CN116323595A - 作为激酶抑制剂的吡唑基-嘧啶衍生物 - Google Patents
作为激酶抑制剂的吡唑基-嘧啶衍生物 Download PDFInfo
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- CN116323595A CN116323595A CN202180064825.8A CN202180064825A CN116323595A CN 116323595 A CN116323595 A CN 116323595A CN 202180064825 A CN202180064825 A CN 202180064825A CN 116323595 A CN116323595 A CN 116323595A
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- Prior art keywords
- methyl
- pyrimidin
- cpd
- pyrazole
- amino
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- BWIHJLOBZMKPKS-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)pyrimidine Chemical class N1C=CC(C=2N=CC=CN=2)=N1 BWIHJLOBZMKPKS-UHFFFAOYSA-N 0.000 title abstract description 6
- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 176
- 238000000034 method Methods 0.000 claims abstract description 101
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 29
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 108010016672 Syk Kinase Proteins 0.000 claims abstract description 18
- 201000011510 cancer Diseases 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 10
- 102000000551 Syk Kinase Human genes 0.000 claims abstract description 9
- 208000035475 disorder Diseases 0.000 claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000002062 proliferating effect Effects 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 180
- -1 3- {2- [ (3, 5-dimethylphenyl) amino ] pyrimidin-4-yl } -1-methyl-N- (propane-2-yl) -1H-pyrazole-5-carboxamide Chemical compound 0.000 claims description 140
- 229910052739 hydrogen Inorganic materials 0.000 claims description 45
- 239000001257 hydrogen Substances 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 42
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 33
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 201000010099 disease Diseases 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 18
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 11
- 210000004027 cell Anatomy 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 230000002074 deregulated effect Effects 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
Abstract
本发明涉及吡唑基‑嘧啶衍生物、其制备方法、包含它们的药物组合物以及它们作为治疗剂的用途。这些化合物是激酶抑制剂,特别是脾酪氨酸激酶(SYK)的抑制剂,并且可用于治疗癌症、细胞增殖性紊乱、病毒感染、免疫紊乱、神经退行性紊乱和心血管疾病。
Description
本发明涉及吡唑基-嘧啶衍生物、其制备方法、包含它们的药物组合物以及它们作为治疗剂的用途,特别是在治疗由蛋白激酶活性失调引起的疾病诸如癌症、细胞增殖性紊乱、病毒感染、免疫紊乱、神经退行性紊乱和心血管疾病中的用途。
发明背景
蛋白激酶(PK)的功能障碍是许多疾病的标志。参与人类癌症的大部分癌基因和原癌基因编码PK。增强的PK活性还与许多非恶性疾病有关,诸如良性前列腺增生、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细胞增殖、肺纤维化、关节炎、肾小球肾炎以及术后狭窄和再狭窄。
PK还与炎性状况以及病毒和寄生虫的繁殖有关。PK还可以在神经退行性紊乱的发病机制和发展中起主要作用。
关于PK功能障碍或失常的一般参考,参见例如,Current Opinion in ChemicalBiology,1999,3,459-465;Nature Rev.Drug Discov.2002;和Carcinogenesis,2008,29,1087-1091。
脾酪氨酸激酶(Syk)是一种72kDa的非受体细胞质酪氨酸激酶。Syk具有类似于ζ相关蛋白-70(ZAP-70)的一级氨基酸序列,并参与受体介导的信号转导。Syk的N-末端结构域包含两个Src同源2(SH 2)结构域,它们与在许多免疫受体复合物的细胞质信号传导结构域中发现的二磷酸化的基于免疫受体酪氨酸的激活基序(immunoreceptor tyrosine-basedactivation motifs,ITAM)结合。C末端包含催化结构域。Syk在许多参与适应性和先天免疫的细胞类型中表达,所述细胞类型包括淋巴细胞(B细胞、T细胞和NK细胞)、粒细胞(嗜碱性粒细胞、嗜中性粒细胞和嗜酸性粒细胞)、单核细胞、巨噬细胞、树突状细胞和肥大细胞。Syk在多种细胞类型中的免疫受体介导的信号传导中起着关键作用,所述细胞类型包括B细胞、巨噬细胞、单核细胞、肥大细胞、嗜酸性粒细胞、嗜碱性粒细胞、嗜中性粒细胞、树突状细胞、血小板和破骨细胞。经典免疫受体包括B细胞和T细胞抗原受体以及各种免疫球蛋白受体(Fc受体)。配体结合导致免疫受体的激活,这导致Src家族激酶被激活,以及受体相关跨膜衔接体(receptor-associated transmembrane adaptors)的细胞质面中的基于免疫受体酪氨酸的激活基序(ITAM)的磷酸化。Syk与衔接体的磷酸化ITAM基序结合,导致Syk的激活以及随后下游信号通路的磷酸化和激活(Mocsai等人,2010:10(6):387)。
Syk对于通过B细胞受体(BCR)信号传导的B细胞激活是必需的。Syk在与磷酸化的BCR结合后被激活,并从而启动BCR激活后的早期信号传导事件。大量证据表明,BCR信号传导也支持患有B细胞白血病或淋巴瘤的患者中恶性B细胞的存活和生长。这些疾病中BCR通路激活的机制包括组织微环境中存在的微生物抗原或自身抗原的连续BCR刺激,激活BCR复合物或下游信号传导组分内的突变和配体非依赖性强直性BCR信号传导(ligand-independent tonic BCR signaling)。用小分子靶向关键的BCR信号传导介导物(诸如Btk或PI3K的δ同种型)已被展示为是抑制BCR信号传导,导致在这些疾病中的治疗性益处的有价值的方法(Burger和Wiestner,Nat.Rev.Cancer 2018:18(3):148)。
因此,Syk活性的抑制可用于治疗其中BCR信号传导对其存活和增殖起作用的某些类型的癌症,诸如非霍奇金淋巴瘤、慢性淋巴细胞白血病、急性髓性白血病、急性淋巴细胞白血病、T细胞淋巴瘤。另外,Syk在ITAM依赖性信号传导中的作用及其在许多细胞类型中的表达表明,抑制Syk活性的化合物可用于治疗涉及免疫系统和炎症的紊乱。这样的紊乱包括I型超敏反应(过敏性鼻炎、过敏性哮喘和特应性皮炎);自身免疫性疾病(类风湿性关节炎、多发性硬化、系统性红斑狼疮、银屑病和免疫性血小板减少性紫癜);(Pamuk和Tsokos,Arthritis Res Ther.2010;12(6):222)。
吡唑基嘧啶衍生物先前被描述为蛋白激酶活性的调节物,并因此可用于治疗由失调的蛋白激酶活性引起的疾病(WO 2012/139930)。
用作Syk和/或JAK激酶的抑制剂的嘧啶-5-羧酰胺化合物在专利申请US20200239458中描述,而作为Syk抑制剂的缩合吡嗪的固体形式在WO 2020172431中描述。
发明详述
本发明人已经发现,如下定义的通式(I)的化合物是激酶抑制剂,并且特别是脾酪氨酸激酶(SYK)的抑制剂。因此,这样的化合物可用于治疗由SYK活性改变引起的疾病。
因此,本发明的第一目的是提供式(I)的取代的吡唑并嘧啶衍生物:
其中:
R1是氢或选自直链或支链(C1-C6)烷基、(C3-C7)环烃基、芳基、杂环基和杂芳基的任选取代的基团;
R2是氢或选自直链或支链(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基和(C3-C7)环烃基的任选取代的基团;
R3和R4独立地为氢、任选地被卤素取代的直链或支链(C1-C6)烷基、杂芳基或杂芳基(C1-C6)烷基或式(II)的基团:
其中:
R5是氢、任选取代的直链或支链(C1-C6)烷基、(C3-C7)环烃基、芳基,或与R6一起可形成任选取代的4至7元环烃基,或与R7或R8一起可形成任选取代的杂环基基团;
R6是氢或甲基或与R3或R4一起可形成任选取代的4至7元杂环基基团;
R7和R8独立地是氢、任选取代的直链或支链(C1-C6)烷基,或可与X一起形成任选取代的4至7元杂环基基团,所述4至7元杂环基基团任选地包含一个另外的选自N、O和S的杂原子,或可与R3或R4一起形成任选取代的5至7元杂环基基团;
X是H、N或O;
条件是,当X是O时,R5不是苯基;
或其药学上可接受的盐。
优选的式(I)的化合物是以下化合物,其中:
R2是任选取代的直链或支链(C1-C6)烷基;
R3和R4独立地是氢或通式(II)的基团;
其中:
R5是氢、任选取代的直链或支链(C1-C6)烷基、(C3-C7)环烃基或苯基,或与R6一起可形成任选取代的4至7元环烃基;
R6是氢;
R7和R8独立地是氢、任选取代的直链或支链(C1-C6)烷基,或可与X一起形成任选取代的4至7元杂环基基团,所述4至7元杂环基基团任选地包含一个另外的选自N、O和S的杂原子;
X是N或O;
R1如上定义;
条件是,当X是O时,R5不是苯基;
或其药学上可接受的盐。
另外优选的式(I)的化合物是以下化合物,其中:
R3是氢或任选地被卤素取代的直链或支链(C1-C6)烷基、杂芳基或杂芳基(C1-C6)烷基;
R4是氢或通式(II)的基团
其中:
R5是氢、任选取代的直链或支链(C1-C6)烷基、(C3-C7)环烃基或苯基,或与R6一起可形成任选取代的4至7元环烃基;
R6是氢;
R7和R8独立地是氢、任选取代的直链或支链(C1-C6)烷基,或可与X一起形成任选取代的4至7元杂环基基团,所述4至7元杂环基基团任选地包含一个另外的选自N、O和S的杂原子;
X是N或O;
R1和R2如上定义;
条件是,当X是O时,R5不是苯基;
或其药学上可接受的盐。
甚至更优选的是式(I)的化合物,其中:
R1是任选取代的芳基、杂环基或杂芳基基团;
R3是氢;
R4是通式(II)的基团:
其中:
R5是氢、任选取代的直链或支链(C1-C6)烷基、(C3-C7)环烃基或苯基,或与R6一起可形成任选取代的4至7元环烃基;
R6是氢;
R7和R8独立地是氢、任选取代的直链或支链(C1-C6)烷基,或可与X一起形成任选取代的4至7元杂环基;
X是N;
R2如上定义;
或其药学上可接受的盐。
另外甚至更优选的是式(I)的化合物,其中:
R1是选自苯基或吲哚基的任选取代的基团;
R2、R3和R4如上定义;
或其药学上可接受的盐。
优选的式(I)的特定化合物(cpd)或其盐是以下列出的化合物:
N-[2-(二甲基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 1);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2R)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 2);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 3);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(丙烷-2-基)-1H-吡唑-5-羧酰胺(cpd 4);
N-[2-(二甲基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd 5);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(甲基氨基)乙基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 6);
N-(2-氨基乙基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 7);
N-(氮杂环丁烷-3-基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺三氟乙酸盐(cpd 8);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(吗啉-4-基)乙基]-1H-吡唑-5-羧酰胺(cpd 9);
N-[2-(二乙氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 10);
N-[(1R,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 11);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(丙烷-2-基氨基)乙基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 12);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd13);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd14);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,N,1-三甲基-1H-吡唑-5-羧酰胺(cpd 15);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-甲氧基乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 16);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-氟乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 17);
3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-N-[2-(二甲基氨基)乙基]-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 18);
3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 19);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(1H-吡唑-3-基)-1H-吡唑-5-羧酰胺(cpd 20);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)(4-甲基哌嗪-1-基)甲酮(cpd 21);
N-[2-(乙酰氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 22);
N-(2-氨基-2-氧代乙基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 23);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(2,2,2-三氟乙基)-1H-吡唑-5-羧酰胺(cpd 24);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(1-甲基-1H-咪唑-5-基)甲基]-1H-吡唑-5-羧酰胺(cpd 25);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 26);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(吡啶-2-基甲基)-1H-吡唑-5-羧酰胺(cpd 27);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(1H-咪唑-2-基甲基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 28);
N-[(2R)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 29);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 30);
N-(1-氮杂双环[2.2.2]辛-3-基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 31);
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸((1R,2R)-2-羟基-环己基)-酰胺(cpd 32);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 33);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-羟乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 34);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,4-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 35);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)(哌嗪-1-基)甲酮盐酸盐(cpd 36);
N-[(1S,2R)-2-氨基环己基]-3-(2-{[3-甲氧基-5-(三氟甲基)苯基]氨基}嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 37);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3-氯-1-甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 38);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 39);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 40);
N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 41);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 42);
N-[3-(二甲基氨基)丙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 43);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(2S)-2-(丙烷-2-基)氮丙啶-1-基]甲酮(cpd 44);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2,2-二甲基丙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 45);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(2-甲基丙基)-1H-吡唑-5-羧酰胺(cpd 46);
N-(环丙基甲基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 47);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氟-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 48);
3-{2-[(4,6-二甲基吡啶-2-基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 49);
3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 50);
1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 51);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基-3-苯基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 52);
N-[(1S,2S)-2-氨基环己基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 53);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 54);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 55);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2R)-1,1,1-三氟丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 56);
N-[(2S)-1-(3,3-二氟氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 57);
1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-3-{2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 58);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氯-1-甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 59);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 60);
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 61);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-(2-{[3-(三氟甲基)苯基]氨基}嘧啶-4-基)-1H-吡唑-5-羧酰胺(cpd 62);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 63);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 64);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-3-{2-[(3-氟-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 65);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-[2-(1,3-苯并间二氧杂环戊烯-5-基氨基)嘧啶-4-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 66);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 67);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-{2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 68);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 69);
3-{2-[(3-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 70);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)-1-氧代丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 71);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[2-(二甲基氨基)乙基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 72);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-3-{2-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 73);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 74);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-3-{2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 75);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 76);
N,N,1-三甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 77);
3-{2-[(3-氰基-5-甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 78);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氰基-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 79);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(5-甲氧基吡啶-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 80);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(3S)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 81);
N-(2-氨基环己基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 82);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(吡咯烷-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 83);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(哌啶-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 84);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(3R)-3-羟基吡咯烷-1-基]甲酮(cpd 85);
[(3S)-3-(二甲基氨基)吡咯烷-1-基](3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 86);
[(3R)-3-(二甲基氨基)吡咯烷-1-基](3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 87);
(3-氨基吡咯烷-1-基)(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 88);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(2S)-2-(羟甲基)吡咯烷-1-基]甲酮(cpd 89);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(3S)-3-羟基吡咯烷-1-基]甲酮(cpd 90);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1R,2S)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 91);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 92);
N-[(2S)-1-羟基丙烷-2-基]-1-甲基-3-{2-[(1,2,3-三甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 93);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 94);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 95);
(1R,4S)-2,5-二氮杂双环[2.2.1]庚-2-基(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮盐酸盐(cpd 96);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(3R)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 97);
N-[(1R,2S)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 98);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 99);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 100);
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 101);
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 102);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 103);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺盐酸盐(cpd 104);
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 105);
N-[(1S)-1-环己基-2-羟乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 106);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(1S)-1-苯基-2-(吡咯烷-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 107);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 108);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-苯基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 109);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 110);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 111);
