CN115368366A - 嘧啶并吡唑类化合物及其应用 - Google Patents
嘧啶并吡唑类化合物及其应用 Download PDFInfo
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- CN115368366A CN115368366A CN202210920243.1A CN202210920243A CN115368366A CN 115368366 A CN115368366 A CN 115368366A CN 202210920243 A CN202210920243 A CN 202210920243A CN 115368366 A CN115368366 A CN 115368366A
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Abstract
本发明公开了一类嘧啶并吡唑化合物及其应用,该化合物对双特异性激酶Mps1(单极纺锤体1,也称TTK))具有很好的抑制活性,可作为Mps1抑制剂,用于制备预防和/或治疗生物体内与Mps1过表达介导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。
Description
技术领域
本发明属于医药技术领域,具体涉及一类嘧啶并吡唑化合物及其在制备预防和/或治疗生物体内与一种双特异性激酶Mps1(单极纺锤体1,也称TTK)过表达介导相关的疾病的药物或癌转移相关的疾病的药物中的用途。
背景技术
乳腺癌是全球女性高发的恶性肿瘤之一。据世界卫生组织国际癌症研究中心(IARC)统计:2008年全球女性乳腺癌新发病例达138万,占当年全部女性恶性肿瘤新发病例的22.9%。全球每年约45.8万人死于乳腺癌。目前全球乳腺癌药物市场约200亿美元,预测到2025年复合增长率约11%,将扩大到384亿美元。据统计,我国每年约有16.9万女性确诊乳腺癌,每年有4.5万女性死于乳腺癌。中国乳腺癌发病相较于欧美国家有其独特的特征,其中绝经前患者占一半以上,发病高峰为40-70岁,整体高于欧美国家,且三阴性乳腺癌(triple-negative breast cancer,TNBC)比例高。三阴性乳腺癌是指癌组织免疫组织化学检查结果为***受体(ER)、孕激素受体(PR)和人表皮生长因子受体(HER2)均为阴性的乳腺癌。三阴性乳腺癌占乳腺癌病理类型的20%,并且30%-40%的TNBC可发展为转移性乳腺癌,内脏转移多见,尤其是肺和脑的转移,同时其预后较差。参与细胞有丝***调控的相关激酶在常见乳腺癌中均出现多度表达,这些激酶的高表达与肿瘤的不良预后具有很大关系。特别是激酶Mps1(单极纺锤体1,也称TTK),Mps1是一种双特异性激酶,是参与着丝点定位和纺锤体组装检查点(SAC)的主要激酶之一,在有丝***中起着重要作用。Mps1表达与高度增殖的细胞和组织有关,因为在许多癌细胞系和肿瘤类型中观察到Mps1被过度表达,尤其是在TNBC患者明显高表达,并与TNBC患者预后不良有很大关联。在某些物种中,Mps1的沉默可防止细胞因纺锤体毒素而发生有丝***停滞,这表明Mps1在纺锤体组装信号传导中的基本功能。
因此,通过药物抑制Mps1激酶或有丝***检查点的其他成分来消除有丝***检查点,提示了一种治疗增殖性疾病的新方法,包括实体瘤,如癌和肉瘤以及白血病和淋巴性恶性肿瘤,或其他与不受控制的细胞增殖有关的疾病。鉴于Mps1在乳腺癌细胞,尤其是TNBC中所扮演的重要作用,通过抑制Mps1高表达,实现对TNBC细胞的抑制及侵袭,具有巨大的研究价值,开发新型骨架结构的Mps1抑制剂将会给TNBC患者治疗带来新的选择和希望。
发明内容
针对现有技术的不足,本发明的目的是提供一类嘧啶并吡唑化合物,该化合物对Mps1激酶均具有很好的抑制活性,可作为Mps1抑制剂,为由Mps1介导的疾病的治疗提供了可能性。
为了实现上述发明目的,本发明采用以下技术手段:
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
式I中,
X选自-CR5R6-、-NR5-、O或S,其中R5、R6各自独立地表示氢、氘、卤素、烷基、芳基或Het;
Y选自-NR7-、O或S,其中R7各自独立地表示氢、氘、卤素、烷基、芳基或Het;
Q选自-NR8CONR9-、-CONR8-、-NR8CO-、-CO-、-NR8SO2NR9-、-SO2NR8-、-NR8SO2-、-SO2-、-NR8-、-NR8(CH2)nNR9-、-NR8(CH2)nO-或-CR8R9,其中n=1、2、3、4或5,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
环A选自3-10元环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基;
R1选自氢、卤素、羟基、烷氧基、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、芳基或Het;
R4选自氢、卤素、羟基、烷氧基、烷基、芳基或Het;
烷基为1-6个碳原子的直链或支链饱和烃基、3-6个碳原子的环状饱和烃基,或连有1-6个碳原子直链或支链饱和烃基的3-6个碳原子的环状饱和烃基;
上述基团中,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;
卤素选自氟、氯、溴或碘。
进一步地,式I中,
X为-NR5-或O,其中R5选自氢、氘、卤素、烷基、芳基或Het;
