CN106946796B - 用作激酶活性调节剂的氨基嘧啶衍生物 - Google Patents
用作激酶活性调节剂的氨基嘧啶衍生物 Download PDFInfo
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- CN106946796B CN106946796B CN201710022892.9A CN201710022892A CN106946796B CN 106946796 B CN106946796 B CN 106946796B CN 201710022892 A CN201710022892 A CN 201710022892A CN 106946796 B CN106946796 B CN 106946796B
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- phenyl
- amino
- pyrimidin
- ethyl
- piperazin
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- 230000000694 effects Effects 0.000 title abstract description 12
- 108091000080 Phosphotransferase Proteins 0.000 title abstract description 9
- 102000020233 phosphotransferase Human genes 0.000 title abstract description 9
- 150000005005 aminopyrimidines Chemical class 0.000 title abstract description 3
- -1 heterocyclic amine compounds Chemical class 0.000 claims abstract description 108
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 28
- 201000011510 cancer Diseases 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 359
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 63
- 150000003839 salts Chemical class 0.000 claims description 40
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 102000004190 Enzymes Human genes 0.000 claims description 11
- 108090000790 Enzymes Proteins 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 230000005764 inhibitory process Effects 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 8
- KDVZJCYZKUTIHP-UHFFFAOYSA-N 6-[4-[2-amino-1-[4-(trifluoromethyl)phenyl]ethyl]piperazin-1-yl]-5-bromopyrimidin-4-amine Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(CN)N(CC1)CCN1C1=NC=NC(N)=C1Br KDVZJCYZKUTIHP-UHFFFAOYSA-N 0.000 claims description 7
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 6
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- RWLZSQDGEYWUSU-UHFFFAOYSA-N 5-bromo-6-[4-[2-(dimethylamino)-1-[4-(trifluoromethyl)phenyl]ethyl]piperazin-1-yl]pyrimidin-4-amine Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(CN(C)C)N(CC1)CCN1C1=NC=NC(N)=C1Br RWLZSQDGEYWUSU-UHFFFAOYSA-N 0.000 claims description 4
- IVIHGYDROQUEOM-UHFFFAOYSA-N 6-[4-[2-amino-1-[4-(trifluoromethyl)phenyl]ethyl]piperidin-1-yl]-5-bromopyrimidin-4-amine Chemical compound C=1C=C(C(F)(F)F)C=CC=1C(CN)C(CC1)CCN1C1=NC=NC(N)=C1Br IVIHGYDROQUEOM-UHFFFAOYSA-N 0.000 claims description 4
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 4
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
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- RXLYPPSAPOEZIY-UHFFFAOYSA-N 2-[[4-[6-amino-5-(4-fluorophenyl)pyrimidin-4-yl]piperazin-1-yl]methyl]-4,5-dichlorophenol Chemical compound C=1C=C(F)C=CC=1C=1C(N)=NC=NC=1N(CC1)CCN1CC1=CC(Cl)=C(Cl)C=C1O RXLYPPSAPOEZIY-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及用作激酶活性调节剂的氨基嘧啶衍生物。本发明提供了通式(I)所示的新的杂环状胺化合物,它们的制备及其用于治疗过度增殖性疾病诸如癌症的用途。
Description
本发明专利申请是申请国际申请号为PCT/US2012/054877,国际申请日为2012年9月12日,进入中国国家阶段的申请号为201280054959.2的发明专利的分案申请。
技术领域
本发明涉及一系列可用于治疗哺乳动物的过度增殖性疾病诸如癌症的杂环状胺化合物。本发明还包括所述化合物在治疗哺乳动物尤其是人的过度增殖性疾病的用途,以及包含所述化合物的药物组合物。
发明背景
蛋白激酶组成一大族担负细胞内多种信号转导过程控制的结构相关酶(Hardie,G.和 Hanks,S.(1 995)The Protein Kinase Facts Book.I和II,Academic Press,SanDiego,CA)。通过它们磷酸化的底物(例如蛋白-酪氨酸、蛋白-丝氨酸/苏氨酸、脂质等),可将激酶分成多族。已确定了一般对应于这些激酶各族的序列模体(例如,Hanks,S.K.,HunteR,T., FASEB J.,9:576-596(1995);Knighton,等人,Science,253:407-414(1991);Hiles 等人,Cell,70:419-429(1 992);Kunz等人,Cell,73:585-596(1993);Garcia-Bustos,等人,EMBO J.,13:2352-2361(1994))。
蛋白激酶可由其调节机制表征。这些机制包括例如自磷酸化作用、由其它激酶转磷酸作用、蛋白质-蛋白质相互作用、蛋白质-脂质相互作用和蛋白质-多核苷酸相互作用。单个蛋白激酶可由多于一种机制调节。
通过将磷酸基团加到靶蛋白,激酶可调节很多不同的细胞过程,包括但不限于增殖、分化、细胞凋亡、运动性、转录、翻译及其他信号传导过程。这些磷酸化事件充当能够调节或调整靶蛋白生物功能的分子通断开关。靶蛋白的磷酸化响应于多种胞外信号(激素、神经递质、生长和分化因子等)、细胞周期事件、环境或营养应激等而发生。适合的蛋白激酶在信号传导通路中起作用以活化或钝化(直接或间接)例如代谢酶、调节蛋白、受体、细胞骨架蛋白、离子通道或泵或转录因子。由蛋白磷酸化控制缺陷导致的不受控的信号传导涉及多种疾病,包括例如炎症、癌症、过敏/哮喘、免疫系统疾病和病症、中枢神经系统疾病和病症及血管生成。
蛋白激酶70S6K,即70kDa核糖体蛋白激酶p70S6K(也称为SK6、p70/p85S6激酶、p70/p85核糖体S6激酶和pp70S6K)是蛋白激酶的AGC亚家族的成员。p70S6K是丝氨酸- 苏氨酸激酶,其是磷脂酰肌醇3激酶(PI3K)/AKT通路的组成部分。p70S6K为PI3K的下游部分,且通过响应多种有丝分裂原、激素和生长因子在多个位点的磷酸化而被激活。由于雷帕霉素起到抑制p70S6K活性的作用,p70S6K活性也受包含mTOR的复合物(TORC1) 的控制。p70S6K通过PI3K下游靶点AKT和调节。Akt直接磷酸化并钝化TSC2,由此激活mTOR。此外,对于被渥曼青霉素抑制而不被雷帕霉素抑制的p70S6K的突变体等位基因的研究表明PI3K通路可以不依赖mTOR活性的调节而对p70S6K产生作用。
酶p70S6K通过S6核糖体蛋白的磷酸化而调控蛋白合成。S6磷酸化与翻译装置(translational apparatus)的mRNA编码组件的翻译的增加相关,所述翻译装置包括核糖体蛋白和翻译延伸因子(其表达增加对细胞生长和增殖是必不可少的)。这些mRNA在其5′转录起始端(称为5′TOP)包含寡嘧啶片段,已证明这对于其在翻译水平的调节是必不可少的。
除了参与翻译之外,p70S6K激活还涉及细胞周期控制、神经细胞分化、在肿瘤转移中重要的细胞运动性和细胞响应的调节、免疫应答和组织修复。p70S6K抗体破坏了大鼠成纤维细胞进入S期所驱动的促有丝分裂响应,这就表明了p70S6K功能在细胞周期中从 G1期至S期的进程中是必不可少的。此外,已经确定在细胞周期的G1期至S期雷帕霉素对细胞周期增殖的抑制是其抑制生成过度磷酸化的激活形式的p70S6K的结果。
p70S6K肿瘤细胞增殖和保护细胞免于细胞凋亡中的作用受到支持,这是基于其在肿瘤组织中参与生长因子受体信号转导、过表达和激活。例如,RNA印迹分析和蛋白质印迹分析表明,PS6K基因的扩增分别伴有mRNA和蛋白质表达的相应增加(Cancer Res.(1999)59:1408-11-PS6K在乳腺癌中定位于染色体区17q23及其扩增的测定 (Localization ofPS6K to Chromosomal Region 17q23and Determination of Its Amplification inBreast Cancer))。
染色体17q23在以下肿瘤和癌症中扩增:高达20%的原发性乳腺肿瘤、87%含有BRCA2突变的乳腺肿瘤和50%含有BRCA1突变的肿瘤以及其它癌症类型,例如胰腺癌、膀胱癌和成神经细胞瘤(参见M.Barlund,O.Monni,J.Kononen,R.Cornelison, J.Torhorst,G.SauteR,O.-P.Kallioniemi和Kallioniemi A.,Cancer Res.,2000,60:5340- 5346)。研究表明,17q23在乳腺癌中的扩增涉及PAT1、RAD51C、PS6K和SIGMA1B基因(Cancer Res.(2000):60,第5371-5375页)。
p70S6K基因已被鉴定为这些部位扩增和过表达的靶点,并且观察到扩增和预后不良之间在统计上显著相关。在用上游激酶mTOR的抑制剂CCI-779(雷帕霉素酯)治疗的肾癌患者中,观察到p70S6K激活的临床抑制。据报道,疾病进程和p70S6K活性抑制之间有显著的线性相关性。在响应能量应激时肿瘤抑制因子LKB1激活AMPK,AMPK磷酸化 TSC1/2复合物,并使得其钝化mTOR/p70S6K通路。LKB1中的突变引起波伊茨-耶格综合征(Peutz-Jegherssyndrome PJS),患有PJS的患者发展为的癌症可能性是一般人群的15 倍。此外,1/3的肺腺癌潜伏有未激活的LKB1突变。p70S6K涉及代谢疾病和障碍。据报道,缺乏p70S6K避免患年龄和饮食诱发的肥胖症并同时提高胰岛素敏感性。基于这些发现,支持了p70S6K在肥胖症、糖尿病、代谢综合征、胰岛素抵抗、高血糖、高氨基酸血症和高脂血症等代谢疾病和障碍中的作用。
在WO 03/064397,WO 04/092154,WO 05/054237,WO 05/056014,WO 05/033086,WO 05/117909,WO 05/039506,WO 06/120573,WO 06/136821,WO 06/071819,WO 06/131835,WO 08/140947,WO 10/093419,WO 10/056563,WO 12/013282,WO 12/016001和WO12/069146中公开了被描述为适于抑制p70S6K的化合物。
发明内容
本发明的目的是提供调节激酶活性的新化合物。该蛋白激酶调节包括但不限于p70S6K抑制和Akt抑制,其用于治疗过度增殖性疾病,尤其是与以上提及的蛋白激酶的活动过度相关的那些,诸如哺乳动物中的癌症,所述化合物在活性以及溶解度、代谢清除率和生物利用度特性方面具有优良的药理性质。
因此,本发明提供了新的杂环状嘧啶基胺和吡啶基胺化合物及其可药用盐、溶剂化物或前药,它们是激酶抑制剂且可用于治疗以上提及的疾病。
所述化合物为通式(I)化合物及其可药用盐、溶剂化物、盐的溶剂化物或前药,
其中:
X是N或CH;
Y是N或CR2;
E是具有1、2、3、4、5、6或7个C原子的无支链的或有支链的烷基连结基团,所述烷基连结基团可以未被取代或者被Hal、OH、CN或NH2单取代或二取代,其中一个CH3基团可以被Cyc1、Cyc2、CONH2、CF3所替代,且其中1、2或3个CH2基团可以被-O-、-NH-,或-CO-所替代,且其中一个CH 基团可以被-N-所替代;
R1是H、CN、CONH2、Hal、LA、O(LA)、Ar、Cyc1或Cyc2;
R2是H、NH2、Hal或CN;
Hal是F、Cl、Br或I;
LA是具有1、2、3、4、5或6个C原子的无支链的或有支链的直链饱和或部分不饱和烃链,其中1、2或3个H原子可以被Hal或OH所替代;
Ar是具有0、1、2、3或4个N、O和/或S原子和5、6、7、8、9或10个骨架原子的单环或二环的芳族碳环或杂环,所述碳环或杂环可以未被取代或相互独立地被Hal、LA、OH、SH、O(LA)、NH2、NH(LA)、N(LA)2、NO2、 CN、OCN、COOH、COO(LA)、CONH2、CONH(LA)、CON(LA)2、 NHCO(LA)、NHCONH(LA)、NHCONH2、CHO和CO(LA)单取代或二取代,和/或被Cyc2或O-Cyc2单取代;
Cyc1是具有0-2个选自O、S、和N原子的杂原子的3-、4-、5-或6-元单环脂族碳环或杂环,所述碳环或杂环可以被Hal、LA、NH2、NH(LA)、N(LA)2、 HO(LA)-单取代或二取代;
Cyc2是具有0-3个选自O、S、和N原子的杂原子的5-或6-元单环芳族碳环或杂环,所述碳环或杂环可以被Hal或LA单取代或二取代;以及
n是1或2。
在另一优选实施例中,本发明的化合物符合通式(I)的子通式1至13,其中
在子通式1中,
X是N,
在子通式2中,
Y是N或CH,
在子通式3中,
R1是Hal、LA、O(LA)、Cyc1或Cyc2,
在子通式4中,
Ar是苯基或吡啶基,它们未被取代或者被Hal、LA或O(LA)单取代或二取代,
在子通式5中,
E是甲基连结基团,它被氨基甲基取代,其中氨基甲基中的氨基未被取代或者被LA单取代或二取代,或者E是甲基连结基团,它被(氮杂环丁烷-1-基)甲基取代,
在子通式6中,
Y是CNH2,
E是-CH(R3)-NH-CO-或–CO-NH-CH(R3)-,
R3是H、CH2CONH2或LA,
在子通式7中,
X是N,
Y是N或CH,
R1是Hal、LA、O(LA)、Cyc1或Cyc2,
在子通式8中,
X是N,
Y是N或CH,
Ar是苯基或吡啶基,它们未被取代或者被Hal、LA或O(LA)单取代或二取代,
在子通式9中,
X是N,
Y是N或CH,
E是甲基连结基团,它被氨基甲基取代,其中氨基甲基中的氨基未被取代或者被LA单取代或二取代,或者E是甲基连结基团,它被 (氮杂环丁烷-1-基)甲基取代,
在子通式10中,
X是N,
Y是CNH2,
E是-CH(R3)-NH-CO-或–CO-NH-CH(R3)-,
R1是Hal、CONH2、LA、O(LA)、Cyc1或Cyc2,
R3是H、CH2CONH2或LA,
在子通式11中,
X是N,
Y是CNH2,
E是-CH(R3)-NH-CO-或–CO-NH-CH(R3)-,
R1是Hal、CONH2、LA、O(LA)、Cyc1或Cyc2,
R3是H、CH2CONH2或LA,
Ar是苯基或吡啶基,它们未被取代或者被Hal、LA或O(LA)单取代或二取代,
在子通式12中,
X是N,
Y是CNH2,
E是-CH(R3)-NH-CO-或–CO-NH-CH(R3)-,
R3是H、CH2CONH2或LA,
Ar是苯基或吡啶基,它们未被取代或者被Hal、LA或O(LA)单取代或二取代,
在子通式13中,
X是N,
Y是N或CH,
E是甲基连结基团,它被氨基甲基取代,其中氨基甲基中的氨基未被取代或者被LA单取代或二取代,或者E是甲基连结基团,它被(氮杂环丁烷-1-基)甲基取代,
Ar是苯基或吡啶基,它们未被取代或者被Hal、LA或O(LA)单取代或二取代,
R1是Hal、LA、O(LA)、Cyc1或Cyc2,
及其可药用盐、溶剂化物、盐的溶剂化物或前药。
在又一优选实施例中,通式(I)中R1的取代基列于组 1中。
组 1:通式(I)中R1的优选取代基:
在又一优选实施例中,通式(I)中Ar的取代基列于组 2中。
组 2:通式(I)中Ar的优选取代基:
在又一优选实施例中,通式(I)中E的取代基列于组 3中。
组 3:通式(I)中E的优选取代基:
本发明化合物可为前药化合物形式。“前药化合物”是指于生物体中在生理学条件下可以通过例如氧化反应、还原反应、水解反应等转化为本发明的生物学活性化合物的衍生物,每种反应均可以在有酶或没有酶的参与的情况下下进行。前药的实例为下述情况的化合物:其中本发明化合物中的氨基基团被酰化、烷基化或磷酸化,例如,二十酰基氨基、丙氨酰氨基、新戊酰氧基甲基氨基;或其中羟基基团被酰化、烷基化、磷酸化或转化为硼酸酯,例如乙酰基氧基、棕榈酰氧基、新戊酰氧基、琥珀酰氧基、富马酰氧基、丙氨酰氧基;或其中羧基基团被酯化或酰胺化;或其中硫羟基基团与载体分子(例如肽)形成二硫桥,所述载体分子选择性地将药物递送至靶点和/或至细胞溶胶。这些化合物可根据已知的方法由本发明化合物制得。前药的其它实例为如下的化合物,其中本发明化合物中的羧酸酯例如被转化为烷基-、芳基-、胆碱、氨基、酰氧基甲酯、亚麻酰基(linolenoyl)-酯。
本发明化合物的代谢物也在本发明范围内。
当本发明化合物或其前药的互变异构(例如,酮-烯醇互变异构)现象存在时,既要求保护它们分别的单个形式(例如,酮或烯醇形式),也要求保护其任意比例的混合物。这同样适用于它们的立体异构体,例如,对映异构体、顺/反异构体、构象异构体等。如有需要,异构体可根据本领域已知的方法(例如液相色谱法)分离。这同样适用于它们的对映异构体,例如,采用手性固定相分离。此外,对映异构体可通过转化为非对映异构体进行分离,即与对映异构纯的辅助化合物偶连,随后分离所得的非对映异构体并裂解辅助残基。或者,本发明化合物的任何对映异构体可用光学纯原料由立体选择性合成获得。
