CN110719913A - 诱导软骨发生的化合物和组合物 - Google Patents
诱导软骨发生的化合物和组合物 Download PDFInfo
- Publication number
- CN110719913A CN110719913A CN201880037287.1A CN201880037287A CN110719913A CN 110719913 A CN110719913 A CN 110719913A CN 201880037287 A CN201880037287 A CN 201880037287A CN 110719913 A CN110719913 A CN 110719913A
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- Prior art keywords
- substituted
- compound
- oxabicyclo
- carboxamide
- hydroxy
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Abstract
本发明提供了一种具有式(I)的化合物或其药学上可接受的盐;或其药学上可接受的盐、互变异构体或立体异构体,其中变量如本文中所定义。本发明进一步提供了包含此类化合物的药物组合物;以及使用此类化合物治疗哺乳动物的关节损害或损伤、诱导透明软骨产生或诱导软骨发生性祖细胞分化为成熟软骨细胞的方法。
Description
相关申请的交叉引用
本申请要求于2017年6月9日提交的美国临时申请序列号62/517,394的权益,将其通过引用以其全文并入本文。
技术领域
本发明涉及用于治疗或预防由关节损伤和关节炎引起的关节损害的组合物和方法。
背景技术
骨关节炎(OA)代表最常见的肌肉骨骼障碍。目前大约有4000万美国人受到影响,且由于人口老龄化和预期寿命延长,预计在未来二十年内,这一数字将增加到6000万,使骨关节炎成为导致残疾的第四大原因。OA的特征在于关节的缓慢退行性破坏,所述关节包括关节软骨(含有细胞和基质,其为关节产生润滑和缓冲)和关节软骨下面的软骨下骨。OA可被认为是多种病因的结果。例如,骨关节炎可能由关节软骨或骨的异常生物力学应力或者遗传或后天异常引起。目前OA治疗包括使用口服NSAID或选择性环氧合酶2(COX-2)抑制剂、关节内(IA)注射药剂例如皮质类固醇和透明质酸、以及手术方法来缓解疼痛。
关节损害例如急性关节损伤(如半月板或韧带撕裂)或关节内骨折也可导致关节炎,例如创伤后关节炎。由于关节软骨的修复能力有限,所以即使很小的不可检测的损害通常也会随着时间的推移而恶化并导致OA。目前关节损伤的治疗可以包括手术和聚焦于使受伤关节再生的其他侵入性方法,以及用药剂治疗以减少疼痛和炎症。
间充质干细胞(MSC)存在于成人关节软骨中,并且在分离后可以在体外程序化以分化为软骨细胞和其他间充质细胞谱系,并且可以用于软骨再生。部分地,所述过程受生长因子(TGFβ、BMP)、血清条件和细胞间接触的调节。
WO 2011/008773描述了肽组合物及这些组合物用于治疗或预防关节炎和关节损伤的用途以及用于诱导间充质细胞分化为软骨细胞的用途。此外,WO 2012/129562描述了小分子化合物、组合物及这些组合物用于改善关节炎和关节损伤的用途以及用于诱导间充质细胞分化为软骨细胞的用途。
尽管手术技术和再生技术已经在软骨恢复、延缓退化和改善关节损害的修复上取得了一些进展,但是仍持续需要改进用于有效软骨再生、治疗关节损害、和改善或预防OA的组合物和方法。
发明内容
本发明涉及用于治疗或预防由关节损伤和关节炎引起的关节损害的组合物和方法。
在一个方面,本发明提供了具有式(I)的化合物或其药学上可接受的盐、或其立体异构体;
其中R0是氢或C1-6烷基;
R2是苯基;5元或6元杂芳基或5元或6元杂环基,各自具有1至3个选自N、O和S的杂原子;其中R2是未经取代或经取代的;
R3是具有1至2个选自N、O和S的杂原子的5元或6元杂芳基;其中R3是未经取代或经取代的;
R1a、R1b、R4a和R4b各自独立地是氢、卤基、羟基、C1-6烷氧基、C1-6烷基、-NR7R8或-NR7-(CR9R10)2-4-OR11;或其中R1a和R1b之一与R4a和R4b之一一起形成环丙基,所述R1a、R1b、R4a和R4b分别附接两个碳原子;
R5、R6、R7、R9、R10和R11各自独立地是氢或C1-6烷基;
R8是氢,C3-7环烷基或具有1-3个选自N、O和S的杂原子的5元或6元杂环基;其中所述R8的C3-7环烷基或5元或6元杂环基是未经取代或经取代的;
可替代地,R5和R6或R7和R8与其附接在-NR5R6或-NR7R8中的氮原子一起分别形成具有1-3个选自N、O和S的杂原子的5元或6元杂环基;
条件是R1a、R1b、R4a和R4b不能全是氢;并且
进一步条件是当R1a、R1b、R4a或R4b是C1-6烷基时,在同一碳环原子上的其他取代基不是氢。
在另一个方面,本发明提供了药物组合物,所述药物组合物包含治疗有效量的具有式(I)或其子式的化合物、或其药学上可接受的盐或立体异构体;和一种或多种药学上可接受的载体。
在又另一方面,本发明提供了组合,特别是药物组合,所述组合包含治疗有效量的具有式(I)或其子式的化合物、或其药学上可接受的盐或立体异构体;和一种或多种治疗活性剂。
本发明的化合物,单独或与一种或多种治疗活性剂组合,可用于治疗、改善或预防急性关节损害或损伤,例如关节炎(骨关节炎、创伤性关节炎、系统性类风湿性关节炎)或退行性椎间盘疾病。此外,本发明的化合物,单独或与一种或多种治疗活性剂组合,可以用于诱导透明软骨产生或用于诱导软骨发生性祖细胞分化为可产生透明软骨细胞外基质的成熟软骨细胞成熟软骨细胞。
除非另有指定,否则术语“本发明的化合物”是指式(I)及其子式(例如,式(1A)、(1B)、(1C)、(1D)、(1E)、(1F)、(1G)、(1H)、(1I)、(1J)、(1K)、(1L)、(2A)、(2B)、(2C)、(2D)、(2E)、(2F)、(2G)、(2H)、(2I)、(2J)、(2K)、(2L))的化合物及其盐以及所有的立体异构体(包括非对映异构体和对映异构体)、旋转异构体、互变异构体和同位素标记的化合物(包括氘取代物)以及内在形成的部分。
具体实施方式
本发明提供了刺激受损关节中透明软骨产生的新型化合物。
在一个方面,本发明提供了用于修复软骨的新型化合物和组合物。还提供了通过向关节、软骨组织、或软骨邻近组织中、或全身性地施用本发明化合物或组合物来治疗、预防或改善关节炎或关节损伤的组合物和方法。此外,本发明提供了用于诱导软骨发生性祖细胞分化为正常的透明软骨细胞的组合物和方法。
定义
出于解释本说明书的目的,将应用下面的定义,并且在适宜的情况下,以单数形式使用的术语还包括复数形式,并且反之亦然。
如本文所用,术语“C1-6烷氧基”是指具有式-ORa的基团,其中Ra是如以上通常所定义的C1-6烷基基团。C1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、戊氧基和己氧基。所述烷氧基的烷基部分可以任选被取代,所述取代基包括下文对烷基基团所述的那些基团。
如本文所用,术语“C1-6烷基”是指仅由碳和氢原子组成的直链或支链烃链基团,所述基团中不存在不饱和,具有通过单键连接到分子的其余部分的从一至六个碳原子。术语“C1-4烷基”应相应地解释。C1-6烷基的实例包括但不限于甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基和1,1-二甲基乙基(叔丁基)。典型的取代基包括但不限于卤基、羟基、烷氧基、氰基、氨基、酰基、芳基、芳基烷基和环烷基或者这些基团之一的异型(heteroform),它们各自可以被对所述特定基团而言适当的取代基取代。
如本文所用的“氨基”指基团-NH2。当氨基被描述为“取代的”或“任选取代的”时,所述术语包括NR’R”,其中R’和R”各自独立为H,或者为烷基、烯基、炔基、酰基、芳基、芳基、环烷基、芳基烷基、环烷基烷基基团或这些基团之一的异型,烷基、烯基、炔基、酰基、芳基、芳基烷基或基团或这些基团之一的异型各自可以任选地被本文所述的适于相应基团的取代基取代。除非另有说明,否则包含氨基部分的本发明的化合物可以包括其被保护的衍生物。适于氨基部分的保护基包括乙酰基、叔丁氧羰基、苄氧羰基等。
如本文所用,术语“氨基C1-6烷基”是指如上定义的C1-6烷基基团,其中C1-6烷基基团的氢原子之一被伯氨基基团替代。氨基C1-6烷基的代表性实例包括但不限于氨基-甲基、2-氨基-乙基、2-氨基-丙基、3-氨基-丙基、3-氨基-戊基和5-氨基-戊基。
如本文所用,术语“C1-4烷基氨基”是指具有式-NH-Ra的基团,其中Ra是如以上所定义的C1-4烷基基团。
如本文所用的“芳族”是指其中组成原子构成不饱和环系的部分,其中在所述环系中的所有原子均为sp2杂化,pi电子的总数等于4n+2。芳族环中的环原子可以仅为碳原子,或者其可以包含碳和非碳原子(参见杂芳基)。
如本文所用的“芳基”是指包含6-14个环原子的单环或多环芳族环组件(assembly),其中所有的环原子均为碳原子。通常,芳基为6元(环原子)单环、10-12元双环或14元稠合三环芳族环系。六至十四元芳基包括但不限于苯基、联苯基、萘基、薁基(薁基)和蒽基(anthracenyl)。芳基可以是未经取代的,或者被1-5个(例如一个或两个或三个)取代基取代,所述取代基独立地选自由以下组成的组:羟基、巯基、氰基、硝基、C1-4烷基、C1-4烯基、C1-4炔基、C1-4烷氧基、硫代C1-4烷基、C1-4烯基氧基、C1-4炔基氧基、卤素、C1-4烷基羰基、羧基、C1-4烷氧基羰基、氨基、C1-4烷基氨基、二-C1-4烷基氨基、C1-4烷基氨基羰基、二-C1-4烷基氨基羰基、C1-4烷基羰基氨基、C1-4烷基羰基(C1-4烷基)氨基、磺酰基、氨磺酰基、烷基氨磺酰基、C1-4烷基氨基磺酰基、芳基、杂芳基、环烷基和杂环基,其中前述取代基各自可以进一步被一个或多个独立地选自卤素、烷基、羟基或C1-4烷氧基基团的取代基取代。当“芳基”与另一个基团一起表示如“芳基烷基”、“芳基氧基烷基”、“芳基氧基羰基”、“芳基氧基-羰基烷基”时,芳基部分应当具有与上述“芳基”定义中所述相同的含义。如本文所用的“双环的”或“双环基”是指两个环的环组件,其中所述两个环稠合到一起、通过单键连接或者通过两个桥接原子连接。所述环可以是碳环基、杂环基或其组合。
如本文所用的“桥接环”是指多环环系,其中两个环共有的两个环原子彼此不直接结合。所述环系中的一个或多个环还可以含有杂原子作为环原子。桥接环的非排他性实例包括降冰片基、氧杂双环[2.2.1]庚烷基、氮杂双环[2.2.1]庚烷基、金刚烷基等。
如本文所用的“环烷基”意指包含3至14个环成员的非芳族、饱和单环、双环、三环、稠合、桥接或螺多元烃环系的基团,其中所有环成员均为碳原子。示例性的单环环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基等。示例性的双环环烷基包括双环[2.2.1]庚烷、双环[3.2.1]辛基、冰片基、降冰片基、十氢萘基、双环[2.1.1]己基、双环[2.2.1]庚基、双环[3.1.1]庚基和双环[2.2.2]辛基。示例性的三环环烷基基团包括例如金刚烷基。环烷基可以是未经取代的,或者被一个或两个或三个或更多个取代基取代,所述取代基独立地选自由以下组成的组:羟基、巯基、氰基、硝基、氧代、烷基亚氨基、C1-4烷基、C1-4烯基、C1-4炔基、C1-4烷氧基、C1-4硫代烷基、C1-4烯基氧基、C1-4炔基氧基、卤素、C1-4烷基羰基、羧基、C1-4烷氧基羰基、氨基、C1-4烷基氨基、二-C1-4烷基氨基、C1-4烷基氨基羰基、二-C1-4烷基氨基羰基、C1-4烷基羰基氨基、C1-4烷基羰基(C1-4烷基)氨基、磺酰基、氨磺酰基、烷基氨磺酰基、C1-4烷基氨基磺酰基,其中上述烃基团(例如烷基、烯基、炔基、烷氧基残基)各自可以进一步被一个或多个残基取代,所述残基在每次出现时独立地选自卤素、羟基或C1-4烷氧基基团。
如本文所用的“氰基”指基团-CN。
如本文所用的“EC50”是指产生50%功效的调节剂的摩尔浓度。
如本文所用的“IC50”是指产生50%抑制作用的抑制剂或调节剂的摩尔浓度。
如本文所用,“稠合环”是指多环组件,其中包含所述环组件的环如此连接,使得两个环共有的环原子彼此直接键合。稠合环组件可以是饱和的、部分饱和的、芳香族的、碳环的、杂环的等。常见稠合环的非排他性实例包括十氢化萘、萘、蒽、菲、吲哚、苯并呋喃、嘌呤、喹啉等。
如本文所用的“卤基(halo)”或“卤素”是指氟、氯、溴和碘。
如本文所用的“卤基取代的C1-6烷基”是指被如以上所定义的一种或多种卤基基团取代的如以上所定义的C1-6烷基基团。卤基取代的C1-6烷基的实例包括但不限于三氟甲基、二氟甲基、氟甲基、三氯甲基、2,2,2-三氟乙基、1,3-二溴丙烷-2-基、3-溴-2-氟丙基和1,4,4-三氟丁烷-2-基。
如本文所用的“杂芳基”是指包含独立地选自氮、氧和硫的1、2、3或4个杂原子的5元或6元芳族单环环基团。杂芳基基团可以经由碳原子或杂原子键合。杂芳基的实例包括但不限于呋喃基、吡咯基、噻吩基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、四唑基、吡嗪基、哒嗪基、嘧啶基或吡啶基。杂芳基可以是未经取代的,或者被一个或更多个取代基取代,所述取代基独立地选自羟基、巯基、氰基、硝基、C1-4烷基、C1-4烯基、C1-4炔基、C1-4烷氧基、硫代C1-4烷基、C1-4烯基氧基、C1-4炔基氧基、卤素、C1-4烷基羰基、羧基、C1-4烷氧基羰基、氨基、C1-4烷基氨基、二-C1-4烷基氨基、C1-4烷基氨基羰基、二-C1-4烷基氨基羰基、C1-4烷基羰基氨基、C1-4烷基羰基(C1-4烷基)氨基、磺酰基、氨磺酰基、烷基氨磺酰基、C1-4烷基氨基磺酰基,其中上述烃基团(例如烷基、烯基、炔基、烷氧基残基)各自可以进一步被一个或多个残基取代,所述残基在每次出现时独立地选自卤素、羟基或C1-4烷氧基基团。当杂芳基与另一个基团一起表示如“杂芳基氧基”、“杂芳基氧基烷基”、“杂芳基氧基羰基”时,杂芳基部分应当具有与上述“杂芳基”的定义所述相同的含义。
如本文所用的“杂原子”指不是碳原子的原子。杂原子的特定实例包括但不限于氮、氧和硫。
如本文所用的“杂环基”或“杂环的”是指包含独立地选自氮、氧和硫的1、2或3个杂原子的稳定的5元或6元非芳族单环环基团。杂环基基团可以经由碳原子或杂原子键合。杂环基的实例包括但不限于氮杂环丁烷基、氧杂环丁烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、哌嗪基、四氢吡喃基、吗啉基或过氢氮杂基(perhydroazepinyl)。杂环基可以是未经取代的,或者被1-5个取代基(例如一个、或两个、或三个)取代,每个取代基独立地选自羟基、巯基、氰基、硝基、氧代、烷基亚氨基、C1-4烷基、C1-4烯基、C1-4炔基、C1-4烷氧基、C1-4硫代烷基、C1-4烯基氧基、C1-4炔基氧基、卤素、C1-4烷基羰基、羧基、C1-4烷氧基羰基、氨基、C1-4烷基氨基、二-C1-4烷基氨基、C1-4烷基氨基羰基、二-C1-4烷基氨基羰基、C1-4烷基羰基氨基、C1-4烷基羰基(C1-4烷基)氨基、磺酰基、氨磺酰基、烷基氨磺酰基、C1-4烷基氨基磺酰基,其中上述烃基团(例如烷基、烯基、炔基、烷氧基残基)各自可以进一步被一个或多个残基取代,所述残基在每次出现时独立地选自卤素、羟基或C1-4烷氧基基团。
如本文所用的羟基是指基团-OH。
如本文所用的“被保护的衍生物”是指抑制剂的衍生物,其中一个或多个反应部位被保护基阻断。被保护的衍生物可用于制备抑制剂,或者它们自身可以具有抑制剂的活性。被保护的基团的实例包括但不限于乙酰基、四氢吡喃、甲氧基甲基醚、β-甲氧基乙氧基甲基醚、对甲氧基苄基、甲基硫代甲基醚、新戊酰、甲硅烷基醚、苄氧羰基、苄基、叔丁氧羰基、对甲氧基苯基、9-芴基甲基氧基羰基、缩醛、缩酮、缩羰酯(acylal)、二噻烷、甲基酯、苄基酯、叔丁基酯和甲硅烷基酯。合适的保护基的详细清单可以在T.W.Greene,ProtectingGroupsinOrganicSynthesis[有机合成中的保护基],第3版,John Wiley&Sons,Inc.[约翰·威利父子公司]1999中找到。
如本文所用的“未经取代或经取代的”或“任选地经取代的”表示取代基结合到指定基团的可用价位上。如本文所用的“未经取代的”表示指定基团不再有非氢取代基。如本文所用的“被取代的”或“任选地被取代”表示指定基团的可用氢原子的至少一个已经被(或者可以被)非氢取代基替代。除非另有说明,取代基的实例可包括但不限于卤基、硝基、氰基、硫代、氧基、羟基、羰基氧基、C1-6烷氧基、6元至10元芳氧基、5元至10元杂芳基氧基、羰基、氧基羰基、氨基羰基、氨基、C1-6烷基氨基、磺酰氨基、亚氨基、磺酰基、亚磺酰基、C1-6烷基、C1-6卤基烷基、羟基C1-6烷基、羰基C1-6烷基、硫代羰基C1-10烷基、磺酰基C1-6烷基、亚磺酰基C1-6烷基、C1-10氮杂烷基、亚氨基C1-6烷基、3元至12元环烷基C1-6烷基、4元至15元杂环烷基C1-6烷基、6元至10元芳基C1-6烷基、5元至10元杂芳基C1-6烷基、10元至12元双环芳基C1-6烷基、9元至12元杂双环芳基C1-6烷基、3元至12元环烷基、4元至12元杂环基、9元至12元双环烷基、3元至12元杂双环烷基、6元至12元芳基和5元至12元杂芳基。
如本文所用的“磺酰基”意指基团-S(O)2-。应当注意,术语“磺酰基”当表示单价取代基时可以替代地是指取代的磺酰基基团-S(=O)2R,其中R为氢或硫原子上的非氢取代基,这形成不同的磺酰基基团,包括磺酸、磺酰胺、磺酸酯和砜。
本文中的任意定义可以与任意其他定义组合使用以描述复合结构基团。按照惯例,任意这类定义的末端元素是与母体部分连接的元素。例如,复合基团烷氧基烷基表示与母体分子通过烷基基团连接的烷氧基基团。
如本文所用,术语“软骨细胞(chondrocyte)”是指分化的软骨细胞(cartilagecell)。软骨细胞产生并维持由胶原蛋白和蛋白聚糖组成的软骨基质。软骨细胞源自软骨发生性祖细胞的分化(CPC)。分化是从不太专化的细胞类型形成专化细胞类型的过程,例如,从软骨发生性祖细胞(CPC)形成软骨细胞。
如本文所用,术语“软骨细胞分化剂”是指诱导软骨发生性细胞分化为成熟软骨细胞的试剂,成熟软骨细胞合成软骨细胞外基质(ECM)。
如本文所用,术语“受试者”是指灵长类动物(例如,人,男性或女性)、狗、兔、豚鼠、猪、大鼠和小鼠。在某些实施例中,所述受试者是灵长类动物。在又其他实施例中,所述受试者是人。
如本文所用,术语“抑制(inhibit、inhibition或inhibiting)”是指减少或抑制给定的病症、症状或障碍、或疾病,或在生物活性或过程的基线活性方面的显著降低。
如本文所用,术语任何疾病或障碍的“治疗(treat、treating或treatment)”是指缓解或改善疾病或障碍(即,减慢或阻止疾病或其至少一种临床症状的发展);或缓解或减轻与所述疾病或障碍相关的至少一种物理参数或生物标记,包括患者可能无法辨别的那些物理参数或生物标记。
如本文所用,术语任何疾病或障碍的“预防(prevent、preventing或prevention)”是指疾病或障碍的预防性治疗;或延迟疾病或障碍的发作或进展。
如本文所用,如果受试者将在生物学上、在医学上或在生活质量上从治疗中获益,则这类受试者是“需要”这种治疗的。
如本文所用,术语本发明的化合物的“治疗有效量”是指将引起受试者的生物或医学响应(例如,酶或蛋白活性的减小或抑制,或改善症状、缓解病症、减慢或延迟疾病进展或预防疾病等)的本发明的化合物的量。在一个非限制性实施例中,术语“治疗有效量”是指本发明的化合物的如下量,当施用至受试者时,所述量有效地(1)至少部分缓解、抑制、预防和/或改善关节损伤和关节炎引起的关节损害。在另一个非限定性实施例中,术语“治疗有效量”是指本发明化合物的如下量,当施用至细胞、或组织、或非细胞生物学材料或介质时,所述量有效地促进软骨发生。
如本文所用,术语“治疗”(treat、treating、treatment)加“改善”(ameliorate、ameliorating)是指成功治疗或改善损伤、病理、病症或症状(例如疼痛)的任何指征,包括任何客观或主观参数,例如消减;缓解;减轻症状或使患者更能忍受症状、损伤、病理或病症;减少症状或病症的发生频率或持续时间;或在某些情况下,预防症状或病症的发作。症状的治疗或改善可以基于任何客观或主观参数;包括,例如身体检查的结果。
如本文所用,“施用”指对特定关节的施用。
如本文所用,术语“药物组合物”是指呈适于经口施用或肠胃外施用的形式的本发明的化合物、或其药学上可接受的盐、以及至少一种药学上可接受的载体。
如本文所用,术语“药学上可接受的载体”是指可用于制备或使用药物组合物的物质,并且包括例如适合的稀释剂、溶剂、分散介质、表面活性剂、抗氧化剂、防腐剂、等渗剂、缓冲剂、乳化剂、吸收延迟剂、盐、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、润湿剂、甜味剂、调味剂、染料及其组合,如本领域技术人员已知的(参见,例如,Remington TheScience and Practice of Pharmacy[雷明顿:药物科学与实践],第22版,PharmaceuticalPress[药物出版社],2013,第1049-1070页)。
如本文所用,术语“一个/种(a/an)”、“所述(the)”以及在本发明的上下文中使用的类似术语(特别是在权利要求的上下文中)应被解释为涵盖单数和复数二者,本文中除非另外指示或与上下文明显相矛盾。
优选的实施例的描述
本发明涉及用于治疗或预防由关节损伤和关节炎引起的关节损害的组合物和方法。
本文描述了本发明的各种列举的实施例。每个实施例中指定的特征可以与其他指定特征组合以提供本发明的另外实施例。
在一个方面,本发明提供了如上所述的具有式(I)的化合物、或其药学上可接受的盐或立体异构体。
实施例1.一种具有式(I)的化合物、或其药学上可接受的盐或立体异构体;
其中R0是氢或C1-6烷基;
R2是苯基;5元或6元杂芳基或5元或6元杂环基,各自具有1至3个选自N、O和S的杂原子;其中R2是未经取代的,或者被1-3个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基、卤基取代的C1-6烷氧基、氰基、C1-6烷基磺酰基、未经取代的苯基或被卤基取代的苯基的取代基取代;
R3是具有1至2个选自N、O和S的杂原子的5元或6元杂芳基;其中R3是未经取代的,或者被1-3个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基或-NR5R6的取代基取代;
R1a、R1b、R4a和R4b各自独立地是氢、卤基、羟基、C1-6烷氧基、
C1-6烷基、-NR7R8或-NR7-(CR9R10)2-4-OR11;或其中R1a和R1b之一与R4a和R4b之一一起形成环丙基,所述R1a、R1b、R4a和R4b分别附接两个碳原子;
R5、R6、R7、R9、R10和R11各自独立地是氢或C1-6烷基;
R8是氢,C3-7环烷基或具有1-3个选自N、O和S的杂原子的5元或6元杂环基;其中所述R8的C3-7环烷基或5元或6元杂环基是未经取代的,或者被羟基或C1-6烷基取代;
可替代地,R5和R6或R7和R8与其附接在-NR5R6或-NR7R8中的氮原子一起分别形成具有1-3个选自N、O和S的杂原子的5元或6元杂环基;
条件是R1a、R1b、R4a和R4b不能全是氢;并且
进一步条件是当R1a、R1b、R4a或R4b是C1-6烷基时,在同一碳环原子上的其他取代基不是氢。
实施例2.根据实施例1所述的化合物,所述化合物选自式(1A)、(1B)、(1C)、(1D)、(1E)、(1F)、(1G)、(1H)、(1I)、(1J)、(1K)、(1L)、(2A)、(2B)、(2C)、(2D)、(2E)、(2F)、(2G)、(2H)、(2I)、(2J)、(2K)和(2L),或其药学上可接受的盐或立体异构体;
实施例3.根据实施例2所述的化合物,所述化合物选自:
(a)式(1A)或(2A);
(b)式(1B)或(2B);
(c)式(1C)或(2C);
(d)式(1D)或(2D);
(e)式(1E)或(2E);
(f)式(1F)或(2F);
(g)式(1G)或(2G)
(h)式(1H)或(2H);
(i)式(1I)或(2I);
(j)式(1J)或(2J);
(k)式(1K)或(2K);以及
(l)式(1L)或(2L);
或其药学上的盐或立体异构体;其中各种取代基如以上实施例中任一项所定义。
实施例3A.根据实施例3所述的具有式(1A)或式(2A)的化合物。
实施例3B.根据实施例3所述的具有式(1B)或式(2B)的化合物。
实施例3C.根据实施例3所述的具有式(1C)或式(2C)的化合物。
实施例3D.根据实施例3所述的具有式(1D)或式(2D)的化合物。
实施例3E.根据实施例3所述的具有式(1E)或式(2E)的化合物。
实施例3F.根据实施例3所述的具有式(1F)或式(2F)的化合物。
实施例3G.根据实施例3所述的具有式(1G)或式(2G)的化合物。
实施例3H.根据实施例3所述的具有式(1H)或式(2H)的化合物。
实施例3I.根据实施例3所述的具有式(1I)或式(2I)的化合物。
实施例3J.根据实施例3所述的具有式(1J)或式(2J)的化合物。
实施例3K.根据实施例3所述的具有式(1K)或式(2K)的化合物。
实施例3L.根据实施例3所述的具有式(1L)或式(2L)的化合物。
实施例4.根据实施例2所述的化合物,所述化合物选自式(1A)、(1C)、(1E)、(1F)、(1G)、(1I)、(1L)、(1K)、(2A)、(2C)、(2E)、(2F)、(2G)、(2I)、(2K)和(2L),或其药学上可接受的盐或立体异构体。
实施例5.根据实施例2所述的化合物,所述化合物选自式(1A)、(1C)、(1G)、(1L)、(2A)、(2C)、(2G)和(2L),或其药学上可接受的盐或立体异构体;其中各种取代基如以上实施例中任一项所定义。在一些实施例中,R1a和R4a是羟基。
实施例5A.根据实施例5所述的化合物,所述化合物选自式(1A)、(1G)、(2A)和(2G),或其药学上可接受的盐或立体异构体;其中各种取代基如以上实施例中任一项所定义。在一些实施例中,R1a和R4a是羟基。
实施例5B.根据实施例5所述的具有式(2A)或(2G)的化合物,或其药学上可接受的盐或立体异构体;其中各种取代基如以上实施例中任一项所定义。在一些实施例中,R1a和R4a是羟基。
实施例6.根据以上实施例中任一项所述的化合物,或其药学上可接受的盐或立体异构体;其中R1a、R1b、R4a和R4b各自独立地是氢、卤基、羟基、C1-6烷氧基、-NR7R8或-NR7-(CR9R10)2-4-OR11;或其中R1a和R1b之一与R4a和R4b之一一起形成环丙基,所述R1a、R1b、R4a和R4b分别附接两个碳原子。
实施例7.根据实施例a6所述的化合物,或其药学上可接受的盐或立体异构体;其中R1a和R1b之一是氢且另一个是羟基、氟、甲氧基、甲基氨基、(2-羟乙基)氨基、二-甲基氨基、吗啉-4-基、甲基、((四氢-2H-吡喃-4-基)氨基)或(3-羟基环丁基)氨基。
实施例8.根据实施例7所述的化合物,或其药学上可接受的盐或立体异构体;其中R1a和R1b之一是氢且另一个是羟基;且R4a和R4b是氢。
实施例9.根据实施例64或5所述的化合物,或其药学上可接受的盐或立体异构体;其中R1a和R1b是氢,且R4a和R4b之一是氢且另一个是羟基或氟。
实施例10.根据实施例6所述的化合物,或其药学上可接受的盐或立体异构体;其中R1a和R1b之一和R4a和R4b之一与碳环原子一起形成与双环稠合的环丙基。
实施例11.根据以上实施例中任一项所述的化合物,或其药学上可接受的盐或立体异构体;其中R2是苯基、吡啶基、吡唑基、噻唑基或哌啶基,其各自是未经取代的,或者被1至2个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基、卤基取代的C1-6烷氧基、氰基、C1-6烷基磺酰基、未经取代的苯基或被卤基取代的苯基的取代基取代。
实施例11A.根据实施例11所述的化合物,其中R2是被1-2个独立地选自氯、氟、三氟甲基、三氟甲氧基、氰基和卤基取代的苯基的取代基取代的苯基。
实施例11B.根据实施例11所述的化合物,其中R2是被1-2个独立地选自氯、甲基、甲氧基和三氟甲基的取代基取代的吡啶基。
实施例11C.根据实施例11所述的化合物,其中R2是吡唑基或噻唑基,各自被甲基取代。
实施例11D.根据实施例11所述的化合物,其中R2是被甲基磺酰基取代的吡啶基。
实施例12.根据实施例11所述的化合物,或其药学上可接受的盐或立体异构体;其中R2选自:
被3,4-二氯、2-三氟甲基、3-三氟甲基、3-氰基-4-氯、2-氰基-4-氯、3-氟-4-氯、3-三氟甲氧基、3-氟-4-三氟甲氧基、或3-氟-4-(2-氟苯基)取代的苯基;
被6-甲氧基或2-三氟甲基取代的吡啶-4-基;
被5,6-二氯、6-甲氧基、5-氯-6-甲基或5-三氟甲基-6-甲基取代的吡啶-3-基;
被4,5-二氯取代的吡啶-2-基;
被1-甲基取代的1H-吡唑-3-基;
被5-甲基取代的噻唑-2-基;以及
被1-甲基磺酰基取代的哌啶-4-基。
实施例13.根据以上实施例中任一项所述的化合物,或其药学上可接受的盐或立体异构体;其中R3是吡啶基、嘧啶基或吡唑基,其各自是未经取代的,或者被1至2个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基或-NR5R6的取代基取代。
实施例13A.根据实施例13所述的化合物,其中R3是未经取代或被1至2个独立地选自氟、三氟甲基、甲基和甲氧基的取代基取代的吡啶基。
实施例13B.根据实施例13所述的化合物,其中R3是未经取代或被1至2个独立地选自氟、三氟甲基、甲基、氨基、二-甲基氨基和吗啉基的取代基取代的嘧啶基。
实施例13C.根据实施例13所述的化合物,其中R3是1-甲基-1H-吡唑-4-基或1-甲基-1H-吡唑-3-基。
实施例14.根据实施例13所述的化合物,或其药学上可接受的盐或立体异构体;其中R3选自:
未经取代或被2-甲基、2-三氟甲基、2-甲氧基、2-氨基、2-氟、2,3-二氟、或2,5-二氟取代的4-吡啶基;
未经取代或被6-甲基、6-甲氧基、或5,6-二氯取代的3-吡啶基;
被6-三氟甲基取代的2-吡啶基;
未经取代或被2-氟、2-甲基、2-氨基、2-三氟甲基、2-吗啉基或2-二-甲基氨基取代的嘧啶-5-基;
被2-甲基取代的嘧啶-4-基;以及
被1-甲基取代的1H-吡唑-4-基或1H-吡唑基-3-基。
实施例15.根据实施例1所述的化合物,或其药学上可接受的盐或立体异构体;其中所述化合物选自表3中的化合物1-181。
实施例15A.根据实施例1所述的化合物,或其药学上可接受的盐或立体异构体;其中所述化合物选自:
(1R,2S,3S,4R,5S)-5-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-8-氧杂双环[3.2.1.02,4]辛烷-6-甲酰胺;
(1R,2R,4S,5S,6R,7R)-N-(5,6-二氯吡啶-3-基)-7-(吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺;
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;以及
(1S,2R,3S,4R,5S,6R)-N-(3,4-二氯苯基)-5,6-二羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。
