CN102892761A - 4-氨基嘧啶衍生物和它们作为腺苷a2a 受体拮抗剂 - Google Patents
4-氨基嘧啶衍生物和它们作为腺苷a2a 受体拮抗剂 Download PDFInfo
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- CN102892761A CN102892761A CN2011800220612A CN201180022061A CN102892761A CN 102892761 A CN102892761 A CN 102892761A CN 2011800220612 A CN2011800220612 A CN 2011800220612A CN 201180022061 A CN201180022061 A CN 201180022061A CN 102892761 A CN102892761 A CN 102892761A
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- Prior art keywords
- pyrazol
- pyrimidine
- bromo
- amine
- compound
- 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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- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 73
- -1 5-bromo-6-((S)-3-fluoropyrrolidine-1-yl)-2-(1H-pyrazol-1-yl) pyrimidine-4-amine 5-bromo-6-[(R)-2-(methoxymethyl) pyrrolidin-1-yl]-2-(1H-pyrazol-1-yl) pyrimidine-4-amine Chemical compound 0.000 claims description 42
- WBUBVCMVKQFIKM-UHFFFAOYSA-N 2-pyrazol-1-ylpyrimidin-4-amine Chemical compound NC1=CC=NC(N2N=CC=C2)=N1 WBUBVCMVKQFIKM-UHFFFAOYSA-N 0.000 claims description 36
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- ABAVCDINTKQVAC-UHFFFAOYSA-N 5-bromo-6-(3,3-difluoroazetidin-1-yl)-2-pyrazol-1-ylpyrimidin-4-amine Chemical compound BrC=1C(N)=NC(N2N=CC=C2)=NC=1N1CC(F)(F)C1 ABAVCDINTKQVAC-UHFFFAOYSA-N 0.000 claims description 3
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- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
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- 229960000193 formoterol fumarate Drugs 0.000 description 1
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- 239000002808 molecular sieve Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 230000003647 oxidation Effects 0.000 description 1
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- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
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- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
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Classifications
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Abstract
式(I)的新的4-氨基-嘧啶衍生物,作为腺苷A2a受体的有效拮抗剂。本发明也提供了制备这些化合物的方法,包含有效量的这些化合物的药物组合物和这些化合物在制备用于治疗病理学感染的药物中的应用,所述病理学感染可以通过腺苷A2a受体的拮抗作用来改善。
Description
发明领域
本发明涉及新的方便地取代作为腺苷A2a受体的拮抗剂的嘧啶衍生物。本发明的其他目的是提供制备这些化合物的方法,包含有效量的这些化合物的药物组合物,这些化合物在制备治疗可由腺苷A2a受体的拮抗作用改善的病理学感染或疾病的药物中的应用。
发明背景
腺苷的作用是通过至少四种特异性的细胞膜受体介导的,所述受体迄今鉴定并分类为受体A1、A2A、A2B和A3,它们属于与G蛋白偶联的受体家族。A1和A3受体通过它们与抑制腺苷酸环化酶的Gi蛋白偶联来向下调节细胞的cAMP水平。相反,A2A和A2B受体与活化腺苷酸环化酶的Gs蛋白偶联,并提高细胞内的cAMP水平。通过这些受体,腺苷调节范围广泛的生理功能。
数个临床前研究表明,腺苷A2A受体拮抗剂对于治疗神经变性疾病,主要是帕金森病、亨廷顿病或阿尔茨海默病具有有效性(Trends inNeurosci.2006,29(11),647-654;Expert Opinion Ther.Patents,2007,17,979-991;Exp.Neurol.2003,184(1),285-284;Prog.BrainRes,2010,183,183-208;J.Alzheimer Dis.2010,Suppl 1,117-126;J.Neurosci.2009,29(47),14741-14751;Neuroscience,2010,166(2),590-603;J.Pharmacol.Exp.Ther.2009,330(1),294-303;Frontiers Biosci.2008,13,2614-2632)。
除了A2A受体拮抗剂治疗治疗神经变性疾病的可喜的应用外,人们认为那些化合物可以用于补充的症状性适应症。这些是基于下列证据:A2A受体激活可以有助于一定范围的神经精神性疾病和障碍的病理生理学,这些疾病和障碍是例如抑郁、白天睡眠过多、腿多动综合征(restlessleg syndrome)、注意缺陷伴多动障碍和认知疲劳(Neurology,2003,61(11Suppl 6),S82-S87;Behav.Pharmacol.2009,20(2),134-145;CNS Drug Discov.2007,2(1),1-21)。
一些作者提示了A2拮抗剂在治疗糖尿病中的应用(WO1999035147;WO2001002400)。
其他研究提示了A2a腺苷受体与伤口愈合或心房颤动的关系(Am JPath,2007,6,1774-1778;Arthritis & Rheumatism,2006,54(8),2632-2642)。
出于这种原因,人们对发现新的、有效且选择性的腺苷A2a受体拮抗剂的兴趣逐渐增加。过去制药公司发现的一些有效的腺苷A2a拮抗剂已经进入到临床试验,显示阳性结果,表明这种化合物种类不仅有望治疗神经变性疾病例如帕金森病、亨廷顿病或阿尔茨海默病,而且也可以用于治疗其他CNS相关的疾病例如抑郁、多动综合征、睡眠障碍和焦虑症(Clin.Neuropharmacol.2010,33,55-60;J.Neurosci.2010,30(48),16284-16292;Parkinsonisn Relat.Disord.2010,16(6),423-426;1Expert Opinion Ther.Patents,2010,20(8),987-1005;Current Opinion in Drug Discovery & Development,2010,13(4),466-480及其中的参考文献;Mov.Disorder s,2010,25(2),S305)。
本发明涉及新的作为腺苷A2a受体的有效拮抗剂的4-氨基-嘧啶衍生物。在文献中的报道表明,下式的4-氨基嘧啶类:
其中R1和R3可以是杂芳基,R2可以是氢原子或取代的烷基链,
是有效的腺苷A2a受体拮抗剂(例如,WO 2005058883A1;WO2008116185)。
然而,我们惊奇地发现,如下面的实例所示,与母体未取代的衍生物相比,通过在嘧啶环的5位引入吸电子取代基,这些化合物作为腺苷A2a受体拮抗剂的效力可以相当大地增强:
Ki(A2a)=300nM Ki(A2a)=6nM(实施例48)
Ki(A2a)=300nM Ki(A2a)=12nM(实施例1)
Ki(A2a)=300nM Ki(A2a)=15nM(实施例46)
发明详述
本发明涉及新的式(I)的嘧啶衍生物:
其中:
-R1代表任选被一个或多个选自卤素、低级烷基、环烷基、低级烷氧基或氰基的取代基取代的五元杂芳环;
-R2独立地代表:
a)氢原子,
b)烷基或环烷基,其任选被取代一个或多个卤素原子或一个或多个环烷基、羟基或烷氧基取代;
-R3独立地代表:
a)卤素原子,
b)氰基,
c)三氟甲基,
d)环丙基或环丁基,
e)任选被一个或多个卤素原子或一个或多个基团例如烷基、环烷基、烷氧基、氨基、单-或二烷基氨基取代的五元杂芳基;
-R4独立地代表:
a)任选被一个或多个卤素原子或一个或多个基团例如烷基、环烷基、烷氧基、氨基、单-或二烷基氨基、烷氧基烷基取代的五元杂芳基,
b)基团N(R5)(R6),其中R5和R6独立地代表:
-氢原子,
-直链或支链的烷基或环烷基,任选被一个或多个卤素原子或一个或多个基团例如环烷基、烷氧基、氨基、单-或二烷基氨基取代,
-R5和R6与和它们相连的氮原子一起形成4-6元的饱和杂环基,其中可以插入其他杂原子,所述杂环基任选被一个或多个卤素原子取代,
c)基团-OR7或-SR7,其中R7独立地代表:
-直链或支链的烷基或环烷基,任选被一个或多个卤素原子或一个或多个基团例如环烷基、烷氧基、氨基、单-或二烷基氨基取代,
-任选被一个或多个卤素原子取代的苯环。
本发明的其他方面是:a)这些化合物的药学可接受的盐,b)包含有效量的所述化合物的药物组合物,c)这些化合物在制备治疗通过腺苷受体的拮抗作用可以改善的疾病的药物中的应用,d)治疗通过腺苷受体的拮抗作用可以改善的疾病的方法,包括施用本发明的这些化合物给需要所述治疗的患者的方法,和e)这些化合物与用于治疗通过腺苷受体的拮抗作用可以改善的疾病病症的其他药物的组合。
本文使用的术语低级烷基包括具有1-8,优选1-6,更优选1-4个碳原子的任选取代的、直链或支链基团。
例子包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基和叔丁基、正戊基、1-甲基丁基、2-甲基丁基、异戊基、1-乙基丙基、1,1-二甲基丙基、1,2-二甲基丙基、正己基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,2-二甲基丁基、2,3-二甲基丁基、2-甲基戊基、3-甲基戊基和异己基。
本文使用的术语低级烷氧基包括分别具有1-8,优选1-6,更优选1-4个碳原子的烷基部分的任选取代的、直链或支链的含氧基团。
优选的烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、三氟甲氧基、二氟甲氧基、羟基甲氧基、2-羟基乙氧基或2-羟基丙氧基。
本文使用的术语低级烷硫基包括包括分别具有1-8,优选1-6,更优选1-4个碳原子的烷基部分的任选取代的、直链或支链的含硫基团。
优选的烷硫基包括甲硫基、乙硫基、正丙硫基、异丙硫基、正丁硫基、仲丁硫基、叔丁硫基、三氟甲硫基、二氟甲硫基、羟基甲硫基、2-羟基乙硫基或2-羟基丙硫基。
除非另有说明,本文使用的术语环基包括碳环和杂环基。所述环基可以包含一个或多个环。碳环基团可以是芳族或脂环,例如环烷基。杂环基团也包括杂芳基。
本文使用的属于“芳族基”典型地包括5-14元芳环系统,例如可以包含一个或多个选自O、S和N的杂原子的5或6元环。当不存在杂原子时,该基团命名为芳基,当存在至少一个杂原子时,将其命名为杂芳基。芳族基可以是单环或多环,例如苯基或萘基。当芳族基或部分具有2个或更多个取代基时,取代基可以相同或不同。
本文使用的术语5-元杂芳环典型地包括包含至少一个杂芳环并包含至少一个选自O、S和N的杂原子的5-元环系统。
例子包括呋喃基、噁二唑基、噁唑基、咪唑基、噻唑基、噻二唑基、噻吩基、吡咯基、三唑基、咪唑烷基和吡唑基。优选的基团是任选取代的吡唑基、三唑基、噻唑基和呋喃基。
当杂芳基具有2个或更多个取代基时,取代基可以相同或不同。
在本文使用时,存在于本发明的基本结构中的一些原子、基团、部分、链或环是“任选取代的”。这就是说,这些原子、基团、部分、链或环可以是未取代的,或者在任意位置被1个或多个例如1,2,3或4个取代基取代,即结合于未取代的原子、基团、部分、链或环上的氢原子被化学可接受的原子、基团、部分、链或环代替。当存在2个或更多个取代基时,各取代基可以相同或不同。
