CN101291917A - Diaryl urea derivatives in the treatment of protein kinase dependent diseases - Google Patents

Abstract

The invention relates to the use of diaryl urea derivatives for the manufacture of pharmaceutical compositions for the treatment of RET dependent disorders, especially RET dependent tumor diseases. The invention further relates to novel N-[4-(pyrimidin-4-yloxy)-phenyl]-N'-phenyl-urea derivatives and their use in the treatment of the animal or human body, especially in the treatment of a protein kinase dependent disease, to pharmaceutical compositions comprising such novel N-[4-pyrimidin-4-yloxy]-phenyl]-N'-phenyl-urea derivatives and to the use of such novel N-[4-(pyrimidin-4-yloxy)-phenyl]-N'-phenyl-urea derivatives for the preparation of pharmaceutical compositions for use in the treatment of protein kinase dependent diseases, especially of proliferative diseases, such as tumour diseases.

Description

The Diarylurea derivatives of treatment protein kinase dependent diseases

Summary of the invention

The present invention relates to Diarylurea derivatives and be used for the treatment of RET dependent conditions, the purposes in the pharmaceutical composition of RET dependent tumors disease especially in preparation.The invention further relates to novel N-[4-(pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives and their treatment animal or human bodies, especially treat the purposes of protein kinase dependent diseases; Relate to the N-[4-that comprises this class novelty (pyrimidine-4-base oxygen base)-phenyl]-pharmaceutical composition of N '-phenyl-urea derivatives and the N-[4-of this class novelty (pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives is used for the treatment of protein kinase dependent diseases, the purposes in the pharmaceutical composition of hyperplasia, for example tumor disease especially in preparation.

Background of invention

Protein kinase (PK) is the enzyme of specific serine in the catalysis cell protein, Threonine or tyrosine residues phosphorylation.The molecular switch of regulating cell proliferation, activation and/or differentiation is served as in these posttranslational modifications of substrate protein white matter.In a lot of morbid states, observe unusual or over-drastic wild-type or mutant PK activity, comprise optimum and the malignant proliferation illness.Under many circumstances, PK inhibitor for treating disease, for example proliferative disorders might have been utilized.

Big and hyperplasia and other PK-relative diseases are numerous in view of protein kinase quantity, thereby need to provide can be used as the compound that the PK inhibitor is treated these PK-relative diseases always.

GENERAL DESCRIPTION OF INVENTION

The proto-oncogene of resetting (RET) during transfection is confirmed to be the sensitive gene of muitiple endocrine neoplasms 2 types (MEN 2), and this is a kind of genetic cancer syndrome, is feature (Eng with medullary thyroid carcinoma (MTC), J.Clin.Oncol., 17,380-93,1999; Takahashi, Cytokine andGrowth Factor Revs., 12,361-73,2001).Hypotype RET/MEN2A is the feature that sports with extracellular domain (for example C634R), and this causes composing type dimerisation and kinase activation.Not too general hypotype RET/MEN2B with activation loop (activation loop) (M918T) sport feature, this causes that composing type activation and substrate specificity sexually revise.RET/MEN2B still has response to its part, so the time and space of GDNF family's members of a clan neural factor is expressed the clinical phenotypes (summary sees Jhiang, Oncogene, 19,5590-7,2000) that can further influence MEN 2B patient.

Papillary thyroid carcinoma (PTC) is the common type (85%) (Lorentz, World Journal of Surgery, 18,547-50,1994) of thyroid malignancy.This tumour is relevant with the somatic mutation of RET proto-oncogene, and this is subjected to activation (Pacini, J.Endocrin.Invest., 23,328-38,2000 of gene rearrangement; Tallini and Asa, Adv.Anat.Pathol., 8,345-54,2001).The proto-oncogene PTC oncogene (RET/PTC) of resetting is the tyrosine-kinase domain of former-RET and the product of other gene fusion.Three kinds of modal modification are RET/PTC1, RET/PTC2 and RET/PTC3 (Pacini, J.Endocrin.Invest., 23,328-38,2000; Tallini and Asa, Adv.Anat.Pathol., 8,345-54,2001).In RET/PTC1, RET/PTC2 and RET/PTC3, tyrosine-kinase domain merges (Tallini and Asa, Adv.Anat.Pathol., 8,345-54,2001) with gene H4, R1 α and ELE1 respectively.

Therefore the various mutants of RET receptor tyrosine kinase are the exploitation targets in cancer, are specially the tempting target of thyroid carcinoma.

Also found RET and various mutant thereof in a lot of different tumor cell lines and tissue in protein and/or mRNA horizontal expression.Therefore the inhibitor of wild-type and mutant RET also is particularly suitable for treating other RET dependence cancers, for example RET dependency colorectal carcinoma, lung cancer, breast cancer and pancreas cancer, and other RET dependency noumenal tumour and leukemia.

Find that now formula I compound is the inhibitor of wild-type and/or mutant RET.Therefore these compounds can be used for treating RET dependence disease, RET dependency hyperplasia especially, RET dependent tumors disease particularly, for example RET dependency colorectal carcinoma, lung cancer, breast cancer and pancreas cancer, and other RET dependency noumenal tumour and leukemia, especially RET dependency thyroid carcinoma.

Detailed Description Of The Invention

The present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, they are formula I compounds

Wherein G does not exist or low-grade alkylidene or C ₃-C ₅Cycloalkylidene, Z are formula Ia groups

Perhaps G does not exist, and Z is a formula Ib group

A is CH, N or N → O, and A ' is N or N → O, and its condition is that to be no more than one can be N → O for A and A ';

N is 1 or 2;

M is 0,1 or 2;

P is 0,2 or 3;

R is 0 to 5;

If p is 0, X is NR, and wherein R is hydrogen or organic moiety, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CHK, and wherein K is low alkyl group or hydrogen, and p is zero, and its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O, S or CH ₂

Y ₂Be O, S or NH;

Its condition is (Y ₁) _n-(Y ₂) _mDo not comprise O-O, S-S, NH-O, NH-S or S-O group;

Each R ₁, R ₂, R ₃And R ₅Be hydrogen or inorganic or organic moiety independently of one another, perhaps any two rudimentary alkylene dioxo base bridges that constitute together via the Sauerstoffatom bonding, one of all the other of these parts are hydrogen or inorganic or organic moiety;

R ₄(if present, if promptly r is not zero) is inorganic or organic moiety;

Or its tautomer; Or its pharmacy acceptable salt.

The invention further relates to as the formula IN-[4-of the disclosed novelty of embodiment (embodiment 1-70) hereinafter (pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives, they are called as " novel The compounds of this invention " hereinafter.Novel The compounds of this invention especially shows the restraining effect to one or more following protein tyrosine kinases: c-Abl, Bcr-Abl, receptor tyrosine kinase Flt-3, RET, vascular endothelial growth factor receptor (VEGF-R) and Tek (Tie2), especially Flt-3, and two or more these combination; Novel The compounds of this invention further also is suitable for suppressing nonreceptor tyrosine kinase Raf, and/or suppresses the mutant of these enzymes, especially Bcr-Abl, for example Glu255 → lysine mutation body.In view of these activity, novel The compounds of this invention can be used for the treatment of the disease of the unusual or overactivity that relates in particular to these kinases types, especially those that mentioned.

The used generic term of context preferably has following meanings in this paper, other has except the indication.

If mention " Diarylurea derivatives is used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation ", this expression also comprises the purposes of this class Diarylurea derivatives treatment RET dependence disease, the method for using this class Diarylurea derivatives treatment RET dependence disease and the pharmaceutical composition that comprises this class Diarylurea derivatives of treatment RET dependence disease.Further also expression comprises the Diarylurea derivatives that is used for the treatment of the RET dependence disease.

Prefix " rudimentary " expression have 1 until and comprise maximum 7, especially 1 until and comprise the group of maximum 4 carbon atoms, relevant group is linear, or ramose, has single or multiple branch.Low alkyl group for example has methyl, ethyl, n-propyl, Zhong Bingji, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, n-hexyl or n-heptyl.

If plural form is used for compound, salt, pharmaceutical composition, disease etc., this also represents single compound, salt etc.

Halogen (element) is iodine, bromine, chlorine or fluorine preferably, especially fluorine, chlorine or bromine.

In view of the free form of Diarylurea derivatives and the substantial connection between their salt form, comprising can be as those salt of intermediate, for example be used for purifying or duscriminant I compound, tautomer or tautomer mixture and their salt, context is arbitrarily to these compounds, especially be understood that also to represent the N-oxide compound or these the salt arbitrarily of tautomer mixture, these compounds of corresponding tautomer, these compounds of these compounds to the appellation of the The compounds of this invention of novelty, as long as suitably and suitable and mention if not other.Tautomer for example may reside under such situation, wherein has the amino of at least one hydrogen bonding or hydroxyl separately and is bonded to carbon atom (for example keto-enol or imine-enamine tautomerism) by two keys and adjacent atom bonding.Preferred tautomer is pyriconyl or pyrimidine ketone group form, the wherein R of compound ₄Be hydroxyl, other parts define suc as formula the I compound.

If mention " compound ... its tautomer; Or its salt " etc., this expression " compound ... the salt of its tautomer or this compound or this tautomer ".

The unsymmetrical carbon of optional existence can exist (R), (S) or (R, S) configuration, preferably (R) or (S) configuration in the formula I compound.Substituting group on two keys or the ring can exist cis-(=Z-) or trans-(=E-) form.These compounds thereby can present isomer mixture or preferred pure isomer.

The pharmacy acceptable salt of salt Diarylurea derivatives preferably of the present invention, especially novel The compounds of this invention.

Salt forming group is group or the atomic group with alkalescence or acid properties.Have at least one basic group or at least one basic group, for example amino, do not generate the secondary amino group of peptide bond or the compound of pyridyl can generate acid salt, for example with mineral acid example hydrochloric acid, sulfuric acid or phosphoric acid; Perhaps with the organic carboxyl acid or the sulfonic acid that are fit to, for example aliphatic monobasic-or binary-carboxylic acid, for example trifluoroacetic acid, acetate, propionic acid, oxyacetic acid, succsinic acid, toxilic acid, fumaric acid, hydroxymaleic acid, oxysuccinic acid, tartrate, citric acid or oxalic acid; Or amino acid, for example arginine or Methionin; Aromatic carboxylic acid, for example phenylformic acid, 2-phenoxy group-phenylformic acid, 2-acetoxyl group-phenylformic acid, Whitfield's ointment, 4-aminosallcylic acid; Aromatic-aliphatic carboxylic acid, for example amygdalic acid or styracin; Heteroaromatic carboxylic acids, for example nicotinic acid or Yi Yansuan; Aliphatic sulfonic acid, for example methylsulfonic acid, ethyl sulfonic acid or 2-ethylenehydrinsulfonic acid; Perhaps aromatic sulfonic acid, for example benzene-, p-toluene-or naphthalene-2-sulfonic acid.When having some basic groups, can generate singly-or many-acid salt.

Compound with acidic-group, carboxyl or phenolic hydroxyl group can generate metal or ammonium salt, for example basic metal or alkaline earth salt, for example sodium, potassium, magnesium or calcium salt, perhaps with ammonia or suitable organic amine such as ternary monoamine such as triethylamine or three-(2-hydroxyethyl)-amine or heterocyclic bases such as N-ethyl-piperidines or N, the ammonium salt that N '-lupetazin generated.The mixture of salt is possible.

Have acid compound simultaneously and can generate inner salt with basic group.

For the purpose of isolated or purified, and at compound further as under the situation of intermediate, also might use pharmaceutically unacceptable salt, for example picrate.But have only pharmaceutically acceptable, nontoxic salt just to can be used for therapeutic purpose, therefore these salt are preferred.

The alkyl that organic moiety R does not preferably replace or replaces, the thiazolinyl that does not replace or replace, the alkynyl that does not replace or replace, the aryl that does not replace or replace, the heterocyclic radical that does not replace or replace, the cycloalkyl that does not replace or replace or the cycloalkenyl group that does not replace or replace; Unsubstituted alkyl preferably.

" replacement " anywhere is used for a part, all mean one or more hydrogen atoms in the each several part, 5 especially at the most, more specifically 3 hydrogen atoms are replaced by the substituting group of respective numbers independently of one another at the most, these substituting groups preferably are independently selected from low alkyl group, for example methyl, ethyl or propyl group; Halo-low alkyl group, for example trifluoromethyl; C ₆-C ₁₆-aryl, especially phenyl or naphthyl (C wherein ₆-C ₁₆-aryl, especially phenyl or naphthyl is unsubstituted or by one or more, especially at the most three parts replace, described substituting group is selected from halogen, carboxyl, elementary alkoxy carbonyl, hydroxyl, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, low-grade alkane acidyl, amino, the N-low-grade alkyl amino, N, N-two-low-grade alkyl amino, N-phenyl-low-grade alkyl amino, N, two (phenyl-low alkyl group)-amino of N-, the lower alkyl amido, halogeno-group, halo-low alkyl group (for example trifluoromethyl), sulfo group, sulfamyl, carbamyl, N-low alkyl group-carbamyl, N-(hydroxy lower alkyl)-carbamyl (for example N-(2-hydroxyethyl)-carbamyl), cyano group, cyano group-low alkyl group and nitro); C ₃-C ₁₀-cycloalkyl, especially cyclopropyl or cyclohexyl; Hydroxyl-C ₃-C ₈-cycloalkyl, for example hydroxyl-cyclohexyl; Heterocyclic radical has 5 or 6 annular atomses and 1 to 3 heteroatoms that is selected from O, N and S, especially piperidyl (especially piperidines-1-yl), piperazinyl (especially piperazine-1-yl), morpholinyl (especially morpholine-1-yl); Hydroxyl; Lower alkoxy, for example methoxyl group; Halo-lower alkoxy, especially 2,2, the 2-trifluoro ethoxy; Phenyl-lower alkoxy; Amino-lower alkoxy, for example 2-amino ethoxy; Lower alkanoyloxy; Hydroxy lower alkyl, for example methylol or 2-hydroxyethyl; Amino; The N-low-grade alkyl amino; N, N-two-low-grade alkyl amino; N-phenyl-low-grade alkyl amino; N, two (phenyl-low alkyl group)-amino of N-; Lower alkyl amido, especially kharophen; Benzoyl-amino; Carbamyl-lower alkoxy; N-low alkyl group-carbamyl-lower alkoxy or N, N-two-low alkyl group-carbamyl-lower alkoxy; Amidino groups; N-hydroxyl-amidino groups; Guanidine radicals; Amino-low alkyl group, for example aminomethyl or 2-amino-ethyl; Amidino groups-low alkyl group, for example 2-amidino groups ethyl; N-hydroxyl-amidino groups-low alkyl group, for example N-hydroxyl-amidino groups-methyl or-the 2-ethyl; Halogen, for example fluorine, chlorine, bromine or iodine; Carboxyl; Elementary alkoxy carbonyl; Phenyl-, naphthyl-or fluorenyl-elementary alkoxy carbonyl, for example carbobenzoxy-(Cbz); Low-grade alkane acidyl; Sulfo group; Lower alkyl alkylsulfonyl, for example methylsulfonyl (CH ₃-S (O) ₂-); Phosphono (P (=O) (OH) ₂); Hydroxyl-lower alkoxy phosphoryl or two-lower alkoxy phosphoryl; Carbamyl; Single-or two-low alkyl group carbamyl; Single-or two-(hydroxy lower alkyl)-carbamyl; Sulfamyl; Single-or two-low-grade alkyl amino alkylsulfonyl; Nitro; Cyano group-low alkyl group, for example cyanogen methyl; And cyano group.Self-evident, substituting group only is located at chemically possible position, those skilled in the art can (in experience or in theory) determine which substituting group be possible, which is not to need not unsuitable effort.For example, being bonded to the carbon atom with unsaturated (for example olefinic) key if having the amino or the hydroxyl of free hydrogen, may be unsettled.

