CN104211702B - Substituted xanthine class compound and its preparation method and application - Google Patents

Substituted xanthine class compound and its preparation method and application Download PDF

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CN104211702B
CN104211702B CN201310206922.3A CN201310206922A CN104211702B CN 104211702 B CN104211702 B CN 104211702B CN 201310206922 A CN201310206922 A CN 201310206922A CN 104211702 B CN104211702 B CN 104211702B
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alkyl
amino
compound
formoxyl
oxygen
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CN104211702A (en
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黄海洪
申竹芳
汪瑾
姜茜
李刚
环奕
林紫云
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Abstract

The invention discloses substituted xanthine class compounds and its preparation method and application.Specifically, the present invention relates to the compound and its stereoisomer of formula (I), pharmaceutically acceptable salt, wherein R1,R2As used in the description.The invention further relates to the pharmaceutical compositions comprising the compounds of this invention, purposes of the compounds of this invention in preparing the drug for treating and/or preventing to over-express the method for related disease or illness with DPP IV hyperactivities or with DPP IV, and the method using the compounds of this invention treatment relevant disease.The compounds of this invention has the effective activity for inhibiting DPP IV.

Description

Substituted xanthine class compound and its preparation method and application
Technical field
The invention belongs to pharmaceutical technology fields.It is related to substituted xanthine class compound shown in logical formula (I), and its pharmaceutically Acceptable salt and its isomers, the preparation of this kind of compound, containing their pharmaceutical composition and this kind of compound pre- Prevent and/or treat diabetes, the application in the diabetes of non-insulin-dependent, the especially use in terms of inhibiting DPP-IV On the way.
Background technology
Diabetes (Diabetes Mellitus, DM) are a kind of metabolic diseases of multi-pathogenesis, are exhausted due to insulin Pair or relative deficiency cause blood glucose rise and cause organism metabolic disorder.2012, global diabetic's number was more than 3.7 Hundred million, wherein death toll reaches 4,800,000（International Diabetes Federation,2012Update）.Diabetes The 3rd big killer that human health is threatened after angiocardiopathy and tumour is had become, it can be divided into insulin-dependent sugar Urine sick (insulin-dependent diabetes mellitus, IDDM, i.e. type 1 diabetes) and non-insulin-depending type sugar Urine is sick (noninsulin-dependent diabetes mellitus, NIDDM, i.e. diabetes B), wherein diabetes B It is most commonly seen, account for 90% of diabetic or more.Although currently on the market have at least insulin, biguanides, sulfonylurea, The antidiabetic medicines such as glycosidase inhibitor and thiazolidinediones, but above-mentioned traditional antidiabetic drug generally all with weight gain, The problems such as side effects such as hypoglycemia and drug effect continuously decrease [Kahn SE, Haffner SM, et al.Glycemic durability of rosiglitazone,metformin,or glyburide monotherapy.[J].N Engl J Med,2006,355:2477-80] therefore there is an urgent need to develop novel drugs.
Glucagon-like-peptide-1 (GLP-1) is a kind of intestines trophic hormone that can stimulate β cells secrete insulins.But in vivo The GLP-1 of secretion can be degraded by serine protease DPP IV to inactivate rapidly, therefore simple GLP-1 can not be at Medicine.DPP-IV inhibitor can increase the concentration of endogenous GIP and GLP-1 in blood, so as to effectively facilitate insulin secretion, Glucagon suppression is horizontal while reducing blood glucose, improves the ability of body itself control blood glucose level, has protection β cells The effect of function, and the side effect of hypoglycemia and weight gain will not be caused, because its action target spot is clear, it has also become 2 types for the treatment of The research and development focus of diabetes medicament.
With, especially to the further investigation of DPP8, finding to DPPs families due to DPP8 and DPP-IV in protein structure and There is certain similitude on substrate type, when the selectivity of DPP-IV inhibitor is poor, while acting on DPP8 and will produce Such as the serious side effect such as alopecia, thrombopenia and anaemia [Havale SH, Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4for 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 inhibitor must have the height to the single target spots of DPP-IV Selectivity, in order to avoid influencing the normal physiological function of other DPPs, this is also the difficult point of new selective DPP-IV inhibitor research and development And key point.
Therefore, there is still a need for the strong selective DPP-IV inhibitors of structure novel, activity to meet clinical treatment for this field Demand.
Invention content
There is novel structure and active strong selective DPP-IV suppression the technical problem to be solved in the present invention is to provide a kind of Preparation.The inventors discovered that the substituted xanthine class compound of a kind of structure novel has stronger inhibitory activity to DPP-IV And selectivity, it can be used for the prevention and treatment of diabetes.It is accomplished the present invention is based on above find.
Summary of the invention
For this purpose, first aspect present invention provides formula (I) compound represented and its stereoisomer, it is pharmaceutically acceptable Salt,
Wherein,
R1It can be independently selected from hydrogen, C1-10Alkyl, C3-7Naphthenic base, C2-10Alkenyl, C2-10Alkynyl, C1-6Alkyl oxy, C2-6 Alkyl formyl radical, C2-6Alkyl oxygen formoxyl, C3-10Cycloalkyl oxy, C3-10Naphthenic base formoxyl, C3-10Cycloalkyloxy group formoxyl, Aryl-C1-3Alkyl, heteroaryl-C1-3Alkyl contains the heteroatomic Heterocyclylalkyl of 3-9 carbon atom and 1-3 selected from nitrogen, oxygen Oxygroup, containing 3-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic Heterocyclylalkyl formoxyl, contain 3-9 carbon atom With 1-3 selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygen formoxyl of oxygen, aryl, aryloxy, aryl formoxyl, aryl oxide first Acyl group is selected from nitrogen, the heteroatomic heterocyclic aryl of oxygen containing 4-9 carbon atom and 1-3, containing 4-9 carbon atom and 1-3 Selected from nitrogen, oxygen heteroatomic heterocyclic aryl oxygroup, contain the 4-9 carbon atom and 1-3 heteroatomic heterocycles selected from nitrogen, oxygen Aryl formoxyl contains the heteroatomic heterocyclic aryl oxygen formoxyl of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen；
R2It can be independently selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, ammonia Base, trifluoromethyl, trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl, benzyl；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally by 1-4（Example Such as 1-3,1-2,1,2 or 3）Group substitution selected from the following：Hydroxyl, halogen, cyano, amino, substituted-amino, nitre Base, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C3-7Naphthenic base, C3-7Heterocyclylalkyl, aryl, C3-7Heteroaryl, C1-6Alkyl oxygen Base, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, C3-7Cycloalkyl oxy, C3-7Naphthenic base formoxyl, C3-7Cycloalkyloxy group first Acyl group, C3-7Heterocyclylalkyl oxygroup, C3-7Heterocyclylalkyl formoxyl, C3-7Heterocyclylalkyl oxygen formoxyl, aryloxy, aryl formyl Base, aryl oxide formoxyl, C4-9Heteroaryl oxygroup, C4-9Heteroaryl formoxyl, C4-9Heteroaryl oxygen formoxyl；
X, Y are identical or different, are 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 identical or different, are each independently selected from 1,2,3,4.
The compound of any one according to a first aspect of the present invention is formula (II) compound represented and its alloisomerism Body, pharmaceutically acceptable salt,
Wherein,
R1Selected from hydrogen, C1-10Alkyl, C3-7Naphthenic base, C2-10Alkenyl, C2-10Alkynyl, C1-6Alkyl oxy, C2-6Alkyl Base, C2-6Alkyl oxygen formoxyl, C3-10Cycloalkyl oxy, C3-10Naphthenic base formoxyl, C3-10Cycloalkyloxy group formoxyl, aryl-C1-3 Alkyl, heteroaryl-C1-3Alkyl, containing 3-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic Heterocyclylalkyl oxygroup, contain Have 3-9 carbon atom and 1-3 selected from nitrogen, the heteroatomic Heterocyclylalkyl formoxyl of oxygen, a containing 3-9 carbon atom and 1-3 Selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygen formoxyl of oxygen, aryl, aryloxy, aryl formoxyl, aryl oxide formoxyl, contain Have 4-9 carbon atom and 1-3 be selected from selected from nitrogen, the heteroatomic heterocyclic aryl of oxygen, containing 4-9 carbon atom and 1-3 nitrogen, The heteroatomic heterocyclic aryl oxygroup of oxygen contains the heteroatomic heterocyclic aryl first of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen Acyl group contains the heteroatomic heterocyclic aryl oxygen formoxyl of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen；
R2Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, trifluoro Methyl, trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl, benzyl；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally by 1-4（Example Such as 1-3,1-2,1,2 or 3）Group substitution selected from the following：Hydroxyl, halogen, cyano, amino, substituted-amino, nitre Base, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C3-7Naphthenic base, C3-7Heterocyclylalkyl, aryl, C3-7Heteroaryl, C1-6Alkyl oxygen Base, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, C3-7Cycloalkyl oxy, C3-7Naphthenic base formoxyl, C3-7Cycloalkyloxy group first Acyl group, C3-7Heterocyclylalkyl oxygroup, C3-7Heterocyclylalkyl formoxyl, C3-7Heterocyclylalkyl oxygen formoxyl, aryloxy, aryl formyl Base, aryl oxide formoxyl, C4-9Heteroaryl oxygroup, C4-9Heteroaryl formoxyl, C4-9Heteroaryl oxygen formoxyl；
X, Y are identical or different, are 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 of any one according to a first aspect of the present invention is formula (IIA) compound represented and its alloisomerism Body, pharmaceutically acceptable salt,
Wherein,
