CN105189464B - 作为n型钙通道阻滞剂的环戊基吡唑 - Google Patents
作为n型钙通道阻滞剂的环戊基吡唑 Download PDFInfo
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- CN105189464B CN105189464B CN201380054099.7A CN201380054099A CN105189464B CN 105189464 B CN105189464 B CN 105189464B CN 201380054099 A CN201380054099 A CN 201380054099A CN 105189464 B CN105189464 B CN 105189464B
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- bases
- alkyl
- methoxyphenyls
- chlorphenyls
- pyrazoles
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明公开了用于治疗包括疼痛在内的多种疾病、综合征、病症和障碍的化合物、组合物和方法。此类化合物由如下的式(I)表示:其中R1、R2、R3、Q和G如本文定义。
Description
相关申请的交叉引用
本专利申请要求2012年8月16日提交的美国临时申请系列号61/683,775的提交的权益的优先权。上述相关美国专利申请的全部公开内容据此以引用方式并入本文以用于所有目的。
关于联邦资助的研究或开发的声明
下文所述的本发明的研究和开发不是联邦资助的。
背景技术
钙离子在生物体和细胞的生理机能和生物化学机能方面起到根本性的作用。钙通过离子通道进入细胞,介导了多种细胞和生理响应,包括基因表达、信号转导、神经递质释放、肌肉收缩和激素分泌。离子通道按门控或开启和关闭离子通量通道的机制来分类。电压门控的离子通道根据等离子体膜上的电压梯度开启或关闭,而配体门控离子通道根据配体对通道的结合开启或关闭。电压门控钙通道的分类将它们分成三类:(i)高电压活化的通道,其包括L-、N-、P-和Q-型通道;(ii)中电压活化的R型通道;和(iii)低电压活化的T型通道。
N型钙通道主要分布于中枢和外周神经元,主要位于突触前神经末端。该通道调控自突触末端的神经递质去极化引发的释放所需的钙通量。疼痛信号自周边至中枢神经系统(CNS)的传播尤其被位于脊髓内的N-型钙通道所介导。抑制浅表背角中的N型钙通道,致使膜兴奋性和神经递质释放下降,导致疼痛缓解。此外,缺乏N型钙通道的昏迷小鼠在动物疼痛模型中表现出减弱的疼痛行为。
已示出,N型钙通道介导与神经性疼痛相关联的神经元敏化进程的发展和维持,因此为止痛药的开发提供有吸引力的目标。当前允许三种N型钙通道调节剂来治疗疼痛:以商品名市售的ω-芋螺毒素MVIIA(齐考诺肽),其有效并且选择性地阻滞N型钙通道,并且适用于严重慢性疼痛的控制;以商品名市售的加巴喷丁和以商品名市售的普瑞巴林以高亲和力与N型钙通道的α2δ子单元相结合,并且适用于纤维肌痛、糖尿病神经性疼痛和/或疱疹后神经痛的治疗。
本发明的目的是提供N型钙通道阻滞剂。本发明的另一个目的是提供通过施用式(I)的化合物,治疗、改善或预防疼痛的方法。本发明的又一个目的是提供可用于治疗、改善或预防疼痛的包含式(I)的化合物的药物组合物。
发明内容
本发明涉及式(I)的化合物及其对映体、非对映体、溶剂化物和药学上可接受的盐。
其中
R1选自C1-4烷基、C1-4烷氧基、三氟甲氧基和三氟甲基;
R2为氢;或R2可与R1以及连接R1和R2二者的苯环形成2,3-二氢苯并呋喃-7-基;
R3为氢、氯、或氟;
Q选自Q1、Q2和Q3;
其中
R4选自氢、C1-4烷基、C1-4烷氧基、氰基、氟、氯、羟基、二(C1-4烷基)氨基、(C1-4烷基)氨基、氨基、C1-4烷基羰基和C1-4烷基磺酰基;
R5和R6各自独立地选自氢、C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、羟基、烯丙基、2-甲基丙-1-烯基、氰基、肟、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、6-(吗啉-4-基)-嘧啶-3-基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基羰氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选地被一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基、吗啉-4-基和C1-4烷氧基羰基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、2-羟基丙-2-基、甲氧基甲基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自4,4,5,5-四甲基-1,3-二氧杂环戊烷-2-基、4,5-二甲基-1,3-二氧杂环戊烷-2-基、1,3-二氧杂环己烷-2-基、4,6-二甲基-1,3-二氧杂环己烷-2-基、(3a,6a)-四氢-3aH-环戊[d][1,3]二氧杂环戊烯-2-基、5,5-二甲基-1,3-二氧杂环己烷-2-基和(3a,7a)-六氢苯并[d][1,3]二氧杂环戊烯-2-基;
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]。
本发明还特别提供了一种药物组合物,所述药物组合物包含以下物质、由以下物质组成和/或基本上由以下物质组成:药学上可接受的载体、药学上可接受的赋形剂和/或药学上可接受的稀释剂以及式(I)的化合物或其药学上可接受的盐形式。
还提供了用于制备药物组合物的方法,所述方法包括以下步骤、由以下步骤组成和/或基本上由以下步骤组成:将式(I)的化合物与药学上可接受的载体、药学上可接受的赋形剂和/或药学上可接受的稀释剂混合。
本发明还特别提供了使用式(I)的化合物治疗或改善受试者(包括人或其它哺乳动物)N型钙通道调节的障碍的方法,其中所述疾病、综合症或病症受N型钙通道调节的影响,如疼痛以及导致此类疼痛的疾病。
本发明还特别提供了用于制备本发明化合物及其药物组合物和药剂的方法。
附图说明
图1示出化合物71在大鼠CFA炎性疼痛热辐射模式中的抗痛觉过敏效应。
具体实施方式
关于取代基,术语“独立地”是指当可能存在超过一个的取代基时,所述取代基可彼此相同或不同的情况。
术语“烷基”无论是单独使用或作为取代基基团的部分使用,均指具有1至8个碳原子的直链或和支化的碳链。因此,指定的碳原子数(例如C1-8)独立地指烷基部分中的碳原子数或指较大的含烷基的取代基的烷基部分。在具有多个烷基基团的取代基基团,如(C1-6烷基)2氨基-中,该二烷基氨基的C1-6烷基基团可相同或不同。
术语“烷氧基”指-O-烷基基团,其中术语“烷基”为如上文所定义。
术语“烯基”和“炔基”是指具有2至更多个碳原子的直链和支化的碳链,其中烯基链含有至少一个双键,并且炔基链含有至少一个三键。
术语“环烷基”指具有3至14个碳原子的饱和的或部分饱和的、单环的或多环的烃环。此类环的示例包括环丙基、环丁基、环戊基、环己基、环庚基和金刚烷基。
术语“苯并稠合环烷基”是指稠合至苯环的5元至8元单环环烷基环。形成环烷基环的环碳原子环成员可为完全饱和的或部分饱和的。
术语“杂环基”是指具有3至10个环成员的非芳族单环或二环环系,所述环成员包含碳原子和1至4个杂原子,所述杂原子独立地选自N、O和S。包括在术语杂环基中的是具有5至7个成员的其中1至2个成员为氮的非芳族环状环,或具有5至7个成员的其中0、1或2个成员为氮并且至多2个成员为氧或硫并且至少一个成员必须为氮、氧或硫的非芳族环状环;其中,所述环任选包含零至一个不饱和键,并且任选地,当所述环具有6或7个成员时,它包含至多2个不饱和键。形成杂环的碳原子环成员可以是完全饱和的或部分饱和的。术语“杂环基”还包括桥联而形成二环的两个5元单环杂环烷基基团。这类基团不被视为完全芳族的且不称为杂芳基基团。当杂环为二环时,杂环的两个环均为非芳族的并且环中的至少一个含有杂原子环成员。杂环基团的示例包括且不限于吡咯啉基(包括2H-吡咯、2-吡咯啉基或3-吡咯啉基)、吡咯烷基、咪唑啉基、咪唑烷基、吡唑啉基、吡唑烷基、哌啶基、吗啉基、硫代吗啉基和哌嗪基。除非另外指明,否则杂环在导致稳定结构的任何杂原子或碳原子上连接到其侧基基团。
术语“苯并稠合的杂环基”是指稠合至苯环的5元至7元单环杂环。所述杂环含有碳原子和1至4个杂原子,所述杂原子独立地选自N、O和S。形成所述杂环的碳原子环成员可为完全饱和的或部分饱和的。除非另外指明,否则苯并稠合的杂环在苯环碳原子上连接到其侧基基团。
术语“芳基”指6至10个碳成员的不饱和芳族单环或二环。芳环的示例包括苯基及萘基。
术语“杂芳基”是指具有5至10个环成员,并含有碳原子和1至4个杂原子的单环芳族环体系或二环芳族环体系,所述杂原子独立地选自N、O和S。具有5或6个成员的芳族环(其中所述环由碳原子组成并具有至少一个杂原子成员)包括于术语杂芳基内。合适的杂原子包括氮、氧和硫。在5元环的情况下,杂芳基环优选含有氮、氧或硫中的一个成员,此外还含有至多3个附加的氮。在6元环的情况下,杂芳环优选含有1至3个氮原子。对于其中6元环具有3个氮原子的情况,最多2个氮原子是相邻的。杂芳基基团的示例包括呋喃基、噻吩基、吡咯基、唑基、噻唑基、咪唑基、吡唑基、异唑基、异噻唑基、二唑基、三唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚基、异吲哚基、苯并呋喃基、苯并噻吩基、吲唑基、苯并咪唑基、苯并噻唑基、苯并唑基、苯并异唑基、苯并噻二唑基、苯并三唑基、喹啉基、异喹啉基和喹唑啉基。除非另外指明,否则杂芳基在导致稳定结构的任何杂原子或碳原子上连接到其侧基基团。
术语“卤素”或“卤”是指氟、氯、溴和碘。
术语“甲酰基”指基团-C(=O)H。
术语“氧代”是指基团(=O)。
每当术语“烷基”或“芳基”或任何一个其前缀词根出现于取代基名称时(如芳基烷基、烷基氨基),该名称应当解释为包括上面针对“烷基”和“芳基”给出的那些限制。碳原子的指定数目(如C1-C6)独立地指烷基部分、芳基部分或较大取代基的烷基部分中的碳原子数目,在所述较大取代基中烷基以其前缀词根出现。就烷基和烷氧基取代基而言,碳原子的指定数目包括在给出的规定范围内包括的所有独立成员。例如C1-6烷基将分别包括甲基、乙基、丙基、丁基、戊基和己基及其亚组合(例如C1-2、C1-3、C1-4、C1-5、C2-6、C3-6、C4-6、C5-6、C2-5等)。
一般来讲,根据贯穿本公开内容使用的标准命名原则,指定侧链的末端部分首先被描述,随后是朝向连接点的相邻官能性。因此,例如“C1-C6烷基羰基”取代基是指下式的基团:
立构中心处的术语“R”指明该立构中心只具有如本领域所定义的R-构型;同样,术语“S”意指该立构中心只具有S-构型。如本文所用,在立构中心处的术语“*R”或“*S”用于指明立构中心是具有纯的但未知的构型。如本文所用,术语“RS”指以R-和S-构型的混合物存在的立构中心。类似地,术语“*RS”或“*SR”是指以R-和S-构型的混合物存在并且相对于分子内另一个立构中心具有未知构型的立构中心。
含有一个未画有立体键标号的立构中心的化合物是2种对映体的混合物。含有2个均未画有立体键标号的立构中心的化合物是4种非对映体的混合物。具有2个均标记为“RS”的立构中心并且画有立体键标号的化合物是具有所画出的相对立体化学的2-组分混合物。具有2个均标记为“*RS”的立构中心并且画有立体键标号的化合物是具有未知相对立体化学的2-组分混合物。未划有立体键标号的未标记立构中心为R-和S-构型的混合物。就画有立体键标号的未标记立构中心而言,绝对的立体化学是如所绘出的。
除非另外指明,否则旨在是分子中特定位置处的任何取代基或变量的定义与其在该分子中其他位置处的定义无关。应当了解,式(I)的化合物上的取代基和取代模式可由本领域的普通技术人员选择,以提供化学稳定并且易于通过本领域已知技术及如本文所述的那些方法合成的化合物。
术语“受试者”指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,最优选指人。
术语“治疗有效量”指包括本发明化合物在内的活性化合物或药剂的量,该量引起研究者、兽医、医生或其他医疗人员所追求的组织系统、动物或人的生物学或医学响应,这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。
术语“组合物”是指包括治疗有效量的规定成分的产品,以及直接或间接地由规定量的规定成分的组合产生的任何产品。
术语“N型钙通道阻滞剂”旨在涵盖与N型钙通道相互作用以显著降低或消除其功能活性,从而降低通过通道的钙离子流并且降低细胞内钙浓度上升的化合物。
使用术语“N型钙通道调节”表示受N型钙通道调节影响的病症,包括受N型钙通道抑制影响的病症,如疼痛、导致此类疼痛的疾病以及致使此类疼痛减弱的治疗
如本文所用,除非另外指明,否则术语“影响”或“受影响的”(当指受N型钙通道抑制影响的疾病、综合征、病症或障碍时)应包括所述疾病、综合征、病症或障碍中的一种或多种症状或临床表现的频率和/或严重性的降低,和/或包括预防所述疾病、综合征、病症或障碍的一种或多种症状或临床表现的发展,或者预防所述疾病、病症、综合征或障碍的发展。
式(I)的化合物可用于治疗、改善和/或预防受N型钙通道抑制影响的疾病、综合征、病症或障碍的方法。此类方法包括以下步骤、由以下步骤组成和/或基本上由以下步骤组成:将治疗有效量的式(I)的化合物或其对映体、非对映体、溶剂化物或药学上可接受的盐形式施用于受试者,所述受试者包括需要此类治疗、改善和/或预防的动物、哺乳动物和人。具体地,式(I)的化合物可用于治疗、改善和/或预防疼痛以及造成此疼痛的疾病、综合征、病症或障碍。更具体地,式(I)的化合物可用于治疗、改善和/或预防急性疼痛、炎性疼痛和/或神经性疼痛,包括向需要其的受试者施用治疗有效量的如本文所定义的式(I)的化合物。
如本文所用,急性疼痛是指快速出现的疼痛,可具有变化的强度,但是是自限制的并且具有相对较短的持续时间。急性疼痛的示例包括但不限于术后疼痛、手术后疼痛、牙痛、烧伤、晒伤、昆虫/动物咬伤和蜇伤、头痛和/或与急性创伤或伤害相关联的任何疼痛。
炎性疼痛是指由炎性疾病、病症、综合征或障碍产生的疼痛,包括但不限于炎性肠病、过敏性肠综合征、内脏痛、偏头痛、术后疼痛、骨关节炎、类风湿性关节炎、背痛、下背痛、关节痛、腹痛、胸痛、分娩痛、肌肉骨骼疾病、皮肤病、牙痛、发热、烧伤、晒伤、蛇咬伤、毒蛇咬伤、蜘蛛咬伤、昆虫蜇伤、神经源性膀胱或膀胱过动症、间质性膀胱炎、尿路感染、鼻炎、接触性皮炎/超敏反应、瘙痒、湿疹、咽炎、粘膜炎、肠炎、肠易激综合征、胆囊炎、胰腺炎、乳房切除术后疼痛综合征、痛经、子宫内膜异位症、由物理创伤所致的疼痛、头痛、窦性头痛、紧张性头痛或蛛网膜炎。
本发明的另一个实施例涉及一种用于治疗、改善和/或预防神经性疼痛的方法。神经性疼痛是指涉及周边或中枢神经系统受损的疾病、综合征、病症和/或障碍,包括癌症疼痛、神经障碍、脊神经和周边神经手术、脑肿瘤、外伤性脑损伤(TBI)、化学疗法引起的疼痛、疼痛迁延化、神经根痛、HIV疼痛、脊髓创伤、慢性疼痛综合征、纤维肌痛、慢性疲劳综合征、狼疮、肉样瘤病、周围神经病变、双侧周围神经病变、糖尿病性神经病变、中枢性疼痛、与脊髓损伤相关联的神经病变、中风、肌萎缩侧索硬化症(ALS)、帕金森氏病、多发性硬化症、坐骨神经炎、下颌关节神经痛、周围神经炎、多发性神经炎、残肢痛、幻肢痛、骨折、口部神经性疼痛、夏科氏痛、I型和II型复杂性区域疼痛综合征(CRPS I/II)、神经根病变、格-巴二氏综合征、感觉异常性股痛、灼口综合征、视神经炎、发热后神经炎、游走性神经炎、节段性神经炎、贡博氏神经炎、神经元炎、颈臂神经痛、颅部神经痛、膝状神经节神经痛、舌咽神经痛、偏头痛性神经痛、特发性神经痛、肋间神经痛、乳房神经痛、摩顿氏神经痛、鼻睫神经痛、枕神经痛、疱疹后神经痛、灼痛、红斑性肢痛病、斯路德氏神经痛、蝶腭神经痛、眶上神经痛、三叉神经痛、外阴痛或翼管神经痛。
本发明的实施例包括式(I)的化合物及其对映体、非对映体、溶剂化物和药学上可接受的盐
其中
a)R1选自C1-4烷基、C1-4烷氧基和三氟甲氧基;
b)R1选自C1-4烷氧基和三氟甲氧基;
c)R2为氢;
d)R3为氢或氯;
e)R3为氢;
f)R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
g)R6为氯;
h)G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、2-甲基丙-1-烯基、氰基、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选被一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基和C1-4烷氧基羰基;
任选被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自4,4,5,5-四甲基-1,3-二氧杂环戊烷-2-基、4,5-二甲基-1,3-二氧杂环戊烷-2-基、1,3-二氧杂环己烷-2-基、4,6-二甲基-1,3-二氧杂环己烷-2-基、(3a,6a)-四氢-3aH-环戊[d][1,3]二氧杂环戊烯-2-基、5,5-二甲基-1,3-二氧杂环己烷-2-基和(3a,7a)-六氢苯并[d][1,3]二氧杂环戊烯-2-基;
i)G选自C1-6烷基、C1-6烷氧基、C1-4烷氧基羰基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、三氟甲基羰基氨基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、
任选被取代基取代的吡啶-3-基,所述取代基独立地选自C1-4烷基、环丙基和C1-4烷氧基羰基;
任选被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基和三甲基甲硅烷基;
任选独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自4,4,5,5-四甲基-1,3-二氧杂环戊烷-2-基、4,5-二甲基-1,3-二氧杂环戊烷-2-基、1,3-二氧杂环己烷-2-基、4,6-二甲基-1,3-二氧杂环己烷-2-基、(3a,6a)-四氢-3aH-环戊[d][1,3]二氧杂环戊烯-2-基、5,5-二甲基-1,3-二氧杂环己烷-2-基和(3a,7a)-六氢苯并[d][1,3]二氧杂环戊烯-2-基;
以及上文实施例a)至i)的任何组合,前提条件是应该理解,其中将相同取代基的不同实施例进行组合的组合方式排除在外。
本发明的一个实施例涉及式(I)的化合物及其对映体、非对映体、溶剂化物和药学上可接受的盐。
其中
R1选自C1-4烷基、C1-4烷氧基和三氟甲氧基;
R2为氢;或R2可与R1以及连接R1和R2二者的苯环形成2,3-二氢苯并呋喃-7-基;
R3为氢或氯;
Q选自Q1、Q2和Q3;
R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R5和R6各自独立地选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、2-甲基丙-1-烯基、氰基、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选被吗啉-4-基或一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基和C1-4烷氧基羰基;
任选被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自4,4,5,5-四甲基-1,3-二氧杂环戊烷-2-基、4,5-二甲基-1,3-二氧杂环戊烷-2-基、1,3-二氧杂环己烷-2-基、4,6-二甲基-1,3-二氧杂环己烷-2-基、(3a,6a)-四氢-3aH-环戊[d][1,3]二氧杂环戊烯-2-基、5,5-二甲基-1,3-二氧杂环己烷-2-基和(3a,7a)-六氢苯并[d][1,3]二氧杂环戊烯-2-基;
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]。
本发明的一个实施例涉及式(I)的化合物及其对映体、非对映体、溶剂化物和药学上可接受的盐。
其中
R1选自C1-4烷基、C1-4烷氧基和三氟甲氧基;
R2为氢;或R2可与R1以及连接R1和R2二者的苯环形成2,3-二氢苯并呋喃-7-基;
R3为氢;
Q选自Q1、Q2和Q3;
R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R5选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R6为氯;
G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、2-甲基丙-1-烯基、氰基、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选被一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基和C1-4烷氧基羰基;
任选被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自4,4,5,5-四甲基-1,3-二氧杂环戊烷-2-基、4,5-二甲基-1,3-二氧杂环戊烷-2-基、1,3-二氧杂环己烷-2-基、4,6-二甲基-1,3-二氧杂环己烷-2-基、(3a,6a)-四氢-3aH-环戊[d][1,3]二氧杂环戊烯-2-基、5,5-二甲基-1,3-二氧杂环己烷-2-基和(3a,7a)-六氢苯并[d][1,3]二氧杂环戊烯-2-基;
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]。
本发明的一个实施例涉及式(I)的化合物及其对映体、非对映体、溶剂化物和药学上可接受的盐。
其中
R1选自C1-4烷氧基和三氟甲氧基;
R2为氢;
R3为氢;
Q选自Q1、Q2和Q3;
R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R5选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R6为氯;
G选自C1-6烷基、C1-6烷氧基、C1-4烷氧基羰基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、三氟甲基羰基氨基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、
任选被取代基取代的吡啶-3-基,所述取代基独立地选自C1-4烷基、环丙基和C1-4烷氧基羰基;
任选被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基和三甲基甲硅烷基;
任选独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自4,4,5,5-四甲基-1,3-二氧杂环戊烷-2-基、4,5-二甲基-1,3-二氧杂环戊烷-2-基、1,3-二氧杂环己烷-2-基、4,6-二甲基-1,3-二氧杂环己烷-2-基、(3a,6a)-四氢-3aH-环戊[d][1,3]二氧杂环戊烯-2-基、5,5-二甲基-1,3-二氧杂环己烷-2-基和(3a,7a)-六氢苯并[d][1,3]二氧杂环戊烯-2-基;
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]。
本发明的其它实施例涉及式(I)的化合物及其药学上可接受的盐形式。
其选自:
2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙醇;
吗啉-4-甲酸2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙酯;
二甲基氨基甲酸2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙酯;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-丙-2-烯-1-基-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲酸乙酯;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲酰胺;
N-{[2-(2-甲氧基苯基)-3-苯基-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}甲磺酰胺;
N-{[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}甲磺酰胺;
2-(2-甲氧基苯基)-3-苯基-2,4,5,6-四氢环戊[c]吡唑-5-甲腈;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲腈;
N-{2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙基}甲磺酰胺;
N-{2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙基}乙酰胺;
{2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙基}氨基甲酸叔丁酯;
3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲酸乙酯;
{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]亚甲基}氨基甲酸叔丁酯;
{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}氨基甲酸叔丁酯;
二乙基氨基甲酸[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲酯;
N-{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}甲磺酰胺;
