CN101410387A - 作为激酶抑制剂的吡啶基-和嘧啶基-取代的吡咯-、噻吩-和呋喃-衍生物 - Google Patents
作为激酶抑制剂的吡啶基-和嘧啶基-取代的吡咯-、噻吩-和呋喃-衍生物 Download PDFInfo
- Publication number
- CN101410387A CN101410387A CNA2007800105016A CN200780010501A CN101410387A CN 101410387 A CN101410387 A CN 101410387A CN A2007800105016 A CNA2007800105016 A CN A2007800105016A CN 200780010501 A CN200780010501 A CN 200780010501A CN 101410387 A CN101410387 A CN 101410387A
- Authority
- CN
- China
- Prior art keywords
- pyrroles
- acid amides
- phenyl
- benzoic acid
- pyrimidine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- -1 pyrimidinyl-substituted pyrrole- Chemical class 0.000 title claims description 130
- 229940043355 kinase inhibitor Drugs 0.000 title description 4
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- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 133
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- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明提供了式(I)化合物,或其药学可接受的盐,其中G、W、R2、R3、R4、R5和R6如说明书所定义。本发明进一步的目的是制备所述式(I)化合物的方法和中间体,包含式(I)化合物的药物组合物及用于治疗细胞增殖障碍的方法。事实上,式(I)化合物在疗法中可用于治疗与失调的蛋白激酶活性相关的疾病例如癌症。
Description
本发明涉及杂戊环,其制备方法,包含其的药物组合物以及其用作治疗剂的用途,特别是在治疗癌症和细胞增殖障碍中的用途。
蛋白激酶(PK)的机能失常是很多疾病的标志。许多与人类癌症相关的致癌基因和原癌基因编码蛋白激酶。蛋白激酶活性的增强还与许多非恶性疾病有关。关于蛋白激酶机能失常或异常调节的综合参考,例如参见,Current Opinion in Chemical Biology 1999,3,459-465。
在本领域已知的几种蛋白激酶中,与癌细胞生长有关的蛋白激酶是Cdc7,一种进化而又保守的丝氨酸-苏氨酸激酶,其在连接细胞周期调节与基因复制中具有关键的作用,对触发DNA复制起点是必需的(参见Montagnoli A.等人,EMBO Journal,2002,Vol.21,No.12,3171;Montagnoli A.等人,Cancer Research 2004,Vol.64,October1,7110)。
在本领域中已知几种作为蛋白激酶抑制剂的杂环化合物。尤其是,例如公开于WO2002/12242的吡咯并吡唑类;公开于WO2000/69846的四氢吲唑类;公开于WO2001/98299的吡咯并吡啶类;公开于WO2003/014090的氨基2,3-二氮杂萘酮类(aminophthalazinone)以及公开于的WO2003/028720氨基吲唑类。WO2001/001986和WO98/35944公开了吡咯衍生物,WO2002/030358中报导了噻唑衍生物以及在WO2005/095386中要求保护作为激酶抑制剂的噻吩。WO2006/012642公开了吡咯衍生物调节一种或多种类固醇细胞核受体的活性,且WO2003/068749公开了呋喃衍生物调节类香草醛受体(vanilloid receptor)。
在EP853083中描述了吡啶基呋喃和吡啶基噻吩作为TNFα生物合成和CAM表达的抑制剂;在WO98/02430中公开了吡啶基吡咯作为白细胞介素和肿瘤坏死因子的拮抗剂;其中还公开了吡咯酸和酯。在WO95/04729中公开了包含呋喃环的哌嗪基苯基甲酰胺衍生物作为5-HT1D受体拮抗剂。在WO2005/100342中公开并要求保护具有抗增殖活性和Erk2激酶抑制活性的嘧啶/吡啶取代吡咯类。在WO2000/006085中公开并要求保护作为CCR5受体调节剂的杂环酰胺类。
本发明人现在发现一些在治疗中作为药剂的化合物,所述药剂针对由异常调节的蛋白激酶活性(更具体地Cdc 7或Cdc 7/Cdks活性)引起和/或与异常调节的蛋白激酶活性(更具体地Cdc7或Cdc7/Cdks活性)相关的疾病。
本发明的另一个目的是提供具有蛋白激酶抑制活性的化合物,且更具体的具有Cdc7或Cdc7/Cdk抑制活性的化合物。尤其是,本发明提供具有蛋白激酶抑制活性的杂戊环,特别是具有Cdc7或Cdc7/Cdk抑制活性的杂戊环。
更具体地,本发明的这些化合物用于治疗各种癌症包括但不限制于:癌例如膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌、和皮肤癌(包括鳞状细胞癌);淋巴细胞系造血肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、何杰金淋巴瘤、非何杰金淋巴瘤、多毛细胞白血病和Burkitt淋巴瘤;骨髓系造血肿瘤,包括急性和慢性髓性白血病、脊髓发育不良综合征和早幼粒细胞性白血病;间质起源的肿瘤(tumors of mesenchymal or igin),包括纤维肉瘤和横纹肌肉瘤;中枢及外周神经系统肿瘤,包括星细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;其它肿瘤,包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化黄瘤(keratoxanthoma)、滤泡状甲状腺癌和卡波西肉瘤。
由于蛋白激酶、特别是Cdc7和Cdks如Cdk2在调节细胞增殖中的关键作用,这些杂戊环还用于治疗各种细胞增殖障癌例如,如良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤、牛皮癣、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、肾小球性肾炎和术后狭窄与再狭窄。
本发明的化合物还可以作为其他蛋白激酶(例如,如不同同种型的蛋白激酶C、Met、PAK-4、PAK-5、ZC-I、STLK-2、DDR-2、Aurora1、Aurora2、Bub-1、PLK、Chk1、Chk2、HER2、raf1、MEK1、MAPK、EGF-R、PDGF-R、FGF-R、IGF-R、VEGF-R、PBK、weel激酶、Src、Abl、Akt,ILK、MK-2、IKK-2、Nek、CK2、GSK3、SULU、PKA、PKC、PDK、RET、KIT、LCK和TRKA)的激酶抑制剂,因此在治疗与其他蛋白激酶相关的疾病中是有效的。
因此,在第一个实施方案中,本发明提供了式(I)化合物:
其中
G为CH或氮原子;
W为氧原子、NR1或S(O)n;n为0、1或2;
R1和R3独立地表示氢原子或任选取代的选自烷基、环烷基、链烯基、炔基、杂环基、杂环烷基、芳基、芳烷基、杂环氧基-烷基和烷氧羰基的基团;
R2为氢原子或卤原子,或任选取代的选自芳基、环烷基和杂环基的基团;
R4为氢原子或卤原子,或任选取代的烷基或链烯基;
R5为氢原子或卤原子;
R6为氢原子或NHR7;
R7为氢原子,任选取代的选自烷基、芳基、环烷基和杂环基的基团,或-CO-R1,其中R1如上所定义;
或其药学上可接受的盐,条件为下述化合物除外:
2,5-二(吡啶-4-基)-噻吩-3-甲酸酰胺,
2,5-二(吡啶-4-基)-噻吩-3-甲酸甲酰胺,
2,5-二(吡啶-4-基)-4-甲基-吡咯-3-甲酸酰胺,
5-吡啶-4-基-呋喃-3-甲酸[4-甲氧基-3-(4-甲基-哌嗪-1-基)-苯基]-酰胺,
5-吡啶-4-基-呋喃-3-甲酸(1-甲基-1,2,3,4-四氢-喹啉-7-基)-酰胺,和
N-[2-氨基-1-(2,4-二氯苄基)乙基]-5-[2-(甲氨基)嘧啶-4-基]噻吩-3-甲酰胺。
式(I)化合物(本发明的目的)可通过包括根据常规技术进行的熟知反应的合成方法以及非常万能的固相和/或组合方法获得,上述方法获得的式(I)化合物均包括在本发明的范围内。
本发明还提供药学组合物,其包括上述定义的式(I)化合物和至少一种药学可接受的赋形剂、载体或稀释剂。
优选地,式(I)化合物的特征在于W为NR1,R1和R3独立地表示氢原子或任选取代的烷基,且R6为NHR7,其中R7为氢原子,或任选取代的芳基。
更优选地,式(I)化合物的特征在于W为NR1;R1表示氢原子或任选取代的烷基;R3和R4表示氢原子,R2为任选取代的芳基或杂环基;且R6为NH2。
甚至更优选的为式(I)化合物,其中W为NH或R3表示氢原子。本发明具体而非限制性的优选式(I)化合物(合适时为其药学可接受的盐的形式)如下:
2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A1),
2-(2-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A2),
2-(3-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A3),
2-(4-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A4),
5-吡啶-4-基-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(A7),
5-吡啶-4-基-2-间-甲苯基-1H-吡咯-3-甲酸酰胺(A8),
5-吡啶-4-基-2-对-甲苯基-1H-吡咯-3-甲酸酰胺(A9),
2-(3-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A11),
2-(4-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A12),
2-(2-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A13),
2-(3-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A14),
2-(2,3-二甲基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A20),
5-吡啶-4-基-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺(C1),
2-呋喃-3-基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(C2),
5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(E1),
5-(3-氟-吡啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(E2),
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(F1),
5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(F2),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F4),
5-(2-氨基-嘧啶-4-基)-2-(4-氟-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F13),
5-(2-氨基-嘧啶-4-基)-2-(5-氟-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F14),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸酰胺(F15),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二氟-苯基)-1H-吡咯-3-甲酸酰胺(F16),
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氟-苯基)-1H-吡咯-3-甲酸酰胺(F17),
5-(2-氨基-嘧啶-4-基)-2-(2,5-二氟-苯基)-1H-吡咯-3-甲酸酰胺(F18),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-苯基)-1H-吡咯-3-甲酸酰胺(F19),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-氟-苯基)-1H-吡咯-3-甲酸酰胺(F23),
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸酰胺(F26),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F28),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-3-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F30),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-5-氟-苯基)-1H-吡咯-3-甲酸酰胺(F31),
5-(2-氨基-嘧啶-4-基)-2-(3-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F33),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二氯-苯基)-1H-吡咯-3-甲酸酰胺(F34),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-3-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F35),
5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F36),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-苯基)-1H-吡咯-3-甲酸酰胺(F38),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-3-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F39),
5-(2-氨基-嘧啶-4-基)-2-(3-甲氧基-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F40),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-3-氟-苯基)-1H-吡咯-3-甲酸酰胺(F41),
5-(2-氨基-嘧啶-4-基)-2-(3-溴-2-氯-苯基)-1H-吡咯-3-甲酸酰胺(F42),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-3-氯-苯基)-1H-吡咯-3-甲酸酰胺(F43),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二溴-苯基)-1H-吡咯-3-甲酸酰胺(F44),
5-(2-氨基-嘧啶-4-基)-2-(3-溴-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F45),
5-(2-氨基-嘧啶-4-基)-2-(3-溴-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F46),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-3-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F47),
5-(2-氨基-嘧啶-4-基)-2-(4-甲氧基-3-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F48),
5-(2-氨基-嘧啶-4-基)-2-(3,4-二甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F49),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F50),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F51),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-4-氟-苯基)-1H-吡咯-3-甲酸酰胺(F52),
5-(2-氨基-嘧啶-4-基)-2-(4-甲氧基-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F53),
5-(2-氨基-嘧啶-4-基)-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺(G1),
5-(2-氨基-嘧啶-4-基)-2-噻吩-2-基-1H-吡咯-3-甲酸酰胺(G2),
5-(2-氨基-嘧啶-4-基)-2-(5-甲基-噻吩-2-基)-1H-吡咯-3-甲酸酰胺(G3),
5-(2-氨基-嘧啶-4-基)-2-(5-氯-噻吩-2-基)-1H-吡咯-3-甲酸酰胺(G4),
5-(2-氨基-5-氯-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(N1),
5-(2-氨基-5-溴-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(N2),
5-(2-氨基-嘧啶-4-基)-4-碘-2-苯基-1H-吡咯-3-甲酸酰胺(N3),
5-(2-氨基-5-氯-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺(N7),
5-(2-氨基-5-溴-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺(N8),
5-(2-氨基-嘧啶-4-基)-2-苯基-噻吩-3-甲酸酰胺(S1),
5-(2-氨基-5-氟-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(V1),和
5-(2-氨基-嘧啶-4-基)-4-氯-2-苯基-1H-吡咯-3-甲酸酰胺(Z1)。
根据本发明更优选的化合物为:5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸酰胺(F15),5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸酰胺(F26)和5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F36),或其药学可接受的盐。
还提供了治疗由改变的Cdc7激酶活性引起和/或与其相关的细胞增殖障碍的方法,所述方法通过给有需要的哺乳动物施用有效量的如上定义的式I化合物。
在上述方法的一个优选实施方案中,所述细胞增殖障碍是癌症。
可以治疗的具体癌症类型包括癌、鳞状细胞癌、骨髓或淋巴细胞系造血肿瘤、间叶组织肿瘤、中枢及外周神经系统肿瘤、黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、滤泡状甲状腺癌和Kaposi肉瘤。
杂戊环的键是芳香性的;所述杂戊环的编号显示如下:
在本说明书中,除非具体说明,下面的术语具有下述含义。
为了方便,芳基、环烷基和杂环基有时统称为“环基”。
术语“烷基”或“Alk”指具有1至6个碳原子的直链或支链单价饱和脂肪族烃基。该术语举例为,例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。“取代烷基”指具有1至3个选自下述的取代基的烷基:烷氧基、取代烷氧基、酰基、酰氨基、酰氧基、氨基、取代氨基、氨酰基、芳基、取代芳基、芳氧基、取代芳氧基、氰基、卤素、羟基、硝基、羧基、羧酸酯、环烷基、取代环烷基、杂环基和取代杂环基。
“环烷基”指具有单个或多个环的3至10个碳原子的环烷基例如包括金刚烷基、环丙基、环丁基、环戊基、环己基、环辛基等。
“取代环烷基”指具有1至5个取代基的环烷基,所述取代基选自:氧代(=O)、硫代(=S)、烷氧基、取代烷氧基、酰基、酰氨基、酰氧基、氨基、取代氨基、氨酰基、芳基、取代芳基、芳氧基、取代芳氧基、氰基、卤素、羟基、硝基、羧基、羧酸酯、环烷基、取代环烷基、杂环基和取代杂环基。
“链烯基”指具有2至6个碳原子的链烯基。所述基团例如为乙烯基、烯丙基、丁-3-烯-1-基等。
“取代链烯基”具有1至3个、优选1至2个取代基的链烯基,所述取代基选自:烷氧基、取代烷氧基、酰基、酰氨基、酰氧基、氨基、取代氨基、氨酰基、芳基、取代芳基、芳氧基、取代芳氧基、氰基、卤素、羟基、硝基、羧基、羧酸酯、环烷基、取代环烷基、杂环基,和取代杂环基,条件为任何羟基取代不与乙烯基(不饱和)碳原子相连。
“炔基”指具有2至6个碳原子的炔基。“取代炔基”指具有1至3个、优选1至2个取代基的炔基,所述取代基选自:烷氧基、取代烷氧基、酰基、酰氨基、酰氧基、氨基、取代氨基、氨酰基、芳基、取代芳基、芳氧基、取代芳氧基、氰基、卤素、羟基、硝基、羧基、羧酸酯、环烷基、取代环烷基、杂环基、和取代杂环基,条件为任何羟基取代不与乙炔(不饱和)碳原子相连。
“烷氧基”指基团“烷基-O-”,例如包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基等。
“取代烷氧基”指基团“取代烷基-O-”。
“酰基”指基团:H-C(O)-、烷基-C(O)-、取代烷基-C(O)-、环烷基-C(O)-、取代环烷基-C(O)-、芳基-C(O)-、取代芳基-C(O)-、杂环基-C(O)-和取代杂环基-C(O)-,其中烷基、取代烷基、环烷基、取代环烷基、芳基、取代芳基、杂环基和取代杂环基如本文所定义。
“酰氨基”指基团-C(O)NR′R′其中每个R′独立地选自氢、烷基、取代烷基、取代芳基、环烷基、取代环烷基、杂芳基、取代杂芳基、杂环基、取代杂环基,且其中每个R′可以与氮原子连接在一起以形成杂环或取代杂环,且其中烷基、取代烷基、环烷基、取代环烷基、芳基、取代芳基、杂环基和取代杂环基如本文所定义;
“酰氧基”指基团:烷基-C(O)O-、取代烷基-C(O)O-、芳基-C(O)O-、取代芳基-C(O)O-、环烷基-C(O)O-、取代环烷基-C(O)O-、杂环基-C(O)O-和取代杂环基-C(O)O-,其中烷基、取代烷基、环烷基、取代环烷基、芳基、取代芳基、杂环基和取代杂环基如本文所定义。
“取代氨基”指基团-NR′R′其中R′如上所定义,条件为两个R′均不为氢。当一个R′为氢且另一个R′为烷基时,所述取代氨基有时在本文中指烷基氨基。当两个R′均为烷基时,所述取代氨基有时在本文中指二烷基氨基。当指单取代氨基时,意味着有一个R′是氢但不是两个都是氢。当指二取代氨基时,意味着R′均不为氢。
“氨酰基”指基团:-NR′C(O)烷基、-NR′C(O)取代烷基、-NR′C(O)环烷基、-NR′C(O)取代环烷基、-NR′C(O)芳基、-NR′C(O)取代芳基、-NR′C(O)杂环基和-NR′C(O)取代杂环基,其中R如上所定义。
“羧基”指-COOH或其盐。
“羧酸酯”指基团:-C(O)O-烷基、-C(O)O-取代烷基、-C(O)O-芳基和-C(O)O-取代芳基,其中烷基、取代烷基、芳基和取代芳基如本文所定义。
“卤”或“卤素”或“X”指氟、氯、溴和碘,且优选为氟、氯或溴。
“芳基”或“Ar”指6至14个碳原子的单价芳香碳环,其具有一个单环(例如苯基)或多个稠合环(例如萘基或蒽基),其中稠合环可以是芳香或不芳香的(例如2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等),只要连接点在芳香碳原子处。优选的芳基包括苯基和萘基。
“取代芳基”指被1至3个取代基取代的芳基,所述取代基选自羟基、酰基、酰氨基、酰氧基、烷基、取代烷基、烷氧基、取代烷氧基、氨基、取代氨基、氨酰基、芳基、取代芳基、芳氧基、取代芳氧基、羧基、羧酸酯,氰基、环烷基、取代环烷基、卤素、硝基、杂环基、取代杂环基、杂环氧基、取代杂环氧基、氨基磺酰基(NH2-SO2-),和取代氨基磺酰基。
“芳氧基”指芳基-O-,例如包括苯氧基、萘氧基等。
“取代芳氧基”指取代芳基-O-。
“杂环基”指具有一个单环或多个稠合环的饱和或不饱和基团,在环中具有1至10个碳原子和1至4个杂原子,所述杂原子选自氮、硫或氧,其中,在稠和环体系中,一个或多个环可以是环烷基,芳基或杂芳基,只要连接点通过杂环。
“取代杂环基”指被1至3个取代基取代的杂环基,所述取代基的定义与取代环烷基的取代基相同。
杂环基的实例包括但不限制于,吡啶基、吡咯基、吲哚基、噻吩基、呋喃基、苯并噻吩基、苯并呋喃基、咪唑基、苯并咪唑基、吡唑基、噻唑基、苯并噻唑基、异噻唑基、噁唑基、异噁唑基、吡嗪基、嘧啶基、哒嗪基、异吲哚基、嘌呤基、喹啉基、异喹啉基、二氢喹啉基、2,3-二氢-1H-吲哚基、喹喔啉基、苯并间二氧杂环戊烯基、茚满基、茚基、三唑基、氮杂环丁烷基、中氮茚基、二氢吲哚基、吲唑基、喹嗪基、酞嗪基、萘基吡啶基、喹唑啉基、噌啉基、蝶啶基、咔唑基、咔啉基、菲啶基、吖啶基、菲罗啉基、吩嗪基、吩噁嗪基、吩噻嗪基、咪唑烷基、咪唑啉基、哌啶基、哌嗪基、二氢吲哚基、邻苯二甲酰亚胺基、1,2,3,4-四氢-异喹啉基、4,5,6,7-四氢苯并[b]噻吩基、噻唑啉基、吗啉基、硫代吗啉基(也指硫吗啉基)、哌啶基、吡咯烷基、吡咯啉基、吡唑啉基、吡唑烷基和四氢呋喃基。
应该注意当指杂环基和取代杂环基时,可以任选氧化可能存在的任何氮原子或硫原子。
根据上面的所有描述,显然,对本领域技术人员而言例如被定义为卤代烷基、烷氧基、烷氧羰基、芳氧基、杂芳氧基、氨基烷基、烷基氨基、烷基氨基烷基、二烷基氨基烷基等的任何基团或取代基,不得不从它们所衍生的基团名称来解释。
在这方面,例如,应该认为被确定为芳烷基或杂环烷基的任何基团为进一步被芳基或杂环基取代的烷基,其中芳基、杂环基和烷基如上所定义。
本发明的式(I)化合物可以具有不对称碳原子,因此可以以单独的光学异构体、外消旋混合物或任何其他主要包括两种光学异构体中一种的混合物存在,意图将这些都包括在本发明的范围内。
在化合物以互变异构体形式存在的情况下,例如酮-烯醇互变异构体,预期将每种互变异构体包括在本发明中,无论其以平衡存在或主要以一种形式存在。
类似的,作为式(I)化合物的所有可能异构体及其混合物的抗肿瘤试剂的用途,以及作为式(I)化合物的两种代谢物和药学可接受的生物前体(也称为药学可接受的前药)的抗肿瘤试剂的用途也在本发明的范围内。
如本文所使用的,术语“药学可接受的盐”指式I化合物的无毒的酸或碱土金属盐。这些盐可以在最后分离和纯化式I化合物的过程中原位制备,或通过分别使碱性官能团或酸性官能团与合适的有机或无机酸或碱反应来制备。代表性的盐包括但不限制于:醋酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡萄糖酸盐、环戊烷丙酸盐、十二烷基硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、palmoate、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐和十一酸盐。此外,含碱性氮原子的基团也可以用试剂例如烷基卤化物季铵化,所述的烷基卤化物例如为氯代甲烷、氯代乙烷、氯代丙烷、氯代丁烷、溴代甲烷、溴代乙烷、溴代丙烷、溴代丁烷、碘代甲烷、碘代乙烷、碘代丙烷和碘代丁烷,二烷基硫酸盐如二甲基硫酸盐、二乙基硫酸盐、二丁基硫酸盐,和二戊基硫酸盐,长链卤化物例如癸基氯、月桂基氯、氯代十四烷、氯代十八烷、癸基溴、月桂基溴、溴代十四烷、溴代十八烷、癸基碘、月桂基碘、碘代十四烷和碘代十八烷,芳烷基卤化物例如苄基溴、溴代苯乙基及其它。由此获得的水溶、油溶或可分散产物。
可以用来形成药学可接受的酸加成盐的酸的实例包括无机酸例如盐酸,硫磺酸、硝酸、氢溴酸、高氯酸和磷酸,及有机酸例如草酸、马来酸、甲磺酸、琥珀酸和柠檬酸、乙酸、三氟乙酸、丙酸、乙醇酸、乳酸、丙二酸、苹果酸、酒石酸、苯甲酸、肉桂酸、扁桃酸、羟乙基磺酸和水杨酸。
在式I化合物的最终分离和纯化过程中可以在原位制备碱加成盐,或分别通过羧酸部分与合适的碱例如药学可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐反应,或与氨、或有机伯胺、仲胺或叔胺反应来制备碱加成盐。药学可接受的盐包括但不限制于基于碱金属和碱土金属的阳离子,例如钠盐、锂盐、钾盐、钙盐、镁盐、铝盐等,以及铵、季铵和胺阳离子,包括但不限制于铵、四甲基铵、四乙铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。其他用于形成碱加成盐的代表性有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。
本文使用的术语“药学可接受的前药”和“药学可接受的生物前体”指本发明化合物的那些前药,其在充分医学判断的范围内适用于与人和低等动物的组织接触而没有过度的毒性、疼痛、过敏反应等,与合理的利益/风险比相符合,且对它们的预期用途有效,以及当可能时为本发明化合物的两性离子形式。术语“前药”指在体内快速转化以产生活性母体药物的式(I)化合物,例如在体内通过在血液中水解。在T.Higuchi和V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series和Edward B.Roche,ea.,Bioreversible Carriers in Drug Design,American PharmaceuticalAssociation and Pergamon Press,1987中提供了这方面的讨论,两者均通过参考并入本文。
如前面指出的,本发明的另一个目的是如上定义的式(I)化合物及其药学可接受的盐的制备方法。
可以使用下述一般方法和步骤从容易获得的原料制备本发明化合物。除非另外指出,原料为已知的化合物或可以根据熟知的步骤从已知化合物制备。将意识到给出了典型的或优选的生产条件(即,反应温度、时间、反应物的摩尔比、溶剂、压力),除非另外指出,还可以使用其他生产条件。最佳反应条件可以根据所使用的特定反应物或溶剂而改变,但所述条件可以由本领域技术人员根据常规优化步骤确定。此外,如对本领域技术人员显而易见的,可能需要常规的保护基团来阻止某些功能团进行不需要的反应。适合各种官能团的保护基团以及适合保护和去保护特定官能团的条件在本领域中是熟知的。例如,在T.W.Greene 和P.G.M.Wuts,Protecting Groups in OrganicSynthesis,第二版,Wiley,New York,1991和其引用的参考文献中描述了多种保护基团。
本发明特别提供了一种方法,包括:
a)使式1E化合物
其中R1、R4、R5、R6和G如上所定义,且环基为任选取代的选自芳基、环烷基和杂环基的基团,
任选在缩合剂的存在下与活化形式的氨偶联,或与式R3-NH2的胺偶联,其中R3如上所定义,由此获得如上定义的式(I)化合物,其中W为NR1,其中R1如权利要求1所定义,且R2为任选取代的芳基、环烷基或杂环基;
b)任选将式(I)化合物转变为另一种不同的式(I)化合物,且如果需要,将式(I)化合物转变成其药学可接受的盐,或将盐转变成游离的化合物(I)。
将1E转变成所需式(I)化合物的偶联可以通过熟知的一级酰胺-形成方法来进行[例如,1-羟基-苯并三唑铵盐(HOBT-NH3),在1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)或O-苯并三唑-1-基-N,N,N′,N′-四甲基脲鎓四氟硼酸盐(TBTU)或CDI与碳酸铵存在下];转变成仲酰胺可以在各种熟知的酰胺形成条件下通过与式R3-NH2的胺偶联来进行,其中R3如上所定义。
同样地,根据本领域熟知的步骤进行式(I)化合物的成盐或将其盐转变成游离化合物(I)也在本发明的范围内。
在下述方案1中描述式1E化合物的制备。
方案1
其中R1、R4、R5、R6、G和环基如上所定义,X为卤原子例如溴或氯,且Alk为C1-C5烷基。
可以通过下述步骤来形成化合物1D:在-20℃至50℃之间的温度下,在合适的碱例如氢化钠存在下,在溶剂如四氢呋喃(THF)或二甲基甲酰胺(DMF)中偶联卤代酮1A与β-酮酯1B;然后将中间体1C暴露于Hantzsch反应条件下,在醋酸铵(当R1=H)或式R1-NH2的胺存在下,在合适的溶剂例如乙醇或乙酸或两者的混合物中,在室温至150℃之间的温度下,任选在微波腔中进行10分钟至16小时。然后可以在标准的碱性条件下皂化酯1D得到式IE的酸。
在一些情况下,当R4不同于氢原子时,1D的酯水解可能得到脱羧的类似物。因此,提供了式I化合物的另一种制备方法,其包括酰胺化式5D化合物:
其中R1、R5、R6、G和环基如上所定义,且R4不是氢原子,和b)任选将式(I)化合物转变为另一种不同的式(I)化合物,且如果需要,将式(I)化合物转变为其药学上可接受的盐或将盐转变为游离的化合物(I)。在这种情况下,根据例如在Synthesis 1978,374中所描述的来实现酰胺化,其通过在合适的溶剂例如乙腈、二氯甲烷或二乙醚中将化合物5D暴露于氯磺酰基异氰酸酯,并用碱处理所得到的氯磺酰胺以获得相应的氨基磺酸。然后在酸性介质例如浓盐酸中水解氨基磺酸得到所需的式(I)化合物。
式1A和1B的化合物,以及该方法的任何其他反应物是已知的,且如果本身不能商购获得,可以根据已知方法容易制备。式IA化合物可以通过卤化来制备,例如通过溴化或氯化合适的杂芳基-乙酮衍生物或活化的等价物。在常规方法下进行所述反应,例如在溴的存在下并在合适溶剂例如氢溴酸水溶液或乙酸和氢溴酸的混合物中,持续约1个小时至约24小时。或者,可以使合适的活化杂芳基衍生物,例如烷基烯醇醚(alkylenolether)或甲硅烷基烯醇醚(silylenolether)与卤素来源(例如N-溴-琥珀酰亚胺(NBS))在合适溶剂例如四氢呋喃/水混合物中反应。
尤其在合适的式IA卤素衍生物中,考虑2-溴-1-吡啶-4-基-乙酮(商购的)、2-溴-1-(3-氟-吡啶-4-基)-乙酮(报导于WO2005013986)、2-溴-1-吡啶-4-基-丙-1-酮(商购的)、2-溴-1-嘧啶-4-基-乙酮(报导于WO2005014572)、1-(2-氨基-嘧啶-4-基)-2-溴-乙酮(商购的)、2-溴-1-(2-氯-吡啶-4-基)-乙酮(报导于WO2004058762)、2-溴-1-(2-甲巯基-嘧啶-4-基)-乙酮(报导于WO2003011838)、1-(2-氨基-5-氟-嘧啶-4-基)-2-溴-乙酮1′A(方案2.1.)和2-溴-1-(2-苯基氨基-嘧啶-4-基)-乙酮1″A(方案2.2.)。
在将合适的杂芳基-乙酮衍生物进行卤化中,考虑例如,1-(3-氟吡啶-4-基)乙酮(商购的)、1-(2-氯吡啶-4-基)乙酮(商购的)、1-(嘧啶-4-基)乙酮(商购的)、1-[2-(甲硫基)嘧啶-4-基]乙酮(商购的)和4-(1-乙氧基-乙烯基)-5-氟-嘧啶-2-基-胺iii(参见方案2.1.)。
可以根据下述反应顺序(方案2.1.)得到中间体1-(2-氨基-5-氟-嘧啶-4-基)-2-溴-乙酮1′A(IA,其中R4=H,R5=F,G=N,R6=NH2,X=Br):
方案2.1.
