CN115038700A - 偕二取代的杂环化合物及其作为idh抑制剂的用途 - Google Patents
偕二取代的杂环化合物及其作为idh抑制剂的用途 Download PDFInfo
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- CN115038700A CN115038700A CN202080093366.1A CN202080093366A CN115038700A CN 115038700 A CN115038700 A CN 115038700A CN 202080093366 A CN202080093366 A CN 202080093366A CN 115038700 A CN115038700 A CN 115038700A
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- phenyl
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- ethyl
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- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
本发明涉及调节异柠檬酸脱氢酶(IDH)的活性的某些偕二取代的杂环化合物。因此,本发明的化合物在治疗由突变的IDH1酶和/或突变的IDH2酶和/或IDH1野生型(wt)酶引起的疾病中是有用的。本发明还提供了用于制备这些化合物的方法、包含这些化合物的药物组合物以及利用包含这些化合物的药物组合物治疗疾病的方法。
Description
本发明涉及调节异柠檬酸脱氢酶(IDH)的活性的某些偕二取代的(gem-disubstituted)杂环化合物。因此,本发明的化合物在治疗由突变的IDH1酶和/或突变的IDH2酶和/或IDH1野生型(wt)酶引起的疾病中是有用的。本发明还提供了用于制备这些化合物的方法、包含这些化合物的药物组合物以及利用包含这些化合物的药物组合物治疗疾病的方法。
发明背景
异柠檬酸脱氢酶(IDH)代表细胞代谢中所涉及的金属依赖性氧化还原酶的家族。这些酶催化异柠檬酸氧化脱羧为α-酮戊二酸,在此过程中产生二氧化碳和NADH或NADPH。
已经确定了该家族的三个不同的成员:作为结构上相关的同源二聚体且使用NADP+作为电子受体的IDH1和IDH2,以及作为异源三聚体复合物且替代地使用NAD+作为电子受体的IDH3。
IDH1位于细胞质和过氧化物酶体中并且代表细胞的NADPH产生的主要来源,而IDH2位于线粒体中作为三羧酸循环(TCA)的组成部分。人类IDH1基因编码414个氨基酸的蛋白质,其氨基酸序列可以作为UniProtKB登录号O75874被找到。人类IDH2基因编码452个氨基酸的蛋白质,其氨基酸序列可以作为UniProtKB登录号P48735被找到。
异柠檬酸脱氢酶1(IDH1)的体细胞杂合突变在约80%的II–III级胶质瘤中和在继发性成胶质细胞瘤中被确定(参见Balss,J.Acta Neuropathol,2008,116,597–602,Watanabe,T.,Am.J.Pathol,2009,174,1149–1153,Yan,H.N.Engl.J.Med.2009,360,765–773)。IDH1突变还在50%的软骨肉瘤(参见Amary MF,J.Pathol 2011,224,334–43)中、在15%–20%的肝内胆管癌(参见Borger DR,Oncol.2012,17,72–9)中,以及以较低的频率(<5%)在其他实体瘤(例如成胶质细胞瘤、结肠直肠癌、食道癌、膀胱癌、黑素瘤、前列腺癌、乳腺腺癌)(参见Cerami E,Cancer Discov.2012,2,401–4)中被发现。
IDH1突变和IDH2突变还在许多造血肿瘤中被观察到,最常见地在10%-15%的急性骨髓性白血病(AML)(参见,例如Mardis ER,N Engl J.Med.2009,361,1058–66,Gross S,J.Exp.Med.2010,207,339–44,Marcucci G,J.Clin.Oncol.2010,28,2348–55)和20%的血管免疫母细胞性T细胞淋巴瘤(参见Cairns RA,Blood 2012,119,1901–3)中被观察到。
有趣的是,IDH1或IDH2的相同突变在患有奥利尔病(Ollier disease)和Maffucci综合征(非遗传性骨骼紊乱)的患者的大多数内生软骨瘤和梭形细胞血管瘤中被确定(参见Amary等人,Nature Genetics,2011,1261-1265;和Pansuriya TC,Nat.Genet.2011,43,1256–61)。
所有的突变已经在杂合子(heterozygosity)中以相互排斥的方式并且在特定组织中被发现。这些突变存在于负责2-氧代戊二酸配位的酶的催化结构域中,并且主要涉及IDH1中的Arg 132(R132)和IDH2中的Arg 140(R140)或Arg 172(R172),它们可以突变为不同的氨基酸。其他突变也在IDH1中被确定,尽管以非常低的频率(例如Arg 100和Gly 97;Dang L,Nature,2009,462,739-44)。在所有情况下,Arg到Cys、His、Lys、Leu或Ser的这些突变点消除了镁结合并且阻止了异柠檬酸到α-酮戊二酸的转化。相反,突变的酶获得了将α-酮戊二酸转化为R(-)-2-羟基戊二酸(R-2-HG)的新生变形活性(neomorphic activity)(参见P.S.Ward等人,Cancer Cell,2010,17,225)。一般来说,2-HG的产生是对映异构体特异性的,导致D-对映异构体(也被称为R对映异构体或R-2-HG)的产生。R(-)-2-羟基戊二酸被示出主要通过抑制若干种DNA和组蛋白脱甲基酶而充当致癌代谢物(oncometabolite)。细胞水平的结果是表观遗传重编程,导致不同的转录资产,这诱导脱分化和肿瘤发生。
在成胶质细胞瘤(GBM)以及其他实体和系统性癌症模型中,IDH1过表达被示出维持较少分化的肿瘤细胞状态(less differentiated tumor cell state)、促进生长、加速肿瘤进展和降低对RTK靶向疗法的易感性。在分子水平上,减弱的IDH1活性导致减少的α-酮戊二酸(α-KG)和NADPH产生、还原型谷胱甘肽的耗尽、增加的反应性氧物质(ROS)水平以及增强的组蛋白甲基化和分化标志物表达。用小分子进行的IDH1的药理学抑制(Pharmacological inhibition)减少GBM肿瘤负担并且增加PDX小鼠的存活率。这些数据还表明,癌症相关的IDH1上调代表一种可操作的(“可成药的”)促癌机制,并且为评价野生型IDH1抑制剂作为抗肿瘤剂提供理论基础(参见Calvert等人,2017,Cell Reports 19,1858–1873)。
因此,抑制IDH酶的活性是肿瘤和其他IDH相关的紊乱的潜在治疗性治疗选择。
因此,对于针对由突变的IDH酶和/或IDH wt功能过度(over-function)引起的和/或与突变的IDH酶和/或IDH wt功能过度相关的疾病有活性的治疗剂存在强烈的医学需求,并且一些努力正在进行以开发具有其α羟基新生变形活性的抑制剂,特别是小分子抑制剂。
某些具有生物学活性的作为激酶抑制剂的吡啶并-吡啶-7-酮衍生物在以Hoffmann La Roche的名义的WO2005/047284中公开。
其他可用作激酶抑制剂的吡啶并-嘧啶-7-酮化合物在以Exelixis Inc.的名义的WO2007044813和WO20087021389中、在以Warner Lambert Co的名义的WO1998/33798中和在以Deciphera Pharmaceuticals Lcc的名义的WO2008/034008中公开。
某些具有生物学活性的作为IDH抑制剂的嘧啶并-噁嗪-2-酮衍生物在以FormaTherapeutics的名义的WO2016/171755A1中公开。
本发明人现在已经发现,下文描述的式(I)的化合物是突变的IDH1酶和/或突变的IDH2酶和/或IDH1 wt酶的抑制剂,并且因此可用于治疗由高水平的2-HG引起的或由IDH wt功能过度引起的疾病。
因此,本发明的第一目的是式(I)的被取代的偕二取代的杂环衍生物:
其中:
X是氮或-CH-;
U是CH、CH2或CMe;
Y是CH、CF或O;
R1a、R1b各自独立地是氢、任选地被取代的直链或支链的(C1-C6)烷基,或者与它们结合至的原子一起可以形成(C3-C6)环烃基;
A是(C3-C6)环烃基、芳基或杂芳基;
R4是氢、卤素、氰基或任选地被取代的直链或支链的(C1-C6)烷基;
R5a和R5b各自独立地是选自任选地被取代的直链或支链的(C1-C6)烷基、(C3-C6)环烃基的基团,或者与它们结合至的原子一起可以形成3元至7元环基烷基或杂环基基团,所述3元至7元环基烷基或杂环基基团含有一个选自O、S、N-R6的杂原子;
其中:
R6是任选地被取代的直链或支链的(C1-C6)烷基、-COOR7或-COR8;
其中:
R7和R8是任选地被取代的直链或支链的(C1-C6)烷基;
M是键、NH、NR6或O,其中R6是根据上文所定义的;
G1是N、CH、CH2或CO;
Z1是CR9aR9b;
Z2是CR10aR10b;
其中:
R9a、R9b、R10a和R10b独立地是氢或任选地被取代的直链或支链的(C1-C6)烷基;
m1是1、2或3;
m2是0、1、2或3;
E是CN、或任选地被取代的直链或支链的(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基或式-COR11的基团;
其中:
R11是任选地被取代的直链或支链的(C2-C6)烷基或(C2-C6)烯基或(C2-C6)炔基;
R2是任选地被取代的选自以下的基团:直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基、芳基-(C1-C6)烷基和杂环基-(C1-C6)烷基;
R3是氢、氯、氰基、CONH2、NH2、NR12aR12b、OR13或任选地被取代的选自直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基、芳基和杂芳基的基团;
其中:
R12a、R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基;
R13是任选地被取代的直链或支链的(C1-C6)烷基;
或其药学上可接受的盐。
优选的式(I)的化合物是以下的化合物,其中:
Y是CH或O;
R3是氢、氯、氰基、CONH2、NH2、NR12aR12b、OR13或任选地被取代的选自直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基的基团;
其中:
R12a、R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基;
R13是任选地被取代的直链或支链的(C1-C6)烷基;
m1是1或2;
m2是0、1或2;并且
在一种实施方案中,更优选的式(I)的化合物是以下的化合物,其中:
A是芳基或杂芳基;
R4是氢、卤素或任选地被取代的直链或支链的(C1-C6)烷基;
R3是氢、氯、氰基、CONH2、NH2、NR12aR12b或任选地被取代的选自直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基的基团;
其中:
R12a、R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基;并且
在另一种实施方案中,更优选的式(I)的化合物是以下的化合物,其中:
R4是氢或卤素;
R3是氢、氯、氰基、CONH2、NH2、NR12aR12b或任选地被取代的选自直链或支链的(C1-C6)烷基的基团;
其中:
R12a、R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基;并且
在另一种实施方案中,更优选的式(I)的化合物是以下的化合物,其中:
R1a、R1b各自独立地是氢、直链或支链的(C1-C3)烷基,或者与它们结合至的原子一起可以形成环丙基基团;
A是苯基基团、吡啶基基团或嘧啶基基团;
R5a和R5b各自独立地是选自直链或支链的(C1-C6)烷基的基团,或者与它们结合至的原子一起可以形成3元至7元环基烷基或杂环基基团,所述3元至7元环基烷基或杂环基基团含有一个选自O或N-R6的杂原子;
其中:
R6是直链或支链的(C1-C6)烷基或COR8;
其中:
R8是直链或支链的(C1-C6)烷基;
R2是直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基;
R3是氢、氯、氰基、NH2、NR12aR12b或直链或支链的(C1-C6)烷基;并且
在另一种实施方案中,更优选的式(I)的化合物是以下的化合物,其中:
R1a、R1b各自独立地是氢、甲基、乙基,或者与它们结合至的原子一起可以形成环丙基基团;
A是苯基基团或吡啶基基团;
R4是氢;
R5a和R5b各自独立地是选自甲基或乙基的基团,或者与它们结合至的原子一起可以形成选自环戊基、环己基、4,4-二氟环己基的任选地被取代的(C3-C6)环烃基基团或选自吡喃基、氧杂环丁烯基、N-甲基哌啶基、N-乙酰基哌啶基的杂环基基团;
R2是甲基、乙基、异丙基或环戊基;
R3是氢、氰基、甲基、NH2、NHMe或N(Me)2;
优选的特定式(I)的化合物或其药学上可接受的盐是下文列出的化合物:
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 1);
2-{[(1S)-1-{4-[2-(4-丙烯酰基哌嗪-1-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 2);
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)氧杂环丁烷-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 3);
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)戊-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 4);
2-{[(1S)-1-(4-{4-[4-(丁-2-炔酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 5);
2-{[(1S)-1-{4-[1-乙酰基-4-(4-丙烯酰基哌嗪-1-基)哌啶-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 6);
2-{[4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-基]甲基}丙-2-烯酸(cpd 7);
2-{[(1S)-1-{4-[4-(4-丙酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 8);
2-{[(1R)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 9);
2-{[(1S)-1-(4-{4-[4-(2,3-二羟基丙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 10);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 11);
2-{[(1S)-1-{6-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-3-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 12);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-甲基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 13);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 14);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 15);
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)环戊基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 16);
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)四氢呋喃-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 17);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-5-甲基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 18);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-氨基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 19);
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 20);
2-{[(1S)-1-(4-{4-[4-(2-甲基丙烯酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 21);
2-{[(1S)-1-(4-{4-[4-(氯乙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 22);
2-{[(1S)-1-(4-{4-[4-(3-氯丙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 23);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(cpd 24);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-(丙-2-基)-1,4-二氢-2H-吡啶并[4,3-d][1,3]噁嗪-2-酮(cpd 25);
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 26);
2-{[(1S)-1-{5-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-2-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 27);
2-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 28);
2-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)氧基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 29);
2-[(1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}环丙基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 30);
2-({4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苄基}氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 31);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)-1-甲基哌啶-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 32);
2-{[(1S)-1-{4-[(2R)-2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 33);
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 34);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(戊-3-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 35);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-(二甲基氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 36);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-(甲基氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 37);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-4-甲腈(cpd 38);
2-{[(1S)-1-(4-{4-[(1-丙烯酰基哌啶-4-基)氧基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 39);
2-[(2-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}丙-2-基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 40);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-5-氨基-1-(丙-2-基)-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(cpd 41);
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)-1-(吗啉-4-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 42);
2-{[(1S)-1-{4-[(2R)-2-(4-丙烯酰基哌嗪-1-基)-1-(吗啉-4-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 43);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-吡啶并[4,3-d][1,3]噁嗪-2-酮(cpd 44);
7-{[(1S)-1-{4-[4-(4-乙基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(cpd 45);
2-{[(1S)-1-{4-[2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 46);
7-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 47);
7-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 48);
2-[(1-{4-[1-(4-丙烯酰基哌嗪-1-基)环戊基]苯基}环丙基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 49);
2-{[(1S)-1-(4-{1-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 50);
8-(丙-2-基)-2-({(1S)-1-[4-(4-{4-[(2H3)丙-2-烯酰基]哌嗪-1-基}四氢-2H-吡喃-4-基)苯基]乙基}氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 51);
2-[(2-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}丙-2-基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 52);
2-{[(1S)-1-(4-{1-[{1-[氯(氟)乙酰基]氮杂环丁烷-3-基}(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd53);
2-{[(1S)-1-(4-{4-[4-(2-氟丙烯酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 54);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-[(2H7)丙-2-基]吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 55);
N-{2-[(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)氨基]-2-氧代乙基}丙-2-烯酰胺(cpd 56);
N2-丙烯酰基-N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-D-丙氨酸酰胺(cpd 57);
N2-丙烯酰基-N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-L-丙氨酸酰胺(cpd 58);
N-{2-[(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)氨基]乙基}丙-2-烯酰胺(cpd 59);
7-{[(1S)-1-(4-{1-[4-(2,3-二羟基丙酰基)哌嗪-1-基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 60);
7-{[(1S)-1-(4-{1-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 61);
N-(1-丙烯酰基氮杂环丁烷-3-基)-N-(4,4-二氟-1-{4-[(1S)-1-{[2-氧代-1-(丙-2-基)-1,2-二氢-1,6-萘啶-7-基]氨基}乙基]苯基}环己基)乙酰胺(cpd62);
7-{[(1R)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 63);
2-{[(1S)-1-(4-{4,4-二氟-1-[4-(4-羟基丁基)哌嗪-1-基]环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 64);
4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲腈(cpd 65);
N-{2-[(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}丙-2-烯酰胺(cpd 66)以及
7-{[(1S)-1-{4-[4,4-二氟-1-(4-丙酰基哌嗪-1-基)环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 67)。
如果立体异构源中心(stereogenic center)或另一种形式的不对称中心存在于本发明的化合物中,则所有形式的这样的一种或更多种光学异构体,包括对映异构体和非对映异构体,意图被包括在本文中。包含立体异构源中心的化合物可以用作外消旋混合物、对映异构体富集的混合物(enantiomerically enriched mixture),或者外消旋混合物可以使用熟知的技术分离,并且可以使用单独的对映异构体。在其中化合物具有不饱和的碳-碳双键的情况下,顺式(Z)异构体和反式(E)异构体两者均在本发明的范围内。
在其中化合物可以以互变异构形式诸如酮-烯醇互变异构体存在的情况下,每种互变异构形式被预期为被包括在本发明内,无论是以平衡存在还是主要以一种形式存在。
式(I)的化合物的药学上可接受的盐包括与无机酸或有机酸的盐,所述无机酸或有机酸例如硝酸、盐酸、氢溴酸、硫酸、高氯酸、磷酸、乙酸、三氟乙酸、丙酸、乙醇酸、乳酸、草酸、富马酸、丙二酸、苹果酸、马来酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、羟乙磺酸和水杨酸。
式(I)的化合物的药学上可接受的盐还包括与无机碱或有机碱的盐,所述无机碱或有机碱例如碱金属或碱土金属,特别是钠、钾、钙、铵或镁的氢氧化物、碳酸盐或碳酸氢盐、无环胺或环状胺。
本发明的另外的目的是其中一个或更多个氢被一个或更多个氘原子替换的式(I)的化合物。
当m2是0时,我们的意图是基团Z2不存在,并且基团G1和N被氢饱和。
对于术语“(C1-C6)烷基”,我们意指可以是直链或支链的仅包含碳-碳单键的脂肪族(C1-C6)烃链。代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、正己基及类似基团。
对于术语“(C3-C6)环烃基(cycloalky)”,除非另有提供,否则我们意指3元至6元全碳单环,该3元至6元全碳单环可以含有一个或更多个双键,但不具有完全共轭的π-电子体系。
(C3-C6)环烃基基团的实例是但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基和环己二烯基。(C3-C6)环烃基环可以被任选地进一步稠合或连接至芳香族和非芳香族的碳环或杂环。
对于术语“杂环基”,我们意指3元至7元饱和的或部分不饱和的碳环,其中一个或更多个碳原子被诸如氮、氧和硫的杂原子替换。杂环基基团的非限制性实例是,例如吡喃基、四氢吡喃基、吡咯烷基、吡咯啉基、咪唑啉基、咪唑烷基、吡唑烷基、吡唑啉基、噻唑啉基、噻唑烷基、二氢呋喃基、四氢呋喃基、四氢吡啶基、1,3-二氧杂环戊烷基、哌啶基、哌嗪基、吗啉基及类似基团。杂环基环可以被任选地进一步稠合或连接至芳香族和非芳香族的碳环或杂环。
对于术语“(C2-C6)烯基”,我们意指含有至少一个碳-碳双键的脂肪族直链或支链的(C2-C6)烃链。代表性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基或2-丁烯基及类似基团。
对于术语“(C2-C6)炔基”,我们意指含有至少一个碳-碳三键的脂肪族直链或支链的(C2-C6)烃链。代表性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-丁炔基或2-丁炔基及类似基团。
对于术语“(C1-C6)烷氧基”,我们意指通过氧原子(-O-)连接至分子的其余部分的任何上文定义的(C1-C6)烷基。
术语“芳基”指的是任选地进一步稠合或通过单键彼此连接的具有从1个至4个环体系的单碳环烃、双碳环烃或多碳环烃,其中碳环中的至少一个是“芳香族的”,其中术语“芳香族的”指的是完全共轭的π-电子键体系。这样的芳基基团的非限制性实例是苯基基团、α-萘基基团或β-萘基基团、α-四氢萘基基团或β-四氢萘基基团、联苯基基团和茚满基基团。
术语“杂芳基”指的是芳香族的杂环,典型地具有从1个至3个选自N、O或S的杂原子的5元至7元杂环;杂芳基环可以被任选地进一步稠合或连接至芳香族和非芳香族的碳环和杂环。这样的杂芳基基团的非限制性实例是,例如,吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、咪唑基、噻唑基、异噻唑基、吡咯基、呋喃基、噁唑基、异噁唑基、吡唑基、噻吩基、噻二唑基、异噁唑基、异噻唑基、噁二唑基、吲唑基、噌啉基、苯并[1,3]间二氧杂环戊烯基、苯并[1,4]二噁英基、苯并噻唑基、苯并噻吩基、苯并呋喃基、异吲哚啉基、苯并咪唑基、苯并噁唑基、喹啉基、异喹啉基、1,2,3-三唑基、1-苯基-1,2,3-三唑基、2,3-二氢吲哚基、2,3-二氢苯并呋喃基、2,3-二氢苯并噻吩基、苯并吡喃基、2,3-二氢苯并噁嗪基、2,3-二氢喹喔啉基及类似基团。
对于术语“卤素”,我们意指氟、氯、溴或碘。
对于术语“多氟化的(C1-C6)烷基”或“多氟化的(C1-C6)烷氧基”,我们意指被多于一个氟原子取代的任何上文定义的(C1-C6)烷基基团或(C1-C6)烷氧基基团,诸如例如三氟甲基、三氟乙基、1,1,1,3,3,3-六氟丙基、三氟甲氧基及类似基团。
对于术语“羟基(C1-C6)烷基”,我们意指具有羟基基团的任何上文定义的(C1-C6)烷基基团,诸如例如羟甲基、2-羟乙基、3-羟丙基及类似基团。
根据本发明并且除非另有提供,否则R1a、R1b、R2、R3、R4、R5a、R5b、R9a、R9b、R10a、R10b和E可以在它们的任何自由位置被一个或更多个基团例如1个至6个基团任选地取代,所述一个或更多个基团独立地选自:羟基、羟基(C1-C6)烷基、卤素、硝基、氧代基团(=O)、氰基、(C1-C6)烷基、多氟化的(C1-C6)烷基、多氟化的(C1-C6)烷氧基、(C2-C6)烯基、(C2-C6)炔基、芳基、芳基(C1-C6)烷基、(C1-C6)烷基芳基、芳基(C1-C6)烷氧基、杂芳基、杂芳基(C1-C6)烷基、(C1-C6)烷基杂芳基、杂环基、杂环基(C1-C6)烷基、(C1-C6)烷基杂环基、(C1-C6)烷基杂环基(C1-C6)烷基、三(C1-C6)烷基甲硅烷基、(C3-C7)环烃基、(C1-C6)烷氧基、芳氧基、杂环基氧基、亚甲基二氧基、(C1-C6)烷基羰基氧基、芳基羰基氧基、二(C1-C6)烷基氨基杂环基(C1-C6)烷基、(C3-C7)环烯基氧基、杂环基羰基氧基、(C1-C6)亚烷基氨基氧基、羧基、(C1-C6)烷氧基羰基、芳氧基羰基、(C3-C7)环烃基氧基羰基、氨基、杂环基(C1-C6)烷氧基羰基氨基、脲基、(C1-C6)烷基氨基、氨基(C1-C6)烷基、二(C1-C6)烷基氨基、芳基氨基、二芳基氨基、杂环基氨基、甲酰基氨基、(C1-C6)烷基羰基氨基、芳基羰基氨基、杂环基羰基氨基、氨基羰基、(C1-C6)烷基氨基羰基、二(C1-C6)烷基氨基羰基、芳基氨基羰基、杂芳基氨基羰基、芳基氨基羰基(C1-C6)烷基、(C3-C7)环烃基氨基羰基、杂环基氨基羰基、(C1-C6)烷氧基羰基氨基、羟基氨基羰基、(C1-C6)烷氧基亚氨基、(C1-C6)烷基磺酰基氨基、芳基磺酰基氨基、杂环基磺酰基氨基、甲酰基、(C1-C6)烷基羰基、芳基羰基、(C3-C7)环烃基羰基、杂环基羰基、杂环基羰基(C1-C6)烷基、(C1-C6)烷基磺酰基、多氟化的(C1-C6)烷基磺酰基、芳基磺酰基、氨基磺酰基、(C1-C6)烷基氨基磺酰基、二(C1-C6)烷基氨基磺酰基、芳基氨基磺酰基、杂环基氨基磺酰基、芳基硫基、(C1-C6)烷基硫基;在任何适当的时候,上文的取代基中的每一个又可以进一步被前面提及的基团中的一个或更多个取代。
从上文的全部中,对于技术人员清楚的是,其名称是复合名称的任何基团,诸如例如“芳基氨基”,必须意图为常规地由其衍生自的部分来解释,例如由被芳基取代的氨基基团来解释,其中芳基是根据上文所定义的。
同样地,任何术语诸如例如(C1-C6)烷基硫基、(C1-C6)烷基氨基、二(C1-C6)烷基氨基、(C1-C6)烷氧基羰基、(C1-C6)烷氧基羰基氨基、杂环基羰基、杂环基羰基氨基、(C3-C7)环烃基氧基羰基及类似基团,包括其中(C1-C6)烷基部分、(C1-C6)烷氧基部分、芳基部分、(C3-C7)环烃基部分和杂环基部分根据上文所定义的基团。
本发明还提供了用于制备根据上文所定义的通式(I)的化合物的工艺,所述工艺通过使用下文所描述的反应路线和合成方案,采用本领域可获得的技术和可容易获得的起始材料进行。本发明的某些实施方案的制备在随后的实施例中被描述,但本领域普通技术人员将认识到所描述的制备可以容易地适于制备本发明的其他实施方案。例如,根据本发明的非示例性化合物的合成可以通过对本领域技术人员明显的修改来进行,例如通过适当地保护干扰基团、通过用本领域已知的其他试剂合适地替换试剂或通过对反应条件进行常规的修改来进行。可选择地,本文所提及的或本领域已知的其他反应将被认为对于制备本发明的其他化合物具有适应性。
本发明的化合物可以使用以下一般方法和程序由可容易获得的起始材料制备。除非另有指示,否则起始材料是已知化合物,或可以由已知化合物根据熟知的程序制备。应理解的是,在描述典型的或优选的工艺条件(即,反应温度、时间、反应物的摩尔比、溶剂、压力)的情况下,除非另有说明,否则还可以使用不同的工艺条件。最佳反应条件可以随着所使用的反应物或溶剂而变化,但这样的条件可以由本领域技术人员通过常规的优化程序来确定。
根据上文所定义的通式(I)的化合物可以根据方案1中描述的一般合成工艺从式(II)的中间体化合物开始制备:
方案1
步骤1a)使式(II)的化合物:
其中X是氮或-CH-;U是CH、CH2或CMe;Y是CH、CF或O;指示单键或双键;R2是任选地被取代的选自以下的基团:直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基、芳基-(C1-C6)烷基和杂环基-(C1-C6)烷基;R3是氢、氯、氰基、CONH2、NH2、NR12aR12b、OR13或任选地被取代的选自直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基、芳基和杂芳基的基团;其中:R12a、R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基;R13是任选地被取代的直链或支链的(C1-C6)烷基;R1a和R1b各自独立地是氢或任选地被取代的直链或支链的(C1-C6)烷基,或者与它们结合至的原子一起可以形成(C3-C6)环烃基;A是(C3-C6)环烃基、芳基或杂芳基;R4是氢、卤素、氰基或任选地被取代的直链或支链的(C1-C6)烷基;R5a和R5b各自独立地是选自任选地被取代的直链或支链的(C1-C6)烷基、(C3-C6)环烃基的基团,或者与它们结合至的原子一起可以形成3元至7元环基烷基或杂环基基团,所述3元至7元环基烷基或杂环基基团含有一个选自O、S、N-R6的杂原子;其中:R6是任选地被取代的直链或支链的(C1-C6)烷基、-COOR7或-COR8;其中:R7和R8是任选地被取代的直链或支链的(C1-C6)烷基;M是键、NH、其中R6是根据上文所定义的NR6、或O;G1是N、CH、CH2或CO;Z1是CR9aR9b;Z2是CR10aR10b;其中:R9a、R9b、R10a和R10b独立地是氢或任选地被取代的直链或支链的(C1-C6)烷基;m1是1、2或3,并且m2是0、1、2或3;
与式(III)的化合物反应:
其中E是CN或任选地被取代的直链或支链的(C1-C6)烷基、(C2-C6)烯基、或式-COR11的基团;R11是任选地被取代的直链或支链的(C2-C6)烷基或(C2-C6)烯基或(C2-C6)炔基;并且Q是羟基、或氯、或溴,以产生通式(I)的化合物,其中X、U、Y、R2、R3、R1a、R1b、A、R4、R5a、R5b、M、G1、Z1、Z2和E是根据上文所定义的。
根据上文所定义的通式(II)的化合物可以根据方案2中描述的一般合成工艺从式(IV)的中间体化合物开始制备:
方案2
因此,本发明的工艺包括以下步骤:
步骤2a)使式(IV)的化合物:
其中R1a、R1b、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据上文在步骤1a下所定义的,并且PG是选自甲酸叔丁酯、甲酸苄酯、甲酸苯酯的保护基团;
步骤2b)使式(VI)的化合物与合适的脱保护剂反应:
其中PG是根据上文在步骤2a中所定义的;
方案3
步骤3a)将式(VII)的中间体化合物的氯:
其中R3是氢、氯或任选地被取代的直链或支链的(C1-C6)烷基,用式(VIII)的胺中间体化合物进行取代:
R2-NH2
(VIII)
其中R2是根据上文在步骤1a中所定义的;
步骤3b)使式(IX)的化合物与还原剂反应:
其中R2和R3是根据上文所定义的;
步骤3c)使所得到的式(X)的化合物与合适的氧化剂试剂反应:
其中R2和R3是根据上文所定义的;
步骤3d)使所得到的式(XI)的化合物与其中T是氢或氟的式T-CH2COOEt(XIV)的试剂反应:
其中R2和R3是根据上文所定义的;
步骤3e)将所得到的式(XII)的中间体化合物与氧化剂试剂混合:
或
步骤3f)使式(X)的化合物与羰基二咪唑或三光气反应:
或
步骤3g)用其中Lg是溴、碘、-OMs、–OTs或羟基且R2是根据上文所定义的式R2-Lg(XV)的烷基化剂将式(XIII)的中间体化合物烷基化:
其中G是氯且R3、X、U、Y和R2是根据上文在步骤1a中所定义的式(IV)的化合物可以按照方案4制备:
方案4
步骤4a)将式(XVI)的中间体化合物的氯:
其中X和R3是根据上文在步骤1a中所定义的,用式(VIII)的胺中间体化合物进行取代:
R2-NH2
(VIII)
其中R2是根据上文在步骤1a中所定义的;
步骤4b)使式(XVII)的化合物与还原剂反应:
其中X、R3和R2是根据上文所定义的;
步骤4c)使所得到的式(XVIII)的化合物与合适的氧化剂试剂反应:
其中X、R3和R2是根据上文所定义的;
然后
步骤4d)使所得到的式(XIX)的化合物与其中T是氢或氟的式T-CH2COOEt(XIV)的化合物反应:
或
步骤4e)使所得到的式(XVIII)的化合物与羰基二咪唑或三光气反应:
如果需要,通过根据熟知的合成条件进行操作来将式(XII)的第一化合物转化为式(XII)的第二化合物。
可能的转化的实例是下文报告的那些:
转化A)按照本领域已知的关于芳基卤化物的钯催化的氰化的条件,通过与氰化物的来源反应来将其中R3是氯的式(XII)的化合物转化为其中R3是CN的式(XII)的化合物:
转化B)通过与胺PG-NH2反应来将其中R3是氯的式(XII)的化合物转化为其中R3是NHPG的式(XII)的化合物:
转化C)通过与其中R12a和R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基的胺HNR12aR12b反应来将其中R3是氯的式(XII)的化合物转化为其中R3是NR12aR12b的式(XII)的化合物:
转化D)通过与其中R13是任选地被取代的直链或支链的(C1-C6)烷基的醇R13-OH反应来将其中R3是氯的式(XII)的化合物转化为其中R3是OR13的式(XII)的化合物:
转化E)通过用合适的剂水解来将其中R3是氰基的式(XII)的化合物转化为其中R3是CONH2的式(XII)的化合物:
如果需要,通过根据熟知的合成条件进行操作来将式(IV)的第一化合物转化为式(IV)的第二化合物。
可能的转化的实例是下文报告的实例:
转化A1)通过用合适的试剂的两步顺序来将其中G是MeS(O)2-的式(IV)的化合物转化为其中G是–OTrif(三氟甲磺酸酯)的式(IV)的化合物:
其中R1a、R1b、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据上文在步骤1a中所报告的且PG是保护基团的式(V)的化合物可以按照下文报告的合成方案5制备:
方案5
步骤5a)在Ritter反应条件下使式(XX)的化合物与ClCH2CN反应:
其中W1是溴、氰基、COR1a且A、R4、R5a、R5b和R1a是根据上文在步骤1a中所定义的,随后用酸性条件、碱性条件或用硫脲对酰胺中间体进行脱保护,以获得式(XXI)的化合物。
步骤5b)使式(XXI)的氨基中间体:
其中W1、A、R4、R5a和R5b是根据上文在步骤5a中所定义的,与式(XXII)的化合物反应:
