CN104211702A - Substituted xanthine compounds, preparation method and applications thereof - Google Patents

Abstract

The invention discloses substituted xanthine compounds, a preparation method and applications thereof, and specifically relates to compounds represented by the formula (I), stereo isomers and pharmaceutically acceptable salts thereof, wherein the R1 and R2 are defined in the description. The invention also relates to a pharmaceutical composition containing the compounds, an application of the pharmaceutical composition in preparation of drugs for treating diseases or symptoms caused by high activity of DPP-IV or overexpression of DPP-IV, and a method using the pharmaceutical composition to treat related diseases. The provided compounds can effectively inhibit the activity of DPP-IV.

Description

Substituted xanthine compound and its preparation method and use

technical field

The invention belongs to the technical field of medicine. It relates to substituted xanthine compounds represented by general formula (I), pharmaceutically acceptable salts and isomers thereof, preparation of such compounds, pharmaceutical compositions containing them and the prevention and/or Application in treating diabetes, non-insulin-dependent diabetes, especially in inhibiting DPP-IV.

Background technique

Diabetes mellitus (DM) is a metabolic disease with multiple etiologies, which is caused by an absolute or relative insufficiency of insulin, resulting in an increase in blood sugar and causing metabolic disorders in the body. In 2012, the number of diabetic patients worldwide exceeded 370 million, of which 4.8 million died (International Diabetes Federation, 2012 Update). Diabetes has become the third major killer of human health after cardiovascular disease and tumors. It can be divided into insulin-dependent diabetes mellitus (IDDM, type 1 diabetes) and non-insulin-dependent diabetes mellitus (noninsulin-dependent diabetes mellitus). Dependent diabetes mellitus, NIDDM, namely type 2 diabetes), of which type 2 diabetes is the most common, accounting for more than 90% of diabetic patients. Although at least insulin, biguanides, sulfonylureas, glycosidase inhibitors and thiazolidinediones and other antidiabetic drugs are currently on the market, the above traditional hypoglycemic drugs are generally accompanied by side effects such as weight gain, hypoglycemia, and Problems such as gradual decrease in drug efficacy [Kahn SE, Haffner SM, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. [J]. N Engl J Med, 2006, 355: 2477-80] Therefore, it is urgent to develop new drugs .

Glucagon-like peptide-1 (GLP-1) is an incretin that stimulates insulin secretion from β cells. However, the GLP-1 secreted in the body will be rapidly degraded by the serine protease dipeptidyl peptidase IV and thus inactivated, so pure GLP-1 cannot be used as a drug. DPP-IV inhibitors can increase the concentration of endogenous GIP and GLP-1 in the blood, thereby effectively promoting insulin secretion, lowering blood sugar while inhibiting glucagon levels, improving the body's ability to control blood sugar levels, and protecting The role of β-cell function, and will not cause side effects of hypoglycemia and weight gain, because of its clear target, has become a hot research and development of drugs for the treatment of type 2 diabetes.

With the in-depth study of the DPPs family, especially DPP8, it was found that because DPP8 and DPP-IV have certain similarities in protein structure and substrate type, when the selectivity of DPP-IV inhibitors is poor, they can act simultaneously DPP8 will produce serious side effects such as alopecia, thrombocytopenia and anemia [HavaleSH, Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type2diabetes. Bioorg Med Chem Lett, 2009, 17: 1783-1802], [ Salvatore T, Progress in the oral treatment of type2diabetes: update on DPP-IV Inhibitors. Curr Diabetes Rev, 2009, 5(2):92-101]. Therefore, DPP-IV inhibitors must have high selectivity for a single DPP-IV target, so as not to affect the normal physiological functions of other DPPs, which is also a difficult and key point in the development of new selective DPP-IV inhibitors.

Therefore, there is still a need for selective DPP-IV inhibitors with novel structure and strong activity in this field to meet the needs of clinical treatment.

Contents of the invention

The technical problem to be solved by the present invention is to provide a selective DPP-IV inhibitor with novel structure and strong activity. The inventors found that a class of substituted xanthine compounds with novel structure has strong inhibitory activity and selectivity to DPP-IV, and can be used for the prevention and treatment of diabetes. The present invention has been accomplished based on the above findings.

Summary of the invention

To this end, the first aspect of the present invention provides compounds represented by formula (I) and their stereoisomers, pharmaceutically acceptable salts thereof,

in,

R ₁ can be independently selected from hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkyloxy, C _{2- 6} alkyl formyl, C _2-6 alkyl oxyformyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkyl formyl, C _3-10 cycloalkyl oxyformyl, aryl- C _1-3 alkyl, heteroaryl-C _1-3 alkyl, heterocycloalkyloxy containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 3-9 heterocycloalkylformyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxy containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen Formyl, aryl, aryloxy, arylformyl, aryloxyformyl, heterocyclic aryl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4 -9 carbon atoms and 1-3 heterocyclic aryloxy groups selected from nitrogen and oxygen heteroatoms, heterocyclic aromatics containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen Formyl, heterocyclic aryloxyformyl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen;

_R can be independently selected from hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, amino, trifluoromethyl , trifluoromethoxy, nitro, cyano, carbamoyl, aminosulfonyl, benzyl;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally replaced by 1-4 (such as 1-3, 1-2, 1, 2 or 3) are substituted with groups selected from the following groups: hydroxyl, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _3-7 heterocycloalkyl, aryl, C _3-7 heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxy Formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 hetero Cycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxyformyl, C _4-9 heteroaryloxy, C _4-9 heteroaryl Formyl, C _4-9 heteroaryloxyformyl;

X, Y are the same or different, each independently selected from C, N, O, S;

m is selected from 1, 2, 3, 4;

n is selected from 2, 3, 4, 5, 6;

p and q are the same or different, each independently selected from 1, 2, 3, and 4.

The compound according to any one of the first aspect of the present invention, which is a compound represented by formula (II) and its stereoisomers, and pharmaceutically acceptable salts thereof,

in,

R ₁ is selected from hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkyloxy, C _2-6 alkyl Formyl, C _2-6 alkyloxyformyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkylformyl, C _3-10 cycloalkyloxyformyl, aryl-C _{1- 3} alkyl, heteroaryl-C _1-3 alkyl, heterocycloalkyloxy containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 3-9 carbon atoms and heterocycloalkylformyl with 1-3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl with 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, Aryl, aryloxy, arylformyl, aryloxyformyl, heterocyclic aryl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4-9 A heterocyclic aryloxy group containing carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, a heterocyclic arylformyl group containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen , a heterocyclic aryloxyformyl group containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen;

_R is selected from hydrogen, _{C 1-6} alkyl, C 1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, amino, trifluoromethyl, trifluoro Methoxy, nitro, cyano, carbamoyl, sulfamoyl, benzyl;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally replaced by 1-4 (such as 1-3, 1-2, 1, 2 or 3) are substituted with groups selected from the following groups: hydroxyl, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _3-7 heterocycloalkyl, aryl, C _3-7 heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxy Formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 hetero Cycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxyformyl, C _4-9 heteroaryloxy, C _4-9 heteroaryl Formyl, C _4-9 heteroaryloxyformyl;

X, Y are the same or different, each independently selected from C, N, O, S;

m is selected from 1, 2, 3, 4;

n is selected from 2,3,4,5,6.

The compound according to any one of the first aspect of the present invention, which is a compound represented by formula (IIA) and its stereoisomers, and pharmaceutically acceptable salts thereof,

in,

R ₁ is selected from hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkyloxy, C _2-6 alkyl Formyl, C _2-6 alkyloxyformyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkylformyl, C _3-10 cycloalkyloxyformyl, aryl-C _{1- 3} alkyl, heteroaryl-C _1-3 alkyl, heterocycloalkyloxy containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 3-9 carbon atoms and heterocycloalkylformyl with 1-3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl with 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, Aryl, aryloxy, arylformyl, aryloxyformyl, heterocyclic aryl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4-9 A heterocyclic aryloxy group containing carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, a heterocyclic arylformyl group containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen , a heterocyclic aryloxyformyl group containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen;

_R is selected from hydrogen, C _1-6 alkyl, C 1-6 alkyloxy _, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, amino, trifluoromethyl, trifluoro Methoxy, nitro, cyano, carbamoyl, sulfamoyl, benzyl;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally replaced by 1-4 (such as 1-3, 1-2, 1, 2 or 3) are substituted with groups selected from the following groups: hydroxyl, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _3-7 heterocycloalkyl, aryl, C _3-7 heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxy Formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 hetero Cycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxyformyl, C _4-9 heteroaryloxy, C _4-9 heteroaryl Formyl, C _4-9 heteroaryloxyformyl;

X, Y are the same or different, each independently selected from C, N, O, S;

m is selected from 1, 2, 3, 4;

n is selected from 2,3,4,5,6.

The compound according to any one of the first aspect of the present invention, which is a compound represented by formula (IIB) and its stereoisomers, and pharmaceutically acceptable salts thereof,

in,

R ₁ is selected from hydrogen, C _1-10 alkyl, C _3-7 cycloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-6 alkyloxy, C _2-6 alkyl Formyl, C _2-6 alkyloxyformyl, C _3-10 cycloalkyloxy, C _3-10 cycloalkylformyl, C _3-10 cycloalkyloxyformyl, aryl-C _{1- 3} alkyl, heteroaryl-C _1-3 alkyl, heterocycloalkyloxy containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 3-9 carbon atoms and heterocycloalkylformyl with 1-3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl with 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, Aryl, aryloxy, arylformyl, aryloxyformyl, heterocyclic aryl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4-9 A heterocyclic aryloxy group containing carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, a heterocyclic arylformyl group containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen , a heterocyclic aryloxyformyl group containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen;

_R is selected from hydrogen, C _1-6 alkyl, C 1-6 alkyloxy _, C _1-6 alkylformyl, C _1-6 alkyloxyformyl, amino, trifluoromethyl, trifluoro Methoxy, nitro, cyano, carbamoyl, sulfamoyl, benzyl;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally replaced by 1-4 (such as 1-3, 1-2, 1, 2 or 3) are substituted with groups selected from the following groups: hydroxyl, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _{3- 7} cycloalkyl, C _3-7 heterocycloalkyl, aryl, C _3-7 heteroaryl, C _1-6 alkyloxy, C _1-6 alkylformyl, C _1-6 alkyloxy Formyl, C _3-7 cycloalkyloxy, C _3-7 cycloalkylformyl, C _3-7 cycloalkyloxyformyl, C _3-7 heterocycloalkyloxy, C _3-7 hetero Cycloalkylformyl, C _3-7 heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxyformyl, C _4-9 heteroaryloxy, C _4-9 heteroaryl Formyl, C _4-9 heteroaryloxyformyl;

X, Y are the same or different, each independently selected from C, N, O, S;

m is selected from 1, 2, 3, 4;

n is selected from 2,3,4,5,6.

