PATENT ABSTRACT
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.

PATENT DESCRIPTION
TECHNICAL FIELD 
     The invention relates to the field of pharmaceutical chemistry and pharmacotherapy, specially to thieno[3,2-d]pyrimidin-4-one compounds, preparation method thereof, a pharmaceutical composition containing such compound and use thereof. 
     BACKGROUND ART 
     Diabetes is a common metabolic disease. It is characterized by abnormally high plasma glucose concentration showed in the fasting state or during the oral glucose tolerance test and hyperglycemia. The World Health Organization divides diabetes into type 1 and type 2 according to the clinical forms, and most diabetes patients suffer from type 2 diabetes mellitus (T2DM). Type 2 diabetes mellitus, also known as non-insulin dependent diabetes mellitus, is accompanied by high vascular complications, such as coronary artery disease, stroke, high blood pressure, kidney disease, peripheral vascular disease, neurological disease and retinopathy. This metabolic disorder has become a public health problem. There are nearly 194 million diabetics in the world according to a survey from World Health Organization and will be increased to 366 million by 2030. Promoting insulin secretion from pancreatic β-cells is the primary means for treating T2DM, however, in addition to therapeutic effects, there would be some side effects, such as: low blood sugar, weight gain, cardiovascular morbid reaction and β-cell death and the like. 
     Studies have shown that the complications in T2DM patients will decrease by 35%, when glycosylated hemoglobin Alc (HbAlc) decreases by 1%. Therefore, how to reduce complications and adverse side effects has been a major theme for treating type 2 diabetes. The targets for treating diabetes validated clinically include peroxisome proliferators-activated receptors (PPAR)α/γ, glucagon like peptidase-1 (GLP-1), dipeptidyl peptidase IV (DPPIV, DPP4) and the like. The DPPIV inhibitors have been a new choice for treating type 2 diabetes, and are relatively safe and effective medicaments so far whether administered alone or in combination. 
     Dipeptidyl peptidase IV (DPPIV; also known as T-cell antigen CD26), is a serine protease with high specificity in the form of dimer. It contains two states, one of which is transmembrane protease, comprising 766 amino acids, widely distributed in the kidney, intestine villus-like wall, cell membrane, hepatocytes, vascular endothelium, T cells, B cells, and NK cells. The other exists in the plasma in the form of dissolved state. The most important enzyme action for DPPIV is hydrolyzing polypeptides which contain alanine or prolinechain in N-terminal of the peptide chain, such as hydrolyzing GLP-1. If the activities of DPPIV can be inhibited, the content of GLP-1 in vivo can be improved indirectly which can induce a series of physiological actions in vivo and achieve the purpose of the treatment of type 2 diabetes. 
     Currently, the most widely used medicaments in clinic are anti-type 2 diabetes medicaments associated with GLP-1, such as (a) GLP-1 analogues resistant to DPPIV; (2) small molecule GLP-1 receptor agonists; and (c) DPPIV inhibitors. As a new oral antidiabetic agent, DPPIV inhibitor can prevent the rapid degradation of incretin hormone and improve the postprandial GLP-1 level with little side effects and good effects. The recent studies have shown that DPPIV inhibitors can reduce the level of glycosylated hemoglobin Alc whether administered alone or in combination with other antidiabetic agents. Also, the risk of hypoglycemia is small so that DPPIV inhibitors have already attracted more and more attention from pharmaceutical firms. 
     The studies on DPPIV inhibitors have already made a great breakthrough. Now the medicaments in the market include sitagliptin from Merck, vildagliptin from Novartis, saxagliptin from Bristol-Myers Squibb, alogliptin from Takeda, linagliptin from Boehringer Ingelheim and the like. Since the serine proteinase also has other families, their selectivity problems should be firstly considered and other side effects should be avoided. Therefore, the study on the DPPIV inhibitors still has a great challenge. 
     SUMMARY OF THE INVENTION 
     One object of the present invention is to provide novel thieno[3,2-d]pyrimidin-4-one compounds with DPPIV inhibitory activity, the structure general formula of which is shown as the following formula (I). 
     Another object of the present invention is to provide a method for synthesizing the novel thieno[3,2-d]pyrimidin-4-one compounds by using 6,7-substituted 2,4-dimethoxy thienyl[3,2-d]pyrimidine as raw materials. 
     A further object of the present invention is to provide a pharmaceutical composition containing the thieno[3,2-d]pyrimidin-4-one compound. 
     A still further object of the present invention is to provide a use of thieno[3,2-d]pyrimidin-4-one compound in the preparation of a medicament for the treatment of diabetes. 
     The compounds according to the present invention can be used as the non-peptide small molecule inhibitor for DPPIV and can achieve the purpose of the treatment of type 2 diabetes by inhibiting the activity of 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 novel promising drugs for treating type 2 diabetes. 
     
       
                 
         
             
             
         
      
     
     wherein, 
     n is an integer from 1 to 3; 
     R 1  and R 2  are identical or different, and not hydrogen simultaneously, and each of R 1  and R 2  is independently H, a halogen, CBr 2 H, CCl 2 H, CF 2 H, a cyano, CF 3 , an aldehyde group, (CH 2 ) m OR 6 , (CH 2 ) m NR 6 R 7 , 
                                
(CH 2 ) m COOR 8 , CONR 9 R 10 , or
 
                                
wherein,
 
     R 1  and R 2  can be linked together to form C3-C6 alkylidene, but not necessarily; 
     m is an integer from 0 to 3; 
     R 6  and R 7  are identical or different, and each of R 6  and R 7  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 RSO 2 , a C5-C7 arylsulfonyl ArSO 2 , 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 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, but not necessarily; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N, the methylene of the heterocyclic group is substituted by carbonyl or sulfonyl, but not necessarily, or the heterocyclic group 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 C1-C4 alkoxy carbonyl, a mercapto, a C1-C4 acyl and a C5-C7 aryl Ar, but not necessarily; the aryl or the benzyl 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, but not necessarily; the heteroaryl contains 1-3 heteroatoms selected from O, S and N, is combined with a phenyl or a C5-C7 heteroaryl, but not necessarily, 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; 
     R 8  is selected from H, a linear or branched saturated or unsaturated C1-C6 hydrocarbyl, a C3-C7 cyclic hydrocarbyl; 
     R 9  and R 10  are identical or 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 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, but not necessarily; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N, the methylene of the heterocyclic group is substituted by carbonyl or sulfonyl, but not necessarily, or the heterocyclic group 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, but not necessarily; the aryl or the benzyl 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, but not necessarily; the heteroaryl contains 1-3 heteroatoms selected from O, S and N, is combined with a phenyl or a C5-C7 heteroaryl, but not necessarily, 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;
 
     P is an integer from 0 to 2; 
     R 11 , R 12  and R 13  are identical or different, each of which is independently selected form 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 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, but not necessarily; 
                                
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 substituted by carbonyl or sulfonyl, but not necessarily, and the heterocyclic group is 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, but not necessarily;
 
     R 3  is selected from NR 14 R 15  or 
                                
wherein R 14  and R 15  are identical or different, and each of R 14  and R 15  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 combined with a phenyl or a C5-C7 heteroaryl, but not necessarily, 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;
 
                                
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 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;
 
     R 4 , and R 5  are identical or different, and each of R 4  and R 5  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 substituted sulfonyl; 
     the halogen is a fluoro, a chloro, a bromo or an iodo. 
     One preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, enantiomer, diastereoisomer, racemate and mixtures thereof, or pharmaceutically acceptable salt thereof, wherein: 
     n is 1; 
     R 1  and R 2  are identical or different, and not hydrogen simultaneously, each of which is independently H, a halogen, CBr 2 H, CCl 2 H, CF 2 H, a cyano, CF 3 , an aldehyde group, (CH 2 ) m OR 6 , (CH 2 ) m NR 6 R 7 , 
                                
(CH 2 ) m COOR 8 , CONR 9 R 10 , or
 
                                
wherein,
 
     R 1  and R 2  can be linked together to form C3-C6 alkylidene, but not necessarily; 
     m is an integer from 0 to 3; 
     R 6  and R 7  are identical or different, and each of R 6  and R 7  is independently selected from H, a linear or branched C1-C6 alkyl, a C3-C7 cycloalkyl, a C1-C3 alkoxy, a 4-7 member heterocyclic group, a C1-C4 alkyloyl RCO, a C5-C7 aroyl ArCO, a C1-C4 alkylsulfonyl RSO 2 , a C5-C7 arylsulfonyl ArSO 2 , 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 C1-C6 alkyl is 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, but not necessarily; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N; the aryl or the benzyl is substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 alkyl, 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, but not necessarily; the heteroaryl contains 1-3 heteroatoms selected from O, S and N, is combined with a phenyl or a C5-C7 heteroaryl, but not necessarily, 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; 
     R 8  is selected from H, a linear or branched C1-C6 alkyl; 
     R 9  and R 10  are identical or different, each of which is independently selected form H, 
                                
a linear or branched C1-C6 alkyl, a C3-C7 cycloalkyl, a 4-7 member 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 C1-C6 alkyl is 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, but not necessarily; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N, and the methylene of the heterocyclic group is substituted by carbonyl or sulfonyl, but not necessarily, or the heterocyclic group is substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 alky, 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, but not necessarily; the aryl or the benzyl can be substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 alkyl, 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, but not necessarily, or is substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 alkyl, 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; 
     R 11 , R 12  and R 13  are identical or different, and each of R 11 , R 12  and R 13  is independently selected form H, a linear or branched C1-C6 alkyl, a C3-C7 cycloalkyl, a phenyl or a benzyl; the phenyl or the benzyl is substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 alky, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, and a C1-C4 alkoxy, but not necessarily; 
                                
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 substituted by carbonyl or sulfonyl, but not necessarily, and is 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, a C1-C4 alkoxy and hydroxamino, but not necessarily;
 
     R 3  is selected from NR 14 R 15  or 
                                
wherein R 14  and R 15  are identical or different, and each of R 14  and R 15  is independently H, a linear or branched C1-C6 alkyl and alkoxy, a C3-C7 cycloalkyl, a C1-C6 alkylamino, a C1-C6 alkylamino hydroxy, a C1-C6 alkyl amidino, a C1-C6 alkyl 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 combined with a phenyl or a C5-C7 heteroaryl, but not necessarily, or is substituted by one or more substituents selected from a halogen, a linear or branched C1-C6 alkyl, 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 substituted by 1-5 substituents selected from H, a linear or branched C1-C6 alkyl, 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;
 
     R 4 , and R 5  are identical or different, and each of R 4  and R 5  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 substituted sulfonyl; 
     the halogen is a fluoro, a chloro, a bromo or an iodo. 
     One preferable embodiment of formula (1) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, diastereoisomer, racemate and mixtures thereof, or pharmaceutically acceptable salt thereof, wherein: 
     n=1; 
     R 1  and R 2  are identical or different, and not hydrogen simultaneously, each of which is independently H, a halogen, CBr 2 H, CCl 2 H, CF 2 H, a cyano, CF 3 , an aldehyde group, (CH 2 ) m OR 6 , (CH 2 ) m NR 6 R 7 , 
                                
(CH 2 ) m COOR 8 , CONR 9 R 10 , or
 
                                
wherein,
 
     R 1  and R 2  can be linked together to form C3-C6 alkylidene, but not necessarily; 
     m is an integer from 0 to 3; 
     R 6  and R 7  are identical or different, and each of R 6  and R 7  is independently selected from H, a linear or branched C1-C3 alkyl, a C3-C5 cycloalkyl, a C1-C3 alkoxy, a 4-7 member heterocyclic group, a C1-C3 alkyloyl RCO, a C5-C7 aroyl ArCO, a C1-C3 alkylsulfonyl RSO 2 , a C5-C7 arylsulfonyl ArSO 2 , 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 C1-C3 alkyl is 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, but not necessarily; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N; the aryl or the benzyl is substituted by a substituent selected from a halogen, a linear or branched C1-C3 alkyl, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, and a trifluoromethoxy, but not necessarily; the heteroaryl contains 1-3 heteroatoms selected from O, S and N; 
     R 8  is selected from H, a linear or branched C1-C3 alkyl and C3-C5 cycloalkyl; 
     R 9  and R 10  are identical or different, each of which is independently selected form H, 
                                
a linear or branched C1-C5 alkyl, a C3-C7 cycloalkyl, a 4-7 member 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 C1-C3 alkyl is 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, but not necessarily; the heterocyclic group contains 1-3 heteroatoms selected from O, S and N, the methylene of the heterocyclic group is substituted by carbonyl or sulfonyl, but not necessarily, or the heterocyclic group is substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 alky, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, and a trifluoromethoxy, but not necessarily; the aryl or the benzyl can be substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 alky, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, and a trifluoromethoxy; the heteroaryl contains 1-3 heteroatoms selected from O, S and N;
 
     P is an integer from 0 to 2; 
     R 11 , R 12  and R 13  are identical or different, and each of R 11 , R 12  and R 13  is independently selected form H, a linear or branched C1-C3 alkyl, a C3-C7 cyclic hydrocarbyl, a phenyl or a benzyl; the phenyl or the benzyl is substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 alky, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, and a trifluoromethoxy, but not necessarily; 
                                
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 substituted by carbonyl or sulfonyl, but not necessarily, and is substituted by 1-2 substituents selected from H, a linear or branched C1-C3 alkyl, a halogen, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a C1-C4 alkoxy carbonyl, and a C1-C4 alkoxy, but not necessarily;
 
     R 3  is selected from NR 14 R 15  or 
                                
wherein R 14  and R 15  are identical or different, and each of R 14  and R 15  is independently H, a linear or branched C1-C3 alkyl and alkoxy, a C3-C5 cycloalkyl, a C1-C3 alkylamino, a C1-C3 alkylamino hydroxy, a C1-C3 alkyl amidino, a C1-C3 alkyl 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 a 3-7 member nitrogen-containing heterocyclic group, and said heterocyclic group further contains 1-4 heteroatoms selected from O, S and N, and is substituted by 1-3 substituents selected from H, a linear or branched C1-C6 alkyl, 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;
 
     R 4 , and R 5  are identical or different, and each of R 4  and R 5  is independently H, a halogen, a linear or branched C1-C6 alkyl, 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 substituted sulfonyl; 
     the halogen is a fluoro, a chloro, a bromo or an iodo. 
     Still another preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: 
     R 3  is NR 10  (CH 2 ) k NH 2 , NR 10  (CH 2 ) k OH, NR 10  (CH 2 ) k NHCNHNH 2 , NR 10  (CH 2 ) k CNHNH 2  or NR 10  (CH 2 ) k NHOH; 
     Wherein, k is an integer from 0 to 4; 
     n, R 1 , R 2 , and R 4 -R 15  are defined as above. 
     A further preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: 
     R 3  is 
     
       
                 
         
             
             
         
      
     
     Wherein 
                                
is an aziridinyl, an azacyclobutyl, a pyrrolidinyl, a piperidyl, an azacycloheptyl, a morpholinyl, a piperazinyl, a homopiperazinyl, a thiomorpholinyl, a thiomorpholinyl with S on the cycle being substituted by sulfoxide or sulphone, an imidazolidinyl, a pyrazinyl or a hexahydropyrimidinyl, and is substituted by 1-3 substituents selected from H, a linear or branched C1-C3 alky, a halogen, a cyano, a nitro, an amino, a hydroxy, a hydroxymethyl, a trifluoromethyl, a trifluoromethoxy, a carboxyl, an acylamino, a carboxylate group, a mercapto, an amidino, a guanidyl and hydroxamino;
 
     n, R 1 , R 2 , and R 4 -R 15  are defined as above. 
     The fourth preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: 
     R 3  is 
                                
and is substituted by 1-3 substituents selected from H, a cyano, an amino, a hydroxy, a trifluoromethyl, an amidino, a guanidyl, a carboxylate group and hydroxamino;
 
     n, R 1 , R 2 , 
                                
and R 4 -R 15  are defined as above.
 
     The fourth preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: 
     n=1 
     R 1  and R 2  are identical or different, and not hydrogen simultaneously, each of R 1  and R 2  is independently H, a halogen, CBr 2 H, CCl 2 H, CF 2 H, a cyano, CF 3 , an aldehyde group, (CH 2 ) m OR 6 , (CH 2 ) m NR 6 R 7 , 
                                
(CH 2 ) m COOR 8 , CONR 9 R 10 , or
 
                                
wherein,
 
     m is an integer from 0 to 3; 
     R 6  and R 7  are identical or different, and each of R 6  and R 7  is independently selected from H, a linear or branched C1-C3 alkyl, a C3-C5 cycloalkyl, a C1-C3 alkoxy, a 4-6 member heterocyclic group, a C1-C3 alkyloyl RCO, a C5-C7 aroyl ArCO, a benzyl and a C5-C7 aryl Ar; the linear or branched C1-C3 alkyl is substituted by one or more substituents selected from a methylsulfonyl, a C1-C3 alkoxy, and a C1-C3 alkoxycarbonyl, but not necessarily; the heterocyclic group contains one heteroatom selected from O, S and N; 
     R 8  is selected from H, and a linear or branched C1-C3 alkyl; 
     R 9  and R 10  are identical or different, each of which is independently selected form H, 
                                
a linear or branched C1-C5 alkyl, a C3-C6 cycloalkyl, a 4-6 member 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 C1-C3 alkyl is 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, but not necessarily; the heterocyclic group contains 1-2 heteroatoms selected from O, S and N; the aryl or the benzyl can be substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 alky, a hydroxy, a hydroxymethyl, a trifluoromethyl and a trifluoromethoxy; the heteroaryl contains 1-2 heteroatoms selected from O, S and N;
 
     P is an integer from 0 to 2; 
     R 11 , R 12  and R 13  are identical or different, and each of R 11 , R 12  and R 13  is independently selected form H, a linear or branched C1-C3 alkyl, a phenyl or a benzyl; the phenyl or the benzyl is substituted by one or more substituents selected from a halogen, a linear or branched C1-C3 alky, and a hydroxyl, but not necessarily; 
                                
is an aziridinyl, an azacyclobutyl, a pyrrolidinyl, a piperidyl, an azacycloheptyl, a morpholinyl, a piperazinyl, a homopiperazinyl, a thiomorpholinyl, a thiomorpholinyl with S on the cycle being substituted by sulfoxide or sulphone, an imidazolidinyl, a pyrazinyl, a hexahydropyrimidinyl or
 
                                
and is substituted by 1-2 substituents selected from H, a linear or branched C1-C3 alkyl, a halogen, a hydroxy, and a C1-C4 alkoxycarbonyl, but not necessarily;
 
     R 4  and R 5  are identical or different, and each of R 4  and R 5  is independently H, a halogen, a methyl, an ethyl, a cyano, a hydroxy, a carboxyl, a methoxyl, an ethoxyl or an aminoacyl; 
     the halogen is a fluoro, a chloro, a bromo or an iodo; 
     R 3  is defined as above. 
     The fourth preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: 
     n=1, 
     R 1  and R 2  are identical or different, and not hydrogen simultaneously, each of which is independently H, a halogen, (CH 2 ) m COOR 8 , CONR 9 R 10 , or 
                                
wherein,
 
     m is an integer from 0 to 3; 
     R 8  is selected from H, or a linear or branched C1-C3 alkyl; 
     R 9  and R 10  are identical or different, each of which is independently selected form H, a linear or branched C1-C3 alkyl, a C3-C6 cycloalkyl, a C4-C6 heterocyclic group, a phenyl or a 5-7 member heteroaryl; wherein the linear or branched C1-C3 alkyl is substituted by a C1-C3 alkoxycarbonyl, but not necessarily; the heterocyclic group contains one heteroatom selected from O, S and N; the heteroaryl contains one heteroatom selected from O, S and N; 
                                
is a pyrrolidinyl, a piperidyl, a morpholinyl, a piperazinyl, a homopiperazinyl, or a thiomorpholinyl, and is substituted by 1-2 substituents selected from H, a linear or branched C1-C3 alkyl, a halogen, a hydroxy, and a C1-C4 alkoxycarbonyl, but not necessarily;
 