在标准条件和钯催化剂(例如双(三苯基膦)二氯化钯)存在下,商购获得的2,4-二氯-5-氟-嘧啶i与(1-乙氧基乙烯基)-叔丁基锡烷在DMF中反应得到相应的4-乙烯基醚ii。通过用乙醇中的浓缩氨水直接处理并用微波加热在2位引入所述氨基(iii),同时用NBS的水溶液溴化所述乙烯基醚得到α-溴-酮(1′A)。
在将甲硅烷基烯醇醚进行卤化中,例如考虑(叔丁基-二甲基-硅烷基)-{4-[1-(叔丁基-二甲基-硅烷氧基)-乙烯基]-嘧啶-2-基}-苯基-胺iv(报导于WO2005014572),根据方案2.2中显示的反应步骤可以从iv获得溴酮1″A(IA,其中R4=R5=H,G=N,R6=NHAr,X=Br)。
方案2.2.
其中Ar表示如上定义的芳基。
可以在常温下,在四氢呋喃水溶液中用N-溴琥珀酰亚胺迅速卤化式(iv)化合物(持续约20小时)。当不能商购获得式IB化合物时,可以根据参考文献采用不同的方法来制备。例如,与β-酮酯同系化的酸可以由酰氯或羧酸通过用2,2-二甲基-1,3-二噁烷-4,6-二酮(Meldrum氏酸)活化而获得(描述于J.Med.Chem.2001,44,90),从酰氯和氢丙二酸乙酯(ethyl hydrogenmalonate)获得(报导于J.Het.Chem.1990,27,1609),或从芳基乙酮与碳酸二乙酯获得(显示于Can.J.Chem.1992,1323)。
或者,如上定义的式(I)化合物可以通过下述步骤获得a′)使式2D化合物,
其中R2是氢原子或卤原子,且R5、R6、和G如上所定义,
任选在缩合剂的存在下与活化形式的氨偶联,或与具有式R3-NH2的氨偶联,其中R3如上所定义,由此获得如上定义的式(I)化合物,其中W为N,R1为氢原子和R2为氢原子或卤原子;
a′1)任选将所得的式(I)化合物(其中R2为卤原子)转变为另一个式(I)化合物,其中R2为氢原子或任选取代的选自如上定义的芳基、环烷基和杂环基的基团;和/或
a′2)将所得的式(I)化合物,其中R1为氢原子,转变为另一个式(I)化合物,其中R1为任选取代的选自烷基、环烷基、链烯基、炔基、杂环基、芳基、杂环氧基-烷基和烷氧羰基的基团;
且如果需要将式(I)化合物转变为其药学上可接受的盐或将盐转变为游离化合物(I)。
通过在下述方案3中所示的类Pinner反应,类似于或对应于文献(例如,I1 Farmaco 1999,54,542或Tetrahedron Letters 1994,35,5989)中报导的方法制备式2D的原料。
方案3
其中R5、R6、X、G、环基和Alk如上所定义。
可以在合适的碱(例如在乙醇中的乙醇钠)的存在下,在常温至回流之间的温度下,通过用氰基酯2A处理如上定义的卤酮IA,持续1至16个小时来获得化合物2B。可以在溶剂如二氯甲烷或乙醚或其混合物中,在-20℃至回流之间的温度下(最常在室温下),通过将2B暴露于氢卤酸(例如在二噁烷中的盐酸或在乙酸中的氢溴酸)来获得卤代吡咯2C。通过卤代吡咯2C的脱卤化作用得到2-未取代吡咯,其可以例如通过氢解完成,得到4A。
或者,可以在卤代酯2C上实现2位上的官能团化以产生酯4D。然后可以在标准碱性条件下将酯2C、4A和4D皂化得到对应的酸2D。
或者,如上定义的式(I)化合物可以通过下述步骤获得:
a′)裂解式3A或3B化合物
其中R3、R5、R6、环基,X,G如上所定义,且标记表示化学分子与之连接的固相载体,且如果需要,将所得的式(I)化合物,其中W为氮原子且R2为卤素或任选取代的选自芳基、环烷基和杂环基的基团,转变成其药学上可接受的盐或将盐转变为游离的化合物(I)。
优选用TFA/DCM实现裂解。
上述制备的目的在于避免形成不想要的副产物。化合物3A和3B的制备显示于方案4。在EDCI和HOBT的存在下,通过室温下在DMF中搅拌过夜将酸2D负载到固相载体(例如树脂,如Rink酰胺MBHA树脂,事先在室温下在20%哌啶的DMF溶液中通过振荡来裂解)上,以形成酰胺3A,在酰胺3A上成功应用碳-碳键形成反应(例如Suzuki反应)得到式3B化合物。
方案4
其中R3、R5、R6、X、G、和环基如上所定义。
式1D的一个具体化合物(称为6D),其中所述环基具有一个取代基,可以任选被转化为式1D的不同化合物(称为7D),如方案5所示。
方案5
其中R1、R4、R5、R6、G、环基和Alk如上所定义,E为卤素、三氟甲磺酸酯基、甲磺酸酯基或甲苯磺酸酯基,且M为芳基、杂芳基、杂环基、链烯基、炔基或任选取代的氨基部分。
具体的环基部分,即合适的取代芳环或杂环,具有一个如上定义的取代基E,可以使用一系列文献中的熟知方法来形成碳-碳或碳-氮键,例如Suzuki、Stille、Sonogashira或Buchwald方法,能产生所需的结果7D,其中基团M如上所定义。
此外,本发明提供了一种方法,其包括:
a)使式7B化合物
其中W为氧原子或硫原子,R4、R5、R6和G如上所定义,且环基为任选取代的选自如上定义的芳基、环烷基和杂环基的基团,
或任选在缩合剂的存在下与活化形式的氨偶联,或与具有式R3-NH2的胺偶联,其中R3如上所定义,由此获得如上定义的式(I)化合物,其中W为氧原子或硫原子,且R2为任选取代的选自芳基、环烷基和杂环基的基团;
b)任选将式(I)化合物转变为另一种不同的式(I)化合物,且如果需要,将式(I)化合物转变成其药学上可接受的盐或将盐转变成游离的化合物(I)。在任选的步骤b)下,当W为硫原子时,可以通过文献中熟知的步骤氧化噻吩环得到对应的1-氧代或1,1-二氧代噻吩。
可以方便地由酮酯1C,例如通过用2,4-双(4-甲氧基苯基)-1,3-二噻-2,4-二磷杂环丁烷-2,4-二硫化物(劳氏试剂)环化获得混合物形式的通式7A的酯(属于噻吩和呋喃系列)。
在色谱分离后,将所述的两个酯分别进行标准的碱水解得到所需的酸7B(方案6)。
方案6
其中R4、R5、R6、G、W、环基和Alk如上所定义。
如上所述,可以任选地在式(I)化合物的芳香杂环成员上直接对其进行修饰以产生其他式(I)衍生物。例如,可以将吡咯8A的嘧啶环直接卤化以产生酰胺8B和8C。该转化可以在合适的溶剂中(例如THF或DMF),分别通过在约100℃下用NCS处理或在室温下用NBS处理来获得。或者,在相同条件下NIS将酰胺8A转变成相应的在吡咯的4位上卤化的酰胺8D。如果同一酰胺8A事先在氨基嘧啶核上进行保护而成为Boc衍生物,也可以在100℃在DMF中用NCS处理和在标准的酸性条件下通过脱保护将其转变成氯酰胺8E。如方案7所示,也可以实现连续双卤化和同时双卤化。当用NIS处理时,溴酰胺8C得到酰胺8F,且通过用NBS处理碘酰胺8D得到相同的结果。通过两当量的卤化剂同时二卤化酰胺8A得到酰胺8G和8H(分别用NBS和NIS处理后)。例如根据Tetr.Lett.1995,36,7043中描述的,经由Stille交叉偶联反应方案,通过直接乙烯化可以将酰胺8D转变为4-乙烯基衍生物8K。在25-200℃之间的温度下,在溶剂(例如二噁烷、DMF或其混合物)中,通过在钯催化剂(例如四(三苯基膦)钯或双(三苯基膦)二氯化钯)存在下,用乙烯基三丁基锡烷处理8D来进行反应。
方案7
其中R3、R5、R6、X、G和环基如上所定义。
式(I)化合物的另一种制备方法包括:
a)使式9化合物
其中L为离去基团,例如卤素、甲磺酰基或甲亚磺酰基,且R3、R5、环基和G如上所定义,
与活化形式的(如双(三甲基甲硅烷基)氨基锂)任选在缩合剂的存在下反应或与肼反应然后还原成胺,或与式R7-NH2的胺,其中R7如上所定义,在Pd催化偶联下反应,由此获得如上定义的式(I)化合物,其中W为NR1,R1为氢原子且R6为NH-R7;
且如果需要,将式(I)化合物转变成其药学上可接受的盐或将盐转变成游离的化合物(I)。
该方法的起始化合物9显示于方案8。
如J.He t.Chem.,1983,20,533中所描述的,卤代吡啶9,其中L为卤素(9A),例如可以由2-溴-1-(2-氯-吡啶-4-基)-乙酮获得,2-溴-1-(2-氯-吡啶-4-基)-乙酮通过卤化1-(2-氯吡啶-4-基)乙酮来制备,而1-(2-氯吡啶-4-基)乙酮由2-氯-4-氰基吡啶获得的。1-[2-(甲硫基)嘧啶-4-基]衍生物9,其中L为CH3-S-(9B),由2-溴-1-(2-甲硫烷基-嘧啶-4-基)-乙酮获得(描述于WO03/011838),可通过氧化(例如用臭氧)将其活化成对应的亚砜或砜9,其中L为CH3-S(O)-或CH3-S(O)2-(9D)。卤代嘧啶衍生物9,其中L为卤素且R5为氟(9C),还可以由2-溴-1-(2-氯-5-氟嘧啶-4-基)乙酮来制备,而2-溴-1-(2-氯-5-氟嘧啶-4-基)乙酮通过卤化1-(2-氯-5-氟嘧啶-4-基)乙酮获得,如WO04/058762所述依次制备。
方案8
其中R3、R5、X和环基如上所定义。
本发明的另一个目的为式ID或IE的中间体
其中G、Alk、环基、R1、R4、R5和R6如上所定义,条件为下述化合物除外:
1H-吡咯-3-甲酸,1-(甲氧基甲基)-4-甲基-2,5-二-4-吡啶基-,乙酯;
1H-吡咯-3-甲酸,2,5-二-4-吡啶基-,甲酯,
1H-吡咯-3-甲酸,4-甲基-2-苯基-5-(4-吡啶基)-,甲酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,与吗啉(1∶1)化合,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基,
1H-吡咯-3-甲酸,4-(甲氧基甲基)-2,5-二-4-吡啶基-,甲酯,
1H-吡咯-3-甲酸,4-丁基-2,5-二-4-吡啶基-,乙酯,
1H-吡咯-3-甲酸,4-(1-甲基乙基)-2,5-二-4-吡啶基-,乙酯,
1H-吡咯-3-甲酸,4-丙基-2,5-二-4-吡啶基-,乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,2-甲氧基乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,丁酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,丙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,1,1-二甲基乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,1-甲基乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,2-丙烯酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,苯基甲酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,甲酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,乙酯和
1H-吡咯-3-甲酸,4-乙基-2,5-二-4-吡啶基-,乙酯。
药理学
式(I)化合物为活性蛋白激酶抑制剂,并因此例如用于限制肿瘤细胞的异常增殖。
在治疗中,它们可用于治疗各种肿瘤(例如前面报导的那些),和用于治疗其他细胞增殖障碍,例如牛皮癣、与动脉硬化症相关的血管平滑细胞增殖和术后狭窄与再狭窄,以及用于治疗阿尔茨海默症。
Cdc7活性的抑制测试
通过基于使用Dowex树脂捕获技术的方法,确定公认Cdc7抑制剂的抑制活性和所选化合物的效力。
所述测试由放射性标记磷酸盐的转移(从激酶转移到受体底物)组成。从未反应的示踪剂中分离所得的33P-标记产物,将其转移到闪烁混合液中并在闪烁计数器中测量发射的光。
根据下述方案进行Cdc7/Dbf4活性的抑制测试。
在用γ33-ATP示踪的ATP存在下,通过Cdc7/Dbf4复合物对MCM2底物进行逆磷酸化(trans-phosphorylated)。在甲酸存在下通过加入Dowex树脂来停止所述方应。Dowex树脂颗粒捕获未反应的γ33-ATP并将其拖到孔的底部,而33P磷酸化的MCM2底物仍然留在溶液中。收集上清夜并转移到Opt iplate板中,通过β计数来评价底物的磷酸化程度。
根据下述方案,在96孔板中进行Cdc7/Dbf4活性的抑制测试。
向板的每个孔加入:
-10μl的测试化合物(在nM至uM的范围内的10个递增的浓度以生成剂量-响应曲线)。测试化合物的溶剂含有3%DMSO(终浓度为1%)
-10μl底物MCM2(6μM终浓度),冷ATP(2μM终浓度)和放射性ATP(与冷ATP为1/5000摩尔比)的混合物。
-10μl酶(Cdc7/Dbf4,2nM终浓度)起始反应。反应的缓冲溶液由50mM HEPES pH 7.9组成,HEPES含有15mM MgCl2、2mM DTT、3uM NaVO3、2mM磷酸甘油和0.2mg/ml BSA。
-在室温下温育60分钟后,在150mM甲酸存在下通过向每个孔中加入150μl的Dowex树脂来停止反应。另外温育60分钟后,取出50μL的悬浮液并转移到含有150μl MicroScint 40(Packard)的96孔OPTIPLATE中;振荡5-10分钟后,在Packard TOP-Countradioactivity reader中读数1分钟。
IC50的测定:在0.0005至10μM范围内的不同浓度下测试抑制剂。通过计算机程序Assay Explorer采用四参数逻辑方程(fourparameter logistic equation)来分析实验数据:
y=底部值+(端值-底部值)/(1+10^((logIC50-x)*斜率))
其中x为抑制剂浓度的对数,y为响应;y从底部开始并以S形到达顶部。
本发明的式(I)化合物显示对Cdc7/Dbf4的IC50值为1~1000nM。特别地,在下面显示了编号为A1、A2、A 3、A4、A5、A6、A7、A8、A9、A10、A11、A12、A20、C1、C2、E1、F1、G1、H1、L1、M2、M3、M4的化合物对Cdc7/Dbf4的IC50值为1~100nM。
此外,已经表征了所选化合物对许多其它激酶的特异性,尤其是Cdk2A、IGF1-R、Aurora-2、AKT1、PLK1、SULU1、ERK2、CK2、GSK3β、PKAα、PKCβ、VEGFR3、PDGFR。
Cdk2/细胞周期蛋白A活性的抑制测试
激酶反应:将在终体积为100μl缓冲溶液(TRI S HCl 10mM pH 7.5,MgCl2 10mM,7.5mM DTT)中的1.5μM组蛋白H1底物、25μMATP(0.2μCiP33γ-ATP)、30ng的杆状病毒共表达Cdk2/细胞周期蛋白A、10μM抑制剂加入到96U形底孔板的每一个孔中。在37℃温育10分钟后,用20μl EDTA 120mM来中止反应。
捕获:从每孔转移100μl到MultiScreen板上,使底物与磷酸纤维素过滤器结合。然后用不含Ca++/Mg++的PBS 150μl/孔洗涤板三次并用MultiScreen过滤系统过滤。
检测:在37℃下干燥过滤器,然后加入100μl/孔的闪烁剂,通过Top-Count仪器中放射性计数来检测33P标记组蛋白H1。
结果:分析数据并表示为参照酶的总活性(=100%)的抑制百分比。
进一步分析所有显示≥50%抑制的化合物,以研究和确定效力(IC50)以及通过Ki计算的抑制剂动力学曲线。
IC 50 测定:所用的方案与上述方案相同,其中在0.0045至10μM范围内的不同浓度下测试抑制剂。通过计算机程序GraphPad Prizm采用四参数逻辑方程来分析实验数据:
y=底部值+(端值-底部值)/(1+10^((logIC50-x)*斜率))
其中x为抑制剂浓度的对数,y为响应;y从底部开始并以S形到达顶部。
Ki计算:ATP和组蛋白H1底物的浓度分别为:ATP为4、8、12、24、48μM(含有按比例稀释的P33γ-ATP)和组蛋白为0.4、0.8、1.2、2.4、4.8μM,在不存在和存在两种不同的适当选择的抑制剂浓度下使用。
通过用于Ki测定的计算机程序“SigmaPlot”来分析实验数据,使用随机双反应系统方程:
其中A=ATP和B=组蛋白H1。
本发明化合物可以作为单独试剂施用,或者,与已知的抗癌治疗例如与下述药剂组合的放射治疗或化学疗法组合:细胞生长抑制剂或细胞毒剂、抗生素类药、烷化剂、抗代谢剂、激素药剂、免疫剂、干扰素类药、环氧化酶抑制剂(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、抗血管生成药(例如血管生成抑制剂)、法尼基转移酶抑制剂、ras-raf信号转导途径抑制剂、细胞周期抑制剂、其它cdk抑制剂、微管蛋白连接剂、拓扑异构酶I抑制剂、拓扑异构酶II抑制剂等。
如果制成固定剂量,所述组合产品在下述剂量范围内使用本发明的化合物,并在批准的剂量范围内使用其它药学活性剂。
当组合制剂不合适时,式(I)化合物可以与已知抗癌药连续使用。
适合于给哺乳动物(例如人)施用的本发明的式(I)化合物可以通过常用途径施用,并根据病人的年龄、体重、情况及施用途径来决定剂量水平。
例如,口服施用式(I)化合物的合适剂量可以为约10-1000mg/剂量,每天1至10次。可以以各种剂型施用本发明化合物,例如口服,以片剂、胶囊、糖衣片剂或膜包衣片剂,液体溶液或悬浮剂的形式;直肠,以栓剂形式;肠胃外,例如肌肉内、或通过静脉内和/或鞘内和/或脊柱内注射或输注。
本发明还包括药物组合物,其包括式(I)化合物或其药学可接受的盐,以及药学可接受的赋形剂(可以为载体或稀释剂)。
含有本发明化合物的药物组合物通常根据常规方法制备并以合适的药学形式施用。
例如,固体口服形式可以包含活性化合物与稀释剂(例如乳糖、右旋蔗糖、蔗糖、纤维素、玉米淀粉或马铃薯淀粉);润滑剂(例如硅石、滑石、硬脂酸、硬脂酸镁或硬脂酸钙、和/或聚乙二醇);粘合剂(例如淀粉、阿拉伯胶、白明胶、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、褐藻酸、褐藻酸盐或羟乙酸淀粉钠);泡腾混合物;染料;甜味剂;润湿剂(例如卵磷脂、聚山梨醇酯、十二烷基硫酸盐);和通常在药学制剂中使用的无毒和药学惰性物质。这些药学制剂可以用已知的方法制备,例如通过混合、成粒、压片、糖包衣或膜包衣方法。
口服施用的液体分散剂例如可以是糖浆、乳化剂和悬浮剂。
例如,糖浆剂包含蔗糖、或蔗糖与甘油和/或甘露醇和山梨糖醇作为载体。
悬浮剂和乳化剂可以包含例如天然胶、琼脂、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。
肌肉内注射的悬浮剂或溶液可以包含活性化合物与药学可接受载体,例如无菌水、橄榄油、油酸乙酯、乙二醇(例如丙二醇)、和如果需要的话,合适量的利多卡因盐酸盐。
静脉内注射或输注用溶液可以包含无菌水作为载体,或优选可以以无菌等渗水性盐溶液的形式或可以包含丙二醇作为载体。
栓剂可以包含活性化合物与药学可接受的载体,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。
为了更好的阐明本发明而不对其进行任何限制,现在给出下述实施例。
实施例
当涉及本发明任何具体的式(I)化合物,任选以药学可接受的盐形式,参见实验部分和权利要求。
涉及下述实施例,使用本文描述的方法或本领域熟知的方法合成本发明化合物。
一般方法
在硅胶上进行快速色谱(Merck grade 9395,60A)。此处指出,在Biotage Horizon 系统上进行色谱分离。采用Biotage/Personal Chemistry SmithCreatorTM进行微波辅助反应。
在Waters X Terra RP 18(4,6x 50mm,3.5μm)柱上进行HPLC,采用装有996Waters PDA检测器和Micromass mod.ZQ单一四极杆质谱仪的Waters 2790HPLC系统,所述质谱仪装有电喷雾(ESI)离子源。流动相A为醋酸胺5mM缓冲溶液(pH 5.5具有乙酸/乙腈95∶5),且流动相B为H2O/乙腈(5∶95)。8分钟内梯度为由10%B至90%B,保持90%B 2分钟。在220nm和254nm处检测UV。流速1mL/min。进样体积10μL。全扫描,质量范围为100至800amu。毛细电压为2.5KV;源温度为120℃;cone为10V。保留时间(HPLC r.t.)表示为220nm或254nm处的分钟数。质谱表示为m/z比。
当需要时,通过制备型HPLC纯化化合物。
-在Waters Symmetry C18(19x 50mm,5μm)柱上,采用装有996Waters PDA检测器和Micromass mod.ZQ单一四极杆质谱仪(电喷雾(ESI)离子源,阳极模式)的Waters制备型HPLC 600。流动相A为含0.01%TFA的水,且流动相B为乙腈。8分钟内梯度由10%B至90%B,保持90%B 2分钟。流速20mL/min。
-在Waters X Terra Prep RP18(19x100mm,5μm)柱上,采用装有2996PDA UV-VI S检测器和Waters ZQ单一四极杆质谱仪的Waters FractionLynx System(FL2)。流动相A为于H2O pH10/乙腈95/5中的0.05%NH4OH,且流动相B为乙腈。8分钟内梯度由0%B至80%B,保持90%B 2分钟。流速为20mL/min。
在装有电喷雾(ESI)离子源的Finnigan MAT LCQ离子阱仪器中测定低分辨质谱(MS)数据。在装有电喷雾(ESI)离子源的Waters Q-TOFUltima仪器上获得高分辨质谱(HRMS),并采用用于锁定质谱校正(Lock Mass correction)的Reserpine(MW 609.28065)。除非另有说明,在装有5mm的双共振探针[1H(15N-31P)I D_PFG Varian]的Mercury VX 400上,在400.45MHz下操作进行1H-NMR谱。化学位移表示为(ppm)。
在实施例和其他地方中,缩写具有下述含义:
AcOH=乙酸
AcONH4=醋酸铵
aq=水溶液
Boc=叔丁氧羰基
tBuONa=叔丁醇钠
CDI=N,N′-羰基二咪唑
CH3CN=乙腈
CISO2NCO=氯磺酰异氰酸酯
conc=浓缩的
CS2CO3=碳酸铯
DCM=二氯甲烷
DIEA=二异丙基乙胺
DMAP=二甲氨基吡啶
DMF=N,N′-二甲基甲酰胺
DMSO-D6=氘化的二甲亚砜
EDCI=1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐
eq=当量
ESI=电喷雾离子化
EtI=碘乙烷
EtNH2=乙胺
EtOAc=醋酸乙酯
EtOH=乙醇
Et2O=乙醚
g=克
h=小时
HBr=氢溴酸
HCl=盐酸
HCOOH=88%甲酸
HCOONH4=甲酸铵
HOBT=羟基苯并三唑
HOBT-NH3=羟基苯并三唑铵盐
HPLC=高效液相色谱
KOH=氢氧化钾
劳氏试剂=2,4-双(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂环丁烷-2,4-二硫化物
LiCl=氯化锂
M=摩尔/L
MBHA树脂=4-甲基二苯甲胺-树脂盐酸盐
米氏酸=2,2-二甲基-1,3-二噁烷-4,6-二酮
MeNH2=甲胺
MeOH=甲醇
mg=毫克
min=分钟
mL=毫升
mmol=毫摩尔
mol=摩尔
N=正常
Na2CO3=碳酸钠
NaH=在矿物油中60%的氢化钠
NaHCO3=碳酸氢钠
NaH2PO4=磷酸二氢钠
NaNO2=亚硝酸钠
NaOH=氢氧化钠
Na2SO4=无水硫酸钠
NBS=N-溴-琥珀酰亚胺
NCS=N-氯-琥珀酰亚胺
NIS=N-碘-琥珀酰亚胺
NH3=氨
Pd(OAc)2=醋酸钯
(Ph3P)2PdCl2=双(三苯基膦)二氯化钯(II)
rt=室温
TBTU=O-苯并三唑-1-基-N,N,N′,N′-四甲基脲鎓四氟硼酸酯
TEA=三乙胺
TFA=三氟乙酸
THF=四氢呋喃
Xantphos=9,9-二甲基-9H-呫吨-4,5-二基)双[二苯基膦]
μL=微升
实施例1
2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A1)
步骤1:吡咯环的形成(3)
在0℃下,将2-溴-1-吡啶-4-基乙酮氢溴酸盐1(1.7g,6.2mmol)加入到3-氧代-3-苯基-丙酸乙酯2(R=H,1g,5.2mmo l)于100mL的无水THF和NaH(0.5g,13.0mmol)的混合物中。溶液在0℃下放置1小时,然后室温下搅拌3小时。除去溶剂并将残余物溶于60mLEtOH中,加入醋酸胺(1.4g,18.7mmol)并将反应混合物室温下放置过夜。用快速色谱(DCM/MeOH 98∶2)纯化粗产物得到920mg(60%)固体状的2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.20(t,J=7.08Hz,3H),4.16(q,J=7.08Hz,2H),7.30(d,J=2.81Hz,1H),7.43(m,3H),7.64(m,2H),7.79(m,2H),8.53(m,2H),12.12(s,1H);ESI(+)MS:m/z 293(MH+).
