CN101115752A

CN101115752A - 4- (4- (imidazol-4-yl) pyrimidin-2-ylamino) benzamides as cdk inhibitors

Info

Publication number: CN101115752A
Application number: CNA2005800479782A
Authority: CN
Inventors: D·安德鲁斯; M·R·芬利; C·格林; C·琼斯
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2004-12-17
Filing date: 2005-12-15
Publication date: 2008-01-30
Also published as: ZA200705073B; GB0427699D0

Abstract

Compounds of the formula: (I): wherein variable groups are as defined within and a pharmaceutically acceptable salts and in vivo hydrolysable esters are described. Also described are processes for their preparation and their use as medicaments, particularly medicaments for producing a cell cycle inhibitory (anti-cell-proliferation) effect in a warm-blooded animal, such as man.

Description

4-(4-(imidazol-4 yl) pyrimidine-2--amino) benzamide as cyclin dependent kinase inhibitor

(or it is at adoptable salt pharmaceutically to the present invention relates to the pyrimidine derivatives class, or its ester of hydrolysis in vivo), they have the activity that suppresses the cell cycle, correspondingly, their inhibition of cell proliferation (for example antitumor) activity is useful, therefore can be used in treatment human or animal's the method.The invention still further relates to the method for producing said these pyrimidine derivatives, contain their drug component and the medicine that has inhibition of cell proliferation effect in warm-blooded animal (for example people) body with these derivative productions with generation.

Cell cycle is the basis of cell survival, adjusting and propagation, is subjected to strict the adjusting, goes on foot all on time, carries out in an orderly manner to guarantee each.The orderly activation and the inactivation that comprise plain dependent kinase (CDK) family members of many cycles by the cell process of cell cycle realization.The activation of CDK is decided by they and the reaction that is called the intracellular protein family of " cycle element ".The cycle element is combined on the CDK, and this combination is the basis of CDK activity in the cell (for example CDK1, CDK2, CDK4 and/or CDK6).Different cycle elements is expressed on the difference of cell cycle and is disappeared, and activates correctly, in an orderly manner and inactivation in the cell cycle to guarantee CDK.

In addition, the downstream of the seemingly many encoding gene signal paths of CDK.The imbalance of the CDK that the rise by the cycle element and/or the removing of endogenous inhibition realize is an important line of delimitation between mitotic division signal path and the tumor cell proliferation seemingly.

Correspondingly, people recognize cell cycle kinase inhibitors, CDK1 particularly, the inhibitor of CDK2 and/or CDK4 (they are respectively at G2/M, and G1/S-S-G2/M and G1-S phase work) should have the activity of inhibition cell proliferation (for example mammalian tumor cell growth).

Expectation is treated the unusual and cell proliferation pathologies associated with the cell cycle by the kinase whose inhibition of cell cycle, tumour (achiblastoma and leukemia) for example, fibroplasia and break up illness, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst is atherosis, stricture of artery, autoimmune disease, acute and chronic inflammation, osteopathy and retinal vessel hyperplasia illness in eye.

WO 02/20512, and WO 07/6435, and WO 03/076436, and WO 03/076434, and WO03/076433 and WO 04/101549 have described some 2-anilino-4-imidazolyl pyrimidines derivative and had the effect that suppresses cell-cycle kinases.The present invention is based on this discovery, that is, one group of new 2-(4-acid amides anilino)-4-(imidazolyl) miazines has the effect that cell-cycle kinases particularly suppresses CDK2 that suppresses, and therefore has the characteristic of inhibition of cell proliferation.Compound of the present invention is not by specially open in above-mentioned any one application, and we find pleasantly surprisedly, these compounds (compound that especially suppresses DCK2) have excellent characteristic at aspect their one or more pharmaceutical actives and/or pharmacokinetics, validity, metabolism and toxicology aspect, this makes them be particularly suitable for to warm-blooded animal, for example the people does in the body and takes in.Especially these compounds have high cell and enzyme effect level, and exposure also has high level in the body.

Correspondingly, the invention provides a kind of as the represented compound of following formula (I):

Wherein:

R ¹Be hydrogen or halogen;

R ²Be halogen, nitrogen, cyano group, hydroxyl, amino, carbonyl, formamyl, sulfydryl, methylthio group, methylsulfonyl, trifluoromethyl, trifluoromethoxy, C _1-6Alkyl, C _1-6Alkoxyl group, C _2-6Thiazolinyl or C _2-6Alkynyl;

P is 0-4; Value wherein can be the same or different;

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Carbon atom can be independently by one or more R ⁵Replace arbitrarily; And if said heterocyclic radical contains one-NH-, then its nitrogen-atoms can be at random by R ⁶Group replace;

R ¹⁹Be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclopropyl methyl, cyclopropyl ethyl or cyclobutyl; R wherein ¹Carbon atom can be at random by one or more R ²¹Replace;

R ²⁰Be methyl, ethyl, sec.-propyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxymethyl, cyclopropyl methyl or cyclopropyl;

R ⁵Be halogen, nitrogen, cyano group, hydroxyl, amino, carbonyl, formamyl, sulfydryl, amino-sulfonyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Silane alcohol base, C _1-6Silane alcohol base oxygen base, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Silane alcohol base amino, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) a a wherein is 0-2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) amino-sulfonyl, N, N-(C _1-6Alkyl) ₂Amino-sulfonyl, C _1-6Alkyl sulfonyl-amino, carbocylic radical, heterocyclic radical, carbocylic radical C _1-6Alkyl-R ⁷, heterocyclic radical C _1-6Alkyl-R ⁸, carbocylic radical-R ⁹-or heterocyclic radical-R ¹⁰-; R wherein ⁵Carbon atom can be at random by one or more R ¹¹Replace; Wherein, if said heterocyclic radical contains one-NH-, then its nitrogen-atoms can be at random by R ¹²Group replace;

R ⁶And R ¹²Be C independently of one another _1-6Alkyl, C _1-6Silane alcohol base, C _1-6Alkyl sulphonyl, C _1-6Alkoxy carbonyl, formamyl, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl; R wherein ⁶And R ¹²Carbon atom separately independently can be arbitrarily by one or more R ¹³Replace;

R ⁷, R ⁸, R ⁹And R ¹⁰Be-O--N (R independently of one another ¹⁴)-,-C (O)-,-(R ¹⁵) C (O)-,-C (O) C (R ¹⁶)-,-S (O) _S-,-SO ₂N (R ¹⁷)-or-N (R ¹⁸) SO ₂-; R wherein ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Be hydrogen or C independently of one another _1-6Alkyl, and s is 0-2;

R ¹¹And R ¹³Be halogen independently of one another, nitrogen, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carbonyl, formamyl, sulfydryl, amino-sulfonyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methyl sulfinyl, ethylsulfinyl-1 base, methyl sulphonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylamino alkylsulfonyl, N-ethylamino alkylsulfonyl, N, N-dimethylamino alkylsulfonyl, N, N-diethylamino alkylsulfonyl or N-methyl-N-ethylamino alkylsulfonyl; And

R ²¹Be halogen, methoxyl group and hydroxyl; Or it is at adoptable salt pharmaceutically or its ester of hydrolysis in vivo.

Correspondingly, the present invention proposes the compound of a kind of formula (I), i.e. formula (Ia):

Wherein:

R ¹Be hydrogen or fluorine;

R ²Be halogen, nitrogen, cyano group, hydroxyl, amino, carbonyl, formamyl, sulfydryl, C _1-6Alkyl, C _1-6Alkoxyl group, C _2-6Thiazolinyl or C _2-6Alkynyl;

P is 0-4; R wherein ²Value can be the same or different.

R ⁵Be halogen, nitrogen, cyano group, hydroxyl, amino, carbonyl, formamyl, sulfydryl, amino-sulfonyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Silane alcohol base, C _1-6Silane alcohol base oxygen base, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Silane alcohol base amino, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) a a wherein is 0-2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) amino-sulfonyl, N, N-(C _1-6Alkyl) ₂Amino-sulfonyl, C _1-6Alkyl sulfonyl-amino, carbocylic radical, heterocyclic radical, carbocylic radical C _1-6Alkyl-R ⁷-, heterocyclic radical C _1-6Alkyl-R ⁸-, carbocylic radical-R ⁹-or heterocyclic radical-R ¹⁰-; R wherein ⁵Carbon atom can be at random by one or more R ¹¹Replace; Wherein, if said heterocyclic radical contains one-NH-, then its nitrogen-atoms can be at random by R ¹²Group replace;

R ¹¹And R ¹³Be halogen independently of one another, nitrogen, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carbonyl, formamyl, sulfydryl, amino-sulfonyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, kharophen, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methyl sulfinyl, ethylsulfinyl-1 base, methyl sulphonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylamino alkylsulfonyl, N-ethylamino alkylsulfonyl, N, N-dimethylamino alkylsulfonyl, N, N-diethylamino alkylsulfonyl or N-methyl-N-ethylamino alkylsulfonyl;

Perhaps a kind of pharmaceutically adoptable salt, or its hydrolyzable in vivo ester.

" alkyl " speech comprises straight chain and branched alkyl group, but mentions one alkyl, as then only refers to the propyl group of straight chain when mentioning " propyl group ".For example, " C ^1-6Alkyl " and " C ^1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl.Yet when mentioning one alkyl group, as say that " propyl group " only refers to the propyl group of straight chain, mention branched alkyl, as mention " sec.-propyl " and then only refer to branched propyl group.Same rule also is applicable to other groups.

Mention and can at random be replaced, should be understood to this definition and comprised all substituting groups in the special groups by " one or more " group, and the substituting group of from two or more special groups, selecting.

One " heterocyclic radical " is a kind of saturated, fractional saturation or undersaturated, monocycle or dicyclo, contains 4-12 atom, and wherein having an atom at least is nitrogen, sulphur or oxygen, except as otherwise noted, these atoms can carbon or nitrogen connect, one of them-CH ₂-group can at random use-C (O)-substitute, and the nitrogen-atoms on the ring can at random have a C _1-6Alkyl group forms a quaternary compound, and perhaps nitrogen-atoms on ring and/or sulphur atom are formed N-oxide compound and/or S-oxide compound by oxidation at random.The example of " heterocyclic radical " and just when comprising morpholino, piperidyl, pyridyl, pyranyl, pyrryl, isothiazolyl, indyl, quinolyl, thienyl, 1,3-benzo oxo base, the sulfo-dipyrryl, pepper azine group, thiazolidyl, pyrrolidyl, thio-morpholinyl, pyrrolinyl, high pepper azine group, 3,5-dioxopiperidine base, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, different  azoles base, N-methylpyrrole base, 4-pyridone, 1-isoquinolone, 2-Pyrrolidone, 4-thiazolidone, oxidation N-pyridine and oxidation N-quinoline.On the one hand, " heterocyclic radical " among the present invention is saturated, fractional saturation or undersaturated, as to contain 5 or 6 atoms a monocycle or a dicyclic compound, wherein having an atom at least is nitrogen, sulphur or oxygen, and it can connect one-CH with carbon or nitrogen outside unless otherwise indicated ₂-Ji can be at random by-C (O)-replacement, a sulphur atom on the ring can at random oxidized formation S-oxide compound.

" carbocylic radical " is saturated, fractional saturation or undersaturated, as to contain a 3-12 atom carbocyclic ring, one of them-CH ₂-Ji can be at random by-C (O)-replacement." carbocylic radical " especially contains the monocycle of 5 or 6 atoms or contains the dicyclo of 9 or 10 atoms.For " carbocylic radical ", suitable have cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, phenyl, naphthyl, tetralyl, 2,3-indanyl or 1-oxo-2, a 3-indanyl.

" C _1-6Alkanoyloxy " example be acetoxyl group." C _1-6Carbalkoxy " example comprise methoxycarbonyl, ethoxycarbonyl, secondary butoxy carbonyl and tertbutyloxycarbonyl." C _1-6Alkoxyl group " example comprise methoxyl group, oxyethyl group and propoxy-." C _1-6Alkyl amido " example comprise formamido group, kharophen and propionamido." C _1-6Alkyl S (O) a, a wherein is 0-2 " example comprise methylthio group, ethylmercapto group, methyl sulfinyl, ethylsulfinyl-1 base, methyl sulphonyl and ethyl sulfonyl." C _1-6Silane alcohol base " example comprise propionyl and ethanoyl." N-(C _1-6Alkyl) amino " example comprise methylamino and ethylamino." N, N-(C _1-6Alkyl) ₂Amino " example comprise two-N-methylamino, two-(N-ethyl) amino and N-ethyl-N-methylaminos." C _2-6Thiazolinyl " example vinyl is arranged, allyl group and 1-propenyl." C _2-6Alkynyl " example ethynyl is arranged, 1-proyl and 2-propynyl." N-(C _1-6Alkyl) amino-sulfonyl " example N-(methyl) amino-sulfonyl and N-(ethyl) amino-sulfonyl are arranged." N, N-(C _1-6Alkyl) ₂Amino-sulfonyl " example N is arranged, N-(dimethyl) amino-sulfonyl and N-(methyl)-N-(ethyl) amino-sulfonyl." N-(C _1-6Alkyl) formamyl " example methylamino carbonyl and ethylamino carbonyl are arranged." N, N-(C _1-6Alkyl) ₂Formamyl " example dimethylamino carbonyl and methylethyl aminocarboxyl are arranged." C _1-6Alkyl sulfonyl amino " example sulfonyloxy methyl amino is arranged, sec.-propyl sulfonamido and tertiary butyl sulfonamido." C _1-6Alkyl sulphonyl " example methyl sulphonyl is arranged, sec.-propyl alkylsulfonyl and tertiary butyl alkylsulfonyl." carbocylic radical C _1-6Alkyl-R ⁷-" example comprise 1-(carbocylic radical) ethyl-R ⁷-, 1-(cyclopropyl) ethyl-R for example ⁷-and 1-phenylethyl-R ⁷-, and 3-(carbocylic radical) propyl group-R ⁷-, 3-(cyclopentyl) propyl group-R for example ⁷-and 3-(naphthyl) propyl group-R ⁷-." heterocyclic radical C _1-6Alkyl-R ⁸-" example comprise 1-(heterocyclic radical) ethyl-R ⁸-, 1-(pyridine-2-yl) ethyl-R for example ⁸-and 1-(morpholinyl) ethyl-R ⁸-, and 3-(heterocyclic radical) propyl group-R ⁸-, 3-(piperazine-1-yl) propyl group-R for example ⁸-and 3-(pyrrolidone-1-yl) propyl group-R ⁷-.

Compound of the present invention at adoptable salt pharmaceutically is, for example, and the acid salt with abundant alkalescence of a compound among the present invention, for example, a kind of mineral acid or organic acid acid salt, for example, hydrochloride, bromate, vitriol, phosphoric acid salt, three fluorate, Citrate trianion or maleate.In addition, to have abundant tart salt be a kind of an alkali metal salt for a compound suitable pharmaceutically adoptable among the present invention, for example, and a kind of sodium salt or sylvite, a kind of alkaline earth salt, for example a kind of calcium salt or magnesium salts, a kind of ammonium salt perhaps can provide the adoptable cationic salt that has organic bases on the physiology, methylamine salt for example, dimethylamine salt, front three amine salt piperidinium salt, alkylbenzyldimethylasaltsum saltsum or three-(2-hydroxyethyl) amine salt.

The ester that contains hydrolyzable in vivo formula (I) compound of carboxyl or hydroxyl is that for example, hydrolyzable produces maternal acid or pure pharmaceutically adoptable ester in human body or animal body.The suitable pharmaceutically adoptable ester that contains carboxyl comprises C _1-6The alkoxy methyl ester, methoxymethyl ester for example, C _1-6Silane alcohol base oxygen ylmethyl ester, trimethyl acetoxyl methyl ester for example, phthalidene ester, C _3-8Cyclo alkoxy carbonyl oxygen base C _1-6Alkyl ester, for example 1-cyclohexyl-carbonyl oxygen base ethyl ester; 1,3-dioxo alkene-2-acyl methyl ester, 5-methyl isophthalic acid for example, 3-dioxo alkene-2-acyl methyl ester; And C _1-6The alkoxy-carbonyl oxy ethyl ester, 1-methoxycarbonyl oxygen base ethyl ester for example, and the ester that forms by any carboxyl of compound of the present invention.

The ester that contains hydrolyzable in vivo formula (I) compound of hydroxyl comprises inorganic ester, as phosphoric acid ester and alpha-acyloxy methyl ethers and relevant compound, these compounds since ester in vivo hydrolytic cleavage produce maternal hydroxyl.The example of alpha-acyloxy methyl ether comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.The ester that can form the hydrolysis in vivo of hydroxyl comprises silane alcohol base; benzoyl; the benzoyl of phenylacetyl and replacement and phenylacetyl; alkoxy carbonyl (producing the alkyl carbonate ester); dialkyl amido formyl radical and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (generation carbamate), dialkyl amido ethanoyl and carbonyl ethanoyl.Have substituent example on the benzoyl and comprise morpholino and piperazine generation, be connected on the 3-position or 4-position of benzoyl ring by a methylene radical with nitrogen-atoms on the ring.

Some formula (I) compound can have chiral centre and/or rotamerism center (E-and Z-isomer), the present invention includes all these and has CDK and suppress active optical diastereomer and geometrical isomer.

The present invention includes any and all have the tautomer that CDK suppresses active formula (I) compound.

Also must understand, some formula (I) compound can be with form solvation and non-solventization, and for example hydrated form exists.Must understand, the present invention includes all these and have CDK and suppress active solvation form.

The particular value of these normal change groups is as follows.These values can be used for any suitable definition, the claim or the part of definition before this or after this.

R ¹Be hydrogen or fluorine.

R ¹Be hydrogen.

R ¹Be fluorine.

R ²Be halogen, cyano group or C _1-6Alkyl.

R ²Be halogen or C _1-6Alkyl.

R ²Be fluorine, chlorine, cyano group or methyl.

R ²Be fluorine, chlorine or methyl.

R ²Be fluorine.

R ²Be chlorine.

R ²Be cyano group.

R ²Be methyl.

P is 0 or 1.

P is 0.

P is 1.

P is 0-1, is 1 o'clock at P, R ²Be arranged in formula (I) compound-C (O) N R ³R ⁴The ortho position of group.

P is 1, R ²Be arranged in formula (I) compound-C (O) N R ³R ⁴The ortho position of group.

P is 0-1, is 1 o'clock at P, R ²Be arranged in formula (I) compound-C (O) N R ³R ⁴Position between group, and R ²Be fluorine or methyl.

P is 1, R ²Be arranged in formula (I) compound-C (O) N R ³R ⁴Position between group, and R ²Be fluorine or methyl.

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Carbon atom can be independently of one another by one or more R ⁵Replace arbitrarily; If said heterocyclic radical contains one-NH-base, then its nitrogen-atoms can be by one from R ⁶Group replace arbitrarily; Wherein

R ⁵Be hydroxyl, N, N-(C _1-6Alkyl) ₂Amino and heterocyclic radical;

R ⁶Be C _1-6Alkyl and C _1-6Alkoxy carbonyl; R wherein ⁶Carbon atom can be independently by one or more R ¹³Replace arbitrarily;

R ¹³Be methoxyl group.

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Carbon atom can be independently of one another by one or more R ⁵Replace arbitrarily; If said heterocyclic radical contains one-NH-base, then its nitrogen-atoms can be by a R ⁶Group replaces arbitrarily; R wherein ⁵Be hydroxyl; R ⁶Be C _1-6Alkyl.

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Carbon atom can be independently of one another by one or more R ⁵Replace arbitrarily; R wherein ⁵Be hydroxyl.

R ³And R ⁴Be hydrogen independently of one another, methyl, ethyl, sec.-propyl, cyclopropyl, THP trtrahydropyranyl, 1,1-two oxo bridge tetrahydro-thienyl or piperidyls; R wherein ³And R ⁴Carbon atom can be independently of one another by one or more R ⁵Replace arbitrarily; Wherein the nitrogen-atoms of said piperidyl can be by one from R ⁶Group replace arbitrarily; Wherein

R ⁵Be hydroxyl, dimethylamino, morpholino, thiomorpholine generation, pyrrolidone-base and piperidyl;

R ⁶Be methyl, ethyl and tert-butoxycarbonyl; R wherein ⁶Carbon atom can be by one or more R ¹³Replace arbitrarily;

R ¹³Be methoxyl group.

R ³And R ⁴Be hydrogen independently of one another, methyl, ethyl, cyclopropyl, tetrahydrofuran base or piperidyl; R wherein ³And R ⁴Carbon atom can be independently of one another by one or more R ⁵Replace arbitrarily; Wherein the nitrogen-atoms of said piperidyl can be by one from R ⁶Group replace arbitrarily; R wherein ⁵Be hydroxyl; R ⁶Be methyl.

