CN115843296B - Cdk9抑制剂及其用途 - Google Patents
Cdk9抑制剂及其用途 Download PDFInfo
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- CN115843296B CN115843296B CN202180049342.0A CN202180049342A CN115843296B CN 115843296 B CN115843296 B CN 115843296B CN 202180049342 A CN202180049342 A CN 202180049342A CN 115843296 B CN115843296 B CN 115843296B
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
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Abstract
本申请提供一种式(I)化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,以及其用于制备由CDK9介导的疾病药物中的用途。
Description
技术领域
本申请属于化学医药领域,具体涉及一种CDK9抑制剂及其用途。
背景技术
细胞周期蛋白依赖性激酶(CDK)是与各种细胞周期蛋白亚基相关的丝氨酸-苏氨酸蛋白激酶。现有超过20种CDK激酶家族成员,其中CDK1、CDK2、CDK3、CDK4和CDK6被认为是细胞周期调控因子;CDK7、CDK8、CDK9和CDK11被认为是转录调控因子。因此,CDK参与了包括细胞周期控制、细胞凋亡、神经元生理学、分化和转录的调控等多种关键的生理过程。大量研究证据表明,CDK在癌症、心血管病症、炎症性疾病、神经退行性疾病和病毒性疾病在内的各种疾病的产生和发展过程中起着关键作用,因而也成为了这些相关疾病创新药物研发非常有效的药物靶标。
细胞周期蛋白依赖性激酶9(CDK9)参与组成正性转录延长因子(P-TEFb),在RNA转录调控过程中发挥关键作用。尤其是对于细胞内半衰期较短,快速降解的蛋白,通过对CDK9激酶活性的抑制来抑制合成这些蛋白所必需的基因转录,进而达到下调这些蛋白的细胞内表达水平的目的。其中就包括关键的致癌基因cMYC和重要的细胞凋亡抑制基因Mcl-1。这两类基因所表达的cMYC致癌蛋白和Mcl-1抗凋亡蛋白对于多种肿瘤细胞的存活和增殖起着关键的促进作用,因此CDK9已经成为广受关注的癌症治疗的重要靶标。
早期,CDK抑制剂的研究主要是非选择性CDK抑制剂的研究和开发(“中国药科大学学报”2017,2,233-241),然而非选择性抑制剂普遍具有对第一类细胞周期调控CDK激酶具有很强的抑制作用,进而对非肿瘤细胞的正常分裂产生明显的抑制作用,在临床研究中体现出有较大的毒性,易产生副作用。因此,有必要进行选择性CDK抑制剂的研究,以便具有更好的选择性和更好的成药性,来降低毒性和减少不良作用。
目前,已有2个CDK9选择性药物处于临床研究阶段。一个是阿斯利康公司的AZD4573(WO2017001354A1),处于临床一期,为针对血液瘤进行的临床研究(NCT03263637);另一个是拜耳公司的BAY 1251152,同样处于临床一期,为针对血液瘤(NCT02745743)和实体瘤(NCT02635672)进行的临床研究。
CDK9选择性抑制剂仍然需要更多的研究,以提供具有良好活性和选择性的候选化合物。
发明内容
本申请公开了一类可作为CDK9选择性抑制剂的化合物以及其在制备预防或治疗CDK9介导的相关疾病药物中的用途。
一方面,本申请提供一种通式(I)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中环A为包含1-3个杂原子的5-10元杂芳基;
环B为环烷基或包含1-3个杂原子的5-10元杂环烷基;
A1和A2各自独立地选自C或N;
Z选自-C(O)-、-CH2-、-S(O)2-、-NH-或-C(O)NH-;
R1选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OR4、-OC(O)R4、-OC(O)OR4、-OC(O)NR4R5、-NR4R5、-SR4、-S(O)R4、-S(O)2R4、-(CH2)nOH或含有0-3个杂原子的3-10元饱和或非饱和环,其中,所述含有0-3个杂原子的3-10元饱和或非饱和环可选地被1-3个R4取代;
R2选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OR4、-OC(O)R4、-OC(O)OR4、-OC(O)NR4R5、-NR4R5、-(CH2)nNR4R5、-SR4、-S(O)R4、-S(O)2R4或-(CH2)nOH;
R3选自氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OR4、-OC(O)R4、-OC(O)OR4、-OC(O)NR4R5、-NR4R5、-(CH2)nNR4R5、-SR4、-S(O)R4、-S(O)2R4或-(CH2)nOH;
每个R4和R5分别独立地选自氢、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6杂环烷基、卤代C3-C6杂环烷基、卤素、=O、-(CH2)nC(O)NR6R7、-C(O)R6、-C(O)OR6、-OR6、-OC(O)R6、-OC(O)OR6、-OC(O)NR6R7、-(CH2)nNR6R7、-SR6、-S(O)R6、-(CH2)nS(O)2R6、-(CH2)nOH或-(CH2)nCN,或者,R4和R5与相邻的原子一起形成含有0-3个杂原子的5-6元饱和或非饱和环,其中,所述含有0-3个杂原子的5-6元饱和或非饱和环可选地被1-3个R6取代;
每个R6和R7分别独立地选自氢、卤素、羰基、羟基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基或卤代C3-C6环烷基;并且
每个m和n分别独立地选自0、1、2或3。
在一些实施方案中,通式(I)为通式(Ia)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中,环B、A1、A2、Z、R1、R2、R3、m和n如前述所定义。
在另一些实施方案中,通式(I)为通式(Ib)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中,环B、A1、A2、Z、R1、R2、R3和n如前述所定义。
在另一些实施方案中,通式(I)为通式(Ic)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中,A1、A2、Z、R1、R2、R3和n如前述所定义,优选地,
A1和A2各自独立地选自C或N;
Z选自-C(O)-、-CH2-或-NH-;
R1选自氢、C1-C6烷基、卤代C1-C6烷基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)OR4、-OR4或含有0-3个杂原子的3-10元饱和或非饱和环(作为非限制性的实例,含有0-3个杂原子的3-10元饱和或非饱和环可以为);
R2选自氢、C1-C6烷基、卤代C1-C6烷基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4或-OR4;
R3选自氢、C1-C6烷基、卤代C1-C6烷基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OR4、-NR4R5或-(CH2)nNR4R5;
每个R4和R5分别独立地选自氢、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6杂环烷基、卤代C3-C6杂环烷基、卤素、-C(O)R6、-C(O)OR6、-OR6或-(CH2)nS(O)2R6,或者,R4和R5与相邻的原子一起形成含有0-3个杂原子的5-6元饱和或非饱和环,其中所述含有0-3个杂原子的5-6元饱和或非饱和环可选地被1-3个R6取代(作为非限制性的实例,R4和R5与相邻的原子一起形成含有0-3个杂原子的5-6元饱和或非饱和环可以为);
每个R6和R7分别独立地选自氢、卤素、羰基、羟基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基或卤代C3-C6环烷基;并且
每个n独立地选自0、1、2或3。
在另一些实施方案中,通式(I)为通式(Id)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中,Z、R1、R2和R3如前述所定义,优选地,
Z选自-C(O)-、-CH2-或-NH-;
R1选自氢、C1-C6烷基、卤代C1-C6烷基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)OR4、-OR4或含有0-3个杂原子的3-10元饱和或非饱和环(作为非限制性的实例,含有0-3个杂原子的3-10元饱和或非饱和环可以为);
R2选自氢、C1-C6烷基、卤代C1-C6烷基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4或-OR4;
R3选自氢、C1-C6烷基、卤代C1-C6烷基、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OR4、-NR4R5或-(CH2)nNR4R5;
每个R4和R5分别独立地选自氢、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6杂环烷基、卤代C3-C6杂环烷基、卤素、-C(O)R6、-C(O)OR6、-OR6或-(CH2)nS(O)2R6,或者,R4和R5与相邻的原子一起形成含有0-3个杂原子的5-6元饱和或非饱和环,其中,所述含有0-3个杂原子的5-6元饱和或非饱和环可选地被1-3个R6取代(作为非限制性的实例,R4和R5与相邻的原子一起形成含有0-3个杂原子的5-6元饱和或非饱和环可以为);
每个R6和R7分别独立地选自氢、卤素、羰基、羟基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基或卤代C3-C6环烷基;并且
每个n独立地选自0、1、2或3。
在另一些实施方案中,通式(I)为通式(Ie)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
其中,R1和R3如前述所定义。
在另一些实施方案中,R1选自氰基、硝基、卤素、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、单氟甲基、甲基、甲氧基或乙氧基。
在另一些实施方案中,R3选自卤素、-CH2NHC(O)CH3或-CH2NH2。
在另一些实施方案中,所述的通式(I)所示的化合物选自:
另一方面,本申请还提供前述化合物、其异构体或其药学上可接受的盐用于制备由CDK介导的疾病药物中的用途。
在一些实施方案中,所述CDK介导的疾病为CDK9介导的疾病。
在另一些实施方案中,所述CDK介导的疾病为癌症、心血管病症、炎症性疾病、神经退行性疾病或病毒性疾病。
在另一些实施方案中,所述CDK介导的疾病为癌症。
在另一些实施方案中,所述癌症为白血病、淋巴瘤、多发性骨髓瘤、肺癌、前列腺癌、头颈癌、乳腺癌、胰腺癌、结直肠癌或黑色素瘤。
另一方面,本申请还提供一种药物组合物,其包含治疗有效量的前述化合物、其异构体或其药学上可接受的盐;以及药学上可接受的载体或赋形剂。
术语:
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“异构体”包括给定结构的对映异构形式、非对映异构形式和几何(或构象)异构形式。例如,本申请包括每个不对称中心的R和S构型、Z和E双键异构体、Z和E构象异构体、单一立体化学异构体及对映异构体、非对映异构体和几何(或构象)异构体混合物。
术语“药学上可接受的盐”指,诸如其酸加成盐和/或碱盐。合适的酸加成盐由酸形成,其形成无毒盐,例如盐酸盐/氯化物。合适的碱盐由碱形成,其形成无毒盐,例如钙盐和钠盐。还可形成酸和碱的半盐,例如半硫酸盐和半钙盐。
术语“治疗有效量”是指本申请化合物的以下量,其(i)治疗具体的疾病、病症或障碍;(ii)减轻、缓解或消除具体的疾病、病症或障碍的一种或多种症状;或(iii)预防或延迟本申请所述具体的疾病、病症或障碍的一种或多种症状的发作。
术语“药学上可接受的载体或赋形剂”是指不破坏用其配制的化合物的药理活性的无毒载体、辅料或媒介物。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更优选含有1至6个碳原子的烷基。含有1至6个碳原子的低级烷基的非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基如上所定义。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子(例如3、4、5或6个碳原子),最优选包含5至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。
术语“稠环烷基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三环,更优选为5元/5元或5元/6元双环烷基。
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更优选为双环或三环。
术语“杂环烷基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;最优选包含3至8个环原子,其中1~3个是杂原子;最优选包含5至6个环原子,其中1~2或1~3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等,优选四氢吡喃基、哌啶基、吡咯烷基。多环杂环烷基包括螺杂环基、稠杂环基和桥杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。
术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更优选为双环或三环。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,含1至3个杂原子;更优选为5元或6元,含1至2个杂原子;优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基和哒嗪基等。
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