N-{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}-2,2,2-三氟乙酰胺;
(2-{3-(4-氯苯基)-2-[2-(三氟甲基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基}乙基)氨基甲酸叔丁酯;
N-(2-{3-(4-氯苯基)-2-[2-(三氟甲基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基}乙基)甲磺酰胺;
3-(2-{3-(4-氯苯基)-2-[2-(三氟甲基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基}乙基)-1,1-二甲基脲;
二甲基氨基甲酸3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
吗啉-4-甲酸3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-醇;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-醇;
3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,6-二氢环戊[c]吡唑-5(4H)-酮;
二甲基氨基甲酸3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
吗啉-4-甲酸3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
二甲基氨基甲酸3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
吗啉-4-甲酸3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲磺酰胺;
N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]丙-2-磺酰胺;
N′-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N-二甲基磺酰胺;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,6-二氢环戊[c]吡唑-5(4H)-酮;
3-(4-氯苯基)-2-(2-乙氧基苯基)-2,6-二氢环戊[c]吡唑-5(4H)-酮;
N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N-甲基甲磺酰胺;
1-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]吡咯烷-2,5-二酮;
3-(4-氯苯基)-2-(2-乙氧基苯基)-5-(1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑;
1-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]吡咯烷-2-酮;
3-(4-氯苯基)-2-(2-乙氧基苯基)-5-[4-(三甲基甲硅烷基)-1H-1,2,3-三唑-1-基]-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-乙氧基苯基)-5-(1H-1,2,3-三唑-1-基)-2,4,5,6-四氢环戊[c]吡唑;
(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-5-(1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑;
N-[(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]丙-2-磺酰胺;
N-[(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-2,2,2-三氟乙酰胺;
N-[(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;
N′-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N-二甲基磺酰胺;
N-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;
(5R)-3-(4-氯苯基)-5-甲氧基-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
N-[(5S)-3-(4-氯苯基)-2-(2,3-二氢-1-苯并呋喃-7-基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;
N-[(5S)-3-(4-氯苯基)-2-(2,3-二氢-1-苯并呋喃-7-基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N-甲基丙-2-磺酰胺;
2-(4-氯-2-甲氧基苯基)-3-(4-氯苯基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
(5Z)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,6-二氢环戊[c]吡唑-5(4H)-酮肟;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
2-乙基丁酸(5R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
N-[(5R)-2-(2-甲氧基苯基)-3-(6-甲氧基吡啶-3-基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N′,N′-三甲基磺酰胺;
N-{(5R)-2-(2-甲氧基苯基)-3-[6-(1-甲基乙氧基)吡啶-3-基]-2,4,5,6-四氢环戊[c]吡唑-5-基}-N,N′,N′-三甲基磺酰胺;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-苯氧基-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(吡啶-3-基氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-[6-(1-甲基乙氧基)吡啶-3-基]-2,4,5,6-四氢环戊[c]吡唑;
(5R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(吡啶-2-基氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(6-吗啉-4-基吡啶-3-基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-吡啶-3-基-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(4,4-二甲基环己基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-1,2,3,4-四氢喹啉;
5-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]吡啶-3-甲酸乙酯;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(1-甲基乙氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-吗啉-4-基-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-[(三甲基甲硅烷基)氧基]-2,4,5,6-四氢环戊[c]吡唑;
2-乙基丁酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷]
(5S)-3-(4-氯苯基)-5-(2-乙基丁氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(6-甲基吡啶-3-基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(6-乙氧基吡啶-3-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
5-[2-氯-6-(1-甲基乙基)吡啶-3-基]-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(四氢-2H-吡喃-2-基氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(6-环丙基吡啶-3-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
环己烷甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
环戊烷甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
环丁烷甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
2-甲基丙酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
(5S)-3-(4-氯苯基)-5-(环己基甲氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环戊基甲氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环丁基甲氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(2-甲基丙氧基)-2,4,5,6-四氢环戊[c]吡唑;
四氢-2H-吡喃-4-甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(四氢-2H-吡喃-4-基甲氧基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环己基氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-5-[(1S,2S,4R)-二环[2.2.1]庚-2-基氧基]-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环戊基氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
4-[2-(2-甲氧基苯基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷]-3-基]苯甲腈;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(1-甲基乙基)-2,4,5,6-四氢环戊[c]吡唑;
4-[2-(2-甲氧基苯基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷]-3-基]-N,N-二甲基苯胺;
3-(6-乙氧基吡啶-3-基)-2-(2-甲氧基苯基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
2-(2-甲氧基苯基)-5′,5′-二甲基-3-(6-甲基吡啶-3-基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
2-(2-甲氧基苯基)-3-(6-甲氧基吡啶-3-基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
5-[2-(2-甲氧基苯基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷]-3-基]-N,N-二甲基吡啶-2-胺;
(4′R,5′R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
(4′S,5′S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
(4′R,6′R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,6′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
(4′S,6′S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,6′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
(4′R,5′S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
(4′R,5′S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
3-(4-氯苯基)-5-环己基-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
4-[2-(2-甲氧基苯基)-5-(2-甲基丙基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[5-(环己基甲基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]-3-基]-N,N-二甲基苯胺;
3-(6-乙氧基吡啶-3-基)-2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-3-(6-甲基吡啶-3-基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
5-[2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]-3-基]-N,N-二甲基吡啶-2-胺;
4-[2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷]-3-基]苯甲腈;
(3aR,7aS)-3′-(4-氯苯基)-2′-(2-甲氧基苯基)-2′,3a,4,5,6,6′,7,7a-八氢-4′H-螺[1,3-苯并二氧杂环戊烯-2,5′-环戊[c]吡唑];
(3aS,6aS)-3′-(4-氯苯基)-2′-(2-甲氧基苯基)-2′,4,5,6,6′,6a-六氢-3aH,4′H-螺[环戊[d][1,3]二氧杂环戊烯-2,5′-环戊[c]吡唑];
(3aR,6aS)-3′-(4-氯苯基)-2′-(2-甲氧基苯基)-2′,4,5,6,6′,6a-六氢-3aH,4′H-螺[环戊[d][1,3]二氧杂环戊烯-2,5′-环戊[c]吡唑];
(3aR,6aS)-3′-(4-氯苯基)-2′-(2-甲氧基苯基)-2′,4,5,6,6′,6a-六氢-3aH,4′H-螺[环戊[d][1,3]二氧杂环戊烯-2,5′-环戊[c]吡唑];
3-(4-氯苯基)-5-(2,6-二甲基吗啉-4-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(4-甲基哌啶-1-基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(3,3-二乙基吡咯烷-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(3,3-二甲基吡咯烷-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(5-氯噻吩-2-基)-2-(2-甲氧基苯基)-5′,5′-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环己烷];
3-(5-氯噻吩-2-基)-2-(2-甲氧基苯基)-4′,4′,5′,5′-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2′-[1,3]二氧杂环戊烷];
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-吡咯烷-1-基-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(3,3-二氟吡咯烷-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
4-[(5S)-5-(4-环戊基-1H-1,2,3-三唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
1-[(5S)-3-(4-氰基苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-1H-1,2,3-三唑-4-甲酸甲酯;
4-[(5S)-5-[4-(1-羟基-1-甲基乙基)-1H-1,2,3-三唑-1-基]-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-{(5S)-2-(2-甲氧基苯基)-5-[4-(2-甲基丙基)-1H-1,2,3-三唑-1-基]-2,4,5,6-四氢环戊[c]吡唑-3-基}苯甲腈;
{乙酸1-[(5S)-3-(4-氰基苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-1H-1,2,3-三唑-4-基}甲酯;
4-[(5S)-5-[4-(甲氧基甲基)-1H-1,2,3-三唑-1-基]-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4-叔丁基-1H-1,2,3-三唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二甲基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-2-(2-甲氧基苯基)-5-(2,4,5-三甲基-1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(2-乙基-4,5-二甲基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(2-乙基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-2-(2-甲氧基苯基)-5-(2-甲基-1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二乙基-1H-1,2,3-三唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-2-(2-甲氧基苯基)-5-(2,4,5-三乙基-1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二乙基-2-甲基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二乙基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈。
对于在医学中的使用,式(I)的化合物的盐是指无毒的“药学上可接受的盐”。然而,其它盐可用于制备式(I)的化合物或其药学上可接受的盐。式(I)的化合物的合适的药学上可接受的盐包括酸加成盐,其可(例如)通过将化合物溶液与药学上可接受的酸(例如盐酸、硫酸、富马酸、马来酸、琥珀酸、乙酸、苯甲酸、柠檬酸、酒石酸、碳酸或磷酸)溶液混合而形成。此外,如果式(I)的化合物含有酸性部分,则其合适的药学上可接受的盐可包括碱金属盐,诸如钠盐或钾盐;碱土金属盐,诸如钙盐或镁盐;以及与合适的有机配体形成的盐,诸如季铵盐。因而,代表性的药学上可接受的盐包括乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、依地酸钙盐、樟脑磺酸盐、碳酸盐、氯化物、克拉维酸盐、柠檬酸盐、二盐酸盐、依地酸盐、乙二磺酸盐、丙酸酯十二烷基硫酸盐、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、乙醇酰对氨基苯胂酸盐、己基间苯二酚盐、海巴明盐、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、异硫代硫酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐、油酸盐、双羟基萘酸盐(扑酸盐)、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸盐、硬脂酸盐、硫酸盐、碱式乙酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙基碘化物和戊酸盐。
可用于药学上可接受的盐制备中代表性的酸和碱包括酸,其包括乙酸、2,2-二氯乙酸、乙酰化的氨基酸、己二酸、藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、D-葡萄糖醛酸、L-谷氨酸、α-氧代-戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、马来酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑酸、磷酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对-甲苯璜酸和十一碳烯酸;和以下碱,所述碱包括氨、L-精氨酸、苯乙苄胺、苄星、氢氧化钙、胆碱、地阿诺、二乙醇胺、二乙胺、2-(二乙基氨基)-乙醇、乙醇胺、乙二胺、N-甲基-葡萄糖胺、海巴明、1H-咪唑、L-赖氨酸、氢氧化镁、4-(2-羟乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟乙基)-吡咯烷、氢氧化钠、三乙醇胺、氨基丁三醇和氢氧化锌。
本发明的实施例包括式(I)的化合物的前药。一般而言,此类前药将为化合物的官能衍生物,其在体内可容易地转化成所需的化合物。因此,在本发明的治疗或预防实施例的方法中,术语“施用”涵盖了治疗或预防对具体描述的化合物或未具体描述的化合物所叙述的多种疾病、病症、综合征和障碍,但该化合物在施用于患者后在体内转化成特定的化合物。选择和制备合适的前药衍生物的常规程序在(例如)“Design of Prodrugs(前药设计)”,H.Bundgaard(编辑),Elsevier,1985中有所描述。
在根据本发明实施例的化合物具有至少一个手性中心的情况下,它们可因此作为对映体存在。在化合物具有两个或更多个手性中心的情况下,它们可另外作为非对映体存在。应当理解,所有的此类异构体及其混合物涵盖在本发明的范围内。此外,化合物的一些结晶形式可作为多晶型存在,并且同样旨在包括在本发明中。此外,一些化合物可与水形成溶剂化物(即水合物)或与常见有机溶剂形成溶剂化物,并且此类溶剂化物也旨在涵盖于本发明的范围内。技术人员将理解,本文所使用的术语化合物旨在包括溶剂化的式(I)的化合物。
在根据本发明某些实施例的化合物的方法产生立体异构体的混合物的情况下,这些异构体可通过常规技术如制备性色谱法进行分离。化合物可以外消旋形式制备,或者单独的对映体可通过对映体特异性合成或通过拆分制备。例如,可通过标准的技术,诸如通过与光学活性的酸(诸如(-)-二对甲苯酰-D-酒石酸和/或(+)-二对甲苯酰-L-酒石酸)成盐来形成非对映体对,然后分级结晶并再生成游离的碱而将化合物拆分成它们的组分对映体。也可通过形成非对映酯或酰胺,然后进行色谱分离并去除手性助剂而拆分化合物。另选地,可用手性HPLC柱拆分化合物。
本发明的一个实施例涉及一种组合物,包括药物组合物,其包含式(I)的化合物的(+)-对映体,由其组成和/或基本上由其组成,其中所述组合物基本上不含所述化合物的(-)-异构体。在本文中,基本上不含意指少于约25%,优选少于约10%,更优选少于约5%,更优选少于约2%,并且更优选少于约1%的(-)-异构体,其可如下计算:
本发明的另一个实施例为一种组合物,包括药物组合物,其包含式(I)的化合物的(-)-对映体,由其组成和基本上由其组成,其中所述组合物基本上不含所述化合物的(+)-异构体。在本发明的上下文中,基本上不含表示少于约25%,优选少于约10%,更优选少于约5%,甚至更优选少于约2%,并且更优选少于约1%的(+)-异构体,其如下计算:
在用于制备本发明多个实施例的化合物的任何过程中,可能有必要和/或期望保护任何所涉及的分子上的敏感性或反应性基团。这可通过常规的保护基团实现,诸如在Protective Groups in Organic Chemistry,第二版,J.F.W.McOmie,Plenum Press,1973;T.W.Greene P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991;以及T.W.Greene P.G.M.Wuts,Protective Groups in Organic Synthesis,第三版,John Wiley&Sons,1999中所述的那些保护基团。可使用本领域已知的方法在方便的后续阶段去除保护基团。
尽管本发明实施例的化合物(包括它们的药学上可接受的盐和药学上可接受的溶剂化物)可单独施用,但它们一般与药学上可接受的载体、药学上可接受的赋形剂和/或药学上可接受的稀释剂(根据施用途径和标准药用或兽医实践而选择)混合施用。因此,本发明的具体实施例涉及药用和兽医用组合物,其包含式(I)的化合物和至少一种药学上可接受的载体、药学上可接受的赋形剂和/或药学上可接受的稀释剂。
以举例的方式,在本发明实施例的药物组合物中,可将式(I)的化合物与任何合适的一种或多种粘合剂、一种或多种润滑剂、一种或多种助悬剂、一种或多种包衣剂、一种或多种增溶剂、以及它们的组合混合。