实施例16.根据实施例15或15A所述的具有式(I)的化合物,其中所述化合物是一水合物。
实施例17.一种药物组合物,所述药物组合物包含根据上述实施例1-16和子实施例中任一项所述的化合物、或其药学上可接受的盐或立体异构体、和一种或多种药学上可接受的载体。
实施例18.一种组合,所述组合包含根据上述实施例1-16和子实施例中任一项所述的化合物、或其药学上可接受的盐或立体异构体、和一种或多种治疗活性剂。
实施例19.根据实施例1-16和子实施例中任一项所述的化合物、或其药学上可接受的盐或对映异构体、以及任选地与第二治疗剂组合;用于治疗、改善或预防哺乳动物的关节炎或关节损伤;或用于软骨修复。
实施例20.根据实施例1-16和子实施例中任一项所述的化合物、或其药学上可接受的盐或对映异构体、以及任选地与第二治疗剂组合;用于制造用于关节炎或关节损伤或软骨修复的药物的用途。
实施例21.一种用于在有需要的哺乳动物中治疗、改善或预防关节炎或关节损伤或用于修复软骨的方法,所述方法包括施用治疗有效量的根据实施例1-16和子实施例中任一项所述的、以及任选地与第二治疗剂组合的化合物;从而治疗、改善或预防所述哺乳动物的关节炎或关节损害,或修复软骨。
实施例22.根据实施例19所述的化合物、根据实施例20所述的用途或根据实施例21所述的方法,其中所述关节炎是骨关节炎、创伤性关节炎或自身免疫性关节炎。
实施例23.根据实施例21所述的方法,其中所述化合物口服施用。
实施例24.一种诱导透明软骨产生的方法或一种诱导软骨发生性祖细胞分化为成熟软骨细胞的方法,所述方法包括使软骨发生性祖细胞与治疗有效量的根据实施例1-16和子实施例中任一项所述的、以及任选地与第二治疗剂组合的化合物接触;从而诱导软骨细胞祖细胞分化为产生透明软骨细胞外基质的成熟软骨细胞。
实施例25.根据实施例24所述的方法,其中所述接触步骤是在哺乳动物体外或体内进行的;并且当在体内进行时,干细胞存在于哺乳动物中。
实施例26.根据实施例24或25所述的方法,其中所述接触步骤发生在基质或生物相容性支架中。
实施例27.根据实施例19所述的化合物、根据实施例20所述的用途或根据实施例21-26中任一项所述的方法,其中所述第二治疗剂是软骨细胞分化剂。
实施例28.根据实施例19所述的化合物、根据实施例20所述的用途或根据实施例21-26中任一项所述的方法,其中所述第二治疗剂选自血管生成素样3蛋白(ANGPTL3)、胰岛素生长因子(IGF1)、SM04690、Janus激酶抑制剂、口服鲑鱼降钙素、SD-6010、维生素D3、胶原蛋白水解物、骨形态发生蛋白7(BMP7)、醋酸卢沙拉肽(rusalatide acetate)、鳄梨大豆非皂化物(ASU)、类固醇、非甾体抗炎药(NSAID)、透明质酸、kartogenin、TPX-100和具有式(II)的化合物;
或其药学上可接受的盐或立体异构体,其中
R1是苯基或5元或6元杂芳基;且R1是未经取代的,或者被1至2个独立地选自卤基、氰基、C1-6烷基、C1-4卤基烷基、-C(O)R13、-C(O)OR13、-NR14aR14b、5元和6元杂环基、苯基、以及5元和6元杂芳基的取代基取代;
其中R13是C1-6烷基或氨基;R14a和R14b独立地选自氢、C1-6烷基、-C(O)R15和-C(O)OR15;且R15是C1-4烷基;并且
其中所述R1的杂环基、苯基或杂芳基取代基是未经取代的,或者被1至2个独立地选自卤基、羟基、和C1-6烷基的取代基取代;
R3是苯基或5元或6元杂芳基;且R3是未经取代的,或者被1至2个独立地选自卤基、氰基、C1-6烷基、C1-6卤基烷基、C1-6烷氧基、C1-6卤基烷氧基、-C(O)R16、-C(O)OR16、5元和6元杂环基以及苯基的取代基取代;其中R16是C1-6烷基;且所述R3的杂环基或苯基是未经取代的,或者被1至2个选自卤素和氰基的取代基取代;
R2和R4独立地是氢或C1-6烷基;或R2和R4一起形成与双环稠合的环丙基,或R2和R4一起形成键,这在与R2和R4附接的两个碳之间产生双键。
实施例29.根据实施例19所述的化合物、根据实施例20所述的用途或根据实施例21-26中任一项所述的方法,其中所述具有式(II)的化合物选自:
(1R,2S,3R,4S)-N-(3,4-二氯苯基)-3-(1-甲基-3-(三氟甲基)-1H-吡唑-5-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1S,2R,3R,4R)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;
(1S,2S,3R,4R)-3-(2-氨基吡啶-4-基)-N-(3,4-二氯苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
(1R,2S,3S,4S)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
N-(2-氯-2’-氟-[1,1’-联苯基]-4-基)-3-(1H-吡唑-5-基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺
(1R,2R,3S,4S)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
(1S,2S,3R,4R)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
(1R,2R,3S,4S)-3-(2-氨基吡啶-4-基)-N-(3,4-二氯苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
(1R,2R,4S,5S)-N-(3,4-二氯苯基)-4-(吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-2-甲酰胺
(1R,2R,3S,4S)-N-(3,4-二氯苯基)-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺;以及
N-(2,2’-二氟-[1,1’-联苯基]-4-基)-3-(吡嗪-2-基)-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺。
实施例30.一种具有式(III)的化合物:
其中Ak是C1-6烷基;
R3是具有1至2个选自N、O和S的杂原子的5元或6元杂芳基;其中R3是未经取代的,或者被1-3个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基或-NR5R6的取代基取代;
R1a、R1b、R4a和R4b各自独立地是氢、卤基、羟基、C1-6烷氧基、C1-6烷基、-NR7R8或-NR7-(CR9R10)2-4-OR11;或其中R1a和R1b之一与R4a和R4b之一一起形成环丙基,所述R1a、R1b、R4a和R4b分别附接两个碳原子;
R5、R6、R7、R9、R10和R11各自独立地是氢或C1-6烷基;
R8是氢,C3-7环烷基或具有1-3个选自N、O和S的杂原子的5元或6元杂环基;其中所述R8的C3-7环烷基或5元或6元杂环基是未经取代的,或者被羟基或C1-6烷基取代;
可替代地,R5和R6或R7和R8与其附接在-NR5R6或-NR7R8中的氮原子一起分别形成具有1-3个选自N、O和S的杂原子的5元或6元杂环基;
条件是R1a、R1b、R4a和R4b不能全是氢;并且
进一步条件是当R1a、R1b、R4a或R4b是C1-6烷基时,在同一碳环原子上的其他取代基不是氢。
取决于起始材料和程序的选择,这些化合物可以呈可能的立体异构体形式或作为其混合物(例如作为纯的光学异构体或作为立体异构体混合物,如外消旋体和非对映异构体混合物)存在,这取决于不对称碳原子的数目。本发明旨在涵盖所有这些可能的立体异构体,包括外消旋混合物、非对映异构体混合物和光学纯的形式。光学活性(R)-和(S)-立体异构体可以使用手性合成子或手性试剂制备,或使用常规技术拆分。如果所述化合物含有双键,则取代基可以是E或Z构型。如果所述化合物含有二取代的环烷基,则环烷基取代基可以具有顺式-或反式-构型。所有互变异构形式也旨在包括在内。
本发明的化合物的任何非对称原子(例如,碳或类似物)能以外消旋或对映异构体富集的形式存在,例如,(R)-、(S)-或(R,S)-构型。在某些实施例中,每个不对称的原子在(R)-或(S)-构型中具有至少50%对映异构体过量、至少60%对映异构体过量、至少70%对映异构体过量、至少80%对映异构体过量、至少90%对映异构体过量、至少95%对映异构体过量或至少99%对映异构体过量。如果可能,在具有不饱和双键的原子上的取代能以顺式-(Z)-或反式-(E)-形式存在。
因此,如本文所用,本发明的化合物可以呈可能的立体异构体、旋转异构体、阻转异构体、互变异构体或其混合物之一的形式,例如,作为基本上纯的几何(顺式或反式)立体异构体、非对映异构体、光学异构体(对映体)、外消旋体或其混合物。
可以基于组分的物理化学差异,例如通过色谱法和/或分级结晶法将任何所得的立体异构体混合物分离成纯的或基本上纯的几何或光学异构体、非对映异构体、外消旋体。
可以通过已知方法将任何所得的终产物或中间体的外消旋体拆分成旋光对映体,例如通过分离用光学活性酸或碱得到的其非对映异构体盐,并释放出光学活性的酸性或碱性化合物。特别地,因此可以采用碱性部分将本发明的化合物拆分成它们的旋光对映体,例如通过用光学活性酸形成的盐的分级结晶,例如酒石酸、联苯甲酰酒石酸、二乙酰酒石酸、二-O,O’-对甲苯甲酰酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸。外消旋产物也可以通过手性色谱法分离,例如使用手性吸附剂的高压液相色谱法(HPLC)。
除非另有说明,否则本文中表示为单一立体异构体的化合物包括对映异构体混合物(例如,所示化合物的对映异构体和对映异构体的混合物)。此外,在将化合物描述为单一位置异构体的情况下,应理解,化合物的样品可能仍包含少量的另一种位置异构体,并且还可能作为对映异构体的混合物存在。通常,在将化合物描述为单一位置异构体或对映异构体的情况下,特定的结构至少占所示化合物及其异构体总重量的90%;优选地,特定的异构体、非对映异构体或对映异构体按重量计至少占包括其他异构体的总重量的95%。
本文给出的任何式也旨在表示未标记的形式以及化合物的同位素标记形式。同位素标记的化合物具有由本文给出的式表示的结构,除了一个或多个原子被具有所选择的原子质量或质量数的原子替代。可以掺入本发明的化合物中的同位素包括例如氢的同位素。
此外,掺入某些同位素,特别是氘(即2H或D)可得到更高代谢稳定性导致的某些治疗优势,例如增加的体内半衰期、或减少的剂量要求、或治疗指数或耐受性的改善。应理解,在此上下文中的氘被认为是具有式(I)的化合物的取代基。氘的浓度可以由同位素富集因子来定义。如本文所用,术语“同位素富集因子”是指同位素丰度与特定同位素的天然丰度之间的比率。如果本发明的化合物中的取代指示氘,这样的化合物具有针对每个指定的氘原子的同位素富集因子为至少3500(在每个指定的氘原子上52.5%氘掺入)、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)或至少6633.3(99.5%氘掺入)。应理解,术语“同位素富集因子”能以与对氘的描述相同的方式应用于任何同位素。
可以掺入本发明的化合物的同位素的其他实例包括氢、碳、氮、氧、磷、氟和氯的同位素,如分别是3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、123I、124I、125I。因此,应理解,本发明包括掺入一种或多种任何上述同位素(包括例如放射性同位素(如3H和14C))的化合物,或其中存在非放射性同位素(如2H和13C)的化合物。这种同位素标记的化合物可用于代谢研究(用14C)、反应动力学研究(例如,用2H或3H)、包括药物或底物组织分布测定的检测或成像技术(例如正电子发射断层扫描(PET)或单光子发射型计算机断层成像(SPECT)),或可用于患者的放射性治疗。特别地,18F或标记的化合物对于PET或SPECT研究可能是特别期望的。同位素标记的具有式(I)的化合物通常可以通过本领域技术人员已知的常规技术或通过与所附实例和制备中所述的那些类似的方法,使用适当的同位素标记的试剂代替未标记的先前使用的试剂来制备。
本发明的化合物是以游离形式、作为其盐形式获得的。如本文所用,术语“盐”是指本发明的化合物的酸加成盐或碱加成盐。“盐”特别包括“药学上可接受的盐”。术语“药学上可接受的盐”是指保留本发明化合物的生物有效性和特性,并且通常不是生物学上或其他方面不合需要的盐。在许多情况下,由于氨基和/或羧基基团或与其类似的基团的存在,本发明的化合物能够形成酸盐和/或碱盐。
可以用无机酸和有机酸形成药学上可接受的酸加成盐。可以衍生出盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。可以衍生盐的有机酸包括,例如,乙酸、丙酸、乙醇酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。
可以用无机碱和有机碱形成药学上可接受的碱加成盐。可以衍生出盐的无机碱包括例如铵盐和来自元素周期表第I至XII列的金属。在某些实施例中,盐衍生自钠、钾、铵、钙、镁、铁、银、锌和铜;特别合适的盐包括铵盐、钾盐、钠盐、钙盐和镁盐。可以衍生出盐的有机碱包括例如伯胺、仲胺和叔胺;取代的胺(包括天然存在的取代的胺);环胺;碱性离子交换树脂等。某些有机胺包括异丙胺、苄星、胆碱盐、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪和氨丁三醇。
在另一个方面,本发明提供了呈以下形式的本发明的化合物:乙酸盐、抗坏血酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、癸酸盐、氯化物/盐酸盐、氯茶碱盐(chlortheophyllonate)、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、谷氨酸盐、戊二酸盐、乙醇酸盐、马尿酸盐、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、乳糖醛酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、粘酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、十八烷酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐、三苯乙酸盐(trifenatate)、三氟乙酸盐或昔萘酸盐形式。
用于制备本发明的化合物的方法
在本文描述的所有方法能够以任何合适顺序进行,除非另外指明或另外与上下文明显相矛盾。
具有式(1A)-(1L)和式(2A)-(2L)的化合物可以按方案1-7中通常说明地进行制备,其中R1涵盖与环碳5或6附接的R1a、R1b、R4a和R4b基团;Ar涵盖R3芳基和杂芳基基团;且R1a、R1b、R2、R3、R4a、R4b、R5和R6如上所定义。在以下方案中,表示为式(1A)-(1L)*和式(2A)-(2L)*的式包括所示的式及其相应对映异构体和位置异构体的混合物。
方案1
中间体GS1b可以经由溴化和与呋喃的狄尔斯-阿德尔(Diels-Alder)反应,由商购获得的丙炔酸甲酯(GS1a)制备。中间体GS1c可以利用包括但不限于环丙烷化和硼氢化/氧化等反应,然后进一步利用官能化(包括甲基化、氟化、氧化和还原),经由GSb1的官能化来制备。中间体GS1d和GS1e可以通过脱溴和共轭加成从GS1c制备。随后的酰胺键的形成可以得到具有式(1A)-(1L)*和式(2A)-(2L)*的化合物。可替代地,GS1c的酰胺键形成和脱溴可以得到GS1f,GS1f在共轭物加成后可以得到具有式(1A)-(1L)*和式(2A)-(2L)*的化合物。
方案2
在方案2中,在银催化剂如硝酸银的存在下,使用N-溴代琥珀酰亚胺或类似的溴化试剂来溴化丙炔酸甲酯(1a)得到中间体1b。在温和加热(约80℃)下,在过量呋喃中进行1b的狄尔斯-阿德尔环加成,提供中间体1c。使用二乙基锌和二碘甲烷,将1c环丙烷化,得到中间体1d。使用硼烷-四氢呋喃复合物,将1c硼氢化,然后用过氧化氢氧化,得到呈醇位置异构体的混合物的中间体1e。使用氧化银和碘甲烷,将1e甲基化,提供呈甲氧基位置异构体的混合物的1f。使用DAST,将1e氟化,得到呈氟位置异构体的混合物的1g。使用DMP,将1e氧化,得到呈酮位置异构体的混合物的1h。用硼氢化钠还原1h,提供呈醇位置异构体的混合物的1i。使用DAST,将1i氟化,得到呈氟位置异构体的混合物的1j。
方案3
在方案3中,使用锌和乙酸,将中间体1d-j脱溴,得到呈位置异构体的混合物的2a。在碱如碳酸钾和配体如BINAP存在下,使用芳基硼酸酯或芳基硼酸与铑催化剂,将2a进行1,4-共轭加成反应,得到呈位置异构体的混合物的2b和2c。使用2b、三甲基铝和胺或苯胺形成酰胺键,提供呈位置异构体的混合物的具有式(1A)-(1L)*的化合物。使用2c、LiHMDS和胺或苯胺形成酰胺键,提供呈位置异构体的混合物的具有式(2A)-(2L)*的化合物。
方案4
在方案4中,使用1d-j、三甲基铝和苯胺形成酰胺键,提供呈位置异构体的混合物的3a。使用锌和乙酸,将中间体3a脱溴,得到呈位置异构体的混合物的3b。在碱如碳酸钾和配体如BINAP存在下,使用芳基硼酸酯或芳基硼酸与铑催化剂,将3b进行1,4-共轭加成反应,得到呈位置异构体的混合物的具有式(1A)-(1L)*和式(2A)-(2L)*的化合物。
方案5
在方案中5,可以使用XtalFluor-E和三乙胺三氟化氢,经由氟化,从4a制备具有式(I)的化合物4b。
方案6
在方案中6,使用四氧化锇和N-甲基吗啉N-氧化物,将1c二羟基化,得到5a。使用(二甲氧基甲基)苯,保护5a中的二醇,得到5b。使用5b、三甲基铝和苯胺形成酰胺键,提供5c。使用锌和乙酸,将中间体5c脱溴,得到5d。在碱如碳酸钾和配体如BINAP存在下,使用芳基硼酸酯或芳基硼酸与铑催化剂,将5d进行1,4-共轭加成反应,得到中间体5e和5f。使用三氯化硼,将中间体5e和5f脱保护,分别得到5g和5h。
方案7
在方案中7,使用XtalFluor-E和三乙胺三氟化氢,将6a氟化,得到6b。使用DMP,将6a氧化,得到6c。使用胺和硼氢化钠,对6c进行还原胺化,得到6d。用甲基溴化镁处理6c,提供6e。使用硼氢化钠,将6c还原,得到6f。
本发明进一步包括本发明方法的任何变体;例如,其中将在其任何阶段可获得的中间体产物用作起始材料,并进行其余步骤;其中起始材料在反应条件下原位形成;或其中将反应组分以其盐或光学纯物质的形式使用。本发明的化合物及中间物还可根据本领域技术人员通常已知的方法彼此转化。
药理学和效用
本发明提供了一种在有需要的哺乳动物中治疗、改善或预防关节炎或关节损伤的方法,所述方法包括向所述哺乳动物施用治疗有效量的本发明的化合物,其中所述受试者患有关节损害或关节炎或处于其风险中。本发明还提供了在人类患者中治疗、改善或预防关节炎或关节损伤的方法,所述方法包括:患者口服施用包含有效量的本发明化合物的组合物,从而在患者中治疗、改善或预防关节炎或关节损伤。在一些实施例中,患者患有关节炎或关节损伤。在一些实施例中,个体不患有关节炎或关节损伤,但有此风险。一些实施例中,关节炎是骨关节炎、创伤性关节炎、或自身免疫性关节炎。
本发明的化合物也可用于诱导软骨发生性祖细胞产生透明软骨。在一些实施例中,本发明提供了用于预防软骨细胞祖细胞的软骨细胞肥大的方法。在一些实施例中,本发明提供了诱导软骨发生性祖细胞分化为成熟软骨细胞的方法,所述方法包括使软骨发生性祖细胞与足够量的本发明化合物接触,从而诱导分化为产生透明软骨细胞外基质的成熟软骨细胞。
CPC可以分化为不同类型的细胞,包括但不限于成骨细胞、透明软骨细胞和肥大软骨细胞。分化是从不太专化的细胞类型形成专化细胞类型的过程,例如,从软骨发生性祖细胞形成软骨细胞。在一些实施例中,所述方法是在体外进行的。在一些实施例中,所述方法在哺乳动物体内进行,并且祖细胞存在于哺乳动物中。
诱导软骨发生性祖细胞进行软骨细胞分化可以使用任何合适量的本发明化合物来完成。在一些实施例中,根据活性组分的特定应用和效力,本发明的化合物能以约0.1mg至约10000mg(例如1.0mg至1000mg,例如10mg至500mg)的量存在。在一些实施例中,本发明的化合物可以每天一次口服施用,剂量为1mg/kg至约300mg/kg。对于严重的骨关节炎,治疗持续时间从一周或更短至长期治疗不等。
预期本发明的化合物、组合物和方法可以用于治疗、改善或预防任何类型的关节软骨损害(例如,关节损害或损伤),包括例如由创伤事件、或腱或韧带撕裂引起的损害。一些实施例中,例如在存在关节炎或关节损害或关节损伤的遗传史或家族史的情况下,或在关节手术之前或期间,施用本发明的化合物或组合物以预防或改善关节炎或关节损害。一些实施例中,使用化合物、组合物和方法治疗关节损害。在特定实施例中,所述关节损害是创伤性关节损伤。在其他实施例中,所述关节损害是由年龄或不活动引起的损害。在又其他实施例中,所述关节损害是由自身免疫障碍引起的损害。在其他实施例中,所述关节损害是由代谢障碍(例如糖尿病)引起的损害。在本发明的一些实施例中,本发明的化合物、组合物和方法可用于治疗、改善或预防骨关节炎。一些实施例中,在有罹患或获得关节炎的风险的受试者中使用所述化合物、组合物和方法以改善或预防关节炎。一些实施例中,在有罹患或获得关节损害的风险的受试者中使用所述化合物、组合物和方法以改善或预防关节损害。
在一些实施例中,本发明的化合物、组合物和方法提供了用于刺激例如已经由于创伤性损伤或软骨病受损的软骨组织中的软骨细胞增殖和透明软骨产生的方法。在特定实施例中,本发明的化合物、组合物和方法可用于治疗关节中例如在关节连接面(例如脊柱、肩膀、肘、腕、手指关节、臀、膝盖、踝和脚关节)处的软骨损害。可受益于治疗的疾病或障碍的实例包括骨关节炎、类风湿性关节炎、其他自身免疫疾病或分离性骨软骨炎。此外,由于某些遗传或代谢障碍而发生软骨损伤或破坏,软骨畸形常常以人类侏儒症的形式出现,和/或软骨损伤或破坏通常是重建手术的结果;因此,无论是单独的还是与其他方法相结合的化合物、组合物和方法都可以是这些患者中的有用疗法。
进一步预期本发明的化合物、组合物和方法可用于治疗、改善或预防各种软骨障碍和/或此类病症的相关症状或影响。用本发明的化合物、组合物和方法治疗、改善和/或预防的示例性病症或障碍包括但不限于系统性红斑狼疮、类风湿性关节炎、青少年慢性关节炎、骨关节炎、退行性椎间盘疾病、脊柱关节病、埃勒斯-当洛斯(Ehlers Danlos)综合征、系统性硬化病(硬皮病)或腱疾病。可能会受益于化合物的治疗以改善相关影响的其他病症或障碍包括特发性炎症性肌病(皮肌炎、多肌炎),舍格伦综合征(Sjogren’s syndrome),系统性血管炎,结节病,自身免疫性溶血性贫血(免疫性全血细胞减少症、阵发性睡眠性血红蛋白尿症),自身免疫性血小板减少症(特发性血小板减少性紫癜、免疫介导的血小板减少),甲状腺炎(格雷夫斯病、桥本氏甲状腺炎、幼年淋巴细胞性甲状腺炎、萎缩性甲状腺炎),糖尿病,免疫介导的肾脏疾病(肾小球性肾炎、肾小管间质性肾炎),中枢和周围神经系统脱髓鞘疾病如多发性硬化、特发性脱髓鞘性多神经病或吉兰-巴雷综合征(Guillain-Barrsyndrome)和慢性炎性脱髓鞘性多神经病,肝胆疾病如传染性肝炎(甲型肝炎、乙型肝炎、丙型肝炎、丁型肝炎、戊型肝炎和其他非嗜肝病毒型肝炎)、自身免疫性慢性活动性肝炎、原发性胆汁性肝硬化、肉芽肿性肝炎、和硬化性胆管炎,炎症性肠病(溃疡性结肠炎:克罗恩病),谷蛋白敏感性肠病和惠普耳氏病,自身免疫性或免疫介导的皮肤病包括大疱性皮肤病、多形性红斑和接触性皮炎、牛皮癣,过敏性疾病例如哮喘、过敏性鼻炎、特应性皮炎、食物过敏和荨麻疹,肺部免疫性疾病例如嗜酸性肺炎、特发性肺纤维化和过敏性肺炎,移植相关的疾病包括移植排斥和移植物抗宿主疾病。
预期本发明的化合物和/或组合物可以促进人皮肤成纤维细胞中胶原蛋白的表达。胶原蛋白是真皮的主要结构组分。胶原蛋白对皮肤健康至关重要,并且已被广泛用于皮肤皱纹处理和皮肤老化,并作为烧伤患者的治愈辅助剂。胶原蛋白是在成纤维细胞中产生的,且人和牛胶原蛋白都被广泛使用。因此,本发明提供了在成纤维细胞中增加胶原蛋白的产生的方法,所述方法通过使成纤维细胞与本发明的化合物或组合物接触,从而增加成纤维细胞中胶原蛋白的产生。可以通过在待治疗区域中直接注射所述化合物来在体内进行所述接触。可以在体外在成纤维细胞群中进行所述接触。
药物组合物、剂型和施用
在另一个方面,本发明提供了药物组合物,所述药物组合物包含本发明的化合物或其药学上可接受的盐、和药学上可接受的载体。在另外的实施例中,所述组合物包含至少两种药学上可接受的载体(例如本文描述的那些)。所述药物组合物可以配制用于特定的施用途径,例如口服施用、肠胃外施用(例如通过注射、输注、透皮或局部施用)和直肠施用。局部施用也可以涉及吸入或鼻内施用。本发明的药物组合物能以固体形式(包括但不限于胶囊、片剂、丸剂、颗粒、粉末或栓剂)、或以液体形式(包括但不限于溶液、悬浮液或乳液)制成。片剂可以根据本领域已知的方法添加薄膜包衣或肠溶包衣。典型地,所述药物组合物是包含活性成分及以下中的一种或多种的片剂或明胶胶囊:
a)稀释剂,例如,乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素和/或甘氨酸;
b)润滑剂,例如,二氧化硅,滑石,硬酯酸、其镁盐或钙盐,和/或聚乙二醇;就片剂而言还包含
c)粘合剂,例如,硅酸镁铝、淀粉糊、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果希望
d)崩解剂,例如,淀粉、琼脂、海藻酸或其钠盐或泡腾混合物;以及
e)吸附剂、着色剂、调味剂及甜味剂。
一般而言,本发明的化合物将以治疗有效量经由本领域中已知的任何常用且可接受的模式单独或与一或多种治疗剂组合施用。在一些实施例中,通过直接注射到关节滑液中、系统性施用(口服或静脉内施用)或直接施用在软骨缺损中而应用本发明的化合物和组合物,单独或与合适的载体复合以延长化合物的释放。一些实施例中,化合物或组合物在生物相容性基质或支架中施用。
本发明的化合物、组合物和方法也可以与在受累及的关节处的外科手术一起使用。本发明的化合物或组合物的施用可以是在外科手术之前进行、期间或一起进行和/或之后进行。例如,本发明的化合物、组合物和方法可以用于扩增培养的软骨细胞群以用于自体或同种异体软骨细胞植入(ACI)。可以移植软骨细胞,任选地伴随与由施用本发明化合物和组合物组成的并行治疗。在这些程序中,例如可以从受损关节的未损伤的小负荷区域通过关节镜收获软骨细胞,并且可以在体外培养,任选地在本发明的化合物和组合物和/或其他生长因子的存在下培养以在移植前增加细胞数。然后任选地将扩增的培养物与本发明的化合物和组合物混合和/或置于关节空间中或直接置于缺损中。在某些实施例中,将扩增的培养物(任选地具有本发明的化合物)置于悬浮在基质或膜中的关节空间中。
在其他实施例中,本发明的化合物和组合物可以与一个或多个骨膜移植物或软骨膜移植物组合使用,所述骨膜移植物或软骨膜移植物含有软骨形成细胞和/或有助于将移植的软骨细胞或软骨细胞前体细胞保持在适当位置。在一些实施例中,本发明的化合物和组合物与其他程序联用以修复软骨损害,所述其他程序包括但不限于关节的灌洗、骨髓的刺激、磨削成形术、软骨下骨钻孔术或近端软骨下骨的微骨折。任选地,在本发明的化合物和组合物的施用以及软骨的生长之后,另外的手术治疗可以有利于适当地勾画新形成的一个或多个软骨表面。
本发明的化合物可以与一种或多种其他的治疗剂同时施用或在所述治疗剂之前或之后施用。本发明的化合物可以通过相同或不同的施用途径分开施用,或在与其他药剂相同的药物组合物中一起施用。治疗剂是例如化学化合物、肽、抗体、抗体片段或核酸,当将所述治疗剂与本发明的化合物组合施用于患者时,所述治疗剂具有治疗活性或增强治疗活性。
在一个实施例中,本发明提供了包含具有式(I)的化合物和至少一种其他的治疗剂的产品,作为组合制剂用于在疗法中同时的、分开的或顺序的使用。在一个实施例中,所述疗法是治疗由关节损伤或关节炎引起的关节损害。作为组合制剂提供的产品包括组合物,所述组合物包含一起处于相同药物组合物中的具有式(I)的化合物和其他治疗剂,或者包含单独形式(例如试剂盒形式)的具有式(I)的化合物和其他治疗剂。
在一个实施例中,本发明提供了药物组合物,所述药物组合物包含具有式(I)的化合物和第二治疗剂。所述第二药剂可以是一种或多种另外的软骨细胞分化剂。软骨细胞分化剂的实例包括但不限于血管生成素样3蛋白(ANGPTL3)、胰岛素生长因子(IGF1)、SM04690(Wnt抑制剂)、Janus激酶抑制剂(如鲁索替尼(Ruxolitinib)、托法替尼(Tofacitinib)、巴瑞替尼(Baricitinib))、口服鲑鱼降钙素、SD-6010(iNOS抑制剂)、维生素D3(胆钙化醇)、胶原蛋白水解物、骨形态发生蛋白7(BMP7)、醋酸卢沙拉肽、鳄梨大豆非皂化物(ASU)、类固醇、非甾体抗炎药(NSAID)、透明质酸、kartogenin和TPX-100。第二药剂可以是如WO 2015/175487中所述的具有式(I)的软骨细胞分化剂。任选地,所述药物组合物可以包含如上所述的药学上可接受的载体。
对于约50-70kg的受试者,本发明的药物组合物或组合可以处于单位剂量为约1-1000mg的一种或多种活性成分,或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg或约1-50mg的活性成分。化合物、药物组合物、或其组合的治疗有效剂量取决于所述受试者的物种、体重、年龄及治疗中的个别病状、病症或疾病或其严重性。具有普通技能的医师、临床医生或兽医可以容易地确定预防、治疗或抑制病症或疾病进展所必需的每种活性成分的有效量。
使用有利的哺乳动物(例如,小鼠、大鼠、狗、猴)或其分离的器官、组织和制品在体外和体内测试中证明上述剂量特性。本发明的化合物能以溶液的形式(例如,水溶液)在体外施用,以及肠内、肠胃外、有利地静脉内(例如,作为悬浮液或在水溶液中)在体内施用。体外剂量可以在约10-3摩尔浓度和10-9摩尔浓度之间的范围内。取决于施用途径,体内治疗有效量可以在约0.1-500mg/kg之间,或约1-100mg/kg之间的范围内。
在一个实施例中,本发明提供了试剂盒,所述试剂盒包含两种或更多种分开的药物组合物,其中至少一种药物组合物含有具有式(I)的化合物。在一个实施例中,所述试剂盒包含用于分别保留所述组合物的装置(例如容器、分开的瓶子、或分开的箔包)。这种试剂盒的实例是泡罩包装,如典型地用于片剂、胶囊及类似物的包装。
本发明的试剂盒可以用于施用不同剂型(例如,口服和肠胃外),用于以不同剂量间隔施用单独组合物或用于相对彼此滴定单独组合物。为了有助于依从性,本发明的试剂盒典型地包含用于施用的用法说明书。
在本发明的组合疗法中,本发明的化合物和其他治疗剂可以由相同或不同的制造商制造和/或配制。此外,可以将本发明的化合物和另一种治疗剂一起形成组合疗法:(i)在将组合产物释放给医师之前(例如,在包含本发明的化合物和其他治疗剂的试剂盒的情况下);(ii)在施用之前不久,由医师自身(或在医师的指导下);(iii)例如,在顺序施用本发明的化合物和其他治疗剂的过程中在患者本身中。
实例
温度以摄氏度给出。最终产物、中间体和起始材料的结构通过标准分析方法(例如,微量分析和光谱特征(例如,MS、IR、NMR))确认。使用的缩写是本领域常规的缩写。