The compound according to any one of the first aspect of the present invention, which is a compound represented by formula (IIIA) and its stereoisomers, and pharmaceutically acceptable salts thereof,

in,

R ₁ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _2-6 alkylformyl, C _2-6 alkyloxyformyl, C _3-8 cycloalkyloxy , C _3-8 cycloalkylformyl, C _3-8 cycloalkyloxyformyl, aryl-C _1-3 alkyl, heteroaryl-C _1-3 alkyl, containing 3-9 carbon atoms and 1-3 heterocycloalkyloxy groups selected from nitrogen and oxygen heteroatoms, heterocycloalkylformyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing Heterocycloalkyloxyformyl, aryl, aryloxy, arylformyl, aryloxyformyl, 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4- A heterocyclic aryl group with 9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, a heterocyclic aryloxy group with 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen , heterocyclic aryl formyl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen Heterocyclic aryloxyformyl;

R ₂ is selected from hydrogen, amino;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally substituted by 1-2 groups selected from the following groups: hydroxyl, halogen, cyano, Amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 cycloalkyl, C _1-6 alkyloxy, C _3-6 heterocycloalkane base, aryl;

X is selected from C, N;

m is selected from 1, 2;

n is selected from 2,3,4.

_R is preferably ethoxyformyl, isopropoxyformyl, tert-butoxyformyl, cycloalkylformyl, substituted cycloalkylformyl, cycloalkyloxyformyl, substituted cycloalkyloxyformyl, aryl Base-C _1-3 alkyl, substituted aryl-C _1-3 alkyl, heteroaryl-C _1-3 alkyl, aryl, substituted aryl, aryl formyl, aryl oxyformyl, substituted Arylformyl, substituted aryloxyformyl, 2-(5-methyl)pyrimidinyl, substituted 2-(5-methyl)pyrimidinyl;

R ₂ is preferably hydrogen, amino;

X is preferably C, N;

m is preferably 1,2; n is preferably 2,3,4.

The compound according to any one of the first aspect of the present invention, which is a compound represented by formula (IIIB) and its stereoisomers, and pharmaceutically acceptable salts thereof,

in,

R ₁ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _2-6 alkylformyl, C _2-6 alkyloxyformyl, C _3-8 cycloalkyloxy , C _3-8 cycloalkylformyl, C _3-8 cycloalkyloxyformyl, aryl-C _1-3 alkyl, heteroaryl-C _1-3 alkyl, containing 3-9 carbon atoms and 1-3 heterocycloalkyloxy groups selected from nitrogen and oxygen heteroatoms, heterocycloalkylformyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing Heterocycloalkyloxyformyl, aryl, aryloxy, arylformyl, aryloxyformyl, 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4- A heterocyclic aryl group with 9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, a heterocyclic aryloxy group with 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen , heterocyclic aryl formyl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen Heterocyclic aryloxyformyl;

R ₂ is selected from hydrogen, amino;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally substituted by 1-2 groups selected from the following groups: hydroxyl, halogen, cyano, Amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 cycloalkyl, C _1-6 alkyloxy, C _3-6 heterocycloalkane base, aryl;

X is selected from C, N;

m is selected from 1, 2;

n is selected from 2,3,4.

_R is preferably ethoxyformyl, isopropoxyformyl, tert-butoxyformyl, cycloalkylformyl, substituted cycloalkylformyl, cycloalkyloxyformyl, substituted cycloalkyloxyformyl, aryl Base-C _1-3 alkyl, substituted aryl-C _1-3 alkyl, heteroaryl-C _1-3 alkyl, aryl, substituted aryl, aryl formyl, aryl oxyformyl, substituted Arylformyl, substituted aryloxyformyl, 2-(5-methyl)pyrimidinyl, substituted 2-(5-methyl)pyrimidinyl;

R ₂ is preferably hydrogen, amino;

X is preferably C, N;

m is preferably 1,2; n is preferably 2,3,4.

The compound according to any one of the first aspect of the present invention, which is a compound represented by formula (IV) and its stereoisomers, and pharmaceutically acceptable salts thereof,

in,

R ₁ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyloxy, C _2-6 alkylformyl, C _2-6 alkyloxyformyl, C _3-8 cycloalkyloxy , C _3-8 cycloalkylformyl, C _3-8 cycloalkyloxyformyl, aryl-C _1-3 alkyl, heteroaryl-C _1-3 alkyl, containing 3-9 carbon atoms and 1-3 heterocycloalkyloxy groups selected from nitrogen and oxygen heteroatoms, heterocycloalkylformyl containing 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing Heterocycloalkyloxyformyl, aryl, aryloxy, arylformyl, aryloxyformyl, 3-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4- A heterocyclic aryl group with 9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, a heterocyclic aryloxy group with 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen , heterocyclic aryl formyl containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen, containing 4-9 carbon atoms and 1-3 heteroatoms selected from nitrogen and oxygen Heterocyclic aryloxyformyl;

R ₂ is selected from hydrogen, C _1-6 alkyl, methoxy, amino;

R ₃ is selected from hydrogen, C _1-6 alkyl, C _1-6 alkyl formyl, carbamoyl, substituted carbamoyl, benzyl;

Wherein said alkyl, cycloalkyl, aryl, heterocyclic aryl, heterocycloalkyl, benzyl and amino are optionally substituted by 1-2 groups selected from the following groups: hydroxyl, halogen, cyano, Amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C _1-6 alkyl, C _1-6 cycloalkyl, C _1-6 alkyloxy, C _3-6 heterocycloalkane base, aryl;

X is selected from C, N;

m is selected from 1, 2;

n is selected from 2,3,4.

_R is preferably ethoxyformyl, isopropoxyformyl, tert-butoxyformyl, cycloalkylformyl, substituted cycloalkylformyl, cycloalkyloxyformyl, substituted cycloalkyloxyformyl, aryl Base-C ₁ alkyl, substituted aryl-C ₁ alkyl, heteroaryl-C ₁ alkyl, heteroaryl-C ₁ alkyl, aryl, substituted aryl, aryl formyl, aryloxymethyl Acyl, substituted arylformyl, substituted aryloxyformyl, 2-(5-methyl)pyrimidinyl, substituted 2-(5-methyl)pyrimidinyl;

R ₂ is preferably hydrogen, amino;

X is preferably C, N;

m is preferably 1,2; n is preferably 2,3,4.

The pharmaceutically acceptable salt described in the present invention is a salt formed by the compound of the present invention and an acid selected from the following: hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, lemon acid, acetic acid or trifluoroacetic acid. Preference is given to hydrochloric acid, p-toluenesulfonic acid or trifluoroacetic acid.

The compound according to any one of the first aspect of the present invention is the target compound of the present invention (represented by structural formula or described by systematic name) prepared in the examples, its stereoisomers, and pharmaceutically acceptable salts thereof.

A compound according to any one of the first aspect of the present invention, which is a compound selected from the group consisting of:

The second aspect of the present invention provides a method for preparing any one of the compounds described in the first aspect of the present invention, which comprises the following steps:

i) at a temperature of 20°C to 50°C (for example, 20°C to 30°C, 30°C to 50°C, or 40°C to 50°C), in a solvent (water/acetic acid in a volume ratio of 2.5:1), the formula The compound represented by 1a is reacted with sodium nitrite for 1-4h to obtain the compound represented by formula 2a.

ii) at a temperature of 0°C to 60°C (eg 0°C to 35°C, 15°C to 35°C, 20°C to 40°C or 20°C to 60°C) in 1-4 equivalents of a reducing agent (eg In the presence of sodium sulfite), react in a solvent (such as 25% ammonia water) for 4-8h to obtain the compound shown in formula 3a.

iii) reacting the compound represented by formula 3a with formic acid in a solvent (eg water) at a temperature of 90°C to 100°C (eg 90°C to 95°C, 90°C to 100°C or 95°C to 100°C) 1-4h, and then react with sodium hydroxide for 1-4h to obtain the compound represented by formula 4a.

iv) at a temperature of 50°C to 80°C (eg, 50°C to 60°C, 60°C to 70°C, or 70°C to 80°C), in the presence of sodium acetate, in a solvent (eg, glacial acetic acid), formula 4a The compound shown is reacted with liquid bromine for 2-4 hours to obtain the compound shown in formula 5a.

v) at a temperature of 60°C to 90°C (eg 60°C to 70°C, 70°C to 80°C or 80°C to 90°C) in the presence of a base (eg N,N-diisopropylethylamine), In a solvent (such as N,N-dimethylformamide), the compound represented by formula 5a is reacted with 1-bromo-2-butyne for 4-7h to obtain the compound represented by formula 6a.

vi) at a temperature of 10°C to 30°C (such as 10°C to 20°C, 20°C to 30°C, or 10°C to 30°C), in a solvent (such as acetone), the compound represented by formula h is mixed with 1- Bromo-3-chloropropane was reacted for 4-7h to obtain a compound represented by formula d; X=C; n=2,3.

At a temperature of -10°C to 30°C (e.g. -10°C to 20°C, 0°C to 10°C, 0°C to 30°C), in the presence of a base and a salt (e.g. sodium hydride, lithium bromide), in a solvent (e.g. In tetrahydrofuran, N,N-dimethylformamide or a mixture of the two), the compound shown in formula h is reacted with 1-bromo-3-chloropropane for 4-7h to obtain the compound shown in formula d; X=N ; n=2,3.

vii) in the presence of a base (eg potassium carbonate) in a solvent (eg N-methyl In pyrrolidone), the compound represented by formula a is reacted with the compound represented by formula d for 7-12h to obtain the compound represented by formula b; n=2,3.

viii) at a temperature of 20°C to 50°C (eg, 20°C to 30°C, 20°C to 40°C, or 30°C to 50°C), in the presence of a base (eg, potassium carbonate) in a solvent (eg, N,N- In dimethylformamide), the compound shown in formula a is reacted with the compound shown in formula e for 7-10h to obtain the compound shown in formula f;

ix) at a temperature of 20°C to 30°C (eg, 20°C to 25°C, 20°C to 30°C, or 25°C to 30°C), in the presence of a base (eg, triethylamine), in a solvent (eg, methylene chloride) ), the compound shown in formula f is reacted with methanesulfonyl chloride for 1-2h to obtain the compound shown in formula g;

At a temperature of 80°C to 110°C (e.g., 80°C to 95°C, 90°C to 100°C, or 85°C to 110°C), in the presence of a base (e.g., triethylamine) and a salt (e.g., potassium iodide), in a solvent ( For example, in dioxane), react the compound represented by formula g with the compound represented by formula h for 3-5h to obtain the compound represented by formula b2.

x) in the presence of a base (e.g. potassium carbonate) in a solvent (e.g. THF, N, In N-dimethylformamide or a mixture of the two), the compound shown in formula b is reacted with the compound shown in formula c for 9-16h to obtain the compound of the present invention shown in formula (II);

Wherein, R ₁ , R ₂ , X, Y, m and n are as defined in the first aspect of the present invention.

The third aspect of the present invention provides a pharmaceutical composition, which comprises a therapeutically and/or preventively effective amount of any one of the compounds described in the first aspect of the present invention and its stereoisomers, pharmaceutically acceptable salts thereof, and any Selected one or more pharmaceutically acceptable carriers or excipients.

