CN101273031A

CN101273031A - Imidazolyl-pyrimidine compounds for use in the treatment of proliferative disorders

Info

Publication number: CN101273031A
Application number: CNA2006800356039A
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: 2005-07-30
Filing date: 2006-07-27
Publication date: 2008-09-24
Also published as: ZA200800409B; GB0515743D0

Abstract

Compounds of formula (I): which possess cell cycle inhibitory activity are described.

Description

The imidazolyl-pyrimidine compounds that is used for the treatment of proliferative disease

The present invention relates to hydrolyzable ester in pyrimidine derivatives or its pharmacy acceptable salt or the body, it is active that described compound has the cell cycle inhibition, and therefore they have inhibition of cell proliferation (for example anticancer) activity, thereby be used for the treatment of the method for human body or animal body.The invention still further relates to method, pharmaceutical composition that contains them for preparing described pyrimidine derivatives and the purposes that is used in warm-blooded animal (for example people) body, producing the medicine of inhibition of cell proliferation effect in preparation thereof.

The cell cycle pair cell is survived, regulates and breeds most important, and carried out without any confusion to guarantee each step by strict regulation and control.The cell process of experience cell cycle arises from cell cycle protein dependent kinase (CDK) several members' of family activation in succession and passivation.They and the interaction that is called as the intracellular protein family of cyclin are depended in the activation of CDK.Cyclin combines with CDK, and the activity of CDK is very important in this association pair cell.Different cyclins is expressed on the difference of cell cycle and is degraded, and guarantees activation and passivation accurately the occurring in sequence by cell cycle progression of CDK.

In addition, CDK appears at the downstream of multiple oncogene signal transduction path.By raising cyclin and/or removing CDK activity that endogenous inhibitor the causes important axle center between the mitogenesis signal transduction path and tumor cell proliferation seemingly of lacking of proper care.

Therefore, the inhibitor (working in G2/M phase, G1/S-S-G2/M phase and G1-S phase respectively) of clear inhibitor, particularly CDK1, CDK2, CDK4 and the CDK6 that recognizes cell-cycle kinases has much value as the activity inhibitor of cell proliferation (for example mammalian cancer cells growth).

General also think consecutive transcription activity that the tumour cell height depends on rna plymerase ii safeguarding the proper level of inhibitor of apoptosis protein, and guarantee the tumour cell survival.The activity that clear particularly CDK1, CDK7, CDK8 and CDK9 regulate rna plymerase ii by the phosphorylation in protein C end territory.Therefore, by these CDK inhibitor, inhibition rna plymerase ii activity will help the apoptosis-promoting effect in tumour cell.

Expection suppresses cell-cycle kinases and have value in treatment and unusual cell cycle and cell proliferation diseases associated, and described disease is cancer (solid tumor and leukemia), fiber proliferative and divide voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma (Kaposi ' ssarcoma), vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel for example.

WO 02/20512, WO 03/076435, WO 03/076436, WO03/076434, WO 03/076433 and WO 04/101549 have introduced some the 2-anilino-4-imidazolyl pyrimidines derivative that suppresses the cell-cycle kinases effect.The present invention is based on following discovery: one group of new 2-(4-heterocycle carbonyl anilino)-4-(imidazolyl) pyrimidine suppresses the effect of cell-cycle kinases (particularly CDK2), thereby has anticellular proliferation properties.All there is not specifically to disclose compound of the present invention in the above-mentioned application, and we expect with regard to one or more pharmacologically actives (particularly as the compound that suppresses CDK2) and/or pharmacokinetics feature, efficacy characteristics, metabolism and toxic characteristic, these compounds have beneficial property, make it be particularly suitable for warm-blooded animal (for example people's) vivo medicine-feeding.Specifically, these compounds generally have very high cell levels and enzyme effect, high water-soluble and favourable protein bound characteristic.

Therefore, the invention provides compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of following formula (I):

Wherein:

R ¹Be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclopropyl methyl, 1-cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl or cyclobutyl; R wherein ¹Can be by one or more R on carbon ⁶The optional replacement;

R ²Be methyl, ethyl, sec.-propyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxymethyl, cyclopropyl methyl or cyclopropyl;

R ³Be hydrogen or halogen;

R ⁴Be hydrogen, ethynyl, halogen, nitro, cyano group, hydroxyl, amino, carboxyl, formamyl, sulfydryl, methylthio group, methylsulfonyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl or methoxyl group;

The A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; Wherein 2 atoms of A ring when the A ring be nitrogen connect 5-7 unit saturated rings the time, can choose wantonly by 1 or 2 atomic bridge connection; And if wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace;

R ⁵Be the substituting group on the carbon, be selected from halogen, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfamyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkyloyl, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a(wherein a is 0-2), C _1-6Alkylsulfonyloxy, C _1-6Carbalkoxy, carbocylic radical, heterocyclic radical, N-(C _1-6Alkyl) sulfamyl or N, N-(C _1-6Alkyl) ₂Sulfamyl; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace; Perhaps R ⁵For-NHR ⁹,-NR ¹⁰R ¹¹Or-O-R ¹²

N is 0-2; R wherein ⁵Value can be identical or different;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁷, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹⁵Independently be selected from C _1-4Alkyl, C _1-4Alkyloyl, C _1-4Alkyl sulphonyl, C _2-4Thiazolinyl alkylsulfonyl, C _2-4Alkynyl alkylsulfonyl, C _1-4Carbalkoxy, formamyl, N-(C _1-4Alkyl) formamyl, N, N-(C _1-4Alkyl) formamyl, carbocylic radical or heterocyclic radical; R wherein ⁷, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹⁵Can be independently by one or more R that are selected from carbon ¹³Optional replacement of group; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁴Replace;

R ⁸Be selected from halogen, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, acetylamino, phenylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;

R ¹³Be selected from halogen, cyano group, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, dimethylamino, carbocylic radical, heterocyclic radical, C _1-3Alkyl and C _1-3Alkoxyl group; With

R ¹⁴Be selected from C _1-3Alkyl, C _1-3Alkyloyl, C _1-3Alkyl sulphonyl, C _1-3Carbalkoxy, formamyl, N-(C _1-3Alkyl) formamyl and N, N-(C _1-3Alkyl) formamyl.

The another feature according to the present invention provides hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body, wherein:

R ¹Be ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclopropyl methyl, 1-cyclopropyl ethyl or cyclobutyl; R wherein ¹Can be by one or more R on carbon ⁶The optional replacement;

R ³Be hydrogen or halogen;

The A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; If wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace;

R ⁵Be selected from halogen, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfamyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkyloyl, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a(wherein a is 0-2), C _1-6Carbalkoxy, N-(C _1-6Alkyl) sulfamyl or N, N-(C _1-6Alkyl) ₂Sulfamyl; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Perhaps R ⁵For-NHR ⁹,-NR ¹⁰R ¹¹Or-O-R ¹²

N is 0-2; R wherein ⁵Value can be identical or different;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁷, R ⁹, R ¹⁰, R ¹¹And R ¹²Independently be selected from C _1-4Alkyl, C _1-4Alkyloyl, C _1-4Alkyl sulphonyl, C _2-4Thiazolinyl alkylsulfonyl, C _2-4Alkynyl alkylsulfonyl, C _1-4Carbalkoxy, formamyl, N-(C _1-4Alkyl) formamyl, N, N-(C _1-4Alkyl) formamyl, carbocylic radical or heterocyclic radical; R wherein ⁷, R ⁹, R ¹⁰, R ¹¹And R ¹²Can on carbon, be selected from R independently ¹³Optional replacement of group, and if wherein described heterocyclic radical contain-the NH-part, then nitrogen can be chosen wantonly by R ¹⁴Replace;

R ⁸Be selected from halogen, cyano group, hydroxyl, trifluoromethoxy, trifluoromethyl, amino, carboxyl, formamyl, sulfamyl, methyl, ethyl, methoxyl group, oxyethyl group, ethanoyl, acetoxyl group, methylamino-, ethylamino, dimethylamino, diethylin, N-methyl-N-ethylamino, acetylamino, N-methylamino formyl radical, N-ethylamino formyl radical, N, the N-formyl-dimethylamino, N, N-diethylamino formyl radical, N-methyl-N-ethylamino formyl radical, methylthio group, ethylmercapto group, methylsulfinyl, the ethyl sulfinyl, methylsulfonyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methyl sulfamyl, N-ethyl sulfamyl, N, N-dimethylamino alkylsulfonyl, N, N-diethyl amino alkylsulfonyl or N-methyl-N-ethyl sulfamyl;

R ¹³Be selected from halogen, cyano group, hydroxyl, amino, trifluoromethyl, trifluoromethoxy, C _1- ₃Alkyl and C _1-3Alkoxyl group; With

R ³Be hydrogen or halogen;

R ⁵Be the substituting group on the carbon, be selected from halogen, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfamyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkyloyl, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a(wherein a is 0-2), C _1-6Carbalkoxy, carbocylic radical, heterocyclic radical, N-(C _1-6Alkyl) sulfamyl or N, N-(C _1-6Alkyl) ₂Sulfamyl; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace; Perhaps R ⁵For-NHR ⁹,-NR ¹⁰R ¹¹Or-O-R ¹²

N is 0-2; R wherein ⁵Value can be identical or different;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁷, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹⁵Independently be selected from C _1-4Alkyl, C _1-4Alkyloyl, C _1-4Alkyl sulphonyl, C _2-4Thiazolinyl alkylsulfonyl, C _2-4Alkynyl alkylsulfonyl, C _1-4Carbalkoxy, formamyl, N-(C _1-4Alkyl) formamyl, N, N-(C _1-4Alkyl) formamyl, carbocylic radical or heterocyclic radical; R wherein ⁷, R ⁹, R ¹⁰, R ¹¹, R ¹²And R ¹⁵Can on carbon, be selected from R independently ¹³Optional replacement of group, and if wherein described heterocyclic radical contain-the NH-part, then nitrogen can be chosen wantonly by R ¹⁴Replace;

R ³Be hydrogen or halogen;

N is 0-2; R wherein ⁵Value can be identical or different;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ³Be hydrogen or halogen;

N is 0-2; R wherein ⁵Value can be identical or different;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

In this specification sheets, term " alkyl " comprises straight chain and branched-chain alkyl, but when mentioning indivedual alkyl for example when " propyl group ", the form of then only refering in particular to straight chain." C for example _1-6Alkyl " and " C _1-4Alkyl " comprise methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl." C _1-3Alkyl " comprise methyl, ethyl, propyl group and sec.-propyl.Yet when mentioning indivedual alkyl for example when " propyl group ", the form of only refering in particular to straight chain is when mentioning indivedual branched-chain alkyls for example when " sec.-propyl ", the form of then only refering in particular to side chain.Similarly convention is applicable to other generic term.Term " halogen " is meant fluorine, chlorine, bromine and iodine.

Should be understood that if optional substituting group is selected from " one or more " group, then this definition comprises all substituting groups that are selected from a regulation group or the substituting group that is selected from two or more regulation groups.

" heterocyclic radical " be contain 4-12 atom, wherein at least one atom is selected from saturated, fractional saturation or the undersaturated monocycle or two rings of nitrogen, sulphur or oxygen, can be that carbon or nitrogen connect, except as otherwise noted, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, and theheterocyclic nitrogen atom can be chosen wantonly and have C _1-6Alkyl also forms quaternary compound, and perhaps theheterocyclic nitrogen atom and/or epithio atom can be chosen oxidized formation N-oxide compound or S-oxide compound wantonly.The example of term " heterocyclic radical " and suitable value are morpholino, piperidyl, pyridyl, pyranyl, pyrryl, isothiazolyl, indyl, quinolyl, thienyl, 1,3-benzodioxole base, thiadiazolyl group, piperazinyl, thiazolidyl, pyrrolidyl, thiomorpholine generation, pyrrolinyl, high piperazinyl, 3,5-two oxa-piperidyls, THP trtrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl isoxazolyl, N-methylpyrrole base, the 4-pyridone, the 1-isoquinolone, 2-Pyrrolidone, the 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide compound.One aspect of the present invention, term " heterocyclic radical " be contain 5 or 6 atoms, wherein at least one atom is selected from saturated, fractional saturation or the undersaturated monocycle or the dicyclo of nitrogen, sulphur or oxygen, can be that carbon or nitrogen connect, except as otherwise noted, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, and the epithio atom can be chosen oxidized formation S-oxide compound wantonly.

" carbocylic radical " is saturated, fractional saturation or undersaturated monocycle or the bicyclic carbocyclic that contains 3-12 atom; Wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement." carbocylic radical " particularly contains the monocycle of 5 or 6 atoms, or contains the dicyclo of 9 or 10 atoms.The suitable value of " carbocylic radical " comprises cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralyl, indanyl or 1-oxo indanyl.

The A ring is " the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing "." the 4-7 unit saturated rings that nitrogen connects; optional other nitrogen, oxygen or the sulphur atom of containing " is the saturated monocycle that contains 4-7 atom, be connected with the phenyl moiety of formula (I) by the nitrogen-atoms that is comprised in the ring, the optional heteroatoms that is selected from nitrogen, sulphur or oxygen in addition that contains of this ring, wherein-CH ₂-group can be chosen wantonly by-C (O)-displacement, and optional sulphur atom can be chosen oxidized formation S-oxide compound wantonly." 5 or 6 yuan of saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing " definition is that wherein said ring only has 5 or 6 atoms with " the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing ".

During the first saturated rings of the 5-7 that two atoms of A ring connect for nitrogen when the A ring, can choose wantonly by 1 or 2 atomic bridge connection.Bridge is 1 atom or 2 atoms of two different pieces of link molecule." 1 or 2 atomic bridge " can be made up of one or two carbon atom, perhaps is made up of a heteroatoms, perhaps is made up of a heteroatoms and a carbon atom.Heteroatoms is selected from oxygen, nitrogen or sulphur.Bridge is in particular a Sauerstoffatom.Perhaps bridge is a carbon atom.The example of " the 5-7 unit saturated rings that nitrogen connects; optional other nitrogen, oxygen or the sulphur atom of containing ... connect by 1 or 2 atomic bridge " comprises 8-oxa--3-azabicyclic [3.2.1] oct-3-yl, 2,5-diazabicylo [2.2.1] heptan-2-base and 3-azabicyclic [3.2.1] oct-3-yl.

" C _1-6Carbalkoxy " and " C _1-4Carbalkoxy " example comprise methoxycarbonyl, ethoxycarbonyl, positive butoxy carbonyl and tertbutyloxycarbonyl." C _1-3Carbalkoxy " example comprise methoxycarbonyl and ethoxycarbonyl." C _1-3Alkoxyl group " example comprise methoxyl group, oxyethyl group and propoxy-." C _1-6Alkyl S (O) _a(wherein a is 0-2) " example comprise methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methylsulfonyl and ethylsulfonyl." C _1-6Alkyloyl ", " C _1-4Alkyloyl " and " C _1-3Alkyloyl " example comprise propionyl and ethanoyl." C _2-6Thiazolinyl " example be vinyl, allyl group and 1-propenyl." C _2-6Alkynyl " example be ethynyl, 1-proyl and 2-propynyl." N-(C _1-6Alkyl) sulfamyl " example be N-(methyl) sulfamyl and N-(ethyl) sulfamyl." N, N-(C _1-6Alkyl) ₂Sulfamyl " example be N, N-(dimethyl) sulfamyl and N-(methyl)-N-(ethyl) sulfamyl." N-(C _1-6Alkyl) formamyl ", " N-(C _1-4Alkyl) formamyl " and " N-(C _1-3Alkyl) formamyl " example be amino-carbonyl and B aminocarbonyl." N, N-(C _1-6Alkyl) ₂Formamyl ", " N, N-(C _1-4Alkyl) ₂Formamyl " and " N, N-(C _1-3Alkyl) ₂Formamyl " example be dimethylamino carbonyl and methyl B aminocarbonyl." C _1-4Alkyl sulphonyl " example comprise methyl sulphonyl, sec.-propyl alkylsulfonyl and tertiary butyl alkylsulfonyl." C _1-3Alkyl sulphonyl " example comprise methyl sulphonyl and sec.-propyl alkylsulfonyl." C _1-4The thiazolinyl alkylsulfonyl " example comprise vinylsulfonyl and allyl group alkylsulfonyl." C _1-4The alkynyl alkylsulfonyl " example comprise ethynyl alkylsulfonyl and proyl alkylsulfonyl." C _1-6Alkylsulfonyloxy " example be mesyloxy and sec.-propyl sulfonyloxy.

The pharmacy acceptable salt that The compounds of this invention is suitable is the acid salt that for example has the The compounds of this invention of enough alkalescence, for example with mineral acid or organic acid acid salt such as hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, trifluoroacetic acid, citric acid or toxilic acids.In addition, the suitable pharmacy acceptable salt that has enough tart The compounds of this invention be an alkali metal salt (for example sodium salt or sylvite), alkaline earth salt (for example calcium salt or magnesium salts), ammonium salt or with the salt that can accept cationic organic bases on the physiology salt of (for example with methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine) is provided.

For example contain hydrolyzable ester in the body of formula (I) compound of carboxyl or hydroxyl and be the pharmaceutically acceptable ester that in human body or animal body hydrolysis produces parent acid or alcohol.The pharmaceutically acceptable ester suitable for carboxyl comprises C _1-6Alkoxyl group methyl esters (for example methoxyl group methyl esters), C _1-6Alkyloyl oxygen base methyl esters (for example new pentane acyloxy methyl esters), phthalidyl ester, C _3-8Cycloalkoxycarbonyl oxygen base C _1-6Alkyl ester (for example 1-cyclohexyl-carbonyl oxygen base ethyl ester), 1,3-dioxole-2-ketone group methyl esters (for example 5-methyl isophthalic acid, 3-dioxole-2-ketone group methyl esters) and C _1-6Alkoxycarbonyloxy ethyl ester (for example 1-methoxycarbonyl oxygen base ethyl ester), and can form at any carboxyl of The compounds of this invention.

Contain hydrolyzable ester in the body of formula (I) compound of hydroxyl comprise inorganic ester (for example phosphoric acid ester) and alpha-acyloxy alkyl oxide and as ester in vivo hydrolysis the result and decompose the related compound that obtains parent hydroxy.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy methoxyl group.For hydroxyl, the formation group of hydrolyzable ester comprises alkyloyl, benzoyl, phenyl acetyl, substituted benzoyl, substituted-phenyl ethanoyl, carbalkoxy (obtaining alkyl carbonate), dialkyl amido formyl radical and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (obtaining carbamate), dialkyl amido ethanoyl and carboxyl ethanoyl in the selected body.Substituent example comprises morpholino and the piperazine-1-base (piperazino) that is connected to benzoyl basic ring 3-position or 4-position from the theheterocyclic nitrogen atom by methylene radical on the benzoyl.

Some formula (I) compound can have chiral centre and/or rotamerism center (E-isomer and Z-isomer), it should be understood that the present invention includes to have CDK inhibition active all these optically active isomers, diastereomer and geometrical isomer.

The present invention relates to have any and all tautomeric forms that CDK suppresses active formula (I) compound.

Should also be understood that some formula (I) compound can the solvation form and the non-solvent form exist, for example exist with hydrated form.It should be understood that the present invention includes and have active all these the solvation forms of CDK inhibition.

The concrete value of variable group is as follows.For definition, claim or the embodiment that this paper limited, if suitably, just can adopt these values.

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

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

R ¹Be ethyl.

R ¹Be sec.-propyl.

R ¹Be the cyclopropyl methyl.

R ¹Be 1-cyclopropyl ethyl.

R ¹Be cyclobutyl.

R ¹Be cyclopentyl.

R ¹Be cyclobutyl.

R ²Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, methoxymethyl or cyclopropyl.

R ²Be the methyl or methoxy methyl.

R ²Be methyl.

R ²Be ethyl.

R ²Be sec.-propyl.

R ²Be difluoromethyl.

R ²Be trifluoromethyl.

R ²Be methoxymethyl.

R ²Be cyclopropyl.

R ³Be hydrogen or fluorine.

R ³Be hydrogen, fluorine or chlorine.

R ³Be hydrogen.

R ³Be fluorine.

R ³Be chlorine.

R ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy.

R ⁴Be hydrogen, fluorine, chlorine, cyano group, methylsulfonyl, methyl or methoxy.

R ⁴Be hydrogen.

R ⁴Be halogen.

R ⁴Be fluorine.

R ⁴Be chlorine.

R ⁴Be cyano group.

R ⁴Be methylsulfonyl.

R ⁴Be methyl.

R ⁴Be methoxyl group.

The A ring is 5 or 6 yuan of saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; If wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace; R wherein ⁷Be C _1-4Alkyl.

The A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; Wherein 2 atoms of A ring when the A ring be nitrogen connect 5-7 unit saturated rings the time, can choose wantonly by 1 or 2 atomic bridge connection; If wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace; Wherein

R ⁷Be selected from C _1-4Alkyl, carbocylic radical or heterocyclic radical; R wherein ⁷Can be by one or more R that are selected from carbon ¹³Optional replacement of group;

R ¹³Be selected from halogen, hydroxyl, C _1-3Alkyl, C _1-3Alkoxyl group, dimethylamino or heterocyclic radical.

The A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; Wherein 2 atoms of A ring when the A ring be nitrogen connect 5-7 unit saturated rings the time, can choose wantonly by 1 or 2 atomic bridge connection; And if wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace; Wherein

R ⁷Be selected from C _1-4Alkyl or carbocylic radical; R wherein ⁷Can on carbon, be selected from R ¹³Optional replacement of group;

R ¹³Be selected from hydroxyl, C _1-3Alkoxyl group, dimethylamino or heterocyclic radical.

R ¹³Be selected from C _1-3Alkoxyl group, dimethylamino or heterocyclic radical.

The A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; If wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace; Wherein

The A ring is morpholino, piperazine-1-base or tetramethyleneimine-1-base; Wherein said piperazine-1-base can be by R on nitrogen ⁷The optional replacement; R wherein ⁷Be C _1-4Alkyl.

The A ring is morpholino, 1,1-dioxo thiomorpholine is for (1,1-dioxothiomorpholino), piperidines-1-base, 1,4-Diazesuberane-1-base, azetidine-1-base, piperazine-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl, tetramethyleneimine-1-base or 2,5-diazabicylo [2.2.1] heptan-5-base; Wherein the A ring can be by R on nitrogen ⁷The optional replacement; Wherein

R ⁷Be selected from methyl, ethyl, sec.-propyl, cyclopropyl, cyclobutyl, phenyl or pyridyl; R wherein ⁷Can be by one or more R that are selected from carbon ¹³Optional replacement of group;

R ¹³Be selected from fluorine, chlorine, hydroxyl, methyl, methoxyl group, dimethylamino or tetramethyleneimine-1-base.

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, 1,4-Diazesuberane-1-base, azetidine-1-base, piperazine-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl, tetramethyleneimine-1-base or 2,5-diazabicylo [2.2.1] heptan-5-base; Wherein said 1,4-Diazesuberane-1-base, piperazine-1-base or 2,5-diazabicylo [2.2.1] heptan-the 5-base can be by R on nitrogen ⁷The optional replacement; Wherein

R ⁷Be selected from methyl, ethyl, sec.-propyl, cyclopropyl or cyclobutyl; R wherein ⁷Can on carbon, be selected from R ¹³Optional replacement of group;

R ¹³Be selected from hydroxyl, methoxyl group, dimethylamino or tetramethyleneimine-1-base.

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, 1,4-Diazesuberane-1-base, azetidine-1-base, 1,1-dioxothimorpholino, piperazine-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl or tetramethyleneimine-1-base; Wherein said 1,4-Diazesuberane-1-base or piperazine-1-base can be by R on nitrogen ⁷The optional replacement; Wherein

R ⁷Be selected from methyl, ethyl, sec.-propyl or cyclopropyl; R wherein ⁷Can on carbon, be selected from R ¹³Optional replacement of group;

R ¹³Be selected from methoxyl group, dimethylamino or tetramethyleneimine-1-base.

A ring is morpholino, piperidines-1-base, 1,4-Diazesuberane-1-base, azetidine-1-base, 1,1-dioxo thiomorpholine generation, piperazine-1-base or tetramethyleneimine-1-base; Wherein said 1,4-Diazesuberane-1-base or piperazine-1-base can be by R on nitrogen ⁷The optional replacement; Wherein

R ⁷Be selected from methyl, ethyl or cyclopropyl; R wherein ⁷Can on carbon, be selected from R ¹³Optional replacement of group;

The A ring is morpholino, piperazine-1-base or tetramethyleneimine-1-base; Wherein said piperazine-1-base can be by R on nitrogen ⁷The optional replacement; R wherein ⁷Be methyl.

The A ring is morpholino, 4-methylpiperazine-1-base or tetramethyleneimine-1-base.

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, the 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base, 4-sec.-propyl piperazine-1-base, the high piperazine of 4-cyclopropyl-1-base, the high piperazine of 4-cyclobutyl-1-base, the high piperazine of 4-(2-hydroxyethyl)-1-base, the high piperazine of 4-sec.-propyl-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl, tetramethyleneimine-1-base, 2,5-diazabicylo [2.2.1] heptan-5-base or 2-ethyl-2,5-diazabicylo [2.2.1] heptan-5-base.

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, the 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-ethyl-1,4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base, 4-sec.-propyl piperazine-1-base, 4-(4-fluorophenyl) piperazine-1-base, 4-(2-fluorophenyl) piperazine-1-base, 4-(2, the 4-difluorophenyl) piperazine-1-base, 4-(3, the 4-difluorophenyl) piperazine-1-base, 4-(2-chloro-phenyl-) piperazine-1-base, 4-(4-chloro-phenyl-) piperazine-1-base, 4-(4-phenyl) piperazine-1-base, 4-(2-p-methoxy-phenyl) piperazine-1-base, 4-(3-p-methoxy-phenyl) piperazine-1-base, 4-(4-p-methoxy-phenyl) piperazine-1-base, 4-(3-aminomethyl phenyl) piperazine-1-base, 4-(2-aminomethyl phenyl) piperazine-1-base, 4-(4-aminomethyl phenyl) piperazine-1-base, 4-(2, the 3-3,5-dimethylphenyl) piperazine-1-base, 4-(2, the 6-3,5-dimethylphenyl) piperazine-1-base, 4-(4-hydroxy phenyl) piperazine-1-base, 4-(2-hydroxy phenyl) piperazine-1-base, 4-(5-chloropyridine-2-yl) piperazine-1-base, the high piperazine of 4-cyclopropyl-1-base, the high piperazine of 4-cyclobutyl-1-base, the high piperazine of 4-(2-hydroxyethyl)-1-base, the high piperazine of 4-(2-methoxy ethyl)-1-base, the high piperazine of 4-sec.-propyl-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl, tetramethyleneimine-1-base, 2,5-diazabicylo [2.2.1] heptan-5-base, 2-methyl-2,5-diazabicylo [2.2.1] heptan-5-base, 2-(2-methoxy ethyl)-2,5-diazabicylo [2.2.1] heptan-5-base, 2-ethyl-2,5-diazabicylo [2.2.1] heptan-5-base or 2-sec.-propyl-2,5-diazabicylo [2.2.1] heptan-5-base.

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base, 4-sec.-propyl piperazine-1-base, the high piperazine of 4-sec.-propyl-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl or tetramethyleneimine-1-base.

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base or tetramethyleneimine-1-base.

The A ring is morpholino.

The A ring is 4-methylpiperazine-1-base.

The A ring is tetramethyleneimine-1-base.

R ⁵For-NR ¹⁰R ¹¹R wherein ¹⁰And R ¹¹Independently be selected from C _1-4Alkyl.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, C _1-6Alkyl, C _1-6Alkylsulfonyloxy, C _1-6Alkyl S (O) _a(wherein a is 2) or heterocyclic radical; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace; Wherein

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from C _1-4Alkyl or carbocylic radical; R wherein ⁹, R ¹⁰, R ¹¹And R ¹⁵Can be independently by one or more R that are selected from carbon ¹³Optional replacement of group;

R ⁸Be selected from hydroxyl, amino and phenylamino; With

R ¹³Be selected from carbocylic radical and C _1-3Alkoxyl group.

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from C _1-4Alkyl or carbocylic radical;

R ⁸Be selected from hydroxyl and amino.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, C _1-6Alkyl, C _1-6Alkyl S (O) _a(wherein a is 2) or heterocyclic radical; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace; Wherein

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from C _1-4Alkyl;

R ⁸Be selected from hydroxyl and amino.

R ⁵For-NR ¹⁰R ¹¹R wherein ¹⁰And R ¹¹Be methyl.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, mesyloxy, morpholino, piperidines-1-base, pyridine-2-base, high piperazine-1-base, piperazine-1-base or tetramethyleneimine-1-base; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; R wherein ⁵Can be by R on nitrogen ¹⁵The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹Wherein

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from methyl, ethyl, propyl group, sec.-propyl, isobutyl-, cyclopropyl or cyclobutyl; R wherein ⁹, R ¹⁰, R ¹¹And R ¹⁵Can be independently by one or more R that are selected from carbon ¹³Optional replacement of group;

R ⁸Be selected from hydroxyl, amino and phenylamino; With

R ¹³Be selected from cyclopropyl and methoxyl group.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, mesyloxy, morpholino, piperidines-1-base, piperazine-1-base or tetramethyleneimine-1-base; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Wherein said piperazine-1-base can be by R on nitrogen ¹⁵The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹Wherein

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from methyl or cyclopropyl;

R ⁸Be selected from hydroxyl and amino.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, piperazine-1-base or tetramethyleneimine-1-base; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Wherein said piperazine-1-base can be by R on nitrogen ¹⁵The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹Wherein

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from methyl;

R ⁸Be selected from hydroxyl and amino.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, mesyloxy, morpholino, piperidines-1-base, dimethylamino, diethylin, sec.-propyl, pyridine-2-base, methylol, methylamino-, aminomethyl, 4-methylpiperazine-1-base, cyclopropylamino, tetramethyleneimine-1-base, high piperazine-1-base, ring fourth amino, phenylamino methyl, N-methyl-N-(cyclopropyl methyl) amino, N-methyl-N-cyclopropylamino, N-methyl-N-isopropyl fourth amino, N-methyl-N-(2-methoxy ethyl) are amino, N-ethyl-N-third amino or N-methyl-N-encircle fourth amino.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, mesyloxy, morpholino, piperidines-1-base, dimethylamino, methylol, methylamino-, aminomethyl, 4-methylpiperazine-1-base, cyclopropylamino or tetramethyleneimine-1-base.

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, dimethylamino, methylol, methylamino-, aminomethyl, 4-methylpiperazine-1-base or tetramethyleneimine-1-base.

N is 0 or 1.

N is 0.

N is 1.

N is 2; R wherein ⁵Value can be identical or different.

Therefore, another aspect of the invention provides hydrolyzable ester in formula (I) compound (as implied above) or its pharmacy acceptable salt or the body, wherein:

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

R ²Be the methyl or methoxy methyl;

R ³Be hydrogen or fluorine;

R ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy;

The A ring is 5 or 6 yuan of saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; If wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace; R wherein ⁷Be C _1-4Alkyl;

R ⁵For-NR ¹⁰R ¹¹R wherein ¹⁰And R ¹¹Independently be selected from C _1-4Alkyl; With

N is 0 or 1.

R ²Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, methoxymethyl or cyclopropyl;

R ³Be hydrogen, fluorine or chlorine;

R ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy;

The A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; Wherein 2 atoms of A ring when the A ring be nitrogen connect 5-7 unit saturated rings the time, can choose wantonly by 1 or 2 atomic bridge connection; If wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace;

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, C _1-6Alkyl, C _1-6Alkyl S (O) _a(wherein a is 2) or heterocyclic radical; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace;

N is 0 or 1;

R ⁸Be selected from hydroxyl and amino;

R ⁹, R ¹⁰, R ¹¹And R ¹⁵Independently be selected from C _1-4Alkyl; With

R ³Be hydrogen or fluorine;

R ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy;

N is 0 or 1;

R ⁸Be selected from hydroxyl and amino;

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

R ³Be hydrogen, fluorine or chlorine;

R ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy;

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, C _1-6Alkyl, C _1-6Alkylsulfonyloxy, C _1-6Alkyl S (O) _a(wherein a is 2) or heterocyclic radical; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace;

N is 0 or 1;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁸Be selected from hydroxyl and amino;

R ³Be hydrogen, fluorine or chlorine;

R ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy;

N is 0 or 1;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁸Be selected from hydroxyl, amino and phenylamino;

R ¹³Be selected from halogen, carbocylic radical, hydroxyl, C _1-3Alkyl, C _1-3Alkoxyl group, dimethylamino or heterocyclic radical.

R ²Be the methyl or methoxy methyl;

R ³Be hydrogen or fluorine;

R ⁴Be hydrogen, fluorine, chlorine, cyano group, methylsulfonyl, methyl or methoxy;

The A ring is morpholino, 4-methylpiperazine-1-base or tetramethyleneimine-1-base;

R ⁵For-NR ¹⁰R ¹¹R wherein ¹⁰And R ¹¹Be methyl; With

N is 0 or 1.

R ³Be hydrogen, fluorine or chlorine;

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base, 4-sec.-propyl piperazine-1-base, the high piperazine of 4-sec.-propyl-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl or tetramethyleneimine-1-base;

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, dimethylamino, methylol, methylamino-, aminomethyl, 4-methylpiperazine-1-base or tetramethyleneimine-1-base;

N is 0 or 1.

R ³Be hydrogen or fluorine;

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base or tetramethyleneimine-1-base;

N is 0 or 1.

R ³Be hydrogen, fluorine or chlorine;

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, mesyloxy, morpholino, piperidines-1-base, dimethylamino, methylol, methylamino-, aminomethyl, 4-methylpiperazine-1-base, cyclopropylamino or tetramethyleneimine-1-base;

N is 0 or 1.

R ³Be hydrogen, fluorine or chlorine;

The A ring is morpholino, 1,1-dioxo thiomorpholine generation, piperidines-1-base, piperazine-1-base, azetidine-1-base, the 4-methyl isophthalic acid, 4-Diazesuberane-1-base, 4-ethyl-1,4-Diazesuberane-1-base, 4-(2-dimethylaminoethyl) piperazine-1-base, 4-(2-methoxy ethyl) piperazine-1-base, 4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-base, 4-cyclopropyl piperazine-1-base, 4-methylpiperazine-1-base, 4-sec.-propyl piperazine-1-base, 4-(4-fluorophenyl) piperazine-1-base, 4-(2-fluorophenyl) piperazine-1-base, 4-(2, the 4-difluorophenyl) piperazine-1-base, 4-(3, the 4-difluorophenyl) piperazine-1-base, 4-(2-chloro-phenyl-) piperazine-1-base, 4-(4-chloro-phenyl-) piperazine-1-base, 4-(4-phenyl) piperazine-1-base, 4-(2-p-methoxy-phenyl) piperazine-1-base, 4-(3-p-methoxy-phenyl) piperazine-1-base, 4-(4-p-methoxy-phenyl) piperazine-1-base, 4-(3-aminomethyl phenyl) piperazine-1-base, 4-(2-aminomethyl phenyl) piperazine-1-base, 4-(4-aminomethyl phenyl) piperazine-1-base, 4-(2, the 3-3,5-dimethylphenyl) piperazine-1-base, 4-(2, the 6-3,5-dimethylphenyl) piperazine-1-base, 4-(4-hydroxy phenyl) piperazine-1-base, 4-(2-hydroxy phenyl) piperazine-1-base, 4-(5-chloropyridine-2-yl) piperazine-1-base, the high piperazine of 4-cyclopropyl-1-base, the high piperazine of 4-cyclobutyl-1-base, the high piperazine of 4-(2-hydroxyethyl)-1-base, the high piperazine of 4-(2-methoxy ethyl)-1-base, the high piperazine of 4-sec.-propyl-1-base, 1,4-oxaza heptane-4-base, 8-oxa--3-azabicyclic [3.2.1] oct-3-yl, tetramethyleneimine-1-base, 2,5-diazabicylo [2.2.1] heptan-5-base, 2-methyl-2,5-diazabicylo [2.2.1] heptan-5-base, 2-(2-methoxy ethyl)-2,5-diazabicylo [2.2.1] heptan-5-base, 2-ethyl-2,5-diazabicylo [2.2.1] heptan-5-base or 2-sec.-propyl-2,5-diazabicylo [2.2.1] heptan-5-base;

R ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, methyl, methylsulfonyl, mesyloxy, morpholino, piperidines-1-base, dimethylamino, diethylin, sec.-propyl, pyridine-2-base, methylol, methylamino-, aminomethyl, 4-methylpiperazine-1-base, cyclopropylamino, tetramethyleneimine-1-base, high piperazine-1-base, ring fourth amino, phenylamino methyl, N-methyl-N-(cyclopropyl methyl) amino, N-methyl-N-cyclopropylamino, N-methyl-N-isopropyl fourth amino, N-methyl-N-(2-methoxy ethyl) are amino, N-ethyl-N-third amino or N-methyl-N-encircle fourth amino;

N is 0 or 1.

