CN114805371B - 含2-氨基嘧啶大环类化合物及其制备方法和用途 - Google Patents
含2-氨基嘧啶大环类化合物及其制备方法和用途 Download PDFInfo
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- CN114805371B CN114805371B CN202110066377.7A CN202110066377A CN114805371B CN 114805371 B CN114805371 B CN 114805371B CN 202110066377 A CN202110066377 A CN 202110066377A CN 114805371 B CN114805371 B CN 114805371B
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Abstract
本发明涉及一种新颖的化合物及其盐,包含所述化合物的药物化合物、制备方法,以及所述化合物的制药用途。具体涉及一种含2‑氨基嘧啶大环类化合物及其制备方法和用途:
Description
技术领域
本发明涉及一种新颖的化合物及其盐,包含所述化合物的药物化合物、制备方法,以及所述化合物的制药用途。具体涉及一种含2-氨基嘧啶大环类化合物及其制备方法和用途,这类化合物能够作为受体酪氨酸激酶抑制剂,尤其是作为ALK激酶抑制剂。
背景技术
蛋白受体酪氨酸激酶(RTKs,receptor tyrosine kinases)在细胞信号转导通路中发挥着重要作用,它将细胞外的信号传递到细胞内,并经过向下游的传导调控肿瘤细胞的增殖、分化、生长及凋亡等生理活动。RTKs与肿瘤的发生发展密切相关,因此,其家族成员已成为抗肿瘤药物研发的主流靶标。
间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)是一种受体酪氨酸激酶,该蛋白属于胰岛素受体超家族,能和多种基因融合,一旦融合后能提高ALK表达水平,激活ALK和异常活化下游磷脂酰肌醇3激酶蛋白激酶B信号传导通路,引起肿瘤细胞生长、增殖、抗凋亡,如系统性组织异常增生、炎性肌纤维细胞癌、非小细胞肺癌等。约3-7%非小细胞肺癌(NSCLC)患者体内肿瘤染色体EML4基因外显子与ALK基因外显子融合,形成EML4-ALK融合酪氨酸激酶,EML4-ALK融合变异体具有高度的致癌性,且ALK在多种肿瘤细胞中高表达。ALK在多种癌症中的突变和异常的活性,已经使其成为一个治疗ALK阳性癌症的药物靶点。
目前,已有多个ALK激酶抑制剂上市或进入临床试验用于治疗ALK阳性的非小细胞肺癌。2010年,辉瑞制药开发的克唑替尼(Crizotinib)被FDA批准用于治疗ALK阳性的非小细胞肺癌,成为第一个上市的ALK激酶抑制剂。克唑替尼彻底改变了携带ALK染色体重组的晚期非小细胞肺癌(NSCLC)患者的治疗。但大部分患者在治疗后的12个月内对克唑替尼产生耐药性,并发生获得性耐药突变,在发生中枢神经系统转移的患者中的疗效更是十分有限。随后催生了对克唑替尼耐药的NSCLC的第二代ALK抑制剂的快速发展,在2014年诺华制药开发的色瑞替尼(Ceritinib)被FDA批准用于ALK阳性的、癌细胞转移的以及使用克唑替尼后复发的非小细胞肺癌患者。虽然第二代ALK抑制剂对发生中枢神经系统转移的克唑替尼耐药的患者显示了治疗活性,但是顽固的肿瘤很快就对这些新抑制剂产生了耐药性。面对克唑替尼及第二代ALK抑制剂的耐药,以及耐药后的无药可用,辉瑞的科学家们开发了第三代ALK抑制剂,即可用于对克唑替尼及第二代ALK抑制剂耐药的、发生中枢神经系统转移的NSCLC患者仍有疗效的药物劳拉替尼(Lorlatinib)。大环类抑制剂劳拉替尼(Lorlatinib)能够保留分子量大小、保留较好亲脂性效率LipE,并可以实现很好的构象限制,同时,进一步降低化合物被外排的性质,提升脑内游离药物浓度。
由于ALK在肿瘤的发生和发展过程中起着关键性的作用,开发新的具有高抑制活性和优异药代动力学性质的新型大环类ALK激酶抑制剂已成为开发新型抗肿瘤药物的关键。
发明内容
本发明的第一目的在于提供一种如通式I的含2-氨基嘧啶大环类化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物:
其中,
X选自C或N;
Z和W不相同,各自独立地选自C、N;
虚线表示可以与碳链形成单键或双键;其中碳链为式I化合物环内所述的碳碳单键;
R1选自氢、卤素、烷基、-CONR7R8、-CONR7(CH2)nNR8、-CONR7(CH2)nOR8、-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8、-CR7R8、芳基或Het,其中n=1、2、3、4或5,R7、R8各自独立地表示氢、氘、烷基、芳基或Het;
