CN108884067B - 可用于治疗癌症和糖尿病的6-杂环基-4-吗啉-4-基吡啶-2-酮化合物 - Google Patents
可用于治疗癌症和糖尿病的6-杂环基-4-吗啉-4-基吡啶-2-酮化合物 Download PDFInfo
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- CN108884067B CN108884067B CN201780015103.7A CN201780015103A CN108884067B CN 108884067 B CN108884067 B CN 108884067B CN 201780015103 A CN201780015103 A CN 201780015103A CN 108884067 B CN108884067 B CN 108884067B
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- pyridin
- methylmorpholin
- pyrrolidin
- methyl
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
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- -1 1-azetidinyl Chemical group 0.000 claims description 73
- 150000003254 radicals Chemical class 0.000 claims description 56
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 50
- 239000001257 hydrogen Substances 0.000 claims description 46
- 229910052739 hydrogen Inorganic materials 0.000 claims description 46
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 238000006467 substitution reaction Methods 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 22
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
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- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
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Abstract
Description
发明领域
本发明提供了新颖的式(I)的6-杂环基-4-吗啉-4-基-吡啶-2-酮化合物,含有这样的化合物的药物组合物,以及用于在治疗包括癌症和糖尿病的疾病中使用这样的化合物的方法。
发明背景
属于磷脂酰肌醇3-激酶(PI3K)家族的酶是若干重要细胞事件的调节剂。此家族由三类I、II和III组成,并且虽然I类组多年来一直是感兴趣的药物靶标,但II、III类被较少地利用。
PI3K III类,液泡蛋白分选34(Vps34,PIK3C3)与其调节亚基p150(Vps15)形成异二聚体,并且该二聚体参与若干复合物调节的囊泡运输事件(several complexesregulating vesicular trafficking event),所述囊泡运输事件例如自噬、内吞、胞吐和微胞饮(Amaravadi等人,Clin Cancer Res.2011,17:654-666;Carpentier等人,2013,Traffic)。该酶负责磷脂酰肌醇(PI)磷酸化为磷脂酰肌醇(3)-磷酸(PI3P)。与PX和FYVE结构域结合的配体导致这些效应子蛋白的募集和移位(delocalization),所述效应子蛋白导致囊泡的形成、伸长和移动(Backer等人,J Biochem.2008,410:1-17)。
自噬是一种分解代谢过程,其中细胞组分通过将它们封闭在双膜囊泡中而被靶向用于降解,所述双膜囊泡是与含蛋白酶的溶酶体融合的自噬体。这是用于细胞处理受损的细胞器和错误折叠的蛋白质并且通过此维持细胞功能的手段。该途径也是将细胞内容物再循环到新的结构单元(building block)中的方式(Boya等人,Nat Cell Biol 2013,15;713–720)。自噬是对如营养缺乏、酸中毒和缺氧的应激状况的细胞应答,而且也是对药物治疗的细胞应答。因此,自噬抑制是增强癌症药物和复敏(resensitization)耐药肿瘤的手段(Nagelkerke等人,Semin Cancer Biol 2014,31;99-105)。大多数晚期肿瘤示出了自噬通量的高上调(Leone等人,Trends in Endocrin Metab 2013,24;209-217)。用于研究自噬通量的确立的标志是在自噬体上检测到呈脂质化LC3蛋白的形式的自噬斑点(autophagicpuncta)。Vps34的抑制导致自噬的抑制,如通过LC3重新分布到斑点中所测量的(Dowdle等人,Nat Cell Biol 2014,16;1069-79)。
如最近所描述的,由于降低的胰岛素受体内化,调节性亚基p150的切除导致增加的体内胰岛素敏感性(Nemazanyy,Nature communn.,2015,6:8283)。激酶死亡杂合动物模型以增加的葡萄糖耐受和增加的胰岛素敏感性证实了此结果(WO2013076501)。
若干疾病状态可以受益于Vps34抑制,包括癌症、炎性疾病、神经退行性紊乱、心血管紊乱、糖尿病和病毒感染(在Rubinsztein等人,Nat Rev 2012,11;709-730中综述)。将受益于Vps34抑制的癌症形式包括但不限于三阴性乳腺癌、胰腺癌、白血病、黑色素瘤和肺癌。因此,对新颖的和有效的Vps34的抑制剂存在需求。
描述用于影响疾病的Vps34抑制剂的先前公开内容包括WO2015150555;WO2015150557;WO2015108861;WO2015108881;WO2012085815;WO2012085244;WO2013190510;Farkas,J.Biol.Chem.,2011 286(45)38904-12。
发明描述
本发明的目的是提供新颖的和有效的Vps34的抑制剂。本发明的另一个目的是提供新颖的和有效的Vps34的抑制剂,所述抑制剂可以被用于治疗癌症和其他疾病,例如糖尿病。
根据本发明的一个方面,提供了式(I)的化合物
其中
R1、R2和R3独立地选自氢、C1-C3卤代烷基和C1-C3烷基;
A表示
其中
X表示CH2、S、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9、O或键;
Y表示N、CH或C;
n选自1、2、3和4;
R4选自氢、卤素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6杂环基、C1-C3氰基烷基、C1-C3卤代烷基、芳基和杂芳基,其中所述芳基和所述杂芳基任选地被一个或更多个R7取代;
R5选自氢、C1-C3氟烷基、C1-C3烷基、C1-C3烷氧基C1-C3烷基和C3-C6环烷基;
R6选自C1-C3烷氧基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、1-吡咯烷基、1-哌啶基和1-氮杂环丁基(azetidinyl);
R7选自C1-C6烷基、C3-C6环烷基、C1-C3烷氧基C1-C3烷基、C1-C3卤代烷基、卤素、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、C1-C3卤代烷氧基和C1-C3烷氧基;
R9选自C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代;
R8选自卤素、C1-C3卤代烷基和C1-C3烷基;以及
其药学上可接受的盐、立体异构体和互变异构体。
在此方面的一个实施方案中,R4选自氢、卤素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6环烷基、C1-C3氰基烷基、C1-C3卤代烷基、芳基和杂芳基,其中所述芳基和所述杂芳基任选地被一个或更多个R7取代;
在此方面的一个实施方案中,Y是N。
在此方面的一个实施方案中,R1和R3独立地选自氢和甲基。
在此方面的一个实施方案中,R2是氢。
在此方面的一个实施方案中,R1是氢。
在此方面的一个实施方案中,R3是甲基。
在此方面的一个实施方案中,R3是氢。
在此方面的一个实施方案中,R5是C1-C3烷基。
在此方面的一个实施方案中,R6是N-C1-C3烷基氨基或N,N-二C1-C3烷基氨基,例如N,N-二C1-C3烷基氨基。
在此方面的一个实施方案中,R6是二甲基氨基。
在此方面的一个实施方案中,R7选自卤素、C1-C3氟烷基、C1-C3氟烷氧基、C1-C3烷氧基、C1-C3烷基、C3-C6环烷基和N,N-二C1-C3烷基氨基。
在此方面的一个实施方案中,R7选自氟、氯、三氟甲基、三氟甲氧基、甲氧基、甲基、乙基、环丙基和二甲基氨基。
在此方面的一个实施方案中,R9选自C1-C3烷氧基、杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代。
在此方面的一个实施方案中,R9选自杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代。
在此方面的一个实施方案中,R9选自四氢呋喃基、苯基和吡啶基,各自任选地被一个或两个R8取代。
在此方面的一个实施方案中,R8是卤素。
在此方面的一个实施方案中,R4中的所述单环杂芳基选自吡啶基、呋喃基、异噁唑基、吡唑基和噻唑基,各自任选地被一个或更多个R7取代。
在此方面的一个实施方案中,R4选自
在此方面的一个实施方案中,R7选自氟、氯、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6环烷基、N,N-二C1-C3烷基氨基。
在此方面的一个实施方案中,R7选自氟、氯、甲基、乙基、甲氧基、三氟甲氧基、三氟甲基、环丙基和N,N-二甲基氨基。
在此方面的一个实施方案中,X表示键。
在此方面的一个实施方案中,R4选自
在此方面的一个实施方案中,A表示:
在此方面的一个实施方案中,X表示CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9或O;并且R5是C1-C3烷基。
在此方面的一个实施方案中,R4选自氢、C1-C6烷基、C3-C6环烷基、C1-C3卤代烷基和苯基,其中苯基任选地被一个或更多个R7取代。
在此方面的一个实施方案中,A表示:
在此方面的一个实施方案中,
X表示CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9、O或键;
R4选自氢、COR6、C1-C3烷基、甲氧基C1-C3烷基、C3-C6环烷基、C1-C3氟烷基、苯基和单环杂芳基,其中所述苯基和所述单环杂芳基任选地被一个或两个R7取代;
R5是C1-C3烷基;
R6是N,N-二C1-C3烷基氨基;并且
R7选自氟、氯、C1-C3烷基、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6环烷基和N,N-二C1-C3烷基氨基。
在此方面的一个实施方案中,Y是CH或C;X是O;并且R4是氢。
在此方面的一个实施方案中,R1和R2是氢。
R3是甲基;
X选自CH2、O、NCOR5、NCOR9、NCOCH2R9和键;
Y是N;
R4是氢、苯基或三氟甲基;
R5是甲基;
R7是甲氧基;
R9选自吡啶基、苯基;并且
R8是氟。
在此方面的一个实施方案中,R1和R2是氢。
R3是甲基;
X选自CH2、O、NCOR5、NCOCH2R9和键;
Y是N;
R4是苯基或三氟甲基,所述苯基被一个或更多个R7取代;
R5是甲基;
R7是甲氧基或卤素,例如甲氧基或氯;
R9是苯基,所述苯基任选地被一个或更多个R8取代;并且
R8是卤素,例如氟。
在此方面的一个实施方案中,R4是三氟甲基或苯基,所述苯基被甲氧基或氯间位取代(meta-substituted)。
在一个实施方案中,根据本发明的化合物是在HOS细胞中自噬的有效抑制剂,如实施例51中所示。
在此方面的一个实施方案中,R7是甲氧基或氯;并且R8是氟。
在此方面的一个实施方案中,A表示:根据此实施方案,具有R4所位于的碳的构型的根据本发明的化合物在体外是Vps34的更有效的抑制剂,如所附实施例50中所示,参见实施例化合物3相对于实施例化合物4和实施例化合物34相对于实施例化合物35的比较。
在此方面的一个实施方案中,R1和R2是氢。
R3是甲基;
X表示NCOR9或NCOCH2R9;
R4是三氟甲基或苯基,所述苯基任选地被甲氧基或氯取代。
R9选自C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代;并且R8选自氟、氯、C1-C3卤代烷基和C1-C3烷基。
在此方面的一个实施方案中,R1和R2是氢。
R3是甲基;
X表示NCOR9或NCOCH2R9;
R4是三氟甲基;
R9选自C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、噁唑基、四氢呋喃基、吗啉基、吡啶基和苯基,其中所述噁唑基、所述四氢呋喃基、所述吗啉基、所述吡啶基和所述苯基任选地被一个或两个R8取代;并且R8选自氟、氯、C1-C3卤代烷基和C1-C3烷基。
在一个实施方案中,根据本发明的化合物容许若干种可能的R9,因为当结合至vps34时,所述化合物的生物活性构象使得R9位于溶剂中,而不是在结合袋(bindingpocket)内。
在此方面的一个实施方案中,
X表示CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9或O;
R1和R3独立地选自氢和甲基;
R2是氢;
R4选自
R5是C1-C3烷基;
R7选自氟、氯、甲基、乙基、甲氧基、三氟甲氧基、三氟甲基、环丙基和N,N-二甲基氨基;
R9选自四氢呋喃基、苯基和吡啶基,各自任选地被一个或两个R8取代;并且
R8是卤素。
在此方面的一个实施方案中,R1、R2和R3独立地选自氢和甲基;并且
A表示
在此方面的一个实施方案中,所述化合物选自:
4-吗啉代-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
1-甲基-4-吗啉代-6-(2-苯基吡咯烷-1-基)吡啶-2-酮;
4-吗啉代-6-[(2S)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮;
4-吗啉代-6-[(2R)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮;
6-(3,6-二氢-2H-吡喃-4-基)-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-四氢吡喃-4-基-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-[2-(3-吡啶基)吡咯烷-1-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
N,N-二甲基-1-[4-[(3R)-3-甲基吗啉-4-基]-6-氧代-1H-吡啶-2-基]吡咯烷-2-甲酰胺;
6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-(2-环己基吡咯烷-1-基)-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(3-氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(1-甲基吡唑-4-基)吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(1,5-二甲基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(1-乙基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(5-甲基-2-呋喃基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(3-苯基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(1-氧代-1,4-噻嗪烷-4-基)-1H-吡啶-2-酮;
6-(1,1-二氧代-1,4-噻嗪烷-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
6-(4-乙酰基哌嗪-1-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-苯基-1-哌啶基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(4-甲基-2-苯基-哌嗪-1-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-(3-环丙基吗啉-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(3-氯苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(3-环丙基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(2-吡啶基)吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(2-噻唑-2-基吡咯烷-1-基)-1H-吡啶-2-酮;
6-[2-(5-甲基异噁唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
1-甲基-4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)-1-哌啶基]吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(8-氧杂-5-氮杂螺[3.5]壬-5-基)-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)-1-哌啶基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[4-乙酰基-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[4-(5-氟吡啶-3-羰基)-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[2-(4-氟苯基)乙酰基]-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[4-(四氢呋喃-2-羰基)-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[4-甲基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;以及
其药学上可接受的盐、互变异构体和立体异构体。
根据本发明的一个方面,提供了式(I)的化合物
其中
R1、R2和R3独立地选自氢、C1-C3卤代烷基和C1-C3烷基;
A表示
其中
X表示CH2、S、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9、O或键;
Y表示N、CH或C;
R4选自氢、卤素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6环烷基、C1-C3氰基烷基、C1-C3卤代烷基、芳基和杂芳基,其中所述芳基和所述杂芳基是单环的或双环的,并且任选地被一个或更多个R7取代;
R5选自氢、C1-C3氟烷基、C1-C3烷基、C1-C3烷氧基C1-C3烷基和C3-C6环烷基;
R6选自C1-C3烷氧基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、1-吡咯烷基、1-哌啶基和1-氮杂环丁基;
R7选自C1-C6烷基、C3-C6环烷基、C1-C3烷氧基C1-C3烷基、C1-C3卤代烷基、卤素、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、C1-C3卤代烷氧基和C1-C3烷氧基;
R9选自C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代;
R8选自卤素、C1-C3卤代烷基和C1-C3烷基;以及
其药学上可接受的盐、立体异构体和互变异构体。
在A环中,“--”表示单键或双键。当所述环中的Y是C(sp2-杂化的季碳)时,所述键是双键。当所述环中的Y是N或CH时,所述键为单键。
在此方面的一个实施方案中,R1和R2是氢;
R3是甲基;
X表示NCOR9或NCOCH2R9;
R4是三氟甲基;
R9选自C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、噁唑基、四氢呋喃基、吗啉基、吡啶基和苯基,其中所述噁唑基、所述四氢呋喃基、所述吗啉基、所述吡啶基和所述苯基任选地被一个或两个R8取代;并且R8选自氟、氯、C1-C3卤代烷基和C1-C3烷基。
在一个实施方案中,根据本发明的化合物容许若干种可能的R9,因为当结合至vps34时,所述化合物的生物活性构象使得R9位于溶剂中,而不是在结合袋内。
在此方面的一个实施方案中,R9选自甲基、甲氧基、环丁基、2-甲基-1,3-噁唑-4-基、2-四氢呋喃基、4-吗啉基、3-吡啶基、3-氟-5-吡啶基。
在此方面的一个实施方案中,Y是N。
在此方面的一个实施方案中,R1和R3独立地选自氢和甲基。
在此方面的一个实施方案中,R2是氢。
在此方面的一个实施方案中,R1是氢。
在此方面的一个实施方案中,R1是甲基。