本发明化合物可以是可药用盐或溶剂化物形式。术语“可药用盐”是指由可药用的无毒碱或酸(包括无机碱或酸和有机碱或酸)制得的盐。在本发明化合物含有一个或多个酸性或碱性基团的情况下,本发明同样包括它们相应的药学上或毒物学上可接受的盐,尤其是它们药学上可利用的盐。因此,含有酸性基团的本发明化合物可以盐形式存在,并且根据本发明,可以作为例如碱金属盐、碱土金属盐或铵盐使用。更多此类盐的精确实例包括:钠盐、钾盐、钙盐、镁盐或含有氨或有机胺(例如,乙基胺、乙醇胺、三乙醇胺或氨基酸)的盐。含有一个或多个碱性基团(即,可被质子化的基团)的本发明化合物可以盐形式存在,并且根据本发明,可以与无机或有机酸形成的加成盐形式存在。适当的酸的实例包括盐酸、氢溴酸、磷酸、硫酸、硝酸、甲磺酸、对甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水杨酸、苯甲酸、甲酸、丙酸、新戊酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、苹果酸、氨基磺酸、苯基丙酸、葡糖酸、抗坏血酸、异烟酸、柠檬酸、己二酸和其它本领知的酸。如果本发明化合物在分子中同时包含酸性和碱性基团,那么除了所述盐形式外,本发明同样包含内盐或内铵盐(两性离子)。所述各盐可通过本领域技术人员已知的常规方法制得,例如使它们在溶剂或分散剂中与有机或无机酸或碱接触,或者使阴离子或阳离子与其它的盐交换。本发明同样包含如下所有本发明化合物的盐,其因低生理学兼容性不适宜在药物中直接使用,但可作为例如化学反应中间体或在可药用盐的制备中使用。
除非另有说明,术语“被取代的”优选是指被上述取代基取代,其中可能有多种不同程度的取代。
这些化合物的所有的生理学可接受的盐、衍生物、溶剂化物、盐的溶剂化物和立体异构体,包括其所有比例的混合物,也符合本发明。
通式(I)化合物可以具有一个或多个手性中心。因此所述化合物可能以多种对映异构形式出现并可能为外消旋形式或旋光体。因此本发明还涉及这些化合物的旋光体(立体异构体)、对映异构体、外消旋物、非对映异构体和水合物及溶剂化物。
因为本发明化合物的外消旋物或立体异构体的药学活性可能存在差异,可能需要使用对映体。在这些情况下,可采用本领域技术人员已知的或甚至在合成上直接采用的化学或物理方法将终产物甚至中间体拆分成为对映异构化合物。
在分子结构中存在外消旋胺的情况下,混合物可与光学活性拆分试剂形成非对映体。合适的拆分试剂实例为具有光学活性的酸类,如R型或S型的酒石酸、二乙酰酒石酸、二苯甲酰酒石酸、扁桃酸、苹果酸和乳酸,合适的N-保护氨基酸类(例如N-苯甲酰脯氨酸或 N苯磺酰脯氨酸),或各种光学活性的樟脑磺酸。借助于光学活性拆分剂(例如固定在硅胶上的二硝基苯甲酰苯基甘氨酸、三醋酸纤维素或碳水化合物的其他衍生物或手性衍生化甲基丙烯酸聚合物)的对映体的色谱拆分法也具有优势。为此目的所使用的合适洗脱剂为含水或含醇的溶剂混合物,例如乙烷/异丙醇/腈,例如比例为82∶15∶3。一种拆分包含酯基 (例如乙酰基酯)的外消旋物的巧妙的方法是使用酶、特别是酯酶类。
另外,本发明涉及包含作为活性成分的本发明化合物或其前药化合物或其可药用盐或其溶剂化物以及包含可药用载体的药物组合物。
“药物组合物”是指一种或多种活性成分和组成载体的一种或多种惰性组分以及由下列直接或间接获得的任意产物:任意两种或多种组分组合、复合、聚集,或者一种或多种组分解离,或者一种或多种组分的其它类型的反应或相互作用。因此,本发明药物组合物包括通过本发明化合物和可药用载体混合而制得的任意组合物。
本发明药物组合物可另外含有一种或多种作为活性成分的其它化合物,例如一种或多种另外的本发明化合物、前药化合物或其它p70S6K抑制剂。药物组合物包括经口、直肠、局部、肠胃外(包括皮下、肌肉内和静脉内)、眼球(眼)、肺(鼻或颊吸入)或鼻给药的适宜组合物,在任何已知的情况中最适宜的途径取决于治疗的病症的性质和严重性以及活性组分的性质。它们可方便地以单位剂量形式存在并采用药物领域已知的任意方法制备。
在一个实施方案中,所述化合物和药物组合物用于治疗以下疾病:癌症,例如脑癌、肺癌、结肠癌、表皮样癌、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、乳腺癌、头癌、颈癌、肾癌、肾的癌、肝癌、卵巢癌、前列腺癌、结直肠癌、子宫癌、直肠癌、食管癌、睾丸癌、妇科癌、甲状腺癌、黑素瘤、恶性血液病,诸如急性髓性白血病、多发性骨髓瘤、慢性髓性白血病、骨髓细胞白血病、神经胶质瘤、卡波西肉瘤,或其它任何类型的实体或液体肿瘤。优选地,治疗的癌症选自乳腺癌、结直肠癌、肺癌、前列腺癌或胰腺癌或成胶质细胞瘤。
本发明还涉及本发明化合物在制备药物中的用途,所述药物用于治疗哺乳动物中与 p70S6K活动过度有关的过度增殖性疾病以及由p70S6K级联所调节的疾病,或用于治疗异常增殖介导的病症,例如癌症和炎症。
本发明还涉及用于治疗哺乳动物中与血管发生或血管生成有关的疾病的化合物或药物组合物,其包含治疗有效量的本发明化合物或其可药用盐、前药或水合物以及可药用的载体。
在一个实施方案中,所述化合物或药物组合物可以用于治疗下列疾病:肿瘤血管生成、慢性炎症(例如类风湿性关节炎、炎性肠疾病)、动脉粥样硬化、皮肤病(例如银屑病、湿疹和硬皮病)、糖尿病、糖尿病性视网膜病、早产儿视网膜病和年龄相关性黄斑变性。
本发明还涉及用于抑制哺乳动物中异常细胞生长的化合物或药物组合物,其包含一定量的本发明化合物或其可药用盐或溶剂化物或前药以及一定量的另外的抗癌治疗药物,其中所述化合物、盐、溶剂化物或前药的量与化学治疗剂的量一起对抑制异常细胞生长是有效的。许多抗癌治疗药物目前在本领域内中是已知的。在一个实施方案中,所述抗癌治疗药物是选自以下的化学治疗剂:有丝分裂抑制剂、烷化剂、抗代谢药、嵌入抗生素(intercalating antibiotics)、生长因子抑制剂、细胞周期抑制剂、酶、拓扑异构酶抑制剂、生物学应答调节剂、抗激素、血管生成抑制剂和抗雄激素。在另一个实施方案中,所述抗癌治疗药物是选自以下的抗体:贝伐单抗、CD40-特异性抗体、chTNT-1/B、地舒单抗、扎木单抗、IGF1R-特异性抗体、林妥珠单抗、依决洛单抗、WX G250、利妥昔单抗、替西木单抗、曲妥单抗和西妥昔单抗。在另一个实施方案中,所述抗癌治疗药物是另一种蛋白激酶的抑制剂,所述蛋白激酶诸如Akt、Axl、Aurora A、Aurora B、dyrk2、epha2、 fgfr3、igf1r、IKK2、JNK3、Vegfr1、Vegfr2、Vegfr3(也称为Flt-4)、KDR、MEK、 MET、Plk1、RSK1、Src、TrkA、Zap70、cKit、bRaf、EGFR、Jak2、PI3K、NPM-Alk、 c-Abl、BTK、FAK、PDGFR、TAK1、LimK、Flt-3、PDK1和Erk。
本发明还涉及抑制哺乳动物中异常细胞生长或治疗过度增殖性疾病的方法,该方法包括向哺乳动物施用一定量的本发明化合物或其可药用盐或溶剂化物或前药,与放射治疗联合使用,其中所述化合物、盐、溶剂化物或前药的量联合放射治疗对抑制哺乳动物中的异常细胞生长或治疗过度增殖性疾病是有效的。施用放射治疗的技术在本领域中是已知的,并且这些技术可用于本文中所述的联合治疗中。在该联合治疗中,本发明化合物的施用可如本文所述确定。一般认为,本发明化合物可以使得异常细胞对放射治疗更为敏感,从而可以杀死和/或抑制此类细胞生长。
因此,本发明还涉及使哺乳动物中的异常细胞对放射治疗敏感化的方法,该方法包括向哺乳动物施用一定量的本发明化合物或其可药用盐、溶剂化物或前药,所述量可以有效地使得异常细胞对放射治疗敏感化。本方法中化合物、盐或溶剂化物的量可根据本文所述的确定所述化合物的有效量的方法进行测定。本发明还涉及抑制哺乳动物中异常细胞生长的方法,其包括一定量的本发明化合物或其可药用盐、溶剂化物、前药或同位素标记的衍生物以及一定量的一种或多种选自抗血管生成剂、信号传导抑制剂和抗增殖性药物。
在实际应用中,根据常规药物配制技术,本发明化合物作为活性成分可以与药用载体结合为紧密混合物。所述载体可根据施用(例如,经口或胃肠外(包括静脉内的)) 所需的制剂形式而采用多种形式。在制备口服剂型组合物时,可使用任何常规药用介质,例如,水、乙二醇、油类、醇类、矫味剂、防腐剂、着色剂等。在口服液体制剂的情况中,可使用任何常规药用介质,例如,混悬剂、酏剂和溶液剂;或载体例如淀粉、糖、微晶纤维素、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。在口服固体制剂情况下,组合物可作为例如粉剂、硬和软胶囊以及片剂形式存在,相对液体剂型来说,优选固体口服剂型。
因为片剂和胶囊容易给药,所以片剂和胶囊代表最有益的口服单位剂型,在此情况下,明显可以采用固体药物载体。如有需要,片剂可通过标准含水或不含水技术包衣。所述组合物和制剂应包含至少0.1%的活性化合物。当然,活性化合物在这些组合物中的百分比可变化,可以有益地在约2%到约60%的单位重量范围内。在所述治疗有用的组合物中的活性化合物的量为能够获得有效剂量的量。活性化合物同样可经鼻内给药,例如,液体滴剂或喷雾剂。
片剂、丸剂、胶囊等可同样包含:粘合剂,例如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,例如磷酸二钙;崩解剂,例如玉米淀粉、土豆淀粉、海藻酸;润滑剂,例如硬脂酸镁;和甜味剂,例如蔗糖、乳糖或糖精。单位剂型为胶囊时,可包含除上述类型材料之外的液体载体,例如脂肪油。
各种不同的其它物质可以作为包衣材料存在,或用于改变单位剂量的物理形式。例如,片剂可用虫胶、糖衣或两者一起包衣。除了活性组分外,糖浆剂或酏剂还可包含:作为甜味剂的蔗糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、着色剂和矫味剂(例如樱桃或橙子口味)。
本发明化合物也可以经肠胃外给药。这些活性化合物的溶液或悬浮液可通过在水中与表面活性剂(例如羟基-丙基纤维素)适当地混合来制备。分散液可由甘油、液态聚乙二醇以及其在油中的混合物制备。在储存和使用的常规条件下,这些制剂可以包含防腐剂以防止微生物的生长。
适宜于注射使用的药物形式包括用于即时制备无菌注射溶液或分散体的无菌注射水溶液或分散体和无菌粉末。在所有情况中,该形式必须为无菌的并必须具有足够的流动性使它们易于注射。在制备和储存的情况下,所述形式必须稳定并且必须能够对抗微生物(例如细菌和真菌)的污染。载体可包括溶剂或分散介质,例如水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇)、其适宜的混合物和植物油。
任何适宜的给药途径可以提供哺乳动物(尤其是人类)有效剂量的本发明化合物。例如,可经口、直肠、局部、肠胃外、眼、肺、鼻等给药。剂型包括片剂、口含片剂、分散剂、混悬剂、溶液剂、胶囊剂、霜剂、软膏剂、气雾剂等。优选本发明化合物经口给药。
施用的活性组分的有效量可取决于该施用的具体化合物、施用模式、待治疗的病症以及待治疗病症的严重性。所述剂量可很容易被本领域技术人员确定。
治疗或预防作为本发明化合物的适应症的癌症、炎症或其它增殖性疾病时,在给予日剂量为约0.01mg到约100mg/kg动物体重时即可以获得大致满意的结果,优选给予单一日剂量。对于大型哺乳动物而言,总的日剂量为约0.2mg到约2000mg,优选为约0.5mg到约1000mg。在70kg的成年人情况中,总的日剂量大致为约0.5mg到 1000mg。所述剂量方案可以调整从而能提供最佳治疗响应。
本发明还涉及药盒(套盒),该药盒包含下列独立包装:
a)有效量的本发明化合物或其生理学可接受的盐、溶剂化物或前药;以及
b)有效量的另外的药物活性成分。
所述药盒包含适当的容器,例如盒子、独立瓶子、袋子或安瓿。药盒可包括例如独立安瓿,每一个含有有效量的本发明化合物和/或其药学上可用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物)以及溶解形式或冻干形式的有效量的另外的药物活性成分。
具体实施方式
实验部分
在本申请中可能出现的某些缩写如下:
缩写
本发明化合物可以根据下文流程和实施例中的方法采用适当的物质制备,在下面的具体的实施例中进一步举例说明。
此外,通过使用本文所述方法,结合本领域的常规技术,可容易地制备本文所要求的其它化合物。然而,不能将实施例中说明的化合物理解为是作为本发明的唯一类型。实施例还说明了本发明化合物的制备的详细描述。本领域技术人员容易理解,下列制备方法的条件和过程的已知变通方法能用于制备这些化合物。
本发明化合物通常以其可药用盐形式分离,诸如如上所述的那些。相应于分离的盐的作为游离胺的碱可以用适宜的碱中和制得,所述碱诸如碳酸氢钠、碳酸钠、氢氧化钠和氢氧化钾水溶液,将释放的作为游离胺的碱用有机溶剂萃取,然后蒸发。通过所述方式分离的作为游离胺的可通过将其溶解于有机溶剂中,然后加入适当的酸,最终蒸发、沉淀或结晶而进一步转化为其它可药用的盐。
通过以下流程和实施例中所述的具体实施方案阐述但不限制本发明。除非在流程中另外说明,否则任何变量具有如上所述的同样意义。
除非另外说明,所有的原料来自商业供应商,且未经进一步纯化地使用。除非另外说明,所有的温度以℃表示,且所有的反应在室温进行。化合物通过二氧化硅色谱或制备型HPLC纯化。
分析方法
使用以下三个方法进行分析性LC/MS:
方法A:使用Discovery C18,5ìm,3x30mm柱,流速400ìL/分钟,进样环5ìL,流动相(A)含0.1%甲酸的水,流动相(B)含0.1%甲酸的甲醇;保留时间以分钟计。方法详述:(I)使用Quaternary Pump G1311A(Agilent),备有UV/VIS二极管阵列检测器 G1315B(Agilent)和Finnigan LCQ Duo MS检测器(ESI+模式),UV-检测在254和 280nm,梯度:15-95%(B)3.2分钟线性梯度,(II)在95%(B)保持1.4分钟,(III)从 95-15%(B)0.1分钟线性梯度,(IV)在15%(B)保持2.3分钟。
方法B:使用Waters Symmetry C18,3.5ìm,4.6x75mm柱,流速1mL/分钟,进样环10ìL,流动相(A)为含0.05%TFA的水,流动相(B)为含0.05%TFA的ACN;保留时间以分钟计。方法详述:(I)使用Binary Pump G1312A(Agilent),备有UV/Vis二极管阵列检测器G1315B(Agilent)和Agilent G1956B(SL)MS检测器(ESI+模式),UV-检测在254和280nm,梯度:20-85%(B)10分钟线性梯度,(II)在85%(B)保持1分钟,(III)从85-20%(B)0.2分钟线性梯度,(IV)在20%(B)保持3.8分钟。
方法C:梯度:4.2分钟/流速:2ml/分钟99:01-0:100水+0.1%(体积)TFA;乙腈+0.1%(体积)TFA;0.0至0.2分钟:99:01;0.2至3.8分钟:99:01→0:100; 3.8至4.2分钟:0:100;柱:Chromolith Performance RP18e;长度100mm,直径 3mm;波长:220nm。
分析型手性HPLC
使用来自Daicel Chemical Industries,Ltd.的ChiralPak AD-H柱(250X4.6mm)在 Agilent 1100系列系统进行分析型手性HPLC。该方法使用5.0ìL进样体积,流速1mL/ 分钟,使用100%甲醇在25℃运行15分钟,且UV-检测在254和280nm。
制备型HPLC
使用Waters Atlantis dC18OBD TM 10ìM(30X250mm)柱或Waters Sunfire PrepC18 OBD 10ìM(30X250mm)柱进行制备型HPLC。所述柱在装备有进样环(10mL)和ISCO UA-6UV/Vis检测器的Waters Prep LC4000 System以60mL/分钟的流速使用。流动相从含有(A)水和(B)HPLC-级乙腈的两个溶剂瓶中吸入。通常的制备使用线性梯度(例如,0-60%溶剂B经历60分钟)。
本发明还涉及根据下文所述流程和操作实施例制备通式(I)的化合物的方法。
以下操作实施例旨在阐明本发明的具体实施方案,并不意欲以任何方式限制说明书或权利要求的范围。
描述中间体和终产物化合物的合成流程
嘧啶氯化物中间体或者通过商业途径购买或者根据流程1和流程2描述的合成路径制备。
流程1
醋酸甲脒与乙基丙二酸二乙酯在乙醇钠存在下于干乙醇中反应,生成5-乙基嘧啶- 4,6-二醇,后者在TEA存在下于甲苯中被POCl3转化为4,6-二氯-5-乙基嘧啶。100℃下4,6-二氯-5-乙基嘧啶再与氨水在正丁醇中反应,生成4-氨基-5-乙基-6-氯嘧啶。
流程2
4-氨基-6-氯嘧啶-5-醇与烷基化试剂反应,得到所希望的嘧啶氯化物中间体。
流程3
嘧啶氯化物中间体1与仲胺2在碱存在下反应,得到化合物3。如果化合物3中的 R1是溴,进行Suzuki偶联反应,生成化合物4。
流程4
4-氧哌啶酮-1-羧酸叔丁酯与2-(4-(三氟甲基)苯基)乙腈在碱性条件下反应,生成化合物5。以Pd(OH)2为催化剂对化合物5进行氢化反应还原双键,并以拉尼镍为催化剂将氰化物转化胺,然后脱Boc,产生中间体6,该中间体与5-溴-6-氯嘧啶-4-胺偶联,得到化合物7。伯胺7用Boc保护,得到中间体8,该中间体8进行Suzuki偶联反应,然后脱Boc保护,生成化合物9。
流程5
5-(4-氟苯基)-6-(哌嗪-1-基)嘧啶-4-胺与芳醛或芳酮在还原性胺化条件下反应,生成所希望的化合物10。
流程6
用仲胺12置换溴化物11,得到酮13,后者被还原为醇14。醇14被亚硫酰氯转化为相应的氯化物15。氯化物15与哌嗪中间体16反应,得到所希望的产物17。
流程7
5-溴-6-氯-嘧啶-4-基胺与仲胺18在碱存在下反应,得到溴化物中间体19。该溴化物中间体19与溴酸或酯进行Suzuki偶联反应,得到酮中间体20。在氰基硼氢化钠存在下用胺使酮中间体20进行还原性胺化反应,得到所希望的产物21。用硼氢化钠还原酮中间体20,生成仲醇22,后者与氯化物进行烷基化反应,被转化为化合物23。化合物25由其相应的氯化物中间体24与相应的醇22制备。
流程8
4-杂环-6-氨基嘧啶26、芳醛、和三甲基氰硅烷进行Strecker反应,得到腈27。还原腈得到伯胺,为所希望的产物28。
流程9
5-溴-6-氯-嘧啶-4-基胺与仲胺29在碱存在下反应,得到溴化物30。该溴化物30与硼酸或酯进行Suzuki偶联反应,得到化合物31。
流程10
1-(叔丁氧基羰基)-4-((叔丁氧基羰基)氨基)哌啶-4-羧酸与胺32进行酰胺偶联反应,接着Boc脱保护,生成胺中间体33,后者与6-氨基-5-取代的-4-氯嘧啶反应,得到化合物34。如果化合物34中的R1是溴,进行Suzuki偶联反应,生成化合物35。
实施例
考虑到本申请中描述的化合物的编号不连续,有意地略去实施例136和209-213。
实施例(1)至(50)的制备参照流程3。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-溴-嘧啶-4-基胺
(“1”)
中间体(1.1):2-哌嗪-1-基-2-(4-三氟甲基-苯基)-乙基胺盐酸盐
4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-羧酸叔丁酯(185 mg;0.5mmol;1.0 eq.)和4M氯化氢的二噁烷溶液(1.8 ml;7.4 mmol;15 eq.)在甲醇(3.00ml)中的混合物室温搅拌过夜。向反应混合物加入醚。滤出沉淀,用醚洗涤沉淀,干燥,得到2-哌嗪-1- 基-2-(4-三氟甲基-苯基)-乙基胺盐酸盐,为乳白色固体,得率为67%。
5-溴-6-氯嘧啶-4-胺(51.6mg;0.24mmol,1.0eq.)、中间体(1.1)(100.0mg;0.24mmol,1.0eq.)和碳酸钾(97.5mg;0.7mmol;3.0eq.)在DMSO(2.00ml)中的混合物在 60℃加热8小时。反应混合物经制备型HPLC纯化(Waters,碱性条件),得到标题化合物,为白色固体,得率为70%。LC-MS:(M+1=445,obsd.=445)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶- 4-基胺(“2”)
