CN101754967A - 苯并咪唑聚(adp-核糖)聚合酶抑制剂 - Google Patents
苯并咪唑聚(adp-核糖)聚合酶抑制剂 Download PDFInfo
- Publication number
- CN101754967A CN101754967A CN200880025066A CN200880025066A CN101754967A CN 101754967 A CN101754967 A CN 101754967A CN 200880025066 A CN200880025066 A CN 200880025066A CN 200880025066 A CN200880025066 A CN 200880025066A CN 101754967 A CN101754967 A CN 101754967A
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- China
- Prior art keywords
- bases
- benzimidazole
- carboxamides
- thiophene
- pyrrolidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PWJFNRJRHXWEPT-UHFFFAOYSA-N ADP ribose Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OCC(O)C(O)C(O)C=O)C(O)C1O PWJFNRJRHXWEPT-UHFFFAOYSA-N 0.000 title abstract 2
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 title abstract 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 title description 2
- SEKJSSBJKFLZIT-UHFFFAOYSA-N LSM-1988 Chemical compound C1=CC(CN(C)C)=CC=C1C1=NC2=CC=CC3=C2N1CCNC3=O SEKJSSBJKFLZIT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 114
- 238000000034 method Methods 0.000 claims abstract description 15
- -1 heteroaryl hydrocarbon Chemical class 0.000 claims description 256
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 195
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 147
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 104
- 229930192474 thiophene Natural products 0.000 claims description 72
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 71
- 239000004215 Carbon black (E152) Substances 0.000 claims description 68
- 150000001925 cycloalkenes Chemical class 0.000 claims description 68
- 229930195733 hydrocarbon Natural products 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000001424 substituent group Chemical group 0.000 claims description 52
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 47
- 125000003342 alkenyl group Chemical group 0.000 claims description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 38
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 35
- 229910052794 bromium Inorganic materials 0.000 claims description 31
- 229910052801 chlorine Inorganic materials 0.000 claims description 31
- 229910052740 iodine Inorganic materials 0.000 claims description 31
- 229910052731 fluorine Inorganic materials 0.000 claims description 29
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 28
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- 125000004366 heterocycloalkenyl group Chemical group 0.000 claims description 26
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- 238000006467 substitution reaction Methods 0.000 claims description 22
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- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 21
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 15
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 12
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
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- 230000001225 therapeutic effect Effects 0.000 claims description 7
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- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 6
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- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 5
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- IRHBPLJGCWXMPV-UHFFFAOYSA-N 2-thiophen-2-ylpiperidine Chemical compound N1CCCCC1C1=CC=CS1 IRHBPLJGCWXMPV-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 4
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Abstract
公开了抑制聚(ADP-核糖)聚合酶(PARP)活性的化合物,含有该化合物的组合物以及使用它们治疗疾病的方法。
Description
发明领域
本发明包含抑制聚(ADP-核糖)聚合酶(PARP)活性的化合物,含有该化合物的组合物以及使用它们治疗疾病的方法。
发明背景
聚(ADP-核糖)聚合酶(PARP)在促进DNA修复、控制RNA转录、调节细胞死亡和调节免疫应答方面起必不可少的作用。PARP抑制剂在变应性脑炎、关节炎、由多柔比星和铂抗肿瘤剂引起的心脏和肾脏中毒、乳房癌、中枢神经系统炎症、宫颈癌、结肠癌、糖尿病及其并发症、成胶质细胞瘤、痛风、出血性休克、低血糖、炎性肠疾病、与心肌梗死有关的缺血性再灌注损伤、肾病、白血病、对乙酰氨基酚用药过度引起的肝脏中毒、淋巴瘤、黑素瘤、多发性硬化、心肌梗死、神经创伤、器官移植、帕金森氏病、细胞毒性癌症治疗增强、肺纤维化、眼、肠、肾脏和骨骼肌的再灌注、逆转录病毒感染、类风湿性关节炎、脓毒症、脓毒性休克、由硫芥子气继发的皮肤损伤、中风以及其它神经菌髓(neural trama)和葡萄膜炎疾病模型中具有功效。
在各种癌症模型中,PARP抑制剂通过提高癌细胞的细胞调亡、限制肿瘤生长、减少转移和延长患肿瘤动物的存活时间,显示出增强的放疗和化疗效力。因此,在治疗领域中,仍需要PARP抑制剂。
发明概述
本发明具有多个实施方案。因此,本发明的一种实施方案涉及为PARP抑制剂的化合物,所述化合物具有式I的结构
及其治疗上可接受的盐、前药、酯、酰胺、前药的盐、酯的盐和酰胺的盐,其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
B1是氢、R3、CO(O)R3A、C(O)NH2、C(O)NHR3A、C(O)N(R3A)2、SO2NH2、SO2NHR3A或SO2N(R3A)2;
R3A是烷基或环烷基;
R3是烷基或链烯基,其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R4、OR4、NH2、NHR4、N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2或OH;
R4是烷基或环烷基;
C1、D1、E1每个独立地是氢、NO2、CN、R5、OR5、CO(O)R5、C(O)NH2、C(O)NHR5、C(O)N(R5)2、NH2、NHR5、N(R5)2、OH、F、Cl、Br或I;
R5是烷基、链烯基或炔基;其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R6、NH2、NHR6、N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、OH、F、Cl、Br或I;
R6是烷基或环烷基;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
另一种实施方案涉及选自下面的化合物:
2-(4-吡啶-3-基-1,3-噻唑-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(4-吡啶-4-基-1,3-噻唑-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(4-甲基-2-吡嗪-2-基-1,3-噻唑-5-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-噻吩-2-基-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-哌啶-4-基-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-甲基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-异丙基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-丙基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-环丁基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡嗪-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-嘧啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡啶-3-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡啶-4-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1H-吡咯-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-甲基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-异丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-(环丙基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-环丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-环戊基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-环己基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-四氢-2H-吡喃-4-基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-(吡啶-2-基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-(吡啶-4-基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-异丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-哌啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-甲基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-丙基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-(环丙基甲基)哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环丁基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-异丁基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡咯烷-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-甲基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-异丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-(环丙基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-异丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环戊基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环己基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(6-吡咯烷-2-基吡啶-3-基)-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-异丙基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-异丁基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-环丁基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-环戊基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-环己基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-四氢-2H-吡喃-4-基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1,3-噁唑-5-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[5-(1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺;
2-{5-[5-(三氟甲基)-1,3,4-噁二唑-2-基]吡啶-2-基}-1H-苯并咪唑-4-甲酰胺;
2-[5-(5-甲基-1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺;
及其治疗上可接受的盐、前药、酯、酰胺、前药的盐、酯的盐和酰胺的盐。
还有另一种实施方案涉及组合物,该组合物包含治疗可接受量的式I化合物或其盐、前药或前药的盐以及赋形剂。
还有另一种实施方案包括在哺乳动物中抑制聚(ADP-核糖)聚合酶的方法,包括给予所述哺乳动物治疗可接受量的式I化合物或其盐、前药或前药的盐。
还有另一种实施方案包括在哺乳动物中治疗癌症的方法,包括给予所述哺乳动物治疗可接受量的式(I)化合物,
或其盐、前药或前药的盐,其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
B1是氢、R3、CO(O)R3A、C(O)NH2、C(O)NHR3A、C(O)N(R3A)2、SO2NH2、SO2NHR3A或SO2N(R3A)2;