其中Z1、Z2、m1和m2是根据上文在步骤1a中所报告的,PG是保护基团,并且Hal是卤素,以产生式(XXIII)的化合物,其中W1、A、R4、R5a、R5b、Z1、Z2和PG是根据上文所定义的,m1和m2是1、2或3,G1是N,并且M是键;
或
步骤5b’)使式(XXI)的氨基中间体与式(XXIIa)的杂环基卤化物反应,
其中Z1、Z2、m1、m2和PG是根据上文在步骤5b中所报告的并且Hal是卤素,然后通过用甲醛或用合适的烷基醛衍生物的还原胺化或通过用合适的卤代酰基衍生物R8CO-hal的酰化或通过用其中R7和R8是根据在步骤1a中所定义的氯甲酸烷基酯衍生物R7OCO-Cl的反应来使所获得的中间体反应;以形成式(XXIII)的化合物,其中PG是根据上文所定义的,W1、A、R4、R5a、R5b、Z1、Z2、m1和m2是根据在步骤1a中所定义的,并且G1是CH且M是NR6,其中R6是根据在步骤1a中所定义的;
或
步骤5b”)使式(XXI)的氨基中间体与式(XXIIb)的被保护的氨基烷基反应
其中Z1、m1和PG是根据上文在步骤5b中所报告的并且FG是选自醛(-CHO)或羧酸(-COOH)的官能团,以产生式(XXIII)的化合物,其中m2是0,PG是根据上文所定义的,W1、A、R4、R5a、R5b、Z1和m1是根据在步骤1a中所定义的,G1是CH2或CO,并且M是NH或NR6,其中R6是根据在步骤1a中所定义的;
或
步骤5a’)使式(XX)的化合物:
其中W1、A、R4、R5a和R5b是根据上文在步骤5a中所定义的,与式(XXIIa)的杂环基卤化物反应:
其中Hal、Z1、Z2、m1、m2和PG是根据上文在步骤5b’中所定义的;以形成式(XXIII)的化合物,其中W1、A、R4、R5a、R5b是根据上文在步骤5a中所定义的;Z1、Z2、m1、m2和PG是根据上文在步骤5b’中所定义的;G1是CH并且M是O;
然后
步骤5c)使获自步骤5b或步骤5b’或步骤5b”或步骤5a’的式(XXIII)的化合物与乙基溴化镁和三氟化硼二乙醚反应:
其中W1是氰基,并且A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文所报告的,以给出期望的式(V)的化合物,其中A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文所定义的,并且R1a和R1b是相同的并且是根据在步骤1a中所定义的,或者R1a与R1b一起是环丙基;
或
步骤5c’)使获自步骤5b或步骤5b’或步骤5b”或步骤5a’的式(XXIII)的化合物与叔丁烷亚磺酰胺反应:
其中W1是COR1a,其中R1a和A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2、PG和R1a是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,以产生式(XXIV)的化合物,其中R1b是氢,并且R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2、PG和R1a是根据上文所定义的;
或
步骤5c”)使获自步骤5b或步骤5b’或步骤5b”或步骤5a’的式(XXIII)的化合物与叔丁烷亚磺酰胺反应:
其中W1是COR1a,并且A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2、PG和R1a是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,以产生式(XXV)的化合物;
然后
步骤5e)使所获得的式(XXV)的化合物与烷基格氏试剂反应:
其中R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,以给出期望的式(XXIV)的化合物;
最后
步骤5d)使根据步骤5c’或步骤5e中所描述获得的式(XXIV)的化合物与酸性脱保护试剂或与碘反应:
其中R1b、R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文在步骤5c’或步骤5e中所定义的,以给出期望的式(V)的化合物,其中R1b、R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据在步骤1a中所定义的并且PG是保护基团;
可选择地,式(XXIII)的化合物也可以通过将另一种式(XXIII)的化合物转化来获得,如下文的转化所描述的:
转化F)其中W1是氰基的式(XXIII)的化合物按照本领域已知的关于芳基卤化物的钯催化的氰化的条件,通过用氰化物的来源将获自步骤5b或步骤5b’或步骤5b”或步骤5a’的其中W1是溴的相应的式(XXIII)的化合物转化来获得;
转化G)其中W1是COR1a,其中R1a是根据在步骤1a中所定义的式(XXIII)的化合物通过用合适的烯醇醚有机金属衍生物将获自步骤5b或步骤5b’或步骤5b”或步骤5a’的其中W1是溴的式(XXIII)的化合物转化,随后水解来获得;
根据方案1制备的式(I)的化合物可以按照本领域技术人员熟知的程序进一步转化为另一种式(I)的化合物。
转化1)将其中E是丙烯酰胺基团的式(I)的化合物转化为其中E是二羟基丙酸基团的化合物
根据步骤1,式(II)的化合物与其中E是-COR11的式(III)的化合物的反应可以以多种方式和操作条件来完成,这在关于酰胺的制备的领域中是广泛已知的。作为实例,当使用酰氯时,反应这样进行:在合适的溶剂诸如例如DCM、THF、1,4-二氧六环、ACN或DMF或类似物中,在从约-10℃至回流的范围内的温度,并且持续合适的时间,例如从约30分钟至约96小时。反应在适当的质子清除剂诸如三乙胺、N,N-二异丙基乙胺或吡啶的存在下进行;或者当涉及羧酸时,反应这样进行:在偶联剂诸如例如2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU)、1,3-二环己基碳二亚胺、1,3-二异丙基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺、N-环己基碳二亚胺-N’-丙基甲基聚苯乙烯或N-环己基碳二亚胺-N’-甲基聚苯乙烯的存在下,在合适的溶剂诸如例如二氯甲烷、四氢呋喃、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺中,在从约-10℃至回流的范围内的温度,并且持续从约30分钟至约48小时的时间。所述反应任选地在合适的催化剂例如4-二甲基氨基吡啶的存在下或在另外的偶联剂诸如N-羟基苯并三唑的存在下进行。
可选择地,当E是任选地被取代的直链或支链的(C1-C6)烷基、(C2-C6)烯基时,式(II)的中间体的烷基化可以在合适的碱诸如Na2CO3、K2CO3、Cs2CO3、NaH、KH及类似物的存在下,在合适的溶剂诸如DMF、DMA、ACN、丙酮、THF及类似物中,在从0℃至回流的范围内的温度进行。
根据步骤2a,来自式(IV)的中间体的离去基团诸如甲基砜、甲基亚砜或氯或三氟甲磺酸酯被式(V)的基团的替换这样进行:使用有机碱诸如DIPEA,任选地用CsF作为反应促进剂,在合适的溶剂诸如ACN、DMSO、1,4-二氧六环中,并且在常规加热或微波辐照下从室温至90℃的范围内的温度,持续从1h至24h的范围内的时间;
可选择地,并且更特别地当G是氯并且X是-CH时,反应可以在本领域技术人员熟知的条件下完成。例如,卤化物可以通过以下置换:采用合适的钯源诸如PEPPSI预催化剂和碱诸如Cs2CO3的布赫瓦尔德-哈特维希胺化反应(Buchwald-Hartwig amination reaction),在溶剂诸如甲苯或ACN中,在常规加热或微波辐照下从60℃至110℃的范围内的温度,并且持续从1h至24h的范围内的时间。
根据步骤2b,当保护基团是氨基甲酸苯酯时,式(VI)的化合物的脱保护可以这样进行:在碱性条件下通过使用例如NaOH、KOH,在溶剂诸如乙醇、异丙醇、1,4-二氧六环中,在回流持续从6h至18h的范围内的时间。可选择地,当保护基团是Boc时,反应这样进行:在酸性条件诸如例如TFA、HCl及类似物下,在溶剂诸如DCM、1,4-二氧六环中,或者采用催化量的CuCl,在合适的溶剂诸如MeOH、EtOH或EtOH/水的混合物中,在从室温至回流的范围内的温度,并且持续从1h至约12h的范围内的时间。可选择地,当保护基团是氨基甲酸苄酯时,反应这样进行:采用Pd/C,在氢源诸如甲酸铵、环己烯、1,3-环己二烯的存在下,在合适的溶剂诸如EtOH或异丙醇中,在回流温度持续从1h至约18h的范围内的时间。
根据步骤3a,式(VII)的化合物的氯被式R2-NH2(VIII)的胺的取代可以这样进行:以纯形式,或在合适的碱诸如Na2CO3、K2CO3、Cs2CO3、TEA、DIPEA及类似物的存在下,在合适的溶剂诸如DMF、DMA、ACN、DMSO及类似物中,在从室温至回流的范围内的温度。
根据该工艺的步骤3b,将式(IX)的酯进行还原以获得式(X)的化合物可以以本领域熟知的不同方式和实验条件进行。可以使用还原剂诸如氢化铝锂或类似物,在合适的溶剂诸如THF中,在从0℃至室温的范围内的温度持续从2h至约24h。优选地,反应在室温在THF中用氢化铝锂方便地进行。
根据该工艺的步骤3c,将式(X)的中间体氧化成式(XI)的醛可以采用二氧化锰(II)、氯铬酸吡啶鎓、邻碘酰基苯甲酸(IBX)、过钌酸四丙基铵(TPAP)、4-甲基吗啉N-氧化物或次氯酸钠/TEMPO/Bu4NHSO4,在溶剂诸如DCM、ACN、THF、EtOAc、丙酮或氯仿中在室温进行。
根据步骤3d,式(XI)的中间体与式(XIV)的中间体的Claisen–Schmidt缩合可以这样进行:在合适的碱诸如Na2CO3、K2CO3、LiOH、Cs2CO3、叔丁醇钾、LiHMDS、KHMDS及类似物的存在下,在合适的溶剂诸如THF、DMF、DMA及类似物中,在从-50℃至回流的范围内的温度,在经典的热条件下或在微波设备中持续从1h至24h的范围内的时间。
根据步骤3e,将式(XII)的中间体的甲基硫基基团氧化以产生其中G是MeS(O)2-或MeS(O)的式(IV)的化合物可以这样进行:在本领域技术人员熟知的氧化剂诸如例如单过硫酸氢钾(oxone)或间氯过氧苯甲酸及类似物的存在下,在合适的溶剂诸如DCM中,或在室温持续从1h至16h的范围内的时间。
根据步骤3f,将式(X)的中间体在氨基甲酰化条件下环化成噁嗪-2-酮可以通过使用三光气、羰基二咪唑或光气在碱诸如DIPEA或TEA的存在下,在约-30℃至室温的温度持续从1h至6h的范围内的时间来完成。
根据步骤3g,式(XIII)的中间体被其中Lg是溴、碘、-OMs或-OTs的式(XV)的中间体的烷基化可以这样进行:在合适的碱诸如Na2CO3、K2CO3、Cs2CO3、NaH、KH及类似物的存在下,在合适的溶剂诸如DMF、DMA、ACN、丙酮、THF及类似物中,在从0℃至回流的范围内的温度。当使用其中Lg是羟基的式(XV)的中间体时,反应优先地这样进行:在Mitsunobu烷基化条件下,在合适的试剂诸如例如偶氮二甲酸二乙酯(DEAD)、偶氮二甲酸二异丙酯(DIAD)、偶氮二甲酸二叔丁酯(DBAD)、1,1’-(偶氮二羰基)二哌啶(ADDP)以及膦试剂诸如例如三甲基膦、三叔丁基膦、三苯基膦及类似物的存在下,在合适的溶剂诸如THF、DMF、DCM、甲苯及类似物中,在从0℃至65℃的范围内的温度。
根据步骤4a,式(XVI)的化合物的氯被式(VIII)的胺的取代可以根据上文在步骤3a中所描述地进行。
根据该工艺的步骤4b,将式(XVII)的酯还原以获得式(XVIII)的化合物可以根据上文在步骤3b中所描述地进行。
根据该工艺的步骤4c,将式(XVIII)的中间体氧化成式(XIX)的醛可以根据上文在步骤3c中所描述地进行。
根据步骤4d,式(XIX)的化合物在步骤3d中报告的Claisen–Schmidt缩合条件下环化,以便提供其中G是氯且X是氮或-CH-的式(IV)的化合物。
根据步骤4e,式(XVIII)的化合物在步骤3f中报告的氨基甲酰化成噁嗪-2-酮的条件下环化,以便提供其中G是氯且X是氮或-CH-,U是CH2,Y是O的式(IV)的化合物。
根据该工艺的转化A,式(XII)的杂芳基氯化物可以以本领域已知的不同的方式和实验条件与氰化物的来源诸如氰化钠、氰化钾按照亲核芳香族取代反应,或者可选择地通过以下反应:使用ZnCN、CuCN或六氰高铁酸钾(II)作为氰化物的来源,在作为催化剂的乙酸钯(II)、作为碱的碳酸钠、碳酸钾或碳酸铯的存在下,在合适的溶剂诸如DMF、N-甲基吡咯烷酮或DMA中,从80℃至回流,持续从4小时至约24小时的范围内的时间(J.Org.Chem.2005,70,1508-1510,Org.Lett.,2011,13(4),第648–651页,Org Lett.2015 17(2),第202–205页)。
根据该工艺的转化B,式(XII)的杂芳基氯化物可以以不同的方式和实验条件与胺PG-NH2在乙腈中在回流下反应持续从1小时至约24小时的范围内的时间。
根据该工艺的转化C,式(XII)的杂芳基氯化物可以以不同的方式和实验条件与式NR12aR12b的胺在合适的溶剂诸如乙腈、DMF、DMA中从rt至回流反应持续从2小时至约24小时的范围内的时间。
根据该工艺的转化D,式(XII)的杂芳基氯化物可以以不同的方式和实验条件与式OR13的醇在合适的溶剂诸如乙腈、THF中在碳酸钾、碳酸铯的存在下从rt至回流反应持续从2小时至约24小时的范围内的时间。
根据该工艺的转化E,式(XII)的杂芳基腈可以与乙酰胺在1,4-二氧六环的存在下在添加Pd(OAc)2的情况下在回流下反应持续从4h至约24h的范围内的时间。
根据该工艺的转化A1,式(IV)的化合物到相应的式(IV)的三氟甲磺酸酯衍生物的转化可以以本领域已知的不同的方式和实验条件来完成。式(IV)的化合物首先与NaOH、KOH或类似物在合适的溶剂诸如水、乙腈、二氧六环、DMSO中从室温至90℃反应持续从1h至约4h的范围内的时间。然后,所获得的羟基衍生物与三氟甲磺酸酐或N-苯基双(三氟甲磺酰基)亚胺(N-phenyltriflimide)在碱诸如DIPEA、TEA、2,6-二甲基吡啶的存在下,在溶剂诸如DCM、THF中,在约-10℃至室温的温度反应持续从1h至6h的范围内的时间。
根据该工艺的步骤5a,式(XX)的化合物到式(XXI)的衍生物的转变可以在腈的酸诱导的亲核加成下完成,随后水解成相应的酰胺。该反应被熟知为Ritter反应,并且用H2SO4和氯乙腈在从0℃至20℃的范围内的温度进行持续6h至12h。如此获得的酰胺与硫脲在乙醇和乙酸中在60℃进一步反应持续6h至12h,以产生式(XXI)的衍生物。
根据步骤5b,式(XXI)的化合物与合适的式(XXII)的被取代的烷基二卤化物反应以给出相应的式(XXIII)的衍生物使用溶剂诸如DIPEA在添加NaI的情况下在回流下持续24h至72h来完成。
根据步骤5a’,式(XX)的化合物与合适的式(XXIIa)的被取代的杂环基卤化物的反应通过使用合适的碱诸如NaH、K2CO3、Cs2CO3、LiHMDS,在合适的溶剂诸如DMF、乙腈、THF、DIPEA中在添加NaI的情况下,在从rt至回流的范围内的温度并且持续从4h至约24h的范围内的时间来完成,以给出相应的式(XXIII)的衍生物。
根据步骤5b’,式(XXI)的化合物与合适的式(XXIIa)的被取代的杂环基卤化物的反应通过以下来完成:使用合适的碱诸如NaH、K2CO3、Cs2CO3、LiHMDS,在合适的溶剂诸如DMF、乙腈、THF、DIPEA中在添加NaI的情况下,在从rt至回流的范围内的温度,并且持续从4h至约24h的范围内的时间。
可选择地,式(XXI)的化合物与合适的式(XXIIa)的杂环基酮的反应在作为合适的催化剂的四乙氧基钛或四异丙氧基钛的存在下在合适的溶剂诸如THF、甲苯、1,4-二氧六环中在从70℃至回流的范围内的温度持续从16h至24h的范围内的时间来完成。将所获得的中间体直接用还原剂诸如NaCNBH3(氰基硼氢化钠)在从20℃至70℃的范围内的温度处理持续从1小时至4小时的范围内的时间,以产生中间体化合物,然后该中间体化合物在还原胺化条件中与甲醛或烷基醛在还原剂诸如NaCNBH3、NaBH(OAc)3及类似物的存在下,在溶剂诸如MeOH、EtOH、2,2,2-三氟乙醇及类似物中,在从rt至40℃的范围内的温度反应并且持续从1h至约24h的范围内的时间。所述还原反应可以任选地在合适的催化剂诸如AcOH、TFA及类似物的存在下进行,或者与合适的卤代酰基衍生物在溶剂诸如DCM、THF、DMF及类似物中,任选地在碱的存在下,在从rt至40℃的范围内的温度反应并且持续从1h至约24h的范围内的时间,或者与氯甲酸烷基酯衍生物在溶剂诸如DCM、THF、DMF、二氧六环及类似物中,任选地在碱的存在下,在从rt至40℃的范围内的温度反应并且持续从1h至约24h的范围内的时间,以产生式(XXIII)的化合物。
根据步骤5b”,式(XXI)的化合物与式(XXIIb)的被保护的氨基烷基醛的反应通过使用还原剂诸如NaCNBH3(氰基硼氢化钠)、NaBH(OAc)3(三乙酰氧基硼氢化钠),在溶剂诸如DCM、THF及类似物中在从20℃至50℃的范围内的温度持续从1小时至4小时的范围内的时间来完成。所述还原反应可以任选地在合适的催化剂诸如AcOH、TFA的存在下进行,以产生中间体化合物,该中间体化合物与三氟乙酸酐在吡啶及类似物的存在下在室温进一步反应并且持续从1h至约24h的范围内的时间,以产生式(XXIII)的化合物。
可选择地,式(XXI)的化合物与其中FG是-COOH的式(XXIIb)的被保护的氨基烷基羧酸的反应可以以多种方式和操作条件来完成,这在关于酰胺的制备的领域中是广泛已知的。作为实例,反应这样进行:在偶联剂诸如例如2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)、1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化物六氟磷酸盐(HATU)、T3P(1-丙烷膦酸酐)的存在下,在合适的溶剂诸如例如二氯甲烷、四氢呋喃、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、乙酸乙酯中,在从约-10℃至回流的范围内的温度,并且持续从约30分钟至约48小时的时间。
根据步骤5c,使式(XXIII)的化合物经历Kulinkovich-Szymoniak反应,该Kulinkovich-Szymoniak反应允许通过乙基格氏试剂在化学计量量的异丙醇钛(IV)的存在下反应制备伯环丙胺,并且在随后的步骤中暴露于三氟化硼二乙醚。反应在二乙醚、甲基叔丁基醚(MTBE)中在从-70℃至0℃的范围内的温度进行持续从1小时至4小时的范围内的时间,以给出相应的式(V)的衍生物。
根据步骤5c’,式(XXIII)的化合物与叔丁烷亚磺酰胺在作为合适的催化剂的四乙氧基钛或四异丙氧基钛的存在下在合适的溶剂诸如THF、甲苯、1,4-二氧六环中在从50℃至回流的范围内的温度反应持续从4h至16h的范围内的时间。将所获得的中间体直接用还原剂诸如NaBH4(硼氢化钠)、三仲丁基硼氢化锂(L-selectride)在从-70℃至0℃的范围内的温度处理持续从1小时至4小时的范围内的时间,以产生式(XXIV)的化合物。
根据步骤5c”,式(XXIII)的化合物与叔丁烷亚磺酰胺在作为合适的催化剂的四乙氧基钛或四异丙氧基钛的存在下在合适的溶剂诸如THF、甲苯、1,4-二氧六环中在从50℃至回流的范围内的温度反应持续从4h至16h的范围内的时间。
根据步骤5e,式(XXV)的化合物与甲基格氏试剂或乙基格氏试剂在二乙醚或THF中在从0℃至室温的范围内的温度反应持续1h至4h,以给出式(XXIV)的化合物。
根据步骤5d,式(XXIV)的化合物与强酸诸如例如盐酸在1,4-二氧六环中或在甲醇中在室温反应持续从1小时至24小时的范围内的时间,以产生式(V)的化合物。
可选择地,式(XXIV)的化合物与碘在溶剂诸如THF和H2O的混合物中在从室温至80℃的范围内的温度反应持续从1小时至24小时的范围内的时间,以产生式(V)的化合物。
可能的转化的实例在下文报告:
根据转化F,式(XXIII)的化合物与合适的氰化物的来源诸如ZnCN、CuCN、K3[Fe(CN)6]或类似物在合适的钯催化剂诸如Pd(OAc)2、PdCl2(PPh3)3、Pd(dppf)Cl2及类似物的存在下反应。反应这样进行:在合适的碱诸如碳酸钠、碳酸钾或碳酸铯及类似物的存在下,在溶剂诸如THF、二氧六环、DMF、乙腈中,在从80℃至回流的范围内的温度,持续从4小时至约24小时的范围内的时间。
根据转化G,式(XXIII)的化合物与合适的烯醇醚有机金属衍生物诸如1-乙氧基乙烯基三正丁基锡在合适的钯催化剂诸如PdCl2(PPh3)3、Pd(dppf)Cl2及类似物的存在下交叉偶联。反应这样进行:在合适的碱诸如TEA、DIPEA及类似物的存在下,在从r.t.至回流的范围内的温度,持续从1小时至约24小时的范围内的时间。如此获得的中间体用含水HCl 6N在室温进一步水解持续从1h至约24h的范围内的时间,以产生式(V)的化合物。
根据转化1),式(I)的丙烯酰胺与四氧化锇在吡啶和叔丁醇中(如在WO211046964中所报告的)在室温反应持续从8小时至24小时的范围内的时间。
从上文的全部中,对于技术人员清楚的是,具有可以被进一步衍生为另一种官能团的官能团的式(I)的任何化合物意图被包括在本发明的范围内,衍生通过根据本领域熟知的方法运作从而得到式(I)的其他化合物。
当根据所述工艺的任何以上变体制备通式(I)的化合物时,在起始材料、试剂或其中间体内的且可能产生不希望的副反应的任选的官能团需要根据常规技术被适当地保护(参见例如,Green,Theodora W.和Wuts,Peter G.M.–Protective Groups in OrganicSynthesis,第四版,John Wiley&Sons Inc.,New York(NY),2012)。同样地,将这些经保护的化合物转化成游离的脱保护的化合物可以根据已知的程序进行。
每一个通式的化合物可以根据文献中熟知的方法被进一步转变成相同通式的其他化合物,如实验部分中所报告的。
根据用于制备式(I)的化合物的工艺的任何变体,起始材料和任何其他反应物是已知的或根据已知方法被容易地制备。
其中R3是氯的式(XI)的中间体根据在WO2016204429A1中所报告地制备。
式(XXI)的化合物也可以根据在Tetrahedron,第72卷,2016,1941-1953中所描述地制备。
式(XX)的化合物可以根据在WO2014086316中所描述地制备。
式(XXII)的化合物可以根据在WO2009065622A1中所描述地制备。
式(III、VII、VIII、XII、XIV、XV、XVI、XXIIa、XXIIb)的化合物是可商购的或者可以用已知的方法制备。
最终化合物可以使用常规程序来分离和纯化,例如色谱法和/或结晶和盐形成。
根据上文所定义的通式(I)的化合物可以被转化为药学上可接受的盐。根据上文所定义的通式(I)的化合物或其药学上可接受的盐可以随后与药学上可接受的载体或稀释剂一起配制,以提供药物组合物。
根据上文所描述的合成工艺,通式(I)的化合物的合成可以以逐步的方式进行,由此,如果需要,在进行后续反应之前,通过标准纯化技术如例如柱色谱法来分离和纯化每一种中间体。可选择地,合成顺序的两个或更多个步骤可以以如本领域已知的所谓的“一锅”程序进行,由此仅分离和纯化由两个或更多个步骤得到的化合物。
在其中通式(I)的化合物含有一个或更多个不对称中心的情况下,所述化合物可以通过本领域技术人员已知的程序分离成单一立体异构体。这样的程序包括标准色谱技术或结晶,标准色谱技术包括使用手性固定相的色谱法。用于分离含有一个或更多个不对称中心的化合物的一般方法例如在Jacques,Jean;Collet,André;Wilen,Samuel H.,Enantiomers,Racemates,and Resolutions,John Wiley&Sons Inc.,New York(NY),1981中被报告。
本发明还提供了治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的方法,该方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
此外,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的方法中使用,该方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
此外,本发明提供了包含式(I)的化合物或其药学上可接受的盐的药物组合物,用于治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病,其包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
在还另一个方面中,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐在制造用于治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的药物中的用途,其包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
另外,本发明提供了治疗由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDH wt功能过度相关的疾病的方法,该方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
此外,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDH wt功能过度相关的疾病的方法中使用,该方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
此外,本发明提供了包含式(I)的化合物或其药学上可接受的盐的药物组合物,用于治疗由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDH wt功能过度相关的疾病,其包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
在还另一个方面中,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐在制造用于治疗由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDH wt功能过度相关的疾病的药物中的用途,其包括向有相应需要的哺乳动物、优选地人类施用有效量的根据上文所定义的式(I)的化合物。
优选地,所述疾病选自由以下组成的组:癌症、细胞增殖性紊乱、免疫相关的紊乱。更优选地,所述疾病是癌症。
根据本发明的最优选的实施方案,所述癌症选自由以下组成的组:癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、包括小细胞肺癌的肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌以及包括鳞状细胞癌的皮肤癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤(Burkitt's lymphoma);骨髓系造血肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括胶质瘤、成胶质细胞瘤、多形性成胶质细胞瘤、星形细胞瘤、少突神经胶质瘤、副神经胶质瘤、成神经细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角膜黄瘤(keratoxanthoma)、诸如甲状腺乳头状癌和甲状腺髓样癌的甲状腺癌、卡波西肉瘤、软骨肉瘤和胆管癌。
其他优选的由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDHwt功能过度相关的疾病是细胞增殖性紊乱,诸如例如良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤病、银屑病、与动脉粥样硬化相关的血管平滑肌细胞增殖、肺纤维化、关节炎、肾小球肾炎以及手术后狭窄和再狭窄。
另外的优选的由突变的IDH酶或增加的2-羟基戊二酸水平引起的和/或与突变的IDH酶或增加的2-羟基戊二酸水平相关的疾病是例如奥利尔病和Maffucci综合征。
另外优选的由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDHwt功能过度相关的疾病是免疫相关的紊乱,包括但不限于:移植排斥、皮肤紊乱如银屑病、过敏、哮喘和自身免疫介导的疾病诸如类风湿性关节炎(RA)、系统性红斑狼疮(SLE)、克罗恩病和肌萎缩性侧索硬化症。任选地,本发明的方法还包括与放射疗法或化学疗法方案组合治疗有相应需要的哺乳动物。
此外,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐,用于在与放射疗法组合或与化学疗法方案组合治疗有相应需要的哺乳动物的方法中使用。
在一种实施方案中,化学疗法方案包括至少一种细胞抑制剂或细胞毒素剂。
细胞抑制剂或细胞毒素剂包括但不限于抗生素类剂、烷基化剂、抗代谢剂、激素剂、免疫剂、干扰素类剂、环氧合酶抑制剂(例如COX-2抑制剂)、基质金属蛋白酶抑制剂、端粒酶抑制剂、酪氨酸激酶抑制剂、抗生长因子受体剂、抗HER剂、抗EGFR剂、抗血管生成剂(例如血管生成抑制剂)、法呢基转移酶抑制剂、ras-raf信号转导通路抑制剂、细胞周期抑制剂、其他cdk抑制剂、微管蛋白结合剂、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、芳香化酶抑制剂、驱动蛋白的抑制剂、治疗性单克隆抗体、mTOR的抑制剂、组蛋白脱乙酰酶抑制剂、低氧响应的抑制剂、PD-1拮抗剂或特异性地结合至PD-1或PD-L1的其抗原结合片段。
如果配制为固定剂量,则这样的组合产品采用在下文所描述的剂量范围内的本发明的化合物和在被批准的剂量范围内的其他药学活性剂。
当组合制剂不合适时,式(I)的化合物可以与已知的抗癌剂依次地使用。
适合于施用至哺乳动物例如人类的本发明的式(I)的化合物可以通过常规途径施用,并且剂量水平取决于患者的年龄、重量和状况以及施用途径。
例如,口服施用式(I)的化合物所采用的合适的剂量可以在每剂从约10mg至约1000mg,每日从1次至5次的范围内。本发明的化合物可以以多种剂型被施用,例如口服地,以片剂、胶囊、糖或膜包衣的片剂、液体溶液或悬浮液的形式;直肠地,以栓剂的形式;肠胃外地,例如肌内地,或通过静脉内和/或鞘内和/或脊柱内的注射或输注。
包含本发明的化合物的药物组合物通常按照常规方法来制备,并且以合适的药物形式被施用。
例如,固体口服形式可以包含与活性化合物一起的稀释剂,例如乳糖、右旋糖、蔗糖(saccharose)、蔗糖(sucrose)、纤维素、玉米淀粉或马铃薯淀粉;润滑剂,例如二氧化硅、滑石粉、硬脂酸、硬脂酸镁或硬脂酸钙和/或聚乙二醇;粘合剂,例如淀粉、阿拉伯胶、明胶、甲基纤维素、羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂,例如淀粉、海藻酸、海藻酸盐或羟基乙酸淀粉钠;泡腾混合物;染料;甜味剂;润湿剂,诸如卵磷脂、聚山梨醇酯、月桂基硫酸酯/盐(laurylsulphate);以及通常用于药物制剂的无毒且药理学上无活性的物质。这些药物制品可以以已知的方式来制造,例如借助于混合工艺、制粒工艺、压片工艺、糖包衣工艺或膜包衣工艺。
用于口服施用的液体分散体可以是例如糖浆、乳剂和悬浮液。
作为实例,糖浆可以包含作为载体的蔗糖或与甘油和/或甘露醇和山梨醇一起的蔗糖。
作为载体的实例,悬浮液和乳剂可以包含天然树胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇。
用于肌内注射的悬浮液或溶液可以包含与活性化合物一起的药学上可接受的载体,例如无菌水、橄榄油、油酸乙酯、二醇例如丙二醇,以及如果需要,合适量的盐酸利多卡因。
用于静脉内注射或输注的溶液可以包含作为载体的无菌水,或者优选地它们可以呈无菌溶液、水溶液、等渗溶液、盐水溶液的形式,或它们可以包含丙二醇作为载体。
栓剂可以包含与活性化合物一起的药学上可接受的载体,例如可可脂、聚乙二醇、聚氧乙烯脱水山梨醇脂肪酸酯表面活性剂或卵磷脂。
本发明还提供了药物组合物,该药物组合物包含治疗有效量的根据上文所定义的式(I)的化合物或其药学上可接受的盐以及至少一种药学上可接受的赋形剂、载体或稀释剂。
本发明还提供了式(I)的化合物的药物组合物,该药物组合物还包含一种或更多种化学治疗剂。化学治疗剂包括但不限于细胞抑制剂或细胞毒素剂、抗生素类剂、烷基化剂、抗代谢剂、激素剂、免疫剂、干扰素类剂、环氧合酶抑制剂(例如COX-2抑制剂)、基质金属蛋白酶抑制剂、端粒酶抑制剂、酪氨酸激酶抑制剂、抗生长因子受体剂、抗HER剂、抗EGFR剂、抗血管生成剂(例如血管生成抑制剂)、法呢基转移酶抑制剂、ras-raf信号转导通路抑制剂、细胞周期抑制剂、其他cdk抑制剂、微管蛋白结合剂、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂、芳香化酶抑制剂、驱动蛋白的抑制剂、治疗性单克隆抗体、mTOR的抑制剂、组蛋白脱乙酰酶抑制剂、低氧响应的抑制剂、PD-1拮抗剂或特异性地结合至PD-1或PD-L1的其抗原结合片段以及类似物。
此外,本发明提供了用于抑制突变的IDH蛋白质活性的体外方法,该方法包括使所述蛋白质与有效量的根据上文所定义的式(I)的化合物接触。
另外,本发明提供了一种产品,该产品包含作为组合制品用于在抗癌疗法中同时、分开或依次使用的根据上文所定义的式(I)的化合物或其药学上可接受的盐以及一种或更多种化学治疗剂。
在还另一个方面中,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐,用于作为药物使用。
最后,本发明提供了根据上文所定义的式(I)的化合物或其药学上可接受的盐在制造具有抗癌活性的药物中的用途。
实验部分
本文使用的简短形式和缩写具有以下含义:
生化测定
IDH1m(R132H或R132C)和IDH2R172K抑制剂的体外测定
将α-酮戊二酸转化为2-羟基戊二酸的IDH突变的酶活性使用NADPH消耗测定来测量。在测定中,在反应结束时,在添加催化过量的心肌黄酶和刃天青(resazurin),以产生与剩余NADPH的量成比例的荧光信号的情况下测量剩余辅因子(remaining cofactor)。IDH1WT酶以及突变亚型IDH1R132H酶、IDH1R132C酶和IDH2R172K酶是可商购的蛋白质(参见例如SinoBiological,Abcam,Active Motif or Creative BioMart)。
将IDH1R132H同源二聚体酶在10μL的测定缓冲液(150mM NaCl,50mM Tris-HCl pH7.6,10mM MgCl2,0.001%Triton X-100,4mMβ-巯基乙醇)中稀释至8nM;添加0.2μL的测试化合物,该测试化合物之前在DMSO中从1mM连续地稀释1至3倍,>10个实验点,并且将混合物在室温孵育持续15分钟。以添加10μL的底物混合物(在测定缓冲液中的12μMNADPH、3.4mMα-酮戊二酸)来启动反应,并且将混合物在室温孵育持续60分钟。反应以添加5μl的检测缓冲液(在IX测定缓冲液中的100μg/mL心肌黄酶、30μM刃天青)终止,并且在作为读板器的ViewLux上在Ex544/Em590处读取之前孵育持续15分钟。
按照与上文相同的测定对化合物的针对IDH1R132C的活性进行测定,具有以下修改:测定缓冲液中IDH1R132C和α-酮戊二酸的最终浓度分别为2nM和0.14mM。
按照与上文相同的测定对化合物的针对IDH2R172K的活性进行测定,具有以下修改:测定缓冲液中IDH2R172K和α-酮戊二酸的最终浓度分别为16nM和0.55mM。
IDH1野生型(wt)的酶测定
将异柠檬酸转化为α-酮戊二酸的IDH1 WT酶活性使用NADPH形成测定来测量。在测定中,在添加催化过量的心肌黄酶和刃天青,以产生与NADPH形成的量成比例的荧光信号的情况下连续测量形成辅因子(forming cofactor)。
将化合物与酶预孵育,然后通过添加NADP+、异柠檬酸、心肌黄酶和相应的底物刃天青来启动反应。心肌黄酶将刃天青还原为高度荧光的试卤灵,伴随NADPH氧化为NADP。具体地,将0.2μL的测试化合物(之前在DMSO中从1mM连续地稀释1至3倍,10个实验点)添加至在10μL的测定缓冲液(150mM NaCl,50mM Tris-HCl pH 7.6,10mM MgCl2,0.001%TritonX-100,4mMβ-巯基乙醇)中的0.016nM IDH1 WT酶;将混合物在室温孵育持续15分钟。以添加10μL的底物混合物(在测定缓冲液中的400μM NADP+、40μM异柠檬酸、5μg/mL心肌黄酶和7μM刃天青)来启动反应,将混合物在室温孵育,并且连续地在作为读板器的ViewLux上在Ex544/Em590处读取反应。
生化活性
根据上文描述的测定确定的代表性化合物对突变体IDH1R132H、IDH1R132C和IDH2R172K的生化效力在表1中作为IC50值(μM)被报告,而根据上文描述的测定确定的对IDH1野生型酶的生化效力在表2中作为IC50值(μM)被报告。
表1
表2
IDHm抑制剂的细胞测定
细胞系HT-1080(可商购的)被保持在E-MEM 10%FCS中,并且在37℃在加湿的5%CO2气氛中孵育。
将细胞以500个细胞/孔的密度接种到96孔黑色平底板中的100μL完全培养基中。在24小时之后,培养基用200μL的新鲜培养基替换,并且使用D300E数字分配器(Tecan)将化合物(溶解于DMSO中)施用至细胞。
在孵育72小时之后,从每个孔中收集100μL,并且用于2HG(R(-)-2-羟基戊二酸)定量。
细胞培养基中的2-HG的水平通过LC-MS/MS来确定。细胞上清液(100μL/孔)在96孔板中用含130μM的内标2-HG-d3的1M含水三氯乙酸(20μL/孔)处理。将板密封,温和地涡旋持续60分钟,以4,000RPM离心持续15分钟,放置在冷藏自动进样器中,注意不要摇动它们,并且将样品的上部的等分试样直接注射在色谱系统中。校准标准品通过用空白细胞培养基将含水2-HG储备溶液十倍稀释来获得,并且准确地以与上文关于样品所描述相同的方式变性。样品和标准品通过在用0.15%含水甲酸洗脱并且在运行结束时用90%甲醇短暂地洗涤的C18柱上的反相色谱法来测定2-HG。2-HG用监测MRM转换147>129(2-HG)和150>132(2-HG-d3)的基于三重四极杆质谱仪的内标方法通过负离子电喷雾电离来确定。
2-HG抑制通过使用Assay Explore(Symyx)软件比较经处理的数据相对于对照数据来计算,其中IC50是使用S形拟合算法确定的。
表3报告了根据上文描述的测定所确定的代表性化合物在细胞系HT-1080(IDH1R132C)中对2HG产生的抑制的IC50值(μM)。
表3
根据表3中报告的,当在具有突变形式的IDH1的细胞系中测试时,本发明的代表性化合物示出对2-HG的细胞产生的剂量依赖性抑制,具有低于5μM的效力。如所预期的,即使在最高剂量(10μM),化合物示出对细胞增殖的任何作用。
式(I)的化合物的制备
关于任选地呈药学上可接受的盐的形式的本发明的式(I)的任何特定的化合物,参见实验部分和权利要求。参考以下实施例,本发明的化合物使用本文所描述的方法或本领域熟知的其他方法合成。
以更好地说明本发明为目的,而不对本发明造成任何限制,给出以下实施例。
如本文中所使用的,在工艺、方案和实施例中所使用的符号和惯例与当代科学文献例如Journal of the American Chemical Society或Journal of BiologicalChemistry中使用的符号和惯例一致。
化合物名称是通过使用ACD Name(通过Advanced Chemistry Development,Inc.)生成的IUPAC名称。
除非另有说明,否则所有材料,包括无水溶剂诸如DMF、THF、DCM,从商业供应商获得,具有最好的等级并且在不进一步纯化的情况下使用。所有涉及空气敏感的化合物或水分敏感的化合物的反应在氮气或氩气气氛下进行。
一般纯化和分析方法
快速色谱法在硅胶(Merck等级9395,60A)上进行。
HPLC设备由Waters AllianceTM HT 2795系统组成,所述系统配备有Waters 996PDA检测器和配备有电喷雾(ESI)离子源的Waters mod.ZQ 2000单四极杆质谱仪。仪器控制、数据采集和数据处理通过Empower 2软件和MassLynx 4.1软件提供。
HPLC使用YMC-Triart C18(4.6×50mm,3μm)柱在25℃以1.2mL/min的流量进行。流动相B是具有乙腈的5mM pH=5.2的乙酸铵缓冲液(95:5),并且流动相C是H2O/乙腈(5:95);梯度为在5分钟内从10%C至90%C,然后在0.1分钟内斜升至100%C。注射体积为10μL。质谱仪以正离子模式和以负离子模式操作,毛细管电压设定为3.5kV(ES+)和2.8kV(ES-);锥体电压是14V(ES+)和28V(ES-);源温度是120℃;质量范围从100amu至800amu的全扫描被设置。
制备型HPLC设备由Shimadzu HPLC系统组成,所述Shimadzu HPLC系统配备有SCL-8A系统控制器、两个LC-8A泵、SPD-6A UV分光光度检测器和手动Rheodyne注射系统。数据采集(模拟信号)和数据处理通过Empower 2软件来提供。纯化使用Waters X-Terra MS RP18(150×30mm,10μm)柱在25℃以15mL/min的流量进行。流动相A是在水/乙腈(95:5)中的0.1%TFA,或可选择地,流动相A是在水/乙腈(95:5)中的0.05%NH3,并且流动相B是H2O/乙腈(5:95);梯度为在15分钟内从10%B至90%B,然后在0.1分钟内斜升至100%B。注射体积最大值500μL。
1H-NMR光谱在28℃的恒温被记录在以400.5MHz操作的并且配备有5mm 1H{15N-31P}z-轴PFG间接检测探针的Varian INOVA400光谱仪上,以及被记录在以499.7MHz操作的并且配备有5mm 1H{13C-15N}三重共振间接检测探针的Varian INOVA 500光谱仪上。化学位移相对于残余溶剂信号(DMSO-d6:1H为2.50ppm)被参照。数据被报告如下:化学位移(δ),多重性(s=单峰,d=双峰,t=三重峰,q=四重峰,br.s=宽单峰,dd=双重双峰,ddd=双重的双重双峰,m=多重峰),耦合常数(J,Hz)和质子数。
如之前所报告的(M.Colombo,F.R.Sirtori,V.Rizzo,Rapid Commun MassSpectrom 2004,18(4),511-517),ESI(+)高分辨率质谱(HRMS)在与Agilent 1100micro-HPLC系统(Palo Alto,US)直接连接的Q-Tof Ultima(Waters,Manchester,UK)质谱仪上获得。
制备1
2-(甲基硫烷基)-4-(丙-2-基氨基)嘧啶-5-甲酸乙酯[(IX),R2=丙-2-基,R3=H]步骤3a和步骤4a
将可商购的4-氯-2-(甲基硫烷基)嘧啶-5-甲酸乙酯(12g,51.4mmol)溶解在ACN300ml中,并且在0℃添加异丙胺(8.8mL,102.8mmol)并在rt搅拌持续3小时。将沉淀的盐过滤并且用EtOAc洗涤,将溶剂在减压下蒸发。将所得到的油溶解在Et2O中,用NH4Cl洗涤,并且然后经Na2SO4干燥。将盐过滤,并且将溶剂在真空下蒸发,以给出产物(7.0g,53%收率),其在没有进一步纯化的情况下继续使用。
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.09(d,J=7.32Hz,1H),4.31-4.37(m,1H),4.25-4.30(m,2H),2.48(s,3H),1.27-1.32(m,3H),1.23(d,J=6.56Hz,6H).