用于合成本发明的化合物的所有起始材料、结构单元、试剂、酸、碱、脱水剂、溶剂和催化剂是可商购获得的或可通过本领域普通技术人员已知的有机合成方法制备(Houben-Weyl第4版1952,Methods of Organic Synthesis[有机合成方法],Thieme[蒂梅出版社],第21卷)。除非另有说明,起始材料通常可从商业来源获得,例如但不限于TCI精细化学品公司(TCI Fine Chemicals)(日本)、奥罗拉精细化学品公司(Aurora FineChemicals LLC)(圣地亚哥,加利福尼亚州)、FCH集团(FCH Group)(乌克兰)、奥德里奇化学公司(Aldrich Chemicals Co.)(密尔沃基,威斯康星州)、阿克洛斯有机公司(AcrosOrganics)(费尔劳恩,新泽西州)、美桥化工有限公司(Maybridge Chemical Company,Ltd.)(康沃尔,英格兰)、美奇丝科学公司(Matrix Scientific)(美国)、安娜敏公司(Enamine Ltd)(乌克兰)、Combi-Blocks公司(Combi-Blocks,Inc.)(圣地亚哥,美国)、奥克伍德公司(Oakwood Products,Inc.)(美国)、阿波罗科学公司(Apollo Scientific Ltd.)(英国)。
本文的实例仅说明本发明,并不限制另外要求保护的本发明的范围。此外,本发明的化合物可以通过本领域普通技术人员已知的有机合成方法制备,如以下实例所示。在需要时,可以根据标准实践,使用常规保护基来保护反应性官能团,例如,参见T.W.Greene和P.G.M.Wuts,“Protective Groups in Organic Chemistry[有机化学中的保护基]”,JohnWiley and Sons[约翰·威利父子公司],1991。
缩写
本文使用的缩写定义如下:“1x”表示一次,“2x”表示两次,“3x”表示三次,“℃”表示摄氏度,“aq”表示水性,“FCC”表示快速柱色谱法,“eq”表示当量(equivalent或equivalents),“g”表示克(gram或grams),“mg”表示毫克(milligram或milligrams),“L”表示升(liter或liters),“mL”表示毫升(milliliter或milliliters),“μL”表示微升(microliter或microliters),“N”表示正常,“M”表示摩尔,“nM”表示纳摩尔,“mol”表示摩尔(mole或moles),“mmol”表示毫摩尔(millimole或millimoles),“min”表示分钟(minute或minutes),“h”或“hrs”表示小时(hour或hours),“RT”表示室温,“ON”表示过夜,“atm”表示大气压,“psi”表示每平方英寸磅数,“conc.”表示浓度,“sat”或“sat’d”表示饱和的,“MW”表示分子量,“mw”或“μwave”表示微波,“mp”表示熔点,“Wt”表示重量,“MS”或“MassSpec”表示质谱分析法,“ESI”表示电喷雾电离质谱,“HR”表示高分辨率,“HRMS”表示高分辨质谱法,“LCMS”或“LC-MS”表示液相色谱质谱,“HPLC”表示高压液相色谱,“RP HPLC”表示反相HPLC,“TLC”或“tlc”表示薄层色谱,“NMR”表示核磁共振光谱,“nOe”表示核欧沃豪斯效应谱,“1H”表示质子,“δ”表示δ(delta),“s”表示单峰,“d”表示双重峰,“t”表示三重峰,“q”表示四重峰,“m”表示多重峰,“br”表示宽峰,“Hz”表示赫兹,“ee”表示“对映异构体过量”,并且“α”、“β”、“R”、“r”、“S”、“s”、“E”、和“Z”是本领域技术人员熟悉的立体化学指定。
以下本文中使用的下列缩写具有相应的含义:
AcOH 乙酸
app 显而易见的
ATP 5’-三磷酸腺苷
BINAP 外消旋2,2’-双(二苯基膦基)-1,1’-联萘基
BOC 叔丁基羧基
BSA 牛血清白蛋白
cProp 环丙基
DAST 二乙基氨基三氟化硫
dd 双二重峰
DCE 二氯乙烷
DCM 二氯甲烷
DIEA 二乙基异丙胺
DME 1,4-二甲氧基乙烷
DMF N,N-二甲基甲酰胺
DMP 戴斯-马丁过碘烷
DMSO 二甲亚砜
EDTA 乙二胺四乙酸
ESI 电喷雾电离
Et3N-3HF 三乙胺三氟化氢
EtOAc 乙酸乙酯
HCl 盐酸
LiHMDS 双(三甲基甲硅烷基)酰胺锂
MeOH 甲醇
MHz 兆赫
MTBE 甲基叔丁醚
m/z 质荷比
NBS N-溴代琥珀酰亚胺
NMO N-甲基吗啉N-氧化物
PE 石油醚
ppm 百万分率
pTsOH 对甲苯磺酸
rac- 外消旋的
Rt 保留时间
TFA 三氟乙酸
THF 四氢呋喃
Tris·HCl 氨基三(羟甲基)甲烷盐酸盐
XtalFluor-E (二乙基氨基)二氟锍四氟硼酸盐
仪器法
实例的表征中使用的LCMS方法
使用ChemStation软件在安捷伦(Agilent)系统上进行分析型LC/MS。
所述系统由以下组成:
·安捷伦G1312二元泵
·安捷伦G1367孔板自动进样器
·安捷伦G1316恒温柱温箱
·安捷伦G1315二极管阵列检测器
·安捷伦6140/6150质谱仪
·SOFTA蒸发光散射检测器
典型的方法条件如下:
·流速:0.9mL/min
·柱:1.8μm 2.1x 50mm沃特斯(Waters)Acquity HSS T3 C18柱
·流动相A:水+0.05%TFA
·流动相B:乙腈+0.035%TFA
·运行时间:2.25分钟
·方法A:除非另有说明,所述系统在1.35分钟内运行从10%B到90%B的梯度。所述梯度后,在100%B下进行0.6分钟的洗涤。所述方法的剩余持续时间将系统恢复到初始条件。
·方法B:所述系统以20%B而不是10%B的梯度开始。
·方法C:所述系统以30%B而不是10%B的梯度开始。
·方法D:所述系统以40%B而不是10%B的梯度开始。
典型的质谱仪扫描范围是100到1000amu。
NMR方法
除非另有说明,否则质子光谱是在带有5mm QNP低温探头的Bruker AVANCE II400MHz或带有5mm QNP探头的Bruker AVANCE III 500MHz上记录的。化学位移以相对于二甲亚砜(δ2.50)、氯仿(δ7.26)、甲醇(δ3.34)、二氯甲烷(δ5.32)、丙酮(δ2.05)或乙腈(δ1.94)的ppm报告。将少量干燥样品(2-5mg)溶于适当的氘代溶剂(0.6mL)中。
实例的纯化中使用的ISCO方法
实例的纯化中使用的制备型HPLC方法
制备型HPLC在沃特斯公司Autoprep系统上使用MassLynx和FractionLynx软件进行。所述系统由以下组成:
·沃特斯2767自动进样器/级分收集器
·沃特斯2525二元泵
·沃特斯515补流泵
·沃特斯2487双波长UV检测器
·沃特斯ZQ质谱仪
典型的方法条件如下:
·流速:100mL/min
·柱:10μm 19x50 mm沃特斯Atlantis T3 C18柱
·注射体积:0-1000μL
·流动相A:水+0.05%TFA
·流动相B:乙腈+0.035%TFA
·运行时间:4.25分钟
在初始条件下保持0.25分钟后,系统在3分钟内运行针对实例适当的从X%B到Y%B的梯度。所述梯度后,在100%B下进行0.5分钟的洗涤。所述方法的剩余持续时间将系统恢复到初始条件。通过FractionLynx软件的质量检测触发级分收集。
实例的纯化中使用的手性制备型HPLC方法
SFC手性筛选在与沃特斯ZQ质谱仪连接的泰尔仪器公司制备型观察仪(TharInstruments Prep Investigator)系统上进行。泰尔公司制备型观察仪系统由以下组成:
·Leap HTC PAL自动进样器
·泰尔公司流体递送模块(0至10mL/min)
·泰尔公司SFC 10位柱箱
·沃特斯2996PDA
·分光公司(Jasco)CD-2095手性检测器
·泰尔公司自动背压调节器
所有的泰尔公司组件都是SuperPure Discovery系列产品线的一部分。所述系统以2mL/min(WhelkO-1柱为4mL/min)流动,并保持在30℃。系统背压设置为125巴。通过具有六个3μm柱的组对每个样品进行筛选:
·3μm 4.6x 50mm ChiralPak AD
·3μm 4.6x 50mm ChiralPak OD
·3μm 4.6x 50mm ChiralPak OJ
·5μm 4.6x 250mm Whelk O-1
·3μm 4.6x 50mm ChiralPak AS
·3μm 4.6x 50mm Lux-Cellulose-2
所述系统在5分钟内运行从5%助溶剂到50%助溶剂的梯度,然后在50%助溶剂下保持0.5分钟,切换回5%助溶剂并在初始条件下保持0.25分钟。在每个梯度之间有4分钟的平衡方法,使5%助溶剂流过下一个有待筛选的柱。筛选的典型溶剂为MeOH、MeOH+20mMNH3、MeOH+0.5%DEA、IPA和IPA+20mM NH3。一旦使用这些梯度方法之一检测到分离,就可以开发出等度方法,并在必要时扩大规模,以在泰尔公司Prep80系统上进行纯化。
中间体
中间体1c-1j按照方案1中的一般程序制备。
中间体1c.甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯
步骤A:向丙炔酸甲酯(200g,2.38mol,198mL)在丙酮(2.50L)中的搅拌溶液中添加AgNO3(36.4g,214mmol,36.0mL)。5min后,分批添加NBS(445g,2.50mol),并将反应混合物在25℃搅拌12h。将反应混合物过滤,将滤液浓缩,并将残余物用10%EtOAc/PE(1500mL)研磨,并将滤液再次浓缩。通过柱色谱法(0-5%EtOAc/PE)纯化残余物,以给出呈黄色油状物的3-溴丙炔酸甲酯(1b),将其直接用于下一步。
步骤B:在0℃下,通过使氮气穿过反应容器2分钟来使3-溴丙炔酸甲酯(1b,200g,1.23mol)、呋喃(419g,6.15mol,445mL)在甲苯(2.50L)中的溶液脱气,然后将反应混合物温热至90℃保持72小时以给出黑色溶液。将反应混合物浓缩,并将残余物通过柱色谱法(2-5%EtOAc/PE)纯化,以给出甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯。分别纯化四批料并合并以得到呈黄色油状物的甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(1c)。1H NMR(400MHz,CDCl3)δ=7.25-7.17(m,2H),5.70(t,J=1.6Hz,1H),5.33(t,J=1.7Hz,1H),3.82-3.75(m,3H)。
中间体1d.甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯
步骤C:在-45℃下,将2,2,2-三氯乙酸(91.2g,558mmol,56.3mL)在1,2-二氯乙烷(300mL)中的溶液添加至二乙基锌(1M,558mL,558mmol)在1,2-二氯乙烷(1200mL)中的冷却溶液。将溶液温热至0℃然后搅拌20min。将二碘甲烷(150g,558mmol,45.0mL)添加至反应混合物并且允许在0℃下再搅拌10min。将甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(1c,60.0g,260mmol)在1,2-二氯乙烷(300mL)中的溶液添加至反应混合物,将其在15℃下搅拌16h。将反应混合物用1M HCl(1200mL)稀释并将水相用DCM(2000mL 2x)萃取。将合并的有机层用饱和水性NaHCO3(1000mL)、盐水(1000mL)洗涤,经Na2SO4干燥,过滤并浓缩以给出黄色油状物。将粗产物通过柱色谱法(0-10%EtOAc/PE)纯化,以给出呈黄色油状物的甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(1d)。1H NMR(400MHz,DMSO-d6)δ4.97-4.92(m,1H),4.89-4.85(m,1H),3.73(s,3H),1.58-1.52(m,2H),1.44-1.38(m,1H),1.04-0.95(m,1H)。
中间体1e
甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基
(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤D:将甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(1c,130g,563mmol,1.00eq)在THF(800mL)中的溶液用BH3-THF(1M,563mL,563mmol)处理并在0℃下搅拌2hr。逐滴添加磷酸盐缓冲液pH=7(1000mL)的溶液,然后缓慢添加H2O2(270mL,2.81mol,30%v/v)和NaOH(2M,338mL,676mmol)的混合物并且将混合物在0℃下搅拌2hr。将反应混合物用乙酸乙酯(500mL 3x)萃取,并将合并的有机层用饱和水性NaHSO3溶液(500mL 2x)、盐水(500mL)洗涤,干燥(Na2SO4)并浓缩。将残余物通过柱色谱法(2-50%EtOAc/PE)纯化以给出所希望的产物。合并两批料,以得到呈醇位置异构体的1.3:1混合物的1e,顺利得到呈黄色油状物的5-羟基产物。醇位置异构体的1.3:1混合物:1H NMR(400MHz,CDCl3)δ5.25-5.02(m,1H),4.94-4.74(m,1H),4.23-4.14(m,1H),3.80-3.78(m,3H),2.14-2.01(m,1H),1.91-1.81(m,1H),1.69-1.60(m,1H)。
中间体1f
甲基(1R,4S,5S)-3-溴-5-甲氧基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基
(1S,4S,6R)-3-溴-6-甲氧基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤E:将1e(500mg,2.01mmol)和氧化银(465mg,2.01mmol)在乙腈(5mL)中的悬浮液在室温下用碘甲烷(0.125mL,2.01mmol)处理并在80℃下温热16h。将反应冷却至室温,并通过硅藻土垫过滤。将溶剂浓缩,并将所得残余物通过使用己烷和EtOAc的柱色谱法纯化,以得到呈甲氧基位置异构体的混合物的1f。LC-MS:Rt=1.25min;MS m/z[M+H]+ 263.0。
中间体1g
甲基(1R,4S,5R)-3-溴-5-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,
4S,6S)-3-溴-6-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤F:将1e(1.00g,4.02mmol)在DCM(80mL)中的溶液在室温下用DAST(3.71mL,28.1mmol)处理且搅拌18h。将反应混合物浓缩并通过FCC(0-50%EtOAc/DCM)纯化,以得到呈氟位置异构体的混合物的1g。LC-MS:Rt=1.15min;MS m/z[M+H]+ 251.1。
中间体1h
甲基3-溴-5-氧代-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基3-溴-6-氧代-7- 氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤G:在0℃下,经5分钟,将1e(2.00g,8.03mmol)在DCM(40mL)中的溶液用戴斯-马丁试剂(10.2g,24.1mmol)分批处理。将反应混合物温热至室温且搅拌6h。将反应冷却至0℃,并用饱和水性碳酸氢钠溶液淬灭。用DCM洗涤水层3次。将合并的有机层经无水硫酸钠干燥。将粗化合物通过二氧化硅柱色谱法纯化,以得到呈酮位置异构体的混合物的1h。LC-MS:Rt=1.10min;MS m/z[M+H]+ 246.9。
中间体1i
甲基(1R,4S,5R)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基
(1S,4S,6S)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤H:将1h(50.0mg,0.202mmol)在THF(2ml)中的溶液在室温下用NaBH4(15.3mg,0.405mmol)处理且在室温下搅拌16h。将反应混合物用EtOAc和饱和水性NH4Cl稀释,用水和盐水洗涤,干燥(Na2SO4),过滤并浓缩,以得到呈醇位置异构体的混合物的1i。LC-MS:Rt=0.57min;MS m/z[M+H]+ 249.0。
中间体1j
甲基(1R,4S,5S)-3-溴-5-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,
4S,6R)-3-溴-6-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯
步骤I:将1i(3.70g,14.9mmol)在DCE(74ml)中的溶液用三乙胺三氟化氢(7.26ml,44.6mmol)处理并然后用XtalFluor-E(6.83g,29.7mmol)处理,并在80℃温热1h。将反应混合物冷却至室温,用DCM稀释,用饱和水性NaHCO3和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC纯化,以得到呈氟位置异构体的混合物的1j。LC-MS:Rt=1.18min;MSm/z[M+H]+ 251.1。
实例
除非另外说明,否则下文所述的实例由对映异构体的混合物组成;且在一些实例中,是醇、氟或甲氧基位置异构体的混合物。在位置异构体的混合物的情况下,主要位置异构体的结构和名称由位置异构体的近似比提供。
实例1:(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(2-甲氧基吡啶-4-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用方案2中的步骤A-C,由甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)制备标题化合物。
步骤A:在0℃下,向1d(4.70g,19.2mmol)在THF(25mL)和水(6mL)中的搅拌溶液中添加乙酸(4.40mL)和分批的Zn(5.00g,77.0mmol)。将反应浆液在室温下搅拌15分钟。将反应过滤,并用饱和碳酸氢钠中和至pH 7。将化合物用乙酸乙酯萃取。将合并的有机层用水和盐水洗涤,并经无水硫酸钠干燥。将溶剂浓缩并在真空下干燥。将粗化合物(1S,2S,4R,5R)-甲基8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯无需进一步纯化即可用于下一步骤中。LC-MS:Rt=1.16min;MS m/z[M+H]+ 167.1。
步骤B:在100℃下,将(1S,2S,4R,5R)-甲基8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(500mg,3.01mmol)、(2-甲氧基吡啶-4-基)硼酸(598mg,3.91mmol)、2,2’-双(二苯基膦基)-1,1’-联萘(187mg,0.301mmol)、氯(1,5-环辛二烯)铑(I)二聚体(74.0mg,0.150mmol)和碳酸钾(208mg,1.50mmol)在二噁烷(10mL)和水(2.5mL)中的混合物在微波中加热1h。将所述材料吸收进硅藻土中并浓缩溶剂。将化合物通过二氧化硅柱色谱法纯化,得到(1S,2S,4R,5R,6S,7S)-甲基7-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酸酯(顺式)和(1S,2S,4R,5R,6R,7S)-甲基7-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酸酯(反式)。顺式LC-MS:Rt=1.15min;MS m/z[M+H]+ 276.1。反式LC-MS:Rt=1.26min;MS m/z[M+H]+ 276.1。
步骤C:在0℃下,在氮气下,向5,6-二氯吡啶-3-胺(68.0mg,0.418mmol)在无水甲苯(2mL)中的搅拌溶液中添加在甲苯中的三甲基铝(2M,0.623mL,1.25mmol)。10分钟之后,移除冰浴且将混合物在室温下搅拌30分钟。添加呈固体的(1S,2S,4R,5R,6S,7S)-甲基7-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酸酯(115mg,0.418mmol)并将反应在室温搅拌1h,并且然后加热至80℃过夜。将反应冷却至0℃并用甲醇淬灭。在氮气流下去除溶剂。将固体吸收于甲醇中,并通过硅藻土垫过滤。将溶剂浓缩,将粗化合物通过二氧化硅柱色谱法纯化,以得到(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(2-甲氧基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺。LC-MS:Rt=1.38min;MS m/z[M+H]+406.0。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),8.03(d,J=2.4Hz,1H),7.84(d,J=5.3Hz,1H),7.77(d,J=2.4Hz,1H),6.83(dd,J=5.3,1.4Hz,1H),6.68(s,1H),4.66(s,1H),4.31(s,1H),3.67(s,3H),3.49(d,J=9.7Hz,1H),3.30(d,J=9.7Hz,1H),1.36-1.26(m,2H),0.45-0.39(m,1H),0.22-0.15(m,1H)。
实例2:外消旋-(1S,2S,4R,5R,6S,7S)-N-(6-甲氧基吡啶-3-基)-7-(6-甲基吡啶-
3-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
根据实例1所述的方案,使用甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)和步骤B中的(6-甲基吡啶-3-基)硼酸和步骤C中的6-甲氧基吡啶-3-胺,合成实例2。LC-MS:Rt=0.95min;MS m/z[M+H]+ 352.0。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.31(d,J=2.1Hz,1H),7.71-7.68(m,1H),7.5502(dd,J=8.0,2.3Hz,1H),7.14(dd,J=8.9,2.7Hz,1H),7.00(d,J=8.0Hz,1H),6.62-6.57(m,1H),4.62(s,1H),4.24(s,1H),3.73(s,3H),3.49(d,J=9.6Hz,1H),3.21(d,J=9.6Hz,1H),2.27(s,3H),1.36-1.29(m,1H),1.29-1.24(m,1H),0.44-0.38(m,1H),0.20-0.15(m,1H)。
实例3和4(对应于峰1和峰2)
(1S,2S,4R,5R,6S,7S)-N-(6-甲氧基吡啶-3-基)-7-(6-甲基吡啶-3-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6R,7R)-N-(6-甲氧基吡啶-3-基)-7-(6-
甲基吡啶-3-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6S,7S)-N-(6-甲氧基吡啶-3-基)-7-(6-甲基吡啶-3-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm Cellulose-2@30℃
流动相:70%CO2/30%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.64min。LC-MS:Rt=1.00min;MS m/z[M+H]+ 352.1。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.31(dd,J=2.4,0.8Hz,1H),7.70(dd,J=2.7,0.7Hz,1H),7.52(dd,J=8.0,2.3Hz,1H),7.14(dd,J=8.8,2.7Hz,1H),7.00(d,J=8.0Hz,1H),6.60(dd,J=8.8,0.7Hz,1H),4.62(s,1H),4.24(s,1H),3.73(s,3H),3.49(d,J=9.6Hz,1H),3.21(d,J=9.6Hz,1H),2.27(s,3H),1.36-1.30(m,1H),1.30-1.21(m,1H),0.44-0.38(m,1H),0.20-0.15(m,1H)。
峰2:SFC保留时间=3.30min。LC-MS:Rt=1.00min;MS m/z[M+H]+ 352.1。1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),8.31(dd,J=2.4,0.8Hz,1H),7.70(dd,J=2.7,0.7Hz,1H),7.52(dd,J=8.0,2.3Hz,1H),7.14(dd,J=8.8,2.7Hz,1H),7.00(d,J=8.0Hz,1H),6.60(dd,J=8.8,0.7Hz,1H),4.62(s,1H),4.24(s,1H),3.73(s,3H),3.49(d,J=9.6Hz,1H),3.21(d,J=9.6Hz,1H),2.27(s,3H),1.36-1.30(m,1H),1.30-1.21(m,1H),0.44-0.38(m,1H),0.20-0.15(m,1H)。
根据实例1所述的方案,使用甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e)和步骤B中的各种硼酸/酯以及步骤C中的各种苯胺合成下述实例5-13,以给出醇位置异构体的混合物。
实例5:(1R,2S,3S,4R,5S)-N-(4,5-二氯吡啶-2-基)-5-羟基-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.62min;MS m/z[M+H]+ 394.1。
实例6:(1R,2S,3S,4R,5S)-N-(5-氯-6-甲基吡啶-3-基)-5-羟基-3-(2-甲基吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.53min;MS m/z[M+H]+ 374.1。1H NMR(500MHz,DMSO-d6)δ9.62(s,1H),8.12(dd,J=5.2,0.8Hz,1H),8.00(d,J=2.2Hz,1H),7.55(d,J=2.3Hz,1H),7.12(s,1H),7.03(dd,J=5.2,1.6Hz,1H),4.95-4.92(m,1H),4.85-4.81(m,1H),4.18(s,1H),4.04-4.00(m,1H),3.26(d,J=9.8Hz,1H),3.04(d,J=9.8Hz,1H),2.38(s,3H),2.27(s,3H),2.04-1.97(m,1H),1.50-1.44(m,1H)。醇位置异构体的约6:1混合物。
实例7和8(对应于峰1和峰2)
(1R,2S,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(2-甲基吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(5,6-二氯吡啶-3-基)-5-羟基-
3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:65%CO2/35%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.28min。LC-MS:Rt=0.95min;MS m/z[M+H]+ 394.2。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.11(d,J=5.2Hz,1H),8.01(d,J=2.4Hz,1H),7.79(d,J=2.4Hz,1H),7.10(s,1H),7.04-7.00(m,1H),4.99-4.93(m,1H),4.87-4.80(m,1H),4.19(s,1H),4.06-4.00(m,1H),3.30-3.25(m,1H),3.07(d,J=9.8Hz,1H),2.26(s,3H),2.05-1.94(m,1H),1.52-1.43(m,1H)。
峰2:SFC保留时间=2.85min。LC-MS:Rt=0.95min;MS m/z[M+H]+ 394.2。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),8.11(d,J=5.2Hz,1H),8.01(d,J=2.4Hz,1H),7.79(d,J=2.4Hz,1H),7.10(s,1H),7.04-7.00(m,1H),4.99-4.93(m,1H),4.87-4.80(m,1H),4.19(s,1H),4.06-4.00(m,1H),3.30-3.25(m,1H),3.07(d,J=9.8Hz,1H),2.26(s,3H),2.05-1.94(m,1H),1.52-1.43(m,1H)。
实例9:(1R,2S,3S,4R,5S)-5-羟基-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.04min;MS m/z[M+H]+ 393.2。1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.10-8.07(m,1H),7.46(s,1H),7.38-7.33(m,1H),7.28-7.22(m,2H),7.12(s,1H),7.03(dd,J=5.2,1.7Hz,1H),4.99-4.92(m,1H),4.88-4.82(m,1H),4.17(s,1H),4.05-3.99(m,1H),3.27(d,J=9.8Hz,1H),3.04(d,J=9.8Hz,1H),2.23(s,3H),2.05-1.96(m,1H),1.51-1.43(m,1H)。醇位置异构体的>20:1混合物。
实例10:(1S,2S,3S,4S,6R)-6-羟基-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.00min;MS m/z[M+H]+ 393.2。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.09(dd,J=5.2,0.8Hz,1H),7.46(s,1H),7.39-7.34(m,1H),7.30-7.23(m,2H),7.13(s,1H),7.06(dd,J=5.2,1.6Hz,1H),4.97-4.91(m,1H),4.59(s,1H),4.51-4.47(m,1H),4.01-3.95(m,1H),3.24(d,J=9.7Hz,1H),3.05(d,J=9.7Hz,1H),2.22(s,3H),2.05-1.97(m,1H),1.53-1.45(m,1H)。醇位置异构体的>20:1混合物。
实例11:外消旋-(1R,2S,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺.
