CN108430973A - RORγ调节剂 - Google Patents
RORγ调节剂 Download PDFInfo
- Publication number
- CN108430973A CN108430973A CN201680043515.7A CN201680043515A CN108430973A CN 108430973 A CN108430973 A CN 108430973A CN 201680043515 A CN201680043515 A CN 201680043515A CN 108430973 A CN108430973 A CN 108430973A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- acetamide
- cyclopropylmethanesulfonyls
- alkyl
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
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Classifications
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
本发明涉及式(I)的化合物或其药用盐。所述化合物可以用作RORγ的抑制剂并且用于治疗RORγ介导的疾病。
Description
维甲酸受体相关性孤儿受体γt(RORγt)不但充当TH17细胞发育的主调节因子,还充当非TH17IL-17产生细胞例如γδT细胞中的关键组件。ROR基因家族为核激素受体超家族的一部分,并由三个成员(RORα、RORβ和RORγ)组成。各基因在不同亚型中表达,主要区别在于其N末端序列。已鉴定了RORγ的两种亚型:RORγ1和RORγ2(还称作RORγt)。术语RORγ在本文中用于描述RORγ1和/或RORγ2二者。
本发明涉及RORγ的调节剂、包含其的药物组合物以及所述化合物用于治疗RORγ介导的疾病或病症特别是自身免疫性疾病和炎性疾病的用途。
本发明提供了含有2-(4-环丙基甲磺酰基苯基)乙酰胺或2-(4-环丙基氨磺酰基苯基)乙酰胺亚结构的新的RORγ调节剂化合物。
本发明涉及式I的化合物
或其药用盐,其中:
A1是NR1或CR1,其中R1是H或甲基,其中甲基如果存在则任选被一个或多个F取代;
环丙基可以任选被一个或多个甲基和一个或多个F取代;
A2-A5分别是N或CR2-CR5,条件是A2-A5中的四个位置A中的不超过两个可以同时是N;
R2-R5独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
R6和R7独立地是H、F、甲基、乙基、羟基或甲氧基或R2和R3一起为羰基,所有烷基如果存在则任选被一个或多个F取代;
R8是H或C(1-6)烷基;
R9选自式II、III、IV和V
其中:
A10-A13分别是N或CR10-CR13,条件是A10-A13中的四个位置A中的不超过两个可以同时是N;
R10-R13独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
X14是C(6-10)芳基或C(1-9)杂芳基,其中所有碳原子任选被卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代;
其中:
A20-A27分别是N或CR20-CR27,条件是A20-A22中的三个位置A中的不超过两个可以同时是N并且A23-A27中的五个位置A中的不超过三个可以同时是N;
R20-R22独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
R23-R27独立地是H、卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基;
X28是C(6-10)芳基或C(1-9)杂芳基,其中所有碳原子任选被卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代;
其中:
A30是N或C;
A31是O、羰基、NR31或CR32;
R31是H或C(1-6)烷基;
R32是H、OH或C(1-3)烷基,其中所有烷基任选被一个或多个F或OH取代;
A33-A42分别是N或CR33-CR42,条件是A33-A37中的五个位置A中的不超过三个可以同时是N并且A38-A42中的五个位置A中的不超过三个可以同时是N;
R33-R42独立地是H、卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基。
如本文所使用的术语C(1-6)烷基是指具有1-6个碳原子的支化或非支化的烷基,例如甲基、乙基、丙基、异丙基、丁基、叔丁基、正戊基和正己基。所有碳原子可任选地被一个或多个卤素取代。
如本文所使用的术语C(1-3)烷是指具有1-3个碳原子的烷基,即甲基、乙基、丙基或异丙基。所有碳原子可任选地被一个或多个卤素取代。
如本文所使用的术语C(1-2)烷基是指具有1-2个碳原子的烷基,即甲基或乙基。所有碳原子可任选地被一个或多个卤素取代。
如本文所使用的术语C(6-10)芳基是指具有6-10个碳原子的芳族烃基,例如苯基或萘基。优选的芳族烃基是苯基。所有碳原子可任选地被一个或多个卤素取代。
如本文所使用的术语C(6)芳基是指具有6个碳原子的芳族烃基,即苯基。所有碳原子可任选地被一个或多个卤素取代。
如本文所使用的术语杂原子是指氮、硫或氧原子。
本文使用的术语氨基是指NH2基团。
本文使用的术语C(1-9)杂芳基是指具有1至9个碳原子和1至4个杂原子的芳族基团,其可以经由氮原子(如果可行)或碳原子连接。实例包括咪唑基、噻二唑基、吡啶基、嘧啶基、呋喃基、吡唑基、异噁唑基、四唑基和喹啉基。所有碳原子可以任选被一个或多个卤素或甲基取代。
本文使用的术语C(1-5)杂芳基是指具有1-5个碳原子和1-4个杂原子的芳族基团,其可以经由氮原子(如果可行)或碳原子连接。实例包括咪唑基、噻二唑基、吡啶基、嘧啶基、呋喃基、吡唑基、异噁唑基和四唑基。所有碳原子可任选被一个或多个卤素或甲基取代。
本文使用的术语环丙基甲基是指被环丙基取代的甲基。所有碳原子任选被一个或多个卤素或甲基取代。
本文使用的术语(二)C(1-3)烷基氨基是指被C(1-3)烷基单取代或二取代的氨基,所述C(1-3)烷基具有与前述定义相同的含义。
术语C(1-3)烷氧基是指具有1-3个碳原子的烷氧基,该烷基是支化或非支化的。所有碳原子任选被一个或多个F取代。
本文使用的术语卤素是指Cl或F。
在以上具有多官能团的定义中,连接位点是在最后的基团。
当在取代基的定义中指出所述取代基的“所有烷基”被任选取代时,其还包括烷氧基的烷基部分。
术语“取代的”是指一个或多个指定原子上的一个或多个氢被指示基团的选择所取代,条件是不超出现有环境下指定原子的正常化合价,以及所述取代导致稳定化合物。取代基和/或变量的组合只有在此组合导致稳定化合物的情况下才是可允许的。“稳定化合物”或“稳定结构”被定义为从反应混合物分离至有用纯度以及配制为有效治疗剂时足够稳固以继续存在的化合物或结构。
术语“任选取代的”是指被指定基团、原子团或部分任选取代。
术语药用盐表示以下那些盐类:其是在医学判断的范围内,适用于与人和低等动物的组织接触使用而无异常毒性、刺激性、过敏反应等,并与合理的收益/风险比相称。药用盐是本领域熟知的。它们可在本发明化合物的最终分离和纯化期间获得,或通过使游离碱官能团与适当的无机酸如盐酸、磷酸或硫酸反应,或者与有机酸如抗坏血酸、柠檬酸、酒石酸、乳酸、马来酸、丙二酸、富马酸、乙醇酸、琥珀酸、丙酸、乙酸、甲磺酸等反应而单独获得。酸官能团可与有机或无机碱如氢氧化钠、氢氧化钾或氢氧化锂反应。
在一个实施方案中,本发明涉及式I的化合物,其中A1是CR1。
在另一个实施方案中,本发明涉及式I的化合物,其中A1是NR1。
在另一个实施方案中,本发明涉及式I的化合物,其中R1是氢。