Alkyl preferably has 20 at the most, more preferably 12 carbon atoms at the most, and is linear or branch's one or many; Preferably low alkyl group, especially C ₁-C ₄-alkyl, particularly methyl, ethyl or n-propyl.Alkyl is unsubstituted or replaces that preferably replaced by one or more substituting groups, described substituting group is independently selected from above those that mention under " replacement ".As organic moiety R, unsubstituted alkyl, preferred low alkyl group are especially preferred.

In part with respect to the alkyl that replaces, hydroxy lower alkyl, especially 2-hydroxyethyl, and/or halo-low alkyl group, trifluoromethyl or 2,2 especially, the 2-trifluoroethyl is especially preferred.

Thiazolinyl preferably has the part of one or more pair of key, preferably has 2 to 20, more preferably 12 carbon atoms at the most; It is linear or branch's one or many (in view of carbonatoms, whenever possible).C preferably ₂-C ₇-thiazolinyl, especially C ₃-C ₄-thiazolinyl, for example allyl group or crot(on)yl.Thiazolinyl can be unsubstituted or replace, especially by one or more, more specifically three substituting group replacements of above mentioning under " replacements " at the most.Such as substituting groups such as amino or hydroxyl (have can free dissociative hydrogen) preferably not with the carbon atom bonding that participates in two keys, also preferably get rid of other stable inadequately substituting groups.Unsubstituted thiazolinyl is preferred, particularly C ₂-C ₇-thiazolinyl.

Alkynyl preferably has the part of one or more 3 keys, preferably has 2 to 20, more preferably 12 carbon atoms at the most; It is linear or branch's one or many (in view of carbonatoms, whenever possible).C preferably ₂-C ₇-alkynyl, especially C ₃-C ₄-alkynyl, for example ethynyl or propine-2-base.Alkynyl can be unsubstituted or replace, especially by one or more, more specifically three substituting group replacements of above mentioning under " replacements " at the most.Such as substituting groups such as amino or hydroxyl (have can free dissociative hydrogen) preferably not with the carbon atom bonding that participates in three key, also preferably get rid of other not sufficiently stable substituting groups.Unsubstituted alkynyl is preferred, particularly C ₂-C ₇-alkynyl.

Aryl preferably has the ring system of no more than 16 carbon atoms, preferably single-, two-or three-ring, and be unsubstituted or preferably as above " replacement " is following is substituted with defining.Preferably; aryl is selected from phenyl; naphthyl; indenyl; Azulene base and anthryl; preferably unsubstituted in each case or low alkyl group (methyl especially; ethyl or n-propyl); halo (fluorine especially; chlorine; bromine or iodine); halo-low alkyl group (especially trifluoromethyl); hydroxyl; lower alkoxy (especially methoxyl group); halo-lower alkoxy (especially 2; 2; the 2-trifluoro ethoxy); amino-lower alkoxy (especially 2-amino-oxyethyl group); low alkyl group (especially methyl or ethyl); carbamyl; the aryl of N-(hydroxy lower alkyl)-carbamyl (especially N-(2-hydroxyethyl)-carbamyl) and/or sulfamyl-replacement, especially corresponding replacement or unsubstituted phenyl.

Preferably a kind of like this heterocyclic group of heterocyclic radical, it is unsaturated, saturated or fractional saturation in the bonding ring; Be preferably monocycle or of the present invention broadly be two the ring or trinucleated; Have 3 to 24, more preferably 4 to 16 annular atomses; Wherein at least with the ring of formula I molecular linkage in one or more, preferred one to four, especially one or two carbon atom heteroatoms of being selected from nitrogen, oxygen and sulphur replaces, the bonding ring preferably has 4 to 12, preferred 5 to 7 annular atomses; Heteroaryl is unsubstituted or by one or more, especially 1 to 3 substituting group replacement, described substituting group is independently selected from as above " replacement " defined substituting group down; Especially be selected from down the heteroaryl of group: Oxyranyle, ring nitrogen vinyl (azirinyl), 1,2-oxathiolane base, imidazolyl, thienyl, furyl, tetrahydrofuran base, pyranyl, the thiapyran base, thianthrenyl, isobenzofuran-base, benzofuryl, chromenyl, the 2H-pyrryl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolidyl, benzimidazolyl-, pyrazolyl, pyrazinyl, pyrazolidyl, pyranyol, thiazolyl, isothiazolyl, dithiazole base oxazolyl isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, piperidyl (especially piperidines-1-yl), piperazinyl (especially piperazine-1-yl), pyridazinyl, morpholinyl (especially morpholino base), parathiazan base (especially parathiazan is for base), the indolizine base, pseudoindoyl, the 3H-indyl, indyl, benzimidazolyl-, the tonka bean camphor base, indazolyl, triazolyl, tetrazyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, the octahydro isoquinolyl, benzofuryl, dibenzofuran group, benzothienyl, the dibenzothiophene base, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, quinazolyl, the cinnolines base, pteridyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl;

Pyridine base, phenanthroline base, furazan base, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, different chromanyl and chromanyl, each these group is unsubstituted or by one to two group substituting group, described substituting group is selected from low alkyl group (the especially methyl or the tertiary butyl), lower alkoxy (especially methoxyl group) and halogeno-group (especially bromine or chlorine).Unsubstituted heterocyclic, especially piperidyl, piperazinyl, parathiazan are preferred for base or morpholino base.

Cycloalkyl is C preferably ₃-C ₁₀-cycloalkyl, especially cyclopropyl, dimethyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or suberyl, cycloalkyl is unsubstituted or by one or more, especially 1 to 3 substituting group replacement, described substituting group is independently selected from as above " replacement " defined substituting group down.

Cycloalkenyl group is C preferably ₅-C ₁₀-cycloalkenyl group, especially cyclopentenyl, cyclohexenyl or cycloheptenyl, cycloalkenyl group be unsubstituted or by one or more, especially 1 to 3 substituting group replaces, described substituting group is independently selected from as above " replacements " time defined substituting group.

Inorganic part is halogen, hydroxyl, amino or nitro preferably.

Key and linker (CH by dotted line (intermittent line) representative ₂) _pIf p is 2 or 3 then existence, if p is zero then does not exist.

The alkyl that organic moiety does not preferably replace or replaces, the thiazolinyl that does not replace or replace, the alkynyl that does not replace or replace, the aryl that does not replace or replace, the heterocyclic radical that does not replace or replace, the cycloalkyl that does not replace or replace, the cycloalkenyl group that does not replace or replace, the alkoxyl group that does not replace or replace, the alkene oxygen base that does not replace or replace, the alkynyloxy group that does not replace or replace, the aryloxy that does not replace or replace, the heterocyclic oxy group that does not replace or replace, the cycloalkyloxy that does not replace or replace, cyclenes oxygen base that does not replace or replace or the alkylamino that does not replace or replace, the alkenyl amino that does not replace or replace, the alkynyl amino that does not replace or replace, the arylamino that does not replace or replace, the heterocyclic radical amino that does not replace or replace, cycloalkyl amino that does not replace or replace or the cycloalkenyl group amino that does not replace or replace.

Organic moiety is alkyl preferably, especially low alkyl group, for example methyl, ethyl or propyl group; Halo-low alkyl group, for example trifluoromethyl; Lower alkoxy, for example methoxyl group; Halo-lower alkoxy, for example 2,2, the 2-trifluoro ethoxy; Halogeno-group, for example chlorine or bromine; Phenyl; Phenyl amino; Hydroxyl-phenyl amino, for example 4-hydroxy phenyl amino; Amino-lower alkoxy-phenyl amino, for example [4-(2-amino-ethyl) oxygen base]-phenyl amino; Carbamyl-phenyl amino, for example 4-sulfamyl-phenyl amino; [N-(hydroxy lower alkyl)-carbamyl]-phenyl amino, for example N-[4-(2-hydroxyethyl)-carbamyl]-phenyl }-amino; 5-or 6-unit saturated heterocyclyl has 1 or 2 heteroatoms that is selected from N, O and S, piperidyl such as piperidines-1-base especially, and piperazinyl such as piperazine-1-base, morpholinyl such as morpholino base, perhaps parathiazan base such as parathiazan are for base.

The alkalescence organic moiety is to be selected from as the definition of the given organic moiety of this paper and to have the part of alkalescence (alkali) character.Preferably, alkaline organic moiety is a piperidyl, especially piperidines-1-base; Piperidyl-low alkyl group, especially piperidines-1-ylmethyl; Low alkyl group-piperazinyl, especially 4-methylpiperazine-1-base or 4-ethyl piperazidine-1-base; Perhaps low alkyl group-piperazinyl-low alkyl group, especially 4-methylpiperazine-1-ylmethyl or 4-ethyl piperazidine-1-ylmethyl.

If any two R ₁, R ₂And R ₃Constitute the rudimentary alkylene dioxo base bridge via the Sauerstoffatom bonding together, described bridge is preferably via the methylene-dioxy (O-CH of Sauerstoffatom and vicinal carbon atom bonding ₂-O) or ethylenedioxy (O-CH ₂-CH ₂-O), one of all the other of these parts are hydrogen or aforesaid inorganic or organic moiety.

Preventative or the preferred therapeutic (comprise and alleviating and/or healing property) of term " treatment tyrosine protein kinase dependence disease " expression is treated described disease, disease especially mentioned in this article.

Formula I compound has valuable pharmacological character, can be used for treating the RET dependence disease, especially RET dependency hyperplasia, RET dependent tumors disease particularly, for example RET dependency colorectal carcinoma, lung cancer, breast cancer and pancreas cancer and other RET dependency noumenal tumour and leukemia, especially RET dependency thyroid carcinoma.

The following mensuration of RET kinase inhibitory activity:

Clone and expression: use baculovirus donor carrier pFB-GSTX3 to generate recombinant baculovirus, the amino acid region 658-1072 (Swiss prot No.Q9BTB0) of this expressing viral people RET-Men2A kytoplasm kinases structure threshold, it is equivalent to the wild type kinase structure threshold of RET (wtRET) and RET-Men2B, because of the activated mutant among the activation ring M918T is different from wtRET.Utilize Auele Specific Primer, from the cDNA library by the encoding sequence of pcr amplification wtRET cytoplasmic structure threshold.By causing the site-directed mutagenesis effect of M918T sudden change, generate RET-Men2B.With Sall and Kpnl digestion, make the dna fragmentation that is increased be suitable for being connected with the pFB-GSTX3 carrier.The connection of these dna fragmentations causes baculovirus donor plasmids pFB-GX3-RET-Men2A and pFB-GX3-RET-Men2B respectively.

Virus generation: the baculovirus donor plasmids transfection that will contain kinases structure threshold to DH10Bac clone (GIBCO), with institute's cells transfected plating on the selectivity agar plate.The colony to viral genome (being carried by bacterium) insertion fusion sequence is not blue.Pick up single white colony, by standard plasmid purifying process isolated viral DNA (rod granule) from bacterium.Use Cellfectin reagent then, with Sf9 cell or Sf21 cell (American Type Culture Collection) at 25cm ²Use the viral DNA transfection in the flask.

Protein expression in the Sf9 cell: contain viral substratum from institute's cells transfected culture collection, be used for infecting, to increase its titre.Gained contained viral substratum and is used for large-scale protein expression after two-wheeled infected.With regard to large-scale protein expression, to 100cm ²Circular tissue culture plate inoculation 5 * 10 ⁷Cell/flat board, the substratum (approximately 5MOI) that contains virus with 1mL infects.After 3 days, scrape from flat board and to get cell, centrifugal 5 minutes at 500rpm.Will be from 10-20 100cm ²Dull and stereotyped cell precipitation is suspended in (25mM Tris-HCl, pH7.5,2mM EDTA, 1%NP40,1mM DTT, 1mM PMSF) in the ice-cold dissolving damping fluid of 50mL again.Cell was stirred on ice 15 minutes, then 5, centrifugal 20 minutes of 000rpm.

The purifying of GST-labelled protein: institute's centrifugal cell lysates is loaded onto 2mL gsh-agarose column (Pharmacia), wash 3 times with 10mL 25mM Tris-HCl pH7.5,2mM EDTA, 1mMDTT, 200mM NaCl.Then the GST-labelled protein is used 25mM Tris-HCl pH7.5,10mM reduced glutathione, 100mM NaCl, 1mM DTT, 10% glycerine wash-out 10 times (each 1mL), be stored under-70 ℃.

The measurement of enzymic activity: in the final volume of 30 μ L, utilize purifying GST-wtRET or GST-RET-Men2B albumen to carry out tyrosine protein kinase and measure, wherein contain 15ngGST-wtRET or GST-RET-Men2B albumen, 20mM Tris-HCl pH7.5,1mMMnCl ₂, 10mM MgCl ₂, 1mM DTT, 3 μ g/mL poly-(Glu, Tyr) 4: 1,1%DMSO, 2.0 μ M ATP (γ-[ ³³P]-ATP 0.1 μ Ci).Be with or without inhibitor in the presence of by measuring ³³P is from [γ ³³P] ATP is to poly-(Glu, Tyr) 4: 1 mix and measure activity.Under these conditions, measure in envrionment temperature, in the flat board of 96-hole and to reach 15 minutes, add 20 μ L 125mM EDTA and stop.Subsequently, 40 μ L reaction mixtures are transferred on the Immobilon-PVDF film (Millipore), this film soaked 5 minutes with methyl alcohol in advance, and 0.5%H is used in the water flushing then ₃PO ₄Soaked 5 minutes, and be fixed on the vacuum manifold that disconnects vacuum source.On the point behind whole samples, connect vacuum, every hole is with 200 μ L 0.5%H ₃PO ₄Flushing.Remove striping, on vibrator, use 1.0%H ₃PO ₄Wash 4 times, once with washing with alcohol.After the drying, be fixed in the framework of Packard TopCount 96-hole at ambient temperature, add 10 μ L/ hole Microscint ^TM(Packard) after, the radioactivity of counting film.By the linear regression analysis of the inhibition per-cent under 4 kinds of concentration (common 0.01,0.1,1 and 10 μ M) in duplicate of each compound, calculate IC ₅₀Value.The protein kinase activity of a unit be defined under 37 ℃ from [ ³³P] ATP shifts 1nmol to substrate protein ³³P/ minute/mg protein.Formula I compound shows the IC between the 0.005 and 5 μ M here ₅₀Value, especially 0.01 to 1 μ M.

If mention term " purposes " about the The compounds of this invention of novelty subsequently, this comprises any one or multiple following invention embodiment respectively: the purposes in treatment (especially tyrosine) protein kinase dependent diseases, preparation be used for the treatment of the pharmaceutical composition of described disease purposes, use novel The compounds of this invention to treat the method for described disease, be used for the treatment of the pharmaceutical composition that comprises novel The compounds of this invention of described disease and be used for the treatment of the The compounds of this invention of the novelty of described disease, as long as suitably with suitable, other has except the regulation.Definite, that treat thereby be the preferred disease of purposes institute of novel The compounds of this invention, (" dependency " also represents " supportive " to be selected from (especially tyrosine) protein kinase dependent of hereinafter mentioning, not only be " only dependency ") disease, especially corresponding hyperplasia, more specifically depend on c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R and/or Tek, the especially active disease of Flt-3, the especially hereinafter disease of under these concrete protein tyrosine kinases, mentioning.Other can be comprised thrombocyte-deutero-growth factor receptors (PDGF-R), fibroblast growth factor acceptor (FGF-R), Regular Insulin-like growth factor 1 acceptor (IGF-1R), Eph acceptor (especially for example EphB4 acceptor), c-Kit, Met, c-Src, Raf and ras by the kinases that The compounds of this invention suppressed of novelty.

Novel The compounds of this invention has valuable pharmacological character, can be used for treating protein kinase dependent diseases, especially protein tyrosine kinase dependence disease, for example medicine of conduct treatment hyperplasia.