LC-MS:Rt=0.92min;MS m/z[M+H]+ 381.1。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.30-8.27(m,2H),8.00(d,J=2.4Hz,1H),7.80(d,J=2.4Hz,1H),7.28-7.23(m,2H),4.98-4.95(m,1H),4.87-4.83(m,1H),4.21(s,1H),4.07-4.02(m,1H),3.36-3.29(m,1H),3.09(d,J=9.8Hz,1H),2.06-1.98(m,1H),1.52-1.44(m,1H)。醇位置异构体的约3:1混合物。
实例11a:(对应于峰1)
(1R,2S,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(吡啶-4-基)-7-氧杂双
环[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例10),得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:65%CO2/35%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.74min。LC-MS:Rt=0.92min;MS m/z[M+H]+ 381.1。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.30-8.26(m,2H),7.99(d,J=2.3Hz,1H),7.80(d,J=2.4Hz,1H),7.26-7.22(m,2H),4.97(s,1H),4.88-4.82(m,1H),4.20(s,1H),4.07-4.00(m,1H),3.36-3.31(m,1H),3.09(d,J=9.8Hz,1H),2.06-1.98(m,1H),1.53-1.43(m,1H)。
实例12:外消旋-(1R,2S,3S,4R,5S)-5-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.96min;MS m/z[M+H]+ 379.2。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.27-8.24(m,2H),7.47(s,1H),7.37-7.31(m,1H),7.27-7.22(m,4H),4.99-4.93(m,1H),4.90-4.83(m,1H),4.18(s,1H),4.06-4.01(m,1H),3.34-3.31(m,1H),3.07(d,J=9.8Hz,1H),2.07-1.95(m,1H),1.52-1.41(m,1H)。醇位置异构体的>20:1混合物。
实例12a:(对应于峰1)
(1R,2S,3S,4R,5S)-5-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-7-氧杂双环
[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-5-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-5-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例11),得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:95%-50%CO2/5%-50%MeOH+0.5%异丙胺(5分钟)
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.59min。LC-MS:Rt=0.96min;MS m/z[M+H]+ 379.2。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.27-8.24(m,2H),7.47(s,1H),7.37-7.31(m,1H),7.27-7.22(m,4H),4.99-4.93(m,1H),4.90-4.83(m,1H),4.18(s,1H),4.06-4.01(m,1H),3.34-3.31(m,1H),3.07(d,J=9.8Hz,1H),2.07-1.95(m,1H),1.52-1.41(m,1H)。
实例13:(1S,2S,3S,4S,6R)-6-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.84min;MS m/z[M+H]+ 379.2。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.26-8.24(m,2H),7.47(s,1H),7.38-7.33(m,1H),7.29-7.23(m,4H),4.97-4.93(m,1H),4.60(s,1H),4.52-4.49(m,1H),4.02-3.96(m,1H),3.32-3.29(m,1H),3.07(d,J=9.6Hz,1H),2.05-1.99(m,1H),1.55-1.47(m,1H)。醇位置异构体的>20:1混合物。
根据实例1所述的方案,使用甲基(1R,4S,5R)-3-溴-5-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6S)-3-溴-6-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1g)和步骤B中的各种硼酸/酯以及步骤C中的各种苯胺合成下述实例14-16。
实例14:(1R,2S,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(2-甲基吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.16min;MS m/z[M+H]+ 395.2。氟位置异构体的混合物。
实例15:(1R,2S,3S,4R,5R)-5-氟-N-(6-甲氧基吡啶-3-基)-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.42min;MS m/z[M+H]+ 358.2。1H NMR(400MHz,DMSO-d6)δ9.48(s,1H),8.18(dd,J=5.1,0.8Hz,1H),7.77-7.73(m,1H),7.26(dd,J=8.8,2.7Hz,1H),7.18(s,1H),7.12-7.09(m,1H),6.62(dd,J=8.8,0.7Hz,1H),5.29-5.08(m,1H),4.90-4.84(m,1H),4.69-4.63(m,1H),3.94-3.89(m,1H),3.74(s,3H),3.40-3.35(m,1H),2.29(s,3H),2.27-2.13(m,1H),1.72-1.58(m,1H)。氟位置异构体的>20:1混合物。
实例16:(1R,2S,3S,4R,5R)-5-氟-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.14min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.11(dd,J=5.1,0.8Hz,1H),7.48(s,1H),7.40-7.34(m,1H),7.30-7.24(m,2H),7.18(d,J=1.6Hz,1H),7.10-7.06(m,1H),5.29-5.08(m,1H),4.91-4.87(m,1H),4.70-4.64(m,1H),3.97-3.90(m,1H),3.44-3.38(m,1H),2.28-2.18(m,1H),2.23(s,3H),1.71-1.59(m,1H)。氟位置异构体的>20:1混合物。
根据实例1所述的方案,使用甲基(1R,4S,5S)-3-溴-5-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1j)和步骤B中的各种硼酸/酯以及步骤C中的各种苯胺合成下述实例17-23。
实例17:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-甲基吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.19min;MS m/z[M+H]+ 395.2。1H NMR(500MHz,DMSO-d6)δ9.60(s,1H),8.13(dd,J=5.2,0.7Hz,1H),7.40-7.35(m,2H),7.11(s,1H),7.02(dd,J=5.3,1.6Hz,1H),6.99(dd,J=8.8,2.4Hz,1H),5.24-5.08(m,1H),4.97-4.92(m,1H),4.63-4.55(m,1H),3.34-3.27(m,1H),3.05(d,J=9.9Hz,1H),2.27(s,3H),2.21-2.11(m,1H),1.85-1.70(m,1H)。氟位置异构体的>20:1混合物。
实例18:(1R,2S,3S,4R,5S)-5-氟-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.15min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.15(dd,J=5.2,0.8Hz,1H),8.06(s,1H),7.43(s,1H),7.32(dd,J=7.9,0.8Hz,1H),7.28-7.24(m,2H),7.15(s,1H),7.05(dd,J=5.2,1.7Hz,1H),5.15-4.98(m,1H),5.06-5.02(m,1H),4.74-4.68(m,1H),3.36-3.30(m,1H),3.07-3.02(m,1H),2.29(s,3H),2.24-2.16(m,1H),1.93-1.79(m,1H)。氟位置异构体的>20:1混合物。
实例19:(1R,2S,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-氟-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.06min;MS m/z[M+H]+ 396.1。1H NMR(400MHz,乙腈-d3)δ8.20-8.14(m,2H),7.97(d,J=2.4Hz,1H),7.75(d,J=2.4Hz,1H),7.12(s,1H),7.04(dd,J=5.2,1.7Hz,1H),5.14-4.97(m,1H),5.03-5.01(m,1H),4.73-4.68(m,1H),3.33(d,J=9.7Hz,1H),3.07(d,J=9.7Hz,1H),2.32(s,3H),2.24-2.13(m,1H),1.93-1.79(m,1H)。氟位置异构体的>20:1混合物。
实例20:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-甲氧基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.36min;MS m/z[M+H]+ 411.2。1H NMR(500MHz,DMSO-d6)δ9.61(s,1H),7.85(dd,J=5.3,0.7Hz,1H),7.40-7.36(m,2H),7.00(dd,J=8.8,2.5Hz,1H),6.83(dd,J=5.3,1.5Hz,1H),6.68(s,1H),5.23-5.08(m,1H),4.97-4.90(m,1H),4.61-4.55(m,1H),3.69(s,3H),3.32(d,J=9.9Hz,1H),3.04(d,J=9.8Hz,1H),2.21-2.11(m,1H),1.83-1.70(m,1H)。氟位置异构体的>20:1混合物。
实例21:(1R,2S,3S,4R,5S)-3-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-5-氟-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.14min;MS m/z[M+H]+ 397.1。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),8.05(s,2H),7.50(d,J=2.4Hz,1H),7.42(d,J=8.8Hz,1H),7.08(dd,J=8.8,2.5Hz,1H),6.32(s,2H),5.23-5.05(m,1H),4.91-4.87(m,1H),4.58-4.52(m,1H),3.19(d,J=9.6Hz,1H),2.94(d,J=9.7Hz,1H),2.20-2.09(m,1H),1.81-1.63(m,1H)。氟位置异构体的>20:1混合物。
实例22:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(6-甲基吡啶-3-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.23min;MS m/z[M+H]+ 395.1。1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),8.29(dd,J=2.3,0.8Hz,1H),7.50(dd,J=8.0,2.4Hz,1H),7.38(d,J=8.7Hz,1H),7.24(d,J=2.4Hz,1H),6.99(d,J=8.0Hz,1H),6.94(dd,J=8.8,2.4Hz,1H),5.26-5.10(m,1H),4.96-4.89(m,1H),4.58-4.53(m,1H),3.36(d,J=9.7Hz,1H),3.01(d,J=9.8Hz,1H),2.25(s,3H),2.21-2.11(m,1H),1.83-1.69(m,1H)。氟位置异构体的>20:1混合物。
实例23:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-氟吡啶-4-基)-7-氧
杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.40min;MS m/z[M+H]+ 399.1。1H NMR(400MHz,DMSO-d6)δ9.80(s,1H),7.97(d,J=5.2Hz,1H),7.44(d,J=2.4Hz,1H),7.40(d,J=8.8Hz,1H),7.21-7.17(m,1H),7.02(dd,J=8.8,2.4Hz,1H),6.96(s,1H),5.25-5.07(m,1H),4.97-4.94(m,1H),4.69-4.64(m,1H),3.47(d,J=9.8Hz,1H),3.11(d,J=9.8Hz,1H),2.24-2.13(m,1H),1.86-1.70(m,1H)。氟位置异构体的>20:1混合物。
实例24:外消旋-(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用方案3中的步骤A-C,由甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)制备标题化合物。
步骤A:在0℃下,在氮气下,向3,4-二氯苯胺(568mg,3.51mmol)在无水甲苯(10mL)中的搅拌溶液中添加在甲苯中的三甲基铝(2M,3.90mL,7.79mmol)。10分钟之后,移除冰浴且将混合物在室温下搅拌30分钟。将反应冷却至0℃,并添加1d(955mg,3.90mmol,溶于2mL的甲苯中),并将反应在室温搅拌6h。将反应冷却至0℃,并用饱和水性NH4Cl和甲醇的溶液淬灭。将悬浮液过滤,并将固体用EtOAc洗涤。将有机层分离并用盐水洗涤,并经无水硫酸钠干燥并浓缩。将粗化合物通过使用DCM和EtOAc的二氧化硅柱色谱法纯化,得到(1S,2S,4R,5R)-7-溴-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酰胺。LC-MS:Rt=1.63min;MS m/z[M+H]+ 373.9。1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.04(d,J=2.3Hz,1H),7.65(dd,J=8.9,2.3Hz,1H),7.60(d,J=8.8Hz,1H),5.15(s,1H),4.87(s,1H),1.70-1.66(m,1H),1.60-1.55(m,1H),1.42-1.39(m,1H),1.02-0.98(m,1H)。
步骤B:在0℃下,向(1S,2S,4R,5R)-7-溴-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酰胺(525mg,1.40mmol)在THF(10mL)和水(2.5mL)中的搅拌溶液中添加乙酸(0.321mL)和分批的Zn(366mg,5.60mmol)。将反应浆液在室温下搅拌15分钟。将反应过滤,并用饱和碳酸氢钠中和至pH~7。将化合物用乙酸乙酯萃取。将合并的有机层用水和盐水洗涤,并经无水硫酸钠干燥并浓缩。将粗化合物通过二氧化硅柱色谱法(己烷:EtOAc)纯化,得到(1S,2S,4R,5R)-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酰胺。LC-MS:Rt=1.54min;MS m/z[M+H]+ 296.0。1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.05(d,J=2.3Hz,1H),7.64(dd,J=8.9,2.4Hz,1H),7.59(d,J=8.8Hz,1H),7.37(d,J=1.7Hz,1H),4.98(s,1H),4.89(d,J=1.7Hz,1H),1.42-1.36(m,3H),0.96-0.90(m,1H)。
步骤C:在100℃下,将(1S,2S,4R,5R)-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02 ,4]辛-6-烯-6-甲酰胺(150mg,0.507mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(133mg,0.608mmol)、2,2-双(二苯基膦基)-1,1-联萘(32mg,0.051mmol)、氯(1,5-环辛二烯)铑(I)二聚体(12mg,0.025mmol)和碳酸钾(35mg,0.253mmol)在1,4-二噁烷(2mL)和水(0.5mL)中的混合物在微波中加热1h。将所述粗反应吸收进硅藻土中并将溶剂浓缩至干燥。将粗化合物通过使用DCM和EtOAc的二氧化硅柱色谱法纯化,得到(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(实例23)和(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(反式)。LC-MS:Rt=1.29min;MS m/z[M+H]+ 389.0。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),8.14(d,J=5.2Hz,1H),7.40-7.37(m,2H),7.16-7.13(m,1H),7.06(dd,J=5.3,1.6Hz,1H),6.99(dd,J=8.8,2.4Hz,1H),4.65(s,1H),4.30(s,1H),3.48(d,J=9.7Hz,1H),3.28(d,J=9.7Hz,1H),2.28(s,3H),1.35-1.23(m,2H),0.44-0.39(m,1H),0.22-0.15(m,1H)。
实例24a和24b(对应于峰1和峰2)
(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6R,7R)-N-(3,4-二氯苯基)-7-(2-甲基吡
啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(实例23),得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.80min。方法B LC-MS:Rt=1.06min;MS m/z[M+H]+ 388.9。1HNMR(400MHz,DMSO-d6)δ9.68(s,1H),8.11(d,J=5.1Hz,1H),7.39(s,1H),7.38(d,J=6.6Hz,1H),7.11(s,1H),7.03-6.97(m,2H),4.65(s,1H),4.29(s,1H),3.46(d,J=9.7Hz,1H),3.26(d,J=9.7Hz,1H),2.26(s,3H),1.35-1.25(m,2H),0.43-0.39(m,1H),0.22-0.16(m,1H)。
峰2:SFC保留时间=3.26min。方法B LC-MS:Rt=1.06min;MS m/z[M+H]+ 388.9。1HNMR(400MHz,DMSO-d6)δ9.68(s,1H),8.11(d,J=5.1Hz,1H),7.39(s,1H),7.38(d,J=6.6Hz,1H),7.11(s,1H),7.03-6.97(m,2H),4.65(s,1H),4.29(s,1H),3.46(d,J=9.7Hz,1H),3.26(d,J=9.7Hz,1H),2.26(s,3H),1.35-1.25(m,2H),0.43-0.39(m,1H),0.22-0.16(m,1H)。
根据实例23所述的方案,使用甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)和步骤A中的各种苯胺以及步骤C中的各种硼酸酯/酸,合成下述实例25-46。
实例25:(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲氧基吡啶-4-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.40min;MS m/z[M+H]+ 405.0。1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),7.83(dd,J=5.3,0.6Hz,1H),7.39(d,J=5.1Hz,1H),7.38(d,J=1.2Hz,1H),7.01(dd,J=8.8,2.4Hz,1H),6.83(dd,J=5.4,1.4Hz,1H),6.69-6.66(m,1H),4.65(s,1H),4.28(s,1H),3.68(s,3H),3.47(d,J=9.7Hz,1H),3.26(d,J=9.7Hz,1H),1.35-1.29(m,1H),1.29-1.24(m,1H),0.44-0.38(m,1H),0.21-0.14(m,1H)。
实例26:(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-氟吡啶-4-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.63min;MS m/z[M+H]+ 393.0。1H NMR(400MHz,DMSO-d6)δ9.83(s,1H),7.95(d,J=5.2Hz,1H),7.45(d,J=2.4Hz,1H),7.40(d,J=8.8Hz,1H),7.19(d,J=5.0Hz,1H),7.02(dd,J=8.9,2.5Hz,1H),6.95(s,1H),4.67(d,J=2.7Hz,1H),4.35(d,J=2.7Hz,1H),3.61(d,J=9.6Hz,1H),3.31(d,J=9.6Hz,1H),1.36-1.25(m,2H),0.44-0.39(m,1H),0.23-0.18(m,1H)。
实例27:(1S,2S,4R,5R,6S,7S)-7-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯基)-
8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.29min;MS m/z[M+H]+ 389.1。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.08(d,J=5.1Hz,1H),7.46(s,1H),7.36(t,J=7.9Hz,1H),7.26(t,J=9.2Hz,2H),7.12(s,1H),7.03(dd,J=5.1,1.2Hz,1H),4.66(s,1H),4.29(s,1H),3.47(d,J=9.7Hz,1H),3.29(d,J=9.7Hz,1H),2.23(s,3H),1.35-1.26(m,2H),0.44-0.41(m,1H),0.21-0.16(m,1H)。
实例28和29(对应于峰1和峰2)
(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6R,7R)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-
8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IB@30℃
流动相:75%CO2/25%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.28min。方法C LC-MS:Rt=1.03min;MS m/z[M+H]+ 375.8。1HNMR(400MHz,DMSO-d6)δ9.93(s,1H),8.82(s,1H),8.61(s,2H),7.40(d,J=8.0Hz,2H),7.01-6.98(m,1H),4.66(s,1H),4.41(s,1H),3.57(d,J=9.5Hz,1H),3.29(d,J=9.7Hz,1H),1.38-1.27(m,2H),0.45-0.40(m,1H),0.24-0.18(m,1H)。
峰2:SFC保留时间=2.76min。方法C LC-MS:Rt=1.03min;MS m/z[M+H]+ 375.9。1HNMR(400MHz,DMSO-d6)δ9.93(s,1H),8.82(s,1H),8.61(s,2H),7.40(d,J=8.0Hz,2H),7.01-6.98(m,1H),4.66(s,1H),4.41(s,1H),3.57(d,J=9.5Hz,1H),3.29(d,J=9.7Hz,1H),1.38-1.27(m,2H),0.45-0.40(m,1H),0.24-0.18(m,1H)。
实例30和31(对应于峰1和峰2)
(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2,3-二氟吡啶-4-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6R,7R)-N-(3,4-二氯苯基)-7-(2,3-二氟吡
啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2,3-二氟吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IA@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.63min。方法D LC-MS:Rt=1.23min;MS m/z[M+H]+ 410.8。1HNMR(400MHz,DMSO-d6)δ10.02(s,1H),7.84(dd,J=5.2,0.9Hz,1H),7.44(d,J=1.7Hz,1H),7.43(d,J=4.6Hz,1H),7.31(t,J=4.9Hz,1H),7.04(dd,J=8.8,2.4Hz,1H),4.67(s,1H),4.44(s,1H),3.89(d,J=9.6Hz,1H),3.36(d,J=9.6Hz,1H),1.42-1.37(m,1H),1.34-1.28(m,1H),0.46-0.40(m,1H),0.24-0.19(m,1H)。
峰2:SFC保留时间=3.19min。方法D LC-MS:Rt=1.23min;MS m/z[M+H]+ 410.8。1HNMR(400MHz,DMSO-d6)δ10.02(s,1H),7.84(dd,J=5.2,0.9Hz,1H),7.44(d,J=1.7Hz,1H),7.43(d,J=4.6Hz,1H),7.31(t,J=4.9Hz,1H),7.04(dd,J=8.8,2.4Hz,1H),4.67(s,1H),4.44(s,1H),3.89(d,J=9.6Hz,1H),3.36(d,J=9.6Hz,1H),1.42-1.37(m,1H),1.34-1.28(m,1H),0.46-0.40(m,1H),0.24-0.19(m,1H)。
实例32:(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(2,3-二氟吡啶-4-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法C LC-MS:Rt=1.29min;MS m/z[M+H]+ 411.8。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.07(d,J=2.4Hz,1H),7.84(d,J=2.4Hz,2H),7.31(t,J=4.9Hz,1H),4.70(s,1H),4.44(s,1H),3.90(d,J=9.6Hz,1H),3.39(d,J=9.6Hz,1H),1.43-1.37(m,1H),1.33-1.28(m,1H),0.46-0.40(m,1H),0.25-0.19(m,1H)。
实例33:(1S,2S,4R,5R,6S,7S)-N-(6-甲氧基吡啶-3-基)-7-(吡啶-4-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=0.92min;MS m/z[M+H]+ 338.0。1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),8.62(d,J=5.9Hz,2H),7.76(dd,J=2.7,0.7Hz,1H),7.73(d,J=5.9Hz,2H),7.31(dd,J=8.9,2.7Hz,1H),6.62(dd,J=8.8,0.7Hz,1H),4.71(s,1H),4.40(s,1H),3.75(dt,J=9.6,0.6Hz,1H),3.73(s,3H),3.39(d,J=9.6Hz,1H),1.40-1.29(m,2H),0.47-0.41(m,1H),0.25-0.18(m,1H)。
实例34:(1S,2S,4R,5R,6S,7S)-7-(2,3-二氟吡啶-4-基)-N-(6-甲氧基吡啶-3-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法C LC-MS:Rt=0.89min;MS m/z[M+H]+ 373.9。1H NMR(400MHz,DMSO-d6)δ9.70(s,1H),7.85(d,J=5.2Hz,1H),7.79(d,J=2.7Hz,1H),7.33(t,J=4.9Hz,1H),7.28(dd,J=8.9,2.7Hz,1H),6.65(dd,J=8.9,0.7Hz,1H),4.67(s,1H),4.42(s,1H),3.88(d,J=9.6Hz,1H),3.74(s,3H),3.35(d,J=9.6Hz,1H),1.42-1.37(m,1H),1.34-1.29(m,1H),0.46-0.40(m,1H),0.23-0.16(m,1H)。
实例35:(1S,2S,4R,5R,6S,7S)-N-(6-甲氧基吡啶-3-基)-7-(6-(三氟甲基)吡啶-
2-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.47min;MS m/z[M+H]+ 406.0。1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),7.90(t,J=7.9Hz,1H),7.76(d,J=2.7Hz,1H),7.63(d,J=8.0Hz,1H),7.60-7.57(m,1H),7.27(dd,J=8.9,2.7Hz,1H),6.59(d,J=8.9Hz,1H),4.66(s,1H),4.48(s,1H),3.78(d,J=9.7Hz,1H),3.72(s,3H),3.36(d,J=9.7Hz,1H),1.42-1.36(m,1H),1.31-1.26(m,1H),0.46-0.41(m,1H),0.23-0.18(m,1H)。
实例36:(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-氟嘧啶-5-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.50min;MS m/z[M+H]+ 394.0。1H NMR(400MHz,DMSO-d6)δ10.03(s,1H),8.57(d,J=1.5Hz,2H),7.43(d,J=6.1Hz,1H),7.42(s,1H),7.04(dd,J=8.8,2.4Hz,1H),4.66(s,1H),4.42(s,1H),3.66(d,J=9.5Hz,1H),3.29(d,J=9.5Hz,1H),1.37-1.26(m,2H),0.46-0.40(m,1H),0.25-0.17(m,1H)。
实例37:(1S,2S,4R,5R,6S,7S)-7-(嘧啶-5-基)-N-(3-(三氟甲基)苯基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.41min;MS m/z[M+H]+ 376.1。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.79(s,1H),8.63(s,2H),7.44(s,1H),7.38(t,J=8.0Hz,1H),7.29-7.24(m,2H),4.68(s,1H),4.41(s,1H),3.59(d,J=9.6Hz,1H),3.30(s,1H),1.40-1.35(m,1H),1.34-1.28(m,1H),0.46-0.41(m,1H),0.23-0.18(m,1H)。
实例38:(1S,2S,4R,5R,6S,7S)-7-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.28min;MS m/z[M+H]+ 375.1。1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),8.28(d,J=6.0Hz,2H),7.48(s,1H),7.36(t,J=7.9Hz,1H),7.29(dd,J=4.6,1.4Hz,2H),7.24(d,J=8.1Hz,2H),4.68(s,1H),4.31(s,1H),3.54(d,J=9.7Hz,1H),3.31(d,J=9.7Hz,1H),1.37-1.32(m,1H),1.31-1.26(m,1H),0.46-0.40(m,1H),0.22-0.16(m,1H)。
实例39:(1S,2S,4R,5R,6S,7S)-7-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.24min;MS m/z[M+H]+ 391.0。1H NMR(400MHz,DMSO-d6)δ9.85(s,1H),8.05(s,2H),7.51(d,J=2.4Hz,1H),7.42(d,J=8.8Hz,1H),7.08(dd,J=8.8,2.4Hz,1H),6.27(s,2H),4.59(s,1H),4.23(s,1H),3.33(d,J=9.3Hz,1H),3.15(d,J=9.5Hz,1H),1.32-1.26(m,1H),1.26-1.20(m,1H),0.42-0.37(m,1H),0.20-0.15(m,1H)。
实例40:(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-吗啉代嘧啶-5-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.55min;MS m/z[M+H]+ 461.1。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.18(s,2H),7.43-7.39(m,2H),7.04(dd,J=8.8,2.4Hz,1H),4.60(s,1H),4.28(s,1H),3.48(s,8H),3.39(d,J=9.4Hz,1H),3.18(d,J=9.5Hz,1H),1.34-1.28(m,1H),1.28-1.23(m,1H),0.44-0.38(m,1H),0.21-0.14(m,1H)。
实例41:(1S,2S,4R,5R,6S,7S)-7-(2-氟吡啶-4-基)-N-(3-(三氟甲基)苯基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.58min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),7.92(d,J=5.2Hz,1H),7.50(d,J=2.0Hz,1H),7.38(t,J=7.9Hz,1H),7.31-7.24(m,2H),7.24-7.18(m,1H),6.96(d,J=1.4Hz,1H),4.69(s,1H),4.35(s,1H),3.62(d,J=9.6Hz,1H),3.33(d,J=9.6Hz,1H),1.39-1.27(m,2H),0.46-0.40(m,1H),0.23-0.17(m,1H)。
实例42:(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲基嘧啶-5-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.35min;MS m/z[M+H]+ 390.0。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),8.48(s,2H),7.41(d,J=8.8Hz,1H),7.30(d,J=2.4Hz,1H),6.98(dd,J=8.8,2.4Hz,1H),4.64(s,1H),4.36(s,1H),3.53(d,J=9.5Hz,1H),3.25(d,J=9.6Hz,1H),2.38(s,3H),1.37-1.31(m,1H),1.30-1.25(m,1H),0.46-0.40(m,1H),0.23-0.17(m,1H)。
实例43:外消旋-(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(吡啶-4-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.17min;MS m/z[M+H]+ 376.0。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.50-8.42(m,2H),8.03(d,J=2.4Hz,1H),7.85(d,J=2.4Hz,1H),7.54-7.49(m,2H),4.70(s,1H),4.39(s,1H),3.68(d,J=9.6Hz,1H),3.40(d,J=9.7Hz,1H),1.41-1.29(m,2H),0.46-0.42(m,1H),0.26-0.18(m,1H)。
实例43a和43b(对应于峰1和峰2)
(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(吡啶-4-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6R,7R)-N-(5,6-二氯吡啶-3-基)-7-(吡啶-
4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(实例43),得到以下所列化合物:
方法细节:
柱:30x 250mm IC@30℃
流动相:65%CO2/35%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.64min。LC-MS:Rt=1.17min;MS m/z[M+H]+ 376.0。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.50-8.42(m,2H),8.03(d,J=2.4Hz,1H),7.85(d,J=2.4Hz,1H),7.54-7.49(m,2H),4.70(s,1H),4.39(s,1H),3.68(d,J=9.6Hz,1H),3.40(d,J=9.7Hz,1H),1.41-1.29(m,2H),0.46-0.42(m,1H),0.26-0.18(m,1H)。
峰2:SFC保留时间=2.80min。LC-MS:Rt=1.17min;MS m/z[M+H]+ 376.0。1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),8.50-8.42(m,2H),8.03(d,J=2.4Hz,1H),7.85(d,J=2.4Hz,1H),7.54-7.49(m,2H),4.70(s,1H),4.39(s,1H),3.68(d,J=9.6Hz,1H),3.40(d,J=9.7Hz,1H),1.41-1.29(m,2H),0.46-0.42(m,1H),0.26-0.18(m,1H)。
实例44:(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(吡啶-4-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.27min;MS m/z[M+H]+ 375.0。1H NMR(500MHz,DMSO-d6)δ9.73(s,1H),8.29-8.25(m,2H),7.41-7.32(m,2H),7.26-7.21(m,2H),7.01-6.96(m,1H),4.69-4.62(m,1H),4.33-4.27(m,1H),3.53-3.48(m,1H),3.30-3.25(m,1H),1.37-1.31(m,1H),1.31-1.25(m,1H),0.45-0.38(m,1H),0.24-0.17(m,1H)。
实例45和46(对应于峰1和峰2)
(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(2-甲基吡啶-4-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6R,7R)-N-(5,6-二氯吡啶-3-基)-7-(2-
甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6S,7S)-N-(5,6-二氯吡啶-3-基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:70%CO2/30%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.50min。LC-MS:Rt=1.19min;MS m/z[M+H]+ 390.0。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.11(d,J=5.2Hz,1H),8.01(d,J=2.4Hz,1H),7.79(d,J=2.4Hz,1H),7.10(s,1H),7.01(dd,J=5.1,1.3Hz,1H),4.66(s,1H),4.32(s,1H),3.48(d,J=9.7Hz,1H),3.31(d,J=10.1Hz,1H),2.25(s,3H),1.36-1.26(m,2H),0.45-0.39(m,1H),0.22-0.16(m,1H)。
峰2:SFC保留时间=2.54min。LC-MS:Rt=1.19min;MS m/z[M+H]+ 390.0。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.11(d,J=5.2Hz,1H),8.01(d,J=2.4Hz,1H),7.79(d,J=2.4Hz,1H),7.10(s,1H),7.01(dd,J=5.1,1.3Hz,1H),4.66(s,1H),4.32(s,1H),3.48(d,J=9.7Hz,1H),3.31(d,J=10.1Hz,1H),2.25(s,3H),1.36-1.26(m,2H),0.45-0.39(m,1H),0.22-0.16(m,1H)。
实例47:外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案3中的步骤A-C,由甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e)制备标题化合物。
步骤A:在0℃下,在氮气下,向3,4-二氯苯胺(44.0g,271mmol)在无水甲苯(100mL)中的搅拌溶液中添加在甲苯中的三甲基铝(2M,313mL,626mmol)。10分钟之后,移除冰浴且将混合物在室温下搅拌30分钟。将反应冷却至0℃且添加甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e,26.0g,104mmol)在600mL甲苯中的混合物,并将反应在室温下搅拌6h。将反应冷却至0℃,并用饱和水性氯化铵(500ml)缓慢淬灭。将悬浮液过滤,并将固体用EtOAc(500mL 3x)和甲醇(100mL 2x)洗涤。将合并的有机层用饱和水性NH4Cl(300mL)、水(300mL)、盐水(300mL)洗涤,并经无水硫酸钠干燥。将粗化合物通过使用PE和EtOAc的二氧化硅柱色谱法纯化,以给出呈醇位置异构体的2:1混合物的(1R,4S,5S)-3-溴-N-(3,4-二氯苯基)-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺和(1S,4S,6R)-3-溴-N-(3,4-二氯苯基)-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺的混合物,顺利得到呈黄色油状物的5-羟基产物。1H NMR(400MHz,CDCl3)δppm 7.99-7.95(m,1H),7.79-7.78(m,1H),7.43-7.38(m,2H),5.38-5.36(m,0.7H),5.18-5.17(m,0.3H),5.02-5.01(m,0.3H),4.88-4.86(m,0.7H),4.29-4.24(m,1H),2.22-2.19(m,0.7H),2.15-2.08(m,0.3H),1.74-1.69(m,1H),0.89-0.85(m,1H)。
步骤B:在0℃下,向(1R,4S,5S)-3-溴-N-(3,4-二氯苯基)-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺和(1S,4S,6R)-3-溴-N-(3,4-二氯苯基)-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺(14.5g,38.3mmol)在THF(240mL)和H2O(60mL)中的混合物的搅拌溶液中添加AcOH(18.0mL)和锌粉(20.0g,306mmol)。将反应浆液在室温下搅拌2h。将反应过滤,并用饱和水性碳酸氢钠中和至pH 7。将化合物用乙酸乙酯(200mL3x)萃取。将合并的有机层用水(200mL)、盐水(100mL)洗涤,并经无水硫酸钠干燥并浓缩。将所得残余物用MTBE(30mL)研磨,然后过滤收集固体以给出呈黄色固体的(1R,4R,5S)-N-(3,4-二氯苯基)-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺和(1S,4S,6R)-N-(3,4-二氯苯基)-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺的位置异构体混合物。1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.03-8.02(d,1H),7.64-7.57(m,2H),7.09-7.07(d,1H),5.15-5.08(m,2H),4.87-4.81(m,1H),3.91-3.89(m,1H),1.76-1.72(m,1H),1.44-1.40(m,1H)。
步骤C:在100℃下,将(1R,4R,5S)-N-(3,4-二氯苯基)-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺和(1S,4S,6R)-N-(3,4-二氯苯基)-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酰胺(250mg,0.833mmol)、吡啶-4-基硼酸(133mg,1.08mmol)、2,2-双(二苯基膦基)-1,1-联萘(52mg,0.083mmol)、氯(1,5-环辛二烯)铑(I)二聚体(21mg,0.042mmol)和碳酸钾(58.0mg,0.416mmol)在1,4-二噁烷(6mL)和水(1.5mL)中的混合物在微波中加热1h。将反应混合物浓缩到硅藻土上,并通过二氧化硅柱色谱法纯化,以得到呈醇位置异构体的约2:1混合物的外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺,顺利得到5-羟基产物。LC-MS:Rt=1.10min;MS m/z[M+H]+ 379.0。