1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 112);
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 113);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(1S,2R)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 114);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1S,2R)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 115);
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 116);
3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 117);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1S,2S)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 118);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氰基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 119);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-N-[(1S,2R)-2-羟基环己基]-1H-吡唑-5-羧酰胺(cpd 120);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-1H-吡唑-5-羧酰胺盐酸盐(cpd 121);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-N-[(3R)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 122)和
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd 123)。
论及本发明的式(I)的任何特定化合物(任选地以药学上可接受的盐形式),参见实验部分和权利要求书。
如果本发明的化合物中存在立体异构源中心(stereogenic center)或另一种形式的异构体中心,本文意图涵盖所有形式的这种异构体或这些异构体,包括对映异构体和非对映异构体。含有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,或者外消旋混合物可以使用众所周知的技术分离,并且可以单独使用单个对映异构体。在其中化合物具有不饱和碳-碳双键的情况下,顺式(Z)和反式(E)异构体两者都在本发明的范围内。
在其中化合物可以以互变异构体形式例如酮-烯醇互变异构体存在的情况下,每种互变异构体形式都被认为包括在本发明中,无论是以平衡形式存在还是主要以一种形式存在。因此,除非另有规定,否则当式(I)的化合物中R2是氢,并且仅指示式(la)或(lb)的下列互变异构形式中的一种时,其余的一种仍应意图被包含在本发明的范围内:
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、水杨酸、琥珀酸和对甲苯磺酸。
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、无环胺或环胺。
本发明的另外的目的是如上定义的式(I)的化合物,以及它们的异构体、互变异构体、水合物、溶剂合物、复合物、代谢物、前药、载体和N-氧化物。
式(I)的化合物的代谢物是将该相同的式(I)的化合物体内转化成的任何化合物(例如在向有相应需要的哺乳动物施用后)。然而,通常不代表限制性实例,在施用式(I)的化合物后,该相同的衍生物可转化为多种易于排泄的化合物,例如包括更可溶的衍生物,如羟基化衍生物。因此,根据由此发生的代谢途径,这些羟基化衍生物中的任一种都可以被视为式(I)的化合物的代谢物。
前药是任何在体内释放根据式(I)的活性母体药物的共价结合的化合物。N-氧化物是其中氮和氧通过配价键拴系的式(I)的化合物。
对于术语“支链或支链(C1-C6)烷基”,因此包括(C1-C4)烷基,我们意图指诸如例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、正己基等的任何基团。
对于术语“支链或支链(C2-C6)烯基”,我们意图指诸如例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-戊烯基、1-己烯基等的任何基团。
对于术语“支链或支链(C2-C6)炔基”,我们意图指诸如例如乙炔基、2-丙炔基、4-戊炔基等的任何基团。
对于术语“(C3-C7)环烃基(cycloalkyl)”,除非另有规定,否则我们意图指3至7元的全碳单环,其可以包含一个或更多个双键,但不具有完全共轭的π-电子体系。环烃基基团的实例不限于是环丙烷、环丁烷、环戊烷、环戊烯、环己烷、环己烯、环己二烯、环庚烷、环庚烯、环庚二烯。
术语“芳基”是指具有1至4个环体系的单碳环、双碳环或多碳环烃,任选地还通过单键彼此稠合或连接,其中至少一个碳环是“芳族的”,其中术语“芳族的”是指完全共轭的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-或β-萘基(naphthyl)基团、α-或β-四氢萘基(tetrahydronaphthalenyl)基团、联苯基基团和茚满基基团。
术语“杂芳基”是指芳族杂环,通常是具有1至3个选自N、O或S的杂原子的5至7元杂环;杂芳基环可以任选地还与芳族和非芳族碳环和杂环稠合或连接。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(benzo[1,3]dioxolyl)、苯并[1,4]二噁英基(benzo[1,4]dioxinyl)、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、2,3-二氢喹喔啉基等。
对于术语“杂环基”,我们意图指其中一个或更多个碳原子被杂原子诸如氮、氧和硫替换的3至7元的饱和或部分不饱和碳环。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、1,3-二噁茂烷基(1,3-dioxolanyl)、哌啶基、哌嗪基、吗啉基等。杂环可以任选地还与芳族和非芳族碳环或杂环稠合或连接。
根据本发明并且除非另有规定,否则任何上述R1、R2、R3和R4基团可任选地在它们的任何自由位置被一个或更多个基团,例如1至6个基团取代,所述基团独立地选自:卤素、硝基、氧代基团(=O)、氰基、(C1-C6)烷基、多氟化烷基、多氟化烷氧基、烯基、炔基、羟基烷基、芳基、芳基烷基、杂环基、(C3-C7)环烃基、羟基、烷氧基、芳氧基、杂环基氧基、亚甲基二氧基、烷基羰基氧基、芳基羰基氧基、环烯氧基(cycloalkenyloxy)、杂环基羰基氧基、亚烷基氨基氧基、羧基、烷氧羰基、芳氧羰基、环烃基氧羰基、杂环基氧基羰基、氨基、脲基、烷基氨基、二烷基氨基、芳基氨基、二芳基氨基、杂环基氨基、甲酰基氨基、烷基羰基氨基、芳基羰基氨基、杂环基羰基氨基、氨基羰基、烷基氨基羰基、二烷基氨基羰基、芳基氨基羰基、杂环基氨基羰基、烷氧基羰基氨基、羟基氨基羰基、烷氧基亚氨基、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、烷基羰基、芳基羰基、环烃基羰基、杂环基羰基、烷基磺酰基、芳基磺酰基、氨基磺酰基、烷基氨基磺酰基、二烷基氨基磺酰基、芳基氨基磺酰基、杂环基氨基磺酰基、芳基硫基、烷基硫基、膦酸酯和烷基膦酸酯。
相应地,只要适合,上述取代基中的每一个都可以被一个或更多个上述基团进一步取代。
在这方面,对于术语“卤素”,我们意图指氟、氯、溴或碘原子。
对于术语“氰基”我们意图指-CN残基。
对于术语“硝基”,我们意图指-NO2基团。
对于术语“烯基”或“炔基”,我们意图指任何还带有双键或三键的前述直链或支链(C2-C6)烷基基团。本发明的烯基或炔基基团的非限制性实例是例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-戊烯基、1-己烯基、乙炔基、2-丙炔基、4-戊炔基等。
对于术语“聚氟化烷基或烷氧基”,我们意图指被多于一个氟原子取代的任何上述直链或支链(C1-C6)烷基或烷氧基基团,诸如例如三氟甲基、三氟乙基、1,1,1,3,3,3-六氟丙基、三氟甲氧基等。
对于术语“烷氧基、芳氧基、杂环基氧基”及其衍生物,我们意图指任何通过氧原子(-O-)连接到分子的其余部分的上述(C1-C6)烷基、芳基或杂环基基团。
综上所述,对本领域技术人员清楚的是,其名称为复合名称的任何基团,诸如例如芳基氨基,需要意图按照其源自部分的常规解释,例如被芳基进一步取代的氨基基团,其中芳基如上定义。
同样地,诸如例如烷基硫基、烷基氨基、二烷基氨基、烷氧基羰基、烷氧基羰基氨基、杂环基羰基、杂环基羰基氨基、环烃基氧基羰基等的任何术语包括其中烷基、烷氧基、芳基、(C3-C7)环烃基和杂环基部分如上定义的基团。
本发明还提供了用于通过使用下述反应路线和合成方案,采用本领域可用的技术和容易可得的起始材料,制备如上定义的式(I)的化合物的方法。在下面的实施例中描述了本发明某些实施方案的制备,但是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用于制备本发明的其他实施方案。例如,根据本发明的非例示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,通过改为本领域已知的其他合适的试剂,或者通过对反应条件进行常规修改来进行。可选地,本文提及的或本领域已知的其他反应将被认为具有用于制备本发明的其他化合物的适应性。
本发明的化合物可以使用以下一般方法和程序从容易可得的起始材料制备。除非另有指明,否则起始材料是已知化合物或可根据众所周知的程序从已知化合物制备。应当理解,除非另有说明,否则在描述了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,也可以使用不同的工艺条件。最佳反应条件可以随所使用的特定反应物或溶剂而变化,但是这样的条件可以由本领域技术人员通过常规优化程序来确定。
式(V)的中间体化合物可以如以下方案1中报告地制备。
方案1
因此,本发明的方法包括以下步骤:
步骤1)使式(III)的化合物:
其中R2是氢或选自直链或支链(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基和(C3-C7)环烃基的任选取代的基团,并且R9是选自直链或支链(C1-C6)烷基的基团,
与二甲基甲酰胺-二烷基缩醛反应;
步骤2)使得到的式(IV)的化合物:
其中R2和R9如上定义,
与式(V)的化合物:
其中R1是氢或选自直链或支链(C1-C6)烷基、(C3-C7)环烃基、芳基、杂环基和杂芳基的任选取代的基团,
反应,从而获得式(VI)的化合物:
其中R1、R2和R9如上定义。
如在步骤2中报告的式(VI)的化合物可以可选地根据以下步骤制备:
步骤3)使式(IV):
其中R2和R9如上述步骤1)中定义,
与碳酸胍反应;
步骤4)在存在钯的情况下,使得到的式(VII)的化合物:
其中R2和R9如上定义
与式(VIII)的化合物:
其中R1如上述步骤2)中定义并且Y是碘或溴,
反应,从而获得式(VI)的化合物:
其中R1、R2和R9如上定义;
或
步骤5)在存在碘和CuI的情况下,使如在步骤3)中报告的获得的得到的式(VII)的化合物:
与亚硝酸异戊酯和二碘甲烷或碘化铯反应,从而获得式(IX)的化合物,其中R2和R9如上定义;
步骤6)然后,在存在钯的情况下,使得到的式(IX)的化合物:
其中R2和R9如上定义,
与式(X)的化合物:
其中R1如上定义,
反应,从而获得式(VI)的化合物:
其中R1、R2和R9如上定义。
本发明的目标式(I)的化合物可以如以下方案2中报告地制备:
方案2
在上述方案中,R1、R2、R3和R4如式(I)中定义;R9是选自以上定义的直链或支链(C1-C6)烷基的基团。
因此,本发明的方法包括以下步骤:
步骤7)使如步骤2、4或6所述获得的式(VI)的化合物:
其中R1是氢或选自直链或支链(C1-C6)烷基、(C3-C7)环烃基、芳基、杂环基和杂芳基的任选取代的基团;R2是氢或选自直链或支链(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基和(C3-C7)环烃基的任选取代的基团,并且R9是选自直链或支链(C1-C6)烷基的基团,
在酸性或碱性水解条件下反应,以获得式(XI)的化合物或相应的盐;
其中R1和R2如上定义;
步骤8)使步骤7中所述的式(XI)的化合物或相应的盐与式(XII)的化合物:
其中R3和R4独立地为氢、任选地被卤素取代的直链或支链
(C1-C6)烷基、杂芳基和杂芳基(C1-C6)烷基或式(II)的基团,
其中:
R5是氢、任选取代的直链或支链(C1-C6)烷基、(C3-C7)环烃基、芳基,或与R6一起可形成任选取代的4至7元环烃基,或与R7或R8一起可形成任选取代的杂环基基团;
R6是氢或甲基或与R3或R4一起可形成任选取代的4至7元杂环基基团;
R7和R8独立地是氢、任选取代的直链或支链(C1-C6)烷基,或可与X一起形成任选取代的4至7元杂环基基团,所述4至7元杂环基基团任选地包含一个另外的选自N、O和S的杂原子,或可与R3或R4一起形成任选取代的5至7元杂环基基团;
X是H、N或O,
反应,从而获得式(I)的化合物
其中R1、R2、R3和R4如上定义。
根据该方法的步骤1,式(IV)的烯胺酮衍生物的合成使用N,N-二甲基甲酰胺-二烷基缩醛,诸如例如二甲基甲酰胺-二叔丁基缩醛,二甲基甲酰胺-二乙基缩醛等,在有或没有合适的溶剂诸如DMF、DMA、甲苯等的情况下,在范围为r.t.至150℃的温度(通过常规加热或微波加热两者)并持续范围为30min至约24h的时间来完成。
根据该方法的步骤2,使式(IV)的化合物与式(V)的衍生物,在存在任选地选自AcOK、EtONa、TEA、K2CO3或Na2CO3的碱的情况下,在合适的溶剂(诸如例如DMF、EtOH或甲苯)中,在范围为r.t.至150℃的温度(通过常规加热或微波加热两者)反应,并持续范围为约1h至约48h的时间。优选地,该反应在微波设备中在EtOH中于150℃进行2小时。
根据该方法的步骤3,使式(IV)的化合物与胍或其盐或受保护的合成等同物诸如Boc-胍,最终在存在选自AcOK、EtONa、TEA、K2CO3或Na2CO3的碱的情况下,在合适的溶剂(诸如例如DMF、EtOH、PrOH、n-BuOH或甲苯)中,在范围为r.t.至150℃的温度(通过常规加热或微波加热两者)反应,并持续范围为约1h至约48h的时间。
根据该方法的步骤4,根据文献中熟知的常规方法,使如上定义的式(VII)的化合物与如上定义的式(VIII)的化合物反应。作为实例,反应可以在合适的溶剂诸如DMF、DME、二噁烷或CH3CN中并在存在Pd2(dba)3、BINAP或2-(二环己基膦基)-2’,4’,6’-三异丙基-1,1’-联苯基(X-phos)和诸如K2CO3、磷酸钾或Cs2CO3的碱的情况下,在范围为r.t.至110℃的温度进行,并持续范围为2h至约24h的时间,以获得式(VI)的化合物。
根据该方法的步骤5,使用亚硝酸异戊酯和二碘甲烷或碘化铯,在存在碘和CuI的情况下,在合适的溶剂诸如二噁烷、THF、Et2O或DME中,在范围为r.t.至约100℃的温度反应,并持续约1h至约16h的时间。
根据该方法的步骤6,式(IX)的化合物与式(X)的化合物的反应,在合适的溶剂诸如二噁烷、DMF、DME或CH3CN中,并在存在催化量的Pd(OAc)2、BINAP或Xantphos和诸如K2CO3、磷酸钾或Cs2CO3的碱的情况下,在范围为r.t.至110℃的温度进行,并持续范围为约2h至约24h的时间。
根据该方法的步骤7,式(VI)的化合物可以通过本领域熟知的碱性或酸性水解条件转换成式(XI)的相应衍生物或其盐。优选地,反应在存在合适的溶剂(诸如低级醇、THF、DMF或其混合物)的情况下,用碱性水溶液诸如氢氧化锂、氢氧化钠或氢氧化钾水溶液(优选地,该反应用在THF/MeOH/水混合物中的氢氧化锂),在范围为约r.t.至约80℃的温度进行,并持续范围为约2h至约24h的时间。根据所采用的操作条件,式(XI)的化合物可以以其酸性形式或可选地作为盐获得。
根据该方法的步骤8,对式(XI)的羧酸进行酰胺化以产生相应的式(I)的化合物,在存在氯化铵或合适的式R3R4NH(XII)的伯胺或仲胺的情况下,在碱性条件下,优选地用DIPEA或TEA,在合适的溶剂诸如DCM、DMF、THF、1,4-二噁烷或DMA中,在合适的缩合剂例如二环己基碳二亚胺(DCC)、1-乙基-3-(3’-二甲基氨基丙基)碳二亚胺(EDC)、3,4-二氢-3-羟基-4-氧代-1,2,3-苯并三嗪(DHBT)、邻苯并三唑基四甲基异脲四氟硼酸盐(TBTU)、苯并三唑-1-基-氧基三吡咯烷基六氟磷酸鏻(PyBOP)或2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐(HBTU)。所述反应任选地在存在合适的催化剂诸如4-二甲基氨基吡啶的情况下,或在存在另外的偶联试剂诸如N-羟基苯并三唑(HOBt)的情况下,在r.t.进行,持续范围为约2h至约24h的时间。
综上所述,对本领域技术人员清楚的是,根据本领域熟知的程序,将式(I)的化合物转化为其药学上可接受的盐,或可选地将相应的盐转化为游离化合物(I)仍在本发明的范围内。当根据该方法的任何变化制备式(I)的化合物时(所有变化都意图在本发明的范围内),起始材料、试剂或其中间体内的任选官能团,以及可能引起不希望的副反应的官能团,都需要根据常规技术得到适当的保护。
对这样的反应中心的保护,以及随后在合成转化结束时的去保护,可以按照例如Green,Theodora W.and Wuts,Peter G.M.-Protective Groups in Organic Synthesis,第三版,John Wiley&Sons Inc.,New York(NY),1999中描述的标准程序来完成。
根据用于制备式(I)的化合物的方法的任何变化,起始材料和任何其他反应物是已知的或根据已知方法容易制备的。
式(III)的化合物可以如WO 2012/139930描述地制备。
式(V)的化合物可以是商购可得的或者可以用已知方法(J.Med.Chem.,2004,vol47,p.4716-4730)制备。
式(VIII)、(X)和(XII)的化合物是商购可得的或者可以用已知方法制备。
最终化合物可以使用常规程序,例如色谱和/或结晶和盐形成,来分离和纯化。
如上定义的通式(I)的化合物可以被转化为药学上可接受的盐。
根据以上描述的合成方法,通式(I)的化合物的合成可以以分步方式进行,由此如果需要,在进行随后的反应之前,通过标准纯化技术,如例如柱色谱,分离和纯化每种中间体。可选地,合成顺序的两个或更多个步骤可以在本领域已知的称为“一锅(one-pot)”程序中进行,由此仅由两个或更多个步骤得到的化合物被分离和纯化。
在通式(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,包括使用手性固定相的色谱或结晶。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,andResolutions,John Wiley&Sons Inc.,New York(NY),1981中报告。
本发明还提供了用于治疗由失调的蛋白激酶活性引起的和/或与之相关的疾病的方法,所述蛋白激酶特别是ABL、ACK1、AKT1、ALK、AUR1、AUR2、BRK、BUB1、CDC7/DBF4、CDK2/CYCA、CHK1、CK2、EEF2K、EGFR1、EphA2、EphB4、ERK2、FAK、FGFR1、FLT3、GSK3beta、Haspin、IGFR1、IKK2、IR、JAK1、JAK2、JAK3、KIT、LCK、LYN、MAPKAPK2、MELK、MET、MNK2、MPS1、MST4、NEK6、NIM1、P38alpha、PAK4、PDGFR、PDK1、PERK、PIM1、PIM2、PIM3、PKAalpha、PKCbeta、PLK1、RET、R0S1、SULU1、Syk、TLK2、TRKA、TYK、VEGFR2、VEGFR3、ZAP70;更特别是PIM1、PIM2、PIM3、MPS1、JAK2、JAK3,更特别是Syk家族激酶,所述方法包括向有相应需要的哺乳动物(更特别地人类)施用有效量的如上定义的式(I)的化合物。
此外,本发明提供如上定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由失调的以上报告的蛋白激酶活性(特别是Syk激酶活性)引起的和/或与之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)施用有效量的如上定义的式(I)的化合物。
本发明的优选方法是治疗由失调的蛋白激酶活性引起的和/或与之相关的疾病,所述疾病选自由癌症、细胞增殖性紊乱、病毒感染、免疫紊乱、神经退行性紊乱和心血管疾病组成的组。更优选地,疾病是癌症。
根据本发明的最优选实施方案,癌症选自由以下组成的组:
上皮癌(carcinoma),诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、肺癌包括小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌和皮肤癌包括鳞状细胞癌;淋巴系的造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、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,包括急性和慢性髓细胞性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质来源的肿瘤,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、胶质母细胞瘤、多形性胶质母细胞瘤、星形细胞瘤、少突胶质细胞瘤、副神经节瘤、神经母细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺癌诸如甲状腺乳头状癌和甲状腺髓样癌、卡波西肉瘤、软骨肉瘤和胆管细胞癌。
本发明的另一优选方法是治疗特定的细胞增殖紊乱,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细胞增殖、肺纤维化、关节炎、肾小球肾炎以及术后狭窄和再狭窄。
本发明的另一优选方法是治疗病毒感染,特别是阻止HIV感染的个体中的AIDS发展。
本发明的另一优选方法是治疗免疫紊乱,诸如炎性疾病和自身免疫性疾病,例如多发性硬化症、类风湿性关节炎(RA)、系统性红斑狼疮、炎性肠病(IBD)、克罗恩病、肠易激综合征、胰腺炎、溃疡性结肠炎、憩室病、重症肌无力、血管炎、银屑病、硬皮病、哮喘、过敏、系统性硬化症、白癜风、关节炎诸如骨关节炎、幼年型类风湿性关节炎、强直性脊柱炎。
本发明的另一优选方法是治疗神经退行性紊乱,诸如阿尔茨海默病、帕金森病和亨廷顿病。
本发明的另一优选方法是治疗特定的心血管疾病,诸如冠心病、心肌病、缺血性心脏病、心力衰竭、高血压性心脏病、炎性心脏病和瓣膜性心脏病。
另外,本发明的方法还提供了肿瘤血管生成和转移抑制以及器官移植排斥和宿主抗移植物病的治疗。
本发明还提供了药物组合物,其包含治疗有效量的式(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、载体和/或稀释剂。
本发明还提供了药物组合物,其包含式(I)的化合物与一种或更多种化疗剂(例如细胞抑制剂或细胞毒性剂)的组合。细胞抑制剂或细胞毒性剂包括但不限于抗生素型剂、烷化剂、抗代谢物剂、激素剂、免疫剂、干扰素型剂、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)、法尼基转移酶抑制剂、ras-raf信号转导通路抑制剂、细胞周期抑制剂、其他cdks抑制剂、微管蛋白结合剂、拓扑异构酶I抑制剂、拓扑异构酶Il抑制剂、芳香化酶抑制剂、驱动蛋白抑制剂、治疗性单克隆抗体、mTOR抑制剂、组蛋白脱乙酰化酶抑制剂、低氧响应抑制剂、PD-1拮抗剂或与PD-1或PD-L1特异性结合的其抗原结合片段等。
如果配制成固定剂量,这样的组合产品采用在以下描述的剂量范围内的本发明的化合物和在批准的剂量范围内的其他药学活性剂。
本发明还提供了用于抑制Syk蛋白激酶活性的体外方法,其包括使Syk激酶与有效量的如上定义的式(I)的化合物接触。
另外,本发明提供了一种产品,其包含如上定义的式(I)的化合物或其药学上可接受的盐以及一种或更多种化疗剂,作为组合制剂用于在抗癌疗法中同时、单独或顺序使用。
适于向哺乳动物(例如向人类)施用的本发明的式(I)的化合物可以通过通常途径施用,并且剂量水平取决于患者的年龄、体重和状况以及施用途径。
例如,用于口服施用式(I)的化合物的合适的剂量可以在每剂量约10mg至约1000mg的范围,每天1至5次。本发明的化合物可以以多种剂型施用,例如口服施用,以片剂、胶囊、糖或薄膜包衣片剂、液体溶液或悬浮液的形式;直肠施用,以栓剂的形式;肠胃外施用,例如肌肉内施用,或通过静脉内和/或鞘内和/或椎管内注射或输注。
含有本发明化合物的药物组合物通常按照常规方法制备,并以合适的药物形式施用。
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、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、海藻酸盐或淀粉乙醇酸钠;泡腾混合物(effervescing mixtures);染料;甜味剂;润湿剂,诸如卵磷脂、聚山梨醇酯、月桂基硫酸盐(laurylsulphates);以及通常在药物制剂中使用的无毒且药理学上无活性的物质。这些药物制剂可以以已知的方式,例如通过混合、制粒、压片、糖衣化或薄膜包衣工艺的方式来制备。
用于口服施用的液体分散体可以是例如糖浆、乳液和悬浮液。
作为实例,糖浆可以包含蔗糖或与甘油和/或甘露醇和山梨醇一起的蔗糖作为载体。
悬浮液和乳液可以包含天然胶、琼脂、海藻酸钠、果胶、甲基纤维素、羧甲基纤维素或聚乙烯醇作为载体的实例。
用于肌肉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、二醇类,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无菌水作为载体,或者优选地它们可以呈无菌、水性、等渗、盐水溶液的形式,或者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。在另一方面,本发明提供了如上定义的式(I)的化合物或其药学上可接受的盐,用于用作药物。
最后,本发明提供了如上定义的式(I)的化合物或其药学上可接受的盐在制备具有抗癌活性的药物中的用途。
实验部分
本文以及整个说明书中使用的简写形式和缩写具有以下含义:
式(I)的化合物的制备
论及本发明的式(I)的任何特定化合物(任选地以药学上可接受的盐形式),参见实验部分和权利要求书。参考以下实施例,使用本文描述的方法或本领域熟知的其他方法合成本发明的化合物。
为了更好地说明本发明而不对其施加任何限制的目的,给出以下实施例。
如本文使用的,在方法、方案和实施例中使用的符号和惯例与当代科学文献(例如,the Journal of the American Chemical Society或the Journal of BiologicalChemistry)中使用的符号和惯例一致。
化合物名称是IUPAC名称,通过使用ACD Name(由Advanced ChemistryDevelopment,Inc.)产生。
除非另有说明,否则所有材料(包括无水溶剂诸如DMF、THF、DCM)均从商业供应商获得,均为最佳等级,且不经进一步纯化地使用。所有涉及空气或水分敏感化合物的反应都是在氮气或氩气气氛下进行的。
一般纯化和分析方法
在以下实施例中描述了本发明的式(I)的一些化合物的合成制备。
根据以下实施例制备的本发明化合物的特征还在于1H NMR和/或HPLC/MS分析数据;按照LCQ或LCT方法中的任一种收集HPLC/MS数据。在硅胶(Merck grade 9395,60A)上进行快速色谱。
HPLC LCQ方法
HPLC-MS/UV分析在配备有电喷雾(ESI)离子源的LCQ DecaXP(Thermo,San Jose,US)离子阱仪器上进行。质谱仪连接到具有UV光电二极管阵列检测器(UV检测215-400nm)的Surveyor HPLC系统(Thermo,San Jose,US)。使用Waters XSelect CSH C18柱50x4.6mm,3.5μm粒度。流动相A是乙酸铵5mM缓冲液(pH 4.5,使用乙酸):乙腈95:5,并且流动相B是乙酸铵5mM缓冲液(pH 4.5,使用乙酸):乙腈5:95。7分钟内梯度从0到100%B,保持100%B 2分钟。流量1mL/min。注入体积10μL。保留时间(HPLC r.t.)以分钟给出。全扫描,质量范围从50到1200amu。加热毛细管温度为200℃,并且喷雾电压值设置为4kV。质量以m/z比给出。
通过使用Xcalibur 1.4SR1软件(Thermo)进行仪器控制、数据采集和处理。
HPLC
LCT方法
HPLC-MS/UV分析和高分辨率质谱(HRMS)在配备有Waters PDAUV检测器2996和由Waters试剂管理器液体泵支持的TOF Waters LCT Premier XE质量检测器(ESI接口)的Waters Alliance LC 2795上进行。测定基于允许在同一运行中通过确定和确认化合物的预期精确质量来补充身份-纯度测定的通用梯度反相色谱。通过在线系列ESI(+)全扫描MS检测完成化合物身份,样品纯度作为216-400nm的积分LC/UV迹线的相对“面积百分比”获得。液相色谱仪配备有在50℃恒温的Waters XBridge CSH C18柱(3.0×30mm,3.5μm粒度)。可选地,使用Supelco柱Ascentis Express C18(2.7×30mm×3um)。
流动相A是高纯度水中的0.05%w/v甲酸,并且流动相B是含有0.035%w/v甲酸的70/25/5(v/v/v)的MeOH/iPrOH/H2O混合物。17.5分钟内梯度从0到100% B,保持100% B 5分钟。流量0.8mL/min,注入量4μL。ESI源在100℃、2.5kV毛细管电压、60V锥体、350℃600L/hr氮气去溶剂化流量和10L/hr氮气锥体流量操作。“正常”Zfocus设置为140。分析器通常优化为7200V飞行管。
为了获得高分辨率质谱,将来自HPLC柱的洗脱液分开,并在其进入MS源之前,将25μL/min与来自Waters试剂管理泵的100μL/min含有0.01%w/v甲酸的MeOH/iPrOH/H2O的30/10/60(v/v/v)混合物和80nM甲氧苄啶(Trimethoprim)的流混合。选择甲氧苄啶作为稳定、可溶性和适合的参考化合物用于实时单点质量校正。在“W”模式下,以2Hz采样速率进行ES(+)全扫描80-1200amu质心数据采集。LCT嵌入式PC提供了实时数据质心和基于甲氧苄啶的实时质量校正。H+参考质量为291.1452Da。对适当强度的MS谱(40至2000个分析物计数)进行平均以获得最终结果。
1H-NMR谱在28℃的恒温在Varian INOVA400波谱仪和Varian INOVA 500波谱仪上记录,Varian INOVA400波谱仪以400.5MHz操作并配备有5mm 1H{15N-31P}z轴PFG间接检测探头,Varian INOVA500波谱仪以499.7MHz操作并配备有5mm 1H{13C-15N}三重共振间接检测探头。化学位移以非氘化残留溶剂信号(DMSO-d5:对于1H 2.50ppm)为参考。数据报告如下:化学位移(δ),多重性(s=单峰,d=双峰,t=三重峰,q=四重峰,qt=五重峰,br.s=宽单峰,dd=双重的双峰,ddd=双重的双重的双峰(doublet of doublets of doublets),m=多重峰),耦合常数(J,Hz)和质子数。
实施例
步骤15-((E)-3-二甲基氨基-丙烯酰基)-2-甲基-2H-吡唑-3-羧酸乙酯[(IV),R2=甲基,R9=乙基]
向CEM反应器中的5-乙酰基-2-甲基-2H-吡唑-3-羧酸乙酯(2g,10.19mmol,1当量)添加N,N-二甲基甲酰胺二乙基缩醛(10.48ml,61.2mmol,6当量)。将混合物在CEM explorer微波仪TM中于140℃搅拌3小时。在真空下除去挥发物,并用己烷冲洗固体并过滤,以95%的产率得到作为2.45g暗黄色粉末的标题化合物。
LC/MS(254nm)HPLC LCT-甲酸Rt 6.73min。
1H NMR(500MHz,DMSO-d6)δppm 7.72(d,J=12.5Hz,1H),7.12(s,1H),5.83(d,J=12.7Hz,1H),4.30(q,J=7.1Hz,2H),4.13(s,3H),3.14(s,3H),2.87(s,3H),1.31(t,J=7.1Hz,3H)。HRMS(ESI)对于C12H18N3O3[M+H]+计算为252.1343,实测为252.1342。
根据该相同的方法,但采用合适的取代的衍生物,制备了以下化合物:
5-((Z)-3-二甲基氨基-丙烯酰基)-2H-吡唑-3-羧酸乙酯[(IV),R2=H,R9=乙基]
5-((Z)-3-二甲基氨基-丙烯酰基)-2-乙基-2H-吡唑-3-羧酸乙酯[(IV),R2=乙基,R9=乙基]
步骤2和步骤3
5-(2-氨基-嘧啶-4-基)-2-甲基-2H-吡唑-3-羧酸乙酯[(VII),R2=甲基,R9=乙基]