步骤2:皂化成羧酸(4)
在100℃下加热在3mL EtOH和3mL 4M aq NaOH中的酯3(440mg,1.5mmol),持续3个小时。在0℃下冷却该反应混合物并用浓HCl酸化,观察到产物沉淀,过滤沉淀的产物并用少量水和丙酮洗涤,干燥得到400mg(88%)固体状的2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸,无需进一步纯化,将其用于下一步。
1H NMR(DMSO-d6/400MHz)δppm 7.51(m,3H),7.68(m,2H),7.75(d,J=2.44Hz,1H),8.28(d,J=6.65Hz,2H),8.74(d,J=6.65Hz,2H),12.51(s,1H);MS:m/z 263[M-H].
步骤3:缩合成酰胺(A1)
在DIEA(0.5mL,2.90mmol)存在下,酸4(380mg,1.44mmol)溶于10mL无水THF。向在0℃下冷却的该溶液加入EDCI(414mg,2.16mmol)和HOBT·NH3(330mg,2.16mmol)。将该反应混合物室温下放置过夜。除去溶剂,加入水并用DCM萃取该浆液。干燥有机层(Na2SO4),蒸发溶剂并通过快速色谱(DCM/MeOH 95∶5)纯化粗产物得到150mg(40%)浅黄色固体状的2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 6.90(bs,2H),7.27(d,J=2.56Hz,1H),7.37(m,1H),7.44(m,2H),7.67-7.71(m,4H),8.53(m,2H),11.82(s,1H);ES I(+)MS:m/z 264(MH+).
使用上述步骤合成下述化合物:
实施例2,步骤-1
2-(2-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.11(t,J=7.07Hz,3H)4.09(t,J=7.07Hz,2H)7.28-7.34(m,5H)7.75(dd,J=1.46,4.63Hz,2H)8.52(m,2H)12.31(s,1H);ESI(+)MS:m/z 311(MH+).
实施例2,步骤-2
2-(2-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 7.33(m,4H)7.72(d,J=2.56Hz,1H)8.22(d,J=6.40Hz,2H)8.72(m,2H)12.73(s,1H);MS:m/z 281[M-H].
实施例2,步骤-3
2-(2-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸盐(A2)
1H NMR(DMSO-d6/400MHz)δppm 7.00(bs,2H),7.29-7.36(m,4H),7.73(d,J=2.43Hz,1H),8.11(d,J=6.59Hz,2H),8.74(d,J=6.59Hz,2H),12.56(s,1H);ESI(+)MS:m/z 282(MH+).
实施例3,步骤-1
2-(3-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.20(t,J=7.10Hz,3H)4.15(q,J=7.10Hz,2H)7.27(m,1H)7.30(d,J=2.81Hz,1H),7.49-7.53(m,3H)7.78(m,2H)8.53(d,J=5.13Hz),12.17(s,1H);ESI(+)MS:m/z 311(MH+).
实施例3,步骤-2
2-(3-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm.25(m,1H)7.31(d,J=2.9Hz,1H)7.40(m,3H)7.80(m,2H)8.50(m,2H);MS:m/z 281[M-H].
实施例3,步骤-3
2-(3-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A3)
1H NMR(DMSO-d6/400MHz)δppm 7.16(bs,2H),7.29(m,2H),7.52(m,2H),7.74(s,1H),8.23(d,J=5.80Hz,2H),8.78(d,J=5.80Hz,2H),12.42(s,1H);ESI(+)MS:m/z 282(MH+).
实施例4,步骤-1
2-(4-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.21(t,J=7.08Hz,3H)4.16(q,J=7.08Hz,2H)7.29-7.34(m,3H)7.69(m,2H)7.78(dd,J=1.60,4.63Hz,2H)8.53(dd,J=1.60,4.63Hz,2H)12.13(s,1H);ESI(+)MS:m/z 311(MH+).
实施例4,步骤-2
2-(4-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 7.62-7.76(m,5H)8.30(bd,J=5.61Hz,2H)8.75(d,J=6.71Hz,2H)12.58(bs,1H);MS:m/z 281[M-H].
实施例4,步骤-3
2-(4-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸盐(A4)
1H NMR(DMSO-d6/400MHz)δppm 7.12(bs,2H),7.32-7.39(m,4H),7.70(d,J=2.43Hz,1H),8.15(d,J=6.59Hz,2H),8.72(d,J=6.59Hz,2H),12.52(s,1H);ESI(+)MS:m/z 282(MH+).
实施例5,步骤-1
2-(3-溴-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.22(t,J=7.07Hz,3H)4.17(q,J=7.11Hz,2H)7.31(d,J=2.80Hz,1H)7.44(t,J=7.86Hz,1H)7.62-7.69(m,2H)7.80(d,J=6.22Hz,2H)7.86(t,J=1.77Hz,1H)8.55(d,J=6.22Hz,2H)12.20(s,1H);ESI(+)MS:m/z316(MH+).
实施例5,步骤-2
2-(3-溴-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 7.46(t,J=7.93Hz,1H)7.65-7.74(m,3H)7.90(s,1H)8.26(d,J=5.73Hz,2H)8.75(d,J=6.46Hz,2H)12.29(bs,1H)12.54(bs,1H);MS:m/z 342[M-H].ESI(+)MS:m/z 343(MH+).
实施例5,步骤-3
2-(3-溴-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸盐(A5)
1H NMR(DMSO-d6/400MHz)δppm 7.14(bs,1H)7.44(t,J=7.93Hz,1H)7.51(bs,1H)7.60-7.65(m,J=9.02Hz,1H)7.69(d,J=2.56Hz,1H)7.71-7.75(m,1H)7.93(t,J=1,83Hz,1H)8.18(d,J=5.85Hz,2H)8.76(d,J=6.83Hz,2H)12.38(bs,1H);ESI(+)MS:m/z 342(MH+).
实施例6,步骤-1
2-(4-溴-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.22(t,J=7.07Hz,3H)4.16(q,J=7.07Hz,2H)7.30(d,J=2.80Hz,1H)7.61(d,J=8.54Hz,2H)7.68(d,J=8.54Hz,2H)7.79(d,J=6.22Hz,2H)8.55(d,J=5.98Hz,2H)12.17(bs,1H);ESI(+)MS:m/z 316(MH+).
实施例6,步骤-2
2-(4-溴-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 7.62-7.76(m,5H)8.30(bd,J=5.61Hz,2H)8.75(d,J=6.71Hz,2H)12.58(bs,1H);MS:m/z 342[M-H].
实施例6,步骤-3
2-(4-溴-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸盐(A6)
1H NMR(DMSO-d6/400MHz)δppm 6.93(bs,1H)7.28(d,J=2.68Hz,1H)7.37(bs,1H)7.62-7.67(m,4H)7.69(d,J=6.22Hz,2H)8.54(d,J=6.22Hz,2H)11.86(s,1H);ESI(+)MS:m/z 342(MH+).
实施例7,步骤-1
7-(3-乙氧羰基-5-吡啶-4-基-1H-吡咯-2-基)-3,4-二氢-1H-异
喹啉-2-甲酸叔丁酯
1H NMR(400MHz,DMSO-d6)δppm 1.20(t,J=7.07Hz,3H)1.44(s,9H)2.84(t,J=5.85Hz,2H)3.60(t,J=5.91Hz,2H)4.14(q,J=7.07Hz,2H)4.56(b s,2H)7.24(d,1H)7.27(d,1H)7.41-7.47(m,2H)7.76(d,J=6.22Hz,2H)8.52(d,J=6.10Hz,2H)12.02(bs,1H);ESI (+)MS:m/z 448(MH+).
实施例7,步骤-2
7-(3-羧基-5-吡啶-4-基-1H-吡咯-2-基)-3,4-二氢-1H-异喹啉
-2-甲酸叔丁酯
MS:m/z 418[M-H].
实施例7,步骤-3
7-(3-氨基甲酰基-5-吡啶-4-基-1H-吡咯-2-基)-3,4-二氢-1H-
异喹啉-2-甲酸叔丁酯(A27)
1H NMR(DMSO-d6/400MHz)δppm 1.44(s,9H)2.82(t,J=5.79Hz,2H)3.59(t,J=5.85Hz,2H)4.54(b s,2H)6.86(b s,2H)7.20(d,J=7.93Hz,1H)7.24(d,J=2.68Hz,1H)7.44(m,1H)7.47(m,1H)7.67(d,J=6.22Hz,2H)8.51(d,J=6.10Hz,2H)11.72(bs,1H);ESI (+)MS:m/z 419(MH+).
通过用酸处理(例如室温下用三氟乙酸处理24小时)得到对应的脱保护类似物。
实施例8
5-吡啶-4-基-2-(1,2,3,4-四氢-异喹啉-7-基)-1H-吡咯-3-甲酸
酰胺(A28)
1H NMR(DMSO-d6/400MHz)δppm 3.07(t,J=6.10Hz,2H)3.38-3.45(m,2H)4.30(t,J=4.33Hz,2H)7.05(bs,1H)7.30(d,J=7.93Hz,1H)7.42(bs,1H)7.58(d,J=8.50Hz,1H)7.57(s,1H)7.69(d,J=2.32Hz,1H)8.18(d,J=6.22Hz,2H)8.73(d,J=6.83Hz,2H)9.38(bs,2H)12.41(bs,1H);ESI(+)MS:m/z 319(MH+).
实施例9
2-(2-甲基-1,2,3,4-四氢-异喹啉-7-基)-5-吡啶-4-基-1H-吡咯
-3-甲酸酰胺(A29)
通过用甲醛和氰基硼氢化钠在化合物A28的四氢异喹啉核上进行还原氨化反应,得到标题化合物A29。
1H NMR(DMSO-d6/400MHz)δppm 2.94(s,3H)3.09(d,J=16.90Hz,1H)3.69(d,J=7.44Hz,1H)4.31(dd,J=14.90,6.60Hz,1H)4.50(d,J=14.88Hz,1H)7.05(bs,1H)7.33(d,J=8.05Hz,1H)7.44(bs,1H)7.54(d,J=1.10Hz,1H)7.61(dd,J=7.93,1.71Hz,1H)7.69(d,J=2.56Hz,1H)8.17(d,J=6.71Hz,2H)8.73(d,J=6.83Hz,2H)10.77(bs,1H)12.42(s,1H);ESI (+)MS:m/z 333(MH+).
实施例10,步骤-1
2,5-二-吡啶-4-基-1H-吡咯-3-甲酸乙酯
1H NMR(400MHz,DMSO-d6)δppm 1.23(t,J=7.07Hz,3H)4.18(q,J=7.07Hz,2H)7.33(d,J=2.8Hz,1H)7.65(dd,J=1.60,4.51Hz,2H)7.80(dd,J=1.71,4.63Hz,2H)8.55(dd,J=1.60,4.51Hz,2H)8.65(dd,J=1.71,4.61Hz,2H)12.30(bs,1H);ESI(+)MS:m/z 294(MH+).
实施例10,步骤-2
2,5-二-吡啶-4-基-1H-吡咯-3-甲酸
1H NMR(400MHz,DMSO-d6)δppm 7.02(b s,1H)7.73(m,2H)8.01(m,2H)8.47(m,4H)11.40(bs,1H);MS:m/z 264[M-H].
实施例10,步骤-3
2,5-二-吡啶-4-基-1H-吡咯-3-甲酸酰胺(C3)
1H NMR(DMSO-d6/400MHz)δppm 7.02(bs,2H),7.29(s,1H),7.71(m,4H),8.56(m,4H),12.01(bs,1H);ESI (+)MS:m/z265(MH+).
实施例11
2-环己基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(Q1)
步骤1:形成吡咯环(6)
向0℃下冷却的3-环己基-3-氧代-丙酸乙酯5(1.6g,8.3mmol)于无水THF(200mL)的溶液中加入NaH(900mg,21mmol)。15分钟后,加入2-溴-1-吡啶-4-基-乙酮氢溴酸1(3g,10.8mmol),并在0℃下搅拌该混合物5个小时。除去溶剂并将残余物溶于EtOH(120mL)。加入醋酸铵(1.9g,25mmol)并室温下搅拌该溶液过夜。除去溶剂后将残余物溶于EtOAc并用饱和Na2CO3水溶液洗涤有机相,然后用水洗涤,干燥(Na2SO4)并浓缩。通过硅胶色谱(洗脱液:EtOAc)纯化粗产物得到白色固体状的2-环己基-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯(1.1g,43%)。
1H NMR(DMSO-d6/400MHz)δppm 1.33(m,1H)1.30(t,J=7.13Hz,3H)1.70-1.88(m,7H)3.44-3.56(m,1H)4.20(q,J=7.15Hz,2H)7.06(d,J=2.68Hz,1H)7.71(d,J=6.22Hz,2H)8.50(d,J=6.22Hz,2H)11.37(bs,1H);ESI(+)MS:m/z 299(MH+).
步骤2:皂化成羧酸(7)
回流酯6(0.58g,1.95mmo l)于4M aq NaOH和EtOH(1∶1,20mL)的溶液3小时,在冰中冷却并用2N HCl酸化。过滤沉淀,用少量水洗涤并干燥。得到白色固体状的2-环己基-5-吡啶-4-基-1H-吡咯-3-甲酸盐酸盐(0.55g,90%)。
1H NMR(DMSO-d6/400MHz)δppm 1.22-1.42(m,3H)1.69-1.89(m,7H)3.50-3.64(m,1H)7.56(d,J=2.56Hz,1H)8.26(d,J=6.71Hz,2H)8.69(d,J=6.71Hz,2H)11.85(s,1H)12.17(b s,1H);MS:m/z 269[M-H].
步骤3:缩合成酰胺(Q1)
室温下搅拌酸7(0.3g,1mmol)、HOBT·NH3(0.3g,2mmol)、TBTU(0.64g,2mmol)、DIEA(1mL,6mmol)于DMF(4mL)的溶液6小时。将反应混合物倒入水中并用EtOAc萃取水相(x3)。用1NNaOH洗涤有机相,然后用水、盐水洗涤,干燥(Na2SO4)并浓缩。通过硅胶色谱(DCM/MeOH 12∶1)纯化粗产物得到白色固体状的2-环己基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(0.12g,43%)。
1H NMR(DMSO-d6/400MHz)δppm 1.62-1.84(m,10H)3.59-3.71(m,1H)6.67(bs,1H)7.13(d,J=2.68Hz,1H)7.21(bs,1H)7.58(d,J=6.22Hz,2H)8.48(d,J=6.10Hz,2H)11.13(bs,1H);ESI(+)MS:m/z 270(MH+).
实施例12
4-(3-氨基甲酰基-5-吡啶-4-基-1H-吡咯-2-基)-哌啶-1-甲酸叔丁酯(Q3)和2-哌啶-4-基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(Q2)
步骤1:形成吡咯环(9)
向0℃下冷却的4-(2-乙氧羰基-乙酰基)-哌啶-1-甲酸叔丁酯8(2.5g,8.3mmol)于无水THF(200mL)的溶液中加入NaH(900mg,21mmol)。15分钟后,加入2-溴-1-吡啶-4-基-乙酮氢溴酸盐1(3g,10.8mmol)并将该混合物在0℃下搅拌5小时。减压下除去溶剂并将残余物溶于EtOH(120mL)。加入醋酸铵(1.9g,25mmol)并在室温下搅拌溶液过夜。除去溶剂后将残余物溶于EtOAc并用饱和Na2CO3水溶液洗涤有机相,然后用水洗涤,干燥(Na2SO4)并浓缩。通过硅胶色谱(洗脱液:EtOAc)纯化该粗产物得到粉红色固体状的4-(3-乙氧羰基-5-吡啶-4-基-1H-吡咯-2-基)-哌啶-1-甲酸叔丁酯(1.55g,47%)。
1H NMR(DMSO-d6/400MHz)δppm 1.30(t,J=7.07Hz,3H)1.45(s,9H)1.71(bd,2H)1.80-1.92(m,2H)2.79(bs,2H)3.64-3.74(m,1H)4.15(bd,J=11.46Hz,2H)4.21(q,J=7.07Hz,2H)7.08(d,J=2.68Hz,1H)7.71(d,J=6.22Hz,2H)8.50(d,J=6.10Hz,2H)11.45(bs,1H);ESI(+)MS:m/z 400(MH+).
步骤2:皂化成羧酸(10)
回流酯9(0.8g,2mmol)于4M aq NaOH和EtOH(1∶1,20mL)的溶液2小时,在冰中冷却并用2N HCl酸化。过滤沉淀,用少量水洗涤并干燥。得到白色固体状的4-(3-羧基-5-吡啶-4-基-1H-吡咯-2-基)-哌啶-1-甲酸叔丁酯盐酸盐(0.54g,66%)。
1H NMR(DMSO-d6/400MHz)δppm 1.43(s,9H)1.67-1.92(m,4H)2.79(bs,2H)3.68-3.79(m,1H)4.13(bd,J=11.58Hz,2H)7.57(d,J=2.56Hz,1H)8.22(d,J=6.83Hz,2H)8.69(d,J=6.83Hz,2H)11.82(b s,1H);MS:m/z 370[M-H].
步骤3:缩合成保护酰胺(Q3)
室温下搅拌酸10(0.53g,1.4mmol)、HOBT·NH3(0.43g,2.8mmol)、TBTU(0.9g,2.8mmol)、DIEA(1.4mL)于DMF(4mL)的溶液15小时。将反应混合物倒入水中并用EtOAc萃取水相(x3)。用1NNaOH洗涤有机相,然后用水、盐水洗涤,干燥(Na2SO4)并浓缩。溶剂蒸发后,沉淀出粗产物。将其过滤并用EtOAc洗涤,然后用Et2O洗涤。得到白色固体状的4-(3-氨基甲酰基-5-吡啶-4-基-1H-吡咯-2-基)-哌啶-1-甲酸叔丁酯(0.25g,47%)。
1H NMR(DMSO-d6/400MHz)δppm 1.45(s,9H)1.67(bd,J=12.32Hz,2H)1.76-1.89(m,2H)2.71(bs,2H)3.81-3.91(m,1H)4.12(bd,J=11.10Hz,2H)6.76(bs,1H)7.18(d,J=2.56Hz,1H)7.29(bs,1H)7.59(d,J=6.22Hz,2H)8.50(d,J=6.10Hz,2H)11.22(bs,1H);ESI(+)MS:m/z 371(MH+).
步骤4:脱保护成酰胺(Q2)
酰胺Q3(30mg,0.08mmol)溶于MeOH(5mL)中,加入2N HCl(1mL)并在搅拌下于50℃温热该澄清溶液5小时。过滤沉淀并用MeOH洗涤。得到白色固体状的2-哌啶-4-基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺二盐酸盐(25mg,90%)。
1H NMR(DMSO-d6/400MHz)δppm 1.96(d,J=13.05Hz,2H)2.09-2.24(m,2H)2.92-3.07(m,2H)3.74-3.87(m,1H)7.01(bs,1H)7.49(bs,1H)7.66(s,1H)8.10(bs,2H)8.56(bs,1H)8.71(d,J=6.34Hz,2H)8.83(bs,1H)11.97(bs,1H);ESI(+)MS:m/z 271(MH+).
实施例13
5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(E1)
步骤1:形成吡咯环(12)
在0℃下,将溴乙酰基氟代吡啶氢溴酸盐11(3.6g,12.0mmol)加入到于200mL无水THF的3-氧代-3-苯基-丙酸乙酯2(R=H,2.0g,10.0mmol)和NaH(0.5g,13.0mmol)的混合物中。在0℃下放置该溶液1小时然后室温下搅拌3小时。除去溶剂并将残余物溶于120mLEtOH,加入醋酸铵(2.7g,36.0mmol),将反应混合物室温下放置过夜,然后在50℃下温热2小时。通过快速色谱(DCM/MeOH 98∶2)纯化粗产物得到1.88g(60%)黄色固体状的5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.25(t,J=7.09Hz,3H),4.23(q,J=7.09Hz,2H),7.30-7.60(m,7H),8.40(m,1H),8.53(m,1H),11.80(s,1H);ESI(+)MS:m/z 311(MH+).
步骤2:皂化成羧酸(13)
在100℃下加热于10mL EtOH和12mL 4M aq NaOH的酯12(1.8g,5.8mmol)4小时。在0℃下冷却反应混合物并用浓HCl酸化,观察到产物沉淀,过滤沉淀,用少量的水和乙酮洗涤并干燥得到固体状的5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸(1.7g,92%),无需进一步纯化即可使用。
1H NMR(DMSO-d6/400MHz)δppm 7.30-7.70(m,7H),8.35(m,1H),8.51(m,1H);MS:m/z 281[M-H].
步骤3:缩合成酰胺(E1)
在DIEA(1.1mL,6.2mmol)存在下,酸13(1.0g,3.1mmol)溶于40mL无水THF。该溶液在0℃下冷却并加入EDCI(0.9g,4.6mmol)和HOBT·NH3(0.7g,4.6mmol)。反应混合物在室温下放置过夜。除去溶剂,加入水并用DCM萃取该混合物。干燥有机层(Na2SO4),蒸发溶剂并通过快速色谱(DCM/MeOH 95∶5)纯化粗产物得到350mg(40%)白色固体状的5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 6.86(bs,2H),7.24(t,J=3.05Hz,1H),7.36-7.45(m,3H),7.65(m,2H),7.94(m,1H),8.39(d,J=5.12Hz,1H),8.56(d,J=3.41Hz,1H),11.84(s,1H);ESI(+)MS:m/z 282(MH+).