对于C11H16ClN2O2[M+H]+的HRMS(ESI)计算值243.0895,实测值243.0901。
根据相同的方法,制备以下化合物:
6-氯-4-乙基氨基-烟酸乙酯[(XVII),R2=乙基,X=CH]
标题化合物作为浅黄色油获得(80%收率)。
1H NMR(DMSO-d6)δ=8.52(s,1H),8.05(t,J=5.2Hz,1H),6.80(s,1H),4.29(q,J=7.2Hz,2H),3.25-3.32(m,2H),1.31(t,J=7.1Hz,3H),1.17(t,J=7.2Hz,3H)。在r.t.、6.27min,LCMS:m/z 229[M+H]+。
对于C10H14ClN2O2[M+H]+的HRMS(ESI)计算值229.0739,实测值229.0745。
6-氯-4-异丙基氨基-烟酸乙酯[(XVII),R2=丙-2-基,X=CH]
1H NMR(DMSO-d6)δ=8.53(s,1H),7.98(d,J=7.9Hz,1H),6.84(s,1H),4.29(q,J=7.1Hz,2H),3.80-3.93(m,1H),1.31(t,J=7.1Hz,3H),1.19(d,J=6.4Hz,6H)。在r.t.、6.72min,LCMS:m/z 243[M+H]+。
制备2
[2-(甲基硫烷基)-4-(丙-2-基氨基)嘧啶-5-基]甲醇[(X),R2=丙-2-基氨基,R3=H]步骤3b和步骤4b
在-5℃经15分钟,将LiAlH4(29mL,4%在THF中)添加到2-(甲基硫烷基)-4-(丙-2-基氨基)嘧啶-5-甲酸乙酯(7g,27.4mmol)在THF(70mL)中的溶液中。除去冷浴并且使之达到室温,然后搅拌持续2h。然后将其冷却至0℃,并且缓慢添加饱和的NaHCO3溶液(31mL)(放热反应)。在30分钟之后,将猝灭的反应混合物过滤,并且将滤饼用AcOEt(50ml)洗涤。将合并的有机洗涤物经Na2SO4干燥并且过滤。将溶剂在真空下蒸发,以给出产物(5.84g,96%收率),其在没有进一步纯化的情况下使用。
以下化合物基本上通过相同的制备方法制备:
(6-氯-4-乙基氨基-吡啶-3-基)-甲醇[(XVIII),R2=乙基,X=CH]
1H NMR(DMSO-d6)δ=7.77(s,1H),6.49(s,1H),6.11(t,J=5.1Hz,1H),5.18(t,J=5.4Hz,1H),4.37(d,J=5.3Hz,2H),3.17(qd,J=7.1,5.7Hz,2H),1.15(t,J=7.2Hz,3H)。在r.t.、4.06min,LCMS:m/z 187[M+H]+。
对于C8H12N2OCl[M+H]+的HRMS(ESI)计算值187.0633,实测值187.0638。
(6-氯-4-异丙基氨基-吡啶-3-基)-甲醇[(XVIII),R2=丙-2-基,X=CH]
1H NMR(DMSO-d6)δ=7.76(s,1H),6.53(s,1H),5.81(d,J=7.8Hz,1H),5.24(t,J=5.4Hz,1H),4.38(d,J=5.2Hz,2H),3.65-3.77(m,1H),1.16(d,J=6.4Hz,6H)。在r.t.、2.74min,LCMS:m/z 201[M+H]+。
对于C9H14ClN2O[M+H]+的HRMS(ESI)计算值201.0789,实测值201.0787。
制备3
2-(甲基硫烷基)-4-(丙-2-基氨基)嘧啶-5-甲醛[(XI),R2=2,2-二甲基-丙基,R3=H]步骤3c和步骤4c
将[2-(甲基硫烷基)-4-(丙-2-基氨基)嘧啶-5-基]甲醇(5.3g,24.84mmol)溶解在DCM(120mL)中,向其中添加在烘箱中在50℃预活化持续4h的MnO2(17.27g,198.7mmol)。将所得到的悬浮液搅拌过夜。固体通过经过硅藻土垫的过滤来除去,硅藻土垫用另外的DCM洗涤,将溶剂在真空中蒸发。粗品在用(n-Hex/EtOAc 9/1)洗脱的硅胶柱上纯化,以提供标题产物(4.08g,78%收率)。
1H NMR(500MHz,DMSO-d6)δ=9.74(s,1H),8.53(s,1H),8.45(d,J=7.32Hz,1H),4.28-4.44(m,1H),2.50(s,3H),1.24(d,J=6.56Hz,6H)。在r.t.、5.9min,LCMS:m/z 212[M+H]+。对于C9H14N3OS[M+H]+的HRMS(ESI)计算值212.0852,实测值212.0856。
根据相同的方法,制备以下化合物:
2-氯-4-(丙-2-基氨基)嘧啶-5-甲醛[(XIX),X=N,R2=丙-2-基]
在r.t.、4.87min,LCMS:m/z 200[M+H]+。
6-氯-4-乙基氨基-吡啶-3-甲醛[(XIX),R2=丙-2-基,X=CH]
1H NMR(DMSO-d6)δ=9.86(d,J=0.6Hz,1H),8.56(t,J=4.7Hz,1H),8.44(s,1H),6.85(s,1H),3.34(s,2H),1.17(t,J=7.2Hz,3H)。在r.t.、4.89min,LCMS:m/z 185[M+H]+。
对于C8H10ClN2O[M+H]+的HRMS(ESI)计算值185.0476,实测值185.0481。
6-氯-4-异丙基氨基-吡啶-3-甲醛[(XIX),R2=丙-2-基,X=CH]
1H NMR(DMSO-d6)δ=9.85(d,J=0.5Hz,1H),8.40-8.49(m,2H),6.90(s,1H),3.90(dt,J=7.9,6.5Hz,1H),1.20(d,J=6.4Hz,6H)。在r.t.、7.84min,LCMS:m/z 199[M+H]+。对于C9H12ClN2O[M+H]+的HRMS(ESI)计算值199.0633,实测值199.0632。
制备4
在-78℃,将LiHMDS(47mL的1M THF溶液,47mmol)添加到THF(78mL)中,并且用EtOAc(5.8mL,53.92mmol)处理。将溶液在-78℃搅拌持续10min,然后一次性添加固体2-(甲基硫烷基)-4-(丙-2-基氨基)嘧啶-5-甲醛(2.6g,12.30mmol),并且将溶液在-78℃搅拌持续10min,然后从冷却浴中除去并且在2h内加温至RT,并且使其在室温搅拌持续另外的4h。将反应在冰浴中冷却并用饱和的NH4Cl溶液(60ml)猝灭,并且用EtOAc(2×1mL)萃取,经Na2SO4干燥,过滤并浓缩,以给出标题化合物的灰白色固体(2.8g)。
1H NMR(500MHz,DMSO-d6)δ=8.86(s,1H),7.88(d,J=9.46Hz,1H),6.57(d,J=9.46Hz,1H),5.68(br.s.,1H),2.60(s,3H),1.54(d,J=7.02Hz,6H)。在r.t.、9.10min,LCMS:m/z 236[M+H]+。对于C11H14N3OS[M+H]+的HRMS(ESI)计算值236.0852,实测值236.0861。
根据相同的方法,制备以下化合物:
在r.t.、4.26min,LCMS:m/z 224[M+H]+。
1H NMR(500MHz,DMSO-d6)δ=8.74(s,1H),8.02(d,J=9.6Hz,1H),7.69(s,1H),6.71(d,J=9.6Hz,1H),4.21(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H)。在r.t.、4.28min,LCMS:m/z 209[M+H]+。
对于C10H10ClN2O[M+H]+的HRMS(ESI)计算值209.0476,实测值209.0485。
1H NMR(500MHz,DMSO-d6)δ=8.71(s,1H),7.96(d,J=9.5Hz,1H),7.79(br.s.,1H),6.63(d,J=9.5Hz,1H),5.14(br.s.,1H),1.50(d,J=6.9Hz,6H)。在r.t.、7.11min,LCMS:m/z 223[M+H]+。
对于C11H12ClN2O[M+H]+的HRMS(ESI)计算值223.0633,实测值223.0633。
制备5
2-(甲基硫烷基)吡啶并[2,3-d]嘧啶-7(8H)-酮(100mg,0.52mmol)、碳酸铯(337mg,1.04mmol)和异丙基碘(77.8μl,0.78mmol)在无水DMF(2mL)中的混合物用氮气吹扫,并且在密封管中在70℃加热持续2h。允许反应混合物冷却至室温并且用水稀释。将产物沉淀、过滤并且用水洗涤。以给出作为浅黄色固体的标题化合物(86mg,70%收率)。1H NMR(401MHz,DMSO-d6)δ=8.85(s,1H),7.87(d,J=9.52Hz,1H),6.57(d,J=9.40Hz,1H),5.69(td,J=6.93,13.73Hz,1H),2.60(s,3H),1.54(d,J=6.96Hz,6H)。在r.t.、5.53min,LCMS:m/z 236[M+H]+。对于C11H14N3OS[M+H]+的HRMS(ESI)计算值236.0852,实测值236.0861。
根据相同的方法,制备以下化合物:
1H NMR(401MHz,DMSO-d6)δ=8.88(s,1H),7.93(d,J=9.40Hz,1H),6.62(d,J=9.52Hz,1H),4.32(q,J=7.04Hz,2H),2.60(s,3H),1.22(t,J=7.02Hz,3H)。在r.t.、4.95min,LCMS:m/z 222[M+H]+。对于C10H12N3OS[M+H]+的HRMS(ESI)计算值222.0696,实测值222.07。
1H NMR(500MHz,DMSO-d6)δ=8.04(d,J=9.61Hz,1H),6.54(d,J=9.46Hz,1H),5.73(br.s,1H),2.61-2.64(m,3H),2.58(s,3H),1.54(d,J=6.86Hz,6H)。在r.t.、5.85min,LCMS:m/z 250[M+H]+。
1H NMR(500MHz,DMSO-d6)δ=8.33(s,1H),5.30(d,J=0.61Hz,2H),3.94(q,J=7.02Hz,2H),2.51(br.s.,3H),1.19(t,J=7.02Hz,3H)。
1H NMR(500MHz,DMSO-d6)δ=8.90(s,1H),6.44(s,1H),5.67(br.s.,1H),2.60(s,3H),2.40(d,J=1.22Hz,3H),1.53(d,J=7.02Hz,6H)。在r.t.、6.67min,LCMS:m/z 250[M+H]+。对于C12H16N3OS[M+H]+的HRMS(ESI)计算值250.1009,实测值250.101。
制备6
将4-氯-8-(2,2-二甲基-丙基)-2-甲基硫烷基-8H-吡啶并[2,3-d]嘧啶-7-酮(60mg,0.2mmol)溶解在DMSO(4.5mL)中,向其中添加三乙胺(300μL)和NaCN(18mg,0.2mmol),并且在50℃搅拌持续1小时。然后添加10mL水并且用AcOEt萃取两次。将有机相用盐水洗涤,并且然后经Na2SO4干燥。将盐过滤,并且将溶剂在真空中蒸发。粗制产物以SiO2色谱柱洗脱剂己烷/AcOEt 8/2纯化,以给出产物(12mg,20%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.94(d,J=9.61Hz,1H),6.83(d,J=9.61Hz,1H),4.28(br.s.,2H),2.63(s,3H),0.91(s,3H)。在r.t.、7.09min,LCMS:m/z 289[M+H]+。对于C14H17N4OS[M+H]+的HRMS(ESI)计算值289.1118,实测值289.1122。
制备7
4-[(2,4-二甲氧基苄基)氨基]-2-(甲基硫烷基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(XII),U=Y=CH,X=N、R2=丙-2-基,R3=NH-2,4-二甲氧基苄基]转化B
向4-氯-8-异丙基-2-甲基硫烷基-8H-吡啶并[2,3-d]嘧啶-7-酮(370mg,1.37mmol)在CH3CN(15mL)中的溶液中添加2,4-二甲氧基苄胺(0.288mL,1.92mmol)和三乙胺(0.268mL,1.92mmol)。将溶液在50℃加热持续3h。将反应混合物蒸发至干燥,并且残余物在硅胶(AcOEt/己烷:1/1)上纯化,以给出浅黄色固体(325mg)。
1H NMR(500MHz,DMSO-d6)δ=8.37(t,J=5.57Hz,1H),8.11(d,J=9.61Hz,1H),7.08(d,J=8.24Hz,1H),6.56(d,J=2.29Hz,1H),6.46(dd,J=2.29,8.39Hz,1H),6.32(d,J=9.46Hz,1H),5.70(br.s.,1H),4.55(d,J=5.64Hz,2H),3.80(s,3H),3.73(s,3H),2.44(s,3H),1.49(d,J=6.86Hz,6H)。在r.t.、3.43min,LCMS:m/z 423[M+Na]+。对于C20H25N4NaO4S[M+Na]+的HRMS(ESI)计算值423.1440,实测值423.1444。
制备8
4-(甲基氨基)-2-(甲基硫烷基)-8-(2,2-二甲基丙基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(XII),U=Y=CH,X=N、R2=2,2-二甲基丙基,R3=NHMe,R4=R5=H]转化C
将4-氯-8-(2,2-二甲基-丙基)-2-甲基硫烷基-8H-吡啶并[2,3-d]嘧啶-7-酮(40mg,0.13mmol)溶解在THF(4mL)中,向其中添加在EtOH(100μL)中的1.0M甲胺,并且在室温搅拌持续12小时。然后添加10mL水,并且用AcOEt萃取两次。将有机相用盐水洗涤,并且然后经Na2SO4干燥。将盐过滤,并且将溶剂在真空中蒸发。粗制产物在SiO2色谱柱DCM/MeOH98/2上纯化,以给出产物(33mg,85%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.11(q,J=4.02Hz,1H),8.01(d,J=9.61Hz,1H),6.39(d,J=9.61Hz,1H),4.27(br.s.,2H),2.93(d,J=4.42Hz,3H),2.52(s,3H),0.89(s,9H)。在r.t.、6.63min,LCMS:m/z 293[M+H]+。对于C14H21N4OS[M+H]+的HRMS(ESI)计算值293.1431,实测值293.1436。
根据相同的方法,制备以下化合物:
1H NMR(500MHz,DMSO-d6)δ=7.93(d,J=9.76Hz,1H),6.25(d,J=9.76Hz,1H),5.72(br.s.,1H),3.21(s,6H),2.50(s,3H),1.50(d,J=7.02Hz,6H)。在r.t.、6.48min,LCMS:m/z 279[M+H]+。对于C13H19N4OS[M+H]+的HRMS(ESI)计算值279.1274,实测值279.1276。
制备9
将2-(甲基硫烷基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3.1mg,13.17mmol)溶解在62mL DCM中。向搅拌的溶液中添加m-CPBA 55%(10.32g,32.93mmol)。允许反应在室温搅拌持续2h。LCMS指示反应已经完成。将样品用50mL的DCM稀释,并且用饱和的NaHCO3(170ml)洗涤两次并且然后用50ml×2洗涤,随后用盐水(50ml)洗涤。将有机相分离,并且经Na2SO4干燥,过滤并在真空中浓缩。用色谱柱洗脱剂EtOAc/丙酮100:1纯化,以给出作为灰白色固体的标题化合物2-(甲基磺酰基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(2.29mg,65%收率)。
1H NMR(500MHz,DMSO-d6)δ=9.27(s,1H),8.07(d,J=9.46Hz,1H),6.88(d,J=9.46Hz,1H),5.65(spt,J=6.80Hz,1H),3.46(s,3H),1.56(d,J=7.02Hz,6H)。在r.t.、4.48min,LCMS:m/z 268[M+H]+。对于C11H13N3O3S[M+H]+的HRMS(ESI)计算值268.0751,实测值268.0746。
根据相同的方法,制备以下化合物:
1H NMR(500MHz,DMSO-d6)δ=9.30(s,1H),8.12(d,J=9.61Hz,1H),6.93(d,J=9.46Hz,1H),4.35(q,J=7.02Hz,2H),3.48(s,3H),1.24(t,J=7.09Hz,3H)。在r.t.、3.53min,LCMS:m/z 254[M+H]+。对于C10H11N3O3S[M+H]+的HRMS(ESI)计算值254.0594,实测值254.0595。
1H NMR(500MHz,DMSO-d6)δ=8.22(d,J=9.76Hz,1H),6.84(d,J=9.76Hz,1H),5.59-5.77(m,1H),3.44(s,3H),2.81(s,3H),1.55(d,J=7.02Hz,6H)。在r.t.、4.34min,LCMS:m/z 282[M+H]+。
1H NMR(500MHz,DMSO-d6)δ=8.90(s,1H),6.44(s,1H),5.67(br.s.,1H),2.60(s,3H),2.40(d,J=1.22Hz,3H),1.53(d,J=7.02Hz,6H)。在r.t.、4.73min,LCMS:m/z 282[M+H]+。对于C12H16N3O3S[M+H]+的HRMS(ESI)计算值282.0907,实测值282.0907。
1H NMR(500MHz,DMSO-d6)δ=8.68(s,1H),5.48(d,J=0.61Hz,2H),3.99(q,J=7.02Hz,2H),3.41(s,3H),1.22(t,J=7.02Hz,3H)。在r.t.、3.43min,LCMS:m/z 258[M+H]+。对于C9H11N3O4S[M+H]+的HRMS(ESI)计算值258.0543,实测值258.054。
4-[(2,4-二甲氧基苄基)氨基]-2-(甲基亚磺酰基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(IV),U=Y=CH,X=N、R2=丙-2-基,R3=4-[(2,4-二甲氧基苄基)氨基],G=MeSO-]
1H NMR(500MHz,DMSO-d6)δ=8.74(t,J=5.57Hz,1H),8.22(d,J=9.76Hz,1H),7.16(d,J=8.24Hz,1H),6.56(d,J=2.44Hz,1H),6.53(d,J=9.61Hz,1H),6.45(dd,J=2.36,8.31Hz,1H),5.75(s,1H),4.48-4.67(m,2H),3.80(s,3H),3.73(s,3H),2.78(s,3H),1.51(d,J=7.02Hz,6H)。在r.t.、3.43min,LCMS:m/z 258[M+H]+。对于C20H25N4NaO4S[M+Na]+的HRMS(ESI)计算值423.1440,实测值423.1444。
制备10
步骤1在rt,向2-(甲基磺酰基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(5g,18.7mmol)在1,4-二氧六环(86mL)中的溶液中添加NaOH 1N(37.4ml,37.4mmol)。将混合物在40℃搅拌持续1h。将混合物冷却至rt并且用DCM(80ml)稀释,将水相分离并且保存。将有机相用NaOH 0.5M(20mL)洗涤,并且将水相添加到先前的水相中。将水溶液用HCl 1N酸化并且用DCM/i-pr-OH的溶液(4×50mL)分配。将有机相经Na2SO4干燥,过滤并且浓缩,以给出作为灰白色固体的2-羟基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(2.65g,Y=65%)。1HNMR(500MHz,DMSO-d6)δ=12.26(br.s.,1H),8.46(s,1H),7.58(d,J=9.46Hz,1H),6.17(d,J=9.46Hz,1H),5.59(br.s.,1H),1.44(d,J=7.02Hz,6H)。LCMS:m/z 204[M-H]-。
步骤2在氮气气氛下在2℃(内部温度),向2-羟基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(3.90g,19.02mmol)在干燥的DCM(78mL)中的溶液中添加2,6-二甲基吡啶(2.65mL,22.8mmol,1.2当量)。然后,经5分钟滴入三氟甲磺酸酐(3.83mL,22.8mmol,1.2当量),将内部温度保持在2℃和10℃之间。在1h之后,反应完成并且用DCM和水稀释。将有机相分离,并且用盐水洗涤并经Na2SO4干燥,并在真空中浓缩。粗品通过硅胶上的快速柱色谱法(DCM:EA=99/1至97.5/2.5)纯化,以提供作为灰白色固体的标题化合物(5.53g,86%收率)。1H NMR(500MHz,DMSO-d6)δ=9.16(s,1H),8.4(d,J=9.46Hz,1H),6.80(d,J=9.46Hz,1H),5.52(m,1H),1.52(d,J=7.02Hz,6H)。LCMS:m/z 338[M+H]+。对于C11H11F3N3O4S[M+H]+的HRMS(ESI)计算值338.0417,实测值338.0412。
制备11
4-(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]步骤5a-步骤5e
步骤1 4-(4-溴苯基)四氢-2H-吡喃-4-甲酸的合成
向4-(4-溴苯基)四氢-2H-吡喃-4-甲酸乙酯(383.2g,1.22mol)在THF/MeOH/H2O(1L/1L/1L)中的溶液中添加LiOH.H2O(308.5g,7.35mol)。将混合物在30℃搅拌持续2天。将大部分溶剂在真空中除去,用2N HCl溶液调节pH=2并且用EtOAc(2L)分配。将溶剂在真空中除去,以给出作为白色固体的4-(4-溴苯基)四氢-2H-吡喃-4-甲酸(314g,90%收率)。
1HNMR(400MHz,DMSO-d6)δ=12.77(s,1H),7.60-7.58(d,J=10.8Hz,2H),7.40-7.37(d,J=10.8Hz,2H),3.85-3.76(m,2H),3.51-3.38(m,2H),1.94-1.84(t,J=21.0Hz,2H),1.27-1.09(m,2H).
根据相同的方法,制备以下化合物:
1-(4-溴苯基)环戊烷甲酸
1HNMR(500MHz,DMSO-d6)δ=12.37(br.s.,1H),7.50-7.52(m,2H),7.27-7.32(m,2H),1.51-1.86(m,6H).
1-(4-溴苯基)环己烷甲酸
1HNMR(500MHz,DMSO-d6)δ=12.47(br.s.,1H),7.51-7.57(m,2H),7.28-7.37(m,2H),2.29(d,J=12.81Hz,2H),1.51-1.73(m,5H),1.34-1.47(m,2H),1.16-1.30(m,1H).
步骤2. 4-(4-溴苯基)四氢-2H-吡喃-4-胺[(XXI)W1=Br,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]的合成
4-(4-溴苯基)四氢-2H-吡喃-4-甲酸(314g,1.10mol)、TEA(189.2g,1.87mol)和DPPA(叠氮磷酸二苯酯)(424g,1.54mol)在无水甲苯(3L)中的混合物用氮气吹扫并且在90℃搅拌持续3h。允许反应混合物冷却至环境温度并且用水(1L)稀释。将水相用EtOAc(1L*2)萃取,并且将合并的有机相用饱和的NaHCO3洗涤两次,随后用盐水洗涤,经Na2SO4干燥并且在真空中浓缩。将粗品悬浮在3.2L的HCl(含水,20%)中并且回流持续3h。向冷溶液中添加甲苯,并且将共沸混合物蒸发。用EtOAc和饱和的NaHCO3稀释,将有机相分离,经Na2SO4干燥并且在真空中浓缩。粗品通过用DCM/EtOH=50/1~30/1的硅胶上的快速柱色谱法纯化,以提供作为浅黄色固体的4-(4-溴苯基)四氢-2H-吡喃-4-胺(215.6g,76%收率)。
1H-NMR(400MHz,CDCl3)δ=7.49-7.47(d,J=8.4Hz,2H),7.37-7.34(d,J=8.4Hz,2H),3.94-3.88(m,2H),3.82-3.77(m,2H),2.18-2.11(m,2H),1.63-1.60(d,J=12.8Hz,2H).
根据相同的方法,制备以下化合物:
1-(4-溴苯基)环戊胺[(XXI)W1=Br,A=苯基,R4=H,R5a和R5b=环戊-3-基]
1HNMR(500MHz,DMSO-d6)δ=7.44(d,J=2.29Hz,4H),1.57-1.93(m,10H).
1-(4-溴苯基)环己胺[(XXI)W1=Br,A=苯基,R4=H,R5a和R5b=环己基]
1HNMR(500MHz,DMSO-d6)δ=7.42(dd,J=8.42,2.29Hz,2H),7.32(dd,J=8.4,2.3Hz,2H),1.84(br.s,2H),1.60-1.64(m,4H),1.39-1.47(m,4H),1.20-1.23(m,2H).
4-(5-溴吡啶-2-基)四氢-2H-吡喃-4-胺[(XXI)W1=Br,A=嘧啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]
1HNMR(500MHz,DMSO-d6)δ=8.67(d,J=2.29Hz,1H),8.05(dd,J=2.36,8.46Hz,1H),7.66(d,J=8.54Hz,1H),3.82(dt,J=2.52,10.87Hz,2H),3.59(td,J=4.29,11.40Hz,2H),2.10-2.20(m,2H),1.54(d,J=13.27Hz,2H).
步骤3. 4-(4-(4-溴苯基)四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIII)W1=Br,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5b
向4-(4-溴苯基)四氢-2H-吡喃-4-胺(215.6g,0.84mol)在DIEA(4L)中的悬浮液中添加双(2-氯乙基)氨基甲酸苯酯(如在WO2009065622中所报告地制备)(308g,1.18mol)。将混合物在130℃搅拌持续72h并且在真空中蒸发。将残余物溶解在DCM(2L)中,用盐水洗涤,经Na2SO4干燥,在真空中浓缩。粗品通过用DCM/丙酮=100/0~20/1的硅胶上的快速柱色谱法纯化,以提供作为灰白色固体的4-(4-(4-溴苯基)四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(149g,40%收率)。
1H-NMR(400MHz,CDCl3)δ=7.53-7.51(d,J=8.4Hz,2H),7.34-7.30(t,J=7.8Hz,2H),7.18-7.11(m,3H),7.05-7.03(d,J=7.6Hz,2H),3.98-3.92(m,2H),3.60-3.51(m,6H),2.35(s,4H),2.20-2.17(m,4H).