术语“卤代烷基”指烷基被一个或多个卤素取代,其中烷基如上所定义。
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代,其中烷氧基如上所定义。
术语“氘代烷基”指烷基被一个或多个氘原子取代,其中烷基如上所定义。
术语“氘代烷氧基”指烷氧基被一个或多个氘原子取代,其中烷氧基如上所定义。
术语“环烷基烷基”指烷基被一个或多个环烷基取代,其中环烷基和烷基如上所定义。
术语“环烷基氧基”指-O-环烷基,其中环烷基如上所定义。
术语“杂环基烷基”指烷基被一个或多个杂环基取代,其中杂环基和烷基如上所定义。
术语“芳基烷基”指烷基被一个或多个芳基取代,其中芳基和烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“羧基”指-C(O)OH。
具体实施方式
实施例1:(R)-N-((1-(6-((4-氰基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(1)
步骤1:(R)-((1-(6-溴-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(2)
搅拌下,将6-溴-3-甲基吡啶甲酸(2.16g,10.00mmol,1eq.)溶于DCM(50mL),在冰水浴温度下加入DIPEA(6.46g,49.99mmol,5eq.)和HATU(5.70g,15.00mmol,1.5eq.)。反应混合物在0℃下搅拌半小时,然后加入(R)-((5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(2.75g,11.00mmol,1.1eq.),反应混合物在环境温度下搅拌过夜。用水和EtOAc处理反应混合物,并分离有机相。有机相用水洗涤,MgSO4干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash 80g,EtOAc/n-Hep=20%~50%),得到透明蜡状物(3.9g,87.01%)。LC-MS(m/z):448.1[M+H]+。
进行VT 1H NMR确认构象异构现象的存在:
室温:1H NMR(400MHz,DMSO-d6)δ7.72(d,J=8.2Hz,1H),7.63(dd,J=8.2,4.2Hz,1H),7.05(t,J=6.2Hz,0.25H),6.85(t,J=6.1Hz,0.65H),4.81(s,0.3H),4.66(t,J=13.4Hz,0.7H),3.77–3.37(m,2H),3.31–3.19(m,1H),2.98(d,J=14.2Hz,1H),2.23(s,2H),2.17(s,1H),2.11(d,J=10.5Hz,1H),1.92–1.63(m,2H),1.40(s,3H),1.33(s,6H).1.230(s,1H);
50℃:1H NMR(400MHz,DMSO-d6)δ7.71(dd,J=8.3,1.9Hz,1H),7.61(dd,J=8.1,4.4Hz,1H),6.91(s,0.3H),6.71(s,0.7H),4.83(s,0.3H),4.69(t,J=13.5Hz,0.7H),3.76–3.24(m,3H),3.03(d,J=14.1Hz,1H),2.24(s,2.5H),2.21(s,0.5H),2.16–1.97(m,1H),1.94–1.64(m,2H),1.42(s,3H),1.34(s,7H)。
步骤2:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-溴-3-甲基吡啶-2-基)甲酮(3)
搅拌下,将(R)-((1-(6-溴-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(2.24g,5.0mmol,1.0eq.)溶于EtOAc(300mL),在冰水浴温度下加入HCl的1,4-二氧六环溶液(4M,20mL,80.00mmol,16eq.),反应混合物在环境温度下搅拌过夜。粗品未经进一步纯化直接用于下一步。LC-MS(m/z):348.0[M+H]+。
步骤3:(R)-N-((1-(6-溴-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(4)
搅拌下,将(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-溴-3-甲基吡啶-2-基)甲酮(1.75g,5.0mmol,1.0eq.)溶于DCM(20mL),在冰水浴温度下加入DIPEA(3.22g,25mmol,5eq.)和HATU(2.85g,7.5mmol,1.5eq.)。反应混合物在0℃下搅拌半小时,然后加入醋酸(0.6g,10.0mmol,2.0eq.),反应混合物在环境温度下搅拌过夜。用水和EtOAc处理反应混合物,并分离有机相。有机相用水洗涤,MgSO4干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash 80g,EtOAc/n-Hep=20%~50%),得到透明蜡状物(1.58g,81.32%)。LC-MS(m/z):390.1[M+H]+。
步骤4:(R)-N-((1-(6-((4-氰基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(1)
将(R)-N-((1-(6-溴-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(50.00mg,0.13mmol,1.0eq.),2-氨基异烟碱腈(53.30mg,0.26mmol,2.0eq.),Pd2(dba)3(11.90mg,0.01mmol,0.1eq.),BINAP(16.17mg,0.26mmol,0.2eq.)和CS2CO3(127.14mg,0.39mmol,3.0eq.)的混合物悬浮于1,4-二氧六环(3.0mL),所得混合物在氮气气氛下加热至90℃反应10小时。通过柱层析(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化反应溶液,得到标题化合物。1H NMR(400MHz,DMSO-d6)δ10.26(s,0.3H),10.21(s,0.7H),8.51–8.42(m,1H),8.24(s,0.7H),8.19(s,0.3H),8.15(t,J=6.3Hz,0.3H),7.95(t,J=6.1Hz,0.7H),7.66(dd,J=8.6,2.3Hz,1H),7.55(d,J=8.5Hz,0.3H),7.46(d,J=8.5Hz,0.7H),7.26(td,J=5.0,1.4Hz,1H),4.83(s,0.3H),4.73(t,J=13.2Hz,0.7H),3.74-3.63(m,1H),3.52–3.36(m,2H),3.31-3.21(m,1H),2.33-2.00(m,5H),1.95-1.71(m,5H)。LC-MS(m/z):429.2[M+H]+。
实施例2:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(5)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.94(s,0.3H),9.85(s,0.7H),8.24(dd,J=5.7,2.3Hz,1H),8.15(t,J=6.2Hz,0.3H),7.97(t,J=6.1Hz,0.7H),7.75–7.44(m,2H),7.34(d,J=4.9Hz,0.7H),7.16(d,J=4.9Hz,0.3H),6.75(t,J=5.5,Hz,1H),4.82(s,0.3H),4.74(s,0.7H),3.81–3.39(m,2H),3.31-3.23(m,2H),2.33-2.07(m,5H),1.98-1.78(m,5H)。LC-MS(m/z):488.2[M+H]+。
实施例3:(R)-N-((5,5-二氟-1-(6-((5-(3-氟环丁基)-1H-吡唑-3-基)氨基)-3-甲基吡啶-2-羰基)哌啶-2-基))甲基)乙酰胺(6)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(6-((5-(3-氟环丁基)-1H-吡唑-3-基)氨基)-3-甲基吡啶-2-羰基)哌啶-2-基))甲基)乙酰胺。LC-MS(m/z):465.2[M+H]+。
实施例4:(R)-N-((1-(6-((3-环丁基-1-甲基-1H-吡唑-5-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(7)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((3-环丁基-1-甲基-1H-吡唑-5-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。LC-MS(m/z):461.2[M+H]+。
实施例5:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-甲基吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(8)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-甲基吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),8.10(d,J=5.4Hz,1H),7.96(t,J=6.2Hz,1H),7.68(s,1H),7.62(d,J=8.5Hz,1H),7.53–7.36(m,1H),6.85–6.70(m,1H),4.84(s,0.4H),4.73(t,J=13.3Hz,0.6H),3.62(s,1H),3.53–3.38(m,3H),2.43–2.02(m,8H),1.99–1.59(m,5H)。LC-MS(m/z):418.2[M+H]+。
实施例6:(R)-N-((5,5-二氟-1-(6-((4-甲氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(9)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(6-((4-甲氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.68(s,0.3H),9.57(s,0.7H),8.12(t,J=6.1Hz,0.3H),8.03(dd,J=5.8,1.3Hz,1H),7.91(t,J=6.1Hz,0.7H),7.77–7.52(m,2H),7.35(d,J=2.3Hz,0.3H),7.32(d,J=2.3Hz,0.7H),6.50(dd,J=5.8,2.4,Hz,0.5H),6.11(dd,J=5.8,2.3Hz,0.5H),4.87–4.64(m,1H),3.77(s,2H),3.70(s,1H),3.63(d,J=14.9Hz,1H),3.54–3.40(m,2H),3.29-3.23(m,1H),2.30-2.00(m,5H),1.92–1.58(m,5H)。LC-MS(m/z):434.2[M+H]+。
实施例7:(R)-N-((1-(6-((5-氯-4-甲氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(10)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((5-氯-4-甲氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.88(s,0.3H),9.77(s,0.7H),8.11(s,1.3H),7.92(t,J=6.1Hz,0.7H),7.71–7.53(m,3H),4.86–4.66(m,1H),3.87(d,J=3.6Hz,3H),3.82–3.38(m,1H),3.30(d,J=10.7Hz,3H),2.27-1.98(m,5H),1.88-1.56(m,5H)。LC-MS(m/z):468.2[M+H]+。
实施例8:(R)-N-((1-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(11)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-(二氟甲氧基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.97(s,0.3H),9.88(s,0.7H),8.23(dd,J=5.7,2.3Hz,1H),8.14(t,J=6.2Hz,0.3H),7.92(t,J=6.1Hz,0.7H),7.71–7.49(m,3H),7.35(d,J=4.9Hz,0.7H),7.17(d,J=4.9Hz,0.3H),6.72(t,J=5.5,Hz,1H),4.81(s,0.3H),4.73(s,0.7H),3.80–3.38(m,2H),3.30-3.23(m,2H),2.32-2.00(m,5H),1.98-1.78(dm,5H)。LC-MS(m/z):470.2[M+H]+。
实施例9:(R)-N-((1-(6-((1H-吡咯并[3,2-c]吡啶-6-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(12)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((1H-吡咯并[3,2-c]吡啶-6-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ11.39(s,0.5H),11.08(s,0.5H),9.49(s,0.5H),9.34(s,0.5H),8.50(d,J=3.4Hz,1H),8.34(d,J=8.4Hz,0.5H),8.10(s,0.5H),7.88(d,J=6.1Hz,0.5H),7.72(s,0.5H),7.57–7.48(m,1.5H),7.36–7.19(m,1.5H),6.45(d,J=2.7Hz,1H),4.90(s,0.5H),4.76(t,J=13.2Hz,0.5H),3.98–3.40(m,3H),3.30-3.24(m,1H),2.37-2.00(d,J=8.5Hz,5H),1.99–1.59(m,5H)。LC-MS(m/z):443.2[M+H]+。
