CN115557947A - 吡唑并[4,3-c]吡啶衍生物及其在医药上的应用 - Google Patents
吡唑并[4,3-c]吡啶衍生物及其在医药上的应用 Download PDFInfo
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- CN115557947A CN115557947A CN202210765506.6A CN202210765506A CN115557947A CN 115557947 A CN115557947 A CN 115557947A CN 202210765506 A CN202210765506 A CN 202210765506A CN 115557947 A CN115557947 A CN 115557947A
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- Prior art keywords
- amino
- pyrazolo
- heterocycloalkyl
- pyridin
- cycloalkyl
- Prior art date
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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Abstract
本发明涉及一种吡唑并[4,3‑c]吡啶衍生物及其在医药上的应用。吡唑并[4,3‑c]吡啶衍生物为TYK2抑制剂,用于预防和/或治疗自身免疫性疾病。
Description
技术领域
本发明涉及一种吡唑并[4,3-c]吡啶衍生物或者其立体异构体及其在医药上的应用。
背景技术
Janus激酶(JAK)是细胞内非受体酪氨酸激酶家族,介导细胞因子产生的信号,并通过JAK-STAT信号通路传导。JAK家族成员有四个,分别是Janus激酶1(JAK1),Janus激酶2(JAK2),Janus激酶3(JAK3)和酪氨酸激酶2(TYK2)。其中,TYK2与I型或II型细胞因子受体的胞质结构域结合,并且当这些受体与细胞因子结合时,TYK2可以被激活。与TYK2激活有关的细胞因子包括干扰素(例如IFN-α、IFN-β、IFN-ε,IFN-κ,IFN-ω、IFN-ζ、IFN-λ等)和白介素(例如IL-4、IL-6、IL-10、IL-11、IL-12、IL-13、IL-23、IL-27、IL-31等)。被激活的TYK2进一步磷酸化信号蛋白,如STAT家族成员,包括STAT1、STAT2、STAT4和STAT6,以传递细胞因子的信号。
TYK2在免疫和非免疫细胞中介导多种抗病毒和免疫调节细胞因子的信号传导,对免疫性和炎症性疾病的病理生物学至关重要。此外,基因靶向小鼠和人TYK2的遗传缺陷确定了TYK2在感染、癌症、(自身)炎症以及先天和适应性免疫反应中的生物学和病理学功能。由于抑制TYK2活性在治疗炎症性疾病、免疫性疾病和癌症方面的前景,因此,TYK2抑制剂的开发具有重要研究和临床价值,引起了制药行业的高度关注。
发明内容
本发明的目的是提供新的TYK2抑制剂。
本发明的一个或多个实施方式中,提供通式(I)所示的化合物或者其立体异构体:
其中:
R1选自C1-6烷基、C1-6烷氧基、C3-8环烷基、C3-8杂环烷基或者NHR2,所述的C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、C1-6烷基、C3-8环烷基或者C3-8杂环烷基的取代基取代;
R2选自C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基,所述的C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、C1-6烷基、C3-8环烷基或者C3-8杂环烷基的取代基取代;
A选自苯基、萘基、5-6元芳香杂环或者C9-11芳香杂双环;
X1、X2、X3各自独立地为N或者CRX;
RX选自H、卤素、羟基、NH2、氰基、C1-6烷基、C1-6烷氧基或者C3-8环烷基;
B为C3-8环烷基。
在本发明的一个或多个实施方式中,所述R1选自C1-6烷基、C1-6烷氧基或者NHR2,所述的C1-6烷基、C1-6烷氧基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
所述R2选自C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基,所述的C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
A选自苯基、萘基、5-6元芳香杂环;
RX选自H、卤素、羟基、NH2或氰基;
B为C3-6环烷基。
在本发明的一个或多个实施方式中,所述R1选自C1-6烷基或者NHR2,所述的C1-6烷基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
所述R2选自C1-6烷基或者C3-8杂环烷基,所述的C1-6烷基者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
A选自5-6元芳香杂环;
RX选自H、卤素、羟基、NH2或氰基。
在本发明的一个或多个实施方式中,本发明的化合物或者其立体异构体选自:
在本发明的一个或多个实施方式中,提供通式(II)所示的化合物或者其立体异构体:
其中:
R3选自C1-6烷基或者NHR4,所述的C1-6烷基任选地进一步被1个或者多个羟基取代;
R4选自C3-8环烷基或者C3-8杂环烷基,所述的C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个羟基取代;
C选自吡唑基或者嘧啶基;
RX1、RX2、RX3、RX4、RX5各自独立地选自H、卤素或者氰基。
在本发明的一个或多个实施方式中,本发明的化合物或者其立体异构体选自:
本发明的一个或多个实施方式提供药物组合物,所述药物组合物包括:
(1)通式(I)或(II)所示的化合物或其立体异构体;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
本发明的一个或多个实施方式提供本发明的化合物或其立体异构体,或者本发明的药物组合物,用于预防和/或治疗自身免疫性疾病。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素包括17F和19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指1至20个碳原子的直链或支链饱和脂肪族烃基,优选为1至8个碳原子的烷基,更优选为1至6个碳原子的烷基,进一步优选为1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体;当烷基被取代基时,可以任选进一步被1个或者多个取代基所取代。
“烷氧基”是指烷基中至少1个碳原子被氧原子取代所形成的基团。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。所述的烷基定义与上文所述的“烷基”定义相同。
“环烷基”是指饱和的环烃基,其环可以为3至10元的单环、4至12元双环或者10至20元多环体系,环碳原子优选3至10个碳原子,进一步优选3至8个碳原子。“环烷基”非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当被取代时,可以任选进一步被0个或者多个取代基所取代。
“杂环烷基”是指取代的或未取代的饱和非芳香环基,其可以是3至8元的单环、4至12元双环或者10至15元三环体系,且包含1至3个选自N、O或S的杂原子,优选3至8元杂环基。“杂环烷基”的环中选择性取代的N、S可被氧化成各种氧化态;“杂环烷基”可以连接在杂原子或者碳原子上;“杂环烷基”可以为桥环或者螺环。“杂环烷基”非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、哌啶基、哌叮基、吗啉基、硫代吗啉基、1,3-二噻烷基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基和氧杂螺[3.3]庚烷基。
“杂环”或“杂环基”是指饱和或不饱和的芳香性杂环或者非芳香性杂环,当为芳香性杂环时,其定义与上文“杂芳基”定义相同;当为非芳香性杂环时,其可以是3至10元(例如3、4、5、6、7、8、9、10元)的单环、4至12元(例如4、5、6、7、8、9、10、11、12元)双环或者10至15元(例如10、11、12、13、14、15元)三环体系,且包含1至4个(例如1、2、3、4个)选自N、O或S的杂原子,优选3至8元杂环基。“杂环基”或“杂环”的环中选择性取代的1至4个(例如1、2、3、4个)N、S可被氧化成各种氧化态;“杂环基”或“杂环”可以连接在杂原子或者碳原子上;“杂环基”或“杂环”可以为并环、桥环或者螺环。所述的“杂环基”或“杂环”可以任选进一步被1个或者多个取代基所取代。
