CN110603254A - 被取代的吡唑化合物以及使用其治疗过度增生性疾病的方法 - Google Patents
被取代的吡唑化合物以及使用其治疗过度增生性疾病的方法 Download PDFInfo
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- CN110603254A CN110603254A CN201780084999.4A CN201780084999A CN110603254A CN 110603254 A CN110603254 A CN 110603254A CN 201780084999 A CN201780084999 A CN 201780084999A CN 110603254 A CN110603254 A CN 110603254A
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- Prior art keywords
- methyl
- pyrazole
- optionally substituted
- thiazol
- carboxylic acid
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- UZZCSVANJZROOJ-UHFFFAOYSA-N methyl 2-[5-(3,4-dichlorophenyl)-1-(2-methylpropyl)-1,2,4-triazol-3-yl]-4-iodo-5-methylpyrazole-3-carboxylate Chemical compound ClC=1C=C(C=CC=1Cl)C1=NC(=NN1CC(C)C)N1N=C(C(=C1C(=O)OC)I)C UZZCSVANJZROOJ-UHFFFAOYSA-N 0.000 description 1
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- FXJWKBXZBSCNKY-UHFFFAOYSA-N methyl 2-[5-butan-2-ylsulfanyl-4-(3,4-dichlorophenyl)-1,3-thiazol-2-yl]-4-(2,6-dimethylpyridin-4-yl)-5-methylpyrazole-3-carboxylate Chemical compound C(C)(CC)SC1=C(N=C(S1)N1N=C(C(=C1C(=O)OC)C1=CC(=NC(=C1)C)C)C)C1=CC(=C(C=C1)Cl)Cl FXJWKBXZBSCNKY-UHFFFAOYSA-N 0.000 description 1
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- WICGATIORFSOJL-UHFFFAOYSA-N methyl 3,4-dichlorobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C(Cl)=C1 WICGATIORFSOJL-UHFFFAOYSA-N 0.000 description 1
- ZRXPLUYQNSLBSB-UHFFFAOYSA-N methyl 4-(3-fluorophenyl)-5-methyl-2-[4-(2-methylprop-1-enyl)-5-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound FC=1C=C(C=CC=1)C=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C=C(C)C)C1=CC=C(C=C1)C(F)(F)F)C ZRXPLUYQNSLBSB-UHFFFAOYSA-N 0.000 description 1
- WZXVKCJYFVZDCT-UHFFFAOYSA-N methyl 4-(3-fluorophenyl)-5-methyl-2-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound FC=1C=C(C=CC=1)C=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C1=CC=C(C=C1)C=1OC(=NN=1)C)SC(C)C)C WZXVKCJYFVZDCT-UHFFFAOYSA-N 0.000 description 1
- GQXIXMKIUSLAIB-UHFFFAOYSA-N methyl 4-(3-fluorophenyl)-5-methyl-2-[5-(2-methylprop-1-enyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound FC=1C=C(C=CC=1)C=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C1=CC=C(C=C1)C(F)(F)F)C=C(C)C)C GQXIXMKIUSLAIB-UHFFFAOYSA-N 0.000 description 1
- JBCGOVLRTBXHBN-UHFFFAOYSA-N methyl 4-(3-fluorophenyl)-5-methyl-2-[5-[3-[(2-methylpropan-2-yl)oxy]-3-oxoprop-1-enyl]-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound C(C)(C)(C)OC(C=CC1=C(N=C(S1)N1N=C(C(=C1C(=O)OC)C1=CC(=CC=C1)F)C)C1=CC=C(C=C1)C(F)(F)F)=O JBCGOVLRTBXHBN-UHFFFAOYSA-N 0.000 description 1
- CGWTUWSVVLDFEO-UHFFFAOYSA-N methyl 4-bromo-2-[4-(4,4-difluoropiperidin-1-yl)-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl]-5-methylpyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)N1CCC(CC1)(F)F)SC(C)C)C CGWTUWSVVLDFEO-UHFFFAOYSA-N 0.000 description 1
- SUHOGTYGAWRVDZ-UHFFFAOYSA-N methyl 4-bromo-2-[4-(4,4-dimethylcyclohexen-1-yl)-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl]-5-methylpyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C1=CCC(CC1)(C)C)SC(C)C)C SUHOGTYGAWRVDZ-UHFFFAOYSA-N 0.000 description 1
- ILVRRIRLMZKBIT-UHFFFAOYSA-N methyl 4-bromo-2-[4-(4-cyanopiperidin-1-yl)-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl]-5-methylpyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)N1CCC(CC1)C#N)SC(C)C)C ILVRRIRLMZKBIT-UHFFFAOYSA-N 0.000 description 1
- SCWMYYVSNAFBAH-UHFFFAOYSA-N methyl 4-bromo-2-[4-(4-cyclopropylpiperazin-1-yl)-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl]-5-methylpyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)N1CCN(CC1)C1CC1)SC(C)C)C SCWMYYVSNAFBAH-UHFFFAOYSA-N 0.000 description 1
- GIWGELKZUXJLPW-UHFFFAOYSA-N methyl 4-bromo-5-methoxy-2-[5-propan-2-ylsulfanyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C1=CC=C(C=C1)C(F)(F)F)SC(C)C)OC GIWGELKZUXJLPW-UHFFFAOYSA-N 0.000 description 1
- NIFMYSKKKXTTIY-UHFFFAOYSA-N methyl 4-bromo-5-methyl-2-(4-morpholin-4-yl-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl)pyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)N1CCOCC1)SC(C)C)C NIFMYSKKKXTTIY-UHFFFAOYSA-N 0.000 description 1
- RHVUZFUEXICSRV-UHFFFAOYSA-N methyl 4-bromo-5-methyl-2-[4-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]-5-propan-2-ylsulfanyl-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C1=CC=C(C=C1)C=1OC(=NN=1)C)SC(C)C)C RHVUZFUEXICSRV-UHFFFAOYSA-N 0.000 description 1
- UCGHFPSJJAEOHR-UHFFFAOYSA-N methyl 4-bromo-5-methyl-2-[5-[4-(trifluoromethyl)phenyl]-4-[4-(trifluoromethyl)piperidin-1-yl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)N1CCC(CC1)C(F)(F)F)C1=CC=C(C=C1)C(F)(F)F)C UCGHFPSJJAEOHR-UHFFFAOYSA-N 0.000 description 1
- PXUOCQHFYGTEOT-UHFFFAOYSA-N methyl 4-bromo-5-methyl-2-[5-propan-2-ylsulfanyl-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)N1CCN(CC1)CC(F)(F)F)SC(C)C)C PXUOCQHFYGTEOT-UHFFFAOYSA-N 0.000 description 1
- LDFMMTSQFOBWCJ-UHFFFAOYSA-N methyl 4-bromo-5-methyl-2-[5-propan-2-ylsulfanyl-4-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound BrC=1C(=NN(C=1C(=O)OC)C=1SC(=C(N=1)C1=CCC(CC1)C(F)(F)F)SC(C)C)C LDFMMTSQFOBWCJ-UHFFFAOYSA-N 0.000 description 1
- LKDAIHSMPLZCDW-UHFFFAOYSA-N methyl 5-acetyloxy-4-bromo-2-[5-propan-2-ylsulfanyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound C(C)(=O)OC1=NN(C(=C1Br)C(=O)OC)C=1SC(=C(N=1)C1=CC=C(C=C1)C(F)(F)F)SC(C)C LKDAIHSMPLZCDW-UHFFFAOYSA-N 0.000 description 1
- SRGCCTKUCZZWLT-UHFFFAOYSA-N methyl 5-methoxy-2-[5-propan-2-ylsulfanyl-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound C(C)(C)SC1=C(N=C(S1)N1N=C(C=C1C(=O)OC)OC)C1=CC=C(C=C1)C(F)(F)F SRGCCTKUCZZWLT-UHFFFAOYSA-N 0.000 description 1
- LXFDTMZIKBSCEK-UHFFFAOYSA-N methyl 5-methyl-2-[5-(2-methylprop-1-enyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]pyrazole-3-carboxylate Chemical compound CC1=NN(C(=C1)C(=O)OC)C=1SC(=C(N=1)C1=CC=C(C=C1)C(F)(F)F)C=C(C)C LXFDTMZIKBSCEK-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/08—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
公开了可用于例如治疗过度增生性病症如癌症的方法、停滞癌细胞中的细胞周期的方法、抑制癌细胞中谷胱甘肽合成的方法中的化合物,以及供使用的相关化合物和其在药剂中的用途。在某些实施例中,所述方法、用途和化合物是参照具有结构式(Ia)、(Ib)、(Ic)、(Id)和(Ie)的化合物提供,其中R1、L1、L2、Q、L3、R3、L4、R4、L5以及R5如本文中所描述。在某些实施例中,本文所公开的化合物针对具有突变型KRAS基因的癌症尤为有效。
Description
相关申请的交叉引用
本申请要求2016年11月30日提交的美国临时专利申请第62/428,271号的优先权益,该案特此以全文引用的方式并入本文中。
技术领域
本公开涉及化合物、包括所述化合物的药物组合物以及使用所述化合物和组合物的方法的领域。更确切地说,本公开涉及使用某些化合物治疗过度增生性病症如癌症的方法。
背景技术
癌症是不受控制的细胞增殖,是以肿瘤形成、生长且在一些情况下转移为特征的多因素疾病。在美国,本年度将有超过150万人被诊断患有癌症,并且超过500,000人将死于癌症。总体而言,估计每三人中就有至少一人在其一生中会发展某种形式的癌症。存在超过200种不同组织病理学类型的癌症,且在美国,乳癌、肺癌、结肠直肠癌和前列腺癌占全部新增病例的一半以上。当前的癌症疗法取决于癌症的位置和分期而变化,但一般包含手术、全身疗法、放射疗法和化学疗法的组合。尽管已经付出大量努力来开发抗癌策略,但其中有许多仍对特定癌症无效。
表示癌症本质的不受控制的细胞增殖不仅涉及对细胞增殖的控制失调,而且还涉及能量代谢的相应调整以便促进细胞生长和分裂。细胞代谢重编程正成为癌细胞的重要分子标志。在有氧条件下,正常细胞加工葡萄糖,先在细胞溶质中通过糖酵解将葡萄糖转化成丙酮酸,且随后在线粒体中转化成二氧化碳;在厌氧条件下,对糖酵解是有利的,并且相对较少的丙酮酸被分配到耗氧线粒体中。当有丰富的生长因子和养分时,致癌信号传导路径引导代谢增强,使得大分子如脂质、蛋白质和核酸的合成增加。净效应是细胞生长和增殖的支持。然而,在肿瘤形成期间,存在恶劣的、缺氧且缺乏养分的环境,由此激发细胞和其维持代谢动态平衡的能力。癌细胞可以通过限制其进行糖酵解的大部分能量代谢对其葡萄糖代谢,并因此对其能量制造重编程,而该重编程被早期生物化学家视为原始且效率低下的。尽管有这些早期信念,但癌细胞的代谢特征不是对受损线粒体被动反应,而是支持合成代谢生长所需的癌基因引导的代谢重编程的结果。允许增加且更高效地利用稀缺养分的癌基因突变是癌症治疗的独特目标。
发明内容
在一方面,本公开提供具有结构式(Ia)-(Ie)中的任一个的化合物:
所述化合物任选地呈药学上可接受的盐或N-氧化物,和/或溶剂化物或水合物形式,其中
L1选自由以下组成的组:化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-C(O)NR6-、-NR6C(O)-、-C(S)NR6-、-NR6C(S)-、-C(O)O-、-OC(O)-、-C(O)S-、-SC(O)-、-C(S)O-、-OC(S)-、-C(S)S-、-SC(S)-、-S(O)1-2O-、-OS(O)1-2-、-S(O)1-2NR6-和-NR6S(O)1-2-;
R1选自由以下组成的组:
氢,
C1-C8烷基、C1-C8烯基和C1-C8炔基,其各自未被取代或被氟代,
环烷基和杂环烷基,其各自任选地被1-2个R1E取代,以及
苯基和单环杂芳基,其各自任选地被1-5个R1E取代,
其中
各R1E独立地选自氧代;任选被取代的C1-C4烷基;C1-C4氟烷基;卤素;-CN;SF5;-N3;-C(O)R1F;-SR1F;-S(O)1-2R1F;-OR1F;-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;-C(O)NR1G(CH2CH2O)nR1G;-NR1GR1F;和-C(O)R1F;
各R1F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R1G独立地选自H和C1-C3烷基;
L2选自由以下组成的组:化学键、-CH2-、-CH(CH3)-或-CH2CH2-;
Q选自由以下组成的组:H、-CH2OH、-C(O)OH、-C(O)OR2A、-C(O)NR2BR2A、-C(O)NR2BS(O)2R2A、-C(O)NR2BS(O)2NR2BR2A、-C(O)R2A、-S(O)2OH、-P(O)(OH)2、-C(OH)(CF3)2、S(O)2R2A、-N(R2B)S(O)2R2A、-S(O)2NR2BR2A、-C(O)NHOH、-C(O)NH-O(C1-C3烷基)和-CO(NH)CN,其中
各R2A独立地选自H和C1-C3烷基,并且
各R2B独立地选自H和C1-C3烷基;
L3是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;
R3是芳基或杂芳基,其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代,
其中
各L3C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R3D独立地选自氧代任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R3E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F、-NR3GS(O)1-2R3F;
各R3F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R3G独立地选自H和C1-C3烷基、C1-C3氟烷基;
L4选自由以下组成的组:化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-C(O)NR6-、-NR6C(O)-、-C(S)NR6-、-NR6C(S)-、-C(O)O-、-OC(O)-、-C(O)S-、-SC(O)-、-C(S)O-、-OC(S)-、-C(S)S-、-SC(S)-、-S(O)1-2O-、-OS(O)1-2-、-S(O)1-2NR6-和-NR6S(O)1-2-;
R4选自由以下组成的组:氢、任选被取代的C1-C8烷基、任选被取代的C1-C8烯基和任选被取代的C1-C8炔基;
L5是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2CH2-、-CH=CH-、-C≡C-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;并且
R5是芳基、杂芳基、环烷基或杂环烷基,其各自(i)任选地被选自以下的单一取代基取代:-L5C-(任选地被1-5个R5D取代的苯基)、-L5C-(任选地被1-5个R5D取代的单环杂芳基)和-L5C-(任选地被1-5个R5D取代的单环环烷基)、-L5C-(任选地被1-5个R5D取代的单环杂环烷基)并且(ii)任选地被1-5个R5E取代,
其中
各L5C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R5D独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R5E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、-SF5、-N3、-C(O)R5F、-SR5F、-S(O)1-2R5F、-OR5F、-NR5GR5F、-C(O)R5F、-C(O)NR5GR5F、-NR5GC(O)R5F、-C(S)NR5GR5F、-NR1GC(S)R5F、-C(O)OR5F、-OC(O)R5F、-C(O)SR5F、-SC(O)R5F、-C(S)OR5F、-OC(S)R5F、-C(S)SR5F、-SC(S)R5F、-S(O)1-2OR5F、-OS(O)1-2R5F、-S(O)1-2NR5GR5F和-NR5GS(O)1-2R5F;
各R5F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R5G独立地选自H和C1-C3烷基;
其中
各R6选自由以下组成的组:氢、C1-C3烷基和-C(O)(C1-C3烷基);
各任选被取代的烷基、烯基和炔基未被取代、被氟代或被一个或两个羟基取代;
各环烷基具有3-10个环碳并且是不饱和或部分不饱和的,并且任选地包含一个或两个稠合环烷基环,各稠合环具有3-8个环成员;
各杂环烷基具有3-10个环成员和1-3个独立地选自氮、氧和硫的杂原子并且是不饱和或部分不饱和的,并且任选地包含一个或两个稠合环烷基环,其各自具有3-8个环成员;
各芳基是苯基或萘基,并且任选地包含一个或两个稠合环烷基或杂环烷基环,各稠合环烷基或杂环烷基环具有4-8个环成员;
各杂芳基是具有1-4个独立地选自氮、氧和硫的杂原子的5-6元单环杂芳基环,或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳基,并且任选地包含一个或两个稠合环烷基或杂环烷基环,各稠合环烷基或杂环烷基环具有4-8个环成员。
在某些此类实施例中,每个任选被取代的烷基、亚烷基、烯基、亚烯基、炔基和亚炔基是未被取代的或被氟代的。例如,在某些此类实施例中,每个任选被取代的烷基、亚烷基、烯基、亚烯基、炔基和亚炔基是未被取代的。
另一方面,本公开提供包括如本文所描述的化合物的药物组合物。
另一方面,本公开提供一种用于治疗有需要受试者的过度增生性病症如癌症的方法。所述方法包含向所述受试者施用有效量的如本文所描述的化合物。
另一方面,本公开提供如本文所描述化合物,其用于治疗过度增生性病症,如癌症。
另一方面,本公开提供如本文所描述的化合物的用途,所述化合物是用于制备供治疗过度增生性病症如癌症用的药剂。
在本公开各种方面的某些实施例中,所述过度增生性病症是造血系统癌症。在本公开的某些替代性实施例中,所述过度增生性病症是实体肿瘤。
在本公开各种方面的某些实施例中,所述过度增生性病症是具有突变型KRAS基因,例如杂合突变型KRAS基因的癌症(例如实体肿瘤如结肠直肠癌、肺癌或胰腺癌)。
本公开另一方面提供一种用于抑制癌细胞中的细胞周期进程的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。在某些此类实施例中,所述癌细胞是造血系统癌细胞。在其它此类实施例中,所述癌细胞是实体肿瘤(例如胰腺癌、肺癌或结肠直肠癌)的癌细胞。在某些此类实施例中,所述癌细胞具有杂合突变型KRAS基因。细胞周期进程可以例如在G0/G1期被抑制。
本公开另一方面提供一种用于诱导癌细胞凋亡的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。在某些此类实施例中,所述癌细胞是造血系统癌细胞。
本公开另一方面提供一种用于诱导针对癌细胞的细胞毒性作用的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。在某些此类实施例中,所述癌细胞是造血系统癌细胞。在其它此类实施例中,所述癌细胞是实体肿瘤(例如胰腺癌、肺癌或结肠直肠癌)的癌细胞。在某些此类实施例中,所述癌细胞具有杂合突变型KRAS基因。
本公开另一方面提供一种用于抑制癌细胞中谷胱甘肽合成的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。在某些此类实施例中,所述癌细胞是造血系统癌细胞。在其它此类实施例中,所述癌细胞是实体肿瘤(例如胰腺癌、肺癌或结肠直肠癌)的癌细胞。在某些此类实施例中,所述癌细胞具有杂合突变型KRAS基因。
在某些实施例中,本文所描述的方法、化合物和用途中使用的化合物是具有以下结构式(I)中的任一个的化合物:
根据本文提供的详细描述,本公开的其它方面和实施例将显而易见。
本文中提到的所有出版物都特此以全文引用的方式并入本文中,其内容不会与本文提供的具体公开内容不一致。
附图说明
图1是显示细胞系对用广泛公开的测试化合物处理的反应性随细胞系的KRAS基因型和KRAS接合性变化的条形图。
图2是显示在用测试化合物处理后三种细胞系(BJAB、HCT116和NHFL)中的谷胱甘肽水平的曲线图。BJAB由深灰色(底部)线表示,HCT116由黑色(中间)线表示,且NHFL由浅灰色(顶部)线表示。
图3是一对条形图,展示在用测试化合物处理(顶图)和甲萘醌处理(底图)之后HCT-116细胞中的谷胱甘肽水平降低,两种处理均在存在和不存在N-乙酰基半胱氨酸(NAC)下进行。
图4A是一组图,呈现由在测试化合物处理之后于HCT116细胞中进行的代表性细胞周期实验收集的流式细胞术数据。图4B是以细胞周期每一阶段中细胞的百分含量表示的图4A中的数据的条形图。
具体实施方式
在一个方面,本公开提供了使用如本文所描述的化合物治疗多种过度增生性病症的方法、化合物和用途。所述化合物一般可以关于以上式(Ia)、(Ib)、(Ic)和(Id)中的任一个或各种亚属化合物定义,在所述结构式中,R1、L1、L2、Q、L3、R3、L4、R4、L5以及R5任选地独立地选自下文所定义的组(Ia)及以下、(1a)及以下、(2a)及以下、(3a)及以下、(4a)及以下、(5a)及以下、(6a)及以下、(7a)及以下、(8a)及以下、(9a)及以下和(10a)及以下(例如其中所述化合物具有如以下实施例的任何组合中所定义的结构式):
在如本文另外描述的化合物的某些实施例中,所述化合物具有以下结构式之一:
(Ia);
(Ib);
(Ic);
(Id);
(Ie)。
在如本文另外描述的化合物的某些实施例中,R1选自以下组(1a)–(1k)之一:
(1a)R1选自由以下组成的组:氢、任选被取代的C1-C8烷基和环烷基,其任选地被1-5个R1E取代;
(1b)R1是氢;
(1c)R1是任选被取代的C1-C8烷基;
(1d)R1是未被取代的C1-C8烷基或被氟代的C1-C8烷基,例如丙基或丁基;
(1e)R1是未被取代的环烷基;
(1f)R1是任选被取代的C1-C8烯基;
(1g)R1是任选地被1-5个RE取代的苯基;
(1h)R1是丙基、丁基或丁烯基;
(1i)R1是三氟甲基取代的苯基、甲氧基取代的苯基或氟取代的苯基。
(1j)R1是被以下取代的苯基:-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;或-C(O)NR1G(CH2CH2O)nR1G;
(1k)R1是羟甲基、甲氧基甲基、羟乙基或甲氧基乙基。
在某些此类实施例中,R1的每一任选被取代的烷基(包含R1E的这些基团)是未被取代的或被氟代的。例如,在某些此类实施例中,R1的每一任选被取代的烷基、烯基和炔基(包含R1E的这些基团)是未被取代的。
在如本文另外描述的化合物的某些实施例中,L1选自以下组(2a)–(2e)之一
(2a)L1是化学键、-S-、-S(O)-或-S(O)2-;
(2b)L1选自化学键、-CH2-、-CH(CH3)-、-CH2CH2-、-C(O)-、-S-、-S(O)1-2-、-O-和-NR6-;
(2c)L1是-O-或-S-。
(2d)L1是化学键(例如当R1是以上(1d)、(1f)、(1g)、(1i)、(1j)或(1k)时);
(2e)L1是-NR6-。
在如本文另外描述的化合物的某些实施例中,L2选自以下组(3a)–(3c)之一
(3a)L2是-CH2-、-CH(CH3)-或-CH2CH2-;
(3b)L2是化学键;
(3c)L2是化学键或-CH2-。
在如本文另外描述的化合物的某些实施例中,Q选自以下组(4a)–(4d)之一
(4a)Q选自由以下组成的组:-CH2OH、-C(O)OH、-C(O)OR2A、-C(O)NR2BR2A、-C(O)NR2BS(O)2R2A、-C(O)NR2BS(O)2NR2BR2A、-C(O)R2A、-S(O)2OH、-P(O)(OH)2、-C(OH)(CF3)2、S(O)2R2A、-N(R2B)S(O)2R2A、-S(O)2NR2BR2A、-C(O)NH-O(C1-C3烷基)、-C(O)NHOH和-CO(NH)CN;
(4b)Q选自由以下组成的组:-CH2OH、-C(O)OH、-C(O)OR2A、-C(O)NR2BR2A、-C(O)NR2BS(O)2R2A、-C(O)NR2BS(O)2NR2BR2A、-C(O)R2A、-S(O)2OH、-P(O)(OH)2。
(4c)Q是-CH2OH、-C(O)OH或-C(O)OR2A;
(4d)Q是-COOH。
在如本文另外描述的化合物的某些实施例中,L3选自以下组(5a)–(5c)之一
(5a)L3是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;
(5b)L3是化学键;
(5c)L3是化学键、-CH2-、-CH(CH3)(OH)-或-CH(OH)-。
在如本文另外描述的化合物的某些实施例中,R3选自以下组(6a)–(6k)之一
(6a)R3是芳基(例如苯基)或杂芳基(例如单环杂芳基),其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代;
(6b)R3是任选地被1-5个R3E取代的芳基(例如苯基、苯并二氧杂环戊烯或二氢-1H-异喹啉);
(6c)R3是芳基(例如苯基、苯并二氧杂环戊烯或二氢-1H-异喹啉),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代;
(6d)R3是芳基(例如苯基、苯并二氧杂环戊烯或二氢-1H-异喹啉),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的苯基)、-L3C-(任选地被1-5个R3D取代的单环杂芳基)、-L3C-(任选地被1-5个R3D取代的单环环烷基)、-L3C-(任选地被1-5个R3D取代的单环杂环烷基)并且(ii)任选地被1-5个R3E取代;
(6e)R3如(6a)-(6d)中所定义,其中所述芳基未被任何R3E取代;
(6f)R3是任选地被1-5个R3E取代的杂芳基(例如异噻唑、吡啶酮、噻二唑、吡嗪、吡唑并嘧啶、吡唑并吡啶、咪唑、苯并呋喃、吲哚、咪唑并吡啶、吡啶、吡唑、异噁唑、三唑并吡啶、苯并咪唑、噻吩、苯并噻吩、呋喃或嘧啶);
(6g)R3是杂芳基(例如异噻唑、吡啶酮、噻二唑、吡嗪、吡唑并嘧啶、吡唑并吡啶、咪唑、苯并呋喃、吲哚、咪唑并吡啶、吡啶、吡唑、异噁唑、三唑并吡啶、苯并咪唑、噻吩、苯并噻吩、呋喃或嘧啶),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代;
(6h)R3是杂芳基(例如异噻唑、吡啶酮、噻二唑、吡嗪、吡唑并嘧啶、吡唑并吡啶、咪唑、苯并呋喃、吲哚、咪唑并吡啶、吡啶、吡唑、异噁唑、三唑并吡啶、苯并咪唑、噻吩、苯并噻吩、呋喃或嘧啶),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的苯基)、-L3C-(任选地被1-5个R3D取代的单环杂芳基)、-L3C-(任选地被1-5个R3D取代的单环环烷基)、-L3C-(任选地被1-5个R3D取代的单环杂环烷基)并且(ii)任选地被1-5个R3E取代;
(6i)R3如(6f)-(6h)中所定义,其中所述杂芳基未被任何R3E取代;
(6j)R3选自由以下组成的组:苯基、苯并二氧杂环戊烯基、二氢-1H-异喹啉基、咪唑基、噁唑基、异噁唑基、异噻唑基、噻唑基、吡啶基和吡嗪基、吡啶酮基、噻二唑基、吡唑并嘧啶基、吡唑并吡啶基、苯并呋喃基、吲哚基、咪唑并吡啶基、吡唑基、三唑并吡啶基、苯并咪唑基、苯并咪唑基、噻吩基、苯并噻吩基、呋喃基和嘧啶基,其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代。
(6k)R3选自由苯基和单环杂芳基(例如吡啶基、吡唑基)组成的组,其任选地被1-5个R3E取代。
在某些此类实施例中,R3的每一任选被取代的烷基、烯基和炔基(包含R3D和R3E的这些基团)是未被取代的或被氟代的。例如,在某些此类实施例中,R3的每一任选被取代的烷基、烯基和炔基(包含R3D和R3E的这些基团)是未被取代的。在某些此类实施例中,L3C是亚甲基或-O-。在某些此类实施例中,R3E取代基的可选数量是1-3个或1-2个。
在如本文另外描述的化合物的某些实施例中,R4选自以下组(7a)–(7d)之一
(7a)R4是氢;
(7b)R4是任选被取代的C1-C8烷基、任选被取代的C1-C8烯基或任选被取代的C1-C8炔基;
(7c)R4是氢或未被取代的C1-C6烷基;
(7d)R4是未被取代的C1-C3烷基。
在某些此类实施例中,R4的每一任选被取代的烷基、烯基和炔基是未被取代的或被氟代的。例如,在某些此类实施例中,R4的每一任选被取代的烷基、烯基和炔基是未被取代的。
在如本文另外描述的化合物的某些实施例中,L4选自以下组(8a)–(8c)之一
(8a)L4选自化学键、-C(O)-、-S-、-S(O)1-2-、-O-和-NR6-;
(8b)L4是化学键;
(8c)L4是-O-(例如当R4是以上(7a)、(7b)、(7c)或(7d)中的任一个时)。
在如本文另外描述的化合物的某些实施例中,L5选自以下组(9a)–(9c)之一
(9a)L5是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2CH2-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;
(9b)L5是化学键;
(9c)L5是化学键、-O-、-S-、-C(O)-或-S(O)1-2-。
在如本文另外描述的化合物的某些实施例中,R5选自以下组(21o)–(21q)之一
(10a)R5是芳基(例如苯基)或杂芳基(例如异噁唑基、吡啶基、咪唑并吡啶基、吡唑基),其各自任选地被1-5个R5E取代;
(10b)R5是任选地被1-5个R5E取代的苯基;
(10c)R5选自由以下组成的组:苯基、异噁唑基、吡啶基、咪唑并吡啶基和吡唑基,其各自任选地被1-5个R5E取代。
(10d)R5是苯基,其被选自以下的单一取代基取代:-L5C-(任选地被1-5个R5D取代的苯基)、-L5C-(任选地被1-5个R5D取代的单环杂芳基)和-L5C-(任选地被1-5个R5D取代的单环环烷基)-L5C-(任选地被1-5个R5D取代的单环杂环烷基)并且(ii)任选地被1-5个R5E取代;
(10e)R5是苯基,其被单一-L5C-(任选地被1-5个R5D取代的单环杂芳基)取代基取代并且(ii)任选地被1-5个R5E取代;
(10f)R5是苯基,其被单一-L5C-(任选地被1-5个R5D取代的单环杂环烷基)取代基取代并且(ii)任选地被1-5个R5E取代;
(10g)以上(10d)、(10e)或(10f),其中L5C是化学键;
(10h)以上(10d)、(10e)或(10f),其中L5C是-O-或-C(O)-;
(10h)R5是任选地被1-5个R5E取代的杂环烷基;
(10i)R5是杂环烷基,其被单一-L5C-(任选地被1-5个R5D取代的单环环烷基)取代基取代并且(ii)任选地被1-5个R5E取代;
(10j)以上(10h)或(10i),其中所述杂环烷基是通过氮原子连接至-L5-的含氮杂环烷基;
(10k)以上(10h)、(10i)或(10j),其中所述杂环烷基是单环的;
(10l)以上(10h)、(10i)或(10j),其中所述杂环烷基是双环的;
(10m)以上(10h)-(10l)中的任一个,其中所述杂环烷基是饱和的;
(10n)R5是任选地被1-5个R5E取代的环烷基;
(10o)以上(10n),其中所述环烷基被1-5个R5E取代;
(10p)以上(10n)或(10o),其中所述环烷基是单环的;
(10q)以上(10n)、(10o)或(10p)中的任一个,其中所述环烷基是饱和的;
在某些此类实施例中,R5的每一任选被取代的烷基、烯基和炔基(包含R5D和R5E的这些基团)是未被取代的或被氟代的。例如,在某些此类实施例中,R5的每一任选被取代的烷基、烯基和炔基(包含R5D和R5E的这些基团)是未被取代的。
用于本公开的方法、化合物和用途中的化合物的各种特定实施例号1-1024包含式(I)的化合物,其各自如以下各行中所定义(或其药学上可接受的盐或N-氧化物,或其溶剂化物或水合物),其中各条目是如以上所定义的组号:
本公开化合物的某些特定实施例是上表实施例1-512的化合物,其中结构式是(Ia)。
例如,本文另外描述的化合物的某些实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia)或(Ie),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、L2、Q、L3、R3、L4、R4、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中R1是未被取代或被氟代的C1-C8烯基。在某些此类实施例中,L1是化学键。
例如,本文另外描述的化合物的某些实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia)或(Ie),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、L2、Q、L3、R3、L4、R4、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中R1是任选地被1-5个RE取代的苯基。在某些此类实施例中,L1是化学键。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、L2、Q、L3、R3、L4、R4、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中R1是被一个、两个或三个取代基取代的苯基,所述取代基各自独立地选自氟、氯、硝基、甲基、甲氧基、乙基、乙氧基、三氟甲基、二氟甲基、氟甲基、三氟甲氧基、五氟乙基和2,2,2-三氟乙氧基。在某些此类实施例中,L1是化学键。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、L2、Q、L3、R3、L4、R4、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中R1是三氟甲基取代的苯基、甲氧基甲基、羟甲基、甲氧基取代的苯基或氟取代的苯基。在某些此类实施例中,L1是化学键。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、L2、Q、L3、R3、L4、R4、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中R1是被以下取代的-苯基:-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;或-C(O)NR1G(CH2CH2O)nR1G。在某些此类实施例中,L1是化学键。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、L2、Q、L3、R3、L4、R4、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个)并且其中R1是羟甲基、甲氧基甲基、羟乙基或甲氧基乙基。在某些此类实施例中,L1是化学键。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L5和R5的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L4-R4是-OH或-O-(未被取代或被氟代的C1-C8烷基),例如甲氧基。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是苯基,其被选自以下的单一取代基取代:-L5C-(任选地被1-5个R5D取代的苯基)、-L5C-(任选地被1-5个R5D取代的单环杂芳基)和-L5C-(任选地被1-5个R5E取代的单环环烷基)-L5C-(任选地被1-5个R5E取代的单环杂环烷基)并且(ii)任选地被1-5个R5E取代。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是R5是苯基,其被单一-L5C-(任选地被1-5个R5D取代的单环杂芳基)取代基取代并且(ii)任选地被1-5个R5E取代。所述单环杂芳基可以是例如噁二唑。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是R5是苯基,其被单一-L5C-(任选地被1-5个R5E取代的单环杂环烷基)取代基取代并且(ii)任选地被1-5个R5E取代。所述单环杂环烷基可以是例如吗啉基,例如吗啉-1-基或氧杂环丁烷基,例如氧杂环丁烷-3-基。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是任选地被1-5个R5E取代的杂环烷基。所述杂环烷基可以例如是通过氮原子连接至-L5-的含氮杂环烷基。在某些此类实施例中,所述杂环烷基是单环的。在其它此类实施例中,所述杂环烷基是双环的。在某些此类实施例中,所述杂环烷基是饱和的。在如本文另外描述的各种实施例中,所述杂环烷基是吗啉基(例如吗啉-1-基)、1,4-二氧杂螺[4,5]癸-烯基(例如1,4-二氧杂螺[4,5]癸-烯-8-基)、哌啶基(例如哌啶-1-基)、氮杂双环[3.2.1]辛基(例如氮杂双环[3.2.1]辛-8-基)、哌嗪基(例如哌嗪-1-基)、吡咯烷基(例如吡咯烷-1-基)或氮杂螺[2.5]辛基(例如氮杂螺[2.5]辛-6-基)。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是杂环烷基,其被单一-L5C-(任选地被1-5个R5E取代的单环环烷基)取代基取代并且(ii)任选地被1-5个R5E取代。所述杂环烷基可以例如是通过氮原子连接至-L5-的含氮杂环烷基。在某些此类实施例中,所述杂环烷基是单环的。在其它此类实施例中,所述杂环烷基是双环的。在某些此类实施例中,所述杂环烷基是饱和的。在如本文另外描述的各种实施例中,所述杂环烷基是吗啉基(例如吗啉-1-基)、1,4-二氧杂螺[4,5]癸-烯基(例如1,4-二氧杂螺[4,5]癸-烯-8-基)、哌啶基(例如哌啶-1-基)、氮杂双环[3.2.1]辛基(例如氮杂双环[3.2.1]辛-8-基)、哌嗪基(例如哌嗪-1-基)、吡咯烷基(例如吡咯烷-1-基)或氮杂螺[2.5]辛基(例如氮杂螺[2.5]辛-6-基)。所述环烷基可以是例如饱和环烷基,如饱和C3-C5环烷基,例如环丙基。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是任选地被1-5个R5E取代的环烷基。在某些此类实施例中,所述环烷基是单环的。在其它此类实施例中,所述环烷基是双环的。在某些此类实施例中,所述环烷基是饱和的。在如本文另外描述的各种实施例中,所述环烷基是环己烯基(例如环己烯-1-基,例如4-三氟甲基环己烯-1-基)或环己基。
