CN114025755A - 以杂环化合物作为激酶抑制剂的治疗用途 - Google Patents
以杂环化合物作为激酶抑制剂的治疗用途 Download PDFInfo
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- CN114025755A CN114025755A CN202080024676.8A CN202080024676A CN114025755A CN 114025755 A CN114025755 A CN 114025755A CN 202080024676 A CN202080024676 A CN 202080024676A CN 114025755 A CN114025755 A CN 114025755A
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Abstract
本公开提供一种如下式I所示的杂环化合物及含有此类化合物中之一的医药组合物:
Description
背景技术
集落刺激因子-1受体(CSF1R)是III类酪氨酸激酶的成员。它在细胞增殖、分化、迁移及存活中扮演重要作用。参见Cannarile et al.,J.Immunother.Cancer,2017,5:53。此种酪氨酸激酶的失调与多种疾病及病症有关,诸如发炎性疾病、神经疾病、心血管疾病、与骨相关的病症及癌症。
近期研究表明,CSF1R与肿瘤相关巨噬细胞(TAMs)的分化有关。参见El-Gamal etal.,J.Med.Chem.,2018,61,5450-5466。具体地,TAMs在其表面表现出CSF1R,其与活性配体(即集落刺激因子-1受体(CSF1R))形成讯号轴。当活化后,CSF1R/CSF1讯号轴将促进单核细胞的增殖,将单核细胞分化成TAMs以及TAMs的存活。
CSF1在几种癌症形式中的过度表达与TAMs的活化及补充至肿瘤部位有关。TAMs改变肿瘤微环境,使其更有利于癌细胞的生长、血管生成及转移。再者,他们可能引起肿瘤组织内的局部免疫抑制,从而导致对癌症治疗的抗性。如此一来,抑制CSF1R/CSF1讯号轴为治疗与CS1F过度表达相关的癌症提供了研究方向。
因此,需要提供在治疗与CSF1R相关的癌症中选择性地抑制CSF1R,表现出良好的安全性,并还具有很高的体内功效的化合物。
发明内容
本公开是基于意外发现,即某些杂环化合物有效地抑制集落刺激因子-1受体(CSF1R)。
根据本公开的实施例,本公开是关于由式I所涵盖的这些杂环化合物及与其类似的其他杂环化合物:
其中,A为H、C1-6烷基或ORr,Rr为H或C1-6烷基;Y1为被(R1)n取代的苯基、被(R2)o取代的5元杂芳基、被(R2)o取代的5元杂环烯基或被(R2)o取代的烯基,其中(R1)n中的R1各自独立为F、Cl、Br、NO2、CN、胺基、C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基或螺胺基,且n为0-4;而(R2)o中的R2各自独立为F、Cl、Br、NO2、CN、胺基、C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基、螺胺基或C1-C6烷氧基,且o为0-5;X1为N或CR3,R3为H、F、Cl、Br、CN、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基;X2为O、S、NH或CH2;Y2为 其中Q1、Q2、Q3、Q4、Q5、Q6、Q7及Q8各自独立为N或CR4,R4为H、F、Cl、Br、CN、胺基、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基;而Z1为O、S或NRr;Z2为O、S或NRr,且G及H分别为C或N及N或C;X3为被删除、CH2、(CH2)2或CH(C≡CH);Y3为C1-C6烷基、芳基、杂芳基、C3-C8环烷基或具有杂原子的C5-C6杂环烷基,其中该杂原子为O或N;以及(X4)m中的X4各自独立为F、Cl、Br、CN、SO2NH2、胺基、C1-C6烷基或C1-C6烷氧基,且m为0-5。
术语「烷基」是指含有1-20个碳原子的直链或支链的一价烃基团,例如:甲基(methyl)、乙基(ethyl)、正丙基(n-propyl)、异丙基(i-propyl)、正丁基(n-butyl)、异丁基(i-butyl)及叔丁基(t-butyl)。术语「卤代烷基」是指被一个或多个卤素原子取代的烷基。术语「烯基」是指含有2-20个碳原子及一个或多个双键的直链或支链的一价或二价烃,例如:乙烯基(ethenyl)、丙烯基(propenyl)、伸丙烯基(propenylene)、烯丙基(allyl)及1,4-丁二烯基(1,4-butadienyl)。术语「炔基」是指含有2-20个碳原子及一个或多个三键的直链或支链的一价或二价烃,例如:乙炔基(ethynyl)、伸乙炔基(ethynylene)、1-丙炔基(1-propynyl)、1-及2-丁炔基(1-and 2-butynyl)以及1-甲基-2-丁炔基(1-methyl-2-butynyl)。术语「芳基」是指一价的6-碳单环、10-碳双环、14-碳三环芳香环系统,例如:苯基(phenyl)、萘基(naphthyl)及蒽基(anthracenyl)。术语「杂芳基」是指具有一个或多个杂原子(诸如O、N、S或Se)的一价芳香族5-8元单环、8-12元双环或11-14元三环系统,例如:咪唑基(imidazolyl)、吡唑基(pyrazoyl)、恶唑基(oxazolyl)、异恶唑基(isoxazolyl)、噻唑基(thiazolyl)、异噻唑基(isothiazolyl)、吡啶基(pyridyl)、吡嗪基(pyrazinyl)、嘧啶基(pyrimidyl)、哒嗪基(pyridazinyl)、呋喃基(furyl)及噻吩基(thienyl)。术语「环烷基」是指具有3至30个碳原子(例如C3-C12)的一价或二价的饱和烃环系统,例如:环丙基(cyclopropyl)、环丁基(cyclobutyl)、环戊基(cyclopentyl)、环戊烯基(cyclopentenyl)、环己基(cyclohexyl)、1,4-环己烯(1,4-cyclohexylene)、环庚基(cycloheptyl)及环辛基(cyclooctyl)。术语「环烯基」是指具有3至30个碳(例如C3-C12)及一个或多个双键的一价或二价的非芳香族烃环系统,例如:环戊烯基(cyclopentenyl)、环己烯基(cyclohexenyl)及环庚烯基(cycloheptenyl)。术语「杂环烷基」是指具有一个或多个杂原子(诸如O、N、S或Se)的一价或二价非芳香族5-8元单环、8-12元双环或11-14元三环系统,例如:哌啶基(piperidinyl)、哌嗪基(piperazinyl)、吡咯烷基(pyrrolidinyl)、二恶烷基(dioxanyl)、吗啉基(morpholinyl)、四氢呋喃基(tetrahydrofuranyl)及四氢吡喃基(tetrahydropyranyl)。术语「杂环烯基」是指具有一个或多个杂原子(诸如O、N、S或Se)及一个或多个双键的一价或二价非芳香族5-8元单环、8-12元双环或11-14元三环系统。术语「胺基」是指-NRR’基团,其中R及R’各自独立为H、烷基(alkyl)、烯基(alkenyl)、炔基(alkynyl)、环烷基(cycloalkyl)、环烯基(cycloalkenyl)、杂环烷基(heterocycloalkyl)、杂环烯基(heterocycloalkenyl)、芳基(aryl)、杂芳基(heteroaryl)、芳烷基(aralkyl)或杂芳烷基(heteroaralkyl)。术语「羰基」是指-C(O)R基团,其中R为H、烷基(alkyl)、烯基(alkenyl)、炔基(alkynyl)、环烷基(cycloalkyl)、环烯基(cycloalkenyl)、杂环烷基(heterocycloalkyl)、杂环烯基(heterocycloalkenyl)、烷氧基(alkoxyl)、胺基(amino)、芳基(aryl)或杂芳基(heteroaryl)。术语「亚硫酰基」是指-S(O)R基团,其中R为H、烷基(alkyl)、烯基(alkenyl)、炔基(alkynyl)、环烷基(cycloalkyl)、环烯基(cycloalkenyl)、杂环烷基(heterocycloalkyl),杂环烯基(heterocycloalkenyl)、烷氧基(alkoxyl)、胺基(amino)、芳基(aryl)或杂芳基(heteroaryl)。术语「亚胺基」是指-C(NR)R’,其中R为H或C1-C6烷基,R’为H、烷基(alkyl)、烯基(alkenyl)、炔基(alkynyl)、环烷基(cycloalkyl)、环烯基(cycloalkenyl)、杂环烷基(heterocycloalkyl)、杂环烯基(heterocycloalkenyl)、烷氧基(alkoxyl)、胺基(amino)、芳基(aryl)或杂芳基(heteroaryl)。术语「螺胺基」是指含有一个N的一价7-11元双环螺基团或含有一个N的一价10-16元三环螺基团。