R1Selected from hydrogen, C1-10Alkyl, C3-7Naphthenic base, C2-10Alkenyl, C2-10Alkynyl, C1-6Alkyl oxy, C2-6Alkyl Base, C2-6Alkyl oxygen formoxyl, C3-10Cycloalkyl oxy, C3-10Naphthenic base formoxyl, C3-10Cycloalkyloxy group formoxyl, aryl-C1-3 Alkyl, heteroaryl-C1-3Alkyl, containing 3-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic Heterocyclylalkyl oxygroup, contain Have 3-9 carbon atom and 1-3 selected from nitrogen, the heteroatomic Heterocyclylalkyl formoxyl of oxygen, a containing 3-9 carbon atom and 1-3 Selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygen formoxyl of oxygen, aryl, aryloxy, aryl formoxyl, aryl oxide formoxyl, contain Have 4-9 carbon atom and 1-3 be selected from selected from nitrogen, the heteroatomic heterocyclic aryl of oxygen, containing 4-9 carbon atom and 1-3 nitrogen, The heteroatomic heterocyclic aryl oxygroup of oxygen contains the heteroatomic heterocyclic aryl first of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen Acyl group contains the heteroatomic heterocyclic aryl oxygen formoxyl of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen；
R2Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, trifluoro Methyl, trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl, benzyl；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally by 1-4（Example Such as 1-3,1-2,1,2 or 3）Group substitution selected from the following：Hydroxyl, halogen, cyano, amino, substituted-amino, nitre Base, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C3-7Naphthenic base, C3-7Heterocyclylalkyl, aryl, C3-7Heteroaryl, C1-6Alkyl oxygen Base, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, C3-7Cycloalkyl oxy, C3-7Naphthenic base formoxyl, C3-7Cycloalkyloxy group first Acyl group, C3-7Heterocyclylalkyl oxygroup, C3-7Heterocyclylalkyl formoxyl, C3-7Heterocyclylalkyl oxygen formoxyl, aryloxy, aryl formyl Base, aryl oxide formoxyl, C4-9Heteroaryl oxygroup, C4-9Heteroaryl formoxyl, C4-9Heteroaryl oxygen formoxyl；
X, Y are identical or different, are 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 of any one according to a first aspect of the present invention is formula (IIB) compound represented and its alloisomerism Body, pharmaceutically acceptable salt,
Wherein,
R1Selected from hydrogen, C1-10Alkyl, C3-7Naphthenic base, C2-10Alkenyl, C2-10Alkynyl, C1-6Alkyl oxy, C2-6Alkyl Base, C2-6Alkyl oxygen formoxyl, C3-10Cycloalkyl oxy, C3-10Naphthenic base formoxyl, C3-10Cycloalkyloxy group formoxyl, aryl-C1-3 Alkyl, heteroaryl-C1-3Alkyl, containing 3-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic Heterocyclylalkyl oxygroup, contain Have 3-9 carbon atom and 1-3 selected from nitrogen, the heteroatomic Heterocyclylalkyl formoxyl of oxygen, a containing 3-9 carbon atom and 1-3 Selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygen formoxyl of oxygen, aryl, aryloxy, aryl formoxyl, aryl oxide formoxyl, contain Have 4-9 carbon atom and 1-3 be selected from selected from nitrogen, the heteroatomic heterocyclic aryl of oxygen, containing 4-9 carbon atom and 1-3 nitrogen, The heteroatomic heterocyclic aryl oxygroup of oxygen contains the heteroatomic heterocyclic aryl first of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen Acyl group contains the heteroatomic heterocyclic aryl oxygen formoxyl of 4-9 carbon atom and 1-3 selected from nitrogen, oxygen；
R2Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, trifluoro Methyl, trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl, benzyl；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally by 1-4（Example Such as 1-3,1-2,1,2 or 3）Group substitution selected from the following：Hydroxyl, halogen, cyano, amino, substituted-amino, nitre Base, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C3-7Naphthenic base, C3-7Heterocyclylalkyl, aryl, C3-7Heteroaryl, C1-6Alkyl oxygen Base, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, C3-7Cycloalkyl oxy, C3-7Naphthenic base formoxyl, C3-7Cycloalkyloxy group first Acyl group, C3-7Heterocyclylalkyl oxygroup, C3-7Heterocyclylalkyl formoxyl, C3-7Heterocyclylalkyl oxygen formoxyl, aryloxy, aryl formyl Base, aryl oxide formoxyl, C4-9Heteroaryl oxygroup, C4-9Heteroaryl formoxyl, C4-9Heteroaryl oxygen formoxyl；
X, Y are identical or different, are 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 of any one according to a first aspect of the present invention is formula (IIIA) compound represented and its alloisomerism Body, pharmaceutically acceptable salt,
Wherein,
R1Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C2-6Alkyl formyl radical, C2-6Alkyl oxygen formoxyl, C3-8Naphthenic base Oxygroup, C3-8Naphthenic base formoxyl, C3-8Cycloalkyloxy group formoxyl, aryl-C1-3Alkyl, heteroaryl-C1-3Alkyl contains 3-9 Carbon atom and 1-3 are selected from nitrogen, oxygen selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygroup of oxygen, containing 3-9 carbon atom and 1-3 Heteroatomic Heterocyclylalkyl formoxyl, contain the 3-9 carbon atom and 1-3 heteroatomic Heterocyclylalkyl oxygen selected from nitrogen, oxygen Formoxyl, aryloxy, aryl formoxyl, aryl oxide formoxyl, containing 4-9 carbon atom and 1-3 is selected from nitrogen, oxygen at aryl Heteroatomic heterocyclic aryl, containing 4-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic heterocyclic aryl oxygroup, contain 4-9 carbon atom and 1-3 are selected selected from nitrogen, the heteroatomic heterocyclic aryl formoxyl of oxygen, containing 4-9 carbon atom and 1-3 From nitrogen, the heteroatomic heterocyclic aryl oxygen formoxyl of oxygen；
R2Selected from hydrogen, amino；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally selected by 1-2 Replace from group below：Hydroxyl, halogen, cyano, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkane Base, C1-6Naphthenic base, C1-6Alkyl oxy, C3-6Heterocyclylalkyl, aryl；
X is selected from C, N；
M is selected from 1,2；
N is selected from 2,3,4.
R1Preferably ethoxycarbonyl, isopropyl oxygen formoxyl, tertiary fourth oxygen formoxyl, naphthenic base formoxyl, substituted cycloalkyl Formoxyl, cycloalkyloxy group formoxyl, substituted cycloalkyl oxygen formoxyl, aryl-C1-3Alkyl, substituted aryl-C1-3Alkyl, heteroaryl Base-C1-3Alkyl, aryl, substituted aryl, aryl formoxyl, aryl oxide formoxyl, substituted aryl formoxyl, substituted aryl oxygen first Acyl group, 2- (5- methyl) pyrimidine radicals, substitution 2- (5- methyl) pyrimidine radicals；
R2Preferably hydrogen, amino；
X is preferably C, N；
M is preferably 1,2；N is preferably 2,3,4.
The compound of any one according to a first aspect of the present invention is formula (IIIB) compound represented and its alloisomerism Body, pharmaceutically acceptable salt,
Wherein,
R1Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C2-6Alkyl formyl radical, C2-6Alkyl oxygen formoxyl, C3-8Naphthenic base Oxygroup, C3-8Naphthenic base formoxyl, C3-8Cycloalkyloxy group formoxyl, aryl-C1-3Alkyl, heteroaryl-C1-3Alkyl contains 3-9 Carbon atom and 1-3 are selected from nitrogen, oxygen selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygroup of oxygen, containing 3-9 carbon atom and 1-3 Heteroatomic Heterocyclylalkyl formoxyl, contain the 3-9 carbon atom and 1-3 heteroatomic Heterocyclylalkyl oxygen selected from nitrogen, oxygen Formoxyl, aryloxy, aryl formoxyl, aryl oxide formoxyl, containing 4-9 carbon atom and 1-3 is selected from nitrogen, oxygen at aryl Heteroatomic heterocyclic aryl, containing 4-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic heterocyclic aryl oxygroup, contain 4-9 carbon atom and 1-3 are selected selected from nitrogen, the heteroatomic heterocyclic aryl formoxyl of oxygen, containing 4-9 carbon atom and 1-3 From nitrogen, the heteroatomic heterocyclic aryl oxygen formoxyl of oxygen；
R2Selected from hydrogen, amino；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally selected by 1-2 Replace from group below：Hydroxyl, halogen, cyano, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkane Base, C1-6Naphthenic base, C1-6Alkyl oxy, C3-6Heterocyclylalkyl, aryl；
X is selected from C, N；
M is selected from 1,2；
N is selected from 2,3,4.
R1Preferably ethoxycarbonyl, isopropyl oxygen formoxyl, tertiary fourth oxygen formoxyl, naphthenic base formoxyl, substituted cycloalkyl Formoxyl, cycloalkyloxy group formoxyl, substituted cycloalkyl oxygen formoxyl, aryl-C1-3Alkyl, substituted aryl-C1-3Alkyl, heteroaryl Base-C1-3Alkyl, aryl, substituted aryl, aryl formoxyl, aryl oxide formoxyl, substituted aryl formoxyl, substituted aryl oxygen first Acyl group, 2- (5- methyl) pyrimidine radicals, substitution 2- (5- methyl) pyrimidine radicals；
R2Preferably hydrogen, amino；
X is preferably C, N；
M is preferably 1,2；N is preferably 2,3,4.
The compound of any one according to a first aspect of the present invention is formula (IV) compound represented and its alloisomerism Body, pharmaceutically acceptable salt,
Wherein,
R1Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C2-6Alkyl formyl radical, C2-6Alkyl oxygen formoxyl, C3-8Naphthenic base Oxygroup, C3-8Naphthenic base formoxyl, C3-8Cycloalkyloxy group formoxyl, aryl-C1-3Alkyl, heteroaryl-C1-3Alkyl contains 3-9 Carbon atom and 1-3 are selected from nitrogen, oxygen selected from nitrogen, the heteroatomic Heterocyclylalkyl oxygroup of oxygen, containing 3-9 carbon atom and 1-3 Heteroatomic Heterocyclylalkyl formoxyl, contain the 3-9 carbon atom and 1-3 heteroatomic Heterocyclylalkyl oxygen selected from nitrogen, oxygen Formoxyl, aryloxy, aryl formoxyl, aryl oxide formoxyl, containing 4-9 carbon atom and 1-3 is selected from nitrogen, oxygen at aryl Heteroatomic heterocyclic aryl, containing 4-9 carbon atom and 1-3 selected from nitrogen, oxygen heteroatomic heterocyclic aryl oxygroup, contain 4-9 carbon atom and 1-3 are selected selected from nitrogen, the heteroatomic heterocyclic aryl formoxyl of oxygen, containing 4-9 carbon atom and 1-3 From nitrogen, the heteroatomic heterocyclic aryl oxygen formoxyl of oxygen；
R2Selected from hydrogen, C1-6Alkyl, methoxyl group, amino；
R3Selected from hydrogen, C1-6Alkyl, C1-6Alkyl formyl radical, carbamoyl, substituted-amino formoxyl, benzyl；
Wherein alkyl, naphthenic base, aryl, heterocyclic aryl, Heterocyclylalkyl, benzyl and the amino is optionally selected by 1-2 Replace from group below：Hydroxyl, halogen, cyano, amino, substituted-amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkane Base, C1-6Naphthenic base, C1-6Alkyl oxy, C3-6Heterocyclylalkyl, aryl；
X is selected from C, N；
M is selected from 1,2；
N is selected from 2,3,4.
