CN117209501A - 磺酰胺衍生物及其用途 - Google Patents
磺酰胺衍生物及其用途 Download PDFInfo
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- CN117209501A CN117209501A CN202210624554.3A CN202210624554A CN117209501A CN 117209501 A CN117209501 A CN 117209501A CN 202210624554 A CN202210624554 A CN 202210624554A CN 117209501 A CN117209501 A CN 117209501A
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Abstract
本申请涉及一种作为RET激酶抑制剂的磺酰胺衍生物及其用途。具体地,本申请涉及式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,以及其在制备用于治疗或预防由RET或RET突变介导的疾病或病症的药物中的用途。
Description
技术领域
本申请属于小分子医药领域,具体地,涉及用于一种作为RET激酶抑制剂的磺酰胺衍生物及其用途。
背景技术
转染重排(rearranged during transfection,RET)作为一种原癌基因,最早是在转化培养的小鼠NTH3T3细胞中被发现并命名,而真正确定RET基因突变及重排与肿瘤相关可追溯到1985年,该基因位于第10号染色体长臂(10q11.2)上,全长60kb,包含21个外显子其编码由1100个氨基酸组成存在于细胞膜上的络氨酸激酶受体,即RET蛋白,并通过受体与配体的结合,刺激细胞内区域发生磷酸化,从而激活下游STAT/PLCγ信号通路,参与调节细胞的存活、迁移、侵袭、生长和分化,持续的信号传递会造成细胞的过度增殖,从而导致肿瘤的发生与进展。
RET是一种跨膜受体酪氨酸激酶。它由胶质细胞源性神经营养因子(GDNF)的成员与其共受体结合激活。GDNF家族包括GDNF-artemin、neurturin和persephin,它们由共同受体表达、共同受体调节神经元的存活、分化和趋化性。RET突变,包括过度表达、基因融合和点突变,与多种人类癌症有关,包括肺癌和甲状腺癌。约10.20%的甲状腺乳头状癌(PTC)和12%的非小细胞肺癌(NSCLC)是由致癌RET融合引起的。此外,在家族性多发性内分泌肿瘤2(MEN2)和散发性甲状腺髓样癌(MTC)中发现RET的激活点突变。
总之,RET基因突变与多种疾病的发生密切相关,如肿瘤、先天性巨结肠、先天性肾脏和泌尿路异常。因此开发RET抑制剂极具潜在的应用价值。
发明内容
本发明的目的在于提供一种新型的作为RET激酶抑制剂的磺酰胺衍生物,此类化合物能够在抑制RET方面具有良好的活性,并表现出优异的效果和作用。
在第一方面,本申请提供了式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,
其中,
R1选自C1-C6烷基、C2-C6烯基、C2-C6炔基、苄基、C3-C10环烷基、3-10元杂环烷基、C5-C10芳基或5-10元杂芳基,并且所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、3-10元杂环烷基、C5-C10芳基或5-10元杂芳基中的一个或多个氢原子任选地被卤素、-CN、-NO2、-NRaRb、-OH、C1-C3烷基、C1-C3烷氧基、C1-C3羟烷基、C1-C3卤代烷基、C1-C3卤代烷氧基或-(C=O)NRaRb取代;
Ra和Rb各自独立地选自H、卤素、C1-C3烷基或C1-C3环烷基,或者Ra和Rb与其所连接的N原子一起形成3-10元杂环烷基;
同位素标记化合物是式I化合物中的一个或多个氢原子被氘取代的氘标记化合物。
Ra和Rb各自独立地选自H、卤素、甲基、乙基、丙基或环丙基,或者Ra和Rb与其所连接的N原子一起形成3-10元杂环烷基,其中所述3-10元杂环烷基任选地包含除所述连接N原子外的一个或多个N、O或S原子;所述卤素各自独立地选自F、Cl、Br或I;
所述烷基各自独立地选自甲基、乙基、正丙基或异丙基;
所述烯基各自独立地选自乙烯、丙烯、1-丁烯或2-丁烯;
所述炔基各自独立地选自乙炔、丙炔、1-丁炔或2-丁炔;
所述烷氧基各自独立地选自甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基;
所述环烷基各自独立地选自单环基,例如环丙基、环丁基、环戊基或环己基,或螺环基,例如螺[2.4]庚烷基;
所述杂环烷基各自独立选自包含一个或多个N、O或S原子的环丙基、环丁基、环戊基或环己基,或螺环基,例如2-氧杂-6-氮杂螺[3.3]庚烷基;
所述芳基各自独立地选自单环基,例如苯基;或双环基,例如萘基;
所述杂芳基各自独立地选自单环基,例如吡嗪、吡唑、吡咯、呋喃、噻吩、噻唑或吡啶;或双环基,例如吡咯并吡啶基、吡咯并吡唑基、苯并吡唑基或苯并吡咯基;
所述羟烷基各自独立地选自羟甲基、羟乙基或羟丙基;
所述卤代烷基各自独立地选自一氟甲基、二氟甲基、三氟甲基、一氯甲基、二氯甲基或三氯甲基;
所述卤代烷氧基各自独立地选自一氟甲氧基、二氟甲氧基、三氟甲氧基、一氯甲氧基、二氯甲氧基或三氯甲氧基。
R1优选为:
在本发明的另一个优选实施方式中,所述式I化合物具有以下结构:
为了简明起见,后文所述“式I化合物”或“本申请的化合物”也可以涵盖式I化合物的任意同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物。
术语“光学异构体”意指,当化合物具有一个或更多个手性中心时,每个手性中心可以存在R构型或S构型,由此构成的各种异构体为光学异构体。光学异构体包括所有的非对映异构体、对映异构体、内消旋体、外消旋体或其混合物形式。例如,通过手性色谱柱或通过手性合成可以分离光学异构体。
术语“几何异构体”意指,当化合物中存在双键时,该化合物可以存在顺式异构体、反式异构体、E型异构体和Z型异构体。几何异构体包括顺式异构体、反式异构体、E型异构体、Z型异构体或其混合物形式。
术语“互变异构体”指因分子中某一原子在两个位置迅速移动而产生的异构体。本领域技术人员可以理解:互变异构体之间可以互相转变,在某一状态下可能会达到一种平衡状态而共存。