R ³And R ⁴Be hydrogen independently of one another, methyl, ethyl or cyclopropyl; R wherein ³And R ⁴Carbon atom can be independently of one another by one or more R ⁵Replace arbitrarily; R wherein ⁵Be hydroxyl.

R ³And R ⁴Be hydrogen independently of one another, methyl, cyclopropyl, the 2-hydroxyethyl, 1-methyl piperidine-4-base, piperidines-3-base, tetrahydropyran-4-base, 1,1-dioxo tetramethylene sulfide-3-base, the 2-dimethyl aminoethyl, 1-methyl-2-dimethyl aminoethyl, piperidines-1-base ethyl, 2-morpholino ethyl, 1-(2-methoxy ethyl) piperidin-4-yl, 2-thiomorpholine be for ethyl, 2-tetramethyleneimine-1-base ethyl and 1-(uncle-butoxy carbonyl) piperidines-3-base.

R ³And R ⁴Be hydrogen independently of one another, methyl, 2-hydroxyethyl, cyclopropyl, tetrahydrofuran (THF)-4-base or 1-methyl piperidine-4-base.

R ³And R ⁴Be hydrogen independently of one another, methyl, 2-hydroxyethyl or cyclopropyl.

R ¹⁹Be ethyl, sec.-propyl, cyclopropyl methyl, 1-cyclopropyl ethyl or cyclobutyl.

R ¹⁹Be ethyl.

R ¹⁹Be sec.-propyl.

R ¹⁹Be the cyclopropyl methyl.

R ¹⁹Be 1-cyclopropyl ethyl.

R ¹⁹Be cyclobutyl.

R ²⁰Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, methoxymethyl or cyclopropyl.

R ²⁰Be methyl.

R ²⁰Be ethyl.

R ²⁰Be sec.-propyl.

R ²⁰Be difluoromethyl.

R ²⁰Be trifluoromethyl.

R ²⁰Be methoxymethyl.

R ²⁰Be cyclopropyl.

R ⁶And R ¹²Be C independently of one another _1-6Alkyl, C _1-6Silane alcohol base, C _1-6Alkyl sulphonyl, C _1-6Alkoxy carbonyl, formamyl, N-(C _1-6Alkyl) formamyl and N, N-(C _1-6Alkyl) ₂Formamyl; R wherein ⁶R ¹²Independently of one another on carbon atom by one or more R ¹³Replace.

Therefore, the present invention further provides the compound (as mentioned above) of formula (I), wherein:

R ¹Be hydrogen or fluorine;

R ²Be halogen, cyano group or C _1-6Alkyl;

P is 0 or 1;

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Separately independently on carbon atom by one or more R ⁵Replace arbitrarily; And if said heterocyclic radical contains one-NH-part, then its nitrogen-atoms can be by R ⁶A group replace arbitrarily;

R ⁵Be hydroxyl, N, N-(C _1-6Alkyl) ₂Amino and heterocyclic radical;

R ⁶Be C _1-6Alkyl and C _1-6Alkoxy carbonyl; R wherein ⁶Carbon atom can be alone by one or more R ¹³Replace arbitrarily;

R ¹³Be methoxyl group;

R ¹⁹Be ethyl, sec.-propyl, cyclopropyl methyl, cyclopropyl ethyl or cyclobutyl;

R ²⁰Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl or cyclopropyl;

Or it is at pharmaceutically adoptable salt or its hydrolyzable in vivo ester.

R ¹Be hydrogen or fluorine;

R ²Be halogen, cyano group or C _1-6Alkyl;

P is 0 or 1;

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Separately independently on carbon atom by one or more R ⁵Replace arbitrarily; And if said heterocyclic radical contains one-NH-part, then its nitrogen-atoms can be by R ⁶A group replace arbitrarily; R wherein ⁵Be hydroxyl, and R ⁶Be C _1-6Alkyl;

R ¹⁹Be ethyl, sec.-propyl, cyclopropyl methyl, 1-cyclopropyl ethyl or cyclobutyl;

R ²⁰Be methyl;

Or it is at adoptable salt pharmaceutically, or its hydrolyzable in vivo ester.

R ¹Be hydrogen or fluorine;

R ²Be halogen or C _1-6Alkyl;

R ³And R ⁴Be hydrogen independently of one another, C _1-6Alkyl or carbocylic radical; R wherein ³And R ⁴Separately independently on carbon atom by one or more R ⁵Replace arbitrarily; R wherein ⁵Be hydroxyl;

R ¹⁹Be sec.-propyl;

R ²⁰Be methyl;

Or it is at adoptable salt pharmaceutically, or its hydrolyzable in vivo ester.

R ¹Be hydrogen or fluorine;

R ²Be fluorine, chlorine, cyano group or methyl;

P is 0 or 1;

R ³And R ⁴Be hydrogen independently of one another, methyl, cyclopropyl, the 2-hydroxyethyl, 1-methyl piperidine-4-base, piperidines-3-base, tetrahydropyran-4-base, 1,1-bicyclic oxygen tetramethylene sulfide-3-base, the 2-dimethyl aminoethyl, 1-methyl-2-dimethyl aminoethyl, piperidines-1-base ethyl, 2-morpholino ethyl, 1-(2-methoxy ethyl) piperidin-4-yl, the 2-thiomorpholine is for ethyl, 2-Pyrrolidone-1-base ethyl, and 1-(tert-butoxycarbonyl) piperidines-3-base;

R ²⁰Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, methoxymethyl or cyclopropyl;

Or it is at adoptable salt pharmaceutically, or its hydrolyzable in vivo ester.

R ¹Be hydrogen or fluorine;

R ²Be fluorine, chlorine, cyano group or methyl;

P is 0 or 1;

R ³And R ⁴Be hydrogen independently of one another, methyl, 2-hydroxyethyl, cyclopropyl, tetrahydrofuran (THF)-4-base or tetrahydropyran-4-base;

R ²⁰Be methyl;

Or it is at adoptable salt pharmaceutically, or its hydrolyzable in vivo ester.

R ¹Be hydrogen or fluorine;

R ²Be fluorine, chlorine or methyl;

P is 0 or 1;

R ³And R ⁴Be hydrogen independently of one another, methyl, 2-hydroxyethyl or cyclopropyl;

R ¹⁹Be sec.-propyl, and

R ²⁰Be methyl;

Or it is at adoptable salt pharmaceutically, or its hydrolyzable in vivo ester.

Another aspect of the present invention, it preferred compound be any among the embodiment, or it is at adoptable salt pharmaceutically, or its hydrolyzable in vivo ester.

Another aspect of the present invention is to have provided embodiment 9,13,14,34,51,79,80,81,90 and the compound of 94 Chinese styles (I) or its at pharmaceutically adoptable salt or its hydrolyzable in vivo ester.

The present invention is compound compound or its pharmaceutically adoptable salt in close relations of those and formula (I) preferably.

Another aspect of the present invention provided preparation formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) method (wherein, unless stated otherwise, formula (I) compound of determining comprises:

Method is the reaction of the pyrimidine of formula (II) a):

Wherein L is an interchangeable group; An aniline with formula (III):

Method b) compound with formula (IV) reacts:

A compound with formula V:

Wherein T is oxygen or sulphur; R ^XCan be identical or different, be selected from C _1-6Alkyl; Or

Method c) with a kind of acid-respons of formula (VI):

Or its a kind of activated derivative; A kind of amine with formula (VII)

HNR ³R ⁴

(VII)

Perhaps

Method d) a kind of pyrimidine reaction of the compound of formula (I) and formula (VIII)

A kind of compound with formula (IX):

Wherein Y is a replaceable group;

After this, if desired:

I) compound of formula (I) is converted to the compound of another kind of formula (I);

Ii) remove all blocking groups;

Iii) form a kind of pharmaceutically adoptable salt or hydrolyzable in vivo ester.

L is a replaceable group, suitable option such as halo group or sulfonyloxy, chlorine for example, bromine, sulfonyloxy methyl oxygen base or toluene-4-sulfonyloxy group.

Y also is a replaceable group, suitable option such as halo group or sulfonyloxy, for example bromo, iodo or trifluoromethyl sulfonyloxy group.Preferred Y is the iodo group.

The special reaction condition of above-mentioned reaction is as follows:

Method a) the pyrimidine of formula (II) and the aniline of formula (III) can react under the condition below:

I) there is suitable solvent to exist, as the acetone in the ketone, ethanol in the alcohols or butanols, or toluene in the aromatic hydrocarbons or N-Methyl pyrrolidone at random have suitable acid to exist, as mineral acid, picture hydrochloric acid or sulfuric acid, or organic acid are as citric acid or fumaric acid (or a kind of suitable Lewis acid), the temperature of temperature range from 0 ℃ to backflow, preferred reflux temperature; Or

Ii) the Buchwald reaction conditions of standard (example is seen J.Am.Chem.Soc., 118,7215; J.Am.Chem.Soc., 119,8451; J.Org.Chem., 62,1568 and 6066), for example have acid chloride to exist, suitable solvent is arranged, as aromatic solvent, as toluene, benzene, dimethylbenzene is with a kind of suitable alkali, as a kind of mineral alkali, as lime carbonate, or organic bases, picture uncle-Ding potassium oxide has suitable ligand to exist, as 2,2 '-two (diphenylphosphino)-1,1 '-dinaphthyl, temperature range is 25-80 ℃.

L is that the pyrimidine of the formula (II) of chlorine can prepare by scheme 1:

Scheme 1:

The aniline of formula (III) has commercially available, or searches the preparation method from document, or by being familiar with the method preparation that these professional personnel know.

Method b) compound of the compound of formula (IV) and formula V can react in a kind of suitable solvent, and as N-Methyl pyrrolidone or butanols, temperature range 100-200 ℃, preferred temperature range is 150-170 ℃.This reaction is preferably carried out under the condition that has a kind of suitable alkali to exist, as sodium hydride, and sodium methoxide or salt of wormwood.

The compound of formula V can prepare by scheme 2:

Scheme 2:

The compound of formula (IV) and formula (Va) all has commercially available, or searches the preparation method from document, or by being familiar with the standard method preparation that these professional personnel know.

Method c) under the condition that has a kind of suitable coupler to exist, acid and amine can be coupled together.The available peptide class coupler of being familiar with the standard that these professional personnel know, perhaps use fmoc-2 imidazole and dicyclohexyl-carbodiimide as suitable coupler, at random there is being a kind of alkali to exist, as triethylamine, pyridine, or 2,6-two-alkyl-pyridine, picture 2,6-lutidine or 2,6-two-tert-butyl pyridine.Suitable solvent comprises dimethyl amine, methylene dichloride, benzene, tetrahydrofuran (THF) and dimethylated methylene amine.In temperature range-40～40 ℃, can carry out coupled reaction easily.

Suitable active acid derivant comprises halogenated acid, example hydrochloric acid, and active ester, for example phenyl-pentafluoride base ester.The coupled reaction that such compound and amine take place is to be familiar with this professional people all to know, for example can react when having above-described alkali and suitable solvent to exist.In temperature range-40～40 ℃, can carry out this reaction easily.

The compound of formula (VI) can by method a), method b) or method c) prepare.

The amine of formula (VII) has commercially available, or searches the preparation method from document, or goes preparation by being familiar with the standard method that these professional personnel know.

Method d) amine of the compound of formula (VIII) and formula (IX) can react under the described standard Buchwald condition of method a.

Formula (VIII) compound synthetic as described in the scheme 1.

The compound of formula (IX) has commercially available, or searches the preparation method from document, or goes preparation by being familiar with the standard method that these professional personnel know.

Will recognize that, the aromatics substitution reaction of available standards imports some cyclic substituting group of the present invention, state on the implementation before the whole bag of tricks or after immediately by conventional functional group modification generation some cyclic substituting group of the present invention, these also all are included among the method for the present invention.These reactions and modification comprise, for example, import a substituting group, substituent reduction reaction, substituent alkylated reaction and substituent oxidizing reaction by the aromatics substitution reaction.The reagent of these methods and reaction conditions are that the people who is engaged in chemical work knows.The specific examples of aromatics substitution reaction comprises with concentrated nitric acid and imports nitro, imports an acyl group with an acyl halide and Lewis acid (as aluminum chloride) under Friedel Crafts condition; Under Friedel Crafts condition, import an alkyl with an alkylogen and Lewis acid (as aluminum chloride); And import a halogeno-group.The special case of modification comprises with nickel catalyzator carries out catalytic hydrogenation reaction or handles and heating becomes an amino with a nitroreduction having under the condition of hydrochloric acid with iron; Alkyl thio-base is oxidized to alkyl sulfinic acid base or alkylsulphonic acid base.

Also will recognize, and in more said reactions, need carry out the protection of necessity to the group of any sensitivity in the compound here.Under the situation that needs maybe must be protected, be familiar with this professional people and all know suitable guard method.Can be with conventional blocking group (T.W.Green is seen in explanation, Protective Groups in Organic Synthesis, John Wileyand Sons, 1991) according to the practice of standard.Therefore, if some groups are like this arranged in the reactant, as amino, carbonyl or hydroxyl need these groups are protected in some reactions of so here mentioning.

For amino or alkylamino, suitable protecting group is, for example; an acyl group; the picture alkyloyl, as ethanoyl, an alkoxy carbonyl; as methoxycarbonyl; ethoxy carbonyl or uncle-alkoxy carbonyl, an aryl methoxy carbonyl is as benzyloxycarbonyl; perhaps aroyl is as benzoyl.The protective condition that goes to above-mentioned blocking group need be decided on these protecting groups.Therefore, acyl group for example can remove with a suitable alkali as alkyloyl or alkoxy carbonyl or an aroyl, as alkali metal hydroxide, as lithium hydroxide or sodium hydroxide.With a suitable acid, hydrochloric acid for example, sulfuric acid; phosphoric acid or trifluoroacetic acid are handled can remove acyl group, as uncle-butoxy carbonyl, carries out hydrogenation reaction with catalyzer such as palladium carbon; perhaps use a kind of Lewis acid, handle as three (trifluoroacetic acid) boron and can remove the aryl methoxy carbonyl, as benzyloxycarbonyl.A kind of suitable alternative protecting group to initial amino group is, for example, phthaloyl can be used a kind of alkylamine, and for example dimethylaminopropyl amine is perhaps handled with diamine and removed phthaloyl.

A kind of suitable protecting group of hydroxyl is an acyl group, for example a kind of alkyloyl, and as ethanoyl, a kind of aroyl, as benzoyl, perhaps a kind of arylmethyl is as benzyl.The protective condition that goes to above-mentioned blocking group need be decided on these protecting groups.Therefore, acyl group for example can be with a suitable alkali as alkyloyl or aroyl, as alkali metal hydroxide, is hydrolyzed as lithium hydroxide or sodium hydroxide and removes.In addition, an arylmethyl can remove with catalysis (palladium carbon) hydrogenation reaction as benzyl.

The appropriate protection base of carbonyl comprises a kind of esterification base, for example methyl or ethyl, and these esterification bases can be with alkali as removing with sodium hydroxide hydrolysis; Perhaps a kind of tert-butyl group can remove this tert-butyl group with this organic acid of trifluoroacetic acid; Perhaps a kind of benzyl group is made catalyzer with palladium carbon and is carried out catalytic hydrogenation reaction and can remove this benzyl group.

These protecting groups can be removed in any stage easily of synthetic with the ordinary method that those skilled in the art are familiar with.

Such as before this definition, the defined compound of the present invention has the inhibition of cell proliferation activity, anti-tumor activity for example believes that these compounds have plain dependent kinase of cycle (CDK) and suppress active.Can assess these character with following method:

Measure

Meaning is released in abbreviation:

The HEPES:N-[2-hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid]

DTT: dithiothreitol (DTT)

PMSF: phenylmethylsulfonyl fluoride

Compound with the vitro kinase analytical method 96 hole form plates measure with flicker approximate analysis method (SPA derives from Amersham) [γ-33-P]-Triphosaden of being combined in the test substrate (the GST-retinoblastoma protein, GST-Rb).Put into generation in each hole and survey compound (being diluted to correct concentration), in the contrast hole or put the contrast of roscovitine, or put dimethyl sulfoxide (DMSO) as positive control as inhibition with dimethyl sulfoxide (DMSO) and water.

Add about partially purified enzyme of 0.2 μ l CDK2/Cyclin E (consumption is decided because of enzymic activity) of cultivating the damping fluid dilution with 25 μ l in each hole, adding 20 μ l GST-Rb/ATP/ATP33 mixed solutions then (cultivates in the damping fluid and contains 0.5 μ g GST-Rb, 0.2 μ M ATP and 0.14 μ Ci[γ-33-P]-Triphosaden), the mixture that forms is shaken gently, at room temperature cultivated then 60 minutes.

In each hole, add 150 μ l stop solutions (containing 0.8mg/ hole albumin A-PVT SPA pearl (Amersham)) then, the 20pM/ hole resists-Thiadiazolidine isomerase, the pH that rabbit igg (deriving from molecular probe), 61mM EDTA and 50mM contain 0.05% sodiumazide is 7.5 HEPES.

, placed 2 hours the sealing of form plate with Topseal-S shrouding device, with 2500rpm, 1124g was with plate rotation 5 minutes.Read the result, 30 seconds of every hole.

It is 7.5 HEPES that the cultivation damping fluid that is used to dilute enzyme and effect mixture contains 50mM pH, 10mM MnCl ₂, 1mM DTT, 100 μ M vanadic acid sodiums, 100 μ M Sodium Fluorides, 10mM Sodium Glycerophosphate, BSA (1mg/ml, final concentration).

Substrate to be measured

Part retinoblastoma protein (Science 1987 Mar13 have only been used in this detection; 235 (4794): 1394-1399; Lee W.H., Bookstein R., Hong F., Young L.J., Shew J.Y., Lee E.Y.), fusion is in the GST fragment.Be carried out to the polymerase chain reaction (PCR) of the amino acid 379-928 (deriving from retinoblastoma plasmid ATCCpLRbRNL) of retinocytoma genes encoding, sequence clone is fused (Smith D.B.andJohnson in the carrier to pGEx, K.S.Gene 67,31 (1988); Wherein contain a tac promotor with abduction delivering, built-in lac I ^qGene is used for any intestinal bacteria (E.coli) host, and zymoplasm splitted coding region-derive from Pharmacia Biotech), with this amplification amino acid 792-928.Again with this sequence clone in pGEx2T.

The retinoblastoma 792-928 sequence that will so obtain with the derivational expression method of standard is expressed in the intestinal bacteria (BL21 (DE3) pLysS cell), as follows purifying.

Tremellose culture of Escherichia coli is suspended in (50mM Pehanorm (Tris) in the NETN damping fluid of 10ml/g, pH7.5,120mM sodium-chlor, the 1mM ethylenediamine tetraacetic acid (EDTA), 0.5%v/v NP-40,1mM PMSF, 1 μ g/ml leupeptin, 1 μ g/ml Trypsin inhibitor,Trasylol and 1 μ g/ml Pepstatin), every 100ml homogenate was through ultrasonic disruption 2 * 45 seconds.After centrifugal, supernatant is installed in the 10ml glutathione agarose gel column (Pharmacia Biotech, Herts, UK), with the flushing of NETN damping fluid.With after kinase buffer liquid (50ml HEPES pH7.5,10mM magnesium chloride, 1mM DTT, 1mM PMSF, 1 μ g/ml leupeptin, 1 μ g/ml Trypsin inhibitor,Trasylol and the 1 μ g/ml Pepstatin) washing protein being eluted with 50mM reductive gsh kinase buffer liquid.The part that will contain GST-Rb (792-927) collects, and spends the night with the dialysis of kinase buffer liquid.Final product sodium laurylsulfonate polyacrylamide gel (SDS-PAGE) electrophoretic analysis, and use 8-16%Tris-glycine gels (Novex, SanDiego, USA).

CDK2 and Cyclin E

Do template with HeLa cell and activated T cells mRNA, the readable open fragment of CDK2 and Cyclin E is separated, be cloned into insect expression vector pVL1393 and go up and (to derive from Invitrogen 1955 catalog number (Cat.No.)s: V1392-20) with the reverse transcriptase PCR method.Baculogold virus multiplicity of infection technology with a kind of standard is expressed in (fall army worm ovary tissue cell, the market is on sale) in the insect SF21 clone in pairs with CDK2 and Cyclin E then.

The example product of Cyclin E/CDK2

The virus that following Example provides every kind of Cyclin E and CDK2 all double infection the (details of TC100+10%FBS (TCS)+0.2%Pluronic) CyclinE/CDK2 product in the SF21 cell of MOI 3.

With being grown in a SF21 cell (2.33 * 10 in the bottle that rolls ⁶The rolling bottle of 10 500ml of the inoculation of cell/ml), inoculation 0.2 * 10 in every bottle ⁶Cell/ml.The bottle that rolls placed on 28 ℃ the rolling frame and inoculate.

