醇(20mL)并将悬浮液浓缩至干粉。将该材料负载于硅胶(80g)上并用0–90%于己烷中的乙酸乙酯洗脱以得到1.08g(76%)为黄色固体的实施例化合物202。100mg产物样品然后通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固的实施例化合物202体:1H NMR(500MHz,CD3OD)δ7.90(d,J=1.5Hz,1H),7.47(d,J=2.0Hz,1H),3.86(d,J=7.5Hz,2H),2.52–2.38(m,1H),2.41(s,3H),2.25(s,3H),1.78–1.68(m,4H),1.60–1.52(m,2H),1.41–1.30(m,2H);ESI m/z 313[M+H]+A solution of 106b (1.30 g, 4.54 mmol), 1,1'-carbonyldiimidazole (1.47 g) and N,N-dimethylaminopyridine (5 mg) in 1,4-dioxane (16 mL) was heated at 80°C for 2 hours and cooled to room temperature. Silica gel (10 g) and methanol (20 mL) were added to the mixture and the suspension was concentrated to dryness. The material was loaded onto silica gel (80 g) and eluted with 0-90% ethyl acetate in hexanes to give 1.08 g (76%) of Example Compound 202 as a yellow solid. A 100 mg sample of the product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example Compound 202 as a white solid: 1 H NMR (500 MHz, CD 3 OD)δ7.90(d,J=1.5Hz,1H),7.47(d,J=2.0Hz,1H),3.86(d,J=7.5Hz,2H),2.52–2.38(m,1H ),2.41(s,3H),2.25(s,3H),1.78–1.68(m,4H),1.60–1.52(m,2H),1.41–1.30(m,2H); ESI m/z 313[M+H] + .

以106c开始,实施例化合物203(76%收率,白色固体)以与实施例化合物202类似的程序合成:1H NMR(500MHz,CD3OD)δ7.89(d,J=1.5Hz,1H),7.46(d,J=2.0Hz,1H),3.94(d,J=7.0Hz,2H),2.86–2.77(m,1H),2.41(s,3H),2.25(s,3H),2.08–1.98(m,2H),1.94–1.80(m,4H);ESI m/z 299[M+H]+Starting from 106c, Example Compound 203 (76% yield, white solid) was synthesized by a procedure similar to Example Compound 202: 1 H NMR (500 MHz, CD 3 OD) δ 7.89 (d, J=1.5 Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 3.94 (d, J=7.0 Hz, 2H), 2.86-2.77 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.08-1.98 (m, 2H), 1.94-1.80 (m, 4H); ESI m/z 299 [M+H] + .

制备4-(1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉(实施例化合物208)和4-(2-(氮杂环丁烷-1-基)-1-(环戊基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例化合物209)Preparation of 4-(1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine (Example Compound 208) and 4-(2-(azetidin-1-yl)-1-(cyclopentylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example Compound 209)

将实施例化合物202(175mg,0.56mmol)和氧氯化磷(V)(4mL)的溶液加热至110℃持续17小时。将反应真空浓缩并加入饱和NaHCO3水溶液(5mL)和乙酸乙酯(20mL)。分离乙酸乙酯层,经Na2SO4干燥,过滤并将滤液浓缩至暗黄色固体。将固体溶解于THF(5mL)中加入吗啉(732mg,8.40mmol)。将所搅拌的溶液加热至70℃持续17小时。向冷却的混合物加入硅胶(5g)和甲醇(20mL)并将悬浮液浓缩至干粉。将该材料负载于硅胶(40g)上并用0–3%于二氯甲烷中的甲醇洗脱以得到143mg(67%)为灰白色固体的产物。产物样品然后通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例化合物208:1H NMR(500MHz,CD3OD)δ8.17(d,J=1.5Hz,1H),7.81(d,J=2.0Hz,1H),4.14(d,J=7.5Hz,2H),3.87(t,J=5.0Hz,4H),3.41(t,J=5.0Hz,4H),2.58–2.49(m,1H),2.43(s,3H),2.27(s,3H),1.75–1.66(m,2H),1.62–1.50(m,4H),1.30–1.19(m,2H).ESIm/z 382[M+H]+A solution of Example Compound 202 (175 mg, 0.56 mmol) and phosphorus (V) oxychloride (4 mL) was heated to 110 ° C for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO 3 aqueous solution (5 mL) and ethyl acetate (20 mL) were added. The ethyl acetate layer was separated, dried over Na 2 SO 4 , filtered and the filtrate was concentrated to a dark yellow solid. The solid was dissolved in THF (5 mL) and morpholine (732 mg, 8.40 mmol) was added. The stirred solution was heated to 70 ° C for 17 hours. Silica gel (5 g) and methanol (20 mL) were added to the cooled mixture and the suspension was concentrated to a dry powder. The material was loaded on silica gel (40 g) and eluted with 0-3% methanol in dichloromethane to obtain 143 mg (67%) of the product as an off-white solid. A sample of the product was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example Compound 208 as a white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.17 (d, J=1.5 Hz, 1 H), 7.81 (d, J=2.0 Hz, 1 H), 4.14 (d, J=7.5 Hz, 2H), 3.87 (t, J=5.0 Hz, 4H), 3.41 (t, J=5.0 Hz, 4H), 2.58-2.49 (m, 1 H), 2.43 (s, 3H), 2.27 (s, 3H), 1.75-1.66 (m, 2H), 1.62-1.50 (m, 4H), 1.30-1.19 (m, 2H). ESI m/z 382[M+H] + .

实施例化合物209使用与对于实施例208使用的程序类似的程序来合成;收获为白色固体的实施例化合物209(166mg,84%):1H NMR(500MHz,CD3OD)δ8.00(d,J=1.5Hz,1H),7.59(d,J=1.5Hz,1H),4.42–4.37(m,4H),4.01(d,J=8.0Hz,2H),2.57–2.44(m,2H),2.50–2.41(m,1H),2.41(s,3H),2.25(s,3H),1.76–1.51(m,6H),1.32–1.22(m,2H)。ESI m/z 352[M+H]+Example compound 209 was synthesized using a procedure similar to that used for Example 208; Example compound 209 (166 mg, 84%) was obtained as a white solid: 1 H NMR (500 MHz, CD 3 OD) δ 8.00 (d, J=1.5 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 4.42-4.37 (m, 4H), 4.01 (d, J=8.0 Hz, 2H), 2.57-2.44 (m, 2H), 2.50-2.41 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 1.76-1.51 (m, 6H), 1.32-1.22 (m, 2H). ESI m/z 352 [M+H] + .

制备4-(1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-1H-咪唑并[4,5-b]吡啶-2-基)吗啉(实施例210)和4-(2-(氮杂环丁烷-1-基)-1-(环丁基甲基)-1H-咪唑并[4,5-b]吡啶-6-基)-3,5-二甲基异噁唑(实施例211)Preparation of 4-(1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-imidazo[4,5-b]pyridin-2-yl)morpholine (Example 210) and 4-(2-(azetidin-1-yl)-1-(cyclobutylmethyl)-1H-imidazo[4,5-b]pyridin-6-yl)-3,5-dimethylisoxazole (Example 211)

实施例210和实施例211使用与对于实施例208使用的程序类似的程序来合成。Example 210 and Example 211 were synthesized using a procedure similar to that used for Example 208.

收获为白色固体的实施例210(176mg,82%收率):1H NMR(500MHz,CD3OD)δ8.16(d,J=1.5Hz,1H),7.80(d,J=2.0Hz,1H),4.24(d,J=7.0Hz,2H),3.88(t,J=5.0Hz,4H),3.41(t,J=5.0Hz,4H),2.93–2.82(m,1H),2.43(s,3H),2.27(s,3H),1.98–1.91(m,2H),1.90–1.76(m,4H)。ESI m/z 368[M+H]+Example 210 was obtained as a white solid (176 mg, 82% yield): 1 H NMR (500 MHz, CD 3 OD) δ 8.16 (d, J = 1.5 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.88 (t, J = 5.0 Hz, 4H), 3.41 (t, J = 5.0 Hz, 4H), 2.93-2.82 (m, 1H), 2.43 (s, 3H), 2.27 (s, 3H), 1.98-1.91 (m, 2H), 1.90-1.76 (m, 4H). ESI m/z 368 [M+H] + .

