CN112262145B - 2-氨基嘧啶啶衍生物及其制备方法和用途 - Google Patents
2-氨基嘧啶啶衍生物及其制备方法和用途 Download PDFInfo
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- CN112262145B CN112262145B CN201980027483.5A CN201980027483A CN112262145B CN 112262145 B CN112262145 B CN 112262145B CN 201980027483 A CN201980027483 A CN 201980027483A CN 112262145 B CN112262145 B CN 112262145B
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- A61P35/00—Antineoplastic agents
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- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
本发明提供了一种具有预防和治疗与IDH突变相关的疾病的氨基嘧啶衍生物、其制备方法和用途。具体地,本发明提供了式I化合物、其立体异构体、外消旋体、或其药学上可接受的盐。所述通式I的化合物具有异柠檬酸脱氢酶1(IDH1)抑制活性,能治疗IDH1突变诱发的癌症。
Description
技术领域
本发明属于化学合成领域,具体地,本发明涉及一种具有突变型IDH抑制活性的2-氨基嘧啶啶衍生物、制备方法和用途。
背景技术
恶性肿瘤是威胁人类健康的重大疾病之一。在世界范围内,2008年有850万人死于肿瘤,并且按照目前的趋势至2020年预计会有2000万新发癌症病例,其中死亡人数将达到1200万。肿瘤的防治已成为各国医药界的重要研究课题。尽管人们对肿瘤的起因和发展有了较深入的了解,并有大量的抗肿瘤药物在临床上使用。然而这些应用广泛的抗肿瘤药物往往存在毒副作用大,易产生耐药等问题,使其临床治疗受到较大的限制。因而研制新型、高效、低毒的抗肿瘤药物具有十分重要的意义。
异柠檬酸脱氢酶(IDH)催化异柠檬酸酯氧化性脱羧至2-氧代戊二酸酯(α-酮戊二酸酯),同时产生二氧化碳和NADPH/NADH。这一过程在细胞的代谢过程中起了重要的作用。根据电子接受剂的不同,这些酶可分为两种不同的亚类,一种利用NAD(+),而另一种利用NADP(+)。已经报道的5种异柠檬酸酯脱氢酶中,3种是NAD(+)依赖性异柠檬酸酯脱氢酶,主要存在于线粒体基质;另外2种是NADP(+)依赖性,即异柠檬酸酯脱氢酶1和异柠檬酸酯脱氢酶2。异柠檬酸脱氢酶1主要存在于细胞质里,而异柠檬酸脱氢酶2主要存在于线粒体里。异柠檬酸脱氢酶的突变发生于很多种类型的癌症,包括但不限于:脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、前列腺癌、甲状腺癌、结肠癌、软骨肉瘤、胆管上皮癌、外周T细胞白血病、黑色素瘤等。
非突变IDH1催化异柠檬酸酯氧化性脱羧成α-酮戊二酸酯,从而在下列正向反应中还原NAD+(NADP+)至NADP(NADPH):
异柠檬酸酯+NAD+(NADP+)→α-酮戊二酸酯+CO2+NADH(NADPH)。
而突变型的异柠檬酸脱氢酶失去了上述正常功能,反而催化α-酮戊二酸酯NAPH-依赖性还原成R(-)-2-羟基戊二酸酯(2HG)。2-羟基戊二酸(2-HG)和α-KG结构相似,导致2-HG与α-KG竞争。上述两方面的原因均会使α-KG依赖的一些双加氧酶包括脯氨酸羟化酶(prolyl hydroxylase,PHD)、DNA羟化酶Tet家族和组蛋白赖氨酸脱甲基酶(histonelysine demethylases,KDMs)等的活性下降,最终导致肿瘤的发生。比如,在有IDH突变的急性白血病人检测到了高浓度2-HG。高浓度的2HG与致癌基因存在很大的关联性。因此,本领域急需研发突变型IDH抑制剂。
发明内容
本发明的目的在于提供一种式I化合物或其药学上可接受的盐,含有该化合物或其药学上可接受的盐的药物组合物,以及该化合物或组合物在预防和治疗与IDH突变相关的疾病中的应用。
本发明的第一方面,提供了一种如下式I所示的化合物,其立体异构体、外消旋体,或其药学上可接受的盐,其同位素取代的类似物:
其中,
n为0、1,2或3
A1选自下组:键、-CH2-、-CH(R)-、-C(R)2-、-CH2O-、-CH(R)O-、-C(R)2O-、-CH2N(R)-、-CH(R)N(R)-、-C(R)2N(R)-、-CH=CH-、-C(R)=CH-、-C(R)=C(R)-、-CH=N-、-C(R)=N-、-NR-、-O-、-S-,
A2、A3、A4、A5、A6、A7、A8、A9、A10各自独立地选自下组:C(R)2-、CH(R)、NR、O、S、CR或N;
B1、B2、B3各自独立地选自下组:CR或N;
虚线表示双键或无;
R选自下组:H、卤素、CN、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基;或两个R共同形成选自下组的基团:取代或未取代的-(CH2)n-结构、取代或未取代的-CH2-O-CH2-结构、取代或未取代的-O-CH2-O-结构;其中,m为2或3;或当两个R连接于同一个碳原子时,两个R基团与该碳原子形成C=O双键(羰基)。
R4、R6各自独立地选自选自下组:氢、氘、甲基、三氘甲基、二氘甲基、一氘甲基、乙基、三氟甲基、二氟甲基、一氟甲基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基;或R4和R6共同形成选自下组的基团:=O(与其相连的碳原子形成羰基),取代或未取代的-(CH2)n-结构、取代或未取代的-CH2-O-CH2-结构;其中,m为2或3;
R1、R2、R3、R5各自独立地为一个或多个对应五元或六元环上任意位置的取代基,选自下组的基团:H、羟基、氰基、卤素、三氟甲基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基;
其中,各个手性中心可以各自独立地为R构型或S构型;
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、羰基(C2-10)烷氧基、羰基(C7-10)芳氧基、酰胺基(C2-10)烷基、未取代或被1-3个选自下组的取代基取代的C6-C12芳基或3-12元杂环基:卤素、未取代或卤代的C1-C6烷基、C1-C6烷氧基。
在另一优选例中,所述的化合物具有如下式II所示的结构:
其中,各基团的定义如本发明第一方面中所述。
在另一优选例中,所述的化合物具有如下式III所示的结构:
其中,各基团的定义如权利要求1中所述。
在另一优选例中,所述的化合物具有如下式IV所示的结构:
其中,各基团的定义如权利要求1中所述。
R7选自:H、羟基、氰基、氨基、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基;
其中,各个手性中心可以各自独立地为R构型或S构型;
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、羰基(C2-10)烷氧基、羰基(C7-10)芳氧基、酰胺基(C2-10)烷基、未取代或被1-3个选自下组的取代基取代的C6-C12芳基或3-12元杂环基:卤素、未取代或卤代的C1-C6烷基、C1-C6烷氧基。
在另一优选例中,n=1,且A1为CR2或O。
在另一优选例中,R选自下组:H、卤素、CN、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基;或两个R共同形成选自下组的基团:取代或未取代的-(CH2)2-结构、取代或未取代的-CH2-O-CH2-结构;或当两个R连接于同一个碳原子时,两个R基团与该碳原子形成C=O双键(羰基)。
在另一优选例中,R1、R2、R3、R4、R5各自独立地为一个或多个对应五元或六元环上任意位置的选自下组的基团:H、卤素、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基。
本发明的第二方面,提供了一种药物组合物,所述的药物组合物包括:(a)作为活性成分的如本发明第一方面所述的式I化合物,或其外消旋体、R-异构体、S-异构体、可药用的盐或它们混合物,同位素取代的类似物和(b)药学上可接受的赋形剂。
在另一优选例中,所述的药物组合物还包括(c)第二活性成分。
在另一优选例中,所述的药物组合物用于治疗或预防携带IDH1突变的实体瘤,优选地,所述的药物组合物用于治疗或预防选自下组的适应症:脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、前列腺癌、甲状腺癌、结直肠癌、软骨肉瘤、胆管癌、白血病、黑色素瘤。
本发明的第三方面,提供了一种如下式I所述的化合物,及其外消旋体、R-异构体、S-异构体、可药用的盐,同位素取代的类似物或它们混合物的用途,用于:(1)制备治疗或预防与突变型IDH活性或表达量相关的疾病的药物组合物;(2)制备突变型IDH抑制剂。
在另一优选例中,所述的疾病为携带IDH1突变的实体瘤,较佳地选自下组:脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、急性白血病、前列腺癌、甲状腺癌、结直肠癌、软骨肉瘤、胆管癌、白血病、黑色素瘤。
在另一优选例中,所述肿瘤选自下组:神经胶质瘤、急性骨髓性白血病、肉瘤、前列腺癌、黑色素瘤、非小细胞肺癌、关节软骨瘤、和胆管瘤。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究,制备了一类具有式I所示结构的化合物,并发现其具有突变型IDH1抑制活性。且所述的化合物在极低浓度(可低至≤100nmol/L)下,即对一系列突变型IDH1产生抑制作用,抑制活性相当优异,因而可以用于治疗与突变型IDH相关的疾病如肿瘤。基于上述发现,发明人完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,在提到具体列举的数值中使用时,术语“约”意指该值可以从列举的值变动不多于1%。例如,如本文所用,表述“约100”包括99和101和之间的全部值(例如,99.1、99.2、99.3、99.4等)。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
基团定义