在此方面的一个实施方案中,R3是甲基。
在此方面的一个实施方案中,R3是氢。
在此方面的一个实施方案中,
X表示CH2、SO、SO2、NR5、NCOR5、O或键;
R4选自氢、COR6、C1-C3烷基、甲氧基C1-C3烷基、C3-C6环烷基、C1-C3氟烷基、苯基和单环杂芳基,其中所述苯基和所述单环杂芳基任选地被一个或两个R7取代;
R5是C1-C3烷基;
R6是N,N-二C1-C3烷基氨基;并且
R7选自氟、氯、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6环烷基、N,N-二C1-C3烷基氨基。
在此方面的一个实施方案中,R4中的所述单环杂芳基选自吡啶基、呋喃基、异噁唑基、吡唑基和噻唑基。
在此方面的一个实施方案中,R4选自
其中
R6是二甲基氨基;并且
R7选自氟、氯、三氟甲基、三氟甲氧基、甲氧基、甲基、乙基、环丙基和二甲基氨基。
在此方面的一个实施方案中,X表示键。
在此方面的一个实施方案中,A表示:
在此方面的一个实施方案中,X表示CH2、SO、SO2、NR5、NCOR5或O;并且
R5是C1-C3烷基。
在此方面的一个实施方案中,A表示:
在此方面的一个实施方案中,Y是CH或C;X是O;并且R4是氢。
在此方面的一个实施方案中
R1和R2是氢;
R3是甲基;
X选自CH2、O和键;
Y是N;
R4是苯基或三氟甲基;并且
R7选自甲氧基、三氟甲基、氯和环丙基。
在此方面的一个实施方案中,
R1和R3独立地选自氢和甲基;
R2是氢;并且
A表示
在此方面的一个实施方案中,提供了选自以下的化合物:
4-吗啉代-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
1-甲基-4-吗啉代-6-(2-苯基吡咯烷-1-基)吡啶-2-酮;
4-吗啉代-6-[(2S)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮;
4-吗啉代-6-[(2R)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮;
6-(3,6-二氢-2H-吡喃-4-基)-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-四氢吡喃-4-基-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-[2-(3-吡啶基)吡咯烷-1-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
N,N-二甲基-1-[4-[(3R)-3-甲基吗啉-4-基]-6-氧代-1H-吡啶-2-基]吡咯烷-2-甲酰胺;
6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-(2-环己基吡咯烷-1-基)-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(3-氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(1-甲基吡唑-4-基)吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(1,5-二甲基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(1-乙基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(5-甲基-2-呋喃基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(3-苯基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(1-氧代-1,4-噻嗪烷-4-基)-1H-吡啶-2-酮;
6-(1,1-二氧代-1,4-噻嗪烷-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
6-(4-乙酰基哌嗪-1-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-苯基-1-哌啶基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(4-甲基-2-苯基-哌嗪-1-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-(3-环丙基吗啉-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(3-氯苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(3-环丙基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(2-吡啶基)吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(2-噻唑-2-基吡咯烷-1-基)-1H-吡啶-2-酮;
6-[2-(5-甲基异噁唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
1-甲基-4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)-1-哌啶基]吡啶-2-酮;以及
其药学上可接受的盐、互变异构体和立体异构体。
在本发明的一个方面中,提供了根据本发明的化合物,用于在治疗或预防疾病中使用。
在本发明的一个方面中,提供了根据本发明的化合物,用于在治疗癌症中使用。典型地,所述癌症选自乳腺癌例如三阴性乳腺癌、胰腺癌、白血病、黑色素瘤和肺癌。
在本发明的一个方面中,提供了根据本发明的化合物,用于在治疗糖尿病中使用。典型地,所述糖尿病是II型糖尿病。
在本发明的一个方面中,提供了根据本发明的化合物,用于在治疗疾病中使用,所述疾病选自炎性疾病、神经退行性紊乱、心血管紊乱和病毒感染。
在本发明的一个方面中,提供了根据本发明的化合物在制备用于治疗癌症的药物中的用途。典型地,所述癌症选自乳腺癌例如三阴性乳腺癌、胰腺癌、白血病、黑色素瘤和肺癌。
在本发明的一个方面中,提供了根据本发明的化合物在制备用于治疗糖尿病的药物中的用途。典型地,所述糖尿病是II型糖尿病。
在本发明的一个方面中,提供了根据本发明的化合物在制备用于治疗疾病的药物中的用途,所述疾病选自炎性疾病、神经退行性紊乱、心血管紊乱和病毒感染。
在本发明的一个方面中,提供了治疗癌症的方法,所述方法包括将治疗有效量的根据本发明的化合物施用至需要其的患者。典型地,所述癌症选自乳腺癌例如三阴性乳腺癌、胰腺癌、白血病、黑色素瘤和肺癌。
在本发明的一个方面中,提供了根据本发明的化合物,用于在治疗癌症中使用,其中所述癌症治疗还包括放射疗法。
在本发明的一个方面中,提供了治疗癌症的方法,所述方法包括将治疗有效量的根据本发明的化合物与放射疗法结合施用至需要其的患者。
本发明的化合物还可以与放射疗法和/或外科介入结合用于癌症治疗。一般而言,与本发明的化合物或组合物组合的细胞毒性剂和/或细胞抑制剂的使用将用于:
(1)与单独施用任一种剂相比,在减少肿瘤的生长或者甚至消除肿瘤方面产生更好的功效,
(2)提供更少量的施用的化疗剂的施用,
(3)提供化疗治疗,该化疗治疗在患者中是良好耐受的,与在单个剂化疗和某些其他联合疗法的情况下观察到的相比,具有更少的有害的药理学并发症,
(4)提供治疗哺乳动物中,特别是人类中的更广泛的不同癌症类型,
(5)在被治疗的患者中提供更高的应答率,
(6)与标准化疗治疗相比,在治疗的患者中提供更长的存活时间,
(7)为肿瘤进展提供更长的时间,和/或
(8)与其中其他癌症剂组合产生拮抗作用的已知情况相比,产生至少与单独使用的剂的那些一样好的功效和耐受性的结果。
在本发明的一个方面中,提供了治疗糖尿病的方法,所述方法包括将治疗有效量的根据本发明的化合物施用至需要其的患者。典型地,所述糖尿病是II型糖尿病。
在本发明的一个方面中,提供了一种治疗选自炎性疾病、神经退行性紊乱、心血管紊乱和病毒感染的疾病的方法,所述方法包括将治疗有效量的根据本发明的化合物施用至需要其的患者。
在本发明的一个方面中,提供了药物组合物,所述药物组合物包含根据本发明的化合物以及药学上可接受的稀释剂、载体和/或赋形剂。
在本发明的一个方面中,提供了药物组合物,所述药物组合物包含治疗有效量的根据权利要求1的化合物和另一种抗癌剂,所述另一种抗癌剂选自烷化剂、抗代谢物、抗癌喜树碱衍生物、植物衍生的抗癌剂、抗生素、酶、铂配位络合物、酪氨酸激酶抑制剂、激素、激素拮抗剂、单克隆抗体、干扰素和生物应答调节剂。
如本文所使用的,术语“C1-C6烷基”意指具有1至6个碳原子的直链和支链的饱和烃基团两者。C1-C6烷基基团的实例包括甲基基团、乙基基团、正丙基基团、异丙基基团、正丁基基团、异丁基基团、仲丁基基团、叔丁基基团、正戊基基团、4-甲基-丁基基团、正己基基团、2-乙基-丁基基团。在未支化的C1-C6烷基基团中,典型的未支化的C1-C6烷基基团是甲基基团、乙基基团、正丙基基团、正丁基基团、正戊基基团和正己基基团。在支化的烷基基团中,可以提及异丙基基团、异丁基基团、仲丁基基团、叔丁基基团、4-甲基-丁基基团和2-乙基-丁基基团。
如本文所使用的,术语“C1-C3烷基”意指具有1至3个碳原子的直链和支链的饱和烃基团两者。C1-C3烷基基团的实例包括甲基基团、乙基基团、正丙基基团和异丙基基团。
如本文所使用的,术语“C1-C6烷氧基”意指基团O-烷基,其中“C1-C6烷基”如上文描述的使用。C1-C6烷氧基基团的实例包括但不限于甲氧基基团、乙氧基基团、异丙氧基基团、正丙氧基基团、正丁氧基基团、正己氧基基团、3-甲基-丁氧基基团。
如本文所使用的,术语“C1-C3烷氧基”意指基团O-烷基,其中“C1-C3烷基”如上文描述的使用。C1-C3烷氧基基团的实例包括但不限于甲氧基、乙氧基、异丙氧基和正丙氧基。
如本文所使用的,术语“C1-C6卤代烷基”意指具有1个至6个碳原子并且其中1个至所有的氢被不同或相同类型的卤素取代的直链和支链的饱和烃基团两者。C1-C6卤代烷基基团的实例包括被1个至3个卤素原子取代的甲基、被1个至5个卤素原子取代的乙基、被1个至7个卤素原子取代的正丙基或异丙基、被1个至9个卤素原子取代的正丁基或异丁基和被1个至9个卤素原子取代的仲丁基或叔丁基基团。
如本文所使用的,术语“C1-C3卤代烷基”意指具有1个至3个碳原子并且其中1个至所有的氢被不同或相同类型的卤素取代的直链和支链的饱和烃基团两者。C1-C3卤代烷基基团的实例包括被1个至3个卤素原子取代的甲基、被1个至5个卤素原子取代的乙基和被1个至7个卤素原子取代的正丙基或异丙基。
如本文所使用的,术语“C1-C3卤代烷氧基”意指具有1个至3个碳原子并且其中1个至所有的氢原子被不同或相同类型的卤素原子取代的直链和支链的饱和烷氧基基团两者。C1-C3卤代烷氧基基团的实例包括被1个至3个卤素原子取代的甲氧基、被1个至5个卤素原子取代的乙氧基和被1个至7个卤素原子取代的正丙氧基或异丙氧基。
如本文所使用的,术语“C1-C3氟烷基”意指具有1个至3个碳原子并且其中1个至所有的氢原子被氟原子取代的直链和支链的饱和烃基团两者。C1-C3氟烷基基团的实例包括被1个至3个氟原子取代的甲基、被1个至5个氟原子取代的乙基和被1个至7个氟原子取代的正丙基或异丙基。
如本文所使用的,术语“C1-C3氟烷氧基”意指具有1个至3个碳原子并且其中1个至所有的氢原子被氟原子取代的直链和支链的饱和烷氧基基团两者。C1-C3氟烷氧基基团的实例包括被1个至3个氟原子取代的甲氧基、被1个至5个氟原子取代的乙氧基和被1个至7个氟原子取代的正丙氧基或异丙氧基。
如本文所使用的,术语“C3-C6环烷基”意指具有3个至6个碳原子的环状饱和烃基团。C3-C6环烷基基团的实例包括环丙基、环丁基、环戊基和环己基。
如本文所使用的,术语“C1-C3烷氧基C1-C3烷基”意指具有1个至3个碳原子的直链和支链的饱和烃基团两者,其被具有1个至3个碳原子的烷氧基基团取代。C1-C3烷氧基C1-C3烷基基团的实例如下所绘。
如本文所使用的,术语“C1-C3氰基烷基”意指具有1个至3个碳原子的直链和支链氰基(CN)衍生物,所述碳原子包括作为氰基基团的一部分的碳原子。C1-C3氰基烷基基团的实例如下所绘。
如本文所使用的,术语“卤素”意指氟、氯、溴或碘。
如本文所使用的,术语“芳基”意指单环的或双环的芳香族碳环基团。芳基基团的实例包括苯基和萘基。萘基基团可以通过1位或2位附接。在双环芳基中,环中的一个可以是部分地饱和的。这样的基团的实例包括茚满基和四氢萘基。
如本文所使用的,术语“单环芳基”意指单环芳香族碳环基团。单环芳基基团的实例包括苯基。
如本文所使用的,术语“杂芳基”意指碳原子的单环芳香族基团或双环芳香族基团,其中从1个至3个的碳原子被一个或更多个独立地选自氮、氧或硫的杂原子替换。在双环芳基中,环中的一个可以是部分地饱和的。这样的基团的实例包括吲哚啉基、苯并二氢呋喃基和1,3-苯并二氧杂环戊烯基。
如本文所使用的,术语“单环杂芳基”意指碳原子的单环芳香族基团,其中从1个至3个的碳原子被一个或更多个独立地选自氮、氧或硫的杂原子替换。
单环杂芳基基团的实例包括但不限于呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、吡啶基、***基、三嗪基、哒嗪基、异噻唑基、异噁唑基、吡嗪基、吡唑基和嘧啶基。
双环杂芳基基团的实例包括但不限于喹喔啉基、喹唑啉基、吡啶并吡嗪基、苯并噁唑基、苯并噻吩基、苯并咪唑基、萘啶基、喹啉基、苯并呋喃基、吲哚基、吲唑基、苯并噻唑基、吡啶并嘧啶基和异喹啉基。
如本文所使用的,术语“杂环基”意指碳原子的环状基团,其中从1个至3个的碳原子被一个或更多个独立地选自氮、氧和硫的杂原子替换。杂环基基团的实例包括但不限于四氢呋喃基、四氢吡喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基和二噁烷基。
取决于式(I)的化合物中存在的取代基,所述化合物可以形成在本发明的范围内的盐。适合于在医学(medicine)中使用的式(I)的化合物的盐是其中抗衡离子是药学上可接受的那些盐。
根据本发明的合适的盐包括与有机或无机的酸或碱形成的那些盐。特别地,与根据本发明的酸形成的合适的盐包括与矿物酸、强有机羧酸形成的那些盐,或者与有机磺酸形成的那些盐,所述强有机羧酸例如1个至4个碳原子的烷烃羧酸,其是未被取代的或被例如卤素取代,例如饱和的或不饱和的二羧酸,例如羟基羧酸,例如氨基酸,所述有机磺酸例如(C1-C4)烷基或芳基磺酸,其是未被取代或被例如卤素取代。药学上可接受的酸加成盐包括由盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、乙酸、三氟乙酸、琥珀酸、高氯酸、富马酸、马来酸、乙醇酸、乳酸、水杨酸、草酰乙酸、甲磺酸、乙磺酸、对甲苯磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸、羟乙基磺酸(isethionic)、抗坏血酸、苹果酸、邻苯二甲酸、天冬氨酸和谷氨酸、赖氨酸和精氨酸形成的那些酸加成盐。
药学上可接受的碱盐包括铵盐;碱金属盐,例如钾和钠的盐;碱土金属盐,例如钙和镁的盐;以及与有机碱的盐,例如二环己胺、N-甲基-D-葡糖胺、吗啉、硫代吗啉、哌啶、吡咯烷、单低级烷基胺、二低级烷基胺或三低级烷基胺,例如乙胺、叔丁胺、二乙胺、二异丙胺、三乙胺、三丁胺或二甲基丙胺,或单羟基低级烷基胺、二羟基低级烷基胺或三羟基低级烷基胺,例如单乙醇胺、二乙醇胺或三乙醇胺。还可以形成相应的内盐。
本发明的化合物可以按原样或以药物组合物的形式被用于预防和/或治疗。虽然活性成分可以被单独地施用,但是它也可以存在于药物组合物中。因此,本发明提供了包含式(I)的化合物以及药学上可接受的稀释剂、赋形剂和/或载体的药物组合物。本发明的药物组合物可以采取如下文所述的药物组合物的形式。
用于口服施用的示例性组合物包括悬浮液,所述悬浮液可以包含例如用于赋予本体(bulk)的微晶纤维素、作为悬浮剂的海藻酸或海藻酸钠、作为粘度增强剂的甲基纤维素以及甜味剂或调味剂,例如本领域已知的那些;以及速释片剂,所述速释片剂可以包含例如微晶纤维素、磷酸二钙、淀粉、硬脂酸镁、硫酸钙、山梨糖醇(sorbitol)、葡萄糖和/或乳糖和/或其他赋形剂、粘合剂、增量剂(extender)、崩解剂、稀释剂和润滑剂,例如本领域已知的那些。合适的粘合剂包括淀粉、明胶、天然糖例如葡萄糖或β-乳糖、玉米甜味剂、天然的和合成的树胶比如***树胶(acacia)、黄蓍胶或海藻酸钠、羧甲基纤维素、聚乙二醇、蜡以及类似物。崩解剂包括而不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶以及类似物。式(I)的化合物也可以通过舌下和/或颊侧施用通过口腔递送。模制片剂、压缩片剂或冻干片剂是可以使用的示例性形式。示例性的组合物包括用快速溶解稀释剂例如甘露醇、乳糖、蔗糖和/或环糊精配制本发明的化合物的那些组合物。还包括在这样的组合物中的可以是高分子量赋形剂,例如纤维素(微晶粉末纤维素(avicel))或聚乙二醇(PEG)。这样的组合物还可以包括帮助粘膜粘附的赋形剂,例如羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、羧甲基纤维素钠(SCMC)、马来酸酐共聚物(例如Gantrez)和控制释放的剂,例如聚丙烯酸共聚物(例如Carbopol 934)。也可以添加润滑剂、助流剂、调味剂、着色剂和稳定剂,以便于制造和使用。在这些剂型中使用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。对于以液体形式的口服施用,口服药物组分可以与任何口服的、无毒的、药学上可接受的惰性载体例如乙醇、甘油、水等组合。
适合于口服施用的本发明的组合物可以作为离散的单位存在,所述离散的单位例如胶囊、扁囊剂、丸剂或片剂,其每个包含预定量的活性成分;作为粉末或颗粒存在;作为在含水液体或非含水液体中的溶液或悬浮液存在,例如,作为酏剂、酊剂、悬浮液或糖浆存在;或者作为水包油液体乳液或油包水液体乳液存在。活性成分也可以作为大丸剂(bolus)、舐剂(electuary)或糊剂存在。
片剂可以通过压制或模制制成,任选地与一种或更多种辅助成分一起制成。压制的片剂可以通过以下来制备:在合适的机器中压制呈自由流动形式诸如粉末或颗粒的活性成分,任选地与粘合剂、润滑剂(lubricant)、惰性稀释剂、润滑剂(lubricating agent)、表面活性剂或分散剂混合。模制的片剂可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉末状化合物的混合物来制成。片剂可以任选地被包衣或刻痕,并且可以被配制以便提供其中的活性成分的缓慢释放或受控释放。本发明的化合物可以例如以适合于立即释放或延长释放的形式施用。通过使用包含本发明化合物的合适的药物组合物,或者特别是在延长释放的情况下,通过使用例如皮下植入物或渗透泵的装置,可以实现立即释放或延长释放。本发明的化合物也可以脂质体施用。
典型的单位剂量组合物是含有如上文所述的有效剂量或其适当部分的活性成分的那些组合物。
应该理解的是,除了上文特别提及的成分以外,本发明的组合物可以包含本领域中常规的关于所讨论的组合物的类型的其他剂,例如适合于口服施用的那些可以包含调味剂。
组合物可以以单位剂型存在,并且可以通过药学领域熟知的任何方法制备。所述方法可以包括使活性成分与构成一种或更多种辅助成分的载体联合的步骤。组合物可以通过使活性成分与液体载体或细分的固体载体或两者均匀地且紧密地联合来制备,并且然后,如果有必要的话,使产品成形为期望的组合物。
本发明的化合物也可以以脂质体递送***的形式施用,所述脂质体递送***例如小单层囊泡、大单层囊泡和多层囊泡。脂质体可以由多种磷脂、1,2-二棕榈酰磷脂酰胆碱、磷脂酰乙醇胺(脑磷脂)、磷脂酰丝氨酸、磷脂酰肌醇、二磷脂酰甘油(心磷脂)或磷脂酰胆碱(卵磷脂)形成。
用于肠胃外施用的组合物包括:含水和非含水的无菌注射溶液,所述无菌注射溶液可以包含抗氧化剂、缓冲剂、抑菌剂(bacteriostat)以及使组合物与意图的接收者的血液等渗的溶质;以及含水和非含水的无菌悬浮液,所述无菌悬浮液可以包含悬浮剂和增稠剂。组合物可以存在于单位剂量或多剂量容器中,例如密封的安瓿和小瓶,并且可以在冷冻干燥的(冻干的)条件中储存,仅需要在使用之前即时添加无菌液体载体例如盐水或注射用水。临时注射溶液和悬浮液可以由先前描述的种类的无菌粉末、颗粒和片剂来制备。用于肠胃外施用的示例性组合物包括可注射溶液或悬浮液,其可以包含例如合适的无毒的、肠胃外可接受的稀释剂或溶剂,例如聚乙二醇、乙醇、1,3-丁二醇、水、林格氏溶液、等渗氯化钠溶液或其他合适的分散剂或润湿剂和悬浮剂,包括合成的甘油单酯或甘油二酯,以及脂肪酸,包括油酸或克列莫佛(Cremaphor)。
用于鼻、气溶胶或吸入施用的示例性组合物包括盐水溶液,其可以包含例如苯甲醇或其他合适的防腐剂、提高生物利用度的吸收促进剂和/或其他增溶剂或分散剂,例如本领域已知的那些。
用于直肠施用的组合物可以作为具有例如可可脂、合成甘油酯(syntheticglyceride esters)或聚乙二醇的常见载体的栓剂存在。这样的载体典型地在常温下是固体,但是在直肠腔中液化和/或溶解以释放药物。
用于在口中局部施用的组合物,例如颊侧或舌下施用的组合物,包括锭剂(lozenge),所述锭剂包含在例如蔗糖和***树胶或黄蓍胶的调味的基础中的活性成分;和锭剂(pastille),所述锭剂包含在例如明胶和甘油或蔗糖和***树胶的基础中的活性成分。用于局部施用的示例性组合物包含局部载体例如Plastibase(用聚乙烯胶凝化的矿物油)。
式(I)的化合物可以作为唯一的药物剂或者与一种或更多种另外的治疗剂组合施用,其中所述组合没有引起不可接受的副作用。本药物组合物包括含有式(I)的化合物和一种或更多种另外的治疗剂的单个药物剂量组合物的施用,以及式(I)的化合物和每个另外的治疗剂以其各自单独的药物剂量组合物的施用。例如,式(I)的化合物和治疗剂可以以单个口服剂量组合物例如胶囊或片剂一起施用至患者,或者每种剂可以以具有单独的剂量的组合物施用。
在使用单独剂量的组合物的情况下,式(I)的化合物和一种或更多种另外的治疗剂可以在基本上同一时间(例如同时地)或在分开地交错的时间(例如顺序地)施用。