收获为白色固体的实施例211(180mg,91%收率):1H NMR(500MHz,CD3OD)δ7.99(d,J=2.0Hz,1H),7.61(d,J=2.0Hz,1H),4.38(m,4H),4.10(d,J=7.0Hz,2H),2.88–2.79(m,1H),2.57–2.48(m,2H),2.41(s,3H),2.25(s,3H),2.04–1.95(m,2H),1.95–1.78(m,4H)。ESIm/z 338[M+H]+。制备1-(环戊基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺(实施例222)Example 211 was obtained as a white solid (180 mg, 91% yield): 1 H NMR (500 MHz, CD 3 OD) δ 7.99 (d, J = 2.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 4.38 (m, 4H), 4.10 (d, J = 7.0 Hz, 2H), 2.88-2.79 (m, 1H), 2.57-2.48 (m, 2H), 2.41 (s, 3H), 2.25 (s, 3H), 2.04-1.95 (m, 2H), 1.95-1.78 (m, 4H). ESI m/z 338 [M+H] + . Preparation of 1-(cyclopentylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine (Example 222)

将实施例202(175mg,0.56mmol)和氧氯化磷(V)(4mL)的溶液加热至110℃持续17小时。将反应真空浓缩且加入饱和NaHCO3水溶液(5mL)和乙酸乙酯(20mL)。分离乙酸乙酯层,经Na2SO4干燥,过滤并将滤液浓缩至暗黄色固体。将固体溶解于丙腈(5mL)中并加入4-氨基四氢吡喃(283mg,28.0mmol),将所搅拌的溶液于微波反应器中加热至180℃持续6小时。向冷却的混合物加入硅胶(10g)和甲醇(20mL)并将悬浮液浓缩至干粉。将该材料负载于硅胶(40g)上并用0–3%于二氯甲烷中的甲醇洗脱以得到黄色固体。材料然后通过用10–90%于H2O中的CH3CN洗脱的Polaris柱反相HPLC纯化并将洁净级分冷冻并冻干以得到为白色固体的实施例222(70mg,31%):1H NMR(500MHz,CD3OD)δ7.94(d,J=1.5Hz,1H),7.50(d,J=2.0Hz,1H),4.17–4.05(m,1H),4.05(d,J=8.0Hz,2H),4.02–3.97(m,2H),3.57(t,J=11.75Hz,2H),2.44–2.36(m,1H),2.41(s,3H),2.25(s,3H),2.08–2.00(m,2H),1.78–1.64(m,6H),1.62–1.54(m,2H),1.38–1.25(m,2H)。ESI m/z 396[M+H]+A solution of Example 202 (175 mg, 0.56 mmol) and phosphorus (V) oxychloride (4 mL) was heated to 110 ° C for 17 hours. The reaction was concentrated in vacuo and saturated NaHCO 3 aqueous solution (5 mL) and ethyl acetate (20 mL) were added. The ethyl acetate layer was separated, dried over Na 2 SO 4 , filtered and the filtrate was concentrated to a dark yellow solid. The solid was dissolved in propionitrile (5 mL) and 4-aminotetrahydropyran (283 mg, 28.0 mmol) was added, and the stirred solution was heated to 180 ° C for 6 hours in a microwave reactor. Silica gel (10 g) and methanol (20 mL) were added to the cooled mixture and the suspension was concentrated to a dry powder. The material was loaded on silica gel (40 g) and eluted with 0-3% methanol in dichloromethane to give a yellow solid. The material was then purified by reverse phase HPLC on a Polaris column eluting with 10-90% CH 3 CN in H 2 O and the clean fractions were frozen and lyophilized to give Example 222 as a white solid (70 mg, 31%): 1 H NMR (500 MHz, CD 3 OD)δ7.94(d,J=1.5Hz,1H),7.50(d,J=2.0Hz,1H),4.17–4.05(m,1H),4.05(d,J=8.0Hz,2H),4.02–3.97(m,2H),3.57(t,J=11.75H z,2H),2.44–2.36(m,1H),2.41(s,3H),2.25(s,3H),2.08–2.00(m,2H),1.78–1.64(m,6H),1.62–1.54(m,2H),1.38–1.25(m,2H). ESI m/z 396[M+H] + .

制备1-(环丁基甲基)-6-(3,5-二甲基异噁唑-4-基)-N-(四氢-2H-吡喃-4-基)-1H-咪唑并[4,5-b]吡啶-2-胺(实施例化合物223)Preparation of 1-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-N-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-b]pyridin-2-amine (Example Compound 223)

实施例化合物223使用与对于实施例化合物222使用的程序类似的程序合成。收获为白色固体的实施例化合物223(45mg,20%收率):1H NMR(500MHz,CD3OD)δ7.93(d,J=2.0Hz,1H),7.52(d,J=2.0Hz,1H),4.17–4.05(m,1H),4.10(d,J=7.5Hz,2H),4.03–3.97(m,2H),3.56(t,J=11.75Hz,2H),2.86–2.78(m,1H),2.41(s,3H),2.25(s,3H),2.08–1.92(m,8H),1.75–1.64(m,2H)。ESI m/z 382[M+H]+Example compound 223 was synthesized using a procedure similar to that used for Example compound 222. Example compound 223 was obtained as a white solid (45 mg, 20% yield): 1 H NMR (500 MHz, CD 3 OD) δ 7.93 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 2.0 Hz, 1H), 4.17-4.05 (m, 1H), 4.10 (d, J = 7.5 Hz, 2H), 4.03-3.97 (m, 2H), 3.56 (t, J = 11.75 Hz, 2H), 2.86-2.78 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 2.08-1.92 (m, 8H), 1.75-1.64 (m, 2H). ESI m/z 382 [M+H] + .

制备4-(1-苄基-7-甲氧基-2-(三氟甲基)-1H-苯并[d]咪唑-6-基)-3,5-二甲基异噁唑(实施例化合物241)Preparation of 4-(1-benzyl-7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (Example Compound 241)

步骤1:向107(136mg,0.627mmol)于THF(6mL)中的溶液加入二碳酸二叔丁酯(137mg,0.627mmol)且将反应在室温搅拌16小时。然后浓缩反应且残余物通过色谱(硅胶,0–25%乙酸乙酯/己烷)纯化以提供灰白色固体,将其溶解于CH2Cl2(3mL)中,加入于CH2Cl2(2mL)中的苯甲醛,之后加入AcOH(2滴)。将反应在室温搅拌1小时且加入NaBH(OAc)3(283mg,1.34mmol)。然后将反应在室温搅拌16小时。将反应用饱和NaHCO3淬灭并用CH2Cl2萃取(2×50mL)。合并的有机液用Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,0–30%乙酸乙酯/己烷)纯化以提供为灰白色固体的108(97mg,38%):1H NMR(500MHz,DMSO–d6)δ8.43(s,1H),7.32–7.26(m,4H),7.23–7.00(m,1H),6.95(s,2H),4.87(t,J=6.9Hz,1H),4.31(d,J=6.9Hz,2H),3.64(s,3H),1.42(s,9H)。Step 1: To a solution of 107 (136 mg, 0.627 mmol) in THF (6 mL) was added di-tert-butyl dicarbonate (137 mg, 0.627 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was then concentrated and the residue was purified by chromatography (silica gel, 0-25% ethyl acetate/hexane) to provide an off-white solid, which was dissolved in CH 2 Cl 2 (3 mL) and added to benzaldehyde in CH 2 Cl 2 (2 mL), followed by AcOH (2 drops). The reaction was stirred at room temperature for 1 hour and NaBH(OAc) 3 (283 mg, 1.34 mmol) was added. The reaction was then stirred at room temperature for 16 hours. The reaction was quenched with saturated NaHCO 3 and extracted with CH 2 Cl 2 (2×50 mL). The combined organic solution was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate/hexanes) to afford 108 (97 mg, 38%) as an off-white solid: 1H NMR (500 MHz, DMSO-d 6 ) δ 8.43 (s, 1H), 7.32-7.26 (m, 4H), 7.23-7.00 (m, 1H), 6.95 (s, 2H), 4.87 (t, J=6.9 Hz, 1H), 4.31 (d, J=6.9 Hz, 2H), 3.64 (s, 3H), 1.42 (s, 9H).

步骤2:向108(135mg,0.332mmol)于CH2Cl2(5mL)中的溶液在0℃加入TFA(0.51mL,6.63mmol)且将反应升温至室温并搅拌16小时。然后浓缩反应以提供109(114mg,90%):ESIm/z 385[M+H]+Step 2: To a solution of 108 (135 mg, 0.332 mmol) in CH2Cl2 (5 mL) at 0°C was added TFA (0.51 mL, 6.63 mmol) and the reaction was warmed to room temperature and stirred for 16 h. The reaction was then concentrated to provide 109 (114 mg, 90%): ESI m/z 385 [M+H] + .

步骤3:使用一般程序B步骤1中使用的程序,以化合物109(114mg,0.296mmol)开始,得到为灰白色固体的实施例化合物241(45mg,38%):1H NMR(300MHz,DMSO–d6)δ7.72(d,J=8.4Hz,1H),7.36–7.26(m,4H),7.03–7.00(m,2H),5.81(s,2H),3.13(s,3H),2.27(s,3H),2.09(s,3H);ESI m/z 402[M+H]+Step 3: Using the procedure used in step 1 of general procedure B, starting from compound 109 (114 mg, 0.296 mmol), Example compound 241 (45 mg, 38%) was obtained as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.72 (d, J=8.4 Hz, 1H), 7.36-7.26 (m, 4H), 7.03-7.00 (m, 2H), 5.81 (s, 2H), 3.13 (s, 3H), 2.27 (s, 3H), 2.09 (s, 3H); ESI m/z 402 [M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-甲脒(实施例化合物243)和1-苄基-6-(3,5-二甲基异噁唑-4-基)-1H-苯并[d]咪唑-2-甲酰胺(实施例化合物244)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamidine (Example Compound 243) and 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazole-2-carboxamide (Example Compound 244)

步骤1:向20(3.00g,10.8mmol)于1,4-二噁烷(60mL)和水(6mL)中的溶液加入3,5-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)异噁唑(2.90g,13.0mmol)、四(三苯基膦)钯(0)(624mg,0.54mmol)和碳酸钾(2.98g,21.6mmol)。反应混合物用氮气吹扫且在90℃加热18小时。将混合物冷却至室温,浓缩并通过色谱(硅胶,0–20%于己烷中的乙酸乙酯)纯化以提供为黄色固体的110(3.18g,99%):1H NMR(500MHz,CDCl3)δ7.38(d,J=8.3Hz,2H),7.34(t,J=7.3Hz,2H),7.28(t,J=7.1Hz,1H),6.78(d,J=7.8Hz,1H),6.55(dd,J=1.8,7.7Hz,1H),6.43(d,J=1.8Hz,1H),4.35(s,2H),3.88(s,1H),3.42(s,2H),2.23(s,3H),2.11(s,3H);ESI m/z 294[M+H]+Step 1: To a solution of 20 (3.00 g, 10.8 mmol) in 1,4-dioxane (60 mL) and water (6 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (2.90 g, 13.0 mmol), tetrakis(triphenylphosphine)palladium(0) (624 mg, 0.54 mmol) and potassium carbonate (2.98 g, 21.6 mmol). The reaction mixture was purged with nitrogen and heated at 90° C. for 18 h. The mixture was cooled to room temperature, concentrated and purified by chromatography (silica gel, 0-20% ethyl acetate in hexanes) to provide 110 (3.18 g, 99%) as a yellow solid: 1H NMR (500 MHz, CDCI 3 ) δ 7.38 (d, J=8.3 Hz, 2H), 7.34 (t, J=7.3 Hz, 2H), 7.28 (t, J=7.1 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.55 (dd, J=1.8, 7.7 Hz, 1H), 6.43 (d, J=1.8 Hz, 1H), 4.35 (s, 2H), 3.88 (s, 1H), 3.42 (s, 2H), 2.23 (s, 3H), 2.11 (s, 3H); ESI m/z 294 [M+H] + .