     R 3  is a pyrrolidinyl, a piperidyl, a morpholinyl, a piperazinyl, a homopiperazinyl, or a thiomorpholinyl, and is substituted by a cyano, an amino or a hydroxyl; 
     R 4  and R 5  are identical or different, and each of R 4  and R 5  is independently H, a fluoro, a chloro, a bromo, a methyl, an ethyl, a cyano, or a hydroxyl. 
     Preferably, the fourth preferable embodiment of formula (I) compound according to the present invention is the following thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein: 
     R 1  and R 2  are identical or different, and not hydrogen simultaneously, each of which is independently H, a halogen, (CH 2 ) m COOR 8 , CONR 9 R 10 , or 
                                
wherein,
 
     m is 0; 
     R 8  is selected from H, or a linear or branched C1-C3 alkyl; 
     R 9  and R 10  are identical or different, each of which is independently selected form H, a linear or branched C1-C3 alkyl, a cyclopropyl, a tetrahydropyran-4-yl or pyridinyl; wherein the linear or branched C1-C3 alkyl is substituted by a C1-C3 alkoxycarbonyl, but not necessarily; 
                                
is a piperidyl, and is substituted by 1-2 substituents selected from H, a linear or branched C1-C3 alkyl, a halogen, a hydroxy, and a C1-C4 alkoxycarbonyl, but not necessarily;
 
     R 3  is a pyrrolidinyl, a piperidyl, a morpholinyl, or a piperazinyl, and is substituted by a cyano, an amino or a hydroxyl; 
     R 4  and R 5  are identical or different, and each of R 4  and R 5  is independently H, a fluoro, a chloro, a bromo, a methyl, an ethyl, a cyano, or a hydroxyl. 
     Specifically, the thieno[3,2-d]pyrimidin-4-one compound, enantiomer, diastereoisomer, racemate and mixtures thereof, and the pharmaceutically acceptable salt thereof according to the present invention is selected from one of the following compounds: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Designation 
                 Structure 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- fluoro-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   1 
               
               
                   
               
               
                 2 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- fluoro-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   2 
               
               
                   
               
               
                 3 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- bromo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   3 
               
               
                   
               
               
                 4 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- bromo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   4 
               
               
                   
               
               
                 5 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- iodo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   5 
               
               
                   
               
               
                 6 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- iodo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   6 
               
               
                   
               
               
                 7 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-7-(trifluoromethyl)thieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   7 
               
               
                   
               
               
                 8 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- chloro-4-oxothieno[3,2-d]pyrimidin-3 (4H)-yl)methyl)benzonitrile 
                                           
   8 
               
               
                   
               
               
                 9 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- chloro-4-oxothieno[3,2-d]pyrimidin-3- (4H)-yl)methyl)benzonitrile 
                                           
   9 
               
               
                   
               
               
                 10 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6,7- dichloro-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   10 
               
               
                   
               
               
                 11 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (methylamino)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   11 
               
               
                   
               
               
                 12 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (ethylamino)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   12 
               
               
                   
               
               
                 13 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-6-(phenylamino)thieno[3,2-d] pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   13 
               
               
                   
               
               
                 14 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (benzylamino)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   14 
               
               
                   
               
               
                 15 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- ((methylamino)methyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   15 
               
               
                   
               
               
                 16 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- ((dimethylamino)methyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   16 
               
               
                   
               
               
                 17 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- -((benzylamino)methyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   17 
               
               
                   
               
               
                 18 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (methylamino)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   18 
               
               
                   
               
               
                 19 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (ethylamino)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   19 
               
               
                   
               
               
                 20 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (benzylamino)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   20 
               
               
                   
               
               
                 21 
                 (R)-2-(3-aminopiperidin-1-yl)-7- bromo-3-(2-chlorobenzyl)thieno[3,2-d]- pyrimidin-4(3H)-one 
                                           
   21 
               
               
                   
               
               
                 22 
                 (R)-2-(3-aminopiperidin-1-y l)-7- bromo-3-(4-chlorobenzyl)thieno[3,2-d]- pyrimidin-4(3H)-one 
                                           
   22 
               
               
                   
               
               
                 23 
                 (R)-2-(3-aminopiperidin-1-yl)-7- bromo-3-(4-methoxybenzyl)thieno- [3,2-d]pyrimidin-4(3H)-one 
                                           
   23 
               
               
                   
               
               
                 24 
                 (R)-2-(3-aminopiperidin-1-yl)-7- bromo-3-(4-methylbenzyl)thieno- [3,2-d]pyrimidin-4(3H)-one 
                                           
   24 
               
               
                   
               
               
                 25 
                 2-((2-((2-aminoethyl)amino)-7-bromo- 4-oxothieno[3,2-d]pyrimidin-3(4H)- yl)methyl)benzonitrile 
                                           
   25 
               
               
                   
               
               
                 26 
                 (R)-2-((2-(3-aminopyrrolidin-1-yl)-7- bromo-4-oxothieno[3,2-d]pyrimidin-3- (4H)-yl)methyl)benzonitrile 
                                           
   26 
               
               
                   
               
               
                 27 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-6,7,8,9-tetrahydrobenzo[4,5]thieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   27 
               
               
                   
               
               
                 28 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (hydroxymethyl)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   28 
               
               
                   
               
               
                 29 
                 2-((7-bromo-2-((2-hydroxyethyl)- amino)-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   29 
               
               
                   
               
               
                 30 
                 2-((2-((2-aminoethyl)(methyl)amino)- 7-bromo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   30 
               
               
                   
               
               
                 31 
                 2-((2-((2-aminoethyl)(phenyl)amino)- 7-bromo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   31 
               
               
                   
               
               
                 32 
                 (R)-2-((2-(3-aminoazepan-1-yl)-7- bromo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   32 
               
               
                   
               
               
                 33 
                 (R)-ethyl 1-(7-bromo-3-(2-cyanobenzyl)-4-oxo- 3,4-dihydrothieno[3,2-d]pyrimidin-2- yl)piperidine-3-carboxylate 
                                           
   33 
               
               
                   
               
               
                 34 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- bromo-6-fluoro-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   34 
               
               
                   
               
               
                 35 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6,7- dibromo-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   35 
               
               
                   
               
               
                 36 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- chloro-6-fluoro-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   36 
               
               
                   
               
               
                 37 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6,7- difluoro-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   37 
               
               
                   
               
               
                 38 
                 (R)-methyl 2-(3-aminopiperidin-1- yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxylate 
                                           
   38 
               
               
                   
               
               
                 39 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidine-6-carboxylic acid hydrochloride 
                                           
   39 
               
               
                   
               
               
                 40 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-cyclopropyl-4-oxo- 3,4-dihydrothieno[3,2-d]pyrimidine- 6-carboxamide 
                                           
   40 
               
               
                   
               
               
                 41 
                 (R)-2-(3-aminopiperidin-1-yl)-N- benzyl-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   41 
               
               
                   
               
               
                 42 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-phenyl-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   42 
               
               
                   
               
               
                 43 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (hydroxymethyl)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   43 
               
               
                   
               
               
                 44 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidine-7-carboxylic acid hydrochloride 
                                           
   44 
               
               
                   
               
               
                 45 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidine-7-carboxamide 
                                           
   45 
               
               
                   
               
               
                 46 
                 (R)-2-(3 -aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-(pyridin-2- ylmethyl)-3,4-dihydrothieno[3,2-d]- pyrimidine-7-carboxamide 
                                           
   46 
               
               
                   
               
               
                 47 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-phenyl-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   47 
               
               
                   
               
               
                 48 
                 (R)-2-(3-aminopiperidin-1-yl)-N- benzyl-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   48 
               
               
                   
               
               
                 49 
                 (R)-3-((2-(3-aminopiperidin-1-yl)-4- oxo-7-(trifluoromethyl)thieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)-2- cyanobenzoic acid 
                                           
   49 
               
               
                   
               
               
                 50 
                 (R)-3-((2-(3-aminopiperidin-1-yl)-4- oxo-7-(trifluoromethyl)thieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)-2- cyanobenzamide 
                                           
   50 
               
               
                   
               
               
                 51 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-7-(trifluoromethyl)thieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)-5- hydroxybenzonitrile 
                                           
   51 
               
               
                   
               
               
                 52 
                 2-((4-oxo-2-(piperazin-1-yl)-7- (trifluoromethyl)thieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   52 
               
               
                   
               
               
                 53 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-4,6,7,8-tetrahydro-3H-cyclopenta- [4,5]thieno[3,2-d]pyrimidin-3-yl)- methyl)benzonitrile 
                                           
   53 
               
               
                   
               
               
                 54 
                 (R)-methyl 1-((2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidin-7-yl)- methyl)piperidine-4-carboxylate 
                                           
   54 
               
               
                   
               
               
                 55 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (morpholinomethyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   55 
               
               
                   
               
               
                 56 
                 (R)-(2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidin-7-yl)methyl acetate 
                                           
   56 
               
               
                   
               
               
                 57 
                 (R)-methyl 2-(3-aminopiperidin-1- yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxylate 
                                           
   57 
               
               
                   
               
               
                 58 
                 (R)-ethyl 2-(2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)acetate 
                                           
   58 
               
               
                   
               
               
                 59 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)-3-methylbutanoate 
                                           
   59 
               
               
                   
               
               
                 60 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(2-hydroxyethyl)-4- oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-7-carboxamide 
                                           
   60 
               
               
                   
               
               
                 61 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-methyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   61 
               
               
                   
               
               
                 62 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)-3-(4-hydroxyphenyl)- propanoate 
                                           
   62 
               
               
                   
               
               
                 63 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N,N-dimethyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   63 
               
               
                   
               
               
                 64 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(4-methylbenzyl)-4- oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-7-carboxamide 
                                           
   64 
               
               
                   
               
               
                 65 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-cyclopropyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   65 
               
               
                   
               
               
                 66 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)-2-phenylacetate 
                                           
   66 
               
               
                   
               
               
                 67 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzy l)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)-3-phenylpropanoate 
                                           
   67 
               
               
                   
               
               
                 68 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-(4- (trifluoromethyl)benzyl)-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   68 
               
               
                   
               
               
                 69 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (morpholine-4-carbonyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   69 
               
               
                   
               
               
                 70 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (4-methylpiperazine-1-carbonyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   70 
               
               
                   
               
               
                 71 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-ethyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   71 
               
               
                   
               
               
                 72 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-isopropyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   72 
               
               
                   
               
               
                 73 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(cyclopropylmethyl)- 4-oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-7-carboxamide 
                                           
   73 
               
               
                   
               
               
                 74 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(2-methoxyethyl)-4- oxo-3,4-dihydrothieno[3,2-d]pyrimidine- 7-carboxamide 
                                           
   74 
               
               
                   
               
               
                 75 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(3-methoxypropyl)-4- oxo-3,4-dihydrothieno[3,2-d]pyrimidine- 7-carboxamide 
                                           
   75 
               
               
                   
               
               
                 76 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-7-(pyrrolidine-1-carbonyl)thieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   76 
               
               
                   
               
               
                 77 
                 (R)-2-(3-aminopiperidln-1-yl)-N-butyl- 3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   77 
               
               
                   
               
               
                 78 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-isopentyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamlde 
                                           
   78 
               
               
                   
               
               
                 79 
                 (R)-2-(3-aminopiperidin-1-yl)-3 -(2- cyanobenzyl)-N-isobutyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   79 
               
               
                   
               
               
                 80 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-cyclohexyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   80 
               
               
                   
               
               
                 81 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-(tetrahydro-2H- pyran-4-yl)-3,4-dihydrothieno[3,2-d]- pyrimidine-7-carboxamide 
                                           
   81 
               
               
                   
               
               
                 82 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(oxetan-3-ylmethyl)-4- oxo-3,4-dihydrothieno[3,2-d]pyrimidine- 7-carboxamide 
                                           
   82 
               
               
                   
               
               
                 83 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidine-7-carbonitrile 
                                           
   83 
               
               
                   
               
               
                 84 
                 (R)-2-((7-amino-2-(3-aminopiperidin- 1-yl)-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitriIe 
                                           
   84 
               
               
                   
               
               
                 85 
                 (R)-N-(2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidin-7-yl) methanesulfonamide 
                                           
   85 
               
               
                   
               
               
                 86 
                 (R)-N-(2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidin-7-yl)acetamide 
                                           
   86 
               
               
                   
               
               
                 87 
                 2-((2-((R)-3-aminopiperidin-1-yl)-4- oxo-7-((((S)-tetrahydrofuran-3-yl)oxy) methyl)thieno[3,2-d]pyrimidin-3(4H)- yl)methyl)benzonitrile 
                                           
   87 
               
               
                   
               
               
                 88 
                 (R)-ethyl 3-(2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)propanoate 
                                           
   88 
               
               
                   
               
               
                 89 
                 (R)-ethyl 4-(2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamido)butanoate 
                                           
   89 
               
               
                   
               
               
                 90 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(2-(methylsulfonyl)- ethyl)-4-oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-7-carboxamide 
                                           
   90 
               
               
                   
               
               
                 91 
                 (S)-methyl 1-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-7- carbonyl)pyrrolidine-2-carboxylate 
                                           
   91 
               
               
                   
               
               
                 92 
                 2-((R)-3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-((S)-2- oxotetrahydrofuran-3-yl)-3,4- dihydrothieno[3,2-d]pyrimidine-7- carboxamide 
                                           
   92 
               
               
                   
               
               
                 93 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(3-hydroxypropyl)-4- oxo-3,4-dihydrothieno[3,2-d]pyrimidine- 7-carboxamide 
                                           
   93 
               
               
                   
               
               
                 94 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- ((benzyloxy)methyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   94 
               
               
                   
               
               
                 95 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (morpholinomethyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)- yl)methyl)benzonitrile 
                                           
   95 
               
               
                   
               
               
                 96 
                 (R)-(2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidin-6-yl)methyl acetate 
                                           
   96 
               
               
                   
               
               
                 97 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidine-6-carboxamide 
                                           
   97 
               
               
                   
               
               
                 98 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (dibromomethyl)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   98 
               
               
                   
               
               
                 99 
                 (R)-methyl 2-(2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamido)acetate 
                                           
   99 
               
               
                   
               
               
                 100 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamido)-3-methylbutanoate 
                                           
   100 
               
               
                   
               
               
                 101 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamido)-3-(4-hydroxyphenyl)- propanoate 
                                           
   101 
               
               
                   
               
               
                 102 
                 (S)-methyl 2-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamido)-3-phenylpropanoate 
                                           
   102 
               
               
                   
               
               
                 103 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-(4- (trifluoromethyl)benzyl)-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   103 
               
               
                   
               
               
                 104 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-methyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   104 
               
               
                   
               
               
                 105 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N,N-dimethyl-4-oxo- 3,4-dihydrothieno[3,2-d]pyrimidine- 6-carboxamide 
                                           
   105 
               
               
                   
               
               
                 106 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(cyclopropylmethyl)-4- oxo-3,4-dihydrothieno[3,2-d]pyrimidine- 6-carboxamide 
                                           
   106 
               
               
                   
               
               
                 107 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-6-(pyrrolidine-1-carbonyl)thieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   107 
               
               
                   
               
               
                 108 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-6-(piperidine-1-carbonyl)thieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   108 
               
               
                   
               
               
                 109 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(2-fluorobenzyl)-4-oxo- 3,4-dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   109 
               
               
                   
               
               
                 110 
                 (R)-2-(3-aminopiperidin-1-yl)-N-(2- chlorobenzyl)-3-(2-cyanobenzyl)-4-oxo- 3,4-dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   110 
               
               
                   
               
               
                 111 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(2-methoxyethyl)-4- oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-6-carboxamide 
                                           
   111 
               
               
                   
               
               
                 112 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(3-methoxypropyl)-4- oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-6-carboxamide 
                                           
   112 
               
               
                   
               
               
                 113 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-ethyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   113 
               
               
                   
               
               
                 114 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(1,1- dioxidothiomorpholine-4-carbonyl)- 4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   114 
               
               
                   
               
               
                 115 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-isopropyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   115 
               
               
                   
               
               
                 116 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-isobutyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   116 
               
               
                   
               
               
                 117 
                 (R)-2-(3-aminopiperidin-1-yl)-N-butyl- 3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   117 
               
               
                   
               
               
                 118 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (morpholine-4-carbonyl)-4-oxothieno- [3,2-d]pyrimidin-3(4H)-yl)methyl)- benzonitrile 
                                           
   118 
               
               
                   
               
               
                 119 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-cyclohexyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   119 
               
               
                   
               
               
                 120 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-(3- (trifluoromethyl)benzyl)-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   120 
               
               
                   
               
               
                 121 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-isopentyl-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   121 
               
               
                   
               
               
                 122 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(4-methylbenzyl)-4- oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-6-carboxamide 
                                           
   122 
               
               
                   
               
               
                 123 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobcnzyl)-N-(2-hydroxyethyl)-4- oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-6-carboxamide 
                                           
   123 
               
               
                   
               
               
                 124 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(4- (hydroxymethyl)piperidine-1-carbonyl)- 4-oxothieno[3,2-d]pyrimidin-3(4H)- yl)methyl)benzonitrile 
                                           
   124 
               
               
                   
               
               
                 125 
                 (S)-methyl 1-(2-((R)-3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carbonyl)pyrrolidine-2-carboxylate 
                                           
   125 
               
               
                   
               
               
                 126 
                 (R)-2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-N-(2-(methylsulfonyl)- ethyl)-4-oxo-3,4-dihydrothieno[3,2-d]- pyrimidine-6-carboxamide 
                                           
   126 
               
               
                   
               
               
                 126 
                 2-((R)-3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-N-((S)-2- oxotetrahydrofuran-3-yl)-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamide 
                                           
   127 
               
               
                   
               
               
                 128 
                 2-((2-((R)-3-aminopiperidin-1-yl)-6- ((S)-2-(hydroxymethyl)pyrrolidine-1- carbonyl)-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   128 
               
               
                   
               
               
                 129 
                 (R)-ethyl 1-(2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carbonyl)piperidine-4-carboxylate 
                                           
   129 
               
               
                   
               
               
                 130 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (((2-(methylsulfonyl)ethyl)amino)- methyl)-4-oxothieno[3,2-d]pyrimidin- 3(4H)-yl)methyl)benzonitrile 
                                           
   130 
               
               
                   
               
               
                 131 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- ((2-methoxyethoxy)methyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   131 
               
               
                   
               
               
                 132 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- ((cyclopropylamino)methyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   132 
               
               
                   
               
               
                 133 
                 (R)-N-(2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidin-7-yl)-4- methylbenzenesulfonamide 
                                           
   133 
               
               
                   
               
               
                 134 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-4- oxo-6-((2-oxo-2-phenylethyl)amino)- thieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   134 
               
               
                   
               
               
                 135 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6- (difluoromethyl)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   135 
               
               
                   
               
               
                 136 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-7- (difluoromethyl)-4-oxothieno[3,2-d]- pyrimidin-3(4H)-yl)methyl)benzonitrile 
                                           
   136 
               
               
                   
               
               
                 137 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(3,3- difluoroazetidine-1-carbonyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   137 
               
               
                   
               
               
                 138 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(3,3- difluoropyrrolidine-1-carbonyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   138 
               
               
                   
               
               
                 139 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(4,4- difluoropiperidine-1-carbonyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   139 
               
               
                   
               
               
                 140 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(3,3- difluoropiperidine-1 -carbonyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)-yl)- methyl)benzonitrile 
                                           
   140 
               
               
                   
               
               
                 141 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(4- fluoropiperidine-1-carbonyl)-4-oxothieno [3,2-d]pyrimidin-3(4H)-yl)methyl) benzonitrile 
                                           
   141 
               
               
                   
               
               
                 142 
                 (R)-2-((2-(3-aminopiperidin-1-yl)-6-(3- fluoroazetidine-1-carbonyl)-4- oxothieno[3,2-d]pyrimidin-3(4H)- yl)methyl)benzonitrile 
                                           
   142 
               
               
                   
               
               