此外,烷基(alkyl)、烯基(alkenyl)、炔基(alkynyl)、芳基(aryl)、杂芳基(heteroaryl)、环烷基(cycloalkyl)、环烯基(cycloalkenyl)、杂环烷基(heterocycloalkyl)、杂环烯基(heterocycloalkenyl)及烷氧基(alkoxyl)可以被取代或未被取代。可能的取代基包括,但不限于:D、CN、NO2、卤素、C1-C20烷基、C2-C20烯基、C2-C20炔基、C1-C10烷氧基、C3-C30环烷基、C3-C30环烯基、C3-C30杂环烷基、C3-C30杂环烯基、芳基、芳氧基、杂芳基、杂芳氧基、胺基、卤素、氧代(O=)(oxo)、硫酮基(S=)(thioxo)、硫代(thio)、甲硅烷基(silyl)、C1-C10烷硫基(alkylthio)、芳硫基(arylthio)、C1-C10烷基磺酰基(alkylsulfonyl)、芳基磺酰基(arylsulfonyl)、酰基胺基(acylamino)、胺基酰基(aminoacyl)、胺基硫酰基(aminothioacyl)、甲脒基(amidino)、巯基(mercapto)、酰胺基(amido)、硫脲基(thioureido)、硫氰酸根(thiocyanato)、磺酰胺基(sulfonamido)、胍基(guanidine)、脲基(ureido)、酰基(acyl)、硫代酰基(thioacyl)、酰氧基(acyloxy)、脲基(carbamido)、胺基甲酰基(carbamyl)、羧基(carboxyl)及羧酸酯(carboxylic ester)。
式I的化合物如果适用的话包括化合物本身以及其盐类、其立体异构体、其溶剂化物、其互变异构体、其氘代类似物(deuterated analogues)及其前驱药。例如可以在阴离子与本公开的杂环化合物上的带正电荷的基团(例如铵盐(ammonium))之间形成盐。适合的阴离子包括氯离子(chloride)、溴离子(bromide)、碘离子(iodide)、硫酸根(sulfate)、硫酸氢根(bisulfate)、胺基磺酸根(sulfamate)、硝酸根(nitrate)、磷酸根(phosphate)、柠檬酸根(citrate)、甲磺酸根(methanesulfonate)、三氟乙酸根(trifluoroacetate)、麸胺酸(glutamate)、葡萄醣醛酸根(glucuronate)、戊二酸根(glutarate)、苹果酸根(malate)、马来酸根(maleate)、琥珀酸根(succinate)、富马酸根(fumarate)、酒石酸根(tartrate)、甲苯磺酸根(tosylate)、水杨酸根(salicylate)、乳酸根(lactate)、萘酸根(naphthalenesulfonate)及醋酸根(acetate)。同样地,也可以在阳离子与杂环化合物上带负电荷的基团(例如羧酸根(carboxylate))之间形成盐。适合的阳离子包括钠离子(sodiumion)、钾离子(potassium ion)、镁离子(magnesium ion)、钙离子(calcium ion)及诸如四甲基铵离子(tetramethylammonium ion)的铵阳离子(ammonium cation)。本公开的杂环化合物的盐类也可以包含季氮原子(quaternary nitrogen atoms)。前驱药的实例包括酯及其他药学上可接受的衍生物,其在给予受试者时能够提供活性杂环化合物。溶剂化物是指在活性杂环化合物与药学上可接受的溶剂(例如水(water)、乙醇(ethanol)、异丙醇(isopropanol)、乙酸乙酯(ethyl acetate)、乙酸(acetic acid)及乙醇胺(ethanolamine))之间形成的复合物。
本公开的另一实施例是关于包含一种或多种由式I所涵盖的杂环化合物的医药组合物。该医药组合物可以用于治疗CSF1R调节的病症。
治疗CSF1R调节的疾病(例如癌症、发炎性疾病、骨疾病或自体免疫疾病)的方法也在本公开的范围内。该方法包括给予需求主体有效剂量的一种或多种上述的杂环化合物。
术语「疗法」或「治疗」是指将本公开的一种或多种杂环化合物给予患有CSF1R调节病症、此类病症或易染此病的主体,以给予治疗或预防效果的目的。「有效剂量」是指给予此种效果所需的活性化合物的剂量。如本领域技术人员所认识的,有效剂量将依据所治疗疾病的类型、给药途径、赋形剂的使用及与其他治疗方法共同使用的可能性而变化。
本公开的医药组合物可以肠胃外(parenterally)、口服(orally)、经鼻(nasally)、经直肠(rectally)、局部(topically)或经颊(buccally)给药。如本公开所用,术语「肠胃外」是指皮下(subcutaneous)、皮内(intracutaneous)、静脉内(intravenous)、腹膜内(intraperitoneal)、肌内(intramuscular)、关节内(intraarticular)、动脉内(intraarterial)、滑膜内(intrasynovial)、胸骨内(intrasternal)、鞘内(intrathecal)、病灶内(intralesional)或颅内注射(intracranial injection)以及任何适合的输注技术。
无菌注射用组合物可以是在无毒的肠胃外可接受的稀释剂或溶剂中的溶液或悬浮液,诸如在1,3-丁二醇(1,3-butanediol)中的溶液。可以使用的可接受的赋形剂及溶剂为甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)及等渗透压的氯化钠溶液。此外,常规上使用不挥发性油作为溶剂或悬浮介质(例如合成的甘油单酯或二酯(mono-ordi-glycerides))。脂肪酸(诸如油酸(oleic acid)及其甘油酯(glyceride)衍生物)可用于制备注射剂,天然药学上可接受的油(诸如橄榄油及蓖麻油,特别是其聚氧乙烯化形式)也可用于制备注射剂。这些油溶液或悬浮液也可以包含长链醇稀释剂或分散剂、羧甲基纤维素(carboxymethyl cellulose)或类似的分散剂。也可以将其他常用的表面活性剂(诸如Tweens及Spans或其他类似的乳化剂或生物利用度增强剂)用于药学上可接受的固体、液体或其他剂型的制备中,以用于配制目的。
口服给药的组合物可以是任何口服可接受的剂型,包括胶囊、片剂、乳剂及水性悬浮液、分散液及溶液。对于片剂来说,常用的载体包括乳糖及玉米淀粉。通常也添加诸如硬脂酸镁(magnesium stearate)的润滑剂。对于以胶囊形式的口服给药而言,有用的稀释剂包括乳糖及干燥的玉米淀粉。当口服给予水性悬浮液或乳剂时,可以将活性成分悬浮或溶解在与乳化剂或悬浮剂结合的油相中。如果需要,可以添加某些甜味剂、调味剂或着色剂。
可以依据药物制剂领域中已知的技术来制备鼻用组合物。例如,可以使用苯甲醇(benzyl alcohol)或其他适合的防腐剂、提升生物利用度的吸收促进剂、碳氟化合物(fluorocarbons)及/或本领域中已知的其他助溶剂或分散剂,将此种组合物制备为在盐水中的溶液。
本公开的医药组合物也可以以栓剂的形式用于直肠给药。
医药组合物中的载体必须在与组合物的活性成分兼容上是「可接受的」,并能够稳定活性成分,且对于治疗的主体无害。一种或多种助溶剂可用作医药赋形剂,用于本公开的活性杂环化合物的输送。其他载体的实例包括胶体氧化硅(colloidal silicon oxide)、硬脂酸镁(magnesium stearate)、纤维素、月桂基硫酸钠(sodium lauryl sulfate)及D&CYellow#10。
在下面的描述中阐述了本公开的细节。由以下几个实施例的详细描述以及所附的权利要求书,本公开的其他特征、目的及优点将变得显而易见。
具体实施例方式
首先详细公开的是式I的杂环化合物:
A、Y1、X1、X2、Y2、X3、Y3、X4及m在上文的发明内容部分中定义。
在一实施例中,式I的化合物的Y1为被(R1)n取代的苯基、被(R2)o取代的5元杂芳基或被(R2)o取代5元杂环烯基,其中(R1)n中的R1各自独立为F、Cl、Br、NO2、CN、C1-C6烷基、C1-C6卤代烷基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基或螺胺基;而(R2)o中的R2各自独立为F、Cl、Br、NO2、CN、胺基、C1-C6烷基、C1-C6卤代烷基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基、螺胺基或C1-C6烷氧基。
在另一实施例中,式I的化合物是由式Ia所涵盖的那些化合物:
其中R1为胺基或C5-C15杂环烷基。
在第四实施例中,本公开的杂环化合物是由式Ib所涵盖的化合物:
通常,式Ib的化合物的X4各自独立为CH3、CH2F、CHF2、CF3或OCH3,且m为0-2。
式I的示例性化合物包括,但不限于以下化合物:
式I的化合物可依据本领域中已知的方法制备。例如参见R.Larock,Comprehensive Organic Transformations(2nd Ed.,VCH Publishers 1999);P.G.M.Wutsand T.W.Greene,Greene’s Protective Groups in Organic Synthesis(4th Ed.,JohnWiley and Sons 2007);L.Fieser and M.Fieser,Fieser and Fieser’s Reagents forOrganic Synthesis(John Wiley and Sons 1994);L.Paquette,ed.,Encyclopedia ofReagents for Organic Synthesis(2nd ed.,John Wiley and Sons 2009);and G.J.Yuet al.,J.Med.Chem.2008,51,6044-6054.
