CN103848811A

CN103848811A - Uracil derivative, preparation method and application thereof

Info

Publication number: CN103848811A
Application number: CN201210510630.4A
Authority: CN
Inventors: 陈栋; 范传文; 何绪军; 程哲; 李成龙
Original assignee: Qilu Pharmaceutical Co Ltd
Current assignee: QILU PHARMACEUTICAL (HAINAN) Co.,Ltd.; Qilu Pharmaceutical Co Ltd
Priority date: 2012-12-04
Filing date: 2012-12-04
Publication date: 2014-06-11
Anticipated expiration: 2032-12-04
Also published as: CN103848811B

Abstract

The invention relates to a uracil derivative shown as a general formula I, salt thereof acceptable in pharmacy, a solvate thereof and a solvate of the salt thereof acceptable in pharmacy. The invention also relates to a preparation method of the uracil derivative and an application thereof as a therapeutic agent, particularly a dipeptidyl peptidase-IV (DDP-IV) inhibitor.

Description

Uracil derivative, its preparation method and application thereof

Technical field

The invention belongs to medical technical field, be specifically related to uracil derivative, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt that a class (3-amino) piperidin-1-yl replaces; The invention still further relates to the preparation method of described derivative and intermediate thereof; Described uracil derivative is to dipeptidyl peptidase-IV (Dipeptidy lpeptidase-IV, DPP-lV) activity has good restraining effect, can serve as the particularly medicine for the preparation for the treatment of, prevention and the alleviation disease relevant to DPP-IV as dipeptidyl peptidase-IV (DPP-IV) inhibitor of therapeutical agent.

Background technology

Dipeptidyl peptidase-IV (Dipeptidyl peptidase-IV, DPP-lV) is a kind of transmembrane serine proteolytic ferment that is present in various human body tissue and organ.The strand of mankind DPP-IV is made up of 766 amino acid, is divided into 5 structural regions, slightly difference of the length in these regions.Solubility DPP-IV is the homodimer of a kind of 210-290K of being approximately, also can polymerization up to the mixture of 900K.

The hydrophobicity spiral that DPP-IV forms by an amino acid whose high glycosylation district and halfcystine enrichment region is combined with film, the serine protease region alpha/δ of carboxyl terminal and lytic enzyme homology; DPP-IV can be rapid and specific cracking peptide chain N-hold deputy proline(Pro) or alanine residue, its effect substrate is included in two kinds of incretin that play an important role in type II diabetes immunne response signal transduction process: pancreas hyperglycemia sample peptide (GLP-1) fragment and gastric inhibitory polypeptide (GIP).GLP-1 and GIP be respectively by stomach mucous membrane L cell and k cell in order to reply the carbohydrate of absorption and fat the incretin of secretion, the two strengthens the insulin secretion of glucose induction by acting on pancreas, thereby adjusting blood sugar concentration, and DPP-lV can be hydrolyzed, produce the disconnected form GLP-19-36 of corresponding N-end-grain cutting and GIP3-42, this product has all been lost insulin-induced activity [Expert Opin.Investing.Drugs, 2004,13 (9): 1091-1102].Therefore, by suppressing DDP-IV activity, can suppress the degraded of the various active peptide including GLP-1, thereby extend action time, and reduce the synthetic of liver glucose, control glucose level.DPP-IV inhibitor can be used for the treatment of, prevention or the disease relevant to DPP-IV such as diabetes-alleviating, hyperglycemia, obesity or insulin resistant disease.

The activity that suppresses DPP-IV with DPP-IV inhibitor, can stop the rapid degraded of the material that is degraded and stablize its endogenic biological activity, thereby can bring into play the therapeutic action of response.DPP-IV inhibitor is also considered to play a role in the cracking of various cytokines (hemopoietic cell), somatomedin and neuropeptide.As DDP-IV can degrade Chemokine CXCL12/SDF-1a(stroma cell derivative factor a), SDF is discharged by marrow stromal cell, can with express the receptor CXCR 4 specific binding of hematopoietic stem/progenitor, CXCL12 is considered to [Ludwig A relevant to going back to the nest of hemopoietic stem cell, J.Leukoc Biol, 2002, 72 (1): 183-191.], therefore, DDP-IV inhibitor is stablizing environment in hematopoiesis, in the process of the mobilization of hemopoietic stem cell from marrow and hematopoietic reconstitution, may play the part of conclusive role, be expected to for the treatment of ischemic cardiac myositis and angiogenic disease.

At present, DPP-lV inhibitor has become a new direction of medicine research, had multiple DPP-IV inhibitor successfully to go on the market, as the Sitagliptin(WO03004498 of Merck company), the Vildagliptin(WO09819998 of Novartis company), the Saxagliptin(WO00168603 of Bristol-Myers Squibb company), the Alogliptin(WO2005095381 of Takeda company), the Linagliptin(WO2004018468 of Boehringer Ingelheim company).Although above-mentioned these medicines have been obtained good clinical effectiveness, but still be necessary to develop the new compound that more activity are higher, toxicity is lower, for the treatment of DPP-IV relative disease provides wider medicament selection space.

Summary of the invention

The object of this invention is to provide that a kind of to have the DPP-lV of inhibition active and can be used for the treatment of DPP-IV relative disease or the compound of palliative medicine.

A first aspect of the present invention provides uracil derivative, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt shown in a class formula I:

Formula I

Wherein:

R ₁be selected from C replacement or unsubstituted straight chain or side chain _1-6the C of straight chain alkyl, replacement or unsubstituted or side chain _2-6c thiazolinyl, replacement or unsubstituted _2-6straight or branched alkynyl;

R ₂be selected from the C that aryl or heteroaryl replace _1-3the C that alkyl, aryl or heteroaryl replace _2-3the C that thiazolinyl, aryl or heteroaryl replace _2-3alkynyl; Wherein aryl or heteroaryl can or encircle or condensed ring for monocycle more, optionally can be by R ₃single, double or three replace; R ₃independently be selected from separately halogen atom, straight or branched by 1～5 halogen atom replacement or unsubstituted C _1-6alkyl, straight or branched are replaced or unsubstituted C by 1～5 halogen atom _1-6alkoxyl group, cyano group or hydroxyl or R ₃the carbon atom being adjacent together forms fused rings.

In a preferred embodiment of the present invention, the uracil derivative shown in above-mentioned formula I, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt: wherein, R ₁be selected from C replacement or unsubstituted straight chain or side chain _1-4the C of straight chain alkyl, replacement or unsubstituted or side chain _2-5c thiazolinyl, replacement or unsubstituted _2-4straight or branched alkynyl;

In some preferred specific embodiment, R ₁be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, vinyl, 1-propylene-1-base, 2-propylene-1-base, 1-methyl-1-propylene-1-base, 1-methyl-2-propylene-1-base, 1-butylene-1-base, 2-butylene-1-base, 3-butene-1-Ji, 2-methyl-1-butene alkene-1-base, 2-methyl-2-butene-1-base, 3-methyl-3-butene-1-Ji, ethynyl, 1-propine-1-base, 2-propine-1-base, ethyl acetylene-1-base, 2-butyne-1-base, 3-butine-1-base; Preferably, R ₁be selected from methyl, ethyl, 2-butyne-1-base, 3-methyl-2-butene-1-base, 3-butine-1-base; More preferably, R ₁be selected from 2-butyne-1-base, 3-methyl-2-butene-1-base; More preferably, R ₁be selected from: 2-butyne-1-base, 3-methyl-2-butene-1-base, methyl.

In another preferred embodiment of the present invention, the uracil derivative shown in above-mentioned formula I, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt: wherein, R ₂be selected from benzyl, phenylcarbonyl group methyl, naphthyl methyl, pyridylmethyl, Pyrimidylmethyl, quinolyl methyl, isoquinolyl methyl, quinazolyl methyl, quinoxalinyl methyl, 4,5-dihydro ring penta [de] quinazolyl methyl;

Preferably, R ₂be selected from: 2-cyano group benzyl, 2-cyano group-5-fluoro-benzyl, (pyridine-2-yl) methyl, (3-cyano group-pyridine-2-yl) methyl, (pyrimidine-2-base) methyl, (5, 6, 7, 8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl, (5, 6, 7, 8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl, (1-cyano group-naphthalene-2-yl) methyl, (quinoline-2-yl) methyl, (isoquinoline 99.9-3-yl) methyl, (4-methyl quinazoline-2-yl) methyl, (4-methyl-6-chloro-quinazoline-2-yl) methyl, (quinoxaline-2-yl) methyl, (4, 5-dihydro ring penta [de] quinazoline-2-yl) methyl,

Further preferably, R ₂be selected from: 2-cyano group benzyl, 2-cyano group-5-fluoro-benzyl, (5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl, (5,6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl, (4-methyl quinazoline-2-yl) methyl, (4-methyl-6-chloro-quinazoline-2-yl) methyl, (4,5-dihydro ring penta [de] quinazoline-2-yl) methyl;

More preferably, R ₂be selected from: (5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl, (4-methyl quinazoline-2-yl) methyl, (4-methyl-6-chloro-quinazoline-2-yl) methyl, (4,5-dihydro ring penta [de] quinazoline-2-yl) methyl.

