CN106715413B - 作为肝x受体调节剂的哌嗪衍生物 - Google Patents
作为肝x受体调节剂的哌嗪衍生物 Download PDFInfo
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- CN106715413B CN106715413B CN201580048232.7A CN201580048232A CN106715413B CN 106715413 B CN106715413 B CN 106715413B CN 201580048232 A CN201580048232 A CN 201580048232A CN 106715413 B CN106715413 B CN 106715413B
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Abstract
提供式(I)的新化合物、其药学上可接受的盐及其药物组合物,其为肝X受体调节剂,在治疗与肝X受体相关的疾病和病症中是有效的。还提供用于治疗动脉粥样硬化、心血管疾病、阿尔茨海默病、皮炎、血脂异常、癌症和其他疾病或病症的式(I)化合物及其药物组合物。
Description
相关申请
本申请要求2014年8月7日提交的美国临时专利申请第62/034274号的 申请日权益,其全部内容通过引用并入本文中。
技术领域
本发明涉及调节肝X受体活性的化合物。
发明背景
在发达国家,动脉粥样硬化是死亡的主要原因,据预测,在发展中国家, 动脉粥样硬化在21世纪会成为死亡的主要原因。肝X受体(LXR)是在调节涉 及脂类代谢和细胞胆固醇体内平衡的基因表达中起重要作用的配体激活型转 录因子。LXR激动剂已表现出提高胆固醇逆向转运(RCT)、促进胆固醇从外 周回运至肝脏以处理和排泄。RCT通过上调外周巨噬细胞中的胆固醇转运体 (ATP结合盒:ABCA1和ABCG1)实现。活性RCT具有抑制动脉粥样硬化进 展的潜力。
LXR有两种异形体:由不同基因编码的LXRα(NR1H3)和LXRβ(NR1H2)。 LXRα表达是组织选择性的,在肝、肠、肾、脂肪组织和肾上腺中可检测到, 所有这些组织对脂类体内平衡很重要,而LXRβ是广泛表达的。两种LXR 都需要类视黄醇X受体(RXR)作为必需的异源二聚体伴侣以识别并共同结合 至LXR应答元件(LXRE),所述LXR应答元件由被四个核苷酸(DR4)隔开的 核心六核苷酸序列的两个同向重复序列组成。两种LXR的配体结合区域相当保守(~78%的氨基酸同源)并应答于由胆固醇(羟固醇)的氧化衍生物组成的 内源配体,所述胆固醇的氧化衍生物用作甾类激素和胆酸合成的中间体。最 有效的这种内源配体是22(R)-羟基胆固醇、24(S)-羟基胆固醇和24(S),25-环 氧胆固醇。这些数据表明LXR在胆固醇调节中的重要作用,其随后通过小鼠 中的基因敲除研究得以证实。非甾类配体也已经被鉴定,利用这些非甾类配 体作为化学探针已经发现了很多LXR调节型基因。若干含LXRE基因涉及 胆固醇代谢、胆固醇逆向转运(RCT)和脂肪生成。涉及炎症和糖类代谢的其 他基因缺乏LXRE,但以配体依赖方式受到LXR抑制。基于这些发现,肝X 受体最近已经成为用作细胞内胆固醇传感器的新靶标,提供了治疗多种疾病 的基础,该疾病包括动脉粥样硬化、糖尿病、阿尔茨海默病、皮肤病、生殖 疾病和癌症(Viennois等人,2011,ExpertOpin.Ther.Targets,15(2):219-232; Hong等人,2014,Nature Reviews Drug Discovery,13:433–444)。另外,已经确 定了LXR激动剂调节肠和肾的磷酸钠(NaPi)转运体,转而调节血清磷酸盐水 平(Caldas等人,2011,Kidney International,80:535-544)。因此,LXR也是肾疾 病的靶标,特别地用于预防高磷血症和相关的心血管并发症。最近,已经将 LXR鉴定为治疗骨质酥松症及相关疾病中的靶标(Kleyer等人,2012,J.Bone Miner.Res.,27(12):2442-51)。
阿尔茨海默病是痴呆的一种最常见形式,其特征为在大脑中积累和沉淀 淀粉样β(Aβ)多肽,导致在受感染个体的大脑中扰乱突触功能和神经元损失。 大脑中的神经元通过裂解淀粉样前体蛋白(APP)产生Aβ多肽,通过流出至外 周循环并由大脑中的蛋白酶降解而正常清除Aβ多肽。
载脂蛋白E(apoE)与阿尔茨海默病的年龄相关性风险有关并对Aβ体内平 衡起重要作用。LXR增加apoE的表达并增加apoE的脂化。通过经脂化的 apoE提高了细胞内和细胞外的Aβ降解两者。LXR激动剂治疗刺激Aβ的蛋 白质降解、减少斑块病理学、改善在表达APP的转基因小鼠中的记忆(Jiang 等人,2008,Neuron,58:681-693)。
在皮肤中,角质细胞是表皮的重要组成。外层即角质层是对水和电解质 运输的渗透屏障的主要成因。表皮中的角质细胞经历导致角质细胞角质化 (“砖”)和在角质层中形成细胞外脂质富集片层膜(“灰浆”)的分化。LXRα和 LXRβ均在角质细胞中表达,LXR的表达和活化促进表皮屏障作用。LXR的 活化与角质细胞分化、片层膜的形成和表皮屏障作用的整体改善有关。因此, 期望LXR活化引起角质细胞分化增加、脂质分泌增加(通过ABCA1、ABCA12) 和片层体形成增加,得到健康表皮(光滑皮肤)。
LXR激动剂的潜在治疗效用已经致使开发了针对两种受体亚型的具有 有效激动的若干高亲和LXR配体。LXR激动剂的治疗效用受其诱导脂肪生 成基因的潜能的约束,该脂肪生成基因包括甾醇应答元件结合蛋白 -1c(SREBP1c)和脂肪酸合成酶(FAS)。临床前研究已经证明LXR的合成调节 因子减少了患有动脉粥样硬化的鼠科模型的病变进展,并且肝脏脂肪生成增 加有限。对新的LXR化学型存在明确的需求,该LXR化学型保持当前LXR 激动剂的抗动脉粥样硬化效力但不具有脂肪生成活性。显示对RCT具有积极 作用而对脂肪生成基因呈中性或抑制的药理学性质的化合物将是对患有动脉 粥样硬化性血脂异常的患者有价值的治疗剂。
雷特综合征(RTT)是伴X染色体的神经障碍,其表现出孤独症特征,大 约10000名女性中有1人患病。伴X染色体基因即甲基CpG结合蛋白 2(MECP2)的突变是RTT的主要原因。具有功能截断或功能缺失突变的半合 子男性通常死于脑病,而在任一性别中的轻微突变与多种智力障碍有关。大 约80%的RTT临床病例显示典型的临床图片,其特征为以典型的四阶段神经 学退化而缺失获得性认知、社交和运动技能,伴随孤独症行为的发展。近日,研究人员显示在无Mecp2的雄性小鼠的脑和肝中胆固醇代谢被扰乱,胆固醇 生物合成的抑制剂(他汀类药物)改善了血脂的全身性失衡,减轻了运动症状 和使得Mecp2突变小鼠寿命增加,这表明在受PTT影响的病人中可以改变 胆固醇体内平衡维持(Buchovecky等人,2013,Nat.Genet.,45:1013)。这些发现 表明在症状发作后,通过基因或药物手段可以改善或甚至逆转疾病。由于 LXR激动剂具有从外周组织主动移除胆固醇的能力,导致从体内消除胆固 醇,因此LXR激动剂对于治疗患有RTT的患者是有效的。
已经提出抑制肝脏中的LXR活性用于治疗肝脏疾病,例如脂肪肝、肝硬 化、非酒精性脂肪性肝病(NAFLD)和非酒精性脂肪变性肝病(NASH)(Ducheix 等人,2013,Biochem.Pharmacol.,86:96-105)。LXR拮抗剂已经显示出向下调 节肝脏中的脂肪生成基因,限制脂质的肝堆积,减少NASH小鼠模型中的血 浆胆固醇水平(Griffett等人,2013,ACSChem.Biol.,8:559-567),和减少喂食 高脂饮食的小鼠中的总胆固醇、甘油三酯和游离脂肪酸的血浆水平(Jwa等人, 2012,Biochem.Pharmacol.,84:1501-1510)。因此,期望肝脏特异性LXR拮抗 剂可用于与肝脏中脂肪堆积相关的代谢疾病的治疗中。LXRα的活化已经显示出引起在皮脂腺细胞中的脂质合成和皮脂分泌(Hong等人,2008,J.Invest. Dermatol.,128:1266-1272)。考虑到过量的皮脂生成是痤疮的主要原因,预期 LXR拮抗剂在治疗皮脂腺相关疾病例如皮脂溢出和痤疮中具有治疗潜力。因 此,LXR拮抗剂在治疗例如皮脂溢出和痤疮以及肝脏疾病例如肝硬化、NASH 和NAFLD中具有治疗潜力,对于抗LXR的新LXR调节剂存在需求。
发明概述
目前已经发现本文描述的化合物和药学上可接受的盐是有用的LXR调 节剂(参见例如表1和表2)。这种化合物包括式(I)的化合物或其药学上可接受 的盐:
其中变量Q、Y、R1、R2、R3和R4为如本文所定义的。
所提供的化合物及其药学上可接受的组合物通过例如充当激动剂、部分 激动剂或拮抗剂而调节LXR,作为治疗剂用于促进胆固醇逆转运和抑制肝脏 脂肪生成并用于预防、改善或治疗包括动脉粥样硬化、心血管疾病、阿尔茨 海默病、皮炎、血脂障碍和癌症的疾病或病症是有效的。
某些实施方案的详细说明
1.本发明化合物的一般说明
在一个实施方案中,本发明提供由结构式I表示的化合物或其药学上可 接受的盐:
其中
Q是1)R10OC(=O)-;2)杂芳环,其任选地由独立选自R21的1个至3个 基团取代;3)式R30-L基团,其中R30任选地由独立选自R31的1个至3个基 团取代;或4)式R40-L基团,其中R40任选地由独立选自R41的1个至3个基 团取代;
R1选自(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基烷基(C1-C3)烷基;芳 基(C1-C3)烷基、卤代(C1-C6)烷基、卤代(C3-C6)环烷基、卤代(C3-C6)环烷基 (C1-C3)烷基、氨基、(C1-C6)烷基氨基、二(C1-C6)烷基氨基、芳基(C1-C3)烷基 氨基和{芳基(C1-C3)烷基}{(C1-C6)烷基}氨基,其中芳基任选地由独立选自卤 素、氰基、CONH2、(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基和卤代(C1-C3) 烷氧基的1个至3个基团取代;
R2选自氢、卤素、氰基、CONH2、羟基(C1-C3)烷基、氨基(C1-C3)烷基、 (C1-C3)烷氧基(C1-C3)烷基、(C1-C3)烷基羰基(C1-C3)烷基和(C1-C3)烷基羰基氨 基(C1-C3)烷基;或R2是5元杂芳基,任选地由独立选自卤素、氰基、甲基、 CF3、甲氧基、甲氧基羰基、乙氧基羰基和CONH2的1个或2个基团取代;
R3是(1)(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C6)环烷基、卤代(C3-C6)环烷 基、(C1-C3)烷氧基(C1-C3)烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基羰基或(C1-C6) 烷氧基羰基(C1-C3)烷基、或氰基(C1-C6)烷基;或(2)芳基、杂芳基、芳基(C1-C3) 烷基或杂芳基(C1-C3)烷基,其各自任选地由选自卤素、氰基、(C1-C3)烷基、 CF3、甲氧基和CONH2的1个至3个取代基取代;
R4是氢或(C1-C6)烷基;
R10选自(C1-C8)烷基、芳基(C1-C3)烷基、卤代(C1-C6)烷基、(C3-C7)环烷基、 (C3-C6)环烷基(C1-C3)烷基、卤代(C3-C7)环烷基和卤代(C3-C6)环烷基(C1-C3)烷 基;
R30是芳环或杂芳环;
R40是(C4-C7)环烷基或杂环基;
R21、R31和R41各自独立选自卤素、羟基、氨基、硝基、(C1-C6)烷基、 卤代(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)烯基、(C1-C6)烷氧基、卤代(C1-C6) 烷氧基、羟基(C1-C6)烷基、羟基(C1-C6)卤代烷基、(C1-C3)烷氧基(C1-C3)烷基、 卤代(C1-C3)烷氧基(C1-C3)烷基、(C1-C3)烷氧基(C1-C3)卤代烷基、(C1-C6)烷硫 基、卤代(C1-C6)烷硫基、(C1-C3)烷硫基(C1-C3)烷基、卤代(C1-C3)烷硫基(C1-C3) 烷基、氰基(C1-C6)烷基、CO2H、(C1-C6)烷氧基羰基、(C1-C6)烷基磺酰基、(C1-C6) 卤代烷基磺酰基、(C1-C3)烷基磺酰基(C1-C3)烷基、卤代(C1-C3)烷基磺酰基(C1-C3)烷基、杂环基、R22R23NCO、R22R23NCO(C1-C3)烷基、R22CONH、 R22CONH(C1-C3)烷基、R22SO2NH、R22SO2NH(C1-C3)烷基、R22R23N、 R22R23N(C1-C3)烷基和芳基(C1-C3)烷基,其中芳基(C1-C3)烷基任选地由R25取 代;
R22选自H、(C1-C6)烷基、卤代(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6) 烷氧基(C1-C6)烷基、(C1-C6)烷氧基羰基(C1-C6)烷基、(C1-C6)烷氧基羰基氨基 (C1-C6)烷基和杂环基,其中杂环基任选地由独立选自R24的1个或2个基团 取代;
R23是氢、(C1-C6)烷基、(C1-C6)烷氧基或卤代(C1-C6)烷基;或R22和R23与其连接的氮一起形成氮杂环丁烷环、吡咯烷环、哌啶环、哌嗪环或吗啉环, 其各自任选地由独立选自R24的1个或2个基团取代;
R24选自卤素、羟基、氨基(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基 和(C1-C6)烷氧基羰基;
R25是羟基(C1-C6)烷基或CO2H;
L是CH2、CHCH3或C(CH3)2;
Y是氢、卤素、氰基、(C1-C3)烷基、甲基、卤代烷基或甲氧基。
本发明的另一方面是包含本发明的化合物和药学上可接受的载体或稀释 剂的药物组合物。
本发明的另一方面还提供一种治疗患有通过上调LXR活性可治疗的疾 病或病症的对象的方法。该方法包括施用有效量的本发明化合物或其药学上 可接受的盐至需要其的对象。
本发明还提供了本发明化合物在制备用于治疗患有通过下调需要其的对 象中LXR活性可治疗的疾病或病症的对象的药剂中的用途。
本文还公开了用于治疗通过下调需要其的对象中LXR活性可以治疗的 疾病或病症的本发明化合物。
本发明的另一方面还提供一种治疗患有通过下调LXR活性可治疗的疾 病或病症的对象的方法。该方法包括施用有效量的本发明化合物或其药学上 可接受的盐至需要其的对象。
本发明还提供了本发明化合物在制备用于治疗患有通过下调需要其的对 象中LXR活性可治疗的疾病或病症的对象的药剂中的用途。
本文还公开了用于治疗通过下调需要其的对象中LXR活性可治疗的疾 病或病症的本发明化合物。
2.化合物和定义
“卤代”或“卤素”意思是氯代、溴代、氟代或碘代。在一个实施方案中, 卤代是氟代。
“烷基”指在分子链中具有1个至15个碳原子的直链烃基或支化烃基。在 一个实施方案中,烷基基团在分子链中具有1个至12个碳原子。在另一个实 施方案中,烷基基团具有1个至6个碳原子。示例性的烷基基团包括但不限 于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、仲丁基、正戊基、3-戊 基、庚基、辛基、壬基、癸基、和十二烷基。
“环烷基”指3个至10个碳原子的单环、双环或三环饱和烃环。在一个实 施方案中,环烷基基团具有3个至6个碳原子。示例性的环烷基环包括环丙 基(c-Pr)、环丁基、环戊基、环己基、环庚基、环辛基、双环[2.2.2]辛基、双 环[2.2.1]庚基、螺[4.4]壬烷、金刚烷基等。
“烷氧基”是通过氧键(-O(烷基))连接到另一部分的烷基基团。非限制性实 例包括甲氧基、乙氧基、丙氧基和丁氧基。
“卤代烷基”或“卤化的烷基”指其中一个或更多个、包括所有的氢由卤素 基团取代的烷基基团,其中每个卤素基团独立选自-F、-Cl、-Br和-I,包括单 卤代、二卤代、三卤代、多卤代和每个卤化基团。例如,术语“卤代甲基”或“卤 化的甲基”指其中1个至3个氢由卤素基团取代的甲基。代表性的卤代烷基基 团包括氟代甲基、二氟甲基、三氟甲基、溴代甲基、1,2-二氯乙基、4-碘代丁 基、2-氟代戊基等。其他实例包括例如但不限于-CH2CF3、-CH(CH2F)2、 -CH(CHF2)2、-CH(CF3)2、-CF(CH3)2、-CF3的基团。
“芳基”指为苯基、萘基、二氢茚基或四氢化萘基的芳香族基团。芳基任 选地由1个至4个取代基取代。示例性的取代基包括烷基、烷氧基、烷硫基、 烷基磺酰基、卤素、三氟甲基、二烷基氨基、硝基、氰基、CO2H、CONH2、 N-单烷基取代的氨基和N,N-二烷基取代的氨基。
“杂芳基”指含有独立选自N、O和S的1个至4个杂原子的5元或6元 杂芳香族基团,其任选地与含有选自N、O和S的0个至4个杂原子的饱和 环或不饱和环稠合,包括例如,如2-噻吩基或3-噻吩基、2-呋喃基或3-呋喃 基、2-吡咯基或3-吡咯基、2-吡啶基、3-吡啶基或4-吡啶基、2-吡嗪基、2- 嘧啶基、4-嘧啶基或5-嘧啶基、3-哒嗪基或4-哒嗪基、1H-吲哚-6-基、1H-吲 哚-5-基、1H-苯并咪唑-6-基、1H-苯并咪唑-5-基、2-喹唑啉基、4-喹唑啉基、 5-喹唑啉基、6-喹唑啉基、7-喹唑啉基或8-喹唑啉基、2-喹喔啉基、3-喹喔啉 基、5-喹喔啉基、6-喹喔啉基、7-喹喔啉基或8-喹喔啉基、2-喹啉基、3-喹啉 基、4-喹啉基、5-喹啉基、6-喹啉基、7-喹啉基或8-喹啉基、1-异喹啉基、3- 异喹啉基、4-异喹啉基、5-异喹啉基、6-异喹啉基、7-异喹啉基或8-异喹啉基、 2-噻唑基、4-噻唑基或5-噻唑基、2-吡唑基、3-吡唑基、4-吡唑基、5-吡唑基、 2-咪唑基、3-咪唑基、4-咪唑基或5-咪唑基。杂芳基任选地被取代。示例性 取代基包括烷基、烷氧基、烷硫基、烷基磺酰基、卤素、三氟甲基、二烷基 氨基、硝基、氰基、CO2H、CONH2、N-单烷基取代的氨基和N,N-二烷基取 代的氨基,或通过氧代形成N-氧化物。
“杂环基”指含有独立选自N、O和S的1个至4个杂原子的4元、5元、 6元和7元饱和杂环或部分不饱和杂环。示例性的杂环基包括吡咯烷、吡咯 烷-2-酮、1-甲基吡咯烷-2-酮、哌啶、哌啶-2-酮、二氢吡啶、四氢吡啶、哌嗪、 1-(2,2,2-三氟乙基)哌嗪、1,2-二氢-2-氧代吡啶、1,4-二氢-4-氧代吡啶、哌嗪-2- 酮、3,4,5,6-四氢-4-氧代嘧啶、3,4-二氢-4-氧代嘧啶、四氢呋喃、四氢吡喃、 四氢噻吩、四氢噻喃、异唑烷、1,3-二氧戊环、1,3-二硫戊烷、1,3-二氧六 环、1,4-二氧六环、1,3-二噻烷、1,4-二噻烷、唑烷-2-酮、咪唑烷-2-酮、咪唑烷-2,4-二酮、四氢嘧啶-2(1H)-酮、吗啉、N-甲基吗啉、吗啉-3-酮、1,3-嗪 -2-酮、硫代吗啉、硫代吗啉-1,1-二氧化物、四氢-1,2,5-噻唑-1,1-二氧化物、 四氢-2H-1,2-噻嗪-1,1-二氧化物、六氢-1,2,6-噻二嗪-1,1-二氧化物、四氢-1,2,5- 噻二唑-1,1-二氧化物、异噻唑烷-1,1-二氧化物、6-氧-1,6-二氢哒嗪-3-基、6- 氧-1,6-二氢哒嗪-4-基、5-氧-4,5-二氢-1H-1,2,4-三唑-3-基和5-氧-4,5-二氢-1H- 咪唑-2-基。杂环基可以任选地由1个至4个取代基取代。示例性的取代基包 括烷基、卤代烷基、卤素和氧代。
“螺环烷基”指与另一个烷基或环烷基共享一个环碳的环烷基基团。本文 提供的本发明化合物包括天然形式和其药学上可接受的盐两者。
某些公开的化合物可以以多种立体异构形式存在。立体异构体是仅在其 空间排布上不同的化合物。对映异构体是成对的立体异构体,其镜像是不可 重叠的,最常见的原因是其含有不对称取代的碳原子作为手性中心。“对映异 构体”指彼此互为镜像且不可重叠的成对分子中的一个。非对映体是含有两个 或更多个不对称取代的碳原子的立体异构体。在结构式中的符号“*”代表手 性碳中心的存在。“R”和“S”代表在一个或更多个手性碳原子周围的取代基构 型。因此,“R*”和“S*”表示在一个或更多个手性碳原子周围取代基的相对构 型。
当化合物指定为用表示单一对映异构体的名称或结构时,除非另有指定, 该化合物是至少50%、60%、70%、80%、90%、95%、99%、99.5%、或99.9% 光学纯(也称为“对映异构体纯”)。光学纯度是所命名的或所描述的对映异构 体的混合物重量除以两种对映异构体混合物的总重量。
“对象”、“患者”和“哺乳动物”在本文中可交换使用。在一个实施方案中, 对象是非人的动物,如非人的灵长类动物(例如猴子、黑猩猩)、家畜(例如马、 牛、猪、鸡或羊)、实验室动物(例如大鼠或小鼠)或宠物(例如狗、猫、豚鼠或 兔子)。在一个优选的实施方案中,对象为人。
“本发明的化合物”指由结构式I、Ia、Ib、Ic、Id、Ie、If、Ig、Ih、Ii、Ij、 Ik、Il、Im、In、Io、Ip表示的化合物;表1中所命名的化合物;表2中所描 述的化合物;作为实施例的最终化合物在本文实施例中所命名或描述的化合 物;或其药学上可接受的盐。“本发明的化合物”还包括如本文所描述的化合 物的天然形式。
“药学上可接受的”指的是在可靠的医学判断范围内,适用于与对象如人 和其他哺乳动物的组织接触而不具有异常毒性、刺激性、过敏反应等并与合 理的受益/风险比相称的组分。
本发明所包括的是本文所公开化合物的药学上可接受的盐。该公开的化 合物具有碱性胺基基团,因此可以与药学上可接受的酸形成药学上可接受的 盐。合适的本发明化合物药学上可接受的酸加成盐包括无机酸盐(无机酸例如 盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸)和有机酸盐(有机酸例如乙酸、 苯磺酸、苯甲酸、柠檬酸、乙磺酸、反丁二烯酸、葡萄糖酸、乙醇酸、羟乙 基磺酸、乳酸、乳糖酸、马来酸、苹果酸、甲磺酸、琥珀酸、对甲苯磺酸和 酒石酸)。具有酸性基团例如羧酸的本发明化合物可以与药学上可接受的碱形 成药学上可接受的盐。合适的药学上可接受的碱性盐包括铵盐、碱金属盐(例 如钠盐和钾盐)和碱土金属盐(例如镁盐和钙盐)。合适的盐的列表在 Remington's PharmaceuticalSciences,第18版,Mack出版公司,宾夕法尼亚 州伊斯顿,1990年,第1445页中找到,其公开内容通过引用并入本文。
“肝X受体或LXR”包括肝X受体的α和β亚型二者。在一个实施方案 中,所公开的化合物选择性地结合并上调LXRβ亚型的活性超过LXRα亚型。 “调节”受体指所关注分子的活性有变化或改变,例如肝X受体的生物活性。 调节可以是所关注分子的特定活性或功能的大小上调(增加)或下调。示例性 的分子活性和功能包括但不限于结合特征、酶活性、细胞受体活化、转录活 性和信号转导。在一个实施方案中,本发明的化合物是LXR激动剂,其例如 上调或下调基因,该基因为LXR的转录靶标(即“LXR靶基因”)。在另一个实 施方案中,本发明的化合物是部分激动剂。在另一个实施方案中,本发明的 化合物是拮抗剂。
如本文所使用的,术语“治疗”指逆转、减轻、延缓如本文描述的疾病或 病症、或其一种或更多种症状的发作或抑制进展。在一些实施方案中,在一 种或更多种症状已经发展后可以施用治疗,即治疗性治疗。在其他实施方案 中,在无症状时可以施用治疗。例如,在症状发作前(例如根据症状史和/或 根据基因或其他易感性因素)可以向易感性个体施用治疗,即预防性治疗。还 可以在症状解决后继续治疗,例如为了预防或延缓其复发。
“疾病”或“病症”指受LXR活性调节或影响或其中涉及LXR活性的任何 情况。疾病或病症包括与以下过程相关的那些或症状由以下过程的并发症引 起的那些:胆固醇转运改变、胆固醇逆向转运、脂肪酸代谢、胆固醇吸收、 胆固醇再吸收、胆固醇分泌、胆固醇排泄或胆固醇代谢。
“有效量”是足够治疗(治疗性地或预防性地)靶病症的化合物量,或是在 适当给药方案中将化合物施用至对象时获得有益临床结果的化合物量。如本 领域技术人员认可的,根据治疗的疾病、疾病严重程度、给药途径、病人的 性别、年龄和总体健康状况、赋形剂使用、与其他治疗性治疗如使用其他药 剂联合使用的可能性以及主治医生或其他医疗提供者的判断,有效剂量也会 不同。例如,有效量是足够降低或改善所治疗病症的严重程度、持续时间或 进展,预防所治疗病症的发展、使得所治疗病症复原、或增强或提高另一治 疗的预防或治疗作用。例如,当将本发明的化合物施用至患有癌症的对象时, 与没有治疗相比,“有益临床结果”包括肿瘤质量减小、转移减少、与癌症相 关症状的严重程度降低和/或对象的寿命延长。
当将本发明的化合物施用至患有病症例如动脉粥样硬化的对象时,与没 有治疗相比,“有益临床结果”包括与病症相关的症状的严重程度降低或数量 减少、胆固醇降低或对象的寿命延长。目前用于治疗病症的药剂的推荐剂量 可以从本领域的多种参考文献中获得,包括但不限于,Hardman等人编,1996, Goodman&Gilman’s The PharmacologicalBasis Of Basis Of Therapeutics第9 版,Mc-Graw-Hill,纽约;Physician’s DeskReference(PDR)第57版,2003, Medical Economics Co.,Inc.,新泽西州蒙特威尔,其各自通过引用整体并入 本文。在某些实施方案中,本发明化合物的有效量是每次治疗0.5mg至2000mg、或0.5mg至1000mg、或0.5mg至500mg、或0.5mg至100mg、或 100mg至1000mg、或20mg至2000mg。典型治疗是每天施用一至三次。
3.示例性化合物详述
在第一个实施方案中,本发明提供式(I)的化合物或其药学上可接受的 盐:
其中变体如上文所述。
在第二个实施方案中,本发明的化合物由结构式(I)表示或是其药学上可 接受的盐,其中Q是1)R10OC(=O)-;2)2-吡啶基、3-吡啶基、4-吡啶基、3- 哒嗪基、2-嘧啶基、4-嘧啶基、2-吡嗪基、2-唑基、2-噻唑基、1,3,4-噻二 唑-2-基、2-吡啶酮-4-基、2-苯并唑基、2-苯并噻唑基、噻唑并[4,5-b]吡啶 -2-基、噻唑并[4,5-c]吡啶-2-基、噻唑并[5,4-c]吡啶-2-基或噻唑并[5,4-b]吡啶 -2-基,其各自任选地由独立选自R21的1个至3个基团取代;3)苯基CH2、 苯基CHMe、吡啶基CH2、呋喃基CH2,其各自任选地由独立选自R31的1 个至3个取代基取代;或4)环己基CH2、双环[3.1.0]己基CH2、螺[2.5]辛基 CH2、哌啶基CH2、吡咯烷基CH2和四氢吡喃基CH2,其各自任选地由独立 选自R41的1个至3个取代基取代;
R1选自Me、-NH2、-NHMe和-NMe-4-甲氧基苄基;
R2选自(1)H、F、Cl、CN、CF3、CH2OH、CH2NH2、CONH2、CH2OAc、 CH2OMe和CH2NHAc或(2)2-唑基、1,3,4-二唑-2-基、1,2,4-二唑-5-基、 2-噻唑基和1,3,4-噻二唑-2-基,其各自任选地由选自甲基、氰基、乙氧基羰 基和CONH2的基团取代;
Y是H、F或Cl;
R3选自i-Pr、i-Bu、t-Bu、CF3、CF2Me、CH2CMe2F、CH2CF3、CH(OMe)Me、 c-Pr、c-己基、苯基、2-Cl-苯基、2-Br-苯基、2-Me-苯基、3-Cl-苯基、3-Me- 苯基、4-F-苯基、4-Cl-苯基、4-Br-苯基、苄基、4-甲基-2-噻唑基、CO2Me、 CMe2OH和CH2CMe2OH;
R4是H或甲基;
R10选自i-Pr、t-Bu、i-Bu、t-BuCH2、苄基、CF3CH2、CF3CHMe、CF3CMe2和2,2,3,3-四氟环丁基;
R21选自F、Cl、Br、CN、NO2、NH2、OH、Me、i-Pr、c-Pr、C(=CH2)Me、 CHF2、CF3、CF2Me、OMe、Oi-Pr、OCHF2、OCH2CF3、CH2OH、CH(OH)Me、 CH(OH)Et、CH(OH)CF3、CMe2OH、CMe(OH)CF3、CH(OMe)CF3、CMe2CN、 C(=O)H、C(=O)Me、SO2Me、CO2H、CO2Me、CO2Et、CONR22R23、CH2NR22R23、CH2NHAc、CH2SMe、CH2NHSO2Me、CH2C6H4R25和4,4-二甲基-2-唑烷基;
R22选自H、Me、Et、n-Bu、t-Bu、CH2CH2OH、CH2CH2OMe、CH2CH2CH2OH、 CH2CH2CMe2OH、CH2CH2CH2OMe、CH2CO2Et、CH2CH2CO2Et、 CH2CH2CH2NHCO2Me、CH2CH2CH2NHCO2t-Bu和N-t-BuOC(=O)-3-氮杂环丁 基;
R23是氢、甲基、乙基或甲氧基;或R22和R23与其连接的氮一起形成氮 杂环丁烷环或吗啉环,其各自任选地由独立选自R24的1个或2个基团取代;
R24是F、OH、OMe或NH2;
R25是CO2H或CMe2OH;
R31选自F、Cl、Br、Me、i-Pr、、CF3、OCHF2、OCF3、CMe(OH)CF3、 CO2Me和CMe2OH;
R41选自F、OH、OMe、Me、异丙基、CHF2、CF3、CH2CF3、CF2CH3和CMe2OH。
在第三个实施方案中,本发明的化合物由结构式(I)表示或是其药学上可 接受的盐,其中Q是吡啶基或嘧啶基,其各自由独立选自R21的1个或2个 基团取代;R1选自甲基、NH2和NHMe;R2是H、F或CH2OH;Y是H;R3是i-Pr;R4是H;其中其余变体如式(I)或第一或第二个实施方案中所描述。
在第四个实施方案中,本发明的化合物由结构式(I)表示或是其药学上可 接受的盐,其中Q是2-吡啶基或2-嘧啶基,其各自由1个CF3基团取代并任 选地由选自R21的第二基团取代;R1是甲基;R2是H、F或CH2OH;Y是H; R3是异丙基;R4是H;其中其余变体如式(I)或第一、第二或第三个实施方案 中所描述。
在第五个实施方案中,至少1个R21是羟基(C1-C4)烷基,其余变体如式 (I)或第一、第二、第三或第四个实施方案中所描述。
在第六个实施方案中,本发明的化合物由结构式(I)表示或是其药学上可 接受的盐,其中Q是苯基CH2或吡啶基CH2,其各自任选地由独立选自R31的1个至3个取代基取代;R1是甲基、NH2和NHMe;R2是H、F或CH2OH; Y是H;R3选自i-Pr、苯基和卤代苯基;R4是H;其中其余变体如式(I)或第 一或第二个实施方案中所描述。
在第七个实施方案中,本发明的化合物由结构式(I)或其药学可接受的盐 表示,其中Q是苯基CH2或3-吡啶基CH2,其各自用1个CF3基团取代和任 选地用选自R31的另一个基团取代;R1是甲基;R2是H、F或CH2OH;Y是 H;R3是异丙基;R4是H;其中其余变量如式(I)或第一或第二个实施方案中 所描述的。
在第八个实施方案中,本发明的化合物由结构式(I)表示或是其药学上可接受 的盐,其中Q是环己基CH2或哌啶基CH2或四氢吡喃基CH2,其各自任选地 由独立选自R41的1个至3个取代基取代;R1是甲基、NH2或NHMe;R2是 H、F或CH2OH;Y是H;R3是异丙基、苯基和卤代苯基;R4是H;其中其 余变体如式(I)或第一或第二个实施方案中所描述。
在第九个实施方案中,本发明的化合物由结构式(I)表示或是其药学上可 接受的盐,其中Q是环己基CH2、3-哌啶基CH2或3-四氢吡喃基CH2,其各 自由1个CF3基团取代和任选地由选自R41的1个其他基团取代;R1是甲基; R2是H、F或CH2OH;Y是H;R3是异丙基;R4是H;其中其余变体如式(I) 或第一或第二个实施方案中所描述。
在第十个实施方案中,式(I)的化合物由结构式Ia或Ib表示或是其药学 上可接受的盐:
其中R4、Q和Y如式(I)或第一个或第二个实施方案中所定义的。
在第十一个实施方案中,式(I)的化合物由结构式Ic、Id、Ie、If、Ig、Ih、 Ii或Ij表示或是其药学上可接受的盐:
其中m是1、2或3;R1、R2、R3、R4、R21和Y如式(I)或第一个、第二个、 第三个、第四个或第五个实施方案中所定义的。
在第十二个实施方案中,式(I)的化合物由结构式Ik、Il、Im、In、Io或 Ip表示或是其药学上可接受的盐:
其中n是0、1或2;A是CH2、NH、NMe或O;R1、R2、R3、R4、R41和Y 如式(I)或第一个、第二个、第八个或第九个实施方案中所定义的。
在一个实施方案中,本发明的化合物是表1中的化合物或其药学上可接 受的盐。
表1:
a使用ChemBioDraw Ultra 13.0生成化合物名称
在另一个实施方案中,本发明的化合物是表2中描述的化合物或其药学 上可接受的盐。
表2.