The present invention on the other hand, preferred The compounds of this invention be any compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body among the embodiment.

The present invention on the other hand, preferred The compounds of this invention is selected from hydrolyzable ester in following compounds or its pharmacy acceptable salt or the body:

(1) 4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] phenyl } pyrimidine-2-amine;

(2) N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;

(3) 5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] phenyl } pyrimidine-2-amine;

(4) 5-chloro-N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;

(5) 5-chloro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] phenyl } pyrimidine-2-amine;

(6) N-{4-[(4-sec.-propyl-1,4-Diazesuberane-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;

(7) N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;

(8) N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-the 3-fluorophenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;

(9) [4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(4-third-2-base-1,4-Diazesuberane-1-yl) ketone;

(10) [4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(methylamino-) tetramethyleneimine-1-yl] ketone.

The preferred aspect of the present invention relates to the aspect of formula (I) compound or its pharmaceutically-acceptable salts.

The present invention provides the preparation method of hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body on the other hand, this method by following method forms (wherein variable group is suc as formula defining in (I), except as otherwise noted):

Method a) makes the pyrimidine of following formula (II):

Aniline reaction with following formula (III):

In the formula (II), L is a displaceable group;

Perhaps

Method b) make the compound of following formula (IV):

Compound reaction with following formula V:

Wherein T is O or S; R ^xCan be identical or different, and be selected from C _1-6Alkyl; Perhaps

Method c) make following formula (VI) acid or its active acid derivant:

Amine reaction with following formula (VII):

Perhaps

Method d) for formula (I) compound; Make the pyrimidine of following formula (VIII):

The compound reaction of following formula (IX):

Wherein Y is a displaceable group;

And afterwards if needed

I) a kind of formula (I) compound is changed into another kind of formula (I) compound;

Ii) slough any protecting group;

Iii) make hydrolyzable ester in pharmacy acceptable salt or the body.

L is a displaceable group, and the suitable value of L is for example halogen or sulfonyloxy (for example chlorine, bromine, mesyloxy or toluene-4-sulfonyloxy).

Y is a displaceable group, and the suitable value of Y is for example halogen or sulfonyloxy (for example bromine, iodine or trifluoro-methanesulfonyl oxy).Preferred Y is an iodine.

The concrete reaction conditions of above-mentioned reaction is as follows.

A) aniline of the pyrimidine of formula (II) and formula (III) can be with suitable alkali (for example mineral alkali for example cesium carbonate or organic bases potassium tert.-butoxide for example) for method, at suitable part for example 2,2 '-two (diphenyl phosphine)-1,1 '-the dinaphthalene existence is down, in 25-80 ℃ temperature range, react under the following conditions:

I) at suitable solvent for example in the presence of ketone (for example acetone) or alcohol (for example ethanol or butanols) or the aromatic hydrocarbons (for example toluene or N-crassitude), choose wantonly at suitable acid mineral acid such as hydrochloric acid or sulfuric acid or when for example acetate or formic acid or suitable Lewis acid organic acids such as (Lewis acid) exist for example, in 0 ℃ of temperature range that extremely refluxes, preferably under reflux temperature, carry out; Perhaps

Ii) standard Buchwald condition (for example referring to J.Am.Chem.Soc., 118,7215; J.Am.Chem.Soc., 119,8451; J.Org.Chem., 62,1568 and 6066), for example in the presence of acid chloride, for example carry out in the aromatic solvent (for example toluene, benzene or dimethylbenzene) at suitable solvent.

Wherein L is that formula (II) pyrimidine of chlorine can be according to flow process 1 preparation:

Flow process 1

The aniline of formula (III) is the commercial compound, and is perhaps on the books in the literature, perhaps can be by standard method preparation known in the art.

Method b) formula (IV) compound and formula V compound in suitable solvent (for example N-Methyl pyrrolidone or butanols), in 100-200 ℃ temperature range, preferably react in 150-170 ℃ scope together.Reaction is preferably carried out in the presence of suitable alkali (for example sodium hydride, sodium methylate or salt of wormwood).

R wherein ³Be the formula V compound of hydrogen, can prepare according to flow process 2:

Flow process 2

For R3 wherein is the formula V compound of halogen, and needs are carried out subsequently halogenation.

Formula (IV) compound and formula (Va) compound are the commercial compound, and be perhaps on the books in the literature, perhaps can be by standard method preparation known in the art.

Method c) acid and amine can be coupled together in the presence of suitable coupling agents.Can be with standard peptide coupling agent known in the art, perhaps for example carbonyl dimidazoles and dicyclohexylcarbodiimide are used as suitable coupling agents, choose wantonly in the presence of catalyzer (for example Dimethylamino pyridine or 4-tetramethyleneimine-1-yl pyridines), choose wantonly at alkali (for example triethylamine, pyridine or 2,6-dialkyl group-pyridine for example 2,6-lutidine or 2, the 6-di-tert-butyl pyridine) carry out when existing.Suitable solvent comprises N,N-DIMETHYLACETAMIDE, methylene dichloride, benzene, tetrahydrofuran (THF) and dimethyl formamide.Coupled reaction can be carried out in-40 ℃ to 40 ℃ temperature range easily.

Suitable active acid derivant comprises acyl halide, for example chloride of acid and active ester (for example pentafluorophenyl esters).The reaction of these type compounds and amine is well-known in the art, and for example they can react in suitable solvent (for example above-mentioned solvent) in the presence of alkali (for example above-mentioned alkali).Reaction can be carried out in-40 ℃ to 40 ℃ temperature range easily.

Can adopt method a), method b) or method c) preparation formula (VI) compound.

Formula (VII) amine is the commercial compound, and is perhaps on the books in the literature, perhaps can be by standard method preparation known in the art.

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

Formula (VIII) compound synthetic sees flow process 1.

Formula (IX) compound is the commercial compound, and is perhaps on the books in the literature, perhaps can be by standard method preparation known in the art.

Should be understood that, some substituting group in the The compounds of this invention different rings substituting group, can introduce by the substitution reaction of standard aromatics, perhaps before aforesaid method or be right after thereafter and produce by conventional modified with functional group, so these are also included within method of the present invention aspect.Such reaction and modification for example comprise introduces substituting group, substituent reduction, substituent alkylation, substituent oxidation by the aromatics substitution reaction.Reagent and reaction conditions used in these method stepss are that chemical field is well-known.The specific examples of aromatics substitution reaction comprises with concentrated nitric acid introduces nitro; Under Friedel Crafts condition, introduce acyl group with for example acyl halide and Lewis acid (for example aluminum chloride); Under Friedel Crafts condition, introduce alkyl with alkylogen and Lewis acid (for example aluminum chloride); Introduce halogen group.The specific examples of modifying comprises for example to be used the nickel catalyzator catalytic hydrogenation or use the iron heat treated in the presence of hydrochloric acid, makes nitroreduction become amino; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.

It is to be further understood that any sensitive group in the protection compound is necessity/needs in reactions more as herein described.Wherein protection be necessary or the example that needs and suitable guard method known to those skilled in the art.Can use protecting group (for example referring to T.W.Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991) commonly used according to standard schedule.Therefore, if reactant comprises for example groups such as amino, carboxyl or hydroxyl, then might in some reaction described herein, protect these groups.

Appropriate protection group for amino or alkylamino has for example acyl group, as alkyloyls such as ethanoyl, and as carbalkoxys such as methoxycarbonyl, ethoxycarbonyl or tertbutyloxycarbonyls, as aryl methoxycarbonyls such as carbobenzoxy-(Cbz)s, or as aroyls such as benzoyls.Deprotection condition for above-mentioned blocking group will change with the selection of blocking group.Therefore, acyl group such as alkyloyl or carbalkoxy or aroyl can be for example by sloughing with suitable alkali such as alkali metal hydroxide hydrolysis such as lithium hydroxide or sodium hydroxide.Perhaps; can slough by handling as acyl groups such as tertbutyloxycarbonyls, can for example slough by hydrogenation in the presence of catalyzer such as palladium on carbon or by handling as three (trifluoroacetic acid) boron with Lewis acid as aryl methoxycarbonyls such as carbobenzoxy-(Cbz)s with suitable sour example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid.Suitable alternative blocking group for primary amino has for example phthaloyl, and it can be sloughed by handling with alkylamine such as dimethylamino propylamine or with hydrazine.

Appropriate protection group for hydroxyl has for example acyl group, as arylmethyls such as aroyls such as alkyloyls such as ethanoyl, benzoyl or benzyls.Deprotection condition for above blocking group will change along with the selection of blocking group.Therefore, for example acyl group such as alkyloyl or aroyl can be for example by sloughing with suitable alkali such as alkali metal hydroxide hydrolysis such as lithium hydroxide or sodium hydroxide.Perhaps, arylmethyl such as benzyl can for example be sloughed through catalyzer hydrogenations such as palladium on carbon.

Appropriate protection group for carboxyl has for example esterified group; for example can be by methyl or the ethyl of for example sloughing with basic hydrolysiss such as sodium hydroxide; perhaps can be by the tertiary butyl of for example sloughing with the acid treatment of organic acids such as trifluoroacetic acid, perhaps can be by the benzyl of sloughing through catalyzer such as palladium on carbon hydrogenation.

The routine techniques that adopts chemical field to know can be removed blocking group in any stage easily of synthetic.

As mentioned above, the compound that the present invention limits has inhibition of cell proliferation activity (for example antitumour activity), and we think because the CDK of compound suppresses active causes.These character can be for example with following method evaluation:

Assay method

This paper uses following abbreviation:

HEPES represents the N-[2-hydroxyethyl] piperazine-N '-[2-ethanesulfonic acid]

DTT represents dithiothreitol (DTT)

PMSF represents phenylmethylsulfonyl fluoride.

In 96 orifice plates of vitro kinase assay method, be incorporated into test substrate (GST-retinoblastoma protein with scintillation proximity assay (SPA-derives from Amersham) mensuration; GST-Rb) [γ-33-P]-adenosine triphosphate in is tested compound.Add testing compound (being diluted to proper concn in DMSO and water) in every hole, control wells adds roscovitine and contrasts as inhibitor, perhaps adds DMSO as positive control.

The about 0.2 μ l CDK2/ cyclin E partially purified enzyme (consumption depends on enzymic activity) that is diluted in 25 μ l incubation buffer is added in each hole, add 20 μ l GST-Rb/ATP/ATP33 mixtures (contain 0.5 μ g GST-Rb and 0.2 μ M ATP and 0.14 μ Ci[γ-33-P]-incubation buffer of adenosine triphosphate) then, the gained mixture is vibrated gently, at room temperature hatched then 60 minutes.

Then, add 150 μ l stop baths, contain the a-protein-PVT in 0.8mg/ hole in the stop bath to each hole SPAThe anti-Thiadiazolidine isomerase in bead (Amersham), 20pM/ hole, rabbit igg (deriving from Molecular Probes), 61mM EDTA and 50mM HEPES (pH 7.5) (containing 0.05% sodiumazide).

Each plate is placed centrifugal after 2 hours (2500rpm, 1124xg) 5 minutes with Topseal-S plate sealer (plate sealer) sealing.Each plate Topcount reading, 30 seconds/hole.

Incubation buffer is used for diluting and contains 50mM HEPES pH7.5,10mM MnCl ₂, 1mM DTT, 100 μ M vanadic acid sodiums, 100 μ M NaF, 10mM Sodium Glycerophosphate, BSA (1mg/ml final concentration) the mixture of enzyme-to-substrate.

The test substrate

In this mensuration, only use the retinoblastoma protein part that merges with GST tag (Science on March 13rd, 1987,235 (4794): 1394-1399; Lee W.H., Bookstein R., Hong F., Young L.J., Shew J.Y., Lee E.Y.).The retinoblastoma gene of coded amino acid 379-928 (deriving from retinoblastoma plasmid ATCC pLRbRNL) is carried out PCR, with this sequence clone to pGEx 2T fusion vector (Smith D.B. and Johnson, K.S.Gene 67,31 (1988)); This carrier comprises the tac promotor that is used for inducible expression, the inside lac I that is used for any intestinal bacteria (E.Coli) host ^qGene and the coding region (deriving from Pharmacia Biotech) that is used for the zymoplasm cutting, amino acid 792-928 is used for increasing.Again with this sequence clone to pGEx 2T.

With standard inducible expression technology, gained retinoblastoma 792-928 sequence is expressed in intestinal bacteria (BL21 (DE3) pLysS cell), as follows purifying.

The intestinal bacteria mashed prod is resuspended to 10ml/g NETN damping fluid (50mM Tris pH7.5,120mM NaCl, 1mM EDTA, 0.5% (volume/volume) NP-40,1mMPMSF, the bright Trypsin inhibitor,Trasylol of 1 μ g/ml, 1 μ g/ml aprotinin and 1 μ g/ml pepstatin), with supersound process (2x45 second/100ml homogenate).After centrifugal, with the supernatant liquor application of sample to 10ml glutathione agarose gel column (Pharmacia Biotech, Herts, UK) in, with the washing of NETN damping fluid.With kinase buffer liquid (50mM HEPES pH 7.5,10mMMgCl ₂, 1mM DTT, 1mM PMSF, the bright Trypsin inhibitor,Trasylol of 1 μ g/ml, 1 μ g/ml aprotinin and 1 μ g/ml pepstatin) after the washing, protein is with the kinase buffer liquid wash-out of 50mM reduced glutathione.Merge the part that contains GST-Rb (792-927), with kinase buffer liquid dialysed overnight.(Novex, San Diego USA), analyze final product with sodium lauryl sulphate (SDS) PAGE (polyacrylamide gel) electrophoresis with the 8-16%Tris-glycine gels.

CDK2 and cyclin E

As template, isolate the open reading-frame (ORF) of CDK2 and cyclin E with HeLa cell and activating T cell mRNA, and be cloned into insect expression vector pVL1393 and (derive from Invitrogen 1995 catalog number (Cat.No.)s: V1392-20) by ThermoScript II-PCR.In insect SF21 cell system (deriving from greedy noctuid (Spodoptera Frugiperda) cell-commercially available prod, meadow of greedy noctuid (the Fall Army Worm) ovary tissue in meadow), make CDK2 and cyclin E carry out dual expression [application standard virus Baculogold coinfection technology] then.

Produce the embodiment of cyclin E/CDK2

The following examples are provided at the detailed description that produces cyclin E/CDK2 in the SF21 cell (TC100+10%FBS (TCS)+0.2% polyoxyethylene poly-oxygen propylene aether segmented copolymer (Pluronic) solution), for each viral cyclin E and CDK2, the MOI of double infection is 3.

To in roller bottle culture, grow to 2.33x10 ⁶The SF21 cell of cell/ml is inoculated into 10x500ml by 0.2x10E6 cell/ml and rolls in the bottle.To roll bottle puts into roller bottle apparatus (28 ℃) and hatches.

After 3 days (72 hours), pair cell is counted, and recording two mean values that roll bottle is 1.86x10E6 cell/ml (99% is viable cell).Infect culture with Geminivirus, each viral MOI is 3.

To be added in the culture behind the viral mixing, and this culture is put back in the roller bottle apparatus (28 ℃).

In infection back 2 days (48 hours) afterwards, 5 liters of cultures have been gathered in the crops.During results, the total cellular score of statistics is 1.58x10E6 cell/ml (99% is viable cell).With cell be placed among Heraeus Omnifuge 2.0 RS by every part of 250ml in 4 ℃ with 2500rpm centrifugal 30 minutes.Abandoning supernatant.

The part copurification of CDK2 and cyclin E

The Sf21 cell is resuspended to lysis buffer (50mM Tris pH 8.2,10mMMgCl ₂, 1mM DTT, 10mM Phosphoric acid glycerol esters, 0.1mM sodium orthovanadate, 0.1mMNaF, 1mM PMSF, the bright Trypsin inhibitor,Trasylol of 1 μ g/ml and 1 μ g/ml aprotinin), homogenate is 2 minutes in 10ml Dounce homogenizer (Dounce homgeniser).After centrifugal, with the supernatant liquor application of sample to Poros HQ/M 1.4/100 anion-exchange column (PE Biosystems, Hertford, UK) in.From 0M NaCl, by the gradient (crossing post) of 0-1M NaCl at the lysis buffer that does not have proteinase inhibitor through 20 column volumes, with CDK2 and cyclin E co-elute.(Santa CruzBiotechnology, California US), detect the co-elute thing by western blotting with anti-CDK2 antibody and anti-cell cyclin E antibody.

Can be by analogy, the assay method of estimating CDK1 and CDK4 inhibition is created in design.CDK2 (EMBL searching number X62071) can use with cyclin A or cyclin E (referring to EMBL searching number M73812), more detail file of this assay method are seen PCT international application no WO99/21845, about the biochemistry of this application and biological assessment part are attached to herein by reference.

Although the pharmacological properties of formula (I) compound changes with structural changes, generally speaking, formula (I) the active available IC that compound had ₅₀Concentration or dosage represent that scope is 250 μ M～1nM.

When testing with above-mentioned external test method, the CDK2 that measures embodiment 14 suppresses the active IC that is ₅₀=3nM.

Activity in vivo

Can pass through standard technique, for example, estimate cytotoxicity, the activity in vivo of The compounds of this invention is estimated by measuring the inhibition of cell growth.

Can be with the fluorescence dye sulfo group rhodamine B (SulforhodamineB that makes protein staining, SRB) make cell dyeing, measure the inhibition of cell growth, therefore obtain the estimated value (being cell) of protein content in the hole (referring to Boyd, M.R. (1989) Status of the NCIpreclinical antitumour drug discovery screen (antitumor drug was found the present situation of screening before the American National ICR was clinical), Prin.Prac Oncol 10:1-12).Therefore, below for measuring cytostatic detail file:

Press the volume of 100ml, with cell inoculation in 96 orifice plates in the suitable medium; For MCF-7, SK-UT-1B and SK-UT-1, substratum can be the Eagle substratum of Dulbecco improvement.Can make the cell attachment grow overnight, then, press the DMSO solution that different concns adds inhibitor compound, the DMSO maximum concentration is 1% (volume/volume).Can measure control board to obtain the cell value before the administration.Can be with cell at 37 ℃ of (5%CO ₂) under hatched 3 days.

When the 3rd day finishes, TCA is added to make final concentration in each plate be 16% (volume/volume).Plate can be hatched under 4 ℃ 1 hour, take out supernatant liquor, each plate washes with tap water.After the drying, can add 100ml SRB dyestuff (1% acetic acid solution of 0.4%SRB) 30 minutes down at 37 ℃.Remove excessive SRB, each plate washs with 1% acetate.Available 10mMTris pH7.5 makes the SRB solubilising with protein bound, and at room temperature vibrates 30 minutes.Can under 540nm, read OD, from the semilogarithmic plot of inhibitor concentration, determine to cause 50% growth inhibiting inhibitor concentration absorbancy.Optical density(OD) is reduced to the compound concentration of the optical density(OD) that is obtained when following when experiment beginning inoculating cell, can be used as the toxicity value.

When with the test of SRB assay method, the typical IC of The compounds of this invention ₅₀Value should be in the 1mM-1nM scope.

Another aspect of the invention provides pharmaceutical composition, and said composition comprises formula (I) pyrimidine derivatives or its pharmacy acceptable salt or the interior hydrolyzable ester of body of definition as mentioned, and pharmaceutically acceptable diluent or carrier.

Composition can be the form (for example as tablet or capsule) that is suitable for oral administration, be applicable to the parenteral injection form (as sterile solution agent, suspensoid or emulsion) of (comprising in intravenously, subcutaneous, intramuscular, the blood vessel or infusion), be applicable to the form of topical or be applicable to the form of rectal administration as suppository as ointment or ointment.

Generally speaking, can pass through ordinary method, adopt vehicle commonly used, the preparation above-mentioned composition.

Usually give warm-blooded animal formula (I) compound in the unitary dose scope by every square metre of animal body surface area 5-5000mg (promptly about 0.1-100mg/kg), this provides treatment to go up effective dosage usually.Unit dosage (for example tablet or capsule) will contain for example activeconstituents of 1-250mg usually.The preferred daily dosage portion that adopts the 1-50mg/kg scope.Yet daily dosage portion will change according to host to be treated, concrete route of administration and the severity of disease to be treated.Therefore, can determine optimal dose by any concrete patient's of treatment doctor.

Another aspect of the invention provides formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of definition as mentioned, is used for the method by therapy for treating human body or animal body.

We find that hydrolyzable ester is effective cell cycle inhibitor (cellular antiproliferative agent) in the compound that the present invention limited or its pharmacy acceptable salt or the body, and we think that this performance results from the CDK inhibition activity.Therefore, the expection The compounds of this invention is used for the treatment of separately or partly by the disease or the medical conditions of the mediation of CDK enzyme, that is to say, described compound can be used for producing the CDK restraining effect in the warm-blooded animal body of this treatment of needs.Therefore, compound of the present invention is provided for treating the method for malignant cell propagation, and this method is a feature to suppress the CDK enzyme, that is to say that described compound can be used to produce separately or part by antiproliferative that suppresses the CDK mediation and possible apoptotic effect.Particularly, especially stop the process that enters the S phase or pass through the S phase, and, produce restraining effect by suppressing the process that CDK1 suppresses to enter the M phase or passes through the M phase by inhibition CDK2 by suppressing CDK2, CDK4 and/or CDK6.Apoptotic effect also comprises by suppressing CDK1, CDK7, CDK8, particularly suppresses CDK9 downward modulation rna plymerase ii activity.This compounds of expection the present invention has multiple anticancer character, because CDK relates to many general human cancers, for example 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.Therefore, the expection The compounds of this invention will have the antitumour activity that resists these cancers.Expect also that in addition The compounds of this invention will have the activity of anti-various leukemia, lymph malignant tumour and solid tumor, cancer and sarcoma in for example various tissues (for example liver, kidney, prostate gland and pancreas).Specifically, expection these compounds of the present invention growth of advantageously slowing down primary solid tumor and recurrent solid tumor (for example colorectal carcinoma, mammary cancer, prostate cancer, lung cancer and skin carcinoma).More particularly, hydrolyzable ester in expection these compounds of the present invention or its pharmacy acceptable salt or the body, suppress the primary solid tumor relevant and the growth of recurrent solid tumor with CDK, especially suppress the tumor growth that its growth and diffusion very depend on CDK, this tumour comprises for example some colon tumor, breast tumor, tumor of prostate, lung tumor, external genital tumor and dermatoma.

Expect also that in addition The compounds of this invention has the activity of anti-other cell breeding disease in multiple other disease, described other disease comprises leukemia, fiber proliferative and branch voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel.

Therefore, the present invention this provide on the one hand as hydrolyzable ester in formula (I) compound of the definition as mentioned of medicine or its pharmacy acceptable salt or the body.

Another aspect of the invention provides as mentioned hydrolyzable ester in formula (I) compound of definition or its pharmacy acceptable salt or the body to be used for producing the purposes of the medicine of cell cycle inhibition in preparation.

One aspect of the present invention, wherein cell cycle inhibition is meant and suppresses CDK1.Another aspect of the invention, this is meant and suppresses CDK2.Another aspect of the invention, this is meant and suppresses CDK4.Another aspect of the invention, this is meant and suppresses CDK5.Another aspect of the invention, this is meant and suppresses CDK6.Another aspect of the invention, this is meant and suppresses CDK7.Another aspect of the invention, this is meant and suppresses CDK8.Another aspect of the invention, this is meant and suppresses CDK9.

Another aspect of the invention provides as mentioned hydrolyzable ester in formula (I) compound of definition or its pharmacy acceptable salt or the body to be used for producing the purposes of the medicine of inhibition of cell proliferation effect in preparation.

Another aspect of the invention provides as mentioned hydrolyzable ester in formula (I) compound of definition or its pharmacy acceptable salt or the body to be used for producing the purposes of the inhibiting medicine of CDK2 in preparation.

Another aspect of the invention provides as mentioned hydrolyzable ester in formula (I) compound of definition or its pharmacy acceptable salt or the body to be used for the treatment of purposes in the medicine of cancer in preparation.

Another aspect of the invention provides as mentioned hydrolyzable ester in formula (I) compound of definition or its pharmacy acceptable salt or the body to be used for the treatment of purposes in the medicine of following disease in preparation: leukemia or lymph malignant tumour 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.

The another feature according to the present invention provides as mentioned hydrolyzable ester in formula (I) compound of definition or its pharmacy acceptable salt or the body to be used for the treatment of purposes in the medicine of following disease in preparation: cancer, fiber proliferative and branch voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel.

Another aspect of the invention is provided at the method that produces cell cycle inhibition in the warm-blooded animal body that needs this treatment, and this method comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of the definition as mentioned that gives described animal effective dose.

Another aspect of the invention is provided at the method that produces the inhibition of cell proliferation effect in the warm-blooded animal body that needs this treatment, and this method comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of the definition as mentioned that gives described animal effective dose.

Another aspect of the invention is provided at and produces the inhibiting method of CDK2 in the warm-blooded animal body that needs this treatment, and this method comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of the definition as mentioned that gives described animal effective dose.

Another aspect of the invention is provided at the method for cancer that treatment needs the warm-blooded animal of this treatment, and this method comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of the definition as mentioned that gives described animal effective dose.

Another aspect of the invention provides treatment to need leukemia or lymph malignant tumour or the following method for cancer of the warm-blooded animal of this treatment: 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 comprise formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of the definition as mentioned that gives described animal effective dose.

Another aspect of the invention provides the method for the following disease of the warm-blooded animal that treatment needs this treatment: cancer, fiber proliferative and branchs voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel, described method comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body of the definition as mentioned that gives described animal effective dose.

Another aspect of the invention provides pharmaceutical composition, and described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned.

Another aspect of the invention provides the pharmaceutical composition as medicine, and described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned.

Another aspect of the invention is provided for producing the pharmaceutical composition of cell cycle inhibition, and described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned.

Another aspect of the invention is provided for producing the pharmaceutical composition of inhibition of cell proliferation effect, and described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned.

Another aspect of the invention is provided for producing the inhibiting pharmaceutical composition of CDK2, and described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned.

Another aspect of the invention is provided for treating the pharmaceutical composition of cancer, and described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned.

Another aspect of the invention is provided for treating the pharmaceutical composition of leukemia or lymph malignant tumour or cancer, described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned, and described cancer comprises 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.

Another aspect of the invention is provided for treating the pharmaceutical composition of following disease, described composition comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body and the pharmaceutically acceptable diluent or carrier of definition as mentioned, and described disease comprises cancer, fiber proliferative and branch voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel.

Another aspect of the invention provides formula (I) compound or its pharmacy acceptable salt or the purposes of the interior hydrolyzable ester of body in producing cell cycle inhibition of definition as mentioned.

Another aspect of the invention provides as mentioned that hydrolyzable ester is producing the active purposes of inhibition of cell proliferation in formula (I) compound of definition or its pharmacy acceptable salt or the body.

Another aspect of the invention provides formula (I) compound or its pharmacy acceptable salt or the purposes of the interior hydrolyzable ester of body in producing the CDK2 restraining effect of definition as mentioned.

Another aspect of the invention provides formula (I) compound or its pharmacy acceptable salt or the purposes of the interior hydrolyzable ester of body in the treatment cancer of definition as mentioned.

Another aspect of the invention provides formula (I) compound or its pharmacy acceptable salt or the purposes of the interior hydrolyzable ester of body in treatment leukemia or lymph malignant tumour or following disease of definition as mentioned: 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.

The another feature according to the present invention provides as mentioned the purposes of hydrolyzable ester in the following disease of treatment in formula (I) compound of definition or its pharmacy acceptable salt or the body: cancer, fiber proliferative and branch voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel.

Start active (for example CDK2 starts) to stop cell to enter DNA synthetic by suppressing the important S phase, can also be used for the toxicity that normal cell in the protective is not subjected to cycle-specific agent.Suppress the process that CDK2 or CDK4 will stop normal cell to enter the cell cycle, this may be limited in the toxicity of the cycle-specific agent that works in S phase, G2 or the mitotic division.These protections can produce the prevention effect of the alopecia relevant with these medicines usually.

Therefore, another aspect of the invention provides (I) compound of formula as defined above or its pharmacy acceptable salt or the interior hydrolyzable ester of body as cytoprotective medicine (cell protective agent).

Therefore, another aspect of the invention is provided for preventing to cause owing to the malignant tumour illness that heals with medicine (I) compound of formula as defined above or its pharmacy acceptable salt or the interior hydrolyzable ester of body of alopecia.

The known example of the treatment malignant neoplastic disease disease drug of alopecia that causes comprises alkylating agent for example ifosfamide and endoxan; Antimetabolite is methotrexate, 5 FU 5 fluorouracil, gemcitabine and cytosine arabinoside for example; Catharanthus alkaloid and analogue be vincristine(VCR), vinealeucoblastine(VLB), vindesine, vinorelbine for example; Taxanes is taxol and docetaxel for example; The topoisomerase I inhibitor is irinotecan and Hycamtin for example; Cytotoxic antibiotics is for example Etoposide and tretinoin of Dx, daunorubicin, mitoxantrone, dactinomycin and mitomycin and other medicines for example.

The present invention on the other hand, hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body, can with above-mentioned one or more medication combined administrations.In this case, can pass through systematic method or non-systemic method afford formula (I) compound.Particularly can pass through non-systemic method afford formula (I) compound, for example topical.

Therefore, by another feature of the present invention, be provided at anti-loss method during one or more malignant tumour illnesss of the warm-blooded animal that heals with medicine (for example people), this method comprises hydrolyzable ester in formula (I) compound that gives described animal effective dose or its pharmacy acceptable salt or the body.

By another feature of the present invention, be provided at anti-loss method during one or more malignant tumour illnesss of the warm-blooded animal that heals with medicine (for example people), this method comprises with simultaneously, sequential or give the mode of the described medicine of significant quantity separately, give hydrolyzable ester in formula (I) compound of described animal effective dose or its pharmacy acceptable salt or the body.

Another aspect of the invention is provided for preventing the pharmaceutical composition of the alopecia that causes owing to the malignant tumour illness that heals with medicine, described composition comprises hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body, and pharmaceutically acceptable diluent or carrier.

Another aspect of the invention provides medicine box, and described medicine box comprises hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body, and the known medicine that is used for the treatment of the malignant tumour illness that causes alopecia.

Another aspect of the invention provides medicine box, and this medicine box comprises:

A) hydrolyzable ester in the formula of first unit dosage (I) compound or its pharmacy acceptable salt or the body;

B) the known medicine that is used for the treatment of the malignant tumour illness that causes alopecia of second unit dosage; With

C) packing material of first formulation and second formulation is housed.

The purposes of the anti-loss medicine during preparation is used for healing with medicine the malignant tumour illness of hydrolyzable ester in formula (I) compound or its pharmacy acceptable salt or the body is provided according to another feature of the invention.

Another aspect of the invention is provided for anti-loss conjoint therapy, this therapy comprises formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body that gives warm-blooded animal (for example people) significant quantity, optional pharmaceutically acceptable diluent or carrier, and simultaneously, sequential or give the medicine that is used for the treatment of the malignant tumour illness of significant quantity separately.

As mentioned above, the required dosage size of the concrete cell breeding disease of therapeutic or prophylactic treatment will change according to the severity of host to be treated, route of administration and disease to be treated.Expection unitary dose scope is for example 1-100mg/kg, preferred 1-50mg/kg.

CDK inhibition activity can be used as monotherapy as defined above, perhaps except that The compounds of this invention, can comprise one or more other material and/or treatments.This treatment can realize by while, each component sequential or that treat separately.In the medical oncology field, using multi-form therapeutic combination, to treat each cancer patients be standard practice.In medical oncology, except that cell cycle suppression therapy as defined above, other composition of this treatment can be: operation, radiotherapy or chemotherapy.This chemotherapy can comprise the curative of three primary categories:

(i) other cell cycle Depressant by working with identical or different as defined above mechanism;

(ii) cytostatic agent, antiestrogen (tamoxifen for example for example, toremifene, raloxifene, droloxifene and idoxifene (iodoxyfene)), progestogen medicine (for example Magace), aromatase inhibitor (Anastrozole for example, letrozole, vorozole (vorazole) and Exemestane), onapristone, antiandrogen (flutamide for example, Nilutamide, bicalutamide and cyproterone acetate), LHRH agonist and antagonist (goserelin acetate for example, Leuprolide), testosterone 5 α-dihydro reductase inhibitor (for example finasteride), (these somatomedins comprise for example Thr6 PDGF BB and pHGF, and these inhibitor comprise growth factor antibodies for anti-invasion agent (for example inhibitors of metalloproteinase such as Marimastat and upar depressant of functions) and somatomedin depressant of functions, growth factor receptor antibody, tyrosine kinase inhibitor and serine/threonine kinase inhibitor); With

(iii) other antiproliferative/antitumor drug and the combination of using in the medical science oncology thereof, for example antimetabolite (for example antifolic such as methotrexate, fluorine pyrimidine such as 5 FU 5 fluorouracil, purine and neplanocin, cytosine arabinoside); Antitumor antibiotics (for example anthracene nucleus class such as Dx, daunomycin, epirubicin and idarubicin, ametycin, dactinomycin, Plicamycin); Platinum derivatives (for example Cisplatin, carboplatin); Alkylating agent (for example mustargen, melphalan, Chlorambucil, busulfan, endoxan, ifosfamide, nitrosourea, plug are for group); Antimitotic drug (for example catharanthus alkaloid such as vincristine(VCR) and taxanes are as safe plain, taxotere); Topoisomerase enzyme inhibitor (for example epipodophyllotoxin class such as Etoposide and teniposide, amsacrine, Hycamtin).This is provided for the medicament production of combination therapy cancer on the one hand the present invention, other antitumorigenic substance that described product comprises formula (I) compound of definition as mentioned and defines as mentioned.

Except that the treatment pharmaceutical use, formula (I) compound and pharmacy acceptable salt thereof also are used as pharmacological tool in the exploitation of test system and the stdn in vitro and in vivo, described test macro is used to estimate the cell cycle active effect of various inhibitor to laboratory animal (for example cat, dog, rabbit, monkey, rat and mouse), is the integral part of seeking the novel therapeutic medicine.

In above-mentioned other medicines composition, step, method, purposes and medication preparation feature are applicable to the alternative and embodiment preferred of The compounds of this invention described herein too.