Y选自-NR7-或O,其中R7各自独立地表示氢、氘、卤素、烷基、芳基或Het;
Q选自-NR8CONR9-、-CONR8-、-NR8CO-、-CO-、-NR8SO2NR9-、-SO2NR8-、-NR8SO2-、-NR8(CH2)nNR9-、-SO2-或-CR8R9,其中n=1、2、3、4或5,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
环A选自3-10元环烷基、3-10元杂环基、6-10元芳基;
R1选自氢、烷氧基、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、烷氧基、烷基、芳基或Het;
R4选自氢、羟基、烷氧基、烷基、芳基或Het。
进一步地,式I中,
X为-NR5-,其中R5选自氢、氘或烷基;
Y选自O;
Q选自-NR8CONR9-、-NR8CO-、-NR8SO2NR9-、-NR8(CH2)nNR9-、-NR8SO2-或-CR8R9,其中n=1、2、3、4或5,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
环A选自6-10元芳基;
R1选自氢、烷氧基、烷基或芳基;
R2选自氢、卤素、羟基、烷氧基或烷基;
R3选自氢、烷氧基或烷基;
R4选自氢、烷氧基、烷基、芳基或Het。
进一步地,式I中,
X为-NH-;
Y选自O;
Q选自-NR8(CH2)nR9N-或-N(CH2)nN-,其中n=1或2,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
R1为氢或烷基;
R2选自氢、卤素或烷基;
R3选自氢、烷氧基或烷基;
R4选自氢、烷氧基、烷基、芳基或Het。
进一步地,所述药学上可接受的盐包括通式I的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。
进一步地,所述药学上可接受的盐包括碱性金属阳离子盐、碱土金属阳离子盐和铵阳离子盐。
进一步地,通式I的化合物为下述化合物中的一种:
一种药物组合物,包括上述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。
上述化合物在制备用于预防和/或治疗Mps1相关疾病的药物中的用途。
进一步地,所述Mps1相关疾病选自但不限于高脂血症或癌症;所述的癌症包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、女性生殖***癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,以及骨髓增生异常综合症。
有益效果:本发明提供的通式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Mps1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Mps1有关的临床病症的药物,如:制备预防和/治疗生物体内与Mps1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
本发明提供了式I的化合物:
药理试验结果表明该化合物对Mps1都具有很好的抑制活性,可作为一类新型的Mps1抑制剂,为由Mps1介导的疾病的治疗提供了可能性。
在本发明中,式I的化合物还可以以其盐、水合物、溶剂合物的形式存在,它们在体内转化为式I的化合物。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。
同时,式I的化合物还可以以多晶或无定形形式存在。
另外,式I的化合物还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。
本发明中涉及的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***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。
本发明还提供了式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、水合物或溶剂合物在制备用于预防和/或治疗Mps1相关疾病的药物中的用途。如:制备预防和/治疗生物体内与Mps1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Mps1相关疾病选自但不限于高脂血症或癌症;所述的癌症包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、女性生殖***癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,骨髓增生异常综合症。
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
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-吗啉基)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-1)
合成路线如下:
化合物I-1-1合成:
向100mL单口瓶中加入4,6-二氯-1H-吡唑并[3,4-d]嘧啶(2.00g,11mmol),N-碘代丁二酰亚胺(3.57g,16mmol),1,4-二氧六环20mL和DMF 5mL,90℃反应8h,TLC监测反应完毕。将反应液倒入25mL冰水中,用EA(50mL*3)萃取,直至水层无产品,停止萃取,浓缩得到粗品,柱层析(PE:EA=8:1)纯化,得到白色固体1.5g,收率38%,MS m/z:315.2[M+H]+。