在另一个实施方案中,本发明涉及式I的化合物,其中R6和R7独立地是H、甲基或羟基。
在又另一个实施方案中,本发明涉及式I的化合物,其中R6和R7两者均是H。
本发明还涉及式I的化合物,其中R8是H或C(1-2)烷基,H是最优选的。
本发明还涉及式I的化合物,其中R8是H。
在又另一个实施方案中,本发明涉及式I的化合物,其中R2是甲基且R3-R5是H。
在另一个实施方案中,本发明涉及式I的化合物,其中R2-R5是H。
在另一个实施方案中,本发明涉及式I的化合物,其中A2-A5中的所有位置A是CR2-R5。
在又另一个实施方案中,本发明涉及式I的化合物,其中A2-A5中的所有位置A是CR2-R5,并且R2-R5中的所有位置R是H。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式II,其中:A10-A13分别是N或CR10-CR13,条件是A10-A13中的四个位置A中的不超过两个可以同时是N;R10-R13独立地是H、氨基、卤素、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;X14是C(6)芳基或C(1-5)杂芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代,其中任选的取代基C(1-3)烷氧基是优选的。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式II并且A10-A13中的所有位置A是碳。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且A10是氮。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且A11是氮。
本发明还涉及式I的化合物,其中R9是式II且R10-R13独立地是H、卤素、甲基或甲氧基。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且R10-R13是H。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且X14是C(6)芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且X14是C(1-5)杂芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且X14是C(6)芳基或C(1-5)杂芳基,其中所有碳原子任选被C(1-3)烷氧基取代。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式II且X14是2-(三氟甲氧基)苯基。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III,其中:A20-A27分别是N或CR20-CR27,条件是A20-A22中的三个位置A中的不超过两个可以同时是N并且A23-A27中的五个位置A中的不超过三个可以同时是N;R20-R22独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;R23-R27独立地是H、卤素、氰基、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基;X28是C(6)芳基或C(1-5)杂芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III并且A20-A22的所有位置A是碳。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且A20是氮。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且A22是氮。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且R20-R22独立地是H、卤素、甲基或甲氧基。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且R20-R22是H。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式III并且A23-A27的所有位置A是碳。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且R23、R25和R27是H。
本发明还涉及式I的化合物,其中R9是式III且R24和R26独立地是H、卤素、氰基、甲氧基或甲基。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且X28是C(6)芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且X28是C(1-5)杂芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且X28是苯基。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且X28是1H-咪唑-1-基。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式III且X28是1H-吡唑-1-基。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式IV或V,其中:A30是N或C;A31是O、羰基、NR31或CR32;R31是H或C(1-6)烷基;R32是H、OH或C(1-6)烷基,其中所有烷基任选被一个或多个F或OH取代;A33-A42分别是N或CR33-CR42,条件是五个位置A33-A37中的不超过三个可以同时是N并且五个位置A38-A42中的不超过三个可以同时是N;R33-R42独立地是H、卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基。
本发明还涉及式I的化合物,其中R9是式IV或V且A30是N。
本发明还涉及式I的化合物,其中R9是式IV或V且A30是C。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式V且A31是羰基。
在另一个实施方案中,本发明涉及式I的化合物,其中R9是式V且A31是氧。
在又另一个实施方案中,本发明涉及式I的化合物,其中R9是式V并且A33-A42的所有位置A是碳。
本发明还涉及那些化合物,其中A1至A42、R1至R42以及本文以上定义的在本发明各方面中的所有取代基的具体定义可在式I化合物的定义内以任意组合出现。
在另一方面中,本发明涉及式I化合物,其具有5或更高的pIC50。在又另一方面中,本发明涉及式I的化合物,其具有超过6的pIC50。在又另一方面中,本发明涉及式I的化合物,其具有超过7的pIC50。在又另一方面中,本发明涉及式I的化合物,其具有超过8的pIC50。
在又另一方面,本发明在于如实施例1-47中所述选择的式I的化合物。
式I化合物可形成盐,其也在本发明的范围内。除非另有说明,否则提及本文中式I化合物被理解为包括提及其盐。
式I化合物可包含不对称或手性中心,且因此以不同立体异构形式存在。意图使式I化合物的所有立体异构形式以及其混合物(包括外消旋混合物)形成本发明的部分。
可基于非对映异构混合物的物理化学差异,通过本领域技术人员熟知的方法例如色谱和/或分步结晶将其分离为其个体非对映体。对映异构体的分离可通过与适当光学活性化合物(例如手性助剂如手性醇或Mosher酰氯)的反应将对映异构体混合物转化为非对映异构混合物,分离非对映体并将个体非对映体转化(例如水解)为相应的纯净对映异构体。对映异构体的分离还可通过使用手性HPLC柱。