实例47a:(对应于峰1)
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-7-氧杂双环
[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例47),得到以下所列化合物:
方法细节:
柱:30x 250mm IC@30℃
流动相:70%CO2/30%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=3.59min。LC-MS:Rt=1.10min;MS m/z[M+H]+ 379.0。1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.55-8.52(m,2H),7.65-7.62(m,2H),7.44(d,J=2.4Hz,1H),7.39(d,J=8.8Hz,1H),7.00(dd,J=8.8,2.4Hz,1H),5.12-4.96(m,1H),4.91-4.86(m,1H),4.26(s,1H),4.08-4.04(m,1H),3.53(d,J=9.7Hz,1H),3.15(d,J=9.8Hz,1H),2.08-2.00(m,1H),1.54-1.47(m,1H)。
根据实例47所述的方案,使用甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e)和步骤A中的各种苯胺以及步骤C中的各种硼酸酯/酸,合成下述实例48-62。
实例48:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-甲基吡啶-3-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.20min;MS m/z[M+H]+ 393.0。1H NMR(500MHz,DMSO-d6)δ9.66(s,1H),8.32(d,J=2.2Hz,1H),7.65-7.59(m,1H),7.38(d,J=8.8Hz,1H),7.27(d,J=2.4Hz,1H),7.11-7.06(m,1H),6.95(dd,J=8.9,2.4Hz,1H),4.98-4.86(m,1H),4.82(d,J=5.5,1.2Hz,1H),4.17(s,1H),4.05-4.02(m,1H),3.37-3.32(m,1H),3.00(d,J=9.7Hz,1H),2.28(s,3H),2.04-1.98(m,1H),1.49-1.43(m,1H)。醇位置异构体的约3:1混合物。
实例49:外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.32min;MS m/z[M+H]+ 409.0。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),7.83(d,J=5.3Hz,1H),7.39(d,J=6.0Hz,1H),7.37(s,1H),6.99(dd,J=8.8,2.4Hz,1H),6.84(dd,J=5.4,1.5Hz,1H),6.68(s,1H),4.96-4.93(m,1H),4.84-4.77(m,1H),4.15(s,1H),4.03-3.98(m,1H),3.68(s,3H),3.27(d,J=9.7Hz,1H),3.01(d,J=9.8Hz,1H),2.03-1.93(m,1H),1.51-1.42(m,1H)。醇位置异构体的约3:1混合物。
实例49a和49b(对应于峰1和峰2)
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡啶-4-基)-7-氧杂
双环[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧
基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例49),得到以下所列化合物:
方法细节:
柱:21x 250mm IF@30℃
流动相:65%CO2/35%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.10min。LC-MS:Rt=1.23min;MS m/z[M+H]+ 409.0。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),7.83(d,J=5.3Hz,1H),7.39(d,J=6.1Hz,1H),7.37(s,1H),6.99(dd,J=8.8,2.4Hz,1H),6.84(dd,J=5.3,1.4Hz,1H),6.68(d,J=0.8Hz,1H),4.97-4.92(m,1H),4.86-4.80(m,1H),4.15(s,1H),4.05-3.97(m,1H),3.68(s,3H),3.27(d,J=9.7Hz,1H),3.01(d,J=9.8Hz,1H),2.02-1.95(m,1H),1.50-1.42(m,1H)。
峰2:SFC保留时间=2.81min。LC-MS:Rt=1.23min;MS m/z[M+H]+ 409.0。1H NMR(400MHz,DMSO-d6)δ9.61(s,1H),7.83(d,J=5.3Hz,1H),7.39(d,J=6.1Hz,1H),7.37(s,1H),6.99(dd,J=8.8,2.4Hz,1H),6.84(dd,J=5.3,1.4Hz,1H),6.68(d,J=0.8Hz,1H),4.97-4.92(m,1H),4.86-4.80(m,1H),4.15(s,1H),4.05-3.97(m,1H),3.68(s,3H),3.27(d,J=9.7Hz,1H),3.01(d,J=9.8Hz,1H),2.02-1.95(m,1H),1.50-1.42(m,1H)。
实例50:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-(三氟甲基)吡啶-
2-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.57min;MSm/z[M+H]+ 447.0。醇位置异构体的混合物。
实例51:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(嘧啶-5-基)-7-氧杂
双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.26min;MSm/z[M+H]+ 380.0。1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.82(s,1H),8.62(s,2H),7.40(d,J=4.5Hz,1H),7.39(d,J=1.9Hz,1H),6.99(dd,J=8.8,2.4Hz,1H),5.03-4.99(m,1H),4.86-4.82(m,1H),4.28(s,1H),4.07-4.02(m,1H),3.38(d,J=9.7Hz,1H),3.05(d,J=9.7Hz,1H),2.07-2.00(m,1H),1.52-1.44(m,1H)。醇位置异构体的约3:1混合物。
实例52:外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-
羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.39min;MSm/z[M+H]+ 397.0。1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),7.95(d,J=5.2Hz,1H),7.44(d,J=2.4Hz,1H),7.40(d,J=8.8Hz,1H),7.21-7.18(m,1H),7.01(dd,J=8.8,2.5Hz,1H),6.96(s,1H),5.00-4.97(m,1H),4.87-4.83(m,1H),4.21(s,1H),4.05-4.00(m,1H),3.41(d,J=9.8Hz,1H),3.07(d,J=9.8Hz,1H),2.05-1.97(m,1H),1.52-1.44(m,1H)。醇位置异构体的约3:1混合物。
实例52a和52b(对应于峰1和峰2)
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环
[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-
羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例52),得到以下所列化合物:
方法细节:
柱:21x 250mm IF@30℃
流动相:95%-50%CO2/5%-50%MeOH+0.5%异丙胺(5分钟)
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=3.15min。LC-MS:Rt=1.30min;MS m/z[M+H]+ 397.0。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.95(d,J=5.2Hz,1H),7.44(d,J=2.4Hz,1H),7.40(d,J=8.8Hz,1H),7.20(d,J=4.9Hz,1H),7.01(dd,J=8.8,2.4Hz,1H),6.96(s,1H),5.04-4.95(m,1H),4.89-4.82(m,1H),4.21(s,1H),4.05-4.00(m,1H),3.41(d,J=9.7Hz,1H),3.07(d,J=9.9Hz,1H),2.05-1.96(m,1H),1.52-1.44(m,1H)。
峰2:SFC保留时间=4.12min。LC-MS:Rt=1.30min;MS m/z[M+H]+ 397.0。1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.95(d,J=5.2Hz,1H),7.44(d,J=2.4Hz,1H),7.40(d,J=8.8Hz,1H),7.20(d,J=4.9Hz,1H),7.01(dd,J=8.8,2.4Hz,1H),6.96(s,1H),5.04-4.95(m,1H),4.89-4.82(m,1H),4.21(s,1H),4.05-4.00(m,1H),3.41(d,J=9.7Hz,1H),3.07(d,J=9.9Hz,1H),2.05-1.96(m,1H),1.52-1.44(m,1H)。
实例53:外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.18min;MS m/z[M+H]+ 393.0。醇位置异构体的约3:1混合物。
实例53a和53b(对应于峰1和峰2)
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双
环[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例53),得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:80%CO2/20%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.14min。LC-MS:Rt=1.10min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.11(dd,J=5.1,0.8Hz,1H),7.40-7.36(m,2H),7.11(s,1H),7.03-7.00(m,1H),6.98(dd,J=8.8,2.4Hz,1H),4.98-4.91(m,1H),4.86-4.80(m,1H),4.17(s,1H),4.04-3.99(m,1H),3.25(d,J=9.7Hz,1H),3.02(d,J=9.7Hz,1H),2.26(s,3H),2.04-1.95(m,1H),1.50-1.42(m,1H)。
峰2:SFC保留时间=2.79min。LC-MS:Rt=1.10min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ9.59(s,1H),8.11(dd,J=5.1,0.8Hz,1H),7.40-7.36(m,2H),7.11(s,1H),7.03-7.00(m,1H),6.98(dd,J=8.8,2.4Hz,1H),4.98-4.91(m,1H),4.86-4.80(m,1H),4.17(s,1H),4.04-3.99(m,1H),3.25(d,J=9.7Hz,1H),3.02(d,J=9.7Hz,1H),2.26(s,3H),2.04-1.95(m,1H),1.50-1.42(m,1H)。
实例54:外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲
基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.48min;MS m/z[M+H]+ 447.0。1H NMR(500MHz,DMSO-d6)δ9.70(s,1H),8.47(d,J=5.0Hz,1H),7.73(s,1H),7.52(dd,J=5.1,1.5Hz,1H),7.37-7.33(m,2H),6.96(dd,J=8.8,2.4Hz,1H),4.99-4.97(m,1H),4.89-4.86(m,1H),4.26(s,1H),4.07-4.03(m,1H),3.49(d,J=9.7Hz,1H),3.10(d,J=9.9Hz,1H),2.06-2.00(m,1H),1.52-1.46(m,1H)。醇位置异构体的约3:1混合物。
实例54a和54b(对应于峰1和峰2)
(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲基)吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺或(1S,2R,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-
(三氟甲基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例54),得到以下所列化合物:
方法细节:
柱:21x 250mm AD@30℃
流动相:80%CO2/20%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=0.80min。LC-MS:Rt=1.42min;MS m/z[M+H]+ 447.0。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.47(d,J=5.0Hz,1H),7.73(s,1H),7.52(dd,J=5.1,1.6Hz,1H),7.38-7.34(m,2H),6.96(dd,J=8.8,2.4Hz,1H),5.04-4.96(m,1H),4.90-4.84(m,1H),4.25(s,1H),4.07-4.00(m,1H),3.49(d,J=9.8Hz,1H),3.10(d,J=9.8Hz,1H),2.06-1.99(m,1H),1.54-1.45(m,1H)。
峰2:SFC保留时间=1.28min。LC-MS:Rt=1.42min;MS m/z[M+H]+ 447.0。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),8.47(d,J=5.0Hz,1H),7.73(s,1H),7.52(dd,J=5.1,1.6Hz,1H),7.38-7.34(m,2H),6.96(dd,J=8.8,2.4Hz,1H),5.04-4.96(m,1H),4.90-4.84(m,1H),4.25(s,1H),4.07-4.00(m,1H),3.49(d,J=9.8Hz,1H),3.10(d,J=9.8Hz,1H),2.06-1.99(m,1H),1.54-1.45(m,1H)。
实例55:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-(二甲基氨基)嘧啶-5-基)-
5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.28min;MS m/z[M+H]+ 423.0。1H NMR(500MHz,DMSO-d6)δ9.71(s,1H),8.15(s,2H),7.40(d,J=8.8Hz,1H),7.35(d,J=2.4Hz,1H),7.03(dd,J=8.9,2.4Hz,1H),4.93-4.89(m,1H),4.80-4.77(m,1H),4.15(s,1H),4.02-3.97(m,1H),3.16(d,J=9.5Hz,1H),2.93(s,6H),2.91(d,J=9.5Hz,1H),2.01-1.96(m,1H),1.46-1.40(m,1H)。醇位置异构体的约3:1混合物。
实例56:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基嘧啶-5-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.20min;MS m/z[M+H]+ 394.0。1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.49(s,2H),7.41(d,J=8.8Hz,1H),7.29(d,J=2.4Hz,1H),6.96(dd,J=8.8,2.4Hz,1H),4.85-4.79(m,1H),4.59-4.53(m,1H),4.24(s,1H),4.06-4.01(m,1H),3.33(d,J=9.6Hz,1H),3.01(d,J=9.7Hz,1H),2.38(s,3H),2.05-1.98(m,1H),1.50-1.43(m,1H)。醇位置异构体的约3:1混合物。
实例57:(1R,2S,3S,4R,5S)-3-(2-氨基吡啶-4-基)-N-(3,4-二氯苯基)-5-羟基-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.10min;MS m/z[M+H]+ 394.0。1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),7.61(d,J=6.3Hz,1H),7.55(d,J=2.4Hz,1H),7.41(d,J=8.8Hz,1H),7.08(dd,J=8.8,2.4Hz,1H),6.86(s,2H),6.64(s,1H),6.58-6.55(m,1H),4.98-4.95(m,1H),4.85-4.82(m,1H),4.16(s,1H),4.03-3.99(m,1H),3.21(d,J=9.9Hz,1H),3.04(d,J=9.8Hz,1H),2.01-1.96(m,1H),1.49-1.43(m,1H)。醇位置异构体的约3:1混合物。
实例58:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2,5-二氟吡啶-4-基)-5-羟
基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.38min;MS m/z[M+H]+ 415.0。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),7.99(d,J=1.3Hz,1H),7.46-7.41(m,2H),7.10-7.05(m,2H),5.06-5.01(m,1H),4.85-4.81(m,1H),4.37(s,1H),4.10-4.03(m,1H),3.63(d,J=10.0Hz,1H),3.11(d,J=9.7Hz,1H),2.06-1.99(m,1H),1.52-1.46(m,1H)。醇位置异构体的约2:1混合物。
实例59:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2,3-二氟吡啶-4-基)-5-羟
基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.40min;MS m/z[M+H]+ 415.0。1H NMR(400MHz,DMSO-d6)δ9.92(s,1H),7.84(d,J=5.2Hz,1H),7.45-7.40(m,2H),7.34(t,J=4.9Hz,1H),7.04(dd,J=8.8,2.5Hz,1H),5.04-5.01(m,1H),4.88-4.83(m,1H),4.30(s,1H),4.10-4.05(m,1H),3.70(d,J=10.0Hz,1H),3.12(d,J=9.7Hz,1H),2.08-2.00(m,1H),1.53-1.46(m,1H)。醇位置异构体的约2:1混合物。
实例60:(1R,2S,3S,4R,5S)-3-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-5-羟基-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.11min;MS m/z[M+H]+ 395.0。1H NMR(500MHz,DMSO-d6)δ9.74(s,1H),8.06(s,2H),7.50(d,J=2.4Hz,1H),7.41(d,J=8.8Hz,1H),7.09-7.06(m,1H),6.25(s,2H),4.92-4.89(m,1H),4.81-4.76(m,1H),4.12(s,1H),4.01-3.97(m,1H),3.13(d,J=9.6Hz,1H),2.91(d,J=9.8Hz,1H),2.00-1.94(m,1H),1.46-1.40(m,1H)。醇位置异构体的约3:1混合物。
实例61:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟嘧啶-5-基)-5-羟基-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.33min;MS m/z[M+H]+ 398.0。1H NMR(500MHz,DMSO-d6)δ9.91(s,1H),8.57(d,J=1.5Hz,2H),7.42-7.41(m,2H),7.03(dd,J=8.8,2.5Hz,1H),5.02-4.98(m,1H),4.86-4.82(m,1H),4.30(s,1H),4.06-4.02(m,1H),3.47(d,J=9.6Hz,1H),3.05(d,J=9.7Hz,1H),2.07-2.01(m,1H),1.52-1.46(m,1H)。醇位置异构体的约2:1混合物。
实例62:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲基)嘧啶-
5-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.03min;MS m/z[M+H]+ 448.1。1H NMR(500MHz,DMSO-d6)δ9.90(s,1H),8.83(s,2H),7.38(d,J=8.8Hz,1H),7.28(d,J=2.4Hz,1H),6.94(dd,J=8.8,2.5Hz,1H),5.08-5.03(m,1H),4.89-4.85(m,1H),4.41(s,1H),4.09-4.05(m,1H),3.53(d,J=9.6Hz,1H),3.11(d,J=9.6Hz,1H),2.09-2.03(m,1H),1.56-1.47(m,1H)。醇位置异构体的约3:1混合物。
实例63:(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-甲氧基-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
根据实例47所述的方案,使用甲基(1R,4S,5S)-3-溴-5-甲氧基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-甲氧基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1f)和步骤A中的3,4-二氯苯胺以及步骤C中的(2-甲基吡啶-4-基)硼酸,合成所述实例63。LC-MS:Rt=1.23min;MS m/z[M+H]+ 407.0。1H NMR(500MHz,DMSO-d6)δ9.61(s,1H),8.11(d,J=5.1Hz,1H),7.39-7.36(m,2H),7.12(s,1H),7.03(d,J=5.4Hz,1H),6.99(dd,J=8.9,2.5Hz,1H),4.86-4.81(m,1H),4.48(s,1H),3.76-3.72(m,1H),3.28-3.24(m,1H),3.21(s,3H),3.06(d,J=9.5Hz,1H),2.27(s,3H),2.03-1.97(m,1H),1.54-1.48(m,1H)。甲氧基位置异构体的约4:1混合物。
实例64:(1R,2S,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(6-甲基吡啶-3-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案4中的步骤A,由(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-甲基吡啶-3-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(中间体4a,实例48)制备标题化合物。
步骤A:在室温下向(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-甲基吡啶-3-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(25mg,0.064mmol)在DCM(1mL)中的搅拌溶液中添加Xtalfluor-E(36mg,0.16mmol)和Et3N-3HF(0.031mL,0.19mmol)并且将反应搅拌16h。将反应冷却至0℃,并用饱和水性碳酸氢钠溶液淬灭。将粗化合物用DCM萃取3次。将合并的有机层经无水硫酸钠干燥、过滤并浓缩。将粗化合物通过二氧化硅柱色谱法纯化,以得到呈氟位置异构体的未知混合物的(1R,2S,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(6-甲基吡啶-3-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.38min;MS m/z[M+H]+395.0。
实例65:(1R,2S,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(2-甲氧基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
根据实例64所述的方案,使用步骤A中的(1R,2S,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(中间体4a,实例49)合成实例65。LC-MS:Rt=1.53min;MS m/z[M+H]+ 411.0。1H NMR(500MHz,DMSO-d6)δ10.13(s,1H),7.97-7.94(m,1H),7.77(d,J=2.5Hz,1H),7.49(d,J=8.8Hz,1H),7.29(dd,J=8.8,2.5Hz,1H),6.69(dd,J=5.5,1.5Hz,1H),6.58(s,1H),5.64(d,J=72.4Hz,1H),4.85-4.80(m,1H),3.79(s,3H),3.70-3.66(m,1H),3.46-3.42(m,1H),3.16-3.13(m,1H),1.99-1.95(m,1H),1.79-1.75(m,1H)。氟位置异构体的约4:1混合物。
实例66:(1S,2S,4R,5R,6R,7S)-N-(4-氯-3-氰基苯基)-7-(2-甲基吡啶-4-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用方案2中的步骤A-B和步骤D,由甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)制备标题化合物。
步骤A:在0℃下,向甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(1d,4.70g,19.2mmol)在THF(25mL)和水(6mL)中的搅拌溶液中添加乙酸(4.40mL)和分批的锌粉(5.00g,77.0mmol)。将反应浆液在室温下搅拌15分钟。将反应过滤,并用饱和水性碳酸氢钠中和至pH~7。将化合物用乙酸乙酯萃取。将合并的有机层用水和盐水洗涤,并经无水硫酸钠干燥。将溶剂浓缩并在真空下干燥。将粗化合物(1S,2S,4R,5R)-甲基8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯无需进一步纯化即可用于下一步骤中。LC-MS:Rt=1.16min;MS m/z[M+H]+ 167.1。
步骤B:在100℃下,将(1S,2S,4R,5R)-甲基8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(800mg,4.81mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(1.27g,5.78mmol)、2,2-双(二苯基膦基)-1,1-联萘(300mg,0.481mmol)、氯(1,5-环辛二烯)铑(I)二聚体(119mg,0.241mol)和碳酸钾(332mg,2.41mmol)在1,4-二噁烷(10mL)和水(2.5mL)中的混合物在微波中加热1h。将硅胶土添加至反应混合物并将溶剂在减压下去除。将化合物通过FCC纯化,以得到(1S,2S,4R,5R,6S,7S)-甲基7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酸酯(顺式)和(1S,2S,4R,5R,6R,7S)-甲基7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酸酯(反式)。顺式LC-MS:Rt=0.88min;MS m/z[M+H]+ 260.1。反式LC-MS:Rt=0.96min;MS m/z[M+H]+ 260.1。
步骤C:在0℃下,向(1S,2S,4R,5R,6R,7S)-甲基7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酸酯(75.0mg,0.289mmol)和5-氨基-2-氯苄腈(44.0mg,0.289mmol)在THF(2mL)中的搅拌溶液中添加LiHMDS(1M,0.434mL,0.434mmol)。将反应在室温搅拌1h。添加LiHMDS(1M,0.434mL,0.434mmol)并且将所述反应继续在室温搅拌4h。添加硅藻土并浓缩溶剂。将粗化合物通过FCC纯化以得到标题化合物(1S,2S,4R,5R,6R,7S)-N-(4-氯-3-氰基苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺。方法B LC-MS:Rt=1.11min;MS m/z[M+H]+ 380.1。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.33(d,J=5.1Hz,1H),8.22(d,J=2.5Hz,1H),7.77(dd,J=8.9,2.5Hz,1H),7.69(d,J=8.9Hz,1H),7.11(s,1H),7.05(d,J=4.0Hz,1H),4.76(d,J=4.9Hz,1H),4.39(s,1H),3.51(d,J=4.8Hz,1H),3.09(t,J=4.8Hz,1H),2.42(s,3H),1.34-1.28(m,1H),1.20-1.15(m,1H),0.43-0.39(m,1H),0.21-0.15(m,1H)。
根据实例66所述的方案,使用甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)和步骤B中的各种硼酸/酯以及步骤D中的各种苯胺,合成下述实例67-76。
实例67:(1S,2S,4R,5R,6R,7S)-N-(4-氯-2-氰基苯基)-7-(2-甲基吡啶-4-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.04min;MS m/z[M+H]+ 380.1。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.34(d,J=5.1Hz,1H),8.04(d,J=2.5Hz,1H),7.77(dd,J=8.8,2.5Hz,1H),7.52(d,J=8.8Hz,1H),7.12(s,1H),7.06(dd,J=5.1,1.3Hz,1H),4.77(d,J=4.9Hz,1H),4.39(s,1H),3.50(d,J=4.8Hz,1H),3.14(t,J=4.9Hz,1H),2.43(s,3H),1.42-1.37(m,1H),1.33-1.27(m,1H),0.45-0.40(m,1H),0.21-0.17(m,1H)。
实例68:(1S,2S,4R,5R,6R,7S)-N-(4-氯-3-氟苯基)-7-(2-甲基吡啶-4-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法C LC-MS:Rt=1.47min;MS m/z[M+H]+ 373.1。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.38(d,J=5.2Hz,1H),7.80(dd,J=12.0,2.3Hz,1H),7.52(t,J=8.7Hz,1H),7.31-7.28(m,1H),7.19(s,1H),7.12(d,J=4.9Hz,1H),4.76(d,J=4.9Hz,1H),4.39(s,1H),3.54(d,J=4.8Hz,1H),3.09(t,J=4.8Hz,1H),2.45(s,3H),1.33-1.28(m,1H),1.18-1.13(m,1H),0.43-0.39(m,1H),0.21-0.15(m,1H)。
实例69:(1S,2S,4R,5R,6R,7S)-7-(2-甲基吡啶-4-基)-N-(3-(三氟甲氧基)苯
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.47min;MS m/z[M+H]+ 405.1。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.34(d,J=5.1Hz,1H),7.80(s,1H),7.46-7.41(m,2H),7.12(s,1H),7.08-7.01(m,2H),4.76(d,J=4.9Hz,1H),4.38(s,1H),3.51(d,J=4.8Hz,1H),3.09(t,J=4.8Hz,1H),2.42(s,3H),1.35-1.29(m,1H),1.19-1.13(m,1H),0.43-0.37(m,1H),0.22-0.16(m,1H)。
实例70:(1S,2S,4R,5R,6R,7S)-7-(2-甲基吡啶-4-基)-N-(5-甲基噻唑-2-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.20min;MS m/z[M+H]+ 342.1。1H NMR(400MHz,DMSO-d6)δ12.12(s,1H),8.55(d,J=5.9Hz,1H),7.51(s,1H),7.44(s,1H),7.14(s,1H),4.87(d,J=4.8Hz,1H),4.48(d,J=1.8Hz,1H),3.73(d,J=4.6Hz,1H),3.21(d,J=4.9Hz,1H),2.58(s,3H),2.34(s,3H),1.37-1.32(m,1H),1.09-1.03(m,1H),0.44-0.38(m,1H),0.23-0.17(m,1H)。
实例71:(1S,2S,4R,5R,6R,7S)-N-(3-氟-4-(三氟甲氧基)苯基)-7-(2-甲基吡啶-
4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.50min;MS m/z[M+H]+ 423.1。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.41(d,J=5.1Hz,1H),7.86(d,J=12.9Hz,1H),7.52(t,J=8.9Hz,1H),7.35(d,J=8.9Hz,1H),7.25(s,1H),7.19(d,J=5.4Hz,1H),4.78(d,J=4.5Hz,1H),4.41(s,1H),3.57(d,J=4.4Hz,1H),3.11(t,J=4.3Hz,1H),2.48(s,3H),1.36-1.28(m,1H),1.21-1.13(m,1H),0.44-0.37(m,1H),0.22-0.16(m,1H)。
实例72和73(对应于峰1和峰2)
(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(2,3-二氟吡啶-4-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺甲酰胺或(1R,2R,4S,5S,6S,7R)-N-(5,6-二氯吡啶-3-
基)-7-(2,3-二氟吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(2,3-二氟吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IA@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.61min。LC-MS:Rt=1.69min;MS m/z[M+H]+ 412.0。1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),8.48(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.00(dd,J=5.2,1.1Hz,1H),7.37(t,J=4.9Hz,1H),4.81(d,J=5.0Hz,1H),4.52(s,1H),3.95(d,J=4.7Hz,1H),3.20-3.11(m,1H),1.38-1.31(m,1H),1.26-1.21(m,1H),0.45-0.39(m,1H),0.24-0.16(m,1H)。
峰2:SFC保留时间=3.23min。LC-MS:Rt=1.69min;MS m/z[M+H]+ 412.0。1H NMR(500MHz,DMSO-d6)δ10.55(s,1H),8.48(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.00(dd,J=5.2,1.1Hz,1H),7.37(t,J=4.9Hz,1H),4.81(d,J=5.0Hz,1H),4.52(s,1H),3.95(d,J=4.7Hz,1H),3.20-3.11(m,1H),1.38-1.31(m,1H),1.26-1.21(m,1H),0.45-0.39(m,1H),0.24-0.16(m,1H)。
实例74:(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(6-甲基吡啶-3-基)-
8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.28min;MS m/z[M+H]+ 390.0。1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.48(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.32(d,J=2.1Hz,1H),7.54(dd,J=8.0,2.3Hz,1H),7.19(d,J=8.0Hz,1H),4.77(d,J=4.9Hz,1H),4.32(s,1H),3.54(d,J=4.7Hz,1H),3.10(t,J=4.8Hz,1H),2.42(s,3H),1.35-1.29(m,1H),1.24-1.17(m,1H),0.44-0.39(m,1H),0.21-0.15(m,1H)。
实例75:(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(嘧啶-5-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.43min;MS m/z[M+H]+ 377.0。1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),9.06(s,1H),8.69(s,2H),8.49(d,J=2.4Hz,1H),8.42(d,J=2.4Hz,1H),4.83(d,J=4.9Hz,1H),4.43(s,1H),3.62(d,J=4.7Hz,1H),3.22(t,J=4.8Hz,1H),1.37-1.32(m,1H),1.28-1.21(m,1H),0.44-0.40(m,1H),0.22-0.17(m,1H)。
实例76:(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(2-甲氧基吡啶-4-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.52min;MS m/z[M+H]+ 406.1。1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.49(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.07(d,J=5.3Hz,1H),6.87(dd,J=5.3,1.4Hz,1H),6.65(s,1H),4.76(d,J=4.9Hz,1H),4.39(s,1H),3.81(s,3H),3.52(d,J=4.8Hz,1H),3.11(t,J=4.8Hz,1H),1.34-1.27(m,1H),1.23-1.17(m,1H),0.43-0.38(m,1H),0.19-0.14(m,1H)。
实例77:外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案2中的步骤A-B和步骤D,由甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e)制备标题化合物。
步骤A:将甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(1e,1.40g,5.62mmol)和AcOH(1.61mL,28.1mmol)在1:1THF:水(15mL)中的溶液用锌粉(735mg,11.2mmol)处理并在室温下搅拌1h。将反应混合物用EtOAc稀释并用饱和水性NaHCO3和盐水洗涤。将水性层用EtOAc进一步萃取,并将合并的EtOAc层干燥(Na2SO4),过滤,并浓缩。将所得的粗(1R,4R,5S)-甲基5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和(1S,4S,6R)-甲基6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯不经纯化直接用于下一步骤。LC-MS:Rt=0.29min;MS m/z[M+H]+ 171.1。
步骤B:将来自步骤A的粗(1R,4R,5S)-甲基5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和(1S,4S,6R)-甲基6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(250mg,1.469mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(386mg,1.763mmol)、2,2-双(二苯基膦基)-1,1-联萘(91mg,0.147mmol)、氯(1,5-环辛二烯)铑(I)二聚体(36.2mg,0.073mmol)和碳酸钾(101mg,0.735mmol)在4:1的1,4-二噁烷:水(15mL)中的溶液用氮气脱气,并在110℃下在微波反应器中温热1h。在相同条件下以相同规模将反应重复四次。将反应混合物合并并浓缩到硅藻土上,且通过FCC纯化,以得到呈醇位置异构体(顺式)的混合物的(1R,2S,3S,4R,5S)-甲基5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酸酯和(1S,2S,3S,4S,6R)-甲基6-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酸酯,以及呈醇位置异构体(反式)的混合物的(1R,2R,3S,4R,5S)-甲基5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酸酯和(1S,2R,3S,4S,6R)-甲基6-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酸酯。顺式:LC-MS:Rt=0.29min;MS m/z[M+H]+ 264.2。反式:LC-MS:Rt=0.33min;MS m/z[M+H]+ 264.2。
步骤C:将(1R,2R,3S,4R,5S)-甲基-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酸酯和(1S,2R,3S,4S,6R)-甲基-6-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酸酯(338mg,1.284mmol)和3,4-二氯苯胺(416mg,2.57mmol)在THF(体积:16mL)中的溶液在室温下用LiHMDS(5.14mL,5.14mmol)处理且在室温下搅拌1h。将反应混合物浓缩到硅藻土上,并通过FCC纯化,以得到呈醇位置异构体的约8:1混合物的外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺,顺利得到5-羟基产物。LC-MS:Rt=1.20min;MS m/z[M+H]+ 393.1。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.34(d,J=5.0Hz,1H),7.97(d,J=2.5Hz,1H),7.55(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.4Hz,1H),7.11(s,1H),7.05(dd,J=5.3,1.7Hz,1H),4.98-4.95(m,1H),4.90-4.87(m,1H),4.23(s,1H),3.98-3.95(m,1H),3.18-3.14(m,1H),2.96-2.93(m,1H),2.43(s,3H),2.09-2.04(m,1H),1.45-1.37(m,1H)。
实例77a和77c(对应于峰1和峰3a)
(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双
环[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
实例77b和77d(对应于峰2和峰3b)
(1S,2R,3S,4S,6R)-N-(3,4-二氯苯基)-6-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双
环[2.2.1]庚烷-2-甲酰胺或(1R,2S,3R,4R,6S)-N-(3,4-二氯苯基)-6-羟基-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈醇位置异构体的约8:1混合物的外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例77),得到以下所列化合物:
方法细节:
柱:21x 250mm AD-H@30℃