视情况而定,含有本发明化合物的固体口服剂型(如片剂或胶囊剂)可一次以至少一种剂型施用。也可能在缓释制剂中施用该化合物。
可在其中施用本发明化合物的另外的口服剂型包括酏剂、溶液剂、糖浆剂和混悬剂;它们各自任选地包含矫味剂和着色剂。
作为另一种选择,式(I)的化合物可通过吸入(气管内或鼻内)施用或以栓剂或阴道栓剂形式施用,或者它们可以洗剂、溶液剂、霜膏、油膏剂或扑粉的形式局部施用。例如,可将它们混入霜膏中,所述霜膏包含聚乙二醇或液态石蜡的水乳液,由其组成和/或基本上由其组成。以霜膏的重量计,它们也可以约1%至约10%的浓度掺入油膏剂中,所述油膏剂包含白蜡或白软石蜡碱以及任何稳定剂和防腐剂(有可能需要),由其组成和/或基本上由其组成。替代的施用方法包括通过使用皮肤贴剂或透皮贴剂来透皮施用。
本发明的药物组合物(以及单独的本发明化合物)也可非肠道注射,例如海绵体内、静脉内、肌内、皮下、皮内或鞘内注射。在这种情况下,该组合物还将包含合适的载体、合适的赋形剂以及合适的稀释剂中的至少一种。
对于非肠道施用,本发明的药物组合物最好以无菌水溶液形式使用,所述无菌水溶液可含有其他物质,例如足够的盐和单糖以制备与血液等渗的溶液。
对于颊面或舌下施用,本发明的药物组合物可以片剂或锭剂形式施用,所述片剂或锭剂可以常规方式配制。
以另一个实例的方式,含有式(I)的化合物中的至少一种作为活性成分的药物组合物可根据常规药物配混技术,通过将一种或多种化合物与药学上可接受的载体、药学上可接受的稀释剂和/或药学上可接受的赋形剂混合而制备。载体、赋形剂和稀释剂可采用各种各样的形式,这取决于所需施用途径(例如口服、肠胃外给药等)。因此对于诸如混悬剂、糖浆剂、酏剂和溶液剂的液体口服制剂,合适的载体、赋形剂和稀释剂包括水、二元醇、油、一元醇、矫味剂、防腐剂、稳定剂、着色剂等;对于诸如散剂、胶囊剂和片剂的固体口服制剂,合适的载体、赋形剂和稀释剂包括淀粉、糖、稀释剂、造粒剂、润滑剂、粘结剂、崩解剂等。固体口服制剂还可以任选地用诸如糖的物质包衣,或包肠溶衣,以调节吸收和崩解的主要部位。对于非肠道施用,载体、赋形剂和稀释剂通常包括无菌水,并且可加入其他成分以增加组合物的溶解度和保存性。注射用混悬剂或溶液剂也可用水性载体与适当添加剂如增溶剂和防腐剂一起制备。
在平均(70kg)的人的每日约1至约4次的服法中,治疗有效量的式(I)的化合物或其药物组合物包含约0.1mg至约3000mg的剂量范围或其中任何特定量或范围,具体约1mg至约1000mg或其中任何特定量或范围;或更具体地约10mg至约500mg或其中任何特定量或范围的活性成分;但是,对于本领域的技术人员显而易见的是:式(I)的化合物的治疗有效量将随着进行治疗的疾病、综合征、病症和障碍而变化。
对于口服施用,药物组合物优选以含有约0.01、约10、约50、约100、约150、约200、约250和约500毫克式(I)的化合物的片剂形式提供。
有利的是,式(I)的化合物可以单次日剂量施用,或者每日总剂量可以每日两次、三次和四次的分剂量施用。
待施用的式(I)的化合物的最佳剂量可容易地确定,并且将随所使用的特定化合物、施用模式、制剂强度以及疾病、综合征、病症或障碍的进展而变化。另外,与待治疗的具体受试者相关联的因素(包括受试者性别、年龄、体重、饮食和施用时间)将导致有需要调整剂量以实现适当的治疗水平和所需的治疗效果。因而上述剂量是一般情况的示例。当然,可能会存在其中较高或较低剂量范围是有益的个别情况,并且这类情况也在本发明的范围内。
式(I)的化合物可以在任何上述组合物和给药方案中施用,或者借助于本领域已确立的那些组合物和给药方案施用,只要式(I)的化合物的使用是需要它的受试者所要求的。
作为N型钙通道阻滞剂,式(I)的化合物可用于治疗和/或预防受试者疾病、综合征、病症或障碍的方法,所述受试者包括动物、哺乳动物和人,其中所述疾病、综合症、病症或障碍受N型钙通道调节的影响。这种方法包括以下步骤,由以下步骤组成和/或基本上由以下步骤组成:将治疗有效量的式(I)的化合物、盐或溶剂化物施用至受试者,所述受试者包括需要此类治疗或预防的动物、哺乳动物和人。具体地,式(I)的化合物用于预防或治疗疼痛如炎性疼痛或神经性疼痛,或引起此类疼痛的疾病、综合征、病症或障碍。
一般合成方法
本发明的代表性化合物可根据下文所述的和在之后的方案和实例中说明的一般合成方法合成。由于方案是举例说明,所以本发明不应被理解为受到所述方案中的化学反应和条件的限制。用于方案和实例中的不同原料可商购获得或者可通过精通本领域的技术人员熟知的方法制备。变量为如本文所定义。
用于本说明书,特别是用于所述方案和实例的缩写为如下:
ACN 乙腈
AcOH 冰醋酸
aq. 含水的
Bn或Bzl 苄基
BOC 叔丁氧羰基
conc. 浓度
DBU 1,8-二氮杂二环[5.4.0]十一碳-7-烯
DCC N,N′-二环己基-碳二亚胺
DCE 1,2-二氯乙烷
DCM 二氯甲烷
DIBALH 二异丁基铝氢化物
DIPEA或DIEA 二异丙基-乙胺
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
EA 乙酸乙酯
EDCI 1-乙基-3-(3-二甲基氨丙基)碳二亚胺
EGTA 乙二醇四乙酸
ESI 电喷射离子化
EtOAc或EA 乙酸乙酯
EtOH 乙醇
h或hr(s) 一个或多个小时
HEK 人胚肾
HEPES (4-(2-羟乙基)-1-哌嗪乙磺酸
HPLC 高效液相色谱法
LAH 氢化铝锂
LDA 二异丙基氨基锂
LHMDS 双(三甲基甲硅烷基)氨基锂
mCPBA 间氯过氧苯甲酸
MeOH 甲醇
MHz 兆赫兹
min 一分钟或几分钟
MS 质谱法
MS 甲磺酰基
NMM N-甲基吗啉
NMR 核磁共振
PCC 氯铬酸吡啶盐
RP 反相
RT 室温
Rt 保留时间
秒 一秒或数秒
TBDMS 叔丁基二甲基甲硅烷基
TEA或Et3N 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TIPS 三异丙基甲硅烷基
TLC 薄层层析
TMS 四甲基硅烷
方案A示出式(I)-A、-A1和-A2化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为官能化乙基基团。
方案A
式A1的化合物是可商购获得的或可通过科学文献中已知的方法制备。式A1化合物可在碱如LHMDS存在下用式A2不饱和烷基溴烷基化,以获得式A3化合物。式A3化合物可在氢化物源如DIBALH或LAH等存在下经历还原,获得式A4化合物。对式A5的Q-取代的醛亲核加成,获得式A6醇。式A6化合物醇可经由氧化剂如Dess-Martin过碘烷、PCC、Swern试剂等的作用,氧化成对应的式A7酮。在氢化物源如三叔丁氧基氢化铝锂等存在下,可实现α/β-不饱和基团的还原,获得式A8化合物。式A9肼环化,获得式A10吡咯并环戊基环。在四氧化锇存在下,式A10的末端烯基基团氧化,获得对应的式A11醛。所述醛经由还原剂如硼氢化钠或氢化铝锂等的作用还原,获得式(I)-A化合物。式(I)-A醇可经由本领域技术人员已知的多种常规方法酰化,获得式(I)-A1化合物。例如,式(I)-A化合物可用式A12酰氯(其中RA为吗啉-4-基或二甲基氨基)酰化,获得式(I)-A1化合物。式A11化合物可在氢化物源如三乙基硅烷或酸如TFA存在下用氨基甲酸叔丁酯处理,获得本发明的式(I)-A2氨基甲酸酯。
方案B示出式(I)-B、-B1和-B2化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为官能化亚甲基基团。
方案B
式B1化合物是可商购获得的或可通过科学文献中已知的方法制备。式B1化合物可在碱性条件下用式B2酰氯处理,获得式B3化合物。式A9肼环化,获得式B4吡唑并环戊基环。用氨基锂处理获得式(I)-B伯酰胺。在氢化物源如氢化铝锂等存在下还原所述酰胺,获得式B5化合物,其随后可用烷基磺酰氯如甲磺酰氯处理,获得式(I)-B1化合物。作为另外一种选择,式(I)-B化合物可用氰尿酰氯处理,获得对应的式(I)-B2氰化物。
方案C示出了式(I)-C和-C1化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为醇或氨基甲酸酯。
方案C
式C1化合物是可商购获得的或可通过科学文献中已知的方法制备。式C1化合物可在路易斯酸如氯化二乙基铝或三氟化硼存在下,用碱如有机锂碱处理,然后加入式C2化合物,获得式C3化合物。醇官能团可被保护,其中“P”为常规的醇保护基团如TIPS、TBDMS或苄基,获得式C4化合物。用氢氧根阴离子处理实施皂化并且移除TMS基团,获得式C5化合物。式C5化合物可在N-溴代琥珀酰亚胺和硝酸银存在下溴化,获得式C6化合物。化合物C6可在氯甲酸异丁酯或其它酰胺类偶联剂如EDCI存在下,用NMM和式A9化合物处理,获得式C7化合物。将四氯化碳和聚合物结合的三苯基膦加入到式C7化合物中,获得式C8化合物,其可在叔胺碱如三乙胺或DIEA存在下加热,获得式C9环化产物。式C9可在过渡金属催化剂、适宜配体存在下,并且在无机碱如碳酸钠存在下,与式C10硼酸交叉偶联,获得式(I)-C化合物。用式A11化合物酰化,获得本发明的式(I)-C1化合物。
方案D示出式(I)-D化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为如本文定义的磺酰胺。
方案D
式(I)-C化合物可用甲磺酰氯处理,获得式D1化合物。用叠氮化钠处理实现对甲磺酸酯基的亲核置换,获得对应的式D2叠氮化物。可经由常规催化剂氢化或通过用三苯基膦处理实现叠氮化物还原,获得式D3胺。式D3化合物可用适宜的取代的磺酰氯(其中RD为例如甲基、异丙基、或二甲基氨基)酰化,获得本发明的式(I)-D化合物。
方案E示出了式(I)-E和-E1的合成途径,其中Q、R1、R2和R3如本文定义,并且G为1,2,3,4-四氢喹啉-3-基、任选取代的吡啶基(其中RE为氢、C1-4烷基、C1-4烷氧基、氯、环丙基、吗啉-4-基、或C1-4烷氧基羰基)、或如本文定义的C3-6环烷基。仅为了进行示意性的说明,方案E示出与任选取代的吡啶基硼酸酯的交叉偶联。
方案E
式(I)-C化合物可经由氧化剂如Dess-Martin过碘烷、PCC、Swern试剂等的作用而氧化,获得对应的式(I)-E酮。用碱如KHMDS、DBU、LDA等以及N-苯基-双(三氟甲磺酰亚胺)或其它三氟甲磺酸化剂处理,获得式E1化合物。式E1化合物可在钯催化剂、适当配体和无机碱存在下与式E2硼酸酯交叉偶联,然后常规氢化,获得式(I)-E1化合物。
方案F示出式(I)-F化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为如本文定义的螺稠杂环基。
方案F
式(I)-E化合物可在路易斯酸如三氟化硼醚合物存在下用式F1化合物(其中F1的碳原子任选被一至四个甲基取代基取代)处理,获得式(I)-F缩酮。
方案G示出式(I)-F化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为环G1、环状胺如吗啉基或任选取代的哌啶基或吡咯烷基环。
方案G
式(I)-E化合物可在氢化物源如氰基硼氢化钠、三乙酰氧基硼氢化钠等存在下,用式G1化合物处理,获得式(I)-G胺。
方案H示出式(I)-H化合物的合成途径,其中Q、R1、R2和R3如本文定义,并且G为烷基取代基RH,其中RH为任选被取代的C1-6烷基、C3-6环烷基(C1-4)烷基、或C3-6环烷基。
方案H
式(I)-E化合物可用式H1烷基溴化镁处理,形成式H2化合物。式H2化合物可在Burgess试剂((N-三乙基铵磺酰基)氨基甲酸酯)存在下经历脱水,获得式H3化合物。烯基官能团的还原可通过常规钯催化氢化实现,获得式(I)-H化合物。
具体实例
实例1
A.-78℃和Ar下向LHMDS(36.8mL的1M THF溶液,36.8mmol,1.1当量)的THF(70mL)溶液中,在1小时内滴加3-乙氧基-2-环戊酮(1a)(4.0mL,33.45mmol,1当量)的THF(40mL)溶液。20分钟后,在10分钟内加入烯丙基溴(1b)(3.19mL,36.8mmol,1.1当量)的THF(40mL)溶液。-78℃下3小时后,加入水和NH4Cl,用醚萃取水溶液,合并有机物,在MgSO4上干燥并且浓缩。经由层析(80g)纯化,用15至40%EA/己烷洗脱,获得化合物1c(3.05g,55%)。1H NMR(氯仿-d)δ:5.68-5.82(m,J=16.9,10.2,6.8,6.8Hz,1H),5.25(s,1H),5.01-5.12(m,2H),4.04(q,J=7.1Hz,2H),2.65-2.75(m,1H),2.57(qd,J=6.6,4.0Hz,2H),2.28-2.39(m,1H),2.11-2.23(m,1H),1.41(t,J=7.1Hz,3H)。ESI-MS(m/z):C15H15ClO2计算值:167.1(M+1);实验值:167.1。
B.0℃下在1小时内向化合物1c(3.05g,18.4mmol,1当量)的THF(30mL)溶液中,加入氢化二异丁基铝(36.7mL 1M的己烷溶液,36.7mmol,2当量)。1小时后,在0℃下滴加1NHCl,然后在2小时内使反应升温至室温。水层用醚萃取,在MgSO4上干燥并且浓缩,获得化合物1d(2.2g粗产物)。化合物1d(1.0g)经由层析(40g)纯化,用10至40%EA/己烷洗脱,获得经纯化的化合物1d(587mg,90%)。1H NMR(氯仿-d)δ:7.64(dd,J=5.7,2.4Hz,1H),6.18(dd,J=5.7,1.9Hz,1H),5.69-5.86(m,J=17.2,9.9,7.0,7.0Hz,1H),5.05-5.21(m,2H),2.97-3.12(m,1H),2.52(dd,J=18.8,6.4Hz,1H),2.16-2.38(m,J=37.7,14.1,6.9,6.9Hz,2H),2.00-2.12(m,1H)。
C.rt下向化合物1d(587mg,4.81mmol,1当量)和4-氯苯甲醛(1e)(541mg,3.85mmol,0.8当量)的甲醇(25mL)溶液中,加入碳酸钠(255mg,2.41mmol,0.5当量)的水(10mL)溶液。1小时后,加入1N HCl,并且蒸发甲醇。水溶液用DCM萃取,并且使有机相在MgSO4上干燥、过滤并且浓缩。经由层析(60g)纯化,用10至25%EA/己烷洗脱,获得化合物1f(721mg,71%)。1H NMR(氯仿-d)δ:7.28-7.36(m,4H),7.13-7.21(m,1H),5.65-5.79(m,1H),5.53(s,1H),5.03-5.12(m,2H),3.45(br.s.,1H),2.89-2.99(m,1H),2.56-2.67(m,1H),2.28(dt,J=13.6,7.0Hz,1H),2.10-2.23(m,2H)。ESI-MS(m/z):C15H15ClO2计算值:245.1(M-17);实验值:245.0。
D.0℃下向化合物1f(1.18g,4.48mmol,1当量)的DCM(40mL)溶液中,加入Dess-Martin过碘烷(2.09g,4.93mmol,1.1当量)。1小时后,加入饱和NaHCO3和饱和硫代硫酸钠,并且将混合物搅拌30分钟。反应混合物用DCM萃取,在MgSO4上干燥,过滤,并且浓缩。经由层析(60g)纯化,用15至25%EA/己烷洗脱,获得化合物1g(660mg,57%)。1H NMR(氯仿-d)δ:7.95(d,J=2.5Hz,1H),7.72-7.79(m,2H),7.41-7.47(m,2H),5.74-5.89(m,1H),5.12-5.22(m,2H),3.14-3.23(m,1H),2.78(dd,J=19.2,6.6Hz,1H),2.28-2.50(m,3H)。ESI-MS(m/z):C15H13ClO2计算值:261.1(M+1);实验值:261.0。
E.0℃下向化合物1g(660mg,2.53mmol,1当量)的THF(20mL)溶液中,加入三叔丁氧基氢化锂铝(3.8mL 1M的THF溶液,3.8mmol,1.5当量)。30分钟后,加入1N HCl,溶液用乙酸乙酯萃取,有机相在MgSO4上干燥,过滤,并且浓缩,获得化合物1h,~80%纯(653mg,98%)。
F.80℃下向化合物1h(415mg,1.58mmol,1当量)的乙酸(20mL)溶液中,加入2-甲氧基苯肼(1i)(252mg,1.82mmol,1.15当量)。1小时后,将溶液冷却至rt并且浓缩。经由层析(40g)纯化,用5至30%EA/己烷洗脱,获得化合物1j(第2个主峰,第1个峰为非期望的区域异构体,227mg,39%)。1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.29-7.36(m,1H),7.16-7.22(m,2H),7.04-7.10(m,2H),7.01(td,J=7.6,1.0Hz,1H),6.88(d,J=8.3Hz,1H),5.81-5.94(m,J=17.1,10.2,6.8,6.8Hz,1H),5.01-5.15(m,2H),3.49(s,3H),2.90-3.07(m,3H),2.47-2.64(m,2H),2.31-2.45(m,2H)。ESI-MS(m/z):C22H21ClN2O计算值:365.1(M+1);实验值:365.3。
G.0℃下向化合物1j(116mg,0.32mmol,1当量)的THF(7mL)溶液中,加入四氧化锇(0.4mL 2.5%的叔丁醇溶液,0.032mmol,0.1当量),然后加入过碘酸钠(411mg,1.92mmol,6当量)的水(5mL)溶液。1小时后,加入硫代硫酸钠的饱和溶液,并且将混合物搅拌30分钟。然后用醚萃取溶液,有机相在MgSO4上干燥,过滤,并且浓缩,获得化合物1k。1H NMR(氯仿-d)δ:9.86(t,J=1.5Hz,1H),7.31-7.40(m,2H),7.17-7.22(m,2H),7.04-7.09(m,2H),7.01(td,J=7.6,1.3Hz,1H),6.88(dd,J=8.3,1.3Hz,1H),3.50(s,3H),3.35-3.45(m,1H),3.06-3.18(m,2H),2.81(ddd,J=7.1,5.3,1.5Hz,2H),2.46-2.62(m,2H)。ESI-MS(m/z):C21H19ClN2O2计算值:367.1(M+1);实验值:367.1。
H.向化合物1k的甲醇(2mL)溶液中,加入硼氢化钠(20mg,0.52mmol,1.7当量)。1小时后,加入水和NH4Cl,水层用乙酸乙酯萃取。有机相在MgSO4上干燥,过滤,并且浓缩。经由层析(24g)纯化,用40至100%EA/己烷洗脱,获得化合物1(61mg,52%)。1H NMR(氯仿-d/MeOH)δ:7.33-7.41(m,2H),7.19-7.24(m,2H),7.06-7.11(m,2H),7.04(td,J=7.7,1.3Hz,1H),6.90-6.96(m,1H),3.71(t,J=6.8Hz,2H),3.51(s,3H),2.96-3.13(m,3H),2.55(dd,J=15.2,7.8Hz,2H),1.91(q,J=6.8Hz,2H)。ESI-MS(m/z):C21H21ClN2O2计算值:369.1(M+1);实验值:369.1。
I.rt下向化合物1(17mg,0.045mmol,1当量)的THF(2mL)溶液中,加入NaHMDS(0.23mL 1M的THF溶液,0.23mmol,5当量)。30分钟后,加入4-吗啉碳酰氯(0.026mL,0.23mmol,5当量),并且将溶液搅拌过夜。将溶液加入到5mL载有含水氯化铵的硅藻土萃取管中,并且加入DCM,收集并且浓缩。经由层析(8g)纯化,用40至100%EA/己烷洗脱,获得化合物2(9.1mg,42%)。1H NMR(氯仿-d)δ:7.31-7.40(m,2H),7.17-7.22(m,2H),7.04-7.09(m,2H),7.01(td,J=7.6,1.3Hz,1H),6.88(dd,J=8.3,1.0Hz,1H),4.20-4.27(m,2H),3.66(br.s.,5H),3.44-3.51(m,7H),2.94-3.09(m,3H),2.56(dd,J=16.4,7.1Hz,2H),1.96-2.04(m,2H)。ESI-MS(m/z):C26H28ClN3O4计算值:482.2(M+1);实验值:482.2。
依照对于实例1上述的方法,并且替换适当的试剂、原料和本领域技术人员已知的纯化方法,制备以下化合物:
Cpd 3:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.34(td,J=7.9,1.6Hz,1H),7.17-7.22(m,2H),7.05-7.09(m,2H),7.01(td,J=7.6,1.3Hz,1H),6.88(dd,J=8.2,1.1Hz,1H),4.20(t,J=6.6Hz,2H),3.49(s,3H),2.96-3.09(m,3H),2.92(s,6H),2.49-2.64(m,2H),1.93-2.04(m,2H)。ESI-MS(m/z):C24H26ClN3O3计算值:440.2(M+1);实验值:440.2。
实例2
向化合物1k(23mg,0.06mmol,1当量)的乙腈(2mL)溶液中,加入氨基甲酸叔丁酯(37mg,0.31mmol,4.95当量)、三乙基硅烷(0.05mL,0.32mmol,5.1当量)和三氟乙酸(0.016mL,0.21mmol,3.3当量)。将小瓶中的溶液加热至50℃过夜。将溶液冷却,加入乙酸乙酯,并且依序用NaHCO3和盐水洗涤溶液。有机相在MgSO4上干燥,过滤,并且浓缩。经由层析(8g)纯化,用30至50%EA/己烷洗脱,获得化合物13(19mg,65%)。1H NMR(氯仿-d)δ:7.36-7.41(m,1H),7.34(t,J=8.0Hz,1H),7.19(d,J=8.6Hz,2H),7.06(d,J=8.3Hz,2H),7.01(t,J=7.6Hz,1H),6.88(d,J=8.3Hz,1H),4.58(br.s.,1H),3.49(s,3H),3.24(d,J=6.1Hz,2H),2.89-3.08(m,3H),2.48-2.61(m,2H),1.77-1.91(m,2H),1.46(s,9H)。ESI-MS(m/z):C26H30ClN3O3计算值:468.2(M+1);实验值:468.2。
依照上文实例2所述的方法,用乙酰胺替代氨基甲酸叔丁酯,制备以下化合物:
Cpd 12:1H NMR(氯仿-d)δ:7.32-7.40(m,2H),7.17-7.24(m,2H),7.04-7.11(m,2H),6.97-7.04(m,1H),6.90(d,J=7.6Hz,1H),5.56(br.s.,1H),3.52(s,3H),3.34-3.43(m,2H),2.92-3.13(m,3H),2.47-2.65(m,2H),2.02(s,3H),1.6-1.8(m,2H)。ESI-MS(m/z):C23H24ClN3O2计算值:410.2(M+1);实验值:410.2。
实例3
A.将化合物13(13mg,0.03mmol,1当量)的DCM(5mL)溶液和三氟乙酸(1mL)搅拌2小时并且浓缩。加入DCM,有机物用NaHCO3洗涤,在MgSO4上干燥,过滤,并且浓缩,获得化合物3a(11mg,100%)。1H NMR(氯仿-d)δ:8.11(br.s.,2H),7.38(t,J=7.8Hz,1H),7.28(d,J=7.6Hz,1H),7.16-7.24(m,J=8.3Hz,2H),7.01-7.09(m,J=8.3Hz,2H),6.98(t,J=7.5Hz,1H),6.90(d,J=8.3Hz,1H),3.52(s,3H),2.83-3.21(m,5H),2.49(br.s.,2H),1.83-2.08(m,2H)。C21H22ClN3O计算值:368.2(M+1);实验值:368.2。
B.向化合物3a(10mg,0.027mmol,1当量)的DCM(2mL)溶液中,加入三乙胺(0.019mL,0.14mmol,5当量)和甲磺酰氯(0.01mL,0.14mmol,5当量)。在1小时后,使溶液浓缩。经由层析(8g)纯化,用50至100%EA/己烷洗脱,获得化合物11(3mg,25%)。1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.17-7.23(m,2H),7.04-7.10(m,2H),6.97-7.04(m,1H),6.88(d,J=8.3Hz,1H),4.23-4.33(m,1H),3.49(s,3H),3.26(q,J=6.7Hz,2H),2.94-3.09(m,6H),2.46-2.62(m,2H),1.93(q,J=6.7Hz,2H)。ESI-MS(m/z):C22H24ClN3O3S计算值:446.1(M+1);实验值:446.1。
依照对于实例3上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 20:1H NMR(氯仿-d)δ:7.75-7.81(m,1H),7.49-7.57(m,2H),7.16-7.25(m,3H),6.97-7.03(m,2H),4.58(br.s.,1H),3.24(br.s.,2H),2.90-3.08(m,3H),2.55(dd,J=14.7,7.1Hz,2H),1.84(q,J=6.8Hz,2H),1.46(s,9H)。ESI-MS(m/z):C26H27ClF3N3O2计算值:506.2(M+1);实验值:506.2。
Cpd 22:1H NMR(氯仿-d)δ:7.75-7.82(m,1H),7.49-7.57(m,2H),7.15-7.25(m,3H),6.96-7.03(m,2H),4.42(br.s.,1H),3.31-3.41(m,2H),2.93-3.09(m,3H),2.92(s,6H),2.49-2.62(m,2H),1.82-1.93(m,2H)。ESI-MS(m/z):C24H24ClF3N4O计算值:477.2(M+1);实验值:477.2。
实例4
A.-78℃和Ar下,在30分钟内向LHMDS(15.8mL 1M的THF溶液,15.8mmol,1.6当量)的THF(15mL)溶液中滴加3-氧代环戊烷甲酸乙酯(4a)(1.55g,9.9mmol,1当量)的THF(15mL)溶液。又30分钟后,加入4-氯苯甲酰氯(4b)(1.25mL,9.9mmol,1当量)的THF(10mL)溶液。1小时后,加入水和NH4Cl,并且将反应混合物搅拌过夜。水层用醚萃取,合并有机物,在MgSO4上干燥,过滤,并且浓缩。经由层析(80g)纯化,用10至40%EA/己烷洗脱,获得化合物4c(83mg,3%)。1H NMR(互变异构混合物,MeOH-d4)δ:7.67-7.74(m,2H),7.43-7.52(m,2H),4.15-4.28(m,2H),3.06-3.24(m,3H),2.48-2.94(m,2H),1.25-1.35(m,3H)。C15H15ClO4计算值:295.1(M+1);实验值:294.9。