当上文所述的“烷基”、“烷氧基”、“杂环基”、“杂环”、“环烷基”或者“杂环烷基”被取代时,可以任选进一步被0、1、2、3、4、5、6、7、8、9或者10个选自F、Cl、Br、I、羟基、巯基、硝基、氰基、氨基、C1-6烷基氨基、=O、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、-NRq4Rq5、=NRq6、-C(=O)OC1-6烷基、-OC(=O)C1-6烷基、-C(=O)NRq4Rq5、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-C(=O)OC6-10芳基、-OC(=O)C6-10芳基、-OC(=O)C5-10杂芳基、-C(=O)OC5-10杂芳基、-OC(=O)C3-8杂环烷基、-C(=O)OC3-8杂环烷基、-OC(=O)C3-8环烷基、-C(=O)OC3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8环烷基、-NHC(=O)C3-8杂环烷基、-NHC(=O)C2-6烯基或者-NHC(=O)C2-6炔基的取代基所取代,且其中所述的取代基C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-8环烷基、C3-8杂环烷基、C6-10芳基、C5-10杂芳基、-NHC(=O)C6-10芳基、-NHC(=O)C5-10杂芳基、-NHC(=O)C3-8杂环烷基或者-NHC(=O)C3-8环烷基任选进一步被1至3个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、-NRq4Rq5或者=O的取代基所取代;Rq1选自C1-6烷基、C1-6烷氧基或者C6-10芳基;Rq2、Rq3选自H或者C1-6烷基;Rq4、Rq5选自H、C1-6烷基、-NH(C=NRq1)NRq2Rq3、-S(=O)2NRq2Rq3、-C(=O)Rq1或者-C(=O)NRq2Rq3,其中所述的C1-6烷基任选进一步被1个或者多个选自OH、F、Cl、Br、I、C1-6烷基、C1-6烷氧基、C6-10芳基、C5-10杂芳基、C3-8环烷基或者C3-8杂环烷基的取代基所取代;或者Rq4与Rq5及N原子形成一个3至8元杂环,所述的环可以含有1个或者多个选自N、O或者S的杂原子。
“药物组合物”是指一种或多种本发明所述化合物、其药学上可接受的盐或前药和其它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其中杂环基未被烷基取代的情况。
具体实施方式
DCM:二氯甲烷;
EA:乙酸乙酯;
MeOH:甲醇;
DIEA:N,N-二异丙基乙胺;
DMF:N,N-二甲基甲酰胺;
PE:石油醚;
NMP:N-甲基吡咯烷酮;
DIEA:N,N-二异丙基乙胺;
TLC:薄层色谱;
SFC:超临界流体色谱法;
UPLC:超高效液相色谱;
X-phos:2-二环己基膦-2',4',6'-三异丙基联苯;
Brettphos-Pd-G3:甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)。
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
中间体1
6-氯-1H-吡唑并[4,3-c]吡啶-1-羧酸叔丁酯(中间体1)
tert-butyl 6-chloro-1H-pyrazolo[4,3-c]pyridine-1-carboxylate
在100mL圆底烧瓶中,将6-氯-1H-吡唑并[4,3-c]吡啶1a(2.3g,14.98mmol)和二碳酸二叔丁酯(3.92g,17.97mmol)溶于二氯甲烷(30mL)中,加入4-二甲氨基吡啶(183mg,1.50mmol),室温反应1小时;反应结束,减压移除有机溶剂,粗产物通过硅胶柱层析(乙酸乙酯:石油醚=1:3~1:1,v/v)纯化得中间体1(2.8g,收率73.6%,白色固体)。
LCMS m/z(ESI)=254.1[M+1].
中间体2
2-((6-氨基嘧啶-4-基)氨基)乙基-1-醇(中间体2)
2-((6-aminopyrimidin-4-yl)amino)ethan-1-ol
在250mL圆底烧瓶中,依次加入6-氯嘧啶-4-胺2a(10g,77.19mmol)、三乙胺(8.6g,84.9mmol)和乙醇胺(47.1g,771.9mmol),升温至95℃反应7小时,反应结束减压移除有机溶剂,粗产物通过硅胶柱层析分离纯化(二氯甲烷:甲醇=10:1~8:1,v/v)得中间体2(7.1g,白色固体,收率59.1%)。
LCMS m/z(ESI)=155.1[M+1].
中间体3
5-溴双环[4.2.0]辛-1(6),2,4-三烯-2-腈(中间体3)
5-bromobicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
在100mL圆底烧瓶中,将2,5-二溴双环[4.2.0]辛-1(6),2,4-三烯3a(1.0g,3.8mmol)和氰化亚铜(520mg,5.7mmol)溶于N-甲基吡咯烷酮(5mL)中,140℃反应3小时;反应结束,减压移除有机溶剂,粗产物通过硅胶柱层析(乙酸乙酯:石油醚=0:1~1:10,v/v)纯化得中间体3(280mg,收率35.9%,白色固体)。
1HNMR(400MHz,DMSO-d6)δ7.59(s,2H),3.31–3.26(m,2H),3.19–3.14(m,2H).
实施例1
5-(6-((6-((2-羟乙基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-碳三烯(化合物1)
5-(6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
第一步:
6-((6-((2-羟乙基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-羧酸叔丁酯(1A)
tert-butyl 6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridine-1-carboxylate
氮气保护下,在100mL三口瓶中,依次加入中间体1(2.8g,11.06mmol)、中间体2(1.87g,12.17mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(1.5g,1.66mmol)、碳酸铯(7.2g,22.12mmol)和1,4-二氧六环(50mL),100℃反应8小时,反应结束冷至室温,加水淬灭,乙酸乙酯萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产物通过硅胶柱层析(二氯甲烷:甲醇=30:1~20:1,v/v)分离纯化得化合物1A(1.13g,淡黄色固体,收率27.5%)。
LCMS m/z(ESI)=372.2[M+1].
第二步:
2-((6-((1H-吡唑并[4,3-c]吡啶-6-基)氨基)嘧啶-4-基)氨基)乙-1-醇(1B)
2-((6-((1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)ethan-1-ol
在100mL圆底烧瓶中,将1A(1.1g,2.96mmol)溶于二氯甲烷(20mL)中,缓慢滴加三氟乙酸,滴加完毕室温反应2小时,反应结束,加水淬灭,饱和碳酸氢钠调节pH至中性,二氯甲烷(20mL×3)萃取,无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产物通过中压制备纯化(水:乙腈=20:80,v/v)得化合物1B(613mg,灰白色固体,收率76.3%)。
LCMS m/z(ESI)=272.1[M+1].
第三步:
5-(6-((6-((2-羟乙基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-碳三烯(化合物1)
5-(6-((6-((2-hydroxyethyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
氮气保护下,在100mL三口瓶中,依次加入1B(100mg,0.369mmol)、中间体3(93mg,0.443mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(51mg,0.0554mmol)、碳酸铯(240mg,0.738mmol)和1,4-二氧六环(20mL),100℃反应8小时,反应结束冷至室温,加水淬灭,乙酸乙酯萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产物通过柱层析(二氯甲烷:甲醇=25:1~15:1,v/v)纯化得化合物1(17mg,白色固体,收率11.5%)。
1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.91(d,1H),8.53(d,1H),8.42(s,1H),8.23(s,1H),7.90(d,1H),7.76(d,1H),7.09(d,1H),6.60(s,1H),4.76(s,1H),3.60–3.55(m,2H),3.51(t,2H),3.28(s,4H);LCMS m/z(ESI)=399.2[M+1].