                 143 
                 (R)-ethyl 3-(2-(3-aminopiperidin- 1-yl)-3-(2-cyanobenzyl)-4-oxo-3,4- dihydrothieno[3,2-d]pyrimidine-6- carboxamido)propanoate 
                                           
   143 
               
               
                   
               
               
                 144 
                 (R)-ethyl 4-(2-(3-aminopiperidin-1-yl)-3-(2- cyanobenzyl)-4-oxo-3,4-dihydrothieno- [3,2-d]pyrimidine-6-carboxamido)- butanoate 
                                           
   144 
               
               
                   
               
             
          
         
       
     
     According to another object of the present invention, the present invention provides a method for preparing the thieno[3,2-d]pyrimidin-4-one compound, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 4  and R 5  are defined as above, specifically, 
     
       
                 
         
             
             
         
      
     
     wherein, a thieno[3,2-d]pyrimidin-4-one compound having the structure formula F, an enantiomer, a diastereoisomer, a racemate and mixtures thereof, or a pharmaceutically acceptable salt thereof is synthesized by using 2,4-dimethoxythienyl[3,2-d]pyrimidine, 7-bromo-2,4-dimethoxythienyl[3,2-d]pyrimidine and 7-methyl-2,4-dimethoxythienyl[3,2-d]pyrimidine as raw material, and performing substitution, chlorination, hydrolysis, benzyl substitution and amino substitution on 6,7-position. 
     Synthesis strategy is shown in the following reaction route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Specific synthesis steps are listed as follows: 
     1) Synthesis of 6,7-substituted-thieno[3,2-d]pyrimidin-2,4-dione compound B1, B2 and B3 
     2,4-dimethoxythieno[3,2-d]pyrimidine, 7-bromo-2,4-dimethoxythieno[3,2-d]pyrimidine or 7-methyl-2,4-dimethoxythieno[3,2-d]pyrimidine is dissolved in tetrahydrofuran, substituted tetrahydrofuran or diethyl ether and stirred for 15-30 minutes at −78° C., and then 1-3 equivalents of 2.5 M n-butyl lithium solution in n-hexane is added dropwise and stirred for another 1-2 hours at −78° C., and then a substituent reagent to be added (F reagent, iodine reagent, boric acid reagent, N,N-dimethyl-formamide reagent and the like) is added dropwise. Upon addition, the reaction mixture is stirred for another 15-30 minutes and then 1 hour at room temperature. Afterwards, the reaction solution is poured into saturated NH 4 Cl solution, and extracted by organic solvent, and then 6,7-substituted-2,4-dimethoxythieno[3,2-d]pyrimidine compound A1, A2 or A3 is obtained by column chromatography; 
     6,7-substituted-2,4-dimethoxythieno[3,2-d]pyrimidine compound A1, A2 or A3 is dissolved in organic acid and 4 equivalents of iodide is added. After stirred for 1-5 hours at reflux, the reaction solution is poured into ice water and stirred for 30 minutes, a large amount of solids are precipitated. The solids are filtered by suction, washed with water and dried, thereby obtaining the product 6,7-substituted-thieno[3,2-d]pyrimidin-2,4-dione compound B1 or B2; 
     Specific synthesis strategy is listed as follows: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     2) Synthesis of 6,7-substituted-2,4-dichlorothieno[3,2-d]pyrimidine compound C 
     6,7-substituted-thieno[3,2-d]pyrimidin-2,4-dione compound B1, B2 or B3 is dissolved in phosphorus oxychloride. After refluxed for 2-18 hours, the reaction solution is poured into ice water and stirred for 30 minutes, and then a large amount of solids are precipitated. The solids are filtered by suction, washed with water and dried, thereby obtaining the product 6,7-substituted-2,4-dichlorothieno[3,2-d]pyrimidine compound C; 
     Synthesis Strategy is Listed as Follows: 
     
       
                 
         
             
             
         
      
     
     3) Synthesis of 6,7-substituted-2-chlorothieno[3,2-d]pyrimidin-4-one compound D 
     6,7-substituted-2,4-dichlorothieno[3,2-d]pyrimidine compound C is dissolved in organic solvent, an appropriate amount of aqueous alkali solution is added under nitrogen and stirred for 2-18 hours at room temperature. The organic solvent is evaporated from the reaction solution and an acid is added to adjust pH to neutral with stirring, and then a large amount of solids are precipitated. The solids are filtered by suction, washed with water and dried, thereby obtaining the product 6,7-substituted-2-chlorothieno[3,2-d]pyrimidin-4-one compound D; 
     Specific synthesis strategy is listed as follows: 
     
       
                 
         
             
             
         
      
     
     4) Synthesis of 6,7-substituted-3-substituted benzyl-2-chlorothieno[3,2-d]pyrimidin-4-one compound E 
     6,7-substituted-2-chlorothieno[3,2-d]pyrimidin-4-one compound D is dissolved in the mixture of glycol dimethyl ether and DMF, 60% of NaH is added at −10˜5° C., then anhydrous lithium bromide is added and then substituted benzyl bromide or benzyl chloride is added and reacted for 4-18 hours at 40-100° C. After cooled, an appropriate amount of water is added, and a large amount of solids are precipitated. The solids are filtered by suction, washed with water and dried, thereby obtaining the product 6,7-substituted-3-substituted benzyl-2-chlorothieno[3,2-d]pyrimidin-4-one compound E; 
     Specific synthesis strategy is listed as follows: 
     
       
                 
         
             
             
         
      
     
     5) Synthesis of 6,7-substituted-3-substituted benzyl-2-substituted aminothieno[3,2-d]pyrimidin-4-one compound F 
     6,7-substituted-3-substituted benzyl-2-chlorothieno[3,2-d]pyrimidin-4-one compound E is dissolved in organic solvent and 1-4 equivalents of alkali is added, and then 
                                
is added and reacted for 1-16 hours at 60-130° C. The reaction solution is exacted, and 6,7-substituted-3-substituted benzyl-2-substituted aminothieno[3,2-d]pyrimidin-4-one compound F is obtained by column chromatography;
 
     Specific synthesis strategy is listed as follows: 
     
       
                 
         
             
             
         
      
     
     In the above preparation methods, the acid used in each step can be organic acid or inorganic acid, the organic acid can be acetic acid, trifluoroacetic acid, or formic acid, the inorganic acid can be hydrochloric acid, sulfuric acid or phosphoric acid; the alkali can be inorganic alkali or organic alkali, the inorganic alkali is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, sodium hydroxide, lithium hydroxide and potassium hydroxide, the organic alkali is selected from triethylamine, pyridine, diazabicyclo (DBU) and N,N-diisopropylethylamine (DIPEA); the organic solvent in step 3) and step 5) can be selected from THF (tetrahydrofunan), acetonitrile, acetone, 1,4-dioxane, alcohols, diethyl ether, N,N-dimethylformamide, glycol dimethyl ether, N,N-dimethylformamide and dimethyl sulfoxide; the F reagent in step 1) can be DAST (diethylaminosulphur trifluoride), the iodine reagent can be iodine or NIS (N-iodosuccinimide); and the boric acid reagent can be triethyl borate. 
     Another aspect of the present invention relates to a pharmaceutical composition for treating diabetes, and the pharmaceutical composition contains the thenyl[3,2-d]pyrimidin-4-one compound of formula (I), or a pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier, and can be used in treatment in vivo and has biocompatibility. The pharmaceutical composition can be prepared into various forms based on different administration routes. The pharmaceutical composition according to the present invention can be used to treat diabetes. 
     The pharmaceutical composition provided in the present invention can be in various forms, such as tablet, capsule, granule, syrup, solution, suspension, aerosol, and the like, and can be present in suitable solid or liquid carrier or diluent and suitable sterilized means for injection or drip. The pharmaceutical composition can also contain odorant, fragrance agent, etc., and the ideal proportion thereof is that formula (I) compound as active ingredient is more than 65% by total weight and the rest is 0.5-40%, or preferably 1-20%, or the most preferably 1-10% of pharmaceutically acceptable carrier, diluent or solution or salt solution by total weight. 
     Structure formula (I) compound described above can be clinically used in mammal including human and animal, and administrated through mouth, nose, skin, lungs, or gastrointestinal tract, preferably through mouth. Preferably, daily dose is 0.01-200 mg/kg body weight with one-time use, or 0.01-100 mg/kg body weight in divided dose. No matter what kind of administration route, the best dose for individual should be determined based on specific treatment. Usually, the most suitable dose is determined by gradually increasing dose from small dose. 
     Formula (I) compound can achieve the purpose of the treatment of type 2 diabetes by inhibiting the activity of DPPIV, indirectly increasing the content of GLP-1 in vivo and inducing a series of physiological actions in vivo. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
         FIG. 1-FIG .  6  show the DPP IV activity in plasma of the ICR mouse after administrated once according to the embodiments of the present invention. 
         FIG. 7-FIG .  10  show oral glucose tolerance curve and the area under the curve after administrated once according to the embodiments of the present invention. 
         FIG. 11-FIG .  12  show oral glucose tolerance curve and the area under the curve after DC291009 was administrated once with multiple doses according to the embodiments of the present invention. 
         FIG. 13  shows the plasma concentration-time curve of metabolite M1 after DC291407 was administrated to the rats by gavage and by intravenous injection according to the embodiments of the present invention, wherein A is the plasma concentration-time curve of metabolite M1 after 20 mg/kg of DC291407 was administrated to the rats by gavage, and B is the plasma concentration-time curve of metabolite M1 after 10 mg/kg of DC291407 was administrated to the rats by intravenous injection. 
     
    
    
     DETAILED DESCRIPTION 
     The present invention will be further illustrated in the following examples. These examples are intended to illustrate the invention, but not limit the invention in any way. All parameters of the examples as well as the rest of the description are described based on the weight unless otherwise indicated. 
     The analysis data for the samples were determined by the following apparatuses, wherein the nuclear magnetic resonance data were determined on GEMINI-300, Bruker AMX-400 or INVOA-600 Nuclear Magnetic Resonance Spectrometer by using TMS (tetramethylsilane) as internal standard, wherein the unit of chemical shift was ppm and that of coupling constant was Hz; and the mass spectrometric data were determined on Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometer or IonSpec 4.7 Tesla mass spectrometer. 
     200-300 mesh of silica gels (Qindao Haiyang Chemical Co.) was used in the column chromatography. TLC silica gel plate was HSGF-254 thin layer chromatography prefabricated plate produced by Yantai Chemical Co. The boiling range of petroleum ether is 60-90° C. The UV light was used and iodine was used to develop the color. The normal reagents and medicaments used in the examples were purchased from CHINA National Medicines Co., LTD unless otherwise stated. The reagents and solvents used in the experiments were determined based on the specific reaction. 
     Example 1 
     Synthesis of Compound 1 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Synthesis of Compound 1-2 
     Compound 1-1 (2 g, 10.2 mmol) was dissolved in 50 ml THF and stirred for 15 minutes at −78□ under nitrogen. 6.1 ml 2.5 M (15.3 mmol) of n-butyllithium in n-hexane was added dropwise and stirred for 1 hour at −78□. NFSI (N-fluorobenzenesulfonimide, 6.42 g, 20.4 mmol) solution in THF (10 ml) was added dropwise, stirred for 15 minutes at −78□ and then stirred for 30 minutes at room temperature. 50 ml of saturated ammonium chloride solution was added. The extraction was performed by using ethyl acetate. 1.56 g of white solid was obtained by column chromatography. 
     The white solid was dissolved in 40 ml glacial acetic acid, and NaI (4.3 g, 29 mmol) was added. The reaction was carried out for 2 hours at 80 □. The reaction solution was poured into ice water and stirred for 30 minutes. A large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 1-2 (1.34 g) in 71% yield. MS: 187.0[M+H] + . 
     Synthesis of Compound 1-3 
     Compound 1-2 (1.34 g, 7.2 mmol) was dissolved in 20 ml phosphorus oxychloride and refluxed overnight. The reaction solution was poured into 200 ml ice water and stirred for 30 minutes. A large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 1-3 (1.12 g) in 69.7% yield. MS: 224.9[M+H]+. 
     Synthesis of Compound 1-4 
     Compound 1-3 (1.12 g, 5.0 mmol) was dissolved in 20 ml THF. 25 ml of 1M sodium hydroxide solution was added and stirred under nitrogen overnight. THF was removed by evaporation and pH value was adjusted to 7 by adding 1M hydrochloric acid solution. A large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 1-4 (0.97 g) in 95% yield. MS:MS: 206.9[M+H] + . 
     Synthesis of Compound 1-5 
     Compound 1-4 (0.97 g, 4.75 mmol) was dissolved in 40 ml the mixture of DME and DMF (2:1, v/v). At 0 □,60% of NaH (0.247 g, 6.18 mmol) was added and stirred for 30 minutes. 1 g of anhydrous lithium bromide was added and stirred for 15 minutes at room temperature. And then 1 g of 2-cyanobenzyl bromide was added and the reaction was carried out at 70□ overnight. 100 ml of water was added and a large amount of solids were precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 1-5 (1.37 g) in 90% yield. MS: 322.0[M+H]+. 
     Synthesis of Compound 1-6 
     Compound 1-5 (1.37 g, 4.3 mmol) was dissolved in 1,4-dioxane, and (R)-3Boc aminopiperidine (0.946 g, 4.73 mmol) was added. 1.5 ml of DIPEA (N,N-diisopropyl ethylamine) (0.946 g, 4.73 mmol) was added and stirred for 1 hour at 120□. The extraction was carried out by using ethyl acetate and then the solvent was removed by rotary evaporation. Compound 1-6 (1.87 g) was obtained by column chromatography in 90% yield. MS: 322.0[M+H]+. 
     Synthesis of Compound 1 
     Compound 1-6 (1.87 g, 3.87 mmol) was dissolved in 40 ml of DCM. 15 ml of TFA was added and stirred for 4 hours at room temperature. The solvent was removed by rotary evaporation and the residue was dissolved in 50 ml ethyl acetate. The mixture was washed with saturated potassium carbonate solution, and then washed with saturated sodium chloride solution. The solvent was removed by rotary evaporation and then Compound 1 (1.32 g) was obtained by column chromatography (DCM: CH 3 OH=5: 1) in 90% yield. MS: 384.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.20(1H, d, J=8.2), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 2 
     Synthesis of Compound 2 
     
       
                 
         
             
             
         
      
     
     Compound 2 was synthesized according to the synthesis method in Example 1, wherein compound 2-1 was used instead of compound 1-1 in Example 1. MS: 384.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.75(1H, d, J=8.2). 
     Example 3 
     Synthesis of Compound 3 
     
       
                 
         
             
             
         
      
     
     Compound 3 was synthesized according to the synthesis method in Example 1, wherein NBS (N-bromosuccinimide) was used instead of NFSI used in the synthesis of compound 1-2 in example 1. MS: 446.0[M+H] + .  1 H-NMR (400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.14(1H, s), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 4 
     Synthesis of Compound 4 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Synthesis of 4-2 
     Compound 4-1 (4 g) and urea (10 g) were loaded into 100 ml eggplant-shaped flask and mixed uniformly. The mixture was heated to 180° C. for 4 hours and 100 ml of water was added. A large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 4-2 (3.5 g) in 81.7% yield. MS: 169.0[M+H] + . 
     Synthesis of 4-3 
     3.5 g of compound 4-2 was dissolved in 60 ml glacial acetic acid. 6.66 g of bromine was added and refluxed for 24 hours. The reaction solution was poured into ice water and a large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 4-3 (4.1 g) in 80% yield. MS: 248.9[M+H] + . 
     Compound 4 was synthesized from compound 4-4 according to the synthesis method in Example 1. MS: 446.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.68(1H, s). 
     Example 5 
     Synthesis of Compound 5 
     
       
                 
         
             
             
         
      
     
     Compound 5 was synthesized according to the synthesis method in Example 1, wherein iodine was used instead of NFSI used in the synthesis of compound 1-2 in example 1. MS: 492.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25 (1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.16(1H, s), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 6 
     Synthesis of Compound 6 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Synthesis of 6-2 
     Compound 1-1 (2 g, 10.2 mmol) was dissolved in 100 ml CCl 4 . Bis(trifluoroacetoxy)iodobenzene (5.2 g, 12.2 mmol) and iodine (5.7 g, 22.4 mmol) were added and stirred at room temperature overnight. The solvent was removed by rotary evaporation and compound 7-2 (1.2 g) was obtained by column chromatography in 36.7% yield. MS: 322.9 [M+H] + . 
     Compound 6 was synthesized from compound 6-3 according to Example 1. MS: 492.0 [M+H + ].  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.69(1H, s). 
     Example 7 
     Synthesis of Compound 7 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Synthesis of 7-2 
     Compound 7-1 (2 g, 10.2 mmol) was dissolved in 100 ml CCl 4 . Bis(trifluoroacetoxy)iodobenzene (5.2 g, 12.2 mmol) and iodine (5.7 g, 22.4 mmol) were added and stirred at room temperature overnight. The solvent was removed by rotary evaporation and compound 7-2 (1.2 g) was obtained by column chromatography in 36.7% yield. MS: 322.9 [M+H] + . 
     Synthesis of 7-3 
     Compound 7-2 (1.2 g, 3.72 mmol) was dissolved in the mixture of NMP and DMF (25 ml, 1:1). 10% of CuI, 10% of phenanthroline and KF (0.42 g, 0.745 mmol) were added. The reaction was carried out at 60° C. for 24 hours. Compound 7-3 (0.68 g) was obtained by extraction and column chromatography in 69% yield. MS: 265.0[M+H] + . 
     Compound 7 was synthesized from compound 7-4 according to the synthesis method in Example 1. MS: 434.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): 31.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.76(1H, s). 
     Example 8 
     Synthesis of Compound 8 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Synthesis of 8-2 
     Compound 8-2 was synthesized according to the synthesis of compound 4-2. 
     Synthesis of 8-3 
     Compound 8-2 (10 g, 59.5 mmol) was added into 30 ml mixture of sulfuric acid and nitric acid (1:1) at 0° C. The reaction was carried out at 0□ for 30 minutes and stirred at room temperature for 2 hours. The reaction solution was poured into ice water and stirred for 30 minutes. A large amount of solids was precipitated. The solids were filtered by suction, washed with water and dried, thereby obtaining the product 8-3 (6.8 g) in 53.6% yield. MS: 213.9[M+H] + . 
     Synthesis of 8-4 
     Compound 8-3 (6.8 g, 31.9 mmol) was dissolved in 40 ml phenyl phosphorylcholine and reacted at 180° C. for 4 hours. The reaction solution was poured into ice water and stirred for 30 minutes. A large amount of solids was precipitated. The solids were filtered by suction, and the product 8-4 (3 g) was obtained in 39.3% yield by column chromatography. MS: 238.9[M+H] + . 
     Compound 8 was synthesized from compound 8-5 according to the synthesis method in Example 1. MS: 400.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.15(1H, s), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 9 
     Synthesis of Compound 9 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Compound 9 was synthesized according to the synthesis of compound 8. MS: 400.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.68(1H, s). 
     Example 10 
     Synthesis of Compound 10 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Compound 10 was synthesized according to the synthesis of compound 8. MS: 434.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 11 
     Synthesis of Compound 11 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Synthesis of Compound 11-2 
     Compound 11-1 (1 g, 4.9 mmol) was dissolved in 30 ml absolute methanol. 4 equivalents of NaOMe was added and refluxed for 2 hours. When the reaction was completed, 30 ml of water was added and a large amount of solids was precipitated. Compound 11-2 was obtained by sunction filtration in 99% yield. MS: 197.1[M+H] + . 
     Compound 11-3 was synthesized according to the synthesis of compound 1-2, wherein iodomethane was used instead of replace NFSI. 
     Compound 11-7 was synthesized according to the synthesis of compound 1-5. 
     Synthesis of Compound 11-8 
     Compound 11-7 (500 mg, 1.6 mmol) was dissolved in 20 ml CCl 4 . 1.5 equivalent of NBS (N-bromosuccinimide) and catalytic amount of benzoyl peroxide were added and refluxed overnight. When the reaction was completed, extraction was performed using dichloromethane. After washed with water, compound 11-8 (250 mg) was obtained by column chromatography in 40% yield. MS: 393.9[M+H] + . 
     Synthesis of Compound 11-9 
     Above compound 11-8 was dissolved in acetonitrile. 2 eq of sodium acetate and catalytic amount of 18-crown ether were added and refluxed for 5 hours. After extracted by ethyl acetate, washed with water, and isolated by column chromatography, a white solid (compound 11-9, 170 mg) was obtained in 72% yield. MS: 374.1[M+H] + . 
     Synthesis of Compound 11-10 
     Refer to the synthesis of compound 1-6. 
     Synthesis of Compound 11-11 
     Compound 11-10 (200 mg 0.372 mmol) was dissolved in methanol. 2 equivalents of 10% aqueous sodium hydroxide solution was added and stirred for 10 minutes. After extracted with ethyl acetate and evaporated to dryness, a foam-like solid 11-11 (180 mg) was obtained in 98% yield. MS: 496.2[M+H] + . 
     Synthesis of Compound 11-12 
     Compound 11-11 (180 mg) was dissolved in 20 ml of acetone and 2.5 equivalents of 2.7 M Jones reagent was added dropwise in ice-bath. Upon the addition, the mixture was stirred at room temperature for 1 hour. After extracted with ethyl acetate, washed with water and evaporated to dryness, a foam-like solid (compound 11-12, 166 mg) was obtained in 90% yield. MS: 510.2 [M+H] + . 
     Synthesis of Compound 11-13 
     Compound 11-12 (166 mg) was dissolved in 20 ml of toluene. 1.5 equivalents of diphenylphosphoryl azide was added and refluxed for 1 hour. 5 ml of water was added and refluxed for another 1 hour. After extracted with ethyl acetate, and isolated by column chromatography, compound 11-13 (109 mg) was obtained in 70% yield. MS: 481.2[M+H] + . 
     Synthesis of Compound 11-14 
     Compound 11-13 (109 mg) was dissolved in 5 ml of DMF. 1.5 equivalents of iodomethane and 2 equivalents of cesium carbonate was added and stirred overnight at room temperature. After extracted with ethyl acetate, washed with water and evaporated to dryness, compound 11-14 (96 mg) was obtained in 85% yield. MS: 495.2[M+H] + . 
     Compound 11 was synthesized according to the synthesis of compound 1. MS: 395.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.73(3H, s), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 6.50(1H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 12 
     Synthesis of Compound 12 
     