Novel The compounds of this invention can prove as follows as the effect of c-Abl protein tyrosine kinase activity inhibitor:

In the flat board of 96-hole, carry out vitro enzyme and measure, as people such as Geissler, Cancer Res, 1992; The described filter-binding assay of 52:4492-4498, and do following improvement.As people such as Bhat, J.Biol.Chem.1997; The described His-mark kinase domain of in baculovirus/Sf9 system, cloning and expressing c-Abl of 272:16170-16175.By two step process, through cobalt metallo-chelate post, succeeded by the protein (c-Abl kinases) of anionresin column purification 37kD, yield is 1-2mg/LSf9 cell people such as (, the reference of being quoted) Bhat.After Coomassie blue stain, judge that by SDS-PAGE the kinase whose purity of c-Abl is＞90%.Measure thing and contain (cumulative volume 30 μ L): c-Abl kinases (50ng), 20mM Tris-HGl pH7.5,10mM MgCl ₂, 10 μ M Na ₃VO ₄, 1mM DTT and 0.06 μ Ci/ measure [γ ³³P]-ATP (5 μ M ATP), use 30 μ g/mL to gather-Ala, Glu, Lys, Tyr-6: 2: 5: 1 (Poly-AEKY, Sigma P1152), in the presence of 1%DMSO.Add 10 μ L 250mM EDTA termination reactions, with 30 μ L reaction mixtures transfer to the Immobilon-PVDF film (Millipore, Bedford, MA, USA) on, this film soaks 5min with methyl alcohol in advance, 0.5%H is used in water flushing then ₃PO ₄Soak 5min, be fixed on the vacuum manifold that disconnects vacuum source.On the point behind whole samples, connect vacuum, every hole is with 200 μ L 0.5%H ₃PO ₄Flushing.Remove striping, on vibrator, use 0.5%H ₃PO ₄Wash 4 times, once with washing with alcohol.Dry at ambient temperature, be fixed in the framework of Packard TopCount 96-hole, add 10 μ L/ hole Microscint ^TM(Packard) after, the counting film.Utilize this pilot system, novel The compounds of this invention shows the inhibition IC of 0.001 to 100 μ M ₅₀Value is generally 0.05 to 5 μ M.

Utilize further cells in vitro to test the restraining effect that can confirm to the autonomous phosphorylation of VEGF-inductive acceptor, described cell is the Chinese hamster ovary celI of transfection for example, its permanent table intelligent VEGF-R2 acceptor (KDR), it is seeded in perfect medium in the 6 porocyte culture plates (contains in 10% foetal calf serum=FCS), at 37 ℃ and 5%CO ₂Following incubation shows about 80% fusion rate until them.Then with the diluted chemical compound that will test in substratum (do not have FCS, contain 0.1% bovine serum albumin), add to cell (contrast comprises the substratum that does not have test compound).After 2 hours, add reorganization VEGF at 37 ℃ of following incubations; Final VEGF concentration is 20ng/ml., after other 5 minutes cell with ice-cold PBS (phosphate buffered saline (PBS)) washed twice, is dissolved in the every hole of 100 μ L dissolving damping fluid immediately at 37 ℃ of following incubations.Then that lysate is centrifugal, to remove nucleus, utilize commercial protein determination (BIORAD) to measure the protein concn of supernatant liquor.Lysate can use then immediately, perhaps if necessary is stored under-20 ℃.

Carry out sandwich ELISA, to measure the VEGF-R2 phosphorylation: with VEGF-R2 monoclonal antibody (Mab 1495.12.14 for example; By H.Towbin, Novartis preparation, perhaps suitable monoclonal antibody) be fixed on black ELISA flat board (from the OptiPlate of Packard ^TMHTRF-96) on.Washing is dull and stereotyped then, with residual ionization protein-binding site with containing tween

(polyoxyethylene (20) Arlacel-20, ICI/Uniquema) 3%

(Juro, (PBST) is saturated for phosphate buffered saline (PBS) Cat.#TB232010).In these flat boards, there is the anti-phosphotyrosine antibody (from the PY20:AP of Zymed) of alkaline phosphatase to be incubated overnight with coupling down at 4 ℃ cell lysates (the every hole of 20 μ g protein) then.(washing is dull and stereotyped once more) uses luminous AP substrate (CDP-Star, instant, Emerald II then; Applied Biosystems) proves combining of anti-phosphotyrosine antibody and the phosphorylation acceptor of being caught.In the dull and stereotyped scintillometer of Packard TopCount trace, measure luminous.Signal difference between positive control (stimulating with VEGF) and the negative control (VEGF of no use stimulates) is equivalent to VEGF-inductive VEGF-R2 phosphorylation (=100%).The activity of confession examination material is calculated as the inhibition per-cent of VEGF-inductive VEGF-R2 phosphorylation, wherein brings out the maximum inhibiting material concentration of half and is defined as IC ₅₀(suppressing 50% inhibition dosage).Novel The compounds of this invention shows the IC of 0.0003 to 20 μ M here ₅₀, preferred 0.001 to 10 μ M.

Similar with it, the VEGF-R1 restraining effect can be as follows: use the Flt-1VEGF receptor tyrosine kinase to test.Detail operations is as follows: with solution, the 3mM manganous chloride (MnCl of 30 μ L kinases (Oncogene 5 for the kinase domain of 10ng Flt-1, people such as Shibuya, 519-24 (1990)) in 20mM Tris-HCl pH7.5 ₂), 3mM magnesium chloride (MgCl ₂), 10mM vanadic acid sodium, 0.25mg/ml polyoxyethylene glycol (PEG) 20000,1mM dithiothreitol (DTT) and 3g/ml poly-(Glu, Tyr) 4: 1 (Sigma, Buchs, Switzerland), 8 μ M[γ ³³P] the The compounds of this invention incubation 10min at room temperature together of the novelty that will test of ATP (0.2 μ Ci), 1% dimethyl sulfoxide (DMSO) and 0 to 100 μ M.Add 10 μ L 0.25M ethylenediamine tetraacetic acid (EDTA) (EDTA) pH7 termination reactions then.Utilize the hyperchannel divider (LAB SYSTEMS, USA), with 20 μ L aliquots containigs be coated in PVDF (poly-difluoroethylene) Immobilon P film (Millipore, USA) on, be connected with vacuum by Millipore microtitration filter manifold.After removing liquid fully, symphysis continued containing 0.5% phosphoric acid (H ₃PO ₄) body lotion in the washing 4 times, with washing with alcohol once, incubation 10min vibrates simultaneously, is fixed on then among the HewlettPackard TopCount Manifold, adds 10 μ L

Radioactivity is measured in (scintillation counting liquid) back.By the linear regression analysis of the inhibition per-cent of each compound under three kinds of conditions (common 0.01,0.1 and 1 μ mol), determine IC ₅₀Value.Can find the IC of novel The compounds of this invention ₅₀Value is in the scope of 0.01 to 100 μ M, preferably in the scope of 0.01 to 50 μ M.

The following mensuration of Flt-3 kinase inhibitory activity: use baculovirus donor carrier pFbacG01 (GIBCO) to generate recombinant baculovirus, the amino acid region amino acid 563-993 of its expressing human Flt-3 kytoplasm kinase domain.From the encoding sequence of human cDNA library (Clontech) by pcr amplification Flt-3 cytoplasmic structure threshold.With BamH1 and Hindlll digestion, make the dna fragmentation that is increased be suitable for being connected with the pFbacG01 carrier.The connection of these dna fragmentations causes baculovirus donor plasmids pFbacG01-Flt-3.Following the carrying out of purifying of generation, the protein expression in the Sf9 cell and the GST-fusion rotein of virus:

Virus generation: baculovirus donor plasmids (pFbacG01-Flt-3) transfection that will contain the Flt-3 kinase domain to DH10Bac clone (GIBCO), with institute's cells transfected plating on the selectivity agar plate.The colony to viral genome (being carried by bacterium) insertion fusion sequence is not blue.Pick up single white colony, by standard plasmid purifying process isolated viral DNA (rod granule) from bacterium.Use Cellfectin reagent then, Sf9 cell or Sf21 cell (American Type Culture Collection) are used the viral DNA transfection in flask.

Protein expression in the Sf9 cell: contain viral substratum from institute's cells transfected culture collection, be used for infecting, to increase its titre.Gained contained viral substratum and is used for large-scale protein expression after two-wheeled infected.With regard to large-scale protein expression, to 100cm ²Circular tissue culture plate inoculation 5 * 10 ⁷Cell/flat board, the substratum (approximately 5MOI) that contains virus with 1mL infects.After 3 days, scrape from flat board and to get cell, centrifugal 5 minutes at 500rpm.Will be from 10-20 100cm ²Dull and stereotyped cell precipitation is suspended in (25mM Tris-HClpH7.5,2mM EDTA, 1%NP40,1mM DTT, 1mM PMSF) in the ice-cold dissolving damping fluid of 50mL again.Cell was stirred on ice 15 minutes, then 5, centrifugal 20 minutes of 000rpm.

The purifying of GST-labelled protein: institute's centrifugal cell lysates is loaded onto 2mL gsh-agarose column (Pharmacia), wash 3 times with 10mL 25mM Tris-HCl pH7.5,2mM EDTA, 1mMDTT, 200mM NaCl.Then the GST-labelled protein is used 25mM Tris-HCl pH7.5,10mM reduced glutathione, 100mM NaCl, 1mM DTT, 10% glycerine wash-out 10 times (each 1mL), be stored under-70 ℃.

The measurement of enzymic activity: in the final volume of 30 μ L, utilize purifying GST-Flt-3 albumen to carry out tyrosine protein kinase and measure, wherein contain 200-1800ng zymoprotein (depending on specific activity), 20mM Tris-HCl pH7.6,3mM MnCl ₂, 3mM MgCl ₂, 1mM DTT, 10 μ MNa ₃VO ₄, 3 μ g/mL poly-(Glu, Tyr) 4: 1,1%DMSO, 8.0 μ M ATP and 0.1 μ Ci[γ ³³P] ATP.Be with or without inhibitor in the presence of, by measuring ³³P is from [γ ³³P] (measure active by Glu, Tyr) mixing of substrate to gathering for ATP.At ambient temperature, in the flat board of 96-hole, measure (30 μ L) and reach 20 minutes, add 20 μ L 125mM EDTA and stop.Subsequently, with 40 μ L reaction mixtures transfer to the Immobilon-PVDF film (Millipore, Bedford, MA, USA) on, this film soaked 5 minutes with methyl alcohol in advance, 0.5%H is used in the water flushing then ₃PO ₄Soaked 5 minutes, and be fixed on the vacuum manifold that disconnects vacuum source.On the point behind whole samples, connect vacuum, every hole is with 200 μ L 0.5%H ₃PO ₄Flushing.Remove striping, on vibrator, use 1.0%H ₃PO ₄Wash 4 times, once with washing with alcohol.Dry at ambient temperature, be fixed in the framework of Packard TopCount 96-hole, add 10 μ L/ hole Microscint ^TM(Packard) after, the counting film.By the linear regression analysis of the inhibition per-cent under 4 kinds of concentration (common 0.01,0.1,1 and 10 μ M) in duplicate of each compound, calculate IC ₅₀Value.The protein kinase activity of a unit be defined under 37 ℃ from [ ³³P] ATP shifts 1nmol to substrate protein ³³P/ minute/mg protein.Novel The compounds of this invention shows the IC between the 0.005 and 20 μ M here ₅₀Value is especially between 0.01 and 10 μ M.

Restraining effect to Flt-3 dependency Ba/F3 cell proliferation:

Depending on mutant (ITD or D835Y; Gilliland and Griffin, Blood, Vol.100, No.5,1532-42 (2002)) measure the potential of compound permeates cell membranes and performance anti-proliferative effect in the Ba/F3 cell of Flt-3 receptor kinase.

The improvement project of 96-hole form YO-PRO-1 assay method is Ba/F3 (DSMZ based on using the kinase whose wild-type IL-3-dependency of expression composing type activatory Flt-3 hematopoietic cell, Braunschweig, German) and people such as sudden change subbreed ITD-Ba/F3 or D835Y-Ba/F3[Weisberg, Cancer Cell1 (5): 433-43 (2002)].

In fresh culture, ultimate density is 3 * 10 with ITD-Flt3-or D835Y-Flt3-BaF3 cell dilution ⁵The every ml of cell is seeded in the flat board of 96-hole (1.5 * 10 with 50 μ L aliquots containigs ⁴The every hole of cell).Subsequently, add 50 μ L 2x compound solutions, make cell incubation 48h.

At first under 10 μ M, 1 μ M and 0.1 μ M concentration test compounds to the antiproliferative and the apoptosis activity of two kinds of clones, triplicate.The cell of handling (being added to ultimate density is 0.1%) with independent DMSO is served as control always.In addition, there is not assay plate blank value in the aperture of cell by convention only containing 100 μ L substratum.

For further characterizing compounds, the allied compound since 10 μ M or 3 μ M carries out ED ₅₀Measure.From these concentration, carry out progressively nine dilutions, reach the ultimate density of 2nM and 0.5nM respectively.

As described in the forefathers by the activity of YO-PRO-1 assay method assessment inhibitor [people such as Idziorek, J.Immunol.Methods; 185:249-58 (1995)].In brief, after the treatment stage of 48h, directly in 100 μ L substratum, add 25 μ L aliquots containig solution in the aperture in the flat board of 96-hole, wherein contain 100mM Trisodium Citrate pH4.0,134mM sodium-chlor and 12.5 μ M YO-PRO-1 stain (YO-PRO-1 iodide, #Y3603, Molecular Probes).This causes final stain concentration is 2.5 μ M.Then with flat board incubation 10min under the envrionment temperature in the dark.The YO-PRO-1 stain is to the following assessment of intracellular picked-up: utilize Cytofluor II 96-hole plate reader (PerSeptiveBiosystems) to carry out first and measure, be provided with as follows: excite (nm) 485/20, emission (nm) 530/25, gain 75.Behind this first reading, add 25 μ L dissolving damping fluid, form by 20mM Trisodium Citrate pH4.0,26.8mM sodium-chlor, 0.4%NP40,20mM EDTA and 20mM to every hole.At room temperature in 60min, finish cytolysis, utilize Cytofluor II 96-hole reader to carry out second and measure, measure and DNA bonded YO-PRO-1 total amount, be provided with same as described above.Utilize this assay method, novel The compounds of this invention is to the ED of two kinds of mutant subbreed performance 0.1nM to 1 μ M ₅₀Value, especially 0.1nM to 100nM.

The Tek kinase inhibitory activity can followingly carry out:

Use baculovirus donor carrier pFbacG01 to generate recombinant baculovirus, the amino acid region amino acid 773-1124 of the people Tek kytoplasm kinase domain that its expression N-end and GST merge.Excise and be connected among the pFbacG01 that digests through EcoRl by EcoRl, Tek is cloned into (FBG-Tie2/Tek) in the pFbacG01 transfer vector again.Following the carrying out of purifying of generation, the protein expression in the Sf9 cell and the GST-fusion rotein of virus:

Virus generation: the transfer vector transfection that will contain kinase domain to DH10Bac clone (GIBCO), with institute's cells transfected plating on the selectivity agar plate.The colony to viral genome (being carried by bacterium) insertion fusion sequence is not blue.Pick up single white colony, by standard plasmid purifying process isolated viral DNA (rod granule) from bacterium.Use Cellfectin reagent then, with Sf9 cell or Sf21 cell (American Type Culture Collection) at 25cm ²Use the viral DNA transfection in the flask.

Protein expression in the Sf9 cell: contain viral substratum from institute's cells transfected culture collection, be used for infecting, to increase its titre.Gained contained viral substratum and is used for large-scale protein expression after two-wheeled infected.With regard to large-scale protein expression, to 100cm ²Circular tissue culture plate inoculation 5 * 10 ⁷Cell/flat board, the substratum (approximately 5MOI) that contains virus with 1mL infects.After 3 days, scrape from flat board and to get cell, centrifugal 5 minutes at 500rpm.Will be from 10-20 100cm ²Dull and stereotyped cell precipitation is suspended in (25mM Tris-HClpH7.5,2mM EDTA, 1%NP40,1mM DTT, 1mM PMSF) in the ice-cold dissolving damping fluid of 50mL again.Cell was stirred on ice 15 minutes, then 5, centrifugal 20 minutes of 000rpm.