根据相同的方法,制备以下化合物:
4-[1-乙酰基-4-(4-溴苯基)哌啶-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=Br,A=苯基,R4=H,R5a和R5b=1-乙酰基哌啶-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.58(d,J=8.54Hz,2H),7.32-7.36(m,2H),7.30(d,J=8.69Hz,2H),7.16-7.21(m,1H),7.01-7.07(m,2H),3.36-3.58(m,7H),2.21-2.35(m,6H),1.98-2.03(m,3H).
4-[1-(4-溴苯基)环戊基]哌嗪-1-甲酸苯酯[(XXIII)W1=Br,A=苯基,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.51-7.58(m,2H),7.30-7.38(m,4H),7.16-7.22(m,1H),7.01-7.07(m,2H),3.51(br.s.,4H),2.30(br.s.,4H),1.98-2.08(m,4H),1.66-1.80(m,2H),1.35-1.49(m,2H).
4-[4-(5-溴吡啶-2-基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=Br,A=嘧啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=8.74(d,J=2.29Hz,1H),8.07(dd,J=2.52,8.46Hz,1H),7.40(d,J=8.39Hz,1H),7.29-7.37(m,2H),7.15-7.22(m,1H),7.01-7.07(m,2H),3.76-3.88(m,2H),3.51(br.s.,2H),3.20-3.31(m,4H),2.23-2.37(m,6H),1.95-2.10(m,2H).
4-[3-(4-溴苯基)四氢呋喃-3-基]哌嗪-1-甲酸苯酯[(XXIII)W1=Br,A=苯基,R4=H,R5a和R5b=四氢呋喃-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.56(d,J=8.54Hz,2H),7.32-7.39(m,4H),7.19(dd,J=7.47,7.32Hz,1H),7.04-7.08(m,2H),4.07(d,J=9.15Hz,1H),3.95-3.97(m,1H),3.93(d,J=9.15Hz,1H),3.64-3.68(m,1H),3.54(br.s,2H),3.33-3.35(m,1H),2.24-2.45(m,7H).
4-[4-(6-氯吡啶-3-基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=Cl,A=嘧啶-3-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(400MHz,氯仿-d)δ=8.33(d,J=2.50Hz,1H)7.54(dd,J=8.38,2.50Hz,1H)7.29-7.40(m,3H)7.15-7.22(m,1H)7.05(d,J=8.13Hz,2H)3.92-4.05(m,2H)3.46-3.72(m,6H)2.39(br t,J=4.50Hz,4H)2.21-2.33(m,2H)2.09-2.21(m,2H)。
步骤4. 4-(4-(4-乙酰基苯基)四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成。转化G
在N2下,向4-[4-(4-溴苯基)四氢-2H-吡喃-4-基]哌嗪-1-氨基甲酸酯(149g,0.34mol)在DMF(1.2L)中的溶液中添加三丁基(1-乙氧基乙烯基)锡(242g,0.67mol)和Pd(PPh3)2Cl2(2.35g,3.35mmol)。将混合物在90℃搅拌过夜。在冷却之后,将反应混合物用KF的水溶液稀释并且在r.t.搅拌持续1h,并且然后将沉淀物过滤并且用EtOAc洗涤。在分离之后,将水相用EtOAc(500mL*5)萃取。将合并的有机物经Na2SO4干燥并且浓缩。将粗品悬浮在2L的DCM和1L的2N HCl(含水)中并且在r.t.搅拌持续2h。将反应混合物用DCM(2L)稀释并且用饱和的NaHCO3洗涤。在分离之后,将水相用DCM(500mL*3)萃取,经Na2SO4干燥,在真空中浓缩。残余物通过用DCM/丙酮=100/0~10/1的硅胶上的快速柱色谱法纯化,以提供作为白色固体的4-(4-(4-乙酰基苯基)四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(63g,45%收率)。1H-NMR(400MHz,CDCl3)δ=8.00-7.98(d,J=8.4Hz,2H),7.36-7.29(m,4H),7.18-7.16(m,1H),7.03-7.01(d,J=7.6Hz,2H),3.99-3.96(t,J=5.8Hz,2H),3.61-3.53(m,6H),2.63(s,3H),2.37(s,4H),2.24-2.23(m,4H)。在Rt=6.19min,LCMS 409;对于C24H29N2O4[M+H]+的HRMS(ESI)计算值409.2122,实测值409.2118。
根据相同的方法,制备以下化合物:
4-[3-(4-乙酰基苯基)戊-3-基]哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=苯基,R4=H,R5a和R5b=乙基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(400MHz,DMSO-d6)δ=7.93(d,J=8.54Hz,2H),7.57(d,J=8.54Hz,2H),7.32-7.39(m,2H),7.16-7.23(m,1H),7.03-7.10(m,2H),3.53(br.s.,2H),3.37(d,J=2.29Hz,1H),2.57(s,3H),1.81-2.07(m,4H),0.76(t,J=7.32Hz,6H).
4-[1-乙酰基-4-(4-乙酰基苯基)哌啶-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=苯基,R4=H,R5a和R5b=1-乙酰基哌啶-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.97(d,J=8.54Hz,2H),7.46-7.52(m,2H),7.29-7.37(m,2H),7.15-7.20(m,1H),6.99-7.06(m,2H),3.37-3.65(m,8H),2.59(s,3H),2.23-2.46(m,8H),1.95-2.07(m,3H).
4-[1-(4-乙酰基苯基)环戊基]哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=苯基,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.94(d,J=8.39Hz,2H),7.49-7.54(m,2H),7.30-7.36(m,2H),7.14-7.22(m,1H),6.98-7.06(m,2H),3.52(br.s.,4H),2.58(s,3H),2.27-2.38(m,4H),2.04-2.13(m,4H),1.71-1.78(m,2H),1.37-1.51(m,2H).
4-[4-(5-乙酰基吡啶-2-基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=吡啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=9.16(d,J=1.68Hz,1H),8.30(dd,J=2.36,8.31Hz,1H),7.55-7.58(m,1H),7.30-7.37(m,2H),7.16-7.20(m,1H),7.00-7.05(m,2H),3.80-3.89(m,2H),3.52(br.s.,2H),3.23-3.32(m,4H),2.64(s,3H),2.28-2.42(m,6H),2.04-2.13(m,2H).
4-[3-(4-乙酰基苯基)四氢呋喃-3,基]哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=吡啶-2-基,R4=H,R5a和R5b=四氢呋喃-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.96(d,J=8.39Hz,2H),7.56(d,J=8.54Hz,2H),7.32-7.37(m,2H),7.16-7.22(m,1H),7.01-7.09(m,2H),4.13(d,J=9.15Hz,1H),3.93-4.01(m,2H),3.65-3.73(m,1H),3.50-3.60(m,2H),3.36-3.45(m,2H),2.59(s,3H),2.26-2.49(m,6H).
4-[4-(5-乙酰基吡啶-3-基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=吡啶-3-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(400Mhz,氯仿-d)δ=8.64(d,1H,J=2.0Hz),8.09(d,1H,J=8.4Hz),7.71(dd,1H,J=2.2,8.4Hz),7.3-7.4(m,2H),7.1-7.2(m,1H),7.03(d,2H,J=7.9Hz),3.9-4.1(m,2H),3.5-3.7(m,6H),2.75(s,3H),2.40(br t,4H,J=4.3Hz),2.2-2.4(m,4H)。
3-{[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基](甲基)氨基}氮杂环丁烷-1-甲酸苄酯[(XXIII)W1=甲基酮,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=N(R6),R6=甲基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
在r.t.、2.29min,LCMS:m/z 423[M+H]+。
步骤5. 4-(4-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIV)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5c’
将四乙氧基钛(3当量,400μL,1.908mmol)、(S)-2-甲基丙烷-2-亚磺酰胺(2当量,154mg,1.272mmol)和4-[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯(260mg,0.636mmol)在THF(20mL)中的混合物加热至80℃过夜,并且然后冷却至室温。在-50℃,向该混合物中添加NaBH4(5当量,120mg,3.18mmol)。然后将混合物缓慢升温至室温(2h)。添加MeOH(2mL)以猝灭过量的NaBH4,并且随后添加水。将所得到的混合物过滤以除去固体,并且将水相用EtOAc萃取两次,经Na2SO4干燥并浓缩。残余物以使用梯度洗脱(100%DCM,然后0%-20%丙酮/DCM)的硅胶柱色谱法系统纯化,以提供4-(4-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(225mg,69%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.41(d,J=8.24Hz,2H),7.31-7.36(m,2H),7.26(d,J=8.39Hz,2H),7.15-7.21(m,1H),7.00-7.05(m,2H),5.64(d,J=6.86Hz,1H),4.39(s,1H),3.83(d,J=7.78Hz,2H),3.52(br.s.,2H),3.36-3.43(m,3H),2.26(br.s.,4H),2.04-2.21(m,4H),1.42(d,J=6.71Hz,3H),1.10-1.13(m,9H).
根据相同的方法,制备以下化合物:
4-(3-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}戊-3-基)哌嗪-1-甲酸苯酯[(XXIV)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=乙基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.29-7.40(m,6H),7.17-7.21(m,1H),7.07(dd,J=0.99,8.46Hz,2H),5.61(d,J=7.02Hz,1H),4.37(五重峰,J=6.75Hz,1H),3.52(br.s.,2H),3.33(m,2H),2.47(br.s.,4H),(1.79-1.97(m,4H),1.41(d,J=6.86Hz,3H),1.09-1.16(m,9H),0.76(t,J=6.94Hz,6H)。
4-(4-{5-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]吡啶-2-基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIV)R1a=甲基,R1b=H,A=吡啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=8.62(d,J=2.14Hz,1H),7.83(dd,J=2.29,8.24Hz,1H),7.37(d,J=8.24Hz,1H),7.30-7.35(m,2H),7.16-7.20(m,1H),7.01-7.05(m,2H),5.79(d,J=7.17Hz,1H),4.46(t,J=6.86Hz,1H),3.79-3.88(m,2H),3.51(br.s.,2H),3.24-3.32(m,4H),2.27-2.37(m,6H),2.02-2.10(m,2H),1.45(d,J=6.86Hz,3H),1.12(s,9H).
4-(1-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}环戊基)哌嗪-1-甲酸苯酯[(XXIV)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=7.36-7.39(m,2H),7.27-7.35(m,4H),7.15-7.20(m,1H),7.00-7.06(m,2H),5.61(d,J=6.86Hz,1H),4.38(t,J=6.71Hz,1H),3.51(br.s.,4H),2.31(br.s.,4H),2.06(d,J=8.54Hz,4H),1.73(br.s.,2H),1.43-1.50(m,2H),1.41(d,J=6.86Hz,3H),1.10-1.14(m,9H).
4.(4-{4-[(1R)-1-{[(R)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIV)R1a=H,R1b=甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=7.41(d,J=8.24Hz,2H),7.30-7.36(m,2H),7.26(d,J=8.24Hz,2H),7.15-7.20(m,1H),7.00-7.05(m,2H),5.64(d,J=6.86Hz,1H),4.39(t,J=6.86Hz,1H),3.84(t,J=8.08Hz,2H),3.53(br.s.,2H),3.35-3.43(m,4H),2.26(br.s.,4H),2.05-2.21(m,4H),1.42(d,J=6.71Hz,3H),1.12(s,9H).
4-(3-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢呋喃-3-基)哌嗪-1-甲酸苯酯[(XXIV)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢呋喃-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=7.38-7.42(m,2H),7.29-7.37(m,4H),7.16-7.21(m,1H),7.02-7.07(m,2H),5.63(d,J=6.86Hz,1H),5.31(s,1H),4.07-4.11(m,1H),3.94-3.98(m,2H),3.67(q,J=7.52Hz,1H),3.54(br.s.,2H),3.38(br.s.,2H),2.24-2.44(m,6H),1.41(d,J=6.71Hz,3H),1.12(s,9H).
4-(4-{5-[(1S)-1-{[(R)-叔丁基亚磺酰基]氨基}乙基]吡啶-3-基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIV)R1a=甲基,R1b=H,A=吡啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(400MHz,氯仿-d)δ=8.50(d,1H,J=1.8Hz),7.54(dd,1H,J=2.1,8.1Hz),7.3-7.4(m,3H),7.1-7.2(m,1H),7.03(d,2H,J=8.0Hz),4.67(五重峰,1H,J=6.7Hz),4.13(q,1H,J=7.1Hz),3.9-4.0(m,3H),3.5-3.7(m,6H),2.39(br s,4H),2.1-2.3(m,4H),1.66(d,3H,J=6.8Hz),1.23(s,8H)。
3-[(4-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)(甲基)氨基]氮杂环丁烷-1-甲酸苄酯[(XXIV)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=N(R6),R6=甲基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
1HNMR(400MHz,氯仿-d)δ=7.27(s,9H),5.03(s,2H),4.56(br dd,J=2.8,6.5Hz,1H),4.03-3.92(m,1H),3.89-3.80(m,2H),3.76-3.59(m,4H),3.55-3.43(m,2H),3.41(d,J=2.4Hz,1H),2.25(s,3H),2.15(br s,4H),1.51(d,J=6.4Hz,3H),1.24(s,9H)。
3-[乙酰基(4-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)氨基]氮杂环丁烷-1-甲酸苄酯[(XXIV)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=N(R6),R6=乙酰基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
1H NMR(500MHz,DMSO-d6)δ=7.29-7.39(m,7H),7.24(d,J=8.38Hz,2H),5.62(d,J=7.00Hz,1H),5.02(s,2H),4.60-4.71(m,1H),3.97-4.41(m,6H),2.64(br s,2H),2.09(s,3H),1.95-2.05(m,5H),1.65-1.89(m,2H),1.38(d,J=6.75Hz,3H),1.10(s,9H).
步骤6. 4-(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5e
向4-(4-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(220mg,0.432mmol)在MeOH(5mL)中的溶液中添加HCl(2mL,8.0mmol,4M在1,4-二氧六环中)。将混合物在室温搅拌持续2h。向该混合物中添加DCM和饱和的NaHCO3溶液,将水相用DCM萃取两次,经Na2SO4干燥并且浓缩,以提供4-(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(200mg,99%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.37(d,J=8.39Hz,2H),7.31-7.34(m,2H),7.23(d,J=8.39Hz,2H),7.16-7.20(m,1H),7.00-7.06(m,2H),3.98(q,J=6.56Hz,1H),3.79-3.87(m,2H),3.52(br.s.,2H),2.25(br.s.,4H),2.03-2.20(m,5H),1.81-2.01(m,1H),1.25(d,J=6.71Hz,3H).
根据相同的方法,制备以下化合物:
4-(4-{4-[(1R)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=H,R1b=甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=7.39(d,J=8.24Hz,2H),7.31-7.35(m,2H),7.25(d,J=8.24Hz,2H),7.16-7.20(m,1H),7.00-7.06(m,2H),4.04(d,J=6.56Hz,1H),3.79-3.88(m,2H),3.52(br.s.,2H),3.35-3.40(m,6H),2.25(br.s.,4H),2.13(dt,J=13.42,17.46Hz,4H),1.29(d,J=6.56Hz,3H).
4-(1-乙酰基-4-{4-[(1S)-1-氨基乙基]苯基}哌啶-4-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=1-乙酰基哌啶-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=7.38(d,J=8.24Hz,2H),7.31-7.36(m,2H),7.27(d,J=8.39Hz,2H),7.15-7.20(m,1H),6.99-7.08(m,2H),4.02(d,J=6.41Hz,1H),3.37-3.65(m,8H),2.21-2.40(m,8H),1.99(s,3H),1.94(d,J=2.90Hz,1H),1.84(d,J=12.96Hz,1H),1.27(d,J=6.71Hz,3H).
4-(4-{5-[(1S)-1-氨基乙基]吡啶-2-基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=吡啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=8.70(d,J=2.14Hz,1H),7.94(dd,J=2.36,8.31Hz,1H),7.46-7.50(m,1H),7.31-7.36(m,2H),7.16-7.21(m,1H),6.98-7.05(m,2H),4.40-4.51(m,1H),3.81-3.89(m,2H),3.52(br.s.,2H),3.24-3.32(m,2H),2.27-2.40(m,6H),2.01-2.14(m,2H),1.52(d,J=6.86Hz,3H).
4-(1-{4-[(1S)-1-氨基乙基]苯基}环戊基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.31-7.36(m,4H),7.27(d,J=8.24Hz,2H),7.18(dd,J=7.4and7.3Hz,1H),7.03(d,J=8.54Hz,2H),3.96(q,J=6.56Hz,1H),3.51(br.s.,2H),3.37-3.40(m,2H),2.31(br.s.,4H),1.99-2.12(m,4H),1.87(br.s.,2H),1.67-1.76(m,2H),1.37-1.48(m,2H),1.25(d,J=6.56Hz,3H).
4-(3-{4-[(1S)-1-氨基乙基]苯基}四氢呋喃-3-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.28-7.39(m,6H),7.16-7.21(m,1H),7.01-7.08(m,2H),4.09(d,J=9.15Hz,1H),3.96-4.02(m,1H),3.94(d,J=8.85Hz,2H),3.66(q,J=7.78Hz,1H),3.54(br.s.,4H),2.23-2.46(m,6H),1.25(d,J=6.71Hz,3H).
4-(4-{5-[(1S)-1-氨基乙基]吡啶-3-基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=吡啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(400MHz,氯仿-d)δ=8.50(d,J=1.96Hz,1H)7.53(dd,J=8.19,2.32Hz,1H)7.33(dd,J=16.44,8.38Hz,3H)7.13-7.22(m,1H)7.04(d,J=7.70Hz,2H)4.19(q,J=6.60Hz,1H)3.91-4.07(m,2H)3.46-3.72(m,6H)2.39(br t,J=4.52Hz,4H)2.14-2.32(m,4H)1.47(d,J=6.72Hz,3H)。
4-(4-{5-[(1R)-1-氨基乙基]吡啶-3-基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=H,R1b=甲基,A=吡啶-2-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=8.46(d,J=1.98Hz,1H),7.68(dd,J=2.29,8.24Hz,1H),7.42-7.53(m,1H),7.29-7.37(m,2H),7.15-7.22(m,1H),7.00-7.07(m,2H),3.99(q,J=6.71Hz,1H),3.81-3.90(m,2H),3.54(br.s.,2H),3.37-3.42(m,4H),2.01-2.31(m,8H),1.29(d,J=6.56Hz,3H).
3-[(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)(甲基)氨基]氮杂环丁烷-1-甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=N(R6),R6=甲基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
1HNMR(500MHz,DMSO-d6)δ=7.23-7.37(m,9H),4.94(br.s.,2H),4.07-4.15(m,1H),3.97(q,J=6.46Hz,1H),3.66-3.73(m,2H),3.53-3.65(m,2H),3.36-3.53(m,2H),3.25-3.33(m,2H),2.13-2.19(m,2H),2.11(s,3H),1.96-2.06(m,2H),1.22(d,J=6.56Hz,3H).
3-[(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)(甲基)氨基]氮杂环丁烷-1-甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=N(R6),R6=甲基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
1HNMR(500MHz,DMSO-d6)δ=7.25-7.36(m,9H),4.95(br.s.,2H),4.19(t,J=6.10Hz,1H),3.97(q,J=6.66Hz,1H),3.59-3.78(m,2H),3.39-3.51(m,2H),2.30-2.44(m,2H),2.14(s,4H),1.87-2.02(m,4H),1.73(br.s.,2H),1.22(d,J=6.56Hz,3H).
4-(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)哌嗪-1-甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苄酯]
1HNMR(500MHz,DMSO-d6)δ=7.21-7.37(m,9H),4.98(s,2H),3.96(q,J=6.56Hz,2H),2.06-2.28(m,8H),1.89(s,3H),1.79(d,J=9.46Hz,5H),1.20-1.25(m,3H).
4-(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.35-7.39(m,2H),7.31-7.35(m,2H),7.27-7.31(m,2H),7.12-7.20(m,1H),6.96-7.07(m,2H),3.97(q,J=6.56Hz,1H),3.53(d,J=3.51Hz,2H),2.53-2.61(m,2H),2.28(br.s.,4H),2.08-2.22(m,4H),1.71-2.03(m,J=6.10Hz,4H),1.24(d,J=6.56Hz,3H).
4-(1-{4-[(1R)-1-氨基乙基]苯基}-4,4-二氟环己基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1HNMR(500MHz,DMSO-d6)δ=7.37-7.40(m,2H),7.32-7.36(m,2H),7.29-7.32(m,2H),7.16-7.22(m,1H),6.98-7.08(m,2H),3.99(q,J=6.56Hz,1H),3.55(br.s.,2H),2.54-2.62(m,2H),2.08-2.36(m,6H),1.63-1.99(m,J=6.10Hz,6H),1.26(d,J=6.71Hz,3H).
制备12
4-(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]步骤5a-步骤5e
步骤a 4-[4-(4-{(1E)-N-[(S)-叔丁基亚磺酰基]乙亚胺酰基}苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(XXV)R1a=甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5c”
将四乙氧基钛(2.5当量,1.57mL,7.5mmol)、(S)-2-甲基丙烷-2-亚磺酰胺(1.5当量,545mg,4.5mmol)和4-[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯(1.22g,3.0mmol)在THF(80mL)中的混合物加热至80℃过夜,并且然后冷却至室温并浓缩。残余物以用梯度洗脱(100%DCM,然后0%-20%丙酮/DCM)的硅胶柱色谱法系统纯化,以提供标题化合物(966mg,63%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.94(d,J=8.39Hz,2H),7.44(d,J=8.54Hz,2H),7.29-7.34(m,2H),7.14-7.21(m,1H),7.00-7.07(m,2H),3.79-3.89(m,2H),3.53(br.s.,2H),3.36-3.42(m,3H),2.73(s,3H),2.24-2.34(m,4H),2.12-2.21(m,4H),1.23(s,9H)
步骤b 4-{4-[4-(2-{[(S)-叔丁基亚磺酰基]氨基}丙-2-基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(XXIV)R1a=R1b=甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5e
在-48℃,向4-[4-(4-{(1E)-N-[(S)-叔丁基亚磺酰基]乙亚胺酰基}苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯(384mg,0.75mmol)在5mL的干燥的DCM中的溶液中添加0.375mL(1.125mmol,1.5当量)的3.0M甲基溴化镁醚溶液。允许混合物加温至室温并且搅拌持续6小时。将反应混合物用饱和的NaHCO3水溶液猝灭,并且将水层用DCM萃取。将合并的有机层经Na2SO4干燥并且浓缩。残余物以用梯度洗脱(100%DCM,然后0%-4%乙醇/DCM)的硅胶柱色谱法系统纯化,以提供标题化合物(182mg,46%收率)。1H NMR(500MHz,DMSO-d6)δ=7.47-7.53(m,2H),7.30-7.36(m,2H),7.25(d,J=8.54Hz,2H),7.16-7.20(m,1H),6.99-7.04(m,2H),5.36(s,1H),3.84(dd,J=7.93,10.22Hz,2H),3.53(br.s.,2H),3.36-3.43(m,3H),2.25(br.s.,3H),2.03-2.21(m,4H),1.58(d,J=4.27Hz,5H),1.09-1.13(m,8H)
步骤c 4-{4-[4-(2-氨基丙-2-基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(V)R1a=R1b=甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5d
在0℃,向4-{4-[4-(2-{[(S)-叔丁基亚磺酰基]氨基}丙-2-基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯(180mg,0.341mmol)在MeOH(5mL)中的溶液中添加HCl 37%(0.25mL)。将混合物在室温搅拌持续1h。向该混合物中添加DCM和饱和的NaHCO3溶液,将水相用DCM萃取两次,经Na2SO4干燥并且浓缩,以提供4-{4-[4-(2-氨基丙-2-基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯(143mg,99%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.52(d,J=8.39Hz,2H),7.30-7.36(m,2H),7.22(d,J=8.39Hz,2H),7.14-7.20(m,1H),7.00-7.06(m,2H),3.79-3.86(m,2H),3.52(br.s.,2H),3.36-3.44(m,3H),2.26(br.s.,4H),2.04-2.20(m,4H),1.90(br.s.,2H),1.34-1.40(m,6H).
根据相同的方法,制备以下化合物:
4-{1-[4-(2-氨基丙-2-基)苯基]-4,4-二氟环己基}哌嗪-1-甲酸苯酯[(V)R1a=R1b=甲基,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]步骤5d
1H NMR(500MHz,DMSO-d6)δ=7.52(d,J=8.39Hz,2H),7.31-7.37(m,2H),7.29(d,J=8.39Hz,2H),7.13-7.22(m,1H),7.03(dd,J=0.92,8.54Hz,2H),3.53(br.s.,2H),3.38(br.s.,2H),2.54-2.62(m,2H),2.28(br.s.,2H),2.05-2.24(m,4H),1.68-1.92(m,4H),1.37(s,6H).
制备13
3-(4-溴苯基)戊-3-胺[(XXI)W1=Br,A=苯基,R4=H,R5a和R5b=乙基]的合成步骤5a
步骤aN-[3-(4-溴苯基)戊-3-基]-2-氯乙酰胺的合成
向醇3-(4-溴苯基)戊-3-醇(2.5g,10mmol)和ClCH2CN(1.5g,20mmol)中添加AcOH(25mL),并且将混合物冷却至0℃。逐滴添加H2SO4(1.6mL,30mmol),将温度保持低于10℃。允许反应混合物达到r.t.,搅拌持续4h并且倾倒入冰水(20mL)中。形成浅粉红色沉淀物并过滤。以获得作为浅粉红色固体的N-[3-(4-溴苯基)戊-3-基]-2-氯乙酰胺(2.7g,85%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.11(s,1H),7.44-7.49(m,2H),7.19-7.24(m,2H),4.05-4.11(m,2H),1.75-2.10(m,4H),0.64(t,J=7.40Hz,6H).
根据相同的方法,制备以下化合物:
2-氯-N-[4-(6-氯吡啶-3-基)四氢-2H-吡喃-4-基]乙酰胺[(XXI)W1=Cl,A=吡啶-3-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]步骤5a
1H NMR(400Mhz,氯仿-d)δ=8.51(d,J=2.45Hz,1H)7.79(dd,J=8.38,2.51Hz,1H)7.33(d,J=8.44Hz,1H)3.84-4.01(m,4H)2.08-2.17(m,2H)1.70(br d,J=13.08Hz,2H)。
步骤b 3-(4-溴苯基)戊-3-胺[(XXI)W1=Br,A=苯基,R4=H,R5a和R5b=乙基]的合成
将氯乙酰胺(2.7g,8.5mmol)和硫脲(800mg 10mmol)溶解在1∶5 AcOH/EtOH的混合物(22mL)中并且回流持续10h。将冷却的反应在水中稀释并且将沉淀物滤出。将滤液用NaOH碱化并且用乙酸乙酯萃取。产物以二氧化硅己烷/AcOEt1∶1纯化,以给出3-(4-溴苯基)戊-3-胺(1.4g,68%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.46-7.52(m,2H),7.35-7.39(m,2H),1.54-1.79(m,4H),0.62(t,J=7.40Hz,6H)
根据相同的方法,制备以下化合物:
4-(6-氯吡啶-3-基)四氢-2H-吡喃-4-胺[(XXI)W1=Cl,A=吡啶-3-基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]
1H NMR(400Mhz,氯仿-d)δ=8.54(d,J=2.65Hz,1H)7.79(dd,J=8.38,2.65Hz,1H)7.32(d,J=8.38Hz,1H)3.77-4.01(m,4H)2.08-2.26(m,2H)1.64(dd,J=13.89,2.43Hz,2H)。
制备14
4-(4-(4-乙酰基苯基)四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIII)W1=甲基酮,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5a、步骤5b
步骤1 2-(4-溴苯基)-2-甲基-1,3-二氧杂环戊烷的制备在25℃~30℃在N2下,向1-(4-溴苯基)乙酮(7.0g,35.2mmol,1当量)和乙二醇(9.8g,158mmol,4.5当量)在甲苯(35mL)中的混合物中一次性添加PTSA(0.669g,3.52mmol,0.1当量)。将混合物在回流搅拌持续36小时并且通过迪安-斯塔克分水器(Dean-Stark trap)来除去水。将混合物冷却至50℃并且在50℃在减压中浓缩。将残余物倾倒入饱和的含水Na2CO3(40mL)中并且搅拌持续20min。将水相用混合的溶剂(石油醚/乙酸乙酯=5/1 40ml,30ml)萃取。将合并的有机相用盐水(30mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩,以给出作为浅黄色油的标题化合物(9.0g,纯度80%)。粗制产物在没有纯化的情况下被用于下一步骤。在r.t.、8.51min,LCMS:m/z 244[M+H]+。
步骤2 4-(4-(2-甲基-1,3-二氧杂环戊烷-2-基)苯基)四氢-2H-吡喃-4-醇[(XX)W1=2-甲基-1,3-二氧杂环戊烷-2-基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]的制备
在-65℃经30min的时间段在N2下,向n-BuLi(2.5M,12.6mL,1.2当量)在THF(13mL)中的溶液中逐滴添加2-(4-溴苯基)-2-甲基-1,3-二氧杂环戊烷(6.4g,26.33mmol,1当量)在THF(10.0mL)中的溶液。在-65℃在20min内,将四氢吡喃-4-酮(2.50g,25.01mmol,2.30mL,0.95当量)添加到上述混合物中。将反应混合物在-65℃搅拌持续30min。TLC(石油醚/乙酸乙酯=3/1,Rf=0.24)示出起始材料被完全消耗。将反应混合物在0℃用饱和的含水NH4Cl猝灭并且在20℃搅拌持续30min(在搅拌期间,形成白色沉淀物)并过滤,以给出白色固体。将白色固体溶解在DCM(150mL)中,将有机相用饱和的含水Na2CO3洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。将粗制产物在20℃用MTBE磨碎持续30min,过滤并且在50℃在干燥的烘箱中干燥持续10h,以给出白色粉末(对于两个步骤,3.43g,37%收率)。在r.t.、6.35min,LCMS:m/z 265[M+H]+。
根据相同的方法,制备以下化合物:
4,4-二氟-1-[4-(2-甲基-1,3-二氧杂环戊烷-2-基)苯基]环己醇[(XX)W1=2-甲基-1,3-二氧杂环戊烷-2-基,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基]
1H NMR(400MHz,氯仿-d)δ=12.23(d,J=8.3Hz,2H),12.17-12.09(m,2H),9.93(s,1H),8.79-8.68(m,2H),8.50-8.39(m,2H),7.11-6.86(m,2H),6.70(br t,J=12.0Hz,4H),6.52(br d,J=12.6Hz,2H),6.30(s,3H)。
步骤3 4-(4-溴苯基)四氢-2H-吡喃-4-胺[(XXI)W1=Br,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]的制备步骤5a
在0℃经30min的时间段在N2下,向在50mL圆底烧瓶中的4-(4-(2-甲基-1,3-二氧杂环戊烷-2-基)苯基)四氢-2H-吡喃-4-醇(6.00g,22.7mmol,1.0当量)和2-氯乙腈(28.5g,378mmol,24mL,16.7当量)的混合物中依次逐滴添加AcOH(1.36g,22.0mmol,1.30mL,1.0当量)和H2SO4(2.23g,22.7mmol,1.21mL,1.0当量)。将混合物在20℃搅拌持续10h。将混合物倾倒入冰-水(w/w=1/1)(50mL)中,并且用饱和的含水Na2CO3(3.9g)碱化至pH9。将水相用二氯甲烷(15mL×3)萃取。将合并的有机相用盐水(20mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。将粗制产物在20℃用MTBE(20mL)磨碎持续10min并过滤,以给出白色固体(4.0g,60.0%收率)。
在20℃在N2下,向N-(4-(4-乙酰基苯基)四氢-2H-吡喃-4-基)-2-氯乙酰胺(6.00g,20.29mol,1当量)在EtOH(30mL)中的溶液中添加硫脲(1.85g,24.34mmol,1.2当量)。在20℃,将AcOH(3.65g,60.8mmol,3.48mL,3当量)添加到上述混合物中。将反应混合物在100℃搅拌持续10h。将混合物冷却至60℃并且在55℃在减压中浓缩。将混合物倾倒入冰-水(w/w=1/1)(10mL)中并且用饱和的含水Na2CO3碱化至pH 9。将水相用二氯甲烷(20mL×3)萃取。将合并的有机相用盐水(20mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。将粗制产物在25℃用MTBE(10mL)磨碎持续10min并过滤,以给出作为浅黄色固体的标题化合物(4.0g,90.0%收率)。在r.t.、4.85min,LCMS:m/z 220[M+H]+。
根据相同的方法,制备以下化合物:
1-[4-(1-氨基-4,4-二氟环己基)苯基]乙酮(XXI)[(XXI)W1=甲基酮,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基]
1H NMR(500MHz,DMSO-d6)δ=7.90(d,J=8.6Hz,2H),7.68(d,J=8.6Hz,2H),2.56(s,3H),2.42-2.23(m,2H),2.03(br s,2H),1.99(s,1H),2.00-1.92(m,1H),1.92-1.82(m,2H),1.92-1.82(m,1H),1.79-1.65(m,2H).