4.用途、配制和施用
药学上可接受的组合物
在一个实施方案中,本文提供了包含本发明化合物和药学上可接受的载 体或稀释剂的药物组合物。
在本发明的药物组合物中,本发明的化合物以有效量存在。人和动物剂 量的相互关系(基于每平方米体表的毫克数)在Freirieich等人,Cancer Chemother.Rep,1966,50:219中描述。体表面积可以由患者的身高和体重大致 确定。参见,例如,ScientificTables,Geigy Pharmaceuticals,纽约州阿兹利, 1970,537。
本文中的LXR调节因子(例如,本发明的化合物)可以以适合所选施用途 径的多种形式配制为药物组合物并施用至对象,例如人。施用这种药物组合 物的典型途径包括但不限于口服、外用、口腔、经皮、吸入、肠胃外、舌下、 直肠、阴道和鼻内。本文中所使用的术语肠胃外施用包括皮下注射、静脉注 射、肌肉注射、鞘内注射、胸腔注射或输注技术。配制药物组合物的方法是 在本领域众所周知的,例如,如“Remington:The Science andPractice of Pharmacy,”费城科学大学编辑,第21版,2005,Lippincott,Williams&Wilkins,宾夕法尼亚州费城中所公开的。各个LXR调节因子可以单独使用或 作为本发明药物组合物的一部分联合使用。
本发明的药物组合物可以通过将本发明的化合物与适当的药学上可接受 的载体、稀释剂或赋形剂组合而制备,可以配制成固体、半固体、液体或气 体形式的制剂,例如片剂、胶囊剂、散剂、颗粒剂、软膏剂、溶液剂、栓剂、 注射剂、吸入剂、凝胶剂、微球剂和气雾剂。因此,本化合物可以与药学上 可接受的赋形剂如惰性稀释剂或可吸收食用的载体组合以全身施用,例如口 服。可将其封装在硬壳的或软壳明胶胶囊中,或压成片剂或直接混合在病人 饮食的食物中。对于口服治疗性施用,该活性化合物可以与一种或更多种赋 形剂组合,并以可吸收片剂、口含片剂、糖锭剂、胶囊剂、酏剂、混悬剂、 糖浆剂、圆片剂等形式使用。
合适的片剂可以通过例如将一种或更多种的本发明化合物与已知赋形剂 混合而获得,该赋形剂如惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、 黏合剂和/或润滑剂。片剂也可以由数层构成。
可以将本发明的化合物适当地配制成施用至对象的药物组合物。因此, 本发明的药物组合物任选地包括一种或更多种药学上可接受的载体和/或稀 释剂,例如乳糖、淀粉、纤维素和葡萄糖。也可以包括其他赋形剂,例如调 味剂;甜味剂;防腐剂,例如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟 基苯甲酸丙酯和对羟基苯甲酸丁酯。在药物赋形剂手册(第5版, Pharmaceutical Press(2005))中可以找到合适赋形剂的更多完整列表。本领域技术人员知道怎样制备适于各种施用途径的剂型。用于选择和制备合适的剂 型的常规流程和组分在例如Remington’s Pharmaceutical Sciences(2003-第20 版)和1999年出版的美国药典:The National Formulary(USP 24NF19)中描述。 载体、稀释剂和/或赋形剂从与药物组合物其他成分相兼容且对其接受者无害 的意义上说是“可接受的”。
通常,对于口服治疗性施用,本发明的化合物可以与赋形剂混合,并以 可吸收片剂、口含片剂、糖锭剂、胶囊剂、酏剂、混悬剂、糖浆剂、圆片剂 等形式使用。
通常对于肠胃外施用,本发明的化合物溶液可以在水中适当地与表面活 性剂如羟丙基纤维素混合而制备。在含或不含醇的甘油、液态聚乙二醇、 DMSO及其混合物中、以及在油中也可以制备分散剂。在储存和使用的常规 条件下,这些制剂含有防腐剂以防止微生物生长。
通常对于注射使用,本发明化合物的无菌水溶液或分散体和无菌粉末用 于临时制备无菌的可注射溶液或分散体。
对于鼻内施用,本发明的化合物可以配制成气雾剂、滴剂、凝胶剂和散 剂。气雾剂剂型一般包含生理学上可接受的水性或非水性溶剂中的活性物质 溶剂或细悬浮剂,通常在密封容器内以无菌形式的单剂量或多剂量存在,该 密封容器可以采取与雾化装置一起使用的药筒或替换物的形式。或者,密闭 容器可以是单一分散装置,如单剂量鼻内吸入器或装有计量阀的气雾分散器, 该计量阀在使用后废弃。当剂型包含气雾分散器时,其包含推进剂,该推进 剂可以是压缩气体如压缩空气或有机推进剂如氟氯烃。气雾剂型还可以采取 泵雾化器的形式。
对于口腔施用或舌下施用,本发明的化合物可以用载体配制成片剂、锭 剂或糖锭剂,该载体如糖、阿拉伯胶、黄芪胶、或明胶和甘油。
对于直肠施用,本发明的化合物可以以含有常规栓剂基质如可可脂的栓 剂形式制备。
本发明化合物的外用和/或局部施用可以通过多种方式实现,包括但不限 于软膏剂、洗剂、糊剂、乳膏剂、凝胶剂、散剂、滴剂、喷雾剂、溶液剂、 吸入剂、贴剂、栓剂、保留灌肠剂、可咀嚼或可吮吸的片剂或微丸和气雾剂。 外用和/或局部施用也可以涉及使用经皮施用,例如经皮贴剂或离子导入设 备。对于外用和/或局部施用,本发明的化合物可以配制成软膏剂、乳膏剂、 乳剂、药膏、散剂、浸渍垫、洗涤剂、溶液剂、凝胶剂、喷雾剂、泡沫剂、 混悬剂、洗剂、粘贴剂、洗发剂或清洗基质。本发明的化合物也可以以脂质 混悬剂或聚合物囊或纳米微球或微球或聚合物贴剂和水凝胶的形式施用以实 现控释。
化合物和药学上可接受组合物的用途
本文提供了一种治疗患有通过调节LXR可治疗的疾病或病症的对象的 方法。在一个实施方案中,通过上调LXR活性调节LXR。该方法包括施用 有效量的本发明化合物。此外,本文中提供了本发明化合物用于制备治疗患 有通过上调对象中LXR活性可治疗的疾病或病症的对象的药剂的用途,该对 象需要该药剂。
本文提供的方法对于用LXR调节特别是LXR激动可治疗的病症是有效 的。
本发明的化合物可用于治疗或预防与以下过程相关的疾病或病症:胆固 醇转运改变、胆固醇逆向转运、脂肪酸代谢、胆固醇吸收、胆固醇重吸收、 胆固醇分泌、胆固醇排泄或胆固醇代谢。代表性的疾病或病症包括但不限于: 血脂异常;癌症,特别是激素依赖性癌症和皮肤癌,激素依赖性癌症包括卵 巢癌、乳腺癌和前列腺癌,皮肤癌包括黑素瘤、基底细胞癌和鳞状细胞癌; 痤疮样皮肤病;皮肤炎性疾病;免疫异常;以表皮屏障功能异常为特征的疾 病;表皮或粘膜分化异常或过度增殖的疾病;心血管疾病;生殖系统病症; 视神经和视网膜异常;疾病中出现的退行性神经病变;自身免疫疾病;对中 枢或外周神经系统的创伤性损伤;神经退行性疾病;由于老化的退行性过程; 肾脏的疾病或病症;骨质酥松症及相关疾病。
在另一个实施方案中,疾病或病症是高血脂、高胆固醇、高脂蛋白、高 甘油三酯、脂肪代谢障碍、肝脂肪变性、非酒精性脂肪肝炎(NASH)、非酒精 性脂肪肝病(NAFLD)、高血糖、胰岛素抵抗、糖尿病、血脂异常、动脉粥样 硬化、胆石症、普通痤疮、皮炎(包括但不限于银屑病、接触性皮炎、特异性 皮炎和湿疹)、皮肤伤口、皮肤老化、光老化、皱纹、糖尿病、尼曼匹克病C 型、帕金森病、阿尔茨海默病、炎症、黄瘤、肥胖症、代谢综合症、X综合 症、中风、外周闭塞性疾病、失忆症、糖尿病性神经病变、蛋白尿症、肾小 球疾病(包括但不限于糖尿病性肾病、高血压性肾病、IGA肾病、局灶节段性 肾小球硬化症)、高磷血症、高磷血症的心血管并发症、急性冠脉综合征、癌 症、多发性硬化症、或骨质酥松症。
在另一个实施方案中,疾病或病症是癌症,包括但不限于:膀胱癌、脑 癌、乳腺癌、结直肠癌、子宫颈癌、胃肠癌、泌尿生殖癌、头颈癌、肺癌、 卵巢癌、胰腺癌、前列腺癌、肾癌、皮肤癌和睾丸癌。癌症可以是实体瘤, 其可以是或可以不是转移性的。癌症还可以作为弥漫性组织出现,如在白血 病中的。
在一些实施方案中,可以通过本文描述的化合物、组合物和方法治疗的 癌症包括但不限于以下:贲门癌,包括例如肉瘤,如血管肉瘤、纤维肉瘤、 横纹肌肉瘤和脂肪肉瘤;粘液瘤;横纹肌瘤;纤维瘤;脂肪瘤和畸胎瘤;肺 癌,包括例如支气管癌,如鳞状细胞癌、未分化小细胞癌、未分化大细胞癌 和腺癌;肺泡癌和细支气管癌;支气管腺瘤;肉瘤;淋巴瘤;软骨错构瘤; 间皮瘤;胃肠癌,包括例如食道癌,如鳞状细胞癌、腺癌、平滑肌肉瘤和淋 巴瘤;胃癌,例如癌、淋巴瘤、平滑肌肉瘤;胰腺癌,如导管腺癌、胰岛瘤、 胰高血糖素瘤、胃泌素瘤、类癌瘤和舒血管肠肽瘤;小肠癌,如腺癌、淋巴 瘤、类癌瘤、Kaposi肉瘤、平滑肌瘤、血管瘤、脂肪瘤、纤维神经瘤和纤维 瘤;大肠癌或结肠癌,如腺癌、管状腺瘤、绒毛状腺瘤、错构瘤和平滑肌瘤; 泌尿生殖道癌,包括例如肾癌,如腺癌、Wilm肿瘤(肾胚细胞瘤)、淋巴瘤 和白血病;膀胱癌和尿道癌,例如鳞状细胞癌、移行细胞癌和腺癌;前列腺 癌,例如腺癌和肉瘤;睾丸癌,例如精原细胞瘤、畸胎瘤、胚胎性癌、畸胎 癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤和脂肪瘤; 肝癌,包括例如肝癌,如肝细胞癌;胆管癌;肝母细胞癌;血管肉瘤;肝细 胞腺瘤;血管瘤;骨癌,包括例如骨原性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤 维性组织细胞瘤、软骨肉瘤、Ewing肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多 发性骨髓瘤、恶性骨巨细胞瘤脊索瘤、骨软骨瘤(骨软骨外生骨疣)、良性软 骨瘤、成软骨细胞瘤、软骨肌瘤样纤维瘤、骨样骨瘤和骨巨细胞瘤;神经系 统癌,包括例如颅骨癌,如骨瘤、血管瘤、肉芽瘤、黄瘤和畸形性骨炎;脑 膜癌,如脑膜瘤、脑膜瘤样肉瘤和神经胶质过多;脑癌,如星形细胞瘤、成 神经管细胞瘤、胶质瘤、室管膜瘤、生殖细胞瘤(松果体瘤)、多形性胶质母 细胞瘤、少突神经胶质瘤、神经鞘瘤、成视网膜细胞瘤和先天性肿瘤;脊髓 癌,如纤维神经瘤、脑膜瘤、胶质瘤和肉瘤;妇科癌,包括例如子宫癌,如 子宫内膜癌;子宫颈癌,如子宫颈癌和宫颈癌前病变;卵巢癌,如卵巢癌, 包括浆液性囊腺癌、粘液性囊腺癌、未分类癌、粒层细胞鞘细胞瘤、Sertoli Leydig细胞瘤、无性细胞瘤和恶性畸胎瘤;外阴癌,如鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤和黑素瘤;阴道癌,如透明细胞癌、鳞状细胞癌、葡萄 状肉瘤和胚胎横纹肌肉瘤;输卵管癌,如癌;血液癌,包括例如血癌,如急 性骨髓性白血病、慢性骨髓性白血病、急性淋巴细胞白血病、慢性淋巴细胞 白血病、骨髓及外骨髓增殖疾病、多发性骨髓瘤和骨髓增生异常综合征、 Hodgkin淋巴瘤、非Hodgkin淋巴瘤(恶性淋巴瘤)和Waldenstrom巨球蛋白 血症;皮肤癌,包括例如恶性黑素瘤、基底细胞癌、鳞状细胞癌、Kaposi肉 瘤、摩尔发育不良痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、银屑病;肾 上腺癌,包括例如成神经细胞瘤。
在另一个实施方案中,疾病或病症是雷特综合征。
在另一个实施方案中,疾病或病症是急性冠脉综合征和相关病况。这些 相关病况包括例如心脏病、心肌梗塞、急性心肌梗塞、非ST段抬高性心肌 梗塞、ST段抬高性心肌梗塞、不稳定型心绞痛、稳定型心绞痛、心绞痛、运 动诱发性心绞痛、冠状动脉疾病、冠心病、急性心肌缺血、缺血性心脏病、 局部缺血、复发性缺血、充血性心脏病、充血性心力衰竭、心肌症、高血压 心脏病、心力衰竭、舒张性心力衰竭、收缩性心力衰竭、肺心病、心脏节律 障碍、心律异常、炎性心脏病、心内膜炎、炎性心脏肥大、心肌炎、脑血管 疾病、外周动脉疾病、再灌注损伤、再狭窄、粥样硬化病变或慢性粥样硬化 炎症。
在另一个实施方案中,疾病或病症是普通痤疮;黑头粉刺;多型粉刺(polymorphs);红斑痤疮;结节囊肿型痤疮;聚合性痤疮;老年性粉刺;继发 性痤疮,包括但不限于日光性痤疮、药物性痤疮和职业性痤疮;鱼鳞癣;鱼 鳞病样病况;Darier氏病;掌跖角化病;粘膜白斑病;粘膜白斑样病况;皮 肤或粘膜(口腔)苔藓病;伴随或不伴随细胞增殖病症的具有炎症性免疫过敏 成分的皮肤病学疾病或感染,包括但不限于皮肤银屑病、粘膜银屑病、指甲 银屑病、银屑病性风湿病,皮肤特异反应性包括湿疹、呼吸特异反应性和齿龈肥大;病毒性或非病毒性起源的良性或恶性真皮增殖或表皮增殖,包括但 不限于寻常疣、扁平疣、疣状表皮发育不良、口腔或菜花样乳头瘤病、和T 淋巴瘤或皮肤T细胞淋巴瘤;可由紫外光诱发的增殖,包括但不限于基底细 胞上皮瘤和棘细胞上皮瘤;癌前皮肤病变,包括但不限于角化棘皮瘤;免疫 皮炎,包括但不限于红斑狼疮;大疱免疫疾病;胶原病,包括但不限于硬皮 病;具有免疫学成分的皮肤病学或全身疾病或感染;归因于暴露于UV辐射的皮肤病症;皮肤的光诱导老化或自然老化;光化性色素沉着;角化病;与 自然老化或日光性老化有关的病状,包括但不限于干燥病;脂肪功能障碍, 包括但不限于痤疮的皮脂溢出过多、简单皮脂溢出、脂溢性皮炎、脂溢样银 屑病、脂溢性湿疹、头皮屑和头皮糠疹;愈合障碍,包括但不限于妊娠纹; 色素沉着异常,包括但不限于色素沉着过度、黄褐斑、色素减退和白癜风; 脱发,包括但不限于化疗相关性脱发和辐射相关性脱发。
在一个实施方案中,疾病或病症是高胆固醇血症、动脉粥样硬化或血脂 异常。在另一个实施方案中,疾病或病症是动脉粥样硬化、阿尔茨海默病、 皮炎或癌症。在又一个实施方案中,疾病或病症是动脉粥样硬化、阿尔茨海 默病、急性冠脉综合征、黑素瘤或特应性皮炎。
本发明还提供用于增加胆固醇逆向转运和/或抑制动脉粥样硬化进展或 促进动脉粥样硬化康复的方法。
本发明还提供治疗与需要增加高密度脂蛋白(HDL)-胆固醇水平有关的 疾病或病症的方法,其包括向需要其的哺乳动物(特别是人)施用有效量的本 发明化合物。
本发明还提供治疗与需要降低低密度脂蛋白(LDL)-胆固醇水平有关的疾 病或病症的方法,其包括向需要其的哺乳动物(特别是人)施用有效量的本发 明化合物。
另外,本文中提供了在对象细胞中提高ATP-结合盒蛋白表达的方法,该 方法利用本发明的化合物和本文中所提供的组合物从而增加对象中的胆固醇 逆向转运。
标准的生理学、药理学和生物化学步骤是本领域已知的,且可用于评价 本发明的化合物调节LXR活性的能力。例如,这种分析包括结合分析、荧光 偏振分析、基于FRET的共激活因子聚集分析和基于细胞的共转染分析。可 以评价本发明的化合物调节基因表达的能力,已知该基因受LXR调节。可以 使用已建立的动物模型以研究本发明化合物的属性,所述属性涉及与疾病或 病症直接相关的参数,该疾病或病症包括动脉粥样硬化、阿尔茨海默病和皮 肤病。因此,可以在动物模型中通过多种施用途径例如口腔填喂而体内检测 本发明的化合物。通常,体内化合物暴露可以在所关注的血浆和组织中检测。 LXR活性(如通过LXR应答基因的基因表达所检测的)可以在所关注的全血 和组织中检测。脂肪可以在血浆和肝脏中定量。
特别地,可以检测本发明化合物对ATP结合盒(ABC)胆固醇转运蛋白例 如ABCA1和ABCG1的活性,对脂肪生成标记的活性,该脂肪生成标记例如 在基因和蛋白质表达水平的SREBP1c。ABC转运蛋白诱导的功能性结果可 以在用于胆固醇流出的细胞模型中和用于反向胆固醇途径和动脉粥样硬化的 动物模型中进行检测。脂肪生成标记可以在动物模型中通过测量血浆和肝脏 甘油三酯水平来检测。
本发明的化合物可以单独使用(即作为单一治疗剂)或与对治疗任一种上 述适应症有效的一种或更多种其他治疗剂联用。药物组合物可以只包含所公 开的化合物作为唯一的药物活性剂或可以包含一种或更多种其他药物活性 剂。
本发明还提供用于治疗或减轻本文中描述的疾病或病症的联合疗法。在 一些实施方案中,联合疗法包括联合施用由式I表示的至少一种化合物与用 于治疗或减轻本文所描述的疾病或病症的一种或更多种药剂。
在一些实施方案中,本发明的化合物与用于治疗糖尿病、血脂障碍、心 血管疾病、高血压或肥胖症的一种或更多种其他药剂联合使用。用于治疗糖 尿病的药剂包括胰岛素,例如(Eli Lilly)、(Sanofi Aventis)、 (NovoNordisk)和(Pfizer);PPARγ激动剂,例如 (马来酸罗格列酮,GSK)和(盐酸吡格列酮,Takeda/Eli Lilly);磺酰脲 类药物,例如(格列美脲,Sanofi Aventis)、(格列本脲,Sanofi Aventis)、(格列本脲,Pfizer)和 和(格列吡嗪,Pfizer);氯茴苯酸类药物,例如(瑞 格列奈,NovoNordisk)、(那格列奈,Novartis)和(米格列奈, Takeda);双胍类药物,例如(盐酸二甲双胍, Bristol Myers Squibb)和(盐酸二甲双胍缓释片,Depomed);噻唑烷 二酮类药物;胰淀素类似物,GLP-1类似物或GLP-1激动剂(包括(艾 塞那肽,Amylin/Eli Lilly)和(重组利拉鲁肽,Novo Nordisk));DPP-IV 抑制剂,包括TradjentaTM(Eli Lilly/BoehringerIngelheim)、(Merck)、 (Novartis)和(Bristol-MyersSquibb/AstraZeneca);PTB-1B 抑制剂;蛋白激酶抑制剂(包括AMP-激活性蛋白激酶抑制剂);胰高血糖素拮 抗剂、糖原合成酶激酶-3β抑制剂;葡萄糖-6磷酸酶抑制剂;糖原磷酸化酶 抑制剂;钠葡萄糖共转运蛋白抑制剂和α-葡糖苷酶抑制剂,例如(阿卡波糖,Bayer)和(米格列醇,Pfizer)。用于治疗血脂障碍和心血管疾病的药剂包括他汀类药物、贝特 类药物和依折麦布。用于治疗高血压的药剂包括α-阻滞剂、β-阻滞剂、钙通 道阻滞剂、利尿剂、血管紧张素转化酶(ACE)抑制剂、ACE和中性肽链内酶 (NEP)双重抑制剂、血管紧张素受体阻滞剂(ARB)、醛固酮合成酶抑制剂、醛 固酮受体拮抗剂、或内皮素受体拮抗剂。用于治疗肥胖症的药剂包括奥利司 他、芬特明、西布曲明和利莫那班。
本发明的实施方案包括在联合疗法中与联合产品一起施用本发明的至少 一种LXR调节剂化合物或其组合物,该联合产品例如(盐酸二甲 双胍和马来酸罗格列酮,GSK);(格列美脲和马来酸罗格列酮, GSK);(格列吡嗪和盐酸二甲双胍,Bristol Myers Squibb); (格列本脲和盐酸二甲双胍,Bristol Myers Squibb)。
在一些实施方案中,联合疗法包括联合施用至少一种本发明的化合物和 一种或更多种选自以下的化合物:例如,β分泌酶(BACE1)抑制剂;γ分泌酶 抑制剂;淀粉样肽聚集抑制剂(例如ELND-005);直接或间接作用性神经保护 性和/或疾病调节性物质;抗氧化剂(例如维他命E或银杏内酯);抗炎物质(例 如Cox抑制剂,NASID);HMG-CoA还原酶抑制剂(他汀类);乙酰胆碱酯酶 抑制剂(例如多奈哌齐、卡巴拉汀、他克林、加兰他敏、美金刚;他克林); NMDA受体拮抗剂(例如美金刚);AMPA受体激动剂;AMPA受体正调节剂、 安帕金、单胺受体再摄取抑制剂、调节神经传递介质浓缩和释放的物质;诱 导生长激素分泌的物质(例如伊布莫仑甲磺酸盐和卡莫瑞林);CB-1受体拮抗 剂或反向激动剂;抗生素(例如盐酸米诺环素或利福平);PDE2抑制剂、PDE4 抑制剂、PDE5抑制剂、PDE9抑制剂、PDE10抑制剂、GABAA受体反向激 动剂、GABAA受体拮抗剂、烟碱受体激动剂或烟碱受体部分激动剂或正向 调节剂、α4β2烟碱受体激动剂或α4β2烟碱受体部分激动剂或正向调节剂、α7 烟碱受体激动剂或α7烟碱部分激动剂或正向调节剂;组胺H3拮抗剂、5HT-4 激动剂或5HT-4部分激动剂、5HT-6拮抗剂、α2-肾上腺素受体拮抗剂、钙拮 抗剂、毒蕈碱受体M1激动剂或毒蕈碱受体M1部分激动剂或正向调节剂、 毒蕈碱受体M2拮抗剂、毒蕈碱受体M4拮抗剂、代谢型谷氨酸受体5正向调节剂、抗抑郁药如西酞普兰、氟西汀、帕罗西汀、舍曲林和曲唑酮;抗焦 虑药,如氯羟去甲安定和去甲羟基安定;抗精神病药物,如阿立哌唑、氯氮 平、氟哌啶醇、奥氮平、奎硫平、利培酮和齐拉西酮,以增加根据本发明化 合物的功效和/或安全性和/或减少不需要的副作用的方式以调节受体或酶的 其他物质。
在一些实施方案中,本文描述的化合物与一种或更多种附加疗法联合使 用,该附加疗法包括缓解疼痛和焦虑、预防缺血复发和预防或限制急性心肌 梗塞进展的疗法。这些附加疗法包括抗血栓形成的治疗,以及冠状动脉造影 后的血管再生。其他附加治疗法包括戒烟、运动和控制高血压和血糖。
在一些实施方案中,本文描述的化合物与用于抗血小板或抗凝血疗法的 一种或更多种药剂联合使用,该药剂包括阿司匹林、氯吡格雷、普拉格雷、 替格瑞洛和糖蛋白IIb/IIIa抑制剂,其包括依替巴肽、替罗非班和阿昔单抗。
在一些实施方案中,本文描述的化合物与用于抗凝血酶治疗的一种或更 多种药剂联合使用,该药剂包括磺达肝素、肝素和比伐卢定。
在一些实施方案中,本文描述的化合物与一种或更多种降血脂药剂联合 使用,该药剂包括他汀类、烟酸、胆汁酸结合树脂和依折麦布。
在一些实施方案中,本文描述的化合物与用于血管再生的一种或更多种 疗法联合使用,该疗法包括冠状动脉造影和搭桥手术。
在一些实施方案中,本文描述的化合物与一种或更多种药剂联合使用, 该药剂包括硝酸盐(舌下、口腔或静脉内)、β阻滞剂、钙拮抗剂(例如地尔硫 卓、戊脉安)和血管舒张肽-转化酶(ACE)抑制剂。
在一些实施方案中,本文描述的化合物与选自抗血小板、硝酸盐、β阻 滞剂、糖蛋白IIB/IIIA抑制剂、抗凝血剂、低分子量肝素、直接凝血酶抑制 剂和二磷酸腺苷受体拮抗剂的一种或更多种药剂联合使用。
在一些实施方案中,本文描述的化合物与用于治疗癌症的一种或更多种 药剂联合使用,该癌症包括但不限于乳腺癌、卵巢癌、前列腺癌、皮肤癌、 肾细胞癌、结直肠癌、胰腺癌、胃癌、白血病和淋巴瘤,该皮肤癌包括黑素 瘤、基底细胞癌和鳞状细胞癌。
在一些实施方案中,本文描述的化合物与免疫疗法联合使用,该免疫疗 法包括但不限于用于治疗本文所公开的疾病或病症的基于细胞的疗法、抗体 疗法和细胞因子疗法。
在某些实施方案中,根据本发明的化合物与一种或更多种被动免疫疗法 联合使用,该被动免疫疗法包括但不限于裸单克隆抗体药物和共轭单克隆抗 体药物。可以使用的裸单克隆抗体药物的实例包括但不限于:利妥昔单抗 抗CD20抗原的抗体;曲妥单抗抗HER2蛋白的 抗体;阿伦单抗(Campath),抗CD52抗原的抗体;西妥昔单抗抗EGFR蛋白的抗体;贝伐单抗其是VEGF蛋白的抗血管生成 抑制剂。
可以使用的共轭单克隆抗体的实例包括但不限于放射性标记抗体替伊莫 单抗放射性标记抗体托西莫单抗抗毒素吉妥单抗 其包含卡奇霉素;BL22,抗CD22单克隆抗体抗毒素共轭剂; 放射性标记抗体,如和brentuximab vedotinado-曲妥单抗emtansine(也称为TDM-1)。
可以使用的治疗性抗体的其他实例包括但不限于 (abciximab),抗血小板上糖蛋白IIb/IIIa受体的抗体; (daclizumab),免疫抑制性人源化抗CD25单克隆抗体; PANOREXTM,鼠科抗-17-IA细胞表面抗原IgG2a抗体;BEC2,鼠科抗个体基因型(GD3表位)IgG抗体;IMC-C225,嵌合型抗EGFR IgG抗体; VITAXINTM,人源化抗αVβ3整合素抗体;Campath 1H/LDP-03,人源化抗 CD52IgG1抗体;Smart M195,人源化抗CD33IgG抗体;LYMPHOCIDETM, 人源化抗CD22IgG抗体;LYMPHOCIDETMY-90;Lymphoscan;(抗CD3;CM3,人源化抗ICAM3抗体;IDEC-114,灵长目源化抗CD80抗体; IDEC-131,人源化抗CD40L抗体;IDEC-151,灵长目源化抗CD4抗体; IDEC-152,灵长目源化抗CD23抗体;SMARTanti-CD3,人源化抗CD3IgG; 5G1.1,人源化抗补体因子5(C5)抗体;D2E7,人源化抗TNF-α抗体;CDP870, 人源化抗TNF-αFab片段;IDEC-151,灵长目源化抗CD4IgG1抗体; MDX-CD4,人抗CD4IgG抗体;CD20-链霉亲和素(+生物素-钇90);CDP571, 人源化抗TNF-αIgG4抗体;LDP-02,人源化抗α4β7抗体;OrthoClone OKT4A,人源化抗CD4IgG抗体;ANTOVATM,人源化抗CD40LIgG抗体; ANTEGRENTM,人源化抗VLA-4IgG抗体;CAT-152,人抗TGF-β2抗体。
在某些实施方案中,根据本发明的化合物与一种或更多种靶向免疫疗法 联合使用,该靶向免疫疗法含有毒素但不含抗体,其包括但不限于地尼白介 素与白喉毒素连接的IL-2。
根据本发明的化合物还可以与用于治疗本文所描述的疾病或病症的辅助 性免疫疗法联合使用。这些辅助性免疫疗法包括但不限于:细胞因子,如粒 细胞-巨噬细胞集落刺激因子(GM-CSF)、粒细胞集落刺激因子(G-CSF)、巨噬 细胞炎性蛋白(MIP)-1-alpha、白介素(包括IL-1、IL-2、IL-4、IL-6、IL-7、IL-12、 IL-15、IL-18、IL-21和IL-27)、肿瘤坏死因子(包括TNF-α)、干扰素(包括IFN-α、 IFN-β和IFN-γ);氢氧化铝(明矾);卡介苗(BCG);钥孔戚血蓝素(KLH);弗 氏不完全佐剂(IFA);QS-21;DETOX;左旋咪唑;二硝基苯基(DNP)及其组合,例如白介素如IL-2与其他细胞因子如IFN-α的组合。
在某些实施方案中,根据本发明的化合物与疫苗疗法联合使用,该疫苗 疗法包括但不限于自体肿瘤细胞疫苗和异体肿瘤细胞疫苗、抗原疫苗(包括多 价抗原疫苗)、树突细胞疫苗;病毒疫苗。
在另一个实施方案中,本公开包括向癌症患者施用有效量的本文所描述 的化合物和一种或更多种附加抗癌疗法,其选自手术、抗癌剂/药物、生物疗 法、放射疗法、抗血管生成疗法、免疫疗法、效应细胞过继转移、基因疗法 或激素疗法。下文描述抗癌剂/药物的实例。
在一个实施方案中,抗癌剂/药物例如是亚德里亚霉素、放线菌素、博来 霉素、长春花碱、顺氯氨铂、阿西维辛;阿柔比星;盐酸阿考达唑;阿克罗 宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;乙酸阿美蒽醌;氨鲁米 特;安丫啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿 扎替派;阿佐霉素;巴马司他;苄替哌;比卡鲁胺、盐酸比生群;双奈法德 马利兰;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌 素C;卡鲁睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡 折来新;西地芬戈;苯丁酸氮芥;西罗霉素;克拉屈滨;甲磺酸克雷斯托; 环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸道诺霉素;地西他滨;右奥马铂;地 扎呱宁;甲磺酸地扎呱宁;地吖醌;阿霉素;盐酸阿霉素;屈洛昔芬;柠檬 酸屈洛昔芬;屈他雄酮丙酸酯;达唑霉素;依达曲沙;盐酸依洛尼塞;依沙 芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸依索 比星;雌氮芥;雌氮芥磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;艾托 卜宁;盐酸法倔唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧 啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;异丙铂;盐酸伊立替康;乙酸兰瑞 肽;来曲唑;乙酸亮丙瑞林;盐酸利阿唑;洛美曲素钠;洛莫司汀;盐酸洛 索蒽醌;马索罗酚;美登素;盐酸氮芥;甲地孕酮;乙酸美仑孕酮;美法仑; 美诺立尔;巯嘌呤;氨甲蝶呤;氨甲蝶呤钠;氯苯氨啶;美妥替哌;米丁度 胺;米托克星;丝裂红素;丝林霉素;米托马星;丝裂霉素;丝裂帕菌素; 米托坦;盐酸米托蒽醌;霉酚酸;诺考达唑;诺加霉素;奥马铂;奥昔舒仑; 培门冬酶;培利霉素;戊氮芥;硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊 舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟菲尔钠;泊非霉素;泼尼莫 司汀;盐酸甲基苄肼;嘌呤霉素;盐酸嘌呤霉素;吡唑霉素;利波腺苷;罗 谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;司 帕霉素;盐酸螺旋锗;螺莫司汀;螺铂;链黑菌素;链脲霉素;磺氯苯脲; 他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫卟吩;替尼泊苷;替 罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;塞替派;噻唑羧胺核苷;替拉扎明; 柠檬酸托瑞米芬;乙酸曲托龙;磷酸曲西立滨;三甲曲沙;三甲曲沙葡萄糖 醛酸酯;曲普瑞林;盐酸妥布氯唑;尿嘧啶氮芥;乌瑞替哌;伐普肽;维替 泊芬;硫酸长春花碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春 匹定;硫酸长春甘酯;硫酸长春罗新;酒石酸长春瑞滨;硫酸长春罗定;硫 酸长春利定;伏罗唑;折尼铂;净司他丁;盐酸佐柔比星;(易普利 姆玛);MekinistTM(曲美替尼);聚乙二醇干扰素α-2b、重组干扰素α-2b; SylatronTM(聚乙二醇干扰素α-2b);(达拉菲尼);(维罗非 尼);纳武单抗。