本文使用的术语卤素原子包括氯、氟、溴或碘原子,典型地是氟、氯或溴原子,最优选氯或氟。当用作前缀时,术语卤素(halo)具有相同的含义。
本文使用的术语药学可接受的盐包括与药学可接受的酸或碱形成的盐。药学可接受的酸包括无机酸例如盐酸、硫酸、磷酸、二磷酸、氢溴酸、氢碘酸和硝酸,以及有机酸,例如柠檬酸、延胡索酸、马来酸、苹果酸、扁桃酸、抗坏血酸、草酸、琥珀酸、酒石酸、苯甲酸、乙酸、甲磺酸、乙磺酸、苯磺酸或对甲苯磺酸。药学可接受的碱包括碱金属(例如,钠或钾)和碱土金属(例如,钙或镁)的氢氧化物和有机碱,例如烷基胺、芳烷基胺和杂环胺。
根据本发明另外优选的盐是季铵化合物,其中1当量的阴离子(X-)与N原子的阳电荷相结合。X-可以是各种矿物酸的阴离子例如氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根,或者有机酸的阴离子例如乙酸根、马来酸根、延胡索酸根、柠檬酸根、草酸根、琥珀酸根、酒石酸根、苹果酸根、扁桃酸根、三氟乙酸根、甲磺酸根和对甲苯磺酸根。X-优选是选自氯离子、溴离子、碘离子、硫酸根、硝酸根、乙酸根、马来酸根、草酸根、琥珀酸根或三氟乙酸根的阴离子。更优选X-是氯离子、溴离子、三氟乙酸根或甲磺酸根。
根据本发明的一个实施方案,在式(I)的化合物中,R1独立地代表任选取代的吡唑、三唑、噻唑或噻吩环。
根据本发明的一个优选的实施方案,在式(I)的化合物中,R1独立地代表任选取代的吡唑、三唑或噻唑,R2代表氢原子。
根据本发明更优选的实施方案,在式(I)的化合物中,R1独立地代表任选取代的吡唑、三唑或噻唑环,R2代表氢原子,R3代表溴原子、氰基或三氟甲基。
根据本发明更优选的实施方案,在式(I)的化合物中,R1和R4独立地代表任选取代的吡唑、三唑、噻唑或噻吩环,R2代表氢原子,R3代表溴原子、氰基或三氟甲基。
根据本发明一个甚至更优选的实施方案,在式(I)的化合物中,R1和R4代表任选被一个或多个取代基取代的吡唑环,基团R2代表氢原子,基团R3代表溴原子、氰基或三氟甲基。
根据本发明另外优选的实施方案,在式(I)的化合物中,R1代表任选取代的吡唑、噻唑或三唑环,R2代表氢原子,R3代表溴原子,R4独立地代表基团-N(R5)(R6),其中R5代表氢原子,R6代表任选被氟原子、氨基、二烷基氨基和烷氧基取代的烷基。
根据本发明另外优选的实施方案,在式(I)的化合物中,R1代表任选取代的吡唑环,R2代表氢原子,R3代表溴原子,R4独立地代表任选被氟原子取代的异丙基、环丙基和环丁基环。
根据本发明另外优选的实施方案,在式(I)的化合物中,R1代表任选取代的吡唑环,R2代表氢原子,R3代表溴原子,R4独立地代表任选取代的氧或硫原子。
本发明的特别个体化合物包括:
5-溴-6-异丙基-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-环丙基-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(4-甲基-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(吡咯烷-1-基)嘧啶-4-胺
5-溴-N4-环戊基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-6-(哌啶-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-吗啉代-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(4-甲基哌嗪-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
6-(氮杂环丁烷-1-基)-5-溴-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环丁基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-6-(2-甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-((R)-2-甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4,N4-二甲基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4,N4-二乙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
{(R)-1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]吡咯烷-2-基}甲醇
1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]氮杂环丁烷-3-醇
{(S)-1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]吡咯烷-2-基}甲醇
1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]吡咯烷-3-醇
5-溴-6-((S)-3-氟吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-[(R)-2-(甲氧基甲基)吡咯烷-1-基]-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-[(S)-3-(二甲基氨基)吡咯烷-1-基]-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(2,5-二甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(3,3-二氟氮杂环丁烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-甲基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-乙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(丙-2-炔基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(2-吗啉代乙基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-异丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(环丙基甲基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-氯-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
5-碘-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
4-氨基-2,6-二-(1H-吡唑-1-基)嘧啶-5-腈
4-氨基-6-N-环戊基氨基-2-(1H-吡唑-1-基)嘧啶-5-腈
5-溴-N-甲基-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-乙基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
N-苄基-5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-(丙-2-炔基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-(2-吗啉代乙基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-[2-(哌啶-1-基)乙基]-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-环丁基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
N-(2-氨基乙基)-5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
N4-叔丁基-5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(4-甲基-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
6-(氮杂环丁烷-1-基)-5-溴-2-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环戊基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-环丙基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-环丁基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(4-甲基-1H-吡唑-1-基)-6-(2-甲基吡咯烷-1-基)嘧啶-4-胺
5-溴-2-(4-甲基-1H-吡唑-1-基)-6-((R)-2-甲基吡咯烷-1-基)嘧啶-4-胺
5-溴-N-环丙基-2-(4-氯-1H-吡唑-1-基)嘧啶-4,6-二胺
6-(氮杂环丁烷-1-基)-5-溴-2-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(3-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(3-三氟甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-[5-(乙氧基羰基)-3-甲基-1H-吡唑-1-基]嘧啶-4-胺
5-溴-6-(3,5-二甲基-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(1H-咪唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(4-氯-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(2H-1,2,3-三唑-2-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(1H-1,2,4-三唑-1-基)嘧啶-4-胺
5-溴-6-异丙氧基-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(4-氯-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(4-氯-1H-吡唑-1-基)-6-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(3,5-二甲基-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环戊基-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(3,5-二甲基-1H-吡唑-1-基)-6-(吡咯烷-1-基)嘧啶-4-胺
5-溴-N4-异丙基-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2,6-二(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-胺
5-(1-甲基-1H-吡唑-4-基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(噻吩-2-基)嘧啶-4-胺
5-环丙基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(噻唑-2-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(噁唑-2-基)嘧啶-4-胺
5-(三氟甲基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二(噻唑-2-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(噻唑-2-基)嘧啶-4-胺
5-溴-6-(1H-吡唑-1-基)-2-(噻唑-2-基)嘧啶-4-胺
5-溴-N4-[1-(二甲基氨基)丙-2-基]-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(1-甲氧基丙-2-基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-6-(1H-吡唑-1-基)-2-(2H-1,2,3-三唑-2-基)嘧啶-4-胺
5-溴-6-乙氧基-2-(1H-吡唑-1-基)嘧啶-4-胺。
本发明的化合物可以通过下述的方法之一来制备,使用具体实施例来描述合成途径,这些具体实施例并不是以任何方式限制本发明的范围。
其中取代基R3是溴或氯原子的衍生物可以通过合成路线1所示的系列反应来制备。
商业销售(Aldrich)的式(II)的衍生物的甲硫基已经使用1.2当量的间氯过苯甲酸在室温下,在作为溶剂的二氯甲烷(DCM)中氧化,得到式(III)的亚砜,其从反应中直接沉淀出来。
式(III)的嘧啶衍生物的5位已经使用N-溴琥珀酰亚胺在二甲基甲酰胺(DMF)中,在室温下溴化,得到式(IV)的衍生物。使用N-氯琥珀酰亚胺在嘧啶环的5位产生氯化的衍生物的类似反应也是本发明的主题。