技术人员将会意识到期望的IC50值取决于所测试化合物。例如,IC50值小于10-5M的化合物将通常被考虑为药物筛选的候选物。优选地,此值小于10-6M。然而,具有较高IC50值但对特定受体具有选择性的化合物可能是甚至更好的侯选物。
本发明化合物抑制RORγ活性。RORγ活性调节的测量可使用例如生物物理学(天然)配体替代研究、生化AlphaScreen或FRET测定、细胞GAL4报告基因测定、细胞IL-17启动子报告基因测定或功能性IL-17ELISA测定,使用例如在TH17极化条件下培养的小鼠脾细胞或人外周血单核细胞(PBMC)。
在所述测定中,配体与RORγ相互作用的测定可通过测量例如辅因子来源肽与RORγ配体结合域的配体调节相互作用,或者使用例如荧光素酶报告基因测定或IL-17ELISA测定测量配体调节RORγ介导的转录的基因产物。
本发明还涉及药物组合物,其包含与药用赋形剂以及任选的其它治疗活性剂混合的具有通式I的化合物或其药用盐。就与组合物的其它组分相容并对其接受者无毒的意义上而言,所述赋形剂必须是“可接受的”。
本发明另外包含与一种或多种其它药物组合的式I化合物。
组合物包括例如适用于口服、舌下、皮下、静脉内、肌内、经鼻、局部或直肠给药等的那些,所有均为用于给药的单位剂型形式。
对于口服给药,活性成分可呈现为离散单元,例如片剂、胶囊、粉末、颗粒、溶液、悬浮液等。
对于肠胃外给药,本发明药物组合物可呈现在单位剂量或多剂量容器中,例如预设量的注射液体,例如在密封小瓶或安瓶中,并还可贮存在仅需在使用前加入无菌液体载体例如水的冷冻干燥(冻干)条件下。
与所述药用赋形剂混合,活性剂可被压制为固体剂量单位,例如丸剂、片剂,或被加工成胶囊或栓剂。借助于药用液体,可将活性剂应用为流体组合物,例如溶液、悬浮液、乳液形式的注射制剂,或应用为喷雾剂例如鼻用喷雾。
对于制备固体剂量单位,预期使用常规添加剂例如填充剂、着色剂、聚合物粘合剂等。通常,可使用不干扰活性化合物功能的任何药用添加剂。可与本发明活性剂一起给药为固体组合物的适当载体包括以适当量使用的乳糖、淀粉、纤维素衍生物等,或其混合物。对于肠胃外给药,可使用水性悬浮液、等渗盐溶液和无菌注射溶液,其包含药用分散剂和/或润湿剂,例如丙二醇或丁二醇。
本发明另外包含如上文所述的药物组合物,其与适用于所述组合物的包装材料组合,所述包装材料包括使用用于如上文所述用途的组合物的说明。
活性成分或其药物组合物的精确给药剂量和方案可伴随着特定化合物、给药途径以及给药药物的个体受试者的年龄和状况而有所不同。
通常,肠胃外给药相比于更加依赖吸收的其它给药方法需要较少的剂量。然而,人用剂量优选包含0.0001-100mg/kg体重。期望剂量可呈现为一个剂量或在全天以适当间隔给药的多个亚剂量。
根据本发明的化合物可以用于治疗。
本发明的一个另外方面在于根据本发明的化合物或其药用盐用于治疗RORγ介导的疾病或者RORγ介导的病症的用途。
本发明的另一方面在于具有通式I的化合物或其药用盐用于治疗自身免疫疾病,具体为表达TH17标志细胞因子的TH17细胞和非TH17细胞发挥显著作用的那些疾病的用途。这些用途包括但不限于治疗治疗类风湿性关节炎、银屑病、炎性肠病、克罗恩病和多发性硬化。
在另一方面中,具有通式I的化合物或其药用盐可用于治疗表达TH17标志细胞因子的TH17细胞和/或非TH17细胞发挥显著作用的炎性疾病,其例如但不限于呼吸系统疾病、骨关节炎和哮喘。而且,具有通式I的化合物或其药用盐可用于治疗表达TH17标志细胞因子的TH17细胞和/或非TH17细胞发挥显著作用的传染疾病,其例如但不限于粘膜利什曼病。
具有通式I的化合物或其药用盐还可用于治疗表达TH17标志细胞因子的TH17细胞和/或非TH17细胞发挥显著作用的其它疾病,其例如但不限于川崎病和桥本氏甲状腺炎。
本发明的又另一方面在于具有通式I的化合物用于治疗以下疾病的用途:多发性硬化、炎性肠病、克罗恩病、银屑病、类风湿性关节炎、哮喘、骨关节炎、川崎病、桥本氏甲状腺炎、癌症和粘膜利什曼病。
在另一方面中,根据本发明的化合物可用于治疗或预防以下疾病的疗法中:多发性硬化、炎性肠病、克罗恩病、银屑病和类风湿性关节炎、哮喘、骨关节炎、川崎病、桥本氏甲状腺炎、癌症和粘膜利什曼病。
在另一方面中,根据本发明的化合物可用于治疗或预防银屑病。
在又另一方面中,根据本发明的化合物可用于治疗炎性肠病。
通过以下实施例示例说明本发明。
示例
如以下实施例中所述的,在某些示例性实施方案中,根据以下一般操作制备化合物。应该理解的是,虽然一般方法描述了本发明的某些化合物的合成,但是可以将以下一般方法和本领域技术人员已知的其它方法应用于如本文所述的所有化合物和亚类和这些化合物中的每一种。
一般制备方法
包括通式A、B和I的化合物的本文所述的化合物可以容易地根据以下反应方案和实施例或其修改形式,使用容易获得的起始物质、试剂和常规合成操作来制备。许多反应也可以在微波条件下或使用常规加热或利用其它技术如固相试剂/清除剂或流式化学进行。在这些反应中,也可以使用本身为本领域技术人员已知但没有更详细地提及的变化形式。例如,在提及具体的酸、碱、试剂、偶联剂、溶剂等的情况下,应理解的是,可以使用其它合适的酸、碱、试剂、偶联剂、溶剂等并且包括在本发明的范围内。此外,根据以下反应方案和实施例,用于制备本发明化合物的其它方法对于本领域技术人员将是显而易见的。在合成中间体和最终产物含有潜在反应性官能团(例如可干扰所需反应的氨基、羟基、巯基和羧酸基团)的情况下,使用中间体的保护形式可能是有利的。用于选择、引入和随后移去保护基的方法是本领域技术人员公知的。通过使用一般反应顺序获得的化合物可能纯度不够。可以使用任何有机化合物的纯化方法,例如结晶或硅胶或氧化铝柱色谱,使用不同的溶剂,以合适的比例来纯化化合物。所有可能的立体异构体都视为在本发明的范围内。在下面的讨论中,除非另有说明,否则变量具有上述含义。
这些实验细节中使用的缩写在下面列出,并且附加的缩写应被认为是合成化学领域的技术人员已知的。
本文使用的缩写如下:r.t.:室温;HATU:2-(7-氮杂-1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐;DMF:二甲基甲酰胺;DiPEA:二异丙基乙胺;DMAP:4-(二甲基氨基)吡啶;DCC:N,N'-二环己基碳二亚胺;mCPBA:3-氯过氧苯甲酸;TFA:三氟乙酸;TFAA:三氟乙酸酐;THF:四氢呋喃;DMSO:二甲基亚砜;PTSA:对甲苯磺酸;PyBOP:(苯并三唑-1-基氧基)三吡咯烷子基鏻六氟磷酸盐;EtOH:乙醇;TLC:薄层色谱;Ph3P:三苯基膦;EDCI:1-乙基-3-(3-二甲基氨基丙基)碳二亚胺;BuLi:正丁基锂;PdCl2(dppf):[1,1'-二(二苯基膦基)二茂铁]二氯化钯(II)。
化学名称是优选的IUPAC名称,使用MarvinSketch版本6.3.0生成。
如果使用化学结构和化学名称提及化学化合物,并且结构与名称之间存在模糊性,则以结构为主。
一般操作
方案1:
条件:i)EDCI,DMAP,CH2Cl2。
如方案1所示,具有式I的本发明的衍生物可以通过有机化学领域已知的方法制备。本发明的化合物可以例如通过式A苯基乙酸衍生物(X是OH)(其中R2、R3、R5、R6、R7、R8和A1具有如前所述的含义)与式B胺衍生物(其中R8和R9具有如前所述的含义)之间的酰胺偶联反应(使用偶联试剂诸如EDCI、HATU、DCC或PyBOP等,在合适的碱诸如DiPEA或催化剂诸如DMAP存在下)获得。
可替换地,可以使用例如SOCl2或草酰氯,将式A苯基乙酸衍生物(X=OH)转化为式A酰氯衍生物(X=Cl)。可以将得到的式A酰氯衍生物(X1=Cl)(其中R2、R3、R5、R6、R7、R8和A1具有如前所述的含义)在适宜的碱诸如Et3N等存在下与式B胺衍生物(其中R8和R9具有如前所述的含义)偶联。
方案2:
条件:i)H2SO4,EtOH,60℃;ii)(溴甲基)环丙烷,K2CO3,CH3CN,r.t.;iii)mCPBA,CH2Cl2,r.t.;iv)2N NaOH,EtOH,r.t.。
方案2示例说明了用于制备式A的2-(4-环丙基甲磺酰基苯基)乙酸衍生物5的一般方法,其中A1是CH2且A2、A3、A4、A5、R6和R7具有如前所述的含义。