本文另外描述的化合物的其它实施例具有以上结构式(Ia)-(Ie)中的任一个,例如结构式(Ia),其中变量如本文任一实施例中另外所描述(例如关于如本文所述的变量L1、R1、L2、Q、L3、R3、L4和R4的任一替代性定义,并且适用时关于上表实施例1-1024中的任一个所描述)并且其中-L5-R5是被一个、两个或三个取代基取代的苯基,所述取代基各自独立地选自氟、氯、硝基、甲基、甲氧基、乙基、乙氧基、三氟甲基、二氟甲基、氟甲基、三氟甲氧基、五氟乙基和2,2,2-三氟乙氧基。在某些此类实施例中,L5是化学键。
在某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例以及以上实施例1-1024中的任一个中,前述实施例中的任一个中所叙述的每一任选被取代的亚烷基、亚烯基和亚炔基是未被取代的。在替代性其它实施例,包含参照式(I)-(Io)所描述的实施例以及以上实施例1-1024中的任一个中,前述实施例中的任一个中所叙述的每一任选被取代的亚烷基、亚烯基和亚炔基是未被取代的或被氟代的。
在某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前一段中所描述的任一实施例中,前述实施例中的任一个中所叙述的每一任选被取代的烷基、烯基和炔基是未被取代的。在替代性其它实施例,包含参照式(I)-(Io)所描述的实施例和以上实施例1-1024中的任一个以及前一段所描述的任一实施例中,前述实施例中的任一个中所叙述的每一任选被取代的烷基、烯基和炔基是未被取代的。
在某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前两段中所描述的任一实施例中,前述实施例中的任一个中所叙述的每一环烷基是3-7元单环环烷基。例如,在某些特定实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前两段中所描述的任一实施例中,前述实施例中的任一个中所叙述的每一环烷基是环丙基、环丁基、环戊基、环戊烯基、环己基或环己烯基。
在某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前三段中所描述的任一实施例中,前述实施例中的任一个中所叙述的每一杂环烷基是具有1-2个选自O、S和N的杂原子的4-7元单环杂环烷基。例如,在某些特定实施例,包含参照式(I)和(Ia)-(If)所描述实施例和以上实施例1-1024中的任一个以及前三段中所描述的任一实施例中,前述实施例中的任一个中所叙述的每一杂环烷基是吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、四氢-2H-吡喃基或四氢-2H-硫代吡喃基。
在某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前四段中所描述的任一实施例中,每一杂芳基是具有1-3个选自O、S和N的杂原子的5-6元单环杂芳基。例如,在某些特定实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前四段中所描述的任一实施例中,每一杂芳基是呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、噁唑基或噻唑基。
在某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前四段中所描述的任一实施例中,每一芳基是苯基。
在如上文所描述的某些其它实施例,包含参照式(I)和(Ia)-(If)所描述的实施例和以上实施例1-1024中的任一个以及前五段中所描述的任一实施例中,R5被1、2或3个选自卤素(例如氯-或氟-)和被氟代的C1-C3烷基(例如三氟甲基、二氟甲基、氟甲基、五氟乙基、三氟乙基)的取代基取代。例如,在如上文所描述的某一实施例中,R5是被一个或两个选自三氟甲基、氟和氯的取代基取代的苯基(例如3-取代、4-取代、3,4-双取代、2,4-双取代或2,5-双取代)。例如,在特定实施例中,R5可以是二氯苯基,例如3,4-二氯苯基,或三氟甲基苯基,例如4-三氟甲基苯基。
在某些实施例中,所述化合物是下表化合物中的一种化合物,其任选地以药学上可接受的盐或N-氧化物、和/或溶剂化物或水合物形式提供。BJAB细胞增殖数据提供于表中:“A”指示EC50测量值小于或等于1μM;“B”指示EC50测量值大于1μM且小于或等于5μM;“C”指示EC50测量值大于5μM且小于或等于10μM;“D”指示EC50测量值大于10μM且小于或等于25μM;“E”指示EC50测量值大于25μM且小于或等于50μM;“F”指示EC50测量值大于50μM且小于或等于100μM;“G”指示在所执行的实验中,不存在小于或等于80μM的EC50测量值;“H”指示在所执行的实验中,不存在小于或等于50μM的EC50测量值;“I”指示在所执行的实验中,不存在小于或等于40μM的EC50测量值;“J”指示在所执行的实验中,不存在小于或等于25μM的EC50测量值;“K”指示在所执行的实验中,不存在小于或等于20μM的EC50测量值;并且“L”指示在所执行的实验中,不存在小于或等于5μM的EC50测量值。
在某些实施例中,本文所描述的化合物可以含有一个或多个不对称碳原子,由此所述化合物可以呈不同立体异构体形式存在。这些化合物可以是例如外消旋体、手性非外消旋或非对映异构体。在这些情况下,单一对映异构体,即光学活性形式,可以通过不对称合成方法或通过拆分外消旋体获得。外消旋体的拆分可以例如通过常规方法实现,如在拆分剂存在下结晶;使用例如手性hPLC柱进行的色谱法;或用拆分试剂使外消旋混合物衍生化以产生非对映异构体,通过色谱法分离非对映异构体并移除所述拆分剂以产生呈对映异构性增浓形式的原始化合物。可以重复以上程序中的任一个以增加化合物的对映异构体纯度。
当本文所描述的化合物含有烯系双键或其它几何不对称中心时,并且除非另外说明,否则预期所述化合物包含顺式构型、反式构型、Z构型和E构型。同样地,还打算包含所有互变异构形式。
在如本文另外描述的方法、化合物和用途的某些实施例中,所述化合物不是以下列出的化合物之一:
1-(4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸甲酯;
1-(4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(乙基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸甲酯;
1-(4-(3,4-二氯苯基)-5-(乙基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸甲酯;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-(甲基磺酰胺基)苯甲基)-1H-吡唑-5-甲酸甲酯;
1-(4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-(甲基磺酰胺基)苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(丙基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸甲酯;
1-(4-(3,4-二氯苯基)-5-(丙基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(5-(丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸甲酯;
1-(5-(丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(丙基硫基)噻唑-2-基)-3-甲基-4-(2-(甲基磺酰胺基)苯甲基)-1H-吡唑-5-甲酸;
N-(2-((5-(4-(氨基甲基)哌啶-1-羰基)-1-(4-(3,4-二氯苯基)-5-(丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-4-基)甲基)苯基)甲烷磺酰胺;
4-溴-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(咪唑并[1,2-a]吡啶-6-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-苯基-1H-吡唑-5-甲酸;
1-(5-(环己基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
4-(苯并呋喃-2-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-氟吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
2-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-2',5,5'-三甲基-4,4'-联(2H-吡唑)-3-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3,5-二氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(5-氯-2-氟苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3,5-二氯苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(5-氯-2-氟苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(4-(3,5-二甲基异噁唑-4-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(5-(异丙基硫基)-4-(1-甲基-1H-吡唑-4-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(5-(异丙基硫基)-4-(吡啶-4-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(5-(异丙基硫基)-4-(吡啶-3-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(4-(咪唑并[1,2-a]吡啶-6-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(5-(仲丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-4-(3,5-二氯苯基)-3-甲基-1H-吡唑-5-甲酸甲酯;
1-(5-(仲丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-4-(3,5-二氯苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(5-(仲丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸甲酯;
1-(5-(仲丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-(2-甲氧基苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-(3-甲氧基苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-(4-甲氧基苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-苯基噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-(羟甲基)-5-甲基异噁唑-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-(甲氧基甲基)-5-甲基异噁唑-4-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-对甲苯基噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-间甲苯基噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-邻甲苯基噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-(苯基乙炔基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(吡啶-3-基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(甲基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-(羟甲基)苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(吡啶-4-基)-1H-吡唑-5-甲酸;
4-(3-(氨基甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(4-(羟甲基)苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-(三氟甲基)苯基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(3-(三氟甲基)苯基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(4-(三氟甲基)苯基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(羟基(苯基)甲基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基亚磺酰基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基磺酰基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
4-([1,2,4]三唑并[4,3-a]吡啶-3-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3,5-二甲基异噁唑-4-基)-3-甲基-1H-吡唑-5-甲酸;
4-(1H-苯并[d]咪唑-2-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-2-甲基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-异丙基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-甲氧基-5-甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(1H-咪唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(吡唑并[1,5-a]吡啶-3-基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(吡唑并[1,5-a]嘧啶-3-基)-1H-吡唑-5-甲酸;
2-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-2',5-二甲基-4,4'-联(2H-吡唑)-3-甲酸;
2-(4-(3,4-二氯苯基)-5-(异丙基磺酰基)噻唑-2-基)-2',5-二甲基-4,4'-联(2H-吡唑)-3-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(1-甲基-1H-苯并[d]咪唑-2-基)-1H-吡唑-5-甲酸;
4-(5-氰基吡啶-3-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-乙氧基吡啶-3-基)-3-甲基-1H-吡唑-5-甲酸;
2'-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-2,5,5'-三甲基-3,4'-联(2H-吡唑)-3'-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(嘧啶-5-基)-1H-吡唑-5-甲酸;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酰胺;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(4,6-二甲基嘧啶-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-N-(吡啶-2-基甲基)-1H-吡唑-5-甲酰胺;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-N-(2-羟乙基)-N,3-二甲基-1H-吡唑-5-甲酰胺;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-N,3-二甲基-N-(5-(三氟甲基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酰胺;
(4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-基)(3-(二乙基氨基)吡咯烷-1-基)甲酮;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(吡嗪-2-基)-1H-吡唑-5-甲酸;
4-(3-氰基-5-甲基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-N-(1H-四唑-5-基)-1H-吡唑-5-甲酰胺;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(5-甲基-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸;
4-(3-氰基-5-甲氧基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氰基-5-(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-(甲氧基甲基)苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-苯甲基-5-甲基异噁唑-4-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-((二甲基氨基)甲基)苯基)-3-甲基-1H-吡唑-5-甲酸;
(1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-苯基-1H-吡唑-5-基)MeOH;
4-(苯并[d][1,3]二氧杂环戊烯-5-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(4-甲氧基嘧啶-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(异噻唑-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(3-甲基异噻唑-5-基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(1-甲基-2-氧代-1,2-二氢吡啶-4-基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟-5-甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-羟基-5-甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-异丙氧基-5-甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(3-甲基-5-(氧杂环丁烷-3-基氧基)苯基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-(二甲基氨基)-5-甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-(1H-咪唑-1-基)-5-甲基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2-(氮杂环丁烷-1-基)-6-甲基吡啶-4-基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-甲基-6-吗啉代吡啶-4-基)-1H-吡唑-5-甲酸;
1-(5-(异丙基硫基)-4-(3-甲氧基苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异戊基硫基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(5-(异丙基硫基)-4-(3-甲氧基苯基)噻唑-2-基)-3-甲基-4-(2-(甲基磺酰胺基)苯甲基)-1H-吡唑-5-甲酸;
1-(5-(仲丁基硫基)-4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-4-(2-硝基苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(1H-吲哚-6-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(3-硝基苯基)-1H-吡唑-5-甲酸;
2-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-5-甲基-4,4'-联(2H-吡唑)-3-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(1H-吲哚-3-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2-氯苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(4-氯苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-甲氧基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-甲氧基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(4-甲氧基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-邻甲苯基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-间甲苯基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-对甲苯基-1H-吡唑-5-甲酸;
4-(4-乙酰胺基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-(甲基磺酰胺基)苯甲基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-(N,N-二甲基氨磺酰基氨基)苯甲基)-3-甲基-1H-吡唑-5-甲酸;
4-(4-氨基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(4-(甲基磺酰胺基)苯基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(3-(甲基磺酰胺基)苯基)-1H-吡唑-5-甲酸;
2-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-2'-(2-甲氧基乙基)-5-甲基-4,4'-联(2H-吡唑)-3-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(1H-吲哚-7-基)-3-甲基-1H-吡唑-5-甲酸;
2-(4-(1H-吲哚-7-基)-3-甲基-1H-吡唑-1-基)-4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑;
2-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-2'-乙基-5-甲基-4,4'-联(2H-吡唑)-3-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-N-(2-甲氧基乙基)-3-甲基-4-间甲苯基-1H-吡唑-5-甲酰胺;
(4-(氨基甲基)哌啶-1-基)(1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-邻甲苯基-1H-吡唑-5-基)甲酮;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(5-甲氧基吡啶-3-基)-3-甲基-1H-吡唑-5-甲酸;
2-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-2'-异丁基-5-甲基-4,4'-联(2H-吡唑)-3-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-(甲基氨基)吡啶-4-基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-1'-(二甲基氨甲酰基)-3-甲基-1H,1'H-[4,4'-联吡唑]-5-甲酸;
(4-(氨基甲基)哌啶-1-基)(4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-基)甲酮;
N-(2-氨基乙基)-4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-N,3-二甲基-1H-吡唑-5-甲酰胺;
(3-氨基氮杂环丁烷-1-基)(4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-基)甲酮;
(4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-基)(吗啉代)甲酮;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-N,N,3-三甲基-1H-吡唑-5-甲酰胺;
(4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-基)(4-(羟甲基)哌啶-1-基)甲酮;
1-(4-(3,4-二氯苯基)-5-异丁基噻唑-2-基)-1',3-二甲基-1H,1'H-[4,4'-联吡唑]-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3,5-二甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-甲氧基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-甲氧基-5-(三氟甲基)苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-甲基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-双(三氟甲基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-N-(甲基磺酰基)-1H-吡唑-5-甲酰胺;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(咪唑并[1,2-a]吡啶-3-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(4-(3,5-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟-5-羟基苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氨基-5-甲基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-羟基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(1-甲基-1H-吲哚-7-基)-1H-吡唑-5-甲酸;
4-(3,4-二氯苯基)-5-(异丙基硫基)-2-(1H-吡唑-1-基)噻唑;
1-(4-(2-氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3-氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(2,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(2,5-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-(苯基乙炔基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-苯甲基-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟-5-甲氧基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-甲氧基-5-甲基苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-甲氧基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-甲基吡啶-4-基)-1H-吡唑-5-甲酸;
1-(4-(1H-吲哚-4-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3-氟苯基)-5-(异丙基硫基)噻唑-2-基)-4-(1H-吲哚-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(1H-吲哚-5-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(环丙基乙炔基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-环丙基-1-(4-环丙基-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-环丙基-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-异丙氧基苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-(2-甲氧基乙氧基)苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3-氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(2,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-溴-1-(4-(6-(3-氟苯基)吡啶-3-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
(R)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-甲基-6-((四氢呋喃-3-基)氧基)吡啶-4-基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-(2-甲氧基乙氧基)-6-甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
(S)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(2-甲基-6-((四氢呋喃-3-基)氧基)吡啶-4-基)-1H-吡唑-5-甲酸;
1-(4-(环己-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(环戊-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-甲氧基苯基)-1-(5-(异丙基硫基)-4-苯基噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(4-(4-氟苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲氧基苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(甲基磺酰基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氟-3-甲氧基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3,5-二氟苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3,5-二氟苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-甲氧基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-甲氧基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-4-(3-甲基-5-(氧杂环丁烷-3-基氧基)苯基)-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2-甲氧基-6-甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟-5-(氧杂环丁烷-3-基氧基)苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(4-(3-氟苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(苯并呋喃-2-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-苯基噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(5-(异丙基硫基)-4-苯基噻唑-2-基)-1',3-二甲基-1H,1'H-[4,4'-联吡唑]-5-甲酸;
4-(2,6-二甲基吡啶-4-基)-1-(4-(4-氟苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-2-甲氧基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-2-甲氧基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3-氯-4-甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(1,5-二甲基-6-氧代-1,6-二氢吡啶-3-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(2-氯-5-(三氟甲氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(5-氰基吡啶-3-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(1,3-二甲基-1H-吡唑-5-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(嘧啶-5-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氰基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3-氟-4-甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(2-氰基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-2-甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(2-甲基-4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-氰基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,5-二氯苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-((2-甲氧基乙基)氨甲酰基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-(二甲基氨甲酰基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-甲氧基苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲氧基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(2-甲基-4-(三氟甲氧基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氯-5-氟苯基)-1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氰基-3-甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-氟噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-异丙基-1H-吡唑-5-甲酸;
1-(4-(4-(二氟甲基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(3,4-二氯苯基)-5-异丙氧基噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-
甲酸;
1-(4-(4-乙基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
2-(4-(2,6-二甲基吡啶-4-基)-3,5-二甲基-1H-吡唑-1-基)-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑;
4-(3-氟苯基)-1-(4-(5-氟吡啶-3-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(苯并呋喃-3-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,4-二氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(4-氟-3-甲基苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(4-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(4-氟-3-甲氧基苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-2,6-二甲基苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-(1,1-二氟乙基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(4-氟-3,5-二甲基苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(2-(三氟甲基)嘧啶-5-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-(乙基氨甲酰基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(2-氨基-4-(三氟甲基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-((4-(三氟甲基)苯基)乙炔基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(5-(三氟甲基)嘧啶-2-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-甲基-1-(4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-N-(2-甲氧基乙基)-N,3-二甲基-1H-吡唑-5-甲酰胺;
N-(2-(2-(2-(2-叠氮基乙氧基)乙氧基)乙氧基)乙基)-4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酰胺;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-N-(2-甲氧基乙基)-3-甲基-1H-吡唑-5-甲酰胺;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-N-(丙基磺酰基)-1H-吡唑-5-甲酰胺;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(2-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(3-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基氨基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(五氟-λ6-硫基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-N-甲氧基-3-甲基-1H-吡唑-5-甲酰胺;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(6-(三氟甲基)吡啶-3-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;以及