实施例14
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(F1)
步骤1:形成吡咯环(15)
在0℃和氩气下,向搅拌的酯2(R=H,1.34g,7mmol)于无水THF(100mL)的溶液中加入NaH(0.7g,17.5mmol)。5分钟后,加入溴酮14(2.5g,8.4mmol)并在室温下搅拌混合物3个小时。蒸发溶剂,将残余物溶于EtOH(65mL),加入醋酸铵(1.6g,21mmol)并在室温下搅拌该溶液过夜。蒸发溶剂至干,通过快速色谱(EtOAc/正己烷7∶3)纯化残余物得到5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸乙酯(0.99g,3.2mmol,46%)。
1H NMR(DMSO-d6/400MHz)δppm 1.20(t,J=7.13Hz,3H)4.14(q,J=7.07Hz,2H)6.45(s,2H)7.10(d,J=5.24Hz,1H)7.33(d,J=2.56Hz,1H)7.40-7.49(m,3H)7.61-7.65(m,2H)8.23(d,J=5.24Hz,1H)12.01(bs,1H);ESI(+)MS:m/z 309(MH+).
步骤2:皂化成羧酸(16)
酯15(3.65g,11.85mmol)于95%EtOH(45mL)的悬浮液中加入4M aq NaOH(45mL)并回流该混合物5小时。蒸发掉大部分的溶剂并将残余物在冰浴中冷却,用浓HCl酸化至pH 5,观察到产物沉淀。过滤沉淀,用少量的冷水洗涤并干燥。得到白色固体状的5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸(3.5g),无需进一步纯化用于下一步。
1H NMR(DMSO-d6/400MHz)δppm 7.35-7.69(m,6H)7.76(bs,2H)8.31(d,J=5.73Hz,1H)12.37(bs,1H);MS:m/z 279[M-H].
步骤3:缩合成酰胺(F1)
在搅拌下,向在冰浴中冷却的酸16(4g,14.3mmol)于无水THF(80mL)、DIEA(5.5g,42.9mmol)和无水DMF(8mL)的悬浮液中加入HOBT·NH3(3.26g,21.4mmol)和EDCI(4.1g,21.4mmol)。室温下搅拌该反应混合物过夜,然后将其倒入搅拌的水和EtOAc的混合物(1∶1)中。用水洗涤有机相,用EtOAc萃取水层并用水洗涤合并的有机层,干燥(Na2SO4)并浓缩,得到沉淀状的标题化合物,过滤该沉淀并用少量冷MeOH洗涤。通过快速色谱(DCM/MeOH/丙酮9∶1∶1)纯化母液,得到所需的酰胺。合并两批产物,悬浮于MeOH并用1.25M HCl的MeOH溶液酸化至pH1。除去溶剂并用乙醚处理残余物。过滤所得的固体,用Et2O洗涤并干燥(Na2SO4),得到白色固体状的5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺盐酸盐(1.6g,5.1mmol,43%)。
1H NMR(DMSO-d6/400MHz)δppm 7.37-7.49(m,4H)7.49-7.52(m,2H)7.61(d,J=2.44Hz,1H)7.65-7.71(m,2H)8.01(bs,3H)8.31(d,J=6.58Hz,1H)12.28(s,1H);ESI(+)MS:m/z 280(MH+).
采用上述步骤合成下述化合物。
实施例15,步骤-1
5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸乙酯
1H NMR(400MHz,DMSO-d6)δppm 1.07(t,J=7.07Hz,3H)2.14(s,3H)4.02(q,J=7.07Hz,2H)6.54(b s,2H)7.04(d,J=5.37Hz,1H)7.22-7.37(m,5H)8.20(d,J=5.37,1H)12.12(bs,1H);ESI(+)MS:m/z 323(MH+).
实施例15,步骤-2
5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸
1H NMR(400MHz,DMSO-d6)δppm 6.34(bs,2H)6.98(d,J=5.24Hz,1H)7.18-7.33(m,5H)8.15(d,J=5.24Hz,1H)11.75(bs,1H);MS:m/z 293[M-H].
实施例15,步骤-3
5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(F2)
1H NMR(DMSO-d6/400MHz)δppm 2.16(s,3H),6.87(bs,2H),7.21-7.34(m,5H),7.62(s,1H),7.74(bs,2H),8.25(d,J=6.47Hz,1H),12.20(bs,1H);ESI(+)MS:m/z 294(MH+).
实施例16,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸乙酯
1H NMR(400MHz,DMSO-d6)δppm 1.11(t,J=7.07Hz,3H)4.06(q,J=7.07Hz,2H)6.43(bs,2H)7.03(d,J=5.24Hz,1H)7.28(m,3H)7.50(m,2H)8.21(d,J=5.24Hz,1H)12.23(bs,1H);ESI(+)MS:m/z 327(MH+).
实施例16,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸
1H NMR(400MHz,DMSO-d6)δppm 6.36(bs,2H)6.97(d,J=5.24Hz,1H)7.23(m,3H)7.39(m,1H)7.58(m,1H)8.17(d,J=5.24Hz,1H)11.69(bs,1H);MS:m/z 297[M-H].
实施例16,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺
(F4)
1H NMR(DMSO-d6/400MHz)δppm 6.92(bs,2H),7.27(m,3H),7.45-7.54(m,2H),7.62(bs,1H),7.84(bs,2H),8.28(d,J=6.58Hz,1H),12.41(bs,1H);ESI(+)MS:m/z 298(MH+).
实施例17,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸
乙酯
1H NMR(400MHz,DMSO-d6)δppm 1.06(t,J=7.07Hz,3H)2.02(s,3H)2.29(s,3H)4.01(q,J=7.07Hz,2H)6.40(bs,2H)7.01(d,J=5.24Hz,1H)7.07-7.16(m,2H)7.23(d,J=6.83Hz,1H)7.29(d,J=2.68Hz,1H)8.18(d,J=5.24Hz,1H)12.03(bs,1H);ESI(+)MS:m/z 337(MH+).
实施例17,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸
1H NMR(400MHz,DMSO-d6)δppm 2.04(s,3H)2.30(s,3H)6.37(b s,2H)7.00(d,J=5.24Hz,1H)7.08-7.17(m,2H)7.23(d,J=6.71Hz,1H)7.27(d,J=2.68Hz,1H)8.18(d,J=5.24Hz,1H)11.64(b s,1H)11.89(bs,1H);MS:m/z 307[M-H].
实施例17,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F15)
1H NMR(DMSO-d6/400MHz)δppm 2.03(s,3H),2.29(s,3H),6.31(bs,2H),6.69(bs,2H),6.94(d,J=5.24Hz,1H),7.08-7.17(m,2H),7.23(d,J=6.95Hz,1H),7.31(d,J=2.68Hz,1H),8.16(d,J=5.24Hz,1H),10.70(b s,1H);ESI(+)MS:m/z 308(MH+).
实施例18,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-氟-苯基)-1H-吡咯-3-甲酸乙
酯
1H NMR(400MHz,DMSO-d6)δppm 1.07(t,J=7.07Hz,3H)4.03(q,J=7.07Hz,2H)6.41(b s,2H)7.00(d,J=5.24Hz,1H)7.25-7.34(m,2H)7.48-7.59(m,2H),8.21(d,J=5.24Hz,1H)12.27(bs,1H);ESI(+)MS:m/z 361(MH+).
实施例18,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-氟-苯基)-1H-吡咯-3-甲酸
1H NMR(400MHz,DMSO-d6)δppm 6.38(bs,2H)6.99(d,J=5.24Hz,1H)7.22-7.30(m,2H)7.50-7.57(m,2H)8.20(d,J=5.24Hz,1H)11.49(bs,1H)12.10(bs,1H);MS:m/z 331[M-H].
实施例18,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-氟-苯基)-1H-吡咯-3-甲酸酰
胺(F23)
1H NMR(DMSO-d6/400MHz)δppm 6.38(bs,2H),6.72(bs,1H),6.92(d,J=5.24Hz,1H),7.22-7.33(m,2H),7.35(d,J=2.56Hz,1H),7.45-7.54(m,2H),8.22(d,J=5.24Hz,1H),11.95(bs,1H);ESI (+)MS:m/z 332(MH+).
实施例19,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸乙
酯
1H NMR(DMSO-d6/400MHz)δppm 1.08(t,J=7.07Hz,3H)4.04(q,J=7.07Hz,2H)6.42(bs,2H)7.01(d,J=5.24Hz,1H)7.29(d,J=2.19Hz,1H)7.49(m,2H)7.73(t,J=1.22Hz,1H)8.22(d,J=5.24Hz,1H)12.30(bs,1H);ESI(+)MS:m/z 377(MH+).
实施例19,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸
MS:m/z 347[M-H].
实施例19,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸酰
胺(F26)
1H NMR(DMSO-d6/400MHz)δppm 6.81(bs,1H)6.95(bs,2H)7.01(d,J=5.73Hz,1H)7.37(bs,1H)7.46(d,J=2.68Hz,1H)7.68(dd,J=1.77,0.55Hz,1H)8.23(d,J=5.73Hz,1H)12.17(bs,1H);ESI(+)MS:m/z 348(MH+).
实施例20,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲基-苯基)-1H-吡咯-3-甲酸
乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.13(t,J=7.07Hz,3H)2.38(s,3H)4.07(q,J=7.07Hz,2H)6.43(bs,2H)7.03(d,J=5.24Hz,1H)7.06-7.15(m,2H)7.29(d,J=2.44Hz,1H)7.38(t,J=8.17Hz,1H)8.22(d,J=5.24Hz,1H)12.15(bs,1H);ESI(+)MS:m/z 341(MH+).
实施例20,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲基-苯基)-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 2.58(s,3H)6.39(bs,2H)7.00(d,J=5.24Hz,1H)7.04-7.13(m,2H)7.26(d,J=2.44Hz,1H)7.37(t,J=8.17Hz,1H)8.21(d,J=5.24Hz,1H)11.78(bs,1H)12.03(bs,1H);MS:m/z 311[M-H].
实施例20,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F28)
1H NMR(DMSO-d6/400MHz)δppm 2.37(s,3H),6.37(bs,2H),6.73(bs,1H),6.95(d,J=5.24Hz,1H),7.02-7.09(m,2H),7.26(bs,1H),7.30(d,J=2.56Hz,1H),7.37(t,J=7.90Hz,1H),8.20(d,J=5.24Hz,1H),11.78(bs,1H);ESI(+)MS:m/z 312(MH+).
实施例21,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2-氯-5-氟-苯基)-1H-吡咯-3-甲酸乙
酯
1H NMR(DMSO-d6/400MHz)δppm 1.07(t,J=7.07Hz,3H)4.05(q,J=7.07Hz,2H)6.42(b s,2H)7.01(d,J=5.24Hz,1H)7.30(d,J=2.44Hz,1H)7.32-7.39(m,1H)7.41(dd,J=8.90,3.05Hz,1H)8.60(dd,J=8.90,5.24Hz,1H)8.23(d,J=5.24Hz,1H)12.32(bs,1H);ESI(+)MS:m/z 361(MH+).
实施例21,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2-氯-5-氟-苯基)-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 6.40(bs,2H)7.00(d,J=5.24Hz,1H)7.26(d,J=2.32Hz,1H)7.30-7.37(m,1H)7.40(dd,J=8.90,3.05Hz,1H)8.59(dd,J=8.90,5.24Hz,1H)8.22(d,J=5.24Hz,1H)11.85(bs,1H)12.20(bs,1H);MS:m/z 331[M-H].
实施例21,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2-氯-5-氟-苯基)-1H-吡咯-3-甲酸酰
胺(F31)
1H NMR(DMSO-d6/400MHz)δppm 6.35(bs,2H),6.75(bs,1H),6.92(d,J=5.24Hz,1H),7.26-7.34(m,3H),7.35(d,J=2.56Hz,1H),7.55(dd,J=8.72,5.30Hz,1H),8.22(d,J=5.24Hz,1H),11.98(bs,1H);ESI(+)MS:m/z 332(MH+).
实施例22,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸乙
酯
1H NMR(DMSO-d6/400MHz)δppm 4.10(q,J=7.07Hz,2H)6.48(b s,2H)7.04(d,J=5.24Hz,1H)7.32(b s,1H)7.38(m,1H)7.54(m,2H)8.24(d,J=5.24Hz,1H)12.32(b s,1H);ES I(+)MS:m/z361(MH+).
实施例22,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 6.32(bs,2H)6.93(d,J=5.24Hz,1H)7.14(s,1H)7.25(m,2H)7.65(t,J=8.17Hz,1H)8.15(d,J=5.25Hz,1H)12.20(bs,1H);MS:m/z 331[M-H].
实施例22,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰
胺(F36)
1H NMR(DMSO-d6/400MHz)δppm 6.37(bs,2H),6.80(bs,1H),6.93(d,J=5.24Hz,1H),7.31-7.37(m,2H),7.41(bs,1H),7.46(dd,J=9.76,1.95Hz,1H),7.49-7.56(m,1H),8.23(d,J=5.24,1H),11.95(bs,1H);ESI(+)MS:m/z 332(MH+).
实施例23,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(2,6-二氟-苯基)-1H-吡咯-3-甲酸乙
酯
1H NMR(DMSO-d6/400MHz)δppm 1.09(t,J=7.07Hz,3H)4.06(q,J=7.07Hz,2H)6.46(bs,2H)7.01(d,J=5.24Hz,1H)7.14-7.26(m,2H)7.34(d,J=2.32Hz,1H)7.49-7.60(m,1H)8.24(d,J=5.24Hz,1H)12.44(bs,1H);ESI(+)MS:m/z 345(MH+).
实施例23,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(2,6-二氟-苯基)-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 6.42(bs,2H)6.99(d,J=5.24Hz,1H)7.12-7.23(m,2H)7.30(d,J=1.95Hz,1H)7.48-7.56(m,1H)8.22(d,J=5.24Hz,1H)11.92(bs,1H)12.32(bs,1H);MS:m/z 315[M-H].
实施例23,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(2,6-二氟-苯基)-1H-吡咯-3-甲酸酰
胺(F37)
1H NMR(DMSO-d6/400MHz)δppm 6.40(b s,2H),6.75(bs,1H),6.89(d,J=5.24Hz,1H),7.09-7.16(m,2H),7.38(d,J=2.44Hz,1H),7.41(bs,1H),7.43-7.52(m,1H),8.22(d,J=5.24Hz,1H),12.10(bs,1H);ESI(+)MS:m/z 316(MH+).
实施例24,步骤-1
5-(2-氨基-嘧啶-4-基)-2-噻吩-2-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.26(t,J=7.07Hz,3H)4.19(q,J=7.07Hz,2H)6.47(bs,2H)7.11(d,J=5.12Hz,1H)7.15(dd,J=5.06,3.72Hz,1H)7.30(d,J=2.07Hz,1H)7.64(dd,J=3.66,1.22Hz,1H)7.67(dd,J=5.06,1.16Hz,1H)8.23(d,J=5.24Hz,1H)11.92(b s,1H);ESI(+)MS:m/z 315(MH+).
实施例24,步骤-2
5-(2-氨基-嘧啶-4-基)-2-噻吩-2-基-1H-吡咯-3-甲酸
MS:m/z 285[M-H].
实施例24,步骤-3
5-(2-氨基-嘧啶-4-基)-2-噻吩-2-基-1H-吡咯-3-甲酸酰胺(G2)
1H NMR(DMSO-d6/400MHz)δppm 6.46(bs,2H)6.91(bs,1H)7.04(d,J=5.37Hz,1H)7.11(dd,J=5.12,3.66Hz,1H)7.30(d,J=1.95Hz,1H)7.44(bs,1H)7.57(dd,J=5.12,1.22Hz,1H)7.66(dd,J=3.66,1.22Hz,1H)8.23(d,J=5.24Hz,1H)11.60(b s,1H);ESI(+)MS:m/z 286(MH+).
实施例25,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(5-甲基-噻吩-2-基)-1H-吡咯-3-甲酸
乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.26(t,J=7.07Hz,3H)2.50(s,3H)4.19(q,J=7.07Hz,2H)6.46(bs,2H)6.84(dd,J=3.54,0.98Hz,1H)7.10(d,J=5.24Hz,1H)7.27(d,J=2.07Hz,1H)7.45(d,J=3.54Hz,1H)8.22(d,J=5.12Hz,1H)11.92(bs,1H);ESI(+)MS:m/z 329(MH+).
实施例25,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(5-甲基-噻吩-2-基)-1H-吡咯-3-甲酸
MS:m/z 299[M-H].
实施例25,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(5-甲基-噻吩-2-基)-1H-吡咯-3-甲酸
酰胺(G3)
1H NMR(DMSO-d6/400MHz)δppm 2.46(d,J=0.73Hz,3H)6.40(bs,2H)6.79(dd,J=3.54,1.10Hz,1H)6.85(bs,1H)7.01(d,J=5.24Hz,1H)7.25(d,J=2.07Hz,1H)7.38(bs,1H)7.44(d,J=3.29Hz,1H)8.21(d,J=5.24Hz,1H)11.45(bs,1H);ESI(+)MS:m/z 300(MH+).
实施例26,步骤-1
5-[5-(2-氨基-嘧啶-4-基)-3-乙氧羰基-1H-吡咯-2-基]-3,4-二
氢-1H-异喹啉-2-甲酸叔丁酯
1H NMR(DMSO-d6/400MHz)δppm 1.08(t,J=7.01Hz,3H)1.44(s,9H)2.51-2.59(m,2H)3.42-3.53(m,2H)4.03(q,J=7.03Hz,2H)4.58(b s,2H)6.45(b s,2H)7.03(d,J=5.24Hz,1H)7.16-7.35(m,4H)8.21(d,J=5.00Hz,1H)12.11(bs,1H);ESI(+)MS:m/z 464(MH+).
实施例26,步骤-2
5-[5-(2-氨基-嘧啶-4-基)-3-羧基-1H-吡咯-2-基]-3,4-二氢
-1H-异喹啉-2-甲酸叔丁酯
MS:m/z 434[M-H].
实施例26,步骤-3
5-[5-(2-氨基-嘧啶-4-基)-3-氨基甲酰基-1H-吡咯-2-基]-3,4-
二氢-1H-异喹啉-2-甲酸叔丁酯(G7)
1H NMR(DMSO-d6/400MHz)δppm 1.44(s,9H)2.58(t,J=5.79Hz,2H)3.48(t,J=6.10Hz,2H)4.58(b s,2H)6.89(bs,1H)7.11-7.39(m,5H)7.64(d,J=2.19Hz,1H)7.75(bs,2H)8.27(d,J=6.34Hz,1H)12.28(bs,1H);ESI(+)MS:m/z 435(MH+).
实施例27
5-(2-氨基-嘧啶-4-基)-2-(1,2,3,4-四氢-异喹啉-5-基)-1H-吡
咯-3-甲酸酰胺(G8)
通过用酸处理实施例26中制备的化合物G 7,例如室温下用三氟乙酸处理24小时,得到相应的脱保护的类似物G8。
1H NMR(DMSO-d6/400MHz)δppm 2.78(t,J=5.91Hz,2H)4.35(t,J=4.51Hz,2H)6.90(bs,1H)7.25(d,J=6.58Hz,1H)7.27-7.30(m,1H)7.31-7.39(m,3H)7.70(d,J=2.44Hz,1H)7.86(bs,3H)8.30(d,J=6.46Hz,1H)9.32(bs,2H)12.44(bs,1H);ESI(+)MS:m/z 335(MH+).
实施例28,步骤-1
5-(2-氨基-嘧啶-4-基)-2-吡啶-2-基-1H-吡咯-3-甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.29(t,3H,J=7.1Hz)4.25(q,2H,J=7.07Hz)6.64(bs,2H)7.16(d,1H,J=5.12Hz)7.4(m,2H)7.9(td,1H,J=7.8,1.83Hz)8.2(d,1H,J=5.12Hz)8.4(d t,1H,J=8.05,0.98Hz)8.7(ddd,1H,J=4.82,1.77,0.98Hz)11.5(bs,1H);ESI(+)MS:m/z 310(MH+).
实施例28,步骤-2
5-(2-氨基-嘧啶-4-基)-2-吡啶-2-基-1H-吡咯-3-甲酸
1H NMR(DMSO-d6/400MHz)δppm 6.46(b s,2H)7.08(d,1H,J=5.12Hz)7.31(m,2H)7.91(t,1H,J=7.87Hz)8.17(d,1H,J=5.12Hz)8.55(d,1H,J=3.90Hz)8.80(bs,1H);MS:m/z 280[M-H].
实施例28,步骤-3
5-(2-氨基-嘧啶-4-基)-2-吡啶-2-基-1H-吡咯-3-甲酸酰胺(G12)
1H NMR(DMSO-d6/400MHz)δppm 6.62(bs,2H),7.03(d,J=5.12Hz,1H),7.16(bs,1H),7.33-7.40(m,2H)7.86-7.93(m,1H),8.25(d,J=5.12Hz,1H),8.28(bs,1H),8.43(d,J=8.17Hz,1H),8.62-8.67(m,1H),11.29(s,1H);ESI(+)MS:m/z 281(MH+).
实施例29,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(1-甲基-1H-吲哚-3-基)-1H-吡咯-3-
甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.12(t,J=7.07Hz,3H)3.87(s,3H)4.08(q,J=7.07Hz,2H)6.41(bs,2H)7.05(d,J=5.24Hz,1H)7.08-7.14(m,1H)7.19-7.25(m,1H)7.33(d,J=2.68Hz,1H)7.47-7.53(m,2H)7.77(s,1H)8.18(d,J=5.24Hz,1H)11.65(bs,1H);ESI (+)MS:m/z 362(MH+).
实施例29,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(1-甲基-1H-吲哚-3-基)-1H-吡咯-3-
甲酸
1H NMR(DMSO-d6/400MHz)δppm 3.87(s,3H)6.40(bs,2H)7.03(d,J=5.24Hz,1H)7.11(t,J=7.80Hz,1H)7.22(t,J=7.80Hz,1H)7.32(d,J=2.56Hz,1H)7.49-7.54(m,2H)7.77(s,1H)8.18(d,J=5.24Hz,1H)11.50(bs,1H);MS:m/z 332[M-H].
实施例29,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(1-甲基-1H-吲哚-3-基)-1H-吡咯-3-
甲酸酰胺(G 13)
1H NMR(DMSO-d6/400MHz)δppm 3.87(s,3H),6.35(bs,2H),6.73(b s,1H),6.91(b s,1H),6.98(d,J=5.24Hz,1H),7.11(t,J=7.07Hz,1H),7.22(t,J=7.07Hz,1H),7.32(d,J=2.68Hz,1H),7.48-7.53(m,2H),7.80(s,1H),8.17(d,J=5.24Hz,1H),11.36(bs,1H);ESI (+)MS:m/z 333(MH+).
实施例30,步骤-1
5-(2-氨基-嘧啶-4-基)-2-(1-甲基-1H-吲哚-2-基)-1H-吡咯-3-
甲酸乙酯
1H NMR(DMSO-d6/400MHz)δppm 1.10(t,J=7.07Hz,3H),3.59(s,3H),4.09(q,J=7.07Hz,2H),6.47(bs,2H),6.66(d,J=0.73Hz,1H),7.10(d,J=5.24Hz,1H),7.10-7.12(m,1H),7.19-7.27(m,1H),7.38(d,J=2.68Hz,1H),7.51(d,7.32Hz,1H),7.62(d,J=7.80Hz,1H)8.24(d,J=5.24Hz,1H)12.33(bs,1H);ESI(+)MS:m/z 362(MH+).
实施例30,步骤-2
5-(2-氨基-嘧啶-4-基)-2-(1-甲基-1H-吲哚-2-基)-1H-吡咯-3-
甲酸
MS:m/z 332[M-H].
实施例30,步骤-3
5-(2-氨基-嘧啶-4-基)-2-(1-甲基-1H-吲哚-2-基)-1H-吡咯-3-
甲酸酰胺(G14)
1H NMR(DMSO-d6/400MHz)δppm 3.58(s,3H),6.38(bs,2H),6.61(d,J=0.61Hz,1H),6.88(bs,1H),7.00(d,J=5.24Hz,1H),7.08(t,J=7.70Hz,1H),7.20(t,J=7.70Hz,1H),7.25(bs,1H),7.41(d,J=2.44Hz,1H),7.47(d,J=7.70Hz,1H),7.59(d,J=7.70Hz,1H),8.22(d,J=5.24Hz,1H),11.98(bs,1H);ESI(+)MS:m/z 333(MH+).
实施例31,步骤-1
5-(2-氨基-嘧啶-4-基)-2-苯并[b]噻吩-5-基-1H-吡咯-3-甲酸乙
酯
1H NMR(DMSO-d6/400MHz)δppm 1.18(t,J=7.07Hz,3H)4.13(q,J=7.07Hz,2H)6.45(s,2H)7.10(d,J=5.24Hz,1H)7.35(d,J=2.56Hz,1H)7.53(d,J=5.12Hz,1H)7.60(dd,J=8.41,1.59Hz,1H)7.82(d,J=5.49Hz,1H)8.06(d,J=8.41Hz,1H)8.13(d,J=1.34Hz,1H)8.22(d,J=5.24Hz,1H)12.06(bs,1H)ESI(+)MS:m/z 365(MH+).
实施例31,步骤-2
5-(2-氨基-嘧啶-4-基)-2-苯并[b]噻吩-5-基-1H-吡咯-3-甲酸
MS:m/z 335[M-H].
实施例31,步骤-3
5-(2-氨基-嘧啶-4-基)-2-苯并[b]噻吩-5-基-1H-吡咯-3-甲酸酰
胺(G15)
1H NMR(DMSO-d6/400MHz)δppm 6.43(bs,2H)6.84(bs,1H)7.04(d,J=5.37Hz,1H)7.31(d,J=2.44Hz,1H)7.34(bs,1H)7.50(dd,J=5.49,0.49Hz,1H)7.62(dd,J=8.41,1.71Hz,1H)7.80(d,J=5.49Hz,1H)8.01(d,J=8.41Hz,1H)8.13(d,J=1.34Hz,1H)8.21(d,J=5.37Hz,1H)11.75(bs,1H);ESI(+)MS:m/z336(MH+).