R2选自氢、卤素、羟基、烷氧基、烷基、芳基或Het;
R3选自氢、卤素、羟基、烷氧基、烷基、芳基、Het或-YR9;
R4选自氢、卤素、羟基、烷氧基、烷基、芳基、Het或-YR9;
其中Y选自-CR5R6-、-SO2-或-CO-,其中R5、R6各自独立地表示氢、氘、卤素、烷基、芳基或Het;R9选自烷基、芳基或Het;
烷基为具有1-6个碳原子的直链或支链饱和烃基;或为具有3-6个碳原子的环状饱和烃基;或为连接具有1-6个碳原子的直链或支链饱和烃基的具有3-6个碳原子的环状饱和烃基;
芳基为选自苯基、萘基、苊基或四氢萘基的碳环,其各自任选被1、2或3个取代基取代,各取代基独立地选自氢、烷基、氰基、卤素、硝基、卤代烷基、羟基、巯基、烷氧基、烷硫基、烷氧基烷基、芳烷基、二芳基烷基、芳基或Het;
Het为选自哌啶基、吡咯基、吡唑基、咪唑基、呋喃基、噻吩基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、嘧啶基、吡嗪基或哒嗪基的单环杂环;或选自喹啉基、喹喔啉基、吲哚基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并呋喃基、苯并噻吩基、2,3-二氢苯并[1,4]二氧杂环己烯基或苯并[1,3]二氧杂环戊烯基的双环杂环;各单环或双环杂环任选被1、2或3个取代基取代,各取代基独立选自卤素、卤代烷基、羟基、烷基或烷氧基;
卤素为选自氟、氯、溴或碘的取代基。
进一步地,式I中,
R1、R2、R3、R4、R9、X、Y如通式I中的定义。
在某些优选的实施方式中,
X选自C或N;
Y选自-CR5R6-、-SO2-或-CO-,其中R5、R6各自独立地表示氢、烷基;
R1选自氢、卤素、烷基、-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8、-CR7R8、芳基或Het,其中n=1、2、3、4或5,R7、R8各自独立地表示氢、氘、烷基、芳基或Het;
R2、R3、R4各自独立地选自氢、卤素、羟基、烷氧基、烷基、芳基或Het;
R9选自烷基、芳基或Het。
在某些更优选的实施方式中,
X选自C或N;
Y选自-SO2-或-CR5R6-;
R1选自-NR7COR8、-NR7R8、-NR7(CH2)nNR8、-NR7(CH2)nOR8,其中n=1、2、3、4或5,R7、R8各自独立地表示氢、氘、烷基、芳基或Het;
R2、R3、R4各自独立地选自氢、卤素、羟基、烷氧基、烷基。
在某些更优选的实施方式中,
X选自C或N;
Y选自-SO2-或-CHR5-;
R1选自-NR7R8、-NR7(CH2)nNR8,其中n=1、2、3、4或5,R7、R8各自独立地表示氢、氘、烷基、芳基或Het;
R2、R3、R4各自独立地选自氢、卤素、羟基、烷氧基、烷基。
在某些更优选的实施方式中,
X选自C;
Y选自-SO2-、-CHCH3-或-CH2-;
R1选自-NR7R8、-NR7(CH2)nNR8,其中n=1、2、3、4或5,R7、R8各自独立地表示氢、烷基;
R2、R3、R4各自独立地选自氢、卤素、烷氧基、烷基。
在一些优选的实施方式中,所述药学上可接受的盐包括但不限于通式I化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸;还包括通式I化合物与无机碱形成的酸式盐。
在一些更优选的实施方式中,所述药学上可接受的盐包括但不限于碱性金属阳离子盐、碱土金属阳离子盐和铵阳离子盐。
本发明通式I的化合物优选以下化合物:
本发明涉及的上述通式I化合物还可以以其盐、水合物、溶剂合物的形式存在,它们在体内转化为通式I化合物。例如,在本发明的范围内,按照本领域已知的工艺,将本发明化合物转化为药学上可接受的盐的形式,并且以盐形式使用它们。
本发明的某些化合物可以以多晶或无定形形式存在。
本发明通式I化合物的所有的互变异构形式均包括在本发明的范围之内。本发明的化合物可以存在特定的几何或立体异构体形式。烷基等取代基中可存在另外的不对称碳原子,所有这些异构体以及它们的混合物,均包括在本发明的范围之内。
本发明中使用的“前药”是指当给予哺乳动物患者时释放活性母体药物的任何共价结合的载体。可通过常规操作或在体内,按可分解为母体化合物的修饰方式,修饰存在于化合物中的官能团,制备前药。前药包括当给予哺乳动物患者时,其中例如:羟基、氨基、巯基或羧基与任何基团连接的分解后分别形成游离羟基、氨基、巯基或羧基的化合物。前药的实例包括但不限于本发明化合物中醇的乙酸酯、甲酸酯和苯甲酸酯衍生物,或者胺官能团甲基胺、乙基胺衍生物。
本发明提供了式I的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物:
药理试验结果表明该化合物对ALK激酶具有很好的抑制活性,可作为一类新型的ALK抑制剂,为由ALK介导的疾病的治疗提供了可能性。
本发明另一目的在于提供一种药物组合物,所述药物组合物包括通式I的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物以及药学上可接受的载体或赋形剂。
本发明的药物组合物可以采用各种已知的方式施用,例如口服、胃肠外施用、通过吸入喷雾施用或经由植入的贮库施用。本发明的药物组合物可单独给药也可与其他抗肿瘤药物联合用药。口服组合物可以是任何口服可接受的剂型,包含但不限于片剂、胶囊剂、乳剂以及混悬剂、分散物和溶液。常用的药学上可接受的载体或赋形剂包括稳定剂、稀释剂、表面活性剂、润滑剂、抗氧化剂、粘合剂、着色剂、填充剂、乳化剂等。
无菌可注射组合物可按照本领域已知的技术使用适合的分散剂或润湿剂和助悬剂来配制。可以使用的药学上可接受的载体和溶剂包括水、甘露醇、氯化钠溶液等。
局部组合物可被配制成油、洗剂、乳膏剂等。用于组合物的载体包括植物油或矿物油、动物脂肪和高分子量醇等。药学上可接受的载体是活性成分在其中可溶的载体。
可以改变本发明的药物组合物中活性成分的实际剂量水平以获得对特定患者、组合物和施用方式而言可以有效实现所需治疗响应、对患者无毒的活性成分的量。所选择的的剂量水平取决于多种因素,包括所用的具体的本发明的化合物或其盐的活性、施用途径、施用时间、所用的具体组合物的排泄速率、治疗的持续时间、与所用的具体组合物组合使用的其它药物、化合物和/或材料、所治疗的患者的年龄、性别、体重、一般健康状况和既往病史以及医学领域中公知的类似因素。
本发明另一目的在于提供通式的化合物或其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物在制备用于防治和/或治疗ALK相关疾病的药物中的用途。如:制备预防和/治疗生物体内与渐变性淋巴瘤酶相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
所述ALK相关疾病选自但不限于非小细胞肺癌、肝癌、乳头状肾细胞癌、胃癌、食道癌、恶性胶质瘤、头颈部鳞状细胞、肾癌、急性白血病、前列腺癌、甲状腺癌、皮肤癌、结肠直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓增生异常综合症或间皮瘤。
有益效果:
本发明制备的通式I的化合物及其药学上可接受的盐、前药、晶型、立体异构体、互变异构体、水合物或溶剂合物作为受体酪氨酸激酶抑制剂,尤其对ALK激酶具有优良的抑制活性。因此,上述化合物可以用于制备治疗与ALK有关的临床病症的药物,如:制备预防和/治疗生物体内与渐变性淋巴瘤酶相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
具体实施方式
下面结合具体实施例描述本发明通式I化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
本发明具体实施例中使用的起始原料、反应试剂等均为市售。本发明可以采用本领域常用的成盐方法制备成盐的形式。
实施例1:56-氟-16-甲氧基-4-甲基-14-(4-甲基哌啶-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-1)
合成路线如下:
中间体3合成:
于100mL单颈瓶中加入2,4-二氟-5-溴硝基苯(5.00g,21.0mmol),甲醇(40mL),降温至0℃,控温加入5mL甲醇钠(4.6mol/L),0℃搅拌2h,自然升至室温反应20h,反应完毕,加入100mL冰水,EA(50mL×3)萃取,直至水层无产品,饱和食盐水洗后无水硫酸钠干燥后柱层析(PE:EA=3:1)得本发明化合物中间体1 2.50g,收率48%,MS m/z:251.2[M+H]+。
于100mL单颈瓶中加入中间体1(2.50g,10mmol)、N-甲基哌嗪10mL,室温反应3h,经TLC(DCM:MeOH=10:1)监测反应结束后,加入30mL冰水,EA(10mL×3)萃取,直至水层无产品,饱和食盐水洗后无水硫酸钠干燥后柱层析(DCM:MeOH=50:1)得本发明化合物中间体23.10g,收率94%,MS m/z:331.2[M+H]+。
于250mL单颈瓶中加入中间体2(3.10g,9.39mmol)、雷尼镍0.50g、乙醇200mL,氢气置换三次,升温至80℃,加入水合肼5mL,继续80℃反应7h,经TLC(DCM:MeOH=10:1)监测反应结束后,降温,过滤,滤饼用乙醇50mL淋洗两次,滤液浓缩得到粗品,柱层析(DCM:MeOH=30:1)得棕黄色中间体3 2.32g,收率82%,MS m/z:301.3[M+H]+。