流动相:80%CO2/20%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.14min。LC-MS:Rt=1.16min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.34(dd,J=5.2,0.8Hz,1H),7.98(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),7.11(s,1H),7.05(dd,J=5.2,1.7Hz,1H),5.00-4.97(m,1H),4.91-4.86(m,1H),4.22(s,1H),3.99-3.94(m,1H),3.19-3.14(m,1H),2.96-2.92(m,1H),2.43(s,3H),2.10-2.04(m,1H),1.44-1.37(m,1H)。
峰2:SFC保留时间=3.56min。LC-MS:Rt=1.16min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.33(dd,J=5.2,0.8Hz,1H),8.00(d,J=2.5Hz,1H),7.58(d,J=8.8Hz,1H),7.44(dd,J=8.8,2.5Hz,1H),7.11(s,1H),7.06(dd,J=5.2,1.7Hz,1H),4.95-4.90(m,1H),4.64-4.59(m,1H),4.57-4.51(m,1H),4.02-3.96(m,1H),3.26-3.21(m,1H),3.00-2.95(m,1H),2.42(s,3H),2.10-2.01(m,1H),1.55-1.48(m,1H)。
峰3:SFC保留时间=4.22min。将使用超临界流体色谱法分离出的第三个洗脱峰浓缩并使用以下条件通过超临界流体色谱法进行重新纯化,得到以下所列化合物:
方法细节:
柱:21x 250mm AS-H@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰3a:SFC保留时间=1.44min。LC-MS:Rt=1.16min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.34(dd,J=5.2,0.8Hz,1H),7.98(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),7.11(s,1H),7.05(dd,J=5.2,1.7Hz,1H),5.00-4.97(m,1H),4.91-4.86(m,1H),4.22(s,1H),3.99-3.94(m,1H),3.19-3.14(m,1H),2.96-2.92(m,1H),2.43(s,3H),2.10-2.04(m,1H),1.44-1.37(m,1H)。
峰3b:SFC保留时间=2.04min。LC-MS:Rt=1.16min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),8.33(dd,J=5.2,0.8Hz,1H),8.00(d,J=2.5Hz,1H),7.58(d,J=8.8Hz,1H),7.44(dd,J=8.8,2.5Hz,1H),7.11(s,1H),7.06(dd,J=5.2,1.7Hz,1H),4.95-4.90(m,1H),4.64-4.59(m,1H),4.57-4.51(m,1H),4.02-3.96(m,1H),3.26-3.21(m,1H),3.00-2.95(m,1H),2.42(s,3H),2.10-2.01(m,1H),1.55-1.48(m,1H)。
根据实例77所述的方案,使用甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e)和步骤B中的各种硼酸/酯以及步骤D中的各种苯胺/胺,合成下述实例78-91。
实例78:(1R,2R,3S,4R,5S)-N-(2-氯-2’-氟-[1,1’-联苯基]-4-基)-5-羟基-3-
(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.89min;MS m/z[M+H]+ 453.2。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.35(dd,J=5.2,0.8Hz,1H),7.93(d,J=2.1Hz,1H),7.51-7.45(m,2H),7.38-7.27(m,4H),7.13(s,1H),7.07(dd,J=5.2,1.6Hz,1H),5.00-4.97(m,1H),4.94-4.89(m,1H),4.24(s,1H),4.01-3.95(m,1H),3.22-3.19(m,1H),3.00-2.96(m,1H),2.44(s,3H),2.12-2.05(m,1H),1.46-1.41(m,1H)。醇位置异构体的约3:1混合物。
实例79:(1R,2R,3S,4R,5S)-5-羟基-3-(2-甲基吡啶-4-基)-N-(1-(甲基磺酰基)
哌啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.20min;MS m/z[M+H]+ 410.2。醇位置异构体的混合物。
实例80:(1R,2R,3S,4R,5S)-N-(4,5-二氯吡啶-2-基)-5-羟基-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.73min;MS m/z[M+H]+ 394.1。1H NMR(500MHz,DMSO-d6)δ11.03(s,1H),8.52(s,1H),8.37-8.32(m,2H),7.10(s,1H),7.04(dd,J=5.3,1.7Hz,1H),5.00-4.95(m,1H),4.95-4.89(m,1H),4.24(s,1H),4.00-3.94(m,1H),3.22-3.18(m,1H),3.13-3.09(m,1H),2.43(s,3H),2.07-1.99(m,1H),1.43-1.36(m,1H)。醇位置异构体的约5:1混合物。
实例81:(1R,2R,3S,4R,5S)-N-(5-氯-6-甲基吡啶-3-基)-5-羟基-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.57min;MS m/z[M+H]+ 374.1。1H NMR(400MHz,DMSO-d6)δ10.37(s,1H),8.45(d,J=2.2Hz,1H),8.34(dd,J=5.2,0.8Hz,1H),8.17(d,J=2.2Hz,1H),7.12(d,J=1.7Hz,1H),7.06(dd,J=5.3,1.7Hz,1H),5.00-4.96(m,1H),4.93-4.87(m,1H),4.22(s,1H),3.99-3.91(m,1H),3.21-3.15(m,1H),2.99-2.94(m,1H),2.47(s,3H),2.43(s,3H),2.11-2.04(m,1H),1.44-1.36(m,1H)。醇位置异构体的约5:1混合物。
实例82:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基嘧啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.83min;MS m/z[M+H]+ 394.1。醇位置异构体的混合物。
实例83和84(对应于峰1和峰2A)
(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(2-甲基吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5R)-N-(5,6-二氯吡啶-3-基)-5-羟基-
3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈醇位置异构体的混合物的外消旋-(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IA@30℃
流动相:80%CO2/20%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.96min。LC-MS:Rt=1.05min;MS m/z[M+H]+ 394.2。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.45(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H),8.34(dd,J=5.2,0.7Hz,1H),7.12(s,1H),7.06(dd,J=5.2,1.7Hz,1H),5.02-4.98(m,1H),4.94-4.89(m,1H),4.23(s,1H),4.00-3.94(m,1H),3.19-3.15(m,1H),3.01-2.94(m,1H),2.43(s,3H),2.12-2.03(m,1H),1.45-1.38(m,1H)。
峰2:将使用超临界流体色谱法(保留时间=3.03min)分离出的第二个洗脱峰浓缩并使用以下条件通过超临界流体色谱法进行重新纯化,得到以下所列化合物:
方法细节:
柱:21x 250mm AD-H@30℃
流动相:80%CO2/20%IPA+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰2A:第一洗脱峰。SFC保留时间=2.18min。LC-MS:Rt=1.05min;MS m/z[M+H]+394.2。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.45(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H),8.34(dd,J=5.2,0.7Hz,1H),7.12(s,1H),7.06(dd,J=5.2,1.7Hz,1H),5.02-4.98(m,1H),4.94-4.89(m,1H),4.23(s,1H),4.00-3.94(m,1H),3.19-3.15(m,1H),3.01-2.94(m,1H),2.43(s,3H),2.12-2.03(m,1H),1.45-1.38(m,1H)。
实例85:(1R,2R,3S,4R,5S)-5-羟基-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.13min;MS m/z[M+H]+ 393.3。1H NMR(400MHz,DMSO-d6)δ10.41(s,1H),8.34(dd,J=5.2,0.8Hz,1H),8.09(s,1H),7.73-7.69(m,1H),7.57-7.52(m,1H),7.43-7.38(m,1H),7.12(s,1H),7.07(dd,J=5.2,1.7Hz,1H),5.02-4.95(m,1H),4.94-4.88(m,1H),4.23(s,1H),4.01-3.94(m,1H),3.22-3.17(m,1H),3.00-2.96(m,1H),2.43(s,3H),2.13-2.04(m,1H),1.45-1.37(m,1H)。醇位置异构体的>20:1混合物。
实例86:(1S,2R,3S,4S,6R)-6-羟基-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.12min;MS m/z[M+H]+ 393.3。1H NMR(400MHz,DMSO-d6)δ10.51(s,1H),8.34(dd,J=5.2,0.7Hz,1H),8.12(s,1H),7.76-7.72(m,1H),7.59-7.53(m,1H),7.45-7.40(m,1H),7.13-7.10(m,1H),7.07(dd,J=5.2,1.7Hz,1H),4.92(s,1H),4.66-4.61(m,1H),4.58-4.53(m,1H),4.05-3.98(m,1H),3.28-3.23(m,1H),3.03-2.98(m,1H),2.42(s,3H),2.10-2.02(m,1H),1.56-1.46(m,1H)。醇位置异构体的>20:1混合物。
实例87:(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-羟基-3-(吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.84min;MS m/z[M+H]+ 380.1。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.50-8.46(m,2H),8.45(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H),7.29-7.25(m,2H),5.04-4.99(m,1H),4.96-4.90(m,1H),4.25(s,1H),4.02-3.95(m,1H),3.26-3.22(m,1H),3.01-2.96(m,1H),2.12-2.04(m,1H),1.48-1.37(m,1H)。醇位置异构体的约5:1混合物。
实例88:(1R,2R,3S,4R,5S)-5-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.11min;MS m/z[M+H]+ 379.2。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.49-8.46(m,2H),8.09(s,1H),7.74-7.70(m,1H),7.57-7.51(m,1H),7.42-7.37(m,1H),7.29-7.25(m,2H),5.01(s,1H),4.96-4.90(m,1H),4.25(s,1H),4.02-3.97(m,1H),3.27-3.22(m,1H),3.02-2.98(m,1H),2.14-2.04(m,1H),1.46-1.37(m,1H)。醇位置异构体的>20:1混合物。
实例89:(1S,2R,3S,4S,6R)-6-羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.08min;MS m/z[M+H]+ 379.2。1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),8.50-8.45(m,2H),8.12(s,1H),7.77-7.73(m,1H),7.59-7.53(m,1H),7.44-7.40(m,1H),7.29-7.24(m,2H),4.94(s,1H),4.69-4.62(m,1H),4.61-4.55(m,1H),4.04-3.97(m,1H),3.32-3.28(m,1H),3.06-3.00(m,1H),2.13-2.03(m,1H),1.58-1.48(m,1H)。醇位置异构体的>20:1混合物。
实例90:外消旋-(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡啶-4-
基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.30min;MS m/z[M+H]+ 398.1。醇位置异构体的混合物。
实例90a和90b(对应于峰1和峰2)
(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧
杂双环[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5R)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡
啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈醇位置异构体的混合物的外消旋-(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例90),得到以下所列化合物:
方法细节:
柱:21x 250mm IF@30℃
流动相:70%CO2/30%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.29min。LC-MS:Rt=1.30min;MS m/z[M+H]+ 398.1。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.45(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H),8.17(d,J=5.2Hz,1H),7.27-7.23(m,1H),7.02(s,1H),5.06-5.02(m,1H),4.97-4.92(m,1H),4.28(s,1H),4.01-3.96(m,1H),3.35-3.33(m,1H),3.04-2.99(m,1H),2.13-2.05(m,1H),1.47-1.38(m,1H)。
峰2:SFC保留时间=1.95min。LC-MS:Rt=1.30min;MS m/z[M+H]+ 398.1。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.45(d,J=2.4Hz,1H),8.38(d,J=2.4Hz,1H),8.17(d,J=5.2Hz,1H),7.27-7.23(m,1H),7.02(s,1H),5.06-5.02(m,1H),4.97-4.92(m,1H),4.28(s,1H),4.01-3.96(m,1H),3.35-3.33(m,1H),3.04-2.99(m,1H),2.13-2.05(m,1H),1.47-1.38(m,1H)。
实例91:(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-3-(2,3-二氟吡啶-4-基)-
5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.35min;MS m/z[M+H]+ 416.1。1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.44(d,J=2.4Hz,1H),8.39(d,J=2.4Hz,1H),8.01(dd,J=5.2,1.2Hz,1H),7.42-7.37(m,1H),5.11-5.08(m,1H),4.96-4.93(m,1H),4.36(s,1H),4.02-3.97(m,1H),3.64-3.60(m,1H),3.05-3.02(m,1H),2.15-2.07(m,1H),1.49-1.40(m,1H)。醇位置异构体的约5:1混合物。
根据实例77所述的方案,使用甲基(1R,4S,5R)-3-溴-5-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6S)-3-溴-6-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1g)和步骤B中的各种硼酸/酯以及步骤D中的各种苯胺,合成下述实例92-102。
实例92和94(对应于峰1和峰3)
(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(2-甲基吡啶-4-基)-7-氧杂双环
[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
实例93和95(对应于峰2和峰4)
(1S,2R,3S,4S,6S)-N-(3,4-二氯苯基)-6-氟-3-(2-甲基吡啶-4-基)-7-氧杂双环
[2.2.1]庚烷-2-甲酰胺或(1R,2S,3R,4R,6R)-N-(3,4-二氯苯基)-6-氟-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈氟位置异构体的混合物的外消旋-(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IF@30℃
流动相:95%-50%CO2/5%-50%MeOH+0.5%异丙胺(5分钟)
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.45min。LC-MS:Rt=1.35min;MS m/z[M+H]+ 395.1。1H NMR(400MHz,乙腈-d3)δ8.50(s,1H),8.36(dd,J=5.2,0.8Hz,1H),7.88(dd,J=2.3,0.6Hz,1H),7.46-7.39(m,2H),7.16(s,1H),7.10(dd,J=5.2,1.7Hz,1H),5.24-5.02(m,1H),4.92-4.87(m,1H),4.65-4.58(m,1H),4.09-4.02(m,1H),3.18-3.11(m,1H),2.46(s,3H),2.23-2.16(m,1H),1.91-1.79(m,1H)。
峰2:SFC保留时间=2.75min。LC-MS:Rt=1.35min;MS m/z[M+H]+ 395.1。1H NMR(400MHz,乙腈-d3)δ8.61(s,1H),8.36(dd,J=5.2,0.7Hz,1H),7.87(d,J=2.4Hz,1H),7.43(d,J=8.8Hz,1H),7.40-7.37(m,1H),7.13(s,1H),7.07(dd,J=5.2,1.7Hz,1H),5.12-4.97(m,1H),4.97-4.95(m,1H),4.68-4.62(m,1H),3.26-3.20(m,1H),2.97-2.91(m,1H),2.46(s,3H),2.41-2.29(m,1H),1.83-1.68(m,1H)。
峰3:SFC保留时间=2.85min。LC-MS:Rt=1.35min;MS m/z[M+H]+ 395.1。1H NMR(400MHz,乙腈-d3)δ8.50(s,1H),8.36(dd,J=5.2,0.8Hz,1H),7.88(dd,J=2.3,0.6Hz,1H),7.46-7.39(m,2H),7.16(s,0H),7.10(dd,J=5.2,1.7Hz,1H),5.24-5.02(m,1H),4.92-4.87(m,1H),4.65-4.58(m,1H),4.09-4.02(m,1H),3.18-3.11(m,1H),2.46(s,3H),2.23-2.16(m,1H),1.91-1.79(m,1H)。
峰4:SFC保留时间=3.12min。LC-MS:Rt=1.35min;MS m/z[M+H]+ 395.1。1H NMR(400MHz,乙腈-d3)δ8.61(s,1H),8.36(dd,J=5.2,0.7Hz,1H),7.87(d,J=2.4Hz,1H),7.43(d,J=8.8Hz,1H),7.40-7.37(m,1H),7.13(s,1H),7.07(dd,J=5.2,1.7Hz,1H),5.12-4.97(m,1H),4.97-4.95(m,1H),4.68-4.62(m,1H),3.26-3.20(m,1H),2.97-2.91(m,1H),2.46(s,3H),2.41-2.29(m,1H),1.83-1.68(m,1H)。
实例96:(1R,2R,3S,4R,5R)-5-氟-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.29min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.37(dd,J=5.1,0.8Hz,1H),8.10(s,1H),7.75-7.71(m,1H),7.55(t,J=8.0Hz,1H),7.45-7.39(m,1H),7.16(s,1H),7.10(dd,J=5.2,1.7Hz,1H),5.25-5.03(m,1H),5.01-4.95(m,1H),4.74-4.68(m,1H),4.06-3.98(m,1H),3.25-3.20(m,1H),2.44(s,3H),2.25-2.10(m,1H),1.82-1.70(m,1H)。氟位置异构体的>20:1混合物。
实例97:(1R,2R,3S,4R,5R)-5-氟-N-(6-甲氧基吡啶-3-基)-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.92min;MS m/z[M+H]+ 358.2。1H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.37(d,J=5.2Hz,1H),8.31(dd,J=2.7,0.7Hz,1H),7.87(dd,J=8.9,2.7Hz,1H),7.15(s,1H),7.09(dd,J=5.2,1.7Hz,1H),6.79(dd,J=8.8,0.7Hz,1H),5.24-5.04(m,1H),4.97-4.91(m,1H),4.71-4.66(m,1H),4.02-3.98(m,1H),3.80(s,3H),3.22-3.15(m,1H),2.44(s,3H),2.24-2.09(m,1H),1.82-1.70(m,1H)。氟位置异构体的>20:1混合物。
实例98:(1R,2R,3S,4R,5R)-N-(5,6-二氯吡啶-3-基)-5-氟-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.21min;MS m/z[M+H]+ 396.2。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.46(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.37(d,J=5.1Hz,1H),7.17-7.14(m,1H),7.09(dd,J=5.2,1.7Hz,1H),5.26-5.05(m,1H),5.01-4.94(m,1H),4.75-4.67(m,1H),4.03-3.97(m,1H),3.27-3.21(m,1H),2.44(s,3H),2.24-2.11(m,1H),1.81-1.67(m,1H)。氟位置异构体的>20:1混合物。
实例99:(1R,2R,3S,4R,5R)-5-氟-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲氧基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.30min;MS m/z[M+H]+ 411.2。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.38(dd,J=5.2,0.8Hz,1H),7.78(s,1H),7.49-7.41(m,2H),7.19-7.15(m,1H),7.10(dd,J=5.2,1.7Hz,1H),7.08-7.04(m,1H),5.26-5.04(m,1H),4.99-4.94(m,1H),4.75-4.66(m,1H),4.04-4.00(m,1H),3.25-3.20(m,1H),2.45(s,3H),2.24-2.09(m,1H),1.81-1.68(m,1H)。氟位置异构体的>20:1混合物。
实例100:(1R,2R,3S,4R,5R)-5-氟-N-(3-氟-4-(三氟甲氧基)苯基)-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.36min;MS m/z[M+H]+ 429.2。1H NMR(400MHz,DMSO-d6)δ10.43(s,1H),8.37(d,J=0.7Hz,1H),7.84(dd,J=12.9,2.5Hz,1H),7.55-7.50(m,1H),7.36-7.32(m,1H),7.15(s,1H),7.09(dd,J=5.2,1.7Hz,1H),5.25-5.04(m,1H),4.99-4.93(m,1H),4.74-4.68(m,1H),4.03-3.99(m,1H),3.25-3.17(m,1H),2.44(s,3H),2.23-2.10(m,1H),1.79-1.65(m,1H)。氟位置异构体的>20:1混合物。
实例101:(1R,2R,3S,4R,5R)-5-氟-N-(1-甲基-1H-吡唑-3-基)-3-(2-甲基吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.43min;MS m/z[M+H]+ 331.3。1H NMR(400MHz,DMSO-d6)δ10.54(s,1H),8.36(dd,J=5.1,0.8Hz,1H),7.55(d,J=2.3Hz,1H),7.12(s,1H),7.06(dd,J=5.2,1.7Hz,1H),6.46(d,J=2.2Hz,1H),5.22-5.01(m,1H),4.95-4.89(m,1H),4.70-4.65(m,1H),4.03-3.98(m,1H),3.71(s,3H),3.20-3.15(m,1H),2.44(s,3H),2.19-2.06(m,1H),1.75-1.61(m,1H)。氟位置异构体的>20:1混合物。
实例102:(1R,2R,3S,4R,5R)-5-氟-3-(2-甲基吡啶-4-基)-N-(5-甲基噻唑-2-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.04min;MS m/z[M+H]+ 348.2。1H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.37(dd,J=5.1,0.7Hz,1H),7.16-7.11(m,2H),7.08(dd,J=5.3,1.7Hz,1H),5.25-5.04(m,1H),5.02-4.97(m,1H),4.75-4.69(m,1H),4.06-4.00(m,1H),3.33-3.27(m,1H),2.44(s,3H),2.34(s,3H),2.24-2.10(m,1H),1.68-1.53(m,1H)。氟位置异构体的约8:1混合物。
根据实例77所述的方案,使用甲基(1R,4S,5S)-3-溴-5-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-氟-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1j)和步骤B中的各种硼酸/酯以及步骤C中的各种苯胺,合成下述实例103-116。
实例103:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-甲氧基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.54min;MS m/z[M+H]+ 411.2。1H NMR(500MHz,DMSO-d6)δ10.37(s,1H),8.10(dd,J=5.3,0.7Hz,1H),7.97(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.4Hz,1H),6.88(dd,J=5.4,1.5Hz,1H),6.66(s,1H),5.16-5.01(m,1H),5.01-4.98(m,1H),4.67(d,J=10.6Hz,1H),3.83(s,3H),3.24-3.19(m,1H),3.02-2.96(m,1H),2.30-2.20(m,1H),1.79-1.64(m,1H)。氟位置异构体的>20:1混合物。
实例104:(1S,2R,3S,4S,6R)-N-(3,4-二氯苯基)-6-氟-3-(2-甲氧基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.55min;MS m/z[M+H]+ 411.1。1H NMR(400MHz,乙腈-d3)δ8.55(s,1H),8.07(dd,J=5.4,0.7Hz,1H),7.86(d,J=2.4Hz,1H),7.43(d,J=8.7Hz,1H),7.37(dd,J=8.8,2.4Hz,1H),6.87(dd,J=5.3,1.5Hz,1H),6.67(dd,J=1.5,0.7Hz,1H),5.11-4.92(m,2H),4.67-4.59(m,1H),3.86(s,3H),3.27-3.21(m,1H),2.97-2.90(m,1H),2.43-2.31(m,1H),1.84-1.65(m,1H)。氟位置异构体的>20:1混合物。
实例105:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-甲基吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.31min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.56(s,1H),8.36(dd,J=5.2,0.8Hz,1H),7.87(d,J=2.4Hz,1H),7.45-7.38(m,2H),7.13(s,1H),7.08-7.06(m,1H),5.13-4.93(m,2H),4.68-4.63(m,1H),3.26-3.22(m,1H),2.96-2.91(m,1H),2.46(s,3H),2.40-2.30(m,1H),1.85-1.77(m,1H)。氟位置异构体的>20:1混合物。
实例106:(1S,2R,3S,4S,6R)-N-(3,4-二氯苯基)-6-氟-3-(2-甲基吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.31min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.52(s,1H),8.36(dd,J=5.2,0.8Hz,1H),7.89(d,J=2.0Hz,1H),7.45-7.38(m,2H),7.18-7.15(m,1H),7.10(dd,J=5.2,1.7Hz,1H),5.23-5.03(m,1H),4.91-4.86(m,1H),4.64-4.59(m,1H),4.08-4.05(m,1H),3.19-3.13(m,1H),2.46(s,3H),2.20-2.11(m,1H),1.91-1.79(m,1H)。氟位置异构体的>20:1混合物。
实例107:(1R,2R,3S,4R,5S)-5-氟-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.29min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.72(s,1H),8.35(dd,J=5.2,0.8Hz,1H),8.02(s,1H),7.68-7.62(m,1H),7.52-7.46(m,1H),7.42-7.36(m,1H),7.14(s,1H),7.07(dd,J=5.2,1.7Hz,1H),5.13-4.95(m,2H),4.70-4.63(m,1H),3.29-3.23(m,1H),2.99-2.92(m,1H),2.45(s,3H),2.43-2.34(m,1H),1.86-1.67(m,1H)。氟位置异构体的>20:1混合物。
实例108:(1S,2R,3S,4S,6R)-6-氟-3-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.29min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.59(s,1H),8.37(dd,J=5.2,0.8Hz,1H),8.03(s,1H),7.71-7.67(m,1H),7.53-7.47(m,1H),7.42-7.37(m,1H),7.18(s,1H),7.11(dd,J=5.3,1.7Hz,1H),5.24-5.03(m,1H),4.94-4.89(m,1H),4.66-4.60(m,1H),4.12-4.07(m,1H),3.21-3.16(m,1H),2.46(s,3H),2.24-2.14(m,1H),1.90-1.81(m,1H)。氟位置异构体的>20:1混合物。
实例109:(1R,2R,3S,4R,5S)-N-(5,6-二氯吡啶-3-基)-5-氟-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.22min;MS m/z[M+H]+ 396.2。1H NMR(400MHz,乙腈-d3)δ8.73(s,1H),8.40(d,J=2.4Hz,1H),8.36(dd,J=5.2,0.8Hz,1H),8.28(d,J=2.4Hz,1H),7.14-7.13(m,1H),7.07(dd,J=5.3,1.7Hz,1H),5.13-4.94(m,2H),4.69-4.62(m,1H),3.27-3.21(m,1H),3.00-2.94(m,1H),2.46(s,3H),2.40-2.30(m,1H),1.86-1.67(m,1H)。氟位置异构体的>20:1混合物。
实例110:(1S,2R,3S,4S,6R)-N-(5,6-二氯吡啶-3-基)-6-氟-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.22min;MS m/z[M+H]+ 396.2。1H NMR(400MHz,乙腈-d3)δ8.69(s,1H),8.42(d,J=2.4Hz,1H),8.37(dd,J=5.2,0.8Hz,1H),8.31(d,J=2.4Hz,1H),7.17(s,1H),7.10(dd,J=5.2,1.7Hz,1H),5.24-5.04(m,1H),4.93-4.89(m,1H),4.64-4.60(m,1H),4.09-4.05(m,1H),3.22-3.18(m,1H),2.46(s,3H),2.25-2.14(m,1H),1.90-1.78(m,1H)。氟位置异构体的>20:1混合物。
实例111:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(2-氟吡啶-4-基)-7-氧
杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.59min;MS m/z[M+H]+ 399.1。1H NMR(400MHz,乙腈-d3)δ8.55(s,1H),8.13(d,J=5.2Hz,1H),7.86(d,J=2.4Hz,1H),7.44(d,J=8.8Hz,1H),7.37(dd,J=8.8,2.4Hz,1H),7.23-7.20(m,1H),6.97-6.93(m,1H),5.13-4.95(m,2H),4.70-4.65(m,1H),3.39-3.34(m,1H),2.99-2.94(m,1H),2.41-2.30(m,1H),1.85-1.69(m,1H)。氟位置异构体的>20:1混合物。
实例112:(1S,2R,3S,4S,6R)-N-(3,4-二氯苯基)-6-氟-3-(2-氟吡啶-4-基)-7-氧
杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.59min;MS m/z[M+H]+ 399.1。1H NMR(400MHz,乙腈-d3)δ8.50(s,1H),8.13(dd,J=5.2,0.7Hz,1H),7.88(d,J=2.2Hz,1H),7.45-7.39(m,2H),7.27-7.23(m,1H),6.99-6.97(m,1H),5.25-5.04(m,1H),4.94-4.89(m,1H),4.68-4.65(m,1H),4.21-4.17(m,1H),3.20-3.15(m,1H),2.25-2.17(m,1H),1.91-1.80(m,1H)。氟位置异构体的约5:1混合物。
实例113:(1R,2R,3S,4R,5S)-3-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-5-氟-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.33min;MS m/z[M+H]+ 397.2。1H NMR(400MHz,乙腈-d3)δ8.57(s,1H),8.18(s,2H),7.85(d,J=2.4Hz,1H),7.43(d,J=8.8Hz,1H),7.37(dd,J=8.8,2.4Hz,1H),5.37(s,2H),5.10-4.92(m,2H),4.56-4.51(m,1H),3.11-3.07(m,1H),2.93-2.89(m,1H),2.44-2.33(m,1H),1.81-1.65(m,1H)。氟位置异构体的>20:1混合物。
实例114:(1S,2R,3S,4S,6R)-3-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-6-氟-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.33min;MS m/z[M+H]+397.2。1H NMR(400MHz,乙腈-d3)δ8.50(s,1H),8.22(s,2H),7.87(dd,J=2.2,0.6Hz,1H),7.44-7.39(m,2H),5.36(s,2H),5.20-5.01(m,1H),4.89-4.84(m,1H),4.54-4.50(m,1H),3.94-3.90(m,1H),3.14-3.07(m,1H),2.21-2.10(m,1H),1.93-1.83(m,1H)。氟位置异构体的约5:1混合物。
实例115:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-氟-3-(6-甲基吡啶-3-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.32min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.55(s,1H),8.37-8.34(m,1H),7.86(d,J=2.4Hz,1H),7.57(dd,J=8.1,2.4Hz,1H),7.43(d,J=8.8Hz,1H),7.37(dd,J=8.8,2.4Hz,1H),7.16(d,J=8.0Hz,1H),5.14-4.93(m,2H),4.61-4.55(m,1H),3.27-3.23(m,1H),2.97-2.92(m,1H),2.45(s,3H),2.44-2.33(m,1H),1.83-1.67(m,1H)。氟位置异构体的>20:1混合物。
实例116:(1S,2R,3S,4S,6R)-N-(3,4-二氯苯基)-6-氟-3-(6-甲基吡啶-3-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.32min;MS m/z[M+H]+ 395.2。1H NMR(400MHz,乙腈-d3)δ8.57(s,1H),8.39(d,J=2.4Hz,1H),7.86(d,J=2.1Hz,1H),7.60(dd,J=8.1,2.4Hz,1H),7.43-7.36(m,2H),7.16(d,J=8.0Hz,1H),5.21-5.01(m,1H),4.91-4.86(m,1H),4.58-4.54(m,1H),4.12-4.06(m,1H),3.18-3.11(m,1H),2.45(s,3H),2.21-2.10(m,1H),1.92-1.81(m,1H)。氟位置异构体的>20:1混合物。
实例117:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用方案3中的步骤A-C,由甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酸酯(中间体1d)制备标题化合物。
步骤A:在0℃下,在N2下,向3,4-二氯苯胺(568mg,3.51mmol)在无水甲苯(10mL)中的搅拌溶液中添加在甲苯中的三甲基铝(2M,3.9mL,7.79mmol)。10分钟之后,移除冰浴且将混合物在室温下搅拌30分钟。将反应冷却至0℃,并添加1d(955mg,3.90mmol,溶于2mL的甲苯中),并将反应在室温搅拌6h。将反应冷却至0℃,并用饱和水性NH4Cl和甲醇的溶液淬灭。将悬浮液过滤,并将固体用EtOAc洗涤。将有机层分离并用盐水洗涤,并经无水硫酸钠干燥并浓缩。将粗化合物通过使用DCM和EtOAc的二氧化硅柱色谱法纯化,得到(1S,2S,4R,5R)-7-溴-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酰胺。LC-MS:Rt=1.63min;MS m/z[M+H]+ 373.9。1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.04(d,J=2.3Hz,1H),7.65(dd,J=8.9,2.3Hz,1H),7.60(d,J=8.8Hz,1H),5.15(s,1H),4.87(s,1H),1.70-1.66(m,1H),1.60-1.55(m,1H),1.42-1.39(m,1H),1.02-0.98(m,1H)。
步骤B:在0℃下,向(1S,2S,4R,5R)-7-溴-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酰胺(525mg,1.40mmol)在THF(10mL)和水(2.5mL)中的搅拌溶液中添加乙酸(0.321mL)和分批的锌粉(366mg,5.60mmol)。将反应浆液在室温下搅拌15分钟。将反应过滤,并用饱和碳酸氢钠中和至pH~7。将化合物用乙酸乙酯萃取。将合并的有机层用水和盐水洗涤,并经无水硫酸钠干燥并浓缩。将粗化合物通过二氧化硅柱色谱法(己烷:EtOAc)纯化,得到(1S,2S,4R,5R)-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02,4]辛-6-烯-6-甲酰胺。LC-MS:Rt=1.54min;MS m/z[M+H]+ 296.0。1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),8.05(d,J=2.3Hz,1H),7.64(dd,J=8.9,2.4Hz,1H),7.59(d,J=8.8Hz,1H),7.37(d,J=1.7Hz,1H),4.98(s,1H),4.89(d,J=1.7Hz,1H),1.42-1.36(m,3H),0.96-0.90(m,1H)。
步骤C:在100℃下,将(1S,2S,4R,5R)-N-(3,4-二氯苯基)-8-氧杂三环[3.2.1.02 ,4]辛-6-烯-6-甲酰胺(150mg,0.507mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(133mg,0.608mmol)、2,2-双(二苯基膦基)-1,1-联萘(32mg,0.051mmol)、氯(1,5-环辛二烯)铑(I)二聚体(12mg,0.025mmol)和碳酸钾(35.0mg,0.253mmol)在1,4-二噁烷(2mL)和水(0.5mL)中的混合物在微波中加热1h。将所述粗反应吸收进硅藻土中并将溶剂浓缩至干燥。将粗化合物通过二氧化硅柱色谱法纯化,得到(1S,2S,4R,5R,6S,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(顺式)和(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-甲基吡啶-4-基)-8-氧杂三环[3.2.1.02 ,4]辛烷-6-甲酰胺(实例117)。方法B LC-MS:Rt=1.33min;MS m/z[M+H]+ 389.0。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.33(d,J=5.1Hz,1H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),7.12-7.10(m,1H),7.05(dd,J=5.2,1.6Hz,1H),4.75(d,J=4.9Hz,1H),4.38(s,1H),3.50(d,J=4.8Hz,1H),3.07(t,J=4.8Hz,1H),2.42(s,3H),1.33-1.28(m,1H),1.18-1.13(m,1H),0.43-0.39(m,1H),0.21-0.15(m,1H)。
根据实例117所述的方案,使用甲基(1S,2S,4R,5R)-7-溴-8-氧杂三环[3.2.1.02 ,4]辛-6-烯-6-甲酸酯(中间体1d)和步骤A中的各种苯胺以及步骤C中的各种硼酸酯/酸,合成下述实例118-137。
实例118:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-甲氧基吡啶-4-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.59min;MS m/z[M+H]+ 405.1。1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.07(d,J=5.3Hz,1H),8.01(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),6.87(dd,J=5.3,1.4Hz,1H),6.47-6.45(m,1H),4.75(d,J=4.9Hz,1H),4.38(s,1H),3.81(s,3H),3.51(d,J=4.8Hz,1H),3.07(t,J=4.9Hz,1H),1.33-1.28(m,1H),1.19-1.13(m,1H),0.42-0.39(m,1H),0.20-0.15(m,1H)。