合成路线1
试剂和条件:(a)间-氯过苯甲酸(1.2当量),DCM,RT;(b)N-溴琥珀酰亚胺(1.2当量),DMF,RT;(c)吡唑(1.3当量),碳酸铯,DMF,RT;(d)3-甲基吡唑(3当量),碳酸铯,DMF,85℃;(e)吡咯烷(3当量),THF,60℃;(f)甲氧基钠,甲醇,RT。
使用二甲基甲酰胺(DMF)作为溶剂,在碱例如碳酸铯存在下,式(IV)的卤化亚砜与不同的商业销售的5-元杂环(例如,吡唑或三唑)衍生物在室温下反应。例如,如果式(IV)的化合物与吡唑在这些条件下反应,则得到式(V)的衍生物。
也可以在85℃下,在碱例如碳酸铯存在下使用DMF作为溶剂,通过5-元杂环衍生物(例如,吡唑或三唑)来取代式(V)的嘧啶衍生物的6位的氯原子。例如,衍生物(V)与吡唑在这些条件下的反应得到了式(VI)的化合物,它是本发明所要求保护的化合物类型的一个例子。
此外,式(V)的嘧啶衍生物也可以与商业销售的伯胺或仲胺、醇和硫醇在室温下反应,得到本发明要求保护的式(I)的化合物。例如,衍生物(V)与吡咯烷或甲氧基钠在这些条件下的反应,使得形成了式(VII)或(VIII)的化合物,它们是所要求保护的式(I)的化合物的具体实例。
为了合成如上述定义的其中嘧啶的5-位的取代基R3是氰基或杂芳基的嘧啶衍生物,可以使用在合成路线2中所述的方法。
合成路线2
试剂和条件:(g)氰化铜(I)(1.1当量),吡啶,微波(MW),250℃下20分钟;(h)噻唑基-2-三丁基锡,碳酸铯,钯催化剂,二噁烷,水,MW,在150℃下20分钟。
使用A.P.Ijzerman等人,Biorganic & Medical Chemistry 2008所述的方法来进行氰基的引入。例如,式(VII)的溴衍生物和氰化铜(I)在250℃下、微波条件下20分钟的反应得到在嘧啶环的5位包含氰基的式(IX)的化合物。
另一方面,式(VI)的溴-衍生物与市售的杂芳基-硼酸以常规的Suzuki偶联反应或者与商业销售的杂芳基-三丁基锡衍生物以常规的Stille反应,得到其中嘧啶环的5位被杂环取代的衍生物。例如,式(VII)的化合物与2-三丁基锡噻唑通过钯催化剂介导的反应得到式(X)的化合物,它是本发明要求保护的化合物的具体实例。
其中嘧啶环4位的氨基被如上定义的烷基R2取代的化合物可以使用合成路线3中所述的合成途径来获得。
合成路线3
试剂和条件:(i)NaNO2(10当量),AcOH,RT;(j)亚硫酰氯(2当量),DMF/DCM,40℃,2h;(k)R2-NH2(3当量),THF,RT,24h。
室温下式(VI)的衍生物与亚硝酸钠在乙酸中反应,得到各自的式(XI)的嘧啶酮。在40℃下该衍生物与亚硫酰氯在DMF/DCM(1/2:v/v)的溶液中反应,导致形成了式(XII)的4-氯-嘧啶衍生物。然后化合物(XII)与市售的胺类以非常好的收率反应,得到期望的式(XIII)的N-嘧啶-4-胺,其是本发明的主题。
如果在通式式(I)中定义的残基R1和R4相同,则也可以根据合成路线4中所述的方法来合成这些衍生物。
合成路线4
试剂和条件:(L)N-溴琥珀酰亚胺(1.2当量),DMF,RT;(m)4-甲基吡唑(4当量),碳酸铯,DMF,85℃。
在DMF中用N-溴琥珀酰亚胺进行市售的式(XIV)的化合物的溴化,得到式(XV)的化合物。在85℃和碳酸铯存在下,式(XIV)的化合物与不同的市售的吡唑类在DMF中反应,导致形成在2和6位被相同的吡唑衍生物取代的嘧啶衍生物,例如式(XVI)的化合物,它是本发明要求保护的式(I)的化合物的具体实例。
以类似的方式,如果在通式(I)中定义的基团R4是烷基或环烷基,则也可以根据在合成路线5中描述的方法来合成这些衍生物。
合成路线5
试剂和条件:(L)N-溴琥珀酰亚胺(1.2当量),DMF,RT;(m)吡唑(4当量),碳酸铯,DMF,85℃。
在DMF中用N-溴琥珀酰亚胺进行市售的式(XVII)的化合物的溴化,得到式(XVIII)的化合物。在85℃和碳酸铯存在下,式(XVIII)的化合物与不同的市售的吡唑类在DMF中反应,导致形成衍生物,例如式(XIX)的化合物,它是本发明要求保护的式(I)的化合物的具体实例。
当嘧啶环的2和6位的取代基是不能通过亲核取代引入的杂环时,可以如合成路线6所述来合成相应的衍生物。
市售衍生物(XVI)与市售的杂芳基-硼酸的频哪醇酯以常规的Suzuki偶联反应或者与市售的杂芳基-三丁基锡衍生物以常规的Stille反应,得到可以通过柱色谱分离的所有可能的取代的混合物。例如,式(XVI)的化合物与2-三丁基锡基噻唑通过钯催化介导的反应,得到式(XX)、(XXI)和(XXII)的化合物。可以通过数种吡唑衍生物溴化和取代这些中间体,得到式(XXIII)、(XIV)和(XV)的化合物,它们代表了本发明要求保护的式(I)的化合物的具体实例。
合成路线6
试剂和条件:(h)(h)噻唑基-2-三丁基锡,氟化铯,钯催化剂,二噁烷,在80℃下24h;(L)N-溴琥珀酰亚胺(1.2当量),DMF,RT;(m)吡唑(4当量),碳酸铯,DMF,85℃。
药理学活性
腺苷A
2a
受体亚型竞争性放射性配体结合分析
来自重组腺苷受体的人膜从Receptor Biology,Inc.(USA)购得。
进行竞争性分析,包括将总体积为0.2ml的来自转染到CHO细胞上的hA1受体的膜,用作放射性配体的[3H]-DPCPX,缓冲液(HEPES 20mM(pH=7.4),10mM MgCl2,100mM NaCl,2单位/ml的腺苷脱氨酶)和未标记配体在25℃下温孵60分钟。R-PIA用于测定非特异性结合。过滤器是在Brandel细胞收集器中的Schleicher&SchuellGF/52过滤器(用0.5%聚乙烯亚胺预浸湿)。用(3x 250μl)HEPES 20mM(pH=7.4),100mM NaCl和10mM MgCl2除去未结合的放射性配体。
进行竞争性分析,包括将总体积为0.2ml的来自转染到HeLa细胞上的hA2a受体的膜,用作放射性配体的[3H]ZM241385,缓冲液(50mMTris-HCl(pH=7.4),10mM MgCl2,1mM EDTA,2单位/ml的腺苷脱氨酶)和未标记配体在25℃下温孵30分钟。NECA用于测定非特异性结合。过滤器是在Brandel细胞收集器中的Schleicher&SchuellGF/52过滤器(用0.5%聚乙烯亚胺预浸湿)。用3x 250μl冰冷50mM Tris-HCl(pH=7.4),10mM MgCl2和1mM EDTA除去未结合的放射性配体。
通过分析6个不同的浓度(范围为10nm-100μM)来确定浓度-响应结合竞争性曲线。通过Cheng-Prusoff等式来计算各化合物的抑制常数(Ki):
Ki=IC50/(1+[L]/KD)
其中IC50是置换50%的放射性配体结合时的化合物浓度,[L]是放射性配体的游离浓度,KD是各放射性配体的解离常数。IC50值是通过用Prism 2.1软件(GraphPad,San Diego,CA),用非线性回归拟合该数据而得到的。
环磷腺苷产生测定
这些分析使用cAMP酶免疫分析试剂盒(Amersham Biosciences),针对被转染的腺苷受体来进行。将CHO-A2A细胞植于(10000个细胞/孔)96-孔培养板中,并在37℃和具有5%CO2的大气下,在包含10%胎牛血清(FCS)和1%L-谷酰胺的Dulbecco's改良伊格尔培养基营养混合物F-12(DMEM F-12)中温孵。用200μl分析介质(DMEM-F12和25mMHEPES pH=7.4)洗涤细胞3次,并用包含30μM咯利普兰和受试化合物的分析介质在37℃下预温孵15分钟。将1μM NECA在37℃下预温孵15分钟(总温孵时间为30分钟)。用试剂盒中提供的溶解缓冲液使反应停止,进行酶免疫测定,以在Ultra Evolution检测器(Tecan)中在450nm下检测细胞内的cAMP。使用GraphPad Prism v2.01(GraphPadSoftware),通过非线性回归来拟合数据。
表1显示了一些实施例在结合分析和第二信使cAMP产生分析中得到的对A2a腺苷受体的抑制常数:
表1
从表1可以看出,式(I)的化合物是腺苷A2a受体的有效拮抗剂。
本发明的衍生物用于治疗或预防已知对于通过用腺苷受体的拮抗剂治疗的改善敏感的疾病,特别是对于用腺苷受体的拮抗剂治疗的改善敏感的那些。这些疾病是例如局部缺血,室上性心律失常,心房颤动,急性肾功能衰竭,哮喘,心肌再灌注损伤,原因在于液体潴留的疾病,变应性反应包括但不限于鼻炎、荨麻疹、硬皮病、关节炎、其他自身免疫性疾病,炎性肠病,糖尿病,肥胖,帕金森病,亨廷顿病,张力障碍例如腿多动综合征,运动障碍例如由长期使用多巴胺或神经抑制药(neuroleptic drug)导致的那些,或者睡眠障碍,充血性心力衰竭,高血压,透析中低血压(intradialytic hypotension),痴呆和焦虑症。
因此,本发明的衍生物及其药学可接受的盐,以及包含这些化合物和/或其盐的药物组合物,可以用于治疗人的疾病的方法,包括给需要这样治疗的患者施用有效量的本发明的嘧啶衍生物或其药学可接受的盐。
本发明也提供药物组合物,其包含作为活性成分的至少一种式(I)的嘧啶衍生物或其药学可接受的盐,和药学可接受的赋形剂例如载体或稀释剂。根据制剂的性质和在应用前是否要进行进一步稀释,活性成分可以占组合物的0.001%-99%重量,优选0.01%-90%重量。优选将该组合物制成适合口服、局部、鼻腔、直肠、经皮或注射施用的形式。
与活性化合物或这些化合物的盐混合以形成本发明的组合物的药学可接受的赋形剂本身是公知的,实际使用的赋形剂尤其是取决于预期施用该组合物的方法。
本发明的组合物优选适合注射和口服施用。在这种情况下,口服的组合物可以采用片剂、缓释片、舌下片剂、胶囊、吸入气雾剂、吸入溶液、干粉吸入剂或液体制剂,例如混合物、酏剂、糖浆或混悬液,它们都包含本发明的化合物;这些制剂可以通过本领域公知的方法来制备。
可以用于组合物制备的稀释剂包括那些液体和固体稀释剂,它们与活性成分相容,如果需要还一起加入着色剂或调味剂。片剂或胶囊可以方便地包含2-500mg的活性成分或等量的其盐。
适合口服施用的液体组合物可以是溶液或混悬液的形式。溶液可以是活性化合物的可溶性盐或其他衍生物的水溶液,例如与蔗糖一起形成糖浆。混悬液可以包含本发明的不溶性活性化合物或其药学可接受的盐,并与水,以及悬浮剂或调味剂一起。
胃肠外注射的组合物可以由可溶性盐来制备,它可以是或可以不是冻干的,可以溶解于无热原的水性介质或其他适当的胃肠外注射用液体中。
有效的剂量通常是在每天2-2000mg活性成分的范围内。每日剂量可以以每天1次或多次治疗,优选1-4次治疗来施用。
通过下列实施例(1-99)包括中间体的制备来说明本发明的化合物的合成,它们不是以任何方式限制本发明的范围。
总述。试剂、原料和溶剂购自商业供应商,并按原样使用。浓缩是指使用Büchi旋转蒸发器真空蒸发。当必要时,通过使用如所述的溶剂系统的硅胶(40-63μm)上的快速色谱来精制。在Varian Gemini 200光谱仪,Varian Gemini 300光谱仪,Varian Inova 400光谱仪和BruckerDPX-250光谱仪上记录光谱数据。在Büchi 535装置上记录熔点。在配有Gilson活塞泵321,Gilson 864真空除气器,Gilson液体处理器215,Gilson 189注射模块,Gilson Valvemate 7000,1/1000分离器,Gilson307操作泵,Gilson 170二极管阵列检测器和Thermoquest Finnigan aQa检测器的Gilson设备上进行HPLC-MS。使用Symmetry C18反相柱( 5μm,19x 100mm,购自WATERS)和水/甲酸铵(0.1%,pH=3)和乙腈/甲酸铵(0.1%,pH=3)作为流动相来进行半制备型精制。
中间体1:6-氯-2-(甲基亚磺酰基)嘧啶-4-胺:在30分钟里向10.0g(57.2mmol)6-氯-2-(甲硫基)嘧啶-4-胺的300ml二氯甲烷搅拌溶液中加入溶于200ml DCM的15.3g(68.6mmo l)间-氯过苯甲酸(77%)(Aldrich)溶液。将该反应混合物在室温下搅拌4小时。过滤所形成的白色沉淀,用DCM洗涤数次,然后干燥后,得到10.4g(94.9%)的中间体1。
1H-RMN(300MHz,DMSO-d6):δ=3.28(s,3H),6.64(s,1H),8.11(s,2H).
中间体2:5-溴-6-氯-2-(甲基亚磺酰基)嘧啶-4-胺:将11.2g(62.6mmol)的N-溴琥珀酰亚胺缓慢加入到10g(52.2mmol)6-氯-2-(甲基亚磺酰基)嘧啶-4-胺的130ml DMF冷却的混悬液中。室温下搅拌50分钟后,过滤沉淀,用冷DMF洗涤,用冷水洗涤数次,并真空干燥。得到11.4g(81%)的白色固体。
1H-RMN(300MHz,DMSO-d6):δ=2.78(s,3H),8.17(d,2H).
中间体3:5-溴-2,6-二氯嘧啶-4-胺:将2g(12.2mmol)的4-氨基-2,6-二氯嘧啶溶于10ml的DMF。向该溶液中加入2.6g(14.6mmol)的N-溴琥珀酰亚胺。将反应混合物在室温下搅拌过夜。将溶液倒至200ml的冷水上。过滤所形成的沉淀并用水洗涤。得到呈白色粉末状的2.7g(91.9%)产物。
1H-RMN(300MHz,DMSO-d6):δ=8.16(d,2H).
中间体4:2,5,6-三氯嘧啶-4-胺:将1g(6.1mmol)的4-氨基-2,6-二氯嘧啶溶于5ml的DMF。向该溶液中加入0.98g(7.32mmol)的N-氯琥珀酰亚胺。将溶液倒至100ml的冷水上。过滤所形成的沉淀,用水洗涤并干燥,得到1.4g(80%)的白色固体。
1H-RMN(300MHz,DMSO-d6):δ=8.24(d,2H).