将5-((E)-3-二甲基氨基-丙烯酰基)-2-甲基-2H-吡唑-3-羧酸乙酯(7.75g,30.84mmol,1当量)和碳酸胍(8.34g,46.26mmol,1.5当量)装载在CEM微波反应器中(分成六批),并悬浮在乙醇(100ml,0.3M)中。将混合物在CEM explorer微波仪中于150℃搅拌2小时。收集六个批次并干燥。将残留物悬浮在水(50ml)中,并在0℃用HCl 1N处理直至pH=2,将悬浮液在0℃搅拌1小时,然后过滤,并用水洗涤固体并干燥。将7.6g粗材料(标题化合物及其相应的酸)溶解在乙醇(115ml)中,并添加96%硫酸(21ml,378mmol,12当量)。将混合物加热回流7h,在真空下除去一半挥发物,用水(200ml)和乙酸乙酯(100ml)稀释混合物。在浓NaOH的搅拌下将pH调节至9,分离各层,并用AcOEt(3×50mL)提取水相。用盐水洗涤合并的有机层,然后用硫酸钠干燥,并且在除去溶剂之后,获得固体,用二异丙醚研磨得到作为淡黄色固体的标题化合物(6.38g,58%)。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.43min。
1H NMR(500MHz,DMSO-d6)δppm 8.28(d,J=5.2Hz,1H),7.32(s,1H),7.06(d,J=5.2Hz,1H),6.67(s,2H),4.32(q,J=7.1Hz,2H),4.19-4.12(m,3H),1.33(t,J=7.1Hz,3H);HRMS(ESI)对于C11H14N5O2[M+H]+计算为248.1142,实测为248.1139。
根据该相同的方法,但采用合适的衍生物和适当的胍衍生物,制备以下化合物:
5-(2-氨基-嘧啶-4-基)-2H-吡唑-3-羧酸乙酯[(VII),R2=H,R9=乙基]
5-(2-氨基-嘧啶-4-基)-2-乙基-2H-吡唑-3-羧酸乙酯[(VII),R2=乙基,R9=乙基]
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二甲基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.56min。
1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H),8.52(d,J=5.1Hz,1H),7.49(s,2H),7.44(s,1H),7.28(d,J=5.1Hz,1H),6.62(s,1H),4.34(q,J=7.1Hz,2H),4.19(s,3H),2.27(s,6H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C19H22N5O2[M+H]+计算为352.1768,实测为352.1765。
5-[2-(1,5-二甲基-1H-吡唑-3-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=1,5-二甲基-1H-吡唑-3-基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 9.60min。
1H NMR(500MHz,DMSO-d6)δppm 10.17(s,1H),8.45(d,J=5.0Hz,1H),7.39(s,1H),7.24(d,J=5.0Hz,1H),6.47(s,1H),4.34(q,J=7.0Hz,2H),4.18(s,3H),3.67(s,3H),2.23(s,3H),1.34(t,J=7.2Hz,3H);HRMS(ESI)对于C16H20N7O2[M+H]+计算为342.1673,实测为342.1674。
2-甲基-5-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸乙酯[(VI),R1=1-甲基-1H-吡唑-4-基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 9.18min。
1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H),8.46(d,J=5.0Hz,1H),7.90(s,1H),7.55(br.s.,1H),7.42(s,1H),7.20(d,J=5.0Hz,1H),4.35(q,J=7.1Hz,2H),4.19(s,3H),3.82(s,3H),1.35(t,J=7.1Hz,3H);HRMS(ESI)对于C15H18N7O2[M+H]+计算为328.1517,实测为328.1517。
2-甲基-5-[2-(四氢-吡喃-4-基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸乙酯[(VI),R1=四氢-吡喃-4-基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 8.79min。
1H NMR(500MHz,DMSO-d6)δppm 8.32(d,J=5.0Hz,1H),7.34(s,1H),7.21(d,J=7.8Hz,1H),7.05(d,J=5.0Hz,1H),4.36-4.33(m,2H),4.16(s,3H),3.98(br.s.,2H),3.92-3.83(m,2H),3.46-3.37(m,2H),1.84(d,J=11.6Hz,2H),1.59-1.43(m,2H),1.34(s,1H);HRMS(ESI)对于C16H22N5O3[M+H]+计算为332.1717,实测为332.1713。
5-[2-(3,5-二甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二甲氧基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 6.84min。
1H NMR(500MHz,DMSO-d6)δppm 9.67(s,1H),8.54(d,J=5.0Hz,1H),7.49-7.45(m,1H),7.32(d,J=5.2Hz,1H),7.20(d,J=2.3Hz,2H),6.14(t,J=2.2Hz,1H),4.33(q,J=7.2Hz,2H),4.19(s,3H),3.76(s,6H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C19H22N5O4[M+H]+计算为384.1667,实测为384.1666。
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二甲基-苯基,R2=H,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 6.6min。
1H NMR(500MHz,DMSO-d6)δppm 14.45(br.s.,1H),9.52(s,1H),8.54(br.s.,1H),7.47(br.s.,2H),7.39(s,1H),7.33(d,J=5.0Hz,1H),6.62(s,1H),4.33(q,J=6.7Hz,2H),2.26(s,6H),1.33(t,J=7.1Hz,3H);HRMS(ESI)对于C18H20N5O2[M+H]+计算为338.1612,实测为338.1607。
可选地,可以与取代的胍进行反应,以直接获得相应的羧酸或其盐。
5-[2-(3,5-二甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,5-二甲氧基-苯基,R2=甲基]
将正丁醇(70mL)中的5-((E)-3-二甲基氨基-丙烯酰基)-2-甲基-2H-吡唑-3-羧酸乙酯(3.64g,14.4mmol)、N-(3,5-二甲氧基-苯基)-盐酸胍(4.0g,17.3mmol,1.2当量)和碳酸钾(3.6g,25.9mmol,1.8当量)的悬浮液在113℃(内部温度)搅拌24h,此后HPLC/MS检查示出完全的转化。将反应混合物冷却至室温,用70mL水和25mL AcOEt稀释,并搅拌直至悬浮的固体完全溶解。分离各相,并用30mL水对有机层提取3次。将水相合并,并在搅拌下用2N HCl(16mL)使其达到酸性pH(约3-4)。将得到的悬浮液搅拌10分钟,然后通过烧结玻璃布氏漏斗过滤,孔隙率4(过滤相当慢)。过滤器上的滤饼用5mL水洗涤两次,然后用10mL MTBE洗涤两次。收集固体并在真空(20-30mm Hg)下在45-50℃的烘箱中干燥,直到重量恒定,得到3.23g作为米色固体的所需产物。产率:63%。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.13min。
1H NMR(500MHz,DMSO-d6)δppm 9.67(s,1H),8.56(d,J=5.0Hz,1H),7.43(s,1H),7.35(d,J=5.0Hz,1H),7.22(d,J=2.3Hz,2H),6.17(t,J=2.3Hz,1H),4.21(s,3H),3.81-3.76(m,6H);HRMS(ESI)对于C17H18N5O4[M+H]+计算为356.1354,实测为356.1366。
步骤45-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二甲基-苯基,R2=甲基,R9=乙基]
将5-(2-氨基-嘧啶-4-基)-2-甲基-2H-吡唑-3-羧酸乙酯(200mg,0.81mmol,1当量)、3,5-二甲基-碘苯(175ul,1.21mmol,1.5当量)和碳酸铯(527mg,1.62mmol,2当量)悬浮在先前脱气的二噁烷(8ml)中,并进行三次真空/氩气循环。在氩气气氛下添加Xphos(85mg,0.18mmol,0.22当量)和三(二亚苄基丙酮)二钯(0)(74mg,0.08mmol,0.1当量),并进行三次真空/氩气循环。将混合物在100℃加热6小时,然后冷却至室温并用水稀释,用AcOEt提取三次,收集有机物并用盐水洗涤,并在降低的压力下去除挥发物。粗制固体通过硅胶上的快速色谱(洗脱剂:DCM:EtOH 99/1)纯化以得到160mg(56%产率)的标题化合物。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.56min。
1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H),8.52(d,J=5.1Hz,1H),7.49(s,2H),7.44(s,1H),7.28(d,J=5.1Hz,1H),6.62(s,1H),4.34(q,J=7.1Hz,2H),4.19(s,3H),2.27(s,6H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C19H22N5O2[M+H]+计算为352.1768,实测为352.1765。
根据该相同的方法,但采用合适的取代的衍生物,制备了以下化合物:
5-[2-(3,5-二氯-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二氯-苯基,R2=甲基,R9=乙基]28%产率
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 8.21min。
1H NMR(500MHz,DMSO-d6)δppm 10.16(s,1H),8.62(d,J=5.2Hz,1H),8.01(d,J=1.8Hz,2H),7.47(s,1H),7.42(d,J=5.2Hz,1H),7.14(t,J=1.9Hz,1H),4.33(q,J=7.2Hz,2H),4.20(s,3H),1.33(t,J=7.1Hz,3H);HRMS(ESI)对于C17H16Cl2N5O2[M+H]+计算为392.0676,实测为392.0675。
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-乙基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二甲基-苯基,R2=乙基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.18min。
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),8.55(d,J=5.2Hz,1H),7.48(s,1H),7.30(d,J=5.2Hz,1H),7.28(s,2H),6.67(s,1H),4.80(q,J=7.1Hz,2H),4.30(q,J=7.1Hz,2H),2.25(s,6H),1.31(t,J=7.0Hz,3H),1.28(t,J=7.2Hz,3H);HRMS(ESI)对于C20H24N5O2[M+H]+计算为366.1925,实测为366.1921。
2-甲基-5-(2-间甲苯基氨基-嘧啶-4-基)-2H-吡唑-3-羧酸乙酯[(VI),R1=2-间甲苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.18min。
1H NMR(500MHz,DMSO-d6)δppm 9.62(s,1H),8.52(d,J=5.0Hz,1H),7.74(s,1H),7.56(d,J=8.2Hz,1H),7.44(s,1H),7.30(d,J=5.0Hz,1H),7.18(t,J=7.9Hz,1H),6.79(d,J=7.3Hz,1H),4.34(q,J=7.0Hz,2H),4.19(s,3H),2.31(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C18H20N5O2[M+H]+计算为338.1612,实测为338.1615。
5-[2-(3,5-二氟-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二氟-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.37min。
1H NMR(500MHz,DMSO-d6)δppm 10.17(s,1H),8.61(d,J=5.2Hz,1H),7.67-7.58(m,2H),7.45(s,1H),7.42(d,J=5.2Hz,1H),6.76(tt,J=2.3,9.2Hz,1H),4.34(q,J=7.0Hz,2H),4.20(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C17H16F2N5O2[M+H]+计算为360.1267,实测为360.1274。
5-{2-[3-氯-4-(4-甲基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3-氯-4-(4-甲基-哌嗪-1-基)-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 5.80min。
1H NMR(500MHz,DMSO-d6)δppm 9.76(s,1H),8.53(d,J=5.0Hz,1H),8.16(br.s.,1H),7.59(dd,J=2.5,8.8Hz,1H),7.45(s,1H),7.31(d,J=5.0Hz,1H),7.13(d,J=8.8Hz,1H),4.34(q,J=7.2Hz,2H),4.19(s,3H),2.93(br.s.,4H),2.47(br.s.,4H),2.23(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C22H27ClN7O2[M+H]+计算为456.1910,实测为456.1901。
5-[2-(3-氰基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3-氰基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 6.73min。
1H NMR(500MHz,DMSO-d6)δppm 10.12(s,1H),8.61(d,J=5.2Hz,1H),8.49(t,J=1.7Hz,1H),7.98(ddd,J=0.8,2.3,8.4Hz,1H),7.52(t,J=7.9Hz,1H),7.46(s,1H),7.41(d,J=5.0Hz,1H),7.41(ddd,J=0.9,1.4,7.5Hz,1H),4.34(q,J=7.1Hz,2H),4.20(s,3H),1.34(t,J=7.2Hz,3H);HRMS(ESI)对于C18H17N6O2[M+H]+计算为349.1408,实测为349.1416。
5-[2-(3,5-二甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-二甲氧基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 6.84min。
1H NMR(500MHz,DMSO-d6)δppm 9.67(s,1H),8.54(d,J=5.0Hz,1H),7.49-7.45(m,1H),7.32(d,J=5.2Hz,1H),7.20(d,J=2.3Hz,2H),6.14(t,J=2.2Hz,1H),4.33(q,J=7.2Hz,2H),4.19(s,3H),3.76(s,6H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C19H22N5O4[M+H]+计算为384.1667,实测为384.1666。
5-[2-(3-甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3-甲氧基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 11.81min。
1H NMR(500MHz,DMSO-d6)δppm 9.70(s,1H),8.54(d,J=5.0Hz,1H),7.75(br.s.,1H),7.46(s,1H),7.32(d,J=5.0Hz,1H),7.27(dd,J=0.8,8.2Hz,1H),7.21-7.15(m,1H),6.57-6.52(m,1H),4.34(q,J=7.1Hz,2H),4.19(s,3H),3.79(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C18H20N5O3[M+H]+计算为354.1561,实测为354.1564。
2-甲基-5-[2-(3,4,5-三甲氧基-苯基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸乙酯[(VI),R1=3,4,5-三甲氧基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 11.04min。
1H NMR(500MHz,DMSO-d6)δppm 9.59(s,1H),8.53(d,J=5.0Hz,1H),7.49-7.48(m,1H),7.34(s,2H),7.30(d,J=5.0Hz,1H),4.33(q,J=7.1Hz,2H),4.18(s,3H),3.82(s,6H),3.63(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C20H24N5O5[M+H]+计算为414.1772,实测为414.1772。
5-[2-(3-氟-5-甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3-氟-5-甲氧基-苯基,R2=甲基,R9=乙基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 12.60min。
1H NMR(500MHz,DMSO-d6)δppm 9.91(s,1H),8.58(d,J=5.2Hz,1H),7.47-7.42(m,2H),7.37(d,J=5.0Hz,1H),7.36-7.31(m,1H),6.41(td,J=2.2,10.8Hz,1H),4.34(q,J=7.0Hz,2H),4.20(s,3H),3.79(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C18H19FN5O3[M+H]+计算为372.1467,实测为372.1465。
5-[2-(3-氰基-5-甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3-氰基-5-甲氧基-苯基,R2=甲基,R9=乙基]87%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 12.08min。
1H NMR(500MHz,DMSO-d6)δppm 10.09(s,1H),8.61(d,J=5.2Hz,1H),7.93-7.90(m,1H),7.88(t,J=1.9Hz,1H),7.46(s,1H),7.41(d,J=5.2Hz,1H),7.02(dd,J=1.4,2.3Hz,1H),4.33(q,J=7.2Hz,2H),4.20(s,3H),3.84(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C19H19N6O3[M+H]+计算为379.1513,实测为379.1514。
5-[2-(5-甲氧基-吡啶-3-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=5-甲氧基-吡啶-3-基,R2=甲基,R9=乙基]37%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 8.62min。
1H NMR(500MHz,DMSO-d6)δppm 9.97(s,1H),8.59(d,J=5.0Hz,1H),8.50(d,J=2.0Hz,1H),8.19(br.s.,1H),7.91(d,J=2.6Hz,1H),7.46(s,1H),7.39(d,J=5.0Hz,1H),4.34(q,J=7.1Hz,2H),4.19(s,3H),3.88(s,3H),1.34(t,J=7.1Hz,3H);HRMS(ESI)对于C17H19N6O3[M+H]+计算为355.1513,实测为355.1518。
5-[2-(3,5-双-三氟甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,5-双-三氟甲基-苯基,R2=甲基,R9=乙基]
5-[2-(3-甲氧基-5-三氟甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3-甲氧基-5-三氟甲基-苯基,R2=甲基,R9=乙基]
5-[2-(4,6-二甲基-吡啶-2-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=4,6-二甲基-吡啶-2-基,R2=甲基,R9=乙基]
2-甲基-5-[2-(3-三氟甲基-苯基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸乙酯[(VI),R1=3-三氟甲基-苯基,R2=甲基,R9=乙基]
5-[2-(苯并[1,3]间二氧杂环戊烯-5-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=苯并[1,3]间二氧杂环戊烯-5-基氨基)-嘧啶-4-基,R2=甲基,R9=乙基]
5-[2-(3,4-二甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯[(VI),R1=3,4-二甲氧基-苯基氨基)-嘧啶-4-基,R2=甲基,R9=乙基]
步骤53-(2-碘嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酸乙酯[(IX),R2=甲基,R9=乙基]
向脱气的无水二噁烷(11ml)中的5-(2-氨基-嘧啶-4-基)-2-甲基-2H-吡唑-3-羧酸乙酯(450mg,1.82mmol,1当量)溶液添加CuI(156mg,0.82mmol,0.45当量)、CsI(708mg,2.73mmol,1.5当量)、碘(323mg,1.28mmol,0.7当量)和亚硝酸异戊酯(535ul,4.01mmol,2.2当量)。将反应混合物在T=90℃加热2小时,然后冷却至室温并用水稀释,用AcOEt提取三次。收集有机物,并用10%氨溶液、Na2S2O5 5%水溶液和盐水洗涤。有机层在无水Na2SO4上干燥并蒸发至干燥。粗产物通过硅胶上的快速色谱(洗脱剂:己烷/AcOEt8/2)纯化以得到230mg(35%产率)的标题化合物。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 6.43min。
1H NMR(500MHz,DMSO-d6)δppm 1.34(t,J=7.1Hz,3H)4.19(s,3H)4.34(q,J=7.1Hz,2H)7.44(s,1H)7.98(d,J=5.2Hz,1H)8.57(d,J=5.2Hz,1H);HRMS(ESI)对于C11H11IN4O2[M+H]+计算为359,实测为359.0013。
步骤61-甲基-3-{2-[(1,2,3-三甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酸乙酯[(VI),R1=1,2,3-三甲基-1H-吲哚-5-基,R2=甲基,R9=乙基]
将3-(2-碘嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酸乙酯(86mg,0.24mmol,1当量)、1,2,3-三甲基-1H-吲哚-5-胺(42mg,0.24mmol,1当量)和K2CO3(99,5mg,0.72mmol,3当量)悬浮在先前脱气的二噁烷(4ml)中,并进行三次真空/氩气循环。在氩气气氛下添加Xantphos(27.8mg,0.048mmol,0.2当量)和Pd(OAc)2(5.4mg,0.024mmol,0.1当量),并进行三次真空/氩气循环。将混合物在100℃加热3小时,然后冷却至室温并用水稀释,用AcOEt提取三次,收集有机物并用盐水洗涤,并在降低的压力下去除挥发物。粗制固体通过硅胶上的快速色谱(洗脱剂:DCM/AcOEt 9/1)纯化以得到10mg(10%产率)的标题化合物。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.38min。
1H NMR(500MHz,DMSO-d6)δppm 1.35(t,J=7.1Hz,3H)2.23(s,3H)2.33(s,3H)3.62(s,3H)4.20(s,3H)4.35(q,J=7.1Hz,2H)7.21(dd,J=8.5,1.5Hz,1H)7.22(d,J=5.0Hz,1H)7.25(d,J=8.7Hz,1H)7.48(s,1H)8.25(br.s.,1H)8.47(d,J=5.0Hz,1H)9.44(s,1H);HRMS(ESI)对于C22H24N6O2[M+H]+计算为405.2034,实测为405.2033。
3-{2-[(3-氯-1-甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酸乙酯[(VI),R1=3-氯-1-甲基-1H-吲哚-5-基,R2=甲基,R9=乙基]
将3-(2-碘嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酸乙酯(140mg,0.39mmol,1当量)、3-氯-1-甲基-1H-吲哚-5-胺(84.5mg,0.47mmol,1.2当量)和碳酸铯(381mg,1.17mmol,3当量)悬浮在先前脱气的二噁烷(8ml)中,并进行三次真空/氩气循环。在氩气气氛下添加Xphos(74.5mg,0.156mmol,0.4当量)和三(二亚苄基丙酮)二钯(0)(71.6mg,0.078mmol,0.2当量),并进行三次真空/氩气循环。将混合物在100℃加热7小时,然后冷却至室温并用水稀释,用AcOEt提取三次,收集有机物并用盐水洗涤,并在降低的压力下去除挥发物。粗制固体通过硅胶上的快速色谱(洗脱剂:DCM/AcOEt 95/5)纯化以得到24mg(15%产率)的标题化合物。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 7.22min。
1H NMR(500MHz,DMSO-d6)δppm 1.35(t,J=7.1Hz,3H)3.76(s,3H)4.21(s,3H)4.34(q,J=7.2Hz,2H)7.29(d,J=5.0Hz,1H)7.37(dd,J=8.9,1.5Hz,1H)7.43(d,J=8.8Hz,1H)7.48(s,1H)7.58(s,1H)8.53(d,J=4.9Hz,1H)8.59(br.s.,1H)9.70(s,1H);HRMS(ESI)对于C20H19ClN6O2[M+H]+计算为411.1331,实测为411.1340。
步骤7
2-甲基-5-(2-间甲苯基氨基-嘧啶-4-基)-2H-吡唑-3-羧酸[(XI),R1=2-间甲苯基,R2=甲基]100%产率
将氢氧化钠2N(10.5ml)添加到乙醇(21ml)中的2-甲基-5-(2-间甲苯基氨基-嘧啶-4-基)-2H-吡唑-3-羧酸乙酯(260mg,0.77mmol,1当量)的溶液中,并将混合物在室温搅拌4小时。添加HCl 2N以达到pH<5,并过滤沉淀物,用水和Et2O洗涤,并在真空中干燥,来以定量产率得到标题化合物。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.26min。
1H NMR(500MHz,DMSO-d6)δppm 9.60(s,1H),8.51(d,J=5.0Hz,1H),7.69(s,1H),7.61(d,J=7.9Hz,1H),7.38(s,1H),7.29(d,J=5.2Hz,1H),7.18(t,J=7.8Hz,1H),6.78(d,J=7.5Hz,1H),4.18(s,3H),2.30(s,3H);HRMS(ESI)对于C16H16N5O2[M+H]+计算为310.1299,实测为310.1302。
根据该相同的方法,但采用合适的取代的衍生物,制备了以下化合物:
5-[2-(3,5-二氟-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,5-二氟-苯基,R2=甲基]定量产率
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.51min。
1H NMR(500MHz,DMSO-d6)δppm 10.16(s,1H),8.60(d,J=5.2Hz,1H),7.68-7.58(m,2H),7.42(d,J=5.2Hz,1H),7.38(s,1H),6.76(tt,J=2.2,9.3Hz,1H),4.19(s,3H);HRMS(ESI)对于C15H12F2N5O2[M+H]+计算为332.0954,实测为332.0956。
5-{2-[3-氯-4-(4-甲基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-氯-4-(4-甲基-哌嗪-1-基)-苯基,R2=甲基]定量产率
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 3.57min。
1H NMR(500MHz,DMSO-d6)δppm 11.99(s,1H),9.69(s,1H),8.48(d,J=5.2Hz,1H),8.03(d,J=2.4Hz,1H),7.72(dd,J=2.1,8.7Hz,1H),7.29(d,J=5.2Hz,1H),7.19(s,1H),7.15(d,J=8.8Hz,1H),4.17(s,3H),2.98(br.s.,4H),2.35(br.s.,3H);HRMS(ESI)对于C20H23ClN7O2[M+H]+计算为428.1597,实测为428.1607。
5-[2-(3-氯-1-甲基-1H-吲哚-5-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-氯-1-甲基-1H-吲哚-5-基,R2=甲基]93%产率
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.53min。
1H NMR(500MHz,DMSO-d6)δppm 13.60(br.s.,1H),9.64(br.s.,1H),8.50(br.s.,1H),8.41(br.s.,1H),7.56-7.33(m,4H),7.26(br.s.,1H),4.19(s,3H),3.76(s,3H);HRMS(ESI)对于C18H16ClN6O2[M+H]+计算为383.1018,实测为383.1006。
1-甲基-3-{2-[(1,2,3-三甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酸[(XI),R1=1,2,3-三甲基-1H-吲哚-5-基,R2=甲基]
可选地,所述酸或其盐可以如以下报告地制备:
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,5-二甲基-苯基,R2=甲基]
将溶解于水(2ml)的一水合氢氧化锂(47.8mg,1.138mmol,2.5当量)和乙醇(1ml)顺序添加到THF(2ml)中的5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸乙酯(160mg,0.455mmol,1当量)的溶液中。将混合物在室温搅拌16h,然后用HCl 1N处理直至达到pH=3。在降低的压力下去除有机物,并过滤沉淀物,并用水和Et2O冲洗以得到132mg(90%产率)的标题化合物,该化合物不经进一步纯化地使用。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.55min。
1H NMR(500MHz,DMSO-d6)δppm 13.66(br.s,1H),9.55(s,1H),8.51(d,J=5.0Hz,1H),7.48(br.s,2H),7.38(s,1H),7.28(d,J=5.0Hz,1H),6.62(br.s,1H),4.18(s,3H),2.26(s,6H);HRMS(ESI)对于C17H18N5O2[M+H]+计算为324.1455,实测为324.1454。
根据该相同的方法,但采用合适的取代的衍生物,制备了以下化合物:
5-[2-(3-甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-甲氧基-苯基,R2=甲基]94%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 9.53min。
1H NMR(500MHz,DMSO-d6)δppm 9.68(s,1H),8.53(d,J=5.2Hz,1H),7.68(s,1H),7.40(s,1H),7.31(d,J=5.2Hz,2H),7.21-7.17(m,1H),6.54(dd,J=2.2,7.9Hz,1H),4.18(s,3H),3.77(s,3H);HRMS(ESI)对于C16H16N5O3[M+H]+计算为326.1248,实测为326.1248。
5-[2-(3,5-二甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,5-二甲氧基-苯基,R2=甲基]92%产率
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 4.13min。
1H NMR(500MHz,DMSO-d6)δppm 9.67(s,1H),8.56(d,J=5.0Hz,1H),7.43(s,1H),7.35(d,J=5.0Hz,1H),7.22(d,J=2.3Hz,2H),6.17(t,J=2.3Hz,1H),4.21(s,3H),3.81-3.76(m,6H);HRMS(ESI)对于C17H18N5O4[M+H]+计算为356.1354,实测为356.1366。
2-甲基-5-[2-(3,4,5-三甲氧基-苯基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸[(XI),R1=3,4,5-三甲氧基-苯基,R2=甲基]80%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 9.02min。
1H NMR(500MHz,DMSO-d6)δppm 9.56(s,1H),8.52(d,J=5.0Hz,1H),7.44(s,1H),7.33(s,2H),7.29(d,J=5.2Hz,1H),4.17(s,3H),3.80(s,6H),3.62(s,3H);HRMS(ESI)对于C18H20N5O5[M+H]+计算为386.1459,实测为386.1471。
5-[2-(3-氟-5-甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-氟-5-甲氧基-苯基,R2=甲基]99%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 10.53min。
1H NMR(500MHz,DMSO-d6)δppm 13.71(br.s.,1H),9.88(s,1H),8.56(d,J=5.0Hz,1H),7.45-7.30(m,4H),6.41(td,J=2.2,10.8Hz,1H),4.18(s,3H),3.78(s,3H);HRMS(ESI)对于C16H15FN5O3[M+H]+计算为344.1154,实测为344.1140。
2-甲基-5-[2-(1-甲基-1H-吡唑-4-基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸[(XI),R1=1-甲基-1H-吡唑-4-基,R2=甲基]72%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 5.87min。
1H NMR(500MHz,DMSO-d6)δppm 13.60(br.s.,1H),9.51(s,1H),8.45(d,J=5.0Hz,1H),7.90(s,1H),7.66-7.53(m,1H),7.37(br.s.,1H),7.20(d,J=5.2Hz,1H),4.18(s,3H),3.82(s,3H);HRMS(ESI)对于C13H14N7O2[M+H]+计算为300.1204,实测为300.1203。
2-甲基-5-[2-(3-三氟甲基-苯基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸[(XI),R1=3-三氟甲基-苯基,R2=甲基]
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 11.49min。
1H NMR(500MHz,DMSO-d6)δppm 9.96(s,1H),8.49(d,J=5.2Hz,1H),8.44(s,1H),8.04(d,J=9.0Hz,1H),7.53(t,J=7.9Hz,1H),7.32(d,J=5.2Hz,1H),7.26(d,J=7.6Hz,1H),7.00(s,1H),4.16(s,3H);HRMS(ESI)对于C16H13F3N5O2[M+H]+计算为364.1016,实测为364.1007。
5-[2-(3-氰基-5-甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-氰基-5-甲氧基-苯基,R2=甲基]96%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 10.05min。
1H NMR(500MHz,DMSO-d6)δppm 10.06(s,1H),8.60(d,J=5.2Hz,1H),7.89(d,J=1.2Hz,2H),7.41(t,J=2.5Hz,2H),7.06-6.98(m,1H),4.19(s,3H),3.83(s,3H);HRMS(ESI)对于C17H15N6O3[M+H]+计算为351.1200,实测为351.1201。
5-[2-(5-甲氧基-吡啶-3-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=5-甲氧基-吡啶-3-基,R2=甲基]87%产率
LC/MS(254nm)HPLC方法(IP)LCT-甲酸Rt 5.40min。
1H NMR(500MHz,DMSO-d6)δppm 10.13(s,1H),8.67(s,1H),8.60(d,J=5.0Hz,1H),8.22(s,1H),8.02(d,J=2.1Hz,1H),7.46-7.38(m,2H),4.19(s,3H),3.90(s,3H);HRMS(ESI)对于C15H15N6O3[M+H]+计算为327.1200,实测为327.1199。
5-[2-(3,5-双-三氟甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,5-双-三氟甲基-苯基,R2=甲基]
5-[2-(3-甲氧基-5-三氟甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-甲氧基-5-三氟甲基-苯基,R2=甲基]
5-[2-(4,6-二甲基-吡啶-2-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=4,6-二甲基-吡啶-2-基,R2=甲基]
5-[2-(3,5-二氯-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,5-二氯-苯基,R2=甲基]
5-[2-(苯并[1,3]间二氧杂环戊烯-5-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=2-(苯并[1,3]间二氧杂环戊烯-5-基,R2=甲基]
5-[2-(1,5-二甲基-1H-吡唑-3-基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=1,5-二甲基-1H-吡唑-3-基,R2=甲基]
2-甲基-5-[2-(四氢-吡喃-4-基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸[(XI),R1=四氢-吡喃-4-基,R2=甲基]
5-[2-(3-氰基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3-氰基-苯基,R2=甲基]
5-[2-(3,4-二甲氧基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸[(XI),R1=3,4-二甲氧基-苯基,R2=甲基]
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-乙基-2H-吡唑-3-羧酸[(XI),R1=3,5-二甲基-苯基,R2=乙基]
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2H-吡唑-3-羧酸[(XI),R1=3,5-二甲基-苯基,R2=H]
步骤8
N-[2-(二甲基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 1)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-(二甲基氨基)乙基,R4=H]
将5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸(25mg,0.077mmol,1当量)和2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基四氟硼酸铵(TBTU)(37mg,0.12mmol,1.5当量)悬浮在无水DMA(1ml)中。在搅拌5分钟之后,添加N,N-二异丙基乙胺(DIPEA)(27ul,0.15mmol,2当量)和2-二甲基胺-乙胺(12.7ul,0.12mmol,1.5当量),并将最终混合物在室温搅拌16h,并且然后用H2O(5ml)稀释,用AcOEt提取三次(3×4ml)。收集有机层并用盐水洗涤,经Na2SO4干燥,在降低的压力下过滤和浓缩。粗制化合物通过硅胶上的快速色谱(洗脱剂DCM/MeOH 9:1)纯化,以52%的产率提供标题化合物。
LC/MS(254nm)HPLC方法(IP)LCQ Deca XP-乙酸盐缓冲液Rt 5.23min。
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.71(t,J=5.1Hz,1H),8.49(d,J=5.2Hz,1H),7.47(s,2H),7.42(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.14(s,3H),3.36(q,J=6.0Hz,2H),2.47(br.s,2H),2.27(s,6H),2.24(br.s.,6H);HRMS(ESI)对于C21H27N7O[M+H]+计算为394.235,实测为394.2357。
根据该相同的方法,但采用最终盐化或受保护的合适胺衍生物,制备了以下化合物:
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2R)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd2)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2R)-1-羟基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.49(d,J=5.0Hz,1H),8.45(d,J=8.2Hz,1H),7.47(s,3H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.75(t,J=5.8Hz,1H),4.13(s,3H),3.98(qd,J=6.5,7.7Hz,1H),3.47-3.41(m,1H),3.34-3.30(m,1H),2.27(s,6H),1.12(d,J=6.7Hz,3H);HRMS(ESI)对于C20H24N6O2[M+H]+计算为381.2034,实测为381.2031。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 3)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-羟基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.49(d,J=5.0Hz,1H),8.45(d,J=8.1Hz,1H),7.47(s,2H),7.25(d,J=5.2Hz,1H),6.61(s,1H),4.74(t,J=5.8Hz,1H),4.13(s,3H),4.03-3.91(m,1H),3.44(td,J=5.6,10.9Hz,1H),2.27(s,6H),1.12(d,J=6.7Hz,3H);HRMS(ESI)对于C20H24N6O2[M+H]+计算为381.2034,实测为381.2036。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(丙烷-2-基)-1H-吡唑-5-羧酰胺(cpd 4)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.59(d,J=7.9Hz,1H),8.49(d,J=5.0Hz,1H),7.48(s,2H),7.46(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.13(s,3H),4.11-4.01(m,1H),2.27(s,6H),1.16(d,J=6.6Hz,6H);HRMS(ESI)对于C20H24N6O[M+H]+计算为365.2085,实测为365.2087。
N-[2-(二甲基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd 5)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=[2-(二甲基氨基)乙基,R4=甲基]
1H NMR(500MHz,DMSO-d6)δppm 9.51(d,J=5.6Hz,1H),8.49(br.s.,1H),7.47(s,2H),7.26(br.s.,1H),7.09-6.91(m,1H),6.60(s,1H),4.05-3.83(m,3H),3.75-3.43(m,2H),3.18-2.95(m,3H),2.34(br.s.,3H),2.25(s,6H),1.95(br.s.,3H);HRMS(ESI)对于C22H29N7O[M+H]+计算为408.2507,实测为408.2518。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(甲基氨基)乙基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 6)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-(甲基氨基)乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),9.00(t,J=5.6Hz,1H),8.67(br.s.,2H),8.50(d,J=5.0Hz,1H),7.46(s,2H),7.26(d,J=5.2Hz,1H),6.62(s,1H),4.16(s,3H),3.58-3.53(m,2H),3.09(quin,J=5.9Hz,2H),2.59(t,J=5.4Hz,3H),2.31-2.22(m,6H);HRMS(ESI)对于C20H26N7OCl[M+H]+计算为380.2194,实测为380.2186。
N-(2-氨基乙基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 7)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-氨基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.94(t,J=5.7Hz,1H),8.50(d,J=5.2Hz,1H),7.92(br.s.,3H),7.48(s,1H),7.46(s,2H),7.26(d,J=5.2Hz,1H),6.62(s,1H),4.16(s,3H),3.50(quin,J=5.8Hz,2H),2.98(sxt,J=5.9Hz,2H),2.27(s,6H);HRMS(ESI)对于C19H24N7OCl[M+H]+计算为366.2037,实测为366.2033。
N-(氮杂环丁烷-3-基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺三氟乙酸盐(cpd 8)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=氮杂环丁烷-3-基,R4=H]
1H NMR(DMSO-d6,500MHz):δppm 9.47(s,1H),9.41(d,J=7.0Hz,1H),8.68(br.s.,2H),8.51(d,J=5.0Hz,1H),7.50(s,1H),7.46(s,2H),7.27(d,J=5.0Hz,1H),6.63(s,1H),4.82(sxt,J=7.8Hz,1H),4.16-4.24(m,2H),4.15(s,3H),4.01-4.12(m,2H),2.28ppm(s,6H);HRMS(ESI)对于C22H24N7O3F3[M+H]+计算为378.2037,实测为378.2034。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(吗啉-4-基)乙基]-1H-吡唑-5-羧酰胺(cpd 9)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-吗啉-4-基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.72(t,J=5.6Hz,1H),8.49(d,J=5.0Hz,1H),7.46(s,2H),7.41(s,1H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.14(s,3H),3.57(t,J=4.6Hz,4H),3.37(q,J=6.3Hz,2H),2.46(t,J=6.7Hz,2H),2.41(br.s.,4H),2.27(s,6H);HRMS(ESI)对于C23H29N7O2[M+H]+计算为436.2456,实测为436.2447。
N-[2-(二乙氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 10)[(I),R1=3,5-二甲基苯基),R2=甲基,R3=2-(二乙氨基)乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.90(br.t,J=4.5Hz,1H),8.50(d,J=5.0Hz,1H),7.46(s,2H),7.43(s,1H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.15(s,3H),3.51(br.q,J=5.3Hz,2H),3.03(br.s.,6H),2.27(s,6H),1.20-1.03(m,6H);HRMS(ESI)对于C23H31N7O[M+H]+计算为422.2663,实测为422.2666。
N-[(1R,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 11)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1R,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.80(d,J=8.8Hz,1H),8.50(d,J=5.0Hz,1H),8.06(br.s.,3H),7.51(s,1H),7.47(s,2H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.15(s,3H),3.92-3.79(m,1H),3.03-2.94(m,1H),2.27(s,6H),2.07(d,J=13.4Hz,1H),1.86(d,J=13.6Hz,1H),1.73(d,J=8.1Hz,2H),1.52-1.35(m,2H),1.33-1.18(m,J=11.2,11.2Hz,2H);HRMS(ESI)对于C23H30N7OCl[M+H]+计算为420.2507,实测为420.2503。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(丙烷-2-基氨基)乙基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 12)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-(丙烷-2-基氨基)乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.98(t,J=5.6Hz,1H),8.50(d,J=5.0Hz,1H),8.51(br.s.,2H),7.48(s,1H),7.46(s,2H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.16(s,3H),3.56(q,J=5.9Hz,2H),3.08(t,J=5.6Hz,2H),2.27(s,6H),1.23(d,J=6.4Hz,6H);HRMS(ESI)对于C22H30N7OCl[M+H]+计算为408.2507,实测为408.2502。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd13)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=H,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.49(d,J=5.0Hz,1H),8.21(br.s.,1H),7.62(br.s.,1H),7.47(s,2H),7.44(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.14(s,3H),2.27(s,6H);HRMS(ESI)对于C17H18N6O[M+H]+计算为323.1615,实测为323.1611。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd14)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=甲基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.45(s,1H),8.73(d,J=4.7Hz,1H),8.49(d,J=5.0Hz,1H),7.46(s,2H),7.39(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.14(s,3H),2.77(d,J=4.6Hz,3H),2.27(s,6H);HRMS(ESI)对于C18H20N6O[M+H]+计算为337.1772,实测为337.1775。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,N,1-三甲基-1H-吡唑-5-羧酰胺(cpd 15)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=二甲基氨基,R4=甲基]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),8.50(d,J=5.2Hz,1H),7.47(s,2H),7.27(d,J=5.0Hz,1H),7.04(s,1H),6.60(s,1H),3.96(s,3H),3.11(s,3H),3.04(s,3H),2.25(s,6H);HRMS(ESI)对于C19H22N6O[M+H]+计算为351.1928,实测为351.1925。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-甲氧基乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 16)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-甲氧基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.82(t,J=5.5Hz,1H),8.49(d,J=5.2Hz,1H),7.47(s,2H),7.45(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.14(s,3H),3.49-3.44(m,2H),3.43-3.38(m,2H),3.27(s,3H),2.27(s,6H);HRMS(ESI)对于C20H24N6O2[M+H]+计算为381.2034,实测为381.2034。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-氟乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 17)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-氟乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),9.01(t,J=5.5Hz,1H),8.50(d,J=5.0Hz,1H),7.49(s,1H),7.46(s,2H),7.25(d,J=5.2Hz,1H),6.61(s,1H),4.62-4.47(m,2H),4.15(s,3H),3.62-3.50(m,2H),2.27(s,6H);HRMS(ESI)对于C19H21N6OF[M+H]+计算为369.1834,实测为369.1831。
3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-N-[2-(二甲基氨基)乙基]-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 18)[(I),R1=3,5-双(三氟甲基)苯基,R2=甲基,R3=2-(二甲基氨基)乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.41(s,1H),9.72(br.s.,1H),8.98(t,J=5.5Hz,1H),8.66(d,J=5.2Hz,1H),8.60(s,2H),7.62(s,1H),7.45(s,1H),7.42(d,J=5.0Hz,1H),4.17(s,3H),3.61(q,J=5.8Hz,2H),3.26(t,J=5.0Hz,1H),2.84(s,6H);HRMS(ESI)对于C21H22N7OF6Cl[M+H]+计算为502.1785,实测为502.1777。
3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 19)[(I),R1=3,5-双(三氟甲基)苯基,R2=甲基,R3=(2S)-1-羟基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.41(s,1H),8.64(d,J=5.2Hz,1H),8.61(s,2H),8.37(d,J=8.1Hz,1H),7.61(s,1H),7.44(s,1H),7.41(d,J=5.2Hz,1H),4.75(t,J=5.8Hz,1H),4.13(s,3H),4.03-3.92(m,1H),3.45(td,J=5.6,10.9Hz,1H),3.34-3.30(m,1H),1.13(d,J=6.7Hz,3H);HRMS(ESI)对于C20H18N6O2F6[M+H]+计算为489.1468,实测为489.146。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(1H-吡唑-3-基)-1H-吡唑-5-羧酰胺(cpd 20)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=1H-吡唑-3-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 12.50(br.s.,1H),11.16(s,1H),9.49(s,1H),8.51(d,J=5.2Hz,1H),7.72(s,1H),7.68(d,J=2.1Hz,1H),7.48(s,2H),7.26(d,J=5.0Hz,1H),6.61(br.s,2H),4.19(s,3H),2.27(s,6H);HRMS(ESI)对于C20H20N8O[M+H]+计算为389.1833,实测为389.1833。
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)(4-甲基哌嗪-1-基)甲酮(cpd 21)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=4-甲基哌嗪-1-基]
1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H),8.50(d,J=5.0Hz,1H),7.47(s,2H),7.27(d,J=5.0Hz,1H),6.97(s,1H),6.61(s,1H),3.95(s,3H),3.79-3.45(m,4H),2.37(br.s.,4H),2.26(s,6H),2.21(s,3H);HRMS(ESI)对于C22H27N7O[M+H]+计算为406.235,实测为406.2351。
N-[2-(乙酰基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 22)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-乙酰氨基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.79(t,J=5.6Hz,1H),8.49(d,J=5.0Hz,1H),7.98(t,J=5.7Hz,1H),7.46(s,2H),7.42(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.14(s,3H),3.31-3.25(m,2H),3.24-3.16(m,2H),2.27(s,6H),1.81(s,3H);HRMS(ESI)对于C21H25N7O2[M+H]+计算为408.2143,实测为408.2156。
N-(2-氨基-2-氧代乙基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 23)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-氨基-2-氧代乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.94(t,J=6.0Hz,1H),8.50(d,J=5.0Hz,1H),7.48(s,1H),7.46(s,2H),7.44(br.s,1H),7.26(d,J=5.2Hz,1H),7.09(br.s,1H),6.61(s,1H),4.14(s,3H),3.80(d,J=6.1Hz,2H),2.27(s,6H);HRMS(ESI)对于C19H21N7O2[M+H]+计算为380.183,实测为380.1829。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(2,2,2-三氟乙基)-1H-吡唑-5-羧酰胺(cpd 24)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2,2,2-三氟乙基氨基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),9.43(t,J=6.3Hz,1H),8.51(d,J=5.0Hz,1H),7.56(s,1H),7.47(s,2H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.15(s,3H),4.09(dq,J=6.1,9.6Hz,2H),2.27(s,6H);HRMS(ESI)对于C19H19N6OF3[M+H]+计算为405.1645,实测为405.1648。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(1-甲基-1H-咪唑-5-基)甲基]-1H-吡唑-5-羧酰胺(cpd 25)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(3-甲基咪唑-4-基)甲基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.45(s,1H),9.16(t,J=5.3Hz,1H),8.49(d,J=5.0Hz,1H),7.56(s,1H),7.48(s,1H),7.46(s,2H),7.25(d,J=5.2Hz,1H),6.84(s,1H),6.61(s,1H),4.44(d,J=5.3Hz,2H),4.15(s,3H),3.63(s,3H),2.25(s,6H);HRMS(ESI)对于C22H24N8O[M+H]+计算为417.2146,实测为417.2155。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 26)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-羟基-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.48(s,1H),8.49(d,J=5.0Hz,1H),8.36(d,J=9.0Hz,1H),7.51(s,1H),7.49(s,2H),7.26(d,J=5.0Hz,1H),6.61(s,1H),4.59(t,J=5.6Hz,1H),4.12(s,3H),3.86-3.74(m,1H),3.57-3.50(m,1H),3.50-3.44(m,1H),2.26(s,6H),1.97-1.85(m,J=6.7,6.7,6.7,6.7,6.7,6.7,6.7Hz,1H),0.91(d,J=6.9Hz,3H),0.89(d,J=6.9Hz,3H);HRMS(ESI)对于C22H28N6O2[M+H]+计算为409.2347,实测为409.2352。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(吡啶-2-基甲基)-1H-吡唑-5-羧酰胺(cpd 27)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=吡啶-2-基甲基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.48(s,1H),9.39(t,J=6.0Hz,1H),8.52(ddd,J=0.9,1.6,4.7Hz,1H),8.50(d,J=5.0Hz,1H),7.78(dt,J=1.8,7.7Hz,1H),7.55(s,1H),7.47(s,2H),7.36(d,J=7.8Hz,1H),7.29(ddd,J=0.9,4.8,7.4Hz,1H),7.27(d,J=5.0Hz,1H),6.61(s,1H),4.56(d,J=5.9Hz,2H),4.16(s,3H),2.26(s,6H);HRMS(ESI)对于C23H23N7O[M+H]+计算为414.2037,实测为414.2043。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(1H-咪唑-2-基甲基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 28)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=1H-咪唑-2-基甲基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 11.85(br.s.,1H),9.46(s,1H),9.24(t,J=5.7Hz,1H),8.49(d,J=5.0Hz,1H),7.50(s,1H),7.45(s,2H),7.25(d,J=5.2Hz,1H),7.03(s,1H),6.82(s,1H),6.60(s,1H),4.47(d,J=5.6Hz,2H),4.17(s,3H),2.26(s,6H);HRMS(ESI)对于C21H22N8O[M+H]+计算为403.199,实测为403.1994。