The purifying of GST-labelled protein: institute's centrifugal cell lysates is loaded onto 2mL gsh-agarose column (Pharmacia), wash 3 times with 10mL 25mM Tris-HCl pH7.5,2mM EDTA, 1mMDTT, 200mM NaCl.Then GST-mark Tek is used 25mM Tris-HCl pH7.5,10mM reduced glutathione, 100mM NaCl, 1mM DTT, 10% glycerine wash-out 10 times (each 1mL), be stored under-70 ℃.

Kinase assays: in the final volume of 30 μ L, utilize purifying GST-Tek albumen to carry out tyrosine protein kinase and measure, wherein contain 15mg/mL GST-Tek, 20mM Tris-HCl pH7.5,3mM MnCl ₂, 3mM MgCl ₂, 1mM DTT, 10 μ M Na ₃VO ₄, 3 μ g/mL poly-(Glu, Tyr) 4: 1,0.25mM PEG, 1%DMSO, 8.0 μ M ATP ([γ ³³P] ATP 0.1 μ Ci).Be with or without inhibitor in the presence of, by measuring ³³P is from [γ ³³P] (measure active by Glu, Tyr) 4: 1 mix to gathering for ATP.At ambient temperature, in the flat board of 96-hole, measure (30 μ L) and reach 10 minutes, add 20 μ L 125mM EDTA and stop.Subsequently, with 40 μ L reaction mixtures transfer to the Immobilon-PVDF film (Millipore, Bedford, MA, USA) on, this film soaked 5 minutes with methyl alcohol in advance, 0.5%H is used in the water flushing then ₃PO ₄Soaked 5 minutes, and be fixed on the vacuum manifold that disconnects vacuum source.On the point behind whole samples, connect vacuum, every hole is with 200 μ L0.5%H ₃PO ₄Flushing.Remove striping, on vibrator, use 1.0%H ₃PO ₄Wash 4 times, once with washing with alcohol.Dry at ambient temperature, be fixed in the framework of Packard TopCount 96-hole, add 10 μ L/ hole Microscint ^TM(Packard) after, the counting film.By the linear regression analysis of the inhibition per-cent under 4 kinds of concentration (common 0.01,0.1,1 and 10 μ M) in duplicate of each compound, calculate IC ₅₀Value.The protein kinase activity of a unit be defined under 37 ℃ from [ ³³P] ATP shifts 1nmol to substrate protein ³³P/ minute/mg protein.Novel The compounds of this invention shows the IC between the 0.001 and 5 μ M here ₅₀Value is especially between 0.01 and 0.2 μ M.

The Bcr-Abl restraining effect can be measured as follows by catching ELISA: obtaining mouse marrow progenitor with p210Bcr-Abl expression vector pGDp210Bcr/Abl (32D-bcr/abl) transfection from J Griffin is 32Dcl3 (people such as Bazzoni, J.Clin Invest.98,521-8 (1996); People such as Zhao, Blood 90,4687-9 (1997)).These cell expressings have constitutive activity abl kinases and are independent of the fusion bcr-abl albumen of the proliferate factor.Make cell at RPMI 1640 (AMIMED; Cat#1-41F01), breeding in 10% foetal calf serum, 2mM glutamine (Gibco) (perfect medium), with 2 * 10 ⁶The aliquots containig of the every bottle of cell be chilled in freezing substratum (95% foetal calf serum, in 5% dimethyl sulfoxide (DMSO) (SIGMA, D-2650)), the preparation work storing solution.After the thawing, use the cell during maximum 10-12 generation to experimentize.Use from the antibody of Upstate Biotechnology anti--ablSH3 structural domain cat.#06-466 carries out ELISA.With regard to the detection of bcr-abl phosphorylation, use anti-phosphotyrosine antibody AbPY20 (cat.#03-7722) with alkaline phosphatase (PY10 (AP)) mark from ZYMED.As a comparison and reference compound, use N-{5-[4-(4-methyl-Piperazino-methyl)-benzamido]-the 2-aminomethyl phenyl-the mesylate form (mesylate) of 4-(3-pyridyl)-2-pyrimidine-amine (STI571) (with Or Commercially available; Novartis).Preparation 10mM stock solution is stored under-20 ℃ in DMSO.With regard to raji cell assay Raji, with stock solution in two steps (1: 100 and 1: 10) be diluted in the perfect medium, obtaining initial concentration is 10 μ M, succeeded by three times of diluents of preparation series in perfect medium.Utilize this technology can not run into solubility problem.Handle similarly for the novel The compounds of this invention of examination.With regard to mensuration, in tissue culture plate at the bottom of the 96-hole circle, 200,000 32D-bcr/abl cell/50 μ L of every hole inoculation.The three times of diluents of series that add the test compound in the every hole of 50 μ L to cell, triplicate.The ultimate density of test compound is for example reduced to 0.01 μ M from 5 μ M.Use untreated cell in contrast.With compound with cell at 37 ℃, 5%CO ₂Following incubation 90min succeeded by at the centrifugal tissue culture plate of 1300rpm (Beckman GPR whizzer), carefully attracts to remove supernatant liquor, notes not removing any settled cell.Add 150 μ L dissolving damping fluid (50mM Tris/HCl pH7.4,150mM sodium-chlor, 5mM EDTA, 1mM EGTA, 1%NP-40 (non-ionic detergent, Roche Diagnostics GmbH, Mannheim, Germany), 2mM sodium orthovanadate, 1mM phenylmethylsulfonyl fluoride, 50 μ g/mL Trypsin inhibitor,Trasylols and 80 μ g/mL leupeptins) the dissolved cell precipitation, it is standby down at-20 ℃ to be used for ELISA or refrigerated storage immediately.To black ELISA flat board (PackardHTRF-96 black flat board; 6005207) be coated with anti--abl SH3 domain antibodies, under 4 ℃, spend the night with the every hole of 200ng 50 μ L PBS.The PBS (PBST) and the 0.5%TopBlock (Juro that contain 0.05% polysorbas20 with 200 μ L/ holes, Cat.#TB 232010) washing 3 times after, at room temperature the residual protein binding site is sealed 4h with 200 μ L/ hole PBST, 3%TopBlock, succeeded by 4 ℃ down be untreated or pass through the 50 μ L lysate incubation 3-4h (the every hole of 20 μ g gross proteins) of the cell of compound treatment.After washing 3 times, add PY20 (AP) that 50 μ L/ holes are diluted to 0.5 μ g/mL in the damping fluid in sealing (Zymed), (4 ℃) are incubated overnight.With regard to whole incubation step, (Costar cat.#3095) covers with dull and stereotyped sealer with flat board.At last, flat board is washed other 3 times with lavation buffer solution, with deionized water wash once, add 90 μ L/ hole AP substrate CPDStarRTU and Emerald II then.To use Packard Top Seal now ^TMThe flat board of the dull and stereotyped sealer of-A (cat.#6005185) sealing is measured the counting (CPS) of per second at room temperature dark place incubation 45min by utilizing the Packard Top Count dull and stereotyped scintillometer of trace (Top Count), quantizes luminous.With regard to the ELISA of final optimization pass version, 50 μ L growth in the tissue culture plate of 96-hole, processing and dissolved cell lysates directly are transferred to the ELISA flat board from these flat boards, the latter scribble in advance the 50ng/ hole from the rabbit polyclonal of Upstate anti--abl-SH3 structural domain AB 06-466.The concentration of anti-Tyrosine O-phosphate AB PY20 (AP) can be reduced to 0.2 μ g/ml.Washing, sealing and the same with the luminous substrate incubation.Quantize following carrying out: calculate be untreated 32D-bcr/abl cell lysates gained ELISA reading (CPS) and mensuration background (whole components, but do not contain cell lysates) difference between the reading, get and do 100%, reflected the composing type phosphorylation bcr-abl protein that is present in these cells.Compound is represented with the minimizing per-cent of bcr-abl phosphorylation the activity of bcr-alb kinase activity.By pushing away in the figure or extrapolating, measure IC from dose response curve ₅₀Value.Novel The compounds of this invention preferably shows the IC of 20nM to 200 μ M here ₅₀Value.

Novel The compounds of this invention also suppresses to participate in the protein tyrosine kinase that the signal by the nutritional factor mediation transmits, the kinases of src kinases family for example, especially for example c-Src kinases, the member of thrombocyte-deutero-somatomedin (PDGF) receptor tyrosine kinase family, for example PDGF-R, c-Kit, VEGF-R and/or FGF-R; All they all participate in animal, especially mammalian cell, the growth regulating that comprises the human cell and conversion.People such as suitable assay method such as Andrejauskas-Buchdunger, Cancer Res.52,5353-8 (1992) is described.

Therefore novel The compounds of this invention can be used for the treatment of protein kinase dependent diseases.Protein kinase dependent diseases is hyperplasia especially, preferred optimum or malignant tumour (for example kidney, liver, suprarenal gland, bladder, breast, stomach, ovary, colon, rectum, prostate gland, pancreas, lung, vagina or thyroid cancer, sarcoma, glioblastoma and a large amount of neck tumour and leukemia) especially.They can cause disappearing of tumour, prevent the formation of metastases and the growth of (little) metastatic tumor.In addition, they can be used in hyperproliferative epidermal (for example psoriasis), hyperplasia of prostate and treatment tumorigenesis, epithelial character are especially arranged, for example breast cancer.Also might use novel The compounds of this invention treatment disease of immune system, have some or discrete protein tyrosine kinase especially as long as involve; In addition, Xin Ying The compounds of this invention also can be used for the treatment of wherein involve at least a protein tyrosine kinase is arranged, especially be selected from specifically mention those the central or peripheral nervous system disease transmitted of signal.

P21ras oncogene is the main contribution factor that people's entity cancer forms and makes progress, and undergos mutation in whole human cancers of 30%.If endogenous GTP enzymic activity alleviates, can mediate the composing type growth signals to downstream effect device such as raf kinases in ras sudden change cancer cells.Suppress raf kinase signal approach and therefore can be used in the effect that suppresses active ras.Can be used as the ras inhibitor novelty The compounds of this invention thereby be particularly suitable for treating the disease that relates to ras overexpression or overactivity.

Vascular endothelial growth factor receptor-2 (VEGF-2; KDR) being expressed by selectivity on nascent blood vessel endothelium, is that normal blood vessels is grown necessary.Exceed minimum size in order to grow, tumour must generate new vascularity.Vasculogenesis or neovascularity rudiment are the core processes of entity tumor growth.With regard to a lot of cancers, the degree of tumor vesselization is a kind of negativity prognostic indicator, and indicating affecting conditions and shifting potentiality increases.Some potential treatment targets have been determined in the effort of doing for the molecular basis of understanding the vasculogenesis relevant with tumour recently, the receptor tyrosine kinase that comprises vasculogenesis sex factor vascular endothelial growth factor (VEGF) is (referring to people such as Zeng, J.Biol.Chem.276 (35), 32714-32719 (2001)).Can be used as the KDR inhibitor novelty The compounds of this invention thereby be particularly suitable for treating the disease that relates to the vegf receptor tyrosine kinase overexpression.In these diseases, what be even more important has a retinopathy, age-related macular degeneration, psoriasis, hemangioblastoma, vascular tumor, arteriosclerosis, inflammatory diseases (for example rheumatoid or rheumatic inflammatory disease, especially sacroiliitis, rheumatoid arthritis for example, perhaps other chronic inflammatory obstacles, chronic asthma for example), artery or post-transplantation atherosclerosis, endometriosis and tumor disease especially, for example so-called noumenal tumour (gi tract especially, pancreas, breast, stomach, uterine cervix, bladder, kidney, prostate gland, ovary, uterine endometrium, lung, the cancer of brain, melanoma, Kaposi, the squamous cell carcinoma of neck, malignant pleural mesothelioma (mesotherioma), lymphoma or multiple myeloma) and liquid tumors (for example leukemia).

Flt-3 (FMD-sample Tyrosylprotein kinase) is especially expressed in for generations at hematopoietic progenitor and lymphatic system and myeloid lineage.Existing document record Flt-3 gene abnormal expression sees adult and leukemia of children, comprise AML (acute myeloid leukaemia), with three being AML (AML/TMDS), ALL (acute lymphoblastic leukemia), CML (chronic myelogenous leukemia) and the myelodysplastic syndrome (MDS) of myelodysplasia, therefore they be preferred disease with novel The compounds of this invention treatment.Reactivity sudden change among the Flt-3 has seen about AML patient of 25 to 30%.Thereby, more and more evidences shows the effect of Flt-3 in human leukemia, the The compounds of this invention that can be used as the novelty of Flt-3 inhibitor especially can be used for treating such disease, and (referring to people such as Tse, Leukemia 15 (7), 1001-1010 (2001); People such as Tomoki, Cancer Chemother.Pharmacol.48 (Suppl.1), S27-S30 (2001); People such as Birkenkamp, Leukemia 15 (12), 1923-1921 (2001); People such as Kelly, Neoplasia 99 (1), 310-318 (2002)).

In chronic myelogenous leukemia (CML), mutual equilibrated chromosome translocation produces the BCR-ABL hybrid gene in the hemopoietic stem cell (HSC).Latter's carinogenicity Bcr-Abl fusion rotein of encoding.The ABL coding is subjected to the closely protein tyrosine kinase of adjusting, it is playsan essential role in regulating cell proliferation, adhesion and apoptosis, and the moulding activated kinases of BCR-ABL fusion gene code set, it transforms HSC and produces phenotype, this phenotype performance clonal expansion is lacked of proper care, is reduced with the ability reduction of bone marrow matrix adhesion with to dead response of mutagenesis stimulated cells program, and this can accumulate it gradually is that virulent transforms more.The gained granulocyte can not be grown and is sophisticated lymphocyte, is released in the circulation, causes that mature cell lacks and infection sensibility increases.The ATP-competitive inhibitor of Bcr-Abl has been described to prevent kinase activator mitogenesis and the dead approach (for example P-3 kinases and STAT5) of anti-cell program, causes the necrocytosis of BCR-ABL phenotype, thereby the therapy of effective antagonism CML is provided.Can be used as the Bcr-Abl inhibitor novelty The compounds of this invention thereby be particularly suitable for treating the disease that relates to its overexpression, especially leukemia, for example CML or ALL.

Novel The compounds of this invention also is particularly suitable for treating hyperplasia, especially small cell lung cancer, atherosclerosis, thrombosis, psoriasis, scleroderma or fibrosis in view of they activity as pdgf receptor inhibitor.

The anti-tumor in vivo activity that experimental results show that The compounds of this invention is also arranged: the active following test of anti-tumor in vivo: for example use breast cancer cell line, for example human estrin dependency breast cancer MCF-7 (ATCC:HTB22) or-75-1 (ATCC:CRL1500), perhaps estrogen-dependent breast cancer MDA-MB468 (ATCC:HTB132) or MDA-MB231 (ATCC:HTB26); Colon carcinoma cell line, for example colorectal carcinoma Colo 205 (ATCC:CCL222); Glioblastoma clone, for example glioblastoma U-87MG (ATCC:HTB14) or U-373MG (ATCC:HTB17); Lung cancer cell line, for example " small cell lung cancer " NCI-H69 (ATCC:HTB119) or NCI-H209 (ATCC:HTB172) or lung cancer NCI-H596 (ATCC:HTB178); Dermatoma clone, for example melanoma Hs294T (ATCC:HTB140) or A375 (ATCC:CRL1619); From the tumor cell line of urogenital system, for example ovarian cancer NIH-Ovcar3 (ATCC:HTB161), and prostate cancer DU145 (ATCC:HTB81) or PC-3 (ATCC:CRL1435), perhaps bladder cancer T24 (ATCC:HTB4); Epithelial cancer, for example epithelial cancer KB31; Perhaps (especially about leukemia) K562 cell (American Type Culture Collection, Mannassas, VA) or people CFU-G cell (on behalf of granular leukocyte colony, CFU-G generate unit, early stage and inevitable (commited) granulocyte generative nature precursor cell of its representative, in blood flow or marrow, circulate), they are implanted in the female or male Balb/c nude mice separately.Other clones comprise that the leukemia cell is, for example K-562, SUPB15, MEG01, Ku812F, MOLM-13, BaF3, CEM/0, JURKAT/0 or U87MG.