R3A是烷基或环烷基;
R3是烷基或链烯基,其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R4、OR4、NH2、NHR4、N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2或OH;
R4是烷基或环烷基;
C1、D1、E1每个独立地是氢、NO2、CN、R5、OR5、CO(O)R5、C(O)NH2、C(O)NHR5、C(O)N(R5)2、NH2、NHR5、N(R5)2、OH 、F、Cl、Br或I;
R5是烷基、链烯基或炔基;其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R6、NH2、NHR6、N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、OH、F、Cl、Br或I;
R6是烷基或环烷基;
其中每个前面的环状部分独立地是未取代的,未被进一步取代的,被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
还有另一种实施方案包括在哺乳动物中治疗变应性脑炎、关节炎、由多柔比星和铂基抗肿瘤剂引起的心脏和肾脏中毒、乳房癌、中枢神经系统炎症、宫颈癌、结肠癌、糖尿病及其并发症、成胶质细胞瘤、痛风、出血性休克、低血糖、炎性肠病、与心肌梗死有关的缺血性再灌注损伤、肾病、白血病、对乙酰氨基酚用药过度引起的肝脏中毒、淋巴瘤、黑素瘤、多发性硬化、心肌梗死、神经创伤、器官移植、帕金森氏病、细胞毒性癌症治疗增强、肺纤维化、眼、肠、肾脏和骨骼肌的再灌注、逆转录病毒感染、类风湿性关节炎、脓毒症、脓毒性休克、由硫芥子气继发的皮肤损伤、中风以及其它神经菌髓和葡萄膜炎的方法,包括给予所述哺乳动物治疗可接受量的式I化合物
或其盐、前药或前药的盐,其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
B1是氢、R3、CO(O)R3A、C(O)NH2、C(O)NHR3A、C(O)N(R3A)2、SO2NH2、SO2NHR3A或SO2N(R3A)2;
R3A是烷基或环烷基;
R3是烷基或链烯基,其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R4、OR4、NH2、NHR4、N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2或OH;
R4是烷基或环烷基;
C1、D1、E1每个独立地是氢、NO2、CN、R5、OR5、CO(O)R5、C(O)NH2、C(O)NHR5、C(O)N(R5)2、NH2、NHR5、N(R5)2、OH、F、Cl、Br或I;
R5是烷基、链烯基或炔基;其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R6、NH2、NHR6、N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、OH、F、Cl、Br或I;
R6是烷基或环烷基;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
发明的详细说明
此详细说明仅仅是为了让本领域普通技术人员知道本发明的原理及其实际应用,以使本领域普通技术人员可以以多种形式修改和使用本发明,使他们很好地适应于特定用途的要求。本说明书及其具体实施例仅仅是用于举例说明的目的。因此,本发明不局限于本申请中所述实施方案,并且可以对其进行多种改变。
本发明化合物的可变部分通过标识符表示(带有数字的和/或字母上标的大写字母)并且可以具体地表达。
不用说,本文所有组合保持适当的原子价,并且具有一个以上原子的单价部分通过它们左端连接,其二价部分从左到右画图。
也不用说,可变部分的具体表达可以与具有相同标识的另一种具体表达是相同的或不同的。
在此所使用的术语″链烯基″是指单价的、具有一个或多个碳-碳双键的直链或支链烃部分,例如C2-链烯基、C3-链烯基、C4-链烯基、C5-链烯基、C6-链烯基等。
在此所使用的术语″亚烯基″是指二价的、具有一个或多个碳-碳双键的直链或支链烃部分,例如C2-亚烯基、C3-亚烯基、C4-亚烯基、C5-亚烯基、C6-亚烯基等。
在此所使用的术语″烷基″是指单价的、饱和的、直链或支链烃部分,例如C1-烷基、C2-烷基、C3-烷基、C4-烷基、C5-烷基、C6-烷基等。
在此所使用的术语″亚烷基″是指二价的、饱和的、直链或支链烃部分,例如C1-亚烷基、C2-亚烷基、C3-亚烷基、C4-亚烷基、C5-亚烷基、C6-亚烷基等。
在此所使用的术语″炔基″是指单价的、具有一个或多个碳-碳三键的直链或支链烃部分,例如C2-炔基、C3-炔基、C4-炔基、C5-炔基、C6-炔基等。
在此所使用的术语″亚炔基″是指二价的、具有一个或多个碳-碳三键的直链或支链烃部分,例如C2-亚炔基、C3-亚炔基、C4-亚炔基、C5-亚炔基、C6-亚炔基等。
在此所使用的术语″环烷烃″是指饱和的环状烃或二环烃部分,例如C4-环烷烃、C5-环烷烃、C6-环烷烃、C7-环烷烃、C8-环烷烃、C9-环烷烃、C10-环烷烃、C11-环烷烃、C12-环烷烃等。
在此所使用的术语″环烷基″是指单价的、饱和的环状的以及二环烃部分,例如C3-环烷基、C4-环烷基、C5-环烷基、C6-环烷基、C7-环烷基、C8-环烷基、C9-环烷基、C10-环烷基、C11-环烷基、C12-环烷基等。
在此所使用的术语″环烯烃″是指具有一个或多个碳-碳双键的环状烃和二环烃部分,例如C5-环烯烃、C6-环烯烃、C7-环烯烃、C8-环烯烃、C9-环烯烃、C10-环烯烃、C11-环烯烃、C12-环烯烃等。
在此所使用的术语″环烯基″是指单价的、具有一个或多个碳-碳双键的环烃部分,例如C4-环烯基、C5-环烯基、C6-环烯基、C7-环烯基、C8-环烯基、C9-环烯基、C10-环烯基、C11-环烯基、C12-环烯基等。
在此所使用的术语″杂芳烃″是指呋喃、咪唑、异噻唑、异噁唑、1,2,3-噁二唑、1,2,5-噁二唑、1,3,4-噁二唑、噁唑、吡嗪、吡唑、哒嗪、吡啶、嘧啶、吡咯、噻唑、1,3,4-噻二唑、噻吩、三嗪和1,2,3-三唑。
在此所使用的术语″杂芳基″是指呋喃基、咪唑基、异噻唑基、异噁唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、四唑基、噻唑基、1,2,3-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻吩基、三嗪基和1,2,3-三唑基。
在此所使用的术语″杂环烷烃″是指具有一个或两个或三个被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个CH部分是未被代替的或被N代替的环烷烃,并且还指具有一个或两个或三个未被代替的或被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个被N代替的CH部分的环烷烃。
在此所使用的术语″杂环烯烃″是指具有一个或两个或三个被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个CH部分是未被代替的或被N代替的环烯烃,并且还指具有一个或两个或三个未被代替的或被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个被N代替的CH部分的环烯烃。
在此所使用的术语″杂环烷基″是指具有一个或两个或三个被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个CH部分是未被代替的或被N代替的环烷基,并且还指具有一个或两个或三个未被代替的或被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个被N代替的CH部分的环烷基。
在此所使用的术语″杂环烯基″是指具有一个或两个或三个被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个CH部分是未被代替的或被N代替的环烯基,并且还指具有一个或两个或三个未被代替的或被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个被N代替的CH部分的环烯基。
在此所使用的术语″全卤代链烯基″是指链烯基,其中每一个氢被F、Cl或Br独立地取代。
在此所使用的术语″全卤代烷基″是指烷基,其中每一个氢被F、Cl或Br独立地取代。
在此所使用的术语″全卤代炔基″是指炔基,其中每一个氢被F、Cl或Br独立地取代。
在此所使用的术语″螺烯基″是指两端与相同的碳原子连接的并且具有一个或多个碳-碳双键的二价烃部分,例如C3-螺烯基、C4-螺烯基、C5-螺烯基等。
在此所使用的术语″螺烷基″是指饱和的、两端与相同的碳原子连接的二价烃部分,例如C2-螺烷基、C3-螺烷基、C4-螺烷基、C5-螺烷基等。
在此所使用的术语″螺杂烯基″是指具有一个或两个被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个CH部分是未被代替的或被N代替的螺烯基,并且还指具有一个或两个未被代替的或被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个被N代替的CH部分的螺烯基。
在此所使用的术语″螺杂烷基″是指具有一个或两个被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个CH部分是未被代替的或被N代替的螺烷基,并且还指具有一个或两个未被代替的或被独立选择的O、S、S(O)、SO2或NH代替的CH2部分以及一个或两个被N代替的CH部分的螺烷基。
在此所使用的术语″环状部分″是指苯、环烷烃、环烷基、环烯烃、环烯基、杂芳烃、杂芳基、杂环烷烃、杂环烷基、杂环烯烃、杂环烯基、苯基、螺烷基、螺烯基、螺杂烷基和螺杂烯基。
本发明的化合物可以含有以R或S构型的不对称取代的碳原子,其中所述的术语″R″和″S″如Pure Appl.Chem.(1976)45,13-10中所定义。包含具有相同数量的R和S构型的不对称取代的碳原子的化合物在那些原子处是外消旋的。相对于另一种构型的一种构型过量的原子被称为构型过量,优选过量约85%-90%,更优选过量约95%-99%,以及尤其更优选过量大于约99%。因此,本发明是指包含外消旋混合物及其化合物的相对、绝对非对映异构体。
本发明的化合物还可以含有以Z或E构型的碳-碳双键或碳-氮双键,其中术语″Z″表示较大的两个取代基在碳-碳或碳-氮双键的相同一侧上,术语″E″表示较大的两个取代基在碳-碳或碳-氮双键的相对侧。本发明的化合物还可以以″Z″和″E″异构体的混合物的形式存在。
含有NH、C(O)H、C(O)OH、C(O)NH2、OH或SH部分的本发明化合物可以具有与其连接的前药形成部分。所述前药形成部分通过代谢过程除去并且在体内释放具有游离NH、C(O)H、C(O)OH、C(O)NH2、OH或SH的化合物。前药可用于调节所述化合物的这些药物动力学性质如溶解度和/或疏水性、胃肠道内的吸收、生物利用度、组织渗透和清除率。
式I化合物的代谢物,由体外或体内代谢过程产生,也可用于治疗与过度表达的(overexpressed)或未调节的(unregulated)聚(ADP-核糖)聚合酶有关的疾病。
式I化合物的某些前体化合物可在体外或体内代谢,生成式I的化合物并由此可用于治疗由过度表达的或未调节的聚(ADP-核糖)聚合酶引起或恶化的疾病。
式I化合物还可以用放射性同位素放射性标记,例如放射性同位素碳(即13C)、氢(即3H)、氮(即15N)、磷(即32P)、硫(即35S)或碘(即125I)。通过使式I化合物和放射性衍生剂反应或通过加入放射性标记的中间体到它们的合成中,放射性同位素可以被并入到式I化合物中。式I的放射性标记化合物可用于预测以及诊断以及用于体内以及体外成像。
式I化合物可以以酸加成盐、碱加成盐或两性离子的形式存在。式I化合物的盐在式I化合物分离期间或在式I化合物提纯之后制备。酸加成盐来源于式I化合物与酸反应的那些。因此,式I化合物的盐包括乙酸盐、己二酸盐、褐藻酸盐、碳酸氢盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、莰佛酸盐、樟脑磺酸盐、二葡糖酸盐、甲酸盐、富马酸盐、甘油磷酸盐、谷氨酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、乳糖酸盐、乳酸盐、马来酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、磷酸盐、苦味酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、三氯乙酸盐、三氟乙酸盐、对甲苯磺酸盐和十一烷酸盐都包括在本发明的范围内。化合物的碱加成盐是来源于式I化合物与阳离子如锂、钠、钾、钙和镁的碳酸氢盐、碳酸盐、氢氧化物或磷酸盐反应的那些。
式I化合物可以通过例如口腔、眼、口服、渗透、胃肠外(肌内、腹膜内、胸骨内、静脉内、皮下)、直肠、局部、经皮和阴道给药。
式I化合物的治疗有效量取决于治疗的接受者、所治疗的疾病和疾病的严重程度、包含式I化合物的组合物、给药次数、给药途径、治疗持续时间、效力、清除率以及是否与另一种药物共同给药。用于使组合物以每日单次剂量或多次剂量给予患者的式I化合物的数量约为0.001-约200mg/kg体重的剂量。单次剂量组合物含有这些数量或其约数的组合。
式I化合物可以在有或者没有赋形剂的情况下施用。赋形剂包括,例如,包胶囊剂和添加剂如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、膨胀剂、填料、调味剂、湿润剂、润滑剂、香料、防腐剂、推进剂、释放剂、灭菌剂、甜味剂、增溶剂、润湿剂以及它们的混合物。
式I化合物还可以用放射性同位素,例如碳(即13C)、氢(即3H)、氮(即15N)、磷(即32P)、硫(即35S)、碘(即125I)等放射性标记。通过使式I化合物和放射性衍生剂反应或通过加入放射性标记的中间体到它们的合成中,可以将放射性同位素掺入到式I化合物中。式I的放射性标记化合物用于预测和诊断以及用于体内和体外成像。
式I化合物可以结合到装置中,所述装置例如,但不局限于动-静脉移植物、胆道支架、旁路移植物、导管、中枢神经系统旁路、冠状动脉支架、给药球囊、外周血管支架和输尿管支架,其每个可以在部位中使用,所述部位例如,但不局限于,用于将式I化合物引入到所选体内组织或器官的脉管系统。式I化合物有效性的一种衡量标准是减少或消除与装置有关的血栓症及其有关的并发症。
式I化合物能用作放射致敏剂以增加放射治疗的效力。放射治疗的实例包括,但不局限于,外粒子束放射治疗、远距放射疗法、血管内近距离放射治疗以及密封源放射治疗和非密封源放射治疗。
用于制备包含式I化合物的口服给药的组合物的赋形剂,包括,例如,琼脂、褐藻酸、氢氧化铝、苄醇、苯甲酸苄酯、1,3-丁二醇、卡波姆(carbomers)、蓖麻油、纤维素、醋酸纤维素、可可脂、玉米淀粉、玉米油、棉子油、交联聚乙烯吡咯烷酮、二酸甘油酯、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、丙三醇、花生油、羟丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、单酸甘油脂、橄榄油、花生油、磷酸钾盐、马铃薯淀粉、聚乙烯吡咯烷酮、丙二醇、林格溶液、红花子油、芝麻油、羧甲基纤维素钠、磷酸钠盐、月桂基硫酸钠、山梨糖醇钠、大豆油、硬脂酸、富马酸十八酯(stearyl fumarate)、蔗糖、表面活性剂、滑石粉、西黄蓍胶、四氢糠醇、三酸甘油酯、水及其混合物。用于制备包含式I化合物的眼内或口服给药的组合物的赋形剂包括例如1,3-丁二醇、蓖麻油、玉米油、棉子油、乙醇、脱水山梨糖醇的脂肪酸酯、胚芽油、花生油、甘油、异丙醇、橄榄油、聚乙二醇、丙二醇、芝麻油、水、以及它们的混合物。用于制备包含式I化合物的渗透给药的组合物的赋形剂包括例如氯氟烃、乙醇、水、它们的混合物。用于制备包含式I化合物的胃肠外给药的组合物的赋形剂包括例如1,3-丁二醇、蓖麻油、玉米油、棉子油、葡萄糖、胚芽油、花生油、脂质体、油酸、橄榄油、花生油、林格溶液、红花油、芝麻油、大豆油、U.S.P.或等渗氯化钠溶液、水和它们的混合物。用于制备包含式I化合物的直肠或阴道给药的组合物的赋形剂包括,例如,可可脂、聚乙二醇、蜡以及它们的混合物。
烟酰胺[2,5′,8-3H]腺嘌呤二核苷酸和链霉抗生素蛋白(strepavidin)SPA微珠获自Amersham Biosiences(UK)。重组人聚(ADP-核糖)聚合酶(PARP)是由大肠杆菌和6-生物素-17-NAD+纯化,获自Trevigen(Gaithersburg,MD)。NAD+、组蛋白、氨基苯甲酰胺、3-氨基苯甲酰胺和小牛胸腺DNA(dcDNA)获自Sigma(St.Louis,MO)。含MCAT序列的茎-环寡核苷酸得自Qiagen。将所述oligos在退火缓冲剂中溶解为1mM,所述退火缓冲剂含有10mM Tris HCl(pH 7.5),1mM EDTA和50mM NaCl,在95℃培养5分钟,在45℃退火45分钟。组蛋白H1(95%电泳纯度)获自Roche(印第安纳波利斯,IN.生物素化的组蛋白H1通过将所述蛋白用磺基-NHS-LC-生物素(PierceRockford,IL)处理进行制备。通过缓慢地和间歇地将3当量的10mM磺基-NHS-LC-生物素加入到在4℃下的在磷酸盐缓冲盐水(pH 7.5)中的100μM组蛋白H1中,温和涡流1分钟,然后在4℃培养1小时,进行所述生物素化反应。链霉抗生物素蛋白涂敷的(FlashPlate Plus)微型板获自Perkin Elmer(波士顿,MA)。
PARP1测定在含有50mM tris(pH 8.0),1mM DTT和4mM MgCl2的PARP分析缓冲液中进行。PARP反应含有1.5μM[3H]-NAD+(1.6μCi/mmol),200nM生物素化的组蛋白H1,200nM slDNA和1nMPARP酶。利用基于SPA微珠检测的自动反应在白色96孔板中于100μL的体积内进行。向含有PARP和DNA的50μL 2x酶混合物中加入50μL 2X NAD+底物混合物引发反应。加入150μL 1.5mM苯甲酰胺(超过其IC501000倍),使这些反应终止。将170μL已停止反应的混合物转移到链霉抗生物素蛋白Flash Plate中,培养1小时,用TopCount微板闪烁计数器计数。本发明代表性化合物的Ki数据(以nM表示)根据各种底物浓度下的抑制曲线确定并表示在表1中。