The fourth aspect of the present invention provides the compound described in any one of the first aspect of the present invention and its stereoisomer, its pharmaceutically acceptable salt, or the pharmaceutical composition described in any one of the third aspect of the present invention in the preparation of Use in medicines for the treatment and/or prevention of diseases or conditions associated with excessive activity of DPP-IV or overexpression of DPP-IV. In one embodiment, the disease or condition associated with hyperactivity of DPP-IV or overexpression of DPP-IV is a disease or condition selected from the group consisting of diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, type 2 Diabetes and more.

The fourth aspect of the present invention also provides the compound described in any one of the first aspect of the present invention and its stereoisomer, its pharmaceutically acceptable salt, or the pharmaceutical composition described in any one of the third aspect of the present invention for preparation Use in medicines for treating and/or preventing diabetes, hyperglycemia, non-insulin-dependent diabetes, type 2 diabetes and the like.

The fourth aspect of the present invention also provides the compound described in any one of the first aspect of the present invention and its stereoisomer, its pharmaceutically acceptable salt, or the pharmaceutical composition described in any one of the third aspect of the present invention in preparation as Use of a DPP-IV inhibitor in a medicament.

The fifth aspect of the present invention provides a method for treating and/or preventing diseases or disorders related to excessive DPP-IV activity or overexpression of DPP-IV in a subject in need, the method comprising administering The subject is administered a therapeutically and/or prophylactically effective amount of any one of the compounds described in the first aspect of the present invention and its stereoisomers, pharmaceutically acceptable salts thereof, or any of the compounds described in the third aspect of the present invention pharmaceutical composition. According to the method according to any one of the fifth aspect of the present invention, wherein the disease or disease related to excessive DPP-IV activity or DPP-IV overexpression is selected from diabetes, hyperglycemia, non-insulin-dependent diabetes mellitus, 2 type diabetes etc.

The fifth aspect of the present invention also provides a method for treating and/or preventing diabetes, hyperglycemia, non-insulin-dependent diabetes, and type 2 diabetes in a subject in need, the method comprising administering or administering a therapeutically and/or preventively effective amount of any one of the compounds according to the first aspect of the present invention and its stereoisomers, pharmaceutically acceptable salts thereof, or any one of the pharmaceutical compositions according to the third aspect of the present invention.

The sixth aspect of the present invention provides the compound described in any one of the first aspect of the present invention and its stereoisomers for the treatment and/or prevention of diseases or conditions related to excessive DPP-IV activity or DPP-IV overexpression body, its pharmaceutically acceptable salt. According to the compound of the sixth aspect of the present invention, wherein the disease or disease associated with excessive DPP-IV activity or DPP-IV overexpression is selected from: diabetes, hyperglycemia, non-insulin-dependent diabetes, type 2 diabetes etc.

The sixth aspect of the present invention also provides the compound described in any one of the first aspect of the present invention and its stereoisomers for the treatment and/or prevention of diabetes, hyperglycemia, non-insulin-dependent diabetes, type 2 diabetes, etc. , a pharmaceutically acceptable salt thereof.

Any aspect of the present invention or the features of any one aspect of the present invention are also applicable to any other aspect or any one of the other aspects, as long as they are not mutually contradictory, of course when they are applicable to each other , if necessary, appropriate modifications can be made to the corresponding features. In the present invention, for example, when referring to "any one of the first aspect of the present invention", the "any one" refers to any sub-aspect of the first aspect of the present invention, and when other aspects are mentioned in a similar manner, it also refers to have a similar meaning.

Detailed description of the invention:

Various aspects and features of the present invention are further described below.

All the documents cited in the present invention are incorporated herein by reference in their entirety, and if the meaning expressed in these documents is inconsistent with the present invention, the expression of the present invention shall prevail. In addition, various terms and phrases used in the present invention have common meanings known to those skilled in the art. Even so, the present invention still hopes to make a more detailed description and explanation of these terms and phrases here. The terms and phrases mentioned are as follows: If there is any inconsistency with the known meaning, the meaning expressed in the present invention shall prevail. The following are definitions of various terms used in the present invention, and these definitions apply to the terms used throughout the specification of this application, unless otherwise stated in specific cases.

The term "alkyloxy" refers to an alkyl-O-, wherein the alkyl group is as described herein.

As used herein, the terms "halo", "halogen", "halogen atom", "halo" and the like mean fluorine, chlorine, bromine or iodine, especially fluorine, chlorine or bromine.

As used herein, the term "alkyl" refers to an alkyl group having the indicated number of carbon atoms, which is straight or branched, and which may include subgroups thereof, for example when referring to "C _{1- 6} alkyl", it may also include C _1-5 alkyl, C _1-4 alkyl, C _2-6 alkyl, C _2-4 alkyl, etc. sub-range groups, as well as specific groups For example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl.

As used herein, the term "aryl" is defined herein alone or in combination as a monocyclic or bicyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like. Similarly, the term "aryloxy-" refers to an aryl group which is attached to the rest of the compound through an oxygen.

As used herein, the term "heterocyclic aryl" refers herein to an aryl group having 1 to 3 heteroatoms as ring atoms, the remaining ring atoms being carbon, including oxygen, sulfur and nitrogen. Examples of heteroaryl include, but are not limited to, pyridyl, pyrimidinyl, imidazolyl, furyl, thienyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, and the like. In one embodiment, the heteroaryl is methyl substituted pyrimidinyl.

As used herein, the term "aryl-C _1-3 alkyl—" refers to an aryl group attached to the rest of the compound through a C _1-3 alkyl group.

As used herein, the term "heteroaryl-C _1-3 alkyl—" refers to a heteroaryl group that is attached to the rest of the compound through a C _1-3 alkyl group.

As used herein, the term "cycloalkyl" refers to a cyclic alkyl group having the indicated number of ring carbon atoms, and it may include subgroups thereof, for example when referring to "C _3-8 cycloalkyl", It may also include sub-range groups represented by C _3-7 cycloalkyl, C _3-6 cycloalkyl, C _3-5 cycloalkyl, C _4-7 cycloalkyl, etc., as well as specific groups such as ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.

As used herein, the term "heterocycloalkyl" refers to a cyclic heteroalkyl group having the specified number of ring atoms, including monocyclic or condensed ring groups, in the ring, having 5 to 9 ring atoms, One or two ring atoms are heteroatoms selected from nitrogen, oxygen or sulfur, and the remaining ring atoms are carbon. These rings can also have one or more double bonds, however, these rings do not have fully conjugated Л electron systems. Heterocycloalkyl includes, but is not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.

As used herein, the term "effective amount" refers to a dose that can achieve treatment and/or prevention of the diseases or conditions described in the present invention in a subject.

As used herein, the term "pharmaceutical composition", which may also refer to a "composition", is useful for achieving the treatment and/or prevention of the diseases or conditions of the present invention in a subject, especially a mammal.

As used herein, the term "subject" may refer to a patient or other animal, particularly a mammal, that receives a compound of formula I of the present invention or a pharmaceutical composition thereof for the treatment and/or prevention of the diseases or conditions described in the present invention, such as People, dogs, monkeys, cows, horses, etc.

As used herein, the term "disease and/or condition" refers to a physical state of the subject that is associated with the disease and/or condition of the present invention. For example, the disease and/or disease in the present invention can refer to a physical state, such as a physical state with high blood sugar, or a disease state, such as hyperglycemia, diabetes and other disease states. Herein, no distinction is made between physical state and disease state, or the two may refer to each other, for example, "hyperglycemia" and "hyperglycemia" may be used interchangeably.

As used herein, unless otherwise specified, "%" refers to percentages by weight/weight, especially in the case of describing solid matter. Of course, when describing a liquid substance, the "%" can refer to a weight/volume percentage (for the case of a solid dissolved in a liquid), or it can refer to a volume/volume percentage (for a case of a liquid dissolved in a liquid).

As described herein, the term "pharmaceutically acceptable", for example, when describing a "pharmaceutically acceptable salt", means that the salt is not only physiologically acceptable to the subject, but also refers to a pharmaceutically useful salt. Synthetic substances, such as salts formed as intermediates for chiral resolution, although the salts of such intermediates cannot be directly administered to the subject, the salts may play a role in obtaining the final product of the present invention .

Still another aspect of the present invention relates to a pharmaceutical composition comprising the compound of the present invention as an active ingredient. The pharmaceutical composition can be prepared according to methods known in the art. Any dosage form suitable for human or animal use can be prepared by combining the compounds of the present invention with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention in its pharmaceutical composition is usually 0.1-95% by weight.

The compound of the present invention or the pharmaceutical composition containing it can be administered in the form of a unit dosage, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and Respiratory tract, skin, vagina, rectum, etc.

The dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form. Liquid dosage form can be solution (including true solution and colloid solution), emulsion (including o/w type, w/o type and double emulsion), suspension, injection (including water injection, powder injection and infusion), eye drops formulations, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) mist, sprays, etc.; semi-solid dosage forms can be ointment, Gels, pastes, etc.

The compound of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.

To prepare the compound of the present invention into tablets, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, solubilizers. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, iso Propanol, etc.; binders can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked poly Vinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecylsulfonate, etc.; lubricants and co-solvents It can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol and the like.

Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

In order to make the administration unit into a capsule, the compound of the present invention as an active ingredient can be mixed with a diluent and a solubilizer, and the mixture can be directly placed in a hard capsule or a soft capsule. The active ingredient compound of the present invention can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard capsules or soft capsules. Various diluents, binders, wetting agents, disintegrants, and solubilizers used in the preparation of tablets of the compound of the present invention can also be used to prepare capsules of the compound of the present invention.

In order to make the compound of the present invention into injection, water, ethanol, isopropanol, propylene glycol or their mixtures can be used as solvent and appropriate amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator commonly used in this field can be added. The solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc. For preparation of freeze-dried powder injection, mannitol, glucose, etc. can also be added as proppants.

In addition, coloring agents, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparations, if necessary.

In order to achieve the purpose of medication and enhance the therapeutic effect, the medicine or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention can vary widely depending on the nature and severity of the disease to be prevented or treated, individual conditions of the patient or animal, administration route and dosage form, etc. Generally speaking, the suitable daily dosage range of the compound of the present invention is 0.001-150 mg/Kg body weight, preferably 0.1-100 mg/Kg body weight, more preferably 1-60 mg/Kg body weight, most preferably 2-30 mg/Kg body weight. The above-mentioned dosage can be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the doctor and the dosage regimen including the use of other therapeutic means.

The compound or composition of the present invention can be taken alone, or used in combination with other therapeutic drugs or symptomatic drugs. When the compound of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.

Beneficial technical effect

All the compounds in the present invention have novel chemical structures, and the in vitro DPP-IV inhibitory activity of most substituted xanthine compounds reaches more than ₅₀ %, and the in vitro DPP-IV inhibitory activity IC of 12 compounds reaches the micromolar level, especially The IC ₅₀ value of 7 compounds reached the level of 10 ^-7 mol/l, and the IC ₅₀ value of 1 compound reached the level of 10 ^-8 mol/l, showing good DPP-IV inhibitory activity and selectivity, thus providing a A non-peptide selective DPP-IV inhibitor with novel structure and strong activity can be used for the prevention and treatment of type 2 diabetes and related diseases.