中间体5:5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺:将1g(3.7mmol)的5-溴-6-氯-2-(甲基亚磺酰基)嘧啶-4-胺(中间体2)悬浮于10ml的DMF中。向该混悬液中加入0.33g(4.8mmol)的吡唑和0.8g的碳酸铯。反应混合物立即转变为淡黄色,将其在室温下搅拌约1-2小时。在如TLC所示几乎完全转变为相应的单取代衍生物时,将溶液倒至100ml的冷水上。过滤所形成的沉淀,用水洗涤并干燥,得到0.66g(65%)的所需产物。
1H-RMN(300MHz,DMSO-d6):5=6.56(dd,1H),7.81(d,1H),8.44(d,1H),8.15(d,2H).
使用所述用于中间体5的方法,由相应的吡唑衍生物开始,合成下列中间体。
中间体6:5-溴-6-氯-2-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.08(s,3H),7.63(s,1H),8.21(s,1H),8.17(d,2H).
中间体7:5-溴-6-氯-2-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=7.94(s,1H),8.57(s,1H),8.13(d,2H).
中间体8:5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4(3H)-酮
将1.84g(6mmol)5-溴-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺(实施例1)溶于20ml醋酸。在5小时里向该溶液中分4批加入4.16g(18.4mmol)NaNO2的8ml水溶液。将该混合物在室温下搅拌30小时。真空除去溶剂,用水洗涤粗残留物,得到1.22g(65.8%)的纯净中间体8。
1H-RMN(300MHz,DMSO-d6):δ=6.50(m,2H),7.73(d,1H),7.75(d,1H),8.30(d,1H),8.53(d,1H).
中间体9:5-溴-4-氯-2,6-二(1H-吡唑-1-基)嘧啶
向1g(3.26mmol)5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4(3H)-酮(中间体8)的10ml DMF和40ml的DCM溶液中滴加0.71ml(9.8mmol)亚硫酰氯的10ml DCM溶液。将反应混合物回流2小时,在结束时通过TLC观测不到原料。用10ml的NaHCO3的饱和溶液和盐水萃取该溶液2次。分离有机层,用MgSO4干燥,并浓缩,得到0.65g(61.5%)的4-氯-嘧啶衍生物。
1H-RM(300MHz,DMSO-d6):δ=6.68(dd,1H),6.73(dd,1H),7.95(d,1H),8.02(d,1H),8.76(d,1H),8.80(d,1H).
中间体10:2,6-二氯-5-碘-嘧啶-4-胺:将1g(6.1mmol)的4-氨基-2,6-二氯嘧啶溶于5ml的DMF.向该溶液中加入0.76g(7.32mmol)的N-碘琥珀酰亚胺。将该溶液在室温下搅拌18小时,然后倒至100ml的冷水上。过滤所形成的沉淀,用水洗涤并干燥,得到1.2g(76%)的淡黄色固体。
1H-RMN(300MHz,DMSO-d6):δ=8.11(d,2H).
中间体11:2,5,6-三氯嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=8.14(d,2H).
中间体12:5-溴-6-氯-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.59(s,3H),2.65(s,3H),6.4(s,1H),8.18(d,2H).
中间体13:5-溴-6-氯-2-(2H-l,2,3-三唑-2-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=7.81(d,1H),8.44(d,1H),8.15(d,2H).
实施例
中间体5的衍生物(R1=吡唑)
实施例1:5-溴-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
向0.15g(0.55mmo l)5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺(中间体5)的3ml DMF溶液中加入0.11g(1.64mmol)的1H-吡唑和0.18g(0.55mmol)的碳酸铯。将该混合物在85℃下搅拌24小时。减压浓缩溶剂DMF。用水洗涤粗残留物,并干燥,得到0.13g(77%)的实施例1。
1H-RM(300MHz,DMSO-d6):δ=6.57(dd,1H),6.60(dd,1H),7.52(s,1H),7.81(d,1H),7.87(d,1H),8.41(s,1H),8.51(d,1H),8.60(d,1H).
也可以使用如实施例68所述的方法并用吡唑代替4-甲基-吡唑,由中间体3来合成标题化合物。
使用实施例1所述的方法,由中间体5和相应的胺或吡唑衍生物开始合成实施例2-33:
实施例2:5-溴-6-(4-甲基-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.12(s,3H),6.57(dd,1H),7.53(s,1H),7.70(s,1H),7.81(d,1H),8.32(s,1H),8.43(d,2H),8.52(d,1H).
实施例3:5-溴-2-(1H-吡唑-1-基)-6-(吡咯烷-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.85(m,4H),3.73(t,4H),6.47(dd,1H),6.85(s,2H),7.69(d,1H),8.45(d,1H).
实施例4:5-溴-N4-环戊基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.55(m,4H),1.70(m,2H),1.96(m,2H),4.40(m,1H),6.26(d,1H),6.48(dd,1H),6.75(s,2H),7.71(d,1H),8.46(d,1H).
实施例5:5-溴-6-(哌啶-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.61(m,6H),3.44(m,4H),6.49(dd,1H),7.07(s,2H),7.72(d,1H),8.45(d,1H).
实施例6:5-溴-6-吗啉代-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=3.48(t,4H),3.71(t,4H),6.50(dd,1H),7.19(s,2H),7.74(d,1H),8.48(d,1H).
实施例7:5-溴-6-(4-甲基哌嗪-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.21(s,3H),2.43(t,4H),3.49(t,4H),6.50(dd,1H),7.12(s,2H),7.73(d,1H),8.46(d,1H).
实施例8:5-溴-N4-环丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RM(300MHz,DMSO-d6):δ=0.61(m,2H),0.71(m,2H),2.90(m,1H),6.48(dd,1H),6.73(d,1H),6.76(s,2H),7.71(d,1H),8.50(d,1H).
实施例9:6-(氮杂环丁烷-1-基)-5-溴-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.23(q,2H),4.29(t,4H),6.46(dd,1H),6.87(s,2H),7.70(d,1H),8.42(d,1H).
实施例10:5-溴-N4-环丁基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,CDC13):δ=1.64(m,2H),2.13(m,2H),2.23(m,2H),4.60(m,1H),6.48(dd,1H),6.72(d,1H),6.76(s,2H),7.70(d,1H),8.46(d,1H).
实施例11:5-溴-6-(2-甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.21(d,3H),1.55(m,1H),1.75(m,1H),1.94(m,1H),2.08(m,1H),3.62(m,1H),3.94(m,1H),4.52(m,1H),6.48(dd,1H),6.88(s,2H),7.71(d,1H),8.42(d,1H).
实施例12:5-溴-6-((R)-2-甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=1.21(d,3H),1.55(m,1H),1.77(m,1H),1.93(m,1H),2.09(m,1H),3.62(m,1H),3.92(m,1H),4.52(m,1H),6.48(dd,1H),6.88(s,2H),7.71(d,1H),8.42(d,1H).
实施例13:5-溴-N4,N4-二甲基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=3.09(s,6H),6.49(dd,1H),7.00(s,2H),7.72(d,1H),8.47(d,1H).
实施例14:5-溴-N4,N4-二乙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.19(t,6H),3.55(c,4H),6.49(dd,1H),6.96(s,2H),7.72(d,1H),8.41(d,1H).
实施例15:((R)-1-(6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基)吡咯烷-2-基)甲醇
1H-RMN(300MHz,DMSO-d6):δ=1.76(m,1H),1.96(m,4H),3.64(m,2H),3.91(m,1H),4.51(m,1H),4.81(t,1H),6.49(dd,1H),6.90(s,2H),7.71(d,1H),8.45(d,1H).
实施例16:1-(6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基)氮杂环丁烷-3-醇
1H-RMN(300MHz,DMSO-d6):δ=4.00(m,2H),4.48(m,3H),5.66(d,1H),6.47(dd,1H),6.90(s,2H),7.70(d,1H),8.43(d,1H).
实施例17:((S)-1-(6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基)吡咯烷-2-基)甲醇
1H-RMN(300MHz,DMSO-d6):δ=1.87(m,5H),3.62(m,2H),3.91(m,1H),4.52(m,1H),4.83(m,1H),6.49(dd,1H),6.90(s,2H),7.72(d,1H),8.46(d,1H).
实施例18:1-(6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基)吡咯烷-3-醇
1H-RMN(300MHz,DMSO-d6):δ=1.83(m,1H),1.90(m,1H),3.58(m,1H),3.74(m,1H),3.88(m,2H),4.32(m,1H),4.96(d,1H),6.47(dd,1H),6.85(s,2H),7.70(d,1H),8.44(d,1H).
实施例19:5-溴-6-((S)-3-氟吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.04(m,1H),2.17(m,1H),3.90(m,3H),4.08(m,1H),5.40(d,I H),6.48(dd,1H),6.96(s,2H),7.71(d,1H),8.47(d,1H).
实施例20:5-溴-6-((R)-2-(甲氧基甲基)吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=1.77(m,2H),1.95(m,2H),3.24(s,3H),3.30(m,1H),3.54(m,1H),3.61(m,1H),3.98(m,1H),4.67(m,1H),6.47(dd,1H),6.90(s,2H),7.69(d,1H),8.39(d,1H).
实施例21:5-溴-6-((S)-3-(二甲基氨基)吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.68(m,1H),2.04(m,1H),2.17(m,6H),2.63(m,1H),3.55(t,1H),3.80(m,3H),6.45(dd,1H),6.86(s,2H),7.68(d,1H),8.43(d,1H).
实施例22:5-溴-6-(2,5-二甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.34(d,6H),1.72(m,2H),2.00(m,2H),4.65(m,2H),6.48(dd,1H),6.85(s,2H),7.71(d,1H),8.39(d,1H).
实施例23:5-溴-6-(3,3-二氟氮杂环丁烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=4.67(t,4H),6.50(dd,1H),7.15(s,2H),7.73(d,1H),8.48(d,1H).
实施例24:5-溴-N4-甲基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=2.91(d,3H),6.47(dd,1H),6.70(s,2H),6.75(m,1H),7.70(d,1H),8.49(d,1H).
实施例25:5-溴-N4-乙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.15(t,3H),3.45(m,2H),6.47(dd,1H),6.71(s,2H),6.75(t,1H),7.70(d,1H),8.46(d,1H).
实施例26:5-溴-N4-(丙-2-炔基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=3.04(t,1H),4.18(d,2H),6.50(dd,1H),6.87(s,2H),7.16(t,1H),7.72(d,1H),8.52(d,1H).
实施例27:5-溴-N4-(2-吗啉代乙基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RM(300MHz,DMSO-d6):δ=2.44(t,4H),2.52(t,2H),3.52(t,2H),3.56(t,4H),6.48(dd,1H),6.61(t,1H),6.76(s,2H),7.70(d,1H),8.45(d,1H).
实施例28:5-溴-N4-异丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.21(d,6H),4.35(m,1H),6.19(d,1H),6.47(dd,1H),6.74(s,2H),7.70(d,1H),8.45(d,1H).
实施例29:5-溴-N4-(环丙基甲基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.30(m,2H),0.41(m,2H),1.13(m,1H),3.29(t,2H),6.48(dd,1H),6.73(s,2H),6.81(t,1H),7.71(d,1H),8.45(d,1H).
