CN111094271A - 吡啶胺-吡啶酮化合物和嘧啶胺-吡啶酮化合物 - Google Patents
吡啶胺-吡啶酮化合物和嘧啶胺-吡啶酮化合物 Download PDFInfo
- Publication number
- CN111094271A CN111094271A CN201880060298.1A CN201880060298A CN111094271A CN 111094271 A CN111094271 A CN 111094271A CN 201880060298 A CN201880060298 A CN 201880060298A CN 111094271 A CN111094271 A CN 111094271A
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- China
- Prior art keywords
- trifluoromethyl
- pyridin
- pharmaceutically acceptable
- acceptable salt
- phenyl
- Prior art date
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- OGUYTQJDMQXKQZ-UHFFFAOYSA-N N1C(C=CC=C1)=O.N1=C(N=CC=C1)N Chemical class N1C(C=CC=C1)=O.N1=C(N=CC=C1)N OGUYTQJDMQXKQZ-UHFFFAOYSA-N 0.000 title abstract description 4
- FAUKQZGBHAOERC-UHFFFAOYSA-N pyridin-2-amine;1h-pyridin-2-one Chemical class NC1=CC=CC=N1.O=C1C=CC=CN1 FAUKQZGBHAOERC-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 196
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 46
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 201000011510 cancer Diseases 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 10
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 9
- 208000036142 Viral infection Diseases 0.000 claims abstract description 8
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 8
- 230000009385 viral infection Effects 0.000 claims abstract description 8
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 7
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- -1 C1-C3Haloalkyl Chemical class 0.000 claims description 159
- 229910052736 halogen Inorganic materials 0.000 claims description 74
- 150000003839 salts Chemical class 0.000 claims description 73
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 150000002367 halogens Chemical class 0.000 claims description 65
- 125000001424 substituent group Chemical group 0.000 claims description 42
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 239000003814 drug Substances 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 17
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 206010021143 Hypoxia Diseases 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
- 125000001188 haloalkyl group Chemical group 0.000 claims description 15
- 230000001146 hypoxic effect Effects 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 239000011737 fluorine Substances 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 150000003254 radicals Chemical class 0.000 claims description 10
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 9
- 125000001544 thienyl group Chemical group 0.000 claims description 9
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 8
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002883 imidazolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 7
- ZNQYDFIGLQKWFG-UHFFFAOYSA-N 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one Chemical compound N(C1=CC=CC=C1)C1=NC=CC(=N1)C1=CC(NC(=C1)C1=C(C=CC=C1)Cl)=O ZNQYDFIGLQKWFG-UHFFFAOYSA-N 0.000 claims description 7
- KKVYWNGJTJAGDA-UHFFFAOYSA-N 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)piperidin-1-yl]-1H-pyridin-2-one Chemical compound N(C1=CC=CC=C1)C1=NC=CC(=N1)C1=CC(NC(=C1)N1C(CCCC1)C(F)(F)F)=O KKVYWNGJTJAGDA-UHFFFAOYSA-N 0.000 claims description 7
- PUSKRRWQMOPUQG-UHFFFAOYSA-N 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one Chemical compound N(C1=CC=CC=C1)C1=NC=CC(=N1)C1=CC(NC(=C1)N1C(COCC1)C(F)(F)F)=O PUSKRRWQMOPUQG-UHFFFAOYSA-N 0.000 claims description 7
- OWCOKHBOLFYWHO-UHFFFAOYSA-N 4-(2-anilinopyrimidin-4-yl)-6-morpholin-4-yl-1H-pyridin-2-one Chemical compound N(C1=CC=CC=C1)C1=NC=CC(=N1)C1=CC(NC(=C1)N1CCOCC1)=O OWCOKHBOLFYWHO-UHFFFAOYSA-N 0.000 claims description 7
- WVOMBCDICRIDRP-UHFFFAOYSA-N 4-(2-anilinopyrimidin-4-yl)-6-pyridin-3-yl-1H-pyridin-2-one Chemical compound N(C1=CC=CC=C1)C1=NC=CC(=N1)C1=CC(NC(=C1)C=1C=NC=CC=1)=O WVOMBCDICRIDRP-UHFFFAOYSA-N 0.000 claims description 7
- XPYHHTPXESGWCC-UHFFFAOYSA-N 4-(2-anilinopyrimidin-4-yl)-6-pyridin-4-yl-1H-pyridin-2-one Chemical compound N(C1=CC=CC=C1)C1=NC=CC(=N1)C1=CC(NC(=C1)C1=CC=NC=C1)=O XPYHHTPXESGWCC-UHFFFAOYSA-N 0.000 claims description 7
- KHHNKBNKRAKFFF-UHFFFAOYSA-N 4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one Chemical compound CC1=NC=CC(=N1)NC1=NC=CC(=C1)C1=CC(NC(=C1)C1=C(C=CC=C1)C(F)(F)F)=O KHHNKBNKRAKFFF-UHFFFAOYSA-N 0.000 claims description 7
- PEWRKYRCKSBJJX-UHFFFAOYSA-N 4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-6-[2-(trifluoromethyl)piperidin-1-yl]-1H-pyridin-2-one Chemical compound CC1=NC=CC(=N1)NC1=NC=CC(=C1)C1=CC(NC(=C1)N1C(CCCC1)C(F)(F)F)=O PEWRKYRCKSBJJX-UHFFFAOYSA-N 0.000 claims description 7
- HPLXYLKQWASIQD-UHFFFAOYSA-N 4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-6-[2-(trifluoromethyl)pyridin-3-yl]-1H-pyridin-2-one Chemical compound CC1=NC=CC(=N1)NC1=NC=CC(=C1)C1=CC(NC(=C1)C=1C(=NC=CC=1)C(F)(F)F)=O HPLXYLKQWASIQD-UHFFFAOYSA-N 0.000 claims description 7
- NGFDAEQNQXUMEO-UHFFFAOYSA-N 4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one Chemical compound CC1=NC=CC(=N1)NC1=NC=CC(=C1)C1=CC(NC(=C1)N1C(COCC1)C(F)(F)F)=O NGFDAEQNQXUMEO-UHFFFAOYSA-N 0.000 claims description 7
- ULEDSARUYZXCMY-UHFFFAOYSA-N 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-1H-pyridin-2-one Chemical compound ClC1=C(C=CC=C1)C1=CC(=CC(N1)=O)C1=CC(=NC=C1)NC1=NC(=NC=C1)C ULEDSARUYZXCMY-UHFFFAOYSA-N 0.000 claims description 7
- PCCBNYMSCHHQPR-UHFFFAOYSA-N 6-(4-methylpyridin-3-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-1H-pyridin-2-one Chemical compound CC1=C(C=NC=C1)C1=CC(=CC(N1)=O)C1=CC(=NC=C1)NC1=NC(=NC=C1)C PCCBNYMSCHHQPR-UHFFFAOYSA-N 0.000 claims description 7
- FYGPTMLGJVEQAS-UHFFFAOYSA-N 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-1H-pyridin-2-one Chemical compound C(C)N1N=C(C(=C1)C1=CC(=CC(N1)=O)C1=CC(=NC=C1)NC1=NC(=NC=C1)C)C(F)(F)F FYGPTMLGJVEQAS-UHFFFAOYSA-N 0.000 claims description 7
- HTDJVWRJWZOQPU-UHFFFAOYSA-N 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-1H-pyridin-2-one Chemical compound FC1=CC=C(C=C1)CS(=O)(=O)N1CC(N(CC1)C1=CC(=CC(N1)=O)C1=CC(=NC=C1)NC1=NC(=NC=C1)C)C(F)(F)F HTDJVWRJWZOQPU-UHFFFAOYSA-N 0.000 claims description 7
- DFIMDSCVZSYJOZ-UHFFFAOYSA-N 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]pyridin-4-yl]-1H-pyridin-2-one Chemical compound C(C)S(=O)(=O)N1CC(N(CC1)C1=CC(=CC(N1)=O)C1=CC(=NC=C1)NC1=NC(=NC=C1)C)C(F)(F)F DFIMDSCVZSYJOZ-UHFFFAOYSA-N 0.000 claims description 7
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
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- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
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- 206010009944 Colon cancer Diseases 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 208000032612 Glial tumor Diseases 0.000 claims description 7
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- 229910003844 NSO2 Inorganic materials 0.000 claims description 7
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- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
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- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 6
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- QPQQQHMUGSHHQZ-UHFFFAOYSA-N 4-[2-(1,3-oxazol-2-ylamino)pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one Chemical compound O1C(=NC=C1)NC1=NC=CC(=C1)C1=CC(NC(=C1)N1C(COCC1)C(F)(F)F)=O QPQQQHMUGSHHQZ-UHFFFAOYSA-N 0.000 claims description 3