可以与治疗癌症的现有方法例如化疗、放疗或外科手术联合施用根据本 发明的化合物。因此,进一步提供治疗癌症的方法,其包括向需要该治疗的 对象施用有效量的根据式I的化合物,或其药学上可接受的盐形式,其中向 对象施用有效量的至少一种附加癌症化疗剂。合适的化疗剂的实例包括以下 任意:阿巴瑞克、ado-曲妥单抗emtansine、阿地白介素、阿仑单抗、阿利维 A酸、别嘌呤醇、六甲蜜胺、阿那曲唑、三氧化二砷、天冬酰胺酶、阿扎胞 苷、贝伐单抗、贝沙罗汀、博来霉素、硼替佐米、保特佐米、静脉内白消安、 口腔白消安、卡普睾酮、卡培他滨、卡铂、卡莫司汀、西妥昔单抗、苯丁酸 氮芥、顺铂、克拉屈滨、氯法拉滨、环磷酰胺、阿糖胞苷、达卡巴嗪、更生 霉素、达肝素钠、达沙替尼、道诺霉素、地西他滨、地尼白介素、地尼白介 素、右雷佐生、多西他赛、阿霉素、屈他雄酮丙酸酯、依库丽单抗、曲妥珠 单抗(emtansine)、表柔比星、艾瑞布林、埃罗替尼、雌氮芥、磷酸依托泊苷、 依托泊苷、依维莫司、依西美坦、柠檬酸芬太尼、非格司亭、氟脲苷、氟达 拉滨、氟尿嘧啶、呋喹替尼、氟维司群、吉非替尼、吉西他滨、吉妥单抗、 乙酸戈舍瑞林、乙酸组氨瑞林、替伊莫单抗、伊达比星、异环磷酰胺、甲磺 酸伊马替尼、干扰素α-2a、伊立替康、伊沙匹隆、二甲苯磺酸拉帕替尼、来 那度胺、来曲唑、亚叶酸、乙酸亮丙瑞林、左旋咪唑、洛莫司汀、氮芥、乙 酸甲地孕酮、美法仑、巯嘌呤、氨甲蝶呤、甲氧沙林、丝裂霉素C、米托坦、 米托蒽醌、苯丙酸诺龙、奈拉滨、诺菲单抗、奥沙利铂、紫杉醇、紫杉醇白 蛋白稳定型纳米颗粒制剂、帕米膦酸二钠、帕尼单抗、培门冬酶、聚乙二醇 非格司亭、培美曲塞二钠、喷司他丁、帕妥珠单抗、哌泊溴烷、普卡霉素、 甲基苄肼、奎纳克林、拉布立酶、利妥昔单抗、索拉菲尼、链脲霉素、索凡 替尼、舒尼替尼、马来酸舒尼替尼、三苯氧胺、替莫唑胺、替尼泊苷、睾内 酯、沙利度胺、硫鸟嘌呤、塞替派、拓扑替康、托瑞米芬、托西莫单抗、曲 妥单抗、维甲酸、尿嘧啶氮芥、戊柔比星、长春花碱、长春新碱、长春瑞滨、 沃利替尼、伏立诺他、唑来膦酸。
在具体的实施方案中,根据本发明的化合物与选自用于治疗乳腺癌的甲 氨蝶呤、紫杉醇白蛋白稳定的纳米颗粒制剂、ado-曲妥单抗emtansine、艾瑞 布林、阿霉素、氟尿嘧啶、依维莫司、阿那曲唑、帕米膦酸二钠、依西美坦、 卡培他滨、环磷酰胺、多西他赛、表柔比星、托瑞米芬、氟维司群、来曲唑、 吉西他滨、盐酸吉西他滨、乙酸戈舍瑞林、曲妥单抗、伊沙匹隆、二甲苯磺 酸拉帕替尼、乙酸甲地孕酮、柠檬酸它莫西芬、帕米膦酸二钠、帕妥珠单抗中的一种或更多种抗癌剂联合使用。
其他抗癌剂/药物包括但不限于:20-epi-1,25-二羟维生素D3;5-乙炔基 尿嘧啶;阿比特龙;阿柔比星;酰基富烯;腺环戊醇;阿多来新;阿地白介 素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;amidox;氨磷汀;氨基乙酰丙 酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;穿心莲内酯;血管生成抑制 剂;拮抗剂D;拮抗剂G;安雷利克斯;抗背部化形成蛋白-1;前列腺癌抗 雄激素;抗雌激素;抗瘤酮;反义寡核苷酸;甘氨酸阿非迪霉素;细胞凋亡 基因调节剂;细胞凋亡调节剂;无嘌呤酸;ara-CDP-DL-PTBA;精氨酸脱氨 酶;asulacrine;阿他美坦;阿莫司汀;axinastatin 1;axinastatin 2;axinastatin 3;阿扎司琼;阿扎毒素;重氮酪氨酸;浆果赤霉素III衍生物;balanol;巴 马司他;BCR/ABL拮抗剂;benzochlorins;苯甲酰星状孢菌素;β内酰胺衍 生物;β-alethine;β-clamycin B;白桦脂酸;bFGF抑制剂;比卡鲁胺;比生 群;双氮丙啶基精胺;双奈法德;bistratene A;比折来新;breflate、溴匹立 明;布朵替坦;丁硫氨酸亚砜胺;卡泊三醇;卡弗他丁C;喜树碱衍生物; 金丝雀痘IL-2;卡培他滨;甲酰胺-氨基-三唑;羧胺三唑;CaRest M3;CARN 700;软骨衍生抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);栗树精胺;杀 菌肽B;西曲瑞克;chlorlns;氯代喹喔啉磺酰胺;西卡前列素;顺卟啉;克 拉屈滨;氯米芬类似物;克霉唑;collismycin A;collismycin B;康布他汀 A4;康布他汀类似物;conagenin;crambescidin 816;克雷斯托;念珠藻素8; 念珠藻素A衍生物;curacin A;环戊蒽醌;cycloplatam;cypemycin;阿糖胞 苷烷磷酯;细胞溶解因子;cytostatin;达昔单抗;地西他滨;脱氢膜海鞘素 B;德舍瑞林;地塞米松;右异环磷酰胺;右雷佐生;右维拉帕米;地吖醌; 膜海鞘素B;didox;二乙基去甲精胺;二氢-5-氮杂胞苷;9-dioxamycin;联 苯螺莫司汀;二十二烷醇;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;duocarmycin SA;伊布硒啉;依考莫司汀;依地福新;依决洛单抗;依洛尼 塞;榄香烯;乙嘧替氟;表柔比星;爱普列特;雌氮芥类似物;雌激素激动 剂;雌激素拮抗剂;依他硝唑;依托泊苷磷酸盐;依西美坦;法倔唑;法扎 拉滨;芬维A胺;非格司亭;非那雄胺;夫拉平度;氟卓斯汀;fluasterone; 氟达拉滨;盐酸氟代柔红霉素;福酚美克;福美司坦;福司曲星;福莫司汀; 德卟啉钆;硝酸镓;加洛他滨;加尼瑞克;白明胶酶抑制剂;吉西他滨;谷 胱甘肽抑制剂;hepsulfam;神经调节蛋白(heregulin);六亚甲基双乙酰胺; 金丝桃素;伊班膦酸;伊达比星;吲哚昔酚;伊决孟酮;依莫福新;伊洛马 司他;咪唑并吖啶酮;咪喹莫特;免疫刺激肽;胰岛素类似生长因子-1受体 抑制剂;碘苄胍;碘阿霉素;甘薯苦醇、4-;伊罗普拉;伊索拉定;isobengazole; isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;片螺素-N三 乙酸盐;兰瑞肽;leinamycin;来格司亭;硫酸香菇多糖;leptolstatin;来曲 唑;白血病抑制因子;亮丙瑞林+雌性激素+黄体酮;亮丙瑞林;左旋咪唑; 利阿唑;线性多胺类似物;亲脂性二糖肽;亲脂性铂化合物;lissoclinamide 7; 洛铂;蚯蚓磷脂;洛美曲素;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾; 勒托替康;德卟啉镥;lysofylline;细胞溶素肽;美坦辛;mannostatin A;马 马司他;马索罗酚;乳腺丝氨酸蛋白酶抑制剂;基质溶解因子抑制剂;基质 金属蛋白酶抑制剂;美诺立尔;麦尔巴隆;美替瑞林;甲硫蛋氨酸酶;甲氧 氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA; 米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;迈托毒素纤维原细胞 生长因子-皂草素;米托蒽醌;莫法罗汀;莫拉司汀;单克隆抗体、人绒膜促 性腺激素;单磷酰基脂质A+乳酸分支杆菌结核杆菌细胞壁sk;莫哌达醇; 多重抗药物基因抑制剂;基于多重肿瘤抑制剂1的治疗;氮芥抗癌剂;mycaperoxide B;分支杆菌细胞壁提取物;myriaporone;N-乙酰基地那林; N-取代苯甲酰胺;那法瑞林;nagrestip;纳洛酮+戊唑辛;napavin;naphterpin; 那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;尼沙 霉素;氮氧化物调节剂;硝基氧抗氧化剂;nitrullyn;O6-苄基鸟嘌呤;奥曲 肽;okicenone;寡核苷酸;奥那司酮;奥坦西隆;奥坦西隆;oracin;口服 细胞因子诱导剂;奥沙利铂奥马铂;奥沙特隆;奥沙利铂;oxaunomycin;palauamine;棕榈酰根霉素;帕米膦酸;人参炔三醇;帕诺米芬;parabactin; 帕折普汀;天门冬酰胺酶;培得星;戊聚糖多硫酸钠;喷司他丁;pentrozole; 全氟溴烷;培磷酰胺;紫苏子醇;phenazinomycin;乙酸苯酯;磷酸酶抑制 剂;溶链菌素;盐酸匹鲁卡品毛果芸香碱;吡柔比星;吡曲克辛;placetin A; placetin B;纤维蛋白溶酶原激活物抑制剂;铂络合物;铂化合物;铂-三胺络 合物;卟菲尔钠;泊非霉素;强的松;丙基双吖啶酮;前列腺素J2;蛋白解酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;微藻蛋白激酶 C抑制剂;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素; 吡唑并啉吖啶;吡哆酰基化的血红蛋白聚氧乙烯共轭物;raf拮抗剂;雷替曲 塞;雷莫司琼;ras法尼基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂; 脱甲基瑞替普汀;依替膦酸钠铼Re 186;根霉素;核糖酶;RII维甲酸;罗 谷亚胺;罗希吐碱;罗莫肽;罗喹美克;rubiginone B1;ruboxyl;沙芬戈;saintopin;SarCNU;sarcophytol A;沙格司亭;Sdi 1模拟物;司莫司汀;衰 老衍生的抑制剂1;有义寡核苷酸;信号转导抑制剂;信号转导调节剂;单 链抗原-结合蛋白;西佐喃;索布佐生;硼卡钠;苯基乙酸钠;solverol;生 长调节素结合蛋白;索纳明;斯帕福斯酸;spicamycin D;螺莫司汀;斯耐 潘定;海绵抑制素1;角鲨胺;干细胞抑制剂;干细胞分化抑制剂;stipiamide; 基质分解素抑制剂;sulfinosine;强效血管活性肠肽拮抗剂;suradista;苏拉 明;苦马豆碱;合成葡糖氨基葡聚糖;他莫司汀;它莫西芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;tellurapyrylium;端粒酶抑制剂; 替莫泊芬;替莫唑胺;替尼泊苷;四氯癸烷氧化物;tetrazomine;菌体胚素; 噻可拉林;促血小板生成素;促血小板生成素模拟物;胸腺法新;促胸腺生 成素受体激动剂;胸腺曲南;促甲状腺激素;锡乙基etiopurpurin;替拉扎明; 二茂钛二氯化物;topsentin;托瑞米芬;全能干细胞因子;转化抑制剂;维 甲酸;三乙酰基尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;tyrphostins;UBC抑制剂;乌苯美司;尿生殖窦衍 生的生长抑制因子;尿激酶受体拮抗剂;伐普肽;variolin B;载体系统;红 细胞基因治疗;维拉雷琐;藜芦胺;verdins;维替泊芬;长春瑞滨;vinxaltine; vitaxin;伏氯唑;扎诺特隆;折尼铂;zilascorb;净司他丁斯酯;5-氟尿嘧啶; 亚叶酸。
在一个实施方案中,抗癌剂/药物是稳定微管的药剂。如本文所使用的, “微管蛋白稳定剂”指由于微管稳定化通过捕获G2-M阶段中的细胞起作用的 抗癌剂/药物。微管稳定剂的实例包括和类似物。微管 稳定剂的其他实例包括但不限于以下市售药物和研发中的药物:圆皮海绵内 酯(也称作NVP-XX-A-296);埃博霉素(例如埃博霉素A、埃博霉素B、埃博 霉素C(也称作脱氧埃博霉素A或dEpoA);埃博霉素D(也称作KOS-862、 dEpoB和脱氧埃博霉素B);埃博霉素E;埃博霉素F;埃博霉素B N-氧化物; 埃博霉素A N-氧化物;16-氮杂-埃博霉素B;21-氨基埃博霉素B(也称作 BMS-310705);21-羟基埃博霉素D(也称作脱氧埃博霉素F和dEpoF)、26-氟 代埃博霉素);FR-182877(Fujisawa,也称作WS-9885B)、BSF-223651(BASF, 也称作ILX-651和LU-223651);AC-7739(Ajinomoto,也称作AVE-8063A和 CS-39.HCl);AC-7700(Ajinomoto,也称作AVE-8062、AVE-8062A、 CS-39-L-Ser.HCl和RPR-258062A);Fijianolide B;Laulimalide;Caribaeoside; 卡巴林;Taccalonolide;Eleutherobin;Sarcodictyin;Laulimalide;Dictyostatin-1;Jatrophane酯;其类似物和衍生物。
在另一个实施方案中,抗癌剂/药物是抑制微管的药剂。如本文所使用的, “微管抑制剂”指通过抑制微管蛋白聚合或微管组装起作用的抗癌剂。微管抑 制剂的实例包括但不限于以下市售药物和研发中的药物:厄布洛唑(也称作 R-55104);尾海兔素10(也称作DLS-10和NSC-376128);羟乙基磺酸米伏布 林(也称作CI-980);长春新碱;NSC-639829;ABT-751(Abbot,也称作E-7010); Altorhyrtins(例如Altorhyrtin A和Altorhyrtin C);Spongistatins(例如 Spongistatin 1、Spongistatin 2、Spongistatin 3、Spongistatin4、Spongistatin 5、 Spongistatin 6、Spongistatin 7、Spongistatin 8和Spongistatin9);盐酸西马多 丁(也称作LU-103793和NSC-D-669356);阿里他汀PE(也称作NSC-654663);Soblidotin(也称作TZT-1027)、LS-4559-P(Pharmacia,也称作LS-4577); LS-4578(Pharmacia,也称作LS-477-P);LS-4477(Pharmacia)、 LS-4559(Pharmacia);RPR-112378(Aventis);硫酸长春新碱;DZ-3358(Daiichi); GS-164(Takeda);GS-198(Takeda);KAR-2(匈牙利科学院);SAH-49960 (Lilly/Novartis);SDZ-268970(Lilly/Novartis);AM-97(Armad/Kyowa Hakko); AM-132(Armad);AM-138(Armad/Kyowa Hakko);IDN-5005(Indena);念珠 藻素52(也称作LY-355703);Vitilevuamide;Tubulysin A;Canadensol;矢车 菊黄素(也称作NSC-106969);T-138067(Tularik,也称作T-67、TL-138067 和TI-138067);COBRA-1(Parker Hughes研究所,也称作DDE-261和 WHI-261);H10(堪萨斯州立大学);H16(堪萨斯州立大学);Oncocidin A1(也 称作BTO-956和DIME);DDE-313(ParkerHughes研究所);SPA-2(Parker Hughes研究所);SPA-1(Parker Hughes研究所,也称作SPIKET-P); 3-IAABU(Cytoskeleton/Mt.Sinai医学院,也称作MF-569);Narcosine(也称作NSC-5366);Nascapine、D-24851(Asta Medica)、A-105972(Abbott); Hemiasterlin;3-BAABU(Cytoskeleton/Mt.Sinai医学院,也称作MF-191); TMPN(亚利桑那州立大学);乙酰丙酮钒;T-138026(Tularik);Monsatrol; Inanocine(也称作NSC-698666);3-IAABE(Cytoskeleton/Mt.Sinai医学院); A-204197(Abbott);T-607(Tularik,也称作T-900607);RPR-115781(Aventis); Eleutherobins(例如Desmethyleleutherobin、Desacetyleleutherobin、 Isoeleutherobin A和Z-Eleutherobin);软海绵素B;D-64131(Asta Medica); D-68144(Asta Medica);Diazonamide A;A-293620(Abbott);NPI-2350(Nereus); TUB-245(Aventis);A-259754(Abbott);Diozostatin;(-)-Phenylahistin(也称作 NSCL-96F037);D-68838(Asta Medica);D-68836(Asta Medica);肌基质蛋白 B;D-43411(Zentaris,也称作D-81862);A-289099(Abbott);A-318315(Abbott); HTI-286(也称作SPA-110,三氟乙酸盐)(Wyeth);D-82317(Zentaris); D-82318(Zentaris);SC-12983(NCI);瑞伐斯他汀磷酸钠;BPR-0Y-007(国民 健康研究所);SSR-250411(Sanofi);康普瑞汀A4;艾瑞布林其 类似物和衍生物。
在另一个实施方案中,根据本发明的化合物与烷基化剂、抗代谢剂、天 然产物或激素联合使用。在本发明的方法中有用的烷基化剂的实例包括但不 限于氮芥(例如氮芥、环磷酰胺、苯丁酸氮芥、美法仑等)、乙烯亚胺和甲基 密胺(例如六甲基密胺、塞替派)、烷基磺酸盐(例如白消安)、亚硝基脲(例如 卡莫司汀、lomusitne、司莫司汀、链脲霉素等)或三氮烯(氨烯咪胺等)。在本 发明的方法中有用的抗代谢剂的实例包括但不限于叶酸类似物(例如甲氨蝶 呤)或嘧啶类似物(例如氟尿嘧啶、氟尿苷、阿糖胞苷)和嘌呤类似物(例如巯嘌 呤、硫鸟嘌呤、喷司他丁)。在本发明的方法中有用的天然产物的实例包括但 不限于长春花生物碱(例如长春花碱、长春新碱)、表鬼臼毒素(例如依托泊苷、 替尼泊苷)、抗生素(例如放线菌素D、道诺霉素、阿霉素、博来霉素、普卡 霉素、丝裂霉素)或酶(例如L-天门冬酰胺酶)。对于治疗癌症有用的激素和拮 抗剂的实例包括但不限于肾上腺皮质类固醇(例如强的松)、孕酮(例如羟孕酮 己酸酯、乙酸甲地孕酮、乙酸甲羟孕酮)、雌激素(例如已烯雌酚、乙炔雌二 醇)、抗雌激素(例如它莫西芬)、雄激素(例如丙酸睾酮、氟甲睾酮)、抗雄激素(例如氟他胺)和促性腺激素释放激素类似物(例如亮丙瑞林)。在用于治疗癌 症的本发明方法中可以使用的其他药剂包括铂络合物(例如顺铂、卡铂)、蒽 二酮(例如米托蒽醌)、经取代的脲(例如羟基脲)、甲基肼衍生物(例如甲基苄 肼)和肾上腺皮质抑制剂(例如米托坦、氨鲁米特)。其他抗癌剂/药物包括但不 限于:酶聚ADP核糖聚合酶(PARP)抑制剂,包括奥拉帕尼、iniparib、rucaparib、 veliparib;血管内皮生长因子(VEGF)受体酪氨酸激酶抑制剂,包括西地尼布; 程序性细胞死亡蛋白1(PD-1)抑制剂,包括纳武单抗(Bristol-MyersSquibb公 司)和派姆单抗(Merck&Co有限公司;MK-3475);MEK抑制剂,包括 cobimetinib;B-Raf酶抑制剂,包括维罗非尼;细胞毒素T淋巴细胞抗原 (CTLA-4)抑制剂,包括tremelimumab;程序性死亡配体1(PD-L1)抑制剂,包 括MEDI4736(AstraZeneca);Wnt路径抑制剂;表皮生长因子受体(EGFR)抑 制剂,包括AZD9291(AstraZeneca)、埃罗替尼、吉非替尼、帕尼单抗和西妥 昔单抗;腺苷A2A受体抑制剂;腺苷A2B受体抑制剂;Wnt路径抑制剂。
本发明的化合物可以与一种或更多种治疗策略联合使用,该治疗策略包 括免疫关卡抑制剂,其包括用于治疗癌症的PD-1抑制剂和CTLA-4抑制剂。
在具体的实施方案中,在本文方法中描述的化合物与一种或更多种抗癌 剂联合使用,该抗癌剂选自用于治疗黑素瘤的(易普利姆玛)、 MekinistTM(曲美替尼)、聚乙二醇干扰素α-2b、重组干扰素α-2b、 SylatronTM(聚乙二醇干扰素α-2b)、(达拉菲尼)、(维罗非 尼)和纳武单抗。
在一些实施方案中,本发明的化合物与用于有效治疗雷特综合征的一种 或更多种其他治疗剂联合使用。在一些实施方案中,本发明的化合物与一种 或更多种附加疗法联合使用,该疗法包括用于治疗癫痫的疗法、肌强直疗法、 物理疗法、职业疗法、语言疗法、营养支持疗法、鼻胃管喂食和胃造口术。
联合治疗包括联合施用本发明的化合物与一种或更多种其他药剂、相继 施用本发明的化合物与一种或更多种其他药剂、施用含有本发明的化合物与 一种或更多种其他药剂的组合物、或同时施用含有本发明的化合物和含有一 种或更多种其他药剂的单独组合物。
范例
如在以下实施例中所描述的,在某些示例性实施方案中,根据以下一般 步骤制备化合物。可以领会的是,尽管一般方法描述了合成本发明的某些化 合物,可以对如本文所描述的所有化合物和每种这些化合物的子类和种类应 用以下一般方法和本领域普通技术人员已知的其他方法。
合成方法概述
根据以下反应方案和实施例或其修改方案,使用现有的原材料、试剂和 常规合成步骤可以容易地制备本发明的化合物。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进行,例如如固相试剂/清除剂或流动化 学。在这些反应中,也可以利用本身是本领域普通技术人员已知的变化方案, 但没有更详细提及。另外,用于制备本发明化合物的其他方法鉴于以下反应 方案和实施例对于本领域普通技术人员会是明显的。在合成中间体和最终产 物含有潜在活性官能团例如氨基、羟基、巯基和羧酸基团的情况下,该官能 团可能干扰所期望的反应,采用中间体的保护形式会是有利的。用于选择、 引入及后续移除保护基团的方法是本领域技术人员已知的。在以下讨论中, 除非另有说明,R1、R2、R3、R4、R10、R21、R22、R23、R24、R25、R30、R31、 R40、R41、A、L、Y、m和n具有上文指出的含义。下文列出在这些实验性 细节中使用的缩写,其他缩写应是合成领域技术人员已知的。另外,可以参 考在以下文献中描述的适当合成方法:March,Advanced Organic Chemistry, 第3版,JohnWiley&Sons,1985,Greene and Wuts,Protective Groups in Organic Synthesis,第二版,John Wiley&Sons,1991和Richard Larock, Comprehensive OrganicTransformations,第4版,VCH publishers Inc.,1989。
一般地,反应方案中的试剂以等摩尔的量使用;然而,在某些情况下, 使用过量的一种试剂驱使反应完成是可取的。在过量试剂可以通过蒸发或萃 取容易去除时的情况下尤其如此。用于中和反应混合物中的HCl的碱一般以 少量或大量过量使用(1.05至5当量)。
可以采用以下缩写:
在第一步骤中,式I的化合物由式II的哌嗪和式III的经取代的苯制备(反 应式1)。在该步骤的第一变化方案中,G1是I、Br、Cl或OSO2CF3,在惰性 气氛下采用钯源和合适的配体。合适的钯源包括Pd2(dba)3,合适的配体包括 Xphos。在该步骤的第二变化方案中,G1是B(OH)2,在空气或氧气气氛下, 通过Cu(OAc)2催化该反应。在该步骤的第三变化方案中,G1是F或Cl,R2是吸电子基团,如氰基或CO2Me,在碱如i-Pr2NEt的存在下通过加热完成该 反应。某些哌嗪II,例如R3=异丙基、异丁基、苄基,其中Q是叔丁氧基羰 基或苄氧基羰基,其是可商购的。
在第二步骤中,式I的化合物由式V的哌嗪和式IV的化合物制备(反应 式2)。当Q是R10OC(O)-时,G2是氯。或者,当Q是t-BuOC(O)-时,G2是 OC(O)Ot-Bu。当Q是杂芳基时,在第一变化方案中,G2是Br、Cl、F或SO2G3, 其中G3是Me或任意取代的苄基,在合适的碱如i-Pr2NEt的存在下通过加热 完成该反应。或者,在第二变化方案中,当Q是杂芳基且G2是Br、I或SO2CF3时,在合适的钯源和配体的存在下完成该反应。合适的钯源包括Pd2(dba)3, 合适的配体包括Xphos。或者,采用Pd(t-Bu3P)2。当Q是R30-L且L是CH2或CHMe时,G2是Cl、Br、I或SO2Me,在如NaHCO3或i-Pr2NEt的弱碱存 在下,优选在偶极非质子溶剂如DMF或MeCN中通过加热完成该反应。
在第三步骤中,使用如NaCNBH3或NaBH(OAc)3的还原剂,式I的化合 物通过用式V的哌嗪还原胺化式VI或式VII的醛制备(反应式3),其中Q是 R30-L或R40-L。
在第四步骤中,通过用式VIII或式IX的羧酸酰化式V的哌嗪、然后通 过还原制备式I的化合物(反应式4),其中Q是R30-L或R40-L。在如CH2Cl2或DMF的溶剂中,在如i-Pr2NEt的碱的存在下,使用如HATU或EDC的肽 偶联剂完成酰胺形成。使用如LiAlH4或BH3的还原剂进行酰胺的还原。
在第五个步骤中,通过从式XI的中间产物除去保护基团PG制备式II 的化合物。通过第二、第三和第四步骤的方法由式X的哌嗪制备式XI的中 间产物。
还由式I的其他化合物通过多种过程转化分子上的基团制备式I的化合 物,该多种过程包括但不限于以下列举的过程:
(a)在DMSO中使用H2O2和K2CO3将氰基转化为CONH2
(b)使用DiBAl或LiBH4将酯基还原为伯醇
(c)使用戴斯马丁高碘烷或斯文氧化反应将伯醇基团氧化为醛,使用格氏试 剂或烷基锂反应将伯醇基团氧化为仲醇
(d)通过与过量格氏试剂或烷基锂反应将酯基转化为叔醇
(e)在钯催化剂的存在下,通过与硼酸三甲酯反应将芳基溴化物、芳基碘化 物或杂芳基卤化物转化为相应的甲基化合物
(f)在钯催化剂的存在下,通过与环丙基硼酸或环丙基三氟硼酸酯/盐反应 将芳基溴化物、芳基碘化物或杂芳基卤化物转化为相应的环丙基化合物
(g)在CuI和脯胺酸钠的存在下,通过与MeSO2Na反应将芳基溴化物转化 为芳基甲基砜
(h)将烷基酯水解为相应的羧酸
(i)将羧酸与乙酰肼反应,然后用POCl3处理得到1,3,4-二唑
(j)将叔醇在如CDCl3或甲苯的溶剂中用如HCl的强酸处理得到烯烃
(k)将伯醇与MsCl反应,然后与仲胺反应得到叔胺
(l)在肽偶联剂如HATU或EDC的存在下,在碱如i-Pr2NEt的存在下将羧 酸与胺反应得到酰胺
(m)使用NCS或NBS,将2-氨基嘧啶在5号位上卤化
(n)用DAST处理叔醇得到相应的氟化合物
分析方法
当提供NMR数据时,在Varian 400(400MHz)或300(300MHz)上获得谱 图,报告为四甲基硅烷的低场ppm,以及参考氘化溶剂附带提及的质子数量、 峰多重性和耦合常数。
通过使用以下色谱条件获得LC-MS数据:
方法1(10-80,2分钟)
方法2(30-90,2分钟)
方法3(0-60,2分钟)
方法4:
HPLC系统:Waters ACQUITY;柱:Waters ACQUITY CSHTM C181.7μM 保护柱:WatersAssy.Frit,0.2μM,2.1mm;柱温:40℃流动相A:TFA: 水(1:1000,v:v)流动相B:TFA:ACN(1:1000,v:v);流速:0.65毫升/分钟; 进样体积:2μL;采集时间:约1.5分钟。
梯度程序
时间(分钟)B%
质谱仪参数
质谱仪:Waters SQD;离子化:正离子电喷雾电离(ESI);扫描方式(每 0.2秒100至1400m/z);ES毛细管电压:3.5kv;ES锥孔电压:25v离子源 温度:120℃;去溶剂化温度:500℃;去溶剂化气流量:氮气设置650(升/ 小时);锥孔气流量:氮气设置50(升/小时)。
实施例1
(R)-2-异丙基-4-(3-(甲磺酰基)苯基)哌嗪-1-羧酸叔丁酯(化合物编号1-1)
将(R)2-异丙基哌嗪-1-羧酸叔丁酯(377mg,1.65毫摩尔)、(3-(甲磺酰基) 苯基)硼酸(660mg,3.30毫摩尔)、Cu(OAc)2.H2O(33mg,0.17毫摩尔)、粉状 筛(930mg)和干燥的1,2-二氯乙烷(8mL)的混合物在O2(1atm,气球)下,在 70℃下加热18小时。用EtOAc(75mL)稀释混合物并通过硅藻土过滤。浓缩 滤液,留下棕色油状物(1.34g)。在40-g二氧化硅柱上进行层析,用己烷中 0至100%的EtOAc梯度洗脱,得到油状物(604mg)。制备型HPLC提供油状 物的标题化合物(329mg,52%)。LC-MS法4tR=0.97分钟,m/z=383,368,327,283。1H NMR(CDCl3)δ0.86(d,3H),1.02(d,3H),1.44(s,9H),2.17-2.30(m, 1H),2.75-2.90(m,2H),3.01(s,3H),3.02-3.15(m,1H),3.48-3.57(m,1H), 3.68-3.74(m,1H),3.95-4.10(m,1H),7.05-7.12(m,1H),7.29-7.45(m,3H)。
使用类似过程制备以下化合物。
实施例2
(R)4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-羧酸叔丁酯(化合物2-1)