Detailed ways

The present invention can be further described by the following examples, however, the scope of the present invention is not limited to the following examples. Those skilled in the art can understand that various changes and modifications can be made in the present invention without departing from the spirit and scope of the present invention. The present invention provides general and/or specific descriptions of the materials and test methods used in the tests. While many of the materials and methods of manipulation which are employed for the purposes of the invention are well known in the art, the invention has been described here in as much detail as possible.

For all of the following examples, standard manipulations and purification methods known to those skilled in the art can be used. All temperatures are in °C (degrees Celsius) unless otherwise indicated. Compound structures were determined by nuclear magnetic resonance spectroscopy (NMR) and/or mass spectroscopy (MS). m.p. is melting point given in °C, uncorrected for temperature.

Preparation of the Example section

The structure of the compound was confirmed by hydrogen nuclear magnetic resonance ( ¹ H NMR) and mass spectrometry (MS). Proton and Carbon NMR shifts (δ) are given in parts per million (ppm). The proton nuclear magnetic resonance spectrum is measured with a Mercury-300 or Mercury-400 nuclear magnetic resonance instrument, deuterated chloroform (CDCl ₃ ) or heavy water (D ₂ O) or deuterated dimethyl sulfoxide (DMSO-d ₆ ) or deuterated methanol (CD ₃ OD) was used as solvent, and tetramethylsilane (TMS) was used as internal standard.

The melting point was determined by a Japanese Yanaco M.P-500D melting point analyzer, and the temperature was not corrected.

High-resolution mass spectrometry was determined by Agilent1100series LC/MSD trap mass spectrometer.

The electronic balance adopts the Japanese Yanaco LY-300 electronic balance.

Column chromatography generally uses 200-300 mesh silica gel as the carrier.

Anhydrous solvents were all worked up by standard methods. Other reagents were commercially available analytically pure.

in,

TFA is trifluoroacetic acid, namely trifluoroacetic acid.

DMF is N,N-Dimethylformamide, that is, N,N-dimethylformamide.

THF is tetrahydrofuran, namely tetrahydrofuran.

NMP is 1-Methyl-2-pyrrolidone, 1-methylpyrrolidone

Preparation example

Synthetic route of Scheme1 intermediate a

Preparation of the first step 6-amino-5-nitroso-1-methyluracil 2a

Dissolve 6-amino-1-methyluracil (10.00g, 70.9mmol) in a mixed solution of 50mL water and 20mL glacial acetic acid, add an aqueous solution of sodium nitrite (7.138g, 103.5mmol) at room temperature 25°C (40 mL), stirred at room temperature for 0.5 h, then raised to 50° C. and stirred for 1 h, and finally moved to room temperature and stirred overnight. After the reaction was detected by TLC, the stirring was stopped, filtered, and the filter cake was washed with water (100 mL) and 95% ethanol (50 mL) to obtain Intermediate 2a, 11.97 g of a purple solid, with a yield of about 99.3%.

¹ H NMR(DMSO-d ₆ ,300MHz)δ:3.166(s,3H,CH ₃ ),9.051(s,2H,NH ₂ ),11.484(s,1H,NH).MS(ESI ⁺ ):m/ z=170.3[M+H] ⁺

Preparation of the second step 5,6-diamino-1-methyluracil 3a

Dissolve 6-amino-5-nitroso-1-methyluracil 2a (11.50g, 67.6mmol) in 200mL ammonia water (25%), add sodium dithionite (41.20g, 236.6 mmol), stir. The temperature in the reaction flask was gradually raised to 35 °C. When the temperature in the bottle no longer rises, heat to 60°C and stir for 1 h. The reaction was then moved to room temperature and stirred for 6 h. After the reaction was complete, the stirring was stopped, filtered, the filter cake was washed with ice water, and dried in vacuum. Intermediate 3a was obtained, 9.28 g of off-white solid, with a yield of 87.9%.

¹ H NMR(DMSO-d ₆ ,300MHz)δ:3.201(s,3H,CH ₃ ),6.104(s,4H,NH ₂ ),10.517(s,1H,NH).MS(ESI ⁺ ):m/ z=157.2[M+H] ⁺ .

Preparation of the third step 3-methyl-1H-2,6-dicarbonylpurine 4a

Dissolve 5,6-diamino-1-methyluracil 3a (10.00g, 64.0mmol) in a mixed solvent of formic acid (3.305mL) and water (74.74mL), heat and reflux at 105°C for 3h and then cool down to 20°C , Added sodium hydroxide (5.12g, 128.1mmol) in water (6.40mL) solution, heated to reflux at 105°C for 1h, and the reaction was complete. Cool to 0°C, adjust the pH to 4 with glacial acetic acid, a yellow-white solid precipitates, filter, wash the filter cake with ice water, and vacuum-dry to obtain intermediate 4a, 10.01 g of white solid, with a yield of about 94.1%.

¹ H NMR(DMSO-d ₆ ,300MHz)δ:3.478(s,3H,CH ₃ ),7.853(s,1H,CH),11.092(s,1H,NH).MS(ESI ⁺ ):m/z =167.3[M+H] ⁺ .

Preparation of the fourth step 8-bromo-3-methyl-1H-2,6-dicarbonylpurine 5a

3-Methyl-1H-2,6-dicarbonylpurine 4a (10.00g, 60.2mmol) and sodium acetate (9.87g, 120.3mmol) were dissolved in glacial acetic acid (90mL), and liquid bromine (11.54g ,72.2mmol), heated and stirred at 65°C for 2h. After the reaction was complete, cool to room temperature 25°C, filter, wash the filter cake with glacial acetic acid (100 mL) and ice water (100 mL), and dry in vacuo to obtain intermediate 5a, 12.23 g of off-white solid, with a yield of about 82.6%.

¹ H NMR(DMSO-d6,300MHz)δ:3.161(s,3H,CH ₃ ),11.194(s,1H,NH),12.566(s,1H,NH).MS(ESI ⁺ ):m/z= 247.2[M+H] ⁺ .

The fifth step is the preparation of 8-bromo-7-[1-(2-butyn)yl]-3-methyl-1H-2,6-dicarbonylpurine a

8-Bromo-3-methyl-1H-2,6-dicarbonylpurine 5a (11.00g, 44.7mmol) and N,N-diisopropylethylamine (5.78g, 44.7mmol) were dissolved in N,N -Dimethylformamide (65mL), stirred at room temperature 25°C for 30min, added 1-bromo-2-butyne (5.95g, 44.7mmol) dropwise, heated and stirred at 80°C for 5h. After the reaction was complete, cool to 0°C, add 200 mL of ice water to the reaction system and stir for 30 min, an off-white solid precipitated, filtered, washed the filter cake with ice water (200 mL), and dried in vacuo to obtain intermediate a, off-white solid 10.26 g , yield 77.5%.

¹ H NMR(DMSO-d ₆ ,300MHz)δ:1.788(s,3H,CH ₃ ),3.305(s,3H,CH ₃ ),5.046(s,2H,CH ₂ ),11.322(s,1H,NH ).MS(ESI ⁺ ):m/z=297.0[M+H] ⁺ .

Synthetic route of Scheme2 intermediate b

The preparation of the first step 4-(3-chloropropyl)piperazine-1-carboxylic acid tert-butyl ester d

Dissolve tert-butyl 1-piperazinecarboxylate (2.00 g, 10.7 mmol) in a mixed solvent of 25 mL of anhydrous DMF and anhydrous THF (1:1), and gradually add sodium hydride ( 0.27g, 11.3mmol) and anhydrous lithium bromide (0.57g, 6.6mmol), stirred at 0°C for 4h. 1-Bromo-2-chloropropane (1.84 g, 11.8 mmol) was added dropwise, and the reaction was moved to room temperature at 25 °C and stirred for 5 h at 0 °C. After the reaction was complete, concentrate under reduced pressure, cool to 0°C, add 50 mL of ice water to the reaction system and stir for 30 min, extract with dichloromethane, combine the organic layers, wash the organic layers with water and saturated brine, dry over anhydrous sodium sulfate, and filter. Concentration under reduced pressure, the obtained crude product was separated by silica gel (200-300 mesh) column chromatography, and dichloromethane-methanol (V:V=30:1) mixture was used as the eluent to obtain intermediate d, 2.18 g of yellow-white solid, Yield 77.4%, MS(ESI ⁺ ):m/z=263.2[M+H] ⁺ .

The second step 7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert-butoxycarbonyl)-1-piperazinyl]propyl}- Preparation of 1H-purine-2,6-dione b

8-Bromo-7-[1-(2-butyn)yl]-3-methyl-1H-2,6-dicarbonylpurine a (0.64g, 3.5mmol) and potassium carbonate (0.96g, 6.9mmol ) was dissolved in 10mL NMP solvent, heated to 70°C, and stirred for 15min. Gradually added tert-butyl 4-(3-chloropropyl)piperazine-1-carboxylate d (1.00 g, 3.8 mmol) and stirred at 70° C. for 6 h. After the reaction was complete, cool to room temperature 0°C, add 100 mL of ice water to the system and stir, extract with ethyl acetate, combine the organic layers, wash the organic layers with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product was separated by silica gel (300-400 mesh) column chromatography, and the dichloromethane-methanol (V:V=30:1) mixture was used as the eluent to obtain intermediate b, 1.71 g of a yellow solid, with a yield of 86.0%. MS(ESI ⁺ ):m/z=523.3[M+H] ⁺ .

The preparation of the first step 4-(5-methylpyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester i

Dissolve tert-butyl 1-piperazinecarboxylate (5.00 g, 26.8 mmol) in a mixed solvent of 30 mL of anhydrous DMF and anhydrous THF (1:1), and gradually add sodium hydride ( 1.29g, 53.7mmol) and anhydrous lithium bromide (2.80g, 32.2mmol), stirred at 0°C for 4h. 2-Chloro-5-methylpyrimidine (3.45g, 26.8mmol) was gradually added at 0°C, stirred for 20min, and the reaction was moved to room temperature at 25°C and stirred for 5h. After the reaction was complete, concentrate under reduced pressure, cool to 0°C, add 100 mL of ice water to the reaction system and stir for 30 min, extract with ethyl acetate, combine the organic layers, wash the organic layers with water and saturated brine, dry over anhydrous sodium sulfate, and filter. Concentration under reduced pressure, the resulting crude product was separated by silica gel (300-400 mesh) column chromatography, using dichloromethane-methanol (V:V=33:1) mixture as eluent, to obtain intermediate i, 6.29 g of off-white solid, Yield 84.2%.

¹ H NMR(CDCl ₃ ,300MHz)δ:1.486(s,9H,Boc),2.132(s,3H,CH ₃ ),3.489(t,4H,J=4.5Hz,CH ₂ ),3.758t,4H, J=4.5Hz,CH ₂ ),8.168(s,2H,in pyrimidine).MS(ESI ⁺ ):m/z=279.3[M+H] ⁺ .