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- UIOXGRUPMOWJJO-UHFFFAOYSA-N 4-[2-[(2-methyl-1,3-thiazol-4-yl)amino]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one Chemical compound CC=1SC=C(N=1)NC1=NC=CC(=C1)C1=CC(NC(=C1)N1C(COCC1)C(F)(F)F)=O UIOXGRUPMOWJJO-UHFFFAOYSA-N 0.000 claims description 3
- JFPPAKQKQSEFDN-UHFFFAOYSA-N 4-[2-[(2-methylpyrazol-3-yl)amino]pyridin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one Chemical compound CN1N=CC=C1NC1=NC=CC(=C1)C1=CC(NC(=C1)C1=C(C=CC=C1)C(F)(F)F)=O JFPPAKQKQSEFDN-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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Abstract
本发明提供了新颖的式(I)的吡啶胺‑吡啶酮化合物和嘧啶胺‑吡啶酮化合物、包含这样的化合物的药物组合物以及用于在治疗疾病中使用这样的化合物的方法,所述疾病包括癌症、II型糖尿病、炎性疾病、神经退行性紊乱、心血管紊乱、自身免疫疾病以及病毒感染;其中R1、R2、R3和Z如说明书中所定义。
Description
发明领域
本发明提供了新颖的式(I)的吡啶胺-吡啶酮(pyridinamine-pyridone)化合物和嘧啶胺-吡啶酮(pyrimidinamine-pyridone)化合物、包含这样的化合物的药物组合物以及用于在治疗疾病中使用这样的化合物的方法,所述疾病包括癌症和II型糖尿病。
发明背景
属于磷脂酰肌醇3-激酶(phosphatidylinositide 3-kinase)(PI3K)的家族的酶是若干重要细胞事件的调节剂。该家族由三类I、II和III组成,并且虽然I类组已经作为感兴趣的药物靶持续许多年,但是II类和III类较少被开发。PI3K III类,液泡蛋白分选蛋白34(vacuolar protein sorting 34)(Vps34,PIK3C3)与其调节亚基p150(Vps15)形成异二聚体(heterodimer),并且此二聚体参与调节囊泡运输事件(vesicular traffickingevent)的若干复合体,所述囊泡运输事件例如自噬、胞吞、胞吐以及微胞饮(micropinocytosis)(Amaravadi等人,Clin Cancer Res.2011,17:654-666;Carpentier等人,2013,Traffic)。该酶是磷脂酰肌醇(PI)磷酸化成磷脂酰肌醇(3)-磷酸(phosphatidylinositol(3)-phosphate)(PI3P)的原因。配体结合至PX和FYVE结构域导致这些效应物蛋白(effector protein)的募集和移位(delocalization),这导致囊泡的形成、伸长(elongation)和移动(Backer等人,J Biochem.2008,410:1-17)。
自噬是其中通过将细胞组分封闭在双膜囊泡中使细胞组分靶向降解的分解代谢过程,所述双膜囊泡是与含蛋白酶的溶酶体融合的自噬体。这是细胞处理受损伤的细胞器和错误折叠的蛋白的手段,并且通过该手段维持细胞功能。该途径还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)。自噬是对应激状况如营养缺乏(nutrient deprivation)、酸中毒和缺氧的细胞应答,而且还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使耐药肿瘤再次敏化(resensitize)的手段(Nagelkerke等人,Semin Cancer Biol 2014,31;99-105)。大多数晚期肿瘤(advanced tumor)示出高的自噬潮(autophagic flux)上调(Leone等人,Trends inEndocrin Metab 2013,24;209-217)。用于研究自噬潮的确定的标记(marker)是对于自噬体呈脂质化LC3蛋白的形式的自噬点纹(autophagic puncta)的检测。Vps34的抑制造成自噬的抑制,如通过LC3再分布到点纹中所测量的(Dowdle等人,Nat Cell Biol 2014,16;1069-79)。
如最近描述的,由于减少的胰岛素受体内化,调节亚基p150的切除导致增加的胰岛素体内敏感性(Nemazanyy,Nature Commun.,2015,6:8283)。激酶死亡杂合动物模型用增加的葡萄糖耐受性(glucose tolerance)和增加的胰岛素敏感性确证了该结果(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、糖尿病例如II型糖尿病以及病毒感染(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乳腺癌例如三阴性乳腺癌、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤(hypoxic tumor)。因此,对于新颖的并且有效的Vps34抑制剂存在需求。
描述用于影响疾病的Vps34抑制剂的先前的公开内容包括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并且有效的Vps34抑制剂。本发明的另一个目的是提供新颖的并且有效的Vps34抑制剂,所述Vps34抑制剂可以被用于治疗癌症和其他疾病例如II型糖尿病。
根据本发明的方面1,提供了一种式(I)的化合物
其中
R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氨基、N-C1-C3烷基氨基以及N,N-二C1-C3烷基氨基;
R2选自氢、C1-C3卤代烷基以及C1-C3烷基;
R3选自A、苯基以及单环杂芳基,所述苯基和所述杂芳基各自任选地被R4、R5、R6和R7中的一个或更多个取代;
R4、R5、R6和R7独立地选自卤素、C1-C6烷基、C3-C4环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氮杂环丁烷、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、NHSO2R8、SO2R9以及羟基;
R8是C1-C3卤代烷基或C1-C3烷基;
R9选自R10、C1-C6烷基、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及C1-C3烷氧基C1-C3烷基,其中所述C1-C6烷基和所述C1-C3烷氧基C1-C3烷基各自任选地被一个R10和/或一个或更多个卤素取代;
R10选自苯基、苄基、单环杂芳基、C3-C6环烷基、杂环基,各自任选地被一个或更多个R11取代;
R11选自卤素、C1-C3卤代烷基、C3-C4环烷基、C1-C3烷基、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及C1-C3烷氧基C1-C3烷基;
A是
R12选自氢、卤素、COR13、C1-C6烷基、C3-C6环烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6环烷基、C1-C3氰基烷基以及C1-C3卤代烷基;
R13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-哌啶基以及1-氮杂环丁基;
Y选自CH2、S、SO、SO2、NR14、NCOR9、NCOOR15、NSO2R9、NCOCH2R9、O或键;
R14选自H、C1-C3卤代烷基、C1-C3烷氧基C1-C3烷基、C1-C3烷基以及C3-C6环烷基;并且
R15选自R10、C1-C6烷基以及C1-C3烷氧基C1-C3烷基,并且其中所述C1-C6烷基和所述C1-C3烷氧基C1-C3烷基各自任选地被一个R10和/或一个或更多个卤素取代;并且
Z是CH或N;
或其药学上可接受的盐。
根据本发明的方面2,提供了例如根据方面1的式(I)的化合物,其中R2是氢或C1-C3烷基。
根据本发明的方面3,提供了例如根据方面1或2中任一项的式(I)的化合物,其中R2是氢。
根据本发明的方面4,提供了例如根据方面1至3中任一项的式(I)的化合物,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氨基、-N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及卤素。
根据本发明的方面5,提供了例如根据方面1至4中任一项的式(I)的化合物,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:C1-C6烷基、C3-C4环烷基以及卤素。
根据本发明的方面6,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R3选自
根据本发明的方面7,提供了例如根据方面1至6中任一项的式(I)的化合物,其中R3选自
根据本发明的方面8,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R3选自
Y选自CH2、NSO2R9、O以及键;
R4选自CF3、氟、环丙基以及甲基;
R5是氟;
R9选自C1-C6烷基、苯基以及苄基,各自任选地被一个或更多个卤素取代;并且
R12选自氢、甲基、环丙基以及CF3。
根据本发明的方面9,提供了例如根据方面1至7中任一项的式(I)的化合物,其中R3选自
Y选自NSO2R9、CH2以及O;
R4选自环丙基、CF3以及氯;
R5是氟;
R9选自C1-C6烷基、苯基以及苄基,各自任选地被一个或更多个卤素取代;并且
R12是环丙基或CF3。
根据本发明的方面10,提供了例如根据方面1至7中任一项的式(I)的化合物,其中R3是
R9选自C1-C6烷基、苯基以及苄基,其中所述苯基和苄基基团能够任选地被一个或更多个卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基取代;并且
R12选自卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
根据本发明的方面11,提供了例如根据方面1至10中任一项的式(I)的化合物,其中R1选自苯基、嘧啶基、噁唑基、咪唑基、吡唑基以及噻唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基以及C1-C6卤代烷基。
根据本发明的方面12,提供了例如根据方面1至11中任一项的式(I)的化合物,其中R1选自苯基、嘧啶基、噁唑基、咪唑基以及噻唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基以及C1-C6卤代烷基。
根据本发明的方面13,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R3选自A、苯基、吡啶基、噻吩基、呋喃基、嘧啶基以及吡唑基,各自任选地并且独立地被一个或更多个R4或R5取代。
根据本发明的方面14,提供了例如根据方面1至8中任一项的式(I)的化合物,其中R3选自A、苯基以及吡啶基,各自任选地并且独立地被一个或更多个R4或R5取代。
根据本发明的方面15,提供了例如根据方面1至8中任一项的式(I)的化合物,其中R3选自苯基、吡啶基、吗啉基、哌啶基、吡咯烷基、噻吩基以及哌嗪基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
根据本发明的方面16,提供了例如根据方面1至7中任一项的式(I)的化合物,其中R4、R5、R6和R7独立地选自氟、氯、C1-C3烷基、C1-C3氟烷基、环丙基以及SO2R9。
根据本发明的方面17,提供了例如根据方面1至8中任一项、方面13、方面14或方面16的式(I)的化合物,其中Y选自CH2、O以及键。
根据本发明的方面18,提供了例如根据方面1至7中任一项或方面13的式(I)的化合物,其中R12选自氢、CON(CH3)2、C1-C3烷基、CF3以及环丙基。
根据本发明的方面19,提供了例如根据方面1至7中任一项、方面13、方面14或方面16的式(I)的化合物,其中R9选自R10、N,N-二C1-C3烷基氨基以及甲氧基C1-C3烷基,所述C1-C3烷基任选地被一个R10取代。
根据本发明的方面20,提供了例如根据方面1至7中任一项、方面13、方面14、方面16或方面19的式(I)的化合物,其中R10选自苯基、苄基、吡啶基、咪唑基、异噁唑基、噁唑基、环丙基、环戊基、吡咯烷基以及四氢呋喃基,各自任选地被一个或更多个甲基和/或氟取代。
根据本发明的方面21,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R3选自苯基、吡啶基、吡咯烷基以及噻吩基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;并且
R12是C1-C6烷基或C1-C6卤代烷基。
根据本发明的方面22,提供了例如根据方面1至3中任一项的式(I)的化合物,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及卤素;
R2是氢;
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
根据本发明的方面23,提供了例如根据方面1至7中任一项的式(I)的化合物,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;并且
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
根据本发明的方面24,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R1选自苯基、嘧啶基、噁唑基、咪唑基或噻唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3选自苯基、吡啶基、吡唑基、吡咯烷基以及噻吩基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基、C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;并且
R12是C1-C6烷基或C1-C6卤代烷基。
根据本发明的方面25,提供了例如根据方面1至7中任一项的式(I)的化合物,其中R1选自苯基、4-嘧啶基、2-甲基嘧啶-4-基、2-环丙基-嘧啶-4-基、2-噁唑基、1-甲基-咪唑-4-基、2-甲基-噻唑-4-基、3,5-二氟苯基以及2-甲基吡唑-3-基;
R2是氢;并且
R3选自2-氯苯基、3-吡啶基、4-吡啶基、4-吗啉基、3-(三氟甲基)吗啉-4-基、2-(三氟甲基)-哌啶-1-基、2-(三氟甲基)苯基、4-甲基-吡啶-3-基、2-(三氟甲基)-吡啶-3-基、1-乙基-3-(三氟甲基)吡唑-4-基、3-环丙基-吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)-吡咯烷-1-基、2-氯-5-氟苯基、3-(三氟甲基)-吡唑啉-4-基、2-(三氟甲基)-吡啶-3-基、3-甲基-噻吩-4-基、2-甲基苯基、1-乙酰基-3-三氟甲基-哌嗪-4-基、2-甲基-哌啶-1-基、2-环丙基-哌啶-1-基、2-甲基-吗啉-4-基、2-三氟甲基-吗啉-4-基以及2-环丙基-吗啉-4-基。
根据本发明的方面26,提供了例如根据方面1至7中任一项的式(I)的化合物,其中R1选自苯基、4-嘧啶基、2-甲基嘧啶-4-基、2-环丙基-嘧啶-4-基、2-噁唑基、1-甲基-咪唑-4-基、2-甲基-噻唑-4-基以及3,5-二氟苯基;
