CN106946871A - 噁二唑联噻唑衍生物及其制备方法和用途 - Google Patents

噁二唑联噻唑衍生物及其制备方法和用途 Download PDF

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CN106946871A
CN106946871A CN201710253201.6A CN201710253201A CN106946871A CN 106946871 A CN106946871 A CN 106946871A CN 201710253201 A CN201710253201 A CN 201710253201A CN 106946871 A CN106946871 A CN 106946871A
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compound
yield
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white solid
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梁英
何海峰
石丽桥
张志刚
柯少勇
杨自文
王开梅
方伟
陈伟
江爱兵
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Hubei Biopesticide Engineering Research Center
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

本发明提供了噁二唑联噻唑衍生物及其制备方法和用途，该化合物为式I所示化合物或其对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物或溶剂合物。R1为氨基或甲基氨基；R2为甲基或三氟甲基；R3为呋喃基或任选取代的苯基；R4为至少一个卤素、氢、硝基、三氟甲基、任选取代的烷氧基。该衍生物能够用于治疗癌症相关疾病。

Description

噁二唑联噻唑衍生物及其制备方法和用途
技术领域
本发明涉及医药领域，具体的，本发明涉及噁二唑联噻唑衍生物及其制备方法和应用，更具体的，本发明涉及式Ι所示化合物以及衍生物及其制备方法、药物组合物、式Ι所示化合物在制备药物中的用途。
背景技术
肿瘤是机体在各种致癌因素作用下，局部组织的某一个细胞在基因水平上失去对其生长的正常调控，导致其克隆性异常增生而形成的异常病变。学界一般将肿瘤分为良性和恶性两大类。
然而，现有肿瘤的治疗手段仍有待改进。
发明内容
本发明旨在解决现有技术中存在的技术问题之一，为此，本发明的一个目的在于提供了一种能够用于制备治疗癌症的药物的化合物。
在本发明的第一方面，提供了一种噁二唑联噻唑衍生物。根据本发明的实施例，该化合物为式I所示化合物或式I所示化合物的对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物或溶剂合物，
其中，
R1为氨基或甲基氨基；
R2为甲基或三氟甲基；
R3为呋喃基或任选取代的苯基；
R4为至少一个卤素、氢、硝基、三氟甲基、任选取代的烷氧基。
发明人惊奇地发现，根据本发明实施例的化合物具有有效地抗癌活性。
根据本发明的实施例，上述化合物还可以具有下列附加技术特征：
根据本发明的一个实施例中，所述卤素为F、Cl、Br。
根据本发明的一个实施例中，所述R3为呋喃基、苯基、任选卤素取代的苯基、三氟甲基取代的苯基，硝基取代的苯基或甲氧基取代的苯基。
根据本发明的一个实施例中，所述R3为呋喃基、苯基、4-氯苯基、2-氯苯基、2,4-二氯苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-三氟甲基苯基、2-三氟甲基苯基、3-三氟甲基苯基、3，5-二(三氟甲基)苯基、3,4,5-三甲氧基苯基、4-甲氧基苯基、4-硝基苯基、3-硝基苯基、2-硝基苯基。
根据本发明的一个实施例中，所述R4为至少一个卤素、氢、硝基、三氟甲基或甲氧基，任选地，所述R4代表两个卤素，任选地，所述两个卤素呈间位关系或邻位关系，任选地，所述两个卤素均为Cl或均为F，任选地，所述R4代表三个甲氧基，任选地，所述三个甲氧基呈邻位关系。
根据本发明的一个实施例中，所述噁二唑联噻唑衍生物为下列化合物或者所述下列化合物的对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物或溶剂合物：
在本发明的第二方面，本发明提供了一种制备前面所述噁二唑联噻唑衍生物的方法，根据本发明的实施例，该方法包括：
(1)使式A所示化合物与取代苯甲醛进行接触，以便获得式B所示化合物；
(2)使所述式B所示化合物与所述式C化合物进行接触，以便获得式I所示化合物；
其中R1、R2、R3、R4是如前面所描述的。
由此，根据本发明的实施例，本发明提出了一条合成路线，可以用于制备式I-1所示化合物。
在100mL三口烧瓶中加入中间体2-甲氨基-4-甲基-5-乙氧羰基-1,3-噻唑A0.04mol(8.00g)、20mL 85％水合肼和5mL无水乙醇，搅拌加热回流反应2h，反应完毕，有大量的白色固体析出，冷却，过滤，并用无水乙醇洗涤滤饼3次,干燥得白色固体5.26g。产率为70.6％。
在25mL三口瓶中加入苯甲醛-N-(2-甲胺基-4-甲基-1,3-噻唑-5-甲酰基)腙2mmol(0.55g)和5mL甲苯，升温至100℃，快速加入5mmol 2,6-二氟苯甲酰异氰酸酯的甲苯溶液5mL,TLC检测反应。反应完后过滤得白色固体0.32g。产率为70.3％。
本发明的第三方面，本发明提供了一种药物组合物，包括前面所述的化合物。
在本发明的第四方面，本发明提供了前面所述的化合物或其药物组合物在制备药物中的用途，所述药物用于治疗癌症，任选地，所述癌症为口腔上皮癌、鼻咽癌、肝癌、胃癌、乳腺癌、宫颈癌。
具体实施方式
下面详细描述本发明的实施例。下面实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
实施例1
化合物I-1
的制备
在100mL三口烧瓶中加入中间体2-甲氨基-4-甲基-5-乙氧羰基-1,3-噻唑(3)0.04mol(8.00g)、20mL 85％水合肼和5mL无水乙醇，搅拌加热回流反应2h，反应完毕，有大量的白色固体析出，冷却，过滤，并用无水乙醇洗涤滤饼3次,干燥得白色固体5.26g。产率为70.6％。
在25mL三口瓶中加入N-(2-甲胺基-4-甲基-1,3-噻唑-5-甲酰基)苯腙2mmol(0.55g)和5mL甲苯，升温至100℃，快速加入5mmol 2,6-二氟苯甲酰异氰酸酯的甲苯溶液5mL,TLC检测反应。反应完后过滤得白色固体0.32g。产率为70％。White solid,yield70％,mp 242～243℃:1H NMR(DMSO-d6,400MHz):δ＝2.65(s,3H,CH3),3.66(s,3H,NCH3),,7.50(dd,8H,Ar-H,J＝129.1,53.5Hz),8.03(s,1H,CH),11.71(s,1H,CONH)；MS(ESI)m/z:458.3(M+1)+,calcd.for C21H17F2N5O3S m/z＝457.10；IR(KBr)(υ/cm-1):3447,3131,1757,1070,1122；Calcd.For C21H17F2N5O3S:C 55.14,H 3.75,N 15.31；Found:C 55.37,H 3.81,N15.65.
以下化合物按照化合物1-1的方法制备，其结构鉴定数据如下：
化合物I-2
White solid,yield 78％,mp 288～289℃:1H NMR(DMSO-d6,400MHz):δ＝2.64(s,3H,CH3),3.67(s,3H,NCH3),,7.08～7.62(m,7H,Ar-H),8.02(s,1H,CH),11.67(s,1H,NH)11.88(s,1H,CONH)；MS(ESI)m/z:492.2(M+1)+,calcd.for C21H16ClF2N5O3S m/z＝491.06；IR(KBr)(υ/cm-1):3440,3131,1713,1070,1147,743；Calcd.For C21H16ClF2N5O3S:C 51.28,H3.28,N 14.24；Found:C 51.35,H 3.57,N 14.41.