Preparation of the second step 4-(5-methylpyrimidin-2-yl)piperazine j

Dissolve 4-(5-methylpyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester i (6.00g, 21.6mmol) in 100mL dichloromethane, add trifluoroacetic acid dropwise at room temperature 25°C (20mL), stirred for 1h. After the reaction was complete, the reaction solution was concentrated under reduced pressure. Dissolve the residue in ethyl acetate (100mL) and 1mol/L sodium hydroxide aqueous solution, stir for 1h, collect the ethyl acetate layer, then extract the water layer with ethyl acetate, combine the organic layers, and use water and saturated salt for the organic layers respectively Washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate j, 3.62 g of a reddish solid, with a yield of 94.2%.

The third step is the preparation of 4-(3-chloropropyl)-1-[(5-methylpyrimidin)-2-yl]piperazine d

Dissolve 4-(5-methylpyrimidin-2-yl)piperazine j (3.413g, 19.1mmol) in 40mL of acetone, add potassium carbonate (2.643g, 19.1mmol), stir at room temperature 25°C for 20min, gradually 1-Bromo-3-chloropropane (1.591 g, 23.0 mmol) was added dropwise and stirring was continued for 5 h. After the reaction was complete, concentrate under reduced pressure, add 50 mL of ice water to the reaction system and stir for 30 min, extract with dichloromethane, combine the organic layers, wash the organic layers with water and saturated brine respectively, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Intermediate d was obtained, 4.19 g of a reddish solid, with a yield of 86.2%.

¹ H NMR(CDCl ₃ ,400MHz)δ:1.992(m,2H,CH ₂ ),2.108(s,3H,CH ₃ ),2.487(m,2H,CH ₂ ),2.498(m,4H,CH ₂ ) ,3.615(m,2H,CH ₂ ),3.765(m,4H,CH ₂ ),8.144(d,2H,J=8.4Hz,CH,in pyrimidine).MS(ESI ⁺ ):m/z=254.1[ M+H] ⁺ .

The fourth step 7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidin-2-yl)-1-piperazinyl Preparation of ]propyl}-1H-purine-2,6-dione b

8-Bromo-7-[1-(2-butyn)yl]-3-methyl-1H-2,6-dicarbonylpurine a (0.302g, 1.2mmol) and potassium carbonate (0.340g, 2.4mmol ) was dissolved in 10mL NMP solvent, heated to 70°C, and stirred for 15min. Gradually added 4-(3-chloropropyl)-1-[(5-methylpyrimidin)-2-yl]piperazine d (0.344g, 1.3mmol) and stirred at 70°C for 6h. After the reaction was complete, cool to 0°C, add 50 mL of ice water to the reaction system, stir for 30 min, extract with ethyl acetate, combine the organic layers, wash the organic layers with water and saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product was separated by silica gel (300-400 mesh) column chromatography, using dichloromethane-methanol (V:V=30:1) mixture as eluent, to obtain intermediate b, 0.60 g of yellow solid, with a yield of 86.9%.

¹ H NMR(CDCl ₃ ,400MHz)δ:1.25(m,2H,CH ₂ ),11.803(s,3H,CH ₃ ),2.036(s,3H,CH ₃ ),2.104(m,2H,CH ₂ ) ,2.538(m,4H,CH ₂ ),3.538(s,3H,CH ₃ ),3.755(m,4H,CH ₂ ),4.113(m,2H,CH ₂ ),8.134(s,2H,CH,in pyrimidine).MS(ESI ⁺ ):m/z=514.1[M+H] ⁺ .

Synthetic route of Scheme3 intermediate 1c

Preparation of the first step (R)-3-amino-2-piperidone 1c-2

Dissolve D-ornithine hydrochloride 1c-1 (5.000g, 29.7mmol) in 45mL of anhydrous methanol, cool to -80°C, and stir for 30min. Thionyl chloride (9.031 g, 75.9 mmol) was added dropwise, stirred at -80°C for 30 min, and then the reaction was moved to room temperature at 25°C and stirred for 24 h. After the reaction was complete, the reaction liquid was concentrated, and 19 mL of water was added to make an aqueous solution, which was purified by 717 (OH ^- ) anion exchange resin, 19 mL of methanol was added to the obtained aqueous solution, and 190 mL of chloroform was added to extract and wash impurities, and the aqueous layer was collected for vacuum freeze-drying to obtain intermediate Body 1c-2, white foamy solid 3.18g, yield 94.2%.

¹ H NMR(CDCl ₃ ,400MHz)δ:1.25(m,2H,CH ₂ ),1.803(s,3H,CH ₃ ),2.036(s,3H,CH ₃ ),2.104(m,2H,CH ₂ ) ,2.538(m,4H,CH ₂ ),3.538(s,3H,CH ₃ ),3.755(m,4H,CH ₂ ),4.113(m,2H,CH ₂ ),8.134(s,2H,CH,) .MS(ESI ⁺ ):m/z=115.15[M+H] ⁺ .

Preparation of the second step (R)-3-aminopiperidine 1c

(R)-3-Amino-2-piperidinone 1c-2 (3.182g, 27.9mmol) was dissolved in 200mL of anhydrous THF at 0°C, cooled to -80°C, and stirred for 1h. A solution of lithium aluminum tetrahydrogen (3.382 g, 89.2 mmol) in THF (100 mL) was added dropwise, and when the temperature in the reaction flask stopped rising, it was heated to reflux at 90° C. for 10 h. After the reaction was complete, it was cooled to 0°C, and 1.87mL of water, 1.87mL of 5N NaOH aqueous solution and 5.68mL of water were successively added to the reaction system. Filter, wash the filter cake with 100mL THF, collect the filtrate, and concentrate under reduced pressure to obtain intermediate 1c, 1.39g of brownish-red oily substance, yield 49.8%.

¹ H NMR (CDCl ₃ , 400MHz) δ: 1.25(m,2H, CH ₂ ), 1.803(s,3H, CH ₃ ), 2.036(s,3H, CH ₃ ), 2.104(m,2H, CH ₂ ) ,2.538(m,4H, CH ₂ ),3.538(s,3H, CH ₃ ),3.755(m,4H, CH ₂ ),4.113(m,2H, CH ₂ ),8.134(s,2H, CH 2 ,) .MS(ESI ⁺ ):m/z=101.19[M+H] ⁺ .

Synthetic route of Scheme4 intermediate 2c

Using 2c-1 (5.000g, 29.7mmol) as the raw material, the intermediate 2c was obtained by using the similar operation steps in Scheme 3, 1.45g of brownish-red oily substance, and the yield was 52.0%.

¹ H NMR(DMSO-d ₆ ,300MHz)δ:4.66-4.64(m,1H,CHC=O),3.79-3.61(m,4H, CH ₂ NH, CH ₂ OH),3.35(br,4H,CH ₂ NCH ₂ in thiomorpholine),2.83-2.61(m,9H,CH ₂ SCH ₂ in thiomorpholine,5H in pyrrolidine),0.93(s,6H,CH3CCH3).MS(ESI ⁺ ):m/z=101.19[M+ H] ⁺

Example

Example 1

Compound 1 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4- (5-Methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5 Preparation of -methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

Dissolve (R)-3-aminopiperidine 1c (0.050g, 0.50mmol) and potassium carbonate (0.124g, 0.90mmol) in 20mL of anhydrous THF, add 20mg of molecular sieves, and stir at room temperature 25°C for 30min. Gradually add 7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidin-2-yl)-1-piperazinyl] Propyl}-1H-purine-2,6-dione b (0.128g, 0.25mmol), heated to 90°C and refluxed for 8h. After the reaction is complete, cool to room temperature 25°C, filter, and concentrate the filtrate under reduced pressure. The obtained crude product is separated by silica gel (300-400 mesh) column chromatography, and the mixture of dichloromethane-methanol (V:V=10:1) is used as the eluent , to obtain compound 1, yellow solid 0.070g, yield 52.3%. m.p.183-184℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.707(s,3H),1.781(m,2H),1.991(m,2H),2.019(s,3H),2.391(m,4H+2H),3.039 (m,2H),3.162(m,2H),3.372(s,3H),3.584(m,4H),3.710(m,4H),3.969(m,2H),4.909(s,2H),8.068( s,2H).HR-MS(ESI-TOF ⁺ ): Calcd. for C ₂₇ H ₃₉ N ₁₀ O ₂ 535.3252, found [M+H] ⁺ 535.3241.

Example 2

Compound 2 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4- (5-Methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5 Preparation of -methylpyrimidine)-1-piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and 2c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 2, 54 mg of yellow solid, with a yield of 51.9%. m.p.183-184℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.707(s,3H),1.799(m,2H),1.989(m,2H),2.019(s,3H),2.391(m,4H+2H),3.039 (m,2H),3.162(m,2H),3.372(s,3H),3.584(m,4H),3.710(m,4H),3.969(m,2H),4.909(s,2H),8.068( s,2H).HR-MS(ESI-TOF ⁺ ): Calcd. for C ₂₇ H ₃₉ N ₁₀ O ₂ 535.3252, found [M+H] ⁺ 535.3244.

Example 3

Compound 3 8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidine) -1-piperazinyl]propyl}-1H-purine-2,6-dione

8-(1-Homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidine)-1 Preparation of -piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 3, 71 mg of yellow solid, with a yield of 68.3%. m.p.186-187℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.707(s,3H),1.802(m,2H),1.989(m,2H),2.019(s,3H),2.391(m,4H+2H),3.039 (m,2H),3.162(m,2H),3.372(s,3H),3.584(m,4H),3.710(m,4H),3.969(m,2H),4.909(s,2H),8.068( s,2H).HR-MS(ESI-TOF ⁺ ): Calcd. for C ₂₇ H ₃₉ N ₁₀ O ₂ 535.3252, found [M+H] ⁺ 535.3243.

Example 4

Compound 4 8-(1-piperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidine)- 1-Piperazinyl]propyl}-1H-purine-2,6-dione

8-(1-piperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[4-(5-methylpyrimidine)-1- Preparation of piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.150g, 0.29mmol) and c (0.103g, 0.58mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 4, 85 mg of yellow solid, with a yield of 55.9%. m.p.189℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.710(s,3H),1.824(m,2H),2.022(s,3H),2.370(m,2H+4H),2.975(m,4H),3.278 (m,4H),3.311(s,3H),3.554(m,4H),4.816(s,2H),8.072(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₆ H ₃₇ N ₁₀ The calculated value of O ₂ is 521.3096, and the measured value is [M+H] ⁺ 521.3093.

Example 5

Compound 5 8-[1-(4-methyl)piperazinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-methyl Oxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

8-[1-(4-methyl)piperazinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-methoxycarbonyl Preparation of )-1-piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 5, 56 mg of yellow solid, and the yield was 53.6%.

Example 6

Compound 6 8-(1-piperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert-butoxycarbonyl)-1 -piperazinyl]propyl}-1H-purine-2,6-dione

8-(1-piperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert-butoxycarbonyl)-1-piper Preparation of azinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and c (0.032g, 0.37mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 6, 51 mg of yellow solid, with a yield of 51.7%.