步骤1:在室温向110(100mg,0.34mmol)于乙酸(2mL)中的溶液加入2,2,2-三氯乙酰亚胺酸甲酯(66mg,0.38mmol)。将反应混合物在室温搅拌1小时,然后加入水。所形成的沉淀通过过滤收获,滤饼用水洗涤,并在真空下于40℃干燥以提供为灰白色固体的111(110mg,77%):1H NMR(300MHz,DMSO-d6)δ7.93(dd,J=0.4,8.4Hz,1H),7.40–7.25(m,4H),7.19–7.11(m,3H),5.96(s,2H),2.21(s,3H),2.03(s,3H);ESI m/z 422[M+H]+Step 1: To a solution of 110 (100 mg, 0.34 mmol) in acetic acid (2 mL) was added methyl 2,2,2-trichloroacetimidate (66 mg, 0.38 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and then water was added. The resulting precipitate was harvested by filtration, the filter cake was washed with water, and dried under vacuum at 40 ° C to provide 111 (110 mg, 77%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.93 (dd, J = 0.4, 8.4 Hz, 1H), 7.40–7.25 (m, 4H), 7.19–7.11 (m, 3H), 5.96 (s, 2H), 2.21 (s, 3H), 2.03 (s, 3H); ESI m/z 422 [M+H] + .

步骤2:向111(100mg,0.238mmol)于乙醇(1mL)中的溶液加入浓氢氧化铵(1mL)。将反应混合物在120℃加热1小时。将混合物冷却至室温并浓缩。残余物通过色谱(硅胶,0–100%于己烷中的乙酸乙酯然后至20%于乙酸乙酯中的甲醇)纯化,之后用10–90%于H2O中的CH3CN洗脱的Polaris C18柱反相HPLC以提供为灰白色固体的实施例化合物243(21mg,25%)和实施例化合物244(29mg,35%)。实施例化合物243:1H NMR(500MHz,DMSO-d6)δ7.77(d,J=8.3Hz,1H),7.49(s,1H),7.36(s,1H),7.33–7.19(m,6H),6.58(s,2H),6.27(s,2H),2.32(s,3H),2.15(s,3H);ESI m/z 346[M+H]+;实施例化合物244:1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),7.92(s,1H),7.82(d,J=8.5Hz,1H),7.63(d,J=1.0Hz,1H),7.33–7.28(m,5H),7.27–7.22(m,1H),6.02(s,2H),2.35(s,3H),2.18(s,3H);ESI m/z 347[M+H]+Step 2: To a solution of 111 (100 mg, 0.238 mmol) in ethanol (1 mL) was added concentrated ammonium hydroxide (1 mL). The reaction mixture was heated at 120°C for 1 hour. The mixture was cooled to room temperature and concentrated. The residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes then to 20% methanol in ethyl acetate), followed by reverse-phase HPLC on a Polaris C18 column eluting with 10-90% CH3CN in H2O to provide Example Compound 243 (21 mg, 25%) and Example Compound 244 (29 mg, 35%) as off-white solids. Example compound 243: 1 H NMR (500 MHz, DMSO-d 6 ) δ 7.77 (d, J = 8.3 Hz, 1H), 7.49 (s, 1H), 7.36 (s, 1H), 7.33-7.19 (m, 6H), 6.58 (s, 2H), 6.27 (s, 2H), 2.32 (s, 3H), 2.15 (s, 3H); ESI m/z 346 [M+H] + ; Example compound 244: 1 H NMR (500 MHz, DMSO-d 6 )δ8.38(s,1H),7.92(s,1H),7.82(d,J=8.5Hz,1H),7.63(d,J=1.0Hz,1H),7.3 3–7.28(m,5H),7.27–7.22(m,1H),6.02(s,2H),2.35(s,3H),2.18(s,3H);ESI m/z 347[M+H] + .

制备1-苄基-6-(3,5-二甲基异噁唑-4-基)-N-(吡啶-3-基)-1H-苯并[d]咪唑-2-胺(实施例化合物248)Preparation of 1-benzyl-6-(3,5-dimethylisoxazol-4-yl)-N-(pyridin-3-yl)-1H-benzo[d]imidazol-2-amine (Example Compound 248)

步骤1:将81(500mg,1.57mmol)和氧氯化磷(V)(2mL)的溶液加热至100℃持续17小时。将反应真空浓缩并加入饱和NaHCO3水溶液(5mL)和乙酸乙酯(20mL)。分离乙酸乙酯层,经Na2SO4干燥,过滤并浓缩。残余物通过色谱(硅胶,0–30%于己烷中的乙酸乙酯)纯化以提供为浅褐色油的112(415mg,78%):ESI m/z 338[M+H]+Step 1: A solution of 81 (500 mg, 1.57 mmol) and phosphorus (V) oxychloride (2 mL) was heated to 100 ° C for 17 hours. The reaction was concentrated in vacuo and saturated aqueous NaHCO 3 (5 mL) and ethyl acetate (20 mL) were added. The ethyl acetate layer was separated, dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by chromatography (silica gel, 0-30% ethyl acetate in hexanes) to provide 112 (415 mg, 78%) as a light brown oil: ESI m / z 338 [M + H] + .

步骤2:将112(20mg,0.06mmol)、吡啶-3-胺(28mg,0.30mmol)和p-TsOH·H2O(22mg,0.12mmol)于NMP中的混合物于微波反应器中在190℃加热2小时。浓缩混合物,且残余物通过色谱(硅胶,0–100%于己烷中的乙酸乙酯)纯化以提供为浅褐色油的实施例化合物248:ESI m/z 396[M+H]+Step 2: A mixture of 112 (20 mg, 0.06 mmol), pyridin-3-amine (28 mg, 0.30 mmol) and p-TsOH.H 2 O (22 mg, 0.12 mmol) in NMP was heated in a microwave reactor at 190° C. for 2 h. The mixture was concentrated and the residue was purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes) to give Example Compound 248 as a light brown oil: ESI m/z 396 [M+H] + .

制备3-(1-苄基-1H-苯并[d]咪唑-6-基)-4-乙基-1H-1,2,4-三唑-5(4H)-酮(实施例化合物249)Preparation of 3-(1-benzyl-1H-benzo[d]imidazol-6-yl)-4-ethyl-1H-1,2,4-triazol-5(4H)-one (Example Compound 249)

步骤1:将113(1.20g,4.51mmol)和肼一水合物(3.27mL,67.65mmol)于EtOH(20mL)中的溶液加热至回流16小时。将混合物冷却至室温,沉淀通过过滤收获,干燥滤饼以提供为灰白色固体的114(1.02g,85%):1H NMR(300MHz,DMSO-d6)δ9.74(s,1H),8.54(s,1H),8.07(s,1H),7.73–7.67(m,2H),7.38–7.26(m,5H),5.54(s,2H),4.47(s,2H)。Step 1: A solution of 113 (1.20 g, 4.51 mmol) and hydrazine monohydrate (3.27 mL, 67.65 mmol) in EtOH (20 mL) was heated to reflux for 16 h. The mixture was cooled to room temperature, the precipitate was harvested by filtration, and the filter cake was dried to afford 114 (1.02 g, 85%) as an off-white solid: 1 H NMR (300 MHz, DMSO-d 6 ) δ 9.74 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 7.73–7.67 (m, 2H), 7.38–7.26 (m, 5H), 5.54 (s, 2H), 4.47 (s, 2H).

步骤2:将114(500mg,1.88mmol)和异氰酸乙酯(160mg,2.26mmol)于THF中的悬浮液在室温搅拌5小时。过滤混合物,滤饼用乙酸乙酯洗涤,并干燥以提供为白色固体的115(610mg,96%):1H NMR(300MHz,DMSO-d6)δ10.09(s,1H),8.57(s,1H),8.14(s,1H),7.81–7.79(m,2H),7.72(d,J=8.4Hz,1H),7.38–7.28(m,5H),6.47(t,J=5.4Hz,1H),5.55(s,2H),3.09–3.00(m,2H),1.00(t,J=7.2Hz,3H)。Step 2: A suspension of 114 (500 mg, 1.88 mmol) and ethyl isocyanate (160 mg, 2.26 mmol) in THF was stirred at room temperature for 5 h. The mixture was filtered, and the filter cake was washed with ethyl acetate and dried to afford 115 (610 mg, 96%) as a white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 10.09 (s, 1H), 8.57 (s, 1H), 8.14 (s, 1H), 7.81-7.79 (m, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.38-7.28 (m, 5H), 6.47 (t, J = 5.4 Hz, 1H), 5.55 (s, 2H), 3.09-3.00 (m, 2H), 1.00 (t, J = 7.2 Hz, 3H).

