CN116903563A - Gpcr调节剂及其应用 - Google Patents
Gpcr调节剂及其应用 Download PDFInfo
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- CN116903563A CN116903563A CN202310421384.3A CN202310421384A CN116903563A CN 116903563 A CN116903563 A CN 116903563A CN 202310421384 A CN202310421384 A CN 202310421384A CN 116903563 A CN116903563 A CN 116903563A
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- membered
- nmr
- carboxylic acid
- compound
- methyl
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- AXORVIZLPOGIRG-UHFFFAOYSA-N β-methylphenethylamine Chemical compound NCC(C)C1=CC=CC=C1 AXORVIZLPOGIRG-UHFFFAOYSA-N 0.000 description 1
Classifications
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Abstract
本发明属于医药技术领域。特别地,本发明涉及可作为GPR132调节剂的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式。本发明还涉及所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的制备方法以及医药用途。
Description
技术领域
本发明属于医药技术领域。特别地,本发明涉及可作为GPR132调节剂的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式。本发明还涉及所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的制备方法以及医药用途。
背景技术
G蛋白偶联受体(G protein-coupled receptors,GPCR)是一类将化学信号从细胞外基质蛋白传递到细胞内的跨膜蛋白,参与和调控生理和病理功能的运作。人类基因组中已鉴定出800多种GPCRs,依据氨基酸序列相似性划分为A、B、C、F类。其中A类(也称视紫红质样GPCR)家族成员最大,由719种GPCR组成。GPCR信号调控涉及配体、GPCR、效应蛋白和下游相应信号通路。配体作用于GPCR后,GPCR激活并发生构象重排,募集效应蛋白,发挥信号传导功能。GPCR信号传导有着高度的生物学复杂性和重要性,因此GPCR成为极具价值的药物靶点。
G蛋白偶联受体132(G protein-coupled receptor 132,GPR132)是七重跨膜的G蛋白偶联受体,属于视紫红质家族(Class A)GPCR。1998年Weng等人发现,B细胞、T细胞在压力诱导下可上调GPR132表达,引起G2期细胞周期阻止,因此将编码该蛋白的基因命名为G2A(G2 accumulation),并认为可能是潜在的抑癌基因。GPR132表达具有组织特异性和细胞类型特异性,主要存在于血液和淋巴组织。GPR132表达主要被发现在巨噬细胞、树突状细胞、中性粒细胞、T细胞、B淋巴细胞等血液细胞中,但在免疫细胞中的表达并无特异性。
据人们目前所了解,GPR132主要在免疫细胞中发挥作用,调节免疫功能,与多种免疫相关疾病和恶性肿瘤有紧密联系。2001年,Le等人发现GPR132缺陷型小鼠发生迟发性自身免疫综合征,提出GPR132是一个潜在的自身免疫病靶点。Parks等人发现在低密度脂蛋白受体缺陷型小鼠种,GPR132缺失可改善动脉粥样硬化病情。Tabea等人发现,GPR132缺陷减少神经损伤部位的免疫细胞数量,降低促炎细胞因子释放,从而减轻炎症反应,因此抑制GPR132有望应用于神经疼痛的缓解和治疗。此外,GPR132可能在肿瘤微环境种扮演重要角色。Chen等人发现在小鼠乳腺癌模型种,GPR132缺陷阻碍巨噬细胞向M2型极化,进而阻碍肿瘤细胞的侵袭和转移,抑制肿瘤肺转移。
发明内容
本申请的本发明人通过深入的研究和创造性的发现,得到了一类苯并呋喃衍生物,其可作为GPR132调节剂(例如拮抗剂),可用于预防或治疗与GPR132相关的疾病,例如动脉粥样硬化、神经性疼痛、乳腺癌、高脂血症、2型糖尿病等,由此提供了下述发明。
化合物
在第一方面,本发明提供了式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,
其中:
A选自6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基;任选地,所述6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基被一个或多个M取代;
M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(=O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基;任选地,所述C1-C6烷氧基被一个或多个选自以下的基团取代:C1-C6卤代烷基、3至6元环烷基;所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代;
R1选自羟基、-NR5R6、C1-C6烷氧基;任选地,所述C1-C6烷氧基被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基;
Q为苯基或苯并5-6元杂芳基环;
R2选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;m选自1、2、3、4;当有多个R2时,各个R2可以相同或不同;
R3、R4、R5、R6各自独立地选自氢、羟基和C1-C6烷基;任选地,所述C1-C6烷基被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基;
R7、R8各自独立地选自C1-C6烷基,q选自1至10之间的整数;
L1、L2各自独立地为不存在或选自-(CH2)n-、3至6元环烷基,n为选自1至6的整数;任选地,-(CH2)n-被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基、氘、氚、羰基;并且,所述化合物不是3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸。
在某些实施方案中,A选自6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基、C2-C6烯基、C2-C6炔基;任选地,所述6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基被一个或多个M取代,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基;任选地,所述C1-C6烷氧基被一个或多个选自以下的基团取代:C1-C6卤代烷基、3至6元环烷基;
R1选自羟基、-NR5R6、C1-C6烷氧基;任选地,所述C1-C6烷氧基被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基;
Q为苯基或苯并5-6元杂芳基环;
R2选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;m选自1、2、3、4;当有多个R2时,各个R2可以相同或不同;R3、R4、R5、R6各自独立地选自氢、羟基和C1-C6烷基;任选地,所述C1-C6烷基被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基;
L1、L2各自独立地为不存在或选自-(CH2)n-、3至6元环烷基,n为选自1至6的整数;任选地,-(CH2)n-被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基、氘、氚;
并且,所述化合物不是3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸。
A选自6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基;任选地,所述6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基被一个或多个M取代;
优选地,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(=O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基;所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代;
优选地,R7、R8各自为甲基,q选自1至4之间的整数;
优选地,A选自6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基、苯并5至6元含氧杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基;任选地,所述6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基或苯并5至6元含氧杂环基被一个或多个M取代;
优选地,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、-P(=O)(CH3)2、CH3CH2O-(CH2CH2O)-;
优选地,A选自苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基、苯并环己烷基;任选地,所述苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基或苯并环己烷基被一个或多个M取代;
优选地,M选自以下基团:卤素(例如氟、氯、溴、碘)、C1-C4烷基、三氟甲基、甲氧基、乙氧基、苯基、C2-C4炔基、C1-C6烷酰基、硝基、羟基、氰基、-NR3R4、-P(=O)(CH3)2、CH3CH2O-(CH2CH2O)-、4至6元杂环基、5至6元杂芳基、苯氧基;所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代。
在某些实施方案中,A选自6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基、C2-C6烯基、C2-C6炔基;任选地,所述6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基被一个或多个M取代。
在某些实施方案中,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基。
在某些实施方案中,R3、R4各自独立地选自氢和羟基。
在某些实施方案中,所述C1-C6烷氧基被一个或多个选自以下的基团取代:C1-C6氟代烷基、环丙基。
在某些实施方案中,A选自6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基、C2-C6烯基、C2-C6炔基;任选地,所述6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基被一个或多个M取代。
在某些实施方案中,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基。
在某些实施方案中,A选自苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基;任选地,所述苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基被一个或多个M取代。
在某些实施方案中,M选自以下基团:卤素(例如氟、氯、溴)、氰基、-NHCH3、C1-C4烷基、C2-C4炔基、三氟甲基、甲氧基、乙氧基、乙酰基、苯基、苯氧基。在某些实施方案中,所述甲氧基或乙氧基被一个或多个三氟甲基或环丙基取代。
在某些实施方案中,R1为羟基或-NHOH。
在某些实施方案中,R2卤素、选自C1-C6烷基(例如甲基)、C1-C6卤代烷基(例如氟代甲基)。
在某些实施方案中,L1不存在或选自-(CH2)n-、环丙基,n为选自1至4的整数;任选地,-(CH2)n-被甲基取代或被氘代;任选地,-(CH2)n-被甲基或羰基取代或被氘代。在某些实施方案中,L2不存在或选自-(CH2)n-、n为选自1至4的整数;任选地,-(CH2)n-被甲基取代或被氘代。
在某些实施方案中,所述5-6元杂芳基选自呋喃基、噻吩基、吡咯基。在某些实施方案中,所述5-6元杂芳基为呋喃基。
在某些实施方案中,所述化合物的结构如式(II)所示:
其中,X选自O、S或NH。
在某些实施方案中,所述化合物的结构如式(III)或(IV)所示:
在某些实施方案中,X为O。
在某些实施方案中,X为S。
在某些实施方案中,X为NH。
在某些实施方案中,A为任选被一个或多个M取代的苯基,M如上文所定义。
在某些实施方案中,本发明的化合物选自表1所示的化合物:
表1
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在某些实施方案中,所述化合物的结构如式(V)所示:
其中,
Core为X选自O、S或NH,
R2如上文所定义。
在某些实施方案中,R2选自氢、卤素(例如氟、氯、溴)、C1-C6烷基(例如甲基)。在某些实施方案中,Core选自:
在某些实施方案中,所述化合物选自表2所示的化合物:
表2
在某些实施方案中,所述化合物的结构如式(VI)所示:
其中,A如上文所定义。
在某些实施方案中,A选自任选被一个或多个M取代的苯基,M选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、硝基、羟基、-NR3R4,R3、R4各自独立地选自氢、C1-C6烷基。
在某些实施方案中,所述化合物选自表3所示的化合物:
表3
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在某些实施方案中,所述化合物的结构如式(VI)所示,其中,A选自任选被一个或多个M取代的以下基团:苯基、5至6元含氮杂芳基;M选自:卤素、C2-C6炔基、C1-C6烷氧基、氰基、P(=O)R7R8、C1-C6烷酰基、CH3CH2O-(CH2CH2O)q-、苯基、4至6元杂环基、5至6元杂芳基,其中,R7、R8各自独立地选自C1-C6烷基,q选自1至10之间的整数,所述苯基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代。
在某些实施方案中,所述化合物选自表4所示的化合物:
表4
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在某些实施方案中,所述化合物的结构如式(VI)所示,其中,A选自任选被一个或多个M取代的以下基团:苯基、萘基、苯并5至6元杂环基(例如苯并5至6元含氧杂环基)、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基);M选自卤素、C1-C6烷基、C1-C6烷氧基。
在某些实施方案中,所述化合物选自表5所示的化合物:
表5
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在某些实施方案中,所述化合物的结构如式(VI)所示,其中,A选自任选被一个或多个M取代的以下基团:C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烷基、5至6元环烯基、5至6元杂芳基、5至6元杂环基;M选自C1-C6烷基、卤素。
在某些实施方案中,所述化合物选自表6所示的化合物:
表6
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在某些实施方案中,本发明化合物的结构如式(VII)所示,
其中,A和L1如上文所定义。
在某些实施方案中,A选自苯基、萘基,L1不存在或选自-(CH2)n-,n为选自1至4的整数;任选地,-(CH2)n-被一个或多个选自以下的基团取代:卤素、C1-C6烷基、羰基。
在某些实施方案中,所述化合物选自表7所示的化合物:
表7
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在某些实施方案中,本发明化合物的结构如式(VII)所示,其中,L1不存在,A选自任选被一个或多个M取代的以下基团:苯基、萘基、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基)、苯并5至6元环烷基,M选自C1-C6烷基、C2-C6炔基、卤素、苯氧基、-NR3R4、5至6元杂环基,R3、R4各自独立地选自C1-C6烷基,所述5至6元杂环基任选地被C1-C6烷基取代。
在某些实施方案中,所述化合物选自表8所示的化合物:
表8
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本发明的化合物的药学上可接受的酯优选为羧酸乙酯。
药物组合物
在第二方面,本申请提供了一种药物组合物,其包含式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式;任选地,所述药物组合物还包含药学上可接受的载体或赋形剂。
在本发明中,所述药物组合物可以是医学领域已知的任何形式。例如,所述药物组合物可以是片剂、丸剂、混悬剂、乳剂、溶液、凝胶剂、胶囊剂、粉剂、颗粒剂、酏剂、锭剂、栓剂、注射剂(包括注射液、冻干粉剂)、吸入剂、喷雾剂等形式。优选剂型取决于预期的给药方式和治疗用途。
在某些实施方案中,所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式,可以以单位剂量形式存在于药物组合物中,以便于施用。
所述化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式、或者所述药物组合物,可以通过本领域已知的任何合适的方法来施用,包括但不限于,口服、直肠、肠胃外或局部给药。
一种示例性施用途径是口服给药。用于口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、悬浮剂、糖浆剂、酏剂等。除活性化合物以外,液体剂型可含有本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂。除惰性稀释剂以外,口服给药的液体剂型也可包括助剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和芳香剂等。用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、锭剂、粉剂、颗粒剂等。除活性化合物以外,固体剂型可含有药学上可接受的惰性赋形剂或载体,例如填充剂、粘合剂、湿润剂、崩解剂、润滑剂及其混合物。
本发明的化合物或药物组合物也可通过非口服途径给药。
因此,另一种示例性的施用途径是肠胃外给药,例如,皮下注射、静脉注射、腹膜内注射、肌肉注射、胸骨内注射和注入。用于肠道外给药的剂型可以为注射制剂,包括注射液、注射用无菌粉末或注射用浓溶液。除活性化合物以外,注射剂型可含有药学上可接受的载体例如无菌水、林格氏液和等渗氯化钠溶液,也可根据药物的性质加入适宜的附加剂例如抗氧化剂、缓冲剂和抑菌剂。
另一种示例性的施用途径是局部给药,例如经皮给药(如通过经皮贴剂或离子电渗装置给药)、眼内给药或者鼻内或吸入给药。用于经皮给药的剂型可以为局部凝胶剂、喷雾剂、软膏剂和霜剂。除活性化合物以外,局部剂型可含有能够提高该活性化合物通过皮肤或其它作用区域的吸收或渗透的成分。当本发明的化合物通过经皮装置给药时,给药将使用存储和多孔膜类型或者固体基质品种的贴剂完成。用于眼部局部给药的剂型可以为滴眼剂,其中本发明的化合物被溶于或者悬浮于适宜的载体中。对于鼻内给药或吸入给药来说,本发明的化合物以溶液剂或悬浮剂的形式从压力喷雾容器中被方便地递送,所述传递是通过患者压握或者泵送而进行的,或者是作为气溶胶喷雾剂制剂从压力容器或喷雾器中使用适宜的抛射剂而传递的。
另一种示例性的施用途径是直肠给药。用于直肠给药的剂型可以为栓剂。
此外,还可以使用药学领域已知的其它载体材料和给药方式。本发明的药物组合物可以通过任何公知的制药工艺制备,例如有效的制剂和给药方法。关于有效制剂和给药方法的上述考虑因素是本领域中公知的,并且描述于标准教科书中。药物的制剂描述在,例如,Hoover,John E.,Remington′s Pharmaceutical Sciences.Mack PublishingCo.,Easton,Pennsylvania,1975;Liberman等人编辑,Pharmaceutical Dosage Forms,MarcelDecker,New York,N.Y.,1980;以及Kibbe等人编辑,Handbook of PharmaceuticalExcipients(第3版),American Pharmaceutical Association,Washington,1999。
在某些实施方案中,所述药物组合物含有本发明的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的量为0.01-2000mg,优选为0.1-1000mg,更优选为1-800mg,更优选为10-600mg,特别优选为50-500mg。
本发明的药物组合物可以包括“治疗有效量”或“预防有效量”的如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式。“预防有效量”是指,足以预防,阻止,或延迟疾病的发生的量。“治疗有效量”是指,足以治愈或至少部分阻止已患有疾病的患者的疾病和其并发症的量。本领域技术人员理解,如本文所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型、它们的代谢物形式的治疗有效量可根据如下因素发生变化:待治疗的疾病的严重度、患者自己的免疫系统的总体状态、患者的一般情况例如年龄,体重和性别,药物的施用方式,以及同时施用的其他治疗等等。
在本发明中,可调整给药方案以获得最佳目的反应(例如治疗或预防反应)。例如,可以单次给药,可以在一段时间内多次给药,或者可以随治疗情况的紧急程度按比例减少或增加剂量。
本发明化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的治疗或预防有效量的典型非极限范围是0.01~1000mg/kg,例如0.1~500mg/kg。应注意的是,剂量可随需要治疗的症状的类型和严重性不同而发生变化。此外,本领域技术人员理解,对于任一特定患者,特定的给药方案应根据患者需要和医生的专业评价而随时间调整;此处给出的剂量范围只用于举例说明目的,而不限定本发明药物组合物的使用或范围。
在某些实施方案中,所述药物组合物还可以包含另外的药学活性剂。
在某些实施方案中,在所述药物组合物中,本发明化合物与所述另外的药学活性剂作为分离的组分或混合的组分提供。因此,本发明化合物与所述另外的药学活性剂可以同时、分开或相继施用。
用途
本发明化合物可作为GPR132的调节剂(例如拮抗剂),用于预防或治疗与GPR132相关的疾病。
因此,在第三方面,本申请提供了化合物用于制备药物中的用途,所述药物用于预防或治疗与GPR132相关的疾病,所述化合物选自式(I)或下表中的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式
在某些实施方案中,所述与GPR132相关的疾病选自肿瘤、代谢性疾病、免疫相关疾病、神经性疼痛。
在某些实施方案中,所述肿瘤选自选自:乳腺癌、黑色素瘤、脑膜瘤、软组织肉瘤、唾液腺肿瘤、原发性肝癌、椎管内肿瘤、纵隔肿瘤、脑癌、骨癌、阴茎癌、骨肉瘤、颅内肿瘤、舌癌、上颌窦癌、甲状腺癌、恶性淋巴瘤、多发性骨髓瘤、脑垂体腺瘤、睾丸肿瘤、非何杰金氏淋巴癌、膀胱癌、白血病、胃癌、鼻咽癌、喉癌、口腔癌、食管癌、肺癌、肾癌、宫颈癌、绒毛膜癌、外阴癌、皮肤癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、结肠癌、直肠癌、大肠癌、卡波西肉瘤、非黑色素瘤皮肤癌(包括鳞状细胞癌和基底细胞癌)、血管瘤、神经胶质瘤。
在某些实施方案中,所述代谢性疾病选自动脉粥样硬化、肥胖、非酒精性脂肪肝病(NAFLD)(例如,单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、高血糖、高脂血症(例如,高胆固醇血症),及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜病、神经病、肾病以及延缓的创伤愈合,或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病)。
在某些实施方案中,所述免疫相关疾病选自:
继发性免疫缺陷:例如由感染(例如风疹、麻疹、麻风、结核病、巨细胞病毒感染、艾滋病病毒感染、球孢子菌感染),蛋白丢失(例如肾病综合征、蛋白丢失性肠病),免疫球蛋白合成不足,淋巴细胞丢失(例如因药物和/或系统感染引起的淋巴细胞丢失),其他疾病(如糖尿病、肝硬变、亚急性硬化性全脑炎)和/或免疫抑制治疗引起的继发性免疫缺陷;以及
自身免疫疾病:例如系统性红斑狼疮、类风湿性关节炎、硬皮病、甲状腺机能亢进、青少年糖尿病、原发性血小板紫癜、自身免疫性溶血性贫血、溃疡性结肠炎、皮肤病、慢性肝病。
治疗方法
在第四方面,本发明提供了一种用于在受试者中预防或治疗与GPR132相关的疾病的方法,所述方法包括向有此需要的受试者施用有效量的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,所述化合物选自式(I)或下表中的化合物
所述与GPR132相关的疾病可以选自上文所述的疾病。
制备方法
在第五方面,本申请还提供了合成式(I)化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式的方法,该方法包括以下步骤:在无机碱或有机碱存在的条件下,通式(I-A)和通式(I-B)化合物反应获得通式(I)化合物:
其中环A、X、L1、R1-R6的定义分别如前文所述;所述无机碱优选自碳酸钾、碳酸钠、氢化钠、氢氧化钠、氢氧化钾、碳酸铯;所述有机碱优选自三乙胺、二异丙基乙基胺;反应溶剂优选自二氯甲烷、乙腈、N,N-二甲基甲酰胺。
本发明还提供一种制备如通式(I)所示的化合物或其可药用盐的方法,该方法包括以下步骤:在无机碱或有机碱存在的条件下,通式(II-A)和通式(II-B)化合物反应获得通式(I)化合物:
其中环A、L1、L2、R1-R6的定义分别如前文所述;所述无机碱优选自碳酸钾、碳酸钠、氢化钠、氢氧化钠、氢氧化钾、碳酸铯;所述有机碱优选自三乙胺、二异丙基乙基胺;反应溶剂优选自二氯甲烷、乙腈、N,N-二甲基甲酰胺。
术语定义
在本发明中,除非另有说明,否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。并且,本文中所涉及的实验室操作步骤均为相应领域内广泛使用的常规步骤。同时,为了更好地理解本发明,下面提供相关术语的定义和解释。
如本文中所使用的,术语“C1-C6烷基”是指含有1-6个碳原子的直链或支链烷烃去掉一个氢原子后得到的基团,优选的C1-C6烷基是C1-C4烷基,其具体实例包括但不限于:甲基、乙基、丙基、正丁基、正戊基、正己基、异丙基、叔丁基或异丁基。
如本文中所使用的,术语“C2-C6烯基”是指含有至少一个双键的、且碳原子数为2-6的直链、支链或环状的烯基,实例包括但不限于:乙烯基、1-丙烯-1-基、烯丙基、1-丁烯-1-基、1-戊烯-1-基、1,3-丁二烯-1-基、1,4-戊二烯-1-基。优选的C2-C6烯基是C2-C4烯基。
如本文中所使用的,术语“C2-C6炔基”是指含有至少一个三键的、碳原子数为2-6的直链或支链的炔基,实例包括但不限于:乙炔基、丙炔基、2-丁炔基、2-戊炔基、3-戊炔基、4-甲基-2-戊炔基、2-己炔基、3-己炔基、5-甲基-2-己炔基。优选的C2-C6炔基是C2-C4炔基。如本文中所使用的,术语“卤素”包括氟、氯、溴和碘。
如本文中所使用的,术语“卤代”是指基团或化合物上的氢被一个或多个卤素原子取代,包括全卤代和部分卤代。
如本文中所使用的,术语“烷氧基”是指,以烷基-O-方式形成的基团,实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、新戊氧基、或正己氧基。
如本文中所使用的,术语“C1-C6酰基”是指以H-(C=O)-或者C1-C6烷基-(C=O)-方式形成的基团,实例包括但不限于甲酰基、乙酰基、正丙酰基、正丁酰基、异丁酰基、正戊酰基、新戊酰基等。如本文中所使用的,术语“环烷基”指饱和或部分不饱和的单环或多环环状烃基,环烷基的环可以包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至10个碳原子,最优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基。
如本文中所使用的,术语“杂环基”指饱和或部分不饱和的单环或多环环状烃基,其包含3至20个环原子,其中一个或多个(例如1、2、3或4个)环原子为选自氮、氧或硫的杂原子。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至10个环原子;最优选包含5至6个环原子,其中含有1至2个选自氮、氧或硫的杂原子。任选地,所述硫原子可以被氧代。单环杂环基的非限制性实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
如本文中所使用的,术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(即共享毗邻碳原子对的环)基团,优选为6-10元,例如苯基、萘基。
如本文中所使用的,术语“杂芳基”指具有共轭的π电子体系的包含杂原子的单环或稠合多环(即共享毗邻碳原子对的环)基团,优选为5至10元杂芳基,包括5至8元单环杂芳基和8至14元稠杂芳基。
如本文中所使用的,术语“5至8元单环杂芳基”是指含有5至8个环原子的具有芳香性的单环环状基团,其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子,同时包括环上的碳原子、氮原子和硫原子被氧代的情况。实例包括但不仅限于呋喃基、噻吩基、吡咯基、噻唑基、异噻唑基、噻二唑基、噁唑基、异噁唑基、噁二唑基、咪唑基、吡唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、吡啶基、2-吡啶酮、4-吡啶酮、嘧啶基、1,4-二氧杂环己二烯基、2H-1,2-噁嗪基、4H-1,2-噁嗪基、6H-1,2-噁嗪基、4H-1,3-噁嗪基、6H-1,3-噁嗪基、4H-1,4-噁嗪基、哒嗪基、吡嗪基、1,2,3-三嗪基、1,3,5-三嗪基、1,2,4,5-四嗪基、氮杂环庚三烯基、1,3-二氮杂环庚三烯基、氮杂环辛四烯基等,优选为“5-6元杂芳基”。
如本文中所使用的,术语“8至14元稠杂芳基”是指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的、含有8至10个环原子的、不饱和的具有芳香性的环状结构,其中至少一个环原子为杂原子,例如氮原子、氧原子或硫原子,同时包括环上的碳原子、氮原子和硫原子被氧代的情况。实例包括但不限于:苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并三唑基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。
如本文中所使用的,术语“被取代”是指基团上的一个或多个氢原子被一个或多个取代基所取代,所述“多个取代基”之间可以相同或不同。例如,“C2烷基被取代”是指C2烷基上的一个或多个氢原子被一个或多个取代基所取代。
如本文中所使用的,术语“药学上可接受的盐”是指,(i)本发明所提供的化合物中存在的酸性官能团(例如-COOH)与适当的无机或者有机阳离子(碱)形成的盐,并且包括但不限于,碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铝盐、铁盐、锌盐、铜盐、镍盐、钴盐等;无机碱盐,如铵盐;有机碱盐,如叔辛基胺盐、二苄基胺盐、吗啉盐、葡糖胺盐、苯基甘氨酸烷基酯盐、乙二胺盐、N-甲基葡糖胺盐、胍盐、二乙胺盐、三乙胺盐、二环己基胺盐、N,N’-二苄基乙二胺盐、氯普鲁卡因盐、普鲁卡因盐、二乙醇胺盐、N-苄基-苯乙基胺盐、哌嗪盐、四甲基胺盐、三(羟甲基)氨基甲烷盐。以及,(ii)本发明所提供的化合物中存在的碱性官能团(例如-NH2)与适当的无机或者有机阴离子(酸)形成的盐,并且包括但不限于,氢卤酸盐,如氢氟酸盐、盐酸盐、氢溴酸盐、氢碘酸盐等;无机酸盐,如硝酸盐、高氯酸盐、硫酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对苯磺酸盐等;有机酸盐,如醋酸盐、苹果酸盐、富马酸盐、琥珀酸盐、柠檬酸盐、酒石酸盐、草酸盐、马来酸盐等;氨基酸盐,如甘氨酸盐、三甲基甘氨酸盐、精氨酸盐、鸟氨酸盐、谷氨酸盐、天冬氨酸盐等。
如本文中所使用的,术语“药学上可接受的酯”是指,本发明所提供的化合物中存在的-COOH与适当的醇(例如甲醇或乙醇)形成的酯,或者本发明所提供的化合物中存在的-OH与适当的酸(例如,羧酸或含氧无机酸)形成的酯。适宜的酯基团包括但不限于,甲酸酯、乙酸酯、丙酸酯、丁酸酯、丙烯酸酯、乙基琥珀酸酯、硬脂肪酸酯或棕榈酸酯。酯在酸或者碱存在的条件下,可以发生水解反应生成相应的酸或醇。
如本文中所使用的,术语“溶剂合物”是指本发明化合物与溶剂分子缔合形成的物质。所述溶剂可以是有机溶剂(例如甲醇、乙醇、丙醇、乙腈等),例如本发明化合物可以与乙醇形成乙醇化物。本发明化合物还可以与水形成水合物。
如本文中所使用的,术语“晶型”是指物质的晶体结构。物质在结晶时由于受各种因素影响,使分子内或分子间键合方式发生改变,致使分子或原子在晶格空间排列不同,形成不同的晶体结构。本发明化合物可以一种晶体结构存在,也可以多种晶体结构存在,即具有“多晶型”。本发明化合物可以不同的晶型存在。
如本文中所使用的,术语“立体异构体”包括构象异构体和构型异构体,其中所述构型异构体主要包括顺反异构体和旋光异构体。本发明化合物可以以立体异构体的形式存在,并因此涵盖所有可能的立体异构体形式,及其任何组合或任何混合物。例如单一对映异构体,单一非对映异构体或以上的混合物。当本发明化合物含有烯烃双键时,除非特别说明,否则其包括顺式异构体和反式异构体,以及其任何组合。
如本文中所使用的,术语“前药”是指可在受试者体内通过例如氧化、还原、水解等反应转化成本发明的化合物。前药自身可或不可具有式(I)化合物的生物活性(例如,调节糖脂代谢活性,抗炎活性,抗氧化活性)。例如,包括羟基或羧基的式(I)化合物可以酯的形式给药,其在体内水解转化成羟基化合物或羧基化合物。类似地,包括氨基的式(I)化合物发生酰化、烷基化或磷酸化,以形成例如二十烷酰基氨基(Eicosanoylamino)、丙氨酰氨基、新戊酰氧甲基氨基的化合物给药。关于前体药物使用的进一步信息可以参见Pro-drugs asNovel Delivery Systems,Vol.14,ACS Symposium Series(T Higuchi and W Stella)和Bioreversible Carriers in Drug Design,Pergamon Press,1987(ed.E B Roche,American Pharmaceutical Association)。根据本发明的一些前体药物实例包括:(i)若式(I)化合物含有羧酸官能团(-COOH),则包括它的酯,例如用(C1-C8)烷基代替氢;(ii)若式(I)化合物含有醇官能团(-OH),则包括它的醚,例如用(C1-C6)烷酰氧基甲基代替氢;和(iii)若式(I)化合物含有伯或仲氨基官能团(-NH2或-NHR,其中R不为H),则包括它的酰胺,例如用(C1-C10)烷酰基代替一个或两个氢。此外,某些式(I)化合物本身可以充当其他式(I)化合物的前体药物。
如本文中所使用的,术语“药学上可接受的载体或赋形剂”是指,在药理学和/或生理学上与受试者和活性成分相容的载体和/或赋形剂,其是本领域公知的(参见例如Remington's Pharmaceutical Sciences.Edited by Gennaro AR,19thed.Pennsylvania:Mack Publishing Company,1995),并且包括但不限于:崩解剂、粘合剂、表面活性剂、助流剂、润滑剂、pH调节剂、离子强度增强剂、维持渗透压的试剂、延迟吸收的试剂、稀释剂、抗氧化剂、着色剂、矫味剂、防腐剂、味道掩蔽剂等。
如本文中使用的,术语“受试者”是指哺乳动物,例如鼠、兔、犬,例如灵长类哺乳动物,例如猴、人。
如本文中使用的,术语“调节剂”是指可以直接或间接与靶标相互作用的分子。所述调节剂包括但不限于激动剂、部分激动剂、反向激动剂和拮抗剂。在本申请的一些实施方案中,调节剂是激动剂。
如本文所用的,术语“激动剂”是指与特定受体结合并且触发在细胞中的反应的分子。激动剂可以模仿与相同受体结合的内源性配体(诸如LPA、前列腺素、激素或神经递质)的作用。
如本文所用的,术语“拮抗剂”是指减弱、抑制或阻止另一种分子的作用或受体位点的活性的分子。拮抗剂包括但不限于竞争性拮抗剂、非竞争性拮抗剂、不竞争性拮抗剂、部分激动剂和反向激动剂。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但是本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。
除非特别指明,否则基本上按照本领域内熟知的以及在各种参考文献中描述的常规方法进行实施例中描述的实验和方法。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规产品。本领域技术人员知晓,实施例以举例方式描述本发明,且不意欲限制本发明所要求保护的范围。本文中提及的全部公开案和其他参考资料以其全文通过引用合并入本文。
化合物的合成和结构表征
实施例1
步骤1:3-甲基苯并呋喃-2-羧酸乙酯
将2-羟基苯乙酮(2.72g,20mmol),溴乙酸乙酯(5.01g,30mmol),碳酸钾(5.52g,40mmol),加入N,N-二甲基甲酰胺(25mL)中加热至160℃反应3h,TLC检测反应完毕后,冷却至室温,减压抽滤出固体,滤饼用乙酸乙酯(25mL)冲洗三次,滤液合并后减压蒸馏除去溶剂,加水(100mL)溶解,乙醚(100mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=15/1~10/1)得白色固体1.54g,收率38%。
步骤2:3-甲基-5-(氯磺酰基)苯并呋喃-2-羧酸乙酯
将3-甲基苯并呋喃-2-羧酸乙酯(3.06g,15mmol)加入三氯甲烷(45mL)中,0℃下搅拌10mins后,滴加氯磺酸(8.70g,75mmol)的三氯甲烷(45mL)溶液,室温搅拌4h,TLC检测反应完毕后,将反应液倒入冰水中,用二氯甲烷(150mL)萃取三次,合并有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经石油醚/乙酸乙酯重结晶得白色固体2.07g,收率46%。
步骤3:3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯
将5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(2.07g,6.86mmol),碳酸钾(1.89g,13.72mmol)溶于无水二氯甲烷(80mL)中,室温下滴加苯乙胺(0.97g,8.23mmol)的无水二氯甲烷(20mL)溶液,室温搅拌3h,TLC检测反应完毕后,减压蒸馏除去溶剂,加水(100mL)溶解,乙酸乙酯(100mL)萃取三次,有机相用饱和氯化钠水溶液洗,加无水硫酸钠干燥,粗品经柱层析分离(PE/EA=10/1~5/1)得白色固体2.33g,收率88%。1H NMR(400MHz,CDCl3)δ8.15(d,J=1.8Hz,1H),7.84(dd,J=8.8,1.9Hz,1H),7.59(d,J=8.8Hz,1H),7.25–7.13(m,3H),7.10–6.99(m,2H),4.77(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.24(q,J=6.9Hz,2H),2.77(t,J=7.0Hz,2H),2.59(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.8,143.0,137.6,135.2,129.4,128.7,126.8,126.2,125.6,121.6,113.0,61.6,44.3,35.8,14.4,9.4.HRMS(ESI)[M+H]+理论值C20H22NO5S:388.1219;实测值:388.1213.