实施例2
2-((6-((1-(6,7-二氢-5H-环戊烯并[b]吡啶-4-基)-1H-吡唑并[4,3-c]吡啶-6-基)氨基)嘧啶-4-基)氨基)乙-1-醇(化合物2)
2-((6-((1-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)ethan-1-ol
氮气保护下,在100mL三口瓶中,依次加入1B(100mg,0.369mmol)、4-氯-6,7-二氢-5H-环戊二烯并[B]吡啶(68mg,0.443mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(51mg,0.0554mmol)、碳酸铯(240mg,0.738mmol)和1,4-二氧六环(20mL),100℃反应8小时,反应结束冷至室温,加水淬灭,乙酸乙酯萃取(20mL×3),无水硫酸钠干燥,过滤,减压移除有机溶剂,粗产物通过硅胶柱层析(二氯甲烷:甲醇=25:1~10:1,/v)纯化得化合物2(43mg,灰白色固体,收率29.8%)。
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.96–8.90(m,1H),8.51(d,2H),8.16(s,1H),8.13(s,1H),7.42(d,1H),7.07(s,1H),6.63(s,1H),4.74(t,1H),3.57–3.45(m,2H),3.32(s,2H),3.14–2.99(m,4H),2.16–2.04(m,2H);LCMS m/z(ESI)=389.2[M+1].
实施例3
2-((6-((1-(6,7-二氢-5H-环戊基[d]嘧啶-4-基)-1H-吡唑基[4,3-c]吡啶-6-基)氨基)嘧啶-4-基)氨基)乙烷-1-醇(化合物3)
2-((6-((1-(6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)pyrimidin-4-yl)amino)ethan-1-ol
氮气保护下,在100mL三口瓶中依次加入1B(600mg,2.21mmol)、4-氯-6,7-二氢-5H-环戊基[d]嘧啶(513mg,3.32mmol)、碳酸铯(1.44g,4.42mmol)、甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(200mg,0.221mmol)和1,4-二氧六环(10mL),升温至100℃反应12小时。TLC监控反应结束,冷至室温,加水50mL,乙酸乙酯(20mL×3)萃取,反相(乙腈:水=30:70,v/v)纯化得化合物3,白色固体(5.0mg,收率0.6%)。
1H NMR(400MHz,DMSO)δ11.24(s,1H),9.03(s,1H),8.93(d,1H),8.70(d,1H),8.48(s,1H),8.43(s,1H),6.50(s,1H),3.58(s,6H),3.03(t,2H),2.18–2.02(m,2H);LC-MS m/z(ESI)=390.2[M+1].
实施例4
2-(4-((1-(6,7-二氢-5H-环戊烷[b]吡啶-4-基)-1H-吡唑[4,3-c]吡啶-6-基)氨基)-1H-吡唑-1-基)乙烷-1-醇(化合物4)
2-(4-((1-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-1H-pyrazol-1-yl)ethan-1-ol
第一步:
6-氯-1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑[4,3-c]吡啶(4A)
6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridine
氮气保护下,在500mL圆底烧瓶中,将6-氯-1H-吡唑并[4,3-c]吡啶1a(20g,130.72mmol)溶于四氢呋喃(200mL)。冰盐浴降温至-10℃,缓慢添加氢化钠(10.5g,261.44mmol),添加完毕后保持此温度反应30min,缓慢滴加2-(三甲基硅烷基)乙氧甲基氯(26.2g,156.86mmol),滴加完毕缓慢升至室温反应2h。反应结束加水100mL,乙酸乙酯(200mL×3)萃取,无水硫酸钠干燥,过滤,减压移除有机相,粗产物通过硅胶柱层析(EA:PE=1:120~1:5,v/v)纯化得4A,淡黄色油状物(27g,收率:73.0%)。
LC-MS m/z(ESI)=284.1[M+1].
第二步:
2-(4-((1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶-6-基)氨基)-1H-吡唑-1-基)乙-1-醇(4B)
2-(4-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-1H-pyrazol-1-yl)ethan-1-ol
氮气保护下,在100mL三口瓶中依次加入4A(2.0g,7.07mmol)、2-(4-氨基-1H-吡唑-1-基)乙醇(1.1g,8.48mmol)、碳酸铯(4.6g,14.14mmol)、BrettPhos-Pd-G3(640mg,0.071mmol)和1,4-二氧六环(30mL),升温至100℃反应12h。冷至室温,加水100mL,乙酸乙酯(20mL×3)萃取,反相纯化(乙腈:水=40:60,v/v)得4B,褐色油状物(1.5g,收率56.8%)。
LC-MS m/z(ESI)=375.2[M+1].
第三步:
2-(4-((1H-吡唑[4,3-c]吡啶-6-基)氨基)-1H-吡唑-1-基)乙烷-1-醇(4C)
2-(4-((1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-1H-pyrazol-1-yl)ethan-1-ol
将化合物4B(1.4g,3.74mmol)溶于二氯甲烷(100mL)中,冰浴下加入三氟乙酸(4.3g,37.4mmol),缓慢升至室温反应2h。反应结束,减压移除有机溶剂,加入甲醇(20mL),搅拌下加入氨甲醇溶液(40mL,7M),反应30min,减压移除溶剂,残留物通过柱层析(DCM:MeOH=50:1~20:1,v/v)纯化得4C,褐色油状物(800mg,收率:87.6%)。
LC-MS m/z(ESI)=245.1[M+1].
第四步:
2-(4-((1-(6,7-二氢-5H-环戊烷[b]吡啶-4-基)-1H-吡唑[4,3-c]吡啶-6-基)氨基)-1H-吡唑-1-基)乙烷-1-醇(化合物4)
2-(4-((1-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)amino)-1H-pyrazol-1-yl)ethan-1-ol
氮气保护下,在100mL三口瓶中依次加入4C(200mg,0.816mmol)、4-氯-6,7-二氢-5H-环戊[b]吡啶(151mg,0.98mmol)、碳酸铯(530mg,1.63mmol)、Brettphos-Pd-G3(74mg,0.082mmol)和1,4-二氧六环(10mL),升温至100℃反应12h。冷至室温,加水100mL,乙酸乙酯(20mL×3)萃取,反相纯化(乙腈:水=25:75)得化合物4,白色固体(23mg,收率7.8%,UPLC=97.24%)。
1H NMR(400MHz,DMSO)δ8.81(d,2H),8.45(d,1H),8.38(s,1H),7.92(s,1H),7.45(s,1H),7.40(d,1H),6.71(s,1H),4.88(t,1H),4.10(t,2H),3.72(q,2H),3.11–2.96(m,4H),2.16–1.97(m,2H);LC-MS m/z(ESI)=362.2[M+1].
实施例5
3-氯-5-氟-4-(6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苄腈(化合物5)
3-chloro-5-fluoro-4-(6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
在100mL圆底烧瓶中,依次加入4C(200mg,0.82mmol)、碳酸钾(226mg,1.64mmol)、3-氯-4,5-二氟苯腈(149mg,0.86mmol)和NMP,升温至70℃反应1h,反应结束倒入水中,过滤得固体,反相纯化(乙腈:水=30:70,v/v)得化合物5,白色固体(36mg,收率:1.8%,UPLC=99.14%)。
1H NMR(400MHz,DMSO)δ8.78(d,2H),8.43(s,1H),8.32(s,1H),8.30–8.25(m,1H),7.83(s,1H),7.42(s,1H),6.23(s,1H),4.85(s,1H),4.08(t,2H),3.70(s,2H);LC-MS m/z(ESI)=398.1[M+1].