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(1-(2,2,2-三氟乙基)-1H-吡唑-4-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸。[段落A61]
在如本文另外描述的化合物的某些实施例中,所述化合物呈N-氧化物形式。但在如上文所描述的某些实施例中,所述化合物不呈N-氧化物形式。
在如本文另外描述的化合物的某些实施例中,所述化合物呈如本文中所描述的化合物或N-氧化物的药学上可接受的盐形式。本领域的普通技术人员应了解,如以下其它细节中所描述,可以提供多种药学上可接受的盐。本领域的普通技术人员应了解,短语“任选地呈药学上可接受的盐或N-氧化物、或溶剂化物或水合物形式”包含呈N-氧化物的药学上可接受的盐形式的化合物。但在如上文所描述的某些实施例中,所述化合物不呈药学上可接受的盐形式。
在如本文另外描述的化合物的某些实施例中,所述化合物呈如本文中所描述的化合物、N-氧化物或盐的溶剂化物(例如水合物)形式。本领域的普通技术人员应了解,可以形成多种溶剂化物和/或水合物。本领域的普通技术人员应了解,短语“任选地呈药学上可接受的盐或N-氧化物、或溶剂化物或水合物形式”包含呈如上文所描述的基础化合物、药学上可接受的盐和N-氧化物的溶剂化物和水合物形式的化合物。但在如上文所描述的某些实施例中,所述化合物不呈溶剂化物或水合物的形式。
本文所描述的化合物可以有效地以包括根据前述方面或本文所述的实施例中的任一个的化合物、N-氧化物、盐、溶剂化物或水合物以及药学上可接受的赋形剂、稀释剂或载体的药物组合物形式提供。所述药物组合物可以例如呈片剂、胶囊或肠胃外配制物形式,但本领域的普通技术人员应了解,所述化合物可以呈多种药物组合物形式提供。
如上所述,在肿瘤形成期间允许增加且更高效地利用稀缺养分的突变是有利的。致癌Ras通过增强GLUT1的表达来刺激葡萄糖摄取,并且刺激合成代谢路径利用葡萄糖和向作为关键细胞抗氧化剂的谷胱甘肽的转化。Ras还调控谷氨酰胺代谢,特别是将葡萄糖和谷氨酰胺碳引导至支持生物合成、氧化还原动态平衡且最终支持细胞存活和生长的路径中。
除这些对细胞代谢的影响外,Ras还被描述为对细胞遵循细胞周期的进展具有影响。确切地说,Ras被认为在早期G1中以及G2中跨限制点传播具有作用。在G1限制点处的Ras活性特别重要,因为这一事件是生长因子信号传导,使得细胞进一步分裂或进入G0或休眠期的关键整合点。Ras协调生长因子信号传导以调控细胞周期蛋白、细胞周期蛋白依赖性激酶和拮抗性细胞周期素依赖性激酶抑制因子的水平。
关于更多的信息,一般参见Hanahan D,Weinberg RA(2011),新一代癌症的标志(Hallmarks of cancer:the next generation.)《细胞(Cell)》144(5):646-674;Ward PS,Thompson CB(2012),代谢重编程:癌症标志甚至Warburg效应都无法预测(MetabolicReprogramming:ACancer Hallmark Even Warburg Did Not Anticipate.)《癌细胞(Cancer Cell)》21(3):297-308;Prabakaran S(2016),Kras重新布置代谢网络(Krasrewires metabolic networks.),《科学信号(Sci Signal)》9(418):ec56-ec56;Kerr EM,Gaude E,Turrell FK,Frezza C,Martins CP(2016),突变型Kras拷贝数确定代谢重编程和治疗敏感性(Mutant Kras copy number defines metabolic reprogramming andtherapeutic susceptibilities.),《自然(Nature)》531(7592):110-113;Flier JS,Mueckler MM,Usher P,Lodish HF(1987),ras或src致癌基因诱导葡萄糖转运和转运蛋白信使RNA水平升高(Elevated levels of glucose transport and transportermessenger RNAare induced by ras or src oncogenes.),《科学(Science)》235(4795):1492-1495;Yun J等人(2009),葡萄糖缺乏促成肿瘤细胞中KRAS路径突变的发生(GlucoseDeprivation Contributes to the Development of KRAS Pathway Mutations in TumorCells.),《科学》325(5947):1555-1559;Son J等人(2013),谷氨酰胺通过KRAS调控的代谢路径支持胰腺癌生长(Glutamine supports pancreatic cancer growth through aKRAS-regulated metabolic pathway.),《自然》496(7443):101-105;Kim MH,Kim H(2013),致癌基因和肿瘤抑制因子调控癌细胞中的谷氨酰胺代谢(Oncogenes and tumorsuppressors regulate glutamine metabolism in cancer cells.),《癌症预防杂志(JCancer Prev)》18(3):221-226;Gaglio D等人(2011),致癌K-Ras分离葡萄糖和谷氨酰胺代谢以支持癌细胞生长(Oncogenic K-Ras decouples glucose and glutamine metabolismto support cancer cell growth.),《分子系统生物学(Mol Syst Biol)》7:523;HitomiM,Stacey DW(1999),在循环NIH 3T3细胞的不同细胞周期期间需要细胞ras和细胞周期蛋白D1(Cellular ras and cyclin D1are required during different cell cycleperiods in cycling NIH 3T3cells.),《分子与细胞生物学(Mol Cell Biol)》19(7):4623-4632;Hitomi M,Stacey DW(2001),在G2期间的Ras依赖性细胞周期参与(Ras-dependent cell cycle commitment during G2phase.),《欧洲生物化学学会联合会快报(FEBS Lett)》490(3):123-131;Foster DA,Yellen P,Xu L,Saqcena M(2010),G1细胞周期进程调控:区分限制点与养分感测细胞生长检查点(Regulation of G1Cell CycleProgression:Distinguishing the Restriction Point from a Nutrient-Sensing CellGrowth Checkpoint(s).),《基因与癌症(Genes Cancer)》1(11):1124-1131;Massagué J(2004),G1细胞周期控制和癌症(G1cell-cycle control and cancer.),《自然》432(7015):298-306;Pardee AB(1974),用于控制正常动物细胞增殖的限制点(A restrictionpoint for control of normal animal cell proliferation.),《美国国家科学院院刊(Proc Natl Acad Sci U S A)》71(4):1286-1290;Martinsson H-S,Starborg M,Erlandsson F,Zetterberg A(2005),G1检查点的单细胞分析—限制点与pRb磷酸化之间的关系(Single cell analysis of G1check points-the relationship between therestriction point and phosphorylation of pRb.),《实验细胞研究(Exp Cell Res)》305(2):383-391;Larsson O,Zetterberg A(1995),用于肿瘤细胞早期G1中有丝分裂的参与程序的存在(Existence of a commitment program for mitosis in early G1intumour cells.),《细胞增殖(Cell Prolif)》28(1):33-43;Yen A,Pardee AB(1978),指数期3T3细胞因其高血清需求而避开G1中期(Exponential 3T3 cells escape in mid-G1from their high serum requirement.),《实验细胞研究(Exp Cell Res)》116(1):103-113;Novák B,Tyson JJ(2004),用于哺乳动物细胞周期限制点控制的模型(Amodel forrestriction point control of the mammalian cell cycle.),《理论生物学杂志(JTheor Biol)》230(4):563-579;Weber JD,Hu W,Jefcoat SC,Raben DM,Baldassare JJ(1997),Ras刺激的细胞外信号相关激酶1和RhoA活性通过独立调控细胞周期蛋白D1和p27KIP1协调血小板源性生长因子诱导的G1进程(Ras-stimulated ExtracellularSignal-related Kinase 1 and RhoA Activities Coordinate Platelet-derivedGrowth Factor-induced G1 Progression through the Independent Regulation ofCyclin D1 and p27KIP1.),《生物化学杂志(J Biol Chem)》272(52):32966-32971;KawadaM等人(1997),Ras通过MAP激酶信号传导路径诱导p27Kip1降解和非锚定依赖性(Inductionof p27Kip1 degradation and anchorage independence by Ras through the MAPkinase signaling pathway.),《癌基因(Oncogene)》15(6):629-637;Deng X,Mercer SE,Shah S,Ewton DZ,Friedman E(2004),Mirk/dyrk1B激酶使细胞周期蛋白依赖性激酶抑制因子p27Kip1稳定于G(0)期(The cyclin-dependent kinase inhibitor p27Kip1 isstabilized in G(0)by Mirk/dyrk1B kinase.),《生物化学杂志(J Biol Chem)》279(21):22498-22504;Ladha MH,Lee KY,Upton TM,Reed MF,Ewen ME(1998),通过p27和细胞周期蛋白D1-CDK4调控退出休眠期(Regulation of exit from quiescence by p27 andcyclin D1-CDK4.),《分子细胞生物学(Mol Cell Biol)》18(11):6605-6615;Fan J,Bertino JR(1997),K-ras通过正调控和负调控路径调节细胞周期(K-ras modulates thecell cycle via both positive and negative regulatory pathways.),《癌基因》14(21):2595-2607。
确切地说,经显示Ras相关致癌基因,KRAS(又称为k-Ras或V-Ki-ras2柯尔斯顿大鼠(Kirsten rat)肉瘤病毒癌基因同源物)对细胞代谢也具有直接影响。结果是代谢回路的整体重新布置。已注意到KRAS对葡萄糖利用、谷胱甘肽合成以及氧化还原平衡和谷氨酰胺代谢具有多效性作用。谷胱甘肽是一种普遍存在的细胞内肽,具有多种功能,包含调节细胞增殖、解毒和抗氧化防御(Lu,Shelly C.,《医学分子问题(Mol Aspects Med.)》2009;30(1-2):42-59)。谷胱甘肽水平增加已经与早期增殖反应(例如刺激细胞自细胞周期的G0期变换至G1期)相关联,并且对于细胞进入S期(同上)至关重要。谷胱甘肽还涉及细胞死亡的调控,由此可能调节细胞凋亡和坏死(同上)。此外,在许多肿瘤中也已报导谷胱甘肽水平增加且此涉及赋予药物和/或放射抗性且阻碍化学疗法(同上)。因此,谷胱甘肽合成抑制剂提供独特的化学治疗目标。
不打算受理论束缚,本发明人认为本文所描述的化合物通过使细胞周期停滞在G0/G1期来发挥针对癌细胞的作用。因此,如上所述,本文所描述的化合物可以用于多种方法和用途中。例如,在本公开的某些实施例中,用于治疗有需要受试者的过度增生性病症的方法包含向所述受试者施用有效量的如本文所描述的化合物。在本公开的其它实施例中,提供了用于治疗过度增生性病症的如本文所描述的化合物。本公开的其它实施例提供了用于制备供治疗过度增生性病症的药剂用的如本文所描述的化合物。在这些实施例中的每一个中,过度增生性病症可以是例如癌症。
本发明人已确定,在某些实施例中,本发明描述的化合物抑制癌细胞中细胞周期的进程。因此,本公开的另一个实施例提供一种用于抑制癌细胞中的细胞周期进程的方法,所述方法包括使癌细胞与有效量的如本文所描述的化合物接触。在某些此类实施例中,细胞周期进程在G0/G1期被抑制。
在某些实施例中,在G0/G1期抑制细胞周期进程将诱导癌细胞凋亡。因此,本公开的另一个实施例提供一种用于诱导癌细胞,如造血系统癌细胞凋亡的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。然而,在其它实施例中,例如在某些实体肿瘤中,实现重要治疗作用可能不需要细胞凋亡。
本发明人已确定,在某些实施例中,本文所描述的化合物可以诱导针对癌细胞的细胞毒性作用(例如通过以上描述的细胞凋亡机制或通过替代性机制)。因此,本公开的另一个实施例提供一种用于诱导针对癌细胞的细胞毒性作用的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。
本发明人已确定,在某些实施例中,本文所描述的化合物可以抑制癌细胞中的谷胱甘肽合成。因此,本公开的另一个实施例提供一种用于抑制癌细胞中的谷胱甘肽合成的方法。所述方法包含使所述癌细胞与有效量的如本文所描述的化合物接触。
本文所描述的方法、化合物和用途可以用于多种不同癌症或多种不同类型癌症的细胞。例如,在如本文另外描述的方法、化合物和用途的某些实施例中,癌症是造血系统癌症。在其它实施例中,癌症是实体肿瘤。
在如本文另外描述的方法、化合物和用途的某些实施例中,癌症是淋巴瘤(例如伯基特氏淋巴瘤(Burkitt's lymphoma)、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤、毛细胞淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤、皮肤T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、双重打击淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症(macroglobulinemia)、原发性中枢神经系统(CNS)淋巴瘤和血管内大B细胞淋巴瘤(ILBCL))。在其它此类实施例中,癌症是白血病(例如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性成骨髓细胞性白血病、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、慢性骨髓单核细胞性白血病(CMML)、侵袭性NK细胞白血病、急性双表型白血病和真性红细胞增多症)、急性和慢性T细胞和B细胞白血病)。在其它此类实施例中,癌症是浆细胞赘瘤(例如多发性骨髓瘤)。
然而,本领域的普通技术人员从本文所提供的公开内容将了解,本文所描述的方法、化合物和用途可以用于多种其它类型的癌症。例如,在如本文另外描述的方法、化合物和用途的某些实施例中,癌症选自阑尾癌、骨癌(例如尤文氏肉瘤(Ewing sarcoma)、骨肉瘤和恶性纤维组织细胞瘤)、支气管肿瘤、原发灶不明性癌瘤、慢性骨髓增生性赘瘤、结肠和直肠癌、头颈癌(包含头颈部鳞状细胞癌(HNSCC))、白血病(例如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性成骨髓细胞性白血病、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、慢性骨髓单核细胞性白血病(CMML)、侵袭性NK细胞白血病、急性双表型白血病和真性红细胞增多症)、急性和慢性T细胞和B细胞白血病)、淋巴瘤(例如伯基特氏淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤、皮肤T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、双重打击淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、原发性中枢神经系统(CNS)淋巴瘤和血管内大B细胞淋巴瘤(ILBCL))、浆细胞赘瘤(例如多发性骨髓瘤)、骨髓发育不良综合症、骨髓发育不良/骨髓增生性赘瘤和慢性骨髓增生性赘瘤、胰腺癌和胰腺神经内分泌肿瘤(例如胰岛细胞瘤)、小肠癌、软组织肉瘤以及鳞状细胞癌。
并且在如本文另外描述的方法、化合物和用途的其它实施例中,癌症选自肾上腺皮质癌瘤、肾上腺皮质癌、AIDS相关癌症(例如卡波西氏肉瘤(Kaposi sarcoma)、AIDS相关淋巴瘤、伯基特氏淋巴瘤和原发性CNS淋巴瘤)、肛门癌、阑尾癌、星形细胞瘤(例如儿童小脑或大脑星形细胞瘤)、胆管癌(例如胆管细胞癌)、膀胱癌、骨癌(例如尤文氏肉瘤、骨肉瘤和恶性纤维组织细胞瘤)、脑肿瘤(例如多形性成胶质细胞瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性神经胶质瘤、室管膜瘤、成神经管细胞瘤、少突神经胶质瘤、幕上原始神经外胚层肿瘤以及视路和下丘脑神经胶质瘤)、脑干神经胶质瘤、乳癌、支气管肿瘤、胃肠类癌肿瘤、类癌肿瘤、原发灶不明性癌瘤、心脏(心)肿瘤、中枢神经系统癌症(例如非典型畸胎样/横纹肌样肿瘤、胚胎肿瘤和生殖细胞肿瘤)、子宫颈癌、儿童癌症、软骨肉瘤、慢性骨髓增生性赘瘤、结肠和直肠癌、颅咽管瘤、促结缔组织增生性小圆细胞肿瘤、乳腺管原位癌(DCIS)、子宫内膜癌、室管膜瘤、上皮样血管内皮瘤(EHE)、食道癌、嗅神经母细胞瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌(例如眼内黑素瘤和成视网膜细胞瘤)、输卵管癌、胆囊癌、胃癌、胃肠道间质瘤(GIST)、妊娠滋养细胞疾病(GTD)、神经胶质瘤、毛细胞白血病、头颈癌(例如头颈部鳞状细胞癌(HNSCC))、肝细胞(肝)癌、组织细胞增多病、朗格罕氏细胞(langerhanscell)、下咽癌、肾癌、朗格罕氏细胞组织细胞增多病、喉癌、喉癌和乳头状瘤病、白血病(例如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性成骨髓细胞性白血病、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、慢性骨髓单核细胞性白血病(CMML)、侵袭性NK细胞白血病、急性双表型白血病和真性红细胞增多症)、急性和慢性T细胞和B细胞白血病)、唇和口腔癌症、肝癌、肺癌(例如小细胞肺癌、非小细胞肺癌(NSCLC)、肺腺癌、肺癌瘤和肺鳞癌)、肺类癌肿瘤、淋巴瘤(例如伯基特氏淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤、皮肤T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、双重打击淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、原发性中枢神经系统(CNS)淋巴瘤和血管内大B细胞淋巴瘤(ILBCL))、雄性乳癌、脑膜瘤、间皮瘤、涉及NUT基因的中线癌瘤、口部癌症、多发性内分泌腺瘤综合症、浆细胞赘瘤(例如多发性骨髓瘤)、蕈样真菌病、骨髓发育不良综合症、骨髓发育不良/骨髓增生性赘瘤和慢性骨髓增生性赘瘤、鼻腔和副鼻窦癌症、鼻咽癌(NPC)、成神经细胞瘤、口腔癌、唇和口腔癌症以及口咽癌、卵巢癌、胰腺癌和胰腺神经内分泌肿瘤(例如胰岛细胞瘤)、副神经节瘤、副甲状腺癌、阴茎癌、咽癌、嗜铬细胞瘤、垂体肿瘤、胸膜肺母细胞瘤、原发性腹膜癌、前列腺癌、成视网膜细胞瘤、横纹肌肉瘤、唾液腺癌、塞扎莱氏综合症(Sézarysyndrome)、皮肤癌(例如基底和鳞状细胞癌、梅克尔氏细胞癌(merkel cell carcinoma)和黑素瘤)、小肠癌、软组织肉瘤、鳞状细胞癌、胃癌、睾丸癌、咽喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、尿道癌、子宫癌和子宫肉瘤、阴道癌、血管肿瘤、外阴癌以及威尔姆斯氏肿瘤(Wilms tumor)。
例如,在如本文另外描述的方法、化合物和用途的几个特定实施例中,癌症是实体肿瘤。在各种实施例中,实体肿瘤可以是例如肺癌、结肠直肠癌或胰腺癌。
在如本文另外描述的方法、化合物和用途的一个特定实施例中,癌症是弥漫性大B细胞淋巴瘤。
本文所提供的数据展示,所述化合物针对具有杂合突变型KRAS基因的癌症特别有效。在>90%的胰腺癌、50%的结肠癌和25%的肺腺癌中都发现KRAS突变。因此,在如本文另外描述的方法、化合物和用途的某些实施例中,癌症具有突变型KRAS基因,例如杂合突变型KRAS基因。
然而,在如本文另外描述的方法、化合物和用途的某些实施例中,癌症或过度增生性病症不是伯基特氏淋巴瘤。
鉴于现有技术,本领域的普通技术人员基于本公开将确定本文所描述的化合物的有效量和剂量。
定义
在本文中使用的术语之前和/或之后可以使用单短划线“-”或双短划线“=”指示所述取代基与其母体部分之间的化学键的键级;单短划线指示单键且双短划线指示双键或在螺环取代基情况下指示一对单键。在无单或双短划线存在下,应理解单键是在取代基与其母体部分之间形成;此外,除非短划线另外指示,否则预期取代基是参照所提及的化学结构从“左至右”阅读。例如,芳基烷基、芳基烷基-和-烷基芳基指示相同的官能团。
为简单起见,化学部分通篇主要被定义且称为单价化学部分(例如烷基、芳基等)。然而,在本领域的技术人员清楚适当结构的情况下,这些术语也被用于传达相应多价部分。例如,尽管“烷基”部分可以指单价基团(例如CH3-CH2-),但在一些情况下,二价连接部分可以是“烷基”,在此情况下,本领域的技术人员应了解,烷基是二价基团(例如-CH2-CH2-),等效于术语“亚烷基”。(类似地,在需要二价部分且将其陈述为“芳基”的情况下,本领域的技术人员应了解,术语“芳基”是指相应二价部分,即亚芳基)。所有原子应理解为具有其形成化学键的正常价数(即,碳是4价、N是3价、O是2价以及S是2价、4价或6价,此取决于S的氧化状态)。本发明所公开的化合物中的氮可以是高价的,例如N-氧化物或四取代的铵盐。有时可以将一个部分例如定义为-B-(A)a,其中a是0或1。在此类实例中,当a是0时,所述部分是-B,且当a是1时,所述部分是-B-A。
如本文所使用,术语“烷基”包含具有设计数目的碳原子,如1至10个碳(即,包含1和10在内)、1至8个碳、1至6个碳、1至3个碳或1、2、3、4、5或6个碳的饱和烃。烷基可以是直链或分支链的并且取决于环境,可以是单价基团或二价基团(即,亚烷基)。例如,部分“-(C1-C6烷基)-O-”表示氧通过具有1至6个碳的亚烷基桥连接并且C1-C3烷基表示甲基、乙基和丙基部分。“烷基”的实例包含例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基、戊基和己基。
术语“烷氧基”表示通过氧桥连接至母体分子部分的具有指定数目的碳原子的烷基。“烷氧基”的实例包含例如甲氧基、乙氧基、丙氧基和异丙氧基。
除非另外说明,否则如本文所使用,术语“烯基”是含有2至10个碳(即,包含2和10在内)、2至8个碳、2至6个碳或2、3、4、5或6个碳且含有至少一个碳-碳双键的不饱和烃。烯基可以是直链或分支链的并且取决于上下文,可以是单价基团或二价基团(即,亚烯基)。例如,部分“-(C2-C6烯基)-O-”表示氧通过具有2至6个碳的亚烯基桥连接。烯基的代表性实例包含但不限于乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基、3-癸烯基以及3,7-二甲基辛-2,6-二烯基。
除非另外说明,否则如本文所使用,术语“炔基”是含有2至10个碳(即,包含2和10在内)、2至8个碳、2至6个碳或2、3、4、5或6个碳且含有至少一个碳-碳三键的不饱和烃。炔基可以是直链或分支链的并且取决于上下文,可以是单价基团或二价基团(即,亚炔基)。例如,部分“-(C2-C6炔基)-O-”表示氧通过具有2至6个碳的亚炔基桥连接。炔基的代表性实例包含但不限于乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、2-戊炔基和1-丁炔基。
术语“芳基”表示具有单环(例如苯基)的芳香环系统,其任选地与其它芳香烃环或非芳香烃环或杂环稠合。“芳基”包含具有多个缩合环的环系统且其中至少一个是碳环和芳香环(例如1,2,3,4-四氢萘基、萘基)。芳基的实例包含苯基、1-萘基、2-萘基、茚满基、茚基、二氢萘基、芴基、四氢萘基和6,7,8,9-四氢-5H-苯并[a]环庚烯基。“芳基”还包含具有第一碳环、芳香环与非芳香族杂环稠合的环系统,例如1H-2,3-二氢苯并呋喃基和四氢异喹啉基。本文中的芳基是未被取代的或当指定为“任选被取代的”时,除非另外说明,否则可以在一个或多个可取代位置中被如所指示的各种基团取代。
术语“卤素”或“卤代”指示氟、氯、溴和碘。在如本文另外描述的每个实施例的某些实施例中,术语“卤素”或“卤代”是指氟或氯。在本文中描述的每个实施例的某些实施例中,术语“卤素”或“卤代”是指氟。术语“氟烷基”指示被至少一个氟取代的烷基(即,如本文另外所描述)。“氟烷基”包含被多个氟取代的烷基,如全氟烷基。氟烷基的实例包含氟甲基、二氟甲基、三氟甲基、五氟乙基、2,2,2-三氟乙基、1,1,1,3,3,3-六氟丙-2-基和2,2,3,3,3-五氟丙-1-基。
术语“杂芳基”是指在芳香环中含有至少一个选自氮、氧和硫的芳香族杂原子的芳香环系统。最常见的是,杂芳基将具有1、2、3或4个杂原子。杂芳基可以与一个或多个非芳香环,例如环烷基或杂环烷基环稠合,其中环烷基和杂环烷基环如本文所描述。在本发明化合物的一个实施例中,杂芳基通过杂芳基芳香环中的原子键结至所述结构的其余部分。在另一个实施例中,杂芳基通过非芳香族环原子键结至所述结构的其余部分。杂芳基的实例包含例如吡啶基、嘧啶基、喹啉基、苯并噻吩基、吲哚基、吲哚啉基、哒嗪基、吡嗪基、异吲哚基、异喹啉基、喹唑啉基、喹喏啉基、酞嗪基、咪唑基、异噁唑基、吡唑基、噁唑基、噻唑基、吲哚嗪基、吲唑基、苯并噻唑基、苯并咪唑基、苯并呋喃基、呋喃基、噻吩基、吡咯基、噁二唑基、噻二唑基、苯并[1,4]噁嗪基、三唑基、四唑基、异噻唑基、萘啶基、异色满基、色满基、异吲哚啉基、异苯并噻吩基、苯并噁唑基、吡啶并吡啶基、嘌呤基、苯并间二氧杂环戊烯基、三嗪基、蝶啶基、苯并噻唑基、咪唑并吡啶基、咪唑并噻唑基、苯并异噁嗪基、苯并噁嗪基、苯并吡喃基、苯并硫代吡喃基、色酮基、色满酮基、吡啶基-N-氧化物、异吲哚啉酮基、苯并二噁烷基、苯并噁唑啉酮基、吡咯基N-氧化物、嘧啶基N-氧化物、哒嗪基N-氧化物、吡嗪基N-氧化物、喹啉基N-氧化物、吲哚基N-氧化物、吲哚啉基N-氧化物、异喹啉基N-氧化物、喹唑啉基N-氧化物、喹喏啉基N-氧化物、酞嗪基N-氧化物、咪唑基N-氧化物、异噁唑基N-氧化物、噁唑基N-氧化物、噻唑基N-氧化物、吲哚嗪基N-氧化物、吲唑基N-氧化物、苯并噻唑基N-氧化物、苯并咪唑基N-氧化物、吡咯基N-氧化物、噁二唑基N-氧化物、噻二唑基N-氧化物、三唑基N-氧化物、四唑基N-氧化物、苯并硫代吡喃基S-氧化物、苯并硫代吡喃基S,S-二氧化物。优选的杂芳基包含吡啶基、嘧啶基、喹啉基、吲哚基、吡咯基、呋喃基、噻吩基和咪唑基、吡唑基、吲唑基、噻唑基和苯并噻唑基。在某些实施例中,各杂芳基选自吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、异噁唑基、吡唑基、噁唑基、噻唑基、呋喃基、噻吩基、吡咯基、噁二唑基、噻二唑基、三唑基、四唑基、异噻唑基、吡啶基-N-氧化物、吡咯基N-氧化物、嘧啶基N-氧化物、哒嗪基N-氧化物、吡嗪基N-氧化物、咪唑基N-氧化物、异噁唑基N-氧化物、噁唑基N-氧化物、噻唑基N-氧化物、吡咯基N-氧化物、噁二唑基N-氧化物、噻二唑基N-氧化物、三唑基N-氧化物和四唑基N-氧化物。优选的杂芳基包含吡啶基、嘧啶基、喹啉基、吲哚基、吡咯基、呋喃基、噻吩基、咪唑基、吡唑基、吲唑基、噻唑基和苯并噻唑基。本文中的杂芳基是未被取代的或当指定为“任选被取代的”时,除非另外说明,否则可以在一个或多个可取代位置中被如所指示的各种基团取代。
术语“杂环烷基”是指含有至少一个杂原子的非芳香族环或环系统,所述杂原子优选地选自氮、氧和硫,其中所述杂原子是在非芳香族环中。杂环烷基可以具有1、2、3或4个杂原子。杂环烷基可以是饱和(即,杂环烷基)或部分不饱和的(即,杂环烯基)。杂环烷基包含具有三至八个环原子的单环基团,以及双环和多环的环系统,包含桥连和稠合系统,其中每个环包含三至八个环原子。杂环烷基环任选地与其它杂环烷基环和/或非芳香族烃环稠合。在某些实施例中,杂环烷基在单一环中具有3至7个成员。在其它实施例中,杂环烷基在单一环中具有5或6个成员。在一些实施例中,杂环烷基在单一环中具有3、4、5、6或7个成员。杂环烷基的实例包含例如氮杂双环[2.2.2]辛基(在每种情况下还包含“奎宁环基”或奎宁环衍生物)、氮杂双环[3.2.1]辛基、2,5-二氮杂双环[2.2.1]庚基、吗啉基、硫代吗啉基、硫代吗啉基S-氧化物、硫代吗啉基S,S-二氧化物、2-噁唑烷酮基、哌嗪基、高哌嗪基、哌嗪酮基、吡咯烷基、氮杂环庚烷基、氮杂环丁烷基、吡咯啉基、四氢吡喃基、哌啶基、四氢呋喃基、四氢噻吩基、3,4-二氢异喹啉-2(1H)-基、异吲哚啉二酮基、高哌啶基、高吗啉基、高硫代吗啉基、高硫代吗啉基S,S-二氧化物、噁唑烷酮基、二氢吡唑基、二氢吡咯基、二氢吡嗪基、二氢吡啶基、二氢嘧啶基、二氢呋喃基、二氢吡喃基、咪唑烷酮基、四氢噻吩基S-氧化物、四氢噻吩基S,S-二氧化物和高硫代吗啉基S-氧化物。特别合意的杂环烷基包含吗啉基、3,4-二氢异喹啉-2(1H)-基、四氢吡喃基、哌啶基、氮杂双环[2.2.2]辛基、γ-丁内酯基(即,氧代基取代的四氢呋喃基)、γ-丁内酰胺基(即,氧代基取代的吡咯烷)、吡咯烷基、哌嗪基、氮杂环庚烷基、氮杂环丁烷基、硫代吗啉基、硫代吗啉基S,S-二氧化物、2-噁唑烷酮基、咪唑烷酮基、异吲哚啉二酮基、哌嗪酮基。本文中的杂环烷基是未被取代的或当指定为“任选被取代的”时,除非另外说明,否则可以在一个或多个可取代位置中被如所指示的各种基团取代。
术语“环烷基”是指饱和(即,环烷基)或部分不饱和(即,环烯基)的非芳香族碳环或环系统。环烷基环任选地与其它环烷基环稠合或以其它方式连接(例如桥连系统)。所公开的化合物中存在的环烷基的某些实例在单一环中具有3至7个成员,如在单一环中具有5或6个成员。在一些实施例中,环烷基在单一环中具有3、4、5、6或7个成员。环烷基的实例包含例如环己基、环戊基、环丁基、环丙基、四氢萘基和双环[2.2.1]庚烷。本文中的环烷基是未被取代的或当指定为“任选被取代的”时,可以在一个或多个可取代位置中被如所指示的各种基团取代。
术语“环系统”涵盖单环,以及稠合和/或桥连多环。
术语“氧代”意思指双键键结的氧,有时表示为=O或例如在描述羰基“C(O)”时可用于显示氧代基取代的碳。
除非另外具体说明,否则术语“被取代”当用于修饰指定基团或自由基时,意思是指定基团或自由基的一个或多个氢原子各自彼此独立地被如下文定义的相同或不同取代基置换。
如本文所使用,短语“药学上可接受的盐”是指药学上可接受的酸和碱加成盐以及溶剂化物。此类药学上可接受的盐包含以下酸的盐:如盐酸、磷酸、氢溴酸、硫酸、亚磺酸、甲酸、甲苯磺酸、甲烷磺酸、硝酸、苯甲酸、柠檬酸、酒石酸、顺丁烯二酸、氢碘酸、链烷酸如乙酸、HOOC-(CH2)n-COOH,其中n是0-4等。无毒药物性碱加成盐包含碱如钠、钾、钙、铵等的盐。本领域的技术人员将认识到多种无毒药学上可接受的加成盐。
药物化学领域的普通技术人员还应理解,所公开的结构意图包含本发明化合物的富含同位素的形式。如本文所使用,“同位素”包含原子数相同但质量数不同的原子。正如本领域的技术人员所知,某些原子,如氢是以不同的同位素形式存在。例如,氢包含三种同位素形式,即氕、氘和氚。考虑本发明化合物,本领域的技术人员将显而易见,某些化合物可以在给定位置处富含在该位置处的原子的特定同位素。例如,具有氟原子的化合物可以呈富含放射性氟同位素18F形式合成。类似地,化合物可以富含氢的重同位素:氘和氚;并且类似地,可以富含碳的放射性同位素,如13C。此类同位素变体化合物经历不同代谢路径并且可以用于例如研究泛素化路径和其在疾病中的作用。当然,在某些实施例中,所述化合物与天然存在的材料具有基本上相同的同位素特性。
如本文所使用,术语“细胞”意图指体外、离体或体内细胞。在一些实施例中,离体细胞可以是从生物体如哺乳动物切除的组织样品的一部分。在一些实施例中,体外细胞可以是细胞培养物中的细胞。在一些实施例中,体内细胞是生活在生物体如哺乳动物中的细胞。
如本文所使用,术语“个体”、“患者”或“受试者”可互换使用,意思指任何动物,包含哺乳动物,优选地小鼠、大鼠、其它啮齿动物、兔、狗、猫、猪、牛、绵羊、马或灵长类动物,并且最优选人类。
如本文所使用,短语“治疗有效量”或“有效量”是指引起研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所寻求的生物或药物反应的活性化合物或药剂的量。
在某些实施例中,有效量可以是适合于以下目的的量:
(i)抑制疾病进展;
(ii)预防用途,例如预防或限制可能易患或另外有患疾病、病况或病症的风险但尚未经历或展示所述疾病的病理或症状的个体发展所述疾病、病况或病症;
(iii)抑制疾病;例如抑制正经历或展示疾病、病况或病症的病理或症状的个体的所述疾病、病况或病症;
(iv)改善所提到的疾病状态,例如改善正经历或展示疾病、病况或病症的病理或症状的个体的所述疾病、病况或病症(即,逆转或改善所述病理和/或症状)如降低疾病的严重程度;或
(v)引起所提到的生物作用。
如此处所使用,术语“治疗(treatment/treating)”意思指(i)改善所提到的疾病状态、病况或病症(或其症状),例如改善正经历或展示疾病、病况或病症的病理或症状的个体的所述疾病、病况或病症(即,逆转或改善病理和/或症状),如降低疾病或其症状的严重程度,或抑制疾病的进展;或(ii)引起所提到的生物作用(例如诱导细胞凋亡或抑制谷胱甘肽合成)。
药物配制物和剂型
本公开的化合物可以呈含有一种或多种药学上可接受的载体、稀释剂或赋形剂的剂量单元配制物形式例如经口、表面、肠胃外、通过吸入或喷雾或经直肠施用。如本文所使用,术语肠胃外包含经皮、皮下、血管内(例如静脉内)、肌肉内或鞘内注射或输注技术等。包含本公开化合物的药剂可以呈如本文所描述的任何适当的配制物和剂型形式提供。
药物组合物可以使用本发明所公开的化合物制备。例如,在一个实施例中,药物组合物包含药学上可接受的载体、稀释剂或赋形剂以及如上文参照结构式中的任一个所描述的化合物。
在本文所公开的药物组合物中,一种或多种本公开的化合物可以与一种或多种药学上可接受的载体、稀释剂或赋形剂且必要时与其它活性成分结合存在。含有本公开化合物的药物组合物可以呈适于口服使用的形式,例如呈片剂、糖衣片、口含片、水性或油性悬浮液、可分散的散剂或颗粒剂、乳液、硬或软胶囊、或糖浆或酏剂形式。
打算供口服使用的组合物可以根据用于制造药物组合物的任何适合方法制备,并且这些组合物可以含有一种或多种选自由以下组成的组的试剂:甜味剂、调味剂、着色剂和防腐剂以便提供药学上最佳且适口的制剂。片剂含有活性成分与适于制造片剂的无毒药学上可接受的赋形剂的混合物。这些赋形剂可以是例如惰性稀释剂,如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒剂和崩解剂,例如玉米淀粉或海藻酸;粘合剂,例如淀粉、明胶或阿拉伯胶;以及润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包覆的,或者其可以通过已知技术包覆。在一些情况下,这些包衣可以通过适合技术制备以延迟在胃肠道中的崩解和吸收并由此在较长时间段内提供持续作用。例如,可以采用时间延迟材料,如单硬脂酸甘油酯或二硬脂酸甘油酯。
供口服使用的配制物还可以呈硬明胶胶囊形式,其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合;或呈软明胶胶囊形式,其中活性成分与水或油介质,例如花生油、液体石蜡或橄榄油混合。
供口服使用的配制物也可以呈口含片形式。
水性悬浮液含有活性物质与适于制造水性悬浮液的赋形剂的混合物。此类赋形剂可以是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄芪胶以及阿拉伯胶;分散剂或湿润剂,如天然存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七亚乙基氧基十六醇,或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物,如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与衍生自脂肪酸及己糖醇酐的偏酯的缩合产物,例如聚乙烯脱水山梨糖醇单油酸酯。水性悬浮液还可以含有一种或多种防腐剂,例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯;一种或多种着色剂;一种或多种调味剂;以及一种或多种甜味剂,如蔗糖或糖精。
油性悬浮液可以通过使活性成分悬浮于植物油,例如花生油、橄榄油、芝麻油或椰子油中,或矿物油如液体石蜡中来配制。油性悬浮液可以含有增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加甜味剂和调味剂以提供适口的口服制剂。这些组合物可以通过添加抗氧化剂如抗坏血酸来保存。
适于通过添加水制备水性悬浮液的可分散的散剂和颗粒剂提供活性成分与分散剂或湿润剂、悬浮剂以及一种或多种防腐剂的混合物。适合的分散剂或湿润剂或悬浮剂是以上文已提到的那些举例说明。也可以存在其它赋形剂,例如甜味剂、调味剂和着色剂。
药物组合物也可呈水包油乳液形式。油相可以是植物油或矿物油或其混合物。适合的乳化剂可以是天然存在的胶状物,如阿拉伯胶或黄芪胶;天然存在的磷脂,例如大豆、卵磷脂;以及衍生自脂肪酸和己醣醇、酐的酯或偏酯,例如脱水山梨糖醇单油酸酯;和所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯脱水山梨糖醇单油酸酯。乳液还可含有甜味剂和调味剂。
在一些实施例中,药学上可接受的载体、稀释剂或赋形剂不是水。在其它实施例中,水占所述组合物不到50%。在一些实施例中,包括不到50%水的组合物具有至少1%、2%、3%、4%或5%水。在其它实施例中,所述组合物中存在痕量的水含量。
在一些实施例中,药学上可接受的载体、稀释剂或赋形剂不是醇。在其它实施例中,醇占所述组合物的不到50%。在一些实施例中,包括不到50%醇的组合物具有至少1%、2%、3%、4%或5%醇。在其它实施例中,所述组合物中存在痕量的醇含量。
糖浆和酏剂可以用甜味剂,例如甘油、丙二醇、山梨糖醇、葡萄糖或蔗糖配制。这些配制物还可以含有缓和剂、防腐剂、调味剂和着色剂。药物组合物可以呈无菌可注射水性或油性悬浮液形式。这一悬浮液可以根据已知技术,使用上文提到的那些适合分散剂或湿润剂和悬浮剂配制。无菌可注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液形式,例如在1,3-丁二醇中的溶液形式。可以采用的可接受的媒剂和溶剂是水、林格氏溶液(Ringer's solution)和等渗氯化钠溶液。此外,还可以采用无菌不挥发性油作为溶剂或悬浮介质。出于此目的,可以采用任何温和的不挥发性油,包含合成单酸甘油酯或二酸甘油酯。此外,脂肪酸,如油酸也可用于制备可注射剂。
例如,对于直肠施用药物,本公开的化合物还可以呈栓剂形式施用。这些组合物可以通过将化合物与适合的非刺激性赋形剂混合来制备,所述赋形剂在正常温度下是固体,但在直肠温度下是液体,并因此将在直肠中熔融以释放药物。这些材料包含可可脂和聚乙二醇。
本公开的化合物还可以通过无菌介质肠胃外施用。取决于所使用的媒剂和浓度,药物可以悬浮或溶解于媒剂中。有利的是,可以将佐剂如局部麻醉剂、防腐剂和缓冲剂溶解于所述媒剂中。
所述组合物可以被配制成活性成分的单位剂型。术语“单位剂型”是指适合以单一剂量用于人类受试者和其他哺乳动物的物理离散单元,每个单元含有经过计算以与适合药物赋形剂结合产生所希望的治疗作用的预定量的活性材料。
活性化合物可在较宽剂量范围内有效,并且一般是以药学有效量施用。然而,应了解,实际施用的化合物的量通常将由医生根据相关情况确定,所述情况包含待治疗的病况、所选择的施用途径、所施用的实际化合物、个体患者的年龄、体重和反应、患者症状的严重程度等。
为了制备固体组合物,如片剂,将主要活性成分与药物赋形剂混合以形成含有本文所描述化合物的均匀混合物的固体预配制组合物。当提到这些预配制组合物是均质组合物时,活性成分典型地均匀分散于整个组合物中,使得所述组合物可以容易地细分成同等有效的单位剂型,如片剂、丸剂和胶囊。接着,将这一固体预配制物细分成含有例如0.1至约500mg本文所描述的化合物活性成分的上述类型的单位剂型。
片剂或丸剂可以被包覆或以其它方式混配以提供实现长期作用优势的剂型。例如,片剂或丸剂可以包括内部剂量和外部剂量组分,后者呈在前者上的包膜形式。这两种组分可以通过肠溶层隔开,所述肠溶层用以在胃中抵抗崩解并且允许内部组分完整地传递到十二指肠中或延迟释放。多种材料可以用于此类肠溶层或包衣,这些材料包含多种聚合酸和聚合酸与如虫胶、鲸蜡醇和乙酸纤维素之类材料的混合物。
施用给患者的化合物或组合物的量将取决于所施用的药物、施用目的如预防或治疗、患者的状态、施用方式等而变化。在治疗应用中,可以对已罹患疾病的患者施用足以治愈或至少部分停滞所述疾病和其并发症的症状的量的组合物。有效剂量将取决于所治疗的疾病状况以及由主治医师根据如疾病严重程度、患者的年龄、体重和一般状况等因素判断。