R1Preferably ethoxycarbonyl, isopropyl oxygen formoxyl, tertiary fourth oxygen formoxyl, naphthenic base formoxyl, substituted cycloalkyl Formoxyl, cycloalkyloxy group formoxyl, substituted cycloalkyl oxygen formoxyl, aryl-C1Alkyl, substituted aryl-C1Alkyl, heteroaryl-C1 Alkyl, heteroaryl-C1Alkyl, aryl, substituted aryl, aryl formoxyl, aryl oxide formoxyl, substituted aryl formoxyl, substitution Aryl oxide formoxyl, 2- (5- methyl) pyrimidine radicals, substitution 2- (5- methyl) pyrimidine radicals；
R2Preferably hydrogen, amino；
X is preferably C, N；
M is preferably 1,2；N is preferably 2,3,4.
Heretofore described pharmaceutically acceptable salt is the compounds of this invention and the salt selected from following acid formation：Salt Acid, p-methyl benzenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.It is preferred that For hydrochloric acid, p-methyl benzenesulfonic acid or trifluoroacetic acid.
The compound of any one according to a first aspect of the present invention, the target compound of the present invention prepared for embodiment (with It is that structural formula indicates or with systematic naming method description) and its stereoisomer, pharmaceutically acceptable salt.
The compound of any one according to a first aspect of the present invention, for selected from following compound：
Second aspect of the present invention provides the method for preparing any one of the first aspect present invention compound comprising with Lower step：
I) at a temperature of 20 DEG C to 50 DEG C (such as 20 DEG C to 30 DEG C, 30 DEG C to 50 DEG C or 40 DEG C to 50 DEG C), in solvent (volume ratio 2.5:1 water/acetic acid) in, formula 1a compounds represented react 1-4h with sodium nitrite, obtain shown in formula 2a Compound.
Ii) in the temperature of 0 DEG C to 60 DEG C (such as 0 DEG C to 35 DEG C, 15 DEG C to 35 DEG C, 20 DEG C to 40 DEG C or 20 DEG C to 60 DEG C) Under, in the presence of reducing agent (such as sodium dithionite) of 1-4 equivalents, 4-8h is reacted in solvent (such as 25% ammonium hydroxide), is obtained To formula 3a compounds represented.
Iii) at a temperature of 90 DEG C to 100 DEG C (such as 90 DEG C to 95 DEG C, 90 DEG C to 100 DEG C or 95 DEG C to 100 DEG C), In solvent (such as water), formula 3a compounds represented react 1-4h with formic acid, then react 1-4h with sodium hydroxide, obtain formula 4a Compound represented.
Iv) at a temperature of 50 DEG C to 80 DEG C (such as 50 DEG C to 60 DEG C, 60 DEG C to 70 DEG C or 70 DEG C to 80 DEG C), in acetic acid In the presence of sodium, in solvent (such as glacial acetic acid), formula 4a compounds represented react 2-4h with bromine, obtain shown in formula 5a Compound.
V) at a temperature of 60 DEG C to 90 DEG C (such as 60 DEG C to 70 DEG C, 70 DEG C to 80 DEG C or 80 DEG C to 90 DEG C), in alkali（Example Such as N, N- diisopropylethylamine）In the presence of, in solvent (such as n,N-Dimethylformamide), formula 5a compounds represented with The bromo- 2- butine of 1- reacts 4-7h, obtains formula 6a compounds represented.
Vi) at a temperature of 10 DEG C to 30 DEG C (such as 10 DEG C to 20 DEG C, 20 DEG C to 30 DEG C or 10 DEG C to 30 DEG C), in solvent In (such as acetone), formula h compounds represented react 4-7h with the bromo- 3- chloropropanes of 1-, obtain formula d compounds represented；X= C；N=2,3.
At a temperature of -10 DEG C to 30 DEG C (such as -10 DEG C to 20 DEG C, 0 DEG C to 10 DEG C, 0 DEG C to 30 DEG C), deposited in alkali and salt Under（Such as sodium hydride, lithium bromide）, in solvent (such as tetrahydrofuran, n,N-Dimethylformamide or the two mixture), Formula h compounds represented react 4-7h with the bromo- 3- chloropropanes of 1-, obtain formula d compounds represented；X=N；N=2,3.
Vii) at a temperature of 50 DEG C to 100 DEG C (such as 50 DEG C to 70 DEG C, 60 DEG C to 80 DEG C or 80 DEG C to 100 DEG C), Alkali（Such as potassium carbonate）In the presence of, in solvent (such as N-Methyl pyrrolidone), shown in formula a compounds represented and formula d Compound react 7-12h, obtain formula b compounds represented；N=2,3.
Viii) at a temperature of 20 DEG C to 50 DEG C (such as 20 DEG C to 30 DEG C, 20 DEG C to 40 DEG C or 30 DEG C to 50 DEG C), in alkali （Such as potassium carbonate）In the presence of, in solvent (such as n,N-Dimethylformamide), shown in formula a compounds represented and formula e Compound react 7-10h, obtain formula f compounds represented；
Ix) at a temperature of 20 DEG C to 30 DEG C (such as 20 DEG C to 25 DEG C, 20 DEG C to 30 DEG C or 25 DEG C to 30 DEG C), in alkali （Such as triethylamine）In the presence of, in solvent (such as dichloromethane), formula f compounds represented react 1- with mesyl chloride 2h obtains formula g compounds represented；
At a temperature of 80 DEG C to 110 DEG C (such as 80 DEG C to 95 DEG C, 90 DEG C to 100 DEG C or 85 DEG C to 110 DEG C), in alkali （Such as triethylamine）And salt（Such as potassium iodide）In the presence of, in solvent (such as dioxane), formula g compounds represented with Formula h compounds represented react 3-5h, obtain formula b2 compounds represented.
X) at a temperature of 50 DEG C to 100 DEG C (such as 50 DEG C to 70 DEG C, 60 DEG C to 80 DEG C or 80 DEG C to 100 DEG C), in alkali （Such as potassium carbonate）In the presence of, in solvent (such as tetrahydrofuran, n,N-Dimethylformamide or the two mixture), formula b Compound represented reacts 9-16h with formula c compounds represented, obtains the compounds of this invention shown in formula (II)；
Wherein, R1, R2, X, Y, the definition of m and n are as described in the first aspect of the invention.
Third aspect present invention provides a kind of pharmaceutical composition, and it includes treatment and/or the present invention of prevention effective dose Any one of first aspect compound and its stereoisomer, pharmaceutically acceptable salt, and optionally one or more Pharmaceutically acceptable carrier or excipient.
Fourth aspect present invention provides any one of first aspect present invention compound and its stereoisomer, medicine Learn any one of acceptable salt or third aspect present invention described pharmaceutical composition prepare for treat and/or prevent with DPP-IV hyperactivities over-express purposes in the drug of related disease or illness with DPP-IV.In an embodiment party It is described with DPP-IV hyperactivities or to over-express related disease or illness with DPP-IV be to be selected from following disease in case Or illness：Diabetes, hyperglycemia, adult-onset diabetes, diabetes B etc..
Fourth aspect present invention additionally provides any one of first aspect present invention compound and its stereoisomer, Any one of pharmaceutically acceptable salt or third aspect present invention described pharmaceutical composition are being prepared for treating and/or preventing Purposes in the drug of diabetes, hyperglycemia, adult-onset diabetes, diabetes B etc..
Fourth aspect present invention additionally provides any one of first aspect present invention compound and its stereoisomer, Any one of pharmaceutically acceptable salt or third aspect present invention described pharmaceutical composition are being prepared as DPP-IV inhibitor Purposes in drug.
Fifth aspect present invention provides one kind and treats and/or prevent and DPP-IV activity mistakes in subject in need Method that is high or over-expressing related disease or illness with DPP-IV, this method include being controlled to subject in need application Any one of the first aspect present invention for the treatment of and/or the prevention effective dose compound and its stereoisomer, it is pharmaceutically acceptable Salt or third aspect present invention any one of them pharmaceutical composition.The method of any one according to a fifth aspect of the present invention, Wherein described over-expresses related disease or illness selected from diabetes, high blood with DPP-IV hyperactivities or with DPP-IV Sugared disease, adult-onset diabetes, diabetes B etc..
Fifth aspect present invention additionally provides one kind and diabetes, high blood is treated and/or prevented in subject in need Sugared disease, adult-onset diabetes, diabetes B method, this method include application to subject in need treat And/or any one of first aspect present invention of prevention effective dose compound and its stereoisomer, it is pharmaceutically acceptable Any one of salt or third aspect present invention described pharmaceutical composition.
Sixth aspect present invention provide for treat and/or prevent with DPP-IV hyperactivities or with DPP-IV it is excessive Any one of first aspect present invention of related disease or illness compound and its stereoisomer are expressed, pharmacy can connect The salt received.Compound according to a sixth aspect of the present invention, wherein described excessive with DPP-IV hyperactivities or with DPP-IV It expresses related disease or illness is selected from：Diabetes, hyperglycemia, adult-onset diabetes, diabetes B etc..
Sixth aspect present invention is additionally provided for treating and/or preventing diabetes, hyperglycemia, non-insulin-dependent Any one of the first aspect present invention of diabetes, diabetes B etc. the compound and its stereoisomer, pharmacy can connect The salt received.
Feature is equally applicable to other either sides possessed by any one of either side or the either side of the present invention Or any one of other either sides, certainly in mutual where applicable, if necessary may be used as long as they will not be conflicting Appropriate modification is made to individual features.In the present invention, it for example, when referring to " any one of first aspect present invention ", is somebody's turn to do " any one " Refer to any son aspect of first aspect present invention, when referring in a similar manner in other aspects, also there is similar meaning.