B.80℃下向化合物4c(83mg,0.28mmol,1当量)的乙酸(3mL)溶液中加入2-甲氧基苯肼游离碱(1i)(43mg,0.31mmol,1.1当量)。30分钟后,将溶液浓缩。经由层析(8g)纯化,用10至25%EA/己烷洗脱,获得化合物5(62mg,56%)。1H NMR(氯仿-d)δ:7.31-7.40(m,2H),7.17-7.23(m,2H),7.05-7.10(m,2H),7.01(td,J=7.7,1.3Hz,1H),6.88(dd,J=8.3,1.0Hz,1H),4.22(q,J=7.1Hz,2H),3.72-3.82(m,1H),3.50(s,3H),3.07-3.22(m,4H),1.31(t,J=7.2Hz,3H)。ESI-MS(m/z):C22H21ClN2O3计算值:397.1(M+1);实验值:397.1。
C.向小瓶内的氨基锂(45mg,1.95mmol,13当量)中加入化合物5(60mg,0.15mmol,1当量)的THF(2mL)溶液,并且将悬浮液加热至65℃过夜。加入甲醇、水和1N HCl,并且用乙酸乙酯萃取反应混合物。合并有机物,在MgSO4上干燥,过滤,并且浓缩。经由层析(8g)纯化,用2至5%甲醇/DCM洗脱,获得化合物6(23mg,42%)。1H NMR(氯仿-d)δ:7.31-7.40(m,2H),7.17-7.23(m,2H),7.04-7.09(m,2H),7.01(td,J=7.7,1.3Hz,1H),6.88(dd,J=8.3,1.0Hz,1H),5.66(br.s.,2H),3.61-3.74(m,1H),3.50(s,3H),3.02-3.23(m,4H)。ESI-MS(m/z):C20H18ClN3O2计算值:368.1(M+1);实验值:368.1。
D.rt下向化合物6(22mg,0.06mmol,1当量)的THF溶液中加入LAH(0.18mL 1M的THF溶液,0.18mmol,3当量)。1小时后,加入额外的LAH(0.18mL)。3小时后,加入饱和酒石酸钾钠,搅拌30分钟,并且加入水。反应混合物用醚萃取,在MgSO4上干燥,过滤,并且浓缩。经由层析(8g)纯化,用2至10%甲醇/DCM和NH3(1%)洗脱,获得化合物4d,为所期望产物与失去Cl的产物(5mg,24%)的混合物。
E.向化合物4d(5mg,0.014mmol,1当量)的DCM(2mL)溶液中加入三乙胺(0.01mL,0.07mmol,5当量)和甲磺酰氯(0.006mL,0.07mmol,5当量)。搅拌过夜后,浓缩溶液。经由HPLC纯化,用20至80至100%乙腈/水洗脱,获得化合物8(1mg,17%)。1H NMR(氯仿-d)δ:7.40(dd,J=15.9,1.8Hz,1H),7.32(dd,J=7.8,1.5Hz,1H),7.21-7.25(m,2H),7.05-7.10(m,2H),7.01(td,J=7.6,1.1Hz,1H),6.89-6.94(m,1H),4.46(br.s.,1H),3.55(s,3H),3.32-3.40(m,2H),3.02-3.26(m,2H),3.01(s,3H),2.71(ddd,J=15.4,9.6,5.6Hz,2H)。ESI-MS(m/z):C21H22ClN3O3S计算值:432.1(M+1);实验值:432.1。
F.向化合物6(7mg,0.02mmol,1当量)的DMF(2mL)溶液中加入氰尿酰氯(11mg,0.06mmol,3当量)。1小时后,加入添加的水,并且用DCM萃取反应混合物。有机相在MgSO4上干燥,过滤,并且浓缩。经由HPLC纯化,用20至80至100%乙腈/水洗脱,获得化合物10(2mg,29%)。1H NMR(氯仿-d)δ:7.36-7.42(m,1H),7.34(dd,J=7.7,1.6Hz,1H),7.21-7.26(m,2H),6.99-7.08(m,3H),6.91(dd,J=8.3,1.0Hz,1H),3.75(quin,J=7.9Hz,1H),3.54(s,3H),3.34-3.43(m,1H),3.15-3.34(m,3H)。ESI-MS(m/z):C20H16ClN3O计算值:350.1(M+1);实验值:350.1。
依照对于实例4上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 14:1H NMR(氯仿-d)δ:7.32-7.39(m,1H),7.30(d,J=6.8Hz,1H),7.15-7.25(m,4H),6.99-7.04(m,2H),4.23(q,J=7.2Hz,2H),3.79(quin,J=8.4Hz,1H),3.11-3.25(m,4H),2.36(q,J=7.7Hz,2H),1.32(t,J=7.1Hz,3H),1.00(t,J=7.6Hz,3H)。ESI-MS(m/z):C23H23ClN2O2计算值:395.2(M+1);实验值:395.2。
Cpd 16:1H NMR(氯仿-d)δ:7.50-7.88(m,1H),7.39-7.48(m,1H),7.27-7.36(m,3H),7.18-7.25(m,2H),7.00-7.07(m,2H),2.96-3.46(m,5H),2.56-2.78(m,2H),2.27(br.s.,2H),1.38-1.55(m,9H),0.98(t,J=7.6Hz,3H)。ESI-MS(m/z):C26H30ClN3O2计算值:452.2(M+1);实验值:452.2。
Cpd 17:1H NMR(氯仿-d)δ:7.32-7.39(m,1H),7.30(d,J=6.6Hz,1H),7.15-7.25(m,4H),6.98-7.04(m,2H),4.17-4.29(m,2H),3.15-3.39(m,5H),3.02(ddd,J=15.7,8.5,2.1Hz,2H),2.69(ddd,J=15.6,13.8,6.2Hz,2H),2.36(q,J=7.6Hz,2H),1.12(br.s.,6H),1.00(t,J=7.6Hz,3H)。ESI-MS(m/z):C26H30ClN3O2计算值:452.2(M+1);实验值:452.2。
Cpd 18:1H NMR(氯仿-d)δ:7.36(td,J=7.3,1.8Hz,1H),7.30(d,J=6.6Hz,1H),7.16-7.25(m,4H),6.97-7.04(m,2H),4.49(t,J=6.3Hz,1H),3.36(t,J=6.7Hz,2H),3.12-3.24(m,1H),3.02-3.11(m,2H),3.00(s,3H),2.65(ddd,J=22.4,15.8,6.1Hz,2H),2.35(q,J=7.6Hz,2H),1.00(t,J=7.6Hz,3H)。ESI-MS(m/z):C22H24ClN3O2S计算值:430.1(M+1);实验值:430.1。
Cpd 19:1H NMR(氯仿-d)δ:7.33-7.40(m,1H),7.28-7.33(m,1H),7.14-7.25(m,4H),6.96-7.04(m,2H),6.69(br.s.,1H),3.57(tq,J=13.1,6.7Hz,2H),3.14-3.26(m,1H),3.05(ddd,J=15.5,8.1,2.9Hz,2H),2.61(ddd,J=15.3,9.2,5.8Hz,2H),2.35(q,J=7.6Hz,2H),1.00(t,J=7.6Hz,3H)。ESI-MS(m/z):C23H21ClF3N3O计算值:448.1(M+1);实验值:448.1。
实例5
A.-45℃和Ar下向三甲基甲硅烷基乙炔(5a)(1.41mL,10.14mmol,1.1当量)的甲苯(24mL)溶液中加入n-BuLi(4.06mL 2.5M的己烷溶液,10.14mmol,1.1当量)。形成悬浮液,并且在10分钟后,使混合物升紊至0℃。10分钟后,加入二乙基氯化铝(10.14mL 1M的己烷溶液,10.14mmol,1.1当量)。1小时后,加入乙酸(R)-乙基环氧乙烷基酯(5b)(1.0mL,9.22mmol,1当量)的甲苯(10mL)溶液,并且将混合物在0℃下搅拌1小时。0℃下向悬浮液中滴加3mL饱和NH4Cl,然后滴加4mL 1N HCl,以沉淀铝盐。搅拌过夜后,将悬浮液过滤通过硅藻土,用乙酸乙酯洗涤。滤液用盐水洗涤,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(40g)纯化,用10至20%EA/己烷洗脱,获得化合物5c(1.28g,61%)。1H NMR(氯仿-d)δ:4.11-4.24(m,3H),3.03(d,J=4.5Hz,1H),2.63-2.72(m,1H),2.41-2.59(m,3H),1.29(t,J=7.2Hz,3H),0.16(s,9H)。
B.0℃下向化合物5c(1.28g,5.58mmol,1当量)的DCM(20mL)溶液中,加入二异丙基乙胺(1.36mL,7.82mmol,1.4当量),然后加入三氟甲磺酸三异丙基甲硅烷基酯(1.81mL,6.7mmol,1.2当量)。加入水后,反应混合物用DCM萃取,在MgSO4上干燥,过滤,并且浓缩获得化合物5d。向化合物5d的乙醇(20mL)溶液中,加入1N NaOH(10mL),并且将反应加热至50℃过夜,然后在80℃下再加热4小时。反应混合物通过加入1NHCl来酸化。移除乙醇,含水混合物用DCM萃取,合并有机物,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(80g)纯化,用0至40%EA/己烷洗脱,获得化合物5e(1.51g,95%)。1H NMR(氯仿-d)δ:4.37-4.45(m,1H),2.83(dd,J=15.4,5.3Hz,1H),2.68(dd,J=15.5,5.9Hz,1H),2.51-2.56(m,2H),2.03-2.05(m,1H),1.03-1.10(m,21H)。
C.rt下向化合物5e(1100mg,3.87mmol,1当量)的丙酮(20mL)溶液中,加入硝酸银(66mg,0.39mmol,0.1当量),然后加入N-溴代琥珀酰亚胺(757mg,4.25mmol,1.1当量)。3小时后,依序将水和1N HCl加入到溶液中。将所得沉淀溶于DCM中,用水洗涤,并且将有机相干燥,过滤,并且浓缩,获得化合物5f(1.53g,~90%纯,98%收率)。1H NMR(氯仿-d)δ:4.39(t,J=5.9Hz,1H),2.59-2.84(m,3H),2.54(d,J=6.1Hz,1H),0.96-1.15(m,21H)。
D.rt和Ar下向化合物5f(1.53g,3.79mmol,1当量)的DCM(20mL)溶液中加入N-甲基吗啉(0.44mL,3.98mmol,1.05当量),然后加入氯甲酸异丁酯(0.52mL,3.98mmol,1.05当量)。20分钟后,加入化合物1i-HCl(794mg,4.55mmol,1.2当量)和N-甲基吗啉(0.50mL,4.55mmol,1.2当量)的DCM(10mL)溶液,并且将溶液搅拌60分钟。依序加入水和1NHCl,反应混合物用DCM萃取,合并有机物,用NaHCO3和盐水洗涤,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(80g)纯化,用10至20至25%EA/己烷洗脱,获得化合物5g(1.42g,78%)。ESI-MS(m/z):C22H35BrN2O3Si计算值:483.2(M+1);实验值:483.0。
E.在配备有顶置式搅拌器、加热架、隔膜和温度探头的1L 3颈圆底烧瓶中,加入(S)-6-溴-N′-(2-甲氧基苯基)-3-(三异丙基甲硅氧基)己烷-5-炔酰肼(5g)(26.27g,54.3mmol,1当量)、乙腈(550mL)和四氯化碳(21.0mL,217mmol,4当量)。在室温下加入一部分聚合物结合的三苯基膦(3mmol/g P,73.6g,221mmol,4当量),并且将悬浮液搅拌1小时。聚合物颜色保持褐色(未变化),并且经由TLC(30%EtOAc的庚烷溶液)检测无反应。将反应加热至50℃保持30分钟,然后使反应在1小时内冷却至室温,过滤通过硅胶(150g),并且用乙腈(600mL)洗涤,由此白色物质通过滤垫。过滤并且蒸发后,收集到仍浑浊的橙色油;加入EtOAc(100mL),用Na2SO4干燥,过滤并且蒸发,提供橙色油状化合物5h(21g),收率75%。粗产物无需进一步纯化即可进入下一反应。1H NMR(氯仿-d)δ:8.07(s,1H),7.32(d,J=7.6Hz,1H),6.92(dt,J=8.2,4.2Hz,1H),6.84(d,J=3.7Hz,2H),4.39(quin,J=5.8Hz,1H),3.89(s,3H),2.85-3.00(m,2H),2.46-2.60(m,2H),1.01-1.12(m,21H)。ESI-MS(m/z):C22H34BrClN2O2Si计算值:464.1(M-36);实验值:464.3。
F.将化合物5h(385mg,0.77mmol,1当量)和三乙胺(0.43mL,3.07mmol,4当量)的二氧杂环己烷(10mL)溶液在90℃下加热20小时。将水加入到反应混合物中,混合物用DCM萃取,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(40g)纯化,用5至10%EA/己烷洗脱,获得化合物5i(300mg,65%)。1H NMR(氯仿-d)δ:7.42(td,J=8.0,1.8Hz,1H),7.28-7.34(m,1H),6.99-7.06(m,2H),5.05(t,J=6.2Hz,1H),3.82(s,3H),3.18(dd,J=15.7,7.3Hz,1H),3.04(dd,J=15.0,7.2Hz,1H),2.83(dd,J=15.8,6.2Hz,1H),2.66(dd,J=15.0,5.9Hz,1H),1.05-1.18(m,21H)。ESI-MS(m/z):C22H33BrN2O2Si计算值:465.2(M+1);实验值:465.2。
F.向化合物5i(197mg,0.42mmol,1当量)的二氧杂环己烷(5mL)溶液中,加入1NHCl(1mL),并且将反应加热至80℃保持3小时。溶液用DCM萃取,在MgSO4上干燥,过滤,并且浓缩,获得化合物5j(124mg,95%)。1H NMR(氯仿-d)δ:7.43(t,J=7.9Hz,1H),7.32(d,J=7.3Hz,1H),7.00-7.08(m,2H),4.94-5.04(m,1H),3.83(s,3H),3.21(dd,J=16.3,6.5Hz,1H),3.08(dd,J=15.6,6.4Hz,1H),2.82(dd,J=16.4,3.9Hz,1H),2.66(dd,J=15.7,3.7Hz,1H),1.97(d,J=6.1Hz,1H)。ESI-MS(m/z):C13H13BrN2O2计算值:309.2(M+1);实验值:309.0。
G.向4-氯苯基硼酸(5k)(76mg,0.49mmol,1.5当量)的二甲氧基乙烷(1mL)溶液中,加入2M Na2CO3(0.1mL)、化合物5j(100mg,0.32mmol,1当量)和(Ph3P)4Pd(19mg,0.016mmol,0.05当量)。通过使氩气鼓泡通过溶液将所述溶液脱气,然后加热至85℃保持3天。将水和盐水加入到反应混合物中,然后用乙酸乙酯萃取。合并的有机相在MgSO4上干燥,过滤,并且浓缩。经由柱层析(12g)纯化,用50至100%EA/己烷洗脱,获得化合物51(80mg,71%)。1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.31-7.37(m,1H),7.17-7.25(m,J=8.3Hz,2H),7.05-7.11(m,J=8.3Hz,2H),7.02(td,J=7.6,1.1Hz,1H),6.88(d,J=8.1Hz,1H),4.97-5.11(m,1H),3.49(s,3H),3.14-3.29(m,2H),2.70-2.90(m,2H),2.08(d,J=5.3Hz,1H)。ESI-MS(m/z):C19H17ClN2O2计算值:341.1(M+1);实验值:341.2。
实例6
A.根据实例5中所述的方法制备化合物25,用(2-(三氟甲氧基)苯基)肼替代步骤D中的化合物1i。
B.向化合物25(22mg,0.056mmol,1当量)的THF(1.5mL)溶液中,加入NaHMDS(0.28mL 1M的THF溶液,0.28mmol,5当量),然后加入二甲基氨基甲酰氯(0.026mL,0.28mmol,5当量)。2小时后,加入饱和NH4Cl,并且将溶液倒在填充有硅藻土的5mL萃取管上,用DCM洗涤,干燥,过滤,并且浓缩。经由层析(8g)纯化,用20至40%EA/己烷洗脱,获得化合物23(14.9mg,57%)。1H NMR(氯仿-d)δ:7.52-7.58(m,1H),7.33-7.46(m,2H),7.19-7.28(m,3H),7.01-7.08(m,2H),5.77(tt,J=7.2,3.6Hz,1H),3.25-3.37(m,2H),2.83-3.01(m,8H)。ESI-MS(m/z):C22H19ClF3N3O3计算值:466.1(M+1);实验值:466.1。
依照对于上文实例6上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 24:1H NMR(氯仿-d)δ:7.55(dd,J=7.5,1.9Hz,1H),7.34-7.46(m,2H),7.20-7.29(m,3H),7.00-7.07(m,2H),5.80(tt,J=7.0,3.7Hz,1H),3.40-3.76(m,8H),3.33(dd,J=16.7,7.1Hz,2H),2.84-3.00(m,2H)。ESI-MS(m/z):C24H21ClF3N3O4计算值:508.1(M+1);实验值:508.1。
Cpd 28:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.35(td,J=8.0,1.8Hz,1H),7.17-7.22(m,2H),7.05-7.10(m,2H),7.02(td,J=7.6,1.3Hz,1H),6.89(dd,J=8.3,1.0Hz,1H),5.73-5.80(m,1H),3.50(s,3H),3.29-3.39(m,2H),2.84-3.00(m,8H)。ESI-MS(m/z):C22H22ClN3O3计算值:412.1(M+1);实验值:412.1。
Cpd 29:1H NMR(氯仿-d)δ:7.32-7.42(m,2H),7.17-7.23(m,2H),7.05-7.10(m,2H),7.02(td,J=7.7,1.3Hz,1H),6.90(dd,J=8.3,1.0Hz,1H),5.80(dt,J=7.3,3.6Hz,1H),3.66(br.s.,4H),3.50(s,7H),3.29-3.40(m,2H),2.85-3.01(m,2H)。ESI-MS(m/z):C24H24ClN3O4计算值:454.2(M+1);实验值:454.2。
Cpd 30:1H NMR(氯仿-d)δ:7.49(dd,J=7.8,1.8Hz,1H),7.32(td,J=8.0,1.8Hz,1H),7.16-7.23(m,2H),7.06-7.13(m,2H),7.04(td,J=7.6,1.1Hz,1H),6.80-6.86(m,1H),5.72-5.81(m,1H),3.71(br.s.,2H),3.33(dd,J=16.5,7.2Hz,2H),2.80-3.02(m,8H),0.98(t,J=6.9Hz,3H)。ESI-MS(m/z):C23H24ClN3O3计算值:426.2(M+1);实验值:426.2。
Cpd 31:1H NMR(氯仿-d)δ:7.49(dd,J=7.8,1.5Hz,1H),7.33(td,J=7.9,1.6Hz,1H),7.16-7.23(m,2H),7.06-7.11(m,2H),7.04(td,J=7.6,1.1Hz,1H),6.80-6.87(m,1H),5.80(tt,J=7.1,3.8Hz,1H),3.57-3.91(m,6H),3.49(br.s.,4H),3.27-3.42(m,2H),2.81-3.02(m,2H),0.98(t,J=7.1Hz,3H)。ESI-MS(m/z):C25H26ClN3O4计算值:468.2(M+1);实验值:468.2。
实例7
A.根据实例5中所述的方法,替换适当的外消旋原料,制备化合物26。
B.rt下向化合物26(200mg,0.53mmol,1当量)的DCM(5mL)溶液中,加入三乙胺(0.15mL,1.06mmol,2当量),然后加入甲磺酰氯(0.062mL,0.79mmol,1.5当量)。搅拌2小时后,加入DCM。有机相用水洗涤,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(24g)纯化,用30至60%EA/己烷洗脱,获得化合物7a(230mg,99%)。1H NMR(氯仿-d)δ:7.32-7.41(m,2H),7.19-7.24(m,2H),6.99-7.09(m,3H),6.89(d,J=8.3Hz,1H),5.73-5.83(m,1H),3.50(s,3H),3.38(ddd,J=16.5,6.8,3.8Hz,2H),3.15(dt,J=16.5,4.4Hz,2H),3.08(s,3H)。ESI-MS(m/z):C20H19ClN2O4S计算值:419.1(M+1);实验值:419.1。
C.rt下向化合物7a(220mg,0.53mmol,1当量)的DMF(5mL)溶液中,加入叠氮化钠(52mg,0.79mmol,1.5当量),并且将溶液升温至100℃。1小时后使反应冷却,加入水,并且用DCM萃取水相。合并的有机相在MgSO4上干燥,过滤,并且浓缩,获得化合物7b(184mg,95%)。1H NMR(氯仿-d)δ:7.31-7.42(m,2H),7.22(d,J=8.6Hz,2H),6.99-7.10(m,3H),6.88(d,J=7.8Hz,1H),4.61-4.73(m,1H),3.50(s,3H),3.16-3.30(m,2H),2.83-2.98(m,2H)。ESI-MS(m/z):C19H16ClN5O计算值:366.1(M+1);实验值:366.1。
D.在氢气酚下向化合物7b(184mg,0.50mmol)的乙酸乙酯(10mL)和乙醇(5mL)溶液中,加入10%Pd/C(50mg)。16小时后,使悬浮液过滤通过硅藻土,用EA洗涤、干燥并且浓缩,获得化合物7c(164mg,96%)。1H NMR(氯仿-d)δ:7.38(dd,J=7.8,1.8Hz,1H),7.31-7.37(m,1H),7.17-7.23(m,2H),7.05-7.10(m,2H),6.97-7.04(m,1H),6.88(d,J=8.3Hz,1H),4.23(quin,J=6.4Hz,1H),3.49(s,3H),3.19(td,J=15.9,7.1Hz,2H),2.51-2.67(m,2H)。ESI-MS(m/z):C19H18ClN3O计算值:340.1(M+1);实验值:340.1。
E.向化合物7c(29mg,0.084mmol,1当量)的DCM(1mL)溶液中,加入三乙胺(0.035mL,0.25mmol,3当量)和甲磺酰氯(0.013mL,0.17mmol,2当量)。2小时后,加入饱和NaHCO3,将反应混合物倒入到填充有硅藻土的5mL萃取管上,用DCM洗涤,并且浓缩。经由层析(8g)纯化,用40至100%EA/己烷洗脱,获得化合物32(33mg,94%)。1H NMR(氯仿-d)δ:7.32-7.40(m,2H),7.18-7.24(m,2H),6.98-7.08(m,3H),6.88(d,J=8.3Hz,1H),5.04(d,J=9.1Hz,1H),4.59-4.72(m,1H),3.50(s,3H),3.27-3.39(m,2H),3.04(s,3H),2.74-2.87(m,2H)。ESI-MS(m/z):C20H20ClN3O3S计算值:418.1(M+1);实验值:418.1。
依照对于上文实例7上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 33:1H NMR(氯仿-d)δ:7.32-7.40(m,2H),7.18-7.24(m,2H),6.99-7.08(m,3H),6.89(d,J=8.3Hz,1H),4.58-4.70(m,1H),4.52(d,J=9.9Hz,1H),3.50(s,3H),3.28-3.39(m,2H),3.22(quin,J=6.9Hz,1H),2.76-2.86(m,2H),1.42(dd,J=6.8,1.3Hz,6H)。ESI-MS(m/z):C22H24ClN3O3S计算值:446.1(M+1);实验值:446.1。
Cpd 34:1H NMR(氯仿-d)δ:7.31-7.39(m,2H),7.18-7.24(m,2H),6.99-7.08(m,3H),6.88(d,J=8.3Hz,1H),4.81(d,J=9.3Hz,1H),4.48-4.61(m,1H),3.49(s,3H),3.30(dd,J=15.9,7.8Hz,2H),2.75-2.87(m,8H)。ESI-MS(m/z):C21H23ClN4O3S计算值:447.1(M+1);实验值:447.1。
Cpd 44:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.23-7.29(m,1H),7.11-7.16(m,2H),6.93-7.03(m,3H),6.77(d,J=7.3Hz,1H),4.50-4.64(m,1H),4.39(d,J=9.3Hz,1H),3.64(br.s.,2H),3.27(dd,J=15.9,7.8Hz,2H),3.15(quin,J=6.8Hz,1H),2.66-2.82(m,2H),1.36(dd,J=6.8,1.3Hz,6H),0.92(t,J=6.9Hz,3H)。ESI-MS(m/z):C23H26ClN3O3S计算值:460.1(M+1);实验值:460.1。
