发明名称 Thienyl [3,2-D] pyrimidin-4-one compounds, preparation method, pharmaceutical compositions and use thereof
摘要 Disclosed are new thienyl [3,2-d] pyrimidin-4-one compounds shown as the general formula (I), preparation method, pharmaceutical compositions and pharmacological use thereof. The compounds are strong DPPIV (dipeptide peptidase IV) inhibitors and can treat type II diabetes through well inhibiting DPPIV indirectly increasing the content of GLP-1 in vivo and inducing a series of physiological actions in vivo. Therefore, the compounds could be developed as new promising drugs for treating diabetes.;
申请公布号 US9045491(B2) 申请公布日期 2015.06.02
申请号 US201214361920 申请日期 2012.10.23
申请人 Shanghai Institute of Materia Medica, Chinese Academy of Sciences;Cisen Pharmaceutical Co., Ltd. 发明人 Liu Hong;Li Jia;Li Jian;Li Jingya;Wang Jiang;Su Mingbo;Lian Jie;Jiang Hualiang;Chen Kaixian
分类号 C07D495/04;A61K31/55 主分类号 C07D495/04
代理机构 Kilpatrick Townsend & Stockton LLP 代理人 Kilpatrick Townsend & Stockton LLP
主权项 1. A thieno[3,2-d]pyrimidin-4-one compound of structural formula I, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, and a pharmaceutically acceptable salt thereof, wherein, n is an integer from 1 to 3; R1 and R2 are identical or different, and not hydrogen simultaneously, and R1 is H, CBr2H, CCl2H, CF2H, a cyano, CF3, an aldehyde group, (CH2)mOR6, (CH2)mNR6R7,  (CH2)mCOOR8, CONR9R10, or R2 is H, a halogen, CBr2H, CCl2H, CF2H, a cyano, CF3, an aldehyde group, (CH2)mOR6, (CH2)mNR6R7,  (CH2)mCOOR8, CONR9R10, or R1 and R2 are linked together to form C3-C6 alkylidene; m is an integer from 0 to 3; R6 and R7 are identical or different, and each of R6 and R7 is independently selected from H, a linear or branched saturated or unsaturated C1-C6 hydrocarbyl, a C3-C7 cyclic hydrocarbyl, a C1-C3 alkoxy, a 4-7 member heterocyclic group, a C1-C4 alkyloyl RCO, a C5-C7 aroyl ArCO, a C1-C4 alkylsulfonyl RSO2, a C5-C7 arylsulfonyl ArSO2, a C5-C7 aroylmethylene, a 5-7 member heteroaroylmethylene, a benzyl, a pyridinedimethylene, a C5-C7 aryl Ar or a 5-7 member heteroaryl; wherein, the linear or branched saturated or unsaturated C1-C6 hydrocarbyl is non-substituted or substituted by one or more substituents selected from a methylsulfonyl, a cyclopropyl, a hydroxy, a C1-C3 alkoxy, a C1-C3 alkoxycarbonyl, and an epoxypropyl; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N, the methylene of the heterocyclic group is non-substituted or substituted by carbonyl or sulfonyl, or the heterocyclic group is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a C1-C4 alkoxy carbonyl, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar; the aryl or the benzyl is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar; the heteroaryl contains 1-3 heteroatoms selected from O, S and N, is combined with a phenyl or a C5-C7 heteroaryl, or is substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar; R8 is selected from H, a linear or branched saturated or unsaturated C1-C6 hydrocarbyl, a C3-C7 cyclic hydrocarbyl; R9 and R10 are different, and each is independently selected form H,  a linear or branched saturated or unsaturated C1-C6 hydrocarbyl, a C3-C7 cyclic hydrocarbyl, a C4-C7 heterocyclic group, a C5-C7 aroylmethylene, a 5-7 member heteroaroylmethylene, a benzyl, a pyridinedimethylene, a C5-C7 aryl Ar or a 5-7 member heteroaryl; wherein the linear or branched saturated or unsaturated C1-C6 hydrocarbyl is non-substituted or substituted by one or more substituents selected from a methylsulfonyl, a cyclopropyl, a hydroxy, a C1-C3 alkoxy, a C1-C3 alkoxycarbonyl, and an epoxypropyl; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N, the methylene of the heterocyclic group is non-substituted or substituted by carbonyl or sulfonyl, or the heterocyclic group is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar; the aryl or the benzyl is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar; the heteroaryl contains 1-3 heteroatoms selected from O, S and N, is optionally combined with a phenyl or a C5-C7 heteroaryl, or is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar; P is an integer from 0 to 2; R11, R12 and R13 are identical or different, each of which is independently selected from H, a linear or branched saturated or unsaturated C1-C6 hydrocarbyl, a C3-C7 cyclic hydrocarbyl, a phenyl or a benzyl; wherein the phenyl or the benzyl is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, and a C1-C4 alkoxy;  is a 3-7 member nitrogen-containing heterocyclic group, the heterocyclic group further contains 1-3 heteroatoms selected from O, S and N, and the methylene of the heterocyclic group is non-substituted or substituted by carbonyl or sulfonyl, and the heterocyclic group is non-substituted or substituted by 1-5 substituents selected from H, a linear or branched C1-C6 hydrocarbyl, a halogen, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, an acylamino, a carboxylate group, C1-C4 alkoxy carbonyl, a mercapto, a C1-C4 alkoxy and hydroxamino; R3 is selected from NR14R15 or  wherein R14 and R15 are identical or different, and each of R14 and R15 is independently H, a linear or branched saturated or unsaturated C1-C6 hydrocarbyl and hydrocarboxyl, a C3-C7 cyclic hydrocarbyl, a C1-C6 hydrocarbyl amino, a C1-C6 hydrocarbyl amino hydroxy, a C1-C6 hydrocarbyl amidino, a C1-C6 hydrocarbyl guanidyl, a benzyl, a C5-C7 aryl Ar or a 5-7 member heteroaryl, and the heteroaryl contains 1-3 heteroatoms selected from O, S and N, is optionally combined with a phenyl or a C5-C7 heteroaryl, or is non-substituted or substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar;  is a 3-7 member nitrogen-containing heterocyclic group, and the heterocyclic group further contains 1-4 heteroatoms selected from O, S and N, and is non-substituted or substituted by 1-5 substituents selected from H, a linear or branched C1-C6 hydrocarbyl, a halogen, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, an acylamino, a carboxylate group, a C1-C4 alkoxy carbonyl, a mercapto, an amidino, a guanidyl and hydroxamino; R4, and R5 are identical or different, and each of R4 and R5 is independently H, a halogen, a linear or branched C1-C6 hydrocarbyl, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, a C1-C4 alkoxy, a mercapto, a C1-C4 acyl, a C1-C4 sulfonyl, a C1-C4 sulfonyl amino, an aminoacyl or a C1-C4 linear or branched alkyl non-substituted or substituted sulfonyl; the halogen is a fluoro, a chloro, a bromo or an iodo.
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