化合物I-3
White solid,yield 79％,mp 282～283℃:1H NMR(DMSO-d6,400MHz):δ＝2.64(s,3H,CH3),3.65(s,3H,NCH3),7.23～7.74(m,7H,Ar-H),8.01(s,1H,CH),11.70(s,1H,NH)；MS(ESI)m/z:492.2(M+1)+,calcd.for C21H16ClF2N5O3S m/z＝491.06；IR(KBr)(υ/cm-1):3444,3243,1747,1071,1123,737；Calcd.For C21H16ClF2N5O3S:C 51.28,H 3.28,N 14.24；Found:C 51.30,H 3.51,N 14.41.
化合物I-4
White solid,yield 80％,mp 279～281℃:1H NMR(DMSO-d6,400MHz):δ＝2.65(s,3H,CH3),3.67(s,3H,NCH3),,6.99～7.96(m,7H,Ar-H),8.25(s,1H,CH),11.68(s,1H,NH),11.82(s,1H,CONH)；MS(ESI)m/z:476.1(M+1)+,calcd.for C21H16F3N5O3S m/z＝475.09；IR(KBr)(υ/cm-1):3444,3131,1714,1070,1144；Calcd.For C21H16F3N5O3S:C 53.05,H 3.39,N14.73；Found:C 53.19,H 3.52,N 14.78.
化合物I-5
White solid,yield 85％,mp 239～240℃:1H NMR(DMSO-d6,400MHz):δ＝2.64(s,3H,CH3),3.66(s,3H,NCH3),,7.09～7.61(m,7H,Ar-H),7.77(s,1H,CH),11.70(s,1H,NH)；MS(ESI)m/z:476.2(M+1)+,calcd.for C21H16F3N5O3S m/z＝475.09；IR(KBr)(υ/cm-1):3443,3131,1746,1070,1121；Calcd.For C21H16F3N5O3S:C 53.05,H 3.39,N 14.73；Found:C53.33,H 3.67,N 14.89.
化合物I-6
White solid,yield 86％,mp 288～290℃:1H NMR(DMSO-d6,400MHz):δ＝2.63(s,3H,CH3),3.67(s,3H,NCH3),6.99～8.00(m,7H,Ar-H),8.34(s,1H,CH),11.68(s,1H,NH)11.89(s,1H,CONH)；MS(ESI)m/z:525.1(M+1)+,calcd.for C21H15Cl2F2N5O3S m/z＝525.02；IR(KBr)(υ/cm-1):3443,3131,1727,1070,1123,743；Calcd.For C21H15Cl2F2N5O3S:C 47.92,H 2.87,N 13.31；Found:C 47.99,H 2.93,N 13.49.
化合物I-7
White solid,yield 87％,mp 267～268℃:1H NMR(DMSO-d6,400MHz):δ＝2.65(s,3H,CH3),3.67(s,3H,NCH3),,7.20～7.92(m,7H,Ar-H),8.07(s,1H,CH),11.72(s,1H,NH)11.89(s,1H,CONH)；MS(ESI)m/z:526.1(M+1)+,calcd.for C22H16F5N5O3S m/z＝525.09；IR(KBr)(υ/cm-1):3443,3229,1752,1067,1323,1122；Calcd.For C22H16F5N5O3S:C 50.29,H3.07,N 13.33；Found:C 50.80,H 3.10,N 13.35.
化合物I-8
White solid,yield 88％,mp 251～252℃:1H NMR(DMSO-d6,400MHz):δ＝2.67(s,3H,CH3),3.66(s,3H,NCH3),3.74(d,9H,OCH3,J＝29.6Hz),7.03～7.67(m,5H,Ar-H),7.97(s,1H,CH),11.59(s,1H,NH)11.71(s,1H,CONH)；MS(ESI)m/z:548.5(M+1)+,calcd.forC24H23F2N5O6S m/z＝547.13；IR(KBr)(υ/cm-1):3442,3131,1749,1071,1128；Calcd.ForC24H23F2N5O6S:C 52.65,H 4.23,N 12.79；Found:C 52.90,H 4.27,N 12.80.
化合物I-9
Light yellow solid,yield 86％,mp 233～234℃:1H NMR(DMSO-d6,400MHz):δ＝2.62(s,3H,CH3),3.65(s,3H,NCH3),6.62(d,1H,C＝CH,J＝1.7Hz),6.86(s,1H，C＝CH)，7.24～7.63(m,3H,Ar-H),7.73(s,1H,OCH＝C),7.95(s,1H,CH),11.71(s,1H,NH)；MS(ESI)m/z:448.1(M+1)+,calcd.for C19H15F2N5O4S m/z＝447.18；IR(KBr)(υ/cm-1):3452,3183,1756,1070,1124；Calcd.For C19H15F2N5O4S:C 51.00,H 3.38,N 15.65；Found:C 51.16,H 3.48,N15.77.
化合物I-10
White solid,yield 87％,mp 220～222℃:1H NMR(DMSO-d6,400MHz):δ＝2.64(s,3H,CH3),3.64(s,3H,NCH3),3.82(d,3H,OCH3),6.87～7.66(m,7H,Ar-H),7.96(s,1H,CH),11.56(s,1H,NH)；MS(ESI)m/z:488.2(M+1)+,calcd.for C22H19F2N5O4S m/z＝487.11；IR(KBr)(υ/cm-1):3450,3256,1746,1071,1123；Calcd.For C22H19F2N5O4S:C 54.20,H 3.93,N14.37；Found:C 54.57,H 3.98,N 14.44.
化合物I-11
White solid,yield 79％,mp>260℃:1H NMR(DMSO-d6):δ＝2.64(d,3H,CH3),7.27～7.99(m,7H,Ar-H),8.14(s,1H,CH),11.42(s,2H,NH2),11.92(s,1H,CONH)；MS(ESI)m/z:511.8(M+1)+,calcd.for C21H14F5N5O3S m/z＝511.07；IR(KBr)(υ/cm-1):3432,3068,1714,1067,1325,1123；Calcd.For C21H14F5N5O3S:C 49.32,H 2.76,N 13.69；Found:C 49.56,H2.77,N 13.72.
化合物I-12
White solid,yield 78％,mp 239～241℃:1H NMR(DMSO-d6):δ＝7.26～7.89(m,7H,Ar-H),8.19(s,1H,CH),11.86(s,2H,NH2),12.43(s,1H,CONH)；MS(ESI)m/z:566.1(M+1)+,calcd.for C21H11F8N5O3S m/z＝565.05；IR(KBr)(υ/cm-1):3431,3131,1712,1068,1325,1131；Calcd.For C21H11F8N5O3S:C 44.61,H 1.96,N 12.39；Found:C 44.73,H 2.03,N12.46.
化合物I-13
White solid,yield 79％,mp 219～221℃:1H NMR(DMSO-d6):δ＝3.71(s,3H,CH3),7.23～7.93(m,7H,Ar-H),8.16(s,1H,CH),11.71(s,2H,NH),12.39(s,1H,CONH)；MS(ESI)m/z:580.2(M+1)+,calcd.for C22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3445,3242,1718,1066,1324,1129；Calcd.For C22H13F8N5O3S:C 45.60,H 2.26,N 12.09；Found:C45.91,H 2.34,N 12.31.
化合物I-14
White solid,yield 80％,mp>260℃:1H NMR(DMSO-d6):δ＝2.64(s,3H,CH3),7.30～8.10(m,7H,Ar-H),8.14(s,1H,CH),11.45(s,2H,NH2),12.00(s,1H,CONH)；MS(ESI)m/z:512.4(M+1)+,calcd.for C21H14F5N5O3S m/z＝511.07；IR(KBr)(υ/cm-1):3443,3217,1703,1062,1314,1117；Calcd.For C21H14F5N5O3S:C 49.32,H 2.76,N 13.69；Found:C 49.36,H2.82,N 13.70.