Cpd 45:1H NMR(氯仿-d)δ:7.41(dd,J=7.7,1.6Hz,1H),7.24-7.31(m,1H),7.12-7.17(m,2H),6.94-7.03(m,3H),6.78(d,J=7.6Hz,1H),6.61(br.s.,1H),5.07(d,J=7.6Hz,1H),3.66(br.s.,2H),3.23-3.43(m,2H),2.65-2.80(m,2H),0.92(t,J=7.1Hz,3H)。ESI-MS(m/z):C22H19C1F3N3O2计算值:450.1(M+1);实验值:450.1。
Cpd 47:1H NMR(氯仿-d)δ:7.46(dd,J=7.7,1.6Hz,1H),7.33(td,J=7.8,1.8Hz,1H),7.18-7.23(m,2H),7.00-7.10(m,3H),6.84(dd,J=8.3,1.0Hz,1H),4.53(br.s.,2H),3.55-3.88(m,2H),3.26-3.38(m,2H),2.76-2.88(m,8H),0.99(t,J=6.9Hz,3H)。ESI-MS(m/z):C22H25ClN4O3S计算值:461.1(M+1);实验值:461.1。
实例8
向化合物32(21mg,0.05mmol,1当量)的THF(2mL)溶液中,加入NaHMDS(0.3mL 1M的THF溶液,0.3mmol,6当量),然后加入碘甲烷(0.019mL,0.3mmol,6当量)。搅拌过夜后,加入NH4Cl,将溶液倒在填充有硅藻土的5mL萃取管上,用DCM洗涤,并且浓缩。经由层析(8g)纯化,用35至70%EA/己烷洗脱,获得化合物37(8.2mg,38%)。1H NMR(氯仿-d)δ:7.31-7.42(m,2H),7.19-7.24(m,2H),6.99-7.10(m,3H),6.89(d,J=8.3Hz,1H),5.21-5.31(m,1H),3.50(s,3H),3.15(dd,J=16.0,8.7Hz,2H),2.84-3.02(m,8H)。ESI-MS(m/z):C21H22ClN3O3S计算值:432.1(M+1);实验值:432.1。
依照对于实例8上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 46:1H NMR(氯仿-d)δ:7.48(dd,J=7.8,1.5Hz,1H),7.30-7.37(m,1H),7.17-7.24(m,2H),7.07-7.12(m,J=8.6Hz,2H),7.04(td,J=7.6,1.0Hz,1H),6.84(d,J=7.6Hz,1H),5.13(br.s.,1H),3.71(br.s.,2H),3.07-3.22(m,2H),2.90-3.04(m,2H),2.84(s,9H),0.99(t,J=6.9Hz,3H)。ESI-MS(m/z):C23H27ClN4O3S计算值:475.2(M+1);实验值:475.2。
Cpd 48:1H NMR(氯仿-d)δ:7.47(dd,J=7.7,1.6Hz,1H),7.29-7.36(m,1H),7.18-7.24(m,2H),7.06-7.11(m,2H),7.04(td,J=7.7,1.3Hz,1H),6.83(dd,J=8.3,1.0Hz,1H),5.06-5.18(m,1H),3.70(br.s.,2H),3.08-3.21(m,2H),2.90-3.03(m,2H),2.84(s,9H),0.99(t,J=6.9Hz,3H)。ESI-MS(m/z):C23H27ClN4O3S计算值:475.2(M+1);实验值:475.2。
Cpd 50:1H NMR(氯仿-d)δ:7.21-7.26(m,2H),7.18(dd,J=7.3,1.0Hz,1H),7.09-7.15(m,2H),6.99-7.05(m,1H),6.81-6.87(m,1H),5.05-5.16(m,1H),4.43(t,J=8.7Hz,2H),3.21(t,J=8.7Hz,2H),3.13(ddd,J=15.9,11.2,8.5Hz,2H),2.89-3.01(m,2H),2.80-2.85(m,9H)。ESI-MS(m/z):C23H25ClN4O3S计算值:473.1(M+1);实验值:473.1。
Cpd 51:1H NMR(氯仿-d)δ:7.22-7.26(m,2H),7.16-7.21(m,1H),7.09-7.15(m,2H),7.02(d,J=7.8Hz,1H),6.84(t,J=7.7Hz,1H),5.11-5.23(m,1H),4.43(t,J=8.7Hz,2H),3.07-3.28(m,5H),2.90-3.05(m,5H),1.39(d,J=6.8Hz,6H)。ESI-MS(m/z):C24H26ClN3O3S计算值:472.1(M+1);实验值:472.1。
Cpd 57:1H NMR(氯仿-d)δ:8.03(d,J=2.3Hz,1H),7.32-7.41(m,2H),7.24-7.32(m,1H),7.02(td,J=7.6,1.1Hz,1H),6.91(d,J=8.6Hz,1H),6.61(d,J=8.8Hz,1H),5.13(t,J=7.7Hz,1H),3.90(s,3H),3.56(s,3H),3.14(dt,J=16.0,7.9Hz,2H),2.89-3.04(m,2H),2.85(s,3H),2.83(s,6H)。ESI-MS(m/z):C22H27N5O4S计算值:458.2(M+1);实验值:458.2。
Cpd 58:1H NMR(氯仿-d)δ:8.01(d,J=2.5Hz,1H),7.31-7.39(m,2H),7.22-7.26(m,1H),7.01(td,J=7.6,1.1Hz,1H),6.91(dd,J=8.8,1.0Hz,1H),6.53(d,J=8.6Hz,1H),5.24(quin,J=6.2Hz,1H),5.12(t,J=7.8Hz,1H),3.56(s,3H),3.07-3.19(m,2H),2.87-3.03(m,2H),2.85(s,3H),2.83(s,6H),1.31(d,J=6.1Hz,6H)。ESI-MS(m/z):C24H31N5O4S计算值:486.2(M+1);实验值:486.2。
实例9
A.依照实例5和7中所述的方法,替换本领域技术人员已知的适当试剂、原料和纯化方法,制备化合物9a。
B.向化合物9a(21mg,0.06mmol,1当量)的甲苯(1mL)溶液中,加入三乙胺(0.05mL,0.36mmol,6当量)和琥珀酸酐(7mg,0.066mmol,1.1当量),并且将反应混合物在110℃下搅拌3天。使溶液浓缩。经由层析(8g)纯化,用40至100%EA/己烷洗脱,获得化合物38(19.3mg,74%)。1H NMR(氯仿-d)δ:7.49(dd,J=7.8,1.8Hz,1H),7.32(td,J=8.0,1.8Hz,1H),7.15-7.23(m,2H),7.07(d,J=8.6Hz,2H),7.03(td,J=7.6,1.3Hz,1H),6.83(dd,J=8.3,1.0Hz,1H),5.27-5.44(m,1H),3.71(br.s.,2H),3.43(dd,J=14.8,9.5Hz,2H),3.06(dd,J=15.2,9.1Hz,2H),2.75(s,4H),1.01(t,J=6.9Hz,3H)。ESI-MS(m/z):C24H22ClN3O3计算值:436.1(M+1);实验值:436.1。
实例10
向化合物9a(21mg,0.06mmol,1当量)的氯仿(1mL)溶液中,加入4-氯丁基氯(0.014mL,0.12mmol,2当量)和20%碳酸钾水溶液(1mL)。3小时后,将反应混合物倒入到填充有硅藻土的5mL萃取管上,用DCM洗涤,并且浓缩。向小瓶内的该中间体的THF(2mL)溶液中,加入NaHMDS(0.3mL 1M的THF溶液,0.3mmol,5当量),并且将溶液升温至65℃。4小时后,加入NH4Cl,将溶液倒在填充有硅藻土的5mL萃取管上,用DCM洗涤,并且浓缩。经由层析(8g)纯化,用EA洗脱,获得化合物40(3.2mg,13%)。1H NMR(氯仿-d)δ:7.49(dd,J=7.8,1.8Hz,1H),7.30-7.36(m,1H),7.18-7.23(m,2H),7.06-7.11(m,2H),7.04(td,J=7.7,1.3Hz,1H),6.80-6.86(m,1H),5.40-5.52(m,1H),3.71(br.s.,2H),3.26-3.47(m,2H),3.05-3.22(m,2H),2.85(dd,J=16.0,6.2Hz,2H),2.38-2.47(m,2H),1.98-2.10(m,2H),0.99(t,J=6.9Hz,3H)。ESI-MS(m/z):C24H24ClN3O2计算值:422.2(M+1);实验值:422.2。
实例11
A.根据实例5中所述的方法,用乙酸(S)-乙基环氧乙烷基酯替换步骤A中的乙酸(R)-乙基环氧乙烷基酯(5b),并且用4-氰基苯基硼酸替换步骤G中的cpd 5k,制备化合物11a。
B.根据实例7步骤B和C中所述的方法,用化合物11a替换化合物26,制备化合物11b。
C.向化合物11b(25mg,0.07mmol,1当量)的THF(1mL)溶液中,加入4-甲基-1-戊炔(11c)(0.011mL,0.11mmol,1.5当量)、CuI(7mg,0.035mmol,0.5当量)和二异丙基乙胺(0.06mL,0.35mmol,5当量),并且将悬浮液在rt下搅拌过夜。加入DCM,并且将溶液滗出并且浓缩。经由柱层析(8g),在40至80%EA/己烷中纯化,获得化合物128。1H NMR(氯仿-d)δ:7.54(d,J=8.3Hz,2H),7.45(dd,J=7.7,1.6Hz,1H),7.38-7.43(m,1H),7.36(s,1H),7.25(d,J=8.3Hz,2H),7.08(t,J=7.7Hz,1H),6.91(d,J=8.3Hz,1H),5.77-5.88(m,1H),3.59(dt,J=16.3,8.3Hz,2H),3.49(s,3H),3.32(dd,J=16.3,6.2Hz,2H),2.60(d,J=7.1Hz,2H),1.91-2.03(m,1H),0.95(d,J=6.6Hz,6H)。ESI-MS(m/z):C26H26N6O计算值:439.2(M+1);实验值:439.2。
依照对于实例11上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 41:1H NMR(氯仿-d)δ:7.60(s,1H),7.51(dd,J=7.7,1.6Hz,1H),7.36(td,J=7.9,1.6Hz,1H),7.18-7.24(m,2H),7.02-7.12(m,3H),6.86(d,J=7.6Hz,1H),5.91(t,J=6.7Hz,1H),3.44-3.90(m,4H),3.30(dd,J=16.2,6.1Hz,2H),1.02(t,J=6.9Hz,3H),0.32(s,9H)。ESI-MS(m/z):C25H28ClN5OSi计算值:478.2(M+1);实验值:478.2。
Cpd 42:1H NMR(氯仿-d)δ:7.73(s,1H),7.64(s,1H),7.51(dd,J=7.7,1.6Hz,1H),7.32-7.40(m,1H),7.18-7.25(m,2H),7.02-7.12(m,3H),6.86(d,J=8.3Hz,1H),5.84-5.98(m,1H),3.43-3.92(m,4H),3.29(dd,J=16.0,5.4Hz,2H),1.02(t,J=6.9Hz,3H)。ESI-MS(m/z):C22H20ClN5O计算值:406.1(M+1);实验值:406.1。
Cpd 124:1H NMR(氯仿-d)δ:7.54(d,J=8.3Hz,2H),7.45(d,J=7.6Hz,1H),7.38-7.44(m,1H),7.35(s,1H),7.25(d,J=8.3Hz,2H),7.08(t,J=7.6Hz,1H),6.91(d,J=8.1Hz,1H),5.82(quin,J=7.1Hz,1H),3.58(dt,J=16.2,8.2Hz,2H),3.49(s,3H),3.32(dd,J=16.2,6.3Hz,2H),3.19(quin,J=8.0Hz,1H),2.05-2.18(m,2H),1.60-1.84(m,6H)。ESI-MS(m/z):C27H26N6O计算值:451.2(M+1);实验值:451.2。
Cpd 125:1H NMR(氯仿-d)δ:8.18(s,1H),7.55(d,J=8.3Hz,2H),7.47(d,J=7.6Hz,1H),7.38-7.45(m,1H),7.24(d,J=8.3Hz,2H),7.09(t,J=7.6Hz,1H),6.92(d,J=8.3Hz,1H),5.86-5.97(m,1H),3.96(s,3H),3.57-3.72(m,2H),3.50(s,3H),3.21-3.37(m,2H)。ESI-MS(m/z):C24H20N6O3计算值:441.2(M+1);实验值:441.2。
Cpd 128:1H NMR(氯仿-d)δ:7.71(s,1H),7.51-7.57(m,2H),7.46(dd,J=7.8,1.7Hz,1H),7.38-7.44(m,1H),7.22-7.27(m,2H),7.04-7.11(m,1H),6.88-6.94(m,1H),5.77-5.89(m,1H),5.22(s,2H),3.54-3.67(m,2H),3.49(s,3H),3.27-3.39(m,2H),2.08(s,3H)。ESI-MS(m/z):C25H22N6O3计算值:455.2(M+1);实验值:455.2。
Cpd 130:1H NMR(氯仿-d)δ:7.51-7.56(m,2H),7.45(dd,J=7.7,1.6Hz,1H),7.41(td,J=7.9,1.7Hz,1H),7.35(s,1H),7.25(d,J=8.6Hz,2H),7.08(td,J=7.6,1.1Hz,1H),6.89-6.94(m,1H),5.76-5.87(m,1H),3.58(dt,J=16.5,8.4Hz,2H),3.49(s,3H),3.28-3.39(m,2H),1.36(s,9H)。ESI-MS(m/z):C26H26N6O计算值:439.2(M+1);实验值:439.2。
Cpd 136:1H NMR(氯仿-d)δ:7.53(d,J=8.6Hz,2H),7.44(dd,J=7.7,1.6Hz,1H),7.40(td,J=7.8,1.7Hz,1H),7.22-7.26(m,2H),7.07(td,J=7.6,1.1Hz,1H),6.90(d,J=8.3Hz,1H),5.50(t,J=8.2Hz,1H),3.54-3.72(m,2H),3.50(s,3H),3.34-3.49(m,2H),2.70(dq,J=10.5,7.7Hz,4H),1.31(t,J=7.6Hz,3H),1.23(t,J=7.7Hz,3H)。ESI-MS(m/z):C26H26N6O计算值:439.2(M+1);实验值:439.2。
实例12
A.根据实例7步骤D,用化合物11b替换化合物7b,制备化合物12a。
B.将小瓶内化合物12a(25mg,0.07mmol,1当量)、乙酸铵(22mg,0.29mmol,4当量)、丙醛(0.021mL,0.29mmol,1当量)和乙二醛(0.033mL 40%的水溶液,0.29mL,1当量)的甲醇(1mL)溶液加热至80℃过夜。使溶液浓缩。经由HPLC纯化,用5至60%ACN/H2O洗脱,获得化合物134(16.3mg,51%)。1H NMR(氯仿-d)δ:7.54(d,J=8.3Hz,2H),7.45(dd,J=7.8,1.7Hz,1H),7.41(td,J=7.9,1.6Hz,1H),7.24(d,J=8.3Hz,2H),7.08(t,J=7.6Hz,1H),7.01(s,1H),6.98(s,1H),6.91(d,J=8.1Hz,1H),5.32-5.43(m,1H),3.38-3.52(m,5H),3.01-3.18(m,2H),2.83(q,J=7.6Hz,2H),1.93-2.39(m,2H),1.39(t,J=7.6Hz,2H)。ESI-MS(m/z):C25H23N5O计算值:410.2(M+1);实验值:410.2。
依照对于实例12上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 39:1H NMR(氯仿-d)δ:7.63(s,1H),7.50(dd,J=7.7,1.6Hz,1H),7.32-7.39(m,1H),7.18-7.25(m,2H),7.00-7.12(m,5H),6.82-6.88(m,1H),5.35(quin,J=6.6Hz,1H),3.76(br.s.,2H),3.50(dd,J=16.2,8.1Hz,2H),3.15(dd,J=15.9,5.8Hz,2H),1.02(t,J=7.1Hz,3H)。ESI-MS(m/z):C23H21ClN4O计算值:405.1(M+1);实验值:405.1。
Cpd 43:1H NMR(氯仿-d)δ:7.66(s,1H),7.50(dd,J=7.8,1.5Hz,1H),7.31-7.40(m,1H),7.18-7.25(m,2H),7.00-7.14(m,5H),6.86(d,J=8.3Hz,1H),5.28-5.43(m,1H),3.74(br.s.,2H),3.37-3.57(m,2H),3.00-3.23(m,2H),1.03(t,J=6.9Hz,3H)。ESI-MS(m/z):C23H21ClN4O计算值:405.1(M+1);实验值:405.1。
Cpd 131:1H NMR(氯仿-d)δ:7.53(d,J=8.3Hz,3H),7.45(d,J=7.6Hz,1H),7.40(t,J=8.0Hz,1H),7.23(d,J=8.3Hz,2H),7.07(t,J=7.6Hz,1H),6.90(d,J=8.3Hz,1H),5.20(quin,J=6.8Hz,1H),3.36-3.54(m,5H),3.01-3.22(m,2H),2.21(s,3H),2.17(s,3H)。ESI-MS(m/z):C25H23N5O计算值:410.2(M+1);实验值:410.2。
Cpd 138:1H NMR(氯仿-d)δ:7.54(d,J=8.1Hz,2H),7.46(d,J=7.8Hz,1H),7.41(t,J=8.0Hz,1H),7.20-7.26(m,2H),7.08(t,J=7.6Hz,1H),6.92(d,J=8.3Hz,1H),5.39(m,J=8.3Hz,1H),3.34-3.52(m,5H),3.15-3.32(m,2H),2.60(q,J=7.4Hz,2H),2.51(q,J=7.4Hz,2H),2.45(s,3H),1.22(t,J=7.6Hz,3H),1.16(t,J=7.5Hz,3H)。ESI-MS(m/z):C28H29N5O计算值:452.2(M+1);实验值:452.2。
Cpd 139:1H NMR(氯仿-d)δ:7.58(s,1H),7.50-7.56(m,J=8.3Hz,2H),7.45(dd,J=7.7,1.6Hz,1H),7.37-7.43(m,1H),7.20-7.26(m,J=8.3Hz,2H),7.08(td,J=7.6,1.1Hz,1H),6.91(d,J=7.6Hz,1H),5.16-5.27(m,1H),3.40-3.55(m,5H),3.03-3.22(m,2H),2.64(q,J=7.5Hz,2H),2.55(q,J=7.6Hz,2H),1.24(t,J=7.6Hz,3H),1.19(t,J=7.6Hz,3H)。ESI-MS(m/z):C27H27N5O计算值:438.2(M+1);实验值:438.2。
实例13
A.根据实例5中所述的方法,用乙酸(S)-乙基环氧乙烷基酯替换步骤A中的乙酸(R)-乙基环氧乙烷基酯(5b),制备化合物13a。
B.rt下向化合物13a(10mg,0.026mmol,1当量)的THF(1mL)和DMF(0.5mL)溶液中,加入NaHMDS(0.13mL 1M的THF溶液,0.13mmol,5当量),然后加入碘甲烷(0.016mL,0.26mmol,10当量)。1小时后,加入水,并且将溶液倒在填充有硅藻土的5mL萃取管上,然后加入DCM,并且将有机相浓缩。经由柱层析(8g)纯化,用25至50%EA/己烷洗脱,获得化合物49(7.2mg,73%)。1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.18-7.23(m,2H),7.04-7.10(m,2H),7.01(td,J=7.6,1.0Hz,1H),6.87(d,J=8.3Hz,1H),4.54-4.64(m,1H),3.48(s,3H),3.43(s,3H),3.11-3.23(m,2H),2.78-2.94(m,2H)。ESI-MS(m/z):C20H19ClN2O2计算值:355.1(M+1);实验值:355.1。
依照对于实例13上述的方法,并且替换适当的试剂、原料和本领域技术人员已知的纯化方法,制备以下化合物:
Cpd 69:1H NMR(氯仿-d)δ:7.30-7.42(m,2H),7.18-7.24(m,2H),7.05-7.11(m,2H),6.98-7.04(m,1H),6.88(d,J=8.3Hz,1H),4.98(t,J=6.4Hz,1H),3.49(s,3H),3.14(td,J=15.1,6.9Hz,2H),2.72-2.87(m,2H),0.19(s,9H)。ESI-MS(m/z):C22H25ClN2O2Si计算值:413.1(M+1);实验值:413.1。
实例14
向化合物5l(50mg,0.15mmol,1当量)的HMPA(2mL)溶液中,加入氢化钠(18mg 60%的油分散体,0.44mmol,3当量)。将溶液鼓泡,并且变成紫色,并且30分钟后,加入2-碘丙烷(0.029mL,0.29mmol,2当量),并且将溶液在rt下搅拌过夜。加入额外的氢化钠(20mg)和2-碘丙烷(0.029mL),并且将反应再次加热至50℃过夜。加入15-冠-5(10mg),并且将反应加热至50℃保持2天。加入NH4Cl溶液,用DCM萃取反应混合物,合并有机相,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(8g)纯化,用25至50%EA/己烷洗脱,获得化合物67(3.4mg,6%)。1HNMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.23(m,2H),7.04-7.10(m,2H),6.97-7.04(m,1H),6.84-6.90(m,1H),4.72-4.82(m,1H),3.77(dt,J=12.3,6.1Hz,1H),3.49(s,3H),3.10-3.23(m,2H),2.74-2.90(m,2H),1.22(dd,J=6.1,1.3Hz,6H)。ESI-MS(m/z):C22H23ClN2O2计算值:383.2(M+1);实验值:383.2。
实例15
向化合物13a(25mg,0.07mmol,1当量)的THF(2mL)溶液中,加入苯酚(9mg,0.09mmol,1.25当量)、DIAD(0.018mL,0.09mmol,1.25当量)和三苯基膦(24mg,0.09mmol,1.25当量),并且将溶液加热至50℃过夜。使溶液浓缩。经由柱层析(8g)纯化,用20至40%EA/己烷洗脱,获得Cpd 58。经由HPLC进一步纯化,用10至100%ACN/H2O洗脱,获得Cpd 58(12.8mg,41%)。1H NMR(氯仿-d)δ:7.40(dd,J=7.8,1.8Hz,1H),7.28-7.38(m,3H),7.17-7.23(m,2H),7.05-7.11(m,2H),7.00-7.05(m,1H),6.92-7.00(m,3H),6.89(d,J=7.3Hz,1H),5.51(tt,J=6.9,3.6Hz,1H),3.50(s,3H),3.31-3.44(m,2H),2.98-3.14(m,2H)。ESI-MS(m/z):C25H21ClN2O2计算值:417.1(M+1);实验值:417.1。
依照对于实例15上述的方法,并且替换适当的试剂、原料和本领域技术人员已知的纯化方法,制备以下化合物:
Cpd 59:1H NMR(氯仿-d)δ:8.36(t,J=1.8Hz,1H),8.25(t,J=3.0Hz,1H),7.41(dd,J=7.7,1.6Hz,1H),7.32-7.38(m,1H),7.23-7.26(m,2H),7.17-7.23(m,2H),7.05-7.11(m,2H),7.03(td,J=7.6,1.3Hz,1H),6.89(dd,J=8.3,1.0Hz,1H),5.54(tt,J=6.9,3.5Hz,1H),3.51(s,3H),3.34-3.46(m,2H),2.99-3.16(m,2H)。ESI-MS(m/z):C24H20ClN3O2计算值:418.1(M+1);实验值:418.1。
实例16
向化合物13a(15mg,0.044mmol,1当量)的甲苯(2mL)溶液中,加入2-溴吡啶(16a)(14mg,0.09mmol,2当量)、3,4,7,8-四甲基-1,10-菲咯啉(1mg,0.004mmol,0.1当量)、碳酸铯(22mg,0.066mmol,1.5当量)和CuI(1mg,0.004mmol,0.1当量),并且将悬浮液加热至110℃保持3小时,然后加热至140℃过夜。用EA使反应过滤通过二氧化硅短柱,并且浓缩。经由柱层析(12g)纯化,用30至100%EA/己烷洗脱,获得化合物61(3mg,15%)。1H NMR(氯仿-d)δ:8.19(dd,J=5.1,1.3Hz,1H),7.58(ddd,J=8.5,6.9,2.0Hz,1H),7.41(dd,J=7.7,1.6Hz,1H),7.31-7.38(m,1H),7.16-7.23(m,2H),7.06-7.12(m,2H),6.98-7.06(m,1H),6.84-6.93(m,2H),6.75(d,J=8.3Hz,1H),6.13(dt,J=6.9,3.3Hz,1H),3.50(s,3H),3.37-3.48(m,2H),2.91-3.11(m,2H)。ESI-MS(m/z):C24H20ClN3O2计算值:418.1(M+1);实验值:418.1。
实例17