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-溴-嘧啶-4-基胺(110.00mg; 0.25mmol;1.0eq.)、(4-氟苯基)硼酸(103.7mg;0.74mmol;3.0eq.)、醋酸钯(2+)(5.5 mg;0.02mmol;0.1eq.)、二环己基(2',6'-二甲氧基联苯基-2-基)膦(20.2mg;0.05mmol;0.2eq.)和碳酸铯(241.4mg;0.74mmol;3.0eq.)在二噁烷(5.00ml)和水(0.50ml) 中的混合物置于密封管内,100℃搅拌过夜。粗产物经反相色谱法纯化(Waters,碱性条件),得到标题化合物,为白色固体,得率为75%。LC-MS:(M+1=461,obsd.= 461)。
6-{4-[(S)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺 (“3”)
通过SFC手性色谱法从实施例(2)分离出标题化合物。LC-MS:(M+1=461,obsd. =461)。
6-{4-[(R)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺 (“4”)
通过SFC手性色谱法从实施例(2)分离出标题化合物。LC-MS:(M+1=461,obsd. =461)。
6-[4-(2-氨基-1-苯基-乙基)-哌嗪-1-基]-5-溴-嘧啶-4-基胺(“5”)
参照实施例(1)的方法,以4-[2-氨基-1-苯基乙基]-哌嗪-1-羧酸叔丁酯代替4-[2-氨基- 1-(4-三氟甲基苯基)-乙基]-哌嗪-1-羧酸叔丁酯制备标题化合物。LC-MS:(M+1=377, obsd.=377)。
6-[4-(2-氨基-1-苯基-乙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶-4-基胺(“6”)
参照实施例(2)的方法,以6-{4-[2-氨基-1-苯基)-乙基]-哌嗪-1-基}-5-溴-嘧啶-4-基胺代替6-{4-[2-氨基-1-(4-三氟甲基苯基)-乙基]-哌嗪-1-基}-5-溴-嘧啶-4-基胺制备标题化合物。LC-MS:(M+1=393,obsd.=393)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡唑-4-基)-嘧 啶-4-基胺 (“7”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=433,obsd.=433)。
(S)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基) 嘧啶-4-胺 (“8”)。
通过SFC柱从实施例(7)手性分离出标题化合物。LC-MS:(M+1=433,obsd.=433)。
(R)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基) 嘧啶-4-胺 (“9”)。
通过SFC柱从实施例(7)手性分离出标题化合物。LC-MS(M+1=433,obsd.= 433)。
5-(4-氟苯基)-6-(4-(2-(吡咯烷-1-基)-1-(4-(三氟甲基)-苯基)-乙基)-哌嗪- 1-基)-嘧啶-4-胺(“10”)
中间体(10.1):1-(2-(吡咯烷-1-基)-1-(4-(三氟甲基)苯基)乙基)哌嗪盐酸盐
在干微波小瓶中,加入4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-羧酸叔丁酯 (160.0mg;0.43mmol;1.0eq.)、碳酸钾(296.1mg;2.14mmol;5.0eq.)、1,4-二溴-丁烷(55.9μl;0.47mmol;1.1eq.)。该小瓶盖上盖子,连接至真空,保持10分钟,然后通入氮气。白色混浊混合物在83℃搅拌过夜。检测到没有起始材料。滤出粗混合物,浓缩,并经10g KPNH柱纯化,得到68mg Boc保护的中间体(8.1)。
25mL烧瓶含有所获得的Boc保护的标题化合物在甲醇(5mL)中的溶液,0℃下缓慢地向该烧瓶加入氯化氢(0.8ml;1.61mmol;10.0eq.)。将得到的溶液加热至室温,搅拌过夜。LCMS检测不到任何起始材料。粗混合物浓缩,直接用在下一步骤中。LC- MS:(M+1=328,obsd.=328)。
中间体(10.2):5-溴-6-(4-(2-(吡咯烷-1-基)-1-(4-(三氟甲基)苯基)-乙基)哌嗪-1-基)嘧啶-4-胺
参照实施例(1)的方法,以中间体(10.1)制备中间体(10.2)。LC-MS:(M+1=499,obsd.=499)。
参照实施例(2)的方法,以中间体(10.2)制备实施例(10)。LC-MS:(M+1=515,obsd.=515)。
5-溴-6-(4-(2-(哌啶-1-基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-4-胺(“11”)
中间体(11.1):1-(2-(哌啶-1-基)-1-(4-(三氟甲基)苯基)乙基)哌嗪盐酸盐
参照中间体(10.1)的方法,以1,5-二溴-戊烷(120.38μl;0.88mmol;1.1eq.)代替1,4-二溴丁烷中间体(11.1)(315mg)制备中间体(11.1)。粗产物浓缩,直接用在下一步骤中。LC-MS:(M+1=342,obsd.=342)。
参照实施例(1)的方法,以中间体(9.1)制备实施例(11)。LC-MS:(M+1=513,obsd.=513)。
5-(4-氟-苯基)-6-{4-[2-哌啶-1-基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}- 嘧啶-4-基胺(“12”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=529,obsd.=529)。
5-(4-氟-苯基)-6-[4-(4-三氟甲基-苄基)-哌嗪-1-基]-嘧啶-4-基胺(“13”)
中间体(13.1):4-(6-氨基-5-溴-嘧啶-4-基)-哌嗪-1-羧酸叔丁酯
参照实施例(1)的方法,以哌嗪-1-羧酸叔丁酯代替4-[2-氨基-1-(4-三氟甲基苯基)-乙基]-哌嗪制备中间体(13.1)。LC-MS:(M+1=358,obsd.=358)。
中间体(13.2):4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-羧酸叔丁酯
参照实施例(2)的方法制备标中间体(13.2)。LC-MS:(M+1=374,obsd.=374)。
中间体(13.3):5-(4-氟-苯基)-6-哌嗪-1-基-嘧啶-4-基胺
中间体(10.2)(370mg;1mmol;1.0eq.)、4M氯化氢的二噁烷溶液(2.5mL,10 mmol,10eq.)在甲醇(2.0ml)中的混合物室温搅拌3小时。反应混合物用醚稀释。滤出沉淀物,用醚洗涤,得到中间体(10.3),为盐酸盐。LC-MS:(M+1=274,obsd.= 274)。
中间体(13.3)(60.0mg;0.22mmol;1.0eq.)、1-溴甲基-4-三氟甲基苯(52.48mg;0.22mmol;1.00eq.)和DIPEA(0.04ml;0.26mmol;1.2eq.)在THF(2.0ml)中的混合物室温搅拌过夜。反应混合物浓缩,经制备型HPLC纯化(Waters,碱性条件),得到标题化合物,为白色固体,得率为76%。LC-MS:(M+1=432,obsd.=432)。
5-溴-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-4- 胺(“14”)
参照实施例(1)的方法,以N,N-二甲基-2-(哌嗪-1-基)-2-(4-(三氟甲基)苯基)乙胺代替 2-哌嗪-1-基-2-(4-三氟甲基-苯基)-乙基胺制备标题化合物。LC-MS:(M+1=474,obsd. =474)
6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(4-氟苯基) 嘧啶-4-胺 (“15”)
参照实施例(2)的方法,以5-溴-6-(4-(2-(二甲基氨基)-1-(4(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-4-胺代替6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)-哌嗪-1-基)-5-溴嘧啶-4- 胺制备标题化合物。LC-MS:(M+1=489,obsd.=489)。
(S)-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(4-氟 苯基)嘧啶-4-胺(“16”)
通过SFC手性色谱法从实施例(15)分离出标题化合物。LC-MS:(M+1=489,obsd.=489)。
(R)-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(4-氟 苯基)嘧啶-4-胺(“17”)
通过SFC手性色谱法从实施例(15)分离出标题化合物。LC-MS:(M+1=489,obsd.=489)。
2-(4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)-N-(2-(二甲基氨基)乙基)- 2-(4-(三氟甲基)苯基)乙酰胺(“18”)
参照实施例(2)的方法,以2-(4-(6-氨基-5-溴嘧啶-4-基)哌嗪-1-基)-N-(2-(二甲基氨基) 乙基)-2-(4-(三氟甲基)苯基)乙酰胺代替6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1- 基)-5-溴嘧啶-4-胺制备标题化合物。LC-MS:(M+1=546,obsd.=546)。
6-(4-(2-氨基-1-(4-(三氟甲基)-苯基)乙基)哌嗪-1-基)-5-乙烯基嘧啶-4-胺(“19”)
参照实施例(2)的方法,以4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊环代替4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=394,obsd.=394)。
5-(6-氨基吡啶-3-基)-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)-苯基)乙基)哌 嗪-1-基)嘧啶-4-胺(“20”)
参照实施例(15)的方法,以(6-氨基吡啶-3-基)溴酸代替4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=487,obsd.=487)。
6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-乙烯基嘧 啶-4-胺 (“21”)
参照实施例(15)的方法,以4,4,5,5-四甲基-2-乙烯基-1,3,2-二氧硼戊环代替4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=421,obsd.=421)。
2-(4-(4-氨基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)-哌嗪-1- 基)嘧啶-5-基)苯基)戊-2-醇(“22”)
参照实施例(15)的方法,以2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯基)戊-2- 醇代替4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=529,obsd.=529)。
4-(4-氨基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧 啶-5-基)苯甲酸甲酯(“23”)
参照实施例(15)的方法,以4-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)苯甲酸甲酯代替4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=529,obsd.=529)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(环己-1-烯-1-基)嘧 啶-4-胺 (“24”)
参照实施例(2)的方法,以甲基2-(环己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环代替4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=447,obsd.=447)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(环戊-1-烯-1-基)嘧 啶-4-胺 (“25”)
参照实施例(2)的方法,以2-(环戊-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊环代替 4-氟苯基硼酸制备标题化合物。LC-MS:(M+1=433,obsd.=433)。
4-(4-氨基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧 啶-5-基)苯甲酸(“26”)
圆底烧瓶含有4-(4-氨基-6-{4-[2-二甲基氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1- 基}-嘧啶-5-基)-苯甲酸甲酯三氟乙酸(36.00mg;0.06mmol;1.00eq.)在THF(2.00ml)和水(2.00ml)中的溶液,向该烧瓶加入1N氢氧化锂一水合物水溶液。混合物室温搅拌4小时,然后浓缩,经Waters制备型HPLC纯化。LC-MS:(M+1=515,obsd.=515)。
6-(4-(2-(氮杂环丁烷-1-基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(4-氟 苯基)嘧啶-4-胺(“27”)
向含有上一步骤获得的1-[2-氯-2-(4-三氟甲基-苯基)-乙基]-氮杂环丁烷(32.26mg; 0.12mmol;1.00eq.)的乙腈(2.00ml)溶液的微波小瓶加入5-(4-氟-苯基)-6-哌嗪-1-基-嘧啶-4-基胺(33.43mg;0.12mmol;1.00eq.),再加入DIPEA(0.06ml;0.37mmol;3.00 eq.)。澄清溶液在60℃搅拌过夜,再在75℃搅拌3小时,混合物浓缩,经Waters制备型HPLC纯化。LC-MS:(M+1=501,obsd.=501)。
5-环丙基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧 啶-4-胺 (“28”)
向含有5-溴-6-{4-[2-二甲基氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-嘧啶-4-基胺(84.00mg;0.18mmol;1.00eq.)在甲苯(3.00ml;28.23mmol;159.07eq.)和水((0.30 ml;16.65mmol;93.84eq.)中的溶液的微波小瓶加入醋酸钯(ii)(3.98mg;0.02mmol; 0.10eq.)、环丙基三氟硼酸钾(52.52mg;0.35mmol;2.00eq.)、碳酸铯(127.21mg; 0.39mmol;2.20eq.)和45-二(联苯基膦)-9,9-二甲基呫吨(20.54mg;0.04mmol;0.20 eq.)。混合物在125℃经受微波30分钟,然后过滤,经Waters制备型HPLC纯化所希望的产物。LC-MS:(M+1=435,obsd.=435)。
5-溴-6-{4-[(1-甲基-1H-咪唑-2-基)-苯基-甲基]-哌嗪-1-基}-嘧啶-4-基胺(“29”)
参照实施例(1)的方法,以1-[(1-甲基-1h-咪唑-2-基)-苯基-甲基]-哌嗪代替2-哌嗪-1- 基-2-(4-三氟甲基-苯基)-乙基胺制备标题化合物。LC-MS:(M+1=429.3,obsd.=429.2)。
5-(4-氟-苯基)-6-{4-[(1-甲基-1H-咪唑-2-基)-苯基-甲基]-哌嗪-1-基}-嘧啶- 4-基胺 (“30”)
参照实施例(2)的方法制备标题化合物,为白色固体,得率为79%。LC-MS:(M+1 =443.5,obsd.=444.3)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-甲氧基嘧啶-4-胺(“31”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=397,obsd.=397)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-乙氧基嘧啶-4-胺(“32”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=411,obsd.=411)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(2,2,2-三氟乙氧基) 嘧啶-4-胺 (“33”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=465,obsd.=465)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(苄基氧基)嘧啶-4- 胺(“34”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=473,obsd.=473)。
4-氨基-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-5-醇(“35”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=483,obsd.=483)。
4-氨基-6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-嘧啶-5-腈(“36”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=392,obsd.=392)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1H-吡咯-3-基)嘧 啶-4-胺(“37”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=432,obsd.=432)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(异噁唑-4-基)嘧啶- 4-胺(“38”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=434,obsd.=434)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1-乙基-1H-吡唑-4- 基)嘧啶-4-胺(“39”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=461,obsd.=461)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡唑- 4-基)-嘧啶-4-基胺(“40”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=447,obsd.=447)。
6-{4-[(S)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡 唑-4-基)-嘧啶-4-基胺(“41”)
通过SFC手性色谱法从实施例(40)分离出标题化合物。LC-MS:(M+1=447,obsd.=447)。