R2是氢;并且
R3选自2-氯苯基、3-吡啶基、4-吡啶基、4-吗啉基、3-(三氟甲基)吗啉-4-基、2-(三氟甲基)-哌啶-1-基、2-(三氟甲基)苯基、4-甲基-吡啶-3-基、2-(三氟甲基)-吡啶-3-基、1-乙基-3-(三氟甲基)吡唑-4-基、3-环丙基-吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)-吡咯烷-1-基、2-氯-5-氟苯基、3-(三氟甲基)-吡唑啉-4-基、2-(三氟甲基)-吡啶-3-基、3-甲基-噻吩-4-基、2-甲基苯基、1-乙酰基-3-三氟甲基-哌嗪-4-基、2-甲基-哌啶-1-基、2-环丙基-哌啶-1-基、2-甲基-吗啉-4-基、2-三氟甲基-吗啉-4-基以及2-环丙基-吗啉-4-基。
根据本发明的方面27,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;并且
Z是CH或N。
根据本发明的方面28,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基或嘧啶基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基或C3-C4环烷基;
R2是氢;
R3选自苯基、吡啶基以及吡唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;
R12是C1-C6烷基或C1-C6卤代烷基;并且
Z是CH或N。
根据本发明的方面29,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基、3,5二氟苯基或2-甲基嘧啶-4-基;
R2是氢;
R3选自2-氯苯基、3-吡啶基、4-吡啶基、1-吗啉基、2-(三氟甲基)-1-哌啶基、3-(三氟甲基)吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)苯基、4-甲基-3-吡啶基、2-(三氟甲基)-3-吡啶基、1-乙基-3-(三氟甲基)吡唑-4-基以及3-环丙基吗啉-4-基;并且
Z是CH或N。
根据本发明的方面30,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;并且
Z是CH或N。
根据本发明的方面31,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基或嘧啶基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3选自苯基或吡啶基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;
R12是C1-C6烷基或C1-C6卤代烷基;并且
Z是CH或N。
根据本发明的方面32,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基、2-甲基嘧啶-4-基、噁唑-2-基、2-甲基噻唑-4-基、2-甲基吡唑-3-基以及1-甲基咪唑-4-基;
R2是氢;
R3选自2-氯苯基、3-吡啶基、4-吡啶基、1-吗啉基、2-(三氟甲基)-1-哌啶基、3-(三氟甲基)吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)苯基、4-甲基-吡啶-3-基、2-(三氟甲基)-吡啶-3-基以及1-乙基-3-(三氟甲基)吡唑-4-基;并且
Z是CH或N。
根据本发明的方面33,提供了例如根据方面1至7中任一项的式(I)的化合物或其药学上可接受的盐,其中R1是苯基或2-甲基嘧啶-4-基;
R2是氢;
R3选自2-氯苯基、3-吡啶基、4-吡啶基、1-吗啉基、2-(三氟甲基)-1-哌啶基、3-(三氟甲基)吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基以及4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基;并且
Z是CH或N。
根据本发明的方面34,提供了选自以下的化合物或其药学上可接受的盐:
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-(噁唑-2-基氨基)-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-[2-[(2-甲基噻唑-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
4-[2-[(2-甲基吡唑-3-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
4-[2-[(2-甲基噻唑-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮;
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(1-甲基咪唑-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;以及
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
根据本发明的方面35,提供了选自以下的化合物或其药学上可接受的盐:
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮;
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;以及
6-(3-环丙基吗啉-4-基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
根据本发明的方面36,提供了选自以下的化合物或其药学上可接受的盐:
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮;
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;以及
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
根据本发明的方面37,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R3选自
根据本发明的方面38,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R4选自氯、CF3以及甲基;R5是C1-C3烷基,例如乙基;并且R12是氢或CF3。
根据本发明的方面39,提供了例如根据方面1至5中任一项的式(I)的化合物,其中Y选自CH2、O以及NSO2R9。
根据本发明的方面40,提供了例如根据方面1至5中任一项的式(I)的化合物,其中R9选自C1-C3烷基以及苄基,所述苄基被氟间位取代。
在本发明的一个方面中,提供了根据本发明的化合物,用于治疗或预防疾病。
在本发明的一个方面中,提供了根据本发明的化合物,用于治疗癌症。典型地,所述癌症选自乳腺癌例如三阴性乳腺癌、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤。
在本发明的一个方面中,提供了根据本发明的化合物,用于治疗缺氧性肿瘤。
在本发明的一个方面中,提供了根据本发明的化合物,用于治疗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,用于治疗疾病,所述疾病选自:炎性疾病、神经退行性紊乱、心血管紊乱、自身免疫疾病以及病毒感染。
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、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤。
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缺氧性肿瘤的药物中。
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II型糖尿病的药物中的用途。
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、自身免疫疾病以及病毒感染。
在本发明的一个方面中,提供了一种治疗癌症的方法,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有相应需要的患者。典型地,所述癌症选自乳腺癌例如三阴性乳腺癌、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤。
在本发明的一个方面中,提供了一种治疗缺氧性肿瘤的方法,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有相应需要的患者。
在本发明的一个方面中,提供了根据本发明的化合物,用于治疗癌症,其中所述癌症的治疗还包括放射疗法。
在本发明的一个方面中,提供了一种治疗癌症的方法,所述方法包括将治疗有效量的根据本发明的化合物结合放射疗法施用至有相应需要的患者。
本发明的化合物还可以结合放射疗法和/或外科手术干预被用于癌症治疗。通常,细胞毒性剂和/或细胞抑制剂与本发明的化合物或组合物组合的使用将用于:
(1)与单独施用任一种剂相比,在减少肿瘤的生长或甚至消除肿瘤方面产生更好的效力,
(2)提供施用较少量的所施用的化疗剂,
(3)相比于在单一的剂化疗和某些其他组合疗法下观察到的,提供具有较少不利的药理学并发症的在患者中良好耐受的化疗治疗,
(4)在哺乳动物,特别是人类中提供治疗较广谱的不同癌症类型,
(5)在经治疗的患者中提供较高的应答率(response rate),
(6)与标准化疗治疗相比,在经治疗的患者中提供较长的存活时间,
(7)对于肿瘤进展提供较长的时间,和/或
(8)与其中其他癌症剂组合产生拮抗效应的已知情况相比,产生至少如单独使用的剂的效力结果和耐受性结果一样好的效力结果和耐受性结果。
在本发明的一个方面中,提供了一种治疗II型糖尿病的方法,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有相应需要的患者。
在本发明的一个方面中,提供了一种治疗疾病的方法,所述疾病选自炎性疾病、神经退行性紊乱、自身免疫疾病以及病毒感染,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有相应需要的患者。
在本发明的一个方面中,提供了一种药物组合物,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,提供了一种药物组合物,所述药物组合物包含治疗有效量的根据本发明的化合物以及另一种抗癌剂,所述抗癌剂选自烷基化剂、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、干扰素以及生物应答修饰剂(biological response modifier)。
如本文使用的,术语“C1-C6烷基”意指具有1个至6个碳原子的直链饱和烃基团和支链饱和烃基团两者。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。在非支链的C1-C6烷基基团中,典型的基团是甲基基团、乙基基团、正丙基基团、正丁基基团、正戊基基团以及正己基基团。在支链的烷基基团中,可以提到异丙基基团、异丁基基团、仲丁基基团、叔丁基基团、4-甲基丁基基团以及2-乙基丁基基团。
如本文使用的,术语“C1-C3烷基”意指具有1个至3个碳原子的直链饱和烃基团和支链饱和烃基团两者。C1-C3烷基基团的实例包括甲基基团、乙基基团、正丙基基团以及异丙基基团。
如本文使用的,术语“C1-C6烷氧基”意指基团O-C1-C6烷基,其中“C1-C6烷基”如上文描述被使用。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。
如本文使用的,术语“C1-C3烷氧基”意指基团O-C1-C3烷基,其中“C1-C3烷基”如上文描述被使用。C1-C3烷氧基基团的实例包括但不限于甲氧基、乙氧基、异丙氧基以及正丙氧基。
如本文使用的,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个至所有氢被不同类型或相同类型的卤素取代的直链饱和烃基团和支链饱和烃基团两者。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以及被1个至9个卤素原子取代的仲丁基基团或叔丁基基团。
如本文使用的,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个至所有氢被不同类型或相同类型的卤素取代的直链饱和烃基团和支链饱和烃基团两者。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以及被1个至7个卤素原子取代的正丙基或异丙基。
如本文使用的,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个至所有氢原子被不同类型或相同类型的卤素原子取代的直链饱和烷氧基基团和支链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以及被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个至所有氢原子被氟原子取代的直链饱和烃基团和支链饱和烃基团两者。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以及被1个至7个氟原子取代的正丙基或异丙基。
如本文使用的,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个至所有氢原子被氟原子取代的直链饱和烷氧基基团和支链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以及被1个至7个氟原子取代的正丙氧基或异丙氧基。
如本文使用的,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、环戊基以及环己基。
如本文使用的,术语“C1-C3烷氧基C1-C3烷基”意指被具有1个至3个碳原子的烷氧基基团取代的具有1个至3个碳原子的直链饱和烃基团和支链饱和烃基团两者。C1-C3烷氧基C1-C3烷基基团的实例被绘制在下文。
如本文使用的,术语“C1-C3氰基烷基”意指具有一个至三个碳原子的直链氰基(CN)衍生物和支链氰基衍生物两者,所述一个至三个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被绘制在下文。
如本文使用的,术语N-C1-C3烷基氨基意指具有一个如上文定义的C1-C3烷基基团的氨基取代基。N-C1-C3烷基氨基的实例被绘制在下文。
如本文使用的,术语N,N-二C1-C3烷基氨基意指具有两个如上文定义的C1-C3烷基基团的氨基取代基。N,N-二C1-C3烷基氨基的实例被绘制在下文。
如本文使用的,术语“卤素(halogen)”意指氟、氯、溴或碘。应理解,当取代基是卤素(halogen)(或卤代(halo))时,其总是结合至碳原子。
如本文使用的,术语“芳基”意指单环芳香族碳环基团。这样的基团的实例包括苯基。
如本文使用的,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。
如本文使用的,术语“杂芳基”意指碳原子的单环或双环芳香族基团,其中碳原子中的从一个至三个被一个或更多个杂原子代替,所述杂原子独立地选自氮、氧或硫。在双环芳基中,环中的一个可以是部分饱和的。这样的基团的实例包括吲哚啉基、二氢苯并呋喃以及1,3-苯并二氧杂环戊烯基。
如本文使用的,术语“单环杂芳基”意指碳原子的单环芳香族基团,其中碳原子中的从一个至三个被一个或更多个杂原子代替,所述杂原子独立地选自氮、氧或硫。
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、吡唑基以及嘧啶基。
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、吡啶并嘧啶基以及异喹啉基。
如本文使用的,术语“杂环基”意指碳原子的环状基团,其中碳原子中的从一个至三个被一个或更多个杂原子代替,所述杂原子独立地选自氮、氧和硫。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、吗啉基以及二噁烷基。