可在参考文献(包括Carey and Sundberg″ADVANCED ORGANIC CHEMISTRY 4THED.″Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-C6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(=O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子,且通过单键与分子的其余部分连接,例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。就本发明而言,术语“烷基”指含有1至6个碳原子的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烃基中的碳原子可以任选地被氧化。环烃基的实例包括但不限于环丙基、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、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)’。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。所述的药物组合物中通常含有有效量的本发明化合物(例如,含有0.01-100mg本发明化合物)。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”包括但不限于神经胶质瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。’在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R″(其中R″为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。
式I化合物
本发明提供一种式I所示的化合物,其立体异构体、外消旋体或其药学上可接受的盐,其同位素取代的类似物:
其中,
n为0、1,2或3
A1选自下组:键、-CH2-、-CH(R)-、-C(R)2-、-CH2O-、-CH(R)O-、-C(R)2O-、-CH2N(R)-、-CH(R)N(R)-、-C(R)2N(R)-、-CH=CH-、-C(R)=CH-、-C(R)=C(R)-、-CH=N-、-C(R)=N-、-NR-、-O-、-S-,
A2、A3、A4、A5、A6、A7、A8、A9、A10各自独立地选自下组:C(R)2-、CH(R)、NR、O、S、CR或N;
B1、B2、B3各自独立地选自下组:CR或N;
虚线表示双键或无;
R选自下组:H、卤素、CN、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基;或两个R共同形成选自下组的基团:取代或未取代的-(CH2)m-结构、取代或未取代的-CH2-O-CH2-结构、取代或未取代的-O-CH2-O-结构;其中,m为2或3;或当两个R连接于同一个碳原子时,两个R基团与该碳原子形成C=O双键(羰基)。
R4、R6各自独立地选自选自下组:氢、氘、甲基、三氘甲基、二氘甲基、一氘甲基、乙基、三氟甲基、二氟甲基、一氟甲基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基;或R4和R6共同形成选自下组的基团:=O(与其相连的碳原子形成羰基),取代或未取代的-(CH2)m-结构、取代或未取代的-CH2-O-CH2-结构;其中,m为2或3;
R1、R2、R3、R5各自独立地为一个或多个对应五元或六元环上任意位置的取代基,选自下组的基团:H、羟基、氰基、卤素、三氟甲基、取代或未取代的C1-C4烷基、取代或未取代的C1-C4烷氧基、取代或未取代的C3-C10环烷基、取代或未取代的C6-C12芳基、取代或未取代的3-12元杂芳基;
其中,各个手性中心可以各自独立地为R构型或S构型;
所述的取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、氨基、氰基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、羰基(C2-10)烷氧基、羰基(C7-10)芳氧基、酰胺基(C2-10)烷基、未取代或被1-3个选自下组的取代基取代的C6-C12芳基或3-12元杂环基:卤素、未取代或卤代的C1-C6烷基、C1-C6烷氧基。
优选地,所述的化合物选自下组:
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式I化合物的制备
下列反应方案示例性的说明了制备式I化合物、其立体异构体或其混合物、或其药学上可接受的盐的方法,其中各基团均如在上文式I化合物的实施方案部分中所述。应理解在下列反应方案中,所述通式中取代基和/或变量的组合只有在这类组合导致稳定的化合物时才是可允许的。
本发明提供一种制备本发明所述化合物的方法,包括步骤:
用式I-1化合物与式I-2化合物反应,得到式I化合物。
其中,各个基团的定义如上文中所述。
本发明的主要优点在于:
1.提供了一种如式I所示的化合物。
2.提供了一种结构新颖的用于预防和治疗与IDH突变相关的疾病的药物组合物。
3.提供了一种制备式I所示的化合物的方法。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
各实施例中:
LCMS仪器:Pump Agilent 1100 UV 检测器:Agilent 1100 DAD
Mass Spectrometer API 3000
层析柱:Waters sunfire C18,4.6×50mm,5um
流动相:A-乙腈 B-H2O(0.1%FA)
中间体A2的合成:
步骤一:7-三氟甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(A2-2)的合成
将化合物2-氨基-5-三氟甲基苯酚(A2-1,2.0g,11.29mmol)和碳酸钾(4.7g,34.00mmol)加入到20mL乙腈中,氮气保护下滴入化合物氯乙酰氯(1.4g,12.40mmol),滴加完毕后,升温至85℃回流,搅拌2小时。反应结束,将反应液浓缩,加入30mL乙酸乙酯和20mL水溶解,分液,有机相再用20mL水洗涤一次。有机相用无水硫酸钠干燥后浓缩,Combi-Flash快速硅胶色谱柱纯化得1.7g粉末状固体7-三氟甲基-2H-苯并[b][1,4]噁嗪-3(4H)-酮(A2-2),收率69.3%。LCMS:m/z=218.0(M+H)+,RT=4.55min。
步骤二:7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-甲酸甲酯(A2-3)的合成
在盛有24ml超干四氢呋喃的圆底烧瓶中加入A2-2(1.6g,7.37mmol),氮气保护下冷却到-30℃后向其中缓慢滴加NaHMDS(4.42ml,8.84mmol,2.0M四氢呋喃溶液),反应30分钟后,向其中缓慢滴加氯磷酸二乙酯(2.54g,14.74mmol),-30℃下搅拌30分钟,室温搅拌30分钟后再冷却到-30℃,向其中依次加入异氰乙酸甲酯(1.46g,14.74mmol)和NaHMDS(7.37ml,14.74mmol,2.0M四氢呋喃溶液),缓慢升到室温搅拌2小时后,TLC检测反应完毕,饱和氯化铵溶液淬灭,水稀释,乙酸乙酯萃取,有机相依次用水和饱和氯化钠溶液洗,无水硫酸钠干燥,过滤,浓缩,Combi-Flash快速硅胶色谱柱纯化得到1.25g黄色固体7-(三氟甲基)-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-甲酸甲酯(A2-3),收率:57.1%。LCMS:m/z=299.0(M+H)+,RT=4.79min。
步骤三:7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-甲醛(A2-4)的合成
将化合物A2-3(1.15g,3.87mmol)溶于35ml超干二氯甲烷中,在氮气保护下冷却到-78℃,缓慢向其中滴加DIBALH(10.32ml,15.48mmol,1.5M甲苯溶液),保持-78℃搅拌40分钟后,滴加预冷至-78℃的甲醇淬灭反应直至无气泡产生。升至室温,加二氯甲烷稀释,加入水和饱和酒石酸钾钠水溶液,搅拌3小时,直至分层。萃取得到有机层用无水硫酸钠干燥,过滤,Combi-Flash快速硅胶色谱柱纯化得到503mg 7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-甲醛(A2-4),收率:48.6%。LCMS:m/z=269.0(M+H)+,RT=4.55min。
步骤四:(S,E)-2-甲基-N-((7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)亚甲基)丙烷-2-亚磺酰胺(A2-5)的合成
将A2-4(480mg,1.79mmol)和(S)-叔丁基亚磺酰胺(390mg,3.22mmol)溶于3ml四氢呋喃溶液中,加入钛酸四乙酯(1.47g,6.44mmol),室温搅拌过夜,加入饱和氯化钠溶液和乙酸乙酯萃取,有机层无水硫酸钠干燥,过滤,Combi-Flash快速硅胶色谱柱纯化得到550mg(S,E)-2-甲基-N-((7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)亚甲基)丙烷-2-亚磺酰胺(A2-5),收率:82.7%。LCMS:m/z=372.0(M+H)+,RT=5.12min。
步骤五:(S)-2-甲基-N-((S)-1-(7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)丙烷-2-亚磺酰胺(A2-6)的合成
在-78℃,氮气保护下,将A2-5(550mg,1.48mmol)溶于30ml超干四氢呋喃中,缓慢滴加甲基溴化镁(8.88ml,8.88mmol,1.0M乙醚溶液),-78℃搅拌1小时后滴加饱和氯化铵溶液淬灭,加入二氯甲烷和水萃取,有机层无水硫酸钠干燥,过滤,Combi-Flash快速硅胶色谱柱纯化得到453mg(S)-2-甲基-N-((S)-1-(7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)丙烷-2-亚磺酰胺(A2-6),收率:78.9%。LCMS:m/z=388.0(M+H)+,RT=4.64min。
步骤六:(S)-1-(7-三氟甲基-4H-苯并[b]咪唑[1,5-d][1,4]噁嗪-3-基)乙胺(A2)的合成
在0℃,氮气保护下,将A2-6(453mg,1.17mmol)溶于4.5ml甲醇中,滴加0.45ml浓盐酸,室温搅拌2小时。加水稀释,旋蒸除掉部分甲醇,加入1N氢氧化钠溶液调pH至11,加入乙酸乙酯萃取3次,有机层用无水硫酸钠干燥,过滤旋干即得(S)-1-(7-三氟甲基-4H-苯并[b]咪唑[1,5-d][1,4]噁嗪-3-基)乙胺(A2)287mg,收率86.7%。粘稠液体,溶解分装,旋干称重备用。LCMS:m/z=267.0(M-NH)+,RT=3.71min。
中间体A4的合成