步骤4 4-(4-(4-乙酰基苯基)四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯的制备步骤5b
在20℃在N2下,向1-(4-(4-氨基四氢-2H-吡喃-4-基)苯基)乙酮(1.50g,6.84mmol,1.0当量)在DIPEA(5mL)中的溶液中添加NaI(150.0mg)。在20℃,将双(2-氯乙基)氨基甲酸苯酯(2.33g,8.89mmol,1.3当量)添加到上述混合物中。将反应混合物在140℃搅拌持续10h。将混合物冷却至40℃并且在100mL分液漏斗中分离。用HCl(2N)将下层酸化至pH6并且用二氯甲烷(20mL×3)萃取。将合并的有机相用盐水(20mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯=20/1,0/1)纯化,以提供粗制产物,将该粗制产物在25℃用MTBE(20mL)磨碎持续10min并过滤,以给出白色固体(1.28g,45.0%收率)。1H NMR(500MHz,DMSO-d6)δ=7.97(d,J=8.39Hz,2H),7.46(d,J=8.54Hz,2H),7.30-7.35(m,2H),7.13-7.21(m,1H),6.99-7.06(m,2H),3.80-3.90(m,2H),3.46-3.60(m,2H),3.33-3.40(m,4H),2.59(s,3H),2.09-2.32(m,8H)。在r.t.、6.02min,LCMS:m/z 409[M+H]+。对于C24H29N2O4[M+H]+的HRMS(ESI)计算值409.2122,实测值409.2113。
制备15
4-{4-[4-(氨基甲基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(V)R1a=R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5a-步骤5d
步骤a 4-[4-(二甲氧基甲基)苯基]四氢-2H-吡喃-4-醇[(XX)W1=二甲氧基甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]的制备
在-65℃经30min的时间段在N2下,向n-BuLi(2.5M,12.6mL,1.2当量)在THF(13mL)中的溶液中逐滴添加1-溴-4-(二甲氧基甲基)苯(6.4g,26.33mmol,1当量)在THF(10.0mL)中的溶液。在-65℃在20min内,将四氢吡喃-4-酮(2.50g,25.01mmol,2.30mL,0.95当量)添加到上述混合物中。将反应混合物在-65℃搅拌持续30min。将反应混合物在0℃用饱和的含水NH4Cl猝灭并且在20℃搅拌持续30min(在搅拌期间,形成白色沉淀物)并过滤,以给出白色固体。将白色固体溶解在DCM(150mL)中,将有机相用饱和的含水Na2CO3洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。粗制产物为白色粉末(3.98g,60%收率)。
1H NMR(500MHz,DMSO-d6)δ=7.47-7.51(m,2H),7.33(d,J=8.24Hz,2H),5.35(s,1H),5.04(s,1H),3.74-3.81(m,2H),3.67-3.72(m,2H),3.23(s,6H),1.95(dt,J=5.11,12.77Hz,2H),1.52(d,J=12.20Hz,2H)。在r.t.、6.35min,LCMS:m/z 253[M+H]+。
步骤b 2-氯-N-[4-(4-甲酰基苯基)四氢-2H-吡喃-4-基]乙酰胺的制备步骤5a
在0℃经30min的时间段在N2下,向在50mL圆底烧瓶中的4-(4-(2-甲基-1,3-二氧杂环戊烷-2-基)苯基)四氢-2H-吡喃-4-醇(6.00g,22.7mmol,1.0当量)和2-氯乙腈(28.5g,378mmol,24mL,16.7当量)的混合物中依次逐滴添加AcOH(1.36g,22.0mmol,1.30mL,1.0当量)和H2SO4(2.23g,22.7mmol,1.21mL,1.0当量)。将混合物在20℃搅拌持续10h。将混合物倾倒入冰-水(w/w=1/1)(50mL)中,并且用饱和的含水Na2CO3(3.9g)碱化至pH9。将水相用二氯甲烷(15mL×3)萃取。将合并的有机相用盐水(20mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。将粗制产物在20℃用MTBE(20mL)磨碎持续10min并过滤,以给出白色固体(4.0g,60.0%收率)。1HNMR(500MHz,DMSO-d6)δ=9.98(s,1H),8.57(s,1H),7.87(d,J=8.39Hz,2H),7.60(d,J=8.39Hz,2H),4.13(s,2H),3.76(dd,J=2.75,11.74Hz,2H),3.60-3.69(m,2H),2.24(d,J=12.96Hz,2H),1.92-2.02(m,2H)。在r.t.、4.07min,LCMS:m/z 282[M+H]+。
步骤c N-(4-{4-[(E)-{[(S)-叔丁基亚磺酰基]亚氨基}甲基]苯基}四氢-2H-吡喃-4-基)-2-氯乙酰胺的制备
将四乙氧基钛(2.5当量,4.0mL,19.08mmol)、(S)-2-甲基丙烷-2-亚磺酰胺(1.5当量,1.38g,11.4mmol)和2-氯-N-[4-(4-甲酰基苯基)四氢-2H-吡喃-4-基]乙酰胺(2.15g,7.63mmol)在甲苯(20mL)中的混合物加热至80℃过夜,并且然后冷却至室温并浓缩。残余物以用梯度洗脱(100%DCM,然后0-20%丙酮/DCM)的硅胶柱色谱法系统纯化,以提供标题化合物(1.76mg,60%收率)。在r.t.、6.85min,LCMS:m/z 385[M+H]+。
步骤d N-{(E)-[4-(4-氨基四氢-2H-吡喃-4-基)苯基]亚甲基}-2-甲基丙烷-2-亚磺酰胺[(XXI)W1=(S)-叔丁基亚磺酰胺亚甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]的制备步骤5a
在20℃在N2下,向N-(4-{4-[(E)-{[(S)-叔丁基亚磺酰基]亚氨基}甲基]苯基}四氢-2H-吡喃-4-基)-2-氯乙酰胺(1.76g,4.58mmol,1当量)在EtOH(30mL)中的溶液中添加硫脲(0.418g,5.50mmol,1.2当量)。在20℃,将AcOH(0.824mL,13.74mmol,3当量)添加到上述混合物中。将反应混合物在100℃搅拌持续10h。将混合物冷却至60℃并且在减压中浓缩。将混合物倾倒入冰-水(w/w=1/1)(10mL)中,并且用饱和的含水Na2CO3碱化至pH9。将水相用二氯甲烷(20mL×3)萃取。将合并的有机相用盐水(20mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。将粗制产物在25℃用MTBE(10mL)磨碎持续10min并过滤,以给出作为灰白色固体的标题化合物(1.27g,90.0%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.52(s,1H),7.89(d,J=8.39Hz,2H),7.69(d,J=8.54Hz,2H),3.82-3.91(m,2H),3.60-3.69(m,2H),1.89-2.02(m,3H),1.53(d,J=11.74Hz,2H),1.18(s,9H).
在r.t.、2.32min,LCMS:m/z 309[M+H]+。
步骤e 4-(4-{4-[(E)-{[(S)-叔丁基亚磺酰基]亚氨基}甲基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(XXIII)W1=(S)-叔丁基亚磺酰胺亚甲基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基]的制备步骤5b
在20℃在N2下,向N-{(E)-[4-(4-氨基四氢-2H-吡喃-4-基)苯基]亚甲基}-2-甲基丙烷-2-亚磺酰胺(1.20g,3.89mmol,1.0当量)在DIPEA(5mL)中的溶液中添加NaI(130.0mg)。在20℃,将双(2-氯乙基)氨基甲酸苯酯(1.32g,5.1mmol,1.3当量)添加到上述混合物中。将反应混合物在140℃搅拌持续48h。将混合物冷却至40℃并且在100mL分液漏斗中分离。用HCl(2N)将下层酸化至pH 6并且用二氯甲烷(20mL×3)萃取。将合并的有机相用盐水(20mL)洗涤,用无水Na2SO4干燥,过滤并且在真空中浓缩。残余物通过硅胶色谱法(石油醚/乙酸乙酯=20/1,0/1)纯化,以提供粗制产物,将该粗制产物在25℃用MTBE(20mL)磨碎持续10min并过滤,以给出白色固体(0.967g,50.0%收率)。在r.t.、6.58min,LCMS:m/z 498[M+H]+。
步骤f 4-{4-[4-(氨基甲基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(V)R1a=R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5d
在0℃,向4-(4-{4-[(E)-{[(S)-叔丁基亚磺酰基]亚氨基}甲基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(910mg,1.82mmol)在MeOH(5mL)中的溶液中添加HCl 37%(0.25mL)。将混合物在室温搅拌持续1h。向该混合物中添加DCM和饱和的Na2CO3溶液,将水相用DCM萃取两次,经Na2SO4干燥并浓缩,以提供作为灰白色固体的标题化合物(715mg,99%收率)。在r.t.、2.35min,LCMS:m/z 396[M+H]+。
制备16
4-{4-[4-(1-氨基环丙基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(V)R1a和R1b=环丙基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]转化F-步骤5c
步骤a 4-[4-(4-氰基苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(XXIII)W1=-CN,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成转化F
在N2下,向4-[4-(4-溴苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯(2g,4.15mmol,1当量)在H2O(4mL)和二氧六环(40mL)中的混合物中依次添加X-phos(1g,2.08mmol,0.5当量)、K3[Fe(CN)6](6.8g,22.29mmol,5当量)和K2CO3(1.15g,8.32mmol,2当量)、Pd(OAc)2(233.47mg,4.16mmol,0.25当量)。将混合物在100℃搅拌持续16h。TLC(PE:EA=1:1,Rf=0.41)指示反应完成,检测到一个具有较大极性的主要新点(new spot)。对于该步骤,2g*4的反应并行运行。四个反应混合物通过添加的THF(200mL)过滤,通过添加H2O(100mL)来猝灭并且用EtOAc(100mL*3)萃取。将合并的有机层用30mL盐水洗涤,经Na2SO4干燥,过滤并且在减压下浓缩,以给出残余物,将该残余物悬浮在DMF(50mL)中并且搅拌持续2h。将混合物过滤并且将滤饼浓缩,以给出标题化合物[5g(总计来自2g*4的溴代衍生物),72.93%收率]。
1H NMR(500MHz,DMSO-d6)δ=7.37-7.27(t,4H),7.24-7.13(m,3H),7.03(d,J=7.9Hz,2H),3.90-3.80(m,2H)3.51-3.38(m,6H),2.36-2.26(m,4H),2.21-2.06(m,4H),0.95(br d,J=15.8Hz,4H).
步骤b 4-{4-[4-(1-氨基环丙基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(V)R1a和R1b=环丙基,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤5c
在3颈瓶中,将4-[4-(4-氰基苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯(1g,2.43mmol,1当量)溶解在THF(35mL)和Et2O(20mL)中,并且获得混浊的悬浮液。在20℃,添加Ti(Oi-Pr)4(875mg,3.08mmol,908.62μL,1.27当量)。将反应在N2下冷却至-65℃。在-65℃在10min内,添加EtMgBr(3M,2.25mL,2.78当量)并且搅拌持续另外10min,然后允许升高20℃,黄色混合物缓慢变成黑色并且在20℃搅拌持续1小时。然后在0℃添加BF3.Et2O(750mg,5.28mmol,652.17μL,2.18当量)并且在20℃搅拌持续1小时。LCMS示出含期望的产物(RT=0.77,m/z=422.3,M+H)的混合物。对于该步骤,1g*5的反应并行运行,并且对于5个反应,通过LCMS检测到15%~30%的期望的化合物。反应混合物通过在0℃添加HCl(1M,7.5mL)来猝灭,并且然后用NaOH(10%,25mL)稀释并一起用EtOAc(100mL*3)萃取。将合并的有机层用30mL盐水洗涤,经Na2SO4干燥,过滤并且在减压下浓缩。粗制残余物通过中性制备型HPLC(HPLC:柱:Agela DuraShell C18250*25mm*10μm;流动相:[水(10mM NH4HCO3)-ACN];B%:15%-45%,22min)纯化。冻干给出作为白色固体的胺[676mg(总计来自5g的起始材料),12.5%收率]。
1H NMR(500MHz,DMSO-d6)δ=7.39-7.26(m,4H),7.24-7.13(m,3H),7.03(br d,J=7.9Hz,2H),3.92-3.76(m,2H),3.40-3.29(m,6H),2.35(br d,J=15.2Hz,2H),2.29-2.07(m,8H),1.03-0.84(m,4H).
根据相同的方法,制备以下化合物:
4-{1-[4-(1-氨基环丙基)苯基]环戊基}哌嗪-1-甲酸苯酯[(V)R1a和R1b=环丙基,A=苯基,R4=H,RSa和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=7.30-7.36(m,2H),7.25(s,4H),7.15-7.20(m,1H),7.04(dd,J=0.99,8.62Hz,2H),3.51(br.s.,2H),3.32-3.34(br.s.,2H),2.30(br.s.,4H),2.04-2.14(m,2H),1.94-2.04(m,2H),1.62-1.81(m,2H),1.34-1.50(m,2H),0.92-0.97(m,2H),0.86-0.92(m,2H).
制备17
3-{[4-(4-溴苯基)四氢-2H-吡喃-4-基](甲基)氨基}氮杂环丁烷-1-甲酸苄酯[(XXIII)W1=Br,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=N(R6),R6=甲基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]-步骤5b’
步骤1在25℃,将Ti(OEt)4(18.70g,81.99mmol,17.00mL,1.5当量)添加到化合物4-(4-溴苯基)四氢-2H-吡喃-4-胺(14g,54.66mmol,1当量)和3-氧代氮杂环丁烷-1-甲酸苄酯(16.82g,81.99mmol,1.5当量)在无水THF(150mL)中的溶液中。将反应在70℃搅拌持续16h。然后将反应冷却至30℃,并且添加NaBH3CN(10.30g,163.97mmol,3当量)。然后将反应在70℃搅拌持续2h。LCMS(t=1.818min,Ms+H=445.1,447.1)示出反应完成。反应混合物通过在25℃添加H2O 100mL和1M HCl 50mL来猝灭,并且然后用EtOAc 200mL稀释。然后,向残余物中添加饱和的Na2CO3 50mL,并且将混合物在20℃搅拌持续3h。残余物通过硅藻土过滤并且用EtOAc 200mL(100mL*2)萃取。将合并的有机层用饱和的NaCl 200mL(100mL*2)洗涤,经Na2SO4干燥,过滤并且在减压下浓缩。残余物通过快速硅胶色谱法(0%~70%乙酸乙酯/石油醚梯度的洗脱剂,含有10%DCM,以100mL/min)纯化,给出作为浅黄色油的3-{[4-(4-溴苯基)四氢-2H-吡喃-4-基]氨基}氮杂环丁烷-1-甲酸苄酯(20g,44.91mmol,82.16%收率)。1HNMR(400MHz,氯仿-d)δ=7.52-7.45(m,2H),7.37-7.31(m,5H),7.25-7.14(m,2H),5.03(s,2H),4.29-4.20(m,1H),3.87-3.80(m,2H),3.75-3.34(m,6H),2.12-2.06(m,2H),1.81(brd,J=13.9Hz,2H)。
步骤2在0℃,将NaBH3CN(11.29g,179.63mmol,5当量)添加到化合物3-{[4-(4-溴苯基)四氢-2H-吡喃-4-基]氨基}氮杂环丁烷-1-甲酸苄酯(16g,35.93mmol,1当量)、甲醛(8.72g,290.42mmol,8.00mL,8.08当量)和AcOH(8.40g,139.88mmol,8.00mL,3.89当量)在无水MeOH(160mL)中的溶液中。将反应在20℃搅拌持续16h。HPLC(t=2.757min)示出反应完成。将反应在真空中浓缩,并且然后用EtOAc 100mL稀释。在0℃,向残余物中添加饱和的Na2CO3 100mL至pH=8,并且用EtOAc 100mL(50mL*2)萃取。将合并的有机层用盐水50mL(25mL*2)洗涤,经Na2SO4干燥,过滤并且在减压下浓缩。残余物通过快速硅胶色谱法(0%~100%乙酸乙酯/石油醚梯度的洗脱剂,含有20%DCM,以100mL/min)纯化,给出作为浅黄色油的标题化合物(15g,32.65mmol,90.89%收率)。1H NMR(400MHz,氯仿-d)δ=7.52-7.43(m,2H),7.37-7.29(m,6H),7.18-7.07(m,2H),5.06-4.99(m,2H),4.27-4.19(m,1H),3.89-3.82(m,2H),3.77-3.60(m,4H),3.51-3.40(m,2H),2.12(br t,J=5.0Hz,4H),1.27(t,J=7.2Hz,3H)。
制备18
3-[乙酰基(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)氨基]氮杂环丁烷-1-甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=N(R6),R6=乙酰基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]步骤5e
向3-[乙酰基(4-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)氨基]氮杂环丁烷-1-甲酸苄酯(140.00mg,237.39μmol,1当量)在THF(1mL)和H2O(0.2mL)中的溶液中添加I2(6.03mg,23.74μmol,4.78μL,0.1当量)。然后将反应在50℃搅拌持续16h。LCMS示出反应完成。在0℃,向反应中缓慢添加Na2SO3(1M,2mL)以猝灭过量的I2。将反应混合物在真空中浓缩至干燥。残余物通过制备型HPLC(柱:Phenomenex Gemini-NX80*40mm*3μm;流动相:[水(10mM NH4HCO3)-ACN];B%:25%-55%,8min)纯化,以产生作为白色固体的标题化合物(60mg,123.57μmol,52.05%收率,100%纯度)。
1HNMR(500MHz,DMSO-d6)δ=7.26-7.42(m,7H),7.20(d,J=8.39Hz,2H),4.93-5.09(m,2H),4.57-4.73(m,1H),4.02-4.34(m,4H),3.94(q,J=6.76Hz,1H),2.61(br.s.,2H),2.07(s,3H),1.93-2.06(m,4H),1.61-1.87(m,3H),1.21(d,J=6.56Hz,3H).
制备19
{2-[(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)氨基]-2-氧代乙基}氨基甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=-CH2-,m1=1,PG=甲酸苄酯]步骤5b”、步骤5c’和步骤5d
(步骤5b”)在0℃,向1-[4-(1-氨基-4,4-二氟环己基)苯基]乙酮(3.9g,15.40mmol,1当量)、DIEA(15.92g,123.18mmol,21.46mL,8当量)和2-(苄氧基羰基氨基)乙酸(3.87g,18.48mmol,1.2当量)在DCM(30mL)中的溶液中添加T3P(14.70g,23.10mmol,13.74mL,50%纯度,1.5当量)的溶液。将所得到的混合物在25℃搅拌持续3小时。TLC(PE:EA=3:1)示出反应完成,示出反应结束,并且在LCMS上观察到期望的产物。将反应混合物浓缩,并且用EA(100mL)稀释,用H2O(35mL)、饱和的盐水水溶液(40mL)洗涤,经Na2SO4干燥,过滤并浓缩,以给出粗品。粗品通过快速硅胶色谱法(ISCO;40g SepaFlash二氧化硅快速柱,0%~60%EA/PE梯度的洗脱剂,以100mL/min)纯化。(2-{[1-(4-乙酰基苯基)-4,4-二氟环己基]氨基}-2-氧代乙基)氨基甲酸苄酯(4.5g,8.99mmol,58.39%收率,88.8%纯度)作为黄色固体获得。根据LCMS(Rt=1.201min,Ms+1=445.3)为88.8%。
(步骤5c’)在20℃,将Ti(OEt)4(5.93g,25.99mmol,5.39mL,3当量)添加到(2-{[1-(4-乙酰基苯基)-4,4-二氟环己基]氨基}-2-氧代乙基)氨基甲酸苄酯(3.85g,8.66mmol,1当量)和(S)叔丁烷亚磺酰胺(3.67g,30.32mmol,3.5当量)在无水THF(80mL)中的溶液中。将反应在80℃搅拌持续16h。TLC(SiO2,PE:EtOAc=1:1)和LCMS示出反应完成。然后将反应冷却至-70℃。在-70℃,将NaBH4(655.37mg,17.32mmol,2当量)缓慢添加到反应中。然后将反应加温至20℃并且搅拌持续2h。TLC(PE:EtOAc=1:1)和LCMS(Rt=1.199min,Ms+1=550.3)示出反应完成。在0℃,向反应中缓慢添加MeOH(5mL)以猝灭过量的NaBH4,然后添加H2O(25mL)。反应混合物通过硅藻土过滤,滤饼通过EtOAc 100mL(50mL*2)洗涤。将残余物用EtOAc 40mL(20mL*2)萃取。将有机相合并,经Na2SO4干燥,过滤并且在真空中浓缩至干燥。粗品通过制备型HPLC(柱:Agela DuraShell C18 250*70mm*10μm;流动相:[水(10mMNH4HCO3)-ACN];B%:45%-63%,20min)纯化;{2-[(1-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}-4,4-二氟环己基)氨基]-2-氧代乙基}氨基甲酸苄酯(3.8g,6.77mmol,78.21%收率,98%纯度)作为黄色固体获得。根据HPLC(Rt=3.424min)为98%纯度。
(步骤5d)将{2-[(1-{4-[(1S)-1-{[(S)-叔丁基亚磺酰基]氨基}乙基]苯基}-4,4-二氟环己基)氨基]-2-氧代乙基}氨基甲酸苄酯(3.8g,6.91mmol,1当量)溶解在HCl/MeOH(4M,307.27mL,177.79当量)中。将反应在25℃搅拌持续2h。LCMS(Rt=0.952min,Ms+1=446.3)示出反应完成。将反应混合物在减压下浓缩。所得到的残余物通过制备型HPLC(柱:Agela DuraShell C18 250*70mm*10μm;流动相:[水(10mM NH4HCO3)-ACN];B%:28%-55%,20min)纯化;化合物{2-[(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)氨基]-2-氧代乙基}氨基甲酸苄酯(1.75g,3.93mmol,56.82%收率,100%纯度)作为白色固体获得。根据LCMS(Rt=0.952min,Ms+1=446.3)为100%纯度。
1HNMR(500MHz,DMSO-d6)δ=8.00(s,1H),7.40(s,1H),7.28-7.38(m,4H),7.27(s,4H),7.17-7.24(m,J=5.95Hz,1H),5.02(s,2H),3.93(q,J=6.66Hz,1H),3.70(d,J=6.25Hz,2H),2.39-2.48(m,J=12.81Hz,2H),1.77-2.16(m,8H),1.21(d,J=6.56Hz,3H).
根据相同的方法,制备以下化合物:
{(2R)-1-[(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)氨基]-1-氧代丙-2-基}氨基甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=CH3,R9b=H,m1=1,PG=甲酸苄酯]
1HNMR(500MHz,DMSO-d6)δ=8.03(s,1H),7.15-7.44(m,10H),4.94-5.08(m,2H),4.03-4.23(m,1H),3.93(q,J=6.41Hz,1H),2.44(br.s.,2H),1.72-2.19(m,6H),1.22(dd,J=6.79Hz,6H).
{(2S)-1-[(1-{4-[(1S)-1-氨基乙基]苯基}-4,4-二氟环己基)氨基]-1-氧代丙-2-基}氨基甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=CH3,R9b=H,m1=1,PG=甲酸苄酯]
1HNMR(500MHz,DMSO-d6)δ=8.03(s,1H),7.15-7.42(m,10H),4.98-5.07(m,2H),4.11-4.21(m,1H),3.93(q,J=6.56Hz,1H),2.44(br.s.,2H),1.75-2.18(m,6H),1.22(t,J=6.25Hz,6H).
制备20
{2-[(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}氨基甲酸苄酯[(V)R1a=甲基,R1b=H,A=苯基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=NR6,R6=三氟乙酰基,G1=CH2,Z1=CH2,m1=1,PG=甲酸苄酯]步骤b”、步骤c’和步骤d
步骤b”向1-[4-(4-氨基四氢-2H-吡喃-4-基)苯基]乙酮(9g,41.04mmol,1当量)和N-(2-氧代乙基)氨基甲酸苄酯(8.72g,45.15mmol,1.1当量)在DCM(90mL)中的溶液中添加HOAc(3.70g,61.57mmol,3.52mL,1.5当量)并且在25℃搅拌持续0.5h。在25℃,将NaBH(OAc)3(17.40g,82.09mmol,2当量)添加到上述混合物中。将反应混合物在25℃搅拌持续2h。TLC(正己烷∶EtOAc=0∶1)指示反应完成。将反应混合物用H2O(25mL)猝灭,通过硅藻土垫过滤,并且然后用DCM(55mL*2)萃取,用盐水(15mL)洗涤,经Na2SO4干燥,过滤并浓缩。粗品通过快速硅胶色谱法(ISCO;80gSepaFlash二氧化硅快速柱,60%~75%EtOAc/正己烷梯度的洗脱剂,以145mL/min)纯化。(2-{[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基]氨基}乙基)氨基甲酸苄酯(4.5g,10.21mmol,24.89%收率,90%纯度)作为黄色固体获得。
1H NMR(400MHz,氯仿-d)δ=9.83(br s,2H),8.06(d,J=8.38Hz,2H),7.82(br d,J=8.13Hz,2H),7.29-7.36(m,5H),4.94(s,2H)6.70(br s,1H),4.01(br d,J=12.01Hz,2H),3.25-3.55(m,4H),2.73(br s,2H)2.54-2.65(m,7H)。
在0℃,向(2-{[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基]氨基}乙基)氨基甲酸苄酯(3.5g,8.83mmol,1当量)在DCM(20mL)中的溶液中添加吡啶(4.19g,52.97mmol,4.28mL,6当量)和三氟乙酸酐(7.42g,35.31mmol,4.91mL,4当量),并且搅拌持续1h。然后将反应混合物在25℃搅拌持续5h。LCMS示出反应结束并且观察到期望的产物。将反应混合物用H2O(15mL)稀释,并且然后用DCM(100mL*2)萃取,用K2CO3(50mL)和盐水(25mL)洗涤,经Na2SO4干燥,过滤并浓缩,以给出粗制产物。粗品通过快速硅胶色谱法(ISCO;80g SepaFlash二氧化硅快速柱,20%~25%EtOAc/正己烷梯度的洗脱剂,以100mL/min)纯化。(2-{[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基](三氟乙酰基)氨基}乙基)氨基甲酸苄酯(3g,5.79mmol,65.55%收率,95%纯度)作为黄色油获得。
1HNMR(500MHz,DMSO-d6)δ=7.90(br d,J=8.31Hz,2H),7.64(br d,J=8.44Hz,3H),7.25-7.42(m,1H),7.25-7.43(m,4H),5.06(s,2H),3.64-3.86(m,4H),3.26-3.34(m,3H),2.75(br d,J=11.98Hz,1H),2.57(s,3H),2.26-2.41(m,2H).
步骤c’在25℃,将Ti(OEt)4(3.89g,17.06mmol,3.54mL,3当量)添加到(2-{[4-(4-乙酰基苯基)四氢-2H-吡喃-4-基](三氟乙酰基)氨基}乙基)氨基甲酸苄酯(2.8g,5.69mmol,1当量)和(R)-2-甲基丙烷-2-亚磺酰胺(2.41g,19.90mmol,3.5当量)在无水THF(70mL)中的溶液中。将反应在80℃搅拌持续16h。LCMS示出反应完成。然后将反应冷却至-70℃。在-70℃,将三仲丁基硼氢化锂(1M,17.06mL,3当量)缓慢添加到反应中并且搅拌持续2h。LCMS HPLC示出反应完成。在0℃,向反应中缓慢添加MeOH(5mL)以猝灭过量的三仲丁基硼氢化物,然后添加H2O(15mL)。反应混合物通过硅藻土过滤;滤饼通过EtOAc 30mL(15mL*2)洗涤。将残余物用EtOAc20mL(10mL*2)萃取。将有机相合并,经Na2SO4干燥,过滤并且在真空中浓缩至干燥。残余物通过制备型HPLC(柱:Agela DuraShell C18 250*80mm*10μm;流动相:[水(10mM NH4HCO3)-ACN];B%:35%-65%,20min)纯化。{2-[(4-{4-[(1S)-1-{[(R)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}氨基甲酸苄酯(2.8g,4.64mmol,81.57%收率,99%纯度)作为无色油。99%ee。
步骤d然后,向{2-[(4-{4-[(1S)-1-{[(R)-叔丁基亚磺酰基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}氨基甲酸苄酯(2g,3.31mmol,99%纯度,1当量)在THF(20mL)和H2O(20mL)中的溶液中添加I2(1.68g,6.63mmol,1.33mL,2当量)。将反应在25℃搅拌持续16h。LCMS示出反应完成。将反应混合物用Na2SO3(2mL)和H2O(10mL)猝灭,并且然后用DCM(25mL*2)萃取,用盐水(15mL)洗涤,经Na2SO4干燥,过滤并浓缩,以给出粗制产物。残余物通过制备型HPLC(柱:Welch Xtimate C18 250*70mm#10μm;流动相:[水(0.05%NH3H2O+10mM NH4HCO3)-ACN];B%:35%-65%,25min)纯化。
{2-[(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}氨基甲酸苄酯(1.25g,2.48mmol,74.93%收率,98%纯度)作为白色固体获得。
1HNMR(500MHz,DMSO-d6)δ=7.60(t,J=5.80Hz,1H),7.16-7.46(m,9H),5.04(s,2H),3.96(q,J=6.66Hz,1H),3.72-3.80(m,J=12.05Hz,2H),3.63(t,J=7.63Hz,2H),3.19-3.28(m,3H),2.70(d,J=11.74Hz,2H),2.03-2.40(m,3H),1.24(d,J=6.56Hz,3H).
制备21
4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤2a
将4-(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(377.17mg 0.921mmol,1.1当量)溶解在DMSO(11ml)中。然后,向该溶液中依次添加2-(甲基磺酰基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(223.7mg,0.837mmol)、CsF(140mg,0.920mmol)和DIPEA(0.175ml,0.1mmol)。然后将反应混合物在75℃加热持续4小时,并且然后将其置于室温。将反应混合物缓慢倾倒在冷的水/盐水上。将沉淀的固体过滤、用水洗涤并且在真空下干燥。所获得的干燥的固体4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(349mg,70%)在没有进一步纯化的情况下继续使用。
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.38(d,J=6.86Hz,1H),7.63(d,J=9.15Hz,1H),7.30-7.42(m,4H),7.24(d,J=8.24Hz,2H),7.14-7.21(m,1H),6.92-7.06(m,2H),6.18(d,J=9.00Hz,1H),5.47(br.s.,1H),5.01(t,J=6.56Hz,1H),3.81(dd,J=4.96,10.90Hz,2H),3.43-3.57(m,2H),3.36-3.40(m,4H),1.94-2.32(m,8H),1.50(d,J=7.02Hz,3H),1.24-1.45(m,6H)。在r.t.、8.67min,LCMS:m/z 597[M+H]+。对于C34H41N6O4[M+H]+的HRMS(ESI)计算值597.3184,实测值597.3157。
根据相同的方法,制备以下化合物:
4-(3-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}戊-3-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=乙基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.36(d,J=7.02Hz,1H),7.63(d,J=9.15Hz,1H),7.28-7.38(m,6H),7.19(dd,J=7.32Hz,1H),6.99-7.09(m,2H),6.16(d,J=9.00Hz,1H),5.41-5.86(m,1H),5.00(t,J=6.86Hz,1H),3.42-3.57(m,2H),3.32(m,2H),2.34-2.49(m,4H),1.77-1.95(m,4H),1.49(d,J=7.02Hz,3H),1.23-1.45(m,6H),0.73(q,J=7.17Hz,6H).
4-(3-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}氧杂环丁烷-3-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=氧杂环丁烷-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
在r.t.、8.95min,LCMS:m/z 569[M+H]+。
4-(2-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}丙-2-基)哌嗪-1-甲酸乙酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=甲基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸乙酯]
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.35(d,J=7.17Hz,1H),7.62(d,J=9.30Hz,1H),7.41(d,J=8.24Hz,2H),7.30(d,J=7.93Hz,2H),6.15(d,J=9.30Hz,1H),5.41-5.67(m,1H),4.98(m,1H),3.95-4.03(m,2H),3.29(br.,s,4H),2.25-2.39(m,4H),1.21-1.53(m,15H),1.10-1.16(m,3H).