化合物I-15
White solid,yield 85％,mp 236～238℃:1H NMR(DMSO-d6):δ＝2.64(s,3H,CH3),3.67(s,3H,NCH3),7.26～7.80(m,7H,Ar-H),8.22(s,1H,CH),11.66(s,2H,NH),11.92(s,1H,CONH)；MS(ESI)m/z:526.3(M+1)+,calcd.for C21H14F5N5O3S m/z＝525.09；IR(KBr)(υ/cm-1):3444,2937,1750,1072,1318,1129；Calcd.For C21H14F5N5O3S:C 50.29,H 3.07,N13.33；Found:C 50.38,H 3.21,N 13.67.
化合物I-16
White solid,yield 88.1％,mp 233.6～234.3℃:1H NMR(DMSO-d6):δ＝7.15～7.67(m,7H,Ar-H),7.80(s,1H,CH),11.86(s,2H,NH2),12.46(s,1H,CONH)；MS(ESI)m/z:566.3(M+1)+,calcd.for C21H11F8N5O3S m/z＝565.05；IR(KBr)(υ/cm-1):3440,3131,1707,1070,1346,1123；Calcd.For C21H11F8N5O3S:C 44.61,H 1.96,N 12.39；Found:C 44.74,H2.00,N 12.44.
化合物I-17
White solid,yield 86％,mp 181～183℃:1HNMR(DMSO-d6):δ＝3.75(s,3H,CH3),7.20～8.25(m,7H,Ar-H),8.52(s,1H,CH),11.75(s,2H,NH),12.48(s,1H,CONH)；MS(ESI)m/z:580.4(M+1)+,calcd.for C22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3443,3131,1715,1070,1315,1123；Calcd.For C22H13F8N5O3S:C 45.60,H 2.26,N 12.09；Found:C45.79,H 2.40,N 12.19.
化合物I-18
White solid,yield 85％,mp>260℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),7.27～8.09(m,7H,Ar-H),8.09(s,1H,CH),11.45(s,1H,CONH),11.88(s,2H,NH2)；MS(ESI)m/z:512.3(M+1)+,calcd.for C21H14F5N5O3S m/z＝511.07；IR(KBr)(υ/cm-1):3444,3218,1729,1070,1331,1122；Calcd.For C21H14F5N5O3S:C 49.32,H 2.76,N 13.69；Found:C 49.60,H2.82,N 13.83.
化合物I-19
White solid,yield 86％,mp>260℃:1H NMR(DMSO-d6):δ＝2.64(s,3H,CH3),3.66(s,3H,NCH3),7.22～8.12(m,7H,Ar-H),8.02(s,1H,CH),11.70(s,1H,NH),11.85(s,1H,CONH)；MS(ESI)m/z:526.3(M+1)+,calcd.for C22H16F5N5O3S m/z＝525.09；IR(KBr)(υ/cm-1):3442,3268,1750,1069,1330,1125；Calcd.For C22H16F5N5O3S:C 50.29,H 3.07,N13.33；Found:C 50.60,H 3.05,N 13.55.
化合物I-20
White solid,yield 86％,mp 227～228℃:1H NMR(DMSO-d6):δ＝7.25～8.07(m,7H,Ar-H),8.21(s,1H,CH),11.87(s,2H,NH2),12.41(s,1H,CONH)；MS(ESI)m/z:566.3(M+1)+,calcd.for C21H11F8N5O3S m/z＝565.05；IR(KBr)(υ/cm-1):3444,3131,1729,1070,1333,1122；Calcd.For C21H11F8N5O3S:C 44.61,H 1.96,N 12.39；Found:C 44.78,H 2.17,N12.48.
化合物I-21
White solid,yield 86％,mp 202～204℃:1HNMR(DMSO-d6):δ＝3.70(s,3H,NCH3),7.24～8.06(m,7H,Ar-H),8.19(s,1H,CH),11.69(s,2H,NH),12.39(s,1H,CONH)；MS(ESI)m/z:580.3(M+1)+,calcd.for C22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3443,3131,1729,1070,1337,1122；Calcd.For C22H13F8N5O3S:C 45.60,H 2.26,N 12.09；Found:C45.90,H 2.33,N 12.05.
化合物I-22
White solid,yield 81％,mp 193～194℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),7.10～7.54(m,6H,Ar-H),8.10(s,1H,CH),11.20(s,2H,NH2),12.59(s,1H,CONHCO)；MS(ESI)m/z:580.3(M+1)+,calcd.for C22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3441,3131,1711,1070,1323,1130；Calcd.For C22H13F8N5O3S:C 45.60,H 2.26,N 12.09；Found:C45.91,H 2.82,N 11.95.
化合物I-23
White solid,yield 64％,mp 199～200℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),3.69(s,3H,NCH3),7.18～7.24(m,4H,Ar-H),7.59(s,2H,Ar-H),8.43(d,1H,CH,J＝32.7Hz),11.69(s,1H,CONH),12.59(s,1H,CONHCO)；MS(ESI)m/z:594.4(M+1)+,calcd.forC23H15F8N5O3S m/z＝593.08；IR(KBr)(υ/cm-1):3444,3230,1754,1096,1324,1142；Calcd.For C23H15F8N5O3S:C 46.55,H 2.55,N 11.80；Found:C 46.51,H 2.68,N 11.99.
化合物I-24
White solid,yield 84％,mp 230～232℃:1H NMR(DMSO-d6):δ＝7.25～8.48(m,6H,Ar-H),8.11(s,1H,CH),11.84(s,2H,NH2),12.60(s,1H,CONH)；MS(ESI)m/z:634.5(M+1)+,calcd.for C22H10F11N5O3S m/z＝633.03；IR(KBr)(υ/cm-1):3439,3207,1695,1142,1358,1142；Calcd.For C22H10F11N5O3S:C 41.72,H 1.59,N 11.06；Found:C 41.93,H 1.60,N11.14.
化合物I-25
White solid,yield 60％,mp 209～211℃:1H NMR(DMSO-d6):δ＝3.74(s,3H,CH3),7.64(s,1H,CH),7.19～8.52(m,6H,Ar-H),11.74(s,1H,NH),12.64(s,1H,CONH)；MS(ESI)m/z:648.4(M+1)+,calcd.for C23H12F11N5O3S m/z＝647.05；IR(KBr)(υ/cm-1):3442,3131,1756,1071,1281,1141；Calcd.For C23H12F11N5O3S:C 42.67,H 1.87,N 10.82；Found:C42.75,H 1.95,N 10.96.
化合物I-26
Light yellow solid,yield 30％,mp 181～183℃:1H NMR(DMSO-d6):δ＝2.88(s,3H,CH3),3.69(s,3H,NCH3),3.81(s,9H,OCH3),7.20～7.94(m,6H,Ar-H),8.08(s,1H,CH),11.46(s,1H,NH),11.83(s,1H,CONH)；MS(ESI)m/z:580.4(M+1)+,calcd.for C25H24F3N5O6Sm/z＝579.14；IR(KBr)(υ/cm-1):3442,3131,1729),1070,1324,1130；Calcd.ForC25H24F3N5O6S:C 51.81,H 4.17,N 12.08；Found:C 52.08,H 4.38,N 12.23.
化合物I-27
White solid,yield 40％,mp 248～249℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),3.70(s,3H,NCH3),7.45～7.93(m,7H,Ar-H),8.09(s,1H,CH),13.79(s,1H,NH),11.90(s,1H,CONH)；MS(ESI)m/z:558.0(M+1)+,calcd.for C22H16Cl2F3N5O3S m/z＝557.03；IR(KBr)(υ/cm-1):3432,3131,1715,1069,1326,1120；Calcd.For C22H16Cl2F3N5O3S:C 47.32,H2.89,N 12.54；Found:C 47.70,H 2.92,N 12.67.