Detailed description of the invention：
It is further described to various aspects of the present invention with feature below.
All documents recited in the present invention, their full content are incorporated herein by reference, and if these are literary When offering expressed meaning and the inconsistent present invention, it is subject to the statement of the present invention.In addition, the various terms that use of the present invention and Phrase has that well known to a person skilled in the art general senses, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explains, the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention Subject to the meaning stated.Here is the definition of a variety of terms used in the present invention, these definition are suitable for the application the whole instruction Term used, unless otherwise indicated in concrete condition.
Term " alkyl oxy " refers to alkyl-O-, and alkyl therein is as described herein.
As described herein, term " halogen ", " halogen ", " halogen atom ", " halogenated " etc. indicate fluorine, chlorine, bromine or iodine, especially It is to indicate fluorine, chlorine or bromine.
As described herein, term " alkyl " refers to the alkyl for specifying number carbon atom number, is linear chain or branched chain Alkyl, and it may include its subbase group, such as " C when referring to1-6Can also include C when alkyl "1-5Alkyl, C1-4Alkane Base, C2-6Alkyl, C2-4The group of the subrange of the expressions such as alkyl, and specific group such as methyl, ethyl, n-propyl, isopropyl Base, normal-butyl, sec-butyl, tertiary butyl, amyl, hexyl.
As described herein, term " aryl " is individually or defined in combination herein monocycle or bicyclic aromatic base Group.The example of aryl includes but not limited to phenyl, naphthalene etc..Similarly, term " aryloxy group-" refers to an aryl, is passed through The other parts of oxygen and compound connect.
As described herein, term " heterocyclic aryl " refers to herein with 1 to 3 hetero atom as annular atom, remaining Annular atom be carbon aryl, hetero atom includes oxygen, sulphur and nitrogen.The example of heteroaryl include but not limited to pyridyl group, pyrimidine radicals, Imidazole radicals, furyl, thienyl, pyrazinyl, quinolyl, isoquinolyl, tetrahydro isoquinolyl etc..In one embodiment, The heteroaryl is methyl substituted pyrimidine radicals.
As described herein, term " aryl-C1-3Alkyl-" refers to aryl group, passes through C1-3Alkyl and compound Other parts connect.
As described herein, term " heteroaryl-C1-3Alkyl-" refers to heteroaryl groups, passes through C1-3Alkyl and chemical combination The other parts of object connect.
As described herein, term " naphthenic base " refers to specifying number the cyclic alkyl of ring carbon atom number, and its " C when may include its subbase group, such as referring to3-8Can also include C when naphthenic base "3-7Naphthenic base, C3-6Naphthenic base, C3-5Ring Alkyl, C4-7The group of the subrange of the expressions such as naphthenic base, and specific group such as cyclopropyl, cyclobutyl, cyclopenta, hexamethylene Base, suberyl etc..
As described herein, term " Heterocyclylalkyl " refers to that there is the cycloheteroalkyl for specifying number annular atom number, packet to refer to Monocycle or condensed ring group in ring there are 5 to 9 annular atoms, wherein one or two annular atom to be selected from the miscellaneous of nitrogen, oxygen or sulphur Atom, remaining annular atom are carbon.These rings can also have one or more double bonds, and but, these rings do not have total conjugated Л electronic systems.Heterocyclylalkyl includes but not limited to pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl etc..
As described herein, term " effective quantity " refers to that can realize treatment in subject and/or prevent of the present invention The dosage of disease or illness.
As described herein, term " pharmaceutical composition " can also refer to " composition ", can be used in subject spy It is not to realize to treat and/or prevent disease or illness of the present invention in mammal.
As described herein, term " subject " can refer to patient or other receive formula Compound I or its medicine Compositions to treat and/or prevent the animal of disease or illness of the present invention, especially mammal, such as people, dog, Monkey, ox, horse etc..
As described herein, term " disease and/or illness " refers to a kind of physical condition of the subject, the body shape State is related with disease of the present invention and/or illness.For example, disease of the present invention and/or illness can both refer to a kind of body State, such as in the physical condition compared with hyperglycemia, a kind of morbid state can also be referred to, such as show as hyperglycemia, diabetes Equal morbid states.Physical condition and morbid state are not distinguished herein or the two can be referred to mutually, such as " hyperglycemia " may be used interchangeably with " hyperglycemia ".
As described herein, as do not specialized, " % " refers to the percentage of w/w, especially in description solids In the case of matter.Certainly, when describing liquid substance, the percentage which can refer to weight/volume (is dissolved in liquid for solid The situation of body), or volume/volume percentage (situation that liquid is dissolved in for liquid) can be referred to.
As described herein, term " pharmaceutically acceptable " indicates the salt for example at description " pharmaceutically acceptable salt " It is not subjected in subject physiologic still, but also can refer to the synthetic for pharmaceutically having use value, for example, for It carries out being formed by the salt as intermediate when chiral resolution, although the salt of this intermediate can not directly give subject, But the salt can work to obtain in final product of the present invention.
Further aspect of the present invention further relates to the pharmaceutical composition using the compounds of this invention as active ingredient.The pharmaceutical composition Object can be prepared according to method well known in the art.Can by by the compounds of this invention with it is one or more pharmaceutically acceptable solid Body or liquid excipient and/or adjuvant combine, and any dosage form used suitable for human or animal is made.The compounds of this invention is in its medicine Content in compositions is usually 0.1-95 weight %.
The compounds of this invention can be administered in a unit containing its pharmaceutical composition, and administration route can be enteron aisle Or non-bowel, such as oral, intravenous injection, intramuscular injection, hypodermic injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, Vagina, rectum etc..
Form of administration can be liquid dosage form, solid dosage forms or semisolid dosage form.Liquid dosage form can be solution（Including True solution and colloidal solution）, emulsion（Including o/w types, w/o types and emulsion）, suspension, injection（Including liquid drugs injection, powder-injection And infusion）, eye drops, nasal drop, lotion and liniment etc.；Solid dosage forms can be tablet（Including ordinary tablet, enteric coatel tablets, lozenge, Dispersible tablet, chewable tablets, effervescent tablet, oral disnitegration tablet）, capsule（Including hard capsule, soft capsule, capsulae enterosolubilis）, granule, dissipate Agent, pellet, dripping pill, suppository, film, patch, gas（Powder）Mist agent, spray etc.；Semisolid dosage form can be ointment, gel Agent, paste etc..
It is sustained release preparation, controlled release preparation, targeting preparation and various that the compounds of this invention, which can be made ordinary preparation, also be made, Particulate delivery system.
In order to which tablet is made in the compounds of this invention, various excipient well known in the art can be widely used, including dilute Release agent, binder, wetting agent, disintegrant, lubricant, cosolvent.Diluent can be starch, dextrin, sucrose, glucose, breast Sugar, mannitol, sorbierite, xylitol, microcrystalline cellulose, calcium sulfate, calcium monohydrogen phosphate, calcium carbonate etc.；Wetting agent can be water, second Alcohol, isopropanol etc.；Adhesive can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, Arabic gum Slurry, gelatine size, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, card Wave nurse, polyvinylpyrrolidone, polyethylene glycol etc.；Disintegrant can be dried starch, microcrystalline cellulose, low substituted hydroxy-propyl fiber Element, crosslinked polyvinylpyrrolidone, croscarmellose sodium, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxy second Alkene sorbitan fatty acid ester, dodecyl sodium sulfate etc.；Lubricant and cosolvent can be talcum powder, silica, tristearin Hydrochlorate, tartaric acid, atoleine, polyethylene glycol etc..
Tablet can also be further made to coating tablet, such as sugar coated tablet, thin membrane coated tablet, enteric coated tablets or double Synusia and multilayer tablet.
In order to which capsule is made in administration unit, active ingredient the compounds of this invention and diluent, cosolvent can be mixed It closes, mixture is placed directly in hard capsule or soft capsule.It also can active ingredient the compounds of this invention is first and diluent, bonding Particle or pellet is made in agent, disintegrant, then is placed in hard capsule or soft capsule.It is used to prepare each dilute of the compounds of this invention tablet Release agent, binder, wetting agent, disintegrant, cosolvent kind can also be used for preparing the capsule of the compounds of this invention.
For injection is made in the compounds of this invention, water, ethyl alcohol, isopropanol, propylene glycol or their mixture can be used Make solvent and appropriate solubilizer commonly used in the art, cosolvent, pH adjusting agent, osmotic pressure regulator is added.Solubilizer or hydrotropy Agent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin etc.；PH adjusting agent can be phosphate, acetate, hydrochloric acid, hydrogen Sodium oxide molybdena etc.；Osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate etc..Such as prepare freeze-dried powder Injection can also be added mannitol, glucose etc. and be used as proppant.
In addition, if desired, colorant, preservative, fragrance, corrigent or other additions can also be added into pharmaceutical preparation Agent.
To reach medication purpose, enhance therapeutic effect, drug of the invention or pharmaceutical composition well known can be given with any Prescription method is administered.
The dosage of the compounds of this invention pharmaceutical composition is according to the property and serious journey to be prevented or be treated disease The individual instances of degree, patient or animal, administration route and dosage form etc. can have large-scale variation.In general, of the present inventionization The daily Suitable dosage ranges for closing object are 0.001-150mg/Kg weight, preferably 0.1-100mg/Kg weight, more preferably 1-60mg/Kg weight, most preferably 2-30mg/Kg weight.Above-mentioned dosage with a dosage unit or can be divided into several dosage lists Position administration, this depends on the clinical experience of doctor and includes the dosage regimen with other treatment means.
The compound of the present invention or composition can individually be taken, or merge use with other treatment drug or symptomatic drugs. When the compound of the present invention and other medicines, which exist, to act synergistically, its dosage should be adjusted according to actual conditions.
Advantageous effects
All compounds all have novel chemical constitution, and most of substituted xanthine class chemical combination object in the present invention Outer DPP-IV inhibitory activity reaches 50% or more, wherein the external DPP-IV inhibitory activity IC of 12 compounds50Reach micromole's water It is flat, the IC of especially 7 compounds50Value reaches 10-7Mol/l is horizontal, the IC of 1 compound50Value reaches 10-8Mol/l is horizontal, Good DPP-IV inhibitory activity and selectivity are shown, to provide the strong non-peptides selection of a kind of structure novel, activity Property DPP-IV inhibitor, can be used for the prevention and treatment of diabetes B and its associated disease.