Embodiment

Now, the present invention will be described by following non-limiting example, except as otherwise noted, otherwise:

(i) temperature with centigradetemperature (℃) expression; Under room temperature or envrionment temperature, promptly in 18-25 ℃ temperature range, operate;

(ii) organic solution is through anhydrous magnesium sulfate drying; Under bath temperature up to 60 ℃ with rotatory evaporator decompression (600-4000 pascal; 4.5-30 evaporating solvent mmhg);

(iii) chromatography is meant the flash chromatography on silica gel method; Tlc (TLC) is carried out on silica-gel plate;

(iv) generally speaking, reaction process is followed the tracks of with TLC, and the reaction times only is used for explanation;

(v) final product has gratifying proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;

(vi) given yield is only in order to illustration purpose, not necessarily by too much testing obtainable yield; Can repeat preparation as the more raw materials of needs;

(vii) when the NMR data that provide are the δ value form of principal character proton, to provide with respect to interior target ppm of tetramethylsilane (TMS) (ppm), except as otherwise noted, otherwise just with full deuterium methyl-sulphoxide (DMSO-d ₆) make solvent and measure at 300MHz;

(viii) chemical symbol has its general implication; Adopt SI units and symbol;

(ix) solvent ratio is with volume: volume (volume/volume) provides; With

(x) adopt 70 electron-volts electronic energy in mass spectrum (MS) operation, chemi-ionization (CI) pattern is used directly to expose probe; Wherein said ionization realizes by electronic impact (EI), fast atom bombardment (FAB) or electron spray(ES) (ESP); Provided the m/z value; In general, only report the ion of indication parent quality; Except as otherwise noted, otherwise the mass ion that provides is MH ⁺

(xi) except as otherwise noted, otherwise do not have to split the compound comprise asymmetric alternate c atoms and/or sulphur atom;

(xii) when pointing out that certain is synthetic when being similar to synthetic that front embodiment introduces, the mmole of each raw material consumption than and the mmole that uses of front embodiment than identical; With

(xvi) use following abbreviation:

The THF tetrahydrofuran (THF);

DMF N, dinethylformamide;

The EtOAc ethyl acetate;

MeOH methyl alcohol;

The ether ether;

EtOH ethanol;

The DCM methylene dichloride;

The DMSO methyl-sulphoxide;

Pd ₂(dba) ₃Two (dibenzalacetones) close palladium;

BINAP 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene;

The TEA triethylamine;

The EDTA ethylenediamine tetraacetic acid (EDTA);

The HBTU phosphofluoric acid O-benzotriazole-1-yl of mixing)-and N, N, N ', N '-tetramethyl-urea

0.060000

DIPEA N, the N-diisopropylethylamine;

DMFDMA N, the dinethylformamide dimethyl acetal;

The HPLC high performance liquid chromatography;

MPLC medium pressure liquid chromatography method;

The RPHPLC reversed-phased high performace liquid chromatographic; With

Xantphos 9,9-dimethyl-4, two (diphenyl phosphine) xanthenes of 5-;

Xvii) when mentioning the SCX-2 post, be meant " ion-exchange " extraction cartridge that is used to adsorb basic cpd, that is to say, contain polypropylene tube, use according to the specification sheets of giving birth to manufacturer (to derive from International SorbentTechnologies Limited, Dyffryn Business Park based on the Phenylsulfonic acid of strong cation exchange sorbent material, Hengeod, Mid Glamorgan, UK, CF82 7RJ).

Embodiment 1

5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-[4-(morpholine-4-base carbonyl) phenyl] phonetic Pyridine-2-amine

Under inert atmosphere, with 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 2,0.20g, 0.85mmol), acid chloride (8mg, 0.034mmol), Xantphos (30mg, 0.051mmol), cesium carbonate (0.42g, 1.3mmol) and (4-iodo-phenyl)-morpholine-4-base-ketone (method 16a of WO 05/044814; 290mg 0.90mmol) is added in the diox (7ml) reflux 6 hours.With silica gel purification (the DCM solution with 0-10%MeOH is eluent), obtain title compound, be yellow solid.Finish to be further purified with RPHPLC, obtain colourless foam shape thing (292mg, 81%).NMR (400.132MHz): 9.78 (s, 1H), 8.59 (d, 1H), 7.73 (d, 2H), 7.38-7.36 (m, 3H), 5.43 (septet, 1H), 3.64-3.56 (m, 4H), 3.54-3.46 (m, 4H), 2.53 (s, 3H), 1.45 (d, 6H); M/z425.

Embodiment 2-115

Following compounds prepares with proper raw material by the method for embodiment 1.

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	2	5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{3-methyl-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz) 9.58 (s, 1H), 8.56 (s, 1H), 7.58 (d, 1H), 7.45 (s, 1H), 7.37 (d, 1H), 7.07 (d, 1H), 5.41 (septet, 1H), 3.66-3.60 (m, 2H), 3.19-3.13 (m, 2H), 2.52 (s, 3H), 2.38-2.32 (m, 2H), 2.24-2.17 (m, 8H), 1.43 (d, 6H)	452	Method 4 and method 2
3	5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-[3-methyl-4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz) 9.59 (s, 1H), 8.57 (d, 1H), 7.58 (d, 1H), 7.46 (s, 1H), 7.37 (d, 1H), 7.11 (d, 1H), 5.40 (septet, 1H), 3.69-3.57 (m, 4H), 3.54-3.47 (m, 2H), 3.21-3.14 (m, 2H), 2.52 (s, 3H), 2.20 (s, 3H), 1.43 (d, 6H)	439	Method 9 and method 2	2			452	Method 4 and method 2
3			439	Method 9 and method 2	4	5-fluoro-N-{3-fluoro-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz) 9.96 (s, 1H), 8.63 (d, 1H), 7.73 (d, 1H), 7.47 (d, 1H), 7.39 (d, 1H), 7.30 (t, 1H), 5.41 (septet, 1H), 3.67-3.57 (m, 2H), 3.30-3.20 (m, 2H), 2.54 (s, 3H), 2.38-2.32 (m, 2H), 2.30-2.23 (m, 2H), 2.20 (s, 3H), 1.46 (d, 6H)	456	Method 5 and method 2
5	N-[3-chloro-4-(morpholine-4-base carbonyl) phenyl]-5-fluoro-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz) 9.87 (s, 1H), 8.62 (d, 1H), 7.88 (s, 1H), 7.67 (d, 1H), 7.38 (d, 1H), 7.30 (d, 1H), 5.36 (septet, 1H), 3.67-3.62 (m, 4H), 3.57-3.52 (m, 2H), 3.19-3.15 (m, 2H), 2.53 (s, 3H), 1.46 (d, 6H)	459	Method 8 and method 2	4			456	Method 5 and method 2

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	6	N-(4-{[3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.77(s，1H)，8.57(d，1H)，7.71 (d，2H)，7.47(d，2H)，5.50-5.35 (m，1H)，3.74-3.41(br m，3H)， 2.77-2.57(m，1H)，2.52(s，3H)， 2.28-1.91(m，8H)，1.79-1.71(m， 1H)，1.44(d，6H)	453	Method 10 and method 2
7	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz) 9.68 (s, 1H), 8.43 (d, 1H), 7.76 (d, 2H), 7.44 (s, 1H), 7.35 (d, 2H), 7.10 (d, 1H), 5.69 (quintet, 1H), 3.57-3.43 (m, 4H), 3.32 (s, 3H), 2.36-2.28 (m, 4H), 2.20 (s, 3H), 1.46 (d, 6H)	420	The embodiment 59 of WO 03/004472 and method 14	6			453	Method 10 and method 2
7			420	The embodiment 59 of WO 03/004472 and method 14	8	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-3-methyl-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz) 9.48 (s, 1H), 8.41 (d, 1H), 7.63 (d, 1H), 7.48 (s, 1H), 7.43 (s, 1H), 7.08 (d, 1H), 7.06 (d, 1H), 5.66 (septets, 1H), and 3.69-3.59 (m, 2H), 3.22-3.12 (m, 2H), 2.51 (s, 3H), 2.40-2.29 (m, 2H), 2.26-2.19 (m, 8H), 1.44 (d, 6H)	434	Method 4 and method 14
9	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-[3-methyl-4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz) 9.49 (s, 1H), 8.41 (d, 1H), 7.65 (d, 1H), 7.49 (s, 1H), 7.43 (s, 1H), 7.11 (d, 1H), 7.07 (d, 1H), 5.65 (septets, 1H), and 3.72-3.58 (m, 4H), 3.55-3.46 (m, 2H), 3.28-3.12 (m, 2H), 2.50 (s, 3H), 2.21 (s, 3H), 1.45 (d, 6H)	421	Method 9 and method 14	8			434	Method 4 and method 14

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	10	N-{3-fluoro-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz) 9.86 (s, 1H), 8.47 (d, 1H), 7.80 (d, 1H), 7.50 (d, 1H), 7.45 (s, 1H), 7.30 (t, 1H), 7.14 (d, 1H), 5.66 (septets, 1H), and 3.67-3.58 (m, 2H), 3.30-3.22 (m, 2H), 2.51 (s, 3H), 2.37-2.31 (m, 2H), 2.30-2.23 (m, 2H), 2.19 (s, 3H), 1.47 (d, 6H)	438	Method 5 and method 14
11	N-[3-fluoro-4-(morpholine-4-base carbonyl) phenyl]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz) 9.88 (s, 1H), 8.47 (d, 1H), 7.81 (d, 1H), 7.52 (d, 1H), 7.45 (s, 1H), 7.34 (t, 1H), 7.15 (d, 1H), 5.66 (septet, 1H), 3.68-3.60 (m, 4H), 3.59-3.52 (m, 2H), 3.32-3.26 (m, 2H), 2.51 (s, 3H), 1.48 (d, 6H)	425	Method 6 and method 14	10			438	Method 5 and method 14
11			425	Method 6 and method 14	12	N-{3-chloro-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz) 9.76 (s, 1H), 8.46 (d, 1H), 7.92 (s, 1H), 7.70 (d, 1H), 7.45 (s, 1H), 7.27 (d, 1H), 7.13 (d, 1H), 5.61 (septets, 1H), and 3.67-3.59 (m, 2H), 3.20-3.13 (m, 2H), 2.50 (s, 3H), 2.39-2.33 (m, 2H), 2.30-2.23 (m, 2H), 2.19 (s, 3H), 1.47 (d, 6H)	454	Method 7 and method 14
13	N-[3-chloro-4-(morpholine-4-base carbonyl) phenyl]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz) 9.77 (s, 1H), 8.47 (d, 1H), 7.93 (s, 1H), 7.72 (d, 1H), 7.45 (s, 1H), 7.30 (d, 1H), 7.13 (d, 1H), 5.61 (septet, 1H), 3.68-3.61 (m, 4H), 3.58-3.54 (m, 2H), 3.20-3.16 (m, 2H), 2.51 (s, 3H), 1.47 (d, 6H)	441	Method 8 and method 14	12			454	Method 7 and method 14

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	14	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-[4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz) 9.70 (s, 1H), 8.43 (d, 1H), 7.78 (d, 2H), 7.44 (s, 1H), 7.38 (d, 2H), 7.10 (d, 1H), 5.69 (quintet, 1H), 3.63-3.60 (m, 4H), 3.55-3.48 (m, 4H), 2.50 (s, 3H), 1.46 (d, 6H)	407	The method 16a of WO 05/044814 and method 14
15	N-(4-{[3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.13MHz) 9.74 (s, 1H), 8.44 (d, 1H), 7.76 (d, 2H), 7.50 (app t, 2H), 7.45 (s, 1H), 7.11 (d, 1H), 5.77-5.64 (m, 1H), 7.73-3.39 (m, 7H and water are overlapping), 2.75-2.58 (m, 1H), 2.23-1.95 (m, 7H), 1.80-1.63 (m, 1H), 1.47 (d, 6H)	434	Method 10 and method 14	14			407	The method 16a of WO 05/044814 and method 14
15			434	Method 10 and method 14	16	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-3-methoxyl group-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz) 9.52 (s, 1H), 8.43 (d, 1H), 7.51 (d, 1H), 7.45 (s, 1H), 7.35 (s, 1H), 7.11-7.07 (m, 2H), 5.65 (septet, 1H), 3.78 (s, 3H), and 3.68-3.52 (m, 2H), 3.21-3.12 (m, 2H), 2.50 (s, 3H), 2.38-2.24 (m, 4H), 2.19 (s, 3H), 1.46 (d, 6H)	450	Method 14 and method 19
17	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-[3-methoxyl group-4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃): 8.38 (d, 1H), 7.40-7.37 (m, 2H), 7.30-7.21 (m, 3H), 6.94 (d, 1H), 5.56 (septet, 1H), 3.85 (s, 3H), 3.83-3.71 (m, 4H), 3.67-3.56 (m, 2H), 3.38-3.26 (m, 2H), 2.59 (s, 3H), 1.53 (d, 6H)	437	Method 14 and method 22	16			450	Method 14 and method 19

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	18	5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-[3-methoxyl group-4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.31 (d, 1H), 7.59 (d, 1H), 7.32 (s, 1H), 7.25-7.19 (m, 3H), 5.49 (septet, 1H), 3.84 (s, 3H), 3.81-3.72 (m, 4H), 3.67-3.55 (m, 2H), 3.34-3.29 (m, 2H), 2.61 (s, 3H), 1.53 (d, 6H)	455	Method 2 and method 20
19	4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl]-N-[4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.43 (d, 1H), 7.68 (d, 2H), 7.48 (s, 1H), 7.43-7.41 (m, 3H), 6.98 (d, 1H), 5.50 (septet, 1H), 4.66 (s, 2H), 3.79-3.59 (m, 8H), 3.41 (s, 3H), 1.57 (d, 6H)	437	The method 16a of WO 05/044814 and method 3	18			455	Method 2 and method 20
19			437	The method 16a of WO 05/044814 and method 3	20	4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl]-N-[3-methyl-4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.41 (d, 1H), 7.56 (d, 1H), 7.42 (s, 1H), 7.41 (s, 1H), 7.32 (s, 1H), 7.14 (d, 1H), 6.95 (d, 1H), 5.46 (septet, 1H), 4.65 (s, 2H), and 3.86-3.80 (m, 2H), 3.80-3.75 (m, 2H), 3.61-3.56 (m, 2H), 3.41 (s, 3H), 3.34-3.27 (m, 2H), 2.33 (s, 3H), 1.56 (d, 6H)	451	Method 9 and method 3
21	N-[3-fluoro-4-(morpholine-4-base carbonyl) phenyl]-4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.44 (d, 1H), 7.81 (d, 1H), 7.44-7.43 (m, 2H), 7.38 (t, 1H), 7.22 (d, 1H), 7.02 (d, 1H), 5.49 (septet, 1H), 4.67 (s, 2H), 3.85-3.75 (m, 4H), 3.69-3.63 (m, 2H), 3.43-3.39 (m, 5H), 1.59 (d, 6H)	455	Method 6 and method 3	20			451	Method 9 and method 3

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	22	4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl]-N-{4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.42 (d, 1H), 7.66 (d, 2H), 7.62 (s, 1H), 7.43-7.40 (m, 3H), 6.97 (d, 1H), 5.51 (septet, 1H), 4.66 (s, 2H), 3.94-3.48 (m, 4H), 3.41 (s, 3H), 2.51-2.37 (m, 4H), 2.33 (s, 3H), 1.57 (d, 6H)	450	The embodiment 59 of WO 03/004472 and method 3
23	4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl]-N-{3-methyl-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.41 (d, 1H), 7.55 (d, 1H), 7.42 (s, 1H), 7.39-7.37 (m, 2H), 7.14 (d, 1H), 6.95 (d, 1H), 5.47 (septet, 1H), 4.65 (s, 2H), 3.89-3.79 (m, 2H), 3.41 (s, 3H), 3.36-3.27 (m, 2H), 2.52-2.45 (m, 2H), 2.36-2.26 (m, 8H), 1.56 (d, 6H)	464	Method 4 and method 3	22			450	The embodiment 59 of WO 03/004472 and method 3
23			464	Method 4 and method 3	24	N-{3-fluoro-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl }-4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.44 (d, 1H), 7.78 (d, 1H), 7.66 (s, 1H), 7.44 (s, 1H), 7.35 (t, 1H), 7.21 (d, 1H), 7.01 (d, 1H), 5.51 (septets, 1H), 4.66 (s, 2H), 3.87-3.78 (m, 2H), 3.48-3.35 (m, 5H), 2.52-2.44 (m, 2H), 2.41-2.35 (m, 2H), 2.33 (s, 3H), 1.58 (d, 6H)	468	Method 5 and method 3
25	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-[4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.39 (d, 1H), 7.71 (d, 2H), 7.58 (s, 1H), 7.44 (d, 2H), 7.32 (s, 1H), 6.93 (d, 1H), 5.42 (quintet, 1H), 3.81-3.54 (m, 8H), 2.60 (s, 3H), 2.50-2.43 (m, 4H), 1.85-1.66 (m, 2H)	419	The method 51 of the method 16a of WO 05/044814 and WO 03/076435	24			468	Method 5 and method 3

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	26	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-[3-methyl-4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.38 (d, 1H), 7.62 (d, 1H), 7.42 (s, 1H), 7.32-7.31 (m, 2H), 7.16 (d, 1H), 6.90 (d, 1H), 5.37 (quintet, 1H), 3.86-3.74 (m, 4H), and 3.62-3.54 (m, 2H), 3.34-3.27 (m, 2H), 2.59 (s, 3H), 2.49-2.42 (m, 4H), 2.34 (s, 3H), 1.84-1.69 (m, 2H)	433	The method 51 of method 9 and WO 03/076435
27	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.39 (d, 1H), 7.69 (d, 2H), 7.47 (s, 1H), 7.43 (d, 2H), 7.32 (s, 1H), 6.92 (d, 1H), 5.43 (quintet, 1H), 3.89-3.47 (m, 8H), 2.60 (s, 3H), 2.50-2.43 (m, 4H), 2.33 (s, 3H), 1.85-1.66 (m, 2H)	432	The embodiment 59 of WO 03/004472 and the method 51 of WO 03/076435	26			433	The method 51 of method 9 and WO 03/076435
27			432		28	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-3-methyl-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.38 (d, 1H), 7.60 (d, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.15 (d, 1H), 6.90 (d, 1H), 5.38 (quintets, 1H), 3.87-3.81 (m, 2H), 3.34-3.28 (m, 2H), 2.59 (s, 3H), 2.52-2.42 (m, 6H), 2.33-2.26 (m, 8H), 1.84-1.66 (m, 2H)	446	The method 51 of method 4 and WO 03/076435
29	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-3-fluoro-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.40 (d, 1H), 7.84 (d, 1H), 7.75 (s, 1H), 7.36 (t, 1H), 7.32 (s, 1H), 7.22 (d, 1H), 6.95 (d, 1H), 5.41 (quintets, 1H), and 3.86-3.79 (m, 2H), 3.47-3.38 (m, 2H), 2.60 (s, 3H), 2.53-2.42 (m, 6H), 2.41-2.35 (m, 2H), 2.33 (s, 3H), 1.86-1.68 (m, 2H)	450	The method 51 of method 5 and WO 03/076435	28			446	The method 51 of method 4 and WO 03/076435

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	30	4-(1-ethyl-2-methyl-1H-imidazoles-5-yl)-N-[4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.36(d， 1H)，7.65(d，2H)，7.55(s，1H)， 7.43(d，2H)，7.37(s，1H)，6.99 (d，1H)，4.51(q，2H)，3.79-3.58 (m，8H)，2.48(s，3H)，1.30(t，3H)	393	The method 30 of the method 16a of WO 05/044814 and WO 02/020512
31	4-(1-ethyl-2-methyl-1H-imidazoles-5-yl)-N-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.35(d， 1H)，7.63(d，2H)，7.55(s，1H)， 7.45(s，1H)，7.42(d，2H)，6.98 (d，1H)，4.50(q，2H)，3.92-3.41 (m，4H)，2.54-2.38(m，7H)， 2.33(s，3H)，1.29(t，3H)	406	The embodiment 59 of WO 03/004472 and the method 30 of WO 02/020512	30			393
31			406		32	4-(1-ethyl-2-methyl-1H-imidazoles-5-yl)-N-3-methyl-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.34(d， 1H)，7.54(s，1H)，7.47(d，1H)， 7.43(s，1H)，7.40(s，1H)，7.14 (d，1H)，6.96(d，1H)，4.50(q， 2H)，3.87-3.80(m，2H)，3.35- 3.28(m，2H)，2.52-2.45(m， 5H)，2.35-2.27(m，8H)，1.27(t， 3H)	420	The method 30 of method 4 and WO 02/020512
33	4-(1-ethyl-2-methyl-1H-imidazoles-5-yl)-N-3-fluoro-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.37(d， 1H)，7.73(d，1H)，7.56(s，1H)， 7.43(s，1H)，7.36(t，1H)，7.20(d， 1H)，7.02(d，1H)，4.52(q，2H)， 3.85-3.80(m，2H)，3.45-3.38 (m，2H)，2.52-2.46(m，5H)， 2.40-2.35(m，2H)，2.33(s，3H)， 1.33(t，3H)	424	The method 30 of method 5 and WO 02/020512	32			420	The method 30 of method 4 and WO 02/020512

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	34	4-(1-ethyl-2-methyl-1H-imidazoles-5-yl)-N-3-methoxyl group-4-[(4-methylpiperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.36(d， 1H)，7.54(s，1H)，7.39(s，1H)， 7.36(s，1H)，7.21(d，1H)，7.14 (d，1H)，6.96(d，1H)，4.50(q， 2H)，3.93-3.73(m，5H)，3.40- 3.27(m，2H)，2.57-2.37(m， 5H)，2.32-2.18(m，5H)，1.29(t， 3H)	436	The method 30 of method 19 and WO 02/020512
35	4-[1-(cyclopropyl methyl)-2-methyl isophthalic acid H-imidazoles-5-yl]-N-[4-(morpholine-4-base carbonyl) phenyl] pyrimidine-2-amine	(400.132MHz，CDCl ₃)：8.18(d， 1H)，7.46(d，2H)，7.36(s，1H)， 7.28(s，1H)，7.25(d，2H)，6.82 (d，1H)，4.25(d，2H)，3.60-3.40 (m，8H)，2.30(s，3H)，0.99-0.89 (m，1H)，0.28-0.23(m，2H)，- 0.01(q，2H)	419	The method 54 of WO 03/076435 and the method 16a of WO 05/044814	34			436	The method 30 of method 19 and WO 02/020512
35			419		36	4-[1-(cyclopropyl methyl)-2-methyl isophthalic acid H-imidazoles-5-yl]-N-{4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.19(d， 1H)，7.45(d，2H)，7.37(s，1H)， 7.34(s，1H)，7.25(d，2H)，6.82 (d，1H)，4.25(d，2H)，3.78-3.27 (m，4H)，2.30(s，3H)，2.28-2.21 (m，4H)，2.15(s，3H)，0.99-0.89 (m，1H)，0.28-0.23(m，2H)，- 0.01(q，2H)	432	The method 54 of WO 03/076435 and the embodiment 59 of WO 03/004472
37	4-[1-(1-cyclopropyl ethyl)-2-methyl isophthalic acid H-imidazoles-5-yl]-N-{4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃)：8.36(d， 1H)，7.61(d，2H)，7.43-7.41(m， 3H)，7.35(s，1H)，6.96(d，1H)， 4.84-4.70(m，1H)，3.98-3.42 (m，4H)，2.64(s，3H)，2.51-2.36 (m，4H)，2.33(s，3H)，1.62(d， 3H)，1.44-1.33(m，1H)，0.69- 0.59(m，1H)，0.44-0.37(m， 1H)，0.22-0.10(m，2H)	446	The embodiment 59 of WO 03/004472 and the method 32 of WO 02/020512	36			432

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	38	4-[4-(3-cyclopropyl methyl-2-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone	(400.132MHz，CDCl ₃)8.20(d， 1H)，7.46(d，2H)，7.28-7.24(m， 2H)，6.84(d，1H)，4.27(d，2H)， 3.74-3.29(m，4H)，2.60(q，2H)， 2.36-2.21(m，4H)，2.17(s，3H)， 1.24(t，3H)，0.99-0.88(m，1H)， 0.28-0.23(m，2H)，0.02-0.03 (m，2H)	446	The method 56 of WO 03/076435 and the embodiment 59 of WO 03/004472
39	4-[4-(3-ethyl-2-sec.-propyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone	(400.132MHz，CDCl ₃) 8.35 (d, 1H), 7.63 (d, 2H), 7.59 (d, 1H), 7.42 (d, 2H), 7.36 (s, 1H), 6.99 (d, 1H), 4.54 (q, 2H), 3.90-3.46 (m, 4H), 3.09 (septet, 1H), 2.52-2.37 (m, 4H), 2.33 (s, 3H), 1.38 (d, 6H), 1.30 (t, 3H)	434	The embodiment 59 of method 27 and WO 03/004472	38			446
39			434	The embodiment 59 of method 27 and WO 03/004472	40	4-[4-(2-cyclopropyl-3-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone	(400.132MHz，CDCl ₃)8.34(d， 1H)，7.64(d，2H)，7.50(s，1H)， 7.43(d，2H)，7.35(s，1H)，6.97 (d，1H)，4.67(q，2H)，3.89-3.51 (m，4H)，2.54-2.38(m，4H)， 2.33(s，3H)，1.92-1.85(m，1H)， 1.36(t，3H)，1.13-1.09(m，2H)， 1.07-1.01(m，2H)	432	The embodiment 59 of method 32 and WO 03/004472
41	4-[4-(3-ethyl-2-trifluoromethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone	(400.132MHz，CDCl ₃)8.49(d， 1H)，7.63(d，2H)，7.62(s，1H)， 7.44(d，2H)，7.31(s，1H)，7.05 (d，1H)，4.70(q，2H)，3.89-3.49 (m，4H)，2.55-2.38(m，4H)， 2.33(s，3H)，1.35(t，3H)	460	The embodiment 59 of method 37 and WO 03/004472	40			432	The embodiment 59 of method 32 and WO 03/004472

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	42	4-[4-(2-difluoromethyl-3-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone	(400.132MHz，CDCl ₃)8.46(d， 1H)，7.64(d，2H)，7.59(s，1H)， 7.44(d，2H)，7.39(s，1H)，7.03 (d，1H)，6.80(t，1H)，4.74(q， 2H)，3.89-3.49(m，4H)，2.50- 2.38(m，4H)，2.33(s，3H)，1.36 (t，3H)	442	The embodiment 59 of method 42 and WO 03/004472
43	4-[4-(2-cyclopropyl-3-sec.-propyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-(4-methyl-piperazine-1-yl)-ketone	(300.072MHz，CDCl ₃) 8.35 (d, 1H), 7.66 (d, 2H), 7.48 (s, 1H), 7.40 (d, 2H), 7.32 (s, 1H), 6.92 (d, 1H), 5.72 (septet, 1H), 3.83-3.47 (m, 4H), 2.49-2.38 (m, 4H), 2.32 (s, 3H), 2.07-1.98 (m, 1H), 1.63 (d, 6H), 1.21-1.16 (m, 2H), 1.08-1.01 (m, 2H)	446	The embodiment 59 of method 46 and WO 03/004472	42			442	The embodiment 59 of method 42 and WO 03/004472
43			446	The embodiment 59 of method 46 and WO 03/004472	44	((S)-3-dimethylamino-tetramethyleneimine-1-yl)-4-[4-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-pyrimidine-2-base is amino]-phenyl }-ketone	(400.132MHz，CDCl ₃) 8.35 (d, 1H), 7.63 (d, 2H), 7.59 (s, 1H), 7.54 (d, 2H), 7.19 (s, 1H), 6.99 (d, 1H), 4.54 (q, 2H), 3.98-3.77 (m, 1H), 3.74-3.35 (m, 3H), 3.08 (septet, 1H), 2.82-2.63 (m, 1H), 2.35-2.02 (m, 7H), 1.89-1.76 (m, 1H), 1.38 (d, 6H), 1.29 (t, 3H)	448	Method 27 and method 47
45	((R)-3-dimethylamino-tetramethyleneimine-1-yl)-4-[4-(3-ethyl-2-sec.-propyl-3H-imidazol-4 yl)-pyrimidine-2-base is amino]-phenyl }-ketone	(400.132MHz，CDCl ₃) 8.35 (d, 1H), 7.63 (d, 2H), 7.58 (s, 1H), 7.54 (d, 2H), 7.28 (s, 1H), 6.99 (d, 1H), 4.54 (q, 2H), 3.98-3.77 (m, 1H), 3.72-3.34 (m, 3H), 3.08 (septet, 1H), 2.81-2.63 (m, 1H), 2.33-2.03 (m, 7H), 1.84 (quintets, 1H), 1.38 (d, 6H), 1.29 (t, 3H)	448	Method 27 and method 48	44			448	Method 27 and method 47

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	46	4-[4-(2-cyclopropyl-3-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-((S)-3-dimethylamino-tetramethyleneimine-1-yl)-ketone	(400.132MHz，CDCl ₃)8.34(d， 1H)，7.63(d，2H)，7.55(d，2H)， 7.49(s，1H)，7.26(s，1H)，6.96 (d，1H)，4.67(q，2H)，3.98-3.34 (m，4H)，2.83-2.61(m，1H)， 2.33-2.03(m，7H)，1.93-1.79 (m，2H)，1.36(t，3H)，1.12-1.08 (m，2H)，1.07-1.00(m，2H)	446	Method 32 and method 47
47	4-[4-(2-cyclopropyl-3-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-((R)-3-dimethylamino-tetramethyleneimine-1-yl)-ketone	(400.132MHz，CDCl ₃)8.34(d， 1H)，7.63(d，2H)，7.54(d，2H)， 7.49(s，1H)，7.42(s，1H)，6.96 (d，1H)，4.66(q，2H)，3.98-3.32 (m，4H)，2.81-2.64(m，1H)， 2.34-2.06(m，7H)，1.90-1.78 (m，2H)，1.35(t，3H)，1.12-1.08 (m，2H)，1.06-1.00(m，2H)	446	Method 32 and method 48	46			446	Method 32 and method 47
47			446	Method 32 and method 48	48	((S)-3-dimethylamino-tetramethyleneimine-1-yl)-4-[4-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-phenyl }-ketone	(400.132MHz，CDCl ₃)8.48(d， 1H)，7.63-7.61(m，3H)，7.55(d， 2H)，7.35(s，1H)，7.04(d，1H)， 4.69(q，2H)，3.96-3.78(m，1H)， 3.71-3.35(m，3H)，2.83-2.61 (m，1H)，2.30(s，3H)，2.22(s， 3H)，2.20-2.04(m，1H)，1.90- 1.79(m，1H)，1.34(t，3H)	474	Method 37 and method 47
49	((R)-3-dimethylamino-tetramethyleneimine-1-yl)-4-[4-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-pyrimidine-2--amino]-phenyl }-ketone	(400.132MHz，CDCl ₃)8.48(d， 1H)，7.63-7.61(m，3H)，7.55(d， 2H)，7.35(s，1H)，7.04(d，1H)， 4.69(q，2H)，3.96-3.78(m，1H)， 3.71-3.35(m，3H)，2.83-2.61 (m，1H)，2.30(s，3H)，2.22(s， 3H)，2.20-2.04(m，1H)，1.90- 1.79(m，1H)，1.34(t，3H)	474	Method 37 and method 48	48			474	Method 37 and method 47

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	50	4-[4-(2-cyclopropyl-3-sec.-propyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-((S)-3-dimethylamino-tetramethyleneimine-1-yl)-ketone	(400.132MHz，CDCl ₃) 8.36 (d, 1H), 7.66 (d, 2H), 7.53 (d, 2H), 7.50 (s, 1H), 7.33 (s, 1H), 6.93 (d, 1H), 5.73 (septet, 1H), 3.99-3.33 (m, 4H), 2.82-2.62 (m, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.18-1.99 (m, 2H), 1.84 (quintet, 1H), 1.63 (d, 6H), and 1.12-1.08 (m, 2H), 1.06-1.00 (m, 2H)	460	Method 46 and method 47
51	4-[4-(2-cyclopropyl-3-sec.-propyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-((R)-3-dimethylamino-tetramethyleneimine-1-yl)-ketone	(400.132MHz，CDCl ₃) 8.36 (d, 1H), 7.66 (d, 2H), 7.53 (d, 2H), 7.33 (s, 1H), 7.31 (s, 1H), 6.93 (d, 1H), 5.73 (septet, 1H), 3.96-3.35 (m, 4H), 2.83-2.62 (m, 1H), 2.31 (s, 3H), 2.22 (s, 3H), 2.19-1.99 (m, 2H), 1.92-1.79 (m, 1H), 1.64 (d, 6H), and 1.20-1.16 (m, 2H), 1.07-1.02 (m, 2H)	460	Method 46 and method 48	50			460	Method 46 and method 47
51			460	Method 46 and method 48	52	4-[4-(2-difluoromethyl-3-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-((S)-3-dimethylamino-tetramethyleneimine-1-yl)-ketone	(400.132MHz，CDCl ₃) 8.45 (d, 1H), 7.64-7.54 (m, 6H), 7.02 (d, 1H), 6.80 (t, 1H), 4.73 (q, 2H), 3.98-3.78 (m, 1H), 3.72-3.34 (m, 3H), 2.84-2.62 (m, 1H), 2.31 (s, 3H), 2.23-2.03 (m, 4H), 1.84 (quintet, 1H), 1.34 (t, 3H)	456	Method 42 and method 47
53	4-[4-(2-difluoromethyl-3-ethyl-3H-imidazoles-4-yl)-pyrimidine-2--amino]-phenyl }-((R)-3-dimethylamino-tetramethyleneimine-1-yl)-ketone	(400.132MHz，CDCl ₃) 8.46 (d, 1H), 7.63 (d, 2H), 7.58 (s, 1H), 7.55 (d, 2H), 7.41 (s, 1H), 7.02 (d, 1H), 6.79 (t, 1H), 4.74 (q, 2H), and 3.98-3.78 (m, 1H), 3.72-3.34 (m, 3H), 2.82-2.61 (m, 1H), 2.31 (s, 3H), 2.22-2.02 (m, 4H), 1.84 (quintet, 1H), 1.35 (t, 3H)	456	Method 42 and method 48	52			456	Method 42 and method 47

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	54	1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) tetramethyleneimine-3-alcohol	9.67(s，1H)，8.42(d，1H)，7.74 (d，2H)，7.48(d，2H)，7.43(s， 1H)，7.09(d，1H)，5.77-5.61(m， 1H)，4.99-4.86(br d，1H)，4.35- 4.18(br d，1H)，3.67-3.39(m， 4H)，2.01-1.71(m，2H)，1.46(d， 6H)	407	Method 14 and method 53
55	1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) tetramethyleneimine-3-alcohol	9.77(s，1H)，8.58(d，1H)，7.70 (d，2H)，7.47(d，2H)，7.37(d， 1H)，5.51-5.35(m，1H)，5.00- 4.85(br d，1H)，4.36-4.16(br d， 1H)，3.71-3.41(m，4H)，2.03- 1.69(m，2H)，1.45(d，6H)	424	Method 2 and method 53	54			407	Method 14 and method 53
55			424	Method 2 and method 53	56	N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.31(d， 1H)，7.64-7.58(m，3H)，7.56- 7.51(m，2H)，7.37-7.34(m， 1H)，5.66-5.55(m，1H)，3.98- 3.77(m，1H)，3.72-3.51(m， 2H)，3.47-3.36(m，1H)，2.82- 2.59(m，4H)，2.31(s，3H)，2.22- 2.05(m，4H)，1.89-1.77(m， 1H)，1.53(d，6H)	452	Method 2 and method 47
57	N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz，CDCl ₃)8.31(d， 1H)，7.65-7.58(m，3H)，7.57- 7.50(m，3H)，5.65-5.54(m， 1H)，3.97-3.77(m，1H)，3.72- 3.50(m，2H)，3.47-3.35(m， 1H)，2.80-2.60(m，4H)，2.31(s， 3H)，2.23-2.04(m，4H)，1.91- 1.77(m，1H)，1.53(d，6H)	452	Method 2 and method 48	56			452	Method 2 and method 47

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	58	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluorine pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.29 (s, 1H), 7.64 (d, 2H), 7.55 (d, 2H), 7.50 (d, 1H), 7.25 (s, 1H), 5.31 (quintet, 1H), 3.98-3.76 (m, 1H), 3.72-3.33 (m, 3H), 2.83-2.56 (m, 4H), 2.51-2.38 (m, 4H), 2.34-2.03 (m, 7H), 1.90-1.67 (m, 3H)	464	Method 55 and method 47
59	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluorine pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.29 (d, 1H), 7.64 (d, 2H), 7.55 (d, 2H), 7.50 (d, 1H), 7.43 (s, 1H), 5.31 (quintet, 1H), 3.96-3.77 (m, 1H), 3.73-3.33 (m, 3H), 2.82-2.59 (m, 4H), 2.48-2.40 (m, 4H), 2.34-2.12 (m, 7H), 1.89-1.65 (m, 3H)	464	Method 55 and method 48	58			464	Method 55 and method 47
59			464	Method 55 and method 48	60	5-chloro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methylpiperazine-1-yl) carbonyl] phenyl } pyrimidine-2-amine	9.98 (s, 1H), 8.64 (s, 1H), 7.74 (d, 2H), 7.34 (d, 2H), 7.27 (s, 1H), 4.83 (septet, 1H), 3.54-3.44 (m, 4H), 2.50 (s, 3H), 2.34-2.28 (m, 4H), 2.20 (s, 3H), 1.37 (d, 6H)	455	The method 5 of WO 05/075461 and the embodiment 59 of WO 03/004472
61	5-chloro-N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.44 (s, 1H), 7.63-7.61 (m, 3H), 7.52-7.51 (m, 3H), 4.96 (septet, 1H), 3.97-3.76 (m, 1H), 3.70-3.38 (m, 3H), 2.88-2.64 (m, 1H), 2.59 (s, 3H), 2.31-2.00 (m, 7H), 1.85 (quintets, 1H), 1.47 (d, 6H)	469	The method 5 of WO 05/075461 and method 48	60			455