实施例2 3-甲基-5-(4-苯基丁基氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用4-苯基丁胺代替苯乙胺,制得标题化合物,得白色固体0.31g,收率75%。1H NMR(400MHz,DMSO-d6)δ8.26–8.20(m,1H),7.96–7.83(m,2H),7.64(t,J=5.9Hz,1H),7.24–7.16(m,2H),7.15–7.03(m,3H),4.37(q,J=7.1Hz,2H),2.78(q,J=6.6Hz,2H),2.57(s,3H),2.44(t,J=7.5Hz,2H),1.47(tt,J=8.6,6.6Hz,2H),1.36(td,J=7.2,4.4Hz,5H).13C NMR(101MHz,DMSO-d6)δ159.2,154.9,142.1,141.9,136.3,128.6,128.1,128.1,126.2,125.6,125.6,121.0,113.0,61.2,42.4,34.6,28.6,27.9,14.1,9.0.HRMS(ESI)[M+H]+理论值C22H26NO5S:416.1526;实测值:416.1526.
实施例3 3-甲基-5-(N-(4-苯基丁-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用1-甲基-3-苯基丙胺代替苯乙胺,制得标题化合物。得白色固体0.43g,收率99%。1H NMR(400MHz,CDCl3)δ8.23(d,J=1.9Hz,1H),7.95(dd,J=8.8,1.9Hz,1H),7.62(d,J=8.8Hz,1H),7.21–7.15(m,3H),7.02–6.95(m,2H),5.04(d,J=8.2Hz,1H),4.47(q,J=7.1Hz,2H),3.36(dq,J=8.2,6.5Hz,1H),2.59(s,5H),1.70(dtd,J=8.7,6.8,1.8Hz,2H),1.45(t,J=7.1Hz,3H),1.07(d,J=6.6Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,155.9,143.0,141.1,136.6,129.4,128.4,128.3,126.3,126.0,125.7,121.6,113.1,61.6,49.8,39.0,31.8,21.8,14.4,9.4.HRMS(ESI)[M+H]-理论值C22H24NO5S:414.1375;实测值:414.1380.
实施例4 3-甲基-5-(N-(2-环己基乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用2-环己基乙胺代替苯乙胺,制得标题化合物。得白色固体0.38g,收率97%。1H NMR(400MHz,CDCl3)δ8.23(dd,J=1.9,0.6Hz,1H),7.93(dd,J=8.8,1.9Hz,1H),7.64(dd,J=8.8,0.6Hz,1H),4.69(t,J=6.1Hz,1H),4.46(q,J=7.1Hz,2H),2.97(td,J=7.1,6.1Hz,2H),2.61(s,3H),1.65–1.50(m,5H),1.44(t,J=7.1Hz,3H),1.33(q,J=7.1Hz,2H),1.29–1.00(m,4H),0.85–0.72(m,2H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.1,135.4,129.5,126.4,125.7,121.7,113.2,61.7,41.2,37.1,34.9,33.0,26.5,26.2,14.5,9.5.HRMS(ESI)[M+H]-理论值C20H26NO5S:392.1532;实测值:392.1526.
实施例5 3-甲基-5-(N-(丁-3-炔-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用丁-3-炔-1-胺代替苯乙胺,制得标题化合物。白色固体0.28g,收率85%。1H NMR(400MHz,CDCl3)δ8.23(dd,J=1.9,0.6Hz,1H),7.94(dd,J=8.8,1.9Hz,1H),7.64(dd,J=8.8,0.6Hz,1H),5.05(t,J=6.4Hz,1H),4.46(q,J=7.1Hz,2H),3.14(dd,J=6.4,6.5Hz,2H),2.60(s,3H),2.36(td,J=6.5,2.6Hz,2H),1.98(t,J=2.6Hz,1H),1.44(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.2,135.4,129.6,126.3,125.7,121.7,113.3,80.3,71.1,61.7,41.8,20.0,14.5,9.5.HRMS(ESI)[M+H]-理论值C16H16NO5S:334.0749;实测值:334.0747.
实施例6 5-(N-(丁-3-烯-1-基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用3-丁烯-1-胺代替苯乙胺,制得标题化合物。得白色固体140mg,产率83.8%。1H NMR(400MHz,CDCl3)δ8.22(d,J=2.0Hz,1H),7.92(dd,J=8.8,2.0Hz,1H),7.65(d,J=8.8Hz,1H),5.68-5.54(m,1H),5.12-4.98(m,2H),4.66(s,1H),4.47(q,J=7.2Hz,2H),3.05(q,J=6.4Hz,2H),2.61(s,3H),2.21(q,J=6.4Hz,2H),1.45(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.90,155.88,143.02,135.32,134.04,129.40,126.21,125.56,121.60,118.27,113.09,61.58,42.15,33.63,14.34,9.34.
实施例7 3-甲基-5-(N-(2-(四氢-2H-吡喃-4-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用4-(2-氨乙基)四氢吡喃代替苯乙胺,制得标题化合物。得白色固体0.35g,收率89%。1H NMR(400MHz,CDCl3)δ8.22(dd,J=1.9,0.6Hz,1H),7.93(dd,J=8.8,1.9Hz,1H),7.64(dd,J=8.8,0.6Hz,1H),4.79(t,J=6.2Hz,1H),4.47(q,J=7.2Hz,2H),3.91–3.83(m,2H),3.27(td,J=11.9,2.2Hz,2H),3.04–2.93(m,2H),2.61(s,3H),1.62–1.37(m,8H),1.33–1.12(m,2H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.2,135.3,129.6,126.3,125.6,121.7,113.2,67.9,61.7,40.6,36.6,32.8,32.2,14.5,9.5.HRMS(ESI)[M+H]-理论值C19H24NO6S:394.1324;实测值:394.1326.
实施例8 3-甲基-5-(N-(2-(噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用2-噻吩乙胺代替苯乙胺,制得标题化合物。得白色固体0.19g,收率49%。1H NMR(400MHz,CDCl3)δ8.18(d,J=1.9Hz,1H),7.87(dd,J=8.8,1.9Hz,1H),7.61(d,J=8.8Hz,1H),7.10(dd,J=5.2,1.2Hz,1H),6.87(dd,J=5.2,3.4Hz,1H),6.73(dd,J=3.4,1.2Hz,1H),4.83(t,J=6.3Hz,1H),4.47(q,J=7.1Hz,2H),3.26(q,J=6.6Hz,2H),2.98(t,J=6.7Hz,2H),2.60(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.1,139.9,135.3,129.5,127.2,126.3,126.0,125.7,124.5,121.7,113.2,61.7,44.5,30.2,14.5,9.5.HRMS(ESI)[M+H]-理论值C18H18NO5S2:392.0626;实测值:392.0625.
实施例9 3-甲基-5-(N-(2-(吡啶-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用3-(2-氨基乙基)吡啶代替苯乙胺,制得标题化合物。得白色固体0.29g,收率76%。1H NMR(400MHz,CDCl3)δ8.37–8.29(m,2H),8.18–8.14(m,1H),7.86(dd,J=8.8,1.9Hz,1H),7.63–7.56(m,1H),7.43(dt,J=7.8,2.0Hz,1H),7.13(dd,J=7.8,4.7Hz,1H),5.61(t,J=6.2Hz,1H),4.46(q,J=7.1Hz,2H),3.25(q,J=6.7Hz,2H),2.80(t,J=6.9Hz,2H),2.58(s,3H),1.44(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,150.1,148.1,143.1,136.6,135.5,133.7,129.5,126.2,125.6,123.6,121.6,113.2,61.7,44.0,33.5,14.5,9.5.HRMS(ESI)[M+H]-理论值C19H19N2O5S:387.1015;实测值:387.1017.
实施例10 3-甲基-5-(N-(2,3-二氢-1H-茚-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用2-氨基茚代替苯乙胺,制得标题化合物。得白色固体0.36g,收率91%。1H NMR(400MHz,DMSO-d6)δ8.30(d,J=1.9Hz,1H),8.09(d,J=6.9Hz,1H),7.99(dd,J=8.8,1.9Hz,1H),7.92(d,J=8.8Hz,1H),7.14–7.04(m,4H),4.38(q,J=7.1Hz,2H),3.93(h,J=7.0Hz,1H),2.92(dd,J=15.9,7.0Hz,2H),2.71(dd,J=15.9,7.0Hz,2H),2.60(s,3H),1.36(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.1,155.0,142.1,140.3,136.8,128.6,126.4,126.2,125.6,124.2,121.1,113.1,61.1,53.9,39.2,14.1,9.0.HRMS(ESI)[M+H]-理论值C21H20NO5S:398.1062;实测值:398.1062.
实施例11 5-(N-(1-萘乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用1-萘乙胺代替苯乙胺,制得标题化合物。得白色固体280mg,收率33%。1H NMR(400MHz,CDCl3)δ8.07(d,J=1.5Hz,1H),7.82(dd,J=6.2,3.5Hz,1H),7.78–7.73(m,2H),7.67(d,J=8.3Hz,1H),7.47(d,J=8.7Hz,1H),7.40(dd,J=6.3,3.3Hz,2H),7.32(t,J=7.6Hz,1H),7.23(d,J=6.9Hz,1H),4.93(s,1H),4.49(q,J=7.1Hz,2H),3.40(q,J=6.7Hz,2H),3.26(t,J=6.9Hz,2H),2.54(s,3H),1.48(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.7,142.8,134.93,133.8,133.5,131.4,129.2,128.8,127.6,127.1,126.1,126.0,125.7,125.6,125.4,123.0,121.4,112.9,61.6,43.5,33.1,14.4,9.3.
实施例12 3-甲基-5-(N-((1R,2S)-2-苯基环丙基)氨磺酰)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用(1R,2S)-2-苯基-环丙胺代替苯乙胺,制得标题化合物。得白色固体147mg,产率99%。1H NMR(400MHz,CDCl3)δ8.13(d,J=2.0Hz,1H),7.92(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.8Hz,1H),7.23-7.09(m,3H),6.87(d,J=6.8Hz,2H),5.66(d,J=2.0Hz,1H),4.45(q,J=7.2Hz,2H),2.42(s,3H),2.40-2.34(m,1H),2.11-2.02(m,1H),1.43(t,J=7.2Hz,3H),1.28-1.20(m,1H),1.09(dd,J=13.6,6.4Hz,1H).13CNMR(101MHz,CDCl3)δ159.94,155.94,142.90,139.73,134.48,129.33,128.39,126.47,126.29,125.95,125.69,122.37,113.06,61.64,34.09,24.28,15.23,14.36,9.18.
实施例13 5-(N-(4-氟代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用4-氟苯乙胺代替苯乙胺,制得标题化合物。得白色固体115mg,收率57%。1H NMR(400MHz,CDCl3)δ8.17(s,1H),7.87(dd,J=8.8,1.8Hz,1H),7.60(d,J=8.8Hz,1H),7.10–6.96(m,2H),6.87(t,J=8.6Hz,2H),5.05(s,1H),4.47(q,J=7.1Hz,2H),3.21(q,J=6.7Hz,2H),2.75(t,J=7.0Hz,2H),2.58(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ161.7(d,J=245.1Hz),159.9,155.8,143.0,135.2,133.4(d,J=3.4Hz),130.2(d,J=7.9Hz),129.4,126.1,125.5,121.5,115.4(d,J=21.2Hz),113.0,61.6,44.4,35.0,14.3,9.3.
实施例14 5-(N-(4-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用4-氯苯乙胺代替苯乙胺,制得标题化合物。得白色固体116mg,收率55%。1H NMR(400MHz,CDCl3)δ8.16(s,1H),7.86(d,J=10.5Hz,1H),7.60(d,J=8.8Hz,1H),7.14(d,J=8.3Hz,2H),6.99(d,J=8.3Hz,2H),5.04(s,1H),4.47(q,J=7.1Hz,2H),3.22(q,J=6.4Hz,2H),2.75(t,J=7.0Hz,2H),2.58(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.8,143.0,136.2,135.1,132.5,130.0,129.4,128.7,126.1,125.5,121.5,113.0,61.6,44.1,35.2,14.4,9.3.
实施例15 3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用3-溴苯乙胺代替苯乙胺,制得标题化合物。无色油状液体0.21g,收率45%。1H NMR(400MHz,CDCl3)δ8.17(d,J=1.9Hz,1H),7.86(dd,J=8.8,1.9Hz,1H),7.61(d,J=8.8Hz,1H),7.31–7.24(m,1H),7.17(t,J=1.9Hz,1H),7.07(t,J=7.7Hz,1H),7.00(dt,J=7.7,1.4Hz,1H),5.01(t,J=6.2Hz,1H),4.47(q,J=7.2Hz,2H),3.24(q,J=6.8Hz,2H),2.75(t,J=7.0Hz,2H),2.59(s,3H),1.46(t,J=7.2Hz,3H).13CNMR(101MHz,CDCl3)δ160.0,155.9,143.1,140.1,135.2,131.8,130.2,129.9,129.5,127.5,126.2,125.6,122.7,121.6,113.2,61.7,44.1,35.5,14.4,9.4.HRMS(ESI)[M-H]-理论值C20H19NO5SBr:464.0167;实测值:464.0168.
实施例16 3-甲基-5-(N-(3-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用3-(三氟甲基)苯乙胺代替苯乙胺,制得标题化合物。得无色油状液体0.18g,收率40%。1H NMR(400MHz,CDCl3)δ8.19(d,J=1.9Hz,1H),7.87(dd,J=8.8,1.9Hz,1H),7.60(d,J=8.8Hz,1H),7.43(d,J=7.7Hz,1H),7.36–7.25(m,3H),5.05(t,J=6.3Hz,1H),4.47(q,J=7.1Hz,2H),3.28(q,J=6.8Hz,2H),2.86(t,J=7.0Hz,2H),2.59(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.2,138.8,135.2,132.3,131.0(q,J=32.3Hz),129.5,129.2,126.2,125.6,125.5(q,J=4.9Hz),123.7(q,J=3.9Hz),122.7,121.6,113.2,61.7,44.1,35.8,14.4,9.4.19F NMR(376MHz,CDCl3)δ-62.66.HRMS(ESI)[M-H]-理论值C21H19NO5SF3:454.0936;实测值:454.0935.
实施例17 3-甲基-5-(N-(3-甲氧基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用3-甲氧基苯乙胺代替苯乙胺,制得标题化合物。得白色固体0.30g,收率72%。1H NMR(400MHz,CDCl3)δ8.15(d,J=1.9Hz,1H),7.84(dd,J=8.7,1.9Hz,1H),7.60(d,J=8.7Hz,1H),7.14(t,J=7.9Hz,1H),6.71(dd,J=8.5,2.1Hz,1H),6.66–6.60(m,1H),6.56(t,J=2.1Hz,1H),4.59(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.72(s,3H),3.25(q,J=6.7Hz,2H),2.73(t,J=6.8Hz,2H),2.60(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,160.0,156.0,143.1,139.2,135.3,129.9,129.5,126.3,125.7,121.7,121.1,114.7,113.1,112.1,61.7,55.2,44.2,35.8,14.5,9.5.HRMS(ESI)[M-H]-理论值C21H22NO6S:416.1168;实测值:416.1170.
实施例18 5-(N-(3-甲基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用3-甲基苯乙胺代替苯乙胺,制得标题化合物。得白色固体277mg,收率35%。1H NMR(400MHz,CDCl3)δ8.19(s,1H),7.89(d,J=8.6Hz,1H),7.54(d,J=8.7Hz,1H),7.15–6.77(m,5H),5.45(d,J=5.6Hz,1H),4.44(q,J=6.9Hz,2H),3.23(q,J=6.9Hz,2H),2.73(t,J=7.3Hz,2H),2.55(s,3H),2.19(s,3H),1.43(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.9,155.7,142.8,138.1,137.8,135.3,129.4,129.3,128.4,127.3,126.3,125.6,125.6,121.5,112.9,61.6,44.5,35.7,21.2,14.3,9.3.
实施例19 3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用1-萘胺代替苯乙胺,制得标题化合物。得黄色固体67mg,收率16%。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.10–8.01(m,2H),7.91–7.74(m,4H),7.50–7.34(m,3H),7.14(dd,J=7.4,1.1Hz,1H),4.36(q,J=7.1Hz,2H),2.47(s,3H),1.34(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.0,155.0,142.1,135.7,133.9,132.3,129.5,128.4,127.9,126.8,126.4,126.2,126.0,125.5,125.4,123.4,123.1,121.2,113.0,61.1,14.1,8.9.HRMS(ESI)[M-H]-理论值C22H18NO5S:408.0906;实测值:408.0911.
实施例20 3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用2-萘胺代替苯乙胺,制得标题化合物。得粉色固体0.38g,收率47%。1H NMR(400MHz,CDCl3)δ8.19–8.14(m,1H),7.85(dd,J=8.8,1.9Hz,1H),7.78–7.65(m,3H),7.60–7.34(m,4H),7.28–7.20(m,1H),4.43(q,J=7.1Hz,2H),2.47(s,3H),1.66(s,1H),1.42(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.1,143.1,134.4,133.9,133.7,131.4,129.6,129.5,127.8,127.6,126.9,126.4,125.8,125.6,122.0,121.4,119.2,113.1,61.7,14.4,9.3.HRMS(ESI)[M-H]-理论值C22H18NO5S:408.0906;实测值:408.0906.
实施例21 3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用2-([1,1'-联苯]-3-基)乙烷-1-胺代替苯乙胺,制得标题化合物。得白色固体0.39g,收率43%。1H NMR(400MHz,CDCl3)δ8.15(d,J=1.9Hz,1H),7.84(dd,J=8.9,1.9Hz,1H),7.57(d,J=8.9Hz,1H),7.51–7.37(m,5H),7.36–7.27(m,2H),7.22(t,J=1.9Hz,1H),7.08–6.98(m,1H),4.61(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.31(q,J=6.8Hz,2H),2.83(t,J=6.8Hz,2H),2.55(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,143.1,141.8,140.7,138.1,135.4,129.5,129.3,128.9,127.7,127.6,127.5,127.1,126.3,125.8,125.7,121.6,113.2,61.7,44.4,35.9,14.5,9.4.HRMS(ESI)[M-H]-理论值C26H26NO5S:464.1532;实测值:464.1525.
实施例22 5-(N-(2-(苯并呋喃-3-基)乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
制备方法同实施例1,不同之处为用2-(苯并呋喃-3-基)乙烷-1-胺代替苯乙胺,制得标题化合物。
实施例23
步骤1:2-(4-乙酰氨基-2-乙酰苯氧基)乙酸乙酯
梨形瓶中加入N-(3-乙酰基-4-羟基苯基)乙酰胺(1.01g,5.23mmol),溴乙酸乙酯(1mL,8.98mmol),碳酸钾(1.33g,9.62mmol)和碘化钾(0.16g,0.97mmol),加入丙酮(30mL),60℃回流反应2h,TLC监测反应完全。反应结束后,加入适量水,二氯甲烷萃取3遍,合并有机相,无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(DCM/MeOH=30:1),得白色固体1.32g,产率90.4%。
步骤2:5-乙酰氨基-3-甲基苯并呋喃-2-羧酸乙酯
梨形瓶中加入2-(4-乙酰氨基-2-乙酰苯氧基)乙酸乙酯(1.32g,4.72mmol),碳酸钾(0.85g,6.15mmol),加入DMF(41mL),140℃回流反应1h,TLC监测反应完全。反应结束后,加入少量EA,硅藻土抽滤,滤液加入饱和氯化钠溶液,EA提取3次,合并有机相,饱和氯化钠溶液洗涤2遍,有机相经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(DCM/MeOH=50:1),得白色固体0.78g,产率63.6%。
步骤3:5-氨基-3-甲基苯并呋喃-2-羧酸乙酯
将5-乙酰氨基-3-甲基苯并呋喃-2-羧酸乙酯(0.78g,2.79mmol)溶于乙醇(16mL),加入3N HCl(16mL),80℃回流反应2h,TLC检测反应完全。反应结束后,加入饱和碳酸氢钠溶液调节pH 7~8,EA提取3次,合并有机相无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(DCM/MeOH=30:1)得淡黄色固体0.44g,产率71.2%.
步骤4:3-甲基-5-((2-苯乙基)磺胺基)苯并呋喃-2-羧酸乙酯
将5-氨基-3-甲基苯并呋喃-2-羧酸乙酯(0.14g,0.65mmol)溶于无水DMF(2mL),依次加入吡啶(0.10g,1.26mmol),2-苯基-乙烷磺酰氯(0.25g,1.22mmol),室温搅拌过夜。反应结束后,EA提取3次,合并有机相,饱和氯化钠溶液洗涤2遍,有机相经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(DCM/MeOH=30:1),得淡黄色油状液体0.10g,产率51.5%。
实施例24 3-甲基-5-((苯甲基)磺胺基)苯并呋喃-2-羧酸乙酯
制备方法同实施例19,不同之处为用苄磺酰氯代替2-苯基-乙烷磺酰氯,制得标题化合物。得浅粉色固体80mg,产率30.3%。1H NMR(400MHz,CDCl3)δ7.46(d,J=8.8Hz,1H),7.41(d,J=2.4Hz,1H),7.35–7.27(m,5H),7.15(dd,J=8.8,2.4Hz,1H),6.90(s,1H),4.45(q,J=7.2Hz,2H),4.32(s,2H),2.54(s,3H),1.44(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.32,151.85,142.16,132.40,130.89,129.90,129.01,128.88,128.44,125.46,122.18,113.36,112.99,61.37,57.67,14.40,9.46.
实施例25 3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸(GPR132-B-160)
将3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯(0.10g,0.27mmol)溶于乙醇(8mL)中,加入氢氧化钠(0.06g,1.46mmol,溶于2mL水),加热至回流反应4h。TLC检测反应完毕后,减压蒸馏除去溶剂,加水(50mL)溶解,调节pH 1~2,大量白色固体析出。抽滤,滤饼减压干燥得白色固体0.67g,收率69%。1H NMR(400MHz,DMSO-d6)δ13.48(s,1H),9.91(s,1H),7.63(d,J=8.8Hz,1H),7.55(d,J=2.4Hz,1H),7.38(dd,J=8.8,2.4Hz,1H),7.29–7.22(m,2H),7.21–7.15(m,3H),3.36–3.32(m,2H),3.04–2.97(m,2H),2.49(s,3H).13C NMR(101MHz,DMSO-d6)δ161.40,151.23,142.62,138.58,134.15,129.69,128.97,128.85,127.00,124.77,122.78,113.42,113.13,51.80,29.53,9.59.
实施例26 3-甲基-5-(N-(4-苯基丁基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-1)
制备方法同实施例25,不同之处为用3-甲基-5-(4-苯基丁基氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体164mg,收率79%。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.20(d,J=1.7Hz,1H),7.94–7.80(m,2H),7.62(t,J=5.9Hz,1H),7.20(t,J=7.4Hz,2H),7.14–7.04(m,3H),2.77(q,J=6.6Hz,2H),2.56(s,3H),2.45(t,J=7.5Hz,2H),1.52–1.43(m,2H),1.35(p,J=6.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,141.9,136.1,128.8,128.1,128.1,125.8,125.6,124.6,120.8,112.9,42.4,34.6,28.6,27.9,9.0.HRMS(ESI)[M-H]-理论值C20H20NO5S:386.1068;实测值:386.1059.
实施例27 3-甲基-5-(N-(4-苯基丁-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-2)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(4-苯基丁-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体165mg,收率79%。1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.18(d,J=2.0Hz,1H),7.94–7.81(m,1H),7.69(d,J=7.7Hz,1H),7.26–7.04(m,3H),6.97(dd,J=6.8,1.9Hz,2H),3.20–3.11(m,1H),2.56(s,3H),2.48–2.32(m,2H),1.55(q,J=7.5Hz,2H),0.93(d,J=6.5Hz,3H).13C NMR(101MHz,DMSO-d6)δ160.8,154.7,143.5,141.5,137.3,128.8,128.1,128.0,125.8,125.6,124.3,120.6,112.9,48.8,38.3,31.2,21.1,9.0.HRMS(ESI)[M-H]-理论值C20H20NO5S:386.1068;实测值:386.1064.