4-(1-乙酰基-4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}哌啶-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=1-乙酰基哌啶-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=8.52-8.60(m,1H),8.36(d,J=6.25Hz,1H),7.57-7.66(m,1H),7.25-7.41(m,6H),7.14-7.21(m,1H),6.90-7.05(m,2H),6.17(d,J=5.49Hz,1H),5.46(br.s,1H),4.97–5.01(m,1H),3.70–3.76(m,2H),3.53–3.62(m,2H),3.15–3.35(m,2H),2.15–2.33(m,8H),1.98(s,3H),1.77–1.96(m,2H)1.30-1.52(m,9H)。在r.t.、8.70min,LCMS:m/z 638[M+H]+。对于C36H43N7O4[M+H]+的HRMS(ESI)计算值638.3450,实测值638.34。
4-(4-{4-[(1R)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=H,R1b=甲基,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.36(d,J=6.86Hz,1H),7.63(d,J=9.30Hz,1H),7.30-7.42(m,4H),7.21-7.27(m,2H),7.17(t,J=7.32Hz,1H),6.90-7.05(m,2H),6.18(d,J=9.30Hz,1H),5.450-5.46(m,1H),4.96-5.03(m,1H),3.76-3.91(m,3H),3.23-3.39(m,6H),2.02-2.31(m,7H),1.47(d,J=6.86hz,3H),1.25-1.46(m,6H)。在r.t.、8.58min,LCMS:m/z 597[M+H]+。对于C34H41N6O4[M+H]+的HRMS(ESI)计算值597.3184,实测值597.3185。
4-(4-{5-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]吡啶-2-基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=嘧啶-2-基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.55-8.63(m,2H),8.20-8.47(m,1H),7.72-7.89(m,1H),7.65(d,J=9.30Hz,1H),7.27-7.39(m,2H),7.15-7.22(m,1H),6.91-7.07(m,2H),6.20(d,J=8.39Hz,1H),5.42-5.79(m,1H),4.97-5.38(m,1H),3.75-3.88(m,2H),3.40-3.54(m,2H),3.18-3.30(4H),2.18-2.34(m,6H),1.97-2.07(m,2H),1.53(d,J=7.02Hz,3H),1.22-1.31(m,6H)。在r.t.、5.95min,LCMS:m/z 598[M+H]+。
4-(4-{4-[(1S)-1-{[4-甲基-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=甲基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.00-8.37(m,1H),7.81(d,J=9.61Hz,1H),7.30-7.45(m,4H),7.23(d,J=8.24Hz,2H),7.14-7.20(m,1H),6.88-7.07(m,2H),6.14-6.20(m,1H),5.45–5.60(br.m,1H),4.48–5.05(br.M,1H),3.81(dd,J=4.96,10.75Hz,4H),3.48(br.m,4H),2.54(s,3H),2.01-2.33(m,8H),1.48(d,J=7.02Hz,3H),0.90–1.42(br m,6H)。在r.t.、6.8min,LCMS:m/z 611[M+H]+。
4-[4-(4-{(1S)-1-[(8-乙基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基]乙基}苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=乙基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.59(s,1H),8.44(d,J=7.02Hz,1H),7.68(d,J=9.30Hz,1H),7.22-7.40(m,4H),7.18(dd,J=7.47,7.32Hz,1H),7.02(,dd,J=2.90,6.71Hz,1H),6.97(d,J=7.78Hz,1H),6.22(d,J=9.30Hz,1H),5.04(t,J=6.94Hz,1H),4.01-4.27(m,2H),3.72-3.92(m,2H),3.46-3.55(m,6H),3.37-3.41(m,2H),1.94-2.33(m,8H),1.49(d,J=7.02Hz,3H),0.83(t,J=6.86Hz,3H)。在r.t.、6.26min,LCMS:m/z 583[M+H]+。
4-[4-(4-{(1S)-1-[(8-环戊基-5-甲基-7-氧代-7,8-二氢吡啶并[2,3-d]嘧啶-2-基)氨基]乙基}苯基)四氢-2H-吡喃-4-基]哌嗪-1-甲酸苯酯[(VI)X=N,U=甲基,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=环戊基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.66(s,1H),8.36(d,J=6.86Hz,1H),7.29-7.42(m,4H),7.23(d,J=8.24Hz,2H),7.15-7.20(m,1H),6.96(d,J=7.93Hz,2H),6.05(d,J=1.07Hz,1H),5.55(d,J=8.85Hz,1H),4.90-5.37(m,1H),3.72-3.89(m,2H),3.49(br.s.,2H),3.39(br.s.,2H),2.30(s,3H),1.93-2.28(m,8H),1.67-1.86(m,5H),1.50(d,J=7.02Hz,3H),1.23-1.47(m,4H)。在r.t.、10.06min,LCMS:m/z 636[M+H]+。
4-(3-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢呋喃-3-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢呋喃-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.57(s,1H),8.38(br.s.,1H),7.63(d,J=9.15Hz,1H),7.27-7.43(m,6H),7.13-7.23(m,1H),6.93-7.09(m,2H),6.17(d,J=7.78Hz,1H),5.42-5.83(m,1H),4.89-5.35(m,1H),4.01-4.13(m,1H),3.88-3.98(m,2H),3.58-3.68(m,1H),3.43-3.56(m,2H),3.28-3.32(m,2H),2.14-2.46(m,6H),1.49(d,J=7.02Hz,3H),1.30-1.45(m,6H)。在r.t.、10.41min,LCMS:m/z 583[M+H]+。
4-(4-{4-[(1S)-1-{[5-甲基-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=CMe,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.64(s,1H),8.35(d,J=6.86Hz,1H),7.22-7.45(m,6H),7.14-7.21(m,1H),6.90-7.06(m,2H),6.05(br.s.,1H),5.45(br.s.,1H),4.94-5.33(m,1H),3.81(dd,J=5.26,10.75Hz,2H),3.43-3.54(m,2H),3.29-3.33(m,4H),2.29(s,3H),2.02-2.28(m,8H),1.49(d,J=7.02Hz,3H),1.23-1.44(m,6H).
在r.t.、9.02min,LCMS:m/z 611[M+H]+。
4-(1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环戊基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.57(s,1H),8.37(d,J=6.86Hz,1H),7.63(d,J=9.30Hz,1H),7.27-7.40(m,6H),7.15-7.21(m,1H),6.91-7.06(m,2H),6.17(d,J=8.24Hz,1H),5.47(br.s.,1H),4.99(t,J=6.86Hz,1H),3.42-3.55(m,3H),3.25-3.33(m,2H),2.17-2.35(m,5H),1.91-2.13(m,4H),1.71(br.s.,2H),1.49(d,J=6.86Hz,3H),1.33-1.44(m,6H)。在r.t.、9.06min,LCMS:m/z581[M+H]+。
4-(4-{4-[(1S)-1-{[7-氧代-8-(戊-3-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=甲基,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=戊-3-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.58(s,1H),8.30-8.44(m,1H),7.66(d,J=9.30Hz,1H),7.29-7.43(m,4H),7.24(d,J=8.24Hz,2H),7.13-7.21(m,1H),6.90-7.03(m,2H),6.08-6.26(m,1H),4.89-5.36(m,2H),3.81(dd,J=3.20,7.17Hz,2H),3.46-3.55(m,2H),1.71-2.25(m,12H),1.48(d,J=7.02Hz,3H),0.63-0.81(m,3H),0.31(t,J=7.32Hz,2H),0.19(t,J=7.32Hz,1H).
4-(4-{4-[(1S)-1-{[4-(二甲基氨基)-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=甲基,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=N(Me)2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=7.64-7.75(m,1H),7.30-7.40(m,4H),7.23(d,J=8.24Hz,2H),7.16-7.20(m,1H),6.93-7.05(m,2H),5.85-5.99(m,1H),5.54(br.s.,1H),4.92-5.15(m,1H),3.76-3.88(m,2H),3.50(br.s.,2H),3.36-3.40(m,2H),2.97-3.13(m,6H),1.97-2.33(m,8H),1.46(d,J=6.87Hz,3H),1.04-1.40(m,6).
制备22
4-{4-[4-(2-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}丙-2-基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=R1b=甲基,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤2a
将4-{4-[4-(2-氨基丙-2-基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯(143mg,0.34mmol,1当量)溶解在1,4-二氧六环(6ml)中。然后,向该溶液中依次添加2-(甲基磺酰基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(104mg,0.308mmol,0.9当量)和DIPEA(0.088ml,1.5当量)。然后将反应混合物在60℃加热持续48小时,并且然后允许加温至室温。将反应混合物缓慢倾倒在冷的水/盐水上。将沉淀的固体过滤、用水洗涤并且在真空下干燥。标题化合物作为固体获得(144mg,77%),并且在没有进一步纯化的情况下继续使用。
1H NMR(DMSO-d6)δ=8.57(s,1H),8.21(br.s.,1H),7.61(d,J=8.85Hz,1H),7.32-7.39(m,4H),7.16-7.24(m,3H),6.94-7.05(m,2H),6.12(d,J=9.15Hz,1H),4.98-5.28(m,1H),3.81(t,J=8.46Hz,2H),3.49(br.s.,2H),3.36-3.43(m,4H),2.12-2.34(m,6H),1.99(br.s.,2H),1.65-1.77(m,6H),0.91-1.35(m,6H)
在r.t.、3.98min,LCMS:m/z 611[M+H]+。
根据相同的方法,制备以下化合物:
4-{4-[4-(1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}环丙基)苯基]四氢-2H-吡喃-4-基}哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a和R1b=环丙基,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.65(s,1H),8.61(s,1H),7.67(d,J=9.30Hz,1H),7.30-7.40(m,1H),7.15-7.22(m,3H),7.08-7.14(m,2H),6.98(d,J=7.78Hz,2H),6.23(d,J=9.30Hz,1H),5.37(br.s,1H),3.72-3.85(m,2H),3.48(br.s.,2H),3.25-3.32(m,4H),1.94-2.31(m,8H),1.03-1.54(m,10H).
制备23
4-(4-{4-[(1S)-1-{[2-氧代-1-(丙-2-基)-1,2-二氢-1,6-萘啶-7-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成步骤2a
在氮气下,向4-(4-{4-[(1S)-1-氨基乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(0.25g,0.61mmol)、7-氯-1-异丙基-1H-[1,6]萘啶-2-酮(0.17g,0.76mmol)和碳酸铯(0.50g,1.53mmol)在甲苯(7mL)中的溶液中添加二氯[1,3-双(2,6-二-3-戊基苯基)咪唑-2-亚基](3-氯吡啶基)钯(II)(0.06g,0.08mmol),并且将混合物在100℃加热过夜。在冷却至室温之后,混合物通过硅胶塞过滤并且用乙酸乙酯洗脱。将滤液在减压下浓缩,并且残余物通过硅胶色谱法(0%至40%丙酮/EtOAc)纯化。
1H NMR(DMSO-d6)δ=8.31(s,1H),7.62(d,J=9.30Hz,1H),7.45-7.49(m,1H),7.40(d,J=8.24Hz,2H),7.30-7.36(m,2H),7.27(d,J=8.24Hz,2H),7.14-7.20(m,1H),6.95-7.02(m,2H),6.43(br.m,1H),6.12(d,J=9.46Hz,1H),4.85-5.07(m,2H),3.76-3.88(m,2H),3.36-3.53(m,6H),2.01-2.30(m,8H),1.48(d,J=6.86Hz,3H),1.41(d,J=6.56Hz,3H),1.22–1.28(br.m,3H)。在r.t.、7.39min,LCMS:m/z 596[M+H]+。对于C35H42N5O4[M+H]+的HRMS(ESI)计算值596.3232,实测值596.3244。
根据相同的方法,制备以下化合物:
4-(4,4-二氟-1-{4-[(1S)-1-{[2-氧代-1-(丙-2-基)-1,2-二氢-1,6-萘啶-7-基]氨基}乙基]苯基}环己基)哌嗪-1-甲酸苄酯[(VI)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苄酯]
1H NMR(DMSO-d6)δ=8.29(s,1H),7.61(d,J=9.30Hz,1H),7.45(d,J=6.25Hz,1H),7.34-7.40(m,2H),7.23-7.34(m,7H),6.17-6.41(m,1H),6.11(d,J=9.15Hz,1H),4.86-5.04(m,3H),2.07-2.28(m,8H),1.72-1.92(m,8H),1.09-1.60(m,9H)。
4-(4,4-二氟-1-{4-[(1S)-1-{[2-氧代-1-(丙-2-基)-1,2-二氢-1,6-萘啶-7-基]氨基}乙基]苯基}环己基)哌嗪-1-甲酸苄酯[(VI)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]
1H NMR(DMSO-d6)δ=8.30(s,1H),7.62(d,J=9.46Hz,1H),7.43-7.53(m,1H),7.37-7.43(m,2H),7.28-7.37(m,4H),7.12-7.20(m,1H),6.99(d,J=7.78Hz,2H),6.17-6.54(m,1H),6.12(d,J=8.85Hz,2H),4.73-5.18(m,2H),3.50(d,J=3.97Hz,2H),3.25-3.33m,2H),2.55(d,J=11.90Hz,2H),2.03-2.34(m,6H),1.80(br.s.,4H),1.48(d,J=6.86Hz,3H),1.18-1.44(m,6H).
7-{[(1S)-1-(4-{1-[(1-苄基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(VI)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NR6,R6=甲基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
1H NMR(DMSO-d6)δ=8.26(s,1H),7.57(d,J=9.30Hz,1H),7.43(d,J=7.17Hz,1H),7.23-7.37(m,10H),6.31-6.47(m,1H),6.09(d,J=9.15Hz,1H),4.94(br.s.,3H),4.15(t,J=6.86Hz,1H),3.40-3.72(m,4H),2.31-2.40(m,2H),2.11(s,3H),1.88-2.02(m,4H),1.71(br.s.,2H),1.21-1.47(m,9H).
7-{[(1S)-1-(4-{1-[(1-苄基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(VI)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NR6,R6=乙酰基,G1=CH,Z1、Z2=-CH2-,m1=m2=1,PG=甲酸苄酯]
1H NMR(DMSO-d6)δ=8.26(s,1H),7.59(d,J=9.30Hz,1H),7.44(d,J=7.02Hz,1H),7.27-7.38(m,7H),7.23(d,J=8.39Hz,2H),6.26-6.57(m,1H),6.10(d,J=9.30Hz,1H),4.83-5.13(m,J=5.19Hz,3H),4.51-4.72(m,1H),4.05-4.34(m,4H),2.54-2.65(m,2H),2.06(s,3H),1.89-2.04(m,4H),1.64-1.86(m,2H),1.21-1.53(m,9H).
制备24
4-(4-{4-[(1S)-1-{[4-甲基-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=NH2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,PG=甲酸苯酯]的合成
向4-(4-{4-[(1S)-1-({4-[(2,4-二甲氧基苄基)氨基]-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基}氨基)乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(175mg,0.227mmol)在CH2Cl2(5mL)中的溶液中添加三氟乙酸(2mL)。将黄色溶液在室温搅拌过夜。添加15mL CH2Cl2,并且将有机溶液用饱和的NaHCO3溶液洗涤,以Na2SO4干燥并蒸发至干燥,以给出170mg的标题化合物。将溶剂蒸发,并且将残余物悬浮。将反应混合物蒸发至干燥,并且残余物在硅胶(AcOEt/己烷:1/1)上纯化,以给出白色固体(170mg)。1H NMR(DMSO-d6)δ=7.84(d,J=9.6Hz,1H),7.51-7.39(m,1H),7.38-7.06(m,7H),7.03-6.87(m,3H),5.00(br.s.,1H),3.90-3.73(m,3H),3.56-3.43(m,3H),2.33-1.98(m,8H)。
制备25
2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]步骤2b
向4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲酸苯酯(149.0mg,0.25mmol)在异丙醇(4.0mL)的混合物中的溶液中添加NaOH(1.0mL,12.5mmol)。将混合物在80℃搅拌8小时,并且然后浓缩至干燥,5%-10%的氨基甲酸异丙酯仍然存在于混合物中。将粗品溶解在DCM和水pH 10中,将有机相分离并且用盐水洗涤,干燥(Na2SO4)并在真空中除去挥发物,以提供作为浅黄色油的2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(109.0mg,92%)。
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.41(m,1H),7.63(d,J=9.30Hz,1H),7.29-7.42(m,2H),7.13-7.24(m,2H),6.16(d,J=9.30Hz,1H),5.49(br.s.,1H),4.91-5.35(m,1H),3.76(d,J=7.47Hz,2H),3.36(m,3H),2.55-2.62(m,4H),1.85-2.20(m,8H)1.49(d,J=6.81Hz 3H),1.21-1.43(m,6H).
根据相同的方法,制备以下化合物:
2-{[(1R)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=H,R1b=甲基,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=7.17Hz,1H),7.63(d,J=9.15Hz,1H),7.30-7.39(m,2H),7.15-7.24(m,2H),6.16(d,J=9.15Hz,1H),5.42-5.56(m,1H),5.02-5.04(m,1H),3.71-3.80(m,2H),3.28-3.37(m,2H),2.55-2.61(m,4H),1.95-2.15(m,8H),1.47(d,J=6.86Hz,3H),1.03-1.44(m,6H).
8-乙基-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=乙基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(500MHz,DMSO-d6)δ=8.58(s,1H),8.42(d,J=7.02Hz,1H),7.68(d,J=9.30Hz,1H),7.32-7.42(m,2H),7.15-7.25(m,2H),6.21(d,J=9.30Hz,1H),5.06(t,J=7.09Hz,1H),4.05-4.30(m,2H),3.64-3.87(m,2H),3.26-3.31(m,2H),2.57-2.69(m,4H),1.88-2.22(m,8H),1.49(d,J=6.86Hz,3H),0.91(t,J=6.71Hz,3H).
2-{[(1S)-1-{6-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-3-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=嘧啶-2-基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.55-8.63(m,2H),8.20-8.47(m,1H),7.72-7.89(m,1H),7.65(d,J=9.30Hz,1H),7.27-7.39(m,3H),7.15-7.22(m,1H),6.91-7.07(m,2H),6.20(d,J=8.39Hz,1H),5.42-5.79(m,1H),4.97-5.38(m,1H),3.75-3.88(m,2H),3.40-3.54(m,2H),3.19-3.30(m,2H),2.16-2.35(m,4H),1.97-2.07(m,2H),1.53(d,J=7.0Hz,3H),1.22-1.45(m,6H).
4-甲基-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=甲基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(500MHz,DMSO-d6)δ=8.29(d,J=7.32Hz,1H),7.80(d,J=9.61Hz,1H),7.27-7.43(m,2H),7.16-7.23(m,2H),6.12(d,J=9.76Hz,1H),5.47-5.57(m,1H),4.98-5.03(m,1H),3.76(d,J=7.17Hz,2H),3.25-3.33(m,2H),2.58(br.s.,4H),2.48(s,3H),1.89-2.22(m,8H),1.47(d,J=7.02Hz,3H),1.12-1.41(m,6H).
8-环戊基-5-甲基-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=CMe,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=环戊基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.64(s,1H),8.35(d,J=6.86Hz,1H),7.31(d,J=7.78Hz,2H),7.19(d,J=7.93Hz,2H),6.01-6.07(m,1H),5.53-5.92(m,1H),4.99(t,J=6.86Hz,1H),3.67-3.90(m,2H),3.27-3.31(m,2H),2.58(br.s.,3H),2.29(s,5H),1.92-2.17(m,8H),1.67-1.88(m,4H),1.55(br.s.,2H),1.49(d,J=7.02Hz,3H),1.35-1.42(m,2H).
2-{[(1S)-1-{4-[3-(哌嗪-1-基)四氢呋喃-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(VI)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢呋喃-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.50-8.59(m,1H),8.37(br.s.,1H),7.62(d,J=9.30Hz,1H),7.20-7.42(m,4H),6.16(d,J=9.00Hz,1H),5.49(br.s.,1H),5.02(br.s.,1H),3.80-4.05(m,5H),2.61-2.71(m,4H),2.08-2.36(m,6H),1.48(d,J=7.02Hz,3H),1.12-1.42(m,6H).
5-甲基-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(VI)X=N,U=C-Me,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.63(s,1H),8.10-8.38(m,1H),7.27-7.43(m,2H),7.11-7.25(m,2H),6.03(s,1H),5.48(br.s.,1H),5.03(br.s.,1H),3.76(d,J=6.71Hz,2H),3.26-3.33(m,2H),2.58(br.s.,5H),2.29(s,3H),1.83-2.24(m,8H),1.49(d,J=6.86Hz,3H),1.27-1.43(m,6H).
2-{[(1S)-1-{4-[1-(哌嗪-1-基)环戊基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.56(s,1H),8.14-8.39(m,1H),7.62(d,J=9.15Hz,1H),7.28-7.39(m,2H),7.23-7.27(m,2H),6.15(d,J=9.15Hz,1H),5.50(br.s.,1H),4.94-5.35(m,1H),2.58(br.s.,4H),2.06-2.29(m,4H),1.82-2.03(m,5H),1.65(br.s.,2H),0.82-1.54(m,11H).
4-氨基-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=NH2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
在r.t.、6.16min,LCMS:m/z 514[M+Na]+。对于C27H38N7NaO2[M+Na]+的HRMS(ESI)计算值514.2907,实测值514.2907。
8-(戊-3-基)-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=戊-3-基,R3=R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.53-8.61(m,1H),8.28-8.42(m,1H),7.66(d,J=9.30Hz,1H),7.27-7.41(m,2H),7.19(d,J=8.08Hz,2H),6.08-6.27(m,1H),4.83-5.39(m,2H),3.71-3.86(m,3H),3.29-3.33(m,2H),2.56-2.66(m,4H),1.70-2.18(m,12H),1.48(d,J=7.0Hz,3H),0.62-0.81(m,3H),0.35(t,J=7.47Hz,3H).
4-(二甲基氨基)-8-(戊-3-基)-2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=N(Me)2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
在r.t.、7.77min,LCMS:m/z 520[M+H]+。对于C29H42N7O2[M+Na]+的HRMS(ESI)计算值520.3395,实测值520.3393。
制备26
2-{[(1S)-1-(4-{4-[氮杂环丁烷-3-基(甲基.)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=甲基]步骤2b
在氮气气氛下,向3-[甲基(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)氨基]氮杂环丁烷-1-甲酸苄酯(200.0mg,0.327mmol)在THF(30.0mL)中的搅拌的溶液中添加甲酸铵(1.4ml的25%水溶液),随后添加10%Pd/C(120mg)。将悬浮液在60℃搅拌持续1小时。通过经过硅藻土垫的过滤除去催化剂并且将滤液在真空下蒸发至干燥,以给出标题产物(150mg,96%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.53-8.58(m,1H),8.37(d,J=7.02Hz,1H),7.58-7.67(m,1H),7.31-7.37(m,2H),7.26(d,J=7.93Hz,2H),6.65(s,1H),6.16(d,J=9.46Hz,1H),5.49(br.s,1H),5.03(br.m,1H),3.69(m,2H),3.06-3.27(m,7H),2.18(s,2H),2.04-2.15(m,3H),1.86-1.97(m,2H),1.50(d,J=6.10Hz,3H),1.35(m,6H)。在r.t.、6.28min,LCMS:m/z 477[M+H]+。对于C27H37N6O2[M+H]+的HRMS(ESI)计算值477.2973,实测值477.2971。
根据相同的方法,制备以下化合物:
2-{[(1S)-1-{4-[4,4-二氟-1-(哌嗪-1-基)环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.37(d,J=6.71Hz,1H),7.62(d,J=9.30Hz,1H),7.22-7.42(m,4H),6.16(d,J=9.30Hz,1H),5.41-5.79(m,1H),4.96-5.33(m,1H),2.55-2.64(m,4H),2.00-2.22(m,8H),1.66-1.79(m,4H),1.17-1.50(m,9H)。在r.t.、8.63min,LCMS:m/z 511[M+H]+。
对于C28H37F2N6O2[M+H]+的HRMS(ESI)计算值511.2992,实测值511.2987。
7-{[(1S)-1-{4-[4,4-二氟-1-(哌嗪-1-基)环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(II)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2]
1H NMR(DMSO-d6)δ=8.19-8.38(m,1H),7.61(d,J=9.30Hz,1H),7.26-7.47(m,5H),6.11(d,J=9.30Hz,1H),4.79-5.16(m,1H),2.67-2.72(m,4H),2.02-2.20(m,8H),1.66-1.82(m,4H),1.15-1.52(m,9H).
N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-D-丙氨酸酰胺[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=N(Me)2,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=CH3,R9b=H,m1=1]
在r.t.、9.60min,LCMS:m/z 513[M+H]+。对于C27H35F2N6O2[M+H]+的HRMS(ESI)计算值513.2784,实测值513.2774。
N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-L-丙氨酸酰胺[(II)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=N(Me)2,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=CH3,R9b=H,m1=1]
在r.t.、9.58min,LCMS:m/z 513[M+H]+。对于C27H35F2N6O2[M+H]+的HRMS(ESI)计算值513.2784,实测值513.2772。
实施例1
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 1,步骤1a
在0℃,向2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(57.0mg,0.12mmol)在DCM(1.0mL)中的溶液中添加丙烯酰氯(0.01mL,0.13mmol)。在30分钟之后,将反应用水猝灭。将混合物用DCM萃取,经Na2SO4干燥,过滤并且浓缩,以产生黄色油。粗制产物通过硅胶色谱法(1%至10%MeOH/DCM)纯化,以给出作为白色泡沫的标题产物(40mg,66%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.31(d,J=6.71Hz,1H),7.61(d,J=9.28Hz,1H),7.33(d,J=7.81Hz,2H),7.21(d,J=8.18Hz,2H),6.63(dd,J=10.50,16.72Hz,1H),6.15(d,J=9.28Hz,1H),5.91-6.03(m,1H),5.55(d,J=10.62Hz,1H),5.42(br.m.1H),5.00(t,J=6.65Hz,1H),3.79(d,J=7.08Hz,2H),3.34-3.54(m,6H),2.12(br.s.,8H),1.49(d,J=6.96Hz,3H),1.42-1.21(br.m.6H)。在r.t.、6.03min,LCMS:m/z531[M+H]+。对于C30H39N6O3[M+H]+的HRMS(ESI)计算值531.3078,实测值531.3067。
根据相同的方法,制备以下化合物:
2-{[(1S)-1-{4-[2-(4-丙烯酰基哌嗪-1-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=甲基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd2
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.35(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.38-7.46(m,2H),7.24-7.36(m,2H),6.73(dd,J=10.45,16.70Hz,1H),6.15(d,J=9.30Hz,1H),5.99-6.10(m,1H),5.63(dd,J=2.14,10.52Hz,1H),5.40-5.56(br.s.,1H),4.98(q,J=6.71Hz,1H),3.46(br.s.,4H),2.22-2.41(m,4H),1.47(d,J=6.71Hz,3H),1.29-1.44(br.m,6H),1.25(s,3H),1.24(s,3H)。在r.t.、6.49min,LCMS:m/z 489[M+H]+。对于C28H37N6O2[M+H]+的HRMS(ESI)计算值489.2973,实测值489.2979。
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)氧杂环丁烷-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=氧杂环丁烷-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 3
1H NMR(500MHz,DMSO-d6)δ=8.51-8.59(m,1H),8.15-8.40(m,1H),7.60-7.64(m,1H),7.33-7.43(m,2H),7.03-7.10(m,2H),6.66(dd,J=10.45,16.70Hz,1H),6.15(d,J=9.30Hz,1H),5.93-6.00(m,1H),5.56(d,J=10.37Hz,1H),5.35-5.42(br.,m,1H),4.99(q,J=7.30Hz,1H),4.69-4.75(m,4H),3.52(br.s.,4H),1.99-2.22(m,4H),1.48(d,J=7.30Hz,3H),1.17-1.32(br.,m,6H)。在r.t.、8.72min,LCMS:m/z 503[M+H]+。对于C28H35N6O3[M+H]+的HRMS(ESI)计算值503.2765,实测值503.2758。
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)戊-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=乙基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd4
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.18-7.39(m,4H),6.68(dd,J=10.45,16.55Hz,1H),6.15(d,J=9.30Hz,1H),6.02(dd,J=1.91,16.55Hz,1H),5.59(dd,J=1.91,10.29Hz,1H),5.37-5.42(br.,m,1H),4.99(t,J=6.63Hz,1H),3.37-3.51(m,4H),2.25-2.41(m,4H),1.75-1.94(m,4H),1.48(d,J=7.02Hz,3H),1.35-1.44(br.,m,6H),0.70(q,J=6.96Hz,6H)。在r.t.、7.73min,LCMS:m/z517[M+H]+。对于C30H41N6O2[M+H]+的HRMS(ESI)计算值517.3286,实测值517.3271。
2-{[(1S)-1-{4-[1-乙酰基-4-(4-丙烯酰基哌嗪-1-基)哌啶-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=N-乙酰基哌啶-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 6
1H NMR(500MHz,DMSO-d6)δ=8.48-8.59(m,1H),8.34(d,J=6.71Hz,1H),7.62(d,J=9.30Hz,1H),7.32(d,J=8.08Hz,2H),7.23(d,J=8.08Hz,2H),6.64(dd,J=10.45,16.70Hz,1H),6.15(d,J=9.30Hz,1H),5.97(d,J=16.47Hz,1H),5.56(d,J=10.68Hz,1H),5.36-5.42(br.,m,1H),4.99(t,J=6.62Hz,1H),3.37-3.57(m,8H),2.08-2.33(m,4H),1.97(s,3H),1.74-1.94(m,4H),1.48(d,J=7.02Hz,3H),1.35-1.44(br.,m,6H)。在r.t.、6.71min,LCMS:m/z 572[M+H]+。对于C32H42N7O3[M+H]+的HRMS(ESI)计算值572.3344,实测值572.3356。
2-{[(1S)-1-{4-[4-(4-丙酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙酰基]cpd 8
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.38(m,1H),7.62(d,J=9.30Hz,1H),7.30-7.43(m,2H),7.20(d,J=8.08Hz,2H),6.15(d,J=9.30Hz,1H),5.35-5.85(m,1H),4.90-5.32(m,1H),3.79(dd,J=5.41,10.75Hz,2H),3.26-3.32(m,6H),1.93-2.28(m,10H),1.48(d,J=7.02Hz,3H),1.35-1.44(br.,m,6H),0.81-0.88(m,3H)。在r.t.、6.38min,LCMS:m/z 533[M+H]+。对于C30H41N6O3[M+H]+的HRMS(ESI)计算值533.3235,实测值533.3232。
2-{[(1R)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=H,R1b=甲基,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 9
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.29-7.42(m,2H),7.18-7.24(m,2H),6.64(dd,J=10.52,16.78Hz,1H),6.15(d,J=9.30Hz,1H),5.96(dd,J=1.98,16.78Hz,1H),5.55(dd,J=1.98,10.52Hz,1H),5.32-5.47(m,1H),4.94-5.12(m,1H),3.79(dd,J=4.96,10.60Hz,2H),3.39-3.49(br.,m,6H),2.10(br.s.,8H),1.48(d,J=7.02Hz,3H),1.23-1.40(br.,m,6H).
在r.t.、6.36min,LCMS:m/z 531[M+H]+。对于C30H39N6O3[M+H]+的HRMS(ESI)计算值531.3078,实测值531.3077。
2-{[(1S)-1-{6-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-3-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=吡啶-3-基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 12
1H NMR(500MHz,DMSO-d6)δ=8.50-8.64(m,2H),8.41(d,J=6.71Hz,1H),7.69-7.85(m,1H),7.63(d,J=9.30Hz,1H),7.31(d,J=8.24Hz,1H),6.64(dd,J=10.29,16.55Hz,1H),6.17(d,J=9.30Hz,1H),5.97(d,J=16.17Hz,1H),5.56(d,J=10.52Hz,1H),5.41(br.s,1H),5.04(q,J=6.71Hz,1H),3.74-3.82(m,2H),3.37-3.45(m,4H),3.15-3.28(m,2H),1.96-2.32(m,8H),1.50(d,J=7.02Hz,3H),1.20-1.42(m,6H).
在r.t.、4.69min,LCMS:m/z 532[M+H]+。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-甲基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=甲基,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 13
1H NMR(500MHz,DMSO-d6)δ=8.27(d,J=6.86Hz,1H),7.80(d,J=9.46Hz,1H),7.31(d,J=7.93Hz,2H),7.19(d,J=8.08Hz,2H),6.63(dd,J=10.37,16.78Hz,1H),6.12(d,J=9.30Hz,1H),5.96(dd,J=2.06,16.70Hz,1H),5.55(dd,J=2.14,10.22Hz,1H),5.44(br.s,1H),4.98(q,J=6.56Hz,1H),3.75-3.82(m,2H),3.38-3.46(m,4H),3.27-3.32(m,2H),2.48(s,3H),2.0-2.18(m,8H),1.47(d,J=7.02Hz,3H),1.18-1.42(m,6H).
在r.t.、4.69min,LCMS:m/z 545[M+H]+。对于C31H41N7O3[M+H]+的HRMS(ESI)计算值545.3235,实测值545.3232。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=乙基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 14
1H NMR(500MHz,DMSO-d6)δ=8.58(s,1H),8.40(d,J=7.17Hz,1H),7.67(d,J=9.30Hz,1H),7.35(d,J=8.10Hz,2H),7.21(d,J=8.10Hz,2H),6.64(dd,J=10.52,16.62Hz,1H),6.20(d,J=9.30Hz,1H),5.96(dd,J=2.13,16.62Hz,1H),5.51-5.64(m,1H),5.03(t,J=6.94Hz,1H),3.91-4.16(m,2H),3.74-3.86(m,2H),3.40-3.47(m,6H),1.94-2.24(m,8H),1.47(d,J=7.17Hz,3H),0.79(t,J=6.86Hz,3H).
在r.t.、4.93min,LCMS:m/z 517[M+H]+。对于C29H37N6O3[M+H]+的HRMS(ESI)计算值517.3078,实测值517.3077。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=CMe,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=环戊基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 15
1H NMR(500MHz,DMSO-d6)δ=8.64(s,1H),8.32(d,J=7.02Hz,1H),7.29(d,J=8.08Hz,2H),7.20(d,J=8.08Hz,2H),6.64(dd,J=10.37,16.62Hz,1H),6.03(s,1H),5.97(dd,J=1.83,16.62Hz,1H),5.54-5.64(m,1H),5.51(q,J=9.01Hz,1H),4.96(q,J=6.94Hz,1H),3.70-3.86(m,2H),3.41-3.51(m,4H),3.29-3.32(m,2H),2.29(s,3H),1.97-2.22(m,8H),1.64-1.92(m,4H),1.47(d,J=7.17Hz,3H),1.23-1.45(m,4H).
在r.t.、8.0min,LCMS:m/z 571[M+H]+。
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 11
1H NMR(500MHz,DMSO-d6)δ=8.29(s,1H),7.61(d,J=9.30Hz,1H),7.43(d,J=6.71Hz,1H),7.37(d,J=8.24Hz,2H),7.23(d,J=8.24Hz,2H),6.66(dd,J=10.52,16.62Hz,1H),6.30(br.s.,1H),6.10(d,J=9.30Hz,1H),5.98(dd,J=2.29,16.62Hz,1H),5.55-5.60(m,1H),4.94(br.s.,2H),3.74-3.86(m,2H),3.46(br.s.,6H),2.00-2.21(m,8H),1.46(d,J=6.71Hz,3H),1.23-1.40(m,6H)。在r.t.、4.72min,LCMS:m/z 530[M+H]+。对于C31H40N5O3[M+H]+的HRMS(ESI)计算值530.3126,实测值530.3128。
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)四氢呋喃-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢呋喃-3-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 17
1H NMR(500MHz,DMSO-d6)δ=8.51-8.60(m,1H),8.12-8.38(m,1H),7.62(d,J=9.30Hz,1H),7.20-7.35(m,4H),6.60-6.72(m,1H),6.15(d,J=9.30Hz,1H),5.91-6.09(m,1H),5.55-5.61(m,1H),5.43(br.s,1H),4.93-5.05(m,1H),3.99-4.10(m,1H),3.85-3.98(m,2H),3.56-3.65(m,1H),3.39-3.53(m,4H),2.09-2.42(m,6H),1.47(d,J=7.02Hz,3H),1.23-1.39(m,6H).