6-{4-[(R)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡 唑-4-基)-嘧啶-4-基胺(“42”)
通过SFC手性色谱法从实施例(40)分离出标题化合物。LC-MS:(M+1=447,obsd.=447)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡唑- 3-基)-嘧啶-4-基胺(“43”)
参照实施例(2)的方法制备标题化合物。LC-MS:(M+1=447,obsd.=447)。
3-[2-{4-[6-氨基-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基]-哌嗪-1-基}-2-(4-三 氟甲基-苯基)-乙基氨基]-2,3-二甲基-丁-2-醇(“44”)
实施例(43)的副产物为标题化合物。LC-MS:(M+1=547,obsd.=547)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-((3-氟氮杂环丁烷- 1-基)甲基)嘧啶-4-胺(“45”)
向3-氟-氮杂环丁烷盐酸盐(17.64mg;0.12mmol;1.05eq.)在1ml DCE中的溶液加入DIEA(0.04ml;0.23mmol;2.00eq.)。室温搅拌10分钟后,加入[2-[4-(6-氨基-5-甲酰基-嘧啶-4-基)-哌嗪-1-基]-2-(4-三氟甲基-苯基)-乙基]-氨基甲酸苄酯(60.00mg;0.11mmol;1.00eq.),再加入三乙酰氧基硼氢化钠(72.18mg;0.34mmol;3.00eq.)。反应混合物室温搅拌过夜。将反应溶液倒入EA,用5%碳酸氢钠和盐水洗涤。分离有机层,干燥,浓缩,得到中间体。
将上述中间体溶解在1ml甲醇中,加入70mg 10%Pd/C,再加入100mg甲酸铵。得到的反应混合物在60℃搅拌1小时。粗产物经制备型HPLC纯化,得到标题化合物。(10mg,得率:15%)。LC-MS:(M+1=454,obsd.=454)。
5-溴-6{4-(4-氯苄基)-哌啶-1-基}嘧啶-4-胺(“46”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=382,obsd=382)。
5-溴-6{4-(4-三氟甲基苄基)-哌啶-1-基}嘧啶-4-胺(“47”)
参照实施例(1)的方法制备标题化合物。LC-MS(M+1=416,obsd=416)。
5-(4-氟苯基)-6{4-(4-三氟甲基苄基)-哌啶-1-基}嘧啶-4-胺(“48”)
参照实施例(2)的方法制备标题化合物。LC-MS(M+1=431,obsd=431)。
5-(4-氟苯基)-6{4-(4-氯苄基)-哌啶-1-基}嘧啶-4-胺(“49”)
参照实施例(2)的方法制备标题化合物。LC-MS(M+1=398,obsd=398)。
5-(4-氟苯基)-6{4-(4-(4-氟苯基)苄基)-哌啶-1-基}嘧啶-4-胺(“50”)
参照实施例(2)的方法制备标题化合物。LC-MS(M+1=457,obsd=457)。
实施例(51)至(59)的制备参照流程4。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-溴-嘧啶-4-基胺(“51”)
中间体(51.1)4-(氰基(4-(三氟甲基)苯基)亚甲基)哌啶-1-羧酸叔丁酯
室温下向4-(三氟甲基)苯基乙腈(2560.9mg;13.83mmol;1.06eq.)在乙醇(50mL)中的溶液滴加21%乙醇钠(5.70ml;15.27mmol;1.17eq.)在乙醇中的溶液。搅拌30分钟后,缓慢地加入1-boc-4-哌啶酮(2600.00mg;13.05mmol;1.00eq.)在乙醇(10mL)中的溶液。反应混合物室温搅拌4小时。用50mL饱和NH4Cl水溶液淬灭反应,浓缩至一半体积。水溶液用醚萃取三次。有机萃取液合并,用盐水洗涤,干燥并浓缩,得到粗产物,该粗产物经Biotage色谱法纯化,洗脱液为乙酸乙酯/己烷(5-30%),得到所希望的产物,为浅黄色固体(3200.00mg,得率:6.9%)。
中间体(51.2)2-(哌啶-4-基)-2-(4-(三氟甲基)苯基)乙胺盐酸盐
使中间体(51.1)(2000.0mg;5.46mmol;1.00eq.)在50ml甲醇中的溶液室温通过H-Qube的20%Pd(OH)2柱,流速:1.5ml/min,循环一次。LCMS显示干净的产物为4-(氰基(4-(三氟甲基)苯基)甲基)哌啶-1-羧酸叔丁酯。向上述溶液加入10ml 7.0N NH3在甲醇中的溶液,再在45℃将溶液置于H-Qube并通过拉尼镍柱,流速:1.5ml/min,循环一次。LCMS显示还原镍的反应完成。反应混合物浓缩,得到4-(2-氨基-1-(4-(三氟甲基) 苯基)乙基)-哌啶-1-羧酸叔丁酯,将后者加入至10ml 4.0M HCl在二噁烷中的溶液中,室温搅拌4小时。过滤收集沉淀物,得到标题化合物,为白色固体(1600mg,得率: 77.7%)。LC-MS:(M+1=273,obsd.=273)。
5-溴-6-氯嘧啶-4-胺(317.78mg;1.45mmol;1.00eq.)、中间体(51.2)(500.00mg;1.45mmol;1.00eq.)和碳酸钾(600.48mg;4.34mmol;3.00eq.)在DMSO(5.00m)中的混合物60℃加热4小时。反应混合物经制备型HPLC纯化(Waters,碱性条件),得到标题化合物。LC-MS:(M+1=444,obsd.=444)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-(4-氟-苯基)-嘧啶- 4-基胺 (“52”)
参照实施例(2)的方法,以6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-溴 -嘧啶-4-基胺代替6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-溴-嘧啶-4-基胺制备标题化合物。LC-MS:(M+1=460,obsd.=460)。
6-{4-[(S)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺 (“53”)
通过SFC手性色谱法从实施例(52)分离出标题化合物。LC-MS:(M+1=460,obsd.=460)。
6-{4-[(R)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺 (“54”)
通过SFC手性色谱法从实施例(52)分离出标题化合物。LC-MS:(M+1=460,obsd.=460)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(1H-吡唑-4-基)嘧 啶-4-胺(“55”)
中间体(55.1)(2-(1-(6-氨基-5-溴嘧啶-4-基)哌啶-4-基)-2-(4-(三氟甲基)苯基)乙基)氨基甲酸叔丁酯
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-溴嘧啶-4-胺(1700mg;3.84 mmol;1.00eq.)和碳酸氢二叔丁酯(837.62mg;3.84mmol;1.00eq.)在THF(50ml)中的混合物室温搅拌过夜。反应混合物浓缩,被送入SNAP柱(100g),用30-80%乙酸乙酯在己烷中的溶液洗脱,得到标题化合物(1400mg,得率:67%)。LC-MS:(M+1 =544,obsd=543/544)。
将中间体(55.1)(280.00mg;0.51mmol;1.00eq.)、4-(4,4,5,5-四甲基-[1,3,2]二氧硼戊环-2-基)-吡唑-1-羧酸叔丁酯(226.93mg;0.77mmol;1.50eq.)和碳酸铯(335mg,1.03mmol,2.0eq.)在二噁烷(3ml)和水(0.25ml)中的混合物脱气,再加入二(三叔丁基膦)钯(0)(39.43mg;0.08mmol;0.15eq.)。得到的混合物在50℃搅拌过夜。反应混合物经SNAP柱纯化,用0-10%甲醇在DCM中的溶液洗脱,得到4-(4-氨基-6-(4-(2-((叔丁氧基羰基)氨基)-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)嘧啶-5-基)-1H-吡唑-1-羧酸叔丁酯(280mg,得率:86%),将后者加入至4ml甲醇和3ml 4.0M HCl在二噁烷中的溶液中,室温搅拌3小时。反应混合物浓缩,得到标题化合物,定量得率。LC-MS:(M+1 =432,obsd.=432)。
(S)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(1H-吡唑-4-基) 嘧啶-4-胺 (“56”)(显示为对映异构体之一,绝对手性未知)。
通过SFC柱从实施例(55)手性分离出标题化合物。LC-MS(M+1=432,obsd.=432)。
(R)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(1H-吡唑-4-基) 嘧啶-4-胺 (“57”)(显示为对映异构体之一,绝对手性未知)。
通过SFC柱从实施例(55)手性分离出标题化合物。LC-MS(M+1=432,obsd.=432)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(1-甲基-1H-吡唑-4- 基)嘧啶-4-胺(“58”)
参照实施例(55)的方法制备标题化合物。LC-MS(M+1=446,obsd.=446)。
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(异噁唑-4-基)嘧啶- 4-胺(“59”)
参照实施例(55)的方法制备标题化合物。LC-MS(M+1=433,obsd.=433)。
实施例(60)至(63)的制备参照流程5。
2-((4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)甲基)-4,5-二氯苯酚(“60”)
5-(4-氟-苯基)-6-哌嗪-1-基-嘧啶-4-基胺(400.0mg;1.46mmol;1.00eq.)、4,5-二氯-2-羟基-苯甲醛(279.5mg;1.46mmol;1.00eq.)、乙酸(87.8mg;1.46mmol;1.00 eq.)和三乙酰氧基硼氢化钠(926.1mg;4.39mmol;3.00eq.)在DCE(10ml)中的反应混合物室温搅拌过夜。反应溶液用DCM稀释,盐水洗涤。有机层干燥,浓缩,加入10ml 醚,搅拌5分钟。滤出沉淀物,得到标题化合物,为乳白色固体(528mg,得率: 80.5%)。LC-MS:(M+1=448,obsd.=448/450)。
2-(1-(4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)乙基)-5-氯苯酚(“61”)
参照实施例(60)的方法,通过5-(4-氟苯基)-6-(哌嗪-1-基)嘧啶-4-胺与1-(4-氯-2-羟基苯基)乙酮反应制备标题化合物。LC-MS:(M+1=428,obsd.=428/430)。
6-(4-(2-(氮杂环丁烷-3-基氧基)-4,5-二氯苄基)哌嗪-1-基)-5-(4-氟苯基)嘧 啶-4-胺 (“62”)
2-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基甲基}-4,5-二氯-苯酚(80.0mg; 0.18mmol;1.00eq.)、3-碘-氮杂环丁烷-1-羧酸叔丁酯(60.6mg;0.21mmol;1.20eq.) 和碳酸铯(116.2mg;0.36mmol;2.00eq.)在DMF(1ml)中的反应混合物于90℃搅拌过夜。将反应溶液倒入水中,用乙酸乙酯萃取。分离出来的有机层用盐水洗涤,干燥和浓缩,再溶解在甲醇(1ml)中,然后加入4.0M HCl在二噁烷(2ml)中的溶液,室温搅拌过夜。反应混合物浓缩,经Waters制备型HPLC(酸性条件)纯化,得到标题化合物(37 mg,得率:33.6%)。LC-MS:(M+1=504,obsd.=504/506)。
6-(4-{1-[2-(氮杂环丁烷-3-基氧基)-4-氯-苯基]-乙基}-哌嗪-1-基)-5-(4-氟- 苯基)-嘧啶-4-基胺(“63”)
参照实施例(62)的方法,使用2-((4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)甲基)- 5-氯苯酚制备标题化合物。LC-MS(M+1=483,obsd.=483)。
实施例(64)至(137)的制备参照流程6。
5-(4-氟苯基)-6{4-[1-(3-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4- 基胺(“64”)
中间体(64.1):1-(3-氟-苯基)-2-哌啶-1-基-乙酮
2-溴-1-(3-氟-苯基)-乙酮(5.0g;23.04mmol;1.0eq.)、哌啶(2.30ml;23.04mmol;1.0eq.)和DIEA(4.89ml;27.65mmol;1.20eq.)在CHCl3(100mL)中的混合物被加热回流过夜。混合物分隔在CHCl3和饱和NaHCO3水溶液之间。分离出来的有机层经 MgSO4干燥、过滤和浓缩。残留物通过快速二氧化硅色谱法纯化,得到标题化合物。 LC-MS:222(M+H)。
中间体(64.2):1-(3-氟-苯基)-2-哌啶-1-基-乙醇
向1-(3-氟-苯基)-2-哌啶-1-基-乙酮中间体(64.1)(1.50g;6.78mmol;1.00eq.)在甲醇(15mL)中的溶液加入硼氢化钠(0.38g;10.17mmol;1.50eq.)以及1mL水和1滴10%NaOH。混合物在50℃搅拌5小时。反应混合物分隔在CHCl3和水之间。分离出来的有机层经MgSO4干燥和浓缩。残留物通过快速二氧化硅色谱法纯化,得到1-(3-氟-苯基)- 2-哌啶-1-基-乙醇。LC-MS:224(M+H)。
中间体(64.3):1-[2-氯-2-(3-氟-苯基)-乙基]-哌啶
向中间体(64.2)(2.00g;8.96mmol;1.00eq.)在DCM(20mL)中的溶液滴加入亚硫酰氯(3.27ml;44.79mmol;5.00eq.),混合物室温搅拌过夜。移除溶剂后,固体悬于乙酸乙酯中,滤出固体,干燥,得到标题化合物。LC-MS:242(M+H)。
中间体(64.3)(50.00mg;0.21mmol;1.00eq.)、5-(4-氟苯基)-6-哌嗪-1-基-嘧啶-4- 基胺(80.12mg;0.21mmol;1.00eq.)和DIEA(0.18ml;1.03mmol;5.00eq.)在乙腈(5 mL)中的混合物于70℃搅拌过夜。混合物经反相HPLC纯化,得到标题化合物。LC- MS:(M+1=479,obsd.=479)。
5-(4-氟苯基)-6{4-[1-(3-三氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶- 4-基胺(“65”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=529,obsd.=529)。
5-(4-氟苯基)-6{4-[1-(3-三氟甲基-苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}- 嘧啶-4-基胺(“66”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=514,obsd.=514)。
5-(4-氟苯基)-6{4-[1-(4-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4- 基胺(“67”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=479,obsd.=479)。
5-溴-6{4-[1-(3-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“68”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=463,obsd=463)。
5-溴-6{4-[1-(3-三氟甲基-苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4- 基胺(“69”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=499,obsd=499)。
5-溴-6{4-[1-(3-三氟甲基-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基 胺(“70”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=513,obsd=513)。
6-{4-[1-(3-三氟甲基-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“71”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=435,obsd=435)。
5-溴-6{4-[1-(4-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“72”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=463,obsd=463)。
6-{4-[1-(3-三氟甲基-苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“73”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=421,obsd=421)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-氟-嘧啶-4-基胺(“74”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=385,obsd=385)。
5-(4-氟苯基)-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4- 基胺(“75”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=465,obsd=465)。
6-{4-[1-(3-氟苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“76”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=385,obsd=385)。
5-溴-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“77”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=449,obsd=449)。
6-{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“78”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=371,obsd=371)。
6-{4-[1-(4-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“79”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=485,obsd=485)。
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-氯-嘧啶-4-基胺(“80”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=401,obsd=401)。