56-氟-16-甲氧基-4-甲基-14-(4-甲基哌啶-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-1)合成:
于50mL单颈瓶中分别加入2-氯-7H-吡咯[2,3-d]嘧啶(0.63g,4.10mmol)、NaH(0.15g,6.25mmol)和DMF 10mL,降温至零度并在该温度下搅拌10min,加入4-溴-2-(1-氯乙基)-1-氟苯(1.08g,4.92mmol),升温至室温反应7h。经TLC(EA:PE=1:1)监测反应结束,加入50mL冰水,EA(10mL×3)萃取,直至水层无产品,饱和食盐水洗后无水硫酸钠干燥后柱层析(PE:EA=3:1)得本发明化合物中间体4 1.30g,收率90%,MS m/z:355.5[M+H]+。
于100mL单颈瓶中分别加入中间体4(1.30g,3.7mmol)、乙烯三氟硼酸钾(0.59g,4.4mmol)、Cs2CO3(3.58g,11.0mmol)、THF 20mL和水4mL,氮气氛围下,加入Pd(OAc)2(0.041g,0.18mmol)和P(Ph)3(0.096g,0.36mmol),氮气置换3次,升温至70℃反应4h,TLC(PE:EA=3:1)监测反应完毕,反应液降至室温,反应液加入冰水30mL,EA(10mL×3)萃取,有机相干燥浓缩,经柱层析(PE:EA=8:1)得黄色固体中间体5 0.89g,收率81%,MS m/z:302.1[M+H]+。
于50mL单颈瓶中分别加入中间体5(0.33g,1.1mmol)、中间体3(0.36g,1.2mmol)、Cs2CO3(1.07g,3.3mmol)和甲苯10mL,氮气氛围下,加入Pd2(dba)3(0.2g,0.22mmol)和xantphos(0.25g,0.44mmol),氮气置换3次,升温至100℃反应8h,TLC(DCM:MeOH=10:1)监测反应完毕,反应液降至室温,反应液加入冰水20mL,EA(8mL×3)萃取,有机相干燥浓缩,经柱层析(DCM:MeOH=50:1)得黄色固体中间体6 0.20g,收率32%,MS m/z:566.3[M+H]+。
于50mL单颈瓶中分别加入中间体6(0.20g,0.35mmol)、Et3N(0.20g,1.9mmol)、和CH3CN 8mL,氮气氛围下,加入Pd(OAc)2(0.063g,0.28mmol)和三(邻甲基苯基膦)(0.22g,0.70mmol),氮气置换3次,升温至100℃反应8h,TLC(DCM:MeOH=10:1)监测反应完毕,反应液降至室温,反应液加入冰水15mL,EA(5mL×3)萃取,有机相干燥浓缩,经柱层析(DCM:MeOH=50:1)得黄色固体中间体7 0.09g,收率53%,MS m/z:485.1[M+H]+。
于10mL单颈瓶中分别加入中间体7(0.03g,0.062mmol)、10%Pd/C(0.005g)、和CH3OH5mL,氢气置换三次,氢气氛围下室温反应3天。TLC(DCM:MeOH=10:1)监测反应完毕,硅藻土过滤,有机相浓缩得到粗品,经柱层析(DCM:MeOH=50:1)得黄色固体I-1 0.013g,收率43%,MS m/z:487.1[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.54(d,J=2.0Hz,1H),7.73(s,1H),7.56(d,J=7.4Hz,1H),7.45-7.39(m,2H),7.22(d,J=1.7Hz,1H),7.03-6.96(m,1H),6.87(ddd,J=10.6,8.1,2.2Hz,1H),6.79(d,J=1.7Hz,1H),6.38(dd,J=3.8,1.9Hz,1H),5.62(d,J=7.1Hz,1H),3.80(d,J=2.0Hz,3H),3.12–2.65(m,12H),2.50(p,J=1.9Hz,3H),1.85(d,J=7.0Hz,3H).
实施例2 16,56-二甲氧基-14-(4-甲基哌啶-1-基)-37H-4-硫杂-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-4,4-二氧化物(I-2)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体15mg,收率50%,MS m/z:535.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.66(s,1H),7.94(s,1H),7.80(d,J=2.2Hz,1H),7.56-7.47(m,2H),7.07(d,J=8.5Hz,1H),6.86(s,1H),6.76(s,1H),6.65(d,J=4.0Hz,1H),3.79(s,3H),3.61(s,3H),3.14-2.83(m,8H),2.55(s,4H),2.29(s,3H)。