       
                 
         
             
             
         
      
     
     Compound 12 was synthesized according to the synthesis of compound 11, wherein iodoethane was used instead of iodomethane. MS: 409.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.14(3H, t), 1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.75(2H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 6.50(1H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 13 
     Synthesis of Compound 13 
     
       
                 
         
             
             
         
      
     
     Compound 13 was synthesized according to the synthesis of compound 11, wherein iodobenzene was used instead of iodomethane, and a catalytic amount of Pd 2  (dba) 3  (tris(dibenzylideneacetone)dipalladium), Xantphos (4,5-bis(diphenylphosphino)-9,9-di-methylxanthene) and 2 equivalents of CsCO 3  were added in to the reaction solution. MS: 457.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 6.60(1H, s), 7.03(9H, m). 
     Example 14 
     Synthesis of Compound 14 
     
       
                 
         
             
             
         
      
     
     Compound 14 was synthesized according to the synthesis of compound 11, wherein benzyl bromide was used instead of iodomethane. MS: 470.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 4.98(2H, s), 5.52(2H, s), 6.60(1H, s), 7.03(9H, m). 
     Example 15 
     Synthesis of Compound 15 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Synthesis of Compound 15-1 
     Compound 11-11 (200 mg) was dissolved in tetrahydrofuran. 1.1 equivalents of methylsulfonyl chloride and 1.2 equivalents of triethylamine were added and stirred at room temperature for 30 minutes. 2 M methylamine solution in tetrahydrofuran was added and stirred at room temperature for 4 hours. After extracted by ethyl acetate, washed with water and isolated by the column chromatography, compound 15-1 (164 mg) was obtained in 80% yield. MS: 509.2 [M+H] + . 
     Compound 15 was synthesized according to the synthesis of compound 1 in Example 1. MS: 409.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.78(3H, s), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 3.52(2H, s), 5.52(2H, s), 6.50(1H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 16 
     Synthesis of Compound 16 
     
       
                 
         
             
             
         
      
     
     Compound 16 was synthesized according to the synthesis method of compound 15, wherein dimethylamine hydrochloride was used instead of methylamine solution in tetrahydrofuran. MS: 423.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.78(6H, s), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 3.52(2H, s), 5.52(2H, s), 6.50(1H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 17 
     Synthesis of Compound 17 
     
       
                 
         
             
             
         
      
     
     Compound 17 was synthesized according to the synthesis method of compound 15, wherein benzylamine was used instead of methylamine solution in tetrahydrofuran. MS: 485.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 3.52(2H, s), 4.98(2H, s), 5.52(2H, s), 6.60(1H, s), 7.03(9H, m). 
     Example 18 
     Synthesis of Compound 18 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 18 was synthesized according to the synthesis method in Example 11. MS: 395.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.73(3H, s), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.15(1H, s), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 19 
     Synthesis of Compound 19 
     
       
                 
         
             
             
         
      
     
     Compound 19 was synthesized according to the synthesis method in Example 18. MS: 409.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.14(3H, t), 1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.70(2H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.15(1H, s), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 20 
     Synthesis of Compound 20 
     
       
                 
         
             
             
         
      
     
     Compound 20 was synthesized according to the synthesis method in Example 18. MS: 470.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 4.98(2H, s), 5.52(2H, s), 7.13(10H, m). 
     Example 21 
     Synthesis of Compound 21 
     
       
                 
         
             
             
         
      
     
     Compound 21 was synthesized according to the synthesis method of compound 4, wherein o-chlorobenzyl bromide was used instead of o-cyanobenzyl bromide. MS: 455.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.13(1H, d, J=5.6), 7.21(1H, t, J=5.6), 7.36(1H, t, J=5.6), 7.52(1H, d, J=4.8), 7.68(1H, s). 
     Example 22 
     Synthesis of Compound 22 
     
       
                 
         
             
             
         
      
     
     Compound 22 was synthesized according to the synthesis method of compound 4, wherein p-chlorobenzyl bromide was used instead of o-cyanobenzyl bromide. MS: 455.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.3(4H, m), 7.70(1H, s). 
     Example 23 
     Synthesis of Compound 23 
     
       
                 
         
             
             
         
      
     
     Compound 23 was synthesized according to the synthesis method of compound 4, wherein p-methoxybenzyl bromide was used instead of o-cyanobenzyl bromide. MS: 451.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 3.62(3H, s), 5.52(2H, s), 6.8(2H, d, J=3.6), 7.2(2H, d, J=3.6), 7.70(1H, s). 
     Example 24 
     Synthesis of Compound 24 
     
       
                 
         
             
             
         
      
     
     Compound 24 was synthesized according to the synthesis method of compound 4, wherein p-methylbenzyl bromide was used instead of o-cyanobenzyl bromide. MS: 435.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.34(3H, s), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.1(4H, m), 7.80(1H, s). 
     Example 25 
     Synthesis of Compound 25 
     
       
                 
         
             
             
         
      
     
     Compound 25 was synthesized according to the synthesis method of compound 4, wherein 2-Boc aminoethylamine was used instead of R-3Boc aminopiperidine. MS: 406.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ2.76(2H, t), 3.1(2H, t), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.68(1H, s). 
     Example 26 
     Synthesis of Compound 26 
     
       
                 
         
             
             
         
      
     
     Compound 26 was synthesized according to the synthesis method of compound 4, wherein R-3Boc aminopyrrolidine was used instead of R-3Boc aminopiperidine. MS: 432.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.69(1H, m), 1.94(1H, m), 2.52(1H, m), 2.65(1H, m), 2.75(2H, m), 3.1(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2), 7.68(1H, s). 
     Example 27 
     Synthesis of Compound 27 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
     
     Compound 27-1 was used to replace compound 4-1 in Example 4, and compounds 27-2, 27-3, 27-4, 27-5, 27-6 and 27 were synthesized according to the synthesis methods of compounds 4-2, 4-4, 4-5, 4-6, 4-7, and 4, respectively, thereby obtaining compound 27. MS: 420.1[M+H] + .  1 H-NMR(400 MHz, CDCl 3 ): δ 7.69-7.60 (m, 2H), 7.52-7.31 (m, 2H), 5.56-5.52 (m, 1H), 5.44-5.40 (m, 1H), 3.35-3.25 (m, 3H), 3.02-2.85 (m, 5H), 2.74-2.68 (m, 3H), 2.21 (t, J=7.6 Hz, 1H), 2.02-1.97 (m, 2H), 1.64-1.58 (m, 3H). 
     Example 28 
     Synthesis of Compound 28 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 28 was synthesized from compound 11-11 according to the synthesis of compound 1 from the reaction of compound 1-6. MS: 396.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 3.89(2H, s), 5.52(2H, s), 6.50(1H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 29 
     Synthesis of Compound 29 
     
       
                 
         
             
             
         
      
     
     Compound 29 was synthesized according to the synthesis method of compound 4, wherein 2-aminoethanol was used instead of R-3Boc aminopiperidine. MS: 406.9[M+H] + . 
     Example 30 
     Synthesis of Compound 30 
     
       
                 
         
             
             
         
      
     
     Compound 30 was synthesized according to the synthesis method of compound 4, wherein N 1 -methyl-N 2 —BOC ethylenediamine was used instead of R-3Boc aminopiperidine. MS: 420.0[M+H] + . 
     Example 31 
     Synthesis of Compound 31 
     
       
                 
         
             
             
         
      
     
     Compound 31 was synthesized according to the synthesis method of compound 4, wherein [(2-aminophenyl)ethyl]-carbamic acid tert-butyl ester was used instead of R-3Boc aminopiperidine. MS: 482.0[M+H] + . 
     Example 32 
     Synthesis of Compound 32 
     
       
                 
         
             
             
         
      
     
     Compound 32 was synthesized according to the synthesis method of compound 4, wherein R-3-Boc amino-cycloheptylamine was used instead of R-3Boc aminopiperidine. MS: 460.0[M+H] + . 
     Example 33 
     Synthesis of Compound 33 
     
       
                 
         
             
             
         
      
     
     Compound 33 was synthesized according to the synthesis method of compound 4, wherein ethyl 3-piperidinecarboxylate was used instead of R-3Boc aminopiperidine. MS: 503.0[M+H] + . 
     Example 34 
     Synthesis of Compound 34 
     
       
                 
         
             
             
         
      
     
     Compound 34 was synthesized according to the synthesis method of compound 1, wherein compound 34-2 was used instead of compound 1-2. MS: 464.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.52(2H, s), 7.03(1H, d, J=8), 7.31(1H, t, J=8), 7.46(1H, t, J=8), 7.62(1H, d, J=7.2). 
     Example 35 
     Synthesis of Compound 35 
     
       
                 
         
             
             
         
      
     
     Compound 35 was synthesized according to the synthesis method of compound 1, wherein compound 35-2 was used instead of compound 1-2. MS: 523.9[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.59(2H, s), 7.08(1H, d, J=8), 7.36(1H, t, J=8), 7.42(1H, t, J=8), 7.67(1H, d, J=7.2). 
     Example 36 
     Synthesis of Compound 36 
     
       
                 
         
             
             
         
      
     
     Compound 36 was synthesized according to the synthesis method of compound 1, wherein compound 36-2 was used instead of compound 1-2. MS: 418.0[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.59(2H, s), 7.04(1H, d, J=8), 7.33(1H, t, J=8), 7.40(1H, t, J=8), 7.61(1H, d, J=7.2). 
     Example 37 
     Synthesis of Compound 37 
     
       
                 
         
             
             
         
      
     
     Compound 37 was synthesized according to the synthesis method of compound 1, wherein compound 37-2 was used instead of compound 1-2. MS: 402.1[M+H] + .  1 H-NMR(400 Hz, CDCl 3 ): δ1.25(1H, m), 1.67(1H, m), 1.76(1H, m), 1.96(1H, m), 2.67(1H, m), 2.88(2H, m), 3.21(1H, m), 3.39(1H, m), 5.59(2H, s), 7.07(1H, d, J=8), 7.35(1H, t, J=8), 7.42(1H, t, J=8), 7.65(1H, d, J=7.2). 
     Example 38 
     Synthesis of Compound 38 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Synthesis of 38-1 
     Compound 11-12 (100 mg) was dissolved in DMF. 1.5 equivalents of iodomethane and 2 equivalents of CsCO 3  were added and stirred at room temperature for 1 hour. After extracted by ethyl acetate, washed with water, and evaporated to dryness, crude compound 38-1 (100 mg) was obtained. 
     Compound 38 was synthesized according to the synthesis method of compound 1.  1 H-NMR (CDCl 3 -d 3 ): δ=7.761(s, 1H), 7.610(d, 1H), 7.493(t, 1H), 7.320(t, 1H), 7180(d,1H), 5.500(quartet, 2H), 3.895(s,3H), 3.680(d,2H), 3.355(m,1H), 3.010(m,2H), 2.150(m, 1H), 1.894(m,2H), 1.644(m, 1H); LC-MS m/z 424.1 [M+H] + . 
     Example 39 
     Synthesis of Compound 39 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Compound 11-12 (100 mg, 0.237 mmol) was dissolved in 20 ml HCl in diethyl ether and stirred at room temperature for 1 hour. After evaporated to dryness, compound 39 (70 mg) was obtained in 80% yield. MS: 410.1[M+H] + . 
     Example 40 
     Synthesis of Compound 40 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Compound 11-12 (100 mg) was dissolved in 10 ml DCM. 1.5 equivalents of cyclopropylamine, 2 equivalents of EDCI, 3.5 equivalents of HOBt and catalytic amount of DMAP were added and stirred overnight at room temperature. After extracted by dichloromethane and isolated by column chromatography, compound 40-1 (75 mg) was obtained in 70% yield. MS: 549.2[M+H] + . 
     Compound 40 was synthesized according to the last step of the synthesis of compound 1. MS: 449.2[M+H] + . 
     Example 41 
     Synthesis of Compound 41 
     
       
                 
         
             
             
         
      
     
     Compound 41 was synthesized according to the synthesis of compound 40, wherein benzylamine was used instead of cyclopropylamine used in the synthesis of compound 40. MS: 499.2 [M+H] + . 
     Example 42 
     Synthesis of Compound 42 
     
       
                 
         
             
             
         
      
     
     Compound 41 was synthesized according to the synthesis of compound 40, wherein phenylamine was used instead of cyclopropylamine used in the synthesis of compound 40. MS: 485.1[M+H] + . 
     Example 43 
     Synthesis of Compound 43 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 43 was obtained according to the synthesis of compound 28.  1 H NMR(CDCl 3 ): δ7.64(m, 2H), 7.52(t, J=7.6 HZ, 1H), 7.37(t, J=7.6 HZ, 1H), 7.23(m, 1H), 5.25-5.72(m, 2H), 4.72(m, 2H), 3.51(m, 2H), 3.31(m, 3H), 1.95(m, 2H), 1.75(m, 1H), 1.56(m, 1H); LC-MS m/z 396.1 [M+H] + . 
     Example 44 
     Synthesis of Compound 44 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 44 was synthesized according to the synthesis method of compound 39. MS: 410.1[M+H] + . 
     Example 45 
     Synthesis of Compound 45 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Synthesis of 45-1 
     Compound 18-10 (100 mg) was dissolved in 20 ml acetonitrile. 1.5 equivalents of di-tert-butyl dicarbonate, 1.5 equivalents of ammonium carbonate and 1.5 equivalents of pyridine were added and stirred overnight at room temperature. After extracted by ethyl acetate, washed with 1M hydrochloric acid, washed with water, evaporated to dryness and isolated by the column chromatography, a white foam-like solid 45-1 (80 mg) was obtained in 81% yield. MS: 509.1[M+H] + . 
     Compound 45 was synthesized according to the synthesis method of compound 1. MS: 409.1 [M+H] + . 
     Example 46 
     Synthesis of Compound 46 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 46 was obtained according to the synthesis method of compound 40, wherein pyridine 2-methyleneamine was used instead of cyclopropylamine used in the synthesis of compound 40. MS: 450.1[M+H] + . 
     Example 47 
     Synthesis of Compound 47 
     
       
                 
         
             
             
         
      
     
     Compound 47 was synthesized according to the synthesis of compound 46, wherein phenylamine was used instead of pyridine 2-methyleneamine used in the synthesis of compound 46. MS: 484.2[M+H] + . 
     Example 48 
     Synthesis of Compound 48 
     
       
                 
         
             
             
         
      
     
     Compound 48 was synthesized according to the synthesis of compound 46, wherein benzylamine was used instead of pyridine 2-methyleneamine used in the synthesis of compound 46. MS: 499.2[M+H] + . 
     Example 49 
     Synthesis of Compound 49 
     
       
                 
         
             
             
         
      
     
     Compound 49 was obtained according to the synthesis of compound 7, wherein 3-bromomethyl-2cyano benzoic acid was used instead of 2-bromomethyl benzonitrile used in the synthesis of compound 7. MS: 478.1[M+H] + . 
     Example 50 
     Synthesis of Compound 50 
     
       
                 
         
             
             
         
      
     
     Compound 50 was obtained according to the synthesis of compound 7, wherein 3-bromomethyl-2cyano benzamide was used instead of 2-bromomethyl benzonitrile used in the synthesis of compound 7. MS: 477.1[M+H] + . 
     Example 51 
     Synthesis of Compound 51 
     
       
                 
         
             
             
         
      
     
     Compound 51 was obtained according to the synthesis of compound 7, wherein 2-bromomethyl-5-hydroxy benzonitrile was used instead of 2-bromomethyl benzonitrile used in the synthesis of compound 7. MS: 450.1[M+H] + . 
     Example 52 
     Synthesis of Compound 52 
     
       
                 
         
             
             
         
      
     
     Compound 52 was obtained according to the synthesis of compound 7, wherein 4-Boc piperazine was used instead of R-3Boc aminopiperidinel used in the synthesis of compound 7. MS: 420.1 [M+H] + . 
     Example 53 
     Synthesis of Compound 53 
     
       
                 
         
             
             
         
      
     
     Compound 53 was synthesized according to the synthesis method of compound 27, wherein compound 53-2 was used instead of compound 27-2. MS: 406.2[M+H] + . 
     Example 54 
     Synthesis of Compound 54 
     
       
                 
         
             
             
         
      
     
     Compound 54 was obtained according to the synthesis of compound 18, wherein methyl piperidine-4-carboxylate was used instead of methylamine solution in tetrahydrofuran in the synthesis of compound 18. MS: 521.2[M+H] + . 
     Example 55 
     Synthesis of Compound 55 
     
       
                 
         
             
             
         
      
     
     Compound 55 was synthesized according to the synthesis of compound 18, wherein morpholine was used instead of methylamine solution in tetrahydrofuran in the synthesis of compound 18. MS: 465.2[M+H] + . 
     Example 56 
     Synthesis of Compound 56 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 56 was synthesized according to the synthesis of compound 1, after compound 18-8 was obtained. MS: 465.2[M+H] + . 
     Example 57 
     Synthesis of Compound 57 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 57 was synthesized according to the synthesis of compound 38. 1H NMR(CDCl3): δ 8.52(s, 1H), 7.65(dd, J=7.6 HZ, 1H), 7.50(m, 1H), 7.36(m, 1H), 7.18(d, J=8 HZ, 1H), 5.25-5.72(m, 2H), 3.91(s, 3H), 3.71(m, 1H), 3.60(m, 1H), 3.39(m, 2H), 3.22(m, 1H), 2.30(m, 1H), 2.00(m, 1H), 1.82(m, 1H), 1.57(m, 1H); LC-MS m/z 424.1 [M+H]+. 
     Example 58 
     Synthesis of Compound 58 
     
       
                 
         
             
             
         
      
     