5-氯-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“81”)
参照实施例(64)的方法制备标题化合物。LC-MS(M+1=405,obsd=405)。
(R)5-(4-氟苯基)-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧 啶-4-基胺 (“82”)
通过手性色谱法从实施例(75)分离出标题化合物。LC-MS(M+1=465,obsd=465)。
(S)-5-(4-氟苯基)-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧 啶-4-基胺 (“83”)
通过手性色谱法从实施例(75)分离出标题化合物。LC-MS(M+1=465,obsd=465)。
6-{4-[2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡唑-4- 基)-嘧啶-4-基胺(“84”)
参照实施例(64)的方法制备化合物,再通过实施例(3)的SFC手性色谱法分离出标题化合物。LC-MS:(M+1=423,obsd.=423)。
4-(1-{4-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷- 1-基-乙基)-苯甲腈(“85”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=430,obsd.=430)。
4-(1-{4-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷- 1-基-乙基)-苯甲酸甲酯(“86”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=463,obsd.=463)。
6-{4-[(S)-2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“87”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=423,obsd.=423)。
4-((S)-1-{4-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁 烷-1-基-乙基)-苯甲腈(“88”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=430,obsd.=430)。
4-((S)-1-{4-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁 烷-1-基-乙基)-苯甲酸甲酯(“89”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=463,obsd.=463)。
6-{4-[2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“90”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=451,obsd.=451)。
3-((R)-1-{4-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁 烷-1-基-乙基)-苯甲腈(“91”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=430,obsd.=430)。
6-{4-[2-氮杂环丁烷-1-基-1-(3-氟-4-甲氧基-苯基)-乙基]-哌嗪-1-基}-5-(4- 氟-苯基)-嘧啶-4-基胺(“92”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=481,obsd.=481)
6-{4-[(R)-2-氮杂环丁烷-1-基-1-(4-甲磺酰基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“93”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=483,obsd.=483)。
6-{4-[(R)-2-氮杂环丁烷-1-基-1-(2,3-二氢-苯并[1,4]二噁英-6-基)-乙基]- 哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“94”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[2-氮杂环丁烷-1-基-1-(3-氟-4-甲氧基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“95”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=453,obsd.=453)。
4-(1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷-1- 基-乙基)-苯甲酸甲酯(“96”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=491,obsd.=491)。
3-((S)-1-{4-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁 烷-1-基-乙基)-苯甲腈(“97”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=430,obsd.=430)。
6-{4-[(S)-2-氮杂环丁烷-1-基-1-(2,3-二氢-苯并[1,4]二噁英-6-基)-乙基]- 哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“98”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[2-氮杂环丁烷-1-基-1-(2-氟-3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“99”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[2-氮杂环丁烷-1-基-1-(2,3-二氟-4-甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“100”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=430,obsd.=430)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-氟-3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“101”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[(S)-2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯 基)-嘧啶-4-基胺(“102”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=451,obsd.=451)。
6-{4-[(R)-2-氮杂环丁烷-1-基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯 基)-嘧啶-4-基胺(“103”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=451,obsd.=451)。
6-{4-[(R)-2-氮杂环丁烷-1-基-1-(3-氟-4-甲氧基-苯基)-乙基]-哌嗪-1-基}- 5-(4-氟-苯基)-嘧啶-4-基胺(“104”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=481,obsd.=481)。
6-{4-[(S)-2-氮杂环丁烷-1-基-1-(3-氟-4-甲氧基-苯基)-乙基]-哌嗪-1-基}- 5-(4-氟-苯基)-嘧啶-4-基胺(“105”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=481,obsd.=481)。
4-(1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷-1- 基-乙基)-苯甲腈(“106”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=458,obsd.=458)。
6-{4-[(R)-2-氮杂环丁烷-1-基-1-(2,3-二氢-苯并[1,4]二噁英-6-基)-乙基]- 哌嗪-1-基}-5-(1H-吡唑-4-基)-嘧啶-4-基胺(“107”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=463,obsd.=463)。
6-{4-[(S)-2-氮杂环丁烷-1-基-1-(2,3-二氢-苯并[1,4]二噁英-6-基)-乙基]-
哌嗪-1-基}-5-(1H-吡唑-4-基)-嘧啶-4-基胺(“108”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=463,obsd.=463)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-氯-3-甲基-苯基)-乙基]-哌嗪-1-基}-5-(1H- 吡唑-4-基)-嘧啶-4-基胺(“109”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=453,obsd.=453)
4-((S)-1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷- 1-基-乙基)-苯甲酸甲酯(“110”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=491,obsd.=491)。
4-((R)-1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷- 1-基-乙基)-苯甲酸甲酯(“111”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[3-氮杂环丁烷-1-基-1-(4-氯-苯基)-丙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“112”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=482,obsd.=482)。
6-{4-[4-氮杂环丁烷-1-基-1-(4-氯-苯基)-丁基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“113”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=496,obsd.=496)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-氟-3-三氟甲氧基-苯基)-乙基]-哌嗪-1-基}- 5-(1H-吡唑-4-基)-嘧啶-4-基胺(“114”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=507,obsd.=507)。
6-{4-[2-氮杂环丁烷-1-基-1-(5,6,7,8-四氢-萘-2-基)-乙基]-哌嗪-1-基}-5- (6-哌嗪-1-基-吡啶-3-基)-嘧啶-4-基胺(“115”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=554,obsd.=554)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-咪唑-1-基-苯基)-乙基]-哌嗪-1-基}-5-(4- 氟-苯基)-嘧啶-4-基胺(“116”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=499,obsd.=499)。
[4-(4-氨基-6-{4-[2-氮杂环丁烷-1-基-1-(3,4-二氯-苯基)-乙基]-哌嗪-1- 基}-嘧啶-5-基)-吡唑-1-基]-乙酸乙酯(“117”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=560,obsd.=560)。
6-(1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷-1- 基-乙基)-3H-苯并噻唑-2-酮(“118”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=506,obsd.=506)。
[4-(4-氨基-6-{4-[2-氮杂环丁烷-1-基-1-(5,6,7,8-四氢-萘-2-基)-乙基]-哌 嗪-1-基}-嘧啶-5-基)-吡唑-1-基]-乙酸乙酯(“119”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=545,obsd.=545)。
6-{4-[2-氮杂环丁烷-1-基-1-(2-氟-4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“120”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-氯-3-氟-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“121”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=457,obsd.=457)
6-{4-[2-氮杂环丁烷-1-基-1-(5,6,7,8-四氢-萘-2-基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“122”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=459,obsd.=459)。
6-{4-[2-氮杂环丁烷-1-基-1-(5,6,7,8-四氢-萘-2-基)-乙基]-哌嗪-1-基}-5- (4-氟-苯基)-嘧啶-4-基胺(“123”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=487,obsd.=487)。
6-{4-[2-氮杂环丁烷-1-基-1-(2,3-二氟-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“124”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=441,obsd.=441)。
3-((S)-1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷- 1-基-乙基)-苯甲腈(“125”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=458,obsd.=458)。
6-{4-[2-氮杂环丁烷-1-基-1-(2,3-二氯-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“126”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=474,obsd.=474)。
6-{4-[2-氮杂环丁烷-1-基-1-(3-氟-4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“127”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=491,obsd.=491)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-甲磺酰基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟- 苯基)-嘧啶-4-基胺(“128”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=511,obsd.=511)。
3-((R)-1-{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-2-氮杂环丁烷- 1-基-乙基)-苯甲腈(“129”)
参照实施例(64)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=458,obsd.=458)。
[4-(4-氨基-6-{4-[2-氮杂环丁烷-1-基-1-(3-氰基-苯基)-乙基]-哌嗪-1-基}- 嘧啶-5-基)-吡唑-1-基]-乙酸甲酯(“130”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=502,obsd.=502)。
6-{4-[2-氮杂环丁烷-1-基-1-(3,4-二氯-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“131”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=474,obsd.=474)。
6-{4-[2-氮杂环丁烷-1-基-1-(4-氯-3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“132”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=507,obsd.=507)。
6-{4-[2-氮杂环丁烷-1-基-1-(3,4-二氯-苯基)-乙基]-哌嗪-1-基}-5-(6-哌嗪- 1-基-吡啶-3-基)-嘧啶-4-基胺(“133”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=569,obsd.=569)。
6-{4-[2-氮杂环丁烷-1-基-1-(2-氯-3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5- (1H-吡唑-4-基)-嘧啶-4-基胺(“134”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=507,obsd.=507)。
6-{4-[2-氮杂环丁烷-1-基-1-(3-氯-4-氟-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“135”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=457,obsd.=457)。
6-{4-[2-氮杂环丁烷-1-基-1-(2-氯-4-氟-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡 唑-4-基)-嘧啶-4-基胺(“137”)
参照实施例(64)的方法制备标题化合物。LC-MS:(M+1=457,obsd.=457)。
实施例(138)至(151)的制备参照流程7。
1-6-氨基-5-(4-氟苯基)嘧啶-4-基)哌啶-4-基-4-(氯苯基)甲醇(“138”)
中间体(138.1):[1-(6-氨基-5-溴-嘧啶-4-基)-哌啶-4-基]-(4-氯-苯基)-甲酮