除非另有指明,本文提到“式I化合物”或“本发明的化合物”时也涵盖该化合物中任一个原子被其同位素原子代替而得到的同位素标记化合物。本发明包括式I化合物的所有药学上可接受的同位素标记化合物,其中,一个或者多个原子被具有与通常在自然界中所发现的原子相同原子序数但是不同原子质量或者质量数的原子所替换。
适用于包含在本发明的化合物中的同位素的实例包括氢的同位素,诸如2H(D)和3H(T),碳的同位素,诸如11C、13C和14C,氯的同位素,诸如37Cl,氟的同位素,诸如18F,碘的同位素,诸如123I和125I,氮的同位素,诸如13N和15N,氧的同位素,诸如15O、17O和18O,以及硫的同位素,诸如35S。
式I的同位素标记化合物一般可以通过本领域技术人员已知的常规技术或者通过使用合适的同位素标记试剂代替先前使用的非标记试剂以类似于在本文所附的实例和制备中所描述的方法,来进行制备。
式I化合物可以药学上可接受的盐的形式存在,比如,式I化合物的酸加成盐和/或碱加成盐。除非另有指明,否则本文所用的“药学上可接受的盐”包括可出现于式I化合物内的酸加成盐或碱加成盐。
式I化合物的药学上可接受的盐类包括其酸加成盐和碱加成盐。适当的酸加成盐是由形成无毒性盐的酸所形成的。其实例包括但不限于:乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己胺磺酸盐、乙二磺酸盐、甲酸盐、反丁烯二酸盐、葡萄庚糖酸盐、葡萄糖酸盐、葡萄糖醛酸盐、六氟磷酸盐、2-(4-羟苄基)苯甲酸盐、氢氯化物/氯化物、氢溴化物/溴化物、氢碘化物/碘化物、2-羟乙磺酸盐、乳酸盐、苹果酸盐、顺丁烯二酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、乳清酸盐、草酸盐、十六酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、葡萄糖二酸盐、硬脂酸盐、水杨酸盐、单宁酸盐、酒石酸盐、甲苯磺酸盐和三氟乙酸盐。适当的碱加成盐是由形成无毒性盐的碱所形成的。其实例包括但不限于:铝、精氨酸、钙、胆碱、二乙胺、二乙醇胺、甘氨酸、赖氨酸、镁、葡甲胺、乙醇胺、钾、钠、氨丁三醇和锌盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。关于合适的盐的综述,参见Handbook of Pharmaceutical Salts:Properties,Selection and Useby Stahland Wermuth(Wiley-VCH,2002)。用于制备本文中所述的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
本发明的某些化合物可以以非溶剂化形式以及溶剂化形式(包括水合形式)存在。一般而言,式I化合物无论以溶剂化形式存在或以未溶剂化形式存在,其都包括在本发明的范围内。
本发明的某些化合物可以不同晶型或不定型形式存在,无论以何种形式存在,式I化合物都包括在本发明的范围内。
为了避免歧义,下面对本文中所使用的术语给出定义。除非另有说明,本文所用术语的含义如下。
术语“药学上可接受的”是指相应的化合物、载体或分子适于给予人。优选地,该术语是指由管理机构例如CFDA(中国)、EMEA(欧洲)、FDA(美国)等任意国家管理机构认证的用于哺乳动物优选人。
“前体药”是指通过与酶、胃酸等在生理条件下在活体内例如通过各自在酶催化下进行的氧化、还原、水解等反应转化为本发明化合物的衍生物。
“代谢物”是指在细胞或有机体优选人中源自本发明任意化合物的所有分子。
术语“羟基”是指-OH;术语“氨基”是指-NH2;术语“氰基”是指-CN;并且术语“苄基”是指苯甲基。
在本文中使用时,术语“被取代”是指基团中的一个或多个(优选1至5个,更优选1至3个)氢原子独立地被相应数目的取代基所代替。
在本文中使用时,术语“各自独立地”是指当取代基的个数超过一个时,这些取代基可以相同也可以不同。
在本文中使用时,术语“任选”或“任选地”表示其所描述的事件可以发生或不发生。例如,一个基团“任选地被取代”表示:该基团可以是未被取代的,也可以是被取代的。
在本文中使用时,术语“烷基”是指饱和的脂族烃,包括直链及支链。在一些实施方式中,烷基基团具有1-8个、或1-6个、或1-3个碳原子。例如,术语“C1-8烷基”是指具有1-8个碳原子的直链或支链原子团。术语“C1-8烷基”在其定义中包括术语“C1-6烷基”、“C1-C3烷基”和“C1-C4烷基”。烷基的实例包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、2-戊基、3-戊基、异戊基、新戊基、(R)-2-甲基丁基、(S)-2-甲基丁基、3-甲基丁基、2,3-二甲基丙基、2,3-二甲基丁基、己基等。烷基基团可任选地被一或多个(例如,1至5个)适当的取代基所取代。
在本文中使用时,术语“卤代烷基”是指具有一或多个卤素取代基的烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。例如,术语“C1-6卤代烷基”是指具有一或多个卤素取代基的C1-6烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。另举一例,术语“C1-4卤代烷基”是指具有一或多个卤素取代基的C1-4烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代);术语“C1-3卤代烷基”是指具有一或多个卤素取代基的C1-3烷基基团(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代);且术语“C1-2卤代烷基”是指具有一或多个卤素取代基的C1-2烷基基团(即,甲基或乙基)(至多全卤代烷基,即,烷基基团的每个氢原子均被卤素原子所取代)。再另举一例,术语“C1卤代烷基”是指具有1、2或3个卤素取代基的甲基基团。卤代烷基基团的例子包括:CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl等。另外,术语“羟烷基”和“氨烷基”具有与“卤代烷基”类似的表示方式。
在本文中使用时,术语“Cn环烷基”是指具有含n个碳原子的环状烷基。