N-[(2R)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 29)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(2R)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.59(s,1H),8.52(d,J=5.03Hz,1H),8.42(d,J=8.39Hz,1H),7.45(s,1H),7.28(d,J=5.03Hz,1H),7.17(d,J=2.29Hz,2H),6.13(t,J=2.21Hz,1H),4.12(s,3H),3.90(d,J=7.93Hz,1H),3.75(s,6H),3.05-3.19(m,4H),2.31-2.48(m,2H),1.94(t,J=6.94Hz,2H),1.09(d,J=6.71Hz,3H);HRMS(ESI)对于C23H29N7O3[M+H]+计算为452.2405,实测为452.2407。
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 30)[(I),R1=氧杂环己烷-4-基,R2=甲基,R3=(2S)-1-(二甲基氨基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 8.39(d,J=8.2Hz,1H),8.30(d,J=5.0Hz,1H),7.37(s,1H),7.14-7.07(m,1H),7.05-7.02(m,1H),4.16-4.07(m,4H),4.01(br.s.,1H),3.88(d,J=11.6Hz,2H),3.40(t,J=11.2Hz,2H),2.40-2.35(m,1H),2.20(d,J=6.7Hz,1H),2.16(s,6H),1.84(d,J=12.4Hz,2H),1.60-1.48(m,2H),1.12(d,J=6.6Hz,3H);HRMS(ESI)对于C19H29N7O2[M+H]+计算为388.2456,实测为388.2455。
N-(1-氮杂双环[2.2.2]辛-3-基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 31)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=1-氮杂双环[2.2.2]辛烷-3-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.69(d,J=6.9Hz,1H),8.49(d,J=5.0Hz,1H),7.53(s,1H),7.51(s,2H),7.27(d,J=5.0Hz,1H),6.62(s,1H),4.12(s,3H),3.93(br.q,J=7.5Hz,1H),3.08(ddd,J=2.2,10.2,13.3Hz,1H),2.86(dddd,J=2.1,4.8,10.8,13.1Hz,1H),2.75-2.60(m,4H),2.27(s,6H),1.85(sxt,J=2.8Hz,1H),1.83-1.71(m,1H),1.65-1.50(m,2H),1.32(dd,J=11.3,13.6Hz,1H);HRMS(ESI)对于C24H29N7O[M+H]+计算为432.2507,实测为432.2505。
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸((1R,2R)-2-羟基-环己基)-酰胺(cpd 32)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1R,2R)-2-羟基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.49(d,J=5.0Hz,1H),8.46(d,J=8.4Hz,1H),7.47(s,3H),7.25(d,J=5.2Hz,1H),6.61(s,1H),4.61(d,J=5.2Hz,1H),4.13(s,3H),3.66-3.54(m,1H),2.27(s,6H),1.90(d,J=9.8Hz,1H),1.83(d,J=8.8Hz,1H),1.65(d,J=8.5Hz,2H),1.33-1.10(m,4H);HRMS(ESI)对于C23H28N6O2[M+H]+计算为421.2347,实测为421.2349。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 33)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-羟基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.49(d,J=5.0Hz,1H),8.38(d,J=8.7Hz,1H),7.49(s,1H),7.48(s,2H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.71(t,J=5.6Hz,1H),4.13(s,3H),3.90-3.75(m,1H),2.26(s,6H),1.74-1.58(m,1H),1.51-1.38(m,1H),0.88(t,J=7.5Hz,3H);HRMS(ESI)对于C21H26N6O2[M+H]+计算为395.219,实测为395.2185。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-羟基乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 34)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-羟基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.45(s,1H),8.71(t,J=5.6Hz,1H),8.49(d,J=5.0Hz,1H),7.46(s,2H),7.44(s,1H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.76(t,J=5.7Hz,1H),4.13(s,3H),3.51(q,J=6.0Hz,2H),3.31(q,J=6.0Hz,2H),2.27(s,6H);HRMS(ESI)对于C19H22N6O2[M+H]+计算为367.1877,实测为367.1872。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,4-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 35)[(I),R1=3,4-二甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.44(s,1H),8.47(d,J=5.0Hz,1H),8.42(d,J=8.2Hz,1H),7.68(d,J=1.8Hz,1H),7.46(s,1H),7.23(dd,J=2.4,8.5Hz,2H),6.89(d,J=8.8Hz,1H),4.13(s,3H),3.91(td,J=7.0,14.4Hz,1H),3.79(s,3H),3.72(s,3H),3.22-3.01(m,4H),2.55-2.35(m.与水部分重叠,2H),1.95(quin,J=6.8Hz,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C23H29N7O3[M+H]+计算为452.2405,实测为452.2413。
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)(哌嗪-1-基)甲酮盐酸盐(cpd 36)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=哌嗪-1-基氨基]
1H NMR(500MHz,DMSO-d6)δppm 9.53(s,1H),9.13(br.s.,2H),8.50(d,J=5.0Hz,1H),7.47(s,2H),7.28(d,J=5.0Hz,1H),7.08(s,1H),6.61(s,1H),3.98(s,3H),3.84(br.s.,4H),3.21(br.s.,4H),2.26(s,6H);HRMS(ESI)对于C21H26N7OCl[M+H]+计算为392.2194,实测为392.2207。
N-[(1S,2R)-2-氨基环己基]-3-(2-{[3-甲氧基-5-(三氟甲基)苯基]氨基}嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 37)[(I),R1=3-甲氧基-5-(三氟甲基)苯基,R2=甲基,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.03(s,1H),8.59(d,J=5.2Hz,1H),8.39(d,J=7.9Hz,1H),7.97(s,1H),7.88(br.s.,3H),7.82(t,J=1.8Hz,1H),7.57(s,1H),7.37(d,J=5.0Hz,1H),6.83(s,1H),4.33(br.s.,1H),4.14(s,3H),3.85(s,3H),1.87-1.56(m,6H),1.52-1.32(m,2H);HRMS(ESI)对于C23H27N7O2F3Cl[M+H]+计算为490.2173,实测为490.2173。
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3-氯-1-甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 38)[(I),R1=3-氯-1-甲基吲哚-5-基,R2=甲基,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.58(s,1H),8.50(d,J=5.0Hz,1H),8.45(d,J=7.8Hz,1H),8.34(br.s.,1H),7.88(br.s.,3H),7.59(s,1H),7.51-7.45(m,2H),7.45-7.40(m,1H),7.27(d,J=5.0Hz,1H),4.32(br.s.,1H),4.14(s,3H),3.76(s,3H),3.42(s,1H),1.88-1.56(m,6H),1.53-1.32(m,2H);HRMS(ESI)对于C24H28N8OCl2[M+H]+计算为479.2069,实测为479.2074。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 39)[(I),R1=3-甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.63(s,1H),8.51(d,J=5.0Hz,1H),8.44(d,J=8.4Hz,1H),7.65-7.59(m,1H),7.46(s,1H),7.38(dd,J=1.1,8.2Hz,1H),7.28(d,J=5.0Hz,1H),7.19(t,J=8.1Hz,1H),6.54(dd,J=2.1,7.8Hz,1H),4.13(s,3H),3.99-3.87(m,1H),3.77(s,3H),3.16(d,J=3.4Hz,4H),2.55-2.35(m.与水部分重叠,2H)2.07-1.88(m,2H),1.11(d,J=6.7Hz,3H);HRMS(ESI)对于C22H27N7O2[M+H]+计算为422.2299,实测为422.2306。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 40)[(I),R1=3,5-二氟苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.10(s,1H),8.59(d,J=5.2Hz,1H),8.45(d,J=8.2Hz,1H),7.67-7.57(m,2H),7.45(s,1H),7.38(d,J=5.2Hz,1H),6.76(tt,J=2.3,9.3Hz,1H),4.14(s,3H),3.96-3.86(m,1H),3.24-3.03(m,4H),2.49-2.36(m,2H),1.94(quin,J=6.9Hz,2H),1.16-1.04(m,3H);HRMS(ESI)对于C21H23N7OF2[M+H]+计算为428.2005,实测为428.2006。
N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 41)[(I),R1=3-甲基苯基,R2=甲基,R3=(2S)-1-羟基-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.56(s,1H),8.50(d,J=5.0Hz,1H),8.35(d,J=9.0Hz,1H),7.75(s,1H),7.59(d,J=8.5Hz,1H),7.52(s,1H),7.28(d,J=5.0Hz,1H),7.17(t,J=7.8Hz,1H),6.78(d,J=7.5Hz,1H),4.60(t,J=5.6Hz,1H),4.13(s,3H),3.84-3.74(m,1H),3.59-3.44(m,2H),2.31(s,3H),1.91(d,J=6.9Hz,1H),0.91(dd,J=6.9,10.2Hz,6H);HRMS(ESI)对于C21H26N6O2[M+H]+计算为395.219,实测为395.2196。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 42)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1,1,1-三氟丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),9.23(d,J=8.7Hz,1H),8.51(d,J=5.0Hz,1H),7.60(s,1H),7.48(s,2H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.81(qd,J=7.6,15.3Hz,1H),4.14(s,3H),2.27(s,6H),1.36(d,J=7.2Hz,3H);HRMS(ESI)对于C20H21N6OF3[M+H]+计算为419.1802,实测为419.1813。
N-[3-(二甲基氨基)丙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 43)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=3-(二甲基氨基)丙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.78(t,J=5.6Hz,1H),8.49(d,J=5.0Hz,1H),7.47(s,2H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.13(s,3H),3.29-3.23(m,2H),2.27(s,6H),2.26-2.22(m,2H),2.13(s,6H),1.64(quin,J=7.0Hz,2H);HRMS(ESI)对于C22H29N7O[M+H]+计算为408.2507,实测为408.2499。
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(2S)-2-(丙烷-2-基)氮丙啶-1-基]甲酮(cpd 44)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(1R,2S)-2-丙烷-2-基氮丙啶-1-基氨基]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),8.50(d,J=5.2Hz,1H),7.47(s,2H),7.28(d,J=5.0Hz,1H),7.26(s,1H),6.61(s,1H),4.49-4.39(m,1H),4.23(s,3H),4.18-4.10(m,2H),2.25(s,6H),1.78(qd,J=6.6,13.2Hz,1H),0.97(d,J=6.7Hz,3H),0.91(d,J=6.7Hz,3H);HRMS(ESI)对于C22H26N6O[M+H]+计算为391.2241,实测为391.2246。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2,2-二甲基丙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 45)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2,2-二甲基丙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.72(t,J=6.3Hz,1H),8.49(d,J=5.0Hz,1H),7.49(s,2H),7.27(d,J=5.0Hz,1H),6.61(s,1H),4.12(s,3H),3.08(d,J=6.4Hz,2H),2.26(s,6H),0.91(s,9H);HRMS(ESI)对于C22H28N6O[M+H]+计算为393.2398,实测为393.2399。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(2-甲基丙基)-1H-吡唑-5-羧酰胺(cpd 46)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-甲基丙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.48(s,1H),8.78(t,J=5.9Hz,1H),8.49(d,J=5.0Hz,1H),7.48(s,2H),7.44(s,1H),7.26(d,J=5.0Hz,1H),6.61(s,1H),4.13(s,3H),3.07(t,J=6.4Hz,2H),2.27(s,6H),1.84(quin,J=6.7,13.5Hz,1H),0.90(d,J=6.7Hz,6H);HRMS(ESI)对于C21H26N6O[M+H]+计算为379.2241,实测为379.2254。
N-(环丙基甲基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 47)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=环丙基甲基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.87(t,J=5.7Hz,1H),8.49(d,J=5.0Hz,1H),7.48(s,2H),7.46(s,1H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.14(s,3H),3.13(t,J=6.3Hz,2H),2.27(s,6H),1.09-0.95(m,1H),0.52-0.37(m,2H),0.29-0.18(m,2H);HRMS(ESI)对于C21H24N6O[M+H]+计算为377.2085,实测为377.209。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氟-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 48)[(I),R1=3-氟-5-甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.84(s,1H),8.56(d,J=5.2Hz,1H),8.47(d,J=6.6Hz,1H),7.45(s,1H),7.39(s,1H),7.38-7.34(m,1H),7.33(d,J=5.0Hz,1H),6.41(td,J=2.3,10.8Hz,1H),4.14(s,3H),4.03-3.88(m,1H),3.78(s,3H),3.30-3.00(m,4H),2.54-2.38(m.与水部分重叠,2H)2.12-1.89(m,2H),1.11(d,J=6.9Hz,3H);HRMS(ESI)对于C22H26N7O2F[M+H]+计算为440.2205,实测为440.2202。
3-{2-[(4,6-二甲基吡啶-2-基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 49)[(I),R1=4,6-二甲基吡啶-2-基,R2=甲基,R3=(2S)-1-羟基-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.44(s,1H),8.56(d,J=5.0Hz,1H),8.38(d,J=9.0Hz,1H),8.12(s,1H),7.55(s,1H),7.37(d,J=5.0Hz,1H),6.73(s,1H),4.60(br.s.,1H),4.13(s,3H),3.87-3.72(m,1H),3.59-3.43(m,2H),2.36(s,3H),2.33(s,3H),1.92(qd,J=6.7,13.5Hz,1H),0.91(dd,J=6.8,9.5Hz,6H);HRMS(ESI)对于C21H27N7O2[M+H]+计算为410.2299,实测为410.2301。
3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 50)[(I),R1=3,5-二氟苯基,R2=甲基,R3=(2S)-1,1,1-三氟丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.12(s,1H),9.20(d,J=8.7Hz,1H),8.61(d,J=5.2Hz,1H),7.68-7.57(m,3H),7.39(d,J=5.0Hz,1H),6.81-6.70(m,1H),4.90-4.73(m,1H),4.15(s,3H),1.37(d,J=7.2Hz,3H);HRMS(ESI)对于C18H15N6OF5[M+H]+计算为427.13,实测为427.1308。
1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 51)[(I),R1=3-甲基苯基,R2=甲基,R3=(2S)-1,1,1-三氟丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.57(s,1H),9.22(d,J=8.7Hz,1H),8.51(d,J=5.2Hz,1H),7.72(s,1H),7.64-7.57(m,2H),7.28(d,J=5.2Hz,1H),7.18(t,J=7.9Hz,1H),6.79(d,J=7.5Hz,1H),4.89-4.73(m,1H),4.15(s,3H),2.31(s,3H),1.37(d,J=7.0Hz,3H);HRMS(ESI)对于C19H19N6OF3[M+H]+计算为405.1645,实测为405.1649。
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基-3-苯基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 52)[(I),R1=3-氯-4-(4-甲基哌嗪-1-基)苯基,R2=甲基,R3=(2S)-1-羟基-3-苯基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.68(s,1H),8.50(d,J=5.2Hz,1H),8.50(d,J=8.2Hz,1H),7.92(d,J=2.4Hz,1H),7.82(dd,J=2.0,8.8Hz,1H),7.42(s,1H),7.32-7.22(m,5H),7.16(d,J=8.8Hz,1H),7.21-7.11(m,1H),4.89(t,J=5.7Hz,1H),4.17-4.07(m,1H),4.03(s,3H),3.56-3.48(m,1H),3.48-3.40(m,1H),2.96(dd,J=4.7,13.9Hz,1H),2.94(br.s,4H),2.75(dd,J=9.7,13.7Hz,1H),2.48(br.s.,4H),2.23(s,3H);HRMS(ESI)对于C29H33N8O2Cl[M+H]+计算为561.2488,实测为561.2498。
N-[(1S,2S)-2-氨基环己基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 53)[(I),R1=3-甲基苯基,R2=甲基,R3=(1S,2S)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.55(s,1H),8.54-8.44(m,2H),7.69(s,1H),7.63(d,J=8.2Hz,1H),7.51-7.48(m,1H),7.27(d,J=5.0Hz,1H),7.19(t,J=7.8Hz,1H),6.79(d,J=7.5Hz,1H),4.16-4.10(m,3H),3.45(d,J=5.2Hz,1H),2.60-2.53(m,1H),2.31(s,3H),1.91-1.80(m,2H),1.66(br.s.,3H),1.38-1.02(m,5H);HRMS(ESI)对于C22H27N7O[M+H]+计算为406.235,实测为406.2348。
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 54)[(I),R1=3-氯-4-(4-甲基哌嗪-1-基)苯基,R2=甲基,R3=(2S)-1,1,1-三氟丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.69(s,1H),9.19(d,J=8.8Hz,1H),8.52(d,J=5.0Hz,1H),7.99(d,J=2.4Hz,1H),7.71(dd,J=2.5,8.8Hz,1H),7.58(s,1H),7.29(d,J=5.2Hz,1H),7.13(d,J=8.8Hz,1H),4.82(qd,J=7.6,15.4Hz,1H),4.14(s,3H),2.93(br.s.,4H),2.47(br.s.,4H),2.23(s,3H),1.37(d,J=7.2Hz,3H);HRMS(ESI)对于C23H26N8OF3Cl[M+H]+计算为523.1943,实测为523.1951。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 55)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1,1,1-三氟丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),9.14(d,J=9.0Hz,1H),8.51(d,J=5.0Hz,1H),7.63(s,1H),7.49(s,2H),7.27(d,J=5.2Hz,1H),6.62(s,1H),4.68-4.50(m,1H),4.15(s,3H),2.27(s,6H),1.89-1.66(m,2H),0.96(t,J=7.3Hz,3H);HRMS(ESI)对于C21H23N6OF3[M+H]+计算为433.1958,实测为433.1959。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2R)-1,1,1-三氟丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 56)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2R)-1,1,1-三氟丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),9.14(d,J=9.0Hz,1H),8.51(d,J=5.0Hz,1H),7.63(s,1H),7.49(s,2H),7.27(d,J=5.2Hz,1H),6.62(s,1H),4.68-4.49(m,1H),4.15(s,3H),2.27(s,6H),1.88-1.64(m,2H),0.96(t,J=7.4Hz,3H);HRMS(ESI)对于C21H23N6OF3[M+H]+计算为433.1958,实测为433.1957。
N-[(2S)-1-(3,3-二氟氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 57)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-(3,3-二氟氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.54(d,J=8.4Hz,1H),8.49(d,J=5.2Hz,1H),7.48(s,2H),7.45(s,1H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.13(s,3H),3.98(quin,J=6.9,13.9Hz,1H),3.73-3.53(m,4H),2.70-2.56(m,2H),2.27(s,6H),1.13(d,J=6.7Hz,3H);HRMS(ESI)对于C23H27N7OF2[M+H]+计算为456.2318,实测为456.232。
1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-3-{2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 58)[(I),R1=3,4,5-三甲氧基苯基,R2=甲基,R3=(2S)-1-吡咯烷-1-基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.53(s,1H),8.51(d,J=5.03Hz,2H),7.50(s,1H),7.31(s,2H),7.26(d,J=5.19Hz,1H),4.07-4.20(m,4H),3.80(s,6H),3.63(s,3H),2.60-2.38(m.与水部分重叠,6H),1.69(br.s.,4H),1.08-1.20(m,3H);HRMS(ESI)对于C25H33N7O4[M+H]+计算为496.2667,实测为496.2666。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氯-1-甲基-1-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 59)[(I),R1=3-氯-1-甲基吲哚-5-基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.56(s,1H),8.49(d,J=5.0Hz,1H),8.41(d,J=8.4Hz,1H),8.28(s,1H),7.51(dd,J=2.0,9.0Hz,1H),7.47(s,1H),7.44(s,1H),7.42(d,J=8.8Hz,1H),7.24(d,J=5.0Hz,1H),4.12(s,3H),3.97-3.84(m,1H),3.76(s,3H),3.23-3.05(m,4H),2.46(dd,J=6.9,11.6Hz,1H),2.37(dd,J=6.7,11.6Hz,1H),1.95(quin,J=6.9Hz,2H),1.11(d,J=6.7Hz,3H);HRMS(ESI)对于C24H27N8OCl[M+H]+计算为479.2069,实测为479.2068。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 60)[(I),R1=3,5-二氯苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.08(s,1H),8.60(d,J=5.2Hz,1H),8.45(d,J=8.4Hz,1H),7.98(d,J=2.0Hz,2H),7.43(s,1H),7.38(d,J=5.0Hz,1H),7.14(t,J=1.8Hz,1H),4.14(s,3H),3.93(br.s.,1H),3.17(br.s,4H),2.42(br.s.,2H),1.96(br.s,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C21H23N7OCl2[M+H]+计算为460.1414,实测为460.1415。