Behind carrier mouse (for example every kind of clone 4-8 mouse) the various cells of subcutaneous injection, (contain minimum 2 * 10 ⁶The 100mL phosphate buffered saline of cell), obtain tumour.Make the gained tumour continuously through at least three transplantations subsequently, begin then to handle.Forene anesthesia (Abbott, Switzerland) under, utilize 13-Trocar pin to animal left side side of body s.c. injection tumor fragment (each about 25mg), for transplanting.(quality is fit to medical 1.0cm test tube, and Dow Chemicals contains the 5mg estradiol, Sigma) to have the mouse of estrogen-dependent tumour to supply the oestrogenic hormon pill in addition to transplanting.In case tumour has reached 100mm ³Mean sizes, begin by convention to handle (just lower or medium tumor load).By the measuring vertical diameter, weekly, twice or three times (depending on the tumor growth of clone) and the last back 24h mensuration tumor growth of handling.Under the situation of tumour, measure gross tumor volume (referring to Evans, B.D., Smith, I.E., Shorthouse, A.J.and Millar, J.J., Brit.J.Cancer, 45:466-468,1982) according to formula L * D * p/6.Anti-tumor activity is represented as T/C% (the average increase of the gross tumor volume of process processing animal multiply by 100 divided by the average increase of control animal gross tumor volume).The minimum average B configuration gross tumor volume that mean tumour volume was compared when tumor regression rate (%) representative began with processing.Putting to death wherein, tumour reaches 1.5 to 2cm ³Each animal of above diameter.Have peripheral leukocytes number and spleen and the thymic weight of the animal of leukemia cell system, assessment leukemia load by inspection.

Exemplary (and non-limiting) dosage regimen of The compounds of this invention or its salt is administration every day, preferred every day 1 to 3 time, continues the long period, if possible until cure diseases, perhaps, then as required, continue the long as far as possible time iff for the retentivity treatment; Select as an alternative, treatment for example 5 days, and/or administration in the 1st, 4 and 9 day, do not have to repeat after the time of treatment at one section at last, also be possible.Select as an alternative, one day treatment several times (for example 2 to 5 times) or successive administration treatment (for example infusion), for example time point shown in the end also is possible.Generally speaking, administration is oral or the parenteral mode, preferred oral.Test compound preferably is diluted in water or aseptic 0.9% salt solution.

Everyone tumor cell line all is from American Type Culture Collection (ATCC, Rockville, MD., USA) obtain, other has except the indication, and cultivates (ATCC culture condition) in containing the suggestion substratum of respective additive, except other mentions.(MA USA) obtains the BALB/c3T3 cell that c-sis-and v-sis-transform for Dana Farber Cancer Institute, Boston from Dr.C.Stiles.They are to cultivate in (DMEM) at " Dulbecco modification EagleShi substratum ", and wherein being supplemented with hygromycin B or the concentration that 10% foetal calf serum and concentration are 0.2mg/mL is the G418 of 0.5mg/mL.In the DMEM that is supplemented with 10% foetal calf serum, support BALB/c AMuLVA.6R.1 cell (ATCC).

The pharmacologically active of The compounds of this invention for example can be as mentioned below in itself clinical study or test method in proved.

The clinical study that is fit to for example has the derandominzation dose escalation study of the open-label of suffering from the patient who above mentions one of tumor disease.Beneficial effect to hyperplasia can directly be determined by these results of study, perhaps changes to determine by research and design well known by persons skilled in the art.Can following definite therapeutic efficiency in this class research: for example under the situation in tumour, after 18 or 24 weeks, per 6 all radiology are estimated tumour, under leukemic situation, for example measure the quantity of abnormal white cell, with the dyeing monocyte and/or by measuring minimum remaining disease (MRD), for example by FACS-LPCMRD or PCR.

Select as an alternative, can utilize the double-blind study of placebo, to confirm the benefit of The compounds of this invention.

The Diarylurea derivatives of formula I can be as preparation as described in the WO 03/099771.Preferably as the hereinafter preparation as described in " embodiment " time of novel The compounds of this invention.

According to preferred implementation of the present invention

Following preferred embodiment in, general expression can use provided below more specifically the definition replace, thereby the invention embodiment that obtains being more preferably.

In preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is formula I ^*Compound

Wherein A, A ', n, m, p, r, X, Y ₁, Y ₂And R ₁-R ₅Have as the defined implication of following formula I compound;

Or its tautomer; Or its pharmacy acceptable salt.

In another preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is a formula I compound, wherein

A is CH, N or N → O, and A ' is N or N → O, and its condition is that to be no more than one can be N → O for A and A ';

N is 1 or 2;

M is 0,1 or 2;

P is 0,2 or 3;

R is 1 to 5;

If p is 0, X is NR, and wherein R is hydrogen or organic moiety, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together,

Its condition is if X is NH, if r＞1, each R ₄Be as defined part under the following formula I independently of one another, but not via-C (=O)-,-C (NR)-or-S (O ₂)-bridge and formula I rest part bonding, perhaps

X is CHK, and wherein K is low alkyl group or hydrogen, and p is zero,

Its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O, S or CH ₂

Y ₂Be O, S or NH;

Its condition is (Y ₁) _n-(Y ₂) _mDo not comprise O-O, S-S, NH-O, NH-S or S-O group;

Each R ₁, R ₂, R ₃And R ₅Be hydrogen or inorganic or organic moiety independently of one another, perhaps any two R ₁, R ₂And R ₃Constitute the rudimentary alkylene dioxo base bridge via the Sauerstoffatom bonding together, one of all the other of these parts are hydrogen or inorganic or organic moiety, and its condition is if G does not exist, and Z is a formula Ia group, R ₁, R ₂And R ₃Can not all be hydrogen,

Further condition is if R ₁, R ₂And R ₃One of be halogeno-group or low alkyl group-alkylsulfonyl, other two can not all be hydrogen;

R ₄Be inorganic or organic moiety, its condition is that m is 0 if n is 1, and p is 0, and r is 1, and X is NH, Y ₁Be O, G does not exist, and Z is a formula Ia group, R ₄Do not constitute picolyl, 2 hydroxy pyrimidine-4-base or 1H-2-oxo-1 with the phenyl ring that contains A and A ', 2-dihydropyridine-4-base; And

G and Z have as implication given under the following formula I;

Or its tautomer; Or its pharmacy acceptable salt.

In further preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is formula I ^*Compound, wherein

A is CH, N or N → O, and A ' is N or N → O, and its condition is that to be no more than one can be N → O for A and A ';

N is 1;

M is 0;

P is 0,2 or 3;

R is 1;

If p is 0, X is NR, and wherein R is hydrogen or low alkyl group, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CH ₂, p is zero,

Its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O or CH ₂

Each R ₁, R ₂And R ₃Be hydrogen independently of one another; Low alkyl group; Halogeno-group, especially bromine or chlorine; Halo-low alkyl group, especially trifluoromethyl; Lower alkoxy, especially methoxyl group; Halo-lower alkoxy, especially 2,2, the 2-trifluoro ethoxy; Phenyl; Piperidyl, especially piperidines-1-base; Piperazinyl, especially piperazine-1-base; Morpholinyl, especially morpholine; The parathiazan base, especially parathiazan is for base, perhaps any two rudimentary alkylene dioxo base bridges that constitute together via the Sauerstoffatom bonding, one of all the other of these parts are one of hydrogen or described part, its condition is R ₁, R ₂And R ₃Can not all be hydrogen, further condition be if R ₁, R ₂And R ₃One of be halogeno-group, other two can not all be hydrogen;

R ₄Be lower alkoxy, methoxyl group especially; Lower alkyl amido, especially kharophen; Hydroxy phenyl amino, especially p-hydroxy phenyl amino; Amino-lower alkoxy-phenyl amino, especially 4-[(2-amino-ethyl) oxygen base phenyl]-amino; Sulfamyl phenyl amino, especially 4-sulfamyl phenyl amino; Carbamyl phenyl amino, especially 4-carbamyl phenyl amino; [N-(hydroxy lower alkyl)-carbamyl]-phenyl amino, especially [N-(2-hydroxyethyl)-carbamyl]-phenyl amino; Perhaps halogeno-group, especially chlorine; And

R ₅Be hydrogen, low alkyl group or halogeno-group, especially hydrogen;

Or its tautomer; Or its pharmacy acceptable salt.

In further especially preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is a formula I compound, wherein

G does not exist, or low-grade alkylidene, especially methylene radical or ethylidene, or C ₃-C ₅Cycloalkylidene, cyclopropylidene especially, Z is a formula Ia group, perhaps

G does not exist, and Z is a formula Ib group;

A is CH or N, and A ' is N or N → O;

N is 1;

M is 0 or 1;

P is 0,2 or 3;

R is 0 or 1;

If p is 0, X is NR, and wherein R is hydrogen or low alkyl group, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CHK, and wherein K is a hydrogen, and p is zero,

Its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O, S or CH ₂

Y ₂Be O;

Its condition is (Y ₁) _n-(Y ₂) _mDo not comprise O-O or S-O group;

Each R ₁, R ₂And R ₃Be hydrogen independently of one another; Low alkyl group, especially methyl, ethyl, n-propyl, sec.-propyl or the tertiary butyl; Low-grade alkenyl, especially pseudoallyl; Hydroxy lower alkyl, especially hydroxyl-propyl group; Lower alkoxy, especially methoxyl group; Halogeno-group, especially chlorine or bromine; Halo-low alkyl group, especially trifluoromethyl; Halo-lower alkoxy, especially trifluoromethoxy or trifluoro ethoxy; Amino-low alkyl group, especially aminomethyl; Amino-lower alkoxy, especially amino ethoxy; Two-low alkyl group-amino, especially diethylin; Hydroxy lower alkyl-amino, especially hydroxyl-propyl group amino; Two-(lower alkoxy-low alkyl group)-amino, especially two-(2-methoxyl group-ethyl)-amino; Two-low alkyl group-amino-low alkyl group, especially dimethylamino methyl; Phenyl; Morpholinyl, especially morpholine-4-base; Piperidyl, especially piperidines-1-base; Piperidyl-low alkyl group, especially piperidines-1-ylmethyl; Low alkyl group-piperazinyl, especially 4-methylpiperazine-1-base or 4-ethyl piperazidine-1-base; Low alkyl group-piperazinyl-low alkyl group, especially 4-methylpiperazine-1-ylmethyl or 4-ethyl piperazidine-1-ylmethyl; Pyridyl, especially pyridine-2-base; Perhaps low alkyl group-imidazolyl, especially 2-or 4-methylimidazole-1-base;

If r is 1, R ₄Be low alkyl group, especially methyl, ethyl or sec.-propyl; Hydroxyl; Aminocarboxyl; Low alkyl group-carbonyl, especially methyl carbonyl; Cyclohexyl; Halogeno-group, especially chlorine or fluorine; Halo-low alkyl group, especially trifluoromethyl; Lower alkoxy, especially methoxyl group; Amino; Low alkyl group-amino, especially methylamino-, ethylamino, isopropylamino or uncle's fourth amino; Two-low alkyl group-amino, especially dimethylamino; Low-grade alkenyl-amino, especially third-2-alkenyl amino or fourth-3-alkenyl amino; Low alkyl group-carbonyl-amino, especially methyl carbon acylamino; Cyano group; Azido-; Hydroxyl-phenyl-amino, especially 3-or 4-hydroxyl-phenyl-amino; List or tri-lower alkoxy-phenyl-amino, especially methoxyl group-phenyl-amino or trimethoxy-phenyl-amino; Lower alkoxy-halo-phenyl-amino, especially methoxyl group-fluoro-phenyl-amino; Phenyl-low-grade alkyl amino, especially benzyl amino; (single or two-lower alkoxy)-phenyl-low-grade alkyl amino, especially methoxyl group-benzyl amino or dimethoxy-benzyl amino; Amino-sulfonyl-phenyl-low-grade alkyl amino, especially amino-sulfonyl-benzyl amino; Amino-lower alkoxy-phenyl-amino, especially amino ethoxy-phenyl-amino; Low alkyl group-amino-alkylsulfonyl-low alkyl group-phenyl amino, especially methylamino--alkylsulfonyl methyl-phenyl amino; Low alkyl group-piperazinyl-low-grade alkyl amino, especially 4-methylpiperazine-1-base-third amino; Morpholinyl-low-grade alkyl amino, especially morpholine-4-base-third amino; Low alkyl group-piperidyl-amino, especially 1-methyl piperidine-4-base is amino; Tetrazyl, especially 1H-tetrazolium-5-base; Low alkyl group-tetrazyl, especially low alkyl group-tetrazolium-5-base, for example 1-methyl isophthalic acid H-tetrazolium-5-base or 2-methyl-2H-tetrazolium-5-base; Perhaps (two-low alkyl group)-amino-low alkyl group-tetrazyl, especially (two-low alkyl group)-amino-low alkyl group-tetrazolium-5-base, for example 2-(3-dimethylamino-propyl)-2H-tetrazolium-5-base; And

R ₅Most preferably be hydrogen; Or low alkyl group, especially methyl; Perhaps halogeno-group, especially chlorine; Or its tautomer; Or its pharmacy acceptable salt.

In the especially preferred embodiment of another kind, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is a formula I compound, wherein

A and A ' are N, and n is 1, and m is 0, and p is 0 or 2, and r is 1, if p is 0, X is NH, if perhaps p is 2, X is a nitrogen, it and (CH ₂) ₂And the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring, Y together ₁Be O, G does not exist, and Z is a formula Ia group, R ₁, R ₂And R ₃Have at least one to be alkaline organic moiety, R ₄Be amino or low-grade alkyl amino, R ₅Be hydrogen;

Or its tautomer; Or its pharmacy acceptable salt.

In another preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is formula I ^*Compound, wherein

A is CH, N or N → O, and A ' is N or N → O, and its condition is that to be no more than one can be N → O for A and A ';

N is 1;

M is 0;

P is 0,2 or 3;

R is 0,1 or 2;

If p is 0, X is NR, and wherein R is hydrogen or low alkyl group, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CH ₂, p is zero,

Its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O or CH ₂

Each R ₁, R ₂And R ₃Be hydrogen independently of one another; Low alkyl group; Halogeno-group, especially bromine or chlorine; Halo-low alkyl group, especially trifluoromethyl; Lower alkoxy, especially methoxyl group; Halo-lower alkoxy, especially 2,2, the 2-trifluoro ethoxy; Phenyl; Piperidyl, especially piperidines-1-base; Piperazinyl, especially piperazine-1-base; Morpholinyl, especially morpholine; The parathiazan base, especially parathiazan is for base, perhaps any two rudimentary alkylene dioxo base bridges that constitute together via the Sauerstoffatom bonding, one of all the other of these parts are one of hydrogen or described part;

If r is not zero, R ₄Be low alkyl group, especially methyl or ethyl; Lower alkoxy, especially methoxyl group; Lower alkyl amido, especially kharophen; Hydroxy phenyl amino, especially p-hydroxy phenyl amino; Amino-lower alkoxyphenyl-amino, especially 4-[(2-amino-ethyl) oxygen base phenyl]-amino; Sulfamyl phenyl amino, especially 4-sulfamyl phenyl amino; Carbamyl phenyl amino, especially 4-carbamyl phenyl amino; [N-(hydroxy lower alkyl)-carbamyl]-phenyl amino, especially [N-(2-hydroxyethyl)-carbamyl]-phenyl amino; Halogeno-group, especially chlorine; Perhaps hydroxyl; And

R ₅Be hydrogen, low alkyl group or halogeno-group, especially hydrogen;

Or its tautomer; Or its pharmacy acceptable salt.