在本文中使用时,术语“n元杂环烷基”是指具有m个形成环的碳原子和(n-m)个形成环的杂原子的环烷基,所述杂原子选自O、S及N。例如,3-7元杂环烷基包括但不限于氧杂环丁烷、硫杂环丁烷、氮杂环丁烷、四氢呋喃、四氢噻吩、吡咯烷、四氢吡喃、四氢噻喃、哌啶、吗啉、哌嗪、氧杂环庚烷、硫杂环庚烷、氮杂环庚烷。杂环烷基可任选地被一或多个适当的取代基所取代。
在本文中使用时,术语“Cn芳基”是指具有含n个碳原子的芳环的芳基,优选为苯基。
在本文中使用时,术语“n元杂芳基”是指具有m个形成芳环的碳原子和(n-m)个形成芳环的杂原子的杂芳基,所述杂原子选自O、S及N。例如,5-6元杂芳基包括但不限于吡嗪、吡唑、吡咯、呋喃、噻吩、噻唑、吡啶。此外,杂芳基可任选地被一或多个适当的取代基所取代。
本文中,与取代基个数、碳原子个数、环原子个数相关的数目范围表示该范围内所有整数的逐个列举,而范围仅是作为一种简化的表示法。例如:“1-4个取代基”表示1、2、3或4个取代基;“3-8个环原子”表示3个、4个、5个、6个、7个或8个环原子。因此,与取代基个数、碳原子个数、环原子个数相关的数目范围也涵盖其任意一个子范围,且每一个子范围也视为被本文公开。
本申请化合物可按有机合成领域技术人员已知的多种方式制备。本领域技术人员可以参照本申请具体实施例的具体化合物的合成路线,对反应原料和反应条件进行适当调整而得到其它化合物的合成方法。
在第二方面,本申请提供了一种药物组合物,其包含式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,以及药学上可接受的载体。
药学上可接受的载体可以是有机或无机惰性载体材料,例如,合适的载体包括水、明胶、阿拉伯树胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇、凡士林、甘露醇、纤维素、纤维素衍生物、糖精钠、葡萄糖、蔗糖、碳酸镁、盐水、甘油、乙醇等。此外,药物组合物还可含有其他药物添加剂,例如调味剂、防腐剂、稳定剂、乳化剂、缓冲剂、稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂等。
本申请的药物组合物的剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、丸剂、栓剂、膜剂、贴片、气雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。本申请的药物组合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
在一些实施方式中,所述药物组合物的剂型选自片剂、颗粒剂、散剂、糖浆剂、吸入剂和注射剂。
用于口服的固体剂型可以包括胶囊、片剂、丸剂、粉末和颗粒。在这种固体剂型中,将活性化合物与至少一种惰性赋型剂(或载体)(例如,柠檬酸钠或磷酸二钙)混合,其中还可以包括:(a)填料或混合剂(例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸);(b)粘结剂(例如,羧基甲基纤维素、褐藻酸酯、凝胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯树胶);(c)保湿剂(例如,丙三醇);(d)崩解剂(例如,琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些合成的硅酸酯、碳酸钠);(e)溶液阻滞剂(例如,石蜡);(f)吸收促进剂(例如,季铵化合物);(g)润湿剂(例如,十六烷醇和单硬脂酸丙三醇酯);(h)吸附剂(例如,高岭土和斑脱土)和(i)润滑剂(例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠)或其混合物混合。
适于肠胃外施用的制剂例如注射剂可以包括适于注射的水性和非水性等渗无菌溶液,以及水性和非水性无菌混悬剂。本文提供的肠胃外制剂任选地包含在单位剂量或多剂量密封容器(例如安瓿)中,并且可以储存在仅需要于即将使用前添加无菌液体载体(例如注射用水)的冷冻干燥(冻干)条件下。用于重构药物组合物(例如在注射前)的合适稀释剂的实例包括抑菌性注射用水、5%葡萄糖水溶液、磷酸盐缓冲盐水、林格氏(Ringer's)溶液、盐水、无菌水、去离子水及其组合。
喷雾剂可含有赋形剂,如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉剂,或这些物质的混合物。喷雾剂可另外含有常规推进剂,例如氯氟烃和挥发性未经取代的烃,例如丁烷和丙烷。吸入剂可包含赋形剂如乳糖,或是包含如聚环氧乙烷-9-月桂基醚,甘氨胆酸盐和脱氧胆酸盐的含水溶液,或是油性溶液以鼻滴剂或喷雾,或凝胶形式施用。
本申请的化合物在其药物组合物中的含量可以根据实际需要(例如剂型、施用方式、施用对象等)进行调整,例如为0.1-95重量%,例如1-95重量%,5-90重量%,10-80重量%等。
具体地,本申请的药物组合物中可以特别地包含0.01-10g(例如0.05g、0.1g、0.5g、1g或5g等)的本申请的化合物。
在第三方面,本申请提供了式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物在制备用于在有需要的受试者中治疗或预防由RET或RET突变介导的疾病或病症的作为RET激酶抑制剂的药物中的用途。式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物可以用于在有需要的受试者中治疗或预防由RET或RET突变介导的疾病或病症。
本申请使用的术语“受试者”是指可潜在地从用式I化合物进行的治疗中受益的任何人类或非人类生物体。示例性受试者包括任何年龄的人类或哺乳动物。优选地,所述受试者是人。
本文使用的术语“治疗”包括在哺乳动物、尤其人类中治疗疾病或病症且包括:(a)抑制感染、疾病或病症,即遏制或延缓感染、疾病或病症的发展;(b)缓解感染、疾病或病症,即引起疾病或病症的消退,和/或(c)感染、疾病或病症的治愈。
本文使用的术语“预防”包括在哺乳动物、尤其人类中进行预防性疗法以旨在降低感染、疾病或病症发生的可能性。可以根据与一般群体相比感染或患有疾病或病症的风险增加为因素来选择接受预防性疗法的患者。“预防”可以包括对尚未呈现感染或临床病况的受试者进行处置,和预防相同或类似感染或临床病况的第二次出现。