According to the derivative shown in the formula I described in first aspect present invention, it is selected from following compounds:

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } cyanobenzene;

2-{[4-(3-(R)-amino piperidine-1-yl)-3-methyl-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl }-4-fluorobenzonitrile;

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl }-4-fluorobenzonitrile;

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(3-methyl-2-butene-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl }-4-fluorobenzonitrile;

6-(3-(R)-amino piperidine-1-yl)-3-[(pyridine-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2,4 (1H, 3H)-diketone;

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } pyridine-3-nitrile;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(pyrimidine-2-base) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } naphthalene-1-nitrile;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(isoquinoline 99.9-3-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(3-methyl-2-butene-1-yl)-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl-6-chloro-quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoxaline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone;

Or its pharmacy acceptable salt.

Preferably, the derivative shown in described formula I is selected from following compounds:

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } cyanobenzene (compound 1);

2-{[4-(3-(R)-amino piperidine-1-yl)-3-methyl-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl }-4-fluorobenzonitrile (compound 2);

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl }-4-fluorobenzonitrile (compound 3);

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(3-methyl-2-butene-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl }-4-fluorobenzonitrile (compound 4);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 8);

6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 9);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 10);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 14);

6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 15);

6-(3-(R)-amino piperidine-1-yl)-1-(3-methyl-2-butene-1-yl)-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 16);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl-6-chloro-quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 17);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 19);

6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 20);

Further preferably, the derivative shown in described formula I is selected from following compounds:

Still more preferably, the derivative shown in described formula I is selected from following compounds:

Most preferably, the derivative shown in described formula I is selected from following compounds:

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 19).

In a preferred embodiment of the present invention, described pharmacy acceptable salt is described compound and the salt that is selected from following acid formation: hydrochloric acid, sulfuric acid, phosphoric acid, oxysuccinic acid, toxilic acid, fumaric acid, lactic acid, phenylformic acid, methylsulfonic acid, citric acid, tartrate, acetic acid or trifluoroacetic acid.

A second aspect of the present invention provides the method for uracil derivative, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt shown in a kind of formula I preparing described in first aspect present invention, and the method comprises the following steps:

(1) compound shown in formula II is reacted with 3-tertbutyloxycarbonyl-amino piperidine, obtain compound III;

(2) compound III removes tertbutyloxycarbonyl under suitable acid exists, and obtains formula Compound I;

Wherein, R ₁, R ₂definition with the definition of this aspect first aspect; X represents leavings group, as halogen atom, the hydroxyl being substituted, sulfydryl, sulfinyl, alkylsulfonyl or alkylsulfonyl oxygen base, and preferably halogen atom, more preferably chlorine atom; Described suitable acid is selected from trifluoroacetic acid, formic acid, hydrochloric acid, acetic acid, is preferably trifluoroacetic acid, hydrochloric acid, most preferably is trifluoroacetic acid.

Compound shown in formula II can obtain by conventional chemical process is synthetic according to prior art or published technical literature.

It is pointed out that in the present invention, term " compound shown in formula I " has identical art-recognized meanings with " Compound I "; Term " compound shown in formula II " has identical art-recognized meanings with " Compound I I "; Term " compound shown in formula III " has identical art-recognized meanings with " compound III "; The derivative pharmacy acceptable salt of uridylic shown in formula I can obtain with corresponding acid-respons by through type I compound, and " solvate " can be by obtaining with corresponding solvent reaction.

The solvate, its chemoproection form, prodrug that a third aspect of the present invention provides the solvate of uracil derivative shown in the formula I described in first aspect present invention, its pharmacy acceptable salt, described uracil derivative and the pharmaceutically receivable salt of described uracil derivative is in the purposes of the medicine for the preparation of as DPP-IV inhibitor or for the preparation of the purposes of the medicine for the treatment of, prevention and the alleviation disease relevant to DPP-IV.

A fourth aspect of the present invention provides the pharmaceutical composition of solvate, its chemoproection form or prodrug and pharmaceutically acceptable vehicle or the carrier of uracil derivative, its pharmacy acceptable salt, the solvate of described derivative and the pharmacy acceptable salt of described derivative shown in a kind of formula I comprising described in first aspect present invention; Described pharmaceutical composition can be served as DPP-IV inhibitor, has the purposes of the medicine of the disease relevant to DPP-IV for the preparation for the treatment of, prevention and alleviation.

In a specific embodiments of the present invention, purposes described in third aspect present invention and fourth aspect, it is characterized in that, the described disease relevant to DPP-IV is selected from diabetes, hyperglycemia, obesity, insulin resistant disease, cancer, ischemic cardiac myositis or angiogenic disease; Preferably, the described disease relevant to DPP-IV is selected from diabetes and hyperglycemia.

All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.

Various technical terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.

Term used herein " halogen " or " halo " refer to fluorine, chlorine, bromine or iodine, and preferred halogen group is fluorine, chlorine or bromine.

The term " alkyl " using in the present invention refers to saturated straight or branched monovalence alkyl, there is 1-6 carbon atom (being C1-6 alkyl), preferably 1-4 carbon atom (being C1-4 alkyl), 1-3 carbon atom (being C1-3 alkyl) or 1-2 carbon atom (being C1-2 alkyl).The example of " alkyl " includes but not limited to methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, 2-methyl butyl, n-hexyl, 4-methyl amyl, 3-methyl amyl, 2-methyl amyl, 1-methyl amyl, 3, 3-dimethylbutyl, 2, 2-dimethylbutyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 2-ethyl-butyl, 1, 2-dimethyl propyl etc., in one embodiment, alkyl is preferably from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl.

" alkoxyl group " of the present invention refers to have the saturated straight chain of 1-6 carbon atom or the alkoxyl group of side chain, preferably 1-4 carbon atom alkoxy, 1-3 carbon atom alkoxy or 1-2 carbon atom alkoxy, the example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, isopentyloxy, 2-methyl butoxy, neopentyl oxygen, , 4-methyl pentyloxy, 3-methyl pentyloxy, 2-methyl pentyloxy, 1-methyl pentyloxy, 3, 3-dimethyl butoxy, 2, 2-dimethyl butoxy, 1, 1-dimethyl butoxy, 1, 2-dimethyl butoxy, 1, 3-dimethyl butoxy, 2, 3-dimethyl butoxy, 2-ethyl butoxy, 1, 2-dimethyl propoxy-, ring propoxy-, cyclobutoxy group, 1-methyl cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc., in one embodiment, alkoxyl group is preferably from methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy, positive hexyloxy.

" thiazolinyl " of the present invention refers to the straight chain that contains 1-3 two keys with 2-6 carbon atom or the thiazolinyl with side chain; Preferably there is the straight chain that contains 1 two key of 2-6 carbon atom or there is the thiazolinyl of side chain; More preferably there is the straight or branched thiazolinyl that contains two keys of 2-5 carbon atom; Described thiazolinyl has cis-trans-isomer, comprises its cis-isomeride and trans-isomer(ide).

" alkynyl " of the present invention refers to the alkynyl that refers to have the straight chain that contains 1-3 three key of 2-6 carbon atom or have side chain; Preferably there is the straight chain that contains 1 three key of 2-6 carbon atom or there is the alkynyl of side chain; More preferably there is the straight or branched alkynes that contains three key of 2-4 carbon atom.

" aryl " of the present invention refers to and comprises and remove the organic radical that hydrogen is derivative, for example a phenyl or naphthyl from aromatic series spit of fland; " heteroaryl " refers to and comprises one to four heteroatomic aryl that is selected from separately O, S and N.

" replacement " of the present invention refers to that described group or part are with one or more substituting groups; " unsubstituted " or " unsubstituted " refers to that described group does not have substituting group.

Pyrimidine derivatives shown in formula I of the present invention comprises its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, deuterated thing, solvate and ester; Formula I compound of the present invention and its isomer, raceme, enantiomorph, diastereomer, enantiomorph enriched substance, deuterated thing, solvate and ester can also form solvate, such as hydrate, alcohol adduct etc.Described derivative can also be prodrug or the form that discharges in vivo described activeconstituents after metabotic change.Selecting and preparing suitable prodrug derivant is technology as well known to those skilled in the art.Generally, for object of the present invention, pharmaceutically acceptable solvent is as suitable with non-solvent compound form in the solvate form thereof of water, ethanol etc.