化合物I-28
White solid,yield 64％,mp 230～232℃:1H NMR(400MHz,DMSO-d6):δ＝3.73(s,3H,NCH3),7.58～8.21(m,8H,Ar-H),8.49(s,1H,CH),11.48(s,1H,CONH),12.57(s,1H,CONHCO)；MS(ESI)m/z:612.2(M+1)+,calcd.for C23H14F9N5O3S m/z＝611.07；IR(KBr)(υ/cm-1):3444,3136,1745,1635,1559,1372,1070；Calcd.For C23H14F9N5O3S:C,45.18；H,2.31；N,11.45；Found:C,45.61；H,2.56；N,11.36.
化合物I-29
White solid,yield 74％,mp 198～199℃:1H NMR(400MHz,DMSO-d6):δ＝2.65(s,3H,CH3),7.38～8.21(m,8H,Ar-H),8.25(s,1H,CH),11.25(s,2H,NH2),12.50(s,1H,CONHCO)；MS(ESI)m/z:544.2(M+1)+,calcd.for C22H15F6N5O3S m/z＝543.08；Calcd.ForC22H15F6N5O3S:C,48.62；H,2.78；N,12.89；Found:C,48.67；H,2.71；N,12.82.
化合物I-30
White solid,yield 67％,mp 221～223℃:1H NMR(400MHz,DMSO-d6):δ＝7.09～7.34(m,8H,Ar-H),7.55(s,1H,CH),11.25(s,2H,NH2),12.51(s,1H,CONHCO)；MS(ESI)m/z:597.9(M+1)+,calcd.for C22H12F9N5O3S m/z＝597.05；Calcd.For C22H12F9N5O3S:C,44.23；H,2.02；N,11.72；Found:C,44.65；H,2.32；N,11.52.
化合物I-31
White solid,yield 70％,mp 232～233℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.59～8.08(m,8H,Ar-H),8.21(s,1H,CH),11.27(s,1H,CONH),12.40(s,1H,CONHCO)；MS(ESI)m/z:612.2(M+1)+,calcd.for C23H14F9N5O3S m/z＝611.07；IR(KBr)(υ/cm-1):3442,3241,1746,1616,1566,1373,1071；Calcd.For C23H14F9N5O3S:C,45.18；H,2.31；N,11.45；Found:C,45.65；H,2.45；N,11.37.
化合物I-32
White solid,yield 80％,mp 193～194℃:1H NMR(DMSO-d6):δ＝3.72(s,3H,NCH3),7.90(s,2H,Ar-H),8.09(s,3H,Ar-H),8.28(s,2H,Ar-H),8.39(s,1H,CH),11.26(s,1H,CONH),12.59(s,1H,CONHCO)；MS(ESI)m/z:680.3(M+1)+,calcd.for C24H13F12N5O3S m/z＝679.05；IR(KBr)(υ/cm-1):3444,3234,1730,1646,1578,1370,1070；Calcd.ForC24H13F12N5O3S:C,42.43；H,1.93；N,10.31；Found:C,42.55；H,1.87；N,10.54.
化合物I-33
White solid,yield 79％,mp 175～176℃:1H NMR(DMSO-d6):δ＝3.72(s,3H,NCH3),7.14(s,1H,Ar-H),7.23(s,1H,Ar-H),7.60(s,1H,Ar-H),7.79(s,2H,Ar-H),8.02(s,2H,Ar-H),8.24(s,1H,Ar-H),8.24(s,1H,CH),11.28(s,1H,CONH),12.46(s,1H,CONHCO)；MS(ESI)m/z:612.1(M+1)+,calcd.for C23H14F9N5O3S m/z＝611.07；IR(KBr)(υ/cm-1):3445,3140,1737,1640,1560,1369,1070；Calcd.For C23H14F9N5O3S:C,45.18；H,2.31；N,11.45；Found:C,45.67；H,2.55；N,11.15.
化合物I-34
White solid,yield 65％,mp 176～177℃:1H NMR(DMSO-d6):δ＝3.72(s,3H,NCH3),7.49～8.25(s,8H,Ar-H),8.27(s,1H,CH),11.59(s,1H,CONH),12.39(s,1H,CONHCO)；MS(ESI)m/z:611.9(M+1)+,calcd.for C23H14F9N5O3S m/z＝611.07；IR(KBr)(υ/cm-1):3447,3131,1757,1646,1569,1372,1070；Calcd.For C23H14F9N5O3S:C,45.18；H,2.31；N,11.45；Found:C,45.67；H,2.51；N,11.35.
化合物I-35
White solid,yield 89％,mp 186～188℃:1H NMR(DMSO-d6):δ＝3.71(s,3H,NCH3),7.28(s,1H,Ar-H),8.02～8.29(m,6H,Ar-H),8.40(s,1H,CH),11.27(s,1H,CONH),12.60(s,1H,CONHCO)；MS(ESI)m/z:680.1(M+1)+,calcd.for C24H13F12N5O3S m/z＝679.05；IR(KBr)(υ/cm-1):3442,3221,1747,1636,1570,1373,1071；Calcd.For C24H13F12N5O3S:C,42.43；H,1.93；N,10.31；Found:C,42.65；H,1.89；N,10.71.
化合物I-36
White solid,yield 71％,mp 202～203℃:1H NMR(DMSO-d6):δ＝3.72(s,3H,NCH3),7.71～8.23(m,8H,Ar-H),8.23(s,1H,CH),11.28(s,1H,CONH),12.41(s,1H,CONHCO)；MS(ESI)m/z:611,9(M+1)+,calcd.for C23H14F9N5O3S m/z＝611.07；IR(KBr)(υ/cm-1):3442,3150,1757,1640,1560,1372,1070；Calcd.For C23H14F9N5O3S:C,45.18；H,2.31；N,11.45；Found:C,45.65；H,2.67；N,11.55.
化合物I-37
White solid,yield 70％,mp 224～225℃:1H NMR(DMSO-d6):δ＝7.60～7.65(m,3H,Ar-H),7.80(s,4H,Ar-H),8.01(s,1H,CH),11.12(s,1H,NH2),12.45(s,1H,CONHCO)；MS(ESI)m/z:566.0(M+1)+,calcd.for C21H11F8N5O3S m/z＝565.05；IR(KBr)(υ/cm-1):3442,3151,1737,1640,1560,1371,1070；Calcd.For C21H11F8N5O3S:C,44.61；H,1.96；N,12.39；Found:C,44.91；H,1.87；N,12.57.
化合物I-38
White solid,yield 78％,mp 224～225℃:1H NMR(DMSO-d6):δ＝3.69(s,3H,NCH3),7.62～7.66(m,3H,Ar-H),7.80(s,3H,Ar-H),8.01(m,1H,Ar-H),8.01(s,1H,CH),11.12(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z:580.1(M+1)+,calcd.forC22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3442,3151,1737,1640,1560,1371,1070；Calcd.For C22H13F8N5O3S:C,45.60；H,2.26；N,12.09；Found:C,45.70；H,2.56；N,12.34.
化合物I-39
White solid,yield 88％,mp 223～224℃:1H NMR(DMSO-d6):δ＝3.70(s,3H,NCH3),7.62～8.08(m,7H,Ar-H),8.08(s,1H,CH),11.12(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z:579.8(M+1)+,calcd.for C22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3442,3141,1747,1646,1560,1373,1071；Calcd.For C22H13F8N5O3S:C,45.60；H,2.26；N,12.09；Found:C,45.92；H,2.56；N,12.65.
化合物I-40
White solid,yield 67％,mp>260℃:1H NMR(DMSO-d6):δ＝3.70(s,3H,NCH3),7.63(s,1H,Ar-H),7.81(s,1H,Ar-H),8.00～8.18(m,2H,Ar-H),8.29(s,2H,Ar-H),8.40(s,1H,CH),11.13(s,1H,CONH),12.60(s,1H,CONHCO)；MS(ESI)m/z:647.9(M+1)+,calcd.forC23H12F11N5O3S m/z＝647.05；IR(KBr)(υ/cm-1):3442,3331,1756,1640,1569,1372,1070；Calcd.For C23H12F11N5O3S:C,42.67；H,1.87；N,10.82；Found:C,42.87；H,1.82；N,10.52.