实施例32
5-(2-氨基-5-氟-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(V1)
步骤1:嘧啶环的烷基化(18)
向2,4-二氯-5-氟-嘧啶17(1.2g,7.24mmol)于DMF(14mL)的溶液中加入三丁基-(1-乙氧基-乙烯基)-锡烷(2.7mL,7.9mmol),接下来加入双(三苯基膦)二氯化钯(II)(100mg,0.145mmol)。在70℃下温热该混合物1小时,冷却,加入饱和的氟化钾溶液(aq),室温下搅拌该混合物18小时。在用水/乙醚稀释并通过C盐过滤后,用水充分洗涤有机相并浓缩。采用Horizon系统(25mm柱)用正己烷/EtOAc 95∶5洗脱来纯化粗产物。得到2-氯-4-(1-乙氧基-乙烯基)-5-氟-嘧啶(1.24g,84%)。
1H NMR(400MHz,DMSO-d6)δppm 1.32(t,J=6.95Hz,3H)3.95(q,J=6.99Hz,2H)4.88(d,J=2.80Hz,1H)5.20(d,J=2.93Hz,1H)8.90(d,J=3.17Hz,1H);ESI(+)MS:m/z 203(MH+).
步骤2:嘧啶环的氨基化(19)
在Parr仪器中,在100℃和振荡下温热烯醇醚18(15.5g,76.73mmol)于无水乙醇(25mL)和30%的氨水(50mL)的溶液1.5个小时。冷却后,除去乙醇并用二氯甲烷萃取该化合物。采用Horizon系统用正己烷/EtOAc1∶1洗脱来纯化粗产物。得到4-(1-乙氧基-乙烯基)-5-氟-嘧啶-2-基胺(9g,49.2mmol,64%)。
1H NMR(400MHz,DMSO-d6)δppm 1.29(t,J=7.01Hz,3H)3.87(q,J=6.95Hz,2H)4.62(d,J=2.44Hz,1H)4.91(dd,J=2.38,0.55Hz,1H)6.64(b s,2H)8.28(d,J=3.54Hz,1H);ESI(+)MS:m/z 184(MH+).
步骤3:溴化成溴酮(20)
向烯醇醚19(510mg,2.78mmol)于THF(25mL)的溶液中加入水(1.7mL),然后加入NBS(515mg,2.78mmol)。室温下搅拌该混合物1.5小时。蒸发溶剂,在甲醇中充分搅拌残余物并过滤。得到1-(2-氨基-5-氟-嘧啶-4-基)-2-溴-乙酮(500mg,77%)。
1H NMR(400MHz,DMSO-d6)δppm 4.70(s,2H)6.94(bs,2H)8.50(d,J=2.93Hz,1H);ESI(+)MS:m/z 235(MH+).
步骤4:形成吡咯环(21)
搅拌下,向在0℃下冷却的酮酯2(192mg,1mmol)于THF(5mL)的溶液中加入氢化钠(80mg,2mmol)。5分钟后,加入溴酮20(234mg,1mmol)于DMF(2mL)的溶液,并在50℃下搅拌该反应混合物8小时。除去THF后,加入乙醇(10mL)和醋酸铵(240mg,3mmol)并室温下搅拌该混合物20小时。除去溶剂后,加入乙酸乙酯,用水洗涤有机相并采用Horizon系统用正己烷/EtOAc 1∶1洗脱来纯化粗产物。得到5-(2-氨基-5-氟-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸乙酯(50mg,16%).ESI(+)MS:m/z 327(MH+)。
步骤5:水解成酸(22)
向酯21(25mg,0.077mmol)于95%EtOH(0.5mL)的悬浮液中加入4M aq NaOH(0.5mL)并回流该混合物2小时。用浓HCl酸化该混合物至pH 5,观察到产物沉淀。过滤沉淀,用少量的冷水洗涤并干燥。得到白色固体状的5-(2-氨基-5-氟-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸(16mg,64%),无需进一步纯化用于下一步。
ESI(+)MS:m/z 299(MH+).
步骤6:缩合成酰胺(V1)
向0℃下搅拌的酸22(16mg,0.054mmol)于DMF(0.5mL)和DIEA(0.03mL)的溶液中加入HOBT.NH3(13mg,0.08mmol)和EDCI(16mg,0.08mmol)。室温下搅拌该混合物20小时。用乙酸乙酯稀释后,用水和饱和碳酸氢钠水溶液洗涤有机相,用Na2SO4干燥并浓缩。通过快速色谱(洗脱液:AcOEt/正己烷9∶1)纯化粗产物。得到标题化合物,产率为74%。
1H NMR(DMSO-d6/400MHz)δppm 6.34(s,2H)6.87(bs,1H)7.27(t,J=2.80Hz,1H)7.33-7.43(m,3H)7.40(s,1H)7.62-7.66(m,2H)8.27(d,J=3.41Hz,1H)11.49(bs,1H).ESI(+)MS:m/z298(MH+).
实施例33
2-苯基-5-(2-苯基氨基-嘧啶-4-基)-1H-吡咯-3-甲酸酰胺(H1)
步骤1:溴化成溴酮(24)
室温下向烯醇甲硅烷基醚23(1g,2.27mmol)于THF(40mL)和水(5mL)的溶液中加入固体NBS(0.43g,62.4mmol),并搅拌该混合物20小时。在溶剂蒸发并用乙酸乙酯进行水溶液后处理,通过快速色谱(洗脱液:正己烷/EtOAc 4∶1)纯化粗产物,得到黄色固体状的2-溴-1-(2-苯基氨基-嘧啶-4-基)-乙酮(0.27g,40%)。
1H NMR(DMSO-d6/300MHz)δppm 4.65(s,2H),6.7(m,1H),6.9(d,1H),7.0(m,2H),7.4(d,2H),8.4(d,1H),9.6(s,1H);ESI(+)MS:m/z 293(MH+).
步骤2.吡咯环的形成(25)
在0℃和氩气下,向搅拌的酯2(150μL,0.87mmol)于无水THF(40mL)的溶液中加入NaH(50mg,1.2mmol)。40分钟后加入溴酮24(260mg,0.89mmol,如WO2005014572所述制备),并室温下搅拌该混合物3小时。蒸发溶剂至干,将残余物溶于EtOH(10mL),加入醋酸铵(343g,4.45mmol)并室温下搅拌该溶液过夜。蒸发溶剂至干,并向粗产物中加入EtOAc和水,分离有机层,用水洗涤,干燥(Na2SO4)并浓缩。用Et2O/EtOAc/正己烷(1∶1∶1)溶解残余物并过滤。得到2-苯基-5-(2-苯基氨基-嘧啶-4-基)-1H-吡咯-3-甲酸乙酯(120mg,36%)。
1H NMR(DMSO-d6/400MHz)δppm 1.20(t,3H)4.14(q,2H)6.90-7.85(m,11H)7.35(d,J=5.27Hz,1H)8.46(d,J=5.27Hz,1H)9.45(s,1H)12.10(s,1H);ESI(+)MS:m/z 385(MH+).
步骤3:皂化成羧酸(26)
向酯25(120mg,0.31mmo l)于95%Et OH(3mL)的溶液中加入4M aq NaOH(4mL)并回流该混合物4小时。蒸发掉大部分的溶剂并在冰浴中冷却残余物,并用浓AcOH酸化至pH 5,观察到产物沉淀。过滤沉淀,用少量冷水洗涤,并干燥。得到白色固体状的2-苯基-5-(2-苯基氨基-嘧啶-4-基)-1H-吡咯-3-甲酸(100mg),无需进一步纯化用于下一步。
MS:m/z 355[M-H].
步骤3:缩合成酰胺(H1)
向酸26(90mg,0.25mmol)于DMF(3mL)的溶液中加入DIEA(120μL,0.67mmol)、EDCI(100mg,0.52mmol)和HOBT·NH3(79mg,0.52mmol)。室温下搅拌该反应混合物过夜,然后将其倒入搅拌的水和EtOAc(1∶1)的混合物中。用水洗涤有机相,用EtOAc萃取水层并用水洗涤合并的有机层,干燥(Na2SO4)并浓缩,得到粗产物,通过快速色谱(DCM/MeOH 96∶4)纯化该粗产物,得到白色固体状的2-苯基-5-(2-苯基氨基-嘧啶-4-基)-1H-吡咯-3-甲酸酰胺(35mg,两步30%)。
1H NMR(300MHz,DMSO-d6)δppm 6.90(s,1H)6.95(t,J=7.33Hz,1H)7.25-7.50(m,7H)7.29(d,J=5.57Hz,1H)7.60(d,2H)7.85(d,J=7.62Hz,2H)8.43(d,J=5.27Hz,1H)9.40(s,1H)11.75(s,1H);ESI(+)MS:m/z 356(MH+).
实施例34
5-(2-氨基-嘧啶-4-基)-1-乙基-2-苯基-1H-吡咯-3-甲酸酰胺(L1)
步骤1:形成吡咯环(27)
在0℃和氩气下,向搅拌的酯2(1.34g,7mmol)于无水THF(100mL)的溶液中加入NaH(0.7g,17.5mmol)。5分钟后,加入溴酮14(2.5g,8.4mmol)并室温下搅拌该混合物3小时。蒸发溶剂,将残余物溶于AcOH(30mL)和2M EtNH2的THF(8.7mL,17.5mmol)中。在170℃下用微波处理该混合物5分钟,然后用EtOAc稀释并用Na HCO3饱和水溶液洗涤。用EtOAc萃取水层并用水洗涤合并的有机层,干燥(Na2SO4)并浓缩。通过快速色谱(DCM/EtOH/丙酮96∶2∶2)纯化残余物,由此得到0.7g 5-(2-氨基-嘧啶-4-基)-1-乙基-2-苯基-1H-吡咯-3-甲酸乙酯(产率为29%)。
ESI(+)MS:m/z 337(MH+).
步骤2:皂化成羧酸(28)
向酯27(0.7g,2.08mmol)于95%EtOH(8mL)的悬浮夜中加入4M aq NaOH(8mL)并在100℃下搅拌该混合物1小时。真空下除去溶剂并用浓HCl将残余物水溶液酸化至pH 5,观察到产物沉淀。过滤该混合物,用少量的冷水洗涤该固体并干燥,由此得到0.66g 5-(2-氨基-嘧啶-4-基)-1-乙基-2-苯基-1H-吡咯-3-甲酸,无需进一步纯化用于下一步。
MS:m/z 307[M-H].
步骤3:缩合成酰胺(L1)
向在冰浴中冷却的酸28(400mg,1.31mmol)于10mL THF和600μL DIEA(3.52mmol)的悬浮液中加入336mg EDCI(1.75mmol)和267mg HOBT·NH3(1.75mmol)并室温下搅拌该混合物过夜。加入EtOAc和水,分离各层,用EtOAc萃取水层并用1M aq NaOH和水洗涤合并的有机层。然后将其干燥(Na2SO4)并浓缩。过滤残余物并用少量冷MeOH洗涤。通过快速色谱(DCM/MeOH/丙酮90∶5∶5)纯化母液得到所需的酰胺。合并两批产物,悬浮于MeOH并用1.25M HCl的MeOH溶液酸化至pH1。除去溶剂并用Et2O处理该残余物。过滤所得的固体,用Et2O洗涤并浓缩,得到380mg 5-(2-氨基-嘧啶-4-基)-1-乙基-2-苯基-1H-吡咯-3-甲酸酰胺盐酸盐(1.1mmol,产率为83%)。
1H NMR(DMSO-d6/400MHz)δppm 1.08(t,J=6.89Hz,3H)4.37(q,J=6.91Hz,2H)6.87(bd,J=21.95Hz,2H)7.18(d,J=6.58Hz,1H)7.38-7.43(m,2H)7.50-7.55(m,3H)7.81(s,1H)8.00(bs,3H)8.23(d,J=6.71Hz,1H);ESI(+)MS:m/z 308(MH+).
实施例35
2-溴-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(R1)和2-(3-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A11)
步骤1:缩合成氰基酯(29)
在0℃下,向钠金属(81mg,3.5mmol)于10mL无水EtOH的悬浮液中加入氰基乙酸乙酯(0.37mL,3.5mmol)。搅拌该溶液直至钠完全溶解。蒸发溶剂得到白色固体,将其逐份加入到搅拌的溴乙酰吡啶1(1.0g,3.5mmol)于无水THF(20mL)和DIEA(0.6mL,3.5mmol)的溶液中。室温下搅拌该反应混合物过夜。除去溶剂,将残余物悬浮于水中并用DCM萃取。用Na2SO4干燥有机萃取物并浓缩。通过快速色谱(DCM/MeOH 95∶5)纯化粗产物得到710mg(87%)红色油状的2-氰基-4-氧代-4-吡啶-4-基-丁酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.23(t,J=7.07Hz,3H),3.88(d,J=5.25Hz,2H),4.21(q,J=7.07Hz,2H),4.64(t,J=5.25Hz,1H),7.89(d,J=6.00Hz,2H),8.85(d,J=6.00Hz,2H);ESI(+)MS:m/z 233(MH+).
步骤2:形成吡咯环(30)
在0℃下,向HBr(33%于AcOH,13mL,43.1mmol)溶液中逐滴加入氰基酯29(1.0g,4.3mmol)溶于Et2O和DCM的溶液。在0℃下放置该反应混合物20分钟,然后室温下放置直到原料消失(2.5h)。过滤该固体并用丙酮和MeOH洗涤。在MeOH中用7N NH3中和吡啶盐。通过快速色谱(DCM/MeOH 95∶5)纯化固体得到800mg(62%)橙色固体状的2-溴-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.31(t,J=7.12Hz,3H),4.24(q,J=7.12Hz,2H),7.26(s,1H),7.71(d,J=6.22Hz,2H)8.54(d,J=6.22Hz,2H),12.85(s,1H);ESI (+)MS:m/z 295(MH+).
步骤3:皂化成羧酸(31)
回流溶于8mL 4M a q NaOH和8mL EtOH的酯30(1.0g,3.74mmol)4个小时。冷却溶液并用AcOH中和。过滤沉淀并用水和丙酮洗涤得到850mg(85%)白色固体状的2-溴-5-吡啶-4-基-1H-吡咯-3-甲酸。
1H NMR(DMSO-d6/400MHz)δppm 7.33(s,1H),7.83(d,J=6.00Hz,2H),8.58(d,J=6.00Hz,2H),12.37(bs,1H),12.91(s,1H);MS:m/z 266[M-H].
步骤4:缩合成酰胺(R1)
在DIEA(1.27mL,7.30mmol)存在下,酸31(450mg,1.68mmol)溶于无水THF(20mL)。向冷却到0℃的溶液中加入EDCI(1.0g,5.5mmol)和HOBT·NH3(812mg,5.34mmol)。反应混合物在室温下放置过夜。蒸发溶剂,加入水并用DCM萃取浆液。通过快速色谱(DCM/MeOH95∶5)纯化粗产物得到150mg(33%)淡黄色固体状的2-溴-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 7.02(s,2H),7.29(s,1H),7.59(d,J=6.25Hz,2H),8.52(d,J=6.25Hz,2H),12.54(s,1H);ESI (+)MS:m/z 267(MH+).
步骤5:Suzuki偶联成酰胺(A11)
向酰胺R1(110mg,0.41mmol)于脱氧化甲苯/EtOH 1∶1(5mL)的溶液中加入脱氧化的1M aq Na2CO3(1.1mL,1.12mmol)、LiCl(57mg,1.35mmol)、方便取代的苯基硼酸(0.67mmol)和(Ph3P)2PdCl2(3mg),在100℃下搅拌该混合物直到原料消失。蒸发溶剂并通过快速色谱(洗脱液:DCM/MeOH 95∶5)纯化粗产物。当所需的产物溶于EtOH时,用2N HCl的Et2O溶液处理直到盐酸盐沉淀,过滤该沉淀得到2-(3-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(产率为68%)。
1H NMR(DMSO-d6/400MHz)δppm 3.83(s,3H),6.66(bs,2H),7.28(m,3H),7.40(m,2H),8.24(d,J=6.82Hz,2H),9.11(d,J=6.82Hz);ESI(+)MS:m/z 294(MH+).
通过使用该步骤得到下述化合物。
实施例36
2-(4-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸盐
(A12)
1H NMR(DMSO-d6/400MHz)δppm 3.84(s,3H),7.07(d,J=8.90Hz,2H),7.33(b s,2H),7.67(d,J=8.90Hz,2H),7.73(s,1H),8.22(d,J=6.50Hz,2H),8.72(d,J=6.50Hz,2H),12.28(s,1H);ESI(+)MS:m/z 294(MH+).
实施例37
2-(2-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸盐
(A10)
1H NMR(DMSO-d6/400MHz)δppm 3.76(s,3H),6.95(bs,2H),7.06(t,J=8.05Hz,1H),7.16(d,J=8.05Hz,1H),7.40(dd,J=1.71Hz,7.44Hz,1H),7.46(m,1H),7.73(s,1H),8.15(d,J=7.00Hz,2H),8.71(d,J=7.00Hz,2H),12.42(s,1H);ESI(+)MS:m/z 294(MH+).
实施例38
2-(4-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A15)
1H NMR(DMSO-d6/400MHz)δppm 7.40(bs,2H),7.70(s,1H),8.02(d,J=8.78Hz,2H),8.19(d,J=6.20Hz,2H),8.32(d,J=8.78Hz,2H),8.77(d,J=6.20Hz,2H),12.57(bs,1H);ESI(+)MS:m/z 309(MH+).
实施例39
5-(2-氨基-嘧啶-4-基)-2-溴-1H-吡咯-3-甲酸酰胺(R2)和5-(2-氨基-嘧啶-4-基)-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺(G1)
步骤1:缩合成氰基酯(32)
在0℃下,将氰基乙酸乙酯(5.3mL,0.05mol)加入到钠金属(1.15g,0.05mol)于150mL无水EtOH的悬浮液中。钠溶解后,浓缩该反应混合物并将所得的固体加入到溴酮14(15g,0.05mol)于300mL无水THF和DIEA(8.8mL,0.05mol)的溶液中。室温下搅拌该反应混合物过夜,浓缩并将残余物悬浮于水中并用DCM萃取。干燥有机萃取液(Na2SO4)并浓缩。通过快速色谱(DCM/MeOH 95∶5)纯化粗产物得到4.5g(37%)油状4-(2-氨基-嘧啶-4-基)-2-氰基-4-氧代-丁酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.21(t,J=7.08Hz,3H),3.73(d,J=5.61Hz,2H),4.18(q,J=7.08Hz,2H),4.58(t,J=5.61Hz,1H),6.97(d,J=4.88Hz,1H),7.04(bs,2H),8.52(d,J=4.88Hz,1H);ESI(+)MS:m/z 249(MH+).
步骤2:形成吡咯环(33)
在0℃下,将氰基酯32(364mg,1.47mmol)于无水Et2O和DCM(1∶1,10mL)的溶液逐滴加入到4.5mL 33%HBr的AcOH中。在0℃下放置该混合物30分钟,然后室温下放置直到原料消失。过滤固体,用丙酮和MeOH洗涤,用7N NH3的MeOH溶液中和得到400mg(88%)5-(2-氨基-嘧啶-4-基)-2-溴-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.26(t,J=7.10Hz,3H),4.20(q,J=7.10Hz,2H),6.43(bs,2H),6.99(d,J=5.24Hz,1H),7.23(s,1H),8.23(d,J=5.24Hz,1H);ESI(+)MS:m/z 312(MH+).
步骤3:皂化成羧酸(34)
在100℃下回流酯33(2g,6mmol)于15mL EtOH和15mL 4M aqNaOH的溶液6小时。用AcOH沉淀该酸,过滤并用丙酮洗涤得到80mg(88%)5-(2-氨基-嘧啶-4-基)-2-溴-1H-吡咯-3-甲酸。
1H NMR(DMSO-d6/400MHz)δppm 6.06(br,2H),6.87(d,J=5.20Hz,1H),7.08(s,1H),8.00(d,J=5.20Hz,1H);MS:m/z 282[M-H].
步骤4:缩合成酰胺(R2)
在0℃下搅拌500mg(1.77mmol)酸34于20mL干燥THF和DIEA(0.6mL,3.54mmol)的溶液。加入EDCI(508mg,2.65mmol)和HOBT.NH3(404mg,2.65mmol)并室温下搅拌该反应混合物过夜。浓缩该溶液并通过制备型HPLC纯化粗产物。得到5-(2-氨基-嘧啶-4-基)-2-溴-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 6.97(d,J=5.57Hz,1H)7.00(bs,1H)7.17(bs,1H)8.24(d,J=5.57Hz,1H)12.66(bs,1H);ESI(+)MS:m/z 283(MH+).
步骤5:Suzuki偶联成酰胺(G1)
溴代酰胺R2(224mg,0.79mmol)溶于EtOH(6mL)和甲苯(6mL)中,并加入LiCl(99mg,2.37mmol)、1M aq Na2CO3(1.97mmol)、3-噻吩硼酸(152mg,1.18mmol)和(Ph3P)2PdCl2(6mg,0.008mmol),将反应混合物加热回流6小时然后室温下过夜。减压下蒸发溶剂并通过快速色谱(DCM/MeOH 9∶1)纯化粗产物得到120mg(53%)5-(2-氨基-嘧啶-4-基)-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 6.36(b s,2H),6.87(b s,2H),7.01(d,J=5.24Hz,1H),7.26(d,J=2.44Hz,1H),7.54(d,J=2.93Hz,5.00,1H),7.65(dd,J=1.22Hz,5.00,1H),8.11(dd,J=1.22Hz,2.93,1H),8.20(d,J=5.24Hz,1H),11.52(b s,1H);ESI(+)MS:m/z 286(MH+).
使用上述步骤合成下述化合物。
实施例40
5-(2-氨基-嘧啶-4-基)-2-(4-氟-2-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F13)
1H NMR(DMSO-d6/400MHz)δppm 2.15(s,3H),6.31(bs,2H),6.69(bs,1H),6.92(d,J=5.24Hz,1H),7.05(td,J=8.41,2.56Hz,1H),7.05(dd,J=7.68,2.56Hz,1H),7.06(bs,1H),7.28(dd,J=8.41,7.68Hz,1H),7.32(d,J=2.56Hz,1H),8.18(d,J=5.24Hz,1H),11.75(bs,1H);ESI (+)MS:m/z 312(MH+).
实施例41
5-(2-氨基-嘧啶-4-基)-2-(5-氟-2-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F14)
1H NMR(DMSO-d6/400MHz)δppm 2.11(s,3H),6.32(bs,2H),6.72(bs,1H),6.93(d,J=5.24Hz,1H),7.04-7.19(m,3H),7.25-7.31(m,1H),7.33(d,J=2.44Hz,1H),8.18(d,J=5.24Hz,1H),11.82(bs,1H);ESI (+)MS:m/z 312(MH+).
实施例42
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F15)
参见实施例17。
实施例43
5-(2-氨基-嘧啶-4-基)-2-(2,3-二氟-苯基)-1H-吡咯-3-甲酸酰
胺(F16)
1H NMR(DMSO-d6/400MHz)δppm 6.38(bs,2H),6.82(bs,1H),6.95(d,J=5.24Hz,1H),7.20-7.28(m,1H),7.28-7.34(m,1H),7.35(d,J=2.56Hz,1H),7.39-7.50(m,2H),8.23(d,J=5.24,1H),12.00(bs,1H);ESI(+)MS:m/z 316(MH+).
实施例44
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氟-苯基)-1H-吡咯-3-甲酸酰
胺(F17)
1H NMR(DMSO-d6/400MHz)δppm 6.41(bs,2H),6.77(bs,1H),6.94(d,J=5.24Hz,1H),7.13(m,1H),7.28(m,1H),7.35(d,J=2.56Hz,1H),7.38(b s,1H),7.54(m,1H),8.23(d,J=5.24Hz,1H),11.93(bs,1H);ESI(+)MS:m/z 316(MH+).
实施例45
5-(2-氨基-嘧啶-4-基)-2-(2,5-二氟-苯基)-1H-吡咯-3-甲酸酰
胺(F18)
1H NMR(DMSO-d6/400MHz)δppm 6.40(bs,2H)6.81(bs,1H)6.94(d,J=5.37Hz,1H)7.33(d,J=2.44Hz,1H)7.42(bs,1H)8.22(d,J=5.24Hz,1H)11.95(bs,1H);ESI(+)MS:m/z 316(MH+).
实施例46
5-(2-氨基-嘧啶-4-基)-2-(2-氯-苯基)-1H-吡咯-3-甲酸酰胺
(F19)
1H NMR(DMSO-d6/400MHz)δppm 6.37(b s,2H),6.69(bs,1H),6.93(d,J=5.24Hz,1H),7.19(bs,1H),7.33(d,J=2.56Hz,1H),7.35-7.45(m,3H),7.48-7.53(m,1H),8.19(d,J=5.24,1H),11.90(bs,1H);ESI(+)MS:m/z 314(MH+).
实施例47
5-(2-氨基-嘧啶-4-基)-2-(3-氯-苯基)-1H-吡咯-3-甲酸酰胺
(F20)
1H NMR(DMSO-d6/400MHz)δppm 6.38(bs,2H),6.90(bs,1H),7.01(d,J=5.24Hz,1H),7.27(d,J=2.44Hz,1H),7.35-7.44(m,2H),7.47(bs,1H),7.59-7.65(m,1H),7.73(t,J=1.22Hz,1H),8.23(d,J=5.24,1H),11.79(bs,1H);ESI (+)MS:m/z 314(MH+).
实施例48
5-(2-氨基-嘧啶-4-基)-2-(4-氯-苯基)-1H-吡咯-3-甲酸酰胺
(F21)
1H NMR(DMSO-d6/400MHz)δppm 6.33(bs,2H),6.86(bs,1H),6.99(d,J=5.24Hz,1H),7.28(d,J=2.07Hz,1H),7.38-7.49(m,3H),7.63-7.70(m,2H),8.21(d,J=5.24,1H),11.74(bs,1H);ESI (+)MS:m/z 314(MH+).