施用给患者的组合物可以呈以上描述的药物组合物形式。这些组合物可以通过常规灭菌技术灭菌或可以无菌过滤。水溶液可以被包装以原样使用,或被冻干,冻干制剂在施用之前与无菌水性载体组合。化合物制剂的pH值典型地将在3与11之间,更优选地是5至9并且最优选是7至8。应理解,使用某些前述赋形剂、载体或稳定剂会导致药物盐的形成。
化合物的治疗剂量可以根据例如治疗所针对的具体用途、化合物的施用方式、患者的健康和状况以及处方医师的判断而变化。药物组合物中本文所描述的化合物的比例或浓度可以取决于多种因素而变化,包含剂量、化学特征(例如疏水性)和施用途径。例如,对于肠胃外施用,本文所描述的化合物可以呈含有约0.1至约10%w/v所述化合物的水性生理缓冲溶液形式提供。一些典型剂量范围是每天每公斤体重约1μg至约1g。在一些实施例中,剂量范围是每天每公斤体重约0.01mg至约100mg。剂量很可能取决于如下变量:疾病或病症的类型和进展程度、特定患者的总体健康状况、所选化合物的相对生物功效、赋形剂的配制以及其施用途径。有效剂量可以从由体外或动物模型测试系统得到的剂量-反应曲线外推。
本文所描述的化合物也可以与一种或多种另外的活性成分组合配制,所述一种或多种另外的活性成分可以包含任何药剂,如抗病毒剂、疫苗、抗体、免疫增强剂、免疫抑制剂、抗炎剂等。
本领域的普通技术人员将例如基于所描述化合物的物理化学特性、达到药学有效量所需的化合物量和所希望的施用途径,将所述化合物配制成本文中的药物配制物。
实例
通用合成方法
有许多可用的通用参考文献提供了可用于合成所公开的化合物的通常已知的化学合成方案和条件(参见例如Smith和March,《March高等有机化学:反应、机理与结构(March's Advanced Organic Chemistry:Reactions,Mechanisms,and Structure)》,第五版,Wiley-Interscience,2001;或Vogel,《实用有机化学教科书,包含定性有机分析(ATextbook of Practical Organic Chemistry,Including Qualitative OrganicAnalysis)》,第四版,纽约(New York):Longman,1978)。
本文所描述的化合物可以通过本领域中已知的任何方式纯化,包含色谱法,如HPLC、制备型薄层色谱法、快速柱色谱法和离子交换色谱法。任何适合固定相都可以使用,包含正相和反相以及离子树脂。最典型地,所公开的化合物是通过硅胶和/或氧化铝色谱法纯化。参见例如《现代液相色谱技术导论(Introduction to Modern LiquidChromatography)》,第2版,L.R.Snyder和J.J.Kirkland编,John Wiley and Sons,1979;和《薄层色谱法(Thin Layer Chromatography)》,E.Stahl编,Springer-Verlag,纽约,1969。
在用于制备主题化合物的任何方法期间,可能需要和/或希望保护任何所关注分子上的敏感性或反应性基团。这可以借助于如标准著作中所描述的常规保护基实现,如J.F.W.McOmie,“有机化学中的保护基(Protective Groups in Organic Chemistry)”,Plenum Press,伦敦(London)和纽约1973;T.W.Greene和P.G.M.Wuts,“有机合成中的保护基(Protective Groups in Organic Synthesis)”,第三版,Wiley,纽约1999;“肽(ThePeptides)”;第3卷(编者:E.Gross和J.Meienhofer),Academic Press,伦敦和纽约1981;“有机化学方法(Methoden der organischen Chemie)”、Houben-Weyl,第4增补版,,第15/l卷,Georg Thieme Verlag,斯图加特(Stuttgart)1974;H.-D.Jakubke和H.Jescheit,“氨基酸、肽、蛋白质(Aminosauren,Peptide,Proteine)”,Verlag Chemie,Weinheim,DeerfieldBeach和Basel 1982;和/或Jochen Lehmann,“碳水化合物的化学:单糖和衍生物(Chemieder Kohlenhydrate:Monosaccharide and Derivate)”,Georg Thieme Verlag,斯图加特1974。这些保护基可以在适宜的后续阶段,使用本领域中已知的方法移除。
考虑到本文所描述的具体制备程序,本文所公开的化合物可以使用本领域的普通技术人员熟悉的程序制备。本领域的技术人员可以采用以下实例中描述的反应工序以符合所希望的目标分子。当然,在某些情况下,本领域的技术人员将使用不同试剂以实现一个或多个独立步骤或使用某些取代基的受保护形式。此外,本领域的技术人员将认识到,本公开的化合物可以使用完全不同的途径合成。
适用于本发明所公开的药物组合物中的化合物包含上表的化合物。以下提供多种示例性合成方法;本领域的普通技术人员将采用本文所描述的程序和/或本领域的普通技术人员熟悉的其它程序制备本文所描述的化合物。
以下合成实例和生物化学数据意图进一步说明某些实施例,而不打算限制本发明所公开的化合物的范围。
化合物1:1-(4-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
3-(2-溴-5-氯苯氧基)氧杂环丁烷
将重氮甲酸二异丙酯(292mg,1.45mmol)添加至2-溴-5-氯苯酚(200mg,0.964mmol)、氧杂环丁烷-3-醇(89mg,1.2mmol)和三苯基膦(379mg,1.45mmol)于THF(4.2mL)中的溶液中。在室温下搅拌反应混合物18小时。添加乙酸乙酯并用1N NaOH(3×)洗涤混合物。有机层用硫酸钠脱水,过滤并减压蒸发。粗产物在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(10%)纯化,得到标题化合物(208mg,0.789mmol,82%)。
2-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂
环戊烷
将脱气的二噁烷添加至3-(2-溴-5-氯苯氧基)氧杂环丁烷(100mg,0.379mmol)、频哪醇二硼烷(116mg,0.455mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(28mg,0.038mmol)和乙酸钾(112mg,1.14mmol)的混合物中。在85℃下加热反应混合物18小时。在硅藻土上过滤混合物并用二噁烷洗涤该垫。蒸发滤液,得到标题化合物(219mg,186%,由NMR分析测定50%w/w),以原样使用。
2-氯-5-(异丙基硫基)噻唑
在-78℃下,将n-BuLi于己烷中的2.5M溶液(20.5mL,51.2mmol)添加至2-氯噻唑(4.9g,41.0mmol)的THF溶液(117mL)中。在相同温度下搅拌反应混合物30分钟。将二异丙基二硫醚(13.1mL,82.0mmol)添加至反应物中并在相同温度下搅拌1.5小时。添加水以淬灭反应且接着添加Et2O。将反应混合物转移至分液漏斗中并用Et2O(3×)萃取水层。合并的有机层经Na2SO4脱水并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至5%梯度)纯化并得到呈黄色液体状的标题化合物(2.31g,11.9mmol,29%)。
4-溴-2-氯-5-(异丙基硫基)噻唑
将溴(72.7μL,1.42mmol)于二氯甲烷(“DCM”)中的2M溶液逐滴添加至2-氯-5-(异丙基硫基)噻唑(250mg,1.29mmol)于DCM中的溶液中。在室温下搅拌反应3小时。添加Na2SO3溶液并用DCM(3×)萃取水层。用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。粗产物在硅胶上通过快速色谱法,使用DCM于己烷中的溶液(50至100%梯度)纯化并得到呈无色液体状的标题化合物(271mg,0.99mmol,77%)。
4-溴-2-肼基-5-(异丙基硫基)噻唑
在玻璃微波小瓶中,将DIPEA(64μL,0.37mmol)添加至盐酸肼(13.0mg,0.18mmol)和4-溴-2-氯-5-(异丙基硫基)噻唑(50.0mg,0.18mmol)于NMP(2mL)中的溶液中。密封小瓶并在微波辐射下将其加热至150℃,保持1小时。粗产物通过反相快速色谱法(C18,使用0至40至70%梯度的MeCN/含10mM NH4CO2H缓冲液的H2O)纯化并在用Et2O萃取并真空干燥后,得到呈黄色固体状的标题化合物(29.0mg,0.11mmol,59%)。
2-(甲氧基亚氨基)-3-(2-硝基苯甲基)-4-氧代戊酸甲酯
将乙酰丙酮酸甲酯(1.0g,6.94mmol)、甲氧基羟胺盐酸盐(0.58g,6.94mmol)和分子筛(2.5g)放入配备氮气进口的火焰干燥的圆底烧瓶中。添加无水DMF(23mL)并用箔覆盖圆底烧瓶,并且在室温下搅拌过夜。用EtOAc(150mL)稀释反应混合物并用水(3×50mL)和盐水(1×50mL)洗涤有机相,用Na2SO4脱水,过滤并真空浓缩,得到呈红色液体状的标题化合物(1.07g,6.16mmol,89%)。
1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将2-(甲氧基亚氨基)-3-(2-硝基苯甲基)-4-氧代戊酸甲酯(4.00g,23.1mmol)溶解于MeOH(115mL)中。添加4-溴-2-肼基-5-(异丙基硫基)噻唑(6.19g,23.1mmol)且接着将12N HCl(7.70mL,92.4mmol)逐滴添加至反应混合物中。将反应混合物加热至回流过夜。真空浓缩粗产物并在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(5至20%梯度)纯化并且在硅胶上通过快速色谱法(干式充填),使用DCM于己烷中的溶液(10至50%梯度)再次纯化并得到呈橙色油状的标题化合物(1.89g,5.02mmol,22%)。
4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将溴(3.32mL,6.64mmol)于MeCN中的2M溶液逐滴添加至1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(500mg,1.33mmol)于DCM/MeCN溶液(7mL,1:1)中的溶液中。在室温下搅拌反应5小时。添加Na2SO3溶液并用Et2O(3×)萃取水层。用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。粗产物在硅胶上通过快速色谱法,使用DCM于己烷中的溶液(20%)纯化并得到呈橙色固体状的标题化合物(421mg,0.93mmol,70%)。
1-(4-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲
基-1H-吡唑-5-甲酸甲酯
将脱气的THF(2mL)添加至4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、2-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(137mg,0.220mmol,50%w/w)、[1,1′-双(二叔丁基膦基)二茂铁]二氯钯(II)(11mg,0.022mmol)和碳酸钾(152mg,1.10mmol)的混合物中。在90℃下加热反应混合物18小时。将混合物与二氧化硅混合并蒸发溶剂以在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(2至40%)纯化,得到呈浅黄色油状的标题化合物(17mg,0.035mmol,16%)。
1-(4-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲
基-1H-吡唑-5-甲酸
在THF和MeOH的1:1溶液(0.35mL)中稀释1-(4-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(17mg,0.035mmol)。添加1M NaOH(0.070mL,0.070mmol)并在室温下搅拌反应18小时。添加1N HCl(1mL),随后添加水(5mL)并用EtOAc(3×5mL)萃取混合物。合并的有机层用硫酸钠脱水,过滤并减压蒸发。粗产物通过半制备型HPLC-MS(柱X-Bridge 30×50),使用MeCN于水(含10mM甲酸铵)中的溶液(50至70%)纯化。冻干产物,得到呈浅黄色固体状的标题化合物(2mg,0.004mmol,12%)。
1H NMR(500MHz,DMSO)δ7.34(d,J=8.2Hz,1H),7.14(dd,J=8.1,1.9Hz,1H),6.83(d,J=1.9Hz,1H),6.64(s,1H),5.38–5.31(m,1H),4.89(t,J=6.8Hz,2H),4.49(dd,J=7.3,5.1Hz,2H),3.21(d,J=6.6Hz,1H),2.25(s,3H),1.14(d,J=6.7Hz,6H);MS(m/z):466.1[M+1]+。
化合物2:1-(4-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
3-(5-溴-2-氯苯氧基)氧杂环丁烷
将重氮甲酸二异丙酯(292mg,1.45mmol)添加至5-溴-2-氯苯酚(200mg,0.964mmol)、氧杂环丁烷-3-醇(89mg,1.2mmol)和三苯基膦(379mg,1.45mmol)于THF(4.2mL)中的溶液中。在室温下搅拌反应混合物18小时。添加乙酸乙酯并用1N NaOH(3×)洗涤混合物。有机层用硫酸钠脱水,过滤并减压蒸发。粗产物在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(10%)纯化,得到标题化合物(222mg,0.842mmol,87%)。
2-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂
环戊烷
将脱气的二噁烷添加至3-(5-溴-2-氯苯氧基)氧杂环丁烷(100mg,0.379mmol)、频哪醇二硼烷(116mg,0.455mmol)、[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(28mg,0.038mmol)和乙酸钾(112mg,1.14mmol)的混合物中。在85℃下加热反应混合物18小时。在硅藻土上过滤混合物并用二噁烷洗涤该垫。蒸发滤液,得到标题化合物(238mg,202%,50%w/w,由NMR分析测定),以原样使用。
1-(4-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲
基-1H-吡唑-5-甲酸甲酯
将脱气的THF(2mL)添加至实例27中所制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、2-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(137mg,0.220mmol,50%w/w)、[1,1′-双(二叔丁基膦基)二茂铁]二氯钯(II)(11mg,0.022mmol)和碳酸钾(152mg,1.10mmol)的混合物中。在90℃下加热反应混合物18小时。将混合物与二氧化硅混合并蒸发溶剂以在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(2至40%)纯化,得到呈浅橙色油状的标题化合物(6.2mg,0.013mmol,66%)。
1-(4-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲
基-1H-吡唑-5-甲酸
在THF和MeOH的1:1溶液(0.13mL)中稀释1-(4-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(6.2mg,0.013mmol)。添加1M NaOH(0.026mL,0.026mmol)并在室温下搅拌反应18小时。添加1N HCl(1mL),随后添加水(5mL)并用EtOAc(3×5mL)萃取混合物。合并的有机层用硫酸钠脱水,过滤并减压蒸发。粗产物通过半制备型HPLC-MS(柱X-Bridge 30×50),使用MeCN于水(含10mM甲酸铵)中的溶液(50至70%)纯化。冻干产物,得到呈浅黄色固体状的标题化合物(1.2mg,0.003mmol,20%)。
1H NMR(500MHz,DMSO)δ7.71–7.66(m,1H),7.57(d,J=8.3Hz,1H),7.36(d,J=1.8Hz,1H),6.71(s,1H),5.43–5.35(m,1H),5.04(t,J=6.8Hz,2H),4.62(dd,J=7.9,4.9Hz,2H),3.33(sept,J=6.7Hz,1H),2.27(s,3H),1.22(d,J=6.7Hz,6H);MS(m/z):466.1[M+1]+。
化合物3:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻唑-2-
基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)硼酸(38.1mg,0.187mmol)和K2CO3(152mg,1.10mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF溶液(2mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(dtbpf)Cl2(14.3mg,0.022mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至50%梯度)纯化并得到呈褐色油状的标题化合物(57.8mg,0.108mmol,49%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻
唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(57.8mg,0.108mmol)、3-氟苯基硼酸(18.2mg,0.130mmol)和Na2CO3(57.3mg,0.541mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(12.5mg,0.011mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(5至40%梯度)纯化,得到呈黄色固体状的标题化合物(25.4mg,0.046mmol,43%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻
唑-2-基)-3-甲基-1H-吡唑-5-甲酸
在25mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(25.4mg,0.046mmol)。添加1M NaOH溶液(92.4μL,0.092mmol)并在室温下搅拌反应16小时。用1M HCl酸化反应混合物并真空浓缩粗产物。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用40-60%MeCN/NH4CO2H10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈白色固体状的标题化合物(3.99mg,0.007mmol,16%)。
1H NMR(500MHz,DMSO)δ8.26(d,J=8.2Hz,2H),8.06(d,J=8.5Hz,2H),7.52–7.33(m,3H),7.12(s,2H),3.37–3.24(m,1H),2.61(s,3H),2.30(s,3H),1.24(d,J=6.7Hz,6H);MS(m/z):536.1[M+1]+。
化合物4:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-
吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、4,4,5,5-四甲基-2-(4-甲基环己-1-烯-1-基)-1,3,2-二氧杂硼杂环戊烷(41.5mg,0.187mmol)和K2CO3(152mg,1.10mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF溶液(2mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(dtbpf)Cl2(14.3mg,0.022mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至10%梯度)纯化并得到呈黄色油状的标题化合物(45.6mg,0.097mmol,44%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-
甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(44.6mg,0.085mmol)、3-氟苯基硼酸(14.3mg,0.102mmol)和Na2CO3(45.2mg,0.427mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(9.86mg,0.009mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。粗产物在硅胶上通过快速色谱法纯化(用DCM湿式装载),使用EtOAc于己烷中的溶液(1%等度洗脱),得到呈黄色油状的标题化合物(40.0mg,0.082mmol,97%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-
甲基-1H-吡唑-5-甲酸
在圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(40.0mg,0.082mmol)。添加1M NaOH溶液(165μL,0.165mmol)并在室温下搅拌反应16小时。用1M HCl酸化反应混合物并真空浓缩粗产物。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用60-80%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈黄色固体状的标题化合物(2.55mg,0.005mmol,7%)。
1H NMR(500MHz,DMSO)δ7.50(dd,J=14.9,7.8Hz,1H),7.35–7.27(m,2H),7.21(s,1H),6.35(s,1H),3.32–3.16(m,1H),2.57(s,1H),2.45–2.35(m,1H),2.32(s,1H),2.28(s,3H),1.86–1.74(m,2H),1.67(s,1H),1.33–1.26(m,1H),1.24(d,J=6.6Hz,6H),0.98(d,J=6.6Hz,3H);MS(m/z):472.1[M+1]+。
化合物5:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲
基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、4,4,5,5-四甲基-2-(4-(三氟甲基)环己-1-烯-1-基)-1,3,2-二氧杂硼杂环戊烷(51.6mg,0.187mmol)和K2CO3(152mg,1.10mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF溶液(2mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(dtbpf)Cl2(14.3mg,0.022mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至10%梯度)纯化并得到呈黄色油状的标题化合物(47.4mg,0.090mmol,41%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-
基)-3-甲基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(47.4mg,0.090mmol)、3-氟苯基硼酸(15.2mg,0.108mmol)和Na2CO3(47.9mg,0.452mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(10.4mg,0.009mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。用EtOAc稀释反应混合物并将其转移至萃取漏斗中。分离各层并用EtOAc(3×)萃取水层。合并的有机层经Na2SO4脱水,过滤并真空浓缩。添加THF/MeOH(2mL,1:1)和1M NaOH(181μL,0.181mmol)并在室温下搅拌反应16小时。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用55-75%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈黄色固体状的标题化合物(12.8mg,0.024mmol,27%)。
1H NMR(500MHz,DMSO)δ7.53–7.42(m,1H),7.30–7.23(m,2H),7.22–7.15(m,1H),6.41(s,1H),3.32–3.22(m,1H),2.74–2.60(m,1H),2.50–2.33(m,3H),2.26(s,3H),2.23–2.15(m,1H),2.07–1.97(m,1H),1.57–1.46(m,1H),1.23(dd,J=6.7,3.4Hz,6H);MS(m/z):526.3[M+1]+。
化合物6:1-(4-(4,4-二甲基环己-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(4-(4,4-二甲基环己-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-
1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、2-(4,4-二甲基环己-2-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(52mg,0.22mmol)、K2CO3(152mg,1.10mmol)和THF(2mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂Pd(dtbpf)Cl2(11mg,0.022mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用0至10%梯度的EtOAc/己烷纯化,得到呈黄色油状的标题化合物(57mg,0.12mmol,54%)。MS(m/z):484.0[M+1]+。
1-(4-(4,4-二甲基环己-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯
基)-3-甲基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-(4,4-二甲基环己-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(53mg,0.11mmol)、(3-氟苯基)硼酸(18mg,0.13mmol)和Na2CO3(58mg,0.55mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(13mg,0.011mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(13mg,0.55mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。在真空下蒸发溶剂并使用半制备型HPLC-MS(柱X-Bridge 30×50,用70-90%MeCN/NH4CO2H10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化产物,冻干后得到呈黄色固体状的标题化合物(13mg,0.027mmol,24%)。
1H NMR(500MHz,DMSO)δ7.52–7.44(m,1H),7.35-7.27(m,2H),7.23-7.15(m,1H),6.33-6.27(m,1H),3.28-3.19(m,1H),2.48-2.42(m,2H),2.28(s,3H),2.00-1.95(m,2H),1.43(t,J=6.4Hz,2H),1.23(d,J=6.7Hz,6H),0.94(s,6H)。MS(m/z):486.1[M+1]+。
化合物7:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)噻唑-2-基)-3-
甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、4,4,5,5-四甲基-2-(1,4-二氧杂螺[4.5]癸-6-烯-8-基)-1,3,2-二氧杂硼杂环戊烷(59mg,0.22mmol)、K2CO3(152mg,1.10mmol)和THF(2mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂Pd(dtbpf)Cl2(11mg,0.022mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用0至20%梯度的EtOAc/己烷纯化,得到呈黄色油状的标题化合物(55mg,0.11mmol,49%)。MS(m/z):514.0[M+1]+。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)噻唑-
2-基)-3-甲基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(53mg,0.10mmol)、(3-氟苯基)硼酸(17mg,0.12mmol)和Na2CO3(54mg,0.51mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(12mg,0.010mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。用EtOAc稀释反应混合物,用水和盐水洗涤。用MgSO4脱水,过滤并真空浓缩。将反应混合物溶解于THF/MeOH的1/1混合物(2mL)中并用1N NaOH(102μL,0.204mmol)处理。1小时后,再添加1N NaOH(102μL,0.204mmol)并持续搅拌16小时。在真空下蒸发溶剂并使用半制备型HPLC-MS(柱X-Bridge30×50,用55-75%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化产物,冻干后得到呈黄色固体状的标题化合物(14mg,0.027mmol,26%)。
1H NMR(500MHz,DMSO)δ7.53-7.45(m,1H),7.34-7.27(m,2H),7.25-7.16(m,1H),6.34-6.28(m,1H),3.92(s,4H),3.32–3.19(m,1H),2.67-2.60(m,2H),2.43–2.36(m,2H),2.28(s,3H),1.77(t,J=6.5Hz,2H),1.25(d,J=6.7Hz,6H)。MS(m/z):516.1[M+1]+。
化合物8:1-(4-(4-氯-3-(吗啉-4-羰基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(4-(4-氯-3-(吗啉-4-羰基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-
1H-吡唑-5-甲酸甲酯
将脱气的THF(2mL)添加至以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(75.0mg,0.165mmol)、(4-氯-3-(吗啉-4-羰基)苯基)硼酸(44mg,0.16mmol)、[1,1′-双(二叔丁基膦基)二茂铁]二氯钯(II)(8.2mg,0.016mmol)和碳酸钾(114mg,0.824mmol)的混合物中。在90℃下加热反应混合物18小时。添加水并用乙酸乙酯(2×)萃取混合物。合并的有机层用硫酸钠脱水,过滤并蒸发。粗产物在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(2至10%)纯化,得到呈浅橙色油状的标题化合物(47mg,0.078mmol,47%)。
1-(4-(4-氯-3-(吗啉-4-羰基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯
基)-3-甲基-1H-吡唑-5-甲酸
在85℃下,将4-溴-1-(4-(4-氯-3-(吗啉-4-羰基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(47mg,0.078mmol)、(3-氟苯基)硼酸(13mg,0.094mmol)、Pd(PPh3)4(9mg,0.008mmol)、Na2CO3(41mg,0.39mmol)于脱气的1,4-二噁烷和H2O(4:1,1.6mL)中的溶液加热18小时。添加LiOH水合物(16mg,0.39mmol)并在微波辐射下,在95℃下加热反应45分钟。添加1N HCl(1mL),随后添加水(5mL)并用EtOAc(3×5mL)萃取混合物。合并的有机层用硫酸钠脱水,过滤并减压蒸发。粗产物通过半制备型HPLC-MS(柱X-Bridge 30×50),使用MeCN于水(含10mM甲酸铵)中的溶液(45至65%)纯化。冻干产物,得到呈灰白色固体状的标题化合物(2mg,0.003mmol,4%)。
1H NMR(500MHz,DMSO)δ8.06(d,J=8.1Hz,1H),7.99(s,1H),7.65(d,J=8.5Hz,1H),7.52–7.44(m,1H),7.41–7.31(m,2H),7.22–7.13(m,1H),3.75–3.62(m,4H),3.61–3.51(m,2H),3.33(1H,在水信号之下),3.22–3.15(m,2H),2.30(s,3H),1.22(d,J=5.8Hz,6H);MS(m/z):552.1[M+1]+。
化合物9:4-(3,4-二氯苯基)-2-(4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-1-基)-5-(异丙基硫基)噻唑
在微波辐射下,在230℃下将1-(4-(3,4-二氯苯基)-5-(异丙基硫基)噻唑-2-基)-4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-5-甲酸(38.0mg,0.071mmol)、亚铬酸铜(12.0mg,0.085mmol)和喹啉(0.6ml)加热15分钟。粗产物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(55至80至100%)纯化,冻干后得到呈米色固体状的标题化合物(24.7mg,0.050mmol,71%)。
1H NMR(500MHz,DMSO)δ9.05(s,1H),8.32(d,J=2.0Hz,1H),8.14(dd,J=8.4,2.1Hz,1H),7.79(d,J=8.5Hz,1H),7.34(s,2H),3.38–3.32(m,J=13.4,6.7Hz,1H),3.29(s,3H),2.47(s,6H),1.23(d,J=6.7Hz,6H);MS(m/z):489.2[M+1]+。
化合物10:2-(4-(3-氟苯基)-3,5-二甲基-1H-吡唑-1-基)-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑
4-碘-3,5-二甲基-1H-吡唑
将3,5-二甲基-1H-吡唑(100mg,1.04mmol)溶解于1.0mL TFA中。整份添加N-碘代琥珀酰亚胺(234mg,1.04mmol)。在室温下搅拌反应1小时。LCMS显示完全反应。添加水和EtOAc并分离各相。用饱和亚硫酸钠水溶液洗涤有机相并经硫酸钠脱水,过滤并浓缩。得到230mg呈白色固体状的粗产物(1.04mmol,99%)。
4-(3-氟苯基)-3,5-二甲基-1H-吡唑
将4-碘-3,5-二甲基-1H-吡唑(231mg,1.04mmol)、硼酸(281mg,2.01mmol)、碳酸钠(551mg,5.20mmol)、二噁烷(5.2ml)和水(1.3ml)装入螺旋盖型管中。使混合物脱气10分钟并添加Pd(PPh3)4(60mg,0.05mmol)。密封管并将混合物加热至85℃。1小时后,无反应。16小时后,碘代吡唑:产物的比率是1:6。将混合物加热至110℃。6小时后,无碘代吡唑起始物质残留,因此将混合物冷却至室温,用水和EtOAc稀释。分离各相并用盐水洗涤水相。将SiO2添加至有机相中并将其浓缩至干。在二氧化硅上的粗品在Isco上使用己烷/EtOAc梯度进行纯化。得到144mg(0.76mmol,73%)呈无色油状的产物。
2-硫氰基-1-(4-(三氟甲基)苯基)乙酮
在室温下,将硫代氰酸钾(9.55g,98.3mmol)添加至2-溴-1-(4-(三氟甲基)苯基)乙酮(25.0g,93.6mmol)于MeCN(178mL)中的搅拌溶液中。将反应混合物加热至回流(90℃),保持2小时,接着将其冷却至室温并用水和EtOAc稀释。用EtOAc(3×)萃取水层。用盐水洗涤合并的有机层,经MgSO4脱水,过滤并真空浓缩,得到标题化合物(23.3g,94.9mmol,97%),不经进一步纯化即使用。
2-氯-4-(4-(三氟甲基)苯基)噻唑
在室温下,将2-硫氰基-1-(4-(三氟甲基)苯基)乙酮(23.3g,94.9mmol)和4M HCl的二噁烷溶液(142mL,569mmol)于二噁烷(95mL)中的混合物搅拌16小时。真空浓缩反应混合物并用NaHCO3饱和水溶液稀释残余物并用EtOAc(2×)萃取。用盐水洗涤合并的有机层,经MgSO4脱水,过滤并真空浓缩,并得到呈褐色固体状的标题化合物(25.0g,94.8mmol,100%)。
2-氯-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑
在-78℃下,将n-BuLi/己烷的2.5M溶液(18.8mL,40.3mmol)添加至2-氯-4-(4-(三氟甲基)苯基)噻唑(10.0g,32.3mmol)的THF溶液(107mL)中。在相同温度下搅拌反应混合物30分钟。将二异丙基二硫醚(10.3mL,64.5mmol)添加至反应物中并在相同温度下搅拌2小时。添加水以淬灭反应且接着添加Et2O。将反应混合物转移至分液漏斗中并分离各层。用Et2O(2×)萃取水层。合并的有机层经Na2SO4脱水并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至1%梯度)纯化并得到呈黄色油状的标题化合物(3.05g,9.03mmol,28%)。
2-(4-(3-氟苯基)-3,5-二甲基-1H-吡唑-1-基)-5-(异丙基硫基)-4-(4-(三氟甲
基)苯基)噻唑
在10mL微波小瓶中放入4-(3-氟苯基)-3,5-二甲基-1H-吡唑(140mg,1.0mmol)、以上制备的噻唑(372mg,1.1mmol)、K2CO3(690mg,5.0mmol)和DMSO(3.3ml)。使氮气在DMSO中鼓泡10分钟。且接着添加CuI(57mg,0.30mmol)。封盖所得溶液并用微波在100℃下加热3小时。LCMS显示40%转化(吡唑:产物比)并完全反应。在油浴中加热混合物3小时。LCMS显示74%转化。持续加热16小时。LCMS显示完全转化。用EtOAc和水稀释混合物,分离各相并用水洗涤有机相3次,接着用盐水洗涤。将二氧化硅添加至有机相中并将其浓缩至干。在SiO2上的粗品在Isco上使用己烷/10%DCM梯度进行纯化。得到151mg(0.307mmol,31%)黄色油状物。这一混合物在反相Isco上,使用C18柱,用50-100%梯度的MeCN/水(10mM甲酸铵,pH 3.8)洗脱进行再纯化。浓缩含产物的洗脱份以移除大部分的乙腈,添加水并且冷冻并冻干烧瓶。得到呈浅黄色固体状的产物(99mg,0.201mmol,20%产率)。
1H NMR(500MHz,DMSO)δ8.24(d,J=8.2Hz,2H),7.87(d,J=8.4Hz,2H),7.53(dd,J=14.2,7.9Hz,1H),7.29–7.18(m,3H),3.39–3.33(m,1H),2.69(s,3H),2.25(s,3H),1.23(d,J=6.7Hz,6H);MS(m/z):492.3[M+1]+。
化合物11:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、XantPhos(12.7mg,0.022mmol)和Cs2CO3(358mg,1.10mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷(2mL)和哌啶(21.7uL,0.220mmol)的溶液,接着将该溶液添加至微波小瓶中,随后添加催化剂RuPhos Palladacycle(17.9mg,0.022mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(1%等度洗脱)纯化,得到呈黄色油状的标题化合物(41.0mg,0.089mmol,41%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡
唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(41.0mg,0.089mmol)、3-氟苯基硼酸(15.0mg,0.108mmol)和Na2CO3(47.3mg,0.446mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(10.3mg,0.009mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(18.7mg,0.446mmol)添加至反应混合物中并在微波辐射下在120℃下搅拌10分钟。用EtOAc和0.1M HCl稀释反应混合物。用EtOAc(2×)萃取水层并用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用55-75%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈黄色固体状的标题化合物(3.24mg,0.007mmol,8%)。
1H NMR(500MHz,DMSO)δ7.55–7.40(m,1H),7.41–7.24(m,2H),7.23–7.05(m,1H),3.59–3.49(m,4H),3.18–3.06(m,1H),2.27(s,3H),1.55(s,6H),1.23(d,J=6.7Hz,6H);MS(m/z):461.2[M+1]+。