Formula I compound of the present invention can use with the form derived from mineral acid or organic acid pharmacy acceptable salt.Term " pharmacy acceptable salt " refers to, within the scope of reliable medical judgment, be suitable for contacting with zootic tissue with the mankind and not occurring excessive toxicity, stimulation, anaphylaxis etc., and with rational effect/risk than the salt matching.Pharmacy acceptable salt is well known in the art.Described salt can be by making the compounds of this invention and suitable organic acid or inorganic acid reaction.

Uracil derivative shown in formula I of the present invention and organic acid or inorganic acid reaction, obtain the pharmaceutically acceptable acid salt of described uracil derivative, for example halogen acid salt, for example hydrochloride, hydrobromate, hydriodate; The salt of other mineral acids and their correspondences, such as vitriol, nitrate, phosphoric acid salt etc.; For example, with alkyl and an arylsulphonate, esilate, tosylate and benzene sulfonate; For example, with the salt of other organic acids and their correspondences, acetate, tartrate, maleate, succinate, Citrate trianion, benzoate, salicylate and ascorbate salt.Further acid salt of the present invention includes but not limited to: adipate, alginate, arginic acid salt, aspartate, hydrosulfate, hydrosulphite, bromide, butyrates, camphorate, camsilate, octylate, muriate, chloro benzoate, cyclopentane propionate, digluconate, dihydrogen phosphate, dinitro-benzoate, dodecyl sulfate, fumarate, mutate (galacterate) (from glactaric acid), galacturonic hydrochlorate, glucoheptose salt, gluconate, glutaminate, glycerophosphate, hemisuccinic acid salt, Hemisulphate, enanthate, hexanoate, hippurate, hydrochloride, hydrobromate, hydriodate, 2-isethionate, iodide, isethionate, isobutyrate, lactic acid salt, Lactobionate, malate, malonate, mandelate, metaphosphate, mesylate, tolyl acid salt, monohydric phosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectate, persulphate, phenylacetic acid salt, 3-phenylpropionic acid salt, phosphoric acid salt, phosphonate and phthalate.Will be appreciated that, how many free alkali forms will be different from their salt forms separately conventionally in physical properties, for example solubleness in polar solvent, but for purposes of the present invention, salt is equivalent to their free alkali forms separately.

Preferably, the compound shown in formula I of the present invention and following organic acid or inorganic acid reaction are prepared its pharmacy acceptable salt: hydrochloric acid, sulfuric acid, phosphoric acid, oxysuccinic acid, toxilic acid, fumaric acid, lactic acid, phenylformic acid, methylsulfonic acid, citric acid, tartrate, acetic acid or trifluoroacetic acid; Be preferably hydrochloride, benzoate or trifluoroacetate.

Compound shown in formula I of the present invention can use as medicine separately, or can have with one or more other DPP-IV class Drug combination similar or that act synergistically machine-processed.Combination therapy realizes by each being treated to component while, order or separating administration.

The active compound amount of gained can change the actual dose level of each activeconstituents in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.Dosage level must according to the activity of particular compound, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and medical history select.But the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.

When treating and/or preventing or other treatment and/or when prevention for above-mentioned, a kind of the compounds of this invention that treats and/or prevents significant quantity can be applied with pure form, or with pharmacy acceptable salt, ester or prodrug forms (in the situation that there are these forms) application.Or described compound can be accepted to contain this target compound and one or more medicines the pharmaceutical composition administration of vehicle.The compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to the reasonable effect/risk of any therapeutic treatment and/or prevention than the compound of the q.s for the treatment of obstacle.But the total daily dosage portion that it should be understood that formula I compound of the present invention and its pharmaceutical composition must maked decision within the scope of medical judgment reliably by attending physician.For any concrete patient, concrete treatment effective dose level must be determined according to many factors, and described factor comprises the severity of treated obstacle He this obstacle; The activity of the particular compound adopting; The concrete composition adopting; Patient's age, body weight, general health situation, sex and diet; Administration time, route of administration and the excretion rate of the particular compound adopting; The treatment time length; The medicine that is used in combination with adopted particular compound or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than level that required result for the treatment of requires, increasing gradually dosage, until obtain required effect for obtaining.In general, particularly people's dosage can be between 0.001～1000mg/kg body weight/day, for example, between 0.01～100mg/kg body weight/day, for example, between 0.01～10mg/kg body weight/day for Mammals for formula I compound of the present invention.

Use the familiar pharmaceutical carrier of those skilled in the art can be prepared into the pharmaceutical composition containing the compounds of this invention of effective dose.Therefore the present invention also provides the pharmaceutical composition that comprises the compounds of this invention formulated together with one or more nontoxic drug acceptable carriers.That described pharmaceutical composition can be mixed with especially is specially for oral administration with solid or liquid form, for parenteral injection or for rectal administration.

Described pharmaceutical composition can be mixed with many formulations, is convenient to administration, for example, and oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, before injection, add injection water to use immediately).In described pharmaceutical composition, carrier comprises: the tackiness agent that oral preparations uses is (as starch, normally corn, wheat or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone), thinner is (as lactose, dextrose, sucrose, N.F,USP MANNITOL, sorbyl alcohol, Mierocrystalline cellulose and/or glycerine), lubricant is (as silicon-dioxide, talcum, stearic acid or its salt, normally Magnesium Stearate or calcium stearate, and/or polyoxyethylene glycol), if and needed, also contain disintegrating agent, as starch, agar, Lalgine or its salt, normally sodiun alginate, and/or effervescent mixture, solubility promoter, stablizer, suspension agent, pigment, correctives etc., the sanitas that injectable preparation uses, solubilizing agent, stablizer etc., matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under stomach condition, can be mixed with enteric coated tablets.

More particularly, pharmaceutical composition of the present invention can be given the mankind and other Mammalss, or be given as oral spray or nasal mist by oral, rectum, parenteral, intravaginal, part (as by powder, ointment or drops), a mouthful cheek.Term used herein " parenteral " refers to comprise the administering mode of intravenously, intramuscular, intraperitoneal, breastbone interior, subcutaneous and intra-articular injection and transfusion.

The composition that is suitable for parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprises that water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester are as ethyl oleate and their suitable mixture.

These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc., can guarantee to prevent the effect of microorganism.Also comprise isotonic agent, such as carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.

In suspensoid, remove active ingredient beyond the region of objective existence and also can contain suspension agent, the mixture of such as ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, inclined to one side aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials etc.

In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or intramuscularly medicine.This can realize by the liquid suspension of the crystal with poorly water-soluble or amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Or, the delay of the medicament forms of parenteral admin absorb by by this medicine dissolution in or be suspended in oily vehicle and realize.

Injectable depot formulations form can be prepared by the microcapsule matrix that forms medicine at biodegradable polymer in as polylactide-PGA.Can, according to the character of the ratio of medicine and polymkeric substance and the concrete polymkeric substance adopting, drug releasing rate be controlled.The example of other biological degradable polymer comprises poe class and polyanhydrides.Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.

Injectable formulation can be for example by filtering or carry out sterilizing by the disinfectant that mixes aseptic solid composite form with bacterial filter, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.

The compounds of this invention or its composition can be by oral method or parenteral administration modes.Oral administration form can be tablet, capsule, Drug coating, and enteron aisle external application preparation has injection and suppository etc.These preparations are prepared according to method appreciated by those skilled in the art.The auxiliary material of conventional use in order to manufacture tablet, capsule, Drug coating auxiliary material used, for example starch, gelatin, gum arabic, silica, polyoxyethylene glycol, liquid dosage form solvent used is as water, ethanol, propylene glycol, vegetables oil (as Semen Maydis oil, peanut oil, olive wet goods).In the preparation that contains the compounds of this invention, also have other auxiliary material, for example tensio-active agent, lubricant, disintegrating agent, sanitas, correctives and pigment etc.The dosage that contains formula I compound of the present invention in tablet, capsule, Drug coating, injection and suppository is that the compound amount existing in unit dosage form is calculated.In unit dosage form, the general content of formula I compound of the present invention is 0.1-1000mg, and preferred unit dosage form contains 1-100mg, and preferred unit dosage form contains 5-20mg.

Specifically, the solid dosage for oral administration that the present invention can provide comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier with the medicine of at least one inertia and mix as Trisodium Citrate or Si Liaodengji dicalcium phosphate feed grade and/or following material: a) weighting agent or extender are as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent is as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks is as glycerine; D) disintegrating agent is as agar, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; E) solution retarding agent is as paraffin; F) absorb accelerator as quaternary ammonium compound; G) wetting agent is as hexadecanol and Zerol; H) sorbent material as kaolin and wilkinite and i) lubricant as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.The in the situation that of capsule, tablet and pill, in described formulation, also can comprise buffer reagent.

The solids composition of similar type uses vehicle such as lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and hard capsule.

The solid dosage of tablet, dragee, capsule, pill and granule can be prepared together with dressing and shell material other clothing materials as known in enteric coating material and field of medicine preparations.These solid dosages can optionally contain opalizer, and its composition also can make it just or preferentially at certain position of enteron aisle optionally with delayed mode release of active ingredients.The example of operable embedding composition comprises polymer substance and wax class.If be applicable to, active compound also can be made into micro-capsule form with one or more above-mentioned vehicle.