包含一种或多种式I的杂环化合物的医药组合物也在本公开的范围内。该医药组合物用于治疗CSF1R调节的病症。
在某些实施例中,医药组合物还包含以下治疗剂中之一:抗增殖剂、消炎剂、免疫调节剂及免疫抑制剂。
在其他实施例中,医药组合物还包含以下治疗剂中之一:例如为阿多来新(adozelesin)、六甲蜜胺(altretamine)、比折来新(bizelesin)、白消安(busulfan)、卡铂(carboplatin)、卡波醌(carboquone)、卡莫司汀(carmustine)、氯芥苯丁酸(chlorambucil)、顺铂(cisplatin)、环磷酰胺(cyclophosphamide)、达喀尔巴嗪(dacarbazine)、雌莫司汀(estramustine)、福莫司汀(fotemustine)、海普法姆(hepsulfam)、异环磷酰胺(ifosfamide)、英丙舒凡(improsulfan)、伊洛福芬(irofulven)、洛莫司汀(lomustine)、盐酸氮芥(mechlorethamine)、美法仑(melphalan)、奥沙利铂(oxaliplatin)、哌泊舒凡(piposulfan)、司莫司汀(semustine)、链脲佐菌素(streptozocin)、替莫唑胺(temozolomide)、噻替派(thiotepa)及曲奥舒凡(treosulfan)的烷基化剂(alkylating agent);例如为阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)、加利昔单抗(galiximab)、吉妥单抗(gemtuzumab)、尼沃单抗(nivolumab)、帕尼单抗(panitumumab)、派姆单抗(pembrolizumab)、帕妥珠单抗(pertuzumab)、利妥昔单抗(rituximab)、托西单抗(tositumomab)、曲妥珠单抗(trastuzumab)及钇90替伊莫单抗(90Y ibritumomabtiuxetan)的抗体;例如为硼替佐米(bortezomib)、格尔德霉素(geldanamycin)及雷帕霉素(rapamycin)的靶向信号转导抑制剂(targeted signal transduction inhibitor);例如为厄洛替尼(erlotinib)、吉非替尼(gefitinib)、夫拉平度(flavopiridol)、甲磺酸伊马替尼(imatinib mesylate)、拉帕替尼(lapatinib)、索拉非尼(sorafenib)、苹果酸舒尼替尼(sunitinib malate)、AEE-788、AG-013736、AMG706、AMN107、BMS-354825、BMS-599626、7-羟基星形孢菌素(7-hydroxystaurosporine)、维拉非尼(vemurafenib)、达拉非尼(dabrafenib)、曲美替尼(trametinib)、考比替尼(cobimetinib)、司美替尼(selumetinib)及瓦他拉尼(vatalanib)的激酶抑制剂;例如为DJ-927、多西他赛(docetaxel)、TPI287、紫杉醇(paclitaxel)及DHA-紫杉醇(DHA-paclitaxel)的紫杉烷(taxane);例如为阿利维A酸(alitretinoin)、贝沙罗汀(bexarotene)、芬维A胺(fenretinide)、异维A酸(isotretinoin)及维A酸(tretinoin)的类维生素A(retinoid);例如为依托泊苷(etoposide)、高三尖杉酯碱(homoharringtonine)、替尼泊苷(teniposide)、长春碱(vinblastine)、长春新碱(vincristine)、长春地辛(vindesine)及长春瑞滨(vinorelbine)的生物碱;例如为博来霉素(bleomycin)、放线菌素(dactinomycin)、柔红霉素(daunorubicin)、阿霉素(doxorubicin)、表柔比星(epirubicin)、伊达比星(idarubicin)、美诺立尔(menogaril)、丝裂霉素(mitomycin)、米托蒽醌(mitoxantrone)、新制癌菌素(neocarzinostatin)、喷司他丁(pentostatin)及普卡霉素(plicamycin)的抗生素;例如为AE-941、ABT-510、2-甲氧基雌二醇(2-methoxyestradiol)、来那度胺(lenalidomide)及沙利度胺(thalidomide)的抗血管生成剂(antiangiogenic agent);例如为安吖啶(amsacrine)、依地卡林(edotecarin)、依喜替康(exatecan)、伊立替康(irinotecan)、7-乙基-10-羟基喜树碱(7-ethyl-10-hydroxy-camptothecin)、鲁比替康(rubitecan)、拓扑替康(topotecan)及9-氨基喜树碱(9-aminocamptothecin)的拓扑异构酶抑制剂(topoisomerase inhibitor);例如由阿扎胞苷(azacitidine)、卡培他滨(capecitabine)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、阿糖胞苷(cytarabine)、地西他滨(decitabine)、氟尿苷(floxuridine)、氟达拉滨(fludarabine)、5-氟尿嘧啶(5-fluorouracil)、呋氟脲嘧啶(ftorafur)、吉西他滨(gemcitabine)、羟基脲(hydroxyurea)、巯基嘌呤(mercaptopurine)、甲氨蝶呤(methotrexate)、奈拉滨(nelarabine)、培美曲塞(pemetrexed)、雷替曲塞(raltitrexed)、硫鸟嘌呤(thioguanine)及三甲曲沙(trimetrexate)的抗代谢物(antimetabolite);例如由阿那曲唑(anastrozole)、雄激素(androgens)、布舍瑞林(buserelin)、乙烯雌酚(diethylstilbestrol)、依西美坦(exemestane)、氟他胺(flutamide)、氟维司群(fulvestrant)、戈舍瑞林(goserelin)、艾多昔芬(idoxifene)、来曲唑(letrozole)、亮丙瑞林(leuprolide)、甲地孕酮(magestrol)、雷洛昔芬(raloxifene)、他莫昔芬(tamoxifen)及托瑞米芬(toremifene)的激素或激素拮抗剂;例如为咪喹莫特(imiquimod)、干扰素-α(interferon-α)及白介素-2(interleukin-2)的生物反应调节剂(biological responsemodiffer);吲哚胺2,3-二加氧酶抑制剂(indoleamine 2,3-dioxygenase inhibitor);例如为3-氨基-2-甲醛硫缩胺基脲(3-amino-2-carboxyaldehyde thiosemicarbazone)、阿曲生坦(altrasentan)、胺麸精(aminoglutethimide)、阿那格雷(anagrelide)、天冬酰胺酶(asparaginase)、苔藓虫素-1(bryostatin-1)、西仑吉肽(cilengitide)、伊利司莫(elesclomol)、甲磺酸艾瑞布尔(eribulin mesylate)、伊沙贝比隆(ixabepilone)、氯尼达明(lonidamine)、马索罗酚(masoprocol)、米托胍腙(mitoguanazone)、奥利默生(oblimersen)、舒林酸(sulindac)、睾内酯酮(testolactone)及噻唑呋林(tiazofurin)的化学治疗剂;雷帕霉素(rapamycin)抑制剂的哺乳动物靶标;磷酸肌醇(phosphoinositide)3-激酶抑制剂;细胞周期蛋白依赖性激酶4(cyclin-dependent kinase 4)抑制剂;蛋白激酶B抑制剂;热激蛋白90抑制剂(heat shock protein 90);法尼基转移酶(farnesyltransferase)抑制剂;芳香酶(aromatase)抑制剂(诸如阿那曲唑(anastrozole)、来曲唑(letrozole)及依西美坦(exemestane));丝裂原活化蛋白激酶(mitogen-activated protein kinase)抑制剂;酪氨酸(tyrosine)激酶抑制剂;表皮生长因子受体抑制剂;程序性细胞死亡蛋白1(programmed cell death protein 1)抑制剂;程序性死亡配体1(programmed death-ligand 1)抑制剂;或白介素8(interleukin 8)受体β抑制剂。