在酸性条件下使用例如H2SO4在乙醇中的溶液酯化4-巯基苯基乙酸衍生物1,得到4-巯基苯基乙酸乙酯衍生物2。在碱诸如K2CO3存在下使用(溴甲基)环丙烷对硫基进行烷基化,得到相应的2-(4-环丙基甲硫基苯基)乙酸乙酯衍生物3。使用例如mCPBA氧化,得到2-(4-环丙基甲磺酰基苯基)乙酸乙酯衍生物4,其在碱性条件(例如NaOH在乙醇中的溶液)下皂化酯基团后,得到相应的式A衍生物5。
方案3:
条件:i)氯磺酸,CH2Cl2,0℃至r.t.;ii)环丙基胺,Et3N,CH2Cl2,r.t.;iii)2NNaOH,EtOH,r.t.。
方案3示例说明了用于制备式A的2-[4-(环丙基氨磺酰基)苯基]乙酸衍生物9的一般方法,其中A1是NH且A2、A3、A4、A5、R6和R7具有如前所述的含义。
2-苯基乙酸乙酯衍生物6与氯磺酸的反应得到2-[4-(氯磺酰基)苯基]乙酸乙酯衍生物7,其在用环丙胺进行亲核取代后得到2-[4-(环丙基氨磺酰基)苯基]乙酸乙酯衍生物8。在碱性条件(例如NaOH在乙醇中的溶液)下皂化酯基团,得到相应的式A衍生物9。
大部分式B的化合物是可商购的、已知的或根据本领域技术人员已知的方法制备。
方案4:
条件:i)三氟甲磺酸酐,CH2Cl2,吡啶、DMAP,r.t.;ii)合适的硼酸,Pd(Ph3)4,K2CO3,EtOH,水,回流;iii)合适的杂芳基,K2CO3,DMF,150℃;iv)Cs2CO3,合适的酚,DMF,110℃;v)锌粉,NH4Cl,THF,水75℃;vi)5或9,EDCI,DMAP,CH2Cl2,60℃。
方案4证实了用于制备式I衍生物15的一般方法,其中R6、R7、R8、A1、A2、A3、A4、A5、A20、A21、A22、A23、A24、A25、A26、A27和X28具有如前所述的含义。
2-氟-4-硝基苯酚衍生物10在适宜的碱诸如吡啶存在下在与三氟甲磺酸酐反应后得到相应的三氟甲磺酸酯衍生物11,其在催化剂例如Pd(Ph3P)4和碱例如K2CO3存在下在Suzuki-偶联反应条件下与合适的芳基硼酸或杂芳基硼酸得到相应的联芳衍生物12。为了获得式I的氮-偶联的杂芳族衍生物,可以使1,2-二氟-4-硝基苯衍生物16与适合的杂芳基化合物在碱例如K2CO3存在下反应,得到相应的联芳衍生物12。在使用碱诸如Cs2CO3与合适的酚反应后,衍生物12得到相应的芳基醚衍生物13。通过在锌或铁存在下使用例如NH4Cl可以还原衍生物13的硝基,得到式B胺衍生物14,其中R4是氢,其可以在例如EDCI和DMAP存在下与式A衍生物5或9缩合,得到式I衍生物15。
方案5:
条件:i)2-氰基乙酸乙酯,硫,吗啉,EtOH,回流;ii)NaOH,EtOH,回流;iii)5或9,EDCI,DMAP,CH2Cl2,60℃;iv)适合的苯甲酰氯,SnCl4,CH2Cl2,回流。
方案5代表了用于制备式I衍生物21的一般方法,其中A30是C,A31是羰基且R6、R7、R8、A1、A2、A3、A4、A5、A33、A34、A35、A36、A37、A38、A39、A40、A41和A42具有如前所述的含义。
可以使取代的苯基甲基酮17与2-氰基乙酸乙酯和硫在吗啉存在下反应,形成相应的噻吩酯18。化合物18的脱酯化提供噻吩氨基式B衍生物19,其可以与式A的苯基乙酸衍生物在例如EDCI和DMAP存在下缩合,得到相应的式I噻吩酰胺衍生物20。SnCl4或AlCl3催化的噻吩环的酰化,得到式I衍生物21。
方案6:
条件:i)二[(4-甲氧基苯基)甲基]胺,NH4SCN,丙酮,0℃;ii)DMF,85℃;iii)TFA,80℃;iv)5或9,EDCI,DMAP,CH2Cl2,60℃。
方案6描述了用于制备式I衍生物27的一般反应方案,其中A30是氮,A31是羰基且R6、R7、A1、A2、A3、A4、A5、A33、A34、A35、A36、A37、A38、A39、A40、A41和A42具有如前所述的含义。
通过缩合酰氯22、硫氰酸酯和二[(4-甲氧基苯基)甲基]胺可以获得被保护的硫代氨基甲酰基酰胺衍生物23。被保护的硫代氨基甲酰基酰胺衍生物23和适当的α-溴酮24(其可以商购获得或通过使用本领域技术人员已知的方法从甲基酮开始合成)之间的反应得到被保护的噻唑酮衍生物25。在酸性条件下脱保护,使用例如TFA,得到式B 2-氨基噻唑衍生物26,其可以在例如EDCI和DMAP存在下与式A衍生物5或9缩合,得到式I衍生物27。
方案7:
条件:i)硫脲,EtOH,80℃;ii)CuBr2,CH3CN,r.t.;iii)适合的酚,Cs2CO3,丙酮,55℃;iv)5或9,EDCI,DMAP,CH2Cl2,60℃。
方案7描述了用于制备式I衍生物33的一般反应方案,其中A30是氮,A31是氧且R6、R7、A1、A2、A3、A4、A5、A33、A34、A35、A36、A37、A38、A39、A40、A41和A42具有如前所述的含义。
与硫脲反应后,α-溴酮衍生物28得到1,3-噻唑-2-胺衍生物29,其在在CuBr2存在下溴化后,得到5-溴-1,3-噻唑-2-胺衍生物30。被适合的酚31取代溴得到式B噻唑衍生物32,其可以在例如EDCI和DMAP存在下与式A衍生物5或9缩合,得到式I衍生物33。
所用的所有构造块都是可商购的、已知的或根据本领域技术人员已知的方法制备的。
实施例
实施例1-47
1:2-(4-环丙基甲磺酰基苯基)-N-(3-苯氧基-4-苯基苯基)乙酰胺。
i)在0℃向2-(4-环丙基甲磺酰基苯基)乙酸(29mg)、3-苯氧基-4-苯基苯胺(30mg)和DMAP(3mg)于CH2Cl2(0.5mL)中的溶液中逐滴加入EDCI(32mg)于CH2Cl2中的溶液。将反应混合物在60℃在微波中搅拌1小时。冷却至室温后,将有机层先后用饱和NaHCO3水溶液、水和盐水洗涤,经MgSO4干燥并减压浓缩。将残余物在SiO2上纯化,使用1%至10%甲醇于CH2Cl2中的溶液作为洗脱剂,得到标题化合物2-(4-环丙基甲磺酰基苯基)-N-(3-苯氧基-4- 苯基苯基)乙酰胺(70mg),为白色固体。MS(ES+)m/z 498.2(M+H)+。
按照针对实施例1所述的操作,制备以下化合物。
2:2-(4-环丙基甲磺酰基苯基)-N-[4-(3-氟苯基)-3-(3-甲氧基苯氧基)苯基]乙酰胺。
MS(ES+)m/z 546.2(M+H)+。
3:2-(4-环丙基甲磺酰基苯基)-N-[3-(3-甲氧基苯氧基)-4-(4-甲基-1H-咪唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 532.2(M+H)+。
4:N-[3-(3-氯苯氧基)-4-(3-氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 550.1(M+H)+。
5:N-[3-(3-氯苯氧基)-4-(3,4-二氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 568.1(M+H)+。
6:N-[3-(3-氰基苯氧基)-4-(3,4-二氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 559.2(M+H)+。
7:2-(4-环丙基甲磺酰基苯基)-N-[3-(3-甲氧基苯氧基)-4-(5-甲基-1H-吡唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 532.2(M+H)+。
8:N-[3-(3-氯苯氧基)-4-(3,5-二氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 567.1(M+H)+。
9:N-[4-(4-氰基苯基)-3-(3-氟苯氧基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 541.2(M+H)+。