     Compound 58 was synthesized according to the synthesis of compound 46, wherein ethyl glycine ester was used instead of pyridine 2-methyleneamine used in the synthesis of compound 46. 1H NMR(CDCl 3 ): δ 8.55(m, 1H), 7.60(m, 1H), 7.48(m, 1H), 7.32(m, 1H), 7.12(m, 1H), 5.43(m, 2H), 4.20(m, 4H), 3.20(m, 2H), 3.05(m, 1H), 2.87(m, 2H), 2.00(m, 1H), 1.76(m, 1H), 1.65(m, 1H), 1.35(m, 1H), 1.26(m, 3H); LC-MS m/z 495.2 [M+H] 30  . 
     Example 59 
     Synthesis of Compound 59 
     
       
                 
         
             
             
         
      
     
     Compound 59 was synthesized according to the synthesis of compound 58, wherein methyl valine ester was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 9.42(d, J=8.8 HZ, 1H), 8.61(s, 1H), 7.66(dd, J=7.6 HZ, 1H), 7.53(m, 1H), 7.37(m, 1H), 7.16(d, J=8 HZ, 1H), 5.55(m, 2H), 4.88(m, 1H), 3.76(s, 3H), 3.55(m, 1H), 3.25(m, 2H), 2.98(m, 2H), 2.05(m, 1H), 1.90(m, 1H), 1.66(m, 1H), 1.50(m, 1H), 1.01(m, 6H); LC-MS m/z 523.2 [M+H]+. 
     Example 60 
     Synthesis of Compound 60 
     
       
                 
         
             
             
         
      
     
     Compound 60 was synthesized according to the synthesis of compound 58, wherein ethanol amine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 8.57(m, 1H), 7.62(m, 1H), 7.51(m, 1H), 7.35(m, 1H), 7.17(m, 1H), 5.43(m, 2H), 3.75(m, 2H), 3.60(m, 2H), 3.3(m, 2H), 3.12(m, 2H), 2.80(m, 1H), 2.05(m, 1H), 1.72(m, 2H), 1.52(m, 1H); LC-MS m/z 453.2 [M+H]+. 
     Example 61 
     Synthesis of Compound 61 
     
       
                 
         
             
             
         
      
     
     Compound 61 was synthesized according to the synthesis of compound 58, wherein methylamine hydrochloride was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 8.56(m, 1H), 7.62(m, 1H), 7.51(m, 1H), 7.35(m, 1H), 7.17(m, 1H), 5.45(m, 2H), 3.48(m, 1H), 3.33(m, 1H), 3.19(m, 2H), 2.99(s, 3H), 2.86(m, 1H), 2.03(m, 1H), 1.86(m, 1H), 1.70(m, 1H), 1.491(m, 1H); LC-MS m/z 423.2 [M+H]+. 
     Example 62 
     Synthesis of Compound 62 
     
       
                 
         
             
             
         
      
     
     Compound 62 was synthesized according to the synthesis of compound 58, wherein methyl tyrosine ester was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 9.32(m, 1H), 8.57(m, 1H), 7.50(m, 2H), 7.31(m, 1H), 7.14(m, 1H), 6.75(m, 4H), 5.30(m, 3H), 3.73(m, 3H), 3.20(m, 6H), 2.86(m, 1H), 1.98(m, 1H), 1.65(m, 2H), 1.44(m, 1H); LC-MS m/z 587.2 [M+H]+. 
     Example 63 
     Synthesis of Compound 63 
     
       
                 
         
             
             
         
      
     
     Compound 63 was synthesized according to the synthesis of compound 58, wherein dimethylamine hydrochloride was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 437.2 [M+H]+. 
     Example 64 
     Synthesis of Compound 64 
     
       
                 
         
             
             
         
      
     
     Compound 64 was synthesized according to the synthesis of compound 58, wherein 4-methylbenzylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 9.19(m, 1H), 8.62(m, 1H), 7.63(m, 1H), 7.50(m, 1H), 7.30(m, 3H), 7.15(m, 3H), 5.49(s, 2H), 4.60(d, J=6.4 HZ, 2H), 3.02(m, 2H), 2.85(m, 1H), 2.55(m, 2H), 1.85(m, 1H), 1.65(m, 1H), 1.50(m, 1H), 1.33(m, 1H); LC-MS m/z 499.2 [M+H]+. 
     Example 65 
     Synthesis of Compound 65 
     
       
                 
         
             
             
         
      
     
     Compound 65 was synthesized according to the synthesis of compound 58, wherein cyclopropylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 449.2 [M+H]+. 
     Example 66 
     Synthesis of Compound 66 
     
       
                 
         
             
             
         
      
     
     Compound 66 was synthesized according to the synthesis of compound 58, wherein methyl 2-phenylglycine ester was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 9.85(d, J=6.6 HZ, 1H), 8.58(s, 1H), 7.64(d, J=7.8 HZ, 1H), 7.50(m, 3H), 7.35(m, 4H), 7.16(m, J=6.9 HZ, 1H), 5.54(m, 2H), 5.29(m, 1H), 3.76(s, 3H), 3.46(m, 1H), 3.20(m, 1H), 3.01(m, 1H), 2.85(m, 2H), 1.98(m, 1H), 1.81(m, 1H), 1.55(m, 2H); LC-MS m/z 557.2 [M+H]+. 
     Example 67 
     Synthesis of Compound 67 
     
       
                 
         
             
             
         
      
     
     Compound 67 was synthesized according to the synthesis of compound 58, wherein methyl phenylalanine ester was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 9.31(m, 1H), 8.62(m, 1H), 7.51(m, 2H), 7.29(m, 5H), 7.07(m, 2H), 5.46(m, 2H), 5.28(m, 1H), 3.79(m, 3H), 3.22(m, 4H), 3.02(m, 1H), 2.91(m, 2H), 1.92(m, 3H), 1.47(m, 1H); LC-MS m/z 571.2 [M+H]+. 
     Example 68 
     Synthesis of Compound 68 
     
       
                 
         
             
             
         
      
     
     Compound 68 was synthesized according to the synthesis of compound 58, wherein p-trifluoromethyl benzylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 9.31(m, 1H), 8.62(m, 1H), 7.51(m, 6H), 7.35(m, 1H), 7.14(m, 1H), 5.50(m, 2H), 4.75(m, 2H), 3.11(m, 2H), 2.90(m, 1H), 2.66(m, 2H), 1.85(m, 1H), 1.65(m, 1H), 1.55(m, 1H), 1.36(m, 1H); LC-MS m/z 567.2 [M+H]+. 
     Example 69 
     Synthesis of Compound 69 
     
       
                 
         
             
             
         
      
     
     Compound 69 was synthesized according to the synthesis of compound 58, wherein morpholine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 7.91(s, 1H), 7.62(d, J=7.6 HZ, 1H), 7.53(m, 1H), 7.35(m, 1H), 7.23(d, J=7.6 HZ, 1H), 5.50(m, 2H), 3.6(m, 11H), 3.07(m, 1H), 2.95(m, 1H), 2.10(m, 1H), 1.83(m, 2H), 1.61(m, 1H); LC-MS m/z 479.2 [M+H]+. 
     Example 70 
     Synthesis of Compound 70 
     
       
                 
         
             
             
         
      
     
     Compound 70 was synthesized according to the synthesis of compound 58, wherein 4-methylpiperazine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 7.96(s, 1H), 7.59(d, J=7.6 HZ, 1H), 7.51(m, 1H), 7.34(m, 1H), 7.24(d, J=8.0 HZ, 1H), 5.40(m, 2H), 3.30(m, 10H), 3.07(m, 2H), 2.82(m, 1H), 2.54(s, 3H), 2.02(m, 1H), 1.78(m, 2H), 1.62(m, 1H); LC-MS m/z 492.2 [M+H]+. 
     Example 71 
     Synthesis of Compound 71 
     
       
                 
         
             
             
         
      
     
     Compound 71 was synthesized according to the synthesis of compound 58, wherein ethylamine hydrochloride was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 437.2 [M+H] + . 
     Example 72 
     Synthesis of Compound 72 
     
       
                 
         
             
             
         
      
     
     Compound 72 was synthesized according to the synthesis of compound 58, wherein isopropylamine was used instead of ethyl glycine ester used in the synthesis of compound 58.MS: 451.2 [M+H] + . 
     Example 73 
     Synthesis of Compound 73 
     
       
                 
         
             
             
         
      
     
     Compound 73 was synthesized according to the synthesis of compound 58, wherein cyclopropylmethylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 463.2 [M+H] + . 
     Example 74 
     Synthesis of Compound 74 
     
       
                 
         
             
             
         
      
     
     Compound 74 was synthesized according to the synthesis of compound 58, wherein 2-methoxyl ethylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 467.2 [M+H] + . 
     Example 75 
     Synthesis of Compound 75 
     
       
                 
         
             
             
         
      
     
     Compound 75 was synthesized according to the synthesis of compound 58, wherein 3-methoxyl propylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 8.98(m, 1H), 8.60(m, 1H), 7.68(m, 1H), 7.55(m, 1H), 7.38(m, 1H), 7.16(m, 1H), 5.54(s, 2H), 3.52(m, 4H), 3.41(m, 1H), 3.34(m, 3H), 3.21(m, 1H), 3.12(m, 1H), 2.91(m, 1H), 2.78(m, 1H), 2.04(m, 1H), 1.85(m, 1H), 1.36(m, 1H); LC-MS m/z 481.2 [M+H]+. 
     Example 76 
     Synthesis of Compound 76 
     
       
                 
         
             
             
         
      
     
     Compound 76 was synthesized according to the synthesis of compound 58, wherein pyrrolidine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 463.2 [M+H] + . 
     Example 77 
     Synthesis of Compound 77 
     
       
                 
         
             
             
         
      
     
     Compound 77 was synthesized according to the synthesis of compound 58, wherein n-butylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 8.84(m, 1H), 8.60(m, 1H), 7.66(m, 1H), 7.53(m, 1H), 7.38(m, 1H), 7.16(m, 1H), 5.56(s, 2H), 3.50(m, 3H), 3.20(m, 2H), 2.92(m, 2H), 2.01(m, 2H), 1.63(m, 3H), 1.45(m, 3H), 0.96(m, 3H); LC-MS m/z 465.2 [M+H]+. 
     Example 78 
     Synthesis of Compound 78 
     
       
                 
         
             
             
         
      
     
     Compound 78 was synthesized according to the synthesis of compound 58, wherein isopentylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 8.85(m, 1H), 8.60(m, 1H), 7.66(m, 1H), 7.53(m, 1H), 7.38(m, 1H), 7.16(m, 1H), 5.55(m, 2H), 3.52(m, 2H), 3.35(m, 1H), 3.15(m, 2H), 2.91(m, 1H), 2.77(m, 1H), 2.01(m, 1H), 1.85(m, 1H), 1.71(m, 2H), 1.54(m, 2H), 1.40(m, 1H), 0.95(m, 614); LC-MS m/z 479.2 [M+H]+. 
     Example 79 
     Synthesis of Compound 79 
     
       
                 
         
             
             
         
      
     
     Compound 79 was synthesized according to the synthesis of compound 58, wherein iso-butylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 465.2 [M+H]+. 
     Example 80 
     Synthesis of Compound 80 
     
       
                 
         
             
             
         
      
     
     Compound 80 was synthesized according to the synthesis of compound 58, wherein cyclohexylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. 1H NMR(CDCl3): δ 8.82(d, J=8.1 HZ, 1H), 8.58(s, 1H), 7.66(d, J=7.5 HZ, 1H), 7.53(m, 1H), 7.38(m, 1H), 7.14(d, J=7.5 HZ, 1H), 5.55(m, 2H), 3.98(m, 1H), 3.40(m, 1H), 3.19(m, 2H), 2.91(m, 2H), 2.05(m, 4H), 1.75(m, 4H), 1.45(m, 3H), 1.25(m, 3H); LC-MS m/z 491.2 [M+H]+. 
     Example 81 
     Synthesis of Compound 81 
     
       
                 
         
             
             
         
      
     
     Compound 81 was synthesized according to the synthesis of compound 58, wherein 4-amino hexahydropyran was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 493.2 [M+H]+. 
     Example 82 
     Synthesis of Compound 82 
     
       
                 
         
             
             
         
      
     
     Compound 82 was synthesized according to the synthesis of compound 58, wherein 3-aminomethyl epoxypropane was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 479.2 [M+H] + . 
     Example 83 
     Synthesis of Compound 83 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Synthesis of compound 83-1 
     Compound 45-1 (100 mg) was dissolved in 8 ml of DMF. 1.2 equivalents of trichlorotriazine was added and stirred for 1 hour at room temperature. After extracted by ethyl acetate, washed with water, and evaporated to dryness, crude product 83-1 (95 mg) was obtained. 
     Compound 83 was synthesized according to the synthesis of compound I. MS: 391.1 [M+H]+. 
     Example 84 
     Synthesis of Compound 84 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 84 was synthesized according to the synthesis of compound 1, after compound 18-11 was obtained. MS: 381.1 [M+H]+. 
     Example 85 
     Synthesis of Compound 85 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Synthesis of Compound 85-1 
     Compound 18-11 (100 mg) was dissolved in tetrahydrofuran. 1.1 equivalents of methylsulfonyl chloride and 1.2 equivalents of triethylamine were added and stirred for 1 hour at room temperature. After extracted by ethyl acetate, washed with water, and evaporated to dryness, 95 mg of crude product 85-1 was obtained. 
     Compound 85 was synthesized according to the synthesis of compound 1. MS: 459.1 [M+H]+. 
     Example 86 
     Synthesis of Compound 86 
     
       
                 
         
             
             
         
      
     
     Compound 86 was synthesized according to the synthesis of compound 85, wherein acetyl chloride was used instead of methylsulfonyl chloride used in the synthesis of compound 85-1. MS: 423.2[M+H]+. 
     Example 87 
     Synthesis of Compound 87 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 87 was synthesized according to the synthesis of compound 15, wherein S-3-hydroxytetrahydrofuran was used instead of methylamine solution in tetrahydrofuran. MS: 466.2[M+H] + . 
     Example 88 
     Synthesis of Compound 88 
     
       
                 
         
             
             
         
      
     
     Compound 88 was synthesized according to the synthesis of compound 58, wherein ethyl alanine ester was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 509.2 [M+H] + . 
     Example 89 
     Synthesis of Compound 89 
     
       
                 
         
             
             
         
      
     
     Compound 89 was synthesized according to the synthesis of compound 58, wherein ethyl 4-amino butanoate was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 523.2 [M+H] + . 
     Example 90 
     Synthesis of Compound 90 
     
       
                 
         
             
             
         
      
     
     Compound 90 was synthesized according to the synthesis of compound 58, wherein 4-mesyl ethylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 515.2 [M+H] + . 
     Example 91 
     Synthesis of Compound 91 
     
       
                 
         
             
             
         
      
     
     Compound 91 was synthesized according to the synthesis of compound 58, wherein methyl proline ester was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 521.2 [M+H] + . 
     Example 92 
     Synthesis of Compound 92 
     
       
                 
         
             
             
         
      
     
     Compound 92 was synthesized according to the synthesis of compound 58, wherein S-2-carbonyl-4-aminotetrahydrofuran was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 493.2 [M+H]+. 
     Example 93 
     Synthesis of Compound 93 
     
       
                 
         
             
             
         
      
     
     Compound 93 was synthesized according to the synthesis of compound 58, wherein 3-hydroxypropylamine was used instead of ethyl glycine ester used in the synthesis of compound 58. MS: 467.2 [M+H]+. 
     Example 94 
     Synthesis of Compound 94 
     
       
                 
         
             
             
         
      
     
     Compound 94 was synthesized according to the synthesis of compound 15, wherein benzyl alcohol was used instead of methylamine solution in tetrahydrofuran used in the synthesis of compound 15-1. MS: 486.2[M+H]+. 
     Example 95 
     Synthesis of Compound 95 
     
       
                 
         
             
             
         
      
     
     Compound 95 was synthesized according to the synthesis of compound 15, wherein morpholine was used instead of methylamine solution in tetrahydrofuran used in the synthesis of compound 15-1. MS: 465.2[M+H]+. 
     Example 96 
     Synthesis of Compound 96 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 96 was synthesized according to the synthesis of compound 56. 1H-NMR (CDCl3-d3): δ=7.632(d, 1H), 7.482(t, 1H), 7.327(t, 1H), 7.167(s, 1H), 7.080(d,1H), 5.515 (quartet, 2H), 5.267(s,2H), 3.365(t,1H), 3.204(s,1H), 3.055(m,1H), 2.893(m, 1H), 2.357(m,1H), 2.108(s, 3H), 2.022(m,1H), 1.781(m,1H), 1.576(m,2H); LC-MS ink 438.2[M+H]+. 
     Example 97 
     Synthesis of Compound 97 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Compound 97 was synthesized according to the synthesis of compound 45. MS: 409.1[M+H] + . 
     Example 98 
     Synthesis of Compound 98 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Synthesis of compound 98-1 
     Compound 11-7 (1 g) was dissolved in CCl 4 . 2.5 equivalent of NBS (N-bromosuccinimide) and catalytic amount of benzoyl peroxide were added and refluxed overnight. After extracted by dichloromethane, washed with water, compound 98-1 (740 mg) was obtained by column chromatography in 51% yield. MS: 471.8[M+H]+. 
     Compound 98 was synthesized according to the synthesis of compound 1. 1H-NMR (CDCl3-d3): δ=7.603(m, 1H), 7.499(m, 1H), 7.369(s, 1H), 7.324(t, 1H), 7.184(d, 1H), 6.820(m, 1H), 5.485(quartet, 2H), 5.293(s, 1H), 3.594(m, 2H), 3.270(m, 1H), 3.022(m, 1H), 2.908(m,2H), 2.105(m, 1H), 1.825(m, 2H), 1.603(m, 1H); LC-MS m/z 538.0[M+H]+. 
     Example 99 
     Synthesis of Compound 99 
     
       
                 
         
             
             
         
      
     
     Compound 99 was obtained according to the synthesis of compound 40, wherein methyl glycine ester was used instead of cyclopropylamine used in the synthesis of compound 40. 1H-NMR(CDCl3-d3): δ=7.756(s, 1H), 7.630(d, 1H), 7.537(t, 1H), 7.368(t, 1H), 7.218(d, 1H), 5.442(quartet, 2H), 4.114(s, 2H), 3.730(s, 3H), 3.590(d, 1H), 3.493(d, 1H), 3.323(d, 1H), 3.180(m, 2H), 2.958(m, 1H), 2.096(s, 1H), 1.820(d, 1H), 1.690(d. 1H); LC-MS m/z 481.2[M+H]+. 
     Example 100 
     Synthesis of Compound 100 
     
       
                 
         
             
             
         
      
     
     Compound 100 was synthesized according to the synthesis of compound 99, wherein methyl valine ester was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.812(s, 1H), 7.540(d, 1H), 7.469(t, 1H), 7.277(t, 1H), 7.194(d, 1H), 5.450(quartet, 2H), 4.593(quartet, 1H), 3.723(s, 3H), 3.608(d, 1H), 3.344(d, 1H), 3.000(m, 2H), 2.280(m, 1H), 2.100(s, 1H), 1.880(d, 1H), 1.910(m, 1H); 1.797(s, 1H), 0.980(t, 6H), 0.900(d, 1H); LC-MS m/z 523.2 [M+H]+. 
     Example 101 
     Synthesis of Compound 101 
     
       
                 
         
             
             
         
      
     
     Compound 101 was synthesized according to the synthesis of compound 99, wherein methyl tyrosine ester was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.580(d, 1H), 7.548(s, 1H), 7.479(t, 1H), 7.315(t, 1H), 7.258(s, 1H), 7.153(d,1H), 6.940(d,2H), 6.710(d,2H), 5.400(quartet, 2H), 4.861(quartet, 1H), 3.711(s, 3H), 3.495(d, 1H), 3.410(s, 1H), 3.200(m, 2H), 3.100(m, 2H), 2.946(m,1H), 2.028(s,1H), 1.742(s,2H); 1.600(s, 1H); LC-MS m/z 587.2 [M+H]+. 
     Example 102 
     Synthesis of Compound 102 
     