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将化合物2-氯-5-三氟甲基苯硼酸(A4-1,1.65g,7.35mmol),丙烯酰胺(0.52g,7.32mmol),氯化烯丙基钯(II)二聚物(134mg,0.37mmol),(1,5-环辛二烯)氯铑(I)二聚体(145mg,0.29mmol),XPhos(350mg,0.73mmol)和磷酸钾(3.40g,16.02mmol)加入到20mL叔戊醇和2mL甲醇的混合溶剂中,氮气保护,110℃下搅拌18小时。反应完成,将反应液经硅胶垫过滤,乙酸乙酯淋洗滤饼,滤液浓缩,Combi-Flash纯化,得1.2g淡黄色固体6-三氟甲基-3,4-二氢喹啉-2(1H)-酮(A4-2),收率73.8%。LCMS:m/z=216.0(M+H)+,RT=4.46min。
以化合物A4-2为原料,后续步骤同中间体A2的合成(步骤三若还原为醇可用适量戴斯马丁氧化剂处理),最终得到(S)-1-(7-三氟甲基-4,5-二氢咪唑[1,5-a]喹啉-3-基)乙胺(A4)。LCMS:m/z=265.1[M-NH]+,RT=3.53min。
中间体A5的合成
步骤一:2-溴-1-异硫氢基-4-三氟甲苯(A5-2)的合成
在封管中将化合物2-溴-4-三氟甲基苯胺(8g,33.33mmol),碘化亚铜(318mg,1.67mmol)和三氟甲磺酸钠(10.4g,66.66mmol)溶于100ml甲苯,氮气鼓泡后加入磷酸二乙酯(9.21g,66.66mmol),110℃搅拌16小时后将反应液倒入水中,乙酸乙酯萃取,有机相饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱分离得5.04g浅绿色固体2-溴-1-异硫氢基-4-三氟甲苯(A5-2),收率53.6%。
步骤二:6-三氟甲基苯并[d]咪唑并[5,1-b[噻唑-3-甲酸甲酯(A5-3)的合成
在氮气保护下,将A5-2(5.04g,17.87mmol),氯化亚铜(177mg,1.79mmol)和碳酸铯(11.64g,35.74mmol)溶于甲苯中,加入异氰基乙酸甲酯(3.54g,35.74mmol),110℃搅拌3小时。浓缩后加入乙酸乙酯和水萃取,有机层饱和氯化钠溶液洗,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱分离得2.33g黄色固体6-三氟甲基苯并[d]咪唑并[5,1-b]噻唑-3-甲酸甲酯(A5-3),收率43.5%。LCMS:m/z=301.0(M+H)+,RT=4.73min。
后续步骤同中间体A2(步骤三若还原为醇可用适量戴斯马丁氧化剂处理),最终得到(S)-1-(6-三氟甲基苯并[d]咪唑[1,5-b]噻唑-3-基)乙胺(A5)。LCMS:m/z=269.0[M-NH]+,RT=3.67min。
中间体A6的合成
步骤一:2-烯丙基-4-三氟甲基苯胺(A6-2)的合成
在氮气保护下将4-氨基-3-溴三氟甲苯(15g,62.49mmol),四(三苯基膦)钯(2.16g,1.87mmol)溶于100ml超干DMF中,加入AIBN(22.92g,69.23mmol),80℃搅拌19小时,冷却后加入乙酸乙酯和水萃取,有机层饱和氯化钠溶液洗,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱分离得8.147g褐色油状物2-烯丙基-4-三氟甲基苯胺(A6-2),收率65%。LCMS:m/z=202.1(M+H)+,RT=5.18min。
步骤二:N-(2-烯丙基-4-三氟甲基苯基)丙烯酰胺(A6-3)的合成
在氮气保护下,将2-烯丙基-4-三氟甲基苯胺(A6-2,8g,39.76mmol)溶于80ml超干四氢呋喃中,加入三乙胺(6.84g,67.59mmol),0℃下滴加丙烯酰氯(4.32g,47.71mmol),反应液缓慢升至室温1小时,继续搅拌1小时后浓缩,加入乙酸乙酯和水萃取,有机层饱和氯化钠溶液洗,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱分离得5.9g白色固体N-(2-烯丙基-4-三氟甲基苯基)丙烯酰胺(A6-3),收率58.1%。LCMS:m/z=256.1(M+H)+,RT=5.00min。
步骤三:7-三氟甲基-1,5-二氢-2H-苯并[b]氮卓-2-酮(A6-4)的合成
将N-(2-烯丙基-4-三氟甲基苯基)丙烯酰胺(A6-3,5.9g,23.11mmol)溶于150ml超干二氯甲烷中,加入Grubbs II催化剂(1.18g,1.39mmol),室温搅拌18小时。浓缩后combi-flash快速硅胶色谱分离得3.51紫色固体7-三氟甲基-1,5-二氢-2H-苯并[b]氮卓-2-酮(A6-4),收率66.8%。LCMS:m/z=228.0(M+H)+,RT=4.15min。
步骤四:7-三氟甲基-1,3,4,5-四氢-2H-苯并[b]氮卓-2-酮(A6-5)的合成
在氮气保护下,将7-三氟甲基-1,5-二氢-2H-苯并[b]氮卓-2-酮(A6-4,3.51g,15.45mmol)溶于30ml超干四氢呋喃和30ml无水乙醇中,加入10%钯/炭(512mg),置换氢气,室温下搅拌18小时,硅藻土过滤,浓缩后combi-flash快速硅胶色谱分离纯化得3.15g白色固体7-三氟甲基-1,3,4,5-四氢-2H-苯并[b]氮卓-2-酮(A6-5),收率98.0%。LCMS:m/z=230.1(M+H)+,RT=4.47min。
后续步骤同中间体A2(步骤三若还原为醇可用适量戴斯马丁氧化剂处理),最终得到(S)-1-(8-三氟甲基-5,6-二氢-4H-苯并[f]咪唑[1,5-a]氮杂卓-3-基)乙胺(A6),LCMS:m/z=279.1[M-NH]+,RT=3.49min。
中间体A9的合成
将3-氯-2-碘苯胺(A9-1,5g,19.73mmol),AIBN(1.29g,7.89mmol),三正丁基氢锡(8.6g,29.60mmol)溶于30ml超干DMSO中,0℃滴加丙烯酸乙甲酯(8.58ml,31.88mmol),120℃搅拌12h。降至室温后加入冰水淬灭,用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩后combi-flash硅胶色谱柱纯化得1.78g褐白色固体5-氯-3,4-二氢喹啉-2(1H)-酮(A9-2),收率49.7%。LCMS:m/z=182.1(M+H)+,RT=4.29min。
后续步骤同中间体A2(步骤三若还原为醇可用适量戴斯马丁氧化剂处理),最终得到(S)-1-(6-氯-4,5-二氢咪唑[1,5-a]喹啉-3-基)乙胺(A9)。LCMS:m/z=231.0[M-NH]+,RT=4.22min。
中间体A13,A14的合成
以2-氨基-5-溴苯酚(A13-1)为原料,通过类似中间体A2的合成方法可得到(S)-N-((S)-1-(7-溴-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺(A13-6)。LCMS:m/z=398.0(M+H)+,RT=4.68min。
在氮气保护下将(S)-N-((S)-1-(7-溴-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺(A13-6,200mg,0.50mmol),四(三苯基膦)钯(35mg,0.03mmol)和氰化锌(35mg,0.30mmol)溶于1ml超干DMF中,80℃搅拌6小时,冷却后加入2N氨水和乙酸乙酯萃取,有机层饱和氯化钠溶液洗,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱分离得166.7mg浅黄色液体(S)-N-((S)-1-(7-氰基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺,收率97.1%。LCMS:m/z=345.1(M+H)+,RT=4.30min。后续步骤同中间体A2(盐酸改用相同体积的盐酸二氧六环溶液),得到(S)-1-(7-氰基-4H-苯并[e]咪唑[1,5-d][1,4]噁嗪-3-基)乙胺(A13)。LCMS:m/z=224.1[M-NH]+,RT=0.57min。
在氮气保护下,将(S)-N-((S)-1-(7-溴-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺(A13-6,140mg,0.35mmol),醋酸钯(11mg,0.018mmol),正丁基二(1-金刚烷基)膦(10mg,0.028mmol),四氟环丙烷基钾(78mg,0.53mmol),碳酸铯(342mg,1.05mmol)溶于5ml甲苯∶水(10∶1)溶液,100℃搅拌7小时,加水和乙酸乙酯萃取,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱分离得86.9mg黄色固体(S)-N-((S)-1-(7-环丙基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)-2-甲基丙烷-2-亚磺酰胺,收率69.0%。LCMS:m/z=360.1(M+H)+,RT=4.84min。后续步骤同中间体A2(盐酸改用相同体积的盐酸二氧六环溶液),得到(S)-1-(7-环丙基-4H-苯并[e]咪唑[1,5-d][1,4]噁嗪-3-基)乙胺(A14)。LCMS:m/z=239.2[M-NH]+,RT=4.02min。
中间体A18的合成
步骤一:6-三氟甲基苯并[d]噻唑(A18-2)的合成
在氮气保护下,将6-三氟甲基苯并[d]噻唑-2-胺(A18-1,6.8g,31.16mmol)溶于60mlTHF中,滴加亚硝酸异戊酯(8.03g,68.55mmol)。回流1.5小时。反应液倒入60ml冰水,加乙酸乙酯萃取,有机相用无水硫酸钠干燥,过滤,浓缩,硅胶色谱柱纯化得6.0g黄色油状液体6-三氟甲基苯并[d]噻唑(A18-2),收率:43.2%。LCMS:m/z=204.0(M+H)+,RT=4.88min。
步骤二:2-氨基-5-三氟甲基苯硫酚(A18-3)的合成
在氮气保护下,将A18-2(6g,29.53mmol)溶于72ml乙醇中,加入85%水合肼(13.2g,223.25mmol),回流3小时。稍冷后冰水浴降至0~10℃,加入60ml水,缓慢加入用50%乙酸水溶液调pH至6-7.加入DCM萃取,有机相饱和氯化钠溶液洗,无水硫酸钠干燥,浓缩得5.6g黄色油状液体,直接用于下一步。收率:98.2%。LCMS:m/z=194.0(M+H)+,RT=4.89min。
步骤三:7-三氟甲基-2H-苯并[b][1,4[噻嗪-3(4H)-酮(A18-4)的合成
将化合物A18-3(5.0g,25.88mmol)和醋酸钠(3.2g,23.52mmol)加入到50mL乙醇中,氮气保护下滴入氯乙酸(2.9g,30.69mmol),滴加完毕后,回流搅拌2.5小时。反应结束,将反应液倒入100ml冰水中,搅拌30分钟后过滤,滤饼用硅胶色谱柱纯化,得3.7g 7-三氟甲基-2H-苯并[b][1,4]噻嗪-3(4H)-酮(A18-4),收率61.4%。LCMS:m/z=234.1(M+H)+,RT=5.78min。