实施例6
5-(6-((1-(2-羟乙基)-1H-吡唑-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-腈(化合物6)
5-(6-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
氮气保护下,在100mL三口瓶中依次加入4C(100mg,0.41mmol)、中间体3(103mg,0.49mmol)、碳酸铯(267mg,0.82mmol)、Brettphos-Pd-G3(37mg,0.041mmol)和1,4-二氧六环(10mL),升温至100℃反应12h。冷至室温,加水淬灭,乙酸乙酯(20mL×3)萃取,反相(乙腈:水=30:70,v/v)纯化得化合物6,白色固体(16mg,收率10.5%,UPLC=97.47%)。
1H NMR(400MHz,DMSO)δ8.81(d,1H),8.45(d,1H),8.38(s,1H),7.92(s,1H),7.45(s,1H),7.88(d,1H),7.74(d,1H),7.40(d,1H),6.71(s,1H),3.88–3.79(m,2H),3.71(m,2H),3.12–2.99(m,4H);LC-MS m/z(ESI)=372.1[M+1].
实施例7
N4-(1-(6,7-二氢-5H-环戊烷[b]吡啶-4-基)-1H-吡唑并[4,3-c]吡啶-6-基)-N6-(四氢呋喃-3-基)嘧啶-4,6-二胺(化合物7)
N4-(1-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-N6-(tetrahydrofuran-3-yl)pyrimidine-4,6-diamine
第一步:
6-氯-N-(四氢呋喃-3-基)嘧啶-4-胺(7B)
6-chloro-N-(tetrahydrofuran-3-yl)pyrimidin-4-amine
在250mL圆底烧瓶中,将4,6-二氯嘧啶7A(10g,67.12mmol)、DIEA(17.3g,134.3mmol)和3-氨基四氢呋喃(6.8g,80.54mmol)溶于DMF(100mL)中,室温反应2h。反应结束,倒入水中,乙酸乙酯萃取,无水硫酸钠干燥干燥,减压移除有机溶剂,残留物通过(EA:PE=1:10,v/v)打浆纯化得7B,白色固体(12g,收率:90.2%)。
LC-MS m/z(ESI)=200.1[M+1].
第二步:
(6-((四氢呋喃-3-基)氨基)嘧啶-4-基)氨基甲酸叔丁酯(7C)
tert-butyl(6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)carbamate
氮气保护下,在250mL圆底烧瓶中,依次加入7B(11g,39.28mmol)、氨基甲酸叔丁酯(6.9g,58.93mmol)、X-Phos(2.8g,5.89mmol)、醋酸钯(1.32g,5.89mmol)、碳酸铯(18.5g,78.56mmol)和1,4-二氧六环(100mL),升温至100℃反应12h,反应结束,冷至室温,过滤除去固体,减压移除有机溶剂,残留物通过柱层析(PE:EA=20:1~10:1,v/v)纯化得7C,白色固体(10.2g,收率:92.7%)。
LC-MS m/z(ESI)=281.2[M+1].
第三步:
N4-(四氢呋喃-3-基)嘧啶-4,6-二胺(7D)
N4-(tetrahydrofuran-3-yl)pyrimidine-4,6-diamine
在250mL圆底烧瓶中,将7C(10g,35.71mmol)溶于二氯甲烷(100mL),冰浴下缓慢滴加三氟乙酸(30mL),滴加完毕升至室温反应2h。反应结束,倒入饱和碳酸氢钠溶液中淬灭。二氯甲烷(100mL×3)萃取,无水硫酸钠干燥,减压移除有机溶剂得7D,褐色油状物(6.1g,收率:90.5%),粗品未经进一步纯化直接用于下一步。
LC-MS m/z(ESI)=181.1[M+1].
第四步:
N4-(四氢呋喃-3-基)-N6-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶-6-基)嘧啶-4,6-二胺(7E)
N4-(tetrahydrofuran-3-yl)-N6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4,6-diamine
氮气保护下,在100mL三口瓶中依次加入7D(4.5g,25.0mmol)、4A(8.5g,30.0mmol)、碳酸铯(16.3g,50.0mmol)、Brettphos-Pd-G3(2.3g,2.5mmol)和1,4-二氧六环(50mL),升温至100℃反应12h。反应结束冷至室温,加水淬灭,乙酸乙酯(100mL×3)萃取,反相纯化得7E,白色固体(6.1g,收率57.0%)。
LC-MS m/z(ESI)=428.2[M+1].
第五步:
N4-(1H-吡唑并[4,3-c]吡啶-6-基)-N6-(四氢呋喃-3-基)嘧啶-4,6-二胺(7F)
N4-(1H-pyrazolo[4,3-c]pyridin-6-yl)-N6-(tetrahydrofuran-3-yl)pyrimidine-4,6-diamine
将化合物7E(6.0g,14.02mmol)溶于二氯甲烷(100mL),冰浴下加入三氟乙酸(16.0g,140.2mmol),缓慢升至室温反应2h。反应结束,减压移除有机溶剂,粗产物加入甲醇(100mL),搅拌下加入氨甲醇溶液(200mL,7M),反应30min,减压移除溶剂,残留物通过柱层析(DCM:MeOH=10:1,v/v)纯化得7F,灰白色固体(3.5g,收率:83.9%)。
LC-MS m/z(ESI)=298.1[M+1].
第六步:
N4-(1-(6,7-二氢-5H-环戊烷[b]吡啶-4-基)-1H-吡唑并[4,3-c]吡啶-6-基)-N6-(四氢呋喃-3-基)嘧啶-4,6-二胺(化合物7)
N4-(1-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-N6-(tetrahydrofuran-3-yl)pyrimidine-4,6-diamine
氮气保护下,在100mL三口瓶中依次加入7F(180mg,0.61mmol)、4-氯-6,7-二氢-5H-环戊二烯并[B]吡啶(112mg,0.73mmol)、碳酸铯(397mg,1.22mmol)、Brettphos-Pd-G3(55mg,0.061mmol)和1,4-二氧六环(10mL),升温至100℃反应12h,反应结束冷至室温,加水淬灭,乙酸乙酯(20mL×3)萃取,反相纯化(乙腈:水=30:70,v/v)得化合物7,白色固体(10mg,收率4.0%)。
1H NMR(400MHz,DMSO)δ9.83-9.76(m,1H),8.93(s,1H),8.50(d,J=4.3Hz,2H),8.17(s,1H),8.10(d,J=3.9Hz,1H),7.42(d,J=5.5Hz,1H),7.35(d,J=5.8Hz,1H),6.67(s,1H),4.34(s,1H),3.88-3.79(m,2H),3.71(dd,J=13.8,8.1Hz,1H),3.52(dd,J=8.8,3.8Hz,1H),3.06(dt,J=14.9,7.5Hz,4H),2.20–2.04(m,3H),1.82(d,J=4.9Hz,1H);LC-MSm/z(ESI)=415.2[M+1].