实例119:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-氟吡啶-4-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.71min;MS m/z[M+H]+ 393.0。1H NMR(400MHz,DMSO-d6)δ10.27(s,1H),8.16(d,J=5.2Hz,1H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),7.23(dt,J=5.2,1.8Hz,1H),7.00(s,1H),4.79(d,J=4.9Hz,1H),4.44(s,1H),3.65(d,J=4.8Hz,1H),3.12(t,J=4.8Hz,1H),1.34-1.30(m,1H),1.20-1.16(m,1H),0.43-0.40(m,1H),0.19-0.17(m,1H)。
实例120:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(6-(三氟甲基)吡啶-2-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.84min;MS m/z[M+H]+ 443.0。1H NMR(400MHz,DMSO-d6)δ10.38(s,1H),8.06(t,J=7.8Hz,1H),8.02(d,J=2.4Hz,1H),7.76(d,J=7.4Hz,1H),7.73(d,J=8.0Hz,1H),7.57(d,J=8.8Hz,1H),7.48(dd,J=8.8,2.4Hz,1H),4.77(d,J=5.0Hz,1H),4.50(s,1H),3.87(d,J=4.8Hz,1H),3.68(t,J=4.9Hz,1H),1.41-1.37(m,1H),1.19-1.14(m,1H),0.42-0.40(m,1H),0.21-0.16(m,1H)。
实例121:外消旋-(1S,2S,4R,5R,6R,7S)-7-(2-甲基吡啶-4-基)-N-(3-(三氟甲
基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.30min;MS m/z[M+H]+ 389.1。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.34(d,J=5.1Hz,1H),8.13(s,1H),7.74(d,J=8.4Hz,1H),7.55(t,J=8.0Hz,1H),7.40(d,J=7.7Hz,1H),7.12(s,1H),7.06(d,J=5.1Hz,1H),4.77(d,J=4.9Hz,1H),4.39(s,1H),3.52(d,J=4.8Hz,1H),3.10(t,J=4.8Hz,1H),2.42(s,3H),1.33-1.28(m,1H),1.21-1.16(m,1H),0.43-0.38(m,1H),0.21-0.15(m,1H)。
实例121a和121b(对应于峰1和峰2)
(1S,2S,4R,5R,6R,7S)-7-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯基)-8-氧杂三
环[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6S,7R)-7-(2-甲基吡啶-4-基)-N-(3-(三
氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6R,7S)-7-(2-甲基吡啶-4-基)-N-(3-(三氟甲基)苯基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(实例121),得到以下所列化合物:
方法细节:
柱:21x 250mm IB@30℃
流动相:90%CO2/10%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.28min。LC-MS:Rt=1.43min;MS m/z[M+H]+ 389.1。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.34(d,J=5.1Hz,1H),8.13(s,1H),7.74(d,J=8.5Hz,1H),7.55(t,J=8.0Hz,1H),7.41(d,J=7.7Hz,1H),7.12(s,1H),7.06(dd,J=5.1,1.4Hz,1H),4.77(d,J=4.9Hz,1H),4.39(s,1H),3.52(d,J=4.8Hz,1H),3.10(t,J=4.8Hz,1H),2.42(s,3H),1.34-1.28(m,1H),1.21-1.15(m,1H),0.43-0.38(m,1H),0.22-0.15(m,1H)。
峰2:SFC保留时间=1.66min。LC-MS:Rt=1.43min;MS m/z[M+H]+ 389.1。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.34(d,J=5.1Hz,1H),8.13(s,1H),7.74(d,J=8.5Hz,1H),7.55(t,J=8.0Hz,1H),7.41(d,J=7.7Hz,1H),7.12(s,1H),7.06(dd,J=5.1,1.4Hz,1H),4.77(d,J=4.9Hz,1H),4.39(s,1H),3.52(d,J=4.8Hz,1H),3.10(t,J=4.8Hz,1H),2.42(s,3H),1.34-1.28(m,1H),1.21-1.15(m,1H),0.43-0.38(m,1H),0.22-0.15(m,1H)。
实例122:外消旋-(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2,3-二氟吡啶-
4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.73min;MS m/z[M+H]+ 411.0。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.01(d,J=2.4Hz,1H),8.00(d,J=5.2Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),7.36(t,J=4.9Hz,1H),4.79(d,J=4.9Hz,1H),4.51(s,1H),3.94(d,J=4.7Hz,1H),3.12(t,J=4.8Hz,1H),1.36-1.31(m,1H),1.21-1.16(m,1H),0.44-0.40(m,1H),0.22-0.17(m,1H)。
实例122a和122b(对应于峰1和峰2)
(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2,3-二氟吡啶-4-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6S,7R)-N-(3,4-二氯苯基)-7-(2,3-二氟吡
啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2,3-二氟吡啶-4-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(实例122),得到以下所列化合物:
方法细节:
柱:21x 250mm IB@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.86min。方法D LC-MS:Rt=1.79min;MS m/z[M+H]+ 411.0。1HNMR(400MHz,DMSO-d6)δ10.29(s,1H),8.03-7.97(m,2H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),7.36(t,J=4.9Hz,1H),4.79(d,J=4.9Hz,1H),4.51(s,1H),3.94(d,J=4.7Hz,1H),3.12(t,J=4.8Hz,1H),1.37-1.31(m,1H),1.22-1.17(m,1H),0.45-0.39(m,1H),0.22-0.17(m,1H)。
峰2:SFC保留时间=2.43min。LC-MS:Rt=1.79min;MS m/z[M+H]+ 410.8。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.03-7.97(m,2H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),7.36(t,J=4.9Hz,1H),4.79(d,J=4.9Hz,1H),4.51(s,1H),3.94(d,J=4.7Hz,1H),3.12(t,J=4.8Hz,1H),1.37-1.31(m,1H),1.22-1.17(m,1H),0.45-0.39(m,1H),0.22-0.17(m,1H)。
实例123:(1S,2S,4R,5R,6R,7S)-N-(6-甲氧基吡啶-3-基)-7-(6-甲基吡啶-3-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.03min;MS m/z[M+H]+ 352.0。1H NMR(400MHz,DMSO-d6)δ9.97(s,1H),8.34-8.32(m,1H),8.31(d,J=2.1Hz,1H),7.87(dd,J=8.9,2.7Hz,1H),7.53(dd,J=8.0,2.4Hz,1H),7.19(d,J=8.0Hz,1H),6.79(dd,J=8.9,0.5Hz,1H),4.74(d,J=4.9Hz,1H),4.29(s,1H),3.80(s,3H),3.53(d,J=4.8Hz,1H),3.05(t,J=4.8Hz,1H),2.42(s,3H),1.33-1.27(m,1H),1.22-1.16(m,1H),0.44-0.39(m,1H),0.21-0.15(m,1H)。
实例124:(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(2,3-二氟吡啶-4-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法C LC-MS:Rt=1.49min;MS m/z[M+H]+ 411.8。1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),8.48(d,J=2.4Hz,1H),8.42(d,J=2.4Hz,1H),8.00(d,J=5.1Hz,1H),7.36(t,J=4.9Hz,1H),4.81(d,J=4.9Hz,1H),4.52(s,1H),3.94(d,J=4.7Hz,1H),3.17(t,J=4.8Hz,1H),1.36-1.30(m,1H),1.26-1.20(m,1H),0.45-0.39(m,1H),0.23-0.18(m,1H)。
实例125:(1S,2S,4R,5R,6R,7S)-N-(6-甲氧基吡啶-3-基)-7-(吡啶-4-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.01min;MS m/z[M+H]+ 338.0。1H NMR(400MHz,DMSO-d6)δ10.00(s,1H),8.48(d,J=5.3Hz,2H),8.35-8.32(m,1H),7.87(dd,J=8.9,2.7Hz,1H),7.28-7.24(m,2H),6.82-6.77(m,1H),4.76(d,J=4.9Hz,1H),4.39(s,1H),3.81(s,3H),3.56(d,J=4.8Hz,1H),3.08(t,J=4.8Hz,1H),1.34-1.28(m,1H),1.21-1.16(m,1H),0.44-0.39(m,1H),0.21-0.15(m,1H)。
实例126:外消旋-(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.46min;MS m/z[M+H]+ 376.0。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),9.06(s,1H),8.68(s,2H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),4.82(d,J=4.9Hz,1H),4.42(s,1H),3.61(d,J=4.7Hz,1H),3.17(t,J=4.8Hz,1H),1.36-1.30(m,1H),1.21-1.16(m,1H),0.45-0.39(m,1H),0.22-0.17(m,1H)。
实例126a和126b(对应于峰1和峰2)
(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺或(1R,2R,4S,5S,6S,7R)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-
8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(嘧啶-5-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺(实例126),得到以下所列化合物:
方法细节:
柱:21x 250mm IB@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.88min。方法B LC-MS:Rt=1.44min;MS m/z[M+H]+ 375.8。1HNMR(400MHz,DMSO-d6)δ10.26(s,1H),9.06(s,1H),8.68(s,2H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),4.82(d,J=4.9Hz,1H),4.42(s,1H),3.61(d,J=4.7Hz,1H),3.18(t,J=4.8Hz,1H),1.36-1.29(m,1H),1.22-1.17(m,1H),0.44-0.39(m,1H),0.23-0.17(m,1H)。
峰2:SFC保留时间=2.43min。方法B LC-MS:Rt=1.44min;MS m/z[M+H]+ 375.9。1HNMR(400MHz,DMSO-d6)δ10.26(s,1H),9.06(s,1H),8.68(s,2H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),4.82(d,J=4.9Hz,1H),4.42(s,1H),3.61(d,J=4.7Hz,1H),3.18(t,J=4.8Hz,1H),1.36-1.29(m,1H),1.22-1.17(m,1H),0.44-0.39(m,1H),0.23-0.17(m,1H)。
实例127:(1S,2S,4R,5R,6R,7S)-7-(2,3-二氟吡啶-4-基)-N-(6-甲氧基吡啶-3-
基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.44min;MS m/z[M+H]+ 374.0。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.35-8.32(m,1H),8.00(dd,J=5.0,0.9Hz,1H),7.88(dd,J=8.9,2.7Hz,1H),7.36(t,J=4.9Hz,1H),6.80(dd,J=8.9,0.5Hz,1H),4.78(d,J=4.9Hz,1H),4.49(s,1H),3.94(d,J=4.7Hz,1H),3.81(s,3H),3.12(t,J=4.8Hz,1H),1.36-1.30(m,1H),1.24-1.19(m,1H),0.44-0.38(m,1H),0.23-0.17(m,1H)。
实例128:(1S,2S,4R,5R,6R,7S)-N-(6-甲氧基吡啶-3-基)-7-(6-(三氟甲基)吡
啶-2-基)-8-氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.76min;MS m/z[M+H]+ 406.1。1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),8.36(d,J=2.7Hz,1H),8.06(t,J=7.8Hz,1H),7.89(dd,J=8.9,2.7Hz,1H),7.76(d,J=7.7Hz,1H),7.72(d,J=8.0Hz,1H),6.80(d,J=8.9Hz,1H),4.77(d,J=5.0Hz,1H),4.49(s,1H),3.87(d,J=4.8Hz,1H),3.81(s,3H),3.66(t,J=4.9Hz,1H),1.40-1.35(m,1H),1.22-1.16(m,1H),0.44-0.39(m,1H),0.22-0.16(m,1H)。
实例129:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-氟嘧啶-5-基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.65min;MS m/z[M+H]+ 394.0。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.64(d,J=1.6Hz,2H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.46(dd,J=8.8,2.4Hz,1H),4.82(d,J=4.9Hz,1H),4.41(s,1H),3.68(d,J=4.6Hz,1H),3.17(t,J=4.8Hz,1H),1.35-1.29(m,1H),1.22-1.16(m,1H),0.45-0.39(m,1H),0.23-0.18(m,1H)。
实例130:(1S,2S,4R,5R,6R,7S)-7-(嘧啶-5-基)-N-(3-(三氟甲基)苯基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.56min;MS m/z[M+H]+ 376.1。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.06(s,1H),8.69(s,2H),8.13(s,1H),7.74(d,J=8.5Hz,1H),7.55(t,J=8.0Hz,1H),7.41(d,J=7.7Hz,1H),4.84(d,J=4.9Hz,1H),4.43(s,1H),3.63(d,J=4.7Hz,1H),3.20(t,J=4.8Hz,1H),1.37-1.32(m,1H),1.24-1.18(m,1H),0.45-0.39(m,1H),0.23-0.17(m,1H)。
实例131:(1S,2S,4R,5R,6R,7S)-7-(吡啶-4-基)-N-(3-(三氟甲基)苯基)-8-氧杂
三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.40min;MS m/z[M+H]+ 375.1。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.48(d,J=5.8Hz,2H),8.13(s,1H),7.74(d,J=8.5Hz,1H),7.55(t,J=7.9Hz,1H),7.41(d,J=7.7Hz,1H),7.27(d,J=6.1Hz,2H),4.79(d,J=4.9Hz,1H),4.41(s,1H),3.58(d,J=4.8Hz,1H),3.11(t,J=4.8Hz,1H),1.36-1.30(m,1H),1.20-1.15(m,1H),0.44-0.40(m,1H),0.22-0.17(m,1H)。
实例132:(1S,2S,4R,5R,6R,7S)-7-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.46min;MS m/z[M+H]+ 391.0。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.10(s,2H),8.02(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),6.52(s,2H),4.73(d,J=4.9Hz,1H),4.25(s,1H),3.34(d,J=4.0Hz,1H),3.03(t,J=4.8Hz,1H),1.29-1.24(m,1H),1.17-1.11(m,1H),0.41-0.36(m,1H),0.18-0.13(m,1H)。
实例133:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-吗啉代嘧啶-5-基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.72min;MS m/z[M+H]+ 461.1。1H NMR(400MHz,DMSO-d6)δ10.24(s,1H),8.26(s,2H),8.02(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),4.75(d,J=4.9Hz,1H),4.27(s,1H),3.64(s,8H),3.41(d,J=4.6Hz,1H),3.05(t,J=4.8Hz,1H),1.31-1.25(m,1H),1.18-1.13(m,1H),0.43-0.38(m,1H),0.20-0.14(m,1H)。
实例134:(1S,2S,4R,5R,6R,7S)-7-(2-氟吡啶-4-基)-N-(3-(三氟甲基)苯基)-8-
氧杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.73min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.16(d,J=5.2Hz,1H),8.13(s,1H),7.74(d,J=8.5Hz,1H),7.56(t,J=8.0Hz,1H),7.44-7.35(m,1H),7.27-7.21(m,1H),7.01(s,1H),4.81(d,J=4.9Hz,1H),4.45(s,1H),3.67(d,J=4.8Hz,1H),3.14(t,J=4.8Hz,1H),1.36-1.30(m,1H),1.21-1.16(m,1H),0.45-0.38(m,1H),0.22-1.16(m,1H)。
实例135:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(2-甲基嘧啶-5-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
方法B LC-MS:Rt=1.53min;MS m/z[M+H]+ 390.0。1H NMR(400MHz,DMSO-d6)δ10.26(s,1H),8.55(s,2H),8.02(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.4Hz,1H),4.80(d,J=4.9Hz,1H),4.37(s,1H),3.56(d,J=4.7Hz,1H),3.13(t,J=4.8Hz,1H),2.58(s,3H),1.35-1.29(m,1H),1.20-1.15(m,1H),0.44-0.38(m,1H),0.22-0.16(m,1H)。
实例136:(1S,2S,4R,5R,6R,7S)-N-(5,6-二氯吡啶-3-基)-7-(吡啶-4-基)-8-氧
杂三环[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.28min;MS m/z[M+H]+ 376.0。1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.67(d,J=5.7Hz,2H),8.50(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),7.61(d,J=5.9Hz,2H),4.87-4.83(m,1H),4.48(s,1H),3.76-3.71(m,1H),3.21-3.17(m,1H),1.38-1.33(m,1H),1.28-1.22(m,1H),0.45-0.40(m,1H),0.24-0.17(m,1H)。
实例137:(1S,2S,4R,5R,6R,7S)-N-(3,4-二氯苯基)-7-(吡啶-4-基)-8-氧杂三环
[3.2.1.02,4]辛烷-6-甲酰胺
LC-MS:Rt=1.41min;MS m/z[M+H]+ 375.0。1H NMR(500MHz,DMSO-d6)δ10.25(s,1H),8.47(d,J=6.1Hz,2H),8.01(d,J=2.5Hz,1H),7.56(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.5Hz,1H),7.25(d,J=6.2Hz,2H),4.77(d,J=4.9Hz,1H),4.40(s,1H),3.56(d,J=4.8Hz,1H),3.09(t,J=4.9Hz,1H),1.35-1.29(m,1H),1.21-1.14(m,1H),0.45-0.40(m,1H),0.21-0.16(m,1H)。
根据实例117所述的方案,使用甲基(1R,4S,5S)-3-溴-5-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1e)和步骤A中的各种苯胺以及步骤C中的各种硼酸酯/酸,合成下述实例138-154。
实例138:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-甲基吡啶-3-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.17min;MS m/z[M+H]+ 393.0。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.31(dd,J=2.5,0.8Hz,1H),7.98(d,J=2.4Hz,1H),7.55(d,J=8.7Hz,1H),7.54-7.52(m,1H),7.41(dd,J=8.8,2.5Hz,1H),7.20(d,J=8.0Hz,1H),4.96(d,J=4.7Hz,1H),4.91-4.87(m,1H),4.16(s,1H),4.00-3.96(m,1H),3.20(d,J=5.3Hz,1H),2.94-2.91(m,1H),2.12-2.05(m,1H),1.43-1.36(m,1H)。醇位置异构体的约4:1混合物。
实例139:外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.46min;MS m/z[M+H]+ 409.0。醇位置异构体的约4:1混合物。
实例139a和139b(对应于峰1和峰2)
(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡啶-4-基)-7-氧杂
双环[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧
基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈醇位置异构体的约4:1混合物的外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例139),得到以下所列化合物:
方法细节:
柱:21x 250mm IB@30℃
流动相:85%CO2/15%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=2.40min。LC-MS:Rt=1.38min;MS m/z[M+H]+ 409.0。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.08(dd,J=5.3,0.7Hz,1H),7.97(d,J=2.5Hz,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),6.87(dd,J=5.3,1.5Hz,1H),6.64(s,1H),5.01-4.94(m,1H),4.92-4.84(m,1H),4.21(s,1H),4.00-3.94(m,1H),3.82(s,3H),3.20-3.16(m,1H),2.97-2.91(m,1H),2.10-2.03(m,1H),1.43-1.36(m,1H)。
峰2:SFC保留时间=3.59min。LC-MS:Rt=1.38min;MS m/z[M+H]+ 409.0。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),8.08(dd,J=5.3,0.7Hz,1H),7.97(d,J=2.5Hz,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),6.87(dd,J=5.3,1.5Hz,1H),6.64(s,1H),5.01-4.94(m,1H),4.92-4.84(m,1H),4.21(s,1H),4.00-3.94(m,1H),3.82(s,3H),3.20-3.16(m,1H),2.97-2.91(m,1H),2.10-2.03(m,1H),1.43-1.36(m,1H)。
实例140:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-(三氟甲基)吡啶-
2-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.69min;MS m/z[M+H]+ 447.0。醇位置异构体的混合物。
实例141:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(嘧啶-5-基)-7-氧杂
双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.37min;MS m/z[M+H]+ 380.0。1H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.07(s,1H),8.69(s,2H),7.98(d,J=2.5Hz,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),5.05-4.99(m,1H),4.98-4.93(m,1H),4.27(s,1H),4.03-3.97(m,1H),3.31-3.28(m,1H),3.05-3.01(m,1H),2.13-2.04(m,1H),1.46-1.35(m,1H)。醇位置异构体的约6:1混合物。
实例142:外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-
羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.54min;MS m/z[M+H]+ 397.0。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.17(d,J=5.1Hz,1H),7.98(d,J=2.4Hz,1H),7.58-7.54(m,1H),7.42(dd,J=8.8,2.5Hz,1H),7.25-7.22(m,1H),7.01(s,1H),5.03-5.01(m,1H),4.94-4.90(m,1H),4.27(s,1H),3.99-3.95(m,1H),3.35-3.31(m,1H),3.00-2.95(m,1H),2.10-2.02(m,1H),1.46-1.37(m,1H)。醇位置异构体的约4:1混合物。
实例142a和142b(对应于峰1和峰2A)
(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环
[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5R)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-
羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈醇位置异构体的约4:1混合物的外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例142),得到以下所列化合物:
方法细节:
柱:21x 250mm AD-H@30℃
流动相:75%CO2/25%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.30min。LC-MS:Rt=1.46min;MS m/z[M+H]+ 397.0。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.17(d,J=5.2Hz,1H),7.98(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.5Hz,1H),7.26-7.22(m,1H),7.01(d,J=1.5Hz,1H),5.05-5.00(m,1H),4.95-4.89(m,1H),4.27(s,1H),4.01-3.95(m,1H),3.33-3.30(m,1H),3.01-2.96(m,1H),2.11-2.03(m,1H),1.46-1.39(m,1H)。
峰2:将使用超临界流体色谱法(保留时间=4.22min)分离出的第二个洗脱峰浓缩并使用以下条件通过超临界流体色谱法进行重新纯化,得到以下所列化合物:
方法细节:
柱:21x 250mm IC@30℃
流动相:80%CO2/20%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰2A:第一洗脱峰。SFC保留时间=1.21min。LC-MS:Rt=1.46min;MS m/z[M+H]+397.0。1H NMR(400MHz,DMSO-d6)δ10.32(s,1H),8.17(d,J=5.2Hz,1H),7.98(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.5Hz,1H),7.26-7.22(m,1H),7.01(d,J=1.5Hz,1H),5.05-5.00(m,1H),4.95-4.89(m,1H),4.27(s,1H),4.01-3.95(m,1H),3.33-3.30(m,1H),3.01-2.96(m,1H),2.11-2.03(m,1H),1.46-1.39(m,1H)。
实例143:(1R,2R,3S,4R,5S)-3-(2-氨基嘧啶-5-基)-N-(3,4-二氯苯基)-5-羟基-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.27min;MS m/z[M+H]+ 395.0。1H NMR(500MHz,DMSO-d6)δ10.27(s,1H),8.10(s,2H),7.97(d,J=2.4Hz,1H),7.55(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.4Hz,1H),6.48(s,2H),4.93-4.90(m,1H),4.88-4.83(m,1H),4.11(s,1H),3.96-3.93(m,1H),3.03-2.99(m,1H),2.91-2.88(m,1H),2.09-2.04(m,1H),1.42-1.34(m,1H)。醇位置异构体的约5:1混合物。
实例144:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-(二甲基氨基)嘧啶-5-
基)-5-羟基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.39min;MS m/z[M+H]+ 423.0。1H NMR(500MHz,DMSO-d6)δ10.27(s,1H),8.22(s,2H),7.97(d,J=2.4Hz,1H),7.55(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.4Hz,1H),4.94-4.91(m,1H),4.89-4.86(m,1H),4.12(s,1H),3.97-3.93(m,1H),3.08(s,6H),3.06-3.04(m,1H),2.91-2.88(m,1H),2.11-2.06(m,1H),1.41-1.35(m,1H)。醇位置异构体的约4:1混合物。
实例145:外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲
基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.63min;MS m/z[M+H]+ 447.0。1H NMR(500MHz,DMSO-d6)δ10.28(s,1H),8.68(d,J=5.0Hz,1H),7.97(d,J=2.4Hz,1H),7.73(s,1H),7.61-7.59(m,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),5.01-4.99(m,1H),4.97-4.93(m,1H),4.28(s,1H),4.04-3.98(m,1H),3.42-3.39(m,1H),3.05-2.99(m,1H),2.13-2.05(m,1H),1.47-1.39(m,1H)。醇位置异构体的约5:1混合物。
实例145a和145b(对应于峰1和峰2)
(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲基)吡啶-4-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺或(1S,2S,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-
(三氟甲基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用以下条件通过超临界流体色谱法手性分离呈醇位置异构体的约5:1混合物的外消旋-(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例145),得到以下所列化合物:
方法细节:
柱:21x 250mm AD-H@30℃
流动相:90%CO2/10%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=3.44min。LC-MS:Rt=1.71min;MS m/z[M+H]+ 447.1。1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.68(d,J=5.1Hz,1H),7.98(d,J=2.4Hz,1H),7.73(s,1H),7.61-7.59(m,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.4Hz,1H),5.03-4.99(m,1H),4.97-4.93(m,1H),4.27(s,1H),4.04-3.98(m,1H),3.43-3.39(m,1H),3.05-2.99(m,1H),2.12-2.05(m,1H),1.47-1.39(m,1H)。
峰2:SFC保留时间=4.56min。LC-MS:Rt=1.71min;MS m/z[M+H]+ 447.0。
1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.68(d,J=5.1Hz,1H),7.98(d,J=2.4Hz,1H),7.73(s,1H),7.61-7.59(m,1H),7.56(d,J=8.8Hz,1H),7.41(dd,J=8.8,2.4Hz,1H),5.03-4.99(m,1H),4.97-4.93(m,1H),4.27(s,1H),4.04-3.98(m,1H),3.44-3.38(m,1H),3.05-2.99(m,1H),2.12-2.05(m,1H),1.48-1.39(m,1H)。
实例146:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2,3-二氟吡啶-4-基)-5-羟
基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.58min;MS m/z[M+H]+ 415.0。1H NMR(500MHz,DMSO-d6)δ10.32(s,1H),8.01(d,J=5.2,Hz,1H),7.97(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.42(dd,J=8.9,2.5Hz,1H),7.38(t,J=4.9Hz,1H),5.09-5.04(m,1H),4.96-4.90(m,1H),4.36(s,1H),4.02-3.96(m,1H),3.63-3.58(m,1H),3.02-2.96(m,1H),2.13-2.05(m,1H),1.47-1.40(m,1H)。醇位置异构体的约5:1混合物。
实例147:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2,5-二氟吡啶-4-基)-5-羟
基-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.57min;MS m/z[M+H]+ 415.0。1H NMR(500MHz,DMSO-d6)δ10.30(s,1H),8.18(d,J=1.3Hz,1H),7.97(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.42(dd,J=8.8,2.5Hz,1H),7.14(dd,J=4.7,2.1Hz,1H),5.08-5.01(m,1H),4.94-4.88(m,1H),4.41(s,1H),4.01-3.97(m,1H),3.54-3.50(m,1H),3.02-2.98(m,1H),2.13-2.07(m,1H),1.46-1.37(m,1H)。醇位置异构体的约4:1混合物。
实例148:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基嘧啶-5-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.37min;MS m/z[M+H]+ 394.0。1H NMR(500MHz,DMSO-d6)δ10.28(s,1H),8.56(s,2H),7.97(dd,J=2.6,1.0Hz,1H),7.55(dd,J=8.8,1.0Hz,1H),7.41(ddd,J=8.8,2.5,1.0Hz,1H),4.99-4.96(m,1H),4.94-4.91(m,1H),4.22(s,1H),4.02-3.97(m,1H),3.26-3.22(m,1H),3.01-2.97(m,1H),2.57(s,3H),2.12-2.06(m,1H),1.44-1.38(m,1H)。醇位置异构体的约4:1混合物。
实例149:(1R,2R,3S,4R,5S)-3-(2-氨基吡啶-4-基)-N-(3,4-二氯苯基)-5-羟基-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.29min;MS m/z[M+H]+ 394.0。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),7.98-7.96(m,1H),7.80(d,J=5.2Hz,1H),7.56(d,J=8.9Hz,1H),7.44-7.40(m,1H),6.37-6.30(m,2H),5.84(s,2H),4.95-4.91(m,1H),4.85-4.81(m,1H),4.20(s,1H),3.95-3.91(m,1H),3.01-2.98(m,1H),2.90-2.86(m,1H),2.07-2.00(m,1H),1.41-1.35(m,1H)。醇位置异构体的约4:1混合物。
实例150:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(吡啶-4-基)-7-氧杂
双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.25min;MS m/z[M+H]+ 379.0。1H NMR(500MHz,DMSO-d6)δ10.31(s,1H),8.50-8.47(m,2H),7.97(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.42(dd,J=8.9,2.5Hz,1H),7.28-7.24(m,2H),4.99-4.96(m,1H),4.93-4.86(m,1H),4.25(s,1H),4.04-3.97(m,1H),3.25-3.20(m,1H),2.99-2.95(m,1H),2.11-2.04(m,1H),1.45-1.38(m,1H)。醇位置异构体的约4:1混合物。
实例151:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-3-(2-氟嘧啶-5-基)-5-羟基-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.44min;MS m/z[M+H]+ 398.0。1H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.65(d,J=1.7Hz,2H),7.99(d,J=2.4Hz,1H),7.58-7.54(m,1H),7.42(dd,J=8.8,2.5Hz,1H),5.04-5.01(m,1H),4.97-4.92(m,1H),4.27(s,1H),4.02-3.95(m,1H),3.39-3.36(m,1H),3.06-3.02(m,1H),2.12-2.04(m,1H),1.46-1.38(m,1H)。醇位置异构体的约2:1混合物。
实例152:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(1-甲基-1H-吡唑-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.95min;MS m/z[M+H]+ 382.1。醇位置异构体的混合物。
实例153:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(1-甲基-1H-吡唑-3-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.97min;MS m/z[M+H]+ 382.1。1H NMR(500MHz,DMSO-d6)δ10.40(s,1H),7.98(d,J=2.4Hz,1H),7.58-7.55(m,2H),7.46(dd,J=8.8,2.4Hz,1H),6.06(d,J=2.2Hz,1H),4.95-4.86(m,1H),4.81-4.76(m,1H),4.20(s,1H),3.97-3.90(m,1H),3.75(s,3H),3.27-3.22(m,1H),3.21-3.17(m,1H),2.04-1.97(m,1H),1.38-1.32(m,1H)。醇位置异构体的约4:1混合物。
实例154:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-(三氟甲基)嘧啶-
5-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.13min;MS m/z[M+H]+ 448.1。1H NMR(500MHz,DMSO-d6)δ10.33(s,1H),8.93(s,2H),7.98(d,J=2.4Hz,1H),7.55(d,J=8.9Hz,1H),7.41(dd,J=8.8,2.5Hz,1H),5.09-5.02(m,1H),5.02-4.95(m,1H),4.36(s,1H),4.05-3.98(m,1H),3.47-3.42(m,1H),3.12-3.07(m,1H),2.15-2.06(m,1H),1.50-1.40(m,1H)。醇位置异构体的约5:1混合物。
实例155:(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-甲氧基-3-(2-甲基吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