3 days (72 hours) back meter cell count, the mean number of two bottle inner cells is 1.86 * 10 ⁶Cell/ml (99% viable cell).Then culture is done double infection with virus, MOI 3 of every kind of virus.

Before in being added to culture, going virus is mixed, again culture is put back on 28 ℃ the rolling frame.

Infect back 2 days (48 hours) results 5L culture.The total cellular score of results is 1.58 * 10 ⁶Cell/ml (99% viable cell).(HeraeusOmnifuge 2.0 RS 250ml lots.), discarded supernatant in 30 minutes with the 2500rpm rotation in 4 ℃ with cell.

The part copurification of CDK2 and Cyclin E

The SF21 cell is suspended from (50mM Tris pH 8.2,10mMMgCl in the dissolving damping fluid again ₂, 1mM DTT, 10mM glycerophosphate, 0.1mM ortho-vanadate, 0.1mM Sodium Fluoride, 1mM PMSF, 1 μ g/ml leupeptin and 1 μ g/ml Trypsin inhibitor,Trasylol), the Dounce homogenizer homogenate of usefulness 10ml 2 minutes.After centrifugal supernatant installed in Poros HQ/M 1.4/100 anion-exchange resin column (PE Biosystems, Hertford, UK).CDK2 and Cyclin E elute together, beginning gradient 0-1M NaCl (the dissolving damping fluid deducts proteinase inhibitor), and the amount of elutriant is the volume of 20 posts.With anti--CDK2 and anti--(SantaCruz Biotechnology, California US) detect eluate with Western blot method Cyclin E antibody.

Evaluation can be by similar conceptual design to the inhibiting detection of CDK1 and CDK4.CDK2 (the EMBL registration number is X62071) can be same with (seeing EMBL registration number M73812) with Cyclin A or Cyclin E.The more detailed content of these detections is included among the PCT international publication No.WO99/21845, and the content of relevant biological chemistry and biological assessment part is listed in herein as a reference.

Though the pharmaceutical properties of formula (I) compound changes along with the change of structure, formula (I) total active available IC that compound possessed ₅₀Concentration or illustrate to the dosage in the 1nM scope at 250 μ M.

Carry out vitro test with above-mentioned condition, the inhibition of CDK2 activity is IC in the example 28 ₅₀=0.003 μ M.

The compounds of this invention active available standards method assessment in vivo for example, is measured the inhibition of cell growth and is estimated cytotoxicity.

The available following method of the inhibition of cell growth detects: with a kind of fluorescence dye thiocyanic acid amine B (SRB) of protein staining that makes with cell dyeing, thereby draw the estimated value (seeing Boyd, M.R. (1989) Status of the NCI preclinicalantitumour drug discovery screen.Prin.Prac Oncol 10:1-12) of the protein (being cell) in the pothole.The cytostatic method that detects is described in detail in detail below:

On 96 hole plates, add suitable substratum 100ml, cell is placed in one; To MCF-7, SK-UT-1B and SK-UT-1 can use the Eagle substratum of Dulbecco ' s modification.Cell is put into substratum spend the night, add the compound as inhibitor of various concentration then, peak concentration is 1%DMSO (v/v).Control board is detected, and the data that obtain are the value of cell before administration.Can be with cell at 37 ℃ of (5%CO ₂) cultivated 3 days.

To the 3rd day add TCA at last onboard, ultimate density is 16% (v/v).Plate was cultivated 1 hour down at 4 ℃, discarded supernatant, wash test plate (panel) with tap water.Dry back was adding 100ml SRB dyestuff (1% acetic acid solution of 0.4%SRB) in 30 minutes under 37 ℃ the temperature.Get rid of unnecessary SRB, with 1% acetate washing test plate (panel).The SRB that is combined on the albumen is dissolved among the Tris of 10mM pH 7.5, and shake is 30 minutes under the room temperature.Read optical density value (ODs) at the 540nm place, mark cell growth with inhibitor concentration-adsorptive capacity semilogarithmic paper and produce 50% inhibitor concentration that suppresses.Make optical density value be reduced to when being lower than on-test the optical density value of cell on the test plate (panel), the compound concentration of this moment is the toxicity value.

Compound of the present invention when testing with SRB, typical half-inhibition concentration value (IC ₅₀) be 1mM～1nM.

A kind of oral dosage of compound can be measured with following method.

Provide to this test sxemiquantitative the numerical value that some time point compound concentrations are reached in the blood.The available data comprise the Cmax (maximum concentration that reaches) and the AUC (area under haemoconcentration/time curve) of this compound.Such test is high-throughout, can obtain the level of every kind of compound in the blood on the basis of oral dosage, because dosage is standardized, test result can directly compare mutually.

High-throughput blood levels test-rat

Unite and use eddy current mixing, ultrasonication and high speed shear hybrid system that compound in 6 is mixed into a kind of (well-bedded) " cocktail " preparation with the propylene glycol.Said preparation is made up of 5 kinds of test compounds (1mg/ml) and a kind of standard substance (0.5mg/ml).The preparation that generates is a kind of solution or a kind of stable (〉=some hrs) suspension.

Said preparation is thrown to 2 male rats (body weight 170～250 gram, dosage 2ml/kg), before the dispensing rat by drinking-water behind fasting≤16 hour (～10ml/kg).Giving the dosage of test group animal is 2mg/kg, and that give standard group is 1mg/kg.

Blood sample is taked by the tail vein of animal in dispensing back 0.5,1,2 and 4 hours, and last blood sample picks up from back 6 hours of dispensing.

Blood sample is centrifugal, take out serum and analyze.Two parts of serum before analyzing being put a certain preset time merge.

With suppressing blank serum pref concentration is the standard serum of the demarcation that contains all 6 kinds of compounds of 0.3ng/ml～3 μ g/ml.With the acetonitrile precipitation of two volumes, then centrifugal extraction sample and standard serum.Then the supernatant water that generates is cooked 10 times of dilutions.

Sample is analyzed with gas chromatography/mass spectrometry (LC/MS-MS), gained concentration is used for measuring Cmax (the compound highest level that detects of a given compound, μ g/ml), AUC 0-6hr (area under curve, μ g/hr/ml) and tmax (record the time of compound highest level, hr), to determine oral dosage.

High-throughput blood levels test-mouse

Can replace rat to do above-mentioned test with mouse, but need make following change:

As giving 10 male mices dispensings to rat dispensing, but mouse non-fasting and hello water in advance before the test.And, be that mouse is put to death blood sampling, 2 mouse of each time point.

In the above-mentioned test, embodiment 25, AP rat (as follows), and normalization dosage is 1mg/kg, and Cmax is 0.3995 μ M, and AUC is 0.8295 μ M.h.AP mouse (as follows), and normalization dosage also is 1mg/kg, and Cmax is 0.68 μ M, and AUC is 1.50 μ M.h.

Notice that used rat is Alderley Park (AP) rat in the above-mentioned experiment.The AP rat is the rat that Wistar breeds, and eighties of last century the forties is introduced into ICI's by Porton Down from Wistar.This strain is introduced a fine variety cultivation again at Sprague Dawleys, has kept the family of a nearly system since nineteen fifty-nine, the rat called after Alpk..APfSD rat of this family.

The mouse of using in the above-mentioned experiment is the AP mouse.The AP mouse is to breed and come from a kind of commercially available kind Schoefields in 1956.This strain is introduced a fine variety the mouse of cultivation in CD-1 CharlesRivers (supplier) outbreed again, and has kept the family of a nearly system, the mouse called after Alpk..APfCD-1 mouse of this family from then on.

Further, the invention provides a kind of drug component, this component comprises the pyrimidine derivatives of formula (I), or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo, as defined before this, with a kind of pharmaceutically adoptable diluent or carrier.

This drug component can be made and be suitable for oral formulation, for example tablet or capsule; The formulation (comprising intravenous injection, subcutaneous injection, intramuscular injection, intravascular injection or perfusion) that is used for the outer injection of digestive tube, as sterile solution, suspension or emulsion; The formulation of local application is as ointment or sweet cream; Or rectal application, as suppository.

In a word, said components can be with conventional vehicle by conventional method preparation.

Under the normal circumstances, with 5-5000mg/m ²The single dose of body surface area is thrown formula (I) compound to warm-blooded animal, and the amount of promptly about 0.1～100mg/kg body weight so under normal circumstances is the dosage that can play result of treatment.A kind of single dose form as a tablet or capsule, contains the 1-250mg activeconstituents usually.Perhaps per daily dose is in the 1-50mg/kg scope.Yet the per daily dose fibrous root adjusts according to the severity of the different and disease of handling of handled host's difference, route of administration.Correspondingly, the medical practitioner that can treat any special case can be judged the suitableeest dosage.

By to further analysis of the present invention, defined before this a kind of formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) is used in the methods of treatment of handling human or animal body.

We find, (or it is at adoptable salt pharmaceutically for the defined compound of the present invention, or its ester of hydrolysis in vivo) be effective cell cycle cycle inhibitor (cellular antiproliferative agent), this specific character it is believed that it is to suppress active from their CDK to inherit.Correspondingly, expect that compound of the present invention is useful separately or partly in treatment disease or processing aspect the illness of CDK enzyme system initiation, that is, this compound is used in and produces a kind of CDK restraining effect in the warm-blooded animal that needs this treatment.So, to suppress with the CDK enzyme be that the propagation of migrating cell of characteristics provides a kind of method to compound of the present invention for treatment, this compound can be used to produce a kind of antiproliferative effect, and this proliferation function be cause because of CDKs or the part cause because of it.A kind of like this compound of the present invention is waited in expectation has anti-tumor activity widely, because human many cancers all relate to CDKs, and such as leukemia and mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, prostate cancer, bladder cancer, carcinoma of the pancreas and ovarian cancer.So the compound of the present invention that just waits in expectation can have the activity of anti-these tumours.Expect also that in addition compound of the present invention can be to leukemia, malignant lymphoma and some parenchymas, as the cancer knurl, and the sarcoma as liver, kidney, prostate gland and pancreas has antitumour activity in the tissue.Especially, expect that these compounds of the present invention can delay the growth of parenchyma of former and recurrence, as colorectal carcinoma, mammary cancer, prostate cancer, lung cancer and skin carcinoma.More particularly, expect these compounds of the present invention, perhaps pharmaceutically adoptable salt, or its in vivo the ester of hydrolysis can suppress the growth of parenchyma of those former and recurrence, these tumours and CDKs are closely related, particularly those its growths and diffusion obviously depend on the tumour of CDKs, comprise some colorectal carcinoma, mammary cancer, prostate cancer, lung cancer, carcinoma vulvae and skin carcinoma.

Further, can expect that the compound among the present invention has the cell-proliferation activity of anti-wider scope other diseases, comprise leukemia, fibroplasia and differentiation infringement, psoriasis, rheumatic arthritis, Kaposi, vascular tumor, ephrosis, sebaceous cyst, atherosclerosis.Aortic stenosis, autoimmune disease, acute and chronic inflammation, orthopaedics is sick and with the outgrowth ophthalmic diseases of retinal vessel.

According to this respect, defined before this formula provided by the invention (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) can be used as medicine; Defined before this formula (I) compound that is used for producing medicine (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) can be used to produce a kind of cell cycle inhibition that is used for the inhibition of cell proliferation of warm-blooded animal (as the people).Particularly, by suppressing CDK2 and CDK4, especially CDK2, preventing to enter or restraining effect by the S phase, and suppress CDK1 to prevent to enter or restraining effect by the M phase.

According to this respect, the present invention further also provides a kind of defined before this formula (I) compound that is used for producing medicine, and (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) is used for the treatment of cancer (parenchyma and leukemia), fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel, particularly treats cancer.

According to this respect, produce the method for cell cycle inhibition (anti-cell hyperplasia) in warm-blooded animal (as the people) body that the present invention further also provides in this treatment of needs, throw the above-claimed cpd of significant quantity promptly directly for said animal.Particularly by suppressing CDK2 and CDK4, especially CDK2, preventing to enter or restraining effect by the S phase, and suppress CDK1 to prevent to enter or restraining effect by the M phase.

According to this respect, produce the method for cell cycle inhibition (anti-cell hyperplasia) in warm-blooded animal (as the people) body that the present invention further also provides in this treatment of needs, promptly give defined before this formula (I) compound that said animal throws significant quantity (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).Particularly by suppressing CDK2 and CDK4, especially CDK2, preventing to enter or restraining effect by the S phase, and suppress CDK1 to prevent to enter or restraining effect by the M phase.

According to this respect, the method for the following disease of treatment in the warm-blooded animal (as the people) that the present invention further also provides in this treatment of needs: cancer (parenchyma and leukemia), fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel.Promptly give defined before this formula (I) compound that said animal throws significant quantity (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).

The cancer that particularly provides a kind of method to treat warm-blooded animal (as the people) is thrown defined before this formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) of significant quantity when they need this treatment.

Furtherly, the present invention also provides a kind of drug component, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier composition.This component can be used to produce cell and suppresses (anti-cell hyperplasia) effect in warm-blooded animal (as the people) body.

Furtherly, the present invention also provides a kind of drug component, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier composition.This component can be used to treat warm-blooded animal (as the people's) cancer (parenchyma and leukemia), fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel.

Furtherly, the present invention also provides a kind of drug component, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier composition.This component can be used to treat warm-blooded animal (as the people's) cancer.

Therefore, according to this respect, the present invention further also provides a kind of defined before this formula (I) compound that is used as medicine (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).

Furtherly, the present invention also provides a kind of use defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) in producing a kind of drug component before this, is used to produce cell cycle inhibition.

Furtherly, the present invention also provides a kind of use defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) in producing a kind of drug component before this, is used to produce the anti-cell proliferative effect.

Furtherly, the present invention also provides a kind of use defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) in producing a kind of drug component before this, is used to produce the CDK2 restraining effect.

Furtherly, the present invention also provides a kind of use defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) in producing a kind of drug component before this, is used for the treatment of cancer.

Furtherly, the present invention also provides a kind of use defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) in producing a kind of drug component before this, be used for the treatment of leukemia or lymph sample malignant diseases or mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, bladder cancer, carcinoma of the pancreas, carcinoma vulvae, skin carcinoma or ovarian cancer.

According to this respect, the present invention further also provide a kind of use before this in producing a kind of drug component defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo), be used for the treatment of cancer, fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel.

Furtherly, the present invention also provides a kind of method that produces cell cycle inhibition in the warm-blooded animal of needs treatment, promptly give defined before this formula (I) compound that said animal throws significant quantity (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).

Furtherly, the present invention also provides a kind of and in the warm-blooded animal of needs treatment CDK2 has been produced inhibiting method, promptly give defined before this formula (I) compound that said animal throws significant quantity (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).

Furtherly, the present invention also provides a kind of its method for cancer for the treatment of in the warm-blooded animal of needs treatment, promptly give defined before this formula (I) compound that said animal throws significant quantity (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).

Furtherly, the present invention also provides a kind of method for the treatment of its following disease in the warm-blooded animal of needs treatment, and these diseases comprise leukemia or lymph sample malignant diseases or mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, bladder cancer, carcinoma of the pancreas, carcinoma vulvae, skin carcinoma or ovarian cancer.This method is exactly to throw defined before this formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) of significant quantity to said animal.

Furtherly, the present invention also provides a kind of method for the treatment of its following disease in the warm-blooded animal of needs treatment, and these diseases comprise cancer, fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel.This method is exactly to throw defined before this formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) of significant quantity to said animal.

Furtherly, the present invention also provides a kind of drug component, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.

Furtherly, the present invention also provides a kind of drug component that is used for as medicine, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.

Furtherly, the present invention also provides a kind of drug component that is used for producing a kind of cell cycle inhibition, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.

Furtherly, the present invention also provides a kind of drug component that is used for producing a kind of anti-cell proliferative effect, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.

Furtherly, the present invention also provides a kind of inhibiting drug component of a kind of CDK2 that is used for producing, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.

Furtherly, the present invention also provides a kind of drug component that is used for treating cancer, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.

Furtherly, the present invention also provides a kind of drug component, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.This component can be used to treat leukemia or lymph sample malignant diseases or mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, bladder cancer, carcinoma of the pancreas, carcinoma vulvae, skin carcinoma or ovarian cancer.

Furtherly, the present invention also provides a kind of drug component, this component thus before defined formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of pharmaceutically adoptable diluent or carrier constitute.This component can be used to treat cancer, fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel.

Furtherly, the present invention also provides the defined before this formula of a kind of usefulness (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) to produce a kind of cell cycle inhibition.

Furtherly, the present invention also provides the defined before this formula of a kind of usefulness (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) to produce the outgrowth effect of a kind of anti-cell.

Furtherly, the present invention also provides the defined before this formula of a kind of usefulness (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) to produce a kind of restraining effect to CDK2.

Furtherly, the present invention also provides the defined before this formula of a kind of usefulness (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) treatment cancer.

Furtherly, the present invention also provides the defined before this formula of a kind of usefulness (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) treatment leukemia or lymph sample malignant diseases or mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, bladder cancer, carcinoma of the pancreas, carcinoma vulvae, skin carcinoma or ovarian cancer.

According to this respect, the present invention further also provides the defined before this formula of a kind of use (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo), be used for the treatment of cancer, fibroplasia and branch voltinism disease, psoriasis, rheumatic arthritis, the rich Ji of card sarcoma, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, stricture of artery, autoimmune disorder, acute and chronic inflammation, orthopaedics is sick and with the outgrowth illness in eye of retinal vessel.

By suppress the requisite S-phase start active (for example starting CDK2) stop cell to enter the DNA building-up process to avoid aspect the special drug toxicity of cycle at the normal somatocyte of protection also be of great use.The inhibition of CDK2 or CDK4 can prevent that normal cell from entering the cell cycle, may be limited to the S-phase, the toxicity of the period specific medicament that G2-phase or m period are had an effect.This protection can prevent the alopecia relevant with these medicaments usually.

Therefore, the present invention also provides a kind of defined before this formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) to be used as cytoprotective furtherly.

Therefore, the present invention also provides a kind of defined before this formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) to be used for preventing the alopecia that causes because with medicament treats pernicious symptom furtherly.

Treatment can cause the medicament of the pernicious symptom of alopecia to comprise alkylating agent, as ifosfamide and ifosfamide; Antimetabolite, as methotrexate, 5-fluodeoxyuridine, gemcitabine and cytosine arabinoside; Vinca alkaloids and analogue, as vincristine(VCR), vinealeucoblastine(VLB), vindesine, vinorelbine; Taxanes such as paclitaxel and docetaxel; Topoisomerase I inhibitor is as irintotecan and topotecan; Cytotoxic antibiotics, as Ah's Mycinomycin II, many promises mycin, mitoxantrone, actinomycin D and mitomycin; And other classes, as etoposide and Vitamin-A Acid.

On the other hand, formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) can be co-administered with one or more above-listed medicaments.Formula (I) compound can be done the dispensing of whole body dispensing or non-whole body, for example local application in this case.

Therefore, another one characteristics of the present invention are to be warm-blooded animal (for example people) provides a kind of anti-alopecia when treating one or more malignant diseases method in medicament, promptly give formula (I) compound that said animal throws significant quantity (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo).

Another one characteristics of the present invention are to be warm-blooded animal (for example people) provides a kind of anti-alopecia when treating one or more malignant diseases method in medicament, promptly (or it is at adoptable salt pharmaceutically at formula (I) compound of throwing significant quantity for said animal, or its ester of hydrolysis in vivo) time, throws the said medicament of significant quantity simultaneously, successively or respectively.

Press furthermore, the present invention also provides a kind of drug component of anti-alopecia when with medicament treatment malignant diseases, this component is by formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo), and said medicament and pharmaceutically adoptable diluent or carrier constitute.

By furthermore, the present invention also provides one group of medicine suit, comprise formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) and a kind of that when treating malignant diseases, use, notify the medicament that causes alopecia.

Press furthermore, the present invention also provides one group of medicine suit, comprising:

A) a kind of formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo), with the fixed dosage form as first module;

B) a kind of that use during malignant diseases in treatment, notify the medicament that causes alopecia, with the fixed dosage form as Unit second; With

C) place the first and second unitary packing boxes.

Another one characteristics of the present invention are to use this medicine that is made of formula (I) compound (or it is at adoptable salt pharmaceutically, or its ester of hydrolysis in vivo) to prevent to take place alopecia when with medicament treatment malignant diseases.

Furthermore, the present invention proposes a kind of combinational therapeutic methods with the prevention alopecia, promptly (or it is at adoptable salt pharmaceutically at formula (I) compound of throwing significant quantity with a kind of pharmaceutically adoptable diluent or carrier, or its ester of hydrolysis in vivo) time, throws a kind of medicament of the significant quantity for warm-blooded animal (for example people) treatment malignant diseases simultaneously, successively or respectively.