使用一种或多种上述杂环化合物治疗CSF1R调节的病症的方法仍在本公开的范围内。例如,疾病可例如为急性髓细胞性白血病(acute myeloid leukemia)、膀胱癌(bladdercancer)、乳腺癌(breast cancer)、子宫颈癌(cervical cancer)、结肠癌(colon cancer)、胃癌(gastric cancer)、胃肠道间质瘤(gastrointestinal stromal tumor)、多形胶质母细胞瘤(glioblastoma multiforme)、肝细胞癌(hepatocellular carcinoma)、霍奇金淋巴瘤(Hodgkin’s lymphoma)、肾癌(kidney cancer)、肝癌(liver cancer)、肺癌(lungcancer)、黑色素瘤(melanoma)、转移性肿瘤(metastatic tumor)、卵巢癌(ovariancancer)、胰腺癌(pancreatic cancer)、色素性绒毛状滑膜炎(pigmented villondularsynovitis)、前列腺癌(prostate cancer)、腱鞘膜巨细胞瘤(tenosynovial giant celltumors)、子宫内膜癌(endometrial cancer)、多发性骨髓瘤(multiple myeloma)、粒细胞性白血病(myelocytic leukemia)、骨癌(bone cancer)、肾癌(renal cancer)、脑癌(braincancer)、骨髓增生性疾病(myeloproliferative disorder)、食道癌(esophagealcancer)、鳞状细胞癌(squamous cell carcinoma)、葡萄膜黑色素瘤(uveal melanoma)、滤泡性淋巴瘤(follicular lymphoma)、大肠癌(colorectal cancer)、头颈癌(head andneck cancer)、星形细胞瘤(astrocytoma)及肺腺癌(pulmonary adenocarcinoma)的癌症;例如为银屑病关节炎(psoriatic arthritis)、关节炎(arthritis)、哮喘(asthma)、甲状腺炎(thyroiditis)、肾小球肾炎(glomerular nephritis)、动脉粥样硬化(atherosclerosis)、银屑病(psoriasis)、薛格连氏症候群(Sjogren′s syndrome)、类风湿性关节炎(rheumatoid arthritis)、系统性红斑狼疮(systemic lupus erythematosus)、皮肤性红斑狼疮(cutaneous lupus erythematosus)、克隆氏症(Crohn′s disease)、溃疡性结肠炎(ulcerative colitis)、I型糖尿病(type Idiabetes)、多发性硬化症(multiplesclerosis)、人类免疫缺陷病毒性脑炎(human immunodeficiency virus encephalitis)、阿兹海默症(Alzheimer′s disease)、肌萎缩性侧索硬化症(amyotrophic lateralsclerosis)及癫痫病(epilepsy)的发炎性疾病(inflammatory disorder)或自体免疫性疾病(autoimmune disease);或例如为骨质疏松症(osteoporosis)、骨关节炎(osteoarthritis)、牙周炎(periodontitis)、假体周围骨溶解(periprostheticosteolysis)及柏哲德氏症(Paget’s disease)的骨疾病。
无需进一步详细阐述,相信本领域的技术人员可以基于上文描述最大程度地利用本公开。因此,以下具体实施例应被解释为仅仅是说明性的,而不以任何方式限制本公开的其余部分。本公开引用的所有出版物均全文引用以作为参考。
实施例1:杂环化合物的合成
下表1中所示的本公开的示例性化合物由方案1、方案2、方案3或方案4中所示的方法制备。表1包括化合物的质谱数据。
所有化学药品及溶剂均购自商业供货商,并按原样使用。除非另有说明,否则所有反应均在干燥氮气气氛下进行。使用默克60 F254(Merck 60 F254)硅胶玻璃背板(5×10cm)由薄层色谱法监测反应,并在紫外线照射(254nm)或通过喷涂磷钼酸(phosphomolybdic acid)试剂(Aldrich)接着在80℃加热下目视检测区域。在CEMDiscover SP系统中进行微波反应。
通过使用默克硅胶60(Merck Kieselgel 60),No.9385,230-400筛目ASTM硅胶作为固定相进行快速管柱色谱。在Varian Mercury-300或Varian Mercury-400光谱仪上测量质子核磁共振波(1H NMR)光谱。相对于溶剂峰的共振,以δ(delta)尺度记录了百万分之几(ppm)的化学位移。以下缩写用于描述耦合:s=单重态;d=双重态;t=三重态;q=四重态;quin=五重态;ABq=AB四重态;AA’XX’=二阶AA’XX’模式;app.=明显的;br=广泛的;以及m=多重态。
液相色谱质谱(LCMS)数据是使用安捷伦MSD-1100 ESI-MS/MS(Agilent MSD-1100ESI-MS/MS),Agilent 1200系列LC/MSD VL或沃特斯Acquity UPLC-ESI-MS/MS(WatersAcquity UPLC-ESI-MS/MS)系统获得的。
在方案1中列出的试剂及溶剂中,SOCl2为亚硫酰氯(thionylchloride);DMF为二甲基甲酰胺(dimethylformamide);PhMe为甲苯(toluene);tBuOK为叔丁醇钾(potassiumtert-butoxide);THF为四氢呋喃(tetrahydrofuran);DMSO为二甲基亚砜(dimethylsulfoxide);以及CH2Cl2为二氯甲烷(methylene chloride)。
4-氯-7-氟喹唑啉(4-Chloro-7-fluoroquinazoline)(B)。在无水PhMe(30mL)中的7-氟喹唑啉-4-醇(7-fluoroquinazolin-4-ol)化合物A(6.32g,38.5mmol)的悬浮液中,添加SOCl2(22mL,7.7eq.)及DMF(2.6mL)。将所得的混合物回流10小时,然后将混合物冷却至室温,以水(200mL)淬火,并用乙酸乙酯(EtOAc;170mL)萃取。以水(300mL)及盐水(30mL)洗涤合并的有机萃取物,以硫酸钠(Na2SO4)干燥,并浓缩得到黄色固体的化合物B(6.08g,86%)。C8H4ClFN2的LCMS(ESI)m/z理论值:182、184;实测值:183、185[M+H]+.1H-NMR(400MHz,CDCl3)δ9.04(s,1H),8.33(dd,J=9.2Hz,4JF,H=6.0Hz,1H),7.71(dd,3JF,H=9.2Hz,J=2.4Hz,1H),7.52(ddd,J=9.2,2.4Hz,3jF,H=8.4Hz,1H)。
4-((7-氟喹唑啉-4-基)氧基)苯胺(4-((7-fluoroquinazolin-4-yl)oxy)aniline)(C)。将在无水THF(100mL)中的4-胺基苯酚(4-aminophenol)F(3.05g,28.0mmol)及t-BuOK(3.14g,28.0mmol)的混合物以0℃搅拌20分钟。随后,将化合物B(4.44g,24.3mmol)缓慢地分批加入,然后将反应混合物以0℃搅拌3小时,在此期间形成悬浮液。之后,将悬浮液通过硅藻土垫过滤,该垫用THF冲洗。蒸发除去滤液中的THF以得到粗残余物。将残余物悬浮在甲醇(MeOH)中,并经超声处理以形成固体。通过过滤收集固体,并干燥得到灰白色固体的标题化合物C(5.47g,88%)。C14H10BrN3O的LCMS(ESI)m/z理论值:255;实测值:256[M+H]+.1H-NMR(400MHz,CDCl3)δ 8.76(s,1H),8.40(dd,J=9.2Hz,4JF,H=6.0Hz,1H),7.61(dd,3JF,H=9.2Hz,J=2.4Hz,1H),7.40(ddd,J=9.2,2.4Hz,3JF,H=8.8Hz,1H),7.04(AA’XX’,JAX=8.8Hz,JAX’=0Hz,2H),6.77(AA’XX’,JAX=8.8Hz,JAX’=0Hz,2H),3.71(br,2H)。
4-(4-胺基苯氧基)-N,N-二甲基喹唑啉-7-胺(4-(4-aminophenoxy)-N,N-dimethylquinazolin-7-amine)(D)。在DMSO(7.1mL)中的化合物C(600mg,2.35mmol)的溶液中,添加在THF(3eq.,3.53mL)中的2M二甲胺(dimethlyamine)。然后将混合物在微波中170℃下照射10分钟。化合物C消耗完后,将反应混合物用EtOAc(30mL)及2%碳酸钠(Na2CO3)溶液(80mL)稀释,并用EtOAc(50mL)萃取。合并的有机萃取液依次用2%Na2CO3溶液(160mL)、水(200mL)及盐水(20mL)洗涤,经Na2SO4干燥并浓缩。将粗残余物悬浮在MeOH中,通过过滤收集悬浮液中的颗粒并干燥,得到为浅黄色固体的标题产物D(207mg,32%)。C16H16N4O的LCMS(ESI)m/z理论值:280;实测值:281[M+H]+.1H-NMR(300MHz,CDCl3):δ8.58(s,1H),8.15(d,J=9.2Hz,1H),7.12(dd,J=9.2Hz,J=2.7Hz,1H),7.03(AA’XX’,JAX=9.0Hz,JAX’=0Hz,JAA’=2.9Hz,JXX’=2.9Hz,2H),6.96(d,J=2.7Hz,1H),6.75(AA’XX’,JAX=9.0Hz,JAX’=0Hz,JAA’=2.9Hz,JXX’=2.9Hz,2H),3.67(br,2H),3.15(s,6H)。