实施例3 16,56-二甲氧基-14-(4-甲基哌啶-1-基)-37H-4-硫杂-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃-4,4-二氧化物(I-3)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体48mg,收率26%,MS m/z:533.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.57(s,1H),8.36(d,J=2.3Hz,1H),8.24(s,1H),7.55(dd,J=8.7,2.3Hz,1H),7.42-7.34(m,2H),7.14(d,J=8.7Hz,1H),6.64(s,1H),6.57-6.52(m,2H),6.41(s,1H),3.79(s,3H),3.71(s,3H),2.46(p,J=1.9Hz,8H),2.22(s,3H)。
实施例4 16,56-二甲氧基-14-(4-甲基哌啶-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-4)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体11mg,收率5%,MS m/z:485.7[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.48(s,1H),7.12-7.09(m,2H),7.03(dd,J=8.2,2.3Hz,1H),6.99(s,1H),6.85(d,J=8.3Hz,1H),6.80(s,1H),4.13(s,2H),3.79(s,6H),2.90-2.75(m,12H),2.26(s,3H)。
实施例5 16,56-二甲氧基-4-甲基-14-(4-甲基哌啶-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-5)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体28mg,收率11%,MS m/z:499.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.51(s,1H),7.49(s,1H),7.36(dd,J=7.7,3.5Hz,3H),6.98(dd,J=8.2,2.1Hz,1H),6.80(s,1H),6.78-6.72(m,1H),6.33(d,J=3.5Hz,1H),5.55(d,J=7.4Hz,1H),3.81(s,3H),3.51(s,3H),2.97-2.84(m,8H),2.54(s,3H),2.28(s,4H),1.82(d,J=7.1Hz,3H)。
实施例6 16,56-二甲氧基-4-甲基-14-(4-甲基哌啶-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃(I-6)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体10mg,收率5%,MS m/z:457.4[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.52(s,1H),7.49(s,1H),7.34(dd,J=7.7,3.5Hz,3H),6.99(dd,J=8.2,2.1Hz,1H),6.80(s,1H),6.78-6.73(m,1H),6.33(d,J=3.5Hz,1H),5.55(d,J=7.4Hz,1H),5.52-5.50(m,2H),3.81(s,3H),3.51(s,3H),2.97-2.85(m,8H),2.53(s,3H),1.84(d,J=7.1Hz,3H)。
实施例7 16,56-二甲氧基-54-(4-甲基哌啶-1-基)-31H-2-硫杂-4-氮杂-3(1,6)-吡唑[3,4-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃-2,2-二氧化物(I-7)
制备方法参考实施例1,以2-氯-7H-吡唑[2,3-d]嘧啶为起始原料,得黄色固体8mg,收率3%,MS m/z:534.1[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.59(s,1H),8.37(d,J=2.4Hz,1H),8.25(s,1H),7.57(dd,J=8.7,2.4Hz,1H),7.43-7.34(m,2H),7.15(d,J=8.7Hz,1H),6.64(s,1H),6.57-6.53(m,1H),6.41(s,1H),3.78(s,3H),3.73(s,3H),2.46(br,8H),2.23(s,3H)。