实施例8
(R)-3-氯-5-氟-4-(6-((6-((四氢呋喃-3-基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苄腈和(S)-3-氯-5-氟-4-(6-((6-((四氢呋喃-3-基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苄腈(化合物8-1和8-2)
(R)-3-chloro-5-fluoro-4-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile and(S)-3-chloro-5-fluoro-4-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
第一步:
3-氯-5-氟-4-(6-((6-((四氢呋喃-3-基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苄腈(化合物8)
3-chloro-5-fluoro-4-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
在100mL圆底烧瓶中,依次加入7F(2.5g,8.39mmol)、碳酸钾(2.3g,16.78mmol)、3-氯-4,5-二氟苯腈(1.53g,8.81mmol)和NMP(30mL),升温至70℃反应1h,反应结束倒入水中,过滤得固体,通过乙酸乙酯(5mL)打浆纯化得化合物8,白色固体(650mg,收率:17.2%,UPLC=98.71%)。
LC-MS m/z(ESI)=451.1[M+1].
第二步:
(R)-3-氯-5-氟-4-(6-((6-((四氢呋喃-3-基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苄腈和(S)-3-氯-5-氟-4-(6-((6-((四氢呋喃-3-基)氨基)嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苄腈(化合物8-1和8-2)
(R)-3-chloro-5-fluoro-4-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile and(S)-3-chloro-5-fluoro-4-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
化合物8(650mg,1.44mmol)通过SFC拆分得到化合物8-1(200mg,收率30.76%,RT=12.567min,100%ee,UPLC=98.69%)和化合物8-2(130mg,收率20.0%,RT=14.701min,100%ee,UPLC=98.94%)。手性HPLC(AD)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物8-1:1H NMR(400MHz,DMSO)δ9.76(s,1H),8.94(s,1H),8.57(s,1H),8.39(s,1H),8.34(dd,J=9.3,1.6Hz,1H),8.11(s,1H),7.62(s,1H),7.33(d,J=5.7Hz,1H),6.64(s,1H),4.33(s,1H),3.89–3.76(m,2H),3.76–3.66(m,1H),3.51(dd,J=8.8,3.9Hz,2H),2.14(dd,J=12.6,7.5Hz,1H),1.88–1.72(m,1H);LCMS m/z(ESI)=441.2[M+1].
化合物8-2:1H NMR(400MHz,DMSO)δ9.77(s,1H),8.94(s,1H),8.57(s,1H),8.39(d,J=1.5Hz,1H),8.34(dd,J=9.3,1.6Hz,1H),8.11(s,1H),7.62(s,1H),7.33(d,J=5.8Hz,1H),6.64(s,1H),4.34(s,1H),3.91–3.76(m,2H),3.75–3.65(m,1H),3.51(dd,J=8.8,3.9Hz,2H),2.21–2.08(m,1H),1.91–1.74(m,1H);LCMS m/z(ESI)=441.2[M+1].
实施例9
(R)-5-(6-(6-(四氢呋喃-3-基)氨基)嘧啶-4-基氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-甲腈和(S)-5-(6-(6-(四氢呋喃-3-基)氨基)嘧啶-4-基氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-甲腈(化合物9-1和9-2)
(R)-5-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrileand(S)-5-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
第一步:
5-(6-(6-(四氢呋喃-3-基)氨基)嘧啶-4-基氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-甲腈(化合物9)
5-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
氮气保护下,在100mL三口瓶中依次加入7F(500mg,1.68mmol)、中间体3(310mg,2.02mmol)、碳酸铯(1.1g,3.36mmol)、Brettphos-Pd-G3(153mg,0.17mmol)和1,4-二氧六环(10mL),升温至100℃反应12h,反应结束冷至室温,加水淬灭,乙酸乙酯(20mL×3)萃取,反相(乙腈:水=30:70,v/v)纯化得化合物9,白色固体(256mg,收率35.9%)。
LC-MS m/z(ESI)=425.2[M+1].
第二步:
(R)-5-(6-(6-(四氢呋喃-3-基)氨基)嘧啶-4-基氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-甲腈和(S)-5-(6-(6-(四氢呋喃-3-基)氨基)嘧啶-4-基氨基)-1H-吡唑并[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-甲腈(化合物9-1和9-2)
(R)-5-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrileand(S)-5-(6-((6-((tetrahydrofuran-3-yl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
化合物9(256mg,0.604mmol)通过SFC拆分得到化合物9-1(70mg,收率27.3%,RT=24.197min,100%ee,UPLC=98.39%)和化合物9-2(67mg,收率26.1%,RT=25.873min,100%ee,UPLC=97.9%)。手性HPLC(AS)流动相:正己烷/乙醇=90/10;柱温:35℃;柱压:80bar;流速:1mL/min;检测器信号通道:215nm@4.8nm;二极管阵列检测器起止波长:200~400nm。
化合物9-1:1H NMR(400MHz,DMSO)δ9.89(s,1H),8.91(s,1H),8.52(s,1H),8.39(s,1H),8.25(s,1H),7.88(d,J=8.6Hz,1H),7.74(d,J=8.6Hz,1H),7.37(d,J=5.7Hz,1H),6.64(s,1H),4.36(s,1H),3.90–3.78(m,2H),3.76–3.67(m,1H),3.60–3.50(m,3H),3.40(d,J=3.8Hz,3H),2.24–2.09(m,1H),1.89–1.75(m,1H);LCMS m/z(ESI)=441.2[M+1].
化合物9-2:1H NMR(400MHz,DMSO)δ9.94(s,1H),8.92(s,1H),8.53(s,1H),8.37(s,1H),8.26(s,1H),7.89(d,J=8.7Hz,1H),7.75(d,J=8.7Hz,1H),7.43(s,1H),6.63(s,1H),4.37(s,1H),3.93–3.78(m,2H),3.76–3.66(m,1H),3.61–3.51(m,3H),3.40(d,J=3.6Hz,4H),2.24–2.10(m,1H),1.83(d,J=4.8Hz,1H);LCMS m/z(ESI)=425.2[M+1].
实施例10
3-氯-5-氟-4-(6-((1s,3s)-3-羟基环丁基)氨基嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苯甲腈(化合物10)
3-chloro-5-fluoro-4-(6-((6-(((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
第一步:
(1s,3s)-3-((6-氯嘧啶-4-基)氨基)环丁醇(10A)
(1s,3s)-3-((6-chloropyrimidin-4-yl)amino)cyclobutan-1-ol
在250mL圆底烧瓶中,将化合物4,6-二氯嘧啶7A(3g,20mmol)、DIEA(7.7g,60mmol)和(1s,3s)-3-氨基环丁烷-1-醇(1.74g,20mmol)溶于DMF(30mL)中,室温反应2h。反应结束,倒入水中,乙酸乙酯萃取,无水硫酸钠干燥,减压移除有机溶剂,残留物通过(EA:PE=1:10,v/v)打浆纯化得10A,白色固体(2.3g,收率:58%)。
LC-MS m/z(ESI)=199.05[M+1].