Liquid dosage form for oral administration comprises pharmaceutically acceptable emulsion, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain the conventional inert diluent in this area except containing active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol, polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.Oral compositions also can comprise auxiliary material, for example wetting agent, emulsifying agent and suspension agent, sweeting agent, correctives and flavouring agent except comprising inert diluent.

Compound of the present invention and composition thereof are also considered for topical.Comprise powder, sprays, ointment and inhalation for the local dosage form that gives the compounds of this invention.Under aseptic condition by active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution are also considered within the scope of the present invention.

The compounds of this invention also can liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials conventionally.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.On any nontoxic, physiology that can form liposome, can accept and metabolizable lipid all can use.The present composition of liposome form, except containing the compounds of this invention, also can contain stablizer, sanitas, vehicle etc.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can be used alone or as a mixture.The method that forms liposome is well known in the art.

Embodiment

Further illustrate the present invention below by concrete Preparation Example and biological test; But, should be appreciated that these embodiment and biological test are only used for specifically describing more in detail the present invention's use, and should not be understood as for limiting in any form the present invention.

Although be well known in the art for realizing material and the working method that the object of the invention uses, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if not specified, working method is well known to a person skilled in the art; Material used is that those skilled in the art use ordinary method to prepare according to disclosed document or prior art, or can be bought and be obtained by market.

In the present invention, unless otherwise indicated, wherein: (i) temperature with degree Celsius (DEG C) represent, operate under room temperature environment and carry out; Described room temperature has implication well-known in the art, particularly, refers to 10-35 DEG C, preferably 15-30 DEG C, most preferably 20-25 DEG C; (ii) organic solvent anhydrous sodium sulfate drying, the steaming of solvent, except by Rotary Evaporators reduction vaporization, is bathed temperature not higher than 60 DEG C; (iii) for reaction process, thin-layer chromatography (TLC) is followed the tracks of; (iv) gained solid intermediate or end product all carry out vacuum-drying, and drying temperature is not higher than 60 DEG C; (v) end product have satisfied proton magnetic resonance (PMR) spectrum ( ¹and mass spectrum (MS) data H-NMR).

embodiment 1:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6- dioxo-1 (6H)-pyrimidyl] methyl } preparation of cyanobenzene (compound 1)

Step 1:1-(2-butyne-1-yl)-6-chloropyrimide-2, the preparation of 4 (1H, 3H)-diketone (intermediate 1)

Intermediate 1

6-chlorouracil (14.5g, 100mmol) is dissolved in to (V in the mixing solutions of 150mL DMF (DMF)/methyl-sulphoxide (DMSO) _dMF/ V _dMSO=6:1), be cooled to 0 DEG C, add sodium hydride (4.2g, 105mmol) in batches, after stirring 5min clock, add lithiumbromide (13.0g, 105mmol), continue to stir 15min, then drip and be dissolved with the bromo-2-butyne (14.0g of 1-, N 105mmol), dinethylformamide solution (50mL), after dropwising, stirring at room temperature 10-12 hour.React complete, reaction solution is poured in frozen water, stir and separate out solid, suction filtration, vacuum-drying obtains faint yellow solid 17.0g, productive rate 85.6%.ES-API(m/z):[M+H] ⁺199.0。

Step 2:2-{[3-(2-butyne-1-yl)-4-is chloro-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of cyanobenzene (intermediate 2)

Intermediate 2

Under room temperature, by intermediate 1 (10.0g, 50mmol), salt of wormwood (8.4g, 61mmol) and sodium iodide (0.1g, 0.7mmol) be added in 100mL DMF, drip and be dissolved with 2-cyano-benzyl bromide (10.8g, N 55mmol), dinethylformamide solution (50mL), after dropwising, stirring at normal temperature is spent the night; React complete, reaction solution is poured in frozen water and separated out solid, suction filtration obtains faint yellow solid 13.5g, productive rate 86.0%.ES-API(m/z):[M+H] ⁺314.1。

Step 3:2-{[4-(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of cyanobenzene (intermediate 3)

Intermediate 3

Under nitrogen protection; by intermediate 2 (3.1g; 10mmol), salt of wormwood (2.1g; 15mmol) and 3-(R)-tertbutyloxycarbonyl-amino piperidine (2.2g; 11mmol) be added to 30mL N; in dinethylformamide, be warming up to 90 DEG C and stir 5 hours, react complete.Reaction solution is poured in 50mL frozen water and separated out solid, suction filtration, filter cake, through column chromatography purification, obtains white solid 4.0g, productive rate 83.9%.ES-API(m/z):[M+H]+478.2。

Step 4:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of cyanobenzene (compound 1)

Compound 1

Intermediate 3 (0.48g, 1.0mmol) is dissolved in the mixing solutions of 20mL methylene dichloride and 4mL trifluoroacetic acid to stirring at room temperature 1 hour.React complete, steam solvent, add 40mL frozen water, by 2mol/L NaOH aqueous solution adjusting pH value to 8, dichloromethane extraction (30mL × 3,), merge organic phase, the water washing of 30mL saturated common salt, anhydrous sodium sulfate drying, steam solvent and obtain faint yellow solid, obtain white solid (compound 1) 0.27g, productive rate 71.1% through column chromatography purification.

E?S-API(m/z):[M+H] ⁺378.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.66(d,1H),7.54(m,1H)，7.36(m,1H)，7.11(d,1H),5.35(d,2H),5.27(d,1H)，4.54(d,2H),3.26-3.40(m,2H),3.09(s,1H),2.65-2.79(m,2H),2.02(m,1H),1.90(m,1H),1.81(s,3H),1.70(m,1H),1.40(m,1H)。

embodiment 2:2-{[4-(3-(R)-amino piperidine-1-yl)-3-methyl-2,3-dihydro-2,6-dioxo -1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (compound 2)

Step 1:1-methyl-6-chloropyrimide-2, the preparation of 4 (1H, 3H)-diketone (intermediate 4)

Intermediate 4

Adopt the method similar to embodiment 1 step 1, prepare intermediate 4 by 6-chlorouracil and methyl iodide, productive rate 76.2%.ES-API(m/z):[M+H] ⁺161.0。

Step 2:2-[(3-methyl-4-is chloro-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl) methyl] preparation of cyanobenzene (intermediate 5)

Intermediate 5

Adopt the method similar to embodiment 1 step 2, prepare intermediate 5, productive rate 87.6% by intermediate 4 and 2-cyano group-4-fluorine bromobenzyl.ES-API(m/z):[M+H] ⁺294.0。

Step 3:2-{[4-(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)-3-methyl-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of cyanobenzene (intermediate 6)

Intermediate 6

Adopt the method similar to embodiment 1 step 3, prepare intermediate 6, productive rate 86.5% by intermediate 5 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺458.2。

Step 4:2-{[4-(3-(R)-amino piperidine-1-yl)-3-methyl-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of cyanobenzene (compound 2)

Compound 2

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 6 preparations and obtain compound 2, productive rate 77.8%.ES-API(m/z):[M+H] ⁺358.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.65(dd,1H),7.03(m,1H),6.99(dd,1H),5.31(s,2H),5.29(s,1H)，3.39(s,3H),3.22(m,1H)，3.02-3.12(m,2H),2.69(m,1H)，2.51(m,1H),2.03(m,1H),1.89(m,1H),1.72(m,1H)，1.33(m,1H)。

embodiment 3:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6- dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (compound 3)

Step 1:2-{[3-(2-butyne-1-yl)-4-is chloro-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (intermediate 7)

Intermediate 7

Adopt the method similar to embodiment 1 step 2, prepare intermediate 7, productive rate 84.1% by intermediate 1 and 2-cyano group-4-fluorine bromobenzyl.ES-API(m/z):[M+H] ⁺332.1。

Step 2:2-{[4-(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (intermediate 8)

Intermediate 8

Adopt the method similar to embodiment 1 step 3, prepare intermediate 8, productive rate 86.7% by intermediate 7 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺496.2。

Step 3:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (compound 3)

Compound 3

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 8 and obtain compound 3, productive rate 86.7%.ES-API(m/z):[M+H] ⁺396.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.65(dd,1H),7.03(m,1H),6.96(dd,1H),5.31(d,3H),4.55(d,2H),3.29-3.41(m,2H),3.11(s,1H),2.63-2.79(m,2H),2.03(m,1H),1.91(m,1H),1.82(s,3H),1.72(m,1H),1.39(m,1H)。

embodiment 4:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(3-methyl-2-butene-1-yl)-2,3- dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (compound 4)

Step 1:1-(3-methyl-2-butene-1-yl)-6-chloropyrimide-2, the preparation of 4 (1H, 3H)-diketone (intermediate 9)