实施例30:5-溴-N4-丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.88(t,3H),1.58(m,2H),3.38(m,2H),6.48(dd,1H),6.73(m,3H),7.70(d,1H),8.44(d,1H).
实施例31:5-溴-N4-丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.88(t,3H),1.58(m,2H),3.38(m,2H),6.48(dd,1H),6.73(m,3H),7.70(d,1H),8.44(d,1H).
实施例32:(R)-N4-仲丁基-5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.87(t,3H),1.18(d,3H),1.53(m,1H),1.60(m,1H),4.18(m,1H),6.13(d,1H),6.47(dd,1H),6.74(s,2H),7.71(d,1H),8.45(d,1H).
实施例33:(S)-N4-仲丁基-5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.87(t,3H),1.18(d,3H),1.53(m,1H),1.60(m,1H),4.18(m,1H),6.14(d,1H),6.48(dd,1H),6.74(s,2H),7.71(d,1H),8.45(d,1H).
中间体1的衍生物(R1=吡唑,R4=-S-R7)
实施例34:5-溴-6-(苯硫基)-2-(1H-吡唑-1-基)嘧啶-4-胺
向0.1g(0.36mmol)5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺(中间体5)的4ml THF溶液中加入74μl(0.73mmol)的苯硫酚和0.178g(0.55mmol)的Cs2CO3。在100℃和微波条件下使该混合物反应15分钟。然后将反应混合物倒至10ml的冷水上。过滤所形成的白色沉淀,用冷水洗涤数次并干燥。
1H-RMN(300MHz,DMSO-d6):δ=6.40(dd,1H),7.39(t,1H),7.54(m,4H),7.62(m,2H),7.68(m,2H).
实施例35:5-溴-6-(甲硫基)-2-(1H-吡唑-1-基)嘧啶-4-胺
将0.05g(0.73mmol)的甲硫醇钠加入到0.1g(0.36mmol)5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺(中间体5)的4ml THF溶液中。将该混合物在室温下搅拌1小时。然后将其倒至10ml的冷水上。过滤所形成的沉淀,用冷水洗涤数次并干燥。
1H-RM(300MHz,DMSO-d6):δ=2.56(s,3H),6.54(dd,1H),7.47(s,2H),7.78(d,1H),8.57(d,1H).
使用实施例35所述的方法,由中间体5开始,使用相应的硫醇盐的钠盐来合成实施例36-38:
实施例36:5-溴-6-(乙硫基)-2-(1H-吡唑-1-基)嘧啶-4-胺
lH-RMN(300MHz,DMSO-d6):δ=1.34(t,3H),3.19(q,2H),6.55(dd,1H),7.46(s,2H),7.79(d,1H),8.52(d,1H).
实施例37:5-溴-6-(丙硫基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.01(t,3H),1.71(m,2H),3.18(t,2H),6.56(dd,1H),7.47(s,2H),7.79(d,1H),8.51(d,1H).
实施例38:5-溴-6-(异丙硫基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.40(d,6H),4.04(m,1H),6.55(dd,1H),7.46(s,2H),7.79(d,1H),8.51(d,1H).
中间体1的衍生物(R1=吡唑,R4=-O-R7)
实施例39:5-溴-6-苯氧基-2-(1H-吡唑-1-基)嘧啶-4-胺
向0.1g(0.36mmol)5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺(中间体5)的4ml THF溶液中加入0.07g(0.73mmol)的苯酚和0.1g(0.73mmol)的K2C03。在100℃和微波条件下使该混合物反应30分钟。然后将反应混合物倒至10ml的冷水上。过滤所形成的白色沉淀,用冷水洗涤数次并干燥。
1H-RMN(300MHz,DMSO-d6):δ=6.45(dd,1H),7.26(m,4H),7.46(m,3H),7.70(d,1H),8.06(d,1H).
使用实施例39所述的方法,由中间体5开始,使用相应的芳基-或杂芳基苯酚(aril-或heteroarilphenols)来合成实施例40-42:
实施例40:5-溴-2-(1H-吡唑-1-基)-6-(吡啶-2-基氧基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.39(dd,1H),6.55(m,2H),7.58(t,1H),7.69(d,1H),7.80(m,1H),8.03(s,2H),8.47(d,1H).
实施例41:5-溴-2-(1H-吡唑-1-基)-6-(吡啶-3-基氧基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.46(dd,1H),7.33(s,2H),7.52(d,1H),7.71(s,1H),7.77(d,1H),8.07(d,1H),8.51(d,1H),8.56(d,1H).
实施例42:6-(5-氯吡啶-3-基氧基)-5-溴-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.48(dd,1H),6.37(s,2H),7.73(s,1H),8.11(m,2H),8.58(m,2H).
实施例43:5-溴-6-甲氧基-2-(1H-吡唑-1-基)嘧啶-4-胺
将3ml(1.5mmol)(0.5M)的甲醇钠的甲醇溶液加入到0.1g(0.36mmol)5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺(中间体5)的4ml THF溶液中。将该混合物在室温下搅拌1小时。然后减压除去溶剂,用冷水洗涤粗残留物数次,过滤并干燥。
1H-RM(300MHz,DMSO-d6):δ=3.99(s,3H),6.54(dd,1H),7.31(s,2H),7.77(d,1H),8.53(d,1H).
使用实施例43所述的方法,由中间体5开始,使用2,2,2-三氟乙醇钠的2,2,2-三氟乙醇溶液来合成下列实施例:
实施例44:6-(2,2,2-三氟乙氧基)-5-溴-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=5.17(m,2H),6.56(dd,1H),7.33(s,2H),7.79(d,1H),8.64(d,1H).
实施例45:5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
将0.10g(0.37mmol)5-溴-6-氯-2-(1H-吡唑-1-基)嘧啶-4-胺(中间体5)和0.05g(0.77mmol)叠氮化钠的二噁烷(10mL)溶液在80℃下搅拌6小时。然后蒸发溶剂,将残留物溶于甲醇,加入在木炭上的Pd(10mg),氢化30分钟。再次蒸发溶剂,残留物在乙醇中结晶。
1H-RMN(300MHz,DMSO-d6):δ=6.46(d,1H),6.70(s,2H),6.74(s,2H),7.69(d,1H),8.48(d,1H).
实施例46:5-氯-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
在85℃下,使1g(5.04mmol)的2,5,6-三氯嘧啶-4-胺(中间体4)与2.1g(30.2mmol)的1H-吡唑和2g(6.05mmol)的Cs 2CO3在5ml DMF溶液中反应24小时。真空除去DMF。用水洗涤粗残留物数次,然后干燥。
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),6.62(dd,1H),7.70(s,1H),7.81(d,1H),7.90(d,1H),8.36(s,1H),8.59(d,1H),8.63(d,1H).
实施例47:5-碘-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
使用实施例32所述的方法,使用中间体10作为原料,已经合成了该化合物。
1H-RMN(300MHz,DMSO-d6):δ=6.56(dd,1H),6.60(dd,1H),7.55(s,2H),7.79(d,1H),7.87(d,1H),8.74(d,1H),8.75(d,1H).
实施例48:4-氨基-2,6-二-(1H-吡唑-1-基)嘧啶-5-腈
在250℃下用微波照射在3ml的吡啶中的0.2g(0.65mmol)的5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺和0.06g(0.72mmol)的氰化铜(I)的混合物20分钟。在如通过TLC所示几乎完全转化成相应的腈后,加入乙酸乙酯,通过硅藻土过滤。用10ml的NaHCO3的饱和溶液和盐水萃取该溶液2次。分离有机层,用MgSO4干燥,并浓缩,得到0.065g(39.6%)的所需产物。
1H-RMN(300MHz,DMSO-d6):δ=6.58(dd,1H),6.63(dd,1H),7.72(s,1H),7.81(d,1H),7.89(d,1H),8.39(s,1H),8.55(d,1H),8.61(d,1H).
实施例49:4-氨基-6-N-环戊基氨基-2-(1H-吡唑-1-基)嘧啶-5-腈
使用实施例34所述的方法并由5-溴-N4-环戊基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺(实施例4)作为起始物质,已经合成了该化合物。
1H-RMN(300MHz,DMSO-d6):δ=1.55(m,4H),1.70(m,2H),1.96(m,2H),4.41(m,1H),6.25(d,1H),6.48(dd,1H),6.74(s,2H),7.73(d,1H),8.48(d,1H).
实施例50:5-溴-N-甲基-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
向0.1g(0.31mmol)5-溴-4-氯-2,6-二(1H-吡唑-1-基)嘧啶(中间体9)的3ml THF溶液中加入0.124g(1.84mmo l)的盐酸甲胺和0.45g(1.38mmol)Ce2CO3。在室温下将反应混合物在反应管中搅拌48小时。真空除去THF,用水洗涤粗产物并干燥。
1H-RMN(300MHz,DMSO-d6):δ=2.89(d,3H),6.58(dd,1H),6.60(dd,1H),7.83(d,1H),7.87(d,1H),7.95(m,1H),8.46(d,1H),8.65(d,1H).
使用实施例50所述的方法并由相应的胺和5-溴-4-氯-2,6-二(1H-吡唑-1-基)嘧啶(中间体9)作为起始物质合成实施例51-57。
实施例51:5-溴-N-乙基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.22(t,3H),3.60(m,2H),6.58(dd,1H),6.60(dd,1H),7.83(d,1H),7.87(d,1H),7.95(t,1H),8.46(d,1H),8.65(d,1H).
实施例52:N-苄基-5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=4.75(d,2H),6.53(dd,1H),6.57(dd,1H),7.30(m,3H),7.44(d,2H),7.79(d,1H),7.82(d,1H),8.43(d,1H),8.51(t,1H),8.55(d,1H).
实施例53:5-溴-N-(丙-2-炔基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=3.14(t,1H),4.32(m,2H),6.59(dd,1H),6.61(dd,1H),7.85(d,1H),7.89(d,1H),8.30(t,1H),8.48(d,1H),8.71(d,1H).
实施例54:5-溴-N-(2-吗啉代乙基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.45(t,4H),2.58(t,2H),3.57(t,2H),3.59(t,4H),6.58(dd,1H),6.60(dd,1H),7.68(t,1H),7.83(d,1H),7.87(d,1H),8.48(d,1H),8.65(d,1H).
实施例55:5-溴-N-[2-(哌啶-1-基)乙基]-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=1.37(m,2H),1.48(m,4H),2.44(m,4H),2.58(t,2H),3.60(m,2H),6.58(dd,1H),6.60(dd,1H),7.66(t,1H),7.83(d,1H),7.87(d,1H),8.48(d,1H),8.65(d,1H).
实施例56:5-溴-N-环丁基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,CDCl3):δ=1.86(m,2H),2.04(m,2H),2.54(m,2H),4.75(m,1H),6.22(d,1H),6.46(dd,1H),6.48(dd,1H),7.81(d,1H),7.82(d,1H),8.42(d,1H),8.53(d,1H).
实施例57:N-(2-氨基乙基)-5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.22(t,3H),3.60(m,2H),6.58(dd,1H),6.60(dd,1H),7.83(d,1H),7.87(d,1H),7.95(t,1H),8.46(d,1H),8.65(d,1H).
实施例58:N4-叔丁基-5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.46(s,9H),5.43(s,1H),6.48(dd,1H),6.76(s,2H),7.71(d,1H),8.37(d,1H).