根据实例117所述的方案,使用甲基(1R,4S,5S)-3-溴-5-甲氧基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯和甲基(1S,4S,6R)-3-溴-6-甲氧基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(中间体1f)和步骤A中的二氯苯胺以及步骤C中的(2-甲基吡啶-4-基)硼酸,合成下述实例155。LC-MS:Rt=1.39min;MS m/z[M+H]+ 407.0。醇位置异构体的混合物。
实例156和157(对应于峰1和峰2)
(1S,2R,3S,4R,5S,6R)-N-(3,4-二氯苯基)-5,6-二羟基-3-(2-甲基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺或(1R,2S,3R,4S,5R,6S)-N-(3,4-二氯苯基)-5,6-二羟
基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案5中的步骤A-E和步骤G,由甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(中间体1c)制备标题化合物,然后通过手性色谱法分离对映异构体。
步骤A:在0℃下,向甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(10.0g,43.3mmol)在1:1丙酮/水(200mL)的溶液中添加NMO(5.85g,43.3mmol),然后逐滴添加在丙酮(15mL)中的四氧化锇(0.220g,0.866mmol)。将所得反应混合物缓慢温热至室温且然后在室温下搅拌过夜。将溶剂浓缩并将所得残余物用DCM(100mL 3x)萃取。将合并的DCM层经无水Na2SO4干燥、过滤并浓缩。将所得残余物通过FCC纯化,以得到甲基3-溴-5,6-二羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(6.5g,54%)。1H NMR(400MHz,CDCl3)δ5.01(d,J=1.4Hz,1H),4.75(d,J=1.4Hz,1H),4.18-3.91(m,2H),3.83(s,3H),3.19(d,J=6.4Hz,1H),3.03(d,J=6.3Hz,1H)。
步骤B:向甲基3-溴-5,6-二羟基-7-氧杂双环[2.2.1]庚-2-烯-2-甲酸酯(3.81g,14.4mmol)在甲苯(150mL)中的悬浮液中添加(二甲氧基甲基)苯(2.63g,17.3mmol)和pTsOH(137mg,0.719mmol)。将所得反应混合物在70℃下加热30min。将反应混合物浓缩并通过FCC纯化,以得到呈非对映异构体的2:1混合物的甲基6-溴-2-苯基-3a,4,7,7a-四氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酸酯。1H NMR(400MHz,CDCl3)δ7.58(m,1H),7.51-7.35(m,6.5H),6.37(s,1H),6.04(s,0.5H),5.32(d,J=1.2Hz,1H),5.22(d,J=1.2Hz,0.5H),5.05(d,J=1.2Hz,1H),4.95(d,J=1.2Hz,0.5H),4.77-4.68(m,2H),4.68-4.63(m,1H),3.85(s,4.5H)。非对映异构体的2:1混合物:
步骤C:在0℃下,向3,4-二氯苯胺(0.628g,3.87mmol)在甲苯(30mL)中的溶液中添加在甲苯(2.10ml,4.20mmol)中的2.0M Me3Al。将反应混合物搅拌1h,并且然后在0℃下逐滴添加甲基6-溴-2-苯基-3a,4,7,7a-四氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酸酯(1.14g,3.23mmol)在甲苯(20mL)中的溶液。允许所得反应混合物温热至室温且在室温下搅拌过夜。将反应混合物用饱和水性NH4Cl溶液淬灭,并用EtOAc和水稀释。将水层用EtOAc萃取,并将合并的有机溶剂用水和盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。将所得残余物通过FCC纯化,以得到(3aS,4S,7S,7aS)-6-溴-N-(3,4-二氯苯基)-2-苯基-3a,4,7,7a-四氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺(450mg,26%)。LC-MS:Rt=1.76min;MS m/z[M+H]+ 482.0。
步骤D:在0℃下,向(3aS,4S,7S,7aS)-6-溴-N-(3,4-二氯苯基)-2-苯基-3a,4,7,7a-四氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺(650mg,1.307mmol)在THF(40mL)和水(10mL)中的搅拌溶液中添加乙酸(0.299mL,5.23mmol),然后分批添加Zn粉(342mg,5.23mmol)。允许所述反应浆液温热至室温并搅拌15分钟。将反应混合物过滤,并用饱和水性碳酸氢钠中和至pH 7。将混合物用乙酸乙酯萃取,并将有机层用水和盐水洗涤,经无水硫酸钠干燥,过滤并浓缩。将所得粗混合物通过RP HPLC纯化,以得到(3aS,4S,7R,7aR)-N-(3,4-二氯苯基)-2-苯基-3a,4,7,7a-四氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺,将其直接用于下一步骤。LC-MS:Rt=1.62and 1.66min;MS m/z[M+H]+404.1。
步骤E:将(3aS,4S,7R,7aR)-N-(3,4-二氯苯基)-2-苯基-3a,4,7,7a-四氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺(180mg,0.445mmol)、2-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶(117mg,0.534mmol)、氯(1,5-环辛二烯)铑(I)二聚体(11.0mg,0.022mmol)、2,2’-双(二苯基膦基)-1,1’-联萘(28mg,0.045mmol)和碳酸钾(30.8mg,0.223mmol)的混合物填充有3:1的1,4-二噁烷/水(16mL),并用氮气吹扫。将所得反应混合物在微波下于100℃温热1h。将反应混合物过滤且通过RP HPLC纯化,以得到(4S,5R,6S,7R)-N-(3,4-二氯苯基)-6-(2-甲基吡啶-4-基)-2-苯基六氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺。LC-MS:Rt=1.43min;MS m/z[M+H]+ 497.2。
步骤G:在0℃下,向(4S,5R,6S,7R)-N-(3,4-二氯苯基)-6-(2-甲基吡啶-4-基)-2-苯基六氢-4,7-环氧苯并[d][1,3]间二氧杂环戊烯-5-甲酰胺(133mg,0.267mmol)和1,2,3,4,5-五甲基苯(119mg,0.802mmol)在DCM(3.0mL)中的溶液中逐滴添加在DCM(1.34mL,1.34mmol)中的1.0M BCl3。将所得反应混合物在0℃下搅拌1h且然后允许温热至室温并搅拌1h。将反应混合物用饱和水性NaHCO3淬灭,并将水层用DCM萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩以获得粗产物,将粗产物通过HPLC纯化以得到呈对映异构体的混合物的外消旋-(1S,2R,3S,4R,5S,6R)-N-(3,4-二氯苯基)-5,6-二羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.06min;MS m/z[M+H]+ 409.1。
使用以下条件通过超临界流体色谱法手性分离外消旋-(1S,2R,3S,4R,5S,6R)-N-(3,4-二氯苯基)-5,6-二羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺,得到以下所列化合物:
方法细节:
柱:21x 250mm IA@30℃
流动相:75%CO2/25%MeOH+0.5%异丙胺
检测:UV@220nm
流速:2mL/min
峰1:SFC保留时间=1.47min。LC-MS:Rt=1.07min;MS m/z[M+H]+ 409.1。1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),8.40(d,J=5.3Hz,1H),8.01(d,J=2.4Hz,1H),7.59(d,J=8.8Hz,1H),7.48(dd,J=8.8,2.5Hz,1H),7.23(d,J=1.7Hz,1H),7.16(dd,J=5.5,1.7Hz,1H),4.98(brs,1H),4.83(brs,1H),4.61(dd,J=5.6,1.6Hz,1H),4.23(d,J=1.5Hz,1H),3.92(q,J=4.6Hz,2H),3.00(t,J=5.5Hz,1H),2.47(s,3H)。
峰2:SFC保留时间=2.54min。LC-MS:Rt=1.07min;MS m/z[M+H]+ 409.2。
根据实例156所述的方案,使用甲基3-溴-7-氧杂双环[2.2.1]庚-2,5-二烯-2-甲酸酯(中间体1c)和步骤C中的各种苯胺以及步骤E中的各种硼酸酯/酸,合成下述实例158-163。
实例158:(1S,2R,3S,4R,5S,6R)-5,6-二羟基-3-(2-甲基吡啶-4-基)-N-(3-(三氟
甲基)苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.05min;MS m/z[M+H]+ 409.2。
实例159:(1S,2R,3S,4R,5S,6R)-5,6-二羟基-3-(吡啶-4-基)-N-(3-(三氟甲基)
苯基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.07min;MS m/z[M+H]+ 395.2。
实例160:(1S,2R,3S,4R,5S,6R)-N-(3,4-二氯苯基)-5,6-二羟基-3-(吡啶-4-
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.08min;MS m/z[M+H]+ 395.1。
实例161:(1S,2R,3S,4R,5S,6R)-5,6-二羟基-3-(2-甲基吡啶-4-基)-N-(2-(三氟
甲基)吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.85min;MS m/z[M+H]+ 410.2。
实例162:(1S,2R,3S,4R,5S,6R)-N-(5,6-二氯吡啶-3-基)-5,6-二羟基-3-(2-甲
基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.96min;MS m/z[M+H]+ 410.1。1H NMR(400MHz,DMSO-d6)δ10.73(s,1H),8.48(d,J=2.4Hz,1H),8.40-8.36(m,2H),7.18(s,1H),7.12(dd,J=5.3,1.7Hz,1H),4.94(s,2H),4.63-4.58(m,1H),4.24-4.21(m,1H),3.96-3.90(m,2H),3.35-3.28(m,1H),3.03-2.97(m,1H),2.45(s,3H)。
实例163:(1S,2R,3S,4R,5S,6R)-5,6-二羟基-N-(6-甲基-5-(三氟甲基)吡啶-3-
基)-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=0.92min;MS m/z[M+H]+ 424.2。1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.78(d,J=2.4Hz,1H),8.41(d,J=2.5Hz,1H),8.39(d,J=5.5Hz,1H),7.22(s,1H),7.16(dd,J=5.4,1.7Hz,1H),4.94(s,1H),4.85(s,1H),4.63-4.58(m,1H),4.24-4.21(m,1H),3.97-3.90(m,2H),3.36-3.32(m,1H),3.05-2.99(m,1H),2.59-2.56(m,3H),2.46(s,3H)。
实例164:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(6-甲基吡啶-3-基)-7-
氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案6中的步骤A,由(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-甲基吡啶-3-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(5a,其中R2=3,4-二氯苯基且Ar=6-甲基吡啶-3-基,实例138)制备标题化合物。
步骤A:在室温下,向(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(6-甲基吡啶-3-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(25mg,0.064mmol)在DCM(1mL)中的搅拌溶液中添加Xtalfluor-E(22mg,0.095mmol)和三乙胺三氟化氢(0.021mL,0.127mmol)。将反应混合物搅拌16h,冷却至0℃并用饱和水性碳酸氢钠溶液淬灭。将粗混合物用DCM萃取3次。将合并的有机层经无水硫酸钠干燥、过滤并浓缩。将粗化合物通过FCC纯化,以得到(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(6-甲基吡啶-3-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.46min;MS m/z[M+H]+ 395.0。1H NMR(500MHz,DMSO-d6)δ10.62(s,1H),8.41(d,J=2.4Hz,1H),7.99(d,J=2.4Hz,1H),7.59-7.56(m,2H),7.49(dd,J=8.8,2.4Hz,1H),7.24(d,J=8.1Hz,1H),5.27(d,J=71.0Hz,1H),4.85-4.77(m,1H),3.81-3.76(m,1H),3.15-3.13(m,1H),3.12-3.09(m,1H),2.44(s,3H),1.99-1.91(m,2H)。醇位置异构体的>20:1混合物。
实例165:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-氟-3-(2-甲氧基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
根据实例164所述的方案,使用步骤A中的(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲氧基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(5a,其中R2=3,4-二氯苯基且Ar=2-甲基吡啶-4-基,实例139),合成实例165。LC-MS:Rt=1.74min;MS m/z[M+H]+ 411.0。1H NMR(500MHz,DMSO-d6)δ10.64(s,1H),8.13-8.12(m,1H),7.99(d,J=2.4Hz,1H),7.58(d,J=8.8Hz,1H),7.49(dd,J=8.8,2.4Hz,1H),6.95-6.92(m,1H),6.75(s,1H),5.31-5.13(m,1H),4.84-4.81(m,1H),3.85(s,3H),3.80-3.76(m,1H),3.25-3.21(m,1H),3.11-3.08(m,1H),1.97-1.91(m,2H)。醇位置异构体的约2:1混合物。
实例166:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-(二甲基氨基)-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案6中的步骤B和C,由(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(5a,其中R2=3,4-二氯苯基且Ar=2-甲基吡啶-4-基,实例77)制备标题化合物。
步骤B:在室温下向(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(200mg,0.509mmol)在THF(5mL)中的搅拌溶液中添加戴斯-马丁试剂(431mg,1.02mmol)并且将所述反应在室温下搅拌16h。将反应混合物用EtOAc稀释,用饱和水性NaHCO3和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC纯化,以得到(1R,2R,3S,4R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-氧代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.22min;MS m/z[M+H]+ 391.0。
步骤C:向(1R,2R,3S,4R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-氧代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(20mg,0.051mmol)在DCM(2mL)中的搅拌溶液中添加一滴在THF中的乙酸和二甲胺(0.153mL,0.307mmol)。将反应冷却至0℃并添加硼氢化钠(4mg,0.102mmol)。将反应在室温搅拌30分钟,然后在50℃温热2h。将反应混合物冷却至室温,并过滤且将滤液浓缩。将粗化合物通过RP HPLC纯化,以得到(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-(二甲基氨基)-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.12min;MS m/z[M+H]+ 420.1。1H NMR(400MHz,DMSO-d6)δ10.21(s,1H),8.35(d,J=5.1Hz,1H),8.00(d,J=2.5Hz,1H),7.55(d,J=8.8Hz,1H),7.43(dd,J=8.8,2.5Hz,1H),7.12(s,1H),7.06(d,J=5.3Hz,1H),4.94-4.87(m,1H),4.48-4.42(m,1H),4.13-4.08(m,1H),3.10-3.04(m,1H),2.43(s,3H),2.42-2.35(m,1H),2.12(s,6H),1.89-1.79(m,1H),1.48-1.40(m,1H)。醇位置异构体的>20:1混合物。
根据实例166所述的方案,使用中间体5a和步骤C中的各种胺,合成下述实例167-177。
实例167:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-(甲基氨基)-3-(2-甲基吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.10min;MS m/z[M+H]+ 406.2。1H NMR(400MHz,DMSO-d6)δ10.44(s,1H),8.37-8.32(m,1H),8.00(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.5Hz,1H),7.14(s,1H),7.08(dd,J=5.2,1.7Hz,1H),4.90-4.84(m,1H),4.49-4.44(m,1H),3.99-3.95(m,1H),3.16(s,1H),3.15-3.11(m,1H),3.09-3.02(m,1H),2.43(s,3H),2.28(s,3H),1.99-1.89(m,1H),1.28-1.20(m,1H)。醇位置异构体的>20:1混合物。
实例168:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-((2-羟乙基)氨基)-3-(2-甲
基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.06min;MS m/z[M+H]+ 436.2。1H NMR(400MHz,DMSO-d6)δ10.47(s,1H),8.35(dd,J=5.1,0.7Hz,1H),8.01(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.45(dd,J=8.8,2.5Hz,1H),7.14(d,J=1.7Hz,1H),7.08(dd,J=5.2,1.7Hz,1H),4.87-4.84(m,1H),4.60-4.54(m,1H),4.48-4.44(m,1H),4.01-3.97(m,1H),3.50-3.43(m,2H),3.22-3.11(m,3H),2.59-2.53(m,2H),2.44(s,3H),2.02-1.93(m,1H),1.28-1.20(m,1H)。醇位置异构体的>20:1混合物。
实例169:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-((四
氢-2H-吡喃-4-基)氨基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.16min;MS m/z[M+H]+ 476.2。醇位置异构体的混合物。
实例170:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-(((1r,3R)-3-羟基环丁基)氨
基)-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.07min;MS m/z[M+H]+ 462.2。醇位置异构体的混合物。
实例171:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-(甲基氨
基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.26min;MS m/z[M+H]+ 410.2。1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.17(d,J=5.2Hz,1H),8.00(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.44(dd,J=8.8,2.4Hz,1H),7.28-7.25(m,1H),7.03(s,1H),4.93-4.86(m,1H),4.56-4.51(m,1H),4.14-4.09(m,1H),3.33-3.30(m,1H),3.16-3.12(m,1H),3.10-3.02(m,1H),2.28(s,3H),1.98-1.90(m,1H),1.27-1.21(m,1H)。醇位置异构体的>20:1混合物。
实例172:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-(二甲基氨基)-3-(2-氟吡啶-
4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.25min;MS m/z[M+H]+ 424.2。1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.17(d,J=5.3Hz,1H),8.00(d,J=2.4Hz,1H),7.56(d,J=8.8Hz,1H),7.46-7.42(m,1H),7.25-7.21(m,1H),7.00(s,1H),4.97-4.92(m,1H),4.55-4.51(m,1H),4.25-4.18(m,1H),3.13-3.08(m,1H),2.43-2.37(m,1H),2.12(s,6H),1.90-1.81(m,1H),1.47-1.39(m,1H)。醇位置异构体的>20:1混合物。
实例173:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-3-(2-氟吡啶-4-基)-5-((2-羟
乙基)氨基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.21min;MS m/z[M+H]+ 440.2。1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),8.18(d,J=5.2Hz,1H),8.00(d,J=2.4Hz,1H),7.57(d,J=8.8Hz,1H),7.44(dd,J=8.8,2.4Hz,1H),7.28-7.24(m,1H),7.03(d,J=1.4Hz,1H),4.91-4.84(m,1H),4.59-4.55(m,1H),4.53(d,J=4.6Hz,1H),4.13(d,J=5.5Hz,1H),3.50-3.43(m,2H),3.36-3.31(m,1H),3.22-3.13(m,2H),2.62-2.52(m,2H),2.04-1.94(m,1H),1.29-1.22(m,1H)。醇位置异构体的>20:1混合物。
实例174:(1R,2R,3S,4R,5R)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡啶-4-基)-5-
(甲基氨基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.11min;MS m/z[M+H]+ 411.2。1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.47(d,J=2.4Hz,1H),8.40(d,J=2.4Hz,1H),8.17(d,J=5.2Hz,1H),7.29-7.25(m,1H),7.04(s,1H),4.94-4.90(m,1H),4.58-4.51(m,1H),4.17-4.12(m,1H),3.33-3.29(m,1H),3.20-3.16(m,1H),3.10-3.04(m,1H),2.27(s,3H),1.99-1.91(m,1H),1.29-1.22(m,1H)。醇位置异构体的>20:1混合物。
实例175:(1R,2R,3S,4R,5R)-N-(5,6-二氯吡啶-3-基)-5-(二甲基氨基)-3-(2-氟
吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.13min;MS m/z[M+H]+ 425.2。1H NMR(400MHz,DMSO-d6)δ10.46(s,1H),8.47(d,J=2.4Hz,1H),8.41(d,J=2.4Hz,1H),8.18(d,J=5.2Hz,1H),7.26-7.24(m,1H),7.02-7.00(m,1H),4.98-4.94(m,1H),4.57-4.53(m,1H),4.25-4.19(m,1H),3.17-3.11(m,1H),2.44-2.36(m,1H),2.12(s,6H),1.91-1.81(m,1H),1.48-1.38(m,1H)。醇位置异构体的>20:1混合物。
实例176:(1R,2R,3S,4R,5R)-N-(5,6-二氯吡啶-3-基)-3-(2-氟吡啶-4-基)-5-
((2-羟乙基)氨基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.08min;MS m/z[M+H]+ 441.2。1H NMR(400MHz,DMSO-d6)δ10.64(s,1H),8.47(d,J=2.4Hz,1H),8.42(d,J=2.3Hz,1H),8.18(d,J=5.2Hz,1H),7.28-7.25(m,1H),7.03(s,1H),4.92-4.86(m,1H),4.60-4.53(m,2H),4.15(d,J=5.6Hz,1H),3.50-3.43(m,2H),3.35-3.29(m,1H),3.24-3.15(m,2H),2.63-2.52(m,2H),2.04-1.94(m,1H),1.26(dd,J=12.8,4.7Hz,1H)。醇位置异构体的>20:1混合物。
实例177:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-吗啉
代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
LC-MS:Rt=1.15min;MS m/z[M+H]+ 462.1。醇位置异构体的混合物。
实例178:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-羟基-5-甲基-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案6中的步骤B和D,由单一对映异构体(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(5a,其中R2=3,4-二氯苯基且Ar=2-甲基吡啶-4-基,实例77a)制备标题化合物。
步骤B:在室温下向(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(200mg,0.509mmol)在THF(5mL)中的搅拌溶液中添加戴斯-马丁试剂(431mg,1.017mmol)并且将所述反应在室温下搅拌16h。将反应混合物用EtOAc稀释,用饱和水性NaHCO3和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC纯化,以得到(1R,2R,3S,4R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-氧代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.22min;MS m/z[M+H]+ 391.0。
步骤D:在室温下将(1R,2R,3S,4R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-氧代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(10.4mg,0.027mmol)在THF(0.5mL)中的溶液用在二乙醚中的3.0M MeMgBr(35.4μl,0.106mmol)处理,并搅拌2h。添加另外的在二乙醚中的3.0M MeMgBr(35.4μl,0.106mmol),并将反应在室温搅拌16h。将反应混合物用饱和水性NH4Cl淬灭,用EtOAc稀释,用水和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC纯化,以得到(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-羟基-5-甲基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.27min;MS m/z[M+H]+ 407.2。
实例179:(1S,2S,3R,4S,5S)-N-(3,4-二氯苯基)-5-羟基-5-甲基-3-(2-甲基吡
啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺
根据实例178所述的方案,使用单一对映异构体(1S,2S,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例77c),合成实例179。LC-MS:Rt=1.27min;MS m/z[M+H]+ 407.2。醇位置异构体的>20:1混合物。
实例180:(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
使用方案6中的步骤B和E,由单一对映异构体(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(5a,其中R2=3,4-二氯苯基且Ar=2-甲基吡啶-4-基,实例77a)制备标题化合物。
步骤B:在室温下向(1R,2R,3S,4R,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(200mg,0.509mmol)在THF(5mL)中的搅拌溶液中添加戴斯-马丁试剂(431mg,1.017mmol)并且将所述反应在室温下搅拌16h。将反应混合物用EtOAc稀释,用饱和水性NaHCO3和盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC纯化,以得到(1R,2R,3S,4R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-氧代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.22min;MS m/z[M+H]+ 391.0。
步骤E:在室温下将(1R,2R,3S,4R)-N-(3,4-二氯苯基)-3-(2-甲基吡啶-4-基)-5-氧代-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(18mg,0.046mmol)在THF(1mL)中的溶液用NaBH4(6.96mg,0.184mmol)处理并且在室温下搅拌18h。将反应混合物用饱和水性NaHCO3稀释,并用EtOAc萃取。将有机层用盐水洗涤,干燥(Na2SO4),过滤,并浓缩。将所得残余物通过FCC纯化,以得到(1R,2R,3S,4R,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺。LC-MS:Rt=1.20min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,乙腈-d3)δ8.59(s,1H),8.35(dd,J=5.2,0.8Hz,1H),7.89(dd,J=2.2,0.6Hz,1H),7.46-7.38(m,2H),7.18-7.16(m,1H),7.10(dd,J=5.2,1.7Hz,1H),4.87-4.79(m,1H),4.42-4.34(m,1H),4.33-4.24(m,1H),4.17-4.13(m,1H),3.65-3.55(m,1H),3.15-3.07(m,1H),2.46(s,3H),2.12-2.02(m,1H),1.54-1.46(m,1H)。醇位置异构体的>20:1混合物。
实例181:(1S,2S,3R,4S,5S)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-
7-氧杂双环[2.2.1]庚烷-2-甲酰胺
根据实例180所述的方案,使用单一对映异构体(1S,2S,3R,4S,5R)-N-(3,4-二氯苯基)-5-羟基-3-(2-甲基吡啶-4-基)-7-氧杂双环[2.2.1]庚烷-2-甲酰胺(实例77c),合成实例181。LC-MS:Rt=1.20min;MS m/z[M+H]+ 393.1。1H NMR(400MHz,乙腈-d3)δ8.60(s,1H),8.36-8.34(m,1H),7.89(dd,J=2.2,0.6Hz,1H),7.46-7.39(m,2H),7.17(s,1H),7.10(dd,J=5.2,1.7Hz,1H),4.86-4.81(m,1H),4.42-4.37(m,1H),4.31-4.24(m,1H),4.17-4.11(m,1H),3.63-3.57(m,1H),3.15-3.09(m,1H),2.46(s,3H),2.11-2.01(m,1H),1.54-1.45(m,1H)。醇位置异构体的>20:1混合物。
实例182.如表1所示,在氧杂双环核心中掺入5S-羟基基团会降低化合物对大鼠和人肝微粒体的CYP3A4抑制作用和固有清除率。
表1
生物学测定
在以下测定中评估本发明的化合物:(1)II型胶原蛋白测定,用于测定软骨发生性分化;(2)碱性磷酸酶(ALP)活性测定,以确定化合物预防正常人关节软骨细胞(NHAC)和C3H10T1/2细胞系中软骨细胞肥大的能力;以及(3)钙通量测定。
表2.实验用试剂
细胞培养
正常人关节软骨细胞(NHAC)购自PromoCell公司(海德堡,德国),并使其在软骨细胞生长培养基(CGM;龙沙公司(Lonza),沃克斯维尔,马里兰州)中生长。C3H10T1/2细胞系(克隆8)购自ATCC(马纳萨斯,弗吉尼亚州),并使其在补充有10%FBS和抗生素/抗真菌剂的DMEM/高葡萄糖(赛默飞世尔科技公司(ThermoFisher scientific),沃尔瑟姆,马萨诸塞州)中生长。人软骨发生性祖细胞(CPC)衍生自人原发性关节软骨细胞(龙沙公司,沃克斯维尔,马里兰州),前者被分离成单个细胞,在间充质干细胞生长培养基(MSCGM;龙沙公司,沃克斯维尔,马里兰州)中克隆生长,并且通过软骨发生性、成骨性和脂肪形成性分化被确认为间充质祖细胞。将细胞进行FACS分选,并证明对于CD166和CD105为>98%阳性。将CPC培养至高达20代,未鉴定出细胞谱、生长或分化率的变化。
II型胶原蛋白测定和定量
为了在原发性CPC中引发软骨发生,在MSCGM中的Costar 96孔板中将8000个细胞铺板/孔。24小时后,移除MSCGM,并用含1%FBS的DMEM代替。然后将测试化合物以指定剂量添加到每个孔中。培养物在37℃下生长18天。诱导软骨发生后10天,培养基中补充50μl含1%FBS的DMEM。
为了检测II型胶原蛋白的存在,将hCPC用10%福尔马林固定20分钟,用含0.1%triton X-100的PBS、0.2mg/ml胶原酶2透化10分钟,在室温下用含5%BSA的PBS封闭1小时,然后在含1%BSA的PBS中在4℃与第一抗体(抗II型胶原蛋白抗体)一起孵育过夜。将细胞用PBS洗涤3次,并与荧光团缀合的第二抗体和Hoechst染料在室温下一起孵育1小时,然后用PBS洗涤3次。
将染色的总强度通过荧光显微术进行成像,和/或通过使用ImageXpress Micro(分子仪器公司,森尼维耳市,加利福尼亚州)的高含量成像进行定量。使用定制的多波长细胞评分应用程序进行数据分析。
NHAC中碱性磷酸酶的染色和定量
为了在NHAC中引发分化,在CGM培养基(龙沙公司)中的Costar96孔板中将16,000个细胞铺板/孔。24小时后,移除MSCGM,并用含1%FBS的DMEM代替。然后将测试化合物以指定剂量添加到每个孔中。培养物在37℃下生长10天。
为了检测肥大细胞的存在,将NHAC用10%福尔马林和Hoeschst染料固定20分钟,在PBS中漂洗,然后用萘酚AS-MX磷酸盐碱性溶液用固蓝RR盐染色。在37℃大约2小时后,一旦观察到细胞变蓝,将其用PBS洗涤三次。
将染色的总强度通过荧光显微镜术、使用651波长进行成像,和/或通过使用ImageXpress Micro(分子仪器公司,森尼维耳市,加利福尼亚州)的高含量成像进行定量。使用定制的多波长细胞评分应用程序进行数据分析。
C3H10T1/2中碱性磷酸酶的染色和定量
为了在C3H10T1/2克隆8(ATCC目录号CCL-226)中引发分化,在含10%FBS和1x抗生素/抗真菌剂(海克隆公司目录号SV30079.01)的DMEM/高葡萄糖(海克隆公司目录号SH30022.01)中在384Perkin Elmer CellCarrier Ultra板中将4,000个细胞铺板/孔。24小时之后,将测试化合物以指定剂量添加到每个孔中。培养物在37℃下生长6天。
为了检测肥大细胞的存在,将C3H10T1/2用4%多聚甲醛和Hoeschst染料固定20分钟,在PBS中漂洗,然后用萘酚AS-MX磷酸盐碱性溶液用固蓝RR盐染色。在37℃大约3小时后,一旦观察到细胞变蓝,将其用PBS洗涤六次。
将染色的ALP通过荧光显微术、使用561波长进行成像,和/或通过使用ImageXpress Micro Confocal(分子仪器公司,森尼维耳市,加利福尼亚州)的高含量成像进行定量。使用定制的多波长细胞评分应用程序进行数据分析,所述应用程序查看每孔中ALP阳性细胞的数量。
钙通量测定和定量
将NHAC以4ul体积以2000个细胞/孔铺板于1536Greiner板中。24小时后,添加4ul钙5染料溶液(含5mM丙磺舒的汉克平衡盐/HEPES缓冲液)并在室温下孵育1小时。使用FLIPR高通量筛选系统(分子仪器公司,森尼维耳市,加利福尼亚州),在470-495nm的激发波长和515-575nm的发射波长下读取荧光。然后将测试化合物以指定剂量添加到每个孔中。在化合物分配之前以及在使用1秒的第一间隔进行60次读取和3秒的第二间隔进行20次读取之后,测量信号。使用分子仪器公司(Molecular Devices)软件分析数据。
表3总结了本发明的化合物在以下测定中的活性。图例:(A)钙通量测定;(B)II型胶原蛋白测定;(C)NHAC中的碱性磷酸酶测定;以及(D)C3H10T1/2中的碱性磷酸酶测定。
表3
应理解,本文描述的实例和实施例仅用于举例说明目的,其各种修饰或改变对于本领域技术人员将是明了的,并包括在本申请的精神和范围内和所附权利要求书的范围内。本文引用的所有出版物、专利、和专利申请都出于所有目的,通过引用特此结合。
Claims (23)
1.一种具有式(I)的化合物、或其药学上可接受的盐或立体异构体;
其中R0是氢或C1-6烷基;
R2是苯基;5元或6元杂芳基或5元或6元杂环基,各自具有1至3个选自N、O和S的杂原子;其中R2是未经取代的,或者被1-3个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基、卤基取代的C1-6烷氧基、氰基、C1-6烷基磺酰基、未经取代的苯基或被卤基或C1-6烷基取代的苯基的取代基取代;
R3是具有1至2个选自N、O和S的杂原子的5元或6元杂芳基;其中R3是未经取代的,或者被1-3个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基或-NR5R6的取代基取代;
R1a、R1b、R4a和R4b各自独立地是氢、卤基、羟基、C1-6烷氧基、C1-6烷基、-NR7R8或-NR7-(CR9R10)2-4-OR11;或其中R1a和R1b之一与R4a和R4b之一一起形成环丙基,所述R1a、R1b、R4a和R4b分别附接两个碳原子;
R5、R6、R7、R9、R10和R11各自独立地是氢或C1-6烷基;
R8是氢,C3-7环烷基或具有1-3个选自N、O和S的杂原子的5元或6元杂环基;其中所述R8的C3-7环烷基或5元或6元杂环基是未经取代的,或者被羟基或C1-6烷基取代;
可替代地,R5和R6或R7和R8与其附接在-NR5R6或-NR7R8中的氮原子一起分别形成具有1-3个选自N、O和S的杂原子的5元或6元杂环基;
条件是R1a、R1b、R4a和R4b不能全是氢;并且
进一步条件是当R1a、R1b、R4a或R4b是C1-6烷基时,在同一碳环原子上的其他取代基不是氢。
3.如权利要求2所述的化合物、或其药学上可接受的盐或立体异构体,其中所述化合物具有式(1A)、式(1C)、式(1G)、式(1L)、式(2A)、式(2C)、式(2G)或式(2L)。
4.如权利要求1-3中任一项所述的化合物,其中R1a和R1b之一是氢且另一个是羟基、氟、甲氧基、甲基氨基、(2-羟乙基)氨基、二-甲基氨基、吗啉-4-基、甲基、((四氢-2H-吡喃-4-基)氨基)或(3-羟基环丁基)氨基。
5.如权利要求4所述的化合物,其中R1a和R1b之一是氢且另一个是羟基;且R4a和R4b是氢。
6.如权利要求1-3中任一项所述的化合物,其中R1a和R1b是氢,且R4a和R4b之一是氢且另一个是羟基或氟。
7.如权利要求1所述的化合物,其中R1a和R1b之一和R4a和R4b之一与碳环原子一起形成与双环稠合的环丙基。
8.如权利要求1-7中任一项所述的化合物,其中R2是苯基、吡啶基、吡唑基、噻唑基或哌啶基,其各自是未经取代的,或者被1至2个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基、卤基取代的C1-6烷氧基、氰基、C1-6烷基磺酰基、未经取代的苯基或被卤基取代的苯基的取代基取代。
9.如权利要求8所述的化合物,其中R2选自:
被3,4-二氯、2-三氟甲基、3-三氟甲基、3-氰基-4-氯、2-氰基-4-氯、3-氟-4-氯、3-三氟甲氧基、3-氟-4-三氟甲氧基、或3-氟-4-(2-氟苯基)取代的苯基;
被6-甲氧基或2-三氟甲基取代的吡啶-4-基;
被5,6-二氯、6-甲氧基、5-氯-6-甲基或5-三氟甲基-6-甲基取代的吡啶-3-基;
被4,5-二氯取代的吡啶-2-基;
被1-甲基取代的1H-吡唑-3-基;
被5-甲基取代的噻唑-2-基;以及
被1-甲基磺酰基取代的哌啶-4-基。
10.如权利要求1-9中任一项所述的化合物,其中R3是吡啶基、嘧啶基或吡唑基,其各自是未经取代的,或者被1至2个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基或-NR5R6的取代基取代。
11.如权利要求10所述的化合物,其中R3选自:
未经取代或被2-甲基、2-三氟甲基、2-甲氧基、2-氨基、2-氟、2,3-二氟、或2,5-二氟取代的吡啶-4-基;
未经取代或被6-甲基、6-甲氧基、或5,6-二氯取代的吡啶-3-基;
被6-三氟甲基取代的吡啶-2-基;
未经取代或被2-氟、2-甲基、2-氨基、2-三氟甲基、2-吗啉基或2-二-甲基氨基取代的嘧啶-5-基;
被2-甲基取代的嘧啶-4-基;以及
被1-甲基取代的1H-吡唑-4-基或1H-吡唑基-3-基。
12.如权利要求1所述的化合物、或其药学上可接受的盐或对映异构体,其中所述化合物选自在表2中的化合物1-181。
13.如权利要求12所述的化合物,其中所述化合物是一水合物。
14.一种具有式(III)的化合物
其中Ak是C1-6烷基;
R3是具有1至2个选自N、O和S的杂原子的5元或6元杂芳基;其中R3是未经取代的,或者被1-3个独立地选自卤基、C1-6烷基、卤基取代的C1-6烷基、C1-6烷氧基或-NR5R6的取代基取代;
R1a、R1b、R4a和R4b各自独立地是氢、卤基、羟基、C1-6烷氧基、C1-6烷基、-NR7R8或-NR7-(CR9R10)2-4-OR11;或其中R1a和R1b之一与R4a和R4b之一一起形成环丙基,所述R1a、R1b、R4a和R4b分别附接两个碳原子;
R5、R6、R7、R9、R10和R11各自独立地是氢或C1-6烷基;
R8是氢,C3-7环烷基或具有1-3个选自N、O和S的杂原子的5元或6元杂环基;其中所述R8的C3-7环烷基或5元或6元杂环基是未经取代的,或者被羟基或C1-6烷基取代;
可替代地,R5和R6或R7和R8与其附接在-NR5R6或-NR7R8中的氮原子一起分别形成具有1-3个选自N、O和S的杂原子的5元或6元杂环基;
条件是R1a、R1b、R4a和R4b不能全是氢;并且
进一步条件是当R1a、R1b、R4a或R4b是C1-6烷基时,在同一碳环原子上的其他取代基不是氢。
15.一种药物组合物,所述药物组合物包含如权利要求1至13中任一项所述的化合物、或其药学上可接受的盐或立体异构体、以及一种或多种药学上可接受的载体。
16.一种组合,所述组合包含如权利要求1-13中任一项所述的化合物、或其药学上可接受的盐或立体异构体、以及一种或多种治疗活性剂。
17.如权利要求1-13中任一项所述的化合物、或其药学上可接受的盐或对映异构体,并且任选地与第二治疗剂组合,用于治疗、改善或预防哺乳动物的关节炎或关节损伤;或用于软骨修复。
18.如权利要求1-13中任一项所述的化合物、或其药学上可接受的盐或对映异构体,并且任选地与第二治疗剂组合,在制造用于关节炎或关节损伤或用于软骨修复的药物中的用途。
19.一种用于在有需要的哺乳动物中治疗、改善或预防关节炎或关节损伤或用于修复软骨的方法,所述方法包括施用治疗有效量的如权利要求1-13中任一项所述的、以及任选地与第二治疗剂组合的化合物;从而治疗、改善或预防所述哺乳动物的关节炎或关节损伤,或修复软骨。
20.如权利要求19所述的方法,其中所述化合物口服施用。
21.一种诱导透明软骨产生的方法或一种诱导软骨发生性祖细胞分化为成熟软骨细胞的方法,所述方法包括使软骨发生性祖细胞与治疗有效量的如权利要求1-16中任一项所述的、以及任选地与第二治疗剂组合的化合物接触;从而诱导软骨细胞祖细胞分化为产生透明软骨细胞外基质的成熟软骨细胞。
22.如权利要求21所述的方法,其中所述接触步骤是在哺乳动物体外或体内进行的;并且当在体内进行时,所述干细胞存在于哺乳动物中。
23.如权利要求21或22所述的方法,其中所述接触步骤发生在基质或生物相容性支架中。
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