化合物12:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-
吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(100mg,0.220mmol)、4-(三氟甲基)哌啶(41.7mg,0.220mmol)、XantPhos(12.7mg,0.022mmol)和Cs2CO3(358mg,1.10mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷(2mL),接着将其添加至微波小瓶中,随后添加催化剂RuPhos Palladacycle(17.9mg,0.022mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(1%等度洗脱)纯化,得到呈黄色油状的标题化合物(52.0mg,0.099mmol,45%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-
甲基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(52.0mg,0.099mmol)、3-氟苯基硼酸(16.6mg,0.118mmol)和Na2CO3(52.3mg,0.493mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(11.4mg,0.010mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(42.0mg,0.493mmol)添加至反应混合物中并在微波辐射下在120℃下搅拌10分钟。用EtOAc和0.1M HCl稀释反应混合物。用EtOAc(2×)萃取水层并用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用55-75%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈黄色固体状的标题化合物(3.41mg,0.007mmol,7%)。
1H NMR(500MHz,DMSO)δ7.52–7.43(m,1H),7.36–7.26(m,2H),7.19(t,J=7.6Hz,1H),4.38(d,J=12.8Hz,2H),3.19–3.07(m,1H),2.95–2.86(m,2H),2.58–2.51(m,1H),2.28(s,3H),1.80(d,J=10.7Hz,2H),1.49(qd,J=12.6,4.1Hz,2H),1.24(d,J=6.7Hz,6H);MS(m/z):529.1[M+1]+。
化合物13:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧基-1H-吡唑-5-甲酸
2-硫氰基-1-(4-(三氟甲基)苯基)乙酮
在室温下,将硫代氰酸钾(9.55g,98.3mmol)添加至2-溴-1-(4-(三氟甲基)苯基)乙酮(25.0g,93.6mmol)于MeCN(178mL)中的搅拌溶液中。将反应混合物加热至回流(90℃),保持2小时,接着将其冷却至室温并用水和EtOAc稀释。用EtOAc(3×)萃取水层。用盐水洗涤合并的有机层,经MgSO4脱水,过滤并真空浓缩,得到标题化合物(23.3g,94.9mmol,97%),不经进一步纯化即使用。
2-氯-4-(4-(三氟甲基)苯基)噻唑
在室温下,将2-硫氰基-1-(4-(三氟甲基)苯基)乙酮(23.3g,94.9mmol)和4M HCl的二噁烷溶液(142mL,569mmol)于二噁烷(95mL)中的混合物搅拌16小时。真空浓缩反应混合物并用NaHCO3饱和水溶液稀释残余物并用EtOAc(2×)萃取。用盐水洗涤合并的有机层,经MgSO4脱水,过滤并真空浓缩,并得到呈褐色固体状的标题化合物(25.0g,94.8mmol,100%)。
2-氯-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑
在-78℃下,将n-BuLi/己烷的2.5M溶液(18.8mL,40.3mmol)添加至2-氯-4-(4-(三氟甲基)苯基)噻唑(10.0g,32.3mmol)的THF溶液(107mL)中。在相同温度下搅拌反应混合物30分钟。将二异丙基二硫醚(10.3mL,64.5mmol)添加至反应物中并在相同温度下搅拌2小时。添加水以淬灭反应且接着添加Et2O。将反应混合物转移至分液漏斗中并分离各层。用Et2O(2×)萃取水层。合并的有机层经Na2SO4脱水并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至1%梯度)纯化并得到呈黄色油状的标题化合物(3.05g,9.03mmol,28%)。
2-肼基-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑
在圆底烧瓶中,将DIPEA(3.2mL,18.2mmol)添加至盐酸肼(1.2g,18.2mmol)和2-氯-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑(3.1g,9.1mmol)于NMP(18mL)中的溶液中。在油浴中将烧瓶加热至135℃,保持2小时。用水稀释反应混合物并用Et2O萃取。用盐水(3×)洗涤合并的有机层,并经Na2SO4脱水,过滤并真空浓缩。由此得到呈蓝色油状的标题化合物(2.85g,8.55mmol,95%)。
3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲
酸甲酯
在0℃下,将2-肼基-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑(1.9g,5.76mmol)于甲苯(5mL)中的溶液缓慢添加至2,5-二氧代己-3-炔二酸二甲酯(900mg,6.33mmol)于甲苯(3mL)和AcOH(4mL)中的溶液中。在室温下搅拌反应1小时并使其回流4小时。真空浓缩反应混合物且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(5至30%梯度)纯化,得到呈黄色油状的标题化合物(714mg,1.61mmol,28%)。
1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧基-1H-吡唑-5-
甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的圆底烧瓶中放入于THF(7mL)中的ADDP(171mg,0.677mmol)和三丁基膦(205mg,1.02mmol),随后添加3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(150mg,0.338mmol)和MeOH(20.6μL,0.507mmol)。将反应混合物加热至80℃,保持3小时。真空浓缩反应混合物并将其溶解于Et2O中以过滤三丁基膦氧化物。真空浓缩滤液且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(10至30%梯度)纯化,得到呈黄色油状的标题化合物(115mg,0.251mmol,74%)。
4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧基-1H-吡
唑-5-甲酸甲酯
将溴于乙腈中的2M溶液(0.45mL,0.900mmol)添加至1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧基-1H-吡唑-5-甲酸甲酯(137mg,0.300mmol)于MeCN/DCM(4mL,1:1mL)中的溶液中。在室温下搅拌反应3小时。添加饱和Na2SO3水溶液并用EtOAc(3×)萃取反应混合物。合并的有机层用硫酸钠脱水,过滤并减压蒸发。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(2至10%)纯化,得到呈黄色油状的标题化合物(98.0mg,0.183mmol,61%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧
基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧基-1H-吡唑-5-甲酸甲酯(98.0mg,0.183mmol)、3-氟苯基硼酸(60.7mg,0.219mmol)和Na2CO3(96.8mg,0.914mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(21.1mg,0.018mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(38.3mg,0.914mmol)添加至反应混合物中并在微波辐射下在120℃下搅拌10分钟。用EtOAc和0.1M HCl稀释反应混合物。用EtOAc(2×)萃取水层并用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用40-60%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈黄色固体状的标题化合物(2.95mg,0.005mmol,3%)。
1H NMR(500MHz,MeOD)δ8.31(d,J=8.1Hz,2H),7.76(d,J=8.3Hz,2H),7.60–7.55(m,2H),7.40–7.34(m,1H),7.02–6.97(m,1H),3.95(s,3H),3.29–3.21(m,1H),1.25(d,J=6.7Hz,6H);MS(m/z):538.2[M+1]+。
化合物14:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-吗啉代噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-吗啉代噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(300mg,0.659mmol)、XantPhos(38.1mg,0.066mmol)和Cs2CO3(1.07g,3.30mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷(3mL)和吗啉(57.4μL,0.659mmol)的溶液,接着将其添加至微波小瓶中,随后添加催化剂RuPhos Palladacycle(53.8mg,0.066mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(5至20%梯度)纯化,得到呈黄色油状的标题化合物(108mg,0.234mmol,36%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-吗啉代噻唑-2-基)-3-甲基-1H-吡唑-5-甲
酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-吗啉代噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(108mg,0.234mmol)、3-氟苯基硼酸(39.3mg,0.281mmol)和Na2CO3(124mg,1.17mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(27.0mg,0.023mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(49.1mg,1.17mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。用EtOAc和0.1M HCl稀释反应混合物。用EtOAc(2×)萃取水层并用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用30-50%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈黄色固体状的标题化合物(18.0mg,0.039mmol,16%)。
1H NMR(500MHz,DMSO)δ7.46(dd,J=14.4,7.6Hz,1H),7.39–7.29(m,2H),3.70–3.63(m,4H),3.58–3.51(m,4H),3.16–3.07(m,J=13.4,6.7Hz,1H),2.27(s,3H),1.24(d,J=6.7Hz,6H);MS(m/z):463.2[M+1]+。
化合物15:4-(3-氟苯基)-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸
2-硫氰基-1-(4-(三氟甲基)苯基)乙酮
在室温下,将硫代氰酸钾(9.55g,98.3mmol)添加至2-溴-1-(4-(三氟甲基)苯基)乙酮(25.0g,93.6mmol)于MeCN(178mL)中的搅拌溶液中。将反应混合物加热至回流(90℃),保持2小时,接着将其冷却至室温并用水和EtOAc稀释。用EtOAc(3×)萃取水层。用盐水洗涤合并的有机层,经MgSO4脱水,过滤并真空浓缩,得到标题化合物(23.3g,94.9mmol,97%),不经进一步纯化即使用。
2-氯-4-(4-(三氟甲基)苯基)噻唑
在室温下,将2-硫氰基-1-(4-(三氟甲基)苯基)乙酮(23.3g,94.9mmol)和4M HCl的二噁烷溶液(142mL,569mmol)于二噁烷(95mL)中的混合物搅拌16小时。真空浓缩反应混合物并用NaHCO3饱和水溶液稀释残余物并用EtOAc(2×)萃取。用盐水洗涤合并的有机层,经MgSO4脱水,过滤并真空浓缩,并得到呈褐色固体状的标题化合物(25.0g,94.8mmol,100%)。
2-氯-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑
在-78℃下,将n-BuLi/己烷的2.5M溶液(18.8mL,40.3mmol)添加至2-氯-4-(4-(三氟甲基)苯基)噻唑(10.0g,32.3mmol)的THF溶液(107mL)中。在相同温度下搅拌反应混合物30分钟。将二异丙基二硫醚(10.3mL,64.5mmol)添加至反应物中并在相同温度下搅拌2小时。添加水以淬灭反应且接着添加Et2O。将反应混合物转移至分液漏斗中并分离各层。用Et2O(2×)萃取水层。合并的有机层经Na2SO4脱水并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至1%梯度)纯化并得到呈黄色油状的标题化合物(3.05g,9.03mmol,28%)。
2-肼基-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑
在圆底烧瓶中,将二异丙基乙胺(3.2mL,18.2mmol)添加至盐酸肼(1.2g,18.2mmol)和2-氯-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑(3.1g,9.1mmol)于N-甲基吡咯烷(“NMP”)(18mL)中的溶液中。在油浴中将烧瓶加热至135℃,保持2小时。用水稀释反应混合物并用Et2O萃取。用盐水(3×)洗涤合并的有机层,并经Na2SO4脱水,过滤并真空浓缩。由此得到呈蓝色油状的标题化合物(2.85g,8.55mmol,95%)。
3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲
酸甲酯
在0℃下,将2-肼基-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑(1.9g,5.76mmol)于甲苯(5mL)中的溶液缓慢添加至2,5-二氧代己-3-炔二酸二甲酯(900mg,6.33mmol)于甲苯(3mL)和AcOH(4mL)中的溶液中。在室温下搅拌反应1小时并使其回流4小时。真空浓缩反应混合物且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(5至30%梯度)纯化,得到呈黄色油状的标题化合物(714mg,1.61mmol,28%)。
4-溴-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-
5-甲酸甲酯
将N-溴代琥珀酰亚胺(188mg,1.06mmol)逐滴添加至3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(469mg,1.06mmol)于MeCN/DCM(8mL,1:1)中的溶液中。在室温下搅拌反应5分钟。并且接着用水和数滴Na2S2O3淬灭。用EtOAc(2×)萃取水层且合并的有机层经Na2SO4脱水,过滤并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至30%梯度)纯化,得到呈粉色固体状的标题化合物(139mg,0.266mmol,25%)。
3-乙酰氧基-4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H- 吡唑-5-甲酸甲酯
将4-溴-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(89mg,0.17mmol)放入乙酸酐(5.00mL)中,随后添加吡啶(2滴)。在室温下搅拌反应1小时且接着蒸发至干。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(5%等度洗脱)纯化,得到呈白色固体状的标题化合物(50mg,0.089mmol,52%)。
4-(3-氟苯基)-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-
1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入3-乙酰氧基-4-溴-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(30.0mg,0.053mmol)、3-氟苯基硼酸(8.93mg,0.064mmol)和KF(10.2mg,0.175mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF(0.5mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PtBu3)2(2.72mg,0.005mmol)。封盖小瓶并在室温下搅拌72小时。粗产物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(40至80%)纯化,得到呈白色固体状的标题化合物(4.00mg,0.007mmol,14%)。
4-(3-氟苯基)-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-
1H-吡唑-5-甲酸
在10mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释4-(3-氟苯基)-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(4.00mg,0.007mmol)。添加1M NaOH溶液(15μL,0.015mmol)并在室温下搅拌反应过夜。粗产物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(35至65%)纯化,冻干后得到呈浅绿色粉末状的标题化合物(0.548mg,0.001mmol,14%)。
1H NMR(500MHz,MeOD)δ8.33–8.28(m,2H),7.74–7.70(m,2H),7.54–7.48(m,2H),7.29–7.20(m,1H),6.82–6.75(m,1H),4.57(br s,1H),3.25–3.17(m,1H),1.22(d,J=6.7Hz,6H);MS(m/z):524.2[M+1]+。
化合物16和17:1-(5-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-3-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸和1-(3-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-5-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
3,4-二氯苯甲酰肼
将水合肼(20.2ml,324mmol)添加至溶于EtOH(108ml)中的3,4-二氯苯甲酸甲酯(4.52g,21.6mmol)中。使反应物回流1.5小时。LCMS指示反应完成。蒸发大部分乙醇并在水中湿磨产物。在高真空下干燥后,得到呈白色固体状的产物(4.42g,21.6mmol)。
N-(5-(3,4-二氯苯基)-1H-1,2,4-三唑-3-基)硝酰胺
使硝基胍(3.04g,29.3mmol)悬浮于1N NaOH(19.5ml,19.5mmol)中。添加3,4-二氯苯甲酰肼(2.00g,9.75mmol)(其停留在表面上,但当加热时进入溶液中)。在75℃下加热反应3小时。添加1N HCl(20mL)以使混合物酸化(产物沉淀)。过滤混合物并用水洗涤。LCMS显示产物是主要物质。在高真空下干燥后得到呈灰白色固体状的产物(2.36g,6.80mmol,70%)。
5-(3,4-二氯苯基)-3-肼基-1H-1,2,4-三唑
在含有N-(5-(3,4-二氯苯基)-1H-1,2,4-三唑-3-基)硝酰胺(250mg,0.91mmol)的烧瓶中添加乙酸(4.56mL)。搅拌悬浮液达到10℃并添加锌粉(298mg,4.56mmol)于水(4.56mL)中的悬浮液。16小时后,将混合物冷却至0℃并添加8M氢氧化钠水溶液(15mL),并且检查pH值达到碱性(pH>10)。将混合物用于下一步骤中。
2-(5-(3,4-二氯苯基)-1H-1,2,4-三唑-3-基)肼甲酸叔丁酯
在含有5-(3,4-二氯苯基)-3-肼基-1H-1,2,4-三唑于水中的粗品溶液(pH<10,来自前一步骤的水相,理论量是223mg,0.91mmol)的烧瓶中添加THF(9mL)。添加二碳酸二叔丁酯(499mg,2.28mmol)。16小时后,LCMS显示无起始物质并有许多产物。用EtOAc将混合物转移至分液漏斗中并分离各相。用EtOAc萃取水相。用盐水洗涤合并的有机相并经硫酸钠脱水,过滤并浓缩。得到呈浅褐色油状的Boc-产物和Boc-杂质的混合物。直接用于下一步骤中。
1-(5-(3,4-二氯苯基)-1H-1,2,4-三唑-3-基)-3-甲基-1H-吡唑-5-甲酸甲酯
在含有前一步骤的粗Boc保护的物质(理论量314mg,0.91mmol)的烧瓶中添加MeOH(9.1mL)。添加酮基-肟(332mg,1.92mmol),随后添加37%的浓HCl水溶液(0.33ml,4.0mmol)。在油浴中将混合物加热至80℃并在1小时和3小时后,LCMS显示仅微量产物。再添加37%的浓HCl水溶液(0.33mL,4.0mmol)并在加热4小时后,无起始物质。使用EtOAc将混合物转移至分液漏斗中并用饱和碳酸氢钠溶液,接着盐水洗涤有机相。有机相经硫酸钠脱水,过滤并浓缩。粗品在Isco上使用装载有DMSO的C18柱,用35-55%梯度的MeCN/水(含有10mM甲酸铵,pH 3.8)洗脱进行纯化。冻干含产物的洗脱份,得到呈灰白色固体状的产物(72mg,0.20mmol,22%)。
1-(5-(3,4-二氯苯基)-1H-1,2,4-三唑-3-基)-4-碘-3-甲基-1H-吡唑-5-甲酸甲
酯
在含有前一步骤的三唑基吡唑(72mg,0.20mmol)的烧瓶中添加TFA(1mL)。添加N-碘代琥珀酰亚胺(115mg,0.51mmol)并在搅拌16小时后,LCMS显示无起始物质并且有纯产物。使用EtOAc将混合物转移至分液漏斗中并用水,接着用饱和碳酸氢钠溶液,接着盐水洗涤有机相。有机相经硫酸钠脱水,过滤并浓缩。得到呈浅黄色油状的粗产物(98mg,0.20mmol,100%)并以原样用于下一步骤中。
1-(3-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-5-基)-4-碘-3-甲基-1H-吡唑-
5-甲酸甲酯和1-(5-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-3-基)-4-碘-3-甲基-1H-
吡唑-5-甲酸甲酯
在含有前一步骤的产物(98mg,0.205mmol)的烧瓶中添加碳酸铯(200mg,0.61mmol)、DMF(2mL),接着添加异丁基碘(189uL,302mg,1.64mmol)。16小时后,无起始物质吡唑并且产物的比率是77:13产物。将混合物添加至C18柱中,用65-100%梯度的MeCN/水(含有10mM甲酸铵,pH 3.8)洗脱。合并含有产物的洗脱份并冻干,得到呈灰白色固体状的产物酯的混合物(110mg,0.205mmol,100%)。
1-(5-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-3-基)-4-(3-氟苯基)-3-甲基-
1H-吡唑-5-甲酸和1-(3-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-5-基)-4-(3-氟苯
基)-3-甲基-1H-吡唑-5-甲酸
将前一步骤的混合物(5:1比率,110mg,0.21mmol)、硼酸(58mg,0.41mmol)、碳酸钠(109mg,1.03mmol)、二噁烷(2.1ml)和水(0.5mL)装入螺旋盖型管中。使混合物脱气10分钟并添加Pd(PPh3)4(24mg,0.021mmol)。密封管并将混合物加热至85℃。16小时后,LCMS显示无产物,因此再添加硼酸(58mg,0.41mmol)、碳酸钠(109mg,1.03mmol)和脱气的水(0.5mL)。使混合物脱气10分钟并添加Pd(PPh3)4(24mg,0.021mmol)。4小时后,LCMS显示无碘代吡唑起始物质,因此将混合物冷却至室温,用2mL的1M HCl水溶液中和并用DMSO将其添加至C18柱中。混合物在Isco上使用25-100%梯度的MeCN/水(含有10mM甲酸铵,pH 3.8)纯化。冻干酯部分,得到呈灰白色固体状的酯混合物(38mg,0.076mmol,37%)。
1-(5-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-3-基)-4-(3-氟苯基)-3-甲基-
1H-吡唑-5-甲酸和1-(3-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-5-基)-4-(3-氟苯
基)-3-甲基-1H-吡唑-5-甲酸
在含有前一步骤的酯混合物(1:3比率的异构体,35mg,70umol)的微波小瓶中添加二噁烷(0.70mL)、甲醇(70uL)以及1M NaOH的水溶液(0.70mL,0.70mmol)。在微波反应器中将混合物加热至100℃,保持20分钟。LCMS显示完全反应。添加1M HCl的水溶液(0.70mL,0.70mmol)且混合物在反相Isco上,使用C18柱,用30-70%梯度的MeCN/水(10mM甲酸铵,pH3.8)洗脱来纯化。合并含有第1种洗脱产物的纯洗脱份,浓缩以移除大部分乙腈,冷冻并冻干。得到呈灰白色固体状的1-(5-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-3-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸(5mg,0.010mmol,15%产率)。合并含有第2种洗脱产物的纯洗脱份,浓缩以移除大部分乙腈,冷冻并冻干。得到呈白色固体状的1-(3-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-5-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸(8mg,0.016mmol,24%产率)。
1H NMR(500MHz,CDCl3)δ7.75(s,1H),7.58(d,J=8.2Hz,1H),7.47(d,J=7.1Hz,1H),7.33(dd,J=14.1,7.7Hz,1H),7.08(d,J=7.4Hz,1H),7.06–6.98(m,2H),4.03(d,J=7.2Hz,2H),2.38–2.31(m,1H),2.28(s,3H),0.87(d,J=6.6Hz,6H)。甲酸OH信号未被发现或隐藏在水信号之下(br s,3.7-2.5ppm);MS(m/z):488.12[M+1]+。
1H NMR(500MHz,CDCl3)δ8.07(d,J=2.0Hz,1H),7.77(dd,J=8.4,2.0Hz,1H),7.42(d,J=8.4Hz,1H),7.32(td,J=8.0,6.0Hz,1H),7.06–6.92(m,3H),4.03(d,J=7.3Hz,2H),2.31–2.22(m,1H),2.20(s,3H),0.88(d,J=6.7Hz,6H);MS(m/z):488.12[M+1]+。
化合物18:1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡
唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上所描述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(300mg,0.659mmol)、4,4-二氟哌啶(104mg,0.659mmol)、XantPhos(38.1mg,0.066mmol)和Cs2CO3(1.07g,3.30mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷(3mL),接着将其添加至微波小瓶中,随后添加催化剂RuPhos Palladacycle(53.8mg,0.066mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用己烷(100%等度洗脱)纯化,得到呈黄色油状的标题化合物(173mg,0.350mmol,53%)。
1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲
基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(173mg,0.349mmol)、3-氟苯基硼酸(58.6mg,0.419mmol)和Na2CO3(185mg,1.75mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(40.4mg,0.035mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。用EtOAc稀释反应混合物。用EtOAc(2×)萃取水层并用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至1%梯度)纯化,得到呈黄色油状的标题化合物(150mg,0.294mmol,84%)。
1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲
基-1H-吡唑-5-甲酸
在25mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸甲酯(150mg,0.294mmol)。添加1M NaOH溶液(588uL,0.588mmol)并在室温下搅拌反应16小时。添加1MHCl溶液(588uL,0.588mmol)和水(2mL)。反应混合物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(40至70%)直接纯化,冻干后得到呈黄色粉末状的标题化合物(31.5mg,0.064mmol,22%)。
1H NMR(500MHz,DMSO)δ7.50(dd,J=14.6,7.9Hz,1H),7.34–7.27(m,2H),7.25–7.18(m,1H),3.74–3.66(m,4H),3.22–3.13(m,1H),2.28(s,3H),2.07–1.95(m,4H),1.25(d,J=6.7Hz,6H);MS(m/z):497.1[M+1]+。
化合物19:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(对映纯–未知立体化学)
在25mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(如以上所描述制备并拆分成对映纯(12.7mg,0.024mmol)。添加1M NaOH溶液(235uL,0.235mmol)并在60℃下搅拌反应16小时。添加1M HCl溶液(235uL,0.235mmol)和水(10mL)。用EtOAc稀释反应混合物并将其转移至萃取漏斗中。分离各层并用EtOAc(3×)萃取水层。合并的有机层经Na2SO4脱水,过滤并真空浓缩,冻干后得到呈黄色固体状的标题化合物(9.00mg,0.017mmol,73%)。
1H NMR(500MHz,MeOD)δ7.49–7.42(m,1H),7.28–7.23(m,1H),7.22–7.17(m,1H),7.15–7.09(m,1H),6.53–6.44(m,1H),3.30–3.21(m,1H),2.80(d,J=18.1Hz,1H),2.59–2.40(m,3H),2.31(s,3H),2.18–2.10(m,1H),1.71–1.56(m,2H),1.30(dd,J=6.7,1.9Hz,6H);MS(m/z):526.1[M+1]+。
化合物19:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(对映纯–未知立体化学)
在25mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释对映纯4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(30.7mg,0.057mmol)(如以上所描述制备并拆分)。添加1M NaOH溶液(569uL,0.569mmol)并在60℃下搅拌反应16小时。添加1M HCl溶液(569uL,0.569mmol)和水(10mL)。用EtOAc稀释反应混合物并将其转移至萃取漏斗中。分离各层并用EtOAc(3×)萃取水层。合并的有机层经Na2SO4脱水,过滤并真空浓缩,冻干后得到呈黄色固体状的标题化合物(20.0mg,0.038mmol,67%)。
1H NMR(500MHz,MeOD)δ7.36(td,J=8.0,6.0Hz,1H),7.18–7.13(m,1H),7.11–7.07(m,1H),7.05–6.99(m,1H),6.41–6.34(m,1H),3.21–3.11(m,1H),2.70(d,J=18.3Hz,1H),2.50–2.30(m,3H),2.21(s,3H),2.08–1.99(m,1H),1.59–1.42(m,2H),1.20(dd,J=6.7,1.9Hz,6H);MS(m/z):526.1[M+1]+。
化合物20:4-(3-氟苯基)-3-甲基-1-(4-(4-(三氟甲基)环己基)噻唑-2-基)-1H-吡唑-5-甲酸
在配备磁力搅拌棒的10mL玻璃小瓶中,将化合物5(20.0mg,0.037mmol)溶解于乙酸(4mL)中。添加Pd/活性碳(3.94mg,0.004mmol)并在氢气氛下,在80℃下搅拌反应混合物16小时。粗产物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(35至65%)纯化,冻干后得到呈白色粉末状的标题化合物(3.00mg,0.007mmol,18%)。
1H NMR(500MHz,MeOD)δ7.47–7.40(m,1H),7.30–7.25(m,1H),7.24–7.18(m,1H),7.13–7.06(m,2H),3.09–3.01(m,1H),2.36–2.28(m,4H),2.27–2.16(m,1H),2.05(d,J=11.6Hz,1H),1.89–1.72(m,3H),1.67–1.56(m,2H),1.54–1.41(m,1H),1.35–1.20(m,1H);MS(m/z):454.1[M+1]+。
化合物22:4-(3-氟苯基)-1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
1-(5-碘-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将大体上如以上关于丁基硫代类似物制备的3-甲基-1-(4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(100mg,0.272mmol)溶解于TFA(1.4ml)中并添加N-碘代琥珀酰亚胺(73mg,0.33mmol)。在室温下搅拌反应混合物45分钟。将反应混合物倒入水中并用EtOAc萃取。依序用NaHCO3饱和水溶液、10%Na2S2O3的水溶液和盐水洗涤有机层。有机层经硫酸镁脱水,过滤并浓缩。产物在硅胶上通过快速色谱法(干式充填),使用0至10%梯度的EtOAc/己烷纯化,得到呈粉色固体状的标题化合物(79mg,0.16mmol,59%)。MS(m/z):493.9[M+1]+。
3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡
唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入1-(5-碘-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(200mg,0.405mmol)、(2-甲基丙-1-烯-1-基)硼酸(49mg,0.49mmol)、K2CO3(280mg,2.03mmol)和THF(3mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂Pd(dtbpf)(26mg,0.041mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。产物在硅胶上通过快速色谱法(干式充填),使用0至10%梯度的EtOAc/己烷纯化,得到呈黄色油状的标题化合物(64mg,0.059mmol,38%)。MS(m/z):422.3[M+1]+。
1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(64mg,0.15mmol)溶解于MeOH/AcOH(3ml)中并添加20%Pd(OH)2/C(16mg)。在氢气氛下净化并搅拌反应混合物16小时。反应混合物经垫过滤并真空浓缩。使粗反应混合物再处于反应条件下,再保持两个循环,蒸发后得到呈浅黄色固体状的标题化合物(36mg,0.084mmol,55%)。MS(m/z):424.2[M+1]+。
4-溴-1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
甲酯
将1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(36mg,0.084mmol)溶解于MeCN/DCM(1mL)中并逐滴添加溴于MeCN中的2M溶液(210μL,0.420mmol)。在室温下搅拌反应混合物16小时,并用10%的Na2S2O3水溶液淬灭。用EtOAc稀释反应混合物,用水和盐水洗涤。有机层经硫酸镁脱水,过滤并浓缩,得到呈黄色固体状的标题化合物(36mg,0.072mmol,85%)。MS(m/z):502.0[M+1]+。
4-(3-氟苯基)-1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡
唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(36mg,0.072mmol)、(3-氟苯基)硼酸(12mg,0.086mmol)和Na2CO3(38mg,0.36mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(8.3mg,0.0072mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(8.5mg,0.36mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用60-80%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈白色固体状的标题化合物(7.5mg,0.015mmol,21%)。
1H NMR(500MHz,DMSO)δ7.83(s,4H),7.53-7.47(m,1H),7.34-7.28(m,2H),7.25-7.18(m,1H),2.89(d,J=7.2Hz,2H),2.30(s,3H),1.96–1.83(m,1H),0.93(d,J=6.6Hz,6H)。MS(m/z):504.0[M+1]+。
化合物23:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-(2,2,2-三氟乙基)哌嗪-1-甲酸叔丁酯
将三氟碘乙烷(0.794mL,8.05mmol)添加至boc-哌嗪(1.25g,6.71mmol)、DIPEA(6.25mL,33.6mmol)和DMF(7mL)的搅拌的溶液中。在室温下搅拌反应混合物72小时。过滤反应物并蒸发滤液。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(20至100%梯度)纯化,得到呈黄色固体状的标题化合物(253mg,0.943mmol,14%)。
1-(2,2,2-三氟乙基)哌嗪盐酸盐
将4-(2,2,2-三氟乙基)哌嗪-1-甲酸叔丁酯(253mg,0.94mmol)溶解于DCM(9mL)中并添加4M HCl的二噁烷溶液(4.72mL,18.9mmol)。在室温下搅拌反应3小时。接着在真空中浓缩产物并与DCM共蒸发3次,得到呈米色固体状的标题化合物(200mg,0.977mmol,100%)。
4-溴-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-基)-3-甲
基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(300mg,0.659mmol)、1-(2,2,2-三氟乙基)哌嗪盐酸盐(135mg,0.659mmol)、XantPhos(38.1mg,0.066mmol)和Cs2CO3(1.07g,3.30mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷(3mL),接着将其添加至微波小瓶中,随后添加催化剂RuPhos Palladacycle(53.8mg,0.066mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(10至30%梯度)纯化,得到呈黄色油状的标题化合物(123mg,0.227mmol,34%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-