取决于式(I)的化合物中存在的取代基,化合物可以形成在本发明的范围内的盐。适合于用于药物的式(I)的化合物的盐是其中抗衡离子是药学上可接受的盐。
根据本发明的合适的盐包括用有机酸或有机碱或无机酸或无机碱形成的盐。特别地,根据本发明的用酸形成的合适的盐包括用无机酸形成的盐;用强的有机羧酸形成的盐,所述强的有机羧酸例如未被取代的或被例如卤素取代的1个至4个碳原子的链烷羧酸,例如饱和的或不饱和的二羧酸,例如羟基羧酸,例如氨基酸;或用有机磺酸形成的盐,所述有机磺酸例如未被取代的或被例如卤素取代的(C1-C4)烷基磺酸或芳基磺酸。药学上可接受的酸加成盐包括由以下形成的盐:盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、乙酸、磷酸、乳酸、丙酮酸、三氟乙酸、琥珀酸、高氯酸、富马酸、马来酸、乙醇酸、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、羟乙磺酸、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。
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,有机碱例如二环己胺、N-甲基-D-葡萄糖胺、吗啉、硫代吗啉、哌啶、吡咯烷、低级单烷基胺、低级二烷基胺或低级三烷基胺,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。此外可以形成对应的内盐(internalsalt)。
本发明的化合物可以按原样或以药物组合物的形式用于预防和/或治疗。虽然单独地施用活性成分是可能的,但是使其存在于药物组合物中也是可能的。因此,本发明提供了一种药物组合物,所述药物组合物包含式(I)的化合物以及药学上可接受的稀释剂、赋形剂和/或载体。本发明的药物组合物可以采取如下文描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:混悬液,所述混悬液可以包含例如用于赋予蓬松度(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(viscosity enhancer)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(immediate release tablet),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、山梨醇、葡萄糖和/或乳糖和/或其他赋形剂、粘合剂、增充剂(extender)、崩解剂、稀释剂以及润滑剂,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、天然树胶和合成树胶例如***胶、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)的化合物还可以通过舌下施用和/或含服施用通过口腔来递送。模制的片剂、压制的片剂或冷冻干燥的片剂是可以使用的示例性形式。示例性组合物包括用快速溶解的稀释剂例如甘露醇、乳糖、蔗糖和/或环糊精配制本发明化合物的组合物。这样的组合物中还可以包含高分子量赋形剂,例如纤维素(avicel)或聚乙二醇(PEG)。这样的组合物还可以包含有助于粘膜粘附的赋形剂,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)以及控制释放的剂,例如聚丙烯酸共聚物(例如卡波姆934)。为了易于制造和使用,还可以添加润滑剂、助流剂、调味剂、着色剂以及稳定剂。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、氯化钠及类似物。对于呈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、水及类似物组合。
适合于口服施用的本发明的组合物可以作为离散单元呈现,离散单元例如各自包含预先确定的量的活性成分的胶囊、扁囊剂、丸剂或片剂;作为粉剂或颗粒剂呈现;作为含水液体或非含水液体中的溶液或悬浮液呈现,例如作为酏剂、酊剂、悬浮液或糖浆;或作为水包油液体乳液或油包水液体乳液呈现。活性成分也可以作为快速推注剂(bolus)、舐剂(electuary)或糊剂呈现。
片剂可以通过任选地与一种或更多种辅助成分一起压制或模制来制备。压制的片剂可以通过在合适的机器中压制任选地与粘合剂、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的呈自由流动形式例如粉剂或颗粒剂的活性成分来制备。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备。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控制释放。本发明的化合物可以例如以适合于速释或延长释放的形式被施用。速释或延长释放可以通过以下来实现:使用包含本发明的化合物的合适的药物组合物,或特别地在延长释放的情况下使用诸如皮下植入物或渗透泵的装置。本发明的化合物还可以经脂质体施用。
典型的单位剂量组合物是包含活性成分的如上文叙述的有效剂量或其适当部分的那些。
应当理解,除了上文特别提及的成分之外,本发明的组合物可以包含本领域关于所讨论的组合物类型常规的其他剂,例如适合于口服施用的那些剂可以包括调味剂。
组合物可以以单位剂型呈现,并且可以通过药学领域熟知的任何方法来制备。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关联的步骤。组合物可以通过以下制备: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关联,并且然后如有必要,使产品成形为期望的组合物。
本发明的化合物还可以以脂质体递送***的形式被施用,例如小单层囊泡、大单层囊泡以及多层囊泡。脂质体可以由多种磷脂形成,所述磷脂为1,2-二棕榈酰基磷脂酰胆碱、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(cardiolipin))或磷脂酰胆碱(卵磷脂)。
用于肠胃外施用的组合物包括可以包含抗氧化剂、缓冲剂、抑细菌剂(bacteriostat)以及致使组合物与预期接受者的血液等渗的溶质的含水和非含水的无菌注射溶液;以及可以包含悬浮剂和增稠剂的含水和非含水的无菌悬浮液。组合物可以呈现在单位剂量或多剂量容器例如密封的安瓿和小瓶(vial)中,并且可以储存在冷冻干燥(冻干)条件中,仅需要在临使用之前添加无菌液体载体例如盐水或注射用水。即时注射溶液和悬浮液可以由先前描述的种类的无菌粉剂、颗粒剂和片剂来制备。用于肠胃外施用的示例性组合物包括可注射的溶液或悬浮液,所述可注射的溶液或悬浮液可以包含例如合适的无毒、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、Ringer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,其他合适的分散剂或润湿剂和悬浮剂包括合成的甘油一酯或甘油二酯以及脂肪酸,脂肪酸包括油酸或Cremaphor。
用于鼻施用、气雾剂施用或吸入施用的示例性组合物包括盐水中的溶液,该盐水中的溶液可以包含例如苄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栓剂呈现,所述栓剂具有通用载体例如可可油、合成甘油酯或聚乙二醇。这样的载体典型地在常温是固体,但在直肠腔中液化和/或溶解以释放药物。
用于在口中局部施用例如含服施用或舌下施用的组合物包括锭剂(lozenge),所述锭剂包含在调味基质中的活性成分,所述调味基质例如蔗糖和***胶或黄蓍胶;和软锭剂(pastille),所述软锭剂包含在基质中的活性成分,所述基质例如明胶和甘油或蔗糖和***胶。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与一种或更多种另外的治疗剂组合被施用,其中该组合不引起不可接受的副作用。该药物组合物包括包含式(I)的化合物和一种或更多种另外的治疗剂的单一药物剂量组合物的施用,以及式(I)的化合物和以其单独的药物剂量组合物的每一种另外的治疗剂的施用。例如,式(I)的化合物和治疗剂可以以单一的口服剂量组合物例如胶囊或片剂一起被施用至患者,或每一种剂可以以单独的剂量在组合物中被施用。
在使用单独的剂量组合物的情况下,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相同的时间(例如同时)或在分开交错的时间(例如依次地)施用。
当然,实现治疗效果所需的活性成分的量将随着特定化合物、施用途径、在治疗下的受试者(包括受试者的类型、物种、年龄、重量、性别和医学状况)以及受试者的肾脏和肝脏功能以及被治疗的特定的紊乱或疾病以及其严重程度而变化。普通技术医师、兽医或临床医生可以容易地确定并且处方预防、抵消或阻止状况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,对于成年人类,将在约0.01mg每kg体重每天(mg/kg/天)至约100mg/kg/天、优选地0.01mg每kg体重每天(mg/kg/天)至10mg/kg/天并且最优选地0.1mg/kg/天至5.0mg/kg/天之间的范围内。对于口服施用,组合物可以以片剂的形式或以离散单元提供的其他呈现形式被提供,离散单元包含0.01毫克、0.05毫克、0.1毫克、0.5毫克、1.0毫克、2.5毫克、5.0毫克、10.0毫克、15.0毫克、25.0毫克、50.0毫克、100毫克和500毫克的活性成分,用于对待被治疗的患者的剂量的症状调节。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一的日剂量被施用,或总的日剂量可以以每日两次、三次或四次的分剂量(divided dose)被施用。此外,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或经由透皮途径、使用本领域普通技术人员熟知的透皮皮肤贴剂的那些形式被施用。为了以透皮递送***的形式施用,剂量施用当然将在整个剂量方案中是连续的而不是间歇的。
化合物的制备
本发明中的化合物可以通过下文描述的工艺被制备为游离碱或其药学上可接受的盐。在这样的工艺的整个以下描述中,应理解在合适的情况下,合适的保护基团将以将被有机合成领域的技术人员容易理解的方式被添加至各种反应物和中间体,并且随后从各种反应物和中间体中移除。用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在T.W.Greene,P.G.M Wutz的Protective Groups in Organic Synthesis,第4版,Wiley-Interscience,New York,2006中被描述。应理解,微波可以可选择地被用于反应混合物的加热。
本发明的另一个方面提供了用于制备式(I)的化合物或其药学上可接受的盐的工艺,其中除非另外指定,否则R1、R2、R3和Z如本文所定义。
所述工艺包括:
(i)对应的式(I)的化合物的形成:
式(I)的化合物可以通过从例如式(II)的化合物开始来获得(方案1),其中RX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RX是F,则转化成(I)可以通过例如使用含水HCl的酸性水解来进行。如果RX是OCH3,则转化成(I)可以通过在合适的溶剂例如氯仿中与例如三甲基甲硅烷基碘化物反应、或通过在合适的溶剂例如乙酸中与HBr反应、或通过在合适的溶剂例如二氯甲烷中与BBr3反应来进行。如果RX是OC(CH3)3,则转化成(I)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RX是OSiR’R”R”’,则转化成(I)可以通过例如在合适的溶剂例如甲醇中的HCl或通过使用四氢呋喃中的四丁基氟化铵来进行。如果在该反应中使用对映异构体纯的或富集的化合物(II),则获得对映异构体纯的或对映异构体富集的化合物(I)。
式(II)的化合物是可商购的化合物,或文献中已知的,或它们通过本领域已知的标准工艺来制备。式(I)或式(II)的化合物可以通过本领域已知的标准工艺例如手性固定相上的色谱法被分离成其对映异构体。
一般方法
使用的所有溶剂是分析级别的,并且可商购的无水溶剂被常规地用于反应。起始材料可购自商业来源或根据文献程序来制备。室温指的是+20℃-25℃。溶剂混合物组成作为体积百分比或体积比被给出。
微波加热在于2.45GHz产生连续辐照的Biotage Initiator微波腔中进行。应理解,微波可以被用于反应混合物的加热。
直相色谱法(Straight phase chromatography)在Merck硅胶60(0.040mm-0.063mm)上手动地进行,或使用ISCOCompanionTM***、使用SiliaSepTM正相快速柱、使用指示的溶剂体系自动地进行。
NMR光谱在装配有合适配置的探针的400MHz(或更高场)NMR光谱仪上记录。除非另外陈述,否则光谱在环境温度被记录。化学位移从TMS(0.00ppm)低场和高场以ppm给出。使用以下参考信号:DMSO-d6的残余溶剂信号δ2.5、CDCl3的残余溶剂信号δ7.26或甲醇-d4的残余溶剂信号δ3.31。对于单峰、双峰、三重峰、四重峰、多重峰和宽峰,共振多重性分别被表示为s、d、t、q、m和br。
高压液相色谱法(HPLC)在反相柱上进行。使用例如流动相A(含水0.1%NH3或含水0.1%乙酸或含水0.1%甲酸)和流动相B(乙腈或甲醇)应用线性梯度。质谱(MS)分析在正离子模式中使用电喷雾电离(ES+)进行。
制备型色谱法在其中Trilution lc作为软件的Gilson-PREP GX271或GX281上在反相柱上运行。使用例如流动相A(含水0.1%NH3或含水0.1%乙酸或含水0.1%甲酸)和流动相B(乙腈或甲醇)应用线性梯度。
用于分离对映异构体的制备型手性色谱法在Thar SFC上使用手性固定相上的超临界流体色谱法运行。使用流动相A(二氧化碳)和流动相B(乙腈或甲醇或乙醇或2-丙醇或其任何混合物)应用线性梯度。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BIOVIA Draw 16.1命名。
缩写
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
DMAc N,N-二甲基乙酰胺
DME 1,2-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
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 液相色谱质谱法
MeCN 乙腈
2-MeTHF 2-甲基四氢呋喃
MeOH 甲醇
min. 分钟
NMR 核磁共振
Pd-118 [1,1'-双(二叔丁基膦基)二茂铁]二氯化钯(II)
PEPPSI-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)
Pd(OAc)2 乙酸钯(II)
PdCl2(dppf) [1,1′-双(二苯基膦基)二茂铁]二氯化钯(II)
quant. 定量的
rt 室温
sat. 饱和的
TFA 三氟乙酸
THF 四氢呋喃
实施例1
4-(2,6-二氯-4-吡啶基)-N-苯基-嘧啶-2-胺
将2,6-二氯吡啶-4-甲酸(2.88g,15mmol)溶解在1,4-二氧六环(75ml)中,并且添加草酰氯(1.35ml,15.75mmol)。将产生的混合物在50℃搅拌持续5min,然后添加DMF(3滴)并且继续搅拌持续45min。当冷却至rt时,添加PdCl2(PPh3)2(210mg,0.3mmol)、CuI(114mg,0.6mmol)、乙炔基三甲基硅烷(2.12ml,15mmol)和三乙胺(6.26ml,45mmol)并且将混合物在rt搅拌持续30min。添加苯基胍硝酸盐(2.97g,15mmol)、K2CO3(5.18g,37.5mmol)和2-乙氧基乙-1-醇(15ml)并且将产生的混合物回流过夜。当冷却至rt时,将混合物通过被DCM/MeOH/NH3(100:3:1)洗脱的硅胶垫过滤,以给出作为黑色胶的产物。从MeOH中重结晶给出作为固体的产物(3.03g,64%)。MS ES+m/z 317[M+H]+。
实施例2
4-(2-叔丁氧基-6-氯-4-吡啶基)-N-苯基-嘧啶-2-胺