1-(4-((7-(二甲基胺基)喹唑啉-4-基)氧基)苯基)-3-苯基脲(1-(4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl)-3-phenylurea)(化合物4,E)。在CH2Cl2(15mL)中的化合物D(165mg,0.588mmol)的溶液中,添加化合物H(108μL,0.883mmol)。将混合物回流10小时,在此期间形成悬浮液。通过过滤收集悬浮液中的颗粒,并用过量的CH2Cl2冲洗,得到为白色固体的标题产物E(214mg,91%)。C23H21N5O2的LCMS(ESI)m/z理论值:399;实测值:400[M+H]+.1H-NMR(400MHz,DMSO-d6):δ8.77(br s,1H),8.71(br s,1H),8.45(s,1H),8.11(d,J=9.6Hz,1H),7.52(AA’XX’,JAX=8.8Hz,JAX’=0Hz,JAA’=2.6Hz,JXX’=2.6Hz,2H),7.47(d,J=5.6Hz,2H),7.32-7.27(m,3H),7.19(AA’XX’,JAX=8.8Hz,JAX’=0Hz,JAA’=2.6Hz,JXX’=2.6Hz,2H),6.97(t,J=7.2Hz,1H),6.88(d,J=2.4Hz,1H),3.12(s,6H)。
化合物1、2、3、5、6、7、9、10、11、12、13、14、15、16、17、18、19、20、21、52及106以类似于化合物4的方式用适当的胺G及异氰酸酯H制备。
在方案2中列出的试剂及溶剂中,Py为吡啶;以及Et3N为三乙胺(triethylamine)。
4-硝基苯基((6-(三氟甲基)吡啶-3-基)甲基)胺基甲酸酯(4-nitrophenyl((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamate)(J)。在CH2Cl2(50mL)中的(6-(三氟甲基)吡啶-3-基)甲胺((6-(trifluoromethyl)pyridin-3-yl)methanamine)I(2.69g,15.3mmol)及Py(1.23mL,15.3mmol)的-30℃溶液中,缓慢加入氯甲酸4-硝基苯酯(4-nitrophenyl chloroformate)(3.85g,19.1mmol)。将反应混合物搅拌8小时,并使其缓慢升温至0℃。随后,将水(50mL)添加至反应混合物,然后将混合物搅拌20分钟,在此期间形成悬浮液。通过硅藻土垫将反应混合物过滤除去悬浮液中的颗粒。滤液用2%硫酸氢钠(sodiumbisulfate)溶液(20mL)、2%碳酸氢钠(sodium bicarbonate)溶液(40mL)、水(20mL)及盐水(3mL)洗涤,经Na2SO4干燥并浓缩。通过管柱色谱法纯化粗残余物,得到为白色固体的标题产物J(3.33g,定量)。C14H10F3N3O4的LCMS(ESI)m/z理论值:341;实测值:342[M+H]+.1H-NMR(400MHz,CDCl3):δ8.73(d,J=1.4Hz,1H),8.26(AA’XX’,JAX=9.2Hz,JAX’=0Hz,JAA’=2.6Hz,JXX’=2.6Hz,2H),7.91(dd,J=8.0,1.4Hz,1H),7.71(d,J=8.0Hz,1H),7.33(AA’XX’,JAX=9.2Hz,JAX’=0Hz,JAA’=2.6Hz,JXX’=2.6Hz,2H),5.68(br t,1H),4.58(d,J=6.4Hz,2H)。
1-(4-((7-(二甲基胺基)喹唑啉-4-基)氧基)苯基)-3-((6-(三氟甲基)吡啶-3-基)甲基)脲(1-(4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)urea)(化合物27,K)。在CH2Cl2(95mL)中的化合物J(2.19g,6.43mmol)及化合物D(1.06g,3.78mmol)的溶液中,添加Et3N(1.05mL)。将反应混合物回流4天,在此期间形成悬浮液。通过过滤收集悬浮液中的颗粒,并用过量的CH2Cl2冲洗,得到为白色固体的标题产物K(1.33g,73%)。C24H21F3N6O2的LCMS(ESI)m/z理论值:482;实测值:483[M+H]+.1H NMR(400MHz,DMSO-d6):δ 8.83(s,1H),8.72(d,J=1.2Hz,1H),8.43(s,1H),8.10(d,J=9.2Hz,1H),8.00(dd,J=8.4,1.2Hz,1H),7.89(d,J=8.4Hz,1H),7.47(AA’XX’,JAX=8.8Hz,JAX’=0Hz,JAA’=2.6Hz,JXX’=2.6Hz,2H),7.29(d,J=9.2,2.4Hz,1H),7.13(AA’XX’,JAX=8.8Hz,JAX’=0Hz,JAA’=2.6Hz,JXX’=2.6Hz,2H),6.87(d,J=2.4Hz,1H),6.84(t,J=6.0Hz,1H),4.44(d,J=6.0Hz,2H),3.12(s,6H)。
1-(4-((7-(二甲基胺基)喹唑啉-4-基)氧基)苯基)-3-((6-甲基吡啶基-3-基)甲基)脲(1-(4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl)-3-((6-methylpyridin-3-yl)methyl)urea)(化合物65,K)C24H21F3N6O2的LCMS(ESI)m/z理论值:428;实测值:429[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.43(s,1H),8.39(d,J=2.4Hz,1H),8.10(d,J=9.2Hz,1H),7.61(dd,J=8.0,2.4Hz,1H),7.46(AA’XX’,JAX=8.8Hz,2H),7.29(dd,J=9.2,2.4Hz,1H),7.22(d,J=8.0Hz,1H),7.13(AA’XX’,JAX=8.8Hz,2H),6.87(d,J=2.4Hz,1H),6.67(t,J=6.0Hz,1H),4.28(d,J=6.0Hz,1H),3.12(s,6H),2.44(s,3H)。
1-(4-((7-(二甲基胺基)喹唑啉-4-基)氧基)苯基)-3-((6-甲基吡啶基-3-基)甲基)脲(1-(4-((7-(dimethylamino)quinazolin-4-yl)oxy)phenyl)-3-((6-methylpyridin-3-yl)methyl)urea)(化合物66,K)C24H21F3N6O2的LCMS(ESI)m/z理论值:444;实测值:445[M+H]+.1H NMR(400MHz,DMSO-d6)δ8.68(s,1H),8.43(s,1H),8.39(d,J=2.4Hz,1H),8.10(d,J=9.2Hz,1H),7.61(dd,J=8.0,2.4Hz,1H),7.46(AA’XX’,JAX=8.8Hz,2H),7.29(dd,J=9.2,2.4Hz,1H),7.22(d,J=8.0Hz,1H),7.13(AA’XX’,JAX=8.8Hz,2H),6.87(d,J=2.4Hz,1H),6.67(t,J=6.0Hz,1H),4.28(d,J=6.0Hz,1H),3.12(s,6H),2.44(s,3H)。
化合物23、24、25、28、30、33、36、39、40、42、43、44、49、50、51、54、55、56、57、58、59、60、63、65、66、87、90、91、92、96及101以类似于化合物27的方式用适当的胺H及苯胺D制备。
在方案3中列出的试剂、溶剂及催化剂中,SOCl2为亚硫酰氯(thionylchloride);RuPhos Pd G3为(2-二环己基膦基-2′,6′-二异丙氧基-1,l′-联苯)[2-2′-氨基-1,1′-联苯]]甲磺酸钯(II)甲磺酸盐((2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-2′-amino-1,1′-biphenyl]]palladium(II)methanesulfonate);RuPhos为2-二环己基膦基-2′,6′-二异丙氧基联苯(2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl);以及Cs2CO3为碳酸铯(cesium carbonate)。
4-氯7-溴喹唑啉(4-Chloro-7-bromoquinazoline)(M)。在无水PhMe(6mL)中的7-溴喹唑啉-4-醇(7-bromoquinazolin-4-ol)L(1.17g,5.20mmol)的悬浮液中,添加SOCl2(6mL)及DMF(0.6mL)。将所得的混合物以95℃搅拌9小时,冷却至室温,以水(100mL)淬火,并用EtOAc(70mL)萃取。以水(200mL)及盐水(5mL)洗涤合并的有机萃取物,用Na2SO4干燥并浓缩,得到为黄色固体的标题产物M(1.26g,99%)。C8H4BrClN2的LCMS(ESI)m/z理论值:242、244、246;实测值:243、245、247[M+H]+.1H-NMR(300MHz,CDCl3):δ9.05(s,1H),8.28(d,J=1.8Hz,1H),8.15(d,J=9.0Hz,1H),7.84(dd,J=9.0,1.8Hz,1H)。