当然,实现治疗效果所需的活性成分的量将随特定的化合物、施用途径、所治疗的受试者(包括受试者的类型、物种、年龄、体重、性别和医学状况和受试者的肾功能和肝功能)、以及所治疗的特定紊乱或疾病及其严重程度而变化。普通熟练的医师、兽医或临床医生可以容易地确定和开出预防、对抗或阻止状况的进展所需的药物的有效量。
本发明的口服剂量,当用于所指示的效果时,对于成年人来说,将在约0.01mg/kg体重/天(mg/kg/天)至约100mg/kg/天之间,优选地在0.01mg/kg体重/天(mg/kg/天)至10mg/kg/天之间,并且最优选地在0.1mg/kg/天至5.0mg/kg/天之间的范围内。对于口服施用,所述组合物可以以片剂的形式或以离散单位提供的其他呈现形式提供,包含0.01、0.05、0.1、0.5、1.0、2.5、5.0、10.0、15.0、25.0、50.0、100和500毫克的活性成分,用于该剂量对待治疗患者的症状调节。药物典型地包含从约0.01mg至约500mg的活性成分,优选地从约1mg至约100mg的活性成分。静脉内地,在恒定速率输注期间,最优选的剂量将在从约0.1mg/kg/分钟至约10mg/kg/分钟的范围内。本发明的化合物可以以单个日剂量施用,或者总日剂量可以以每日两次、每日三次或每日四次的分剂量施用。此外,用于本发明的化合物可以经由局部使用合适的鼻内媒介物以鼻内形式施用,或者经由透皮途径,使用本领域普通技术人员熟知的那些形式的透皮皮肤贴剂施用。为了以透皮递送***的形式施用,剂量施用当然在整个剂量方案中是连续的而不是间歇的。
实施例
下文附随的是本发明的多个非限制性实施例。
下表列出了本节中使用的缩写。
缩写 含义
Amphos (4-(N,N-二甲基氨基)苯基)二叔丁基膦
anh. 无水的
aq. 含水的
BuLi 丁基锂
DCM 二氯甲烷
DIPEA N,N-二异丙基乙胺
DMAc N,N-二甲基乙酰胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DTT 二硫苏糖醇
EtOAc 乙酸乙酯
EtOH 乙醇
h 小时
HPLC 高压(或高效)液相色谱法
KOtBu 叔丁醇钾
LCMS 液相色谱法质谱法
LiOtBu 叔丁醇锂
MeCN 乙腈
2-MeTHF 2-甲基四氢呋喃
MeOH 甲醇
min. 分钟
NMR 核磁共振
PEPPSITM-iPr [1,3-双(2,6-二异丙基苯基)咪唑-2-亚基](3-氯吡啶基)二氯化钯(II)
Pd2(dba)3 三(二亚苄基丙酮)二钯(0)
Pd(OAc)2 乙酸钯(II)
quant. 定量的
rt 室温
sat. 饱和的
TFA 三氟乙酸
THF 四氢呋喃
XantPhos 4,5-双(二苯基膦基)-9,9-二甲基呫吨
XPhos 2-二环己基膦基-2',4',6'-三异丙基联苯
化合物的制备
下文描述的方案1和方案2说明了本发明的式(I)的化合物的一般合成路线,但是不意图是限制性的。本发明中的化合物可以被制备为游离碱或其药学上可接受的盐。在整个以下对这样的工艺的描述中,应当理解的是,在适当的情况下,合适的保护基团将以有机合成领域中的技术人员将容易理解的方式被添加至各种反应物和中间体中,并且随后从各种反应物和中间体中除去。对于使用这样的保护基团的常规程序以及合适的保护基团的实例例如描述在Protective Groups in Organic Synthesis,T.W.Greene,P.G.M Wutz,第4版,Wiley-Interscience,New York,2006中。应当理解的是,微波可以可选择地被用于加热反应混合物。
除非另有说明,否则A、R1、R2、R3、R4、R5、R6、R7、R8和R9如式(I)中所定义。
(i)对应的式(III)的化合物的形成
式(III)的化合物可以通过例如从式(II)的化合物开始(方案1),并且在过渡金属催化剂的影响下使所述化合物(II)与合适的偶联配偶体(partner)A*反应来获得,在所述式(II)中LG表示离去基团,例如卤素(例如氯、溴或碘),或烷基磺酸酯、芳基磺酸酯或卤代烷基磺酸酯(例如三氟甲磺酸酯),所述偶联配偶体A*表示合适的作为游离碱或盐(例如HCl或TFA或乙酸)的环状胺或者合适的硼酸或硼酸衍生物,如在例如Metal-Catalyzed Cross-Coupling Reactions,第2版,完全修订和增补版,A.de Meijere和F.Diederich,WileyVCH,2004中描述的。
方案1
反应可以通过将式(II)的化合物与合适的偶联配偶体A*偶联来进行。反应可以使用合适的金属催化剂进行,例如钯催化剂,例如二叔丁基膦基二茂铁二氯化钯(II)(di-tert-butylphosphinoferrocene palladium(II)dichloride)、四(三苯基膦)钯(0)、二苯基膦基二茂铁二氯化钯(palladium diphenylphosphinoferrocene dichloride)、乙酸钯(II)或双(二亚苄基丙酮)钯(0)。任选地,使用合适的配体,例如三苯基膦、三叔丁基膦或2-(二环己基膦基)联苯或2-二环己基膦基-2',4',6'-三异丙基联苯。合适的碱,例如,烷基胺,例如三乙胺,或碱金属或碱土金属碳酸盐或氢氧化物或磷酸盐例如碳酸钾、碳酸钠、碳酸铯或氢氧化钠或磷酸钾可以被用于反应中。所述反应可以在+20℃和+160℃之间的温度范围内,在合适的溶剂中进行,所述溶剂例如甲苯、四氢呋喃、2-甲基-四氢呋喃、二噁烷、二甲氧基乙烷、乙腈、水、乙醇、N,N-二甲基乙酰胺或N,N-二甲基甲酰胺、或其混合物。如果对映体纯的或富集的化合物(II)被用于在该反应中,则获得对映体纯的或对映体富集的化合物(III)。
(ii)对应的式(I)的化合物的形成
方案2
式(I)的化合物可以通过从例如式(III)的化合物开始获得(方案2),其中R10可以是F、OCH3、OC(CH3)3或OSiR’R”R”’(其中R’、R”和R”’独立地是芳基(例如苯基)或烷基(例如甲基或叔丁基))。如果R10是F,则到(I)的转化可以通过例如使用含水的HCl的酸性水解来进行。如果R10是OCH3,则到(I)的转化可以通过在合适的溶剂例如氯仿中与例如TMSI反应,或者通过在合适的溶剂例如乙酸中与HBr反应,或者通过在合适的溶剂例如二氯甲烷中与BBr3反应来进行。如果R10是OC(CH3)3,则到(I)的转化可以通过在合适的溶剂例如二氯甲烷中与例如三氟乙酸反应来进行。如果R10是OSiR’R”R”’,则到(I)的转化可以通过例如在合适的溶剂例如甲醇中的HCl或者通过使用在四氢呋喃中的四丁基氟化铵来进行。如果对映体纯的或富集的化合物(III)被用于该反应中,则获得对映体纯的或对映体富集的化合物(I)。
式(II)、式(III)的化合物和偶联配偶体A*是可商购的化合物,或者在文献中是已知的,或者它们通过本领域中已知的标准工艺来制备。式(I)、式(II)或式(III)的化合物可以通过本领域中已知的标准工艺通过例如在手性固定相上的色谱法被分离成其对映体。
一般方法
使用的所有溶剂都是分析级的,并且可商购的无水溶剂常规地被用于反应。起始材料可购自商业来源或者根据文献程序来制备。室温指的是+20-25℃。溶剂混合物组合物作为体积百分比或体积比率给出。微波加热在Biotage Initiator微波腔中进行,产生在2.45GHz的连续辐照。应当理解的是,微波可以被用于加热反应混合物。
在Merck硅胶60(0.040-0.063mm)上手动进行直相色谱法,或者使用指定的溶剂体系,使用ISCOCompanionTM***使用SiliaSepTM正相快速柱自动进行直相色谱法(straight phase chromatography)。
NMR光谱被记录在装配有合适配置的探针的400MHz(或更高场)的NMR谱仪上。除非另有说明,否则在环境温度下记录光谱。在CDCl3、DMSO-d6或CD3OD中获得NMR光谱。化学位移以从TMS(0.00ppm)的低场或高场的ppm给出。以下参考信号被使用:DMSO-d5的残留溶剂信号δ2.5或CHCl3的残留溶剂信号δ7.26或CD2HOD的残留溶剂信号δ3.31。对于单峰、双峰、三重峰、四重峰、多重峰和宽峰,共振多重性分别表示为s、d、t、q、m和br。
在反相柱上进行高压(高效)液相色谱法(HPLC)。使用例如流动相A(含水的0.1%NH3或含水的0.1%乙酸或含水的0.1%甲酸)和B(乙腈或甲醇)施加线性梯度。质谱法(MS)分析是在正离子模式下使用电喷雾离子化(ES+)进行的。
制备型色谱法在Gilson-PREP GX271或GX281上运行,其中Trilution lc作为在反相柱上的软件。使用例如流动相A(含水的0.1%NH3或含水的0.1%乙酸或含水的0.1%甲酸)和B(乙腈或甲醇)施加线性梯度。
用于分离对映体的制备型手性色谱法在手性固定相上使用超临界流体色谱法在Thar SFC上运行。使用流动相A(二氧化碳)和B(乙腈或甲醇或乙醇或2-丙醇或其任何混合物)施加线性梯度。可以使用添加剂(例如二乙胺或异丙胺或氨或甲酸或TFA)。
化合物已经使用Accelrys Draw 4.1SP1命名。
中间体实施例1
4-(2,6-二氯-4-吡啶基)吗啉
将2,6-二氯-4-碘-吡啶(6g,21.91mmol)、吗啉(2ml,23.12mmol)、PPh3(350mg,1.33mmol)、Pd(OAc)2(150mg,0.67mmol)和新研磨的K3PO4(13g,61.24mmol)吸收在DMF(40ml)中并且剧烈搅拌产生的混合物,同时用氮气脱气持续5分钟。将混合物放入到(lowered into)预加热的油浴中并在100℃搅拌持续1小时。当冷却至室温时,将混合物倒入水(150ml)和EtOAc(50ml)中。将有机层分离并且水层用EtOAc(3x30ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的10-60%EtOAc洗脱,以给出标题化合物(2.53g,49%)。MS ES+m/z 233[M+H]+。
中间体实施例2
4-(2-叔丁氧基-6-氯-4-吡啶基)吗啉
将4-(2,6-二氯-4-吡啶基)吗啉(3.2g,13.73mmol)、KOtBu(3.85g,34.32mmol)和分子筛(~10珠,4-8目)吸收在无水甲苯(50ml)中并在90℃搅拌持续2小时。当冷却至室温时,混合物用EtOAc(30ml)、盐水(40ml)和水(20ml)稀释。将有机层分离并且水层用EtOAc(2x25ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的0-40%EtOAc洗脱,以给出标题化合物(3.4g,91%)。MS ES+m/z 271[M+H]+。
中间体实施例3
4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-基)-4-吡啶基]吗啉
将4-(2-叔丁氧基-6-氯-4-吡啶基)吗啉(3.55g,13.11mmol)、2-苯基吡咯烷(2.8g,19.02mmol)、PEPPSITM-iPr(460mg,0.68mmol)和KOtBu(2.5g,22.28mmol)吸收在无水1,4-二噁烷(50ml)中并用氮气脱气持续5分钟。将产生的混合物在50℃搅拌持续1小时。当冷却至室温时,添加盐水(25ml)、水(15ml)和EtOAc(25ml)。将有机层分离并且水层用EtOAc(2x20ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的0-50%EtOAc洗脱,以给出标题化合物(5g,99%)。MS ES+m/z 382[M+H]+。
实施例1
4-吗啉代-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮
将4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-基)-4-吡啶基]吗啉(5g,13.11mmol)溶解在DCM(40ml)中,并在室温缓慢地添加TFA(2.92ml,39.32mmol)。将产生的混合物在室温搅拌持续1小时。添加更多的TFA(2ml,26.92mmol),并在室温继续搅拌持续2.5小时。浓缩混合物,并且将残余物吸收在EtOAc(50ml)中并冷却至0℃。缓慢地添加28%NH4OH(30ml),并剧烈地搅拌混合物持续10分钟。滤出沉淀物,用水(2x 5ml)、EtOAc(2x5ml)洗涤并干燥。将固体悬浮在EtOAc:庚烷(1:1,30ml)中,并且在室温搅拌持续15分钟并且然后过滤。滤饼用EtOAc:庚烷(1:1,2x10ml)洗涤,然后悬浮在戊烷(10ml)中,过滤并干燥,以给出标题化合物(2.3g,54%)。1H NMR(500MHz,DMSO-d6)δ7.30(t,2H),7.24-7.16(m,3H),5.07-4.98(m,2H),4.91(s,1H),3.78-3.71(m,1H),3.67-3.55(m,4H),3.52-3.42(m,1H),3.11-3.01(m,2H),3.01-2.95(m,2H),2.36-2.29(m,1H),1.94-1.82(m,2H),1.82-1.75(m,1H)。MS ES+m/z 326[M+H]+。
实施例2
1-甲基-4-吗啉代-6-(2-苯基吡咯烷-1-基)吡啶-2-酮
将4-吗啉代-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮(75mg,0.23mmol)和K2CO3(50mg,0.36mmol)吸收在MeCN(1ml)中。添加碘甲烷(0.02ml,0.32mmol)并且混合物在室温搅拌持续30分钟。添加DMAc(0.5ml)并且混合物在室温搅拌过夜。添加MeOH(1ml)和碘甲烷(0.05ml,0.8mmol),并在室温继续搅拌过夜。过滤混合物并通过制备型HPLC纯化以给出标题化合物(5mg,6%)。MS ES+m/z 340[M+H]+。
中间体实施例4
4-[2-叔丁氧基-6-[(2S)-2-苯基吡咯烷-1-基]-4-吡啶基]吗啉
将4-(2-叔丁氧基-6-氯-4-吡啶基)吗啉(120mg,0.44mmol)、(2S)-2-苯基吡咯烷(98mg,0.66mmol)、Pd2(dba)3(20mg,0.02mmol)、XantPhos(25mg,0.04mmol)和KOtBu(150mg,1.33mmol)吸收在甲苯(3ml)中,并且将产生的混合物在100℃搅拌过周末。添加更多的Pd2(dba)3(20mg,0.02mmol)、XantPhos(25mg,0.04mmol)和KOtBu(150mg,1.33mmol),并且在100℃继续搅拌过夜。添加更多的Pd2(dba)3(20mg,0.02mmol)、XantPhos(25mg,0.04mmol)和KOtBu(150mg,1.33mmol),并且在100℃继续搅拌持续5h。当冷却至室温时,添加EtOAc(5ml)和盐水(10ml)。将混合物过滤,分离有机层并且水层用EtOAc(2x5ml)提取。合并的有机物经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的0-40%EtOAc洗脱,以给出标题化合物(75mg,44%)。MS ES+m/z 382[M+H]+。
实施例3
4-吗啉代-6-[(2S)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮
将4-[2-叔丁氧基-6-[(2S)-2-苯基吡咯烷-1-基]-4-吡啶基]吗啉(75mg,0.2mmol)溶解在DCM(3ml)中,并添加TFA(73μl,0.98mmol)。将产生的混合物在室温搅拌持续3小时,浓缩并且通过制备型HPLC纯化,以给出标题化合物(23mg,36%)。1H NMR(500MHz,DMSO-d6)δ7.38-7.26(m,2H),7.26-7.12(m,3H),5.08-4.94(m,2H),4.88(s,1H),3.78-3.68(m,1H),3.65-3.52(m,4H),3.50-3.41(m,1H),3.13-2.89(m,4H),2.38-2.27(m,1H),1.96-1.82(m,2H),1.82-1.71(m,1H)。MS ES+m/z 326[M+H]+。
实施例4
4-吗啉代-6-[(2R)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮
将4-(2-叔丁氧基-6-氯-4-吡啶基)吗啉(300mg,1.11mmol)、(2R)-2-苯基吡咯烷(245mg,1.66mmol)、Pd2(dba)3(51mg,0.06mmol)、XPhos(53mg,0.11mmol)和KOtBu(373mg,3.32mmol)吸收在甲苯(5ml)中,并且将产生的混合物在105℃搅拌持续2小时。当冷却至室温时,添加EtOAc(5ml)和盐水(10ml)。将混合物过滤,分离有机层并且水层用EtOAc(2x5ml)提取。合并的有机物经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的0-40%EtOAc洗脱。将产生的材料吸收在DCM(5ml)中并且添加TFA(0.31ml,4.19mmol)。反应混合物在室温搅拌持续45分钟。添加更多的TFA(0.31ml,4.19mmol),并且继续搅拌持续1小时。浓缩混合物,并且将残余物吸收在EtOAc(5ml)和2M含水的HCl(2ml)中。将有机层分离并且水层用EtOAc(2x3ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并通过制备型HPLC纯化,以给出标题化合物(52mg,19%)。1H NMR(500MHz,DMSO-d6)δ9.50(br s,1H),7.34-7.27(m,2H),7.24-7.15(m,3H),5.04-4.96(m,2H),4.88(br s,1H),3.78-3.68(m,1H),3.63-3.53(m,4H),3.49-3.41(m,1H),3.07-3.00(m,2H),3.00-2.93(m,2H),2.38-2.26(m,1H),1.94-1.81(m,2H),1.78(dd,1H)。MS ES+m/z 326[M+H]+。
中间体实施例5
4-(2,6-二氯-4-吡啶基)-3-甲基-吗啉
将2,6-二氯-4-碘-吡啶(1.5g,5.48mmol)、3-甲基吗啉(0.61ml,6.02mmol)、PPh3(144mg,0.55mmol)、Pd(OAc)2(61mg,0.27mmol)和新研磨的K3PO4(3.49g,16.43mol)吸收在DMF(30ml)中,并将产生的混合物在100℃搅拌持续1小时。当冷却至室温时,将混合物倒入水(50ml)中并用EtOAc(3x 15ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的0-60%EtOAc洗脱,以给出标题化合物(800mg,59%)。MS ES+m/z 247[M+H]+。
中间体实施例6
4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉
将4-(2,6-二氯-4-吡啶基)-3-甲基-吗啉(2.2g,8.9mmol)、KOtBu(2.5g,22.26mmol)和分子筛(~10珠,4-8目)吸收在无水甲苯(40ml)中并在90℃搅拌持续2小时。当冷却至室温时,混合物用EtOAc(30ml)、盐水(40ml)和水(20ml)稀释。将有机层分离并且水层用EtOAc(2x25ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在硅胶柱上纯化,所述硅胶柱用在庚烷中的0-40%EtOAc洗脱,以给出标题化合物(2.2g,87%)。MS ES+m/z 285[M+H]+。
实施例5
6-(3,6-二氢-2H-吡喃-4-基)-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮
将4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(0.2g,0.7mmol)、2-(3,6-二氢-2H-吡喃-4-基)-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(dioxaborolane)(0.18g,0.84mmol)、PdCl2(amphos)(4.97mg,7.02μmol)和K2CO3(291.18mg,2.11mol)溶解在2-MeTHF(3ml)和水(1ml)中,并且将产生的混合物在微波反应器中在135℃加热持续1小时。当冷却至室温时,添加盐水(5ml)、水(4ml)和EtOAc(5ml)。将有机层分离并且水层用EtOAc(2x10ml)提取。将合并的有机物用盐水洗涤,经MgSO4干燥,过滤并且浓缩。将粗制的材料吸收在DCM(5ml)中并且添加TFA(345.93mg,3.03mmol)。将反应混合物在室温搅拌过夜。浓缩混合物,并且将产生的残余物溶解在EtOAc中并且用饱和的含水NaHCO3(2x10ml)洗涤。将有机层浓缩并且通过制备型HPLC纯化,以给出作为固体的产物(80mg,41%)。
1H NMR(400MHz,DMSO-d6)δ10.46(br s,1H),6.51(br s,1H),5.99(s,1H),5.32(s,1H),4.18(br s,2H),3.96(br d,1H),3.88(br d,1H),3.79-3.57(m,4H),3.49-3.33(m,2H),3.02(td,1H),2.37(br s,2H),1.08(d,3H)。MS ES+m/z 277[M+H]+。
实施例6
4-(3-甲基吗啉-4-基)-6-四氢吡喃-4-基-1H-吡啶-2-酮
在氮气下,将6-(3,6-二氢-2H-吡喃-4-基)-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮(80mg,0.29mmol)、10%碳载Pd(120mg,1.16mmol)和甲酸铵(110mg,1.74mmol)溶解在MeOH(4ml)中,并且将产生的混合物在50℃搅拌持续1小时。当冷却至室温时,过滤混合物并在制备型HPLC上纯化,以给出作为固体的产物(30mg,37%)。1H NMR(400MHz,CD3OD)δ6.05(s,1H),5.54(s,1H),4.06–3.94(m,4H),3.80-3.68(m,2H),3.61-3.42(m,4H),3.20(td,1H),2.76-2.66(m,1H),1.86-1.72(m,4H),1.26-1.18(m,3H)。MS ES+m/z 279[M+H]+。