基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(123mg,0.227mmol)、3-氟苯基硼酸(38.1mg,0.272mmol)和Na2CO3(120mg,1.13mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(26.2mg,0.023mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。用EtOAc稀释反应混合物。用EtOAc(2×)萃取水层并用盐水洗涤合并的有机层,经Na2SO4脱水,过滤并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至15%梯度)纯化,得到呈黄色油状的标题化合物(41.3mg,0.074mmol,33%)。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-
基)-3-甲基-1H-吡唑-5-甲酸
在25mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(41.3mg,0.076mmol)。添加1M NaOH溶液(381uL,0.381mmol)并在室温下搅拌反应16小时。添加1M HCl溶液(381uL,0.381mmol)和水(2mL)。反应混合物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(40至70%)直接纯化,冻干后得到呈黄色粉末状的标题化合物(32.0mg,0.059mmol,77%)。
1H NMR(500MHz,DMSO)δ7.56–7.46(m,J=14.4,8.0Hz,1H),7.28(d,J=8.4Hz,2H),7.26–7.19(m,J=9.0Hz,1H),3.59–3.53(m,4H),3.21(dd,J=20.5,10.2Hz,2H),3.17–3.07(m,J=13.4,6.7Hz,1H),2.73–2.66(m,4H),2.28(s,3H),1.24(d,J=6.7Hz,6H);MS(m/z):544.1[M+1]+。
化合物24:1-(4-(4-氰基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(4-(4-氰基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-
5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(150mg,0.330mmol)、哌啶-4-甲腈(36mg,0.33mmol)、Cs2CO3(537mg,1.65mmol)、XantPhos(19mg,0.033mmol)和二噁烷(3mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂RuPhosPd G1(27mg,0.033mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用70-90%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,蒸发后得到呈黄色固体状的标题化合物(29mg,0.059mmol,18%)。MS(m/z):484.0[M+1]+。
1-(4-(4-氰基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-
1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-(4-氰基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(29mg,0.059mmol)、(3-氟苯基)硼酸(9.9mg,0.071mmol)和Na2CO3(31mg,0.29mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(6.8mg,0.0059mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(7.0mg,0.29mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用50-70%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈浅黄色固体状的标题化合物(2.3mg,0.0047mmol,8%)。
1H NMR(500MHz,MeOD)δ7.41(td,J=8.0,6.1Hz,1H),7.37-7.34(m,1H),7.33–7.28(m,1H),7.07–7.01(m,1H),4.02-3.95(m,2H),3.54-3.47(m,2H),3.22-3.10(m,1H),3.01-2.91(m,1H),2.32(s,3H),2.09–1.98(m,2H),1.93–1.80(m,2H),1.30(d,J=6.7Hz,6H)。MS(m/z):486.1[M+1]+。
化合物25:1-(4-(4-环丙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(4-(4-环丙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡
唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(150mg,0.330mmol)、1-环丙基哌嗪(42mg,0.33mmol)、Cs2CO3(537mg,1.65mmol)、XantPhos(19mg,0.033mmol)和二噁烷(3mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂RuPhos Pd G1(27mg,0.033mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。产物在硅胶上通过快速色谱法(干式充填),使用0至10%梯度的EtOAc/己烷纯化,得到呈黄色油状的标题化合物(28mg,0.055mmol,17%)。MS(m/z):500.0[M+1]+。
1-(4-(4-环丙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲
基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-(4-环丙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(28mg,0.055mmol)、(3-氟苯基)硼酸(9.2mg,0.066mmol)和Na2CO3(29mg,0.28mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(6.3mg,0.0055mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(6.6mg,0.28mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用35-55%MeCN/NH4CO2H 10mM洗脱一次,pH 3.8/流量45ml/min/10分钟,且接着用35-55%MeCN/NH4CO3H 10mM洗脱,pH 10/流量45ml/min/10分钟)纯化,冻干后得到呈黄色固体状的标题化合物(3.0mg,0.0060mmol,11%)。
1H NMR(500MHz,MeOD)δ7.46–7.40(m,1H),7.39-7.35(m,1H),7.35–7.31(m,1H),7.09-7.03(m,1H),3.93-3.75(m,4H),3.40-3.32(m,4H),3.26–3.15(m,1H),2.76-2.60(m,1H),2.34(s,3H),1.31(d,J=6.7Hz,6H),0.95-0.81(s,4H)。MS(m/z):502.1[M+1]+。
化合物26:1-(4-(4-乙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(4-(4-乙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-
5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(150mg,0.330mmol)、1-乙基哌嗪(38mg,0.33mmol)、Cs2CO3(537mg,1.65mmol)、XantPhos(19mg,0.033mmol)和二噁烷(3mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂RuPhosPd G1(27mg,0.033mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用50-70%MeCN/NH4CO2H 10mM洗脱一次,pH 3.8/流量45ml/min/10分钟)纯化,蒸发后得到呈黄色固体状的标题化合物(49mg,0.10mmol,31%)。MS(m/z):488.0[M+1]+。
1-(4-(4-乙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-
1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-(4-乙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(49mg,0.10mmol)、(3-氟苯基)硼酸(17mg,0.12mmol)和Na2CO3(53mg,0.50mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(12mg,0.010mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(12mg,0.50mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用35-55%MeCN/NH4CO2H 10mM洗脱一次,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈白色固体状的标题化合物(1.1mg,0.0022mmol,2%)。
1H NMR(500MHz,MeOD)δ8.49(s,1H),7.43(td,J=7.9,6.0Hz,1H),7.40–7.32(m,2H),7.09–7.02(m,1H),4.06-3.63(m,4H),3.40-3.27(m,4H),3.27–3.12(m,3H),2.34(s,3H),1.36(t,J=7.3Hz,3H),1.31(d,J=6.7Hz,6H)。甲酸铵盐。MS(m/z):490.1[M+1]+。
化合物27:1-(4-(4-乙酰基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
1-(4-(4-乙酰基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-溴-3-甲基-1H-吡
唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(150mg,0.330mmol)、1-(哌嗪-1-基)乙酮(42mg,0.33mmol)、Cs2CO3(537mg,1.65mmol)、XantPhos(19mg,0.033mmol)和二噁烷(3mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂RuPhos Pd G1(27mg,0.033mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用65-85%MeCN/NH4CO2H 10mM洗脱一次,pH3.8/流量45ml/min/10分钟)纯化,蒸发后得到呈黄色油状的标题化合物(30mg,0.059mmol,18%)。
MS(m/z):502.0[M+1]+。
1-(4-(4-乙酰基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲
基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入1-(4-(4-乙酰基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-溴-3-甲基-1H-吡唑-5-甲酸甲酯(30mg,0.059mmol)、(3-氟苯基)硼酸(10mg,0.071mmol)和Na2CO3(31mg,0.30mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(12mg,0.010mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(7.1mg,0.30mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用40-60%MeCN/NH4CO2H 10mM洗脱一次,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈黄色固体状的标题化合物(4.1mg,0.0081mmol,14%)。
1H NMR(500MHz,MeOD)δ7.43(td,J=8.0,6.1Hz,1H),7.36-7.32(m,1H),7.31–7.27(m,1H),7.09-7.03(m,1H),3.74–3.60(m,8H),3.26-3.13(m,1H),2.34(s,3H),2.14(s,3H),1.31(d,J=6.7Hz,6H)。MS(m/z):504.1[M+1]+。
化合物28:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-1-(5-(异丙基硫基)-4-(4-甲基哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-
5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物1所述制备的4-溴-1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(150mg,0.330mmol)、4-甲基哌啶(33mg,0.33mmol)、Cs2CO3(537mg,1.65mmol)、XantPhos(19mg,0.033mmol)和二噁烷(3mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂RuPhosPd G1(27mg,0.033mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用80-100%MeCN/NH4CO2H 10mM洗脱一次,pH 3.8/流量45ml/min/10分钟)纯化,蒸发后得到呈黄色油状的标题化合物(9.5mg,0.020mmol,6%)。MS(m/z):473.1[M+1]+。
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基哌啶-1-基)噻唑-2-基)-3-甲基-
1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(5-(异丙基硫基)-4-(4-甲基哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(9.5mg,0.020mmol)、(3-氟苯基)硼酸(3.4mg,0.024mmol)和Na2CO3(11mg,0.10mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(2.3mg,0.0020mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(2.4mg,0.10mmol)添加至反应混合物中并在微波辐射下在110℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用65-85%MeCN/NH4CO2H 10mM洗脱一次,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈黄色固体状的标题化合物(1.6mg,0.0034mmol,17%)。
1H NMR(500MHz,MeOD)δ7.45–7.39(m,1H),7.35-7.31(m,1H),7.31-7.26(m,1H),7.010-7.03(m,1H),4.43-4.34(m,2H),3.23-3.10(m,1H),2.95-2.86(m,2H),2.32(s,3H),1.74-1.62(m,2H),1.61-1.49(m,1H),1.38-1.19(m,2H)1.29(d,J=6.7Hz,6H),0.98(d,J=6.6Hz,3H)。MS(m/z):475.2[M+1]+。
化合物29:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,MeOD)δ7.43(td,J=7.9,6.1Hz,1H),7.40–7.37(m,1H),7.37–7.32(m,1H),7.09–7.03(m,1H),4.43-3.50(m,4H),3.42–3.31(m,4H),3.29-3.14(m,1H),2.91(s,3H),2.35(s,3H),1.31(d,J=6.7Hz,6H)。MS(m/z):476.1[M+1]+
化合物30:4-(3-氟苯基)-3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸
5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-胺
使硫代氨基脲(480mg,5.26mmol)和4-(三氟甲基)苯甲酸(1.00g,5.26mmol)悬浮于氧氯化磷(1.40mL)中并在75℃下加热30分钟。在冷却至室温后,添加水(5.5mL)并使反应混合物回流4小时。将反应混合物冷却至室温并通过在搅拌下逐滴添加6N NaOH溶液将其碱化至pH 8。过滤沉淀物并用水洗涤,得到呈白色固体状的标题化合物(1.09g,4.44mmol,85%)。
2-氯-5-(4-(三氟甲基)苯基)-1,3,4-噻二唑
将5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-胺(700mg,2.85mmol)和铜(18mg,0.29mmol)于浓盐酸(2.8mL)和乙酸(14mL)中的搅拌的悬浮液冷却至0℃。向所述悬浮液中逐份添加亚硝酸钠(206mg,2.99mmol)于水(0.94mL)中的溶液且接着在室温下搅拌反应混合物16小时。在冷却至0℃后,再添加亚硝酸钠(41mg,0.59mmol)于水(0.20mL)中的溶液并在室温下持续搅拌3小时。将反应混合物逐滴添加至冷水溶液(150mL)中并过滤沉淀物,得到呈黄色固体状的标题化合物(627mg,2.37mmol,83%)。
2-肼基-5-(4-(三氟甲基)苯基)-1,3,4-噻二唑
在82℃下,在二噁烷中搅拌2-氯-5-(4-(三氟甲基)苯基)-1,3,4-噻二唑(425mg,1.61mmol)和水合肼(176mg,1.93mmol)。3小时后,再添加水合肼(65mg,0.71mmol)并在82℃下持续搅拌16小时。再将水合肼(60mg,0.66mmol)添加至悬浮液中并且还需要4小时来完成反应。过滤黄色沉淀物并用Et2O冲洗,得到呈黄色固体状的标题化合物(346mg,1.33mmol,83%)。
3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸甲酯
将2-(甲氧基亚氨基)-4-氧代戊酸甲酯(127mg,0.734mmol)溶解于MeOH(4mL)中并添加2-肼基-5-(4-(三氟甲基)苯基)-1,3,4-噻二唑(191mg,0.734mmol),随后逐滴添加12NHCl(245μL,2.94mmol)。将反应混合物加热至回流,保持5小时。浓缩反应混合物。通过在DCM中湿磨来移除残留起始物质。浓缩滤液且粗产物在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(0至50%梯度)纯化,得到呈黄色油状的标题化合物(55.6mg,0.151mmol,21%)。
4-溴-3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸
甲酯
将3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸甲酯(88mg,0.24mmol)溶解于TFA(1.2ml)中并添加N-溴代琥珀酰亚胺(47mg,0.26mmol)。在室温下搅拌反应混合物2小时,随后再添加N-溴代琥珀酰亚胺(12mg,0.067mmol)并持续搅拌16小时。再添加N-溴代琥珀酰亚胺(12mg,0.067mmol)并且再持续搅拌16小时。将反应混合物缓慢添加至冰水中并过滤固体,用水洗涤并干燥,得到呈黄色固体状的标题化合物(84mg,0.19mmol,78%)。
4-(3-氟苯基)-3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡
唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸甲酯(42mg,0.094mmol)、(3-氟苯基)硼酸(16mg,0.11mmol)和Na2CO3(50mg,0.47mmol)。使氮气鼓泡穿过二噁烷/水的溶液(1.2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(11mg,0.00095mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(11mg,0.47mmol)添加至反应混合物中并在微波辐射下在115℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用40-60%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈白色固体状的标题化合物(6.4mg,0.014mmol,15%)。
1H NMR(500MHz,DMSO)δ8.23(d,J=8.2Hz,2H),7.95(d,J=8.2Hz,2H),7.48-7.36(m,3H),7.18–7.09(m,1H),2.32(s,3H);MS(m/z):448.9[M+1]+
化合物31:4-(3-氟苯基)-1-(5-((2-甲氧基乙基)(甲基)氨基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
1-(4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将2-(甲氧基亚氨基)-4-氧代戊酸甲酯(1.00g,5.77mmol)溶解于MeOH(60mL)中并添加如所描述制备的4-(3,4-二氯苯基)-2-肼基噻唑(1.52g,5.77mmol),随后逐滴添加12NHCl(1.82mL,23.1mmol)。将反应混合物加热至回流过夜。用EtOAc稀释反应混合物并将其转移至萃取漏斗中。分离各层并用EtOAc(3×)萃取水层。合并的有机层经Na2SO4脱水,过滤并真空浓缩。粗产物在硅胶上通过快速色谱法(干式充填),使用1:2:18EtOAc/DCM/己烷于1:9DCM/己烷中的溶液(0至100%梯度)纯化,得到呈黄色固体状的标题化合物(1.23g,2.19mmol,38%)。
1-(4-(3,4-二氯苯基)-5-氟噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将1-(4-(3,4-二氯苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(500mg,1.36mmol)溶解于MeCN/DCE(4mL,1:1)中。添加SelectFluor(577mg,1.63mmol)并在80℃下搅拌反应18小时。真空浓缩粗产物并在硅胶上通过快速色谱法(用DCM湿式装载),使用EtOAc于己烷中的溶液(5至20%梯度)纯化,得到呈白色固体状的标题化合物(190mg,0.492mmol,36%)。
4-溴-1-(4-(3,4-二氯苯基)-5-氟噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将溴(0.126mL,2.46mmol)添加至1-(4-(3,4-二氯苯基)-5-氟噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(190mg,0.492mmol)于MeCN/DCM(5mL,1:1mL)中的溶液中。在室温下搅拌反应5小时。添加饱和Na2SO3水溶液并用EtOAc(3×)萃取反应混合物。合并的有机层用硫酸钠脱水,过滤并减压蒸发。粗产物在硅胶上通过快速色谱法(干式充填),使用DCM于己烷中的溶液(10至40%)纯化,得到呈白色固体状的标题化合物(42.6mg,0.092mmol,19%)。
1-(4-(3,4-二氯苯基)-5-氟噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-(3,4-二氯苯基)-5-氟噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(42.6mg,0.092mmol)、3-氟苯基硼酸(15.4mg,0.110mmol)和Na2CO3(48.5mg,0.458mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(10.6mg,0.009mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(19.2mg,0.458mmol)添加至反应混合物中并在微波辐射下在120℃下搅拌10分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用55-75%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/11分钟)纯化,冻干后得到呈白色固体状的标题化合物(8.93mg,0.019mmol,21%)。
1H NMR(500MHz,DMSO)δ7.92(t,J=1.1Hz,1H),7.76(d,J=1.1Hz,2H),7.48(dd,J=14.4,8.0Hz,1H),7.41–7.30(m,J=15.4,9.1Hz,2H),7.19(t,J=7.6Hz,1H),3.33(1H,在水信号之下),2.29(s,3H);MS(m/z):466.9[M+1]+。
4-(3-氟苯基)-1-(5-((2-甲氧基乙基)(甲基)氨基)-4-(4-(三氟甲基)苯基)噻
唑-2-基)-3-甲基-1H-吡唑-5-甲酸
在配备磁力搅拌棒的5mL玻璃微波小瓶中放入1-(5-氟-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸(10mg,0.021mmol)和(2-甲氧基乙基)甲基胺(246mg,2.75mmol)。封盖小瓶并将其放入80℃的油浴中,保持16小时。使反应混合物升温至90℃并且再搅拌3天。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用55-75%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈浅黄色固体状的标题化合物(3.3mg,0.0062mmol,29%)。
1H NMR(500MHz,MeOD)δ8.38(d,J=8.3Hz,2H),7.68(d,J=8.3Hz,2H),7.50-7.44(m,1H),7.33-7.29(m,1H),7.28–7.23(m,1H),7.16-7.09(m,1H),3.56(t,J=5.3Hz,2H),3.28(s,3H),3.20(t,J=5.3Hz,2H),2.89(s,3H),2.35(s,3H);MS(m/z):535.1[M+1]+
化合物32:1-(4-(4,4-二甲基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.47-7.46(m,1H),7.34-7.30(m,2H),7.17(bs,1H),3.59-3.53(m,4H),3.11(q,J=5.0Hz,1H),2.27(s,3H),1.38-1.34(m,4H),1.23(d,J=6.7Hz,6H),0.95(s,6H)。MS(m/z):489.2[M+1]+。
化合物33:1-(4-(4-(叔丁氧基羰基)哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.53-7.48(m,1H),7.30-7.28(m,2H),7.24-7.21(m,1H),3.53-3.51(m,4H),3.40(bs,4H),3.19-3.14(m,1H),2.28(s,3H),1.41(s,9H),1.24(d,J=6.7Hz,6H)。MS(m/z):562.2[M+1]+。
化合物34:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(3-(三氟甲基)吡咯烷-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.53-7.49(m,1H),7.30-7.27(m,2H),7.25-7.21(m,1H),3.82-3.70(m,3H),3.64-3.59(m,1H),3.06-3.01(m,1H),2.28(s,3H),2.25-2.18(m,1H),2.06-1.99(m,1H),1.22(d,J=6.7,Hz,6H)。MS(m/z):515.1[M+1]+。.
化合物35:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸盐酸盐
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,MeOD)δ8.45(bs,1H),7.44-7.39(m,1H),7.37-7.31(m,2H),7.06-7.03(m,1H),3.85-3.83(m,4H),3.28-3.26(m,4H),3.23-3.17(m,1H),2.33(s,3H),1.29(d,J=6.7Hz,6H)。MS(m/z):462.1[M+1]+。
化合物36:4-(3-氟苯基)-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸
4-碘-1-(5-碘-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
将如以上所描述制备的3-甲基-1-(4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(1.86g,5.06mmol)溶解于TFA(25ml)中并添加N-碘代琥珀酰亚胺(2.39g,10.6mmol)。在室温下搅拌反应混合物1小时30分钟,随后再添加N-碘代琥珀酰亚胺(190mg,0.844mmol)并持续搅拌4小时。将反应混合物缓慢添加至冰水中并过滤固体,用水洗涤并干燥,得到呈粉色固体状的标题化合物(2.45g,3.96mmol,78%)。
4-碘-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-
1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的玻璃微波小瓶中放入4-碘-1-(5-碘-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(800mg,1.29mmol)、(2-甲基丙-1-烯-1-基)硼酸(129mg,1.29mmol)和K2CO3(893mg,6.46mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF溶液(13mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(dtbpf)Cl2(84.2mg,0.129mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。用EtOAc稀释反应混合物,用水和盐水洗涤。有机层用硫酸镁脱水,过滤并减压蒸发。粗产物在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(0至10%梯度)纯化,得到呈黄色固体状的标题化合物(172mg,0.314mmol,24%)。
4-(3-氟苯基)-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻
唑-2-基)-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-碘-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(172mg,0.314mmol)、3-氟苯基硼酸(52.8mg,0.377mmol)和Na2CO3(167mg,1.57mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(3mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(36.3mg,0.0314mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。粗产物在硅胶上通过快速色谱法,使用EtOAc于己烷中的溶液(0至10%梯度)纯化,得到呈黄色固体状的标题化合物(111mg,0.215mmol,69%)。
4-(3-氟苯基)-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻
唑-2-基)-1H-吡唑-5-甲酸
在5mL玻璃微波小瓶中放入4-(3-氟苯基)-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(20mg,0.039mmol)和LiOH(4.6mg,0.19mmol)。添加二噁烷/水溶液(2mL,4:1)。在微波辐射下,将小瓶加热至110℃,保持15分钟。粗产物使用半制备型HPLC-MC(X-Bridge 30×50,用60-80%MeCN/AmForm 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈黄色固体状的标题化合物(8.2mg,0.016mmol,42%)。
1H NMR(500MHz,DMSO)δ7.89(d,J=8.3Hz,2H),7.81(d,J=8.3Hz,2H),7.51-7.44(m,1H),7.39-7.30(m,2H),7.22-7.14(m,1H),6.41–6.36(m,1H),2.30(s,3H),1.95(s,3H),1.90(s,3H);MS(m/z):502.0[M+1]+。
化合物37:4-(3-氟苯基)-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸
4-溴-1-(4,5-二溴噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
在0℃下,向如以上关于化合物1所述制备的1-(4-溴-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(27.9g,74.07mmol)于MeCN(570mL)中的溶液中添加Br2(21mL)于MeCN(170mL)中的溶液。使反应混合物升温至室温并搅拌2.5小时。过滤反应混合物并将母液转移至萃取漏斗中。分离各层,用DCM(3×)萃取水层。合并的有机层经MgSO4脱水,过滤并真空浓缩,得到呈黄色固体状的标题化合物产物(8.76g,19.0mmol,26%)。
4-溴-1-(4-溴-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的20mL玻璃微波小瓶中放入4-溴-1-(4,5-二溴噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(1.50g,3.26mmol)、(4-(三氟甲基)苯基)硼酸(619mg,3.26mmol)和K2CO3(2.25g,16.3mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF溶液(11mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(dtbpf)Cl2(212mg,0.326mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(1至5%梯度)纯化且接着在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(60至100%)再纯化,冻干后得到呈白色粉末状的标题化合物(490mg,0.933mmol,29%)。
4-溴-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-
1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-1-(4-溴-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(200mg,0.381mmol)、(2-甲基丙-1-烯-1-基)硼酸(38.0mg,0.381mmol)和K2CO3(263mg,1.90mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过THF溶液(2mL)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(dtbpf)Cl2(24.8mg,0.0381mmol)。封盖小瓶并将其放入90℃的油浴中,保持16小时。在真空下蒸发溶剂且粗产物在硅胶上通过快速色谱法(干式充填),使用EtOAc于己烷中的溶液(0至5%梯度)纯化,得到呈白色固体状的标题化合物(62.0mg,0.124mmol,33%)。
4-(3-氟苯基)-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻
唑-2-基)-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(62.0mg,0.124mmol)、3-氟苯基硼酸(20.8mg,0.149mmol)和Na2CO3(65.7mg,0.620mmol),执行氮气和真空循环(2×)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(13.8mg,0.012mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。粗产物在硅胶上通过快速色谱法,使用EtOAc于己烷中的溶液(1%等度洗脱)纯化,得到呈无色油状的标题化合物(27.0mg,0.052mmol,42%)。
4-(3-氟苯基)-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻
唑-2-基)-1H-吡唑-5-甲酸
在25mL圆底烧瓶中,用THF/MeOH(2mL,1:1)稀释4-(3-氟苯基)-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(27.0mg,0.052mmol)。添加1M NaOH溶液(262μL,0.262mmol)并在室温下搅拌反应16小时。添加1MHCl溶液(262μL,0.262mmol)和水(2mL)。反应混合物在C-18柱上通过反相色谱法,用MeCN于水(含有10mM NH4CO2H)中的溶液(35至75%)直接纯化,冻干后得到呈白色粉末状的标题化合物(3.00mg,0.006mmol,11%)。
1H NMR(500MHz,MeOD)δ7.75(d,J=8.3Hz,2H),7.69(d,J=8.2Hz,2H),7.43–7.30(m,3H),7.06–6.99(m,1H),6.14–6.09(m,1H),2.33(s,3H),2.14(d,J=1.0Hz,3H),1.88(d,J=1.1Hz,3H);MS(m/z):502.1[M+1]+。
化合物38:1-(4,5-双(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物37类似的方式制备。1H NMR(500MHz,DMSO)δ7.82(d,J=8.2Hz,2H),7.73(d,J=8.4Hz,2H),7.65(dd,J=8.1,3.6Hz,4H),7.53–7.46(m,1H),7.40–7.33(m,2H),7.23–7.17(m,1H),2.32(s,3H)。MS(m/z):592.2[M+1]+。
化合物39:2-(4-(3-氟苯基)-3-甲基-1H-吡唑-1-基)-4,5-双(4-(三氟甲基)苯基)噻唑
标题化合物是以与如以上所描述的化合物37类似的方式制备。1H NMR(500MHz,DMSO)δ8.94(s,1H),7.82(d,J=8.3Hz,2H),7.78(d,J=8.3Hz,2H),7.73(d,J=8.2Hz,2H),7.66(d,J=8.0Hz,2H),7.54–7.48(m,3H),7.22–7.15(m,1H),2.48(s,3H)。MS(m/z):548.2[M+1]+。
化合物40:1-(4-(4-(叔丁基)哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.53-7.48(m,1H),7.29-7.21(m,3H),4.37(d,J=12.9Hz,2H),3.15-3.10(m,1H),2.76(t,J=11.6Hz,2H),2.28(s,3H),1.66(d,J=12.6Hz,2H),1.27-1.20(m,8H),1.18-1.14(m,1H),0.85(s,9H)。MS(m/z):517.2[M+1]+。
化合物41:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(6-氮杂螺[2.5]辛-6-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.47(bs,1H),7.31(bs,2H),7.18(bs,1H),3.62-3.60(m,4H),3.16-3.11(m,1H),2.27(s,3H),1.40-1.38(m,4H),1.24(d,J=6.7Hz,6H),0.32(s,4H)。MS(m/z):487.2[M+1]+。