10:N-[3-(3-氯苯氧基)-4-(3-氰基苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 557.1(M+H)+。
11:2-(4-环丙基甲磺酰基苯基)-N-[4-(3-氟苯基)-3-[3-(三氟甲基)苯氧基]苯基]乙酰胺。
MS(ES+)m/z 584.2(M+H)+。
12:2-(4-环丙基甲磺酰基苯基)-N-[3-(3-氟苯氧基)-4-(4-氟苯基)苯基]乙酰胺。
MS(ES+)m/z 534.2(M+H)+。
13:2-(4-环丙基甲磺酰基苯基)-N-[3-(3,5-二氟苯氧基)-4-(3-氟苯基)苯基]乙酰胺。
MS(ES+)m/z 552.2(M+H)+。
14:2-[4-(环丙基氨磺酰基)苯基]-N-[3-(3-甲氧基苯氧基)-4-(4-甲基-1H-咪唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 533.2(M+H)+。
15:2-[4-(环丙基氨磺酰基)苯基]-N-[3-(3-甲氧基苯氧基)-4-(5-甲基-1H-吡唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 533.2(M+H)+。
16:2-[4-(环丙基氨磺酰基)苯基]-N-[4-(3-氟苯基)-3-(3-甲氧基苯氧基)苯基]乙酰胺。
MS(ES+)m/z 547.2(M+H)+。
17:N-[3-(3-氯苯氧基)-4-(3-氟苯基)苯基]-2-[4-(环丙基氨磺酰基)苯基]乙酰胺。
MS(ES+)m/z 551.2(M+H)+。
18:N-[3-(3-氯苯氧基)-4-(3,4-二氟苯基)苯基]-2-[4-(环丙基氨磺酰基)苯基]乙酰胺。
MS(ES+)m/z 569.2(M+H)+。
19:2-[4-(环丙基氨磺酰基)苯基]-N-[4-(3-氟苯基)-3-[3-(三氟甲基)苯氧基]苯基]乙酰胺。
MS(ES+)m/z 585.2(M+H)+。
20:2-(4-环丙基甲磺酰基苯基)-N-(5-苯氧基-4-苯基-1,3-噻唑-2-基)乙酰胺。
MS(ES+)m/z 505.1(M+H)+。
21:2-(4-环丙基甲磺酰基苯基)-N-[4-苯基-5-(吡啶-3-基氧基)-1,3-噻唑-2-基]乙酰胺。
MS(ES+)m/z 506.1(+H)+。
22:N-(5-苯甲酰基-4-苯基-1,3-噻唑-2-基)-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 517.1(M+H)+。
23:N-[5-(4-氯苯甲酰基)-4-(3-氯苯基)-1,3-噻唑-2-基]-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 585.0(M+H)+。
24:2-(4-环丙基甲磺酰基苯基)-N-(4-苯基噻吩-2-基)乙酰胺。
MS(ES+)m/z 412.1(M+H)+。
25:2-(4-环丙基甲磺酰基苯基)-N-[4-(吡啶-3-基)噻吩-2-基]乙酰胺。
MS(ES+)m/z 413.1(M+H)+。
26:N-(5-苯甲酰基-4-苯基-1,3-噻唑-2-基)-2-[4-(环丙基氨磺酰基)苯基]乙酰胺。
MS(ES+)m/z 517.1(M+H)+。
27:N-(5-苯甲酰基-4-苯基噻吩-2-基)-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 516.1(M+H)+。
28:N-{3-氯-4-[2-(三氟甲氧基)苯基]苯基}-2-(4-环丙基甲磺酰基苯基)乙酰胺。
MS(ES+)m/z 524.1(M+H)+。
29:2-(4-环丙基甲磺酰基苯基)-N-{3-甲基-4-[2-(三氟甲氧基)苯基]苯基}乙酰胺。
MS(ES+)m/z 504.1(M+H)+。
30:2-(4-环丙基甲磺酰基苯基)-N-{3,5-二氯-4-[2-(三氟甲氧基)苯基]苯基}乙酰胺。
MS(ES+)m/z 558.0(M+H)+。
31:2-(4-环丙基甲磺酰基苯基)-N-{4-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺。
MS(ES+)m/z 505.1(M+H)+。
32:2-(4-环丙基甲磺酰基苯基)-N-{6-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺。
MS(ES+)m/z 505.1(M+H)+。
33:N-{3-氯-4-[2-(三氟甲氧基)苯基]苯基}-2-[4-(环丙基氨磺酰基)苯基]乙酰胺。
MS(ES+)m/z 525.0(M+H)+。
34:2-[4-(环丙基氨磺酰基)苯基]-N-{6-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺。
MS(ES+)m/z 506.0(M+H)+。
35:2-[4-(环丙基氨磺酰基)苯基]-N-{4-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺。
MS(ES+)m/z 506.0(M+H)+。
36:2-[4-(环丙基氨磺酰基)苯基]-N-{3-甲基-4-[2-(三氟甲氧基)苯基]苯基}乙酰胺。
MS(ES+)m/z 505.0(M+H)+。
37:2-(4-环丙基甲磺酰基苯基)-N-{4,6-二甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺。
MS(ES+)m/z 519.1(M+H)+。
38:2-(4-环丙基甲磺酰基苯基)-N-[4-(4-甲基-1H-咪唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 410.1(M+H)+。
39:2-(4-环丙基甲磺酰基苯基)-N-[4-(5-甲基-1H-咪唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 410.1(M+H)+。
40:2-(4-环丙基甲磺酰基苯基)-N-[4-(3-甲基-1H-吡唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 410.1(M+H)+。
41:2-(4-环丙基甲磺酰基苯基)-N-[4-(5-甲基-1H-吡唑-1-基)苯基]乙酰胺。MS(ES+)m/z 410.1(M+H)+。
42:2-(4-环丙基甲磺酰基苯基)-N-[4-(4-甲基-1H-吡唑-1-基)苯基]乙酰胺。MS(ES+)m/z 410.1(M+H)+。
43:2-(4-环丙基甲磺酰基苯基)-N-[4-(1,3-噁唑-5-基)苯基]乙酰胺。
MS(ES+)m/z 397.1(M+H)+。
44:2-(4-环丙基甲磺酰基苯基)-N-[4-(1H-吡唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 396.1(M+H)+。
45:2-(4-环丙基甲磺酰基苯基)-N-[4-(1H-咪唑-1-基)苯基]乙酰胺。
MS(ES+)m/z 396.1(M+H)+。
46:2-(4-环丙基甲磺酰基苯基)-N-[4-(1H-1,2,4-三唑-1-基)苯基]乙酰胺。MS(ES+)m/z 397.1(M+H)+。
47:2-(4-环丙基甲磺酰基苯基)-N-[4-(1,2,4-噁二唑-3-基)苯基]乙酰胺。
MS(ES+)m/z 398.1(M+H)+。
实施例48
RORγGAL4报告基因测定
在RORγGAL4报告基因测定中测试实施例抑制剂1-47的抑制RORγ活性的能力。测定操作和结果如下所述。
RORγGAL4报告基因测定描述
建立使用荧光素酶读数的GAL4单杂交报告系统以测定293FT细胞中的RORγ抑制。将RORγ配体结合域(LBD)融合至酵母GAL4DNA结合域(DBD)并置于人巨细胞病毒(CMV)立即早期启动子控制下,其使用表达载体pFN26A(Promega)和标准重组DNA克隆方法。为充当测定对照而产生相似载体,其中GAL4-DBD融合至单纯疱疹病毒蛋白16(VP16),所述蛋白是一种构成性转录激活因子。