实施例10:(R)-N-((1-(6-((5-(叔丁基)异噻唑-3-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(13)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((5-(叔丁基)异噻唑-3-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.18(s,0.3H),10.05(s,0.7H),8.13(t,J=6.1Hz,0.3H),7.92(t,J=6.0Hz,0.7H),7.84–7.76(m,0.3H),7.67(d,J=8.6Hz,0.7H),7.60(dd,J=8.6,5.8Hz,1H),7.20(s,0.7H),7.13(s,0.3H),4.80(s,0.4H),4.73(t,J=13.4Hz,0.6H),3.75–3.37(m,2H),3.31-3.23(m,2H),2.35-2.00(m,5H),1.91-1.67(m,5H),1.35(s,9H)。LC-MS(m/z):466.2[M+H]+。
实施例11:(R)-N-((1-(6-((4-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)-5-氟吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(14)
将4-溴-5-氟吡啶-2-胺(0.19g,1mmol,1.0eq.),3-(3,3,4,4-四甲基-1λ3,2,5-溴二氧戊环-1-基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑(0.606g,2mmol,2.0eq.),Pd2(dba)3(70mg,0.01mmol,0.1eq.),BINAP(112mg,0.2mmol,0.2eq.)和K3PO4(636mg,3mmol,3.0eq.)的混合物悬浮于1,4-二氧六环(3.0mL),所得混合物在氮气气氛下加热至90℃反应10小时。通过柱层析(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化反应溶液,得到4-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)-5-氟吡啶-2-胺。1H NMR(400MHz,DMSO-d6)δ7.83(dd,J=24.6,3.0Hz,2H),6.57(d,J=5.5Hz,1H),5.76(s,2H),4.13(t,J=7.3Hz,2H),3.05(t,J=7.4Hz,2H),2.68–2.52(m,2H)。LC-MS(m/z):219.3[M+H]+。
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)-5-氟吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。LC-MS(m/z):528.2[M+H]+。
实施例12:(R)-N-((1-(6-((5-(3,3-二氟环丁基)-1H-吡唑-3-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(15)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((5-(3,3-二氟环丁基)-1H-吡唑-3-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1HNMR(400MHz,DMSO-d6)δ11.95(s,1H),9.29(s,1H),8.11(t,J=6.2Hz,0.3H),7.93(t,J=6.1Hz,0.7H),7.47(d,J=10.5Hz,1H),7.02(d,J=8.5Hz,1H),6.34(s,1H),4.80(s,0.3H),4.71(t,J=13.3Hz,0.7H),3.69(d,J=30.5Hz,1H),3.53–3.40(m,2H),3.22(dd,J=13.7,6.7Hz,2H),3.09–2.82(m,2H),2.78–2.58(m,2H),2.37–1.56(m,10H)。LC-MS(m/z):483.2[M+H]+。
实施例13:(R)-N-((1-(6-((4-环丁氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(16)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-环丁氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.70(s,0.3H),9.57(s,0.7H),8.15(t,J=6.1Hz,0.3H),8.01(dd,J=5.8,1.9Hz,1H),7.92(t,J=6.1Hz,0.7H),7.69–7.53(m,2H),7.32(d,J=2.3Hz,0.3H),7.28(d,J=2.3Hz,0.7H),6.40(dd,J=5.8,2.3Hz,1H),4.86-4.66(m,2H),3.76–3.35(m,2H),3.32–3.17(m,2H),2.48–2.36(m,4H),2.34–1.97(m,6H),1.96–1.57(m,6H)。LC-MS(m/z):474.2[M+H]+。
实施例14:(R)-N-((1-(6-((4-(叔丁基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(17)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-(叔丁基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,Chloroform-d)δ8.28(s,0.6H),8.18(d,J=5.6Hz,0.4H),7.78(d,J=8.7Hz,1H),7.57(t,J=7.5Hz,1H),7.06–6.91(m,1H),6.29(s,1H),5.04(d,J=16.6Hz,1H),4.25–4.01(m,1H),3.96–3.80(m,1H),3.73–3.48(m,1H),3.32–3.00(m,1H),2.27(s,1H),2.24(s,2H),2.20–2.03(m,2H),2.00(s,2H),1.98(s,1H),1.95–1.68(m,2H),1.41–1.21(m,9H)。LC-MS(m/z):461.3[M+H]+。
实施例15:(R)-N-((1-(6-((4-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(18)
将4-碘吡啶-2-胺(0.173g,1mmol,1.0eq.),3-(3,3,4,4-四甲基-1λ3,2,5-硼二氧戊环-1-基)-5,6-二氢-4H-吡咯并[1,2-b]吡唑(0.606g,2mmol,2.0eq.),Pd2(dba)3(70mg,0.01mmol,0.1eq.),BINAP(112mg,0.2mmol,0.2eq.)和K3PO4(636mg,3mmol,3.0eq.)的混合物悬浮于1,4-二氧六环(3.0mL),所得混合物在氮气气氛下加热至90℃反应10小时。通过柱层析(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化反应溶液,得到4-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-2-胺。LC-MS(m/z):201.1[M+H]+。
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-(5,6-二氢-4H-吡咯并[1,2-b]吡唑-3-基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.71(s,0.3H),9.60(s,0.7H),8.15(t,J=6.2Hz,1H),7.94–7.52(m,4H),7.03(dt,J=5.3,1.7Hz,1H),6.71–6.51(m,1H),4.88–4.69(m,1H),4.10(q,J=7.2Hz,2H),3.75–3.41(m,2H),3.32–3.16(m,2H),3.12–2.98(m,2H),2.68-2.58(m,2H),2.11(d,J=16.8Hz,5H),1.93–1.53(m,5H)。LC-MS(m/z):510.2[M+H]+。
实施例16:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-硝基吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(19)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-硝基吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.47(s,0.3H),10.35(s,0.7H),8.67(d,J=2.1Hz,0.3H),8.55(d,J=5.5Hz,1H),8.49(d,J=2.0Hz,0.7H),8.15(t,J=6.1Hz,0.3H),7.92(t,J=6.1Hz,0.7H),7.77–7.50(m,3H),4.75(t,J=13.2Hz,1H),3.80–3.38(m,3H),3.30(d,J=2.0Hz,1H),2.38–1.97(m,5H),1.93–1.62(m,5H)。LC-MS(m/z):449.2[M+H]+。
实施例17:(R)-N-((1-(6-((4-环戊基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(20)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-环戊基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.66(s,0.3H),9.57(s,0.7H),8.23–8.13(m,0.4H),8.09(d,J=5.1Hz,1H),7.94(t,J=6.1Hz,0.6H),7.70-7.55(m,3H),6.77(d,J=5.3Hz,1H),4.81-4.71(m,1H),3.79–3.21(m,6H),2.89(p,J=8.2Hz,1H),2.37–1.35(m,16H)。LC-MS(m/z):472.2[M+H]+。
实施例18:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(吡咯烷-1-基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(21)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(吡咯烷-1-基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.37(s,0.4H),9.23(s,0.6H),8.15(s,0.3H),7.94(t,J=6.0Hz,0.7H),7.80(d,J=5.9Hz,1H),7.73–7.44(m,2H),6.99(d,J=2.1Hz,0.3H),6.80(d,J=2.1Hz,0.7H),6.10(dd,J=5.9,2.1Hz,1H),4.73(t,J=13.6Hz,1H),3.78–3.50(m,3H),3.48–3.27(m,3H),2.27-2.04(d,J=16.0Hz,7H),2.00–1.79(m,7H),1.72(s,2H)。LC-MS(m/z):473.2[M+H]+。
实施例19:(R)-N-((5,5-二氟-1-(3-甲基-6-(吡啶-2-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(22)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-(吡啶-2-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.74(s,0.3H),9.65(s,0.7H),8.22(dd,J=4.7,2.7Hz,1H),8.11(t,J=6.2Hz,0.3H),7.91(t,J=6.1Hz,0.7H),7.75–7.52(m,4H),6.86(dd,J=7.1,4.9Hz,1H),4.82(s,0.3H),4.73(t,J=13.4Hz,0.7H),3.80–3.60(m,1H),3.55–3.36(m,2H),3.32–3.19(m,1H),2.37–1.98(m,5H),1.93-1.66(m,5H)。LC-MS(m/z):404.2[M+H]+。
实施例20:(R)-N-((5,5-二氟-1-(3-甲基-6-(嘧啶-2-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(23)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-(嘧啶-2-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.56(dd,J=4.7,1.0Hz,2H),8.22(d,J=8.6Hz,0.3H),8.15(d,J=8.5Hz,0.7H),8.08(t,J=6.1Hz,0.3H),7.93(t,J=6.2Hz,0.7H),7.69(dd,J=8.6,5.0Hz,1H),6.96(t,J=4.8Hz,1H),4.79(s,0.3H),4.71(t,J=13.5Hz,0.7H),3.75–3.61(m,1H),3.58–3.36(m,2H),3.24(dt,J=13.4,6.4Hz,1H),2.37–1.97(m,5H),1.92-1.58(m,5H)。LC-MS(m/z):405.2[M+H]+。
实施例21:(R)-N-((1-(6-((4-氯吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(24)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-氯吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.03(s,0.3H),9.98(s,0.7H),8.20(dd,J=5.4,2.0Hz,1H),8.13(t,J=6.2Hz,0.3H),8.05(d,J=1.9Hz,0.7H),7.97–7.85(m,1H),7.66–7.56(m,1.3H),7.47(d,J=8.5Hz,0.7H),6.99-6.96(m,1H),4.82(s,0.4H),4.73(t,J=13.3Hz,0.6H),3.74–3.58(m,1H),3.57–3.35(m,2H),3.32-3.22(m,1H),2.34-2.08(m,5H),1.99-1.67(m,5H)。LC-MS(m/z):438.1[M+H]+。