实施例7
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮
将4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(200mg,0.7mmol)、2-(3-甲氧基苯基)吡咯烷(150mg,0.84mmol)、PEPPSITM-iPr(24mg,0.04mmol)和KOtBu(160mg,1.4mmol)吸收在无水1,4-二噁烷(5ml)中并用氮气脱气持续5分钟。将产生的混合物在90℃搅拌持续1小时。当冷却至室温时,添加盐水(5ml)、水(4ml)和EtOAc(5ml)。将有机层分离并且水层用EtOAc(2x10ml)提取。将合并的有机物用盐水洗涤,过滤并且浓缩。将产生的残余物溶解在DCM(10ml)中并且在室温缓慢地添加TFA(0.38ml,5.06mmol)。将产生的混合物在室温搅拌过夜。浓缩混合物并且通过制备型HPLC纯化,以给出标题化合物(90mg,37%)。1H NMR(500MHz,DMSO-d6)δ9.50(br s,1H),7.23(td,1H),6.71-6.82(m,3H),4.90-5.02(m,1H),4.88(br s,1H),4.81(br s,1H),3.68-3.84(m,5H),3.57-3.67(m,2H),3.33-3.55(m,4H),3.18(br d,1H),3.09(br d,1H),2.81-2.93(m,1H),2.27-2.48(m,1H),1.83-1.95(m,2H),1.79(br dd,1H),1.05(d,1H),0.77(br d,2H)。MS ES+m/z 370[M+H]+。
实施例8
4-(3-甲基吗啉-4-基)-6-[2-(3-吡啶基)吡咯烷-1-基)-1H-吡啶-2-酮
如实施例7所述制备标题化合物,从4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(200mg,0.7mmol)和3-吡咯烷-2-基吡啶(120mg,0.84mmol)开始,以给出产物(80mg,34%)。1H NMR(500MHz,DMSO-d6)δ10.72(br s,1H),8.40-8.49(m,2H),7.57(t,1H),7.33(dt,1H),5.10(br d,1H),4.96-5.05(m,1H),4.93(br s,1H),3.72-3.86(m,2H),3.59-3.70(m,2H),3.37-3.55(m,3H),3.16-3.31(m,1H),3.11(br d,1H),2.87(qd,1H),2.30-2.48(m,1H),1.81-1.97(m,6H),1.04(d,2H),0.76(br d,1H)。MS ES+m/z 341[M+H]+。
实施例9
4-(3-甲基吗啉-4-基)-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮
如实施例7所述制备标题化合物,从4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(200mg,0.7mmol)和2-苯基吡咯烷(120mg,0.84mmol)开始,以给出产物(110mg,46%)。1HNMR(500MHz,DMSO-d6)δ9.54(br s,1H),7.26-7.36(m,2H),7.17-7.26(m,3H),4.89-5.06(m,2H),4.73-4.88(m,1H),3.70-3.86(m,2H),3.55-3.65(m,2H),3.33-3.55(m,4H),3.17(br d,1H),3.08(br d,1H),2.79-2.94(m,1H),2.28-2.48(m,1H),2.08(s,1H),1.84-1.97(m,2H),1.75-1.84(m,1H),1.04(d,1H),0.74(br d,2H)。MS ES+m/z 340[M+H]+。
中间体实施例7
(3R)-4-(2,6-二氯-4-吡啶基)-3-甲基-吗啉
如中间体实施例5所述制备标题化合物,用(R)-3-甲基吗啉替换3-甲基吗啉,以给出产物(900mg,66%)。MS ES+m/z 247[M+H]+。
中间体实施例8
(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉
如中间体实施例6所述制备标题化合物,从(3R)-4-(2,6-二氯-4-吡啶基)-3-甲基-吗啉(700mg)开始,以给出产物(510mg,63%)。1H NMR(400MHz,CDCl3)δ6.29(s,1H),5.92-5.81(m,1H),4.04-3.92(m,1H),3.85-3.69(m,3H),3.65-3.52(m,1H),3.29-3.10(m,2H),1.59-1.53(m,9H),1.21(d,3H)。MS ES+m/z 285[M+H]+。
中间体实施例9
1-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-N,N-二甲基-吡咯烷-2-甲酰胺
将(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(250mg,0.88mmol)、N,N-二甲基吡咯烷-2-甲酰胺HCl盐(188mg,1.05mmol)、PEPPSITM-iPr(30mg,0.044mmol)和KOtBu(197mg,1.76mmol)吸收在无水1,4-二噁烷(5ml)中并用氮气脱气持续5分钟。将产生的混合物在90℃搅拌持续1小时。当冷却至室温时,混合物通过硅藻土(celite)过滤,并且滤液用水稀释并用乙酸乙酯提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在用20%EtOAc/石油醚洗脱的硅胶柱上纯化,以给出标题化合物(160mg,46%)。MS ES+m/z 391[M+H]+。
实施例10
N,N-二甲基-1-[4-[(3R)-3-甲基吗啉-4-基]-6-氧代-1H-吡啶-2-基]吡咯烷-2-甲酰胺
在0℃将TFA(0.29ml,3.8mmol)添加到在DCM(3ml)中的1-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-N,N-二甲基-吡咯烷-2-甲酰胺(150mg,0.38mmol)的溶液中,并将产生的混合物在室温搅拌过夜。将反应混合物用饱和的含水NaHCO3碱化并且用DCM提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在用5%MeOH/DCM洗脱的硅胶柱上纯化,以给出标题化合物(50mg,39%)。1H NMR(400MHz,CDCl3)δ5.21-5.02(m,2H),4.83(s,1H),3.95(br d,1H),3.81-3.69(m,3H),3.64-3.53(m,2H),3.41(dt,,1H),3.27-3.14(m,2H),3.09(s,3H),2.92(d,3H),2.39-2.32(m,1H),2.09-1.93(m,3H),1.27-1.15(m,3H)。MS ES+m/z 335[M+H]+。
中间体实施例10
(3R)-4-[2-叔丁氧基-6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和2-(1-甲氧基-1-甲基-乙基)吡咯烷(302mg,2.11mmol)开始,以给出产物(375mg,54%)。MS ES+m/z 392[M+H]+。
实施例11
(R)和(S)6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(350mg,0.89mmol)开始,以给出作为非对映异构体混合物的产物(170mg,57%)。1H NMR(400MHz,CDCl3)δ10.48(br s,1H),5.25(s,1H),4.94-4.91(m,1H),3.96(br dd,1H),3.83-3.72(m,4H),3.62-3.54(m,1H),3.37-3.15(m,7H),2.07-1.86(m,4H),1.32-1.18(m,6H),1.08(d,3H)。MS ES+m/z 336[M+H]+。通过SFC的手性分离给出两种异构体。
实施例11-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ10.70-10.44(m,1H),5.33-5.21(m,1H),4.99-4.88(m,1H),3.96(br dd,1H),3.85-3.71(m,4H),3.58(td,1H),3.39-3.29(m,5H),3.28-3.16(m,2H),2.08-1.85(m,4H),1.27-1.19(m,6H),1.09(s,3H)。MS ES+m/z 336[M+H]+。
实施例11-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ10.62-10.40(m,1H),5.25(s,1H),4.93(s,1H),3.96(brdd,1H),3.85-3.68(m,4H),3.58(td,1H),3.41-3.26(m,5H),3.19(td,1H),2.10-1.87(m,5H),1.28-1.17(m,6H),1.08(s,3H)。MS ES+m/z 336[M+H]+。
中间体实施例11
(3R)-4-[2-叔丁氧基-6-(2-环己基吡咯烷-1-基)-4-吡啶基]-3-甲基-吗啉
如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和2-环己基吡咯烷(323mg,2.11mmol)开始,以给出产物(310mg,44%)。MS ES+m/z 402[M+H]+。
实施例12
(R)和(S)6-(2-环己基吡咯烷-1-基)-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-(2-环己基吡咯烷-1-基)-4-吡啶基]-3-甲基-吗啉(300mg,0.75mmol)开始,以给出作为非对映异构体混合物的产物(218mg,81%)。1H NMR(400MHz,CDCl3)δ5.19(s,1H),4.82(br s,1H),3.97(br d,1H),3.83-3.72(m,3H),3.68-3.55(m,2H),3.39(br s,1H),3.33-3.18(m,3H),2.04-1.88(m,4H),1.80-1.61(m,7H),1.27-1.22(m,3H),1.16-0.96(m,4H)。MS ES+m/z 346[M+H]+。通过SFC的手性分离给出两种异构体。
实施例12-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.17(br s,1H),4.81(br s,1H),3.97(br d,1H),3.81-3.70(m,3H),3.68-3.56(m,2H),3.38(br s,1H),3.31-3.17(m,3H),2.06-1.87(m,4H),1.81-1.50(m,8H),1.23(br d,3H),1.17-1.08(m,3H)。MS ES+m/z 346[M+H]+。
实施例12-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.19(br s,1H),4.82(br s,1H),3.97(br d,1H),3.82-3.56(m,5H),3.39(br s,1H),3.32-3.16(m,3H),1.99(br s,4H),1.74(br s,8H),1.24(brd,3H),1.14-1.00(m,3H)。MS ES+m/z 346[M+H]+。
中间体实施例12
(3R)-4-[2-叔丁氧基-6-[2-(3-氟苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续3小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(650mg,2.28mmol)和2-(3-氟苯基)吡咯烷(453mg,2.74mmol)开始,以给出产物(373mg,39%)。MS ES+m/z 414[M+H]+。
实施例13
(R)和(S)6-[2-(3-氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(3-氟苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(430mg,1.04mmol)开始,以给出作为非对映异构体混合物的产物(300mg,81%)。1H NMR(400MHz,CDCl3)δ7.29(br d,1H),6.99-6.94(m,2H),6.88(br d,1H),5.14(dd,1H),4.81-4.64(m,2H),3.95-3.88(m,1H),3.77-3.64(m,3H),3.58-3.45(m,3H),3.19-3.05(m,2H),2.49-2.37(m,1H),2.08-1.92(m,3H),1.20(d,1.5H),0.97(br d,1.5H)。MS ES+m/z 358[M+H]+。通过SFC的手性分离给出两种异构体。
实施例13-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.31(br d,1H),7.01-6.94(m,2H),6.87(br d,1H),5.16(br s,1H),4.79-4.72(m,2H),3.92(br d,1H),3.73-3.62(m,4H),3.58-3.45(m,2H),3.19-3.06(m,2H),2.48-2.38(m,1H),2.08-1.94(m,3H),1.20(br d,3H)。MS ES+m/z 358[M+H]+。
实施例13-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.30(br d,1H),7.00-6.93(m,2H),6.88(br d,1H),5.16(s,1H),4.75(br dd,1H),4.67(s,1H),3.92(br d,1H),3.75(br d,1H),3.67(s,2H),3.59-3.47(m,3H),3.13-3.08(m,2H),2.45(qd,1H),2.10-1.94(m,3H),0.98(d,3H)。MS ES+m/z358[M+H]+。
中间体实施例13
(3R)-4-[2-叔丁氧基-6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续16小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(700mg,2.46mmol)和2-(2,5-二氟苯基)吡咯烷(541mg,2.95mmol)开始,以给出产物(600mg,57%)。MS ES+m/z 432[M+H]+。
实施例14
(R)和(S)6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(650mg,1.5mmol)开始,以给出作为非对映异构体混合物的产物(450mg,80%)。1H NMR(400MHz,CDCl3)δ7.06(dt,1H),6.95(br s,1H),6.78-6.71(m,1H),5.50(br s,1H),5.13-5.05(m,1H),4.93(br d,1H),4.00-3.91(m,2H),3.75-3.46(m,5H),3.25-3.06(m,2H),2.54-2.42(m,1H),2.17-2.00(m,3H),1.26-1.19(m,1.5H),0.98(d,1.5H)。MS ES+m/z 376[M+H]+。通过SFC的手性分离给出两种异构体。
实施例14-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.31(br d,1H),7.01-6.94(m,2H),6.87(br d,1H),5.16(br s,1H),4.79-4.72(m,2H),3.92(br d,1H),3.73-3.62(m,4H),3.58-3.45(m,2H),3.19-3.06(m,2H),2.48-2.38(m,1H),2.08-1.94(m,3H),1.20(br d,3H)。MS ES+m/z 358[M+H]+。
实施例14-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.30(br d,1H),7.00-6.93(m,2H),6.88(br d,1H),5.16(s,1H),4.75(br dd,1H),4.67(s,1H),3.92(br d,1H),3.75(br d,1H),3.67(s,2H),3.59-3.47(m,3H),3.13-3.08(m,2H),2.45(qd,1H),2.10-1.94(m,3H),0.98(d,3H)。MS ES+m/z358[M+H]+。
中间体实施例14
(3R)-4-[2-叔丁氧基-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续16小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和2-[3-(三氟甲氧基)苯基]吡咯烷(488mg,2.11mmol)开始,以给出产物(170mg,20%)。MS ES+m/z 480[M+H]+。
实施例15
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(225mg,0.46mmol)开始,以给出作为非对映异构体混合物的产物(120mg,60%)。1H NMR(400MHz,CDCl3)δ7.38-7.33(m,1H),7.12(br d,,2H),7.04(br s,1H),5.14(dd,1H),4.77(ddd,1H),4.68-4.59(m,1H),3.93-3.74(m,2H),3.70-3.46(m,5H),3.16-3.01(m,2H),2.50-2.39(m,1H),2.09-2.01(m,2H),1.98-1.91(m,1H),1.19(d,1.5H),0.92(d,1.5H)。MS ES+m/z 424[M+H]+。通过SFC的手性分离给出两种异构体。
实施例15-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.38-7.34(m,1H),7.12(br d,2H),7.05(s,1H),5.14(d,1H),4.75(dd,1H),4.61(d,,1H),3.90(br d,1H),3.82-3.76(m,1H),3.65(s,2H),3.59-3.46(m,3H),3.10-3.07(m,2H),2.46(qd,1H),2.09-1.91(m,3H),0.92(d,3H)。MS ES+m/z424[M+H]+。
实施例15-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.40-7.34(m,1H),7.13(br t,2H),7.05-6.99(m,1H),5.15(s,1H),4.77(br d,1H),4.69(s,1H),3.91(br d,1H),3.74-3.46(m,6H),3.17-3.02(m,2H),2.50-2.40(m,1H),2.08-1.93(m,3H),1.19(br d,,3H)。MS ES+m/z 424[M+H]+。
中间体实施例15
(3R)-4-[2-叔丁氧基-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续3小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(700mg,2.46mmol)和2-[3-(三氟甲基)苯基]吡咯烷(636mg,2.95mmol)开始,以给出产物(800mg,70%)。MS ES+m/z 464[M+H]+。
实施例16
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(800mg,1.72mmol)开始,以给出作为非对映异构体混合物的产物(300mg,42%)。1H NMR(400MHz,CDCl3)δ7.54-7.51(m,1H),7.47-7.42(m,2H),7.39-7.35(m,1H),5.14(dd,1H),4.89-4.78(m,1H),4.68-4.58(m,1H),3.93-3.76(m,2H),3.71-3.45(m,5H),3.16-3.01(m,2H),2.52-2.41(m,1H),2.10-2.00(m,2H),1.98-1.92(m,1H),1.19(d,1.5H),0.88(br d,1.5H)。MS ES+m/z 408[M+H]+。通过SFC的手性分离给出两种异构体。
实施例16-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.55-7.51(m,1H),7.49-7.44(m,2H),7.37(br d,1H),5.13(s,1H),4.79(br dd,1H),4.62(s,1H),3.90(br d,1H),3.80-3.74(m,1H),3.65(s,2H),3.58-3.46(m,3H),3.09(br d,2H),2.54-2.44(m,1H),2.11-2.04(m,2H),2.00-1.93(m,1H),0.92(d,3H)。MS ES+m/z 408[M+H]+。
实施例16-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.56-7.44(m,3H),7.37(br d,1H),5.16(s,1H),4.82(brd,1H),4.71(s,1H),3.91(br d,1H),3.71-3.47(m,6H),3.17-3.03(m,2H),2.50-2.43(m,1H),2.09-1.98(m,3H),1.20(br d,3H)。MS ES+m/z 408[M+H]+。
中间体实施例16