As above said, for specific cell proliferative diseases, the drug dose that is used as treatment or prevention need be decided according to the severity of the object of being treated, route of administration and the disease that will treat.The unitary dose scope of imagination is 1-100mg/kg, and preferred unitary dose is 1-50mg/kg.

Defined before this CDK suppresses activity and can be used as single treatment, or is used in except that compound of the present invention in other one or more materials and/or the therapy.This combinational therapeutic methods can be by simultaneously, throw various drug components successively or respectively carries out.In the medical science oncology, with the treatment of different modes co-administered be very normal thing in a cancer patients.In the medical science oncology, except that defined cell cycle before this suppresses the therapy, other therapies of this combination therapy can be: surgical operation therapy, radiotherapy or chemotherapy.This chemotherapy comprises three kinds of main treatment contents:

(i) other cell cycle inhibitors of having an effect with the identical or different mechanism of those cell cycle inhibitors of preceding definition therewith;

(ii) cytostatics, for example estrogen antagonist is (as tamoxifen, toremifene, raloxifene, droloxifene, iodoxyfene), progestogen (as megestrol), the aromatics enzyme inhibitors (as anastrozole, letrazole, vorazole, exemestane), antiprogestin, and androgen antagonist (as Sch-13521, the nitro isobutylamine, bicalutamide, cyproterone acetate), GnRF stimulant and antagonist are (as goserelin acetate, luprolide), testosterone 5 α-dihydro reductase inhibitor (as finasteride), anti-invasion agent (for example inhibitors of metalloproteinase, as marimastat and urokinase proplasmin activated receptor depressant of functions) and somatomedin depressant of functions are (as somatomedin, comprise PDGF and pHGF, these inhibitor comprise growth factor antibodies, growth factor receptor antibody, tyrosine kinase inhibitor and serine/threonine kinase inhibitor); With

Anti-hyperplasia/the antitumor drug and the combination drug of the two, for example antimetabolite (as the methotrexate of anti-folate, the 5 FU 5 fluorouracil of fluorine miazines, purine and neplanocin, cytosine arabinoside) that (iii) are used for the medical science oncology; Anti-tumour antibody (for example the Zorubicin of anthracene nucleus class, many promises mycin, epirubicin and darubicin, Mitomycin-C, actinomycin, Plicamycin); Platinum derivatives (as the cis cisplatin, the carbon cisplatin); Alkylating agent (mustargen for example, melphalan, Chlorambucil, busulfan, endoxan, ifosfamide, nitrosourea, thiophene is for group); Anti-nuclear fission agent (taxol of the vincristine(VCR) of vinca alkaloids and Japanese yew phenols for example, taxotere); The topoisomerase inhibitor (for example etoposide of epipodophyllotoxin class and teniposide, the pyridine of amine benzene bifurcation, topotecan).Press this respect, the present invention also provides a kind of medicine, and preceding thus defined formula (I) compound of this medicine and defined before this another antitumorigenic substance constitute, acting in conjunction treatment cancer.

Except being used as medicine, formula (I) compound and pharmaceutically adoptable salt thereof also can be used as instrument pharmaceutically, using laboratory animal, for example cat, dog, rabbit, monkey, rat and mouse experimentize when seeking new medicine, develop and make external and body in the active restraining effect of experimental standard aspect cell cycle estimate.

Also use the drug component of the compound of the invention described above herein, program, method is used and the drug manufacture characteristics displaced and preferred mode.

Embodiment

Below will the present invention be described with non-restrictive example, among these embodiment, unless specialize, otherwise:

(i) temperature with ceslius scale (℃) expression, the operation at room temperature or at ambient temperature carry out promptly 18～25 ℃;

(ii) organic solution is passed through anhydrous magnesium sulfate drying; The evaporation of solvent with rotatory evaporator bathe 60 ℃ of decompressions down of temperature (600～4000Pa, 4.5～30mmHg) carry out;

(iii) chromatography refers to use the flash-point chromatography of silicagel column; Thin-layer chromatographic analysis (TLC) carries out with silica-gel plate;

(iv) in general, carry out TLC after the reaction process, only provide the reaction times for explanation;

(v) end product has complete proton NMR spectrum (NMR) and/or mass spectrum data;

(vi) can be by continuously reacting the product that obtains for those, output (yield) data only are explanation usefulness, and also nonessential; More if desired product can repeat preparation;

(vii) to main characteristic proton, if provide the NMR data, be interior mark then with tetramethylsilane (TMS) with δ-value form, except as otherwise noted, otherwise with full deuterium dimethyl sulfoxide (DMSO) (DMSO-d ₆) make solvent, detect at 300MHz, provide relative hundred (ppm) numerical value very much;

(viii) chemical symbol is represented their common meanings; Also use SI units and symbol;

(ix) solvent ratio is represented with volume ratio (v/v); With

(x) use forthright probe, under chemical ioni zation (CI) pattern, do mass spectroscopy with the electron energy of 70 electron-volts (eV); The ionization journey is subjected to the influence of electronic impact (EI), fast atom bombardment(FAB) (FAB) or electrospray (ESP); Provide the value of m/z; Usually only report the ion that can provide its parent's quality; Outside the person, a large amount of ions of being quoted are (MH) unless otherwise indicated ⁺

(xi) unless otherwise indicated outside the person, compound all contains the carbon atom of an asymmetric replacement and/or still undissolved sulphur atom;

(xii) if the similar compound of certain compound that synthetic compound had been described in certain example before being described as being, the mmole consumption of the compound that then used amount equals to describe in the previous example;

(xvi) use following shortenings:

The THF tetrahydrofuran (THF)

DMF N, N-dimethylated methylene amine

The EtOAc ethyl acetate

MeOH methyl alcohol

The ether ether

EtOH ethanol

HATU O-(7-azepine benzo triazol-1-yl)-1,1-3,3-tetramethyl-alditol hexafluoro

Phosphoric acid ester

The DCM methylene dichloride

The cPr cyclopropyl

The RPHPLC RPLC

HBTU O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-alditol phosphofluoric acid ester

DIPEA N, the N-diisopropylethylamine

DPPF 1,1 '-two (diphenylphosphino) ferrocene

Pd ₂(dba) ₃Two (dibenzyl subunit acetone) palladium

The TEA triethylamine

DMFDMA N, the dinethylformamide dimethyl-acetal

The DMSO dimethyl sulfoxide (DMSO)

XANTPHOS 9,9-dimethyl-4, two (diphenylphosphino) xanthenes of 5-

Embodiment 1

4-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-3, N, N-trimethylammonium-benzene Methane amide

Under logical nitrogen condition in advance with 4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 18,0.15g, 0.69mmol), Pd (OAc) ₂(10mg, 0.02mmol), XANTPHOS (36mg, 0.06mmol), cesium carbonate (0.45g, 1.38mmol) with 4-bromo-3-methyl-N, N-dimethyl-benzamide (intermediate 4 of GB2276160; 0.9mmol, 218mg) be blended in the 5ml two  alkane, the logical nitrogen heating of reactant 24 hours.Reactant is poured directly on the silicagel column, uses CDM, 10%MeOH/DCM finally uses the 2.5%MeOH/DCM wash-out.Obtain the foam (81%) of 0.21g white.

NMR(400.132MHz，CDCl ₃)8.35(d，1H)，8.02(d，1H)，7.38(s，1H)，7.33(s，1H)，7.28(d，1H)，6.93(d，1H)，6.86(s，1H)，5.58(septet，1H)，3.07(s，6H)，2.57(s，3H)，2.35(s，3H)，1.44(d，6H)；m/z 379.

Embodiment 2-20

Following compounds is pressed the method for embodiment 1 with identical macro preparation, uses suitable amide parent material (if no commercially available preparation method that then provides) and 4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 18).

Ex	R	R1	R2	R3	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	Nucleus magnetic resonance	m/z	Amide	2	H	F	Me	Me	(400.132MHz，CDCl ₃) 8.39 (d, 1H), 7.76 (d, 1H), 7.39 (s, 1H), 7.36 (t, 2H), 7.18 (d, 1H), 6.99 (d, 1H), 5.64 (septet, 1H), 3.12 (s, 3H), 2.97 (s, 3H), 2.60 (s, 3H), 1.55 (d, 6H)	383	Method 8
3	F	H	Me	Me	(400.132MHz，CDCl ₃) 8.49 (t, 1H), 8.40 (d, 1H), 7.39 (s, 1H), 7.31 (s, 1H), 7.27-7.22 (m, 3H), 6.99 (d, 1H), 5.60 (septet, 1H), 3.07 (s, 6H), 2.60 (s, 3H), 1.54 (d, 6H)	383	Method 63	2	H	F	Me	Me		383	Method 8
3	F	H	Me	Me		383	Method 63	4	H	Cl	Me	Me	(400.132MHz，CDCl ₃) 8.39 (d, 1H), 7.82 (s, 1H), 7.45 (d, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 7.26 (d, 1H), 6.97 (d, 1H), 5.59 (septet, 1H), 3.14 (s, 3H), 2.90 (s, 3H), 2.60 (s, 3H), 1.54 (d, 6H)	399	Method 11
5	H	F	H	cPr	(400.132MHz，CDCl ₃) 8.41 (d, 1H), 8.07 (t, 1H), 7.84 (d, 1H), 7.51 (s, 1H), 7.40 (s, 1H), 7.21 (d, 1H), 7.01 (d, 1H), 6.77 (d, 1H), 5.63 (septet, 1H), 2.98-2.90 (m, 1H), 2.60 (s, 3H), 1.56 (d, 6H), 0.87 (q, 2H), 0.65-0.61 (m, 2H)	395	Method 10	4	H	Cl	Me	Me		399	Method 11
5	H	F	H	cPr		395	Method 10	6	H	Me	Me	Me	(400.132MHz，CDCl ₃) 7.83 (d, 1H), 7.03 (d, 1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 6.61 (d, 1H), 6.39 (d, 1H), 5.08 (septet, 1H), 2.60 (s, 3H), 2.34 (s, 3H), 2.05 (s, 3H), 1.77 (s, 3H), 0.98 (d, 6H)	379	Method 6
7	H	Cl	H	cPr	(400.132MHz) 9.74 (s, 1H), 8.47 (d, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.69 (d, 1H), 7.46 (s, 1H), 7.35 (d, 1H), 7.14 (d, 1H), 5.63 (septet, 1H), 2.83-2.79 (m, 1H), 1.49 (d, 6H), 0.71-0.66 (m, 2H), 0.55-0.51 (m, 2H)	411	Method 12	6	H	Me	Me	Me		379	Method 6

Ex	R	R1	R2	R3	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	Nucleus magnetic resonance	m/z	Amide	8	H	Me	H	Me	(400.132MHz，CDCl ₃) 8.36 (d, 1H), 7.57 (d, 1H), 7.35 (s, 1H), 7.32 (d, 2H), 7.27 (s, 1H), 6.92 (d, 1H), 5.88 (s, 1H), 5.59 (septet, 1H), 2.99 (d, 3H), 2.57 (s, 3H), 2.47 (s, 3H), 1.51 (d, 6H)	365	Method 7
9	H	F	H	Me	(299.954MHz，CDCl ₃) 8.40 (d, 1H), 8.08 (t, 1H), 7.85 (d, 1H), 7.40-7.38 (m, 2H), 7.20 (d, 1H), 7.01 (d, 1H), 6.69 (d, 1H), 5.63 (septet, 1H), 3.03 (d, 3H), 2.60 (s, 3H), 1.56 (d, 6H)	369	Method 9	8	H	Me	H	Me		365	Method 7
9	H	F	H	Me		369	Method 9	10	H	Cl	H	H	(299.955MHz) 9.72 (s, 1H), 8.45 (d, 1H), 7.88 (s, 1H), 7.69-7.66 (m, 2H), 7.44-7.40 (m, 3H), 7.12-7.11 (d, 1H), 5.61 (septet, 1H), 1.47 (d, 6H)	371	Method 5
11	H	F	H	H	(400.132MHz) 9.92 (s, 1H), 8.49 (d, 1H), 7.80 (d, 1H), 7.69 (t, 1H), 7.53 (d, 1H), 7.47 (s, 1H), 7.45 (brs, 1H), 7.38 (brs, 1H), 7.17 (d, 1H), 5.68 (septet, 1H), 1.50 (d, 6H)	355	Method 4	10	H	Cl	H	H		371	Method 5
11	H	F	H	H		355	Method 4	12	H	Me	H	H	(299.954MHz，CDCl ₃) 8.37 (d, 1H), 7.62 (d, 1H), 7.47 (d, 1H), 7.39-7.33 (m, 3H), 6.94 (d, 1H), 5.85 (brs, 2H), 5.59 (septet, 1H), 2.58 (s, 3H), 2.53 (s, 3H), 1.53 (d, 6H)	351	Method 13
13	H	H	H	Me	(400.132 MHz，CDCl ₃) 8.38 (d, 1H), 7.76 (d, 2H), 7.67 (d, 2H), 7.42 (s, 1H), 7.38 (s, 1H), 6.96 (d, 1H), 6.22 (brs, 1H), 5.65 (septet, 1H), 3.01 (d, 3H), 2.59 (s, 3H), 1.53 (d, 6H)	351	Method 2	12	H	Me	H	H		351	Method 13
13	H	H	H	Me		351	Method 2	14	H	H	Me	Me	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.65 (d, 2H), 7.43 (d, 2H), 7.38 (s, 1H), 7.13 (s, 1H), 6.95 (d, 1H), 5.65 (septet, 1H), 3.07 (s, 6H), 2.59 (s, 3H), 1.53 (d, 6H)	365	Method 1

Embodiment 21

2-fluoro-4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-N, N-two Methyl-benzamide

Under logical nitrogen condition in advance with 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 17,0.15g, 0.69mmol), Pd (OAc) ₂(10mg, 0.02mmol), XANTPHOS (36mg, 0.06mmol), cesium carbonate (0.45g, 1.38mmol) with 4-bromo-2-fluoro-N, N-dimethyl-benzamide (method 8,0.70mmol, 173mg) be blended in the 5ml two  alkane, the logical nitrogen heating of reactant 24 hours.Reactant is poured directly on the silicagel column, uses CDM, 10%MeOH/DCM finally uses the 2.5%MeOH/DCM wash-out.Obtain the foam (59%) of 150mg white.

NMR (400.132MHz, CDCl ₃) 8.32 (d, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7.3.7-7.33 (m, 2H), 7.16 (d, 1H), 5.56 (septet, 1H), 3.12 (s, 3H), 2.97 (s, 3H), 2.62 (s, 3H), 1.54 (d, 6H); M/z 401.

Embodiment 22-55

Following compounds is pressed the method for embodiment 21 with identical macro preparation, uses suitable amide parent material (if no commercially available preparation method that then provides) and suitable amine.

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	22	H	Cl	Me	Me	iPr	F	(400.132MHz，CDCl ₃) 7.79 (d, 1H), 7.23 (s, 1H), 7.07 (d, 1H), 6.89 (d, 1H), 6.74-6.70 (m, 2H), 4.99 (septet, 1H), 2.61 (s, 3H), 2.38 (s, 3H), 2.09 (s, 3H), 1.01 (d, 6H)	417	Method 11 and method 17
23	H	Me	Me	Me	iPr	F	(400.132MHz，CDCl ₃) 8.29 (d, 1H), 7.58 (d, 1H), 7.50 (d, 1H), 7.31 (s, 1H), 7.14 (d, 1H), 7.10 (s, 1H), 5.53 (septet, 1H), 3.13 (s, 3H), 2.87 (s, 3H), 2.61 (s, 3H), 2.29 (s, 3H), 1.51 (d, 6H)	397	Method 6 and method 17	22	H	Cl	Me	Me	iPr	F		417	Method 11 and method 17
23	H	Me	Me	Me	iPr	F		397	Method 6 and method 17	24	Me	H	Me	Me	iPr	F	(299.954MHz, cdcl3) δ 8.27 (d, 1H), 7.93 (d, 1H), 7.59 (d, 1H), 7.34-7.32 (m, 1H), 7.30-7.25 (m, 1H), 6.83 (s, 1H), 5.51 (septet, 1H), 3.07 (s, 6H), 2.58 (s, 3H), 2.33 (s, 3H), 1.43 (d, 6H)	397	Method 17 and Intermediate 4 in GB2276160
25	H	F	H	cPr	iPr	F	(400.132MHz) 8.64 (d, 1H), 8.03 (s, 1H), 7.72 (d, 1H), 7.55 (t, 1H), 7.46 (d, 1H), 7.39 (d, 1H), 5.42 (septet, 1H), 2.86-2.79 (m, 1H), 2.54 (s, 3H), 1.48 (d, 6H), 0.69 (q, 2H), 0.57-0.53 (m, 2H)	413	Method 10 and method 17	24	Me	H	Me	Me	iPr	F		397	Method 17 and Intermediate 4 in GB2276160
25	H	F	H	cPr	iPr	F		413	Method 10 and method 17	26	F	H	Me	Me	iPr	F	(400.132MHz，CDCl ₃) 8.39 (t, 1H), 8.33 (d, 1H), 7.60 (d, 1H), 7.30-7.22 (m, 3H), 5.52 (septet, 1H), 3.07 (s, 6H), 2.62 (s, 3H), 1.54 (d, 6H)	401	Method 17 methods 63

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	27	H	Cl	H	cPr	iPr	F	(400.132MHz) 8.63 (d, 1H), 8.29 (d, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.38 (d, 1H), 7.34 (d, 1H), 5.38 (septet, 1H), 2.84-2.77 (m, 1H), 2.54 (s, 3H), 1.48 (d, 6H), 0.71-0.66 (m, 2H), 0.55-0.51 (m, 2H)	429	Method 12 and method 17
28	H	Me	H	Me	iPr	F	(400.132MHz，CDCl ₃) 8.29 (d, 1H), 7.57 (d, 1H), 7.52 (d, 1H), 7.34 (d, 1H), 7.27 (s, 1H), 7.14 (s, 1H), 5.83 (s, 1H), 5.51 (septet, 1H), 2.99 (d, 3H), 2.60 (s, 3H), 2.47 (s, 3H), 1.52 (d, 6H)	383	Method 7 and method 17	27	H	Cl	H	cPr	iPr	F		429	Method 12 and method 17
28	H	Me	H	Me	iPr	F		383	Method 7 and method 17	29	H	F	H	Me	iPr	F	(400.132MHz) 10.01 (s, 1H), 8.65 (d, 1H), 7.92 (t, 1H), 7.74 (d, 1H), 7.64 (t, 1H), 7.48 (d, 1H), 7.40 (d, 1H), 5.42 (septet, 1H), 2.78 (d, 3H), 2.55 (s, 3H), 1.48 (d, 6H)	387	Method 9 and method 17
30	H	Cl	H	H	iPr	F	(400.132MHz) 9.90 (s, 1H), 8.68 (d, 1H), 7.90 (s, 1H), 7.74 (s, 1H), 7.70 (d, 1H), 7.49-7.47 (m, 2H), 7.44 (d, 1H), 5.43 (septet, 1H), 2.59 (s, 3H), 1.53 (d, 6H)	389	Method 5 and method 17	29	H	F	H	Me	iPr	F		387	Method 9 and method 17
30	H	Cl	H	H	iPr	F		389	Method 5 and method 17	31	H	F	H	H	iPr	F	(400.132MHz) 10.03 (s, 1H), 8.66 (d, 1H), 7.73 (d, 1H), 7.69 (t, 1H), 7.49 (d, 1H), 7.43-7.42 (m, 2H), 7.37 (s, 1H), 5.42 (septet, 1H), 2.56 (s, 3H), 1.49 (d, 6H)	373	Method 4 and method 17