在一些实施方式中,所述由RET或RET突变介导的疾病或病症可以选自癌症、代谢性疾病、炎症、疼痛、发育疾病中的一种或多种。在另一些实施方式中,所述由RET或RET突变介导的疾病或病症可以选自甲状腺癌、非小细胞肺癌、胸膜间皮瘤、结肠癌、胰腺癌、肺腺癌、乳腺癌、卵巢癌、II型多发性内分泌瘤、结直肠癌、慢性粒细胞白血病、唾液腺癌、宫颈癌、前列腺癌、糖尿病、肠易激综合征、肠易激综合征相关的疼痛、神经性疼痛、先天性巨结肠症中的一种或多种。
在第四方面,本申请提供了一种治疗或预防由RET或RET突变介导的疾病或病症的方法,所述方法包括向有需要的受试者施用治疗有效量的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物。
在一些实施方式中,本发明化合物可以通过口服、肠胃外、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、经肺、经呼吸道、经阴道、经直肠、腹膜内、病灶内、病灶周围等途径施用。
“治疗有效量”是指本申请化合物当单独或组合给药时有效治疗或预防由RET或RET突变介导的疾病或病症的量。
具体施用剂量将取决于施用途径、疾病的严重程度、患者的年龄和体重,以及主治医师在确定最适合特定患者的个体方案和剂量水平时通常考虑的其他因素。例如,本申请的化合物的日剂量可以特别地为0.001-150mg/kg体重(例如0.1mg/kg体重、1mg/kg体重、10mg/kg体重或100mg/kg体重等)。
具体的施用频率可以由相关领域的技术人员确定,例如为1天1次、2天1次、3天1次、4天1次、5天1次、6天1次、1天2次、1天3次等。
本领域技术人员能够理解,在本申请的一个方面中描述的定义和优选项同样适用于其他方面。本领域技术人员能够明了本申请各个方面的实施方式可以以各种方式组合,而不偏离本申请的主题和思想,这些组合也包括在本申请的范围内。
具体实施方式
本申请式I化合物可以用有机合成领域的技术人员所熟悉的多种方法合成。以下具体实施例中给出了一些示例性的式I化合物的合成方法,这些方法是合成化学领域所公知的。显然,参照本专利中的示例性方案,本领域技术人员可以适当调整反应物、反应条件和保护基团而容易地设计其他式I化合物的合成路线。
下面进一步结合实施例来阐述本发明;但这些实施例并不限制本发明的范围。除非另有声明,各实施例中所用的所有反应物均从商业途径获得;合成实验和产物分析检测中所用仪器设备等均为有机合成中通常使用的常规仪器和设备。
在以下实施例中,本发明的示例性化合物的结构通过核磁共振(NMR)和/或液质联用色谱(LC-MS)来确定。NMR化学位移(δ)以百万分之一(ppm)的单位给出。NMR的测定是用BrukerAVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代甲醇(CD3OD)和氘代氯仿(CDCl3),内标为四甲基硅烷(TMS)。
液质联用色谱LC-MS的测定用Agilent 1200Infinity Series质谱仪。HPLC的测定使用安捷伦1200DAD高压液相色谱仪。薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。另外,在无特殊说明的情况下,本发明的所有反应均在连续的磁力搅拌下,在干燥氮气或氩气氛下进行,溶剂为干燥溶剂,反应温度单位为摄氏度。
此外,实施例中使用的缩略语具有如下所示含义:
Pd(dppf)Cl2:1,1'-二(二苯膦基)二茂铁二氯化钯(II);Na2CO3:碳酸钠;NaOH:氢氧化钠;BOC:叔丁氧羰基;EA:乙酸乙酯;PE:石油醚;MeOH:甲醇;EtOH:乙醇;DIEA:N,N-二异丙基乙胺;DMSO:二甲基亚砜;TEA:三乙胺;DMAP:4-二甲氨基吡啶;Dioxane:二氧六环;DMF:N,N-二甲基甲酰胺;NMP:N-甲基吡咯烷酮;THF:四氢呋喃;DCM:二氯甲烷;TFA:三氟乙酸;TLC:薄层色谱法;Structure:结构式。
实施例1:4-(6-(4-(烯丙基磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈的合成(I-1)
步骤A:4-(5-(5-氰基-7H-吡咯[2,3-d]嘧啶-4-基吡啶-2-基)哌嗪-1-甲酸叔丁基(3)
氮气保护下,向4-氯-7H-吡咯[2,3-d]嘧啶-5-甲氰(化合物1,1g,5.62mmol)的二氧六环(15mL)和水(3mL)的混合溶液中加入4-(5-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(化合物2,2.80g,7.30mmol),碳酸钠(1.80g,16.85mmol)和1,1'-二(二苯膦基)二茂铁二氯化钯(II)(230mg),将该反应混合体系加热至80℃左右反应大约2小时,TLC检测反应完成后,将反应液倾倒入水中并过滤,水相用乙酸乙酯提取并干燥,浓缩,柱层析纯化得到黄色国体化合物4-(5-(5-氰基-7H-吡咯[2,3-d]嘧啶-4-基吡啶-2-基)哌嗪-1-甲酸叔丁基(化合物3,1g,43.86%)。
LC-MS(m/z):406[M+H]+
1H NMR(400MHz,CDCl3)δ11.91(s,1H),9.05(s,1H),8.91(d,J=2Hz,1H),8.20(m,1H),8.01(d,J=16.4Hz,1H),6.82(d,J=8.8Hz,1H),3.74(m,4H),3.60(m,4H),1.52(s,9H).
步骤B:4-(6-(哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(4)
室温下,向化合物3(1g,2.5mmol)的二氯甲烷(10mL)溶液中加入三氟乙酸(4.30g,37.50mmol),将该反应混合物在室温下继续搅拌16小时,TLC检测反应完成后,将反应混合物浓缩至干,向残余物中加入二氯甲烷(20mL)和饱和碳酸钠的水溶液(10mL),分出有机相并用饱和食盐水洗涤,无水硫酸钠干燥,浓缩有机相,再次向残余物中加入甲基叔丁基醚(12mL)打浆,过滤得到黄色固体4-(6-(哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(化合物4,1g,100%)
LC-MS(m/z):306[M+H]+
1H NMR(400MHz,DMSO-d6)δ13.39(s,1H),8.96(s,1H),8.87(s,1H),8.79(s,1H),8.75(d,J=2Hz,1H),8.18(m,1H),7.13(d,J=8.8Hz,1H),3.87(m,4H),3.22(m,4H).