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	62	5-chloro-N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.45 (s, 1H), 7.63 (d, 2H), 7.56-7.51 (m, 4H), 4.97 (septet, 1H), 3.99-3.76 (m, 1H), 3.72-3.34 (m, 3H), 2.87-2.64 (m, 1H), 2.60 (s, 3H), 2.37-2.03 (m, 7H), 1.86 (quintet, 1H), 1.48 (d, 7H)	469	The method 5 of WO 05/075461 and method 47
63	5-chloro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methyl-1,4-Diazesuberane-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.45 (s, 1H), 7.61 (d, 2H), 7.52 (d, 2H), 7.39 (d, 2H), 4.96 (septet, 1H), 3.86-3.71 (m, 2H), 3.64-3.47 (m, 2H), 2.84-2.76 (m, 1H), 2.70-2.54 (m, 6H), 2.47-2.33 (m, 3H), 2.06-1.84 (m, 2H), 1.48 (d, 6H)	469	The method 5 of WO 05/075461 and method 56	62			469	The method 5 of WO 05/075461 and method 47
63			469	The method 5 of WO 05/075461 and method 56	64	4-(2-cyclopropyl-1-sec.-propyl-1H-imidazoles-5-yl)-N-{4-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) carbonyl] phenyl } pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.36 (d, 1H), 7.65 (d, 2H), 7.53 (s, 1H), 7.40 (d, 2H), 7.33 (s, 1H), 6.93 (d, 1H), 5.72 (septet, 1H), 3.86-3.72 (m, 2H), and 3.65-3.50 (m, 2H), 2.85-2.54 (m, 4H), 2.47-2.33 (m, 3H), 2.06-1.86 (m, 3H), 1.63 (d, 6H), and 1.20-1.16 (m, 2H), 1.07-1.02 (m, 2H)	460	Method 46 and method 56
65	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.38 (d, 1H), 7.70-7.68 (m, 2H), 7.58-7.52 (m, 3H), 7.31 (s, 1H), 6.91 (d, 1H), 5.43 (quintet, 1H), 3.96-3.35 (m, 4H), 2.76-2.59 (m, 4H), 2.50-2.43 (m, 4H), 2.33-2.05 (m, 8H), and 1.89-1.68 (m, 2H)	447	The method 51 of WO 03/076435 and method 47	64			460	Method 46 and method 56

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	66	4-(1-cyclobutyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(400.132MHz，CDCl ₃) 8.38 (d, 1H), 7.70-7.68 (m, 2H), 7.56-7.52 (m, 3H), 7.31 (s, 1H), 6.91 (d, 1H), 5.43 (quintet, 1H), 3.94-3.38 (m, 4H), 2.76-2.59 (m, 4H), 2.50-2.43 (m, 4H), 2.34-2.06 (m, 8H), and 1.89-1.66 (m, 2H)	447	The method 51 of WO 03/076435 and method 48
67	N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.69 (s, 1H), 8.44 (d, 1H), 7.76 (d, 2H), 7.50 (br d, 2H), 7.44 (s, 1H), 7.11 (d, 2H), 5.77-5.64 (m, 1H), 3.79-3.43 (br t, 3H), 3.38-3.79 (m, 1H are covered by the water peak), 2.81-2.59 (m, s), 2.28-1.95 (m, 7H), 1.81-1.64 (br m, 1H), 1.47 (m, 6H)	434	Method 14 and method 48	66			447	The method 51 of WO 03/076435 and method 48
67			434	Method 14 and method 48	68	N-{4-[(4-sec.-propyl-1,4-Diazesuberane-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	9.17 (s, 1H), 8.39 (d, 1H), 7.71 (d, 2H), 7.37 (s, 1H), 7.30 (d, 2H), 7.03 (d, 1H), 5.61 (septet, 1H), 3.55-3.48 (m, 4H), and 2.94-2.84 (m, 1H), 2.68-2.66 (m, 2H), 2.63 (t, 2H), 2.49 (s, 3H), 1.74-1.68 (m, 2H), 1.47 (d, 6H), 0.98 (d, 6H)	462	Method 14 and method 58
69	N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.69 (s, 1H), 8.44 (d, 1H), 7.76 (d, 2H), 7.50 (br d, 2H), 7.44 (s, 1H), 7.10 (d, 1H), 5.77-5.64 (m, 1H), 3.78-3.41 (br t, 3H), 3.40-3.17 (m, 1H are covered by the water peak), 2.79-2.58 (m, 1H), 2.50 (s, 3H are covered by the DMSO peak), 2.27-1.96 (m, 7H), and 1.81-1.63 (br m, 1H), 1.51-1.43 (m, 6H)	434	Method 14 and method 47	68			462	Method 14 and method 58

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	70	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-3-methyl-4-[(4-methyl-1,4-Diazesuberane-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	9.02 (s, 1H), 8.38 (d, 1H), 7.58 (dd, 1H), 7.47 (d, 1H), 7.36 (s, 1H), 7.06 (d, 1H), 7.00 (d, 1H), 5.57 (septets, 1H), and 3.80-3.12 (m, 4H), 2.66-2.52 (m, 4H), 2.48 (s, 3H), 2.30 (s, 3H), 2.22 (s, 3H), 1.83-1.69 (m, 2H), 1.45 (d, 6H)	448	Method 14 and method 59
71	N-{3-fluoro-4-[(4-methyl-1,4-Diazesuberane-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	9.41 (s, 1H), 8.43 (d, 1H), 7.71 (dd, 1H), 7.50 (dd, 1H), 7.38 (s, 1H), 7.23 (t, 1H), 7.08 (d, 1H), 5.58 (septets, 1H), and 3.78-3.30 (m, 4H), 2.66-2.52 (m, 4H), 2.50 (s, 3H), 2.30 (s, 3H), 1.86-1.71 (m, 2H), 1.48 (d, 6H)	452	Method 14 and method 60	70			448	Method 14 and method 59
71			452	Method 14 and method 60	72	N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-the 3-fluorophenyl)-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	9.86 (d, 1H), 8.47 (d, 1H), 7.79 (d, 1H), 7.49 (d, 1H), 7.46 (s, 1H), 7.40-7.30 (m, 1H), 7.15 (d, 1H), 5.73-5.60 (m, 1H), 3.76-3.58 (m, 1H), (3.49-3.35 m, 2H are covered by the water peak), and 3.24-3.09 (m, 1H), 2.81-2.65 (m, 1H), 2.51 (s, 3H are covered by the DMSO peak), 2.16 (d, 6H), 2.05-1.97 (m, 1H), 1.82-1.66 (m, 1H), 1.48 (d, 6H)	452	Method 14 and method 62
73	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-[3-methyl-4-(1,4-oxaza heptane-4-base carbonyl) phenyl] pyrimidine-2-amine	9.01 (s, 1H), 8.38 (d, 1H), 7.59 (dd, 1H), 7.49 (s, 1H), 7.35 (s, 1H), 7.09 (d, 1H), 7.00 (d, 1H), 5.56 (septet, 1H), 3.78-3.39 (m, 8H), 2.48 (s, 3H), 2.23 (s, 3H), 1.86-1.74 (m, 2H), 1.46 (d, 6H)	435	Method 14 and method 63	72			452	Method 14 and method 62

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	74	N-[3-fluoro-4-(1,4-oxaza heptane-4-base carbonyl) phenyl]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.43 (s, 1H), 8.43 (d, 1H), 7.73 (dd, 1H), 7.52 (dd, 1H), 7.38 (s, 1H), 7.26 (t, 1H), 7.08 (d, 1H), 5.58 (septet, 1H), 3.84-3.42 (m, 8H), 2.50 (s, 3H), 1.89-1.75 (m, 2H), 1.49 (d, 6H)	439	Method 14 and method 64
75	N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-the 3-fluorophenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.97 (d, 1H), 8.65 (d, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.42-7.40 (m, 2H), 5.49-5.35 (m, 1H), 3.76-3.57 (m, 1H), 3.48-3.33 (m, 2H are covered by the water peak), 3.24-3.08 (m, 1H), 2.79-2.62 (m, 1H), 2.51 (s, 3H is covered by the DMSO peak), 2.54 (s, 3H), 2.22-1.95 (m, 7H), 1.82-1.64 (m, 1H), 1.46 (d, 6H)	470	Method 2 and method 62	74			439	Method 14 and method 64
75			470	Method 2 and method 62	76	N-(4-{[(3S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-the 3-fluorophenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.96 (d, 1H), 8.63 (d, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.41-7.30 (m, 2H), 5.49-5.34 (m, 1H), 3.75-3.57 (m, 1H), 3.47-3.34 (m, 2H is covered by the water peak), and 3.24-3.08 (m, 1H), 2.79-2.63 (m, 1H), 2.54 (s, 3H), 2.21-1.96 (m, 7H), 1.81-1.65 (m, 1H), 1.47 (d, 6H)	470	Method 2 and method 61
77	N-(4-{[(3R)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl }-the 3-aminomethyl phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.57 (d, 1H), 8.57 (d, 1H), 7.57 (d, 1H), 7.44 (s, 1H), 7.39-7.35 (m, 1H), 7.14 (t, 1H), 5.48-5.34 (m, 1H), 3.77-3.60 (m, 1H), 3.47-2.93 (m, 3H are covered by the water peak), 2.77-2.62 (m, 1H), 2.52 (s, 3H), 2.23-1.94 (m, 10H), 1.81-1.64 (m, 1H), 1.44 (d, 6H)	466	Method 2 and method 67	76			470	Method 2 and method 61

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	78	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-4-[8-oxa--3-azabicyclic [3.2.1] oct-3-yl carbonyl] and phenyl } pyrimidine-2-amine	9.21 (s, 1H), 8.40 (d, 1H), 7.74 (d, 2H), 7.36 (s, 1H), 7.32 (d, 2H), 7.03 (d, 1H), 5.60 (septet, 1H), 4.28 (s, 2H), 3.77 (d, 2H), 3.19 (d, 2H), 2.49 (s, 3H), 1.82 (dd, 2H), 1.71 (d, 2H), 1.47 (d, 6H)	433	Method 14 and method 65
79	[4-[[4-[3-(cyclobutylmethyl)-2-methyl-3H-imidazol-4 yl] pyrimidine-2-base] amino] phenyl]-(4-methylpiperazine-1-yl) ketone	9.24 (s, 1H), 8.37 (d, 1H), 7.72 (d, 2H), 7.53 (s, 1H), 7.34 (d, 2H), 7.07 (d, 1H), 4.63 (d, 2H), 3.51 (t, 4H), 2.57-2.49 (m, 1H blur because of being covered by the DMSO peak), 2.40 (s, 3H), 2.34 (t, 4H), 2.22 (s, 3H), 1.83-1.48 (m, 6H)	446	The embodiment 59 of WO 03/004472 and method 78	78			433	Method 14 and method 65
79			446	The embodiment 59 of WO 03/004472 and method 78	80	[4-[[4-[3-(cyclobutylmethyl)-2-methyl-3H-imidazol-4 yl] pyrimidine-2-base] amino] phenyl]-(4-methyl-1,4-Diazesuberane-1-yl) ketone	9.20 (s, 1H), 8.37 (d, 1H), 7.71 (d, 2H), 7.53 (s, 1H), 7.32 (d, 2H), 7.07 (d, 1H), 4.63 (d, 2H), and 3.58-3.53 (m, 4H), 2.64-2.50 (m, 4H+1H blurs because of being covered by the DMSO peak), 2.40 (s, 3H), 2.30 (s, 3H), 1.83-1.48 (m, 8H)	460	Method 56 and method 78
81	[4-[[4-[3-(cyclobutylmethyl)-2-methyl-3H-imidazol-4 yl] pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(dimethylamino) tetramethyleneimine-1-yl] ketone	9.21 (s, 1H), 8.38 (d, 1H), 7.71 (d, 2H), 7.53 (s, 1H), 7.47 (d, 2H), 7.07 (d, 1H), 4.63 (d, 2H), 3.66-3.56 (m, 2H), 3.51-3.45 (m, 1H), 3.34-3.30 (m, 1H), 2.81-2.75 (m, 1H), 2.56-2.50 (m, 1H, blur because of being covered by the DMSO peak), 2.40 (s, 3H), 2.18 (s, 6H), 2.06-1.98 (m, 1H), and 1.82-1.64 (m, 5H), 1.58-1.49 (m, 2H)	460	Method 47 and method 78	80			460	Method 56 and method 78

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	82	[4-[[4-(3-cyclopentyl-2-methyl-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(4-methylpiperazine-1-yl) ketone	9.22 (s, 1H), 8.41 (d, 1H), 7.73-7.71 (m, 2H), 7.34 (s, 1H), 7.34-7.31 (m, 2H), 7.02 (d, 1H), 5.59 (quintet, 1H), 3.52-3.50 (m, 4H), 2.48 (s, 3H), 2.35-2.33 (m, 4H), 2.22 (s, 3H), 2.11-2.04 (m, 2H), 2.00-1.92 (m, 2H), and 1.84-1.76 (m, 2H), 1.60-1.51 (m, 2H)	446	The embodiment 59 of WO 03/004472 and method 84
83	[4-[[4-(3-cyclopentyl-2-methyl-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) ketone	9.20 (s, 1H), 8.41 (d, 1H), 7.72-7.69 (m, 2H), 7.34 (s, 1H), 7.31-7.29 (m, 2H), 7.01 (d, 1H), 5.59 (quintet, 1H), 3.58-3.53 (m, 4H), 2.62-2.55 (m, 4H), 2.48 (the Me peak blurs because of being covered by the DMSO peak for s, 3H), 2.30 (s, 3H), 2.11-2.04 (m, 2H), 2.00-1.92 (m, 2H), and 1.84-1.76 (m, 4H), 1.60-1.52 (m, 2H)	460	Method 56 and method 84	82			446	The embodiment 59 of WO 03/004472 and method 84
83			460	Method 56 and method 84	84	[4-[[4-(3-cyclopentyl-2-methyl-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-dimethylamino tetramethyleneimine-1-yl] ketone	9.23 (s, 1H), 8.41 (d, 1H), 7.73-7.71 (m, 2H), 7.47-7.44 (m, 2H), 7.34 (s, 1H), 7.02 (d, 1H), 5.59 (quintet, 1H), 3.65-3.57 (m, 2H), 3.51-3.45 (m, 1H), 3.33-3.29 (m, 1H), 2.78 (quintet, 1H), 2.48 (s, 3H, the methyl peak blurs because of being covered by the DMSO peak), 2.18 (s, 6H), 2.11-1.92 (m, 5H), 1.84-1.73 (m, 3H), 1.60-1.52 (m, 2H)	460	Method 47 and method 84

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	85	[4-[[4-(3-cyclopentyl-2-methyl-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(4-third-2-base-1,4-Diazesuberane-1-yl) ketone	9.19 (s, 1H), 8.41 (d, 1H), 7.72-7.69 (m, 2H), 7.34 (s, 1H), 7.29 (m, 2H), 7.01 (d, 1H), 5.60 (five heavy Yi, 1H), 3.55-3.50 (m, 4H), 2.92-2.84 (m, 1H blur because of being covered by the water peak), 2.69-2.61 (m, 4H), 2.48 (s, 3H, aromatics methyl peak blurs because of being covered by the DMSO peak), 2.11-2.04 (m, 2H), and 2.00-1.92 (m, 2H), 1.84-1.68 (m, 4H), 1.60-1.52 (m, 2H), 0.97 (d, 6H)	488	Method 58 and method 84
86	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(1S, 4S)-2-propyl group-2,5-diazabicylo [2.2.1] heptan-5-yl] ketone	9.23 (s, 1H), 8.41 (d, 1H), 7.74 (d, 2H), 7.45 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 4.40 (s, 1H), 3.49 (s, 1H), 3.46 (d, 1H), 3.39 (dd, 1H), 2.85 (dd, 1H), 2.65 (d, 1H), 2.54-2.41 (m, 5H), 1.77 (d, 1H), 1.68 (d, 1H), 1.48 (d, 6H), 1.41 (sextet, 2H), 0.88 (t, 3H)	460	Method 14 and method 70	85			488	Method 58 and method 84
86			460	Method 14 and method 70	87	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-(4-third-2-base-1,4-Diazesuberane-1-yl) ketone	9.27 (s, 1H), 8.48 (d, 1H), 7.67 (d, 2H), 7.36 (d, 1H), 7.30 (d, 2H), 5.41 (septet, 1H), 3.54-3.49 (m, 4H), 2.93-2.84 (m, 1H), 2.66 (t, 2H), 2.63 (t, 2H), 2.52 (s, 3H), 1.74-1.69 (m, 2H), 1.45 (d, 6H), 0.97 (d, 6H)	480	Method 2 and method 58

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	88	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino]-2-methyl-phenyl]-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) ketone	9.10 (s, 1H), 8.46 (d, 1H), 7.53 (dd, 1H), 7.43 (s, 1H), 7.35 (d, 1H), 7.05 (d, 1H), 5.38 (septet, 1H), 3.77-3.15 (m, 4H), 2.59-2.53 (m, 4H), 2.51 (s, 3H), 2.30 (s, 3H), 2.21 (s, 3H), 1.85-1.67 (m, 2H), 1.44 (d, 6H)	466	Method 2 and method 59
89	[2-fluoro-4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl]-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) ketone	9.50 (s, 1H), 8.52 (d, 1H), 7.64 (dd, 1H), 7.47 (dd, 1H), 7.37 (d, 1H), 7.23 (t, 1H), 5.38 (septet, 1H), 3.76-3.27 (m, 4H), 2.65-2.54 (m, 4H), 2.52 (s, 3H), 2.30 (s, 3H), 1.86-1.72 (m, 2H), 1.47 (d, 6H)	470	Method 2 and method 60	88			466	Method 2 and method 59
89			470	Method 2 and method 60	90	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino]-2-methyl-phenyl]-(1,4-oxaza heptane-4-yl) ketone	(500.133MHz，CDCl ₃) 9.12 (s, 1H), 8.47 (d, 1H), 7.54 (dd, 1H), 7.45 (s, 1H), 7.35 (d, 1H), 7.08 (d, 1H), 5.37 (septet, 1H), 3.74-3.29 (m, 8H), 2.51 (s, 3H), 2.22 (s, 3H), 1.85-1.72 (m, 2H), 1.44 (d, 6H)	453	Method 2 and method 63
91	[2-fluoro-4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl]-(1,4-oxaza heptane-4-yl) ketone	(500.133MHz，CDCl ₃) 9.52 (s, 1H), 8.53 (d, 1H), 7.65 (dd, 1H), 7.48 (dd, 1H), 7.36 (d, 1H), 7.26 (t, 1H), 5.38 (septet, 1H), 3.75-3.42 (m, 8H), 2.52 (s, 3H), 1.89-1.74 (m, 2H), 1.47 (d, 6H)	457	Method 2 and method 64	90			453	Method 2 and method 63
91			457	Method 2 and method 64	92	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-(8-oxa--3-azabicyclic [3.2.1] suffering-3-yl) ketone	9.33 (s, 1H), 8.49 (d, 1H), 7.69 (d, 2H), 7.35 (d, 1H), 7.32 (d, 2H), 5.40 (septet, 1H), 4.28 (s, 2H), 3.76 (d, 2H), 3.19 (d, 2H), 2.52 (s, 3H), 1.84-1.79 (m, 2H), 1.73-1.68 (m, 2H), 1.45 (d, 6H)	451	Method 2 and method 65

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	93	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-[(1S, 4S)-2-propyl group-2,5-diazabicylo [2.2.1] heptan-5-yl] ketone	9.35 (s, 1H), 8.49 (d, 1H), 7.69 (d, 2H), 7.44 (d, 2H), 7.36 (d, 1H), 5.40 (septet, 1H), 4.46-4.33 (m, 1H), 3.48 (s, 1H), 3.45 (d, 1H), 3.38 (dd, 1H), 2.85 (dd, 1H), 2.64 (d, 1H), 2.54-2.40 (m, blur because of being covered by the DMSO peak, 5H), 1.77 (d, 1H), 1.68 (d, 1H), 1.46 (d, 6H), 1.40 (sextet, 2H), 0.88 (t, 3H)	478	Method 2 and method 70
94	[2-chloro-4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl]-(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) ketone	9.44 (s, 1H), 8.52 (d, 1H), 7.82 (d, 1H), 7.65 (dd, 1H), 7.36 (d, 1H), 7.22 (d, 1H), 5.35 (septet, 1H), 3.75-3.60 (m, 2H), and 3.40-3.20 (m, 2H), 2.71-2.53 (m, 3H), 2.52 (s, 3H), 2.35-2.24 (m, 4H), 1.92-1.65 (m, 2H), 1.47 (d, 6H)	487	Method 2 and method 68	93			478	Method 2 and method 70
94			487	Method 2 and method 68	95	[2-chloro-4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl]-(1,4-oxaza heptane-4-yl) ketone	9.46 (s, 1H), 8.53 (d, 1H), 7.83 (d, 1H), 7.66 (dd, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 5.34 (septet, 1H), 3.83-3.54 (m, 6H), 3.44-3.24 (m, 2H), 2.52 (s, 3H), 1.99-1.67 (m, 2H), 1.47 (d, 6H)	474	Method 2 and method 69
96	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl H4-(2-hydroxyethyl)-1,4-Diazesuberane-1-base 1 ketone	9.30 (s, 1H), 8.48 (d, 1H), 7.67 (d, 2H), 7.36 (d, 1H), 7.31 (d, 2H), 5.41 (septet, 1H), 3.98-3.81 (m, 1H), 3.57-3.46 (m, 6H), 2.75 (t, 2H), 2.70 (t, 2H), 2.60 (t, 2H), 2.51 (s, 3H), 1.76 (quintet, 2H), 1.45 (d, 6H)	482	Method 2 and method 71	95			474	Method 2 and method 69

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	97	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-(1,4-oxaza heptane-4-yl) ketone	9.32 (s, 1H), 8.49 (d, 1H), 7.68 (d, 2H), 7.36 (d, 1H), 7.32 (d, 2H), 5.41 (septet, 1H), 3.72-3.67 (m, 4H), 3.63-3.58 (m, 4H), 2.52 (s, 3H), 1.83 (quintet, 2H), 1.46 (d, 6H)	439	Method 2 and method 72
98	[2-chloro-4-[[4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-(4-methyl-1,4-Diazesuberane-1-yl) ketone	9.33 (s, 1H), 8.42 (d, 1H), 7.87 (d, 1H), 7.69 (dd, 1H), 7.37 (s, 1H), 7.22 (d, 1H), 7.07 (d, 1H), 5.53 (septets, 1H), and 3.74-3.60 (m, 2H), 3.36-3.20 (m, 2H), 2.72-2.52 (m, 4H), 2.49 (s, 3H), 2.35-2.24 (m, 3H), 1.92-1.65 (m, 2H), 1.48 (d, 6H)	469	Method 14 and method 68	97			439	Method 2 and method 72
98			469	Method 14 and method 68	99	[2-chloro-4-[[4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-(1,4-oxaza heptane-4-yl) ketone	9.35 (s, 1H), 8.43 (d, 1H), 7.88 (d, 1H), 7.70 (dd, 1H), 7.38 (s, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 5.54 (septet, 1H), 3.83-3.55 (m, 6H), 3.46-3.25 (m, 2H), 2.49 (s, 3H), 1.98-1.68 (m, 2H), 1.48 (d, 6H)	456	Method 14 and method 69
100	[4-(2-hydroxyethyl)-1,4-Diazesuberane-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.19 (s, 1H), 8.39 (d, 1H), 7.72 (d, 2H), 7.37 (s, 1H), 7.31 (d, 2H), 7.03 (d, 1H), 5.61 (septet, 1H), 4.02-3.80 (m, 1H), 3.54 (m, 4H), 3.49 (t, 2H), 2.77-2.74 (m, 2H), 2.72-2.70 (m, 2H), 2.60 (t, 2H), 2.49 (s, 3H), 1.79-1.74 (m, 2H), 1.47 (d, 6H)	464	Method 14 and method 71	99			456	Method 14 and method 69

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	101	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(1,4-oxaza heptane-4-yl) ketone	9.21 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.37 (s, 1H), 7.33 (d, 2H), 7.03 (d, 1H), 5.60 (septet, 1H), 3.72-3.68 (m, 4H), 3.62-3.59 (m, 4H), 2.93 (s, 3H), 1.83 (quintet, 2H), 1.47 (d, 6H)	421	Method 14 and method 72
102	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(tetramethyleneimine-1-yl) tetramethyleneimine-1-yl] ketone	9.69 (s, 1H), 8.44 (d, 1H), 7.76 (d, 2H), 7.50 (d, 2H), 7.44 (s, 1H), 7.10 (d, 1H), 5.70 (septet, 1H), 3.71-3.38 (m, 4H), and 2.81-2.60 (m, 1H), 2.58-2.30 (m, 7H blurs because of being covered by the DMSO peak), and 2.10-1.93 (m, 1H), 1.88-1.59 (m, 5H), 1.47 (d, 6H)	460	Method 14 and method 86	101			421	Method 14 and method 72
102			460	Method 14 and method 86	103	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(piperidino) tetramethyleneimine-1-yl] ketone	9.20 (s, 1H), 8.40 (d, 1H), 7.72 (d, 2H), 7.46 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.60 (septet, 1H), 3.67-3.64 (m, 2H), 3.61-3.57 (m, 1H), 3.49-3.43 (m, 1H), 3.33-3.30 (m, 1H), 2.49 (s, 3H), 2.47-2.42 (m, 2H), 2.38-2.33 (m, 2H), 2.08-2.02 (m, 1H), 1.80-1.72 (m, 1H), 1.53-1.46 (m, 10H), 1.43-1.37 (m, 2H)	474	Method 14 and method 99
104	[(3S)-3-(cyclopropylamino) tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	9.68 (s, 1H), 8.44 (d, 1H), 7.76 (d, 2H), 7.49 (d, 2H), 7.44 (s, 1H), 7.10 (d, 1H), 5.71 (septet, 1H), 3.62-3.53 (m, 2H), and 3.51-3.34 (m, 2H), 2.55-2.35 (m, 5H), 2.12-1.90 (m, 2H), 1.84-1.71 (m, 1H), 1.47 (d, 6H), 0.40-0.09 (m, 4H)	446	Method 14 and method 89	103			474	Method 14 and method 99

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	105	(4-cyclopropyl-1,4-Diazesuberane-1-yl)-[4-[[4-(2-methyl-3-third-2-base-3H-imidazoles 4-yl) pyrimidine-2-base] amino] phenyl] ketone	9.64 (s, 1H), 8.43 (d, 1H), 7.74 (d, 2H), 7.44 (s, 1H), 7.33 (d, 2H), 7.09 (d, 1H), 5.70 (septet, 1H), 3.65-3.38 (m, 4H), 2.90-2.68 (m, 4H), 2.51 (s, 3H), 1.97-1.63 (m, 3H), 1.46 (d, 6H), 0.49-0.37 (m, 2H), 0.32-0.24 (m, 2H)	460	Method 14 and method 101
106	1,4-Diazesuberane-1-base-[4-[[4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.66 (d, 2H), 7.42-7.35 (m, 4H), 6.95 (d, 1H), 5.64 (septet, 1H), 4.04-3.45 (m, 4H), 3.20-2.64 (m, 5H), 2.59 (s, 3H), 2.07-1.75 (m, 2H), 1.53 (d, 6H)	420	Method 14 and method 100	105			460	Method 14 and method 101
106			420	Method 14 and method 100	107	(4-cyclobutyl-1,4-Diazesuberane-1-yl)-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.64 (d, 2H), 7.40 (d, 1H), 7.38 (s, 1H), 7.15 (s, 1H), 6.95 (d, 1H), 5.64 (septet, 1H), 3.90-3.68 (m, 2H), 3.66-3.44 (m, 2H), 3.03-2.33 (m, 8H), 2.18-1.57 (m, 9H), 1.53 (d, 6H)	474	Method 14 and method 102
108	[(3S)-3-methylamino-tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.65 (d, 2H), 7.54 (d, 2H), 7.38 (s, 1H), 7.28 (s, 1H), 6.95 (d, 1H), 5.66 (septet, 1H), 3.92-3.17 (m, 5H), 2.59 (s, 3H), 2.52-2.36 (m, 3H), 2.23-1.98 (m, 1H), 1.81 (sextet, 1H), 1.72-1.61 (m, 1H), 1.53 (d, 6H)	420	Method 14 and method 90	107			474	Method 14 and method 102

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	109	[(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.22 (s, 1H), 8.40 (d, 1H), 7.74 (d, 2H), 7.44 (d, 2H), 7.36 (s, 1H), 7.04 (d, 1H), 5.60 (septet, 1H), 4.46 (brs, 1H), 3.62 (s, 1H), 3.51 (dd, 1H), 3.24 (d, 1H), 2.97 (d, 1H), 1.71 (d, 1H), 1.60 (d, 1H), 1.48 (d, 6H)	418	Method 14 and method 105
110	[4-[[5-chloro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-(4-third-2-base-1,4-Diazesuberane-1-yl) ketone	(400.132MHz，CDCl ₃) 8.44 (s, 1H), 7.60 (d, 2H), 7.52 (s, 1H), 7.39 (d, 2H), 7.25 (s, 1H), 4.96 (septet, 1H), 3.82-3.70 (m, 2H), 3.54-3.45 (m, 2H), 3.02-2.75 (m, 2H), 2.75-2.59 (m, 5H), 1.96-1.70 (m, 3H), 1.48 (d, 6H), 1.01 (d, 6H)	497	The method 5 of WO 05/075461 and method 58	109			418	Method 14 and method 105
110			497	The method 5 of WO 05/075461 and method 58	111	(4-cyclobutyl-1,4-Diazesuberane-1-yl)-[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.30 (d, 1H), 7.60-7.58 (m, 3H), 7.40 (d, 2H), 7.08 (s, 1H), 5.57 (septet, 1H), 3.81-3.72 (m, 2H), 3.59-3.49 (m, 2H), 2.95-2.77 (m, 1H), 2.68-2.58 (m, 4H), 2.55-2.41 (m, 3H), 2.11-1.59 (m, 8H), 1.53 (d, 6H)	492	Method 2 and method 102
112	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(methylamino-) tetramethyleneimine-1-yl] ketone	(400.132MHz，CDCl ₃) 8.30 (d, 1H), 7.61-7.58 (m, 3H), 7.54 (d, 2H), 7.22 (s, 1H), 5.58 (septet, 1H), 3.89-3.63 (m, 2H), 3.58-3.20 (m, 3H), 2.62 (s, 3H), 2.48-2.39 (m, 3H), 2.23-1.96 (m, 1H), 1.84-1.74 (m, 1H), 1.53 (d, 6H)	438	Method 2 and method 90	111			492	Method 2 and method 102

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	113	[(3R)-3-dimethylamino tetramethyleneimine-1-yl]-[2-methyl-4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.47 (d, 1H), 8.41 (d, 1H), 7.63 (d, 1H), 7.47 (s, 1H), 7.43 (d, 1H), 7.14 (t, 1H), 7.07 (d, 1H), 5.72-5.60 (m, 1H), 3.77-3.60 (m, 1H), (3.47-3.29 m, 1H are covered by the water peak), 3.27-2.94 (m, 2H are covered by the water peak), 2.75-2.62 (m, 1H), 2.50 (s, 3H are covered by the DMSO peak) .2.19 (d, 6H), 2.15-1.92 (m, 4H), 1.83-1.63 (m, 1H), 1.45 (d, 6H)	448	Method 14 and method 67
114	[(3S)-3-dimethylamino tetramethyleneimine-1-yl]-[2-fluoro-4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.86 (d, 1H), 8.47 (d, 1H), 7.79 (d, 1H), 7.49 (d, 1H), 7.46 (s, 1H), 7.39-7.30 (m, 1H), 7.15 (d, 1H), 5.73-5.59 (m, 1H), 3.75-3.58 (m, 1H), (3.47-3.33 m, 2H are covered by the water peak), and 3.23-3.08 (m, 1H), 2.77-2.64 (m, 1H), 2.50 (s, 3H are covered by the DMSO peak), 2.21-1.96 (m, 7H), 1.81-1.66 (m.1H), 1.48 (d, 6H)	452	Method 14 and method 61	113			448	Method 14 and method 67
114			452	Method 14 and method 61	115	[(3S)-3-dimethylamino tetramethyleneimine-1-yl]-[2-methyl-4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.47 (d, 1H), 8.41 (d, 1H), 7.63 (d, 1H), 7.47 (s, 1H), 7.43 (d, 1H), 7.14 (t, 1H), 7.07 (d, 1H), and 5.72-5.60 (m, 1H), 3.77-3.60 (m, 1H), 3.47-3.32 (m, 1H is covered by the water peak), 3.27-2.95 (m, 2H are covered by the water peak), 2.75-2.63 (m, 1H), 2.50 (s, 3H are covered by the DMSO peak), 2.19 (d, 6H), 2.15-1.92 (m, 4H), 1.83-1.63 (m, 1H), 1.45 (d, 6H)	448	Method 14 and method 66

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	116	[4-[[4-[2-(methoxymethyl)-3-third-2-base-3H-imidazol-4 yl] pyrimidine-2-base] amino] phenyl]-(4-third-2-base-1,4-Diazesuberane-1-yl) ketone	9.66 (s, 1H), 8.50 (d, 1H), 7.74 (d, 2H), 7.50 (s, 1H), 7.31 (d, 2H), 7.11 (d, 1H), 5.53 (septet, 1H), 4.57 (s, 2H), 3.59 (m, 2H), 3.41 (m, 2H), 3.31 (s, 3H), 2.86 (m, 1H), 2.68 (m, 1H), 2.65-2.54 (m, 3H), 1.80-1.58 (m, 2H), 1.47 (d, 6H), 0.97 (m, 6H)	492	Method 3 and method 58
117	(3-(3S)-dimethylamino tetramethyleneimine-1-yl)-[4-[[4-[2-(methoxymethyl)-3-third-2-base-3H-imidazoles-4-yl] pyrimidine-2-base] amino] phenyl] ketone	9.71 (s, 1H), 8.51 (d, H), 7.77 (m, 2H), 7.54-7.46 (m, 3H), 7.14 (d, 2H), 5.53 (septet, 1H), 4.57 (s, 2H), 3.74-3.43 (m, 3H), 3.34 (m, 1H), 2.77-2.58 (m, 2H), 2.22-2.04 (m, 6H), 1.72 (m, 1H), 1.48 (d, 6H)	464	Method 3 and method 47	116			492	Method 3 and method 58
117			464	Method 3 and method 47	118	[4-[[4-[2-(methoxymethyl)-3-third-2-base-3H-imidazol-4 yl] pyrimidine-2-base] amino] phenyl]-(4-methyl-1,4-Diazesuberane-1-yl) ketone	(+D4AcOH) 8.49 (d, 1H), 7.76 (d, 2H), 7.51 (s, 1H), 7.34 (d, 2H), 7.12 (d, 1H), 5.52 (septet, 1H), 4.58 (s, 2H), 3.68-3.40 (m, 4H), 3.29 (s, 3H), 2.68-2.55 (m, 2H), 2.35-2.21 (m, 3H), 1.90-1.72 (m, 2H), 1.48 (d, 6H)	464	Method 3 and method 56
119	[3-(3S)-(ring fourth amino) tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	9.21 (s, 1H), 8.40 (d, 1H), 7.72 (d, 2H), 7.45 (d, 2H), 7.37 (s, 1H), 7.03 (d, 1H), 5.61 (septet, 1H), 3.60-3.55 (m, 2H), 3.47-3.42 (m, 1H), 3.26 (quintet, 1H), 3.22-3.18 (m, 2H), 2.49 (s, 3H), 2.16-2.05 (m, 2H), 2.00-1.94 (m, 1H), 1.72-1.52 (m, 5H), 1.47 (d, 6H)	460	Method 14 and method 91	118			464	Method 3 and method 56