化合物42:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲氧基-4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.50-7.46(m,1H),7.32-7.29(m,2H),7.21-7.18(m,1H),4.24(d,J=13.1Hz,2H),3.39(s,3H),3.18-3.13(m,1H),3.05(t,J=11.9Hz,2H),2.28(s,3H),1.91(d,J=12.6Hz,2H),1.76(td,J=13.5,4.4Hz,2H),1.24(d,J=6.7Hz,6H)。MS(m/z):559.1[M+1]+。
化合物43:4-(3-氟苯基)-1-(4-(4-甲氧基苯基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物37类似的方式制备。1H NMR(500MHz,DMSO)δ7.79(d,J=8.2Hz,2H),7.64(d,J=8.2Hz,2H),7.54-7.46(m,1H),7.41–7.36(m,2H),7.36-7.31(m,2H),7.26-7.17(m,1H),6.95–6.90(m,2H),3.77(s,3H),2.32(s,3H)。MS(m/z):554.0[M+1]+。
化合物44:1-(4,5-双(4-甲氧基苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物37类似的方式制备。1H NMR(500MHz,DMSO)δ7.56–7.46(m,1H),7.43–7.29(m,6H),7.27-7.14(m,1H),7.03–6.97(m,2H),6.92-6.85(m,2H),3.80(s,3H),3.75(s,3H),2.30(s,3H)。MS(m/z):516.4[M+1]+。
化合物45:4-(3-氟苯基)-1-(5-(4-甲氧基苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物37类似的方式制备。1H NMR(500MHz,DMSO)δ7.70(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.54-7.47(m,1H),7.340-7.30(m,4H),7.27-7.18(m,1H),7.05-7.00(m,2H),3.81(s,3H),2.32(s,3H)。MS(m/z):553.9[M+1]+。
化合物46:1-(4-(4-(叔丁基)-3-氧代哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,DMSO)δ7.44-7.40(m,2H),7.36-7.34(m,1H),7.12-7.09(m,1H),4.19(s,2H),3.77-3.75(m,2H),3.46-3.44(m,2H),3.12-3.07(m,1H),2.26(s,3H),1.38(s,9H),1.23(d,J=6.7Hz,6H)。MS(m/z):532.1[M+1]+。
化合物47:4-(3-氟苯基)-3-甲基-1-(5-(3-(甲基氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸
1-(5-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-
基)-4-碘-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒的5mL玻璃微波小瓶中放入如化合物36中所制备的4-碘-1-(5-碘-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(500mg,0.807mmol)、丙烯酸叔丁酯(113μL,0.888mmol)、K2CO3(558mg,4.035mmol)和催化剂Pd(dtbpf)Cl2(53mg,0.0807mmol)。将THF(8.1mL,0.1M)添加至微波管并使氮气流鼓泡穿过褐色混合物5分钟。封盖小瓶并在90℃的油浴中搅拌16小时。16小时后,在硅胶柱上使用流动相0-5%EtOAc/己烷纯化反应物。减压蒸发含产物的洗脱份,得到呈灰白色泡沫状的标题化合物(215mg,0.347mmol,43%)。
1-(5-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-
基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒的5mL玻璃微波小瓶中放入1-(5-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-碘-3-甲基-1H-吡唑-5-甲酸甲酯(105mg,0.169mmol)、(3-氟苯基)硼酸(24mg,0.169mmol)、Na2CO3(90mg,0.845mmol)和催化剂Pd(PPh3)4(20mg,0.0169mmol)。将用氮气流脱氧5分钟的THF:水(1.7mL,4:1,0.1M)添加至微波管中。封盖小瓶并在90℃的油浴中搅拌16小时。16小时后,在硅胶柱上使用流动相0-5%EtOAc/己烷纯化反应物。减压蒸发含产物的洗脱份,得到呈无色油状的标题化合物(69mg,0.117mmol,70%)。
1-(5-(3-(叔丁氧基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟
苯基)-3-甲基-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒的10mL圆底烧瓶中放入1-(5-(3-(叔丁氧基)-3-氧代丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸甲酯(68mg,0.115mmol)、催化剂Pd(OH)2(15mg)和MeOH:AcOH(1mL,1:1,0.1M)。烧瓶配备氢气球。用氢气和真空净化反应物三次。在氢气氛下,在室温下搅拌反应16小时。16小时后,反应物经celite过滤并用甲醇洗涤滤饼。在硅胶柱上使用流动相0-5%EtOAc/己烷纯化反应物。减压蒸发含产物的洗脱份,得到呈黄色油状的标题化合物(50mg,0.0848mmol,75%)。
3-(2-(4-(3-氟苯基)-5-(甲氧基羰基)-3-甲基-1H-吡唑-1-基)-4-(4-(三氟甲
基)苯基)噻唑-5-基)丙酸
在室温下,在配备磁力搅拌棒的10mL圆底烧瓶中放入1-(5-(3-(叔丁氧基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸甲酯(50mg,0.0848mmol)、CeCl3·7H2O(47mg,0.127mmol)、NaI(16mg,0.110mmol)和MeCN(0.7mL,0.1M)。在回流下加热反应2小时。2小时后,用EtOAc稀释反应物并用0.5M HCl处理。用EtOAc萃取化合物三次。合并的有机层经Na2SO4脱水,过滤并减压蒸发,得到呈橙色固体状的标题化合物(38mg,0.0729mmol,86%)。
4-(3-氟苯基)-3-甲基-1-(5-(3-(甲基氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯
基)噻唑-2-基)-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒的10mL圆底烧瓶中放入3-(2-(4-(3-氟苯基)-5-(甲氧基羰基)-3-甲基-1H-吡唑-1-基)-4-(4-(三氟甲基)苯基)噻唑-5-基)丙酸(48mg,0.0899mmol)、HATU(51mg,0.134mmol)、MeNH2(67μL,0.134mmol)和汉氏碱(Hunig's base)(39μL,0.224mmol)的DMF溶液(0.9mL,0.1M)。橙色溶液在5分钟内变为浅黄色。5分钟后,用HPLC-MS分析反应混合物指示反应完成。将化合物蒸发至干。将浅黄色残余物转移至微波小瓶中,该小瓶中添加有LiOH(21mg,0.899mmol)和THF:水(4:1,2mL,0.04M)。封盖微波小瓶并在微波辐射下在110℃下加热15分钟。过滤反应物且粗产物使用半制备型HPLC-MC(X-Bridge 30×50,用40-60%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45mL/min/11分钟)纯化,冻干后得到呈白色固体状的标题化合物(8mg,0.015mmol,17%)。
1H NMR(500MHz,DMSO)δ7.93-7.87(m,3H),7.83-7.81(m,2H),7.46-7.39(m,2H),7.36-7.34(m,1H),7.13-7.10(m,1H),3.19(t,J=7.2Hz,2H),2.58(d,J=4.6Hz,3H),2.53-2.51(m,2H),2.28(s,3H);MS(m/z):533.0[M+1]+。
化合物48:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2-甲氧基乙氧基)-4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物11类似的方式制备。1H NMR(500MHz,DMSO)δ14.16(s,1H),7.54–7.47(m,1H),7.28(d,J=7.7Hz,2H),7.24(t,J=8.1Hz,1H),4.22(d,J=13.2Hz,2H),3.72–3.67(m,2H),3.53–3.48(m,2H),3.28(s,3H),3.20–3.08(m,3H),2.29(s,3H),1.93(d,J=12.8Hz,2H),1.77(td,J=13.4,4.4Hz,2H),1.24(d,J=6.7Hz,6H)。MS(m/z):603.3[M+1]+。
化合物49:4-(3-氟苯基)-1-(5-(4-((2-甲氧基乙基)氨甲酰基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ8.56(t,J=5.3Hz,1H),7.87–7.81(m,2H),7.65(d,J=8.3Hz,2H),7.58(d,J=8.3Hz,2H),7.49-7.40(m,3H),7.33-7.25(m,2H),7.19-7.10(m,1H),3.42–3.34(m,4H),3.21(s,3H),2.26(s,3H)。MS(m/z):625.2[M+1]+。
化合物50:4-(3-氟苯基)-1-(5-(4-((2-甲氧基乙基)(甲基)氨甲酰基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.75–7.62(m,4H),7.54-7.42(m,5H),7.41-7.32(m,2H),7.26-7.16(m,1H),3.69–3.35(m,4H),3.17(s,3H),2.98(s,3H),2.32(s,3H)。MS(m/z):639.2[M+1]+。
化合物51:4-(3-氟苯基)-1-(5-(4-(2-甲氧基乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ9.92(s,1H),7.72–7.66(m,2H),7.66-7.57(m,4H),7.44–7.36(m,1H),7.36–7.27(m,4H),7.13-7.05(m,1H),3.96(s,2H),3.32(s,3H),2.24(s,3H)。MS(m/z):611.2[M+1]
化合物52:4-(3-氟苯基)-1-(5-(4-(2-(2-甲氧基乙氧基)乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ9.87(s,1H),7.77–7.65(m,6H),7.49–7.36(m,5H),7.17-7.07(m,1H),4.11(s,2H),3.72–3.65(m,2H),3.57–3.51(m,2H),3.31(s,3H),2.31(s,3H)。MS(m/z):655.1[M+1]+
化合物53:4-(3-氟苯基)-1-(5-(3-((2-甲氧基乙基)氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物47类似的方式制备。1H NMR(500MHz,DMSO)δ8.49(bs,1H),7.97-7.95(m,2H),7.73-7.71(m,2H),7.42-7.30(m,3H),7.04-7.00(m,1H),3.44-3.42(m,2H),3.38-3.32(m,4H),3.32(s,3H),2.64(t,J=7.4Hz,2H),2.33(s,3H)。MS(m/z):577.1[M+1]+。
化合物54:4-(3-氟苯基)-1-(5-(3-((2-甲氧基乙基)(甲基)氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物47类似的方式制备。1H NMR(500MHz,MeOD)δ7.91-7.90(m,2H),7.75-7.74(m,2H),7.47-7.42(m,1H),7.29-7.27(m,1H),7.24-7.22(m,1H),7.12-7.08(m,1H),3.58-3.49(m,4H),3.35-3.32(m,2H),3.33-3.29(m,3H),3.07-2.96(m,3H),2.91(t,J=7.1Hz,1H),2.85(t,J=7.0Hz,1H),2.32(d,J=1.3Hz,3H)。MS(m/z):591.1[M+1]+。
化合物55:4-(3-氟苯基)-1-(5-(4-(2-甲氧基-N-甲基乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.73-7.64(m,4H),7.52–7.32(m,7H),7.22-7.15(m,1H),4.02-3.86(m,2H),3.23(s,3H),3.22(s,3H),2.33(s,3H)。MS(m/z):625.2[M+1]+
化合物56:4-(3-氟苯基)-1-(5-(4-(2-(2-甲氧基乙氧基)-N-甲基乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.72-7.63(m,4H),7.51–7.33(m,7H),7.21-7.13(m,1H),4.08-3.91(m,2H),3.55-3.44(m,2H),3.42-3.35(m,2H),3.22(s,3H),3.20(s,3H),2.31(s,3H)。MS(m/z):669.4[M+1]+
化合物57:4-(3-氟苯基)-1-(5-(甲氧基甲基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.90–7.81(m,4H),7.56–7.46(m,1H),7.36–7.28(m,2H),7.25–7.18(m,1H),4.77(s,2H),3.42(s,3H),2.31(s,3H)。MS(m/z):492.0[M+1]+
化合物58:1-(5-(4-(2-(2-乙氧基乙氧基)乙氧基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.66-7.56(m,4H),7.48-7.41(m,1H),7.32-7.24(m,4H),7.20-7.11(m,1H),7.00–6.94(m,2H),4.08(dd,J=5.4,3.8Hz,2H),3.69(dd,J=5.4,3.8Hz,2H),3.52(dd,J=5.8,3.8Hz,2H),3.43(dd,J=5.8,3.9Hz,2H),3.37(q,J=7.0Hz,2H),2.25(s,3H),1.03(t,J=7.0Hz,3H)。MS(m/z):656.3[M+1]+
化合物59:4-(3-氟苯基)-1-(5-(3-氟苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.70(d,J=8.4Hz,2H),7.65(d,J=8.4Hz,2H),7.54-7.45(m,2H),7.41-7.34(m,2H),7.33–7.28(m,2H),7.27-7.24(m,1H),7.23-7.17(m,1H),2.32(s,3H)。MS(m/z):542.0[M+1]+
化合物60:4-(3-氟苯基)-1-(5-(羟甲基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.91–7.80(m,4H),7.57–7.45(m,1H),7.36–7.27(m,2H),7.26–7.16(m,1H),6.13(s,1H),4.85(d,J=4.0Hz,2H),2.31(s,3H)。MS(m/z):478.1[M+1]+
化合物61:4-(3-氟苯基)-3-甲基-1-(5-(4-(三氟甲基)苯基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-1H-吡唑-5-甲酸
4-溴-3-甲基-1-(5-(4-(三氟甲基)苯基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-
基)-1H-吡唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入如以上关于化合物37所描述制备的4-溴-1-(4-溴-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(131mg,0.249mmol)、4-(三氟甲基)哌啶(47.3mg,0.249mmol)、Cs2CO3(406mg,1.25mmol)、XantPhos(14mg,0.025mmol)和二噁烷(2.5mL)。使氮气在溶剂中鼓泡10分钟,随后添加催化剂RuPhos Pd G1(20mg,0.025mmol)。封盖小瓶并将其放入105℃的油浴中,保持16小时。粗产物在硅胶上通过快速色谱法,使用乙酸乙酯于己烷中的溶液(0至10%梯度)纯化,得到呈黄色油状的标题化合物(74mg,0.12mmol,50%)。
4-(3-氟苯基)-3-甲基-1-(5-(4-(三氟甲基)苯基)-4-(4-(三氟甲基)哌啶-1-基)
噻唑-2-基)-1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒和氮气流的5mL玻璃微波小瓶中放入4-溴-3-甲基-1-(5-(4-(三氟甲基)苯基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-1H-吡唑-5-甲酸甲酯(74mg,0.12mmol)、(3-氟苯基)硼酸(21mg,0.15mmol)和Na2CO3(66mg,0.62mmol)。使氮气鼓泡穿过二噁烷/水的溶液(2mL,4:1)且接着将该溶液添加至微波小瓶中,随后添加催化剂Pd(PPh3)4(14mg,0.012mmol)。封盖小瓶并放入85℃的油浴中,保持16小时。将LiOH(15mg,0.62mmol)添加至反应混合物中并在微波辐射下在115℃下搅拌15分钟。产物使用半制备型HPLC-MS(柱X-Bridge 30×50,用60-80%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45ml/min/10分钟)纯化,冻干后得到呈浅黄色固体状的标题化合物(4.2mg,0.0070mmol,6%)。
1H NMR(500MHz,MeOD)δ7.91(d,J=8.2Hz,2H),7.74(d,J=8.2Hz,2H),7.50–7.43(m,1H),7.38–7.32(m,1H),7.32–7.27(m,1H),7.15-7.08(m,1H),3.59-3.50(m,2H),3.00-2.91(m,2H),2.36(s,3H),2.39-2.25(m,1H),1.95-1.88(m,2H),1.81-1.68(m,2H);MS(m/z):599.1[M+1]+
化合物62:4-(3-氟苯基)-1-(4-(3-氟苯基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,MeOD)δ7.76(d,J=8.2Hz,2H),7.66(d,J=8.2Hz,2H),7.51–7.45(m,1H),7.38–7.28(m,5H),7.15-7.10(m,1H),7.09-7.04(m,1H),2.38(s,3H)。MS(m/z):542.1[M+1]+
化合物63:4-(3-氟苯基)-1-(5-(1-羟乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以下所描述的化合物64类似的方式制备。1H NMR(500MHz,MeOD)δ8.52(bs,1H),7.96(d,J=8.1Hz,2H),7.72(d,J=8.0Hz,2H),7.43-7.31(m,3H),7.05-7.01(m,1H),5.30(q,J=6.2Hz,1H),2.34(s,3H),1.61(d,J=6.3Hz,3H)。MS(m/z):492.1[M+1]+。
化合物64:4-(3-氟苯基)-1-(5-(2-羟乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
4-溴-3-甲基-1-(4-(4-(三氟甲基)苯基)-5-乙烯基噻唑-2-基)-1H-吡唑-5-甲酸
甲酯
在室温下,在配备磁力搅拌棒的5mL玻璃微波小瓶中放入如以上关于化合物36所描述制备的4-溴-1-(5-溴-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯(200mg,0.380mmol)、乙烯基三氟硼酸钾(51mg,0.380mmol)、K2CO3(158mg,1.14mmol)和催化剂Pd(dtbpf)Cl2(25mg,0.0380mmol)。将THF(1.9mL,0.2M)添加至微波管中并使氮气流鼓泡穿过褐色混合物5分钟。封盖小瓶并在90℃的油浴中搅拌16小时。16小时后,在硅胶柱上使用流动相0-5%EtOAc/己烷纯化反应物。减压蒸发含产物的洗脱份,得到呈灰白色固体状的标题化合物(104mg,0.220mmol,58%)。
4-(3-氟苯基)-3-甲基-1-(4-(4-(三氟甲基)苯基)-5-乙烯基噻唑-2-基)-1H-吡
唑-5-甲酸甲酯
在室温下,在配备磁力搅拌棒的5mL玻璃微波小瓶中放入4-溴-3-甲基-1-(4-(4-(三氟甲基)苯基)-5-乙烯基噻唑-2-基)-1H-吡唑-5-甲酸甲酯(101mg,0.213mmol)、(3-氟苯基)硼酸(30mg,0.213mmol)、Na2CO3(68mg,0.639mmol)和催化剂Pd(PPh3)4(25mg,0.0213mmol)。将用氮气流脱氧5分钟的THF:水(2.1mL,4:1,0.1M)添加至微波管中。封盖小瓶并在90℃的油浴中搅拌16小时。16小时后,在硅胶柱上使用流动相0-5%EtOAc/己烷纯化反应物。减压蒸发含产物的洗脱份,得到呈白色固体状的标题化合物(77mg,0.159mmol,75%)。
4-(3-氟苯基)-1-(5-(2-羟乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-
1H-吡唑-5-甲酸
在室温下,在配备磁力搅拌棒的10mL圆底烧瓶中放入溶于无水THF(0.5mL,0.1M)中的4-(3-氟苯基)-3-甲基-1-(4-(4-(三氟甲基)苯基)-5-乙烯基噻唑-2-基)-1H-吡唑-5-甲酸甲酯(22mg,0.0451mmol)。将溶液冷却至0℃并逐滴添加硼烷DMS(225μL,0.451mmol)。使反应物升温至室温并在氮气氛下搅拌16小时。16小时后,在0℃下30%过氧化氢的水溶液(250μL)和溶于水(250μL)中的NaOH(18mg,0.451mmol)。在室温下搅拌反应16小时。用EtOAc萃取反应物三次。合并的有机层经Na2SO4脱水,过滤并蒸发。将白色固体转移至微波小瓶中,该小瓶中添加有LiOH(11mg,0.451mmol)和THF:水(1.5mL;4:1,0.03M)。封盖微波小瓶并在微波辐射下在110℃下加热15分钟。过滤反应物且粗产物使用半制备型HPLC-MC(X-Bridge30×50,用40-60%MeCN/NH4CO2H 10mM洗脱,pH 3.8/流量45mL/min/11分钟)纯化,冻干后得到呈白色固体状的标题化合物(1mg,0.002mmol,5%)。
1H NMR(500MHz,MeOD)δ7.96(d,J=8.1Hz,2H),7.71(d,J=7.7Hz,2H),7.42-7.30(m,3H),7.05-7.01(m,1H),3.86(t,J=6.2Hz,2H),3.20(t,J=6.2Hz,2H),2.33(s,3H);MS(m/z):492.1[M+1]+。
化合物65:4-(3-氟苯基)-1-(5-(4-(2-甲氧基乙氧基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物36类似的方式制备。1H NMR(500MHz,DMSO)δ7.71-7.63(m,4H),7.53–7.46(m,1H),7.39-7.32(m,4H),7.24-7.16(m,1H),7.06–7.00(m,2H),4.16–4.12(m,2H),3.70–3.66(m,2H),3.32(s,3H),2.31(s,3H)。MS(m/z):598.2[M+1]+。
化合物66:4-(3-氟苯基)-1-(5-(1-甲氧基乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物64类似的方式制备。1H NMR(500MHz,MeOD)δ7.88(d,J=7.9Hz,2H),7.74(d,J=8.1Hz,2H),7.44-7.39(m,1H),7.36-7.34(m,1H),7.31-7.29(m,1H),7.07-7.03(m,1H),4.89-4.87(m,1H),3.26(s,3H),2.34(s,3H),1.63(d,J=6.3Hz,3H)。MS(m/z):506.1[M+1]+。
化合物67:4-(3-氟苯基)-1-(4-(4-异丙基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物12类似的方式制备。1H NMR(500MHz,MeOD)δ7.44-7.40(m,1H),7.29(d,J=7.6Hz,1H),7.24(d,J=9.7Hz,1H),7.08-7.05(m,1H),4.41(d,J=12.8Hz,2H),3.17-3.12(m,1H),2.82(t,J=12.3Hz,2H),2.30(s,3H),1.71(d,J=12.2Hz,2H),1.48-1.40(m,1H),1.37-1.31(m,2H),1.28(d,J=6.7Hz,6H),1.23–1.18(m,1H),0.91(d,J=6.7Hz,6H)。MS(m/z):503.3[M+1]+。
化合物68:4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(3-甲氧基-3-(三氟甲基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
标题化合物是以与如以上所描述的化合物47类似的方式制备。1H NMR(500MHz,DMSO)δ7.50–7.41(m,1H),7.38–7.27(m,2H),7.24–7.08(m,1H),4.77(s,2H),3.37(s,3H),3.16–3.07(m,1H),2.28(s,3H),2.09–1.82(m,8H),1.23(d,J=6.7Hz,6H)。MS(m/z):585.1[M+1]+。
BJAB数据
在37℃/5%CO2下,将BJAB细胞(DSMZ)维持在RPMI 1640生长培养基+10%FBS中并在第34代之前使用。将细胞以2500个细胞/孔接种于白色Corning Costar 96孔分析板中的50μL培养基中。在细胞培养基/FBS+0.2%DMSO中制备测试化合物的连续稀释液,并将其转移至分析板中,体积是50μL(DMSO最终浓度是0.1%)。在37℃下,将板维持约72小时。根据制造商的说明书,使用Cell Titer Glo试剂(Promega)评价化合物对细胞增殖的影响。简单点说,每孔添加100μL试剂,并在培育10分钟之后,在读板仪(Tecan F200PRO)上测定发光值。计算在每种化合物浓度下相对于未处理对照的发光信号的百分比,并且通过非线性回归分析,使用Prism(GraphPad)由剂量反应数据测定EC50值。数据显示于以上化合物表中。mTor抑制剂Torin1(Liu等人(2010)《药物化学杂志(J.Med.Chem.)》53,7146.)用作对照。数据概述于以上提供的化合物表中。
针对各种测试化合物的进一步研究指示,细胞活力以剂量依赖性方式降低,并且测试化合物在处理后48小时以剂量依赖性方式诱导细胞死亡。
生物实例
本发明人已确定,尽管初始数据表明它们抑制RNA的翻译起始,但如由本文所提供的数据所描述,由如本文所描述的化合物引起的重要生物作用是抑制细胞周期进程。尽管不打算受理论束缚,但本发明人猜测,本文所公开的化合物破坏细胞周期的G0/G1期,由此防止癌细胞进一步增殖。
以下实例提供对本公开化合物,特别是对在本文所述化合物的广泛范围内且IC50值在“A”范围内的测试化合物的活性的四次测量。测试化合物被认为是如本文所描述的活性化合物的代表。第一次测量是肿瘤细胞系对测试化合物的总体敏感性。第二次是KRAS基因型在细胞针对测试化合物的敏感性中的作用。第三次是测试化合物对关键细胞代谢物谷胱甘肽的影响。并且第四次是测试化合物对细胞周期的影响。
实例1:抗癌活性
测试一组96个肿瘤和3个正常细胞系对测试化合物的敏感性。在标准培养基中培养这些细胞系并将其以所需涂板密度吸取至96孔板中。在化合物测试之前,使细胞适应24小时。制备化合物于DMSO中的20mM储备液。为制备剂量反应曲线,在DMSO中连续稀释化合物并使用Tecan D300e数字施配器施配至所述板各孔中。最终DMSO浓度是0.15%。在培育72小时之后,使用(Promega)方案测定细胞数量。在本分析中,测量ATP作为细胞数量的替代。通过将未处理细胞与处理过的细胞相比较并计算保留的信号的百分比来测定化合物的活性。化合物活性是以最大功效水平的EC50测量并且使用这两个值来计算活性面积曲线。
在所述96个肿瘤细胞系中,有39个肿瘤(40%)对测试化合物展示显著反应(通过估计IC50的能力确定;表1)。其中,造血系统肿瘤展示极大的反应富集。所有造血系统肿瘤中有超过89%的肿瘤对化合物起反应,而28.5%的实体肿瘤有实质性反应。
表1.肿瘤反应性的概述
各种细胞系的数据提供于下表2中:
表2.具体肿瘤反应
实例2:KRAS对活性的影响
接下来,测定实体肿瘤系中KRAS等位基因的基因型。使用COSMIC数据库,可以测定77个实体肿瘤细胞系中74个的KRAS基因型和接合性(纯合型或杂合型)(表3)。
表3.关于KRAS基因型的肿瘤反应性
仅20%的具有野生型KRAS等位基因的细胞类型对测试化合物起反应。相比之下,65%的在KRAS等位基因中带有突变的细胞类型对测试化合物起反应。当所述分析扩展至KRAS等位基因是纯合型还是杂合型时,结果存在明显差异(表4)。在KRAS等位基因中带有杂合突变的细胞系显示最大反应性。
表4.关于KRAS接合性的肿瘤反应性
关于KRAS在对所用测试化合物的反应中的作用的最终分析汇集基于化合物活性面积的数据。所有细胞系的反应都包含在使用杜凯氏全对偶HSD测试(Tukey's All PairsHSD test)进行的分析中。数据在图1中以活性面积随KRAS基因型和KRAS接合性变化的标绘图呈现。测试化合物在含有KRAS突变型杂合基因型的细胞系中的平均反应性明显高于相应野生型细胞系。
实例3:细胞代谢和活性
在使用三个细胞系处理后谷胱甘肽水平的测量:将BJAB、HCT116和正常人肺成纤维细胞(NHLF)分别维持在RPMI培养基(Wisent)、McCoy培养基(Wisent)或FGM-2培养基(Lonza)中。为测量总谷胱甘肽,将5000个细胞/孔(BJAB或HCT116)或10,000个细胞/孔(NHLF)转移至透明底96孔分析板(Thermo Fisher)中,体积是50μL。在含潮湿纸的未密封塑料袋中,在37℃下于5%CO2中培育板过夜。在培养基加0.4%DMSO中连续稀释测试化合物,并将每孔50μL各稀释液转移至分析板中。在含潮湿纸的未密封塑料袋中,在37℃下于5%CO2中培育分析板指定时间。为测量总谷胱甘肽,通过将所提供的荧光素-NT(1:100)、谷胱甘肽S-转移酶(1:100)和DTT(1mM最终浓度)稀释至GSH-GloTM反应缓冲液中来制备GSH-GloTM试剂(Promega),并将100μL添加至分析板中,随后在室温下培育30分钟,且接着添加100μL荧光素检测试剂。在室温下,在暗处将板维持10分钟。使用Tecan Infinite 200Pro测量发光。
图2表示由典型实验得到数据,显示测试化合物以剂量依赖性方式降低细胞谷胱甘肽水平。生长和存活对测试化合物敏感的细胞系(BJAB和HCT116)展示细胞谷胱甘肽水平的剂量依赖性降低,而不敏感的细胞系(NHLF)则不变化。
为评价增殖(与谷胱甘肽水平测量并行进行),将在以上描述的培养基中的每孔50μL细胞添加至透明96孔板(TPP)中。在指定时间,通过添加50μL冷50%三氯乙酸(TCASigma),将细胞固定,并在4℃下培育至少45分钟,随后用蒸馏水冲洗。将每孔50μL体积的含0.4%(w/v)磺酰罗丹明B(Sulforhodamine B,SRB;Sigma)的1%乙酸添加至各孔中以测定总蛋白质含量。在大量1%乙酸中冲洗板数次,以移除过量染料,接着将总蛋白质溶解于200μl的10mM未缓冲的Tris碱中,搅动30分钟。在Tecan Infinite 200Pro上,在560nm下测量吸光度。
对谷胱甘肽水平的影响:将BJAB和HCT116细胞分别维持在RPMI培养基(Wisent)或McCoy培养基(Wisent)中。将5000个细胞/孔转移至透明底96孔分析板(Thermo Fisher)中,体积是50μL。在含潮湿纸的未密封塑料袋中,在37℃下于5%CO2中培育板过夜。将甲萘醌(Sigma)溶解于DMSO中并在10%热灭活FBS加培养基中稀释至20μM和5μM(各自为0.2%DMSO)。从细胞中轻轻地抽吸出培养基并用50μl稀释过的甲萘醌或作为对照的0.2%DMSO更换。在10%热灭活FBS加培养基中将测试化合物稀释至80μM(0.2%DMSO),接着进一步稀释至5μM、1μM、0.5μM和0.05μM(在0.2%DMSO中)。将50μL测试化合物溶液添加至含或不含甲萘醌的各孔中。在指定情况下,添加1μL 100mM的N-乙酰基半胱氨酸(Sigma)于水中的溶液。在含潮湿纸的敞开式塑料袋中,在37℃和5%CO2下培育分析板指定时间。根据以上描述的程序测定总谷胱甘肽水平。
在培养基中包含N-乙酰基半胱氨酸防止由甲萘醌引起的谷胱甘肽减少。图3上图表示测试化合物介导的HCT116细胞中谷胱甘肽水平降低。在N-乙酰基半胱氨酸存在或不存在下谷胱甘肽水平不存在差异。图3下图展示甲萘醌介导的HCT116细胞中谷胱甘肽水平降低。这一数据表明,测试化合物以不同于影响线粒体功能并诱导细胞ROS的试剂的方式减少细胞谷胱甘肽。不受特定理论束缚,由于N-乙酰基半胱氨酸无法恢复谷胱甘肽水平,故相信经过处理的细胞中谷胱甘肽水平的缺少是由在用测试化合物处理之后无法合成谷胱甘肽引起。
实例3:化合物处理过的细胞的细胞周期分析
将在补充有热灭活胎牛血清的McCoy培养基中生长的HCT116细胞(3×105个细胞)涂铺于6孔板中并使其粘附过夜。通过用血清饥饿(0%FBS)、5μM测试化合物或DMSO媒剂对照处理细胞24小时来制备一式两份样品。在收集之前两小时,用10μM 5-乙炔基-2'-脱氧尿苷(EdU,Thermo Fisher)标记复制的DNA。收集黏附细胞和漂浮的细胞并将其固定于4%三聚甲醛于PBS中的溶液中,在室温下保持15分钟。接下来,在室温下,使细胞在0.25%v/vtriton X-100/0.5%BSA/PBS溶液中保持20分钟实现透性化。之后用OG488-叠氮化物进行点击反应以检测EdU并入情况如下:在含有100mM Tris-HCl pH7.6、4mM CuSO4、10μMOG488-叠氮化物和100mM抗坏血酸的反应混合物中培育细胞30分钟。通过在0.5%BSA/PBS洗涤缓冲液中反复洗涤以移除过量试剂。将细胞再悬浮于500μL DAPI染色溶液(含1μg/mLDAPI和50μg/mL RNA酶A的PBS)中。
在配备有蓝光(488nm)、红光(633nm)和紫光(405nm)激光器的LSRII流式细胞仪(BD Biosciences)中执行流式细胞术分析。使用488nm激发并用505LP镜和530/30BP滤光片检测执行OG488分析。使用405nm激发并用442/16BP滤光片检测执行DAPI分析。电压设置是:FSC=324,SSC=276,OG488=215,DAPI=351。使用线性轴标度,利用DAPI执行细胞周期分析。对于EdU使用对数标度。使用第6版FCS Express软件(DeNovo Software)执行数据分析。
图4A呈现由在用测试化合物处理之后于HCT116细胞中进行的代表性细胞周期实验收集的流式细胞术数据。数据以细胞标记数据的点图表示,其中每一通道被门控以进行检测和定量。图4B是以细胞周期每一阶段中细胞的百分比表示的图4A中的数据的条形图。数据明确地展示血清饥饿通过将细胞停滞于G0/G1期来影响细胞。测试化合物展示在G1、S和G2/M中细胞的分布类似,表明测试化合物将细胞停滞于G0/G1期。
应理解,本文所描述的实例和实施例仅出于说明目的,并且根据这些实例和实施例,本领域的技术人员将想到各种修改或变化且这些修改或变化被并入本申请的精神和范围以及所附权利要求书的范围内。
Claims (106)
1.一种具有结构式(Ia)-(Ie)中的任一个的化合物,
所述化合物任选地呈药学上可接受的盐或N-氧化物,和/或溶剂化物或水合物形式,其中
L1选自由以下组成的组:化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-C(O)NR6-、-NR6C(O)-、-C(S)NR6-、-NR6C(S)-、-C(O)O-、-OC(O)-、-C(O)S-、-SC(O)-、-C(S)O-、-OC(S)-、-C(S)S-、-SC(S)-、-S(O)1-2O-、-OS(O)1-2-、-S(O)1-2NR6-和-NR6S(O)1-2-;
R1选自由以下组成的组:
氢,
C1-C8烷基、C1-C8烯基和C1-C8炔基,其各自未被取代或被氟代,
环烷基和杂环烷基,其各自任选地被1-2个R1E取代,以及
苯基和单环杂芳基,其各自任选地被1-5个R1E取代,
其中
各R1E独立地选自氧代;任选被取代的C1-C4烷基;C1-C4氟烷基;卤素;-CN;SF5;-N3;-C(O)R1F;-SR1F;-S(O)1-2R1F;-OR1F;-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;-C(O)NR1G(CH2CH2O)nR1G;-NR1GR1F;和-C(O)R1F;
各R1F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R1G独立地选自H和C1-C3烷基;
L2选自由以下组成的组:化学键、-CH2-、-CH(CH3)-或-CH2CH2-;
Q选自由以下组成的组:H、-CH2OH、-C(O)OH、-C(O)OR2A、-C(O)NR2BR2A、-C(O)NR2BS(O)2R2A、-C(O)NR2BS(O)2NR2BR2A、-C(O)R2A、-S(O)2OH、-P(O)(OH)2、-C(OH)(CF3)2、S(O)2R2A、-N(R2B)S(O)2R2A、-S(O)2NR2BR2A、-C(O)NHOH、-C(O)NH-O(C1-C3烷基)和-CO(NH)CN,其中
各R2A独立地选自H和C1-C3烷基,并且
各R2B独立地选自H和C1-C3烷基;
L3是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;
R3是芳基或杂芳基,其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代,
其中
各L3C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R3D独立地选自氧代任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R3E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F、-NR3GS(O)1-2R3F;
各R3F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R3G独立地选自H和C1-C3烷基、C1-C3氟烷基;
L4选自由以下组成的组:化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-C(O)NR6-、-NR6C(O)-、-C(S)NR6-、-NR6C(S)-、-C(O)O-、-OC(O)-、-C(O)S-、-SC(O)-、-C(S)O-、-OC(S)-、-C(S)S-、-SC(S)-、-S(O)1-2O-、-OS(O)1-2-、-S(O)1-2NR6-和-NR6S(O)1-2-;
R4选自由以下组成的组:氢、任选被取代的C1-C8烷基、任选被取代的C1-C8烯基和任选被取代的C1-C8炔基;
L5是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2CH2-、-CH=CH-、-C≡C-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;并且
R5是芳基、杂芳基、环烷基或杂环烷基,其各自(i)任选地被选自以下的单一取代基取代:-L5C-(任选地被1-5个R5D取代的苯基)、-L5C-(任选地被1-5个R5D取代的单环杂芳基)和-L5C-(任选地被1-5个R5D取代的单环环烷基)、-L5C-(任选地被1-5个R5D取代的单环杂环烷基)并且(ii)任选地被1-5个R5E取代,
其中
各L5C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R5D独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R5E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、-SF5、-N3、-C(O)R5F、-SR5F、-S(O)1-2R5F、-OR5F、-NR5GR5F、-C(O)R5F、-C(O)NR5GR5F、-NR5GC(O)R5F、-C(S)NR5GR5F、-NR1GC(S)R5F、-C(O)OR5F、-OC(O)R5F、-C(O)SR5F、-SC(O)R5F、-C(S)OR5F、-OC(S)R5F、-C(S)SR5F、-SC(S)R5F、-S(O)1-2OR5F、-OS(O)1-2R5F、-S(O)1-2NR5GR5F和-NR5GS(O)1-2R5F;
各R5F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R5G独立地选自H和C1-C3烷基;
其中