步骤C:4-(6-(4-(烯丙基磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-1)
室温下,向化合物4(40mg,0.13mmol)的二氯甲烷溶液中加入烯丙基磺酰氯(18.4mg,0.13mmol)和三乙胺(66mg,0.66mmol),将该反应混合物在室温下搅拌1小时,反应完成后,将反应混合物倾倒至水中,并用二氯甲烷提取水相,将有机相用无水硫酸钠干燥,过滤并浓缩至干得到粗品,制备色谱分离得产品I-1。
LC-MS(m/z):410[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.94(s,1H),8.82(d,J=2.4Hz,1H),8.15(dd,J=9.2Hz,2.4Hz,1H),7.99(s,1H),6.86(d,J=8.8Hz,1H),5.97-5.90(m,1H),5.47-5.42(m,2H),3.82-3.78(m,4H),3.49-3.39(m,4H).
实施例2:4-(6-(4-((3-氟-4-甲氧基苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-2)
以化合物4和3-氟-4-甲氧基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-2。
LC-MS(m/z):494[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.86(s,1H),8.69(s,1H),8.06(s,2H),7.56-7.49(m,2H),7.14(d,J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),4.01(s,3H),3.95(s,4H),3.36-3.32(m,4H).
实施例3:4-(6-(4-((3,4-二甲氧基苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-3)
以化合物4和3,4-二甲氧基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-3。
LC-MS(m/z):506[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.86(s,1H),8.72(d,J=2.4Hz,1H),8.05(dd,J=8.8Hz,2.4Hz,1H),7.93(s,1H),7.37-7.34(m,1H),7.19(s,1H),6.95(d,J=8.4Hz,1H),6.74(d,J=8.8Hz,1H),3.90-3.88(m,6H),3.79-3.78(m,4H),3.38-3.34(m,4H).
实施例4:4-(6-(4-((2-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-4)
以化合物4和2-氟苯磺酰氯为原料,参照实施例1步骤C合成化合物I-4。
LC-MS(m/z):464[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.89(s,1H),8.75(d,J=2.4Hz,1H),8.08(dd,J=9.2Hz,2.4Hz,1H),7.93(s,1H),7.86-7.82(m,1H),7.60-7.56(m,1H),7.31-7.20(m,2H),6.77(d,J=8.8Hz,1H),3.81-3.79(m,4H),3.37-3.20(m,4H).
实施例5:4-(6-(4-((3-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-5)
以化合物4和3-氟-苯磺酰氯为原料,参照实施例1步骤C合成化合物I-5。
LC-MS(m/z):464[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.91(s,1H),8.74(s,1H),8.10(d,J=8.8Hz,1H),8.06(s,1H),7.61(s,2H),7.52-7.50(m,1H),7.39-7.37(m,1H),6.84(d,J=9.2Hz,1H),3.85(s,4H),3.19(s,4H).
实施例6:4-(6-(4-((3-氯苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-6)
以化合物4和3-氯苯磺酰氯为原料,参照实施例1步骤C合成化合物I-6。
LC-MS(m/z):480[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.87-8.83(m,1H),8.72-8.69(m,1H),8.06-8.02(m,1H),7.95-7.92(m,1H),7.74-7.70(m,1H),7.61-7.60(m,1H),7.55-7.53(m,1H),7.49-7.33(m,1H),7.31-7.29(m,1H),6.76-6.71(m,1H),3.77(d,J=4.4Hz,4H),3.11(d,J=4.8Hz,4H).
实施例7:4-(6-(4-((4-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-7)
以化合物4和4-氟苯磺酰氯为原料,参照实施例1步骤C合成化合物I-7。
LC-MS(m/z):464[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.92(d,J=8.8Hz,1H),8.75(d,J=7.2Hz,1H),8.14-8.09(m,2H),7.86-7.83(m,2H),7.34-7.28(m,2H),6.87(t,J=8.4Hz,1H),4.08-4.06(m,4H),3.39-3.33(m,4H).
实施例8:4-(6-(4-((2-氯-4-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-8)
以化合物4和2-氯-4-氟苯磺酰氯为原料,参照实施例1步骤C合成化合物I-8。
LC-MS(m/z):498[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.68(d,J=9.2Hz,1H),8.51(t,J=6.0Hz,1H),7.90-7.86(m,3H),7.15-7.11(m,1H),7.00-6.83(m,1H),6.68-6.64(m,1H),3.59(s,4H),3.21(s,4H).
实施例9:4-(6-(4-((3-氯-2-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-9)
以化合物4和2-氟-3-氯苯磺酰氯为原料,参照实施例1步骤C合成化合物I-9。
LC-MS(m/z):498[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.91(s,1H),8.74(d,J=14.4Hz,1H),8.33-8.11(m,1H),7.82-7.73(m,3H),7.36-7.32(m,1H),6.90(d,J=8.4Hz,1H),3.87-3.84(m,4H),3.39-3.17(m,4H).
实施例10:4-(6-(4-((4-(三氟甲氧基)苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-10)
以化合物4和4-三氟甲氧基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-10。
LC-MS(m/z):530[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.83(t,J=7.6Hz,1H),8.67(t,J=6.0Hz,1H),8.04-8.00(m,1H),7.94(s,1H),7.78-7.76(m,2H),7.34-7.28(m,2H),6.72(d,J=9.2Hz,1H),3.39-3.29(m,4H),3.11-3.10(m,4H).
实施例11:4-(6-(4-((4-氰基苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-11)
以化合物4和4-氰基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-11。
LC-MS(m/z):471[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.91(s,1H),8.74(d,J=2.0Hz,1H),8.09(t,J=6.4Hz,1H),8.03(s,1H),7.95-7.89(m,4H),6.82(d,J=8.8Hz,1H),3.86-3.84(m,4H),3.21-3.18(m,4H).
实施例12:4-(6-(4-((4-氯苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-12)
以化合物4和4-氯苯磺酰氯为原料,参照实施例1步骤C合成化合物I-12。
LC-MS(m/z):480[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.87(s,1H),8.73(d,J=1.6Hz,1H),8.07(t,J=2.4Hz,1H),7.93(s,1H),7.73-7.68(m,2H),7.54-7.49(m,2H),6.74(d,J=9.2Hz,1H),3.81-3.64(m,4H),3.12-3.10(m,4H).