In the especially preferred embodiment of another kind, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is a formula I compound, wherein

G does not exist, or low-grade alkylidene, especially methylene radical or ethylidene, or C ₃-C ₅Cycloalkylidene, cyclopropylidene especially, Z is a formula Ia group, perhaps

G does not exist, and Z is a formula Ib group;

A is CH or N, and A ' is N or N → O;

N is 1;

M is 0 or 1;

P is 0,2 or 3;

R is 1;

If p is 0, X is NR, and wherein R is hydrogen or low alkyl group, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CHK, and wherein K is a hydrogen, and p is zero,

Its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O, S or CH ₂

Y ₂Be O;

Its condition is (Y ₁) _n-(Y ₂) _mDo not comprise O-O or S-O group;

Each R ₁, R ₂And R ₃Be hydrogen independently of one another; Low alkyl group, especially methyl, ethyl, n-propyl, sec.-propyl or the tertiary butyl; Low-grade alkenyl, especially pseudoallyl; Hydroxy lower alkyl, especially hydroxyl-propyl group; Lower alkoxy, especially methoxyl group; Halogeno-group, especially chlorine or bromine; Halo-low alkyl group, especially trifluoromethyl; Halo-lower alkoxy, especially trifluoromethoxy or trifluoro ethoxy; Amino-low alkyl group, especially aminomethyl; Amino-lower alkoxy, especially amino ethoxy; Two-low alkyl group-amino, especially diethylin; Hydroxy lower alkyl-amino, especially hydroxyl-propyl group amino; Two-(lower alkoxy-low alkyl group)-amino, especially two-(2-methoxyl group-ethyl)-amino; Two-low alkyl group-amino-low alkyl group, especially dimethylamino methyl; Phenyl; Morpholinyl, especially morpholine-4-base; Piperidyl, especially piperidines-1-base; Piperidyl-low alkyl group, especially piperidines-1-ylmethyl; Low alkyl group-piperazinyl, especially 4-methylpiperazine-1-base or 4-ethyl piperazidine-1-base; Low alkyl group-piperazinyl-low alkyl group, especially 4-methylpiperazine-1-ylmethyl or 4-ethyl piperazidine-1-ylmethyl; Pyridyl, especially pyridine-2-base; Perhaps low alkyl group-imidazolyl, 2-or 4-methylimidazole-1-base especially, its condition is if G does not exist, Z is a formula Ia group, R ₁, R ₂And R ₃Can not all be hydrogen, further condition be if R ₁, R ₂And R ₃One of be halogeno-group, other two can not all be hydrogen;

R ₄Be low alkyl group, especially methyl, ethyl or sec.-propyl; Hydroxyl; Aminocarboxyl; Low alkyl group-carbonyl, especially methyl carbonyl; Cyclohexyl; Halogeno-group, especially chlorine or fluorine; Halo-low alkyl group, especially trifluoromethyl; Lower alkoxy, especially methoxyl group; Amino; Low alkyl group-amino, especially methylamino-, ethylamino, isopropylamino or uncle's fourth amino; Two-low alkyl group-amino, especially dimethylamino; Low-grade alkenyl-amino, especially third-2-alkenyl amino or fourth-3-alkenyl amino; Low alkyl group-carbonyl-amino, especially methyl carbon acylamino; Cyano group; Azido-; Hydroxyl-phenyl-amino, especially 3-or 4-hydroxyl-phenyl-amino; List or tri-lower alkoxy-phenyl-amino, especially methoxyl group-phenyl-amino or trimethoxy-phenyl-amino; Lower alkoxy-halo-phenyl-amino, especially methoxyl group-fluoro-phenyl-amino; Phenyl-low-grade alkyl amino, especially benzyl amino; (single or two-lower alkoxy)-phenyl-low-grade alkyl amino, especially methoxyl group-benzyl amino or dimethoxy-benzyl amino; Amino-sulfonyl-phenyl-low-grade alkyl amino, especially amino-sulfonyl-benzyl amino; Amino-lower alkoxy-phenyl-amino, especially amino ethoxy-phenyl-amino; Low alkyl group-amino-alkylsulfonyl-low alkyl group-phenyl amino, especially methylamino--alkylsulfonyl methyl-phenyl amino; Low alkyl group-piperazinyl-low-grade alkyl amino, especially 4-methylpiperazine-1-base-third amino; Morpholinyl-low-grade alkyl amino, especially morpholine-4-base-third amino; Low alkyl group-piperidyl-amino, especially 1-methyl piperidine-4-base is amino; Tetrazyl, especially 1H-tetrazolium-5-base; Low alkyl group-tetrazyl, especially low alkyl group-tetrazolium-5-base, for example 1-methyl isophthalic acid H-tetrazolium-5-base or 2-methyl-2H-tetrazolium-5-base; Perhaps (two-low alkyl group)-amino-low alkyl group-tetrazyl, (two-low alkyl group)-amino-low alkyl group-tetrazolium-5-base especially, 2-(3-dimethylamino-propyl)-2H-tetrazolium-5-base for example, its condition is if X is NH, R ₄Be not aminocarboxyl or low alkyl group-carbonyl, further condition is that m is 0 if n is 1, and p is 0, and r is 1, and X is NH, Y ₁Be O, G does not exist, and Z is a formula Ia group, R ₄Do not constitute picolyl, 2 hydroxy pyrimidine-4-base or 1H-2-oxo-1 with the phenyl ring that contains A and A ', 2-dihydropyridine-4-base;

R ₅Most preferably be hydrogen; Or low alkyl group, especially methyl; Perhaps halogeno-group, especially chlorine; Or its tautomer; Or its pharmacy acceptable salt.

In further highly preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is a formula I compound, wherein

A and A ' are N, and n is 1, and m is 0, and p is 0 or 2, and r is 1, if p is 0, X is NH, if perhaps p is 2, X is a nitrogen, it and (CH ₂) ₂And the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring, Y together ₁Be O, G does not exist, and Z is a formula Ia group, R ₁, R ₂And R ₃Have at least one to be alkaline organic moiety, R ₄Be amino or low-grade alkyl amino, R ₅Be hydrogen;

Or its tautomer; Or its pharmacy acceptable salt.

In further highly preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is formula I ^*Compound, wherein

A, A ', n, m, p, Y ₁, Y ₂, R ₁, R ₂, R ₃And R ₄Has following formula I ^*The implication that provides down, r is 1 to 5, and if p is 0, X is NR, and wherein R is hydrogen or organic moiety, and if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) ₂And the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CH ₂, p is zero;

If p is zero, the key of dotted line representative does not exist;

Its condition is if X is NH, each R ₄If present, be as following formula I independently of one another ^*Following defined part, but not via-C (=O)-,-C (NR)-or-S (O ₂)-bridge and formula I ^*The rest part bonding, substituent R ₁, R ₂And R ₃Be selected from following part, wherein with respect to this ring and formula I ^*The molecule rest part (indicate each position (o=ortho position, position between m=, p=contraposition) via the position of NH-C (=O)-X-part) bonding:

If have only R ₁Be not hydrogen:

R ₁=p-low alkyl group, especially p-methyl, p-ethyl, p-n-propyl;

M-halo-low alkyl group, especially m-trifluoromethyl; Perhaps

Phenyl, p-piperidines-1-base and p-piperazine-1-base;

If R ₁And R ₂Be not hydrogen:

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-halogeno-group, especially p-bromine;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-halo-lower alkoxy, especially p-(2,2, the 2-trifluoro ethoxy);

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=m-lower alkoxy, especially m-methoxyl group;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-phenyl;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-piperidines-1-base or p-piperazine-1-base;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-N-morpholino base or p-N-parathiazan are for base;

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-halogeno-group, especially p-bromine (less preferred);

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-halo-lower alkoxy, p-2 especially, 2,2-trifluoro ethoxy;

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-phenyl; Perhaps

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-piperidines-1-base or p-piperazine-1-base; If perhaps R ₁, R ₂And R ₃Be not hydrogen:

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=m-lower alkoxy, m-methoxyl group especially, R ₃=p-lower alkoxy, especially p-methoxyl group; Perhaps

R ₁=lower alkoxy, methoxyl group especially, R ₂And R ₃Constitute rudimentary alkylene dioxo base together, especially-O-CH ₂-CH ₂-O-bridge;

R ₅Be hydrogen, low alkyl group or halogeno-group, especially hydrogen;

Its condition is that m is 0 if n is 1, and p is 0, and r is 1, and X is NH and Y ₁Be O, R ₄Do not constitute picolyl, 2 hydroxy pyrimidine-4-base or 1H-2-oxo-1 with the phenyl ring that contains A and A ', 2-dihydropyridine-4-base;

Or its tautomer; Or its pharmacy acceptable salt.

In further especially preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is formula I ^*Compound, wherein

A is CH, N or N → O, and A ' is N or N → O, and its condition is that to be no more than one can be N → O for A and A ';

N is 1;

M is 0;

P is 0,2 or 3;

R is 1 or 2;

If p is 0, X is NR, and wherein R is hydrogen or low alkyl group, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CH ₂, p is zero,

Its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O or CH ₂

R ₁, R ₂And R ₃Be selected from following part, wherein with respect to this ring and formula I ^*The molecule rest part (is indicated each position (o=ortho position, position between m=, p=contraposition) via the position of NH-C (=O)-X-part) bonding: if having only R ₁Be not hydrogen:

R ₁=p-low alkyl group, especially p-methyl, p-ethyl, p-n-propyl;

M-halo-low alkyl group, especially m-trifluoromethyl; Perhaps

Phenyl, p-piperidines-1-base and p-piperazine-1-base;

If R ₁And R ₂Be not hydrogen:

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-halogeno-group, especially p-bromine;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-halo-lower alkoxy, especially p-(2,2, the 2-trifluoro ethoxy);

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=m-lower alkoxy, especially m-methoxyl group;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-phenyl;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-piperidines-1-base or p-piperazine-1-base;

R ₁=m-halo-low alkyl group, m-trifluoromethyl especially, R ₂=p-N-morpholino base or p-N-parathiazan are for base;

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-halogeno-group, especially p-bromine (less preferred);

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-halo-lower alkoxy, p-2 especially, 2,2-trifluoro ethoxy;

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-phenyl; Perhaps

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=p-piperidines-1-base or p-piperazine-1-base; If perhaps R ₁, R ₂And R ₃Be not hydrogen:

R ₁=m-lower alkoxy, m-methoxyl group especially, R ₂=m-lower alkoxy, m-methoxyl group especially, R ₃=p-lower alkoxy, especially p-methoxyl group; Perhaps

R ₁=lower alkoxy, methoxyl group especially, R ₂And R ₃Constitute rudimentary alkylene dioxo base together, especially-O-CH ₂-CH ₂-O-bridge;

If r is not zero, R ₄Be lower alkoxy, methoxyl group especially; Lower alkyl amido, especially kharophen; Hydroxy phenyl amino, especially p-hydroxy phenyl amino; Amino-lower alkoxyphenyl-amino, especially 4-[(2-amino-ethyl) oxygen base phenyl]-amino; Sulfamyl phenyl amino, especially 4-sulfamyl phenyl amino; Carbamyl phenyl amino, especially 4-carbamyl phenyl amino; [N-(hydroxy lower alkyl)-carbamyl]-phenyl amino, especially [N-(2-hydroxyethyl)-carbamyl]-phenyl amino; Perhaps halogeno-group, especially chlorine;

R ₅Be halogeno-group, chlorine especially; Low alkyl group, especially methyl; Perhaps preferred hydrogen; Or its tautomer; Or its pharmacy acceptable salt.

In another kind of highly preferred embodiment, the present invention relates to Diarylurea derivatives and be used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation, wherein this Diarylurea derivatives is formula I compound or its pharmaceutically acceptable salt that is selected from WO 03/099771 embodiment.

Most preferably, the present invention relates to novel The compounds of this invention or its pharmaceutically acceptable salt.

The purposes of Xin Ying The compounds of this invention or its pharmacy acceptable salt further preferably, wherein the protein kinase dependent diseases that will treat is the protein tyrosine kinase dependence disease, especially hyperplasia (preferred optimum or especially malignant tumour), especially depend on the disease of any one or multiple following protein kinase: c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R, Tek, PDGF-R, FGF-R, IGF-IR, Eph acceptor (especially for example EphB4 acceptor), c-Kit, Met, c-Src, Raf and/or ras, especially c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R and/or Tek, the most especially Flt-3.

Pharmaceutical composition

The present invention also relates in particular to the pharmaceutical composition that comprises novel The compounds of this invention; Relate to novel The compounds of this invention in therapeutic (in the present invention is more aspect the generalized and the preventative) purposes of treatment (especially tyrosine) protein kinase dependent diseases or the method for treatment (especially tyrosine) protein kinase dependent diseases, preferred disease especially mentioned above; The The compounds of this invention and the preparation of drug combination that is particularly useful for described purposes that relate to the novelty that is used for described purposes.

The present invention also relates to the prodrug of novel The compounds of this invention, be converted into novel The compounds of this invention itself in their bodies.Therefore the appellation of any The compounds of this invention to novelty is understood that also to represent the corresponding prodrug of novel The compounds of this invention, as long as suitably and suitable.

The compounds of this invention can be used for preparation example such as pharmaceutical composition, wherein comprise the formula I compound of pharmacy effective dose or its pharmacy acceptable salt as activeconstituents, and or be mixed with that one or more of significant quantity are inorganic or organic, the pharmaceutical acceptable carrier of solid or liquid.

The present invention also relates to pharmaceutical composition, it is suitable for the warm-blooded animal administration, especially human (perhaps from warm-blooded animal, especially human deutero-cell or clone, lymphocyte for example), be used for the treatment of or in more broad aspect of the present invention prevention (antagonism) in response to protein kinase activity, especially the disease that suppresses of protein tyrosine kinase activity, especially above about the purposes of the The compounds of this invention of novelty as one of disease of preferably mentioning, it is The compounds of this invention or its pharmacy acceptable salt of effective a certain amount of novelty that described composition comprises with regard to described restraining effect, and at least a pharmaceutically acceptable carrier.

Pharmaceutical composition according to the present invention is that enterally administering such as nose, rectum or oral or administered parenterally such as intramuscular or intravenously are to warm-blooded animal (especially human) administration, it comprises the pharmacological component of effective dose, independent or and the pharmaceutically acceptable carrier of significant quantity.The dosage of activeconstituents depends on the mode of kind, body weight, age and the individual condition of warm-blooded animal, individual pharmacokinetic data available, the disease that will treat and administration.

The present invention also relates to disease that treatment suppresses in response to (especially tyrosine) protein kinase, especially above about the purposes of the The compounds of this invention of novelty method as one of disease of preferably mentioning, described method comprise preventative or especially therapeutic give the The compounds of this invention of the novelty of (resisting described disease) significant quantity, especially to need warm-blooded animal, for example people administration of this class treatment owing to one of described disease.

Formula I compound or its pharmacy acceptable salt to the people's of warm-blooded animal, the about 70kg of for example body weight dosage preferably from about 3mg to about 30g, more preferably approximately 10mg to about 1.5g, most preferably from about 100mg to about 1000mg for each person every day, preferably being divided into for example can be 1 to 3 single dose of identical size.Usually, children's half of dosage of accepting to be grown up.

Pharmaceutical composition comprises about 1% to about 95%, preferably approximately 20% activeconstituents to about 90%.According to pharmaceutical composition of the present invention for example can be unit dosage form, for example ampoule, bottle, suppository, drageeing, tablet or capsular form.

Pharmaceutical composition of the present invention prepares according to known mode itself, for example by dissolving, freeze-drying, mixing, granulation or the moulding process of routine.