化合物I-1-2合成:
向100mL单口瓶中加入化合物I-1-1(1.25g,4.00mmol),CH2Cl2 20mL和DMF 2mL,降温至0℃,加入钠氢(0.19g,4.80mmol),0℃反应20min,缓慢滴入三甲基硅基乙氧甲基氯0.8mL,0℃反应0.5h,TLC(PE:EA=4:1)监测反应完毕,将反应液倒入10mL冰水中,EA(30mL*3)萃取,硫酸钠干燥,柱层析(PE:EA=10:1)得黄色油状物1.26g,收率72%,MS m/z:446.2[M+H]+。
化合物I-1-3合成:
向50mL单口瓶中加入化合物I-1-2(1.26g,2.80mmol),1,4-二氧六环6mL,降温至0℃,加入钠氢(0.34g,8.50mmol),0℃反应30min,缓慢滴入环戊醇0.6mL,升温至室温反应4h,TLC(PE:EA=4:1)监测反应完毕,将反应液倒入5mL冰水中,EA(10mL*3)萃取,硫酸钠干燥,浓缩至干,柱层析(PE:EA=10:1)得黄色油状物1.23g,收率88%,MS m/z:495.4[M+H]+。
化合物I-1-4合成:
向50mL单口瓶中加入I-1-3(1.23g,2.40mmol),3,5-二甲氧基苯硼酸(0.50g,2.70mmol)、Na2CO3(0.66g,6.20mmol)、1,4-二氧六环15mL和水5mL,氮气氛围下,加入Pd(dppf)Cl2(0.18g,0.24mmol),氮气置换3次,升温至70℃反应5h,TLC(PE:EA=4:1)监测反应完毕,反应液降至室温,反应液加入冰水5mL,EA(5mL*3)萃取,有机相干燥浓缩,经柱层析(PE:EA=5:1)得黄色固体0.73g,收率58%,MS m/z:506.1[M+H]+。
化合物I-1-5合成:
向50mL单口瓶中加入I-1-4(0.37g,0.73mmol),4-***啉基-2-甲氧基苯胺(0.23g,1.00mmol)、Cs2CO3(0.70g,2.20mmol)和1,4-二氧六环7mL,氮气氛围下,加入Pd2(dba)3(0.04g,0.07mmol)和BINAP(0.04g,0.07mmol),氮气置换3次,升温至120℃反应9h,TLC(PE:EA=1:1)监测反应完毕,反应液降至室温,反应液加入冰水5mL,EA(5mL*3)萃取,有机相干燥浓缩,经柱层析(PE:EA=1:1)得黄色固体0.31g,收率63%,MS m/z:677.1[M+H]+。化合物I-1合成:
向50mL单口瓶中加入I-1-5(0.31g,0.45mmol)和CH2Cl2 20mL,降温至0℃,加入三氟乙酸5mL,0℃反应4h,TLC(DCM:MeOH=10:1)监测反应完毕,将反应液倒入10mL冰水中,CH2Cl2(20mL*3)萃取,硫酸钠干燥,柱层析(DCM:MeOH=30:1)得黄色固体0.19g,收率76%,MS m/z:547.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):13.15(s,1H),8.06-7.81(m,3H),7.64(ddd,J=8.4,5.0,2.0Hz,1H),7.51(dd,J=3.5,2.0Hz,1H),7.02(t,J=8.1Hz,1H),6.67(dd,J=4.3,2.5Hz,2H),6.53(td,J=9.2,2.5Hz,1H),5.70-5.53(m,2H),3.89-3.79(m,12H),3.76(t,J=4.8Hz,6H),3.11(t,J=4.8Hz,5H),1.99(ddd,J=13.6,9.0,4.1Hz,3H),1.88-1.57(m,5H)。
实施例2
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-(N-甲基哌嗪))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-2)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体150mg,收率53%,MS m/z:560.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):13.16(s,1H),7.87(t,J=4.3Hz,2H),7.63(dd,J=8.4,2.0Hz,1H),7.51(d,J=2.0Hz,1H),7.01(d,J=8.5Hz,1H),6.66(d,J=2.5Hz,1H),6.52(dd,J=8.8,2.5Hz,1H),3.89-3.76(m,9H),3.17(t,J=4.7Hz,4H),2.67-2.54(m,4H),2.32(s,3H),2.07-1.91(m,2H),1.86-1.56(m,5H)。
实施例3
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-(N-乙酰基哌嗪))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-3)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体130mg,收率45%,MS m/z:588.3[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):13.14(s,1H),8.09-7.81(m,2H),7.64(ddd,J=8.2,5.4,2.0Hz,1H),7.51(d,J=2.2Hz,1H),7.02(t,J=8.3Hz,2H),6.76-6.67(m,2H),6.56(td,J=9.4,9.0,2.6Hz,2H),3.93-3.75(m,14H),3.60(q,J=6.1Hz,7H),3.12(dt,J=23.9,5.2Hz,6H),2.06(s,5H),2.04-1.95(m,1H),1.86-1.57(m,2H)。