步骤3:将115(337mg,1.0mmol)于3N NaOH(5mL)中的悬浮液加热至回流16小时。用2N HCl将混合物调节至pH8,然后用CH2Cl2萃取(3×50mL)。将合并的有机层经Na2SO4干燥,过滤并浓缩。将残余物用EtOAc/CH2Cl2研磨以提供为灰白色固体的实施例化合物249:1HNMR(300MHz,DMSO-d6)δ11.85(s,1H),8.59(s,1H),7.81–7.76(m,2H),7.43(dd,J=8.1,1.5Hz,1H),7.35–7.28(m,5H),5.58(s,2H),3.63(q,J=7.2,Hz2H),0.98(t,J=7.2Hz,3H);ESI m/z 320[M+H]+Step 3: A suspension of 115 (337 mg, 1.0 mmol) in 3N NaOH (5 mL) was heated to reflux for 16 h. The mixture was adjusted to pH 8 with 2N HCl and then extracted with CH 2 Cl 2 (3×50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was triturated with EtOAc/ CH2Cl2 to provide Example Compound 249 as an off-white solid: 1H NMR (300 MHz, DMSO- d6 ) δ 11.85 (s, 1H), 8.59 (s, 1H), 7.81-7.76 (m, 2H), 7.43 (dd, J=8.1, 1.5 Hz, 1H), 7.35-7.28 (m, 5H), 5.58 (s, 2H), 3.63 (q, J=7.2, Hz 2H), 0.98 (t, J=7.2 Hz, 3H); ESI m/z 320 [M+H] + .

表2:实施例化合物Table 2: Example compounds

实施例1:结合单独BET溴结构域的四乙酰化组蛋白H4的抑制Example 1: Inhibition of tetraacetylated histone H4 binding to individual BET bromodomains

将蛋白质克隆且过度表达为具有N-末端6xHis标签,然后通过镍亲和、接着尺寸排阻色谱法进行纯化。简言之,用重组表达载体转化大肠杆菌BL21(DE3)细胞,所述载体编码来自Brd2、Brd3、Brd4的N-末端镍亲和标记的溴结构域。将细胞培养物在37℃下摇动孵育至适当密度并且用IPTG诱导过夜。将溶解细胞的上清液上样至Ni-IDA柱上用于纯化。级分洗脱蛋白质、浓缩并且通过尺寸排阻色谱法进一步纯化。级分代表单体蛋白的级分、浓缩、等分并且冷冻在-80℃下用于在随后实验中使用。The protein was cloned and overexpressed with an N-terminal 6xHis tag and then purified by nickel affinity followed by size exclusion chromatography. Briefly, E. coli BL21 (DE3) cells were transformed with a recombinant expression vector encoding the N-terminal nickel affinity-tagged bromodomains of Brd2, Brd3, and Brd4. The cell culture was incubated with shaking at 37°C to an appropriate density and induced overnight with IPTG. The supernatant of the lysed cells was loaded onto a Ni-IDA column for purification. The protein was eluted in fractions, concentrated, and further purified by size exclusion chromatography. The fractions represented fractions of the monomeric protein, concentrated, aliquoted, and frozen at -80°C for use in subsequent experiments.

四乙酰化组蛋白H4与BET溴结构域的结合通过时间分辨荧光共振能量转移(TR-FRET)方法进行确认。将N-末端His标记的溴结构域(200nM)和生物素化的四乙酰化组蛋白H4肽(25-50nM,Millipore)在铕穴状化合物标记的链霉亲和素(Cisbio目录号610SAKLB)和XL665-标记的单克隆抗-His抗体(Cisbio目录号61HISXLB)存在下在白色96孔微量滴定板(Greiner)中孵育。对于抑制测定,将连续稀释的测试化合物以0.2%最终DMSO浓度添加至这些反应。最终缓冲液浓度是30mM HEPES pH7.4、30mM NaCl、0.3mM CHAPS、20mM磷酸盐pH7.0、320mM KF、0.08%BSA)。在室温下孵育2小时之后,通过FRET通过SynergyH4板阅读器(Biotek)在665和620nm下测量荧光。第一Brd4溴结构域的说明性结果在以下示出。通过665nm荧光相对于620nm的降低来显示结合抑制活性。从剂量响应曲线确定IC50值。Binding of tetraacetylated histone H4 to BET bromodomains was confirmed by time-resolved fluorescence resonance energy transfer (TR-FRET). N-terminal His-tagged bromodomains (200 nM) and biotinylated tetraacetylated histone H4 peptides (25-50 nM, Millipore) were incubated in the presence of Europium cryptate-labeled streptavidin (Cisbio catalog number 610SAKLB) and XL665-labeled monoclonal anti-His antibody (Cisbio catalog number 61HISXLB) in white 96-well microtiter plates (Greiner). For inhibition assays, serially diluted test compounds were added to these reactions at a final DMSO concentration of 0.2%. Final buffer concentrations were 30 mM HEPES pH 7.4, 30 mM NaCl, 0.3 mM CHAPS, 20 mM phosphate pH 7.0, 320 mM KF, 0.08% BSA). After incubation for 2 hours at room temperature, fluorescence was measured at 665 and 620 nm using a Synergy H4 plate reader (Biotek) by FRET. Illustrative results for the first Brd4 bromodomain are shown below. Binding inhibitory activity was demonstrated by a decrease in 665 nm fluorescence relative to 620 nm. IC 50 values were determined from dose response curves.

IC50值小于或等于0.3μM的化合物被认为是高活性的(+++);IC50值为0.3至3μM的化合物被认为是很有活性的(++);IC50值为3至30μM的化合物被认为是活性的(+)。Compounds with IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with IC50 values between 3 and 30 μM were considered active (+).

表3:如通过FRET测量的四乙酰化组蛋白H4与Brd4溴结构域1(BRD4(1)结合的抑制Table 3: Inhibition of tetraacetylated histone H4 binding to Brd4 bromodomain 1 (BRD4(1) as measured by FRET

实施例2:癌细胞系中c-myc表达的抑制Example 2: Inhibition of c-myc expression in cancer cell lines

将MV4-11细胞(CRL-9591)以2.5x104个细胞/孔的密度接种于96孔U型底板中并且用递增浓度的于含有10%FBS和青霉素/链霉素的IMDM培养基中的测试化合物或DMSO(0.1%)处理,且在37℃孵育3小时。一式三份的孔用于每个浓度。细胞通过离心来沉淀并根据制造商说明书使用mRNA Catcher PLUS试剂盒来收获。分离的经洗脱的mRNA然后用于使用RNA UltraSenseTM一步试剂盒(Life Technologies)的组分连同用于cMYC和亲环蛋白的Applied Biosystems引物-探针的一步定量实时PCR反应中。实时PCR板在VIaTM7实时PCR仪器(Applied Biosystems)上运行,分析数据,将cMYC的Ct值针对内部对照标准化,之后确定每种样品相对于对照的倍数表达。MV4-11 cells (CRL-9591) were seeded in 96-well U-bottom plates at a density of 2.5 x 104 cells/well and treated with increasing concentrations of test compounds or DMSO (0.1%) in IMDM culture medium containing 10% FBS and penicillin/streptomycin and incubated at 37°C for 3 hours. Triplicate wells were used for each concentration. Cells were precipitated by centrifugation and harvested using an mRNA Catcher PLUS kit according to the manufacturer's instructions. The isolated eluted mRNA was then used for a one-step quantitative real-time PCR reaction using components of an RNA UltraSense one-step kit (Life Technologies) together with Applied Biosystems primers-probes for cMYC and cyclophilin. The real-time PCR plate was run on a VIa 7 real-time PCR instrument (Applied Biosystems) to analyze the data, normalize the Ct value of cMYC to an internal control, and then determine the multiple expression of each sample relative to the control.

IC50值小于或等于0.3μM的化合物被认为是高活性的(+++);IC50值为0.3至3μM的化合物被认为是很有活性的(++);IC50值为3至30μM的化合物被认为是活性的(+)。Compounds with IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with IC50 values between 3 and 30 μM were considered active (+).

表4:人AML MV4-11细胞中c-myc活性的抑制Table 4: Inhibition of c-myc activity in human AML MV4-11 cells

实施例3:癌细胞系中细胞增殖的抑制Example 3: Inhibition of cell proliferation in cancer cell lines

MV4-11细胞:96-孔板接种有5x104个细胞/孔的指数生长的人AML MV-4-11(CRL-9591)细胞中且立即用在30μM至0.2μM范围内的测试化合物两倍稀释液处理。一式三份的孔用于每个浓度,以及仅培养基孔和三个DMSO对照孔。将细胞和化合物孵育在37℃、5%CO2孵育72小时,然后向各孔加入20μL CellTiter Aqueous One Solution(Promega)且在37℃、5%CO2孵育另外的3-4h。在分光光度计中于490nm获取吸光度且在从空白孔校正后计算相对于DMSO处理的孔的增殖百分比。使用GraphPad Prism软件计算IC50MV4-11 cells: 96-well plates were seeded with exponentially growing human AML MV-4-11 (CRL-9591) cells at 5x10 cells/well and immediately treated with two-fold dilutions of test compounds ranging from 30 μM to 0.2 μM. Triplicate wells were used for each concentration, as well as medium-only wells and three DMSO control wells. Cells and compounds were incubated at 37°C, 5% CO2 for 72 hours, after which 20 μL of CellTiter Aqueous One Solution (Promega) was added to each well and incubated at 37°C, 5% CO2 for an additional 3-4 hours. Absorbance was acquired at 490 nm in a spectrophotometer and the percentage of proliferation relative to the DMSO-treated wells was calculated after correction from the blank wells. IC50 was calculated using GraphPad Prism software.