实施例28 3-甲基-5-(N-(2-环己基乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-3)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(2-环己基乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体168mg,收率85%。1H NMR(400MHz,DMSO-d6)δ8.20(d,J=1.9Hz,1H),7.92–7.81(m,2H),7.54(t,J=5.8Hz,1H),2.75(q,J=6.5Hz,2H),2.57(s,3H),1.59–1.46(m,5H),1.25–0.96(m,6H),0.73(q,J=10.4,9.9Hz,2H).13C NMR(101MHz,DMSO-d6)δ160.8,154.8,143.6,135.9,128.9,125.8,124.2,120.8,112.8,40.2,36.3,34.0,32.4,26.0,25.6,9.0.HRMS(ESI)[M-H]-理论值C18H22NO5S:364.1219;实测值:364.1216.
实施例29 3-甲基-5-(N-(丁-3-炔-1-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-4)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(丁-3-炔-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体147mg,收率88%。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.23(d,J=1.8Hz,1H),7.94–7.82(m,3H),2.93–2.84(m,2H),2.81(t,J=2.6Hz,1H),2.58(s,3H),2.28(td,J=7.1,2.6Hz,2H).113C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,135.8,128.9,125.9,124.7,121.0,113.0,81.5,72.4,41.6,19.3,9.0.HRMS(ESI)[M-H]-理论值C14H12NO5S:306.0436;实测值:306.0435.
实施例30 5-(N-(丁-3-烯-1-基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-5)
制备方法同实施例25,不同之处为用5-(N-(丁-3-烯-1-基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体103mg,产率80.5%。1H NMR(400MHz,DMSO-d6)δ8.22(d,J=1.6Hz,1H),7.90(dd,J=8.8,1.6Hz,1H),7.86(d,J=8.7Hz,1H),7.67(t,J=6.0Hz,1H),5.76-5.64(m,1H),5.06–4.92(m,2H),2.86-2.76(m,2H),2.57(s,3H),2.16-2.07(m,2H).13C NMR(101MHz,DMSO-d6)δ161.14,155.33,143.59,136.39,135.78,129.29,126.37,125.18,121.14,117.14,113.41,42.58,33.85,9.50.HRMS(ESI)[M-H]-理论值C14H14NO5S:308.0598;实测值:308.0590.
实施例31 3-甲基-5-(N-(2-(四氢-2H-吡喃-4-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-6)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(2-(四氢-2H-吡喃-4-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体161mg,收率81%。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.26–8.16(m,1H),7.94–7.83(m,2H),7.58(t,J=5.9Hz,1H),3.80–3.68(m,2H),3.20–3.09(m,2H),2.78(q,J=6.7Hz,2H),2.57(s,3H),1.55–1.36(m,3H),1.29(t,J=6.9Hz,2H),1.09–0.94(m,2H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,136.0,128.8,125.9,124.7,120.9,112.9,66.9,39.7,35.9,32.3,31.4,9.0.HRMS(ESI)[M-H]-理论值C17H20NO6S:366.1011;实测值:366.1015.
实施例32 3-甲基-5-(N-(2-(噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-7)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(2-(噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体146mg,收率99%。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.21(dd,J=1.8,0.7Hz,1H),7.95–7.79(m,3H),7.29(dd,J=5.1,1.2Hz,1H),6.90(dd,J=5.1,3.3Hz,1H),6.84(dq,J=3.3,1.2Hz,1H),3.03–2.96(m,2H),2.90(t,J=7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,140.7,135.8,128.9,126.9,125.9,125.5,124.8,124.2,121.0,113.0,44.2,29.6,9.1.HRMS(ESI)[M-H]-理论值C16H14NO5S2:364.0313;实测值:364.0318.
实施例33 3-甲基-5-(N-(2-(吡啶-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-8)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(2-(吡啶-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体172mg,收率88%。1H NMR(400MHz,DMSO-d6)δ8.36(s,2H),8.17(d,J=2.0Hz,1H),7.90–7.79(m,2H),7.75(t,J=5.9Hz,1H),7.57(dt,J=7.8,2.0Hz,1H),7.24(dd,J=7.8,4.7Hz,1H),3.05(q,J=6.7Hz,2H),2.70(t,J=7.0Hz,2H),2.57(s,3H).13CNMR(101MHz,DMSO-d6)δ160.7,154.8,149.8,147.3,143.2,136.3,135.7,134.3,128.8,125.8,124.6,123.3,120.9,112.9,43.5,32.2,9.0.HRMS(ESI)[M-H]-理论值C17H15N2O5S:359.0702;实测值:359.0708.
实施例34 3-甲基-5-(N-(2,3-二氢-1H-茚-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-9)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(2,3-二氢-1H-茚-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体127mg,收率79%。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.28(d,J=1.9Hz,1H),8.07(d,J=6.8Hz,1H),7.97(dd,J=8.8,1.9Hz,1H),7.89(d,J=8.8Hz,1H),7.08(p,J=4.6Hz,4H),3.99–3.87(m,1H),2.93(dd,J=15.9,7.0Hz,2H),2.71(dd,J=15.9,7.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,140.4,136.7,128.8,126.5,126.0,124.7,124.2,121.0,113.0,54.0,39.2,9.0.HRMS(ESI)[M-H]-理论值C19H16NO5S:370.0749;实测值:370.0747.
实施例35 5-(N-(1-萘乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-10)
制备方法同实施例25,不同之处为用5-(N-(1-萘乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体216mg,收率83%。1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),7.93–7.81(m,4H),7.78(d,J=8.8Hz,1H),7.72(d,J=8.0Hz,1H),7.50–7.42(m,2H),7.37(t,J=7.5Hz,1H),7.32(d,J=6.6Hz,1H),3.24–3.05(m,4H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.2,143.6,136.1,134.9,133.8,131.7,129.2,129.0,127.4,127.4,126.5,126.2,126.0,125.9,125.0,123.7,121.3,113.3,43.8,33.0,9.5.
实施例36 3-甲基-5-(N-((1R,2S)-2-苯基环丙基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-11)
制备方法同实施例25,不同之处为用3-甲基-5-(N-((1R,2S)-2-苯基环丙基)氨磺酰)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体75mg,产率57.7%。1H NMR(400MHz,DMSO-d6)δ8.16(d,J=4.0Hz,1H),8.04(t,J=1.2Hz,1H),7.86(d,J=1.2Hz,2H),7.20-7.07(m,3H),6.84-6.76(m,2H),2.39(s,3H),2.32-2.25(m,1H),1.77-1.70(m,1H),1.14-1.04(m,2H).13C NMR(101MHz,DMSO-d6)δ161.77,155.45,143.73,140.78,135.67,129.27,128.58,126.42,126.19,125.96,124.92,121.95,113.51,34.91,23.78,14.83,9.30.HRMS(ESI)[M-H]-理论值C19H16NO5S:370.0755;实测值:370.0746.
实施例37 5-(N-(4-氟代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-12)
制备方法同实施例25,不同之处为用5-(N-(4-氟代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得到白色固体115mg,收率99%。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.16(s,1H),7.92–7.78(m,2H),7.73(t,J=5.8Hz,1H),7.16(dd,J=8.5,5.7Hz,2H),7.01(t,J=8.9Hz,2H),3.00(q,J=7.0Hz,2H),2.66(t,J=7.1Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.3(d,J=241.7Hz),161.2,155.3,143.6,136.3,135.3(d,J=3.0Hz),130.9(d,J=7.9Hz),129.3,126.3,125.1,121.3,115.3(d,J=21.0Hz),113.3,44.5,34.7,9.5.
实施例38 5-(N-(4-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-13)
制备方法同实施例25,不同之处为用5-(N-(4-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得到白色固体116mg,收率99%。1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.15(s,1H),7.89–7.78(m,1H),7.73(t,J=5.8Hz,1H),7.30–7.09(m,4H),3.01(q,J=6.9Hz,2H),2.66(t,J=7.0Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,137.7,135.8,130.8,130.6,128.8,128.0,125.8,124.6,120.8,112.8,43.7,34.4,9.0.
实施例39 3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-14)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体148mg,收率99%。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.16(d,J=1.7Hz,1H),7.89–7.79(m,2H),7.73(t,J=5.8Hz,1H),7.32(tq,J=3.7,1.7Hz,2H),7.20–7.11(m,2H),3.02(q,J=6.7Hz,2H),2.67(t,J=7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.8,154.9,143.3,141.7,135.8,131.5,130.3,129.1,128.9,127.9,125.9,124.6,121.5,120.9,112.9,43.6,34.6,9.1.HRMS(ESI)[M-H]-理论值C18H15NO5SBr:435.9854;实测值:435.9857.
实施例40 3-甲基-5-(N-(3-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-15)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(3-溴苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。1HNMR(400MHz,DMSO-d6)δ13.70(s,1H),8.16(d,J=1.8Hz,1H),7.88–7.72(m,3H),7.52–7.43(m,4H),3.07(q,J=6.6Hz,2H),2.78(t,J=6.9Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,140.2,135.8,133.0,129.1(d,J=5.5Hz),128.8(d,J=5.8Hz),125.8,125.6,125.3(d,J=4.0Hz),124.6,122.9(d,J=3.9Hz),120.9,112.9,43.5,34.7,9.0.19F NMR(376MHz,DMSO-d6)δ-61.06.HRMS(ESI)[M-H]-理论值C19H15NO5SF3:426.0623;实测值:426.0622.
实施例41 3-甲基-5-(N-(3-甲氧基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-16)
制备方法同实施例25,不同之处为用3-甲基-5-(N-(3-甲氧基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体188mg,收率89%。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),8.18(d,J=1.7Hz,1H),7.91–7.79(m,2H),7.72(t,J=5.8Hz,1H),7.12(t,J=7.7Hz,1H),6.73–6.66(m,3H),3.68(s,3H),3.05–2.95(m,2H),2.64(t,J=7.3Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,159.2,154.8,143.2,140.2,135.8,129.2,128.8,125.8,124.6,120.9,114.3,112.9,111.6,54.8,43.9,35.2,9.0.HRMS(ESI)[M-H]-理论值C19H18NO6S:388.0855;实测值:388.0862.
实施例42 5-(N-(3-甲基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧(GPR132-B-17)
制备方法同实施例25,不同之处为用5-(N-(3-甲基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体249mg,收率97%。1H NMR(400MHz,DMSO-d6)δ8.18(s,1H),7.85(q,J=8.8Hz,2H),7.74(t,J=5.7Hz,1H),7.10(t,J=7.4Hz,1H),6.97–6.87(m,3H),2.98(q,J=7.0Hz,2H),2.62(t,J=7.4Hz,2H),2.57(s,3H),2.20(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,143.8,139.0,137.7,136.3,129.7,129.3,128.6,127.3,126.3,126.1,124.9,121.3,113.3,44.5,35.6,21.4,9.5.
实施例43 3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸
制备方法同实施例25,不同之处为用3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体102mg,收率92%。1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),10.27(s,1H),8.08–7.99(m,2H),7.90–7.71(m,4H),7.50–7.33(m,3H),7.13(dd,J=7.5,1.1Hz,1H),2.46(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.2,135.5,133.9,132.3,129.5,128.7,127.9,126.8,126.2,126.1,126.0,125.5,124.5,123.3,123.1,121.1,112.9,8.9.HRMS(ESI)[M-H]-理论值C20H14NO5S:380.0593;实测值:380.0600.
实施例44 3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸
制备方法同实施例25,不同之处为用3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体181mg,收率87%。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),10.57(s,1H),8.29(d,J=1.9Hz,1H),7.90(dd,J=8.8,1.9Hz,1H),7.83–7.71(m,4H),7.62(d,J=2.2Hz,1H),7.46–7.29(m,3H),2.50(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.4,135.3,134.8,133.2,130.0,129.1,128.8,127.4,127.2,126.6,125.8,125.0,124.4,121.4,120.4,116.1,113.0,8.9.HRMS(ESI)[M-H]-理论值C20H14NO5S:380.0593;实测值:380.0594.
实施例45 3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸
制备方法同实施例25,不同之处为用3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得粉色固体216mg,收率91%。1H NMR(400MHz,DMSO-d6)δ8.13(d,J=1.9Hz,1H),7.88–7.71(m,3H),7.62–7.56(m,2H),7.46–7.40(m,4H),7.32(dt,J=10.4,7.5Hz,2H),7.13(d,J=7.5Hz,1H),3.07(q,J=6.8Hz,2H),2.75(t,J=6.8Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ161.6,154.5,140.2,139.4,135.4,129.4,128.8,127.8,127.3,127.1,126.7,124.9,124.6,120.4,112.5,44.0,35.2,9.0.HRMS(ESI)[M-H]-理论值C24H22NO5S:436.1219;实测值:436.1211.
实施例46 5-(N-(2-(苯并呋喃-3-基)乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-21)
制备方法同实施例25,不同之处为用5-(N-(2-(苯并呋喃-3-基)乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。
实施例47 3-甲基-5-((2-苯乙基)磺胺基)苯并呋喃-2-羧酸(GPR132-B-161)
制备方法同实施例25,不同之处为用3-甲基-5-((2-苯乙基)磺胺基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得浅黄色固体68mg,产率69%。1H NMR(400MHz,DMSO-d6)δ13.48(s,1H),9.91(s,1H),7.63(d,J=8.8Hz,1H),7.55(d,J=2.4Hz,1H),7.38(dd,J=8.8,2.4Hz,1H),7.29–7.22(m,2H),7.21-7.16(m,3H),3.37-3.31(m,2H),3.04–2.97(m,2H),2.49(s,3H).13C NMR(101MHz,DMSO-d6)δ161.40,151.23,142.62,138.58,134.15,129.69,128.97,128.84,126.99,124.77,122.78,113.42,113.13,51.80,29.53,9.59.HRMS(ESI)[M-H]-理论值C18H16NO5S:358.0755;实测值:358.0743.
实施例48 3-甲基-5-((苯甲基)磺胺基)苯并呋喃-2-羧酸(GPR132-B-22)
制备方法同实施例25,不同之处为用3-甲基-5-((苯甲基)磺胺基)苯并呋喃-2-羧酸乙酯代替3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,制得标题化合物。得白色固体73mg,产率99%。1H NMR(400MHz,DMSO-d6)δ9.88(s,1H),7.60(d,J=8.8Hz,1H),7.45(d,J=2.4Hz,1H),7.38–7.27(m,6H),4.48(s,2H),2.49(s,3H).13C NMR(101MHz,CDCl3)δ161.45,150.89,142.54,134.46,131.45,130.01,129.59,128.82,128.66,124.79,122.11,112.95,112.23,57.43,9.59.HRMS(ESI)[M-H]-理论值C17H14NO5S:344.0598;实测值:344.0596.
实施例49
3-甲基-6-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-52)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-6-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体38mg,收率74%。1H NMR(400MHz,DMSO-d6)δ7.98(d,J=1.5Hz,1H),7.91(d,J=8.3Hz,1H),7.82(t,J=5.8Hz,1H),7.71(dd,J=8.3,1.5Hz,1H),7.25–7.18(m,2H),7.19–7.10(m,3H),3.03–2.93(m,2H),2.67(t,J=7.5Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ152.1,138.6,132.5,130.8,128.7,128.6,128.3,128.3,126.2,122.0,121.0,110.5,44.1,35.2,9.1.HRMS(ESI)[M-H]- calcdfor C18H17NO5S:358.0749;found:358.0744.
实施例50
3-甲基-5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸(GPR132-B-53)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.39(d,J=2.1Hz,1H),8.15(d,J=8.4Hz,1H),7.98(dd,J=8.5,2.3Hz,1H),7.30–7.19(m,5H),7.15(t,J=6.6Hz,1H),3.17(dt,J=6.6,5.8Hz,2H),2.81(tt,J=5.8,0.9Hz,2H),2.66(s,3H).13C NMR(101MHz,DMSO-d6)δ167.6,145.0,141.7,137.2,137.2,135.2,128.9,128.9,127.2,126.7,126.6,123.9,121.9,44.9,35.7,13.3.HRMS(ESI)[M-H]- calcd for C18H17NO4S2:374.0526;found:374.0526.
实施例51
5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸(GPR132-B-54)
将5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯(0.18g,0.46mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体146mg,产率87.4%。
1H NMR(400MHz,DMSO-d6)δ13.76(s,1H),8.48(d,J=1.8Hz,1H),8.30(s,1H),8.25(d,J=8.6Hz,1H),7.89–7.79(m,2H),7.29–7.07(m,5H),3.05–2.95(m,2H),2.68(t,J=7.5Hz,2H).13C NMR(101MHz,DMSO)δ163.6,144.9,139.1,138.8,137.9,137.6,131.1,129.1,128.7,126.6,125.0,124.6,124.4,44.6,35.7.HRMS(ESI)[M-H]- calcd forC17H15NO4S2:360.0370;found:360.0370.
实施例52
6-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸(GPR132-B-55)
将6-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯(0.12g,0.31mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体105mg,产率94.6%。
1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.20(s,1H),8.17(d,J=8.4Hz,1H),7.84(t,J=6.0Hz,1H),7.80(dd,J=8.4,1.6Hz,1H),7.27-7.18(m,2H),7.18-7.09(m,3H),3.02(q,J=6.8Hz,2H),2.68(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ163.59,141.63,141.47,139.34,139.08,138.99,129.99,129.11,128.72,126.98,126.67,123.03,122.68,44.55,35.75.HRMS(ESI)[M-H]- calcd for C17H14NO4S2:360.0370;found:360.0364.
实施例53
3-氯-5-(N-苯乙基氨基磺酰基)-1H-吲哚-2-羧酸(GPR132-B-56)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ12.52(s,1H),8.06(s,1H),7.73(dd,J=8.8,2.0Hz,1H),7.69–7.60(m,2H),7.25–7.08(m,5H),2.95(q,J=7.2Hz,2H),2.66(t,J=7.2Hz,2H).13C NMR(101MHz,DMSO-d6)δ161.56,139.18,136.55,133.38,129.08,128.72,126.63,126.12,124.83,123.75,119.31,114.42,110.62,44.57,35.66.HRMS(ESI)[M-H]- calcd for C17H15ClN2O4S:377.0368;found:377.0368.
实施例54
2-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-3-羧酸(GPR132-B-57)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.15(d,J=2.2Hz,1H),7.97(dd,J=9.1,2.3Hz,1H),7.65(d,J=9.0Hz,1H),7.30–7.19(m,5H),7.14(t,J=6.6Hz,1H),3.17(dt,J=6.6,5.8Hz,2H),2.81(tt,J=5.8,0.9Hz,2H),2.67(s,3H).13C NMR(101MHz,DMSO-d6)δ167.5,162.8,156.9,137.2,135.5,128.9,128.9,128.6,127.5,126.7,120.8,111.7,110.3,44.9,35.7,14.7.HRMS(ESI)[M-H]- calcd for C18H17NO5S:358.0755;found:358.0755.
实施例55
3-甲基-5-(N-(2-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-58)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体189mg,收率93%。.1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.19(d,J=1.7Hz,1H),7.92–7.77(m,3H),7.27–7.16(m,2H),7.11–7.02(m,2H),3.04–2.95(m,2H),2.71(t,J=7.3Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,160.6(d,J=243.5Hz),154.9,143.1,135.8,131.3(d,J=4.9Hz),128.8,128.4(d,J=8.2Hz),125.8,125.2(d,J=15.6Hz),124.7,124.3(d,J=3.3Hz),120.9,115.0(d,J=21.9Hz),112.9,42.6,28.7(d,J=2.1Hz),9.0.19F NMR(376MHz,DMSO-d6)δ-118.87.19F NMR(376MHz,DMSO)δ-118.87.HRMS(ESI)[M-H]- calcdfor C18H15NO5SF:376.0655;found:376.0655.
实施例56
5-(N-(2-溴代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-60)
将5-(N-(2-溴代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(248.0mg,0.5mmol),LiOH(24.0mg,1.0mmol)溶于THF(4mL)和H2O(2.5mL)混合溶液中,室温下反应。TLC监测反应完全后,减压蒸馏将THF旋干,向体系中滴加HCl(1M),直到溶液呈酸性,白色沉淀产生。抽滤得到白色固体124.2mg,收率57%。1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.97–7.81(m,3H),7.50(d,J=7.9Hz,1H),7.32–7.25(m,2H),7.18–7.07(m,1H),3.04(q,J=6.9Hz,2H),2.81(t,J=7.4Hz,2H),2.59(s,3H).13C NMR(101MHz,DMSO-d6)δ160.8,154.8,143.5,137.6,135.7,132.4,131.2,128.9,128.5,127.7,125.8,124.3,123.7,120.9,112.9,42.1,35.5,9.0.HRMS(ESI)[M-H]- calcd for C18H15BrNO5S:435.9860;found:435.9846.
实施例57
5-(N-(2-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-59)
根据GPR132-B-60的合成步骤,得到白色固体51mg,收率46%。1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.82(s,1H),7.78–7.63(m,2H),7.37–7.13(m,4H),2.99(q,J=7.7,7.2Hz,2H),2.78(t,J=7.3Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ
163.7,154.5,136.4,135.0,133.4,131.7,130.6,129.6,128.7,127.6,124.0,120.1,112.5,42.6,33.5,9.5.HRMS(ESI)[M-H]- calcd for C18H15ClNO5S:392.0365;found:392.0356.
实施例58
5-(N-(2-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-61)
梨形瓶中加入中间体酯(0.22g,0.44mmol),LiOH(0.02g,1.0mmol),加入乙醇(8mL)及H2O(2mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体195mg,产率94%。
1H NMR(400MHz,DMSO-d6)δ13.67(br,1H),8.20(d,J=2.0Hz,1H),7.89(dd,J=8.8,1.6Hz,1H),7.85–7.82(m,2H),7.73(dd,J=8.0,1.2Hz,1H),7.30–7.26(m,1H),7.24(dd,J=7.6,2.0Hz,1H),6.93–6.88(m,1H),3.00(q,J=6.8Hz,2H),2.77(t,J=7.6Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.34,143.57,141.34,139.49,136.24,130.70,129.29,128.99,128.89,126.37,125.17,121.45,113.43,101.06,42.86,9.54.HRMS(ESI)[M-H]- calcd for C18H15INO5S-:483.9721;found:483.9712.
实施例59
3-甲基-5-(N-(2-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-62)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得黄色固体149mg,收率73%。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=1.8Hz,1H),7.92–7.76(m,3H),7.05(d,J=1.8Hz,4H),2.96–2.88(m,2H),2.71–2.62(m,2H),2.56(s,3H),2.14(s,3H).13C NMR(101MHz,DMSO-d6)δ161.0,154.7,144.2,136.7,135.8,135.7,130.0,129.1,129.0,126.3,125.8,125.6,123.6,120.7,112.8,42.9,32.8,18.7,9.0.HRMS(ESI)[M-H]- calcd for C19H18NO5S:372.0906;found:372.0907.
实施例60
3-甲基-5-(N-(2-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-63)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体212mg,收率92%。1HNMR(400MHz,DMSO-d6)δ13.70(s,1H),8.20(d,J=1.9Hz,1H),7.94–7.81(m,3H),7.64–7.51(m,2H),7.45–7.33(m,2H),3.05–2.97(m,2H),2.84(t,J=7.6Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.2,136.8,135.8,132.5,131.8,128.9,127.2(d,J=29.1Hz),127.0,125.8,125.7(q,J=5.8,5.4Hz),124.6,123.1,120.9,113.0,43.6,32.2,9.0.19F NMR(376MHz,DMSO-d6)δ-58.44.HRMS(ESI)[M-H]- calcd for C19H15NO5SF3:426.0623;found:426.0628.
实施例61
5-(N-(2-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-64)
根据GPR132-B-60的合成步骤,得到白色固体117mg,收率91%。1H NMR(400MHz,DMSO-d6)δ13.79(s,1H),8.18(s,1H),7.86(q,J=8.8Hz,2H),7.71(t,J=5.8Hz,1H),7.14(t,J=7.7Hz,1H),7.05(d,J=6.6Hz,1H),6.86(d,J=8.2Hz,1H),6.80(t,J=7.4Hz,1H),3.68(s,3H),2.95(q,J=7.4,7.0Hz,2H),2.64(t,J=7.5Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,157.5,155.3,143.8,136.4,130.6,129.3,128.2,126.7,126.3,124.9,121.3,120.6,113.3,111.1,55.6,42.9,30.7,9.5.HRMS(ESI)[M-H]- calcd forC19H18NO6S:388.0860;found:388.0854.
实施例62
5-(N-(2-羟基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-65)
1H NMR(400MHz,DMSO-d6)δ9.31(s,1H),8.18(dd,J=5.2,1.7Hz,1H),7.94–7.86(m,1H),7.83(d,J=8.6Hz,1H),7.69(t,J=5.8Hz,1H),7.00–6.87(m,2H),6.74–6.68(m,1H),6.64(t,J=7.4Hz,1H),2.94(dq,J=11.6,6.2Hz,2H),2.61(dd,J=8.7,6.4Hz,2H),2.56(d,J=5.9Hz,3H).13C NMR(101MHz,DMSO)δ160.7,155.2,154.8,143.3,135.9,130.3,128.8,127.4,125.9,124.6,124.5,120.9,118.8,114.8,112.8,42.5,30.3,9.0.HRMS(ESI)[M-H]- calcd for C18H17NO6S:374.0698;found:374.0702.
实施例63
3-甲基-5-(N-(3-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-66)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(3-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体182mg,收率89%。1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.17(d,J=1.8Hz,1H),7.90–7.79(m,2H),7.74(t,J=5.8Hz,1H),7.25(q,J=7.4Hz,1H),6.95(dd,J=11.3,8.1Hz,3H),3.02(q,J=6.8Hz,2H),2.69(t,J=7.1Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ162.1(d,J=243.0Hz),160.7,154.9,143.1,141.7(d,J=7.6Hz),135.8,130.0(d,J=8.5Hz),128.8,125.9,124.9(d,J=2.6Hz),124.7,120.9,115.4(d,J=20.9Hz),113.0,112.8(d,J=7.1Hz),43.6,34.8,9.0.19F NMR(376MHz,DMSO-d6)δ-113.80.HRMS(ESI)[M-H]- calcd for C18H15NO5SF:376.0655;found:376.0660.
实施例64
5-(N-(3-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-67)
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根据GPR132-B-60的合成步骤,得到白色固体110mg,收率80%。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.16(s,1H),7.84(q,J=8.7Hz,2H),7.74(t,J=5.7Hz,1H),7.29–7.06(m,4H),3.03(q,J=6.6Hz,2H),2.68(t,J=6.9Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,143.7,141.8,136.2,133.3,130.4,129.3,129.0,127.9,126.6,126.3,125.0,121.3,113.3,44.0,35.1,9.5.HRMS(ESI)[M-H]- calcd for C18H15ClNO5S:392.0365;found:392.0357.
实施例65
5-(N-(3-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-69)
梨形瓶中加入中间体酯(0.19g,0.36mmol),LiOH(0.029g,1.2mmol),加入乙醇(8mL)及H2O(2mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体161mg,产率91%。
1H NMR(400MHz,DMSO-d6)δ13.69(br,1H),8.17(d,J=1.6Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.82(d,J=8.4Hz,1H),7.73(d,J=5.6Hz,1H),7.51-7.48(m,2H),7.16(d,J=7.6Hz,1H),7.02(t,J=7.6Hz,1H),3.01(q,J=6.4Hz,2H),2.64(t,J=7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.31,143.57,142.00,137.74,136.24,135.36,130.80,129.29,128.72,126.31,125.19,121.35,113.36,95.20,44.10,34.97,9.56.HRMS(ESI)[M-H]- calcd for C18H15INO5S-:483.9721;found:483.9720.
实施例66
3-甲基-5-(N-(3-硝基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-73)
1H NMR(400MHz,DMSO-d6)δ8.10(d,J=1.8Hz,1H),7.96(dd,J=8.7,1.9Hz,2H),7.78(td,J=9.6,8.6,7.2Hz,3H),7.60(d,J=7.6Hz,1H),7.49(t,J=7.8Hz,1H),3.11(q,J=6.4Hz,2H),2.81(t,J=6.7Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO)δ160.9,154.7,147.5,141.1,135.8,135.7,129.5,128.9,125.5,123.9,123.5,121.1,120.7,112.7,43.4,34.4,9.0.HRMS(ESI)[M-H]- calcd for C18H16N2O7S:403.0600;found:403.0602.
实施例67
5-(N-(3-羟基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-74)
梨形瓶中加入中间体酯(0.12g,0.29mmol),LiOH(0.016g,0.58mmol),加入乙醇(4mL)及H2O(1mL),室温反应6h,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体56mg,产率50%。
1H NMR(400MHz,DMSO-d6)δ13.66(s,1H),9.23(s,1H),8.23–8.20(m,1H),7.91–
7.88(m,1H),7.85(dd,J=8.8,0.8Hz,1H),7.72(t,J=6.2Hz,1H),7.01(t,J=7.6Hz,1H),6.57–6.52(m,3H),2.95(q,J=6.8Hz,2H),2.60–2.50(m,5H).13C NMR(101MHz,DMSO-d6)δ161.13,157.74,155.34,143.58,140.47,136.30,129.67,129.31,126.37,125.19,121.40,119.66,115.99,113.66,113.37,44.52,35.76,9.49.HRMS(ESI)[M-H]-calcd for C18H16NO6S-:374.0968;found:374.0700.