将配有搅拌棒的50mL RBF用(R)2-异丙基哌嗪-1-羧酸叔丁酯(250mg,1.1 毫摩尔)、4-溴-1-氟-2-(甲磺酰基)苯(277mg,1.1毫摩尔)、Pd2(dba)3(66mg, 0.066毫摩尔)、X-phos(157mg,0.33毫摩尔)和Cs2CO3(892mg,2.74毫摩尔) 充满。用橡胶隔片密封烧瓶,用N2吹扫10分钟。通过注射器注入干燥甲苯 (5mL)和干燥叔丁醇(1mL),将混合物在110℃下加热20小时。用EtOAc(90mL) 稀释混合物,用水(10mL)和盐水(10mL)冲洗,并在Na2SO4上干燥。除去固 体,留下黄色固体(730mg),其在40-g二氧化硅柱上通过层析纯化,用己烷 中的0至100%EtOAc梯度洗脱,得到(R)4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基 哌嗪-1-羧酸叔丁酯(420mg,95%)。1H NMR(CDCl3)δ0.88(d,3H),1.00(d,3H), 1.44(s,9H),2.22-2.34(m,1H),2.68-2.71(m,2H),3.02-3.14(m,1H),3.18(s, 3H),3.36-3.44(m,1H),3.54-3.62(m,1H),3.70-3.90(m,1H),4.00-4.15(m,1H), 7.05-7.18(m,2H),7.36-7.39(m,1H)。19F NMR(CDCl3)δ-122.5。LC-MS法4 tR=1.01分钟,m/z=423,401,345。
使用类似过程制备以下化合物。
实施例3
(R)4-(4-氰基-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-羧酸叔丁酯(化合物编号3-1)
步骤1
将(R)2-异丙基哌嗪-1-羧酸叔丁酯(360mg,1.58毫摩尔)、2-溴-4-氟苯甲 腈(316mg,1.58毫摩尔)、i-Pr2NEt(0.6mL,3.3毫摩尔)和DMSO(4mL)的搅拌 溶液在120℃下加热2小时。将混合物冷却至室温,在下一步骤中直接使用。
步骤2
向混合物添加NaSO2Me(1.61g,15.8毫摩尔)和脯胺酸(55mg,0.47毫摩 尔)。用N2喷洒混合物10分钟,添加CuI(54mg,0.28毫摩尔)。在N2下,在 110℃下加热混合物16小时。将混合物冷却,用EtOAc(100mL)稀释,用水 (2×10mL)和盐水(10mL)清洗,并在Na2SO4上干燥。除去溶剂,留下橙色油 状物(677mg)。在40-g二氧化硅柱上进行层析,用己烷中的0至100%EtOAc 梯度洗脱,得到(R)4-(3-溴-4-氰基苯基)-2-异丙基哌嗪-1-羧酸叔丁酯(403mg,62%)和标题化合物(75mg,11%)。LC-MS法4tR=0.96分钟,m/z=408,352, 308。
参照类似步骤使用步骤1中的2-溴-4-氟-1-(三氟甲基)苯制备化合物编号 3-2,即(R)-2-异丙基-4-(3-(甲磺酰基)-4-(三氟甲基)苯基)哌嗪-1-羧酸叔丁基 酯。LC-MS m/z=473,395,351。
使用步骤2中的条件由(R)-5-溴-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基 哌嗪-1-基)-4-甲基嘧啶制备化合物编号3-3,即(R)-2-(4-(4-氟-3-(甲磺酰基)苯 基)-2-异丙基哌嗪-1-基)-4-甲基-5-(甲磺酰基)嘧啶。LC-MS m/z=471。
实施例4
(R)4-(4-氨基甲酰基-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-羧酸叔丁酯(化合物4-1)
向DMSO(1mL)中的(R)4-(4-氰基-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-羧 酸叔丁酯(21mg,0.052毫摩尔)的搅拌溶液添加固体K2CO3(4mg,0.029毫摩 尔)和30%的H2O2(0.1mL)。将混合物在室温下搅拌7小时,用MeOH稀释, 通过制备型HPLC纯化,得到标题化合物(9.6mg,44%)。LC-MS法4tR=0.85 分钟,m/z=370,326。
使用类似过程由相应的腈制备以下化合物。
a在手性柱上分离异构体,立体化学为任意指定的。
实施例5
(2R)-2,2,3,3-四氟环丁基-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-羧酸酯 (化合物编号5-1)
向CH2Cl2(1mL)中的(R)-1-(4-氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪(10mg, 32微摩尔)和i-Pr2NEt(25μL,0.14毫摩尔)的搅拌溶液添加乙醚(0.6mL,0.06 毫摩尔)中的0.11M 2,2,3,3-四氟环丁基氯甲酸酯。在室温下搅拌该混合物1 小时并浓缩。残余物通过制备型HPLC纯化,得到油状物的标题化合物(7mg, 44%)。LC-MS法4tR=1.03分钟,m/z=471。
通过类似步骤制备以下化合物。
实施例6
(S)-2-(2-羟丙-2-基)-4-(3-(甲磺酰基)苯基)哌嗪-1-羧酸叔丁酯(化合物6-1)
向干燥THF(2mL)中的(S)-4-(3-(甲磺酰基)苯基)哌嗪-2-羧酸甲酯(28mg, 0.084毫摩尔)的搅拌冰冷悬浮液添加Et2O(0.1mL,0.22毫摩尔)中的2.2M MeLi。使混合物加热至室温并搅拌过夜。添加水(2mL),然后添加 Boc2O(100mg)。将混合物搅拌1天,浓缩以留下含水残余物,其在盐水(10mL) 和EtOAc(100mL)之间分层。将有机层通过Na2SO4干燥、浓缩、留下油状物 (18mg)。制备型HPLC提供油状物的标题化合物(1.3mg,4%)。1H NMR (CD3OD)δ1.24(s,3H),1.26(s,3H),1.42(s,9H),3.03-3.10(m,1H),3.09(s, 3H),3.21-3.33(m,1H),3.44-3.56(m,2H),3.84-3.92(m,1H),4.10-4.20(m,2H), 7.22-7.52(m,4H)。LC-MS m/z=399,343,325。
实施例7
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶
步骤1
向CH2Cl2(5mL)中的(R)4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-羧酸 叔丁酯(420mg,1.05毫摩尔)搅拌溶液添加二氧六环(5mL,20毫摩尔)中的 4M HCl。将混合物在室温下搅拌2小时并浓缩,得到作为其HCl盐的(R)-1-(4- 氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪(415mg,定量)。LC-MS法4tR=0.57分 钟,m/z=301。
步骤2
将(R)-1-(4-氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪盐酸盐(34mg,0.1毫摩 尔)、2-氯-4-(三氟甲基)嘧啶(28mg,0.15毫摩尔)、Pr2NEt(0.11mL,0.6毫摩 尔)和正丙醇(0.5mL)的混合物在150℃微波下加热2小时。将混合物用甲醇 (1mL)稀释,通过制备型HPLC纯化,得到固体的(R)-2-(4-(4-氟-3-(甲磺酰基) 苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶TFA盐(26mg,46%)。1H NMR (CD3OD)δ0.90(d,3H),1.11(d,3H),2.42-2.55(m,1H),2.74-2.86(m,2H),3.23 (s,3H),3.28-3.38(m,1H),3.60-3.66(m,1H),3.80-3.86(m,1H),4.66-4.74(m, 1H),4.80-4.85(m,1H),6.83(d,1H),7.22-7.35(m,2H),7.39-7.42(m,1H),8.56 (d,1H)。19F NMR(CD3OD)-72.5,-78.0,-125.0。LC-MS法4tR=1.08分钟, m/z=448。
使用类似于以上描述的步骤制备以下化合物。
a在手性柱上分离异构体,立体化学为任意指定的。
使用类似于以上描述的步骤制备以下化合物。
使用类似于以上描述的步骤制备以下化合物。
使用类似于以上描述的步骤结合实施例18中的步骤制备以下化合物。
实施例8
(R)-2-(2-(4-氟苯基)-4-(3-(甲磺酰基)苯基)哌嗪-1-基)-4-(三氟甲基)嘧啶
步骤1
向12mL甲醇中的外消旋化合物1(1180mg,6.56毫摩尔)溶液添加7mL 甲醇中的N-乙酰-L-亮氨酸(1920mg,11.09毫摩尔)溶液。在室温下,向该溶 液沿烧瓶壁向下缓慢添加64mL的EtOAc。15小时后,将产生的沉淀物过滤 掉,用EtOAc清洗,在高真空下干燥。在干燥后,将白色固体添加至4N NaOH(30mL),产物用CH2Cl2(4×30mL)萃取。合并CH2Cl2层,在Na2SO4上 干燥,蒸发以得到白色固体物质。由EtOAc(~15mL)重结晶该物质,在室温 下静置~24小时后得到白色结晶化合物3。在由EtOAc母液三次结晶后,收 集其他结晶物质。蒸发母液以得到白色固体的300mg化合物2,其在随后的 受Boc保护物质(参见下一步的化合物4)的手性HPLC分析后确定为93%的 对映异构体。基于在先文献,将该化合物指定为R异构体。(Fink,D.M.等人, PCT国际申请WO2006086705“Preparation of substituted bisaryl and heteroaryl compounds as selective 5HT2a antagonists”;2006年8月17日)。在 2分钟色谱分析中,LC-MS tR=0.210分钟,MS(ESI)m/z 181.19[M+H]+。 1H NMR(CD3OD)δ7.34-7.30(2H,m),7.01-6.97(2H,m),3.67(dd,J=2.8, 11.0Hz,1H),2.98-2.94(m,1H),2.90-2.81(m,3H),2.73(dd,J=3.6,13.0Hz, 1H),2.57(dd,J=10.4,12.2Hz,1H)。
步骤2
在室温下向甲醇(10mL)中的化合物2(300mg,1.67毫摩尔)溶液添加 Et3N(0.58mL,4.18毫摩尔)。在室温下,以5分钟周期向该溶液滴加2mL甲 醇中Boc2O(363mg,1.67毫摩尔)溶液。在室温下搅拌2小时后,通过旋转蒸 发仪除去甲醇。将粗产物溶解于15mL的CH2Cl2,用水(10mL)清洗两次。将 CH2Cl2层在Na2SO4上干燥,蒸发以得到粗化合物4。通过ISCO急骤层析纯 化,得到465mg的化合物4(99%产率)。化合物4的手性HPLC分析显示了 27:1混合的对映体混合物(93%ee)。基于在先文献,将较多的对映体指定为R 异构体。(Fink,D.M.等人,PCT国际申请WO2006086705“Preparation of substituted bis aryland heteroaryl compounds as selective 5HT2a antagonists”; 2006年8月17日)。在2分钟色谱分析中,LC-MS tR=1.022分钟,MS(ESI) m/z 281.31[M+H]+。1H NMR(CDCl3)7.39-7.34(m,2H),7.04-7.00(m,2H), 4.03(bs,2H),3.68(dd,J=2.8,10.6Hz,1H),3.06(d,J=9.2Hz,1H),2.89-2.83 (m,2H),2.68(bs,1H),1.72(bs,1H),1.47(s,9H)。
步骤3
将二氧六环(3mL)中的4(50mg,0.18毫摩尔)、5(0.04mL,0.36毫摩尔) 和K2CO3(75mg,0.54毫摩尔)的悬浮液在密封瓶中加热至100℃持续24小时。 将混合物通过硅藻土板过滤,用EtOAc清洗硅藻土。通过旋转蒸发仪除去溶 剂,得到粗化合物6。使用ISCO急骤层析纯化,得到68mg的化合物6(89% 产率)。在3分钟色谱分析中,LC-MS tR=2.275分钟,MS(ESI)m/z 427.38 [M+H]+。1H NMR(CDCl3)8.52(d,J=5.2Hz,1H),7.33-7.29(m,2H),7.01-6.96(m,2H),6.82(d,J=5.2Hz,1H),5.97(bs,1H),4.66(d,J=12.4Hz, 1H),4.55(bs,1H),4.09-3.89(m,1H),3.40(d,J=12.4Hz,1H),3.22(bs,1H), 3.07(bs,1H),1.44(s,9H)。
步骤4
在室温下,向2mL的CH2Cl2中的6(23mg,0.054毫摩尔)溶液添加1mL 的TFA。在室温下搅拌1小时后,在旋转蒸发下除去溶剂,将粗哌嗪中间体 (TFA盐)置于高真空下1小时。不经进一步纯化将该物质直接用于下一步骤。
步骤5
在单独的烧瓶中,在室温下搅拌3mL二氯乙烷中的化合物7(22mg,0.11 毫摩尔)、Cu(OAc)2(1mg,0.005毫摩尔)和4A MS(25mg)悬浮液5分钟。在室 温下,添加1mL二氯乙烷中的以上粗哌嗪(TFA盐)、Et3N(0.015mL,0.108 毫摩尔)和吡啶(0.009mL,0.108毫摩尔)溶液。排出浅蓝色反应混合物,用 O2净化,在40℃下、在1atm的O2下搅拌24小时。然后将混合物通过硅藻 土过滤,蒸发,在Gilson-HPLC上纯化,得到6mg的化合物8(23%产率)。 在3分钟色谱分析中,LC-MS tR=2.09分钟,MS(ESI)m/z 481.35[M+H]+。 1H NMR(CD3OD)8.61(d,J=4.8Hz,1H),7.50-7.45(m,3H),7.41(t,J=2.0 Hz,1H),7.33(dd,J=1.2,7.4Hz,1H),7.27(dd,J=2.0,8.4Hz,1H),7.04-6.98 (m,2H),6.94(d,J=5.2Hz,1H),6.02(t,J=4.0Hz,1H),4.79-4.73(m,1H), 4.27-4.23(m,1H),3.82-3.78(m,1H),3.68-3.61(m,1H),3.52(dd,J=4.4,13.2 Hz,1H),3.19-3.13(m,1H),3.09(s,3H)。
实施例9
(R)2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧 酸乙酯
向二氧六环(2mL)中的(R)-1-(4-氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪 (73mg,0.24毫摩尔)和Pr2NEt(0.175mL,0.97毫摩尔)搅拌溶液添加2-氯-4-(三 氟甲基)嘧啶-5-羧酸乙酯(62mg,0.24毫摩尔)。在室温下搅拌该混合物1天并 浓缩。在EtOAc(90mL)中采集残余物,用5%的HCl水溶液(10mL)和盐水 (10mL)清洗,并在Na2SO4上干燥。除去溶剂,留下油状物(112mg)。在40-g 硅胶柱上进行层析,用EtOAc/己烷梯度洗脱,得到油状物的标题化合物 (36mg,29%)。LC-MS法4tR=1.12分钟,m/z=541,519。
使用类似于以上描述的步骤制备以下化合物。
实施例10
(R)-2-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶 -5-基)丙-2-醇
在室温下,向干燥THF(4mL)中的(R)2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异 丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯(292mg,0.56毫摩尔)搅拌溶液 添加THF(0.94mL,0.56毫摩尔)中的0.6M LaCl3.2LiCl。在室温下搅拌混合 物1小时,在冰浴中冷却,用THF(0.95mL,2.8毫摩尔)中的3M MeMgBr处 理。维持冰浴2小时,然后使其溶化。在另外2小时(内部温度=15℃)后,添 加NaHCO3的饱和水溶液(10mL)。用EtOAc(100mL)萃取混合物。用盐水(10mL) 清洗有机层,在Na2SO4上干燥并浓缩,得到橙色油状物(228mg),其通过制 备型HPLC纯化。含有标题化合物的级分用固体K2CO3处理,在室温以上不 经加热地合并和浓缩。用盐水(15mL)稀释含水残余物并用CH2CI2(3×50mL) 萃取。在Na2SO4和K2CO3上干燥有机层并浓缩以得到标题化合物(96mg, 33%)。LC-MS法4tR=1.01分钟,m/z=505,487。1HNMR(CD3OD)δ0.80 (d,3H),1.11(d,3H),1.58(s,6H),2.42-2.55(m,1H),2.73-2.86(m,2H),3.22(s, 3H),3.25-3.38(m,1H),3.58-3.64(m,1H),3.80-3.86(m,1H),4.63-4.68(m,1H),4.78-4.86(m,1H),7.21-7.34(m,2H),7.38-7.42(m,1H),8.76(s,1H)。
依照类似于以上描述的步骤制备以下化合物。
依照类似于以上描述的步骤由相应的甲酯或乙酯制备以下化合物。
a,b在手性柱上分离异构体,立体化学为任意指定的。
实施例11
(R)-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5- 基)甲醇
将干燥甲苯(4mL)中的(R)2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯(136mg,0.27毫摩尔)搅拌溶液冷却至 -70℃,用2分钟滴加甲苯(1mL,1毫摩尔)中的1M DiBAL。将混合物在-70℃ 下搅拌1.5小时,添加罗谢尔盐水溶液(1mL)。使混合物加温至室温,用盐水 (10mL)稀释并用EtOAc(2×60mL)萃取。将合并的有机层在Na2SO4上干燥, 浓缩以留下油状物(135mg)。将14mg的试样通过制备型HPLC纯化,得到油 状物的标题化合物(6mg)。LC-MS法4tR=0.94分钟,m/z=477。1H NMR (CD3OD)δ0.80(d,3H),1.13(d,3H),2.42-2.56(m,1H),2.74-2.90(m,2H),3.22 (s,3H),3.30-3.40(m,1H),3.60-3.66(m,1H),3.82-3.86(m,1H),4.59(s,2H), 4.66-4.72(m,1H),4.82-4.86(m,1H),7.23-7.36(m,2H),7.38-7.43(m,1H),8.60 (s,1H)。
依照类似于以上描述的步骤制备以下化合物。
a在手性柱上分离异构体,立体化学为任意指定的。
依照类似于以上描述的步骤由相应的甲基酯或乙基酯制备以下化合物。
实施例12
1-(2-((R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶 -5-基)乙醇(化合物编号12-1)
步骤1
向干燥CH2Cl2(10mL)中的(R)-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌 嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲醇(120mg,0.25毫摩尔)搅拌冰冷溶液添加 戴斯-马丁高碘烷(534mg,1.26毫摩尔)。使冰浴溶化,将混合物搅拌3小时。 添加NaHCO3饱和水溶液(20mL)和固体Na2S2O3(0.5g),将混合物搅拌0.5小 时。用CH2Cl2(2×40mL)萃取混合物。将合并的有机层用盐水(10mL)清洗, 在Na2SO4上干燥并浓缩以留下棕色油状物的粗(R)-2-(4-(4-氟-3-(甲磺酰基) 苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-甲醛(120mg)。
步骤2
向干燥THF(5mL)中的(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-甲醛(120mg,0.25毫摩尔)搅拌冰冷溶液添加 THF(0.25mL,0.75毫摩尔)中的3M MeMgBr。将混合物在冰浴中搅拌2小时, 用NH4Cl饱和水溶液(20mL)淬灭,用EtOAc(80mL)萃取。将有机层用盐水 (10mL)清洗,在Na2SO4上干燥,浓缩以留下油状物(117mg)。在40-g硅胶柱 上进行层析,得到油状物的标题化合物(59mg,%)。LC-MS法4tR=0.99分 钟,m/z=491。1H NMR(CDCl3)δ0.80(d,3H),1.09(d,3H),1.47(d,3H), 2.38-2.46(m,1H),2.76-2.88(m,2H),3.20(s,3H),3.24-3.37(m,1H),3.49-3.55 (m,1H),3.67-3.74(m,1H),4.61-4.67(m,1H),4.79-4.85(m,1H),5.11-5.20(q, 1H),7.07-7.18(m,2H),7.37-7.41(m,1H),8.77(s,1H)。
在手性柱上分离差向异构醇以得到化合物编号12-2、其观测到的分子量 为491.2,化合物编号12-3、其观测到的分子量为491.2。
依照类似步骤制备以下化合物。
a在手性柱上分离异构体,立体化学为任意指定的。
实施例13
(R)-1-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶 -5-基)乙酮(化合物编号13-1)
依照上文步骤1中的流程制备标题化合物。LC-MS法4tR=1.01分钟, m/z=489。1HNMR(CD3OD)δ0.82(d,3H),1.16(d,3H),2.48-2.58(m,4H), 2.78-2.92(m,2H),3.22(s,3H),3.36-3.44(m,1H),3.66-3.72(m,1H),3.84-3.90 (m,1H),4.68-4.84(m,1H),4.86-5.00(m,1H),7.22-7.38(m,2H),7.40-7.45(m, 1H),8.93(s,1H)。
依照类似流程制备以下化合物。
实施例14
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(丙-1-烯-2-基)-4-(三 氟甲基)嘧啶(化合物编号14-1)
使CDCl3(1mL)中的(R)-2-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)丙-2-醇(5mg)溶液在室温下静置1小时。将混合物 用于2g二氧化硅SPE柱,其用己烷(15mL)洗脱,然后用己烷(15mL)中的10% EtOAc洗脱以得到两个级分。将极性较大的洗脱液浓缩以得到油状物的标题 化合物(1mg)。LC-MS法4tR=1.16分钟,m/z=487。
依照类似过程制备以下化合物。
实施例15
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-((3-氟氮杂环丁-1-基) 甲基)-4-(三氟甲基)嘧啶(化合物编号15-1)
向CH2Cl2(5mL)中的(R)-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲醇(51mg,0.11毫摩尔)和Pr2NEt(0.055mL,0.31 毫摩尔)的冰冷搅拌溶液添加甲基磺酰氯(0.001mL,0.13毫摩尔)。使冰浴溶 化,将混合物在室温下搅拌2天。将混合物用EtOAc(80mL)稀释,用5%的 HCl水溶液(10mL)和3:1盐水/NaHCO3饱和水溶液(10mL)清洗,并在Na2SO4上干燥。除去溶剂,留下油状物(52mg),其在MeCN(2mL)中采集。向该溶液 添加Pr2NEt(0.075mL,0.42毫摩尔)和3-氟氮杂环丁烷盐酸盐(24mg,0.21毫摩尔)。将混合物在室温下搅拌2小时,通过制备型HPLC纯化,得到其TFA 盐的标题化合物(38mg,53%)。LC-MS法4tR=0.69分钟,m/z=534。1H NMR (CD3OD)δ0.82(d,3H),1.14(d,3H),2.47-2.58(m,1H),2.77-2.90(m,2H), 3.23(s,3H),3.35-3.45(m,1H),3.65-3.72(m,1H),3.83-3.90(m,1H),4.38-4.50 (m,2H),4.54(s,2H),4.58-4.80(m,3H),4.82-4.86(m,1H),5.31-5.38(m,0.5H), 5.45-5.52(m,0.5H),7.23-7.36(m,2H),7.39-7.43(m,1H),8.64(s,1H)。
依照类似过程制备以下化合物。
实施例16
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧 酸(化合物编号16-1)
向甲醇(10mL)、THF(5mL)和水(5mL)中的(R)2-(4-(4-氟-3-(甲磺酰基)苯 基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯(223mg,0.43毫摩尔) 搅拌溶液添加LiOH·H2O(150mg,3.6毫摩尔)。在室温下搅拌该混合物26小 时并浓缩。用5%的HCl水溶液(20mL)和EtOAc(90mL)稀释含水残余物。有 机层分离,用盐水(10mL)清洗,在Na2SO4上干燥并浓缩以提供(R)-2-(4-(4- 氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸(241mg, 定量),其不经进一步纯化而使用。LC-MS法4tR=0.98分钟,m/z=491。
依照类似过程制备以下化合物。
实施例17
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-N,N-二甲基-4-(三氟甲 基)嘧啶-5-甲酰胺(化合物编号17-1)
向THF(0.1mL,0.2毫摩尔)、Pr2NEt(15μL,82微摩尔)和CH2Cl2(1mL) 中的(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶 -5-羧酸(10mg,20微摩尔)、2M Me2NH搅拌溶液添加HATU(12mg,32微摩 尔)。将混合物搅拌过夜并浓缩。残余物通过制备型HPLC纯化以得到标题化 合物(3.4mg,32%)。LC-MS法4tR=0.93分钟,m/z=518。1H NMR(CD3OD) δ0.83(d,3H),1.12(d,3H),2.45-2.55(m,1H),2.81-2.93(m,2H),2.94(s,3H), 3.08(s,3H),3.22(s,3H),3.35-3.45(m,1H),3.62-3.68(m,1H),4.82-4.87(d, 1H),4.68-4.72(m,1H),5.83-5.89(m,1H),7.22-7.37(m,2H),7.39-7.43(m,1H), 8.46(s,1H)。
依照类似过程制备以下酰胺:
a,b在手性柱上分离异构体,立体化学为任意指定的。
实施例18
(R)-2-氟-5-(3-异丙基-4-(5-(三氟甲基)吡啶-2-基)哌嗪-1-基)苯磺酰胺(化合物 编号18-1)
向二氯甲烷(3mL)中的双(4-甲氧基苄基)胺(226mg,0.88毫摩尔)搅拌溶 液添加三乙基胺(200μL,1.46毫摩尔)和磺酰氯1(200mg,0.73毫摩尔)。将 获得的混合物在室温下搅拌10小时。用NaHCO3(5mL)饱和水溶液淬灭反应 混合物,用二氯甲烷(2×10mL)萃取。有机相在Na2SO4上干燥、过滤并浓缩。 通过高真空干燥残余物以得到磺胺2,其直接用于下一步骤。在2分钟色谱 分析中,LC-MS tR=1.89分钟,MS(ESI)m/z 516[M+23]+。
步骤1
向无水DMSO(0.35mL)中的2-氟-5-(三氟甲基)吡啶(125mg,0.75毫摩尔)、 CsF(137mg,0.9毫摩尔)溶液添加3(80mg,0.3毫摩尔)。使用200W的微波 功率,将反应混合物用2分钟从室温递进升温至180℃,然后保持在该温度。 持续2小时。在冷却至室温后,将获得的反应混合物用H2O(10mL)稀释,用 EtOAc(2×10mL)萃取。用盐水清洗有机层,在无水Na2SO4上干燥,在真空 下过滤并浓缩。通过硅胶层析(己烷/EtOAc)纯化残余物以得到产物4(62mg, 50%产率)。在2分钟色谱分析中,LC-MS tR=1.96分钟,MS(ESI)m/z 408.06 [M+H]+。
步骤2
向在甲醇(3mL)中的4(62mg,0.15毫摩尔)溶液添加Pd/C(重量/重量10%, 20mg)。在室温下、在H2下(1atm)将该混合物搅拌过夜。当TLC和LCMS显 示原料用尽时,将混合物用N2净化,在真空下过滤并浓缩以得到粗产物5。 其不经进一步纯化直接用于下一步骤。在2分钟色谱分析中,LC-MS tR=1.12 分钟,MS(ESI)m/z 274.32[M+H]+。
步骤3