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	120	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(methyl-propyl group-amino) tetramethyleneimine-1-yl] ketone	9.24 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.46 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.65-3.57 (m, 2H), 3.49-3.44 (m, 1H), 3.31 (dd, 1H), 3.03 (quintet, 1H), 2.49 (s, 3H), 2.38-2.28 (m, 2H), 2.18 (s, 3H), 2.06-1.99 (m, 1H), 1.81-1.74 (m, 1H), 1.47 (d, 6H), 1.45-1.39 (m, 2H), 0.85 (t, 3H)	462	Method 14 and method 92
121	(3-(3S)-diethylin tetramethyleneimine-1-yl)-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	9.24 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.46 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.66-3.56 (m, 2H), 3.49-3.43 (m, 1H), and 3.30-3.23 (m, 2H), 2.60-2.52 (m, 4H), 2.49 (s, 3H), 2.06-1.99 (m, 1H), 1.80-1.73 (m, 1H), 1.47 (d, 6H), 0.96 (t, 6H)	462	Method 14 and method 94	120			462	Method 14 and method 92
121			462	Method 14 and method 94	122	[(3S)-3-(azepan-1-yl) tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl] ketone	9.21 (s, 1H), 8.40 (d, 1H), 7.72 (d, 2H), 7.45 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.66-3.57 (m, 2H), and 3.48-3.43 (m, 1H), 3.32-3.23 (m, 2H), 2.70-2.60 (m, 5H), 2.08-2.01 (m, 1H), 1.82-1.73 (m, 1H), and 1.63-1.52 (m, 6H), 1.47 (d, 6H) (the methyl peak is covered by the DMSO peak)	488	Method 14 and method 95

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	123	[(3S)-3-(2-methoxy ethyl-methyl-amino) tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	9,20 (s, 1H), 8.40 (d, 1H), 7.72 (d, 2H), 7.46 (d, 2H), 7.36 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.66-3.57 (m, 2H), 3.49-3.45 (m, 2H), 3.42 (t, 3H), 3.32 (dd, 1H), 3.23 (s, 3H), 3.11 (quintet, 1H), 2.63-2.54 (m, 3H), 2.49 (s, 3H), 2.06-2.00 (m, 1H), 1.82-1.74 (m, 1H), 1.47 (d, 6H)	478	Method 14 and method 96
124	[(3S)-3-(methyl-(2-methyl-propyl) amino) tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.65 (d, 2H), 7.55-7.49 (m, 3H), 7.42-7.38 (m, 1H), 6.95 (d, 1H), 5.67 (septet, 1H), 3.90-3.77 (m, 1H), 3.64-3.30 (m, 3H), 3.05-2.82 (m, 1H), 2.59 (s, 3H), 2.23-1.96 (m, 6H), 1.90-1.63 (m, 2H), 1.53 (d, 6H), 0.93-0.82 (m, 6H)	476	Method 14 and method 97	123			478	Method 14 and method 96
124			476	Method 14 and method 97	125	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-and 3-(third-2-base is amino) tetramethyleneimine-1-yl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.65 (d, 2H), 7.54 (d, 2H), 7.38 (s, 1H), 7.28 (s, 1H), 6.95 (d, 1H), 5.65 (septet, 1H), 3.99-3.21 (m, 4H), 3.00-2.75 (m, 1H), 2.59 (s, 3H), 2.27-1.68 (m, 4H), 1.53 (d, 6H), 1.15-0.99 (m, 6H)	448	Method 14 and method 98

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	126	[4-(2-methoxy ethyl)-1,4-Diazesuberane-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.64 (d, 2H), 7.39 (d, 2H), 7.37 (d, 2H), 6.95 (d, 1H), 5.65 (septet, 1H), 3.83-3.71 (m, 2H), 3.62-3.42 (m, 4H), and 3.36-3.30 (m, 3H), 2.95-2.86 (m, 1H), 2.83-2.66 (m, 5H), 2.59 (s, 3H), 2.05-1.92 (m, 1H), 1.90-1.77 (m, 1H), 1.53 (d, 6H)	478	Method 14 and method 103
127	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-[4-(2-methoxy ethyl)-1,4-Diazesuberane-1-yl] ketone	(400.132MHz，CDCl ₃) 8.30 (d, 1H), 7.60 (d, 2H), 7.58 (s, 1H), 7.39 (d, 2H), 7.31 (s, 1H), 5.57 (septet, 1H), 3.83-3.43 (m, 6H), 3.38-3.29 (m, 3H), 2.93-2.66 (m, 6H), 2.61 (s, 3H), 2.06-1.78 (m, 2H), 1.52 (d, 6H)	496	Method 2 and method 103	126			478	Method 14 and method 103
127			496	Method 2 and method 103	128	(4-ethyl-1,4-Diazesuberane-1-yl)-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.66-7.62 (m, 2H), 7.42-7.37 (m, 3H), 7.22 (s, 1H), 6.95 (d, 1H), 5.65 (septet, 1H), 3.82-3.74 (m, 2H), 3.59-3.49 (m, 2H), and 2.83-2.79 (m, 1H), 2.72-2.51 (m, 7H), 2.02-1.93 (m, 1H), 1.87-1.77 (m, 2H), 1.53 (d, 6H), 1.12-1.02 (m, 3H)	448	Method 14 and method 104
129	(4-ethyl-1,4-Diazesuberane-1-yl)-[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.30 (d, 1H), 7.61-7.57 (m, 3H), 7.41-7.38 (m, 2H), 7.19 (s, 1H), 5.57 (septet, 1H), 3.8-3.73 (m, 2H), 3.59-3.49 (m, 2H), 2.83-2.78 (m, 1H), 2.72-2.49 (m, 7H), 2.01-1.94 (m, 1H), 1.87-1.79 (m, 2H), 1.53 (d, 6H), 1.12-1.01 (m, 3H)	466	Method 2 and method 104	128			448	Method 14 and method 104

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	130	[4-[[5-chloro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-((3S)-3-methylamino-tetramethyleneimine-1-yl) ketone	(400.132MHz，CDCl ₃) 8.45 (s, 1H), 7.61 (d, 2H), 7.54-7.52 (m, 3H), 7.38 (s, 1H), 4.96 (septet, 1H), 3.89-3.62 (m, 2H), 3.56-3.19 (m, 2H), 2.59 (s, 3H), 2.48-2.38 (m, 3H), 2.24-2.00 (m, 1H), 1.85-1.76 (m, 1H), 1.48 (d, 6H)	454	The method 5 of WO 05/075461 and method 90
131	[(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.31 (d, 1H), 7.64-7.49 (m, 5H), 7.17 (s, 1H), 5.56 (septets, 1H), and 4.94-4.40 (m, 1H), 3.87-3.57 (m, 2H), 3.43-3.03 (m, 3H), 2.62 (s, 3H), 1.91-1.68 (m, 2H), 1.54 (d, 6H)	436	Method 2 and method 105	130			454	The method 5 of WO 05/075461 and method 90
131			436	Method 2 and method 105	132	[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-[(3R)-and 3-methylamino-tetramethyleneimine-1-yl] ketone	(400.132MHz，CDCl ₃) 8.30 (d, 1H), 7.61-7.59 (m, 3H), 7.54 (d, 2H), 7.29 (s, 1H), 5.58 (septet, 1H), 3.91-3.62 (m, 2H), 3.58-3.42 (m, 1H), 3.39-3.20 (m, 2H), 2.61 (s, 3H), 2.48-2.39 (m, 3H), 2.22-2.00 (m, 1H), 1.86-1.74 (m, 2H), 1.53 (d, 6H)	438	Method 2 and method 108
133	[(3R)-3-methylamino-tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	(400.132MHz，CDCl ₃) 8.37 (d, 1H), 7.65 (d, 2H), 7.54 (d, 2H), 7.44 (s, 1H), 7.38 (s, 1H), 6.95 (d, 1H), 5.66 (septet, 1H), 3.90-3.63 (m, 2H), and 3.58-3.45 (m, 1H), 3.39-3.19 (m, 1H), 2.59 (s, 3H), 2.48-2.39 (m, 3H), 2.23-2.00 (m, 1H), 1.86-1.59 (m, 3H), 1.53 (d, 6H)	420	Method 14 and method 108	132			438	Method 2 and method 108

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	134	[4-[[5-chloro-4-(2-methyl-3-third-2-base-3H-imidazoles-4-yl) pyrimidine-2-base] amino] phenyl]-[(3R)-and 3-methylamino-tetramethyleneimine-1-yl] ketone	(400.132MHz，CDCl ₃) 8.45 (s, 1H), 7.61 (d, 2H), 7.54-7.52 (m, 3H), 7.38 (s, 1H), 4.96 (septet, 1H), 3.89-3.62 (m, 2H), 3.56-3.19 (m, 2H), 2.59 (s, 3H), 2.48-2.38 (m, 3H), 2.24-2.00 (m, 1H), 1.85-1.76 (m, 1H), 1.48 (d, 6H)	454	The method 5 of WO 05/075461 and method 108

Embodiment 135

5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methylpiperazine-1-yl) carbonyl] Phenyl } pyrimidine-2-amine hydrochlorate

With 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 2,64mg, 0.272mmol), 1-(4-the benzoyl bromide)-4-methylpiperazine (embodiment 59 of WO 03/004472; 92mg, 0.325mmol), BINAP (51mg, 0.082mmol) and sodium tert-butoxide (31mg, 0.323mmol) with 1,4-diox (2.0ml) mixing.Feed argon gas 5 minutes in the mixture, add Pd (OAc) then ₂(9.1mg 0.045mmol), feeds argon gas once more.Reaction mixture in the sealed tube is put into microwave reactor in 110 ℃ of heating 30 minutes.Vacuum evaporating solvent makes resistates at DCM and rare NaHCO ₃Distribute between (aqueous solution).Water extracts with DCM, the organic phase drying (Na of merging ₂SO ₄), filter the back evaporation.Rough free alkali preparation HPLC purifying is dissolved in DCM then, adds the diethyl ether solution (2 equivalent HCl) of 0.1M HCl, separates out the hydrochloric acid adduct of product from solution.Evaporating solvent, resistates is water-soluble, and lyophilize obtains title compound (43mg, 36%, solid).NMR(D ₂O)8.54(d，J＝2.0Hz，1H)，7.79(d，J＝2.0Hz，1H)，7.63(d，J＝8.8Hz，2H)，7.48(d，J＝8.6Hz，2H)，5.39-5.26(m，1H)，4.29-3.83(m，2H)，3.79-3.33(m，4H)，3.32-3.09(m，2H)，2.95(s，3H)，2.79(s，3H)，1.52(d，J＝6.8Hz，6H)；MS(ESI)m/z 437。

Embodiment 136

5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{3-methoxyl group-4-[(4-methylpiperazine- The 1-yl) carbonyl] phenyl } pyrimidine-2-amine hydrochlorate

With 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 2; 49.8mg; 0.212mmol), 1-(4-chloro-2-anisoyl)-4-methylpiperazine (method 11; 45mg; 0.167mmol), cesium carbonate (110mg, 0.338mmol) with anhydrous 1,4-diox (2ml) mixing; feed argon gas in the mixture after 5 minutes, add Pd ₂(dba) ₃(9.3mg, 0.010mmol) and Xantphos (11.3mg, 0.024mmol).In mixture, feed argon gas, then in sealed tube in 90 ℃ of heated overnight.Solvent removed in vacuo is dissolved in DCM with resistates, with rare NaHCO ₃(aqueous solution) washing.Organic layer drying (Na ₂SO ₄), filter the back evaporation.Rough free alkali preparation HPLC purifying is dissolved in DCM then, adds the diethyl ether solution (2 equivalent HCl) of 0.1M HCl, separates out the hydrochloric acid adduct of product from solution.Evaporating solvent, resistates is water-soluble, and lyophilize obtains title compound (60mg, 53%, solid).NMR：11.38(br s，1H)，10.06(s，1H)，8.85(d，J＝2.0Hz，1H)，8.12(d，J＝1.8Hz，1H)，7.49(dd，J＝8.3，1.8Hz，1H)，7.39(s，1H)，7.20(d，J＝8.3Hz，1H)，5.30-5.15(m，1H)，4.58(d，J＝13.3Hz，1H)，3.81(s，3H)，3.57-3.13(m，6H)，3.13-2.87(m，2H)，2.82(s，3H)，2.79(br s，3H)，1.51(d，J＝7.0Hz，6H)；m/z(ESI)468。

Embodiment 137-138

Following compounds prepares with proper raw material by the method for embodiment 136.

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	137	N-{3-chloro-4-[(4-methylpiperazine-1-yl) carbonyl] phenyl }-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine hydrochlorate	11.78(br s，1H)，10.31(s，1H)， 8.88(d，J＝1.8Hz，1H)，8.12(d， J＝2.0Hz，1H)，7.94(br s，1H)， 7.71(dd，J＝8.3，2.0Hz，1H)，7.38 (br s，1H)，5.30-5.17(m，1H)， 4.57(d，J＝13.1Hz，1H)，4.20- 2.89(m，8H)，2.83(s，3H)，2.76 (s，3H)，1.51(d，J＝7.1Hz，6H)	472	Method 2 and 1-(2,4 dichloro benzene formyl radical)-4-methylpiperazine 1

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	138	5-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-2-[(4-methylpiperazine-1-yl) carbonyl] the benzonitrile hydrochloride	11.79(br s，1H)，10.54(s，1H)， 8.91(d，J＝1.76Hz，1H)，8.29(d， J＝2.01Hz，1H)，8.11(d，J＝1.83 Hz，1H)，8.02(dd，J＝8.53，2.26 Hz，1H)，7.62(d，J＝8.53Hz，1H)， 5.26(s，1H)，4.57(br s，1H)， 3.75-2.95(m，8H)，2.82(s，3H)， 2.77(s，3H)，1.52(d，J＝7.03Hz， 6H)	463	Method 2 and method 13

¹Prasad, R.N. etc., J.Med.Chem.1968,6,1144-1150

Embodiment 139

5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-[4-[(4-methylpiperazine-1-yl) carbonyl]- 3-(methylsulfonyl) phenyl] pyrimidine-2-amine hydrochlorate

With anhydrous 1,4-diox (2ml) is added to 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 2,52mg, 0.22mmol), 1-[4-bromo-2-(methylsulfonyl) benzoyl]-4-methylpiperazine (Bruce, R.B. etc., J.Med.Chem.1968,5,1031-1034; 71.0mg, 0.197mmol) and sodium tert-butoxide (30.9mg, 0.32mmol) in.In mixture, feed argon gas, add Pd (OAc) ₂(2mg, 0.009mmol) and Pd (t-Bu ₃P) ₂(6.1mg feeds argon gas after 0.012mmol) again.With the mixture in the sealed tube in 120 ℃ of heating.After stirring is spent the night, add Pd (t-Bu ₃P) ₂(12.4mg 0.024mmol), added following reagent: CsCO after 24 hours ₃(107mg, 0.33mmol), X-Phos (11.3mg, 0.024mmol) and Pd ₂(dba) ₃(11.1mg, 0.012mmol).The gained mixture was heated 20 hours in 90 ℃ of oil baths.Mixture washs with EtOAc through behind the diatomite filtration.Organic phase washes with water, dry (Na ₂SO ₄), filter the final vacuum evaporation.(gradient is the MeCN solution of MeCN/5%TEA to resistates with purified by flash chromatography; The MeCN solution of 0-5%TEA).The part that will contain product combines, vacuum-evaporation.Resistates is dissolved in DCM, and organic phase is washed with EDTA (aqueous solution, pH 1).EDTA (aqueous solution) uses NaHCO mutually ₃(aqueous solution) neutralization (pH 7), product extracts with DCM.Organic phase drying (Na ₂SO ₄), filter the final vacuum evaporation.Resistates is dissolved in the DCM/ ether, and (1: 1,10ml), the diethyl ether solution (2.0 equivalent) through dropping 1M HCl was separated out title compound.The collecting precipitation thing is used the DCM rinsing after filtration, water-soluble after, lyophilize obtains title compound (96mg, 74%, yellow solid).NMR：11.47-11.25(m，1H)，10.41(s，1H)，8.90(d，J＝1.5Hz，1H)，8.30(s，1H)，8.21(d，J＝8.5Hz，1H)，8.12(s，1H)，7.52(d，J＝8.0Hz，1H)，5.29-5.12(m，1H)，4.64-4.48(m，1H)，3.62-3.04(m，6H)，2.84-2.71(m，7H)，2.76(br s，4H)，1.52(d，J＝7.0Hz，6H)；MS(ESI)m/z 516。

Embodiment 140

5-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-2-[(4-methyl piperazine Piperazine-1-yl) carbonyl] benzonitrile

Under inert atmosphere, with 4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 14,0.20g, 0.92mmol), PdOAc2 (16mg, 0.068mmol), Xantphos (60mg, 0.10mmol), cesium carbonate (0.42g, 1.3mmol) and 5-chloro-2-(4-methyl-piperazine-1-carbonyl)-benzonitrile (method 13,0.32g, 1.20mmol) be added in the diox (7ml), heated 1 hour in 150 ℃ with microwave.With flash chromatography on silica gel method purifying (the DCM solution with 0-10%MeOH is elutriant), obtain required compound, be yellow foam.Be further purified with RPHPLC, obtain required compound (204mg, 50%, colourless foam shape thing).NMR (400.132MHz): 9.95 (s, 1H), 8.49 (d, 1H), 8.26 (s, 1H), 8.01 (d, 1H), 7.48 (d, 1H), 7.46 (s, 1H), 7.17 (d, 1H), 5.60 (septets, 1H), and 3.70-3.58 (m, 2H), 3.32-3.22 (m, 2H), 2.51 (s, 3H), 2.42-2.27 (m, 4H), 2.20 (s, 3H), 1.48 (d, 6H); M/z 445.

Embodiment 141-144

Following compounds prepares with proper raw material by the method for embodiment 137.

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	141	5-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-2-(morpholine-4-base carbonyl) benzonitrile	(400.132MHz): 9.96 (s, 1H), 8.50 (d, 1H), 8.27 (s, 1H), 8.02 (d, 1H), 7.52 (d, 1H), 7.47 (s, 1H), 7.18 (d, 1H), 5.59 (septet, 1H), 3.72-3.53 (m, 6H), 3.40-3.21 (m, 2H), 2.51 (s, 3H), 1.49 (d, 6H)	432	Method 14 and method 16
142	5-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino }-2-(morpholine-4-base carbonyl) benzonitrile	(400.132MHz)：10.06(s，1H)， 8.65(d，1H)，8.21(s，1H)，7.98(d， 1H)，7.52(d，1H)，7.40(d，1H)， 5.37(s，1H)，3.76-3.50(m，6H)， 3.37-3.21(m，2H)，2.54(s，3H)， 1.47(d，6H)	450	Method 2 and method 16	141			432	Method 14 and method 16
142			450	Method 2 and method 16	143	5-(4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl] and pyrimidine-2-base } amino)-2-(morpholine-4-base carbonyl) benzonitrile	(400.132MHz，CDCl ₃) 8.46 (d, 1H), 8.23 (s, 1H), 7.82-7.80 (m, 2H), 7.45 (s, 1H), 7.41 (d, 1H), 7.05 (d, 1H), 5.42 (septet, 1H), 4.66 (s, 2H), 3.89-3.67 (m, 6H), 3.48-3.36 (m, 5H), 1.59 (d, 6H)	462	Method 3 and method 16
144	5-(4-[1-sec.-propyl-2-(methoxymethyl)-1H-imidazoles-5-yl] and pyrimidine-2-base } amino)-2-[(4-methylpiperazine-1-yl) carbonyl] benzonitrile	(400.132MHz，CDCl ₃) 8.45 (d, 1H), 8.21 (d, 1H), 7.78 (dd, 1H), 7.71 (s, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.04 (d, 1H), 5.43 (septets, 1H), 4.66 (s, 2H), 3.90-3.80 (m, 2H), 3.43-3.36 (m, 5H), 2.57-2.49 (m, 2H), 2.46-2.38 (m, 2H), 2.33 (s, 3H), 1.60 (d, 6H)	475	Method 3 and method 13	143			462	Method 3 and method 16

Embodiment 145

[(2S)-and 1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl Base) tetramethyleneimine-2-yl] methyl alcohol

To 4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenylformic acid sodium salt (method 50; 240mg) and in the suspension of DMF (8ml) stirring add HBTU (257mg).Mixture was stirred 20 minutes at ambient temperature, add L-dried meat ammonia alcohol (81mg) then.Mixture was at room temperature stirred 18 hours, use EtOAc (80ml) dilution then, after 2N NaOH (80ml) washing, water layer is used EtOAc (80ml) extraction once more.The vacuum concentration organism, resistates is with anti-phase preparation HPLC purifying then.The part that will contain product is injected 10g SCX-2 post, with the Me0H washing, uses methyl alcohol/ammonia (methanolic ammonia) wash-out then.The evaporation alkaline eluant obtains title compound (177mg, 63%, white solid).NMR(300.074MHz)9.65(s，1H)，8.42(d，1H)，7.74(d，2H)，7.46-7.43(m，3H)，7.08(d，1H)，5.71-5.64(m，1H)，4.75(br s，1H)，4.16-4.08(m，1H)，3.56-3.34(m，4H)，2.50(s，3H)，1.94-1.82(m，3H)，1.75-1.64(m，1H)，1.46(d，6H)；m/z 421。

Embodiment 146-174

The method that following compounds is pressed embodiment 145 is with suitable acid and amine feedstock production.

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	146	1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) piperidines-4-alcohol	(399.902MHz).9.22(s，1H)，8.40 (d，1H)，7.72(d，2H)，7.38(s， 1H)，7.31(d，2H)，7.03(d，1H)， 5.66-5.57(m，1H)，4.38(br s， 1H)，3.81-3.75(m，3H)，3.25- 3.17(m，2H)，2.48(s，3H)，1.79- 1.73(m，2H)，1.46(d，6H)，1.43- 1.35(m，2H)；m/z 421.	421	Method 50
147	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[3-(methylsulfonyl) tetramethyleneimine-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(300.074MHz).9.70(s，1H)，8.43 (d，1H)，7.77(d，2H)，7.49(d， 2H)，7.45(s，1H)，7.10(d，1H)， 5.72-5.63(m，1H)，4.02-3.96 (m，1H)，3.89-3.82(m，2H)， 3.71-3.54(m，2H)，3.03(s，3H)， 3.03(s，3H)，2.32-2.24(m，2H)， 1.46(d，6H)	469	Method 50	146			421	Method 50

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	148	[(2R)-and 1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) tetramethyleneimine-2-yl] methyl alcohol	(300.074MHz)9.65(s，1H)，8.42 (d，1H)，7.74(d，2H)，7.46-7.43 (m，3H)，7.08(d，1H)，5.71-5.64 (m，1H)，4.75(br s，1H)，4.16- 4.08(m，1H)，3.56-3.34(m， 4H)，2.50(s，3H)，1.94-1.82(m， 3H)，1.75-1.64(m，1H)，1.46(d， 6H)	421	Method 50
149	(3S)-and 1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) piperidines-3-alcohol	(300.074MHz).9.64(s，1H)，8.41 (d，1H)，7.73(d，2H)，7.43(s， 1H)，7.33(d，2H)，7.08(d，1H)， 5.71-5.64(m，1H)，4.86(s，1H)， 3.75-3.60(m，1H)，3.52-3.45 (m，1H)，3.18-3.07(m，2H)， 2.96-2.83(m，1H)，2.49(s，3H)， 1.89-1.80(m，1H)，1.73-1.66 (m，1H)，1.45(d，6H)，1.41-1.35 (m，2H)	421	Method 50	148			421	Method 50
149			421	Method 50	150	(3R)-and 1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) piperidines-3-alcohol	(300.074MHz)9.64(s，1H)，8.41 (d，1H)，7.73(d，2H)，7.43(s， 1H)，7.33(d，2H)，7.08(d，1H)， 5.71-5.64(m，1H)，4.86(s，1H)， 3.75-3.60(m，1H)，3.52-3.45 (m，1H)，3.18-3.07(m，2H)， 2.96-2.83(m，1H)，2.49(s，3H)， 1.89-1.80(m，1H)，1.73-1.66 (m，1H)，1.45(d，6H)，1.41-1.35 (m，2H)	421	Method 50

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	151	[1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) piperidyl-2-yl] methyl alcohol	(300.074MHz).9.61(s，1H)，8.40 (d，1H)，7.71(d，2H)，7.43(s， 1H)，7.32(d，2H)，7.07(d，1H)， 5.71-5.65(m，1H)，4.73(br s， 1H)，4.30-3.90(m，2H)，3.64- 3.48(m，2H)，2.98-2.84(m， 1H)，2.49(s，3H)，1.74-1.50(m， 6H)，1.44(d，6H)	435	Method 50
152	N-(4-{[(is anti-)-2,5-lupetazin-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(300.074MHz).9.67(s，1H)，8.43 (d，1H)，7.76(d，2H)，7.44(s， 1H)，7.33(d，2H)，7.09(d，1H)， 5.72-5.62(m，1H)，3.49-3.33 (m，4H)，2.49(s，3H)，2.08-2.04 (m，1H)，1.97-1.95(m，1H)， 1.46(d，6H)，1.19-1.05(m，6H)	476	Method 50	151			435	Method 50
152			476	Method 50	153	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-4-[(4-methyl isophthalic acid, 4-Diazesuberane-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(300.074MHz).9.63(s，1H)，8.41 (d，1H)，7.73(d，2H)，7.42(s， 1H)，7.32(d，2H)，7.07(d，1H)， 5.73-5.64(m，1H)，3.66-3.39 (m，4H)，2.68(s，3H)，2.64-2.56 (m，1H)，2.49(s，3H)，2.29-2.22 (m，3H)，1.86-1.71(m，2H)， 1.45(d，6H)	448	Method 50
154	1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) aza-cyclobutane-3-alcohol	(300.074MHz)9.74(s，1H)，8.43 (d，1H)，7.77(d，2H)，7.57(d， 2H)，7.43(s，1H)，7.10(d，1H)， 5.75-5.62(m，1H)，4.55-4.39 (m，2H)，4.33-4.17(m，1H)， 4.10-3.95(m，1H)，3.85-3.72 (m，1H)，2.69(s，3H)，1.46(d， 6H)	393	Method 50	153			448	Method 50

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	155	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-4-[(4-tetramethyleneimine-1-phenylpiperidines-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	(399.902MHz).9.22(s，1H)，8.39 (d，1H)，7.72(d，2H)，7.37(s， 1H)，7.32(d，2H)，7.03(d，1H)， 5.65-5.57(m，1H)，3.98-3.91 (m，2H)，3.11-3.04(m，2H)， 2.55-2.50(m，4H)，2.49(s，3H)， 2.38-2.30(m，1H)，1.85-1.79 (m，2H)，1.70-1.66(m，4H)， 1.47(d，6H)，1.44-1.37(m，2H)	474	Method 50
156	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[4-(4-methylpiperazine-1-yl) piperidines-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(399.902MHz).9.22(s，1H)，8.39 (d，1H)，7.72(d，2H)，7.37(s， 1H)，7.32(d，2H)，7.03(d，1H)， 5.63-5.57(m，1H)，4.09-4.03 (m，2H)，2.94-2.90(m，2H)， 2.52-2.50(m，4H)，2.49(s，3H)， 2.46-2.42(m，1H)，2.34-2.31 (m，4H)，2.16(s，3H)，1.81-1.75 (m，2H)，1.47(d，6H)，1.43-1.34 (m，2H)	503	Method 50	155			474	Method 50
156			503	Method 50	157	N-[4-(4-[2-(dimethylamino) ethyl] and piperazine-1-yl } carbonyl) phenyl]-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(399.902MHz).9.26(s，1H)，8.41 (d，1H)，7.74(d，2H)，7.38(s， 1H)，7.34(d，2H)，7.04(d，1H)， 5.66-5.58(m，1H)，3.54-3.47 (m，4H)，3.19-3.07(m，4H)， 2.74-2.70(m，2H)，2.57-2.49 (m，2H)，2.47(s，3H)，2.23(s， 6H)，1.47(d，6H)	477	Method 50
158	N-{4-[(1,1-titanium dioxide thiomorpholine-4-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(399.902MHz).9.31(s，1H)，8.40 (d，1H)，7.76(d，2H)，7.43(d， 2H)，7.37(s，1H)，7.04(d，1H)， 5.63-5.56(m，1H)，3.95-3.89 (m，4H)，3.21-3.16(m，4H)， 2.93(s，3H)，1.47(d，6H)	413	Method 50	157			477	Method 50

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	159	N-{4-[(4-cyclopropyl piperazine-1-yl) carbonyl] phenyl }-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz).9.73(s，1H)，8.44 (d，1H)，7.77(d，2H)，7.45(s， 1H)，7.35(d，2H)，7.11(d，1H)， 5.74-5.67(m，1H)，3.53-3.39 (m，8H)，2.51(s，3H)，1.68-1.63 (m，1H)，1.46(d，6H)，0.44-0.42 (m，2H)，0.34-0.32(m，2H)	446	Method 50
160	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[4-(2-methoxy ethyl) piperazine-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(400.132MHz).9.72(s，1H)，8.44 (d，1H)，7.76(d，2H)，7.45(s， 1H)，7.34(d，2H)，7.10(d，1H)， 5.73-5.66(m，1H)，3.55-3.31 (m，12H)，3.23(s，3H)，2.44(s， 3H)，1.46(d，6H)	464	Method 50	159			446	Method 50
160			464	Method 50	161	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[4-(2-tetramethyleneimine-1-base ethyl) piperazine-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(400.132MHz).9.72(s，1H)，8.44 (d，1H)，7.76(d，2H)，7.45(s， 1H)，7.34(d，2H)，7.10(d，1H)， 5.74-5.67(m，1H)，3.55-3.34 (m，12H)，2.62-2.49(m，4H)， 2.44(s，3H)，1.69-1.61(m，4H)， 1.46(d，6H)	503	Method 50
162	N-{4-[(4-cyclopropyl piperazine-1-yl) carbonyl] phenyl }-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(400.132MHz)9.82(s，1H)，8.60 (d，1H)，7.72(d，2H)，7.38(d， 1H)，7.35(d，2H)，5.48-5.40(m， 1H)，3.52-3.38(m，8H)，2.50(s， 3H)，1.69-1.63(m，1H)，1.45(d， 6H)，0.45-0.41(m，2H)，0.35- 0.31(m，2H)	464	Method 52	161			503	Method 50
162			464	Method 52	163	N-(4-{[is anti--2,5-lupetazin-1-yl] carbonyl } phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.76(s，1H)，8.58(d，1H)，7.72 (d，2H)，7.37-7.29(m，3H)，5.46 -5.38(m，1H)，4.06(s，1H)，3.48 -3.39(m，2H)，3.28-3.25(m， 1H)，2.88-2.95(m，1H)，2.51(s， 3H)，2.05(s，1H)，1.96(s，1H)， 1.44(d，6H)，1.18-1.14(m，3H)， 1.10-1.06(m，3H)	494 (+ MeCN)	Method 52

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	164	5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-(4-{[4-(4-methylpiperazine-1-yl) piperidines-1-yl] carbonyl } phenyl) pyrimidine-2-amine	9.74(s，1H)，8.57(d，1H)，7.69 (d，2H)，7.36(d，1H)，7.32(d， 2H)，5.47-5.35(m，1H)，2.93- 2.81(m，2H)，2.52(s，3H)，2.47- 2.38(m，6H)，2.31-2.25(m， 4H)，2.12(s，3H)，1.79-1.71(m， 2H)，1.44(d，6H)，1.39-1.27(m， 3H)	521	Method 52
165	N-[4-(4-[2-(dimethylamino) ethyl] and piperazine-1-yl } carbonyl) phenyl]-5-fluoro-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-amine	9.75(s，1H)，8.57(d，1H)，7.70 (d，2H)，7.36(d，1H)，7.32(d， 2H)，5.47-5.37(m，1H)，3.50- 3.43(m，4H)，2.52(s，3H)，2.44- 2.30(m，8H)，2.12(s，6H)，1.44 (d，6H)	495	Method 52	164			521	Method 52
165			495	Method 52	166	N-{4-[(1,1-titanium dioxide thiomorpholine-4-yl) carbonyl] phenyl }-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.80(s，1H)，8.58(d，1H)，7.73 (d，2H)，7.44(d，2H)，7.37(d， 1H)，5.48-5.37(m，1H)，3.90- 3.84(m，4H)，3.27-3.21(m， 4H)，2.52(s，3H)，1.45(d，6H)	473	Method 52
167	5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl)-N-{4-[(4-methyl-1,4-Diazesuberane-1-yl) carbonyl] phenyl } pyrimidine-2-amine	9.73(s，1H)，8.57(s，1H)，7.68 (d，2H)，7.38-7.29(m，3H)，5.48 -5.38(m，1H)，3.61-3.36(m， 4H)，2.72-2.61(m，2H)，2.50(s， 3H)，2.42-2.34(m，2H)，2.25(s， 3H)，1.85-1.69(m，2H)，1.43(d， 6H)	452	Method 52	166			473	Method 52

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	168	[(2S)-and 1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-yl] amino } benzoyl) tetramethyleneimine-2-yl] methyl alcohol	9.75(s，1H)，8.57(d，1H)，7.69 (d，2H)，7.44(d，2H)，7.37(d， 1H)，5.48-5.39(m，1H)，4.74(s， 1H)，4.16-4.07(m，1H)，3.60- 3.33(m，4H)，2.52(s，3H)，1.96- 1.83(m，3H)，1.75-1.63(m， 1H)，1.44(d，6H)	439	Method 52
169	[1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) piperidyl-2-yl] methyl alcohol	9.71(s，1H)，8.56(s，1H)，7.67 (d，2H)，7.37-7.30(m，3H)，5.48 -5.39(m，1H)，4.73(s，1H)，3.63 -3.46(m，2H)，3.41-3.32(m， 2H)，2.98-2.85(m，1H)，2.52(s， 3H)，1.75-1.45(m，6H)，1.43(d， 6H)	453	Method 52	168			439	Method 52
169			453	Method 52	170	[(2R)-and 1-(4-{[5-fluoro-4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl) pyrimidine-2-yl] amino } benzoyl) tetramethyleneimine-2-yl] methyl alcohol	9.75(s，1H)，8.57(d，1H)，7.69 (d，2H)，7.44(d，2H)，7.37(d， 1H)，5.48-5.39(m，1H)，4.74(s， 1H)，4.16-4.07(m，1H)，3.60- 3.33(m，4H)，2.52(s，3H)，1.96- 1.83(m，3H)，1.75-1.63(m， 1H)，1.44(d，6H)	439	Method 52
171	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-4-[(4-sec.-propyl piperazine-1-yl) and carbonyl] phenyl } pyrimidine-2-amine	9.67(s，1H)，8.43(d，1H)，7.76 (d，2H)，7.44(s，1H)，7.35(d， 2H)，7.10(d，1H)，5.74-5.64(m， 1H)，3.54-3.43(m，4H)，3.41- 3.36(m，1H)，2.51(s，3H)，2.47- 2.43(m，4H)，1.47(d，6H)，0.97 (d，6H)	448	Method 50	170			439	Method 52

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	172	N-(4-{[4-(dimethylamino) piperidines-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	9.66(s，1H)，8.43(d，1H)，7.75 (d，2H)，7.44(s，1H)，7.34(d， 2H)，7.10(d，1H)，5.72-5.65(m， 1H)，3.40-3.32(m，2H)，3.00- 2.83(m，2H)，2.50(s，3H)，2.39- 2.33(m，1H)，2.19(s，6H)，1.79- 1.73(m，2H)，1.46(d，6H)，1.38- 1.28(m，2H)	448	Method 50
173	(3R)-and 1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) tetramethyleneimine-3-alcohol	9.69(s，1H)，8.44(d，1H)，7.76 (d，2H)，7.50(d，2H)，7.45(s， 1H)，7.10(d，1H)，5.72-5.67(m， 1H)，4.99-4.90(m，1H)，4.34- 4.23(m，1H)，3.66-3.55(m， 2H)，3.53-3.44(m，1H)，2.51(s， 3H)，1.98-1.88(m，1H)，1.85- 1.77(m，1H)，1.48(d，6H)	407	Method 50	172			448	Method 50
173			407	Method 50	174	(3S)-and 1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl) tetramethyleneimine-3-alcohol	9.69(s，1H)，8.44(d，1H)，7.76 (d，2H)，7.50(d，2H)，7.45(s， 1H)，7.10(d，1H)，5.72-5.67(m， 1H)，4.99-4.90(m，1H)，4.34- 4.23(m，1H)，3.66-3.55(m， 2H)，3.53-3.44(m，1H)，2.51(s， 3H)，1.98-1.88(m，1H)，1.85- 1.77(m，1H)，1.48(d，6H)	407	Method 50

Embodiment 175

N-(4-{[4-(aminomethyl) piperidines-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles- The 5-yl) pyrimidine-2-amine

To 4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenylformic acid sodium salt (method 50; 240mg) and in the suspension of DMF (8ml) stirring add HBTU (257mg).Mixture was stirred 20 minutes at ambient temperature, add (tertbutyloxycarbonyl-4-aminomethyl) piperidines (81mg) then.Mixture was at room temperature stirred 18 hours, use EtOAc (80ml) dilution then, after 2N NaOH (80ml) washing, water layer is used EtOAc (80ml) extraction again.The vacuum concentration organism, resistates is with anti-phase preparation HPLC purifying then.The part that will contain product is injected 10g SCX-2 post, with the MeOH washing, uses methyl alcohol/ammonia wash-out then.The evaporation alkaline eluant obtains white solid.After this solid is dissolved in MeOH (1ml), add hydrogenchloride De dioxane solution (4M, 4ml).This solution was stirred 3 hours at ambient temperature, then vacuum concentration.The gained solid is dissolved in MeOH, and is added on the 10g SCX-2 post.Pillar washs back methyl alcohol/ammonia wash-out with MeOH.The evaporation alkaline eluant obtains title compound (85mg, 30%, white solid).NMR(399.902MHz).8.46(s，1H)，8.41(d，1H)，7.79(d，2H)，7.74(d，2H)，7.37(s，1H)，7.05(d，1H)，5.65-5.58(m，1H)，3.20-3.10(m，4H)，3.09-2.95(m，2H)，2.58-2.51(m，2H)，2.50(s，3H)，1.72-1.63(m，3H)，1.49(d，6H)，1.21-1.11(m，2H)；m/z 434。

Embodiment 176-178

Following compounds prepares with proper raw material by the method for embodiment 175.