       
                 
         
             
             
         
      
     
     Compound 102 was synthesized according to the synthesis of compound 99, wherein methyl phenylalanine ester was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.733(s, 1H), 7.540(d, 1H), 7.439(t, 1H), 7.214(m, 7H), 5.410(quartet, 2H), 4.930(quartet, 1H), 3.677(s, 3H), 3.620(d, 2H), 3.390(s, 1H), 3.210(m, 2H), 3.007(s, 1H), 2.941(s,1H), 2.071(s,1H), 1.947(s,1H); 1.771(s,1H), 1.538(s,1H); LC-MS m/z 571.2 [M+H]+. 
     Example 103 
     Synthesis of Compound 103 
     
       
                 
         
             
             
         
      
     
     Compound 103 was synthesized according to the synthesis of compound 99, wherein p-trifluoromethyl benzylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.792(s, 1H), 7.528(d, 1H), 7.445(m, 5H), 7.260(t, 1H), 7.154(d,1H), 5.354(quartet, 2H), 4.549(s, 2H), 3.518(s, 2H), 3.340(s. 1H), 3.014(s, 1H), 2.889(s, 1H), 2.009(s, 1H), 1.830(s, 1H), 1.717(s,1H), 1.532(s,1H); LC-MS m/z 567.2[M+H]+. 
     Example 104 
     Synthesis of Compound 104 
     
       
                 
         
             
             
         
      
     
     Compound 104 was synthesized according to the synthesis of compound 99, wherein methylamine hydrochloride was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.684(s, 1H), 7.625(d, 1H), 7.530(t, 1H), 7.363(t, 1H), 7.210(d, 1H), 5.440(quartet, 2H), 3.587(d, 1H), 3.471(m, 1H), 3.305(m, 1H), 3.177(m, 2H), 2.912(s,3H), 2.105(d, 1H), 1.789(m, 1H), 1.680(m,2H); LC-MS m/z 423.2[M+H]+. 
     Example 105 
     Synthesis of Compound 105 
     
       
                 
         
             
             
         
      
     
     Compound 105 was synthesized according to the synthesis of compound 99, wherein dimethylamine hydrochloride was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.600(d, 1H), 7.484(t, 1H), 7.403(s, 1H), 7.314(t, 1H), 7.161(d, 1H), 5.490(quartet, 2H), 3.538(d, 2H), 3.279(m, 1H), 3.140(d, 6H), 3.026(s,1H), 2.948(t,1H), 2.069(s, 1H), 1.850(s, 2H), 1.600(m,1H); LC-MS m/z 437.2[M+H]+. 
     Example 106 
     Synthesis of Compound 106 
     
       
                 
         
             
             
         
      
     
     Compound 106 was synthesized according to the synthesis of compound 99, wherein cyclopropylmethylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.710(s, 1H), 7.650(d, 1H), 7.535(t, 1H), 7.374(t, 1H), 7.170(d, 1H), 5.487(quartet, 2H), 3.450(d, 2H), 3.274(d, 2H), 3.160(s, 1H), 2.987(m,1H), 2.902(t,1H), 2.036(s, 1H), 1.794(s,1H), 1.667(m,1H), 1.553(d,1H), 1.084(s, 1H), 0.540(m,2H), 0.278(m,2H); LC-MS m/z 463.2[M+H]+. 
     Example 107 
     Synthesis of Compound 107 
     
       
                 
         
             
             
         
      
     
     Compound 107 was synthesized according to the synthesis of compound 99, wherein pyrrolidine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.620(d, 1H), 7.529(s, 1H), 7.492(t, 1H), 7.327(t, 1H), 7.121(d, 1H), 5.495(t, 2H), 3.740(t, 3H), 3.450(d, 1H), 3.264(m, 1H), 3.084(d,1H), 2.962(t,1H), 2.872(m,1H), 2.864(t, 1H), 1.970(m, 5H), 1.790(m,1H), 1.600(m,2H); LC-MS m/z 463.2[M+H]+. 
     Example 108 
     Synthesis of Compound 108 
     
       
                 
         
             
             
         
      
     
     Compound 108 was synthesized according to the synthesis of compound 99, wherein piperidine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.644(d, 1H), 7.504(t, 1H), 7.344(t, 1H), 7.310(s, 1H), 7.116(d, 1H), 5.523(quartet, 2H), 3.630(s, 4H), 3.390(d, 1H), 3.249(s, 1H), 3.088(d,1H), 2.940(m,2H), 2.013(m,1H), 1.824(s, 1H), 1.650(d, 8H); LC-MS m/z 477.2[M+H]+. 
     Example 109 
     Synthesis of Compound 109 
     
       
                 
         
             
             
         
      
     
     Compound 109 was synthesized according to the synthesis of compound 99, wherein 2-fluorobenzylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.632(s, 1H), 7.572(d, 1H), 7.453(t, 1H), 7.385(t, 1H), 7.298(t, 1H), 7.192(m,1H), 7.094(t,1H), 7.035(t,1H), 6.966(t,1H), 5.542(t, 2H), 4.595(d, 2H), 3.436(d, 1H), 3.253(s, 1H), 3.012(m, 2H), 2.815(d,1H), 1.991(s,1H), 1.719(s, 1H), 1.566(s, 2H); LC-MS m/z 517.2[M+H]+. 
     Example 110 
     Synthesis of Compound 110 
     
       
                 
         
             
             
         
      
     
     Compound 110 was synthesized according to the synthesis of compound 99, wherein 2-chlorobenzylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.666(s, 1H), 7.584(d, 1H), 7.440(m, 2H), 7.308(m, 2H), 7.179(m, 2H), 7.105(d,1H), 5.442(t, 2H), 4.635(d, 2H), 3.409(d, 1H), 3.203(s, 1H), 3.052(d, 1H), 2.928(t,1H), 2.824(t,1H), 1.967(s,1H), 1.717(s,1H), 1.532(m,2H); LC-MS m/z 533.1 [M+H]+. 
     Example 111 
     Synthesis of Compound 111 
     
       
                 
         
             
             
         
      
     
     Compound III was synthesized according to the synthesis of compound 99, wherein 2-methoxylethylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.590(d, 2H), 7.458(t, 1H), 7.303(t, 1H), 7.058(d, 1H), 5.421(s, 2H), 3.497(m,3H), 3.309(m, 5H), 3.040(m, 2H), 2.755(m, 2H), 1.927(m, 1H), 1.710(m, 1H), 1.589(m, 1H), 1.341(m, 1H); LC-MS m/z 467.2[M+H]+. 
     Example 112 
     Synthesis of Compound 112 
     
       
                 
         
             
             
         
      
     
     Compound 112 was synthesized according to the synthesis of compound 99, wherein 3-methoxylpropylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.695(d, 1H), 7.646(s, 1H), 7.568(t, 1H), 7.411(t, 1H), 7.178(d, 1H), 5.525 (s, 2H), 3.567(m, 5H), 3.406(m, 3H), 3.169(m, 2H), 2.903(m, 2H), 2.045(m, 1H), 1.918(m, 2H), 1.816(m, 1H), 1.699(m, 1H), 1.481(m, 1H); LC-MS m/z 481.2[M+H]+. 
     Example 113 
     Synthesis of Compound 113 
     
       
                 
         
             
             
         
      
     
     Compound 113 was synthesized according to the synthesis of compound 99, wherein ethylamine hydrochloride was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.697(t, 2H), 7.570(t, 1H), 7.568(t, 1H), 7.413(t, 1H), 7.175(d, 1H), 5.521(s, 2H), 3.416(m, 3H), 3.157(m, 2H), 2.889(m, 2H), 2.040(m, 1H), 1.811(m,1H), 1.682(m,1H), 1.445(m,1H), 1.270(s, 3H); LC-MS m/z 437.2 [M+H]+. 
     Example 114 
     Synthesis of Compound 114 
     
       
                 
         
             
             
         
      
     
     Compound 114 was synthesized according to the synthesis of compound 99, wherein 1,1-di-O-thiomorpholine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.664(d, 1H), 7.542(t, 1H), 7.422(s, 1H), 7.384(t, 1H), 7.172(d, 1H), 5.495 (t, 2H), 4.192(s,4H), 3.425(d, 1H), 3.079(m,5H), 2.903(m, 3H), 2.021(m,1H), 1.811(m,1H), 1.670(m,1H), 1.491(m,1H); LC-MS m/z 527.1 [M+H]+. 
     Example 115 
     Synthesis of Compound 115 
     
       
                 
         
             
             
         
      
     
     Compound 115 was synthesized according to the synthesis of compound 99, wherein isopropylamine was used instead of methyl glycine ester used in the synthesis of compound 99. MS: 451.2 [M+H]+. 
     Example 116 
     Synthesis of Compound 116 
     
       
                 
         
             
             
         
      
     
     Compound 116 was synthesized according to the synthesis of compound 99, wherein isobutylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.713(s, 1H), 7.555(d, 1H), 7.473(t, 1H), 7.296(t, 1H), 7.158(d,1H), 5.426(t, 2H), 3.576(d,1H), 3.482(s, 1H), 3.201(m,3H), 3.020(m, 1H), 2.854(m,1H), 2.82(m,1H), 1.905(m,1H), 1.762(s,2H), 1.583(s,1H), 0.915(d,6H); LC-MS m/z 465.2[M+H]+. 
     Example 117 
     Synthesis of Compound 117 
     
       
                 
         
             
             
         
      
     
     Compound 117 was synthesized according to the synthesis of compound 99, wherein n-butylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR (CDCl3-d3): δ=7.713(s, 1H), 7.564(d, 1H), 7.483(t, 1H), 7.307(t, 1H), 7.183(d, 1H), 5.434 (quartet, 2H), 3.577(m,2H), 3.373(m, 3H), 3.044(m,1H), 2.898(m, 1H), 2.092(s,1H), 1.833(d,2H), 1.587(m,3H), 1.354(m,2H), 0.881(t,3H); LC-MS m/z 465.2[M+H]+. 
     Example 118 
     Synthesis of Compound 118 
     
       
                 
         
             
             
         
      
     
     Compound 118 was synthesized according to the synthesis of compound 99, wherein morpholine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.620(d, 1H), 7.505(t, 1H), 7.368(s, 1H), 7.340(t, 1H), 7.172(d,1H), 5.498 (quartet, 2H), 3.721(s,8H), 3.486(m, 2H), 3.197(m,1H), 3.064(m, 1H), 2.954(m,1H), 2.058(m,1H), 1.821(m,2H), 1.616(m,1H); LC-MS m/z 479.2[M+H]+. 
     Example 119 
     Synthesis of Compound 119 
     
       
                 
         
             
             
         
      
     
     Compound 119 was synthesized according to the synthesis of compound 99, wherein cyclohexane was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.673(s, 1H), 7.568(d, 1H), 7.483(t, 1H), 7.304(t, 1H), 7.169(d,1H), 5.446 (quartet, 2H), 3.864(s,1H), 3.540(m, 2H), 3.261(m,1H), 3.026(s, 1H), 2.877(m,1H), 2.060(m,1H), 1.948(s,2H), 1.789(m,4H), 1.610(d,2H), 1.338(m,4H), 1.162(m,1H); LC-MS m/z 491.2 [M+H]+. 
     Example 120 
     Synthesis of Compound 120 
     
       
                 
         
             
             
         
      
     
     Compound 120 was synthesized according to the synthesis of compound 99, wherein 3-trifluoromethylbenzylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.693(s, 1H), 7.597(s, 1H), 7.520(d, 2H), 7.425(t, 2H), 7.332(t,1H), 7.284(d,1H), 7.140(d,2H), 5.368(m, 2H), 4.576(s,1H), 3.522(s,2H), 3.292(s, 1H), 2.987(s,1H), 2.853(s, 1H), 2.010(s,1H), 1.761(d,1H), 1.519(s,1H); LC-MS m/z 567.2[M+H]+. 
     Example 121 
     Synthesis of Compound 121 
     
       
                 
         
             
             
         
      
     
     Compound 121 was synthesized according to the synthesis of compound 99, wherein isopentylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.673(s, 1H), 7.572(d, 1H), 7.483(t, 1H), 7.310(t, 1H), 7.168(d,1H), 5.442 (quartet, 2H), 3.501(m,2H), 3.410(quartet, 2H), 3.219(s, 1H), 3.047(s, 1H), 2.872(s, 1H), 2.067(s, 1H), 1.773(s, 2H), 1.610(m, 2H), 1.500(quartet, 2H), 0.890(d, 6H); LC-MS m/z 479.2 [M+H]+. 
     Example 122 
     Synthesis of Compound 122 
     
       
                 
         
             
             
         
      
     
     Compound 122 was synthesized according to the synthesis of compound 99, wherein 4-methylbenzylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.645(s, 1H), 7.520(d, 1H), 7.420(t, 1H), 7.264(t, 1H), 7.194(d, 2H), 7.110(d, 1H), 7.010(d, 2H), 5.390(quartet, 2H), 4.469(s, 2H), 3.482(m, 2H), 3.244(m, 1H), 2.936(s, 1H), 2.828(s, 1H), 2.218(s, 3H), 2.004(s, 1H), 1.738(m, 2H), 1.510(s, 1H); LC-MS m/z 513.2[M+H]+. 
     Example 123 
     Synthesis of Compound 123 
     
       
                 
         
             
             
         
      
     
     Compound 123 was synthesized according to the synthesis of compound 99, wherein 2-hydroxyethylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.580(d, 2H), 7.459(t, 1H), 7.288(t, 1H), 7.080(d, 1H), 5.400 (quartet, 2H), 3.669(m, 2H), 3.452(m, 2H), 3.317(m, 1H), 3.094(m, 2H), 2.845(quartet, 2H), 1.923(m, 1H), 1.705(s, 1H), 1.575(m, 1H), 1.401(m, 1H); LC-MS m/z 453.2[M+H]+. 
     Example 124 
     Synthesis of Compound 124 
     
       
                 
         
             
             
         
      
     
     Compound 124 was synthesized according to the synthesis of compound 99, wherein 4-hydroxymethyl piperidine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.690(d, 1H), 7.580(m, 1H), 7.417(t, 1H), 7.328(s, 1H), 7.231(d, 1H), 5.524(quartet, 2H), 4.130(quartet, 1H), 3.794(s, 5H), 3.500(m, 1H), 3.354(m, 1H), 3.164(m, 1H), 3.068(quartet, 1H), 2.940(t, 1H), 2.106(m, 1H), 1.856(m, 4H), 1.680(m, 2H), 1.271(m, 3H); LC-MS m/z 507.2 [M+H]+. 
     Example 125 
     Synthesis of Compound 125 
     
       
                 
         
             
             
         
      
     
     Compound 125 was synthesized according to the synthesis of compound 99, wherein methyl L-proline ester was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.600(d, 2H), 7.490(m, 1H), 7.321(t, 1H), 7.139(d, 1H), 5.484(t, 2H), 4.637(quartet, 1H), 3.900(m, 2H), 3.735(s, 3H), 3.535(d, 1H), 3.392(m, 1H), 3.084(m, 2H), 2.917(t, 1H), 2.280(m, 1H), 2.078(m, 4H), 1.800(m, 1H), 1.623(m, 2H); LC-MS m/z 521.2[M+H]+. 
     Example 126 
     Synthesis of Compound 126 
     
       
                 
         
             
             
         
      
     
     Compound 126 was synthesized according to the synthesis of compound 99, wherein 2-mesyl ethylamine was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.705(s, 1H), 7.680(d, 1H), 7.570(t, 1H), 7.402(t, 1H), 7.221(d, 1H), 5.494 (quartet, 2H), 3.918(t, 2H), 3.452(m, 4H), 3.377(m, 1H), 3.171(m, 2H), 3.057(s, 3H), 3.078(d, 1H), 1.849(m, 1H), 1.696(m,2H); LC-MS m/z 515.1 [M+H]+. 
     Example 127 
     Synthesis of Compound 127 
     
       
                 
         
             
             
         
      
     
     Compound 127 was synthesized according to the synthesis of compound 99, wherein S-2-carbonyl-4-amino tetrahydrofuran was used instead of methyl glycine ester used in the synthesis of compound 99. MS: 493.2 [M+H]+. 
     Example 128 
     Synthesis of Compound 128 
     
       
                 
         
             
             
         
      
     
     Compound 128 was synthesized according to the synthesis of compound 99, wherein L-proline was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.638(d, 1H), 7.554(s, 1H), 7.510(t, 1H), 7.348(t, 1H), 7.145(d, 1H), 5.494 (quartet, 2H), 4.402(s, 1H), 3.736(m, 5H), 3.410(d, 1H), 3.289(s, 1H), 3.137(m, 1H), 3.000(m, 2H), 2.068(m, 3H), 1.834(m, 3H), 1.633(s, 2H); LC-MS m/z 493.2[M+H]+. 
     Example 129 
     Synthesis of Compound 129 
     
       
                 
         
             
             
         
      
     
     Compound 129 was synthesized according to the synthesis of compound 99, wherein methyl piperidine-4-carboxylate was used instead of methyl glycine ester used in the synthesis of compound 99. 1H-NMR(CDCl3-d3): δ=7.628(d, 1H), 7.500(t, 1H), 7.337(m, 2H), 7.145(d, 1H), 5.506 (quartet, 2H), 4.143(quartet, 2H), 3.454(m, 2H), 3.373(s, 1H), 3.093(m, 4H), 2.934(m, 1H), 2.590(m, 1H), 2.009(m, 3H), 1.743(m, 5H), 1.251(t, 3H); LC-MS m/z 549.2206[M+H]+. 
     Example 130 
     Synthesis of Compound 130 
     
       
                 
         
             
             
         
      
     
     Compound 130 was synthesized according to the synthesis of compound 15, wherein 2-mesyl ethylamine was used instead of methylamine solution in tetrahydrofuran used in the synthesis of compound 15-1. MS: 501.2[M+H]+. 
     Example 131 
     Synthesis of Compound 131 
     
       
                 
         
             
             
         
      
     
     Compound 131 was synthesized according to the synthesis of compound 15, wherein 2-methoxyl-ethanol was used instead of methylamine solution in tetrahydrofuran used in the synthesis of compound 15-1. MS: 454.2[M+H]+. 
     Example 132 
     Synthesis of Compound 132 
     
       
                 
         
             
             
         
      
     
     Compound 132 was synthesized according to the synthesis of compound 15, wherein cyclopropylamine was used instead of methylamine solution in tetrahydrofuran used in the synthesis of compound 15-1. MS: 435.2[M+H]+. 
     Example 133 
     Synthesis of Compound 133 
     
       
                 
         
             
             
         
      
     
     Compound 133 was synthesized according to the synthesis of compound 85, wherein p-toluensulfonyl chloride was used instead of methylsulfonyl chloride. MS: 535.2[M+H]+. 
     Example 134 
     Synthesis of Compound 134 
     
       
                 
         
             
             
         
      
     
     Compound 134 was synthesized according to the synthesis of compound 11, wherein bromo-acetophenone was used instead of iodomethane used in the synthesis of compound 11. MS: 499.2 [M+H]+. 
     Example 135 
     Synthesis of Compound 135 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     Synthesis of Compound 135-1 
     Compound 11-11 (100 mg) was dissolved in 10 ml dichloromethane. 1.1 equivalents of Dess-Martin Periodinane was added and stirred at room temperature for 2 hours. After extracted by dichloromethane, washed with water and evaporated to remove the solvent, compound 135-1 (80 mg) was obtained by column chromatography in 80% yield. MS: 494.2[M+H] + . 
     Synthesis of Compound 135-2 
     Compound 135-1 (80 mg) was dissolved in dichloromethane, and biethylaminosulphur trifluoride was added at −78° C. under nitrogen. The mixture was heated to room temperature and stirred overnight. The reaction solution was poured into saturated and ice-cooled sodium bicarbonate solution and stirred for 15 minutes. After extracted by dichloromethane, and washed with water, compound 135-2 (56 mg) was obtained by column chromatography in 67% yield. MS: 516.2 [M+H] + . 
     Compound 135 was synthesized according to the synthesis of compound 1. MS: 416.1 [M+H] + . 
     Example 136 
     Synthesis of Compound 136 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
     