向甲苯(1.5mL)中的溴化物2(170mg,0.37毫摩尔)、胺5(50mg,0.18毫 摩尔)、Xphos(24mg,0.05毫摩尔)和碳酸铯(150mg,0.46毫摩尔)混合物添加 Pd2(dba)3(21mg,0.023毫摩尔)。将混合物用氮气净化,将试管密封。将其在 100℃的油浴中加热5小时。冷却至室温后,将反应混合物过滤并浓缩。通过 硅胶层析(己烷/EtOAc)纯化残余物以得到产物6(54mg,43%产率)。在2分钟 色谱分析中,LC-MS tR=2.17分钟,MS(ESI)m/z 687.49[M+H]+。
步骤4
在0℃下,向二氯甲烷(1mL)中的6(34mg,0.05毫摩尔)溶液添加 TfOH(9μL,0.1毫摩尔)。在0℃下将反应混合物搅拌15分钟,然后用饱和 NaHCO3溶液中和。将混合物用DCM(3×10mL)萃取,合并的有机层在无水 Na2SO4上干燥,在真空下过滤并浓缩。通过硅胶层析(己烷/EtOAc=1/1)纯化 残余物以得到标题化合物(15mg,70%产率)。在2分钟色谱分析中,LC-MS tR =1.70分钟,MS(ESI)m/z 447.03[M+H]+。1H NMR(CD3OD 400MHz):δ 8.31(s,1H),7.78(d,J=8.8Hz,1H),7.42-7.41(m,1H),7.22-7.05(m,2H),7.03 (d,J=9.6Hz,1H),4.45(d,J=13.2Hz,1H),4.32(d,J=8.4Hz,1H),3.83(d,J =12.4Hz,1H),3.62(d,J=8.4Hz,1H),3.48-3.41(m,1H),2.90-2.81(m,2H), 2.80-2.53(m,1H),1.13(d,J=6.8Hz,3H),0.84(d,J=6.8Hz,3H)。
实施例19
(R)-(2-(4-(4-(羟甲基)-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧 啶-5-基)甲醇(化合物编号19-1)
步骤1
向甲苯(7mL)中的胺7(740mg,3.0毫摩尔)、溴化物8(1.05g,3.6毫摩尔)、 Xphos(160mg,0.33毫摩尔)和碳酸铯(2.93g,9.0毫摩尔)混合物添加 Pd2(dba)3(140mg,0.15毫摩尔)。将混合物用氮气净化并将试管密封。将其在 100℃的油浴中加热10小时。冷却至室温后,将反应混合物过滤并浓缩。通 过硅胶层析(EtOAc/己烷=40/60)纯化残余物以得到偶联产物9(1.17g,86%产 率)。在2分钟色谱分析中,LC-MS tR=1.66分钟,MS(ESI)m/z 463[M+23]+。
步骤2
在0℃下,向二氯甲烷(10mL)中的9(1.17g,2.65毫摩尔)溶液添加 TFA(2mL)。将反应混合物在室温下搅拌1小时。在反应完成后,将反应混合 物用饱和NaHCO3中和,并用EtOAc(3×25mL)萃取。将有机层在盐水、无 水Na2SO4上干燥,过滤,浓缩以得到粗游离胺10,其不经进一步纯化直接 用于下一步骤。在2分钟色谱分析中,LC-MS tR=0.65分钟,MS(ESI)m/z 341.2[M+H]+。
步骤3
向DMSO(5.5mL)中的10(2.65毫摩尔,来自步骤2)溶液添加2-氯-4-(三 氟甲基)嘧啶-5-羧酸乙酯(1.35g,5.3毫摩尔)和DIEA(1.4mL,7.95毫摩尔)。 在60℃下,使混合物搅拌2小时。在反应完成后,用H2O(30mL)稀释混合物 并用EtOAc萃取(2×30mL)。将有机层用盐水清洗,在无水Na2SO4上干燥, 在真空中过滤并浓缩。通过硅胶层析(EtOAc/己烷=30/70)纯化残余物以提供 产物11(1.39g,94%产率)。在2分钟色谱分析中,LC-MS tR=1.88分钟,MS(ESI)m/z 559.3[M+H]+。
步骤4
在0℃下,向干燥甲苯(45mL)中的11(1.39g,2.5毫摩尔)溶液缓慢添加二 异丁基氢化铝(甲苯中的1.0M,15mL,15毫摩尔)。在添加后,将混合物在0℃ 下搅拌2小时,用NH4Cl溶液(5mL)淬灭。将反应混合物倒入酒石酸钾钠 (1.0M,40mL)的剧烈搅拌溶液中,剧烈搅拌直到两相清晰分离。分离有机层, 并用EtOAc萃取水层(3×30mL)。将有机层用盐水清洗,在无水Na2SO4上干 燥,在真空下过滤并浓缩。通过硅胶层析(EtOAc/己烷=60/40)纯化粗产物得 到标题化合物(960mg,79%产率)。在2分钟色谱分析中,LC-MS tR=1.48 分钟,MS(ESI)m/z 489.3[M+H]+。1H NMR(CD3OD 400MHz):δ8.61(s, 1H),7.56(d,J=2.4Hz,1H),7.54(d,J=8.4Hz,1H),7.27(dd,J1=2.4Hz J2= 8.4Hz,1H),4.91(s,2H),4.86-4.84(m,1H),4.70(d,J=10.4Hz,1H),4.61(s, 2H),3.97(d,J=12.4Hz,1H),3.75(d,J=10.4Hz,1H),3.40-3.33(m,1H),3.22 (s,3H),2.94-2.83(m,2H),2.50-2.41(m,1H),1.13(d,J=6.8Hz,3H),0.82(d,J =6.8Hz,3H)。
使用相似过程制备以下化合物。
实施例20
(R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基-1-(5-(三氟甲基)吡啶-3-基)哌嗪(化 合物编号20-1)
将(R)-1-(4-氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪(20mg,0.067毫摩尔)、 3-溴-5-(三氟甲基)吡啶(19mg,0.085毫摩尔)、叔丁醇钠(10mg,0.1毫摩尔)、 Pd(t-Bu3)2(4mg,0.009毫摩尔)和干燥甲苯(1mL)的搅拌混合物置于N2气氛下, 在100℃的油浴中加热1天。浓缩后,在MeCN(2mL)、H2O(0.5mL)和HOAc(3 滴)中采集残余物,过滤并通过制备型HPLC纯化,得到油状物的标题化合物 (0.6mg,2.5%)。LC-MS法4tR=0.95分钟,m/z=446。1H NMR(CD3OD)δ 0.86(d,3H),1.10(d,3H),2.42-2.55(m,1H),2.95-3.10(m,2H),3.23(s,3H),3.50-3.65(m,2H),3.78-3.91(m,3H),7.22-7.32(m,2H),7.39-7.44(m,1H),7.61 (m,1H),8.12(m,1H),8.48(m,1H)。
使用相似过程制备以下化合物。
实施例21
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)吡啶-3-胺 (化合物编号21-1)
向甲醇(1mL)和水(1mL)中的(R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基 -1-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪(10mg,0.02毫摩尔)搅拌溶液添加铁 粉(36mg,0.75毫摩尔)和NH4Cl(22mg,0.4毫摩尔)。将混合物在70℃的油 浴中加热1.5小时,冷却至室温,用甲醇(1mL)稀释,过滤并通过制备型HPLC 纯化以得到其TFA盐的标题化合物(1.4mg,10%)。LC-MS法4tR=1.03分 钟,461。
实施例22
(R)-5-氯-4-环丙基-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)嘧啶(化 合物编号22-1)和(R)-5-氯-2-(4-(2-氯-4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪 -1-基)-4-环丙基嘧啶(化合物编号22-2)
将DMF(0.5mL)中的(R)-4-环丙基-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙 基哌嗪-1-基)嘧啶TFA盐(14mg,0.026毫摩尔)和N-氯代琥珀酰亚胺(5.3mg, 0.04毫摩尔)搅拌溶液在100℃的微波下加热2小时。将混合物用甲醇稀释, 并通过制备型HPLC纯化以得到两种产物。
油状物的(R)-5-氯-4-环丙基-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪 -1-基)嘧啶(0.7mg)。LC-MS法4tR=1.17分钟,m/z=455,453。1H NMR (CD3OD)δ0.89(d,3H),1.05-1.17(m,7H),2.32-2.47(m,1H),2.72-2.87(m, 2H),3.22(s,3H),3.25-3.35(m,2H),3.53(m,1H),3.76-3.83(m,1H),4.50-4.57 (m,1H),4.66-4.76(m,1H),7.22-7.32(m,2H),7.36-7.39(m,1H),8.09(s,1H)。
油状物的(R)-5-氯-2-(4-(2-氯-4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-环丙基嘧啶(3.9mg,%)。LC-MS法4tR=1.19分钟,m/z=491,490,489, 488,487。1HNMR(CD3OD)δ0.88(d,3H),1.04(d,3H),1.05-1.18(m,4H), 2.32-2.39(m,1H),2.65-2.80(m,2H),2.81-2.87(m,1H),3.17-3.33(m,3H),3.37 (s,3H),4.49-4.55(m,1H),4.66-4.71(m,1H),7.24-7.32(m,1H),7.48-7.54(m, 1H),8.09(s,1H)。
使用相似过程制备以下化合物。
实施例23
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-异丙基-6-(三氟甲基) 嘧啶(化合物编号23-1)
将二氧六环中的2-((4-氟苄基)磺酰基)-4-异丙氧基-6-(三氟甲基)嘧啶 (37mg,0.098毫摩尔)和(R)-1-(4-氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪(29mg, 0.097毫摩尔)溶液在120℃的微波下加热12小时。制备型HPLC提供油状物 的标题化合物(4.4mg,9%)。LC-MS法4tR=1.25分钟,m/z=505。1H NMR (CD3OD)δ0.93(d,3H),1.11(d,3H),1.38(d,6H),2.40-2.55(m,1H), 2.75-2.90(m,3H),3.22(s,3H),3.59-3.66(m,1H),3.81-3.85(m,1H),4.60-4.67 (m,1H),4.77-4.84(m,1H),5.32-5.40(m,1H),6.19(s,1H),7.23-7.43(m,3H)。
实施例24
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-6-(三氟甲基)嘧啶-4-醇 (化合物编号24-1)
向冰HOAc(0.1mL)中的(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪 -1-基)-4-异丙氧基-6-(三氟甲基)嘧啶(3.8mg)搅拌溶液添加浓H2SO4(0.1mL)。 将混合物在90℃下加热15分钟。制备型HPLC提供油状物的标题化合物 (0.9mg)。LC-MS法4tR=0.94分钟,m/z=463。
实施例25
(R)-2-(2-(4-(4-(羟甲基)-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基) 嘧啶-5-基)-2-甲基丙腈(化合物编号25-1)
步骤1
在N2下,向无水甲苯(10mL)中的(R)2-(4-(叔丁氧基羰基)-2-异丙基哌嗪 -1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯(600mg,1.34毫摩尔)溶液添加 DIBAL-H(2.01mL,2.01毫摩尔,甲苯中的1M)。在-78℃下搅拌反应混合物 30分钟。在-78℃下用饱和NH4Cl溶液(10mL)淬灭反应混合物。过滤混合物, 然后将滤液用水(50mL)稀释并用EtOAc(3×50mL)萃取。将合并的有机层用 盐水(100mL)清洗,在无水Na2SO4上干燥,在减压下过滤并浓缩。通过在硅 胶上的柱层析纯化残余物,得到黄色油状物的(R)4-(5-羟甲基)-4-(三氟甲基) 嘧啶-2-基)-3-异丙基哌嗪-1-羧酸叔丁酯(457mg,84%)。
步骤2
在N2下,向无水CH2Cl2(6mL)中的(R)4-(5-(羟甲基)-4-(三氟甲基)嘧啶-2- 基)-3-异丙基哌嗪-1-羧酸叔丁酯(450mg,1.11毫摩尔)和Et3N(561.7mg,5.55 毫摩尔)溶液添加MsCl(254.2mg,2.22毫摩尔)。在室温下搅拌反应混合物8 小时。向混合物添加水(30mL)并用EtOAc(3×30mL)萃取。将合并的有机层用 盐水(50mL)清洗,在无水Na2SO4上干燥,在减压下过滤并浓缩。通过在硅 胶上的柱层析纯化残余物,得到黄色油状物的(R)4-(5-氯甲基)-4-(三氟甲基) 嘧啶-2-基)-3-异丙基哌嗪-1-羧酸叔丁酯(289.4mg,61%)。
步骤3
向DMF(3mL)中的(R)4-(5-(氯甲基)-4-(三氟甲基)嘧啶-2-基)-3-异丙基哌 嗪-1-羧酸叔丁酯(289mg,0.68毫摩尔)溶液添加NaCN(50mg,1.02毫摩尔)。 在室温下搅拌反应混合物3小时。向混合物添加水(20mL)中并用 EtOAc(3×20mL)萃取。将合并的有机层用盐水(50mL)清洗,在无水Na2SO4上干燥,在减压下过滤并浓缩。通过制备型TLC用4/1的石油醚/EtOAc纯化 残余物,得到黄色油状物的(R)4-(5-(氰基甲基)-4-(三氟甲基)嘧啶-2-基)-3-异 丙基哌嗪-1-羧酸叔丁酯(177mg,63%)。
步骤4
在-78℃下、在N2下,向无水THF(3mL)中的(R)4-(5-(氰基甲基)-4-(三氟 甲基)嘧啶-2-基)-3-异丙基哌嗪-1-羧酸叔丁酯(60mg,0.15毫摩尔)溶液添加 KHMDS(0.75mL,0.75毫摩尔,THF中的1M)。在-78℃下搅拌反应混合物 30分钟。然后向反应混合物添加MeI(85.2mg,0.6毫摩尔)。在室温下搅拌反 应混合物1小时。向混合物添加水(10mL)中并用EtOAc(3×10mL)萃取。将合 并的有机相用盐水(25mL)清洗,在无水Na2SO4上干燥,在减压下过滤并浓 缩。通过制备型TLC用5/1的石油醚/EtOAc纯化残余物,得到白色固体的 (R)4-(5-(2-氰基丙-2-基)-4-(三氟甲基)嘧啶-2-基)-3-异丙基哌嗪-1-羧酸叔丁酯 (60mg,94%)。
步骤5
向CH2Cl2(2.5mL)中的(R)4-(5-(2-氰基丙-2-基)-4-(三氟甲基)嘧啶-2- 基)-3-异丙基哌嗪-1-羧酸叔丁酯(20mg,0.0453毫摩尔)溶液添加TFA(0.5mL)。 在室温下将反应混合物搅拌1小时。在减压下浓缩混合物以提供黄色固体的 粗(R)-2-(2-(2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)-2-甲基丙腈TFA盐 (15mg,71%),其不经进一步纯化直接用于下一步骤。
步骤6
向无水甲苯(1mL)中的(R)-2-(2-(2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)-2-甲基丙腈TFA盐(15mg,0.044毫摩尔)、4-溴-2-(甲磺酰基)苄基乙酸酯 (16.3mg,0.053毫摩尔)、X-phos(4.2mg,8.8微摩尔)和Cs2CO3(115mg,0.352 毫摩尔)溶液添加Pd2(dba)3(9.8mg,8.8微摩尔)。在N2下、在100℃下将反应 混合物搅拌3小时。在减压下浓缩反应混合物以得到粗(R)-4-(4-(5-(2-氰基丙 -2-基)-4-(三氟甲基)嘧啶-2-基)-3-异丙基哌嗪-1-基)-2-(甲磺酰基)苄基乙酸酯, 其不经进一步纯化直接用于下一步骤。
步骤7
向H2O(0.5mL)和CH3OH(0.5mL)中的(R)-4-(4-(5-(2-氰基丙-2-基)-4-(三氟 甲基)嘧啶-2-基)-3-异丙基哌嗪-1-基)-2-(甲磺酰基)苄基乙酸酯(0.044毫摩尔) 添加NaOH(18mg,0.44毫摩尔)。在室温下搅拌反应混合物1小时。向混合 物添加水(10mL)中并用EtOAc(3×10mL)萃取。将合并的有机层用盐水(25mL) 清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩。通过碱性制备型HPLC 纯化残余物以得到白色固体的(R)-2-(2-(4-(4-羟甲基)-3-(甲磺酰基)苯基)-2-异 丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)-2-甲基丙腈(5.3mg,23%)。在2分钟 色谱分析中,LC-MS tR=1.214分钟,MS(ESI)m/z 526.2[M+H]+。1HNMR (CD3OD):δ8.73(s,1H),7.56-7.54(m,2H),7.27(dd,J1=2.4,8.4Hz,1H),4.91 (s,2H),4.86-4.80(m,1H),4.67(d,J=9.6Hz,1H),3.97(d,J=12.4Hz,1H), 3.76(d,J=12.0Hz,1H),3.42-3.38(m,1H),3.28(s,3H),2.94-2.83(m,2H), 2.51-2.41(m,1H),1.84(s,6H),1.14(d,J=6.4Hz,3H),0.83(d,J=6.4Hz, 3H)。
实施例26
(R)-2-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)噻唑 -5-基)丙-2-醇(化合物编号26-1)
步骤1
向甲苯(5mL)中的2-溴-4-(三氟甲基)噻唑-5-羧酸乙酯(100mg,0.33摩尔) 和(R)-1-(4-氟-3-(甲磺酰基)苯基)-3-异丙基哌嗪(99mg,0.33毫摩尔)溶液添加 X-phos(7.6mg,0.016毫摩尔)、Pd2dba3(15mg,0.016毫摩尔)和碳酸铯(326mg, 1毫摩尔)。在N2下,在100℃下将混合物搅拌3小时。向混合物添加水(20mL) 并用EtOAc萃取(3×30mL)。将合并有机相在无水Na2SO4上干燥,过滤,在 减压条件下浓缩。通过制备型TLC用2/1的石油醚/EtOAc纯化残余物,得到 (R)2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-羧 酸乙酯(60mg,35%)。
步骤2:
在N2下、在0℃下向THF(2mL)中(R)2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异 丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-羧酸乙酯(30mg,57微摩尔)溶液添加 MeMgBr(0.19mL,0.57毫摩尔,Et2O中的3M)。然后在室温下搅拌反应混合 物2小时。将混合物用饱和的NH4Cl溶液(10mL)淬灭,用EtOAc(3×20mL) 萃取。将合并的有机层在无水Na2SO4上干燥,过滤,在减压条件下浓缩。通 过制备型TLC用3/1的石油醚/EtOAc纯化残余物以得到标题化合物(9.00mg, 31%)。在2分钟色谱分析中,LC-MS tR=1.271分钟,m/z 510.1[M+H]+。 1H NMR(CD3OD):δ7.20(dd,J=3.2,5.6Hz,1H),7.38-7.26(m,2H),4.06(d, J=13.6Hz,1H),3.81(d,J=12.4Hz,1H),3.72(d,J=10.8Hz,1H),3.60(d,J= 11.6Hz,1H),3.53-3.47(m,1H),3.26(s,3H),2.98-2.88(m,2H),2.52-2.48(m, 1H),1.61(s,6H),1.11(d,J=6.8Hz,3H),0.97(d,J=6.8Hz,3H)。
使用相似过程制备以下化合物。
实施例27
(R)-2-(2-(4-(4-(羟甲基)-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基) 噻唑-5-基)丙-2-醇(化合物编号27-1)
步骤1
向甲苯(10mL)中的(R)3-异丙基哌嗪-1-羧酸叔丁酯(413mg,1.81摩尔)和 2-溴-4-(三氟甲基)噻唑-5-羧酸乙酯(550mg,1.81毫摩尔)溶液添加 X-phos(43mg,0.09毫摩尔)、Pd2dba3(82mg,0.09毫摩尔)和碳酸铯(2.94g, 9.05毫摩尔)。在N2下、在90℃下将混合物搅拌4小时。向混合物添加水(20mL) 并用EtOAc(3×30mL)萃取。将合并的有机层在无水Na2SO4上干燥,过滤, 在减压条件下浓缩。通过制备型TLC用二氯甲烷纯化残余物,得到(R)2-(4-(叔 丁氧基羰基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-羧酸乙酯(140mg,17%)。
步骤2
在0℃下向二氯甲烷(8mL)中的(R)2-(4-(叔丁氧基羰基)-2-异丙基哌嗪-1- 基)-4-(三氟甲基)噻唑-5-羧酸乙酯(140mg,0.31毫摩尔)溶液添加TFA(2mL)。 在室温下搅拌混合物2小时。将反应混合物在减压下浓缩,向残余物添加饱 和NaHCO3溶液(10mL)并用EtOAc(3×20mL)萃取。合并的有机层在无水 Na2SO4上干燥,过滤并在减压下浓缩以得到粗(R)2-(2-异丙基哌嗪-1- 基)-4-(三氟甲基)噻唑-5-羧酸乙酯(120mg,100%)。
步骤3
向甲苯(5mL)中的(R)2-(2-异丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-羧酸乙 酯(120mg,0.34摩尔)和4-溴-2-(甲磺酰基)苄基醋酸酯(104.6mg,0.34毫摩尔) 溶液添加X-phos(8.1mg,0.017毫摩尔)、Pd2dba3(15.7mg,0.017毫摩尔)和碳 酸铯(331.5mg,1.02毫摩尔)。在N2下、在90℃下将混合物搅拌4小时。向 混合物添加水(20mL)并用EtOAc(3×30mL)萃取。将合并的有机层在无水 Na2SO4上干燥,过滤并在减压条件下浓缩。通过制备型TLC用2/1的石油 醚/EtOAc纯化残余物,得到(R)2-(4-(4-(乙酰氧基甲基)-3-(甲磺酰基)苯基)-2- 异丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-羧酸乙酯(80mg,41%)。
步骤4
在N2下、在-78℃下向THF(1mL)中的(R)2-(4-(4-(乙酰氧基甲基)-3-(甲磺 酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-羧酸乙酯(25mg,43微摩 尔)溶液添加MeLi(0.268mL,0.43毫摩尔,1.3M)。在N2下、在-78℃下将混 合物搅拌2小时。将混合物用饱和NH4Cl溶液(10mL)淬灭并用EtOAc(3×20mL) 萃取。将合并的有机层在无水Na2SO4上干燥,过滤并在减压条件下浓缩。通 过碱性制备型HPLC纯化残余物以得到(R)-2-(2-(4-(4-(羟甲基)-3-(甲磺酰基) 苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)噻唑-5-基)丙-2-醇(0.4mg,1.8%)。在 2分钟色谱分析中,LC-MS tR=1.197分钟,m/z 522.2[M+H]+。1H NMR(CD3OD):δ7.57-7.55(m,2H),7.29-7.26(m,1H),4.88(s,2H),4.07-4.03(m, 1H),3.94-3.91(m,1H),3.74-3.65(m,2H),3.53-3.50(m,1H),3.22(s,3H), 3.03-2.97(m,2H),2.39-2.47(m,1H),1.62-1.60(m,6H),1.13-1.09(m,3H), 0.97-0.92(m,3H)。
实施例28
(R)-(2-(2-异丙基-4-(3-(甲磺酰基)-4-(4-甲基噻唑-2-基)苯基)哌嗪-1-基)-4-(三 氟甲基)嘧啶-5-基)甲醇(化合物编号28-1)
步骤1
向THF(1L)中的4-溴-2-氟苯甲酸甲酯(25g,0.11摩尔)溶液添加 NaSMe(11.3g,0.16摩尔)。在回流下搅拌混合物过夜。向混合物添加水(1L), 将混合物在减压下浓缩。用EtOAc(3×500mL)萃取水层。将合并的有机层用 盐水(500mL)清洗,在无水Na2SO4上干燥,过滤并浓缩以得到白色固体的粗 4-溴-2-(甲硫基)苯甲酸甲酯(粗25.6g,90%),其不经进一步纯化直接用于下 一步骤。1H NMR(DMSO-d6):δ7.82(dd,J=2.8,8.4Hz,1H),7.48(s,1H),7.45(dd,J=1.6,6.4Hz,1H),3.83(s,3H),2.46(s,3H)。
步骤2
向CH2Cl2(500mL)中的4-溴-2-(甲硫基)苯甲酸甲酯(粗10.8g,0.041摩尔) 溶液添加m-CPBA(21.4g,0.124摩尔)。在室温下搅拌该混合物过夜。将混合 物相继用饱和Na2S2O3溶液(300mL)、饱和NaHCO3溶液(300mL)和盐水 (300mL)冲洗,在无水Na2SO4上干燥,过滤并在减压下浓缩。通过在硅胶层 析柱上用石油醚:EtOAc 3:1洗脱以纯化残余物,得到白色固体的4-溴-2-(甲磺 酰基)苯甲酸甲酯(7.9g,65%)。1H NMR(CDCl3):δ8.28(d,J=2.0Hz,1H),7.82 (dd,J=2.0,8.4Hz,1H),7.60(d,J=8.0Hz,1H),3.97(s,3H),3.37(s,3H)。
步骤3
向甲醇(3mL)和H2O(1mL)中的4-溴-2-(甲磺酰基)苯甲酸甲酯(1.0g,3.4 毫摩尔)溶液添加NaOH(410mg,10.2毫摩尔)。将混合物在60℃下搅拌4h。 在减压下浓缩混合物,将混合物用1N HCl溶液调节至pH=4。用EtOAc (3×20mL)萃取水层。合并的有机层用盐水清洗,在无水Na2SO4上干燥,过 滤并在减压下浓缩以得到白色固体的粗4-溴-2-(甲磺酰基)苯甲酸(粗800mg, 84%),其不经进一步纯化直接用于下一步骤。在2分钟色谱分析中,LC-MStR=0.850分钟。MS(ESI)m/z 262.9[M+H–H2O]+,300.9[M+Na]+。1H NMR(DMSO-d6):δ8.08(d,J=2.0Hz,1H),8.02(dd,J=2.0,8.0Hz,1H), 7.68(d,J=8.4Hz,1H),3.42(s,3H)。
步骤4
向DMF(20mL)中的4-溴-2-(甲磺酰基)苯甲酸(粗1.4g,5.0毫摩尔)溶液 添加HATU(2.85g,7.5毫摩尔)、NH4Cl(800mg,15毫摩尔)和DIPEA(1.94g, 15毫摩尔)。在室温下搅拌该混合物过夜。向混合物添加水(40mL)并用 EtOAc(3×50mL)萃取。将合并的有机层用水(3×50mL)和盐水清洗,在无水 Na4SO4上干燥,过滤并在减压下浓缩。通过在硅胶层析柱上用石油醚:EtOAc 1:5洗脱纯化残余物,得到白色固体的粗4-溴-2-(甲磺酰基)苯甲酰胺(1.1g, 79%)。在2分钟的色谱分析中,LC-MS tR=0.663分钟,MS(ESI)m/z 277.9 [M+H]+。
步骤5
向甲苯(1mL)中的4-溴-2-(甲磺酰基)苯甲酰胺(20mg,0.072毫摩尔)溶液 添加劳森试剂(87mg,0.22毫摩尔)。在100℃下搅拌混合物2小时。将混合 物过滤,将滤液在减压下浓缩。通过制备型TLC纯化残余物,得到黄色固体 的4-溴-2-(甲磺酰基)硫代苯甲酰胺(15.0mg,71%)。在2分钟的色谱分析中, LC-MS tR=0.874分钟,MS(ESI)m/z 293.9[M+H]+。
步骤6
向乙醇(1mL)中的4-溴-2-(甲磺酰基)硫代苯甲酰胺(20mg,0.068毫摩尔) 溶液添加1-氯丙-2-酮(13mg,0.136毫摩尔)。在回流下搅拌混合物过夜。在 减压下浓缩混合物以得到黄色油状物的粗2-(4-溴-2-(甲磺酰基)苯基)-4-甲基 噻唑(粗17mg,75%),其不经进一步纯化直接用于下一步骤。在2分钟的色 谱分析中,LC-MS tR=1.117分钟,MS(ESI)m/z331.9[M+H]+。
步骤7
向甲苯(1mL)中的2-(4-溴-2-(甲磺酰基)苯基)-4-甲基噻唑(17.0mg,0.051 毫摩尔)溶液添加(R)2-(2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯 (18mg,0.051毫摩尔)、X-phos(5.0mg,0.010毫摩尔)、Pd2dba3(5mg,0.005 毫摩尔)和Cs2CO3(50mg,0.154毫摩尔)。在回流下搅拌混合物过夜。向混合 物添加水(10mL)并用EtOAc(3×10mL)萃取。将合并的有机层用盐水冲洗,在 无水Na2SO4上干燥,过滤并在减压下浓缩。通过制备型TLC纯化残余物, 得到黄色固体的(R)2-(2-异丙基-4-(3-(甲磺酰基)-4-(4-甲基噻唑-2-基)苯基)哌 嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯(15.0mg,49%)。在2分钟的色谱分析 中,LC-MS tR=1.442分钟。MS(ESI)m/z 598.1[M+H]+。