5-溴-6-氯-嘧啶-4-基胺(2.0g,9.59mmol,1.0eq)、4-氯苯基-哌啶-4-基-甲酮(2.36 g,10.55mmol,1.10eq)和碳酸钾(6.63g,47.97mmol,5.0eq)在DMF(5mL)中的混合物在50℃搅拌过夜。将反应混合物倒入水中,收集沉淀物,得到中间体(138.1)。 LC-MS(M+1:396,obsd:396)。
中间体(138.2):{1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌啶-4-基}-(4-氯-苯基)-甲酮
中间体(84.1)(2.0g,5.05mmol,1.0eq)、4-氟苯基溴酸(707.24mg,5.05mmol,1.0eq)、醋酸钯(113.48mg,0.5mmol,1.0eq)、s-膦(415.01mg,1.01mmol,0.2eq)和碳酸铯(3293.76mg,10.11mmol,2.0eq)在1,4-二噁烷(10mL)和水(1.0mL)中的混合物置于密封小瓶中,在50℃搅拌过夜。经过一般操作后,粗产物经制备型HPLC纯化,得到中间体(138.2)。LC-MS(M+1:411,obsd:411)。
向中间体(138.2)(500mg,1.22mmol,1.0eq)在甲醇(15mL)中的溶液加入硼氢化钠(70mg,1.85mmol,1.5eq)。混合物搅拌过夜。浓缩后,混合物用乙酸乙酯稀释,盐水洗涤。有机层经MgSO4干燥,浓缩,再经快速二氧化硅色谱法纯化,得到标题化合物。MS-LC(M+1:414,obsd:414)。
1-6-氨基-5-(4-氟苯基)嘧啶-4-基)哌啶-4-基-4-(4-氟苯基)苯基)甲醇(“139”)
参照实施例(138)的方法制备标题化合物。LC-MS(M+1=473,obsd=473)。
1-6-氨基-5-(4-氟苯基)嘧啶-4-基)哌啶-4-基-4-(氟苯基)甲醇(“140”)
参照实施例(138)的方法制备标题化合物。LC-MS(M+1=397,obsd=397)。
1-6-氨基-5-(乙烯基嘧啶-4-基)哌啶-4-基-4-(氟苯基)甲醇(“141”)
参照实施例(138)的方法制备标题化合物。LC-MS(M+1=329,obsd=329)。
5-(4-氟苯基)-6{4-氨基(4-氯苯基)甲基-哌啶-1-基}嘧啶-4-胺(“142”)
向中间体(138.2)(150mg,0.38mmol,1.0eq)和醋酸铵(337mg,4.3mmol,12eq.) 在甲醇(5mL)中的溶液加入氰基硼氢化钠(1.90mmol,5eq)。混合物回流2天。浓缩后,混合物用乙酸乙酯稀释,盐水洗涤。有机层经MgSO4干燥,浓缩,再通过快速二氧化硅色谱法纯化,得到标题化合物。LC-MS(M+1=413,obsd=413)。
5-(4-氟苯基)-6{4-氨基(4-氟苯基)甲基-哌啶-1-基}嘧啶-4-胺(“143”)
参照实施例(142)的方法制备标题化合物。LC-MS(M+1=396,obsd=396)。
5-(4-氟苯基)-6{4-氨基(4-(4-氟苯基)苯基)甲基-哌啶-1-基}嘧啶-4-胺(“144”)
参照实施例(142)的方法制备标题化合物。LC-MS(M+1=472,obsd=472)。
6-(4-((环戊基氨基)(4-氟苯基)甲基)哌啶-1-基)-5-(4-氟苯基)嘧啶-4-胺(“145”)
参照实施例(142)的方法制备标题化合物。LC-MS(M+1=464,obsd=464)。
5-(4-氟苯基6-(4-((4-氟苯基)(2-(吡咯烷-1-基)乙氧基)甲基)-哌啶-1-基)嘧 啶-4-胺 (“146”)
向实施例(138)(150mg,0.38mmol,1.0eq)在DMF(10mL)中的溶液加入氢化钠(75.67mg,1.89mmol,5.0eq)。混合物搅拌10分钟,然后加入1-(2-氯-乙基)吡咯烷盐酸盐(77.22mg,0.45mmol,1.2eq)。混合物在70℃搅拌过夜。经过一般操作程序后,由反相HPLC纯化,得到标题化合物。LC-MS(M+1=494,obsd=494)。
5-(4-氟苯基6-(4-((4-氟苯基)(2-(二甲基氨基)乙氧基)甲基)哌啶-1-基)嘧啶- 4-胺 (“147”)
参照实施例(146)的方法制备标题化合物。LC-MS(M+1=468,obsd=468)。
5-(4-氟苯基-6-(4-((4-氟苯基)(吡咯烷-1-基)甲基)哌啶-1-基)嘧啶-4-胺(“148”)
中间体(148.1):6-{4-[氯-(4-氟-苯基)-甲基]-哌啶-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺
向实施例(140)(700mg,1.77mmol,1.0eq)在DCM(10mL)中的溶液滴加入亚硫酰氯(0.32mL,4.41mmol,2.5eq)。混合物搅拌过夜。除去溶剂后,固体悬于乙酸乙酯中,过滤后得到中间体(94.1)。LC-MS(M+1:415,obsd:415)。
中间体(148.1)(50mg,0.12mmol,1.0eq)、吡咯烷(17.14mg,0.24mmol,2eq) 和DIEA(77.88mg,0.60mmol,5eq)在NMP(3mL)中的混合物在120℃搅拌过夜。经反相HPLC纯化得到标题化合物。LC-MS(M+1=450,obsd=450)。
5-(4-氟苯基-6-(4-((4-氟苯基)(3-二氟吡咯烷-1-基)甲基)哌啶-1-基)嘧啶-4- 胺(“149”)
参照实施例(148)的方法制备标题化合物。LC-MS(M+1=486,obsd=486)。
1-(6-氨基-5-(4-氟苯基嘧啶-4-基)(4-((4-氟苯基))甲基)-二甲基ethane-1,2- di胺 (“150”)
参照实施例(148)的方法制备标题化合物。LC-MS(M+1=467,obsd=467)。
5-(4-氟苯基)-(6-(4-氟苯基哌啶-4-基甲基)氨基)甲基)哌啶-1-基)嘧啶-4-胺(“151”)
参照实施例(148)的方法制备标题化合物。LC-MS(M+1=493,obsd=493)。
实施例(152)至(194)的制备参照流程8。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(3-三氟甲基-苯基)-乙腈(“152”)
在带有搅拌棒的圆底烧瓶中,将5-(4-氟-苯基)-6-哌嗪-1-基-嘧啶-4-基胺(1eq)和3- 三氟甲基-苯甲醛(1.05eq)溶解在乙腈中。用橡胶隔片密封所述烧瓶,然后排空再回灌氩气。向该密封烧瓶加入三甲基氰硅烷(1.05eq),在室温下搅拌直至反应完成。加入等量的氯化铵(饱和水溶液)淬灭反应,然后用乙酸乙酯萃取。有机层经硫酸钠干燥,过滤,浓缩,得到标题化合物。LC-MS:(M+1=457,obsd.=457)。
6-{4-[2-氨基-1-(3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶- 4-基胺 (“153”)
0℃下,边搅拌边向实施例(152)(76.0mg;0.17mmol;1.0eq.)和氯化钴(2.2mg;0.02mmol;0.1eq.)在甲醇(5.0ml)中的混合物分批加入硼氢化钠(32.8mg;0.83mmol;5.0eq.)。上述加入完成后,让反应在室温下进行并搅拌直至LCMC确认反应完成。混合物经反相HPLC纯化,得到标题化合物。LC-MS:(M+1=461,obsd.=461)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-氟-3-三氟甲基-苯 基)-乙腈 (“154”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=475,obsd.=475)。
6-{4-[2-氨基-1-(4-氟-3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“155”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=479,obsd.=479)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(3,4-二氯-苯基)-乙腈(“156”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=457,obsd.=457)。
6-{4-[2-氨基-1-(3,4-二氯-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4- 基胺(“157”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=461,obsd.=461)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-氟-苯基)-乙腈(“158”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=407,obsd.=407)。
6-{4-[2-氨基-1-(4-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“159”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=411,obsd.=411)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(3-氯-4-氟-苯基)-乙腈(“160”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=441,obsd.=441)。
6-{4-[2-氨基-1-(3-氯-4-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶- 4-基胺(“161”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=445,obsd.=445)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-氯-苯基)-乙腈(“162”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=423,obsd.=423)。
6-{4-[2-氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“163”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=427,obsd.=427)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-氯-3-氟-苯基)-乙腈(“164”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=441,obsd.=441)。
6-{4-[2-氨基-1-(4-氯-3-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶- 4-基胺(“165”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=445,obsd.=445)。
[4-(6-氨基-5-溴-嘧啶-4-基)-哌嗪-1-基]-(3-三氟甲基-苯基)-乙腈(“166”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=442,obsd.=442)。
[4-(6-氨基-5-溴-嘧啶-4-基)-哌嗪-1-基]-(4-三氟甲基-苯基)-乙腈(“167”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=442,obsd.=442)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-三氟甲基-苯基)-乙腈(“168”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=442,obsd.=442)。
6-{4-[2-氨基-1-(3-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“169”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=411,obsd.=411)。
6-{4-[2-氨基-1-(2-氟-4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“170”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=479,obsd.=479)。
6-[4-((1R,2R)-1-氨基甲基-2-苯基-丙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶- 4-基胺 (“171”)
参照实施例(153)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=421,obsd.=421)
6-[4-((1R,2S)-1-氨基甲基-2-苯基-丙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶- 4-基胺 (“172”)
参照实施例(153)的方法制备化合物,再通过SFC手性色谱法分离出标题化合物。LC-MS:(M+1=421,obsd.=421)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(6-氯-吡啶-3-基)-乙腈(“173”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=424,obsd.=424)。
6-{4-[2-氨基-1-(6-氯-吡啶-3-基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶- 4-基胺(“174”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=428,obsd.=428)。
6-{4-[(R)-2-氨基-1-(6-氯-吡啶-3-基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧 啶-4-基胺 (“175”)
通过SFC手性色谱法从实施例(174)分离出标题化合物。LC-MS:(M+1=428, obsd.=428)。
6-{4-[(S)-2-氨基-1-(6-氯-吡啶-3-基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧 啶-4-基胺 (“176”)
通过SFC手性色谱法从实施例(174)分离出标题化合物。LC-MS:(M+1=428, obsd.=428)
6-{4-[2-氨基-1-(6-氯-吡啶-3-基)-乙基]-哌嗪-1-基}-5-乙基-嘧啶-4-基胺(“177”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=362,obsd.=362)。
6-{4-[2-氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-5-乙基-嘧啶-4-基胺(“178”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=361,obsd.=361)。
6-{4-[(S)-2-氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-5-乙基-嘧啶-4-基胺(“179”)
通过SFC手性色谱法从实施例(178)分离出标题化合物。LC-MS:(M+1=361, obsd.=361)
6-{4-[(R)-2-氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-5-乙基-嘧啶-4-基胺(“180”)
通过SFC手性色谱法从实施例(178)分离出标题化合物。LC-MS:(M+1=361, obsd.=361)
6-{4-[2-氨基-1-(2,3-二氢-苯并[1,4]二恶英-6-基)-乙基]-哌嗪-1-基}-5-乙 基-嘧啶-4-基胺(“181”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=385,obsd.=385)。
2-(4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)-2-(6-甲氧基吡啶-3-基)乙 腈(“182”)
参照实施例(152)的方法制备标题化合物。LC-MS(M+1=420,obsd.=420)。
6-(4-(2-氨基-1-(6-甲氧基吡啶-3-基)乙基)哌嗪-1-基)-5-(4-氟苯基)嘧啶-4- 胺(“183”)
参照实施例(153)的方法制备标题化合物。LC-MS(M+1=424,obsd.=424)。
2-(4-(6-氨基-5-(1H-吡唑-4-基)嘧啶-4-基)哌嗪-1-基)-2-(4-(甲基磺酰基)苯 基)乙腈 (“184”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=439,obsd.=439)。
6-(4-(2-氨基-1-(4-(甲基磺酰基)苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基)嘧 啶-4-胺 (“185”)
参照实施例(153)的方法制备标题化合物。LC-MS(M+1=443,obsd.=443)。
6-(4-(2-氨基-1-(4-(三氟甲氧基)苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基)嘧 啶-4-胺 (“186”)
参照实施例(153)的方法制备标题化合物。LC-MS(M+1=449,obsd.=449)。
6-(4-(2-氨基-1-(4-氯-3-氟苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基)嘧啶-4- 胺(“187”)
参照实施例(153)的方法制备标题化合物。LC-MS(M+1=417,obsd.=417)。
6-[4-(2-氨基-1-环己基-乙基)-哌嗪-1-基]-5-乙基-嘧啶-4-基胺(“188”)
向[4-(6-氨基-5-乙基-嘧啶-4-基)-哌嗪-1-基]-环己基-乙腈(28.00mg;0.09mmol; 1.00eq.)在THF(4.00ml;49.37mmol;579.16eq.)中的溶液加入9-BBN氢化锂(0.38 ml;0.38mmol;4.50eq.)在THF中的溶液,混合物在50℃加热数小时。LC-MS分析显示反应未完成,仍然存在起始材料。多加入0.1ml 9-BBN氢化锂溶液,60℃反应混合物搅拌过夜。LC-MS分析显示反应完成。反应混合物经玻璃膜注射头过滤器过滤,蒸干。残留物溶解在DMSO(3ml)中,经反相HPLC(Waters,碱性缓冲液)纯化,得到标题化合物(13.9mg;0.04mmol),为白色玻璃,得率为47.2%。LC-MS:(M+1=333.4, obsd.=333.3)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(6-三氟甲基-吡啶-3- 基)-乙腈 (“189”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=458.4,obsd.=458.2)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-吡啶-3-基-乙腈(“190”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=390.4,obsd.=390.2)。