     Compound 136 was synthesized according to the synthesis of compound 135. 1H NMR(CDCl3): δ 8.05(s, 1H), 7.66(m, 1H), 7.51(m, 1H), 7.36(m, 1H), 6.85-7.13(m, 2H), 5.52(m, 2H), 3.42(m, 1H), 3.26(m, 1H), 3.15(m, 1H), 2.96(m, 2H), 2.01(m, 1H), 1.79(m, 1H), 1.62(m, 2H); LC-MS m/z 416.1 [M+H]+. 
     Example 137 
     Synthesis of Compound 137 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 137 was synthesized according to the synthesis of compound 99, wherein 3,3-difluoroazetidine was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 485.1 [M+H] + . 
     Example 138 
     Synthesis of Compound 138 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 138 was synthesized according to the synthesis of compound 99, wherein 3,3-difluorotetrahydropyrrolidine was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 499.2[M+H] + . 
     Example 139 
     Synthesis of Compound 139 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 139 was synthesized according to the synthesis of compound 99, wherein 4,4-difluoropiperidine was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 513.2[M+H]+. 
     Example 140 
     Synthesis of Compound 140 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 140 was synthesized according to the synthesis of compound 99, wherein 3,3-difluoropiperidine was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 513.2[M+H]+. 
     Example 141 
     Synthesis of Compound 141 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 141 was synthesized according to the synthesis of compound 99, wherein 4-fluoropiperidine was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 495.2[M+H]+. 
     Example 142 
     Synthesis of Compound 142 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 142 was synthesized according to the synthesis of compound 99, wherein 3-fluoroazetidine was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 467.2[M+H]+. 
     Example 143 
     Synthesis of Compound 143 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 143 was synthesized according to the synthesis of compound 99, wherein ethyl alanine ester was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 509.2[M+H]+. 
     Example 144 
     Synthesis of Compound 144 
     
       
                 
         
             
             
         
      
     
     Synthesis route: 
     Compound 143 was synthesized according to the synthesis of compound 99, wherein ethyl 4-aminobutanoate was used instead of methyl glycine ester used in the synthesis of compound 99. LC-MS m/z 523.2[M+H]+. 
     EXPERIMENTAL EXAMPLE 
     Example 1 
     Activity Tests in vitro 
     Screening method: dipeptidyl peptidase IV (DPP IV) activity screening, dipeptidyl peptidase 7 (DPP 7), dipeptidyl peptidase 8 (DPP 8) activity screening, and dipeptidyl peptidase 9 (DPP 9) activity screening. 
     Instruments: Microplate Reader (PerkinElmer, USA). 
     Materials: human DPP IV, obtained extracellular fragment of protease DPP IV (aa29-766), was expressed and purified by our laboratory using baculovirus expression system Bac-to-Bac (purchased from GIBCO company) in accordance with the conventional experimental technology; human DPP 8 was obtained in insect cells by our laboratory using baculovirus expression system Bac-to-Bac (purchased from GIBCO company) in accordance with the conventional experimental technology; Human DPP 9 was obtained in insect cells by our laboratory using baculovirus expression system Bac-to-Bac (purchased from GIBCO company) in accordance with the conventional experimental technology; and the substrate Ala-Pro-AMC was synthesized by GL Biochem (Shanghai) Ltd. 
     Principle of Activity test: DPP IV, DPP 8 and DPP 9 can specifically hydrolyze the substrate Ala-Pro-AMC to form product AMC, and AMC is excited by 355 nm of UV light to generate 460 nm of emission light. The linear change of fluorescence value at 460 nm in unit time was dynamically measured and DPP IV activity was obtained by calculation. Sitagliptin (CAS: 486460-32-6, synthesized according to the conventional experimental technique in the art, see: Journal of Medicinal Chemistry 48 (2005) 141-151.), positive medicament Alogliptin (3 mg/kg, CAS: 850649-62-6, synthesized according to the conventional experimental technique in the art, see: Journal of Medicinal Chemistry 50 (2007) 2297-2300.), and positive medicament LAF237 (15 mg/kg, Vildagliptin, CAS: 274901-16-5, synthesized according to the conventional experimental technique in the art, see: Journal of Medicinal Chemistry 46 (2003) 2774-2789.) were used as control compound in the experiment. 
     Sample treatment: the sample was dissolved in DMSO and stored in low temperature. The concentration of DMSO in the final system was controlled so that the detected activity was not affected. 
     The activity of sample was tested under the selected single concentration from preliminary screening, for example, 20 μg/mL. For the sample which showed activity in a certain condition, for example, inhibition rate (% Inhibition) was more than 50, the dependent relationship between activity and dose, i.e. IC 50  value was determined by nonlinear fitting sample activity over sample concentration. The software for calculation was Graphpad Prism 4 and the model used for fitting was sigmoidal dose-response (variable slope). For most inhibitor screening models, the bottom and top of the fitting curve were set to 0 and 100. In general, each sample in the test was set in duplication or more (n≧2) and the results were represented by Standard Deviation (SD) or Standard Error (SE). 
     Experimental Results: 
     The results of the activities of the compounds were shown in table 1, and showed that the compounds of the invention have good DPPIV inhibitory activity. 
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 The detection results of activities in vitro of the compounds 
               
             
          
           
               
                   
                   
                 DPP IV 
                 DPP 7 
                 DPP 8 
                 DPP 9 
                 FAP 
               
               
                   
                   
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
               
               
                 No. 
                 DC No. 
                 (nM) 
                 (μM) 
                 (μM) 
                 (μM) 
                 (μM) 
               
               
                   
               
             
          
           
               
                 1 
                   
                 34.70 
                   
                   
                   
                   
               
               
                 4 
                   
                 8.78 
                   
                   
                   
                   
               
               
                 8 
                   
                 45.63 
                   
                   
                   
                   
               
               
                 9 
                   
                 36.81 
                   
                   
                   
                   
               
               
                 10 
                   
                 90.00 
                   
                   
                   
                   
               
               
                 27 
                   
                 35.50 
                   
                   
                   
                   
               
               
                 28 
                 DC291408 
                 10.16 
                 N.I. 
                 27.03 
                 35.22 
                 85.86 
               
               
                 38 
                 DC291407 
                 11.52 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 39 
                 DC291410 
                 28.30 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 40 
                 DC291419 
                 18.33 
                 N.I. 
                 N.I. 
                 266.19 
                 213.40 
               
               
                 43 
                 DC291004 
                 18.90 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 44 
                 DC291002 
                 9.76 
                 39.22 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 45 
                 DC291011 
                 3.57 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 54 
                 DC291003 
                 238.07 
                 39.22 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 55 
                 DC291005 
                 17.76 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 56 
                 DC291006 
                 11.26 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 57 
                 DC291009 
                 20.02 
                 69.53 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 58 
                 DC291010 
                 8.72 
                 N.I. 
                 14.35 
                 N.I. 
                 N.I. 
               
               
                 59 
                 DC291012 
                 26.6 
                 N.I. 
                 34.98 
                 187.42 
                 49.52 
               
               
                 60 
                 DC291013 
                 13.28 
                 N.I. 
                 36.76 
                 109.99 
                 57.06 
               
               
                 61 
                 DC291014 
                 13.87 
                 N.I. 
                 45.94 
                 253.61 
                 30.28 
               
               
                 62 
                 DC291015 
                 49.16 
                 N.I. 
                 12.28 
                 54.78 
                 37.38 
               
               
                 63 
                 DC291016 
                 27.48 
                 N.I. 
                 47.86 
                 189.23 
                 169.82 
               
               
                 64 
                 DC291017 
                 33.2 
                 52.02 
                  5.81 
                 39.74 
                 9.38 
               
               
                 65 
                 DC291018 
                 30.21 
                 N.I. 
                 44.79 
                 137.47 
                 75.54 
               
               
                 66 
                 DC291019 
                 35.85 
                 N.I. 
                 14.39 
                 47.14 
                 18.81 
               
               
                 67 
                 DC291020 
                 13.75 
                 N.I. 
                 24.87 
                 53.04 
                 28.09 
               
               
                 68 
                 DC291021 
                 22.96 
                 144.79  
                  8.16 
                 100.40 
                 8.78 
               
               
                 69 
                 DC291022 
                 32.1 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 70 
                 DC291023 
                 18.65 
                 N.I. 
                 38.89 
                 94.49 
                 135.64 
               
               
                 71 
                 DC291024 
                 14.27 
                 144.21  
                 26.79 
                 237.68 
                 52.15 
               
               
                 72 
                 DC291025 
                 15.14 
                 N.I. 
                 30.15 
                 149.02 
                 39.38 
               
               
                 73 
                 DC291026 
                 8.92 
                 158.79  
                  9.08 
                 66.81 
                 14.58 
               
               
                 74 
                 DC291027 
                 10.64 
                 N.I. 
                 18.44 
                 92.92 
                 30.56 
               
               
                 75 
                 DC291028 
                 8.15 
                 N.I. 
                 22.97 
                 91.67 
                 28.33 
               
               
                 76 
                 DC291029 
                 81.58 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 77 
                 DC291030 
                 11.14 
                 29.99 
                 49.42 
                 N.I. 
                 45.18 
               
               
                 78 
                 DC291031 
                 28.78 
                 27.10 
                 60.41 
                 406.53 
                 64.28 
               
               
                 79 
                 DC291032 
                 15.10 
                 357.22  
                 46.98 
                 226.43 
                 40.92 
               
               
                 80 
                 DC291033 
                 25.96 
                 N.I. 
                 25.72 
                 115.15 
                 28.72 
               
               
                 81 
                 DC291034 
                 20.16 
                 N.I. 
                 59.36 
                 347.95 
                 44.01 
               
               
                 82 
                 DC291035 
                 65.93 
                 N.I. 
                 18.12 
                 N.I. 
                 16.48 
               
               
                 83 
                 DC291036 
                 16.14 
                 38.23 
                 316.54  
                 N.I. 
                 160.11 
               
               
                 84 
                 DC291037 
                 24.19 
                 N.I. 
                 62.04 
                 N.I. 
                 91.34 
               
               
                 85 
                 DC291038 
                 37.12 
                 N.I. 
                 338.54  
                 N.I. 
                 255.04 
               
               
                 86 
                 DC291039 
                 20.85 
                 N.I. 
                 317.81  
                 N.I. 
                 120.83 
               
               
                 87 
                 DC291040 
                 26.49 
                 N.I. 
                 N.I. 
                 N.I. 
                   
               
               
                 88 
                 DC291041 
                 14.81 
                 N.I. 
                 54.91 
                 N.I. 
                   
               
               
                 89 
                 DC291042 
                 14.28 
                 N.I. 
                 39.43 
                 N.I. 
                   
               
               
                 90 
                 DC291043 
                 14.27 
                 N.I. 
                 102.21  
                 N.I. 
                   
               
               
                 91 
                 DC291044 
                 36.35 
                 N.I. 
                 88.0 
                 N.I. 
                   
               
               
                 92 
                 DC291045 
                 21.70 
                 N.I. 
                 76.66 
                 N.I. 
                   
               
               
                 93 
                 DC291046 
                 14.76 
                 N.I. 
                 60.69 
                 N.I. 
                   
               
               
                 94 
                 DC291402 
                 10.43 
                 N.I. 
                 34.25 
                 55.05 
                 96.77 
               
               
                 95 
                 DC291404 
                 59.17 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 96 
                 DC291405 
                 11.56 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 97 
                 DC291409 
                 20.40 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 98 
                 DC291411 
                 9.95 
                 N.I. 
                 27.03 
                 35.22 
                 85.86 
               
               
                 99 
                 DC291412 
                 24.73 
                 N.I. 
                 65.96 
                 179.17 
                 177.53 
               
               
                 100 
                 DC291413 
                 28.30 
                 N.I. 
                 43.13 
                 117.17 
                 118.53 
               
               
                 101 
                 DC291414 
                 30.59 
                 N.I. 
                 13.46 
                 14.85 
                 42.04 
               
               
                 102 
                 DC291415 
                 38.43 
                 N.I. 
                 27.84 
                 32.63 
                 68.49 
               
               
                 103 
                 DC291416 
                 53.79 
                 N.I. 
                 N.I. 
                 86.84 
                 144.79 
               
               
                 104 
                 DC291417 
                 17.11 
                 N.I. 
                 N.I. 
                 254.20 
                 239.43 
               
               
                 105 
                 DC291418 
                 26.98 
                 N.I. 
                 N.I. 
                 257.03 
                 200.44 
               
               
                 106 
                 DC291420 
                 18.29 
                 N.I. 
                 76.18 
                 127.30 
                 116.63 
               
               
                 107 
                 DC291421 
                 24.06 
                 N.I. 
                 39.70 
                 122.13 
                 98.59 
               
               
                 108 
                 DC291422 
                 11.84 
                 N.I. 
                 15.15 
                 111.14 
                 26.97 
               
               
                 109 
                 DC291423 
                 15.63 
                 N.I. 
                 62.07 
                 91.80 
                 101.36 
               
               
                 110 
                 DC291424 
                 24.78 
                 N.I. 
                 80.58 
                 51.20 
                 132.81 
               
               
                 111 
                 DC291425 
                 18.93 
                 N.I. 
                 112.49  
                 131.25 
                 N.I. 
               
               
                 112 
                 DC291426 
                 23.85 
                 N.I. 
                 69.06 
                 158.57 
                 213.42 
               
               
                 113 
                 DC291427 
                 18.75 
                 N.I. 
                 165.95  
                 303.38 
                 172.58 
               
               
                 114 
                 DC291428 
                 22.24 
                 N.I. 
                 56.17 
                 307.25 
                 52.18 
               
               
                 115 
                 DC291429 
                 14.48 
                 N.I. 
                 181.24  
                 167.21 
                 145.63 
               
               
                 116 
                 DC291430 
                 18.62 
                 N.I. 
                 95.27 
                 N.I. 
                 126.16 
               
               
                 117 
                 DC291431 
                 15.99 
                 N.I. 
                 63.23 
                 78.51 
                 118.29 
               
               
                 118 
                 DC291432 
                 18.45 
                 N.I. 
                 83.57 
                 N.I. 
                 80.18 
               
               
                 119 
                 DC291433 
                 20.62 
                 N.I. 
                 94.03 
                 N.I. 
                 112.53 
               
               
                 120 
                 DC291434 
                 28.56 
                 N.I. 
                 53.79 
                 49.74 
                 87.44 
               
               
                 121 
                 DC291435 
                 26.85 
                 N.I. 
                 N.I. 
                 N.I. 
                 N.I. 
               
               
                 122 
                 DC291436 
                 26.25 
                 N.I. 
                 N.I. 
                 53.11 
                 N.I. 
               
               
                 123 
                 DC291437 
                 19.83 
                 N.I. 
                 222.51  
                 N.I. 
                   
               
               
                 124 
                 DC291438 
                 26.87 
                 N.I. 
                 43.89 
                 N.I. 
                   
               
               
                 125 
                 DC291439 
                 33.84 
                 N.I. 
                 15.51 
                 171.59 
                   
               
               
                 126 
                 DC291440 
                 20.07 
                 N.I. 
                 55.91 
                 N.I. 
                   
               
               
                 127 
                 DC291441 
                 24.58 
                 N.I. 
                 52.67 
                 N.I. 
                   
               
               
                 128 
                 DC291442 
                 30.66 
                 N.I. 
                 39.04 
                 N.I. 
                   
               
               
                 129 
                 DC291443 
                 33.86 
                 N.I. 
                 16.29 
                 N.I. 
                   
               
               
                   
                 Sitagliptin 
                 25.92 
                 160.96  
                 25.22 
                 39.15 
                 31.24 
               
               
                   
                 Vildagliptin 
                 66.79 
                 N.I. 
                  1.96 
                 0.20 
                 3.72 
               
               
                   
                 Alogliptin 
                 16.30 
                 N.I. 
                 274.97  
                 1328.28 
                 863.55 
               
               
                   
               
               
                 N.I.: No Inhibition. 
               
             
          
         
       
     
     Example 2 
     Study on DPP IV Inhibitory Activity in vivo 
     Animals: ICR mouse (8-10 weeks old; sex: male; 25 g-30 g of body weight, purchased from Shanghai SLAC Laboratory Animal Center). 
     Step: ICR mouse fasted overnight and was administrated with the tested compound (3 mg/kg), positive medicament Alogliptin (3 mg/kg), or positive medicament LAF237 (3 mg/kg) through mouth. Meanwhile the solvent group was used as blank control. The blood was taken from orbital venous plexus of the mouse before administration, and 30, 60, 2 h, 4 h, 6 h, 8 h and 240 h after administration, respectively and loaded into Eppendorf tube (Qizhong Industrial (Shanghai) co., Ltd.) treated by anticoagulant. The plasma was obtained by centrifugation and DPP IV activity was determined. 
     Results: 23 compounds were selected for DPP IV activity experiment of ICR mouse in vivo according to the test results of DPP IV activity and selectivity in vitro. The test results were shown in  FIG. 1 ,  FIG. 2 ,  FIG. 3 ,  FIG. 4 ,  FIG. 5  and  FIG. 6 . After single dose, DC derivatives can significantly reduce DPP IV activity of ICR mouse plasma, wherein the hypoglycemic ability in vivo of 11 compounds including DC291004, DC291005, DC291009, DC291010, DC291402, DC291405, DC291407, DC291408, DC291411, DC291041 and DC291422 (3 mg) is comparable to that of Alogliptin (3 mg), and better than that of Vildagliptin (LAF237, 15 mg). 
     Example 3 
     Hypoglycemic Effect in vivo 
     Acute hypoglycemic effect of single dose through mouth on the normal ICR mouse 
     Animal: ICR mouse (8-10 weeks old, sex: male, weight: 25-30 g, purchased from Shanghai SLAC Laboratory Animal Center). 
     Step: 
     1. Two days before the experiment, the food consumption was recorded and the daily food consumption of each animal was calculated; 
     2. The animals fasted overnight (⅓ of daily food consumption was provided, about 2 g); 
     3. The blood glucose was measured on the second day. According to the blood glucose, the animals were randomly divided into 4 groups with 8 mice in each group: the solvent control group (0.5% methylcellulose, MC), the compound test group (3 mg/kg), the control group of positive medicament Alogliptin (3 mg/kg), the control group of positive medicament LAF237 (15 mg/kg); 
     4. The medicament was administrated through gavage (1 mouse/min). After 6 hours, the blood glucose was measured. Glucose was administrated through gavage according to the body weight (2.5 g/kg). The blood glucose value was monitored at 30 min, 60 min, 90 min, and 120 min after administration. 
     Results: 20 compounds were selected for oral glucose tolerance test (OGTT) in vivo of ICR mouse according to the results of DPP IV activities of ICR mouse plasma and the test results were shown in  FIG. 7 ,  FIG. 8 ,  FIG. 9 ,  FIG. 10 ,  FIG. 11  and  FIG. 12 . After single dose, DC derivatives can dose-dependently significantly improve the glucose tolerance of ICR mouse, wherein the hypoglycemic ability in vivo of 7 compounds including DC291004, DC291009, DC291402, DC291407, DC291411, DC291034 and DC291036 is comparable to that of Alogliptin ( FIGS. 7-10 ). Moreover, oral glucose tolerance tests were performed for compounds DC291009 and DC291407 after multiple single-dose administration. The results showed that the hypoglycemic ability in vivo of compound DC291009 or compound DC291407 is comparable to that of Alogliptin ( FIGS. 11-12 ). 
     Example 4 
     Experimental Method for Safety Evaluation 
     Male normal ICR mice, 28-34 g of body weight (purchased from Shanghai SLAC Laboratory Animal Center), were randomly divided into model group and drug group according to the body weight with 4 mice each group. After grouping, each compound was administrated once through gavage according to the dose of 100 mg/kg at the same time. After that, the mice in each group were observed in succession for one week, and the food consumption and weight of the mouse were monitored. The experimental results were as follows. 
     