步骤8
在N2下、在-78℃下向甲苯(1mL)中的(R)2-(2-异丙基-4-(3-(甲磺酰 基)-4-(4-甲基噻唑-2-基)苯基)哌嗪-1-基)-4-(三氟甲基)嘧啶-5-羧酸乙酯 (15mg,0.025毫摩尔)溶液添加DIBAL-H(0.075mL,0.075毫摩尔,甲苯中 1M)。在-78℃下搅拌混合物2小时。添加饱和NH4Cl溶液(5mL)并将混合物 过滤。用EtOAc(3×10mL)萃取滤液。将合并的有机层用盐水冲洗,在无水 Na2SO4上干燥,过滤并在减压下浓缩。通过制备型TLC纯化残余物,得到 白色固体的(R)-(2-(2-异丙基-4-(3-(甲磺酰基)-4-(4-甲基噻唑-2-基)苯基)哌嗪 -1-基)-4-(三氟甲基)嘧啶-5-基)甲醇(14.50mg,63%)。在2分钟色谱分析中, LC-MS tR=1.268分钟。MS(ESI)m/z 556.2[M+H]+。1H NMR(CDCl3):δ 8.55(s,1H),7.69(d,J=2.8Hz,1H),7.47(d,J=8.4Hz,1H),7.06(dd,J=2.8, 8.4Hz,1H),6.98(s,1H),4.84(d,J=13.6Hz,1H),4.70-4.68(m,3H),3.94(d,J =12.4Hz,1H),3.76(d,J=12.0Hz,1H),3.50(s,3H),3.39-3.32(m,1H), 3.07-2.97(m,2H),2.48(s,3H),2.39-2.33(m,1H),1.89(brs,1H),1.11(d,J= 6.4Hz,3H),0.83(d,J=6.4Hz,3H)。
实施例29
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-甲氧基-4-(三氟甲基) 嘧啶(化合物编号29-1)
步骤1
在N2下,向二氧六环(3mL)中的(R)4-(5-溴-4-(三氟甲基)嘧啶-2-基)-3-异 丙基哌嗪-1-羧酸苄酯(250mg,0.514毫摩尔)、4,4,4',4',5,5,5',5'-八甲基-2,2'- 双(1,3,2-二氧硼戊环)(196mg,0.77毫摩尔)和KOAc(151mg,1.54毫摩尔)溶 液添加Pd(dppf)Cl2(19mg,0.026毫摩尔)。在100℃下搅拌反应混合物2小时。 过滤混合物,向滤液添加水(10mL)并用EtOAc(3×10mL)萃取。将合并的有机 层用盐水清洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制备 型TLC用石油醚:EtOA=8:1纯化粗产物以得到黄色油状物的(R)3-异丙基 -4-(5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2基)-4-(三氟甲基)嘧啶-2-基)哌嗪-1- 羧酸苄酯(240mg,88%)。
步骤2
向THF(2mL)中的(R)3-异丙基-4-(5-(4,4,5,5-四甲基-1,3,2-二氧硼戊环-2-基)-4-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸苄酯(250mg,0.47毫摩尔)和 AcOH(1mL)溶液添加H2O2(5mL)。在室温下搅拌反应混合物3小时。在用饱 和Na2S2O3溶液淬灭反应后,将混合物用EtOAc(3×20mL)萃取。将合并的有 机层用饱和Na2S2O3溶液清洗,在无水Na2SO4上干燥,过滤并浓缩以得到 (R)4-(5-羟基-4-(三氟甲基)嘧啶-2-基)-3-异丙基哌嗪-1-羧酸苄酯(180mg, 90%),其不经进一步纯化直接用于下一步骤。
步骤3
在N2下,向DMF(5mL)中的(R)4-(5-羟基-4-(三氟甲基)嘧啶-2-基)-3-异丙 基哌嗪-1-羧酸苄酯(180mg,0.42毫摩尔)和K2CO3(290mg,2.1毫摩尔)溶液 添加MeI(89.5mg,0.63毫摩尔)。在室温下搅拌反应混合物2小时。将反应 混合物用水(20mL)处理并用EtOAc(3×20mL)萃取。将合并的有机层用盐水清 洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制备型TLC用 石油醚:EtOAc=3:1纯化粗产物以得到黄色油状物的(R)3-异丙基-4-(5-甲氧基 -4-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸苄酯(80mg,43%)。
步骤4
在室温下将HBr/AcOH(6mL)中的(R)3-异丙基-4-(5-甲氧基-4-(三氟甲基) 嘧啶-2-基)哌嗪-1-羧酸苄酯(75mg,0.17毫摩尔)溶液搅拌1小时。将反应混 合物用水(10mL)处理并用EtOAc(3×10mL)萃取。将含水层用饱和NaHCO3溶 液调节至pH=8-9,用EtOAc(3×10mL)萃取。将合并的有机层用盐水清洗,在 无水Na2SO4上干燥,过滤并浓缩以得到(R)-2-(2-异丙基哌嗪-1-基)-5-甲氧基 -4-(三氟甲基)嘧啶,其不经进一步纯化直接用于下一步骤。
步骤5
在N2下,向无水甲苯(1mL)中的(R)-2-(2-异丙基哌嗪-1-基)-5-甲氧基 -4-(三氟甲基)嘧啶(15mg,49微摩尔)、4-溴-1-氟-2-(甲磺酰基)苯(15mg,59 微摩尔)、Cs2CO3(128mg,392微摩尔)和X-phos(1.2mg,2.5微摩尔)在混合 物添加Pd2(dba)3(3mg,2.5微摩尔)。在100℃下搅拌反应混合物5小时。过 滤混合物,向滤液添加水(10mL)并用EtOAc(3×10mL)萃取。将合并的有机层 用盐水清洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制备型 TLC用石油醚:EtOAc=3:1纯化粗产物,得到白色固体的(R)-2-(4-(4-氟-3-(甲 磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-甲氧基-4-(三氟甲基)嘧啶(17.00mg, 72%)。在2分钟色谱分析中,LC-MS tR=1.328分钟,MS(ESI)m/z 477.1 [M+H]+。1H NMR(CD3OD):δ8.49(s,1H),7.48-7.41(m,1H),7.38-7.26(m, 2H),4.89-4.74(m,1H),4.63-4.59(m,1H),3.92(s,3H),3.84(d,J=12.4Hz, 1H),3.73-3.61(m,1H),3.39-3.33(m,1H),3.25(s,3H),2.89-2.78(m,2H), 2.54-2.45(m,1H),1.13(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H)。
实施例30
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-醇 (化合物编号30-1)
步骤1
在N2下、在-78℃下向无水CH2Cl2(0.5mL)中的(R)-2-(4-(4-氟-3-(甲磺酰 基)苯基)-2-异丙基哌嗪-1-基)-5-甲氧基-4-(三氟甲基)嘧啶(10mg,21微摩尔) 溶液添加BBr3(0.5mL)。在-78℃下搅拌反应混合物3小时,然后在室温下搅 拌17小时。在-78℃下用甲醇(1mL)淬灭反应后,向混合物添加水(10mL),含 水层用EtOAc(3×10mL)萃取。将合并的有机层用盐水清洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制备型TLC用石油醚:EtOAc=1:1 纯化粗产物,得到白色固体的(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪 -1-基)-4-(三氟甲基)嘧啶-5-醇(1.60mg,17%)。在2分钟色谱分析中,LC-MS tR=1.215分钟,MS(ESI)m/z 463.1[M+H]+。1H NMR(CD3OD):δ8.24(s, 1H),7.42-7.38(m,1H),7.36-7.25(m,2H),4.70(d,J=13.2Hz,1H),4.56(d,J= 10.0Hz,1H),3.83(d,J=12.0Hz,1H),3.61(d,J=12.0Hz,1H),3.25(s,3H), 2.88-2.77(m,3H),2.56-2.43(m,1H),1.12(d,J=6.8Hz,3H),0.83(d,J=6.8 Hz,3H)。
实施例31
(R)-2-4-((2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧 啶-5-基)甲基)苯基)丙-2-醇(化合物编号31-1)
步骤1
在-78℃下、在N2下,向THF(5mL)中的(R)-4-(5-溴-4-(三氟甲基)嘧啶-2- 基)-3-异丙基哌嗪-1-羧酸苄酯(250mg,0.51毫摩尔)溶液滴加n-BuLi(0.72mL, 0.67毫摩尔,己烷中2.5M)。在-78℃下将混合物搅拌5分钟,在N2下,在-78℃ 下添加4-甲酰基苯甲酸甲酯(93mg,0.57毫摩尔)。在-78℃下搅拌混合物30 分钟。在-78℃下用饱和NH4Cl溶液(5mL)淬灭反应。用EtOAc(3×10mL)萃取 含水层。将合并的有机层用盐水(20mL)清洗,在无水Na2SO4上干燥,过滤 并在减压下浓缩。通过制备型TLC(石油醚/EtOAc 3/1)纯化残余物,得到白色固体的(3R)-4-(5-(羟基(4-(甲氧基羰基)苯基)甲基)-4-(三氟甲基)嘧啶-2-基)-3- 异丙基哌嗪-1-羧酸苄酯(100mg,34%)。在10-80AB_2MIN.M色谱分析中 (Welch Xtimate C18,2.1*30mm,3um),LC-MS tR=1.395分钟,MS(ESI)m/z 573.2[M+H]+。
步骤2
在N2下,向CH2Cl2(0.5mL)中的(3R)-4-(5-(羟基(4-(甲氧基羰基)苯基)甲 基)-4-(三氟甲基)嘧啶-2-基)-3-异丙基哌嗪-1-羧酸苄酯(100mg,0.17毫摩尔) 溶液添加Et3SiH(0.5mL)和TFA(0.5mL)。在室温下将混合物搅拌4小时。过 滤形成的混合物,在减压下浓缩滤液以提供黄色固体的粗(R)3-异丙基 -4-(5-(4-(甲氧基羰基)苄基)-4-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸苄酯(90mg, 95%),其不经进一步纯化直接用于下一步骤。在10-80AB_2MIN.M色谱分析 中(Welch Xtimate C18,2.1*30mm,3um),LC-MS tR=1.605分钟,MS(ESI) m/z 557.2[M+H]+。
步骤3
向EtOAc(2mL)中的(R)3-异丙基-4-(5-(4-(甲氧基羰基)苄基)-4-(三氟甲基) 嘧啶-2-基)哌嗪-1-羧酸苄酯(20mg,0.036毫摩尔)溶液添加Pd/C(15mg,10%, 重量/重量)。在室温下,在H2下(30psi)搅拌混合物过夜。过滤混合物,在减 压下将混合物浓缩以提供黄色固体的粗(R)-4-((2-(2-异丙基哌嗪-1-基)-4-(三 氟甲基)嘧啶-5-基)甲基)苯甲酸甲酯(15mg,100%),其不经进一步纯化直接用 于下一步骤。在10-80AB_2MIN.M色谱分析中(Xtimate C18,2.1*30mm,3 um),LC-MS tR=1.031分钟,MS(ESI)m/z 423.2[M+H]+。
步骤4
向甲苯(3mL)中的(R)4-((2-(2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基) 甲基)苯甲酸甲酯(60mg,0.14毫摩尔)溶液添加4-溴-1-氟-2-(甲磺酰基)苯 (72mg,0.28毫摩尔)、X-phos(14mg,0.03毫摩尔)、Cs2CO3(139mg,0.43毫 摩尔)和Pd2(dba)3(26mg,0.03毫摩尔)。在100℃下搅拌混合物过夜。向混合 物添加水(5mL)并用EtOAc(3×5mL)萃取。将合并的有机层用盐水(15mL)清 洗,在无水Na2SO4上干燥,过滤并在减压下浓缩。通过制备型TLC用石油 醚/EtOAc 3/1纯化残余物,得到(R)-4-((2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲基)苯甲酸甲酯(47mg,56%)。在 10-80AB_2MIN.M色谱分析中(Welch Xtimate C18,2.1*30,mm,3um),LC-MS tR=1.444分钟,MS(ESI)m/z 595.2[M+H]+。
步骤5
在N2下,在0℃下向THF(25mL)中的(R)4-((2-(4-(4-氟-3-(甲磺酰基)苯 基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲基)苯甲酸甲酯(10mg, 0.017毫摩尔)溶液滴加MeMgBr(0.06mL,0.17毫摩尔,THF中3M)。在室温 下搅拌混合物2小时。将混合物用饱和NH4Cl溶液(5mL)淬灭并用 EtOAc(3×10mL)萃取。将合并的有机层用盐水(20mL)清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩。通过制备型TLC用石油醚/EtOAc 3/1纯化残 余物,用中性制备型HPLC分离以得到白色固体的(R)-2-(4-((2-(4-(4-氟-3-(甲 磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲基)苯基)丙-2-醇 (3.30mg,33%)。在10-80AB_2min色谱分析中(Welch Shim-pack XR-ODS, 3.0*30mm,3um),LC-MS tR=1.270分钟,MS(ESI)m/z 595.4[M+H]+。 1H NMR(CDCl3):δ8.21(s,1H),7.44-7.41(m,3H),7.18-7.12(m,4H),4.81(d, J=12.8Hz,1H),4.63(d,J=10.0Hz,1H),3.96(s,2H),3.72(d,J=12.4Hz, 1H),3.53(d,J=11.6Hz,1H),3.35-3.28(m,1H),3.22(s,3H),2.91-2.79(m, 2H),2.51-2.40(m,1H),1.58(s,6H),1.10(d,J=6.4Hz,3H),0.83(d,J=6.4Hz, 3H)。
实施例32
(R)-4-((2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶 -5-基)甲基)苯甲酸(化合物编号32-1)
向MeOH(1mL)和H2O(0.3mL)中的(R)4-((2-(4-(4-氟-3-(甲磺酰基)苯 基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲基)苯甲酸甲酯(10mg, 0.017毫摩尔)溶液添加NaOH(6.7mg,0.17毫摩尔)。在室温搅拌该混合物过 夜。向混合物添加水(5mL)并用1NHCl溶液调节至pH=5。用EtOAc(3×5mL) 萃取含水层。用盐水(15mL)清洗合并的有机层,在无水Na2SO4上干燥,过 滤并在减压下浓缩。通过制备型TLC(石油醚/EtOAc 3/1)和TFA制备型HPLC 分离纯化残余物,得到白色固体的(R)-4-((2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶-5-基)甲基)苯甲酸(2.30mg,23%)。在 10-80AB_2min色谱分析中(Welch Shim-pack XR-ODS,3.0*30mm,3um), LC-MS tR=1.211分钟,MS(ESI)m/z 581.3[M+H]+。1H NMR(CDCl3):δ 8.22(s,1H),8.03(d,J=8.4Hz,2H),7.42(dd,J=2.8,5.6Hz,1H),7.27(s,1H), 7.25(s,1H),7.18-7.12(m,2H),4.82(d,J=14.0Hz,1H),4.63(d,J=9.6Hz, 1H),4.05(s,2H),3.72(d,J=12.0Hz,1H),3.54(d,J=11.2Hz,1H),3.36-3.30 (m,1H),3.22(s,3H),2.89-2.80(m,2H),2.47-2.43(m,1H),1.10(d,J=6.8Hz,3H),0.83(d,J=6.8Hz,3H)。
实施例33
(R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基-1-(2-(甲氧基吡啶-4-基)哌嗪(化合物 编号33-1)
步骤1
在N2下,向无水甲苯(4mL)中的(R)-3-异丙基哌嗪-1-羧酸叔丁酯(300mg, 1.32毫摩尔)、4-溴-2-甲氧基吡啶(264mg,1.58毫摩尔)、X-phos(33mg,0.07 毫摩尔)和Cs2CO3(3.46g,10.6毫摩尔)溶液添加Pd2(dba)3(78mg,0.07毫摩尔)。 在100℃下搅拌反应混合物5小时。过滤混合物,向滤液添加水(20mL)并用 EtOAc(3×20mL)萃取。将合并的有机层用盐水清洗,在无水Na2SO4上干燥, 过滤并浓缩以得到粗产物。通过制备型TLC用石油醚:EtOAc=3:1纯化粗产 物以得到黄色油状物的(R)-3-异丙基-4-(2-甲氧基吡啶-4-基)哌嗪-1-羧酸叔丁 酯(80mg,18%)。
步骤2
向CH2Cl2(5mL)中的(R)-3-异丙基-4-(2-甲氧基吡啶-4-基)哌嗪-1-羧酸叔 丁酯(80mg,0.24毫摩尔)溶液添加TFA(1mL)。在室温下搅拌反应混合物2 小时。将反应混合物在减压下浓缩,向滤液添加饱和NaHCO3溶液(10mL)并 用EtOAc(3×20mL)萃取。将有机层在无水Na2SO4上干燥,过滤并浓缩以得 到粗(R)-2-异丙基-1-(2-甲氧基吡啶-4-基)哌嗪(56mg,100%),其不经进一步 纯化直接用于下一步骤。
步骤3
在N2下,向无水甲苯(2mL)中的(R)-2-异丙基-1-(2-甲氧基吡啶-4-基)哌嗪(56mg,0.24毫摩尔)、4-溴-1-氟-2-(甲磺酰基)苯(73.4mg,0.29毫摩尔)、 X-phos(5.7mg,0.012毫摩尔)和Cs2CO3(625.9mg,1.92毫摩尔)溶液添加 Pd2(dba)3(13.4mg,0.012摩尔)。在100℃下搅拌反应混合物2小时。过滤混 合物,向滤液添加水(10mL)并用EtOAc(3×10mL)萃取。将合并的有机层用盐 水清洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制备型TLC 用石油醚:EtOAc=1:1纯化粗产物,得到黄色固体的(R)-4-(4-氟-3-(甲磺酰基) 苯基)-2-异丙基-1-(2-甲氧基吡啶-4-基)哌嗪(73.00mg,75%)。在2分钟色谱分 析中(Xtimate C18,2.1*30mm)中,LC-MS tR=0.885分钟,MS(ESI)m/z 408.1 [M+H]+。1H NMR(CD3OD):δ7.74(d,J=6.4Hz,1H),7.40-7.38(m,1H), 7.33-7.25(m,2H),6.55(dd,J=2.8,6.4Hz,1H),6.15(d,J=2.4Hz,1H), 3.90-3.87(m,1H),3.86(s,3H),3.85-3.79(m,2H),3.60(d,J=11.6Hz,1H), 3.46-3.37(m,1H),3.25(s,3H),2.93-2.84(m,2H),2.54-2.45(m,1H),1.10(d,J =6.4Hz,3H),0.86(d,J=6.8Hz,3H)。
实施例34
1-(4-(4-氟-3-(甲磺酰基)苯基)-1-(5-(三氟甲基)吡啶-2-基)哌嗪-2-基)-2-甲基丙 -2-醇(化合物编号34-1)
将干燥THF(3mL)中的2-(4-(4-氟-3-(甲磺酰基)苯基)-1-(5-(三氟甲基)吡 啶-2-基)哌嗪-2-基)乙酸甲酯(8.9mg,0.019毫摩尔)溶液冷却至0℃。添加 LaCl3·2LiCl(THF中0.6M,2当量)。在0℃下搅拌混合物1小时。添加 CH3MgBr(THF中3M,40μL,6当量)。在加温至室温并搅拌2小时前在0℃ 下搅拌混合物30分钟。将混合物用5%HCl溶液淬灭,用Gilson纯化以得到 6.8mg产物(76%产率)。LC-MS(1分钟方法):tR=0.96分钟,m/z 476(M+1)。 1HNMR(CD3OD)δ8.37(s,1H),7.81(dd,J=9.6Hz,1H),7.42(dd,J=5.6Hz, 1H),7.34(m,1H),7.26(t,J=9.2Hz,1H),7.05(d,J=9.6Hz,1H),4.29(d,1H), 3.87(d,1H),3.68(d,1H),3.53(td,1H),3.22(s,3H),3.08(dd,1H),2.96(td,1H), 2.19(dd,1H),1.75(dd,1H),1.29(d,6H)。19F NMR(CD3OD)δ-125.5,-63.3。
实施例35
2-(2-氟-2-甲基丙基)-4-(4-氟-3-(甲磺酰基)苯基)-1-(5-(三氟甲基)吡啶-2-基)哌 嗪(化合物编号35-1)
将CH2Cl2(2mL)中的1-(4-(4-氟-3-(甲磺酰基)苯基)-1-(5-(三氟甲基)吡啶 -2-基)哌嗪-2-基)-2-甲基丙-2-醇(5.5mg,0.016毫摩尔)溶液冷却至0℃。添加 DAST(2滴,过量)。15分钟后,将混合物加温至室温,搅拌2.5小时。将其 用5%HCl溶液淬灭,用Gilson纯化以得到1.27mg产物(23%产率)。LC-MS(1 分钟方法):tR=1.05分钟,m/z 478(M+1)。1HNMR(CD3OD)δ8.38(s,1H), 7.75(dd,J=9.2Hz,1H),7.43(dd,J=5.6Hz,1H),7.33(m,1H),7.26(t,J=9.6Hz, 1H),6.91(d,J=9.2Hz,1H),5.04(M,1H),4.38(d,1H),3.84(d,1H),3.66(d,1H), 3.41(m,1H),3.13(s,3H),3.00(dd,1H),2.89(td,1H),2.46(td,1H),1.93(s,2H), 1.74(m,1H),1.43(dd,6H)。19F NMR(CD3OD)δ-125.2,-63.1,-49.0。
实施例36
(R)-4-氯-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶 (化合物编号36-1)
将二氯乙烷/叔丁醇(1:1,5mL)中的2,4-二氯-5-(三氟甲基)嘧啶(22mg, 1.02当量)溶液冷却至0℃。添加ZnCl2(乙醚中1.0M,220μL,2.2当量)。1 小时后,在0℃下添加二氯乙烷/叔丁醇(1:1,2mL)中的(R)-1-(4-氟-3-(甲磺酰 基)苯基)-3-异丙基哌嗪(30mg,0.1毫摩尔)溶液,然后添加三乙胺(20μL,1.5 当量)。将混合物搅拌过夜,同时冰/水浴自行溶化。将混合物用Gilson纯化 以得到14.5mg产物(30%产率)。LC-MS(1分钟方法):tR=1.11分钟,m/z 481(M+1)。1H NMR(CD3OD)δ8.53(s,1H),7.41(dd,J=5.6Hz,1H),7.33(m, 1H),7.27(t,J=9.2Hz,1H),5.04(m,1H),4.90-4.58(m,2H),3.86(d,1H), 3.66(d,1H),3.38(dd,1H),3.23(s,3H),2.84(m,2H),2.50(m,1H),1.12(d,3H), 0.83(d,3H)。19F NMR(CD3OD)δ-124.8,-63.0。
实施例37
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-甲基-5-(三氟甲基)嘧 啶(化合物编号37-1)
将(R)-4-氯-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶(13.5mg,0.028毫摩尔)、2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼杂环己 烷(7mg,2当量)、双(三苯基膦)二氯化钯(II)(2mg,10摩尔%)、碳酸铯(15mg, 过量)和干燥1,4-二氧六环(1mL)的混合物脱气,用氮气再充气3次。在微波 炉中将混合物在140℃下加热45分钟。在浓缩和酸化后,将残余物用Gilson 纯化以得到10.5mg产物(81%产率)。LC-MS(1分钟方法):tR=1.12分钟, m/z 461(M+1)。H1NMR(CD3OD)δ8.41(s,1H),7.40(dd,J=5.6Hz,1H),7.32(m, 1H),7.27(t,J=9.2Hz,1H),4.96(m,1H),4.77(d,1H),3.83(d,1H),3.63(d,1H),3.33(m,1H),3.23(s,3H),2.79(m,2H),2.49(m,1H),2.46(s,3H),1.12(d,3H), 0.82(d,3H)。F19NMR(CD3OD)δ-125.1,-62.0。
通过相似过程制备以下化合物。
实施例38
1-(2-((R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶 -4-基)乙-1-醇(化合物编号38-1)
步骤1
将(R)-4-氯-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶(28mg,0.058毫摩尔)、三丁基(1-乙氧基乙烯)锡(42mg,2当量)、双 (三苯基膦)二氯化钯(II)(4mg,10摩尔%)和干燥甲苯(2.5mL)的混合物脱气, 用氮气再充气3次。在微波炉中将混合物在140℃下加热45分钟。在浓缩和 酸化后,将残余物用Gilson纯化以得到22.6mg产物(75%产率)。LC-MS(1 分钟方法):tR=1.14分钟,m/z 517(M+1)。
步骤2
在室温下搅拌(R)-4-(1-乙氧基乙烯基)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶(22.6mg,0.044毫摩尔)、5%HCl/乙腈(1:1, 4mL)的混合物3小时。粗产物在浓缩后不经进一步纯化用于下一步骤。LC-MS (1分钟方法):tR=1.05分钟,m/z 489(M+1)。
步骤3
将THF/甲醇(1:1,2mL)中的(R)-1-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙 基哌嗪-1-基)-5-(三氟甲基)嘧啶-4-基)乙-1-酮(0.015毫摩尔)溶液冷却至0℃。 添加硼氢化钠(3mg,5当量)。10分钟后,将混合物加温至室温,搅拌1小时。 将其用1%HCl淬灭,浓缩并用Gilson纯化以得到2.9mg产物(2个步骤40% 产率)。LC-MS(1分钟方法):tR=1.03分钟,m/z 491(M+1)。1H NMR(CD3OD) δ8.50(s,1H),7.42(dd,J=6Hz,1H),7.33(m,1H),7.27(t,J=9.6Hz,1H),4.94(q, 1H),3.86(d,1H),3.66(d,1H),3.36(m,1H),3.22(s,3H),2.83(m,2H),2.49(m, 1H),1.45(s,3H),1.14(d,3H),0.83(d,3H)。19F NMR(CD3OD)δ-125.1,-59.6
实施例39
(R)-2-(2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶 -4-基)丙-2-醇(化合物编号39-1)
由实施例34的过程制备标题化合物。通过制备型HPLC纯化粗产物以 提供所期望的产物。LC-MS(1分钟方法):tR=1.78分钟,m/z 505(M+1)。1H NMR(CD3OD)δ8.56(s,1H),7.41(dd,J=5.6Hz,1H),7.32(m,1H),7.26(t, J=9.2Hz,1H),4.88(d,1H),4.72(d,1H),3.84(d,1H),3.64(d,1H),3.34(m,1H), 3.23(s,3H),2.83(m,2H),2.49(m,1H),1.56(s,3H),1.12(d,3H),0.82(d,3H)。19F NMR(CD3OD)δ-125.1,-56.1。
实施例40
(R)-5-环丙基-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基) 嘧啶(化合物编号40-1)