实施例13:4-(6-(4-((2,4-二氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-13)
以化合物4和2,4-二氟苯磺酰氯为原料,参照实施例1步骤C合成化合物I-13。
LC-MS(m/z):482[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.95(s,1H),8.78(s,1H),8.19-8.17(m,2H),7.97-7.96(m,1H),7.17(s,2H),6.97-6.95(m,1H),3.89-3.84(m,4H),3.39-3.27(m,4H).
实施例14:4-(6-(4-((2,5-二氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-14)
以化合物4和2,5-二氟苯磺酰氯为原料,参照实施例1步骤C合成化合物I-14。
LC-MS(m/z):482[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.90-8.87(m,1H),8.73-8.72(m,1H),8.07-8.05(m,1H),7.95-7.93(m,1H),7.73-7.68(m,2H),7.54-7.31(m,2H),6.74(d,J=9.2Hz,1H),3.81-3.64(m,4H),3.12-3.05(m,4H).
实施例15:4-(6-(4-((4-(三氟甲基)苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-15)
以化合物4和4-三氟甲基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-15。
LC-MS(m/z):514[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.90(s,1H),8.72(s,1H),7.99(s,2H),7.97-7.88(m,2H),7.60(s,2H),6.93-6.84(m,1H),3.85(s,4H),3.21(s,4H).
实施例16:4-(6-(4-(噻吩-2-基-磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-16)
以化合物4和2-噻吩-磺酰氯为原料,参照实施例1步骤C合成化合物I-16。
LC-MS(m/z):452[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.87-8.85(m,1H),8.73-8.71(m,1H),8.05(t,J=8.4Hz,1H),7.95-7.92(m,1H),7.62(t,J=5.6Hz,1H),7.53(t,J=6.8Hz,1H),7.13-7.12(m,1H),6.76(t,J=10.4Hz,1H),3.80-3.79(m,4H),3.25-3.14(m,4H).
实施例17:4-(6-(4-((1-甲基-1H-吡唑-4-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-17)
以化合物4和1-甲基-1H-吡唑-4-磺酰氯为原料,参照实施例1步骤C合成化合物I-17。
LC-MS(m/z):450[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.79(s,1H),8.71(s,1H),8.11-8.07(m,2H),7.94(s,1H),7.73(s,1H),6.84(d,J=9.2Hz,1H),3.96(s,3H),3.84-3.81(m,4H),3.12-3.09(m,4H).
实施例18:4-(6-(4-(吡啶-3-基-磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-18)
以化合物4和吡啶-3-磺酰氯为原料,参照实施例1步骤C合成化合物I-18。
LC-MS(m/z):447[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.94(s,1H),8.85(s,1H),8.77(t,J=3.2Hz,1H),8.70(s,1H),8.07-8.02(m,2H),7.93(s,1H),7.53-7.28(m,1H),6.74(d,J=9.2Hz,1H),3.79-3.75(m,4H),3.19-3.15(m,4H).
实施例19:4-(6-(4-(环丙烷基磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-19)
以化合物4和环丙烷磺酰氯为原料,参照实施例1步骤C合成化合物I-19。
LC-MS(m/z):410[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.94-8.93(m,1H),8.79(s,1H),8.19-8.16(m,2H),7.00-6.97(m,1H),3.88(s,4H),3.48-3.36(m,4H),2.46-2.44(m,1H),1.34-1.30(m,2H),1.20-1.10(m,2H),
实施例20:4-(6-(4-(间甲基苯基-磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-20)
以化合物4和3-甲基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-20。
LC-MS(m/z):460[M+H]+
1H NMR(400MHz,CDCl3)δ9.00(s,1H),8.83(d,J=2.4Hz,1H),8.14(dd,J=8.8Hz,2.4Hz,1H),7.96(s,1H),7.60(d,J=4.8Hz,2H),7.44(d,J=6.8Hz,2H),6.76(d,J=8.8Hz,1H),3.86(t,J=4.8Hz,4H),3.16(t,J=5.2Hz,4H),2.46(s,3H).
实施例21:4-(6-(4-(异丙基磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-21)
以化合物4和异丙基磺酰氯为原料,参照实施例1步骤C合成化合物I-21。
LC-MS(m/z):412[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.94(s,1H),8.81(s,1H),8.15(s,1H),8.07(s,1H),6.90(s,1H),3.82-3.68(m,4H),3.53(s,1H),3.45-3.29(m,4H),1.41-1.22(m,6H).
实施例22:4-(6-(4-((2,3-苯丙二氢呋喃-5-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-22)
以化合物4和2,3-二氢苯并呋喃-5-磺酰氯为原料,参照实施例1步骤C合成化合物I-22。
LC-MS(m/z):488[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.87(s,1H),8.70(d,J=2.4Hz,1H),8.08-8.05(m,2H),7.58-7.54(m,2H),6.88-6.80(m,2H),4.68(t,J=8.8Hz,2H),3.81(t,J=4.8Hz,4H),3.38-3.27(m,2H),3.10(t,J=5.2Hz,4H).
实施例23:4-(6-(4-(吗啉磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-23)
以化合物4和4-吗啉磺酰氯为原料,参照实施例1步骤C合成化合物I-23。
LC-MS(m/z):455[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.89(s,1H),8.77(d,J=2.4Hz,1H),8.10(dd,J=8.8Hz,2.4Hz,1H),7.94(s,1H),6.81(d,J=9.2Hz,1H),7.77-3.69(m,8H),3.39-3.32(m,4H),3.35-3.22(m,4H).
实施例24:4-(6-(4-(丙基磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-24)
以化合物4和1-丙基磺酰氯为原料,参照实施例1步骤C合成化合物I-24。
LC-MS(m/z):412[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.95-8.92(m,1H),8.80-8.78(m,1H),8.18-8.19(m,2H),6.97-6.88(m,1H),4.47-4.41(m,4H),3.86-3.71(m,2H),3.78-3.25(m,2H),2.04-1.91(m,2H),1.25-1.13(m,3H),0.91-0.88(m,2H).