化合物I-41
White solid,yield 77％,mp 214～215℃:1H NMR(DMSO-d6):δ＝7.60～7.85(m,7H,Ar-H),8.11(s,1H,CH),11.15(s,1H,NH2),12.45(s,1H,CONHCO)；MS(ESI)m/z:566.3(M+1)+,calcd.for C21H11F8N5O3S m/z＝565.05；Calcd.For C21H11F8N5O3S:C,44.61；H,1.96；N,12.39；Found:C,44.98；H,1.99；N,12.59.
化合物I-42
White solid,yield 85％,mp 220～222℃:1H NMR(DMSO-d6):δ＝3.70(s,3H,NCH3),7.64～8.03(m,7H,Ar-H),8.08(s,1H,CH),11.15(s,1H,CONH),12.44(s,1H,CONHCO)；MS(ESI)m/z:580.0(M+1)+,calcd.for C22H13F8N5O3S m/z＝579.06；IR(KBr)(υ/cm-1):3440,3241,1747,1640,1569,1371,1070；Calcd.For C22H13F8N5O3S:C,45.60；H,2.26；N,12.09；Found:C,45.76；H,2.53；N,12.39.
化合物I-43
White solid,yield 78％,mp 196～199℃:1H NMR(DMSO-d6):δ＝2.53(s,3H,CH3),7.16～7.32(m,4H,Ar-H),7.45～7.66(m,3H,Ar-H),8.01(s,1H,CH),11.50(s,1H,NH2),12.41(s,1H,CONHCO)；MS(ESI)m/z:543.9(M+1)+,calcd.for C21H14Cl2F3N5O3S m/z＝543.01；IR(KBr)(υ/cm-1):；Calcd.For C21H14Cl2F3N5O3S:C,46.34；H,2.59；N,12.87；Found:C,46.78；H,2.76；N,12.59.
化合物I-44
White solid,yield 80％,mp 189～190℃:1H NMR(DMSO-d6):δ＝7.66～7.99(m,7H,Ar-H),8.10(s,1H,CH),11.50(s,2H,NH2),12.41(s,1H,CONHCO)；MS(ESI)m/z:597.9(M+1)+,calcd.for C21H11Cl2F6N5O3S m/z＝596.99；Calcd.For C21H11Cl2F6N5O3S:C,42.16；H,1.85；N,11.71；Found:C,42.60；H,1.98；N,11.75.
化合物I-45
White solid,yield 88％,mp 199～200℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.16～7.82(m,7H,Ar-H),7.99(s,1H,CH),11.50(s,1H,NH),12.41(s,1H,CONHCO)；MS(ESI)m/z:612.0(M+1)+,calcd.for C22H13Cl2F6N5O3S m/z＝611.00；IR(KBr)(υ/cm-1):3442,3232,1746,1640,1560,1373,1070；Calcd.For C22H13Cl2F6N5O3S:C,43.15；H,2.14；N,11.44；Found:C,43.65；H,2.44；N,11.56.
化合物I-46
White solid,yield 76％,mp 240～242℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),7.55～7.74(m,5H,Ar-H),7.92(s,2H,Ar-H),8.09(s,1H,CH),11.79(s,1H,NH2),12.40(s,1H,CONHCO)；MS(ESI)m/z:543.9(M+1)+,calcd.for C21H14Cl2F3N5O3S m/z＝543.01；Calcd.For C21H14Cl2F3N5O3S:C,46.34；H,2.59；N,12.87；Found:C,46.56；H,2.87；N,12.56.
化合物I-47
White solid,yield 86％,mp>260℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),3.70(s,3H,NCH3),7.54～8.06(m,7H,Ar-H),8.19(s,1H,CH),11.49(s,1H,CONH),12.38(s,1H,CONHCO)；MS(ESI)m/z:557.9(M+1)+,calcd.for C22H16Cl2F3N5O3S m/z＝557.03；IR(KBr)(υ/cm-1):3440,3234,1756,1649,1563,1373,1070；Calcd.For C22H16Cl2F3N5O3S:C,47.32；H,2.89；N,12.54；Found:C,47.72；H,2.67；N,12.34.
化合物I-48
White solid,yield 66％,mp 238～239℃:1H NMR(DMSO-d6):δ＝7.85～8.10(m,7H,Ar-H),8.19(s,1H,CH),11.85(s,1H,NH2),12.55(s,1H,CONHCO)；MS(ESI)m/z:598.0(M+1)+,calcd.for C21H11Cl2F6N5O3S m/z＝596.99；Calcd.For C21H11Cl2F6N5O3S:C,42.16；H,1.85；N,11.71；Found:C,42.55；H,1.98；N,11.65.
化合物I-49
White solid,yield 86％,mp>260℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.54～8.06(m,7H,Ar-H),8.19(s,1H,CH),11.49(s,1H,CONH),12.38(s,1H,CONHCO)；MS(ESI)m/z:612.0(M+1)+,calcd.for C22H13Cl2F6N5O3S m/z＝611.00；IR(KBr)(υ/cm-1):3440,3234,1756,1649,1563,1373,1070；Calcd.For C22H13Cl2F6N5O3S:C,43.15；H,2.14；N,11.44；Found:C,43.45；H,2.34；N,11.54.
化合物I-50
White solid,yield 86％,mp 222～224℃:1H NMR(DMSO-d6):δ＝2.63(s,3H,CH3),7.55～7.74(m,6H,Ar-H),8.10(s,1H,CH),11.54(s,1H,NH2),12.40(s,1H,CONHCO)；MS(ESI)m/z:(M+1)+,calcd.for C22H13Cl2F6N5O3S m/z＝611.00；Calcd.For C22H13Cl2F6N5O3S:C,43.15；H,2.14；N,11.44；Found:C,43.55；H,2.54；N,11.35.
化合物I-51
White solid,yield 89％,mp 244～245℃:1H NMR(DMSO-d6):δ＝2.65(s,3H,CH3),3.70(s,3H,NCH3),7.45～7.64(m,5H,Ar-H),7.92(d,2H,Ar-H,J＝6.9Hz),8.09(s,1H,CH),11.79(s,1H,CONH),11.90(s,1H,CONHCO)；MS(ESI)m/z:558.0(M+1)+,calcd.forC22H16Cl2F3N5O3S m/z＝557.03；IR(KBr)(υ/cm-1):3442,3142,1715,1647,1567,1372,1069；Calcd.For C22H16Cl2F3N5O3S:C,47.32；H,2.89；N,12.54；Found:C,47.62；H,2.69；N,12.45
化合物I-52
White solid,yield 89％,mp 244～245℃:1H NMR(DMSO-d6):δ＝7.55～7.74(m,5H,Ar-H),7.92(s,2H,Ar-H),8.11(s,1H,CH),11.45(s,1H,NH2),12.45(s,1H,CONHCO)；MS(ESI)m/z:598.0(M+1)+,calcd.for C21H11Cl2F6N5O3S m/z＝596.99；Calcd.ForC21H11Cl2F6N5O3S:C,42.16；H,1.85；N,11.71；Found:C,42.56；H,1.95；N,11.41
化合物I-53
White solid,yield 69％,mp>260℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.54～7.93(m,7H,Ar-H),8.16(s,1H,CH),11.50(s,1H,CONH),12.38(s,1H,CONHCO)；MS(ESI)m/z:612.0(M+1)+,calcd.for C22H13Cl2F6N5O3S m/z＝611.00；IR(KBr)(υ/cm-1):3444,3132,1756,1667,1577,1371,1070；Calcd.For C22H13Cl2F6N5O3S:C,43.15；H,2.14；N,11.44；Found:C,43.34；H,2.52；N,11.31.