Specific implementation mode
The present invention can be further described by the following examples, however, the scope of the present invention and unlimited In following embodiments.One of skill in the art, can be with it is understood that under the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.The present invention carries out the material and test method that are arrived used in experiment general And/or specific description.Although to realize the present invention many materials and operating method used in purpose be it is known in the art that But the present invention is still described in detail as far as possible herein.
For following whole embodiments, standard operation well known by persons skilled in the art and purification process can be used.It removes Non- to be otherwise noted, all temperature are indicated with DEG C (degree Celsius).The structure of compound is by nuclear magnetic resoance spectrum (NMR) and/or matter (MS) is composed come what is determined.M.p. it is with DEG C fusing point provided, the non-correction up of temperature.
Prepare embodiment part
The structure of compound be by nuclear magnetic resonance spectroscopy (1H NMR) and mass spectrum (MS) come what is determined.Nuclear magnetic resonance spectroscopy And carbon spectral displacement (δ) is provided with the unit of hundred a ten thousandths (ppm).Nuclear magnetic resonance spectroscopy Mercury-300 or Mercury- 400 type nmr determinations, deuterochloroform (CDCl3) or heavy water (D2) or deuterated dimethyl sulfoxide (DMSO-d O6) or it is deuterated Methanol (CD3OD) make solvent, tetramethylsilane (TMS) is internal standard.
Fusing point is measured using Japan's Yanaco M.P-500D type melting point detectors, and temperature does not correct.
High resolution mass spectrum uses Agilent1100series LC/MSD trap mass spectrometer LC-MS Instrument measures.
Electronic balance is using Japan's Yanaco LY-300 type electronic balances.
It is carrier that column chromatography, which generally uses 200~300 mesh silica gel,.
Anhydrous solvent is handled by standard method.Other reagents are that commercially available analysis is pure.
Wherein,
TFA is trifluoroaceticacid, i.e. trifluoroacetic acid.
DMF is N, N-Dimethylformamide, i.e. n,N-Dimethylformamide.
THF is tetrahydrofuran, i.e. tetrahydrofuran.
NMP is 1-Methyl-2-pyrrolidone, 1- methyl pyrrolidones
Preparation example
The synthetic route of Scheme1 intermediates a
The preparation of first step 6- amino -5- nitroso -1- methyluracils 2a
The mixing that 6- amino -1- methyluracils (10.00g, 70.9mmol) are dissolved in 50mL water and 20mL glacial acetic acid is molten In liquid, at 25 DEG C of room temperature, the aqueous solution (40mL) of sodium nitrite (7.138g, 103.5mmol) is added, 0.5h is stirred at room temperature, Then 50 DEG C of stirring 1h are risen to, finally moves to and is stirred overnight at room temperature.TLC detections stop stirring after the reaction was complete, and water is used in filtering (100mL) and 95% ethyl alcohol (50mL) wash filter cake, obtain intermediate 2a, violet solid 11.97g, yield about 99.3%.
1H NMR(DMSO-d6,300MHz)δ:3.166(s,3H,CH3),9.051(s,2H,NH2),11.484(s,1H, NH).MS(ESI+):m/z=170.3[M+H]+
The preparation of second step 5,6- diaminostilbenes-methyluracil 3a
6- amino -5- nitroso -1- methyluracils 2a (11.50g, 67.6mmol) are dissolved in 200mL ammonium hydroxide (25%) In, at 25 DEG C of room temperature, sodium dithionite (41.20g, 236.6mmol), stirring is added.Temperature gradually rises in reaction bulb To 35 DEG C.When in bottle temperature no longer increase after be heated to 60 DEG C, stir 1h.Then reaction is moved to, 6h is stirred at room temperature.It has reacted Stop stirring after complete, filtering washs filter cake with ice water, is dried in vacuo.Obtain intermediate 3a, beige solid 9.28g, yield 87.9%。
1H NMR(DMSO-d6,300MHz)δ:3.201(s,3H,CH3),6.104(s,4H,NH2),10.517(s,1H, NH).MS(ESI+):m/z=157.2[M+H]+.
Third walks the preparation of 3- methyl-1 H-2,6- dicarbapentaborane purine 4a
5,6- diaminostilbenes-methyluracil 3a (10.00g, 64.0mmol) is dissolved in formic acid (3.305mL) and water (74.74mL) in the mixed solvent, is cooled to 20 DEG C after being heated to reflux 3h at 105 DEG C, be added sodium hydroxide (5.12g, Water (6.40mL) solution 128.1mmol), is heated to reflux after 1h that the reaction was complete in 105 DEG C.It is cooled to 0 DEG C, with glacial acetic acid tune pH To 4, there is white-yellowish solid precipitation, filter, filter cake is washed with ice water, is dried in vacuo, obtains intermediate 4a, white solid 10.01g, Yield about 94.1%.
1H NMR(DMSO-d6,300MHz)δ:3.478(s,3H,CH3),7.853(s,1H,CH),11.092(s,1H, NH).MS(ESI+):m/z=167.3[M+H]+.
The preparation of the bromo- 3- methyl-1s H-2,6- dicarbapentaborane purine 5a of 4th step 8-
By 3- methyl-1 H-2,6- dicarbapentaborane purine 4a (10.00g, 60.2mmol) and sodium acetate (9.87g, It 120.3mmol) is dissolved in glacial acetic acid (90mL), bromine (11.54g, 72.2mmol) is added dropwise, in 65 DEG C of heating stirring 2h. After the reaction was complete, 25 DEG C are cooled to room temperature, filtering washs filter cake with glacial acetic acid (100mL) and ice water (100mL), is dried in vacuo, Obtain intermediate 5a, off-white powder 12.23g, yield about 82.6%.
1H NMR(DMSO-d6,300MHz)δ:3.161(s,3H,CH3),11.194(s,1H,NH),12.566(s,1H, NH).MS(ESI+):m/z=247.2[M+H]+.
The preparation of the 5th bromo- 7- of step 8- [1- (2- butine) base] -3- methyl-1 H-2,6- dicarbapentaborane purine a
By the bromo- 3- methyl-1s H-2,6- dicarbapentaborane purine 5a (11.00g, 44.7mmol) of 8- and N, N- diisopropylethylamine (5.78g, 44.7mmol) is dissolved in n,N-Dimethylformamide (65mL), stirs 30min at 25 DEG C of room temperature, 1- is added dropwise Bromo- 2- butine (5.95g, 44.7mmol), in 80 DEG C of heating stirring 5h.After the reaction was complete, it is cooled to 0 DEG C, into reaction system 200mL ice water is added and stirs 30min, there is off-white powder precipitation, filters, washs filter cake with ice water (200mL), be dried in vacuo Intermediate a, off-white powder 10.26g, yield 77.5%.
1H NMR(DMSO-d6,300MHz)δ:1.788(s,3H,CH3),3.305(s,3H,CH3),5.046(s,2H, CH2),11.322(s,1H,NH).MS(ESI+):m/z=297.0[M+H]+.
The synthetic route of Scheme2 intermediates b
The preparation of first step 4- (3- chloropropyls) piperazine -1- t-butyl formates d
The 1- piperazinecarboxylic acids tert-butyl ester (2.00g, 10.7mmol) is dissolved in 25mL anhydrous DMFs and anhydrous THF (1:1) mixing In solvent, under protection of argon gas, be gradually added in 0 DEG C sodium hydride (0.27g, 11.3mmol) and anhydrous lithium bromide (0.57g, 6.6mmol), 4h is stirred at 0 DEG C.The bromo- 2 cbloropropane isopropyl chlorides of 1- (1.84g, 11.8mmol) are added dropwise, move reaction at 0 DEG C To 25 DEG C of stirring 5h of room temperature.The reaction was complete, is concentrated under reduced pressure, and is cooled to 0 DEG C and the stirring of 50mL ice water is added into reaction system 30min is extracted with dichloromethane, merges organic layer, and organic layer uses water and saturated common salt water washing, anhydrous sodium sulfate dry respectively It is dry, it filters, is concentrated under reduced pressure, gained crude product is through silica gel (200-300 mesh) pillar layer separation, methylene chloride-methanol（V:V=30:1） Mixed liquor is eluant, eluent, obtains intermediate d, white-yellowish solid 2.18g, yield 77.4%, MS (ESI+):m/z=263.2[M+H]+.
Second step 7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- tertbutyloxycarbonyls) -1- piperazinyls] third Base } -1H- purine -2,6- diketone b preparation
By the bromo- 7- of 8- [1- (2- butine) base] -3- methyl-1 H-2,6- dicarbapentaborane purine a (0.64g, 3.5mmol) and carbon Sour potassium (0.96g, 6.9mmol) is dissolved in 10mLNMP solvents, is heated to 70 DEG C, stirs 15min.It is gradually added 4- (3- chlorine third Base) piperazine -1- t-butyl formates d (1.00g, 3.8mmol), 6h is stirred at 70 DEG C.Postcooling that the reaction was complete to 0 DEG C of room temperature, Ice water 100mL stirrings are added into system, are extracted with ethyl acetate, merge organic layer, organic layer uses water and saturated common salt respectively Water washing, anhydrous sodium sulfate drying, is filtered, and is concentrated under reduced pressure, gained crude product is through silica gel (300-400 mesh) pillar layer separation, dichloro Methane-methanol（V:V=30:1）Mixed liquor is eluant, eluent, obtains intermediate b, yellow solid 1.71g, yield 86.0%, MS (ESI+): m/z=523.3[M+H]+.
The preparation of first step 4- (5- methylpyrimidine -2- bases) piperazine -1- t-butyl formates i
The 1- piperazinecarboxylic acids tert-butyl ester (5.00g, 26.8mmol) is dissolved in 30mL anhydrous DMFs and anhydrous THF (1:1) mixing In solvent, under protection of argon gas, be gradually added in 0 DEG C sodium hydride (1.29g, 53.7mmol) and anhydrous lithium bromide (2.80g, 32.2mmol), 4h is stirred at 0 DEG C.It is gradually added the chloro- 5- methylpyrimidines (3.45g, 26.8mmol) of 2- at 0 DEG C, stirs Reaction is moved to 25 DEG C of stirring 5h of room temperature by 20min.The reaction was complete, is concentrated under reduced pressure, is cooled to 0 DEG C and is added into reaction system 100mL ice water stirs 30min, is extracted with ethyl acetate, and merges organic layer, and organic layer uses water and saturated common salt water washing respectively, Anhydrous sodium sulfate is dried, and is filtered, and is concentrated under reduced pressure, gained crude product is through silica gel (300-400 mesh) pillar layer separation, dichloromethane-first Alcohol（V:V=33:1）Mixed liquor is eluant, eluent, obtains intermediate i, off-white powder 6.29g, yield 84.2%.