       
         
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 The effect of single dose on the body weight (g) of normal ICR mouse 
               
             
          
           
               
                   
                 Before 
                 After administration 
               
             
          
           
               
                 Group 
                 administration 
                 1 d 
                 2 d 
                 3 d 
                 4 d 
                 5 d 
                 6 d 
                 7 d 
               
               
                   
               
               
                 Normal 
                     31 ± 1.2 
                 31.3 ± 1.1 
                 32.1 ± 1.1 
                 32.3 ± 1.2 
                 32.8 ± 1.3 
                 32.9 ± 1.3 
                 33.3 ± 1.4 
                 33.6 ± 1.3 
               
               
                 Control Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291407 (100 
                 29.7 ± 1.8 
                 30.0 ± 1.6 
                  30.0 ± 1.7* 
                  29.7 ± 1.9* 
                  30.0 ± 1.5* 
                  30.5 ± 1.5* 
                  30.4 ± 1.8* 
                  30.6 ± 1.9* 
               
               
                 mg/kg) Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291004 (100 
                 30.2 ± 0.7 
                 30.3 ± 1.0 
                 30.8 ± 0.9 
                 31.0 ± 1.2 
                 31.6 ± 1.2 
                 32.0 ± 1.6 
                 32.0 ± 1.2 
                 32.5 ± 1.3 
               
               
                 mg/kg) Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291009 (100 
                 30.8 ± 2.2 
                 31.3 ± 2.0 
                 31.5 ± 2.3 
                 31.8 ± 2.3 
                 32.3 ± 2.2 
                 32.4 ± 2.5 
                 32.6 ± 2.6 
                  33± 2.6 
               
               
                 mg/kg) Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291411 (100 
                     30 ± 1.5 
                 30.5 ± 1.6 
                 31.2 ± 1.6 
                 31.0 ± 1.7 
                 31.5 ± 1.9 
                 31.8 ± 1.5 
                 31.6 ± 1.8 
                 32.1 ± 1.7 
               
               
                 mg/kg Group 
               
               
                   
               
               
                 *p &lt; 0.05 versus model group. 
               
             
          
         
       
     
     It can be seen from table 2 that compared with the normal control group, the weight of the ICR mouse began to show significant statistical difference (p&lt;0.05) relative to the control group from the second day after single dose of DC291407 (100 mg/kg), which lasted until 7 days after administration (i.e. at the end of the experiment). However, the body weight was not consistently decreased during this period and retained around 30.0 g which did not significantly differ from the weights of the normal control group and other drug groups. Therefore, it was speculated that DC291407 possibly had no effect on body weight. There were no significant statistical differences between other groups and the normal control group. 
     
       
         
               
             
               
               
               
             
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 The effect of single dose on the food consumption (g · 
               
               
                 day −1  · cage −1 ) of normal ICR mouse 
               
             
          
           
               
                 Administration 
                 Before 
                 After administration 
               
             
          
           
               
                 dosage 
                 administration 
                 1 d 
                 2 d 
                 3 d 
                 4 d 
                 5 d 
                 6 d 
                 7 d 
               
               
                   
               
               
                 Normal 
                 22.3 
                 19.6 
                 20.4 
                 21.5 
                 20.2 
                 20.9 
                 21.9 
                 21.5 
               
               
                 Control Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291407 (100 
                 21.4 
                 18.4 
                 18.5 
                 19.0 
                 19.4 
                 22.3 
                 22.6 
                 23.5 
               
               
                 mg/kg) Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291004 (100 
                 22.5 
                 18.7 
                 21.0 
                 21.1 
                 21.5 
                 21.9 
                 21.5 
                 24.1 
               
               
                 mg/kg) Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291009 (100 
                 23.3 
                 21.2 
                 21.3 
                 22.6 
                 22.8 
                 22.2 
                 21.9 
                 23.8 
               
               
                 mg/kg) Group 
                   
                   
                   
                   
                   
                   
                   
                   
               
               
                 DC291411 (100 
                 20.8 
                 19.3 
                 21.3 
                 18.8 
                 18.3 
                 17.7 
                 20.5 
                 21.9 
               
               
                 mg/kg) Group 
               
               
                   
               
             
          
         
       
     
     It can be seen form table 3 that because of high dose of administrated medicament, the food consumption of mouse in each group decreased significantly from one day after administration, and then began to restore and substantially restored to the level of pre-administration at 7 days after administration. 
     
       
         
               
             
               
               
               
               
             
           
               
                 TABLE 4 
               
             
             
               
                   
               
               
                 The effect of single dose on the important  
               
               
                 viscera index (%) of normal ICR mouse 
               
             
          
           
               
                   
                 Liver 
                 Kidney 
                 Spleen 
               
               
                 Group 
                 index 
                 index 
                 index 
               
               
                   
               
               
                 Normal Control Group 
                 4.9 ± 0.3 
                 1.5 ± 0.0 
                 0.3 ± 0.1 
               
               
                 DC291407 (100 mg/kg) Group 
                 5.3 ± 0.4 
                 1.5 ± 0.2 
                  0.4 ± 0.0* 
               
               
                 DC291004 (100 mg/kg) Group 
                 5.3 ± 0.3 
                 1.5 ± 0.1 
                 0.4 ± 0.0 
               
               
                 DC291009 (100 mg/kg) Group 
                 5.3 ± 0.2 
                 1.4 ± 0.1 
                 0.4 ± 0.1 
               
               
                 DC291411 (100 mg/kg) Group 
                 5.0 ± 0.4 
                 1.4 ± 0.1 
                 0.4 ± 0.0 
               
               
                   
               
               
                 *p &lt; 0.05 versus model group. 
               
             
          
         
       
     
     It can be seen from table 4 that on the 7 th  day after administrated, the liver index and spleen index of administrated ICR mouse in each group increased to a certain extent. However, there was a statistical difference between spleen index of DC29147 group and that of normal control group, while there was no statistical difference among other groups. The kidney index of DC291407 or DC291004 group did not significantly differ from that of normal control group, and the kidney index of DC291411 or DC291009 group is slightly lower than that of normal control group. However, there was no statistical difference. 
     Experimental Conclusion 
     The test results showed that after DC291407 (100 mg/kg) was administrated, there was statistical difference between the weight from the second day after administration to the 7 th  day after administration and that of the normal control group, while the value did not greatly differ from that of each other group, therefore, there was possibly no practical significance. Moreover, compared with the normal control group, the spleen index significantly increased on the 7 th  day after administration, while the value did not greatly differ from that of each other group, therefore, biological significance was not obvious. For other drug groups, DC291004 (100 mg/kg), DC291009 (100 mg/kg) and DC291411 (100 mg/kg), compared with the normal control group, there was no statistical difference for both of body weight and viscera index, and the liver index and spleen index slightly increased on the 7 th  day after administration. Summing up, DC291407, DC291004, DC291009 and DC291411 in this experiment did not reflect obvious acute toxicity. 
     Example 5 
     Study on Pharmacokinetics 
     The concentration of metabolite M1 (4071001), metabolite M2 (407002) or metabolite M3 (407003) in plasma was determined by LC-MS/MS method after DC291407 was administrated to the rats through gavage and intravenous injection. 
     As shown in  FIG. 13 , after 20 mg/kg of DC291407 was administrated to th healthy 
     Sprague-Dawley (SD) rats (purchased from Shanghai SLAC Laboratory Animal Center) through gavage, the plasma mainly contained hydrolysis-metabolite M1 (specially, a demethylated product from DC291407). In addition, relatively low concentration of M2 (specially, acetylizated (below 20 ng/ml) was detected in the samples collected within one hour after administration, and the prototype compound and metabolite M3 (specially, acetylizated DC291407) can not be detected in plasma. 
     After 10 mg/kg of DC291407 was administered to the rats through vein, the plasma mainly contained hydrolysis-metabolite M1. In addition, relatively low concentration of prototype compound and M2 were detected, and metabolite M3 can not be detected in plasma. 
     After normalization of the dose, the absolute bioavailability was 22.1% after 20 mg/kg of DC291407 was administered to the rats through gavage, based on AUC of metabolite M1. 
     The LC/MS/MS used is triple quadruple LC/MS 6460 from Agilent. 
     Specific administration regimen is as follows: 
     Six healthy male Sprague-Dawley (SD) rats with the weight of 180-220 g were randomly divided into 2 groups. The rats in each group were administrated with the tested compound by gavage or intravenous injection, respectively. Details are shown in the following table: 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                   
                 The  
                   
                   
                 Adminis- 
                 Adminis- 
               
               
                   
                 number 
                   
                 Adminis- 
                 tration 
                 tration 
               
               
                   
                 of  
                   
                 tration 
                 dosage  
                 volume  
               
               
                 Group 
                 animals 
                 Compound 
                 route 
                 (mg/kg) 
                 (ml/kg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 3 
                 DC291407 
                 gavage 
                 20 
                 10 
               
               
                 2 
                 3 
                 DC291407 
                 vein 
                 10 
                 5.0 
               
               
                   
               
             
          
         
       
     
     The compound was dissolved in 6.7% DMSO/6.7% Tween/86.6% normal saline. 
     The rats fasted for 12 h and can drink water ad libitum. 2 h after dosing, the rats were provided with food all together. The time point for collecting blood samples and the sample processing are listed as follows. 
     Intragastric administration: 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0 and 24 h after administration; 
     Intravenous administration: 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h after administration. At above time point, 0.3 ml venous blood was taken from retrobulbar venous plexus of the rat and loaded into heparinization tube. After centrifuged at 11000 rpm for 5 min, the plasma was separated and frozen at −20° C. in a refrigerator. 
     
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
             
             
               
                   
               
               
                 Plasma concentrations (ng/mL) of metabolite M1 after 20 mg/kg 
               
               
                 of DC291407 was administered to the rats through gavage 
               
             
          
           
               
                 Animal 
                 Time (h) 
               
             
          
           
               
                 No. 
                 0 
                 0.25 
                 0.5 
                 1.0 
                 2.0 
                 3.0 
                 4.0 
                 6.0 
                 8.0 
                 24 
               
               
                   
               
             
          
           
               
                 1 
                 BLQ 
                 3454 
                 4435 
                 3326 
                 690 
                 476 
                 500 
                 138 
                 97.1 
                 13.0 
               
               
                 2 
                 BLQ 
                 3427 
                 3404 
                 1771 
                 1091 
                 299 
                 105 
                 57.3 
                 58.9 
                 13.0 
               
               
                 3 
                 BLQ 
                 10255 
                 10087 
                 6789 
                 1569 
                 872 
                 565 
                 173 
                 49.5 
                 14.3 
               
               
                 Average 
                   
                 5712 
                 5975 
                 3962 
                 1117 
                 549 
                 390 
                 123 
                 68.5 
                 13.4 
               
               
                 standard 
                   
                 3934 
                 3598 
                 2569 
                 440 
                 293 
                 249 
                 59 
                 25.2 
                 0.7 
               
               
                 deviation 
               
               
                   
               
               
                 BLQ: Below the lower detection limit of the measuring method (Below the lower quantification). 
               
             
          
         
       
     
     
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
             
             
               
                   
               
               
                 Plasma concentrations (ng/mL) of metabolite M2 after 20 mg/kg 
               
               
                 of DC291407 was administered to the rats through gavage 
               
             
          
           
               
                 Animal 
                 Time (h) 
               
             
          
           
               
                 No. 
                 0 
                 0.25 
                 0.5 
                 1.0 
                 2.0 
                 3.0 
                 4.0 
                 6.0 
                 8.0 
                 24 
               
               
                   
               
             
          
           
               
                 1 
                 BLQ 
                 3.87 
                 4.79 
                 3.88 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 2 
                 BLQ 
                 3.24 
                 3.94 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 3 
                 BLQ 
                 16.3 
                 16.9 
                 10.7 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
             
             
               
                   
               
               
                 Plasma concentrations (ng/mL) of prototype compound after 10 mg/kg of 
               
               
                 DC291407 was administered to the rats through intravenous injection 
               
             
          
           
               
                 Animal 
                 Time (h) 
               
             
          
           
               
                 No. 
                 0.083 
                 0.25 
                 0.50 
                 1.0 
                 2.0 
                 4.0 
                 6.0 
                 8.0 
                 24 
               
               
                   
               
             
          
           
               
                 4 
                 63.4 
                 49.7 
                 27.4 
                 11.3 
                 4.75 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 5 
                 60.7 
                 34.4 
                 31.7 
                 11.9 
                 3.94 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 6 
                 53.4 
                 20.3 
                 9.72 
                 6.61 
                 3.44 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 Average 
                 59.2 
                 34.8 
                 23.0 
                 9.9 
                 4.05 
                   
                   
                   
                   
               
               
                 standard 
                 5.2 
                 14.7 
                 11.7 
                 2.9 
                 0.66 
                   
                   
                   
                   
               
               
                 deviation 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
             
             
               
                   
               
               
                 Plasma concentrations (ng/mL) of metabolite M1 after 10 mg/kg of DC291407 
               
               
                 was administered to the rats through intravenous injection 
               
             
          
           
               
                 Animal 
                 Time (h) 
               
             
          
           
               
                 No. 
                 0.083 
                 0.25 
                 0.50 
                 1.0 
                 2.0 
                 4.0 
                 6.0 
                 8.0 
                 24 
               
               
                   
               
             
          
           
               
                 4 
                 39818 
                 28858 
                 11784 
                 5628 
                 401 
                 55.4 
                 30.9 
                 24.8 
                 15.2 
               
               
                 5 
                 41730 
                 29247 
                 7251 
                 4634 
                 214 
                 68.1 
                 41.4 
                 48.5 
                 13.3 
               
               
                 6 
                 53535 
                 29592 
                 9426 
                 3891 
                 314.7 
                 85.5 
                 49.3 
                 38.5 
                 10.8 
               
               
                 Average 
                 45028 
                 29232 
                 9487 
                 4717 
                 310 
                 69.7 
                 40.5 
                 37.3 
                 13.1 
               
               
                 standard 
                 7429 
                 367 
                 2267 
                 872 
                 93 
                 15.1 
                 9.2 
                 11.9 
                 2.2 
               
               
                 deviation 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
             
               
               
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 9 
               
             
             
               
                   
               
               
                 Plasma concentrations (ng/mL) of metabolite M2 after 10 mg/kg of DC291407 
               
               
                 was administered to the rats through intravenous injection 
               
             
          
           
               
                 Animal 
                 Time (h) 
               
             
          
           
               
                 No. 
                 0.083 
                 0.25 
                 0.50 
                 1.0 
                 2.0 
                 4.0 
                 6.0 
                 8.0 
                 24 
               
               
                   
               
             
          
           
               
                 4 
                 126 
                 866 
                 144 
                 36.0 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 5 
                 209 
                 132 
                 153 
                 30.9 
                 7.18 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 6 
                 15.0 
                 20.3 
                 9.39 
                 3.26 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
                 BLQ 
               
               
                 Average 
                 117 
                 339 
                 102 
                 23.4 
                   
                   
                   
                   
                   
               
               
                 standard 
                 98 
                 459 
                 81 
                 17.6 
                   
                   
                   
                   
                   
               
               
                 deviation 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 10 
               
             
             
               
                   
               
               
                 Pharmacokinetic parameters of metabolite M1 after 20 mg/kg 
               
               
                 of DC291407 was administered to the rats through gavage 
               
             
          
           
               
                 Animal 
                 T max   
                 C max   
                 AUC 0-t   
                 AUC 0-∞   
                 MRT 
                 t 1/2   
                 F 
               
               
                 No. 
                 (h) 
                 (ng/mL) 
                 (ng · h/mL) 
                 (ng · h/mL) 
                 (h) 
                 (h) 
                 (%) 
               
               
                   
               
             
          
           
               
                 1 
                 0.50 
                 4435 
                 8191 
                 8292 
                 2.86 
                 5.37 
                   
               
               
                 2 
                 0.25 
                 3427 
                 5758 
                 5907 
                 3.15 
                 7.97 
                   
               
               
                 3 
                 0.25 
                 10255 
                 15633 
                 15706 
                 1.74 
                 3.55 
                   
               
               
                 Average 
                 0.33 
                 6039 
                 9860 
                 9968 
                 2.58 
                 5.63 
                 22.1 
               
               
                 standard 
                 0.14 
                 3686 
                 5145 
                 5110 
                 0.75 
                 2.22 
                   
               
               
                 deviation 
                   
                   
                   
                   
                   
                   
                   
               
               
                 CV % 
                 43.3 
                 61.0 
                 52.2 
                 51.3 
                 28.9 
                 39.4 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 11 
               
             
             
               
                   
               
               
                 Pharmacokinetic parameters of prototype drug after 10 mg/kg of 
               
               
                 DC291407 was administered to the rats through intravenous injection 
               
             
          
           
               
                 Animal 
                 AUC 0-t   
                 AUC 0-∞   
                 MRT 
                 t 1/2   
                 CL 
                 V ss   
               
               
                 No. 
                 (ng · h/mL) 
                 (ng · h/mL) 
                 (h) 
                 (h) 
                 (L/h/kg) 
                 (L/kg) 
               
               
                   
               
             
          
           
               
                 4 
                 42.4 
                 45.9 
                 0.68 
                 0.51 
                 218 
                 148 
               
               
                 5 
                 40.9 
                 43.9 
                 0.67 
                 0.53 
                 228 
                 154 
               
               
                 6 
                 24.8 
                 29.8 
                 0.98 
                 1.01 
                 335 
                 328 
               
               
                 Average 
                 36.0 
                 39.9 
                 0.78 
                 0.68 
                 260 
                 210 
               
               
                 standard 
                 9.7 
                 8.8 
                 0.17 
                 0.28 
                 65 
                 102 
               
               
                 deviation 
                   
                   
                   
                   
                   
                   
               
               
                 CV % 
                 27.0 
                 22.0 
                 22.3 
                 41.3 
                 25.0 
                 48.7 
               
               
                   
               
             
          
         
       
     
     
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 12 
               
             
             
               
                   
               
               
                 Pharmacokinetic parameters of metabolite M1 after 10 mg/kg of 
               
               
                 DC291407 was administered to the rats through intravenous injection 
               
             
          
           
               
                 Animal 
                 T max   
                 C max   
                 AUC 0-t   
                 AUC 0-∞   
                 MRT 
                 t 1/2   
               
               
                 No. 
                 (h) 
                 (ng/mL) 
                 (ng · h/mL) 
                 (ng · h/mL) 
                 (h) 
                 (h) 
               
               
                   
               
             
          
           
               
                 4 
                 0.083 
                 39818 
                 22692 
                 23114 
                 1.60 
                 19.2 
               
               
                 5 
                 0.083 
                 41730 
                 20658 
                 20834 
                 1.01 
                 9.18 
               
               
                 6 
                 0.083 
                 53535 
                 23472 
                 23603 
                 0.79 
                 8.40 
               
               
                 Average 
                 0.083 
                 45028 
                 22274 
                 22517 
                 1.13 
                 12.3 
               
               
                 standard 
                 0.0 
                 7429 
                 1453 
                 1478 
                 0.42 
                 6.0 
               
               
                 deviation 
                   
                   
                   
                   
                   
                   
               
               
                 CV % 
                 0.0 
                 16.5 
                 6.5 
                 6.6 
                 36.9 
                 49.2 
               
               
                   
               
             
          
         
       
     
     It can be seen from table 5 to table 12, after 20 mg/kg of DC291407 was administered to the rats through gavage, the plasma mainly contained hydrolysis-metabolite Ml. In addition, relatively low concentration of M2 (below 20 ng/ml) was detected in the samples collected within one hour after administration, and prototype compound and metabolite M3 can not be detected. After 10 mg/kg of DC291407 was administrated to the rats through intravenous injection, the plasma mainly contained hydrolysis-metabolite M1. Moreover, relatively low concentration of prototype compound and M2 can be detected while no metabolite M3 can be detected. 
     After normalizing the dosage, absolute bioavailability was 22.1%, half-life was 5.63 h and AUC was 9860 ng·h/mL after 20 mg/kg of DC291407 was administered to the rats through gavage, based on the AUC of metabolite M1.