Example 7

Compound 7 8-[1-(4-methyl)piperazinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-iso Propoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

8-[1-(4-methyl)piperazinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-isopropoxy Preparation of carbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.20mmol) and c (0.59g, 0.59mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 7, 52 mg of yellow solid, and the yield was 50.4%.

Example 8

Compound 8 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -ethoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethyl Preparation of Oxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.200g, 0.41mmol) and 1c (0.081g, 0.81mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 8, 107 mg of yellow solid, and the yield was 51.2%. m.p.183℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.075(s,3H),1.144(m,2H),1.515(m,2H),1.655(s,3H),1.744(m,4H),1.959(m ,4H),2.011(m,4H),2.174(m,2H),2.324(m,2H),2.780(m,1H),2.851(m,1H),2.994(m,2H),3.166(s, 3H), 3.519(m,1H), 3.563(m,1H), 3.873(m,2H), 3.976(m,2H), 4.748(s,2H).HR-MS ₍ ESI-TOF ⁺ ):C Calculated value for H ₄₀ N ₇ O ₄ 514.3136, found value [M+H] ⁺ 514.3130.

Example 9

Compound 9 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -ethoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethyl Preparation of Oxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.200g, 0.41mmol) and 2c (0.081g, 0.81mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 9, 103 mg of yellow solid, with a yield of 49.9%. m.p.183℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.075(s,3H),1.139(m,2H),1.498(m,2H),1.662(s,3H),1.749(m,4H),1.957(m ,4H),2.011(m,4H),2.174(m,2H),2.324(m,2H),2.780(m,1H),2.851(m,1H),2.994(m,2H),3.166(s, 3H), 3.519(m,1H), 3.563(m,1H), 3.873(m,2H), 3.976(m,2H), 4.748(s,2H).HR-MS ₍ ESI-TOF ⁺ ):C Calculated value for H ₄₀ N ₇ O ₄ 514.3136, found value [M+H] ⁺ 514.3128.

Example 10

Compound 10 8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethoxycarbonyl)-1 -piperidinyl]propyl}-1H-purine-2,6-dione

8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethoxycarbonyl)-1-piper Preparation of pyridyl]propyl}-1H-purine-2,6-dione

Using b (0.200g, 0.41mmol) and c (0.081g, 0.81mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 10, 110 mg of yellow solid, with a yield of 52.9%. m.p.188℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.066(s,3H),1.518(m,2H),1.664(s,3H),1.751(m,4H),2.011(m,4H),2.174(m ,2H),2.324(m,2H),2.780(m,1H),2.851(m,1H),2.994(m,2H),3.166(s,3H),3.519(m,1H),3.563(m, 1H), 3.873(m,2H), 3.691(m,4H), 3.976(m,2H), 4.748(s,2H).HR-MS(ESI-TOF ⁺ ): Calculation of C ₂₆ H ₄₀ N ₇ O ₄ Value 514.3136, measured value [M+H] ⁺ 514.3128.

Example 11

Compound 11 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -ethoxycarbonyl)-1-piperazinyl]propyl}-1H-purine-2,6-dione

8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethyl Preparation of Oxycarbonyl)-1-piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.20mmol) and 1c (0.042g, 0.40mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 11, 52 mg of yellow solid, and the yield was 50.2%. m.p.182-184℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.062(s,3H),1.129(m,2H),1.519(m,2H),1.654(s,3H),1.729(m,4H),1.966(m ,4H),2.011(m,4H),2.174(m,2H),2.324(m,2H),2.851(m,1H),2.994(m,2H),3.166(s,3H),3.519(m, 1H), 3.563(m,1H), 3.873(m,2H), 3.976(m,2H), 4.751(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₄ H ₃₇ N ₉ O ₄ calculation Value, 515.3153 measured value [M+H] ⁺ 515.3127.

Example 12

Compound 12 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -isopropoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-iso Preparation of propoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.200g, 0.39mmol) and 1c (0.079g, 0.79mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 12, 99 mg of yellow solid, with a yield of 49.2%. m.p.180-182℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.161(d,6H,J=6Hz),1.230(m,2H),1.742(s,3H),1.831(m,4H),1.961(m,4H) ,2.033(m,2H+1H),2.271(m,2H),2.451(t,2H,J=6.9Hz),2.916(m,2H),3.126(m,2H),3.429(s,3H), 3.562(m,1H),3.671(m,1H),3.965(m,2H),4.900(s,2H),4.921(m,1H).HR-MS(ESI-TOF ⁺ ):C ₂₇ H ₄₂ N The calculated value of ₇ O ₄ is 528.3293, and the measured value is [M+H] ⁺ 528.3302.

Example 13

Compound 13 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -isopropoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-iso Preparation of propoxycarbonyl)-1-piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.200g, 0.39mmol) and 2c (0.079g, 0.79mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 13, 96 mg of yellow solid, with a yield of 46.2%. m.p.180-182℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.158(d,6H,J=6Hz),1.228(m,2H),1.742(s,3H),1.831(m,4H),1.959(m,4H) ,2.033(m,2H+1H),2.271(m,2H),2.451(t,2H,J=6.9Hz),2.916(m,2H),3.126(m,2H),3.429(s,3H), 3.562(m,1H),3.671(m,1H),3.965(m,2H),4.900(s,2H),4.921(m,1H).HR-MS(ESI-TOF ⁺ ):C ₂₇ H ₄₂ N The calculated value of ₇ O ₄ is 528.3293, and the measured value is [M+H] ⁺ 528.3289.

Example 14

Compound 14 8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-isopropoxycarbonyl)- 1-piperidinyl]propyl}-1H-purine-2,6-dione

8-(1-Homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-isopropoxycarbonyl)-1- Preparation of piperidinyl]propyl}-1H-purine-2,6-dione

Using b (0.100g, 0.20mmol) and c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 14, 53 mg of yellow solid, and the yield was 51.0%. m.p.185℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.161(d,6H,J=6Hz),1.742(s,3H),1.831(m,4H),,2.044(m,2H),2.271(m,2H ),2.453(t,2H,J=6.8Hz),2.916(m,2H),3.126(m,2H),3.429(s,3H),3.562(m,1H),3.671(m,1H),3.687 (m,4H),3.965(m,2H),4.900(s,2H),4.921(m,1H).HR-MS(ESI-TOF ⁺ ):C ₂₇ H ₄₂ N ₇ O ₄ calculated value 528.3293, measured Value[M+H] ⁺ 528.3294.

Example 15

Compound 15 8-(1-piperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-isopropoxycarbonyl)-1 -piperidinyl]propyl}-1H-purine-2,6-dione

8-(1-piperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-isopropoxycarbonyl)-1-piper Preparation of pyridyl]propyl}-1H-purine-2,6-dione

Using b (0.150g, 0.29mmol) and c (0.103g, 0.58mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 15, 77 mg of yellow solid, with a yield of 50.7%. m.p.187-190℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.157(d,6H,J=6Hz),1.219(m,2H),1.733(s,3H),1.819(m,4H),1.962(m,4H) ,2.033(m,3H),2.271(m,2H),2.451(t,2H,J=6.9Hz),2.916(m,2H),3.126(m,2H),3.429(s,3H),3.562( m,1H),3.671(m,1H),3.965(m,2H),4.900(s,2H),4.921(m,1H).HR-MS(ESI-TOF ⁺ ):C ₂₆ H ₄₀ N ₇ O ₄ Calculated value 514.3136, measured value [M+H] ⁺ 514.3139.

Example 16

Compound 16 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -tert-butoxycarbonyl)-1-piperazinyl]propyl}-1H-purine-2,6-dione

8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert Preparation of butoxycarbonyl)-1-piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.180g, 0.34mmol) and 1c (0.119g, 1.19mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 16, 78 mg of yellow solid, with a yield of 41.7%. m.p.181-182℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.346(s,9H),1.487(m,2H),1.693(s,3H),1.782(m,1H),1.944(m,1H),1.825(m ,2H),1.962(m,4H),2.419(m,4H),2.520(m,2H),2.851(m,1H),3.009(m,2H),3.209(m,2H),3.291(m, 4H), 3.371(s,3H), 3.605(m,2H), 4.016(m,2H), 4.809(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₇ H ₄₂ N ₈ O ₄ calculation Value 542.3316, measured value [M+H] ⁺ 542.3342.

Example 17

Compound 17 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -tert-butoxycarbonyl)-1-piperazinyl]propyl}-1H-purine-2,6-dione

8-[(3S)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert Preparation of butoxycarbonyl)-1-piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.180g, 0.34mmol) and 2c (0.119g, 1.19mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 17, 72 mg of yellow solid, with a yield of 39.2%. m.p.181-182℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.351(s,9H),1.476(m,2H),1.689(s,3H),1.778(m,1H),1.944(m,1H),1.825(m ,2H),1.953(m,4H),2.419(m,4H),2.520(m,2H),2.851(m,1H),3.009(m,2H),3.209(m,2H),3.291(m, 4H), 3.371(s,3H), 3.605(m,2H), 4.016(m,2H), 4.809(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₇ H ₄₂ N ₈ O ₄ calculation Value 542.3316, measured value 542.3354.

Example 18

Compound 18 8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert-butoxycarbonyl)- 1-Piperazinyl]propyl}-1H-purine-2,6-dione

8-(1-Homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-tert-butoxycarbonyl)-1- Preparation of piperazinyl]propyl}-1H-purine-2,6-dione

Using b (0.180g, 0.34mmol) and c (0.119g, 1.19mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 18, 78 mg of yellow solid, with a yield of 42.4%. m.p.187℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.339(s,9H),1.693(s,3H),1.825(m,2H),2.419(m,4H),2.520(m,2H),3.009(m ,2H),3.209(m,2H),3.291(m,4H),3.371(s,3H),3.605(m,2H),3.691(m,4H),4.023(m,2H),4.894(s, 2H).HR-MS(ESI-TOF ⁺ ): Calcd. for C ₂₇ H ₄₂ N ₈ O ₄ 542.3316, found [M+H] ⁺ 542.3289.

Example 19

Compound 19 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{2-[(4 -tert-butoxycarbonyl)-1-piperazinyl]ethyl}-1H-purine-2,6-dione

8-[(3R)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{2-[(4-tert Preparation of butoxycarbonyl)-1-piperazinyl]ethyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and 1c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 19, 52 mg of yellow solid, and the yield was 51.4%. m.p.183-184℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.351(s,9H),1.484(m,2H),1.689(s,3H),1.793(m,1H),1.948(m,1H),1.966(m ,4H),2.423(m,4H),2.520(m,2H),2.851(m,1H),3.009(m,2H),3.209(m,2H),3.291(m,4H),3.371(s, 3H), 3.605(m,2H), 4.016(m,2H), 4.809(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₆ H ₄₀ N ₈ O ₄ calculated value 529.3245, measured value [M +H] ⁺ 529.3249.