1H NMR(CDCl3,300MHz)δ:1.486(s,9H,Boc),2.132(s,3H,CH3),3.489(t,4H,J= 4.5Hz,CH2),3.758t,4H,J=4.5Hz,CH2),8.168(s,2H,in pyrimidine).MS(ESI+):m/z=279.3 [M+H]+.
The preparation of second step 4- (5- methylpyrimidine -2- bases) piperazine j
4- (5- methylpyrimidine -2- bases) piperazine -1- t-butyl formates i (6.00g, 21.6mmol) is dissolved in 100mL dichloros In methane, trifluoroacetic acid (20mL) is added dropwise at 25 DEG C of room temperature, stirs 1h.After the reaction was complete, reaction solution is concentrated under reduced pressure.It will Residue is dissolved in ethyl acetate (100mL) and 1mol/L sodium hydrate aqueous solutions, stirs 1h, collects ethyl acetate layer, then use Ethyl acetate aqueous layer extracted, merges organic layer, and organic layer uses water and saturated common salt water washing, anhydrous sodium sulfate drying, mistake respectively Filter is concentrated under reduced pressure, obtains intermediate j, reddish Solid 3.62g, yield 94.2%.
Third walks the preparation of 4- (3- chloropropyls) -1- [(5- methylpyrimidines) -2- bases] piperazine d
4- (5- methylpyrimidine -2- bases) piperazine j (3.413g, 19.1mmol) is dissolved in 40mL acetone, potassium carbonate is added (2.643g, 19.1mmol) stirs 20min at 25 DEG C of room temperature, be added dropwise the bromo- 3- chloropropanes of 1- (1.591g, 23.0mmol), continue to stir 5h.The reaction was complete, is concentrated under reduced pressure, and 50mL ice water is added into reaction system and stirs 30min, with two Chloromethanes extracts, and merges organic layer, and organic layer uses water and saturated common salt water washing, anhydrous sodium sulfate drying to filter, decompression respectively Concentration, obtains intermediate d, reddish Solid 4.19g, yield 86.2%.
1H NMR(CDCl3,400MHz)δ:1.992(m,2H,CH2),2.108(s,3H,CH3),2.487(m,2H,CH2), 2.498(m,4H,CH2),3.615(m,2H,CH2),3.765(m,4H,CH2),8.144(d,2H,J=8.4Hz,CH,in pyrimidine).MS(ESI+):m/z=254.1[M+H]+.
4th step 7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methylpyrimidine -2- bases) -1- piperazines Base] propyl -1H- purine -2,6- diketone b preparation
By the bromo- 7- of 8- [1- (2- butine) base] -3- methyl-1 H-2,6- dicarbapentaborane purine a (0.302g, 1.2mmol) and carbon Sour potassium (0.340g, 2.4mmol) is dissolved in 10mLNMP solvents, is heated to 70 DEG C, stirs 15min.It is gradually added 4- (3- chlorine third Base) -1- [(5- methylpyrimidines) -2- bases] piperazine d (0.344g, 1.3mmol), 6h is stirred at 70 DEG C.Postcooling that the reaction was complete 50mL ice water is added into reaction system to 0 DEG C and stirs 30min, is extracted with ethyl acetate, merges organic layer, organic layer is used respectively Water and saturated common salt water washing, anhydrous sodium sulfate drying, are filtered, and are concentrated under reduced pressure, gained crude product is through silica gel (300-400 mesh) column color Spectrum separation, methylene chloride-methanol（V:V=30:1）Mixed liquor is eluant, eluent, obtains intermediate b, yellow solid 0.60g, yield 86.9%。
1H NMR(CDCl3,400MHz)δ:1.25(m,2H,CH2),11.803(s,3H,CH3),2.036(s,3H,CH3), 2.104(m,2H,CH2),2.538(m,4H,CH2),3.538(s,3H,CH3),3.755(m,4H,CH2),4.113(m,2H, CH2),8.134(s,2H,CH,in pyrimidine).MS(ESI+):m/z=514.1[M+H]+.
The synthetic route of Scheme3 intermediates 1c
The preparation of the first step (R) -3- amino -2- piperidones 1c-2
D-Orn hydrochloride 1c-1 (5.000g, 29.7mmol) is dissolved in 45mL absolute methanols, is cooled to -80 DEG C, Stir 30min.Thionyl chloride (9.031g, 75.9mmol) is added dropwise, reaction is moved into room after stirring 30min at -80 DEG C 25 DEG C of stirrings of temperature are for 24 hours.Concentration of reaction solution after the reaction was complete is added 19mL water and aqueous solution is made, by 717 (OH-) anion friendship Purifying resin is changed, 19mL methanol is added into obtained aqueous solution, adds 190mL chloroform extracting and washing impurity, it is true to collect water layer Vacuum freecing-dry obtains intermediate 1c-2, white foam solid 3.18g, yield 94.2%.
1H NMR(CDCl3,400MHz)δ:1.25(m,2H,CH2),1.803(s,3H,CH3),2.036(s,3H,CH3), 2.104(m,2H,CH2),2.538(m,4H,CH2),3.538(s,3H,CH3),3.755(m,4H,CH2),4.113(m,2H, CH2),8.134(s,2H,CH,).MS(ESI+):m/z=115.15[M+H]+.
The preparation of second step (R) -3- amino piperidines 1c
(R) -3- amino -2- piperidones 1c-2 (3.182g, 27.9mmol) is dissolved at 0 DEG C in the anhydrous THF of 200mL, - 80 DEG C are cooled to, 1h is stirred.THF (100mL) solution of tetrahydrochysene lithium aluminium (3.382g, 89.2mmol) is added dropwise, works as reaction bulb After interior temperature no longer increases, 10h is heated to reflux at 90 DEG C.After the reaction was complete, it is cooled to 0 DEG C, is added successively into reaction system Enter 1.87mL water, the 5N NaOH aqueous solutions and 5.68mL water of 1.87mL.Filtering washs filter cake with 100mL THF, collects filtrate, It is concentrated under reduced pressure, obtains intermediate 1c, brownish red grease 1.39g, yield 49.8%.
1H NMR(CDCl3,400MHz)δ:1.25(m,2H,CH2 ),1.803(s,3H,CH3 ),2.036(s,3H,CH 3), 2.104(m,2H,CH2 ),2.538(m,4H,CH2 ),3.538(s,3H,CH 3),3.755(m,4H,CH2 ),4.113(m,2H,CH2 ),8.134(s,2H,CH,).MS(ESI+):m/z=101.19[M+H]+.
The synthetic route of Scheme4 intermediates 2c
It is that raw material obtains intermediate 2c using similar operations step in Scheme3 with 2c-1 (5.000g, 29.7mmol), Brownish red grease 1.45g, yield 52.0%.
1H NMR(DMSO-d6,300MHz)δ:4.66-4.64(m,1H,CHC=O),3.79-3.61(m,4H,CH2 NH,CH2 OH),3.35(br,4H,CH2NCH2in thiomorpholine),2.83-2.61(m,9H,CH2SCH2in thiomorpholine,5H in pyrrolidine),0.93(s,6H,CH3CCH3).MS(ESI+):m/z=101.19[M+H]+
Embodiment
Embodiment 1
1 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methylpyrimidines) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methyl Pyrimidine) -1- piperazinyls] propyl -1H- purine -2,6- diketone preparation
(R) -3- amino piperidines 1c (0.050g, 0.50mmol) and potassium carbonate (0.124g, 0.90mmol) are dissolved in 20mL In anhydrous THF, molecular sieve 20mg is added, in 25 DEG C of stirring 30min of room temperature.It is gradually added 7- (2- butynyls) -3,7- dihydros -3- Methyl-1-{ 3- [4- (5- methylpyrimidine-2- bases)-1- piperazinyls] propyl }-1H- purine-2,6- diketone b (0.128g, 0.25mmol), it is heated to the 8h that flows back at 90 DEG C.Filtrate, gained is concentrated under reduced pressure in postcooling that the reaction was complete to 25 DEG C of room temperature, filtering Crude product is through silica gel (300-400 mesh) pillar layer separation, methylene chloride-methanol（V:V=10:1）Mixed liquor is eluant, eluent, obtains chemical combination Object 1, yellow solid 0.070g, yield 52.3%.m.p.183-184℃;
1H NMR(CD3OD,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+):C27H39N10O2Calculated value 535.3252, it is real Measured value [M+H]+535.3241.
Embodiment 2
2 8- of compound [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methylpyrimidines) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methyl Pyrimidine) -1- piperazinyls] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and 2c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 2, yellow solid 54mg, yield 51.9%.m.p.183-184℃;
1H NMR(CD3OD,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+):C27H39N10O2Calculated value 535.3252, it is real Measured value [M+H]+535.3244.
Embodiment 3
{ [(5- methyl is phonetic by 4- by 3- for 3 8- of compound (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s - Pyridine) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methylpyrimidines) -1- piperazines Piperazine base] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 3, yellow solid 71mg, yield 68.3%.m.p.186-187℃;
1H NMR(CD3OD,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+):C27H39N10O2Calculated value 535.3252, it is real Measured value [M+H]+535.3243.
Embodiment 4
{ [(5- methyl is phonetic by 4- by 3- for 4 8- of compound (1- piperazinyls) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s - Pyridine) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- (1- piperazinyls) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [4- (5- methylpyrimidines) -1- piperazines Base] propyl -1H- purine -2,6- diketone preparation
With b (0.150g, 0.29mmol) and c (0.103g, 0.58mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 4, yellow solid 85mg, yield 55.9%.m.p.189℃;
1H NMR(CD3OD,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+):C26H37N10O2Calculated value 521.3096, measured value [M+H]+521.3093.