将4-(2,6-二氯吡啶-4-基)-N-苯基嘧啶-2-胺(3g,9.46mmol)、分子筛(3g)和KOtBu(2.65g,23.65mmol)溶解在甲苯(50ml)中,并且将产生的混合物在90℃搅拌持续3h。当冷却至rt时,添加水(50ml)、含水2M HCl(20ml)和EtOAc(50ml),并且将产生的沉淀物过滤掉并且丢弃。将有机层分离并且水层用EtOAc(2×25ml)萃取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤并且浓缩。将产生的残余物与活性炭一起溶解在DCM(50ml)中,并且将混合物在rt搅拌持续15min。通过硅藻土过滤以及浓缩滤液给出作为胶的产物(1.5g,45%)。MS ES+m/z 355[M+H]+。
实施例3
4-[2-叔丁氧基-6-(2-氯苯基)-4-吡啶基]-N-苯基-嘧啶-2-胺
将4-[2-(叔丁氧基)-6-氯吡啶-4-基]-N-苯基嘧啶-2-胺(650mg,1.13mmol)、(2-氯苯基)硼酸(344mg,2.2mmol)、Pd-118(60mg,0.09mmol)和K2CO3(760mg,5.5mmol)溶解在DME:H2O:EtOH(6:3:1,15ml)中,并且将产生的混合物在75℃搅拌过夜。添加更多的(2-氯苯基)硼酸(344mg,2.2mmol)和Pd-118(60mg,0.09mmol),并且将混合物在75℃搅拌持续4h。当冷却至rt时,将混合物浓缩并且将产生的残余物溶解在水(20ml)和EtOAc(50ml)中。将混合物在rt搅拌持续10min,并且然后过滤。向滤液添加EtOAc(20ml),并且将有机层分离。水层用EtOAc(2×10ml)萃取,并且合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并且在被庚烷中的0-50%EtOAc洗脱的硅胶柱上纯化,随后是制备型HPLC,以给出作为固体的产物(140mg,18%)。MS ES+m/z 431[M+H]+。
实施例4
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮
在rt,将TFA(0.1ml,1.35mmol)添加至4-[2-(叔丁氧基)-6-(2-氯苯基)吡啶-4-基]-N-苯基嘧啶-2-胺(130mg,0.3mmol)在DCM(8ml)中的溶液,并且将产生的混合物在rt搅拌持续2h,添加更多的TFA(0.1ml,1.35mmol)并且继续搅拌持续2h。将混合物浓缩并且将产生的残余物溶解在MeOH(10ml)中。添加NH4OH(28%,3ml),并且将混合物在rt搅拌持续1h。将沉淀物过滤掉,用水、MeOH洗涤并且干燥。将固体溶解在沸腾的吡啶(15ml)中,并且允许冷却至rt。在搅拌下,向混浊的溶液添加MeOH(10ml),并且在rt 10min之后,将混合物在冰箱中冷却持续15min。将产生的沉淀物过滤掉,依次用MeOH和戊烷洗涤并且干燥,以给出作为固体的产物(30mg,25%)。1H NMR(500MHz,DMSO-d6)δppm 12.15(s,1H),9.77(s,1H),8.62(d,1H),7.79(d,2H),7.69-7.56(m,2H),7.51(dq,2H),7.30(q,2H),7.18(s,1H),6.97(t,1H)。MS ES+m/z 375[M+H]+。
实施例5
4-[2-叔丁氧基-6-(3-吡啶基)-4-吡啶基]-N-苯基-嘧啶-2-胺
使用(吡啶-3-基)硼酸,如实施例3中描述的来制备标题化合物,以给出产物(435mg,97%)。MS ES+m/z 398[M+H]+。
实施例6
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮
从2-丙醇中重结晶,如实施例4中描述的来制备标题化合物,以给出作为固体的产物(14mg,14%)。1H NMR(500MHz,DMSO-d6)δppm 12.08(s,1H),9.81(s,1H),9.14(s,1H),8.72–8.58(m,2H),8.31(d,1H),7.82(d,2H),7.68–7.51(m,3H),7.38–7.27(m,3H),6.99(t,1H)。MS ES+m/z 342[M+H]+。
实施例7
4-[2-叔丁氧基-6-(4-吡啶基)-4-吡啶基]-N-苯基-嘧啶-2-胺
使用(吡啶-4-基)硼酸,如实施例3中描述的来制备标题化合物,以给出产物(100mg,64%)。MS ES+m/z 398[M+H]+。
实施例8
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮
从2-丙醇中重结晶,如实施例4中描述的来制备标题化合物,以给出作为固体的产物(20mg,21%)。1H NMR(500MHz,DMSO-d6)δppm 11.85(s,1H),9.83(s,1H),8.76(d,2H),8.67(d,1H),7.98(s,2H),7.82(d,2H),7.62(d,1H),7.44-7.24(m,3H),7.00(t,1H)。MS ES+m/z 342[M+H]+。
实施例9
4-(2-叔丁氧基-6-吗啉代-4-吡啶基)-N-苯基-嘧啶-2-胺
将4-(2-叔丁氧基-6-氯-4-吡啶基)-N-苯基-嘧啶-2-胺(190mg,0.54mmol)、Pd(OAc)2(8mg,0.04mmol)和XantPhos(19mg,0.03mmol)溶解在甲苯(6ml)中。添加吗啉(185μl,2.14mmol)和KOtBu(180mg,1.61mmol),并且将产生的混合物在100℃搅拌过夜。当冷却至rt时,添加EtOAc和盐水,将有机层分离,并且水层用EtOAc萃取。合并的有机物用盐水洗涤,经MgSO4干燥,过滤,浓缩并且在被庚烷中的20%EtOAc洗脱的硅胶柱上纯化,以给出产物(60mg,28%)。MS ES+m/z 406[M+H]+。
实施例10
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮
如实施例4中描述的来制备标题化合物,以给出作为固体的产物(26mg,50%)。1HNMR(400MHz,DMSO-d6)δppm 3.33(s,1H)3.47(br.s.,4H)3.65-3.79(m,4H)6.62(s,1H)6.85(br.s.,1H)6.97(t,1H)7.31(t,2H)7.42(s,1H)7.82(d,2H)8.58(d,1H)9.72(s,1H)。MS ES+m/z 350[M+H]+。
实施例11
4-苄氧基-2,6-二氯-吡啶
在0℃,将60%NaH(945mg,24.7mmol)逐份地添加至2,4,6-三氯吡啶(4.5g,24.7mmol)在DMF(25ml)中的溶液。在20min之后,逐滴地添加苯基甲醇(2.7g,24.7mmol),并且将混合物搅拌持续3h。添加水(30ml),并且将沉淀物过滤掉。将固体溶解在EtOAc中,经MgSO4干燥,过滤并且浓缩,以给出作为固体的产物(5g,80%)。MS ES+m/z 254[M+H]+。
实施例12
4-苄氧基-2-叔丁氧基-6-氯-吡啶
将4-苄氧基-2,6-二氯-吡啶(5g,19.7mmol)和KOtBu(2.2g,19.7mmol)溶解在干燥的2-MeTHF(25ml)中,并且将混合物在70℃搅拌持续2h。当冷却至rt时,将混合物过滤,浓缩并且在被庚烷中的30%EtOAc洗脱的硅胶柱上纯化,以给出产物(4g,70%)。MS ES+m/z 292[M+H]+。
实施例13
4-苄氧基-2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶
将4-苄氧基-2-叔丁氧基-6-氯-吡啶(4g,13.7mmol)、2-(三氟甲基)哌啶(2.3g,15.1mmol)、PEPPSI-iPr(146mg,1.37mmol)和KOtBu(3.85g,34.3mmol)溶解在1,4-二氧六环(30ml)中,并且将混合物在90℃搅拌持续2h。当冷却至rt时,添加水和EtOAc,并且将有机层分离,过滤,浓缩并且在被庚烷中的30%EtOAc洗脱的硅胶柱上纯化,以给出产物(4.1g,73%)。MS ES+m/z 409[M+H]+。
实施例14
2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶-4-醇
将在MeOH和EtOAc中的4-苄氧基-2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶(3.5g,8.57mmol)和10%Pd/C(600mg,0.56mmol)的混合物在rt氢化(1.5巴)持续2h。将混合物通过硅藻土过滤并且浓缩,以给出产物(2.7g,定量的)。MS ES+m/z 319[M+H]+。
实施例15
[2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]-4-吡啶基]三氟甲磺酸酯
在0℃,将2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]吡啶-4-醇(2.7g,8.48mmol)和Et3N(1.66ml,11.9mmol)溶解在DCM(20mL)中。在5分钟内逐滴地添加三氟甲基磺酰基三氟甲磺酸酯(2.54ml,11.9mmol),并且搅拌持续1h。混合物用饱和的含水NaHCO3(2×20mL)洗涤,浓缩并且在被庚烷中的20%EtOAc洗脱的硅胶柱上纯化,以给出产物(3.5g,92%)。MSES+m/z 451[M+H]+。
实施例16
2-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6-[2-(三氟甲基)-1-哌啶基]吡啶
将4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(2.96g,11.7mmol),[2-叔丁氧基-6-[2-(三氟甲基)-1-哌啶基]-4-吡啶基]三氟甲磺酸酯(3.5g,7.77mmol),KOAc(1.14g,11.7mmol)和PdCl2(dppf)(215mg,0.29mmol)溶解在甲苯(10ml)中并且在90℃搅拌持续5h。当冷却至rt时,将混合物浓缩并且将残余物溶解在EtOAc中,用水洗涤,浓缩并且在被庚烷中的0-60%EtOAc洗脱的硅胶柱上纯化,以给出产物(2.15g,65%)。MS ES+m/z 347[M+H]+。
实施例17
N-(4-氯-2-吡啶基)-2-甲基-嘧啶-4-胺
将2-溴-4-氯-吡啶(250mg,1.25mmol)、2-甲基嘧啶-4-胺(107mg,0.9mmol)、PdCl2(dppf)(14mg,0.015mmol)和dppf(43mg,0.07mmol)溶解在甲苯中。添加在THF中的1M KOtBu(167mg,1.4mmol),并且将产生的混合物在110℃搅拌过夜。后处理(work up)和在硅胶柱上进行色谱法的纯化给出作为固体的产物(100mg,36%)。MS ES+m/z 221[M+H]+。
实施例18
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮
将1-[3-叔丁氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苯基]-2-(三氟甲基)哌啶(100mg,0.23mmol)、K2CO3(81mg,0.59mmol)、N-(4-氯-2-吡啶基)-2-甲基-嘧啶-4-胺(52mg,0.23mmol)和PdCl2(dppf)(15mg,0.02mmol)溶解在1,4-二氧六环(3ml)和水(1ml)中,并且将产生的混合物在90℃搅拌持续2h。当冷却至rt时,添加水和EtOAc,并且将有机层分离并且浓缩。将残余物溶解在DCM(3ml)中,添加TFA(0.5ml,6.7mmol),并且将混合物在rt搅拌持续30min。将混合物浓缩,溶解在MeOH中,过滤,并且通过制备型HPLC纯化,以给出作为固体的产物(7mg,6%)。1H NMR(500MHz,甲醇-d4)δppm 1.17-1.33(m,1H),1.54-1.66(m,1H),1.68-1.77(m,2H),1.81(br d,3H),2.08(br d,1H),2.57(s,3H),3.15-3.29(m,1H),3.86(br d,1H),5.16(br s,1H),6.21-6.27(m,2H),7.17(dd,1H),7.38(d,1H),8.07(br s,1H),8.23(d,1H),8.32(d,1H)。MS ES+m/z 431[M+H]+。
实施例19
2-苯氨基-1H-嘧啶-6-酮
将2-甲基硫烷基-1H-嘧啶-6-酮(5g,35.21mmol)和苯胺(3.2g,35.21mmol)溶解在二甘醇二甲醚(50ml)中,并且将产生的混合物在170℃搅拌持续5h。当冷却至rt时,添加水,并且将形成的沉淀物过滤掉,用水洗涤并且干燥,以给出作为固体的产物(3g,46%)。MS ES+m/z 188[M+H]+。
实施例20
4-氯-N-苯基-嘧啶-2-胺
将PCl5(1g,5.34mmol)逐份地添加至2-苯氨基-1H-嘧啶-6-酮(1.5g,5.34mmol)在POCl3(5ml)中的溶液,并且将产生的混合物在110℃搅拌过夜。当冷却至rt时,添加冰/水并且混合物用EtOAc萃取。合并的有机物经Na2SO4干燥,过滤,浓缩并且在硅胶柱上纯化,以给出作为固体的产物(840mg,76%)。MS ES+m/z 206[M+H]+。
实施例21
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮
使用4-氯-N-苯基-嘧啶-2-胺,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(11mg,8%)。1H NMR(500MHz,DMSO-d6)δppm 1.52(br s,1H),1.70(br s,2H),1.78(br d,2H),2.02(br d,1H),3.09(br t,1H),4.22(br s,1H),5.54(br s,1H),6.65(s,1H),6.95-7.04(m,2H),7.31(t,2H),7.44(d,1H),7.83(d,2H),8.60(d,1H),9.72(s,1H),10.47(br s,1H)。MS ES+m/z 416[M+H]+。
实施例22
4-(4-苄氧基-6-叔丁氧基-2-吡啶基)-3-(三氟甲基)吗啉
使用3-(三氟甲基)吗啉,如实施例13中描述的来制备标题化合物,以给出作为油的产物(1g,50%)。MS ES+m/z 411[M+H]+。
实施例23
2-叔丁氧基-6-[3-(三氟甲基)吗啉-4-基]吡啶-4-醇
如实施例14中描述的来制备标题化合物,以给出产物(780mg,99%)。MS ES+m/z321[M+H]+。
实施例24
[2-叔丁氧基-6-[3-(三氟甲基)吗啉-4-基]-4-吡啶基]三氟甲磺酸酯
如实施例15中描述的来制备标题化合物,以给出作为油的产物(800mg,81%)。MSES+m/z 453[M+H]+。
实施例25
4-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-3-(三氟甲基)吗啉
如实施例16中描述的来制备标题化合物,以给出产物(270mg,33%)。MS ES+m/z431[M+H]+。
实施例26
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮
使用4-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-3-(三氟甲基)吗啉,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(6mg,6%)。1H NMR(500MHz,甲醇-d4)δppm2.52-2.62(m,3H),3.50-3.69(m,2H),3.70-3.85(m,2H),4.04(dd,1H),4.30(d,1H),5.05-5.19(m,1H),6.34(m,2H),7.20(dd,1H),7.45(d,1H),8.04(s,1H),8.25(d,1H),8.30-8.40(m,1H)。MS ES+m/z 433[M+H]+。
实施例27
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮
使用4-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-3-(三氟甲基)吗啉和4-氯-N-苯基-嘧啶-2-胺,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(15mg,17%)。1H NMR(500MHz,DMSO-d6)δppm 3.33-3.38(m,1H),3.53-3.59(m,1H),3.77(br d,1H),4.00(br dd,2H),4.21(d,1H),5.29(br dd,1H),6.71(s,1H),6.96(s,1H),6.98-7.01(m,1H),7.32(t,2H),7.43(d,1H),7.84(d,2H),8.61(d,1H),9.72(s,1H),10.33-10.82(m,1H)。MS ES+m/z 418[M+H]+。
实施例28
1-[(4-氟苯基)甲基磺酰基]-3-(三氟甲基)哌嗪
将2-(三氟甲基)-哌嗪(2g,13mmol)和TEA(2.17ml,15.6mmol)溶解在DCM(30ml)中。在0℃,以小份添加(4-氟苯基)甲磺酰氯(2.71g,13mmol),并且将混合物在rt搅拌过夜。添加水(45ml)并且混合物用DCM(2×80mL)萃取。合并的有机物用盐水洗涤两次,经Na2SO4干燥,过滤并且浓缩,以给出作为固体的产物(3.5g,83%)。MS ES+m/z 327[M+H]+。
实施例29
1-(4-苄氧基-6-叔丁氧基-2-吡啶基)-4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪
将在无水脱气的1,4-二氧六环(50ml)中的1-[(4-氟苯基)甲基磺酰基]-3-(三氟甲基)哌嗪(1.2g,3.68mmol)、4-苄氧基-2-叔丁氧基-6-氯-吡啶(1.34g,4.6mmol)、Cs2CO3(2.4g,7.35mmol)、XantPhos(206mg,0.37mmol)和Pd(OAc)2(83mg,0.37mmol)的混合物在氩气下回流过夜。添加水并且混合物用EtOAc萃取。合并的有机物经Na2SO4干燥,过滤,浓缩并且在被庚烷中的0-100%EtOAc洗脱的硅胶柱上纯化,以给出产物(1.25g,58%)。MS ES+m/z582[M+H]+。
实施例30
2-叔丁氧基-6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]吡啶-4-醇
如实施例14中描述的来制备标题化合物,以给出产物(1.22g,96%)。MS ES+m/z492[M+H]+。
实施例31
[2-叔丁氧基-6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]三氟甲磺酸酯
如实施例15中描述的来制备标题化合物,以给出产物(700mg,45%)。MS ES+m/z624[M+H]+。
实施例32
1-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪
如实施例16中描述的来制备标题化合物,以给出产物(490mg,73%)。MS ES+m/z602[M+H]+。
实施例33
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮
使用1-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(14mg,14%)。1H NMR(500MHz,DMSO-d6)δppm 2.85-2.94(m,1H),3.15(br d,1H),3.13-3.14(m,1H),3.17-3.18(m,1H),3.22(br t,1H),3.27-3.31(m,1H),3.62(br d,1H),3.89(br d,1H),4.33(br d,1H),4.52(s,2H),5.57(br s,1H),6.31(s,1H),6.65(br s,1H),7.24(t,2H),7.32(dd,1H),7.48(dd,2H),7.62(br d,1H),8.04(s,1H),8.35(d,1H),8.39(d,1H),10.23(s,1H)。MS ES+m/z 604[M+H]+。
实施例34
1-乙基磺酰基-3-(三氟甲基)哌嗪
使用乙磺酰氯,如实施例28中描述的来制备标题化合物,以给出作为固体的产物(3g,98%)。MS ES+m/z 247[M+H]+。
实施例35
1-(4-苄氧基-6-叔丁氧基-2-吡啶基)-4-乙基磺酰基-2-(三氟甲基)哌嗪
使用1-乙基磺酰基-3-(三氟甲基)哌嗪,如实施例29中描述的来制备标题化合物,以给出作为固体的产物(2.53g,67%)。MS ES+m/z 502[M+H]+。
实施例36
2-叔丁氧基-6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]吡啶-4-醇
如实施例14中描述的来制备标题化合物,以给出产物(1.94g,85%)。MS ES+m/z412[M+H]+。
实施例37
[2-叔丁氧基-6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-吡啶基]三氟甲磺酸酯
如实施例15中描述的来制备标题化合物,以给出产物(1.56g,62%)。MS ES+m/z544[M+H]+。
实施例38
1-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-4-乙基磺酰基-2-(三氟甲基)哌嗪
如实施例16中描述的来制备标题化合物,以给出产物(1.2g,86%)。MS ES+m/z440[M+H]+(硼酸)。
实施例39
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮
使用1-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-4-乙基磺酰基-2-(三氟甲基)哌嗪,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(7mg,7%)。1H NMR(500MHz,DMSO-d6)δppm 1.24(t,3H),2.50(br s,3H),2.97-3.05(m,1H),3.13(q,2H),3.23-3.30(m,2H),3.67(br d,1H),3.95(br d,1H),4.36(br d,1H),5.63(br s,1H),6.31(s,1H),6.67(s,1H),7.33(dd,1H),7.63(d,1H),8.04(s,1H),8.35(d,1H),8.39(d,1H),10.23(s,1H),10.66(br s,1H)。MS ES+m/z524[M+H]+。
实施例40
4-[2-(噁唑-2-基氨基)-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮
使用4-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-3-(三氟甲基)吗啉和N-(4-氯-2-吡啶基)噁唑-2-胺,如实施例18中描述的来制备标题化合物(Tetrahedron Letters(2012),53,(24),3038-3043),以给出作为固体的产物(5mg,5%)。1H NMR(500MHz,DMSO-d6)δppm3.23-3.31(m,1H),3.40-3.57(m,1H),3.75(br d,1H),3.94-4.04(m,2H),4.19(d,1H),5.28-5.35(m,1H),6.27(s,1H),6.57(s,1H),7.05-7.10(m,1H),7.29(br d,1H),7.73(s,1H),8.28-8.35(m,2H),10.84(br s,2H)。MS ES+m/z 408[M+H]+。
实施例41
N-(4-氯-2-吡啶基)-2-甲基-噻唑-4-胺
将在1,4-二氧六环(30ml)中的4-溴-2-甲基-噻唑(1.5g,8.52mmol)、4-氯吡啶-2-胺(1.3g,10.22mmol)和Cs2CO3(6.92g,21.3mmol)的混合物用氮气脱气持续20min。添加Pd2(dba)3(0.389g,0.42mmol)和Xantphos(0.24g,0.42mmol),并且将产生的混合物在90℃搅拌持续16h。当冷却至rt时,将混合物通过硅藻土过滤,浓缩并且通过制备型HPLC纯化,以给出作为固体的产物(600mg,31%)。1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.15(d,1H),7.37(s,1H),7.03(d,1H),6.85-6.84(m,1H),2.61(s,3H)。MS ES+m/z 226[M+H]+。
实施例42
4-[2-[(2-甲基噻唑-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮
使用4-[6-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-2-吡啶基]-3-(三氟甲基)吗啉和N-(4-氯-2-吡啶基)-2-甲基-噻唑-4-胺,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(20mg,21%)。1H NMR(500MHz,DMSO-d6)δppm2.62-2.65(m,3H),3.32(br s,1H),3.54(td,1H),3.71-3.80(m,1H),3.93-4.05(m,2H),4.20(d,1H),5.30(br dd,1H),6.22(s,1H),6.53(s,1H),7.08(dd,1H),7.23(s,1H),7.43(s,1H),8.27(d,1H),10.00(s,1H),10.57(br s,1H)。MS ES+m/z 438[M+H]+。
实施例43
4-苄氧基-2-叔丁氧基-6-[2-(三氟甲基)苯基]吡啶
将4-苄氧基-2-叔丁氧基-6-氯-吡啶(1.46g,5mmol)、[2-(三氟甲基)苯基]硼酸(950mg,5mmol)、K2CO3(1.73g,12.5mmol)和PdCl2(dppf)(366mg,0.5mmol)溶解在1,4-二氧六环(25ml)和水(5ml)中,并且将产生的混合物在90℃搅拌持续2h。当冷却至rt时,混合物用水和EtOAc稀释。将有机层分离并且水层用EtOAc萃取。合并的有机物通过硅藻土过滤,经Na2SO4干燥,过滤,浓缩并且在被庚烷中的0-80%EtOAc洗脱的硅胶柱上纯化,以给出作为固体的产物(1.58g,79%)。MS ES+m/z 402[M+H]+。
实施例44
2-叔丁氧基-6-[2-(三氟甲基)苯基]吡啶-4-醇
如实施例14中描述的来制备标题化合物,以给出产物(948mg,72%)。MS ES+m/z312[M+H]+。
实施例45
[2-叔丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]三氟甲磺酸酯
如实施例15中描述的来制备标题化合物,以给出产物(720mg,54%)。MS ES+m/z388[M-tBu]+。
实施例46
2-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6-[2-(三氟甲基)苯基]吡啶
如实施例16中描述的来制备标题化合物,以给出产物(450mg,76%)。MS ES+m/z340[M+H]+(硼酸)。
实施例47
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
使用2-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6-[2-(三氟甲基)苯基]吡啶,如实施例18中描述的来制备标题化合物,以给出作为固体的产物(10mg,9%)。1H NMR(500MHz,DMSO-d6)δppm2.47(s,3H),6.46-6.63(m,1H),6.76-6.82(m,1H),7.30-7.37(m,1H),7.58-7.64(m,1H),7.65-7.68(m,1H),7.71-7.76(m,1H),7.78-7.84(m,1H),7.88-7.93(m,1H),8.03-8.10(m,1H),8.32-8.44(m,2H),10.18-10.31(m,1H),11.25-11.87(m,1H)。MS ES+m/z 424[M+H]+。
实施例48
4-氯-N-(2-甲基吡唑-3-基)吡啶-2-胺
使用2-甲基吡唑-3-胺和2-溴-4-氯-吡啶,如实施例41中描述的来制备标题化合物。在被DCM中的0-5%MeOH洗脱的硅胶柱上的纯化给出作为固体的产物(1.2g,定量的)。MSES+m/z 209[M+H]+。
实施例49
4-[2-叔丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-N-(2-甲基吡唑-3-基)吡啶-2-胺
将在1,4-二氧六环(2ml)和水(0.5ml)中的4-氯-N-(2-甲基吡唑-3-基)吡啶-2-胺(58mg,0.28mmol)、2-叔丁氧基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-6-[2-(三氟甲基)苯基]吡啶(117mg,0.28mmol)、K2CO3(77mg,0.56mmol)和PdCl2(dppf)(20mg,0.03mmol)的混合物加热并且在90℃搅拌持续6h。当冷却至rt时,混合物用水和EtOAc稀释。将有机层分离并且水层用EtOAc萃取。合并的有机物用盐水洗涤,经Na2SO4干燥,过滤,浓缩并且在被DCM中的0-6%MeOH洗脱的硅胶柱上纯化,以给出作为固体的产物(94mg,51%收率,70%纯度)。MS ES+m/z 468[M+H]+。
实施例50
4-[2-[(2-甲基吡唑-3-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
在0℃,将TFA(1.05ml,14.1mmol)添加至4-[2-叔丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-N-(2-甲基吡唑-3-基)吡啶-2-胺(94mg,0.14mmol,70%)在DCM(7ml)中的溶液,并且将产生的混合物在0℃搅拌持续1h。将混合物浓缩,用甲苯追赶(chase)并且通过制备型HPLC纯化,以给出作为固体的产物(11mg,19%)。1H NMR(500MHz,DMSO-d6)δppm 3.68(s,3H),6.28(d,1H),6.51(br s,1H),6.72(d,1H),7.02-7.11(m,2H),7.34(d,1H),7.65(d,1H),7.71-7.82(m,2H),7.89(d,1H),8.20(d,1H),8.93(s,1H),12.03(br s,1H)。MS ES+m/z412[M+H]+。
实施例51
N-[4-[2-叔丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-2-吡啶基]-2-甲基-噻唑-4-胺
使用N-(4-氯-2-吡啶基)-2-甲基-噻唑-4-胺,如实施例49中描述的来制备标题化合物,以给出作为固体的产物(145mg,60%收率,80%纯度)。MS ES+m/z 485[M+H]+。
实施例52
4-[2-[(2-甲基噻唑-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
如实施例50中描述的来制备标题化合物,以给出作为固体的产物(45mg,43%)。1HNMR(500MHz,DMSO-d6)δppm 2.53-2.65(m,3H),6.48(br s,1H),6.63-6.79(m,1H),7.08(dd,1H),7.26(s,1H),7.43(s,1H),7.66(d,1H),7.72-7.83(m,2H),7.90(d,1H),8.28(d,1H),10.05(s,1H),12.02(br s,1H)。MS ES+m/z 429[M+H]+。
实施例53
N-[4-(2-叔丁氧基-6-氯-4-吡啶基)-2-吡啶基]-2-甲基-嘧啶-4-胺
将在1,4-二氧六环(25ml)中的N-(4-氯-2-吡啶基)-2-甲基-嘧啶-4-胺(1.08g,4.89mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(1.55g,6.12mmol)、KOAc(961mg,9.79mmol)和PdCl2(dppf)(358mg,0.49mmol)的混合物在100℃搅拌过夜。当冷却至rt时,添加2-叔丁氧基-6-氯-4-碘-吡啶(Bioorganic&Medicinal Chemistry Letters(2012),22,(5),1940-1943,1.53g,4.89mmol)、K2CO3(1.35g,9.79mmol)、PdCl2(dppf)(179mg,0.25mmol)和水(6ml),并且将反应加热并且在85℃搅拌持续2h。当冷却至rt时,添加水(25ml)并且混合物用EtOAc萃取。合并的有机物经Na2SO4干燥,过滤,浓缩并且在被庚烷中的25%-100%EtOAc洗脱的硅胶柱上纯化,以给出作为固体的产物(1.61g,80%收率,90%纯度)。MS ES+m/z 370[M+H]+。