Intermediate 9

Adopt the method similar to embodiment 1 step 1, prepare intermediate 9, productive rate 91.8% by 6-chlorouracil and the bromo-3-methyl-2-butene of 1-.ES-API(m/z):[M+H] ⁺215.1。

Step 2:2-{[3-(3-methyl-2-butene-1-yl)-4-is chloro-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (intermediate 10)

Intermediate 10

Adopt the method similar to embodiment 1 step 2, prepare intermediate 10, productive rate 84.9% by intermediate 9 and 2-cyano group-4-fluorine bromobenzyl.ES-API(m/z):[M+H] ⁺348.1。

Step 3:2-{[4-(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)-3-(3-methyl-2-butene-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (intermediate 11)

Intermediate 11

Adopt the method similar to embodiment 1 step 3, prepare intermediate 11, productive rate 82.3% by intermediate 10 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺512.3。

Step 4:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(3-methyl-2-butene-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of-4-fluorobenzonitrile (compound 4)

Compound 4

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 11 and obtain compound 4, productive rate 76.6%.ES-API(m/z):[M+H] ⁺412.3。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.64(dd,1H),7.03(m,1H),6.97(dd,1H),5.35(s,1H)，5.30(s,2H),5.27(s,1H)，4.46(s,2H),3.33(m,1H)，3.07-3.16(m,2H),2.56-2.68(m,2H),2.02(m,1H),1.87(m,1H),1.71(m,7H),1.37(m,1H)。

embodiment 5:6-(3-(R)-amino piperidine-1-yl)-3-[(pyridine-2-yl) methyl]-1-(2-butyne-1- base) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 5)

Step 1:3-[(pyridine-2-yl) methyl]-1-(2-butyne-1-yl)-6-chloropyrimide-2, the preparation of 4 (1H, 3H)-diketone (intermediate 12)

Intermediate 12

Adopt the method similar to embodiment 1 step 2, prepare intermediate 12 by intermediate 1 and 2-chloromethylpyridine, productive rate 87.6%.ES-API(m/z):[M+H] ⁺290.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(pyridine-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 13)

Intermediate 13

Adopt the method similar to embodiment 1 step 3, prepare intermediate 13, productive rate 80.9% by intermediate 12 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺454.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-3-[(pyridine-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 5)

Compound 5

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 13 and obtain compound 5, productive rate 79.7%.ES-API(m/z):[M+H] ⁺354.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.61(d,1H),7.86(m,1H)，7.60(d,1H)，7.21(m,1H),5.36(d,2H),5.28(d,1H)，4.59(d,2H),3.31-3.41(m,2H),3.10(s,1H),2.66-2.79(m,2H),2.01(m,1H),1.88(m,1H),1.79(s,3H),1.71(m,1H),1.38(m,1H)。

embodiment 6:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6- dioxo-1 (6H)-pyrimidyl] methyl } preparation of pyridine-3-nitrile (compound 6)

Step 1:2-{[3-(2-butyne-1-yl)-4-is chloro-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of pyridine-3-nitrile (intermediate 14)

Intermediate 14

Adopt the method similar to embodiment 1 step 2, prepare intermediate 14 by intermediate 1 and 2-brooethyl-nicotinonitrile, productive rate 91.6%.ES-API(m/z):[M+H] ⁺315.1。

Step 2:2-{[4-(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of pyridine-3-nitrile (intermediate 15)

Intermediate 15

Adopt the method similar to embodiment 1 step 3, prepare intermediate 15, productive rate 86.1% by intermediate 18 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺479.2。

Step 3:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of pyridine-3-nitrile (compound 6)

Compound 6

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 15 and obtain compound 6, productive rate 76.7%.ES-API(m/z):[M+H] ⁺379.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：9.11(d,1H),8.56(d,1H)，7.78(m,1H)，5.46(s,2H),5.31(s,1H)，4.56(d,2H),3.32-3.45(m,2H),3.12(m,1H),2.65-2.76(m,2H),2.01(m,1H),1.89(m,1H),1.81(s,3H),1.70(m,1H),1.39(m,1H)。

embodiment 7:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(pyrimidine-2-base) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 7)

The chloro-3-[(pyrimidine-2-base of step 1:1-(2-butyne-1-yl)-6-) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 16)

Intermediate 16

Adopt the method similar to embodiment 1 step 2, prepare intermediate 16, productive rate 78.6% by intermediate 1 and 2-chloromethyl pyrimidine.ES-API(m/z):[M+H] ⁺291.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(pyrimidine-2-base) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 17)

Intermediate 17

Adopt the method similar to embodiment 1 step 3, prepare intermediate 17, productive rate 83.9% by intermediate 16 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺455.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(pyrimidine-2-base) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 7)

Compound 7

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 24 and obtain compound 7, productive rate 76.7%.ES-API(m/z):[M+H] ⁺355.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.68(d,1H),8.59(d,1H)，7.18(m,1H)，5.48(s,2H),5.35(s,1H)，4.56(s,2H),3.32-3.45(m,2H),3.10(m,1H),2.61-2.76(m,2H),2.01(m,1H),1.90(m,1H),1.81(s,3H),1.73(m,1H),1.38(m,1H)。

embodiment 8:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene -4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 8)

Step 1:2-chloromethyl-5, the preparation of 6,7,8-tetrahydrochysene-4-methyl quinazoline (intermediate 18)

Intermediate 18

2-acetyl cyclohexanone (2.8g, 20mmol), salt of wormwood (4.1g, 30mmol) and hydrochloric acid chloroethene amidine (2.8g, 22mmol) are added in 30mL propyl carbinol to return stirring 5 hours.React complete, decompression steams solvent, residuum is poured in 50mL water, ethyl acetate extraction (30mL × 3), merge organic phase, the water washing of 30mL saturated common salt once, anhydrous sodium sulfate drying, decompression steams solvent and obtains yellow solid, obtain weak yellow liquid 2.3g through column chromatography purification, productive rate 58.9%.ES-API(m/z):[M+H] ⁺197.1。

Step 2:1-(2-butyne-1-yl) the chloro-3-[(5 of-6-, 6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 19)

Intermediate 19

Adopt the method similar to embodiment 1 step 2, prepare intermediate 19 by intermediate 1 and intermediate 18, productive rate 76.1%.ES-API(m/z):[M+H] ⁺359.1。

Step 3:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 20)

Intermediate 20

Adopt the method similar to embodiment 1 step 3, prepare intermediate 20, productive rate 83.3% by intermediate 19 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺523.2。

Step 4:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 8)

Compound 8

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 20 and obtain compound 8, productive rate 71.0%.ES-API(m/z):[M+H] ⁺423.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：5.29(s,1H),5.24(s,2H),4.57(d,2H)，3.38-3.48(m,2H),3.26(m,1H),2.75(m,3H),2.56(m,3H),2.31(s,3H),2.00(m,1H),1.89(m,1H),1.79-1.82(m,7H),1.71(m,1H),1.35(m,1H)。

embodiment 9:6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinoline azoles quinoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 9)

The chloro-3-[(5 of step 1:1-methyl-6-, 6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 21)

Intermediate 21

Adopt the method similar to embodiment 1 step 2, prepare intermediate 21 by intermediate 4 and intermediate 18, productive rate 80.1%.ES-API(m/z):[M+H] ⁺321.1。

Step 2:1-methyl-6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 22)

Intermediate 22

Adopt the method similar to embodiment 1 step 3, prepare intermediate 22, productive rate 75.8% by intermediate 21 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺485.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 9)

Compound 9

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 22 and obtain compound, productive rate 72.6%.ES-API(m/z):[M+H] ⁺385.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：5.57(s,2H),5.34(s,1H),3.43(s,3H),3.33(m,1H),3.20(m,2H),2.70-2.75(m,3H),2.49-2.56(m,3H),2.31(s,3H),2.00(m,1H),1.89(m,1H),1.79-1.82(m,4H),1.71(m,1H),1.35(m,1H)。

embodiment 10:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene -4-trifluoromethyl quinazoline-2-yl) methyl] pyrimidine-2, the system of 4 (1H, 3H)-diketone (compound 10) standby

Step 1:2-chloromethyl-5, the preparation of 6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline (intermediate 23)

Intermediate 23

2-trifluoroacetyl group pimelinketone (5.0g, 26mmol), salt of wormwood (4.6g, 33mmol) and hydrochloric acid chloroethene amidine (4.0g, 31mmol) are added in 30mL Virahol, and 50 DEG C are stirred 3 hours; React complete, decompression steams solvent, residuum is poured in 100mL water, and ethyl acetate extraction (100mL × 2) merges organic phase, the water washing of 100mL saturated common salt once, anhydrous sodium sulfate drying, decompression steams solvent and obtains yellow solid, through column chromatography purification, obtain faint yellow solid 4.6g, productive rate 70.8%.ES-API(m/z):[M+H]+251.1。