Embodiment 5
5 8- of compound [1- (4- methyl) piperazinyl] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- first Oxygen carbonyl) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- [1- (4- methyl) piperazinyl] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- methoxycarbonyl groups) - 1- piperidyls] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 5, yellow solid 56mg, yield 53.6%.
Embodiment 6
6 8- of compound (1- piperazinyls) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- tertiary butyloxycarbonyls Base) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- (1- piperazinyls) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- tertbutyloxycarbonyls) -1- piperazines Base] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and c (0.032g, 0.37mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 6, yellow solid 51mg, yield 51.7%.
Embodiment 7
{ [(4- is different by 3- for -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-by 7 8- of compound [1- (4- methyl) piperazinyl] Propylene carbonyl oxygen) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- [1- (4- methyl) piperazinyl] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- isopropyl oxygen carbonyls Base) -1- piperidyls] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.20mmol) and c (0.59g, 0.59mmol) for raw material, walked using similar operations in embodiment 1 Suddenly, compound 7, yellow solid 52mg, yield 50.4% are obtained.
Embodiment 8
8 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- carbethoxyl groups) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- ethoxy carbonyls Base) -1- piperidyls] propyl -1H- purine -2,6- diketone preparation
With b (0.200g, 0.41mmol) and 1c (0.081g, 0.81mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 8, yellow solid 107mg, yield 51.2%.m.p.183℃;
1H NMR(CD3OD,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+):C26H40N7O4Calculated value 514.3136, measured value [M+H]+514.3130.
Embodiment 9
9 8- of compound [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- carbethoxyl groups) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- ethoxy carbonyls Base) -1- piperidyls] propyl -1H- purine -2,6- diketone preparation
With b (0.200g, 0.41mmol) and 2c (0.081g, 0.81mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 9, yellow solid 103mg, yield 49.9%.m.p.183℃;
1H NMR(CD3OD,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+):C26H40N7O4Calculated value 514.3136, measured value [M+H]+514.3128.
Embodiment 10
10 8- of compound (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- ethoxy carbonyls Base) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- carbethoxyl groups) -1- piperidines Base] propyl -1H- purine -2,6- diketone preparation
With b (0.200g, 0.41mmol) and c (0.081g, 0.81mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 10, yellow solid 110mg, yield 52.9%.m.p.188℃;
1H NMR(CD3OD,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+):C26H40N7O4Calculated value 514.3136, measured value [M+H]+514.3128.
Embodiment 11
11 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- carbethoxyl groups) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- ethoxy carbonyls Base) -1- piperazinyls] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.20mmol) and 1c (0.042g, 0.40mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 11, yellow solid 52mg, yield 50.2%.m.p.182-184℃;
1H NMR(CD3OD,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+):C24H37N9O4Calculated value, 515.3153 measured values [M+H]+515.3127.
Embodiment 12
12 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- butyloxycarbonyls) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- isopropyl oxygen Carbonyl) -1- piperidyls] propyl -1H- purine -2,6- diketone preparation
With b (0.200g, 0.39mmol) and 1c (0.079g, 0.79mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 12, yellow solid 99mg, yield 49.2%.m.p.180-182℃;
1H NMR(CD3OD,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+):C27H42N7O4Calculated value 528.3293, measured value [M+H]+528.3302.
Embodiment 13
13 8- of compound [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- butyloxycarbonyls) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- isopropyl oxygen Carbonyl) -1- piperidyls] propyl -1H- purine -2,6- diketone preparation
With b (0.200g, 0.39mmol) and 2c (0.079g, 0.79mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 13, yellow solid 96mg, yield 46.2%.m.p.180-182℃;
1H NMR(CD3OD,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+):C27H42N7O4Calculated value 528.3293, measured value [M+H]+528.3289.
Embodiment 14
14 8- of compound (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- isopropyl oxygen Carbonyl) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- butyloxycarbonyls) -1- piperazines Piperidinyl] propyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.20mmol) and c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 14, yellow solid 53mg, yield 51.0%.m.p.185℃;
1H NMR(CD3OD,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+):C27H42N7O4Calculated value 528.3293, measured value [M+H]+528.3294.
Embodiment 15
15 8- of compound (1- piperazinyls) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- isopropyl oxygen carbonyls Base) -1- piperidyls] propyl } -1H- purine -2,6- diketone
8- (1- piperazinyls) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- butyloxycarbonyls) -1- piperidines Base] propyl -1H- purine -2,6- diketone preparation
With b (0.150g, 0.29mmol) and c (0.103g, 0.58mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 15, yellow solid 77mg, yield 50.7%.m.p.187-190℃;
1H NMR(CD3OD,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+):C26H40N7O4Calculated value 514.3136, measured value [M+H]+514.3139.
Embodiment 16
16 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- tertbutyloxycarbonyls) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(the tertiary fourth oxygen of 4- Carbonyl) -1- piperazinyls] propyl -1H- purine -2,6- diketone preparation
With b (0.180g, 0.34mmol) and 1c (0.119g, 1.19mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 16, yellow solid 78mg, yield 41.7%.m.p.181-182℃;
1H NMR(CD3OD,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+):C27H42N8O4Calculated value 542.3316, measured value [M+H]+542.3342.
Embodiment 17
17 8- of compound [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- tertbutyloxycarbonyls) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(the tertiary fourth oxygen of 4- Carbonyl) -1- piperazinyls] propyl -1H- purine -2,6- diketone preparation
With b (0.180g, 0.34mmol) and 2c (0.119g, 1.19mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 17, yellow solid 72mg, yield 39.2%.m.p.181-182℃;
1H NMR(CD3OD,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+):C27H42N8O4Calculated value 542.3316, measured value 542.3354.
Embodiment 18
18 8- of compound (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(the tertiary fourth oxygen of 4- Carbonyl) -1- piperazinyls] propyl } -1H- purine -2,6- diketone
8- (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- tertbutyloxycarbonyls) -1- piperazines Piperazine base] propyl -1H- purine -2,6- diketone preparation
With b (0.180g, 0.34mmol) and c (0.119g, 1.19mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 18, yellow solid 78mg, yield 42.4%.m.p.187℃;
1H NMR(CD3OD,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+):C27H42N8O4Calculated value 542.3316, measured value [M+H]+542.3289.
Embodiment 19
19 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 2- [(4- tertbutyloxycarbonyls) -1- piperazinyls] ethyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 2- [(the tertiary fourth oxygen of 4- Carbonyl) -1- piperazinyls] ethyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and 1c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 19, yellow solid 52mg, yield 51.4%.m.p.183-184℃;
1H NMR(CD3OD,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+):C26H40N8O4Calculated value 529.3245, measured value [M+H]+529.3249.
Embodiment 20
20 8- of compound [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 2- [(4- tertbutyloxycarbonyls) -1- piperazinyls] ethyl } -1H- purine -2,6- diketone
8- [(3S) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 2- [(the tertiary fourth oxygen of 4- Carbonyl) -1- piperazinyls] ethyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and 2c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 20, yellow solid 49mg, yield 49.2%.m.p.183-184℃;
1H NMR(CD3OD,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+):C26H40N8O4Calculated value 529.3245, measured value [M+H]+529.3251.
Embodiment 21
21 8- of compound (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 2- [(the tertiary fourth oxygen of 4- Carbonyl) -1- piperazinyls] ethyl } -1H- purine -2,6- diketone
8- (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 2- [(4- tertbutyloxycarbonyls) -1- piperazines Piperazine base] ethyl -1H- purine -2,6- diketone preparation
With b (0.100g, 0.19mmol) and c (0.039g, 0.39mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 21, yellow solid 55mg, yield 54.5%.m.p.188-189℃;
1H NMR(CD3OD,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+):C26H40N8O4Calculated value 529.3245, measured value [M+ H]+529.3241.
Embodiment 22
22 8- of compound [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- carbethoxyl groups) -1- piperidyls] butyl } -1H- purine -2,6- diketone
8- [(3R) -3- amino -1- piperidyls] -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- ethoxy carbonyls Base) -1- piperidyls] butyl -1H- purine -2,6- diketone preparation
With b (0.040g, 0.05mmol) and c (0.010g, 0.10mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 22,16 mg of yellow solid, yield 47.5%.
1H NMR(CD3OD,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+):C27H42N7O4Calculated value 528.3293, measured value [M+H]+528.3281.
Embodiment 23
23 8- of compound (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- ethoxy carbonyls Base) -1- piperidyls] butyl } -1H- purine -2,6- diketone
8- (1- high piperazine bases) -7- (2- butynyls) -3,7- dihydro -3- methyl-1s-{ 3- [(4- carbethoxyl groups) -1- piperidines Base] butyl -1H- purine -2,6- diketone preparation
With b (0.040g, 0.05mmol) and c (0.010g, 0.10mmol) for raw material, using similar operations in embodiment 1 Step obtains compound 23, yellow solid 18mg, yield 48.6%.
1H NMR(CD3OD,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+):C26H40N8O4 Calculated value 528.3293, measured value [M+H]+528.3302.
Test example part
Test example 1, DPP-IV inhibitor in-vitro screening method
Reagent：
1. reaction substrate：Gly-Pro-p-nitroanilide hydrochloride (Sigma, G0513), use ddH2O 0.026M storing liquids are dissolved into, -20 DEG C are kept in dark place.
2.DPP-IV enzymes：Recombination human source DPP-IV albumen（Sigma, D4943）, -20 DEG C of preservations.
3. sample to be tested：DMSO is dissolved as 10-2M, 4 DEG C of preservations.
4. positive control drug：Sitagliptin is dissolved as 10 with DMSO-2M, 4 DEG C of preservations.
5.2×Hepes buffer：1.6g NaCl, 0.074g KCl, 0.027g Na2HPO4·2H2O, 0.2g Glucose, 1g Hepes are dissolved in 90ml ddH2In O, with NaOH tune pH value to 7.05, it is settled to 100ml, 0.22 μm is filtered, and 4 DEG C preserve.
6.Tis-HCl buffer：In 6.06g Tris to 1L distilled water, with HCl tune pH value to 8.0.