将(R)-5-溴-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-4-(三氟甲基)嘧啶(12mg,0.023毫摩尔)、环丙基硼酸(8mg,4当量)、双(三苯基膦)二 氯化钯(II)(2mg,10摩尔%)、碳酸铯(8mg,过量)和干燥甲苯/水(2:1,1.5mL) 的混合物脱气,用氮气再充气3次。在微波炉中将混合物在120℃下加热30 分钟。在浓缩和酸化后,将残余物用制备型HPLC纯化以得到10.3mg产物 (93%产率)。LC-MS(1分钟方法):tR=1.15分钟,m/z 487(M+1)。1H NMR (CD3OD)δ8.28(s,1H),7.39(dd,J=5.6Hz,1H),7.30(m,1H),7.25(t,J=9.2Hz,1H),4.79(d,1H),4.64(d,1H),3.82(d,1H),3.61(d,1H),3.31(m,1H),3.22(s,3H), 2.79(m,2H),2.47(m,1H),1.92(m,1H),1.21(s,3H),1.12(d,3H),0.96(q,2H), 0.81(d,3H),0.68(q,2H)。19F NMR(CD3OD)δ-125.2,-68.7
依照类似过程制备以下化合物。
实施例41
2,2,2-三氟-1-(2-((R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)嘧啶-5-基) 乙-1-醇(化合物编号41-1)
将干燥THF(5mL)中的(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)嘧啶-5-甲醛(23mg,0.057毫摩尔)溶液冷却至0℃。添加TMSCF3(60μL, 过量)。缓慢添加TBAF溶液(THF中1.0M,85μL,1.5当量)。混合物变黄。 15分钟后,将其加温至室温,搅拌1小时。LC-MS测得反应完成。将混合 物通过饱和NH4Cl溶液(1.5mL)淬灭,浓缩并用Gilson纯化以得到21.4mg产 物(79%产率)。LC-MS(1分钟方法):tR=0.99分钟,m/z 477(M+1)。1H NMR(CD3OD)δ8.40(s,1H),7.39(dd,J=5.6Hz,1H),7.30(m,1H),7.25(t,J=9.2Hz, 1H),4.98(q,1H),4.82(d,1H),4.68(d,1H),3.83(d,1H),3.63(d,1H),3.33(m,1H), 3.22(s,3H),2.83(m,2H),2.48(m,1H),1.12(d,3H),0.82(d,3H)。19F NMR (CD3OD)δ-125.1,-80.8。
实施例42
2-((R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(2,2,2-三氟-3-甲氧基 乙基)嘧啶(化合物编号42-1)
将干燥THF(4mL)中的2,2,2-三氟-1-(2-((R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)嘧啶-5-基)乙-1-醇(20mg,0.042毫摩尔)溶液冷却至0℃。添 加NaH(5mg,过量)。搅拌15分钟后,添加碘甲烷(~50μL,过量)。10分钟 后,将混合物加温至室温,搅拌3.5小时。将混合物用饱和NH4Cl溶液淬灭, 浓缩并用Gilson纯化以得到15.2mg产物(74%产率)。LC-MS(1分钟方法): tR=1.11分钟,m/z 491(M+1)。1H NMR(CD3OD)δ8.35(s,1H),7.40(dd, J=5.6Hz,1H),7.31(m,1H),7.25(t,J=9.2Hz,1H),4.86(d,1H),,4.68(m,1H), 3.84(d,1H),3.62(d,1H),3.42(s,3H),3.34(m,1H),3.22(s,3H),2.81(m,2H), 2.48(m,1H),1.12(d,3H),0.83(d,3H)。19F NMR(CD3OD)δ-125.2,-79.1。
实施例43
(R)-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶-4-甲 腈(化合物编号43-1)
将(R)-4-氯-2-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)-5-(三氟甲基)嘧啶(8.4mg,0.017毫摩尔)、Zn(CN)2(12mg,6当量)、Pd(PPh3)4(2mg,10 摩尔%)、干燥DMF(1mL)的混合物脱气,用N2气体再充气三次。将混合物 放入微波炉,在12℃下加热45分钟。将混合物过滤,通过制备型HPLC纯 化以得到5.8mg产物(70%产率)。LC-MS(1分钟方法):tR=1.09分钟,m/z 472(M+1)。1H NMR(CD3OD)δ8.76(s,1H),7.42(dd,J=5.6Hz,1H),7.34(m,1H), 7.27(t,J=9.5Hz,1H),4.92(m,1H),4.79-4.62(m,1H),3.87(d,1H),3.68(d,1H), 3.42(td,1H),3.23(s,3H),2.91-2.79(m,2H),2.53(m,1H),1.16(s,3H),0.84(s,3H)。19F NMR(CD3OD)δ-125.5,-62.2
实施例44
(R)-1-(2-(二氟甲氧基)吡啶-4-基)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪 (化合物编号44-1)
步骤1
将HOAc(5mL)中的30%HBr中的(R)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙 基-1-(2-甲氧基吡啶-4-基)哌嗪(60.0mg,0.15毫摩尔)溶液在90℃下搅拌20小 时。向反应混合物添加水(10mL),用EtOAc(3×10mL)萃取含水层。将合并的 有机层用盐水(10mL)清洗,在无水Na2SO4上干燥,过滤并浓缩以提供粗产 物。通过制备型TLC用CH2Cl2:CH3OH=9:1纯化粗产物,得到黄色固体的 (R)-4-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪-1-基)吡啶-2(1H)-酮(35.0mg, 60%)。在2分钟色谱分析中,LC-MS tR=0.919分钟,MS(ESI)m/z 394.1[M+H]+。1H NMR(CD3OD):δ7.42-7.40(m,1H),7.35-7.23(m,3H),6.32(dd,J =2.4,7.6Hz,1H),5.72(d,J=2.4Hz,1H),3.92-3.81(m,3H),3.64(d,J=12.0 Hz,1H),3.48-3.40(m,1H),3.26(s,3H),2.95-2.86(m,2H),2.55-2.49(m,1H), 1.12(d,J=6.4Hz,3H),0.89(d,J=6.8Hz,3H)。
步骤2
在N2下,向DMF(0.5mL)中的(R)-4-(4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基 哌嗪-1-基)吡啶-2(1H)-酮(5mg,13微摩尔)和K2CO3(3mg,19.5微摩尔)溶液 添加ClCF2CO2Na(2.5mg,19.5微摩尔)。在80℃下搅拌反应混合物2小时。 用水(10mL)处理反应混合物并用EtOAc(3×10mL)萃取。将合并的有机层用盐 水(10mL)清洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制 备型TLC用石油醚:EtOAc 2:1洗脱纯化粗产物,得到白色固体的(R)-1-(2-(二 氟甲氧基)吡啶-4-基)-4-(4-氟-3-(甲磺酰基)苯基)-2-异丙基哌嗪(1.70mg, 30%)。在2分钟色谱分析中,LC-MS tR=1.115分钟,MS(ESI)m/z 444.2 [M+H]+。1H NMR(CD3OD):δ7.81(d,J=6.4Hz,1H),7.42-7.41(m,1H),7.40 (t,J=73.8Hz,1H),7.33-7.26(m,2H),6.72(dd,J=2.4,6.0Hz,1H),6.34(d,J =2.4Hz,1H),3.93(d,J=13.6Hz,1H),3.85-3.82(m,2H),3.63(d,J=11.6Hz, 1H),3.50-3.42(m,1H),3.26(s,3H),2.96-2.87(m,2H),2.56-2.48(m,1H),1.13 (d,J=6.4Hz,3H),0.86(d,J=6.4Hz,3H)。
通过相似过程制备以下化合物。
实施例45
(S)-2-苄基-1-(3-氯-4-(三氟甲基)苄基)-4-(3-(甲磺酰基)苯基)哌嗪(化合物编号 45-1)
将(S)-3-苄基-1-(3-(甲磺酰基)苯基)哌嗪盐酸盐(20.5mg,0.056毫摩尔)、 3-氯-4-(三氟甲基)苄基溴化物(15.5mg,0.057毫摩尔)、粉状NaHCO3(14mg, 0.17毫摩尔)和干燥DMF(1mL)的搅拌溶液在50℃下加热16小时。制备型 HPLC提供标题化合物的TFA盐(15.5mg,43%)。LC-MS方法4tR=0.87分 钟,m/z=523,525;1H NMR(CD3OD)δ3.06(s,3H),3.14-3.24(m,1H), 3.30-3.60(m,6H),3.81-3.88(m,1H),4.44-4.54(m,1H),4.80-4.88(m,2H), 7.09-7.15(m,1H),7.25-7.50(m,8H),7.69-7.75(m,1H),7.88-7.98(m,2H)。
实施例46
1-(3-氯-4-(三氟甲基)苄基)-4-(3-(甲磺酰基)苯基)-2-苯基哌嗪(化合物编号46-1)
步骤1
在0℃下,在N2下,向无水CH2Cl2(10mL)中的(3-氯-4-(三氟甲基)苯基) 甲醇(300mg,1.43毫摩尔)溶液缓慢滴加SOCl2(4.2mL,57.14毫摩尔)。在0℃ 下搅拌反应混合物10分钟,在40℃下搅拌23小时。在减压下去除溶剂以提 供粗产物。通过制备型TLC用石油醚:EtOAc=3:1纯化粗产物以得到无色油 状物的2-氯-4-(氯甲基)-1-(三氟甲基)苯(234mg,72%)。
步骤2
在N2下,向无水DMF(6mL)中的2-氯-4-(氯甲基)-1-(三氟甲基)苯(200mg, 0.88毫摩尔)和1-(3-(甲磺酰基)苯基)-3-苯基哌嗪(182mg,0.58毫摩尔)溶液添 加NaHCO3(221mg,2.63毫摩尔)。在100℃下搅拌反应混合物2小时。向反 应混合物添加水(50mL)并用EtOAc(3×30mL)萃取。将合并的有机层用盐水 (30mL)清洗,在无水Na2SO4上干燥,过滤并浓缩以得到粗产物。通过制备 型TLC用石油醚:EtOAc=3:1纯化粗产物,得到黄色固体的1-(3-氯-4-(三氟甲 基)苄基)-4-(3-(甲磺酰基)苯基)-2-苯基哌嗪(289mg,99%)。在2分钟色谱分 析中,LC-MS tR=1.433分钟,m/z 509.3[M+H]+。1H NMR(CD3OD):δ7.68 (d,J=8.0Hz,1H),7.57-7.52(m,3H),7.46-7.38(m,5H),7.35-7.30(m,2H), 7.25(d,J=9.2Hz,1H),3.81-3.70(m,3H),3.54(dd,J=3.6,10.0Hz,1H), 3.08-2.92(m,4H),3.00(s,3H),2.42(dt,J=3.6,15.2Hz,1H)。
在手性柱上通过HPLC分离异构体,得到(R)-1-(3-氯-4-(三氟甲基)苄 基)-4-(3-(甲磺酰基)苯基)-2-苯基哌嗪(化合物编号46-2)和(S)-1-(3-氯-4-(三氟 甲基)苄基)-4-(3-(甲磺酰基)苯基)-2-苯基哌嗪(化合物编号46-3)。
依照相似过程制备以下化合物。
a,b,c,d,e,f,g,h,i在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
依照相似过程制备以下化合物。
a,b,c在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
依照相似过程制备以下化合物。
a,b在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
实施例47
(2-(甲磺酰基)-4-(3-苯基-4-((6-(三氟甲基)吡啶-3-基)甲基)哌嗪-1-基)苯基)甲 醇(化合物编号47-1)
步骤1
向甲苯(6mL)中的4-溴-2-(甲磺酰基)苯甲酸甲酯(200mg,0.68毫摩尔)溶 液添加2-苯基-1-((6-(三氟甲基)吡啶-3-基)甲基)哌嗪(219mg,0.68毫摩尔)、 BINAP(31mg,0.068毫摩尔)、Pd2dba3(60mg,0.068毫摩尔)和Cs2CO3(665mg, 2.04毫摩尔)。在N2下,在回流下搅拌混合物8小时。过滤混合物,向滤液 添加水(10mL)并用EtOAc(3×10mL)萃取。将合并的有机层用盐水清洗,在无 水Na2SO4上干燥,过滤并在减压下浓缩。通过制备型TLC纯化残余物以得 到黄色油状物的2-(甲磺酰基)-4-(3-苯基-4-((6-(三氟甲基)吡啶-3-基)甲基)哌 嗪-1-基)苯甲酸甲酯(171mg,47%)。
步骤2
在0℃下,在N2下,向无水甲醇(2mL)中的2-(甲磺酰基)-4-(3-苯基 -4-((6-(三氟甲基)吡啶-3-基)甲基)哌嗪-1-基)苯甲酸甲酯(30mg,0.056毫摩尔) 溶液添加NaBH4(6.4mg,0.169毫摩尔)。在室温下搅拌混合物4小时。混合 物用饱和NH4Cl溶液(5mL)淬灭,在减压下浓缩,用EtOAc(10mL)溶解残余 物。将有机层用水(3×10mL)和盐水(10mL)清洗,在无水Na4SO4上干燥,过 滤并在减压下浓缩。通过制备型TLC纯化残余物以得到黄色固体的(2-(甲磺 酰基)-4-(3-苯基-4-((6-(三氟甲基)吡啶-3-基)甲基)哌嗪-1-基)苯基)甲醇(15.90mg,56%)。在2分钟色谱分析中,LC-MS tR=0.941分钟,m/z 528.2 [M+Na]+。1H NMR(CDCl3):δ8.57(s,1H),7.73(d,J=7.6Hz,1H),7.56(d, J=8.0Hz,1H),7.44-7.43(m,3H),7.35-7.27(m,4H),6.99(dd,J=2.8,8.4Hz, 1H),4.74(d,J=5.6Hz,2H),3.81(d,J=14.0Hz,1H),3.61(d,J=12.4Hz,2H), 3.46(dd,J=2.4,10.8Hz,1H),3.07(s,3H),3.03-2.95(m,1H),2.94-2.85(m, 3H),2.36(dt,J=2.8,11.6Hz,1H)。
使用类似于以上的步骤制备以下化合物。
实施例48
(S)-4-(4-(3-(甲磺酰基)苯基)-2-苯基哌嗪-1-基)甲基)-1-(三氟甲基)环己醇(化 合物编号48-1)
向(S)-(4-羟基-4-(三氟甲基)环己基)(4-(3-(甲磺酰基)苯基)-2-苯基哌嗪-1-基)甲酮(17mg,0.034毫摩尔)添加THF(2mL,2.0毫摩尔)中的1M BH3。在 回流下加热混合物3小时,冷却至室温,用1M NaOH水溶液(5mL)处理。浓 缩混合物。含水残余物在CH2Cl2(100mL)和盐水(10mL)之间分层。将有机层 在Na2SO4上干燥,浓缩以留下油状物(16mg)。制备型HPLC提供油状物的标 题化合物(6mg,35%)。LC-MS方法4tR=0.70分钟,m/z=497。1HNMR (CD3OD)δ0.89-1.03(m,1H),1.30-1.60(m,5H),1.77-1.84(m,1H),1.85-1.99 (m,1H),2.10-2.18(m,1H),2.92-3.01(m,1H),3.09(s,3H),3.13-3.23(m,1H), 3.40-3.50(m,3H),3.98-4.18(m,3H),4.50-4.61(m,1H),7.34-7.67(m,9H)。
通过相似过程制备以下化合物。
a,b,c,d,e,f,g,h,i,j,k,l,m,n,o在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
通过相似过程制备以下化合物。
a,b,c在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
通过相似过程制备以下化合物。
a,b在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
通过相似过程制备以下化合物。
a,b,c,d在手性柱上通过HPLC分离异构体,立体化学为任意指定的。
实施例49
(4-((3S)-3-异丙基-4-((6-(三氟甲基)四氢-2H-吡喃-3-基)甲基)哌嗪-1-基)-2-(甲 磺酰基)苯基)甲醇(化合物编号49-1、49-2)
步骤1
在0℃下,在N2下向无水DMF(10mL)中的1,1,1-三氟戊-4-烯-2-醇 (500mg,3.57毫摩尔)溶液添加NaH(171mg,4.29毫摩尔,矿物中60%)。在 0℃下搅拌混合物10分钟。然后加入2-(溴甲基)丙烯酸乙酯(682mg,3.57毫 摩尔)。在N2下,在室温下搅拌混合物溶液3小时。向混合物添加水(20mL) 并用EtOAc(3×20mL)萃取。将合并的有机层用盐水(20mL)清洗,在无水 Na2SO4上干燥,过滤,在减压下浓缩。通过制备型TLC用石油醚/EtOAc 10/1 纯化残余物,得到灰色固体的2-((1,1,1-三氟戊-4-烯-2-基)氧)甲基)丙烯酸乙 酯(322mg,36%)。
步骤2
在N2下,向CH2Cl2(8mL)中的2-(((1,1,1-三氟戊-4-烯-2-基)氧)甲基)丙烯 酸乙酯(350mg,1.39毫摩尔)溶液添加格拉布II催化剂(118mg,0.14毫摩尔)。 在室温下搅拌混合物3小时。在减压下浓缩混合物。通过制备型TLC用石油 醚/EtOAc 10/1纯化残余物,得到灰色固体的6-(三氟甲基)-5,6-二氢-2H-吡喃 -3-羧酸乙酯(246mg,79%)。
步骤3
向无水甲醇(10mL)中的6-(三氟甲基)-5,6-二氢-2H-吡喃-3-羧酸乙酯 (480mg,2.14毫摩尔)在溶液添加Pd(OH)2/C(200mg,20%,重量/重量)。在 室温下,在H2下(30psi)搅拌混合物过夜。过滤混合物,在减压下将混合物浓 缩以提供黄色固体的粗6-(三氟甲基)四氢-2H-吡喃-3-羧酸乙酯(365mg,75%), 其不经进一步纯化直接用于下一步骤。
步骤4
向甲醇(10mL)和H2O(3mL)中的6-(三氟甲基)四氢-2H-吡喃-3-羧酸乙酯 (480mg,2.12毫摩尔)溶液添加LiOH(446mg,10.62毫摩尔)。在室温下搅拌 混合物3小时。用1N HCl溶液调节混合物至pH=6。向混合物添加H2O(15mL) 并用EtOAc(3×20mL)萃取。将合并的有机层用水(40mL)清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩以得到黄色固体的粗6-(三氟甲基)四氢-2H-吡 喃-3-羧酸(350mg,83%),其不经进一步纯化直接用于下一步骤。
步骤5
向无水CH2Cl2(2mL)中的6-(三氟甲基)四氢-2H-吡喃-3-羧酸(20mg,0.10 毫摩尔)溶液添加SOCl2(120mg,1.01毫摩尔)。在N2下,在0℃下将混合物 搅拌3小时。在减压下浓缩混合物以得到黄色油状物的粗6-(三氟甲基)四氢 -2H-吡喃-3-碳酰氯(22mg,100%),其不经进一步纯化直接用于下一步骤。
步骤6
在N2下,向无水甲苯(10mL)中的(S)-2-异丙基哌嗪-1-羧酸叔丁酯(400mg, 1.76毫摩尔)溶液添加4-溴-2-(甲磺酰基)苯甲酸甲酯(1.03g,4.8毫摩尔)、 X-phos(80mg,0.17毫摩尔)、Cs2CO3(1.50g,4.62毫摩尔)和Pd2(dba)3(200mg, 0.22毫摩尔)。在100℃下搅拌反应混合物过夜。用水(20mL)淬灭反应并用 EtOAc(4×20mL)萃取。将合并的有机层在无水Na2SO4上干燥,过滤,浓缩, 然后通过制备型TLC用石油醚/EtOAc 5/1纯化,得到灰色固体的(S)2-异丙基 -4-(4-(甲氧基羰基)-3-(甲磺酰基)苯基)哌嗪-1-羧酸叔丁酯(500mg,65%产率)。
步骤7
向无水CH2Cl2(4mL)中的(S)-2-异丙基-4-(4-(甲氧基羰基)-3-(甲磺酰基)苯 基)哌嗪-1-羧酸叔丁酯(300mg,0.79毫摩尔)在溶液添加TFA(1mL)。在室温 下搅拌混合物2小时。向混合物添加饱和NaHCO3溶液(10mL)并用 CH2Cl2(3×10mL)萃取。将合并的有机层用盐水(25mL)清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩以得到黄色固体的粗(S)-4-(3-异丙基哌嗪-1- 基)-2-(甲磺酰基)苯甲酸甲酯(280mg,100%),其不经进一步纯化直接用于下 一步骤。
步骤8
向无水CH2CI2(5mL)中的(S)-4-(3-异丙基哌嗪-1-基)-2-(甲磺酰基)苯甲酸 甲酯(80mg,0.23毫摩尔)溶液添加Et3N(71mg,0.70毫摩尔)和6-(三氟甲基) 四氢-2H-吡喃-3-碳酰氯(50mg,0.23毫摩尔)。在N2下,在室温下搅拌混合物 2小时。向混合物添加水(10mL)并用EtOAc(3×10mL)萃取。将合并的有机 层用盐水(20mL)清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩。通过 制备型TLC用石油醚/EtOAc 1/1纯化残余物,得到灰色固体的4-((3S)-3-异 丙基-4-(6-(三氟甲基)四氢-2H-吡喃-3-羰基)哌嗪-1-基)-2-(甲磺酰基)苯甲酸甲 酯(40mg,33%)。通过制备型tlc将该化合物分离为两对异构体(A和B)。
步骤9
在0℃下,在N2下,向无水THF(2mL)中的4-((3S)-3-异丙基-4-(6-(三氟 甲基)四氢-2H-吡喃-3-羰基)哌嗪-1-基)-2-(甲磺酰基)苯甲酸甲酯异构体 A(20mg,0.04毫摩尔)溶液滴加BH3-Me2S(0.13mL,1.35毫摩尔,10M)。在 N2下,在70℃下搅拌混合物2小时。向混合物添加水(5mL)并用EtOAc(3×5mL) 萃取。将合并的有机层用盐水(10mL)清洗,在无水Na2SO4上干燥,过滤, 在减压下浓缩。通过制备型TLC用石油醚/EtOAc 1/1和SFC分离纯化残余物 以提供白色固体的化合物编号49-1、(4-((S)-3-异丙基-4-(((3R,6S)-6-(三氟甲基)四氢-2H-吡喃-3-基)甲基)哌嗪-1-基)-2-(甲磺酰基)苯基)甲醇(1.50mg,22%) 和化合物编号49-2、(4-((S)-3-异丙基-4-(((3R,6R)-6-(三氟甲基)四氢-2H-吡喃 -3-基)甲基)哌嗪-1-基)-2-(甲磺酰基)苯基)甲醇(1.70mg,22%)。
白色固体的化合物编号49-1(1.50mg,22%)。在2分钟色谱分析中(Welch XtimateC18,2.1*30mm,3um),LC-MS tR=0.852分钟,MS(ESI)m/z 479.1 [M+H]+。1H NMR(CDCl3):δ7.49(d,J=2.8Hz,1H),7.38(d,J=8.4Hz,1H), 7.05(dd,J=2.8Hz,8.4Hz,1H),4.81(s,2H),4.17-4.13(m,1H),3.69-3.66(m, 1H),3.44-3.41(m,2H),3.17(s,3H),3.14-2.86(m,5H),2.56(dd,J=8.0Hz, 12.4Hz,1H),2.44-2.38(m,1H),2.22-2.08(m,3H),2.04-2.00(m,1H),1.98-1.83 (m,2H),1.68-1.62(m,1H),1.19-1.12(m,1H),1.02(d,J=6.8Hz,3H),0.93(d, J=6.8Hz,3H)。在15分钟色谱分析中(柱:OJ-H;方法名称: OJ-H_3_5_40_2.35ml.met,ee=100%),异构体SFC tR=7.63分钟。
白色固体的化合物编号49-2(1.70mg,22%)。在2分钟色谱分析中(Welch XtimateC18,2.1*30mm,3um),LC-MS tR=0.859分钟,MS(ESI)m/z 479.1 [M+H]+。
1H NMR(CDCl3):δ7.49(d,J=2.8Hz,1H),7.37(d,J=8.4Hz,1H),7.04 (dd,J=2.8Hz,8.4Hz,1H),4.81(s,2H),4.38-4.29(m,1H),3.71-3.62(m,1H), 3.51-3.42(m,2H),3.17(s,3H),3.14-3.08(m,2H),3.00-2.90(m,2H),2.86-2.78 (m,1H),2.61-2.52(m,1H),2.36-2.28(m,1H),2.18-2.02(m,3H),2.01-1.87(m, 3H),1.71-1.65(m,1H),1.21-1.13(m,1H),1.02(d,J=6.4Hz,3H),0.90(d,J= 6.8Hz,3H)。在15分钟色谱分析中(柱:OJ-H;方法名称: OJ-H_3_5_40_2.35ml.met,ee=100%),异构体SFC tR=9.85分钟。
(4-((3S)-3-异丙基-4-((6-(三氟甲基)四氢-2H-吡喃-3-基)甲基)哌嗪-1- 基)-2-(甲磺酰基)苯基)甲醇(化合物编号49-3、49-4)
在0℃下,在N2下向无水THF(2mL)中的4-((3S)-3-异丙基-4-(6-(三氟甲 基)四氢-2H-吡喃-3-羰基)哌嗪-1-基)-2-(甲磺酰基)苯甲酸甲酯异构体 B(20mg,0.04毫摩尔)溶液滴加BH3-Me2S(0.13mL,1.35毫摩尔,10M)。在 N2下,在70℃下将混合物搅拌2小时。向混合物添加水(5mL)并用 EtOAc(3×5mL)萃取。将合并的有机层用盐水(10mL)清洗,在无水Na2SO4上 干燥,过滤,在减压下浓缩。通过制备型TLC用石油醚/EtOAc 1/1和SFC 分离纯化残余物以提供白色固体的化合物编号49-3、(4-((S)-3-异丙基 -4-(((3S,6S)-6-(三氟甲基)四氢-2H-吡喃-3-基)甲基)哌嗪-1-基)-2-(甲磺酰基)苯 基)甲醇(1.60mg,21%)和化合物编号49-4、(4-((S)-3-异丙基-4-(((3S,6R)-6-(三 氟甲基)四氢-2H-吡喃-3-基)甲基)哌嗪-1-基)-2-(甲磺酰基)苯基)甲醇(1.70mg, 22%)。
白色固体的化合物编号49-3(1.60mg,21%)。在2分钟色谱分析中(Welch XtimateC18,2.1*30mm,3um),LC-MS tR=0.743分钟,MS(ESI)m/z 479.1 [M+H]+。
1H NMR(CDCl3):δ7.45-7.42(m,1H),7.33-7.31(m,1H),7.02-6.98(m, 1H),4.75(s,2H),3.97-3.90(m,1H),3.72-3.62(m,2H),3.45-3.35(m,2H),3.10 (s,3H),3.06-2.85(m,5H),2.39-2.15(m,4H),1.99-1.86(m,1H),1.75-1.61(m, 4H),1.03-0.98(m,3H),0.95-0.85(m,3H)。在15分钟色谱分析中(柱:OJ-H; 方法名称:OJ-H_3_5_40_2.35ml.met,ee=94.7%),异构体SFC tR=5.34分 钟。
白色固体的化合物编号49-4(1.70mg,22%)。在2分钟色谱分析中(Welch XtimateC18,2.1*30mm,3um),LC-MS tR=0.747分钟,MS(ESI)m/z 479.1 [M+H]+。1H NMR(CDCl3):δ7.42(d,J=2.8Hz,1H),7.30(d,J=8.4Hz, 1H),6.98(dd,J=2.8Hz,8.4Hz,1H),4.74(d,J=6.8Hz,2H),4.05(d,J=11.6 Hz,1H),3.72-3.66(m,1H),3.56-3.49(m,1H),3.40-3.36(m,2H),3.10(s,3H), 3.08-2.98(m,2H),2.92-2.78(m,3H),2.36-2.26(m,1H),2.19-2.10(m,2H), 2.06-1.99(m,1H),1.76-1.70(m,3H),1.62-1.60(m,2H),0.96(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H)。在15分钟色谱分析中(柱:OJ-H;方法名称: OJ-H_3_5_40_2.35ml.met,ee=89.3%),异构体SFC tR=5.71分钟。
通过相似过程制备以下化合物。
a,b在手性柱上通过HPLC分离异构体,&和#中心的立体化学为任意指定的。
实施例50
4-((S)-3-异丙基-4-(((1s,4R)-4-(三氟甲基)环己基)甲基)哌嗪-1-基)-2-(甲磺酰 基)苯甲腈(化合物编号50-1)
步骤1