实施例4
3-(3,4-二甲氧基苯基)-4-(环己基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-4)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体80mg,收率54%,MS m/z:602.1[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.13(s,1H),7.90(s,1H),7.79(d,J=8.7Hz,1H),7.65(dd,J=8.4,2.0Hz,1H),7.52(d,J=2.1Hz,1H),7.02(d,J=8.4Hz,1H),6.66(d,J=2.6Hz,1H),6.52(dd,J=8.8,2.5Hz,1H),3.82(d,J=6.5Hz,10H),2.82(s,1H),2.73-2.59(m,2H),2.09-1.94(m,5H),1.70(ddd,J=23.8,10.6,6.3Hz,3H),1.61-1.48(m,3H)。
实施例5
3-(3,4-二甲氧基苯基)-4-(环丙基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-5)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体65mg,收率28%,MS m/z:560.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.18(s,1H),10.05(s,1H),8.01-7.88(m,2H),7.50(d,J=7.0Hz,1H),7.03(d,J=8.5Hz,1H),6.69(d,J=2.4Hz,1H),6.56(dd,J=8.8,2.5Hz,1H),4.66-4.43(m,1H),3.86-3.79(m,10H),3.17(s,1H),2.79(d,J=3.0Hz,6H),2.68(t,J=12.1Hz,2H),2.07(d,J=11.9Hz,2H),1.72(dd,J=12.1,4.0Hz,2H),1.22(s,2H),0.84(dt,J=13.9,4.4Hz,4H)。
实施例6
3-(3-甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-6)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体220mg,收率73%,MS m/z:558.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):10.30(s,1H),7.98(d,J=15.0Hz,1H),7.89(d,J=8.7Hz,1H),7.60(d,J=7.7Hz,1H),7.54(t,J=1.9Hz,1H),7.36(q,J=7.7Hz,1H),6.97(dd,J=8.2,2.5Hz,1H),6.72(d,J=2.6Hz,1H),6.58(dd,J=8.9,2.4Hz,1H),5.62(d,J=39.5Hz,1H),3.85(d,J=7.5Hz,3H),3.81(d,J=2.0Hz,3H),3.31(d,J=4.3Hz,1H),3.17(s,3H),2.80(d,J=4.5Hz,6H),2.72(s,1H),2.09(d,J=10.9Hz,2H),2.04-1.89(m,2H),1.86–1.69(m,5H),1.67-1.58(m,2H),1.28-1.19(m,1H)。
实施例7
3-(3,5-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-7)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体62mg,收率25%,MS m/z:589.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):10.16(s,1H),7.89(d,J=9.1Hz,1H),7.16(d,J=2.1Hz,1H),7.04(d,J=2.2Hz,1H),6.87(d,J=2.2Hz,1H),6.73(d,J=5.0Hz,1H),6.63(d,J=10.6Hz,2H),5.63(s,1H),5.40(s,1H),3.91-3.79(m,9H),3.51(s,1H),3.34(s,1H),3.17(s,3H),2.80(d,J=4.3Hz,6H),2.10(d,J=11.9Hz,2H),1.97(d,J=9.6Hz,2H),1.88-1.52(m,8H),1.22(s,1H)。
实施例8