(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物在110℃搅拌持续6小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和2-(3-甲氧基苯基)吡咯烷(374mg,2.1mmol)开始,以给出产物(550mg,73%)。MS ES+m/z 426[M+H]+。
实施例17
(R)和(S)6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(500mg,1.17mmol)开始,以给出作为非对映异构体混合物的产物(325mg,75%)。1H NMR(400MHz,CDCl3-d)δ7.25-7.22(m,1H)6.81-6.75(m,2H)6.70(s,1H)5.13(dd,1H)4.77-4.69(m,2H)3.95-3.89(m,1H)3.79(d,3H)3.75-3.65(m,4H)3.60-3.43(m,3H)3.21-3.06(m,2H)2.47-2.36(m,1H)2.12-1.93(m,3H)1.20(d,1H)1.00(d,1H)。MS ES+m/z 370[M+H]+。通过SFC的手性分离给出两种异构体。
实施例17-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.27(br s,0.5H)7.23(s,0.5H)6.81-6.75(m,2H)6.70(s,1H)5.13(d,1H)4.77-4.71(m,2H)3.92(br dd,1H)3.79(s,3H)3.72-3.65(m,4H)3.58-3.43(m,2H)3.21-3.06(m,2H)2.46-2.36(m,1H)2.08-1.93(m,3H)1.20(d,3H)。MS ES+m/z 370[M+H]+。
实施例17-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.24-7.22(m,1H)6.80-6.75(m,2H)6.71(s,1H)5.12(d,1H)4.72-4.68(m,2H)3.91(br d,1H)3.78(s,3H)3.73(td,1H)3.67(d,2H)3.60-3.47(m,3H)3.16-3.05(m,2H)2.47-2.37(m,1H)2.10-1.93(m,3H)0.99(d,3H)。MS ES+m/z 370[M+H]+。
中间体实施例17
(3R)-4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-基)-4-吡啶基]-3-甲基-吗啉
除了混合物在110℃搅拌持续6小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(400mg,1.4mmol)和2-苯基吡咯烷(384mg,2.53mmol)开始,以给出产物(325mg,58%)。MS ES+m/z 396[M+H]+。
实施例18
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-(2-苯基吡咯烷-1-基)-4-吡啶基]-3-甲基-吗啉(320mg,0.86mmol)开始,以给出作为非对映异构体混合物的产物(230mg,55%)。1H NMR(400MHz,CDCl3)δppm 7.32(br dd,3H)7.17(br d,2H)5.13(dd,1H)4.79-4.67(m,2H)3.94-3.88(m,1H)3.72-3.45(m,6H)3.19-3.05(m,2H)2.48-2.37(m,1H)2.11-1.94(m,3H)1.25(s,1H)1.20(br d,1H)0.97(d,1H)。MS ES+m/z 340[M+H]+。通过SFC的手性分离给出两种异构体。
实施例18-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.36-7.28(m,3H)7.17(br d,2H)5.13(d,1H)4.79-4.73(m,2H)3.91(br dd,1H)3.71-3.45(m,6H)3.19-3.04(m,2H)2.47-2.37(m,1H)2.08-1.93(m,3H)1.27(dd,1H)1.20(d,2H)。MS ES+m/z 340[M+H]+。
实施例18-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.34-7.29(m,2H)7.25-7.15(m,3H)5.12(d,1H)4.76-4.66(m,2H)3.90(br d,1H)3.75(td,1H)3.65(s,2H)3.57-3.46(m,3H)3.13-3.07(m,2H)2.49-2.39(m,1H)2.10-1.93(m,3H)0.95(d,3H)。MS ES+m/z 340[M+H]+。
中间体实施例18
(3R)-4-[2-叔丁氧基-6-[2-(1-甲基吡唑-4-基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物在90℃搅拌持续16小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(1g,3.42mmol)和1-甲基-4-吡咯烷-2-基-吡唑(638mg,4.2mmol)开始,以给出产物(800mg,57%)。MS ES+m/z 400[M+H]+。
实施例19
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-[2-(1-甲基吡唑-4-基)吡咯烷-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(1-甲基吡唑-4-基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(800mg,1.99mmol)开始,以给出作为非对映异构体混合物的产物(500mg,73%)。1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.19(d,1H),5.15(s,1H),4.80(dd,2H),3.94(br d,1H),3.84(d,3H),3.71(s,3H),3.61-3.51(m,2H),3.41-3.32(m,1H),3.25-3.11(m,2H),2.36-2.24(m,1H),2.10-2.02(m,2H),1.97-1.91(m,1H),1.22(d,1.5H),1.14(br d,1.5H)。MS ES+m/z 344[M+H]+。通过SFC的手性分离给出两种异构体。
实施例19-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.19(s,1H),5.15(d,1H),4.84-4.80(m,2H),3.94(br dd,1H),3.84(s,3H),3.74-3.66(m,3H),3.61-3.52(m,2H),3.36(q,1H),3.25-3.11(m,2H),2.34-2.24(m,1H),2.08-2.02(m,2H),1.96-1.90(m,1H),1.21(d,3H)。MS ES+m/z 344[M+H]+。
实施例19-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.32(s,1H),7.19(s,1H),5.15(d,1H),4.83-4.79(m,2H),3.96-3.91(m,1H),3.83(s,3H),3.73-3.68(m,3H),3.63-3.51(m,2H),3.38(q,1H),3.22-3.11(m,2H),2.35-2.26(m,1H),2.10-2.01(m,2H),1.97-1.91(m,1H),1.13(d,3H)。MS ES+m/z 344[M+H]+。
中间体实施例19
(3R)-4-[2-叔丁氧基-6-[2-(1,5-二甲基吡唑-3-基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物在100℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和1,5-二甲基-3-吡咯烷-2-基-吡唑(342mg,2.1mmol)开始,以给出产物(400mg,55%)。MS ES+m/z 414[M+H]+。
实施例20
(R)和(S)6-[2-(1,5-二甲基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(1,5-二甲基吡唑-3-基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(400mg,0.96mmol)开始,以给出作为非对映异构体混合物的产物(200mg,58%)。1H NMR(400MHz,CDCl3)δ5.82(d,1H)5.15(br s,1H)4.87(br s,1H)4.77(br d,1H)3.94(brdd,1H)3.77-3.70(m,6H)3.59-3.51(m,2H)3.35(brs,1H)3.26-3.14(m,2H)2.35-2.29(m,1H)2.22-2.09(m,6H)1.20(d,1.5H)1.14(d,1.5H)。MSES+m/z 358[M+H]+。通过SFC的手性分离给出两种异构体。
实施例20-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.83(s,1H)5.15(d,1H)4.87(d,1H)4.78-4.75(m,1H)3.94(br dd,1H)3.77-3.68(m,6H)3.60-3.49(m,2H)3.37-3.30(m,1H)3.26-3.11(m,2H)2.34-2.29(m,1H)2.21(s,3H)2.17-2.05(m,3H)1.20(d,3H)。MS ES+m/z 358[M+H]+。
实施例20-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.81(s,1H)5.14(d,1H)4.87(d,1H)4.76(dd,1H)3.94(dd,1H)3.77-3.68(m,6H)3.59-3.51(m,2H)3.39-3.33(m,1H)3.25-3.11(m,2H)2.37-2.29(m,1H)2.22-2.04(m,6H)1.14(d,3H)。MS ES+m/z 358[M+H]+。
中间体实施例20
(3R)-4-[2-叔丁氧基-6-[2-(1-乙基吡唑-3-基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续10小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和1-乙基-3-吡咯烷-2-基-吡唑(348mg,2.11mmol)开始,以给出产物(380mg,52%)。MS ES+m/z 414[M+H]+。
实施例21
(R)和(S)6-[2-(1-乙基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(1-乙基吡唑-3-基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(370mg,0.89mmol)开始,以给出作为非对映异构体混合物的产物(260mg,81%)。1H NMR(400MHz,CDCl3)δ7.31-7.29(m,1H)6.03(d,1H)5.15(br d,1H)4.85(br d,2H)4.16-4.12(m,2H)3.93(br dd,1H)3.76-3.70(m,3H)3.55-3.51(m,2H)3.35(br d,1H)3.25-3.15(m,2H)2.19(d,1H)2.14-1.88(m,3H)1.50-1.47(m,3H)1.20(d,3H)。MS ES+m/z 358[M+H]+。通过SFC的手性分离给出两种异构体。
实施例21-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.30(s,1H)6.03(d,1H)5.14(s,1H)4.85(br s,2H)4.13(q,2H)3.93(br d,1H)3.75-3.69(m,3H)3.58-3.52(m,2H)3.41-3.34(m,1H)3.24-3.14(m,2H)2.39-2.32(m,1H)2.17(br d,3H)1.48(t,3H)1.13(br d,3H)。MS ES+m/z 358[M+H]+。
实施例21-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.31(s,1H)6.05(s,1H)5.16(s,1H)4.87-4.83(m,2H)4.14(q,2H)3.93(br d,1H)3.76-3.69(m,3H)3.54(br d,2H)3.35(br d,1H)3.25-3.13(m,2H)2.37-2.31(m,1H)2.20(br d,3H)1.51-1.47(m,3H)1.20(br d,3H)。MS ES+m/z 358[M+H]+。
中间体实施例21
(3R)-4-[2-叔丁氧基-6-[2-(5-甲基-2-呋喃基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续16小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(600mg,2.11mmol)和2-(5-甲基-2-呋喃基)吡咯烷(383mg,2.53mmol)开始,以给出产物(420mg,50%)。MS ES+m/z 400[M+H]+。
实施例22
(R)和(S)6-[2-(5-甲基-2-呋喃基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(5-甲基-2-呋喃基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(420mg,1.05mmol)开始,以给出作为非对映异构体混合物的产物(250mg,69%)。1H NMR(400MHz,CDCl3)δ6.06-6.03(m,1H),5.86(br s,1H),5.17-5.15(m,1H),4.87(d,1H),4.75(br d,,1H),3.95(br dd,1H),3.78-3.70(m,3H),3.61-3.53(m,2H),3.41-3.33(m,1H),3.24-3.12(m,2H),2.27-2.15(m,6H),2.08-2.01(m,1H),1.24-1.14(m,3H)。MS ES+m/z 344[M+H]+。通过SFC的手性分离给出两种异构体。
实施例22-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ6.04(d,1H),5.86(br s,1H),5.16(s,1H),4.86(s,1H),4.74(br d,1H),3.95(br d,1H),3.72(s,3H),3.60-3.52(m,2H),3.39-3.34(m,1H),3.25-3.16(m,2H),2.27-2.16(m,6H),2.06(br s,1H),1.16(br d,3H)。MS ES+m/z 344[M+H]+。
实施例22-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ6.05(d,1H),5.87(br s,1H),5.17(s,1H),4.87(s,1H),4.74(br d,1H),3.95(br d,1H),3.78-3.71(m,3H),3.61-3.51(m,2H),3.37-3.18(m,3H),2.27-2.16(m,6H),2.06(br s,1H),1.22(d,3H)。MS ES+m/z 344[M+H]+。
中间体实施例22
3-[1-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]吡咯烷-2-基]-N,N-二甲基-苯胺
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和N,N-二甲基-3-吡咯烷-2-基-苯胺(100mg,0.53mmol)开始,以给出产物(136mg,88%)。MS ES+m/z 439[M+H]+。
实施例23
(R)和(S)6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从3-[1-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]吡咯烷-2-基]-N,N-二甲基-苯胺(136mg,0.31mmol)开始,以给出作为非对映异构体混合物的产物(33mg,28%)。1H NMR(500MHz,DMSO-d6)δ7.14-7.04(m,1H),6.63-6.53(m,2H),6.50-6.39(m,1H),4.94-4.74(m,3H),3.86-3.79(m,1H),3.75-3.69(m,1H),3.62(br d,2H),3.56-3.42(m,4H),3.18(br d,1H),3.08(br d,1H),2.88-2.85(m,6H),2.39-2.25(m,1H),1.97-1.87(m,2H),1.80(br d,1H),1.09-1.00(m,1.5H),0.77(br d,1.5H)。MS ES+m/z 383[M+H]+。
中间体实施例23
(3R)-4-[2-叔丁氧基-6-(3-甲基吗啉-4-基)-4-吡啶基]-3-甲基-吗啉
除了混合物在110℃搅拌持续6小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和3-甲基吗啉(213mg,2.1mmol)开始,以给出产物(470mg,76%)。MS ES+m/z 350[M+H]+。
实施例24
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-(3-甲基吗啉-4-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-(3-甲基吗啉-4-基)-4-吡啶基]-3-甲基-吗啉(500mg,1.42mmol)开始,以给出作为非对映异构体混合物的产物(230mg,55%)。1H NMR(400MHz,CDCl3)δ5.30(s,1H)5.08(d,1H)4.00-3.55(m,10H)3.32-3.16(m,3H)3.08(br t,1H)1.26-1.17(m,6H)。MS ES+m/z 294[M+H]+。通过SFC的手性分离给出两种异构体。
实施例24-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.29(d,1H),5.07(d,1H),3.95(br d,3H),3.85-3.69(m,7H),3.25-3.19(m,3H),3.05(br d,1H),1.22-1.17(m,6H)。MS ES+m/z 294[M+H]+。
实施例24-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.28(br s,1H),5.03(br s,1H),3.99-3.72(m,10H),3.33-3.18(m,4H),1.25-1.18(m,6H)。MS ES+m/z 294[M+H]+。
中间体实施例24
(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]-4-吡啶基]-3-甲基-吗啉
如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)和2-(三氟甲基)哌啶(323mg,2.11mmol)开始,以给出产物(575mg,81%)。MS ES+m/z 402[M+H]+。
实施例25
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]-4-吡啶基]-3-甲基-吗啉(500mg,1.24mmol)开始,以给出作为非对映异构体混合物的产物(230mg,53%)。1H NMR(300MHz,DMSO-d6)δ9.71(br s,1H),5.59-5.55(m,1H),5.32(br s,2H),3.89(br s,3H),3.69-3.65(m,2H),3.61(br s,2H),3.34-3.32(m,2H),1.91(brs,1H),1.65(br s,5H),1.06(br s,3H)。MS ES+m/z 346[M+H]+。通过SFC的手性分离给出两种异构体。
实施例25-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.29(d,1H),5.20(d,1H),4.78-4.74(m,1H),3.99-3.95(m,1H),3.83-3.75(m,3H),3.63-3.58(m,1H),3.39(br d,1H),3.24-3.18(m,3H),2.13-2.03(m,2H),1.80-1.69(m,4H),1.21(d,3H)。MS ES+m/z 346[M+H]+。
实施例25-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.30(d,1H),5.20(d,1H),4.75-4.70(m,1H),3.97(br dd,1H),3.81-3.74(m,3H),3.64-3.59(m,1H),3.39(br d,1H),3.31-3.20(m,3H),2.11-1.99(m,2H),1.80-1.69(m,4H),1.23(d,3H)。MS ES+m/z 346[M+H]+。
中间体实施例25
4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-苯基-吗啉
如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(400mg,1.4mmol)和3-苯基吗啉(275mg,1.69mmol)开始,以给出产物(360mg,62%)。MS ES+m/z 412[M+H]+。
实施例26