化合物I-54
White solid,yield 85％,mp 246～245℃:1H NMR(DMSO-d6,400MHz):δ＝3.72(s,3H,CH3NH),7.79(s,1H,CH),7.33～7.79(m,8H,Ar),11.29(s,1H,CH3NH),12.42(s,1H,NH)；MS(ESI)m/z 562.3(M+1)+,calcd.for C22H14F7N5O3S m/z＝561.07；IR(KBr)(υ/cm-1):3444,3132,1756,1667,1577,1371,1070；Calcd.For C22H14F7N5O3S:C,47.06；H,2.51；N,12.47；Found:C,47.66；H,2.71；N,12.87.
化合物I-55
White solid,yield 88％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝2.63(s,3H,CH3),7.26～8.09(m,8H,Ar),8.19(s,1H,CH),11.63(s,2H,NH2),11.89(s,1H,NH)；MS(ESI)m/z 494.1(M+1)+,calcd.for C21H15F4N5O3S m/z＝493.08；IR(KBr)(υ/cm-1):3440,3115,1750,1660,1565,1370,1072；Calcd.For C21H15F4N5O3S:C,51.12；H,3.06；N,14.19；Found:C,51.52；H,3.4；N,14.29.
化合物I-56
White solid,yield 80％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝7.23～7.88(m,8H,Ar),7.99(s,1H,CH),12.05(s,1H,NH)；MS(ESI)m/z 548.3(M+1)+,calcd.forC21H12F7N5O3S m/z＝547.05；IR(KBr)(υ/cm-1):3444,3116,1755,1666,1580,1370,1070；Calcd.For C21H12F7N5O3S:C,46.08；H,2.21；N,12.79；Found:C,46.45；H,2.43；N,12.67..
化合物I-57
White solid,yield 89％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝3.72(s,3H,CH3NH),7.32～7.95(m,8H,Ar),8.19(s,1H,CH),11.28(s,1H,CH3NH),12.39(s,1H,NH)；MS(ESI)m/z 562.1(M+1)+,calcd.for C22H14F7N5O3S m/z＝561.07；Calcd.For C22H14F7N5O3S:C,47.06；H,2.51；N,12.47；Found:C,47.43；H,2.65；N,12.36..
化合物I-58
White solid,yield 83％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝2.63(s,3H,CH3),7.35～8.41(m,7H,Ar),8.13(s,1H,CH),11.60(s,2H,NH2),12.05(s,1H,NH)；MS(ESI)m/z 562.3(M+1)+,calcd.for C22H14F7N5O3S m/z＝561.07；Calcd.For C22H14F7N5O3S:C,47.06；H,2.51；N,12.47；Found:C,47.36；H,2.56；N,12.73.
化合物I-59
White solid,yield 79％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝3.72(s,3H,CH3NH),7.33～8.38(m,7H,Ar),8.47(s,1H,CH),11.29(s,1H,CH3NH),12.59(s,1H,NH)；MS(ESI)m/z 630.3(M+1)+,calcd.for C23H13F10N5O3S m/z＝629.06；Calcd.For C23H13F10N5O3S:C,43.89；H,2.08；N,11.13；Found:C,43.65；H,2.32；N,11.32.
化合物I-60
White solid,yield 85％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝2.65(s,3H,CH3)，3.68(s,3H,CH3NH),7.33～7.93(m,8H,Ar),8.09(s,1H,CH),11.45(s,1H,CH3NH),11.88(s,1H,NH)；MS(ESI)m/z 508.2(M+1)+,calcd.For C22H17F4N5O3S m/z＝507.10；Calcd.For C22H17F4N5O3S:C,52.07；H,3.38；N,13.80；Found:C,52.32；H,3.31；N,13.68.
化合物I-61
White solid,yield 86％,mp 247～249℃:1H NMR(DMSO-d6,400MHz):δ＝3.74(s,3H,CH3NH),7.30～7.94(m,8H,Ar),8.17(s,1H,CH),11.32(s,1H,CH3NH),11.39(s,1H,NH)；MS(ESI)m/z 562.1(M+1)+,calcd.for C22H14F7N5O3S m/z＝561.07；Calcd.ForC22H14F7N5O3S:C,47.06；H,2.51；N,12.47；Found:C,47.24；H,2.61；N,12.38.
化合物I-62
White solid,yield 78％,mp180～182℃:1H NMR(DMSO-d6):δ＝3.69(s,3H,NCH3),7.47～7.58(m,4H,Ar-H),8.01～8.13(m,3H,Ar-H),7.81(s,1H,CH),11.78(s,1H,CONH),11.87(s,1H,CONHCO)；MS(ESI)m/z 614.3(M+1)+,Calcd.For C21H13Cl2F6N6O3S m/z＝613.01；IR(KBr)(υ/cm-1):3444,3132,1744,1649,1577,1373,1069；Calcd.ForC21H13Cl2F6N6O3S:C,41.06；H,2.13；N,13.68；Found:C,41.46；H,2.19；N,13.32.
化合物I-63
White solid,yield 89％,mp 244～245℃:1H NMR(DMSO-d6):δ＝2.60(s,3H,CH3),7.65～7.74(m,5H,Ar-H),7.82(s,2H,Ar-H),8.10(s,1H,CH),11.45(s,1H,NH2),12.45(s,1H,CONHCO)；MS(ESI)m/z 546.2(M+1)+,Calcd.For C20H14Cl2F3N6O3S m/z＝545.02；Calcd.For C20H14Cl2F3N6O3S:C,43.97；H,2.58；N,15.38；Found:C,43.57；H,2.38；N,15.17.
化合物I-64
White solid,yield 86％,mp>260℃；1H NMR(DMSO-d6):δ＝2.64(s,3H,CH3),3.66(s,3H,NCH3),7.22～8.12(m,7H,Ar-H),8.12(s,1H,CH),11.70(s,1H,CONH),11.85(s,1H,CONHCO)；MS(ESI)m/z 560.1(M+1)+,Calcd.For C21H16Cl2F3N6O3S m/z＝559.03；IR(KBr)(υ/cm-1):3442,3268,1750,1653,1566,1371,1069；Calcd.For C21H16Cl2F3N6O3S:C,45.01；H,2.88；N,15.00；Found:C,45.32；H,2.58；N,15.34.
化合物I-65
White solid,yield 87％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝2.65(s,3H,CH3),7.25～7.29(m,3H,Ar-H),7.57(s,3H,Ar-H),8.10(s,1H,CH),11.45(s,2H,NH2),12.45(s,1H,CONHCO)；MS(ESI)m/z 613.9(M+1)+,Calcd.For C21H13Cl2F6N6O3S m/z＝613.01；Calcd.For C21H13Cl2F6N6O3S:C,41.06；H,2.13；N,13.68；Found:C,41.43；H,2.32；N,13.56.
化合物I-66
White solid,yield 87％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝2.65(s,3H,CH3),3.67(s,3H,NCH3),,7.20～7.24(m,2H,Ar-H),7.57(s,3H,Ar-H),7.91(d,2H,Ar-H,J＝7.9Hz),8.07(s,1H,CH),11.72(s,1H,CONH),11.89(s,1H,CONHCO)；MS(ESI)m/z 560.5(M+1)+,Calcd.For C21H16Cl2F3N6O3S m/z＝559.03；IR(KBr)(υ/cm-1):3443,3229,1752,1067,1323,1122；Calcd.For C21H16Cl2F3N6O3S:C,45.01；H,2.88；N,15.00；Found:C,45.23；H,2.66；N,15.23.