实施例68
5-(N-(3-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-75)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.14(t,J=6.6Hz,1H),7.01(t,J=7.9Hz,1H),6.94(ddq,J=8.1,2.2,1.1Hz,1H),6.53–6.45(m,2H),4.25(d,J=5.5Hz,1H),4.13(d,J=5.5Hz,1H),3.18(dt,J=6.7,5.7Hz,2H),2.75(tt,J=5.7,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,147.4,143.1,136.6,134.6,128.5,127.6,125.5,125.0,120.2,118.5,115.8,114.4,113.3,45.0,35.3,10.0.HRMS(ESI)[M-H]-calcd for C18H18N2O5S:373.0864;found:373.0864.
实施例69
3-甲基-5-(N-(3-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-76)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.18–7.09(m,2H),6.92(ddq,J=7.7,2.2,1.1Hz,1H),6.55–6.46(m,2H),5.68(q,J=4.8Hz,1H),3.18(dt,J=6.6,5.8Hz,2H),2.94(d,J=4.8Hz,3H),2.81(tt,J=5.8,1.1Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,149.5,143.1,135.4,134.6,129.9,127.6,125.5,125.0,122.7,120.2,115.0,113.3,113.2,45.0,35.1,30.3,10.0.HRMS(ESI)[M-H]- calcd for C19H20N2O5S:387.1020;found:387.1020.
实施例70
5-(N-(3-(二甲基氨基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-77)
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按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.18–7.08(m,2H),6.91(dtd,J=7.9,2.1,0.9Hz,1H),6.60(tt,J=2.3,1.0Hz,1H),6.55(ddd,J=7.5,2.2,1.1Hz,1H),3.18(dt,J=6.6,5.8Hz,2H),2.96(s,6H),2.78(tt,J=5.6,0.9Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,151.6,143.1,138.0,134.6,129.7,127.6,125.5,125.0,122.0,120.2,115.7,113.3,112.6,45.0,40.4,35.1,10.0.HRMS(ESI)[M-H]- calcd forC20H22N2O5S:401.1177;found:401.1177.
实施例71
5-(N-(4-溴苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸(GPR132-B-80)
根据GPR132-B-60的合成步骤,得到白色固体117.0mg,收率79%。1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.15(s,1H),7.89–7.78(m,2H),7.74(t,J=5.8Hz,1H),7.37(d,J=8.3Hz,2H),7.09(d,J=8.3Hz,2H),3.01(q,J=6.9Hz,2H),2.65(t,J=7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,143.7,138.6,136.2,131.4,129.3,126.2,125.0,121.3,119.7,113.3,44.1,34.9,9.5.HRMS(ESI)[M-H]- calcd forC18H15BrNO5S:435.9860;found:435.9850.
实施例72
5-(N-(4-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-81)
梨形瓶中加入中间体酯(0.10g,0.19mmol),LiOH(0.017g,0.67mmol),加入乙醇(4mL)及H2O(1mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体94mg,产率97%。
1H NMR(400MHz,DMSO-d6)δ13.70(br,1H),8.15(d,J=1.6Hz,1H),7.85(dd,J=8.8,1.6Hz,1H),7.82(d,J=8.8Hz,1H),7.73(t,J=6.0Hz,1H),7.54(d,J=7.6Hz,2H),6.94(d,J=8.8Hz,2H),2.98(q,J=6.8Hz,2H),2.62(t,J=7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.29,143.65,138.99,137.35,136.24,131.65,129.29,126.28,125.08,121.34,113.31,92.35,44.12,35.04,9.52.HRMS(ESI)[M-H]- calcd forC18H15INO5S-:483.9721;found:483.9712.
实施例73
3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸(GPR132-B-82)
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将3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸乙酯(0.16g,0.41mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体133mg,产率87.5%。
1H NMR(400MHz,DMSO-d6)δ8.16(d,J=2.0Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.82(d,J=8.8Hz,1H),7.72(d,J=5.6Hz,1H),6.99(s,4H),3.01-2.91(m,2H),2.61(t,J=7.2Hz,2H),2.56(s,3H),2.20(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.31,143.58,136.33,136.00,135.55,129.29,129.23,128.95,126.33,125.12,121.34,113.30,44.62,35.24,21.00,9.48.HRMS(ESI)[M-H]- calcd for C19H19NO5S:372.0911;found:372.0911.
实施例74
5-(N-(4-三氟甲基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸(GPR132-B-83)
根据GPR132-B-60的合成步骤,得到白色固体117.0mg,收率79%。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.20–8.13(m,1H),7.90–7.73(m,3H),7.56(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),3.06(q,J=6.7Hz,2H),2.78(t,J=6.9Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,144.2,143.7,136.2,130.0,129.3,127.5,127.2,126.2,125.4(q,J=3.8Hz),125.0,121.3,113.3,43.9,35.3,9.5.19F NMR(376MHz,DMSO-d6)δ-63.23.HRMS(ESI)[M-H]- calcd for C19H15F3NO5S:426.0629;found:426.0619.
实施例75
5-(N-(4-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-84)
根据GPR132-B-60的合成步骤,得到白色固体114mg,收率59%。1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.16(d,J=1.5Hz,1H),7.91–7.78(m,2H),7.70(t,J=5.8Hz,1H),7.03(d,J=8.5Hz,2H),6.76(d,J=8.5Hz,2H),3.67(s,3H),2.96(q,J=7.1Hz,2H),2.60(t,J=7.3Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,158.1,155.3,143.6,136.3,130.9,130.1,129.3,126.3,125.1,121.3,114.1,113.3,55.3,44.8,34.8,9.5.HRMS(ESI)[M-H]- calcd for C19H18NO6S:388.0860;found:388.0852.
实施例76
5-(N-(4-硝基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-85)
根据GPR132-B-60的合成步骤,得到白色固体73mg,收率62%。1H NMR(400MHz,DMSO-d6)δ13.73(s,1H),8.09(s,1H),8.02(d,J=8.4Hz,2H),7.84–7.75(m,3H),7.39(d,J=8.4Hz,2H),3.11(q,J=6.3Hz,2H),2.81(t,J=6.6Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,155.3,147.6,146.4,143.7,136.2,130.5,129.3,126.2,124.9,123.6,121.2,113.2,43.7,35.3,9.5.HRMS(ESI)[M-H]- calcd for C18H15N2O7S:403.0605;found:403.0600.
实施例77
5-(N-(4-羟基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-86)
根据GPR132-B-60的合成步骤,得到白色固体147mg,收率87%。1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.17(d,J=11.8Hz,1H),7.89(s,1H),7.83(d,J=9.4Hz,1H),7.74–7.66(m,1H),7.13(d,J=8.6Hz,1H),6.94–6.87(m,2H),6.61(d,J=8.4Hz,1H),3.01–2.86(m,2H),2.65(t,J=7.0Hz,1H),2.57–2.54(m,4H).13C NMR(101MHz,DMSO-d6)δ161.1,156.4,155.3,147.9,143.6,138.6,130.7,129.9,129.3,127.5,125.1,122.3,44.1,34.9,9.5.HRMS(ESI)[M-H]- calcd for C18H16NO6S:374.0704;found:374.0702.
实施例78
5-(N-(4-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-87)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.14(t,J=6.6Hz,1H),6.90(dt,J=8.0,1.0Hz,2H),6.48–6.42(m,2H),4.04(d,J=5.7Hz,1H),3.98(d,J=5.7Hz,1H),3.17(dt,J=6.7,5.8Hz,2H),2.82(tt,J=5.7,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ
165.0,157.9,145.9,143.1,134.6,129.6,128.3,127.6,125.5,125.0,120.2,115.2,113.3,44.9,35.2,10.0.HRMS(ESI)[M-H]- calcd for C18H18N2O5S:373.0864;found:373.0864.
实施例79
3-甲基-5-(N-(4-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-88)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.14(t,J=6.6Hz,1H),6.96(dt,J=7.5,1.1Hz,2H),6.62–6.56(m,2H),5.48(q,J=4.8Hz,1H),3.17(dt,J=6.7,5.8Hz,2H),2.91(d,J=4.8Hz,3H),2.82(tt,J=5.7,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,147.6,143.1,134.6,131.1,130.1,127.6,125.5,125.0,120.2,113.4,113.3,44.9,35.8,30.2,10.0.HRMS(ESI)[M-H]- calcd for C19H20N2O5S:387.1020;found:387.1020.
实施例80
5-(N-(2-(5-溴吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-90)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.51(dt,J=20.9,1.8Hz,2H),8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.48(t,J=2.0Hz,1H),7.16(t,J=6.6Hz,1H),3.23(q,J=6.2Hz,2H),2.93(t,J=6.2Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,148.1,148.0,143.1,135.4,134.6,133.7,127.6,125.5,125.0,120.2,119.9,113.3,44.9,32.4,10.0.HRMS(ESI)[M-H]-calcd for C17H15BrN2O5S:436.9812;found:436.9812.
实施例81
5-(N-(2-(5-甲氧基吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-91)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.30(t,J=1.8Hz,1H),8.19(d,J=2.4Hz,1H),8.12(t,J=1.8Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.16(t,J=6.6Hz,1H),6.95(t,J=2.0Hz,1H),3.91(s,2H),3.23(q,J=6.3Hz,2H),2.92(t,J=6.2Hz,2H),2.58(s,2H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,155.7,143.1,143.1,135.1,134.6,133.6,127.6,125.5,125.0,120.2,117.9,113.3,55.8,44.9,33.0,10.0.HRMS(ESI)[M-H]- calcd for C18H18N2O6S:389.0813;found:389.0813.
实施例82
3-甲基-5-(N-(3-(三氟甲氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-92)
将3-甲基-5-(N-(3-(三氟甲氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸乙酯(0.17g,0.36mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体147mg,产率91.9%。
1H NMR(400MHz,DMSO-d6)δ8.18(d,J=1.6Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.80(d,J=9.2Hz,2H),7.37–7.30(m,1H),7.17(d,J=7.6Hz,1H),7.11(d,J=6.4Hz,2H),3.04(q,J=6.8Hz,2H),2.73(t,J=7.2Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.16,155.31,148.75,143.66,142.08,136.18,130.42,129.29,128.35,126.27,125.02,121.62,121.37,118.97,113.29,43.96,35.04,9.43.19F NMR(376MHz,DMSO-d6)δ-58.72.HRMS(ESI)[M-H]- calcd for C19H16F3NO6S:442.0578;found:442.0578.
实施例83
5-(N-(3-乙炔基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-24)
梨形瓶中加入中间体酯(0.18g,0.43mmol),LiOH(0.034g,1.2mmol),加入乙醇(6mL)及H2O(1.5mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量淡黄色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得淡黄色固体131mg,产率80%。
1H NMR(400MHz,DMSO-d6)δ13.67(br,1H),8.17(d,J=2.0Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.82(d,J=8.8Hz,1H),7.73(t,J=6.0Hz,1H),7.32–7.16(m,4H),4.12(s,1H),3.01(q,J=6.4Hz,2H),2.67(t,J=7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.31,143.55,139.78,136.24,132.42,129.99,129.96,129.29,129.01,126.32,125.18,122.04,121.36,113.35,83.95,80.92,44.12,35.17,9.50.HRMS(ESI)[M-H]- calcd for C20H16NO5S-:382.0755;found:382.0749.
实施例84
5-(N-(3-氰基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-26)
梨形瓶中加入中间体酯(0.24g,0.59mmol),LiOH(0.028g,1.2mmol),加入乙醇(8mL)及H2O(2mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量淡黄色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得淡黄色固体196mg,产率86%。
1H NMR(400MHz,DMSO-d6)δ13.66(br,1H),8.18–8.15(m,1H),7.86–7.80(m,2H),7.75(t,J=5.8Hz,1H),7.60–7.58(m,2H),7.49(d,J=7.6Hz,1H),7.42(t,J=7.8Hz,1H),3.07(q,J=6.4Hz,2H),2.74(t,J=7.0Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.30,143.59,140.88,136.26,134.37,132.77,130.43,129.78,129.28,126.27,125.14,121.33,119.27,113.35,111.56,43.78,34.91,9.50.HRMS(ESI)[M-H]- calcd forC19H15N2O5S-:383.0707;found:383.0709.
实施例85
5-(N-(3-(二甲基磷酰基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-95)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.44(dddd,J=13.4,7.3,2.3,1.3Hz,1H),7.32–7.18(m,3H),7.14(t,J=6.6Hz,1H),3.17(dt,J=6.6,5.7Hz,2H),2.78(tt,J=5.7,1.0Hz,2H),2.58(s,3H),1.97(s,6H).13C NMR(101MHz,DMSO-d6)δ165.6,156.7,143.1,139.2,139.1,135.3,134.9,134.3,130.6,130.6,129.8,129.7,129.3,129.3,127.8,127.8,127.8,127.1,126.6,119.4,113.0,45.0,35.4,35.4,18.6,17.9,10.3.31P NMR(202MHz,DMSO-d6)δ34.2.HRMS(ESI)[M-H]- calcd for C20H22NO6PS:434.0833;found:434.0833.
实施例86
5-(N-(3-(1,1-二氟乙基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-96)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.41–7.30(m,3H),7.21–7.12(m,2H),3.17(dt,J=6.6,5.7Hz,2H),2.82(tt,J=5.6,1.0Hz,2H),2.58(s,3H),2.33(t,J=20.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,138.2(t,J=32.0Hz),137.3(t,J=2.0Hz),134.6,130.1(t,J=2.0Hz),130.0,127.6,126.8(t,J=3.9Hz),125.5,125.0,124.9(t,J=3.9Hz),121.5(t,J=221.1Hz),120.2,113.3,45.0,35.9,25.6(t,J=27.1Hz),10.0.19F NMR(472MHz,DMSO-d6)δ-95.99.HRMS(ESI)[M-H]- calcd forC20H19F2NO5S:422.0879;found:422.0879.
实施例87
5-(N-(3-乙酰苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-25)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.14(d,J=2.0Hz,1H),7.84(dd,J=8.8,2.0Hz,1H),7.80(s,1H),7.78(d,J=4.8Hz,1H),7.73–7.70(m,1H),7.68(d,J=2.2Hz,1H),7.42–7.41(m,1H),7.36(d,J=7.6Hz,1H),3.06(q,J=6.4Hz,2H),2.75(t,J=7.0Hz,2H),2.55(s,3H),2.51(s,3H).13C NMR(101MHz,DMSO-d6)δ198.25,161.14,155.26,143.55,139.78,137.17,136.24,134.06,129.26,129.00,128.81,126.65,126.29,125.13,121.31,113.30,44.24,35.29,27.08,9.48.HRMS(ESI)[M-H]- calcd forC20H18NO6S-:400.0860;found:400.0862.
实施例88
5-(N-(3-乙氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-98)
梨形瓶中加入中间体酯(0.19g,0.44mmol),LiOH(0.022g,0.93mmol),加入乙醇(4mL)及H2O(1mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体157mg,产率87%。
1H NMR(400MHz,DMSO-d6)δ13.69(br,1H),8.18(d,J=1.6Hz,1H),7.87(dd,J=8.8,1.6Hz,1H),7.82(d,J=8.8Hz,1H),7.72(t,J=5.6Hz,1H),7.11(t,J=7.8Hz,1H),6.68(dd,J=8.0,2.0Hz,2H),6.64(t,J=2.0Hz,1H),3.92(q,J=6.8Hz,2H),3.00(q,J=6.8Hz,2H),2.63(t,J=7.4Hz,2H),2.57(s,3H),1.28(t,J=6.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.15,158.90,155.31,143.54,140.65,136.31,129.66,129.26,126.33,125.18,121.37,121.23,115.18,113.33,112.48,63.15,44.36,35.64,15.09,9.49.HRMS(ESI)[M-H]- calcd for C20H20NO6S-:402.1017;found:402.1018.
实施例89
3-甲基-5-(N-(3-(2,2,2-三氟乙氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸(GPR132-B-27)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ13.68(br,1H),8.19(d,J=1.6Hz,1H),7.88(dd,J=8.8,2.0Hz,1H),7.83(d,J=8.8Hz,1H),7.74(t,J=5.8Hz,1H),7.20–7.16(m,1H),6.85–6.80(m,3H),4.67(q,J=8.8Hz,2H),3.02(q,J=6.8Hz,2H),2.66(t,J=7.4Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,157.32,155.31,143.56,141.06,136.30,129.89,129.28,126.32,125.17,124.47(q,J=279.1Hz),122.97,121.38,115.66,113.35,112.95,64.94(q,J=34.3Hz),44.21,35.56,9.46.19F NMR(376MHz,DMSO-d6)δ-72.63.HRMS(ESI)[M-H]- calcd for C20H17F3NO6S-:456.0734;found:456.0727.
实施例90
5-(N-(3-(2-乙氧基乙氧基)苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-100)
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梨形瓶中加入中间体酯(0.18g,0.38mmol),LiOH(0.020g,0.84mmol),加入乙醇(4mL)及H2O(1mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体126mg,产率75%。
1H NMR(400MHz,DMSO-d6)δ13.68(br,1H),8.18(d,J=2.0Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.83(d,J=8.8Hz,1H),7.72(t,J=5.6Hz,1H),7.12(t,J=8.0Hz,1H),6.72–6.68(m,3H),3.99(t,J=4.2Hz,2H),3.65(t,J=4.8Hz,2H),3.48(q,J=6.8Hz,2H),3.00(q,J=6.8Hz,2H),2.63(t,J=7.4Hz,2H),2.57(s,3H),1.12(t,J=6.8Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.15,158.87,155.31,143.55,140.70,136.32,129.69,129.27,126.34,125.19,121.43,121.38,115.26,113.36,112.59,68.81,67.35,66.13,44.35,35.64,15.54,9.49.HRMS(ESI)[M-H]- calcd for C22H24NO7S-:446.1279;found:446.1274.
实施例91
5-(N-(3-(3,3-二氟氮杂环丁烷-1-基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-101)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.18–7.11(m,2H),7.00(dddt,J=7.3,3.5,2.4,1.2Hz,2H),6.74(tt,J=2.1,1.0Hz,1H),4.02(t,J=20.9Hz,4H),3.18(dt,J=6.6,5.8Hz,2H),2.78(tt,J=5.6,0.9Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,148.7(t,J=3.9Hz),143.1,138.2,134.6,130.2,127.6,125.5,125.0,122.3,120.2,117.1,116.9(t,J=216Hz),113.4,113.3,60.9(t,J=27.1Hz),45.0,35.1,10.0.19F NMR(376MHz,DMSO-d6)δ-122.4.HRMS(ESI)[M-H]- calcd for C21H20F2N2O5S:449.0988;found:449.0988.
实施例92
3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-102)
按照实施例25所用方法,中间体乙酯替换为3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得粉色固体216mg,收率91%。1HNMR(400MHz,DMSO-d6)δ8.13(d,J=1.9Hz,1H),7.88–7.71(m,3H),7.62–7.56(m,2H),7.46–7.40(m,4H),7.32(dt,J=10.4,7.5Hz,2H),7.13(d,J=7.5Hz,1H),3.07(q,J=6.8Hz,2H),2.75(t,J=6.8Hz,2H),2.53(s,3H).13C NMR(101MHz,DMSO-d6)δ161.6,154.5,140.2,139.4,135.4,129.4,128.8,127.8,127.3,127.1,126.7,124.9,124.6,120.4,112.5,44.0,35.2,9.0.HRMS(ESI)[M+H]+ calcd for C24H22NO5S:436.1219;found:436.1211.
实施例93
3-甲基-5-(N-(3-(噻吩-3-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-103)
按照实施例25乙酯所用方法合成。1H NMR(00MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.59(t,J=1.7Hz,1H),7.52–7.35(m,5H),7.20–7.11(m,2H),3.17(dt,J=6.6,5.7Hz,2H),2.84(tt,J=5.8,1.0Hz,3H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,141.2,139.1,137.1,134.6,128.7,128.1,128.0,127.6,127.0,126.6,125.6,125.5,125.0,122.9,120.2,113.3,45.0,35.8,10.0.HRMS(ESI)[M-H]- calcd for C22H19NO5S2:440.0632;found:440.0632.
实施例94
3-甲基-5-(N-(3(噻吩-2-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-104)
梨形瓶中加入中间体酯(0.36g,0.78mmol),LiOH(0.042g,1.7mmol),加入乙醇(8mL)及H2O(2mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体334mg,产率97%。
1H NMR(400MHz,DMSO-d6)δ8.18(d,J=2.0Hz,1H),7.87(dd,J=8.6,1.6Hz,1H),7.80(d,J=8.8Hz,1H),7.76(t,J=5.8Hz,1H),7.50(d,J=4.8Hz,1H),7.43–7.38(m,3H),7.25(t,J=7.8Hz,1H),7.10(t,J=4.4Hz,1H),7.07(d,J=7.6Hz,1H),3.08(q,J=6.8Hz,2H),2.72(t,J=7.2Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO-d6)δ161.13,155.30,143.78,143.56,140.09,136.34,134.13,129.44,129.28,128.80,128.45,126.30,126.20,125.95,125.14,124.00,123.81,121.33,113.31,44.31,35.50,9.47.HRMS(ESI)[M-H]-calcd for C22H18NO5S2 -:440.0700;found:440.0627.
实施例95
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-4-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-105)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(3-(1-甲基-1H-吡唑-4-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得黄色固体41mg,收率41%。1H NMR(400MHz,DMSO-d6)δ8.16(d,J=1.8Hz,1H),8.03(s,1H),7.85(dd,J=8.7,1.8Hz,1H),7.81–7.72(m,3H),7.39–7.27(m,2H),7.19(t,J=7.6Hz,1H),6.94(d,J=7.6Hz,1H),3.84(s,3H),3.11–2.96(m,2H),2.68(t,J=7.3Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO)δ154.7,139.1,135.9,135.7,132.5,129.0,128.7,127.6,126.3,125.5,125.2,122.8,121.8,120.7,112.7,43.9,38.6,35.2,9.0.HRMS(ESI)[M+H]+ calcd forC22H22N3O5S:440.1280;found:440.1273.
实施例96
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-5-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-106)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(3-(1-甲基-1H-吡唑-5-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得灰色固体88mg,收率57%。1H NMR(400MHz,DMSO-d6)δ8.23–8.18(m,1H),7.91–7.73(m,3H),7.44(d,J=1.9Hz,1H),7.39–7.27(m,3H),7.20(dt,J=7.2,1.7Hz,1H),6.34(d,J=1.9Hz,1H),3.81(s,3H),3.07(q,J=6.8Hz,2H),2.75(t,J=7.1Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.8,143.2,142.6,139.4,137.8,135.8,130.1,128.8,128.8,128.7,128.7,126.3,125.8,124.6,120.9,112.9,105.7,43.8,37.4,35.0,9.0.HRMS(ESI)[M+H]+ calcdfor C22H22N3O5S:440.1280;found:440.1273.
实施例97
5-(N-(2-氟-4-氯苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸(GPR132-B-107)
根据GPR132-B-60的合成步骤,得到白色固体108.6mg,收率80%。1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.90–7.74(m,3H),7.25(t,J=8.3Hz,2H),7.13(dd,J=8.2,1.8Hz,1H),3.02(q,J=6.8Hz,2H),2.69(t,J=6.9Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,160.9(d,J=247.3Hz),155.3,143.9,136.2,133.0(d,J=5.7Hz),132.2(d,J=10.3Hz),129.3,126.2,1245.0(d,J=15.7Hz),124.9,124.8,121.2,116.1(d,J=26.0Hz),113.3.19F NMR(376MHz,DMSO-d6)δ-113.46.HRMS(ESI)[M-H]- calcd for C18H14ClFNO5S:410.0271;found:410.0262.
实施例98
3-甲基-5-(N-(2-氟-3-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-108)
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按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-氟-3-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体143mg,收率68%。1HNMR(400MHz,DMSO-d6)δ8.17–8.13(m,1H),7.86–7.78(m,3H),7.10–6.89(m,3H),3.08–2.86(m,2H),2.67(d,J=7.9Hz,2H),2.59–2.52(m,3H),2.13(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,154.7,135.6,129.7,129.0,128.6,125.5,124.9,123.7,120.7,112.8,42.6,28.9,14.1,9.0.19F NMR(376MHz,DMSO-d6)δ-123.64.HRMS(ESI)[M-H]- calcd for C19H18FNO5S:390.0811;found:390.0805.
实施例99
5-(N-(2-(2,3-二氢苯并呋喃-7-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-109)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.19(t,J=6.5Hz,1H),7.10(ddq,J=16.3,8.1,1.2Hz,2H),7.00–6.93(m,1H),4.49(dd,J=5.2,3.2Hz,2H),3.26–3.05(m,4H),2.91(td,J=5.9,1.0Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,158.9,157.9,143.1,134.6,127.7,127.6,127.6,125.9,125.5,125.0,121.0,120.2,118.2,113.3,73.4,42.3,30.6,29.1,10.0.HRMS(ESI)[M-H]- calcd for C20H19NO6S:400.0860;found:400.0860.
实施例100
5-(N-(2-(2,3-二氢苯并[b][1,3]二氧杂环戊烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-110)
梨形瓶中加入中间体酯(0.31g,0.75mmol),LiOH(0.06g,2.8mmol),加入乙醇(12mL)及H2O(3mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体270mg,产率91%。
1H NMR(400MHz,DMSO-d6)δ13.70(s,1H),8.18(d,J=1.8Hz,1H),7.88(dd,J=8.8,1.8Hz,1H),7.84(d,J=8.7Hz,1H),7.79(t,J=5.9Hz,1H),6.73–6.67(m,2H),6.62(dd,J=5.4,3.7Hz,1H),5.91(s,2H),3.07–2.96(m,2H),2.63(t,J=7.5Hz,2H),2.57(s,3H).13CNMR(101MHz,DMSO-d6)δ161.14,155.32,147.10,145.72,143.56,136.32,129.28,126.34,125.18,123.16,121.81,121.36,120.14,113.34,107.27,100.89,42.54,29.89,9.49.HRMS(ESI)[M-H]- calcd for C19H17NO7S:402.0653;found:402.0653.
实施例101
5-(N-(2-(2,2-二氟苯并[d][1,3]二氧杂环戊-4-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-111)
梨形瓶中加入中间体酯(0.24g,0.5mmol),LiOH(0.07g,0.28mmol),加入乙醇(8mL)及H2O(2mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体145mg,产率66%。
1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.16(s,1H),7.88–7.77(m,3H),7.16(d,J=7.9Hz,1H),7.07(t,J=7.9Hz,1H),7.01(d,J=7.9Hz,1H),3.08(q,J=6.7Hz,2H),2.75(t,J=7.0Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.13,155.31,143.59,142.84,141.77,136.21,131.34(t,J=255.6Hz),129.26,126.24,125.87,125.11,124.54,121.96,121.32,113.33,108.54,42.30,29.29,9.42.19F NMR(376MHz,CDCl3)δ-49.73.HRMS(ESI)[M-H]-calcd for C19H15F2NO7S:438.0465;found:438.0465.
实施例102
5-(N-(2-(2,3-二氢苯并[b][1,4]二氧杂环己烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-112)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.4Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.22(t,J=6.5Hz,1H),6.92–6.85(m,1H),6.78–6.69(m,2H),4.29(s,4H),3.21–3.14(m,2H),2.93(td,J=6.0,1.1Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,145.6,144.3,143.1,134.6,127.6,125.8,125.5,125.0,124.1,122.9,120.2,113.3,113.2,65.1,63.7,42.2,30.5,10.0.HRMS(ESI)[M-H]- calcd for C20H19NO7S:416.0809;found:416.0809.
实施例103
5-(N-(2,4-二氟苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-114)
梨形瓶中加入中间体酯(0.10g,0.24mmol),LiOH(0.013g,0.51mmol),加入乙醇(4mL)及H2O(1mL),室温反应2.5h,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体92mg,产率95%。
1H NMR(400MHz,DMSO-d6)δ13.68(br,1H),8.16(s,1H),7.88–7.82(m,2H),7.79(t,J=5.8Hz,1H),7.27(dd,J=15.2,8.8Hz,1H),7.10–7.04(m,1H),6.97–6.92(m,1H),2.99(q,J=7.8Hz,2H),2.68(t,J=7.2Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.32,143.58,136.27,132.78,132.72,132.68,132.62,129.29,126.28,125.13,122.06,121.91,121.32,113.36,111.75,111.71,111.54,111.50,104.22,103.96,103.70,42.96,28.63,9.47.19F NMR(376MHz,DMSO-d6)δ-112.83,-114.35.HRMS(ESI)[M-H]- calcd forC18H14F2NO5S-:394.0566;found:394.0561.