表1
实施例 | PARP-1(Ki,nM) |
1 | 14.5 |
2 | 11.8 |
3 | 28 |
实施例 | PARP-1(Ki,nM) |
4 | 20.9 |
5 | 32 |
6 | 45 |
7 | 61 |
8 | 50 |
9 | 44 |
10 | 3.1 |
11 | 2 |
12 | 9 |
13 | 2.4 |
14 | 3.2 |
15 | 5 |
16 | 6 |
17 | 10 |
18 | 6 |
19 | 8 |
20 | 5 |
21 | 4 |
22 | 3 |
23 | 8 |
实施例 | PARP-1(Ki,nM) |
24 | 12 |
25 | 10 |
26 | 6 |
27 | 8 |
28 | 7 |
29 | 14 |
30 | 16 |
31 | 11 |
32 | 23 |
33 | 21 |
34 | 7 |
35 | 7 |
36 | 5 |
37 | 7 |
38 | 6 |
39 | 11 |
40 | 10 |
41 | 5 |
42 | 12 |
43 | 3 |
实施例 | PARP-1(Ki,nM) |
44 | 41 |
45 | 11 |
46 | 17 |
47 | 14 |
48 | 14 |
49 | 17 |
50 | 0.8 |
51 | 1.8 |
52 | 14 |
53 | 317 |
这些数据证明,式I的代表性化合物能够作为聚(ADP-核糖)聚合酶的抑制剂。
在癌症、中风、缺血和炎症中涉及的PARP描述在Pharm.Res.52,2005中。在其它疾病状态中涉及的PARP报导在Cancer Chemo.Pharmacol.22(1988),303;Proc.Natl.Acad.Sci.USA 94(1997),679-683 D;Int.J.Immunopharmacol.17(1995),265-271;Inflammation20(1996),203-215;Rheumatol.Int.15(1995),171-172;Proc.Natl.Acad.Sci.USA 95(1998),3867-3872;Eur.J.Pharmacol.342(1998),67-76和Nature Medicine(1999),5314-19中。
还预期式I化合物将与下列物质一起使用时是有用的:烷化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂剂、抗增殖剂、aurora激酶抑制剂、Bcr-Abl激酶抑制剂、生物反应调节剂、依赖细胞周期蛋白激酶抑制剂、细胞周期抑制剂、环加氧酶-2抑制剂、白血病病毒癌基因同系物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白脱乙酰酶(HDAC)抑制剂、激素治疗、免疫剂、插入抗生素、激酶抑制剂、哺乳动物瑞帕霉素(rapomycin)靶标抑制剂、促分裂原活化胞外信号调节激酶抑制剂、非甾体抗炎药(NSAID)、铂化疗药、polo样激酶抑制剂、蛋白酶体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类视色素/deltoids植物生物碱、拓扑异构酶抑制剂等。
烷化剂包括六甲蜜胺、AMD-473、AP-5280、apaziquone、苯达莫司汀、brostallicin、白消安、卡巴醌、卡莫司汀(BCNU)、苯丁酸氮芥、CloretazineTM(VNP 40101M)、环磷酰胺、氨烯咪胺(decarbazine)、雌莫司汀、福莫司汀、葡磷酰胺(glufosfamide)、异环磷酰胺、KW-2170、洛莫司汀(CCNU)、马磷酰胺、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司丁、氮芥N-氧化物、雷莫司汀、替莫唑胺、塞替派、苏消安、氯乙环磷酰胺等。
血管生成抑制剂包括内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、表皮生长因子受体(EGFR)抑制剂、胰岛素生长因子-2受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板衍生生长因子受体(PDGFR)抑制剂、血小板反应蛋白类似物血管内皮细胞生长因子受体酪氨酸激酶(VEGFR)抑制剂等。
Aurora激酶抑制剂包括AZD-1152、MLN-8054、VX-680等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-032、BMS-387、CVT-2584、flavopyridol、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib(CYC-202、R-roscovitine)、ZK-304709等。
COX-2抑制剂包括ABT-963、(艾托考昔)、(伐地考昔)、BMS347070、西乐葆TM(CELEBREXTM)(塞来考昔)、COX-189(罗美考昔)、CT-3、(地拉考昔)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基-1H-吡咯)、MK-663(艾托考昔)、NS-398、帕瑞考昔、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、(罗非考昔)等。
EGFR抑制剂包括ABX-EGF、抗-EGFr免疫脂质体、EGF-疫苗、EMD-7200、(西妥昔单抗)、HR3、IgA抗体、(吉非替尼)、(埃罗替尼或OSI-774)、TP-38、EGFR融合蛋白、(拉帕替尼)等。
ErbB2受体抑制剂包括CP-724-714、CI-1033(卡奈替尼)、(曲妥单抗)、(拉帕替尼)、(2C4,帕妥珠单抗)、TAK-165、gW-572016(ionafarnib)、gW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER-2疫苗)、抗-HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三官能团双特异性抗体、mABAR-209、mAB 2B-1等。
组蛋白脱乙酰酶抑制剂包括酯肽(depsipeptide)、LAQ-824、MS-275、trapoxin、N-辛二酰苯胺异羟肟酸(SAHA)、TSA、丙戊酸等。
HSP-90抑制剂包括17-AAG-nab、17-AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、NCS-683664、PU24FC1、PU-3、根赤壳菌素、SNX-2112、STA-9090VER49009等。
MEK抑制剂包括ARRY-142886、ARRY-438162 PD-325901、PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司(everolimus)、RAD-001、雷帕霉素、temsirolimus等。
非甾体抗炎药包括(双水杨酯)、(双氟尼酸)、(布洛芬)、(酮洛芬)、(萘丁美酮)、(吡罗昔康)、布洛芬(ibuprofin)乳膏、和(萘普生)、(双氯芬酸)、(吲哚美辛)、(舒林酸)、(甲苯酰吡咯乙酸)、(依托度酸)、(酮咯酸)、(奥沙普嗪)等。
PDGFR抑制剂包括C-451、CP-673、CP-868596等。
Polo样激酶抑制剂包括BI-2536等。
血小板反应蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1等。
VEGFR抑制剂包括(贝伐单抗)、ABT-869、AEE-788、ANGIOZYMETM、axitinib(AG-13736)、AZD-2171、CP-547,632、IM-862、Macugen(pegaptamib)、(索拉非尼、BAY43-9006)、帕唑帕尼(pazopanib)(GW-786034)、(PTK-787、ZK-222584)、(舒尼替尼、SU-11248)、VEGF trap、瓦他拉尼、ZACTIMATM(凡德他尼、ZD-6474)等。
抗代谢剂包括(培美曲塞二钠、LY231514、MTA)、5-阿扎胞苷、(卡培他滨)、卡莫氟、(克拉屈滨)、氯法齐明(clofarabine)、阿糖胞苷、阿糖胞苷酯、胞嘧啶阿拉伯糖苷、地西他滨、去铁胺、去氧氟尿苷、依氟鸟氨酸、EICAR、依诺他滨、ethnylcytidine、氟达拉滨、羟基脲、5-氟尿嘧啶(5-FU)单独或与亚叶酸联合、(吉西他滨)、羟基脲、(美法仑)、巯嘌呤、6-巯基嘌呤核糖核苷、甲氨蝶呤、麦考酚酸、奈拉滨、诺拉曲塞、ocfosate、pelitrexol、喷司他丁、雷替曲塞、利巴韦林、triapine(非洛地平+雷米普利)、曲美沙特、S-1、噻唑呋林、替加氟、TS-1、阿糖腺苷、UFT等。
抗生素包括插入抗生素(intercalating antibiotics)阿柔比星、放线菌素D、氨柔比星、安那霉素(annamycin)、阿霉素、(博来霉素)、柔红霉素、或(多柔比星)、依沙芦星、表柔比星、加柔比星、(伊达比星)、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、瑞必克霉素(rebeccamycin)、stimalamer、链脲霉素、(戊柔比星)、净司他丁(zinostatin)等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、becatecarin、贝洛替康、BN-80915、(伊立替康盐酸盐)、喜树碱、(右雷佐生)、双氟菲替康(diflomotecan)、edotecarin、或(表柔比星)、依托泊苷、依沙替康、10-羟基喜树碱、吉马替康、勒托替康、米托蒽醌、orathecin、吡柔比星、pixantrone、卢比替康、索布佐生、SN-38、tafluposide、托泊替康等。
抗体包括(贝伐单抗)、CD40-特异性抗体、chTNT-1/B、denosumab、(西妥昔单抗)、(zanolimumab)、IGF1R-特异性抗体、lintuzumab、(依决洛单抗)、(WX G250)、(美罗华)、ticilimumab、trastuzimab等。
激素治疗剂包括(阿那曲唑)、(依西美坦)、阿佐昔芬、(比卡鲁胺)、(西曲瑞克)、degarelix、地洛瑞林、(曲洛司坦)、地塞米松、(氟他米特)、(雷洛昔芬)、法倔唑、(托瑞米芬)、(氟维司群)、(来曲唑)、福美坦、糖皮质激素、或(度骨化醇)、拉索昔芬、醋酸亮丙瑞林、(megesterol)、(米非司酮)、NILANDRONTM(尼鲁米特)、(枸橼酸它莫西芬)、PLENAXISTM(阿巴瑞克)、泼尼松、(非那司提)、瑞洛司坦(rilostane)、(布舍瑞林(buserelin))、(促黄体素释放激素(LHRH))、vantas、(曲洛司坦或modrastane)、(伏司瑞林(fosrelin)、戈舍瑞林)等。
Deltoids和类视色素包括西奥骨化醇(EB 1089、CB 1093)、lexacalcitrol(KH 1060)、维甲酰酚胺(fenretinide)、(aliretinoin)、(liposomal tretinoin)、(贝沙罗汀)、LGD-1550等。
植物生物碱包括,但不局限于,长春新碱、长春花碱、去乙酰长春酰胺、长春瑞滨等。
免疫试剂的实例包括干扰素以及其它免疫增强剂。干扰素包括干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、(干扰素γ-1b),干扰素γ-n1,及其组合等。其它物质包括BAM-002、(他索纳明)、(托西莫单抗)、(阿仑单抗)、CTLA4(细胞毒性淋巴细胞抗原4)、氨烯咪胺、地尼白介素、依帕珠单抗、(来格司亭)、蘑菇多糖、白细胞α干扰素、咪喹莫特、MDX-010、黑素瘤疫苗、米妥莫单抗、莫拉司亭、MYLOTARGTM(吉姆单抗奥佐米星)、(非格司亭)、OncoVAC-CL、(oregovomab)、pemtumomab(Y-muHMFG1)、sargaramostim、裂裥多糖、替西白介素、乌苯美司、VIRULIZINZ-100、WF-10、(阿地白介素)、(胸腺法新)、(达(克)珠单抗、(90Y-Ibritumomab tiuxetan)等。
生物反应调节物是改变活有机体或生物反应的防御机制的物质,例如组织细胞的存活、生长或分化,指引它们具有抗肿瘤活性并包括云芝多糖、蘑菇多糖、西佐喃、picibanil PF-3512676(CpG-8954)、乌苯美司等。
嘧啶类似物包括阿糖胞苷(ara C)、胞嘧啶阿拉伯糖苷、去氧氟尿苷、(氟达拉滨)、5-FU(5-氟尿嘧啶)、氟尿嘧啶脱氧核苷、(吉西他滨)、(ratitrexed)、TROXATYLTM(triacetyluridine troxacitabine)等。
抗有丝分裂剂包括倍他布林(batabulin)、epothilone D(KOS-862)、N-(2-((4-羟基苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆(BMS 247550)、紫杉醇、(紫杉萜)、PNU100940(109881)、patupilone、XRP-9881、长春氟宁、ZK-EPO等。
本发明的化合物还涉及用作放射致敏剂以增加放疗的效力。放射治疗的实例包括,但不局限于,外粒子束放射治疗、远距放射疗法、血管内近距离放射治疗以及密封源放射治疗和非密封源放射治疗。
此外,式I化合物可以与其它化疗剂联合使用,例如ABRAXANETM(ABI-007)、ABT-100(法尼基转移酶抑制剂)、 或(洛伐他汀)、(poly I:poly C12U、一种合成RNA)、APTOSYNTM(exisulind)、(帕米膦酸)、arglabin、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄-1,4-二烯)、(tazarotne)、AVE-8062、BEC2(米妥莫单抗)、恶病质素或cachexin(肿瘤坏死因子)、canvaxin(疫苗)、CeaVacTM(癌症疫苗)、基因重组IL-2(celmoleukin)、(二盐酸组胺)、CERVARIXTM(人乳头瘤病毒疫苗)、(C:(环磷酰胺);H:(羟基多柔比星);O:长春新碱();P:泼尼松),CyPatTM、combrestatin A4P、DAB(389)EGF或TransMID-107R TM(白喉毒素)、达卡巴嗪、更生霉素、5,6-二甲基呫吨酮-4-乙酸(DMXAA)、eniluracil、EVIZONTM(角鲨胺乳酸盐)、(T4N5脂质体洗液)、discodermolide、DX-8951f(依沙替康甲磺酸盐)、enzastaurin、EPO906、(四价人乳头瘤病毒(类型6、11、16、18)重组体疫苗)、胃和结肠直肠癌疫苗(gastrimmune)、genasense、GMK(神经节苷脂缀合疫苗)、(前列腺癌疫苗)、卤夫酮、histerelin、羟基脲(hydroxycarbamide)、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekin besudotox)、IL-13-假单胞菌属外毒素、干扰素-α、干扰素-γ、JUNOVANTM或MEPACTTM(mifamurtide)、lonafarnib、5,10-亚甲基四氢叶酸、米替福新(十六烷基胆碱磷酸(hexadecylphosphocholine))、(AE-941)、(曲美沙特葡糖醛酸盐)、(喷司他丁)、(一种核糖核酸酶)、(黑素瘤疫苗治疗)、OncoVAX(IL-2疫苗)、ORATHECINTM(卢比替康)、(基于抗体的细胞药物)、MAb(鼠单克隆抗体)、paditaxel、PANDIMEXTM(来自人参的皂甙元,包含20(S)原人参萜二醇(aPPD)和20(S)原人参萜三醇(aPPT))、帕尼单抗、-VF(研究中的癌症疫苗)、培门冬酶、PEG干扰素A、phenoxodiol、丙卡巴肼、rebimastat、(catumaxomab)、(lenalidomide)、RSR13(efaproxiral)、LA(lanreotide)、(阿昔曲丁)、十字孢碱(链霉菌属星状孢子)、talabostat(PT100)、(贝沙罗汀)、(DHA-紫杉醇)、TELCYTATM(TLK286)、temilifene、(替莫唑胺)、tesmilifene、沙利度胺、(STn-KLH)、thymitaq(2-氨基-3,4-二氢-6-甲基-4-氧代-5-(4-吡啶基硫基)喹唑啉二盐酸盐)、TNFeradeTM(adenovector:含有肿瘤坏死因子-α基因的DNA载体)、或(波生坦)、维甲酸(Retin-A)、汉防己碱、(三氧化二砷)、ukrain(来自白屈菜植物的生物碱的衍生物)、vitaxin(抗-αβ3抗体)、(motexafin gadolinium)、XINLAYTM(阿曲生坦)、XYOTAXTM(paclitaxel poliglumex)、YONDELISTM(trabectedin)、ZD-6126、右雷佐生(dexrazoxane)、zometa(zolendronicacid)、佐柔比星等。
可以预期,式I化合物同样能抑制来源于儿科癌或新生物的细胞的生长,所述儿科癌或新生物包括胚胎性横纹肌肉瘤、儿科急性淋巴母细胞性白血病、儿科急性髓性白血病、儿科泡状横纹肌肉瘤、儿科退行发育室管膜瘤、儿科退行发育大细胞淋巴瘤、儿科退行发育成神经管细胞瘤、中枢神经系统的儿科非典型畸胎样/杆状肿瘤、儿科双表型急性白血病、儿科伯基特氏淋巴瘤、尤因族肿瘤的儿科癌症例如原发性神经外胚层肿瘤、儿科弥散退行发育胚胎性癌肉瘤、儿科良好组织胚胎性癌肉瘤、儿科成胶质细胞瘤、儿科成神经管细胞瘤、儿科成神经细胞瘤、儿科成神经细胞瘤-衍生的髓细胞组织增生、儿科前B-细胞癌(例如白血病)、儿科骨肉瘤、儿科杆状肾肿瘤、儿科横纹肌肉瘤和儿科T-细胞癌例如淋巴瘤和皮肤癌等(美国专利申请系列号10/988,338共同所有),Cancer Res.,2000,60,6101-10);和自身免疫性疾病包括获得性免疫缺损疾病综合征、自身免疫淋巴组织增生综合征、溶血性贫血、炎性疾病和血小板减少症等(Current Allergy andAsthma Reports 2003,3:378-384;Br.J.Haematol.2000 Sep;110(3):584-90;Blood 2000 Feb 15;95(4):1283-92;和New EnglandJournal of Medicine 2004 Sep;351(14):1409-1418)。