各R6选自由以下组成的组:氢、C1-C3烷基和-C(O)(C1-C3烷基);
各任选被取代的烷基、烯基和炔基未被取代、被氟代或被一个或两个羟基取代;
各环烷基具有3-10个环碳并且是不饱和或部分不饱和的,并且任选地包含一个或两个稠合环烷基环,各稠合环具有3-8个环成员;
各杂环烷基具有3-10个环成员和1-3个独立地选自氮、氧和硫的杂原子并且是不饱和或部分不饱和的,并且任选地包含一个或两个稠合环烷基环,其各自具有3-8个环成员;
各芳基是苯基或萘基,并且任选地包含一个或两个稠合环烷基或杂环烷基环,各稠合环烷基或杂环烷基环具有4-8个环成员;
各杂芳基是具有1-4个独立地选自氮、氧和硫的杂原子的5-6元单环杂芳基环,或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳基,并且任选地包含一个或两个稠合环烷基或杂环烷基环,各稠合环烷基或杂环烷基环具有4-8个环成员。
2.根据权利要求1所述的化合物,其中所述化合物具有结构式(Ia)。
3.根据权利要求1所述的化合物,其中所述化合物具有结构式(Ib)。
4.根据权利要求1所述的化合物,其中所述化合物具有结构式(Ic)。
5.根据权利要求1所述的化合物,其中所述化合物具有结构式(Id)。
6.根据权利要求1所述的化合物,其中所述化合物具有结构式(Ie)。
7.根据权利要求1至6中任一项所述的化合物,其中R1选自由以下组成的组:氢、任选被取代的C1-C8烷基和环烷基,其任选地被1-5个R1E取代。
8.根据权利要求1至6中任一项所述的化合物,其中R1是氢。
9.根据权利要求1至6中任一项所述的化合物,其中R1是任选被取代的C1-C8烷基。
10.根据权利要求1至6中任一项所述的化合物,其中R1是未被取代的C1-C8烷基或被氟代的C1-C8烷基。
11.根据权利要求1至6中任一项所述的化合物,其中R1是未被取代的环烷基。
12.根据权利要求1至6中任一项所述的化合物,其中R1是任选被取代的C1-C8烯基,例如丁烯基。
13.根据权利要求1至6中任一项所述的化合物,其中R1是任选地被1-5个RE取代的苯基。
14.根据权利要求1至6中任一项所述的化合物,其中R1是三氟甲基取代的苯基、甲氧基取代的苯基或氟取代的苯基。
15.根据权利要求1至6中任一项所述的化合物,其中R1是被以下取代的苯基:-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;或-C(O)NR1G(CH2CH2O)nR1G。
16.根据权利要求1至6中任一项所述的化合物,其中R1是羟甲基、甲氧基甲基、羟乙基或甲氧基乙基。
17.根据权利要求1至16中任一项所述的化合物,其中L1是化学键、-O-、-S-、-S(O)-或-S(O)2-。
18.根据权利要求1至16中任一项所述的化合物,其中L1是-S-。
19.根据权利要求1至16中任一项所述的化合物,其中L1是化学键。
20.根据权利要求1至16中任一项所述的化合物,其中L1是-NR6-。
21.根据权利要求1至20中任一项所述的化合物,其中L2是化学键。
22.根据权利要求1至20中任一项所述的化合物,其中L2是-CH2-、-CH(CH3)-或-CH2CH2-。
23.根据权利要求1至20中任一项所述的化合物,其中L2是化学键或-CH2-。
24.根据权利要求1至20中任一项所述的化合物,其中Q是-C(O)OH。
25.根据权利要求1至20中任一项所述的化合物,其中Q选自由以下组成的组:-CH2OH、-C(O)OH、-C(O)OR2A、-C(O)NR2BR2A、-C(O)NR2BS(O)2R2A、-C(O)NR2BS(O)2NR2BR2A、-C(O)R2A、-S(O)2OH、-P(O)(OH)2。
26.根据权利要求1至20中任一项所述的化合物,其中Q是-CH2OH、-C(O)OH或-C(O)OR2A。
27.根据权利要求1至26中任一项所述的化合物,其中L3是化学键。
28.根据权利要求1至26中任一项所述的化合物,其中L3是-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-。
29.根据权利要求1至26中任一项所述的化合物,其中L3是化学键、-CH2-、-CH(CH3)(OH)-或-CH(OH)-。
30.根据权利要求1至29中任一项所述的化合物,其中R3是芳基(例如苯基)或杂芳基(例如单环杂芳基),其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代。
31.根据权利要求1至29中任一项所述的化合物,其中R3是芳基(例如苯基、苯并二氧杂环戊烯或二氢-1H-异喹啉),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代。
32.根据权利要求1至29中任一项所述的化合物,其中R3是芳基(例如苯基、苯并二氧杂环戊烯或二氢-1H-异喹啉),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的苯基)、-L3C-(任选地被1-5个R3D取代的单环杂芳基)、-L3C-(任选地被1-5个R3D取代的单环环烷基)、-L3C-(任选地被1-5个R3D取代的单环杂环烷基)并且(ii)任选地被1-5个R3E取代。
33.根据权利要求1至29中任一项所述的化合物,其中R3是杂芳基(例如异噻唑、吡啶酮、噻二唑、吡嗪、吡唑并嘧啶、吡唑并吡啶、咪唑、苯并呋喃、吲哚、咪唑并吡啶、吡啶、吡唑、异噁唑、三唑并吡啶、苯并咪唑、噻吩、苯并噻吩、呋喃或嘧啶),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代;
34.根据权利要求1至29中任一项所述的化合物,其中R3是杂芳基(例如异噻唑、吡啶酮、噻二唑、吡嗪、吡唑并嘧啶、吡唑并吡啶、咪唑、苯并呋喃、吲哚、咪唑并吡啶、吡啶、吡唑、异噁唑、三唑并吡啶、苯并咪唑、噻吩、苯并噻吩、呋喃或嘧啶),其(i)被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的苯基)、-L3C-(任选地被1-5个R3D取代的单环杂芳基)、-L3C-(任选地被1-5个R3D取代的单环环烷基)、-L3C-(任选地被1-5个R3D取代的单环杂环烷基)并且(ii)任选地被1-5个R3E取代。
35.根据权利要求1至29中任一项所述的化合物,其中R3选自由以下组成的组:苯基、苯并二氧杂环戊烯基、二氢-1H-异喹啉基、咪唑基、噁唑基、异噁唑基、异噻唑基、噻唑基、吡啶基和吡嗪基、吡啶酮基、噻二唑基、吡唑并嘧啶基、吡唑并吡啶基、苯并呋喃基、吲哚基、咪唑并吡啶基、吡唑基、三唑并吡啶基、苯并咪唑基、苯并咪唑基、噻吩基、苯并噻吩基、呋喃基和嘧啶基,其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的芳基)、-L3C-(任选地被1-5个R3D取代的杂芳基)、-L3C-(任选地被1-5个R3D取代的环烷基)、-L3C-(任选地被1-5个R3D取代的杂环烷基)并且(ii)任选地被1-5个R3E取代。
36.根据权利要求30至35中任一项所述的化合物,其中所述R3取代基未被任何R3E取代。
37.根据权利要求30至36中任一项所述的化合物,其中L3C是亚甲基或-O-。
38.根据权利要求1至29中任一项所述的化合物,其中R3是任选地被1-5个R3E取代的芳基(例如苯基)。
39.根据权利要求1至29中任一项所述的化合物,其中R3是任选地被1-5个R3E取代的杂芳基(例如异噻唑、吡啶酮、噻二唑、吡嗪、吡唑并嘧啶、吡唑并吡啶、咪唑、苯并呋喃、吲哚、咪唑并吡啶、吡啶、吡唑、异噁唑、三唑并吡啶、苯并咪唑、噻吩、苯并噻吩、呋喃或嘧啶)。
40.根据权利要求1至29中任一项所述的化合物,其中R3选自由苯基和单环杂芳基(例如吡啶基、吡唑基)组成的组,其任选地被1-5个R3E取代。
41.根据权利要求1至40中任一项所述的化合物,其中R4是任选被取代的C1-C8烷基、任选被取代的C1-C8烯基或任选被取代的C1-C8炔基。
42.根据权利要求1至40中任一项所述的化合物,其中R4是任选被取代的C1-C8烷基。
43.根据权利要求1至40中任一项所述的化合物,其中R4是氢或未被取代的C1-C6烷基。
44.根据权利要求1至40中任一项所述的化合物,其中R4是未被取代的C1-C3烷基。
45.根据权利要求1至44中任一项所述的化合物,其中L4是化学键。
46.根据权利要求1至44中任一项所述的化合物,其中L4选自化学键、-C(O)-、-S-、-S(O)1-2-、-O-和-NR6-。
47.根据权利要求1至44中任一项所述的化合物,其中L4是-O-。
48.根据权利要求1至47中任一项所述的化合物,其中L5是化学键。
49.根据权利要求1至47中任一项所述的化合物,其中L5是化学键、-O-、-S-、-C(O)-或-S(O)1-2-。
50.根据权利要求1至49中任一项所述的化合物,其中R5是芳基(例如苯基)或杂芳基(例如异噁唑基、吡啶基、咪唑并吡啶基、吡唑基),其各自任选地被1-5个R5E取代。
51.根据权利要求1至49中任一项所述的化合物,其中R5是任选地被1-5个R5E取代的苯基。
52.根据权利要求1至49中任一项所述的化合物,其中R5选自由以下组成的组:苯基、异噁唑基、吡啶基、咪唑并吡啶基和吡唑基,其各自任选地被1-5个R5E取代。
53.根据权利要求1至49中任一项所述的化合物,其中R5是苯基,其被选自以下的单一取代基取代:-L5C-(任选地被1-5个R5D取代的苯基)、-L5C-(任选地被1-5个R5D取代的单环杂芳基)和-L5C-(任选地被1-5个R5D取代的单环环烷基)-L5C-(任选地被1-5个R5D取代的单环杂环烷基)并且(ii)任选地被1-5个R5E取代。
54.根据权利要求1至49中任一项所述的化合物,其中R5是苯基,其被单一-L5C-(任选地被1-5个R5D取代的单环杂芳基)取代基取代并且(ii)任选地被1-5个R5E取代。
55.根据权利要求1至49中任一项所述的化合物,其中R5是苯基,其被单一-L5C-(任选地被1-5个R5D取代的单环杂环烷基)取代基取代并且(ii)任选地被1-5个R5E取代。
56.根据权利要求53至55中任一项所述的化合物,其中L5C是化学键;
57.根据权利要求53至55中任一项所述的化合物,其中L5C是-O-或-C(O)-。
58.根据权利要求1至49中任一项所述的化合物,其中R5是任选地被1-5个R5E取代的杂环烷基。
59.根据权利要求1至49中任一项所述的化合物,其中R5是杂环烷基,其被单一-L5C-(任选地被1-5个R5D取代的单环环烷基)取代基取代并且(ii)任选地被1-5个R5E取代。
60.根据权利要求58至59中任一项所述的化合物,其中所述杂环烷基是通过氮原子连接至所述-L5-的含氮杂环烷基。
61.根据权利要求58至60中任一项所述的化合物,其中所述杂环烷基是单环的。
62.根据权利要求58至60中任一项所述的化合物,其中所述杂环烷基是双环的。
63.根据权利要求58至62中任一项所述的化合物,其中所述杂环烷基是饱和的。
64.根据权利要求1至49中任一项所述的化合物,其中R5是任选地被1-5个R5E取代的环烷基。
65.根据权利要求64所述的化合物,其中所述环烷基被1-5个R5E取代。
66.根据权利要求64或权利要求65所述的化合物,其中所述环烷基是单环的。
67.根据权利要求64至66中任一项所述的化合物,其中所述环烷基是饱和的。
68.根据权利要求2所述的化合物,其中
L1是-S-、-O-、-S(O)-、-S(O)2-或化学键;
R1是未被取代或被氟代的C1-C8烷基、未被取代或被氟代的C1-C8烯基、未被取代或被氟代的C1-C8炔基或被1-5个R1E取代的苯基,
其中
各R1E独立地选自氧代;任选被取代的C1-C4烷基;C1-C4氟烷基;卤素;-CN;SF5;-N3;-C(O)R1F;-SR1F;-S(O)1-2R1F;-OR1F;-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;-C(O)NR1G(CH2CH2O)nR1G;-NR1GR1F;和-C(O)R1F;
各R1F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R1G独立地选自H和C1-C3烷基;
L2是化学键或-CH2-;
Q是-COOH;
L3是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;
R3是苯基或单环杂芳基,其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的苯基)、-L3C-(任选地被1-5个R3D取代的单环杂芳基)、-L3C-(任选地被1-5个R3E取代的单环C3-C6环烷基)、-L3C-(任选地被1-5个R3E取代的单环C4-C6杂环烷基)并且(ii)任选地被1-5个R3E取代,
其中
各L3C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R3D独立地选自任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R3E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F、-NR3GS(O)1-2R3F;
各R3F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R3G独立地选自H和C1-C3烷基、C1-C3氟烷基;
L4选自由以下组成的组:化学键、-C(O)-、-S-、-S(O)1-2-、-O-和-NR6-;
R4选自由以下组成的组:未被取代、羟基化、C1-C4烷氧基化或被氟代的C1-C8烷基、未被取代或被氟代的C1-C8烯基和未被取代或被氟代的C1-C8炔基;
L5是化学键、-C(O)-、-S-、-S(O)1-2-、-O-或-NR6-;
R5是苯基、单环杂芳基、单环杂环烷基或单环环烷基,其各自任选地被1-5个R5E取代,
其中
各R5E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、-SF5、-N3、-C(O)R5F、-SR5F、-S(O)1-2R5F、-OR5F、-NR5GR5F、-C(O)R5F、-C(O)NR5GR5F、-NR5GC(O)R5F、-C(S)NR5GR5F、-NR1GC(S)R5F、-C(O)OR5F、-OC(O)R5F、-C(O)SR5F、-SC(O)R5F、-C(S)OR5F、-OC(S)R5F、-C(S)SR5F、-SC(S)R5F、-S(O)1-2OR5F、-OS(O)1-2R5F、-S(O)1-2NR5GR5F和-NR5GS(O)1-2R5F;
各R5F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R5G独立地选自H和C1-C3烷基;
其中
各R6选自由以下组成的组:氢、C1-C3烷基和-C(O)(C1-C3烷基);
各任选被取代的烷基、烯基和炔基未被取代、被氟代或被一个或两个羟基取代;
各环烷基具有3-7个环碳并且是不饱和或部分不饱和的;
各杂环烷基具有3-7个环成员和1-3个独立地选自氮、氧和硫的杂原子并且是不饱和或部分不饱和的;
各杂芳基是具有1-4个独立地选自氮、氧和硫的杂原子的5-6元单环杂芳基环,或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳基。
69.根据权利要求68所述的化合物,其中
R3是任选地被1-5个R3E取代的苯基,其中
各L3C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R3D独立地选自任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R3E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F、-NR3GS(O)1-2R3F;
各R3F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R3G独立地选自H和C1-C3烷基、C1-C3氟烷基;
R5是苯基、吗啉基、环己基、环己烯基、哌啶基、哌嗪基或吡咯烷基,其任选地被1-5个R5E取代,其中
各R5E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、-SF5、-N3、-C(O)R5F、-SR5F、-S(O)1-2R5F、-OR5F、-NR5GR5F、-C(O)R5F、-C(O)NR5GR5F、-NR5GC(O)R5F、-C(S)NR5GR5F、-NR1GC(S)R5F、-C(O)OR5F、-OC(O)R5F、-C(O)SR5F、-SC(O)R5F、-C(S)OR5F、-OC(S)R5F、-C(S)SR5F、-SC(S)R5F、-S(O)1-2OR5F、-OS(O)1-2R5F、-S(O)1-2NR5GR5F和-NR5GS(O)1-2R5F;
各R5F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R5G独立地选自H和C1-C3烷基。
70.根据权利要求68或权利要求69所述的方法、化合物或用途,其中
L1是-S-;
L2是化学键;并且
L3是化学键。
71.根据权利要求68至70中任一项所述的化合物,其中
L4是化学键;并且
L5是化学键。
72.根据权利要求1和3至6中任一项所述的化合物,其中
L1是-S-、-O-、-S(O)-、-S(O)2-或化学键;
R1是未被取代或被氟代的C1-C8烷基、未被取代或被氟代的C1-C8烯基、未被取代或被氟代的C1-C8炔基或被1-5个R1E取代的苯基,
其中
各R1E独立地选自氧代;任选被取代的C1-C4烷基;C1-C4氟烷基;卤素;-CN;SF5;-N3;-C(O)R1F;-SR1F;-S(O)1-2R1F;-OR1F;-(OCH2CH2O)n-R1G,其中n是1-4;-N(R1G)C(O)CH2-O-(CH2CH2O)nR1G,其中n是0-3;-C(O)NR1G(CH2CH2O)nR1G;-NR1GR1F;和-C(O)R1F;
各R1F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R1G独立地选自H和C1-C3烷基;
L2是化学键或-CH2-;
Q是-COOH;
L3是化学键、-C(O)-、-S-、-S(O)1-2-、-O-、-NR6-、-CH2-、-CH(CH3)(OH)-或-CH(OH)-;
R3是苯基或单环杂芳基,其各自(i)任选地被选自以下的单一取代基取代:-L3C-(任选地被1-5个R3D取代的苯基)、-L3C-(任选地被1-5个R3D取代的单环杂芳基)、-L3C-(任选地被1-5个R3E取代的单环C3-C6环烷基)、-L3C-(任选地被1-5个R3E取代的单环C4-C6杂环烷基)并且(ii)任选地被1-5个R3E取代,
其中
各L3C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R3D独立地选自任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R3E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F、-NR3GS(O)1-2R3F;
各R3F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R3G独立地选自H和C1-C3烷基、C1-C3氟烷基;
L4选自由以下组成的组:化学键、-C(O)-、-S-、-S(O)1-2-、-O-和-NR6-;
R4选自由以下组成的组:未被取代、羟基化、C1-C4烷氧基化或被氟代的C1-C8烷基、未被取代或被氟代的C1-C8烯基和未被取代或被氟代的C1-C8炔基;
L5是化学键、-C(O)-、-S-、-S(O)1-2-、-O-或-NR6-;
R5是苯基、单环杂芳基、单环杂环烷基或单环环烷基,其各自任选地被1-5个R5E取代,
其中
各R5E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、-SF5、-N3、-C(O)R5F、-SR5F、-S(O)1-2R5F、-OR5F、-NR5GR5F、-C(O)R5F、-C(O)NR5GR5F、-NR5GC(O)R5F、-C(S)NR5GR5F、-NR1GC(S)R5F、-C(O)OR5F、-OC(O)R5F、-C(O)SR5F、-SC(O)R5F、-C(S)OR5F、-OC(S)R5F、-C(S)SR5F、-SC(S)R5F、-S(O)1-2OR5F、-OS(O)1-2R5F、-S(O)1-2NR5GR5F和-NR5GS(O)1-2R5F;
各R5F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R5G独立地选自H和C1-C3烷基;
其中
各R6选自由以下组成的组:氢、C1-C3烷基和-C(O)(C1-C3烷基);
各任选被取代的烷基、烯基和炔基未被取代、被氟代或被一个或两个羟基取代;
各环烷基具有3-7个环碳并且是不饱和或部分不饱和的;
各杂环烷基具有3-7个环成员和1-3个独立地选自氮、氧和硫的杂原子并且是不饱和或部分不饱和的;
各杂芳基是具有1-4个独立地选自氮、氧和硫的杂原子的5-6元单环杂芳基环,或具有1-5个独立地选自氮、氧或硫的杂原子的8-10元双环杂芳基。
73.根据权利要求72所述的化合物,其中
R3是任选地被1-5个R3E取代的苯基,其中
各L3C是化学键、亚甲基、亚乙基、-C(O)-、-S-、-S(O)1-2-、-O-或-NR3G-;
各R3D独立地选自任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F和-NR3GS(O)1-2R3F;
各R3E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、SF5、-N3、-C(O)R3F、-SR3F、-S(O)1-2R3F、-OR3F、-NR3GR3F、-C(O)R3F、-C(O)NR3GR3F、-NR3GC(O)R3F、-C(S)NR3GR3F、-NR3GC(S)R3F、-C(O)OR3F、-OC(O)R3F、-C(O)SR3F、-SC(O)R3F、-C(S)OR3F、-OC(S)R3F、-C(S)SR3F、-SC(S)R3F、-S(O)1-2OR3F、-OS(O)1-2R3F、-S(O)1-2NR3GR3F、-NR3GS(O)1-2R3F;
各R3F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R3G独立地选自H和C1-C3烷基、C1-C3氟烷基;
R5是苯基、吗啉基、环己基、环己烯基、哌啶基、哌嗪基或吡咯烷基,其任选地被1-5个R5E取代,其中
各R5E独立地选自氧代、任选被取代的C1-C4烷基、C1-C4氟烷基、卤素、-CN、-SF5、-N3、-C(O)R5F、-SR5F、-S(O)1-2R5F、-OR5F、-NR5GR5F、-C(O)R5F、-C(O)NR5GR5F、-NR5GC(O)R5F、-C(S)NR5GR5F、-NR1GC(S)R5F、-C(O)OR5F、-OC(O)R5F、-C(O)SR5F、-SC(O)R5F、-C(S)OR5F、-OC(S)R5F、-C(S)SR5F、-SC(S)R5F、-S(O)1-2OR5F、-OS(O)1-2R5F、-S(O)1-2NR5GR5F和-NR5GS(O)1-2R5F;
各R5F独立地选自H、C1-C3烷基和C1-C3氟烷基,并且
各R5G独立地选自H和C1-C3烷基。
74.根据权利要求72或权利要求73所述的化合物,其中
L1是-S-;
L2是化学键;并且
L3是化学键。
75.根据权利要求72至74中任一项所述的化合物,其中
L4是化学键;并且
L5是化学键。
76.根据权利要求1至49和68至75中任一项所述的化合物,其中R5是三氟甲基苯基、卤代苯基或二卤代苯基。
77.根据权利要求1至49和68至75中任一项所述的化合物,其中R5是被一个或两个选自三氟甲基、氟和氯的取代基取代的苯基(例如3-取代、4-取代、3,4-双取代、2,4-双取代或2,5-双取代)。
78.根据权利要求1至77中任一项所述的化合物,其中各任选被取代的亚烷基、亚烯基和亚炔基是未被取代的。
79.根据权利要求1至78中任一项所述的化合物,其中各任选被取代的烷基、烯基和炔基是未被取代的。
80.根据权利要求1至79中任一项所述的化合物,其中各环烷基是3-7元单环环烷基。
81.根据权利要求1至80中任一项所述的化合物,其中各杂环烷基是具有1-2个选自O、S和N的杂原子的4-7元单环杂环烷基。
82.根据权利要求1至81中任一项所述的化合物,其中各杂芳基是具有1-3个选自O、S和N的杂原子的5-6元单环杂芳基。
83.根据权利要求1至82中任一项所述的化合物,其中各芳基是苯基。
84.根据权利要求1至83中任一项所述的化合物,其中所述化合物不是以上段落61中所列化合物之一。
85.一种选自以下的化合物,
1-(4-(4-氯-2-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-(氧杂环丁烷-3-基氧基)苯基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(5-甲基-1,3,4-噁二唑-2-基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4,4-二甲基环己-1-烯-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(1,4-二氧杂螺[4.5]癸-7-烯-8-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氯-3-(吗啉-4-羰基)苯基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3,4-二氯苯基)-2-(4-(2,6-二甲基吡啶-4-基)-3-甲基-1H-吡唑-1-基)-5-(异丙基硫基)噻唑;
2-(4-(3-氟苯基)-3,5-二甲基-1H-吡唑-1-基)-5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲氧基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-吗啉代噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-羟基-1-(5-(异丙基硫基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸;
1-(5-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-3-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(3-(3,4-二氯苯基)-1-异丁基-1H-1,2,4-三唑-5-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4,4-二氟哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(三氟甲基)环己-1-烯-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸甲酯;
4-(3-氟苯基)-3-甲基-1-(4-(4-(三氟甲基)环己基)噻唑-2-基)-1H-吡唑-5-甲酸
4-(3-氟苯基)-1-(5-异丁基-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2,2,2-三氟乙基)哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-氰基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-环丙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-乙基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-乙酰基哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲基哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-甲基-1-(5-(4-(三氟甲基)苯基)-1,3,4-噻二唑-2-基)-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-((2-甲氧基乙基)(甲基)氨基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸
1-(4-(4,4-二甲基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-(叔丁氧基羰基)哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(3-(三氟甲基)吡咯烷-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(哌嗪-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-甲基-1-(5-(2-甲基丙-1-烯-1-基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-甲基-1-(4-(2-甲基丙-1-烯-1-基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸;
1-(4,5-双(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
2-(4-(3-氟苯基)-3-甲基-1H-吡唑-1-基)-4,5-双(4-(三氟甲基)苯基)噻唑
1-(4-(4-(叔丁基)哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(6-氮杂螺[2.5]辛-6-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-甲氧基-4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(4-(4-甲氧基苯基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4,5-双(4-甲氧基苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-甲氧基苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(4-(4-(叔丁基)-3-氧代哌嗪-1-基)-5-(异丙基硫基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-甲基-1-(5-(3-(甲基氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(4-(2-甲氧基乙氧基)-4-(三氟甲基)哌啶-1-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-((2-甲氧基乙基)氨甲酰基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-((2-甲氧基乙基)(甲基)氨甲酰基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-(2-甲氧基乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-(2-(2-甲氧基乙氧基)乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(3-((2-甲氧基乙基)氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(3-((2-甲氧基乙基)(甲基)氨基)-3-氧代丙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-(2-甲氧基-N-甲基乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-(2-(2-甲氧基乙氧基)-N-甲基乙酰胺基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(甲氧基甲基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
1-(5-(4-(2-(2-乙氧基乙氧基)乙氧基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-4-(3-氟苯基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(3-氟苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(羟甲基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-3-甲基-1-(5-(4-(三氟甲基)苯基)-4-(4-(三氟甲基)哌啶-1-基)噻唑-2-基)-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(4-(3-氟苯基)-5-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(1-羟乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(2-羟乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(4-(2-甲氧基乙氧基)苯基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(5-(1-甲氧基乙基)-4-(4-(三氟甲基)苯基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;
4-(3-氟苯基)-1-(4-(4-异丙基哌啶-1-基)-5-(异丙基硫基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸;和
4-(3-氟苯基)-1-(5-(异丙基硫基)-4-(3-甲氧基-3-(三氟甲基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-2-基)-3-甲基-1H-吡唑-5-甲酸,
所述化合物任选地呈药学上可接受的盐或N-氧化物,或溶剂化物或水合物形式。
86.根据权利要求1至85所述的化合物,其中所述化合物呈N-氧化物形式。
87.根据权利要求1至86中任一项所述的化合物,其中所述化合物呈药学上可接受的盐形式。
88.根据权利要求1至86中任一项所述的化合物,其中所述化合物呈所述基础化合物形式。
89.根据权利要求1至88中任一项所述的化合物,其中所述化合物呈溶剂化物或水合物形式。
90.一种用于治疗有需要受试者的过度增生性病症,例如癌症的方法,所述方法包括向所述受试者施用有效量的根据权利要求1至89中任一项所述的化合物。
91.根据权利要求1至89中任一项所述的化合物,所述化合物用于治疗过度增生性病症,例如癌症。
92.一种根据权利要求1至89中任一项所述的化合物的用途,所述化合物用于制备供治疗过度增生性病症,例如癌症用的药剂。
93.一种用于抑制癌细胞中的细胞周期进程的方法,所述方法包括使所述癌细胞与有效量的根据权利要求1至89中任一项所述的化合物接触。
94.根据权利要求93所述的方法,其中细胞周期进程在所述细胞周期的G0/G1期被抑制。
95.一种用于诱导癌细胞凋亡的方法,所述方法包括使所述癌细胞与有效量的根据权利要求1至89中任一项所述的化合物接触。
96.一种用于诱导针对癌细胞的细胞毒性作用的方法,所述方法包括使所述癌细胞与有效量的根据权利要求1至89中任一项所述的化合物接触。
97.一种用于抑制癌细胞中谷胱甘肽合成的方法,所述方法包括使所述癌细胞与有效量的根据权利要求1至89中任一项所述的化合物接触。
98.根据权利要求90至97中任一项所述的方法、化合物或用途,其中所述癌症是造血系统癌症。
99.根据权利要求90至97中任一项所述的方法、化合物或用途,其中所述癌症选自淋巴瘤(例如伯基特氏淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤、皮肤T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、双重打击淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、原发性中枢神经系统(CNS)淋巴瘤和血管内大B细胞淋巴瘤(ILBCL))、白血病(例如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性成骨髓细胞性白血病、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、慢性骨髓单核细胞性白血病(CMML)、侵袭性NK细胞白血病、急性双表型白血病和真性红细胞增多症)、急性和慢性T细胞和B细胞白血病)以及浆细胞赘瘤(例如多发性骨髓瘤)。
100.根据权利要求90至97中任一项所述的方法、化合物或用途,其中所述癌症选自由以下组成的组:肾上腺皮质癌瘤、肾上腺皮质癌、AIDS相关癌症(例如卡波西氏肉瘤、AIDS相关淋巴瘤、伯基特氏淋巴瘤和原发性CNS淋巴瘤)、肛门癌、阑尾癌、星形细胞瘤(例如儿童小脑或大脑星形细胞瘤)、胆管癌(例如胆管细胞癌)、膀胱癌、骨癌(例如尤文氏肉瘤、骨肉瘤和恶性纤维组织细胞瘤)、脑肿瘤(例如多形性成胶质细胞瘤、小脑星形细胞瘤、大脑星形细胞瘤/恶性神经胶质瘤、室管膜瘤、成神经管细胞瘤、少突神经胶质瘤、幕上原始神经外胚层肿瘤以及视路和下丘脑神经胶质瘤)、脑干神经胶质瘤、乳癌、支气管肿瘤、胃肠类癌肿瘤、类癌肿瘤、原发灶不明性癌瘤、心脏(心)肿瘤、中枢神经系统癌症(例如非典型畸胎样/横纹肌样肿瘤、胚胎肿瘤和生殖细胞肿瘤)、子宫颈癌、儿童癌症、软骨肉瘤、慢性骨髓增生性赘瘤、结肠和直肠癌、颅咽管瘤、促结缔组织增生性小圆细胞肿瘤、乳腺管原位癌(DCIS)、子宫内膜癌、室管膜瘤、上皮样血管内皮瘤(EHE)、食道癌、嗅神经母细胞瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌(例如眼内黑素瘤和成视网膜细胞瘤)、输卵管癌、胆囊癌、胃癌、胃肠道间质瘤(GIST)、妊娠滋养细胞疾病(GTD)、神经胶质瘤、毛细胞白血病、头颈癌(例如头颈部鳞状细胞癌(HNSCC))、肝细胞(肝)癌、组织细胞增多病、朗格罕氏细胞、下咽癌、肾癌、朗格罕氏细胞组织细胞增多病、喉癌、喉癌和乳头状瘤病、白血病(例如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性成骨髓细胞性白血病、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、慢性骨髓单核细胞性白血病(CMML)、侵袭性NK细胞白血病、急性双表型白血病和真性红细胞增多症)、急性和慢性T细胞和B细胞白血病)、唇和口腔癌症、肝癌、肺癌(例如小细胞肺癌、非小细胞肺癌(NSCLC)、肺癌瘤和肺鳞癌)、肺类癌肿瘤、淋巴瘤(例如伯基特氏淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤、皮肤T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、双重打击淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、原发性中枢神经系统(CNS)淋巴瘤和血管内大B细胞淋巴瘤(ILBCL))、雄性乳癌、脑膜瘤、间皮瘤、涉及NUT基因的中线癌瘤、口部癌症、多发性内分泌腺瘤综合症、浆细胞赘瘤(例如多发性骨髓瘤)、蕈样真菌病、骨髓发育不良综合症、骨髓发育不良/骨髓增生性赘瘤和慢性骨髓增生性赘瘤、鼻腔和副鼻窦癌症、鼻咽癌(NPC)、成神经细胞瘤、口腔癌、唇和口腔癌症以及口咽癌、卵巢癌、胰腺癌和胰腺神经内分泌肿瘤(例如胰岛细胞瘤)、副神经节瘤、副甲状腺癌、阴茎癌、咽癌、嗜铬细胞瘤、垂体肿瘤、胸膜肺母细胞瘤、原发性腹膜癌、前列腺癌、成视网膜细胞瘤、横纹肌肉瘤、唾液腺癌、塞扎莱氏综合症、皮肤癌(例如基底和鳞状细胞癌、梅克尔氏细胞癌和黑素瘤)、小肠癌、软组织肉瘤、鳞状细胞癌、胃癌、睾丸癌、咽喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、尿道癌、子宫癌和子宫肉瘤、阴道癌、血管肿瘤、外阴癌以及威尔姆斯氏肿瘤。
101.根据权利要求90至97中任一项所述的方法、化合物或用途,其中所述癌症选自由以下组成的组:阑尾癌、骨癌(例如尤文氏肉瘤、骨肉瘤和恶性纤维组织细胞瘤)、支气管肿瘤、原发灶不明性癌瘤、慢性骨髓增生性赘瘤、结肠和直肠癌、头颈癌(包含头颈部鳞状细胞癌(HNSCC))、白血病(例如急性成淋巴细胞性白血病(ALL)、急性骨髓性白血病(AML)、急性成骨髓细胞性白血病、慢性淋巴细胞性白血病(CLL)、慢性骨髓性白血病(CML)、慢性嗜中性粒细胞性白血病(CNL)、慢性骨髓单核细胞性白血病(CMML)、侵袭性NK细胞白血病、急性双表型白血病和真性红细胞增多症)、急性和慢性T细胞和B细胞白血病)、淋巴瘤(例如伯基特氏淋巴瘤、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、毛细胞淋巴瘤、套细胞淋巴瘤、T细胞淋巴瘤、皮肤T细胞淋巴瘤、B细胞淋巴瘤、弥漫性大B细胞淋巴瘤、双重打击淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症、原发性中枢神经系统(CNS)淋巴瘤和血管内大B细胞淋巴瘤(ILBCL))、浆细胞赘瘤(例如多发性骨髓瘤)、骨髓发育不良综合症、骨髓发育不良/骨髓增生性赘瘤和慢性骨髓增生性赘瘤、胰腺癌和胰腺神经内分泌肿瘤(例如胰岛细胞瘤)、小肠癌、软组织肉瘤以及鳞状细胞癌。
102.根据权利要求90至97中任一项所述的方法、化合物或用途,其中所述癌症是弥漫性大B细胞淋巴瘤。
103.根据权利要求90至97中任一项所述的方法、化合物或用途,其中所述癌症是结肠直肠癌。
104.根据权利要求90至103中任一项所述的方法、化合物或用途,其中所述癌症具有突变型KRAS基因。
105.根据权利要求90至103中任一项所述的方法、化合物或用途,其中所述癌症具有杂合突变型KRAS基因。
106.根据权利要求86至105中任一项所述的方法、化合物或用途,其中所述过度增生性病症或癌症不是伯基特氏淋巴瘤。
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CA3152025A1 (en) | 2019-09-24 | 2021-04-01 | David BRIERE | Combination therapies |
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