为监控化合物对于RORγ的抑制效应,使用转录报告基因构建体。pGL4.35载体(Promega)包含9拷贝的GAL4上游激活序列(UAS)。该序列响应结合含有GAL4DNA结合域的融合蛋白而驱动荧光素酶报告基因luc2P的转录,所述融合蛋白如例如通过上述GAL4-RORγ-LBD和GAL4-VP16表达载体所表达。为使GAL4融合蛋白驱动荧光素酶报告基因的表达,使用标准转染技术在293FT细胞中整体转染pGL4.35表达载体和适当的GAL4融合蛋白表达载体。
转染后第二天,将细胞置于96孔板中,加入测试化合物并培养板过夜。随后,使用荧光素酶检测试剂和发光读数定量萤火虫荧光素酶活性。
详细测定描述
采用GAL4融合蛋白表达载体(如上所述)和转录报告基因构建体(pGL4.35,Promega)转染293FT细胞(Invitrogen)。将60μL TransIT-293转染试剂(Mirus Bio)滴加至1500μl Opti-MEM I减血清培养基(Reduced Serum Medium,Invitrogen)并在室温(RT)培养5至20分钟。将1500μL该试剂混合物加至5μg GAL4融合蛋白表达载体以及5μg转录报告基因构建体,并在室温培养20分钟。
为从T75烧瓶收获293FT细胞,首先使培养基脱除细胞。随后,用磷酸盐缓冲盐水(PBS)(Lonza)洗涤细胞,之后除去PBS。为分离细胞,将1ml TrypLE Express(Invitrogen)加至烧瓶,然后在室温培养直至可看到细胞开始分离。将细胞收集在5mL测定培养基(DMEM培养基(Lonza),10%透析FBS(Invitrogen)和Pen/Strep(Lonza))中以实现单细胞悬液。旋下10x106个细胞并将其再悬于10mL测定培养基中。随后,将细胞悬浮液加至转染混合管,并接着总体转移至T75烧瓶(Greiner),然后在37℃和5%CO2下过夜(16-24小时)培养。
对于化合物筛选,收获细胞(如上所述)并计数。旋下13x106个细胞,抽吸上清液并将细胞再悬于17.3mL测定培养基中以获得0.75x106个细胞/mL的细胞悬浮液。以80μL细胞悬浮液(60,000细胞)/孔将其置于白色、平底、组织培养处理的、96孔筛选板(Greiner)中。
从10mM二甲基亚砜(DMSO)储备溶液开始稀释测试化合物至DMSO中500x最终测试浓度的连续稀释液。随后,在测定培养基中的两个10倍稀释步骤将这些溶液稀释至5x最终测试浓度。5x测试化合物溶液的最终DMSO浓度为1%。将20μL 5x测试化合物溶液加至之前用80μl细胞悬浮液点板的96孔板的各测试孔,导致最终测试浓度为0.2%DMSO。
37℃和5%CO2下培养板过夜(16-24小时)。
对于荧光素酶读数,使荧光素酶试剂(Britelite Plus,Perkin Elmer)达到室温。向筛选板的各测试孔中加入100μL 2.5倍稀释的Britelite Plus试剂,然后在室温培养10分钟。使用Wallac Victor酶标仪(Perkin Elmer)测量荧光素酶发光信号。
使用GraphPad Prism软件(GraphPad Software)由荧光素酶信号计算测试化合物的半数最大抑制浓度(IC 50)值。
发现所有示例性的式I的化合物(实施例1-47)均具有大于5的平均pIC50值。
发现实施例1-14、16-37、40–44和46-47具有大于或等于6的平均pIC50值。
发现实施例2-13、22、23、26-34、36和37具有大于或等于7的平均pIC50值。
Claims (15)
1.式I的化合物或其药用盐
其中
A1是NR1或CR1,其中R1是H或甲基,其中甲基如果存在则任选被一个或多个F取代;
环丙基可以任选被一个或多个甲基和一个或多个F取代;
A2-A5分别是N或CR2-CR5,条件是A2-A5中的四个位置A中的不超过两个可以同时是N;
R2-R5独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
R6和R7独立地是H、F、甲基、乙基、羟基或甲氧基或R2和R3一起为羰基,所有烷基如果存在则任选被一个或多个F取代;
R8是H或C(1-6)烷基;
R9选自式II、III、IV和V
其中:
A10-A13分别是N或CR10-CR13,条件是A10-A13中的四个位置A中的不超过两个可以同时是N;
R10-R13独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
X14是C(6-10)芳基或C(1-9)杂芳基,其中所有碳原子任选被卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代;
其中:
A20-A27分别是N或CR20-CR27,条件是A20-A22中的三个位置A中的不超过两个可以同时是N并且A23-A27中的五个位置A中的不超过三个可以同时是N;
R20-R22独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
R23-R27独立地是H、卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基;
X28是C(6-10)芳基或C(1-9)杂芳基,其中所有碳原子任选被卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代;
其中:
A30是N或C;
A31是O、羰基、NR31或CR32;
R31是H或C(1-6)烷基;
R32是H、OH或C(1-3)烷基,其中所有烷基任选被一个或多个F或OH取代;
A33-A42分别是N或CR33-CR42,条件是A33-A37中的五个位置A中的不超过三个可以同时是N并且A38-A42中的五个位置A中的不超过三个可以同时是N;
R33-R42独立地是H、卤素、氨基、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基。
2.权利要求1的化合物,其中A1是CR1。
3.权利要求1的化合物,其中A1是NR1。
4.权利要求1-3的化合物,其中R1是氢。
5.权利要求1-4的化合物,其中R6和R7两者均是H。
6.权利要求1-5的化合物,其中R8是H。
7.权利要求1-6的化合物,其中A2-A5中的所有位置A是CR2-R5,并且R2-R5中的所有位置R是H。
8.权利要求1-7的化合物,其中R9是式II,其中:
A10-A13分别是N或CR10-CR13,条件是A10-A13中的四个位置A中的不超过两个可以同时是N;
R10-R13独立地是H、氨基、卤素、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
X14是C(6)芳基或C(1-5)杂芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
9.权利要求1-7的化合物,其中R9是式III,其中:
A20-A27分别是N或CR20-CR27,条件是A20-A22中的三个位置A中的不超过两个可以同时是N并且A23-A27中的五个位置A中的不超过三个可以同时是N;
R20-R22独立地是H、卤素、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-6)烷基;
R23-R27独立地是H、卤素、氰基、氨基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基;
X28是C(6)芳基或C(1-5)杂芳基,其中所有碳原子任选被卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基取代。
10.权利要求1-7的化合物,其中R9是式IV或V,其中:
A30是N或C;
A31是O、羰基、NR31或CR32;
R31是H或C(1-6)烷基;