化合物I-67
White solid,yield 77％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝3.70(s,3H,CH3),7.53～7.67(m,4H,Ar-H),7.76(s,2H,Ar-H),7.91～8.25(m,3H,Ar-H),8.44(s,1H,CH),11.09(s,1H,CONH),12.50(s,1H,CONHCO)；MS(ESI)m/z(M+1)+,Calcd.For C20H15F3N7O5Sm/z＝522.08；IR(KBr)(υ/cm-1):3442,3142,1757,1646,1574,1373,1069；Calcd.ForC20H15F3N7O5S:C,45.98；H,2.89；N,18.77；Found:C,45.86；H,2.78；N,18.65.
化合物I-68
White solid,yield 77％,mp 227～229℃:1H NMR(DMSO-d6,400MHz):δ＝3.73(s,3H,NCH3),7.73～7.90(m,5H,Ar-H),8.14～8.25(m,3H,Ar-H),8.27(s,1H,CH),11.61(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 591.3(M+1)+,Calcd.For C21H14F6N7O5S m/z＝590.07；IR(KBr)(υ/cm-1):3444,3031,1756,1640,1570,1373,1071；Calcd.ForC21H14F6N7O5S:C,42.72；H,2.39；N,16.61；Found:C,42.52；H,2.43；N,16.51.
化合物I-69
White solid,yield 77％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝3.71(s,3H,CH3),7.55～7.87(m,4H,Ar-H),7.96(s,2H,Ar-H),7.99～8.25(m,3H,Ar-H),8.40(s,1H,CH),11.19(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z546.0(M+1)+,Calcd.ForC21H15F6N6O3S m/z＝545.08；IR(KBr)(υ/cm-1):3440,3140,1757,1646,1574,1373,1070；Calcd.For C21H15F6N6O3S:C,46.24；H,2.77；N,15.41；Found:C,46.52；H,2.65；N,15.32.
化合物I-70
White solid,yield 87％,mp 174～176℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.57～8.39(m,8H,Ar-H),8.41(s,1H,CH),11.35(s,1H,CONH),12.42(s,1H,CONHCO)；MS(ESI)m/z 590.9(M+1)+,Calcd.For C21H14F6N7O5S m/z＝590.07；IR(KBr)(υ/cm-1):3442,3142,1745,1644,1570,1371,1070；Calcd.For C21H14F6N7O5S:C,42.72；H,2.39；N,16.61；Found:C,42.66；H,2.43；N,16.32.
化合物I-71
White solid,yield 77％,mp190～191℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.80～7.91(m,3H,Ar-H),8.32～8.52(m,3H,Ar-H),8.52(s,1H,CH),8.72(d,2H,Ar-H,J＝16.2Hz),11.38(s,1H,CONH),12.47(s,1H,CONHCO)；MS(ESI)m/z 590.9(M+1)+,Calcd.For C21H14F6N7O5S m/z＝590.07；IR(KBr)(υ/cm-1):3440,3222,1744,1646,1573,1372,1070；Calcd.For C21H14F6N7O5S:C,42.72；H,2.39；N,16.61；Found:C,42.62；H,2.28；N,16.36.
化合物I-72
White solid,yield 85％,mp>260℃:1H NMR(DMSO-d6):δ＝3.70(s,3H,NCH3),7.84～8.33(m,7H,Ar-H),8.15(s,1H,CH),11.25(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 558.4M+,Calcd.For C20H13F5N7O5S m/z＝558.06；IR(KBr)(υ/cm-1):3440,3241,1747,1640,1569,1371,1070；Calcd.For C20H13F5N7O5S:C,43.02；H,2.35；N,17.56；Found:C,43.38；H,2.38；N,17.39.
化合物I-73
White solid,yield 80％,mp>260℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.94～8.23(m,7H,Ar-H),8.20(s,1H,CH),11.25(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 558.4M+,Calcd.For C20H13F5N7O5S m/z＝558.06；IR(KBr)(υ/cm-1):3440,3241,1747,1640,1569,1371,1070；Calcd.For C20H13F5N7O5S:C,43.02；H,2.35；N,17.56；Found:C,43.38；H,2.38；N,17.39.
化合物I-74
White solid,yield 85％,mp 195～196℃:1H NMR(DMSO-d6,400MHz):δ＝3.69(s,3H,NCH3),7.64～7.70(m,4H,Ar-H),7.98～8.03(m,3H,Ar-H),8.03(s,1H,CH),11.16(s,1H,CONH),12.53(s,1H,CONHCO)；MS(ESI)m/z 558.4M+,Calcd.For C20H13F5N7O5S m/z＝558.06；IR(KBr)(υ/cm-1):3444,3342,1747,1639,1570,1373,1069；Calcd.ForC20H13F5N7O5S:C,43.02；H,2.35；N,17.56；Found:C,43.38；H,2.38；N,17.39.
化合物I-75
White solid,yield 86％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝3.73(s,3H,CH3),7.69～8.34(m,8H,Ar-H),8.37(s,1H,CH),11.45(s,1H,CONH),12.50(s,1H,CONHCO)；MS(ESI)m/z 513.9(M+1)+,Calcd.For C20H14F5N6O3S m/z＝513.08；IR(KBr)(υ/cm-1):3444,3342,1757,1665,1570,1370,1072；Calcd.For C20H14F5N6O3S:C,46.79；H,2.75；N,16.37；Found:C,46.68；H,2.78；N,16.45.
化合物I-76
White solid,yield 66％,mp>260℃:1H NMR(DMSO-d6,400MHz):δ＝3.71(s,3H,CH3),7.65(s,2H,Ar-H),8.31～8.54(m,5H,Ar-H),8.37(s,1H,CH),11.37(s,1H,CONH),12.52(s,1H,CONHCO)；MS(ESI)m/z 591.3(M+1)+,Calcd.For C20H13Cl2F3N7O5S m/z＝590.00；IR(KBr)(υ/cm-1):3444,3344,1757,1659,1569,1372,1070；Calcd.ForC20H13Cl2F3N7O5S:C,40.62；H,2.22；N,16.58；Found:C,40.52；H,2.34；N,16.67.
化合物I-77
White solid,yield 79％,mp 206～208℃:1H NMR(DMSO-d6,400MHz):δ＝3.71(s,3H,NCH3),7.95～8.10(m,8H,Ar-H),8.25(s,1H,CH),11.55(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 568.1(M+1)+,Calcd.For C20H14F3N8O7S m/z＝567.07；IR(KBr)(υ/cm-1):3444,3031,1756,1640,1570,1373,1070；Calcd.For C20H14F3N8O7S:C,42.33；H,2.49；N,19.75；Found:C,42.44；H,2.56；N,19.79.
化合物I-78
White solid,yield 79％,mp 206～208℃:1H NMR(DMSO-d6,400MHz):δ＝3.71(s,3H,NCH3),7.70～7.95(m,5H,Ar-H),8.16～8.29(m,3H,Ar-H),8.30(s,1H,CH),11.60(s,1H,CONH),12.55(s,1H,CONHCO)；MS(ESI)m/z 568.0(M+1)+,Calcd.For C20H14F3N8O7S m/z＝567.07；IR(KBr)(υ/cm-1):3444,3031,1756,1640,1570,1373,1070；Calcd.ForC20H14F3N8O7S:C,42.33；H,2.49；N,19.75；Found:C,42.54；H,2.57；N,19.73.
化合物I-79
White solid,yield 77％,mp 227～229℃:1H NMR(DMSO-d6,400MHz):δ＝3.73(s,3H,NCH3),7.73～7.90(m,5H,Ar-H),8.14～8.25(m,3H,Ar-H),8.27(s,1H,CH),11.61(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 568.0(M+1)+,Calcd.For C20H14F3N8O7S m/z＝567.07；IR(KBr)(υ/cm-1):3444,3031,1756,1640,1570,1373,1071；Calcd.ForC20H14F3N8O7S:C,42.33；H,2.49；N,19.75；Found:C,42.59；H,2.67；N,19.63.