第二步:
叔丁基(6-((1s,3s)-3-羟基环丁基)氨基)嘧啶-4-基氨基甲酸酯(10B)
tert-butyl(6-(((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)carbamate
氮气保护下,在250mL圆底烧瓶中,依次加入10A(2.3g,11.6mmol)、氨基甲酸叔丁酯(2.8g,23.2mmol)、X-Phos(0.86g,2.32mmol)、醋酸钯(260mg,1.16mmol)、碳酸铯(9.5g,29mmol)和1,4-二氧六环(50mL),升温至100℃反应12h,反应结束,冷至室温,过滤除去固体,减压移除有机溶剂,残留物通过柱层析(PE:EA=20:1~10:1,v/v)纯化得10B,白色固体(2.1g,收率:64.6%)。
LC-MS m/z(ESI)=280.2[M+1].
第三步:
叔丁基(6-((1s,3s)-3-((叔丁基二甲基硅氧基)环丁基)氨基)嘧啶-4-基氨基甲酸酯(10C)
N4-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)pyrimidine-4,6-diamine
在100mL圆底烧瓶中,将10B(2.1g,7.5mmol)溶于四氢呋喃(30mL),冰浴下加入氢化钠(360mg,15mmol),叔丁基二甲基氯硅烷(2.6g,15mmol)加料完毕升至室温反应2h,反应结束,倒入饱和碳酸氢钠溶液中淬灭,乙酸乙酯(100mL×3)萃取,无水硫酸钠干燥,减压移除有机溶剂得10C,淡黄色固体(1.5g,收率:90.5%),粗品,未纯化直接用于下一步。
LC-MS m/z(ESI)=394.2[M+1].
第四步:
N4-((1s,3s)-3-((叔丁基二甲基硅基)氧基)环丁基)嘧啶-4,6-二胺(10D)
N4-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)pyrimidine-4,6-diamine
在250mL圆底烧瓶中,将10C(1.5g,3.8mmol)溶于二氯甲烷(40mL),氮气保护冰浴下缓慢滴加溴化锌(4.28g,19mmol),滴加完毕升至室温反应2h,反应结束,倒入饱和碳酸氢钠溶液中淬灭,二氯甲烷(100mL×3)萃取,无水硫酸钠干燥,减压移除有机溶剂得10D,黄色固体(1g,收率:93.5%),粗品未纯化直接用于下一步。
LC-MS m/z(ESI)=294.2[M+1].
第五步:
N4-((1s,3s)-3-((叔丁基二甲基硅基)氧基)环丁基)-N6-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶-6-基)嘧啶-4,6-二胺(10E)
N4-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4,6-diamine
氮气保护下,在100mL三口瓶中依次加入10D(200mg,20.67mmol)、4A(200mg,0.67mmol)、碳酸铯(549mg,1.68mmol)、Brettphos-Pd-G3(60.7mg,0.067mmol)和1,4-二氧六环(10mL),升温至100℃反应12h,反应结束冷至室温,加水淬灭,乙酸乙酯(10mL×3)萃取,反相纯化得10E,白色固体(130mg,收率36.0%)。
LC-MS m/z(ESI)=541.3[M+1].
第六步:
N4-((1s,3s)-3-((叔丁基二甲基硅基)氧基)环丁基)-N6-(1H-吡唑并[4,3-c]吡啶-6-基)嘧啶-4,6-二胺(10F)
N4-((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N6-(1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4,6-diamine
将化合物10E(130mg,0.24mmol)溶于二氯甲烷(9mL),冰浴下加入三氟乙酸(3mL),缓慢升至室温反应2h。反应结束,减压移除有机溶剂,粗产物加入甲醇(10mL),搅拌下加入氨甲醇溶液(10mL,7M),反应30min,得粗品10F,褐色油状物(130mg,收率:99%)。
LC-MS m/z(ESI)=411.2[M+1].
第七步:
4-(6-((6-((1s,3s)-3-((叔丁基二甲基硅氧基)环丁基)氨基)嘧啶-4-基)氨基)-1H-吡唑[4,3-c]吡啶-1-基)-3-氯-5-氟苯甲腈(10G)
4-(6-((6-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)amino)pyrimidin-4-yl)amin o)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-chloro-5-fluorobenzonitrile
在100mL圆底烧瓶中,依次加入10F(130mg,0.31mmol)、碳酸钾(107mg,0.79mmol)、3-氯-4,5-二氟苯腈(56mg,0.78mmol)和氮甲基吡咯烷酮(5mL)。升温至70℃反应1h,反应结束后将反应液倒入水中,萃取得10G,未纯化,黄色油状物(110mg)。
1H NMR(400MHz,DMSO)δ9.83–9.76(m,1H),8.93(s,1H),8.50(d,J=4.3Hz,2H),8.17(s,1H),8.10(d,J=3.9Hz,1H),7.42(d,J=5.5Hz,1H),7.35(d,J=5.8Hz,1H),6.67(s,1H),4.34(s,1H),3.88–3.79(m,2H),3.71(dd,J=13.8,8.1Hz,1H),3.52(dd,J=8.8,3.8Hz,1H),3.06(dt,J=14.9,7.5Hz,4H),2.20–2.04(m,3H),1.82(d,J=4.9Hz,1H);LC-MSm/z(ESI)=564.2[M+1].
第八步
3-氯-5-氟-4-(6-((1s,3s)-3-羟基环丁基)氨基嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苯甲腈(化合物10)
3-chloro-5-fluoro-4-(6-((6-(((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
在100mL圆底烧瓶中,加入10G(110mg,0.19mmol)四氢呋喃(5mL)溶解,加入三乙胺三氢氟酸盐(64.7mg,0.38mmol),反应0.5h。反应完全,反相纯化(乙腈:水=30:70,v/v)得化合物10,白色固体(78mg,收率:91%,UPLC=96.72%)。
1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.91(s,1H),8.62(s,1H),8.47(s,1H),8.22(s,1H),7.91(d,1H),7.75(d,1H),7.13(s,1H),6.45–6.39(m,1H),4.75(s,1H),3.50–3.45(m,1H),2.31–2.22(m,2H),2.03–1.93(m,2H);LC-MS m/z(ESI)=450.1[M+1].
实施例11
3-氯-5-氟-4-(6-((1r,3r)-3-羟基环丁基)氨基嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苯甲腈(化合物11)
3-chloro-5-fluoro-4-(6-((6-(((1r,3r)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
第一步:
(1r,3r)-3-((6-氯嘧啶-4-基)氨基)环丁醇(11A)
(1s,3s)-3-((6-chloropyrimidin-4-yl)amino)cyclobutan-1-ol
在250mL圆底烧瓶中,将化合物4,6-二氯嘧啶7A(3g,20mmol)、DIEA(7.7g,60mmol)和(1r,3r)-3-氨基环丁烷-1-醇(1.74g,20mmol)溶于DMF(30mL)中,室温反应2h。反应结束,倒入水中,乙酸乙酯萃取,无水硫酸钠干燥干燥,减压移除有机溶剂,残留物通过(EA:PE=1:10,v/v)打浆纯化得11A,白色固体(2.6g,收率63.2%)。
LC-MS m/z(ESI)=199.05[M+1].
第二步:
叔丁基(6-((1r,3r)-3-羟基环丁基)氨基)嘧啶-4-基氨基甲酸酯(11B)
tert-butyl(6-(((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)carbamate
氮气保护下,在250mL圆底烧瓶中,依次加入11A(2.6g,13.2mmol)、氨基甲酸叔丁酯(2.9g,26.4mmol)、X-Phos(1.02g,2.64mmol)、醋酸钯(294mg,1.32mmol)、碳酸铯(9.5g,29mmol)和1,4-二氧六环(50mL),升温至100℃反应12h。冷至室温,过滤除去固体,减压移除有机溶剂,残留物通过柱层析(PE:EA=20:1~5:1,v/v)纯化得11B,白色固体(2.3g,收率:67.3%)。
LC-MS m/z(ESI)=280.2[M+1].