实施例104
5-(N-(5-溴-2-氟苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-115)
梨形瓶中加入中间体酯(0.12g,0.25mmol),LiOH(0.013g,0.51mmol),加入乙醇(4mL)及H2O(1mL),室温反应4h,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色略带淡黄色固体96mg,产率85%。
1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),8.19(d,J=1.6Hz,1H),7.90–7.80(m,3H),7.24–7.21(m,1H),7.10–7.05(m,2H),3.02–2.97(m,2H),2.72(t,J=7.4Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ162.25,161.14,159.83,155.33,143.56,136.25,131.76,131.72,129.30,128.93,128.85,126.33,125.75,125.60,125.19,124.77,124.74,121.40,115.61,115.39,113.41,43.04,29.20,9.49.HRMS(ESI)[M-H]- calcd forC18H14FBrNO5S-:453.9766;found:453.9764.
实施例105
3-甲基-5-(N-(2-氟-5-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-116)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-氟-5-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体163mg,收率77%。1HNMR(400MHz,DMSO-d6)δ8.16(s,1H),7.99–7.68(m,3H),7.12–6.81(m,3H),3.08–2.89(m,2H),2.65(t,J=7.5Hz,2H),2.56(s,3H),2.18(s,3H).13C NMR(101MHz,DMSO-d6)δ161.2,158.8(d,J=240.6Hz),154.7,135.7,133.2,131.5(d,J=4.7Hz),129.1,128.6(d,J=8.4Hz),125.5,124.7(d,J=16.1Hz),120.7,114.7(d,J=22.0Hz),112.8,42.7,28.8,20.1,9.0.19F NMR(376MHz,DMSO-d6)δ-124.06.HRMS(ESI)[M-H]- calcd for C19H18FNO5S:390.0811;found:390.0811.
实施例106
5-(N-(2-氟-5-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-117)
将5-(N-(2-氟-5-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.39g,0.40mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体143mg,产率89.9%。
1H NMR(400MHz,DMSO-d6)δ8.17(d,J=2.0Hz,1H),7.91-7.72(m,3H),6.96(t,J=9.2Hz,1H),6.78-6.66(m,2H),3.67(s,3H),3.01(q,J=6.8Hz,2H),2.67(t,J=7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.16,155.34(d,J=236.4Hz),155.32,154.17,143.61,136.30,129.30,126.46(d,J=17.6Hz),126.26,125.11,121.32,116.60(d,J=4.6),116.03,115.80,113.33,55.85,42.96,29.36,9.45.19F NMR(376MHz,DMSO-d6)δ-129.74.HRMS(ESI)[M-H]- calcd for C19H17FNO6S:406.0766;found:406.0764.
实施例107
5-(N-(4-氟-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-118)
将5-(N-(4-氟-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.18g,0.41mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体158mg,产率94.0%。
1H NMR(400MHz,DMSO-d6)δ8.14(d,J=1.6Hz,1H),7.85(dd,J=8.8,2.0Hz,1H),7.81(d,J=8.8Hz,1H),7.72(t,J=6.0Hz,1H),6.98(dd,J=11.6,8.0Hz,1H),6.89(dd,J=8.4,2.0Hz,1H),6.68-6.62(m,1H),3.74(s,3H),3.03(q,J=6.8Hz,2H),2.63(t,J=7.2Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.15,155.28,151.81,149.41,147.10(d,J=10.7Hz),143.57,136.36,135.86(d,J=3.6Hz),129.26,126.28,125.11,121.27,121.18(d,J=6.8Hz),115.83,115.66,114.62,113.26,56.17,44.38,35.22,9.45.19F NMR(376MHz,DMSO-d6)δ-139.14.HRMS(ESI)[M-H]- calcd for C19H17FNO6S:406.4766;found:406.0764.
实施例108
5-(N-(4-氯-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-119)
将5-(N-(4-氯-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.14g,0.31mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体117mg,产率89.1%。
1H NMR(400MHz,DMSO-d6)δ8.13(d,J=1.2Hz,1H),7.85(dd,J=8.8,2.0Hz,1H),7.79(d,J=8.8Hz,1H),7.74(t,J=5.6Hz,1H),7.18(d,J=8.0Hz,1H),6.87(d,J=2.0Hz,1H),6.68(dd,J=8.0,2.0Hz,1H),3.77(s,3H),3.06(q,J=6.8Hz,2H),2.66(t,J=6.8Hz,2H),2.55(s,3H).13C NMR(101MHz,DMSO-d6)δ161.17,155.27,154.55,143.67,139.80,136.36,129.76,129.27,126.21,125.00,122.06,121.21,119.26,113.67,113.20,56.24,44.18,35.35,9.45.HRMS(ESI)[M-H]- calcd for C19H17ClNO6S:422.0471;found:422.0470.
实施例109
5-(N-(3,4-二甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-120)
根据GPR132-B-60的合成步骤,得到白色固体95mg,收率69%。1H NMR(400MHz,DMSO-d6)δ13.69(s,1H),8.16(d,J=1.3Hz,1H),7.91–7.77(m,2H),7.70(t,J=5.7Hz,1H),6.79–6.52(m,3H),3.68(s,6H),3.00(q,J=7.0Hz,2H),2.60(t,J=7.3Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ161.1,155.3,148.9,147.7,143.5,136.4,131.5,129.2,126.3,125.1,121.3,121.0,113.3,113.0,112.1,55.9,55.8,44.7,35.2,9.5.HRMS(ESI)[M-H]- calcd for C20H20NO7S:418.0966;found:418.0954.
实施例110
5-(N-(3,4-亚甲二氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-121)
根据GPR132-B-60的合成步骤,得到白色固体98mg,收率78%。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.16(s,1H),7.90–7.78(m,2H),7.69(t,J=5.7Hz,1H),6.72(d,J=7.9Hz,1H),6.68(s,1H),6.57(d,J=7.9Hz,1H),5.91(s,2H),2.97(q,J=6.9Hz,2H),2.58(d,J=10.3Hz,5H).13C NMR(101MHz,DMSO-d6)δ161.2,155.3,147.5,146.0,143.6,136.3,132.9,129.3,126.3,125.1,122.1,121.3,113.3,109.5,108.4,101.1,44.7,35.3,9.5.HRMS(ESI)[M-H]- calcd for C19H16NO7S:402.0653;found:402.0643.
实施例111
3-甲基-5-(N-(2-(萘-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-122)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-(萘-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体91mg,收率93%。1H NMR(400MHz,DMSO-d6)δ13.71(s,1H),8.15(d,J=1.8Hz,1H),7.92–7.73(m,6H),7.60(s,1H),7.48–7.39(m,2H),7.34–7.26(m,1H),3.15(q,J=6.8Hz,2H),2.86(t,J=7.1Hz,2H),2.52(s,3H).13CNMR(101MHz,DMSO-d6)δ160.7,154.8,143.1,136.3,135.9,133.0,131.7,128.8,127.7,127.3,127.3,127.2,126.8,125.9,125.8,125.3,124.6,120.8,112.8,43.9,35.3,9.0.HRMS(ESI)[M-H]- calcd for C22H18NO5S:408.0906;found:408.0908.
实施例112
5-(N-(3,5-二甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-123)
梨形瓶中加入中间体酯(0.23g,0.52mmol),LiOH(0.029g,1.2mmol),加入乙醇(8mL)及H2O(2mL),室温过夜反应,TLC监测反应完全。反应结束后,加入适量3N HCl调节pH至1,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,干燥后得白色固体162mg,产率74%。
1H NMR(400MHz,DMSO-d6)δ13.69(br,1H),8.17(d,J=1.6Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.82(d,J=8.8Hz,1H),7.71(t,J=6.0Hz,1H),6.26(d,J=2.4Hz,2H),6.24(t,J=2.4Hz,1H),3.66(s,6H),3.02(q,J=7.2Hz,2H),2.59(t,J=7.2Hz,2H),2.56(s,3H).13CNMR(101MHz,DMSO-d6)δ161.15,160.74,155.31,143.53,141.39,136.40,129.26,126.31,125.18,121.32,113.27,107.13,98.43,55.41,44.25,35.87,9.46.HRMS(ESI)[M-H]- calcd for C20H20NO7S-:418.0966;found:418.0966.
实施例113
5-(N-(3-吲哚基乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-125)
根据GPR132-B-60的合成步骤,得到白色固体82mg,收率65%。1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.20(d,J=10.4Hz,1H),7.94–7.67(m,3H),7.31(dd,J=22.9,7.8Hz,2H),7.10(s,1H),7.01(t,J=7.3Hz,1H),6.91(t,J=7.3Hz,1H),4.38(q,J=6.9Hz,1H),3.05(q,J=6.8Hz,2H),2.79(t,J=7.2Hz,2H),2.56(s,3H).13C NMR(101MHz,DMSO-d6)δ159.6,155.3,155.2,136.6,136.3,129.4,127.4,126.6,126.1,123.4,121.3,121.2,118.6,118.3,113.2,111.8,111.3,43.9,25.8,9.5.HRMS(ESI)[M-H]- calcd forC20H17N2O5S:397.0864;found:397.0855.
实施例114
5-(正丁基磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-127)
将3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸乙酯(0.13g,0.38mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体119mg,产率99%。
1H NMR(400MHz,DMSO-d6)δ8.20(d,J=2.0Hz,1H),7.90(dd,J=8.8,2.0Hz,1H),7.84(d,J=8.8Hz,1H),7.58(t,J=6.0Hz,1H),2.73(q,J=6.8Hz,2H),2.57(s,3H),1.37-1.27(m,2H),1.27-1.15(m,2H),0.76(t,J=7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.14,155.28,143.62,136.48,129.26,126.31,125.08,121.31,113.33,42.67,31.50,19.64,13.86,9.46.HRMS(ESI)[M-H]- calcd for C14H17NO5S:310.0755;found:310.0753.
实施例115
5-(N-(3-碘丁-3-烯-1-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-129)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),6.73(t,J=5.1Hz,1H),5.80(q,J=1.0Hz,1H),5.72(q,J=1.0Hz,1H),2.99(q,J=5.3Hz,2H),2.58(s,3H),2.44(tt,J=5.4,1.0Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.6,156.7,143.1,134.9,127.8,127.1,126.6,126.3,119.4,113.0,109.5,44.0,41.6,10.3.HRMS(ESI)[M-H]- calcd for C14H14INO5S:433.9565;found:433.9565.
实施例116
5-(N-(2-环戊基乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸(GPR132-B-131)
将5-(N-(2-环戊基乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.39mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体75mg,产率53.9%。
1H NMR(400MHz,DMSO-d6)δ8.20(d,J=2.0Hz,1H),7.89(dd,J=8.8,2.0Hz,1H),7.85(d,J=8.8Hz,1H),7.58(t,J=6.0Hz,1H),2.73(dd,J=14.8,6.0Hz,2H),2.56(s,3H),1.75-1.54(m,3H),1.53 -1.30(m,7H),0.99-0.86(m,2H).13C NMR(101MHz,DMSO-d6)δ161.15,155.29,143.58,136.42,129.26,126.35,125.13,121.34,113.36,42.40,37.13,35.67,32.32,24.99,9.47.HRMS(ESI)[M-H]- calcd for C17H20NO5S:350.1068;found:350.1057.
实施例117
3-甲基-5-(N-(2-(噻吩-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-133)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.27–7.20(m,2H),7.14(t,J=6.6Hz,1H),6.66(dd,J=5.2,1.7Hz,1H),3.17(dt,J=6.7,5.2Hz,2H),2.77(t,J=5.2Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,137.0,134.6,127.6,127.5,125.5,125.5,125.0,124.5,120.2,113.3,44.7,30.9,10.0.HRMS(ESI)[M-H]- calcd for C16H15NO5S2:364.0319;found:364.0319.
实施例118
5-(N-(2-(5-氯噻吩-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-134)
1H NMR(400MHz,DMSO-d6)δ8.07(d,J=1.8Hz,1H),7.84(t,J=5.8Hz,1H),7.78(dd,J=8.7,1.9Hz,1H),7.72(d,J=8.7Hz,1H),6.87(d,J=3.8Hz,1H),6.71(dd,J=3.7,1.0Hz,1H),2.97(q,J=6.5Hz,2H),2.83(t,J=6.8Hz,2H),2.54(s,3H).13C NMR(101MHz,DMSO)δ162.2,154.3,140.5,134.8,129.9,126.3,125.6,125.5,124.2,120.0,112.2,43.7,29.8,9.0.HRMS(ESI)[M-H]- calcd for C16H14ClNO5S2:400.0080;found:400.0074.
实施例119
3-甲基-5-(N-(2-(5-溴噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-135)
按照实施例25所用方法,将中间体酯替换为3-甲基-5-(N-(2-(5-溴噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体205mg,收率86%。1HNMR(400MHz,DMSO-d6)δ13.74(s,1H),8.19(d,J=1.8Hz,1H),7.91–7.80(m,3H),6.97(d,J=3.7Hz,1H),6.68(d,J=3.7Hz,1H),3.01–2.93(m,2H),2.85(t,J=6.7Hz,2H),2.57(s,3H).13C NMR(101MHz,DMSO-d6)δ160.7,154.9,143.3,143.1,135.7,129.9,128.9,126.6,125.8,124.6,121.0,112.9,108.7,43.7,29.8,9.1.HRMS(ESI)[M-H]- calcd forC16H14BrNO5S2:441.9419;found:441.9413.
实施例120
3-甲基-5-(N-(2-(4-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-136)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-(4-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得褐色固体48mg,收率48%。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=1.8Hz,1H),7.92–7.77(m,3H),6.83(s,1H),6.61(s,1H),2.98(q,J=6.7Hz,2H),2.82(t,J=7.2Hz,2H),2.57(s,3H),2.09(s,3H).13C NMR(101MHz,DMSO-d6)δ160.9,154.8,143.8,140.5,136.7,135.7,129.0,127.7,125.7,124.1,120.9,119.0,112.9,44.1,29.7,15.3,9.0.HRMS(ESI)[M-H]- calcd for C17H16NO5S2:378.0470;found:378.0473.
实施例121
3-甲基-5-(N-(2-(3-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-137)
按照实施例25所用方法,中间体乙酯替换为3-甲基-5-(N-(2-(3-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得灰黄色固体161mg,收率79%。1H NMR(400MHz,DMSO-d6)δ8.02(d,J=1.9Hz,1H),7.83(t,J=5.8Hz,1H),7.77–7.65(m,2H),6.62–6.53(m,2H),2.95(q,J=6.8Hz,2H),2.80(t,J=7.2Hz,2H),2.52(s,3H),2.33(s,3H).13C NMR(101MHz,DMSO-d6)δ163.0,153.9,151.4,138.5,137.3,134.5,130.4,125.2,124.9,123.4,119.5,116.3,112.0,44.3,29.7,14.9,9.0.HRMS(ESI)[M-H]- calcdfor C17H16NO5S2:378.0470;found:378.0465.
实施例122
5-(N-(2-(环己-1-烯-1-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-138)
将5-(N-(2-(环己-1-烯-1-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.16g,0.41mmol)溶于乙醇(8mL),加入氢氧化锂(0.02g,0.83mmol,溶于2mL水),室温搅拌反应3h。反应结束后,浓缩除去乙醇,加入适量水,搅拌下加入3N HCl调节pH 2~3,析出大量白色固体。抽滤,滤饼用蒸馏水洗涤,烘干得白色固体133mg,产率89.9%。
1H NMR(400MHz,DMSO-d6)δ8.21(d,J=2.0Hz,1H),7.90(dd,J=8.8,2.0Hz,1H),7.85(d,J=8.8Hz,1H),7.55(t,J=6.0Hz,1H),5.30-5.26(m,1H),2.86-2.77(m,2H),2.57(s,3H),1.97(t,J=6.8Hz,2H),1.89-1.81(m,2H),1.80-1.70(m,2H),1.51–1.35(m,4H).13CNMR(101MHz,DMSO-d6)δ161.15,155.30,143.63,136.51,134.63,129.29,126.36,125.08,122.79,121.35,113.32,41.68,37.82,27.96,25.04,22.73,22.24,9.48.HRMS(ESI)[M-H]-calcd for C18H21NO5S:362.1068;found:362.1068.
实施例123
5-(N-(2-氟-2-苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-23)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.44–7.23(m,5H),6.96(t,J=7.7Hz,1H),5.41(dt,J=46.4,4.6Hz,1H),3.76–3.52(m,2H),2.58(s,3H).13C NMR(400MHz,DMSO-d6)δ165.0,157.9,143.1,137.6(d,J=32.0Hz),135.2,128.9(d,J=1.9Hz),128.3,127.6,126.3(d,J=4.1Hz),125.5,125.0,120.2,113.3,91.4(d,J=268.0Hz),48.1(d,J=27.2Hz),10.0.HRMS(ESI)[M-H]- calcd for C18H16FNO5S:376.0660;found:376.0660.
实施例124
3-甲基-5-(N-(1-苯基丙-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-140)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.16(d,J=2.3Hz,1H),7.95(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.40–7.11(m,5H),6.72(d,J=10.1Hz,1H),3.48(dh,J=10.1,7.0Hz,1H),2.92–2.79(m,2H),2.58(s,3H),1.13(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.8,143.1,137.9,135.3,129.0,128.8,127.5,127.2,125.3,125.0,120.1,113.2,51.6,42.6,20.0,10.0.HRMS(ESI)[M-H]- calcd for C19H19NO5S:372.0911;found:372.0911.
实施例125
3-甲基-5-(N-(2-苯基乙酰基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-141)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(2-苯基乙酰基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体61mg,收率55%。1H NMR(400MHz,DMSO-d6)δ13.07(s,1H),8.29(d,J=2.0Hz,1H),7.99(dd,J=8.8,2.0Hz,1H),7.87(d,J=8.8Hz,1H),7.33–7.17(m,3H),7.17–7.09(m,2H),3.55(s,2H),2.56(s,3H).13CNMR(101MHz,DMSO-d6)δ169.5,160.6,155.4,143.5,134.5,133.9,129.3,128.7,128.3,126.9,126.7,124.6,122.4,112.9,42.0,9.0.HRMS(ESI)[M-H]- calcd for C18H15NO6S:372.0542;found:372.0544.
实施例126
3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-144)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体102mg,收率92%。1H NMR(400MHz,DMSO-d6)δ13.68(s,1H),10.27(s,1H),8.08–7.99(m,2H),7.90–7.71(m,4H),7.50–7.33(m,3H),7.13(dd,J=7.5,1.1Hz,1H),2.46(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.2,135.5,133.9,132.3,129.5,128.7,127.9,126.8,126.2,126.1,126.0,125.5,124.5,123.3,123.1,121.1,112.9,8.9.HRMS(ESI)[M-H]- calcd for C20H14NO5S:380.0593;found:380.0600.
实施例127
3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-145)
按照实施例25所用方法,将中间体乙酯替换为3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯,其余条件均一致。得白色固体181mg,收率87%。1H NMR(400MHz,DMSO-d6)δ13.72(s,1H),10.57(s,1H),8.29(d,J=1.9Hz,1H),7.90(dd,J=8.8,1.9Hz,1H),7.83–7.71(m,4H),7.62(d,J=2.2Hz,1H),7.46–7.29(m,3H),2.50(s,3H).13C NMR(101MHz,DMSO-d6)δ160.6,155.0,143.4,135.3,134.8,133.2,130.0,129.1,128.8,127.4,127.2,126.6,125.8,125.0,124.4,121.4,120.4,116.1,113.0,8.9.HRMS(ESI)[M-H]-calcd for C20H14NO5S:380.0593;found:380.0594.
实施例128
3-甲基-5-(N-(萘-1-基甲基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-146)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.21–8.11(m,2H),7.98(dd,J=9.0,2.2Hz,1H),7.92–7.81(m,2H),7.64(d,J=9.0Hz,1H),7.56–7.46(m,2H),7.43–7.35(m,2H),7.29(t,J=7.3Hz,1H),4.36(d,J=7.3Hz,2H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,135.3,133.7,133.6,131.6,128.8,128.4,127.7,127.6,127.5,126.4,125.8,125.5,125.0,124.5,120.2,113.3,46.6,10.0.HRMS(ESI)[M-H]- calcd for C21H17NO5S:394.0755;found:394.0755.
实施例129
5-(N-(2-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-28)
按照实施例25所用方法合成。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.55(dd,J=6.7,1.3Hz,1H),7.42–7.32(m,2H),7.25(td,J=6.6,1.8Hz,1H),3.22(s,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,139.3,134.5,132.5,130.3,127.7,125.0,124.6,124.3,120.3,119.7,113.1,112.8,83.8,78.6,10.0.HRMS(ESI)[M-H]- calcd forC18H13NO5S:354.0442;found:354.0442.
实施例130
5-(N-(1H-吲哚-4-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-150)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.52(d,J=6.6Hz,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.43(t,J=7.9Hz,1H),7.27(dd,J=7.9,1.3Hz,1H),7.20(dd,J=6.6,3.7Hz,1H),7.04(dd,J=7.7,1.5Hz,1H),6.85(d,J=3.7Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,135.5,135.0,134.5,127.7,125.0,124.6,123.5,123.4,122.1,120.3,113.1,112.8,107.1,100.6,10.0.HRMS(ESI)[M-H]- calcd for C18H14N2O5S:369.0551;found:369.0551.
实施例131
5-(N-(苯并呋喃-5-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-151)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.76(d,J=1.6Hz,1H),7.67–7.62(m,2H),7.45(d,J=8.4Hz,1H),7.24(dd,J=8.4,2.2Hz,1H),6.89(t,J=1.8Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,152.6,145.2,143.1,134.6,133.9,129.1,127.7,125.0,124.6,120.3,118.2,113.2,113.1,110.8,105.5,10.0.HRMS(ESI)[M-H]- calcd for C18H13NO6S:370.0319;found:370.0319.
实施例132
5-(N-(2,3-二甲基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-152)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.02(t,J=7.8Hz,1H),6.94–6.84(m,2H),2.58(s,3H),2.26(d,J=0.7Hz,3H),2.08(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,137.9,137.3,134.5,129.3,127.7,126.8,125.0,124.7,124.6,120.3,119.5,113.1,20.3,14.2,10.0.HRMS(ESI)[M-H]- calcd for C18H17NO5S:358.0755;found:358.0755.
实施例133
5-(N-(2-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-153)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.78(dd,J=7.7,1.3Hz,1H),7.65(d,J=9.0Hz,1H),7.34–7.22(m,2H),6.93(ddd,J=7.7,6.7,1.7Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.6,156.8,143.1,140.7,139.0,134.9,128.7,127.8,127.1,126.7,126.4,121.0,119.5,112.8,93.7,10.3.HRMS(ESI)[M-H]- calcd for C16H12INO5S:455.9408;found:455.9408.
实施例134
5-(N-(4-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-154)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.76–7.70(m,2H),7.65(d,J=8.9Hz,1H),6.99–6.93(m,2H),2.58(s,3H).13CNMR(101MHz,DMSO-d6)δ165.6,156.8,143.1,137.9,137.1,135.0,127.8,127.1,126.4,122.2,119.5,112.9,88.5,10.3.HRMS(ESI)[M-H]- calcd for C16H12INO5S:455.9408;found:455.9408.
实施例135
3-甲基-5-(N-(3-苯氧基苯基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-155)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.41–7.26(m,3H),7.10(tt,J=7.2,1.5Hz,1H),7.05–6.97(m,3H),6.82(t,J=2.2Hz,1H),6.52(ddd,J=7.7,2.2,1.1Hz,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,157.4,157.2,143.1,139.6,134.6,129.9,129.8,127.7,125.0,124.6,124.5,120.3,118.9,114.8,113.4,113.1,112.1,10.0.HRMS(ESI)[M-H]- calcdfor C22H17NO6S:422.0704;found:422.0704.
实施例136
3-甲基-5-(N-(3-(4-甲基哌嗪-1-基)苯基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-156)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.08(dd,J=8.1,7.2Hz,1H),6.73(ddd,J=8.1,2.2,1.3Hz,1H),6.50–6.35(m,2H),3.23(ddd,J=5.3,4.0,1.0Hz,4H),2.85–2.76(m,2H),2.61–2.51(m,5H),2.29(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,151.9,143.1,139.7,134.6,129.5,127.7,125.0,124.6,120.3,116.7,113.1,109.4,107.6,54.1,48.7,45.3,10.0.HRMS(ESI)[M-H]- calcd for C21H23N3O5S:428.1286;found:428.1286.
实施例137
3-甲基-5-(N-(5,6,7,8-四氢萘-1-基)氨磺酰基)苯并呋喃-2-羧酸(GPR132-B-157)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.08(t,J=8.1Hz,1H),6.92(dd,J=8.1,1.2Hz,1H),6.81(dq,J=7.7,1.0Hz,1H),2.89–2.69(m,4H),2.58(s,3H),1.81–1.68(m,4H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,138.6,138.2,134.5,127.8,127.7,126.2,125.0,124.6,122.2,120.3,119.2,113.1,29.6,24.9,22.8,22.5,10.0.HRMS(ESI)[M-H]- calcdfor C20H19NO5S:384.0911;found:384.0911.
实施例138
5-(N-(4-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-158)
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按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.55(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.53–7.47(m,2H),7.11–7.05(m,2H),3.04(s,1H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,143.1,138.9,134.6,132.4,127.7,125.0,124.6,120.3,120.2,114.0,113.1,81.4,78.9,10.0.HRMS(ESI)[M-H]- calcd forC18H13NO5S:354.0422;found:354.0422.
实施例139
5-(N-(3-(二甲基氨基)苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸(GPR132-B-159)
按照实施例25所用方法合成。
1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.10(dd,J=8.2,7.2Hz,1H),6.85(t,J=2.3Hz,1H),6.76(ddd,J=8.1,2.2,1.2Hz,1H),6.49(ddd,J=7.3,2.2,1.2Hz,1H),2.97(s,6H),2.58(s,3H).13C NMR(101MHz,DMSO-d6)δ165.0,157.9,152.0,143.1,140.9,134.6,129.2,127.7,125.0,124.6,120.3,116.4,113.1,110.1,107.1,40.4,10.0.HRMS(ESI)[M-H]-calcd for C18H18N2O5S:373.0864;found:373.0864.
实施例140
3-甲基-6-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成,将氨的甲醇溶液替换为2-苯乙胺,将5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯替换为6-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯,其余条件均一致。得白黄色固体56mg,收率30%。1HNMR(400MHz,Chloroform-d)δ8.01(t,J=1.1Hz,1H),7.73(t,J=1.1Hz,2H),7.37–7.11(m,4H),7.08–7.02(m,2H),4.73(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.28–3.19(m,2H),2.76(t,J=7.1Hz,2H),2.61(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,153.2,143.9,139.2,137.6,132.7,130.6,128.9,128.8,128.8,126.9,125.0,122.1,121.6,111.9,61.7,44.4,35.9,14.4,9.4.HRMS(ESI)[M+H]+ calcd for C20H22NO5S:388.1219;found:388.1213.
实施例141
3-甲基-5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯(M-GPR132-B-53)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成合成。1HNMR(400MHz,Chloroform-d)δ8.38(d,J=2.1Hz,1H),8.14(d,J=8.4Hz,1H),7.96(dd,J=8.5,2.3Hz,1H),7.30–7.19(m,5H),7.15(t,J=6.6Hz,1H),4.32(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.9Hz,2H),2.81(tt,J=5.8,0.9Hz,2H),2.65(s,3H),1.37(t,J=6.3Hz,3H).
实施例142
5-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯
将苯乙胺(0.10g,0.82mmol)溶于DMF(2.5mL),加入6-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯(0.30g,0.98mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1.5)得白色固体179mg,产率55.8%。
1H NMR(400MHz,CDCl3)δ8.35(d,J=2.0Hz,1H),8.05(s,1H),7.90(d,J=8.4Hz,1H),7.82(dd,J=8.4,2.0Hz,1H),7.25-7.10(m,3H),7.09-7.03(m,2H),5.31(t,J=6.0Hz,1H),4.42(q,J=7.2Hz,2H),3.25(q,J=6.8Hz,2H),2.78(t,J=7.2Hz,2H),1.42(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.17,145.53,138.28,137.79,136.97,136.55,130.36,128.74,128.64,126.70,124.88,124.19,123.73,62.12,44.47,35.85,14.34.
实施例143
6-(N-苯乙基氨磺酰)苯并[b]噻吩-2-羧酸乙酯
将苯乙胺(0.10g,0.82mmol)溶于DMF(2.5mL),加入6-(氯磺酰基)苯并[b]噻吩-2-羧酸乙酯(0.30g,0.98mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1.5)得白色固体127mg,产率39.6%。
1H NMR(400MHz,CDCl3)δ8.33(s,1H),8.08(s,1H),7.93(d,J=8.8Hz,1H),7.78(dd,J=8.8,1.6Hz,1H),7.24-7.13(m,3H),7.09-7.03(m,2H),5.11(t,J=6.0Hz,1H),4.43(q,J=7.2Hz,2H),3.26(q,J=6.8Hz,2H),2.78(t,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.13,141.73,141.33,138.13,137.65,129.54,128.74,128.70,126.80,126.25,122.83,122.49,62.16,44.43,35.85,14.32.