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 61)[(I),R1=3,5-二氯苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.10(s,1H),8.60(d,J=5.2Hz,1H),8.32(d,J=9.2Hz,1H),7.99(d,J=2.0Hz,2H),7.45(s,1H),7.40(d,J=5.2Hz,1H),7.13(t,J=1.9Hz,1H),4.12(s,3H),3.83-3.68(m,1H),3.22-2.95(m,4H),2.47(d,J=6.1Hz,2H),1.92(quin,J=6.9Hz,2H),1.80(dspt,J=6.4Hz,1H),0.87(t,J=7.3Hz,6H);HRMS(ESI)对于C23H27N7OCl2[M+H]+计算为488.1727,实测为488.174。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-(2-{[3-(三氟甲基)苯基]氨基}嘧啶-4-基)-1H-吡唑-5-羧酰胺(cpd 62)[(I),R1=3-(三氟甲基)苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.03(s,1H),8.57(d,J=5.2Hz,1H),8.41(d,J=8.4Hz,1H),8.36(t,J=1.9Hz,1H),8.08(dd,J=1.3,8.2Hz,1H),7.54(t,J=8.0Hz,1H),7.43(s,1H),7.35(d,J=5.2Hz,1H),7.30(d,J=7.6Hz,1H),4.13(s,3H),3.97-3.85(m,1H),3.20-3.07(m,4H),2.48-2.44(m,1H),2.41-2.37(m,1H),2.02-1.88(m,2H),1.11(d,J=6.7Hz,3H);HRMS(ESI)对于C22H24N7OF3[M+H]+计算为460.2067,实测为460.2072。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 63)[(I),R1=3,5-双(三氟甲基)苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.40(s,1H),8.64(d,J=5.0Hz,1H),8.60(s,2H),8.39(d,J=8.4Hz,1H),7.61(s,1H),7.42(d,J=5.2Hz,1H),7.40(s,1H),4.13(s,3H),3.97-3.85(m,1H),3.22-3.05(m,4H),2.47-2.42(m,1H),2.42-2.37(m,1H),2.01-1.87(m,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C23H23N7OF6[M+H]+计算为528.1941,实测为528.1951。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 64)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.59(s,1H),8.52(d,J=5.0Hz,1H),8.42(d,J=8.4Hz,1H),7.46(s,1H),7.28(d,J=5.0Hz,1H),7.17(d,J=2.1Hz,2H),6.13(t,J=2.2Hz,1H),4.13(s,3H),3.96-3.85(m,1H),3.75(s,6H),3.20-3.05(m,4H),2.48-2.32(m,2H),1.95(t,J=6.9Hz,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C23H29N7O3[M+H]+计算为452.2405,实测为452.2408。
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-3-{2-[(3-氟-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 65)[(I),R1=3-氟-5-甲氧基苯基,R2=甲基,R3=(2S)-1-(二甲基氨基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.84(s,1H),8.56(d,J=5.19Hz,1H),8.49(br.s.,1H),7.46(s,1H),7.40(s,1H),7.32-7.37(m,2H),6.41(dt,J=10.87,2.27Hz,1H),4.14(m,4H),3.78(s,3H),2.54-2.05(m.br.,8H)1.14(d,J=6.41Hz,3H);HRMS(ESI)对于C21H26N7O2F[M+H]+计算为428.2205,实测为428.2202。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-[2-(1,3-苯并间二氧杂环戊烯-5-基氨基)嘧啶-4-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 66)[(I),R1=1,3-苯并间二氧杂环戊烯-5-基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.46(d,J=5.0Hz,1H),8.43(d,J=8.2Hz,1H),7.48(d,J=2.0Hz,1H),7.41(s,1H),7.25(dd,J=2.1,8.5Hz,1H),7.24(d,J=5.0Hz,0H),6.85(d,J=8.5Hz,1H),5.97(s,2H),4.13(s,3H),3.97-3.84(m,1H),3.21-3.04(m,4H),2.47(dd,J=7.0,11.6Hz,1H),2.38(dd,J=6.1,11.6Hz,1H),1.95(quin,J=6.9Hz,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C22H25N7O3[M+H]+计算为436.2092,实测为436.21。
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 67)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(2S)-1-(二甲基氨基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.60(s,1H),8.52(d,J=5.2Hz,1H),8.46(d,J=8.4Hz,1H),7.46(s,1H),7.28(d,J=5.0Hz,1H),7.17(d,J=2.3Hz,2H),6.13(t,J=2.2Hz,1H),4.13(s,3H),4.17-4.07(m,1H),3.75(s,6H),2.43-2.31(m,1H),2.18(br.s.,7H),1.12(d,J=6.7Hz,3H);HRMS(ESI)对于C22H29N7O3[M+H]+计算为440.2405,实测为440.2404。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-{2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 68)[(I),R1=3,4,5-三甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H),8.50(d,J=5.0Hz,1H),8.40(d,J=8.2Hz,1H),7.49(s,1H),7.31(s,2H),7.26(d,J=5.2Hz,1H),4.13(s,3H),3.94-3.86(m,1H),3.80(s,6H),3.63(s,3H),3.13(dd,J=6.8,16.2Hz,4H),2.45-2.31(m,2H),2.04-1.87(m,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C24H31N7O4[M+H]+计算为482.2511,实测为482.2514。
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 69)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(2S)-1-吡咯烷-1-基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.60(s,1H),8.52(d,J=5.0Hz,1H),8.48(d,J=8.4Hz,1H),7.46(s,1H),7.28(d,J=5.0Hz,1H),7.18(d,J=2.3Hz,2H),6.13(t,J=2.3Hz,1H),4.12(s,3H),4.12-4.06(m,1H),3.75(s,6H),2.49-2.39(m,5H),1.67(t,J=2.9Hz,4H),1.14(d,J=6.6Hz,3H);HRMS(ESI)对于C24H31N7O3[M+H]+计算为466.2561,实测为466.256。
3-{2-[(3-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 70)[(I),R1=3-甲氧基苯基,R2=甲基,R3=(2S)-1-吡咯烷-1-基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.63(s,1H),8.55-8.46(m,2H),7.65-7.61(m,2H),7.37(dd,J=1.2,8.1Hz,1H),7.29(d,J=5.2Hz,1H),7.19(t,J=8.2Hz,1H),6.54(dd,J=1.8,8.1Hz,1H),4.13(s,4H),3.77(s,3H),2.62-2.51(m,6H),1.69(br.s.,4H),1.16(d,J=6.7Hz,3H);HRMS(ESI)对于C23H29N7O2[M+H]+计算为436.2456,实测为436.2455。
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)-1-氧代丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 71)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(2S)-1-(二甲基氨基)-1-氧代丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.62(s,1H),8.87(d,J=7.5Hz,1H),8.52(d,J=5.0Hz,1H),7.59(s,1H),7.28(d,J=5.0Hz,1H),7.18(d,J=2.1Hz,2H),6.12(t,J=2.2Hz,1H),4.88(t,J=7.2Hz,1H),4.12(s,3H),3.75(s,6H),3.06(s,3H),2.86(s,3H),1.32-1.26(m,3H);HRMS(ESI)对于C22H27N7O4[M+H]+计算为454.2198,实测为454.2198。
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[2-(二甲基氨基)乙基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 72)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=2-(二甲基氨基)乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.60(s,1H),8.64(t,J=5.7Hz,1H),8.52(d,J=5.0Hz,1H),7.42(s,1H),7.28(d,J=5.0Hz,1H),7.17(d,J=2.3Hz,2H),6.13(t,J=2.2Hz,1H),4.13(s,3H),3.75(s,6H),2.40(t,J=6.7Hz,2H),2.19(s,6H);HRMS(ESI)对于C21H27N7O3[M+H]+计算为426.2248,实测为426.224。
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-3-{2-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 73)[(I),R1=1,5-二甲基吡唑-3-基,R2=甲基,R3=(2S)-1-(二甲基氨基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.52(s,1H),8.49(d,J=8.2Hz,1H),8.42(d,J=5.2Hz,1H),7.44(s,1H),7.21(d,J=5.0Hz,1H),6.56(s,1H),4.17-4.04(m,4H),3.63(s,3H),2.40(dd,J=7.9,12.0Hz,1H),2.26(s,3H),2.22-2.19(m,1H),2.17(s,6H),1.16-1.11(m,3H);HRMS(ESI)对于C19H27N9O[M+H]+计算为398.2412,实测为398.2413。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 74)[(I),R1=1,5-二甲基吡唑-3-基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.53(s,1H),8.47(d,J=8.2Hz,1H),8.42(d,J=5.0Hz,1H),7.44(s,1H),7.21(d,J=5.0Hz,1H),6.57(s,1H),4.13(s,3H),3.97-3.87(m,1H),3.63(s,3H),3.29-3.02(m,4H),2.47(d,J=7.0Hz,0H),2.42-2.35(m,1H),2.27(s,3H),1.94(quin,J=6.9Hz,2H),1.11(d,J=6.7Hz,3H);HRMS(ESI)对于C20H27N9O[M+H]+计算为410.2412,实测为410.2407。
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-3-{2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 75)[(I),R1=1-甲基吡唑-4-基,R2=甲基,R3=(2S)-1-(二甲基氨基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(br.s.,1H),8.46(d,J=8.4Hz,1H),8.43(d,J=5.0Hz,1H),7.97(br.s.,1H),7.61-7.40(m,2H),7.17(d,J=5.0Hz,1H),4.14(s,3H),4.11(s,0H),3.84(s,3H),2.40(dd,J=7.9,12.2Hz,1H),2.24-2.19(m,1H),2.17(s,6H),1.14(d,J=6.7Hz,3H);HRMS(ESI)对于C20H27N9O[M+H]+计算为410.2412,实测为410.2407。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 76)[(I),R1=氧杂环己烷-4-基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 8.36(d,J=8.2Hz,1H),8.30(d,J=4.9Hz,1H),7.37(s,1H),7.09(br.s.,1H),7.03(d,J=5.0Hz,1H),4.11(s,3H),4.06-3.95(m,1H),3.94-3.83(m,3H),3.40(t,J=11.4Hz,2H),3.12(qd,J=6.5,19.5Hz,4H),2.48-2.44(m,1H),2.39-2.33(m,1H),1.94(quin,J=6.9Hz,2H),1.84(d,J=12.4Hz,2H),1.59-1.47(m,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C20H29N7O2[M+H]+计算为400.2456,实测为400.2455。
N,N,1-三甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 77)[(I),R1=氧杂环己烷-4-基,R2=甲基,R3=甲基,R4=甲基]
1H NMR(500MHz,DMSO-d6)δppm 8.30(d,J=4.9Hz,1H),7.15(d,J=7.6Hz,1H),7.03(d,J=5.2Hz,1H),6.96(br.s.,1H),3.98(br.s.,1H),3.91(s,3H),3.89-3.84(m,2H),3.43-3.36(m,1H),3.04(d,J=19.7Hz,6H),1.83(d,J=12.0Hz,2H),1.56-1.44(m,2H);HRMS(ESI)对于C16H22N6O2[M+H]+计算为331.1877,实测为331.187。
3-{2-[(3-氰基-5-甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 78)[(I),R1=3-氰基-5-甲氧基苯基,R2=甲基,R3=(2S)-1-(二甲基氨基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.01(s,1H),8.59(d,J=5.2Hz,1H),8.44(d,J=8.4Hz,1H),7.91(t,J=2.1Hz,1H),7.83(t,J=1.5Hz,1H),7.46(s,1H),7.36(d,J=5.2Hz,1H),7.01(dd,J=1.3,2.4Hz,1H),4.13(s,3H),4.10(s,0H),3.83(s,3H),2.41-2.34(m,1H),2.22-2.18(m,1H),2.17(s,5H),1.13(d,J=6.6Hz,3H);HRMS(ESI)对于C22H26N8O2[M+H]+计算为435.2252,实测为435.2252。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氰基-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 79)[(I),R1=3-氰基-5-甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.01(s,1H),8.59(d,J=5.2Hz,1H),8.41(d,J=8.4Hz,1H),7.91(t,J=2.1Hz,1H),7.83(t,J=1.5Hz,1H),7.46(s,1H),7.36(d,J=5.0Hz,1H),7.01(dd,J=1.4,2.3Hz,1H),4.13(s,3H),3.96-3.87(m,1H),3.83(s,3H),3.19-3.06(m,4H),2.46(dd,J=7.0,11.6Hz,1H),2.40-2.33(m,1H),1.94(quin,J=7.0Hz,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C23H26N8O2[M+H]+计算为447.2252,实测为447.2251。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(5-甲氧基吡啶-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 80)[(I),R1=5-甲氧基吡啶-3-基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.89(s,1H),8.56(d,J=5.2Hz,1H),8.52(d,J=2.0Hz,1H),8.44(d,J=8.4Hz,1H),8.12(t,J=2.3Hz,1H),7.91(d,J=2.6Hz,1H),7.47(s,1H),7.34(d,J=5.0Hz,1H),4.14(s,3H),3.95-3.88(m,1H),3.86(s,3H),3.19-3.06(m,4H),2.46(dd,J=7.0,11.7Hz,1H),2.40-2.32(m,1H),1.94(quin,J=6.9Hz,2H),1.10(d,J=6.7Hz,3H);HRMS(ESI)对于C21H26N8O2[M+H]+计算为423.2252,实测为423.2252。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(3S)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 81)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(3S)-哌啶-3-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.99-8.90(br.s.1H,8.85(d,J=7.8Hz,1H),8.87-8.80(br.s.,1H),8.50(d,J=5.03Hz,1H),7.52(s,1H),7.47(s,2H),7.26(d,J=5.2Hz,1H),6.62(s,1H),4.14(s,3H),3.33(m与水信号部分重叠,2H),3.22-3.14(m,1H),2.92-2.77(m,2H),2.27(s,6H),1.95-1.50(m,4H);HRMS(ESI)对于C22H28N7OCl[M+H]+计算为406.235,实测为406.2349。
N-(2-氨基环己基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 82)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm(s,1H),8.79(d,J=8.7Hz,1H),8.50(d,J=5.2Hz,1H),7.85(br.s.,3H),7.51(s,1H),7.48(s,2H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.15(s,3H),3.88-3.80(m,1H),3.00-2.90(m,1H),2.27(s,6H),2.10-1.20(m,8H);HRMS(ESI)对于C23H30N7OCl[M+H]+计算为420.2507,实测为420.2503。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(吡咯烷-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 83)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-吡咯烷-1-基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.86(br.s.,1H),8.50(d,J=5.0Hz,1H),7.48-7.42(m,3H),7.26(d,J=5.2Hz,1H),6.62(s,1H),4.15(s,3H),3.44(br.s.,2H),2.70(br.s.2H),1.79(br.s.4H),;HRMS(ESI)对于C23H29N7O[M+H]+计算为420.2507,实测为420.2491。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(哌啶-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 84)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=2-哌啶-1-基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.72(br.s.,1H),8.49(d,J=5.0Hz,1H),7.46(s,2H),7.41(s,1H),7.26(d,J=5.0Hz,1H),6.62(s,1H),4.14(s,3H),3.34(br.s.与水信号部分重叠,2H),2.41(br.s.,6H),2.27(s,6H),1.67-1.30(m,6H);HRMS(ESI)对于C24H31N7O[M+H]+计算为434.2663,实测为434.2661。
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(3R)-3-羟基吡咯烷-1-基]甲酮(cpd 85)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(3R)-3-羟基吡咯烷-1-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.53和9.52(2xs,1H),8.50(d,J=5.0Hz,1H),7.48(d,J=2.7Hz,2H),7.27(d,J=5.0Hz,1H),7.22和7.16(2xs,1H),6.60(s,1H),5.07(t,J=3.9Hz,1H),4.35和4.31(2xm,1H),4.05(s,3H),3.81-3.40(m,4H),2.25(s,6H),2.03-1.80(m,2H);HRMS(ESI)对于C21H24N6O2[M+H]+计算为393.2034,实测为393.203。
[(3S)-3-(二甲基氨基)吡咯烷-1-基](3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 86)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(3S)-3-(二甲基氨基)吡咯烷-1-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.52(s,1H),8.50(d,J=5.2Hz,1H),7.48(s,2H),7.28和7.26(2xd J=5.2Hz,1H),7.18和7.17(2xs,1H),6.60(s,1H),4.04和4.03(2xs,3H),3.86-3.21(m,4H),2.80-2.70(m,1H),2.25(s,6H),2.19(s,3H),2.14(s,3H),2.12-2.00(m,1H),1.84-1.70(m,1H);HRMS(ESI)对于C23H29N7O[M+H]+计算为420.2507,实测为420.2506。
[(3R)-3-(二甲基氨基)吡咯烷-1-基](3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 87)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(3R)-3-(二甲基氨基)吡咯烷-1-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.52(s,1H),8.50(d,J=5.2Hz,1H),7.48(s,2H),7.28和7.26(2xd J=5.2Hz,1H),7.18和7.17(2xs,1H),6.60(s,1H),4.04和4.03(2xs,3H),3.86-3.21(m,4H),2.80-2.70(m,1H),2.25(s,6H),2.19(s,3H),2.14(s,3H),2.12-2.00(m,1H),1.84-1.70(m,1H);HRMS(ESI)对于C23H29N7O[M+H]+计算为420.2507,实测为420.2503。
(3-氨基吡咯烷-1-基)(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 88)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=3-氨基吡咯烷-1-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.54和9.52(2xs,1H),8.50(d,J=5.0Hz,1H),7.48(s,2H),7.27和7.26(2xd,J=5.0Hz,1H),7.22和7.15(2xs,1H),6.60(s,1H),4.05(s,3H),3.84-3.22(m,5H),2.25(s,6H),2.04-1.95(m,1H),1.73-1.64(m,1H);HRMS(ESI)对于C21H25N7O[M+H]+计算为392.2194,实测为392.2194。
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(2S)-2-(羟甲基)吡咯烷-1-基]甲酮(cpd 89)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(2S)-2-(羟甲基)吡咯烷-1-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.51(s,1H),8.49(d,J=5.0Hz,1H),7.48(s,2H),7.26(d,J=5.0Hz,1H),7.18和7.10(2xs,1H),6.60(s,1H),4.91和4.82(2xt,J=5.8Hz,1H),4.18和4.12(2xm,1H),4.03和3.93(2xs,3H),3.70-3.15(m,4H),2.25(s,6H),2.00-1.74(m,4H);HRMS(ESI)对于C22H26N6O2[M+H]+计算为407.219,实测为407.2193。
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(3S)-3-羟基吡咯烷-1-基]甲酮(cpd 90)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(3S)-3-羟基吡咯烷-1-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.53和9.52(2xs,1H),8.50(d,J=5.0Hz,1H),7.48(s,2H),7.27(d,J=5.0Hz,1H),7.22和7.16(2xs,1H),6.60(s,1H),5.09和5.08(2xd,J=4.6Hz,1H),4.35和4.32(2xm,1H),4.05和4.04(2xs,3H),3.78-3.54(m,4H),2.25(s,6H),2.03-1.80(m,2H);HRMS(ESI)对于C21H24N6O2[M+H]+计算为393.2034,实测为393.2027。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1R,2S)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 91)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1R,2S)-2-羟基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.49(d,J=5.0Hz,1H),8.15(d,J=7.8Hz,1H),7.49(s,1H),7.48(s,2H),7.25(d,J=5.0Hz,1H),6.61(s,1H),4.65(d,J=3.8Hz,1H),4.12(s,3H),3.85(m,1H),3.83(m,1H),2.26(s,6H),1.77-1.25(m,8H);HRMS(ESI)对于C23H28N6O2[M+H]+计算为421.2347,实测为421.2345。
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 92)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),8.50(d,J=5.0Hz,1H),8.47(d,J=7.9Hz,1H),7.87(br.s.,3H),7.60(s,1H),7.51(s,2H),7.27(d,J=5.0Hz,1H),6.62(s,1H),4.33(m,1H),4.14(s,3H),3.37(m与水信号重叠,1H),2.28(s,6H),1.80-1.34(m,8H);HRMS(ESI)对于C23H30N7OCl[M+H]+计算为420.2507,实测为420.2509。