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-(3-苯基吗啉-4-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-苯基-吗啉(350mg,0.85mmol)开始,以给出作为非对映异构体混合物的产物(100mg,33%)。1H NMR(400MHz,CDCl3)δ7.36-7.27(m,3H),7.25-7.19(m,2H),5.35-5.21(m,1H),5.08-4.98(m,1H),4.49-4.43(m,0.5H),4.33-4.27(m,0.5H),4.01-3.82(m,4H),3.74-3.58(m,3H),3.57-3.38(m,3H),3.15-2.93(m,3H),1.17-1.06(m,1.5H),0.78-0.63(m,1.5H)。MS ES+m/z 356[M+H]+。通过SFC的手性分离给出两种异构体。
实施例26-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.36-7.28(m,3H),7.25-7.19(m,2H),5.26(br s,1H),5.02(br s,1H),4.35-4.26(m,1H),4.00-3.87(m,4H),3.72-3.62(m,4H),3.52-3.42(m,2H),3.00(br s,3H),0.76-0.66(m,3H)。MSES+m/z 356[M+H]+。
实施例26-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.40-7.27(m,3H),7.23(br s,2H),5.35-5.21(m,1H),5.09-4.90(m,1H),4.57-4.36(m,1H),4.11-3.73(m,5H),3.71-3.29(m,4H),3.71-3.29(m,1H),3.20-2.90(m,3H),1.13(br d,3H)。MS ES+m/z 356[M+H]+。
中间体实施例26
4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-1,4-噻嗪烷1-氧化物
除了混合物在70℃搅拌过夜之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和1,4-噻嗪烷1-氧化物(67mg,0.56mmol)开始,以给出产物(70mg,54%)。MS ES+m/z 368[M+H]+。
实施例27
4-[(3R)-3-甲基吗啉-4-基]-6-(1-氧代-1,4-噻嗪烷-4-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-1,4-噻嗪烷1-氧化物(70mg,0.19mmol)开始,以给出产物(14mg,24%)。1HNMR(500MHz,DMSO-d6)δ5.61(br s,1H),5.27(s,1H),3.95-3.84(m,4H),3.82-3.73(m,2H),3.71-3.64(m,1H),3.64-3.57(m,1H),3.52-3.42(m,1H),2.99(td,1H),2.92-2.81(m,2H),2.67-2.59(m,2H),2.04-2.11(m,2H),1.07(d,3H)。MS ES+m/z 312[M+H]+。
中间体实施例27
4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-1,4-噻嗪烷1,1-二氧化物
除了混合物在70℃搅拌过夜之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和1,4-噻嗪烷1,1-二氧化物(71mg,0.53mmol)开始,以给出产物(86mg,64%)。MS ES+m/z 384[M+H]+。
实施例28
6-(1,1-二氧代-1,4-噻嗪烷-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-1,4-噻嗪烷1,1-二氧化物(86mg,0.22mmol)开始,以给出产物(38mg,52%)。1H NMR(500MHz,DMSO-d6)δ5.72(br s,1H),5.37(br s,1H),3.96-3.86(m,6H),3.72-3.65(m,1H),3.63-3.57(m,1H),3.50-3.43(m,1H),3.38(m,2H),3.18(br d,1H),3.09-3.05(m,3H),3.03–2.94(m,1H),1.07(d,3H)。MS ES+m/z 328[M+H]+。
中间体实施例28
1-[4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]哌嗪-1-基]乙酮
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和1-哌嗪-1-基乙酮(67mg,0.562mmol)开始,以给出产物(67mg,48%)。MS ES+m/z 378[M+H]+。
实施例29
6-(4-乙酰基哌嗪-1-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从1-[4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]哌嗪-1-基]乙酮(67mg,0.18mmol)开始,以给出产物(31mg,54%)。1H NMR(500MHz,DMSO-d6)δ5.42(br s,1H),5.20(br s,1H),3.97-3.83(m,2H),3.76-3.63(m,1H),3.63-3.54(m,1H),3.54-3.39(m,5H),3.32-3.28(m,2H),3.27-3.16(m,3H),2.99(td,1H),2.03(s,3H),1.07(d,3H)。MS ES+m/z 321[M+H]+。
中间体实施例29
(3R)-4-[2-叔丁氧基-6-[(2R)-2-苯基-1-哌啶基]-4-吡啶基]-3-甲基-吗啉
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和(2R)-2-苯基哌啶(85mg,0.53mmol)开始,以给出产物(137mg,91%)。MS ES+m/z 410[M+H]+。
实施例30
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-苯基-1-哌啶基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[(2R)-2-苯基-1-哌啶基]-4-吡啶基]-3-甲基-吗啉(137mg,0.33mmol)开始,以给出产物(30mg,25%)。1H NMR(500MHz,DMSO)δ10.07(br s,1H),7.39-7.09(m,5H),5.42-5.27(m,1H),5.12-5.04(m,1H),5.03-4.92(m,1H),3.87-3.78(m,1H),3.75-3.69(m,1H),3.63-3.58(m,1H),3.57-3.52(m,1H),3.52-3.45(m,1H),3.42-3.29(m,2H),3.26-3.19(m,1H),3.15-3.09(m,1H),2.93-2.83(m,1H),2.01-1.91(m,1H),1.87-1.78(m,1H),1.71-1.55(m,1H),1.54-1.43(m,2H),0.86-0.73(m,3H)。MS ES+m/z 354[M+H]+。
中间体实施例30
(3R)-4-[2-叔丁氧基-6-(4-甲基-2-苯基-哌嗪-1-基)-4-吡啶基]-3-甲基-吗啉
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和1-甲基-3-苯基-哌嗪(93mg,0.53mmol)开始,以给出产物(149mg,95%)。MS ES+m/z 425[M+H]+。
实施例31
4-[(3R)-3-甲基吗啉-4-基]-6-(4-甲基-2-苯基-哌嗪-1-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-(4-甲基-2-苯基-哌嗪-1-基)-4-吡啶基]-3-甲基-吗啉(149mg,0.35mmol)开始,以给出产物(42mg,32%)。1HNMR(500MHz,DMSO)δ7.41-7.09(m,5H),5.84-5.68(m,1H),5.41-5.20(m,1H),5.19-4.88(m,1H),3.88-3.78(m,1H),3.78-3.68(m,1H),3.65-3.50(m,2H),3.47-3.08(m,5H),3.02-2.94(m,0.5H),2.94-2.81(m,1H),2.73-2.63(m,1H),2.61-2.55(m,0.5H),2.45-2.38(m,0.5H),2.37-2.28(m,0.5H),2.17(s,3H),1.09-0.97(m,1.5H),0.84-0.71(m,1.5H)。MS ES+m/z369[M+H]+。
中间体实施例31
4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)吗啉
除了混合物在70℃搅拌过夜之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和3-(三氟甲基)吗啉盐酸盐(101mg,0.53mmol)开始,以给出产物(74mg,52%)。MS ES+m/z 404[M+H]+。
实施例32
4-[(3R)-3-甲基吗啉-4-基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)吗啉(74mg,0.18mmol)开始,以给出产物(16mg,26%)。1HNMR(500MHz,DMSO)δ6.39-6.32(m,0.5H),5.87-5.79(m,0.5H),5.69-5.58(m,1H),5.44-5.36(m,1H),5.24-5.09(m,1H),4.21-4.09(m,1H),3.99-3.82(m,3H),3.75-3.63(m,3H),3.63-3.55(m,1H),3.55-3.27(m,4H),3.26-3.15(m,1H),3.08-2.92(m,1H),1.16-0.99(m,3H)。MS ES+m/z 348[M+H]+。
中间体实施例32
(3R)-4-[2-叔丁氧基-6-(3-环丙基吗啉-4-基)-4-吡啶基]-3-甲基-吗啉
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和3-环丙基吗啉(67mg,0.56mmol)开始,以给出产物(93mg,70%)。MS ES+m/z 376[M+H]+。
实施例33
6-(3-环丙基吗啉-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)吗啉(93mg,0.25mmol)开始,以给出产物(6mg,7%)。1H NMR(500MHz,CD3OD)δ5.30(d,1H),5.15(t,1H),3.84-3.73(m,5H),3.70-3.53(m,4H),3.52-3.46(m,1H),3.46-3.36(m,1H),3.33-3.18(m,3H),3.08–2.99(m,1H),2.91-2.78(m,2H),2.73-2.63(m,1H),1.32-1.21(m,1H),1.08(d,1H),1.05(d,2H),0.37-0.22(m,3H),0.14--0.07(m,3H)。MS ES+m/z 320[M+H]+。
中间体实施例33
(3R)-4-[2-叔丁氧基-6-[(2S)-2-(三氟甲基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和(2S)-2-(三氟甲基)吡咯烷(73mg,0.53mmol)开始,以给出产物(79mg,58%)。MS ES+m/z 388[M+H]+。
实施例34
4-[(3R)-3-甲基吗啉-4-基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[(2S)-2-(三氟甲基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(79mg,0.2mmol)开始,以给出产物(36mg,53%)。1H NMR(500MHz,DMSO-d6)δ9.74(br s,1H),5.44(s,1H),5.34(s,1H),4.99(m,1H),3.94-3.83(m,2H),3.72-3.64(m,1H),3.64-3.54(m,2H),3.46(td,1H),3.39-3.34(m,2H),3.31-3.22(m,1H),2.99(td,1H),2.05–1.97(m,3H),1.07(d,3H)。MS ES+m/z 332[M+H]+。
中间体实施例34
(3R)-4-[2-叔丁氧基-6-[(2R)-2-(三氟甲基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
除了混合物在70℃搅拌持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和(2R)-2-(三氟甲基)吡咯烷(73mg,0.53mmol)开始,以给出产物(76mg,56%)。MS ES+m/z 388[M+H]+。
实施例35
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[(2R)-2-(三氟甲基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(76mg,0.2mmol)开始,以给出产物(34mg,52%)。1H NMR(500MHz,DMSO-d6)δ9.75(br s,1H),5.44(s,1H),5.33(s,1H),4.98(m,1H),3.89(m,2H),3.73-3.65(m,1H),3.65-3.55(m,2H),3.46(td,1H),3.32-3.24(m,2H),2.99(td,1H),2.12–1.95(m,4H),1.07(d,3H)。MS ES+m/z 332[M+H]+。
实施例36
(R)和(S)6-[2-(3-氯苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
将(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(1g,3.52mmol)、2-(3-氯苯基)吡咯烷(764mg,4.2mmol)、氯(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯基)[2-(2’-氨基-1,1’-联苯基)]钯(II)(110mg,0.35mmol)和K3PO4(1.5g,7.04mmol)吸收在无水1,4-二噁烷(10ml)中并用氮气脱气持续5分钟。将产生的混合物在微波反应器中在100℃加热持续1小时。当冷却至室温时,混合物通过硅藻土过滤,并且滤液用水稀释并用EtOAc提取。合并的有机物用盐水洗涤,过滤,浓缩并在用20%EtOAc/石油醚洗脱的硅胶柱上纯化。将中间体溶解在DCM(10ml)中并且在0℃缓慢地添加TFA(1.87ml,24.5mmol)。反应混合物在室温搅拌持续1小时,然后用饱和的含水NaHCO3碱化并且用DCM提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并在用5%MeOH/DCM洗脱的硅胶柱上纯化,以给出标题化合物(190mg,14%)。1H NMR(400MHz,CDCl3)δ7.27(br s,1H),7.25-7.24(m,1H),7.17(s,1H),7.07(br d,1H),5.15(dd,1H),4.77-4.64(m,2H),3.95-3.89(m,1H),3.76-3.65(m,3H),3.59-3.45(m,3H),3.20-3.06(m,2H),2.49-2.38(m,1H),2.08-1.91(m,3H),1.21(d,1.5H),0.99(d,1.5H)。MS ES+m/z 374[M+H]+。通过SFC的手性分离给出两种异构体。
实施例36-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,DMSO-d6)δ7.33(d,1H),7.29-7.26(m,1H),7.22(s,1H),7.15(brd,1H),5.05-4.90(m,3H),3.83(br dd,1H),3.73-3.40(m,6H),3.19(br d,1H),2.86(dt,1H),2.35-2.27(m,1H),1.93-1.77(m,3H),1.04(d,3H)。MS ES+m/z 374[M+H]+。
实施例36-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,DMSO-d6)δ7.33(d,1H),7.28-7.24(m,2H),7.17(br d,1H),4.99-4.79(m,3H),3.84-3.73(m,2H),3.62-3.33(m,5H),3.10(br d,1H),2.88(dt,1H),2.38-2.30(m,1H),1.93-1.75(m,3H),0.77(br d,3H)。MS ES+m/z 374[M+H]+。
实施例37
6-[2-(3-环丙基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
将2-环丙基-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷(189mg,1.13mmol)、氯(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯基)[2-(2’-氨基-1,1’-联苯基)]钯(II)(29mg,0.09mmol)和0.5M的含水K3PO4(5ml)吸收在THF(10ml)中,并且产生的混合物用氩气脱气持续15分钟。添加6-[2-(3-氯苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮(350mg,0.93mmol),并且将产生的混合物在微波反应器中在100℃加热持续1小时。反应混合物通过硅藻土过滤,并且滤液用水稀释并用乙酸乙酯提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并通过制备型HPLC纯化(使用在MeCN中的0.1%甲酸)。粗产物在用5%MeOH/DCM洗脱的硅胶柱上进一步纯化,以给出标题化合物(45mg,4%)。1H NMR(400MHz,CDCl3)δ7.19(td,,1H),6.95-6.88(m,3H),5.12(dd,1H),4.77-4.66(m,2H),3.95-3.89(m,1H),3.72-3.64(m,3H),3.59-3.43(m,3H),3.21-3.09(m,2H),2.41(br dd,1H),2.10-1.92(m,3H),1.86(td,1H),1.21(br d,2H),1.00-0.93(m,3H),0.68-0.63(m,2H)。MSES+m/z 380[M+H]+。
中间体实施例35
(3R)-4-[2-叔丁氧基-6-[2-(2-吡啶基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉
将(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(750mg,2.64mmol)、2-吡咯烷-2-基吡啶(469mg,3.16mmol)和KOtBu(591mg,5.3mmol)吸收在无水1,4-二噁烷(10ml)中,并且产生的反应混合物用氮气脱气持续15分钟。然后添加XPhos(207mg,0.26mmol)和Pd(OAc)2(59mg,0.26mmol),并将反应混合物在110℃在密封管中搅拌持续16小时。当冷却至室温时,混合物通过硅藻土过滤,并且滤液用水稀释并用EtOAc提取。合并的有机物用盐水洗涤,过滤,浓缩并在用20%EtOAc/石油醚洗脱的硅胶柱上纯化,以给出标题化合物(470mg,45%)。MS ES+m/z 397[M+H]+。
实施例38
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-[2-(2-吡啶基)吡咯烷-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(2-吡啶基)吡咯烷-1-基]-4-吡啶基]-3-甲基-吗啉(470mg,1.18mmol)开始,以给出作为非对映异构体混合物的产物(230mg,57%)。1H NMR(400MHz,CDCl3)δ8.61-8.57(m,1H),7.69-7.63(m,1H),7.19(br t,2H),5.15(br d,1H),4.88-4.82(m,1H),4.73-4.67(m,1H),3.90(br d,1H),3.82-3.74(m,1H),3.71-3.46(m,5H),3.17-3.02(m,2H),2.54-2.41(m,1H),2.21-2.05(m,3H),1.17(br d,1.5H),0.93(br d,1.5H)。MS ES+m/z 341[M+H]+。通过SFC的手性分离给出两种异构体。
实施例38-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ8.60(d,1H),7.66(dt,1H),7.23-7.17(m,2H),5.16(d,1H),4.87(dd,1H),4.73(d,1H),3.91(dd,1H),3.77-3.62(m,4H),3.56-3.48(m,2H),3.18-3.02(m,2H),2.46(qd,1H),2.22-2.06(m,3H),1.18(d,3H)。MS ES+m/z 341[M+H]+。
实施例38-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ8.58(dd,1H),7.64(dt,1H),7.21-7.16(m,2H),5.14(d,1H),4.84(dd,1H),4.67(d,1H),3.92-3.80(m,2H),3.66-3.46(m,5H),3.14-3.03(m,2H),2.54-2.44(m,1H),2.18-2.05(m,3H),0.93(d,3H)。MS ES+m/z 341[M+H]+。