实施例144
3-氯-5-(N-苯乙基氨基磺酰基)-1H-吲哚-2-羧酸乙酯(M-GPR132-B-56)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.47(d,J=2.3Hz,1H),7.92(dd,J=7.9,2.2Hz,1H),7.60(d,J=8.0Hz,1H),7.30–7.19(m,5H),7.14(t,J=6.6Hz,1H),4.35(q,J=6.4Hz,2H),3.17(dt,J=6.5,5.8Hz,2H),2.81(tt,J=5.8,0.9Hz,2H),1.37(t,J=6.4Hz,3H).
实施例145
2-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-3-羧酸乙酯(M-GPR132-B-57)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.17(d,J=2.2Hz,1H),7.96(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.30–7.19(m,5H),7.14(t,J=6.6Hz,1H),4.35(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.9Hz,2H),2.81(tt,J=5.8,0.9Hz,2H),2.70(s,3H),1.36(t,J=6.4Hz,3H).
实施例146
3-甲基-5-(N-(2-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,所用胺原料替换为2-氟苯乙胺,其余条件均一致。得白色固体0.32g,收率79%。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J=1.9,0.6Hz,1H),7.85(dd,J=8.8,1.9Hz,1H),7.59(dd,J=8.8,0.6Hz,1H),7.21–6.83(m,4H),4.72(t,J=6.3Hz,1H),4.47(q,J=7.1Hz,2H),3.26(q,J=6.8Hz,2H),2.85–2.77(m,2H),2.59(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ162.5,160.0,156.0,143.1,135.4,131.2(d,J=4.7Hz),129.5,128.8(d,J=8.2Hz),126.3,125.7,124.7(d,J=15.5Hz),124.4(d,J=3.6Hz),121.7,115.5(d,J=22.0Hz),113.2,61.7,43.2,29.8(d,J=2.0Hz),14.5,9.4.19F NMR(376MHz,Chloroform-d)δ-118.27.HRMS(ESI)[M-H]-calcd for C20H19NO5SF:404.0968;found:404.0968.
实施例147
5-(N-(2-溴代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
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将5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(226mg,0.75mmol)溶于无水二氯甲烷(3mL)中,加入2-(2-溴苯基)乙胺(72μL,0.5mmol),向体系中滴加DIPEA(206μL,1.25mmol),室温下反应,直到TLC监测反应完全。减压蒸馏除去溶剂,加水(10mL)溶解,乙酸乙酯(10mL)萃取三次,有机相用饱和氯化钠水溶液(10mL)洗一次,加无水硫酸钠干燥,粗产品经柱层析分离(PE/EA=5/1),得白色固体248.0mg,收率100%。1H NMR(400MHz,Chloroform-d)δ8.19(s,1H),7.87(d,J=10.3Hz,1H),7.56(d,J=8.8Hz,1H),7.37(d,J=8.0Hz,2H),7.13(d,J=4.3Hz,2H),7.03–6.94(m,1H),5.21(s,1H),4.47(q,J=7.1Hz,2H),3.28(q,J=6.3Hz,2H),2.90(t,J=7.1Hz,3H),2.58(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,142.9,137.1,135.2,132.8,131.1,129.3,128.4,127.6,126.2,125.6,124.3,121.6,113.0,61.6,42.6,36.3,14.4,9.4.
实施例148
5-(N-(2-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体120mg,收率57%。1H NMR(400MHz,Chloroform-d)δ8.19(d,J=1.5Hz,1H),7.87(d,J=10.6Hz,1H),7.56(d,J=8.8Hz,1H),7.22–7.15(m,1H),7.14–7.05(m,3H),5.20(t,J=6.1Hz,1H),4.46(q,J=7.1Hz,2H),3.28(q,J=6.9Hz,2H),2.90(t,J=7.1Hz,2H),2.58(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,142.9,135.4,135.2,133.9,131.1,129.5,129.3,128.2,126.9,126.2,125.6,121.6,113.0,61.6,42.6,33.8,14.3,9.3.
实施例149
5-(N-(2-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.18(d,J=2.0Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.66(dd,J=7.6Hz,1.6Hz,1H),7.57(d,J=8.8Hz,2H),7.20-7.16(m,1H),7.11(dd,J=7.6Hz,2.0Hz,1H),6.84-6.80(m,1H),4.99(t,J=6.0Hz,1H),4.46(q,J=7.2Hz,2H),3.24(q,J=6.8Hz,2H),2.89(t,J=6.8Hz,2H),2.59(s,3H),1.44(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.93,155.82,142.91,140.32,139.62,135.15,130.24,129.35,128.69,128.59,128.54,128.50,126.19,125.61,121.65,113.08,100.33,61.61,42.81,40.57,14.36,9.42.
实施例150
3-甲基-5-(N-(2-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,所用胺原料替换为2-甲基苯乙胺,其余条件均一致。得黄色固体0.30g,收率74%。1H NMR(400MHz,Chloroform-d)δ8.17(dd,J=1.9,0.6Hz,1H),7.86(dd,J=8.8,1.9Hz,1H),7.60(dd,J=8.8,0.6Hz,1H),7.14–6.98(m,4H),4.68(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.21(td,J=7.2,6.2Hz,2H),2.80(t,J=7.2Hz,2H),2.60(s,3H),2.19(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.1,136.4,135.8,135.4,130.7,129.5,129.4,127.1,126.3,126.3,125.7,121.7,113.2,61.7,43.2,33.4,19.3,14.5,9.5.HRMS(ESI)[M-H]-calcd for C21H22NO5S:400.1219;found:400.1218.
实施例151
3-甲基-5-(N-(2-(三氟甲基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得白色固体0.28g,收率62%。1H NMR(400MHz,Chloroform-d)δ8.19(dd,J=1.9,0.6Hz,1H),7.88(dd,J=8.8,1.9Hz,1H),7.64–7.54(m,2H),7.42(t,J=7.3Hz,1H),7.29(t,J=7.3Hz,2H),4.77(t,J=6.4Hz,1H),4.48(q,J=7.1Hz,2H),3.32–3.22(m,2H),2.98(t,J=7.3Hz,2H),2.61(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,136.4,135.4,132.1,131.7,129.5,128.9(d,J=29.9Hz),127.1,126.4(d,J=5.8Hz),126.2,125.7,124.5(d,J=273.7Hz),121.7,113.2,61.7,44.2,33.2,14.5,9.4.19F NMR(376MHz,Chloroform-d)δ-59.41.HRMS(ESI)[M-H]- calcd for C21H19NO5SF3:454.0936;found:454.0942.
实施例152
5-(N-(2-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸
根据实施例147的合成步骤,得到白色固体137mg,收率66%。1H NMR(400MHz,Chloroform-d)δ8.13(d,J=1.5Hz,1H),7.81(dd,J=8.8,1.8Hz,1H),7.55(d,J=8.8Hz,1H),7.13(t,J=7.8Hz,1H),6.97(d,J=7.3Hz,1H),6.83–6.65(m,2H),5.02(t,J=5.7Hz,1H),4.48(q,J=7.1Hz,2H),3.70(s,3H),3.24(q,J=6.6Hz,2H),2.76(t,J=6.8Hz,2H),2.59(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,157.3,155.7,142.8,135.3,130.6,129.2,128.1,126.2,126.0,125.6,121.5,120.6,112.8,110.3,61.6,55.2,43.2,30.5,14.4,9.4.
实施例153
5-(N-(2-羟基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
1H NMR(400MHz,DMSO-d6)δ9.29(s,1H),8.23–8.19(m,1H),7.97–7.83(m,2H),7.70(t,J=5.8Hz,1H),6.96(ddq,J=5.6,3.9,1.7Hz,2H),6.74–6.60(m,2H),4.37(q,J=7.0Hz,2H),2.95(t,J=6.3Hz,2H),2.66–2.53(m,5H),1.35(t,J=7.0Hz,3H).13C NMR(101MHz,DMSO)δ159.2,155.2,154.9,142.0,136.1,130.3,128.6,127.4,126.2,125.6,124.6,121.0,118.8,114.8,113.0,61.1,42.5,30.3,14.1,9.0.HRMS(ESI)[M-H]- calcdfor C20H21NO6S:402.1011;found:402.1014.
实施例154
3-甲基-5-(N-(3-氟苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成,所用胺原料替换为3-氟苯乙胺,其余条件均一致。得橙色固体0.31g,收率76%。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J=1.9,0.6Hz,1H),7.86(dd,J=8.8,1.9Hz,1H),7.61(dd,J=8.8,0.6Hz,1H),7.17(ddd,J=8.4,7.6,6.0Hz,1H),6.90–6.81(m,2H),6.74(dt,J=9.7,2.0Hz,1H),4.74(t,J=6.3Hz,1H),4.47(q,J=7.1Hz,2H),3.24(q,J=6.8Hz,2H),2.77(t,J=6.9Hz,2H),2.59(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ163.0(d,J=246.6Hz),160.0,156.0,143.2,140.3(d,J=7.3Hz),135.3,130.3(d,J=8.3Hz),129.6,126.2,125.7,124.5(d,J=2.9Hz),121.7,115.7(d,J=21.2Hz),113.9(d,J=21.0Hz),113.2,61.7,44.1,35.7(d,J=1.8Hz),14.5,9.4.HRMS(ESI)[M-H]- calcd forC20H19NO5SF:404.0968;found:404.0973.
实施例155
5-(N-(3-氯代苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体147mg,收率70%。1H NMR(400MHz,Chloroform-d)δ8.17(s,1H),7.87(d,J=8.8Hz,1H),7.59(d,J=8.8Hz,1H),7.11(d,J=5.9Hz,2H),7.00(s,1H),6.95(t,J=5.0Hz,2H),5.16(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.24(q,J=6.8Hz,2H),2.75(t,J=7.0Hz,2H),2.58(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.0,139.8,135.1,134.3,129.8,129.4,128.8,126.9,126.8,126.1,125.6,121.5,113.1,61.6,44.1,35.5,14.3,9.3.
实施例156
5-(N-(3-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.17(d,J=1.6Hz,1H),7.86(dd,J=8.4,2.0Hz,1H),7.59(d,J=8.8Hz,1H),7.45(d,J=7.6Hz,1H),7.36(s,1H),7.03(d,J=7.6Hz,1H),6.90(t,J=7.6Hz,1H),5.18(t,J=6.0Hz,1H),4.46(q,J=7.2Hz,2H),3.22(q,J=6.8Hz,2H),2.71(t,J=7.2Hz,2H),2.58(s,3H),1.45(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.92,155.81,142.95,140.22,137.60,135.74,135.10,130.29,129.40,128.04,126.15,125.61,121.55,113.12,94.60,61.64,44.10,35.34,14.38,9.45.
实施例157
3-甲基-5-(N-(3-硝基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.17(d,J=1.9Hz,1H),8.01(ddd,J=8.0,2.4,1.3Hz,1H),7.92(t,J=2.0Hz,1H),7.86(dd,J=8.8,1.9Hz,1H),7.60(d,J=8.8Hz,1H),7.48–7.35(m,2H),4.47(q,J=7.1Hz,2H),3.30(q,J=6.8Hz,2H),2.91(t,J=6.8Hz,2H),2.58(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.0,148.4,143.2,140.0,135.2,135.1,129.7,129.6,126.2,125.6,123.7,122.0,121.7,113.3,61.8,44.0,35.8,14.5,9.4.HRMS(ESI)[M-H]-calcd for C20H20N2O7S:431.0913;found:431.0913.
实施例158
5-(N-(3-羟基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.14(d,J=1.2Hz,1H),7.82(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.4Hz,1H),7.06(t,J=8.0Hz,1H),6.67–6.64(m,1H),6.59–6.56(m,2H),5.77(s,1H),4.80(t,J=6.0Hz,1H),4.47(q,J=7.2Hz,2H),3.22(q,J=6.4Hz,2H),2.70(t,J=6.8Hz,2H),2.58(s,3H),1.45(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.04,156.10,155.88,142.95,139.35,135.00,129.92,129.40,126.18,125.67,121.57,120.81,115.76,113.88,113.09,61.67,44.08,35.52,14.34,9.34.
实施例159
5-(N-(3-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-75)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.14(t,J=6.6Hz,1H),7.01(t,J=7.9Hz,1H),6.94(ddq,J=8.1,2.3,1.1Hz,1H),6.53–6.45(m,2H),4.34(q,J=6.4Hz,2H),4.25(d,J=5.5Hz,1H),4.13(d,J=5.5Hz,1H),3.18(dt,J=6.7,5.7Hz,2H),2.75(tt,J=5.7,1.0Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例160
3-甲基-5-(N-(3-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-76)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.18–7.09(m,2H),6.92(ddq,J=7.7,2.2,1.1Hz,1H),6.55–6.46(m,2H),5.68(q,J=4.8Hz,1H),4.34(q,J=6.4Hz,2H),3.18(dt,J=6.6,5.8Hz,2H),2.94(d,J=4.8Hz,3H),2.81(tt,J=5.8,1.1Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例161
5-(N-(3-(二甲基氨基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-77)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.18–7.08(m,2H),6.91(dtd,J=7.9,2.1,1.0Hz,1H),6.62–6.52(m,2H),4.34(q,J=6.4Hz,2H),3.18(dt,J=6.6,5.8Hz,2H),2.96(s,6H),2.78(tt,J=5.6,0.9Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例162
5-(N-(4-溴苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯
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按照实施例147步骤,得白色固体156.0mg,收率67%。1H NMR(400MHz,Chloroform-d)δ8.16(d,J=1.8Hz,1H),7.86(dd,J=8.8,1.9Hz,1H),7.61(d,J=8.8Hz,1H),7.30(d,2H),6.93(d,J=8.3Hz,2H),4.95(t,J=6.1Hz,1H),4.48(q,J=7.1Hz,2H),3.23(q,J=6.6Hz,2H),2.74(t,J=6.9Hz,2H),2.59(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.1,136.7,135.1,131.7,130.4,129.4,126.1,125.5,121.5,120.6,113.0,61.6,44.1,35.3,14.4,9.4.
实施例163
5-(N-(4-碘苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=2.0Hz,1H),7.85(dd,J=8.8,2.0Hz,1H),7.60(d,J=8.8Hz,1H),7.48(d,J=8.4Hz,2H),6.80(d,J=8.4Hz,2H),5.06(t,J=6.0Hz,1H),4.47(q,J=7.2Hz,2H),3.21(q,J=6.8Hz,2H),2.72(t,J=6.8Hz,2H),2.58(s,3H),1.46(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,155.82,143.04,137.62,137.35,135.07,130.76,129.41,126.12,125.53,121.54,113.06,91.98,61.63,44.04,35.36,14.39,9.42.
实施例164
3-甲基-5-(N-(4-甲基苯基乙基)磺胺基)苯并呋喃-2-羧酸乙酯
将对甲基苯乙胺(0.076g,0.56mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1)得白色固体160mg,产率80.4%。
1H NMR(400MHz,CDCl3)δ8.17(d,J=2.4Hz,1H),7.87(dd,J=8.8,2.0Hz,1H),7.54(d,J=8.8Hz,1H),6.93(q,J=8.1Hz,4H),5.31(t,J=6.1Hz,1H),4.44(q,J=7.2Hz,2H),3.20(q,J=7.2Hz,2H),2.71(t,J=7.2Hz,2H),2.54(s,3H),2.21(s,3H),1.43(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,155.76,142.86,136.11,135.30,134.68,129.31,129.22,128.55,126.27,125.61,121.55,112.90,61.58,44.54,35.33,20.92,14.35,9.31.
实施例165
5-(N-(4-三氟甲基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯
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按照实施例147步骤,得白色固体158.1mg,收率69%。1H NMR(400MHz,Chloroform-d)δ8.22–8.13(m,1H),7.87(dd,J=8.8,2.0Hz,1H),7.63–7.56(m,1H),7.44(d,J=8.1Hz,2H),7.19(d,J=7.9Hz,2H),5.24(t,J=6.0Hz,1H),4.46(q,J=7.1Hz,2H),3.26(q,J=6.6Hz,2H),2.86(t,J=7.1Hz,2H),2.57(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,143.0,142.0,135.1,129.4,129.1,129.1,128.8,126.1,125.4(q,J=4.0Hz),122.7,121.5,113.0,61.6,44.0,35.7,143,9.3.
实施例166
5-(N-(4-甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体125mg,收率60%。1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.86(d,J=10.4Hz,1H),7.58(d,J=8.8Hz,1H),6.95(d,J=8.5Hz,2H),6.72(d,J=8.5Hz,2H),4.99(s,1H),4.47(q,J=7.1Hz,2H),3.72(s,3H),3.19(d,J=10.3Hz,2H),2.70(t,J=6.9Hz,2H),2.58(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,158.4,155.8,142.9,135.2,129.6,129.6,129.3,126.2,125.6,121.5,114.0,112.9,61.6,55.2,44.5,34.8,14.4,9.3.
实施例167
5-(N-(4-硝基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体125mg,收率60%。1H NMR(400MHz,Chloroform-d)δ8.21–8.14(m,1H),8.13–8.04(m,2H),7.89(d,J=8.7Hz,1H),7.65(d,J=8.7Hz,1H),7.28(d,J=8.3Hz,2H),4.82(t,J=5.9Hz,1H),4.49(q,J=7.1Hz,2H),3.31(q,J=6.7Hz,2H),2.94(t,J=6.8Hz,2H),2.61(s,3H),1.48(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.8,155.9,146.9,145.4,143.2,135.0,129.7,129.5,126.0,125.3,123.8,121.5,113.1,61.7,43.7,36.0,14.3,9.3.
实施例168
5-(N-(4-羟基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体182mg,收率91%。1H NMR(400MHz,Chloroform-d)δ8.16(s,1H),7.84(d,J=8.7Hz,1H),7.59(dd,J=25.8,8.8Hz,1H),6.99(d,J=8.4Hz,1H),6.84(dd,J=20.5,8.4Hz,2H),6.68(d,J=8.3Hz,1H),4.46(q,J=7.0Hz,2H),3.17(t,J=6.9Hz,2H),2.70(dt,J=28.1,6.9Hz,2H),2.56(s,3H),1.43(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,148.1,143.3,137.2,135.1,130.0,129.7,127.3,126.1,122.4,115.5,113.2,61.7,44.1,35.3,14.3,9.3.
实施例169
5-(N-(4-氨基苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-87)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.14(t,J=6.6Hz,1H),6.90(dt,J=8.0,1.0Hz,2H),6.48–6.42(m,2H),4.34(q,J=6.4Hz,2H),4.04(d,J=5.7Hz,1H),3.98(d,J=5.7Hz,1H),3.17(dt,J=6.7,5.8Hz,2H),2.82(tt,J=5.7,1.0Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例170
3-甲基-5-(N-(4-(甲氨基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-88)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.14(t,J=6.6Hz,1H),6.96(dt,J=7.5,1.1Hz,2H),6.62–6.56(m,2H),5.48(q,J=4.8Hz,1H),4.34(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.8Hz,2H),2.91(d,J=4.8Hz,3H),2.82(tt,J=5.8,1.0Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例171
5-(N-(2-(5-溴吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-90)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.54(t,J=1.9Hz,1H),8.49(t,J=1.8Hz,1H),8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.48(t,J=2.0Hz,1H),7.16(t,J=6.6Hz,1H),4.34(q,J=6.4Hz,2H),3.23(q,J=6.3Hz,2H),2.93(t,J=6.2Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例172
5-(N-(2-(5-甲氧基吡啶-3-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-91)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.30(t,J=1.8Hz,1H),8.18(d,J=2.2Hz,1H),8.12(t,J=1.8Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.16(t,J=6.6Hz,1H),6.95(t,J=2.0Hz,1H),4.34(q,J=6.4Hz,2H),3.91(s,3H),3.23(q,J=6.3Hz,2H),2.92(t,J=6.2Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例173
3-甲基-5-(N-(3-(三氟甲氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸乙酯
将2-(3-(三氟甲氧基)苯基)乙烷-1-胺(0.1g,0.49mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1)得白色固体175mg,产率74.9%。
1H NMR(400MHz,CDCl3)δ8.16(d,J=2.0Hz,1H),7.85(dd,J=8.8,2.0Hz,1H),7.53(d,J=8.8Hz,1H),7.16(t,J=8.0Hz,1H),7.01-6.92(m,2H),6.87(s,1H),5.45(t,J=6.0Hz,1H),4.42(q,J=7.2Hz,2H),3.22(q,J=6.8Hz,2H),2.77(t,J=7.2Hz,2H),2.52(s,3H),1.40(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.90,155.80,149.26(d,J=1.8Hz),142.94,140.25,135.13,129.84,129.35,127.13,126.09,125.50,121.50,121.13,120.33(q,J=258.2Hz),118.92,112.98,61.59,44.05,35.52,14.22,9.18.19F NMR(376MHz,CDCl3)δ-57.81.
实施例174
5-(N-(3-乙炔基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=2.0Hz,1H),7.85(dd,J=8.8,2.0Hz,1H),7.58(d,J=8.8Hz,1H),7.24(d,J=7.6Hz,1H),7.14–7.10(m,2H),7.04(d,J=8.0Hz,1H),5.17(t,J=6.0Hz,1H),4.45(q,J=7.2Hz,2H),3.22(q,J=6.8Hz,2H),3.02(s,1H),2.74(t,J=6.8Hz,2H),2.57(s,3H),1.44(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.92,155.80,142.91,138.02,135.11,132.23,130.40,129.37,129.29,128.59,126.16,125.63,122.34,121.53,113.06,83.23,77.50,61.60,44.11,35.49,14.35,9.36.
实施例175
5-(N-(3-氰基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.13(d,J=2.0Hz,1H),7.83(dd,J=8.8,2.0Hz,1H),7.53(d,J=8.8Hz,1H),7.38–7.35(m,1H),7.33–7.30(m,2H),7.25(t,J=7.6Hz,1H),5.58(t,J=6.2Hz,1H),4.40(q,J=7.2Hz,2H),3.20(q,J=6.8Hz,2H),2.80(t,J=7.2Hz,2H),2.51(s,3H),1.39(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ159.88,155.75,142.96,139.58,135.08,133.46,132.30,130.30,129.36,129.33,126.09,125.50,121.51,118.65,113.06,112.30,61.64,43.92,35.43,14.31,9.33.
实施例176
5-(N-(3-(二甲基磷酰基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-95)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.44(dddd,J=13.4,7.3,2.3,1.3Hz,1H),7.31–7.19(m,3H),7.14(t,J=6.6Hz,1H),4.34(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.7Hz,2H),2.78(tt,J=5.6,1.0Hz,2H),2.60(s,3H),1.97(s,6H),1.39(t,J=6.3Hz,3H).
实施例177
5-(N-(3-(1,1-二氟乙基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-96)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.41–7.30(m,3H),7.21–7.12(m,2H),4.34(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.7Hz,2H),2.82(tt,J=5.6,1.0Hz,2H),2.60(s,3H),2.33(t,J=20.9Hz,3H),1.39(t,J=6.3Hz,3H).
实施例178
5-(N-(3-乙酰苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.12(d,J=2.0Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.74–7.71(m,1H),7.67(s,1H),7.58(d,J=8.8Hz,1H),7.31–7.28(m,2H),5.28(br,1H),4.46(q,J=7.2Hz,2H),3.27(q,J=5.6Hz,2H),2.85(t,J=7.0Hz,2H),2.57(s,3H),2.52(s,3H),1.45(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ198.05,159.88,155.79,142.96,138.46,137.32,135.21,133.56,129.37,128.84,128.35,126.89,126.12,125.55,121.51,113.04,61.59,44.13,35.72,26.59,14.33,9.32.
实施例179
5-(N-(3-乙氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=2.0Hz,1H),7.85(dd,J=8.8,2.0Hz,1H),7.55(d,J=8.8Hz,1H),7.07(t,J=7.8Hz,1H),6.64(dd,J=8.0,2.4Hz,1H),6.60(d,J=7.2Hz,1H),6.54(t,J=6.2Hz,1H),5.23(t,J=6.0Hz,1H),4.45(q,J=7.2Hz,2H),3.88(q,J=6.8Hz,2H),3.22(q,J=6.8Hz,2H),2.72(t,J=7.0Hz,2H),2.56(s,3H),1.44(t,J=7.2Hz,3H),1.33(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ159.90,159.09,155.76,142.85,139.26,135.22,129.55,129.31,126.22,125.61,121.52,120.81,114.94,112.93,112.42,63.21,61.57,44.28,35.75,14.77,14.34,9.31.
实施例180
3-甲基-5-(N-(3-(2,2,2-三氟乙氧基)苯乙基)氨磺酰)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=2.0Hz,1H),7.84(dd,J=8.8,2.0Hz,1H),7.54(d,J=8.8Hz,1H),7.11(t,J=8.0Hz,1H),6.71(d,J=7.6Hz,1H),6.68(dd,J=8.0,2.4Hz,1H),6.63(t,J=2.0Hz,1H),5.20(t,J=6.0Hz,1H),4.44(q,J=7.2Hz,2H),4.25(q,J=8.0Hz,2H),3.22(q,J=6.8Hz,2H),2.73(t,J=7.2Hz,2H),2.55(s,3H),1.43(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,157.46,155.79,142.95,139.84,135.13,129.85,129.36,126.12,125.55,123.33(q,J=279.1Hz),122.77,121.52,115.50,113.00,112.75,65.60(q,J=35.7Hz),61.61,44.15,35.67,14.28,9.25.19F NMR(376MHz,CDCl3)δ-73.98.
实施例181
5-(N-(3-(2-乙氧基乙氧基)苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,CDCl3)δ8.12(d,J=1.6Hz,1H),7.82(dd,J=8.6,2.0Hz,1H),7.53(d,J=8.8Hz,1H),7.04(t,J=7.6Hz,1H),6.67–6.64(m,1H),6.58(d,J=6.8Hz,2H),5.18(t,J=6.2Hz,1H),4.42(q,J=7.2Hz,2H),3.97(t,J=4.8Hz,2H),3.69(t,J=4.8Hz,2H),3.52(q,J=7.2Hz,2H),3.17(q,J=6.8Hz,2H),2.68(t,J=7.0Hz,2H),2.53(s,3H),1.40(t,J=7.2Hz,3H),1.17(t,J=7.0Hz,3H).13C NMR(101MHz,CDCl3)δ159.89,158.98,155.75,142.84,139.27,135.23,129.54,129.30,126.20,125.62,121.51,121.13,115.16,112.96,112.52,68.85,67.26,66.76,61.55,44.25,35.77,15.12,14.33,9.32.
实施例182
5-(N-(3-(3,3-二氟氮杂环丁烷-1-基)苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-101)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.18–7.11(m,2H),7.00(dddt,J=7.3,3.5,2.4,1.2Hz,2H),6.74(tt,J=2.1,1.0Hz,1H),4.34(q,J=6.4Hz,2H),4.02(t,J=20.9Hz,4H),3.18(dt,J=6.6,5.8Hz,2H),2.78(tt,J=5.6,0.9Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例183
3-甲基-5-(N-(2-([1,1’-二苯基]-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得白色固体0.39g,收率43%。1H NMR(400MHz,Chloroform-d)δ8.15(d,J=1.9Hz,1H),7.84(dd,J=8.9,1.9Hz,1H),7.57(d,J=8.9Hz,1H),7.51–7.37(m,5H),7.36–7.27(m,2H),7.22(t,J=1.9Hz,1H),7.08–6.98(m,1H),4.61(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.31(q,J=6.8Hz,2H),2.83(t,J=6.8Hz,2H),2.55(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.1,141.8,140.7,138.1,135.4,129.5,129.3,128.9,127.7,127.6,127.5,127.1,126.3,125.8,125.7,121.6,113.2,61.7,44.4,35.9,14.5,9.4.HRMS(ESI)[M+H]+ calcd for C26H26NO5S:464.1532;found:464.1525.
实施例184
3-甲基-5-(N-(3-(噻吩-3-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-103)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.59(t,J=1.7Hz,1H),7.52–7.35(m,5H),7.20–7.11(m,2H),4.34(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.7Hz,2H),2.84(tt,J=5.8,1.0Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例185
3-甲基-5-(N-(3(噻吩-2-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
梨形瓶中加入4(0.47g,2.3mmol),5(0.70g,2.3mmol),DIPEA(0.43g,3.3mmol),加入DMF 3ml,室温反应5h,TLC监测反应完全。反应结束后,EA/H2O萃取3次,合并有机相,Na2SO4干燥,过滤浓缩,硅胶柱层析纯化(PE:EA=4:1),得白色固体0.36g,产率33%。
1H NMR(400MHz,CDCl3)δ8.15(d,J=2.0Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.59(d,J=8.8Hz,1H),7.44(d,J=8.8Hz,1H),7.28–7.25(m,2H),7.23–7.21(m,2H),7.06(dd,J=5.2,3.6Hz,1H),6.99(d,J=7.6Hz,1H),4.68(t,J=6.0Hz,1H),4.49(q,J=7.2Hz,2H),3.32(q,J=6.8Hz,2H),2.81(t,J=6.8Hz,2H),2.57(s,3H),1.48(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.88,155.83,143.72,142.94,138.24,135.14,134.80,129.40,129.27,128.02,127.78,126.16,126.02,125.56,124.98,124.36,123.17,121.48,113.03,61.55,44.15,35.66,14.37,9.33.