以A18-4为原料,后续步骤同中间体A2,最终得到(S)-1-(7-三氟甲基-4H-苯并[b]咪唑[1,5-d][1,4]噻嗪-3-基)乙胺(A18),LCMS:m/z=283.0[M-NH]+,RT=3.54min。
使用如上方法,由相应或类似的市售的商业试剂分别合成得到中间体。
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中间体B1的合成:
步骤一:((2R,3R)-3-(叔丁氧基)-1-羟基丁烷-2-基)氨基甲酸苄酯(B1-2)的合成
将化合物N-苄氧羰基-O-叔丁基-L-苏氨酸二环己胺盐(B1-1)(10.0g,20.38mmol)加入到200mL四氢呋喃中,冷却至-25℃,氮气保护下搅拌。加入氯甲酸异丁酯(3.3g,24.16mmol)和N-甲基吗啡啉(2.5g,24.71mmol,1.2eq),保持-25℃下搅拌15分钟。过滤,滤液冷却至-20℃,加入硼氢化钠(1.5g,39.65mmol),缓慢滴入40mL水,滴加时间约为0.5-1小时。滴加完毕后,反应液升至室温搅拌30分钟。将反应液倒入200mL冰水中,乙酸乙酯萃取(200mL×2),合并有机相,用200mL水洗涤一次,200mL饱和食盐水洗涤一次,有机相用无水硫酸钠干燥后浓缩,得((2R,3R)-3-(叔丁氧基)-1-羟基丁烷-2-基)氨基甲酸苄酯(B1-2),直接用于下一步。LCMS:m/z=318.2(M+Na)+,RT=3.55min。
步骤二:(R)-4-((R)-1-(叔丁氧基)乙基)-3-(4-甲氧基苄基)噁唑烷-2-酮(B1-3)的合成
将化合物B1-2(6.0g,20.31mmol)溶于100mL DMF中,溶液氮气保护下冷却至0℃。分批加入氢化钠(60%,1.6g,40.00mmol),搅拌30分钟。加入对甲氧基苄氯(4.8g,30.65mmol)和四丁基碘化胺(0.8g,2.16mmol),反应液升至室温,搅拌过夜(16小时)。反应结束,将反应液倒入200mL冰水中淬灭,用乙酸乙酯萃取(100mL×3),合并有机相,并用100mL水洗涤两次,100mL饱和食盐水洗涤一次。有机相用无水硫酸钠干燥后浓缩,Combi-Flash快速硅胶色谱柱纯化,得淡黄色油状物(R)-4-((R)-1-(叔丁氧基)乙基)-3-(4-甲氧基苄基)噁唑烷-2-酮(B1-3)5.9g,收率94.5%。LCMS:m/z=308.1(M+H)+,RT=5.19min。
步骤三:(R)-4-((R)-1-羟乙基)-3-(4-甲氧基苄基)噁唑烷-2-酮(B1-4)的合成
将化合物B1-3(5.9g,19.19mmol)溶于40mL二氯甲烷中,加入40mL三氟乙酸,氮气保护,室温下搅拌30分钟。反应液浓缩,浓缩物加入50mL二氯甲烷再次浓缩,重复三次除去三氟乙酸。Combi-Flash快速硅胶色谱柱纯化,得3.4g白色固体(R)-4-((R)-1-羟乙基)-3-(4-甲氧基苄基)噁唑烷-2-酮(B1-4),收率70.7%。LCMS:m/z=252.1(M+H)+,RT=3.53min。
步骤四:(R)-4-((S)-1-氟乙基)-3-(4-甲氧基苄基)噁唑烷-2-酮(B1-5)的合成
将化合物B1-4(3.4g,13.53mmol)溶于45mL乙腈中,氮气保护下冷却至0℃。加入全氟氟代丁磺酰(7.4mL,40.59mmol)、三乙胺(17.0mL,121.77mmol)和三乙胺三氢氟酸盐(6.8mL,40.59mmol),保持0℃继续搅拌1小时。将反应液倒入90mL冰水中淬灭,乙酸乙酯萃取(90mL×3),合并有机相,用150mL水洗涤一次,150mL饱和食盐水洗涤一次,有机相用无水硫酸钠干燥后浓缩,Combi-Flash快速硅胶色谱柱纯化,得2.8g油状物(R)-4-((S)-1-氟乙基)-3-(4-甲氧基苄基)噁唑烷-2-酮(B1-5),收率81.4%。LCMS:m/z=254.1(M+H)+,RT=4.25min。
步骤五:(R)-4-((S)-1-氟乙基)噁唑烷-2-酮(B1-6)的合成
将化合物B1-5(2.8g,11.05mmol)加入到56mL三氟乙酸中,氮气保护下加热至65℃搅拌过夜(16小时)。反应结束,浓缩反应液,残留物过硅胶色谱柱纯化,得1.4g淡蓝色油状物(R)-4-((S)-1-氟乙基)噁唑烷-2-酮(B1-6)。收率95.1%。LCMS:m/z=134.1(M+H)+,RT=0.95min。
步骤六:(R)-4-((S)-1-氟乙基)-3-(2-氟嘧啶-4-基)-噁唑烷-2-酮(B1)的合成
将化合物B1-6(850mg,6.38mmol)和2,4-二氟嘧啶(740mg,6.37mmol)加入到10mLDMF中,混合物氮气保护下冷却至0℃。加入氢化钠(310mg,7.75mmol),搅拌30分钟后,将反应液升至室温继续搅拌2小时。反应结束,将反应液倒入30mL冰水中淬灭,乙酸乙酯萃取(30mL×3),合并有机相,并用60mL水洗涤一次,60mL饱和食盐水洗涤一次。有机相浓缩后Combi-Flash快速硅胶色谱柱纯化,得1.1g白色结晶状固体(R)-4-((S)-1-氟乙基)-3-(2-氟嘧啶-4-基)-噁唑烷-2-酮(B1),收率75.2%。LCMS:m/z=230.1(M+H)+,RT=3.90min。
中间体B5的合成:
步骤一:(S)-2-氨基-2-环丙基乙醇(B5-2)的合成
在氮气保护下将L-环丙基甘氨酸(1g,8.69mmol)溶于10ml超干四氢呋喃中,冰浴至0℃,缓慢滴加1.0M氢化铝锂四氢呋喃溶液(17.55ml,17.55mmol),随后缓慢升至室温搅拌16小时。缓慢滴加水淬灭反应,硅藻土过滤,四氢呋喃洗涤,滤液旋干即得546mg黄色液体(S)-2-氨基-2-环丙基乙醇(B5-2)粗品。LCMS:m/z=102.2(M+H)+,RT=0.55min。
步骤二:(S)-4-环丙基噁唑烷-2-酮(B5-3)的合成
向步骤一产物(B5-2)中加入碳酸钾(75mg,0.54mmol)和碳酸二乙酯(1.595g,13.5mmol),架上刺形分馏柱与蒸馏装置,搅拌并缓慢加热至130℃5h,冷却至室温后将残留物用二氯甲烷溶解并过滤,滤液用二氯甲烷和饱和碳酸氢钠溶液萃取洗涤,有机层用无水硫酸钠干燥,过滤,浓缩后得673mg(S)-4-环丙基噁唑烷-2-酮,直接用于下一步。LCMS:m/z=128.1(M+H)+,RT=1.65min。
后续步骤同中间体B1的合成步骤六,最终得到(S)-4-环丙基-3-(2-氟嘧啶-4-基)噁唑烷-2-酮(B5)。LCMS:m/z=224.1[M+H]+,RT=4.51min。
中间体B7的合成
将1-氨甲基-1-环丙醇(B7-1,5g,57.39mmol)和羰基二咪唑(9.31g,57.39mmol)溶于170ml超干四氢呋喃中,室温搅拌过夜,旋干得7.24g黄色油状液体4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(B7-2)粗品,直接用于下一步。LCMS:m/z=114.2(M+H)+,RT=1.15min。
后续步骤同中间体B1的合成步骤六,最终得到6-(2-氟嘧啶-4-基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(B7)。LCMS:m/z=210.1[M+H]+,RT=4.40min。
中间体B8的合成
氮气保护下,将N-(叔丁氧基羰基)-L-缬氨酸甲酯(B8-1,5g,21.62mmol)溶于50ml超干四氢呋喃中,0℃滴加甲级溴化镁(25.2ml,75.67mmol,3.0M乙醚溶液),10min后室温搅拌48小时。0℃滴加饱和氯化铵溶液淬灭,分层,水层用EA萃取。无水硫酸钠干燥,旋干。加入叔丁醇钾(222mg,1.99mmol)溶于13ml超干四氢呋喃中,室温搅拌3小时,加入饱和氯化铵溶液,乙酸乙酯萃取,有机层饱和氯化钠洗,无水硫酸钠干燥,Combiflash快速硅胶色谱分离得148.7mg白色固体(S)-4-异丙基-5,5-二甲基噁唑烷-2-酮(B8-3)。LCMS:m/z=158.1(M+H)+,RT=3.55min。
后续步骤同中间体B1的合成步骤六。最终得到(S)-3-(2-氟嘧啶-4-基)-4-异丙基-5,5-二甲基-噁唑烷-2-酮(B8)。LCMS:m/z=254.1[M+H]+,RT=4.85min。
中间体B9的合成
步骤一:(S)-(3-甲基-1-吗啉基-1-氧丁烷-2-基)氨基甲酸叔丁酯(B9-2)的合成
将(S)-Boc缬氨酸(5g,23.01mmol)溶于100ml超干二氯甲烷中,加入DCC(6.17g,29.91mmol)和HOBT(3.42g,25.31mmol),搅拌10min后滴加吗啉(3g,34.52mmol),室温搅拌17h,过滤,滤液用1M稀盐酸洗,饱和碳酸氢钠洗,无水硫酸钠干燥,过滤浓缩后combi-flash快速硅胶色谱纯化得5.43g透明黏稠液体(S)-(3-甲基-1-吗啉基-1-氧丁烷-2-基)氨基甲酸叔丁酯(B9-2)。
步骤二:(S)-(2-甲基-4-氧-3-戊基)氨基甲酸叔丁酯(B9-3)的合成
氮气保护下,将B9-2(5.43g,18.96mmol)溶于90ml超干四氢呋喃中,0℃滴加甲基溴化镁(47.4ml,47.40mmol,1.0M四氢呋喃溶液),0℃搅拌1小时,室温1小时。0℃滴加1M稀盐酸淬灭,乙醚萃取,Combiflash快速硅胶色谱纯化得728mg浅黄色液体(S)-(2-甲基-4-氧-3-戊基)氨基甲酸叔丁酯(B9-3)。LCMS:m/z=116.2(M+H)+,RT=4.72min。
步骤三:((3S)-2-羟基-4-甲基戊烷-3-基)氨基甲酸叔丁酯(B9-4)的合成
0℃,将B9-3(728mg,3.38mmol)溶于7ml无水甲醇,分批加入硼氢化钠(256mg,6.76mmol),室温搅拌1小时,加入1M稀盐酸淬灭,乙酸乙酯和水萃取,有机层无水硫酸钠干燥,过滤浓缩得765mg白色胶体((3S)-2-羟基-4-甲基戊烷-3-基)氨基甲酸叔丁酯粗品(B9-4),直接用于下一步。LCMS:m/z=118.2(M+H-100)+,RT=4.18min。
后续步骤同中间体B8,最终得到(4S)-3-(2-氟嘧啶-4-基)-4-异丙基-5-甲基-噁唑烷-2-酮(B9),LCMS:m/z=240.1[M+H]+,RT=4.88min。
中间体B10的合成
在茄形烧瓶中加入3-氧杂环丁酮(B10-1,1g,13.88mmol),三乙胺(281mg,2.78mmol),缓慢加入TMS-CN(1.65g,16.66mmol)(放热),搅拌1小时后旋干,将残留物溶于10ml乙醚中,滴入苯基溴化镁(6.01ml,18.04mmol,3.0M乙醚溶液),再加入5ml乙醚,搅拌4小时。缓慢加入3ml甲醇,缓慢加入硼氢化钠(630mg,16.66mmol),缓慢加入12ml甲醇(放气),搅拌过夜,小心滴加6ml水和20ml 10%盐酸,剧烈搅拌4小时后加入乙醚,有机层用20ml 10%盐酸萃取,水层用乙醚洗两次,水层加入6N氢氧化钠溶液,奶白色溶液用DCM萃1次,EA/THF(1∶1)1次,EA2次,再分别用饱和碳酸氢钠溶液洗,无水硫酸钠干燥,旋干即得1.99g黄色液体(S)-3-(氨基(苯基)甲基)环氧丙烷-3-醇(B10-2)粗品。LCMS:m/z=180.1(M+H)+,RT=2.54min。