IC50值小于或等于0.3μM的化合物被认为是高活性的(+++);IC50值为0.3至3μM的化合物被认为是很有活性的(++);IC50值为3至30μM的化合物被认为是活性的(+)。Compounds with IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with IC50 values between 3 and 30 μM were considered active (+).

表5:人AML MV-4-11细胞中细胞增殖的抑制Table 5: Inhibition of cell proliferation in human AML MV-4-11 cells

实施例4:hIL-6mRNA转录的抑制Example 4: Inhibition of hIL-6 mRNA transcription

在该实施例中,将组织培养细胞中的hIL-6mRNA定量以在用本发明的化合物处理时测量hIL-6的转录抑制。In this example, hIL-6 mRNA was quantified in tissue culture cells to measure transcriptional inhibition of hIL-6 upon treatment with compounds of the invention.

在该实施例中,将组织培养细胞中的hIL-6mRNA定量以在用本发明的化合物处理时测量hIL-6的转录抑制。In this example, hIL-6 mRNA was quantified in tissue culture cells to measure transcriptional inhibition of hIL-6 upon treatment with compounds of the invention.

将人白血病单核细胞淋巴瘤U937细胞(CRL-1593.2)以3.2×104个细胞/孔的密度在96-孔板中接种于含有10%FBS和青霉素/链霉素的100μL RPMI-1640中,并且在37℃下在5%CO2中在60ng/mL PMA(佛波醇-13-肉豆蔻酸酯-12-乙酸酯)中分化成巨噬细胞持续3天,之后添加目标化合物。将细胞用于0.1%DMSO中的递增浓度的测试化合物预处理1小时,之后用1ug/mL来自大肠杆菌的脂多糖刺激。一式三份的孔用于每个浓度。将细胞在37℃、5%CO2下孵育3小时,之后收获细胞。在收获时间,除去培养基并且将细胞在200μL PBS中漂洗。根据制造商说明书使用mRNA Catcher PLUS试剂盒来收获细胞。经洗脱的mRNA用于使用RNAUltraSenseTM一步试剂盒(Life Technologies)的组分连同用于hIL-6和亲环蛋白的Applied Biosystems引物-探针的一步定量实时PCR反应中。实时PCR板在VIaTM7实时PCR仪器(Applied Biosystems)上运行,分析数据,将hIL-6的Ct值针对内部对照标准化,之后确定每种样品相对于对照的倍数表达。Human leukemia monocytic lymphoma U937 cells (CRL-1593.2) are seeded in 100 μ L RPMI-1640 containing 10% FBS and penicillin/streptomycin at a density of 3.2 × 104 cells/well in 96-well plates and differentiated into macrophages for 3 days at 37°C in 5% CO2 in 60ng/mL PMA (phorbol-13-myristate-12-acetate), followed by addition of target compound. Cells are pretreated for 1 hour with increasing concentrations of test compounds in 0.1% DMSO, followed by stimulation with 1ug/mL lipopolysaccharide from Escherichia coli. Triplicate wells are used for each concentration. Cells are incubated at 37°C, 5% CO2 for 3 hours, followed by harvesting. At harvest time, culture medium is removed and cells are rinsed in 200 μ L PBS. mRNA Catcher PLUS test kit is used to harvest cells according to manufacturer's instructions. Eluted mRNA was used in a one-step quantitative real-time PCR reaction using components of the RNAUltraSense One-Step Kit (Life Technologies) along with Applied Biosystems primer-probes for hIL-6 and cyclophilin. Real-time PCR plates were run on a VIa 7 real-time PCR instrument (Applied Biosystems), and data were analyzed, with hIL-6 Ct values normalized to an internal control before determining the fold expression of each sample relative to the control.

IC50值小于或等于0.3μM的化合物被认为是高活性的(+++);IC50值为0.3至3μM的化合物被认为是很有活性的(++);IC50值为3至30μM的化合物被认为是活性的(+)。Compounds with IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with IC50 values between 3 and 30 μM were considered active (+).

表6:hIL-6mRNA转录的抑制Table 6: Inhibition of hIL-6 mRNA transcription

实施例5:IL-17mRNA转录的抑制Example 5: Inhibition of IL-17 mRNA transcription

在该实施例中,将人外周血单核细胞中的hIL-17mRNA定量以在用本发明的化合物处理时测量hIL-17的转录抑制。In this example, hIL-17 mRNA was quantified in human peripheral blood mononuclear cells to measure transcriptional inhibition of hIL-17 upon treatment with compounds of the invention.

将人外周血单核细胞在96孔板中接种(2.0×105个细胞/孔)于含有20ng/ml IL-2和青霉素/链霉素的45μL OpTimizer T细胞扩增培养基中。将细胞用测试化合物(在2倍浓度下45μL)处理,并且然后将细胞在37℃下孵育1小时,之后在培养基中添加10μg/ml的10倍储备OKT3抗体。将细胞在37℃下孵育6小时,然后收获细胞。在收获时间,将细胞离心(800rpm,5分钟)。除去用过的培养基并且将细胞溶解溶液(70μL)添加至各孔中的细胞并且在室温下孵育5-10分钟,以允许完全细胞溶解和脱离。然后根据所提供的方案使用“mRNACatcher PLUS板”(Invitrogen)制备mRNA。在最后一次洗涤之后,在不使孔干燥的情况下吸取尽可能多的洗涤缓冲液。然后将洗脱缓冲液(E3,70μL)添加至各孔。然后通过在68℃下将mRNA Catcher PLUS板用洗脱缓冲液孵育5分钟并且然后立即将板置于冰上来洗脱mRNA。Human peripheral blood mononuclear cells were seeded in 96-well plates (2.0 × 10 5 cells / well) in 45 μL OpTimizer T cell expansion medium containing 20 ng / ml IL-2 and penicillin / streptomycin. The cells were treated with test compounds (45 μL at 2 times the concentration) and then incubated at 37 ° C for 1 hour, after which 10 times the reserve OKT3 antibody of 10 μg / ml was added to the culture medium. The cells were incubated at 37 ° C for 6 hours and then harvested. At the harvest time, the cells were centrifuged (800 rpm, 5 minutes). The spent culture medium was removed and cell lysis solution (70 μL) was added to the cells in each well and incubated at room temperature for 5-10 minutes to allow complete cell lysis and detachment. mRNA was then prepared using "mRNACatcher PLUS Plate" (Invitrogen) according to the provided protocol. After the last wash, as much wash buffer as possible was drawn without drying the wells. Elution buffer (E3, 70 μL) was then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer at 68°C for 5 minutes and then immediately placing the plate on ice.

分离的经洗脱的mRNA然后用于使用Ultra Sense试剂盒的组分连同AppliedBiosystems引物-探针混合物的一步定量RT-PCR反应中。分析实时PCR数据,将hIL-17的Ct值针对内部对照标准化,之后相对于对照确定每个未知样品的诱导倍数。The isolated, eluted mRNA was then used in a one-step quantitative RT-PCR reaction using components of the Ultra Sense kit along with an Applied Biosystems primer-probe mix. Real-time PCR data were analyzed and the Ct values for hIL-17 were normalized to an internal control before determining the fold induction of each unknown sample relative to the control.

IC50值小于或等于0.3μM的化合物被认为是高活性的(+++);IC50值为0.3至3μM的化合物被认为是很有活性的(++);IC50值为3至30μM的化合物被认为是活性的(+)。Compounds with IC50 values less than or equal to 0.3 μM were considered highly active (+++); compounds with IC50 values between 0.3 and 3 μM were considered very active (++); and compounds with IC50 values between 3 and 30 μM were considered active (+).

表7:hIL-17mRNA转录的抑制Table 7: Inhibition of hIL-17 mRNA transcription

实施例6:hVCAM mRNA转录的抑制Example 6: Inhibition of hVCAM mRNA transcription

在该实施例中,将组织培养细胞中的hVCAMmRNA定量以在用本公开的化合物处理时测量hVCAM的转录抑制。In this example, hVCAM mRNA was quantified in tissue culture cells to measure transcriptional inhibition of hVCAM upon treatment with compounds of the present disclosure.

将人脐静脉内皮细胞(HUVEC)在96孔板中(4.0×103个细胞/孔)接种于100μL EGM培养基中并且孵育24小时,之后添加目标化合物。将细胞用测试化合物预处理1小时,之后用肿瘤坏死因子-α刺激。将细胞孵育另外24小时,之后收获细胞。在收获时间,从HUVEC中除去用过的培养基并且在200μL PBS中漂洗。然后将细胞溶解溶液(70μL)添加至各孔中的细胞并且在室温下孵育约5-10分钟,以允许完全细胞溶解和脱离。然后根据所提供的方案使用“mRNA Catcher PLUS板”(Invitrogen)来制备mRNA。在最后一次洗涤之后,在不使孔干燥的情况下吸出尽可能多的洗涤缓冲液。然后将洗脱缓冲液(E3,70μL)添加至各孔。然后通过在68℃下将mRNA Catcher PLUS板用洗脱缓冲液孵育5分钟并且然后立即将板置于冰上来洗脱mRNA。Human umbilical vein endothelial cells (HUVEC) are seeded in 100 μL EGM culture medium in 96-well plates (4.0 × 10 3 cells/well) and incubated for 24 hours before adding the target compound. The cells are pretreated with the test compound for 1 hour and then stimulated with tumor necrosis factor-α. The cells are incubated for another 24 hours before harvesting. At the harvest time, the spent culture medium is removed from the HUVEC and rinsed in 200 μL PBS. Cell lysis solution (70 μL) is then added to the cells in each well and incubated at room temperature for about 5-10 minutes to allow complete cell lysis and detachment. mRNA is then prepared using "mRNA Catcher PLUS plates" (Invitrogen) according to the protocol provided. After the last wash, as much wash buffer as possible is aspirated without drying the holes. Elution buffer (E3, 70 μL) is then added to each well. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer at 68°C for 5 minutes and then immediately placing the plate on ice.