实施例186
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-4-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得黄色固体0.13g,收率23%。1H NMR(400MHz,Chloroform-d)δ8.13(dd,J=1.9,0.8Hz,1H),7.83(dd,J=8.8,1.9Hz,1H),7.65(d,J=0.8Hz,1H),7.59–7.50(m,2H),7.26(d,J=1.8Hz,1H),7.20(t,J=7.6Hz,1H),7.11(t,J=1.8Hz,1H),6.93–6.85(m,1H),4.78(t,J=6.1Hz,1H),4.47(q,J=7.1Hz,2H),3.92(s,3H),3.29(q,J=6.8Hz,2H),2.79(t,J=6.8Hz,2H),2.56(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ160.0,155.9,143.1,138.3,136.7,135.3,133.2,129.5,129.3,127.0,126.7,126.3,125.8,125.6,124.0,122.8,121.6,113.1,61.7,44.3,39.2,35.9,14.5,9.4.HRMS(ESI)[M+H]+ calcd for C24H26N3O5S:468.1593;found:468.1585.
实施例187
3-甲基-5-(N-(3-(1-甲基-1H-吡唑-5-基)苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得黄色液体0.18g,收率65%。1H NMR(400MHz,Chloroform-d)δ8.20(dd,J=1.9,0.6Hz,1H),7.89(dd,J=8.8,1.9Hz,1H),7.62(dd,J=8.8,0.6Hz,1H),7.49(d,J=1.9Hz,1H),7.35(t,J=7.9Hz,1H),7.28(s,1H),7.18–7.09(m,2H),6.25(d,J=1.9Hz,1H),4.98(t,J=6.3Hz,1H),4.48(q,J=7.1Hz,2H),3.86(s,3H),3.29(q,J=6.8Hz,2H),2.86(t,J=7.1Hz,2H),2.60(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,138.6,138.5,135.4,131.3,129.5,129.3,129.1,128.9,127.2,126.2,125.6,121.6,113.2,106.2,61.7,44.3,37.6,36.0,14.5,9.5.HRMS(ESI)[M+H]+ calcd for C24H26N3O5S:468.1593;found:468.1586.
实施例188
5-(N-(2-氟-4-氯苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-甲酸乙酯
按照实施例147步骤,得白色固体144.2mg,收率66%。1H NMR(400MHz,Chloroform-d)δ8.16(d,J=1.8Hz,1H),7.86(dd,J=8.8,2.0Hz,1H),7.59(d,J=8.8Hz,1H),7.03(t,J=8.0Hz,1H),6.92(ddd,J=17.3,8.9,2.1Hz,2H),5.15(t,J=6.3Hz,1H),4.47(q,J=7.1Hz,2H),3.24(q,J=6.8Hz,2H),2.78(t,J=6.9Hz,2H),2.59(s,3H),1.46(t,J=7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.80(d,J=248.9Hz),159.9,155.8,143.0,135.1,133.3(d,J=10.3Hz),131.9(d,J=5.7Hz),129.4,126.1,125.5,124.5(d,J=3.6Hz),123.4(d,J=15.8Hz),121.5,116.1(d,J=25.5Hz),113.0,61.6,42.8,29.2,14.3,9.3.
实施例189
3-甲基-5-(N-(2-氟-3-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得黄色固体0.41g,收率33%。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J=1.9,0.6Hz,1H),7.85(dd,J=8.8,1.9Hz,1H),7.62–7.52(m,1H),7.01–6.92(m,1H),6.92–6.81(m,2H),4.86(t,J=6.8Hz,1H),4.46(q,J=7.1Hz,2H),3.25(q,J=6.8Hz,2H),2.80–2.71(m,2H),2.58(s,3H),2.14(d,J=2.2Hz,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,159.7(d,J=244.2Hz),155.9,143.0,135.3,130.3(d,J=5.1Hz),129.4,128.5(d,J=4.6Hz),126.3,125.7,125.0(d,J=17.7Hz),124.3(d,J=16.3Hz),123.8(d,J=4.3Hz),121.6,113.1,61.7,43.2(d,J=1.7Hz),29.7(d,J=2.4Hz),14.5(d,J=4.5Hz),14.4,9.4.19F NMR(376MHz,Chloroform-d)δ-122.90.HRMS(ESI)[M+H]+ calcd for C21H23NO5SF:420.1281;found:420.1279.
实施例190
5-(N-(2-(2,3-二氢苯并呋喃-7-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-109)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.19(t,J=6.5Hz,1H),7.10(ddq,J=16.3,8.1,1.2Hz,2H),7.00–6.93(m,1H),4.49(dd,J=5.2,3.2Hz,2H),4.34(q,J=6.4Hz,2H),3.21–3.09(m,4H),2.91(td,J=5.9,1.0Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例191
5-(N-(2-(2,3-二氢苯并[b][1,3]二氧杂环戊烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.14(d,J=1.9Hz,1H),7.83(dd,J=8.8,1.9Hz,1H),7.56(d,J=8.7Hz,1H),6.67–6.59(m,2H),6.48(dd,J=7.3,1.8Hz,1H),5.80(s,2H),4.97–4.87(m,1H),4.46(q,J=7.1Hz,2H),3.26(q,J=6.6Hz,2H),2.72(t,J=6.9Hz,2H),2.57(s,3H),1.44(t,J=7.3Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,155.78,147.10,145.58,142.90,135.25,129.32,126.16,125.58,122.73,121.76,121.49,119.11,112.92,107.36,100.60,61.59,42.67,29.91,14.35,9.34.
实施例192
5-(N-(2-(2,2-二氟苯并[d][1,3]二氧杂环戊-4-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=1.9Hz,1H),7.83(dd,J=8.7,1.9Hz,1H),7.51(d,J=8.7Hz,1H),6.86–6.74(m,3H),5.48(t,J=6.2Hz,1H),4.42(q,J=7.1Hz,2H),3.27(q,J=6.8Hz,2H),2.80(t,J=7.0Hz,2H),2.53(s,3H),1.41(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.93,155.78,143.29,142.90,142.02,135.14,131.23(t,J=255.6Hz),129.31,126.07,125.54,124.73,123.59,121.47,120.56,112.95,107.90,61.61,42.41,29.64,29.57,14.25,9.18.19F NMR(376MHz,CDCl3)δ-49.72.
实施例193
5-(N-(2-(2,3-二氢苯并[b][1,4]二氧杂环己烷-5-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-112)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.22(t,J=6.6Hz,1H),6.89(t,J=8.1Hz,1H),6.78–6.69(m,2H),4.34(q,J=6.4Hz,2H),4.29(s,4H),3.21–3.14(m,2H),2.93(td,J=5.9,1.0Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例194
5-(N-(2,4-二氟苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=1.6Hz,1H),7.86(dd,J=8.8,1.6Hz,1H),7.58(d,J=8.8Hz,1H),7.07–7.01(m,1H),6.71–6.61(m,2H),5.07(t,J=6.4Hz,1H),4.45(q,J=7.2Hz,2H),3.20(q,J=6.8Hz,2H),2.76(t,J=6.8Hz,2H),2.57(s,3H),1.44(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ162.67(dd,J=89.1,12.0Hz),160.21(dd,J=89.1,12.0Hz),159.90,155.83,142.99,135.17,131.73(dd,J=9.6,6.3Hz),129.39,126.11,125.52,121.51,120.54(dd,J=16.0,3.7Hz),113.02,111.22(dd,J=21.1,3.7Hz),103.77(t,J=25.8Hz),61.61,43.00,29.13,14.32,9.28.19F NMR(376MHz,CDCl3)δ-111.80,-113.99.
实施例195
5-(N-(5-溴-2-氟苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
梨形瓶中加入化合物3(0.086g,0.39mmol),化合物4(0.131g,0.43mmol),N,N-二异丙基乙胺(DIPEA,0.076g,0.59mmol),加入无水DMF 2ml,室温过夜反应。TLC监测反应完全。反应结束后,加入适量EA,少量H2O洗涤3次,合并水相,少量EA洗涤两次,合并有机相,Na2SO4干燥,过滤浓缩,硅胶柱层析纯化(PE:EA=4:1),得白色固体0.19g,产率99%。
1H NMR(400MHz,CDCl3)δ8.16(d,J=1.9Hz,1H),7.85(dd,J=8.7,1.9Hz,1H),7.60(d,J=8.7Hz,1H),7.17(m,1H),7.08(m,1H),7.01(m,1H),6.93(m,1H),4.48(q,J=7.0Hz,3H),3.28(q,J=6.7Hz,2H),2.81(t,J=6.9Hz,2H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ159.93,155.88,142.99,135.23,131.17,129.41,128.77,126.15,125.60,124.31,121.56,115.57,115.36,113.08,61.60,43.04,29.68,14.36,9.36.19F NMR(376MHz,CDCl3)δ-118.26,-120.28.
实施例196
3-甲基-5-(N-(2-氟-5-甲基苯乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得白色固体0.59g,收率45%。1H NMR(400MHz,Chloroform-d)δ8.16(dd,J=1.9,0.6Hz,1H),7.85(dd,J=8.7,1.9Hz,1H),7.59(dd,J=8.7,0.6Hz,1H),6.96–6.88(m,1H),6.84–6.75(m,2H),4.66(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.25(q,J=6.2Hz,2H),2.79–2.71(m,2H),2.60(s,3H),2.21(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,159.4(d,J=242.6Hz),156.0,143.1,135.4,133.8,131.6(d,J=4.7Hz),129.5,129.1(d,J=7.9Hz),126.3,125.7,124.1(d,J=15.9Hz),121.7,115.2(d,J=22.0Hz),113.1,61.7,43.2,29.7,20.6,14.5,9.5.19F NMR(376MHz,Chloroform-d)δ-123.68.HRMS(ESI)[M+H]+calcd for C21H23NO5SF:420.1281;found:420.1275.
实施例197
5-(N-(2-氟-5-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
将2-(2-氟-5-甲氧基苯基)乙烷-1-胺(0.10g,0.59mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:2)得白色固体171mg,产率79.2%。
1H NMR(400MHz,CDCl3)δ8.14(d,J=2.0Hz,1H),7.84(dd,J=8.8,2.0Hz,1H),7.53(d,J=8.8Hz,1H),6.80-6.71(m,1H),6.60-6.52(m,2H),5.27-5.18(m,1H),4.43(q,J=7.2Hz,2H),3.64(s,3H),3.22(q,J=6.8Hz,2H),2.73(t,J=7.2Hz,2H),2.54(s,3H),1.42(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.91,156.58,155.75,155.51,154.23,142.81,135.27,129.29,126.13,125.62,125.44(d,J=16.8Hz),121.47,116.08(d,J=4.4Hz),112.63(d,J=21.9Hz),112.95,112.86,61.58,55.57,43.01,29.78,14.31,9.27.19F NMR(376MHz,CDCl3)δ-129.34.
实施例198
5-(N-(4-氟-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
将2-(4-氟-3-甲氧基苯基)乙烷-1-胺(0.12g,0.71mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:2)得白色固体180mg,产率83.4%。
1H NMR(400MHz,CDCl3)δ8.12(d,J=2.0Hz,1H),7.83(dd,J=8.8,2.0Hz,1H),7.53(d,J=8.8Hz,1H),6.79(dd,J=11.2,8.2Hz,1H),6.62(dd,J=8.2,2.0Hz,1H),6.53-6.47(m,1H),5.33(t,J=6.0Hz,1H),4.41(q,J=7.2Hz,2H),3.71(s,3H),3.17(q,J=6.8Hz,2H),2.69(t,J=7.2Hz,2H),2.51(s,3H),1.40(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.86,155.75,152.36,149.93,147.39(d,J=10.7Hz),142.94,135.16,134.16(d,J=3.8Hz),129.34,126.10,125.47,121.44,120.38(d,J=6.7Hz),115.78(d,J=18.3Hz),113.85,112.91,61.59,56.04,44.34,35.46,14.28,9.23.19F NMR(376MHz,CDCl3)δ-138.17.
实施例199
5-(N-(4-氯-3-甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
将2-(4-氯-3-甲氧基苯基)乙烷-1-胺(0.09g,0.48mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.17g,0.56mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1.5)得白色固体142mg,产率64.8%。
1H NMR(400MHz,CDCl3)δ8.10(d,J=2.0Hz,1H),7.81(dd,J=8.8,2.0Hz,1H),7.52(d,J=8.8Hz,1H),7.05(d,J=8.0Hz,1H),6.59(d,J=2.0Hz,1H),6.52(dd,J=8.0,2.0Hz,1H),5.33(t,J=6.0Hz,1H),4.41(q,J=7.2Hz,2H),3.71(s,3H),3.19(q,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H),2.51(s,3H),1.40(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.86,155.75,154.81,142.97,137.97,135.10,129.98,129.34,126.06,125.45,121.43,121.36,120.55,112.91,112.62,61.60,55.94,44.16,35.63,14.31,9.27.
实施例200
5-(N-(3,4-二甲氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体124mg,收率55%。1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.84(d,J=10.4Hz,1H),7.57(d,J=8.8Hz,1H),6.67(d,J=8.6Hz,1H),6.57(d,J=5.1Hz,2H),5.06(t,J=6.0Hz,1H),4.44(q,J=7.1Hz,2H),3.75(d,J=12.6Hz,6H),3.20(q,J=6.7Hz,2H),2.70(t,J=6.9Hz,2H),2.55(s,3H),1.43(t,J=7.1Hz,3H).13CNMR(101MHz,Chloroform-d)δ159.8,155.7,149.0,147.8,142.9,135.2,130.1,129.3,126.1,125.5,121.5,120.7,112.9,111.8,111.38,61.6,55.8,55.8,44.5,35.3,14.3,9.3.
实施例201
5-(N-(3,4-亚甲二氧基苯乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照实施例147步骤,得白色固体135mg,收率63%。1H NMR(400MHz,Chloroform-d)δ8.17(dd,J=1.9,0.6Hz,1H),7.86(dd,J=8.7,1.9Hz,1H),7.61(dd,J=8.7,0.6Hz,1H),6.64(d,J=7.8Hz,1H),6.54–6.47(m,2H),5.87(s,2H),4.85(t,J=6.2Hz,1H),4.48(q,J=7.1Hz,2H),3.20(q,J=6.7Hz,2H),2.68(t,J=6.8Hz,2H),2.60(s,3H),1.46(t,J=7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ159.9,155.8,147.8,146.3,142.9,135.2,131.2,129.3,126.2,125.6,121.7,121.5,113.0,108.9,108.3,101.0,61.6,44.4,35.4,14.4,9.3.
实施例202
3-甲基-5-(N-(2-(萘-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得黄色固体0.12g,收率46%。1H NMR(400MHz,Chloroform-d)δ8.06(dd,J=1.9,0.6Hz,1H),7.79(dd,J=8.8,1.9Hz,1H),7.76–7.71(m,1H),7.65(dd,J=8.8,2.9Hz,2H),7.51(dd,J=8.8,0.6Hz,1H),7.49–7.36(m,3H),7.13(dd,J=8.4,1.8Hz,1H),4.62(t,J=6.1Hz,1H),4.48(q,J=7.1Hz,2H),3.36(q,J=6.6Hz,2H),2.92(t,J=6.7Hz,2H),2.50(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,155.9,143.0,135.3,135.0,133.5,132.4,129.5,128.6,127.7,127.5,127.4,126.8,126.4,126.3,125.9,125.6,121.5,113.0,61.7,44.3,36.0,14.5,9.4.HRMS(ESI)[M-H]- calcd for C24H22NO5S:436.1219;found:436.1217.
实施例203
5-(N-(3,5-二甲氧基苯乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.13(d,J=1.6Hz,1H),7.83(dd,J=8.8,2.0Hz,1H),7.54(d,J=8.8Hz,1H),6.19(t,J=2.0Hz,1H),6.14(d,J=2.4Hz,2H),5.09(t,J=6.4Hz,1H),4.43(q,J=7.2Hz,2H),3.65(s,6H),3.20(q,J=6.8Hz,2H),2.66(t,J=6.8Hz,2H),2.54(s,3H),1.42(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.83,159.87,155.73,142.81,140.06,135.23,129.29,126.17,125.60,121.45,112.86,106.65,98.33,61.53,55.11,44.18,35.96,14.30,9.24.
实施例204
5-(N-(3-吲哚基乙氨基)磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
根据实施例147的合成步骤,得到白色固体136mg,收率64%。1H NMR(400MHz,Chloroform-d)δ8.13–8.05(m,2H),7.77(dd,J=8.8,1.9Hz,1H),7.54(d,J=8.8Hz,1H),7.34(t,J=7.4Hz,2H),7.16(t,J=8.0Hz,1H),7.04–6.95(m,2H),4.57–4.45(m,2H),3.34(q,J=6.4Hz,2H),2.97(t,J=6.5Hz,2H),2.58(s,3H),1.49(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,155.8,142.8,136.4,135.0,129.3,126.7,126.1,125.6,122.6,122.4,121.5,119.5,118.3,112.9,111.4,111.3,61.6,43.0,25.5,14.4,9.4.
实施例205
5-(正丁基磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
将正丁胺(0.06g,0.82mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1)得白色固体130mg,产率77.4%。
1H NMR(400MHz,CDCl3)δ8.20(d,J=2.0Hz,1H),7.91(dd,J=8.8,2.0Hz,1H),7.56(d,J=8.8Hz,1H),5.34(t,J=6.0Hz,1H),4.40(q,J=7.2Hz,2H),2.90(q,J=7.2Hz,2H),2.53(s,3H),1.45-1.34(m,5H),1.29-1.15(m,2H),0.74(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ159.89,155.73,142.83,135.36,129.27,126.22,125.58,121.53,112.91,61.53,42.96,31.47,19.62,14.28,13.45,9.26.
实施例206
5-(N-(3-碘丁-3-烯-1-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-129)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,CDCl3)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),6.73(t,J=5.1Hz,1H),5.80(q,J=1.0Hz,1H),5.72(q,J=1.0Hz,1H),4.34(q,J=6.4Hz,2H),2.99(q,J=5.3Hz,2H),2.60(s,3H),2.44(tt,J=5.4,1.1Hz,2H),1.39(t,J=6.3Hz,3H).
实施例207
5-(N-(2-环戊基乙基)氨磺酰)-3-甲基苯并呋喃-2-羧酸乙酯
将2-环戊基-乙胺(0.045g,0.40mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.10g,0.33mmol)和DIPEA(0.25mL),室温下搅拌反应2h。TLC检测反应完全,加入适量水,乙酸乙酯提取3次,合并有机相,饱和食盐水洗涤一遍,经无水硫酸钠干燥后,过滤浓缩,硅胶柱层析纯化(PE:DCM:EA=9:1:1)得白色固体151mg,产率99%。
1H NMR(400MHz,CDCl3)δ8.22(d,J=2.0Hz,1H),7.93(dd,J=8.8,2.0Hz,1H),7.60(d,J=8.8Hz,1H),5.12(t,J=6.0Hz,1H),4.44(q,J=7.2Hz,2H),2.93(dd,J=14.8,6.4Hz,2H),2.57(s,3H),1.74-1.57(m,3H),1.54-1.33(m,9H),1.01-0.88(m,2H).13C NMR(101MHz,CDCl3)δ159.93,155.79,142.89,135.30,129.33,126.24,125.63,121.59,113.00,61.59,42.69,37.20,35.74,32.35,24.94,14.34,9.34.
实施例208
3-甲基-5-(N-(2-(噻吩-3-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-133)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=2.2Hz,1H),7.96(dd,J=9.2,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.27–7.20(m,2H),7.14(t,J=6.6Hz,1H),6.66(dd,J=5.2,1.7Hz,1H),4.34(q,J=6.4Hz,2H),3.17(dt,J=6.6,5.2Hz,2H),2.77(t,J=5.2Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例209
5-(N-(2-(5-氯噻吩-2-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.18(dd,J=1.9,0.6Hz,1H),7.88(dd,J=8.8,1.9Hz,1H),7.63(dd,J=8.8,0.6Hz,1H),6.66(d,J=3.7Hz,1H),6.52(dt,J=3.7,1.0Hz,1H),4.47(q,J=7.1Hz,2H),3.22(q,J=6.5Hz,2H),2.89(td,J=6.6,1.0Hz,2H),2.61(s,3H),1.45(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ160.0,156.1,143.2,138.8,135.2,129.6,128.5,126.3,126.1,125.7,125.5,121.7,113.3,61.7,44.3,30.7,14.5,9.5.HRMS(ESI)[M+H]+ calcd for C18H18ClNO5S2:428.0393;found:428.0386.
实施例210
3-甲基-5-(N-(2-(5-溴噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得白色固体296mg,收率34%。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=1.9Hz,1H),7.87(dd,J=8.8,1.9Hz,1H),7.64(d,J=8.8Hz,1H),6.80(d,J=3.6Hz,1H),6.51(d,J=3.6Hz,1H),4.78(t,J=6.3Hz,1H),4.47(q,J=7.1Hz,2H),3.26–3.17(m,2H),2.95–2.86(m,2H),2.61(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.2,141.7,135.1,129.9,129.6,126.6,126.3,125.7,121.7,113.3,110.6,61.7,44.2,30.7,14.5,9.5.HRMS(ESI)[M-H]- calcd for C18H17BrNO5S2:469.9732;found:469.9729.
实施例211
3-甲基-5-(N-(2-(4-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯(GPR132-B-1024)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,得棕色油状物0.12g,收率17%。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=1.9Hz,1H),7.88(dd,J=8.7,1.9Hz,1H),7.61(d,J=8.8Hz,1H),6.65(t,J=1.3Hz,1H),6.52(d,J=1.4Hz,1H),4.94(t,J=6.2Hz,1H),4.46(q,J=7.1Hz,2H),3.23(q,J=6.6Hz,2H),2.90(t,J=6.7Hz,2H),2.59(s,3H),2.13(s,3H),1.44(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,155.9,143.0,139.7,137.8,135.3,129.5,128.4,126.3,125.7,121.7,119.5,113.1,61.7,44.5,30.3,15.7,14.4,9.4.HRMS(ESI)[M+H]+ calcd for C19H22NO5S2:408.0939;found:408.0931.
实施例212
3-甲基-5-(N-(2-(3-甲基噻吩-2-基)乙基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,所用胺原料为2-(3-甲基噻吩)乙胺,其余条件均一致。得黄色固体0.31g,收率38%。1H NMR(400MHz,Chloroform-d)δ8.18(d,J=1.8Hz,1H),7.87(dd,J=8.7,1.9Hz,1H),7.63(d,J=8.8Hz,1H),6.50(m,2H),4.69(t,J=6.2Hz,1H),4.47(q,J=7.1Hz,2H),3.22(q,J=6.5Hz,2H),2.88(t,J=6.5Hz,2H),2.61(s,3H),2.37(s,3H),1.45(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.0,143.1,139.1,137.5,135.3,129.5,126.4,125.9,125.7,125.2,121.7,113.2,61.7,44.5,30.3,15.3,14.5,9.5.HRMS(ESI)[M+H]+ calcd forC19H22NO5S2:408.0939;found:408.0933.
实施例213
5-(N-(2-(环己-1-烯-1-基)乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯
将2-(1-环己烯基)乙胺(0.07g,0.56mmol)溶于DMF(2.5mL),加入5-(氯磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(0.15g,0.49mmol),DIPEA(0.25mL),室温搅拌反应2h。TLC监测反应完全,加入适量水,乙酸乙酯提取3次,有机相合并,经无水硫酸钠干燥,过滤浓缩,硅胶柱层析纯化(PE/DCM/EA=9:1:1)得白色固体161mg,产率83.0%。
1H NMR(400MHz,CDCl3)δ8.18(d,J=2.4Hz,1H),7.89(dd,J=8.8,2.4Hz,1H),7.56(d,J=8.8Hz,1H),5.27(s,1H),5.03(t,J=6.0Hz,1H),4.39(q,J=7.2Hz,2H),2.96(q,J=6.8Hz,2H),2.53(s,3H),2.00(t,J=6.8Hz,2H),1.82(s,2H),1.63(s,2H),1.46-1.33(m,7H).13C NMR(101MHz,CDCl3)δ159.83,155.73,142.86,135.30,133.36,129.27,126.23,125.53,124.44,121.55,112.89,61.51,40.86,37.40,27.57,25.05,22.56,22.10,14.29,9.26.
实施例214
3-甲基-5-(N-(1-苯基丙-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-140)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.15(d,J=2.3Hz,1H),7.94(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.2Hz,1H),7.35–7.09(m,5H),6.72(d,J=10.1Hz,1H),4.34(q,J=6.4Hz,2H),3.48(dh,J=10.1,7.0Hz,1H),2.92–2.79(m,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H),1.13(d,J=7.0Hz,3H).
实施例215
5-(N-(2-氟-2-苯乙基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-23)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,CDCl3)δ8.19(d,J=2.3Hz,1H),7.97(dd,J=9.0,2.2Hz,1H),7.64(d,J=9.0Hz,1H),7.44–7.23(m,5H),6.96(t,J=7.7Hz,1H),5.41(dt,J=46.4,4.6Hz,1H),3.76–3.52(m,2H),3.22(q,J=6.3Hz,2H),2.58(s,3H),1.39(t,J=6.3Hz,3H).
实施例216
3-甲基-5-(N-(2-苯基乙酰基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,所用胺原料为2-苯基乙酰胺,其余条件均一致。得白色固体33mg,收率8%。1H NMR(400MHz,Chloroform-d)δ8.40(d,J=2.0Hz,1H),7.99(dd,J=8.8,2.0Hz,1H),7.56(d,J=8.8Hz,1H),7.31–7.24(m,3H),7.13(dd,J=6.5,2.9Hz,2H),4.48(q,J=7.1Hz,2H),3.59(s,2H),2.59(s,3H),1.46(t,J=7.1Hz,3H).13C NMR(101MHz,Chloroform-d)δ168.9,160.0,156.6,143.2,133.6,132.4,129.4,129.4,129.3,128.0,127.3,125.9,123.8,113.0,61.8,43.6,14.4,9.5.HRMS(ESI)[M+H]+ calcd for C20H20NO6S:402.1011;found:402.1004.
实施例217
3-甲基-5-(N-(萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,所用胺原料为1-萘胺,其余条件均一致。得黄色固体67mg,收率16%。1H NMR(400MHz,DMSO-d6)δ10.29(s,1H),8.10–8.01(m,2H),7.91–7.74(m,4H),7.50–7.34(m,3H),7.14(dd,J=7.4,1.1Hz,1H),4.36(q,J=7.1Hz,2H),2.47(s,3H),1.34(t,J=7.1Hz,3H).13C NMR(101MHz,DMSO-d6)δ159.0,155.0,142.1,135.7,133.9,132.3,129.5,128.4,127.9,126.8,126.4,126.2,126.0,125.5,125.4,123.4,123.1,121.2,113.0,61.1,14.1,8.9.HRMS(ESI)[M-H]- calcdfor C22H18NO5S:408.0906;found:408.0911.
实施例218
3-甲基-5-(N-(萘-2-基)氨磺酰基)苯并呋喃-2-羧酸乙酯
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法,所用胺原料为2-萘胺,其余条件均一致。得粉色固体0.38g,收率47%。1H NMR(400MHz,Chloroform-d)δ8.19–8.14(m,1H),7.85(dd,J=8.8,1.9Hz,1H),7.78–7.65(m,3H),7.60–7.34(m,4H),7.28–7.20(m,1H),4.43(q,J=7.1Hz,2H),2.47(s,3H),1.66(s,1H),1.42(t,J=7.2Hz,3H).13C NMR(101MHz,Chloroform-d)δ160.0,156.1,143.1,134.4,133.9,133.7,131.4,129.6,129.5,127.8,127.6,126.9,126.4,125.8,125.6,122.0,121.4,119.2,113.1,61.7,14.4,9.3.HRMS(ESI)[M-H]- calcd for C22H18NO5S:408.0906;found:408.0906.
实施例219
3-甲基-5-(N-(萘-1-基甲基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-146)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.21–8.11(m,2H),7.97(dd,J=9.1,2.3Hz,1H),7.89(dt,J=7.5,1.5Hz,1H),7.87–7.81(m,1H),7.64(d,J=9.1Hz,1H),7.56–7.46(m,2H),7.43–7.35(m,2H),7.29(t,J=7.3Hz,1H),4.38–4.30(m,4H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例220
5-(N-(2-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-28)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,DMSO-d6)δ9.18(s,1H),8.26(d,J=2.3Hz,1H),8.00(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.55(dd,J=6.7,1.3Hz,1H),7.42–7.32(m,2H),7.25(td,J=6.6,1.8Hz,1H),4.34(q,J=6.3Hz,2H),3.22(s,1H),2.58(s,3H),1.39(t,J=6.3Hz,3H).