实施例8 16,56-二甲氧基-14-(4-甲基哌啶-1-基)-39H-4-硫杂-2-氮杂-3(2,9)-嘌呤-1,5(1,3)-二苯杂环七蕃-6-烯烃-4,4-二氧化物(I-8)
制备方法参考实施例1,以2-氯-嘌呤为起始原料,得黄色固体14mg,收率7%,MSm/z:534.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.79(s,1H),8.66(d,J=2.4Hz,1H),8.47(s,1H),8.35(s,1H),7.58(dd,J=8.8,2.4Hz,1H),7.46-7.37(m,2H),7.18(d,J=8.8Hz,1H),6.66(s,1H),6.57-6.55(m,1H),3.79(s,3H),3.74(s,3H),2.48(br,8H),2.25(s,3H)。
实施例9 56-氟-16-甲氧基-4-甲基-14-(四氢吡咯-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-9)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体37mg,收率27%,MS m/z:458.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.46(s,1H),7.86(s,1H),7.31(t,J=2.7Hz,1H),7.12(t,J=5.7Hz,1H),6.94(dd,J=11.0,8.3Hz,1H),6.86(d,J=7.1Hz,1H),6.48(s,1H),6.30(d,J=3.6Hz,1H),6.22(s,1H),5.41(q,J=7.3Hz,1H),3.86(s,3H),3.25(s,4H),2.80-2.65(m,4H),1.81(d,J=5.9Hz,4H),1.77(d,J=7.2Hz,3H)。
实施例10 4-{56-氟-16-甲氧基-4-甲基-36,37-二氢-35H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-14-基}吗啉(I-10)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体69mg,收率48%,MS m/z:476.4[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.11(s,1H),7.51(d,J=1.5Hz,1H),7.13(t,J=6.3Hz,1H),7.08-7.01(m,1H),6.80(d,J=7.4Hz,1H),6.73(d,J=1.1Hz,1H),6.42(d,J=1.1Hz,1H),4.05(td,J=8.7,4.0Hz,1H),3.96(td,J=8.8,5.0Hz,2H),3.85(d,J=1.2Hz,3H),3.73(t,J=4.6Hz,4H),2.81(m,J=39.8,34.5,9.6Hz,10H),1.51(d,J=7.1Hz,3H)。
实施例11 56-氟-16-甲氧基-4-甲基-14-(吗啉-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃(I-11)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体29mg,收率15%,MS m/z:472.6[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.13(s,1H),7.51(d,J=1.5Hz,1H),7.17(t,J=6.3Hz,1H),7.08-7.01(m,1H),6.80(d,J=7.4Hz,1H),6.73(d,J=1.1Hz,1H),6.62-6.55(m,4H),6.41(d,J=1.1Hz,1H),4.06(td,J=8.7,4.0Hz,1H),3.96(t,J=4.6Hz,4H),3.86(s,3H),3.73(t,J=4.6Hz,4H),1.52(d,J=7.1Hz,3H)。