Step 2:1-(2-butyne-1-yl) the chloro-3-[(5 of-6-, 6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 24)

Intermediate 24

Adopt the method similar to embodiment 1 step 2, prepare intermediate 24 by intermediate 1 and intermediate 23, productive rate 79.0%.ES-API(m/z):[M+H] ⁺413.1。

Step 3:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(5,6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 25)

Intermediate 25

Adopt the method similar to embodiment 1 step 3, prepare intermediate 25, productive rate 81.5% by intermediate 24 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺577.3。

Step 4:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(5,6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 10)

Compound 10

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 25 and obtain compound 10, productive rate 68.4%.ES-API(m/z):[M+H] ⁺477.3。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：5.46(s,1H),5.26(s,2H),4.59(s,2H)，3.41-3.49(m,2H),3.28(m,1H),2.50-2.59(m,3H),2.30-2.36(m,3H),2.01(m,1H),1.88(m,1H),1.79-1.83(m,7H),1.70(m,1H),1.40(m,1H)。

embodiment 11:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro -2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of naphthalene-1-nitrile (compound 11)

Step 1:2-{[3-(2-butyne-1-yl)-4-is chloro-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of naphthalene-1-nitrile (intermediate 26)

Intermediate 26

Adopt the method similar to embodiment 1 step 2, prepare intermediate 26, productive rate 92.6% by intermediate 1 and 2-(brooethyl) naphthalene-1-nitrile.ES-API(m/z):[M+H] ⁺364.1。

Step 2:2-{[4-(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of naphthalene-1-nitrile (intermediate 27)

Intermediate 27

Adopt the method similar to embodiment 1 step 3, prepare intermediate 27, productive rate 80.8% by intermediate 26 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺528.3。

Step 3:2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } preparation of naphthalene-1-nitrile (compound 11)

Compound 11

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 27 and obtain compound 11, productive rate 76.6%.ES-API(m/z):[M+H] ⁺428.3。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.16(d,1H),7.92(m,2H)，7.56(m,1H)，7.50(m,1H),7.28(d,1H),5.43(s,2H),5.31(s,1H),4.55(s,2H),3.30-3.45(m,2H),3.10(m,1H),2.60-2.76(m,2H),1.91-2.01(m,2H),1.80(s,3H),1.72(m,1H),1.36(m,1H)。

embodiment 12:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 12)

The chloro-3-[(quinoline-2-of step 1:1-(2-butyne-1-yl)-6-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 28)

Intermediate 28

Adopt the method similar to embodiment 1 step 2, prepare intermediate 28 by intermediate 1 and 2-chloromethyl quinoline, productive rate 70.4%.ES-API(m/z):[M+H] ⁺340.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(quinoline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 29)

Intermediate 29

Adopt the method similar to embodiment 1 step 3, prepare intermediate 29, productive rate 81.9% by intermediate 28 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺504.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 12)

Compound 12

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 29 and obtain compound 12, productive rate 77.8%.ES-API(m/z):[M+H] ⁺404.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.05(d,1H),7.95(d,1H)，7.70(d,1H),7.60(m,1H),7.36(m,1H),7.10(d,1H),5.45(s,2H),5.34(s,1H),4.56(s,2H),3.31-3.45(m,2H),3.11(m,1H),2.56-2.72(m,2H),1.90-2.01(m,2H),1.80(s,3H),1.71(m,1H),1.37(m,1H)。

embodiment 13:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(isoquinoline 99.9-3- base) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 13)

The chloro-3-[(isoquinoline 99.9-3-of step 1:1-(2-butyne-1-yl)-6-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 30)

Intermediate 30

Adopt the method similar to embodiment 1 step 2, prepare intermediate 30, productive rate 75.8% by intermediate 1 and 3-chloromethyl isoquinoline 99.9.ES-API(m/z):[M+H] ⁺340.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(isoquinoline 99.9-3-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 31)

Intermediate 31

Adopt the method similar to embodiment 1 step 3, prepare intermediate 31, productive rate 82.5% by intermediate 30 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺504.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(isoquinoline 99.9-3-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 13)

Compound 13

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 31 and obtain compound 13, productive rate 72.0%.ES-API(m/z):[M+H] ⁺404.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：9.05(d,1H),7.91(m,1H)，7.70(d,1H),7.59(m,1H),7.39(m,1H),7.22(d,1H),5.40(s,2H),5.31(s,1H),4.56(s,2H),3.30-3.45(m,2H),3.10(m,1H),2.56-2.70(m,2H),1.90-2.02(m,2H),1.81(s,3H),1.70(m,1H),1.36(m,1H)。

embodiment 14:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl quinoline azoles quinoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 14)

The chloro-3-[(4-methyl quinazoline-2-of step 1:1-(2-butyne-1-yl)-6-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 32)

Intermediate 32

Adopt the method similar to embodiment 1 step 2, prepare intermediate 32, productive rate 86.5% by intermediate 1 and 2-chloromethyl-4-methyl quinazoline.ES-API(m/z):[M+H] ⁺355.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(4-methyl quinazoline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 33)

Intermediate 33

Adopt the method similar to embodiment 1 step 3, prepare intermediate 33, productive rate 80.1% by intermediate 32 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺519.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 14)

Compound 14

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 33 and obtain compound 14, productive rate 66.7%.ES-API(m/z):[M+H] ⁺419.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.02(d,1H),7.88(d,1H)，7.78(m,1H)，7.53(m,1H),5.48(s,2H),5.34(s,1H),4.59(s,2H),3.31-3.46(m,2H),3.10(m,1H),2.89(s,3H),2.61-2.78(m,2H),1.90-2.01(m,2H),1.81(s,3H),1.73(m,1H),1.37(m,1H)。

embodiment 15:6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1h , 3h the preparation of)-diketone (compound 15)

The chloro-3-[(4-methyl quinazoline-2-of step 1:1-methyl-6-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 34)

Intermediate 34

Adopt the method similar to embodiment 1 step 2, prepare intermediate 34, productive rate 86.5% by intermediate 1 and 2-chloromethyl-4-methyl quinazoline.ES-API(m/z):[M+H] ⁺317.1。

Step 2:1-methyl-6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 35)

Intermediate 35

Adopt the method similar to embodiment 1 step 3, prepare intermediate 35, productive rate 80.1% by intermediate 34 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺481.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 15)

Compound 15

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 35 and obtain compound 15, productive rate 66.7%.ES-API(m/z):[M+H] ⁺381.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.02(d,1H),7.89(d,1H)，7.78(m,1H)，7.53(m,1H),5.46(s,2H),5.34(s,1H),3.43(s,3H),3.33(m,1H),3.12(m,2H),2.90(s,3H),2.62-2.69(m,2H),2.06(m,1H),1.86(m,1H),1.70(m,1H),1.40(m,1H)。

embodiment 16:6-(3-(R)-amino piperidine-1-yl)-1-(3-methyl-2-butene-1-yl)-3-[(4- methyl quinazoline-2-yl) methyl] pyrimidine-2,4 (1h , 3h the preparation of)-diketone (compound 16)

Step 1:1-(3-methyl-2-butene-1-yl) the chloro-3-[(4-methyl quinazoline-2-of-6-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 36)

Intermediate 36

Adopt the method similar to embodiment 1 step 2, prepare intermediate 36, productive rate 78.9% by intermediate 9 and 2-chloromethyl-4-methyl quinazoline.ES-API(m/z):[M+H] ⁺371.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(4-methyl quinazoline-2-yl) methyl]-1-(3-methyl-2-butene-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 37)

Intermediate 37

Adopt the method similar to embodiment 1 step 3, prepare intermediate 37, productive rate 79.2% by intermediate 36 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺535.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(3-methyl-2-butene-1-yl)-3-[(4-methyl quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 16)

Compound 16

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 37 and obtain compound 16, productive rate 70.1%.ES-API(m/z):[M+H] ⁺435.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.02(d,1H),7.88(d,1H)，7.78(m,1H)，7.53(m,1H),5.46(s,2H),5.35(s,1H),5.27(m,1H),4.47(s,2H),3.33(m,1H),3.08-3.18(m,2H),2.89(s,3H),2.47-2.64(m,2H),2.06(m,1H),1.86(m,2H),1.70(s,6H),1.37(m,1H)。

embodiment 17:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl-6- chloro-quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 17)

The preparation of step 1:2-chloromethyl-4-methyl-6-chloro-quinazoline (intermediate 38)

Intermediate 38

By 2-amino-5-chloro-acetophenone (8.5g, 50mmol) be dissolved in 150mL1, in 4-dioxane, solution is cooled to 10 DEG C, then pass into hydrogen chloride gas, after 2 hours, drip 1 of chloromethyl cyanide (4.5g, 60mmol), 4-dioxane solution (50mL), stirs under room temperature 7 hours; React complete, add 200mL frozen water, and then regulate reacting liquid pH value to 8 with the 2mol/L NaOH aqueous solution, ethyl acetate extraction (100mL × 2), merges organic phase, washes once anhydrous sodium sulfate drying with 100mL saturated common salt.Decompression steams solvent and obtains yellow solid 9.0g, productive rate 78.9%.ES-API(m/z):[M+H]+228.1。