N-[(2S)-1-羟基丙烷-2-基]-1-甲基-3-{2-[(1,2,3-三甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 93)[(I),R1=1,2,3-三甲基吲哚-5-基,R2=甲基,R3=(2S)-1-羟基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.32(s,1H),8.44(d,J=5.0Hz,1H),8.43(d,J=7.3Hz,1H),8.10(br.s.,1H),7.46(s,1H),7.29(dd,J=8.7,2.0Hz,1H),7.25(d,J=8.7Hz,1H),7.18(d,J=5.0Hz,1H),4.75(t,J=5.8Hz,1H),4.13(s,3H),3.99(m,1H),3.62(s,3H),3.47-3.30(m与水信号部分重叠,2H),2.32(s,3H),2.20(s,3H),1.13(d,J=6.7Hz,3H);HRMS(ESI)对于C23H27N7O2[M+H]+计算为434.2299,实测为434.2291。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 94)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-吡咯烷-1-基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.54(d,J=8.1Hz,1H),8.49(d,J=5.0Hz,1H),7.48(s,2H),7.45(s,1H),7.25(d,J=5.0Hz,1H),6.62(s,1H),4.13(s,3H),4.17-4.07(m,1H),2.60-2.35(m与DMSO信号部分重叠,6H),2.27(s,6H),1.72-1.62(m,4H),1.14(d,J=6.6Hz,3H);HRMS(ESI)对于C24H31N7O[M+H]+计算为434.2663,实测为434.2684。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 95)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.50(s,1H),8.55(br.s.,1H),8.52(d,J=5.0Hz,1H),7.51(s,2H),7.48(s,1H),7.29(d,J=5.0Hz,1H),6.65(s,1H),4.17(s,3H),4.05-3.94(m,1H),3.50-3.10(m与水信号部分重叠,6H),2.30(s,6H),2.10-1.93(m,2H),1.14(d,J=6.7Hz,3H);HRMS(ESI)对于C23H29N7O[M+H]+计算为420.2507,实测为420.252。
(1S,4R)-2,5-二氮杂双环[2.2.1]庚-2-基(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮盐酸盐(cpd 96)[(I),R1=3,5-二甲基苯基,R2=甲基,NR3R4=(1S,4R)-2,5-二氮杂双环[2.2.1]庚烷-2-基氨基]
1H NMR(500MHz,DMSO-d6)(构象异构体混合物)δppm 9.55和9.54(2xs,1H),9.45和9.38(2x br.s.,1H),9.07和8.97(2x br.s.,1H),8.51和8.50(2xd,J=5.2Hz,1H),7.48和7.45(2xs,2H),7.30和7.27(2xd,J=5.2Hz,1H),7.18和7.12(2xS,1H),6.61(s,1H),4.87和4.82(2xs,1H),4.50和4.44(2xs,1H),4.09和4.02(2xs,3H),3.95-3.24(m,4H),2.26(s,6H),2.22-1.80(m,2H);HRMS(ESI)对于C22H26N7OCl[M+H]+计算为404.2194,实测为404.2199。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(3R)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 97)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(3R)-哌啶-3-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.85(m,4H),8.50(d,J=5.19Hz,1H),7.52(s,1H),7.47(s,2H),7.26(d,J=5.03Hz,1H),6.62(s,1H),4.14(s,3H),3.42-2.74(m.br.,5H)2.27(s,6H),1.98-1.53(m.br.,4H);HRMS(ESI)对于C22H28N7OCl[M+H]+计算为406.235,实测为406.235。
N-[(1R,2S)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 98)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1R,2S)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),8.50(d,J=5.03Hz,1H),8.47(d,J=8.08Hz,1H),7.87(d,J=3.66Hz,3H),7.60(s,1H),7.51(s,2H),7.27(d,J=5.03Hz,1H),6.62(s,1H),4.33(br.s.,1H),4.14(s,3H),3.35(m与水信号重叠,1H),2.28(s,6H),185-1.30(m.8H);HRMS(ESI)对于C23H30N7OCl[M+H]+计算为420.2507,实测为420.2514。
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 99)[(I),R1=(3,5-二氯苯基),R2=甲基,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.12(s,1H),8.62(d,J=5.19Hz,1H),8.43(d,J=7.78Hz,1H),8.02(d,J=1.83Hz,2H),7.90(d,J=3.51Hz,3H),7.59(s,1H),7.40(d,J=5.03Hz,1H),7.15(t,J=1.83Hz,1H),4.32(br.s.,1H),4.14(s,3H),3.48-3.40(m与水信号重叠,1H),1.86-1.32(m,8H);HRMS(ESI)对于C21H24N7OCl3[M+H]+计算为460.1414,实测为460.1419。
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 100)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.62(s,1H),8.53(d,J=5.03Hz,1H),8.43(d,J=7.78Hz,1H),7.89(d,J=3.36Hz,3H),7.60(s,1H),7.31(d,J=5.19Hz,1H),7.20(d,J=2.14Hz,2H),6.13(t,J=2.21Hz,1H),4.31(br.s.,1H),4.13(s,3H),3.76(s,6H),3.48-3.40(m与水信号重叠,1H),1.88-1.33(m,8H);HRMS(ESI)对于C23H30N7O3Cl[M+H]+计算为452.2405,实测为452.2396。
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 101)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1S,2S)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.52(d,J=8.39Hz,1H),8.49(d,J=5.03Hz,1H),7.49(s,1H),7.48(s,2H),7.25(d,J=5.03Hz,1H),6.61(s,1H),4.13(s,3H),3.40-3.50(m,1H),2.54(td,J=10.90,4.10Hz,1H),2.27(s,6H),1.90-1.17(m,8H);HRMS(ESI)对于C23H29N7O[M+H]+计算为420.2507,实测为420.2515。
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 102)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.85(d,J=7.78Hz,1H),8.50(d,J=5.19Hz,1H),7.52(s,1H),7.47(s,2H),7.26(d,J=5.03Hz,1H),6.62(s,1H),4.14(s,3H),4.13-4.09(m.br.,1H),3.90-3.20(m与水信号重叠,6H)(2.27(s,6H),2.17-2.07(m.br.,2H),1.85-1.74(m,1H)0.93-0.85(m,6H);HRMS(ESI)对于C25H33N7O[M+H]+计算为448.282,实测为448.2822。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 103)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-3-甲基-1-吡咯烷-1-基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.49(d,J=5.0Hz,1H),8.41(d,J=9.0Hz,1H),7.50(s,2H),7.48(s,1H),7.27(d,J=5.0Hz,1H),6.61(s,1H),4.11(s,3H),4.03-3.92(m,1H),2.59(dd,J=9.1,12.1Hz,1H),2.53-2.47(m.与DMSO信号重叠,2H)2.47(dd,J=4.7,12.2Hz,1H),2.40(s,2H),2.27(s,6H),1.94-1.77(m,1H),1.65(br.s.,4H),0.90(d,J=8.2Hz,3H),0.89(d,J=8.4Hz,3H);HRMS(ESI)对于C26H35N7O[M+H]+计算为462.2976,实测为462.2983。
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺盐酸盐(cpd 104)[(I),R1=3,5-二甲基苯基,R2=H,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 14.5-13.5(br.s.,1H),9.49(s,1H),8.53(d,J=5.19Hz,1H),8.21(br.s.,1H),7.90(d,J=2.90Hz,3H),7.54(br.s.,1H),7.48(s,2H),7.34(d,J=5.03Hz,1H),6.63(s,1H),4.33(br.s.,1H),3.50-3.40(m与水信号重叠,1H),2.27(s,6H),1.90-1.17(m,8H);HRMS(ESI)对于C22H28N7OCl[M+H]+计算为406.235,实测为406.236。
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 105)[(I),R1=3,5-二甲基苯基,R2=H,R3=(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 13.98(br.s.,1H),9.45(s,1H),8.51(d,J=3.66Hz,1H),8.22(br.s.,1H),7.48(s,3H),7.31(d,J=5.03Hz,1H),6.62(s,1H),3.70-3.82(m,1H),3.20-3.05(m.4H),3.17(d,J=4.88Hz,2H),2.27(s,6H),1.92(quin,J=6.63Hz,2H),1.80(dq,J=13.17,6.54Hz,1H),0.87(dd,J=9.76,6.86Hz,6H);HRMS(ESI)对于C24H31N7O[M+H]+计算为434.2663,实测为434.2668。
N-[(1S)-1-环己基-2-羟乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 106)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1S)-1-环己基-2-羟基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.49(d,J=5.19Hz,1H),8.37(d,J=9.00Hz,1H),7.51(s,1H),7.50(s,2H),7.26(d,J=5.19Hz,1H),6.61(s,1H),4.57(t,J=5.72Hz,1H),4.12(s,3H),3.74-3.86(m,1H),3.50-3.58(m,1H),3.44-3.50(m,1H),2.27(s,6H),1.80-0.95(m.11H);HRMS(ESI)对于C25H32N6O2[M+H]+计算为449.266,实测为449.2665。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(1S)-1-苯基-2-(吡咯烷-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 107)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1S)-1-苯基-2-吡咯烷-1-基乙基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.50(s,1H),9.15(d,J=8.4Hz,1H),8.50(d,J=5.0Hz,1H),7.60(s,1H),7.51(s,2H),7.43(d,J=7.3Hz,2H),7.33(t,J=7.5Hz,2H),7.28-7.25(m,2H),6.63(s,1H),5.19-5.10(m,1H),4.10(s,3H),2.97(t,J=10.9Hz,2H),2.60-2.48(m,4H),2.30(s,6H),1.67(br.s.,4H);HRMS(ESI)对于C29H33N7O[M+H]+计算为496.282,实测为496.2823。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 108)[(I),R1=3-甲基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.55(s,1H),8.50(d,J=5.19Hz,1H),8.46(d,J=8.39Hz,1H),7.69(s,1H),7.63(d,J=8.24Hz,1H),7.46(s,1H),7.27(d,J=5.03Hz,1H),7.18(t,J=7.78Hz,1H),6.79(d,J=7.63Hz,1H),4.14(s,3H),3.92(dquin,J=13.93,6.77,6.77,6.77,6.77Hz,1H),3.38-3.29(m.与水信号重叠,2H),3.04-3.24(m,4H),2.32(s,3H),2.00-1.90(m.2H),1.10(d,J=6.71Hz,3H);HRMS(ESI)对于C22H27N7O[M+H]+计算为406.235,实测为406.2349。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-苯基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 109)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(2S)-1-羟基-3-苯基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.47(s,1H),8.55(d,J=8.5Hz,1H),8.49(d,J=5.2Hz,1H),7.48(s,2H),7.44(s,1H),7.31-7.12(m,6H),6.62(s,1H),4.87(t,J=5.6Hz,1H),4.18-4.08(m,1H),4.04(s,3H),3.54-3.46(m,1H),3.46-3.40(m,1H),2.95(dd,J=4.7,13.7Hz,1H),2.73(dd,J=9.5,13.9Hz,1H),2.29(s,6H);HRMS(ESI)对于C26H28N6O2[M+H]+计算为457.2347,实测为457.2354。
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 110)[(I),R1=3-氯-4-(4-甲基哌嗪-1-基)苯基,R2=甲基,R3=(2S)-1-羟基丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.67(s,1H),8.51(d,J=5.03Hz,1H),8.41(d,J=8.08Hz,1H),7.95(d,J=2.44Hz,1H),7.76(dd,J=8.77,2.36Hz,1H),7.47(s,1H),7.27(d,J=5.19Hz,1H),7.14(d,J=8.85Hz,1H),4.76(t,J=5.80Hz,1H),4.13(s,3H),3.94-4.03(m,1H),3.45-3.36(m,2H),2.93(br.s.,4H),2.54-2.43(m.br,与水部分重叠,4H),2.23(s,3H)1.14(d,J=6.71Hz,3H);HRMS(ESI)对于C23H29N8O2Cl[M+H]+计算为485.2175,实测为485.2172。
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 111)[(I),R1=3-氯-4-(4-甲基哌嗪-1-基)苯基,R2=甲基,R3=(2S)-1-羟基-3-甲基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.69(s,1H),8.51(d,J=5.2Hz,1H),8.31(d,J=9.0Hz,1H),8.02(d,J=2.6Hz,1H),7.70(dd,J=2.5,8.8Hz,1H),7.51-7.46(m,1H),7.28(d,J=5.2Hz,1H),7.12(d,J=8.8Hz,1H),4.61(t,J=5.6Hz,1H),4.12(s,3H),3.84-3.74(m,1H),3.60-3.44(m,2H),2.92(br.s.,4H),2.52-2.40(br.s.,与水部分重叠,4H)2.23(s,3H),1.98-1.87(m,1H),0.91(dd,J=6.8,9.7Hz,6H);HRMS(ESI)对于C25H33N8O2Cl[M+H]+计算为513.2488,实测为513.2498。
1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 112)[(I),R1=3-甲基苯基,R2=甲基,R3=(2S)-3-甲基-1-吡咯烷-1-基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.56(s,1H),8.50(d,J=5.2Hz,1H),8.39(d,J=9.0Hz,1H),7.79(s,1H),7.56(d,J=8.4Hz,1H),7.50-7.47(m,1H),7.28(d,J=5.0Hz,1H),7.16(t,J=7.8Hz,1H),6.79(d,J=7.5Hz,1H),4.12(s,3H),3.98(td,J=4.4,9.3Hz,1H),2.63-2.57(m,1H),2.52-2.47(br.m.,与水部分重叠,3H),2.44-2.38(m,2H),2.32(s,3H),1.86(dd,J=6.6,12.4Hz,1H),1.65(br.s.,4H),0.90(t,J=7.3Hz,6H);HRMS(ESI)对于C25H33N7O[M+H]+计算为448.282,实测为448.2827。
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 113)[(I),R1=3,5-二氟苯基,R2=甲基,R3=(1S,2S)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.11(s,1H),8.59(d,J=5.03Hz,1H),8.49(d,J=8.39Hz,1H),7.62(dd,J=10.45,2.21Hz,2H),7.50(s,1H),7.38(d,J=5.03Hz,1H),6.76(tt,J=9.21,2.31Hz,1H),4.14(s,3H),3.41-3.50(m,1H),2.55(td,J=10.50,3.50Hz,1H),1.93-1.18(m,8H);HRMS(ESI)对于C21H23N7OF2[M+H]+计算为428.2005,实测为428.2004。
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(1S,2R)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 114)[(I),R1=3-氯-4-(4-甲基哌嗪-1-基)苯基,R2=甲基,R3=(1S,2R)-2-羟基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.69(s,1H),8.51(d,J=5.18Hz,1H),8.13(d,J=7.78Hz,1H),7.97(d,J=2.59Hz,1H),7.76(dd,J=8.69,2.44Hz,1H),7.49(s,1H),7.28(d,J=5.19Hz,1H),7.13(d,J=8.85Hz,1H),4.68(d,J=3.81Hz,1H),4.13(s,3H),3.78-3.92(m,2H),2.92(br.s.,4H),2.54-2.42(m.br.,与水部分重叠,4H),2.23(s,3H),1.78-1.15(m,8H);HRMS(ESI)对于C26H33N8O2Cl[M+H]+计算为525.2488,实测为525.2492。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1S,2R)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 115)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1S,2R)-2-羟基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.48(s,1H),8.49(d,J=5.03Hz,1H),8.16(d,J=7.78Hz,1H),7.49(s,1H),7.48(s,2H),7.25(d,J=5.19Hz,1H),6.61(s,1H),4.64(d,J=3.81Hz,1H),4.12(s,3H),3.78-3.90(m,2H),2.27(s,6H),1.84-1.17(m,8H);HRMS(ESI)对于C23H28N6O2[M+H]+计算为421.2347,实测为421.2345。
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 116)[(I),R1=3,5-二氯苯基,R2=甲基,R3=(1S,2S)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.10(s,1H),8.62-8.59(m,1H),8.49(d,J=8.4Hz,1H),8.00-7.97(m,2H),7.47(s,1H),7.38(d,J=5.0Hz,1H),7.13(t,J=1.8Hz,1H),4.15-4.11(m,3H),3.49-3.41(m,1H),2.59-2.52(m,1H),1.88-1.09(m.8H);HRMS(ESI)对于C21H23N7OCl2[M+H]+计算为460.1414,实测为460.1427。
3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 117)[(I),R1=3,5-二氯苯基,R2=甲基,R3=(2S)-3-甲基-1-吡咯烷-1-基丁烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.10(s,1H),8.60(d,J=5.0Hz,1H),8.37(d,J=9.2Hz,1H),8.00(d,J=1.8Hz,2H),7.45(s,1H),7.40(d,J=5.0Hz,1H),7.13(t,J=1.8Hz,1H),4.17-4.08(m,3H),4.03-3.93(m,1H),2.63-2.54(m,2H),2.44-2.36(m,4H),1.86(dd,J=6.8,12.4Hz,1H),1.65(br.s.,4H),0.90(dd,J=7.1,7.9Hz,6H);HRMS(ESI)对于C24H29N7OCl2[M+H]+计算为502.1884,实测为502.1893。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1S,2S)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 118)[(I),R1=3,5-二甲基苯基,R2=甲基,R3=(1S,2S)-2-羟基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.46(s,1H),8.49(d,J=5.0Hz,1H),8.46(d,J=8.2Hz,1H),7.47(s,3H),7.25(d,J=5.2Hz,1H),6.61(s,1H),4.61(d,J=5.2Hz,1H),4.13(s,3H),3.66-3.53(m,1H),3.42-3.28(m,与水重叠,1H),2.27(s,6H),1.97-1.76(m,2H),1.64(br.s,2H),1.35-1.13(m,4H);HRMS(ESI)对于C23H28N6O2[M+H]+计算为421.2347,实测为421.235。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氰基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺甲酸盐(cpd 119)[(I),R1=3-氰基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 10.04(s,1H),8.59(d,J=5.0Hz,1H),8.44(d,J=8.4Hz,1H),8.31(t,J=1.7Hz,1H),8.28(s,1H),8.14(dd,J=1.2,8.4Hz,1H),7.52(t,J=8.0Hz,1H),7.47(s,1H),7.41(d,J=7.8Hz,1H),7.36(d,J=5.0Hz,1H),4.14(s,3H),3.99-3.84(m,1H),3.24-3.09(m,4H),2.55-2.48(m,与水部分重叠1H)2.43-2.38(m,1H),1.95(quin,J=7.0Hz,2H),1.11(d,J=6.7Hz,3H);HRMS(ESI)对于C23H26N8O3[M+H]+计算为417.2146,实测为417.2161。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-N-[(1S,2R)-2-羟基环己基]-1H-吡唑-5-羧酰胺(cpd 120)[(I),R1=3,5-二甲基苯基,R2=乙基,R3=(1S,2R)-2-羟基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.49(s,1H),8.49(d,J=5.19Hz,1H),8.16(d,J=7.63Hz,1H),7.49(s,2H),7.48(s,1H),7.26(d,J=5.19Hz,1H),6.61(s,1H),4.64(d,J=3.97Hz,1H),4.54(q,J=7.17Hz,2H),3.79-3.90(m,2H),2.26(s,6H),1.80-1.28(m,8H),1.38(t,J=7.17Hz,3H);HRMS(ESI)对于C24H30N6O2[M+H]+计算为435.2503,实测为435.2502。
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-1H-吡唑-5-羧酰胺盐酸盐(cpd 121)[(I),R1=3,5-二甲基苯基,R2=乙基,R3=(1S,2R)-2-氨基环己基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.51(s,1H),8.51(d,J=5.03Hz,1H),8.46(d,J=7.93Hz,1H),7.88(d,J=4.27Hz,3H),7.61(s,1H),7.52(s,2H),7.28(d,J=5.03Hz,1H),6.62(s,1H),4.66-4.45(m,2H),4.34(br.s.,1H),3.74-3.50(m,1H),2.28(s,6H),1.88-1.31(m,8H),1.42(t,J=7.17Hz,3H);HRMS(ESI)对于C24H32N7OCl[M+H]+计算为434.2663,实测为434.2658。
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-N-[(3R)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 122)[(I),R1=3,5-二甲基苯基,R2=乙基,R3=(3R)-哌啶-3-基,R4=H]
1H NMR(500MHz,DMSO-d6)δppm 9.50(s,1H),8.95(d,J=9.46Hz,1H),8.86(d,J=7.47Hz,1H),8.78-8.89(m,1H),8.50(d,J=5.03Hz,1H),7.52(s,1H),7.48(s,2H),7.27(d,J=5.19Hz,1H),6.62(s,1H),4.56(m,2H),4.09-4.22(m,1H),3.40-2.73(m,4H)2.27(s,6H),1.95-1.55(m.4H),1.39(t,J=7.17Hz,3H);HRMS(ESI)对于C23H30N7OCl[M+H]+计算为420.2507,实测为420.2513。
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd 123)[(I),R1=3,5-二甲氧基苯基,R2=甲基,R3=(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基,R4=甲基]
1H NMR(500MHz,DMSO-d6)δppm 9.62(s,1H),8.49-8.55(m,1H),7.31(d,J=5.03Hz,1H),7.18(m.3H),6.13(br.s.,1H),4.00(m.6H),3.76-3.60(m.br.1H)3.74(s.6H),3.16-3.10(m.2H),3.06-2.69(m.br.4H),2.04-1.60(m.br.2H),1.25(m.3H);HRMS(ESI)对于C24H31N7O3[M+H]+计算为466.2561,实测为466.2564。
以KinaseGlo和ADPGlo测定形式对SYK进行生化激酶抑制测定
重组蛋白SYK FL通过昆虫细胞中的杆状病毒感染作为His GST-融合蛋白在NMS产生。通过SDS-PAGE判断,内部蛋白(in-house protein)制品有>80%的均匀性,并通过N-末端序列分析和电喷雾质谱对它们进行表征。
将SYK以1μM浓度与激酶缓冲液(50mM Hepes pH 7.5、10mM MgCl2、1mM DTT、3μMNa3VO4和0.2mg/mL BSA)中的400μM ATP在28℃预激活60分钟,然后马上进行激酶反应。
KinaseGlo测定形式
将化合物从10μM到0.0005μM进行3倍连续稀释,然后在存在最终体积为20μL的激酶缓冲液(50mM Hepes pH 7.5、10mM MgCl2、1mM DTT、3μM Na3VO4和0.2mg/mL BSA)中的ATP2.5μM、肽底物BioDBn*327 125uM和预激活的酶2.5nM的情况下,在rt孵育60分钟。DMSO的最终浓度为1%。测定以自动化的形式在384孔板(Perkin Elmer cat.#6005301)上运行。
ADPGlo测定形式
将5微升的溶解在3% DMSO中的从10μM到0.0006μM进行4倍连续稀释的试验化合物移液到384孔Optiplate(n*6005310-Perkin Elmer)中。将5微升在其特定激酶缓冲液中稀释的1.8nM的重组预激活的SYK溶液添加到含有化合物的板中,并在室温孵育30分钟。添加5微升在激酶缓冲液中稀释的ATP(腺苷5’-三磷酸二钠盐(Promega))和肽底物BioDBn*327(TwinHelix)的混合物以开始反应。
预激活的SYK、ATP和BioDBn*327的最终浓度分别为0.6nM、60μM和125μM。
数据分析
每个384孔板包含至少一条标准cpd曲线和用于Z’和信号背景评估的参考孔(总酶活性相比于完全抑制的酶)(J.Biomol.Screening,1999,4,67-73)。
所有关于板稀释、分布和抑制的原始数据的信息都通过条形码读取进行追踪,并存储在Oracle DB中。每个分子的数据通过内部定制版本的SW软件包“Assay Explorer”进行分析,该软件包使用以下4参数逻辑方程提供用于IC50确定的八个稀释曲线的S形拟合:
y=底部+(顶部-底部)/(1+10^((logIC50-x)*斜率))
其中x是抑制剂浓度的对数,y是响应;
IC50被定义为抑制50%最大磷酸化所需的化合物浓度。
在以上描述的特定体外激酶测定中,进行式(I)的本发明代表性化合物对Syk的测试。