第三步:
叔丁基(6-((1s,3s)-3-((叔丁基二甲基硅氧基)环丁基)氨基)嘧啶-4-基氨基甲酸酯(11C)
N4-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)pyrimidine-4,6-diamine
在100mL圆底烧瓶中,将11B(2.3g,8.5mmol)溶于四氢呋喃(30mL),冰浴下加入氢化钠(392mg,17mmol),叔丁基二甲基氯硅烷(2.9g,17mmol)加料完毕升至室温反应2h。冰浴冷却下将反应液倒入饱和碳酸氢钠溶液(20mL)中淬灭,乙酸乙酯(100mL×3)萃取,无水硫酸钠干燥,减压移除有机溶剂得11C,淡黄色固体(1.7g,收率:38.2%),粗品未纯化直接用于下一步。
LC-MS m/z(ESI)=394.2[M+1].
第四步:
N4-((1r,3r)-3-((叔丁基二甲基硅基)氧基)环丁基)嘧啶-4,6-二胺(10D)
N4-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)pyrimidine-4,6-diamine
在250mL圆底烧瓶中,将11C(1.7g,4.0mmol)溶于二氯甲烷(40mL),氮气保护冰浴下缓慢滴加溴化锌(4.63g,20mmol),滴加完毕升至室温反应2h。倒入饱和碳酸氢钠溶液中(30ml)淬灭,DCM(100mL×3)萃取,无水硫酸钠干燥,减压移除有机溶剂得11D,黄色固体(1.3g,收率:96.5%),粗品,未纯化直接用于下一步。
LC-MS m/z(ESI)=294.2[M+1].
第五步:
N4-((1r,3r)-3-((叔丁基二甲基硅基)氧基)环丁基)-N6-(1-((2-(三甲基硅基)乙氧基)甲基)-1H-吡唑并[4,3-c]吡啶-6-基)嘧啶-4,6-二胺(11E)
N4-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N6-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4,6-diamine
氮气保护下,在100mL三口瓶中依次加入11D(200mg,0.67mmol)、4A(200mg,0.67mmol)、碳酸铯(549mg,1.68mmol)、Brettphos-Pd-G3(60.7mg,0.067mmol)和1,4-二氧六环(10mL),升温至100℃反应12h。反应结束冷至室温,加水淬灭,乙酸乙酯(10mL×3)萃取,反相纯化得11E,白色固体(110mg,收率29.6%)。
LC-MS m/z(ESI)=541.3[M+1].
第六步:
N4-((1r,3r)-3-((叔丁基二甲基硅基)氧基)环丁基)-N6-(1H-吡唑并[4,3-c]吡啶-6-基)嘧啶-4,6-二胺(11F)
N4-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-N6-(1H-pyrazolo[4,3-c]pyridin-6-yl)pyrimidine-4,6-diamine
将化合物11E(110mg,0.20mmol)溶于DCM(9mL),冰浴下加入三氟乙酸(3mL),缓慢升至室温反应2h。反应结束,减压移除有机溶剂,粗产物加入甲醇(10mL),搅拌下加入氨甲醇溶液(10mL,7M),反应30min,得粗品11F,褐色油状物(110mg,收率:99%)。
LC-MS m/z(ESI)=411.2[M+1].
第七步:
4-(6-((6-((1r,3r)-3-((叔丁基二甲基硅氧基)环丁基)氨基)嘧啶-4-基)氨基)-1H-吡唑[4,3-c]吡啶-1-基)-3-氯-5-氟苯甲腈(11G)
4-(6-((6-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)-3-chloro-5-fluorobenzonitrile
在100mL圆底烧瓶中,依次加入11F(110mg,0.29mmol)、碳酸钾(107mg,0.79mmol)、3-氯-4,5-二氟苯腈(56mg,0.78mmol)和氮甲基吡咯烷酮(5mL),升温至70℃反应1h,反应结束倒入水中,萃取得11G,未纯化,黄色油状物(110mg)。
LC-MS m/z(ESI)=564.2[M+1].
第八步
3-氯-5-氟-4-(6-((1r,3r)-3-羟基环丁基)氨基嘧啶-4-基)氨基)-1H-吡唑并[4,3-c]吡啶-1-基)苯甲腈(化合物11)
3-chloro-5-fluoro-4-(6-((6-(((1r,3r)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)benzonitrile
在100mL圆底烧瓶中,加入11G(110mg,0.19mmol),四氢呋喃(5mL)溶解,加入三乙胺三氢氟酸盐(64.7mg,0.38mmol),反应0.5h。反应完全后除去溶剂,反相纯化(乙腈:水=30:70,v/v)得化合物11(白色固体58mg,收率:75%,UPLC=96.97%)。
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.87(s,1H),8.62(s,1H),8.44(s,1H),8.25(s,1H),7.93(d,1H),7.76(d,1H),7.15(s,1H),6.42–6.38(m,1H),4.76(s,1H),3.56–3.47(m,1H),2.31–2.25(m,2H),2.02–1.96(m,2H);LC-MS m/z(ESI)=450.1[M+1].
实施例12
第一步
5-(6-((6-((1s,3s)-3-((叔丁基二甲基硅氧基)环丁基)氨基)嘧啶-4-基)氨基)-1H-吡唑[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-碳三烯(12A)
5-(6-((6-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
氮气保护下,在100mL三口瓶中依次加入10F(130mg,0.31mmol)、中间体3(128mg,0.62mmol)、碳酸铯(202mg,0.62mmol)、Brettphos-Pd-G3(27mg,0.031mmol)和1,4-二氧六环(10mL)。升温至100℃反应12h,TLC监控反应结束,冷却至室温。加水淬灭,乙酸乙酯(20mL×3)萃取,反相纯化(乙腈:水=30:70,v/v)得12A,白色固体(52mg,收率10.5%)。
LC-MS m/z(ESI)=538.3[M+1].
第二步
5-(6-((6-((1s,3s)-3-羟基环丁基)氨基)嘧啶-4-基)氨基)-1H-吡唑[4,3-c]吡啶-1-基)双环[4.2.0]辛-1(6),2,4-三烯-2-碳三烯(化合物12)
5-(6-((6-(((1s,3s)-3-hydroxycyclobutyl)amino)pyrimidin-4-yl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)bicyclo[4.2.0]octa-1(6),2,4-triene-2-carbonitrile
在100mL圆底烧瓶中,加入12A(52mg,0.1mmol)四氢呋喃(5mL)溶解,加入三乙胺三氢氟酸盐(60mg,0.3mmol),反应0.5h反应完全,反相纯化(乙腈:水=30:70,v/v)得化合物12,白色固体(20mg,收率:41%,UPLC=95.22%)。
1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.87(d,1H),8.62(s,1H),8.44(s,1H),8.25(s,1H),7.93(d,1H),7.76(d,1H),7.15(d,1H),6.36–6.28(m,1H),4.76(s,1H),3.42–3.38(m,1H),3.28(s,4H),2.27–2.20(m,2H),2.05–1.98(m,2H);LC-MS m/z(ESI)=424.2[M+1].