实施例12 56-氟-16-甲氧基-4-甲基-14-(吗啉-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-12)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体10mg,收率11%,MS m/z:474.1[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.15(s,1H),7.51(d,J=1.5Hz,1H),7.16(t,J=6.3Hz,1H),7.08-7.03(m,1H),6.81(d,J=7.4Hz,1H),6.71(d,J=1.1Hz,1H),6.63-6.56(m,2H),6.43(d,J=1.1Hz,1H),4.07(td,J=8.7,4.0Hz,1H),3.96(t,J=4.6Hz,4H),3.86(s,3H),3.73(t,J=4.6Hz,4H),2.83-2.64(m,4H),1.54(d,J=7.1Hz,3H)。
实施例13 56-氟-16-甲氧基-4-甲基-14-二甲氨基-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃(I-13)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体19mg,收率18%,MS m/z:430.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.53(s,1H),8.25(s,1H),7.70(d,J=4.7Hz,2H),7.35(s,1H),7.19(t,J=6.1Hz,1H),7.06(dd,J=10.6,8.4Hz,1H),6.69(s,1H),6.58(d,J=12.6Hz,1H),6.41(d,J=12.7Hz,1H),6.33(d,J=3.6Hz,1H),5.56(s,1H),3.85(s,3H),2.81(s,6H),1.81(d,J=7.1Hz,3H)。
实施例14 56-氟-16-甲氧基-4-甲基-14-(哌啶-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃(I-14)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体7mg,收率3%,MS m/z:470.4[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.47(s,1H),7.88(s,1H),7.32(t,J=2.7Hz,1H),7.11(t,J=5.7Hz,1H),6.95(dd,J=11.0,8.3Hz,1H),6.88(d,J=7.1Hz,1H),6.62-6.55(m,3H),6.30(d,J=3.6Hz,1H),6.22(s,1H),5.41(q,J=7.3Hz,1H),3.86(s,3H),2.80-2.65(m,4H),1.77(d,J=7.2Hz,3H),1.21-0.99(m,6H)。
实施例15 56-氟-16-甲氧基-4-甲基-14-二甲氨基-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃(I-15)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体13mg,收率7%,MS m/z:432.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):7.49(s,1H),7.14(d,J=7.5Hz,3H),7.09-6.92(m,2H),6.79(d,J=15.1Hz,2H),4.63(d,J=7.1Hz,1H),3.78(s,3H),2.86(dt,J=12.4,7.6Hz,4H),2.65(s,6H),1.56(d,J=7.2Hz,3H)。
实施例16 56-氟-16-甲氧基-4-甲基-14-二甲氨基-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃盐酸盐(I-16)
取10mg 56-氟-16-甲氧基-4-甲基-14-二甲氨基-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃溶于5mL盐酸乙醇(1mol/L),室温反应3h,TLC检测原料反应完全。反应液直接浓缩得黄色固体,用甲醇冲洗、打浆、过滤,滤饼用甲醇洗涤3次,滤饼烘干得黄色固体5mg,收率43%,MS m/z:432.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):9.33(s,1H),9.04(s,1H),7.49(s,1H),7.15(d,J=7.5Hz,3H),7.09-6.92(m,2H),6.79(d,J=15.1Hz,2H),4.64(d,J=7.1Hz,1H),3.77(s,3H),2.86(dt,J=12.4,7.6Hz,4H),2.65(s,6H),1.56(d,J=7.2Hz,3H)。