实施例54
N-[4-[2-叔丁氧基-6-(4-甲基-3-吡啶基)-4-吡啶基]-2-吡啶基]-2-甲基-嘧啶-4-胺
使用N-[4-(2-叔丁氧基-6-氯-4-吡啶基)-2-吡啶基]-2-甲基-嘧啶-4-胺和(4-甲基-3-吡啶基)硼酸(1.5当量),如实施例49中描述的来制备标题化合物,以给出作为固体的产物(75mg,70%)。MS ES+m/z 427[M+H]+。
实施例55
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮
如实施例50中描述的来制备标题化合物,以给出作为固体的产物(55mg,58%)。1HNMR(500MHz,DMSO-d6)δppm 2.36-2.41(m,3H),2.48-2.50(m,3H),6.62(br s,1H),6.74(brs,1H),7.37-7.42(m,2H),7.68(d,1H),8.05(s,1H),8.36(d,1H),8.40(d,1H),8.54(d,1H),8.57(s,1H),10.26(s,1H),12.06(br s,1H)。MS ES+m/z 371[M+H]+。
实施例56
N-[4-[2-叔丁氧基-6-[2-(三氟甲基)-3-吡啶基]-4-吡啶基]-2-吡啶基]-2-甲基-嘧啶-4-胺
使用N-[4-(2-叔丁氧基-6-氯-4-吡啶基)-2-吡啶基]-2-甲基-嘧啶-4-胺和[2-(三氟甲基)-3-吡啶基]硼酸(1.5当量),如实施例49中描述的来制备标题化合物,以给出作为固体的产物(110mg,92%)。MS ES+m/z 481[M+H]+。
实施例57
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮
如实施例50中描述的来制备标题化合物,以给出作为固体的产物(50mg,54%)。1HNMR(500MHz,DMSO-d6)δppm 2.46-2.49(m,3H),6.68(br s,1H),6.83(br s,1H),7.35(dd,1H),7.62(d,1H),7.87(dd,1H),8.07(s,1H),8.19(d,1H),8.36(d,1H),8.41(d,1H),8.88(d,1H),10.29(s,1H),11.71-12.58(m,1H)。MS ES+m/z 425[M+H]+。
实施例58
N-[4-[2-叔丁氧基-6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-吡啶基]-2-吡啶基]-2-甲基-嘧啶-4-胺
使用N-[4-(2-叔丁氧基-6-氯-4-吡啶基)-2-吡啶基]-2-甲基-嘧啶-4-胺和[1-乙基-3-(三氟甲基)吡唑-4-基]硼酸(1.2当量),如实施例49中描述的来制备标题化合物,以给出作为固体的产物(194mg,66%)。MS ES+m/z 498[M+H]+。
实施例59
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮
如实施例50中描述的来制备标题化合物,以给出作为固体的产物(2mg,1%)。1HNMR(500MHz,DMSO-d6)δppm 1.42-1.46(m,3H),2.48-2.49(m,3H),4.24-4.31(m,2H),6.65-6.67(m,1H),6.66-6.74(m,1H),7.26-7.31(m,1H),7.61-7.67(m,1H),7.97-8.02(m,1H),8.35(d,1H),8.38-8.41(m,1H),8.41-8.45(m,1H),8.43-8.43(m,1H),10.31-10.36(m,1H)。MS ES+m/z 442[M+H]+。
实施例60
4-氯-N-(1-甲基咪唑-4-基)吡啶-2-胺
使用1-甲基咪唑-4-胺和2,4-二氯吡啶并且将混合物在微波反应器中在160℃加热持续1h,如实施例41中描述的来制备标题化合物,以给出作为固体的产物(0.1g,12%)。1H NMR(400MHz,DMSO-d6)δ10.04(s,1H),8.59(s,1H),8.17(d,1H),7.48(s,1H),6.98-6.95(m,2H),3.80(s,3H)。MS ES+m/z 209[M+H]+。
实施例61
4-[2-叔丁氧基-6-[2-(三氟甲基)苯基]-4-吡啶基]-N-(1-甲基咪唑-4-基)吡啶-2-胺
使用4-氯-N-(1-甲基咪唑-4-基)吡啶-2-胺,如实施例49中描述的来制备标题化合物,以给出作为固体的产物(50mg,21%收率,80%纯度)。MS ES+m/z 468[M+H]+。
实施例62
4-[2-[(1-甲基咪唑-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮
如实施例50中描述的来制备标题化合物,以给出作为固体的产物(18mg,37%)。1HNMR(500MHz,DMSO-d6)δppm 3.63(s,3H),6.28-6.56(m,1H),6.67(br s,1H),6.93(d,1H),7.18(s,1H),7.28(d,1H),7.35(s,1H),7.65(d,1H),7.70-7.82(m,2H),7.89(d,1H),8.20(d,1H),9.27(s,1H),11.44-12.43(m,1H)。MS ES+m/z 412[M+H]+。
实施例63
6-(2-氯苯基)-4-羟基-1H-吡啶-2-酮
在氮气气氛下,在-78℃,将3-氧代丁酸乙酯(6.33ml,50mmol)逐滴地添加至60%NaH(1.92g,50mmol)在2-MeTHF(60ml)中的悬浮液。在5min之后,移除冷却浴,并且将混合物在rt搅拌持续20min。将混合物冷却回至-78℃,并且在20min内缓慢地添加1.6M n-BuLi(31.25ml,50mmol)。将产生的溶液在-78℃搅拌持续30min。将2-氯苯甲腈(6.88g,50mmol)作为固体一次性地添加,并且将反应混合物在解冻冷却浴(thawing cooling bath)上搅拌过夜。将混合物冷却至0℃并且缓慢地添加MeOH(15ml)。移除冷却浴,并且将混合物在rt搅拌持续30min并且然后再次冷却至0℃。混合物通过缓慢添加浓HCl来中和并且将产生的沉淀物过滤掉,用EtOH、戊烷洗涤并且干燥,以给出作为固体的产物(11.08g,87%)。MS ES+m/z 222[M+H]+。
实施例64
2,4-二氯-6-(2-氯苯基)吡啶
将6-(2-氯苯基)-4-羟基-1H-吡啶-2-酮(5g,22.56mmol)溶解在POCl3(40ml)中,并且缓慢地添加N,N-二甲基苯胺(5.5ml,43.4mmol)。将产生的混合物回流过夜。当冷却至rt时,将混合物倾倒入冰(600ml)上,并且在rt搅拌持续30min。将沉淀物过滤掉并且用水洗涤。将固体溶解在EtOAc(100ml)中,经Na2SO4干燥,过滤并且浓缩,以给出作为固体的产物(7g,83%)。MS ES+m/z 258[M+H]+。
实施例65
4-氯-6-(2-氯苯基)-1H-吡啶-2-酮
将2,4-二氯-6-(2-氯苯基)吡啶(5.7g,22.05mmol)和KOtBu(6.19g,55.12mmol)溶解在甲苯(75ml)中,并且将产生的混合物在100℃搅拌持续2h。当冷却至rt时,添加水(40ml)并且将有机层分离。使用浓HCl使得水层为略酸性并且用EtOAc(2×40ml)萃取。合并的有机物用盐水(50ml)洗涤,经Na2SO4干燥,过滤并且浓缩。将产生的残余物溶解在DCM(30ml)中并且添加TFA(5ml,67.3mmol)。将反应混合物在rt搅拌持续1h,浓缩并且将产生的残余物溶解在MeOH(25ml)中。添加30%NH4OH(20ml)和水(20ml),并且将混合物在rt搅拌过夜。将形成的沉淀物过滤掉,用水、EtOH、戊烷洗涤并且干燥,以给出作为固体的产物(4.13g,78%)。MS ES+m/z 240[M+H]+。
实施例66
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮
将在1,4-二氧六环(1.5ml)中的N-(4-氯-2-吡啶基)-2-甲基-嘧啶-4-胺(132mg,0.6mmol)、4,4,5,5-四甲基-2-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1,3,2-二氧杂环戊硼烷(190mg,0.75mmol)和PdCl2(dppf)(22mg,0.06mmol)的混合物在密封管中在100℃搅拌持续15h。当冷却至rt时,添加4-氯-6-(2-氯苯基)-1H-吡啶-2-酮(144mg,0.6mmol)、K2CO3(83mg,0.6mmol)、PdCl2(dppf)(11mg,0.03mmol)、1,4-二氧六环(1ml)和水(0.5ml),并且将产生的混合物用氩气冲洗,加热并且在85℃搅拌持续2h。当冷却至rt时,添加水(25ml)并且混合物用DCM萃取。合并的有机物经Na2SO4干燥,过滤,浓缩并且通过制备型HPLC纯化,以给出作为固体的产物(20mg,9%)。1H NMR(500MHz,DMSO-d6)δppm 2.48-2.50(m,3H),6.66(br s,1H),6.74(s,1H),7.37(dd,1H),7.46-7.56(m,2H),7.59-7.68(m,3H),8.05(s,1H),8.36(d,1H),8.40(d,1H),10.27(s,1H),11.57-12.34(m,1H)。MS ES+m/z 390[M+H]+。
实施例67
使用起始材料的合适的变化,以及如有必要反应条件的定制等来合成以下化合物:
6-(3-环丙基吗啉-4-基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
实施例68
Vps34生物化学测定
在DMSO中以最终测定浓度的100倍制备本发明的化合物的稀释系列(在10个点中,n1=n0/3)。将化合物在测定缓冲液中进一步稀释成测定浓度的4倍(Life technologies缓冲液Q,PV5125,稀释5倍,用2mM DTT和2mM MnCl2补充)。将2.5μL的稀释的化合物添加至384孔测定板,随后是2.5μL的16.5nM Vps34酶(Life technologies,PV5126)。将酶和化合物在rt预孵育持续15min。然后,将包含测定缓冲液中20μM ATP(Life technologies,PV3227)和200μM PI:PS底物(Life technologies,PV5122)的5μL的底物混合物添加至包含化合物和酶的孔。通过移液若干次进行混合。将反应在室温孵育持续1h。然后添加如在Adapta激酶测定试剂盒说明书(Life technologies,PV5099)中描述制备的包含TR-FRET缓冲液中AdaptaEu-抗-ADP抗体(2.3nM)、Alexa Fluor 647ADP示踪剂(9nM)和EDTA(30mM)的5μL的停止检测混合物(stop-detection mix),以猝灭反应。通过移液若干次进行混合。然后,将测定板在室温孵育持续30min,并且用Artemis微量板读取器(Artemis micro plate reader)读取。计算与DMSO处理的对照样品相比的化合物百分比抑制。通过使用Dotmatics软件,将化合物浓度相对于百分比抑制拟合,以产生IC50值。
实施例化合物有效地抑制Vps34,并且测定的结果在表1中示出(中值IC50 nMAdapta)。
表1.Vps34测定的中值IC50值
实施例69
高含量筛选自噬测定(High Content Screening Autophagy assay)
稳定地表达绿色荧光蛋白(GFP)标记的LC3(GFP-LC3)的人类骨肉瘤细胞(HOS)被用于确定专有化合物的对于自噬的抑制作用。为了该目的,在5nM的巴佛洛霉素A1(Sigma-Aldrich)的存在下,通过使用500nM的mTOR抑制剂KU-0063794来激活自噬。立刻地,将细胞在处于DMEM–High修饰的培养基(Hi-Clone Cat#SH30285.01)中的透明底部96孔板中铺板过夜。在实验开始时,移除培养基,并且用包含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代替。在6小时之后,移除培养基,细胞用冰冷的磷酸盐缓冲盐水(PBS)洗涤两次,并且在室温用4%多聚甲醛固定持续20分钟。然后,在添加在PBS中以1μg/ml的Hoechst 33342用于核染色之前,将细胞用冰冷的PBS洗涤两次。在4℃孵育过夜之后,将细胞用PBS洗涤一次以移除过量的染料,并且将100μl的PBS添加至每个孔。使用ImageXpress自动显微镜(Molecular Devices Inc.)以20×放大率获取图像,每孔6张图像,并且用MetaXpress软件分析以确定LC3-GFP焦点(foci)。每细胞焦点面积的值被用于产生剂量应答曲线,并且使用GraphPad Prism软件中的非线性拟合分析来计算IC50值。
测试的实施例化合物有效地抑制HOS细胞中的自噬。测定的结果在表2中示出(中值IC50μM HOS-LC3)。
表2.Vps34测定和HOS细胞测定中的自噬的中值IC50值。
Claims (52)
1.一种式(I)的化合物
其中
R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氨基、N-C1-C3烷基氨基以及N,N-二C1-C3烷基氨基;
R2选自氢、C1-C3卤代烷基以及C1-C3烷基;
R3选自A、苯基以及单环杂芳基,所述苯基和所述杂芳基各自任选地被R4、R5、R6和R7中的一个或更多个取代;
R4、R5、R6和R7独立地选自卤素、C1-C6烷基、C3-C4环烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、氮杂环丁烷、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基、NHSO2R8、SO2R9以及羟基;
R8是C1-C3卤代烷基或C1-C3烷基;
R9选自R10、C1-C6烷基、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及C1-C3烷氧基C1-C3烷基,其中所述C1-C6烷基和所述C1-C3烷氧基C1-C3烷基各自任选地被一个R10和/或一个或更多个卤素取代;
R10选自苯基、苄基、单环杂芳基、C3-C6环烷基、杂环基,各自任选地被一个或更多个R11取代;
R11选自卤素、C1-C3卤代烷基、C3-C4环烷基、C1-C3烷基、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及C1-C3烷氧基C1-C3烷基;
A是
R12选自氢、卤素、COR13、C1-C6烷基、C3-C6环烷基、C1-C3烷氧基C1-C3烷基、C1-C6烷氧基、C3-C6环烷基、C1-C3氰基烷基以及C1-C3卤代烷基;
R13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-哌啶基以及1-氮杂环丁基;
Y选自CH2、S、SO、SO2、NR14、NCOR9、NCOOR15、NSO2R9、NCOCH2R9、O或键;
R14选自H、C1-C3卤代烷基、C1-C3烷氧基C1-C3烷基、C1-C3烷基以及C3-C6环烷基;
R15选自R10、C1-C6烷基以及C1-C3烷氧基C1-C3烷基,并且其中所述C1-C6烷基和所述C1-C3烷氧基C1-C3烷基各自任选地被一个R10和/或一个或更多个卤素取代;并且
Z是CH或N;
或其药学上可接受的盐。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中R2是氢或C1-C3烷基。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐,其中R2是氢。
4.根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氨基、-N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及卤素。
5.根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:C1-C6烷基、C3-C4环烷基以及卤素。