实施例22:(R)-N-((5,5-二氟-1-(3-甲基-6-(嘧啶-4-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(25)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-(嘧啶-4-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.30(s,0.3H),10.22(s,0.7H),8.71(t,J=1.6Hz,1H),8.43(d,J=5.9Hz,0.3H),8.39(d,J=5.9Hz,0.7H),8.13(t,J=6.2Hz,0.3H),7.91(t,J=6.1Hz,0.7H),7.80–7.57(m,3H),4.83(s,0.4H),4.73(t,J=13.3Hz,0.6H),3.83–3.42(m,2H),3.42–3.34(m,1H),3.31-3.26(m,1H),2.28-2.09(m,5H),1.97-1.68(m,5H)。LC-MS(m/z):405.2[M+H]+。
实施例23:(R)-N-((5,5-二氟-1-(3-甲基-6-(吡嗪-2-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(26)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-(吡嗪-2-基氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.13(s,0.3H),10.03(s,0.7H),9.02(d,J=1.5Hz,0.7H),8.99(d,J=1.5Hz,0.3H),8.23(dt,J=2.9,1.5Hz,1H),8.12(t,J=6.2Hz,0.3H),8.08(d,J=2.7Hz,1H),7.91(t,J=6.1Hz,0.7H),7.67(d,J=13.4Hz,2H),4.82(s,0.3H),4.73(t,J=13.4Hz,0.7H),3.75-3.63(m,1H),3.52–3.35(m,2H),3.33–3.22(m,1H),2.34-2.08(m,5H),1.91-1.70(m,5H)。LC-MS(m/z):405.2[M+H]+。
实施例24:(R)-N-((1-(6-((4-(二氟甲基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(27)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((1-(6-((4-(二氟甲基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.07(s,0.3H),9.98(s,0.7H),8.37(dd,J=5.4,1.8Hz,1H),8.14(t,J=6.1Hz,0.3H),7.92(d,J=6.5Hz,1.7H),7.64(d,J=6.0Hz,2H),7.26–6.76(m,2H),4.87–4.67(m,1H),3.73-3.61(m,1H),3.58–3.37(m,1H),3.30–3.17(m,2H),2.28-2.00(m,5H),1.95-1.64(m,5H)。LC-MS(m/z):454.2[M+H]+。
实施例25:(R)-N-((5,5-二氟-1-(6-((4-(氟甲基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(28)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(6-((4-(氟甲基)吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.88(s,0.3H),9.80(s,0.7H),8.24(t,J=4.8Hz,1H),8.13(t,J=6.2Hz,0.3H),7.93(t,J=6.1Hz,0.7H),7.78(s,1H),7.73–7.66(m,0.5H),7.63-7.58(m,1.5H),6.92–6.81(m,1H),5.51(s,0.3H),5.47(s,0.7H),5.40(s,0.3H),5.36(s,0.7H),4.80(s,0.4H),4.73(t,J=13.3Hz,0.6H),3.77–3.59(m,1H),3.56–3.37(m,1H),3.32-3.24(m,2H),2.30-2.08(m,5H),1.94-1.64(m,5H)。LC-MS(m/z):436.3[M+H]+。
实施例26:(R)-N-((5,5-二氟-1-(3-甲基-6-((3-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(29)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((3-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ8.95(s,0.3H),8.89(s,0.7H),8.24(dd,J=7.7,4.8,Hz,1H),8.07(t,J=6.2Hz,0.3H),8.01–7.89(m,1.7H),7.79(d,J=7.1Hz,1H),7.68(d,J=8.5Hz,1H),7.07-7.02(m,1H),4.78(s,0.4H),4.71(t,J=13.4Hz,0.6H),3.76–3.60(m,1H),3.56–3.38(m,2H),3.25-3.17(m,1H),2.27-2.06(m,5H),1.82-1.71(m,5H)。LC-MS(m/z):488.2[M+H]+。
实施例27:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(30)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.26(s,0.3H),10.18(s,0.7H),8.48(d,J=5.0Hz,1H),8.22(d,J=12.5Hz,1H),8.15(t,J=6.1Hz,0.3H),7.92(t,J=6.1Hz,0.7H),7.66(d,J=8.6,Hz,1H),7.56(d,J=8.5Hz,1H),7.18(d,J=4.4Hz,1H),4.90–4.64(m,1H),3.75–3.57(m,1H),3.55–3.41(m,1H),3.33–3.16(m,2H),2.32-2.30(m,5H),1.91-1.65(m,5H)。LC-MS(m/z):472.2[M+H]+。
实施例28:(R)-((1-(6-((4-氰基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(31)
使用类似于实施例1中化合物1的合成方法,得到(R)-((1-(6-((4-氰基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):487.4[M+H]+。
实施例29:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)甲磺酰胺(32)
步骤1:(R)-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯(33)
使用类似于实施例28中化合物31的合成方法,得到(R)-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):546.2[M+H]+。
步骤2:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(34)
使用类似于实施例1中化合物3的合成方法,得到(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮。LC-MS(m/z):446.2[M+H]+。
步骤3:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)甲磺酰胺(32)
搅拌下,将(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(45mg,0.1mmol,1eq.)溶于DCM(5mL),在冰水浴温度下加入甲磺酸酐(35mg,0.2mmol,2eq.)。反应混合物在0℃下搅拌半小时,然后加入DIPEA(39mg,0.3mmol,3eq.),反应混合物在环境温度下搅拌过夜。用水和EtOAc处理反应混合物,并分离有机相。有机相用水洗涤,MgSO4干燥,并浓缩至干。粗品通过柱层析纯化(BiotageRening Flash 80g,EtOAc/n-Hep=80%~100%),得到标题化合物(25mg,47.80%)。1HNMR(400MHz,DMSO-d6)δ10.17(s,0.3H),10.11(s,0.7H),8.32(dd,J=5.7,3.0Hz,1H),7.96(s,0.7H),7.85(s,0.3H),7.70–7.45(m,2H),7.39(t,J=6.6Hz,0.3H),7.12(t,J=6.6Hz,0.7H),6.94–6.82(m,1H),4.80(s,0.3H),4.72(t,J=13.3Hz,0.7H),3.71–3.36(m,2H),3.30–3.20(m,1H),3.19–3.06(m,1H),2.97(s,1H),2.79(s,2H),2.31–1.65(m,7H)。LC-MS(m/z):524.1[M+H]+。
实施例30:(R)-N-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(35)
步骤1:(R)-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(36)
使用类似于实施例28中化合物31的合成方法,得到(R)-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。1H NMR(400 MHz,Chloroform-d)δ8.14–8.02(m,0.7H),7.86(d,J=8.6 Hz,0.3H),7.59–7.46(m,1H),7.19(s,1H),6.65–6.39(m,2H),5.17-5.00(m,1H),4.08(q,J=6.9,5.9 Hz,2H),3.96–3.36(m,3H),3.24–2.97(m,1H),2.29(s,2H),2.25(s,1H),2.22–1.84(m,4H),1.79–1.27(m,12H)。LC-MS(m/z):506.3[M+H]+。
步骤2:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-基)甲酮(37)
使用类似于实施例1中化合物3的合成方法,得到(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-基)甲酮。1H NMR(400 MHz,Methanol-d4)δ8.03(t,J=6.2 Hz,1H),7.68(dd,J=12.0,8.8 Hz,1H),7.52(d,J=8.5Hz,1H),6.88(d,J=2.3Hz,0.4H),6.80(d,J=2.2 Hz,0.6H),6.57(dd,J=5.8,2.0 Hz,1H),5.20–4.94(m,1H),4.20–4.06(m,2H),3.71–3.48(m,2H),3.27-3.00(m,2H),2.29–1.74(m,7H),1.43(td,J=7.0,1.5 Hz,3H)。LC-MS(m/z):406.2[M+H]+。
步骤3:(R)-N-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(35)
使用类似于实施例1中化合物4的合成方法,得到(R)-N-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺。1H NMR(400 MHz,DMSO-d6)δ9.67(s,0.3H),9.56(s,0.7H),8.13(s,1H),8.03(d,J=5.5 Hz,1H),7.92(s,0.4H),7.75–7.66(m,0.6H),7.59(q,J=8.7,8.3 Hz,1 H),7.37(s,1H),6.49(d,J=5.6Hz,1H),6.11(d,J=5.7 Hz,0.6H),5.95(s,0.4H),5.80(s,1H),4.76(dd,J=28.5,14.7Hz,1H),4.22–3.90(m,3H),3.70(s,1H),2.28-2.09(m,5H),1.92-1.68(m,5H),1.32(dt,J=10.4,6.8 Hz,3H)。LC-MS(m/z):448.2[M+H]+。
实施例31:(4,4-二氟氮杂-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(38)
步骤1:3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶甲酸乙酯(39)
使用类似于实施例1中化合物1的合成方法,得到3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶甲酸乙酯。LC-MS(m/z):342.1[M+H]+。
步骤2:3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶甲酸(40)
搅拌下,将3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶甲酸乙酯(0.5g,1.47mmol,1.0eq.)和一水合LiOH(614.75mg,14.65mmol,10.0eq.)溶于H2O/EtOH(1:5),室温下搅拌3小时。反应混合物使用2N HCl中和至pH=4,并用EtOAc萃取。有机相用MgSO4干燥,真空干燥得到3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶甲酸。LC-MS(m/z):314.1[M+H]+。
步骤3:(4,4-二氟氮杂-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(38)