实施例25:4-(6-(4-((6-氯吡啶-3-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-25)
以化合物4和6-氯吡啶-3-磺酰氯为原料,参照实施例1步骤C合成化合物I-25。
LC-MS(m/z):481[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.78(s,1H),8.63(dd,J=12.8Hz,2.4Hz,2H),7.99-7.93(m,2H),7.90(s,1H),7.46(d,J=8.8Hz,1H),6.70(d,J=8.8Hz,1H),3.73(t,J=5.2Hz,4H),3.11-3.04(m,4H).
实施例26:4-(6-(4-((3-(三氟甲基)苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-26)
以化合物4和3-三氟甲基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-26。
LC-MS(m/z):514[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.94(s,1H),8.76(s,2H),8.14-8.06(m,4H),7.99-7.98(m,1H),7.86-7.84(m,1H),6.91(d,J=8.8Hz,1H),4.18(s,4H),3.24(s,4H).
实施例27:4-(6-(4-((2-氟-4-甲基苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-27)
以化合物4和2-氟-4-甲基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-27。
LC-MS(m/z):478[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.88(s,1H),8.73(s,1H),8.08-8.05(m,1H),7.93(s,1H),7.67(t,J=7.2Hz,1H),7.08-6.99(m,2H),6.76-6.75(m,1H),3.79(s,4H),3.36-3.33(m,4H),2.60(s,3H).
实施例28:4-(6-(4-(哌啶-1-基-磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-28)
以化合物4和哌啶-1-磺酰氯为原料,参照实施例1步骤C合成化合物I-28。
LC-MS(m/z):453[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.95(s,1H),8.82(s,1H),8.18-8.16(m,1H),8.08(s,1H),6.91(d,J=8.4Hz,1H),3.82-3.65(m,6H),3.39(s,7H),1.68-1.63(m,5H).
实施例29:4-(6-(4-((3-氯-4-甲基苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-29)
以化合物4和3-氯-4-甲基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-29。
LC-MS(m/z):494[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.92(s,1H),8.73(s,1H),8.14-8.10(m,2H),7.78(s,1H),7.62-7.58(m,1H),7.51-7.49(m,1H),6.89(d,J=8.8Hz,1H),3.86-3.81(m,4H),3.18-3.12(m,4H),2.44(s,3H).
实施例30:4-(6-(4-((5-氯噻吩-2-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-30)
以化合物4和5-氯噻吩-2-磺酰氯为原料,参照实施例1步骤C合成化合物I-30。
LC-MS(m/z):486[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.89(s,1H),8.72(d,J=2.0Hz,1H),8.11-8.09(m,2H),7.54(s,1H),7.06(d,J=4.0Hz,1H),6.88(d,J=9.2Hz,1H),3.86(t,J=4.8Hz,4H),3.21(t,J=4.8Hz,4H).
实施例31:4-(6-(4-((4-甲氧基苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-31)
以化合物4和4-甲氧基苯磺酰氯为原料,参照实施例1步骤C合成化合物I-31。
LC-MS(m/z):476[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.81(s,1H),8.65(d,J=2.4Hz,1H),8.01-7.98(m,1H),7.64(s,1H),7.61-7.59(m,2H),7.20-6.95(m,2H),6.70(d,J=8.8Hz,1H),3.78-3.51(m,4H),3.49-3.40(m,3H),3.39-3.22(m,4H).
实施例32:4-(6-(4-((3-氯-4-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-32)
以化合物4和3-氯-4-氟苯磺酰氯为原料,参照实施例1步骤C合成化合物I-32。
LC-MS(m/z):498[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.93(s,1H),8.76(s,1H),8.12(dd,J=8.8Hz,2.0Hz,1H),8.08(s,1H),7.90(d,J=5.2Hz,1H),7.76-7.73(m,1H),7.41(t,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),3.87(t,J=4.8Hz,4H),3.21(t,J=4.4Hz,4H),
实施例33:4-(6-(4-((1H-吡唑-4-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-33)
以化合物4和1H-吡唑-4-磺酰氯为原料,参照实施例1步骤C合成化合物I-33。
LC-MS(m/z):436[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.89(s,2H),8.71(s,1H),8.20(s,1H),8.13-8.10(m,1H),6.94(d,J=8.8Hz,2H),3.87-3.85(m,4H),3.24-3.18(m,4H).
实施例34:4-(6-(4-((3,5-氟苯基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-34)
以化合物4和3,5-二氟苯基甲基磺酰氯为原料,参照实施例1步骤C合成化合物I-34。
LC-MS(m/z):496[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.96(s,1H),8.82(s,1H),8.18-8.15(m,1H),8.09(s,1H),7.46(s,1H),7.06-6.89(m,3H),4.30(s,2H),3.84-3.79(m,4H),3.39(s,4H).
实施例35:4-(6-(4-((5-甲基异唑-4-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-35)
以化合物4和5-甲基-4-异噁唑磺酰氯为原料,参照实施例1步骤C合成化合物I-35。
LC-MS(m/z):451[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.94(s,1H),8.77-8.76(m,1H),8.19(dd,J=8.8Hz,2.0Hz,1H),8.09(s,1H),6.96(d,J=9.2Hz,1H),3.88-3.87(m,4H),3.11-3.47(s,4H),2.67(s,3H).
实施例36:4-(6-(4-((6-甲氧基吡啶-3-基)磺酰基)哌嗪-1-基)吡啶-3-基)-7H-吡咯[2,3-d]嘧啶-5-甲腈(I-36)
以化合物4和6-甲氧基吡啶-3-磺酰氯为原料,参照实施例1步骤C合成化合物I-36。
LC-MS(m/z):477[M+H]+
1H NMR(400MHz,CDCl3&CD3OD)δ8.93(s,1H),8.76(s,1H),8.61(s,1H),8.12-8.10(m,2H),8.97-8.96(m,1H),6.95-6.87(m,2H),4.04(s,3H),3.88-3.84(m,4H),3.38-3.29(m,4H).