3-(4-甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-8)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体210mg,收率81%,MS m/z:558.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):10.20(s,1H),7.91(dd,J=12.4,8.4Hz,3H),6.99(d,J=8.2Hz,2H),6.72(s,1H),6.59(d,J=8.8Hz,1H),5.65(s,1H),4.51(d,J=7.1Hz,4H),3.83(s,3H),3.80(s,3H),3.39-3.27(m,1H),3.16(s,2H),2.83-2.69(m,6H),2.17-1.88(m,3H),1.88-1.55(m,6H),1.38-1.16(m,2H)。
实施例9
4-[(3-((2,6-二甲基)氨基甲酰基)吡咯基]-N-[(2-甲氧基-4-(N-甲基哌嗪))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-9)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体36mg,收率22%,MS m/z:552.1[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.52(s,1H),9.73(s,1H),8.62(d,J=6.2Hz,2H),8.32(s,1H),7.94(s,1H),7.76(d,J=8.7Hz,1H),7.12(s,3H),6.94(d,J=3.3Hz,1H),6.67(d,J=2.5Hz,1H),6.54(dd,J=8.7,2.5Hz,1H),3.82(s,3H),3.19(t,J=4.9Hz,4H),2.56(t,J=5.0Hz,4H),2.29(s,3H),2.21(s,6H)。
实施例10
4-[(3-((2,6-二乙基)氨基甲酰基)吡咯基]-N-[(2-甲氧基-4-(N-甲基哌嗪))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-10)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体24mg,收率23%,MS m/z:580.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.55(s,1H),9.78(s,1H),8.65(d,J=4.8Hz,2H),8.34(s,1H),7.94(s,1H),7.76(d,J=8.5Hz,1H),7.26-7.19(m,1H),7.14(d,J=7.5Hz,2H),6.95(d,J=3.3Hz,1H),6.67(d,J=2.5Hz,1H),6.53(dd,J=8.8,2.5Hz,1H),3.82(s,3H),3.19(t,J=5.0Hz,4H),2.57(t,J=7.3Hz,8H),2.29(s,3H),1.12(t,J=7.6Hz,6H)。
实施例11
4-[(3-((2,6-二甲基)氨基甲酰基)吡咯基]-N-[(2-甲氧基-4-(N-乙酰基哌嗪))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-11)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体60mg,收率48%,MS m/z:580.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.51(s,1H),9.58(s,1H),8.55(d,J=12.6Hz,2H),8.36(s,1H),7.95(t,J=2.7Hz,1H),7.79(d,J=8.7Hz,1H),7.13(s,3H),6.94(dd,J=3.3,1.6Hz,1H),6.71(d,J=2.5Hz,1H),6.56(dd,J=8.8,2.5Hz,1H),3.83(s,3H),3.60(dt,J=10.8,5.4Hz,4H),3.14(dt,J=23.2,5.2Hz,4H),2.22(s,6H),2.06(s,3H)。
实施例12
4-[(3-((2,6-二乙基)氨基甲酰基)吡咯基]-N-[(2-甲氧基-4-(N-乙酰基哌嗪))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-12)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体30mg,收率22%,MS m/z:608.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.50(s,1H),9.54(s,1H),8.54(d,J=12.8Hz,2H),8.35(s,1H),7.94(t,J=2.7Hz,1H),7.79(d,J=8.7Hz,1H),7.24(dd,J=8.4,6.6Hz,1H),7.16(d,J=7.5Hz,2H),6.94(dd,J=3.3,1.6Hz,1H),6.71(d,J=2.5Hz,1H),6.56(dd,J=8.7,2.5Hz,1H),3.83(s,3H),3.60(q,J=5.6Hz,4H),3.14(dt,J=24.1,5.2Hz,4H),2.58(q,J=7.6Hz,4H),2.06(s,3H),1.13(t,J=7.6Hz,6H)。
实施例13