使用类似于实施例1中化合物2的合成方法,得到(4,4-二氟氮杂-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮。1H NMR(400MHz,DMSO-d6)δ10.15(d,J=2.4Hz,1H),8.32(d,J=5.7Hz,1H),7.85(d,J=11.9Hz,1H),7.70–7.51(m,2H),6.86(d,J=5.8Hz,1H),3.78–3.51(m,2H),3.26(t,J=6.2Hz,2H),2.38–2.20(m,1H),2.14-2.06(m,5H),1.93–1.64(m,3H)。LC-MS(m/z):431.1[M+H]+。
实施例32:(R)-((1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯(41)
使用类似于实施例31中化合物38的合成方法,得到(R)-((1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):510.1[M+H]+。
实施例33:(S)-N-(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-3-基)乙酰胺(42)
使用类似于实施例31中化合物38的合成方法,得到(S)-N-(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-3-基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.18(s,0.3H),10.12(s,0.7H),8.32(dd,J=5.8,1.6Hz,1H),8.09(d,J=7.5Hz,0.3H),7.92(d,J=7.1Hz,0.7H),7.82–7.60(m,3H),6.86(d,J=5.7Hz,1H),4.73–4.51(m,1H),4.14–3.80(m,1H),3.70–3.38(m,3H),2.35(d,J=14.7Hz,1H),2.22–1.94(m,4H),1.87(s,1H),1.70(s,2H)。LC-MS(m/z):474.2[M+H]+。
实施例34:(R)-N-(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-3-基)乙酰胺(43)
使用类似于实施例31中化合物38的合成方法,得到(R)-N-(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-3-基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.18(s,0.3H),10.12(s,0.7H),8.32(dd,J=5.7,1.6Hz,1H),8.09(d,J=7.5Hz,0.3H),7.92(d,J=7.1Hz,0.7H),7.84–7.59(m,3H),6.86(d,J=5.7Hz,1H),4.66(s,1H),3.86(s,1H),3.69–3.38(m,3H),2.43–2.29(m,1H),2.22–1.95(m,4H),1.78(d,J=69.0Hz,3H)。LC-MS(m/z):474.2[M+H]+。
实施例35:N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(44)
使用类似于实施例31中化合物38的合成方法,得到N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.15(s,0.3H),10.10(s,0.7H),8.32(dd,J=5.7,4.4Hz,1H),8.15(t,J=6.1Hz,0.3H),7.98–7.86(m,1.7H),7.64(dd,J=8.7,1.8Hz,1H),7.56(d,J=8.5Hz,0.3H),7.49(d,J=8.5Hz,0.7H),6.87(d,J=2.4Hz,1H),4.82(s,0.3H),4.72(t,J=13.3Hz,0.7H),3.74–3.37(m,3H),3.32–3.11(m,1H),2.35–1.96(m,5H),1.93-1.66(m,5H)。LC-MS(m/z):488.2[M+H]+。
实施例36:(R)-N-((1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(45)
使用类似于实施例31中化合物38的合成方法,得到(R)-N-((1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.14(s,0.7H),10.08(s,0.3H),8.32(d,J=5.7Hz,1H),8.12–7.80(m,2H),7.60(dd,J=8.5,3.8Hz,1H),7.52(d,J=8.5Hz,0.6H),7.44(d,J=8.4Hz,0.4H),6.87(d,J=5.6Hz,1H),4.78(q,J=7.2Hz,0.5H),4.47(dd,J=9.7,5.2Hz,0.5H),3.75–3.48(m,3H),3.27–2.76(m,4H),2.15(s,1H),2.11(s,2H),2.02–1.33(m,6H)。LC-MS(m/z):452.2[M+H]+。
实施例37:(六氢-1H-吡咯并[1,2-a][1,4]二氮杂-2-2(3H)-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(46)
使用类似于实施例31中化合物38的合成方法,得到(六氢-1H-吡咯并[1,2-a][1,4]二氮杂-2-2(3H)-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮。1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),8.32(d,J=5.6Hz,1H),8.17(s,1H),7.82(d,J=16.8Hz,1H),7.71–7.46(m,1H),6.86(d,J=5.7Hz,1H),4.14(dd,J=13.7,2.5Hz,1H),3.69(q,J=5.3Hz,1H),3.42–3.23(m,2H),3.15–2.87(m,3H),2.70–2.59(m,1H),2.48–2.23(m,2H),2.21–2.12(m,3H),2.02(ddd,J=17.2,7.8,3.7Hz,1H),1.93–1.83(m,1H),1.82–1.41(m,3H)。LC-MS(m/z):436.2[M+H]+。
实施例38:(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)(吡咯烷-1-基)甲酮(47)
步骤1:5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-甲酸甲酯(47-1)
搅拌下,将3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶甲酸(0.313g,1.0mmol,1eq.)溶于DCM(5mL),在冰水浴温度下加入DIPEA(0.39g,3.0mmol,3eq.)和HATU(0.57g,1.50mmol,1.5eq.)。反应混合物在0℃下搅拌半小时,然后加入5,5-二氟哌啶-2-羧酸甲酯(0.2g,1.10mmol,1.1eq.),反应混合物在环境温度下搅拌过夜。用水和EtOAc处理反应混合物,并分离有机相。有机相用水洗涤,MgSO4干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash 25g,EtOAc/n-Hep=20%~50%),得到标题化合物(0.32g,67.01%)。
步骤2:5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-羧酸(47-2)
搅拌下,将5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-甲酸甲酯(0.25g,0.53mmol,1.0eq.)和一水合LiOH(222.4mg,5.3mmol,10.0eq.)溶于H2O/EtOH(1:5),室温下搅拌3小时。反应混合物使用2N HCl中和至pH=4,并用EtOAc萃取。有机相用MgSO4干燥,真空干燥得到标题化合物。LC-MS(m/z):461.4[M+H]+
步骤3:(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)(吡咯烷-1-基)甲酮(47)
搅拌下,将5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-羧酸(0.12g,0.25mmol,1.0eq.)溶于DCM(5mL),在冰水浴温度下加入DIPEA(0.097g,0.75mmol,3eq.)和HATU(0.14g,0.38mmol,1.5eq.)。反应混合物在0℃下搅拌半小时,然后加入四氢吡咯(0.36g,0.5mmol,2.0eq.),反应混合物在环境温度下搅拌过夜。用水和EtOAc处理反应混合物,并分离有机相。有机相用水洗涤,MgSO4干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash 80g,EtOAc/n-Hep=20%~50%),得到(5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)(吡咯烷-1-基)甲酮。1H NMR(400MHz,DMSO-d6)δ10.18(s,1H),8.33(d,J=5.7Hz,1H),7.86–7.58(m,3H),6.88(d,J=5.6Hz,1H),5.46(s,0.4H),4.70(t,J=13.8Hz,0.6H),4.22(s,1H),4.05-3.87(m,1H),3.71–3.43(m,2H),3.17-3.01(m,2H),2.38–1.99(m,5H),1.98–1.69(m,4H),1.67–1.20(m,2H)。LC-MS(m/z):514.3[M+H]+。
实施例39:(R)-1-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)吡咯烷酮-2-酮(48)
步骤1:(R)-1-(((1-(6-溴-3-甲基吡啶啉基)-5,5-二氟哌啶-2-基)甲基)吡咯烷-2-酮(48-1)
搅拌下,将(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-溴-3-甲基吡啶-2-基)甲酮(0.35g,1.0mmol,1eq.),DIPEA(0.39g,3.0mmol,3eq.)加入到5mL二氯甲烷中,室温下滴加4-氯丁酰氯(0.21g,1.5mmol,1.5eq.),反应2小时,旋干溶剂,加入5mL DMF,冰浴下加入60%氢化钠(0.12g,3.0mmol,3.0eq.)室温下反应12小时,反应液带入冰水中,乙酸乙酯萃取,有机层用无水硫酸镁干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash25g,EtOAc/n-Hep=20%~50%),得到标题化合物,LC-MS(m/z):416.0[M+H]+。
步骤2:(R)-1-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)吡咯烷酮-2-酮(48)
使用类似于实施例1中化合物4的合成方法,得到(R)-1-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)吡咯烷酮-2-酮。1HNMR(400MHz,DMSO-d6)δ10.11(d,J=4.4Hz,1H),8.32(dd,J=7.0,5.7Hz,1H),7.86(d,J=27.2Hz,1H),7.71–7.45(m,2H),6.87(d,J=9.2,Hz,1H),5.03(s,0.5H),4.73(t,J=13.3Hz,0.6H),3.96–3.39(m,4H),3.31–3.14(m,1H),2.99(td,J=8.8,5.7Hz,1H),2.90–2.79(m,1H),2.40–2.00(m,7H),2.01–1.59(m,3H)。LC-MS(m/z):514.2[M+H]+。
实施例40:N-乙基-5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-羧酰胺(49)
使用类似于实施例38中化合物47的合成方法,得到N-乙基-5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-羧酰胺。1H NMR(400MHz,DMSO-d6)δ10.19(s,1H),8.32(dd,J=5.7,1.9Hz,1H),8.24(t,J=6.2Hz,0.5H),7.84(d,J=2.5Hz,1H),7.79(s,0.5H),7.68-7.62(m,1.5H),7.55(d,J=8.6Hz,0.5H),6.87(tt,J=6.2,1.3Hz,1H),5.23(s,0.4H),4.71(t,J=13.5Hz,0.6H),4.23–3.59(m,1H),3.51–3.37(m,1H),3.23–3.08(m,1H),3.05–2.89(m,1H),2.34–1.99(m,5H),1.98–1.80(m,2H),1.07(t,J=7.2Hz,1H),0.87(t,J=7.2Hz,2H)。LC-MS(m/z):488.2[M+H]+。
实施例41:N-((1S,5R)-5-乙酰氨基-3,3-二氟环己基)-3-甲基-6-((4-4-三氟甲氧基吡啶-2-基)氨基)吡啶-2-羰基酰胺(50)
使用类似于实施例31中化合物38的合成方法,得到N-((1S,5R)-5-乙酰氨基-3,3-二氟环己基)-3-甲基-6-((4-4-三氟甲氧基吡啶-2-基)氨基)吡啶-2-羰基酰胺。1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.50(d,J=8.2Hz,1H),8.33(d,J=5.7Hz,1H),8.04(d,J=7.8Hz,1H),7.91(s,1H),7.70–7.50(m,2H),6.88(d,J=5.7Hz,1H),4.05-4.97(m,1H),3.93–3.74(m,1H),2.45–2.14(m,5H),2.11–1.54(m,7H)。LC-MS(m/z):488.4[M+H]+。
实施例42:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)环丙烷甲酰胺(51)