Example 20

Compound 20 8-[(3S)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{2-[(4 -tert-butoxycarbonyl)-1-piperazinyl]ethyl}-1H-purine-2,6-dione

8-[(3S)-3-Amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{2-[(4-tert Preparation of butoxycarbonyl)-1-piperazinyl]ethyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and 2c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 20, 49 mg of yellow solid, with a yield of 49.2%. m.p.183-184℃;

¹ H NMR(CD ₃ OD,300MHz)δ:1.335(s,9H),1.489(m,2H),1.691(s,3H),1.778(m,1H),1.949(m,1H),1.949(m ,4H),2.419(m,4H),2.520(m,2H),2.851(m,1H),3.009(m,2H),3.209(m,2H),3.291(m,4H),3.371(s, 3H), 3.605(m,2H), 4.016(m,2H), 4.801(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₆ H ₄₀ N ₈ O ₄ calculated value 529.3245, measured value [M +H] ⁺ 529.3251.

Example 21

Compound 21 8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{2-[(4-tert-butoxycarbonyl)- 1-Piperazinyl]ethyl}-1H-purine-2,6-dione

8-(1-Homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{2-[(4-tert-butoxycarbonyl)-1- Preparation of piperazinyl]ethyl}-1H-purine-2,6-dione

Using b (0.100g, 0.19mmol) and c (0.039g, 0.39mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 21, 55 mg of yellow solid, and the yield was 54.5%. m.p.188-189℃;

¹ H NMR(CD ₃ OD,400MHz)δ:1.349(s,9H),1.689(s.3H),1.983(m,2H),2.415(m,4H),2.527(t,2H,J=6.4Hz ),3.009(m,2H),3.147(m,2H),3.296(m,4H),3.365(s,3H),3.691(m,4H),4.023(m,2H),4.896(s,2H) .HR-MS(ESI-TOF ⁺ ): Calcd. for C ₂₆ H ₄₀ N ₈ O ₄ 529.3245, found [M+H] ⁺ 529.3241.

Example 22

Compound 22 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4 -ethoxycarbonyl)-1-piperidinyl]butyl}-1H-purine-2,6-dione

8-[(3R)-3-amino-1-piperidinyl]-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethyl Preparation of Oxycarbonyl)-1-piperidinyl]butyl}-1H-purine-2,6-dione

Using b (0.040g, 0.05mmol) and c (0.010g, 0.10mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 22, 16 mg of yellow solid, with a yield of 47.5%.

¹ H NMR(CD ₃ OD,300MHz)δ:1.166(d,5H),1.489(m,2H),1.691(s,3H),1.778(m,1H),1.949(m,1H),1.949(m ,4H),2.419(m,4H),2.520(m,2H),2.851(m,1H),3.009(m,2H),3.209(m,2H),3.291(m,4H),3.371(s, 3H), 3.605(m,2H), 4.014(m,2H), 4.039(m,2H), 4.808(s,2H).HR-MS(ESI-TOF ⁺ ): Calculation of C ₂₇ H ₄₂ N ₇ O ₄ Value 528.3293, measured value [M+H] ⁺ 528.3281.

Example 23

Compound 23 8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethoxycarbonyl)-1 -piperidinyl]butyl}-1H-purine-2,6-dione

8-(1-homopiperazinyl)-7-(2-butynyl)-3,7-dihydro-3-methyl-1-{3-[(4-ethoxycarbonyl)-1-piper Preparation of pyridyl]butyl}-1H-purine-2,6-dione

Using b (0.040g, 0.05mmol) and c (0.010g, 0.10mmol) as raw materials, the similar operation steps in Example 1 were used to obtain compound 23, 18 mg of yellow solid, with a yield of 48.6%.

¹ H NMR(CD ₃ OD,300MHz)δ:1.141(m,3H),1.188(m,2H),1.528(m,2H),1.689(s.3H),1.983(m,2H),2.415(m ,4H),2.527(t,2H,J=6.4Hz),3.009(m,2H),3.147(m,2H),3.296(m,4H),3.365(s,3H),3.691(m,4H) ,4.023(m,2H),4.896(s,2H).HR-MS(ESI-TOF ⁺ ):C ₂₆ H ₄₀ N ₈ O ₄ Calculated value 528.3293, found value [M+H] ⁺ 528.3302.

Test case part

Test example 1, DPP-IV inhibitor in vitro screening method

Reagent:

1. Reaction substrate: Gly-Pro-p-nitroanilide hydrochloride (Sigma, G0513), dissolved in ddH ₂ O to a 0.026M stock solution, and stored at -20°C in the dark.

2. DPP-IV enzyme: recombinant human DPP-IV protein (Sigma, D4943), stored at -20°C.

3. Sample to be tested: dissolved in DMSO to 10 ^-2 M, stored at 4°C.

4. Positive control drug: Sitagliptin was dissolved in DMSO to 10 ^-2 M and stored at 4°C.

5.2×Hepes buffer: 1.6g NaCl, 0.074g KCl, 0.027g Na ₂ HPO ₄ 2H ₂ O, 0.2g Glucose, 1g Hepes dissolved in 90ml ddH ₂ O, adjust pH value to 7.05 with NaOH, dilute to 100ml , filtered at 0.22 μm, and stored at 4°C.

6. Tis-HCl buffer: Add 6.06g Tris to 1L distilled water, adjust the pH to 8.0 with HCl.

Detection method

The sample and the positive drug Sitagliptin were diluted with ddH ₂ O to a solution with a concentration of 10 ^-4 M, and DPP-IV was prepared with Tis/HCl buffer (pH=8.0) with a concentration of 2mU/mL. Substrate Gly-Pro-p-nitroanilide working solution was diluted with Hepes buffer (pH=7.05) to a concentration of 0.26mM. The experiment set up negative control group, positive control group and sample group. The total volume of the reaction was 100 μL, in which the negative control group was added with 10 μL of ddH ₂ O, 50 μL of DPP-IV enzyme working solution and 40 μL of substrate working solution; the positive control group was added with 10 μL of Sitagliptin solution, 50 μL of DPP-IV enzyme working solution and 40 μL of substrate working solution ; Add 10 μL of sample solution, 50 μL of DPP-IV working solution and 40 μL of substrate working solution to the sample group. The inhibitory effect of the sample on DPP-IV was evaluated by monitoring the change of absorbance at 405 nm at 37° C. within 60 min.

The calculation method of the inhibition rate of the sample to DPP-IV is as follows:

Inhibition rate (%)=(ΔOD _60-0 negative control group-ΔOD _60-0 sample group)/ΔOD _60-0 negative control group×100%

It is generally believed that the positive control Sitagliptin has an inhibition rate of 90-100% at 10 ^-5 M, which can be considered reliable in this experiment, and a sample with an inhibition rate greater than 40% is considered effective.

positive compound IC ₅₀ The calculation of:

1. For the active compounds (that is, the inhibitory activity is greater than 50%) in the initial screening (the concentration of the test compound is 10 ^-5 M), set different concentration gradients, namely 10 ^-8 , 10 ^-7 , 10 ^-6 and 10 ^{- 5} M for DPP-IV inhibition experiments.

2. Draw the concentration-response curve of the reaction concentration and inhibition rate of the compound, and the fitting formula obtained by statistical processing, Y is the inhibition rate, X is the compound concentration, when Y is 50%, that is, when the activity of 50% inhibition rate is reached, the corresponding The concentration of the compound is the half effective inhibitory concentration (IC ₅₀ ) of the compound, and the test results are shown in Table 1.

Table 1 The assay results of the embodiment compounds of the present invention inhibiting DPP-IV activity

in conclusion:

Among the tested compounds, the in vitro DPP-IV inhibitory activity of 12 examples reached more than 50%, and the IC ₅₀ of 12 examples reached the μM level. Example 14 had the highest in vitro DPP-IV inhibitory activity.

Test Example 2, DPP-IV inhibitor selectivity evaluation method (in vitro evaluation method of DPP8 inhibitory activity)

1. Reaction substrate: same as the in vitro screening method for DPP-IV inhibitors.

2. DPP8 enzyme: recombinant human DPP8/9 protein, purified and freeze-dried, stored at -20°C.

3. Sample: Same as the in vitro screening method for DPP-IV inhibitors.

4. Positive control drug: the compound (S)-4-(2-amino-(R)-3-methylpentanoyl)isoindoline hydrochloride was dissolved in DMSO to 10 ⁻² M, and stored at 4°C.

5.2×Hepes buffer: Same as the in vitro screening method for DPP-IV inhibitors.

6. Tis/HCl buffer: Same as the in vitro screening method for DPP-IV inhibitors.

Evaluation method

The sample and the positive drug were diluted with ddH ₂ O to a solution with a concentration of 10 ^-4 M, and the DPP8 enzyme was prepared with Tis/HClbuffer (pH=8.0) at a concentration of 60ng/mL. The substrate Gly-Pro-p-nitroanilide working solution was diluted with Hepes buffer (pH=7.05) to a concentration of 0.52mM. The experiment set up negative control group, positive control group and sample group. The total volume of the reaction is 100 μL, in which the negative control group is added with 10 μL of ddH ₂ O, 50 μL of DPP8 enzyme working solution and 40 μL of substrate working solution; the positive control group is added with 10 μL of positive control drug solution, 50 μL of DPP8 enzyme working solution and 40 μL of substrate working solution; 10 μL of sample solution, 50 μL of DPP8 enzyme working solution and 40 μL of substrate working solution were added to the group. By monitoring the change of absorbance at 405 nm at 37°C within 60 min, the selectivity of the DPP-IV inhibitor, that is, the DPP8/9 inhibitory activity, was evaluated.

The selectivity of DPP-IV inhibitors (DPP8 inhibitory) is calculated as follows:

Inhibition rate (%)=(ΔOD _60-0 negative control group-ΔOD _60-0 sample group)/ΔOD _60-0 negative control group×100% The test results are shown in Table 2

Table 2 Example compounds of the present invention inhibit the assay results of DPP8 activity

The inhibition rate at the same concentration of the positive drug was 96.7%.

in conclusion:

The five tested compounds with DPP-IV inhibitory activity have no obvious inhibitory activity on DPP8, indicating that these five compounds are highly selective for DPP-IV.

Claims (13)

1. A compound represented by the general formula (I) and stereoisomers thereof, and pharmaceutically acceptable salts thereof,

wherein,

R₁can be independently selected from hydrogen and C_1-10Alkyl radical, C_3-7Cycloalkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-10Cycloalkyl oxy, C_3-10Cycloalkylcarboxyl radical, C_3-10Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heterocycloalkyloxy having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkylcarbonyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, aryl, aryloxy, arylformyl, aryloxycarbonyl, heterocycloaryl having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxy having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloyl having 4 to 9 carbon atoms and 1 to 3 heteroatoms, A heterocycloaryloxoformyl group of a heteroatom of oxygen;

R₂can be independently selected from hydrogen and C_1-6Alkyl radical, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyloxoformyl, amino, trifluoromethyl, trifluoromethoxy, nitro, cyano, carbamoyl, aminosulfonyl, benzyl;

wherein said alkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino groups are optionally substituted with 1 to 4 (e.g., 1 to 3, 1 to 2, 1, 2, or 3) groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl, aryl, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

x and Y are the same or different and are each independently selected from C, N, O, S;

m is selected from 1, 2, 3 and 4;

n is selected from 2, 3, 4, 5 and 6;

p and q are the same or different and are each independently selected from 1, 2, 3, 4.