如此分离的经洗脱的mRNA然后用于使用Ultra Sense试剂盒的组分连同AppliedBiosystems引物-探针混合物的一步定量实时PCR反应中。分析实时PCR数据,将hVCAM的Ct值针对内部对照标准化,之后相对于对照确定每个未知样品的诱导倍数。The eluted mRNA thus isolated was then used in a one-step quantitative real-time PCR reaction using components of the Ultra Sense kit together with an Applied Biosystems primer-probe mix. Real-time PCR data were analyzed and the Ct values for hVCAM were normalized to an internal control before determining the fold induction of each unknown sample relative to the control.

实施例7:hMCP-1mRNA转录的抑制Example 7: Inhibition of hMCP-1 mRNA transcription

在该实施例中,将人外周血单核细胞中的hMCP-1mRNA定量以在用本公开的化合物处理时测量hMCP-1的转录抑制。In this example, hMCP-1 mRNA was quantified in human peripheral blood mononuclear cells to measure transcriptional inhibition of hMCP-1 upon treatment with compounds of the present disclosure.

将人外周血单核细胞在96孔板中(1.0×105个细胞/孔)接种于含有10%FBS和青霉素/链霉素的45μL RPMI-1640中。将细胞用测试化合物(在2倍浓度下45μL)处理,并且然后将细胞在37℃下孵育3小时,之后收获细胞。在收获时间,将细胞转移至V型底板并且离心(800rpm,5分钟)。除去用过的培养基并且将细胞溶解溶液(70μL)添加至各孔中的细胞并且在室温下孵育5-10分钟,以允许完全细胞溶解和脱离。然后根据所提供的方案使用“mRNACatcher PLUS板”(Invitrogen)来制备mRNA。在最后一次洗涤之后,在不使孔干燥的情况下吸取尽可能多的洗涤缓冲液。然后将洗脱缓冲液(E3,70μL)添加至各孔。然后通过在68℃下将mRNA Catcher PLUS板用洗脱缓冲液孵育5分钟并且然后立即将板置于冰上来洗脱mRNA。Human peripheral blood mononuclear cells (1.0 × 105 cells/well) are seeded in 45 μ L RPMI-1640 containing 10% FBS and penicillin/streptomycin in 96-well plates. Cells are processed with test compounds (45 μ L under 2 times of concentration), and then cells are incubated 3 hours at 37 ° C, and harvested afterwards. At harvest time, cells are transferred to V-type bottom plate and centrifuged (800rpm, 5 minutes). Remove spent culture medium and cell lysis solution (70 μ L) is added to the cell in each hole and at room temperature incubated 5-10 minute, to allow complete cell dissolution and break away from. Then mRNA is prepared according to provided scheme using " mRNACatcher PLUS plate " (Invitrogen). After the last wash, draw as much wash buffer as possible without making the hole dry. Then elution buffer (E3, 70 μ L) is added to each hole. The mRNA was then eluted by incubating the mRNA Catcher PLUS plate with elution buffer at 68°C for 5 minutes and then immediately placing the plate on ice.

分离的经洗脱的mRNA然后用于使用Ultra Sense试剂盒的组分连同AppliedBiosystems引物-探针混合物的一步定量实时PCR反应中。分析实时PCR数据,将hMCP-1的Ct值针对内部对照标准化,之后相对于对照确定每个未知样品的诱导倍数。The isolated eluted mRNA was then used in a one-step quantitative real-time PCR reaction using components of the Ultra Sense kit together with an Applied Biosystems primer-probe mix. Real-time PCR data were analyzed and the Ct values for hMCP-1 were normalized to an internal control before determining the fold induction of each unknown sample relative to the control.

实施例8:hApoA-1mRNA转录的上调。Example 8: Upregulation of hApoA-1 mRNA transcription.

在该实施例中,将组织培养细胞中的ApoA-I mRNA定量以在用本发明的化合物处理时测量ApoA-I的转录上调。In this example, ApoA-I mRNA was quantified in tissue culture cells to measure transcriptional upregulation of ApoA-I upon treatment with compounds of the invention.

使用100μL DMEM/孔(补充有青霉素/链霉素和10%FBS的Gibco DMEM)将Huh7细胞(2.5×105个/孔)接种在96孔板中,24小时之后添加目标化合物。在48小时处理之后,从Huh-7细胞中除去用过的培养基并且置于冰上(用于立即使用)或于-80℃下(用于将来使用),使用来自Abcam的“LDH细胞毒性测定试剂盒II”。将剩余在板中的细胞用100μL PBS漂洗。Huh7 cells (2.5×10 5 cells/well) were seeded in a 96-well plate using 100 μL DMEM/well (Gibco DMEM supplemented with penicillin/streptomycin and 10% FBS), and the target compound was added 24 hours later. After 48 hours of treatment, the spent medium was removed from the Huh-7 cells and placed on ice (for immediate use) or at -80°C (for future use) using the "LDH Cytotoxicity Assay Kit II" from Abcam. The remaining cells in the plate were rinsed with 100 μL PBS.

然后将85μL的细胞溶解溶液添加至各孔中并且在室温下孵育5-10分钟,以允许完全细胞溶解和脱离。然后根据所提供的方案使用来自Life Technologies的“mRNA CatcherPLUS板”来制备mRNA。在最后一次洗涤之后,在不使孔干燥的情况下吸取尽可能多的洗涤缓冲液。然后将洗脱缓冲液(E3,80μL)添加至各孔。然后通过在68℃下将mRNA Catcher PLUS板用洗脱缓冲液孵育5分钟并且然后在4℃下孵育1分钟来洗脱mRNA。将mRNA洗脱的Catcher板保持在冰上用以使用或储存在-80℃下。Then 85 μ L of cell lysis solution is added in each well and incubated at room temperature for 5-10 minutes, to allow complete cell dissolution and break away. Then mRNA is prepared according to the scheme provided using " mRNA CatcherPLUS plates " from Life Technologies. After the last wash, as much wash buffer as possible is drawn without drying the holes. Then elution buffer (E3, 80 μ L) is added to each well. Then by incubating the mRNA Catcher PLUS plates with elution buffer at 68 ℃ for 5 minutes and then at 4 ℃ for 1 minute to elute the mRNA. The Catcher plates of mRNA elution are kept on ice for use or stored at -80 ℃.

分离的经洗脱的mRNA然后用于使用Ultra Sense试剂盒的组分连同LifeTechnologies引物-探针混合物的一步实时PCR反应中。分析实时PCR数据,使用Ct值,以相对于对照(即,相对于每个独立DMSO浓度的对照)确定每个未知样品的诱导倍数。The isolated eluted mRNA was then used in a one-step real-time PCR reaction using components of the Ultra Sense kit along with Life Technologies primer-probe mixes. Real-time PCR data were analyzed using Ct values to determine the fold induction of each unknown sample relative to the control (i.e., relative to the control at each independent DMSO concentration).

EC170值小于或等于0.3μM的化合物被认为是高活性的(+++);EC170值为0.3至3μM的化合物被认为是很有活性的(++);EC170值为3至30μM的化合物被认为是活性的(+)。Compounds with EC170 values less than or equal to 0.3 μM were considered highly active (+++); compounds with EC170 values between 0.3 and 3 μM were considered very active (++); and compounds with EC170 values between 3 and 30 μM were considered active (+).

表8:hApoA-1mRNA转录的上调。Table 8: Upregulation of hApoA-1 mRNA transcription.

实施例化合物Example compounds ApoA-1活性ApoA-1 activity 77 ++++++

实施例9:使用MV4-11细胞急性髓性白血病异种移植物模型的无胸腺裸小鼠菌株中的体内功效:Example 9: In vivo efficacy in an athymic nude mouse strain using an MV4-11 cell acute myeloid leukemia xenograft model:

将MV4-11细胞(ATCC)在标准细胞培养条件下生长并且将6-7周龄雌性小鼠的(NCr)nu/nu fisol菌株以于100μL PBS+100μL Matrigel中5×106个细胞/动物注射在左下侧腹中。到MV4-11细胞注射之后约第18天,将小鼠基于平均约120mm3的肿瘤体积(L x W xH)/2)随机化。将小鼠每日两次75mg/kg和每日两次120mg/kg口服给药于10mL/kg体重剂量体积下的EA006制剂中的化合物。用电子微型测径器取得肿瘤测量值并且从给药期开始隔日测量体重。将平均肿瘤体积、肿瘤生长抑制(TGI)%和体重变化%相对于媒介物对照动物进行比较。在Excel中使用学生t检验来计算平均值、统计分析和组间比较。MV4-11 cells (ATCC) were grown under standard cell culture conditions and 6-7 week old female mice of the (NCr) nu/nu fisol strain were injected in the left lower flank at 5×10 6 cells/animal in 100 μL PBS+100 μL Matrigel. Approximately 18 days after the MV4-11 cell injection, mice were randomized based on an average tumor volume of approximately 120 mm 3 (L x W x H)/2). Mice were orally administered the compound in the EA006 formulation at a dose volume of 10 mL/kg body weight at 75 mg/kg twice daily and 120 mg/kg twice daily. Tumor measurements were taken with an electronic microcaliper and body weights were measured every other day starting from the dosing period. Mean tumor volume, tumor growth inhibition (TGI) % and body weight change % were compared to vehicle control animals. Mean values, statistical analyses and group comparisons were calculated using Student's t-test in Excel.