实施例49
5-(2-氨基-嘧啶-4-基)-2-(4-异丁基-苯基)-1H-吡咯-3-甲酸酰
胺(F22)
1H NMR(DMSO-d6/400MHz)δppm 0.90(d,J=6.58Hz,6H),1.80-1.95(m,1H),2.48(m,2H),6.35(bs,2H),6.80(bs,1H),7.01(d,J=5.24Hz,1H),7.19(d,J=8.17Hz,2H),7.25(d,J=2.56Hz,1H),7.28(bs,1H),7.56(d,J=8.17Hz,2H),8.19(d,J=5.24Hz,1H),11.56(bs,1H);ESI (+)MS:m/z 336(MH+).
实施例50
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-氟-苯基)-1H-吡咯-3-甲酸酰
胺(F23)
1H NMR(DMSO-d6/400MHz)δppm 6.38(bs,2H),6.72(bs,1H),6.92(d,J=5.24Hz,1H),7.22-7.33(m,2H),7.35(d,J=2.56Hz,1H),7.45-7.54(m,2H),8.22(d,J=5.24Hz,1H),11.95(bs,1H);ESI (+)MS:m/z 336(MH+).
实施例51
5-(2-氨基-嘧啶-4-基)-2-(2,5-二甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F24)
1H NMR(DMSO-d6/400MHz)δppm 2.11(s,3H)2.31(s,3H)6.41(bs,2H)6.70(bs,1H)6.83(bs,1H)6.98(d,J=5.37Hz,1H)7.1-7.18(m,3H)7.34(d,J=2.68Hz,1H)8.19(d,J=5.37Hz,1H)11.74(bs,1H);ESI (+)MS:m/z 308(MH+).
实施例52
5-(2-氨基-嘧啶-4-基)-2-(5-氯-2-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F25)
1H NMR(DMSO-d6/400MHz)δppm 2.12(s,3H),6.35(bs,2H),6.73(bs,1H),6.93(d,J=5.24Hz,1H),7.22(bs,1H),7.25-7.30(m,2H),7.32-7.36(m,2H),8.20(d,J=5.24Hz,1H),11.85(bs,1H);ESI (+)MS:m/z 328(MH+).
实施例53
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸酰
胺(F26)
参见实施例19。
实施例54
5-(2-氨基-嘧啶-4-基)-2-(5-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰
胺(F27)
1H NMR(DMSO-d6/400MHz)δppm 6.37(bs,2H)6.80(bs,1H)6.93(d,J=5.24Hz,1H)7.28(t,J=9.21Hz,1H)7.33(d,J=2.44Hz,1H)7.44(b s,1H)7.47(ddd,J=8.84,4.33,2.80Hz,1H)7.55(dd,J=6.22,2.68Hz,1H)8.22(d,J=5.24Hz,1H)11.98(bs,1H);ESI (+)MS:m/z 332(MH+).
实施例55
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F28)
1H NMR(DMSO-d6/400MHz)δppm 2.37(s,3H),6.37(bs,2H),6.73(bs,1H),6.95(d,J=5.24Hz,1H),7.02-7.09(m,2H),7.26(bs,1H),7.30(d,J=2.56Hz,1H),7.37(t,J=7.90Hz,1H),8.20(d,J=5.24Hz,1H),11.78(bs,1H);ESI(+)MS:m/z 312(MH+).
实施例56
5-(2-氨基-嘧啶-4-基)-2-(2-氟-5-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F29)
1H NMR(DMSO-d6/400MHz)δppm 2.33(s,3H)6.42(bs,2H)6.75(bs,1H)6.97(d,J=5.37Hz,1H)7.11(dd,J=9.88,8.41Hz,1H)7.19-7.25(m,1H)7.31(b s,1H)7.30(dd,J=6.77,2.01Hz,1H)7.32(d,J=2.44Hz,1H)8.21(d,J=5.37Hz,1H)11.85(bs,1H);ESI(+)MS:m/z 312(MH+).
实施例57
5-(2-氨基-嘧啶-4-基)-2-(2-氟-3-甲基-苯基)-1H-吡咯-3-甲酸
酰胺(F30)
1H NMR(DMSO-d6/400MHz)δppm 2.27(d,J=1.71Hz,3H)6.39(bs,2H)6.74(bs,1H)6.95(d,J=5.24Hz,1H)7.12(t,J=7.56Hz,1H)7.28(b s,1H)8.20(d,J=5.37Hz,1H)11.81(bs,1H);ESI(+)MS:m/z 312(MH+).
实施例58
5-(2-氨基-嘧啶-4-基)-2-(5-氯-2-氟-3-甲基-苯基)-1H-吡咯
-3-甲酸酰胺(F32)
1H NMR(DMSO-d6/400MHz)δppm 2.26(s,3H),6.41(bs,2H),6.80(bs,1H),6.95(d,J=5.24Hz,1H),7.32(d,J=2.32Hz,1H),7.33-7.37(m,1H),7.38-7.47(m,2H),8.21(d,J=5.24Hz,1H),11.95(bs,1H);ESI(+)MS:m/z 346(MH+).
实施例59
5-(2-氨基-嘧啶-4-基)-2-(3-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰
胺(F33)
1H NMR(DMSO-d6/400MHz)δppm 6.41(bs,2H)6.81(bs,1H)6.94(d,J=5.24Hz,1H)7.23-7.27(m,1H)7.35(d,J=2.44Hz,1H)7.42(bs,1H)7.43-7.47(m,1H)8.23(d,J=5.24Hz,1H)12.02(bs,1H);ESI (+)MS:m/z 332(MH+).
实施例60
5-(2-氨基-嘧啶-4-基)-2-(2,3-二氯-苯基)-1H-吡咯-3-甲酸酰
胺(F34)
1H NMR(DMSO-d6/400MHz)δppm 6.35(b s,2H),6.73(bs,1H),6.90(d,J=5.24Hz,1H),7.34(b s,1H),7.38-7.42(m,2H),7.65-7.70(m,2H),8.21(d,J=5.24Hz,1H),12.00(bs,1H);ESI(+)MS:m/z 349(MH+).
实施例61
5-(2-氨基-嘧啶-4-基)-2-(2-氟-3-甲氧基-苯基)-1H-吡咯-3-甲
酸酰胺(F35)
1H NMR(DMSO-d6/400MHz)δppm 3.86(s,3H)6.39(bs,2H)6.74(bs,1H)6.95(d,J=5.24Hz,1H)6.99-7.03(m,1H)7.12-7.16(m,1H)7.18-7.20(m,1H)7.29(bs,1H)7.30(d,J=2.44Hz,1H)8.21(d,J=5.24Hz,1H)11.86(bs,1H);ESI(+)MS:m/z 328(MH+).
实施例62
5-(2-氨基-嘧啶-4-基)-2-苯并[b]噻吩-5-基-1H-吡咯-3-甲酸酰
胺(G15)
实施例63
2-溴-5-(3-氟-吡啶-4-基)-1H-吡咯-3-甲酸酰胺(R3)和5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(E1)
步骤1:缩合成氰基酯(35)
在0℃下,将氰基乙酸乙酯(715μL,6.7mmol)加入到钠金属(154mg,6.7mmol)于20mL无水BtOH的悬浮液中。搅拌该溶液直到钠完全溶解。蒸发溶剂并将该固体加入溴酮11(2g,6.7mmol)和DIEA(1.16mL,6.7mmol)于40mL无水THF的溶液中。室温下搅拌该混合物过夜。蒸发溶剂,将该残余物悬浮于水中并用DCM萃取。干燥有机萃取物(Na2SO4)并通过快速色谱(DCM/MeOH 98∶2)纯化粗产物得到油状的2-氰基-4-(3-氟-吡啶-4-基)-4-氧代-丁酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.22(t,J=7.07Hz,3H),3.78(m,2H),4.20(q,J=7.07Hz,2H),4.61(t,J=5.37Hz,1H),7.81(m,1H),8.64(dd,J=1.22,5.00Hz,1H),8.82(d,J=2.56Hz,1H);ESI(+)MS:m/z 251(MH+).
步骤2:吡咯环的形成(36)
将氰基酯35(1.0g,4mmol)于无水Et2O(3mL)和DCM(2mL)的溶液加入到33%HBr的AcOH(12mL)中,在0℃下冷却。搅拌该反应化合物3小时,过滤沉淀,用丙酮和MeOH洗涤并用7N NH3的MeOH溶液中和。蒸发溶剂得到1.0g(80%)固体状的2-溴-5-(3-氟-吡啶-4-基)-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.26(t,J=7.07Hz,3H),4.20(q,J=7.07Hz,2H),7.08(d,J=3.53Hz,1H),7.30(bs,1H),7.83(m,1H),8.39(dd,J=0.85,5.12Hz,1H),8.55(d,J=3.41Hz,1H);ESI(+)MS:m/z 314(MH+).
步骤3:皂化成羧酸(37)
酯36溶于8mL EtOH和8mL 1M aq NaOH,并在100℃下加热6小时。用AcOH沉淀产物,过滤固体并用丙酮洗涤得到700mg(77%)2-溴-5-(3-氟-吡啶-4-基)-1H-吡咯-3-甲酸。
1H NMR(DMSO-d6/400MHz)δppm 6.98(d,J=5.12Hz,1H),7.81(q,J=5.12Hz,1H),8.13(d,J=5.60Hz,1H),8.25(d,J=4.02Hz,1H);MS:m/z 284[M-H].
步骤4:缩合成酰胺(R3)
在DIEA(1.27mL,7.30mmol)存在下,酸37(1.68mmol)溶于无水THF(20mL)。向冷却到0℃的该溶液中加入EDCI(1.0g,5.5mmol)和HOBT·NH3(812mg,5.34mmol)。反应混合物在室温下放置过夜。蒸发溶剂,加入水并用DCM萃取浆液。通过快速色谱(DCM/MeOH 98∶2)纯化粗产物得到黄色固体状的2-溴-5-(3-氟-吡啶-4-基)-1H-吡咯-3-甲酸酰胺(产率为42%)。
1H NMR(DMSO-d6/400MHz)δppm 7.09(s,2H)7.35(s,1H)7.98(d,J=4.83Hz,1H)8.47(d,J=4.84Hz,1H)8.61(d,J=0.91Hz,1H)12.05(s,1H);ESI(+)MS:m/z 285(MH+).
步骤5:Suzuki偶联成酰胺(E1)
向酰胺R3(0.8mmol)于脱氧化甲苯/EtOH 1∶1(10mL)的溶液中加入脱氧化的1M aq Na2CO3(2.2mL,2.2mmol)、LiCl(2.7mmol),苯基硼酸(1.4mmol)和(Ph3P)2PdCl2(6mg),并在100℃下搅拌该混合物直到原料消失。蒸发溶剂并通过快速色谱(洗脱液:DCM/MeOH95∶5)纯化粗产物。当所需的产物溶于EtOH时,用2N HCl的Et2O溶液处理直到盐酸盐沉淀,将沉淀过滤得到5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(产率为74%)。
实施例64
2-(4-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A12)
向溶于脱氧化EtOH/甲苯1∶1(2mL)的酯30(40mg,0.135mmol)中加入4-甲氧基苯基硼酸(31mg,0.2mmol)、LiCl(17mg,0.4mmol)、脱氧化1M aq Na2CO3(340μL,0.34mmol)和(Ph3P)2PdCl2(1mg)并在回流下搅拌该反应化合物直到原料消失(2.5h)。蒸发溶剂,加入水并用DCM萃取浆液并用水洗涤。干燥有机层(Na2SO4)并通过快速色谱(DCM/MeOH 95∶5)纯化粗产物得到28mg(70%)固体状的2-(4-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯38。
1H NMR(DMSO-d6/400MHz)δppm 1.20(t,J=7.00Hz,3H),3.82(s,3H),4.10(q,J=7.00Hz,2H),7.10(d,J=8.80Hz,2H),7.70(d,J=8.80Hz,2H),7.68(s,1H),8.25(d,J=6.40Hz,2H),8.70(d,J=6.40Hz,2H),12.30(s,1H);ESI (+)MS:m/z 323(MH+).
如已经在实施例1中所述,可以将酯38转为酰胺A12。
实施例65
5-吡啶-4-基-2-对-甲苯基-1H-吡咯-3-甲酸酰胺(A9)
步骤1:缩合成酰胺(39)
室温下通过与20mL DMF中的DIEA(0.65mL,3.74mmol)、EDCI(537mg,2.8mmol)和HOBT(379mg,2.8mmol)搅拌过夜,将酸31(500mg,1.87mmol)负载到Rink酰胺MBHA树脂(1.38g,0.935mmol,理论负载0.68mmol/g)上。取代率为78%,并且该树脂事先用20%哌啶的DMF溶液裂解。
步骤2:Suzuki偶联成酰胺(40)
在100℃下加热载体上的酰胺39(100mg,0.052mmol)与于2mL脱氧化DMF和0.1mL脱氧水中的4-甲基苯基硼酸(35mg,0.26mmol)、LiCl(9mg,0.208mmol)、Cs2CO3(85mg,0.26mmol)和(PhP3)2PdCl2(7.0mg,0.01mmol)过夜。
步骤3:裂解成酰胺(A9)
用TFA/DCM 95∶5裂解酰胺40。浓缩该溶液并通过制备型HPLC纯化粗产物得到固体状的5-吡啶-4-基-2-对-甲苯基-1H-吡咯-3-甲酸酰胺(产率为54%)。
1H NMR(DMSO-d6/400MHz)δppm 2.37(s,3H),7.00(bs,2H),7.25(d,J=8.00Hz,2H),7.34(d,J=2.56Hz,1H),7.58(d,J=8.00Hz,2H),7.79(d,J=6.22Hz,2H),8.56(d,J=6.22Hz,2H),11.85(s,1H);ESI (+)MS:m/z 278(MH+).
使用上述步骤合成下述化合物。
实施例66
2-(3-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A11)
1H NMR(DMSO-d6/400MHz)δppm 3.83(s,3H),6.66(bs,2H),7.28(m,3H),7.40(m,2H),8.24(d,J=6.82Hz,2H),9.11(d,J=6.82Hz,2H),12.32(s,1H);ESI (+)MS:m/z 294(MH+).
实施例67
2-(2-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A13)
1H NMR(DMSO-d6/400MHz)δppm 6.96(bs,2H),7.37(s,1H),7.58-7.65(m,4H),7.79(m,1H),8.07(dd,J=1.22,8.17Hz,1H),8.55(d,J=6.22Hz,2H),12.19(s,1H);ESI (+)MS:m/z 309(MH+).
实施例68
2-(3-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A14)
1H NMR(DMSO-d6/400MHz)δppm 7.30(bs,2H),7.35(d,J=2.69Hz,1H),7.76(m,3H),8.15(m,1H),8.22(m,1H),8.58(dd,J=1.58,4.63Hz,2H),8.61(t,J=1.81Hz,1H),12.07(s,1H);ESI (+)MS:m/z 309(MH+).
实施例69
5-吡啶-4-基-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(A7)
1H NMR(DMSO-d6/400MHz)δppm 2.19(s,3H),6.78(bs,2H),7.25-7.38(m,5H),7.64(d,J=5.90Hz,2H),8.50(d,J=5.90Hz,2H),11.90(s,1H);ESI(+)MS:m/z 278(MH+).
实施例70
5-吡啶-4-基-2-间-甲苯基-1H-吡咯-3-甲酸酰胺(A8)
1H NMR(DMSO-d6/400MHz)δppm 2.20(s,3H),6.90(bs,2H),7.20-7.40(m,5H),7.70(d,J=6.00Hz,2H),8.55(d,J=6.00Hz,2H),11.88(s,1H);ESI(+)MS:m/z 278(MH+).
实施例71
2-呋喃-3-基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(C2)
1H NMR(DMSO-d6/400MHz)δppm 7.17(s,1H),7.30(bs,2H),7.64(s,1H),7.77(s,1H),8.03(d,J=6.30Hz,2H),8.52(s,1H),8.69(d,J=6.30Hz,2H),11.88(s,1H);ESI(+)MS:m/z254(MH+).
实施例72
5-吡啶-4-基-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺(C1)
1H NMR(DMSO-d6/400MHz)δppm 7.30(bs,2H),7.57(d,J=2.56Hz,1H),7.62(m,2H),8.03(d,J=6.50Hz,2H),8.14(m,1H),8.66(d,J=6.50Hz,2H),12.01(s,1H);ESI(+)MS:m/z 270(MH+).
实施例73
2-(2,5-二甲基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A19)
1H NMR(DMSO-d6/400MHz)δppm 2.12(s,3H),2.31(s,3H),6.72(bs,2H),7.13(m,2H),7.29(d,J=2.81Hz,1H),7.62(dd,J=1.58,4.63Hz,2H),8.48(dd,J=1.58,4.63Hz,2H),11.86(s,1H);ESI(+)MS:m/z 292(MH+).
实施例74
2-(2,3-二甲基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A20)
1H NMR(DMSO-d6/400MHz)δppm 2.06(s,3H),2.31(s,3H),6.65(bs,2H),7.16-7.32(m,4H),7.63(d,J=5.40Hz,2H),8.49(d,J=5.40Hz,2H),11.88(s,1H);ESI(+)MS:m/z 292(MH+).
实施例75
2-(3,4-二甲基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A21)
1H NMR(DMSO-d6/400MHz)δppm 2.28(s,3H),2.55(s,3H),7.20(m,1H),7.22(d,J=2.81Hz,1H),7.38(m,1H),7.43(s,1H),7.69(d,J=5.85Hz,2H),8.51(m,2H),11.72(s,1H);ESI(+)MS:m/z 292(MH+).
实施例76
2-(3-乙酰氨基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A18)
1H NMR(DMSO-d6/400MHz)δppm 2.06(s,3H),6.99(bs,2H),7.28(m,1H),7.36(m,1H),7.57(d,J=2.44Hz,1H),7.65(d,J=8.17Hz,1H),7.79(s,1H),8.03(d,J=6.20Hz,2H),8.66(d,J=6.20Hz,2H),10.05(s,1H),12.21(s,1H);ESI(+)MS:m/z321(MH+).
实施例77
2-(2-氰基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A22)
1H NMR(DMSO-d6/400MHz)δppm 6.88(bs,2H),7.39(s,1H),7.59(m,1H),7.64(m,3H),7.75(t,J=7.19Hz,1H),7.88(d,J=7.08Hz,1H),8.56(d,J=4.75Hz,2H),12.21(s,1H);ESI(+)MS:m/z 289(MH+).
实施例78
2-(3-氰基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A23)
1HNMR(DMSO-d6/400MHz)δppm 6.99(bs,2H),7.32(d,J=2.56Hz,1H),7.64(t,J=7.56Hz,1H),7.69(d,J=6.10Hz,2H),7.82(m,2H),8.03(m,2H),8.14(m,1H),8.56(d,J=6.10Hz,2H),11.95(s,1H);ESI(+)MS:m/z 289(MH+).
实施例79
2-(3-乙酰基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A16)
1H NMR(DMSO-d6/400MHz)δppm 2.64(s,3H),6.94(bs,2H),7.31(d,J=2.68Hz,1H),7.57(t,J=7.80Hz,1H),7.70(dd,J=1.59,4.64Hz,2H),7.93(m,2H),8.28(t,J=1.71Hz,1H),8.54(m,2H),11.94(s,1H);ESI(+)MS:m/z 306(MH+).
实施例80
2-(3-羟甲基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A17)
1H NMR(DMSO-d6/400MHz)δppm 4.57(s,2H),5.25(s,1H),6.90(bs,2H),7.29(d,J=2.68Hz,1H),7.36(m,2H),7.52(m,1H),7.58(s,1H),7.74(d,J=5.90Hz,2H),8.53(d,J=5.90Hz,2H),11.86(s,1H);ESI (+)MS:m/z 294(MH+).
实施例81
5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(F2)
步骤1:缩合成酰胺(41)
室温下通过与1.5mL DMF中的IEA(24μL,0.14mmol)、EDCI(20mg,0.105mmol)和HOBT(14mg,0.105mmol)搅拌过夜,将酸34(20mg,0.07mmol)负载到Rink酰胺MBHA树脂(52mg,0.035mmol,理论负载0.68mmol/g)上。该树脂事先用20%哌啶的DMF溶液裂解。
步骤2:Suzuki偶联并裂解成酰胺(F2)
在100℃下加热载体上的酰胺41(0.035mmol)、2-甲基苯基硼酸(24mg,0.175mmol)、LiCl(6mg,0.14mmol)、Cs2CO3(57mg,0.175mmol)和(PhP3)2PdCl2(5.0mg,0.07mmol)于1mL DMF和50μL H2O的溶液过夜。用TFA/DCM 95∶5裂解树脂上的产物。浓缩溶液,并通过制备型HPLC纯化粗产物得到固体状的5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺。
使用上述步骤合成下述化合物。
实施例82
5-(2-氨基-嘧啶-4-基)-2-(2-乙基-苯基)-1H-吡咯-3-甲酸酰胺
(F3)
1H NMR(DMSO-d6/400MHz)δppm 0.99(t,J=7.56Hz,3H),2.50(m,2H),6.30(bs,2H),6.67(bs,2H),6.93(d,J=5.24Hz,1H),7.23(m,2H),7.30-7.40(m,3H),8.15(d,J=5.24Hz,1H),11.77(bs,1H);ESI (+)MS:m/z 308(MH+).
实施例83
5-(2-氨基-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺
(F4)
1H NMR(DMSO-d6/400MHz)δppm 6.92(bs,2H),7.27(m,3H),7.45-7.54(m,2H),7.62(bs,1H),7.84(bs,2H),8.28(d,J=6.58Hz,1H),12.41(bs,1H);ESI (+)MS:m/z 298(MH+).
实施例84
5-(2-氨基-嘧啶-4-基)-2-萘-1-基-1H-吡咯-3-甲酸酰胺(F5)
1H NMR(DMSO-d6/400MHz)δppm 6.33(bs,2H),6.65(bs,2H),6.96(d,J=5.27Hz,1H),7.40-7.60(m,5H),7.98(m,2H),8.17(d,J=5.27Hz,1H),11.95(bs,1H);ESI (+)MS:m/z 330(MH+).
实施例85
5-(2-氨基-嘧啶-4-基)-2-萘-2-基-1H-吡咯-3-甲酸酰胺(F6)
1H NMR(DMSO-d6/400MHz)δppm 6.37(bs,2H),6.87(bs,1H),7.05(d,J=5.24Hz,1H),7.32(d,J=2.32Hz,1H),7.39(bs,1H),7.51-7.59(m,2H),7.78(dd,J=8.41,1.71Hz,1H),7.88-7.97(m,3H),8.16(d,J=1.22Hz,1H),8.23(d,J=5.24Hz,1H),11.80(bs,1H);ESI (+)MS:m/z 330(MH+).
实施例86
5-(2-氨基-嘧啶-4-基)-2-(4-苯氧基-苯基)-1H-吡咯-3-甲酸酰
胺(F7)
1H NMR(DMSO-d6/400MHz)δppm 6.35(bs,2H),6.81(bs,1H),6.98-7.11(m,5H),7.15-7.21(m,1H),7.27(d,J=2.19Hz,1H),7.34(bs,1H),7.40-7.46(m,2H),7.67(d,J=8.90Hz,2H),8.20(d,J=5.24Hz,1H),11.62(bs,1H);ESI(+)MS:m/z 372(MH+).
实施例87
5-(2-氨基-嘧啶-4-基)-2-联苯-4-基-1H-吡咯-3-甲酸酰胺(F8)
1H NMR(DMSO-d6/400MHz)δppm 6.35(bs,2H),6.85(bs,1H),6.90-7.15(m,5H),7.15-7.25(m,2H),7.34(bs,1H),7.40-7.45(m,2H),7.70(d,J=8.90Hz,2H),8.18(d,J=5.24Hz,1H),11.73(bs,1H);ESI (+)MS:m/z 356(MH+).
实施例88
5-(2-氨基-嘧啶-4-基)-2-联苯-3-基-1H-吡咯-3-甲酸酰胺(F9)
1H NMR(DMSO-d6/400MHz)δppm 6.89(bs,2H),7.02(d,J=5.24Hz,1H),7.30(d,J=2.44Hz,1H),7.34-7.43(m,2H),7.46-7.53(m,4H),7.61-7.68(m,2H),7.74(d,J=8.41Hz,2H),7.96(t,J=1.70Hz,1H),8.21(d,J=5.24Hz,1H),11.78(bs,1H);ESI(+)MS:m/z 356(MH+).
实施例89
5-(2-氨基-嘧啶-4-基)-2-联苯-2-基-1H-吡咯-3-甲酸酰胺(F10)
1H NMR(DMSO-d6/400MHz)δppm 6.33(bs,2H),6.90(bs,1H),7.03(d,J=5.24Hz,1H),7.28(d,J=2.44Hz,1H),7.34-7.56(m,6H),7.56-7.79(m,4H),8.20(d,J=5.24Hz,1H),11.78(bs,1H);ESI (+)MS:m/z 356(MH+).
实施例90
5-(2-氨基-嘧啶-4-基)-2-(2-甲氧基-苯基)-1H-吡咯-3-甲酸酰
胺(F11)
1H NMR(DMSO-d6/400MHz)δppm 3.75(s,3H),6.34(bs,2H),6.69(bs,1H),6.88-7.04(m,3H),7.08(d,J=6.10Hz,1H),7.23(d,J=2.56Hz,1H),7.32-7-41(m,2H),8.16(d,J=5.37Hz,1H),11.50(bs,1H);ESI (+)MS:m/z 310(MH+).
实施例91
5-(2-氨基-嘧啶-4-基)-2-苯并[1,3]间二氧杂环戊烯-5-基-1H-
吡咯-3-甲酸酰胺(F12)
1H NMR(DMSO-d6/400MHz)δppm 6.06(s,2H),6.35(bs,2H),6.82(bs,1H),6.97(d,J=8.05Hz,1H),7.01(d,J=5.24Hz,1H),7.16(dd,J=8.05,1.34Hz,1H),7.23-7.25(m,3H),8.20(d,J=5.24Hz,1H),11.52(bs,1H);ESI(+)MS:m/z 324(MH+).