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	176	N-(4-{[(3R)-3-amino-pyrrolidine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(399.902MHz).9.24(s，1H)，8.40 (d，1H)，7.73(d，2H)，7.46(d， 2H)，7.36(s，1H)，7.03(d，1H)， 5.66-5.56(m，1H)，3.65-3.58 (m，2H)，3.51-3.42(m，2H)， 3.17-3.13(m，1H)，2.79(br s， 2H)，2.49(s，3H)，2.03-1.95(m， 1H)，1.66-1.59(m，1H)，1.47(d， 6H)	406	Method 50 and (3R)-3-(t-butoxycarbonyl amino) tetramethyleneimine

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	177	N-(4-{[(3S)-3-amino-pyrrolidine-1-yl] carbonyl } phenyl)-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine	(399.902MHz).9.24(s，1H)，8.40 (d，1H)，7.73(d，2H)，7.46(d， 2H)，7.36(s，1H)，7.03(d，1H)， 5.66-5.56(m，1H)，3.65-3.58 (m，2H)，3.51-3.42(m，2H)， 3.17-3.13(m，1H)，2.79(br s， 2H)，2.49(s，3H)，2.03-1.95(m， 1H)，1.66-1.59(m，1H)，1.47(d， 6H)	406	Method 50 and (3S)-3-(t-butoxycarbonyl amino) tetramethyleneimine
178	4-(1-sec.-propyl-2-methyl-1H-imidazoles-5-yl)-N-(4-{[3-(methylamino-) tetramethyleneimine-1-yl] carbonyl } phenyl) pyrimidine-2-amine	(300.074MHz).9.67(s，1H)，8.42 (d，1H)，7.74(d，2H)，7.47(d， 2H)，7.43(s，1H)，7.08(d，1H)， 5.73-5.67(m，1H)，3.61-3.52 (m，2H)，3.28-3.07(m，3H)， 2.53(s，3H)，2.33-2.16(m，4H)， 2.02-1.88(m，1H)，1.76-1.66 (m，1H)，1.45(d，6H)	420	Method 50 and 3-(N-tertbutyloxycarbonyl-N-methylamino-) tetramethyleneimine	177			406

Embodiment 179-199

Embodiment 179-199 prepares by following universal method:

With 4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } phenylformic acid lithium salts (method 106; 2.47g) and HBTU (2.73g) stirred at ambient temperature 1 hour with dry DMF (97ml).4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base with five equilibrium] amino } phenylformic acid lithium salts and the HBTU/DMF solution (2ml) of being joined is added to that the back adds DIPEA (0.45mmol) in the corresponding amine (0.18mmol).With gained solution vortex 66 hours at ambient temperature.To be dissolved in DCM after the DMF solution for vacuum concentration, with the sodium bicarbonate aqueous solution vortex.Separating the organic layer final vacuum concentrates.Use the RPHPLC purifying, obtain title compound.

The embodiment numbering	Compound	NMR/m/z	Amine
The embodiment numbering	Compound	NMR/m/z	Amine	179	[4-(4-fluorophenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.69(s，1H)，8.44(m，1H)，7.79 (m，2H)，7.44(s，1H)，7.40(m， 2H)，7.11-7.04(m，3H)，6.98 (m，2H)，5.69(m，1H)，3.65(m， 4H)，3.12(m，4H)，2.50(m，3H)， 1.47(d，6H)；m/z 500	1-(4-fluorophenyl) piperazine
180	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(4-phenylpiperazine-1-yl) ketone	m/z 482	The 1-phenylpiperazine	179			1-(4-fluorophenyl) piperazine
180		m/z 482	The 1-phenylpiperazine	181	[4-(2-p-methoxy-phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 512	1-(2-p-methoxy-phenyl) piperazine
182	[(2S)-2-(anilino methyl) tetramethyleneimine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z 496	(S)-(+)-2-(anilino methyl) tetramethyleneimine	181		m/z 512	1-(2-p-methoxy-phenyl) piperazine
182		m/z 496	(S)-(+)-2-(anilino methyl) tetramethyleneimine	183	[4-(2-fluorophenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	(400.132MHz，CDCl ₃)8.39(d， 1H)，7.69(m，2H)，7.46(m，2H)， 7.39(s，1H)，7.18(s，1H)，7.11- 6.93(m，5H)，5.65(m，1H)，3.83 (m，4H)，3.11(m，4H)，2.60(s， 3H)，1.55(d，6H)；m/z 500	1-(2-fluorophenyl) piperazine
184	[4-(4-p-methoxy-phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 512	1-(4-p-methoxy-phenyl) piperazine	183			1-(2-fluorophenyl) piperazine

The embodiment numbering	Compound	NMR/m/z	Amine
The embodiment numbering	Compound	NMR/m/z	Amine	185	[4-(3-p-methoxy-phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 512	1-(3-p-methoxy-phenyl) piperazine
186	[4-(4-chloro-phenyl-) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z 516	1-(4-chloro-phenyl-) piperazine	185		m/z 512	1-(3-p-methoxy-phenyl) piperazine
186		m/z 516	1-(4-chloro-phenyl-) piperazine	187	[4-(4-hydroxy phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.68(s，1H)，8.85(s，1H)，8.44 (d，1H)，7.79(m，2H)，7.44(s， 1H)，7.40(d，2H)，7.10(d，1H)， 6.82(d，2H)，6.67(d，2H)，5.70 (m，1H)，3.64(m，4H)，2.99(m， 4H)，2.50(s，3H)，1.47(d，6H)； m/z 498	1-(4-hydroxy phenyl) piperazine
188	[4-(4-aminomethyl phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z496	1-(4-aminomethyl phenyl) piperazine	187			1-(4-hydroxy phenyl) piperazine
188		m/z496	1-(4-aminomethyl phenyl) piperazine	189	[4-(2-hydroxy phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z 498	N-(2-hydroxy phenyl) piperazine
190	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(4-pyridin-4-yl-piperidino) ketone	m/z482	1,2,3,4,5,6-six hydrogen-[4,4 ']-dipyridyl	189		m/z 498	N-(2-hydroxy phenyl) piperazine
190		m/z482	1,2,3,4,5,6-six hydrogen-[4,4 ']-dipyridyl	191	[4-(2,4 difluorobenzene base) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 518	1-(2,4 difluorobenzene base) piperazine

The embodiment numbering	Compound	NMR/m/z	Amine
The embodiment numbering	Compound	NMR/m/z	Amine	192	[4-(2, the 6-3,5-dimethylphenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	9.68(s，1H)，8.44(d，1H)，7.78 (d，2H)，7.44(s，1H)，7.41(d， 2H)，7.10(d，1H)，6.96(m，3H)， 5.70(m，1H)，3.62(m，4H)，3.04 (m，4H)，2.50(s，3H)，2.30(s， 6H)，1.47(d，6H)；m/z 510	1-(2, the 6-3,5-dimethylphenyl) piperazine
193	[4-(2-chloro-phenyl-) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z 516	1-(2-chloro-phenyl-) piperazine	192			1-(2, the 6-3,5-dimethylphenyl) piperazine
193		m/z 516	1-(2-chloro-phenyl-) piperazine	194	[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-(2-pyridine-2-base tetramethyleneimine-1-yl) ketone	m/z 468	2-tetramethyleneimine-2-yl pyridines
195	[4-(2-aminomethyl phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z 496	1-(o-tolyl) piperazine	194		m/z 468	2-tetramethyleneimine-2-yl pyridines
195		m/z 496	1-(o-tolyl) piperazine	196	[4-(3-aminomethyl phenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	m/z496	1-(3-aminomethyl phenyl) piperazine
197	[4-(5-chloropyridine-2-yl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 517	1-(5-chloropyridine-2-yl) piperazine	196		m/z496	1-(3-aminomethyl phenyl) piperazine
197		m/z 517	1-(5-chloropyridine-2-yl) piperazine	198	[4-(2, the 3-3,5-dimethylphenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 510	1-(2, the 3-3,5-dimethylphenyl) piperazine

The embodiment numbering	Compound	NMR/m/z	Amine
The embodiment numbering	Compound	NMR/m/z	Amine	199	[4-(3, the 4-difluorophenyl) piperazine-1-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-yl] amino] phenyl] ketone	m/z 518	1-(3, the 4-difluorophenyl) piperazine

Embodiment 200

[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3R)-3- Mesyloxy tetramethyleneimine-1-yl] ketone

(embodiment 173 for tetramethyleneimine-3-alcohol with (3R)-1-(4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } benzoyl); 3.8g) and TEA (1.92ml) be added among the DCM, make reaction mixture be cooled to 0 ℃ (ice bath) after, slowly add methylsulfonyl chloride (0.781ml).The reaction mixture stirring after 1 hour, is added entry (50ml), use DCM (3 * 100ml) extractions then.The organism that merges after drying, solvent removed in vacuo.The gained solid is dissolved in the minimum hot acetonitrile, and after drying is filtered in cooling, obtains title compound (3.6g, white solid).NMR 9.26 (s, 1H), 8.42 (d, 1H), 7.76 (d, 2H), 7.49 (d, 2H), 7.39 (s, 1H), 7.05 (d, 1H), 5.60 (septet, 1H), 5.31-5.27 (m, 1H), 3.87 (dd, 1H), 3.72 (d, 1H), 3.67-3.60 (m, 2H), 3.16 (s, 3H), 2.87 (s, 3H), 2.29-2.17 (m, 2H), 1.48 (d, 6H); M/z 48.

Embodiment 201

[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3S)-3- (morpholine-4-yl) tetramethyleneimine-1-yl] ketone

With [4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(3R)-and 3-mesyloxy tetramethyleneimine-1-yl] (embodiment 200 for ketone; 0.1g) and morpholine (0.09g) De diox (10ml) solution in 100 ℃ the heating 48 hours.With the reaction mixture vacuum concentration, resistates is added on the SCX-2 post (MeOH), with the MeOH washing, use 7NNH then ₃The MeOH eluant solution.Crude product obtains title compound (0.04g, colorless solid) by silica gel column chromatography purifying (with the DCM eluant solution of 0-10%MeOH).NMR (500.133MHz) .9.22 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.46 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.60 (septet, 1H), 3.69-3.64 (m, 2H), 3.62-3.57 (m, 5H), 3.51-3.45 (m, 1H), 3.35 (dd, 1H), 2.47-2.45 (m, 1H), 2.40-2.34 (m, 2H), 2.09-2.02 (m, 1H), 1.83-1.75 (m, 1H), 1.47 (d, 6H); M/z 476.

Embodiment 202-204

Following compounds prepares with proper raw material by the method for embodiment 201.

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	202	(3S)-and 3-[N-(cyclobutyl)-N-(methyl) amino] tetramethyleneimine-1-yl }-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.22 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.45 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.61-3.54 (m, 2H), 3.47-3.41 (m, 1H), 3.32 (dd, 1H), 3.11-2.98 (m, 2H), 2.49 (s, 3H), 2.09 (s, 3H), 1.99-1.75 (m, 6H), 1.62-1.51 (m, 2H), 1.47 (d, 6H)	474	Embodiment 200 and N-methyl ring butylamine
203	(3S)-and 3-[N-(cyclopropyl methyl)-N-(methyl) amino] tetramethyleneimine-1-yl }-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.22 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.46 (d, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.66-3.57 (m, 2H), 3.49-3.44 (m, 1H), 3.32 (dd, 1H), 3.09 (quintet, 1H), 2.31-2.26 (m, 5H), 2.06-2.00 (m, 1H), 1.82-1.74 (m, 1H), 1.47 (d, 6H), 0.87-0.80 (m, 1H), 0.48-0.44 (m, 2H), 0.10-0.07 (m, 2H)	474	Embodiment 200 and N-(cyclopropyl methyl) methylamine	202			474	Embodiment 200 and N-methyl ring butylamine

The embodiment numbering	Compound	NMR	m/z	SM
The embodiment numbering	Compound	NMR	m/z	SM	204	(3S)-and 3-[N-(cyclopropyl)-N-(methyl) amino] tetramethyleneimine-1-yl }-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone	9.21 (s, 1H), 8.40 (d, 1H), 7.73 (d, 2H), 7.46 (d, 2H), 7.36 (s, 1H), 7.04 (d, 1H), 5.61 (septet, 1H), 3.68-3.64 (m, 1H), 3.60-3.55 (m, 1H), 3.50-3.39 (m, 2H), 3.15 (quintet, 1H), 2.28 (s, 3H), 2.10-2.03 (m, 1H), 1.93-1.85 (m, 1H), 1.73-1.69 (m, 1H), 1.47 (d, 6H), 0.48-0.39 (m, 2H), 0.36-0.28 (m, 2H)	460	Embodiment 200 and N-methyl cyclopropylamine

Embodiment 205

[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]-[(1S, 4S)- 3-third-2-base-3,6-diazabicylo [2.2.1] heptan-6-yl] ketone

Will [(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] (embodiment 109 for ketone; 100mg),

Molecular sieve (1g) and acetone (28mg) are added in the methyl alcohol (10ml), stir 10 minutes.Add sodium triacetoxy borohydride (66mg), reactant was stirred 66 hours at ambient temperature.Add sodium triacetoxy borohydride (33mg) and acetone (28mg) again, reaction mixture, is added sodium triacetoxy borohydride (33mg) and acetone (28mg) again and heated 5 hours after 16 hours in 50 ℃ of heating.Make the reaction mixture cooling, filtration is also passed through the SCX-2 post, uses MeOH, 3.5N NH successively ₃MeOH solution, 7N NH ₃The MeOH eluant solution of MeOH solution, 1%TEA after, use the MeOH eluant solution of 2%TEA at last.Use the RPHPLC purifying again, obtain title compound (62mg, colourless foam shape thing); NMR (500.133MHz) 9.22 (s, 1H), 8.40 (d, 1H), 7.75-7.72 (m, 2H), 7.46-7.43 (m, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.60 (septet, 1H), 4.45-4.36 (m, 1H), 3.68 (s, 1H), 3.47-3.36 (m, 2H), 2.99-2.96 (m, 1H), 2.64-2.59 (m, 2H), 2.50-2.48 (m, 3H blur because of being covered by the DMSO peak), 1.75-1.69 (m, 2H), and 1.48-1.46 (m, 6H), 1.02-0.99 (m, 6H); M/z 460.

Embodiment 206

[(1S, 4S)-3-methyl-3,6-diazabicylo [2.2.1] heptan-6-yl]-[4-[[4-(2-methyl-3-third-2- Base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone

Will [(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] (embodiment 109 for ketone; 100mg) be dissolved in MeOH (5ml), add formalin (37% (weight) then; 0.22ml), gained solution was stirred 10 minutes at ambient temperature.Disposable adding sodium cyanoborohydride (23mg) stirred the mixture 2 hours.Add 2M NaOH solution (3ml) afterwards, stirred reaction mixture is after 30 minutes, with DCM (3 * 20ml) extractions.Organism drying (the MgSO that merges ₄), filter final vacuum except that desolvating.Use the RPHPLC purifying, grind with ether then, obtain title compound, be colorless solid; NMR (500.133MHz, DMSO) 9.22 (s, 1H), 8.40 (d, 1H), 7.75-7.72 (m, 2H), 7.45-7.42 (m, 2H), 7.36 (s, 1H), 7.04 (d, 1H), 5.60 (septet, 1H), 4.44-4.35 (m, 1H), 3.49-3.46 (m, 1H), 3.39-3.35 (m, 2H), 2.79 (d, 1H), 2.67-2.64 (m, 1H), 2.50-2.48 (m, 3H blur because of being covered by the DMSO peak), 2.33 (s, 3H), 1.80 (d, 1H), 1.68 (d, 1H), 1.48-1.46 (m, 6H); M/z 432.

Embodiment 207

[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl]- [(1S, 4S)-3-methyl-3,6-diazabicylo [2.2.1] heptan-6-yl] ketone

With [(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-[4-[[5-fluoro-4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone (embodiment 131), with the method alternative embodiment 109 preparation title compounds of embodiment 206.NMR (500.133MHz, DMSO) 9.33 (s, 1H), 8.49 (d, 1H), 7.69 (d, 2H), 7.44 (d, 2H), 7.36 (d, 1H), 5.40 (septets, 1H), and 4.42-4.36 (m, 1H), 3.49-3.45 (m, 1H), 3.39-3.35 (m, 2H), 2.79 (dd, 1H), 2.65 (d, 1H), 2.52 (s, 3H), 2.34 (s, 3H), 1.80 (d, 1H), 1.68 (d, 1H), 1.46 (d, 6H); M/z 450.

Embodiment 208

[(1S, 4S)-3-(2-methoxy ethyl)-3,6-diazabicylo [2.2.1] heptan-6-yl]-[4-[[4-(2-first Base-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] ketone

Will [(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-[4-[[4-(2-methyl-3-third-2-base-3H-imidazol-4 yl) pyrimidine-2-base] amino] phenyl] (embodiment 109 for ketone; 100mg), 2-bromo-ethyl-methyl ether (0.034ml) and TEA (0.067ml) be added among the DMA (5ml), 70 ℃ of heating 18 hours down.Make the reaction mixture cooling then, vacuum concentration by quick SCX post, is used MeOH, 7N NH successively ₃The MeOH eluant solution.With RPHPLC purifying once more, obtain title compound (23mg, light yellow solid); NMR (500.133MHz, DMSO) 9.22 (s, 1H), 8.40 (d, 1H), 7.75-7.72 (m, 2H), 7.46-7.43 (m, 2H), 7.37 (s, 1H), 7.04 (d, 1H), 5.60 (septet, 1H), 4.44-4.36 (m, 1H), 3.59-3.53 (m, 2H), 3.48-3.36 (m, 4H), 3.26 (s, 3H), and 2.75-2.63 (m, 3H), 2.50-2.48 (m, 3H, blur because of being covered by the DMSO peak), 1.79-1.67 (m, 2H), 1.47 (d, 6H); M/z 476.

The preparation of raw material

Method 1

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

At ambient temperature, in～5 minutes to (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, 25mmol) and in the stirred solution of MeOH (100ml) add (1-chloromethyl-4-fluoro-1, and 4-diazotization two ring [2.2.2] octanes two (a tetrafluoro borate) (14.16g, 40mmol). in batchesMake temperature remain on 25-30 ℃ through cooling off slightly.Stir after 90 minutes, reaction mixture is cooled off in ice/acetone, filter.With filtrate evaporated under reduced pressure, resistates is dissolved in DCM.With ammoniacal liquor, salt water washing, dry (Na ₂SO ₄) the back reduction vaporization.Title compound separates (using 10%EtOH/EtOAc, 3.5%EtOH/DCM successively) with two independent posts through silica gel MPLC, for golden stickiness oily matter, leaves standstill post crystallization several weeks.Yield=2.50g (42%).NMR:1.40 (d, 6H), 2.38 (s, 3H), 3.05 (s, 6H), 4.70 (septuple Yi, 1H), 6.96 (d, 1H), 7.08 (s, 1H); Fluorine NMR (376MHz) :-166.7 (d); M/z 240.

Method 2

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 1; 4.0g, 16.7mmol) and Guanidinium carbonate (6.6g is 37mmol) with the pre-mixing of butanols (80ml), reflux 30 hours.Make reactant cooling back water (200ml) quencher, (2 * 200ml) extractions, dry final vacuum removes and desolvates reactant, obtains yellow solid with DCM then.This solid is dissolved among the minimum hot DCM, makes it to cool off the back then and add ether.Pale solid is separated out, and filters after drying.Repeat this method, 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/z 236.

Method 3

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

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), prepare title compound with identical amount, NMR (400.132MHz, CDCl by the method for method 2 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 4

(4-bromo-2-methyl-phenyl)-(4-methyl-piperazine-1-yl)-ketone

With bromo methyl acid (10g, 46.5mmol) and HBTU (23g 60.5mmol) is dissolved in DMF (150ml), add then N methyl piperazine (6.0g, 60.5mmol) and DIPEA (21ml, 121mmol).After reaction stirred was spent the night, vacuum was removed DMF, jelly 2.0N NaOH (100ml) quencher, and (3 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains the stickiness jelly with ether.With silica gel purification (the DCM solution with 0-10%MeOH is elutriant), obtain title compound, be stickiness oily matter.Oily matter is dissolved in minimum ether, adds isohexane, obtain colorless solid, filter after drying (11.8g, 86%).NMR(CDCl ₃)：7.40(s，1H)，7.36(d，1H)，7.04(d，1H)，3.86-3.79(m，2H)，3.27-3.21(m，2H)，2.51-2.45(m，2H)，2.32-2.29(m，8H)；m/z298。

Method 5-9

With method 4 described steps, prepare following compounds in a similar manner.

Method	Compound	NMR	m/z	Raw material
Method	Compound	NMR	m/z	Raw material	5	(4-bromo-2-fluoro-phenyl)-(4-methyl-piperazine-1-yl)-ketone	(CDCl ₃)7.35(d，1H)，7.33-7.22 (m，2H)，3.86-3.79(m，2H)， 3.27-3.21(m，2H)，2.51-2.45 (m，2H)，2.32-2.29(m，8H)	301	4-bromo-2-fluorobenzoic acid, N methyl piperazine
6	(4-bromo-2-fluoro-phenyl)-morpholine-4-base-ketone	(CDCl ₃)7.40(d，1H)，7.33-7.31 (m，1H)，7.30-7.26(m，1H)， 3.87-3.74(m，4H)，3.67-3.58 (m，2H)，3.40-3.29(m，2H)	289	4-bromo-2-fluorobenzoic acid, morpholine	5	(4-bromo-2-fluoro-phenyl)-(4-methyl-piperazine-1-yl)-ketone		301	4-bromo-2-fluorobenzoic acid, N methyl piperazine
6	(4-bromo-2-fluoro-phenyl)-morpholine-4-base-ketone		289	4-bromo-2-fluorobenzoic acid, morpholine	7	(4-bromo-2-chloro-phenyl)-(4-methyl-piperazine-1-yl)-ketone	(400.132MHz，CDCl ₃)7.59(s， 1H)，7.46(d，1H)，7.17(d，1H)， 3.89-3.75(m，2H)，3.32-3.18 (m，2H)，2.54-2.46(m，2H)， 2.44-2.28(m，5H)	319	4-bromo-2-chloro-benzoic acid, N methyl piperazine
8	(4-bromo-2-chloro-phenyl)-morpholine-4-base-ketone	(400.132MHz，CDCl ₃)7.60(s， 1H)，7.48(d，1H)，7.18(d，1H)， 3.91-3.83(m，1H)，3.79-3.74 (m，3H)，3.72-3.66(m，1H)， 3.62-3.57(m，1H)，3.31-3.26 (m，1H)，3.23-3.18(m，1H)	306	4-bromo-2-chloro-benzoic acid, morpholine	7	(4-bromo-2-chloro-phenyl)-(4-methyl-piperazine-1-yl)-ketone		319	4-bromo-2-chloro-benzoic acid, N methyl piperazine
8	(4-bromo-2-chloro-phenyl)-morpholine-4-base-ketone		306	4-bromo-2-chloro-benzoic acid, morpholine	9	(4-bromo-2-methyl-phenyl)-morpholine-4-base-ketone	(CDCl ₃)7.40(s，1H)，7.36(d， 1H)，7.04(d，1H)，3.83-3.73(m， 4H)，3.61-3.56(m，2H)，3.26- 3.20(m，2H)，2.30(s，3H)	285	4-bromo-2-tolyl acid, morpholine

Method 10

1-(4-iodobenzene formyl radical)-N, N-dimethyl pyrrolidine-3-amine

Under inert atmosphere, with N, N-dimethyl pyrrolidine-3-amine (5.0g, 43.8mmol) and TEA (7.3ml 52.5mmol) stirs with THF (200ml).In 5 minutes, add in batches 4-iodobenzene formyl chloride (11.7g, 43.8mmol).Stirred lasting other 16 hours, vacuum evaporating solvent distributes resistates between EtOAc (200ml) and 1M NaOH (100ml) then.Organism water (100ml) and salt solution (100ml) washing, dry and evaporation obtains title compound (12.3g, 74%, colorless solid).NMR(400.13MHz)：7.83(d，2H)，7.32(ap.t，2H)，3.75-3.58(m，1H)，3.52-3.38(m，2H)，3.31-3.16(m，1H)，2.78-2.59(m，1H)，2.18(s，3H)，2.11(s，3H)，2.10-1.98(m，1H)，1.81-1.63(m，1H)；m/z 345。

Method 11

1-(4-chloro-2-anisoyl)-4-methylpiperazine

With thionyl chloride (5ml) be added to 4-chloro-O-Anisic Acid (0.501g, 2.68mmol) in.After adding a dry DMF, reaction mixture was stirred 30 minutes under refluxing.Solvent removed in vacuo is with resistates and toluene coevaporation.Resistates is dissolved in anhydrous DCM (5ml) again, drip successively N methyl piperazine (0.277mg, 2.77mmol), (0.28g 2.77mmol), stirred the gained mixture 15 minutes TEA at ambient temperature.With reaction mixture dilution (DCM), use saturated NaHCO ₃(aqueous solution), water washing, dry (Na ₂SO ₄), filter final vacuum and concentrate, obtain the title compound of quantitative yield.This product need not to be further purified, and just can be used for next step.NMR：7.18(d，J＝8.0Hz，1H)，7.17(d，J＝2.0Hz，1H)，7.05(dd，J＝8.0，1.8Hz，1H)，3.81(s，3H)，3.67-3.51(m，2H)，3.14-3.04(m，2H)，2.38-2.27(m，2H)，2.27-2.19(m，2H)，2.18(s，3H)。

Method 12

1-(4-chloro-2-iodobenzene formyl radical)-4-methylpiperazine

(0.523g 1.85mmol) is dissolved in thionyl chloride (2.5ml) and the dry DMF with 4-chloro-2-iodo-benzoic acid.Reaction mixture stirring under refluxing was evaporated excessive thionyl chloride after 1 hour.Resistates is dissolved in anhydrous DCM (5ml), add in batches N methyl piperazine (0.194g, 1.94mmol) after, add TEA (0.196g, 1.94mmol).Mixture stirred at ambient temperature spend the night.With mixture diluted (DCM), use saturated NaHCO then ₃(aqueous solution) washing, dry (Na ₂SO ₄), filter the final vacuum evaporation.Product flash chromatography on silica gel method purifying (CHCl ₃/ MeOH gradient; 0-5%MeOH), obtain title compound (0.415g, 61%, solid).NMR：7.97(d，J＝2.0Hz，1H)，7.54(dd，J＝8.3，2.0Hz，1H)，7.26(d，J＝8.3Hz，1H)，3.69-3.53(m，2H)，3.08(t，J＝5.0Hz，2H)，2.38(t，J＝5.1Hz，2H)，2.36-2.21(m，2H)，2.19(s，3H)；MS(ESI)m/z 365。

Method 13

5-chloro-2-[(4-methylpiperazine-1-yl) carbonyl] benzonitrile

With 1-(4-chloro-2-iodobenzene formyl radical)-4-methylpiperazine (method 12,400mg, 1.70mmol), zinc acetate (17.2mg, 0.079mmol), zinc cyanide (109mg, 0.928mmol), zinc powder (8.0mg, 0.122mmol), Pd ₂(dba) ₃(44mg, 0.048mmol) and 1,1 '-two (diphenyl phosphine) ferrocene (117mg, 0.211mmol) with anhydrous 1,4-diox (1.5ml) mixing feeds argon gas.Mixture in the sealed tube was heated 45 minutes down at 90-95 ℃.Reaction mixture is used the EtOAc rinsing through behind the diatomite filtration.The saturated NaHCO of organic phase ₃(aqueous solution) washing, dry (Na ₂SO ₄), filter the final vacuum evaporation.Crude product purified by flash chromatography (DCM/MeOH gradient; 0-5%MeOH), obtain title compound (280mg, 62%).NMR：8.16(d，J＝2.0Hz，1H)，7.87(dd，J＝8.3，2.0Hz，1H)，7.59(d，J＝8.3Hz，1H)，3.71-3.59(m，2H)，3.24-3.14(m，2H)，2.43-2.32(m，2H)，2.32-2.22(m，2H)，2.19(s，3H)；MS(ESI)m/z 264。

Method 14

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

(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 is 40mmol) with the pre-mixing of 2-methyl cellosolve (80ml), reflux 30 hours.After making the reactant cooling, water (50ml) quencher.Reactant is used DCM then, and (2 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains yellow solid.This solid is dissolved among the minimum hot DCM, makes it to cool off the back then and add ether.The pale solid of separating out is filtered after drying.Repeat this method, 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 15

(4-chloro-2-iodo-phenyl)-morpholine-4-base-ketone

With 4-chloro-2-iodo-benzoic acid (5.0g, 17.7mmol) and HBTU (8.7g 23mmol) is dissolved in DMF (150ml), successively to wherein add morpholine (2.0g, 23mmol), DIPEA (8.2ml, 46mmol).After reaction stirred was spent the night, vacuum was removed DMF, jelly 2.0N NaOH (100ml) quencher, and (3 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains brown solid with DCM.With silica gel purification (the DCM solution with 0-3.5%MeOH is elutriant), obtain title compound (5.8g, 94%, pale solid).NMR(CDCl ₃)7.84(s，1H)，7.39(d，1H)，7.13(d，1H)，3.91-3.73(m，5H)，3.62-3.51(m，1H)，3.33-3.24(m，1H)，3.21-3.12(m，1H)；m/z 352。

Method 16

5-chloro-2-(morpholine-4-carbonyl)-benzonitrile

With (4-chloro-2-iodo-phenyl)-morpholine-4-base-ketone (method 15; 5.8g, 16.5mmol), cupric cyanide (5.2g, 58mmol), Pd ₂(dba) ₃(0.45g, 0.50mmol), 1,1 '-two (diphenyl phosphine) ferrocene (0.82g, 1.48mmol) and Et ₄(2.6g 15.5mmol) is added in the diox (75ml) NCN, and reflux is 3 hours under inert atmosphere.Make reactant pass through diatomite filtration, solvent removed in vacuo obtains the stickiness brown solid.With silica gel purification (the DCM solution with 0-2.5%MeOH is elutriant), obtain title compound, be brown solid.Solid is added among the MeOH (50ml), carries out supersound process after the heating, gained solid filtering after drying (3.1g, 76%).NMR(CDCl ₃)7.71(s，1H)，7.65(d，1H)，7.42(d，1H)，3.92-3.64(m，6H)，3.39-3.25(m，2H)；m/z 251。

Method 17

(4-benzyloxy-2-methoxyl group-phenyl)-(4-methyl-piperazine-1-yl)-ketone

With 4-benzyloxy-2-methoxyl group-phenylformic acid (7.0g, 27mmol) and HBTU (13.3g 35mmol) is added among the DMF (100ml), add then N methyl piperazine (3.5g, 35mmol) and DIPEA (12.5ml, 70mmol).The reactant stirring after 1 hour, is added 2.0NaOH (100ml), and (3 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains yellow oil (8.5g, 92%) with ether.NMR(CDCl ₃)7.44-7.33(m，5H)，7.17(d，1H)，6.58(d，1H)，6.54(s，1H)，5.07(s，2H)，3.87-3.72(m，5H)，3.32-3.24(m，2H)，2.53-2.40(m，2H)，2.37-2.23(m，5H)。

Method 18

(4-hydroxyl-2-methoxyl group-phenyl)-(4-methyl-piperazine-1-yl)-ketone

With (4-benzyloxy-2-methoxyl group-phenyl)-(4-methyl-piperazine-1-yl)-ketone (method 17; 7.0g, 20.5mmol), (6.6g 103mmol) is added among the MeOH, reflux 1 hour for 10% palladium on carbon (0.3g) and ammonium formiate.Solvent removed in vacuo obtains white solid.Add DCM (100ml), it is used supersound process 20 minutes, reactant is filtered, the dry final vacuum of filtrate removes and desolvates, and obtains white solid (5.0g), need not to be further purified just and can use; M/z 251.