R32是H、OH或C(1-6)烷基,其中所有烷基任选被一个或多个F或OH取代;
A33-A42分别是N或CR33-CR42,条件是五个位置A33-A37中的不超过三个可以同时是N并且五个位置A38-A42中的不超过三个可以同时是N;
R33-R42独立地是H、卤素、氰基、C(1-3)烷氧基、(二)C(1-3)烷基氨基或C(1-3)烷基。
11.权利要求1中所定义的化合物,其选自:
2-(4-环丙基甲磺酰基苯基)-N-(3-苯氧基-4-苯基苯基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(3-氟苯基)-3-(3-甲氧基苯氧基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[3-(3-甲氧基苯氧基)-4-(4-甲基-1H-咪唑-1-基)苯基]乙酰胺;
N-[3-(3-氯苯氧基)-4-(3-氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
N-[3-(3-氯苯氧基)-4-(3,4-二氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
N-[3-(3-氰基苯氧基)-4-(3,4-二氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[3-(3-甲氧基苯氧基)-4-(5-甲基-1H-吡唑-1-基)苯基]乙酰胺;
N-[3-(3-氯苯氧基)-4-(3,5-二氟苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
N-[4-(4-氰基苯基)-3-(3-氟苯氧基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
N-[3-(3-氯苯氧基)-4-(3-氰基苯基)苯基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(3-氟苯基)-3-[3-(三氟甲基)苯氧基]苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[3-(3-氟苯氧基)-4-(4-氟苯基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[3-(3,5-二氟苯氧基)-4-(3-氟苯基)苯基]乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-[3-(3-甲氧基苯氧基)-4-(4-甲基-1H-咪唑-1-基)苯基]乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-[3-(3-甲氧基苯氧基)-4-(5-甲基-1H-吡唑-1-基)苯基]乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-[4-(3-氟苯基)-3-(3-甲氧基苯氧基)苯基]乙酰胺;
N-[3-(3-氯苯氧基)-4-(3-氟苯基)苯基]-2-[4-(环丙基氨磺酰基)苯基]乙酰胺;
N-[3-(3-氯苯氧基)-4-(3,4-二氟苯基)苯基]-2-[4-(环丙基氨磺酰基)苯基]乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-[4-(3-氟苯基)-3-[3-(三氟甲基)苯氧基]苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-(5-苯氧基-4-苯基-1,3-噻唑-2-基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-苯基-5-(吡啶-3-基氧基)-1,3-噻唑-2-基]乙酰胺;
N-(5-苯甲酰基-4-苯基-1,3-噻唑-2-基)-2-(4-环丙基甲磺酰基苯基)乙酰胺;
N-[5-(4-氯苯甲酰基)-4-(3-氯苯基)-1,3-噻唑-2-基]-2-(4-环丙基甲磺酰基苯基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-(4-苯基噻吩-2-基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(吡啶-3-基)噻吩-2-基]乙酰胺;
N-(5-苯甲酰基-4-苯基-1,3-噻唑-2-基)-2-[4-(环丙基氨磺酰基)苯基]乙酰胺;
N-(5-苯甲酰基-4-苯基噻吩-2-基)-2-(4-环丙基甲磺酰基苯基)乙酰胺;
N-{3-氯-4-[2-(三氟甲氧基)苯基]苯基}-2-(4-环丙基甲磺酰基苯基)乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-{3-甲基-4-[2-(三氟甲氧基)苯基]苯基}乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-{3,5-二氯-4-[2-(三氟甲氧基)苯基]苯基}乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-{4-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-{6-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺;
N-{3-氯-4-[2-(三氟甲氧基)苯基]苯基}-2-[4-(环丙基氨磺酰基)苯基]乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-{6-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-{4-甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺;
2-[4-(环丙基氨磺酰基)苯基]-N-{3-甲基-4-[2-(三氟甲氧基)苯基]苯基}乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-{4,6-二甲基-5-[2-(三氟甲氧基)苯基]吡啶-2-基}乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(4-甲基-1H-咪唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(5-甲基-1H-咪唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(3-甲基-1H-吡唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(5-甲基-1H-吡唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(4-甲基-1H-吡唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(1,3-噁唑-5-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(1H-吡唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(1H-咪唑-1-基)苯基]乙酰胺;
2-(4-环丙基甲磺酰基苯基)-N-[4-(1H-1,2,4-三唑-1-基)苯基]乙酰胺和
2-(4-环丙基甲磺酰基苯基)-N-[4-(1,2,4-噁二唑-3-基)苯基]乙酰胺。
12.权利要求1-11中的任一项的化合物或其药用盐,其用于治疗。
13.权利要求1-11中的任一项的化合物或其药用盐,其用于治疗RORγ介导的疾病或病症。
14.药物组合物,其包含权利要求1-11中的任一项的式I的化合物或其药用盐和一种或多种药用赋形剂。