化合物I-80
White solid,yield 87％,mp 209～210℃:1H NMR(DMSO-d6):δ＝3.71(s,3H,NCH3),7.42～8.15(m,9H,Ar-H),8.31(s,1H,CH),11.50(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 523.7(M+1)+,Calcd.For C20H15F3N7O5S m/z＝522.08；IR(KBr)(υ/cm-1):3442,2937,1750,1639,1570,1373,1070；Calcd.For C20H15F3N7O5S:C,45.98；H,2.89；N,18.77；Found:C,45.88；H,2.75；N,18.64.
化合物I-81
White solid,yield 79％,mp 219～220℃:1H NMR(DMSO-d6):δ＝3.72(s,3H,NCH3),7.29～8.15(m,8H,Ar-H),8.25(s,1H,CH),11.59(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 568.0(M+1)+,Calcd.For C20H14F3N8O7S m/z＝567.07；IR(KBr)(υ/cm-1):3444,2937,1750,1639,1570,1373,1072；Calcd.For C20H14F3N8O7S:C,42.33；H,2.49；N,19.75；Found:C,42.58；H,2.57；N,19.65.
化合物I-82
White solid,yield 79％,mp 219～220℃:1H NMR(DMSO-d6):δ＝3.73(s,3H,NCH3),7.30～8.06(m,8H,Ar-H),8.23(s,1H,CH),11.56(s,1H,CONH),12.40(s,1H,CONHCO)；MS(ESI)m/z 568.1(M+1)+,Calcd.For C20H14F3N8O7S m/z＝567.07；IR(KBr)(υ/cm-1):3444,2937,1750,1639,1570,1373,1072；Calcd.For C20H14F3N8O7S:C,42.33；H,2.49；N,19.75；Found:C,42.56；H,2.58；N,19.65.
化合物I-83
White solid,yield 87％,mp 210～212℃:1H NMR(DMSO-d6):δ＝3.70(s,3H,NCH3),7.40～8.16(m,9H,Ar-H),8.33(s,1H,CH),11.55(s,1H,CONH),12.45(s,1H,CONHCO)；MS(ESI)m/z 523.0(M+1)+,Calcd.For C20H15F3N7O5S m/z＝522.08；IR(KBr)(υ/cm-1):3442,2937,1750,1639,1570,1373,1070；Calcd.For C20H15F3N7O5S:C,45.98；H,2.89；N,18.77；Found:C,45.78；H,2.76；N,18.68.
实施例2抗肿瘤活性试验
化合物抗癌活性
供试靶标：口腔底癌细胞KB；人鼻咽癌细胞CNE2；人肝癌细胞HepG-2；BGC-823(人胃癌细胞)；人乳腺癌细胞MCF-7；Hela(人宫颈癌细胞)。
试验方法：MTT体外细胞毒试验方法
取对数生长期的人癌细胞制成2×104个细胞/mL的细胞悬液，按0.19mL/孔接种到96孔板，于37℃、5％CO2培养24小时后，按0.01mL/孔加入不同浓度的样品溶液，另设生理盐水对照孔，每浓度设4个平行孔，加药后再培养72小时，培养结束前3小时按0.01mL/孔加入浓度为10mg/mL的3-(4，5-二甲基噻唑-2)-2，5-二苯基四氮唑溴盐(MTT)，培养结束时吸出培养液，每孔加0.1mL的二甲基亚砜(DMSO)，于测量波长540nm参比波长655nm下测量OD值。按下式计算细胞生长抑制率(IR)，以简化概率单位法计算半数抑制浓度(IC50)。IR％＝(1-平均OD值加药组/平均OD值对照组)×100％。测定结果见表1至表3。
表1
表2
表3
从表2数据可以看到：对于癌细胞BGC-823，化合物I-14、I-24、I-25抑制活性较为突出，IC50值5.19μg/mL、6.88μg/mL、5.28μg/mL。
从表3数据可以看到：对于癌细胞BGC-823，化合物I-28、I-35、I-45、I-49均表现出特别的抑制活性，IC50值分别为3.76μg/mL、4.81μg/mL、4.21μg/mL和4.45μg/mL。
上述所列化合物对相应癌细胞的抑制活性均远远高于阳性对照药物5-氟尿嘧啶。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
尽管已经示出和描述了本发明的实施例，本领域的普通技术人员可以理解：在不脱离本发明的原理和宗旨的情况下可以对这些实施例进行多种变化、修改、替换和变型，本发明的范围由权利要求及其等同物限定。

Claims (9)

1.一种噁二唑联噻唑衍生物，其特征在于，所述噁二唑联噻唑衍生物为式I所示化合物或式I所示化合物的对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物或溶剂合物，
其中，
R1为氨基或甲基氨基；
R2为甲基或三氟甲基；
R3为呋喃基或任选取代的苯基；
R4为至少一个卤素、氢、硝基、三氟甲基、任选取代的烷氧基。
2.根据权利要求1所述的噁二唑联噻唑衍生物，其特征在于，所述卤素为F、Cl、Br。
3.根据权利要求1所述的噁二唑联噻唑衍生物，其特征在于，所述R3为呋喃基、苯基、任选卤素取代的苯基、三氟甲基取代的苯基，硝基取代的苯基或甲氧基取代的苯基，任选地，所述卤素为F、Cl、Br。
4.根据权利要求1所述的噁二唑联噻唑衍生物，其特征在于，所述R3为呋喃基、苯基、4-氯苯基、2-氯苯基、2,4-二氯苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-三氟甲基苯基、2-三氟甲基苯基、3-三氟甲基苯基、3，5-二(三氟甲基)苯基、3,4,5-三甲氧基苯基、4-甲氧基苯基、4-硝基苯基、3-硝基苯基、2-硝基苯基。
5.根据权利要求1所述的噁二唑联噻唑衍生物，其特征在于，所述R4为至少一个卤素、氢、硝基、三氟甲基或甲氧基，任选地，所述R4代表两个卤素，任选地，所述两个卤素呈间位关系或邻位关系，任选地，所述两个卤素均为Cl或均为F，任选地，所述R4代表三个甲氧基，任选地，所述三个甲氧基呈邻位关系。
6.根据权利要求1所述的噁二唑联噻唑衍生物，其特征在于，所述噁二唑联噻唑衍生物为下列化合物或者所述下列化合物的对映异构体、非对映异构体、外消旋体、药学上可接受的盐、结晶水合物或溶剂合物：
7.一种制备权利要求1～6任一项所述噁二唑联噻唑衍生物的方法，其特征在于，包括：
(1)使式A所示化合物与取代苯甲醛进行接触，以便获得式B所示化合物；
(2)使所述式B所示化合物与所述式C化合物进行接触，以便获得式I所示化合物；
其中R1、R2、R3、R4是如权利要求1～6任一项中所定义的。
8.一种药物组合物，其特征在于，包括：权利要求1～6任一项所定义的。
9.权利要求1～6任一项所述的噁二唑联噻唑衍生物或者权利要求8所述的药物组合物在制备药物中的用途，所述药物用于治疗癌症，任选地，所述癌症为口腔上皮癌、鼻咽癌、肝癌、胃癌、乳腺癌、宫颈癌。
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CN101875643A (zh) * 2009-11-06 2010-11-03 湖北省生物农药工程研究中心 含吡啶或噻唑芳甲酰脲类化合物及其制备方法和用途
CN101939319A (zh) * 2007-12-20 2011-01-05 诺瓦提斯公司 联噻唑衍生物、它们的制备方法以及它们作为药物的用途

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