实施例92
5-(2-氨基-嘧啶-4-基)-2-(5-氯-噻吩-2-基)-1H-吡咯-3-甲酸酰
胺(G4)
1H NMR(DMSO-d6/400MHz)δppm 6.40(b s,2H),6.98(bs,1H),7.03(d,J=5.24Hz,1H),7.11(d,J=3.20Hz,1H),7.32(s,1H),7.59(bs,1H),7.63(d,J=3.20Hz,1H),8.23(d,J=5.24Hz,1H),11.70(bs,1H);ESI(+)MS:m/z 320(MH+).
实施例93
5-(2-氨基-嘧啶-4-基)-2-苯并[b]噻吩-2-基-1H-吡咯-3-甲酸酰
胺(G5)
1H NMR(DMSO-d6/400MHz)δppm 6.42(bs,2H),6.99(bs,1H),7.08(d,J=5.12Hz,1H),7.32(s,1H),7.33-7.41(m,2H),7.56(bs,1H),7.84(bs,1H),7.91-8.03(m,2H),8.25(d,J=5.12Hz,1H),11.82(bs,1H);ESI (+)MS:m/z 336(MH+).
实施例94
5-(2-氨基-嘧啶-4-基)-2-苯并[b]噻吩-3-基-1H-吡咯-3-甲酸酰
胺(G6)
1H NMR(DMSO-d6/400MHz)δppm 6.35(bs,2H),6.76(bs,1H),6.99(d,J=5.24Hz,1H),7.20(s,1H),7.35-7.42(m,3H),7.51-7.57(m,1H),7.90(s,1H),8.00-8.06(m,1H),8.20(d,J=5.24Hz,1H),11.91(bs,1H);ESI (+)MS:m/z 336(MH+).
实施例95
5-(2-氨基-嘧啶-4-基)-2-苯并呋喃-2-基-1H-吡咯-3-甲酸酰胺
(G9)
1H NMR(DMSO-d6/400MHz)δppm 6.53(bs,2H),7.07(bs,1H),7.11(d,J=5.12Hz,1H),7.27(td,J=7.56,0.98Hz,1H),7.34(t d,J=7.56,0.98Hz,1H),7.42(s,1H),7.61(dd,J=7.56,0.98Hz,1H),7.65(bs,1H),7.70(dd,J=7.56,0.98Hz,1H),7.87(d,J=0.98Hz,1H),8.26(d,J=5.12Hz,1H),11.61(bs,1H);ESI (+)MS:m/z 320(MH+).
实施例96
5-(2-氨基-嘧啶-4-基)-2-二苯并呋喃-1-基-1H-吡咯-3-甲酸酰
胺(G10)
1H NMR(DMSO-d6/400MHz)δppm 6.52(bs,2H),6.82(bs,1H),7.03(d,J=5.38Hz,1H),7.36(bs,1H),7.38-7.56(m,3H),7.64-7.73(m,2H),8.16(dd,J=7.68,1.22Hz,1H),8.19(d,J=7.68Hz,1H),8.24(d,J=5.38Hz,1H),12.00(bs,1H);ESI(+)MS:m/z 370(MH+).
实施例97
5-(2-氨基-嘧啶-4-基)-2-吡啶-3-基-1H-吡咯-3-甲酸酰胺(G11)
1H NMR(DMSO-d6/400MHz)δppm 6.63(bs,2H),7.23(d,J=5.24Hz,1H),7.15(bs,1H),7.32-7.38(m,1H),7.66(s,1H),7.85-7.91(m,1H),8.20(d,J=5.24Hz,1H),8.28(bs,1H),8.60-8.66(m,1H),8.77-8.86(m,1H),11.37(s,1H);ESI(+)MS:m/z 281(MH+).
实施例98
5-(2-氨基-嘧啶-4-基)-2-吡啶-2-基-1H-吡咯-3-甲酸酰胺(G12)
1H NMR(DMSO-d6/400MHz)δppm 6.62(bs,2H),7.03(d,J=5.12Hz,1H),7.16(bs,1H),7.33-7.40(m,2H)7.86-7.93(m,1H),8.25(d,J=5.12Hz,1H),8.28(bs,1H),8.43(d,J=8.17Hz,1H),8.62-8.67(m,1H),11.29(s,1H);ESI(+)MS:m/z 281(MH+).
实施例99
5-(3-氟-吡啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(E2)
步骤1:缩合成酰胺(42)
使用2.5mL DMF中的DIEA(61μL,0.35mmol)、EDCI(50mg,0.26mmol)、HOBT(35mg,0.26mmol)将酸37(50mg,0.175mmol)负载在Rink酰胺MBHA树脂(128mg,0.087mmol,理论负载0.68mmol/g)上。室温下搅拌该反应混合物过夜。首先用含20%哌啶的DMF溶液裂解树脂。
步骤2:Suzuki偶联并裂解成酰胺(E2)
在100℃下加热载体上的酰胺42(0.087mmol)、2-甲基苯基硼酸(60mg,0.44mmol)、LiCl(15mg,0.35mmol)、Cs2CO3(142mg,0.435mmol)和(PhP3)2PdCl2(12mg,0.0175mmol)于1.5mL DMF和75μLH2O的溶液过夜。用TFA/DCM 95∶5切割树脂上的产物。浓缩溶液并通过制备型HPLC纯化粗产物得到白色固体状的5-(3-氟-吡啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 2.16(s,3H),6.86(bs,2H),7.23(bs,1H),7.18-7.38(m,4H),7.91-7.98(m,1H),8.39(d,J=5.12Hz,1H),8.56(d,J=3.41Hz,1H),11.95(bs,1H);ESI(+)MS:m/z 296(MH+).
实施例100
5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(P1)
步骤1:形成吡咯环(43)
在0℃下向氰基酯29(550mg,2.37mmol)于Et2O(1mL)的溶液中逐滴加入4N HCl的二噁烷溶液(6mL,23.7mmol)。在0℃下放置该反应混合物10分钟然后室温下搅拌6小时。过滤固体并用Et2O洗涤得到500mg(84%)黄色固体状的2-氯-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯。无需进一步纯化使用该产物。
1H NMR(DMS0-d6/400MHz)δppm 1.34(t,J=7.07Hz,3H),4.27(q,J=7.07Hz,2H),7.73(s,1H),8.25(d,J=5.61Hz,2H),8.78(m,2H);ESI (+)MS:m/z 251(MH+).
步骤2:脱卤化成酯(44)
在氩气和室温下搅拌酯43(630mg,2.2mmol)于30mL MeOH、HCOONH4(1.26g,19.8mmol)和10%Pd/C(630mg)的混合物直到原料消失。通过C盐过滤除去催化剂并浓缩滤液。加入饱和的NaHCO3水溶液并用EtOAc萃取浆液得到300mg(63%)固体状的5-吡啶-4-基-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.30(t,J=7.07Hz,3H),4.24(q,J=7.07Hz,2H),7.20(m,1H),7.63(m,1H),7.68(dd,J=1.50,4.60Hz,2H),7.20(m,1H),7.63(m,1H),7.68(dd,J=1.50,4.60Hz,2H),8.52(dd,J=1.50,4.60Hz,2H),12.27(s,1H);ESI(+)MS:m/z 217(MH+).
步骤3:皂化成酸(45)
在100℃下加热于4M aq NaOH(4.6mL)和EtOH(4mL)的酯44(200mg,0.92mol)1小时。冷却该反应混合物至0℃并通过加入浓HCl沉淀产物。过滤固体得到160mg(78%)白色固体状的5-吡啶-4-基-1H-吡咯-3-甲酸。
1H NMR(DMSO-d6/400MHz)δppm 7.60(s,1H),7.81(m,1H),8.14(d,J=5.49Hz,2H),8.72(m,2H),12.70(s,1H);MS:m/z187[M-H].
步骤4:缩合成酰胺(P1)
向在0℃下冷却的酸45(137mg,0.61mmol)于DIEA(213μL,1.22mmol)和无水THF(8mL)的溶液中加入EDCI(175mg,0.09mmol)和HOBT·NH3(137mg,0.9mmol)并室温下搅拌该溶液过夜。浓缩该溶液,加入水并用DCM萃取该产物。用水洗涤有机层,干燥并浓缩得到固体,用Et2O研磨该固体得到50mg(44%)5-吡啶-4-基-1H-吡咯-3-甲酸酰胺。
1H NMR(DMSO-d6/400MHz)δppm 6.98(bs,2H)7.61(bs,1H)7.79-7.82(m,1H)8.06(d,J=6.58Hz,2H)8.71(d,J=6.83Hz,2H)12.57(s,1H);ESI(+)MS:m/z 188(MH+).
实施例101
1-乙基-2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(D1)
向酰胺A1(R=H,31mg,0.118mmol)于DMF(0.5mL)的溶液中加入Cs2CO3(100mg,0.235mmol)和EtI(19μL,0.235mmol)。在60℃下用微波处理该混合物15分钟(“降温及加热”技术)然后除去溶剂。向该残余物中加入EtOAc和水,分离各层,用EtOAc萃取水层并用水洗涤合并的有机层,干燥(Na2SO4),过滤并浓缩。通过快速色谱(DCM/MeOH 95∶5)纯化该粗产物得到标题化合物。将其悬浮于MeOH中并用1.25M HCl的MeOH溶液酸化至pH1。除去溶剂后,用Et2O处理残余物,过滤所得的固体,用Et2O洗涤并干燥得到1-乙基-2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺的盐酸盐(9mg,产率为26%)。
1H NMR(DMSO-d6/400MHz)δppm 0.88(t,J=7.13Hz,3H)4.02(q,J=7.11Hz,2H)6.86(s,2H)7.29(s,1H)7.39-7.58(m,5H)7.95(d,J=6.58Hz,2H)8.80(d,J=6.71Hz,2H);ESI(+)MS:m/z 292(MH+).
实施例102
4-甲基-2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(B1)
步骤1:形成吡咯环(47)
在0℃下,将2-溴-1-吡啶-4-基-丙-1-酮氢溴酸盐46(0.6g,2mmol)加入到于300mL干燥THF的3-氧代-3-苯基-丙酸乙酯2(R=H,0.3g,1.56mmol)和NaH(0.18g)的混合物中。在0℃下放置该溶液1小时,然后在50℃下搅拌4小时。除去溶剂并将残余物溶于20mLEtOH,加入醋酸铵(0.7g,9.3mmol)并将反应混合物在室温下放置过夜。浓缩该反应混合物,加入水并用EtOAc萃取浆液。用水洗涤合并的有机层,干燥(Na2SO4),过滤并浓缩。通过快速色谱(DCM/MeOH 95∶5)纯化粗产物得到170mg(36%)固体状的4-甲基-2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/300MHz)δppm 1.08(t,J=7.03Hz,3H)2.41(s,3H)4.08(q,J=7.03Hz,2H)7.21-7.71(m,7H)8.58(dd,J=4.69,1.76Hz,2H)11.77(s,1H);ESI(+)MS:m/z 307(MH+).
步骤2:脱羧化成吡咯(48)
在100℃下加热溶于1.5mL EtOH和2.2mL 4M aq NaOH的酯47(0.17g,0.56mmol)直到完全脱羧(5h)。浓缩该反应混合物,加入水并用EtOAc萃取浆液。用水洗涤合并的有机层,干燥(Na2SO4),过滤并浓缩得到白色固体状的4-(3-甲基-5-苯基-1H-吡咯-2-基)-吡啶(92mg,70%)。
1H NMR(DMSO-d6/400MHz)δppm 2.30(s,3H)6.52-6.54(m,1H)7.18-7.26(m,1H)7.35-7.43(m,2H)7.58(dd,J=4.69,1.76Hz,2H)7.73-7.79(m,2H)8.53(dd,J=4.69,1.47Hz,2H)11.21(s,1H);ESI(+)MS:m/z 235(MH+).
步骤3:氨基磺酸的形成(49)
向溶于CH3CN(3mL)的吡咯48(90mg,0.39mmol)加入ClSO2NCO并在室温下搅拌该反应化合物直到原料消失。加入水并用10%aq KOH将pH调节到8。用EtOAc(x 2)萃取后并在减压下浓缩该水溶液,过滤沉淀,用少量水洗涤并干燥。得到白色固体状的(4-甲基-2-苯基-5-吡啶-4-基-1H-吡咯-3-羰基)-氨基磺酸(产率为90%)。
1H NMR(DMSO-d6/400MHz)δppm 2.27(s,3H)7.22-7.34(m,1H)7.34-7.45(m,2H)7.55(dd,J=4.76,1.59Hz,2H)7.62-7.66(m,2H)8.54(dd,J=4.63,1.46Hz,2H)9.28(s,1H)11.29(s,1H);MS:m/z 356[M-H].
步骤4:酰胺的形成(B1)
在室温下通过在浓HCl中溶解酸49来将其水解。用2N NaOH碱化酸性水溶液,并用EtOAc(x3)萃取。通过快速色谱(DCM/MeOH 95∶5,然后93∶7)纯化该粗产物得到4-甲基-2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺,产率为85%。
1H NMR(DMSO-d6/500MHz)δppm 2.41(s,3H)7.39(t,J=7.48Hz,1H)7.47(t,J=7.48Hz,2H)7.71(d,J=7.32Hz,2H)8.16(d,J=7.02Hz,2H)8.73(d,J=7.02Hz,2H);ESI(+)MS:m/z 278(MH+).
实施例103
2-[4-(4-甲基-哌嗪-1-基)-苯基]-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯(51)
在130℃下将酯50(30mg,0.08mmol,如实施例1所述得到),Pd(OAc)2(1mg,0.0045mmol)、(2-联苯基)二环己基膦(3mg,0.008mmol)、tBuONa(16mg,0.17mmol)、1-甲基哌嗪(60μL,0.54mmol)于甲苯(1mL)和无水DMF(0.2mL)的混合物进行微波反应20分钟。在C盐上过滤后,并用水溶液进行后处理(EtOAc/水),得到粗产物2-[4-(4-甲基-哌嗪-1-基)-苯基]-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯。
1H NMR(DMSO-d6/400MHz)δppm 1.25(t,J=7.07Hz,3H),2.86(bs,3H),3.11-3.54(m,8H),4.20(q,J=7.07Hz,2H),7.12(d,J=8.80Hz,2H),7.64(d,J=8.80Hz,2H),7.78-7.82(m,1H),8.34-8.41(m,2H),8.75(d,J=6.46Hz,2H),12.49(bs,1H);ESI(+)MS:m/z 391(MH+).
使用上述步骤并由根据实施例1所述得到的对应溴苯酯衍生物起始,制备下述化合物:
2-(3-吗啉-4-基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯(52)
1H NMR(DMSO-d6/400MHz)δppm 1.19(t,J=7.07Hz,3H)3.14-3.20(m,4H)3.73-3.79(m,4H)4.13(q,J=7.07Hz,2H)7.01(dd,J=8.17,2.19Hz,1H)7.08(d,J=7.68Hz,1H)7.18(t,J=1.70Hz,1H)7.26(d,J=2.80Hz,1H)7.31(t,J=7.93Hz,1H)7.77(dd,J=4.69,1.52Hz,2H)8.51(d,J=5.85Hz,2H)12.03(bs,1H);ESI (+)MS:m/z 306(MH+).
2-(4-吗啉-4-基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸乙酯(53)
ESI (+)MS:m/z 306(MH+).
使用已经在实施例1中描述的方法,分别将上述酯水解得到下述酸:
2-[4-(4-甲基-哌嗪-1-基)-苯基]-5-吡啶-4-基-1H-吡咯-3-甲酸
(54)
1H NMR(DMSO-d6/400MHz)δppm 2.83(bs,3H),3.09-3.53(m,8H),7.10(d,J=8.80Hz,2H),7.63(d,J=8.80Hz,2H),7.92(s,1H),8.05-8.21(m,2H),8.58-8.69(m,2H),12.23(bs,1H);ESI(+)MS:m/z 361[M-H].
2-(3-吗啉-4-基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸(55)
1H NMR(DMSO-d6/400MHz)δppm 3.13-3.17(m,4H)3.73-3.78(m,4H)6.90(dt,J=7.19,2.13Hz,1H)7.10(s,1H)7.22(s,1H)7.24(s,1H)7.43(s,1H)7.71(dd,J=4.76,1.59Hz,2H)8.46(d,J=6.22Hz,2H)11.52(bs,1H);MS:m/z 348[M-H].
2-(4-吗啉-4-基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸(56)
MS:m/z 348[M-H].
通过已经在实施例1中描述的标准酰胺化方法,分别将上述酸转变成下述酰胺:
实施例104
2-[4-(4-甲基-哌嗪-1-基)-苯基]-5-吡啶-4-基-1H-吡咯-3-甲酸
酰胺(A24)
1H NMR(DMSO-d6/400MHz)δppm 2.82(bs,3H),3.15-3.52(m,8H),7.08(d,J=8.80Hz,2H),7.67(d,J=8.80Hz,2H),7.94(s,1H),7.97-8.11(m,2H),8.56-8.72(m,2H),12.04(bs,1H);ESI(+)MS:m/z 362(MH+).
实施例105
2-(3-吗啉-4-基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺盐酸
盐(A25)
1H NMR(DMSO-d6/400MHz)δppm 3.14-3.21(m,4H)3.74-3.79(m,4H)7.04(dd,J=8.23,2.13Hz,1H)7.15(d,J=7.68Hz,1H)7.31(s,1H)7.33(t,J=7.93Hz,1H)7.71(d,J=2.56Hz,1H)8.23(d,J=6.71Hz,2H)8.73(d,J=6.95Hz,2H)12.34(bs,1H)15.08(bs,1H);ESI(+)MS:m/z 349(MH+).
实施例106
2-(4-吗啉-4-基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A26)
1H NMR(DMSO-d6/400MHz)δppm 3.15-3.20(m,4H),3.73-3.79(m,4H),6.82(bs,1H),6.99(d,J=8.80Hz,2H),7.08(bs,1H),7.23(d,J=2.68Hz,1H),7.56(d,J=8.80Hz,2H),7.68(d,J=6.35Hz,2H),8.49(d,J=6.35Hz,2H),11.63(bs,1H);ESI(+)MS:m/z 349(MH+).
实施例107
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸甲酰胺(M1)
向酸16(R=H,20mg,0.07mmol)于无水DMF的溶液中加入CDI(25mg,2eq.)并在45℃下搅拌该混合物1小时。冷却到室温后,用0.5mL 33%MeNH2的EtOH溶液处理该溶液。搅拌该混合物过夜,过滤并将滤液倒入水中。用EtOAc(x2)萃取后浓缩该有机层,溶于EtOH并用过量的1.25M HCl的MeOH溶液处理。加入Et2O并过滤黄色结晶性固体,用Et2O洗涤并回收。得到8mg(产率为37%)5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸甲酰胺。
1H NMR(DMSO-d6/400MHz)δppm 2.70(d,J=4.63Hz,3H)7.36(d,J=6.58Hz,1H)7.39-7.49(m,3H)7.53(d,J=2.44Hz,1H)7.64-7.70(m,2H)7.84(bs,3H)8.02(bq,J=4.51Hz,1H)8.29(d,J=6.46Hz,1H)12.20(bs,1H);ESI(+)MS:m/z 294(MH+).
使用上述步骤合成下述化合物。
实施例108
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸异丙酰胺(M2)
1H NMR(DMSO-d6/400MHz)δppm 1.09(t,J=6.58Hz,6H),3.93-4.06(m,1H),6.36(bs,2H),7.04(d,J=5.24Hz,1H),7.23(d,J=2.44Hz,1H),7.30-7.43(m,3H),7.59-7.67(m,3H),8.21(d,J=5.24Hz,1H),11.61(bs,1H);ESI(+)MS:m/z 322(MH+).
实施例109
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸苯甲酰胺(M3)
1H NMR(DMSO-d6/400MHz)δppm 4.37(d,J=6.10Hz,2H),6.37(bs,2H),7.05(d,J=5.24Hz,1H),7.18-7.44(m,9H),7.64(d,J=8.30Hz,2H),8.21(d,J=5.24Hz,1H),8.48(t,J=6.10Hz,1H),11.70(bs,1H);ESI(+)MS:m/z 370(MH+).
实施例110
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸环己基甲酰胺
(M4)
1H NMR(DMSO-d6/400MHz)δppm 0.79-0.94(m,2H),1.06-1.27(m,4H),1.40-4.52(m,1H),1.57-1.74(m,4H),2.99(t,J=6.46Hz,2H),6.36(bs,2H),7.04(d,J=5.24Hz,1H),7.23(d,J=2.44Hz,1H),7.29-7.46(m,3H),7.63(d,J=8.15Hz,2H),7.82(t,J=5.85Hz,1H),8.21(d,J=5.24Hz,1H),11.63(bs,1H);ESI(+)MS:m/z 376(MH+).
实施例111
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸苯乙酰胺(M5)
1H NMR(DMSO-d6/400MHz)δppm 2.80(t,J=7.35Hz,2H),3.42(q,J=7.35Hz,2H),6.37(bs,2H),7.03(d,J=5.24Hz,1H),7.18-7.42(m,9H),7.60(d,J=8.30Hz,2H),7.98(t,J=7.35Hz,1H),8.21(d,J=5.24Hz,1H),11.65(bs,1H);ESI(+)MS:m/z384(MH+).
实施例112
5-(2-氨基-嘧啶-4-基)-2-苯基-噻吩-3-甲酸酰胺(S1)的合成
步骤1:酮酯烷基化(57)
在0℃下向搅拌的3-氧代-3-苯基-丙酸乙酯2(2g,10mmol)和NaH(1g,2.5eq,25mmol)于干燥THF(200mL)的溶液中加入1-(2-氨基-嘧啶-4-基)-2-溴-乙酮14(3.56g,1.2eq,12mmol)。在0℃下搅拌该反应化合物30分钟,然后加入更多的14(0.5eq,1.48g)并在室温下搅拌该反应化合物过夜。除去溶剂后,在DCM中稀释该残余物并用盐水洗涤,干燥(Na2SO4)并减压下除去溶剂得到4-(2-氨基-嘧啶-4-基)-2-苯甲酰基-4-氧代-丁酸乙酯(3.27g,97%)。ESI(+)MS:m/z 328(MH+).
步骤2:环形成(58+59)
在N2下回流酯57(3.27g,10mmol)和劳氏试剂(2.43g,0.66eq,6mmol)于甲苯(100mL)的混合物4小时。除去溶剂后,在DCM中溶解该残余物,过滤并通过Horizon系统(己烷/EtOAc 9∶1,然后DCM/MeOH 98∶2)洗脱。然后将噻吩和呋喃衍生物的混合物再次通过Horizon系统(DCM/MeOH 99∶1)得到第一级分为噻吩衍生物58(250mg)和第二级分为黄色固体状的呋喃衍生物59(236mg)。
5-(2-氨基-嘧啶-4-基)-2-苯基-噻吩-3-甲酸乙酯(58)
1H NMR(DMSO-d6/400MHz)δppm:1.14(t,3H),4.16(q,2H),6.73(m,2H),7.20(d,1H),7.53(m,5H),8.18(s,1H),8.30(d,1H);ESI(+)MS:m/z 326(MH+).
5-(2-氨基-嘧啶-4-基)-2-苯基-呋喃-3-甲酸乙酯(59)
1H NMR(DMSO-d6/400MHz)δppm:1.29(t,3H),4.27(q,2H),6.76(m,2H),7.07(d,1H),7.52(m,3H),8.03(m,2H),8.34(d,1H);ESI(+)MS:m/z 310(MH+).
步骤3:皂化成羧酸(60)
向酯58(220mg,0.68mmol)于1∶1H2O/EtOH(9mL)的溶液中加入4M aq NaOH(10eq),并在100℃下搅拌该混合物1小时。冷却到室温后,用2M HCl酸化该溶液得到固体状的5-(2-氨基-嘧啶-4-基)-2-苯基-噻吩-3-甲酸,将其过滤,用水洗涤并在减压下干燥(185mg,90%)。
1H NMR(DMSO-d6/400MHz)δppm 7.28(d,1H),7.43-7.58(m,5H),8.25(s,1H),8.31(d,1H);ESI(+)MS:m/z 296[M-H].
步骤4:缩合成酰胺(S1)
在0℃下,向酸60(185mg,0.62mmol)和D I EA(218μL,1.26mmol,2eq)于干燥THF(4mL)的混合物中加入EDCI(141.7mg,0.93mmol)和HOBT.NH3(141.5mg,0.93mmol)。室温下搅拌该反应化合物过夜。溶剂蒸发后,用DCM溶解该残余物并用水洗涤。干燥有机层(Na2SO4),浓缩并通过用DCM/己烷再沉淀来纯化所得的固体,得到黄色固体状的5-(2-氨基-嘧啶-4-基)-2-苯基-噻吩-3-甲酸酰胺(87mg,48%)。
1H NMR(DMSO-d6/400MHz)δppm:6.69(bs,2H),7.10(d,1H),7.38-7.44(m,5H),7.56(d,2H),7.71(bs,1H),8.29(d,1H);ESI(+)MS:m/z 297(MH+).
实施例113
5-(2-氨基-嘧啶-4-基)-2-苯基-呋喃-3-甲酸酰胺(T1)的合成
步骤1:皂化成羧酸(61)
向酯59(221mg,0.71mmol)于1∶1H2O/EtOH(9mL)的溶液中加入4M aq NaOH(10eq)并在100℃下搅拌该反应化合物1小时。冷却到室温后,用2M HCl酸化该溶液得到白色固体状的5-(2-氨基-嘧啶-4-基)-2-苯基-呋喃-3-甲酸,将其过滤,用水洗涤并在减压下干燥(定量)。
1H NMR(DMSO-d6/400MHz)δppm 6.75(d,2H),7.06(d,1H),7.51(m,3H),8.0(d,2H),8.33(d,1H);ESI(+)MS:m/z 280[M-H].