实施例17 56-氟-16-甲氧基-4-甲基-14-(哌嗪-1-基)-37H-2-氮杂-3(2,7)-吡咯[2,3-d]嘧啶-1,5(1,3)-二苯杂环七蕃-6-烯烃(I-17)
制备方法参考实施例1,以2-氯-7H-吡咯[2,3-d]嘧啶为起始原料,得黄色固体15mg,收率17%,MS m/z:471.4[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):8.53(s,1H),8.23(s,1H),7.74(t,J=11.5Hz,2H),7.36(s,1H),7.19(ddd,J=7.8,5.1,2.2Hz,1H),7.06(dd,J=10.7,8.4Hz,1H),6.67(s,1H),6.62(d,J=12.7Hz,1H),6.41(d,J=12.7Hz,1H),6.33(d,J=3.6Hz,1H),5.56(s,1H),3.85(s,3H),3.40(s,4H),3.02-2.82(m,7H),1.91(s,1H)。
实施例18:生物学活性
(1)本发明化合物的ALK抑制活性测定
所合成的化合物用荧光共振能量转移(FRET)法测定对ALK的抑制活性(具体实施办法参考文献:Lebakken CS,Kang HC,Vogel KW,A fluorescence lifetime-basedbinding assay to characterize kinase inhibitors.J Biomol Screen.2007.12(6):828–841.),并与阳性对照药比较,筛选出活性较好的化合物。ALK通过直接购买试剂盒获得。
所合成的化合物用ELISA分析法测定对Ba/F3 EML4-ALK细胞的抑制活性(具体实施办法参考文献:CN202010347120),并与阳性对照药比较,筛选出活性较好的化合物。
(2)下表是部分化合物的体外ALK激酶活性及体外癌细胞活性测试结果:
(表中化合物代号对应于前面的化合物代号)
从上表可知:本发明的上述化合物及其医学上可接受的盐具有ALK抑制作用,可为制备治疗/预防与ALK相关疾病的药物提供依据。
药理测试结果表明,药理测试结果表明,本发明中2-氨基嘧啶大环类化合物同时具有较好的ALK激酶及该激酶高表达肺癌细胞株Ba/F3 EML4-ALK抑制活性,部分化合物单一浓度抑制率与阳性对照药Brigatinib布加替尼相当或优于阳性对照,可用于预防或治疗与ALK激酶抑制剂有关的临床疾病。
本发明的上述化合物及其医学上可接受的盐具有ALK激酶及Ba/F3 EML4-ALK细胞抑制作用,可用作医药品中的有效成分。因此,含有上述化合物作为有效成分的药物,可以用于制备治疗与ALK有关的临床病症的药物,如:制备预防和/治疗生物体内与渐变性淋巴瘤酶相关的细胞异常增殖、形态变化以及运动功能亢进等相关的疾病的药物以及与血管新生或癌转移相关的疾病的药物中的用途。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (8)
1.化合物或其药学上可接受的盐,其特征在于选自如下结构:
。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐选自权利要求1所述化合物I-1至I-15和化合物I-17与酸形成的酸加成盐。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐选自化合物与无机碱形成的酸式盐。
4.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于:所述酸选自盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸或琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
5.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于:所述药学上可接受的盐选自碱性金属阳离子盐、碱土金属阳离子盐和铵阳离子盐。
6.一种药物组合物,其特征在于:包括权利要求1-5任一项所述的化合物或其药学上可接受的盐以及药学上可接受的载体或赋形剂。
7.根据权利要求1-5任一项所述的化合物或其药学上可接受的盐在制备用于防治和/或治疗ALK相关疾病的药物中的用途。
8.根据权利要求7所述的用途,其特征在于:所述ALK相关疾病选自非小细胞肺癌、肝癌、乳头状肾细胞癌、胃癌、食道癌、恶性胶质瘤、头颈部鳞状细胞、肾癌、急性白血病、前列腺癌、甲状腺癌、皮肤癌、结肠直肠癌、胰腺癌、卵巢癌、乳腺癌、骨髓增生异常综合症或间皮瘤。
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