4-((7-溴喹唑啉-4-基)氧基)苯胺(4-((7-Bromoquinazolin-4-yl)oxy)aniline)(N)。将在无水THF(15mL)中的4-胺基苯酚(4-aminophenol)(0.678g,6.21mmol)及t-BuOK(0.668g,5.95mmol)的混合物以0℃搅拌20分钟。随后,将4-氯-7-溴喹唑啉M(4-chloro-7-bromoquinazoline M)(1.26g,5.17mmol)缓慢地分批加入,然后将反应混合物以0℃搅拌3小时,在此期间形成悬浮液。将该悬浮液通过硅藻土垫过滤,该垫用THF(20mL)冲洗,并将所得的滤液蒸发以得到粗固体。将粗固体悬浮于MeOH(6mL)中,并经超声处理。通过过滤收集悬浮液中的颗粒并干燥,得到为灰白色固体的标题产物N(1.461g,89%)。C14H10BrN3O的LCMS(ESI)m/z理论值:315、317;实测值:316、318[M+H]+。
1-(4-((7-溴喹唑啉-4-基)氧基)苯基)-3-((6-(三氟甲基)吡啶-3-基)甲基)脲(1-(4-((7-Bromoquinazolin-4-yl)oxy)phenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)urea)(O;化合物31)。在CH2Cl2(6mL)中的4-((7-溴喹唑啉-4-基)氧基)苯胺N(4-((7-Bromoquinazolin-4-yl)oxy)aniline N)(305mg,0.964mmol)及化合物Q(461mg,1.35mmol)的溶液中,添加Et3N(0.27mL)。将所得的混合物回流1.5天,在此期间形成悬浮液。通过过滤收集悬浮液中的颗粒,并用过量的CH2Cl2冲洗,得到为白色固体的标题产物O(462mg,93%)。C22H15BrF3N5O2的LCMS(ESI)m/z理论值:517、519;实测值:518、520[M+H]+.1HNMR(400MHz,DMSO-d6):δ8.87(s,1H),8.74(s,1H),8.72(br s,1H),8.30(d,J=8.8Hz,1H),8.24(d,J=2.0Hz,1H),8.00(dd,J=8.0,1.6Hz,1H),7.93(dd,J=8.8,2.0Hz,1H),7.90(d,J=8.0Hz,1H),7.50(AA’XX’,JAX=9.0Hz,JAX’=0Hz,2H),7.21(AA’XX’,JAX=9.0Hz,JAX’=0Hz,2H),6.86(t,J=6.0Hz,1H),4.44(d,J=6.0Hz,2H)。
1-(4-((7-(3,5-二甲基哌嗪-1-基)喹唑啉-4-基)氧基)苯基)-3-((6-(三氟甲基)吡啶-3-基)甲基)脲(1-(4-((7-(3,5-Dimethylpiperazin-1-yl)quinazolin-4-yl)oxy)phenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)urea)(P;化合物34)。将新鲜蒸馏的THF(4mL)用氩气净化20分钟,然后添加化合物O(50mg,0.097mmol)、Cs2CO3(47mg,0.15mmol)、顺式2,6-二甲基哌嗪(cis-2,6-dimethylpiperazine)(17mg,0.15mmol)、Ruphos(4.1mg,0.009mmol)及Ruphos Pd G3(4.1mg,0.005mmol)以形成悬浮液。将所得的混合物在氩气下搅拌5分钟。随后,将反应混合物回流整夜。通过硅藻土垫过滤所得的浅黄色溶液,并将滤液浓缩以得到残余物。残余物通过管柱色谱法纯化,得到为白色固体的标题产物P(49mg,92%)。C28H28F3N7O2的LCMS(ESI)m/z理论值:551;实测值:552[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.85(s,1H),8.72(d,J=1.6Hz,1H),8.46(s,1H),8.09(d,J=9.2Hz,1H),8.00(dd,J=8.0,1.6Hz,1H),7.90(d,J=8.0Hz,1H),7.51(dd,J=9.2,2.4Hz,1H),7.47(AA’XX’,JAX=9.2Hz,JAX’=0Hz,2H),7.17-7.13(m,3H),6.85(t,J=5.6Hz,1H),4.44(d,J=5.6Hz,2H),3.91-3.88(m,2H),2.87-2.82(m,2H),2.39-2.33(m,2H),1.06(d,J=6.4Hz,6H)。
1-(4-((7-(4-羟基哌啶-1-基)喹唑啉-4-基)氧基)苯基)-3-((6-(三氟甲基)吡啶-3-基)甲基)脲(1-(4-((7-(4-hydroxypiperidin-1-yl)quinazolin-4-yl)oxy)phenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)urea)(P;化合物30)。与化合物34类似,由化合物31制得化合物30,并获得白色固体。C28H28F3N7O2的LCMS(ESI)m/z理论值:538;实测值:539[M+H]+.1H NMR(400MHz,DMSO-d6):δ8.82(br s,1H),8.72(d,J=1.2Hz,1H),8.45(s,1H),8.08(d,J=9.2Hz,1H),8.00(dd,J=8.0,1.2Hz,1H),7.89(d,J=8.0Hz,1H),7.51-7.45(m,3H),7.15-7.11(m,3H),6.84(t,J=6.0Hz,1H),4.76(d,J=4.0Hz,2H),4.44(d,J=6.0Hz,2H),3.87-3.81(m,2H),3.77-3.72(m,1H),3.21-3.14(m,1H),1.87-1.83(m,2H),1.51-1.43(m,2H)。
类似于化合物34以制备化合物24、96、97、98、99、100。
在方案3中列出的试剂、溶剂及催化剂中,POCl3为磷酰氯(phosphorylchloride);CuI为碘化铜(copper iodide);1,10-phen为1,10-菲咯啉(1,10-phenanthroline);K2CO3为碳酸钾(potassium carbonate);以及tBuOH为叔丁醇(tert-butanol)。
7-(二甲基胺基)喹唑啉-4(3H)-酮(7-(Dimethylamino)quinazolin-4(3H)-one)(R)。在2-甲氧基乙醇(2-methoxyethanol)(60mL)中的7-氟喹唑啉-4(3H)-酮(7-fluoroquinazolin-4(3H)-one)A(1.65g,10.1mmol)及二甲胺(dimethylamine)(2M于THF中,20mL,40.2mmol)的溶液于250mL密封管中以130℃搅拌1天,在此期间形成固体。随后,将反应混合物冷却至室温,并减压浓缩。将所得的残余物悬浮在MeOH(8mL)中,并过滤得到为棕色固体的标题产物R(1.5g,79%)。C10H11N3O的LCMS(ESI)m/z理论值:189;实测值:190[M+H]+.1H NMR(300MHz,DMSO-d6):δ11.69(br,1H),7.91(s,1H),7.88(d,J=9.0Hz,1H),6.93(dd,J=9.0,2.4Hz,1H),6.98(d,J=2.4Hz,1H),3.04(s,6H).
4-氯-N,N-二甲基喹唑啉-7-胺(4-Chloro-N,N-dimethylquinazolin-7-amine)(S)。在无水PhMe(10mL)中的7-(二甲基氨基)喹唑啉-4(3H)-酮(7-(dimethylamino)quinazolin-4(3H)-one)R(910mg,4.81mmol)的悬浮液中,添加POCl3(4mL),然后将所得的混合物以95℃搅拌12小时。将反应混合物冷却至0℃,以冰水(100mL)淬火,并用饱和碳酸钠溶液中和,直到溶液的颜色从亮橙色变为浅黄色。随后,将反应混合物用EtOAc(170mL)萃取,并将有机萃取液用水(200mL)及盐水(20mL)洗涤,用Na2SO4干燥并浓缩,得到为黄色固体的标题产物S(948mg,95%)。[M+H]+.1H-NMR(300MHz,CDCl3):δ8.77(s,1H),8.03(d,J=9.3Hz,1H),7.20(dd,J=9.3,2.7Hz,1H),6.96(d,J=2.7Hz,1H),3.18(s,1H)。
4-((1H-吲哚-5-基)氧基)-N,N-二甲基喹唑啉-7-胺(4-((1H-indol-5-yl)oxy)-N,N-dimethylquinazolin-7-amine)(T)。用氩气净化DMF(4mL)。随后,添加4-氯-N,N-二甲基喹唑啉-7-胺(4-Chloro-N,N-dimethylquinazolin-7-amine)S(322mg,1.55mmol)、5-羟基吲哚(5-hydroxyindole)(413mg,3.10mmol)、K2CO3(429mg,3.10mmol)、CuI(29.5mg,0.155)及1,10-phen(27.9mg,0.155mmol)以形成反应混合物,将其在氩气下以90℃搅拌3小时,然后将反应混合物用EtOAc(15mL)及水(15mL)稀释,并通过硅藻土垫过滤。滤液用EtOAc(60mL)萃取,而有机萃取液用水(120mL)及盐水(5mL)洗涤,经Na2SO4干燥并浓缩。将残余物悬浮在MeOH中,并通过过滤收集颗粒,得到为白色固体的标题产物T(381mg,81%)。C18H16N4O的LCMS(ESI)m/z理论值:304;实测值:305[M+H]+.