中间体6的衍生物(R1=4-甲基-吡唑)
使用实施例1所述的方法并由中间体6和相应的胺或吡唑衍生物开始合成实施例59-65:
实施例59:5-溴-2-(4-甲基-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.09(s,3H),6.60(dd,1H),7.50(s,1H),7.63(s,1H),7.87(d,1H),8.36(s,1H),8.38(s,1H),8.60(d,1H).
实施例60:6-(氮杂环丁烷-1-基)-5-溴-2-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.06(s,3H),2.23(m,2H),4.28(t,4H),6.81(s,2H),7.51(s,1H),8.19(s,1H).
实施例61:5-溴-N4-环戊基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.55(m,4H),1.70(m,2H),1.96(m,2H),2.08(s,3H),4.40(m,1H),6.19(d,1H),6.69(s,2H),7.52(s,1H),8.23(s,1H).
实施例62:5-溴-N4-环丙基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.62(m,2H),0.72(m,2H),2.08(s,3H),2.91(m,1H),6.18(d,1H),6.68(s,2H),7.51(s,1H),8.22(s,1H).
实施例63:5-溴-N4-环丁基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.63(m,2H),1.85(m,2H),2.08(m,2H),2.10(s,3H),4.59(m,1H),6.18(d,1H),6.69(s,2H),7.53(s,1H),8.23(s,1H).
实施例64:5-溴-2-(4-甲基-1H-吡唑-1-基)-6-(2-甲基吡咯烷-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.20(d,3H),1.56(m,1H),1.75(m,1H),1.94(m,1H),2.07(m,1H),2.09(s,3H),3.62(m,1H),3.94(m,1H),4.52(m,1H),6.80(s,2H),7.52(s,1H),8.20(s,1H).
实施例65:5-溴-2-(4-甲基-1H-吡唑-1-基)-6-((R)-2-甲基吡咯烷-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.21(d,3H),1.57(m,1H),1.77(m,1H),1.93(m,1H),2.08(m,1H),2.12(s,3H),3.63(m,1H),3.93(m,1H),4.52(m,1H),6.80(s,2H),7.52(s,1H),8.20(s,1H).
中间体7的衍生物(R1=4-氯-1H-吡唑)
使用实施例1所述的方法并由中间体7和相应的胺或吡唑衍生物合成实施例66和67:
实施例66:5-溴-N-环丙基-2-(4-氯-1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=0.60(m,2H),0.70(m,2H),2.88(m,1H),6.71(d,1H),6.80(s,2H),7.73(s,1H),8.35(s,1H).
实施例67:6-(氮杂环丁烷-1-基)-5-溴-2-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.12(q,2H),4.28(t,4H),6.77(s,2H),7.72(s,1H),8.35(s,1H).
在嘧啶环的2和6位包含相同取代基的衍生物:
实施例68:5-溴-2,6-二-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
将0.2ml(2.47mmol)的4-甲基-1H-吡唑和0.4g(1.24mmol)的碳酸铯加入到0.15g(0.62mmol)5-溴-2,6-二氯嘧啶-4-胺(中间体3)的3ml DMF溶液中。将该混合物在85℃下加热24小时。真空浓缩DMF。用水洗涤残留物,并干燥,得到0.16g(78.7%)的白色固体。
1H-RMN(300MHz,DMSO-d6):δ=2.07(s,3H),2.10(s,3H),7.69(s,1H),7.72(s,1H),8.31(s,1H),8.39(s,1H),8.16(d,2H).
通过实施例68使用的方法,使用相应吡唑的衍生物,合成下列衍生物:
实施例69:5-溴-2,6-二-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=7.71(s,1H),7.74(s,1H),8.36(s,1H),8.41(d,1H),8.16(d,2H).
实施例70:5-溴-2,6-二-(3-甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=2.08(t,3H),2.11(t,3H),6.54(d,1H),6.60(d,1H),7.62(d,1H),7.68(d,1H),7.40(d,2H).
实施例71:5-溴-2,6-二-(3-三氟甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.49(d,1H),6.56(d,1H),7.60(d,1H),7.65(d,1H),7.35(d,2H).
实施例72:5-溴-2,6-二-[5-(乙氧基羰基)-3-甲基-1H-吡唑-1-基]嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.25(m,6H),4.24(m,4H),2.02(s,3H),2.08(s,3H),6.49(d,1H),6.54(d,1H),7.38(d,2H).
使用实施例1所述的方法,由中间体5开始,使用相应的胺或吡唑衍生物合成下列实施例:
实施例73:5-溴-6-(3,5-二甲基-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.11(s,6H),6.04(s,1H),6.58(dd,1H),7.54(s,1H),7.82(d,1H),8.42(s,1H),8.53(d,1H).
实施例74:5-溴-6-(1H-咪唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),7.40(d,1H),7.52(s,1H),7.81(d,1H),7.85(d,1H),8.41(s,1H),8.31(s,1H),8.51(d,1H).
实施例75:5-溴-6-(4-氯-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),7.51(s,1H),7.65(s,1H),7.81(d,1H),8.26(s,1H),8.41(s,1H),8.52(d,1H).
实施例76:5-溴-2-(1H-吡唑-1-基)-6-(2H-1,2,3-三唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.58(dd,1H),7.55(s,1H),7.96(d,2H),7.81(d,1H),8.41(s,1H),8.54(d,1H).
实施例77:5-溴-2-(1H-吡唑-1-基)-6-(1H-l,2,4-三唑-1-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=6.58(dd,1H),7.55(s,1H),7.81(d,1H),8.41(s,1H),8.46(s,1H),8.54(d,1H),8.66(s,1H).
实施例78:5-溴-6-异丙氧基-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.32(d,6H),5.36(m,1H),6.52(dd,1H),7.31(s,2H),7.74(d,1H),8.52(d,1H).
实施例79:5-溴-2-(4-氯-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.61(dd,1H),7.50(s,1H),7.58(s,1H),7.89(d,1H),8.26(s,1H),8.38(s,1H),8.62(d,1H).
实施例80:5-溴-2-(4-氯-1H-吡唑-1-基)-6-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.06(s,3H),7.36(s,2H),7.59(s,1H),7.66(s,1H),8.27(s,1H),8.34(s,1H).
实施例81:5-溴-2-(3,5-二甲基-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.08(s,6H),6.01(s,1H),6.60(dd,1H),7.52(s,1H),7.88(d,1H),8.40(s,1H),8.61(d,1H).
实施例82:5-溴-N4-环戊基-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.55(m,4H),1.70(m,2H),1.96(m,2H),2.06(s,6H),4.40(m,1H),6.01(s,1H),6.25(d,1H),6.73(s,2H).
实施例83:5-溴-2-(3,5-二甲基-1H-吡唑-1-基)-6-(吡咯烷-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.86(m,4H),2.06(s,6H),3.73(t,4H),6.02(s,1H),6.83(s,2H).
实施例84:5-溴-N4-异丙基-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.16(d,6H),2.08(s,6H),4.23(m,1H),6.00(s,1H),6.12(d,1H),6.72(s,2H).
通过实施例68的方法,使用3,5-二甲基-1H-吡唑作为原料合成下列衍生物:
实施例85:5-溴-2,6-二(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=2.06(s,6H),2.11(s,6H),6.02(s,1H),6.05(s,1H),7.49(s,1H),8.39(s,1H).
在嘧啶环的5位(R3)上包含杂环的衍生物:
实施例86:5-(1-甲基-1H-吡唑-4-基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
在140℃下,用微波照射在3ml二噁烷和0.5ml水中的0.1g(0.33mmol)的5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺(实施例1),0.10g(0.49mmol)的1-甲基吡唑-4-硼酸频哪醇酯,0.23(0.72mmol)的碳酸铯和5mg(6.5μmol)的[1,1'-二(二苯基膦)二茂络铁]二氯钯(II)二氯甲烷络合物的混合物30分钟。在冷却至室温后,加入乙酸乙酯并通过硅藻土过滤。用10ml的NaHCO3的饱和溶液和盐水萃取该溶液2次。分离有机层,用MgSO4干燥,并浓缩。使用硅胶并以二氯甲烷和甲醇作为洗脱剂,通过柱色谱精制残留物,得到45.5mg(45.3%)的所需产物。
1H-RMN(300MHz,DMSO-d6):δ=4.05(s,3H),6.56(dd,1H),6.59(dd,1H),7.25(s,1H),7.45(s,1H),7.52(s,1H),7.80(d,1H),7.86(d,1H),8.40(s,1H),8.51(d,1H),8.59(d,1H).
通过实施例86的方法,使用相应的硼酸频哪醇酯,合成下列衍生物:
实施例87:2,6-二(1H-吡唑-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.56(dd,1H),6.60(dd,1H),7.28(d,1H),7.48(s,1H),7.52(s,1H),7.80(d,1H),7.86(d,1H),8.40(s,1H),8.51(d,1H),8.60(d,1H),13.55(d,1H).
实施例88:2,6-二(1H-吡唑-1-基)-5-(噻吩-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),6.60(dd,1H),6.58(dd,1H),7.02(d,1H),7.18(d,1H),7.53(s,1H),7.80(d,1H),7.86(d,1H),8.41(s,1H),8.51(d,1H),8.60(d,1H).
实施例89:5-环丙基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=0,41(m,2H),0,65(m,2H),1,61(m,1H),6.57(dd,1H),6.61(dd,1H),7.54(s,1H),7.81(d,1H),7.88(d,1H),8.42(s,1H),8.51(d,1H),8.60(d,1H).
实施例90:2,6-二(1H-吡唑-1-基)-5-(噻唑-2-基)嘧啶-4-胺
根据Morgan in Chem.Eur.J.2010,16,4279-4283所述的方法进行该反应。
用氩气吹扫玻璃瓶中的8.9mg(13.1μmol)的Pd-PEPPSI-IPr-催化剂,0.1g(0.33mmol)的5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺(实施例1),0.1g(0.65mmol)的氟化铯和活化的、压碎的分子筛(33mg)的混合物,并加入1ml的二噁烷。然后加入0.15(0.39mmol)的2-三丁基锡基噻唑,将该反应在80℃下搅拌24小时。通过硅藻土/CsF过滤该混合物。真空除去溶剂。使用硅胶并以二氯甲烷和甲醇作为洗脱剂,通过柱色谱精制残留物,得到47.9mg(47.2%)的所需产物。
1H-RM(300MHz,DMSO-d6):δ=6.57(dd,1H),6.58(dd,1H),7.34(d,1H),7.52(s,1H),7.81(d,1H),7.86(d,1H),7.92(d,1H),8.41(s,1H),8.51(d,1H),8.60(d,1H).
通过实施例90所使用的方法,使用2-三丁基锡基噁唑合成下列衍生物:
实施例91:5-(噁唑-2-基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),6.56(dd,1H),7.28(d,1H),7.51(s,1H),7.81(d,1H),7.85(d,1H),7.90(d,1H),8.40(s,1H),8.50(d,1H),8.58(d,1H).