在r.t.、7.77min,LCMS:m/z 517[M+H]+。
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)环戊基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 16
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.33(d,J=6.86Hz,1H),7.62(d,J=9.30Hz,1H),7.20-7.37(m,4H),6.64(dd,J=10.37,16.62Hz,1H),6.15(d,J=9.30Hz,1H),5.97(dd,J=1.91,16.70Hz,1H),5.52-5.61(m,1H),5.42(br.s,1H),4.98(t,J=7.02Hz,1H),3.39-3.52(m,4H),2.09-2.29(m,4H),1.91-2.08(m,4H),1.68(br.s.,2H),1.31-1.51(m,9H)。在r.t.、7.01min,LCMS:m/z 515[M+H]+。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-5-甲基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=C-Me,Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 18
1H NMR(500MHz,DMSO-d6)δ=8.62(s,1H),8.31(d,J=6.71Hz,1H),7.27-7.42(m,2H),7.13-7.26(m,2H),6.63(dd,J=10.52,16.62Hz,1H),6.03(s,1H),5.85-5.99(m,1H),5.51-5.60(m,1H),5.39(br.s,1H),4.99(t,J=6.86Hz,1H),3.79(dd,J=5.57,11.06Hz,2H),3.40-3.49(m,2H),3.28-3.33(m,4H),2.28(s,3H),2.08(d,J=9.91Hz,8H),1.47(d J=7.0Hz,3H),1.23-1.39(m,6H)。在r.t.、6.81min,LCMS:m/z 545[M+H]+。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-氨基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=NH2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 19
1H NMR(500MHz,DMSO-d6)δ=7.83(d,J=9.61Hz,1H),7.35-7.47(m,1H),7.16-7.33(m,4H),6.97(br.s.,2H),6.64(dd,J=10.60,16.40Hz,1H),5.83-6.06(m,2H),5.56(d,J=10.07Hz,1H),4.90-5.32(m,2H),3.71-3.90(m,2H),3.40-3.51(m,4H),3.28-3.32(m,2H),1.92-2.27(m,8H),1.43(d,J=7.02Hz,3H),1.21-1.35(m,6H)。在r.t.、5.88min,LCMS:m/z546[M+H]+。
2-{[(1S)-1-(4-{4-[4-(2-甲基丙烯酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=2-甲基丙烯酰基]cpd 21
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.36(d,J=7.02Hz,1H),7.62(d,J=9.30Hz,1H),7.33(d,J=7.93Hz,2H),7.20(d,J=8.08Hz,2H),6.15(d,J=9.15Hz,1H),5.37-5.87(m,1H),5.05(s,1H),4.99(d,J=6.71Hz,1H),4.73(s,1H),3.71-3.84(m,2H),3.28-3.33(m,6H),1.94-2.33(m,8H),1.62-1.78(m,3H),1.48(d,J=6.76Hz,3H),1.23-1.41(m,6H)。在r.t.、6.93min,LCMS:m/z 545[M+H]+。对于C31H41N6O3[M+H]+的HRMS(ESI)计算值545.3078,实测值545.306。
2-{[(1S)-1-(4-{4-[4-(氯乙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=氯乙酰基]cpd 22
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.35(d,J=7.17Hz,1H),7.62(d,J=9.15Hz,1H),7.31-7.43(m,2H),7.21(d,J=8.08Hz,2H),6.15(d,J=9.30Hz,1H),5.38-5.76(m,1H),4.88-5.33(m,1H),4.11-4.33(m,2H),3.71-3.86(m,2H),3.28-3.33(m,6H),1.94-2.29(m,8H),1.48(d,J=6.86Hz,3H),1.23-1.41(m,6H)。在r.t.、6.64min,LCMS:m/z554[M+H]+。
2-{[(1S)-1-(4-{4-[4-(3-氯丙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=3-氯丙酰基]cpd 23
1H NMR(500MHz,DMSO-d6)δ=8.57(br.s,1H),8.43(br.s,1H),7.62(d,J=9.15Hz,1H),7.45-7.57(m,2H),7.21-7.33(m,2H),6.17(d,J=9.15Hz,1H),5.42(br.s,1H),5.05(br.s,1H),4.33-4.43(m,2H),3.73-3.99(m,2H),3.55-3.70(m,4H),3.28-3.32(m,2H),2.65-2.96(m,2H),1.99-2.29(m,8H),1.50(br.s,3H),1.21-1.41(m,6H)。在r.t.、6.93min,LCMS:m/z 567[M+H]+。对于C30H40ClN6O3[M+H]+的HRMS(ESI)计算值567.2845,实测值567.2852。
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 20
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.33(d,J=7.17Hz,1H),7.62(d,J=9.15Hz,1H),7.18-7.32(m,4H),6.63(dd,J=10.45,16.55Hz,1H),6.15(d,J=9.30Hz,1H),5.96(dd,J=1.83,16.78Hz,1H),5.51-5.58(m,1H),5.25-5.40(m,1H),4.95-5.01(m,1H),3.39-3.46(m,2H),1.85-2.25(m,10H),1.58-168(m,2H),1.47(d,J=7.02Hz,3H),1.20-1.44(m,10H).
在r.t.、7.28min,LCMS:m/z 529[M+H]+。对于C31H41N6O3[M+H]+的HRMS(ESI)计算值529.3286,实测值529.3282。
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮[(I)X=N,U=CH2,Y=O、R1a=甲基,R1b=H,A=苯基,R2=乙基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 24
1H NMR(500MHz,DMSO-d6)δ=7.99(br.s.,1H),7.86(br.s.,1H),7.32(d,J=6.86Hz,2H),7.19(d,J=8.39Hz,2H),6.66(dd,J=10.45,16.70Hz,1H),5.99(dd,J=2.29,16.62Hz,1H),5.58(dd,J=2.29,10.37Hz,1H),5.09(s,2H),4.92(br.s,1H),3.80(d,J=7.63Hz,3H),3.36-3.48(m,6H),1.99-2.22(m,8H),1.43(d,J=7.02Hz,3H),0.77-0.88(m,3H).
在r.t.、4.06min,LCMS:m/z 521[M+H]+。对于C28H37N6O4[M+H]+的HRMS(ESI)计算值521.2871,实测值521.2867。
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-(丙-2-基)-1,4-二氢-2H-吡啶并[4,3-d][1,3]噁嗪-2-酮[(I)X=CH,U=CH2,Y=O、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 25
在r.t.、6.65min,LCMS:m/z 534[M+H]+。
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-吡啶并[4,3-d][1,3]噁嗪-2-酮[(I)X=CH,U=CH2,Y=O、R1a=甲基,R1b=H,A=苯基,R2=乙基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 44
1H NMR(500MHz,DMSO-d6)δ=7.72(s,1H),7.34(d,J=8.39Hz,2H),7.21(d,J=8.24Hz,2H),7.05(d,J=7.47Hz,1H),6.67(dd,J=10.45,16.70Hz,1H),6.03-6.07(m,1H),6.00(dd,J=2.44,16.62Hz,1H),5.57-5.60(m,1H),5.06(s,2H),4.98(br.s.,1H),3.76-3.85(m,2H),3.56-3.73(m,2H),3.41-3.50(m,6H),2.00-2.22(m,8H),1.41(d,J=6.86Hz,3H),1.23(br.s,3H).
在r.t.、2.49min,LCMS:m/z 520[M+H]+。对于C29H38N5O4[M+H]+的HRMS(ESI)计算值520.2919,实测值520.2924。
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 26
1H NMR(500MHz,DMSO-d6)δ=8.50-8.58(m,1H),8.34(d,J=6.86Hz,1H),7.62(d,J=9.15Hz,1H),7.23-7.40(m,4H),6.64(dd,J=10.52,16.62Hz,1H),6.15(d,J=9.15Hz,1H),5.96(dd,J=1.83,16.47Hz,1H),5.52-5.61(m,1H),5.40(br.s,1H),4.98(t,J=6.63Hz,1H),3.39-3.50(m,4H),2.14(br.s,8H),1.78(br.s,4H),1.47(d,J=7.02Hz,3H),0.9-1.42(m,6H).
在r.t.、8.60min,LCMS:m/z 565[M+H]+。对于C31H37F2N6O2[M+H]+的HRMS(ESI)计算值565.3097,实测值565.3086。
7-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(I)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 47
1H NMR(500MHz,DMSO-d6)δ=8.28(s,1H),7.60(d,J=9.30Hz,1H),7.43(d,J=6.71Hz,1H),7.37(d,J=8.39Hz,2H),7.37(d,J=8.39Hz,2H),6.66(dd,J=10.45,16.70Hz,1H),6.15-6.52(br.s,1H),6.10(d,J=9.30Hz,1H),5.98(dd,J=2.36,16.70Hz,1H),5.60(dd,J=2.3,10.50Hz,1H),4.57-5.44(m,2H),3.40-3.49(m,2H),3.29-3.32(m,2H),2.52-2.59(m,4H),2.16(br.s.,4H),1.78(br.s.,4H),1.48(d,J=6.71Hz,3H),1.34-1.41(m,3H),1.03(d,J=6.10Hz,3H)。在r.t.、6.62min,LCMS:m/z 564[M+H]+。对于C32H40F2N5O2[M+H]+的HRMS(ESI)计算值564.3145,实测值564.3157。
7-{[(1R)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(I)X=CH,U=Y=CH、R1a=H,R1b=甲基,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 63
在r.t.、6.62min,LCMS:m/z 564[M+H]+。对于C32H40F2N5O2[M+H]+的HRMS(ESI)计算值564.3145,实测值564.3150。
7-{[(1S)-1-{4-[4,4-二氟-1-(4-丙酰基哌嗪-1-基)环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(I)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙酰基]cpd 67
在r.t.、6.67min,LCMS:m/z 566[M+H]+。对于C32H42F2N5O2[M+H]+的HRMS(ESI)计算值566.6970,实测值566.6968。
2-{[(1S)-1-{5-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-2-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=吡啶-2-基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 27
1H NMR(500MHz,DMSO-d6)δ=8.57-8.61(m,1H),8.43-8.50(m,1H),8.31-8.37(m,1H),7.58-7.68(m,2H),7.26-7.32(m,1H),6.61-6.69(m,1H),6.10-6.22(m,1H),5.94-6.02(m,1H),5.54-5.60(m,1H),5.34(br s,1H),4.97-5.07(m,1H),3.74-3.87(m,2H),3.39-3.53(m,4H),3.26-3.32(m,2H),1.99-2.26(m,8H),1.46-1.56(m,3H),1.01-1.05(m,6H).
在r.t.、5.54min,LCMS:m/z 532[M+H]+。对于C29H38N7O2[M+H]+的HRMS(ESI)计算值532.3031,实测值532.3035。
2-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=甲基,E=丙烯酰基]cpd 28
1H NMR(500MHz,DMSO-d6)δ=8.57(d,J=3.66Hz,1H),8.13-8.44(m,1H),7.64(dd,J=3.97,9.30Hz,1H),7.25-7.43(m,4H),6.16(d,J=9.46Hz,1H),5.91-6.02(m,2H),5.43-5.58(m,1H),5.00-5.09(m,1H),4.02-4.12(m,2H),3.76-3.82(m,1H),3.64-3.75(m,4H),3.38-3.63(m,2H),3.19-3.31(m,2H),1.95-2.21(m,6H),1.50(d,J=6.67Hz,3H),1.15-1.44(m,3H),0.91(d,J=7.51Hz,3H).
在r.t.、7.25min,LCMS:m/z 531[M+H]+。对于C30H39N6O3[M+H]+的HRMS(ESI)计算值531.3078,实测值531.3077。
7-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(I)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=甲基,E=丙烯酰基]cpd 48
1H NMR(500MHz,DMSO-d6)δ=8.29(s,1H),7.61(dd,J=2.67,9.23Hz,1H),7.25-7.52(m,5H),5.86-6.13(m,3H),5.44-5.60(m,1H),5.00(br.s,1H),4.05-4.15(m,1H),3.84(dd,J=7.93和8.39Hz,1H),3.65-3.76(m,4H),3.51-3.57(m,1H),3.39-3.44(m,2H),3.24-3.32(m,2H),2.08(s,3H),1.99-2.05(m,4H),1.48(d,J=6.86Hz,3H),1.22-1.41(m,6H)。在r.t.、5.62min,LCMS:m/z 530[M+H]+。对于C31H40N5O3[M+H]+的HRMS(ESI)计算值530.3126,实测值530.3127。
2-{[(1S)-1-(4-{1-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=甲基,E=丙烯酰基]cpd 50
1H NMR(500MHz,DMSO-d6)δ=8.57(d,J=3.36Hz,1H),8.33-8.44(m,1H),8.20(br.s.,1H),7.63(d,J=9.15Hz,1H),7.27-7.43(m,4H),6.16(d,J=9.30Hz,1H),6.01-6.10(m,1H),5.97(d,J=19.37Hz,1H),5.41-5.59(m,2H),5.04(br.s.,1H),4.16(br.s.,1H),3.49-3.96(m,3H),3.37-3.49(m,1H),2.07-2.42(m,4H),1.95(d,J=8.69Hz,4H),1.70(br.s.,2H),1.49(d,J=6.71Hz,3H),1.07-1.43(m,3H),1.03(d,J=6.10Hz,3H).
在r.t.、9.57min,LCMS:m/z 565[M+H]+。对于C31H39F2N6O2[M+H]+的HRMS(ESI)计算值565.3097,实测值565.3077。
7-{[(1S)-1-(4-{1-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氢基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[(I)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=甲基,E=丙烯酰基]cpd 61
1H NMR(500MHz,DMSO-d6)δ=8.29(s,1H),7.61(dd,J=1.98,9.30Hz,1H),7.41-7.51(m,1H),7.28-7.41(m,4H),6.18-6.53(m,1H),6.04-6.16(m,2H),5.89-6.03(m,2H),5.45-5.64(m,1H),4.75-5.20(m,1H),4.09-4.25(m,1H),3.87-3.93(m,1H),3.76-3.84(m,1H),3.57-3.52(m,2H),2.29-2.43(m,2H),2.12(s,3H),1.84-2.05(m,4H),1.73(br.s.,2H),1.13-1.57(m,9H).
在r.t.、8.12min,LCMS:m/z 564[M+H]+。对于C32H40F2N6O2[M+H]+的HRMS(ESI)计算值564.3145,实测值564.3140。
N-(1-丙烯酰基氮杂环丁烷-3-基)-N-(4,4-二氟-1-{4-[(1S)-1-{[2-氧代-1-(丙-2-基)-1,2-二氢-1,6-萘啶-7-基]氨基}乙基]苯基}环己基)乙酰胺[(I)X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=乙酰基,E=丙烯酰基]cpd 62
1H NMR(500MHz,DMSO-d6)δ=8.26(s,1H),7.60(d,J=9.15Hz,1H),7.40-7.47(m,1H),7.36(d,J=8.24Hz,2H),7.24(d,J=8.39Hz,2H),6.33-6.53(m,1H),6.20-6.31(m,1H),5.94-6.14(m,2H),5.60-5.68(m,1H),4.86-5.21(m,1H),4.57-4.73(m,J=5.26,9.38Hz,1H),4.50(t,J=6.18Hz,1H),4.31-4.44(m,1H),4.20(t,J=7.55Hz,1H),3.97-4.15(m,1H),2.56-2.68(m,2H),1.93-2.11(m,7H),1.65-1.86(m,2H),1.09-1.59(m,9H).
在r.t.、8.79min,LCMS:m/z 592[M+H]+。对于C33H40F2N6O3[M+H]+的HRMS(ESI)计算值592.3094,实测值592.3092。
2-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)氧基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=吡啶-2-基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=O,G1=CH,Z1、Z2=-CH2-,m1=m2=1,E=丙烯酰基]cpd 29
在r.t.、6.28min,LCMS:m/z 518[M+H]+。
2-[(1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}环丙基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a和R1b=-CH2-CH2-,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 30
1H NMR(500MHz,DMSO-d6)δ=8.61(s,1H),8.59(s,1H),7.65(d,J=9.30Hz,1H),7.03-7.18(m,4H),6.64(dd,J=10.37,16.62Hz,1H),6.20(d,J=9.30Hz,1H),5.99(dd,J=2.29,16.62Hz,1H),5.53-5.59(m,1H),5.27(br.s.,1H),3.77(dd,J=3.43,7.40Hz,2H),3.43(d,J=3.05Hz,4H),3.19-3.31(m,2H),1.96-2.23(m,8H),1.01-1.52(m,10H)。在r.t.、6.31min,LCMS:m/z 543[M+H]+。对于C31H39N6O3[M+H]+的HRMS(ESI)计算值543.3078,实测值543.3087。
2-({4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苄基}氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 31
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.38(t,J=5.95Hz,1H),7.64(d,J=9.30Hz,1H),7.18-7.33(m,4H),6.65(dd,J=10.45,16.85Hz,1H),6.18(d,J=9.15Hz,1H),5.98(d,J=16.62Hz,1H),5.57(d,J=10.68Hz,1H),5.39-5.53(br.s 1H),4.56-4.60(m,1H),4.53(d,J=5.64Hz,1H),3.76-3.83(m,2H),3.40-3.48(m,4H),3.28-3.32(m,2H),2.03-2.18(m,8H),1.20-1.28(m,3H),1.03(d,J=6.10Hz,3H)。在r.t.、5.54min,LCMS:m/z517[M+H]+。对于C29H37N6O3[M+H]+的HRMS(ESI)计算值517.2922,实测值517.2921。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)-1-甲基哌啶-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=1-甲基哌啶-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 32
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.34(d,J=7.02Hz,1H),7.62(d,J=9.30Hz,1H),7.30(d,J=7.93Hz,2H),7.19(d,J=7.93Hz,2H),6.63(dd,J=10.45,16.85Hz,1H),6.15(d,J=9.30Hz,1H),5.96(d,J=16.62Hz,1H),5.55(d,J=10.68Hz,1H),5.24-5.45(m,1H),4.99(q,J=7.47Hz,1H),3.38-3.48(m,4H),3.26-3.32(m,4H),1.96-2.22(m,11H),1.48(d,J=7.02Hz,3H),1.23-1.44(m,3H),1.03(d,J=6.10Hz,3H)。在r.t.、6.18min,LCMS:m/z 544[M+H]+。对于C31H41N7O2[M+H]+的HRMS(ESI)计算值544.3395,实测值544.3405。
2-{[(1S)-1-{4-[(2R)-2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a=甲基,R5b=乙基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 33
在r.t.、7.02min,LCMS:m/z 503[M+H]+。
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a=乙基,R5b=甲基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 34
在r.t.、7.02min,LCMS:m/z 503[M+H]+。
2-{[(1S)-1-{4-[2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a=乙基,R5b=甲基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 46
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.35(t,J=7.47Hz,1H),7.62(d,J=9.30Hz,2H),7.36(d,J=7.02Hz,2H),7.30(d,J=8.02Hz,1H),6.73(ddd,J=3.81,10.45,16.70Hz,1H),6.16(d,J=9.00Hz,1H),6.07(dd,J=2.06,16.70Hz,1H),5.63(d,J=10.52Hz,1H),5.25-5.55(br.s,1H),5.00(d,J=6.56Hz,1H),3.49(d,J=7.47Hz,2H),3.30-3.33(m,2H),2.17-2.47(m,4H),1.64-1.75(m,1H),1.53-1.58(m,1H),1.48(d,J=6.86Hz,3H),1.15-1.40(m,6H),1.10(s,3H),0.45-0.52(m,3H)。在r.t.、7.02min,LCMS:m/z503[M+H]+。对于C29H39N6O2[M+H]+的HRMS(ESI)计算值503.3129,实测值503.3109。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(戊-3-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=戊-3-基,R3=R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 35
1H NMR(500MHz,DMSO-d6)δ=8.6(s,1H),8.25-8.45(m,1H),7.65(d,J=9.30Hz,1H),7.26-7.40(m,2H),7.20(d,J=8.24Hz,2H),6.55-6.70(m,1H),6.08-6.23(m,1H),5.96(d,J=16.47Hz,1H),5.56(d,J=10.52Hz,1H),4.87-5.31(m,2H),3.72-3.85(m,2H),3.45(br.s.,4H),3.29-3.32(m,2H),1.69-2.25(m,12H),1.46(d,J=7.02Hz,3H),0.63-0.78(m,3H),0.12(t,J=7.32Hz,3H).
在r.t.、7.02min,LCMS:m/z 559[M+H]+。对于C32H43N6O3[M+H]+的HRMS(ESI)计算值559.3391,实测值559.3392。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-(二甲基氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=N(Me)2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 36
1H NMR(500MHz,DMSO-d6)δ=7.67-7.74(m,1H),7.64(d,J=7.17Hz,1H),7.28-7.37(m,2H),7.19(d,J=8.39Hz,2H),6.59-6.74(m,1H),5.84-6.04(m,2H),5.53-5.61(m,1H),5.47(br.s,1H),4.93-5.11(m,1H),3.72-3.85(m,2H),3.44(dd,J=5.11,6.94Hz,4H),3.29-3.32(m,2H),2.94-3.11(m,6H),2.00-2.24(m,8H),1.20-1.50(m,9H)。在r.t.、7.57min,LCMS:m/z 574[M+H]+。对于C32H44N7O3[M+H]+的HRMS(ESI)计算值574.35,实测值574.3489。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-(甲基氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=NHMe,R4=H,R5a=乙基,R5b=甲基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 37
1H NMR(500MHz,DMSO-d6)δ=7.70-7.80(m,1H),7.50-7.62(m,2H),7.27-7.42(m,2H),7.19(d,J=7.78Hz,2H),6.64(dd,J=10.52,16.62Hz,1H),5.86-6.04(m,2H),5.52-5.65(m,2H),4.94-5.20(m,1H),3.79(d,J=5.64Hz,2H),3.40-3.47(m,4H),3.28-3.32(m,4H),2.89(d,J=3.97Hz,3H),2.11(br.s.,6H),1.21-1.63(m,9H).
在r.t.、6.98min,LCMS:m/z 560[M+H]+。对于C31H42N7O3[M+H]+的HRMS(ESI)计算值560.3344,实测值560.3359。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-4-甲腈[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=CN,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 38
在r.t.、7.25min,LCMS:m/z 556[M+H]+。
2-{[(1S)-1-(4-{4-[(1-丙烯酰基哌啶-4-基)氧基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=O,G1=CH,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 39
在r.t.、7.82min,LCMS:m/z 546[M+H]+。
2-[(2-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}丙-2-基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=R1b=Me,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 40
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.17(br.s.,1H),7.59(d,J=9.15Hz,1H),7.34(d,J=8.39Hz,2H),7.18(d,J=8.39Hz,2H),6.65(dd,J=10.37,16.62Hz,1H),6.10(d,J=7.78Hz,1H),5.92-6.05(m,1H),5.54-5.62(m,1H),5.04(br.s.,1H),3.79(t,J=8.46Hz,2H),3.36-3.48(m,6H),2.15(br.s.,6H),1.95(br.s.,2H),1.68(s,6H),1.05(br.s.,6H)。在r.t.、6.59min,LCMS:m/z 545[M+H]+。对于C31H41N6O3[M+H]+的HRMS(ESI)计算值545.3235,实测值545.3246。
2-[(2-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}丙-2-基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=R1b=Me,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 52
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.18(br.s,1H),7.59(d,J=9.00Hz,1H),7.33(d,J=8.39Hz,2H),7.25(d,J=8.39Hz,2H),6.65(dd,J=10.45,16.70Hz,1H),6.09(d,J=9.00Hz,1H),5.99(dd,J=1.98,16.62Hz,1H),5.58(dd,J=1.91,10.45Hz,1H),4.99(br.s.,1H),3.39-3.53(m,4H),3.29-3.31(m,2H),2.52-2.61(m,2H),2.01-2.33(m,6H),1.70-1.88(m,2H),1.67(s,6H),1.44-1.56(m,3H),1.03(d,J=6.10Hz,3H).
在r.t.、9.96min,LCMS:m/z 579[M+H]+。对于C32H41F2N6O2[M+H]+的HRMS(ESI)计算值579.3254,实测值579.3255。
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-5-氨基-1-(丙-2-基)=1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮[(I)X=N,U=CH2,Y=O、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=NH2,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 41
在r.t.、5.78min,LCMS:m/z 550[M+H]+。
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)-1-(吗啉-4-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=R4=H,R5a=甲基,R5b=吗啉-4-基-甲烷基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 42
在r.t.、6.98min,LCMS:m/z 574[M+H]+。
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)-1-(吗啉-4-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=R4=H,R5a=吗啉-4-基-甲烷基,R5b=甲基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 43
1H NMR(500MHz,DMSO-d6)δ=8.47-8.57(m,1H),8.36(d,J=7.47Hz,1H),7.62(d,J=9.30Hz,1H),7.43(d,J=8.08Hz,2H),7.30(d,J=8.08Hz,2H),6.72(dd,J=10.45,16.55Hz,1H),6.14(d,J=8.69Hz,1H),6.06(dd,J=2.29,16.62Hz,1H),5.63(dd,J=2.14,10.52Hz,1H),5.53(br.s.,1H),4.98(br.s.,1H),3.42-3.55(m,4H),2.96-3.21(m,4H),2.59(d,J=13.27Hz,1H),2.38-2.47(m,1H),2.23-2.33(m,3H),2.07(br.s.,2H),1.62-1.78(m,2H),1.32-1.53(m,9H),1.27(s,3H).
在r.t.、7.14min,LCMS:m/z 574[M+H]+。对于C32H44N7O3[M+H]+的HRMS(ESI)计算值574.35,实测值574.3479。
2-[(1-{4-[1-(4-丙烯酰基哌嗪-1-基)环戊基]苯基}环丙基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a和R1b=-CH2-CH2-,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=环戊基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 49
1H NMR(500MHz,DMSO-d6)δ=8.62(s,1H),8.60(s,1H),7.66(d,J=9.30Hz,1H),7.20(d,J=8.39Hz,2H),7.02-7.12(m,2H),6.65(dd,J=10.52,16.62Hz,1H),6.21(d,J=9.15Hz,1H),6.00(dd,J=2.36,16.70Hz,1H),5.58(dd,J=2.36,10.45Hz,1H),5.29(br.s.,1H),3.39-3.52(m,4H),3.27-3.32(m,2H),2.07-2.22(m,4H),1.87-1.93(m,2H),1.63-1.73(m,2H),1.50-1.57(m,2H),1.25-1.41(m,4H),0.93-1.1(m,6H).
在r.t.、7.63min,LCMS:m/z 527[M+H]+。对于C31H39N6O2[M+H]+的HRMS(ESI)计算值527.3129,实测值527.3132。
8-(丙-2-基)-2-({(1S)-1-[4-(4-{4-[(2H3)丙-2-烯酰基]哌嗪-1-基}四氢-2H-吡喃-4-基)苯基]乙基}氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=-[(2H3)丙烯酰基]]cpd 51
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.09-8.41(m,1H),7.62(d,J=9.30Hz,1H),7.26-7.44(m,2H),7.20(d,J=8.24Hz,2H),6.16(d,J=9.15Hz,1H),5.33-5.84(m,1H),4.99(q,J=6.71Hz,1H),3.70-3.87(m,2H),3.38-3.51(m,4H),3.28-3.32(m,2H),2.10(br.s.,8H),1.48(d,J=7.02Hz,3H),1.10-1.43(m,3H),1.03(d,J=6.10Hz,3H).
在r.t.、7.60min,LCMS:m/z 534[M+H]+。对于C30H39N6O3[M+H]+的HRMS(ESI)计算值534.3267,实测值534.3265。
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-[(2H7)丙-2-基]吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=-(2H7)丙-2-基,R3=R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丙烯酰基]cpd 55
1H NMR(500MHz,DMSO-d6)δ=8.55(s,1H),8.31(d,J=6.59Hz,1H),7.61(d,J=9.52Hz,1H),7.33(d,J=7.93Hz,2H),7.20(d,J=8.30Hz,2H),6.63(dd,J=10.62,16.60Hz,1H),6.15(d,J=9.15Hz,1H),5.96(d,J=15.50Hz,1H),5.55(d,J=10.99Hz,1H),5.00(br.s.,1H),3.79(d,J=7.20Hz,2H),3.44(br.s.,4H),3.23-3.28(m,2H),2.11(br.s.,8H),1.48(d,J=7.20Hz,3H)。在r.t.、6.74min,LCMS:m/z 538[M+H]+。对于C30H39N6O3[M+H]+的HRMS(ESI)计算值538.7073,实测值538.7072。
实施例2
N-{2-[(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)氨基]-2-氧代乙基}丙-2-烯酰胺[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=R9b=H,m1=1,E=丙烯酰基]cpd 56,步骤1a
在-10℃,向N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)甘氨酸酰胺(150mg,0.30mmol)和DIPEA(100μL,0.6mmol)在DCM(10.0mL)中的溶液中添加丙烯酰氯(27μL,0.3mmol)。在30分钟之后,将反应用水猝灭。将混合物用DCM萃取,经Na2SO4干燥,过滤并且浓缩,以产生黄色油。粗制产物通过硅胶色谱法(1%至10%MeOH/DCM)纯化,以给出作为白色泡沫的标题产物(99mg,60%收率)。1H NMR(500MHz,DMSO-d6)δ=8.54(s,1H),8.35(d,J=7.02Hz,1H),8.26(t,J=5.80Hz,1H),8.05-8.12(m,1H),7.61(d,J=9.15Hz,1H),7.22-7.39(m,4H),6.27(dd,J=10.22,17.08Hz,1H),6.15(d,J=9.30Hz,1H),6.08(dd,J=2.14,17.08Hz,1H),5.58(dd,J=2.14,10.22Hz,1H),5.52(br.s,1H),4.99(br.m,1H),3.87(d,J=5.64Hz,2H),2.37-2.46(m,2H),1.78-2.14(m,6H),1.22-1.52(m,9H)。在r.t.、11.08min,LCMS:m/z553[M+H]+。对于C29H35F2N6O3[M+H]+的HRMS(ESI)计算值553.2733,实测值553.2726。
根据相同的方法,制备以下化合物:
N2-丙烯酰基-N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-D-丙氨酸酰胺[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=CH3,R9b=H,m1=1,E=丙烯酰基]cpd 57
1H NMR(500MHz,DMSO-d6)δ=8.54(s,1H),8.34(d,J=7.02Hz,1H),8.21(d,J=6.86Hz,1H),8.08(s,1H),7.61(d,J=9.15Hz,1H),7.25-7.34(m,4H),6.29(dd,J=10.29,17.16Hz,1H),6.15(d,J=9.46Hz,1H),6.09(dd,J=1.98,17.23Hz,1H),5.58(dd,J=2.14,10.22Hz,1H),5.53(br.s,1H),4.99(br.m,1H),4.45(dq,J=8.13和6.86Hz,1H),2.37-2.46(m,2H),1.77-2.11(m,6H),1.22-1.52(m,12H)。在r.t.、11.27min,LCMS:m/z 567[M+H]+。对于C30H37F2N6O3[M+H]+的HRMS(ESI)计算值567.2890,实测值567.2887。
N2-丙烯酰基-N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-L-丙氨酸酰胺[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NH,G1=CO,Z1=CR9aR9b,R9a=H,R9b=CH3,m1=1,E=丙烯酰基]cpd 58
1H NMR(500MHz,DMSO-d6)δ=8.54(s,1H),8.14-8.40(m,2H),8.10(s,1H),7.61(d,J=9.30Hz,1H),7.16-7.39(m,4H),6.29(dd,J=10.29,17.16Hz,1H),6.14(d,J=9.15Hz,1H),6.09(dd,J=2.14,17.08Hz,1H),5.37-5.74(m,2H),4.99(br.s.,1H),4.45(t,J=7.02Hz,1H),2.36-2.47(m,2H),1.69-2.16(m,6H),1.03-1.58(m,12H).
在r.t.、11.30min,LCMS:m/z 567[M+H]+。
N-{2-[(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}丙-2-烯酰胺[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=NR6,R6=三氟乙酰基,G1=-CH2,Z1=-CH2,m1=1,E=丙烯酰基]cpd66
在r.t.、4.59min,LCMS:m/z 601[M+H]+。
N-{2-[(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)氨基]乙基}丙-2-烯酰胺[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=NH,G1=CH2,Z1=-CH2,m1=1,E=丙烯酰基]cpd 59
在r.t.、8.25min,LCMS:m/z 505[M+H]+。
实施例3
2-{[(1S)-1-(4-{4-[4-(丁-2-炔酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=丁-2-炔酰基]cpd 5
向2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(166.0mg,0.349mmol)、DIPEA(140μL,0.803mmol)和2-丁炔酸(36mg,0.419mmol)在DMF(4.0mL)中的溶液中添加HATU(163mg,0.419mmol)。将混合物在室温搅拌持续2h。将混合物用水洗涤,经硫酸镁干燥并且在真空中浓缩。残余物通过硅胶色谱法(1%至5%EtOH/DCM)纯化,以给出作为白色固体的标题产物(84.6mg,44%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.35(d,J=7.17Hz,1H),7.63(d,J=9.15Hz,1H),7.29-7.41(m,2H),7.20(d,J=8.08Hz,2H),6.16(d,J=9.15Hz,1H),5.43(br.s.,1H),5.00(t,J=6.79Hz,1H),3.79(dd,J=4.96,10.75Hz,2H),3.50-3.60(m,2H),3.36-3.40(br.,m,4H),1.99-2.27(m,8H),1.93(s,3H),1.49(d,J=7.02Hz,3H),1.17-1.45(br.,m,6H)。在r.t.、6.92min,LCMS:m/z 543[M+H]+。对于C31H39N6O3[M+H]+的HRMS(ESI)计算值543.3078,实测值543.306。
实施例4
2-{[4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-基]甲基}丙-2-烯酸[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=甲基丙-2-烯酸]cpd 7
在rt在K2CO3(35.5mg,0.257mmol)的存在下,向2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(60.0mg,0.126mmol)在乙腈(6.0mL)中的溶液中添加2-溴甲基丙烯酸(28μL,0.166mmol)。在2h之后,将反应过滤并且用乙腈洗涤。将有机部分在真空中蒸发以产生黄色油。粗制产物通过硅胶色谱法(具有1%的水的1%至7%MeOH/DCM)纯化,以给出作为白色泡沫的标题产物(44mg,58%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.36(d,J=7.47Hz,1H),7.63(d,J=9.30Hz,1H),7.32-7.42(m,2H),7.22(d,J=8.24Hz,2H),6.16(d,J=9.30Hz,1H),6.00(s,1H),5.52(br.s.,1H),5.27-5.50(br.,m,1H),5.04(t,J=6.71Hz,1H),3.75(d,J=9.30Hz,2H),3.26(br.,m,6H),3.12(s,2H),2.41(br.,m,4H),1.90-2.13(m,4H),1.50(d,J=6.86Hz,3H),1.24-1.45(br.,m,6H)。在r.t.、7.44min,LCMS:m/z 561[M+H]+。对于C31H41N6O4[M+H]+的HRMS(ESI)计算值561.3184,实测值561.3181。
根据相同的方法,制备以下化合物:
7-{[(1S)-1-{4-[4-(4-乙基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮[(I)X=N,U=CH2,Y=O、R1a=甲基,R1b=H,A=苯基,R2=乙基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=乙基]cpd 45
1H NMR(500MHz,DMSO-d6)δ=7.99(s,1H),7.88(br.s.,1H),7.34(d,J=7.78Hz,2H),7.19(d,J=8.24Hz,2H),5.10(s,2H),4.94(br.s.,1H),3.54-4.03(m,6H),1.91-2.32(m,10H),1.44(d,J=7.02Hz,3H),1.23(br.s,3H),0.88(t,J=7.17Hz,3H)。在r.t.、4.57min,LCMS:m/z 495[M+H]+。对于C27H39N6O3[M+H]+的HRMS(ESI)计算值495.3078,实测值495.3079。
2-{[(1S)-1-(4-{4,4-二氟-1-[4-(4-羟基丁基)哌嗪-1-基]环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟-环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=4-羟基丁基]cpd 64
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.42(m,1H),7.62(d,J=9.15Hz,1H),7.30-7.43(m,2H),7.18-7.31(m,2H),6.15(d,J=9.15Hz,1H),5.47(br.s.,1H),4.88-5.35(m,1H),4.39(br.s.,1H),3.30(br.s.,2H),1.90-2.48(m,14H),1.74(br.s.,4H),0.92-1.55(m,13H).