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-环己基-乙腈(“191”)
参照实施例(152)的方法制备标题化合物。LC-MS:(M+1=395.5,obsd.=395.3)。
6-{4-[2-氨基-1-(2-氟-5-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“192”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=479.4,obsd.=479.3)。
6-[4-(2-氨基-1-吡啶-3-基-乙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶-4-基胺(“193”)
参照实施例(153)的方法制备标题化合物。LC-MS:(M+1=394.4,obsd.=394.2)。
6-{4-[2-氨基-1-(6-三氟甲基-吡啶-3-基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)- 嘧啶-4-基胺(“194”)
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(6-三氟甲基-吡啶-3-基)-乙腈(20.00 mg;0.04mmol;1.00eq.)在15ml甲醇中以及在50mg Pd/C 10%存在下进行加氢反应,室温下在Parr振荡器中搅拌过夜,并用反相低压色谱法纯化(Yamazen,碱性缓冲液),得到标题化合物。LC-MS:(M+1=462.4,obsd.=462.5)。
实施例(195)至(208)的制备参照流程9。
N-[3-氨基-1-(6-氨基-5-溴-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲酰 胺(“195”)
60℃下5-溴-6-氯嘧啶-4-胺(272.7mg;1.24mmol;1.02eq.)、N-[(3-氨基吡咯烷-3-基)-甲基]-2,4-二氟苯甲酰胺二盐酸盐(400.0mg;1.22mmol;1.0eq.)、碳酸钾(336.8mg;2.44mmol;2.0eq.)在DMSO(5.00ml)中的混合物搅拌过夜。对反应混合物作一般操作处理,粗产物经反相制备型HPLC(Waters,碱性条件)纯化,得到标题化合物,得率为76%。LC-MS:(M+1=427,obsd.=427)。
N-[3-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲 酰胺(“196”)
4-氨基-6-氯嘧啶-5-腈(72.0mg;0.47mmol;1.02eq.)、N-[(3-氨基吡咯烷-3-基)甲基]-2,4-二氟苯甲酰胺二盐酸盐(150.0mg;0.46mmol;1.0eq.)、碳酸钾(126.3mg;0.91mmol;2.0eq.)在DMSO(2.00ml)中的混合物搅拌2小时。对反应混合物作一般操作处理,粗产物经反相制备型HPLC(Waters,乙腈/0.1%NH4OH水溶液)纯化,得到标题化合物,得率为70%。LC-MS:(M+1=374,obsd.=374)。
4-氨基-6-{3-氨基-3-[(2,4-二氟-苯甲酰基氨基)-甲基]-吡咯烷-1-基}-嘧啶- 5-羧酰胺 (“197”)
室温下将过氧化氢(0.38ml;4.29mmol;40.0eq.)滴加入N-{[3-氨基-1-(6-氨基-5- 氰基嘧啶-4-基)吡咯烷-3-基]甲基}-2,4-二氟苯甲酰胺(40.0mg;0.11mmol;1.0eq.)和碳酸钾(118.45mg;0.86mmol;8.0eq.)在DMSO(3.0ml)中的混合物中。所得到的混合物在40℃搅拌2小时。对反应混合物作一般操作处理,粗产物经反相色谱法 (Yamazen,乙腈/0.1%NH4OH水溶液)纯化,得到标题化合物,得率为40%。LC- MS:(M+1=392,obsd.=392)。
N-{3-氨基-1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二 氟-苯甲酰胺(“198”)
N-{[3-氨基-1-(6-氨基-5-溴嘧啶-4-基)吡咯烷-3-基]甲基}-2,4-二氟苯甲酰胺(70.0 mg;0.16mmol;1.0eq.)、4-氟苯基溴酸(45.8mg;0.33mmol;2.0eq.)、醋酸钯(1.8 mg;0.01mmol;0.05eq.)、二环己基(2',6'-二甲氧基联苯基-2-基)膦(6.7mg;0.02 mmol;0.10eq.)以及碳酸铯(160.1mg;0.49mmol;3.0eq.)在二噁烷(4ml)和水(0.5ml) 中的混合物置于微波小瓶中,100℃加热30分钟。对反应混合物作一般操作处理,粗产物经制备型HPLC(Waters,乙腈/0.1%NH4OH水溶液)纯化,得到标题化合物,得率为61%。LC-MS:(M+1=443,obsd.=443)。
N-{3-氨基-1-[6-氨基-5-(4-氰基-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4- 二氟-苯甲酰胺(“199”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=450,obsd.=450)。
N-{3-氨基-1-[6-氨基-5-(4-苯氧基-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2, 4-二氟-苯甲酰胺(“200”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=517,obsd.=517)。
N-{3-氨基-1-[6-氨基-5-(6-甲氧基-吡啶-3-基)-嘧啶-4-基]-吡咯烷-3-基甲 基}-2,4-二氟-苯甲酰胺(“201”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=456,obsd.=456)。
N-{3-氨基-1-[6-氨基-5-(4-三氟甲基-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}- 2,4-二氟-苯甲酰胺(“202”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=493,obsd.=493)。
N-[3-氨基-1-(6-氨基-5-苯基-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲
酰胺(“203”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=425,obsd.=425)。
N-{3-氨基-1-[6-氨基-5-(3-氟-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二 氟-苯甲酰胺(“204”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=443,obsd.=443)。
N-[3-氨基-1-(6-氨基-5-吡啶-4-基-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟- 苯甲酰胺 (“205”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=426,obsd.=426)。
N-{3-氨基-1-[6-氨基-5-(6-哌嗪-1-基-吡啶-3-基)-嘧啶-4-基]-吡咯烷-3-基 甲基}-2,4-二氟-苯甲酰胺(“206”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=510,obsd.=510)。
N-[4-氨基-1-(6-氨基-5-溴-嘧啶-4-基)-哌啶-4-基甲基]-2,4-二氟-苯甲酰胺(“207”)
中间体207.1:N-(4-氨基-哌啶-4-基甲基)-2,4-二氟-苯甲酰胺二盐酸盐
室温下向4-氨基-4-氨基甲基-哌啶-1-羧酸叔丁酯(250mg;1.1mmol;1.0eq.)在吡啶(12ml)中的溶液缓慢地加入0.1M 2,4-二氟-苯甲酰氯(182.8mg;1.04mmol;0.95 eq.)的DCM溶液。当LC-MS显示没有起始材料剩下时,加入0.5mL甲醇淬灭反应混合物。反应混合物浓缩至干,得到4-氨基-4-[(2,4-二氟-苯甲酰基氨基)-甲基]-哌啶-1-羧酸叔丁酯。
粗的4-氨基-4-[(2,4-二氟-苯甲酰基氨基)-甲基]-哌啶-1-羧酸叔丁酯(300mg;0.82 mmol;1.0eq.)和4M氯化氢在1,4-二噁烷(2.0ml;8.1mmol;10eq.)的溶液置于甲醇(2ml)中室温搅拌2小时。LC-MS显示反应完成。加入醚。滤出沉淀物,用醚洗涤,干燥,得到中间体(207.1),为乳白色固体,得率为68%。
参照实施例(195)的方法,以中间体(207.1)代替N-[(3-氨基吡咯烷-3-基)-甲基]-2,4- 二氟苯甲酰胺二盐酸盐制备实施例(207)。LC-MS:(M+1=441,obsd.=441)。
N-{4-氨基-1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌啶-4-基甲基}-2,4-二氟- 苯甲酰胺 (“208”)
参照实施例(198)的方法制备标题化合物。LC-MS:(M+1=457,obsd.=457)。
实施例(214)至(247)的制备参照流程10。
4-氨基-1-(6-氨基-5-乙基-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-3-羟 基-丙基]-酰胺(“214”)
中间体214.1:(S)-4-氨基-N-(1-(4-氯苯基)-3-羟基丙基)哌啶-4-羧酰胺
向4-叔丁氧基羰基氨基-哌啶-1,4-二羧酸一叔丁酯(1350.00mg;3.92mmol;1.00eq.)在DMF(10ml)中的溶液加入HATU(1639.48mg;4.31mmol;1.10eq.),室温搅拌 40分钟。加入DIEA(1.48ml;8.23mmol;2.10eq.),然后加入(S)-3-氨基-3-(4-氯-苯基)- 戊-1-醇(1013.56mg;3.92mmol;1.00eq.)。反应混合物搅拌多3小时。将反应溶液倒入水(100ml)中,用乙酸乙酯萃取。分离出来的有机层用盐水洗涤,干燥和浓缩。残留物用醚处理,得到白色固体,将该白色固体加入至5ml甲醇、10ml 4.0M HCl在二噁烷中的溶液中,室温搅拌过夜。滤出沉淀物,用醚洗涤,得到中间体(214.1),为白色固体。
6-氯-5-乙基-嘧啶-4-基胺(50.0mg;0.32mmol;1.0eq.)、中间体(214.1)(140.3mg;0.33mmol;1.05eq.)和DIEA(131.54mg;0.95mmol;3.00eq.)在DMSO(1.5ml) 中的反应混合物在120℃搅拌24小时。粗产物经HPLC纯化,得到标题化合物(得率: 31%)。LC-MS(M+1=433,obsd.=433)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-丙基]- 酰胺(“215”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=424,obsd.=424)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(R)-1-(4-氯-苯基)-2,2,2- 三氟乙基]-酰胺(“216”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=464,obsd.=464)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-2-氨基甲酰基-1-(4- 氯-苯基)乙基]-酰胺(“217”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=453,obsd.=453)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-乙 基]-酰胺 (“218”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=400,obsd.=400)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-丙 基]-酰胺 (“219”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=414,obsd.=414)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(R)-1-(4-氯-苯基)-2,2, 2-三氟乙基]-酰胺(“220”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=454,obsd.=454)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-2-氨基甲酰基-1-(4- 氯-苯基)-乙基]-酰胺(“221”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=443,obsd.=443)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-乙基]- 酰胺(“222”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=410,obsd.=410)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-3-羟基-1-(4-三氟甲 基-苯基)-丙基]-酰胺(“223”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=473,obsd.=473)。
4-氨基-1-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌啶-4-羧酸[(S)-1-(4-氯- 苯基)-乙基]-酰胺(“224”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=441,obsd.=441)。
4-氨基-1-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌啶-4-羧酸[(S)-1-(4-氯- 苯基)-丙基]-酰胺(“225”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=455,obsd.=455)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸((S)-3-羟基-1-苯基-丙 基)-酰胺 (“226”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=396,obsd.=396)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸((S)-3-羟基-1-对甲苯基- 丙基)-酰胺 (“227”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=410,obsd.=410)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸((S)-3-羟基-1-苯基-丙基)- 酰胺(“228”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=405,obsd.=405)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-3-羟基-1-(4-甲氧 基-苯基)-丙基]-酰胺(“229”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=426,obsd.=426)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-3-羟基-1-(4-三氟甲 基-苯基)-丙基]-酰胺(“230”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=464,obsd.=464)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸((S)-3-羟基-1-吡啶-4- 基-丙基)-酰胺(“231”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=397,obsd.=397)。
4-氨基-6-[4-氨基-4-((S)-3-羟基-1-对甲苯基-丙基氨基甲酰基)-哌啶-1-基]- 嘧啶-5-羧酸酰胺(“232”)
手性
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=428,obsd.=428)。
4-氨基-6-{4-氨基-4-[(S)-3-羟基-1-(4-三氟甲基-苯基)-丙基氨基甲酰基]-哌 啶-1-基}-嘧啶-5-羧酸酰胺(“233”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=482,obsd.=482)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(R)-1-(4-氯-苯基)-2-甲氧 基-乙基]-酰胺(“234”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=440,obsd.=440)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-3-羟 基-丙基]-酰胺 (“235”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=440,obsd.=440)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氟-苯基)-3-羟 基-丙基]-酰胺 (“236”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=423,obsd.=423)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸((S)-3-羟基-1-对甲苯基-丙 基)-酰胺 (“237”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=419,obsd.=419)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(S)-3-羟基-1-(4-甲氧基- 苯基)-丙基]-酰胺(“238”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=435,obsd.=435)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸((S)-3-羟基-1-吡啶-4-基- 丙基)-酰胺 (“239”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=406,obsd.=406)。