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	32	H	Me	H	H	iPr	F	(400.132MHz) 9.60 (s, 1H), 8.58 (s, 1H), 7.59 (d, 1H), 7.54 (brs, 1H), 7.43 (s, 1H), 7.38 (d, 2H), 7.13 (s, 1H), 5.43 (septet, 1H), 2.53 (s, 3H), 2.38 (s, 3H), 1.46 (d, 6H)	369	Method 13 and method 17
33	H	Cl	H	Me	iPr	F	(299.954MHz，CDCl ₃) 8.32 (d, 1H), 7.79-7.76 (m, 2H), 7.60 (d, 1H), 7.43 (d, 1H), 7.15 (s, 1H), 6.43 (s, 1H), 5.50 (septet, 1H), 3.03 (d, 3H), 2.62 (s, 3H), 1.55 (d, 6H)	404	Method 19 and method 17	32	H	Me	H	H	iPr	F		369	Method 13 and method 17
33	H	Cl	H	Me	iPr	F		404	Method 19 and method 17	34	H	H	H	Me	iPr	F	(400.132MHz) 9.81 (s, 1H), 8.60 (d, 1H), 8.26-8.22 (m, 1H), 7.79 (d, 2H), 7 .73 (d, 2H), 7.39 (d, 1F), 5.48 (septet, 1H), 2.78 (d, 3H), 2.54 (s, 3H), 1.47 (d, 6H)	369	Method 2 and method 17
35	H	H	Me	Me	iPr	F	(400.132MHz，CDCl ₃) 8.30 (d, 1H), 7.60-7.58 (m, 3H), 7.43 (d, 2H), 7.17 (s, 1H), 5.58 (septet, 1H), 3.07 (s, 6H), 2.61 (s, 3H), 1.53 (d, 6H)	383	Method 1 and method 17	34	H	H	H	Me	iPr	F		369	Method 2 and method 17
35	H	H	Me	Me	iPr	F		383	Method 1 and method 17	36	H	H	H	cPr	iPr	F	(400.132MHz) 9.80 (s, 1H), 8.60 (d, 1H), 8.23 (d, 1H), 7.78 (d, 2H), 7.73 (d, 2H), 7.39 (d, 1H), 5.47 (septet, 1H), 3.29 (s, 3H), 2.86-2.79 (m, 1H), 2.54 (s, 3H), 1.47 (d, 6H), 0.71-0.67 (m, 2H), 0.58-0.54 (m, 2H)	395	Method 3 and method 17

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	37	H	Me	H	cPr	iPr	F	(400.132MHz) 9.59 (s, 1H), 8.57 (d, 1H), 8.10 (d, 1H), 7.59 (d, 1H), 7.44 (s, 1H), 7.37 (d, 1H), 7.25 (d, 1H), 5.42 (septets, 1H), 2.84-2.78 (m, 1H), 2.53 (s, 3H), 2.33 (s, 3H), 1.46 (d, 6H), 0.69-0.65 (m, 2H), 0.54-0.50 (m, 2H)	409	Method 22 and method 17
38	H	H	H	cPr	Et	F	9.70(s，1H)，8.54(d，1H)，8.22(d，1H)，7.77(d，2H)，7.68(d，2H)，7.58(d，1H)，4.58(q，2H)，2.85-2.78(m，1H)，2.43(s，3H)，1.17(t，3H)，0.70-0.64(m，2H)，0.58-0.53(m，2H)	381	Method 26 and method 3	37	H	Me	H	cPr	iPr	F		409	Method 22 and method 17
38	H	H	H	cPr	Et	F		381	Method 26 and method 3	39	H	H	H	cPr	cBu	F	9.86(s，1H)，8.58(d，1H)，8.22(d，1H)，7.80-7.73(m，4H)，7.32(d，1H)，5.27(quin.，1H)，2.85-2.78(m，1H)，2.49(s，3H)，2.40-2.30(m，4H)，1.72-1.57(m，2H)，0.70-0.64(m，2H)，0.57-0.53(m，2H)	407	Method 28 and method 3
40	H	F	Me	H	Et	H	(400.132MHz)9.87(s，1H)，8.45(d，1H)，7.99-7.97(m，1H)，7.81(d，1H)，7.71(s，1H)，7.65(t，1H)，7.50(d，1H)，7.25(d，1H)，4.60(q，2H)，2.78(d，3H)，2.42(s，3H)，1.22(t，3H)	355	Method 30 ofWO 02/020512 and method 9	39	H	H	H	cPr	cBu	F		407	Method 28 and method 3

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	41	H	Me	Me	H	Et	H	(400.132MHz，CDCl ₃)8.34(d，1H)，7.52(s，1H)，7.49(d，1H)，7.37-7.34(m，2H)，7.20(s，1H)，6.96(d，1H)，5.92-5.85(m，1H)，4.50(q，2H)，3.00(d，3H)，2.48(s，3H)，2.46(s，3H)，1.27(t，3H)	351	Method 30 of WO 02/020512 and method 7
42	H	H	Me	H	Et	H	(400.132MHz)9.61(s，1H)，8.35(d，1H)，8.21(q，1H)，7.73(d，2H)，7.69(d，2H)，7.62(s，1H)，7.133(d，1H)，4.53(q，2H)，2.71(d，3H)，2.34(s，3H)，1.13(t，3H)	337	Method 30 of WO 02/020512 and method 2	41	H	Me	Me	H	Et	H		351	Method 30 of WO 02/020512 and method 7
42	H	H	Me	H	Et	H		337	Method 30 of WO 02/020512 and method 2	43	H	H	Me	H	cBu	H	(400.132MHz，CDCl ₃) 8.39 (d, 1H), 7.78 (d, 2H), 7.73 (s, 1H), 7.70 (d, 2H), 7.31 (s, 1H), 6.93 (d, 1H), 6.39-6.38 (q, 1H), 5.39 (quintet, 1H), 3.02 (d, 3H), 2.57 (s, 3H), 2.44 (q, 4H), 1.83-1.66 (m, 2H)	363	Method 51 of WO 03/076435 and method 2
44	H	F	Me	H	cBu	H	(400.132MHz，CDCl ₃) 8.42 (d, 1H), 8.09 (t, 1H), 7.91 (d, 1H), 7.72 (s, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 6.98 (d, 1H), 6.77-6.72 (m, 1H), 5.40 (quintet, 1H), 3.04 (d, 3H), 2.61 (s, 3H), 2.50-2.43 (m, 4H), 1.85-1.71 (m, 2H)	381	Method 51 of WO 03/076435 and method 9	43	H	H	Me	H	cBu	H		363	Method 51 of WO 03/076435 and method 2
44	H	F	Me	H	cBu	H		381	Method 51 of WO 03/076435 and method 9	45	H	H	Me	H	cPr-CH ₂-	H	(400.132MHz)9.56(s，1H)，8.26(d，1H)，8.12(q，1H)，7.64(d，2H)，7.59(d，2H)，7.50(s，1H)，7.03(d，1H)，4.41(d，2H)，2.62(d，3H)，2.26(s，3H)，0.94-0.84(m，1H)，0.19-0.14(m，2H)，-0.01(q，2H)	363	Method 54 of WO 03/076435 and method 2

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	46	H	F	Me	H	cPr-CH ₂-	H	(400.132MHz)9.72(s，1H)，8.27(d，1H)，7.82-7.74(m，1H)，7.61(d，1H)，7.49-7.44(m，2H)，7.31(d，1H)，7.06(d，1H)，4.39(d，2H)，2.59(d，3H)，2.23(s，3H)，0.94-0.84(m，1H)，0.19-0.14(m，2H)，-0.01(q，2H)	381	Method 54 ofWO 03/076435 and method 9
47	H	F	Me	H	cPr- CH(Me)-	H	(400.132MHz)9.88(s，1H)，8.51(d，1H)，8.03-8.01(m，1.H)，7.79(d，1H)，7.69(t，1H)，7.56(s，1H)，7.52(d，1H)，7.23(d，1H)，4.97-4.84(m，1H)，2.82(d，3H)，2.60(s，3H)，1.67(d，3H)，1.55-1.46(m，1H)，0.65-0.58(m，1H)，0.42-0.27(m，2H)，0.02--0.04(m，1H)	395	Method 57 ofWO 03/076435 and method 9	46	H	F	Me	H	cPr-CH ₂-	H		381	Method 54 ofWO 03/076435 and method 9
47	H	F	Me	H	cPr- CH(Me)-	H		395	Method 57 ofWO 03/076435 and method 9	48	H	H	Me	H	cPr- CH(Me)-	H	(400.132MHz)9.72(s，1H)，8.48(d，1H)，8.35(q，1H)，7.86(d，2H)，7.76(d，2H)，7.57(s，1H)，7.19(d，1H)，5.06-4.93(m，1H)，2.84(d，3H)，2.61(s，3H)，1.66(d，3H)，1.55-1.46(m，1H)，0.63-0.56(m，1H)，0.43-0.36(m，1H)，0.28-0.20(m，1H)，0.02--0.04(m，1H)	377	Method 57 ofWO 03/076435 and method 2
49	H	F	HO- (CH ₂) ₂-	H	iPr	F	(400.132MHz，CDCl ₃) 7.91 (d, 1H), 7.63 (t, 1H), 7.35 (d, 1H), 7.17 (d, 1H), 6.79 (s, 1H), 6.75 (d, 1H), 6.68-6.64 (m, 1H), 5.11 (septet, 1H), 3.42 (q, 2H), 3.23 (q, 2H), 2.22-2.20 (m, 4H), 1.13 (d, 6H)	417	Method 14 and method 17	48	H	H	Me	H	cPr- CH(Me)-	H		377	Method 57 ofWO 03/076435 and method 2

Embodiment 56-74

Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide
Ex	R	R1	R2	R3	R4	R5	Nucleus magnetic resonance	m/z	Amide	56	Et	F	H	Me	cPr - CH ₂-	H	(400.132MHz)9.74(s，1H)，8.29(d，1H)，7.80-7.78(m，1H)，7.62(d，1H)，7.52(s，1H)，7.47(t，1H)，7.32(d，1H)，7.07(d，1H)，4.40(d，2H)，2.60-2.56(m，5H)，1.10(t，3H)，0.93-0.79(m，1H)，0.18-0.13(m，2H)，0.01--0.02(m，2H)	395	Method 9 and method 56inWO03/076435
57	Et	H	H	Me	cPr - CH ₂-	H	(400.132MHz)9.57(s，1H)，8.27(d，1H)，8.15-8.10(m，1H)，7.65(d，2H)，7.60(d，2H)，7.53(s，1H)，7.04(d，1H)，4.42(d，2H)，2.63-2.57(m，5H)，1.12(t，3H)，0.93-0.83(m，1H)，0.19-0.15(m，2H)，0.02--0.03(m，2H)	377	Method 2 and method 56inWO03/076435	56	Et	F	H	Me	cPr - CH ₂-	H		395	Method 9 and method 56inWO03/076435
57	Et	H	H	Me	cPr - CH ₂-	H		377	Method 2 and method 56inWO03/076435	58	Me OC H ₂-	F	H	Me	iPr -	H	(400.132MHz) 9.99 (s, 1H), 8.55 (d, 1H), 7.99-7.97 (m, 1H), 7.84 (d, 1H), 7.64 (t, 1H), 7.52-7.50 (m, 2H), 7.21 (d, 1H), 5.53 (septet, 1H), 4.58 (s, 2H), 3.31 (s, 3H), 2.78 (d, 3H), 1.52 (d, 6H)	399	Method 9 and method 60
59	Me OC H ₂-	H	H	Me	iPr -	H	(400.132MHz) 9.80 (s, 1H), 8.51 (d, 1H), 8.28 (q, 1H), 7.79 (s, 4H), 7.51 (s, 1H), 7.16 (d, 1H), 5.58 (septet, 1H), 4.58 (s, 2H), 3.31 (s, 3H), 2.78 (d, 3H), 1.51 (d, 6H)	381	Method 2 and method 60	58	Me OC H ₂-	F	H	Me	iPr -	H		399	Method 9 and method 60
59	Me OC H ₂-	H	H	Me	iPr -	H		381	Method 2 and method 60	60	iPr-	H	H	Me	Et	H	(400.132MHz) 9.69 (s, 1H), 8.42 (d, 1H), 8.27 (q, 1H), 7.80 (d, 2H), 7.76 (d, 2H), 7.70 (s, 1H), 7.20 (d, 1H), 4.63 (q, 2H), 3.16 (septet, 1H), 2.78 (d, 3H), 1.27 (d, 6H), 1.19 (t, 3H)	365	Method 2 and method 35

Embodiment 75

N-(1,1-dioxy tetrahydrochysene-3-thienyl)-4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine -2-yl] amino } benzamide

At the 4-{[4-that is stirring (1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } (method 56 adds 257mgHBTU in DMF 240mg) (8ml) suspension to the phenylformic acid sodium salt.Mixture was stirred 20 minutes at ambient temperature, add the amino tetramethylene sulfide-S of 170mg3-then, S-dioxide hydrochloride and 139 μ l DIPEA.Mixture was stirred 18 hours at ambient temperature, then with 80ml EtOAc dilution, again with 80ml NaOH washing.Water layer extracts with 80ml EtOAc again, with the organism vacuum concentration.Enriched material RPHPLC purifying.The part that will contain product is poured on the SCX-2 post of a 10g, with the MeOH washing, uses the carbinolamine wash-out then.With alkaline eluate evaporation drying, obtain 150mg (49%) title compound, be a kind of white solid state thing.

NMR 9.73(s，1H)，8.52(d，1H)，8.44(d，1H)，7.85-7.77(m，4H)，7.45(s，1H)，7.11(d，1H)，5.71-5.64(m，1H)，4.73-4.63(m，1H)，3.53-3.37(m，2H)，3.25-3.02(m，2H)，2.50(s，3H)，2.47-2.37(m，1H)，2.28-2.14(m，1H)，1.47(d，6H)；m/z 455.

Embodiment 76-89

Following compounds is pressed the method for embodiment 75 with identical macro preparation, uses suitable amide parent material (if no commercially available preparation method that then provides) and suitable acid.

Embodiment 90

4-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino] benzamide

At the 4-[4-of 165mg (3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino] benzonitrile (method 20; 0.52mmol) the middle EtOH (5.0ml) that adds, water (2.5ml) and KOH (54mg, 0.1mmol).With reactant reflux 12 hours, vacuum was removed EtOH, and (3 * 50ml) extract, dry and remove and desolvate, and produce a kind of white decorating film with DCM.In this decorating film, add 3ml DCM, add ether again.The decorating film filtration drying is obtained 94mg (54%) title compound.

NMR (400.132MHz) 9.72 (s, 1H), 8.45 (d, 1H), 7.84 (d, 2H), 7.79-7.77 (m, 3H), 7.46 (s, 1H), 7.15-7.12 (m, 2H), 5.74 (septet, 1H), 2.52 (s, 3H), 1.49 (d, 6H); M/z 336.

Embodiment 91

4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-benzamide

At 4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-benzonitrile (method 21; 180mg, 0.54mmol) the middle EtOH (5.0ml) that adds, water (2.5ml) and KOH (54mg, 0.1mmol).With reactant reflux 12 hours, vacuum was removed EtOH, and (3 * 50ml) extract, dry and remove and desolvate, and produce a kind of white decorating film with DCM.In this decorating film, add 3ml DCM, add ether again.With decorating film filtration drying (108mg, 57%).

NMR (400.132MHz) 9.82 (s, 1H), 8.61 (d, 1H), 7.83 (d, 2H), 7.79 (brs, 1H), 7.73 (d, 2H), 7.39 (d, 1H), 7.14 (brs, 1H), 5.48 (septet, 1H), 2.54 (s, 3H), 1.47 (d, 6H); M/z 355.

Embodiment 92

2-cyano group-N-cyclopropyl-4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] Amino } benzamide

In rare gas element with 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 17; 0.20g, 0.85mmol), PdOAc ₂(16mg, 0.068mmol), XANTPHOS (60mg, 0.10mmol), (0.42g is 1.3mmol) with 4-chloro-2-cyano group-N-cyclopropyl-benzamide (method 24 for cesium carbonate; 0.24g, 1.10mmol) be added in the 7ml two  alkane, with 150 ℃ of heating of microwave 1 hour.Use silica gel purification,, produce a kind of yellow foam, be further purified, obtain the title compound (187mg, 53%) of colourless foam shape with RPHPLC with the 0～10%MeOH wash-out among the DCM.

NMR (399.902MHz, DMSO-d ₆+ AcOH-d ₄, 373K) 11.48 (brs, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.41 (s, 1H), 5.35 (septet, 1H), 2.68-2.62 (m, 1H), 2.52 (s, 3H), 1.45 (d, 6H), 0.99-0.93 (m, 2H), 0.91-0.87 (m, 2H); M/z420.

Embodiment 93

2-cyano group-N-cyclopropyl-4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } Benzamide

The preparation method of title compound is identical with embodiment 92, only uses 4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 18) replacement method 17.

NMR (399.902MHz, DMSO-d ₆+ AeOH-d ₄, 373K) 8.44 (d, 1H), 8.27 (s, 1H), 7.95 (d, 1H), 7.62 (d, 1H), 7.41 (s, 1H), 7.08 (d, 1H), 5.52 (septet, 1H), 2.68-2.62 (m, 1H), 2.49 (s, 3H), 1.45 (d, 6H), 0.99-0.93 (m, 2H), 0.91-0.87 (m, 2H); M/z 402.

Embodiment 94

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-pyrimidine-2-base] amino }-N-(1-methyl Piperidin-4-yl) benzamide

In rare gas element with 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 17; 149mg, 0.63mmol), 4-iodo-N-(1-methyl piperidine-4-yl) benzamide (method 29,239mg, 0.69mmol), acid chloride (9mg, 0.04mmol), XANTPHOS (33mg, 0.057mmol) and cesium carbonate (412mg 1.26mmol) in 7ml 1, reflux to stir in the 4-two  alkane 1 hour.With the reaction mixture cooling, filter, will filter the thing reduction vaporization, residual thing RPHPLC method purifying.The development that adds diethyl ether, the title compound of generation is a kind of colourless solids (190mg, 67%).

NMR9.78(s，1H)，8.58(d，1H)，7.99(d，1H)，7.79(d，2H)，7.71(d，2H)，7.37(d，1H)，7.50-7.39(m，1H)，3.78-3.62(m，1H)，2.76(d，2H)，2.52(s，3H)，2.15(s，3H)，1.98(t，2H)，1.81-1.67(m，2H)，1.58(apparent t，3H)，1.46(d，6H)；m/z 452.

Embodiment 95

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-pyrimidine-2-base] amino }-N-(tetrahydrochysene- 2H-pyrans-4-yl) benzamide

Method and yardstick with the foregoing description 94 prepare this routine title compound, only use 4-iodo-N-(tetrahydrochysene-2H-pyrans-4-yl) benzamide (method 30) to replace 4-iodo-N-(1-methyl piperidine-4-yl) benzamide (method 29), produce a kind of colourless decorating film (160mg, 58%).

NMR 9.79(s，1H)，8.59(d，1H)，8.07(d，1H)，7.80(d，2H)，7.72(d，2H)，7.37(d，1H)，5.51-5.38(m，1H)，4.05-3.91(m，1H)，3.87(d，2H)，3.37(app t，2H)，2.53(s，3H)，1.74(d，2H)，1.65-1.49(m，2H)，1.46(d，6H)；m/z 439.

Embodiment 96

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-pyrimidine-2-base] amino }-the top pyridine of N-piperazine -3-yl-benzamide

At the tertiary butyl 3-[(4-{[5-fluoro-4-that is stirring (1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-pyrimidine-2-base] amino } benzoyl) amino] (embodiment 97 for piperidines-1-carboxylicesters; 50mg adds the 0.2ml trifluoroacetic acid in 1ml DCM solution 0.093mmol).Mixture was stirred 2 hours, removal of solvent under reduced pressure then, (SCX-2 1g) with the residue purifying, obtains the title compound (29mg, 71%) of white solid state with ion exchange chromatography.

NMR 9.78(s，1H)，8.58(s，1H)，7.88(d，1H)，7.79(d，2H)，7.71(d，2H)，7.37(d，1H)，5.32-5.35(m，1H)，3.88-3.70(m，1H)，3.00-2.66(m，2H)，2.52(s，3H under DMSO)，2.45-2.30(m，4H under DMSO)，1.90-1.56(m，2H)，1.46(d，6H)；m/z 438.

Embodiment 97

Tertiary butyl 3-[(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-pyrimidine-2-base] amino } Benzoyl) amino] piperidines-1-carboxylicesters

With 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-pyrimidine-2-base amine (method 17; 149mg, 0.63mmol), tertiary butyl 3-[(4-phenyl-iodide formyl) amino] piperidines-1-carboxylicesters (method 61; 297mg, 0.69mmol), acid chloride (9mg, 0.04mmol), XANTPHOS (33mg, 0.057mmol) and cesium carbonate (412mg, 7ml two  alkane solution 1.26mmol) reflux in rare gas element and stirred 1 hour.Make the reaction mixture cooling, filter.To filter the thing reduction vaporization, resistates RPHPLC purifying obtains the title compound (232mg, 69%) of white solid state with ether development.

NMR9.79(s，1H)，8.59(d，1H)，8.01(d，1H)，7.80(d，2H)，7.72(d，2H)，7.37(d，1H)，5.53-5.36(m，1H)，4.04-3.64(m，3H)，2.86-2.69(m，2H)，2.53(s，3H under DMSO)2.54-2.35(m，2H underDMSO)，1.94-1.63(m，2H)，1.46(d，6H)，1.37(s，9H).

The preparation of parent material

Method 1

4-bromo-N, N-dimethyl-benzamide

(5.0g 22.8mmol) is added among the 100ml DCM, and (7.0ml 50.2mmol), then slowly adds 20ml dimethylamine (THF of 2.0N) again to add TEA in this mixture again with the 4-bromo-benzoyl chloride.This reactant was stirred 1 hour, and then the 2.0N hydrochloric acid with 50ml makes the reactant quenching, and (removal of solvent under reduced pressure generates white solid state compound (5.1g, 98%) for 2 * 100ml) abstraction reaction things, drying with DCM.