中间体实施例36
(3R)-4-[2-叔丁氧基-6-(2-噻唑-2-基吡咯烷-1-基)-4-吡啶基]-3-甲基-吗啉
如中间体实施例35所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(400mg,1.4mmol)和2-吡咯烷-2-基噻唑盐酸盐(321mg,1.69mmol)开始,以给出产物(110mg,19%)。MS ES+m/z 403[M+H]+。
实施例39
(R)和(S)4-[(3R)-3-甲基吗啉-4-基]-6-(2-噻唑-2-基吡咯烷-1-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-(2-噻唑-2-基吡咯烷-1-基)-4-吡啶基]-3-甲基-吗啉(100mg,0.24mmol)开始,以给出作为非对映异构体混合物的产物(10mg,12%)。1H NMR(400MHz,CDCl3)δ7.75(dd,1H)5.25-5.12(m,2H)4.88(br s,1H)3.92(br d,1H)3.72-3.64(m,4H)3.54-3.48(m,2H)3.21-3.11(m,2H)2.48(br d,1H)2.28-2.14(m,4H)1.25(s,1H)1.19(br d,1H)1.01(br d,1H)。MS ES+m/z 347[M+H]+。
实施例40
(R)和(S)6-[2-(5-甲基异噁唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
将(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.76mmol)、5-甲基-3-吡咯烷-2-基-异噁唑(321mg,2.11mmol)和KOtBu(3.94mg,3.5mmol)吸收在甲苯(10ml)中并且产生的反应混合物用氮气脱气持续15分钟。然后添加XPhos(138mg,0.17mmol)和Pd(OAc)2(39mg,0.17mmol),并将反应混合物在110℃在密封管中搅拌持续16小时。当冷却至室温时,混合物通过硅藻土过滤,并且滤液用水稀释并用EtOAc提取。合并的有机物用盐水洗涤,过滤,浓缩并通过制备型HPLC纯化(使用在MeCN中的0.1%甲酸),以给出作为非对映异构体混合物的产物(200mg,33%)。1H NMR(400MHz,CDCl3)δ5.83(br d,1H)5.17(br s,1H)4.92-4.87(m,2H)3.94(br d,1H)3.74-3.68(m,4H)3.52(br d,2H)3.24-3.10(m,2H)2.38(d,4H)2.12(br s,3H)1.20(br d,1.5H)1.05(br d,1.5H)。MS ES+m/z 345[M+H]+。通过SFC的手性分离给出两种异构体。
实施例40-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.84(s,1H)5.16(s,1H)4.92-4.89(m,2H)3.94(br dd,1H)3.75-3.68(m,4H)3.55-3.49(m,2H)3.24-3.19(m,1H)3.12(br dd,1H)2.38(s,4H)2.12(brt,3H)1.20(br d,3H)。MS ES+m/z345[M+H]+。
实施例40-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ5.83(s,1H)5.16(br s,1H)4.90(br s,2H)3.92(br s,1H)3.70(br d,4H)3.53(br s,2H)3.16(br s,2H)2.37(s,4H)2.12(br s,3H)1.06(br s,3H)。MS ES+m/z 345[M+H]+。
实施例41
1-甲基-4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)-1-哌啶基]吡啶-2-酮
将LiOtBu(111mg,1.39mmol)和甲基碘(0.19ml,1.39mmol)添加到在丙酮(10ml)中的4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮(240mg,0.7mmol)的溶液中,并将产生的混合物在80℃搅拌持续1小时。当冷却至室温时,浓缩该混合物。添加水(2mL)并且混合物用EtOAc(3x10mL)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并通过制备型HPLC纯化,以给出作为固体的产物(40mg,12%)。1H NMR(400MHz,DMSO-d6)VT 90℃:δ5.80(s,1H),5.31(d,1H),4.04-3.85(m,3H),3.67-3.61(m,2H),3.50-3.43(m,1H),3.26-3.18(m,5H),3.06-3.02(m,1H),2.88-2.85(m,1H),2.00-1.99(m,1H),1.83-1.81(m,1H),1.70-1.60(m,4H),1.08(d,3H)。MS ES+m/z 360[M+H]+。
中间体实施例37
5-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-8-氧杂-5-氮杂螺[3.5]壬烷
除了混合物在微波反应器中在130℃加热持续2小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(100mg,0.35mmol)和8-氧杂-5-氮杂螺[3.5]壬烷(54mg,0.42mmol)开始,以给出产物(86mg,65%)。MS ES+m/z 376[M+H]+。
实施例42
4-[(3R)-3-甲基吗啉-4-基]-6-(8-氧杂-5-氮杂螺[3.5]壬-5-基)-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从5-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-8-氧杂-5-氮杂螺[3.5]壬烷(130mg,0.35mmol)开始,以给出产物(35mg,31%)。1H NMR(500MHz,DMSO-d6):δ10.21(br.s,1H),5.21(s,1H),5.11(s,1H),3.88-3.83(m,2H),3.69-3.58(m,4H),3.48-3.42(m,3H),3.31-3.28(m,1H),3.18-3.17(m,2H),2.99-2.96(m,1H),2.08-2.00(m,4H),1.64-1.61(m,2H),1.07(d,3H)。MS ES+m/z 320[M+H]+。
中间体实施例38
4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)吗啉
除了混合物在微波反应器中在150℃加热持续3小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(400mg,1.4mmol)和3-(三氟甲基)吗啉(330mg,1.68mmol)开始,以给出产物(330mg,58%)。MS ES+m/z 404[M+H]+。
实施例43
4-[(3R)-3-甲基吗啉-4-基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-三氟甲基-吗啉(350mg,0.87mmol)开始,以给出作为非对映异构体混合物的产物(200mg,65%)。MS ES+m/z 348[M+H]+。通过SFC的手性分离给出两种异构体。
实施例43-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(400MHz,DMSO-d6):δ9.9-9.6(br.s,1H),5.62(d,1H),5.38(s,1H),5.15(br.s,1H),4.13(d,1H),3.91-3.86(m,2.3H),3.67-3.58(m,3H),3.5-3.4(m,2H),3.38-3.25(m,3H),3.17(q,1H),3.01-2.95(m,1H),1.06(d,3H)。MS ES+m/z 348[M+H]+。
实施例43-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,DMSO-d6):δ9.9-9.6(br.s,1H),5.62(s,1H),5.38(s,1H),5.15(br.s,1H),4.13(d,1H),3.91-3.86(m,3H),3.68-3.57(m,4H),3.49-3.42(m,2H),3.286(s,1H),3.17(q,1H),3.01-2.94(m,1H),1.06(d,3H)。MS ES+m/z 348[M+H]+。
中间体实施例39
(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)-1-哌啶基]-4-吡啶基]-3-甲基-吗啉
除了混合物搅拌持续4小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(500mg,1.7mmol)和2-(3-甲氧基苯基)哌啶(404mg,2.11mmol)开始,以给出产物(460mg,61%)。MS ES+m/z 440[M+H]+。
实施例44
6-[2-(3-甲氧基苯基)-1-哌啶基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[2-(3-甲氧基苯基)-1-哌啶基]-4-吡啶基]-3-甲基-吗啉(460mg,1mmol)开始,以给出作为非对映异构体混合物的产物(390mg,98%)。MS ES+m/z 384[M+H]+。通过SFC的手性分离给出两种异构体。
实施例44-1,洗脱的第一异构体,具有未知的绝对构型:
1H NMR(500MHz,CDCl3)δ7.20(t,1H),6.83-6.71(m,3H),5.21(d,1H),5.11(d,1H),4.28(br dd,1H),3.92(br d,1H),3.75(s,3H),3.68(d,2H),3.59-3.43(m,3H),3.16-3.03(m,3H),2.01-1.85(m,2H),1.81-1.70(m,4H),0.89(d,3H)。MS ES+m/z 384[M+H]+。
实施例44-2,洗脱的第二异构体,具有未知的绝对构型:
1H NMR(400MHz,CDCl3)δ7.26-7.20(m,1H),6.84-6.74(m,3H),5.22(d,1H),5.11(d,1H),4.56(br t,1H),3.92(br dd,1H),3.77(s,3H),3.72-3.62(m,3H),3.54(dt,1H),3.41-3.31(m,2H),3.20-3.04(m,2H),2.10-1.93(m,2H),1.73(br dd,4H),1.19(d,3H)。MSES+m/z 384[M+H]+。
中间体实施例40
4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)哌嗪-1-羧酸叔丁基酯
除了混合物在微波反应器中在130℃加热持续3小时之外,如中间体实施例9所述制备标题化合物,从(3R)-4-(2-叔丁氧基-6-氯-4-吡啶基)-3-甲基-吗啉(200mg,0.7mmol)和3-(三氟甲基)哌嗪-1-羧酸叔丁基酯(214mg,0.84mmol)开始,以给出产物(150mg,43%)。MS ES+m/z 503[M+H]+。
中间体实施例41
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)哌嗪-1-羧酸叔丁基酯(300mg,0.6mmol)开始,以给出产物(150mg,72%)。MS ES+m/z 347[M+H]+。
实施例45
6-[4-乙酰基-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
在0℃,将乙酰氯(0.04ml,0.53mmol)和Et3N(0.1ml,0.7mmol)添加到在DCM(2ml)中的4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮(100mg,0.35mmol)的溶液中。将混合物在0℃搅拌持续30分钟。添加水(5ml),并且混合物用DCM(3×5ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤并且浓缩。将残余物吸收在EtOH(1ml)中,并且在室温添加在EtOH(3ml)中的3M甲胺。将产生的混合物在室温搅拌持续1小时,浓缩并且通过制备型HPLC纯化,以给出产物(60mg,53%)。1H NMR(400MHz,DMSO-d6):δ9.77(br.s,1H),5.65(s,1H),5.43(s,1H),5.33(bs,1H),3.90-3.86(m,4H),3.67-3.63(m,2H),3.51-3.45(m,2H),3.34-3.28(m,3H),3.20-3.18(m,2H),3.08-3.01(m,2H),2.01(s,2H),1.10-1.08(m,3H)。MS ES+m/z 389[M+H]+。
实施例46
6-[4-(5-氟吡啶-3-羰基)-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
在0℃,向在DMF(2ml)中的4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮(100mg,0.3mmol)和5-氟吡啶-3-羧酸(45mg,0.32mmol)的搅拌的溶液中添加DIPEA(0.15ml,0.87mmol)和T3P(0.17ml,0.58mmol)。反应混合物在室温搅拌持续1小时。将混合物倒入冰冷的水(10mL)中并且用EtOAc(3x10mL)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并通过制备型HPLC纯化,以给出产物(30mg,22%)。1H NMR(400MHz,DMSO-d6)VT at 90℃:δ9.40(br.s,1H),8.64(d,1H),8.43(s,1H),7.77(d,1H),5.67(s,1H),5.44(s 1H),5.40(br.s,1H),4.31(br.s,1H),3.93-3.67(m,4H),3.67-3.60(m,2H),3.50-3.45(m,2H),3.34-2.23(m,3H),3.07-2.96(m,1H),1.10-1.07(m,3H)。MS ES+m/z 470[M+H]+。
实施例47
6-[4-[2-(4-氟苯基)乙酰基]-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮
如实施例49所述制备标题化合物,用2-(4-氟苯基)乙酸(49mg,0.32mmol)替换5-氟吡啶-3-羧酸,以给出产物(40mg,28%)。1H NMR(400MHz,DMSO-d6)VT 90℃:δ9.40(br.s,1H),7.22(t,2H),7.06(t,2H),5.64(s,1H),5.43(s,1H),5.34(br.s,1H),4.46(br.s,1H),4.00-3.86(m,4H),3.76-3.60(m,4H),3.48(t,1H),3.34-3.03(m,5H),1.09(t,3H)。MS ES+m/z 483[M+H]+。
实施例48
4-[(3R)-3-甲基吗啉-4-基]-6-[4-(四氢呋喃-2-羰基)-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮
如实施例49所述制备标题化合物,用四氢呋喃-2-羧酸(36mg,0.32mmol)替换5-氟吡啶-3-羧酸。通过SFC的纯化提供了两种产物。
实施例48-1,洗脱的第一异构体,具有未知的绝对构型(10mg,8%):
1H NMR(400MHz,DMSO-d6)VT at 90℃:δ9.40(br.s,1H),5.65(s,1H),5.42(s,1H),5.34(br.s,1H),4.62-4.59(m,1H),4.49(br.s,1H),4.11-4.08(m,1H),3.93-3.85(m,3H),3.75(t,2H),3.67-3.60(m,2H),3.50-3.45(m,1H),3.34-3.17(m,3H),3.08-3.04(m,2H),2.15-2.11(m,1H),1.97-1.90(m,1H),1.87-1.81(m 2H),1.10-1.08(m,3H)。MS ES+m/z 445[M+H]+。
实施例48-2,洗脱的第二异构体,具有未知的绝对构型(15mg,12%):
1H NMR(400MHz,DMSO-d6)VT at 90℃:δ9.45(br s,1H),5.65(s,1H),5.42(s,1H),5.34(br.s,1H),4.66-4.62(m,1H),4.49(br.s,1H),4.04-4.02(m,1H),3.89-3.85(m,3H),3.82-3.71(m,2H),3.67-3.60(m,2H),3.51-3.45(m,1H),3.34-3.28(m,1H),3.20-3.18(m,2H),3.08-3.04(m,2H),2.05-2.00(m,2H),1.88-1.80(m,2H),1.11-1.08(m,3H)。MS ES+m/z445[M+H]+。
中间体实施例42
(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-3-甲基-吗啉
在0℃,将氢化铝锂(56mg,1.5mmol)添加到在THF(5ml)中的4-[6-叔丁氧基-4-[(3R)-3-甲基吗啉-4-基]-2-吡啶基]-3-(三氟甲基)哌嗪-1-羧酸叔丁基酯(250mg,0.5mmol)的溶液中。反应混合物在室温搅拌过夜并且用饱和的含水Na2SO4和EtOAc猝灭。将混合物通过硅藻土过滤,并且将滤液浓缩,以给出产物(120mg,60%)。MS ES+m/z 403[M+H]+。
中间体实施例43
(3R)-4-[2-叔丁氧基-6-[4-甲基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-3-甲基-吗啉
在室温,将37%含水的甲醛(0.05ml,0.56mmol)和乙酸(0.03ml,0.56mmol)添加到在MeOH(2ml)中的(3R)-4-[2-叔丁氧基-6-[2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-3-甲基-吗啉(75mg,0.19mmol)的溶液中。10分钟后,添加NaBH3CN(35mg,0.56mmol),并且将混合物在室温搅拌持续1小时。浓缩混合物,并且将产生的残余物吸收在水(10ml)和EtOAc(10ml)中。将有机层分离并且水层用EtOAc(2x10ml)提取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并通过制备型HPLC纯化,以给出作为固体的产物(30mg,38%)。MS ES+m/z417[M+H]+。
实施例49
4-[(3R)-3-甲基吗啉-4-基]-6-[4-甲基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮
如实施例10所述制备标题化合物,从(3R)-4-[2-叔丁氧基-6-[4-甲基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]-3-甲基-吗啉(60mg,0.14mmol)开始,以给出产物(25mg,48%)。1HNMR(400MHz,DMSO-d6):δ9.33(br.s,1H),5.57(s,1H),5.36(s,1H),5.26-5.24(m,1H),3.87-3.66(m 3H),3.63-3.59(m,2H),3.50-3.44(m,1H),3.33-3.17(m,2H),3.06-3.01(m,2H),2.77-2.75(m,1H),2.19(s,3H),2.15-2.12(m,1H),1.94-1.89(m,1H),1.10-1.07(m,3H)。MS ES+m/z 361[M+H]+。
实施例50
Vps34生物化学测定
在DMSO中以最终测定浓度的100倍(在10个点中n1=n0/3)制备本发明化合物的稀释系列。将化合物进一步在测定缓冲液中稀释至测定浓度的4倍(Life technologies缓冲液Q,PV5125,稀释5倍,补充有2mM DTT和2mM MnCl2)。将2.5μl的稀释的化合物添加至384孔测定板,随后添加2.5μl的16.5nM的Vps34酶(Life technologies,PV5126)。酶和化合物在室温预温育持续15分钟。然后将5μl的含有在测定缓冲液中的20μM ATP(Lifetechnologies,PV3227)和200μM PI:PS底物(Life technologies,PV5122)的底物混合物添加到含有化合物和酶的孔中。通过用移液管吸取(pipetting)若干次进行混合。将反应在室温温育持续1小时。然后添加5μl终止检测混合物以猝灭反应,所述终止检测混合物如在Adapa激酶测定试剂盒说明书(Life technologies,PV5099)中所述制备,包含在TR-FRET缓冲液中的Adapta Eu-抗-ADP抗体(2.3nM)、Alexa Fluor 647ADP示踪剂(9nM)和EDTA(30mM)。通过用移液管吸取若干次进行混合。然后将测定板在室温温育持续30分钟,并用Artemis微板读取器读取。计算与DMSO处理的对照样品相比的化合物的抑制百分比。通过使用Dotmatics软件,拟合化合物浓度相对于抑制百分比以产生IC50值。
实施例化合物有效地抑制Vps34,并且测定的结果示于表1中(中值IC50μMAdapta)。
表1.对于Vps34测定的中值IC50值
实施例51
高含量筛选自噬测定