式I的化合物可以通过化学合成方法制备,其实例表示在下文中。不用说,方法中的步骤次序可以改变,具体提及的那些试剂、溶剂和反应条件可以被替换,并且根据需要,易受攻击的部分可以被保护和脱保护,例如,根据需要,C(O)OH、C(O)和C(O)H、NH、C(O)NH2、OH和SH部分可以被保护和脱保护。
C(O)OH部分的保护基包括,但不局限于,乙酰氧基甲基、烯丙基、苯甲酰基甲基、苄基、苄氧基甲基、叔丁基、叔丁基二苯基甲硅烷基、二苯甲基、环丁基、环己基、环戊基、环丙基、二苯基甲基甲硅烷基、乙基、对甲氧基苄基、甲氧基甲基、甲氧基乙氧基甲基、甲基、甲硫基甲基、萘基、对硝基苄基、苯基、正丙基、2,2,2-三氯乙基、三乙基甲硅烷基、2-(三甲基甲硅烷基)乙基、2-(三甲基甲硅烷基)乙氧基甲基、三苯甲基等。
C(O)和C(O)H部分的保护基包括,但不局限于,1,3-二氧基缩酮、二乙基缩酮、二甲基缩酮、1,3-二噻烷基缩酮、O-甲基肟、O-苯基肟等。
NH部分的保护基包括,但不局限于,乙酰基、丙氨酰基、苯甲酰基、苄基(苯基甲基)、亚苄基、苄氧羰基(Cbz)、叔丁氧羰基(Boc)、3,4-二甲氧基苄氧羰基、二苯甲基、二苯基磷酰基、甲酰基、甲磺酰基、对甲氧基苄氧羰基、苯乙酰基、邻苯二甲酰基、琥珀酰基、三氯乙氧羰基、三乙基甲硅烷基、三氟乙酰基、三甲基甲硅烷基、三苯甲基、三苯甲硅烷基、对甲苯磺酰基等。
OH和SH部分的保护基包括,但不局限于,乙酰基、烯丙基、烯丙氧羰基、苄氧羰基(Cbz)、苯甲酰基、苄基、叔丁基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、3,4-二甲氧基苄基、3,4-二甲氧基苄氧羰基、1,1-二甲基-2-丙烯基、二苯甲基、甲酰基、甲磺酰基、甲氧基乙酰基、4-甲氧基苄氧羰基、对甲氧基苄基、甲氧羰基、甲基、对甲苯磺酰基、2,2,2-三氯乙氧羰基、2,2,2-三氯乙基、三乙基甲硅烷基、三氟乙酰基、2-(三甲基甲硅烷基)乙氧羰基、2-三甲基甲硅烷基乙基、三苯甲基、2-(三苯膦基)乙氧羰基等。
保护基的详尽论述在T.H.greene和P.G.M.Wuts,Protective groupsin Organic Synthesis,3rd Ed.,John Wiley&Sons,New York(1999)中。
下列缩写具有所示的含义。
ADDP是指1,1′-(偶氮二羰基)二哌啶;AD-mix-β是指(DHQD)2PHAL、K3Fe(CN)6、K2CO3和K2SO4)的混合物;9-BBN是指9-硼杂双环(3.3.1)壬烷;CDI是指羰基二咪唑;(DHQD)2PHAL是指氢化奎尼定1,4-酞嗪二基乙醚;DBU是指1,8-二氮杂双环(5.4.0)十一-7-烯;DIBAL是指二异丁基氢化铝;DIEA是指二异丙基乙胺;DMAP是指N,N-二甲基氨基吡啶;DMF是指N,N-二甲基甲酰胺;dmpe是指1,2-二(二甲基膦基)乙烷;DMSO是指二甲亚砜;dppb是指1,4-二(二苯基膦基)丁烷;dppe是指1,2-二(二苯基膦基)乙烷;dppf是指1,1′-二(二苯基膦基)二茂铁;dppm是指1,1-二(二苯基膦基)甲烷;EDAC是指1-(3-二甲基氨基丙基)-3-乙基碳二亚胺;Fmoc是指芴基甲氧羰基;HATU是指O-(7-氮杂苯并三唑-1-基)-N,N′N′N′-四甲基脲鎓六氟磷酸盐;HMPA是指六甲基磷酰胺;IPA是指异丙醇;MP-BH3是指大孔甲基聚苯乙烯三乙铵氰基硼氢化物;PyBOP是指苯并三唑-1-基-氧基三吡咯烷基鏻六氟磷酸盐;TEA是指三乙胺;TFA是指三氟乙酸;THF是指四氢呋喃;NCS是指N-氯琥珀酰亚胺;NMM是指N-甲基吗啉;NMP是指N-甲基吡咯烷和PPh3是指三苯基膦;BOC是指二碳酸二叔丁酯;C-18是指二甲基-十八烷基硅烷;DCI是指直接引入的化学电离;DME是指1,2-二甲氧基乙烷;ESI是指电喷射离子化;HPLC是指高压液相色谱;MS是指质谱;在1H NMR中所使用的符号“δ”是指1H NMR化学位移;在1H NMR中所使用的缩写“br”是指宽的1H NMR信号;在1H NMR中所使用的缩写“d”是指双1H NMR峰;在1H NMR中所使用的缩写“dd”是指双1H NMR二重峰;在1H NMR中所使用的缩写“m”是指多重1H NMR峰;在1H NMR中所使用的缩写“q”是指四重1H NMR峰;在1H NMR中所使用的缩写“s”是指1H NMR单峰;以及在1H NMR中所使用的缩写“t”是指三重1H NMR峰。
式I的化合物
一种实施方案包括式I的化合物,
及其治疗上可接受的盐、前药、酯、酰胺、前药的盐、酯的盐和酰胺的盐,其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
B1是氢、R3、CO(O)R3A、C(O)NH2、C(O)NHR3A、C(O)N(R3A)2、SO2NH2、SO2NHR3A或SO2N(R3A)2;
R3A是烷基或环烷基;
R3是烷基或链烯基,其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R4、OR4、NH2、NHR4、N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2或OH;
R4是烷基或环烷基;
C1、D1、E1每个独立地是氢、NO2、CN、R5、OR5、CO(O)R5、C(O)NH2、C(O)NHR5、C(O)N(R5)2、NH2、NHR5、N(R5)2、OH、F、Cl、Br或I;
R5是烷基、链烯基或炔基;其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R6、NH2、NHR6、N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、OH、F、Cl、Br或I;
R6是烷基或环烷基;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
式I的实施方案
属于式I化合物范围内的使人感兴趣的化合物的所选子类表示在如下所述的各种实施方案中,其中A1、A2、R1A、R2A、B1、R3、R3A、R4、C1、D1、E1、R5、R6、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A可以如式I的化合物所定义以及如本说明书各个实施方案中所定义。
在式I的一种实施方案中,B1、C1、D1和E1之一是氢以及其余如式I中所述。
在式I的另一种实施方案中,B1、C1、D1和E1之二是氢以及其余如式I中所述。
在式I的另一种实施方案中,B1、C1、D1和E1之三是氢以及其余如式I中所述。
式II的实施方案
在一种实施方案中,本发明部分涉及一类式II结构的化合物
及其治疗上可接受的盐、前药、酯、酰胺、前药的盐、酯的盐和酰胺盐,其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
B1是氢、R3,CO(O)R3A、C(O)NH2、C(O)NHR3A、C(O)N(R3A)2、SO2NH2、SO2NHR3A或SO2N(R3A)2;
R3A是烷基或环烷基;
R3是烷基或链烯基,其每个是未取代的或被一个或两个取代基取代,所述取代基独立地选自R4,OR4、NH2、NHR4、N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2或OH;
R4是烷基或环烷基;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
在式II的另一种实施方案中,B1是H,如式III中所述:
其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
在式II的另一种实施方案中,B1是H,如式III中所述,其中A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个取代基取代或进一步取代的,所述取代基独立地选自R7、CF3、CF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个取代基取代,所述取代基独立地选自R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
式III中A1的实施方案
在式III的一种实施方案中,A1是未稠合的杂芳基;以及A2、R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1是未稠合的杂芳基;A2是杂芳基或杂环烷基,其每个是未稠合的或与R2A稠合;以及R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1是未稠合的杂芳基;A2是杂芳基或杂环烷基,其每个是未稠合的;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1是未稠合的杂芳基;A2是杂芳基,其是未稠合的或与R2A稠合;以及R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1是未稠合的杂芳基;A2是未稠合的杂芳基;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1是未稠合的杂芳基;A2是杂环烷基,其是未稠合的或与R2A稠合;以及R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1是未稠合的杂芳基;A2是未稠合的杂环烷基;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2、R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2是杂芳基或杂环烷基,其每个是未稠合的或与R2A稠合;以及R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2是杂芳基或杂环烷基,其每个是未稠合的;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2是杂芳基,其是未稠合的或与R2A稠合;以及R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2是未稠合的杂芳基;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2是杂环烷基,其是未稠合的或与R2A稠合;以及R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2是未稠合的杂环烷基;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
式III中A2的实施方案
在式III的一种实施方案中,A1是未稠合的杂芳基;A2选自
其中R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
A2选自:
其中R2A、R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
在式III的另一种实施方案中,A1选自
其中A2选自:
其每个是未稠合的;以及R7、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被取代。
环上的任选取代基
在式III的一种实施方案中,A1是未稠合的杂芳基;A2选自
其中R2A、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被R7或CF3取代。
在式III的另一种实施方案中,A1选自
A2选自:
其中R2A、R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被R7或CF3取代。
在式III的另一种实施方案中,A1选自
其中A2选自:
其每个是未稠合的;以及R8、R9、R10、R11、R8A、R9A、R10A、R12、R13、R14、R15、R16、R17、R13A、R14A和R15A如式III中所述,其中A1和A2是未取代的或如式III中所述被R7或CF3取代。
在式III的一种实施方案中,A1是未稠合的杂芳基;A2选自
其中A1和A2是未取代的或如式III中所述被R7或CF3取代;每个R7是R10或R11;R10是环烷基或杂环烷基;其每个是未稠合的;每个R11是烷基,其是未取代的或被R12取代;每个R12是R14或R15;其每个是未稠合的;R14是杂芳基以及R15是环烷基,其每个是未稠合的。
在式III的另一种实施方案中,A1选自
A2选自:
其中A1和A2是未取代的或如式III中所述被R7或CF3取代;每个R7是R10或R11;R10是环烷基或杂环烷基;其每个是未稠合的;每个R11是烷基,其是未取代的或被R12取代;每个R12是R14或R15;其每个是未稠合的;R14是杂芳基以及R15是环烷基,其每个是未稠合的。
在式III的另一种实施方案中,A1选自
其中A2选自:
其每个是未稠合的;其中A1和A2是未取代的或如式III中所述被R7或CF3取代;每个R7是R10或R11;R10是环烷基或杂环烷基;其每个是未稠合的;每个R11是烷基,其是未取代的或被R12取代;每个R12是R14或R15;其每个是未稠合的;R14是杂芳基以及R15是环烷基,其每个是未稠合的。
方案
在此所使用的起始原料是市场上可买到的或可以通过本领域普通技术人员公知的常规方法制备。本发明的化合物可以使用通用合成方案和下面详述的实验步骤中所示的方法制备。所述通用合成方案仅仅是用于举例说明性的而不是用于限制本发明的范围。
方案1
如方案1所示,通过式(1)化合物、式(2)化合物,其中X是H、I、Br、Cl或OSO2CF3,1,1′-羰基二咪唑和吡啶反应,接着所得产物与冰乙酸反应,式(1)化合物可以转化为式(3)化合物。
方案2
如方案2所示,式(3)化合物其中X是I、Br、Cl或OSO2CF3,例如使用在Palladium Reagents And Catalysts:New Perspectives For The21st Century,By J.Tsuji,John Wiley&Sons,Ltd.,Chichester,2004,1-670中所述的方法,可以转化为式I化合物。
方案3
HO2C-A1-X→HO2C-A1-A2
(2) (5)
如方案3所示,例如使用如Tsuji,op.cit中所述的方法,式(2)化合物可以转化为式(5)化合物。
方案4
如方案4所示,通过式(4)化合物、式(6)化合物和碱反应,式(4)化合物可以转化为式I化合物。碱包括氢化钠、碳酸钾等。该反应典型地在溶剂如DMF或THF中在约0℃至25℃的低温下进行。
下面所提供的实施例被认为是最有用的并且容易地理解本发明的方法和概念方面的描述。
实施例1
2-(4-吡啶-3-基-1,3-噻唑-2-基)-1H-苯并咪唑-4-甲酰胺
在环境温度下,向2-(3-吡啶基)-1,3-噻唑-4-羧酸(300mg)在吡啶(5mL)和DMF(5mL)中的混合物中加入CDI(248mg)。将所述混合物在40℃加热2小时,用2,3-二氨基苯甲酰胺二盐酸盐(326mg)处理,在环境温度下搅拌16小时,浓缩。将浓缩物在冰乙酸(20mL)中在110℃加热2小时,冷却,浓缩。将浓缩物在乙酸乙酯和碳酸氢钠溶液之间进行分配,过滤析出的固体,用水和乙酸乙酯洗涤。1H NMR(DMSO-d6)δ7.38(t,J=7.8Hz,1H),7.60-7.67(m,1H),7.78(d,J=7.8Hz,1H),7.81(brs,1H),7.90(dd,J=7.46,1.0Hz,1H),8.44-8.50(m,1H),8.74-8.76(m,1H),8.74(s,1H),9.29(brs,1H),9.34(d,J=1.7Hz,1H),13.44(brs,1H).
实施例2
2-(4-吡啶-4-基-1,3-噻唑-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例1中所述制备,用2-(4-吡啶基)-1,3-噻唑-4-羧酸代替2-(3-吡啶基)-1,3-噻唑-4-羧酸。1H NMR(DMSO-d6)δ7.38(t,J=7.8Hz,1H),7.78(d,J=8.1Hz,1H),7.83(brs,1H),7.91(d,J=7.8Hz,1H),8.05-8.06(m,1H),8.07-8.08(m,1H),8.80-8.81(m,1H),8.81-8.83(m,2H),9.28(brs,1H),13.48(brs,1H).
实施例3
2-(4-甲基-2-吡嗪-2-基-1,3-噻唑-5-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例1中所述制备,用4-甲基-2-(2-吡嗪基)-1,3-噻唑-5-羧酸代替2-(3-吡啶基)-1,3-噻唑-4-羧酸。1H NMR(DMSO-d6)δ2.89(s,3H)7.37(t,J=7.8Hz,1H),7.75(s,1H),7.77(brs,1H),7.89(d,J=7.7Hz,1H),8.74-8.76(m,1H),8.78(d,J=2.8Hz,1H),9.08(brs,1H),9.34(d,J=1.5Hz,1H),13.09(brs,1H).
实施例4
2-(2-噻吩-2-基-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例1中所述制备,用2-(2-噻吩基)-1,3-噻唑-4-羧酸代替2-(3-吡啶基)-1,3-噻唑-4-羧酸。1H NMR(DMSO-d6)δ7.23(t,J=4.3Hz,1H),7.36(t,J=7.7Hz,1H),7.75(d,J=7.7Hz,1H),7.78(d,J=2.5Hz,1H),7.81(s,1H),7.82(brs,1H),7.89(d,J=7.4Hz,1H),8.57(s,1H),9.27(brs,1H),13.30(brs,1H).