在r.t.、9.36min,LCMS:m/z 583[M+H]+。对于C32H45F2N6O2[M+H]+的HRMS(ESI)计算值583.3567,实测值583.3566。
实施例5
4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲腈[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=甲腈]cpd 65
在0℃在DIPEA(19μL,0.113mmol)的存在下,向2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(54.0mg,0.113mmol)在DCM(10.0mL)中的溶液中添加溴化氰(12μL,0.113mmol)。在1h之后,使反应达到室温持续2h,然后用水和DCM稀释。将有机部分经Na2SO4干燥并且在真空中蒸发,以产生黄色油。粗制产物通过硅胶色谱法(1%至7%EtOH/DCM 2/98直至10/90)纯化,以给出作为白色泡沫的标题产物(30mg,52%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.57(s,1H),8.37(d,J=7.02Hz,1H),7.63(d,J=9.15Hz,1H),7.36(d,J=7.78Hz,1H),7.22(d,J=8.24Hz,1H),6.16(d,J=9.15Hz,1H),5.25-5.52(m,1H),5.03(t,J=6.79Hz,1H),3.68-3.82(m,2H),3.27-3.32(m,2H),3.07-3.13(m,4H),1.99-2.27(m,8H),1.50(d,J=7.02Hz,3H),
在r.t.、6.94min,LCMS:m/z 502[M+H]+。对于C28H36N7O2[M+H]+的HRMS(ESI)计算值502.2925,实测值502.2917。
实施例6
2-{[(1S)-1-(4-{4-[4-(2,3-二羟基丙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=2,3-二羟基丙酰基]cpd 10
将2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(52mg,0.099mmol)、OsO4(2.5wt%在t-BuOH中,1.52mL,0.122mmol)和吡啶(9μL)的混合物在室温搅拌持续18小时。将混合物用饱和的含水NaHSO3溶液(1.5mL)处理并且搅拌持续另外一小时。将含水混合物用EtOAc(30mL、15mL和5mL)萃取。将合并的有机萃取物干燥(Na2SO4),过滤并且在真空中蒸发。将粗品溶解在少量的二氯甲烷中,并且通过快速色谱法(二氧化硅,在CH2Cl2中的5%MeOH至在CH2Cl2中的10%MeOH)纯化,以提供作为白色固体的标题化合物(34mg,收率65%)。
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.13-8.36(m,1H),7.62(d,J=9.30Hz,1H),7.30-7.44(m,2H),7.22(d,J=8.24Hz,2H),6.16(d,J=9.30Hz,1H),5.37-5.79(m,1H),4.94-5.32(m,1H),4.71-4.84(m,1H),4.57(q,J=6.00Hz,1H),4.17(br.s.,1H),3.79(d,J=5.64Hz,2H),3.36-3.50(m,4H),3.24-3.32(m,4H),1.96-2.33(m,8H),1.48(d,J=7.02Hz,3H),1.26-1.43(br.,m,6H)。在r.t.、5.84min,LCMS:m/z 565[M+H]+。对于C30H41N6O4[M+H]+的HRMS(ESI)计算值565.3133,实测值565.3141。
根据相同的方法,制备以下化合物:
7-{[(1S)-1-(4-{1-[4-(2,3-二羟基丙酰基)哌嗪-1-基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮[X=CH,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=2,3-二羟基丙酰基]cpd 60
1H NMR(500MHz,DMSO-d6)δ=8.28(s,1H),7.60(d,J=9.30Hz,1H),7.42(d,J=6.10Hz,1H),7.33-7.39(m,2H),7.28-7.33(m,2H),6.36(br.s.,1H),6.10(d,J=9.30Hz,1H),4.99(d,J=5.19Hz,1H),4.79(dd,J=2.90,7.17Hz,1H),4.53-4.63(m,1H),4.13-4.23(m,1H),3.45-3.56(m,2H),3.39-3.45(m,2H),3.25-3.32(m,4H),2.54(br.s.,1H),2.28(br.s.,2H),1.96-2.20(m,4H),1.69-1.86(m,4H),1.11-1.51(m,6H),0.99-1.07(m,3H).
在r.t.、5.83min,LCMS:m/z 598[M+H]+。对于C32H42F2N6O4[M+H]+的HRMS(ESI)计算值598.32,实测值598.3192。
实施例7
2-{[(1S)-1-(4-{1-[{1-[氯(氟)乙酰基]氮杂环丁烷-3-基}(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=H,R4=H,R5a和R5b=4,4-二氟环己基,M=NR6,G1=CH,Z1、Z2=-CH2-,m1=m2=1,R6=甲基,E=丙烯酰基]cpd 53
在环境温度,向2-{[(1S)-1-(4-{1-[氮杂环丁烷-3-基(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(150mg,0.294mmol)和氯氟乙酸钠(80mg,0.588mmol)在干燥的CH2Cl2(5.0mL)中的搅拌的溶液中添加DIPEA(50.0μL,0.294mmol)和T3P(50wt.%在AcOEt中,262.0μL,0.441mmol)。在搅拌持续3h之后,将反应混合物用AcOEt和饱和的NaHCO3稀释。将有机层分离,并且将水相用AcOEt萃取三次。将合并的有机层用盐水洗涤,经MgSO4干燥并且在真空中浓缩。残余物通过硅胶上的快速柱色谱法(CH2Cl2/EtOH=98∶2至9∶1)纯化,以给出作为灰白色固体的标题化合物(79.2mg,45%收率)。
1H NMR(500MHz,DMSO-d6)δ=8.56(s,1H),8.12-8.42(m,1H),7.61(d,J=9.30Hz,1H),7.36(s,4H),6.58-6.79(m,1H),6.16(d,J=9.30Hz,1H),5.34-5.84(m,1H),4.88-5.32(m,1H),4.21-4.36(m,2H),3.44-4.00(m,4H),2.07-2.42(m,4H),1.95(d,J=8.69Hz,4H),1.71(br.s.,2H),1.48(d,J=6.70Hz,3H),1.16-1.43(m,3H),1.03(d,J=6.10Hz,3H)。在r.t.、10.97min,LCMS:m/z 605[M+H]+。对于C30H37ClF3N6O2[M+H]+的HRMS(ESI)计算值605.2613,实测值605.2617。
根据相同的方法,但采用2-{[(1S)-1-{4-[4-(哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮和2-氟丙烯酸,制备以下化合物:
2-{[(1S)-1-(4-{4-[4-(2-氟丙烯酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮[(I)X=N,U=Y=CH、R1a=甲基,R1b=H,A=苯基,R2=丙-2-基,R3=R4=H,R5a和R5b=四氢-2H-吡喃-4-基,M=键,G1=N,Z1、Z2=-CH2-,m1=m2=2,E=2-氟丙烯酰基]cpd 54
1H NMR(500MHz,DMSO-d6)δ=8.58(s,1H),8.36(d,J=6.71Hz,1H),7.64(d,J=9.30Hz,1H),7.34(d,J=7.93Hz,2H),7.22(d,J=7.93Hz,2H),6.17(d,J=9.15Hz,1H),5.24-5.56(m,1H),5.18(dd,J=3.97,18.15Hz,1H),4.89-5.08(m,2H),3.71-3.85(m,2H),3.51-3.65(m,4H),3.26-3.32(m,2H),1.95-2.31(m,8H),1.26-1.61(m,9H)。在r.t.、7.19min,LCMS:m/z549[M+H]+。对于C30H38FN6O3[M+H]+的HRMS(ESI)计算值549.2984,实测值549.2984。
Claims (36)
1.一种式(I)的化合物:
其中:
X是氮或-CH-;
U是CH、CH2或CMe;
Y是CH、CF或O;
R1a、R1b各自独立地是氢、任选地被取代的直链或支链的(C1-C6)烷基,或者与它们结合至的原子一起能够形成(C3-C6)环烃基;
A是(C3-C6)环烃基、芳基或杂芳基;
R4是氢、卤素、氰基或任选地被取代的直链或支链的(C1-C6)烷基;
R5a和R5b各自独立地是选自任选地被取代的直链或支链的(C1-C6)烷基、(C3-C6)环烃基的基团,或者与它们结合至的原子一起能够形成3元至7元环基烷基或杂环基基团,所述3元至7元环基烷基或杂环基基团含有一个选自O、S、N-R6的杂原子;
其中:
R6是任选地被取代的直链或支链的(C1-C6)烷基、-COOR7或-COR8;
其中:
R7和R8是任选地被取代的直链或支链的(C1-C6)烷基;
M是键、NH、NR6或O,其中R6是根据上文所定义的;
G1是N、CH、CH2或CO;
Z1是CR9aR9b;
Z2是CR10aR10b;
其中:
R9a、R9b、R10a和R10b独立地是氢或任选地被取代的直链或支链的(C1-C6)烷基;
m1是1、2或3;
m2是0、1、2或3;
E是CN、或任选地被取代的直链或支链的(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基或式-COR11的基团;
其中:
R11是任选地被取代的直链或支链的(C2-C6)烷基或(C2-C6)烯基或(C2-C6)炔基;
R2是任选地被取代的选自以下的基团:直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基、芳基-(C1-C6)烷基和杂环基-(C1-C6)烷基;
R3是氢、氯、氰基、CONH2、NH2、NR12aR12b、OR13或任选地被取代的选自直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基、芳基和杂芳基的基团;
其中:
R12a、R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基;
R13是任选地被取代的直链或支链的(C1-C6)烷基;
或其药学上可接受的盐。
5.根据权利要求4所述的式(I)的化合物或其药学上可接受的盐,其中:
R1a、R1b各自独立地是氢、直链或支链的(C1-C3)烷基,或者与它们结合至的原子一起能够形成环丙基基团;
A是苯基基团、吡啶基基团或嘧啶基基团;
R5a和R5b各自独立地是选自直链或支链的(C1-C6)烷基的基团,或者与它们结合至的原子一起能够形成3元至7元环基烷基或杂环基基团,所述3元至7元环基烷基或杂环基基团含有一个选自O或N-R6的杂原子;
其中:
R6是直链或支链的(C1-C6)烷基或COR8;
其中:
R8是直链或支链的(C1-C6)烷基;
R2是直链或支链的(C1-C6)烷基、(C3-C6)环烃基-(C1-C6)烷基;
R3是氢、氯、氰基、NH2、NR12aR12b或直链或支链的(C1-C6)烷基;并且
6.根据权利要求5所述的式(I)的化合物或其药学上可接受的盐,其中:
R1a、R1b各自独立地是氢、甲基、乙基,或者与它们结合至的原子一起能够形成环丙基基团;
A是苯基基团或吡啶基基团;
R4是氢;
R5a和R5b各自独立地是选自甲基或乙基的基团,或者与它们结合至的原子一起能够形成选自环戊基、环己基、4,4-二氟环己基的任选地被取代的(C3-C6)环烃基基团或选自吡喃基、氧杂环丁烯基、N-甲基哌啶基、N-乙酰基哌啶基的杂环基基团;
R2是甲基、乙基、异丙基或环戊基;
R3是氢、氰基、甲基、NH2、NHMe或N(Me)2;
7.根据权利要求1所述的式(I)的化合物或其药学上可接受的盐,选自由以下组成的组:
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 1);
2-{[(1S)-1-{4-[2-(4-丙烯酰基哌嗪-1-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 2);
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)氧杂环丁烷-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 3);
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)戊-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 4);
2-{[(1S)-1-(4-{4-[4-(丁-2-炔酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 5);
2-{[(1S)-1-{4-[1-乙酰基-4-(4-丙烯酰基哌嗪-1-基)哌啶-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 6);
2-{[4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-基]甲基}丙-2-烯酸(cpd 7);
2-{[(1S)-1-{4-[4-(4-丙酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 8);
2-{[(1R)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 9);
2-{[(1S)-1-(4-{4-[4-(2,3-二羟基丙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 10);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 11);
2-{[(1S)-1-{6-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-3-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 12);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-甲基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 13);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-乙基吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 14);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 15);
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)环戊基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 16);
2-{[(1S)-1-{4-[3-(4-丙烯酰基哌嗪-1-基)四氢呋喃-3-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 17);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-5-甲基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 18);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-氨基-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 19);
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 20);
2-{[(1S)-1-(4-{4-[4-(2-甲基丙烯酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 21);
2-{[(1S)-1-(4-{4-[4-(氯乙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 22);
2-{[(1S)-1-(4-{4-[4-(3-氯丙酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 23);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(cpd 24);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-(丙-2-基)-1,4-二氢-2H-吡啶并[4,3-d][1,3]噁嗪-2-酮(cpd 25);
2-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 26);
2-{[(1S)-1-{5-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]吡啶-2-基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 27);
2-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 28);
2-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)氧基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 29);
2-[(1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}环丙基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 30);
2-({4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苄基}氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 31);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)-1-甲基哌啶-4-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 32);
2-{[(1S)-1-{4-[(2R)-2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 33);
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 34);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-(戊-3-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 35);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-(二甲基氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 36);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-4-(甲基氨基)-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 37);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-4-甲腈(cpd 38);
2-{[(1S)-1-(4-{4-[(1-丙烯酰基哌啶-4-基)氧基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 39);
2-[(2-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}丙-2-基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 40);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-5-氨基-1-(丙-2-基)-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(cpd 41);
2-{[(1S)-1-{4-[(2S)-2-(4-丙烯酰基哌嗪-1-基)-1-(吗啉-4-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 42);
2-{[(1S)-1-{4-[(2R)-2-(4-丙烯酰基哌嗪-1-基)-1-(吗啉-4-基)丙-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 43);
7-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-吡啶并[4,3-d][1,3]噁嗪-2-酮(cpd 44);
7-{[(1S)-1-{4-[4-(4-乙基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-1-乙基-1,4-二氢-2H-嘧啶并[4,5-d][1,3]噁嗪-2-酮(cpd 45);
2-{[(1S)-1-{4-[2-(4-丙烯酰基哌嗪-1-基)丁-2-基]苯基}乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 46);
7-{[(1S)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 47);
7-{[(1S)-1-(4-{4-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 48);
2-[(1-{4-[1-(4-丙烯酰基哌嗪-1-基)环戊基]苯基}环丙基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 49);
2-{[(1S)-1-(4-{1-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 50);
8-(丙-2-基)-2-({(1S)-1-[4-(4-{4-[(2H3)丙-2-烯酰基]哌嗪-1-基}四氢-2H-吡喃-4-基)苯基]乙基}氨基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 51);
2-[(2-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}丙-2-基)氨基]-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 52);
2-{[(1S)-1-(4-{1-[{1-[氯(氟)乙酰基]氮杂环丁烷-3-基}(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd53);
2-{[(1S)-1-(4-{4-[4-(2-氟丙烯酰基)哌嗪-1-基]四氢-2H-吡喃-4-基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 54);
2-{[(1S)-1-{4-[4-(4-丙烯酰基哌嗪-1-基)四氢-2H-吡喃-4-基]苯基}乙基]氨基}-8-[(2H7)丙-2-基]吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 55);
N-{2-[(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)氨基]-2-氧代乙基}丙-2-烯酰胺(cpd 56);
N2-丙烯酰基-N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-D-丙氨酸酰胺(cpd 57);
N2-丙烯酰基-N-(4,4-二氟-1-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}环己基)-L-丙氨酸酰胺(cpd 58);
N-{2-[(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)氨基]乙基}丙-2-烯酰胺(cpd 59);
7-{[(1S)-1-(4-{1-[4-(2,3-二羟基丙酰基)哌嗪-1-基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 60);
7-{[(1S)-1-(4-{1-[(1-丙烯酰基氮杂环丁烷-3-基)(甲基)氨基]-4,4-二氟环己基}苯基)乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 61);
N-(1-丙烯酰基氮杂环丁烷-3-基)-N-(4,4-二氟-1-{4-[(1S)-1-{[2-氧代-1-(丙-2-基)-1,2-二氢-1,6-萘啶-7-基]氨基}乙基]苯基}环己基)乙酰胺(cpd 62);
7-{[(1R)-1-{4-[1-(4-丙烯酰基哌嗪-1-基)-4,4-二氟环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 63);
2-{[(1S)-1-(4-{4,4-二氟-1-[4-(4-羟基丁基)哌嗪-1-基]环己基}苯基)乙基]氨基}-8-(丙-2-基)吡啶并[2,3-d]嘧啶-7(8H)-酮(cpd 64);
4-(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)哌嗪-1-甲腈(cpd 65);
N-{2-[(4-{4-[(1S)-1-{[7-氧代-8-(丙-2-基)-7,8-二氢吡啶并[2,3-d]嘧啶-2-基]氨基}乙基]苯基}四氢-2H-吡喃-4-基)(三氟乙酰基)氨基]乙基}丙-2-烯酰胺(cpd 66)以及
7-{[(1S)-1-{4-[4,4-二氟-1-(4-丙酰基哌嗪-1-基)环己基]苯基}乙基]氨基}-1-(丙-2-基)-1,6-萘啶-2(1H)-酮(cpd 67)。
8.一种用于制备根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐的工艺,所述工艺包括以下步骤:
步骤1a)使式(II)的化合物:
与式(III)的化合物反应:
所述式(II)的化合物能够根据包括以下步骤的工艺由式(IV)的化合物制备:
步骤2a)使式(IV)的化合物:
其中R1a、R1b、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据权利要求1中所定义的,并且PG是选自甲酸叔丁酯、甲酸苄酯、甲酸苯酯的保护基团;
步骤2b)使式(VI)的化合物与合适的脱保护剂反应:
其中PG是根据上文在步骤2a中所定义的;
所述式(IV)的化合物:
步骤3a)将式(VII)的中间体化合物的氯:
其中R3是氢、氯或任选地被取代的直链或支链的(C1-C6)烷基,用式(VIII)的胺中间体化合物进行取代:
R2-NH2
(VIII)
其中R2是根据权利要求1中所定义的;
步骤3b)使式(IX)的化合物与还原剂反应:
其中R2和R3是根据上文在步骤3a中所定义的;
步骤3c)使所得到的式(X)的化合物与合适的氧化剂试剂反应:
其中R2和R3是根据上文在步骤3a中所定义的;
步骤3d)使所得到的式(XI)的化合物与其中T是氢或氟的式T-CH2COOEt(XIV)的试剂反应:
其中R2和R3是根据上文在步骤3a中所定义的;
步骤3e)将所得到的式(XII)的中间体化合物与氧化剂试剂混合:
其中U、Y和是根据权利要求1中所定义的,并且R2和R3是根据上文在步骤3a中所定义的,以给出式(IV)的化合物,其中G是MeS(O)2-或MeS(O)-,X是N,并且R2、R3、U、Y和是根据上文所定义的;
或
步骤3f)使所述式(X)的化合物与羰基二咪唑或三光气反应:
或
步骤3g)用其中Lg是溴、碘、-OMs、–OTs或羟基且R2是根据上文在步骤3e中所定义的式R2-Lg(XV)的烷基化剂将式(XIII)的中间体化合物烷基化:
其中G是氯,R3、X、U、Y和R2是根据权利要求1中所定义的所述式(IV)的化合物能够根据包括以下步骤的工艺制备:
步骤4a)将式(XVI)的中间体化合物的氯:
其中X和R3是根据权利要求1中所定义的,用式(VIII)的胺中间体化合物进行取代:
R2-NH2
(VIII)
其中R2是根据权利要求1中所定义的;
步骤4b)使式(XVII)的化合物与还原剂反应:
其中X、R3和R2是根据上文在步骤4a中所定义的;
步骤4c)使所得到的式(XVIII)的化合物与合适的氧化剂试剂反应:
其中X、R3和R2是根据上文在步骤4b中所定义的;
然后
步骤4d)使所得到的式(XIX)的化合物与其中T是氢或氟的式T-CH2COOEt(XIV)的化合物反应:
或
步骤4e)使所得到的式(XVIII)的化合物与羰基二咪唑或三光气反应:
如果需要,根据包括以下转化的工艺将式(XII)的第一化合物转化为式(XII)的第二化合物:
转化A)通过与氰化物的来源反应来将其中R3是氯的式(XII)的化合物转化为其中R3是CN的式(XII)的化合物:
转化B)通过与胺PG-NH2反应来将其中R3是氯的式(XII)的化合物转化为其中R3是NHPG的式(XII)的化合物:
转化C)通过与其中R12a和R12b各自独立地选自氢或任选地被取代的直链或支链的(C1-C6)烷基的胺HNR12aR12b反应来将其中R3是氯的式(XII)的化合物转化为其中R3是NR12aR12b的式(XII)的化合物:
转化D)通过与其中R13是任选地被取代的直链或支链的(C1-C6)烷基的醇R13-OH反应来将其中R3是氯的式(XII)的化合物转化为其中R3是OR13的式(XII)的化合物:
转化E)通过用合适的剂水解来将其中R3是氰基的式(XII)的化合物转化为其中R3是CONH2的式(XII)的化合物:
如果需要,根据包括以下转化的工艺将式(IV)的第一化合物转化为式(IV)的第二化合物:
转化A1)通过用合适的试剂的两步顺序来将其中G是MeS(O)2-的式(IV)的化合物转化为其中G是–OTrif(三氟甲磺酸酯)的式(IV)的化合物:
其中R1a、R1b、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据权利要求1中所报告的且PG是保护基团的所述式(V)的化合物能够根据包括以下步骤的工艺制备:
步骤5a)使式(XX)的化合物与ClCH2CN反应:
其中W1是溴、氰基、COR1a且A、R4、R5a、R5b和R1a是根据权利要求1中所定义的,随后用酸性条件、碱性条件或用硫脲对酰胺中间体进行脱保护,以获得式(XXI)的化合物;
步骤5b)使式(XXI)的氨基中间体:
其中W1、A、R4、R5a和R5b是根据上文在步骤5a中所定义的,与式(XXII)的化合物反应:
其中Z1、Z2、m1和m2是根据权利要求1中所报告的,PG是保护基团,并且Hal是卤素,以产生式(XXIII)的化合物,其中W1、A、R4、R5a、R5b、Z1、Z2和PG是根据上文所定义的,m1和m2是1、2或3,G1是N,并且M是键;
或
步骤5b’)使所述式(XXI)的氨基中间体与式(XXIIa)的杂环基卤化物反应,
其中Z1、Z2、m1、m2和PG是根据上文在步骤5b中所报告的并且Hal是卤素,然后通过用甲醛或用合适的烷基醛衍生物的还原胺化或通过用合适的卤代酰基衍生物R8CO-hal的酰化或通过用其中R7和R8是根据权利要求1中所定义的氯甲酸烷基酯衍生物R7OCO-Cl的反应来使所获得的中间体反应;以形成式(XXIII)的化合物,其中PG是根据上文所定义的,W1、A、R4、R5a、R5b、Z1、Z2、m1和m2是根据权利要求1中所定义的;G1是CH并且M是NR6,其中R6是根据权利要求1中所定义的;
或
步骤5b”)使所述式(XXI)的氨基中间体与式(XXIIb)的被保护的氨基烷基反应
其中Z1、m1和PG是根据上文在步骤5b中所报告的并且FG是选自醛(-CHO)或羧酸(-COOH)的官能团,以产生式(XXIII)的化合物,其中m2是0,G1是CH2或CO,M是NH或NR6,PG是根据上文在步骤5b中所定义的,并且W1、A、R4、R5a、R5b、Z1、m1和R6是根据权利要求1中所定义的;
或
步骤5a’)使式(XX)的化合物:
其中W1、A、R4、R5a和R5b是根据上文在步骤5a中所定义的,与式(XXIIa)的杂环基卤化物反应:
其中Hal、Z1、Z2、m1、m2和PG是根据步骤5b’中所定义的;以形成式(XXIII)的化合物,其中W1、A、R4、R5a、R5b是根据步骤5a中所定义的;Z1、Z2、m1、m2和PG是根据上文在步骤5b’中所定义的;G1是CH并且M是O;
然后
步骤5c)使获自步骤5b或步骤5b’或步骤5b”或步骤5a’的式(XXIII)的化合物与乙基溴化镁和三氟化硼二乙醚反应:
其中W1是氰基,并且A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据步骤5b或步骤5b’或步骤5b”或步骤5a’中所报告的,以给出期望的式(V)的化合物,其中A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,并且R1a和R1b是相同的并且是根据权利要求1中所定义的;或者R1a与R1b一起是环丙基;
或
步骤5c’)使获自步骤5b或步骤5b’或步骤5b”或步骤5a’的式(XXIII)的化合物与叔丁烷亚磺酰胺反应:
其中W1是COR1a,其中R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2、PG和R1a是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,以产生式(XXIV)的化合物,其中R1b是氢,并且R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2、PG和R1a是根据上文所定义的;
或
步骤5c”)使获自步骤5b或步骤5b’或步骤5b”或步骤5a’的式(XXIII)的化合物与叔丁烷亚磺酰胺反应:
其中W1是COR1a,并且A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2、PG和R1a是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,以产生式(XXV)的化合物;
然后
步骤5e)使所获得的式(XXV)的化合物与烷基格氏试剂反应:
其中R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文在步骤5b或步骤5b’或步骤5b”或步骤5a’中所定义的,以给出期望的式(XXIV)的化合物;
最后
步骤5d)使根据步骤5c’或步骤5e中所描述获得的所述式(XXIV)的化合物与酸性脱保护试剂或与碘反应:
其中R1b、R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1、m2和PG是根据上文在步骤5c’或步骤5e中所定义的,以给出期望的式(V)的化合物,其中R1b、R1a、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据权利要求1中所定义的并且PG是保护基团;
可选择地,式(XXIII)的化合物也能够通过将另一种式(XXIII)的化合物转化来获得,相应的转化如下:
转化F)其中W1是氰基的式(XXIII)的化合物按照本领域已知的关于芳基卤化物的钯催化的氰化的条件,通过用氰化物的来源将获自步骤5b或步骤5b’或步骤5b”或步骤5a’的其中W1是溴的相应的式(XXIII)的化合物转化来获得;
转化G)其中W1是COR1a,其中R1a是根据权利要求1中所定义的式(XXIII)的化合物通过用合适的烯醇醚有机金属衍生物将获自步骤5b或步骤5b’或步骤5b”或步骤5a’的其中W1是溴的所述式(XXIII)的化合物转化,随后水解来获得;
根据步骤1a制备的式(I)的化合物能够根据包括以下转化的工艺进一步转化为另一种式(I)的化合物:
转化1)将其中E是丙烯酰胺基团的式(I)的化合物转化为其中E是二羟基丙酸基团且X、U、Y、R2、R3、R1a、R1b、A、R4、R5a、R5b、M、G1、Z1、Z2、m1和m2是根据权利要求1中所定义的化合物:
9.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的方法中使用,所述方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据权利要求1中所定义的式(I)的化合物。
10.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由突变的IDH酶引起的和/或与突变的IDH酶相关的疾病的方法中使用,所述方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据权利要求1中所定义的式(I)的化合物。
11.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由IDH wt功能过度引起的和/或与IDH wt功能过度相关的疾病的方法中使用,所述方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据权利要求1中所定义的式(I)的化合物。
12.根据权利要求9至11中任一项所述的用于使用的化合物,其中所述疾病选自由以下组成的组:癌症、细胞增殖性紊乱和免疫相关的紊乱。
13.根据权利要求12所述的用于使用的化合物,其中所述疾病是癌症。
14.根据权利要求13所述的用于使用的化合物,其中所述癌症选自由以下组成的组:癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、包括小细胞肺癌的肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌以及包括鳞状细胞癌的皮肤癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;骨髓系造血肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括胶质瘤、成胶质细胞瘤、多形性成胶质细胞瘤、星形细胞瘤、少突神经胶质瘤、副神经胶质瘤、成神经细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角膜黄瘤、诸如甲状腺乳头状癌和甲状腺髓样癌的甲状腺癌、卡波西肉瘤、软骨肉瘤和胆管癌。
15.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐,用于作为药物使用。
16.一种治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的方法,所述方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据权利要求1中所定义的式(I)的化合物。
17.一种治疗由突变的IDH酶引起的和/或与突变的IDH酶相关的疾病的方法,所述方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据权利要求1中所定义的式(I)的化合物。
18.一种治疗由IDH wt功能过度引起的和/或与IDH wt功能过度相关的疾病的方法,所述方法包括向有相应需要的哺乳动物、优选地人类施用有效量的根据权利要求1中所定义的式(I)的化合物。
19.根据权利要求16至18中任一项所述的方法,其中所述疾病选自由以下组成的组:癌症、细胞增殖性紊乱和免疫相关的紊乱。
20.根据权利要求19所述的方法,其中所述疾病是癌症。
21.根据权利要求20所述的方法,其中所述癌症选自由以下组成的组:癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、包括小细胞肺癌的肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌以及包括鳞状细胞癌的皮肤癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;骨髓系造血肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括胶质瘤、成胶质细胞瘤、多形性成胶质细胞瘤、星形细胞瘤、少突神经胶质瘤、副神经胶质瘤、成神经细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角膜黄瘤、诸如甲状腺乳头状癌和甲状腺髓样癌的甲状腺癌、卡波西肉瘤、软骨肉瘤和胆管癌。
22.一种药物组合物,包含与药学上可接受的赋形剂、载体或稀释剂联合的根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐。
23.根据权利要求22所述的药物组合物,还包含一种或更多种化学治疗剂。
24.一种产品或试剂盒,包括作为组合制品用于在抗癌疗法中同时、分开或依次使用的根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐以及一种或更多种化学治疗剂。
25.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐在制造具有抗癌活性的药物中的用途。
26.根据权利要求16至18中任一项所述的方法,与放射疗法或与化学疗法方案组合。
27.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐在制造用于治疗由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的药物中的用途。
28.根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐在制造用于治疗由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDH wt功能过度相关的疾病的药物中的用途。
29.根据权利要求27至28中任一项所述的用途,其中所述疾病选自由以下组成的组:癌症、细胞增殖性紊乱和免疫相关的紊乱。
30.根据权利要求29所述的用途,其中所述疾病是癌症。
31.根据权利要求30所述的用途,其中所述癌症选自由以下组成的组:癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、包括小细胞肺癌的肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌以及包括鳞状细胞癌的皮肤癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;骨髓系造血肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括胶质瘤、成胶质细胞瘤、多形性成胶质细胞瘤、星形细胞瘤、少突神经胶质瘤、副神经胶质瘤、成神经细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角膜黄瘤、诸如甲状腺乳头状癌和甲状腺髓样癌的甲状腺癌、卡波西肉瘤、软骨肉瘤和胆管癌。
32.包含根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐的药物组合物,用于治疗患有由增加的2-羟基戊二酸水平引起的和/或与增加的2-羟基戊二酸水平相关的疾病的哺乳动物。
33.包含根据权利要求1中所定义的式(I)的化合物或其药学上可接受的盐的药物组合物,用于治疗患有由突变的IDH酶或IDH wt功能过度引起的和/或与突变的IDH酶或IDH wt功能过度相关的疾病的哺乳动物。
34.根据权利要求32至33中任一项所述的药物组合物,其中所述疾病选自由以下组成的组:癌症、细胞增殖性紊乱和免疫相关的紊乱。
35.根据权利要求34所述的药物组合物,其中所述疾病是癌症。
36.根据权利要求35所述的药物组合物,其中所述癌症选自由以下组成的组:癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、包括小细胞肺癌的肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌以及包括鳞状细胞癌的皮肤癌;淋巴系造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、B细胞淋巴瘤、血管免疫母细胞性T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤和伯基特淋巴瘤;骨髓系造血肿瘤,包括急性和慢性骨髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质起源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括胶质瘤、成胶质细胞瘤、多形性成胶质细胞瘤、星形细胞瘤、少突神经胶质瘤、副神经胶质瘤、成神经细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角膜黄瘤、诸如甲状腺乳头状癌和甲状腺髓样癌的甲状腺癌、卡波西肉瘤、软骨肉瘤和胆管癌。
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