实施例92:5-(三氟甲基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
通过Buchwald在Science 2010,328,1679-1681中所述的方法来进行该反应。
将11.3mg(20μmol)Pd(dba)2和15.8mg(29.4μmol)2-(二环己基膦)3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯的3ml二噁烷溶液加入到0.1g(0.33mmol)的5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺(实施例1),0.04g(0.65mmol)的氟化钾的混合物中。然后加入0.093g(0.65mmol)的三甲基(三氟甲基)硅烷,将该反应在140℃下搅拌20小时。通过硅藻土过滤该混合物,并真空浓缩。使用硅胶并以二氯甲烷和甲醇作为洗脱剂,通过柱色谱精制残留物,得到41.6mg(43.1%)的所需产物。
1H-RMN(300MHz,DMSO-d6):δ=6.55(dd,1H),6.58(dd,1H),7.51(s,1H),7.80(d,1H),7.86(d,1H),8.40(s,1H),8.50(d,1H),8.58(d,1H).
包含通过碳-碳键与嘧啶环的2或6位相连的杂环的衍生物:
使用实施例90所述的方法,由2,6-二氯嘧啶-4-胺和2-(三丁基锡基)噻唑开始,以常规的Stille反应合成中间体14-16。使用硅胶并以环己烷和乙酸乙酯作为洗脱剂,通过柱色谱精制所形成的这三种中间体:
中间体14:2-氯-6-(噻唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.80(s,1H),7.50(s,2H),7.64(d,1H),8.09(d,1H).
中间体15:6-氯-2-(噻唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.78(s,1H),7.49(s,2H),7.56(d,1H),8.04(d,1H).
中间体16:2,6-二(噻唑-2-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=6.84(s,1H),7.51(s,2H),7.57(d,1H),7.65(d,1H),8.06(d,1H),8.11(d,1H).
根据所述用于合成中间体3的方法,由相应的噻唑嘧啶-4-胺衍生物和N-溴琥珀酰亚胺作为起始物质,合成下列中间体:
中间体17:5-溴-2-氯-6-(噻唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=7.41(d,1H),8.01(d,1H),8.16(s,2H).
中间体18:5-溴-6-氯-2-(噻唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=7.35(d,1H),7.96(d,1H),8.17(s,2H).
实施例93:5-溴-2,6-二(噻唑-2-基)嘧啶-4-胺
使用中间体16作为原料,根据所述用于合成中间体3的方法来合成该化合物:
1H-RMN(300MHz,DMSO-d6):δ=7.35(d,1H),7.41(d,1H),7.96(d,1H),8.01(d,1H),8.18(s,2H).
使用如实施例1所述的方法,由相应的中间体17、18和吡唑开始合成94-95的实施例:
实施例94:5-溴-2-(1H-吡唑-1-基)-6-(噻唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),7.40(d,1H),7.53(s,1H),7.81(d,1H),8.00(d,1H),8.40(s,1H),8.42(d,1H).
实施例95:5-溴-6-(1H-吡唑-1-基)-2-(噻唑-2-基)嘧啶-4-胺
1H-RM(300MHz,DMSO-d6):δ=6.60(dd,1H),7.36(d,1H),7.51(s,1H),7.87(d,1H),7.97(d,1H),8.42(s,1H),8.60(d,1H).
实施例96:5-溴-N4-[1-(二甲基氨基)丙-2-基]-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.18(d,3H),2.15(s,6H),2.20(m,1H),2.43(m,1H),4.27(m,1H),6.18(d,1H),6.46(dd,1H),6.77(s,2H),7.68(d,1H),8.42(d,1H).
实施例97:5-溴-N4-(1-甲氧基丙-2-基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
1H-RMN(300MHz,DMSO-d6):δ=1.15(d,3H),3.32(s,3H),3.40(d,2H),4.43(m,1H),6.15(d,1H),6.46(dd,1H),6.77(s,2H),7.68(d,1H),8.42(d,1H).
实施例98:5-溴-6-(1H-吡唑-1-基)-2-(2H-1,2,3-三唑-2-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=6.57(dd,1H),6.60(dd,1H),7.52(s,1H),7.81(d,1H),7.87(d,1H),8.41(s,1H),8.51(d,1H),8.60(d,1H).
实施例99:5-溴-6-乙氧基-2-(1H-吡唑-1-基)嘧啶-4-胺
1H-RMN(300MHz,DMSO-d6):δ=1.29(d,6H),5.29(m,2H),6.54(dd,1H),7.31(s,2H),7.77(d,1H),8.54(d,1H).
Claims (27)
1.式(I)的化合物:
其中
-R1代表任选被一个或多个选自卤素、烷基、环烷基、烷氧基或氰基的取代基取代的五元杂芳环;
-R2独立地代表:
a)氢原子,
b)环烷基或烷基,其任选独立地被一个或多个卤素原子、烷基、环烷基或烷氧基取代;
-R3独立地代表:
a)卤素原子,
b)氰基,
c)三氟甲基,
d)环丙基或环丁基,
e)任选被一个或多个卤素原子或一个或多个基团例如烷基、环烷基、烷氧基、氨基、单-或二烷基氨基取代的五元杂芳基;
-R4独立地代表:
a)任选被一个或多个卤素原子或一个或多个基团例如烷基、环烷基、烷氧基、烷硫基、氨基、单-或二烷基氨基取代的五元杂芳基,
b)基团-N(R5)(R6),其中R5和R6独立地代表:
-氢原子,
-3-6个碳原子的直链或支链的烷基或环烷基,任选被一个或多个卤素原子或一个或多个基团例如环烷基、羟基、烷氧基、氨基、单-或二烷基氨基取代,
-或R5和R6与和它们相连的氮原子一起形成4-6元的饱和杂环基,其中可以插入其他杂原子,所述杂环基任选被一个或多个卤素原子或一个或多个烷基、羟基、低级烷氧基、氨基、单-或二烷基氨基取代,或者,
c)基团-OR7或-SR7,其中R7独立地代表:
-直链或支链的烷基或环烷基,任选被一个或多个卤素原子或一个或多个基团例如烷基、烷氧基、氨基、单-或二烷基氨基取代,
-任选被一个或多个卤素原子取代的苯环。
2.根据权利要求1的化合物,其中R1任选代表吡唑、噻唑或三唑环,任选被一个或两个卤素原子或者一个或两个甲基或三氟甲基取代。
3.根据权利要求2的化合物,其中R2代表氢原子。
4.根据权利要求3的化合物,其中R3任选代表溴原子、氯原子或或氰基。
5.根据权利要求4的化合物,其中R4代表吡唑环,其通过所述吡唑环的氮原子与嘧啶环的2位相连,所述吡唑环任选被一个或两个卤素原子或一个或两个甲基或三氟甲基取代。
6.根据权利要求4的化合物,其中R4代表2-噻唑环,所述噻唑环任选被一个或两个卤素原子或一个或两个甲基或三氟甲基取代。
7.根据权利要求4和5的化合物,其中R4代表如权利要求1定义的基团-N(R5)(R6)。
8.根据权利要求7的化合物,其中R5代表氢原子,R6代表任选被卤素原子、三氟甲基、氨基、烷基氨基取代的烷基或环烷基。
9.根据权利要求1的化合物,其中R3代表溴或氯原子。
10.根据权利要求9的化合物,其中R1和R4独立地代表都任选被一个或两个卤素原子或一个或两个甲基或三氟甲基取代的吡唑或噻唑环。
11.根据权利要求10的化合物,其中R2代表氢原子。
12.根据权利要求9的化合物,其中R1和R4代表任选被一个或两个卤素原子、甲基或三氟甲基取代的吡唑环。
13.根据权利要求12的化合物,其中R2代表氢原子。
14.根据权利要求9的化合物,其中R1代表任选被一个或两个卤素原子、甲基或三氟甲基取代的吡唑或噻唑环,R4代表基团-N(R5)(R6)。
15.根据权利要求9的化合物,其中R1代表任选被一个或两个卤素原子、甲基或三氟甲基取代的吡唑或噻唑环,R4代表基团SR7或OR7,其中R7代表任选被氟原子取代的直链或支链烷基。
16.根据权利要求1的化合物,其是下列化合物之一:
5-溴-6-异丙基-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-环丙基-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(4-甲基-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(吡咯烷-1-基)嘧啶-4-胺
5-溴-N4-环戊基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-6-(哌啶-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-吗啉代-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(4-甲基哌嗪-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
6-(氮杂环丁烷-1-基)-5-溴-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环丁基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-6-(2-甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-((R)-2-甲基吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4,N4-二甲基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4,N4-二乙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
{(R)-1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]吡咯烷-2-基}甲醇
1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]氮杂环丁烷-3-醇
{(S)-1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]吡咯烷-2-基}甲醇
1-[6-氨基-5-溴-2-(1H-吡唑-1-基)嘧啶-4-基]吡咯烷-3-醇
5-溴-6-((S)-3-氟吡咯烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-[(R)-2-(甲氧基甲基)吡咯烷-1-基]-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-[(S)-3-(二甲基氨基)吡咯烷-1-基]-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(2,5-二甲基吡咯烷-1-基)-2-(lH-吡唑-1-基)嘧啶-4-胺
5-溴-6-(3,3-二氟氮杂环丁烷-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-甲基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-乙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(丙-2-炔基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(2-吗啉代乙基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-异丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(环丙基甲基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-丙基-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-氯-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
5-碘-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
4-氨基-2,6-二-(1H-吡唑-1-基)嘧啶-5-腈
4-氨基-6-N-环戊基氨基-2-(1H-吡唑-1-基)嘧啶-5-腈
5-溴-N-甲基-2,6-二-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-乙基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
N-苄基-5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-(丙-2-炔基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-(2-吗啉代乙基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-[2-(哌啶-1-基)乙基]-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N-环丁基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
N-(2-氨基乙基)-5-溴-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
N4-叔丁基-5-溴-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(4-甲基-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
6-(氮杂环丁烷-1-基)-5-溴-2-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环戊基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-环丙基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-环丁基-2-(4-甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(4-甲基-1H-吡唑-1-基)-6-(2-甲基吡咯烷-1-基)嘧啶-4-胺
5-溴-2-(4-甲基-1H-吡唑-1-基)-6-((R)-2-甲基吡咯烷-1-基)嘧啶-4-胺
5-溴-N-环丙基-2-(4-氯-1H-吡唑-1-基)嘧啶-4,6-二胺
6-(氮杂环丁烷-1-基)-5-溴-2-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(4-氯-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(3-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-(3-三氟甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二-[5-(乙氧基羰基)-3-甲基-1H-吡唑-1-基]嘧啶-4-胺
5-溴-6-(3,5-二甲基-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(1H-咪唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-6-(4-氯-1H-吡唑-1-基)-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(2H-1,2,3-三唑-2-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(1H-1,2,4-三唑-1-基)嘧啶-4-胺
5-溴-6-异丙氧基-2-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(4-氯-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(4-氯-1H-吡唑-1-基)-6-(4-甲基-1H-吡唑-1-基)嘧啶-4-胺