表9:急性髓性白血病异种移植物模型的无胸腺裸小鼠菌株中的体内功效Table 9: In vivo efficacy in an athymic nude mouse strain of acute myeloid leukemia xenograft model

实施例化合物Example compounds 体内活性In vivo activity 实施例7Example 7 活性active

实施例10:使用OCI-3 AML细胞急性髓性白血病异种移植物模型的无胸腺裸小鼠菌株中的体内功效Example 10: In vivo efficacy in an athymic nude mouse strain using the OCI-3 AML cell acute myeloid leukemia xenograft model

将OCI-3 AML细胞(DMSZ)在标准细胞培养条件下生长并且将6-7周龄雌性小鼠的(NCr)nu/nu fisol菌株以于100μL PBS+100μL Matrigel中10×106个细胞/动物注射在左下侧腹中。到OCI-3 AML细胞注射之后约第18-21天,将小鼠基于平均约100-300mm3的肿瘤体积(L x W x H)/2)随机化。将小鼠按连续给药方案每日两次30mg/kg和按服5天停2天的给药方案每天2.5至45mg/kg口服给药于10mL/kg体重剂量体积下的EA006制剂中的化合物。用电子微型测径器取得肿瘤测量值并且从给药期开始隔日测量体重。将平均肿瘤体积、肿瘤生长抑制(TGI)%和体重变化%相对于媒介物对照动物进行比较。在Excel中使用学生t检验来计算平均值、统计分析和组间比较。OCI-3 AML cells (DMSZ) were grown under standard cell culture conditions and 6-7 week old female mice of the (NCr) nu/nu fisol strain were injected in the left lower flank at 10×10 6 cells/animal in 100 μL PBS+100 μL Matrigel. Approximately 18-21 days after the OCI-3 AML cell injection, mice were randomized based on an average tumor volume of approximately 100-300 mm 3 (L x W x H)/2). Mice were orally administered the compound in the EA006 formulation at a dose volume of 10 mL/kg body weight at a continuous dosing schedule of 30 mg/kg twice daily and a dosing schedule of 5 days on and 2 days off. Tumor measurements were obtained with an electronic microcaliper and body weights were measured every other day from the start of the dosing period. Mean tumor volume, tumor growth inhibition (TGI) % and body weight change % were compared to vehicle control animals. Mean values, statistical analysis and group comparisons were calculated using the Student's t-test in Excel.

实施例11:目标接合的评价。Example 11: Evaluation of target engagement.

将MV4-11细胞(ATCC)在标准细胞培养条件下生长并且将6-7周龄雌性小鼠的(NCr)nu/nu fisol菌株以于100μL PBS+100μL Matrigel中5×106个细胞/动物注射在左下侧腹中。到MV4-11细胞注射之后约第28天,将小鼠基于平均约500mm3的肿瘤体积(L x W xH)/2)随机化。将小口服给药于10mL/kg体重剂量体积下的EA006制剂中的化合物且Bcl2给药后6小时收获肿瘤以及进行作为PD生物标记的c-myc基因表达分析。MV4-11 cells (ATCC) were grown under standard cell culture conditions, and 6-7 week old female mice of the (NCr) nu/nu fisol strain were injected in the left lower flank at 5×10 6 cells/animal in 100 μL PBS + 100 μL Matrigel. Approximately 28 days after MV4-11 cell injection, mice were randomized based on an average tumor volume of approximately 500 mm 3 (L x W x H)/2). Compounds were orally administered in the EA006 formulation at a dose volume of 10 mL/kg body weight, and tumors were harvested 6 hours after Bcl2 administration and analyzed for c-myc gene expression as a PD biomarker.

实施例12:小鼠内毒素血症模型测定中的体内功效。Example 12: In vivo efficacy in a mouse endotoxemia model assay.

将亚致死剂量的内毒素(大肠杆菌细菌脂多糖)施用至动物以产生全身性炎症反应,通过细胞因子分泌的增加来监测炎症反应。将化合物以75mg/kg剂量口服施用至C57/Bl6小鼠以评估在用0.5mg/kg剂量的脂多糖(LPS)腹膜内激发3小时之后IL-6和IL-17细胞因子的抑制。Sublethal doses of endotoxin (E. coli bacterial lipopolysaccharide) were administered to animals to produce a systemic inflammatory response, which was monitored by an increase in cytokine secretion. The compound was orally administered to C57/Bl6 mice at a dose of 75 mg/kg to assess the inhibition of IL-6 and IL-17 cytokines 3 hours after intraperitoneal challenge with a 0.5 mg/kg dose of lipopolysaccharide (LPS).

实施例13:在大鼠胶原诱导的关节炎中的体内功效Example 13: In vivo efficacy in rat collagen-induced arthritis

大鼠胶原诱导的关节炎是已广泛地用于许多抗关节炎剂的临床前测试的多发性关节炎的实验模型。在施用胶原之后,此模型产生可测量的多关节炎症、与血管翳形成相关的显著软骨破坏以及轻度至中度骨吸收和骨膜骨增生。在此模型中,在研究的第1天和第7天将胶原施用至大鼠的雌性Lewis菌株并且在第11天至第17天用化合物给药。使用在疾病已经形成之后施用治疗的模型,评价测试化合物以评估在关节炎大鼠中抑制炎症(包括爪肿胀)、软骨破坏和骨吸收的潜力。Rat collagen-induced arthritis is an experimental model of polyarthritis that has been widely used in the preclinical testing of many anti-arthritis agents. After using collagen, this model produces measurable polyarticular inflammation, significant cartilage destruction relevant to pannus formation, and slight to moderate bone resorption and periosteal bone hyperplasia. In this model, collagen was applied to the female Lewis strain of rats and administered with compound on the 11th to 17th day at the 1st day and the 7th day of research. Use the model that uses treatment after the disease has formed, evaluate the potentiality that test compound suppresses inflammation (comprising paw swelling), cartilage destruction and bone resorption in arthritis rats with assessment.

实施例14:在MS的实验性自身免疫性脑脊髓炎(EAE)模型中的体内功效实验性自身免疫性脑脊髓炎(EAE)是T-细胞介导的CNS的自身免疫性疾病,其与人多发性硬化症(MS)共有许多临床和组织病理学特征。EAE是最常用的MS动物模型。Th1和Th17谱系两者的T细胞已经显示诱导EAE。细胞因子IL-23、IL-6和IL-17(其对于Th1和Th17分化来说是关键的或由这些T细胞产生)在EAE发展中起关键和必要作用。因此,靶向这些细胞因子的产生的药物可能在MS的治疗中具有治疗潜力。Embodiment 14: in vivo efficacy in experimental autoimmune encephalomyelitis (EAE) model of MS Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease of the CNS mediated by T-cells, which has many clinical and histopathological features with human multiple sclerosis (MS). EAE is the most commonly used animal model of MS. T cells of both Th1 and Th17 lineages have been shown to induce EAE. Cytokines IL-23, IL-6 and IL-17 (which are critical for Th1 and Th17 differentiation or produced by these T cells) play a key and necessary role in EAE development. Therefore, the medicine targeting the production of these cytokines may have therapeutic potential in the treatment of MS.

自对EAE小鼠免疫的时间起以每日两次50至125mg/kg施用式I或Ia的化合物。在该模型中,通过雌性C57Bl/6小鼠中MOG35-55/CFA免疫和百日咳毒素注射来诱导EAE。Compounds of Formula I or Ia are administered at 50 to 125 mg/kg twice daily starting from the time of immunization of EAE mice.In this model, EAE is induced by MOG 35-55 /CFA immunization and pertussis toxin injection in female C57B1/6 mice.

表10:在MS的实验性自身免疫性脑脊髓炎(EAE)模型中的体内功效Table 10: In vivo efficacy in the experimental autoimmune encephalomyelitis (EAE) model of MS

实施例化合物Example compounds 体内活性In vivo activity 实施例7Example 7 活性active

实施例15:对来自用外部MOG刺激而激发的脾细胞和淋巴细胞培养物的T细胞功能的离体效应Example 15: Ex vivo effects on T cell function from splenocytes and lymphocyte cultures primed with external MOG stimulation

小鼠用MOG/CFA免疫且按每日两次方案同时用化合物处理11天。收获腹股沟淋巴结和脾,对于淋巴细胞和脾细胞建立培养物以及用外部抗原(MOG)激发72小时。来使用Cytometric Bead Array测定对于TH1、Th2和Th17细胞因子自这些培养物的上清液分析。Mice were immunized with MOG/CFA and treated with compound twice daily for 11 days. Inguinal lymph nodes and spleens were harvested, and cultures of lymphocytes and splenocytes were established and challenged with external antigen (MOG) for 72 hours. Supernatants from these cultures were analyzed for TH1, Th2, and Th17 cytokines using Cytometric Bead Array assays.

实施例16:MM1.s细胞的多发性骨髓瘤异种移植模型的无胸腺裸小鼠菌株中的体内功效Example 16: In vivo efficacy of MM1.s cells in athymic nude mice strains of multiple myeloma xenograft models

将MM1.s细胞(ATCC)在标准细胞培养条件下生长并且将6-7周龄雌性小鼠的(NCr)nu/nu fisol以于100μL PBS+100μL Matrigel中10×106个细胞/动物注射在左下侧腹中。到MM1.s细胞注射之后约第21天,将小鼠基于平均约120mm3的肿瘤体积(L x W x H)/2)随机化。将小鼠每日两次75mg/kg口服给药于10mL/kg体重剂量体积下的EA006制剂中的化合物。用电子微型测径器取得肿瘤测量值并且从给药期开始隔日测量体重。将平均肿瘤体积、肿瘤生长抑制(TGI)%和体重变化%相对于媒介物对照动物进行比较。在Excel中使用学生t检验来计算平均值、统计分析和组间比较。MM1.s cells (ATCC) were grown under standard cell culture conditions and (NCr)nu/nu fisol of 6-7 week old female mice was injected in the left lower flank at 10×10 6 cells/animal in 100 μL PBS+100 μL Matrigel. About the 21st day after the MM1.s cell injection, mice were randomized based on an average tumor volume of approximately 120 mm 3 (L x W x H)/2). Mice were orally administered 75 mg/kg twice daily with a compound in an EA006 formulation at a 10 mL/kg body weight dose volume. Tumor measurements were taken with an electronic microcaliper and body weight was measured every other day starting from the dosing period. Average tumor volume, tumor growth inhibition (TGI) % and body weight change % were compared with respect to vehicle control animals. Student's t test was used in Excel to calculate mean values, statistical analysis and group comparisons.