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-哌嗪)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-13)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体50mg,收率20%,MS m/z:546.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.19(s,1H),7.92(t,J=4.4Hz,2H),7.63(dd,J=8.3,1.9Hz,1H),7.51(d,J=2.0Hz,1H),7.01(d,J=8.4Hz,1H),6.71(d,J=2.5Hz,1H),6.56(dd,J=8.9,2.4Hz,1H),3.91-3.77(m,10H),3.32(d,J=5.7Hz,5H),3.17(d,J=5.2Hz,5H),1.99(dt,J=13.3,5.7Hz,2H),1.87-1.58(m,6H),1.30-1.20(m,1H)。
实施例14
3-氰基-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-14)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体18mg,收率46%,MS m/z:477.3[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):14.19(s,1H),10.01(s,1H),8.41(s,1H),7.61(d,J=8.6Hz,1H),6.69(d,J=4.9Hz,1H),6.57(t,J=9.4Hz,1H),3.87(s,1H),3.81(d,J=8.8Hz,3H),2.78(d,J=4.8Hz,6H),2.69(d,J=11.6Hz,2H),2.09(d,J=11.8Hz,2H),1.97(s,2H),1.79(dd,J=23.2,13.6Hz,6H),1.64(s,2H),1.24(s,2H)。
实施例15
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-哌啶)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-15)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体60mg,收率20%,MS m/z:545.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.14(s,1H),8.04-7.78(m,3H),7.64(ddd,J=8.1,5.5,2.0Hz,1H),7.51(t,J=2.5Hz,1H),7.02(t,J=8.4Hz,1H),6.58(d,J=47.0Hz,3H),3.86-3.78(m,13H),3.12(t,J=5.3Hz,5H),2.06-1.91(m,2H),1.88-1.47(m,18H)。
实施例16
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-16)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体37mg,收率9%,MS m/z:588.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.11(s,1H),7.92(s,1H),7.78(d,J=8.6Hz,1H),7.64(dd,J=8.6,2.0Hz,1H),7.52(d,J=2.0Hz,1H),7.03(d,J=8.6Hz,1H),6.68(d,J=2.6Hz,1H),6.52(dd,J=8.8,2.5Hz,1H),3.81(d,J=6.5Hz,10H),2.80(s,1H),2.73-2.56(m,2H),2.09-1.94(m,4H),1.72(ddd,J=23.8,10.6,6.3Hz,3H),1.61-1.48(m,2H)。
实施例17
3-(3,5-二甲氧基苯基)-N-[(2-丙酰氨基)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-17)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体10mg,收率8%,MS m/z:417.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):9.16(s,1H),7.99(d,J=9.1Hz,1H),7.53(d,J=2.1Hz,1H),7.42-7.27(m,5H),6.79-6.50(m,3H),5.63(s,1H),5.40(s,1H),3.88(s,6H)。
实施例18
3-氯-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-18)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体18mg,收率15%,MS m/z:487.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):14.17(s,1H),10.01(s,1H),8.40(s,1H),7.61(d,J=8.6Hz,1H),6.70(d,J=4.8Hz,1H),6.57(t,J=9.4Hz,1H),3.88(s,1H),3.81(d,J=8.6Hz,3H),2.78(d,J=4.8Hz,6H),2.67(d,J=11.6Hz,2H),2.08(d,J=11.8Hz,2H),1.97(s,2H),1.79(dd,J=23.2,13.6Hz,6H),1.64(s,2H),1.23(s,2H)。