5-溴-2-(3,5-二甲基-1H-吡唑-1-基)-6-(1H-吡唑-1-基)嘧啶-4-胺
5-溴-N4-环戊基-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2-(3,5-二甲基-1H-吡唑-1-基)-6-(吡咯烷-1-基)嘧啶-4-胺
5-溴-N4-异丙基-2-(3,5-二甲基-1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-2,6-二(3,5-二甲基-1H-吡唑-1-基)嘧啶-4-胺
5-(1-甲基-1H-吡唑-4-基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(噻吩-2-基)嘧啶-4-胺
5-环丙基-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(噻唑-2-基)嘧啶-4-胺
2,6-二(1H-吡唑-1-基)-5-(噁唑-2-基)嘧啶-4-胺
5-(三氟甲基)-2,6-二(1H-吡唑-1-基)嘧啶-4-胺
5-溴-2,6-二(噻唑-2-基)嘧啶-4-胺
5-溴-2-(1H-吡唑-1-基)-6-(噻唑-2-基)嘧啶-4-胺
5-溴-6-(1H-吡唑-1-基)-2-(噻唑-2-基)嘧啶-4-胺
5-溴-N4-[1-(二甲基氨基)丙-2-基]-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-N4-(1-甲氧基丙-2-基)-2-(1H-吡唑-1-基)嘧啶-4,6-二胺
5-溴-6-(1H-吡唑-1-基)-2-(2H-1,2,3-三唑-2-基)嘧啶-4-胺
5-溴-6-乙氧基-2-(1H-吡唑-1-基)嘧啶-4-胺。
17.权利要求1-16任一项的化合物,用于治疗对于通过腺苷受体的拮抗作用的改善敏感的病理学病症或疾病。
18.权利要求1-16任一项的化合物,用于治疗对于通过腺苷A2a受体的拮抗作用的改善敏感的病理学病症或疾病。
19.根据权利要求1-16的化合物,用于治疗病理学病症或疾病,其中所述病理学病症或疾病是局部缺血,室上性心律失常,心房颤动,急性肾功能衰竭,心肌再灌注损伤,原因在于液体潴留的疾病,变应性反应包括但不限于鼻炎、荨麻疹、硬皮病、关节炎、其他自身免疫性疾病,炎性肠病,糖尿病,肥胖,帕金森病,亨廷顿病,张力障碍例如腿多动综合征,运动障碍例如由长期使用多巴胺或神经抑制药导致的那些,或者睡眠障碍,充血性心力衰竭,高血压,透析中低血压,痴呆,焦虑症和青光眼。
20.根据权利要求19的化合物,用于治疗病理学病症或疾病,其中所述病理学病症或疾病是心律失常、心房颤动、帕金森病、亨廷顿病、阿尔茨海默病、张力障碍例如腿多动综合征、运动障碍例如由长期使用多巴胺或神经抑制药导致的那些、或者睡眠障碍、痴呆、焦虑症和糖尿病。
21.一种药物组合物,包含与药学可接受的稀释剂或载体混合的权利要求1-16任一项定义的化合物。
22.一种治疗患有对于通过腺苷A2a受体的拮抗作用的改善敏感的病理学病症或疾病的患者的方法,其包括给所述患者施用有效量的权利要求1-16任一项定义的化合物。
23.一种组合产品,包含根据权利要求1-16任一项的化合物与另一种用于治疗以下疾病的化合物,所述疾病例如局部缺血,室上性心律失常,心房颤动,急性肾功能衰竭,心肌再灌注损伤,原因在于液体潴留的疾病,变应性反应包括但不限于鼻炎、荨麻疹、硬皮病、关节炎、其他自身免疫性疾病,炎性肠病,糖尿病,肥胖,帕金森病,亨廷顿病,阿尔茨海默病,张力障碍例如腿多动综合征,运动障碍例如由长期使用多巴胺或神经抑制药导致的那些,或者睡眠障碍,充血性心力衰竭,高血压,透析中低血压,痴呆,焦虑症和糖尿病,所述权利要求1-16任一项的化合物与另一种化合物用于同时、分别或连续使用。
24.一种组合产品,包含根据权利要求1-16任一项的化合物与左旋多巴、多巴胺激动剂、MAO-B抑制剂、乙酰胆碱酯酶抑制剂或用于治疗帕金森病、亨廷顿病和阿尔茨海默病的任何药物。
25.包含根据权利要求1-16任一项的化合物与左旋多巴、多巴胺激动剂、MAO-B抑制剂、乙酰胆碱酯酶抑制剂或的组合产品用于治疗疾病例如帕金森病、亨廷顿病、阿尔茨海默病、张力障碍例如腿多动综合征、运动障碍例如由长期使用多巴胺或神经抑制药导致的那些、或者睡眠障碍、痴呆、焦虑症的应用。
26.一种组合产品,包含根据权利要求1-16任一项的化合物与胰岛素、二甲双胍、GLP-激动剂、磺脲类、DPP-IV抑制剂或用于治疗糖尿病的任何药物。
27.包含根据权利要求1-16任一项的化合物与胰岛素、二甲双胍、GLP-激动剂、磺脲类、DPP-IV抑制剂或用于治疗糖尿病的任何药物的组合产品的应用。
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---|---|---|---|---|
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US11376255B2 (en) | 2018-09-11 | 2022-07-05 | iTeos Belgium SA | Thiocarbamate derivatives as A2A inhibitors, pharmaceutical composition thereof and combinations with anticancer agents |
JP2022503879A (ja) * | 2018-09-27 | 2022-01-12 | アイテオ ベルギウム エスエー | がん治療におけるentファミリートランスポーター阻害剤の使用及びそのアデノシン受容体アンタゴニストとの組み合わせ |
BE1026612B1 (fr) | 2018-09-27 | 2020-07-02 | Iteos Therapeutics S A | Utilisation d’un inhibiteur d’un transporteur de la famille ent dans le traitement du cancer et combinaison de celui-ci avec un antagoniste de recepteur de l’adenosine |
BR112021011874A2 (pt) | 2018-12-20 | 2021-09-08 | Novartis Ag | Regime de dosagem e combinação farmacêutica compreendendo derivados de 3-(1-oxoisoindolin-2-il)piperidina-2,6-diona |
WO2020128637A1 (en) | 2018-12-21 | 2020-06-25 | Novartis Ag | Use of il-1 binding antibodies in the treatment of a msi-h cancer |
US20220056123A1 (en) | 2018-12-21 | 2022-02-24 | Novartis Ag | Use of il-1beta binding antibodies |
US20220025036A1 (en) | 2018-12-21 | 2022-01-27 | Novartis Ag | Use of il-1beta binding antibodies |
CN113329792B (zh) | 2019-02-15 | 2024-06-28 | 诺华股份有限公司 | 取代的3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途 |
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KR20220062500A (ko) | 2019-09-16 | 2022-05-17 | 서피스 온콜로지, 인크. | 항-cd39 항체 조성물 및 방법 |
TW202124446A (zh) | 2019-09-18 | 2021-07-01 | 瑞士商諾華公司 | 與entpd2抗體之組合療法 |
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EP4240491A1 (en) | 2020-11-06 | 2023-09-13 | Novartis AG | Cd19 binding molecules and uses thereof |
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WO2024134541A1 (en) | 2022-12-20 | 2024-06-27 | iTeos Belgium SA | Heterocyclic compounds as ent inhibitors and compounds for use in the treatment of cancers |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005058883A1 (en) * | 2003-12-15 | 2005-06-30 | Almirall Prodesfarma Ag | 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists |
WO2008110891A2 (en) * | 2007-03-09 | 2008-09-18 | Orchid Research Laboratories Limited, | New heterocyclic compounds |
WO2008116185A2 (en) * | 2007-03-21 | 2008-09-25 | Neurocrine Biosciences, Inc. | Substituted pyrimidines as adenosine receptor antagonists |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2315736A1 (en) | 1998-01-05 | 1999-07-15 | Eisai Co., Ltd. | Purine compounds and adenosine a2 receptor antagonist as preventive or therapeutic for diabetes mellitus |
AU778450B2 (en) | 1999-07-02 | 2004-12-09 | Eisai R&D Management Co., Ltd. | Fused imidazole compounds and remedies for diabetes mellitus |
ATE293962T1 (de) * | 2000-02-25 | 2005-05-15 | Hoffmann La Roche | Adenosin-rezeptor modulatoren |
JP4460292B2 (ja) * | 2001-10-17 | 2010-05-12 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | ピリミジン誘導体、これらの化合物を含む医薬組成物、その使用及びその調製方法 |
TWI330183B (zh) * | 2001-10-22 | 2010-09-11 | Eisai R&D Man Co Ltd | |
EP1894930A4 (en) * | 2005-06-23 | 2010-06-23 | Kyowa Hakko Kirin Co Ltd | THIAZOLE DERIVATIVE |
EP2121662A1 (en) * | 2006-12-04 | 2009-11-25 | Neurocrine Biosciences, Inc. | Substituted pyrimidines as adenosine receptor antagonists |
WO2009032694A1 (en) * | 2007-08-28 | 2009-03-12 | Dana Farber Cancer Institute | Amino substituted pyrimidine, pyrollopyridine and pyrazolopyrimidine derivatives useful as kinase inhibitors and in treating proliferative disorders and diseases associated with angiogenesis |
-
2010
- 2010-03-31 ES ES201030489A patent/ES2365960B1/es active Active
-
2011
- 2011-03-29 ES ES11719879.6T patent/ES2534227T3/es active Active
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-
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- 2012-09-27 ZA ZA2012/07259A patent/ZA201207259B/en unknown
-
2015
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005058883A1 (en) * | 2003-12-15 | 2005-06-30 | Almirall Prodesfarma Ag | 2, 6 bisheteroaryl-4-aminopyrimidines as adenosine receptor antagonists |
WO2008110891A2 (en) * | 2007-03-09 | 2008-09-18 | Orchid Research Laboratories Limited, | New heterocyclic compounds |
WO2008116185A2 (en) * | 2007-03-21 | 2008-09-25 | Neurocrine Biosciences, Inc. | Substituted pyrimidines as adenosine receptor antagonists |
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KR20130028732A (ko) | 2013-03-19 |
ZA201207259B (en) | 2013-09-25 |
JP5725383B2 (ja) | 2015-05-27 |
ES2365960A1 (es) | 2011-10-14 |
WO2011121418A9 (en) | 2012-04-05 |
RS53939B1 (en) | 2015-08-31 |
WO2011121418A1 (en) | 2011-10-06 |
ES2534227T3 (es) | 2015-04-20 |
CN102892761B (zh) | 2015-02-04 |
CY1116328T1 (el) | 2017-02-08 |
EA021565B1 (ru) | 2015-07-30 |
EP2552909A1 (en) | 2013-02-06 |
CA2795009A1 (en) | 2011-10-06 |
JP2013523711A (ja) | 2013-06-17 |
PL2552909T3 (pl) | 2015-08-31 |
DK2552909T3 (en) | 2015-04-13 |
HRP20150366T1 (hr) | 2015-05-22 |
SMT201500097B (it) | 2015-07-09 |
AU2011234144B2 (en) | 2014-04-24 |
PT2552909E (pt) | 2015-04-23 |
EP2552909B1 (en) | 2015-03-11 |
AU2011234144A1 (en) | 2012-10-25 |
BR112012024870B1 (pt) | 2020-11-17 |
EA201201343A1 (ru) | 2013-03-29 |
KR101441781B1 (ko) | 2014-09-17 |
SI2552909T1 (sl) | 2015-06-30 |
MX2012011240A (es) | 2012-11-30 |
BR112012024870A2 (pt) | 2016-06-14 |
US20130053308A1 (en) | 2013-02-28 |
ME02100B (me) | 2015-10-20 |
US8796284B2 (en) | 2014-08-05 |
CA2795009C (en) | 2016-06-21 |
ES2365960B1 (es) | 2012-06-04 |
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