实施例5
2-(2-哌啶-4-基-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺
在环境温度下,向2-(1-(叔丁氧羰基)哌啶-4-基)-1,3-噻唑-4-羧酸(1.03g)在吡啶(8mL)和DMF(8mL)中的溶液中加入CDI(562mg)。将所述混合物在40℃加热2小时,用2,3-二氨基苯甲酰胺二盐酸盐(739mg)处理,在环境温度下搅拌16小时,浓缩。将浓缩物在冰乙酸(30mL)中在110℃搅拌2小时,冷却,浓缩。将浓缩物在二氯甲烷(20mL)和TFA(8mL)中在环境温度下搅拌1小时,用乙腈处理,浓缩。将浓缩物用HPLC提纯(Zorbax C-8,0.1%TFA/乙腈/水)。将所述产物溶于二氯甲烷(5mL)和甲醇(5mL)中,用在乙醚(10mL)中的1M盐酸处理,浓缩。1H NMR(DMSO-d6)δ1.93-2.09(m,2H),2.26-2.37(m,2H),3.02-3.16(m,2H),3.38-3.47(m,2H),3.49-3.55(m,1H),7.38(t,J=7.8Hz,1H),7.77(d,J=7.1Hz,1H),7.80(s,1H),7.90(d,J=7.5Hz,1H),8.64(s,1H),8.72(brs,1H),8.94(brs,1H),9.11(brs,1H).
实施例6
2-(2-(1-甲基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺
向实施例5(50mg)在甲醇(8mL)中的溶液中加入在水(28μL)和TEA(21μL)中的37wt%甲醛。将所述溶液搅拌1小时,用氰基硼氢化钠(28mg)和氯化锌(II)(20mg)处理,搅拌60小时,浓缩。浓缩物用HPLC提纯(Zorbax C-8,0.1%TFA/乙腈/水)。将所述盐溶于二氯甲烷(2mL)和甲醇(2mL)中,用在乙醚(4mL)中的1M盐酸处理,浓缩。1H NMR(DMSO-d6)δ2.12-2.23(m,2H),2.32-2.41(m,2H),2.78(d,J=4.6Hz,3H),3.10-3.20(m,2H),3.41-3.48(m,1H),3.50-3.59(m,2H),7.45(t,J=7.8Hz,1H),7.80-7.82(m,1H),7.82-7.85(m,1H),7.94(d,J=6.7Hz,1H),8.82(brs,1H),8.98(brs,1H),10.84(brs,1H).
实施例7
2-(2-(1-异丙基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例6中所述以盐酸盐的形式制得,用丙酮代替甲醛。1H NMR(DMSO-d6)δ1.33(d,J=6.7Hz,6H),2.27-2.43(m,4H),3.12-3.23(m,2H),3.46-3.56(m,4H),7.46(t,J=7.8Hz,1H),7.80-7.83(m,1H),7.83-7.87(m,1H),7.94(d,J=7.6Hz,1H),8.85(brs,1H),8.97(brs,1H),10.68(brs,1H).
实施例8
2-(2-(1-丙基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例6中所述以盐酸盐的形式制得,用丙醛代替甲醛。1H NMR(DMSO-d6)δ0.94(t,J=7.3Hz,3H),1.73-1.83(m,2H),2.17-2.28(m,2H),2.33-2.40(m,2H),2.97-3.05(m,2H),3.05-3.17(m,2H),3.43-3.51(m,1H),3.56-3.65(m,2H),7.44(t,J=7.8Hz,1H),7.79-7.82(m,1H),7.82-7.85(m,1H),7.93(d,J=7.6Hz,1H),8.79(brs,1H),9.00(brs,1H),10.69(brs,1H).
实施例9
2-(2-(1-环丁基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例6中所述以盐酸盐的形式制得,用环丁酮代替甲醛。1H NMR(DMSO-d6)δ1.71-1.81(m,2H),2.16-2.26(m,4H),2.33-2.41(m,3H),2.42-2.48(m,2H),2.89-2.98(m,2H),3.44-3.50(m,2H),3.60-3.67(m,1H),7.45(t,J=7.8Hz,1H),7.79-7.82(m,1H),7.82-7.86(m,1H),7.94(d,J=7.0Hz,1H),8.82(brs,1H),8.98(brs,1H),11.24(brs,1H).
实施例10
2-(5-吡啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例10A
2-(5-溴噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例1中所述制备,用5-溴-2-噻吩羧酸代替2-(3-吡啶基)-1,3-噻唑-4-羧酸。1H NMR(DMSO-d6)δ7.33(brs,1H),7.39(d,J=3.1Hz,1H),7.71(m,3H),7.84(brs,1H),8.99(brs,1H),13.48(brs,1H).
实施例10B
2-(5-吡啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
将实施例10A(184mg)、三-邻-甲苯基膦(52mg)、三(二亚苄基丙酮)二钯(0)(52mg)、2-(三-正丁基甲锡烷基)吡啶(420mg)和三乙胺(238μL)在DMF(5mL)中的混合物在75℃加热过夜。将所述混合物冷却,用二氯甲烷稀释,用快速色谱分离(用在2∶1乙酸乙酯/己烷中的0-15%甲醇)。用HPLC(Zorbax,C-18,流动相A:0.1%TFA在H2O中;B:0.1%TFA在乙腈中;0-100%梯度)进一步提纯,得到标题化合物。1HNMR(DMSO-d6)δ7.34-7.39(m,2H),7.74-7.76(m,2H),7.86-7.95(m,3H),8.00-8.05(m,1H),8.02(s,1H),8.60(d,J=4.6Hz,1H),9.04(brs,1H).
实施例11
2-(5-吡嗪-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例10B中所述以三氟乙酸盐的形式制得,用2-(三-正丁基甲锡烷基)吡嗪代替2-(三-正丁基甲锡烷基)吡啶。1H NMR(DMSO-d6)δ7.35(t,J=7.8Hz,1H),7.73(s,1H),7.75(d,J=7.7Hz,1H),7.86(d,J=7.7Hz,1H),8.03(d,J=3.7Hz,1H),8.09(d,J=4.0Hz,1H),8.57(d,J=2.4Hz,1H),8.63(s,1H),8.99(s,1H),9.31(d,J=1.2Hz,1H).
实施例12
2-(5-嘧啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例10B中所述以三氟乙酸盐的形式制得,用2-(三-正丁基甲锡烷基)嘧啶代替2-(三-正丁基甲锡烷基)吡啶。1H NMR(DMSO-d6)δ7.37(t,J=7.8Hz,1H),7.44(t,J=4.9Hz,1H),7.75(s,1H),7.77(d,J=7.4Hz,1H),7.88(d,J=7.4Hz,1H),8.02-8.06(m,2H),8.87(d,J=4.9Hz,2H),9.04(s,1H).
实施例13
2-(5-吡啶-3-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例10B中所述以三氟乙酸盐的形式制得,用3-(三-正丁基甲锡烷基)吡啶代替2-(三-正丁基甲锡烷基)吡啶。1H NMR(DMSO-d6)δ7.37(t,J=7.6Hz,1H),7.67(dd,J=7.9,4.9Hz,1H),7.76(d,J=7.9Hz,1H),7.82(s,1H),7.87(d,J=4.0Hz,1H),7.88(s,1H),8.05(d,J=3.7Hz,1H),8.39(d,J=8.24Hz,1H),8.65(d,J=4.9Hz,1H),8.99(brs,1H),9.13(d,J=2.1Hz,1H).
实施例14
2-(5-吡啶-4-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例10B中所述以三氟乙酸盐的形式制得,用4-(三-正丁基甲锡烷基)吡啶代替2-(三-正丁基甲锡烷基)吡啶。1H NMR(DMSO-d6)δ7.38(t,J=7.7Hz,1H),7.78(d,J=7.1Hz,1H),7.81(brs,1H),7.88(d,J=7.7Hz,1H),8.11(d,J=6.4Hz,2H),8.16(d,J=7.7Hz,1H),8.77(d,J=6.4Hz,2H),8.94(brs,1H).
实施例15
2-(5-(1H-吡咯-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
向在1,2-二甲氧基乙烷/水/乙醇(7/3/2,10mL)中的实施例10A(100mg)、1-(叔丁氧羰基)吡咯-2-硼酸(100mg)和二氯二(三苯基膦)钯(II)(21mg)中加入2M碳酸钠溶液(1.5mL)。将所述混合物在80℃下加热1小时,浓缩。将浓缩物在乙酸乙酯和盐水之间进行分配,有机相用盐水洗涤,用硫酸镁干燥,过滤,浓缩。在THF(10mL)中的所述浓缩物用TFA(1mL)处理,搅拌过夜,浓缩。浓缩物用HPLC提纯(Zorbax,C-18,流动相A:0.1%TFA在水中;B:0.1%TFA在乙腈中;0-100%梯度)。1H NMR(DMSO-d6)δ6.15-6.17(m,1H),6.53-6.54(m,1H),6.93-6.94(m,1H),7.19-7.43(m,3H),7.72(d,J=7.0Hz,1),7.79(s,1H),7.85(d,J=7.6Hz,1H),7.92(d,J=3.7Hz,1H),9.02(s,1H),11.57(s,1H).
实施例16
2-(5-((2R)-吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例16A
(R)-2-(5-甲氧羰基噻吩-2-基)吡咯烷-1-羧酸叔丁酯
在-78℃下,向N-Boc-吡咯烷(3mL)和(-)-金雀花碱(sparteine)(3.9mL)在叔丁基甲醚(36mL)中的溶液中加入在环己烷(12.21mL)中的1.4M仲丁基锂。将所述溶液搅拌3小时,加入在乙醚(10.2mL)中的1M氯化锌。将所述混合物搅拌30分钟,温热至环境温度30分钟。加入5-溴噻吩-2-羧酸甲酯(3.15g)、四氟硼酸三-叔丁基膦(249mg)和乙酸钯(II)(153mg),所述混合物在环境温度下搅拌过夜,用浓氨水(1mL)处理,搅拌30分钟,通过硅藻土()过滤。所述滤液用0.5M盐酸溶液和水洗涤,浓缩。浓缩物进行硅胶快速色谱分离,用乙酸乙酯/己烷洗脱。
实施例16B
(R)-2-(5-羧基噻吩-2-基)吡咯烷-1-羧酸叔丁酯
向实施例16A(2.8g)在THF(20mL)中的混合物中加入在水(5mL)中的氢氧化锂一水合物(500mg)。将所述混合物在环境温度下搅拌过夜,在乙酸乙酯和0.5M盐酸之间进行分配。所述萃取物用水洗涤,用硫酸镁干燥,过滤,浓缩。
实施例16C
(R)-2-(5-(4-氨基甲酰基-1H-苯并咪唑-2-基)噻吩-2-基)吡咯烷-1-羧酸叔丁基酯
向实施例16B(2.4g)在吡啶(20mL)和DMF(20mL)中的溶液中加入CDI(1.6g),所述混合物在40℃搅拌1小时。加入2,3-二氨基苯甲酰胺二盐酸盐(1.8g),所述混合物在环境温度下搅拌过夜,浓缩。将浓缩物在乙酸(20mL)中在80℃搅拌4小时,浓缩。浓缩物在乙酸乙酯和饱和碳酸氢钠溶液之间进行分配,所述萃取液用水洗涤,浓缩。浓缩物用硅胶快速色谱法提纯,用在己烷中的40-80%乙酸乙酯洗脱。
实施例16D
2-(5-((2R)-吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
将实施例16C(2.2g)在TFA(50mL)中的溶液在环境温度下搅拌30分钟。浓缩后,浓缩物用HPLC提纯(Zorbax,C-18,流动相A:0.1%TFA在水中;B:0.1%TFA在乙腈中;0-100%梯度)。1H NMR(CD3OD)δ2.19-2.29(m,1H),2.28-2.41(m,2H),2.55-2.67(m,1H),3.43-3.56(m,2H),5.01(dd,J=9.3,6.9Hz,1H),7.36(d,J=3.7Hz,1H),7.39(d,J=4.6Hz,1H),7.71(d,J=7.6Hz,1H),7.79(d,J=3.7Hz,1H),7.93(d,J=7.6Hz,1H).
实施例17
2-(5-((2R)-1-甲基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例16D(50mg)在甲醇(20mL)中的溶液用在水中的37wt%甲醛(114μL)处理,搅拌过夜。加入氰基硼氢化钠(315mg),将所述溶液搅拌3小时,浓缩。将浓缩物溶于甲醇和TFA中,用HPLC提纯(ZorbaxC-8,0.1%TFA/乙腈/水)。1H NMR(CD3OD)δ2.30(m,2H),2.47(m,1H),2.74(m,1H),2.94(s,3H),3.31-3.40(m,1H),3.88(m,1H),4.81(m,1H),7.40(t,J=7.7Hz,1H),7.51(d,J=3.7Hz,1H),7.73(d,J=7.6Hz,1H),7.86(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例18
2-(5-((2R)-1-异丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用丙酮代替甲醛。1H NMR(CD3OD)δ1.40(dd,J=11.6,6.7Hz,6H),2.26-2.31(m,2H),2.35-2.48(m,1H),2.62-2.68(m,1H),3.40-3.47(m,1H),3.55-3.73(m,2H),4.98-5.10(m,1H),7.39(t,J=7.8Hz,1H),7.50(d,J=4.0Hz,1H),7.74(d,J=8.2Hz,1H),7.84(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例19
2-(5-((2R)-1-丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用丙醛代替甲醛。1H NMR(CD3OD)δ0.99(t,J=6.9Hz,3H),1.59-1.73(m,1H),1.75-1.85(m,1H),2.25-2.37(m,2H),2.36-2.49(m,1H),2.60-2.75(m,1H),3.02-3.13(m,1H),3.18-3.30(m,1H),3.31-3.42(m,1H),3.80-3.98(m,1H),4.78-4.89(m,1H),7.40(t,J=7.8Hz,1H),7.51(d,J=4.0Hz,1H),7.74(d,J=7.9Hz,1H),7.86(d,J=4.0Hz,1H),7.95(d,J=6.7Hz,1H).