后续步骤同中间体B7,最终得到(S)-7-(2-氟嘧啶-4-基)-8-苯基-2,5-二氧杂-7-氮杂螺[3.4]辛烷-6-酮(B10)。LCMS:m/z=302.1[M+H]+,RT=4.47min。
使用如上方法,用相应或类似的原料得到中间体B2-B10。
化合物1的合成:
(R)-3-(2-(((S)-1-(7-氯-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基胺)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A1(30mg,0.12mmol)和B1(27.5mg,0.12mmol)溶于1.4mlDMSO中,加入DIPEA(46.5mg,0.36mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(2-(((S)-1-(7-氯-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基胺)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 1,白色固体,45.1mg,81.8%)。LCMS:m/z=459.0(M+H)+,RT=4.44min。1HNMR(400MHz,Chloroform-d)δ8.19(d,J=5.8Hz,1H),7.89(s,1H),7.46(d,J=5.8Hz,1H),7.33(d,J=8.5Hz,1H),7.07(d,J=2.1Hz,1H),7.01(dd,J=8.5,2.2Hz,1H),5.68(br,1H),5.37-4.78(m,4H),4.74-4.58(m,1H),4.51(d,J=3.3Hz,1H),4.36(t,J=9.0Hz,1H),1.60(d,J=6.9Hz,3H),1.24(br,3H).化合物2的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-三氟甲基-4H-苯并[b]咪唑[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A2(40mg,0.14mmol)和B1(32.1mg,0.14mmol)溶于1.5ml DMSO中,加入DIPEA(54mg,0.42mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-三氟甲基-4H-苯并[b]咪唑[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 2,白色固体,49.7mg,71.5%)。LCMS:m/z=493.0(M+H)+,RT=4.77min。1H NMR(400MHz,Chloroform-d)δ8.11(d,J=5.8Hz,1H),7.90(s,1H),7.44(d,J=8.1Hz,1H),7.38(d,J=5.8Hz,1H),7.27-7.19(m,2H),6.70-5.40(br,1H),5.34-4.78(m,4H),4.59(dd,J=26.7,8.5Hz,1H),4.42(dd,J=8.9,3.3Hz,1H),4.29(t,J=9.0Hz,1H),1.55(d,J=6.9Hz,3H),1.17(d,J=17.8Hz,3H).
化合物3的合成
(S)-4-异丙基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A4(55.2mg,0.19mmol)和B2(46mg,0.19mmol)溶于1.5ml DMSO中,加入DIPEA(74mg,0.57mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-4-异丙基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 3,白色固体,35.3mg,37.0%)。LCMS:m/z=487.0(M+H)+,RT=4.48min。δ8.18(d,J=5.8Hz,1H),7.99(s,1H),7.59-7.46(m,3H),7.43(d,J=5.8Hz,1H),5.70(br,1H),5.19(br,1H),4.68(br,1H),4.35-4.20(m,2H),3.18-2.82(m,4H),2.51(br,1H),1.59(d,J=6.8Hz,3H),0.90(d,J=6.9Hz,3H),0.81(d,J=6.5Hz,3H).
化合物4的合成
(R)-3-(2-(((S)-1-(7-氯-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A3(41.5mg,0.16mmol)和B1(37mg,0.16mmol)溶于1.6ml DMSO中,加入DIPEA(62mg,0.48mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(2-(((S)-1-(7-氯-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 4,白色固体,47.3mg,61.8%)。LCMS:m/z=457.0(M+H)+,RT=4.22min。1H NMR(400MHz,Chloroform-d)δ8.21(d,J=5.7Hz,1H),7.93(s,1H),7.46(d,J=5.7Hz,1H),7.35-7.24(m,3H),5.75(br,1H),5.17(br,2H),4.82-4.61(m,1H),4.54(dd,J=8.8,3.4Hz,1H),4.39(t,J=8.9Hz,1H),3.20-2.75(m,4H),1.58(d,J=6.8Hz,3H),1.33(d,J=19.1Hz,3H).
化合物5的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A4(80mg,0.28mmol)和B1(64mg,0.28mmol)溶于3ml DMSO中,加入DIPEA(108mg,0.84mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 5,白色固体,26mg,18.6%)。LCMS:m/z=491.0(M+H)+,RT=4.70min。1H NMR(400MHz,Chloroform-d)δ8.19(s,1H),7.98(s,1H),7.60-7.39(m,4H),5.72(br,1H),5.16(br,2H),4.76-4.61(m,1H),4.52(d,J=8.4Hz,1H),4.37(t,J=8.6Hz,1H),3.15-2.80(d,J=63.1Hz,4H),1.57(d,J=6.6Hz,3H),1.32(d,J=21.3Hz,3H).
化合物6的合成
(R)-3-(5-氟-2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A4(49.4mg,0.17mmol)和B3(44.8mg,0.17mmol)溶于1.5ml DMSO中,加入DIPEA(66mg,0.51mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(5-氟-2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 6,白色固体,20.5mg,22.9%)。LCMS:m/z=509.0(M+H)+,RT=4.39min。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=2.8Hz,1H),7.98(s,1H),7.58-7.46(m,3H),5.86(br,1H),5.15-4.87(m,2H),4.75-4.61(m,1H),4.50(p,J=8.6Hz,2H),3.13-2.84(m,4H),1.56(d,J=6.8Hz,3H),1.27(dd,J=23.2,6.3Hz,3H).
化合物7的合成
(R)-3-(6-氯-2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A4(60.1mg,0.21mmol)和B4(70mg,0.25mmol)溶于1.7ml DMSO中,加入DIPEA(81mg,0.63mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(6-氯-2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 7,白色固体,15.7mg,14.0%)。LCMS:m/z=525.0(M+H)+,RT=5.13min。1H NMR(400MHz,Chloroform-d)δ7.97(s,1H),7.60-7.45(m,4H),5.92(d,J=7.3Hz,1H),5.40-4.87(m,2H),4.81-4.28(m,3H),3.39-2.77(m,4H),1.59(d,J=6.5Hz,3H),1.42-1.23(m,3H).
化合物8的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(6-三氟甲基苯并[d]咪唑并[5,1-b]噻唑-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A5(32.2mg,0.11mmol)和B1(25mg,0.11mmol)溶于1.5ml DMSO中,加入DIPEA(43mg,0.33mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(6-三氟甲基苯并[d]咪唑并[5,1-b]噻唑-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 8,白色固体,36.5mg,65.4%)。LCMS:m/z=495.1(M+H)+,RT=4.78min。1HNMR(400MHz,Chloroform-d)δ8.29(s,1H),8.24(d,J=5.8Hz,1H),7.78(s,1H),7.73(d,J=8.4Hz,1H),7.63(d,J=8.4Hz,1H),7.51(d,J=5.8Hz,1H),6.21(br,1H),5.17(br,1H),4.65(dd,J=26.7,7.4Hz,1H),4.58-4.40(m,2H),4.36(t,J=8.9Hz,1H),1.67(d,J=6.9Hz,3H),1.06(br,3H).