实施例19
3-溴-4-(环戊基氧基)-N-[(2-甲氧基-4-(N,N-二甲基氨基哌啶))苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-19)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体8mg,收率4%,MS m/z:531.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):14.18(s,1H),10.03(s,1H),8.44(s,1H),7.63(d,J=8.6Hz,1H),6.71(d,J=4.8Hz,1H),6.57(t,J=9.2Hz,1H),3.88(s,1H),3.83(d,J=8.6Hz,3H),2.77(d,J=4.8Hz,6H),2.66(d,J=11.4Hz,2H),2.08(d,J=11.4Hz,2H),1.97(s,2H),1.78(dd,J=23.2,13.6Hz,6H),1.66(s,2H),1.24(s,2H)。
实施例20
3-(3,4-二甲氧基苯基)-4-(环戊基硫基)-N-[(2-甲氧基-4-吗啉基)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-20)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体78mg,收率56%,MS m/z:563.2[M+H]+。
1H-NMR(400MHz,CDCl3)δ(ppm):13.16(s,1H),8.06-7.80(m,3H),7.66(dd,J=8.4,5.0,1H),7.50(dd,J=3.5,2.0Hz,1H),7.04(t,J=8.1Hz,1H),6.67(dd,J=4.3,2.5Hz,2H),6.52(td,J=9.2,2.5Hz,1H),5.70-5.54(m,2H),3.89-3.78(m,12H),3.76(t,J=4.8Hz,6H),3.11(t,J=4.8Hz,5H),1.99(ddd,J=13.6,9.0,4.1Hz,3H),1.88-1.56(m,5H)。
实施例21
3-(3,4-二甲氧基苯基)-4-(环戊氨基)-N-[(2-甲氧基-4-吗啉基)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺(I-21)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得黄色固体70mg,收率55%,MS m/z:546.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):13.16(s,1H),8.06-7.77(m,4H),7.65(dd,J=8.4,5.0,1H),7.51(dd,J=3.5,2.0Hz,1H),7.05(t,J=8.1Hz,1H),6.66(dd,J=4.3,2.5Hz,2H),6.50(td,J=9.2,2.5Hz,1H),5.70-5.53(m,2H),3.89-3.78(m,12H),3.74(t,J=4.8Hz,6H),3.11(t,J=4.8Hz,5H),1.98(ddd,J=13.6,9.0,4.1Hz,3H),1.88-1.55(m,5H)。
实施例22
3-(3,4-二甲氧基苯基)-4-(环戊基氧基)-N-[(2-甲氧基-4-吗啉基)苯基]-1H-吡唑并[3,4-d]嘧啶-6-胺盐酸盐(I-22)
制备方法参考实施例1,以4,6-二氯-1H-吡唑并[3,4-d]嘧啶为起始原料,得白色固体90mg,收率89%,MS m/z:547.2[M+H]+。
1H-NMR(400MHz,DMSO-d6)δ(ppm):13.75(s,1H),13.16(s,1H),8.06-7.81(m,3H),7.64(ddd,J=8.4,5.0,2.0Hz,1H),7.51(dd,J=3.5,2.0Hz,1H),7.02(t,J=8.1Hz,1H),6.67(dd,J=4.3,2.5Hz,2H),6.53(td,J=9.2,2.5Hz,1H),5.70-5.53(m,2H),3.89-3.79(m,12H),3.76(t,J=4.8Hz,6H),3.11(t,J=4.8Hz,5H),1.99(ddd,J=13.6,9.0,4.1Hz,3H),1.88-1.57(m,5H)。
实施例23:生物学活性
1.目标化合物的Mps1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Mps1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。Mps1通过直接购买试剂盒获得。
2.目标化合物的MDA-MB-468和MDA-MB-231细胞抑制活性测定
a.细胞复苏,培养细胞至对数生长期;b.配制化合物:供试品溶解在DMSO中,浓度为30mM,以1∶3比例梯度稀释,共10个梯度;c.将4~6*104/ml密度的细胞,接种到384孔板中,每个孔中接种25μL,加入化合物,化合物的终浓度为30,10,3.33,1.11,0.37,0.123,0.041,0.014,0.005,0.002mM;c.化合物与细胞孵育72h,通过CTG方法检测细胞活性。
下表是部分化合物的体外Mps1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Mps1抑制作用,可为制备治疗/预防与Mps1相关疾病的药物提供依据。