生物测试例
1.TYK2的酶活性(ADP-Glo)检测实验
使用重组的人TYK2蛋白(Carna biosciences,08-147)其催化结构域为氨基酸871-1187及相应的底物IRS1(Signalchem,I40-58-1MG)。在白色384孔板(Perkin Elmer,6007290)中,加入溶于反应缓冲液(Promega,V915B)的10ng TYK2蛋白和1μL待测化合物(化合物最高浓度为20/10μM,进行5倍梯度稀释,稀释10个浓度,双复孔),室温反应120min,反应体积为5μL。每孔加入5μL ADP Glo试剂(Promega,V912B)终止反应,消耗所有剩余ATP。室温孵育40min,加入10μL溶解于酶检测缓冲液(Promega,V913B)的酶检测试剂(Promega,V914B),在荧光素酶/荧光素反应中检测新生成的ATP的量(ADP转化为ATP)。室温孵育30min,用Envis ion多功能酶标仪读取发光值。最后使用XLFIT软件用非线性拟合公式得到化合物的IC50(半数抑制浓度)。酶活性由相对光量数值(RUL,relative light units)计算得出。待测化合物抑制酶活的能力由抑制率抑制率体现。其结果如表1所示。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
X:化合物浓度log值
Y:抑制率(%)
抑制率(%)=[1-(待测化合物RUL-阴性对照RUL平均值)/(阳性对照平均值-阴性对照平均值)]×100%.
阴性对照:无TYK2酶
阳性对照:无抑制剂
表1 TYK2酶活性实验
结论:本发明化合物对TYK2的酶活性具有显著的抑制作用。
2.HEK-BlueTMIL-23细胞的SEAP报告基因检测实验
在384孔细胞培养板(Corining,3701)铺入细胞,将培养板放置于37℃,5%CO2恒温培养箱培养24h,将稀释好的待测化合物(化合物最高浓度为20/10μM,进行5倍梯度稀释,稀释10个浓度,双复孔)加入细胞中,37℃,5%CO2孵育1h后加入稀释好的刺激因子IL23(R&D,1290-IL-010),继续放置于37℃,5%CO2恒温培养箱共孵育24h。另取384孔细胞培养板(Corining,3701),加入配置好的QU ANTI-BlueTMSolution(Invitrogen,rep-qbs3),再加入孵育后的细胞上清,放置于37℃,5%CO2恒温培养箱反应1h,用Envision多功能酶标仪读取发光值,最后使用XLFIT软件用非线性拟合公式得到化合物的IC50(半数抑制浓度)。其结果如表2所示。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
X:化合物浓度log值
Y:抑制率(%)
抑制率(%)=100×(阴性对照平均值-化合物读值)/(阴性对照平均值-阳性对照平均值)
阴性对照:DMSO
阳性对照:无IL-23
表2 HEK-BlueTMIL-23细胞的SEAP报告基因检测实验
结论:本发明化合物在细胞中对IL-23通路有显著的抑制活性。
3.HEK-DualTMIFNγ细胞的SEAP报告基因检测实验
在384孔细胞培养板(Corining,3701)铺入细胞,将培养板放置于37℃,5%CO2恒温培养箱培养24h,将稀释好的待测化合物(化合物最高浓度为20/10μM,进行5倍梯度稀释,稀释10个浓度,双复孔)加入细胞中,37℃,5%CO2孵育1h后加入稀释好的刺激因子IFNγ(R&D,285-IF-100),继续放置于37℃,5%CO2恒温培养箱共孵育24h。另取384孔细胞培养板(Corining,3701),加入配置好的QUAN TI-BlueTMSolution(Invitrogen,rep-qbs3),再加入孵育后的细胞上清,放置于37℃,5%CO2恒温培养箱反应1h,用Envision多功能酶标仪读取发光值,最后使用XLFIT软件用非线性拟合公式得到化合物的IC50(半数抑制浓度)。
Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)×HillSlope))
X:化合物浓度log值
Y:抑制率(%)
抑制率(%)=100×(阴性对照平均值-化合物读值)/(阴性对照平均值-阳性对照平均值)
阴性对照:DMSO
阳性对照:无IFNγ
结果:化合物1和化合物2的IC50均大于10μM。
结论:本发明化合物在细胞中对IFNγ通路没有抑制活性,表明本发明化合物对TYK2的抑制作用具有高选择性。
本发明说明书对具体实施方案进行了详细描述,本领域技术人员应认识到,上述实施方案是示例性的,不能理解为对本发明的限制,对于本领域技术人员来说,在不脱离本发明原理的前提下,通过对本发明进行若干改进和修饰,这些改进和修饰获得技术方案也落在本发明的权利要求书的保护范围内。
Claims (8)
1.一种通式(I)所示的化合物或者其立体异构体:
其中:
R1选自C1-6烷基、C1-6烷氧基、C3-8环烷基、C3-8杂环烷基或者NHR2,所述的C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、C1-6烷基、C3-8环烷基或者C3-8杂环烷基的取代基取代;
R2选自C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基,所述的C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基、C1-6烷基、C3-8环烷基或者C3-8杂环烷基的取代基取代;
A选自苯基、萘基、5-6元芳香杂环或者C9-11芳香杂双环;
X1、X2、X3各自独立地为N或者CRX;
RX选自H、卤素、羟基、NH2、氰基、C1-6烷基、C1-6烷氧基或者C3-8环烷基;
B为C3-8环烷基。
2.根据权利要求1所述的化合物或者其立体异构体,所述R1选自C1-6烷基、C1-6烷氧基或者NHR2,所述的C1-6烷基、C1-6烷氧基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
所述R2选自C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基,所述的C1-6烷基、C1-6烷氧基、C3-8环烷基或者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
A选自苯基、萘基、5-6元芳香杂环;
RX选自H、卤素、羟基、NH2或氰基;
B为C3-6环烷基。
3.根据权利要求1所述的化合物或者其立体异构体,所述R1选自C1-6烷基或者NHR2,所述的C1-6烷基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
所述R2选自C1-6烷基或者C3-8杂环烷基,所述的C1-6烷基者C3-8杂环烷基任选地进一步被1个或者多个选自卤素、羟基的取代基取代;
A选自5-6元芳香杂环;
RX选自H、卤素、羟基、NH2或氰基。
7.一种药物组合物,所述药物组合物包括:
(1)权利要求1~6任一项所述的化合物或其立体异构体;
(2)任选的一种或者多种其他活性成分;以及
(3)药学上可接受的载体和/或赋形剂。
8.权利要求7所述的药物组合物或者权利要求1~6任一项所述的化合物或其立体异构体,用于预防和/或治疗自身免疫性疾病。
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TW202115060A (zh) * | 2019-08-19 | 2021-04-16 | 比利時商葛萊伯格有限公司 | 用於治療發炎病症之新穎化合物及其醫藥組合物 |
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CN106459048A (zh) * | 2014-05-14 | 2017-02-22 | 辉瑞公司 | 吡唑并吡啶类和吡唑并嘧啶类 |
TW202115060A (zh) * | 2019-08-19 | 2021-04-16 | 比利時商葛萊伯格有限公司 | 用於治療發炎病症之新穎化合物及其醫藥組合物 |
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