A.0℃下向化合物5l(670mg,1.97mmol,1当量)的DCM(60mL)溶液中,加入Dess-Martin过碘烷(917mg,2.16mmol,1.1当量),并且将反应搅拌1.5小时。加入饱和NaHCO3和硫代硫酸钠,并且将反应混合物搅拌30分钟。此时,用DCM萃取水相,合并有机相,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(40g)纯化,用25至50%EA/己烷洗脱,获得化合物35(579mg,87%)。1H NMR(氯仿-d)δ:7.35-7.44(m,2H),7.21-7.26(m,3H),7.07-7.12(m,2H),7.05(td,J=7.6,1.1Hz,1H),6.88-6.94(m,1H),3.47-3.58(m,7H)。ESI-MS(m/z):C19H15ClN2O2计算值:339.1(M+1);实验值:339.0。
B.-78℃和Ar(g)下,向化合物35(271mg,0.8mmol,1当量)的THF(17mL)溶液中,加入KHMDS(1.92mL 0.5M的甲苯溶液,0.96mmol,1.2当量)。30分钟后,加入N-苯基双(三氟甲烷磺酰亚胺)(343mg,0.96mmol,1.2当量)的THF(3mL)溶液,并且使反应混合物在2小时内升温至rt。加入甲醇并且浓缩溶液。经由柱层析(24g)纯化,用15至30%EA/己烷洗脱,获得化合物17a(131mg,35%,60:40的异构体混合物)。ESI-MS(m/z):C20H14ClF3N2O4S计算值:471.1(M+1);实验值:471.1。
C.向化合物17a(15mg,0.032mmol,1当量)的DME(1.6mL)溶液中,加入Pd(Ph3P)4(4mg,0.0032mmol,0.1当量)、2M碳酸钠(0.25mL)和2-异丙氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)吡啶(17b)(17mL,0.064mmol,2当量)。通过鼓泡通入Ar(g)使溶液脱气,并且加热至80℃保持30分钟。将溶液倒在填充有硅藻土的5mL萃取管上,加入DCM,并且将有机相浓缩。将残余物溶于乙酸乙酯(5mL)和甲醇(3mL)中,加入PtO2(5mg),并且将反应混合物置于氢气氛下过夜。使催化剂通过硅藻土过滤,并且将滤液浓缩。经由柱层析(8g)纯化,用20至40%EA/己烷洗脱,获得不纯的化合物60(存在-Cl)。经由HPLC进一步纯化,用10至70%ACN/H2O洗脱,获得所期望纯度的化合物60(2.6mg,17%)。1H NMR(氯仿-d)δ:8.11(d,J=2.5Hz,1H),7.57(dd,J=8.5,2.7Hz,1H),7.42(dd,J=7.7,1.6Hz,1H),7.32-7.39(m,1H),7.17-7.23(m,2H),7.06-7.12(m,2H),7.00-7.06(m,1H),6.86-6.93(m,1H),6.67(d,J=8.6Hz,1H),5.28(quin,J=6.2Hz,1H),3.99-4.12(m,1H),3.51(s,3H),3.26(td,J=16.2,8.5Hz,2H),2.83-3.01(m,2H),1.35(d,J=6.3Hz,6H)。ESI-MS(m/z):C27H26ClN3O2计算值:460.2(M+1);实验值:460.2。
依照对于实例17上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 63:1H NMR(氯仿-d)δ:8.63(d,J=2.0Hz,1H),8.51(dd,J=4.8,1.5Hz,1H),7.69(d,J=8.1Hz,1H),7.42(dd,J=7.7,1.6Hz,1H),7.32-7.40(m,1H),7.27-7.31(m,1H),7.17-7.24(m,J=8.6Hz,2H),7.07-7.12(m,J=8.6Hz,2H),7.00-7.07(m,1H),6.90(d,J=8.3Hz,1H),4.06-4.19(m,1H),3.52(s,3H),3.33(td,J=15.3,8.5Hz,2H),2.89-3.08(m,2H)。ESI-MS(m/z):C24H20ClN3O计算值:402.1(M+1);实验值:402.1。
Cpd 64:1H NMR(氯仿-d)δ:7.38(dd,J=7.8,1.8Hz,1H),7.30-7.36(m,1H),7.17-7.22(m,2H),7.05-7.11(m,2H),7.01(td,J=7.6,1.3Hz,1H),6.88(d,J=8.3Hz,1H),3.49(s,3H),2.84-2.98(m,2H),2.63-2.75(m,1H),2.49-2.62(m,2H),1.62-1.73(m,2H),1.42(d,J=6.6Hz,2H),1.17-1.30(m,5H),0.91(d,J=4.8Hz,6H)。ESI-MS(m/z):C27H31ClN2O计算值:435.2(M+1);实验值:435.2。
Cpd 65:1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.18-7.23(m,2H),7.06-7.11(m,2H),6.94-7.04(m,3H),6.88(dd,J=8.3,1.0Hz,1H),6.64(td,J=7.4,1.1Hz,1H),6.50(d,J=8.1Hz,1H),3.40-3.51(m,4H),2.61-3.10(m,8H),2.17(s,1H)。ESI-MS(m/z):C28H26ClN3O计算值:456.2(M+1);实验值:456.2。
Cpd 66:1H NMR(氯仿-d)δ:9.12(d,J=2.0Hz,1H),8.78(d,J=2.3Hz,1H),8.30(t,J=2.0Hz,1H),7.43(dd,J=7.7,1.6Hz,1H),7.32-7.40(m,1H),7.17-7.24(m,2H),7.07-7.14(m,2H),7.04(td,J=7.6,1.3Hz,1H),6.90(dd,J=8.3,1.0Hz,1H),4.43(q,J=7.2Hz,2H),4.20(t,J=8.3Hz,1H),3.53(s,3H),3.28-3.43(m,2H),3.04(dd,J=15.5,8.5Hz,2H),1.37-1.47(m,3H)。ESI-MS(m/z):C27H24ClN3O3计算值:474.2(M+1);实验值:474.2。
Cpd 73:1H NMR(氯仿-d)δ:8.46-8.55(m,1H),7.58(dd,J=8.0,2.1Hz,1H),7.42(dd,J=7.7,1.6Hz,1H),7.32-7.40(m,1H),7.18-7.25(m,2H),7.06-7.17(m,3H),6.99-7.06(m,1H),6.90(d,J=8.1Hz,1H),4.10(quin,J=8.3Hz,1H),3.52(s,3H),3.30(td,J=15.5,8.5Hz,2H),2.85-3.05(m,2H),2.55(s,3H)。ESI-MS(m/z):C25H22ClN3O计算值:416.2(M+1);实验值:416.2。
Cpd 74:1H NMR(氯仿-d)δ:8.12(d,J=2.5Hz,1H),7.59(dd,J=8.6,2.5Hz,1H),7.42(dd,J=7.7,1.6Hz,1H),7.36(td,J=8.0,1.8Hz,1H),7.17-7.24(m,2H),7.06-7.12(m,2H),7.03(td,J=7.6,1.1Hz,1H),6.85-6.93(m,1H),6.72(d,J=8.6Hz,1H),4.35(q,J=7.1Hz,2H),4.06(quin,J=8.3Hz,1H),3.51(s,3H),3.27(td,J=16.3,8.3Hz,2H),2.83-3.01(m,2H),1.40(t,J=7.1Hz,3H)。ESI-MS(m/z):C26H24ClN3O2计算值:446.2(M+1);实验值:446.2。
Cpd 75:1H NMR(氯仿-d)δ:7.67(d,J=7.8Hz,1H),7.42(dd,J=7.8,1.5Hz,1H),7.33-7.39(m,1H),7.20(d,J=8.6Hz,2H),7.06-7.13(m,3H),7.00-7.06(m,1H),6.90(d,J=8.1Hz,1H),4.50(quin,J=7.8Hz,1H),3.52(s,3H),3.34(dd,J=15.9,8.6Hz,2H),2.80-3.12(m,3H),1.29(d,J=7.1Hz,6H)。ESI-MS(m/z):C27H25Cl2N3O计算值:478.1(M+1);实验值:478.1。
Cpd 77:1H NMR(氯仿-d)δ:8.44(d,J=2.0Hz,1H),7.54(dd,J=8.0,2.1Hz,1H),7.41(dd,J=7.7,1.6Hz,1H),7.35(td,J=8.0,1.8Hz,1H),7.17-7.23(m,2H),7.06-7.13(m,3H),7.03(td,J=7.6,1.1Hz,1H),6.86-6.92(m,1H),4.07(quin,J=8.3Hz,1H),3.51(s,3H),3.19-3.35(m,2H),2.82-3.03(m,2H),1.98-2.08(m,1H),0.94-1.04(m,4H)。ESI-MS(m/z):C27H24ClN3O计算值:442.2(M+1);实验值:442.2。
实例18
向化合物5l(25mg,0.07mmol,1当量)的二氯乙烷(2mL)悬浮液中,加入3,4-二氢-2H-吡喃(18a)(33mg,0.37mmol,5当量)和对甲苯磺酸(13mg,0.07mmol,1当量),并且将反应混合物在rt下搅拌2小时。加入MP碳酸盐,搅拌20分钟,过滤,并且浓缩。经由柱层析(8g)纯化,用20至40%EA/己烷洗脱,获得化合物76(16.4mg,50%)。1H NMR(氯仿-d)δ:7.30-7.42(m,2H),7.16-7.23(m,2H),7.04-7.11(m,2H),7.01(t,J=7.7Hz,1H),6.84-6.91(m,1H),4.96-5.07(m,1H),4.74-4.82(m,1H),3.94(ddd,J=11.1,7.6,3.3Hz,1H),3.52-3.61(m,1H),3.49(d,J=2.8Hz,3H),3.11-3.31(m,2H),2.74-3.04(m,2H),1.69-1.95(m,2H),1.46-1.65(m,4H)。ESI-MS(m/z):C24H25ClN2O3计算值:425.2(M+1);实验值:425.2。
实例19
A.向化合物5l(40mg,0.12mmol,1当量)的THF(2mL)溶液中,加入氢化钠(23mg60%的油分散体,0.59mmol,5当量)。30分钟后,加入环己烷碳酰氯(0.08mL,0.59mmol,5当量),并且将溶液在rt下搅拌过夜。加入饱和NH4Cl,并且将溶液倒在填充有硅藻土的5mL萃取管上。用DCM洗涤填充有硅藻土的萃取管,并且浓缩滤液。经由柱层析(8g)纯化,用20至40%EA/己烷洗脱,获得化合物78(30mg,56%)。1H NMR(氯仿-d)δ:7.39(dd,J=7.8,1.5Hz,1H),7.32-7.38(m,1H),7.17-7.24(m,2H),7.04-7.09(m,2H),7.02(td,J=7.6,1.1Hz,1H),6.89(dd,J=8.3,1.0Hz,1H),5.82(tt,J=7.3,3.9Hz,1H),3.50(s,3H),3.27-3.39(m,2H),2.75-2.94(m,2H),2.32(tt,J=11.2,3.7Hz,1H),1.92(d,J=12.9Hz,2H),1.71-1.80(m,2H),1.61-1.68(m,1H),1.40-1.52(m,2H),1.22-1.35(m,3H)。ESI-MS(m/z):C26H27ClN2O3计算值:451.2(M+1);实验值:451.2。
B.rt下向化合物78(21mg,0.047mmol,1当量)的氯仿(1mL)溶液中,加入三乙基硅烷(0.3mL,1.86mmol,40当量),然后加入溴化铟(330mg,0.93mmol,20当量)。将小瓶内的悬浮液置于氩气氛下,并且在65℃下搅拌过夜。加入水,并且搅拌混合物,直至橙色消失。将反应混合物倒在填充有硅藻土的5mL萃取管上,用DCM冲洗所述管,并且浓缩滤液。经由柱层析(8g)纯化,用10至20%EA/己烷洗脱,获得化合物82(4.8mg,23%)。1H NMR(氯仿-d)δ:7.29-7.43(m,2H),7.16-7.23(m,J=8.6Hz,2H),7.04-7.10(m,J=8.6Hz,2H),7.01(t,J=7.6Hz,1H),6.87(d,J=8.1Hz,1H),4.59-4.70(m,1H),3.49(s,3H),3.27-3.37(m,2H),3.10-3.22(m,2H),2.84(ddd,J=21.6,15.9,5.2Hz,2H),1.59-1.84(m,6H),1.17-1.33(m,3H),0.89-1.01(m,2H)。ESI-MS(m/z):C26H29ClN2O2计算值:437.2(M+1);实验值:437.2。
依照对于实例19上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 55:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.32-7.38(m,1H),7.17-7.24(m,2H),7.05-7.10(m,2H),6.98-7.05(m,1H),6.89(dd,J=8.3,1.0Hz,1H),5.87(tt,J=7.5,3.9Hz,1H),3.50(s,3H),3.29-3.41(m,2H),2.78-2.96(m,2H),2.23(tt,J=8.6,5.5Hz,1H),1.46-1.73(m,4H),0.91(td,J=7.5,1.0Hz,6H)。ESI-MS(m/z):C25H27ClN2O3计算值:439.2(M+1);实验值:439.2。
Cpd 70:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.32-7.38(m,1H),7.16-7.24(m,2H),7.05-7.10(m,2H),7.02(td,J=7.6,1.1Hz,1H),6.86-6.92(m,1H),5.82-5.91(m,1H),3.47-3.53(m,3H),3.30-3.40(m,2H),2.78-2.96(m,2H),2.23(tt,J=8.6,5.6Hz,1H),1.47-1.72(m,4H),0.86-0.96(m,6H)。ESI-MS(m/z):C25H27ClN2O3计算值:439.2(M+1);实验值:439.2。
Cpd 72:1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.16-7.22(m,2H),7.04-7.10(m,2H),7.01(td,J=7.7,1.3Hz,1H),6.88(dd,J=8.3,1.0Hz,1H),4.61-4.70(m,1H),3.49(s,3H),3.36-3.45(m,2H),3.11-3.23(m,2H),2.77-2.91(m,2H),1.29-1.54(m,5H),0.90(t,J=7.5Hz,6H)。ESI-MS(m/z):C25H29ClN2O2计算值:425.2(M+1);实验值:425.2。
Cpd 79:1H NMR(氯仿-d)δ:7.32-7.42(m,2H),7.17-7.23(m,2H),7.05-7.09(m,2H),6.99-7.05(m,1H),6.89(dd,J=8.3,1.0Hz,1H),5.83(tt,J=7.4,3.9Hz,1H),3.50(s,3H),3.34(dd,J=16.7,7.3Hz,2H),2.80-2.95(m,2H),2.75(quin,J=8.0Hz,1H),1.56-1.96(m,8H)。ESI-MS(m/z):C25H25ClN2O3计算值:437.2(M+1);实验值:437.2。
Cpd 80:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.35(td,J=7.9,1.6Hz,1H),7.17-7.23(m,2H),7.04-7.09(m,2H),7.02(td,J=7.6,1.1Hz,1H),6.86-6.92(m,1H),5.83(tt,J=7.3,3.8Hz,1H),3.50(s,3H),3.34(dd,J=16.7,7.3Hz,2H),3.16(quin,J=8.3Hz,1H),2.78-2.96(m,2H),2.13-2.37(m,4H),1.84-2.04(m,2H)。ESI-MS(m/z):C24H23ClN2O3计算值:423.1(M+1);实验值:423.1。
Cpd 81:1H NMR(氯仿-d)δ:7.31-7.43(m,2H),7.16-7.24(m,J=8.6Hz,2H),7.05-7.10(m,J=8.3Hz,2H),7.02(t,J=7.6Hz,1H),6.89(d,J=8.3Hz,1H),5.83(tt,J=7.3,3.8Hz,1H),3.50(s,3H),3.34(dd,J=16.7,7.3Hz,2H),2.77-2.96(m,2H),2.57(dt,J=14.0,6.9Hz,1H),1.19(dd,J=7.1,1.0Hz,6H)。ESI-MS(m/z):C23H23ClN2O3计算值:411.1(M+1);实验值:411.1。
Cpd 83:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.23(m,2H),7.04-7.10(m,J=8.6Hz,2H),7.01(td,J=7.6,1.0Hz,1H),6.88(d,J=8.3Hz,1H),4.63-4.72(m,1H),3.46-3.51(m,3H),3.35-3.45(m,2H),3.11-3.23(m,2H),2.77-2.93(m,2H),2.18(dt,J=15.0,7.4Hz,1H),1.70-1.83(m,2H),1.47-1.65(m,4H),1.19-1.33(m,2H)。ESI-MS(m/z):C25H27ClN2O2计算值:423.2(M+1);实验值:423.2。
Cpd 84:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.23(m,2H),7.04-7.09(m,2H),7.01(td,J=7.6,1.1Hz,1H),6.88(d,J=8.3Hz,1H),4.62-4.72(m,1H),3.43-3.57(m,5H),3.11-3.23(m,2H),2.76-2.92(m,2H),2.60(dt,J=14.8,7.4Hz,1H),2.03-2.15(m,2H),1.83-2.00(m,2H),1.69-1.81(m,2H)。ESI-MS(m/z):C24H25ClN2O2计算值:409.2(M+1);实验值:409.2。
Cpd 85:1H NMR(氯仿-d)δ:7.30-7.45(m,2H),7.20(d,J=8.6Hz,2H),7.05-7.13(m,2H),6.97-7.05(m,1H),6.88(d,J=8.3Hz,1H),4.62-4.74(m,1H),3.49(s,3H),3.25-3.37(m,2H),3.11-3.25(m,2H),2.76-2.96(m,2H),1.81-1.98(m,1H),0.94(d,J=6.6Hz,6H)。ESI-MS(m/z):C23H25ClN2O2计算值:397.2(M+1);实验值:397.2。
Cpd 86:1H NMR(氯仿-d)δ:7.32-7.42(m,2H),7.17-7.23(m,2H),7.05-7.09(m,2H),6.99-7.05(m,1H),6.89(dd,J=8.3,1.0Hz,1H),5.85(tt,J=7.3,3.7Hz,1H),3.97(d,J=11.9Hz,2H),3.50(s,3H),3.29-3.48(m,4H),2.78-2.95(m,2H),2.51-2.62(m,1H),1.73-1.90(m,4H)。ESI-MS(m/z):C25H25ClN2O4计算值:453.2(M+1);实验值:453.2。
Cpd 87:1H NMR(氯仿-d)δ:7.30-7.42(m,2H),7.16-7.23(m,J=8.6Hz,2H),7.04-7.10(m,J=8.3Hz,2H),7.01(t,J=7.6Hz,1H),6.88(d,J=8.3Hz,1H),4.61-4.71(m,1H),3.98(dd,J=11.2,3.9Hz,2H),3.49(s,3H),3.33-3.45(m,4H),3.11-3.23(m,2H),2.76-2.91(m,2H),1.87(br.s.,1H),1.67(br.s.,2H),1.29-1.43(m,2H)。ESI-MS(m/z):C25H27ClN2O3计算值:439.2(M+1);实验值:439.2。
实例20
向化合物35(24mg,0.07mmol,1当量)和2,2-二甲基-1,3-丙二醇(148mg,1.42mmol,20当量)的DCM(1mL)溶液中,加入BF3醚合物(0.009mL,0.07mmol,1当量),并且将溶液在rt下搅拌过夜。加入水,并且用EA萃取水相。合并有机相,用盐水洗涤,并且在MgSO4上干燥,过滤,并且浓缩。经由柱层析(8g)纯化,用15至30%EA/己烷洗脱,获得化合物71(27.8mg,88%)。1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.23(m,2H),7.03-7.09(m,2H),7.01(td,J=7.6,1.1Hz,1H),6.84-6.89(m,1H),3.61(q,J=11.1Hz,4H),3.47(s,3H),3.26(s,2H),3.20(s,2H),1.08(s,3H),1.00(s,3H)。ESI-MS(m/z):C24H25ClN2O3计算值:425.2(M+1);实验值:425.2。
依照对于实例20上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 52:1H NMR(氯仿-d)δ:7.33(d,J=8.3Hz,1H),7.19-7.26(m,2H),7.03-7.08(m,2H),7.00(dd,J=8.3,2.0Hz,1H),6.85(d,J=2.0Hz,1H),3.95-4.09(m,4H),3.47(s,3H),3.27(s,2H),3.18(s,2H),1.83-1.97(m,1H),1.69-1.81(m,1H)。ESI-MS(m/z):C22H20C12N2O3计算值:431.1(M+1);实验值:431.1。
Cpd 54:1H NMR(氯仿-d)δ:7.38(dd,J=7.8,1.8Hz,1H),7.34(td,J=8.0,1.8Hz,1H),7.17-7.23(m,2H),7.03-7.08(m,2H),7.01(td,J=7.6,1.1Hz,1H),6.87(dd,J=8.3,1.0Hz,1H),3.97-4.09(m,4H),3.47(s,3H),3.28(s,2H),3.19(s,2H),1.84-1.97(m,1H),1.69-1.80(m,1H)。ESI-MS(m/z):C22H21ClN2O3计算值:397.1(M+1);实验值:397.1。
Cpd 91:1H NMR(氯仿-d)δ:7.49-7.55(m,J=8.3Hz,2H),7.42(dd,J=7.8,1.5Hz,1H),7.32-7.40(m,1H),7.20-7.25(m,J=8.3Hz,2H),7.04(t,J=7.7Hz,1H),6.87(d,J=8.3Hz,1H),3.62(q,J=11.4Hz,4H),3.45(s,3H),3.25(d,J=15.7Hz,4H),1.09(s,3H),1.00(s,3H)。ESI-MS(m/z):C25H25N3O3计算值:416.2(M+1);实验值:416.2。
Cpd 93:1H NMR(氯仿-d)δ:7.29-7.39(m,2H),6.94-7.05(m,3H),6.90(d,J=8.1Hz,1H),6.56(d,J=8.8Hz,2H),3.57-3.69(m,4H),3.55(s,3H),3.23(d,J=11.4Hz,4H),2.91(s,6H),1.07(s,3H),1.00(s,3H)。ESI-MS(m/z):C26H31N3O3计算值:434.2(M+1);实验值:434.2。
Cpd 94:1H NMR(氯仿-d)δ:8.02(d,J=2.3Hz,1H),7.30-7.41(m,2H),7.22-7.27(m,1H),7.00(t,J=7.3Hz,1H),6.89(d,J=8.3Hz,1H),6.56(d,J=8.6Hz,1H),4.31(q,J=7.0Hz,2H),3.56-3.68(m,4H),3.54(s,3H),3.26(s,2H),3.21(s,2H),1.36(t,J=7.1Hz,3H),1.07(s,3H),1.01(s,3H)。ESI-MS(m/z):C25H29N3O4计算值:436.2(M+1);实验值:436.2。
Cpd 95:1H NMR(氯仿-d)δ:8.31-8.41(m,1H),7.31-7.44(m,2H),7.25(d,J=2.3Hz,1H),6.96-7.06(m,2H),6.88(d,J=8.3Hz,1H),3.62(q,J=11.3Hz,4H),3.51(s,3H),3.27(s,2H),3.23(s,2H),2.50(s,3H),1.08(s,3H),1.00(s,3H)。ESI-MS(m/z):C24H27N3O3计算值:406.2(M+1);实验值:406.2。
Cpd 96:1H NMR(氯仿-d)δ:8.04(d,J=2.3Hz,1H),7.30-7.41(m,2H),7.22-7.29(m,3H),7.00(t,J=7.6Hz,1H),6.89(d,J=8.3Hz,1H),6.59(d,J=8.6Hz,1H),3.90(s,3H),3.56-3.68(m,4H),3.54(s,3H),3.26(s,2H),3.21(s,2H),1.07(s,3H),1.01(s,3H)。ESI-MS(m/z):C24H27N3O4计算值:422.2(M+1);实验值:422.2。
Cpd 97:1H NMR(氯仿-d)δ:8.08(d,J=2.3Hz,1H),7.29-7.39(m,2H),7.10(dd,J=9.0,2.4Hz,1H),6.98(t,J=7.6Hz,1H),6.91(d,J=8.1Hz,1H),6.33(d,J=9.1Hz,1H),3.53-3.67(m,7H),3.25(s,2H),3.21(s,2H),3.05(s,6H),1.05(s,3H),1.01(s,3H)。ESI-MS(m/z):C25H30N4O3计算值:435.2(M+1);实验值:435.2。