The solution of activeconstituents and suspension, the especially isoosmotic aqueous solution or suspension are a kind of preferred types of service, for example comprise independent activeconstituents or and the situation of the lyophilised compositions of carrier such as mannitol under, might make this class solution or suspension before use.Pharmaceutical composition can be sterilized and/or can be comprised vehicle, the for example salt and/or the buffer reagent of sanitas, stablizer, moistening and/or emulsifying agent, solubilizing agent, adjusting osmotic pressure, prepare according to known mode itself, for example by the dissolving or the freeze-drying process of routine.Described solution or suspension can comprise viscosity increases material, for example Xylo-Mucine, carboxymethyl cellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspension in the oil comprises the vegetalitas that is customarily used in the injection purpose, synthetic or semi-synthetic oil as oil ingredient.Especially can mention the liquid aliphatic acid esters, wherein contain have 8 to 22, especially the longer chain fatty acid of 12 to 22 carbon atoms is as acid constituents, for example lauric acid, tridecanoic acid, tetradecanoic acid, pentadecylic acid, palmitinic acid, margaric acid, stearic acid, eicosanoic acid, docosoic or corresponding unsaturated acid, for example oleic acid, elaidic acid, erucic acid, brasidic acid or linolic acid, add antioxidant if necessary, for example vitamin-E, β-Hu Luobusu or 3,5-two-tertiary butyl-4-hydroxy toluene.The alkoxide component of these fatty acid esters has maximum 6 carbon atoms, and is single-or many-hydroxyl, for example single-, two-or three-hydroxyl alcohol, for example methyl alcohol, ethanol, propyl alcohol, butanols or amylalcohol or their isomer, still especially glycol and glycerine.Therefore mention the example of following fatty acid ester: oleic acid ethyl ester, tetradecanoic acid isopropyl esters, palmitinic acid isopropyl esters, " Labrafil M 2375 " (the polyoxyethylene triolein, Gattefosse, Paris), " Miglyol 812 " (chain length C ₈To C ₁₂The triglyceride level of saturated fatty acid, Huls AG, Germany), but especially vegetables oil, for example Oleum Gossypii semen, Prunus amygdalus oil, sweet oil, Viscotrol C, sesame oil, soybean oil, more specifically peanut oil.

Injectable composition is to prepare under aseptic condition according to ways customary; This also is applicable to ampoule or bottle introduces composition and sealed vessel.

The oral administration pharmaceutical composition can followingly obtain: merge activeconstituents and solid carrier, if necessary with the gained granulating mixture, if desired or necessary, after adding appropriate excipients, mixture is processed into tablet, drageeing core or capsule.Also they might be incorporated in the plasticity carrier that allows metering diffusion or release of active ingredients.

The carrier that is fit to is weighting agent, for example carbohydrate, for example lactose, sucrose, mannitol or Sorbitol Powder especially; The phosphoric acid salt of cellulosics and/or calcium, for example tricalcium phosphate or secondary calcium phosphate; And tackiness agent, for example starch paste for example adopts corn, wheat, paddy rice or yam starch, gelatin, tragacanth gum, methylcellulose gum, Vltra tears, Xylo-Mucine and/or polyvinylpyrrolidone; And/or if necessary, disintegrating agent, for example above-mentioned starch and/or carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or its salt, for example sodiun alginate.Vehicle is flowing regulator and lubricant especially, for example silicic acid, talcum, stearic acid or its salt, for example Magnesium Stearate or calcium, and/or polyoxyethylene glycol.The drageeing core has dressing suitable, optional enteric solubility, especially use priming, wherein can comprise gum arabic, talcum, polyvinylpyrrolidone, polyoxyethylene glycol and/or titanium dioxide, the perhaps dressing solution in being fit to organic solvent, perhaps with regard to the enteric coating preparation, use the solution of the cellulosics that is fit to, for example ethyl cellulose phthalic ester or hydroxypropylmethylcellulose phthalate.

Capsule is the dry-packing capsule made by gelatin and the soft seal capsule made by gelatin and softening agent such as glycerine or Sorbitol Powder.The capsule of dry-packing can comprise the particle form of activeconstituents, for example and weighting agent, for example lactose; Tackiness agent, for example starch, and/or glidant, for example talcum or Magnesium Stearate also have stablizer if necessary.In soft capsule, activeconstituents preferably is dissolved or suspended in the suitable oiliness vehicle, and for example fatty oil, paraffin oil or liquid macrogol also might add stablizer and/or antiseptic-germicide.Can be to tablet or drageeing dressing or capsule shell adding stain or pigment, for example for the various dose of distinguishing purpose or indication activeconstituents.

Formula I compound, especially novel The compounds of this invention also can be advantageously used in and other antiproliferative combinations.This class antiproliferative includes but not limited to aromatization enzyme inhibitor, estrogen antagonist, the topoisomerase I inhibitor, the topoisomerase II inhibitor, microtubule active agent, alkylating agent, inhibitors of histone deacetylase, farnesyl tranfering enzyme inhibitor, cox 2 inhibitor, the MMP inhibitor, the mTOR inhibitor, the neoplasia resisting metabolic antagonist, platinic compound, reduce the compound and further anti-angiogenic compounds of protein kinase activity, the GnRF agonist, androgen antagonist, bengamide, bis-phosphonic acids compounds, steroid, anti proliferative antibody, 17-(allyl amino)-17-de-methoxy geldanamycin (17-AAG) and Temozolomide (

).

Term used herein " aromatization enzyme inhibitor " relates to and suppresses estrogen production, the compound that transforms to oestrone and estradiol respectively of substrate Androstenedione and testosterone just.This term includes but not limited to steroid, especially Exemestane and formestane, and particularly on-steroidal, especially aminoglutethimide, R 83842, fadrozole, Anastrozole, very especially letrozole.Exemestane for example can be with its commercial form administration, and for example trade mark is AROMASIN ^TMFormestane for example can be with its commercial form administration, and for example trade mark is LENTARON ^TMFadrozole for example can be with its commercial form administration, and for example trade mark is AFEMA ^TMAnastrozole for example can be with its commercial form administration, and for example trade mark is ARIMIDEX ^TMLetrozole for example can be with its commercial form administration, and for example trade mark is FEMARA ^TMOr FEMAR ^TMAminoglutethimide for example can be with its commercial form administration, and for example trade mark is ORIMETEN ^TM

Comprise aromatization enzyme inhibitor and be particularly useful for treating the hormone receptor positive breast tumor as the present invention of neoplasia resisting agent combination.

Term used herein " estrogen antagonist " relates to the compound of antagonism estrogen effect on the estrogen receptor level.This term includes but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.Tamoxifen for example can be with its commercial form administration, and for example trade mark is NOLVADEX ^TMRALOXIFENE HCL for example can be with its commercial form administration, and for example trade mark is EVISTA ^TMFulvestrant can be as US 4,659, and 516 described preparations perhaps for example can be with its commercial form administration, and for example trade mark is FASLODEX ^TM

Term used herein " topoisomerase I inhibitor " includes but not limited to topotecan, irinotecan, 9-nitrocamptothecin and macromole camptothecine conjugate PNU-166148 (compd A 1 among the WO 99/17804).Irinotecan for example can be with its commercial form administration, and for example trade mark is CAMPTOSAR ^TMTopotecan for example can be with its commercial form administration, and for example trade mark is HYCAMTIN ^TM

Term used herein " topoisomerase II inhibitor " includes but not limited to that anthracyclines (antracycline) Zorubicin (comprises Liposomal formulation, for example CAELYX ^TM), epirubicin, idarubicin and Nai Mo be than star (nemorubin), anthraquinone class mitoxantrone and losoxantrone and podophillotoxines Etoposide and teniposide.Etoposide for example can be with its commercial form administration, and for example trade mark is ETOPOPHOS ^TMTeniposide for example can be with its commercial form administration, and for example trade mark is VM 26-BRISTOL ^TMZorubicin for example can be with its commercial form administration, and for example trade mark is ADRIBLASTIN ^TMEpirubicin for example can be with its commercial form administration, and for example trade mark is FARMORUBICIN ^TMIdarubicin for example can be with its commercial form administration, and for example trade mark is ZAVEDOS ^TMMitoxantrone for example can be with its commercial form administration, and for example trade mark is NOVANTRON ^TM

Term " microtubule active agent " relates to microtubule stabilization and the agent of microtubule stabilization removal, include but not limited to taxanes safe plain (paclitaxel) and docetaxel (docetaxel), catharanthus alkaloid, vinealeucoblastine(VLB) for example, Vinblastine sulphate especially, vincristine(VCR), especially vincristine sulphate, and vinorelbine, discodermolide (discodermolide) and esperamicin (epothilone), for example epothilone B and D.Docetaxel for example can be with its commercial form administration, and for example trade mark is TAXOTERE ^TMVinblastine sulphate for example can be with its commercial form administration, and for example trade mark is VINBLASTIN R.P. ^TMVincristine sulphate for example can be with its commercial form administration, and for example trade mark is FARMISTIN ^TMDiscodermolide for example can be as US 5,010,099 described obtaining.

Term used herein " alkylating agent " includes but not limited to endoxan, ifosfamide and melphalan.Endoxan for example can be with its commercial form administration, and for example trade mark is CYCLOSTIN ^TMIfosfamide for example can be with its commercial form administration, and for example trade mark is HOLOXAN ^TM

Term " inhibitors of histone deacetylase " relates to the inhibition of histone deacetylase and possesses the compound of antiproliferative activity.This comprises WO 02/22577 disclosed compound, especially N-hydroxyl-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and its pharmacy acceptable salt.Further especially comprise Vorinostat (SAHA).

Term " farnesyl tranfering enzyme inhibitor " relates to the compound that suppresses farnesyl tranfering enzyme and possess antiproliferative activity.

Term " cox 2 inhibitor " relates to the compound that suppresses cyclo-oxygenase 2 type enzymes (COX-2) and possess antiproliferative activity, for example celecoxib (

), Lip river cloth of fragrant former times (

) and Rumi draw and examine former times (COX189).

Term " MMP inhibitor " relates to the compound that suppresses matrix metalloproteinase (MMP) and possess antiproliferative activity.

Term " mTOR inhibitor " relates to the compound that suppresses Mammals rapamycin target (mTOR) and possess antiproliferative activity, for example sirolimus ( ), everolimus (Certican ^TM), CCI-779 and ABT578.

Term " neoplasia resisting antimetabolic product " includes but not limited to the salt of 5 FU 5 fluorouracil, Tegafur, capecitabine, CldAdo, cytosine arabinoside, fludarabine phosphate, floxuridine (fluorouridine), gemcitabine, Ismipur, hydroxyurea, methotrexate, edatrexate and this compounds, also has ZD 1694 (RALTITREXED in addition ^TM), LY231514 (ALIMTA ^TM), LY264618 (LOMOTREXOL ^TM) and OGT719.

Term used herein " platinic compound " includes but not limited to carboplatin, cis-platinum and oxaliplatin.Carboplatin for example can be with its commercial form administration, and for example trade mark is CARBOPLAT ^TMOxaliplatin for example can be with its commercial form administration, and for example trade mark is ELOXATIN ^TM

Term used herein " reduces the compound and further anti-angiogenic compounds of protein kinase activity " and includes but not limited to reduce following active compound, for example vascular endothelial growth factor (VEGF), Urogastron (EGF), c-Src, protein kinase C, Thr6 PDGF BB (PDGF), Bcr-Abl, c-Kit, Flt-3, insulin-like growth factor I receptor (IGF-IR) and cell cycle protein dependent kinase (CDK) have the anti-angiogenic compounds that is different from the mechanism of action that reduces protein kinase activity.

Reduce the active compound of VEGF especially suppress vegf receptor, especially the tyrosine kinase activity of vegf receptor compound and with VEGF bonded compound, particularly general and concrete those disclosed compound, protein and monoclonal antibody: WO 98/35958 (description formula I compound), WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 01/55114, WO 01/58899 and EP 0769947 in following document; People such as M.Prewett in Cancer Research 59 (1999) 5209-5218, people such as F.Yuan is at Proc.Natl.Acad.Sci.USA (vol.93,14765-14770, in December, 1996) in, people such as Z.Zhu is at Cancer Res.58,1998, among the 3209-3214 and people such as J.Mordenti at ToxicologicPathology, vol.27, no.1,14-21, those described in 1999; WO 00/37502 and WO94/10202; Angiostatin ^TM, as people such as M.S.O ' Reilly, Cell 79,1994, and 315-328 is described; Endostatin ^TM, as people such as M.S.O ' Reilly, Cell 88,1997, and 277-285 is described;

Reduce the active compound of EGF especially suppress the EGF acceptor, especially the tyrosine kinase activity of EGF acceptor compound and with EGF bonded compound, particularly general and concrete those disclosed compound: WO 97/02266 (describing formula IV compound), EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and WO96/33980 especially in following document;

Reduce compound and SH2 interaction inhibitor that the active compound of c-Src includes but not limited to following defined inhibition c-Src protein tyrosine kinase activity, for example be disclosed among WO 97/07131 and the WO 97/08193 those;

The compound that suppresses the c-Src protein tyrosine kinase activity includes but not limited to belong to the compound of array structure kind down: Pyrrolopyrimidine, pyrrolo-[2,3-d] pyrimidine especially; The purine class; Pyrazolopyrimidines type, pyrazolo [3,4-d] pyrimidine especially; Pyrazolopyrimidines type, pyrazolo [3,4-d] pyrimidine especially; With Pyridopyrimidine class, pyrido [2,3-d] pyrimidine especially.Preferably, this term relates to those compounds that are disclosed among WO 96/10028, WO 97/28161, WO 97/32879 and the WO 97/49706;

The compound of reduction protein kinase C activity especially is disclosed in those staurosporine derivatives (being described in the pharmaceutical preparations among the WO 00/48571) among the EP 0296110, and these compounds are inhibitors of protein kinase C;

The active compound of reduction IGF-IR especially is disclosed in those compounds among the WO 02/92599;

Reduce protein kinase activity and also can have with the further particular compound that The compounds of this invention is united use Imatinib (

), PKC412, Iressac ^TM(ZD1839), 6-[4-(4-ethyl-piperazine-1-ylmethyl)-phenyl]-7H-pyrrolo-[2,3-d] pyrimidine-4-yl }-((R)-1-phenyl-ethyl)-amine (AEE788) and its pharmaceutically acceptable salt (seeing WO 03/13541 in addition), 1-(4-chloro-anilino)-4-(4-pyridyl-methyl)-phthalazines (PTK787) and its pharmacy acceptable salt (seeing WO98/35958 in addition), ZD6474, GW2016, CHIR-200131, CEP-7055/CEP-5214, CP-547632, KRN-633 and SU5416;

Have the anti-angiogenic compounds that is different from the mechanism of action that reduces protein kinase activity and include but not limited to for example Thalidomide (THALOMID), celecoxib (Celebrex) and ZD6126.

Term used herein " GnRF agonist " includes but not limited to abarelix, Coserelin and acetic acid Rayleigh.Coserelin is disclosed in US 4,100, in 274, for example can be with its commercial form administration, and for example trade mark is ZOLADEX ^TMAbarelix for example can be as US 5,843,901 described preparations.

Term used herein " androgen antagonist " includes but not limited to bicalutamide (CASODEX ^TM), it for example can be as US 4,636,505 described preparations.

Term " bengamide " relates to bengamide and it has the derivative of anti proliferative properties.

Term used herein " bis-phosphonic acids compounds " includes but not limited to according to bent phosphonic acids (etridonicacid), clodronic acid (clodronic acid), tiludronic acid (tiludronic aicd), pamidronic acid (pamidronic acid), clinic effect of alendronate (alendronic acid), Ibandronic acid (ibandronicacid), risedronic acid (risedronic acid) and Zoledronic acid (zoledronic acid).For example can be according to bent phosphonic acids with its commercial form administration, for example trade mark is DIDRONEL ^TMClodronic acid for example can be with its commercial form administration, and for example trade mark is BONEFOS ^TMTiludronic acid for example can be with its commercial form administration, and for example trade mark is SKELID ^TMPamidronic acid for example can be with its commercial form administration, and for example trade mark is AREDIA ^TMClinic effect of alendronate for example can be with its commercial form administration, and for example trade mark is FOSAMAX ^TMIbandronic acid for example can be with its commercial form administration, and for example trade mark is BONDRANAT ^TMRisedronic acid for example can be with its commercial form administration, and for example trade mark is ACTONEL ^TMZoledronic acid for example can be with its commercial form administration, and for example trade mark is ZOMETA ^TM

Term " steroid " comprise hydrocortisone, dexamethasone (

), medrat dragon and prednisolone.

Term used herein " anti proliferative antibody " includes but not limited to Si Tumanbu (Trastuzumab) (Herceptin ^TM), Si Tumanbu-DM1, erlotinib (Tarceva ^TM), bevacizumab (Avastin ^TM), sharp appropriate uncommon agate (

), PRO64553 (anti-CD 40) and 2C4 antibody.