使用类似于实施例1中化合物4的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)环丙烷甲酰胺。1HNMR(400MHz,DMSO-d6)δ10.16(s,0.3H),10.10(s,0.7H),8.37(t,J=6.2Hz,0.3H),8.32(t,J=5.3Hz,1H),8.18(t,J=6.1Hz,0.7H),7.95(s,0.7H),7.89(s,0.3H),7.67–7.54(m,1.3H),7.47(d,J=8.5Hz,0.7H),6.87(d,J=10.0Hz,1H),4.84(s,0.3H),4.74(t,J=13.4Hz,0.7H),3.75–3.57(m,1H),3.55–3.37(m,2H),3.30-3.19(m,1H),2.30-1.85(m,5H),1.78–1.14(m,3H),0.77–0.45(m,4H)。LC-MS(m/z):514.2[M+H]+。
实施例43:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)-N-甲基乙酰胺(52)
步骤1:(R)-N-((1-(6-溴-3-甲基吡啶啉基)-5,5-二氟哌啶-2-基)甲基)-N-甲基乙酰胺(52-1)
搅拌下,(R)-N-((1-(6-溴-3-甲基吡啶啉基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(0.39g,1.0mmol,1eq.)溶于DMF(5mL)中,0℃下加入60%氢化钠(0.12g,3mmol,3eq.),0℃反应2小时,再加入碘甲烷(0.28g,2.0mmol,2eq.)室温反应12小时,加水淬灭,反应液倒入冰水中,乙酸乙酯萃取(3*30ml),有机层用无水硫酸镁干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash 25g,EtOAc/n-Hep=10%~50%),得到标题化合物。LC-MS(m/z):404.1[M+H]+。
步骤2:(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)-N-甲基乙酰胺(52)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)-N-甲基乙酰胺。1HNMR(400MHz,DMSO-d6)δ10.11(d,J=6.0Hz,0.8H),10.06(s,0.2H),8.33(t,J=6.2Hz,1H),7.91(s,0.4H),7.86(s,0.6H),7.67-7.64(m,1H),7.59–7.46(m,1H),6.88(t,J=7.4Hz,1H),4.83-4.69(m,1H),4.10–3.40(m,3H),3.26(s,1H),3.08(s,1H),2.64(s,2H),2.37–2.02(m,5H),2.01–1.56(m,5H)。LC-MS(m/z):502.2[M+H]+。
实施例44:(R)-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸甲酯(53)
步骤1:(R)-((1-(6-溴-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸甲酯(54)
使用类似于实施例1中化合物2的合成方法,得到(R)-((1-(6-溴-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸甲酯。LC-MS(m/z):406.1[M+H]+。
步骤2:(R)-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸甲酯(53)
使用类似于实施例1中化合物1的合成方法,得到(R)-((1-(6-((4-乙氧基吡啶-2-基)氨基)-3-甲基吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸甲酯。1H NMR(400MHz,DMSO-d6)δ9.68(s,0.3H),9.56(s,0.7H),8.02(dd,J=5.9,4.0Hz,1H),7.80–7.50(m,2H),7.39(dd,J=20.0,2.4Hz,1H),7.22(t,J=6.0Hz,1H),6.55–6.43(m,1H),4.81(s,0.4H),4.73(t,J=13.4Hz,0.6H),4.18–3.96(m,2H),3.86–3.59(m,1H),3.55(s,1H),3.42(s,2H),3.23(t,J=20.4Hz,2H),3.04(dd,J=13.8,6.8Hz,1H),2.30–1.60(m,6H),1.40-1.24(m,4H)。LC-MS(m/z):464.2[M+H]+。
实施例45:(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)-N-甲基异烟酰胺(55)
步骤1:(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)异烟酸甲酯(56)
使用类似于实施例1中化合物1的合成方法,得到(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)异烟酸甲酯。1H NMR(400MHz,DMSO-d6)δ10.10(s,0.3H),9.96(s,0.7H),8.40(dd,J=5.1,0.8Hz,1H),8.21(d,J=1.2Hz,0.3H),8.16–8.11(m,1H),7.89(t,J=6.1Hz,0.7H),7.73(dd,J=11.4,8.6Hz,1H),7.63(dd,J=8.6,3.4Hz,1H),7.28(dt,J=5.2,1.2Hz,1H),4.81(s,0.3H),4.75(t,J=13.4Hz,0.7H),3.87(s,3H),3.76–3.64(m,1H),3.63–3.37(m,2H),3.28(s,1H),2.34–1.97(m,5H),1.93-1.65(m,5H)。LC-MS(m/z):462.2[M+H]+。
步骤2:(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)异烟酸(57)
在15分钟内向(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)异烟酸甲酯(0.1g,0.2mmol)的MeOH(10mL)溶液中缓慢加入LiOH水溶液(1M,2mL,2.0mmol)。在搅拌下使反应混合物升温至室温过夜。真空除去有机溶剂,并将残余的水溶液用EA分液,将合并的水相用1N HCl酸化至pH=2,然后将有机相用水萃取(两次)。合并的有机萃取物经MgSO4干燥并浓缩,得到(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)异烟酸(0.06g,67.1%)。1H NMR(400MHz,DMSO-d6)δ10.04(s,0.3H),9.89(s,0.7H),8.36(dd,J=5.3,1.6Hz,1H),8.25(s,0.4H),8.14(t,J=6.1Hz,0.3H),8.03(s,0.6H),7.90(t,J=6.1Hz,0.7H),7.82(d,J=8.5Hz,0.7H),7.70(d,J=8.6Hz,0.3H),7.63(dd,J=8.7,2.4Hz,1H),7.26(td,J=4.8,1.4Hz,1H),4.82(s,0.4H),4.74(t,J=13.3Hz,0.6H),3.80–3.54(m,1H),3.42(d,J=14.2Hz,1H),3.32–3.17(m,2H),2.70–2.53(m,2H),2.36–1.90(m,4H),1.87-1.65(m,4H)。LC-MS(m/z):448.2[M+H]+。
步骤3:(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)-N-甲基异烟酰胺(55)
搅拌下,将(R)-2-((6-(2-(乙酰氨基甲基)-5,5-二氟哌啶-1-羰基)-5-甲基吡啶-2-基)氨基)异烟酸(0.045g,0.1mmol,1.0eq.)溶于DCM(2mL),在冰水浴温度下加入DIPEA(0.07g,0.5mmol,5eq.)和HATU(0.06g,0.15mmol,1.5eq.)。反应混合物在0℃下搅拌半小时,然后加入甲氨盐酸盐(0.015g,0.2mmol,2.0eq.),反应混合物在环境温度下搅拌过夜。用水和EtOAc处理反应混合物,并分离有机相。有机相用水洗涤,MgSO4干燥,并浓缩至干。粗品通过柱层析纯化(Biotage Rening Flash 25g,n-Hep/EtOAc=50%~100%),得到标题化合物(0.03g,65.21%)。1H NMR(400MHz,DMSO-d6)δ9.97(s,0.4H),9.80(s,0.6H),8.60(d,J=4.7Hz,0.4H),8.54(d,J=4.7Hz,0.6H),8.31(t,J=5.0Hz,1H),8.12(t,J=6.1Hz,0.4H),8.03(s,0.6H),7.89(d,J=7.3Hz,1H),7.77(t,J=1.1Hz,0.7H),7.72(d,J=8.6Hz,0.3H),7.62(dd,J=8.6,3.3Hz,1H),7.17(d,J=5.2,Hz,0.3H),7.13(d,J=5.3,Hz,0.7H),4.83(s,0.3H),4.72(t,J=13.4Hz,0.7H),3.86–3.54(m,2H),3.45-3.41(m,1H),3.31–3.19(m,1H),2.77(dd,J=4.6,3.4Hz,3H),2.27-2.05(m,5H),1.97–1.58(m,5H)。LC-MS(m/z):461.2[M+H]+。
实施例46:(R)-N-((5,5-二氟-1-((2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯基)磺酰基)哌啶-2-基)甲基)乙酰胺(58)
步骤1:(R)-N-((1-((5-溴-2-甲基苯基)磺酰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(59)
向N-(5,5-二氟-哌啶-2-基甲基)-乙酰胺(0.19g,1.0mmol)的溶液中添加DIPEA(0.39g,3.0mmol),然后滴加苯乙酰氯(0.27g,1mmol)的DCM(2mL)溶液。反应液在25℃下搅拌2小时,然后依次用10%HCl,10%NaHCO3和水洗涤,MgSO4干燥,过滤,然后蒸发溶剂,得到不纯的酰胺,将其从乙醇中重结晶,得到(R)-N-((1-((5-溴-2-甲基苯基)磺酰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(0.2g,47.6%)。
步骤2:(R)-N-((5,5-二氟-1-((2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯基)磺酰基)哌啶-2-基)甲基)乙酰胺(58)
使用类似于实施例1中化合物1的合成方法,得到(R)-N-((5,5-二氟-1-((2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯基)磺酰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),8.28(d,J=5.7Hz,1H),8.18(s,1H),7.95(d,J=7.8Hz,1H),7.76(s,1H),7.32(d,J=8.3Hz,1H),6.89–6.62(m,2H),3.81(d,J=12.2Hz,2H),3.65-3.53(m,2H),3.30-3.05(m,1H),2.40(s,3H),2.18-2.02(m,2H),1.82-1.61(m,5H)。LC-MS(m/z):523.1[M+H]+。
实施例47:N-((1R,5S)-3,3-二氟-5-((3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)氨基)环己基)乙酰胺(60)
步骤1:6-氯-5-甲基-N-(4-(三氟甲氧基)吡啶-2-基)吡啶-2-胺(61)
使用类似于实施例1中化合物1的合成方法,得到6-氯-5-甲基-N-(4-(三氟甲氧基)吡啶-2-基)吡啶-2-胺。LC-MS(m/z):304.1[M+H]+。
步骤2:N-((1R,5S)-3,3-二氟-5-((3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)氨基)环己基)乙酰胺(60)
使用类似于实施例1中化合物1的合成方法,得到N-((1R,5S)-3,3-二氟-5-((3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)氨基)环己基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.52(s,1H),8.25(d,J=5.7Hz,1H),7.96(d,J=7.5Hz,1H),7.82(d,J=2.1Hz,1H),7.18(dd,J=7.8,0.9Hz,1H),6.76(dd,J=5.3,2.7Hz,1H),6.65(d,J=7.8Hz,1H),5.66(d,J=8.6Hz,1H),4.26(d,J=11.4Hz,1H),3.87(s,1H),2.39–2.19(m,2H),2.15-1.89(s,5H),1.85–1.41(m,5H)。LC-MS(m/z):460.2[M+H]+。
实施例48:(R)-N-((5,5-二氟-1-((3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲基)哌啶-2-基)甲基)乙酰胺(62)
步骤1:(R)-6-((2-(氨基甲基)-5,5-二氟哌啶-1-基)甲基)-5-甲基-N-(4-(三氟甲氧基)吡啶-2-基)吡啶-2-胺(63)
向(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(0.22g,0.5mmol)与THF(5mL)的混合物中滴加BH3DMS(0.5mL,5.0mmol)。然后将混合物在80℃搅拌4h。通过添加MeOH将混合物淬灭,然后浓缩。将残余物通过硅胶柱层析纯化(PE:EA=1:10),得到(R)-6-((2-(氨基甲基)-5,5-二氟哌啶-1-基)甲基)-5-甲基-N-(4-(三氟甲氧基)吡啶-2-基)吡啶-2-胺(0.1g,46.5%收率)。
步骤2:(R)-N-((5,5-二氟-1-((3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲基)哌啶-2-基)甲基)乙酰胺(62)