2. The compound according to claim 1, wherein the compound is represented by the general formula (II),

wherein,

R₁selected from hydrogen, C_1-10Alkyl radical, C_3-7Cycloalkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-10Cycloalkyl oxy, C_3-10Cycloalkylcarboxyl radical, C_3-10Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heterocycloalkyloxy having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkylcarbonyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, aryl, aryloxy, arylformyl, aryloxycarbonyl, heterocycloaryl having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxy having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloyl having 4 to 9 carbon atoms and 1 to 3 heteroatoms, A heterocycloaryloxoformyl group of a heteroatom of oxygen;

R₂selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyloxy, C_1-6Alkyl radicalFormyl radical, C_1-6Alkyloxoformyl, amino, trifluoromethyl, trifluoromethoxy, nitro, cyano, carbamoyl, aminosulfonyl, benzyl;

wherein said alkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino groups are optionally substituted with 1 to 4 (e.g., 1 to 3, 1 to 2, 1, 2, or 3) groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl, aryl, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

x and Y are the same or different and are each independently selected from C, N, O, S;

m is selected from 1, 2, 3 and 4;

n is selected from 2, 3, 4, 5 and 6.

3. A compound according to claim 2, and stereoisomers and pharmaceutically acceptable salts thereof, said compound being represented by formula (IIA),

wherein,

R₁selected from hydrogen, C_1-10Alkyl radical, C_3-7Cycloalkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-10A cycloalkyloxy group,C_3-10Cycloalkylcarboxyl radical, C_3-10Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heterocycloalkyloxy having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkylcarbonyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, aryl, aryloxy, arylformyl, aryloxycarbonyl, heterocycloaryl having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxy having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloyl having 4 to 9 carbon atoms and 1 to 3 heteroatoms, A heterocycloaryloxoformyl group of a heteroatom of oxygen;

R₂selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyloxoformyl, amino, trifluoromethyl, trifluoromethoxy, nitro, cyano, carbamoyl, aminosulfonyl, benzyl;

wherein said alkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino groups are optionally substituted with 1 to 4 (e.g., 1 to 3, 1 to 2, 1, 2, or 3) groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl, aryl, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

x and Y are the same or different and are each independently selected from C, N, O, S;

m is selected from 1, 2, 3 and 4;

n is selected from 2, 3, 4, 5 and 6.

4. The compound according to claim 2, wherein the compound is represented by the general formula (IIB),

wherein,

R₁selected from hydrogen, C_1-10Alkyl radical, C_3-7Cycloalkyl radical, C_2-10Alkenyl radical, C_2-10Alkynyl, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-10Cycloalkyl oxy, C_3-10Cycloalkylcarboxyl radical, C_3-10Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heterocycloalkyloxy having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkylcarbonyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkyloxyformyl having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, aryl, aryloxy, arylformyl, aryloxycarbonyl, heterocycloaryl having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxy having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloyl having 4 to 9 carbon atoms and 1 to 3 heteroatoms, A heterocycloaryloxoformyl group of a heteroatom of oxygen;

R₂selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyloxoformyl, amino, trifluoromethyl, trifluoromethoxy, nitro, cyano, carbamoyl, aminosulfonyl, benzyl;

wherein said alkyl and cycloalkyl groupsAryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino are optionally substituted with 1-4 (e.g., 1-3, 1-2, 1, 2, or 3) groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_3-7Cycloalkyl radical, C_3-7Heterocycloalkyl, aryl, C_3-7Heteroaryl group, C_1-6Alkyloxy, C_1-6Alkyl formyl radical, C_1-6Alkyl oxoformyl, C_3-7Cycloalkyl oxy, C_3-7Cycloalkylcarboxyl radical, C_3-7Cycloalkanoyloxyformyl radical, C_3-7Heterocycloalkyloxy, C_3-7Heterocycloalkylformyl radical, C_3-7Heterocycloalkyloxyformyl, aryloxy, arylformyl, aryloxycarbonyl, C_4-9Heteroaryloxy radical, C_4-9Heteroaryl formyl, C_4-9A heteroaryloxycarbonyl group;

x and Y are the same or different and are each independently selected from C, N, O, S;

m is selected from 1, 2, 3 and 4;

n is selected from 2, 3, 4, 5 and 6.

5. A compound according to claim 3, wherein the compound is represented by the general formula (IIIA),

wherein,

R₁selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-8Cycloalkyl oxy, C_3-8Cycloalkylcarboxyl radical, C_3-8Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heterocycloalkyloxy containing 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloalkylcarboxyl containing 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygenA group, a heterocycloalkyloxyformyl group having 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, an aryl group, an aryloxy group, an arylformyl group, an aryloxycarbonyl group, a heterocycloaryl group having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, a heterocycloaryloxy group having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, a heterocycloarylformyl group having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, a heterocycloaryloxycarbonyl group having 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen;

R₂selected from hydrogen, amino;

wherein said alkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino groups are optionally substituted with 1-2 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_1-6Cycloalkyl radical, C_1-6Alkyloxy, C_3-6Heterocycloalkyl, aryl;

x is selected from C, N;

m is selected from 1 and 2;

n is selected from 2, 3 and 4.

6. The compound according to claim 4, wherein the compound is represented by the general formula (IIIB),

wherein,

R₁selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-8Cycloalkyl oxy, C_3-8Cycloalkylcarboxyl radical, C_3-8Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heterocycloalkyloxy containing 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygenHeterocycloalkylcarbonyl, heterocycloalkyloxyformyl, aryl, aryloxy, arylformyl, aryloxycarbonyl, heterocycloaryl having from 4 to 9 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxy having from 4 to 9 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloarylformyl having from 4 to 9 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxycarbonyl having from 4 to 9 carbon atoms and from 1 to 3 heteroatoms selected from nitrogen and oxygen;

R₂selected from hydrogen, amino;

wherein said alkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino groups are optionally substituted with 1-2 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_1-6Cycloalkyl radical, C_1-6Alkyloxy, C_3-6Heterocycloalkyl, aryl;

x is selected from C, N;

m is selected from 1 and 2;

n is selected from 2, 3 and 4.

7. The compound according to claim 2, wherein the compound is represented by the general formula (IV),

wherein,

R₁selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyloxy, C_2-6Alkyl formyl radical, C_2-6Alkyl oxoformyl, C_3-8Cycloalkyl oxy, C_3-8Cycloalkylcarboxyl radical, C_3-8Cycloalkanoyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C1-3 alkyl, heterocycloalkyloxy containing 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygenHeterocycloalkylcarbonyl of a heteroatom, heterocycloalkyloxyformyl of 3 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, aryl, aryloxy, arylformyl, aryloxycarbonyl, heterocycloaryl of 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxy of 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloarylformyl of 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen, heterocycloaryloxycarbonyl of 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from nitrogen and oxygen;

R₂selected from hydrogen, C_1-6Alkyl, methoxy, amino;

R₃selected from hydrogen, C_1-6Alkyl radical, C_1-6Alkyl formyl, carbamoyl, substituted carbamoyl, benzyl;

wherein said alkyl, cycloalkyl, aryl, heterocycloaryl, heterocycloalkyl, benzyl, and amino groups are optionally substituted with 1-2 groups selected from: hydroxy, halogen, cyano, amino, substituted amino, nitro, trifluoromethyl, trifluoromethoxy, C_1-6Alkyl radical, C_1-6Cycloalkyl radical, C_1-6Alkyloxy, C_3-6Heterocycloalkyl, aryl;

x is selected from C, N;

m is selected from 1 and 2;

n is selected from 2, 3 and 4.

8. A compound according to any one of claims 1 to 7, wherein,

R₁selected from the group consisting of ethoxyformyl, isopropoxyformyl, tert-butoxycarbonyl, cycloalkylformyl, substituted cycloalkylformyl, cycloalkyloxy-formyl, substituted cycloalkyloxy-formyl, aryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, heteroaryl-C_1-3Alkyl, aryl, substituted aryl, arylformyl, aryloxycarbonyl, substituted arylformyl, substituted aryloxycarbonyl, 2- (5-methyl) pyrimidinyl, substituted 2- (5-methyl) pyrimidinyl;

R₂selected from hydrogen, amino;

x is selected from C, N;

m is selected from 1 and 2;

n is selected from 2, 3 and 4.

9. A compound according to any one of claims 1 to 8, and stereoisomers thereof, and pharmaceutically acceptable salts thereof, which is a compound selected from the group consisting of:

10. a process for the preparation of a compound according to any one of claims 1 to 9, comprising the steps of:

(i)

reacting the compound of formula a with the compound of formula d in a solvent (e.g., N-methylpyrrolidone) at a temperature of 50 ℃ to 100 ℃ (e.g., 50 ℃ to 70 ℃,60 ℃ to 80 ℃, or 80 ℃ to 100 ℃) in the presence of a base (e.g., potassium carbonate) for 7-12h to obtain the compound of formula b 1;

wherein n =2, 3.

(ii)

Reacting the compound of formula a with the compound of formula e in a solvent (e.g., N-dimethylformamide) in the presence of a base (e.g., potassium carbonate) at a temperature of 20 ℃ to 50 ℃ (e.g., 20 ℃ to 30 ℃,20 ℃ to 40 ℃, or 30 ℃ to 50 ℃) for 7-10h to obtain the compound of formula f;

(iii)

reacting the compound of formula f with methanesulfonyl chloride in the presence of a base (e.g., triethylamine) at a temperature of 20 ℃ to 30 ℃ (e.g., 20 ℃ to 25 ℃,20 ℃ to 30 ℃, or 25 ℃ to 30 ℃) in a solvent (e.g., dichloromethane) for 1-2h to obtain a compound of formula g;

reacting the compound of formula g with the compound of formula h in a solvent (e.g., dioxane) at a temperature of 80 ℃ to 110 ℃ (e.g., 80 ℃ to 95 ℃, 90 ℃ to 100 ℃, or 85 ℃ to 110 ℃) in the presence of a base (e.g., triethylamine) and a salt (e.g., potassium iodide) for 3-5h to obtain the compound of formula b 2; (iv)

reacting the compound of formula b with the compound of formula c in a solvent (e.g., tetrahydrofuran, N-dimethylformamide, or a mixture of both) in the presence of a base (e.g., potassium carbonate) at a temperature of 50 ℃ to 100 ℃ (e.g., 50 ℃ to 70 ℃,60 ℃ to 80 ℃, or 80 ℃ to 100 ℃) for 9-16h to obtain the compound of the invention of formula II.

Wherein R is₁、R₂X, Y, m, n are as defined in any one of claims 1 to 9.

11. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a compound of any one of claims 1 to 9, and stereoisomers thereof, pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.

12. Use of a compound according to any one of claims 1 to 9, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for the manufacture of a medicament for use in a method for the treatment and/or prevention of diseases or conditions associated with DPP-IV hyperactivity or DPP-IV overexpression.

13. Use according to claim 12, wherein the disease or condition associated with DPP-IV hyperactivity or DPP-IV overexpression is a disease or condition selected from the group consisting of: diabetes, hyperglycemia, non-insulin dependent diabetes, type2diabetes.