Cpd 98:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.22(m,J=8.6Hz,2H),7.03-7.09(m,2H),7.00(t,J=7.6Hz,1H),6.87(d,J=8.1Hz,1H),3.69-3.82(m,2H),3.47(s,3H),3.06-3.24(m,4H),1.29-1.36(m,6H)。ESI-MS(m/z):C23H23ClN2O3计算值:411.1(M+1);实验值:411.1。
Cpd 99:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.33(td,J=7.9,1.6Hz,1H),7.16-7.23(m,2H),7.03-7.09(m,2H),7.01(td,J=7.7,1.3Hz,1H),6.83-6.91(m,1H),3.68-3.83(m,2H),3.47(s,3H),3.05-3.23(m,4H),1.32(dd,J=5.6,1.5Hz,6H)。ESI-MS(m/z):C23H23ClN2O3计算值:411.1(M+1);实验值:411.1。
Cpd 100:1H NMR(氯仿-d)δ:7.31(dd,J=7.7,1.6Hz,1H),7.22-7.29(m,1H),7.08-7.15(m,J=8.6Hz,2H),6.96-7.02(m,J=8.3Hz,2H),6.90-6.96(m,1H),6.80(d,J=8.3Hz,1H),3.93-4.10(m,2H),3.40(s,3H),3.03-3.23(m,4H),1.65(t,J=7.3Hz,2H),1.13-1.27(m,8H)。ESI-MS(m/z):C24H25ClN2O3计算值:425.2(M+1);实验值:425.2。
Cpd 101:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.15-7.21(m,2H),7.03-7.08(m,2H),7.00(td,J=7.6,1.1Hz,1H),6.87(d,J=8.3Hz,1H),4.04-4.17(m,2H),3.47(s,3H),3.09-3.30(m,4H),1.72(t,J=7.2Hz,2H),1.22-1.29(m,8H)。ESI-MS(m/z):C24H25ClN2O3计算值:425.2(M+1);实验值:425.2。
Cpd 102:1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.15-7.23(m,J=8.6Hz,2H),7.04-7.10(m,J=8.6Hz,2H),7.00(t,J=7.6Hz,1H),6.87(d,J=8.3Hz,1H),4.27-4.37(m,2H),3.48(s,3H),3.20(br.s.,2H),3.10(s,2H),1.21(d,J=6.1Hz,6H)。ESI-MS(m/z):C23H23ClN2O3计算值:411.1(M+1);实验值:411.1。
Cpd 103:1H NMR(氯仿-d)δ:7.39(dd,J=7.7,1.6Hz,1H),7.30-7.37(m,1H),7.16-7.23(m,2H),7.04-7.09(m,2H),6.98-7.04(m,1H),6.87(d,J=8.3Hz,1H),4.31(dt,J=5.9,4.5Hz,2H),3.48(s,3H),3.24(s,2H),3.06(s,2H),1.22(d,J=6.1Hz,6H)。ESI-MS(m/z):C23H23ClN2O3计算值:411.1(M+1);实验值:411.1。
Cpd 107:1H NMR(氯仿-d)δ:7.28-7.37(m,2H),6.93-7.03(m,3H),6.89(d,J=8.1Hz,1H),6.56(d,J=8.8Hz,2H),3.53(s,3H),3.11-3.22(m,4H),2.91(s,6H),1.26-1.32(m,12H)。ESI-MS(m/z):C27H33N3O3计算值:448.3(M+1);实验值:448.3。
Cpd 108:1H NMR(氯仿-d)δ:8.02(d,J=2.5Hz,1H),7.29-7.39(m,2H),7.23(dd,J=8.6,2.5Hz,1H),6.95-7.04(m,1H),6.88(d,J=7.6Hz,1H),6.55(d,J=8.6Hz,1H),4.30(q,J=7.1Hz,2H),3.53(s,3H),3.09-3.26(m,4H),1.36(t,J=7.1Hz,3H),1.28(d,J=6.3Hz,12H)。ESI-MS(m/z):C26H31N3O4计算值:450.2(M+1);实验值:450.2。
Cpd 109:1H NMR(氯仿-d)δ:8.36(d,J=1.8Hz,1H),7.29-7.41(m,2H),7.23(dd,J=8.1,2.3Hz,1H),6.95-7.04(m,2H),6.87(d,J=8.1Hz,1H),3.50(s,3H),3.12-3.27(m,4H),2.50(s,3H),1.29(d,J=6.6Hz,12H)。ESI-MS(m/z):C25H29N3O3计算值:420.2(M+1);实验值:420.2。
Cpd 110:1H NMR(氯仿-d)δ:8.09(d,J=2.0Hz,1H),7.28-7.36(m,2H),7.07(dd,J=9.0,2.4Hz,1H),6.94-7.01(m,1H),6.91(d,J=8.6Hz,1H),6.32(d,J=8.8Hz,1H),3.58(s,3H),3.18(d,J=6.8Hz,4H),3.05(s,6H),1.28(d,J=6.6Hz,12H)。ESI-MS(m/z):C26H32N4O3计算值:449.3(M+1);实验值:449.3。
Cpd 111:1H NMR(氯仿-d)δ:7.51(d,J=8.1Hz,2H),7.32-7.49(m,2H),7.21(d,J=8.3Hz,2H),7.05(d,J=7.6Hz,1H),6.87(d,J=8.3Hz,1H),3.44(s,3H),3.12-3.33(m,4H),1.21-1.43(m,12H)。ESI-MS(m/z):C26H27N3O3计算值:430.2(M+1);实验值:430.2。
Cpd 112:1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.16-7.23(m,2H),7.04-7.10(m,J=8.6Hz,2H),6.97-7.04(m,1H),6.87(d,J=8.3Hz,1H),4.14-4.22(m,2H),3.48(s,3H),3.25(br.s.,2H),3.11(s,2H),1.75-1.85(m,4H),1.50-1.60(m,2H),1.27-1.40(m,2H)。ESI-MS(m/z):C25H25ClN2O3计算值:437.2(M+1);实验值:437.2。
Cpd 114:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.22(m,2H),7.03-7.08(m,2H),6.97-7.03(m,1H),6.84-6.89(m,1H),4.70(d,J=3.9Hz,2H),3.47(s,3H),3.27(s,2H),3.02(s,2H),1.96(dd,J=13.6,6.2Hz,2H),1.81(tt,J=12.3,6.0Hz,2H),1.61(dt,J=12.3,6.3Hz,1H),1.38-1.54(m,1H)。ESI-MS(m/z):C24H23ClN2O3计算值:423.1(M+1);实验值:423.1。
Cpd 115:1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.16-7.22(m,2H),7.04-7.09(m,2H),6.98-7.04(m,1H),6.84-6.90(m,1H),4.72(d,J=4.4Hz,2H),3.48(s,3H),3.16-3.28(m,2H),3.06(s,2H),1.95(dd,J=13.7,5.9Hz,2H),1.78(d,J=6.1Hz,1H),1.61(dt,J=12.2,6.3Hz,1H),1.41-1.54(m,2H)。ESI-MS(m/z):C24H23ClN2O3计算值:423.1(M+1);实验值:423.1。
Cpd 120:1H NMR(氯仿-d)δ:7.45(t,J=8.0Hz,1H),7.36(d,J=7.4Hz,1H),7.05(t,J=7.6Hz,1H),7.00(d,J=8.6Hz,1H),6.71(d,J=3.9Hz,1H),6.53(d,J=3.9Hz,1H),3.69(s,3H),3.56-3.67(m,4H),3.23(d,J=7.4Hz,4H),1.09(s,3H),1.00(s,3H)。ESI-MS(m/z):C22H23ClN2O3S计算值:431.1(M+1);实验值:431.1。
Cpd 121:1H NMR(氯仿-d)δ:7.41-7.51(m,1H),7.35(dd,J=7.8,1.7Hz,1H),7.02-7.10(m,1H),6.99(d,J=8.3Hz,1H),6.70(d,J=3.9Hz,1H),6.50(d,J=3.9Hz,1H),3.68(s,3H),3.18(s,4H),1.30(s,12H)。ESI-MS(m/z):C23H25ClN2O3S计算值:445.1(M+1);实验值:445.1。
实例21
向化合物35(30mg,0.09mmol,1当量)的DCM(2mL)和乙酸(0.01mL)溶液中,加入吗啉(16mg,0.18mmol,2当量)。30分钟后,加入氰基硼氢化钠(22mg,0.35mmol,4当量),并且将溶液搅拌过夜。加入DCM,并且依序用NaHCO3和水洗涤反应混合物,在MgSO4上干燥,过滤,并且浓缩。经由柱层析(8g)纯化,用50至100%EA/己烷以及2至5%MeOH/DCM+1%NH3洗脱,获得化合物68(24.8mg,67%)。1H NMR(氯仿-d)δ:7.30-7.42(m,2H),7.17-7.24(m,2H),7.04-7.10(m,J=8.6Hz,2H),7.01(td,J=7.6,1.1Hz,1H),6.88(d,J=8.1Hz,1H),3.79(t,J=4.5Hz,4H),3.59-3.71(m,1H),3.49(s,3H),2.94-3.10(m,2H),2.77-2.92(m,2H),2.62(br.s.,4H)。ESI-MS(m/z):C23H24ClN3O2计算值:410.2(M+1);实验值:410.2。
依照对于实例21上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 117:1H NMR(氯仿-d)δ:7.29-7.42(m,2H),7.21(d,J=8.3Hz,2H),7.07(d,J=8.1Hz,2H),7.01(t,J=7.6Hz,1H),6.88(d,J=8.1Hz,1H),3.54-3.92(m,2H),3.49(s,3H),2.80-3.17(m,3H),2.14-2.31(m,2H),1.73(d,J=12.2Hz,2H),1.31-1.54(m,3H),0.97(d,J=5.6Hz,3H)。ESI-MS(m/z):C25H28ClN3O计算值:422.2(M+1);实验值:422.2。
Cpd 118:1H NMR(氯仿-d)δ:7.30-7.40(m,2H),7.17-7.23(m,2H),7.04-7.09(m,2H),7.01(td,J=7.6,1.1Hz,1H),6.88(d,J=7.6Hz,1H),3.81(t,J=7.9Hz,1H),3.49(s,3H),2.92-3.12(m,6H),2.74(q,J=10.3Hz,2H),1.72(t,J=7.0Hz,2H),1.41-1.57(m,4H),0.80-0.89(m,6H)。ESI-MS(m/z):C27H32ClN3O计算值:450.2(M+1);实验值:450.2。
Cpd 119:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.6Hz,1H),7.30-7.36(m,1H),7.16-7.23(m,2H),7.04-7.10(m,2H),6.97-7.04(m,1H),6.87(d,J=7.3Hz,1H),3.56(t,J=7.9Hz,1H),3.49(s,3H),2.90-3.05(m,2H),2.79-2.90(m,2H),2.69-2.79(m,2H),2.47(s,2H),1.65(t,J=6.8Hz,2H),1.13(s,6H)。ESI-MS(m/z):C25H28ClN3O计算值:422.2(M+1);实验值:422.2。
Cpd 123:1H NMR(氯仿-d)δ:7.30-7.42(m,2H),7.17-7.25(m,J=8.6Hz,2H),7.04-7.10(m,J=8.6Hz,2H),7.01(td,J=7.6,1.1Hz,1H),6.88(d,J=8.3Hz,1H),3.65(quin,J=7.7Hz,1H),3.49(s,3H),2.92-3.13(m,4H),2.74-2.92(m,4H),2.25-2.42(m,2H)。ESI-MS(m/z):C23H22ClF2N3O计算值:430.1(M+1);实验值:430.1。
实例22
A.向化合物5l(50mg,0.15mmol,1当量)的DCM(2mL)悬浮液中,加入环己烯(0.045mL,0.44mmol,3当量)、N-(苯硒基)邻苯二甲酰亚胺(47mg,0.15mmol,1当量)和BF3-醚合物(0.002mL,0.015mmol,0.1当量)。3小时后,加入1N NaOH,并且用DCM萃取反应混合物。合并的有机相在MgSO4上干燥,过滤,并且浓缩。经由柱层析(12g)纯化,用20至40%EA/己烷洗脱,获得化合物22a(40mg,47%,非对映体的混合物)。ESI-MS(m/z):C31H31ClN2O2Se计算值:579.1(M+1);实验值:579.1。
B.向化合物22a(40mg,0.07mmol,1当量)的苯(2mL)溶液中,加入Bu3SnH(0.072mL,0.28mmol,4当量)和AIBN(12mg,0.07mmol,1当量),并且将小瓶内的反应混合物加热至80℃过夜。将溶液浓缩,经由柱层析(8g)纯化,用7至15至20%EA/己烷洗脱,获得不纯的化合物88。经由HPLC进一步纯化,用30至100%ACN/H2O洗脱,获得所期望纯度的化合物88(16mg,54%)。1H NMR(氯仿-d)δ:7.37(dd,J=7.7,1.6Hz,1H),7.33(td,J=7.9,1.6Hz,1H),7.16-7.22(m,2H),7.04-7.10(m,2H),7.01(td,J=7.6,1.1Hz,1H),6.84-6.90(m,1H),4.78-4.87(m,1H),3.49(s,3H),3.35-3.45(m,1H),3.10-3.23(m,2H),2.75-2.90(m,2H),1.97(d,J=9.9Hz,2H),1.74-1.81(m,2H),1.55-1.61(m,1H),1.14-1.41(m,5H)。ESI-MS(m/z):C25H27ClN2O2计算值:423.2(M+1);实验值:423.2。
依照对于实例22上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 89:1H NMR(氯仿-d)δ:7.38(dd,J=7.8,1.5Hz,1H),7.30-7.37(m,1H),7.20(d,J=8.1Hz,2H),7.07(dd,J=8.6,1.8Hz,2H),6.98-7.04(m,1H),6.88(d,J=8.3Hz,1H),4.68-4.78(m,1H),3.54(d,J=6.6Hz,1H),3.49(s,3H),3.10-3.23(m,2H),2.74-2.91(m,2H),2.36(d,J=4.3Hz,1H),2.26(br.s.,1H),1.39-1.68(m,5H),0.98-1.16(m,3H)。ESI-MS(m/z):C26H27ClN2O2计算值:435.2(M+1);实验值:435.2。
Cpd 90:1H NMR(氯仿-d)δ:7.30-7.41(m,2H),7.17-7.23(m,2H),7.05-7.10(m,2H),6.99-7.04(m,1H),6.88(d,J=8.3Hz,1H),4.68-4.77(m,1H),4.04-4.13(m,1H),3.50(s,3H),3.11-3.24(m,2H),2.84(ddd,J=21.9,15.7,5.7Hz,2H),1.48-1.87(m,6H),0.81-1.03(m,2H)。ESI-MS(m/z):C24H25ClN2O2计算值:409.2(M+1);实验值:409.2。
实例23
A.rt和氩气下向无水CeCl3(36mg,0.15mmol,0.5当量)的THF(5mL)悬浮液中,加入化合物23a(100mg,0.3mmol,1当量),然后加入环己基甲基溴化镁(23b)(1.82mL 0.5M的THF溶液,0.91mmol,3当量)。搅拌过夜后,加入水和1N HCl,用醚萃取反应混合物,并且合并有机相,在MgSO4上干燥,过滤,并且浓缩。经由层析(12g)纯化,用30至60至100%EA/己烷洗脱,获得化合物23c(12mg,9%)。ESI-MS(m/z):C27H29N3O2计算值:428.2(M+1);实验值:428.2。
B.rt和氩气下向化合物23c(12mg,0.028mmol,1当量)的THF(2mL)溶液中,加入Burgess试剂(33mg,0.14mmol,5当量)。在1小时后,加入水,用DCM萃取,合并有机物,在MgSO4上干燥并浓缩。经由层析(4g)纯化,用15至30%EA/己烷洗脱,获得化合物23d(3mg,26%,异构体混合物)。ESI-MS(m/z):C27H27N3O计算值:410.2(M+1);实验值:410.2。
C.将化合物23d(3mg)和10%Pd/C(5mg)的甲醇(5mL)溶液置于氢气氛下过夜。将反应过滤通过硅藻土并且浓缩。经由HPLC纯化,获得化合物106(1.2mg,38%)。1H NMR(氯仿-d)δ:7.51(d,J=8.3Hz,2H),7.42(d,J=7.6Hz,1H),7.33-7.39(m,1H),7.24(d,J=8.6Hz,2H),7.04(t,J=7.2Hz,1H),6.88(d,J=7.6Hz,1H),3.46(s,3H),2.91-3.13(m,3H),2.43-2.55(m,2H),1.64-1.83(m,4H),1.48-1.56(m,3H),1.13-1.32(m,4H),0.80-1.00(m,2H)。ESI-MS(m/z):C27H29N3O计算值:412.2(M+1);实验值:412.2。
依照对于实例23上述的方法并且替换本领域技术人员已知的适当试剂、原料和纯化方法,制备以下化合物:
Cpd 104:1H NMR(氯仿-d)δ:7.38(dd,J=7.7,1.1Hz,1H),7.33(t,J=8.0Hz,1H),7.16-7.22(m,J=8.6Hz,2H),7.05-7.11(m,J=8.3Hz,2H),6.97-7.04(m,1H),6.88(d,J=8.3Hz,1H),3.49(s,3H),2.83-2.97(m,2H),2.48-2.73(m,3H),1.74(br.s.,5H),1.44(br.s.,1H),1.15-1.35(m,3H),0.78-1.12(m,2H)。ESI-MS(m/z):C25H27ClN2O计算值:407.2(M+1);实验值:407.2。
Cpd 105:1H NMR(氯仿-d)δ:7.51(d,J=8.6Hz,2H),7.42(dd,J=7.7,1.6Hz,1H),7.33-7.39(m,1H),7.24(d,J=8.6Hz,2H),7.00-7.08(m,1H),6.85-6.91(m,1H),3.46(s,3H),2.91-3.10(m,3H),2.42-2.58(m,2H),1.66-1.78(m,1H),1.47-1.56(m,2H),0.96(d,J=6.6Hz,6H)。ESI-MS(m/z):C24H25N3O计算值:372.2(M+1);实验值:372.2。
下文示例的表1中的化合物根据本文所述的方案和具体实例制备。
表1.式(I)的化合物
生物学实例
体外测定
实例1
功能分析:N型钙通道对抗
使用共表达N型钙通道子单元的α1B(Cav2.2),β3和α2δ子单元的稳定细胞系(HEK亲本)。在包含少量葡萄糖的Dulbecco’s Modified Eagle培养基中,例行使这些细胞作为单层生长,所述培养基用10%FBS、2mM L-谷氨酰胺、100I.U./mL青霉素、100μg/mL链霉素、400μg/mL G418和200μg/mL Zeocin(分流比=1∶5)增补。使细胞在37℃下5%CO2中。如果可用,将式(I)的化合物由纯化合物配制为10mM的DMSO原液。否则,使用机构内部提供的5或10mMDMSO原液。
通过采用Hamamatsu Corporation(Bridgewater,NJ,U.S.A.)的功能性药物筛选体系(FDSS),在BD钙分析染料(BD Biosciences,Franklin Lakes,NJ,U.S.A.)存在下测定钙介导的荧光信号的强度,评定对KCl去极化的钙流响应。
分析前二十四小时,将细胞以培养基中5,000个细胞每孔的密度接种于透明基底的聚-D-赖氨酸涂覆的384孔板(BD Biosciences)中,并且在5%CO2中,在37℃下生长过夜。评定当天,移除生长培养基,并且在37℃和5%CO2下用BD钙分析染料(BD Biosciences)将细胞承载35分钟,然后在室温下承载25分钟。使用FDSS,使细胞接触不同浓度的式(I)的代表性化合物,并且测定细胞内钙,5分钟后加入50mM KCl,以再次进行3分钟测定。
计算和配方
式(I)的代表性化合物的IC50值由六点浓度-响应实验测定,并且代表需要抑制50%最大响应所需的所述化合物浓度。由FDSS软件输出加入50mM KCl后获得的最大荧光强度(FI),并且使用GraphPad Prism 3.02(Graph Pad Software Inc.,San Diego,CA,U.S.A.)进一步分析。将数据在50mM KCl存在下对于每个条件由重复的四个孔获得的最大平均计数归一化,并且在缓冲剂存在下的最小平均计数归一化。使用反曲浓度-响应或反曲浓度-响应(可变斜率)的非线性回归曲线拟合分析生成理论曲线,并且报导经由GraphPadPrism确定的最佳拟合曲线的IC50值。所得数据示于表2中。
表2.
实例2
自动电生理分析
细胞在T175烧瓶中生长至50%-90%融合。使用时,用Detachin(Genlantis,SanDiego,CA,U.S.A.)以酶促方法处理细胞,离心、淋洗,并且重新悬浮于以25mM HEPES(Sigma-Aldrich,St.Louis,MO,U.S.A.)增补的293SFM II培养基(Life Technologies,Grand Island,NY,U.S.A.)中,至2-3×106细胞/mL的浓度。将细胞加入到QPatch-HT(Sophion Biosciences,North Brunswick,NJ,U.S.A.)上的自动细胞制备台,并且在温和搅拌下,在10至30分钟恢复周期后,开始实施分析方案。自动细胞制备期间,收集细胞、离心并且重新悬浮于细胞外(EC)溶液中,所述溶液包含132mM NaCl、1.8mM CaCl2、5.4mM KCl、0.8mM MgCl2、10mM葡萄糖和10mM HEPES(pH=7.4),用蔗糖调节至约315m0sm。用细胞内溶液涂布QPlate,所述溶液包含135mM CsCl、10mM EGTA、4MgATP、0.3NaGTP和20mM HEPES(pH=7.2),用去离子水和EC溶液调节至约290m0sm。用QPatch-HT机器人移液器将细胞加入到准备好的QPlate孔中。
对于确定在稳定的全细胞膜片钳中的细胞,将EC溶液替换为钡(Ba)/三乙铵(TEA)溶液,所述溶液包含140mM TEA-Cl、10mM BaCl2、0.8mM MgCl2、10mM葡萄糖和10mM HEPES(pH=7.4)。制得高浓度(40mM)BaCl2,用TEA-Cl(90mM)调节以保持同渗容摩。自-80mV静态电位,每30秒向细胞递送一次一系列去极化脉冲(5Hz下15个脉冲,+20mV),递送八个系列(共4分钟),并且测定对照期间(无化合物)的所得电流。对于每次后续添加具有或不具有化合物的对照缓冲液(共三个周期,每个周期四个系列),重复该方案。将每个药物浓度存在下每个周期最后系列的第1次和第15次脉冲产生的电流相对于对照期间相应脉冲(分别代表低频和高频刺激)下产生的电流归一化。对每个细胞分析第二和第三药物施用期间的数据。最后进行包含60-100μM CdCl2的Ba/TEA溶液的加入,以阻隔所有N型电流,并且使每个细胞的电流归零。使用QPatch-HT的“分流”特征进行所有缓冲液/化合物的加入,所述QPatch-HT在每个记录周期开始时加入三份重复的5μL溶液。
为研究闭态失活,使细胞经历-80至+10mV的通道活化50ms去极化步骤脉冲,然后经历5s非活化步骤,电压以10mV增量在-130至-60mV范围内,接着经历50ms的-80至+10mV的步骤,以评定剩余电流。将来自激发电压脉冲的电流相对于-130mV步骤后测试脉冲的峰值归一化,并且拟合Boltzman公式,获得V1/2。将Roscovitine(Sigma-Aldrich)配制成100mM的二甲基亚砜原液,并且稀释至指定的工作浓度。将Tetrandrine(Sigma-Aldrich)配制成4mM的酸性水原液(pH=2.0),然后在外部溶液中稀释至工作浓度。将ω-Conotoxin MVIIA(Sigma-Aldrich)配制成具有0.1%牛血清白蛋白V(Life Technologies)的0.3mg/mL的水原液。首先将式(I)的化合物稀释到二甲基亚砜中,然后稀释到10%pluronic F-127的水溶液(Life Technologies)中,超声1分钟,并且稀释到EC缓冲液中。在所有实验中,进行载体对照物的平行测定。
除非另外指明,电生理结果之间比较的统计值采用单向方差分析,两两相比采用费希尔最小二乘法判定测试。所得数据示于下表3和4中。
表3.