Method 19

Three fluoro-methylsulfonic acid 3-methoxyl group-4-(4-methyl-piperazine-1-carbonyl)-phenylesters

With (4-hydroxyl-2-methoxyl group-phenyl)-(4-methyl-piperazine-1-yl)-ketone (method 18; 5.0g, 20mmol) and TEA be added among the DCM (100ml) postcooling to 0 ℃, (4.4ml 26mmol), stirs reactant 1 hour slowly to add trifluoromethanesulfanhydride anhydride then.Add trifluoromethanesulfanhydride anhydride (0.3 equivalent) again, continue to stir 1 hour.Add entry (100ml), vacuum is removed DCM, and (2 * 100ml) extractions, dry final vacuum removes and desolvates remaining aqueous solution, obtains the dark oil thing with ether.With silica gel purification (the DCM solution with 0-2.5%MeOH is elutriant), obtain title compound (4.2g, 55%, black jelly).NMR(CDCl ₃)：7.34(d，1H)，6.94(d，1H)，6.82(s，1H)，3.97-3.89(m，2H)，3.87(s，3H)，3.44-3.31(m，2H)，2.77-2.69(m，2H)，2.62-2.54(m，2H)，2.51(s，3H)；m/z 383。

Method 20

(4-benzyloxy-2-methoxyl group-phenyl)-morpholine-4-base-ketone

With 4-benzyloxy-2-methoxyl group-phenylformic acid (7.0g, 27mmol) and HBTU (13.3g 35mmol) is added to DMF (100ml), to wherein add morpholine (3.0g, 35mmol) and DIPEA (12.5ml, 70mmol).After 1 hour, with 2.0NaOH (100ml) quencher, (3 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains yellow oil with ether with the reactant stirring.(8.4g，94％)。NMR(CDCl ₃)7.44-7.32(m，5H)，7.19(d，1H)，6.59(d，1H)，6.53(s，1H)，5.07(s，2H)，3.80-3.69(m，7H)，3.64-3.53(m，2H)，3.32-3.20(m，2H)；m/z 328。

Method 21

(4-hydroxyl-2-methoxyl group-phenyl)-morpholine-4-base-ketone

With (4-benzyloxy-2-methoxyl group-phenyl)-morpholine-4-base-ketone (method 20; 8.8g, 27mmol), ammonium formiate (4.3g, 67.2mmol) and 10% palladium on carbon (0.3g) be added among the MeOH (150ml) reflux 2 hours.Reactant is filtered final vacuum except that desolvating, obtain white solid.This solid obtains title compound (5.1g, 80%, white solid) with silica gel purification (the DCM solution of 0%-5%MeOH is elutriant).NMR(400.132MHz)9.73(s，1H)，6.99(d，1H)，6.43(s，1H)，6.39(d，1H)，3.74(s，3H)，3.64-3.54(m，4H)，3.54-3.45(m，2H)，3.20-3.09(m，2H)；m/z 238。

Method 22

Three fluoro-methylsulfonic acid 3-methoxyl group-4-(morpholine-4-carbonyl)-phenylesters

With (4-hydroxyl-2-methoxyl group-phenyl)-morpholine-4-base-ketone (method 21; 1.0g, 4.22mmol) and 2-[N, two (trifyl) amino of N-]-(1.80g 4.6mmol) is added among the THF (30ml), in 55 ℃ of heated overnight the 5-chloropyridine.Reactant water (50ml) quencher, (3 * 50ml) extractions, dry final vacuum removes and desolvates, and obtains yellow oil with ether.With silica gel purification (the DCM solution of 0%-1%MeOH is elutriant), obtain title compound (1.4g, 90%, yellow jelly).NMR(CDCl ₃)7.34(d，1H)，6.82(d，1H)，3.88(s，3H)，3.83-3.72(m，4H)，3.66-3.57(m，2H)，3.29-3.18(m，2H)；m/z 370。

Method 23

N-ethyl-N-(5-methyl-isoxazole-4-bases)-isobutyramide

With ethyl-(5-methyl-isoxazole-4-bases)-amine hydrochlorate (15g 0.092mol) is added among the DCM (200ml), add TEA (32ml, 0.23mol) after, slowly add isobutyryl chloride (10.7g, 0.10mol).After reactant stirred 30 minutes, solvent removed in vacuo.Resistates water (150ml) is handled, and (3 * 150ml) extractions, dry final vacuum removes and desolvates, and obtains yellow oil (12.9g, 72%) with ether.NMR(300.072MHz，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 24

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

With N-ethyl-N-(5-methyl-isoxazole-4-bases)-isobutyramide (method 23; 15.6g, 0.08mol) and 10%Pd/C (3.9g) be added among the EtOH, under 4 normal atmosphere, stir and spend the night.Reactant is filtered, and solvent removed in vacuo obtains pale solid.Add ether (150ml), reactant, is filtered and drying after 10 minutes with supersound process.Obtain 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 25

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

With N-{1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-N-ethyl-isobutyramide (method 24; 11g, 0.056mol) and NaOH (2.7g 0.067mol) is added among the EtOH (150ml) reflux 4 hours.In reactant, add solid NH ₄(4.4g's Cl 0.084mol), spends the night its stirring.With gained soup compound vacuum concentration, add ether (200ml), stir 10 minutes after-filtration.With the filtrate vacuum concentration, obtain orange.Distill with the vacuum distillation apparatus (bulb-to-bulb distillation) (0.76mmbar/120 ℃) of ball, obtain transparent oily matter (8.2g, 81%) ball.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 26

(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)-ethyl ketone (method 25; 7.0g, 0.039mol) and DMFDMA (13.3ml 0.078mol) is added among the DMF, 130 ℃ of down heating 6 hours.Solvent removed in vacuo obtains the black jelly.(50ml) is added in the jelly with ether, obtains golden solid, and it is filtered after drying, obtains 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/z 236。

Method 27

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 26; 6.5g, 0.028mol) and Guanidinium carbonate (12.5g 0.069mol) is added in the butanols (100ml) reflux 5 days.Solvent removed in vacuo obtains yellow jelly.With silica gel column chromatography purifying (with the DCM solution of 0-5%MeOH), obtain title compound, be yellow solid.After adding DCM (5ml) and ether (50ml),, obtain title compound (5.0g, 77%, white solid) with the suspension filtered after drying.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 28

Ethylene-acetic acid ethyl-(5-methyl-isoxazole-4-bases)-acid amides

With ethyl-(5-methyl-isoxazole-4-bases)-amine hydrochlorate (15g 0.092mol) is added among the DCM (200ml), to wherein add TEA (32ml, 0.23mol) after, slowly add the cyclopropyl formyl chloride (10.2g, 0.10mol).After reactant stirred 30 minutes, solvent removed in vacuo.Resistates water (150ml) is then handled, and (3 * 150ml) extractions, dry final vacuum removes and desolvates, and obtains yellow oil (12.2g, 69%) with ether.Need not to be further purified and just can be used for method 29.

Method 29

N-{1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-N-ethyl-cyclopropyl base acid amides

With ethylene-acetic acid ethyl-(5-methyl-isoxazole-4-bases)-acid amides (method 28; 12.2g, 0.08mol) and 10%Pd/C (3.0g) be added among the EtOH (300ml), under 4 normal atmosphere, stir and spend the night, reactant is filtered, solvent removed in vacuo obtains pale solid.Add ether (150ml), it after 10 minutes, is filtered after drying with supersound process, obtain white solid.(9.2g，59％)；m/z 197。

Method 30

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

With N-{1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-N-ethyl-cyclopropyl base acid amides (method 29; 9.2g, 0.047mol) and NaOH (2.3g 0.056mol) is added among the EtOH (150ml) reflux 4 hours.In reactant, add solid NH ₄(4.4g's Cl 0.084mol), spends the night the reactant stirring.With gained soup compound vacuum concentration, add ether (200ml), stir 10 minutes after-filtration.Vacuum is removed filtrate, obtains orange.Distill with the vacuum distillation apparatus (0.50mbar/110 ℃) of ball, obtain transparent oily matter (5.0g, 60%) ball.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 31

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

With 1-(3-ethyl-2-cyclopropyl-3H-imidazol-4 yl)-ethyl ketone (method 30; 3.5g, 0.020mol) and DMFDMA (6.7ml 0.039mol) is added among the DMF (50ml), 130 ℃ of down heating 6 hours.Solvent removed in vacuo obtains yellow solid.Add DCM (3.0ml), ether (50ml) successively, with reactant 10 minutes after-filtration of supersound process.Obtain yellow 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/z 234。

Method 32

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 31; 3.4g, 0.015mol) and Guanidinium carbonate (6.6g 0.036mol) is added in the butanols (60ml) reflux 4 days.Solvent removed in vacuo adds entry (50ml), and (3 * 75ml) extractions, dry final vacuum removes and desolvates resistates, obtains pale solid with DCM.Add DCM, ether successively,, obtain white solid (2.75g, 83%) gained solid filtering after drying.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/z 230。

Method 33

N-ethyl-2,2,2-three fluoro-N-(5-methyl-isoxazole-4-base)-ethanamide

(15g 0.092mol) is dissolved in pyridine (100ml) with ethyl-(5-methyl-isoxazole-4-bases)-amine hydrochlorate.To wherein add trifluoroacetic anhydride (16.9ml, 0.12mol), after reaction stirred is spent the night, solvent removed in vacuo.The saturated NH of gained resistates ₄Cl (200ml) quencher, (3 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains yellow oil (18g, 88%) 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 34

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

Under nitrogen atmosphere, make N-ethyl-2,2,2-three fluoro-N-(5-methyl-isoxazole-4-base)-ethanamide (method 33; 18.0g, 0.081mol) under 4 normal atmosphere, reacted 3 days with 10%Pd/C (4.0g).Reactant is filtered, and solvent removed in vacuo obtains pale solid, adds DCM (30ml) and ether (100ml).Reactant was stirred 10 minutes, filter after drying, obtain white solid (11.6g, 64%); M/z 225.

Method 35

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

With N-{1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-N-ethyl-2,2,2-three fluoro-ethanamide (methods 34; 11.6g, 0.051mol) and salt of wormwood (14.4g 0.103mol) is added in the diox (180ml) reflux 2 hours.Make the reactant cooling, filter, solvent removed in vacuo obtains yellow oil.With silica gel column chromatography purifying (with the isohexane solution of 0-40% ether), obtain title compound (8.9g, 85%, transparent oily matter).NMR(400.132MHz，CDCl ₃)7.79(s，1H)，4.50(q，2H)，2.54(s，3H)，1.40(t，3H)；m/z207。

Method 36

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

With 1-(3-ethyl-2-trifluoromethyl-3H-imidazol-4 yl)-ethyl ketone (method 35; 7.0g, 0.034mol) and DMFDMA (11.6ml 0.068mol) is added among the DMF (90ml), 130 ℃ of down heating 1 hour.Solvent removed in vacuo obtains yellow solid.With silica gel column chromatography purifying (with the DCM solution of 0-5%MeOH), obtain title product, be yellow solid.Add ether, isohexane successively,, obtain title compound (7.6g, 85%) gained solid filtering after drying.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 37

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 36; 6.0g, 0.023mol) and Guanidinium carbonate (8.3g 0.046mol) is added in the 2-methoxy ethoxy ether (80ml), 140 ℃ of down heating 2 days.Make the reactant cooling, solvent removed in vacuo obtains yellow solid.Add entry (100ml), (3 * 100ml) extractions, dry final vacuum removes and desolvates reactive system, obtains yellow solid with DCM.With silica gel column chromatography purifying (with the DCM solution of 0-5%MeOH), obtain title compound, be yellow solid.Add ether (20ml), isohexane (50ml) successively.Obtain pale solid, it is filtered after drying (5.9g, 100%); M/z 258.

Method 38

N-ethyl-2,2-two fluoro-N-(5-methyl-isoxazole-4-base)-ethanamide

With ethyl-(5-methyl-isoxazole-4-base)-amine hydrochlorate (15g, 0.092mol) and TEA be added among the DCM (300ml), make it to be cooled to 0 ℃ after, slowly add two fluoracyl chlorides (11.5g, 0.10mol).After reactant stirred 1 hour, solvent removed in vacuo.The saturated NH of gained resistates ₄Cl (200ml) quencher, (3 * 200ml) extract, and dry final vacuum removes and desolvates, and obtains yellow oil (9.0g, 48%) with ether; M/z 203 (M-H) ^-

Method 39

N-{1-[1-amino-first-(Z)-subunit]-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-isoxazole-4-base)-ethanamide (method 38 with 10% palladium on carbon (3.0g); 9.0g, 0.044mol).Reactant is filtered, and solvent removed in vacuo adds DCM, and reactant is filtered, and obtains pale solid (3.0g, 33%); M/z 207.

Method 40

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

With N-{1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-N-ethyl-2,2-two fluoro-ethanamide (methods 39; 3.0g, 0.014mol) and salt of wormwood (3.9g 0.028mol) is added in the diox (50ml), and reflux is spent the night.Reactant is filtered final vacuum except that desolvating, obtain yellow oil.With silica gel column chromatography purifying (is elutriant with ether), obtain title compound, be yellow solid (2.4g, 92%).NMR(400.132 MHz，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 41

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

With 1-(2-difluoromethyl-3-ethyl-3H-imidazol-4 yl)-ethyl ketone (method 40; 2.4g, 0.013mol) and DMFDMA (4.4ml 0.026mol) is added among the DMF (50ml), 130 ℃ of down heating 20 minutes.Solvent removed in vacuo obtains yellow solid.Add DCM (3.0ml), ether (50ml) successively, with 10 minutes after-filtration of supersound process.Obtain yellow 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 42

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 41; 2.7g, 0.011mol) and Guanidinium carbonate (4.0g 0.022mol) is added in the ethylene glycol ethyl ether (30ml), 137 ℃ of down heating 2 days.Solvent removed in vacuo obtains yellow solid.Add DCM (5.0ml), ether (50ml) successively, with gained solid filtering after drying.Obtain white solid (2.5g, 96%).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/z240。

Method 43

Ethylene-acetic acid 1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-sec.-propyl-acid amides

Under 4 normal atmosphere, with ethylene-acetic acid sec.-propyl-(5-methyl-isoxazole-4-bases)-acid amides (method 36 of WO 03/076434; 18g, 0.086mol) and the EtOH solution and the H-H reaction of 10% palladium on carbon (3.0g).Reactant is filtered, and solvent removed in vacuo obtains solid, behind the adding ether, with solid filtering (7.9g, 44%); M/z 211.

Method 44

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

With ethylene-acetic acid { 1-[1-amino-first-(Z)-subunit]-2-oxo-propyl group }-sec.-propyl-acid amides (method 43; 7.9g, 0.038mol) and sodium hydroxide (2.28g 0.057mol) is added among the EtOH (150ml), and reflux is spent the night.Solvent removed in vacuo, the saturated NH of gained solid ₄Cl (100ml) handles, and (3 * 100ml) extractions, dry final vacuum removes and desolvates, and obtains the dark oil thing with ether.With silica gel column chromatography purifying (using 100% ether), obtain title compound (3.9g, 53%, yellow oil).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 45

(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)-ethyl ketone (method 44; 3.74g, 0.019mol) and DMFDMA (6.66ml 0.039mol) is added among the DMF, 130 ℃ of down heating 4 hours.Solvent removed in vacuo obtains orange jelly, adds DCM, ether successively, obtains title compound, is yellow solid, and it is filtered after 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 46

4-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-pyrimidine-2-base amine/001

With (E)-1-(2-cyclopropyl-3-sec.-propyl-3H-imidazol-4 yl)-3-dimethylamino-acrylketone (method 45; 4.5g, 0.019mol) and Guanidinium carbonate (6.55g 0.036mol) is added in the ethylene glycol ethyl ether (75ml), 142 ℃ of down heating 2 days.Solvent removed in vacuo, (3 * 150ml) extractions, dry final vacuum removes and desolvates, and obtains yellow solid with DCM to add entry (100ml) back.Add DCM, ether successively, the mixture stirring after 30 minutes, is filtered after drying (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 47

((S)-3-dimethylamino-tetramethyleneimine-1-yl)-(4-iodo-phenyl)-ketone

With 4-iodobenzene formyl chloride (5g, 0.019mol) and TEA (6.6ml 0.048mol) is added among the DCM (100ml), is cooled to 0 ℃.To wherein slowly add (S)-dimethylamino tetramethyleneimine (2.2g, 0.019mol), reactant stirred 1 hour after, solvent removed in vacuo to 90% volume.2.0M NaOH (50ml) quencher of gained soup compound, (3 * 200ml) extractions, dry final vacuum removes and desolvates, and obtains yellow solid with ether.Add ether, reactive system 10 minutes after-filtration of supersound process.Obtain pale solid (3.9g, 60%).NMR(300.072MHz，CDCl ₃)7.75(d，2H)，7.25(d，2H)，3.94-3.78(m，1H)，3.66-3.25(m，3H)，2.81-2.62(m，1H)，2.30(s，3H)，2.21(s，3H)，2.16-2.02(m，1H)，1.97-1.76(m，1H)；m/z 345。

Method 48

((R)-3-dimethylamino-tetramethyleneimine-1-yl)-(4-iodo-phenyl)-ketone

By the mode that is similar to method 47, prepare title compound (5.1g, 78%) by 4-iodobenzene formyl chloride and (R)-dimethylamino tetramethyleneimine.NMR(300.072MHz，CDCl ₃)7.75(d，2H)，7.25(d，2H)，3.94-3.78(m，1H)，3.66-3.25(m，3H)，2.81-2.62(m，1H)，2.30(s，3H)，2.21(s，3H)，2.16-2.02(m，1H)，1.97-1.76(m，1H)；m/z 345。

Method 49

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

To 4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 14; 7.8g add in) De diox (200ml) solution 4-iodo ethyl benzoate (9.445g), acid chloride (II) (461mg), Xantpos (1.785g) and cesium carbonate (22.29g).Make the mixture degassing, feed argon gas again, reflux is 3 hours then.Make mixture be cooled to room temperature, solids removed by filtration is then with the filtrate vacuum concentration.With silica gel purification (the DCM solution with 2-5%MeOH is elutriant), obtain title compound (3.82g, 31%, yellow solid).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/z366。

Method 50

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 49; 3.82g) be dissolved in THF (130ml) after, add NaOH (419mg) water (20ml) solution.With mixture reflux 2 days.With the mixture vacuum concentration, water-soluble then (400ml) is with EtOAc (2 * 300ml) washings.With the water layer vacuum concentration, obtain title compound (3.53g, 94%, white solid).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 51

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

To 5-fluoro-4-(3-sec.-propyl-2-methyl-3H-imidazol-4 yl)-pyrimidine-2-base amine (method 2; 5.32g add in) De diox (100ml) solution 4-iodo ethyl benzoate (3.59g), acid chloride (II) (305mg), Xantphos (1.18g) and cesium carbonate (14.74g).Make the mixture degassing, feed argon gas again, reflux is 3 hours then.Make mixture be cooled to room temperature, solids removed by filtration is then with the filtrate vacuum concentration.With silica gel purification (the DCM solution with 2-5%MeOH is elutriant), obtain title compound (2.75g, 32%, yellow solid).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 52

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

To 4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } ethyl benzoate (method 51; 2.75g) with the stirred solution of EtOH (70ml) in add water (15ml) solution of lithium hydroxide (301mg).With mixture reflux 18 hours, vacuum concentration distributed between water (300ml) and EtOAc (300ml) then.Water layer uses EtOAc (200ml) washing final vacuum to concentrate again, obtains title compound (2.07g, 80%, white solid).NMR9.56(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/z 356。

Method 53

1-(4-iodobenzene formyl radical) tetramethyleneimine-3-alcohol

By the mode that is similar to method 10, prepare title compound by pyrrolin alcohol (pyrrolinol) and 4-iodobenzene formyl chloride.NMR 7.78 (d, 2H), 7.28 (d, 2H), 4.96 (dd, 1H), 4.35-4.18 (br d, 1H), 3.60-3.15 (m, 4H is with water peak overlapping (overlapping water)), 2.00-1.65 (m, 2H); M/z 318.

Method 54

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

By the mode that is similar to method 1, replace (2E)-3-(dimethylamino)-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone with (2E)-3-(dimethylamino)-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 37 of WO 03/076435), the preparation title compound.NMR(300.074MHz，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 55

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

By the mode that is similar to method 2, replace (2Z)-3-(dimethylamino)-2-fluoro-1-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone with (2Z)-3-(dimethylamino)-2-fluoro-1-(1-cyclobutyl-2-methyl isophthalic acid H-imidazoles-5-yl) third-2-alkene-1-ketone (method 54), the preparation title compound.NMR (300.074MHz, 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 56

1-(4-iodobenzene formyl radical)-4-methyl isophthalic acid, the 4-Diazesuberane

By the mode that is similar to method 10, prepare title compound by high piperazine of N-methyl and 4-iodobenzene formyl chloride.NMR(400.132MHz，CDCl ₃)7.79(d，2H)，7.18(d，2H)，3.84-3.79(m，2H)，3.54-3.52(m，1H)，3.48(t，1H)，2.79-2.77(m，1H)，2.70-2.66(m，1H)，2.62-2.55(m，2H)，2.45(s，3H)，2.07-2.00(m，1H)，1.91-1.84(m，1H)；m/z 345。

Method 57

1-sec.-propyl-1, the 4-Diazesuberane

With 1,4-Diazesuberane-1-t-butyl formate (17g) and acetone (10g) are added among the MeOH (150ml), stir 20 minutes down at 0 ℃.In 20 minutes, slowly add NaCNBH ₃(6.4g), simultaneously temperature is remained on below 0 ℃.Make reactant be warmed up to envrionment temperature after adding, stirred weekend.With the reactant vacuum concentration, obtain yellow residue, with its water (100ml) quencher, (3 * 100ml) extractions, dry final vacuum removes and desolvates, and obtains transparent stickiness oily matter (20g) with ether.This oily matter is added among TFA (50ml) and the DCM (50ml), reactant is stirred 16 hours final vacuums concentrate.Reactant water (30ml) quencher, salt of wormwood is saturated fully up to the aqueous solution to wherein adding, and (solvent removed in vacuo obtains title compound (5.2g, yellow oil) carefully for 3 * 200ml) extractions, drying with EtOAc with it then.NMR(400.132MHz，CDCl ₃)2.94-2.86(m，5H)，2.68-2.63(m，4H)，1.74-1.68(m，2H)，1.01(d，6H)。

Method 58

1-benzoyl-4-sec.-propyl-1, the 4-Diazesuberane

By the mode that is similar to method 10, by 1-sec.-propyl-1,4-Diazesuberane (method 57) and 4-iodobenzene formyl chloride prepare title compound.NMR(400.132MHz，CDCl ₃)7.74(d，2H)，7.13(d，2H)，3.75-3.72(m，2H)，3.40(t，2H)，2.96-2.84(m，1H)，2.79-2.77(m，1H)，2.67(t，1H)，2.62-2.56(m，2H)，1.92-1.87(m，1H)，1.71-1.67(m，1H)，1.03-0.97(m，6H)；m/z 373。

Method 59

1-(4-bromo-2-methyl benzoyl)-4-methyl isophthalic acid, 4-two atmosphere heterocycle heptane

By the mode that is similar to method 4, prepare title compound by high piperazine of N-methyl and 4-bromo-2-tolyl acid.NMR (400.132MHz, CDCl ₃) 7.38 (s, 1H), 7.34 (d, 1H), 7.04 (t, 1H), 3.86-3.76 (m, 2H), 3.34 (t, 1H), 3.27 (t, 1H), 2.75-2.73 (m, 1H), 2.69-2.50 (m, 2H), 2.50-2.43 (m, 1H), 2.37 (s, 3H), 2.30 (s, 3H), 1.99 (quintet, 1H), 1.80 (quintet, 1H) (rotational isomers); M/z 313.

Method 60

1-(4-bromo-2-fluoro benzoyl)-4-methyl isophthalic acid, the 4-Diazesuberane

By the mode that is similar to method 4, prepare title compound by high piperazine of N-methyl and 4-bromo-2-fluorobenzoic acid.NMR(400.132MHz，CDCl ₃)7.35(d，1H)，7.30(d，1H)，7.24(t，1H)，3.83-3.77(m，2H)，3.45-3.43(m，1H)，3.38(t，1H)，2.75-2.73(m，1H)，2.65-2.62(m，1H)，2.58-2.56(m，1H)，2.54-2.52(m，1H)，2.38(d，3H)，2.02-1.96(m，1H)，1.88-1.82(m，1H)；m/z 317。

Method 61

(3S)-and 1-(4-bromo-2-fluoro benzoyl)-N, N-dimethyl pyrrolidine-3-amine

By the mode that is similar to method 4, by (3S)-N, N-dimethyl pyrrolidine-3-amine and 4-bromo-2-fluorobenzoic acid prepare title compound.NMR(300.072MHz，CDCl ₃)7.38-7.27(m，3H)，3.98-3.81(m，1H)，3.63-3.17(m，3H)，2.85-2.68(m，1H)，2.30(s，3H)，2.21(s，3H)，2.19-2.04(m，1H)，1.92-1.77(m，1H)；m/z316。

Method 62

(3R)-and 1-(4-bromo-2-fluoro benzoyl)-N, N-dimethyl pyrrolidine-3-amine

By the mode that is similar to method 4, by (3R)-N, N-dimethyl pyrrolidine-3-amine and 4-bromo-2-fluorobenzoic acid prepare title compound.NMR(300.072MHz，CDCl ₃)7.38-7.27(m，3H)，3.97-3.81(m，1H)，3.63-3.17(m，3H)，2.84-2.68(m，1H)，2.30(s，3H)，2.21(s，3H)，2.17-2.02(m，1H)，1.90-1.77(m，1H)；m/z316。

Method 63

4-(4-bromo-2-methyl benzoyl)-1,4-oxaza heptane

By the mode that is similar to method 4, by 1,4-oxaza heptane and 4-bromo-2-tolyl acid prepare title compound.NMR (400.132MHz, CDCl ₃) 7.39 (d, 1H), 7.35 (d, 1H), 7.05 (d, 1H), 3.90-3.80 (m, 4H), 3.76 (t, 1H), 3.64-3.57 (m, 1H), 3.36-3.32 (m, 2H), 2.30 (d, 3H), 2.03 (quintet, 1H), 1.75 (quintet, 1H); M/z 300.

Method 64

4-(4-bromo-2-fluoro benzoyl)-1,4-oxaza heptane

By the mode that is similar to method 4, by 1,4-oxaza heptane and 4-bromo-2-fluorobenzoic acid prepare title compound.NMR (400.132MHz, CDCl ₃) 7.36 (d, 1H), 7.33-7.29 (m, 1H), 7.24 (t, 1H), 3.87-3.80 (m, 4H), 3.76 (t, 1H), 3.66 (t, 1H), 3.46-3.42 (m, 2H), 2.04 (quintet, 1H), 1.82 (quintet, 1H); M/z 304.

Method 65

3-(4-iodobenzene formyl radical)-8-oxa--3-azabicyclic [3.2.1] octane

By the mode that is similar to method 10, prepare title compound by 8-oxa--3-azabicyclic [3.2.1] octane and 4-iodobenzene formyl chloride.NMR (400.132MHz, CDCl ₃) 7.76 (d, 2H), 7.12 (d, 2H), 4.50-4.16 (m, 3H), 3.50-3.24 (m, 2H), 3.19-3.06 (m, 1H), 2.06-1.82 (m, 3H), 1.77-1.48 (m, 1H) (rotational isomer); M/z 344.

Method 66

(3S)-and 1-(4-bromo-2-methyl benzoyl)-N, N-dimethyl pyrrolidine-3-amine

By the mode that is similar to method 4, prepare title compound by (3S)-NN-dimethyl pyrrolidine-3-amine and 4-bromo-2-tolyl acid.NMR(300.072MHz，CDCl ₃)7.39(s，1H)，7.35(d，1H)，7.06(d，1H)，4.00-3.84(m，1H)，3.61-3.35(m，1H)，3.31-3.23(m，1H)，3.18-2.95(m，1H)，2.80-2.63(m，1H)，2.29(s，6H)，2.19-2.03(m，4H)，1.90-1.74(m，1H)；m/z 312。

Method 67

(3R)-and 1-(4-bromo-2-methyl benzoyl)-N, N-dimethyl pyrrolidine-3-amine

By the mode that is similar to method 4, by (3R)-N, N-dimethyl pyrrolidine-3-amine and 4-bromo-2-tolyl acid prepare title compound.NMR(300.072MHz，CDCl ₃)7.39(s，1H)，7.35(d，1H)，7.07(dd，1H)，4.00-3.84(m，1H)，3.61-3.35(m，1H)，3.31-2.95(m，2H)，2.81-2.64(m，1H)，2.30(s，6H)，2.19-2.02(m，4H)，1.90-1.76(m，1H)；m/z 312。

Method 68

(4-bromo-2-chloro-phenyl)-(4-methyl isophthalic acid, ketone of 4-Diazesuberane-1-)

By the mode that is similar to method 4, prepare title compound by high piperazine of N-methyl and 4-bromo-2-chloro-benzoic acid, just with the distillation under vacuum purifying (180 ℃, 0.80mmHg).NMR7.73(d，1H)，7.59(dd，1H)，7.28(d，1H)，3.71-3.63(m，2H)，3.28-3.19(m，2H)，2.95-2.89(m，1H)，2.69-2.64(m，1H)，2.62-2.52(m，2H)，2.29(d，3H)，1.90-1.82(m，1H)，1.75-1.67(m，1H)；m/z 332。

Method 69

(4-bromo-2-chloro-phenyl)-(1,4-oxaza heptane-4-yl) ketone

By the mode that is similar to method 4, by 1,4-oxaza heptane and 4-bromo-2-chloro-benzoic acid prepare title compound, just with the distillation under vacuum purifying (182 ℃, 0.58mmHg).NMR 7.74(s，1H)，7.60(d，1H)，7.31(d，1H)，3.79-3.66(m，5H)，3.61-3.55(m，1H)，3.34-3.25(m，2H)，1.95-1.87(m，1H)，1.77-1.69(m，1H)；m/z 319。

Method 70

(4-iodophenyl)-[(1S, 4S)-2-propyl group-2,5-diazabicylo [2.2.1] heptan-5-yl] ketone

By the mode that is similar to method 10, by (1S, 4S)-2-propyl group-2,5-diazabicylo [2.2.1] heptane and 4-iodobenzene formyl chloride prepare title compound.NMR 7.80 (d, 2H), 7.27 (d, 2H), 3.48 (s, 1H), 3.45-3.38 (m, 1H), 3.32 (dd, 1H), 2.93 (s, 1H), 2.83 (d, 1H), 2.61 (d, 1H), 2.54-2.39 (m, 2H), 1.77 (d, 1H), 1.68 (d, 1H), 1.40 (sextet, 2H), 0.87 (t, 3H); M/z 372.

Method 71

[4-(2-hydroxyethyl)-1,4-Diazesuberane-1-yl]-(4-iodophenyl) ketone

By the mode that is similar to method 10, prepare title compound by 2-(1,4-Diazesuberane-1-yl) ethanol and 4-iodobenzene formyl chloride.NMR(400.132MHz，CDCl ₃)7.75(d，2H)，7.13(d，2H)，3.80-3.72(m，2H)，3.62-3.50(m，2H)，3.50-3.42(m，2H)，2.92-2.81(m，1H)，2.81-2.60(m，6H)，2.01-1.92(m，1H)，1.83-1.74(m，1H)；m/z 375。

Method 72

(4-iodophenyl)-(1,4-oxaza heptane-4-yl) ketone

By the mode that is similar to method 10, by 1,4-oxaza heptane and 4-iodobenzene formyl chloride prepare title compound.NMR(400.132MHz，CDCl ₃)7.76(d，2H)，7.14(d，2H)，3.89-3.72(m，5H)，3.69-3.59(m，1H)，3.54-3.45(m，2H)，2.09-1.97(m，1H)，1.87-1.75(m，1H)；m/z 332。

Method 73

N-(5-methyl isophthalic acid, 2-oxazole-4-yl) tetramethylene methane amide

At ambient temperature, (26.7ml) is added drop-wise to the 5-methyl isophthalic acid with the cyclobutylmethyl acyl chlorides, in the stirred solution of 2-oxazole-4-amine hydrochlorate (30g) and TEA (80ml) and DCM (450ml).After reaction mixture stirred 30 minutes, water (150ml), 10% aqueous citric acid solution (2 * 100ml), NaHCO ₃Saturated aqueous solution (2 * 100ml) washings.(2 * 100ml) extract the organic extract drying (Na of merging to water layer again with DCM ₂SO ₄), filter final vacuum and concentrate.Resistates grinds with ether (250ml), filters after drying, obtains title compound (35.3g, light brown solid).NMR (300.072MHz, CDCl ₃) 8.52 (s, 1H), 6.60 (br.s, 1H), 3.14 (quintet, 1H), 2.45-2.16 (m, 5H), 2.11-1.84 (m, 2H); M/z181.

Method 74

N-(cyclobutylmethyl)-5-methyl isophthalic acid, 2-oxazole-4-amine hydrochlorate

Under inert atmosphere, envrionment temperature, in 30 minutes, borane-dimethyl sulphide complex compound (the THF solution of 200ml 2M) is added to N-(5-methyl isophthalic acid, 2-oxazole-4-yl) tetramethylene methane amide (method 73; 32.7g) with the stirred solution of THF (150ml) in.Reaction mixture was stirred 30 minutes at ambient temperature, and reflux (warning: heat release and boiling) is 2 hours then.Make reaction mixture be cooled to 0 ℃, add MeOH carefully after, stirred at ambient temperature 3 hours.Drip the dioxane solution (55ml) of 4M HCl, stir 1 hour final vacuum except that desolvating.Add ether,, obtain title compound (36.9g, colorless solid) gained solid filtering after drying.NMR 8.68(s，1H)，3.20(d，2H)，2.58(m，1H)，2.49(s，3H)，2.06-1.92(m，2H)，1.88-1.64(m，4H)；m/z 166。

Method 75

N-(cyclobutylmethyl)-N-(5-methyl isophthalic acid, 2-oxazole-4-yl) ethanamide

In 30 minutes, diacetyl oxide (35ml) is added to N-(cyclobutylmethyl)-5-methyl isophthalic acid, 2-oxazole-4-amine hydrochlorate (method 74; 37.3g) and the stirred suspension of sodium acetate (15.1g) and acetate (250ml) in.After reaction mixture stirred 16 hours at ambient temperature, vacuum concentration.Resistates stirred 1 hour with 10% wet chemical (400ml), used DCM (1 * 300ml, 2 * 100ml) extractions then.Organic extract washs with salt solution (100ml), dry (Na ₂SO ₄), vacuum concentration obtains title compound (36.2g, yellow oil).NMR(300.072MHz，CDCl ₃)8.08(s，1H)，3.63(d，2H)，2.41(m，1H)，2.34(s，3H)，2.05-1.80(m，7H)，1.74-1.57(m，2H)；m/z 209。

Method 76

N-[(E)-1-amino-3-oxo-but-1-ene-2-yl]-N-(cyclobutylmethyl) ethanamide

Under nitrogen atmosphere, with N-(cyclobutylmethyl)-N-(5-methyl isophthalic acid, 2-oxazole-4-yl) ethanamide (method 75; 36.0g) and EtOH (360ml) solution of 10%Pd/C (8.0g) under 4 normal atmosphere, stirred 16 hours.Make reaction mixture pass through diatomite filtration (the DCM solution of 10%MeOH), solvent removed in vacuo.The gained resistates grinds the final vacuum drying with ether, obtains title compound (31.4g, colorless solid).NMR 7.46(m，1H)，6.95(br.，1H)，6.66(br.，1H)，3.39-3.16(m，2H)，2.29(m，1H)，2.03(s，1H)，1.95-1.79(m，2H)，1.75-1.63(m，2H)，1.61(s，3H)，1.60-1.47(m，2H)；m/z 211。

Method 77

(E)-1-[3-(cyclobutylmethyl)-2-methyl-imidazol-4 yl]-3-dimethylamino-third-2-alkene-1-ketone

With N-[(E)-1-amino-3-oxo-but-1-ene-2-yl]-N-(cyclobutylmethyl) ethanamide (method 76; 33.4g) and NaOH (7.63g) be added among the EtOH (250ml) reflux 3 hours.With the reaction mixture vacuum concentration, add aqueous ammonium chloride solution (200ml), (3 * 300ml) extract water layer with ether.The organism that merges after drying, solvent removed in vacuo obtains orange (30g), distillation then (106 ℃, 0.69mbar).Gained colorless oil (30g) and DMFDMA (53ml) are added among the DMF (250ml), heated 4 hours down at 130 ℃.Solvent removed in vacuo obtains yellow solid.Add DCM (20ml), ether (100ml) successively,, obtain title compound (35.3g, yellow solid) with 10 minutes after-filtration of supersound process.NMR (400.132MHz, CDCl ₃) 7.65 (d, 1H), 7.49 (s, 1H), 5.52 (d, 1H), 4.41 (d, 2H), 3.07-2.89 (m, 6H), 2.72 (septet, 1H), 2.42 (s, 3H), 2.01-1.92 (m, 2H), 1.86-1.70 (m, 4H); M/z 248.

Method 78

4-[3-(cyclobutylmethyl)-2-methyl-imidazol-4 yl] pyrimidine-2-amine

With (E)-1-[3-(cyclobutylmethyl)-2-methyl-imidazol-4 yl]-3-dimethylamino-third-2-alkene-1-ketone (method 77; 1.5g) and guanidine (2.6g) with propyl carbinol (60ml) reflux 30 hours.Solvent removed in vacuo obtains yellow solid, after its water (60ml) quencher, with DCM (3 * 70ml) extractions.The organism that merges after drying, vacuum concentration obtains yellow solid, and it is dissolved among the minimum hot DCM, makes it cooling.With gained solid filtering after drying, obtain title compound (1.35g, colorless solid).NMR 8.17 (d, 1H), 7.23 (s, 1H), 6.74 (d, 1H), 6.57 (s, 2H), 5.38 (quintet, 1H), 2.51-2.35 (m, 7H), 1.83-1.69 (m, 2H); M/z 230.

Method 79

N-cyclopentyl-5-methyl isophthalic acid, 2-oxazole-4-amine

With the 5-methyl isophthalic acid, 2-oxazole-4-amine hydrochlorate (20g), cyclopentanone (13.9ml) and sodium acetate (12.3g) are added among the MeOH (200ml), stir 1 hour down at 0 ℃.In 20 minutes, slowly add NaCNBH ₃(11.5g), simultaneously temperature is remained on below 0 ℃.After adding, after making reaction mixture be warming up to envrionment temperature and stirring 16 hours, solvent removed in vacuo.The gained solid is dissolved in NH ₄In the Cl saturated aqueous solution (100ml), (be followed successively by 2 * 200ml, 1 * 100ml) extraction with ether.With the organic extract drying that merges, filter final vacuum except that desolvating, obtain yellow oil.Oily matter is with silica gel column chromatography purifying (the isohexane solution with the 10-50% ether is elutriant).Solvent removed in vacuo obtains title compound (17.2g, yellow oil).NMR (300.072MHz, CDCl ₃) 8.03 (s, 1H), 3.51 (quintet, 1H), 2.31 (s, 3H), 1.94-1.83 (m, 2H), 1.79-1.54 (m, 4H), 1.47-1.37 (m, 2H); M/z 167.