15.权利要求14的药物组合物,其进一步包含至少一种另外的治疗活性剂。
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EP15170764.3A EP3101008A1 (en) | 2015-06-05 | 2015-06-05 | Ror gamma (rory) modulators |
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PCT/EP2016/062712 WO2016193470A1 (en) | 2015-06-05 | 2016-06-03 | Ror gamma (rory) modulators |
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KR (1) | KR20180040558A (zh) |
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CN111658651A (zh) * | 2020-06-08 | 2020-09-15 | 重庆医科大学附属第一医院 | CQMU151在制备治疗Th17细胞介导自身免疫病药物中的应用 |
WO2021228215A1 (zh) * | 2020-05-15 | 2021-11-18 | 上海辉启生物医药科技有限公司 | 可用作RORγ调节剂的联芳基类化合物 |
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EP3101009A1 (en) | 2015-06-05 | 2016-12-07 | Lead Pharma Cel Models IP B.V. | Ror gamma (rory) modulators |
ES2927631T3 (es) | 2015-12-15 | 2022-11-08 | Astrazeneca Ab | Compuestos de isoindol |
BR112019000603A2 (pt) | 2016-07-14 | 2019-04-30 | Cadila Healthcare Limited | composto, composição farmacêutica, método para o tratamento de doenças e uso do composto |
AR109042A1 (es) | 2016-07-14 | 2018-10-24 | Cadila Healthcare Ltd | COMPUESTOS MODULARES DE RORg |
TWI705958B (zh) | 2016-12-05 | 2020-10-01 | 荷蘭商領導醫藥控股責任有限公司 | RORγ調節子 |
EP3581561A4 (en) | 2017-02-09 | 2020-12-09 | Fudan University | BIARYL COMPOUND, MANUFACTURING METHOD AND USE THEREOF |
US11034654B2 (en) | 2017-06-14 | 2021-06-15 | Astrazeneca Ab | 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators |
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2015
- 2015-06-05 EP EP15170764.3A patent/EP3101008A1/en not_active Withdrawn
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2016
- 2016-06-03 AU AU2016272018A patent/AU2016272018B2/en not_active Ceased
- 2016-06-03 PL PL16730288T patent/PL3303292T3/pl unknown
- 2016-06-03 MX MX2017015739A patent/MX2017015739A/es unknown
- 2016-06-03 WO PCT/EP2016/062712 patent/WO2016193470A1/en active Application Filing
- 2016-06-03 RU RU2017145929A patent/RU2727191C2/ru active
- 2016-06-03 KR KR1020187000280A patent/KR20180040558A/ko not_active Application Discontinuation
- 2016-06-03 EP EP16730288.4A patent/EP3303292B1/en active Active
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2021228215A1 (zh) * | 2020-05-15 | 2021-11-18 | 上海辉启生物医药科技有限公司 | 可用作RORγ调节剂的联芳基类化合物 |
CN113666853A (zh) * | 2020-05-15 | 2021-11-19 | 上海辉启生物医药科技有限公司 | 可用作RORγ调节剂的联芳基类化合物 |
CN111658651A (zh) * | 2020-06-08 | 2020-09-15 | 重庆医科大学附属第一医院 | CQMU151在制备治疗Th17细胞介导自身免疫病药物中的应用 |
CN111658651B (zh) * | 2020-06-08 | 2021-08-03 | 重庆医科大学附属第一医院 | CQMU151在制备治疗Th17细胞介导自身免疫病药物中的应用 |
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JP2018518481A (ja) | 2018-07-12 |
BR112017026224A2 (pt) | 2018-09-11 |
IL256037B (en) | 2021-02-28 |
EP3303292A1 (en) | 2018-04-11 |
PL3303292T3 (pl) | 2020-09-07 |
PT3303292T (pt) | 2020-05-27 |
IL256037A (en) | 2018-01-31 |
AU2016272018B2 (en) | 2020-08-27 |
WO2016193470A1 (en) | 2016-12-08 |
US20180170863A1 (en) | 2018-06-21 |
EP3303292B1 (en) | 2020-03-18 |
CN108430973B (zh) | 2021-09-21 |
MX2017015739A (es) | 2018-05-02 |
RU2727191C2 (ru) | 2020-07-21 |
CA2988008A1 (en) | 2016-12-08 |
ES2794751T3 (es) | 2020-11-19 |
AU2016272018A1 (en) | 2018-01-04 |
US10259782B2 (en) | 2019-04-16 |
RU2017145929A3 (zh) | 2019-12-04 |
KR20180040558A (ko) | 2018-04-20 |
EP3101008A1 (en) | 2016-12-07 |
JP6843076B2 (ja) | 2021-03-17 |
RU2017145929A (ru) | 2019-07-10 |
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