药理测试结果表明,本发明中嘧啶并嘧啶酮具有较好的Mps1激酶、MDA-MB-468细胞和MDA-MB-231细胞抑制活性,部分化合物IC50值与BAY 1161909相当或优于阳性对照,可用于预防或治疗与Mps1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Mps1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Mps1有关的临床病症的药物,如:制备预防和/治疗生物体内与Mps1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 (10)
1.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:
式I中,
X选自-CR5R6-、-NR5-、O或S,其中R5、R6各自独立地表示氢、氘、卤素、烷基、芳基或Het;
Y选自-NR7-、O或S,其中R7各自独立地表示氢、氘、卤素、烷基、芳基或Het;
Q选自-NR8CONR9-、-CONR8-、-NR8CO-、-CO-、-NR8SO2NR9-、-SO2NR8-、-NR8SO2-、-SO2-、-NR8-、-NR8(CH2)nNR9-、-NR8(CH2)nO-或-CR8R9,其中n=1、2、3、4或5,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
环A选自3-10元环烷基、3-10元杂环基、6-10元芳基、5-10元杂芳基;
R1选自氢、卤素、羟基、烷氧基、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、芳基或Het;
R4选自氢、卤素、羟基、烷氧基、烷基、芳基或Het;
烷基为1-6个碳原子的直链或支链饱和烃基、3-6个碳原子的环状饱和烃基,或连有1-6个碳原子直链或支链饱和烃基的3-6个碳原子的环状饱和烃基;
上述基团中,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;
卤素选自氟、氯、溴或碘。
2.根据权利要求1所述的化合物,其特征在于:式I中,
X为-NR5-或O,其中R5选自氢、氘、卤素、烷基、芳基或Het;
Y选自-NR7-或O,其中R7各自独立地表示氢、氘、卤素、烷基、芳基或Het;
Q选自-NR8CONR9-、-CONR8-、-NR8CO-、-CO-、-NR8SO2NR9-、-SO2NR8-、-NR8SO2-、-NR8(CH2)nNR9-、-SO2-或-CR8R9,其中n=1、2、3、4或5,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
环A选自3-10元环烷基、3-10元杂环基、6-10元芳基;
R1选自氢、烷氧基、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、烷氧基、烷基、芳基或Het;
R4选自氢、羟基、烷氧基、烷基、芳基或Het。
3.根据权利要求1所述的化合物,其特征在于:式I中,
X为-NR5-,其中R5选自氢、氘或烷基;
Y选自O;
Q选自-NR8CONR9-、-NR8CO-、-NR8SO2NR9-、-NR8(CH2)nNR9-、-NR8SO2-或-CR8R9,其中n=1、2、3、4或5,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
环A选自6-10元芳基;
R1选自氢、烷氧基、烷基或芳基;
R2选自氢、卤素、羟基、烷氧基或烷基;
R3选自氢、烷氧基或烷基;
R4选自氢、烷氧基、烷基、芳基或Het。
4.根据权利要求1所述的化合物,其特征在于:式I中,
X为-NH-;
Y选自O;
Q选自-NR8(CH2)nR9N-或-N(CH2)nN-,其中n=1或2,R8、R9各自独立地表示氢、氘、烷基、芳基或Het;
R1为氢或烷基;
R2选自氢、卤素或烷基;
R3选自氢、烷氧基或烷基;
R4选自氢、烷氧基、烷基、芳基或Het。
5.根据权利要求1所述的化合物,其特征在于:所述药学上可接受的盐包括通式I的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。
6.根据权利要求5所述的化合物,其特征在于:所述药学上可接受的盐包括碱性金属阳离子盐、碱土金属阳离子盐和铵阳离子盐。
8.一种药物组合物,其特征在于:包括权利要求1所述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。
9.权利要求1所述的化合物在制备用于预防和/或治疗激酶Mps1相关疾病的药物中的用途。
10.根据权利要求9所述的应用,其特征在于:所述激酶Mps1相关疾病选自但不限于高脂血症或癌症;所述的癌症包括肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、乳腺癌、乳腺导管癌、头颈癌、子宫内膜癌、宫体癌、直肠癌、肝癌、肾癌、肾盂癌、食管癌、食管腺癌、神经胶质瘤、***癌、甲状腺癌、女性生殖***癌症、原位癌、淋巴瘤、神经纤维瘤病、骨癌、皮肤癌、脑癌、结肠癌、睾丸癌、胃肠道间质瘤、口腔癌、咽癌、多发性骨髓瘤、白血病、非霍奇金淋巴瘤、大肠绒毛腺瘤、黑色素瘤、细胞瘤和肉瘤,及骨髓增生异常综合症。
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