化合物9的合成
(S)-4-异丙基-3-(2-(((S)-1-(8-三氟甲基-5,6-二氢-4H-苯并[f]咪唑并[1,5-a]氮杂卓-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A6(46.6mg,0.16mmol)和B2(46mg,0.19mmol)溶于1.7ml DMSO中,加入DIPEA(62mg,0.48mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-4-异丙基-3-(2-(((S)-1-(8-三氟甲基-5,6-二氢-4H-苯并[f]咪唑并[1,5-a]氮杂卓-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 9,白色固体,58.1mg,73.5%)。LCMS:m/z=501.2(M+H)+,RT=4.49min。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=5.8Hz,1H),7.71(s,1H),7.64(d,J=8.2Hz,1H),7.60(s,1H),7.45(d,J=5.8Hz,1H),7.42(d,J=8.2Hz,1H),5.79(br,1H),5.24(br,1H),4.72(br,1H),4.35-4.25(m,2H),2.75-2.50(m,5H),2.12(br,2H),1.62(d,J=6.7Hz,3H),0.94(d,J=7.0Hz,3H),0.85(d,J=6.9Hz,3H).
化合物10的合成
(4R)-4-((S)-1-氟乙基)-3-(2-(((1S)-1-(5-甲基-7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A7(41.9mg,0.14mmol)和B1(34mg,0.15mmol)溶于1ml超干DMSO中,加入DIPEA(54mg,0.42mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(4R)-4-((S)-1-氟乙基)-3-(2-(((1S)-1-(5-甲基-7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 10,白色固体,46.1mg,65.3%)。LCMS:m/z=505.1(M+H)+,RT=4.94min。1H NMR(400MHz,Chloroform-d)δ8.20(dd,J=5.7,2.0Hz,1H),7.99(s,1H),7.55(d,J=5.6Hz,2H),7.49(d,J=8.8Hz,1H),7.45(dd,J=5.7,4.0Hz,1H),5.72(br,1H),5.17(br,2H),4.69(dd,J=26.7,7.1Hz,1H),4.59-4.44(m,1H),4.37(t,J=8.9Hz,1H),3.19-2.68(m,3H),1.57(dd,J=6.8,2.4Hz,3H),1.45-1.10(m,6H).
化合物11的合成
(R)-3-(2-(((S)-1-(7-氟-4,5-二氢嘧啶[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A8(36.6mg,0.16mmol)和B 1(41.2mg,0.18mmol)溶于1.2ml DMSO中,加入DIPEA(62mg,0.48mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(2-(((S)-1-(7-氟-4,5-二氢嘧啶[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 11,白色固体,46.6mg,66.9%)。LCMS:m/z=441.2(M+H)+,RT=3.96min。1H NMR(400MHz,Chloroform-d)δ8.21(d,J=5.7Hz,1H),7.91(s,1H),7.46(d,J=5.7Hz,1H),7.36(dd,J=8.5,4.7Hz,1H),7.08-6.96(m,2H),5.66(d,J=7.7Hz,1H),5.17(br,2H),4.70(dd,J=26.2,7.4Hz,1H),4.53(dd,J=8.8,3.4Hz,1H),4.38(t,J=8.9Hz,1H),2.95(d,J=70.2Hz,4H),1.58(d,J=6.8Hz,3H),1.33(dd,J=22.9,5.6Hz,3H).
化合物12的合成
(S)-4-异丙基-3-(2-(((S)-1-(7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噻嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A18(34.1mg,0.11mmol)和B2(29mg,0.12mmol)溶于1.5ml DMSO中,加入DIPEA(43mg,0.33mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-4-异丙基-3-(2-(((S)-1-(7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噻嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 12,白色固体,14.2mg,24.7%)。LCMS:m/z=505.1(M+H)+,RT=4.92min。1HNMR(400MHz,Chloroform-d)δ8.17(d,J=5.6Hz,1H),7.97(s,1H),7.72(s,1H),7.56-7.45(m,3H),5.23(br,1H),4.67(br,1H),4.35-4.15(m,4H),4.03(d,J=13.9Hz,1H),2.48(br,1H),1.65(d,J=6.7Hz,3H),0.96-0.87(m,3H),0.82(d,J=5.8Hz,3H).
化合物13的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(8-三氟甲基-5,6-二氢-4H-苯并[f]咪唑并[1,5-a]氮杂卓-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A6(41.5mg,0.14mmol)和B1(34mg,0.15mmol)溶于1.6ml DMSO中,加入DIPEA(54mg,0.42mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(8-三氟甲基-5,6-二氢-4H-苯并[f]咪唑并[1,5-a]氮杂卓-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 13,白色固体,61.4mg,86.6%)。LCMS:m/z=505.1(M+H)+,RT=4.34min。1H NMR(400MHz,Chloroform-d)δ8.19(d,J=5.7Hz,1H),7.67(s,1H),7.61(d,J=8.2Hz,1H),7.57(s,1H),7.45(d,J=5.7Hz,1H),7.39(d,J=8.1Hz,1H),5.77(br,1H),5.19(br,2H),4.80-4.60(m,1H),4.52(dd,J=8.8,3.4Hz,1H),4.38(t,J=8.7Hz,1H),2.78-2.49(m,4H),2.25-1.80(m,2H),1.58(d,J=6.7Hz,3H),1.33(dd,J=22.9,5.4Hz,3H).
化合物14的合成
(4R)-4-((S)-1-氟乙基)-3-(2-(((1S)-1-(4-甲基-7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A11(45.3mg,0.15mmol)和B1(39mg,0.17mmol)溶于1ml DMSO中,加入DIPEA(58mg,0.45mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(4R)-4-((S)-1-氟乙基)-3-(2-(((1S)-1-(4-甲基-7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 14,白色固体,51.6mg,68.2%)。LCMS:m/z=505.0(M+H)+,RT=4.81min。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=5.7Hz,1H),7.98(s,1H),7.55(s,2H),7.49(d,J=8.6Hz,1H),7.44(d,J=5.7Hz,1H),5.76(br,1H),5.45-5.00(m,2H),4.69(d,J=21.5Hz,1H),4.52(dt,J=8.5,3.7Hz,1H),4.37(t,J=8.6Hz,1H),3.70-3.35(d,J=63.6Hz,1H),3.07(dd,J=15.5,5.4Hz,1H),2.852.70(m,1H),1.58(d,J=6.7Hz,3H),1.34(dd,J=23.1,6.6Hz,3H),1.11(d,J=7.1Hz,3H).
化合物15的合成
(4R)-4-((S)-1-氟乙基)-3-(2-(((1S)-1-(4-甲基-7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A12(42.6mg,0.14mmol)和B1(34mg,0.15mmol)溶于1ml DMSO中,加入DIPEA(54mg,0.42mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(4R)-4-((S)-1-氟乙基)-3-(2-(((1S)-1-(4-甲基-7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 15,白色固体,23.2mg,32.7%)。LCMS:m/z=507.1(M+H)+,RT=5.23min。1H NMR(400MHz,Chloroform-d)δ8.22(d,J=5.8Hz,1H),7.97(d,J=2.5Hz,1H),7.55-7.47(m,2H),7.37-7.29(m,2H),5.71(q,J=6.7Hz,1H),5.59(q,J=6.5Hz,1H),5.21(br,2H),4.70(ddd,J=26.5,9.1,2.1Hz,1H),4.54(dt,J=8.3,4.1Hz,1H),4.39(t,J=9.0Hz,1H),1.72-1.52(m,6H),1.35(dd,J=23.1,5.9Hz,3H).
化合物16的合成
(S)-8-苯基-7-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-2,5-二氧杂-7-氮杂螺[3.4]辛烷-6-酮
将A4(64.5mg,0.23mmol)和B10(75mg,0.25mmol)溶于1.6ml DMSO中,加入DIPEA(89mg,0.69mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-8-苯基-7-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-2,5-二氧杂-7-氮杂螺[3.4]辛烷-6-酮(Compound 16,白色固体,33.1mg,25.7%)。LCMS:m/z=563.2(M+H)+RT=5.01min。1H NMR(400MHz,Chloroform-d)δ8.07(d,J=5.7Hz,1H),7.92(s,1H),7.46(dt,J=18.7,8.4Hz,3H),7.35(d,J=5.6Hz,1H),7.30-7.05(m,5H),5.80-5.40(m,2H),5.20-4.59(m,3H),4.52(d,J=8.4Hz,1H),4.03(d,J=8.2Hz,1H),2.94-2.05(m,4H),1.48(br,3H).
化合物17的合成
(4S)-4-异丙基-5-甲基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A4(55.4mg,0.20mmol)和B9(53mg,0.22mmol)溶于1.3ml DMSO中,加入DIPEA(78mg,0.60mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(4S)-4-异丙基-5-甲基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 17,白色固体,53.1mg,53.0%)。LCMS:m/z=501.2(M+H)+RT=5.04min。1H NMR(400MHz,Chloroform-d)δ8.16(d,J=5.7Hz,1H),7.98(s,1H),7.57-7.45(m,3H),7.41(d,J=5.7Hz,1H),5.71(br,1H),5.19(br,1H),4.72(br,2H),3.18-2.82(m,4H),2.22(br,1H),1.57(d,J=6.8Hz,3H),1.51(d,J=6.3Hz,3H),0.93(d,J=6.3Hz,6H).
化合物18得合成
(S)-4-异丙基-5,5-二甲基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
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将A4(64.7mg,0.23mmol)和B8(63mg,0.25mmol)溶于1.6ml DMSO中,加入DIPEA(89mg,0.69mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-4-异丙基-5,5-二甲基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 18,白色固体,60.6mg,51.2%)。CMS:m/z=515.2(M+H)+,RT=5.06min。1H NMR(400MHz,Chloroform-d)δ8.15(d,J=5.7Hz,1H),7.98(s,1H),7.57-7.45(m,3H),7.40(d,J=5.7Hz,1H),5.70(br,1H),5.18(br,1H),4.47(s,1H),3.15-2.80(m,4H),2.18(br,1H),1.56(d,J=6.8Hz,3H),1.50(s,3H),1.35(s,3H),0.90(d,J=6.4Hz,6H).