表4.
活有机体内的分析
实例3
完全弗氏佐剂(CFA)诱导的痛觉过敏
啮齿目动物的完全弗氏佐剂(CFA)脚底注射造成长期持续的炎性反应,其特征在于对热和机械性刺激的显著过敏,其峰值介于注射后24-72小时之间,并且可持续几周。该测试预测许多有效临床试剂的止痛效应、抗异常疼痛效应和/或抗痛觉过敏效应,所述临床试剂包括对乙酰氨基酚、NSAIDS如阿司匹林和布洛芬、鸦片类物质如吗啡、以及尤其N型钙通道阻滞剂齐考诺肽,其以商品名市售,用于控制严重的慢性疼痛,包括若干类型的神经性疼痛。
为了评估式(I)测试化合物是否会逆转已建立的超敏反应,将100μL的CFA(悬浮于1∶1的盐水与热杀灭的肺结核分枝杆菌的矿物油乳液中)注入到斯普拉-道来大鼠(通常为150-350g范围内的雄性)的单个后爪中。
将每只大鼠置于温热的玻璃表面上的测试箱中,并使其适应大约10min。然后使辐射热刺激(光束)透过玻璃依次聚焦于各后爪的跖面上。当脚爪移动或到达截止时间(在约5安培下,辐射加热20秒)时,通过光电续电器自动关闭热刺激。记录每只动物在注射CFA之前对热刺激的最初(基线)反应潜伏期。在足跖注射CFA后24小时,接着再评估动物对热刺激的反应潜伏期,并将其与动物基线反应时间比较。只有表现出响应潜伏(即痛觉过敏)期降低至少25%的大鼠才被包括在进一步的分析中。在CFA注射后的潜伏期评估后,即刻将测试化合物或载体(通常为聚乙二醇硬脂酸酯、羟丙基甲基纤维素,羟丙基β-环糊精或PEG-400)腹膜内注射或口服施用于大鼠中。以固定的时间间隔(通常为30、60和120分钟)评估后化合物处理退缩潜伏期。式(I)的化合物71的所得数据示于图1中。
尽管上述说明书提出了本发明的原理,以示例为目的提供了实例,但应该理解本发明的实施涵盖落入以下权利要求书及它们的等同形式范围内的所有通常的变型、改变和/或修改。
Claims (31)
1.一种式(I)的化合物及其对映体、非对映体和药学上可接受的盐,
其中
R1选自C1-4烷基、C1-4烷氧基、三氟甲氧基和三氟甲基;
R2为氢;或R2可与R1以及连接R1和R2二者的苯环形成2,3-二氢苯并呋喃-7-基;
R3为氢、氯、或氟;
Q选自Q1、Q2和Q3;
其中
R4选自氢、C1-4烷基、C1-4烷氧基、氰基、氟、氯、羟基、二(C1-4烷基)氨基、(C1-4烷基)氨基、氨基、C1-4烷基羰基和C1-4烷基磺酰基;
R5和R6各自独立地选自氢、C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、羟基、烯丙基、2-甲基丙-1-烯基、氰基、肟、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、6-(吗啉-4-基)-嘧啶-3-基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基羰氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选地被一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基、吗啉-4-基和C1-4烷氧基羰基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、2-羟基丙-2-基、甲氧基甲基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]。
2.根据权利要求1所述的化合物,其中R1选自C1-4烷基、C1-4烷氧基和三氟甲氧基。
3.根据权利要求2所述的化合物,其中R1选自C1-4烷氧基和三氟甲氧基。
4.根据权利要求1所述的化合物,其中R2为氢。
5.根据权利要求1所述的化合物,其中R3为氢或氯。
6.根据权利要求5所述的化合物,其中R3为氢。
7.根据权利要求1所述的化合物,其中R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基。
8.根据权利要求1所述的化合物,其中R6为氯。
9.根据权利要求1所述的化合物,其中G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、2-甲基丙-1-烯基、氰基、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选地被一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基和C1-4烷氧基羰基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自
10.根据权利要求9所述的化合物,其中G选自C1-6烷基、C1-6烷氧基、C1-4烷氧基羰基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、三氟甲基羰基氨基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、
任选地被一个取代基取代的吡啶-3-基,所述取代基独立地选自C1-4烷基、环丙基和C1-4烷氧基羰基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自
11.根据权利要求1所述的式(I)的化合物及其对映体、非对映体和药学上可接受的盐,
其中
R1选自C1-4烷基、C1-4烷氧基和三氟甲氧基;
R2为氢;或R2可与R1以及连接R1和R2二者的苯环形成2,3-二氢苯并呋喃-7-基;
R3为氢或氯;
Q选自Q1、Q2和Q3;
其中
R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R5和R6各自独立地选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、2-甲基丙-1-烯基、氰基、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选地被一个选自吗啉-4-基的取代基取代或一至两个各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基和C1-4烷氧基羰基的取代基取代的吡啶-3-基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]。
12.根据权利要求1所述的式(I)的化合物及其对映体、非对映体和药学上可接受的盐,
其中
R1选自C1-4烷基、C1-4烷氧基和三氟甲氧基;
R2为氢;或R2可与R1以及连接R1和R2二者的苯环形成2,3-二氢苯并呋喃-7-基;
R3为氢;
Q选自Q1、Q2和Q3;
其中
R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R5选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R6为氯;
G选自C1-6烷基、羟基(C1-4)烷基、C1-6烷氧基、2-甲基丙-1-烯基、氰基、苯氧基、C1-4烷氧基羰基、C3-6环烷基、4,4-二甲基-环己基、C3-6环烷基(C1-4)烷基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、二(C1-4烷基)氨基羰基氨基-C1-4烷基、三氟甲基羰基氨基、三氟甲基羰基氨基-C1-4烷基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、1,2,3,4-四氢喹啉-3-基、氨基羰基、
任选地被一至两个取代基取代的吡啶-3-基,所述取代基各自独立地选自C1-4烷基、C1-4烷氧基、氯、环丙基和C1-4烷氧基羰基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基、C1-4烷基羰氧基-C1-4烷基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]。
13.根据权利要求1所述的式(I)的化合物及其对映体、非对映体和药学上可接受的盐,
其中
R1选自C1-4烷氧基和三氟甲氧基;
R2为氢;
R3为氢;
Q选自Q1、Q2和Q3;
其中
R4选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R5选自C1-4烷基、C1-4烷氧基、氰基、氯、和二(C1-4烷基)氨基;
R6为氯;
G选自C1-6烷基、C1-6烷氧基、C1-4烷氧基羰基、C3-6环烷氧基、C1-6烷基羰氧基、二(C1-4烷基)氨基羰氧基、二(C1-4烷基)氨基羰氧基-C1-4烷基、C1-4烷氧基羰基氨基-C1-4烷基、C3-6环烷基(C1-4)烷氧基、C3-6环烷基羰氧基、二(C1-4烷基)氨基磺酰基-氨基、二(C1-4烷基)氨基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基-(N-甲基)氨基、C1-4烷基磺酰基氨基、C1-4烷基磺酰基氨基-C1-4烷基、C1-4烷基羰基氨基-C1-4烷基、三氟甲基羰基氨基、2,5-二氧代-吡咯烷-1-基、2-氧代-吡咯烷-1-基、3,3-二氟-吡咯烷-1-基、3,3-二乙基-吡咯烷-1-基、3,3-二甲基-吡咯烷-1-基、吡啶氧基、三甲基甲硅氧基、氧代、(四氢-2H-吡喃-2-基)氧基、吗啉-4-基、2,6-二甲基-吗啉-4-基、吗啉-4-基羰氧基、吗啉-4-基羰氧基-C1-4烷基、4-甲基-哌啶-1-基、(1,2,4)-二环[2.2.1]庚-2-基氧基、四氢-2H-吡喃-4-基(C1-4)烷氧基、
任选地被一个取代基取代的吡啶-3-基,所述取代基独立地选自C1-4烷基、环丙基和C1-4烷氧基羰基;
任选地被一至两个取代基取代的1H-1,2,3-三唑-1-基,所述取代基各自独立地选自C1-4烷基、C3-6环烷基、C1-4烷氧基羰基和三甲基甲硅烷基;
任选地独立地被一至三个C1-3烷基取代基取代的1H-咪唑-1-基;
以及
螺稠杂环基,所述螺稠杂环基独立地选自
前提条件是式(I)的化合物不是N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;或
3-(4-氯苯基)-2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]。
14.一种式(I)的化合物及其药学上可接受的盐形式,
所述化合物选自:
2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙醇;
吗啉-4-甲酸2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙酯;
二甲基氨基甲酸2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙酯;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-丙-2-烯-1-基-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲酸乙酯;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲酰胺;
N-{[2-(2-甲氧基苯基)-3-苯基-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}甲磺酰胺;
N-{[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}甲磺酰胺;
2-(2-甲氧基苯基)-3-苯基-2,4,5,6-四氢环戊[c]吡唑-5-甲腈;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲腈;
N-{2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙基}甲磺酰胺;
N-{2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙基}乙酰胺;
{2-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]乙基}氨基甲酸叔丁酯;
3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-甲酸乙酯;
{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]亚甲基}氨基甲酸叔丁酯;
{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}氨基甲酸叔丁酯;
二乙基氨基甲酸[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲酯;
N-{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}甲磺酰胺;
N-{[3-(4-氯苯基)-2-(2-乙基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲基}-2,2,2-三氟乙酰胺;
(2-{3-(4-氯苯基)-2-[2-(三氟甲基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基}乙基)氨基甲酸叔丁酯;
N-(2-{3-(4-氯苯基)-2-[2-(三氟甲基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基}乙基)甲磺酰胺;
3-(2-{3-(4-氯苯基)-2-[2-(三氟甲基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基}乙基)-1,1-二甲基脲;
二甲基氨基甲酸3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
吗啉-4-甲酸3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,4,5,6-四氢环戊[c]吡唑-5-醇;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-醇;
3-(4-氯苯基)-2-[2-(三氟甲氧基)苯基]-2,6-二氢环戊[c]吡唑-5(4H)-酮;
二甲基氨基甲酸3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
吗啉-4-甲酸3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
二甲基氨基甲酸3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
吗啉-4-甲酸3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]甲磺酰胺;
N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]丙-2-磺酰胺;
N'-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N-二甲基磺酰胺;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,6-二氢环戊[c]吡唑-5(4H)-酮;
3-(4-氯苯基)-2-(2-乙氧基苯基)-2,6-二氢环戊[c]吡唑-5(4H)-酮;
N-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N-甲基甲磺酰胺;
1-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]吡咯烷-2,5-二酮;
3-(4-氯苯基)-2-(2-乙氧基苯基)-5-(1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑;
1-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]吡咯烷-2-酮;
3-(4-氯苯基)-2-(2-乙氧基苯基)-5-[4-(三甲基甲硅烷基)-1H-1,2,3-三唑-1-基]-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-乙氧基苯基)-5-(1H-1,2,3-三唑-1-基)-2,4,5,6-四氢环戊[c]吡唑;
(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-5-(1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑;
N-[(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]丙-2-磺酰胺;
N-[(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-2,2,2-三氟乙酰胺;
N-[(5R)-3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;
N'-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N-二甲基磺酰胺;
N-[3-(4-氯苯基)-2-(2-乙氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;
(5R)-3-(4-氯苯基)-5-甲氧基-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
N-[(5S)-3-(4-氯苯基)-2-(2,3-二氢-1-苯并呋喃-7-基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;
N-[(5S)-3-(4-氯苯基)-2-(2,3-二氢-1-苯并呋喃-7-基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N-甲基丙-2-磺酰胺;
2-(4-氯-2-甲氧基苯基)-3-(4-氯苯基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
(5Z)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,6-二氢环戊[c]吡唑-5(4H)-酮肟;
3-(4-氯苯基)-2-(2-甲氧基苯基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
2-乙基丁酸(5R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
N-[(5R)-2-(2-甲氧基苯基)-3-(6-甲氧基吡啶-3-基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-N,N',N'-三甲基磺酰胺;
N-{(5R)-2-(2-甲氧基苯基)-3-[6-(1-甲基乙氧基)吡啶-3-基]-2,4,5,6-四氢环戊[c]吡唑-5-基}-N,N',N'-三甲基磺酰胺;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-苯氧基-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(吡啶-3-基氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-[6-(1-甲基乙氧基)吡啶-3-基]-2,4,5,6-四氢环戊[c]吡唑;
(5R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(吡啶-2-基氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(6-吗啉-4-基吡啶-3-基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-吡啶-3-基-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(4,4-二甲基环己基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-1,2,3,4-四氢喹啉;
5-[3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]吡啶-3-甲酸乙酯;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(1-甲基乙氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-吗啉-4-基-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-[(三甲基甲硅烷基)氧基]-2,4,5,6-四氢环戊[c]吡唑;
2-乙基丁酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
(5S)-3-(4-氯苯基)-5-(2-乙基丁氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(6-甲基吡啶-3-基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(6-乙氧基吡啶-3-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
5-[2-氯-6-(1-甲基乙基)吡啶-3-基]-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(四氢-2H-吡喃-2-基氧基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(6-环丙基吡啶-3-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
环己烷甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
环戊烷甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
环丁烷甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
2-甲基丙酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
(5S)-3-(4-氯苯基)-5-(环己基甲氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环戊基甲氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环丁基甲氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(2-甲基丙氧基)-2,4,5,6-四氢环戊[c]吡唑;
四氢-2H-吡喃-4-甲酸(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基酯;
(5S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(四氢-2H-吡喃-4-基甲氧基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环己基氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-5-[(1S,2S,4R)-二环[2.2.1]庚-2-基氧基]-3-(4-氯苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
(5S)-3-(4-氯苯基)-5-(环戊基氧基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
4-[2-(2-甲氧基苯基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷]-3-基]苯甲腈;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(1-甲基乙基)-2,4,5,6-四氢环戊[c]吡唑;
4-[2-(2-甲氧基苯基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷]-3-基]-N,N-二甲基苯胺;
3-(6-乙氧基吡啶-3-基)-2-(2-甲氧基苯基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
2-(2-甲氧基苯基)-5',5'-二甲基-3-(6-甲基吡啶-3-基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
2-(2-甲氧基苯基)-3-(6-甲氧基吡啶-3-基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
5-[2-(2-甲氧基苯基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷]-3-基]-N,N-二甲基吡啶-2-胺;
(4'R,5'R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
(4'S,5'S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
(4'R,6'R)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4',6'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
(4'S,6'S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4',6'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
(2'R,4'R,5'S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
(2'S,4'R,5'S)-3-(4-氯苯基)-2-(2-甲氧基苯基)-4',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
3-(4-氯苯基)-5-环己基-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
4-[2-(2-甲氧基苯基)-5-(2-甲基丙基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[5-(环己基甲基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]-3-基]-N,N-二甲基苯胺;
3-(6-乙氧基吡啶-3-基)-2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
2-(2-甲氧基苯基)-4',4',5',5'-四甲基-3-(6-甲基吡啶-3-基)-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
5-[2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]-3-基]-N,N-二甲基吡啶-2-胺;
4-[2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷]-3-基]苯甲腈;
(3aR,7aS)-3'-(4-氯苯基)-2'-(2-甲氧基苯基)-2',3a,4,5,6,6',7,7a-八氢-4'H-螺[1,3-苯并二氧杂环戊烯-2,5'-环戊[c]吡唑];
(2'S,3aS,6aS)-3'-(4-氯苯基)-2'-(2-甲氧基苯基)-2',4,5,6,6',6a-六氢-3aH,4'H-螺[环戊[d][1,3]二氧杂环戊烯-2,5'-环戊[c]吡唑];
(2'R,3aR,6aS)-3'-(4-氯苯基)-2'-(2-甲氧基苯基)-2',4,5,6,6',6a-六氢-3aH,4'H-螺[环戊[d][1,3]二氧杂环戊烯-2,5'-环戊[c]吡唑];
(3aR,6aS)-3'-(4-氯苯基)-2'-(2-甲氧基苯基)-2',4,5,6,6',6a-六氢-3aH,4'H-螺[环戊[d][1,3]二氧杂环戊烯-2,5'-环戊[c]吡唑];
3-(4-氯苯基)-5-(2,6-二甲基吗啉-4-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-(4-甲基哌啶-1-基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(3,3-二乙基吡咯烷-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(3,3-二甲基吡咯烷-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
3-(5-氯噻吩-2-基)-2-(2-甲氧基苯基)-5',5'-二甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环己烷];
3-(5-氯噻吩-2-基)-2-(2-甲氧基苯基)-4',4',5',5'-四甲基-2,6-二氢-4H-螺[环戊[c]吡唑-5,2'-[1,3]二氧杂环戊烷];
3-(4-氯苯基)-2-(2-甲氧基苯基)-5-吡咯烷-1-基-2,4,5,6-四氢环戊[c]吡唑;
3-(4-氯苯基)-5-(3,3-二氟吡咯烷-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑;
4-[(5S)-5-(4-环戊基-1H-1,2,3-三唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
1-[(5S)-3-(4-氰基苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-1H-1,2,3-三唑-4-甲酸甲酯;
4-[(5S)-5-[4-(1-羟基-1-甲基乙基)-1H-1,2,3-三唑-1-基]-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-{(5S)-2-(2-甲氧基苯基)-5-[4-(2-甲基丙基)-1H-1,2,3-三唑-1-基]-2,4,5,6-四氢环戊[c]吡唑-3-基}苯甲腈;
{乙酸1-[(5S)-3-(4-氰基苯基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-5-基]-1H-1,2,3-三唑-4-基}甲酯;
4-[(5S)-5-[4-(甲氧基甲基)-1H-1,2,3-三唑-1-基]-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4-叔丁基-1H-1,2,3-三唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二甲基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-2-(2-甲氧基苯基)-5-(2,4,5-三甲基-1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(2-乙基-4,5-二甲基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(2-乙基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-2-(2-甲氧基苯基)-5-(2-甲基-1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二乙基-1H-1,2,3-三唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-2-(2-甲氧基苯基)-5-(2,4,5-三乙基-1H-咪唑-1-基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二乙基-2-甲基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈;
4-[(5S)-5-(4,5-二乙基-1H-咪唑-1-基)-2-(2-甲氧基苯基)-2,4,5,6-四氢环戊[c]吡唑-3-基]苯甲腈。
15.一种药物组合物,所述组合物包含权利要求1或14所述的化合物以及药学上可接受的载体、药学上可接受的赋形剂和药学上可接受的稀释剂中的至少一种。
16.根据权利要求15所述的药物组合物,其中所述组合物为固体口服剂型。
17.根据权利要求15所述的药物组合物,其中所述组合物为糖浆、酏剂或混悬剂。
18.根据权利要求1或14所述的化合物在制备治疗炎性疼痛的药物中的用途。
19.根据权利要求18所述的用途,其中所述炎性疼痛归因于炎性肠病、肠易激综合征、内脏疼痛、术后疼痛、背痛、腹痛、胸痛、分娩痛、肌肉骨骼疾病、皮肤病、牙痛、发热、烧伤、晒伤、蛇咬伤、蜘蛛咬伤、昆虫蜇伤、膀胱过动症、间质性膀胱炎、尿路感染、鼻炎、超敏反应、瘙痒、咽炎、粘膜炎、肠炎、胆囊炎、胰腺炎、痛经、子宫内膜异位症、由物理创伤所致的疼痛、头痛或蛛网膜炎。
20.根据权利要求19所述的用途,其中所述头痛是偏头痛、窦性头痛或紧张性头痛。
21.根据权利要求19所述的用途,其中所述蛇咬伤是毒蛇咬伤。
22.根据权利要求19所述的用途,其中所述膀胱过动症是神经源性膀胱过动症。
23.根据权利要求19所述的用途,其中所述超敏反应是接触性皮炎。
24.根据权利要求19所述的用途,其中所述超敏反应是湿疹。
25.根据权利要求19所述的用途,其中所述背痛是下背痛。
26.根据权利要求19所述的用途,其中所述术后疼痛是乳房切除术后疼痛综合征。
27.根据权利要求19所述的用途,其中所述肌肉骨骼疾病是骨关节炎或关节痛。
28.根据权利要求27所述的用途,其中所述骨关节炎是类风湿性关节炎。
29.根据权利要求1或14所述的化合物在制备治疗神经性疼痛的药物中的用途。
30.根据权利要求29所述的用途,其中所述神经性疼痛为癌症疼痛;神经障碍、脊神经和周边神经手术、脑肿瘤、外伤性脑损伤(TBI)、化学疗法引起的疼痛;疼痛迁延化、神经根痛、HIV疼痛、脊髓创伤、慢性疼痛综合征、纤维肌痛、慢性疲劳综合征、狼疮、肉样瘤病、周围神经病变、糖尿病性神经病变、中枢性疼痛、与脊髓损伤相关联的神经病变、中风、肌萎缩侧索硬化症(ALS)、帕金森氏病、多发性硬化症、坐骨神经炎、下颌关节神经痛、残肢痛、幻肢痛、骨折、口部神经性疼痛、夏科氏痛、I型和II型复杂性区域疼痛综合征(CRPS I/II)、神经根病变、格-巴二氏综合征、感觉异常性股痛、灼口综合征、视神经炎、发热后神经炎、游走性神经炎、节段性神经炎、贡博氏神经炎、神经元炎、颈臂神经痛、颅部神经痛、膝状神经节神经痛、舌咽神经痛、偏头痛性神经痛、特发性神经痛、肋间神经痛、乳房神经痛、摩顿氏神经痛、鼻睫神经痛、枕神经痛、疱疹后神经痛、灼痛、红斑性肢痛病、斯路德氏神经痛、蝶腭神经痛、眶上神经痛、三叉神经痛、外阴痛或翼管神经痛。
31.根据权利要求30所述的用途,其中所述周围神经病变是双侧周围神经病变或周围神经炎。
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