实施例221
5-(N-(1H-吲哚-4-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-150)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。1H NMR(400MHz,Chloroform-d)δ8.52(d,J=6.6Hz,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.43(t,J=7.9Hz,1H),7.27(dd,J=7.9,1.3Hz,1H),7.20(dd,J=6.6,3.7Hz,1H),7.04(dd,J=7.7,1.5Hz,1H),6.85(d,J=3.6Hz,1H),4.34(q,J=6.4Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例222
5-(N-(苯并呋喃-5-基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-151)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.84(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.76(d,J=1.6Hz,1H),7.67–7.62(m,2H),7.45(d,J=8.4Hz,1H),7.24(dd,J=8.4,2.2Hz,1H),6.89(t,J=1.8Hz,1H),4.34(q,J=6.4Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例223
5-(N-(2,3-二甲基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-152)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.99(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.02(t,J=7.8Hz,1H),6.94–6.84(m,2H),4.34(q,J=6.4Hz,2H),2.60(s,3H),2.26(d,J=0.7Hz,3H),2.08(s,3H),1.39(t,J=6.3Hz,3H).
实施例224
5-(N-(2-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-153)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.54(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.78(dd,J=7.7,1.3Hz,1H),7.65(d,J=9.0Hz,1H),7.32–7.22(m,2H),6.93(ddd,J=7.7,6.7,1.7Hz,1H),4.34(q,J=6.4Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例225
5-(N-(4-碘苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-154)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.66(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.76–7.70(m,2H),7.65(d,J=9.0Hz,1H),6.99–6.93(m,2H),4.34(q,J=6.4Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例226
3-甲基-5-(N-(3-苯氧基苯基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-155)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.39–7.32(m,2H),7.29(t,J=7.8Hz,1H),7.10(tt,J=7.2,1.5Hz,1H),7.05–6.99(m,3H),6.82(t,J=2.2Hz,1H),6.52(ddd,J=7.7,2.2,1.1Hz,1H),4.34(q,J=6.4Hz,2H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例227
3-甲基-5-(N-(3-(4-甲基哌嗪-1-基)苯基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-156)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.75(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.08(dd,J=8.1,7.2Hz,1H),6.72(dd,J=2.2,1.3Hz,1H),6.46–6.36(m,2H),4.34(q,J=6.4Hz,2H),3.23(ddd,J=5.3,4.0,1.0Hz,4H),2.84–2.76(m,2H),2.61–2.53(m,5H),2.29(s,3H),1.39(t,J=6.3Hz,3H).
实施例228
3-甲基-5-(N-(5,6,7,8-四氢萘-1-基)氨磺酰基)苯并呋喃-2-羧酸乙酯(M-GPR132-B-157)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.21(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.08(t,J=8.1Hz,1H),6.92(dd,J=8.1,1.2Hz,1H),6.81(dq,J=7.7,1.0Hz,1H),4.34(q,J=6.4Hz,2H),2.89–2.69(m,4H),2.60(s,3H),1.81–1.68(m,4H),1.39(t,J=6.3Hz,3H).
实施例229
5-(N-(4-乙炔基苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-158)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.55(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.53–7.47(m,2H),7.11–7.05(m,2H),4.34(q,J=6.4Hz,2H),3.04(s,1H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
实施例230
5-(N-(3-(二甲基氨基)苯基)氨磺酰基)-3-甲基苯并呋喃-2-羧酸乙酯(M-GPR132-B-159)
按照3-甲基-5-(N-苯乙基氨磺酰基)苯并呋喃-2-羧酸乙酯所用方法合成。
1H NMR(400MHz,Chloroform-d)δ9.76(s,1H),8.25(d,J=2.3Hz,1H),7.98(dd,J=9.0,2.2Hz,1H),7.65(d,J=9.0Hz,1H),7.10(dd,J=8.2,7.2Hz,1H),6.85(t,J=2.3Hz,1H),6.76(ddd,J=8.1,2.2,1.2Hz,1H),6.49(ddd,J=7.3,2.2,1.2Hz,1H),4.34(q,J=6.4Hz,2H),2.97(s,6H),2.60(s,3H),1.39(t,J=6.3Hz,3H).
生物活性测试
1.1 G蛋白激活
Gi BRET探针是根据之前的文献报道(Olsen等人,2020)生成的,包括Gαi-RLuc8、Gβ3和Gγ9-GFP2。GPR132和Gi BRET探针在HEK293细胞中瞬时共转染。转染24小时后,将细胞以每孔5×104个细胞的密度分布到96孔微孔板中,再培养24小时。细胞用Tyrode缓冲液洗涤两次,用不同浓度(10-11-10-5M)的化合物配体和Tyrode缓冲液刺激2分钟,再加入10-5M的9-HODE刺激。然后加入荧光素酶底物腔肠素400a(5μM)后,使用配备BRET过滤器组的Mithras LB940酶标仪测量BRET信号。BRET信号计算为510nm/400nm处的发射光比。
上述实验中EC50数值较低的化合物,具有良好的GPR132拮抗活性。
1.2细胞培养与传代
人胚胎肾细胞系HEK293A传代培养,培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10%FBS的MEM培养基,置于95%空气和5%二氧化碳的湿润气氛下37℃恒温培养。当细胞融合至90%时,弃去旧培养基,用2mL PBS洗涤细胞2次,弃去PBS后加入2mL 0.25%胰蛋白酶-0.25%EDTA混合消化液,置显微镜下观察,当细胞变圆后迅速加入2mL完全培养基终止消化,轻轻吹打,收集细胞。800rpm,4℃,离心5min,弃去上清,用完全培养基重悬细胞,分瓶培养,隔天换液。
人肝癌细胞系HepG2传代培养,培养条件为含有青霉素(终浓度为100U/mL)、链霉素(终浓度为100μg/mL)以及10%FBS的DMEM培养基,余同HEK293A传代培养相同。
胰岛素细胞株(INS-1细胞)传代培养。培养条件:DMEM(Dulbecco's modifiedEagle'smedium)培养基中培养,其中还需要添加10%(v/v)胎牛血清(FBS)、2mM L-谷氨酰胺(L-glutamine)、100U/mL青霉素和100μg/mL链霉素。置于37℃、5%CO2、95%空气的细胞培养箱中培养。
1.3细胞增殖抑制实验
通过MTT法检测化合物的细胞增殖抑制能力。HepG2和HEK293细胞以30%的密度接种于96孔板,孵育18h使细胞贴壁后,移除原有培养基,每孔加入给定浓度的待测化合物,对照组加入等量的DMSO。每个化合物设置三个复孔。给药48h后,MTT法检测细胞活力,空白组为不加入细胞的孔,随后用酶标仪在490nm处读取其OD值。细胞活力的计算公式为:细胞活力(%)=(OD待测-OD空白)/(OD对照-OD空白)×100。
上述实验中对HEK293细胞活力高、CC50数值较高的化合物,具有良好的安全性。对HepG2细胞抑制率较高、EC50数值较低的化合物,可以较好地抑制肿瘤细胞的增殖。
1.4细胞胰岛素水平检测
培养胰岛素分泌细胞:首先选取胰岛素细胞株(INS-1细胞)进行培养。培养条件:DMEM(Dulbecco's modified Eagle's medium)培养基中培养,其中还需要添加10%(v/v)胎牛血清(FBS)、2mM L-谷氨酰胺(L-glutamine)、100U/mL青霉素和100μg/mL链霉素。置于37℃、5%CO2、95%空气的细胞培养箱中培养。INS-1细胞接种于96孔板内培养贴壁,每组3个平行,使用高糖培养基培养细胞24h,随后使用PBS清洗2次后,加入含2%FBS无葡萄糖的KRBH液孵育30min,弃上清,再加入含5mmol/L或25mmol/L葡萄糖的KRBH液刺激1h后取上清,采用大鼠胰岛素酶联免疫分析(ELISA)检测胰岛素含量。
具体步骤如下:
■标准品的加样:设置标准品孔和样本孔,标准品孔各加不同浓度的标准品50μL。
■加样:分别设空白孔(空白对照孔不加样品及酶标试剂,其余各步操作相同)、待测样品孔。在酶标包被板上待测样品孔中先加样品稀释液40μL,然后再加待测样品10μL(样品终稀释度为5倍)。加样将样品加于酶标板孔底部,尽量不触及孔壁,轻轻晃动混匀。
■加酶:每孔加入酶标试剂100μL,空白孔除外。
■温育:用封板膜封板后置37℃温育60分钟。
■配液:将20倍浓缩洗涤液用蒸馏水20倍稀释后备用。
■洗涤:小心揭掉封板膜,弃去液体,甩干,每孔加满洗涤液,静置30秒后弃去,如此重复5次,拍干。
■显色:每孔先加入显色剂A50μL,再加入显色剂B50μL,轻轻震荡混匀,37℃避光显色15分钟.
■终止:每孔加终止液50μL,终止反应(此时蓝色立转黄色)。
■测定:以空白孔调零,450nm波长依序测量各孔的吸光度(OD值)。测定应在加终止液后15分钟以内进行。
根据标准品绘制标准曲线,可计算出待测样品中的胰岛素含量。进一步计算出胰岛素分泌率,胰岛素分泌促进情况计算公式为:分泌促进率(%)=胰岛素含量待测-胰岛素含量对照/胰岛素含量对照×100。
上述实验中胰岛素分泌促进率较高,EC50数值较低的化合物,可以较好地促进胰岛素分泌进而提高葡萄糖耐量,改善胰岛素抵抗,降低血糖水平。
1.5细胞TC/TG检测
细胞TC/TG用南京建成TG测试盒、TC测试盒检测。HepG2细胞用0.5mmol/L FFA(油酸与棕榈酸酯按照2:1混合)和溶剂或不同浓度(20μM、40μM、80μM)的化合物孵育24h。吸弃培养液,用0.01M,pH 7.4PBS清洗一遍细胞。用细胞刮板刮下细胞,加入2-5mL,0.01M,pH7.4PBS,收集细胞悬液后,1000×g,4℃,离心10min收集细胞,按照106个细胞加入300-500μL匀浆介质的比例加入异丙醇,进行机械匀浆,充分破碎至无明显的细胞沉淀。10000×g,4℃,离心10min,取上清置于冰上待测。取2.5μL蒸馏水、标准品或样品分别与250μL蒸馏水混匀,37℃孵育10分钟,酶标仪510nm测定各孔吸光度值。TC/TG浓度计算公式:样品浓度(mmol/g protein)=(OD样品-OD空白)/(OD标准-OD空白)×标准品浓度(mmol/L)/蛋白浓度(g protein/L)。
BCA法蛋白定量
蛋白标准品的准备:a.取1.2mL蛋白标准配制液加入到一管蛋白标准(30mg BSA))中,充分溶解后配制成25mg/mL的蛋白标准溶液。b.取适量25mg/mL蛋白标准,稀释至终浓度为0.5mg/mL。BCA工作液配制:根据样品数量,按50体积BCA试剂A加1体积BCA试剂B(50:1)配制适量BCA工作液,充分混匀。蛋白浓度测定:a.将标准品按0、1、2、4、8、12、16、20μL加到96孔板的标准品孔中,加标准品稀释液补足到20μL,相当于标准品浓度分别为0、0.025、0.05、0.1、0.2、0.3、0.4、0.5mg/mL。b.加适当体积样品到96孔板的样品孔中。如果样品不足20μL,需加标准品稀释液补足到20μL。c.各孔加入200μL BCA工作液,37℃放置20-30分钟。d.用酶标仪测定A562 nm波长处的吸光度。e.根据标准曲线和使用的样品体积计算出样品的蛋白浓度。
上述实验中TC/TG降低率较高、EC50数值较低的化合物,可以较好地降低血液和/或肝脏中的脂肪含量。
1.6急性高脂血症动物实验
雄性C57BL/6小鼠随机分为8组,Control组、Model组、SIPI-7623组(10mg/kg、30mg/kg和100mg/kg)和受试物组(3个剂量)。Model组、SIPI-7623组和受试物组腹腔注射600mg/kg的Triton WR-1339,Control组注射同等体积生理盐水。在注射诱导剂前1个小时和注射诱导剂后23h灌胃给与化合物处理,1h后,收集血液样品和组织样品。
1.7高脂饮食动物实验
雄性C57BL/6小鼠随机分为6组,Control组、HFD组、SIPI-7623组(40mg/kg)和受试物组(3个剂量)。Control组给予正常饮食,HFD组、SIPI-7623组和受试物组给予高脂饮食。Control组和HFD组灌胃给与溶剂,其他组给予相应剂量化合物处理。每天记录小鼠体重。化合物灌胃处理8周后,收集血液样品和组织样品。高脂饮食成分见下表。
小鼠正常饲料(Standard chow)和高脂饲料(High fat diet)配方组成
1.8饮食诱导肥胖动物实验
雄性C57BL/6小鼠分为2组,Control组正常饮食、HFD组给予高脂饮食。高脂饮食12周后,HFD组随机分为9组:HFD组、受试物组(3个剂量)、SIPI-7623(40mg/kg)、Atorvastatin(10mg/kg)和受试物(10mg/kg)+Atorvastatin(10mg/kg)。Control组和HFD组灌胃给与溶剂,其他组给予相应剂量化合物处理。每周记录小鼠体重。化合物灌胃处理8周后,收集血液样品和组织样品。高脂饮食成分见上表。
1.9db/db鼠动物实验
雄性db/db小鼠随机分为5组,实验分组为db/db组、受试物组(3个剂量)和吡格列酮(7mg/kg)。db/db组给予溶剂灌胃处理,其他组给予对应化合物灌胃处理4周。每周记录小鼠体重,并检测空腹血糖。化合物灌胃4周后,收集血液样品和组织样品进行后续实验。
2.0小鼠血糖测定
1、罗氏血糖仪包括:血糖仪、采血笔、血糖试纸。
2、用酒精棉球擦拭小鼠尾尖,打开采血笔上的采样针,扎破小鼠尾尖;用血糖试纸蘸取尾尖血液,血液必须完全覆盖试纸测试区;打开血糖仪,将血糖试纸插入血糖仪,读取并记录血糖值。每只小鼠测定血糖前都应该更换采样针和血糖试纸。
2.1葡萄糖耐量试验(Glucose tolerance test,GTT)
葡萄糖耐量试验在受试物灌胃给药后第5周(实验第17周)进行。小鼠禁食16h后,腹腔注射葡萄糖(1.5g/kg),在注射葡萄糖后0、15、30、60、90、120min分别用血糖仪测定小鼠的血糖水平。
2.2胰岛素耐量试验(Insulin tolerance test,ITT)
胰岛素耐量试验在受试物灌胃给药后第6周(实验第18周)进行。小鼠禁食4h后,腹腔注射胰岛素(1U/kg),在注射胰岛素后0、15、30、60、90、120min分别用血糖仪测定小鼠的血糖水平。
2.3动物取材
1、小鼠称重后,使用戊巴比妥钠腹腔注射麻醉。
2、内眦取血,取20μL全血,用全血稀释液进行稀释,进行血常规检测;剩余全血常温静置2h,3000rpm,4℃,离心10min,取上层血清,进行血生化检测。
3、小鼠取完血后,打开胸腔和腹腔,分别取出肝、肠、白色脂肪和褐色脂肪组织。
4、肝脏分出一部分4%甲醛固定,用于石蜡切片和冰冻切片,剩余组织-80℃冻存。
5、肠道组织用PBS冲洗后,刮取肠道上皮细胞-80℃冻存。
6、对白色脂肪和褐色脂肪组织进行称重。
2.4肝脏中胆固醇和甘油三酯检测
1、取适量肝脏组织,加入研磨珠以PBS为buffer进行组织匀浆。
2、将匀浆液等分为两部分,一部分加入氯仿甲醇抽提,测定胆固醇和甘油三酯。向其中一管加入4倍体积氯仿甲醇抽提液(氯仿:甲醇=2:1),涡旋使其充分混匀,静置至分层,2000rpm,4℃,离心30min,吸出下层液体于新离心管,在真空浓缩仪中挥发干净溶剂,加入适量3%Triton X-100,恒温水浴摇床50-60℃溶解。用TC和TG试剂盒测定浓度。
5、取另一管匀浆液,12000rpm,4℃,离心15min,取上清,用BCA试剂盒测定蛋白浓度。
6、脂质含量=脂质浓度/蛋白浓度
2.5肝脏油红O染色
1、取相同部位相同大小的新鲜肝脏组织放置于4%中性甲醛中固定,送至检测公司制备切片并进行油红O染色。
2、取回已经制备好的切片用扫描仪扫描切片并拍照。
2.6组织HE染色
1、取相同部位相同大小的新鲜肝脏组织放置于4%中性甲醛中固定,送至检测公司制备切片并进行HE染色。
2、取回已经制备好的切片用扫描仪扫描切片并拍照。
表9部分化合物的GPR132拮抗活性
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表10部分化合物的GPR132拮抗活性GPR132拮抗活性结果表示
A:0.0001μM<EC50<0.1μM
B:0.1μM<EC50<1μM
C:1μM<EC50<10μM
D:10μM<EC50<100μM
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表11部分化合物的促进胰岛素分泌活性
受试化合物 | 化合物编号 | EC50(μM) |
实施例25 | GPR132-B-160 | 0.7 |
实施例27 | GPR132-B-2 | 2.96 |
实施例31 | GPR132-B-6 | 1.21 |
实施例32 | GPR132-B-7 | 0.52 |
实施例35 | GPR132-B-10 | 0.78 |
实施例48 | GPR132-B-22 | 6.31 |
实施例62 | GPR132-B-65 | 19.5 |
实施例79 | GPR132-B-88 | 24.7 |
实施例80 | GPR132-B-90 | 8.2 |
实施例91 | GPR132-B-101 | 1.57 |
实施例101 | GPR132-B-111 | 5.95 |
实施例111 | GPR132-B-122 | 30.1 |
实施例116 | GPR132-B-131 | 0.31 |
实施例131 | GPR132-B-151 | 9.15 |
表12部分化合物的促进胰岛素分泌活性
促进胰岛素分泌活性结果表示
A:0.0001μM<EC50<1μM
B:0.1μM<EC50<10μM
C:1μM<EC50<100μM
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实验结果表明,本发明化合物具有以下一个或多个方面的效果:(1)具有良好的GPR132拮抗活性;
(2)具有良好的安全性;
(3)可以提高葡萄糖耐量;
(4)可以改善胰岛素抵抗;
(5)可以降低血糖水平;
(6)可以降低血脂水平;
(7)可以降低肝脏中的脂肪含量;
(8)可以抑制肿瘤细胞的增殖。
综上,本发明的化合物可作为GPR132拮抗剂,用于预防和/或治疗与GPR132相关的疾病,例如肿瘤或代谢性疾病。
尽管本发明的具体实施方式已经得到详细的描述,本领域技术人员将会理解:根据已经公开的所有教导,可以对那些细节进行各种修改和替换,这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
Claims (20)
1.式(I)所示的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,
其中:
A选自6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基;任选地,所述6至10元芳基、5至14元杂芳基、3至6元环烷基、3至6元杂环基、苯并3至6元环烷基被一个或多个M取代;
M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(=O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基;任选地,所述C1-C6烷氧基被一个或多个选自以下的基团取代:C1-C6卤代烷基、3至6元环烷基;所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代;
R1选自羟基、-NR5R6、C1-C6烷氧基;任选地,所述C1-C6烷氧基被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基;
Q为苯基或苯并5-6元杂芳基环;
R2选自氢、卤素、C1-C6烷基、C1-C6卤代烷基;m选自1、2、3、4;当有多个R2时,各个R2可以相同或不同;
R3、R4、R5、R6各自独立地选自氢、羟基和C1-C6烷基;任选地,所述C1-C6烷基被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基;
R7、R8各自独立地选自C1-C6烷基,q选自1至10之间的整数;
L1、L2各自独立地为不存在或选自-(CH2)n-、3至6元环烷基,n为选自1至6的整数;任选地,-(CH2)n-被一个或多个选自以下的基团取代:苯基、卤素、硝基、氰基、羟基、C1-C6烷基、氘、氚、羰基;并且,所述化合物不是3-甲基-5-(N-苯乙基氨磺酰)苯并呋喃-2-羧酸。
2.根据权利要求1所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,A选自6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基、苯并5至6元杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基;任选地,所述6至10元芳基、5至8元单环杂芳基、8至14元稠杂芳基、5至6元环烷基、5至6元杂环基、苯并5至6元环烷基被一个或多个M取代;
优选地,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、P(=O)R7R8、CH3CH2O-(CH2CH2O)q-、4至6元杂环基、5至6元杂芳基;所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代;
优选地,R7、R8各自为甲基,q选自1至4之间的整数;
优选地,A选自6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基、苯并5至6元含氧杂环基、C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烯基;任选地,所述6至10元芳基、5至6元含硫或含氮单环杂芳基、8至10元含氧稠杂芳基(例如苯并5至6元含氧杂芳基)、8至10元含氮稠杂芳基(例如苯并5至6元含氮杂芳基)、5至6元环烷基、5至6元含氧杂环基、5至6元含氮杂环基、苯并5至6元环烷基或苯并5至6元含氧杂环基被一个或多个M取代;
优选地,M选自以下基团:卤素、硝基、羟基、氰基、-NR3R4、C1-C6烷基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6烷酰基、C1-C6酰胺基、苯基、苯氧基、-P(=O)(CH3)2、CH3CH2O-(CH2CH2O)-;
优选地,A选自苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基、苯并环己烷基;任选地,所述苯基、萘基、噻吩基、吡啶基、苯并呋喃基、环己基、四氢吡喃基、哌嗪基、二氢茚基、C2-C6烯基、C2-C6炔基、C1-C6烷基、2,3-二氢苯并呋喃基、2,3-二氢苯并[b][1,3]二氧杂环戊烷基、2,3-二氢苯并[b][1,4]二氧杂环己烷基、吲哚基、环己烯基或苯并环己烷基被一个或多个M取代;
优选地,M选自以下基团:卤素(例如氟、氯、溴、碘)、C1-C4烷基、三氟甲基、甲氧基、乙氧基、苯基、C2-C4炔基、C1-C6烷酰基、硝基、羟基、氰基、-NR3R4、-P(=O)(CH3)2、CH3CH2O-(CH2CH2O)-、4至6元杂环基、5至6元杂芳基、苯氧基;所述苯基、苯氧基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代。
3.根据权利要求1或2所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,R1为羟基或-NHOH。
4.根据权利要求1-3任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,R2选自卤素、C1-C6烷基(例如甲基)、C1-C6卤代烷基(例如氟代甲基)。
5.根据权利要求1-4任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,L1不存在或选自-(CH2)n-、环丙基,n为选自1至4的整数;任选地,-(CH2)n-被甲基或羰基取代或被氘代;
优选地,L2不存在或选自-(CH2)n-、n为选自1至4的整数;任选地,-(CH2)n-被甲基取代或被氘代。
6.根据权利要求1-5任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,所述5-6元杂芳基选自呋喃基、噻吩基、吡咯基;
优选地,所述化合物的结构如式(II)所示:
其中,X选自O、S或NH,A、R1、R2、L1如权利要求1-5任一项所定义;
优选地,所述化合物的结构如式(III)或(IV)所示:
优选地,X为O、S或NH,A、R1、R2、L1如权利要求1-5任一项所定义。
7.根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,所述化合物选自表1所示的化合物:
表1
8.根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,所述化合物的结构如式(V)所示:
其中,Core为X选自O、S或NH,R2如权利要求1或4任一项所定义;
优选地,R2选自氢、卤素、C1-C6烷基;
优选地,Core选自:
优选地,所述化合物选自表2所示的化合物:
表2
9.根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,所述化合物的结构如式(VI)所示:
其中,A如权利要求1或2任一项所定义。
10.根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,A选自任选被一个或多个M取代的苯基,M选自卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、硝基、羟基、-NR3R4,R3、R4各自独立地选自氢、C1-C6烷基;
优选地,所述化合物选自表3所示的化合物:
表3
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11.根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,A选自任选被一个或多个M取代的以下基团:苯基、5至6元含氮杂芳基;M选自:卤素、C2-C6炔基、C1-C6烷氧基、氰基、P(=O)R7R8、C1-C6烷酰基、CH3CH2O-(CH2CH2O)q-、苯基、4至6元杂环基、5至6元杂芳基,其中,R7、R8各自独立地选自C1-C6烷基,q选自1至10之间的整数,所述苯基、4至6元杂环基、5至6元杂芳基任选地被卤素或C1-C6烷基取代;
优选地,所述化合物选自表4所示的化合物:
表4
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12.根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,A选自任选被一个或多个M取代的以下基团:苯基、萘基、苯并5至6元杂环基(例如苯并5至6元含氧杂环基)、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基);M选自卤素、C1-C6烷基、C1-C6烷氧基;
优选地,所述化合物选自表5所示的化合物:
表5
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13.根据权利要求9所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,A选自任选被一个或多个M取代的以下基团:C1-C6烷基、C2-C6烯基、C2-C6炔基、5至6元环烷基、5至6元环烯基、5至6元杂芳基、5至6元杂环基;M选自C1-C6烷基、卤素;
优选地,所述化合物选自表6所示的化合物:
表6
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14.根据权利要求1-6任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,所述化合物如式(VII)所示,
其中,A和L1如权利要求1、2或5任一项所定义。
15.根据权利要求14所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,A选自苯基、萘基,L1不存在或选自-(CH2)n-,n为选自1至4的整数;任选地,-(CH2)n-被一个或多个选自以下的基团取代:卤素、C1-C6烷基、羰基;
优选地,所述化合物选自表7所示的化合物:
表7
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16.根据权利要求14所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,其中,L1不存在,A选自任选被一个或多个M取代的以下基团:苯基、萘基、苯并5至6元杂芳基(例如苯并5至6元含氮或含氧杂芳基)、苯并5至6元环烷基,M选自C1-C6烷基、C2-C6炔基、卤素、苯氧基、-NR3R4、5至6元杂环基,R3、R4各自独立地选自C1-C6烷基,所述5至6元杂环基任选地被C1-C6烷基取代;
优选地,所述化合物选自表8所示的化合物:
表8
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17.根据权利要求1-16任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式,所述药学上可接受的酯为羧酸乙酯。
18.一种药物组合物,其包含根据权利要求1-17任一项所述的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式;任选地,所述药物组合物还包含药学上可接受的载体或赋形剂。
19.化合物用于制备药物中的用途,所述药物用于预防或治疗与GPR132相关的疾病,所述化合物选自根据权利要求1-17任一项所述的化合物或下表中的化合物、其药学上可接受的盐或酯、前药、立体异构体、水合物、溶剂合物、晶型或它们的代谢物形式:
20.根据权利要求19所述的用途,其中,所述与GPR132相关的疾病选自肿瘤、代谢性疾病、免疫相关疾病、神经性疼痛;
优选地,所述肿瘤选自选自:乳腺癌、黑色素瘤、脑膜瘤、软组织肉瘤、唾液腺肿瘤、原发性肝癌、椎管内肿瘤、纵隔肿瘤、脑癌、骨癌、阴茎癌、骨肉瘤、颅内肿瘤、舌癌、上颌窦癌、甲状腺癌、恶性淋巴瘤、多发性骨髓瘤、脑垂体腺瘤、睾丸肿瘤、非何杰金氏淋巴癌、膀胱癌、白血病、胃癌、鼻咽癌、喉癌、口腔癌、食管癌、肺癌、肾癌、宫颈癌、绒毛膜癌、外阴癌、皮肤癌、子宫内膜癌、卵巢癌、前列腺癌、胰腺癌、结肠癌、直肠癌、大肠癌、卡波西肉瘤、非黑色素瘤皮肤癌(包括鳞状细胞癌和基底细胞癌)、血管瘤、神经胶质瘤;
优选地,所述代谢性疾病选自动脉粥样硬化、肥胖、非酒精性脂肪肝病(NAFLD)(例如,单纯性脂肪肝或非酒精性脂肪性肝炎(NASH))、代谢综合征、2型糖尿病、1型糖尿病、胰岛素抵抗、高胰岛素血症、葡萄糖不耐受、高血糖、高脂血症(例如,高胆固醇血症),及这些疾病的继发性并发症(例如,糖尿病并发症,如视网膜病、神经病、肾病以及延缓的创伤愈合,或者动脉粥样硬化、冠心病、高血压、中风等心脑血管疾病);
优选地,所述免疫相关疾病选自:
继发性免疫缺陷:例如由感染(例如风疹、麻疹、麻风、结核病、巨细胞病毒感染、艾滋病病毒感染、球孢子菌感染),蛋白丢失(例如肾病综合征、蛋白丢失性肠病),免疫球蛋白合成不足,淋巴细胞丢失(例如因药物和/或系统感染引起的淋巴细胞丢失),其他疾病(如糖尿病、肝硬变、亚急性硬化性全脑炎)和/或免疫抑制治疗引起的继发性免疫缺陷;以及
自身免疫疾病:例如系统性红斑狼疮、类风湿性关节炎、硬皮病、甲状腺机能亢进、青少年糖尿病、原发性血小板紫癜、自身免疫性溶血性贫血、溃疡性结肠炎、皮肤病、慢性肝病。
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