NMR(299.954MHz，CDCl ₃)7.57(d，2H)，7.30(d，2H)，3.10(s，3H)，2.98(s，3H)；m/z 228

Method 2

4-bromo-N-methyl-benzamide

(5.0g 22.8mmol) is added among the 100ml DCM, and (7.0ml 50.2mmol), then slowly adds 20ml dimethylamine (THF of 2.0N) again to add TEA in this mixture again with the 4-bromo-benzoyl chloride.This reactant was stirred 1 hour, and then the 2.0N hydrochloric acid with 50ml makes the reactant quenching, and (removal of solvent under reduced pressure generates white solid state compound (4.8g, 98%) for 2 * 100ml) abstraction reaction things, drying with DCM.

NMR(299.954MHz，CDCl ₃)7.62(d，2H)，7.55(d，2H)，6.16(s，3H)，3.00(d，6H)；m/z 215

Method 3

4-bromo-N-cyclopropyl-benzamide

With the 4-bromo-benzoyl chloride (5.0g 22.8mmol) is added among the 100ml DCM, in this mixture, add again TEA (7.0ml, 50.2mmol), then slowly add again cyclopropylamine (1.7g, 29.6mmol).This reactant was stirred 1 hour, and then the 2.0N hydrochloric acid with 50ml makes the reactant quenching, and (removal of solvent under reduced pressure generates white solid state compound (4.7g, 86%) for 2 * 100ml) abstraction reaction things, drying with DCM.

NMR(299.954MHz，CDCl ₃)7.60(d，2H)，7.54(d，2H)，6.27(s，1H)，2.93-2.85(m，1H)，0.87(q，2H)，0.64-0.59(m，2H)；m/z 241.

Method 4

4-bromo-2-fluorobenzamide

With 4-bromo-2-fluoro-cyanobenzene (2.0g, 10mmol) and Sodium peroxoborate (3.0g 20mmol) is dissolved in two  alkane (40ml) and the water (40ml) reflux 1 hour.Add other 2.0g Sodium peroxoborate, reactant was refluxed 1 hour.Make the reactant cooling, (removal of solvent under reduced pressure generates the white solid state compound for 2 * 100ml) abstraction reaction things, drying with DCM.Add ether and make remaining initial compounds dissolving, solids was stirred 10 minutes, filter, produce title compound (1.7g, 88%).

NMR(400.132MHz)7.74(brs，1H)，7.68(brs，1H)，7.64(d，1H)，7.61(t，1H)，7.50(d，1H).

Method 5

4-bromo-2-chlorobenzamide

With 4-bromo-2-chloro-cyanobenzene (2.0g, 9.3mmol) and Sodium peroxoborate (4.3g 28mmol) is dissolved in two  alkane (40ml) and the water (40ml) reflux 1 hour.Add other 2.0g Sodium peroxoborate, reactant was refluxed 1 hour.Make the reactant cooling, (removal of solvent under reduced pressure generates the white solid state compound for 2 * 100ml) abstraction reaction things, drying with DCM.Add ether and make remaining initial compounds dissolving, solids is stirred 10 minutes after-filtration (1.35g, 62%).

NMR(299.954MHz，CDCl ₃)12.61(s，1H)，12.50(s，1H)，12.38-12.31(m，2H)，12.13(d，1H).

Method 6

4-bromo-2-methyl-N, N-dimethyl-benzamide

(1.0g 4.65mmol) is added among the DCM (50ml), and (0.61ml 6.97mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-tolyl acid.Add dimethylamine (20ml, the THF solution of 2N) in this reactant, reactant was further stirred 10 minutes before quenching with the 50ml saturated sodium bicarbonate again, (2 * 100ml) extract, and drying produces the xanchromatic jelly after the removal of solvent under reduced pressure with ether.Make this jelly purifying with column chromatography, with 40% ether/isohexane, 60% ether/isohexane, use the ether wash-out at last.Obtain a kind of limpid jelly (1.0g, 89%).

NMR(299.954MHz，CDCl ₃)7.38(s，1H)，7.35(d，1H)，7.04(d，1H)，3.12(s，3H)，2.83(s，3H)，2.27(s，3H)；m/z 243.

Method 7

4-bromo-2-methyl-N-methyl-benzamide

(1.0g 4.65mmol) is added among the DCM (50ml), and (0.61ml 6.97mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-tolyl acid.Add methylamine (30ml, the THF solution of 2N) in this reactant, again with the further stirring of reactant 10 minutes, (2 * 100ml) extract, and drying produces white solids after the removal of solvent under reduced pressure with ether before quenching with the 60ml saturated sodium bicarbonate.This solids is dissolved among the indivisible DCM, adds ether and isohexane, up to the solids that is settled out white.With this solids filtration drying (1.0g, 94%).

NMR(299.954MHz，CDCl ₃)7.37(s，1H)，7.32(d，1H)，7.20(d，1H)，5.76(brs，1H)，2.98(d，3H)，2.41(s，3H)；m/z 229.

Method 8

4-bromo-2-fluoro-N, N-dimethyl-benzamide

(2.0g 9.1mmol) is added among the DCM, and (1.2ml 13.7mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-fluorobenzoic acid.(6.3ml 48mmol), and then adds the 10ml dimethylamine to add triethylamine in this reactant.(2.0N 50ml) further stirs reactant 10 minutes before the quenching again, with DCM (2 * 100ml) extractions, drying, removal of solvent under reduced pressure using hydrochloric acid.With column chromatography with the jelly purifying that obtains, with 20% ether/isohexane, 40% ether/isohexane, use the ether wash-out at last.Obtain a kind of limpid jelly (1.2g, 54%).

NMR(299.954MHz，CDCl ₃)7.36(d，1H)，7.31-7.24(m，2H)，3.12(s，3H)，2.92(s，3H)；m/z 247.

Method 9

4-bromo-2-fluoro-N-methyl-benzamide

(2.0g 9.1mmol) is added among the DCM, and (1.2ml 13.7mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-fluorobenzoic acid.(6.3ml 46.0mmol), adds methylamine (10ml, the THF solution of 2N) again to add triethylamine in this reactant.(2.0N 50ml) further stirs reactant 10 minutes before the quenching again, with DCM (2 * 100ml) extractions, drying, removal of solvent under reduced pressure using hydrochloric acid.Make the solids that obtains by a silicon plug purifying, use the DCM wash-out, the yellow solids that obtains is added in 20% ether/isohexane, filter and dry preceding the stirring 10 minutes.Obtain a kind of solids (1.1g, 52%) of white.

NMR(299.954MHz，CDCl ₃)8.00(t，1H)，7.41(d，1H)，7.31(d，1H)，6.64(brs，1H)，3.03(d，3H)；m/z 232.

Method 10

4-bromo-2-fluoro-N-cyclopropyl-benzamide

(2.0g 9.1mmol) is added among the DCM, and (1.2ml 13.7mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-fluorobenzoic acid.In this reactant, add triethylamine (6.3ml, 46.0mmol), add again cyclopropylamine (1.06g, 18mmol).(2.0N 50ml) further stirs reactant 10 minutes before the quenching again, and (removal of solvent under reduced pressure produces a kind of solids for 2 * 100ml) extractions, drying with DCM using hydrochloric acid.This solids is dissolved in the 30ml ether, filters and dry preceding the stirring 10 minutes.Obtain a kind of solids (1.4g, 60%) of white.

NMR(299.954MHz，CDCl ₃)7.99(t，1H)，7.40(d，1H)，7.29(d，1H)，6.69(brs，1H)，2.97-2.89(m，1H)，0.88(q，2H)，0.65-0.60(m，2H)；m/z 259.

Method 11

4-bromo-2-chloro-N, N-dimethyl-benzamide

(1.0g 4.3mmol) is added among the DCM, and (0.5ml 5.5mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-chloro-benzoic acid.(2.9ml 21.3mmol), adds the 10ml dimethylamine again to add triethylamine in this reactant.(2.0N 50ml) further stirs reactant 10 minutes before the quenching again, and (removal of solvent under reduced pressure produces a kind of jelly for 2 * 100ml) extractions, drying with DCM using hydrochloric acid.With column chromatography with this jelly purifying, with 20% ether/isohexane, 40% ether/isohexane, use the ether wash-out at last.Obtain a kind of limpid jelly (1.05g, 95%).

NMR(299.954MHz，CDCl ₃)7.58(d，1H)，7.46(dd，1H)，7.17(d，1H)，3.12(s，3H)，2.86(s，3H)；m/z 263.

Method 12

4-bromo-2-chloro-N-cyclopropyl-benzamide

(1.0g 4.3mmol) is added among the DCM, and (0.5ml 5.5mmol) and 4 DMF, stirs reactant up to there not being gas release come out (about 30 minutes) to add oxalyl chloride again with 4-bromo-2-chloro-benzoic acid.In this reactant, add triethylamine (2.9ml, 21.3mmol), add again cyclopropylamine (0.48g, 8.5mmol).(2.0N 50ml) further stirs reactant 10 minutes before the quenching again, and (removal of solvent under reduced pressure produces a kind of solids for 2 * 100ml) extractions, drying with DCM using hydrochloric acid.Add ether in this solids, stirred 10 minutes before filtering, filter, drying obtains a kind of white solid state thing (1.0g, 86%).M/z 275。

Method 13

4-bromo-2-methyl benzamide

With 4-bromo-2-cyano group cyanobenzene (10g, 51mmol) be added to EtOH/ water (4: 1,180ml) in, again to wherein add KOH (6.3g, 112mmol), with reactant reflux 6 hours.With reactant cooling (solid precipitation).EtOH is removed in decompression, up to 25% of remaining original volume.Solids is filtered drying.

NMR(299.955MHz)7.71(s，1H)，7.45(s，1H)，7.40-7.38(m，2H)，7.28(d，1H)，2.34(s，3H)；m/z 215.

Method 14

4-bromo-2-fluoro-N-(2-hydroxyl-ethyl)-benzamide

With 4-bromo-2-fluorobenzoic acid (2.0g, 9.2mmol), HATU (4.1g, 11.0mmol) and DIPEA (2.4ml 13.7mmol) is pre-mixed in 70ml DCM, stirs 10 minutes.(0.83g, 13.7mmol), reactant is in the stirring 1 hour that takes a step forward with the 50ml water quenching to wherein adding 2 hydroxy ethylamine.(removal of solvent under reduced pressure produces a kind of xanchromatic jelly for 2 * 100ml) abstraction reaction things, drying with DCM.With this jelly of column chromatography purification, with 20% ether/isohexane, 40% ether/isohexane, use the ether wash-out at last.Obtain a kind of solids (2.15g, 90%) of cured shape.

NMR(299.954MHz，CDCl ₃)7.97(t，1H)，7.41(d，1H)，7.32(d，1H)，7.07(s，1H)，3.84(q，2H)，3.65(q，2H)，2.44(t，1H)；m/z 264

Method 15

4-bromo-N-(2-hydroxyl-ethyl)-benzamide

With the 4-bromo-benzoic acid (5.0g, 24.9mmol), DMTMM (8.8g, 30mmol) and DIPEA (6.1ml 38mmol) is pre-mixed in 70ml DCM, stirs 10 minutes.(1.82g, 30mmol), reactant is in the stirring 1 hour that takes a step forward of quenching with 50ml 2N hydrochloric acid to wherein adding 2 hydroxy ethylamine.(removal of solvent under reduced pressure produces a kind of xanchromatic solids for 2 * 100ml) abstraction reaction things, drying with DCM.This solids is dissolved among the hot DCM of 20ml,, adds the 20ml ether the solution cooling.Generation white solid precipitation is filtered drying.

NMR(299.955MHz)8.44(s，1H)，7.78(d，2H)，7.62(d，2H)，4.69(t，1H)，3.49(t，2H)，3.29(t，2H)；m/z 245.

Method 16

(2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1- Ketone

With (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 24 of WO 03/076436; 5.53g MeOH 25mmol) (100ml) solution at room temperature stirs, gradation adding in 5 minutes (1-chloromethyl-4-fluoro-1, and 4-phenodiazine drone dicyclo [2.2.2] octane two (a tetrafluoro borate) (14.16g, 40mmol).Cooling makes temperature remain on 25～30 ℃ a little.Stir after 90 minutes and make reaction mixture cooling and filtration with ice/acetone.To filter the thing reduction vaporization, residue is put among the DCM.With ammoniacal liquor, salt water washing, dry (Na ₂SO ₄), reduction vaporization.Use two pillars (10%EtOH/EtOAc, 3.5%EtOH/DCM then) as gold size respectively, do silica gel column chromatography with the MPLC method and separate title compound, storing is separated out crystallization after several weeks.Product=2.50g (42%).

NMR1.40 (d, 6H), 2.38 (s, 3H), 3.05 (s, 6H), 4.70 (septet, 1H), 6.96 (d, 1H), 7.08 (s, 1H); Fluorine NMR (376MHz) :-166.7 (d); M/z 240.

Method 17

5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 16,4.0g, 16.7mmol) and Guanidinium carbonate (6.6g 37mmol) is pre-mixed in the 80ml butanols, reflux 30 hours.Make the reaction mixture cooling, use the 200ml water quenching, (removal of solvent under reduced pressure produces a kind of xanchromatic solid for 2 * 200ml) abstraction reaction things, drying to use DCM then.This solid is dissolved among a spot of temperature DCM, and cooling then adds ether.Produce milky precipitation, filter drying.Repeat this process and obtain second batch of product (3.18g, 81%).

NMR (299.954MHz, CDCl ₃) 8.15 (d, 1H), 7.54 (d, 1H), 7.26 (s, 1H), 5.40 (septet, 1H), 4.88 (s, 2H), 2.59 (s, 3H), 1.56 (d, 6H); M/z236

Method 18

4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 24 of WO 03/076436; 4.0g, 18mmol) and Guanidinium carbonate (7.2g 40mmol) is pre-mixed in the 80ml 2-methyl cellosolve, reflux 30 hours.Make the reaction mixture cooling, use the 50ml water quenching.(removal of solvent under reduced pressure produces a kind of xanchromatic solid for 2 * 200ml) abstraction reaction things, drying to use DCM then.This solid is dissolved among a spot of temperature DCM, and cooling then adds ether.Produce milky precipitation, filter drying.Repeat this process and obtain second batch of product (3.18g, 81%).

NMR (299.954MHz, CDCl ₃) 8.22 (d, 1H), 7.33 (s, 1H), 6.80 (d, 1H), 5.45 (septet, 1H), 5.10 (s, 2H), 2.56 (s, 3H), 1.54 (d, 6H); M/z 218.

Method 19

4-bromo-2-chloro-N-methyl-benzamide

(0.24g, (method 5,0.9g is in THF 3.85mmol) (20ml) solution 5.0mmol) to be added to 4-bromo-2-chloro-benzamide with sodium hydride.This reactant was stirred 10 minutes, and (0.36ml 5.8mmol), stirs reactant then and spends the night to add methyl-iodide.With the saturated NH of 20ml ₄Cl quenches reactant, and (removal of solvent under reduced pressure produces a kind of jelly for 2 * 200ml) extractions, drying with DCM.With DCM, 1%MeOH/DCM, finally this jelly is done stratographic analysis, produce the mix products of an a kind of alkylation and dialkyl groupization with 2.5%MeOH/DCM.Add ether/isohexane (1: 1) in this mix products, the dialkyl group substance dissolves stays needed adducts, this adducts is filtered dry (0.12g, 13%).

Method 20

4-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-the benzo acetonitrile

With the foregoing description 1 described method and this title compound of macro preparation, but replace 4-bromo-3-methyl-N, N-dimethyl-benzamide with 4-bromo-cyano group cyanobenzene.Obtain white foam shape product (165mg, 75%).

NMR (400.132MHz, CDCl ₃) 8.41 (d, 1H), 7.76 (d, 2H), 7.60 (d, 2H), 7.40 (s, 1H), 7.29 (s, 1H), 7.02 (d, 1H), 5.58 (septet, 1H), 2.61 (s, 3H), 1.55 (d, 6H); M/z 319.

Method 21

4-[5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-the benzo acetonitrile

With the foregoing description 1 described method and this title compound of macro preparation, but replace 4-bromo-3-methyl-N, N-dimethyl-benzamide with 4-bromo-cyano group cyanobenzene.Obtain white foam shape product (190mg, 88%).

NMR (400.132MHz) 8.34 (s, 1H), 7.72 (d, 2H), 7.65-7.58 (m, 3H), 7.22 (s, 1H), 5.52 (septet, 1H), 2.62 (s, 3H), 1.57 (d, 6H); M/z 336.

Method 22

4-bromo-N-cyclopropyl-2-methyl-benzamide

With the bromo-tolyl acid (10g, 46.5mmol) and HBTU (23g 60.5mmol) is dissolved among the 150ml DMF, add cyclopropylamine (3.5g, 60.5mmol), add again DIPEA (21ml, 121mmol).The reactant stirring is spent the night, and DMF is removed in decompression, and resulting jelly quenches with 100ml 2.0N NaOH, and precipitated solid is filtered, be dissolved among the DCM, and drying, removal of solvent under reduced pressure, the product that obtains is milky solid (10.2g, 87%).

NMR(CDCl ₃)7.35(s，1H)，7.30(d，1H)，7.15(d，1H)，6.03(brs，1H)，2.91-2.82(m，1H)，2.39(s，3H)，0.90-0.83(m，2H)，0.63-0.57(m，2H)；m/z 254.

Method 23

4-chloro-N-cyclopropyl-2-iodo-benzamide

With 2-iodo-4-chloro-benzoic acid (10g, 35.5mmol) and HBTU (17.5g 46mmol) is added among the 100ml DMF, add again cyclopropylamine (2.6g, 46mmol) and DIPEA (17.5ml, 92mmol).The reactant stirring is spent the night, quench with 100ml 2.0N NaOH, (removal of solvent under reduced pressure produces a kind of luteotestaceous solids for 3 * 200ml) extractions, drying with DCM.Make it pass through a silicon pad, use the DCM wash-out, make the filtrate concentrating under reduced pressure, produce a kind of yellow solids.Add the 200ml ether, with this slurry ultrasonication 20 minutes, add the 100ml isohexane then, this system was stirred 10 minutes, filter, drying produces a kind of colourless solid (9.3g, 82%).

NMR(CDCl ₃)7.82(s，1H)，7.34(d，1H)，7.28(d，1H)，5.99(s，1H)，2.94-2.84(m，1H)，0.91-0.84(m，2H)，0.71-0.66(m，2H)；m/z 322.

Method 24

4-chloro-2-cyano group-N-cyclopropyl-2-iodo-benzamide

With 4-chloro-N-cyclopropyl-2-iodo-benzamide (method 23,8.0g, 25 mmol), and cupric cyanide (I) (9.0g, 100mmol), Pd ₂(dba) ₃(0.9g, 1mmol), (1.7g, 3mmol) (3.9g 25mmol) is added in the 80ml two  alkane reflux 2 hours to DPPF with the cyaniding Tetrylammonium.Reactant is filtered, and filtrate is removed in decompression, produces a kind of black solid.With this black solid of 200ml water treatment, (removal of solvent under reduced pressure produces a kind of brown solid, uses the silica gel chromatography purifying for 2 * 200ml) extractions, drying, and the DCM liquid wash-out with 0-2.5%MeOH obtains a kind of brown solid compounds with DCM.This brown solid is added among the 50mlMeOH, heats ultrasonication then.With the solid filtering drying (4.4g, 80%) that obtains.

NMR(CDCl ₃)8.77(brs，1H)，7.88(s，1H)，7.74(d，1H)，7.59(d，1H)，2.66-2.56(m，1H)，1.16-1.10(m，2H)，0.97-0.92(m，2H)；m/z 221.

Method 25

(2Z)-3-(dimethylamino)-2-fluoro-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone

Title compound uses (2E)-3-(dimethylamino)-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 23 of WO 03/076436) to replace (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone by preparing with method 16 similar methods.

NMR 1.2 (t, 3H), 2.38 (s, 3H), 3.05 (s, 6H), 4.18 (q, 2H), 6.96 (d, 1H), 7.34 (s, 1H); Fluorine NMR (376MHz)-168.2 (d); M/z 226.

Method 26

5-fluoro-4-(3-ethyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

Title compound is by preparing with method 17 similar methods, use (2Z)-3-(dimethylamino)-2-fluoro-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 25) to replace (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 16,4.0g, 16.7mmol).

NMR 8.24(d，1H)，7.45(d，1H)，6.53(br.s，2H)，4.50(q，2H)，2.40(s，3H)，1.24(t，3H)；m/z 222.