实施例20
2-(5-((2R)-1-(环丙基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用环丙基甲醛代替甲醛。1H NMR(CD3OD)δ0.24-0.33(m,1H),0.40-0.45(m,1H),0.65-0.79(m,2H),1.01-1.17(m,2H),2.26-2.38(m,2H),2.38-2.49(m,1H),2.63-2.76(m,1H),3.03-3.10(m,1H),3.11-3.20(m,1H),3.38-3.49(m,1H),3.95-4.05(m,1H),7.39(t,J=7.8Hz,1H),7.49(d,J=3.7Hz,1H),7.74(d,J=7.9Hz,1H),7.84(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例21
2-(5-((2R)-1-环丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用环丁酮代替甲醛。1H NMR(CD3OD)δ1.76-1.89(m,2H),1.95-2.04(m,1H),2.12-2.22(m,1H),2.23-2.35(m,4H),2.40-2.45(m,1H),2.63-2.76(m,1H),3.25-3.36(m,2H),3.70-3.75(m,1H),3.93-4.05(m,1H),7.39(t,J=7.8Hz,1H),7.47(d,J=3.7Hz,1H),7.74(d,J=8.2Hz,1H),7.82(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例22
2-(5-((2R)-1-环戊基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用环戊酮代替甲醛。1H NMR(CD3OD)δ1.60-1.69(m,2H),1.73-1.91(m,3H),2.02-2.13(m,1H),2.12-2.24(m,1H),2.27-2.36(m,2H),2.35-2.48(m,2H),2.60-2.74(m,1H),3.38-3.54(m,1H),3.66-3.76(m,1H),3.78-3.89(m,1H),4.94-5.07(m,1H),7.39(t,J=7.9Hz,1H),7.49(d,J=4.0Hz,1H),7.74(d,J=8.2Hz,1H),7.83(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例23
2-(5-((2R)-1-环己基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用环己酮代替甲醛。1H NMR(CD3OD)δ1.17-1.26(m,1H),1.27-1.45(m,2H),1.45-1.68(m,3H),1.67-1.95(m,2H),1.85-1.93(m,1H),1.94-2.09(m,2H),2.10-2.20(m,1H),2.22-2.34(m,1H),2.34-2.47(m,1H),2.59-2.72(m,1H),3.44-3.55(m,1H),3.59-3.71(m,1H),5.10-5.20(m,1H),7.39(t,J=7.9Hz,1H),7.50(d,J=3.7Hz,1H),7.74(d,J=7.0Hz,1H),7.85(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例24
2-(5-((2R)-1-四氢-2H-吡喃-4-基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用四氢-吡喃-4-酮代替甲醛。1H NMR(CD3OD)δ1.70-1.77(m,1H),1.77-1.91(m,2H),1.95-2.03(m,1H),2.05-2.19(m,1H),2.25-2.37(m,1H),2.37-2.50(m,2H),2.57-2.75(m,1H),3.37-3.51(m,1H),3.59-3.74(m,2H),3.90-3.97(m,1H),3.97-4.04(m,1H),4.04-4.12(m,1H),5.10-5.19(m,1H),7.40(t,J=7.9Hz,1H),7.52(d,J=3.7Hz,1H),7.74(d,J=7.0Hz,1H),7.85(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例25
2-(5-((2R)-1-(吡啶-2-基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用吡啶-2-甲醛代替甲醛。1H NMR(CD3OD)δ2.25-2.38(m,2H),2.42-2.54(m,1H),2.66-2.80(m,1H),3.39-3.52(m,1H),3.68-3.79(m,1H),4.42(d,J=7.7Hz,1H),4.55(d,J=7.7Hz,1H),5.09(dd,J=9.8,7.3Hz,1H),7.38(d,J=3.7Hz,1H),7.40(t,J=7.9Hz,1H),7.41-7.46(m,1H),7.48(d,J=7.6Hz,1H),7.69-7.75(m,1H),7.77(d,J=4.0Hz,1H),7.84-7.92(m,1H),7.95(dd,J=7.6,1.2Hz,1H),8.63(d,J=4.0Hz,1H).
实施例26
2-(5-((2R)-1-(吡啶-4-基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用吡啶-4-甲醛代替甲醛。1H NMR(CD3OD)δ2.03-2.21(m,3H),2.40-2.58(m,1H),2.65-2.80(m,1H),3.31-3.38(m,1H),3.98(d,J=15.6Hz,1H),4.34(d,J=15.6Hz,1H),4.39(t,J=7.0Hz,1H),7.28(d,J=3.7Hz,1H),7.41(t,J=7.8Hz,1H),7.74(d,J=7.0Hz,1H),7.79(d,J=4.0Hz,1H),7.94(d,J=7.6Hz,1H),8.00(d,J=6.4Hz,2H),8.73(d,J=6.7Hz,2H).
实施例27
2-(5-((2R)-1-异丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用2-甲基-丙醛代替甲醛。1H NMR(CD3OD)δ1.00(dd,J=13.7,6.7Hz,6H),2.01-2.13(m,1H),2.28-2.38(m,2H),2.38-2.52(m,1H),2.59-2.74(m,1H),3.00-3.12(m,2),3.32-3.41(m,1H),3.90-4.12(m,1H),4.80-4.92(m,1H),7.40(t,J=7.8Hz,1H),7.52(d,J=3.7Hz,1H),7.75(d,J=7.9Hz,1H),7.86(d,J=4.0Hz,1H),7.96(d,J=7.6Hz,1H).
实施例28
2-(5-哌啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例28A
5-(吡啶-2-基)噻吩-2-羧酸甲酯
向5-溴-噻吩-2-羧酸甲酯(2g)、三-2-呋喃基膦(400mg)和三(二亚苄基丙酮)二钯(0)(400mg)中加入DMF(50mL)、2-(三丁基甲锡烷基)吡啶(4g)和TEA(1mL),所述混合物在80℃加热7小时,冷却,在乙酸乙酯和盐水之间进行分配。水相用乙酸乙酯萃取,将萃取液干燥,过滤,浓缩。浓缩物进行硅胶快速色谱分离,用在己烷中的20-70%乙酸乙酯洗脱。
实施例28B
5-(哌啶-2-基)噻吩-2-羧酸甲酯
将在甲醇(100mL)中的实施例28A(1.7g)和10%钯/碳(170mg)在60psi氢气下进行搅拌,直到所有起始物料都消耗完为止,过滤,浓缩。
实施例28C
2-(5-(甲氧羰基)噻吩-2-基)哌啶-1-羧酸苄酯
向实施例28B(0.3g)、碳酸钾(0.36g)、二噁烷(20mL)和水(5mL)的混合物中加入氯甲酸苄基酯(0.23mL),所述混合物搅拌4小时。加入哌嗪,将所述混合物搅拌30分钟,在乙酸乙酯和盐水之间进行分配。萃取液用盐水洗涤,用硫酸镁干燥,过滤,浓缩。浓缩物进行硅胶快速色谱分离,用在己烷中的10-50%乙酸乙酯洗脱。
实施例28D
5-(1-(苄氧羰基)哌啶-2-基)噻吩-2-羧酸
向在THF(10mL)中的实施例28C(0.4g)中加入在水(3mL)中的氢氧化锂水合物(132mg)。将所述混合物在环境温度下搅拌过夜,在乙酸乙酯和0.5M盐酸之间进行分配。萃取液用水洗涤,用硫酸镁干燥,过滤,浓缩。浓缩物进行硅胶快速色谱分离,用乙酸乙酯洗脱。
实施例28E
2-(5-(4-氨基甲酰基-1H-苯并咪唑-2-基)噻吩-2-基)哌啶-1-羧酸苄酯
向实施例28D(0.35g)在吡啶(10mL)和DMF(10mL)中的溶液中加入CDI(0.23g),所述混合物在40℃加热1小时。加入2,3-二氨基苯甲酰胺二氯化物(0.22g),所述混合物在环境温度下搅拌过夜,浓缩。将浓缩物在乙酸(20mL)中在80℃搅拌4小时,浓缩。将浓缩物在乙酸乙酯和饱和碳酸氢钠溶液之间进行分配。将萃取液用水洗涤,浓缩,浓缩物进行硅胶快速色谱分离,用在己烷中的40-80%乙酸乙酯洗脱。
实施例28F
2-(5-哌啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例28E(0.21g)在TFA(10mL)中的溶液在环境温度下搅拌过夜,浓缩。浓缩物用HPLC提纯(Zorbax,C-18,流动相A:0.1%TFA在水中;B:0.1%TFA在乙腈中;0-100%梯度)。1H NMR(DMSO-d6)δ1.62-1.76(m,1H),1.84-1.96(m,2H),2.00-2.08(m,1H),2.10-2.20(m,1H),2.19-2.28(m,1H),3.06-3.13(m,1H),3.34-3.47(m,1H),4.36-4.50(m,1H),7.02(s,1H),7.28(t,J=7.9Hz,1H),7.38(d,J=4.0Hz,1H),7.65(d,J=7.0Hz,1H),7.81(d,J=4.0Hz,1H),7.98(d,J=7.3Hz,1H),9.40(s,1H),9.50(s,1H),10.10(s,1H).
实施例29
2-(5-(1-甲基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例28F代替实施例16D。1H NMR(CD3OD)δ1.63-1.86(m,1H),1.86-2.00(m,1H),2.00-2.11(m,2H),2.11-2.23(m,1H),2.30-2.39(m,1H),2.75(s,3H),3.17-3.28(m,1H),3.68-3.73(m,1H),4.58(dd,J=12.3,2.8Hz,1H),7.38(t,J=7.9Hz,1H),7.43(d,J=3.7Hz,1H),7.75(dd,J=8.0,1.2Hz,1H),7.85(d,J=3.7Hz,1H),7.95(dd,J=7.7,1.2Hz,1H).
实施例30
2-(5-(1-丙基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例28F代替实施例16D以及用丙醛代替甲醛。1H NMR(CD3OD)δ0.89(t,J=7.4Hz,3H),1.47-1.63(m,1H),1.70-1.98(m,3H),1.99-2.15(m,2H),2.17-2.23(m,1H),2.26-2.35(m,1H),2.83-2.95(m,1H),2.96-3.10(m,1H),3.10-3.25(m,1H),3.78(d,J=12.9Hz,1H),4.70(dd,J=12.0,2.8Hz,1H),7.36(t,J=7.6Hz,1H),7.43(d,J=3.7Hz,1H),7.75(dd,J=8.0,1.2Hz,1H),7.85(d,J=3.7Hz,1H),7.96(d,J=7.7Hz,1H).
实施例31
2-(5-(1-(环丙基甲基)哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述制备,用实施例28F代替实施例16D以及用环丙基甲醛代替甲醛。1H NMR(CD3OD)δ0.22-0.30(m,1H),0.30-0.40(m,1H),0.66-0.81(m,2H),1.00-1.10(m,1H),1.72-1.84(m,1H),1.91-2.15(m,3H),2.15-2.26(m,1H),2.28-2.36(m,1H),2.82-2.90(m,1H),2.95-3.02(m,1H),3.19-3.28(m,1H),4.01(d,J=13.1Hz,1H),4.69(dd,J=12.2,2.7Hz,1H),7.40(t,J=7.7Hz,1H),7.42(d,J=3.7Hz,1H),7.75(dd,J=8.0,1.2Hz,1H),7.83(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例32
2-(5-(1-环丁基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述制备,用实施例28F代替实施例16D以及用环丁酮代替甲醛。1H NMR(CD3OD)δ1.34-1.48(m,1H),1.51-1.81(m,3H),1.82-2.12(m,4H),2.11-2.37(m,4H),2.88-3.00(m,1H),3.66(d,J=12.6Hz,1H),3.74-3.88(m,1H),4.60(dd,J=12.0,2.8Hz,1H),7.40(t,J=7.7Hz,1H),7.42(d,J=3.7Hz,1H),7.74(dd,J=8.1,1.1Hz,1H),7.81(d,J=3.7Hz,1H),7.95(dd,J=7.5,1.1Hz,1H).
实施例33
2-(5-(1-异丁基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述制备,用实施例28F代替实施例16D以及用2-甲基-丙醛代替甲醛。1H NMR(CD3OD)δ0.91(d,J=6.7Hz,3H),0.96(d,J=6.4Hz,3H),1.00-1.07(m,2H),1.87-1.97(m,1H),1.97-2.11(m,4H),2.92(d,J=7.1Hz,2H),2.98-3.21(m,1H),3.86(d,J=12.6Hz,1H),4.57-4.71(m,1H),7.40(t,J=7.7Hz,1H),7.45(d,J=4.0Hz,1H),7.74(dd,J=8.1,1.1Hz,1H),7.85(d,J=4.0Hz,1H),7.96(dd,J=7.7,1.2Hz,1H).
实施例34
2-(5-吡咯烷-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例34A
2-(5-(甲氧羰基)噻吩-2-基)-1H-吡咯-1-羧酸叔丁酯
5-溴噻吩-2-羧酸甲酯(4g)、1-(叔丁氧羰基)吡咯-2-硼酸(3.8g)、二氯二(三苯基膦)钯(II)(1.2g)和2M碳酸钠溶液(18mL)在DME/水/乙醇(7/3/2,200mL)中的混合物在60℃加热4小时,冷却,在乙酸乙酯和盐水之间进行分配。将萃取液用水洗涤,浓缩,浓缩物进行硅胶快速色谱分离,用在己烷中的5-40%乙酸乙酯洗脱。
实施例34B
2-(5-(甲氧羰基)噻吩-2-基)吡咯烷-1-羧酸叔丁酯
向实施例34A(3.7g)在乙酸(200mL)中的溶液中加入5%铂/碳(370mg)。将所述混合物在60psi氢气下摇动,直到所有起始物料都消耗完毕为止,过滤,浓缩。将浓缩物在乙酸乙酯和饱和碳酸氢钠溶液之间进行分配。将萃取液用水洗涤,浓缩。将浓缩物进行硅胶快速色谱分离,用在己烷中的10-30%乙酸乙酯洗脱。
实施例34C
5-(1-(叔丁氧羰基)吡咯烷-2-基)噻吩-2-羧酸
向实施例34B(2.7g)在THF(50mL)中的混合物中加入在水(5mL)中的氢氧化锂(0.2g)。将所述混合物在环境温度下搅拌过夜,在乙酸乙酯和0.5M盐酸之间进行分配。萃取物用水洗涤,用硫酸镁干燥,过滤,浓缩。将浓缩物进行硅胶快速色谱分离,用乙酸乙酯洗脱。
实施例34D
2-(5-(4-氨基甲酰基-1H-苯并咪唑-2-基)噻吩-2-基)吡咯烷-1-羧酸叔丁酯
向实施例34C(2.4g)在吡啶(100mL)和DMF(100mL)中的溶液中加入CDI(1.6g)。将所述混合物在40℃加热1小时,用2,3-二氨基苯甲酰胺二盐酸盐(1.8g)处理,在环境温度下搅拌过夜,浓缩。将浓缩物在乙酸(50mL)中在80℃加热过夜,浓缩。将浓缩物进行硅胶快速色谱分离,用乙酸乙酯洗脱。
实施例34E
2-(5-吡咯烷-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
实施例34D(2.1g)在二氯甲烷(20mL)和TFA(5mL)中的溶液在环境温度下搅拌过夜,浓缩。浓缩物用HPLC提纯(Zorbax,C-18,流动相A:0.1%TFA在水中;B:0.1%TFA在乙腈中;0-100%梯度)。1H NMR(CD3OD)δ2.19-2.27(m,1H),2.27-2.41(m,2H),2.57-2.68(m,1H),3.43-3.57(m,2H),5.01(dd,J=9.4,6.9Hz,1H),7.36(t,J=7.7Hz,1H),7.42(d,J=4.6Hz,1H),7.73(dd,J=8.1,1.1Hz,1H),7.81(d,J=4.0Hz,1H),7.94(dd,J=7.7,0.9Hz,1H).