在室温下过夜搅拌水(2mL)和THF(6mL)中的(S)-2-异丙基哌嗪-1-羧酸叔 丁酯(1g,4.4毫摩尔)、NaHCO3(1.1g,13.2毫摩尔)、CbzCl(1.1g,6.6毫摩尔) 的混合物。向混合物添加水(20mL)并用EtOAc(3×20mL)萃取。将合并的有机 层在无水Na2SO4上干燥,过滤,在减压条件下浓缩。通过在硅胶层析柱上用 石油醚/EtOAc 50/1洗脱纯化残余物以提供无色油状物的粗(S)-4-苄基-1-叔丁 基-2-异丙基哌嗪-1,4-二羧酸酯(1.8g,90%),其不经进一步纯化直接用于下一 步骤。在2分钟色谱分析中,LC-MS tR=1.276分钟,m/z 263.2[M+H-Boc]+
步骤2
向无水CH2Cl2(10mL)中的(S)-4-苄基-1-叔丁基-2-异丙基哌嗪-1,4-二羧酸 酯(1.8g,4.9毫摩尔)溶液添加TFA(1mL)。在室温下搅拌混合物3小时。在 浓缩后,用CH2Cl2(10mL)稀释混合物,然后将有机层用饱和NaHCO3溶液 (2×10mL)、水(10mL)和盐水(10mL)清洗,在无水Na2SO4上干燥,过滤并在 减压下浓缩以提供无色油状物的粗(S)-苄基-3-异丙基哌嗪-1-羧酸酯 (1.5g,>100%),其不经进一步纯化直接用于下一步骤。
步骤3
在室温下将无水DMF(2mL)中的(S)-苄基-3-异丙基哌嗪-1-羧酸酯 (200mg,0.76毫摩尔)、顺式-4-(三氟甲基)环己烷羧酸(299.2mg,1.53毫摩尔)、 HATU(288.8mg,0.76毫摩尔)和Et3N(230.3mg,2.28毫摩尔)的混合物搅拌 4小时。向混合物添加水(5mL)并用EtOAC(3×5mL)萃取。将合并的有机层用 水(10mL)清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩。通过制备型 TLC用石油醚/EtOAc 3/1纯化残余物以得到黄色油状物的(S)-苄基-3-异丙基 -4-((顺式)-4-(三氟甲基)环己烷羰基)哌嗪-1-羧酸酯(150mg,51%)。
步骤4
在N2下,向无水THF(1mL)中的(S)-苄基-3-异丙基-4-((顺式)-4-(三氟甲 基)环己烷羰基)哌嗪-1-羧酸酯(50mg,0.11毫摩尔)溶液添加 BH3-Me2S(0.11mL,1.1毫摩尔,10M)。在60℃下搅拌混合物2小时。向混 合物缓慢添加MeOH(5mL)并在减压下浓缩。通过制备型TLC用石油 醚:EtOAc 5:1纯化残余物以得到无色油状物的(S)-苄基-3-异丙基-4-(((顺 式)-4-(三氟甲基)环己基)甲基)哌嗪-1-羧酸酯(35mg,74%)。在2分钟色谱分 析中,LC-MS tR=1.162分钟,m/z 427.2[M+H]+。
步骤5
在室温下将HBr/HOAc(0.5mL,37%)中的(S)-苄基-3-异丙基-4-(((顺 式)-4-(三氟甲基)环己基)甲基)哌嗪-1-羧酸酯(35mg,0.08毫摩尔)溶液搅拌 2小时。将反应混合物用水(10mL)处理并用EtOAc(3×10mL)萃取。将含水层 用饱和NaHCO3溶液调节至pH=8-9,用EtOAc(3×10mL)萃取。将合并的有机 层用盐水清洗,在无水Na2SO4上干燥,过滤并在减压下浓缩以得到黄色油状 物的粗(S)-2-异丙基-1-(((顺式)-4-(三氟甲基)环己基)甲基)哌嗪(24mg,100%), 其不经进一步纯化直接用于下一步骤。在2分钟色谱分析中,LC-MS tR=0.742分钟,m/z 293.2[M+H]+。
步骤6
在N2下,在100℃下将无水甲苯(0.5mL)中的(S)-2-异丙基-1-(((顺 式)-4-(三氟甲基)环己基)甲基)哌嗪(20mg,0.07毫摩尔)、4-溴-2-(甲磺酰基) 苯甲腈(21.4mg,0.08毫摩尔)、Cs2CO3(66.7mg,0.21毫摩尔)、X-phos(8.4mg, 0.01毫摩尔)和Pd2(dba)3(12.5mg,0.01毫摩尔)溶液搅拌6小时。向混合物添 加水(5mL)并用EtOAc(3×5mL)萃取。将合并的有机层用水(2×10mL)和盐水 (10mL)清洗,在无水Na4SO4上干燥,过滤并在减压下浓缩。通过制备型HPLC 分离纯化残余物以提供无色油状物的4-((S)-3-异丙基-4-(((顺式)-4-(三氟甲基) 环己基)甲基)哌嗪-1-基)-2-(甲磺酰基)苯甲腈(2.4mg,8%)。在2分钟色谱分 析中,LC-MS tR=0.954分钟,m/z 472.1[M+H]+。1H NMR(CD3OD):δ7.76 (d,J=8.8Hz,1H),7.50(d,J=2.8Hz,1H),7.17(dd,J=2.8Hz,8.8Hz,1H), 3.71-3.66(m,2H),3.28(s,3H),3.25-3.23(m,1H),3.18-3.14(m,1H),2.88-2.82 (m,1H),2.50-2.44(m,1H),2.28-2.27(m,1H),2.26-2.20(m,1H),2.19-2.15(m, 1H),2.13-2.10(m,1H),1.93-1.91(m,1H),1.83-1.52(m,8H),1.06(d,J=6.8Hz, 3H),0.97(d,J=6.8Hz,3H)。
使用相似过程制备以下化合物。
a,b在手性柱上通过HPLC分离异构体,*处的立体化学为任意指定的。
实施例51
(2S)-2-异丙基-4-(3-(甲磺酰基)苯基)-1-((四氢-2H-吡喃-3-基)甲基)哌嗪(化合 物编号51-1)
向(S)-3-异丙基-1-(3-(甲磺酰基)苯基)哌嗪(10mg,0.035毫摩尔)、四氢 -2H-吡喃-3-甲醛(8mg,0.070毫摩尔)、乙酸(4μL,0.070毫摩尔)和1,2-二氯 乙烷(1mL)的搅拌溶液添加NaBH(OAc)3(37mg,18毫摩尔)。过夜搅拌混合物。 浓缩后,在MeOH中收集残余物,通过制备型HPLC纯化,得到为其TFA 盐的标题化合物(19mg,定量)。LC-MS方法4tR=0.56分钟,m/z=381。1H NMR(CD3OD)δ1.05-1.13(m,3H),1.14-1.22(m,3H),1.44-158(m,1H),1.62-1.75(m,2H),1.90-2.25(m,3H),2.52-2.65(m,1H),2.90-3.10(m,1H),3.13 (s,3H),3.15-3.25(m,1H),3.30-3.45(m,5H),4.45-3.55(m,1H),3.75-3.95(m, 4H),7.34-7.40(m,1H),7.45-7.59(m,3H)。
使用相似过程制备以下化合物。
a在手性柱上通过HPLC分离异构体,环己烷环的顺反立构为任意指定的。
实施例52
(2S)-2-异丙基-1-((1-甲基-6-(三氟乙基)哌啶-3-基)甲基)-4-(3-(甲磺酰基)苯基) 哌嗪(化合物编号52-1)
在室温下将(2S)-2-异丙基-4-(3-(甲磺酰基)苯基)-1-((6-(三氟甲基)哌啶-3-基)甲基)哌嗪(12mg,0.027毫摩尔)、甲醛(37%水溶液,200μL,过量)、甲醇 (1.5mL)、乙酸(3滴)的混合物搅拌1.5小时。添加硼氢化钠(~12mg,过量), 将混合物在室温下搅拌30分钟。LC-MS测得反应完成。将混合物用1%HCl 淬灭,浓缩,通过Gilson纯化以得到4.2mg(34%)标题化合物。LC-MS(1分 钟方法):tR=0.58分钟,m/z 462(M+1)。1H NMR(CD3OD)δ7.58-7.46(m,3H), 7.38(d,J=8Hz,1H),3.92(d,1H),3.84(m,2H),3.48-3.32(m,3H),3.23(m,2H), 3.12(s,3H),3.06(m,1H),2.82(m,2H),2.59(d,3H),2.32(m,1H),1.93(m,2H),1.82(m,1H),1.58(m,1H),1.21(d,3H),1.11(d,3H)。
实施例53
(S)-4,4-二甲基-1-((4-(3-(甲磺酰基)苯基)-2-苯基哌嗪-1-基)甲基)环己-1-醇(化 合物编号53-1和53-2)
实施例54
(R)-N-(4-(3-异丙基-4-(4-(三氟甲基)嘧啶-2-基)哌嗪-1-基)-2-(甲磺酰基)苄基) 乙酰胺(化合物编号54-1)
使用相似过程制备以下化合物。
生物学测试例1
LXRα/β放射性配体结合分析
在竞争性结合分析中评估本发明的化合物,其中在放射性标记的LXR 配体[3H]TO901317存在下,将不同浓度的化合物用LXR配体结合域(LBD) 孵育。通过闪烁迫近分析法(SPA)测量与[3H]T0901317络合的LXR-LBD量, 该SPA利用LXR-LBD对聚赖氨酸包覆的硅酸钇珠的非特异性结合。在96 孔板中,在含有2.5%DMSO、1%丙三醇、2mM EDTA、2mM CHAPS和5mM DTT的80μL磷酸盐缓冲盐水(PBS)缓冲液中,用15nM[3H]TO901317(25至 40Ci/mmol)和不同浓度的测试化合物在室温下孵育部分纯化的LXRαLBD 蛋白或LXRβLBD蛋白(15-45nM)30分钟。将聚赖氨酸SPA珠(50μg)添加至 每个孔并将总体积调节至120μL。将孔板在定轨摇床上振荡20分钟,然后在 室温下再放置10分钟,然后以2000转每分钟短暂离心1分钟。在液体闪烁计数器(Perkin Elmer,沃尔瑟姆,马萨诸塞州)上测量SPA信号,根据总结合(DMSO对照)和非特异性结合(5μM的未标记的TO901317)对照,将 结果用于计算IC50值。根据等式1计算Ki值,其中[RL]在分析中是 [3H]TO901317的最终浓度,通过直接滴定这些蛋白的放射性配体分别测定 20nM和10nM的TO901317的Kd值,该TO901317对应于LXRα和LXRβ 的LBD。
生物学测试例2
LXR荧光素酶转录报告基因分析
LXR荧光素酶转录报告基因分析测量LXR配体通过LXR的配体结合域 (LBD)促进转录活性的能力。分析可以在“激动剂”模式运行以证明本发明化 合物的激动剂活性,也可以用本发明的LXR拮抗剂化合物在“拮抗剂”模式运 行。将HEK293细胞置于100mm培养皿中,生长至80至90%覆盖,用表达 质粒和荧光素酶报告质粒pG5-Luc(Promega,麦迪逊,威斯康辛州)分批转染, 该表达质粒含有与LXRαLBD或LXRβLBD融合的Gal4DNA结合域,该荧 光素酶质粒具有萤火虫荧光素酶基因(luc+)上游的Gal4应答元件。用 LipofectamineTM2000(LifeTechnologies,格兰德岛,纽约州)根据制造商建议 方案完成转染。转染后5小时,在没有除去转染培养基的条件下,将DMEM 中的15mL 10%的炭处理FBS(Hyclone,#SH30070.03)添加至转染皿,将细胞 在37℃下过夜培养。第二天,将转染的细胞胰蛋白酶化,用PBS冲洗,重悬于10%炭处理的DMEM培养基,置于96孔板,每孔60000至80000个细 胞/100μL。将细胞在37℃孵育~4小时,然后加入100μL不同浓度的测试化 合物或对照配体(最终DMSO浓度为0.2%)。在用物质孵育细胞16小时后, 弃除培养基,加入Bright-GloTM荧光素酶试剂(Cat.#E2610,Promega,麦迪 逊,威斯康辛州)以溶解细胞并引发荧光素酶反应。作为荧光素酶活性的测量, 在多标签读数器(Perkin Elmer,沃尔瑟姆,马萨诸塞州)上检测发光。与在化合物不存在下孵育的细胞,在测试化合物的存在下,转录活性表 达为荧光成倍变化。用XLfitTM程序(IDBS,吉尔福德,英国)计算EC50值。
为了证明化合物对抗转录的能力(“拮抗剂”模式),同样地实施该分析, 除了T0901317(完全LXR激动剂)包括在测试化合物或对照中以引起接近最 大转录活化,该T0901317最终浓度为200nM。
生物学测试例3
人LXRα和LXRβ辅激活子补充FRET分析
该分析基于LXR-LBD(LXRα和LXRβ)补充辅激活子肽并与其相互作用 的活性。以“激动剂”模式运行该分析以表征显示LXR激动剂活性的本发明化 合物,以“拮抗剂”模式运行以表征具有LXR拮抗剂活性的本发明化合物,该 分析引起在完全LXR激动剂T0901317的存在下辅激活子肽的浓度依赖性释 放。通过时间分辨荧光能量共振转移(TR-FRET)来测量在S-转移酶标记的谷 胱甘肽(GST)、重组人LXRα-LBD或重组人LXRβ-LBD和荧光素共轭的辅激 活子肽SRC2-3(Cat#PV4588,Life Technologies,格兰德岛,NY)之间的相互 作用。以80μL的总体积,在含有150mM NaCl和5mM DDT的20mM TRIS-HCl 缓冲剂,pH 8中,在96孔板半区域黑色Opti板(Cat#3686,Corning,Lowell, MA)中进行分析。将测试化合物溶解在DMSO中,还在DMSO中制备半对 数(3.162×)系列稀释物,如40×溶液。
将2μL的DMSO溶液转移到孔板,立即向孔添加38μL的10nM LXRα-LBD或LXRβ-LBD(2×)。在室温下,在轨道微振动器(DPC5) 上振荡板5分钟,其后向所有孔添加40μL的200nM荧光素-SRC2-3肽和20nM 铽-抗GST抗体(Cat#PV3550,Life Technologies,格兰德岛,NY)溶液(4×)。 在室温下密封板并摇动板2分钟,在室温下培养2小时而不搅动。在多标签读数器(Perkin Elmer,Waltham,MA)上,通过在340nm(UV2-TRF滤 波器)激发,在施用LANCE/DELPHIA镜的520nm(荧光素过滤器)和 495nm(Terbium)检测所激发的能量来读板。分别设置延迟时间和窗口时间为 100微秒和200微秒。通过将荧光素信号(520)标准化为铽信号(495)获得 TR-FRET比值。基于由DMSO对照(最小SRC2-3补充)获得的低TR-FRET 比值和由5μM T0901317(完全SRC2-3补充)观测的高信号来计算百分比对照/辅激活子补充值。将百分比对照vs.化合物浓度数据纳入四参数模型,对应于 浓度响应曲线拐点的浓度作为由拟合计算EC50值。
当以“拮抗剂模式”进行该分析时,添加250nM T0901317(完全LXR激动 剂)以引起最大SRC2-3补充。简要来说,向含有测试化合物的系列稀释物的 所有孔添加5μL T091317(4.25μM)17×溶液。
基于由250nM T0901317(~75%SRC2-3补充)获得的高TR-FRET比值和 由拮抗剂化合物(SRC2-3释放)观测的低信号来计算百分比抑制/辅激活子释 放值。
表3:LXR结合和激动活性
a使用生物学测试例1的过程测量;b使用生物学测试例2激动剂模式的过程 测量;c使用生物学测试例3激动剂模式的过程测量;%表明可检测处的效率。
表4:LXR拮抗剂活性
a使用生物学测试例2拮抗剂模式的过程测量;b使用生物学测试例3拮抗剂 模式的过程测量;%表明可检测处的效率。
Claims (18)
1.一种由以下结构式表示的化合物或其药学上可接受的盐:
其中
Q是
1)R10OC(=O)-;
2)杂芳环,其任选地由独立选自R21的1个至3个基团取代;
3)式R30-L基团,其中R30任选地由独立选自R31的1个至3个基团取代;或
4)式R40-L基团,其中R40任选地由独立选自R41的1个至3个基团取代;
R1选自(C1-C6)烷基、(C3-C6)环烷基、(C3-C6)环烷基烷基(C1-C3)烷基;芳基(C1-C3)烷基、卤代(C1-C6)烷基、卤代(C3-C6)环烷基、卤代(C3-C6)环烷基(C1-C3)烷基、氨基、(C1-C6)烷基氨基、二(C1-C6)烷基氨基、芳基(C1-C3)烷基氨基和{芳基(C1-C3)烷基}{(C1-C6)烷基}氨基,其中芳基任选地由独立选自卤素、氰基、CONH2、(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基和卤代(C1-C3)烷氧基的1个至3个基团取代;
R2选自氢、卤素、氰基、CONH2、羟基(C1-C3)烷基、氨基(C1-C3)烷基、(C1-C3)烷氧基(C1-C3)烷基、(C1-C3)烷基羰基(C1-C3)烷基和(C1-C3)烷基羰基氨基(C1-C3)烷基;或R2是5元杂芳基,其任选地由独立选自卤素、氰基、甲基、CF3、甲氧基、甲氧基羰基、乙氧基羰基和CONH2的1个或2个基团取代;
R3是(1)(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C6)环烷基、卤代(C3-C6)环烷基、(C1-C3)烷氧基(C1-C3)烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基羰基或(C1-C6)烷氧基羰基(C1-C3)烷基或氰基(C1-C6)烷基;或(2)芳基、杂芳基、芳基(C1-C3)烷基或杂芳基(C1-C3)烷基,其各自任选地由选自卤素、氰基、(C1-C3)烷基、CF3、甲氧基和CONH2的1个至3个取代基取代;
R4是氢或(C1-C6)烷基;
R10选自(C1-C8)烷基、芳基(C1-C3)烷基、卤代(C1-C6)烷基、(C3-C7)环烷基、(C3-C6)环烷基(C1-C3)烷基、卤代(C3-C7)环烷基和卤代(C3-C6)环烷基(C1-C3)烷基;
R30是芳基或含有独立选自N、O和S的1个至4个杂原子的5元或6元杂芳香族基团;
R40是(C4-C7)环烷基或杂环基;
R21、R31和R41各自独立选自卤素、羟基、氨基、硝基、(C1-C6)烷基、卤代(C1-C6)烷基、(C3-C6)环烷基、(C1-C6)烯基、(C1-C6)烷氧基、卤代(C1-C6)烷氧基、羟基(C1-C6)烷基、羟基(C1-C6)卤代烷基、(C1-C3)烷氧基(C1-C3)烷基、卤代(C1-C3)烷氧基(C1-C3)烷基、(C1-C3)烷氧基(C1-C3)卤代烷基、(C1-C6)烷硫基、卤代(C1-C6)烷硫基、(C1-C3)烷硫基(C1-C3)烷基、卤代(C1-C3)烷硫基(C1-C3)烷基、氰基(C1-C6)烷基、CO2H、(C1-C6)烷氧基羰基、(C1-C6)烷基磺酰基、(C1-C6)卤代烷基磺酰基、(C1-C3)烷基磺酰基(C1-C3)烷基、卤代(C1-C3)烷基磺酰基(C1-C3)烷基、杂环基、R22R23NCO、R22R23NCO(C1-C3)烷基、R22CONH、R22CONH(C1-C3)烷基、R22SO2NH、R22SO2NH(C1-C3)烷基、R22R23N、R22R23N(C1-C3)烷基和芳基(C1-C3)烷基,其中芳基(C1-C3)烷基任选地由R25取代;
R22选自H、(C1-C6)烷基、卤代(C1-C6)烷基、羟基(C1-C6)烷基、(C1-C6)烷氧基(C1-C6)烷基、(C1-C6)烷氧基羰基(C1-C6)烷基、(C1-C6)烷氧基羰基氨基(C1-C6)烷基和杂环基,其中杂环基任选地由独立选自R24的1个或2个基团取代;
R23是氢、(C1-C6)烷基、(C1-C6)烷氧基或卤代(C1-C6)烷基;或R22和R23和与其连接的氮一起形成氮杂环丁烷环、吡咯烷环、哌啶环、哌嗪环或吗啉环,其各自任选地由独立选自R24的1个或2个基团取代;
R24选自卤素、羟基、氨基(C1-C3)烷基、卤代(C1-C3)烷基、(C1-C3)烷氧基和(C1-C6)烷氧基羰基;
R25是羟基(C1-C6)烷基或CO2H;
L是CH2、CHCH3或C(CH3)2;
Y是氢、卤素、氰基、(C1-C3)烷基、甲基、卤代烷基或甲氧基,其中
杂芳环指含有独立选自N、O和S的1个至4个杂原子的5元或6元杂芳香族基团,其任选地与含有选自N、O和S的0个至4个杂原子的饱和环或不饱和环稠合;
杂环基指含有独立选自N、O和S的1个至4个杂原子的4元、5元、6元和7元饱和杂环或部分不饱和杂环;
芳基指苯基。
2.根据权利要求1所述的化合物,其中
Q是
1)R10OC(=O)-;
2)2-吡啶基、3-吡啶基、4-吡啶基、3-哒嗪基、2-嘧啶基、4-嘧啶基、2-吡嗪基、2-唑基、2-噻唑基、1,3,4-噻二唑-2-基、2-吡啶酮-4-基、2-苯并唑基、2-苯并噻唑基、噻唑并[4,5-b]吡啶-2-基、噻唑并[4,5-c]吡啶-2-基、噻唑并[5,4-c]吡啶-2-基或噻唑并[5,4-b]吡啶-2-基,其各自任选地由独立选自R21的1个至3个基团取代;
3)苯基CH2、苯基CHMe、吡啶基CH2、呋喃基CH2,其各自任选地由独立选自R31的1个至3个取代基取代;或
4)环己基CH2、双环[3.1.0]己基CH2、螺[2.5]辛基CH2、哌啶基CH2、吡咯烷基CH2和四氢吡喃基CH2,其各自任选地由独立选自R41的1个至3个取代基取代;
R1选自Me、-NH2、-NHMe和-NMe-4-甲氧基苄基;
R2选自(1)H、F、Cl、CN、CF3、CH2OH、CH2NH2、CONH2、CH2OAc、CH2OMe和CH2NHAc或(2)2-唑基、1,3,4-二唑-2-基、1,2,4-二唑-5-基、2-噻唑基和1,3,4-噻二唑-2-基,其各自任选地由选自甲基、氰基、乙氧基羰基和CONH2的基团取代;
Y是H、F或Cl;
R3选自i-Pr、i-Bu、t-Bu、CF3、CF2Me、CH2CMe2F、CH2CF3、CH(OMe)Me、c-Pr、c-己基、苯基、2-Cl-苯基、2-Br-苯基、2-Me-苯基、3-Cl-苯基、3-Me-苯基、4-F-苯基、4-Cl-苯基、4-Br-苯基、苄基、4-甲基-2-噻唑基、CO2Me、CMe2OH和CH2CMe2OH;
R4是H或甲基;
R10选自i-Pr、t-Bu、i-Bu、t-BuCH2、苄基、CF3CH2、CF3CHMe、CF3CMe2和2,2,3,3-四氟环丁基;
R21选自F、Cl、Br、CN、NO2、NH2、OH、Me、i-Pr、c-Pr、C(=CH2)Me、CHF2、CF3、CF2Me、OMe、Oi-Pr、OCHF2、OCH2CF3、CH2OH、CH(OH)Me、CH(OH)Et、CH(OH)CF3、CMe2OH、CMe(OH)CF3、CH(OMe)CF3、CMe2CN、C(=O)H、C(=O)Me、SO2Me、CO2H、CO2Me、CO2Et、CONR22R23、CH2NR22R23、CH2NHAc、CH2SMe、CH2NHSO2Me、CH2C6H4R25和4,4-二甲基-2-唑烷基;
R22选自H、Me、Et、n-Bu、t-Bu、CH2CH2OH、CH2CH2OMe、CH2CH2CH2OH、CH2CH2CMe2OH、CH2CH2CH2OMe、CH2CO2Et、CH2CH2CO2Et;CH2CH2CH2NHCO2Me、CH2CH2CH2NHCO2t-Bu和N-t-BuOC(=O)-3-氮杂环丁基;
R23是氢、甲基、乙基或甲氧基;或R22和R23和与其连接的氮一起形成氮杂环丁烷环或吗啉环,其各自任选地由独立选自R24的1个或2个基团取代;
R24是F、OH、OMe或NH2;
R25是CO2H或CMe2OH;
R31选自F、Cl、Br、Me、i-Pr、CF3、OCHF2、OCF3、CMe(OH)CF3、CO2Me和CMe2OH;
R41选自F、OH、OMe、Me、i-Pr、CHF2、CF3、CH2CF3、CF2CH3和CMe2OH。
3.根据权利要求1或2所述的化合物,其中
Q是吡啶基或嘧啶基,其各自由独立选自R21的1个或2个基团取代;
R1选自甲基、NH2和NHMe;
R2是H、F或CH2OH;Y是H;
R3是i-Pr;
R4是H。
4.根据权利要求1或2所述的化合物,其中
Q是2-吡啶基或2-嘧啶基,其各自由1个CF3基团取代和任选地由选自R21的第二基团取代;
R1是甲基。
5.根据权利要求1或2所述的化合物,其中至少1个R21是羟基(C1-C4)烷基。
6.根据权利要求1或2所述的化合物,其中
Q是苯基CH2或吡啶基CH2,其各自任选地由独立选自R31的1个至3个取代基取代;
R1是甲基、NH2或NHMe;
R2是H、F或CH2OH;
Y是H;
R3选自i-Pr、苯基和卤代苯基;
R4是H。
7.根据权利要求1或2所述的化合物,其中
Q是苯基CH2或3-吡啶基CH2,其各自由1个CF3基团取代并任选地由选自R31的另一个基团取代;
R1是甲基;
R3是异丙基。
8.根据权利要求1或2所述的化合物,其中
Q是环己基CH2、哌啶基CH2或四氢吡喃基CH2,其各自任选地由独立选自R41的1个至3个取代基取代;
R1是甲基、NH2或NHMe;
R2是H、F或CH2OH;
Y是H;
R3是异丙基、苯基或卤代苯基;
R4是H。
9.根据权利要求1或2所述的化合物,其中
Q是环己基CH2、3-哌啶基CH2或3-四氢吡喃基CH2,其各自由1个CF3基团取代并任选地由选自R41的另一个基团取代;
R1是甲基;
R3是异丙基。
10.根据权利要求1所述的化合物,其中所述化合物是式Ia或Ib的化合物或其药学上可接受的盐:
11.根据权利要求1所述的化合物,其中所述化合物由结构式Ic、Id、Ie、If、Ig、Ih、Ii或Ij表示或是其药学上可接受的盐:
其中m是1、2或3。
12.根据权利要求1所述的化合物,其中所述化合物由结构式Ik、Il、Im、In、Io或Ip表示或是其药学上可接受的盐:
其中n是0、1或2;A是CH2、NH、NMe或O。
13.一种药物组合物,其包含药物载体或稀释剂和权利要求1至12中任一项所述的化合物或其药学上可接受的盐。
14.权利要求1至12中任一项所述的化合物或其药学上可接受的盐在制备用于治疗通过上调LXR活性可治疗的疾病或病症的药剂中的用途。
15.根据权利要求14所述的用途,其中所述疾病或病症是血脂异常;癌症;痤疮样皮肤病;皮肤炎性疾病;免疫异常;以表皮屏障功能紊乱为特征的疾病;表皮或粘膜分化异常或过度增殖的疾病;心血管疾病;视神经和视网膜病状;疾病中发生的退行性神经病变;自身免疫病;对中枢或外周神经系统的创伤性损伤;神经退行性疾病;由于老化的退行性过程;或者肾脏的疾病或病症。
16.根据权利要求15所述的用途,其中所述疾病或病症是高血脂、高胆固醇血症、高脂蛋白血症、高甘油三酯血症、脂肪代谢障碍、肝脂肪变性、非酒精性脂肪肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、高血糖症、胰岛素抵抗、糖尿病、血脂障碍、动脉粥样硬化、胆石病、普通痤疮、皮炎、银屑病、湿疹、皮肤创伤、皮肤老化、光老化、皱纹、糖尿病、C型尼曼匹克病、帕金森病、阿尔茨海默病、炎症、黄瘤、肥胖症、代谢综合症、X综合症、卒中、外周闭塞性疾病、失忆症、糖尿病性神经病变、蛋白尿症、肾小球疾病、糖尿病性肾病、高血压性肾病、IGA肾病、局灶节段性肾小球硬化症、高磷血症、高磷血症的心血管并发症、急性冠脉综合征、癌症或多发性硬化症。
17.根据权利要求16所述的用途,其中所述疾病或病症是动脉粥样硬化、阿尔茨海默病、急性冠脉综合征、黑素瘤或过敏性皮炎。
18.根据权利要求16所述的用途,其中所述疾病或病症是接触性皮炎或过敏性皮炎。
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UY37659A (es) * | 2017-04-10 | 2018-10-31 | Phenex Fxr Gmbh | Moduladores del receptor x del hígado (lxr) |
CN111635356A (zh) * | 2018-11-23 | 2020-09-08 | 厦门大学 | Carm1小分子抑制剂的化合物、可药用盐、药物组合及用途 |
US20220257596A1 (en) | 2019-07-15 | 2022-08-18 | Novartis Ag | Methods for treating meibomian gland dysfunction with liver x receptor agonists |
CN114470216A (zh) * | 2020-10-23 | 2022-05-13 | 和记黄埔医药(上海)有限公司 | 多受体酪氨酸激酶抑制剂与化疗剂的药物组合及其使用方法 |
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US10144715B2 (en) | 2018-12-04 |
EP3177617B1 (en) | 2019-10-09 |
CN106715413A (zh) | 2017-05-24 |
EP3177617A1 (en) | 2017-06-14 |
EA031480B1 (ru) | 2019-01-31 |
BR112017002260A2 (pt) | 2017-11-21 |
JP2017523222A (ja) | 2017-08-17 |
IL250247A0 (en) | 2017-03-30 |
US20170226067A1 (en) | 2017-08-10 |
IL250247B (en) | 2020-07-30 |
AU2015301207B2 (en) | 2020-01-30 |
JP6605583B2 (ja) | 2019-11-13 |
CA2956360A1 (en) | 2016-02-11 |
KR20170032468A (ko) | 2017-03-22 |
WO2016022521A1 (en) | 2016-02-11 |
SG11201700655WA (en) | 2017-02-27 |
AU2015301207A1 (en) | 2017-03-02 |
MX2017001603A (es) | 2017-09-07 |
ES2768685T3 (es) | 2020-06-23 |
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