Method 27

(2Z)-3-(dimethylamino)-2-fluoro-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1- Ketone

Title compound uses (2E)-3-(dimethylamino)-1-(1-ethyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 23 of WO 03/076436) to replace (2E)-3-(dimethylamino)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 37 of WO 03/076436) to replace (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone by preparing with method 16 similar methods.

NMR(CDCl ₃)7.27-7.17(m，1H)，6.85(d，1H)，5.06-4.91(m，1H)，3.12-3.05(m，6H)，2.54-2.39(m，7H)，1.74(m，2H)；m/z 252.

Method 28

5-fluoro-4-(3-cyclobutyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

Title compound uses (2Z)-3-(dimethylamino)-2-fluoro-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 27) to replace (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone by preparing with method 17 similar methods.

NMR (CDCl ₃) 8.26 (d, 1H), 7.21 (d, 1H), 6.58 (br.s, 1H), 5.17 (quintet, 1H), 3.45 (s, 3H), 2.42-2.29 (m, 4H), 1.80-1.64 (m, 2H); M/z 248.

Method 29

4-iodo-N-(1-methyl piperidine-4-yl) benzamide

In a kind of rare gas element with 1-methyl piperidine-4-amine (5.0g, 43.8mmol) and triethylamine (7.3ml 52.5mmol) stirs in 200ml THF.(11.7g 43.8mmol) adds wherein in batches with 4-phenyl-iodide formyl chloride in 5 minutes time surpassing.Ceaselessly stirred 16 hours, reduction vaporization falls solvent then, and the residue partition is in the 1M NaOH of 200ml EtOAc and 100ml.With 100ml water and 100ml salt water washing organic composition, drying, evaporation, the title compound of generation is colourless solid (13.2g, 88%).

NMR 8.26(d，1H)，7.82(d，2H)，7.61(d，2H)，3.77-6.62(m，1H)，2.74(d，2H)，2.14(s，3H)，1.92(t，2H)，1.97-1.85(m，2H)，1.55(ap.q，2H)；m/z 345.

Method 30

4-iodo-N-(tetrahydrochysene-2H-pyrans-4-yl) benzamide

In a kind of rare gas element with tetrahydrochysene-2H-pyrans-4-amine (5.0g, 49.4mmol) and triethylamine (8.3ml 59.3mmol) stirs in 200ml THF.(13.2g 49.4mmol) adds wherein in batches with 4-phenyl-iodide formyl chloride in 5 minutes time surpassing.Ceaselessly stirred 16 hours, solvent is removed in decompression then.The solid that generates ultrasonication 10 minutes in 100ml 1M NaOH solution is then by filtering with (3 * 100ml) wash and separate with fresh water.With the solid that obtains at 60 ℃ of drying under reduced pressure 24 hours (13.2g, 88%).

NMR8.32(d，1H)，7.83(d，2H)，7.62(d，2H)，4.05-3.90(m，1H)，3.86(d，2H)，3.36(app t，2H)，1.73(d，2H)，1.64-1.46(m，2H)；m/z 332.

Method 31

N-ethyl-N-(5-methyl-different  azoles-4-yl)-isobutyramide

With hydrochloric acid ethyl-N-(5-methyl-different  azoles-4-yl)-amine (15g 0.092mmol) is added among the 200ml DCM, add again TEA (32ml, 0.23mol), slowly add again isobutyl chloride (10.7g, 0.10mol).Reactant was stirred 30 minutes, and solvent is removed in decompression.Use the 150ml water treatment residue, (3 * 150ml) extract, and drying subtracts and removes solvent night, produce xanchromatic oily matter (12.9g, 72%) with ether.

NMR(CDCl ₃)8.14(s，1H)，3.61(q，2H)，2.46-2.37(m，4H)，1.09(t，3H)，1.03(d，6H)；m/z 197.

Method 32

N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-isobutyramide

(method 31,15.6g 0.08mol) are added among the EtOH with 10% palladium carbon (3.9g), stir under 4 normal atmosphere and spend the night with N-ethyl-N-(5-methyl-different  azoles-4-yl)-isobutyramide.Reactant is filtered, and solvent is removed in decompression, produces a kind of milky solid.Add the 150ml ether,, filter drying reflection ultrasonication 10 minutes.Obtain a kind of white solid (11g, 69%).

NMR(400.132MHz)7.57(t，1H)，6.99(brs，1H)，6.79(brs，1H)，3.39-3.31(m，3H)，2.43.-2.33(m，1H)，2.09(s，3H)，0.92-0.81(m，9H)；m/z 199.

Method 33

1-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-ethane ketone

With N-{1-[1-amino-first-(Z)-Ji Yaji]-2-oxo-propyl group }-the N-ethyl- Isobutyramide(method 32; 11g, 0.056mol) and NaOH (2.7g 0.067mol) is added among the 150ml EtOH, reflux 4 hours.In this reactant, add solid state N H ₄XCl (4.4g, 0.084mol), spend the night by stirring.With the slurry concentrating under reduced pressure that generates, add the 200ml ether, this mixture was stirred 10 minutes, filter then.Filtrate decompression is concentrated, produce saffron oily matter.With this oily matter distillation, produce limpid oil (11g, 69%) with two bulb distillers (0.76mmbar/120 ℃).

NMR (400.132MHz, CDCl ₃) 7.74 (s, 1H), 4.34 (q, 2H), 3.04 (septet, 1H), 2.44 (s, 3H), 1.35 (d, 6H), 1.32 (t, 3H); M/z 181.

Method 34

(E)-3-dimethylamino-1-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-acrylketone

With 1-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-ethane ketone (method 33; 7.0g, 0.039mol) and DMFDMA (13.3ml 0.078mol) is added among the DMF, 130 ℃ the heating 6 hours.Removal of solvent under reduced pressure produces a kind of jelly of low key tone.Add the 50ml ether and produce a kind of flavous solids in this jelly, filtration drying promptly generates this title compound (7.7g, 84%).

NMR(400.132MHz，CDCl ₃)7.66(d，1H)，7.54(s，1H)，5.52(d，1H)，4.42(q，2H)，3.09-2.89(m，9H)，1.36-1.33(m，9H)；m/z236

Method 35

4-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (E)-3-dimethylamino-1-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-acrylketone (method 34; 6.5g, 0.028mol) and Guanidinium carbonate (12.5g 0.069mol) is added in the 100ml butanols, reflux 5 days.Removal of solvent under reduced pressure produces a kind of xanchromatic jelly.With the DCM solution of 0-5%MeOH with silica gel column chromatography with this jelly purifying, this title compound of generation is a kind of xanchromatic solid.Add 5ml DCM and 50ml ether, this suspension is filtered, drying, this title compound of generation is a kind of solid (5.0g, 77%) of white.

NMR (400.132MHz) 8.14 (d, 1H), 7.53 (s, 1H), 6.84 (d, 1H), 6.56 (brs, 2H), 4.54 (q, 2H), 3.13 (septet, 1H), 1.25-1.20 (m, 9H); M/z 232.

Method 36

Cyclopropane-carboxylic acid ethyl-(5-methyl-different  azoles-4-yl)-acid amides

With hydrochloric acid ethyl-(5-methyl-different  azoles-4-yl)-amine (15g 0.092mol) is added among the 200ml DCM, add hereinto TEA (32ml, 0.23mol), slowly add again the cyclopropyl carbonyl chloride (10.2g, 0.10mol).This reactant was stirred 30 minutes, then removal of solvent under reduced pressure.Use the 150ml water treatment residue, (removal of solvent under reduced pressure produces a kind of xanchromatic oil (12.2g, 69%) for 3 * 150ml) extractions, drying, and this thing no longer is further purified and directly uses with ether.

Method 37

N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-cyclopropyl acid amides

With cyclopropane-carboxylic acid ethyl-(5-methyl-different  azoles-4-yl)-acid amides (method 36; 12.2g, 0.08mol) be added among the 300ml EtOH with 10% palladium carbon (3g), under 4 normal atmosphere, stir and spend the night.This reactant is filtered, and removal of solvent under reduced pressure produces a kind of milky solid.Add the 150ml ether, ultrasonication 10 minutes is filtered, and drying produces a kind of white solid.(9.2g，59％)；m/z 197。

Method 38

1-(3-ethyl-2-cyclopropyl-3H-imidazol-4 yl)-ethane ketone

With N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-cyclopropyl acid amides (method 37; 9.2g, 0.047mol) and NaOH (2.3g 0.056mol) is added among the 150ml EtOH, reflux 4 hours.In this reactant, add solid state N H ₄Cl (4.4g, 0.084mol), spend the night by stirring.With the slurry concentrating under reduced pressure that generates, add the 200ml ether, this mixture was stirred 10 minutes, filter then.Filtrate is removed in decompression, produces a kind of saffron oil.With this oil distillation, obtain a kind of limpid oil (5.0g, 60%) with two ball distillers (0.50mbar/110 ℃).

NMR(400.132MHz，CDCl ₃)7.64(s，1H)，4.48(q，2H)，2.42.(s，3H)，1.87-1.80(m，1H)，1.37(t，3H)，1.13-1.08(m，2H)，1.08-1.02(m，2H)；m/z 179.

Method 39

(E)-1-(2-cyclopropyl-3-ethyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone

With 1-(3-ethyl-2-cyclopropyl-3H-imidazol-4 yl)-ethane ketone (method 38; 3.5g, 0.020mol) and DMFDMA (6.7ml 0.039mol) is added among the 50ml DMF, 130 ℃ the heating 6 hours.Removal of solvent under reduced pressure produces a kind of xanchromatic solid.Add 3.0ml DCM, add the 50ml ether again,, filter then this reactant ultrasonication 10 minutes.Obtain a kind of xanchromatic solid (3.4g, 72%).

NMR(400.132MHz，CDCl ₃)7.65(d，1H)，7.45(s，1H)，5.50(d，1H)，4.56(q，2H)，3.13-2.88(m，6H)，1.87-1.81(m，1H)，1.39(t，3H)，1.09-1.06(m，2H)，1.02-0.98(m，2H)；m/z234.

Method 40

4-(3-ethyl-2-cyclopropyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (E)-1-(2-cyclopropyl-3-ethyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone (method 39; 3.4g, 0.015mol) and Guanidinium carbonate (6.6g 0.036mol) is added in the 60ml butanols, reflux 4 days.Removal of solvent under reduced pressure adds 50ml water, and (removal of solvent under reduced pressure produces a kind of Off-white solid for 3 * 75ml) extraction residues, drying with DCM.Add DCM, add ether then, with the solid filtering that generates, drying obtains a kind of white solid (3.4g, 72%).

NMR(400.132MHz，CDCl ₃)8.19(d，1H)，7.95(s，1H)，6.83(d，1H)，4.94(brs，2H)，4.64(q，2H)，1.90-1.84(m，1H)，1.41(t，3H)，1.11-1.07(m，2H)，1.05-0.99(m，2H)；m/z230.

Method 41

N-ethyl-2,2,2-three fluoro-N-(5-methyl-different  azoles-4-yl)-ethanamide

With the hydrochloric acid ethyl-(5-methyl-different  azoles-4-yl)-(15g 0.092mol) is dissolved in the 100ml pyridine amine.(16.9ml 0.12mol), spends the night this reactant stirring, then removal of solvent under reduced pressure to add trifluoroacetic anhydride in this solution.Residue is quenched with the 200ml saturated ammonium chloride, and (removal of solvent under reduced pressure produces a kind of xanchromatic oil (18g, 88%) for 3 * 200ml) extractions, drying with ether.

NMR(400.132MHz，CDCl ₃)8.03(s，1H)，3.55(q，2H)，2.26(s，3H)，1.05(t，3H)；m/z 223.

Method 42

N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-2,2,2-three fluoro-ethanamides

With N-ethyl-2,2,2-three fluoro-N-(5-methyl-different  azoles-4-yl)-ethanamide (method 41; 18.0g, 0.081mol) in 4 atmospheric hydrogen environment, reacted 3 days with 10% palladium carbon (4.0g).Reactant is filtered, and removal of solvent under reduced pressure produces a kind of milky solid, adds 30ml DCM and 100ml ether.Reactant was stirred 10 minutes, filter, drying produces a kind of white solid (11.6g, 64%); M/z 225.

Method 43

1-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-ethane ketone

With N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-2,2,2-three fluoro-ethanamide (methods 42; 11.6g, 0.051mol) and salt of wormwood (14.4g 0.103mol) is added in the 180ml two  alkane reflux 2 hours.Make the reactant cooling, filter, removal of solvent under reduced pressure produces xanchromatic oil.With this oily purifying, with the isohexane liquid wash-out of 0-40% ether, the title compound that obtains is a kind of limpid oil (8.9g, 85%) with silica gel column chromatography.

NMR(400.132MHz，CDCl ₃)7.79(s，1H)，4.50(q，2H)，2.54(s，3H)，1.40(t，3H)；m/z 207.

Method 44

(E)-3-dimethylamino-1-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-acrylketone

With 1-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-ethane ketone (method 43; 7.0g, 0.034mol) and DMFDMA (11.6ml 0.068mol) is added among the 90ml DMF, 130 ℃ the heating 1 hour.Removal of solvent under reduced pressure produces a kind of xanchromatic solid.With the DCM liquid of 0-5%MeOH with silica gel column chromatography with this solids purifying, the title compound of generation is a kind of xanchromatic solid.Add ether, add isohexane again, obtaining solids is filtered, drying generates title compound (7.6g, 85%).

NMR(400.132MHz，CDCl ₃)7.74(d，1H)，7.55(s，1H)，5.53(d，1H)，4.57(q，2H)，3.17(brs，3H)，2.93(brs，3H)，1.42(t，3H)；m/z 262.

Method 45

4-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (E)-3-dimethylamino-1-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-acrylketone (method 44; 6.0g, 0.023mol) and Guanidinium carbonate (8.3g 0.046mol) is added in the 80ml 2-methoxy (ethoxy) ether, 140 ℃ the heating 2 days.Make the reactant cooling, removal of solvent under reduced pressure produces a kind of yellow solid.Add 100ml water, (removal of solvent under reduced pressure produces a kind of yellow solid for 3 * 100ml) extractions, drying with DCM.With the DCM liquid of 0-5%MeOH with silica gel column chromatography with this solids purifying, the title compound of generation is a kind of xanchromatic solid.Add the 20ml ether, add the 50ml isohexane again, produce a kind of milky solid.With this solid filtering, dry (5.9g, 100%); M/z 258.

Method 46

N-ethyl-2,2-two fluoro-N-(5-methyl-different  azoles-4-yl)-ethanamide

With hydrochloric acid ethyl-(5-methyl-different  azoles-4-yl)-amine (15g, 0.092mol) and TEA be added among the 300ml DCM, make this reactant be cooled to 0 ℃, slowly add two fluoracyl chlorides (11.5g, 0.10mol).Reactant was stirred 1 hour, then removal of solvent under reduced pressure.Residue obtained with the saturated ammonium chloride quenching of 200ml, (removal of solvent under reduced pressure produces a kind of xanchromatic oil (9.0g, 48%) for 3 * 200ml) extractions, drying with ether.M/z 203(M-H) ^-。

Method 47

N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-2,2-two fluoro-ethanamides

Under 4 normal atmosphere, handle N-ethyl-2,2-two fluoro-N-(5-methyl-different  azoles-4-yl)-ethanamide (method 46 with 3.0g palladium carbon; 9.0g, 0.044mol).Reactant is filtered, and removal of solvent under reduced pressure adds DCM, and the filtering reaction thing produces a kind of milky solid (3.0g, 33%).M/z 207。

Method 48

1-(2-difluoromethyl-3-ethyl-3H-imidazol-4 yl)-ethane ketone

With N-{1-[1-amino-methylene-(Z)-yl]-2-oxo-propyl group }-N-ethyl-2,2-two fluoro-ethanamide (methods 47; 3.0g, 0.014mol) and salt of wormwood (3.9g 0.028mol) is added in the 50ml two  alkane, and reflux spends the night.Reactant is filtered, and removal of solvent under reduced pressure produces a kind of xanchromatic oil.With this oily purifying, do elutriant with ether with silica gel column chromatography, the title compound of generation is a kind of xanchromatic solid (2.4g, 92%).

NMR(400.132MHz，CDCl ₃)7.74(s，1H)，6.78(t，1H)，4.54(q，2H)，2.51(s，3H)，1.40(t，3H)；m/z 189.

Method 49

(E)-1-(2-difluoromethyl-3-ethyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone

With 1-(2-difluoromethyl-3-ethyl-3H-imidazol-4 yl)-ethane ketone (method 48; 2.4g, 0.013mol) and DMFDMA (4.4ml 0.026mol) is added among the 50ml DMF, 130 ℃ the heating 20 minutes.Removal of solvent under reduced pressure produces a kind of xanchromatic solid.Add 3.0mlDCM, add the 50ml ether again, ultrasonication 10 minutes is filtered then.Obtain a kind of xanchromatic solid (2.7g, 85%).

NMR(400.132MHz，CDCl ₃)7.71(d，1H)，7.52(s，1H)，6.75(t，1H)，5.52(d，1H)，4.61(q，2H)，3.19-2.88(m，6H)，1.42(t，3H)；m/z 244.

Method 50

4-(2-difluoromethyl-3-ethyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (E)-1-(2-difluoromethyl-3-ethyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone (method 49; 2.7g, 0.011mol) and Guanidinium carbonate (4.0g 0.022mol) is added in the 30ml ethylene glycol ethyl ether, 137 ℃ the heating 2 days.Removal of solvent under reduced pressure produces a kind of xanchromatic solid.Add 5.0ml DCM, add the 50ml ether again,, obtain a kind of solid (2.5g, 96%) of white the solid filtering drying that obtains.

NMR(400.132MHz)8.27(d，1H)，7.72(s，1H)，7.23(t，1H)，6.97(d，1H)，6.71(s，2H)，4.70(q，2H)，1.30(t，3H)；m/z 240.

Method 51

N-[(Z)-1-ethanoyl-2-amido vinyl]-N-sec.-propyl cyclopropylene carboxylic acid amides

Under 4 normal atmosphere, make cyclopropylene carboxylic acid sec.-propyl-(5-methyl-different  azoles-4-yl)-acid amides (method 36 of WO03/076434,18g, 0.086mol) and the EtOH solution and the H-H reaction of 10% palladium carbon (3.0g).Reactant is filtered, and removal of solvent under reduced pressure produces a kind of solid, adds ether, with this solid filtering (7.9g, 44%); M/z 211.

Method 52

1-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-ethane ketone

With N-[(Z)-1-ethanoyl-2-amido vinyl]-N-sec.-propyl cyclopropylene carboxylic acid amides (method 51; 7.9g, 0.038mol) and NaOH (2.28g 0.057mol) is added among the 150ml EtOH, and reflux spends the night.Removal of solvent under reduced pressure is handled the solid generated with the 100ml saturated ammonium chloride, with ether (3 * 100ml) extract, drying, removal of solvent under reduced pressure produces a kind of oil of black.Make eluent with 100% ether and make it purifying with silica gel column chromatography, the title compound of generation is a kind of xanchromatic oil (3.9g, 53%).

NMR(400.132MHz，CDCl ₃)7.65(s，1H)，5.63-5.48(m，1H)，2.44(s，3H)，1.98-1.91(m，1H)，1.57(d，6H)，1.17-1.11(m，2H)，1.07-1.03(m，2H)；m/z 193.

Method 53

(E)-1-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone

With 1-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-ethane ketone (method 52; 3.74g, 0.019mol) and DMFDMA (6.66ml 0.039mol) is added among the DMF, 130 ℃ the heating 4 hours.Removal of solvent under reduced pressure produces a kind of saffron glue, adds DCM, adds diethyl ether again, and the title compound that obtains is a kind of xanchromatic solid, with this xanchromatic solid filtering and drying (4.5g, 96%).

NMR (400.132MHz, CDCl ₃) 7.63 (d, 1H), 7.40 (s, 1H), 5.61 (septet, 1H), 5.50 (d, 1H), 3.12-2.88 (m, 6H), 1.98-1.92 (m, 1H), 1.60 (d, 6H), 1.13-1.09 (m, 2H), 1.03-0.98 (m, 2H); M/z 248.

Method 54

4-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-pyrimidine-2-base amine

With (E)-1-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone (method 53; 4.5g, 0.019mol) and Guanidinium carbonate (6.55g 0.036mol) is added in the 75ml ethylene glycol ethyl ether, 142 ℃ the heating 2 days.Removal of solvent under reduced pressure adds 100ml water, and (3 * 100ml) extract, and dry back removal of solvent under reduced pressure produces a total yellow solid with DCM.Add DCM, add diethyl ether then, this mixture was stirred 30 minutes, filter then, dry (3.6g, 78%).