使用类似于实施例1中化合物4的合成方法,得到(R)-N-((5,5-二氟-1-((3-甲基-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ9.99(s,0.4H),9.87(s,0.6H),8.30(d,J=7.1Hz,1H),8.23(s,1H),8.06(s,0.5H),7.56(d,J=8.4Hz,0.5H),7.43(d,J=8.3Hz,1H),7.21(s,1H),6.90–6.76(m,1H),5.05(d,J=18.8Hz,1H),4.05-3.95(m,1H),3.46–3.30(m,1H),3.08(t,J=10.2Hz,1H),2.84-2.67(m,3H),2.36-2.11(m,5H),2.07–1.76(m,4H),1.58-1.48(s,1H)。LC-MS(m/z):474.4[M+H]+。
实施例49:(R)-N-((5,5-二氟-1-(3-氟-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(64)
步骤1:(R)-((1-(6-氯-3-氟吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(65)
搅拌下,将6-氯-3-氟吡啶甲酸(0.2g,1.14mmol,1.0eq.)溶于DCM(3mL),在室温下加入SOCl2(677.72mg,5.70mmol,5.0eq.),反应混合物80℃下搅拌2h。将反应混合物真空蒸发,得到黄色固体。搅拌下,向(R)-((5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(313.67mg,1.25mmol,1.1eq.)和DIPEA(441.73mg,3.42mmol,3.0eq.)的搅拌溶液中,加入先前获得的酰氯产物的DCM溶液,反应混合物在室温下搅拌2h。粗品通过柱层析纯化(Biotage Rening Flash 20g,EtOAc/n-Hep=30%),得到标题化合物(416mg,89.5%收率)。LC-MS(m/z):407.8[M+H]+。
步骤2:(R)-((5,5-二氟-1-(3-氟-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶基)哌啶-2-基)甲基)氨基甲酸叔丁酯(66)
将(R)-((1-(6-氯-3-氟吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(150mg,367.81μmol,1eq.),4-(三氟甲氧基)吡啶-2-胺(79.50mg,441.38μmol,1.2eq.),Pd2(dba)3(16.85mg,18.39μmol,0.05eq.),BINAP(22.90mg,36.78μmol,0.1eq.),Cs2CO3(239.68mg,735.63μmol,2.0eq.)的混合物悬浮于1,4-二氧六环(3.0mL),并将所得混合物在氮气气氛下加热至90℃反应3小时。通过柱层析(Biotage Rening Flash 10g,EtOAc/n-Hep=100%~甲醇/EtOAc=10%)纯化反应溶液,然后进行反相柱层析(MeCN/水=40%),得到标题化合物(95mg,47.0%)。1H NMR(400MHz,Chloroform-d)δ8.65(d,J=9.3Hz,0.3H),8.29–8.24(m,1H),8.02(dd,J=9.0,3.3Hz,0.4H),7.86–7.66(m,1H),7.60–7.42(m,1H),7.18–6.61(m,2H),5.38(t,J=5.2,0.6H),5.13–4.97(m,1H),4.89(d,J=6.5Hz,0.4H),4.00(s,1H),3.80–2.99(m,4H),2.28–1.70(m,4H),1.65–1.43(m,9H)。LC-MS(m/z):549.5[M+H]+。
步骤3:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3-氟-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(67)
搅拌下,将(R)-((5,5-二氟-1-(3-氟-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶基)哌啶-2-基)甲基)氨基甲酸叔丁酯(80mg,145.60μmol,1.0eq.)溶于DCM(3mL),冰水浴温度下加入HCl的EA溶液(4M,3.64mL,100eq.)。反应混合物室温搅拌过夜。将混合物用饱和NaHCO3水溶液中和,并用DCM萃取。通过真空蒸发除去溶剂,得到标题化合物(50mg,76.4%产率)。1H NMR(400MHz,Chloroform-d)δ8.30–8.22(m,1H),8.13–7.87(m,1H),7.70(td,J=8.8,8.3,3.6Hz,1H),7.53–7.38(m,2H),6.75(s,0.5H),6.74(s,0.5H),5.07–4.97(m,1H),3.79–3.66(m,1H),3.51–2.65(m,4H),2.26–1.77(m,5H)。LC-MS(m/z):449.4[M+H]+。
步骤4:(R)-N-((5,5-二氟-1-(3-氟-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(64)
搅拌下,将CH3COOH(3.01mg,50.07μmol,1.5eq.),HATU(19.04mg,50.07μmol,1.5eq.),DIPEA(12.94mg,100.14μmol,3.0eq.)溶于DCM(3mL),室温下滴加(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3-氟-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(15mg,33.38μmol,1.0eq.)的DCM(2mL)溶液。反应混合物室温下搅拌2h。混合物用盐水洗涤并用DCM萃取。粗品通过反相柱层析纯化(MeCN/水=30%),得到标题化合物(10.5mg,64.0%)。1H NMR(400MHz,DMSO-d6)δ10.32(s,0.2H),10.29(s,0.8H),8.36–8.33(m,1H),8.09(t,J=6.2Hz,0.2H),7.93(t,J=6.1Hz,0.8H),7.83–7.75(m,2H),7.70(d,J=3.5Hz,0.5H),7.68(d,J=3.5Hz,0.2H),6.93–6.89(m,1H),4.83–4.75(m,0.3H),4.70–4.60(m,1H),3.87–3.37(m,3H),3.10(dt,J=13.8,5.7Hz,1H),2.35–1.82(m,4H),1.74–1.67(m,3H)。LC-MS(m/z):491.4[M+H]+。
实施例50:(R)-N-((5,5-二氟-1-(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯甲酰基)哌啶-2-基)甲基)乙酰胺(68)
步骤1:(R)-((1-(5-溴-2-甲基苯甲酰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(69)
使用类似于实施例49中化合物65的合成方法,得到(R)-((1-(5-溴-2-甲基苯甲酰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):446.3[M+H]+。
步骤2:(R)-((5,5-二氟-1-(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯甲酰基)哌啶-2-基)甲基)氨基甲酸叔丁酯(70)
使用类似于实施例49中化合物66的合成方法,得到(R)-((5,5-二氟-1-(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯甲酰基)哌啶-2-基)甲基)氨基甲酸叔丁酯。1HNMR(400MHz,Chloroform-d)δ8.22–8.09(m,1H),7.52–7.31(m,1H),7.25–6.94(m,2H),6.72–6.44(m,3H),5.94–4.91(m,2H),3.91–3.35(m,4H),3.24–2.90(m,2H),2.36–2.24(m,3H),2.20–1.78(m,4H),1.49–1.26(m,9H)。LC-MS(m/z):544.5[M+H]+。
步骤3:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯基)甲酮(71)
使用类似于实施例49中化合物67的合成方法,得到(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯基)甲酮。LC-MS(m/z):444.4[M+H]+。
步骤4:(R)-N-((5,5-二氟-1-(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯甲酰基)哌啶-2-基)甲基)乙酰胺(68)
使用类似于实施例49中化合物64的合成方法,得到(R)-N-((5,5-二氟-1-(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯甲酰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,Chloroform-d)δ8.21(s,0.8H),8.10(s,0.2H),7.36(d,J=8.4Hz,1H),7.25–7.18(m,1H),7.14–6.66(m,2H),6.66–6.44(m,2H),6.17(d,J=42.9Hz,1H),5.42–5.37(m,0.2H),5.10–5.01(m,0.8H),4.25–4.06(m,1H),3.99–2.95(m,4H),2.40–1.62(m,10H)。LC-MS(m/z):486.4[M+H]+。
实施例51:(R)-N-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)异烟酰基)哌啶-2-基)甲基)乙酰胺(72)
步骤1:(R)-((1-(2-溴-5-甲基异烟碱酰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(73)
使用类似于实施例49中化合物65的合成方法,得到(R)-((1-(2-溴-5-甲基异烟碱酰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):448.3[M+H]+。
步骤2:(R)-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)异烟酰基)哌啶-2-基)甲基)氨基甲酸叔丁酯(74)
使用类似于实施例49中化合物66的合成方法,得到(R)-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)异烟酰基)哌啶-2-基)甲基)氨基甲酸叔丁酯。1HNMR(400MHz,DMSO-d6)δ10.06(t,J=24.7Hz,1H),8.33–8.16(m,2H),7.86–7.43(m,2H),7.12–6.81(m,2H),4.77(d,J=67.8Hz,1H),3.75–3.39(m,2H),3.24–2.93(m,2H),2.32–1.64(m,7H),1.49–1.11(m,9H)。LC-MS(m/z):545.5[M+H]+。
步骤3:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-4-基)甲酮(75)
使用类似于实施例49中化合物67的合成方法,得到(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-4-基)甲酮。LC-MS(m/z):445.4[M+H]+。
步骤4:(R)-N-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)异烟酰基)哌啶-2-基)甲基)乙酰胺(72)
使用类似于实施例49中化合物64的合成方法,得到(R)-N-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)异烟酰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.12(s,0.4H),10.07(s,0.6H),8.30(dd,J=5.7,1.5Hz,1H),8.23–7.91(m,2H),7.83–7.43(m,2H),6.88–6.85(m,1H),4.78(dt,J=50.4,9.7Hz,1H),3.83–3.38(m,3H),3.28–3.10(m,1H),2.36–1.80(m,7H),1.73(s,3H)。LC-MS(m/z):487.4[M+H]+。
实施例52:(R)-N-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-羰基)哌啶-2-基)甲基)乙酰胺(76)
步骤1:(R)-((1-(2-氯-5-甲基嘧啶-4-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(77)
使用类似于实施例49中化合物65的合成方法,得到(R)-((1-(2-氯-5-甲基嘧啶-4-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):404.8[M+H]+。
步骤2:(R)-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯(78)
使用类似于实施例49中化合物66的合成方法,得到(R)-((5,5-二氟-1-(2-甲基-5-((4-(三氟甲氧基)吡啶-2-基)氨基)苯甲酰基)哌啶-2-基)甲基)氨基甲酸叔丁酯。1HNMR(400MHz,Chloroform-d)δ8.50(d,J=9.7Hz,1H),8.37–8.29(m,2H),8.18(d,J=11.4Hz,1H),6.81(dd,J=11.1,5.6Hz,1H),5.81(s,0.5H),5.06–4.96(m,1H),4.91(t,J=4,0.5H),3.75(s,1H),3.67–3.16(m,4H),2.25(d,J=17.6Hz,3H),2.18–1.73(m,4H),1.49(d,J=3.4Hz,9H)。LC-MS(m/z):546.5[M+H]+。
步骤3:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)甲酮(79)