化合物19的合成
(S)-6-(2-((1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮
将A4(54.7mg,0.19mmol)和B7(43.9mg,0.21mmol)溶于1.2ml DMSO中,加入DIPEA(74mg,0.57mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-6-(2-((1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-氧杂-6-氮杂螺[2.4]庚烷-5-酮(Compound 19,白色固体,51.6mg,57.7%)。LCMS:m/z=471.1(M+H)+,RT=5.04min。1H NMR(400MHz,Chloroform-d)δ8.16(d,J=5.7Hz,1H),7.98(s,1H),7.58-7.46(m,3H),7.40(d,J=5.7Hz,1H),5.80(br,1H),5.20(br,1H),4.16(s,2H),3.15-2.84(m,4H),1.57(d,J=6.8Hz,3H),1.26(br,2H),0.80(br,2H).19F NMR(376MHz,Chloroform-d)δ-62.28.
化合物20的合成
(S)-4-苯基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A4(62.8mg,0.22mmol)和B6(62mg,0.24mmol)溶于1.5ml DMSO中,加入DIPEA(85mg,0.66mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-4-苯基-3-(2-(((S)-1-(7-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 20,白色固体,63mg,55.0%)。LCMS:m/z=521.1(M+H)+,RT=4.80min。1H NMR(400MHz,Chloroform-d)δ8.15(d,J=5.7Hz,1H),7.96(s,1H),7.59-7.44(m,4H),7.35-7.14(m,5H),6.03-5.48(m,2H),5.25-4.50(m,2H),4.24(dd,J=8.6,3.6Hz,1H),3.00-2.20(m,4H),1.53(d,J=6.4Hz,3H).
化合物21的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噻嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A18(30.6mg,0.10mmol)和B1(25mg,0.11mmol)溶于1.2ml DMSO中,加入DIPEA(39mg,0.30mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-三氟甲基-4H-苯并[b]咪唑并[1,5-d][1,4]噻嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 21,白色固体,32.9mg,63.3%)。LCMS:m/z=509.1(M+H)+,RT=4.98min。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=5.8Hz,1H),7.95(s,1H),7.71(s,1H),7.57-7.43(m,3H),5.59(br,1H),5.20(br,2H),4.67(dd,J=26.6,7.0Hz,1H),4.52(dd,J=8.9,3.4Hz,1H),4.37(t,J=9.0Hz,1H),4.29-3.96(m,2H),1.62(d,J=6.8Hz,3H),1.31(d,J=22.4Hz,3H).
化合物22的合成
(S)-3-(2-(((S)-1-(7-氯-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)-4-环丙基噁唑烷-2-酮
将A1(45mg,0.18mmol)和B5(45mg,0.20mmol)溶于1.2ml DMSO中,加入DIPEA(70mg,0.54mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(S)-3-(2-(((S)-1-(7-氯-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)-4-环丙基噁唑烷-2-酮(Compound 22,白色固体,69.1mg,84.8%)。LCMS:m/z=453.0(M+H)+,RT=4.77min。1H NMR(400MHz,Chloroform-d)δ8.20(d,J=5.8Hz,1H),7.90(s,1H),7.44(d,J=5.8Hz,1H),7.34(d,J=8.5Hz,1H),7.09(d,J=2.2Hz,1H),7.03(dd,J=8.5,2.2Hz,1H),5.55(br,1H),5.30(d,J=13.4Hz,1H),5.24-5.08(m,2H),4.51(br,1H),4.33(t,J=8.4Hz,1H),4.09(dd,J=8.8,2.4Hz,1H),1.62(d,J=6.9Hz,3H),1.18(br,1H),0.66-0.15(m,4H).
化合物23的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A15(45.8mg,0.20mmol)和B1(50.4mg,0.22mmol)溶于1.5ml DMSO中,加入DIPEA(77.5mg,0.60mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-甲基-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound23,白色固体,54.7mg,62.2%)。LCMS:m/z=437.2(M+H)+,RT=4.13min。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=5.7Hz,1H),7.91(s,1H),7.42(d,J=5.7Hz,1H),7.26(d,J=8.6Hz,1H),7.10-7.03(m,2H),5.83(br,1H),5.14(br,2H),4.79-4.60(m,1H),4.51(dd,J=8.9,3.4Hz,1H),4.36(t,J=8.9Hz,1H),3.10-2.75(m,4H),2.31(s,3H),1.56(d,J=6.8Hz,3H),1.30(d,J=18.9Hz,3H).
化合物24的合成
(R)-3-(2-(((S)-1-(7-氟-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A16(46.1mg,0.20mmol)和B1(50.4mg,0.22mmol)溶于1.5ml DMSO中,加入DIPEA(77.5mg,0.60mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(2-(((S)-1-(7-氟-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound24,白色固体,55.2mg,63.1%)LCMS:m/z=443.1(M+H)+,RT=4.63min。1HNMR(400MHz,Chloroform-d)δ8.21(d,J=5.7Hz,1H),7.91(s,1H),7.46(d,J=5.7Hz,1H),7.36(dd,J=8.5,4.7Hz,1H),7.08-6.96(m,2H),5.66(d,J=7.7Hz,1H),5.17(br,2H),4.70(dd,J=26.2,7.4Hz,1H),4.53(dd,J=8.8,3.4Hz,1H),4.38(t,J=8.9Hz,1H),2.95(d,J=70.2Hz,4H),1.58(d,J=6.8Hz,3H),1.33(dd,J=22.9,5.6Hz,3H).
化合物25的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-甲氧基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A17(42.8mg,0.17mmol)和B1(43.5mg,0.19mmol)溶于1.2ml DMSO中,加入DIPEA(65.9mg,0.51mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(7-甲氧基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 25,白色固体,58.2mg,75.3%)。LCMS:m/z=455.1(M+H)+,RT=4.17min。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=5.8Hz,1H),7.84(s,1H),7.44(d,J=5.8Hz,1H),7.30(d,J=8.7Hz,1H),6.62-6.54(m,2H),5.82(br,1H),5.34-4.92(m,4H),4.75-4.56(m,1H),4.48(dd,J=8.8,3.3Hz,1H),4.34(t,J=9.0Hz,1H),3.76(s,3H),1.59(d,J=6.9Hz,3H),1.21(br,3H).
化合物26的合成
(R)-3-(2-(((S)-1-(7-环丙基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-yl)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A14(34.5mg,0.14mmol)和YUX-A(34.4mg,0.15mmol)溶于1.5ml DMSO中,加入DIPEA(54mg,0.42mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(2-(((S)-1-(7-环丙基-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-3-yl)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 26,白色固体,36.5mg,56.2%)。LCMS:m/z=465.1(M+H)+,RT=4.97min。1H NMR(400MHz,Chloroform-d)δ8.19(d,J=5.7Hz,1H),7.87(s,1H),7.46(d,J=5.7Hz,1H),7.27(d,J=8.0Hz,1H),6.79-6.70(m,2H),5.71(br,1H),5.31-4.89(m,4H),4.65(dd,J=25.8,7.7Hz,1H),4.50(dd,J=8.7,2.9Hz,1H),4.36(t,J=9.0Hz,1H),1.84(tt,J=8.5,5.1Hz,1H),1.60(d,J=6.8Hz,3H),1.24(br,3H),0.96(q,J=6.3Hz,2H),0.66(q,J=4.9Hz,2H).
化合物27的合成
3-((S)-1-((4-((R)-4-((S)-1-氟乙基)-2-氧噁唑烷-3-基)嘧啶-2-基)氨基)乙基)-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-7-腈
将A13(38.3mg,0.16mmol)和B1(41.3mg,0.18mmol)溶于1.6ml DMSO中,加入DIPEA(62mg,0.48mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得3-((S)-1-((4-((R)-4-((S)-1-氟乙基)-2-氧噁唑烷-3-基)嘧啶-2-基)氨基)乙基)-4H-苯并[b]咪唑并[1,5-d][1,4]噁嗪-7-腈(Compound 27,白色固体,64.2mg,89.3%)。LCMS:m/z=450.0(M+H)+,RT=4.30min。1HNMR(400MHz,Chloroform-d)δ8.17(d,J=5.8Hz,1H),7.96(s,1H),7.49(d,J=8.6Hz,1H),7.45(d,J=5.7Hz,1H),7.38-7.31(m,2H),5.64(br,1H),5.40-4.95(m,4H),4.72-4.56(m,1H),4.49(dd,J=8.8,3.2Hz,1H),4.36(t,J=9.0Hz,1H),1.59(d,J=6.9Hz,3H),1.25(d,J=16.6Hz,3H).
化合物28的合成
(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(8-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮
将A10(40.7mg,0.14mmol)和B1(35mg,0.15mmol)溶于1.2ml DMSO中,加入DIPEA(54mg,0.42mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-4-((S)-1-氟乙基)-3-(2-(((S)-1-(8-三氟甲基-4,5-二氢咪唑并[1,5-a]喹啉3-基)乙基)氨基)嘧啶-4-基)噁唑烷-2-酮(Compound 28,白色固体,52.3mg,71.0%)。LCMS:m/z=491.1(M+H)+,RT=4.43min。1HNMR(400MHz,Chloroform-d)δ8.19(d,J=5.7Hz,1H),7.99(s,1H),7.61(s,1H),7.44(d,J=5.7Hz,1H),7.41(s,2H),5.74(br,1H),5.17(br,2H),4.80-4.58(m,1H),4.52(dd,J=8.9,3.4Hz,1H),4.37(t,J=8.9Hz,1H),3.15-2.80(m,4H),1.57(d,J=6.8Hz,3H),1.41-1.23(m,3H).