NMR (400.132MHz, CDCl ₃) 8.22 (d, 1H), 7.28 (s, 1H), 6.79 (d, 1H), 5.57 (septet, 1H), 5.01 (brs, 2H), 2.03-1.96 (m, 1H), 1.64 (d, 6H), 1.17-1.13 (m, 2H), 1.05-1.00 (m, 2H); M/z 244.

Method 55

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } ethyl benzoate

In 4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 18; 7.8g) two  alkane (200ml) solution in add 4-iodobenzoic acid ethyl ester (9.445g), acid chloride (461mg), XANTPHOS (1.785g) and cesium carbonate (22.29g).With this mixture degassing, logical nitrogen cleans, and reflux is 3 hours then.Make the mixture cool to room temperature, the solids removed by filtration composition makes filtrate decompression concentrate then.Make product purification with silica gel column chromatography, do elutriant with the DCM of 2-5%MeOH, the title compound of generation is a kind of yellow solid (3.82g, 31%).

NMR 9.87(s，1H)，8.46(d，1H)，7.90-7.83(m，4H)，7.45(s，1H)，7.14(d，1H)，5.72-5.63(m，1H)，4.27(q，2H)，2.49(s，3H)，1.47(d，6H)，1.30(t，3H)；m/z 366.

Method 56

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } the phenylformic acid sodium salt

With 4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } ethyl benzoate (method 55; 3.82g) be dissolved among the 130ml THF, add water (20ml) solution of NaOH (419mg) then.With this mixture reflux 2 days.Make this mixture concentrating under reduced pressure, be dissolved in then in the 400ml water, with EtOAc (2 * 300ml) washings.The water layer concentrating under reduced pressure is produced the title compound (3.53g, 94%) of white solid state.

NMR 9.43(s，1H)，8.38(d，1H)，7.79(d，2H)，7.56(d，2H)， 7.41(s，1H)，7.03(d，1H)，5.82-5.72(m，1H)，2.49(s，3H)，1.44(d，6H)；m/z 338.

Method 57

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenylformic acid second Ester

In 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 17; 5.32g) two  alkane (100ml) solution in add 4-iodobenzoic acid (3.59g), acid chloride (II) (305mg), XANTPHOS (1.18g) and Strontium carbonate powder (14.74g).Make this mixture degassing, clean with nitrogen, reflux is 3 hours then.With the mixture cool to room temperature, remove by filter solid state component again, then filtrate decompression is concentrated.With the silica gel column chromatography purifying,, generate yellow solid-state title compound (2.75g, 32%) with the DCM eluant solution of 2-5%MeOH.

NMR 9.97(s，1H)，8.62(d，1H)，7.88(d，2H)，7.80(d，2H)，7.38(d，1H)，5.47-5.38(m，1H)，4.27(q，2H)，2.53(s，3H)，1.46(d，6H)，1.30(t，3H)；m/z 384.

Method 58

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } lithium benzoate Salt

With 4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } ethyl benzoate (method 57; 2.75g) EtOH (70ml) solution stirring water (15ml) solution of adding lithium hydroxide (301mg).With this mixture reflux 18 hours, concentrating under reduced pressure then divided water (300ml) and EtOAc (300ml) and comes.Further wash water layer with EtOAc (200ml), concentrating under reduced pressure, the title compound (2.07g, 80%) of generation white solid state.

NMR 9.56(s，1H)8.53(d，1H)，7.80(d，2H)，7.53(d，2H)，7.36(d，1H)，5.56-5.46(m，1H)，2.51(s，3H)，1.43(d，6H)；m/z356.

Method 59

4-bromo-2-fluoro-N-(1-methyl piperidine-4-yl) benzamide

With 4-bromo-2-fluorobenzoic acid (5.0g, 0.023mol) and HBTU (9.5g 0.025mol) is dissolved among the DMF (75ml).Add hereinto methyl piperidine-4-amine (2.9g, 0.025mol), then add again DIPEA (8.8ml, 0.051mol).This reactant was stirred 90 minutes, and DMF is removed in decompression then.With 50ml 2.0M NaOH the solids that generates is quenched, (3 * 100ml) extract with DCM.With the organic phase drying, removal of solvent under reduced pressure produces brown mud, the cooling after fixing.This solid is dissolved among the DCM, adds ether up to producing solid precipitation.Then title compound is filtered out and dry (7.3g, 100%).

NMR 8.47(d，1H)，7.65(d，1H)，7.54-7.47(m，2H)，4.06-3.91(m，1H)，3.38-3.34(m，2H)，3.09(t，2H)，2.74(s，3H)，2.04-1.98(m，2H)，1.74(q， 2H)；m/z 316.

Method 60

4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazol-4 yl]-pyrimidine-2-base amine

Title compound is with Guanidinium carbonate and 3-(dimethylamino)-1-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl] third-2-alkene-1-ketone (method 50 of WO 03/076434) by the step of method 17 with identical scale production.

NMR (400.132MHz, CDCl ₃): 8.26 (d, 1H), 7.38 (s, 1H), 6.82 (d, 1H), 5.30 (septet, 1H), 5.14 (s, 2H), 4.64 (s, 3H), 3.39 (s, 3H), 1.59 (d, 6H); M/z 248.

Method 61

Tert-butyl 3-[(4-phenyl-iodide formyl radical) amino] piperidines-1-carboxylicesters

With tert-butyl 3-amino piperidine-1-carboxylicesters (1.0g, 5.0mmol) and triethylamine (1.4g 10.0mmol) is placed among the 10ml THF and stirs in inert gas environment.Gradation adding 4-benzyl iodide chlorine in the time more than 1 minute (1.33g, 5.0mmol).Continue to stir 2 hours.Reduction vaporization falls solvent useless, and recrement is divided into EtOAc (25ml) and 1M NaOH (10ml).Water (10ml) and salt solution (10ml) washing organism, drying, evaporation, the title compound of generation is white solid (1.7g, 5.0mmol, 80%).

NMR 8.26(d，1H)，7.83(d，2H)，7.61(d，2H)，4.00-3.65(m，3H)，2.79(app t，2H)，1.95-1.63(m，2H)，1.59-1.37(m，11H)；m/z 431.

Method 62

4-bromo-3-fluorobenzoic acid

(24.4g 0.128mol) is added to KMnO with 4-bromo-3-toluene fluoride ₄(24g is 0.154mol) and in the mixture of water (150ml).This mixture 95 ℃ of heating 2 hours, is added other 24g KMnO then ₄, after 2 hours, add 24g KMnO at 95 ℃ of reheat ₄, continue to remain on 95 ℃ 18 hours.Then that this is hot mixture filters with the diatomite filter bed, washes with water.Make filtrate be acidified to pH 2 with 2N hydrochloric acid, with the supernatant filtration of white, drying obtains the 7.33g product.(2 * 250ml) extract filtrate, make the organic extraction drying, and reduction vaporization generates other product with EtOAc.Two parts of products are merged (7.92g, 28%).

NMR：7.68(d，1H)，7.74(d，1H)，7.82-7.87(m，1H)；M/z(M-H)-217.

Method 63

4-bromo-3-fluoro-N, dinethylformamide

(7.0ml, (method 62,7.92g is in the DCM that contains DMF (250ml) suspension 36.33mmol) 79.92mmol) to be added to 4-bromo-3-fluorobenzoic acid with oxalyl chloride.This mixture was stirred 18 hours, then concentrating under reduced pressure.Residue is dissolved among the 250ml DCM, adds 17ml dimethylated methylene amine (the EtOH solution of 5.6M), this mixture was at room temperature stirred 2 hours.Reaction mixture NaHCO ₃(3 * 150ml) and salt solution (150ml) washing, drying, concentrating under reduced pressure obtains title compound (5.01g, 56%).

NMR 7.56-7.62(t，1H)，7.19(d，1H)，7.09(d，1H)，3.09(s，3H)，2.99(s，3H)；M/z 248.

Embodiment 98

The following describes the representational pharmaceutical dosage forms that contains formula (I) compound that is used for the treatment of or prevents human diseases, perhaps pharmaceutically adoptable salt, or its hydrolyzable in vivo ester (reaching following compounds X herein):

(a): tablet I	The mg/ sheet
(a): tablet I	The mg/ sheet	Compounds X	100
Lactose Ph.Eur	182.75	Compounds X	100
Lactose Ph.Eur	182.75	Carmellose sodium salt	12.0
Corn starch paste (5%w/v paste)	2.25	Carmellose sodium salt	12.0
Corn starch paste (5%w/v paste)	2.25	Magnesium Stearate	3.0

(b): tablet II	Mg/sheet
(b): tablet II	Mg/sheet	Compounds X	50
Lactose Ph.Eur	223.75	Compounds X	50
Lactose Ph.Eur	223.75	Carmellose sodium salt	6.0
W-Gum	15.0	Carmellose sodium salt	6.0
W-Gum	15.0	Povidone	2.25
Magnesium Stearate	3.0	Povidone	2.25

(c): tablet III	The mg/ sheet
(c): tablet III	The mg/ sheet	Compounds X	1.0
Lactose Ph.Eur	93.25	Compounds X	1.0
Lactose Ph.Eur	93.25	Carmellose sodium salt	4.0
Corn starch paste (5%w/v paste)	0.75	Carmellose sodium salt	4.0
Corn starch paste (5%w/v paste)	0.75	Magnesium Stearate	1.0

(d): capsule	The mg/ ball
(d): capsule	The mg/ ball	Compounds X	10
Lactose Ph.Eur	488.5	Compounds X	10
Lactose Ph.Eur	488.5	Magnesium Stearate	1.5

(e): injection I	(50mg/ml)
(e): injection I	(50mg/ml)	Compounds X	5.0％w/v
1M NaOH solution	15.0％v/v	Compounds X	5.0％w/v
1M NaOH solution	15.0％v/v	0.1M hydrochloric acid	(transferring to pH 7.6)
Polyethylene glycol 400	4.5％w/v	0.1M hydrochloric acid	(transferring to pH 7.6)
Polyethylene glycol 400	4.5％w/v	Water for injection	To 100%

(f): injection II	10mg/ml
(f): injection II	10mg/ml	Compounds X	1.0％w/v
Sodium phosphate BP	3.6％w/v	Compounds X	1.0％w/v
Sodium phosphate BP	3.6％w/v	0.1M NaOH solution	15.6％v/v
Water for injection	To 100%	0.1M NaOH solution	15.6％v/v

(g): injection III	(1mg/ml is buffered to pH6)
(g): injection III	(1mg/ml is buffered to pH6)	Compounds X	0.1％w/v
Sodium phosphate BP	2.26％w/v	Compounds X	0.1％w/v
Sodium phosphate BP	2.26％w/v	Citric acid	0.38％w/v
Polyethylene glycol 400	3.5％w/v	Citric acid	0.38％w/v
Polyethylene glycol 400	3.5％w/v	Water for injection	To 100%

Note

Above-mentioned prescription can obtain by the method for knowing in the pharmacy skill that makes things convenient for.Tablet (a)-(c) can be made coated tablet by method easily, for example makes coated tablet with the rhodia phthalic ester.

Claims

1. the compound of a formula (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester:

Wherein:

R ¹Be hydrogen or halogen;

R ²Be halogen, nitrogen, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, methylthio group, methylsulfonyl, trifluoromethyl, trifluoromethoxy, C _1-6Alkyl, C _1-6Alkoxyl group, C _2-6Thiazolinyl or C _2-6Alkynyl;

P is 0-4, wherein R ²Value can be identical or different;

R ³And R ⁴Be respectively hydrogen, C separately separately _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Carbon atom can be individually by one or more R ⁵Replace arbitrarily; And if said heterocycle contains one-NH-part, then its nitrogen-atoms can be by a R ⁶Group replaces arbitrarily;

R ¹⁹Be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclopropyl methyl, 1-cyclopropyl ethyl or cyclobutyl; R wherein ¹Carbon atom can be by one or more R ²¹Replace arbitrarily;

R ⁵Be halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, amino-sulfonyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkanoylamino, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) a wherein a is 0～2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) amino-sulfonyl, N, N-(C _1-6Alkyl) ₂Amino-sulfonyl, C _1-6Alkyl amino sulfonyl amino, carbocylic radical, heterocyclic radical, carbocylic radical C _1-6Alkyl-R ⁷-, heterocyclic radical C _1-6Alkyl-R ⁸-, carbocylic radical-R ⁹-or heterocyclic radical-R ¹⁰-; R wherein ⁵Carbon atom can be by one or more R ¹¹Replace arbitrarily; And if said heterocyclic radical contains one-NH-part, then its nitrogen-atoms can be by a R ¹²Group replaces arbitrarily;

R ⁶And R ¹²Be separately C separately _1-6Alkyl, C _1-6Alkyloyl, C _1-6Alkyl amino sulfonyl, amino-sulfonyl carbonyl, formamyl, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, benzyl, carbobenzoxy-(Cbz), benzoyl and benzenesulfonyl; R wherein ⁶And R ¹²Carbon atom separately can be separately by one or more R ¹³Replace arbitrarily;

R ⁷, R ⁸, R ⁹And R ¹⁰Be-O--N (R separately separately ¹⁴) ,-C (O)-,-N (R ¹⁵) C (O)-,-C (O) N (R ¹⁶)-,-S (O) _s-,-SO ₂N (R ¹⁷)-or-N (R ¹⁸) SO ₂-; R wherein ¹⁴, R ¹⁵, R ¹⁶, R ¹⁷And R ¹⁸Be separately hydrogen or C separately _1-6Alkyl, s are 0～2;

R ¹¹And R ¹³Be separately halogen separately, nitro, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfydryl, amino-sulfonyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methyl sulfenyl, ethyl sulfenyl, methyl sulfinyl, ethylsulfinyl-1 base, methyl sulphonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylamino alkylsulfonyl, N-ethylamino alkylsulfonyl, N, N-dimethylamino alkylsulfonyl, N, N-diethylamino alkylsulfonyl or N-methyl-N-ethylamino alkylsulfonyl; And

R ²¹Be halogen, methoxyl group and hydroxyl.

2. the compound of the formula of claim 1 (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester, wherein R ¹Be hydrogen or fluorine.

3. the compound of the formula of claim 1 or claim 2 (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester, wherein R ²Be halogen, cyano group or C _1-6Alkyl.

4. the compound of the formula (I) of each claim or its pharmacy acceptable salt or its hydrolyzable in vivo ester among the claim 1-3, p wherein is 0 or 1.

5. the compound of the formula (I) of each claim or its pharmacy acceptable salt or its hydrolyzable in vivo ester, wherein R among the claim 1-4 ³And R ⁴Be respectively hydrogen, C separately separately _1-6Alkyl, carbocylic radical or heterocyclic radical; R wherein ³And R ⁴Carbon atom can be individually by one or more R ⁵Replace arbitrarily; And if said heterocycle contains one-NH-part, then its nitrogen-atoms can be by a R ⁶Group replaces arbitrarily; Wherein

R ⁵Be hydroxyl, N, N-(C _1-6Alkyl) ₂Amino and heterocyclic radical;

R ⁶Be C _1-6Alkyl and C _1-6Alkoxy carbonyl, wherein R ⁶Carbon atom can be separately by one or more R ¹³Replace arbitrarily;

R ¹³Be methoxyl group.

6. the compound of the formula (I) of each claim or its pharmacy acceptable salt or its hydrolyzable in vivo ester among the claim 1-5, R wherein ¹⁹Be ethyl, sec.-propyl, cyclopropyl methyl, 1-cyclopropyl ethyl or cyclobutyl.

7. the compound of the formula (I) of each claim or its pharmacy acceptable salt or its hydrolyzable in vivo ester, wherein R among the claim 1-6 ²⁰Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, methoxymethyl or cyclopropyl.

8. the compound of a formula (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester:

Wherein:

R ¹Be hydrogen or fluorine;

R ²Be fluorine, chlorine, cyano group or methyl;

P is 0 or 1;

R ³And R ⁴Be respectively hydrogen, methyl, cyclopropyl separately separately, the 2-hydroxyethyl, 1-methyl piperidine-4-base, piperidines-3-base, tetrahydropyran-4-base, 1,1-diepoxy tetramethylene sulfide-3-base, the 2-dimethyl aminoethyl, 1-methyl-2--dimethyl aminoethyl, piperidines-1-base ethyl, 2-morpholino ethyl, 1-(2-methoxy ethyl) piperidin-4-yl, 2-parathiazan be for ethyl, 2-tetramethyleneimine-1-base ethyl and 1-(tert-butoxycarbonyl) piperidines-3-base;

9. the compound of a formula (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester:

Be selected from:

2-fluoro-4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-methyl-benzamide;

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-methyl-benzamide;

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N, the N-dimethyl benzamide;

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-methyl-benzamide;

4-[4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl) pyrimidine-2--amino]-benzamide;

4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-(1-methyl piperidine-4-yl) benzamide;

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-(2-piperidines-1-base ethyl) benzamide;

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-(2-morpholino-4-base ethyl) benzamide;

4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-[1-(2-methoxy ethyl) piperidin-4-yl] benzamide; With

2-fluoro-4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-N-(1-methyl piperidine-4-yl) benzamide.

10. preparation formula (I) compound or its pharmacy acceptable salt or its method of hydrolyzable ester in vivo, this method comprises:

Method a) makes the pyrimidine of formula (II)

Wherein L is replaceable group

Aniline reaction with formula (III)

Perhaps

Method b) makes the compound of formula (IV)

Compound reaction with formula V

Wherein T is oxygen or sulphur, R ^xCan be the same or different, be C _1-6Alkyl;

Perhaps

Method c) make formula (VI) acid or its reactive derivative

Amine (HNR with formula (VII) ³R ⁴) reaction;

Perhaps

Method d), makes the pyrimidine of formula (VIII) for the compound of preparation formula (I)

Compound reaction with formula (IX)

Wherein Y is a replaceable group;

And, if after this need:

I) compound of formula (I) is converted into the compound of another kind of formula (I);

Ii) remove any blocking group;

Iii) generate a kind of pharmaceutically adoptable salt or hydrolyzable in vivo ester.

11. a pharmaceutical composition, it comprises compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester and the pharmaceutically acceptable diluent or carrier of the formula (I) of each claim among the claim 1-9.

12. be used as compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester of the formula (I) of each claim among the claim 1-9 of medicine.

13. the compound of the formula of each claim (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester are used for the purposes of the medicine of inhibition of cell proliferation effect among the claim 1-9 in preparation.

14. the compound of the formula of each claim (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester are used for producing the purposes of the inhibiting medicine of CDK2 among the claim 1-9 in production.

15. the compound of the formula of each claim (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester are used for the treatment of purposes in the medicine of tumour in preparation among the claim 1-9.

16. the compound of the formula of each claim (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester are used for the treatment of purposes in the medicine of leukemia or malignant lymphoma or mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, bladder cancer, carcinoma of the pancreas, carcinoma vulvae, skin carcinoma or ovarian cancer in preparation among the claim 1-9.

17. the compound of the formula of each claim (I) or its pharmacy acceptable salt or its hydrolyzable in vivo ester are used for the treatment of purposes in the medicine of tumour, fibroplasia and differentiation infringement, psoriasis, rheumatic arthritis, the multiple sarcoma hemorrhagic of skin, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosis, stricture of artery, autoimmune disease, acute and chronic inflammation, osteopathy and retinal vessel hyperplasia illness in eye in preparation among the claim 1-9.

18. produce the method for this anti-cell proliferative effect in needing the warm-blooded animal of anti-cell proliferative effect treatment, it comprises compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester of the formula (I) of each claim among the claim 1-9 of significant quantity of throwing to said animal.

19. produce the inhibiting method of this CDK2 in the warm-blooded animal that need treat with the CDK2 restraining effect, it comprises compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester of the formula (I) of each claim among the claim 1-9 of significant quantity of throwing to said animal.

20. in the warm-blooded animal that needs are treated treatment its suffer from the method for tumour, it comprises compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester of the formula (I) of each claim among the claim 1-9 of significant quantity of throwing to said animal.

21. the method for treatment its cases with leukemia or malignant lymphoma or mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, liver cancer, kidney, prostate cancer, bladder cancer, carcinoma of the pancreas, carcinoma vulvae, skin carcinoma or ovarian cancer in the warm-blooded animal that needs are treated comprises compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester of the formula (I) of each claim among the claim 1-9 of significant quantity of throwing to said animal.

22. in the warm-blooded animal that needs are treated treatment its suffer from the method for tumour, fibroplasia and differentiation infringement, psoriasis, rheumatic arthritis, skin pilosity sarcoma hemorrhagic, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosis, stricture of artery, autoimmune disease, acute and chronic inflammation, osteopathy and retinal vessel hyperplasia illness in eye, it comprises compound or its pharmacy acceptable salt or its hydrolyzable in vivo ester of the formula (I) of each claim among the claim 1-9 of significant quantity of throwing to said animal.