使用类似于实施例49中化合物67的合成方法,得到(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-基)甲酮。LC-MS(m/z):446.4[M+H]+。
步骤4:(R)-N-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-羰基)哌啶-2-基)甲基)乙酰胺(76)
使用类似于实施例49中化合物64的合成方法,得到(R)-N-((5,5-二氟-1-(5-甲基-2-((4-(三氟甲氧基)吡啶-2-基)氨基)嘧啶-4-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.43(s,0.8H),10.40(s,0.2H),8.61(s,0.8H),8.58(s,0.2H),8.40–8.36(m,1H),8.26(s,0.3H),8.25–8.22(m,0.7H),8.13(t,J=6.2Hz,0.3H),7.93(t,J=6.1Hz,0.7H),7.01–6.96(m,1H),4.83–4.75(m,0.4H),4.67(t,J=13.2Hz,0.6H),3.76–3.37(m,4H),3.25–3.18(m,1H),2.35–1.79(m,7H)。LC-MS(m/z):488.4[M+H]+。
实施例53:(R)-N-((5,5-二氟-1-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(80)
步骤1:(R)-((1-(6-氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(81)
使用类似于实施例49中化合物65的合成方法,得到(R)-((1-(6-氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):389.8[M+H]+。
步骤2:(R)-((5,5-二氟-1-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯(82)
使用类似于实施例49中化合物66的合成方法,得到(R)-((5,5-二氟-1-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):531.5[M+H]+。
步骤3:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮(83)
使用类似于实施例49中化合物67的合成方法,得到(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-基)甲酮。LC-MS(m/z):431.4[M+H]+。
步骤4:(R)-N-((5,5-二氟-1-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺(80)
使用类似于实施例49中化合物64的合成方法,得到(R)-N-((5,5-二氟-1-(6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)哌啶-2-基)甲基)乙酰胺。1H NMR(400MHz,DMSO-d6)δ10.27(s,0.2H),10.23(s,0.8H),8.36(d,J=5.7Hz,1H),8.15–7.78(m,3H),7.68(d,J=8.5Hz,0.3H),7.59(d,J=8.4Hz,0.7H),7.02–6.89(m,2H),4.77(s,0.3H),4.62(t,J=13.3Hz,0.7H),4.10(s,1H),3.77–3.36(m,3H),3.14(dt,J=13.1,5.9Hz,1H),2.33–1.83(m,4H),1.74–1.69(m,3H)。LC-MS(m/z):473.4[M+H]+。
实施例54:(R)-N-((1-(3-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(84)
步骤1:(R)-((1-(3,6-二氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(85)
使用类似于实施例49中化合物65的合成方法,得到(R)-((1-(3,6-二氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯。LC-MS(m/z):424.3[M+H]+。
步骤2:(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3,6-二氯吡啶-2-基)甲酮(86)
搅拌下,将(R)-((1-(3,6-二氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)氨基甲酸叔丁酯(0.2g,471.40μmol,1.0eq.)溶于DCM(3mL),冰水浴温度下加入HCl的EA(4M,2mL,16.97eq.)溶液。反应混合物室温下搅拌过夜。将混合物用饱和NaHCO3水溶液中和,并用DCM萃取。通过真空蒸发除去溶剂,得到标题化合物(140mg,91.6%收率)。LC-MS(m/z):324.2[M+H]+。
步骤3:(R)-N-((1-(3,6-二氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(87)
搅拌下,将CH3COOH(27.79mg,462.74μmol,1.5eq.),HATU(175.95mg,462.74μmol,1.5eq.),DIPEA(119.61mg,925.49μmol,3.0eq.)溶于DCM(5mL),室温下滴加(R)-(2-(氨基甲基)-5,5-二氟哌啶-1-基)(3,6-二氯吡啶-2-基)甲酮(100.00mg,308.50μmol,1.0eq.)的DCM(2mL)溶液,反应混合物室温搅拌2h。混合物用盐水洗涤并用DCM萃取。粗品通过反相柱层析纯化(MeCN/水=30%),得到标题化合物(10.5mg,64.0%)。LC-MS(m/z):366.2[M+H]+。
步骤4:(R)-N-((1-(3-氯-6-((4-(三氟甲氧基)吡啶-2-基)氨基)吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(84)
将(R)-N-((1-(3,6-二氯吡啶-2-羰基)-5,5-二氟哌啶-2-基)甲基)乙酰胺(70.00mg,191.16μmol,1.0eq.),4-(三氟甲氧基)吡啶-2-胺(37.45mg,210.27μmol,1.1eq.),Pd2(dba)3(8.76mg,9.56μmol,0.05eq.),BINAP(11.90mg,19.12μmol,0.1eq.),Cs2CO3(124.57mg,382.32μmol,2.0eq.)悬浮于1,4-二氧六环(3.0mL),并将所得混合物在氮气气氛下加热至90℃反应3小时。通过柱层析(Biotage Rening Flash 10g,EtOAc/n-Hep=100%)纯化反应溶液,然后进行反相柱层析(MeCN/水=60%),得到标题化合物(53mg,54.6%)。1H NMR(400MHz,DMSO-d6)δ10.45(s,0.2H),10.39(s,0.8H),8.37–8.35(m,1H),8.08(t,J=6.2Hz,0.3H),7.91–7.86(m,1.7H),7.79(s,1H),7.74(d,J=9.0Hz,0.3H),7.70(d,J=9.0Hz,0.7H),6.96–6.92(m,1H),4.83–4.75(m,0.3H),4.69(t,J=13.2Hz,0.7H),3.77–3.38(m,3H),3.30–3.28(m,1H),2.36–1.78(m,4H),1.72(s,3H)。LC-MS(m/z):507.8[M+H]+。
生物学评价
实验例1CDK9、2、7、1激酶活性抑制测定
CDK9激酶为本公司自制或以市售方式获得。CDK1、2、7均购自Carna Biosciences,Inc。ADP-GloTM试剂盒购自Promega corporation。二硫苏糖醇(DTT)、Tween-20、二甲基亚砜(DMSO)、bovine serum albumin(BSA)和Tris碱以可获得的最高纯度水平从Sigma获得。
CDK抑制测定的一般程序:测定在由50μM DTT,0.1% BSA,40mM Tris-HCl、pH=7.5,20mM MgCl2组成的缓冲液中执行。利用缓冲液将DMSO溶解的化合物和CDK酶进行稀释,将1μL 5% DMSO的化合物溶液和2μL的CDK酶溶液添加到白色低体积384孔微量滴定板中,室温孵育20分钟。Ultra pure ATP,底物多肽(购自金斯瑞生物科技有限公司)一起稀释至缓冲液中,加入到化合物和酶的混合溶液中,每孔加入2μL,室温孵育2小时。不同CDK酶对应的底物及ATP反应浓度见表1。
表1
反应结束后,每个反应孔加入5μL ADP-GloTM试剂,室温孵育40分钟后,每个反应孔再加入10μL检测试剂,室温孵育30分钟。使用Tecan(Switzerland)多功能酶标仪Spark进行读板,检测化学发光Luminescence值。通过使用Prism 7(La Jolla,15 CA)在S形剂量反应曲线中拟合化学发光强度比值相对于抑制剂浓度来获得抑制剂的IC50值。
本申请代表性化合物的CDK9、2、7、1激酶活性抑制测定IC50值见表2。
表2
注:空白表示未测。
结果表明,本申请的代表性化合物能有效抑制CDK9的激酶活性,且IC50与临床候选化合物相当。与此同时,本申请代表性化合物对关键的细胞周期调控激酶CDK1和2的抑制活性远低于参比临床候选化合物,表现了良好的选择性,部分化合物达到了数千倍的选择性。
实验例2肿瘤细胞增殖抑制实验
急性髓性白血病(AML)细胞系,MOLM-13购自南京科佰生物科技有限公司。RPMI1640培养基、青霉素-链霉素双抗购自ThermoFisher(Waltham,MA,USA)。经认证的胎牛血清(FBS)购自Biological Industries(Israel)。康宁384孔细胞培养板购自CORNING(USA)。Cell-Titer 购自Promega Corporation(Madison,WI,USA)。
为了评估合成化合物对MOLM-13细胞增殖的抑制能力,将处于指数增长的MOLM-13细胞接种于含20%牛血清和1%青霉素-链霉素双抗的RPMI1640培养基,密度为500,000cell/mL,384孔板,每孔20μL,并放置在37℃、5% CO2的培养箱中过夜。将化合物粉末溶解在DMSO中,配制浓度为2mM的存储母液,并进一步配制12个3倍梯度浓度稀释液。将1μL梯度稀释DMSO溶液添加到99μL细胞培养基(测定中化合物的最终最高浓度为10μM,并且DMSO的最终浓度为0.5%)。将培养基中的20μL化合物溶液按照梯度加到384板的每个铺有细胞的测试孔中。在加入化合物溶液后,将384孔板放置于37℃,5% CO2培养箱中孵育16小时。采用Promega(Madison,WI,USA)的CellTiter-Glo检测试剂盒,通过定量检测测试孔中存在的ATP,测定细胞活力。20分钟的孵育后使用Tecan公司的Spark多功能酶标仪在化学发光的程序下进行读数。在Prism 7(LaJolla,CA)中使用S形剂量反应模型(可变斜率,四个参数)确定化合物使细胞成活率抑制50%的浓度(IC50值)。
本申请代表性化合物的MOLM-13细胞增殖抑制活性抑制测定IC50值见表3。
表3
结果表明,本申请的代表性化合物能有效地抑制MOLM-13细胞的增殖,大部分代表性化合物的IC50与临床候选化合物AZD4573相当,且明显优于临床候选化合物BAY1251152。
Claims (10)
1.一种通式(Ie)所示的化合物:
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其可药用的盐,
R1选自C1-C6烷基、卤代C1-C6烷基、卤素、氰基、硝基、-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OR4、-OC(O)R4、-OC(O)OR4、-OC(O)NR4R5、-NR4R5、-SR4、-S(O)R4、-S(O)2R4或含有0-3个杂原子的3-10元饱和或非饱和环,其中,所述含有0-3个杂原子的3-10元饱和或非饱和环可选地被1-3个R4取代;
R3选自-C(O)NR4R5、-C(O)R4、-C(O)OR4、-OC(O)R4、-OC(O)OR4、-OC(O)NR4R5、-(CH2)nNR4R5、-S(O)R4或-S(O)2R4;
每个R4和R5分别独立地选自氢、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基、卤代C3-C6环烷基、C3-C6杂环烷基、卤代C3-C6杂环烷基、卤素、=O、-(CH2)nC(O)NR6R7、-C(O)R6、-C(O)OR6、-OR6、-OC(O)R6、-OC(O)OR6、-OC(O)NR6R7、-(CH2)nNR6R7、-SR6、-S(O)R6、-(CH2)nS(O)2R6、-(CH2)nOH或-(CH2)nCN,或者,R4和R5与相邻的原子一起形成含有0-3个杂原子的5-6元饱和或非饱和环,其中,所述含有0-3个杂原子的5-6元饱和或非饱和环可选地被1-3个R6取代;
每个R6和R7分别独立地选自氢、卤素、羰基、羟基、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C3-C6环烷基或卤代C3-C6环烷基;并且
n独立地选自0、1、2或3。
2.根据权利要求1所述的通式(Ie)所示的化合物,其中R1选自氰基、硝基、卤素、三氟甲基、三氟甲氧基、二氟甲基、二氟甲氧基、单氟甲基、甲基、甲氧基或乙氧基。
3.根据权利要求1所述的通式(Ie)所示的化合物,其中R3选自-CH2NHC(O)CH3或-CH2NH2。
4.一种化合物,其选自:
5.权利要求1-4 中任一项化合物、其异构体或其药学上可接受的盐用于制备由CDK介导的疾病药物中的用途。
6.根据权利要求5所述的用途,其中,所述CDK介导的疾病为CDK9介导的疾病。
7.根据权利要求5所述的用途,其中,所述CDK介导的疾病为癌症、心血管病症、炎症性疾病、神经退行性疾病或病毒性疾病。
8.根据权利要求5所述的用途,其中,所述CDK介导的疾病为癌症。
9.根据权利要求8所述的用途,其中,所述癌症为白血病、淋巴瘤、多发性骨髓瘤、肺癌、前列腺癌、头颈癌、乳腺癌、胰腺癌、结直肠癌或黑色素瘤。
10.一种药物组合物,其包含治疗有效量的权利要求1-4任一项所述的化合物、其异构体或其药学上可接受的盐;以及药学上可接受的载体或赋形剂。
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