从本文公开的本公开的说明书和实践考虑,本公开的其它实施方案将是对于本领域的技术人员显而易见的。意图本说明书和实施例应被视为仅示例性的,本公开的确切范围和精神由以下权利要求书指示。Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure disclosed herein. It is intended that the specification and examples be considered exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims (12)

1.治疗有效量的选自式IIb”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急性髓性白血病的药物中的用途:1. Use of a therapeutically effective amount of a compound selected from Formula IIb or its stereoisomers or pharmaceutically acceptable salts in the preparation of a medicament for treating acute myeloid leukemia: 其中:in: Z选自氢、氘、氨基、C1-C6烷基、C1-C6硫代烷基、C1-C6烯基和C1-C6烷氧基;Z is selected from hydrogen, deuterium, amino, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkenyl and C 1 -C 6 alkoxy; X选自–NH-、–CH2-、和-CH(CH3)-,其中一个或多个氢可独立地被氘或卤素替代;X is selected from -NH-, -CH 2 -, and -CH(CH 3 )-, wherein one or more hydrogens may be independently replaced by deuterium or halogen; R4选自任选取代的3-6元碳环;以及 R4 is selected from an optionally substituted 3-6 membered carbocyclic ring; and D1选自如下5-元单环杂环: D1 is selected from the following 5-membered monocyclic heterocycles: 其任选地被一个或多个独立地选自氘和C1-C4烷基的基团取代,所述基团中的每个可任选地被F、-OH和/或-NH2取代;which is optionally substituted with one or more groups independently selected from deuterium and C 1 -C 4 alkyl, each of which may be optionally substituted with F, -OH and/or -NH 2 ; 其中,所述化合物不是wherein the compound is not 2.根据权利要求1所述的用途,其中R4选自C3-C6环烷基和苯基环,其任选地被独立地选自氘、C1-C4烷基、C1-C4烷氧基、卤素、-CF3、CN和-C1-C4硫代烷基的一个或多个基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。2. The method according to claim 1, wherein R4 is selected from C3 - C6 cycloalkyl and phenyl ring, which are optionally substituted by one or more groups independently selected from deuterium, C1 - C4 alkyl, C1 - C4 alkoxy, halogen, -CF3 , CN and -C1 - C4 thioalkyl, wherein each alkyl, alkoxy and thioalkyl group may be optionally substituted by F, Cl or Br. 3.根据权利要求2所述的用途,其中R4为苯基环,其任选地被独立地选自氢、氘、C1-C4烷基、C1-C4烷氧基、氨基、卤素、酰胺、-CF3、CN、-N3、C1-C4酮、-S(O)C1-C4烷基、-SO2C1-C4烷基、-C1-C4硫代烷基、羧基和/或酯的基团取代,所述基团各自可任选地被以下取代:氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代。3. The method according to claim 2, wherein R4 is a phenyl ring optionally substituted by a group independently selected from hydrogen, deuterium, C1 - C4 alkyl, C1 - C4 alkoxy, amino, halogen, amide, -CF3, CN, -N3 , C1 - C4 ketone, -S(O)C1- C4 alkyl, -SO2C1-C4 alkyl , -C1 -C4 thioalkyl , carboxyl and/or ester, each of which may be optionally substituted by hydrogen, F, Cl, Br, -OH, -NH2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo. 4.根据权利要求3所述的用途,其中的C1-C4烷基选自甲基、乙基、丙基、异丙基和丁基;C1-C4烷氧基选自甲氧基、乙氧基和异丙氧基;卤素选自F和Cl;并且-C1-C4硫代烷基选自–SMe、-SEt、-SPr和-SBu。The use according to claim 3, wherein C1 - C4 alkyl is selected from methyl, ethyl, propyl, isopropyl and butyl; C1 - C4 alkoxy is selected from methoxy, ethoxy and isopropoxy; halogen is selected from F and Cl; and -C1 - C4 thioalkyl is selected from -SMe, -SEt, -SPr and -SBu. 5.根据权利要求1所述的用途,其中D1是其任选地被一个或多个独立地选自氘和C1-C4烷基的基团取代,所述基团中的每个可任选地被F、-OH和/或-NH2取代。The use according to claim 1 , wherein D 1 is optionally substituted by one or more groups independently selected from deuterium and C 1 -C 4 alkyl, each of which may be optionally substituted by F, —OH and/or —NH 2 . 6.根据权利要求1所述的用途,其中D1选自6. The use according to claim 1, wherein D 1 is selected from 7.根据权利要求6所述的用途,其中D17. The use according to claim 6, wherein D 1 is 8.根据权利要求1所述的用途,其中X选自–CH2-和-CH(CH3)-,其中一个或多个氢可独立地被氘或卤素替代。The use according to claim 1 , wherein X is selected from —CH 2 — and —CH(CH 3 )—, wherein one or more hydrogens can be independently replaced by deuterium or halogen. 9.根据权利要求8所述的用途,其中-X-R4选自–CH2-芳基。9. The use according to claim 8, wherein -XR4 is selected from -CH2 -aryl. 10.根据权利要求1所述的用途,其中的化合物选自式IIb"的化合物10. The use according to claim 1, wherein the compound is selected from the compound of formula IIb 或其立体异构体或药学上可接受的盐,or a stereoisomer or a pharmaceutically acceptable salt thereof, 其中:in: Z选自氢、氘、氨基、C1-C6烷基、C1-C6硫代烷基、C1-C6烯基和C1-C6烷氧基;Z is selected from hydrogen, deuterium, amino, C 1 -C 6 alkyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkenyl and C 1 -C 6 alkoxy; D1 D1 is X选自–CH2-和–CH(CH3)-;并且X is selected from -CH 2 - and -CH(CH 3 )-; and R4为苯基环,其任选地被一个或多个独立地选自氘、C1-C4烷基、C1-C4烷氧基、卤素、-CF3、CN和-C1-C4硫代烷基的基团的基团取代,其中每个烷基、烷氧基和硫代烷基可任选地被F、Cl或Br取代。R 4 is a phenyl ring optionally substituted with one or more groups independently selected from deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, —CF 3 , CN, and —C 1 -C 4 thioalkyl, wherein each alkyl, alkoxy, and thioalkyl group may be optionally substituted with F, Cl, or Br. 11.治疗有效量的式IIb"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急性髓性白血病的药物中的用途:11. Use of a therapeutically effective amount of a compound of formula IIb" or a stereoisomer or pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acute myeloid leukemia: 其中:in: X选自–NH-、–CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2CH2O-、-CH2CH2NH-、-C(O)-、-C(O)CH2-、-C(O)CH2CH2-和-CH2C(O)-,其中一个或多个氢可独立地被氘、羟基、甲基、卤素、-CF3或酮替代;X is selected from -NH-, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 O-, -CH 2 CH 2 NH-, -C(O)-, -C(O)CH 2 -, -C(O)CH 2 CH 2 -, and -CH 2 C(O)-, wherein one or more hydrogens may be independently replaced by deuterium, hydroxy, methyl, halogen, -CF 3 , or ketone; R4选自任选取代的3-6元碳环和杂环; R4 is selected from optionally substituted 3-6 membered carbocyclic and heterocyclic rings; D1选自如下5-元单环杂环: D1 is selected from the following 5-membered monocyclic heterocycles: 其任选地被氢、氘、C1-C4烷基、C1-C4烷氧基、氨基、卤素、酰胺、-CF3、CN、-N3、C1-C4酮、-S(O)C1-C4烷基、-SO2C1-C4烷基、-C1-C4硫代烷基、-COOH和/或酯取代,所述基团中的每个可任选地被氢、F、Cl、Br、-OH、-NH2、-NHMe、-OMe、-SMe、氧代和/或硫代-氧代取代;并且which is optionally substituted with hydrogen, deuterium, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, halogen, amide, -CF 3 , CN, -N 3 , C 1 -C 4 ketone, -S(O)C 1 -C 4 alkyl, -SO 2 C 1 -C 4 alkyl, -C 1 -C 4 thioalkyl, -COOH and/or ester, each of which may be optionally substituted with hydrogen, F, Cl, Br, -OH, -NH 2 , -NHMe, -OMe, -SMe, oxo and/or thio-oxo; and Z选自:Z is selected from: -Me,-CF3,-Et,CH3CH2O-,CF3CH2-,-SMe,-SOMe,-SO2Me,-CN,-Me, -CF 3 , -Et, CH 3 CH 2 O-, CF 3 CH 2 -, -SMe, -SOMe, -SO 2 Me, -CN, 其中,所述化合物不是wherein the compound is not 12.治疗有效量的如权利要求1-11中任一项所定义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急性髓性白血病的药物中的用途,其中所述的化合物与其它疗法组合施用。12. Use of a therapeutically effective amount of a compound as defined in any one of claims 1 to 11 or a stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating acute myeloid leukemia, wherein the compound is administered in combination with other therapies.
HK42019000070.3A 2013-06-21 2019-12-19 Bicyclic bromodomain inhibitors HK40010367B (en)

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