The chloro-3-[(4-methyl-6-of step 1:1-(2-butyne-1-yl)-6-chloro-quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 39)

Intermediate 39

Adopt the method similar to embodiment 1 step 2, prepare intermediate 39 by intermediate 1 and intermediate 38, productive rate 81.0%.ES-API(m/z):[M+H] ⁺389.2。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(4-methyl-6-chloro-quinazoline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 40)

Intermediate 40

Adopt the method similar to embodiment 1 step 3, prepare intermediate 40, productive rate 78.5% by intermediate 39 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺553.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4-methyl-6-chloro-quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 17)

Compound 17

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 40 and obtain compound, productive rate 68.7%.ES-API(m/z):[M+H] ⁺453.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.96(d,1H)，7.86(m,2H)，5.47(s,2H),5.36(s,1H),4.59(s,2H),3.30-3.46(m,2H),3.11(m,1H),2.90(s,3H),2.62-2.78(m,2H),1.91-2.02(m,2H),1.80(s,3H),1.71(m,1H),1.39(m,1H)。

embodiment 18:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoxaline-2- base) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 18)

The chloro-3-[(quinoxaline-2-of step 1:1-(2-butyne-1-yl)-6-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 41)

Intermediate 41

Adopt the method similar to embodiment 1 step 2, prepare intermediate 41, productive rate 76.4% by intermediate 1 and 2-chloromethyl quinoxaline.ES-API(m/z):[M+H] ⁺341.1。

Step 2:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(quinoxaline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 42)

Intermediate 42

Adopt the method similar to embodiment 1 step 3, prepare intermediate 42, productive rate 85.9% by intermediate 41 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺505.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoxaline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 18)

Compound 18

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 42 and obtain compound 18, productive rate 71.8%.ES-API(m/z):[M+H] ⁺405.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：8.71(d,1H),8.01(m,2H)，7.66(m,1H),7.60(m,1H),5.46(s,2H),5.35(s,1H),4.55(s,2H),3.30-3.45(m,2H),3.09(m,1H),2.57-2.72(m,2H),1.89-2.01(m,2H),1.81(s,3H),1.72(m,1H),1.40(m,1H)。

embodiment 19:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 19)

The preparation of step 1:4-kharophen indane (intermediate 43)

Intermediate 43

4-aminoidan (13.5g, 101mmol) is joined in the round-bottomed flask of 500mL, add 50mL ethanol, stirring and dissolving also cools to 0 DEG C, then add be dissolved with acetic anhydride (19mL,

Ethanolic soln 200mL 201mmol), stirring at room temperature 12 hours; React complete, remove solvent under reduced pressure, obtain white solid 17.0g, productive rate 97.1%.ES-API(m/z):[M+H] ⁺176.0。

The preparation of step 2:7-acetylaminohydroxyphenylarsonic acid 1-indone (intermediate 44)

Intermediate 47

Intermediate 43 (5.0g, 29mmol) is joined in the round-bottomed flask of 250mL, add 150mL acetone, after stirring, adding 40mL massfraction is 15% MgSO ₄the aqueous solution, cools to 0 DEG C, adds potassium permanganate (13.7g, 87mmol), then stirring at room temperature 15 hours.React complete, by reaction solution through diatomite filtration, filter cake is used chloroform and water washing successively, filtrate separates water, and with 50mL chloroform extraction once, merge organic phase, the water washing of 70mL saturated common salt once, anhydrous sodium sulfate drying 10 hours, filtration, filtrate steam solvent and obtain white solid 4.2g, productive rate 76.6%.ES-API(m/z):[M+H] ⁺190.0。

Step 3:7-amino-2, the preparation of 3-bihydrogen-1-indenone (intermediate 45)

Compound 45

Intermediate 44 (4.0g, 21mmol) is joined in the round-bottomed flask of 100mL, then add 50mL6mol/L hydrochloric acid, be warming up to 90 DEG C and stir 4h; React complete, be cooled to 0 DEG C, with 2mol/L NaOH aqueous solution adjusting reacting liquid pH value to 8, ethyl acetate extractive reaction liquid (30mL × 3), merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, decompression steams solvent and obtains yellow solid 2.8g, productive rate 90.7%.ES-API(m/z):[M+H] ⁺148.0。

Step 4:2-chloromethyl-4, the preparation of 5-dihydro ring penta [de] quinazoline (intermediate 46)

Intermediate 46

Intermediate 45 (1.5g, 10mmol) is dissolved in to 20mL1, in 4-dioxane, solution is cooled to 10 DEG C, then passes into hydrogen chloride gas, after 2 hours, drip chloromethyl cyanide (0.9g, Isosorbide-5-Nitrae-dioxane solution 12mmol), stirs under room temperature 5 hours.React complete, add 50mL frozen water, with 2mol/L NaOH aqueous solution adjusting reacting liquid pH value to 8, ethyl acetate extraction (30mL, extract 2 times), merge organic phase, the water washing of 20mL saturated common salt, anhydrous sodium sulfate drying, revolves and steams solvent and obtain white solid 1.9g, productive rate 92.2%.ES-API(m/z):[M+H] ⁺205.1。

Step 5:1-(2-butyne-1-yl) the chloro-3-[(4 of-6-, 5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 47)

Intermediate 47

Adopt the method similar to embodiment 1 step 2, prepare intermediate 47 by intermediate 1 and intermediate 46, productive rate 78.8%.ES-API(m/z):[M+H] ⁺367.1。

Step 6:6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 48)

Intermediate 48

Adopt the method similar to embodiment 1 step 3, prepare intermediate 48, productive rate 81.6% by intermediate 47 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺531.3。

Step 7:6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 19)

Compound 19

Adopt the method similar to embodiment 1 step 4, slough 3-(R)-tertbutyloxycarbonyl by intermediate 48 and obtain compound 19, productive rate 65.7%.ES-API(m/z):[M+H] ⁺431.3。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.79(m,1H),7.62(d,1H)，7.38(d,1H)，5.65(s,2H),5.51(s,1H),4.55(m,2H),3.48(m,1H),3.33-3.41(m,5H),3.25(m,1H),2.80(m,2H),2.05(m,1H),1.90(m,1H),1.79(s,3H),1.68(m,1H),1.51(m,1H)。

embodiment 20:6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4,5-dihydro ring penta [de] quinoline azoles quinoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 20)

Step 1:1-(2-butyne-1-yl) the chloro-3-[(4 of-6-, 5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 49)

Intermediate 49

Adopt the method similar to embodiment 1 step 2, prepare intermediate 49 by intermediate 4 and intermediate 46, productive rate 81.8%.ES-API(m/z):[M+H] ⁺329.1。

Step 2:1-methyl-6-[(3-(R)-(tertbutyloxycarbonyl amido) piperidin-1-yl)]-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (intermediate 50)

Intermediate 50

Adopt the method similar to embodiment 1 step 3, prepare intermediate 50, productive rate 76.6% by intermediate 49 and 3-(R)-tertbutyloxycarbonyl-amino piperidine.ES-API(m/z):[M+H] ⁺493.2。

Step 3:6-(3-(R)-amino piperidine-1-yl)-1-methyl-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2, the preparation of 4 (1H, 3H)-diketone (compound 20)

Compound 20

Adopt the method similar to embodiment 1 step 4, prepared productive rate 62.7% by intermediate 50.ES-API(m/z):[M+H] ⁺393.2。

¹H-NMR(600MHz,CDCl ₃,δ _ppm)：7.80(m,1H),7.63(d,1H)，7.38(d,1H),5.50(s,2H),5.33(s,1H),3.38-3.43(m,7H),3.29(m,1H),3.11(m,2H),2.57-2.69(m,2H),2.05(m,1H),1.88(m,1H),1.69(m,1H),1.38(m,1H)。

biological test

Test example: DPP-IV suppresses active mensuration

DPP-IV(is purchased from BPS-Bioscience, Cat.80040) for application baculovirus expression system is expressed and purified pure enzyme, reaction system at the buffered soln of PH=7.5 (purchased from BPS-Bioscience, Cat.80300) in, carry out, enzyme reaction substrate is Ala-Pro-7-amino-4-methylcoumarin (Ala-Pro-AMC) (purchased from BPS-Bioscience, Cat.80305).

DPP-IV degradable enzyme reaction substrate Ala-Pro-AMC generates product A MC(7-amino-4-methylcoumarin), AMC is produced the utilizing emitted light of 460nm by the ultraviolet excitation of 355nm.Measure the activity of DPP-IV in the lift velocity of 460nm place fluorescent value with Scanlab varioSCAN dynamic measurement AMC.