5-((7-(二甲基氨基)喹唑啉-4-基)氧基)-N-((6-(三氟甲基)吡啶-3-基)甲基)-1H-吲哚-1-羧酰胺(5-((7-(dimethylamino)quinazolin-4-yl)oxy)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-indole-1-carboxamide)(U;化合物67)。在无水THF(5mL)中的4-(4-胺基-3-甲氧基苯氧基)-N,N-二甲基喹唑啉-7-胺(4-(4-amino-3-methoxyphenoxy)-N,N-dimethylquinazolin-7-amine)T(170mg,0.95mmol)的溶液中,添加NaH(60%于油中,112mg,2.79mmol)。将所得的混合物在室温搅拌20分钟。随后,将混合物冷却至-60℃,并分三部分添加4-硝基苯基((6-(三氟甲基)吡啶-3-基)甲基)氨基甲酸酯(4-nitrophenyl((6-(trifluoromethyl)pyridin-3-yl)methyl)carbamate)V(574mg,1.68mmol),然后将混合物缓慢升温至0℃,搅拌1小时,并用饱和氯化铵(ammoniumchloride)溶液淬火。减压下去除溶剂,并将所得的残余物用EtOAc(35mL)稀释,用水(80mL)及盐水(3mL)洗涤,经Na2SO4干燥并浓缩。通过管柱色谱法纯化粗残余物,得到为白色固体的标题产物U(171mg,65%)。C26H21F3N6O2的LCMS(ESI)m/z理论值:506;实测值:507[M+H]+.1HNMR(400MHz,DMSO-d6):δ8.94(t,J=5.6Hz,1H),8.82(d,J=1.6Hz,1H),8.41(s,1H),8.27(d,J=8.8Hz,1H),8.15(d,J=9.2Hz,1H),8.10(dd,J=8.0,1.6Hz,1H),7.96(d,J=3.6Hz,1H),7.92(d,J=8.0Hz,1H),7.50(d,J=2.4Hz,1H),7.31(dd,J=9.2,2.4Hz,1H)7.16(dd,J=8.8,2.4Hz,1H),6.88(d,J=2.4Hz,1H),6.74(d,J=3.6Hz,1H),4.64(d,J=5.6Hz,2H),3.13(s,6H)。
化合物29、35、38、64、68、69、83及89以类似于化合物67的方式制备。
表1示例性杂环化合物
实施例2:CSF1R激酶试验
进行研究以测试实施例1中描述的某些化合物在抑制CSF1R激酶活性中的作用。此项研究的结果显示在下表2中(请参阅第2栏)。
使用CSF1R Kinase-Glo试验测定CSF1R激酶的活性。含有CSF1R激酶域的重组N末端GST-CSF1R(CSF1R残基L534-C972)在Sf9昆虫细胞中表现并纯化。激酶试验是在96孔板中以30℃进行180分钟,被测化合物的最终体积为50μl,其中包括以下成分:25mM Tris-HClpH 7.4、4mM MnCl2、10mM MgCl2、0.01%BSA、0.5mM Na3VO4、0.02%Triton X-100、40μMATP,2mM DTT及20μM poly(Glu,Tyr)4∶1胜肽以及600ng重组GST-CSF1R。培养后,添加50μlKinase-Glo Plus试剂(Promega,麦迪逊,威斯康星州,美国),并将混合物以25℃培养20分钟。将每种反应混合物的70μL等分试样转移至黑色微量滴定板,并在Wallac Vector 1420多标记计数器(PerkinElmer,Shelton,康涅狄格州,美国)上测量发光。通过将反应速率与对照孔中的速率(即在没有测试化合物的情况下)进行比较以获得抑制百分率值。通过使用GraphPad Prism版本6软件(GraphPad,圣地亚哥,加利福尼亚州,美国),以由测试化合物浓度的范围决定的一系列抑制百分率值计算出IC50值。
实施例3:细胞增殖试验
使用3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑(3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)(MTS)进行了细胞存活率试验研究以评估实施例1中描述的某些化合物的体内抗癌活性。这些研究的结果显示在下表2中(请参阅第3栏及第4栏)。
细胞株及培养:
细胞株M-NFS(CRL-1838TM)及BaF3-CSF1R-1600是从美国典型培养物收藏中心(ATCC,马纳萨斯,弗吉尼亚州,美国)获得。稳定的BaF3-CSF1R-1600细胞株表现由N末端ETS变异基因6蛋白(ETV6残基M1-G337)及CSF1R酪胺酸激酶(CSF1R残基L533-C972)组成的ETV6-CSF1R融合蛋白。在外加有10%胎牛血清、0.05mM的2-ME、10μ/ml青霉素(penicillin)及10g/ml链霉素(streptomycin)的RPMI1640培养基中于37℃及5%CO2下培养M-NSF-60及BaF3-CSF1R-1600细胞。
MTS细胞存活率试验:
将MNFS-60及BaF3-CSF1R-1600细胞分别以每孔10000个细胞/100μl及8000个细胞/100μl的密度接种到96孔板中培养16小时,并用溶媒或各种浓度的测试化合物在培养基中测试72小时。依据制造商推荐的方案,使用MTS方法(Promega,麦迪逊,威斯康星州,美国)对活细胞进行定量。通过使用盘式分析仪(Victor 2)测量在490nm处的吸收度来确定结果。GI50值定义为与DMSO处理(溶媒)对照相比引起细胞存活率降低50%的化合物的量,并使用Prism GraphPad Prism版本6软件(GraphPad)进行计算。
表2 CSF1R激酶试验以及M-NFS-60及BaF3-CSF1R细胞试验中杂环化合物的抑制活性
a++++:IC50<20nM;+++:20nM<IC50<100nM;++:100nM<IC50<1000nM;+:1000nM<IC50
b++++:GI50<20nM;+++:20nM<GI50<100nM;++:100nM<GI50<1000nM;+:1000nM<GI50
实施例4:激酶选择性谱
进行了一项研究以确定化合物27及67的激酶选择性。更具体地,当与其他七个激酶(即Aurora A、Aurora B、酪氨酸蛋白激酶组)(c-Kit)、fms样酪氨酸激酶3(FLT3)、血小板衍生生长因子受体(PDGFR)A、PDGFR B及盘状蛋白域受体酪氨酸激酶1(DDR1)的抑制活性相比,测试了每种化合物对CSF1R激酶的抑制活性。此项研究的结果显示在下表3。
使用「HotSpot」试验平台在Reaction Biology公司(www.reactionbiology.com,Malvern,PA)上进行激酶组的体外分析。简而言之,在含有20mM Hepes pH 7.5、10mMMgCl2、1mM EGTA、0.02%Brij35、0.02mg/ml BSA、0.1mM Na3VO4、2mM DTT及1%DMSO的反应缓冲溶液中制备特定的激酶/基质对以及所需的辅因子。添加化合物27或67。20分钟后,将ATP(Sigma公司,圣路易斯,密苏里州)(Sigma,St.Louis MO)及33P ATP(珀金埃尔默公司,沃尔瑟姆,麻萨诸塞州)(Perkin Elmer,Waltham MA)的混合物添加到所得的反应溶液中,以使最终浓度为10μM。反应以室温进行120分钟,然后将反应溶液点在P81离子交换滤纸上(Whatman公司,皮斯卡特维,纽泽西州)(Whatman Inc.,Piscataway,NJ)。通过在0.75%磷酸中对过滤器大量洗涤以除去未结合的磷酸盐。减去源自包含无活性酶的对照反应的背景后,激酶活性被确定为测试样品中与溶媒(DMSO)反应相比剩余激酶活性的百分率。使用Prism(Graph Pad软件)获得每种化合物对每种激酶的IC50值及剂量反应曲线。表示为IC50比值的选择性是通过将激酶(例如Aurora A)的IC50值除以CSF1R的值来决定的。
表3激酶选择性谱
++++:IC50比值>1000;+++:1000>IC50比值>100;++:100>IC50比值>10;+:10>IC50比值>1
其他实施例
此说明书中公开的所有特征可以以任何组合进行结合。此说明书中公开的每个特征可以由具有相同、等同或相似目的的替代特征取代。因此,除非另有明确地说明,否则所公开的每个特征仅是一系列等同或相似特征的示例。
再者,依据以上描述,本领域技术人员可以容易地确定本公开的实质特征,并在不脱离其精神及范围的情况下,可以对本公开进行各种改变及修改以使其适用于各种用途及条件。因此,其他实施例也在本公开的保护范围之内。
Claims (31)
1.一种式I的化合物:
其中,
A为H、C1-C6烷基或ORr,Rr为H或C1-C6烷基;
Y1为被(R1)n取代的苯基、被(R2)o取代的5元杂芳基、被(R2)o取代的5元杂环烯基或被(R2)o取代的烯基,其中(R1)n中的R1各自独立为F、Cl、Br、NO2、CN、胺基、C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基或螺胺基,且n为0-4;而(R2)o中的R2各自独立为F、Cl、Br、NO2、CN、胺基、C1-C6烷基、C1-C6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基、螺胺基或C1-C6烷氧基,且o为0-5;
X1为N或CR3,R3为H、F、Cl、Br、CN、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基;
X2为O、S、NH或CH2;
Y2为 其中Q1、Q2、Q3、Q4、Q5、Q6、Q7及Q8各自独立为N或CR4,R4为H、F、Cl、Br、CN、胺基、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基;而Z1为O、S或NRr;Z2为O、S或NRr,且G及H分别为C或N及N或C;
X3为被删除、CH2、(CH2)2或CH(C≡CH);
Y3为C1-C6烷基、芳基、杂芳基、C3-C8环烷基或具有一个杂原子的C5-C6杂环烷基,其中该杂原子为O或N;以及
(X4)m中的X4各自独立为F、Cl、Br、CN、SO2NH2、胺基、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基,且m为0-5。
2.根据权利要求1所述的化合物,其中Y1为被(R1)n取代的苯基、被(R2)o取代的5元杂芳基或被(R2)o取代的5元杂环烯基,其中(R1)n中的R1各自独立为F、Cl、Br、NO2、CN、C1-C6烷基、C1-C6卤代烷基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基或螺胺基;而(R2)o中的R2各自独立为F、Cl、Br、NO2、CN、胺基、C1-C6烷基、C1-C6卤代烷基、C2-C6炔基、C3-C8环烷基、C5-C15杂环烷基、芳基、杂芳基、羰基、亚硫酰基、亚胺基、螺胺基或C1-C6烷氧基。
10.根据权利要求7所述的化合物,其中R1为胺基。
17.根据权利要求16所述的化合物,其中X4各自独立为CH3、CH2F、CHF2、CF3或OCH3,且m为0-2。
19.根据权利要求18所述的化合物,其中X4各自独立为CH3、CH2F、CHF2、CF3或OCH3,且m为0-2。
21.根据权利要求20所述的化合物,其中X4各自独立为CH3、CH2F、CHF2、CF3或OCH3,且m为0-2。
25.一种医药组合物,包括:权利要求1所述的化合物及其药学上可接受的载体。
26.根据权利要求25所述的医药组合物,还包括选自抗增殖剂、消炎剂、免疫调节剂或免疫抑制剂的治疗剂。
27.根据权利要求25所述的医药组合物,还包括治疗剂,该治疗剂为:烷基化剂,其选自阿多来新、六甲蜜胺、比折来新、白消安、卡铂、卡波醌、卡莫司汀、氯芥苯丁酸、顺铂、环磷酰胺、达喀尔巴嗪、雌莫司汀、福莫司汀、海普法姆、异环磷酰胺(ifosfamide)、英丙舒凡、伊洛福芬、洛莫司汀、盐酸氮芥、美法仑、奥沙利铂、哌泊舒凡、司莫司汀、链脲佐菌素、替莫唑胺、噻替派及曲奥舒凡;
抗体,其选自阿仑单抗、贝伐单抗、西妥昔单抗、加利昔单抗、吉妥单抗、尼沃单抗、帕尼单抗、派姆单抗、帕妥珠单抗、利妥昔单抗、托西单抗、曲妥珠单抗及钇90替伊莫单抗;
靶向信号转导抑制剂,其选自硼替佐米、格尔德霉素及雷帕霉素;
激酶抑制剂,其选自厄洛替尼、吉非替尼、夫拉平度、甲磺酸伊马替尼、拉帕替尼、索拉非尼、苹果酸舒尼替尼、AEE-788、AG-013736、AMG706、AMN107、BMS-354825、BMS-599626、7-羟基星形孢菌素、维拉非尼、达拉非尼、曲美替尼、考比替尼、司美替尼及瓦他拉尼;
紫杉烷,其选自DJ-927、多西他赛、TPI 287、紫杉醇及DHA-紫杉醇;
类维生素A(retinoid),其选自阿利维A酸、贝沙罗汀、芬维A胺、异维A酸及维A酸;
生物碱,其选自依托泊苷、高三尖杉酯碱、替尼泊苷、长春碱、长春新碱、长春地辛及长春瑞滨;
抗生素,其选自博来霉素、放线菌素、柔红霉素、阿霉素、表柔比星、伊达比星、美诺立尔、丝裂霉素、米托蒽醌、新制癌菌素、喷司他丁及普卡霉素;
抗血管生成剂,其选自AE-941、ABT-510、2-甲氧基雌二醇、来那度胺及沙利度胺;
拓扑异构酶抑制剂,其选自安吖啶)、依地卡林、依喜替康、伊立替康、7-乙基-10-羟基喜树碱、鲁比替康、拓扑替康及9-氨基喜树碱;
抗代谢物,其选自由阿扎胞苷、卡培他滨、克拉屈滨、氯法拉滨、阿糖胞苷、地西他滨、氟尿苷、氟达拉滨、5-氟尿嘧啶、呋氟脲嘧啶、吉西他滨、羟基脲、巯基嘌呤、甲氨蝶呤、奈拉滨、培美曲塞、雷替曲塞、硫鸟嘌呤及三甲曲沙所组成的群组;
激素或激素拮抗剂,其选自由阿那曲唑、雄激素、布舍瑞林、乙烯雌酚、依西美坦、氟他胺、氟维司群、戈舍瑞林、艾多昔芬、来曲唑、亮丙瑞林、甲地孕酮、雷洛昔芬、他莫昔芬及托瑞米芬所组成的群组;
生物反应调节剂,其选自咪喹莫特、干扰素-α及白介素-2;
吲哚胺2,3-二加氧酶抑制剂;
化学治疗剂,其选自3-氨基-2-甲醛硫缩胺基脲、阿曲生坦、胺麸精、阿那格雷、天冬酰胺酶、苔藓虫素-1、西仑吉肽、伊利司莫、甲磺酸艾瑞布尔、伊沙贝比隆、氯尼达明、马索罗酚、米托胍腙、奥利默生、舒林酸、睾内酯酮及噻唑呋林;
雷帕霉素抑制剂的哺乳动物靶标;
磷酸肌醇3-激酶抑制剂;
细胞周期蛋白依赖性激酶4抑制剂;
蛋白激酶B抑制剂;
热激蛋白90抑制剂;
法尼基转移酶抑制剂;
芳香酶抑制剂;
丝裂原活化蛋白激酶抑制剂;
酪氨酸激酶抑制剂;
表皮生长因子受体抑制剂;
程序性细胞死亡蛋白1抑制剂;
程序性死亡配体1抑制剂;或
白介素8受体β抑制剂。
28.一种治疗CSF1R调节性疾病的方法,包括:给予需求主体有效量的权利要求1的化合物,其中该疾病是选自癌症、发炎性疾病或自体免疫疾病及骨疾病。
29.根据权利要求28所述的方法,其中该疾病是选自急性髓细胞性白血病、膀胱癌、乳腺癌、子宫颈癌、结肠癌、胃癌、胃肠道间质瘤、多形胶质母细胞瘤、肝细胞癌、霍奇金淋巴瘤、肾癌、肝癌、肺癌、黑色素瘤、转移性肿瘤、卵巢癌、胰腺癌、色素性绒毛状滑膜炎、前列腺癌、腱鞘膜巨细胞瘤、子宫内膜癌、多发性骨髓瘤、粒细胞性白血病、骨癌、肾癌、脑癌、骨髓增生性疾病、食道癌、鳞状细胞癌、葡萄膜黑色素瘤、滤泡性淋巴瘤、大肠癌、头颈癌、星形细胞瘤及肺腺癌的癌症。
30.根据权利要求28所述的方法,其中该疾病是选自银屑病关节炎、关节炎、哮喘、甲状腺炎、肾小球肾炎、动脉粥样硬化、银屑病、薛格连氏症候群、类风湿性关节炎、系统性红斑狼疮、皮肤性红斑狼疮、克隆氏症、溃疡性结肠炎、I型糖尿病、多发性硬化症、人类免疫缺陷病毒性脑炎、阿兹海默症、肌萎缩性侧索硬化症及癫痫病的发炎性疾病或自体免疫性疾病。
31.根据权利要求28所述的方法,其中该疾病是选自骨质疏松症、骨关节炎、牙周炎、假体周围骨溶解及柏哲德氏症的骨疾病。
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Cited By (1)
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WO2023168740A1 (zh) * | 2022-03-08 | 2023-09-14 | 安徽中科拓苒药物科学研究有限公司 | 喹啉类化合物的新用途 |
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US20220213064A1 (en) | 2022-07-07 |
EP3952865A1 (en) | 2022-02-16 |
AU2020271855A1 (en) | 2021-11-04 |
EP3952865A4 (en) | 2023-05-03 |
TW202104212A (zh) | 2021-02-01 |
WO2020210481A8 (en) | 2020-11-19 |
KR20210151818A (ko) | 2021-12-14 |
TWI757722B (zh) | 2022-03-11 |
JP2022528780A (ja) | 2022-06-15 |
CA3132855A1 (en) | 2020-10-15 |
WO2020210481A1 (en) | 2020-10-15 |
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