下表A报告了如以上报告进行的式(I)的化合物对Syk激酶的体外活性数据。如本领域技术人员可以理解的,大多数化合物显示出对Syk的IC50值<0.5μM,并因此在针对由失调的Syk激酶活性引起的和/或与之相关的疾病(诸如癌症)的疗法中特别有利。
表A
为了支持本申请的化合物相对于现有技术申请WO 2012/139930中描述的最接近的化合物的非预期的活性,我们在以下表B中报告了针对三种参考化合物(即化合物7、14和39)获得的Syk测定的结构和生化数据。
表B
从以上数据中,对本领域技术人员清楚的是,本发明的式(I)的化合物对Syk激酶高度有效,同时现有技术的化合物可以被认为是无活性的。
序列表
<110> 内尔维亚诺医疗科学公司
<120> 作为激酶抑制剂的吡唑基-嘧啶衍生物
<130> NMS 115
<150> 20197710.5
<151> 2020-09-23
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 20
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 人工的
<220>
<221> MOD_RES
<222> (20)..(20)
<223> 酰胺化
<400> 1
Lys Lys Lys Lys Lys Glu Gln Glu Asp Glu Pro Glu Gly Asp Tyr Phe
1 5 10 15
Glu Trp Leu Glu
20
Claims (21)
1.一种式(I)的化合物:
其中:
R1是氢或选自直链或支链(C1-C6)烷基、(C3-C7)环烃基、芳基、杂环基和杂芳基的任选取代的基团;
R2是氢或选自直链或支链(C1-C6)烷基、(C2-C6)烯基、(C2-C6)炔基和(C3-C7)环烃基的任选取代的基团;
R3和R4独立地为氢、任选地被卤素取代的直链或支链(C1-C6)烷基、杂芳基或杂芳基(C1-C6)烷基或式(II)的基团:
其中:
R5是氢、任选取代的直链或支链(C1-C6)烷基、(C3-C7)环烃基、
芳基,或与R6一起可形成任选取代的4至7元环烃基,或与R7或R8一起可形成任选取代的杂环基基团;
R6是氢或甲基或与R3或R4一起可形成任选取代的4至7元杂环基基团;
R7和R8独立地是氢、任选取代的直链或支链(C1-C6)烷基,或可与X一起形成任选取代的4至7元杂环基基团,所述4至7元杂环基基团任选地包含一个另外的选自N、O和S的杂原子,或可与R3或R4一起形成任选取代的5至7元杂环基基团;
X是H、N或O;
条件是,当X是O时,R5不是苯基;
或其药学上可接受的盐。
5.根据权利要求1至4中任一项所述的式(I)的化合物或其药学上可接受的盐,其中:
R1是选自苯基或吲哚基的任选取代的基团;
R2、R3和R4根据权利要求4中定义。
6.根据权利要求1至5中任一项所述的式(I)的化合物或其药学上可接受的盐,选自由以下组成的组:
N-[2-(二甲基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 1);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2R)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 2);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 3);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(丙烷-2-基)-1H-吡唑-5-羧酰胺(cpd 4);
N-[2-(二甲基氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd 5);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(甲基氨基)乙基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 6);
N-(2-氨基乙基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 7);
N-(氮杂环丁烷-3-基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺三氟乙酸盐(cpd 8);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(吗啉-4-基)乙基]-1H-吡唑-5-羧酰胺(cpd 9);
N-[2-(二乙氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 10);
N-[(1R,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 11);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(丙烷-2-基氨基)乙基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 12);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd13);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd14);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N,N,1-三甲基-1H-吡唑-5-羧酰胺(cpd15);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-甲氧基乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 16);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-氟乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 17);
3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-N-[2-(二甲基氨基)乙基]-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 18);
3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 19);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(1H-吡唑-3-基)-1H-吡唑-5-羧酰胺(cpd 20);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)(4-甲基哌嗪-1-基)甲酮(cpd 21);
N-[2-(乙酰氨基)乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 22);
N-(2-氨基-2-氧代乙基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 23);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(2,2,2-三氟乙基)-1H-吡唑-5-羧酰胺(cpd 24);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(1-甲基-1H-咪唑-5-基)甲基]-1H-吡唑-5-羧酰胺(cpd 25);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 26);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(吡啶-2-基甲基)-1H-吡唑-5-羧酰胺(cpd 27);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(1H-咪唑-2-基甲基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 28);
N-[(2R)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 29);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 30);
N-(1-氮杂双环[2.2.2]辛-3-基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 31);
5-[2-(3,5-二甲基-苯基氨基)-嘧啶-4-基]-2-甲基-2H-吡唑-3-羧酸((1R,2R)-2-羟基-环己基)-酰胺(cpd 32);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 33);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2-羟乙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 34);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,4-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 35);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)(哌嗪-1-基)甲酮盐酸盐(cpd 36);
N-[(1S,2R)-2-氨基环己基]-3-(2-{[3-甲氧基-5-(三氟甲基)苯基]氨基}嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 37);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3-氯-1-甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 38);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 39);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 40);
N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 41);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 42);
N-[3-(二甲基氨基)丙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 43);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(2S)-2-(丙烷-2-基)氮丙啶-1-基]甲酮(cpd 44);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-(2,2-二甲基丙基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 45);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-(2-甲基丙基)-1H-吡唑-5-羧酰胺(cpd 46);
N-(环丙基甲基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 47);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氟-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 48);
3-{2-[(4,6-二甲基吡啶-2-基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 49);
3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 50);
1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 51);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基-3-苯基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 52);
N-[(1S,2S)-2-氨基环己基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 53);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-1-甲基-N-[(2S)-1,1,1-三氟丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 54);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1,1,1-三氟丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 55);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2R)-1,1,1-三氟丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 56);
N-[(2S)-1-(3,3-二氟氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 57);
1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-3-{2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 58);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氯-1-甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 59);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 60);
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 61);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-(2-{[3-(三氟甲基)苯基]氨基}嘧啶-4-基)-1H-吡唑-5-羧酰胺(cpd 62);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-(2-{[3,5-双(三氟甲基)苯基]氨基}嘧啶-4-基)-1-甲基-1H-吡唑-5-羧酰胺(cpd 63);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 64);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-3-{2-[(3-氟-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 65);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-[2-(1,3-苯并间二氧杂环戊烯-5-基氨基)嘧啶-4-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 66);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 67);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-{2-[(3,4,5-三甲氧基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 68);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 69);
3-{2-[(3-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 70);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)-1-氧代丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 71);
3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N-[2-(二甲基氨基)乙基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 72);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-3-{2-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 73);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(1,5-二甲基-1H-吡唑-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 74);
N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-3-{2-[(1-甲基-1H-吡唑-4-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 75);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd 76);
N,N,1-三甲基-3-[2-(四氢-2H-吡喃-4-基氨基)嘧啶-4-基]-1H-吡唑-5-羧酰胺(cpd77);
3-{2-[(3-氰基-5-甲氧基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-(二甲基氨基)丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 78);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氰基-5-甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 79);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(5-甲氧基吡啶-3-基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 80);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(3S)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 81);
N-(2-氨基环己基)-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 82);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(吡咯烷-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 83);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[2-(哌啶-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 84);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(3R)-3-羟基吡咯烷-1-基]甲酮(cpd 85);
[(3S)-3-(二甲基氨基)吡咯烷-1-基](3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 86);
[(3R)-3-(二甲基氨基)吡咯烷-1-基](3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 87);
(3-氨基吡咯烷-1-基)(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮(cpd 88);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(2S)-2-(羟甲基)吡咯烷-1-基]甲酮(cpd 89);
(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)[(3S)-3-羟基吡咯烷-1-基]甲酮(cpd 90);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1R,2S)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 91);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 92);
N-[(2S)-1-羟基丙烷-2-基]-1-甲基-3-{2-[(1,2,3-三甲基-1H-吲哚-5-基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 93);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-1-(吡咯烷-1-基)丙烷-2-基]-1H-吡唑-5-羧酰胺(cpd 94);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 95);
(1R,4S)-2,5-二氮杂双环[2.2.1]庚-2-基(3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-基)甲酮盐酸盐(cpd 96);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(3R)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 97);
N-[(1R,2S)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 98);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 99);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺盐酸盐(cpd 100);
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 101);
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 102);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 103);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺盐酸盐(cpd 104);
N-[(2S)-1-(氮杂环丁烷-1-基)-3-甲基丁烷-2-基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 105);
N-[(1S)-1-环己基-2-羟乙基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 106);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-甲基-N-[(1S)-1-苯基-2-(吡咯烷-1-基)乙基]-1H-吡唑-5-羧酰胺(cpd 107);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-1H-吡唑-5-羧酰胺(cpd 108);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-1-羟基-3-苯基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 109);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基丙烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 110);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(2S)-1-羟基-3-甲基丁烷-2-基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 111);
1-甲基-3-{2-[(3-甲基苯基)氨基]嘧啶-4-基}-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 112);
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二氟苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 113);
3-(2-{[3-氯-4-(4-甲基哌嗪-1-基)苯基]氨基}嘧啶-4-基)-N-[(1S,2R)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 114);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1S,2R)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 115);
N-[(1S,2S)-2-氨基环己基]-3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 116);
3-{2-[(3,5-二氯苯基)氨基]嘧啶-4-基}-1-甲基-N-[(2S)-3-甲基-1-(吡咯烷-1-基)丁烷-2-基]-1H-吡唑-5-羧酰胺(cpd 117);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-N-[(1S,2S)-2-羟基环己基]-1-甲基-1H-吡唑-5-羧酰胺(cpd 118);
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3-氰基苯基)氨基]嘧啶-4-基}-1-甲基-1H-吡唑-5-羧酰胺(cpd 119);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-N-[(1S,2R)-2-羟基环己基]-1H-吡唑-5-羧酰胺(cpd 120);
N-[(1S,2R)-2-氨基环己基]-3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-1H-吡唑-5-羧酰胺盐酸盐(cpd 121);
3-{2-[(3,5-二甲基苯基)氨基]嘧啶-4-基}-1-乙基-N-[(3R)-哌啶-3-基]-1H-吡唑-5-羧酰胺盐酸盐(cpd 122)和
N-[(2S)-1-(氮杂环丁烷-1-基)丙烷-2-基]-3-{2-[(3,5-二甲氧基苯基)氨基]嘧啶-4-基}-N,1-二甲基-1H-吡唑-5-羧酰胺(cpd 123)。
7.用于制备根据权利要求1中定义的式(I)的化合物或其药学上可接受的盐的方法,所述方法包括以下步骤:
步骤1)使式(III)的化合物:
其中R2根据权利要求1中定义并且R9是选自直链或支链(C1-C6)烷基的基团,
与二甲基甲酰胺-二烷基缩醛混合;
步骤2)使得到的式(IV)的化合物:
其中R2和R9根据以上定义,
与式(V)的化合物:
其中R1根据权利要求1中定义,
反应,从而获得式(V)的化合物:
其中R1、R2和R9根据以上定义;
可选地,在步骤2中报告的式(V)的化合物能够根据以下步骤制备:步骤3)使式(IV)
其中R2和R9根据上述步骤1)中定义,
与碳酸胍反应;
步骤4)在存在钯的情况下,使得到的式(VII)的化合物:
其中R2和R9根据以上定义,
与式(VIII)的化合物:
其中R1根据权利要求1中定义,并且Y是碘或溴,
反应,从而获得式(VI)的化合物
其中R1、R2和R9根据以上定义;
或
步骤5)在存在碘和CuI的情况下,使根据在步骤3)中报告获得的得到的式(VII)的化合物:
与亚硝酸异戊酯和二碘甲烷或碘化铯反应,从而获得式(IX)的化合物,其中R2和R9根据以上定义;
步骤6)然后,在存在钯的情况下,使得到的式(IX)的化合物:
其中R2和R9根据以上定义,
与式(X)的化合物:
其中R1根据权利要求1定义,
反应,从而获得式(VI)的化合物:
其中R1、R2和R9根据以上定义;
式(I)的化合物能够根据包括以下步骤的方法制备:
步骤7)使根据步骤2、4或6中所述获得的式(VI)的化合物
其中R1和R2根据权利要求1定义,并且R9是选自直链或支链(C1-C6)烷基的基团,
在酸或碱性水解条件下反应,以获得式(XI)的化合物或相应的盐;
其中R1和R2根据以上定义;
步骤8)使步骤7中所述的式(XI)的化合物或相应的盐与式(XII)的化合物
其中R3和R4根据权利要求1中定义,
反应,从而获得式(I)的化合物
其中R1、R2、R3和R4根据权利要求1中定义。
8.权利要求1中定义的式(I)的化合物或其药学上可接受的盐,用于在治疗由失调的Syk激酶活性引起的和/或与之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中定义的式(I)的化合物。
9.根据权利要求8所述的用于使用的化合物,其中所述疾病选自由癌症、细胞增殖性紊乱和免疫相关紊乱组成的组。
10.根据权利要求9所述的用于使用的化合物,其中所述疾病是癌症。
11.根据权利要求10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:上皮癌,诸如上皮癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、肺癌包括小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌和皮肤癌,包括鳞状细胞癌;淋巴系的造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、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,包括急性和慢性髓细胞性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质来源的肿瘤,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、胶质母细胞瘤、多形性胶质母细胞瘤、星形细胞瘤、少突胶质细胞瘤、副神经节瘤、神经母细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺癌诸如甲状腺乳头状癌和甲状腺髓样癌、卡波西肉瘤、软骨肉瘤和胆管细胞癌。
12.权利要求1中定义的式(I)的化合物或其药学上可接受的盐,用作药物。
13.一种治疗由失调的Syk激酶活性引起的和/或与之相关的疾病的方法,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中定义的式(I)的化合物。
14.根据权利要求13所述的方法,其中所述疾病选自由癌症、细胞增殖性紊乱和免疫相关紊乱组成的组。
15.根据权利要求14所述的方法,其中所述疾病是癌症。
16.根据权利要求15所述的方法,其中所述癌症选自由以下组成的组:上皮癌,诸如上皮癌,诸如上皮癌,诸如膀胱癌、乳腺癌、肾癌、肝癌、结肠癌、肺癌包括小细胞肺癌、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、前列腺癌和皮肤癌,包括鳞状细胞癌;淋巴系的造血肿瘤,包括白血病、急性淋巴细胞白血病、急性成淋巴细胞白血病、慢性淋巴细胞白血病、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,包括急性和慢性髓细胞性白血病、骨髓增生异常综合征和早幼粒细胞白血病;间充质来源的肿瘤,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、胶质母细胞瘤、多形性胶质母细胞瘤、星形细胞瘤、少突胶质细胞瘤、副神经节瘤、神经母细胞瘤和神经鞘瘤;以及其他肿瘤,包括黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺癌诸如甲状腺乳头状癌和甲状腺髓样癌、卡波西肉瘤、软骨肉瘤和胆管细胞癌。
17.一种药物组合物,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中定义的式(I)的化合物或其药学上可接受的盐。
18.根据权利要求17所述的药物组合物,还包含一种或更多种化疗剂。
19.一种产品或药盒,包含根据权利要求1中定义的式(I)的化合物或其药学上可接受的盐,以及一种或更多种化疗剂,作为在抗癌疗法中同时、单独或顺序使用的组合制品。
20.权利要求1中定义的式(I)的化合物或其药学上可接受的盐在制备具有抗癌活性的药物中的用途。
21.根据权利要求13所述的方法,与放射疗法或与化疗方案组合。
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