步骤2:缩合成酰胺(T1)
在0℃下向酸61(172mg,0.61mmol)和DIEA(213μL,1.22mmol)于干燥THF(4mL)的混合物中加入EDCI(139.6mg,0.92mmol)和HOBT.NH3(140mg,0.92mmol)。在室温下搅拌该反应化合物过夜。溶剂蒸发后,用DCM溶解该残余物并用水洗涤。用EtOAc萃取水相,干燥有机层(Na2SO4)并浓缩得到黄色固体状的5-(2-氨基-嘧啶-4-基)-2-苯基-呋喃-3-甲酸酰胺(80mg,48%)。
1H NMR(DMSO-d6/400MHz)δppm:6.69(bs,2H),7.01(d,1H),7.41-7.48(m,4H),7.53(s,1H),7.92(bs,1H),8.05(d,2H),8.33(d,1H);ESI(+)MS:m/z 281(MH+).
实施例114
5-(2-氨基-5-溴-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(N2)
向于DMF(2mL)的酰胺F1(280mg,1mmol)中加入NBS(180mg,1mmol)并在室温下搅拌该混合物15小时。将该反应混合物倒入搅拌的水中,过滤沉淀,充分洗涤并干燥。得到黄色固体状的标题化合物(270mg,75%)。
1H NMR(DMSO-d6/400MHz)δppm 6.65(s,2H)6.89(s,1H)7.23-7.46(m,4H)7.64-7.68(m,2H)7.64(d,J=2.68Hz,1H)7.64(d,J=2.68Hz,1H)8.35(s,1H)11.27(s,1H);ESI(+)MS:m/z358(MH+).
使用上述步骤由F4合成下述化合物:
实施例115
5-(2-氨基-5-溴-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰
胺(N8)
1H NMR(DMSO-d6/400MHz)δppm 6.60(bs,2H),6.80(bs,1H),7.18-7.30(m,2H),7.31-7.56(m,3H),7.71(s,1H),8.36(s,1H),11.55(bs,1H);ESI(+)MS:m/z 377(MH+).
使用上述步骤由F1合成下述化合物,在100℃下的DMF中使用N-氯代琥珀酰亚胺作为卤化剂进行20小时(产率为72%)。
实施例116
5-(2-氨基-5-氯-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(N1)
1H NMR(DMSO-d6/400MHz)δppm 6.62(s,2H)6.88(s,1H)7.31-7.46(m,4H)7.58(d,J=2.68Hz,1H)7.58(d,J=2.68Hz,1H)7.64-7.69(m,2H)8.27(s,1H)11.27(s,1H);ESI(+)MS:m/z 314(MH+).
使用上述步骤由F4合成下述化合物:
实施例117
5-(2-氨基-5-氯-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰
胺(N7)
1H NMR(DMSO-d6/400MHz)δppm 6.58(bs,2H),6.81(bs,1H),7.19-7.31(m,2H),7.36-7.59(m,3H),7.67(s,1H),8.29(s,1H),11.60(bs,1H);ESI(+)MS:m/z 332(MH+).
实施例118
5-(2-氨基-嘧啶-4-基)-4-碘-2-苯基-1H-吡咯-3-甲酸酰胺(N3)
向于DMF(1mL)的酰胺F1(140mg,0.5mmol)中加入NIS(110mg,0.5mmol)并在室温下搅拌该混合物4小时。将该反应混合物倒入到搅拌的水中,过滤沉淀,充分洗涤并干燥。得到绿色固体状的标题化合物(145mg,72%)。
1H NMR(DMSO-d6/400MHz)δppm:6.57(s,2H)7.31-7.37(m,2H)7.39(s,1H)7.40-7.47(m,2H)7.56(s,1H)7.62-7.68(m,2H)8.31(d,J=5.37Hz,1H)11.74(s,1H);ESI(+)MS:m/z 406(MH+).
实施例119
5-(2-氨基-嘧啶-4-基)-4-氯-2-苯基-1H-吡咯-3-甲酸酰胺(Z1)
步骤1:氨基嘧啶(62)的保护
室温下搅拌酰胺F1(850mg,3mmol)、(Boc)2O(1.7g,8mmol)和DMAP(50mg)于THF(20mL)和DMF(1mL)的溶液48小时。将该混合物倒入水中并过滤沉淀。将其溶于乙酸乙酯,用水洗涤,干燥(Na2SO4)并浓缩。通过快速色谱(EtOAc/正己烷9∶1)纯化该残余物(由单、二-和三-Boc衍生物组成)得到二-Boc衍生物62(14%).ESI(+)MS:m/z 480(MH+)。
步骤2:吡咯环(63)的氯化
在100℃下搅拌酰胺62(165mg,0.34mmol)和N-氯代琥珀酰亚胺(46mg,0.34mmol)于DMF(1mL)的溶液2小时。冷却后将该混合物倒入搅拌的水中,用乙酸乙酯萃取并用水洗涤,干燥(Na2SO4)并浓缩。通过快速色谱(EtOAc/正己烷5∶1)纯化该残余物得到63(80mg,45%).ESI (+)MS:m/z 514(MH+)。
步骤3:氨基嘧啶的脱保护(Z1)
向63(80mg,0.156mmol)于MeOH(1mL)的溶液中加入4N HCl的二噁烷(3mL)溶液并在室温下搅拌该混合物20小时,然后在50℃下搅拌1小时。浓缩后,在搅拌下加入乙醚并搅拌该混合物30分钟。过滤沉淀,用二乙醚洗涤并干燥。得到标题化合物(45mg,82%)。
1H NMR(DMSO-d6/400MHz)δppm 6.47(bs,2H),7.15(d,J=5.24Hz,1H),7.35(t,J=8.50Hz,1H),7.39-7.45(m,3H),7.60(bs,1H),7.64(d,J=8.54Hz,2H),8.29(d,J=5.24Hz,1H),11.64(bs,1H);ESI (+)MS:m/z 314(MH+).
实施例120
5-(2-氨基-5-溴-嘧啶-4-基)-4-溴-2-苯基-1H-吡咯-3-甲酸酰胺(N4)
向于DMF(1.5mL)的酰胺F1(140mg,0.5mmol)中加入NBS(180mg,1mmol)并在室温下搅拌该混合物15小时。将该反应混合物倒入搅拌的水中,过滤沉淀,充分洗涤并干燥。得到橙色固体状的标题化合物(195mg,90%)。
1H NMR(DMSO-d6/400MHz)δppm 6.96(s,2H)7.28-7.34(m,1H)7.35(s,1H)7.38-7.45(m,2H)7.48(s,1H)7.56-7.63(m,2H)8.46(s,1H)12.01(s,1H);ESI(+)MS:m/z 438(MH+).
使用上述步骤由F1合成下述化合物,使用N-碘代琥珀酰亚胺作为卤化剂。
实施例121
5-(2-氨基-5-碘-嘧啶-4-基)-4-碘-2-苯基-1H-吡咯-3-甲酸酰胺
(N5)
1H NMR(DMSO-d6/400MHz)δppm 6.91(bs,2H),7.25-7.33(m,1H),7.35(bs,2H),7.38-7.46(m,2H),7.59(d,J=8.30Hz,2H),8.57(s,1H),11.96(s,1H);ESI(+)MS:m/z 532(MH+).
实施例122
5-(2-氨基-5-溴-嘧啶-4-基)-4-碘-2-苯基-1H-吡咯-3-甲酸酰胺(N 6)
向于DMF(1.5mL)的酰胺N 3(120mg,0.3mmol)中加入NBS(60mg,0.34mmol)并在室温下搅拌该混合物15小时。将该反应混合物倒入搅拌的水中,过滤沉淀,充分洗涤并干燥。得到橙色固体状的标题化合物。
1H NMR(DMSO-d6/400MHz)δppm:6.95(s,2H)7.24-7.34(m,2H)7.36-7.46(m,3H)7.55-7.61(m,2H)8.45(s,1H)12.01(s,1H);ESI(+)MS:m/z 485(MH+).
实施例123
5-(2-氨基-5-溴-嘧啶-4-基)-4-碘-2-苯基-1H-吡咯-3-甲酸酰胺(N6)
向于DMF(1.5mL)的酰胺N2(243mg,0.68mmol)中加入NIS(160mg,0.71mmol),并在50℃下搅拌该混合物4小时,然后在室温下搅拌过夜。将该反应混合物倒入搅拌的水中,过滤沉淀,充分洗涤并干燥。得到橙色固体状的标题化合物(270mg,82%)。
实施例124
5-(2-氨基-嘧啶-4-基)-2-苯基-4-乙烯基-1H-吡咯-3-甲酸酰胺(O1)
向搅拌的N3(50mg,0.125mmol)于二噁烷(5mL)和DMF(0.5mL)的溶液中加入2,6-二甲基-4-叔丁基苯酚(5mg)、四(三苯基膦)钯(5mg)和四丁基乙烯基锡烷(145μL)。在110℃下温热该混合物8小时,冷却并浓缩。通过快速色谱(DCM/MeOH 20∶1)纯化粗产物得到浅黄色固体状的标题化合物(产率为24%)。
1H NMR(DMSO-d6/400MHz)δppm:5.15(dd,J=11.58,2.07Hz,1H),5.64(dd,J=11.58,1.95Hz,1H),6.49(bs,2H),6.97(d,J=5.24Hz,1H),7.28-7.37(m,2H),7.40-7.57(m,3H),7.61-7.71(m,3H),8.23(d,J=5.24Hz,1H),11.40(bs,1H);ESI(+)MS:m/z 306(MH+).
实施例125
5-(2-氨基-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(U1)
步骤1:吡咯环的形成(65)
在0℃下,向酮酯2(350mg,2mmol)于THF(45mL)的溶液中加入NaH(180mg,4.5mmol)并在0℃下搅拌该混合物20分钟。加入溴酮盐酸盐64(635mg,2mmol)并在0℃下搅拌该反应化合物2小时,然后在室温下搅拌2小时。除去溶剂后,加入无水乙醇(25mL)和醋酸铵(500mg,6.5mmol)并在室温下搅拌该混合物20小时。除去溶剂并用乙酸乙酯和水溶解该残余物。干燥有机相并用快速色谱(洗脱液:DCM/MeOH 95∶5)处理。得到5-(2-氯-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸乙酯(340mg,50%)。
1H NMR(DMSO-d6/400MHz)δppm:1.19(t,J=7.07Hz,3H),4.14(q,J=7.07Hz,2H),7.38-7.52(m,4H),7.62-7.68(m,2H),7.80(d,J=5.37,1H),7.97(s,1H),8.33(d,J=5.37Hz,1H),12.37(bs,1H);ESI (+)MS:m/z 327(MH+).
步骤2:吡啶环的胺化(66)
在140℃下在微波腔中搅拌酯65(120mg,0.37mmol)、氨基甲酸叔丁酯(215mg,1.84mmol)、Xantphos(16mg,0.028mmol)、醋酸钯(4.1mg,0.0183mmo l)和碳酸铯(240mg,0.73mmol)于二噁烷(3mL)的混合物20分钟。用甲醇溶解该残余物,通过C盐过滤,用乙酸乙酯和水处理,干燥并浓缩。通过快速色谱(洗脱液:DCM/EtOAc 95∶5)纯化该残余物。得到5-(2-氨基-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸乙酯(45mg,40%)。ESI(+)MS:m/z 308(MH+).
步骤3:缩合成酰胺(U1)
回流下温热酯66(42mg,0.15mmol)于乙醇(0.5mL)和4N NaOH(0.5mL)的溶液2小时。用乙酸酸化该混合物并在减压下汽提。该残余物(粗酸67)溶于DMF(2mL)并室温下用HOBT.NH3(42mg,0.27mmol)、EDCI(52mg,0.27mmol)和DIPEA(0.12mL)处理3天(在第一天和第二天后分别加入相同量的反应试剂)。浓缩并用乙酸乙酯进行含水后处理,通过反相快速色谱在Waters FractionLynx系统(参见一般方法)上纯化该残余物。得到标题化合物(33mg,80%)。
1H NMR(DMSO-d6/400MHz)δppm 5.81(bs,2H)6.74(s,1H),6.81(bs,1H),6.88(d,J=5.78Hz,1H),7.02(d,J=2.68Hz,1H),7.25(bs,1H),7.31-7.46(m,3H),7.65(d,J=8.17Hz,2H),7.90(d,J=5.78Hz,1H),11.64(bs,1H);ESI (+)MS:m/z 308(MH+).
所选式(I)化合物(根据实施例中描述的方法制备)列于表X中。该表显示表征数据(HRMS计算值和实验室)和结构,其中没有显示碳上的氢原子。
表X.所选式I化合物的结构和数据
Claims (25)
1.式(I)化合物:
其中
G为CH或氮原子;
W为氧原子、NR1或S(O)n;n为0、1或2;
R1和R3独立地表示氢原子或任选取代的选自烷基、环烷基、链烯基、炔基、杂环基、杂环烷基、芳基、芳烷基、杂环氧基-烷基和烷氧羰基的基团;
R2为氢原子或卤原子,或任选取代的选自芳基、环烷基和杂环基的基团;
R4为氢原子或卤原子,或任选取代的烷基或链烯基;
R5为氢原子或卤原子;
R6为氢原子或NHR7;
R7为氢原子,任选取代的选自烷基、芳基、环烷基和杂环基的基团,或-CO-R1,其中R1如上所定义;
或其药学上可接受的盐,条件为下述化合物除外:
2,5-二(吡啶-4-基)-噻吩-3-甲酸酰胺,
2,5-二(吡啶-4-基)-噻吩-3-甲酸甲酰胺,
2,5-二(吡啶-4-基)-4-甲基-吡咯-3-甲酸酰胺,
5-吡啶-4-基-呋喃-3-甲酸[4-甲氧基-3-(4-甲基-哌嗪-1-基)-苯基]-酰胺,
5-吡啶-4-基-呋喃-3-甲酸(1-甲基-1,2,3,4-四氢-喹啉-7-基)-酰胺,和
N-[2-氨基-1-(2,4-二氯苄基)乙基]-5-[2-(甲氨基)嘧啶-4-基]噻吩-3-甲酰胺。
2.权利要求1的式(I)化合物,其特征在于W为NR1,R1和R3独立地表示氢原子或任选取代的烷基,且R6为NHR7其中R7为氢原子或任选取代的芳基。
3.权利要求1或2的式(I)化合物,其特征在于W为NR1;R1表示氢原子或任选取代的烷基;R3和R4表示氢原子,R2为任选取代的芳基或杂环基;且R6为NH2。
4.前述权利要求中任一项的式(I)化合物,其中W为NH或R3表示氢原子。
5.前述权利要求中任一项的式(I)化合物,或其药学可接受的盐,其选自下述化合物:
2-苯基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A1),
2-(2-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A2),
2-(3-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A3),
2-(4-氟-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A4),
5-吡啶-4-基-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(A7),
5-吡啶-4-基-2-间-甲苯基-1H-吡咯-3-甲酸酰胺(A8),
5-吡啶-4-基-2-对-甲苯基-1H-吡咯-3-甲酸酰胺(A9),
2-(3-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A11),
2-(4-甲氧基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A12),
2-(2-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A13),
2-(3-硝基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A14),
2-(2,3-二甲基-苯基)-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(A20),
5-吡啶-4-基-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺(C1),
2-呋喃-3-基-5-吡啶-4-基-1H-吡咯-3-甲酸酰胺(C2),
5-(3-氟-吡啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(E1),
5-(3-氟-吡啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(E2),
5-(2-氨基-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(F1),
5-(2-氨基-嘧啶-4-基)-2-邻-甲苯基-1H-吡咯-3-甲酸酰胺(F2),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F4),
5-(2-氨基-嘧啶-4-基)-2-(4-氟-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F13),
5-(2-氨基-嘧啶-4-基)-2-(5-氟-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F14),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸酰胺(F15),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二氟-苯基)-1H-吡咯-3-甲酸酰胺(F16),
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氟-苯基)-1H-吡咯-3-甲酸酰胺(F17),
5-(2-氨基-嘧啶-4-基)-2-(2,5-二氟-苯基)-1H-吡咯-3-甲酸酰胺(F18),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-苯基)-1H-吡咯-3-甲酸酰胺(F19),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-氟-苯基)-1H-吡咯-3-甲酸酰胺(F23),
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸酰胺(F26),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F28),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-3-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F30),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-5-氟-苯基)-1H-吡咯-3-甲酸酰胺(F31),
5-(2-氨基-嘧啶-4-基)-2-(3-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F33),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二氯-苯基)-1H-吡咯-3-甲酸酰胺(F34),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-3-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F35),
5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F36),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-苯基)-1H-吡咯-3-甲酸酰胺(F38),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-3-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F39),
5-(2-氨基-嘧啶-4-基)-2-(3-甲氧基-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F40),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-3-氟-苯基)-1H-吡咯-3-甲酸酰胺(F41),
5-(2-氨基-嘧啶-4-基)-2-(3-溴-2-氯-苯基)-1H-吡咯-3-甲酸酰胺(F42),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-3-氯-苯基)-1H-吡咯-3-甲酸酰胺(F43),
5-(2-氨基-嘧啶-4-基)-2-(2,3-二溴-苯基)-1H-吡咯-3-甲酸酰胺(F44),
5-(2-氨基-嘧啶-4-基)-2-(3-溴-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F45),
5-(2-氨基-嘧啶-4-基)-2-(3-溴-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F46),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-3-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F47),
5-(2-氨基-嘧啶-4-基)-2-(4-甲氧基-3-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F48),
5-(2-氨基-嘧啶-4-基)-2-(3,4-二甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F49),
5-(2-氨基-嘧啶-4-基)-2-(2-氟-4-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F50),
5-(2-氨基-嘧啶-4-基)-2-(2-氯-4-甲氧基-苯基)-1H-吡咯-3-甲酸酰胺(F51),
5-(2-氨基-嘧啶-4-基)-2-(2-溴-4-氟-苯基)-1H-吡咯-3-甲酸酰胺(F52),
5-(2-氨基-嘧啶-4-基)-2-(4-甲氧基-2-甲基-苯基)-1H-吡咯-3-甲酸酰胺(F53),
5-(2-氨基-嘧啶-4-基)-2-噻吩-3-基-1H-吡咯-3-甲酸酰胺(G1),
5-(2-氨基-嘧啶-4-基)-2-噻吩-2-基-1H-吡咯-3-甲酸酰胺(G2),
5-(2-氨基-嘧啶-4-基)-2-(5-甲基-噻吩-2-基)-1H-吡咯-3-甲酸酰胺(G3),
5-(2-氨基-嘧啶-4-基)-2-(5-氯-噻吩-2-基)-1H-吡咯-3-甲酸酰胺(G4),
5-(2-氨基-5-氯-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(N1),
5-(2-氨基-5-溴-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(N2),
5-(2-氨基-嘧啶-4-基)-4-碘-2-苯基-1H-吡咯-3-甲酸酰胺(N3),
5-(2-氨基-5-氯-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺(N7),
5-(2-氨基-5-溴-嘧啶-4-基)-2-(2-氟-苯基)-1H-吡咯-3-甲酸酰胺(N8),
5-(2-氨基-嘧啶-4-基)-2-苯基-噻吩-3-甲酸酰胺(S1),
5-(2-氨基-5-氟-嘧啶-4-基)-2-苯基-1H-吡咯-3-甲酸酰胺(V1)和
5-(2-氨基-嘧啶-4-基)-4-氯-2-苯基-1H-吡咯-3-甲酸酰胺(Z1)。
6.前述权利要求中任一项的式(I)化合物或其药学可接受的盐,其为:
5-(2-氨基-嘧啶-4-基)-2-(2,3-二甲基-苯基)-1H-吡咯-3-甲酸酰胺(F15),
5-(2-氨基-嘧啶-4-基)-2-(2,4-二氯-苯基)-1H-吡咯-3-甲酸酰胺(F26)和
5-(2-氨基-嘧啶-4-基)-2-(4-氯-2-氟-苯基)-1H-吡咯-3-甲酸酰胺(F36)。
9.权利要求1的式(I)化合物的制备方法,所述方法包括:
a′)使式2D化合物
其中R2为氢原子或卤原子,且R5、R6和G如权利要求1所定义,
任选在缩合剂的存在下与活化形式的氨偶联,或与式R3-NH2的胺偶联,其中R3如权利要求1所定义,由此获得式(I)化合物,其中W为N,R1为氢原子且R2为氢原子或卤原子;
a′1)任选将所得的其中R2为卤原子的式(I)化合物转变为另一种式(I)化合物,其中R2为氢原子或任选取代的选自芳基、环烷基和杂环基的基团和/或
a′2)将所得的其中R1为氢原子的式(I)化合物转变为另一种式(I)化合物,其中R1为任选取代的选自烷基、环烷基、链烯基、炔基、杂环基、芳基、杂环氧基-烷基和烷氧羰基的基团;
且如果需要,将式(I)化合物转变成其药学可接受的盐或将盐转变成游离的化合物(I)。
13.治疗细胞增殖障碍的方法,所述细胞增殖障碍由改变的蛋白激酶活性引起和/或与改变的蛋白激酶活性相关,所述方法包括给有此需要的哺乳动物施用有效量的权利要求1定义的式(I)化合物。
14.权利要求13的治疗细胞增殖障碍方法,所述细胞增殖障碍由改变的Cdc 7激酶引起和/或与改变的Cdc 7激酶相关。
15.权利要求13或14的方法,其中所述细胞增殖障碍为选自下述的癌症:癌、淋巴细胞系造血肿瘤,骨髓系造血肿瘤;间质起源的肿瘤;中枢及外周神经系统肿瘤;黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化黄瘤、滤泡状甲状腺癌和卡波西肉瘤。
16.权利要求13或14的方法,其中所述细胞增殖障碍选自:良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤、牛皮癣、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、肾小球性肾炎和术后狭窄与再狭窄。
17.权利要求13的方法,其进一步包括给有此需要的哺乳动物进行与至少一种细胞生长抑制剂或细胞毒剂组合的放射疗法或化学疗法。
18.权利要求13的方法,其中所述有此需要的哺乳动物为人。
19.抑制Cdc7激酶活性的方法,其包括将所述激酶与有效量的权利要求1的化合物接触。
20.药物组合物,其包括治疗有效量的权利要求1定义的式(I)化合物或其药学可接受的盐,以及至少一种药学可接受的赋形剂、载体和/或稀释剂。
21.权利要求20的药物组合物,其进一步包括一种或多种化疗剂。
22.产品或药盒,其包括权利要求1定义的式(I)化合物或其药学可接受的盐,或权利要求18定义的药物组合物,以及一种或多种化疗剂,作为在抗癌治疗中同时、分别或连续使用的组合制剂。
23.权利要求1定义的式(I)化合物或其药学可接受的盐,用作药物。
24.权利要求1定义的式(I)化合物或其药学可接受的盐用于制备具有抗癌活性的药物的用途。
25.式1D或1E的中间体:
其中G、Alk、环基、R1、R4、R5和R6如权利要求1所定义,条件为下述化合物除外:
1H-吡咯-3-甲酸,1-(甲氧基甲基)-4-甲基-2,5-二-4-吡啶基-,乙酯;
1H-吡咯-3-甲酸,2,5-二-4-吡啶基-,甲酯,
1H-吡咯-3-甲酸,4-甲基-2-苯基-5-(4-吡啶基)-,甲酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,与吗啉(1∶1)化合,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基,
1H-吡咯-3-甲酸,4-(甲氧基甲基)-2,5-二-4-吡啶基-,甲酯,
1H-吡咯-3-甲酸,4-丁基-2,5-二-4-吡啶基-,乙酯,
1H-吡咯-3-甲酸,4-(1-甲基乙基)-2,5-二-4-吡啶基-,乙酯,
1H-吡咯-3-甲酸,4-丙基-2,5-二-4-吡啶基-,乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,2-甲氧基乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,丁酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,丙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,1,1-二甲基乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-1-甲基乙酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,2-丙烯酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,苯基甲酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,甲酯,
1H-吡咯-3-甲酸,4-甲基-2,5-二-4-吡啶基-,乙酯和
1H-吡咯-3-甲酸,4-乙基-2,5-二-4-吡啶基-,乙酯。
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JP2002521408A (ja) * | 1998-07-28 | 2002-07-16 | スミスクライン・ビーチャム・コーポレイション | 化合物および方法 |
US20040181066A1 (en) | 2001-08-01 | 2004-09-16 | Fraley Mark E. | Tyrosine kinase inhibitors |
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AU2003297431A1 (en) | 2002-12-20 | 2004-07-22 | Pharmacia Corporation | Mitogen activated protein kinase-activated protein kinase-2 inhibiting compounds |
AU2005228899A1 (en) * | 2004-03-30 | 2005-10-13 | Novartis Vaccines And Diagnostics, Inc. | Substituted thiophene derivatives as anti-cancer agents |
MX2008012422A (es) * | 2006-03-27 | 2008-10-09 | Nerviano Medical Sciences Srl | Derivados de furano y tiofeno, pirrol substituido con pirimidinil y piridil como inhibidores de cinasa. |
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CN102666527A (zh) * | 2009-11-04 | 2012-09-12 | 内尔维阿诺医学科学有限公司 | 5-(2-氨基-嘧啶-4-基)-2-芳基-1h-吡咯-3-甲酰胺的制备方法 |
CN102666528A (zh) * | 2009-11-11 | 2012-09-12 | 内尔维阿诺医学科学有限公司 | 晶体cdc7 抑制剂盐 |
CN102666528B (zh) * | 2009-11-11 | 2014-04-16 | 内尔维阿诺医学科学有限公司 | 晶体cdc7 抑制剂盐 |
CN103502241A (zh) * | 2011-04-19 | 2014-01-08 | 内尔维阿诺医学科学有限公司 | 作为激酶抑制剂的取代的嘧啶基-吡咯类活性剂 |
CN103502241B (zh) * | 2011-04-19 | 2016-03-23 | 内尔维阿诺医学科学有限公司 | 作为激酶抑制剂的取代的嘧啶基-吡咯类活性剂 |
CN107857758A (zh) * | 2017-12-31 | 2018-03-30 | 窦玉玲 | 一种酰胺类化合物及其作为hsp90抑制剂和抗肿瘤药物的应用 |
CN107987063A (zh) * | 2017-12-31 | 2018-05-04 | 窦玉玲 | 一种hsp90抑制剂及其在抗肿瘤药物的应用 |
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