化合物29的合成
(R)-3-(2-(((S)-1-(6-氯-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮
将A9(44.5mg,0.18mmol)和B1(46mg,0.20mmol)溶于1.2ml DMSO中,加入DIPEA(70mg,0.54mmol)。100℃搅拌1.5小时。加入水和乙酸乙酯萃取,有机层用无水硫酸钠干燥,过滤,浓缩后,Combi-Flash快速硅胶色谱柱分离,冻干得(R)-3-(2-(((S)-1-(6-氯-4,5-二氢咪唑并[1,5-a]喹啉-3-基)乙基)氨基)嘧啶-4-基)-4-((S)-1-氟乙基)噁唑烷-2-酮(Compound 29,白色固体,57.5mg,70.0%)。LCMS:m/z=457.1(M+H)+,RT=4.47min。1H NMR(400MHz,Chloroform-d)δ8.21(d,J=5.7Hz,1H),7.95(s,1H),7.46(d,J=5.7Hz,1H),7.34(dd,J=7.0,2.2Hz,1H),7.31-7.19(m,2H),5.81(br,1H),5.18(br,2H),4.85-4.60(m,1H),4.54(dd,J=8.9,3.4Hz,1H),4.40(t,J=8.9Hz,1H),3.25-2.73(m,4H),1.59(d,J=6.8Hz,3H),1.47-1.18(m,3H).
测试例1本发明化合物在分子水平对IDH1酶活性的影响
对照化合物:AG120,CAS:1448346-63-1;IDH305,CAS:1628805-46-8
试剂、耗材与仪器:
底物α-KG,NADPH,Diaphorase和Resazurin均购自Sigma;其余所有试剂均购自国药集团化学试剂有限公司。
反应微孔96板(COSTAR,3915)购自Costar公司。
实验读板用多功能酶标仪为Molecular Devices公司产品,型号:spectramax i3。
实验用水为Millipore蒸馏水。
化合物配制:化合物12000g离心5min,加入DMSO配制成20mM储液,涡旋均匀后超声10min待用,-20℃保存。
试验方法:IDH1转换α-KG至2HG的酶活功能用NADPH的消耗来测量。在酶促反应结束后,加入催化过量的diaphorase和reazurin,产生的荧光信号能够反映出剩余的NADPH的量。
对IDH1 R132 H酶活影响的检测:96孔板中,加入50μL酶体系(150mM NaCl,20mMTris pH=7.5,10mM MgCl2,0.05%(w/v)bovine serum albumin,100ng IDH1 R132H),1μL化合物,室温避光孵育60min。50μL的底物α-KG和NADPH的混合液(底物α-KG终浓度1mM,NADPH终浓度20μM),室温避光孵育60min。检测反应:每孔加入50μL 1×detection buffer稀释的0.01unit diaphroase和30μM resazurin,室温避光孵育10min。读板:用PerkinElmer at Ex 544Em 590.测板。IC50值采用GraphPad Prism软件计算求得。
对IDH1 R132C酶活影响的检测:96孔板中,加入50μL酶体系(50mM K2HPO4(pH=6.5),40mM NaHCO3,10%甘油,5mM MgCl2,0.03%(w/v)bovine serum albumin,80ng IDH1R132C),1μL化合物,室温避光孵育60min。50μL的底物α-KG和NADPH的混合液(底物α-KG终浓度2mM,NADPH终浓度20μM),室温避光孵育60min。检测反应:每孔加入50μL 1×detectionbuffer稀释的0.01unit diaphroase和30μM resazurin,室温避光孵育10min。读板:用spectramax i3在Ex 544Em 590,测板。IC50值采用GraphPad Prism软件计算求得。
结果
表1显示了本发明部分化合物的IC50值。
字母A代表IC50小于50nM;
字母B代表IC50为50nM至500nM;
字母C代表IC50大于500nM;
结果如下表中所示。
结果显示,本发明化合物在极低浓度(≤100nm)下,即可有效抑制IDH1各种突变型(包括IDH1 R132C突变型和IDH1R132H突变型)的活性。
测试例2:本发明化合物对纤维肉瘤细胞株HT1080的2HG抑制测定
本实验采用如下方法测定了本发明化合物对纤维肉瘤细胞株HT1080的2HG浓度水平抑制活性。
细胞样品制备:将表达IDH1的突变体IDH1-R132C的人纤维肉瘤细胞系HT1080在含有10%胎牛血清的DMEM培养基中进行培养。使用胰蛋白酶消化细胞后以10000个细胞/孔的细胞密度接种于24孔细胞培养板中。将细胞在37℃,5%CO2细胞培养箱中培养。培养过夜后,将测试化合物加入到细胞中。DMSO的终浓度为0.1%,并以DMSO作为对照。然后将培养板置于细胞培养箱中培养48小时。
2HG的检测:使用BioVision公司的PicoProbeTM D-2-Hydroxyglutarate(D2HG)Assay Kit测量2-HG。每孔取500uL细胞上清液,加到10kD离心柱中,12000g,离心10分钟,以去除酶活影响。每个样品取2.5uL加到384孔白色平底反应板(CORNING,3576)中。25uL反应体系(21.425uL D2HG Assay Buffer,0.5uL D2HG Enzyme,0.5uL D2HG Developer,0.075uL PicoProbe),混匀后,37℃孵育60分钟。读板:用spectramax i3在Ex 544Em 590,测板。IC50值采用GraphPad Prism软件计算求得。
抑制率及IC50的计算
样品的抑制率通过下列公式求得:
IC50值采用GraphPad Prism软件计算求得。部分化合物对HT1080 2HG水平抑制活性列于表二.
表二:
阳性药:AG120,IC50为25nM
结果显示,本申请的化合物在不同细胞株中均表现出对于2HG的抑制活性,其半活抑制浓度均在100nM以下,部分化合物可以低至约10nM。
测试例3:本发明化合物的药代动力学测定
本申请采用以下方法测定本申请的化合物药代动力学参数。
研究使用的健康雄性成年大鼠/小鼠,每组动物单次灌胃给药5-100mg/Kg。禁食从给药前10小时至给药后4小时。给药后不同时间点后采血,并测定化合物血浆含量(LC-MS/MS)。血浆浓度----时间关系用专业软件分析(winnonlin),计算化合物的药代动力学参数。
结果显示,本发明化合物有着优异的药代动力学性质和透脑性。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (24)
1.一种如下式II所示的化合物,其立体异构体或药学上可接受的盐:
其中,
n为0、1或2;
A1选自下组:-CH2-、-CH(R8)-、-C(R8)2-、-O-或-S-;
A4、A5、A6、A7和A8各自独立地为CR9;
B1、B2、B3各自独立地为CR10或N;
虚线表示双键或无;
R选自下组:卤素取代或未取代的C1-C4烷基、C3-C10环烷基、和C6-C12芳基;或两个R共同形成-(CH2)m-结构或-CH2-O-CH2-结构,其中,m为2或3;R4、R6各自独立地选自选自下组:氢和C1-C4烷基;
R1、R2和R3各自独立地为一个或多个对应五元或六元环上任意位置的取代基,选自下组的基团:H、氰基、卤素、卤素取代或未取代的C1-C4烷基、卤素取代或未取代的C1-C4烷氧基和C3-C10环烷基;
R8为氢或C1-C4烷基;
R9为氢;
R10为氢或卤素;
其中,各个手性中心各自独立地为R构型或S构型。
2.如权利要求1所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,所述的化合物具有如下式III所示的结构:
其中,各基团的定义如权利要求1中所述。
3.如权利要求2所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,所述的化合物具有如下式IV所示的结构:
其中,B1-B3、A1、A4-A8、R1-R4和R的定义如权利要求1中所述;R7选自:H和卤素。
4.如权利要求1所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,所述的化合物具有如下式IV所示的结构:
其中,B1-B3、A1、A4-A8、R1-R4和R的定义如权利要求1中所述;R7为CH3。
5.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,R1为H或卤素。
6.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,R2为氢或C1-C4烷基;
7.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,R3为卤素、氰基、卤素取代或未取代的C1-C4烷基、未取代的C1-C4烷氧基、或C3-C8环烷基。
8.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,R4为H或C1-C4烷基,R6为H。
9.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,B1为N,B2为CR10,B3为N,R10为H或卤素。
10.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,n=1,且A1为-C(R8)2-或O,其中,R8为H或C1-C4烷基。
11.如权利要求1-4中任一项所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,n为1,A1为-CH2-、-CH(R8)-、-O-或-S-,R8为C1-C4烷基。
12.如权利要求1所述的化合物,其立体异构体或药学上可接受的盐,其特征在于,所述的化合物选自下组:
13.一种药物组合物,其特征在于,所述的药物组合物包括:(a)作为活性成分的如权利要求1-12任一所述的式II化合物,或其立体异构体或药学上可接受的盐,或它们的混合物,和(b)药学上可接受的赋形剂。
14.如权利要求13所述的药物组合物,其特征在于,所述的药物组合物还包括(c)第二活性成分。
15.如权利要求13所述的药物组合物,其特征在于,所述的药物组合物用于治疗或预防携带IDH1突变的实体瘤。
16.如权利要求15所述的药物组合物,其特征在于,所述的药物组合物用于治疗或预防选自下组的适应症:脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、前列腺癌、甲状腺癌、结直肠癌、软骨肉瘤、胆管癌和黑色素瘤。
17.如权利要求13所述的药物组合物,其特征在于,所述的药物组合物用于治疗或预防白血病。
18.如权利要求17所述的药物组合物,其特征在于,所述白血病为急性白血病。
19.权利要求1-12中任一项所述式II化合物,其立体异构体或药学上可接受的盐,或它们的混合物的用途,其特征在于,用于:(1)制备治疗或预防与突变型IDH活性或表达量相关的疾病的药物组合物;(2)制备突变型IDH抑制剂。
20.如权利要求19所述的用途,其特征在于,所述的疾病为携带IDH1突变的实体瘤。
21.如权利要求20所述的用途,其特征在于,所述实体瘤选自下组:脑胶质瘤、胶质母细胞瘤、副神经细胞瘤、前列腺癌、甲状腺癌、结直肠癌、软骨肉瘤、胆管癌和黑色素瘤。
22.如权利要求19所述的用途,其特征在于,所述疾病为白血病。
23.如权利要求22所述的用途,其特征在于,所述白血病为急性白血病。
24.如权利要求19所述的用途,其特征在于,所述疾病选自下组:神经胶质瘤、急性骨髓性白血病、肉瘤、前列腺癌、黑色素瘤、非小细胞肺癌、关节软骨瘤和胆管瘤。
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