生物学评价
以下结合测试例进一步描述解释本公开的内容,但这些测试例并非意味着限制本公开的范围。
测试例1:化合物对RETWT的体外激酶学活性测试
化合物配制:将化合物溶解在100%DMSO中,配制成10mM储存液,-20℃冻存,在配置10mM的DMSO溶液时,化合物超声30min后变清澈;
激酶反应过程:(1)配制1×Kinase buffer。(2)化合物浓度梯度的配制:受试化合物测试起始浓度为0.1μM,在384source板中稀释成100倍终浓度的100%DMSO溶液,用Precision 3倍稀释化合物,10个浓度。使用分液器Echo550向目的板OptiPlate-384F转移250nL 100倍终浓度的化合物。阳性和阴性对照孔加入250nL DMSO。(3)用1×Kinasebuffer配制2.5倍终浓度的激酶溶液。(4)在化合物孔和阳性对照孔分别加10μL的2.5倍终浓度的激酶溶液;在阴性对照孔中加10μL的1×Kinase buffer。(5)1000rpm离心30秒,反应板振荡混匀后室温孵育10分钟。(6)用1×Kinase buffer配制5/3倍终浓度的ATP和Kinasesubstrate的混合溶液。(7)加入15μL的5/3倍终浓度的ATP和底物的混合溶液,起始反应。(8)将384孔板1000rpm离心30秒,振荡混匀后室温孵育相应的时间。(9)加入30μL终止检测液停止激酶反应,1000rpm离心30秒,振荡混匀。(10)用Caliper EZ Reader读取转化率。测试结果如下表1所示。
表1:示例性化合物的活性结果
以上详细描述了本发明的优选实施方式,但是,本发明并不限于上述实施方式中的具体细节,在本发明的技术构思范围内,可以对本发明的技术方案进行多种简单变型,这些简单变型均属于本发明的保护范围。
另外需要说明的是,在上述具体实施方式中所描述的各个具体技术特征,在不矛盾的情况下,可以通过任何合适的方式进行组合,为了避免不必要的重复,本发明对各种可能的组合方式不再另行说明。
此外,本发明的各种不同的实施方式之间也可以进行任意组合,只要其不违背本发明的思想,其同样应当视为本发明所公开的内容。
Claims (11)
1.式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,
其中,
R1选自C1-C6烷基、C2-C6烯基、C2-C6炔基、苄基、C3-C10环烷基、3-10元杂环烷基、C5-C10芳基或5-10元杂芳基,并且所述C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C10环烷基、3-10元杂环烷基、C5-C10芳基或5-10元杂芳基中的一个或多个氢原子任选地被卤素、-CN、-NO2、-NRaRb、-OH、C1-C3烷基、C1-C3烷氧基、C1-C3羟烷基、C1-C3卤代烷基、C1-C3卤代烷氧基或-(C=O)NRaRb取代;
Ra和Rb各自独立地选自H、卤素、C1-C3烷基或C1-C3环烷基,或者Ra和Rb与其所连接的N原子一起形成3-10元杂环烷基。
2.根据权利要求1所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,其中,
所述同位素标记化合物是式I化合物中的一个或多个氢原子被氘取代的氘标记化合物。
3.根据权利要求1所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,其中,
Ra和Rb各自独立地选自H、卤素、甲基、乙基、丙基或环丙基,或者Ra和Rb与其所连接的N原子一起形成3-10元杂环烷基,其中所述3-10元杂环烷基任选地包含除所述连接N原子外的一个或多个N、O或S原子。
4.根据权利要求1所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,其中,
所述卤素各自独立地选自F、Cl、Br或I;
所述烷基各自独立地选自甲基、乙基、正丙基或异丙基;
所述烯基各自独立地选自乙烯、丙烯、1-丁烯或2-丁烯;
所述炔基各自独立地选自乙炔、丙炔、1-丁炔或2-丁炔;
所述烷氧基各自独立地选自甲氧基、乙氧基、丙氧基、异丙氧基、环丙氧基;
所述环烷基各自独立地选自单环基,例如环丙基、环丁基、环戊基或环己基,或螺环基,例如螺[2.4]庚烷基;
所述杂环烷基各自独立选自包含一个或多个N、O或S原子的环丙基、环丁基、环戊基或环己基,或螺环基,例如2-氧杂-6-氮杂螺[3.3]庚烷基;
所述芳基各自独立地选自单环基,例如苯基;或双环基,例如萘基;
所述杂芳基各自独立地选自单环基,例如吡嗪、吡唑、吡咯、呋喃、噻吩、噻唑或吡啶;或双环基,例如吡咯并吡啶基、吡咯并吡唑基、苯并吡唑基或苯并吡咯基;
所述羟烷基各自独立地选自羟甲基、羟乙基或羟丙基;
所述卤代烷基各自独立地选自一氟甲基、二氟甲基、三氟甲基、一氯甲基、二氯甲基或三氯甲基;
所述卤代烷氧基各自独立地选自一氟甲氧基、二氟甲氧基、三氟甲氧基、一氯甲氧基、二氯甲氧基或三氯甲氧基。
5.根据权利要求1所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,其中R1选自以下结构中的一种:
6.根据权利要求1-5中任一项所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,其具有以下结构中的一种:
7.一种药物组合物,其包含根据权利要求1-6中任一项所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物,以及药学上可接受的载体。
8.根据权利要求7所述的药物组合物,其剂型选自片剂、颗粒剂、散剂、糖浆剂、吸入剂和注射剂。
9.根据权利要求1-6中任一项所述的式I化合物或其同位素标记化合物、或其光学异构体、几何异构体、互变异构体或异构体混合物、或其药学上可接受的盐、或其前体药、或其代谢物在制备作为RET激酶抑制剂的药物中的用途,所述药物用于在有需要的受试者中治疗或预防由RET或RET突变介导的疾病或病症。
10.根据权利要求9所述的用途,其中所述由RET或RET突变介导的疾病或病症选自癌症、代谢性疾病、炎症、疼痛、发育疾病中的一种或多种。
11.根据权利要求9所述的用途,其中所述由RET或RET突变介导的疾病或病症选自甲状腺癌、非小细胞肺癌、胸膜间皮瘤、结肠癌、胰腺癌、肺腺癌、乳腺癌、卵巢癌、II型多发性内分泌瘤、结直肠癌、慢性粒细胞白血病、唾液腺癌、宫颈癌、前列腺癌、糖尿病、肠易激综合征、肠易激综合征相关的疼痛、神经性疼痛、先天性巨结肠症中的一种或多种。
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