Detection method
Sample and positive drug Sitagliptin ddH2O is diluted to a concentration of 10-4The solution of M, DPP-IV Tis/HCl buffer（pH=8.0）It prepares, a concentration of 2mU/mL.Substrate Gly-Pro-p-nitroanilide working solutions Hepes buffer（pH=7.05）Dilution, a concentration of 0.26mM.Negative control group, positive controls and sample sets are set up in experiment.Reaction is total Volume is 100 μ L, and wherein negative control group adds ddH2O10 μ L, DPP-IV enzymes working solution 50 μ L and 40 μ L of substrate working solution；It is positive Control group adds 10 μ L, DPP-IV enzymes working solution of Sitagliptin solution, 50 μ L and 40 μ L of substrate working solution；It is molten that sample sets are loaded product 10 μ L, DPP-IV working solution of liquid, 50 μ L and 40 μ L of substrate working solution.It is reacted at 37 DEG C by monitoring, extinction under 405nm in 60min Degree variation, to evaluate inhibiting effect of the sample to DPP-IV.
Sample is as follows to the inhibiting rate computational methods of DPP-IV：
Inhibiting rate (%)=(Δ OD60-0Negative control group-Δ OD60-0Sample sets)/Δ OD60-0Negative control group × 100%
It is generally acknowledged that positive control Sitagliptin is 10-5Inhibiting rate is that 90-100% is believed that this experiment reaction when M Reliably, sample inhibiting rate thinks effective more than 40%.
Positive compound IC50Calculating：
1. for screening for the first time（A concentration of the 10 of untested compound-5M）(i.e. inhibitory activity is more than active compound 50%), different concentration gradients i.e. 10 are set-8, 10-7, 10-6With 10-5M carries out DPP-IV Inhibition tests.
2. the reaction density of compound and inhibiting rate are drawn concentration-response curve, the fitting that statistical procedures obtain is public Formula, Y are inhibiting rate, and X is compound concentration, and when Y is 50%, that is, corresponding compound concentration is when reaching 50% inhibiting rate activity Half effective inhibition concentration (the IC of the compound50), test result is shown in Table 1.
1 compound of the embodiment of the present invention of table inhibits the active measurement results of DPP-IV
Conclusion：
In test-compound, there is the external DPP-IV inhibitory activity of 12 embodiments to reach 50% or more, wherein 12 embodiments IC50Reach a μM level.Embodiment 14 has highest external DPP-IV inhibitory activity.
Test example 2, DPP-IV inhibitor selective evaluation method（DPP8 inhibitory activity in-vitro evaluation methods）
1. reaction substrate：With DPP-IV inhibitor in-vitro screening method.
2.DPP8 enzymes：Recombination human source DPP8/9 albumen, after purified freeze-drying, -20 DEG C of preservations.
3. sample：With DPP-IV inhibitor in-vitro screening method.
4. positive control drug：Compound (S) -4- (2- amino-(R) -3- methylvaleryls) isoindoline hydrochloride is used DMSO is dissolved as 10-2M, 4 DEG C of preservations.
5.2×Hepes buffer：With DPP-IV inhibitor in-vitro screening method.
6.Tis/HCl buffer：With DPP-IV inhibitor in-vitro screening method.
Evaluation method
Sample and positive medicinal ddH2O is diluted to a concentration of 10-4The solution of M, DPP8 enzymes Tis/HCl buffer（pH= 8.0）It prepares, a concentration of 60ng/mL.Substrate Gly-Pro-p-nitroanilide working solutions Hepes buffer（pH= 7.05）Dilution, a concentration of 0.52mM.Negative control group, positive controls and sample sets are set up in experiment.Reaction total volume is 100 μ L, wherein negative control group add ddH2O10 μ L, DPP8 enzymes working solution 50 μ L and 40 μ L of substrate working solution；Positive controls add the positive Compare 10 μ L, DPP8 enzymes working solution of drug solns, 50 μ L and 40 μ L of substrate working solution；Sample sets add 10 μ L, DPP8 enzyme works of sample solution Make 40 μ L of 50 μ L of liquid and substrate working solution.It is reacted at 37 DEG C by monitoring, absorbance change under 405nm in 60min, to evaluate The selectivity of DPP-IV inhibitor, i.e. DPP8/9 inhibitions.
The selectivity of DPP-IV inhibitor（DPP8 inhibitions）Computational methods are as follows：
Inhibiting rate (%)=(Δ OD60-0Negative control group-Δ OD60-0Sample sets)/Δ OD60-0Negative control group × 100% tries It tests and the results are shown in Table 2
2 compound of the embodiment of the present invention of table inhibits the active measurement results of DPP8
Inhibiting rate under positive drug same concentrations is 96.7%.
Conclusion：
Tested 5 have DPP-IV inhibitory activity compounds, have no apparent inhibitory activity to DPP8, show this 5 chemical combination Object has high selectivity to DPP-IV.

Claims (13)

1. a kind of compound and its stereoisomer by leading to formula (I) expression, pharmaceutically acceptable salt,
Wherein,
R1It can be independently selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2It can be independently selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, three Methyl fluoride, trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl；
Wherein pyridyl group, pyrimidine radicals and the pyrazinyl is optionally replaced by 1-4 groups selected from the following：Hydroxyl, halogen, cyanogen Base, amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen Formoxyl；
X, Y are identical or different, are each independently selected from C, N；
M is selected from 1,2；
N is selected from 3；
P and q are each independently selected from 1.
2. compound according to claim 1 and its stereoisomer, pharmaceutically acceptable salt, the compound by Shown in logical formula (II),
Wherein,
R1Selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, trifluoromethyl, Trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl；
Wherein pyridyl group, pyrimidine radicals and the pyrazinyl is optionally replaced by 1-4 groups selected from the following：Hydroxyl, halogen, cyanogen Base, amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen Formoxyl；
X, Y are identical or different, are each independently selected from C, N；
M is selected from 1,2；
N is selected from 3.
3. compound according to claim 2 and its stereoisomer, pharmaceutically acceptable salt, the compound is such as By shown in general formula (IIA),
Wherein,
R1Selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, trifluoromethyl, Trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl；
Wherein pyridyl group, pyrimidine radicals and the pyrazinyl is optionally replaced by 1-4 groups selected from the following：Hydroxyl, halogen, cyanogen Base, amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen Formoxyl；X, Y are identical or different, are each independently selected from C, N；
M is selected from 1,2；
N is selected from 3.
4. compound according to claim 2 and its stereoisomer, pharmaceutically acceptable salt, the compound is such as By shown in general formula (IIB),
Wherein,
R1Selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2Selected from hydrogen, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl oxygen formoxyl, amino, trifluoromethyl, Trifluoromethoxy, nitro, cyano, carbamoyl, amino-sulfonyl；
Wherein described pyridyl group, pyrimidine radicals and pyrazinyl is optionally replaced by 1-4 groups selected from the following：Hydroxyl, halogen, Cyano, amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C1-6Alkyl oxy, C1-6Alkyl formyl radical, C1-6Alkyl Oxygen formoxyl；
X, Y are identical or different, are each independently selected from C, N；
M is selected from 1,2；
N is selected from 3.
5. compound according to claim 3 and its stereoisomer, pharmaceutically acceptable salt, the compound is such as By shown in general formula (IIIA),
Wherein,
R1Selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2Selected from hydrogen, amino；
Wherein described pyridyl group, pyrimidine radicals and pyrazinyl is optionally replaced by 1-2 groups selected from the following：Hydroxyl, halogen, Cyano, amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C1-6Naphthenic base, C1-6Alkyl oxy；
X is selected from C, N；
M is selected from 1,2；
N is selected from 3.
6. compound according to claim 4 and its stereoisomer, pharmaceutically acceptable salt, the compound is such as By shown in general formula (IIIB),
Wherein,
R1Selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2Selected from hydrogen, amino；
Wherein pyridyl group, pyrimidine radicals and the pyrazinyl is optionally replaced by 1-2 groups selected from the following：Hydroxyl, halogen, cyanogen Base, amino, nitro, trifluoromethyl, trifluoromethoxy, C1-6Alkyl, C1-6Naphthenic base, C1-6Alkyl oxy；
X is selected from C, N；
M is selected from 1,2；
N is selected from 3.
7. such as by logical formula (IV) compound represented and its stereoisomer, pharmaceutically acceptable salt,
Wherein,
R1Selected from pyridyl group, pyrimidine radicals and pyrazinyl；
R2Selected from hydrogen, C1Alkyl, methoxyl group, amino；
R3Selected from hydrogen, C1Alkyl, C1Alkyl formyl radical；
Wherein pyridyl group, pyrimidine radicals and the pyrazinyl is optionally replaced by 1-2 groups selected from the following：Hydroxyl, halogen, cyanogen Base, amino, nitro, trifluoromethyl, trifluoromethoxy, C1Alkyl, C1Naphthenic base, C1Alkyl oxy；
X is selected from C, N；
M is selected from 1,2；
N is selected from 3.
8. compound according to any one of claims 1 to 7 and its stereoisomer, pharmaceutically acceptable salt, the change It closes in object,
R1Selected from 2- (5- methyl) pyrimidine radicals；
R2Selected from hydrogen, amino；
X is selected from C, N；
M is selected from 1,2；
N is selected from 3.
9. a kind of compound and its stereoisomer, pharmaceutically acceptable salt, which is characterized in that the compound is selected from as follows Group：
10. the method for preparing compound described in claim 2 comprising following steps：
(i)
At a temperature of 50 DEG C to 100 DEG C, in the presence of a base, in a solvent, formula a compounds represented are changed with shown in formula d It closes object and reacts 7-12h, obtain formula b compounds represented；
(ii)
At a temperature of 50 DEG C to 100 DEG C, in the presence of a base, in a solvent, formula b compounds represented are changed with shown in formula c It closes object and reacts 9-16h, obtain Formula II compound represented；
Wherein, R1、R2, the definition of X, Y, m, n it is as claimed in claim 2.
11. a kind of pharmaceutical composition, it includes any one of the claim 1 to 9 of the treatment and/or prevention effective dose compounds And its stereoisomer, pharmaceutically acceptable salt, and optional one or more pharmaceutically acceptable carriers or excipient.
12. any one of claim 1 to 9 compound and its stereoisomer, pharmaceutically acceptable salt or right are wanted 11 described pharmaceutical compositions are asked to prepare for treating and/or preventing with DPP-IV hyperactivities or over-expressed with DPP-IV Purposes in the drug of related disease or illness.
13. purposes according to claim 12, wherein described with DPP-IV hyperactivities or related with DPP-IV overexpressions Disease or illness be selected from following disease or illness：Diabetes, hyperglycemia.
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