Method 80

N-cyclopentyl-N-(5-methyl isophthalic acid, 2-oxazole-4-yl) ethanamide

In 20 minutes, diacetyl oxide (18.9ml) is added to N-cyclopentyl-5-methyl isophthalic acid in batches, 2-oxazole-4-amine (method 79; 16.0g) with the stirred solution of acetate (160ml) in.After 1 hour, solvent removed in vacuo, gained soup compound K ₂CO ₃The aqueous solution (50ml, warning: discharge CO ₂) handle.(3 * 50ml) extract the organism drying (Na of merging to water layer with DCM ₂S0 ₄), solvent removed in vacuo.The gained solid is dry under high vacuum, obtain title compound (19.0g, yellow solid).NMR 8.64 (s, 1H), 4.77 (quintet, 1H), 2.33 (s, 3H), 1.80-1.74 (m, 2H), 1.69 (s, 3H), 1.51-1.41 (m, 4H), 1.24-1.08 (m, 2H); M/z 209.

Method 81

N-[(E)-1-amino-3-oxo-but-1-ene-2-yl]-N-cyclopentyl-diethylstilbestrol amine

By the mode that is similar to method 76,, obtain colorless solid (16.0g) by N-cyclopentyl-N-(5-methyl isophthalic acid, 2-oxazole-4-yl) ethanamide (method 80) preparation title compound.NMR 7.59 (t, 1H), 6.84 (d, 2H), 4.44 (quintet, 1H), 2.06 (s, 3H), 1.80-1.59 (m, 5H), 1.49-1.19 (m, 6H); M/z 211.

Method 82

1-(3-cyclopentyl-2-methyl-imidazol-4 yl) ethyl ketone

With N-[(E)-1-amino-3-oxo-but-1-ene-2-yl]-N-cyclopentyl-ethanamide (method 81; 16.0g) and NaOH (3.66g) be added among the EtOH (200ml) reflux 4 hours.Add NH ₄Cl (6.11g), mixture stirred 16 hours at ambient temperature after, vacuum concentration.Add ether (350ml), mixture was stirred 10 minutes, filter final vacuum then and concentrate.With the underpressure distillation of gained yellow oil (0.55mbar/100 ℃), obtain title compound (10.08g, transparent oily matter).NMR (400.132MHz, CDCl ₃) 7.73 (s, 1H), 5.22 (quintet, 1H), 2.50 (s, 3H), 2.45 (s, 3H), 2.04-1.97 (m, 6H), 1.71-1.66 (m, 2H); M/z 193.

Method 83

(E)-1-(3-cyclopentyl-2-methyl-imidazol-4 yl)-3-dimethylamino-third-2-alkene-1-ketone

With 1-(3-cyclopentyl-2-methyl-imidazol-4 yl) ethyl ketone (method 82; 10.08g) and DMFDMA (17.9ml) be added among the DMF (150ml), 130 ℃ of down heating 6 hours.Solvent removed in vacuo adds DCM (10ml), ether (100ml) successively.Mixture after 10 minutes, filters after drying with supersound process, obtains title compound (9.74g, yellow solid).NMR (400.132MHz, CDCl ₃) 7.62 (d, 1H), 7.48 (s, 1H), 5.52 (d, 1H), 5.35 (quintet, 1H), 2.99 (s, 6H), 2.49 (s, 3H), 2.14-1.91 (m, 6H), 1.72-1.61 (m, 2H); M/z 248.

Method 84

4-(3-cyclopentyl-2-methyl-imidazol-4 yl) pyrimidine-2-amine

With (E)-1-(3-cyclopentyl-2-methyl-imidazol-4 yl)-3-dimethylamino-third-2-alkene-1-ketone (method 83; 3.00g) and Guanidinium carbonate (4.38g) be added in the 2-methyl cellosolve (50ml), 140 ℃ of down heating 36 hours.Reaction mixture cooling final vacuum is removed desolvate, obtain yellow solid.Add entry (50ml), (3 * 50ml) extract reactive system, the dry final vacuum of the organism that merges is removed desolvate with DCM.The gained yellow solid filters after grinding with DCM, ether successively, and vacuum-drying obtains title compound (2.46g, pale solid).NMR (400.132MHz, CDCl ₃) 8.23 (d, 1H), 7.33 (s, 1H), 6.80 (d, 1H), 5.41 (quintet, 1H), 5.01 (s, 2H), 2.54 (s, 3H), 2.17-2.02 (m, 4H), 1.97-1.87 (m, 2H), 1.74-1.64 (m, 2H); M/z 244.

Method 85

(3S)-3-tetramethyleneimine-1-base tetramethyleneimine

With (3R)-3-mesyloxy tetramethyleneimine-1-t-butyl formate (JCS PerkinTransactions 1,1993,13,1421-4; 26g, 0.098mol) and tetramethyleneimine (15.3g 0.215mol) is added among the DMF, 80 ℃ of down heating 36 hours.Solvent removed in vacuo obtains brown liquid.Underpressure distillation (200 ℃ 1.0mmHg) are removed volatile matter, the NaOH aqueous solution (50ml) quencher of gained jelly.Water layer is saturated with solid carbonic acid potassium, uses DCM (3 * 200ml) extractions then.The organism that merges after drying, solvent removed in vacuo obtains brown oil.With column chromatography purifying (the DCM solution of 0-50%MeOH is elutriant), obtain brown oil, with its underpressure distillation (40 ℃, 0.56mmHg), obtain title compound, be transparent oily matter.NMR (400.132MHz, CDCl ₃) 3.08-3.01 (m, 2H), 2.94-2.88 (m, 1H), 2.82-2.78 (m, 1H), 2.64 (quintet, 1H), 2.55-2.48 (m, 4H), 2.25 (s, 1H), 1.97-1.89 (m, 1H), 1.82-1.75 (m, 4H), 1.73-1.64 (m, 1H).

Method 86

(4-iodophenyl)-[(3S)-and 3-tetramethyleneimine-1-base tetramethyleneimine-1-yl] ketone

By the mode that is similar to method 10, prepare title compound by (3S)-3-tetramethyleneimine-1-base tetramethyleneimine (method 85) and 4-iodobenzene formyl chloride.NMR (400.132MHz, CDCl ₃Rotational isomer) 7.75 (d, 2H), 7.25 (d, 2H), 3.92-3.78 (m, 1H), 3.65-3.33 (m, 3H), 2.91-2.68 (m, 1H), 2.61-2.42 (m, 4H), 2.21-2.00 (m, 1H), 1.99-1.89 (m, 1H), 1.87-1.75 (m, 4H); M/z 371.

Method 87

[(3R)-3-hydroxyl pyrrolidine-1-yl]-(4-iodophenyl) ketone

DCM (200ml) drips of solution of 4-iodobenzene formyl chloride (20g) is added in DCM (300ml) solution of (3R)-tetramethyleneimine-3-alcohol (6.9g) and TEA (23ml).The reactant stirring after 1 hour, is added NH ₄Cl saturated aqueous solution (200ml).(3 * 200ml) extractions, the organism of merging is solvent removed in vacuo after drying, obtains yellow solid with DCM for water layer.Crude product is dissolved in the minimum hot acetonitrile, makes it cooling then, filter after drying, obtain title compound (21.2g, light yellow solid).NMR 7.77(d，2H)，7.28(d，2H)，4.63(d，1H)，4.34-4.22(m，1H)，3.62-3.50(m，2H)，3.49-3.39(m，1H)，3.34-3.22(m，1H)，2.00-1.91(m，1H)，1.85-1.76(m，1H)；m/z 318。

Method 88

(4-iodophenyl)-[(3R)-and 3-mesyloxy tetramethyleneimine-1-yl] ketone

DCM (20ml) drips of solution of methylsulfonyl chloride (5.25ml) is added to [(3R)-3-hydroxyl pyrrolidine-1-yl]-(4-iodophenyl) ketone (method 87; 19.5g) and DCM (200ml) solution of TEA (12.8ml) in.The reaction mixture stirring after 1 hour, is added NH ₄Cl saturated aqueous solution (150ml).(3 * 200ml) extractions, dry final vacuum removes and desolvates water layer, obtains yellow solid, and it is dissolved in the hot acetonitrile of minimum, separates out colorless solid behind the adding ether with DCM.After adding ether again,, obtain title compound, be colorless solid the suspension filtered after drying.NMR 7.81(d，2H)，7.31(d，2H)，5.30-5.26(m，1H)，3.83-3.80(dd，1H)，3.70-3.63(m，1H)，3.60-3.57(m，2H)，3.16(s，3H)，2.31-2.15(m，2H)；m/z 396。

Method 89

[(3S)-3-(cyclopropylamino) tetramethyleneimine-1-yl]-(4-iodophenyl) ketone

With (4-iodophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 88; 3.0g) and cyclopropylamine (4.4g) be added in the diox (40ml), in sealed tube in 109 ℃ the heating 5 days.Add K ₂CO ₃Saturated aqueous solution (50ml), (3 * 100ml) extract water layer with ether.The organism that merges after drying, vacuum concentration obtains yellow jelly.With silica gel purification (with the DCM eluant solution of 0-5%MeOH), obtain title compound (1.72g, stickiness yellow oil).NMR(400.132MHz，CDCl ₃)7.37(d，2H)，6.89(d，2H)，3.49-3.35(m，1H)，3.29-3.15(m，2H)，3.09-2.87(m，2H)，1.83-1.75(m，1H)，1.70-1.63(m，1H)，1.49-1.41(m，1H)，1.31-1.18(m，1H)，0.13-0.17(m，4H)；m/z 357。

Method 90

[(3S)-3-(cyclopropylamino) tetramethyleneimine-1-yl]-(4-iodophenyl) ketone

With (4-iodophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 88; 4.0g) and methylamine (the THF solution of 2.0M; 50ml) under microwave radiation, heated 4 hours in 150 ℃.With the reactant vacuum concentration, add K ₂CO ₃Behind the aqueous solution (50ml), with DCM (3 * 100ml) extractions.The organism that merges after drying, solvent removed in vacuo obtains orange jelly.With silica gel purification (with the DCM eluant solution of 0-20%MeOH), obtain title compound, be yellow jelly.NMR(400.132MHz，CDCl ₃)7.75(d，2H)，7.28-7.24(m，2H)，3.83-3.31(m，4H)，3.25-3.19(m，1H)，2.47-2.37(m，3H)，2.21-1.98(m，1H)，1.84-1.74(m，1H)；m/z 331。

Method 91

[(3S)-3-(ring fourth amino) tetramethyleneimine-1-yl]-(4-iodophenyl) ketone

By the mode that is similar to method 89, prepare title compound by (4-iodophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 88) and ring butylamine; NMR (500.133MHz, DMSO) 7.78 (d, 2H), 7.27 (d, 2H), 3.57-3.48 (m, 2H), 3.43-3.34 (m, 1H), 3.26 (quintet, 1H), 3.22-3.11 (m, 3H), 2.16-2.04 (m, 2H), 1.96 (sextet, 1H), 1.72-1.52 (m, 5H); M/z 371.

Method 92

(4-iodophenyl)-[(3S)-and 3-(methyl-propyl group-amino) tetramethyleneimine-1-yl] ketone

By the mode that is similar to method 89, prepare title compound by (4-iodophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 88) and N-methyl-prop-1-amine; NMR (500.133MHz, DMSO) 7.79 (d, 2H), 7.27 (d, 2H), 3.63-3.49 (m, 2H), 3.44-3.38 (m, 1H), 3.25 (dd, 1H), 3.05 (quintet, 1H), 2.37-2.27 (m, 2H), 2.16 (s, 3H), 2.04-1.98 (m, 1H), 1.82-1.74 (m, 1H), 1.42 (sextet, 2H), 0.84 (t, 3H); M/z 373.

Method 93

(4-bromophenyl)-[(3R)-and 3-mesyloxy tetramethyleneimine-1-yl] ketone

DCM (200ml) solution of 4-bromo-benzoyl chloride (15g) slowly is added in the stirred solution of (3R)-tetramethyleneimine-3-alcohol (6.0g) and TEA (21ml) and DCM (300ml) by dropping funnel.The reactant stirring after 1 hour, is added saturated NH ₄Cl (200ml) is with DCM (3 * 200ml) extractions.The organism that merges after drying, vacuum concentration obtains yellow solid.This solid is dissolved in the minimum hot acetonitrile, and cooled and filtered obtains light yellow solid.Isolating solid (13.4g) and TEA (10.3ml) are dissolved among the DCM (200ml), add DCM (20ml) solution of methylsulfonyl chloride (4.54ml) then with dropping funnel.The reactant stirring after 1 hour, is added saturated NH ₄Cl (150ml) is with DCM (3 * 200ml) extractions.The organism that merges after drying, vacuum concentration obtains yellow jelly.Add acetonitrile and ether then, will carry out supersound process after the mixture heating up, obtain title compound (16g, pale solid); NMR (400.132MHz, CDCl ₃, rotational isomer) 7.56 (d, 2H), 7.44-7.37 (m, 2H), 5.38-5.25 (m, 1H), 3.94-3.59 (m, 4H), 3.13-3.02 (m, 3H), 2.39-2.35 (m, 1H), 2.31-2.11 (m, 1H); M/z 349.

Method 94

(4-bromophenyl)-[(3S)-and 3-diethylin tetramethyleneimine-1-yl] ketone

With (4-bromophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 93; 2.5g) and diethylamine (10g) be added in the diox (30ml), 100 ℃ down heating exhaust up to observing raw material.With the reaction mixture vacuum concentration, be added to then on the 50g SCX post (MeOH), use MeOH, 7N NH then successively ₃The MeOH eluant solution.With silica gel purification (with the DCM eluant solution of 0-2.5%MeOH), obtain title compound (1.1g, orange jelly); NMR (500.133MHz, DMSO) 7.60 (d, 2H), 7.43 (d, 2H), 3.63-3.49 (m, 2H), 3.44-3.38 (m, 1H), 3.30-3.20 (m, 2H), 2.58-2.50 (m, 4H), 2.05-1.98 (m, 1H), 1.80-1.73 (m, 1H), 0.96 (t, 6H); M/z 326.

Method 95

[(3S)-3-(azepan-1-yl) tetramethyleneimine-1-yl]-(4-bromophenyl) ketone

By the mode that is similar to method 94, prepare title compound by (4-bromophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 93) and azepan; NMR (500.133MHz, DMSO) 7.60 (d, 2H), 7.43 (d, 2H), 3.64-3.49 (m, 2H), 3.43-3.38 (m, 1H), 3.28-3.21 (m, 2H), 2.66-2.57 (m, 4H), 2.06-2.00 (m, 1H), 1.80-1.72 (m, 1H), 1.61-1.52 (m, 8H); M/z 353.

Method 96

(4-bromophenyl)-[(3S)-and 3-(2-methoxy ethyl-methyl-amino) tetramethyleneimine-1-yl] ketone

By the mode that is similar to method 94, prepare title compound by (4-bromophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 93) and 2-methoxyl group-N-methyl-ethamine; NMR (500.133MHz, DMSO) 7.60 (d, 2H), 7.43 (d, 2H), 3.64-3.49 (m, 2H), 3.41 (m, 3H), 3.28-3.24 (m, 4H), 3.12 (quintet, 1H), 2.63-2.53 (m, 2H), 2.23 (s, 3H), 2.05-1.99 (m, 1H), 1.82-1.74 (m, 1H); M/z 343.

Method 97

(4-bromophenyl)-[(3S)-and 3-(methyl-(2-methyl-propyl) amino) tetramethyleneimine-1-yl] ketone

By the mode that is similar to method 94, by (4-bromophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 93) and N, 2-dimethyl propylene-1-amine prepares title compound; NMR (500.133MHz, DMSO) 7.60 (d, 2H), 7.43 (d, 2H), 3.62-3.50 (m, 2H), 3.44-3.38 (m, 1H), 3.28-3.25 (m, 1H), 3.04 (quintet, 1H), 2.16 (s, 3H), 2.14-1.98 (m, 3H), 1.82-1.66 (m, 2H), 0.84 (d, 6H); M/z 340.

Method 98

(4-bromophenyl)-[(3S)-and 3-(third-2-base is amino) tetramethyleneimine-1-yl] ketone

With (4-bromophenyl)-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 93; 2.5g) and third-2-amine (3.12g) be dissolved in the diox (50ml), under microwave radiation in 150 ℃ the heating 8 hours.With the reaction mixture vacuum concentration, be dissolved in MeOH after, be added on the 50g SCX post and (use MeOH, 7N NH successively ₃The MeOH eluant solution).With silica gel purification (with the DCM eluant solution of 0-5%MeOH), obtain title compound (1.6g, orange jelly); NMR (500.133MHz, DMSO) 7.60 (d, 2H), 7.43 (d, 2H), 3.63-3.49 (m, 2H), 3.45-3.33 (m, 2H), 3.17-3.10 (m, 1H), 2.81-2.71 (m, 1H), 2.05-1.98 (m, 1H), 1.69-1.63 (m, 1H), 1.00-0.97 (m, 6H); M/z 312.

Method 99

(4-iodophenyl)-[(3S)-and 3-(piperidino) tetramethyleneimine-1-yl] ketone

With (4-iodophenyl) in the sealed tube-[(3R)-3-mesyloxy tetramethyleneimine-1-yl] ketone (method 88; 2.0g) and piperidines (1.84g) De diox (10ml) solution in 101 ℃ the heating 3 days.With the reaction mixture vacuum concentration, be dissolved in behind the MeOH by 50g SCX post, use MeOH, 7N NH more successively ₃The MeOH eluant solution.The gained solid suspension in hot acetonitrile, is filtered then, obtain title compound, be colorless solid.NMR 7.79(d，2H)，7.27(d，2H)，3.65-3.49(m，2H)，3.44-3.38(m，1H)，3.25(dd，1H)，2.95-2.84(m，1H)，2.45-2.40(m，2H)，2.37-2.30(m，2H)，2.07-2.01(m，1H)，1.80-1.72(m，1H)，1.54-1.47(m，4H)，1.41-1.37(m，2H)；m/z385。

Method 100

1,4-Diazesuberane-1-base-(4-iodophenyl) ketone

With 1,4-Diazesuberane-1-t-butyl formate (15.7g) slowly is added in the solution of 4-iodobenzene formyl chloride (20g) and TEA (23ml) and DCM (300ml).The reactant stirring after 30 minutes, is added 2M NaOH (100ml), and (3 * 200ml) extract water layer with DCM.The organism drying that merges, solvent removed in vacuo obtains yellow jelly (33g), and it is dissolved in DCM (200ml), adds TFA (150ml), reaction mixture is stirred 1 hour final vacuum concentrate.Add 2M NaOH (100ml), water layer is saturated with solid carbonic acid potassium then.(3 * 200ml) extract water layer, and dry final vacuum removes and desolvates, and obtains colorless solid, and it is dissolved among the hot DCM of minimum with DCM; Add ether then up to the solution becomes muddiness.Stirred solution is separated out up to solid, and it is filtered after drying, obtains title compound (20.8g, colorless solid).NMR(400.132MHz，CDCl ₃)7.74(d，2H)，7.14(d，2H)，3.78-3.73(m，2H)，3.47-3.39(m，2H)，3.07-3.04(m，1H)，2.97-2.89(m，2H)，2.86-2.83(m，1H)，1.96-1.87(m，1H)，1.74-1.67(m，2H)；m/z 331。

Method 101

(4-cyclopropyl-1,4-Diazesuberane-1-yl)-(4-iodophenyl) ketone

With 1,4-Diazesuberane-1-base-(4-iodophenyl) ketone (method 100; 4.0g), acetate (3.6g), molecular sieve (6g) and (1-oxyethyl group cyclopropyl) oxygen base trimethyl silane (4.1g) be added among the MeOH and stirred 10 minutes.Add NaCNBH ₃(1.17g), with reactant reflux 24 hours.Solvent removed in vacuo obtains the stickiness jelly, adds 2M NaOH (50ml) then, with DCM (3 * 100ml) extractions.The organism that merges after drying, vacuum concentration obtains transparent oily matter.Underpressure distillation (0.56mmHg, 138 ℃) obtains title compound (2.92g, transparent oily matter).NMR(400.132MHz，CDCl ₃)7.74(d，2H)，7.12(d，2H)，3.79-3.69(m，2H)，3.47-3.39(m，2H)，3.01-2.91(m，1H)，2.89-2.71(m，3H)，1.98-1.68(m，3H)，0.49-0.36(m，4H)；m/z 371。

Method 102

(4-cyclobutyl-1,4-Diazesuberane-1-yl)-(4-iodophenyl) ketone

With 1,4-Diazesuberane-1-base-(4-iodophenyl) ketone (method 100; 3.5g) and cyclobutanone (1.48g) be added among the MeOH (100ml), stirred 20 minutes down at 0 ℃.In 20 minutes, slowly add NaCNBH ₃(1.02g), simultaneously temperature is remained on below 0 ℃.After adding, reactant is warming up to after the envrionment temperature stirred 2 days.Then with the reaction mixture vacuum concentration, behind the adding 2M NaOH (50ml), with ether (3 * 100ml) extractions.The organism that merges after drying, solvent removed in vacuo obtains transparent stickiness oily matter.By silica gel column chromatography purifying (with the DCM eluant solution of 0-5%MeOH), obtain title compound (3.1g, transparent stickiness oily matter).NMR(400.132MHz，CDCl ₃)7.74(d，2H)，7.13(d，2H)，3.76-3.74(m，2H)，3.46-3.40(m，2H)，2.95-2.82(m，1H)，2.63-2.60(m，1H)，2.51-2.49(m，1H)，2.44-2.39(m，2H)，2.08-1.91(m，2H)，1.89-1.57(m，6H)；m/z 385。

Method 103

(4-iodophenyl)-[4-(2-methoxy ethyl)-1,4-Diazesuberane-1-yl] ketone

With 1,4-Diazesuberane-1-base-(4-iodophenyl) ketone (method 100; 1.5g), TEA (1.2ml) and 2-methoxyl group monobromethane (0.95g) be added among the DMA (50ml), 70 ℃ of heating 66 hours down.With the reaction mixture vacuum concentration, be dissolved in MeOH after, be added on the 50gSCX post and (use MeOH, 7N NH successively ₃The MeOH eluant solution).With silica gel purification (with the DCM eluant solution of 0-5%MeOH), obtain title compound (1.02g, orange jelly); NMR (400.132MHz, CDCl ₃) 7.74 (d, 2H), 7.13 (d, 2H), 3.78-3.73 (m, 2H), 3.51-3.39 (m, 4H), 3.36-3.32 (m, 3H), 2.88-2.86 (m, 1H), 2.77-2.67 (m, 5H), 2.00-1.93 (m, 1H), 1.83-1.75 (m, 1H); M/z 389.

Method 104

(4-ethyl-1,4-Diazesuberane-1-yl)-(4-iodophenyl) ketone

With 1,4-Diazesuberane-1-base-(4-iodophenyl) ketone (method 100; 3.0g) and acetaldehyde (0.56ml) be dissolved among the MeOH (150ml), stir 10 minutes at ambient temperature after, disposable adding sodium cyanoborohydride (0.69g).After 2 hours, add acetaldehyde (0.56ml) again, restir reactant 2 hours.Add 2M NaOH solution (11ml) afterwards, reaction mixture is stirred 1 hour final vacuum concentrate.Resistates is distributed, water layer DCM extracting twice between DCM and water.The organic extract of merging is filtered by phase separation separatory membrane (PTFE filter membrane), and vacuum evaporating solvent obtains light yellow oil, uses RPHPLC purifying (1.39g) again; NMR (400.132MHz, CDCl ₃) 7.76-7.72 (m, 2H), 7.15-7.11 (m, 2H), 3.79-3.73 (m, 2H), 3.48-3.39 (m, 2H), and 2.80-2.77 (m, 1H), 2.70-2.66 (m, 1H), 2.63-2.49 (m, 4H), 2.00-1.92 (m, 1H), 1.82-1.76 (m, 1H), 1.11-1.01 (m, 3H); M/z 359.

Method 105

[(1S, 4S)-2,5-diazabicylo [2.2.1] heptan-5-yl]-(4-iodophenyl) ketone hydrochloride

With 4-iodobenzene formyl chloride (5.37g) with (1S, 4S)-2,5-diazabicylo [2.2.1] heptane-2-t-butyl formate (4.0g) is dissolved in DCM (150ml), adds TEA (4.2ml), and reaction mixture was stirred 1 hour.Add 2.0M NaOH (50ml) afterwards, reaction mixture with DCM (3 * 100ml) extraction, the organism of merging after drying, solvent removed in vacuo obtains colorless solid (8.9g).This solid is dissolved among DCM (150ml) and the TFA (100ml), stirs 1 hour final vacuum and concentrate.Add K ₂CO ₃Saturated aqueous solution (50ml), (3 * 100ml) extract water layer with DCM then, with the organism drying that merges, solvent removed in vacuo obtains the stickiness yellow jelly, and it is dissolved in acetonitrile, add 4.0N HCl De dioxane solution (5.0ml) after-filtration, drying obtains title compound (4.3g, light yellow solid).NMR 9.63(brs，1H)，7.83(d，2H)，7.33(d，2H)，4.72-4.59(m，1H)，4.39(s，1H)，3.74(d，1H)，3.58(dd，1H)，3.38(dd，1H)，3.27(dd，1H)，2.07(d，1H)，1.93(d，1H)；m/z329。

Method 106

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

By the mode that is similar to method 52, by 4-{[4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } ethyl benzoate (method 49) replacement 4-{[5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-base] amino } ethyl benzoate (method 51) preparation title compound; NMR (400.132MHz, DMSO) 9.51 (s, 1H), 8.40 (d, 1H), 7.85 (d, 2H), 7.61 (d, 2H), 7.43 (s, 1H), 7.05 (d, 1H), 5.78 (m, 1H), 2.50 (s, 3H), 1.45 (d, 6H); M/z 338.

Method 107

(4-iodophenyl)-[(3S)-and 3-mesyloxy tetramethyleneimine-1-yl] ketone

By the mode that is similar to method 93, replace (3R)-tetramethyleneimine-3-alcohol preparation title compound by (3S)-tetramethyleneimine-3-alcohol; NMR (400.132MHz, CDCl ₃) (rotational isomer) 7.78 (d, 2H), 7.34-7.20 (m, 2H), 5.37-5.25 (m, 1H), 3.93-3.47 (m, 4H), 3.16-3.02 (m, 4H), 2.42-2.32 (m, 1H), 2.31-2.11 (m, 1H); M/z 396.

Method 108

(4-iodophenyl)-[(3R)-and 3-methylamino-tetramethyleneimine-1-yl] ketone

By the mode that is similar to method 90, use (4-iodophenyl)-[(3S)-and 3-mesyloxy tetramethyleneimine-1-yl] ketone (method 107) replacement (4-iodophenyl)-[(3R)-and 3-mesyloxy tetramethyleneimine-1-yl] ketone (method 88) preparation title compound; NMR (400.132MHz, CDCl ₃) (rotational isomer) 7.78 (d, 2H), 7.34-7.20 (m, 2H), 5.37-5.25 (m, 1H), 3.93-3.47 (m, 4H), 3.16-3.02 (m, 4H), 2.42-2.32 (m, 1H), 2.31-2.11 (m, 1H); M/z 396.

Embodiment 209

Illustrate the representative drugs formulation that contains hydrolyzable ester (calling compounds X in the following text) in formula (I) compound or its pharmacy acceptable salt or the body of technology personal care or preventive use below:

(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	Cross-linked carboxymethyl cellulose is received	12.0
Corn starch paste (5% (weight/volume) paste)	2.25	Cross-linked carboxymethyl cellulose is received	12.0
Corn starch paste (5% (weight/volume) paste)	2.25	Magnesium Stearate	3.0

(b): tablet II	The mg/ sheet
(b): tablet II	The mg/ sheet	Compounds X	50
Lactose Ph.Eur	223.75	Compounds X	50
Lactose Ph.Eur	223.75	Cross-linked carboxymethyl cellulose is received	6.0
W-Gum	15.0	Cross-linked carboxymethyl cellulose is received	6.0
W-Gum	15.0	Polyvinylpyrrolidone (5% (weight/volume) paste)	2.25
Magnesium Stearate	3.0	Polyvinylpyrrolidone (5% (weight/volume) paste)	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	Cross-linked carboxymethyl cellulose is received	4.0
Corn starch paste (5% (weight/volume) paste)	0.75	Cross-linked carboxymethyl cellulose is received	4.0
Corn starch paste (5% (weight/volume) paste)	0.75	Magnesium Stearate	1.0

(d): capsule	The mg/ capsule
(d): capsule	The mg/ capsule	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% (weight/volume)
The 1M sodium hydroxide solution	15.0% (volume/volume)	Compounds X	5.0% (weight/volume)
The 1M sodium hydroxide solution	15.0% (volume/volume)	0.1M hydrochloric acid	(regulating pH to 7.6)
Poly(oxyethylene glycol) 400	4.5% (weight/volume)	0.1M hydrochloric acid	(regulating pH to 7.6)
Poly(oxyethylene glycol) 400	4.5% (weight/volume)	Water for injection	To 100%

(f): injection II	10mg/ml
(f): injection II	10mg/ml	Compounds X	1.0% (weight/volume)
Sodium phosphate BP	3.6% (weight/volume)	Compounds X	1.0% (weight/volume)
Sodium phosphate BP	3.6% (weight/volume)	0.1M sodium hydroxide solution	15.0% (volume/volume)
Water for injection	To 100%	0.1M sodium hydroxide solution	15.0% (volume/volume)

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

Note

Can obtain above-mentioned preparation by the well-known ordinary method of pharmacy field.Tablet (a)-(c) can carry out enteric coating by ordinary method, for example uses the cellulose acetate phthalate dressing.

Claims

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

Wherein:

R ³Be hydrogen or halogen;

R ⁵Be the substituting group on the carbon, be selected from halogen, cyano group, hydroxyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfamyl, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, C _1-6Alkyloyl, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, wherein a is the C of 0-2 _1-6Alkyl S (O) _a, C _1-6Alkylsulfonyloxy, C _1-6Carbalkoxy, carbocylic radical, heterocyclic radical, N-(C _1-6Alkyl) sulfamyl or N, N-(C _1-6Alkyl) ₂Sulfamyl; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace; Perhaps R ⁵For-NHR ⁹,-NR ¹⁰R ¹¹Or-O-R ¹²

N is 0-2; R wherein ⁵Value can be identical or different;

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

2. hydrolyzable ester, wherein R in the formula of claim 1 (I) compound or its pharmacy acceptable salt or the body ¹Be ethyl, sec.-propyl, cyclopropyl methyl, 1-cyclopropyl ethyl, cyclobutylmethyl, cyclopentyl or cyclobutyl.

3. hydrolyzable ester, wherein R in the formula of claim 1 or claim 2 (I) compound or its pharmacy acceptable salt or the body ²Be methyl, ethyl, sec.-propyl, difluoromethyl, trifluoromethyl, methoxymethyl or cyclopropyl.

4. hydrolyzable ester, wherein R in each formula (I) compound or its pharmacy acceptable salt or the body among the claim 1-3 ³Be hydrogen, fluorine or chlorine.

5. hydrolyzable ester, wherein R in each formula (I) compound or its pharmacy acceptable salt or the body among the claim 1-4 ⁴Be hydrogen, halogen, cyano group, methylsulfonyl, methyl or methoxy.

6. hydrolyzable ester in each formula (I) compound or its pharmacy acceptable salt or the body among the claim 1-5, wherein the A ring is the 4-7 unit saturated rings that nitrogen connects, optional other nitrogen, oxygen or the sulphur atom of containing; Wherein 2 atoms of A ring when the A ring be nitrogen connect 5-7 unit saturated rings the time, can choose wantonly by 1 or 2 atomic bridge connection; And if wherein the A ring contains other nitrogen-atoms, then nitrogen can be chosen wantonly by R ⁷Replace; Wherein

7. hydrolyzable ester, wherein R in each formula (I) compound or its pharmacy acceptable salt or the body among the claim 1-6 ⁵Be the substituting group on the carbon, be selected from hydroxyl, amino, C _1-6Alkyl, C _1-6Alkylsulfonyloxy, wherein a is 2 C _1-6Alkyl S (O) _aOr heterocyclic radical; R wherein ⁵Can be independently by one or more R on carbon ⁸The optional replacement; Perhaps R ⁵For-NHR ⁹Or-NR ¹⁰R ¹¹If wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly by R ¹⁵Replace; Wherein

R ⁶Be selected from halogen, methoxyl group and hydroxyl;

R ⁸Be selected from hydroxyl, amino and phenylamino; With

R ¹³Be selected from carbocylic radical and C _1-3Alkoxyl group.

8. hydrolyzable ester in each formula (I) compound or its pharmacy acceptable salt or the body among the claim 1-7, wherein n is 0 or 1.

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

Wherein:

R ³Be hydrogen, fluorine or chlorine;

N is 0 or 1.

10. hydrolyzable ester in the compound of a following formula (I) or its pharmacy acceptable salt or the body:

Described formula (I) compound is selected from:

(2) N-(4-{[(3 S)-3-(dimethylamino) tetramethyleneimine-1-yl] carbonyl } phenyl)-5-fluoro-4-(1-sec.-propyl-2-methyl isophthalic acid H-imidazoles-5-yl) pyrimidine-2-amine;

11. one kind be used for preparing claim 1-10 each formula (I) compound or its pharmacy acceptable salt or body in the method for hydrolyzable ester, this method is made up of following method:

Method a) makes the pyrimidine of following formula (II):

Aniline reaction with following formula (III):

In the formula (II), L is a displaceable group;

Perhaps

Method b) make the compound of following formula (IV):

Compound reaction with following formula V:

Method c) make following formula (VI) acid or its active acid derivant:

Amine reaction with following formula (VII):

Perhaps

Compound reaction with following formula (IX):

Wherein Y is a displaceable group;

And afterwards if needed

Ii) slough any protecting group;

Iii) make hydrolyzable ester in pharmacy acceptable salt or the body.

12. a pharmaceutical composition, described composition comprise among the claim 1-10 each formula (I) compound or its pharmacy acceptable salt or body in hydrolyzable ester, and pharmaceutically acceptable diluent or carrier.

13. one kind as among the claim 1-10 of medicine each formula (I) compound or its pharmacy acceptable salt or body in hydrolyzable ester.

14. among the claim 1-10 in each formula (I) compound or its pharmacy acceptable salt or the body hydrolyzable ester be used for producing the purposes of the medicine of inhibition of cell proliferation effect in preparation.

15. the interior hydrolyzable ester of each formula (I) compound or its pharmacy acceptable salt or body is used for producing the purposes of the inhibiting medicine of CDK2 among the claim 1-10 in preparation.

16. among the claim 1-10 in each formula (I) compound or its pharmacy acceptable salt or the body hydrolyzable ester be used for the treatment of purposes in the medicine of cancer in preparation.

17. among the claim 1-10 in each formula (I) compound or its pharmacy acceptable salt or the body hydrolyzable ester be used for the treatment of purposes in the medicine of following disease in preparation: leukemia or lymph malignant tumour 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.

18. among the claim 1-10 in each formula (I) compound or its pharmacy acceptable salt or the body hydrolyzable ester be used for the treatment of purposes in the medicine of following disease in preparation: cancer, fiber proliferative and branch voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel.

19. a method that in the warm-blooded animal body of this treatment of needs, produces the inhibition of cell proliferation effect, this method comprise among the claim 1-10 that gives described animal effective dose each formula (I) compound or its pharmacy acceptable salt or body in hydrolyzable ester.

20. one kind produces the inhibiting method of CDK2 in the warm-blooded animal body of this treatment of needs, this method comprise among the claim 1-10 that gives described animal effective dose each formula (I) compound or its pharmacy acceptable salt or body in hydrolyzable ester.

21. a method for cancer for the treatment of the warm-blooded animal that needs this treatment, this method comprise among the claim 1-10 that gives described animal effective dose each formula (I) compound or its pharmacy acceptable salt or body in hydrolyzable ester.

22. leukemia or a lymph malignant tumour or following method for cancer for the treatment of the warm-blooded animal that needs this treatment: 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 comprise among the claim 1-10 that gives described animal effective dose each formula (I) compound or its pharmacy acceptable salt or body in hydrolyzable ester.

23. method for the treatment of the following disease of the warm-blooded animal that needs this treatment: cancer, fiber proliferative and branchs voltinism disease, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, acute and chronic nephropathy, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acute and chronic inflammation, osteopathy and with the outgrowth eye disease of retinal vessel, this method comprise among the claim 1-10 that gives described animal effective dose each formula (I) compound or its pharmacy acceptable salt or the interior hydrolyzable ester of body.