Measuring method: (compound 1 prepared by embodiment 1 to embodiment 20 is to compound 20 and positive control drug by test-compound solution, dissolve by dimethyl sulfoxide (DMSO) (DMSO), concentration is in 0.64 ~ 200nmol/L concentration range, test every three times of concentration gradients), enzyme (DPP-IV, starting point concentration is 0.1ng/ μ L) and reaction buffered soln mix, incubate in advance 15min at 37 DEG C, add enzyme reaction substrate (starting point concentration is 5 μ mol/L) to start reaction, METHOD FOR CONTINUOUS DETERMINATION 460nm fluorescent value 5min.Blank group, solvent control group and positive controls are set simultaneously.Wherein in blank group, substitute test-compound solution with equal-volume DMSO, and do not add enzyme reaction substrate; Solvent control group substitutes test-compound solution with equal-volume DMSO; Positive controls with Alogliptin[its preparation method referring to Journal of Medicinal Chemistry, 2007,50,2297-2300] substitute test-compound.The final volume that responds is 100 μ L.3 multiple holes of each sample concentration.

First (base consumption is below 20% to calculate the reaction initial period of enzyme, base consumption and time are linear) in the increment (unit: RFU/ second) of fluorescence intensity, represent the initial velocity (enzyme reaction initial period unit time in product growing amount) of enzyme with this, then the active percentage ratio of the each concentration group of calculation sample, formula is as follows:

Wherein V _samplerepresent the initial velocity of the each concentration group of sample, V _dMSOrepresent the initial velocity of DMSO group.

Taking concentration value as X-coordinate, activity value is ordinate zou, then adopts GRAPHPADPRISM5 software to do dose-effect curve matching, calculates IC ₅₀value.Shown in segment bounds I, the biological activity test of compound the results are shown in Table 1.

Compound shown in table 1. segment bounds I suppresses active to DPP-IV

Tested person compound thing	IC ₅₀(DPP-IV?nmol/L)
		Compound 1	69.8
Compound 2	150
		Compound 3	74.3
Compound 4	165
		Compound 5	/
Compound 6	/
		Compound 7	/
Compound 8	15.6
		Compound 9	>200
Compound 10	46.7
		Compound 11	/
Compound 12	/
		Compound 13	/
Compound 14	6.74
		Compound 15	>200
Compound 16	126

Compound 17	5.78
		Compound 18	/
Compound 19	3.56
		Compound 20	>200
Alogliptin	41.7

Note: "/" represents not carry out this test of pesticide effectiveness of this compound

Alogliptin:(R)-2-((6-(3-amino piperidine-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-yl) methyl) benzonitrile

Wherein, Alogliptin proposes as the positive control of test.Can find out that by the data in table 1 compound of the present invention is active to the good inhibition of having of DPP-IV; Particularly the DPP-IV of compound 8, compound 14, compound 17, compound 19 inhibition activity is obviously better than Alogliptin, is inhibiting 3～10 times of Alogliptin, and therefore, the compounds of this invention has more excellent biological activity.

In sum, formula I compound of the present invention can suppress DPP-IV well, can be used in the disease that treatment, prevention and alleviation are relevant to DPP-IV, the diseases such as such as diabetes, hyperglycemia, obesity, insulin resistant disease, cancer, ischemic cardiac myositis or angiogenic disease.

Claims

1. uracil derivative, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt shown in a class formula I:

Formula I

Wherein:

2. uracil derivative according to claim 1, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt, is characterized in that R ₁be selected from C replacement or unsubstituted straight chain or side chain _1-4the C of straight chain alkyl, replacement or unsubstituted or side chain _2-5c thiazolinyl, replacement or unsubstituted _2-4straight or branched alkynyl.

3. uracil derivative according to claim 1, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt, is characterized in that R ₁be selected from methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, isobutyl-, vinyl, 1-propylene-1-base, 2-propylene-1-base, 1-methyl-1-propylene-1-base, 1-methyl-2-propylene-1-base, 1-butylene-1-base, 2-butylene-1-base, 3-butene-1-Ji, 2-methyl-1-butene alkene-1-base, 2-methyl-2-butene-1-base, 3-methyl-3-butene-1-Ji, ethynyl, 1-propine-1-base, 2-propine-1-base, ethyl acetylene-1-base, 2-butyne-1-base, 3-butine-1-base; Preferably, R ₁be selected from methyl, ethyl, 2-butyne-1-base, 3-methyl-2-butene-1-base, 3-butine-1-base; More preferably, R ₁be selected from: 2-butyne-1-base, 3-methyl-2-butene-1-base, methyl.

4. uracil derivative according to claim 1, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt, is characterized in that R ₂be selected from benzyl, phenylcarbonyl group methyl, naphthyl methyl, pyridylmethyl, Pyrimidylmethyl, quinolyl methyl, isoquinolyl methyl, quinazolyl methyl, quinoxalinyl methyl, 4,5-dihydro ring penta [de] quinazolyl methyl;

Further preferably, R ₂be selected from: 2-cyano group benzyl, 2-cyano group-5-fluoro-benzyl, (5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl, (5,6,7,8-tetrahydrochysene-4-trifluoromethyl quinazoline-2-yl) methyl, (4-methyl quinazoline-2-yl) methyl, (4-methyl-6-chloro-quinazoline-2-yl) methyl, (4,5-dihydro ring penta [de] quinazoline-2-yl) methyl; More preferably, R ₂be selected from: (5,6,7,8-tetrahydrochysene-4-methyl quinazoline-2-yl) methyl, (4-methyl quinazoline-2-yl) methyl, (4-methyl-6-chloro-quinazoline-2-yl) methyl, (4,5-dihydro ring penta [de] quinazoline-2-yl) methyl.

5. uracil derivative according to claim 1, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt, is characterized in that, described uracil derivative is selected from following compounds:

6-(3-(R)-amino piperidine-1-yl)-3-[(pyridine-2-yl) methyl]-1-(2-butyne-1-yl) pyrimidine-2,4 (1H, 3H)-diketone (compound 5);

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } pyridine-3-nitrile (compound 6);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(pyrimidine-2-base) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 7);

2-{[4-(3-(R)-amino piperidine-1-yl)-3-(2-butyne-1-yl)-2,3-dihydro-2,6-dioxo-1 (6H)-pyrimidyl] methyl } naphthalene-1-nitrile (compound 11);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 12);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(isoquinoline 99.9-3-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 13);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(quinoxaline-2-yl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (compound 18);

6-(3-(R)-amino piperidine-1-yl)-1-(2-butyne-1-yl)-3-[(4,5-dihydro ring penta [de] quinazoline-2-yl) methyl] pyrimidine-2,4 (1H, 3H) diketone (compound 19);

Preferably, described uracil derivative is selected from following compounds:

Further preferably, described uracil derivative is selected from following compounds:

Still more preferably, described uracil derivative is selected from following compounds:

Most preferably, described uracil derivative is selected from following compounds:

6. a method of preparing the uracil derivative shown in formula I claimed in claim 1, the method comprises the following steps:

Wherein, R ₁, R ₂definition as the definition in claim 1; X represents leavings group, can be selected from halogen atom, the hydroxyl being substituted, sulfydryl, sulfinyl, alkylsulfonyl or alkylsulfonyl oxygen base, preferably halogen atom, more preferably chlorine atom; Described suitable acid is selected from trifluoroacetic acid, formic acid, hydrochloric acid, acetic acid, is preferably trifluoroacetic acid, hydrochloric acid, most preferably is trifluoroacetic acid.

7. uracil derivative according to claim 1, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt, it is characterized in that, described pharmacy acceptable salt is described compound and the salt that is selected from following acid formation: hydrochloric acid, sulfuric acid, phosphoric acid, oxysuccinic acid, toxilic acid, fumaric acid, lactic acid, phenylformic acid, methylsulfonic acid, citric acid, tartrate, acetic acid or trifluoroacetic acid.

8. a pharmaceutical composition, said composition comprises one or more in uracil derivative claimed in claim 1, its pharmacy acceptable salt, the solvate of described derivative or the solvate of described pharmacy acceptable salt, and optional pharmaceutically acceptable vehicle or carrier.

9. the uracil derivative described in claim 1-5 any one, its pharmacy acceptable salt, the solvate of described derivative and the solvate of described pharmacy acceptable salt or composition claimed in claim 8 are for the preparation of the purposes of the medicine as DPP-IV inhibitor or for the preparation of the purposes of the medicine for the treatment of, prevention and the alleviation disease relevant to DPP-IV.

10. purposes according to claim 9, is characterized in that, the described disease relevant to DPP-IV is selected from diabetes, hyperglycemia, obesity, insulin resistant disease, cancer, ischemic cardiac myositis, angiogenic disease; Preferably diabetes and hyperglycemia.