10.根据权利要求1至9中任一项所述的化合物或其药学上可接受的盐,其中R1选自苯基、嘧啶基、噁唑基、咪唑基、吡唑基以及噻唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基以及C1-C6卤代烷基。
11.根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐,其中R3选自A、苯基、吡啶基、噻吩基、呋喃基、嘧啶基以及吡唑基,各自任选地并且独立地被一个或更多个R4或R5取代。
12.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R3选自A、苯基以及吡啶基,各自任选地并且独立地被一个或更多个R4或R5取代。
13.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R3选自苯基、吡啶基、吗啉基、哌啶基、吡咯烷基、噻吩基以及哌嗪基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
14.根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐,其中R4、R5、R6和R7独立地选自氟、氯、C1-C3烷基、C1-C3氟烷基、环丙基以及SO2R9。
15.根据权利要求1至7中任一项或权利要求11至12中任一项所述的化合物或其药学上可接受的盐,其中Y选自CH2、O以及键。
16.根据权利要求1至6中任一项或权利要求11所述的化合物或其药学上可接受的盐,其中R12选自氢、CON(CH3)2、C1-C3烷基、CF3以及环丙基。
17.根据权利要求1至6中任一项、权利要求11至12中任一项或权利要求14所述的化合物或其药学上可接受的盐,其中R9选自R10、N,N-二C1-C3烷基氨基以及甲氧基C1-C3烷基,所述C1-C3烷基任选地被一个R10取代。
18.根据权利要求1至6中任一项或权利要求11、权利要求12、权利要求14或权利要求17所述的化合物或其药学上可接受的盐,其中R10选自苯基、苄基、吡啶基、咪唑基、异噁唑基、噁唑基、环丙基、环戊基、吡咯烷基以及四氢呋喃基,各自任选地被一个或更多个甲基和/或氟取代。
19.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R3选自苯基、吡啶基、吡咯烷基以及噻吩基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;并且
R12是C1-C6烷基或C1-C6卤代烷基。
20.根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C3-C4环烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、氨基、N-C1-C3烷基氨基、N,N-二C1-C3烷基氨基以及卤素;
R2是氢;并且
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
21.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;并且
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基。
22.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1选自苯基、嘧啶基、噁唑基、咪唑基或噻唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3选自苯基、吡啶基、吡唑基、吡咯烷基以及噻吩基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基、C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;并且
R12是C1-C6烷基或C1-C6卤代烷基。
23.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1选自苯基、4-嘧啶基、2-甲基嘧啶-4-基、2-环丙基-嘧啶-4-基、2-噁唑基、1-甲基-咪唑-4-基、2-甲基-噻唑-4-基、3,5-二氟苯基以及2-甲基吡唑-3-基;
R2是氢;并且
R3选自2-氯苯基、3-吡啶基、4-吡啶基、4-吗啉基、3-(三氟甲基)吗啉-4-基、2-(三氟甲基)-哌啶-1-基、2-(三氟甲基)苯基、4-甲基-吡啶-3-基、2-(三氟甲基)-吡啶-3-基、1-乙基-3-(三氟甲基)吡唑-4-基、3-环丙基-吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)-吡咯烷-1-基、2-氯-5-氟苯基、3-(三氟甲基)-吡唑啉-4-基、2-(三氟甲基)-吡啶-3-基、3-甲基-噻吩-4-基、2-甲基苯基、1-乙酰基-3-三氟甲基-哌嗪-4-基、2-甲基-哌啶-1-基、2-环丙基-哌啶-1-基、2-甲基-吗啉-4-基、2-三氟甲基-吗啉-4-基以及2-环丙基-吗啉-4-基。
24.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3是苯基或单环5元-6元杂芳基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;并且
Z是CH或N。
25.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或嘧啶基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基或C3-C4环烷基;
R2是氢;
R3选自苯基、吡啶基以及吡唑基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;
R12是C1-C6烷基或C1-C6卤代烷基;并且
Z是CH或N。
26.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基、3,5-二氟苯基或2-甲基嘧啶-4-基;
R2是氢;
R3选自2-氯苯基、3-吡啶基、4-吡啶基、1-吗啉基、2-(三氟甲基)-1-哌啶基、3-(三氟甲基)吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)苯基、4-甲基-3-吡啶基、2-(三氟甲基)-3-吡啶基、1-乙基-3-(三氟甲基)吡唑-4-基以及3-环丙基吗啉-4-基;并且
Z是CH或N。
27.根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐,其中R1是苯基或嘧啶基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;
R2是氢;
R3选自苯基或吡啶基,各自任选地被一个或更多个选自以下的取代基取代:卤素、C1-C6烷基、C1-C6卤代烷基以及C3-C4环烷基;或R3是A;
Y是CH2、O、NSO2-C1-C6烷基或NSO2-苄基,其中所述苄基任选地被一个或更多个卤素取代;
R12是C1-C6烷基或C1-C6卤代烷基;并且
Z是CH或N。
28.根据权利要求1所述的化合物或其药学上可接受的盐,其中R1是苯基、2-甲基嘧啶-4-基、噁唑-2-基、2-甲基噻唑-4-基、2-甲基吡唑-3-基以及1-甲基咪唑-4-基;
R2是氢;
R3选自2-氯苯基、3-吡啶基、4-吡啶基、1-吗啉基、2-(三氟甲基)-1-哌啶基、3-(三氟甲基)吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基、4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基、2-(三氟甲基)苯基、4-甲基-吡啶-3-基、2-(三氟甲基)-吡啶-3-基以及1-乙基-3-(三氟甲基)吡唑-4-基;并且
Z是CH或N。
29.根据权利要求1所述的化合物或其药学上可接受的盐,其中R1是苯基或2-甲基嘧啶-4-基;
R2是氢;
R3选自2-氯苯基、3-吡啶基、4-吡啶基、1-吗啉基、2-(三氟甲基)-1-哌啶基、3-(三氟甲基)吗啉-4-基、4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基以及4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基;并且
Z是CH或N。
30.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物选自
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-(噁唑-2-基氨基)-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-[2-[(2-甲基噻唑-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
4-[2-[(2-甲基吡唑-3-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
4-[2-[(2-甲基噻唑-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮;
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(1-甲基咪唑-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;以及
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
31.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物选自
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮;
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;以及
6-(3-环丙基吗啉-4-基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
32.根据权利要求1所述的化合物或其药学上可接受的盐,其中所述化合物选自
4-(2-苯氨基嘧啶-4-基)-6-(2-氯苯基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(3-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-(4-吡啶基)-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-吗啉代-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[2-(三氟甲基)-1-哌啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
4-(2-苯氨基嘧啶-4-基)-6-[3-(三氟甲基)吗啉-4-基]-1H-吡啶-2-酮;
6-[4-[(4-氟苯基)甲基磺酰基]-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
6-[4-乙基磺酰基-2-(三氟甲基)哌嗪-1-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)苯基]-1H-吡啶-2-酮;
6-(4-甲基-3-吡啶基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;
4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-6-[2-(三氟甲基)-3-吡啶基]-1H-吡啶-2-酮;
6-[1-乙基-3-(三氟甲基)吡唑-4-基]-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮;以及
6-(2-氯苯基)-4-[2-[(2-甲基嘧啶-4-基)氨基]-4-吡啶基]-1H-吡啶-2-酮。
33.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗或预防疾病。
34.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗癌症。
35.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗癌症,其中所述癌症选自乳腺癌例如三阴性乳腺癌、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤。
36.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗缺氧性肿瘤。
37.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗癌症,其中所述癌症的治疗还包括放射疗法。
38.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗II型糖尿病。
39.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐,用于治疗疾病,所述疾病选自炎性疾病、神经退行性紊乱、心血管紊乱、自身免疫疾病以及病毒感染。
40.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途。
41.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐在制备用于治疗癌症的药物中的用途,其中所述癌症选自乳腺癌例如三阴性乳腺癌、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤。
42.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐在制备用于治疗缺氧性肿瘤的药物中的用途。
43.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐在制备用于治疗II型糖尿病的药物中的用途。
44.根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐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、自身免疫疾病以及病毒感染。
45.一种治疗癌症的方法,包括将治疗有效量的根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐施用至有相应需要的患者。
46.根据权利要求45所述的方法,其中所述癌症选自乳腺癌例如三阴性乳腺癌、膀胱癌、肝癌、***、胰腺癌、白血病、淋巴瘤、肾癌、结肠癌、神经胶质瘤、***癌、卵巢癌、黑色素瘤和肺癌以及缺氧性肿瘤。
47.根据权利要求45所述的方法,结合放射疗法。
48.一种治疗缺氧性肿瘤的方法,包括将治疗有效量的根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐施用至有相应需要的患者。
49.一种治疗II型糖尿病的方法,包括将治疗有效量的根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐施用至有相应需要的患者。
50.一种治疗疾病的方法,所述疾病选自炎性疾病、神经退行性紊乱、自身免疫疾病以及病毒感染,所述方法包括将治疗有效量的根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐施用至有相应需要的患者。
51.一种药物组合物,包含根据权利要求1至32中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的稀释剂、载体和/或赋形剂。
52.一种药物组合物,包含治疗有效量的根据权利要求1所述的化合物或其药学上可接受的盐以及另一种抗癌剂,所述抗癌剂选自烷基化剂、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、干扰素以及生物应答修饰剂。
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