实施例35
2-(5-(1-甲基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述制备,用实施例34E代替实施例16D。1H NMR(CD3OD)δ2.30(m,2H),2.47(m,1H),2.74(m,1H),2.94(s,3H),3.31-3.40(m,1H),3.88(m,1H),4.81(m,1H),7.40(t,J=7.7Hz,1H),7.51(d,J=3.7Hz,1H),7.73(d,J=7.6Hz,1H),7.86(d,J=4.0Hz,1H),7.95(d,J=7.6Hz,1H).
实施例36
2-(5-(1-异丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用丙酮代替甲醛。1H NMR(CD3OD)δ1.40(dd,J=12.2,6.7Hz,6H),2.20-2.35(m,2H),2.34-2.46(m,1H),2.67(dd,J=12.0,4.73Hz,1H),3.39-3.52(m,1H),3.58-3.64(m,1H),3.64-3.73(m,1H),5.00-5.08(m,1H),7.40(t,J=7.8Hz,1H),7.51(d,J=3.7Hz,1H),7.76(d,J=8.2Hz,1H),7.85(d,J=4.0Hz,1H),7.95(d,J=6.7Hz,1H).
实施例37
2-(5-(1-丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用丙醛代替甲醛。1H NMR(CD3OD)δ0.99(t,J=7.4Hz,3H),1.56-1.74(m,1H),1.74-1.81(m,1H),2.25-2.38(m,2H),2.37-2.50(m,1H),2.64-2.76(m,1H),3.02-3.07(m,1H),3.18-3.28(m,1H),3.32-3.41(m,1H),3.80-3.90(m,1H),4.78-4.89(m,1H),7.42(t,J=7.8Hz,1H),7.51(d,J=3.7Hz,1H),7.75(d,J=7.1Hz,1H),7.86(d,J=3.7Hz,1H),7.96(d,J=6.7Hz,1H).
实施例38
2-(5-(1-(环丙基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用环丙基甲醛代替甲醛。1H NMR(CD3OD)δ0.30-0.33(m,1H),0.40-0.44(m,1H),0.63-0.81(m,2H),0.98-1.18(m,1H),2.26-2.39(m,2H),2.39-2.51(m,1H),2.61-2.80(m,1H),3.01-3.11(m,1H),3.11-3.21(m,1H),3.38-3.53(m,1H),3.92-4.07(m,1H),4.80-4.90(m,1H),7.40(t,J=7.8Hz,1H),7.49(d,J=4.0Hz,1H),7.74(d,J=7.9Hz,1H),7.85(d,J=3.7Hz,1H),7.94(d,J=7.6Hz,1H).
实施例39
2-(5-(1-异丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用2-甲基丙醛代替甲醛。1H NMR(CD3OD)δ1.00(dd,J=13.7,6.7Hz,6H),2.01-2.15(m,1H),2.27-2.39(m,2H),2.39-2.55(m,1H),2.59-2.76(m,1H),3.00-3.12(m,2H),3.32-3.41(m,1H),3.90-4.12(m,1H),4.80-4.92(m,1H),7.40(t,J=7.8Hz,1H),7.52(d,J=3.7Hz,1H),7.74(d,J=8.0Hz,1H),7.86(d,J=4.0Hz,1H),7.95(d,J=6.7Hz,1H).
实施例40
2-(5-(1-环丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用环丁酮代替甲醛。1H NMR(CD3OD)δ1.75-1.90(m,2H),1.95-2.04(m,1H),2.10-2.23(m,1H),2.23-2.35(m,4H),2.40-2.45(m,1H),2.63-2.76(m,1H),3.25-3.36(m,2H),3.70-3.75(m,1H),3.93-4.05(m,1H),7.40(t,J=7.8Hz,1H),7.47(d,J=4.0Hz,1H),7.74(d,J=8.0Hz,1H),7.82(d,J=3.7Hz,1H),7.95(d,J=7.7Hz,1H).
实施例41
2-(5-(1-环戊基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用环戊酮代替甲醛。1H NMR(CD3OD)δ1.60-1.69(m,2H),1.72-1.91(m,3H),1.97-2.13(m,1H),2.13-2.25(m,1H),2.25-2.36(m,2H),2.35-2.48(m,2H),2.60-2.74(m,1H),3.38-3.56(m,1H),3.66-3.89(m,2H),4.94-5.06(m,1H),7.39(t,J=7.9Hz,1H),7.50(d,J=4.0Hz,1H),7.74(d,J=7.1Hz,1H),7.84(d,J=3.99Hz,1H),7.95(d,J=7.7Hz,1H).
实施例42
2-(5-(1-环己基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺
此实施例如实施例17中所述以三氟乙酸盐的形式制得,用实施例34E代替实施例16D以及用环己酮代替甲醛。1H NMR(CD3OD)δ1.17-1.26(m,1H),1.30-1.40(m,2H),1.40-1.60(m,3H),1.69-1.75(m,1H),1.85-1.93(m,1H),1.93-2.01(m,1H),2.02-2.05(m,1H),2.13-2.24(m,1H),2.25-2.32(m,1H),2.38-2.48(m,1H),2.60-2.72(m,1H),3.20-3.39(m,1H),3.50-3.56(m,1H),3.60-3.68(m,1H),5.10-5.18(m,1H),7.40(t,J=7.8Hz,1H),7.50(d,J=3.7Hz,1H),7.74(d,J=8.0Hz,1H),7.85(d,J=3.7Hz,1H),7.95(d,J=7.4Hz,1H).
实施例43
2-(6-吡咯烷-2-基吡啶-3-基)-1H-苯并咪唑-4-甲酰胺
在环境温度下,向6-(1-(叔丁氧羰基)吡咯烷-2-基)烟酸(3g,10.6mmol)在吡啶(10mL)和N,N-二甲基甲酰胺(50mL)中的混合物中加入1,1′-羰基二咪唑(2.2g,16mmol)。将所述混合物在40℃加热1小时,用2,3-二氨基苯甲酰胺二盐酸盐(2.4g,10.6mmol)处理,在环境温度下搅拌16小时,浓缩。将残余物在乙酸(100mL)中在110℃加热2小时,冷却,浓缩。残余物用硅胶快速色谱法提纯,使用乙酸乙酯洗脱,得到所述非环状中间体。将此中间体溶于二氯甲烷(100mL)和三氟乙酸(20mL)中,所述混合物在室温下搅拌16小时,浓缩。残余物用HPLC提纯(Zorbax C-8,0.1%三氟乙酸/乙腈/水),得到标题化合物。1H NMR(甲醇-d4)2.04-2.36(m,3H),2.49-2.74(m,1H),3.39-3.72(m,2H),4.98(t,J=7.63Hz,1H),7.17-7.49(m,1H),7.69(d,J=8.14Hz,1H),7.81(d,J=8.14Hz,1H),7.99(d,J=7.46Hz,1H),8.64(dd,J=8.31,2.20Hz,1H),9.42(s,1H).
实施例44
2-[6-(1-异丙基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
标题化合物如实施例6中所述以三氟乙酸盐的形式制备,用丙酮代替甲醛以及用实施例43代替实施例5。1H NMR(甲醇-d4)δ1.34(dd,J=7.97,6.61Hz,6H),1.98-2.31(m,3H),2.56-2.77(m,1H),3.41-3.57(m1H),3.58-3.84(m,2H),4.99-5.13(m,1H),7.31-7.52(m,1H),7.73(d,J=7.46Hz,1H),7.82(d,J=7.12Hz,1H),8.00(d,J=7.46Hz,1H),8.67(dd,J=8.31,2.20Hz,1H),9.46(d,J=2.37Hz,1H).
实施例45
2-[6-(1-异丁基吡咯烷-2-基)-吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
标题化合物如实施例6中所述以三氟乙酸盐的形式制备,用异丁醛代替甲醛以及用实施例43代替实施例5。1H NMR(甲醇-d4)δ0.97(dJ=6.74Hz,3H),1.10(d,J=6.74Hz,3H),1.86-2.39(m,3H),2.50-2.82(m1H),3.12(d,J=7.14Hz,2H),3.24-3.52(m,2H),3.88-4.10(m,1H),4.66-4.96(m,1H),7.20-7.54(m,1H),7.70(d,J=7.93Hz,1H),7.81(d,J=7.93Hz,1H),8.00(d,J=6.74Hz,1H),8.68(dd,J=8.13,2.18Hz,1H),9.48(d,J=1.98Hz,1H).
实施例46
2-[6-(1-环丁基吡咯烷-2-基)-吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
标题化合物如实施例6中所述以三氟乙酸盐的形式制备,用环丁酮代替甲醛以及用实施例43代替实施例5。1H NMR(甲醇-d4)δ1.63-1.89(m,2H),1.84-2.04(m,2H),2.08-2.45(m,6H),2.47-2.72(m,1H),3.66-3.88(m,1H),3.97(t,J=8.53Hz,1H),4.67-4.98(m,1H),7.23-7.55(m,1H),7.70(d,J=8.33Hz,1H),7.81(d,J=7.14Hz,1H),8.00(d,J=6.74Hz,1H),8.64(dd,J=8.13,2.18Hz,1H),9.50(d,J=2.38Hz,1H).
实施例47
2-[6-(1-环戊基吡咯烷-2-基)-吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
标题化合物如实施例6中所述以三氟乙酸盐的形式制备,用环戊酮代替甲醛以及用实施例43代替实施例5。1H NMR(甲醇-d4)δ1.37-1.52(m,1H),1.51-1.69(m,2H),1.67-2.01(m,4H),2.02-2.38(m,4H),2.56-2.80(m,1H),3.41-3.56(m,1H),3.69-3.96(m,2H),4.92-5.05(m,1H),7.43(t,J=7.73Hz,1H),7.72(d,J=7.93Hz,1H),7.81(d,J=7.14Hz,1H),8.00(d,J=7.54Hz,1H),8.67(dd,J=8.13,2.18Hz,1H),9.48(d,J=1.98Hz,1H).
实施例48
2-[6-(1-环己基吡咯烷-2-基)-吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
标题化合物如实施例6中所述以三氟乙酸盐的形式制备,用环己酮代替甲醛以及用实施例43代替实施例5。1H NMR(甲醇-d4)δ1.10-1.58(m,5H),1.68(d,J=12.29Hz,1H),1.77-1.94(m,2H),1.96-2.29(m,5H),2.57-2.75(m,1H),3.32-3.41(m,1H),3.42-3.61(m,1H),3.65-3.93(m,1H),5.13(dd,J=8.53,6.54Hz,1H),7.32-7.48(m,1H),7.72(d,J=8.33Hz,1H),7.81(d,J=7.14Hz,1H),7.99(d,J=7.54Hz,1H),8.67(dd,J=8.13,2.18Hz,1H),9.46(d,J=1.59Hz,1H).
实施例49
2-[6-(1-四氢-2H-吡喃-4-基吡咯烷-2-基)-吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
所述标题化合物如实施例6中所述以三氟乙酸盐的形式制备,用二氢-2H-吡喃-4(3H)-酮代替甲醛以及用实施例43代替实施例5。1HNMR(甲醇-d4)δ1.57-1.75(m,1H),1.75-1.94(m,2H),1.95-2.08(m,1H),2.08-2.32(m,3H),2.55-2.84(m,1H),3.25-3.46(m,2H),3.46-3.77(m,2H),3.72-4.14(m,3H),5.15(dd,J=8.65,6.27Hz,1H),7.13-7.59(m,1H),7.72(d,J=7.80Hz,1H),7.81(d,J=7.12Hz,1H),7.99(d,J=6.44Hz,1H),8.68(dd,J=8.31,2.20Hz,1H),9.47(d,J=1.36Hz,1H).
实施例50
2-[6-(1,3-噁唑-5-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
实施例50A
6-(噁唑-5-基)烟酸
向6-甲酰基烟酸甲酯(60mg,0.363mmol)在甲醇(3mL)中的悬浮液中加入在甲醇中的甲醇钠(0.5M,2.91mL,1.45mmol)。将甲苯磺酰甲基异氰化物(85mg,0.436mmol)加入到所述反应中,所述混合物在回流下加热过夜。冷却后,将反应混合物浓缩。残余物用5%柠檬酸/50%盐水(1∶1)处理,用乙酸乙酯萃取。将所述悬浮液过滤,用水洗涤,在真空中干燥,得到标题化合物。MS(DCI/NH3)m/z:191.0(M+1)+.
实施例50B
N-(2-氨基-3-氨基甲酰基苯基)-6-(噁唑-5-基)烟酰胺
将实施例50A(60.0mg,0.316mmol)在吡啶(1.5mL)和N,N-二甲基甲酰胺(1.5mL)的混合物中的溶液用1,1′-羰基二咪唑(56.3mg,0.347mmol)在45℃处理2小时。冷却后,加入2,3-二氨基苯甲酰胺(HCl盐)(70.7mg,0.316mmol),所述混合物在室温下搅拌5小时。浓缩后,残余物用20%盐水和乙酸乙酯处理。将固体过滤,用乙酸乙酯和水洗涤,在真空中干燥,得到标题化合物。此物质没有进一步提纯就用于下一步。
实施例50C
2-[6-(1,3-噁唑-5-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺
将实施例50B(24.0mg,0.074mmol)在乙酸(1mL)中的悬浮液加热至80℃3小时,冷却。所述溶液浓缩,用HPLC提纯(Zorbax,C-18,250x2.54柱,流动相A:0.1%三氟乙酸在H2O中;B:0.1%三氟乙酸在CH3CN中;0-100%梯度),得到三氟乙酸盐形式的标题化合物。MS(DCI/NH3)m/z:306.2(M+H)+.1H NMR(二甲亚砜-d6/D2O)7.45(t,J=7.78Hz,1H),7.84(d,J=8.24Hz,1H),7.93(d,J=7.63Hz,1H),7.96(s,1H),8.01(d,J=8.24Hz,1H),8.60(s,1H),8.71(dd,J=8.39,2.29Hz,1H),9.44(d,J=1.53Hz,1H).