稳定地表达绿色荧光蛋白(GFP)标记的LC3(GFP-LC3)的人骨肉瘤细胞(HOS)被用于确定对专有化合物的自噬的抑制作用。为此目的,在以5nM的巴佛洛霉素(Bafilomycin)A1(Sigma-Aldrich)的存在下,通过使用以500nM的mTOR抑制剂KU-0063794来激活自噬。不久,细胞在DMEM-高度改良的培养基(Hi-Clone Cat#SH30285.01)中在透明底部96孔板中平板接种(plating)过夜。在实验开始时,移除培养基,并用含有mTOR抑制剂、巴佛洛霉素A1和媒介物或如所指示的测试化合物的新鲜培养基替换。在6小时后,移除培养基,用冰冷却的磷酸盐缓冲盐水(PBS)洗涤细胞两次,并在室温用4%多聚甲醛固定持续20分钟。然后用冰冷的PBS洗涤细胞两次,然后添加在PBS中的以1μg/ml的Hoechst 33342用于核染色。在4℃温育过夜后,用PBS洗涤细胞一次以除去过量的染料,并向每个孔中添加100μl的PBS。使用ImageXpress自动化显微镜(Molecular Devices Inc.)以20倍放大率、每孔6张图像采集图像,并用MetaXpress软件分析,以识别LC3-GFP焦点(foci)。每个细胞的焦点面积值用于产生剂量应答曲线,并且IC50值使用GraphPad Prism软件中的非线性拟合分析计算。
测试的实施例化合物有效地抑制HOS细胞中的自噬。测定的结果示于表2中(中值IC50μM HOS-LC3)。
表2.对于Vps34测定和在HOS细胞测定中的自噬的中值IC50值。
Claims (41)
1.一种式(I)的化合物:
其中
R1、R2和R3独立地选自氢、C1-C3卤代烷基和C1-C3烷基;
A表示
其中
X表示CH2、S、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9、O或键;
Y表示N、CH或C;
n选自1、2、3和4;
R4选自氢、卤素、COR6、C1-C6烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6环烷基、C3-C6杂环基、C1-C3氰基烷基、C1-C3卤代烷基、苯基和单环杂芳基,所述单环杂芳基选自呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、吡啶基、***基、三嗪基、哒嗪基、异噻唑基、异噁唑基、吡嗪基、吡唑基和嘧啶基,并且其中所述苯基和所述单环杂芳基任选地被一个或更多个R7取代;
R5选自氢、C1-C3氟烷基、C1-C3烷基、C1-C3烷氧基C1-C3烷基和C3-C6环烷基;
R6选自C1-C3烷氧基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、1-吡咯烷基、1-哌啶基和1-氮杂环丁基;
R7选自C1-C6烷基、C3-C6环烷基、C1-C3烷氧基C1-C3烷基、C1-C3卤代烷基、卤素、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、C1-C3卤代烷氧基和C1-C3烷氧基;
R9选自C1-C3烷基、C1-C3烷氧基、C3-C6环烷基、杂环基、苯基和单环杂芳基,其中所述单环杂芳基选自呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、噁二唑基、噻二唑基、吡啶基、***基、三嗪基、哒嗪基、异噻唑基、异噁唑基、吡嗪基、吡唑基和嘧啶基,并且所述杂环基选自四氢呋喃基、四氢吡喃基、吡咯烷基、哌啶基、哌嗪基、吗啉基和二噁烷基,并且其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代;
R8选自卤素、C1-C3卤代烷基和C1-C3烷基;以及
其药学上可接受的盐、立体异构体和互变异构体。
2.根据权利要求1所述的化合物,其中Y是N。
3.根据权利要求1所述的化合物,其中R1和R3独立地选自氢和甲基。
4.根据权利要求1所述的化合物,其中R2是氢。
5.根据权利要求1所述的化合物,其中R1是氢。
6.根据权利要求3所述的化合物,其中R3是甲基。
7.根据权利要求3所述的化合物,其中R3是氢。
8.根据权利要求1所述的化合物,其中R5是C1-C3烷基。
9.根据权利要求1所述的化合物,其中R6是二甲基氨基。
10.根据权利要求1所述的化合物,其中R9选自C1-C3烷氧基、杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代。
11.根据权利要求1所述的化合物,其中R9选自杂环基、苯基和单环杂芳基,其中所述杂环基、所述苯基和所述单环杂芳基任选地被一个或两个R8取代。
12.根据权利要求1所述的化合物,其中R9选自四氢呋喃基、苯基和吡啶基,各自任选地被一个或两个R8取代。
13.根据权利要求12所述的化合物,其中R8是卤素。
14.根据权利要求1所述的化合物,其中R4中的所述单环杂芳基选自吡啶基、呋喃基、异噁唑基、吡唑基和噻唑基,各自任选地被一个或更多个R7取代。
16.根据权利要求15所述的化合物,其中R7选自氟、氯、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6环烷基、N,N-二C1-C3烷基氨基。
17.根据权利要求15所述的化合物,其中R7选自氟、氯、甲基、乙基、甲氧基、三氟甲氧基、三氟甲基、环丙基和N,N-二甲基氨基。
18.根据权利要求1所述的化合物,其中X表示键。
21.根据权利要求1所述的化合物,
其中X表示CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9或O;并且R5是C1-C3烷基。
22.根据权利要求21所述的化合物,其中R4选自氢、C1-C6烷基、C3-C6环烷基、C1-C3卤代烷基和苯基,其中苯基任选地被一个或更多个R7取代。
24.根据权利要求1所述的化合物,
其中
X表示CH2、SO、SO2、NR5、NCOR5、NCOR9、NCOCH2R9、O或键;
R4选自氢、COR6、C1-C3烷基、甲氧基C1-C3烷基、C3-C6环烷基、C1-C3氟烷基、苯基和单环杂芳基,其中所述苯基和所述单环杂芳基任选地被一个或两个R7取代;
R5是C1-C3烷基;
R6是N,N-二C1-C3烷基氨基;并且
R7选自氟、氯、C1-C3烷基、C1-C3烷氧基、C1-C3氟烷氧基、C1-C3氟烷基、C3-C6环烷基和N,N-二C1-C3烷基氨基。
25.根据权利要求1所述的化合物,其中Y是CH或C;X是O;并且R4是氢。
26.根据权利要求1所述的化合物,
其中
R1和R2是氢;
R3是甲基;
X选自CH2、O、NCOR5、NCOR9、NCOCH2R9和键;
Y是N;
R4是氢、苯基或三氟甲基;
R5是甲基;
R7是甲氧基;
R9选自吡啶基、苯基;并且
R8是氟。
28.根据权利要求1所述的化合物,所述化合物选自:
4-吗啉代-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
1-甲基-4-吗啉代-6-(2-苯基吡咯烷-1-基)吡啶-2-酮;
4-吗啉代-6-[(2S)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮;
4-吗啉代-6-[(2R)-2-苯基吡咯烷-1-基]-1H-吡啶-2-酮;
6-(3,6-二氢-2H-吡喃-4-基)-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-四氢吡喃-4-基-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-[2-(3-吡啶基)吡咯烷-1-基)-1H-吡啶-2-酮;
4-(3-甲基吗啉-4-基)-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
N,N-二甲基-1-[4-[(3R)-3-甲基吗啉-4-基]-6-氧代-1H-吡啶-2-基]吡咯烷-2-甲酰胺;
6-[2-(1-甲氧基-1-甲基-乙基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-(2-环己基吡咯烷-1-基)-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(3-氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(2,5-二氟苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲氧基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-[3-(三氟甲基)苯基]吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(2-苯基吡咯烷-1-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(1-甲基吡唑-4-基)吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(1,5-二甲基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(1-乙基吡唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(5-甲基-2-呋喃基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-[3-(二甲基氨基)苯基]吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(3-苯基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(1-氧代-1,4-噻嗪烷-4-基)-1H-吡啶-2-酮;
6-(1,1-二氧代-1,4-噻嗪烷-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
6-(4-乙酰基哌嗪-1-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-苯基-1-哌啶基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(4-甲基-2-苯基-哌嗪-1-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-(3-环丙基吗啉-4-基)-4-[(3R)-3-甲基吗啉-4-基)-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2S)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)吡咯烷-1-基]-1H-吡啶-2-酮;
6-[2-(3-氯苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[2-(3-环丙基苯基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[2-(2-吡啶基)吡咯烷-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(2-噻唑-2-基吡咯烷-1-基)-1H-吡啶-2-酮;
6-[2-(5-甲基异噁唑-3-基)吡咯烷-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
1-甲基-4-[(3R)-3-甲基吗啉-4-基]-6-[(2R)-2-(三氟甲基)-1-哌啶基]吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-(8-氧杂-5-氮杂螺[3.5]壬-5-基)-1H-吡啶-2-酮;
6-[2-(3-甲氧基苯基)-1-哌啶基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[4-乙酰基-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[4-(5-氟吡啶-3-羰基)-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[2-(4-氟苯基)乙酰基]-2-(三氟甲基)哌嗪-1-基]-4-[(3R)-3-甲基吗啉-4-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[4-(四氢呋喃-2-羰基)-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;
4-[(3R)-3-甲基吗啉-4-基]-6-[4-甲基-2-(三氟甲基)哌嗪-1-基]-1H-吡啶-2-酮;以及
其药学上可接受的盐、互变异构体和立体异构体。
29.根据权利要求1至28中任一项所述的化合物,用于在治疗或预防疾病中使用。
30.根据权利要求1至28中任一项所述的化合物,用于在治疗癌症中使用。
31.根据权利要求1至28中任一项所述的化合物,用于在治疗癌症中使用,所述癌症选自三阴性乳腺癌、胰腺癌、白血病、黑色素瘤和肺癌。
32.根据权利要求1至28中任一项所述的化合物,用于在治疗糖尿病中使用。
33.根据权利要求1至28中任一项所述的化合物,用于在治疗糖尿病中使用,所述糖尿病是II型糖尿病。
34.根据权利要求1至28中任一项所述的化合物,用于在治疗疾病中使用,所述疾病选自炎性疾病、神经退行性紊乱、心血管紊乱和病毒感染。
35.根据权利要求1至28中任一项所述的化合物在制备用于治疗癌症的药物中的用途。
36.根据权利要求1至28中任一项所述的化合物在制备用于治疗癌症的药物中的用途,所述癌症选自三阴性乳腺癌、胰腺癌、白血病、黑色素瘤和肺癌。
37.根据权利要求1至28中任一项所述的化合物在制备用于治疗糖尿病的药物中的用途。
38.根据权利要求1至28中任一项所述的化合物在制备用于治疗糖尿病的药物中的用途,所述糖尿病是II型糖尿病。
39.根据权利要求1至28中任一项所述的化合物在制备用于治疗疾病的药物中的用途,所述疾病选自炎性疾病、神经退行性紊乱、心血管紊乱和病毒感染。
40.一种药物组合物,所述药物组合物包含根据权利要求1至28中任一项所述的化合物以及药学上可接受的稀释剂、载体和/或赋形剂。
41.一种药物组合物,所述药物组合物包含治疗有效量的根据权利要求1所述的化合物和另一种抗癌剂,所述另一种抗癌剂选自烷化剂、抗代谢物、抗癌喜树碱衍生物、植物衍生的抗癌剂、抗生素、酶、铂配位络合物、酪氨酸激酶抑制剂、激素、激素拮抗剂、单克隆抗体、干扰素和生物应答调节剂。
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CA3015005A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
PL3672941T3 (pl) | 2017-08-23 | 2022-06-13 | Sprint Bioscience Ab | Związki pirydylopirydonu |
CN116589462A (zh) | 2017-08-23 | 2023-08-15 | 思普瑞特生物科学公司 | 氮杂吲哚基吡啶酮化合物和二氮杂吲哚基吡啶酮化合物 |
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CN116041321A (zh) | 2017-08-23 | 2023-05-02 | 思普瑞特生物科学公司 | 吡啶胺-吡啶酮化合物和嘧啶胺-吡啶酮化合物 |
EP3774783A1 (en) | 2018-04-10 | 2021-02-17 | Neuropore Therapies, Inc. | Tri-substituted aryl and heteroaryl derivatives as modulators of pi3-kinase and autophagy pathways |
EP3774792B1 (en) | 2018-04-10 | 2022-09-14 | Neuropore Therapies, Inc. | Morpholine derivates as inhibitors of vps34 |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015030057A1 (ja) * | 2013-08-29 | 2015-03-05 | 富士フイルム株式会社 | 新規なモルホリン誘導体またはその塩 |
CN104603113A (zh) * | 2012-06-22 | 2015-05-06 | 赛诺菲 | 包含经取代吗啉的新型2,3-二氢-1H-咪唑并{1,2-a}嘧啶-5-酮和1,2,3,4-四氢嘧啶并{1,2-a}嘧啶-6-酮衍生物、其制备及其制药用途 |
CN105143209A (zh) * | 2013-03-14 | 2015-12-09 | 诺华股份有限公司 | 作为激酶抑制剂的联芳基酰胺化合物 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2507100C (en) | 2002-11-21 | 2012-10-09 | Chiron Corporation | 2,4,6-trisubstituted pyrimidines as phosphotidylinositol (pi) 3-kinase inhibitors and their use in the treatment of cancer |
GB2465405A (en) | 2008-11-10 | 2010-05-19 | Univ Basel | Triazine, pyrimidine and pyridine analogues and their use in therapy |
CA2766909C (fr) | 2009-07-02 | 2018-06-05 | Sanofi | Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one,leur preparation et leur utilisation pharmaceutique |
BR112013015449A2 (pt) | 2010-12-21 | 2016-09-20 | Novartis Ag | compostos de bi-heteroarila como inibidores de vps23 |
SI2655375T1 (sl) | 2010-12-23 | 2015-03-31 | Sanofi | Derivati pirimidinona, njihova priprava in njihova farmacevtska uporaba |
GB201120317D0 (en) | 2011-11-24 | 2012-01-04 | Queen Mary & Westfield College | Screening method |
WO2015108881A1 (en) | 2014-01-14 | 2015-07-23 | Millennium Pharmaceuticals, Inc. | Heteroaryls and uses thereof |
GEP20196983B (en) | 2014-01-14 | 2019-06-25 | Millennium Pharm Inc | Heteroaryls and uses thereof |
MA39822A (fr) | 2014-04-03 | 2018-02-06 | Janssen Pharmaceutica Nv | Dérivés de pyrimidine bicycle |
MA39823A (fr) | 2014-04-03 | 2018-01-09 | Janssen Pharmaceutica Nv | Dérivés de pyridine macrocyclique |
CA2960790A1 (en) | 2014-09-17 | 2016-03-24 | Verseon Corporation | Pyrazolyl-substituted pyridone compounds as serine protease inhibitors |
CA3015005A1 (en) * | 2016-02-19 | 2017-08-24 | Sprint Bioscience Ab | 6-heterocyclyl-4-morpholin-4-ylpyridine-2-one compounds useful for the treatment of cancer and diabetes |
US11077113B2 (en) * | 2016-02-19 | 2021-08-03 | Sprint Bioscience Ab | 6-aryl-4-morpholin-1-ylpyridone compounds useful for the treatment of cancer and diabetes |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104603113A (zh) * | 2012-06-22 | 2015-05-06 | 赛诺菲 | 包含经取代吗啉的新型2,3-二氢-1H-咪唑并{1,2-a}嘧啶-5-酮和1,2,3,4-四氢嘧啶并{1,2-a}嘧啶-6-酮衍生物、其制备及其制药用途 |
CN105143209A (zh) * | 2013-03-14 | 2015-12-09 | 诺华股份有限公司 | 作为激酶抑制剂的联芳基酰胺化合物 |
WO2015030057A1 (ja) * | 2013-08-29 | 2015-03-05 | 富士フイルム株式会社 | 新規なモルホリン誘導体またはその塩 |
Non-Patent Citations (1)
Title |
---|
Nucleophile Substitutionen am (Z)-Perchlor-l,3-butadien-1-carbonitril mit Natriumphenolat und sekundaren aliphatischen Aminen;Alfred Roedig et al.;《Chem. Ber.》;19821231;第115卷;1733-1738 * |
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