4-氨基-1-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌啶-4-羧酸[(R)-1-(4-氯- 苯基)-2-甲氧基-乙基]-酰胺(“240”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=471,obsd.=471)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(R)-1-(4-氯-苯基)-2-甲 氧基-乙基]-酰胺(“241”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=430,obsd.=430)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-3-羟 基-丙基]-酰胺(“242”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=430,obsd.=430)。
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氟-苯基)-3-羟 基-丙基]-酰胺(“243”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=414,obsd.=414)。
4-氨基-6-{4-氨基-4-[(S)-1-(4-氯-苯基)-乙基氨基甲酰基]-哌啶-1-基}-嘧 啶-5-羧酸酰胺(“244”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=418,obsd.=418)。
4-氨基-6-{4-氨基-4-[(S)-1-(4-氯-苯基)-丙基氨基甲酰基]-哌啶-1-基}-嘧 啶-5-羧酸酰胺(“245”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=432,obsd.=432)。
4-氨基-6-{4-氨基-4-[(R)-1-(4-氯-苯基)-2-甲氧基-乙基氨基甲酰基]-哌啶- 1-基}-嘧啶-5-羧酸酰胺(“246”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=448,obsd.=448)。
4-氨基-1-(6-氨基-5-氯-嘧啶-4-基)-哌啶-4-羧酸[(R)-1-(4-氯-苯基)-2-甲氧 基-乙基]-酰胺(“247”)
参照实施例(214)的方法制备标题化合物。LC-MS:(M+1=448,obsd.=448)。
N-{(R)-3-氨基-1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2, 4-二氟-苯甲酰胺(“248”)
通过SFC手性色谱法从实施例(198)分离出标题化合物。LC-MS:(M+1=443, obsd.=443)。
N-{(S)-3-氨基-1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2, 4-二氟-苯甲酰胺(“249”)
通过SFC手性色谱法从实施例(198)分离出标题化合物。LC-MS:(M+1=443, obsd.=443)。
生物活性
实施例部分的化合物的IC50-值都是通过以下P70S6K酶试验的方案获得的。
P70S6K酶试验
将P70S6K抑制剂化合物稀释,并铺于96孔板中。将包含以下组分的反应混合液加入该化合物板中以开始酶反应;将P70S6K(3nM,T412E突变体,Millipore)与24ìM ATP在试验缓冲液中混合,所述缓冲液包含100mM Hepes(pH 7.5)、5mM MgCl2、 1mM DTT、0.015%Brij和1ìM底物肽FITC-AHA-AKRRRLSSLRA-OH(源自S6核糖体蛋白质序列,FITC=异硫氰酸荧光素,AHA=6-氨基己酸)。将该反应物在25℃孵育90分钟,之后加入10mM EDTA以停止该反应。在Caliper Life Sciences Lab Chip 3000分析底物和产物(磷酸化的)肽的比例,压力为-1.4psi,下游电压和下游电压分别为-3000和-700。在获得色谱图上,解析出产物峰在底物峰之前。
表1 列出了实施例部分的化合物在P70S6K酶抑制试验中获得的值。
表1 :通式(I)所示的化合物对p70S6K酶的抑制
序列表
<110> 默克专利有限公司
<120> 用作激酶活性调节剂的新的杂环状胺
<130> P 11/151 WO
<150> 61/533,606
<151> 2011-09-12
<160> 1
<170> PatentIn版本3.5
<210> 1
<211> 11
<212> PRT
<213> 人工序列
<220>
<223> 底物
<400> 1
Ala Lys Arg Arg Arg Leu Ser Ser Leu Arg Ala
1 5 10
Claims (9)
1.一种化合物,其选自:
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-溴-嘧啶-4-基胺(“1”);
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“2”);
6-{4-[(R)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“4”);
6-[4-(2-氨基-1-苯基-乙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶-4-基胺(“6”);
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1H-吡唑-4-基)-嘧啶-4-基胺(“7”);
(R)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺(“9”);
5-(4-氟苯基)-6-(4-(2-(吡咯烷-1-基)-1-(4-(三氟甲基)-苯基)-乙基)-哌嗪-1-基)-嘧啶-4-胺(“10”);
5-(4-氟-苯基)-6-{4-[2-哌啶-1-基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“12”);
5-(4-氟-苯基)-6-[4-(4-三氟甲基-苄基)-哌嗪-1-基]-嘧啶-4-基胺(“13”);
5-溴-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-4-胺(“14”);
(S)-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(4-氟苯基)嘧啶-4-胺(“16”);
(R)-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(4-氟苯基)嘧啶-4-胺(“17”);
5-(6-氨基吡啶-3-基)-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)-苯基)乙基)哌嗪-1-基)嘧啶-4-胺(“20”);
6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-乙烯基嘧啶-4-胺(“21”);
2-(4-(4-氨基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)-哌嗪-1-基)嘧啶-5-基)苯基)戊-2-醇(“22”);
4-(4-氨基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-5-基)苯甲酸甲酯(“23”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(环己-1-烯-1-基)嘧啶-4-胺(“24”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(环戊-1-烯-1-基)嘧啶-4-胺(“25”);
4-(4-氨基-6-(4-(2-(二甲基氨基)-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)嘧啶-5-基)苯甲酸(“26”);
5-(4-氟-苯基)-6-{4-[(1-甲基-1H-咪唑-2-基)-苯基-甲基]-哌嗪-1-基}-嘧啶-4-基胺(“30”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-甲氧基嘧啶-4-胺(“31”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(2,2,2-三氟乙氧基)嘧啶-4-胺(“33”);
4-氨基-6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-嘧啶-5-腈(“36”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1H-吡咯-3-基)嘧啶-4-胺(“37”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(异噁唑-4-基)嘧啶-4-胺(“38”);
6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌嗪-1-基)-5-(1-乙基-1H-吡唑-4-基)嘧啶-4-胺(“39”);
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基胺(“40”);
6-{4-[(S)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基胺(“41”);
6-{4-[(R)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡唑-4-基)-嘧啶-4-基胺(“42”);
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(1-甲基-1H-吡唑-3-基)-嘧啶-4-基胺(“43”);
5-(4-氟苯基)-6{4-(4-三氟甲基苄基)-哌啶-1-基}嘧啶-4-胺(“48”);
5-(4-氟苯基)-6{4-(4-氯苄基)-哌啶-1-基}嘧啶-4-胺(“49”);
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-溴-嘧啶-4-基胺(“51”);
6-{4-[2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“52”);
6-{4-[(R)-2-氨基-1-(4-三氟甲基-苯基)-乙基]-哌啶-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“54”);
(S)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺(“56”);
(R)-6-(4-(2-氨基-1-(4-(三氟甲基)苯基)乙基)哌啶-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺(“57”);
2-((4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)甲基)-4,5-二氯苯酚(“60”);
2-(1-(4-(6-氨基-5-(4-氟苯基)嘧啶-4-基)哌嗪-1-基)乙基)-5-氯苯酚(“61”);
5-(4-氟苯基)-6{4-[1-(3-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“64”);
5-(4-氟苯基)-6{4-[1-(3-三氟甲基-苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“66”);
5-(4-氟苯基)-6{4-[1-(4-氟-苯基)-2-哌啶-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“67”);
5-(4-氟苯基)-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“75”);
(R)5-(4-氟苯基)-6{4-[1-(4-氟苯基)-2-吡咯烷-1-基-乙基]-哌嗪-1-基}-嘧啶-4-基胺(“82”);
1-6-氨基-5-(4-氟苯基)嘧啶-4-基)哌啶-4-基-4-(氯苯基)甲醇(“138”);
1-6-氨基-5-(4-氟苯基)嘧啶-4-基)哌啶-4-基-4-(4-氟苯基)苯基)甲醇(“139”);
1-6-氨基-5-(4-氟苯基)嘧啶-4-基)哌啶-4-基-4-(氟苯基)甲醇(“140”);
5-(4-氟苯基)-6{4-氨基(4-氯苯基)甲基-哌啶-1-基}嘧啶-4-胺(“142”);
5-(4-氟苯基)-6{4-氨基(4-氟苯基)甲基-哌啶-1-基}嘧啶-4-胺(“143”);
5-(4-氟苯基)-6{4-氨基(4-(4-氟苯基)苯基)甲基-哌啶-1-基}嘧啶-4-胺(“144”);
5-(4-氟苯基6-(4-((4-氟苯基)(2-(吡咯烷-1-基)乙氧基)甲基)-哌啶-1-基)嘧啶-4-胺(“146”);
5-(4-氟苯基6-(4-((4-氟苯基)(2-(二甲基氨基)乙氧基)甲基)哌啶-1-基)嘧啶-4-胺(“147”);
1-(6-氨基-5-(4-氟苯基嘧啶-4-基)(4-((4-氟苯基))甲基)-二甲基乙烷-1,2-二胺(“150”);
6-{4-[2-氨基-1-(3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“153”);
6-{4-[2-氨基-1-(4-氟-3-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“155”);
6-{4-[2-氨基-1-(3,4-二氯-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“157”);
6-{4-[2-氨基-1-(4-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“159”);
6-{4-[2-氨基-1-(3-氯-4-氟-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“161”);
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-氯-苯基)-乙腈(“162”);
6-{4-[2-氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“163”);
{4-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌嗪-1-基}-(4-氯-3-氟-苯基)-乙腈(“164”);
6-{4-[2-氨基-1-(2-氟-4-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“170”);
6-[4-((1R,2R)-1-氨基甲基-2-苯基-丙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶-4-基胺(“171”);
6-{4-[2-氨基-1-(6-氯-吡啶-3-基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“174”);
6-{4-[(S)-2-氨基-1-(6-氯-吡啶-3-基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“176”);
6-{4-[2-氨基-1-(4-氯-苯基)-乙基]-哌嗪-1-基}-5-乙基-嘧啶-4-基胺(“178”);
6-(4-(2-氨基-1-(6-甲氧基吡啶-3-基)乙基)哌嗪-1-基)-5-(4-氟苯基)嘧啶-4-胺(“183”);
6-(4-(2-氨基-1-(4-氯-3-氟苯基)乙基)哌嗪-1-基)-5-(1H-吡唑-4-基)嘧啶-4-胺(“187”);
6-{4-[2-氨基-1-(2-氟-5-三氟甲基-苯基)-乙基]-哌嗪-1-基}-5-(4-氟-苯基)-嘧啶-4-基胺(“192”);
6-[4-(2-氨基-1-吡啶-3-基-乙基)-哌嗪-1-基]-5-(4-氟-苯基)-嘧啶-4-基胺(“193”);
N-[3-氨基-1-(6-氨基-5-溴-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲酰胺(“195”);
N-[3-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲酰胺(“196”);
N-{3-氨基-1-[6-氨基-5-(4-氰基-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二氟-苯甲酰胺(“199”);
N-{3-氨基-1-[6-氨基-5-(6-甲氧基-吡啶-3-基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二氟-苯甲酰胺(“201”);
N-{3-氨基-1-[6-氨基-5-(4-三氟甲基-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二氟-苯甲酰胺(“202”);
N-[3-氨基-1-(6-氨基-5-苯基-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲酰胺(“203”);
N-{3-氨基-1-[6-氨基-5-(3-氟-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二氟-苯甲酰胺(“204”);
N-[3-氨基-1-(6-氨基-5-吡啶-4-基-嘧啶-4-基)-吡咯烷-3-基甲基]-2,4-二氟-苯甲酰胺(“205”);
N-{4-氨基-1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-哌啶-4-基甲基}-2,4-二氟-苯甲酰胺(“208”);
4-氨基-1-[6-氨基-5-(1H-吡唑-4-基)-嘧啶-4-基]-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-乙基]-酰胺(“224”);
4-氨基-1-(6-氨基-5-氰基-嘧啶-4-基)-哌啶-4-羧酸[(S)-1-(4-氯-苯基)-3-羟基-丙基]-酰胺(“242”);和
N-{(S)-3-氨基-1-[6-氨基-5-(4-氟-苯基)-嘧啶-4-基]-吡咯烷-3-基甲基}-2,4-二氟-苯甲酰胺(“249”),
或其可药用盐。
2.一种药物组合物,所述药物组合物包含作为活性成分的如权利要求1所述的化合物或其可药用盐以及可药用载体。
3.如权利要求1所述的化合物或其可药用盐在制备用于治疗癌症的药物中的用途,其中需要P70S6K酶的调节。
4.如权利要求3所述的用途,其中所述P70S6K酶的调节包括P70S6K酶的抑制。
5.如权利要求3所述的用途,所述癌症选自以下组内:脑癌、肺癌、表皮样癌、鳞状细胞癌、膀胱癌、胃癌、胰腺癌、头癌、颈癌、肾的癌、肝癌、前列腺癌、结直肠癌、食管癌、睾丸癌、妇科癌、甲状腺癌、黑素瘤、恶性血液病、神经胶质瘤和卡波西肉瘤。
6.如权利要求5所述的用途,所述癌症是多发性骨髓瘤。
7.如权利要求5所述的用途,所述癌症选自以下组内:慢性髓性白血病和骨髓细胞白血病。
8.如权利要求5所述的用途,所述恶性血液病是急性髓性白血病;所述妇科癌选自卵巢癌、乳腺癌和子宫癌;所述结直肠癌选自结肠癌和直肠癌;所述肾的癌是肾癌。
9.一种套盒,该套盒包含下列独立包装:
a)有效量的如权利要求1所述的化合物或其可药用盐,以及
b)有效量的另外的药物活性成分。
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