实施例51
2-[5-(1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺
实施例51A
6-(2-氨基-3-氨基甲酰基苯基氨基甲酰基)烟酸甲酯
5-(甲氧羰基)吡啶甲酸(3.33g,18.4mmol)在吡啶(20mL)和N,N-二甲基甲酰胺(35mL)的混合物中的溶液用1,1′-羰基二咪唑(3.28g,20.2mmol)在45℃处理2小时。冷却后,加入2,3-二氨基苯甲酰胺(HCl盐)(4.12g,18.4mmol),所述混合物在室温下搅拌过夜。将所述混合物浓缩,残余物在没有进一步提纯的情况下就用于下一步。
实施例51B
6-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)烟酸甲酯
将在乙酸(40mL)中的来自实施例51A的粗产物加热至90℃1.5小时。冷却后,将所述悬浮液过滤。滤饼用乙酸洗涤,在饱和NaHCO3中搅拌30分钟。将固体过滤,用水和乙醚洗涤,在真空中干燥,得到灰白色固体形式的标题化合物。MS(DCI/NH3)m/z:297.1(M+H)+.
实施例51C
6-(4-氨基甲酰基-1H-苯并[d]咪唑-2-基)烟酸
在室温下,向实施例51B(2.00g,6.75mmol)在四氢呋喃(36mL)和甲醇(12mL)中的悬浮液中加入氢氧化锂(0.850g,20.3mmol)在水(8mL)中的乳浊液。4小时后,蒸除大部分溶剂。将残余物溶于水中,用5%柠檬酸酸化至pH 5。过滤沉淀,用水洗涤,在真空中干燥,得到标题化合物。MS(DCI/NH3)m/z:283.1(M+H)+.
实施例51D
2-(5-(肼羰基)吡啶-2-基)-1H-苯并[d]咪唑-4-甲酰胺
在0℃下,向实施例51C(1.40g,4.96mmol)和TFFH(氟代N,N,N′,N′四甲基甲脒六氟磷酸盐,1.57g,5.95mmol)在N,N-二甲基甲酰胺(18mL)中的悬浮液中加入三乙胺(1.38mL,9.92mmol)和肼(0.311mL,9.92mmol)。将所述混合物在室温下搅拌过夜。将水(60mL)加入到所述悬浮液中,过滤固体,用水和乙醚洗涤,在真空中干燥,得到标题化合物。MS(DCI/NH3)m/z:297.1(M+H)+.
实施例51E
2-[5-(1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺
实施例51D(70.0mg,0.236mmol)和原甲酸三甲酯(1.50mL,13.6mmol)在二甲亚砜(0.5mL)中的混合物在微波反应器(CEM Explorer)中在150℃加热30分钟。浓缩后,残余物用超临界流体色谱法(SFC)提纯,使用Princeton SFC pyridine 5μm(21.2mm×150mm)柱和10-50%甲醇(A)和二氧化碳(B)的梯度以40mL/min的流速洗脱,得到标题化合物。MS(APCI)m/z:307.1(M+H)+.1H NMR(二甲亚砜-d6)7.38(t,J=7.83Hz,1H),7.73-7.82(m,2H),7.91(d,J=7.06Hz,1H),8.55-8.70(m,2H),9.31(s,1H,brd),9.36(d,J=1.84Hz,1H),9.49(s,1H).
实施例52
2-{5-[5-(三氟甲基)-1,3,4-噁二唑-2-基]吡啶-2-基}-1H-苯并咪唑-4-甲酰胺
向实施例51D(70mg,0.236mmol)在N,N-二甲基甲酰胺(6mL)中的悬浮液中加入三氟乙酸(0.018mL,0.236mmol)和2-氯-1,3-二甲基咪唑啉鎓氯化物(84mg,0.496mmol)。15分钟后,滴加三乙胺(0.165mL,1.18mmol),将所述反应搅拌过夜。将水加入到所述悬浮液中,将固体过滤,用水和乙醚洗涤,浓缩。所述粗产物用HPLC提纯(Zorbax,C-18,250x2.54柱,流动相A:0.1%三氟乙酸在H2O中;B:0.1%三氟乙酸在CH3CN中;0-100%梯度),得到三氟乙酸盐形式的标题化合物。MS(DCI/NH3)m/z:375.1(M+H)+.1H NMR(二甲亚砜-d6)7.43(t,J=7.67Hz,1H),7.80(d,J=7.06Hz,1H),7.84(s,1H),7.94(d,J=8.29Hz,1H),8.63-8.74(m,2H),9.15(s,1H,brd),9.41(s,1H).
实施例53
2-[5-(5-甲基-1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺
向实施例51D(70mg,0.236mmol)在N,N-二甲基甲酰胺(6mL)中的悬浮液中加入乙酸(0.014mL,0.236mmol)和2-氯-1,3-二甲基咪唑啉鎓氯化物(84mg,0.496mmol)。15分钟后,滴加三乙胺(0.165mL,1.181mmol)。将所述反应搅拌5小时。将水加入到所述悬浮液中,接着过滤固体。将所述滤液浓缩,用HPLC提纯(Zorbax,C-18,250x2.54柱,流动相A:0.1%三氟乙酸在H2O中;B:0.1%三氟乙酸在CH3CN中;0-100%梯度),得到三氟乙酸盐形式的标题化合物。MS(DCI/NH3)m/z:321.1(M+H)+.1H NMR(二甲亚砜-d6)2.34(s,3H),7.43(t,J=7.82Hz,1H),7.81(d,J=7.36Hz,1H),7.85(s,1H),7.94(d,J=7.36Hz,1H),8.50(d,J=8.29Hz,1H),8.66(d,J=8.29Hz,1H),9.13(s,1H,brd),9.24(s,1H),12.34(s,1H).
上文是为了举例说明本发明,而不是为了限制本发明。对本领域普通技术人员来说显而易见的改变和变化都在如权利要求书中所限定的本发明的范围内。
Claims (17)
1.式I的化合物
或其盐,其中
A1是杂芳基,其被A2取代并且是未稠合的或与苯、杂芳烃或R1A稠合;R1A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
A2是杂芳基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R2A稠合;R2A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
B1是氢、R3、CO(O)R3A、C(O)NH2、C(O)NHR3A、C(O)N(R3A)2、SO2NH2、SO2NHR3A.或SO2N(R3A)2;
R3A是烷基或环烷基;
R3是烷基或链烯基,其每个是未取代的或被一个或两个独立选择的下述取代基取代:R4、OR4、NH2、NHR4、N(R4)2、C(O)NH2、C(O)NHR4、C(O)N(R4)2或OH;
R4是烷基或环烷基;
C1、D1、E1每个独立地是氢、NO2、CN、R5、OR5、CO(O)R5、C(O)NH2、C(O)NHR5、C(O)N(R5)2、NH2、NHR5、N(R5)2、OH、F、Cl、Br或I;
R5是烷基、链烯基或炔基;其每个是未取代的或被一个或两个独立选择的下述取代基取代:R6、NH2、NHR6、N(R6)2、C(O)NH2、C(O)NHR6、C(O)N(R6)2、OH、F、Cl、Br或I;
R6是烷基或环烷基;
其中每个前面的环状部分独立地是未取代的、未进一步取代的、被一个或两个或三个或四个或五个独立选择的下述取代基取代或进一步取代的:R7、OR7、SR7、S(O)R7、SO2R7、C(O)R7、CO(O)R7、OC(O)R7、OC(O)OR7、NO2、NH2、NHR7、N(R7)2、CH2R7、C(O)NH2、C(O)NHR7、C(O)N(R7)2、C(O)NHOH、C(O)NHOR7、C(O)NHSO2R7、C(O)NR7SO2R7、SO2NH2、SO2NHR7、SO2N(R7)2、CF3、CF2CF3、C(O)H、C(O)OH、C(N)NH2、C(N)NHR7、C(N)N(R7)2、CNOH、CNOCH3、OH、(O)、N3、CF3、CF2CF3、OCF3、OCF2CF3、F、Cl、Br或I;
R7是R8、R9、R10或R11;
R8是苯基,其每个是未稠合的或与苯、杂芳烃或R8A稠合;R8A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R9是杂芳基,其是未稠合的或与苯、杂芳烃或R9A稠合;R9A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R10是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R10A稠合;R10A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R11是烷基、链烯基或链烯基,其每个是未取代的或被一个、两个、三个、四个或五个独立选择的下述取代基取代:R12、OR12、SR12、S(O)R12、SO2R12、NH2、NHR12、N(R12)2、C(O)R12、C(O)NH2、C(O)NHR12、C(O)N(R12)2、NHC(O)R12、NR12C(O)R12、NHSO2R12、NR12SO2R12、NHC(O)OR12、NR12C(O)OR12、SO2NH2、SO2NHR12、SO2N(R12)2、NHC(O)NH2、NHC(O)R12NHC(O)N(R12)2、NR12C(O)N(R12)2、OH、(O)、C(O)OH、CN、CF3、OCF3、CF2CF3、F、Cl、Br或I;
R12是R13、R14、R15或R16;
R13是苯基,其是未稠合的或与苯、杂芳烃或R13A稠合;R13A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R14是杂芳基,其是未稠合的或与苯、杂芳烃或R14A稠合;R14A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R15是环烷基、环烯基、杂环烷基或杂环烯基,其每个是未稠合的或与苯、杂芳烃或R15A稠合;R15A是环烷烃、环烯烃、杂环烷烃或杂环烯烃;
R16是烷基、链烯基或链烯基,其每个是未取代的或被R17取代;和
R17是苯基、杂芳基、环烷基、环烯基或杂环烷基。
2.权利要求1的化合物,其中C1、D1和E1是氢。
3.权利要求2的化合物,其中B1是氢。
4.权利要求3的化合物,其中A1是杂芳基,其是未稠合的。
8.权利要求7的化合物,其中A1和A2是未取代的或被R7或CF3取代。
9.权利要求7的化合物,其中A1和A2是未取代的或被R10、R11或CF3取代。
10.权利要求7的化合物,其中A1和A2是未取代的或被环烷基、杂环烷基、烷基或CF3取代。
11.权利要求7的化合物,其中A1和A2是未取代的或被环烷基、杂环烷基、烷基或CF3取代;其中所述烷基是未取代的或被R12取代;R12是R14或R15;R14是未稠合的杂芳基;以及R15是未稠合的环烷基。
12.权利要求11的化合物,其是
2-(4-吡啶-3-基-1,3-噻唑-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(4-吡啶-4-基-1,3-噻唑-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(4-甲基-2-吡嗪-2-基-1,3-噻唑-5-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-噻吩-2-基-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-哌啶-4-基-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-甲基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-异丙基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-丙基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(2-(1-环丁基哌啶-4-基)-1,3-噻唑-4-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡嗪-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-嘧啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡啶-3-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡啶-4-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1H-吡咯-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-甲基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-异丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-(环丙基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-环丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-环戊基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-环己基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-四氢-2H-吡喃-4-基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-(吡啶-2-基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-(吡啶-4-基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-((2R)-1-异丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-哌啶-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-甲基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-丙基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-(环丙基甲基)哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环丁基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-异丁基哌啶-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-吡咯烷-2-基噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-甲基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-异丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-丙基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-(环丙基甲基)吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-异丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环丁基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环戊基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(5-(1-环己基吡咯烷-2-基)噻吩-2-基)-1H-苯并咪唑-4-甲酰胺,
2-(6-吡咯烷-2-基吡啶-3-基)-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-异丙基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-异丁基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-环丁基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-环戊基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-环己基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1-四氢-2H-吡喃-4-基吡咯烷-2-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[6-(1,3-噁唑-5-基)吡啶-3-基]-1H-苯并咪唑-4-甲酰胺;
2-[5-(1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺;
2-{5-[5-(三氟甲基)-1,3,4-噁二唑-2-基]吡啶-2-基}-1H-苯并咪唑-4-甲酰胺;
2-[5-(5-甲基-1,3,4-噁二唑-2-基)吡啶-2-基]-1H-苯并咪唑-4-甲酰胺;或其药学上可接受的盐。
13.包含权利要求1的化合物及药学上可接受的赋形剂的药物组合物。
14.一种在哺乳动物中治疗癌症的方法,包括给予所述哺乳动物治疗可接受量的权利要求1的化合物。
15.一种在哺乳动物中减小肿瘤体积的方法,包括给予所述哺乳动物治疗可接受量的权利要求1的化合物。
16.一种在哺乳动物中治疗癌症的方法,包括给予所述哺乳动物治疗可接受量的权利要求1的化合物并联合放射治疗。
17.一种在哺乳动物中治疗癌症的方法,包括给予所述哺乳动物治疗可接受量的权利要求1的化合物以及选自替莫唑胺、达卡巴嗪、环磷酰胺、卡莫司汀、美法仑、洛莫司汀、卡铂、顺铂、5-FU+/-亚叶酸、吉西他滨、甲氨蝶呤、博来霉素、伊立替康、喜树碱或托泊替康的化疗剂。
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WO2014201972A1 (zh) * | 2013-06-17 | 2014-12-24 | 上海汇伦生命科技有限公司 | 苯并咪唑-2-哌嗪杂环类化合物、其药物组合物及其制备方法和用途 |
CN104981468A (zh) * | 2013-06-17 | 2015-10-14 | 上海汇伦生命科技有限公司 | 苯并咪唑-2-哌嗪杂环类化合物、其药物组合物及其制备方法和用途 |
CN104981468B (zh) * | 2013-06-17 | 2018-01-05 | 上海汇伦生命科技有限公司 | 苯并咪唑‑2‑哌嗪杂环类化合物、其药物组合物及其制备方法和用途 |
US10196381B2 (en) | 2013-06-17 | 2019-02-05 | Shanghai Huilun Life Science &Technology Co., Ltd | Benzimidazole-2-piperazine heterocyclic compound, pharmaceutical composition containing the same, preparation method and use thereof |
KR20210155826A (ko) * | 2013-06-17 | 2021-12-23 | 상하이 휘룽 라이프 사이언스 & 테크놀로지 코., 엘티디 | 벤조이미다졸-2-피페라진 헤테로고리 화합물, 및 그 약물 조성물 |
KR102443509B1 (ko) | 2013-06-17 | 2022-09-15 | 상하이 휘룽 라이프 사이언스 & 테크놀로지 코., 엘티디 | 벤조이미다졸-2-피페라진 헤테로고리 화합물, 및 그 약물 조성물 |
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WO2009012280A3 (en) | 2009-08-27 |
JP2014237665A (ja) | 2014-12-18 |
US20090030016A1 (en) | 2009-01-29 |
US20120046303A1 (en) | 2012-02-23 |
CA2690761A1 (en) | 2009-01-22 |
US8067613B2 (en) | 2011-11-29 |
EP2183248A2 (en) | 2010-05-12 |
WO2009012280A2 (en) | 2009-01-22 |
JP2010533728A (ja) | 2010-10-28 |
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