With regard to the treatment of acute myeloid leukaemia (AML), formula I compound, especially novel The compounds of this invention can be united use with standard leukemia therapy, are particularly useful for treating the therapy of AML.Definite, compound of the present invention can be used for treating the medication combined administration of AML, for example daunorubicin, Zorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412 with for example farnesyl tranfering enzyme inhibitor and/or other.

Can be by the structure of code, common name or the determined activeconstituents of trade name from the current edition of classic " the Merck index " or from database, Patents International (for example IMS World Publications) for example.

Above-mentioned can unite the compound of use with formula I compound can be as preparation and administration as described in for example above-cited document in this area.

Embodiment (novel The compounds of this invention)

The following example plays sets forth invention and the effect of unrestricted its scope.

Temperature is by degree centigrade measurement.Unless indication is arranged in addition, reaction takes place at room temperature.

R _fValue shows the ratio of the distance that distance that each material moves and the place ahead eluent move, and uses cited separately solvent systems, (Merck, Darmstadt Germany) go up and measure R at the silica gel thin-layer flat board by tlc _fValue.

Abbreviation:

Anal. ultimate analysis (with regard to shown in regard to the atom, calculate and observed value between difference≤0.4%)

Aq is moisture

The saturated solution of salt solution NaCl in water

The Boc tertbutyloxycarbonyl

The Bu butyl

Conc. dense

D days

The DIPE diisopropyl ether

The DIPEA diisopropylethylamine

The DMAP Dimethylamino pyridine

DME 1, the 2-glycol dimethyl ether

The DMF dimethyl formamide

DMSO-d ₆Full deuterated dimethyl sulfoxide

The equiv equivalent

The ether diethyl ether

The EtOAc ethyl acetate

EtOH alcohol

Ex. embodiment

H hour

The HPLC high pressure liquid chromatography

The L liter

The Me methyl

MeOH methyl alcohol

Min minute

M.p. fusing point

The MPLC medium pressure liquid chromatography

-Combi Flash system: malleation SiO ₂

-Gilson system: anti-phase Nucleosil C18 (H ₂O/CH ₃CN+TFA)

Generally speaking, use NaHCO ₃After the neutralization, products therefrom is a free alkali

The MS mass spectrum

NEt ₃Triethylamine

The NMR nucleus magnetic resonance

R _fRf value (TLC)

The rt room temperature

The TBDMS tertiary butyl-dimethyl-silyl

The tBu tertiary butyl

THF tetrahydrofuran (THF) (from the Na/ benzophenone, distilling)

The TFA trifluoroacetic acid

The TLC thin-layer chromatography

t _RetRetention time (HPLC)

Two (trichloromethyl) carbonic ethers of triphosgene

The HPLC condition:

^A t _Ret : the retention time of system A [min]: linear gradient 20-100%CH ₃CN (0.1%TFA) and H ₂O (0.1%TFA) 13min+5min 100%CH ₃CN (0.1%TFA); Detect wavelength 215nm; Flow velocity 1ml/min, 25 or 30 ℃; Pillar: Nucleosil 120-3C18 (125 * 3.0mm).

^B t _Ret : the retention time of system B [min]: linear gradient 20-100%CH ₃CN (0.1%TFA) and H ₂O (0.1%TFA) 7min; Detect wavelength 215nm; Flow velocity 1ml/min, 25 or 30 ℃; Pillar: Nucleosil 100-3C18HD (125 * 4.0mm).

^C t _Ret : the retention time of system C [min]: linear gradient 20-100%CH ₃CN (0.1%TFA) and H ₂O (0.1%TFA) 7min+2min 100%CH ₃CN (0.1%TFA); Detect wavelength 215nm; Flow velocity 1ml/min, 30 ℃; Pillar: Nucleosil 100-3C18HD (125 * 4mm).

^D t _Ret : the retention time of system D [min]: linear gradient 20-100%CH ₃CN (0.1%TFA) and H ₂O (0.1%TFA) 5min+1.5min 100%CH ₃CN (0.1%TFA); Detect wavelength 215nm; Flow velocity 1ml/min, 30 ℃; Pillar: Nucleosil 100-3C18HD (70 * 4mm).

Embodiment 1:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(azetidine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

To N ₂The 3ml THF solution of 935mg under the atmosphere (3.78mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) adds the 20ml ethereal solution of 870mg (3.78mMol) 3-(azetidine-1-ylmethyl)-5-trifluoromethyl-aniline (step 1.6).After rt stirred 3h, the partial concentration reaction mixture diluted with ether in a vacuum, and crystallization goes out title compound thus, can leach, and washs with ether: MS:[M+1] ⁺=478; ¹H-NMR (CDCl ₃): 8.58 (s, 1H), 7.61 (s, 1H), 7.46 (s, 1H), 7.44 (d, 8.6Hz, 2H), 7.24 (s, 1H), 7.12 (d, 8.6Hz, 2H), 6.93 (s, 1H), 6.89 (s, 1H), 6.81 (s, 1H), 3.59 (s, 2H), 3.24 (t, 7.0Hz, 2 * 2H), 2.11 (q, 7.0Hz, 2H).

Raw material is prepared as follows:

Step 1.1:4-chloro-6-(4-nitro-phenoxy group)-pyrimidine

6.5L H to ice-cold 214g (5.35Mol) NaOH ₂O solution adds 744g (5.35Mol) 4-nitrophenols.Drip 797g (5.35Mol) 4 then in 60min, the 6.5L acetone soln of 6-dichloro pyrimidine stirs 18h with mixture at 65 ℃.Reaction mixture is cooled to 10 ℃, leaches sedimentary crude product, use 400ml H ₂O/ acetone washing in 1: 1: m.p.:127-128 ℃; Ultimate analysis C ₁₀H ₆ClN ₃O ₃: C, H, N, Cl, O; MS:[M]=251; ¹H-NMR (DMSO-d ₆): 8.70 (s, 1H, pyrimidyl), 8.34 (d, 9Hz, 2H, phenyl), 7.59 (s, 1H, pyrimidyl), 7.57 (d, 9Hz, 2H, phenyl).

Step 1.2:4-(6-chloro-pyrimidine-4-base-oxygen base)-aniline

In the presence of the 33g Raney nickel, with 2: 1 solution of 10L MeOH/THF of 1095g (4.3Mol) 4-chloro-6-(4-nitro-phenoxy group)-pyrimidine at rt hydrogenation 4h.Reaction soln is filtered, concentrate.Crystallization from EtOAc obtains title compound: ultimate analysis C ₁₀H ₈ClN ₃O:C, H, N, Cl, O; MS:[M+1] ⁺=222; ¹H-NMR (DMSO-d ₆): 8.60 (s, 1H), 7.12 (s, 1H), 6.86 (d, 9Hz, 2H, phenyl), 6.57 (d, 9Hz, 2H, phenyl), 5.13 (s, 2H, NH ₂).

Step 1.3:4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine

Instrument: 18 liters of reaction vessels, dropping funnel and condensers.Will be at N ₂(20% toluene solution, 1.43L 2.9Mol) are cooled to approximately-20 ℃ to the phosgene solution of usefulness 10L dilution with toluene under the atmosphere.The 4.4L CH that in 30min, adds 250g (1.12Mol) 4-(6-chloro-pyrimidine-4-base-oxygen base)-aniline then ₂Cl ₂Solution.The gained suspension is heated to distillation removes about 4.5L solvent.Continue distillation (110 ℃ of boiling points), in reaction vessel, obtain clear soln (≈ 3L), be cooled to rt, concentrate in a vacuum.Distillation gained wax shape crude product obtains title compound under 0.2mbar, is solid: m.p.:103 ℃.

Step 1.4:(3-nitro-5-trifluoromethyl-phenyl)-(azetidine-1-yl)-ketone

In ice bath, at N ₂Under the atmosphere, mix 9.77g (41.6mMol) 3-nitro-5-trifluoromethyl-phenylformic acid (Lancaster), 150ml CH ₂Cl ₂, several DMF and 5.8ml (67mMol) oxalyl chloride, stir 17h at rt then.Concentrate gained solution in a vacuum.Resistates is dissolved in 50ml CH ₂Cl ₂, be added drop-wise to the 50ml CH of ice-cold 5.9ml (87mMol) azetidine ₂Cl ₂In the solution.After stirring 15min, mixture 1N HCl, rare Na ₂CO ₃Solution, water and salt water washing.Water layer strips twice with EtOAc, merges organic phase, dry (Na ₂SO ₄), concentrate.Crystallization from hexane obtains title compound; M.p.:91 ℃; MS:[M+1] ⁺=275.

Step 1.5:(3-amino-5-trifluoromethyl-phenyl)-(azetidine-1-yl)-ketone

In the presence of the 2g Raney nickel, hydrogenation 10.39g (37.9mMol) in 200ml ethanol (3-nitro-5-trifluoromethyl-phenyl)-(azetidine-1-yl)-ketone, by diatomite filtration, partial concentration filtrate, with the hexane dilution, obtain the crystallinity title compound; M.p.:154 ℃; MS:[M+1] ⁺=245.

Step 1.6:3-(azetidine-1-ylmethyl)-5-trifluoromethyl-aniline

To N ₂Under the atmosphere in ice bath the 75ml THF solution of refrigerative 8.62g (35.3mMol) (3-amino-5-trifluoromethyl-phenyl)-(azetidine-1-yl)-ketone drip and to contain 10.6ml (95%; 106mMol) BH ₃-Me ₂The 15ml THF of S.Gained solution is stirred 2d at rt, stir 4h at 65 ℃ then.After being cooled to rt, add the dense HCl/H of 50ml ₂O 1: 1 stirs 15h with mixture at rt, stirs 7h at 65 ℃.Pour mixture into EtOAc and 10%Na ₂CO ₃In the solution, isolate water, use the EtOAc extracting twice.With organic layer water and salt solution washed twice, dry (Na ₂SO ₄), concentrate.Column chromatography is handled (SiO ₂95: 5 → EtOAc/EtOH/Et of EtOAc/EtOH ₃N 95: 5: 1), obtain title compound; M.p.:60-61 ℃; MS:[M+1] ⁺=231.

Embodiment 2:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea

At N ₂Under the atmosphere, will contain 250mg (0.52mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-the 3ml 33%MeNH of N '-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea ₂EtOH solution in ice bath, stir 4h.Add ≈ 1g SiO to solution then ₂, enriched mixture in a vacuum.The gained powder is placed MPLC post (SiO ₂) top, with MeOH (+1%NH ₃ ^Aq)/CH ₂Cl ₂3: 97 → 1: 9 → 1: 4 wash-out obtains title compound: MS:[M+1] ⁺=473; ¹H-NMR (CD ₃OD+CDCl ₃): 8.11 (s, 1H), 7.95 (m, 1H), 7.46 (s, 1H), 7.45 (d, 7.4Hz, 2H), 7.17 (s, 1H), 7.03 (d, 7.4Hz, 2H), 5.59 (s, 1H), 3.90 (s, 2H), 3.63 (m, 2 * 2H), 2.81 (s, H ₃C), 2.30 (m, 2H).

Embodiment 3:N-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea

With 300mg (0.63mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea and 82mg (1.26mMol) NaN ₃Mixture in 5ml DMF stirs 16h at 40 ℃, stirs 5h at 60 ℃.Reaction mixture is poured in the water, with 3 parts of EtOAc extractions.With organic layer water and salt water washing, dry (Na ₂SO ₄), concentrate.Resistates is dissolved in 20ml THF again, filters, filtrate is directly used in the step of hydrogenation of Ex.4.Concentrated filtrate can obtain title compound: MS:[M+1 in a vacuum] ⁺=485; ¹H-NMR (CDCl ₃): 8.53 (s, 1H), 7.96 (s, 1H), 7.94 (s, 1H), 7.57 (s, 1H), 7.53 (s, 1H), 7.45 (d, 8.6Hz, 2H), 7.17 (s, 1H), 7.04 (d, 8.6Hz, 2H), 6.25 (s, 1H), 3.58 (s, 2H), 3.27 (t, 7.0Hz, 2 * 2H), 2.11 (q, 7.0Hz, 2H).

Embodiment 4:N-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea

Hydrogenation N-[4-in the presence of 60mg Pd/C 10%, in 20ml THF (6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea (0.63mMol).After leaching catalyzer, add ≈ 1g SiO to filtrate ₂, enriched mixture in a vacuum.The gained powder is placed MPLC post (SiO ₂) top, with EtOH (+1%NEt ₃1: 49 → 4: 46 → 1: 4 wash-out of)/EtOAc obtains title compound: MS:[M+1] ⁺=459; ¹H-NMR (CD ₃OD): 8.08 (s, 1H), 7.82 (s, 1H), 7.54 (s, 1H), 7.52 (d, 9.0Hz, 2H), 7.24 (s, 1H), 7.09 (d, 9.0Hz, 2H), 5.75 (s, 1H), 3.68 (s, 2H), 3.35 (t, 7.2Hz, 2 * 2H), 2.16 (q, 7.2Hz, 2H).

Embodiment 5:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

At N ₂Under the atmosphere, the 3ml THF drips of solution of 1.00g (4.0mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) is added in the 33ml ethereal solution of 1.31g (4.3mMol) 3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-aniline (step 5.3).After rt stirs 4h, concentrated reaction mixture in a vacuum.Column chromatography is handled (SiO ₂CH ₂Cl ₂/ MeOH 9: 1 → 88: 12 → 85: 15) obtains title compound: m.p.:101 ℃; MS:[M+1] ⁺=549; ¹H-NMR (CDCl ₃): 8.57 (s, 1H), 7.64 (s, 1H), 7.48 (s, 1H), 7.47 (d, 9Hz, 2H), 7.28 (s, 1H), 7.19 (m, 1H), 7.13 (s, 1H), 7.12 (d, 9Hz, 2H), 6.92 (s, 1H), 3.49 (s, 2H), 2.69 (septet, 6.3Hz, 1H), 2.58 (m, 4H), 2.52 (m, 4H), 1.08 (d, 6.3Hz, 6H).

Raw material is prepared as follows:

Step 5.1:(3-nitro-5-trifluoromethyl-phenyl)-(4-sec.-propyl piperazine-1-yl)-ketone

In ice bath, at N ₂Under the atmosphere, mix 9.00g (38.3mMol) 3-nitro-5-trifluoromethyl-phenylformic acid (Lancaster), 150ml CH ₂Cl ₂, several DMF and 5.3ml (61mMol) oxalyl chloride, stir 4.5h at rt then.Concentrate gained solution in a vacuum.Resistates is dissolved in 50ml CH ₂Cl ₂, be added drop-wise to the 50ml CH of ice-cold 10.3g (80mMol) 1-sec.-propyl piperazine ₂Cl ₂In the solution.After stirring 140min, the rare Na of mixture ₂CO ₃Solution, water and salt water washing.Water layer strips twice with EtOAc, merges organic phase, dry (Na ₂SO ₄), concentrate.Crystallization from the DIPE/ hexane obtains title compound; M.p.:70-71 ℃; MS:[M+1] ⁺=346.

Step 5.2:(3-amino-5-trifluoromethyl-phenyl)-(4-sec.-propyl piperazine-1-yl)-ketone

As described in step 1.5,, obtain title compound at hydrogenation 9.2g (27mMol) in the presence of the 2g Raney nickel, in 200ml ethanol (3-nitro-5-trifluoromethyl-phenyl)-(4-sec.-propyl piperazine-1-yl)-ketone; M.p.:89-90 ℃; MS:[M+1] ⁺=316.

Step 5.3:3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-aniline

To N ₂The 70ml THF that contains 7.0g (22mMol) (3-amino-5-trifluoromethyl-phenyl)-(4-sec.-propyl piperazine-1-yl)-ketone under the atmosphere drips 67ml (1M THF solution, 67mMol) BH ₃-THF.Gained solution is stirred 18h at rt, add the dense HCl/H of 100ml then ₂O1: 1, mixture is stirred 5h at rt.Reaction mixture is extracted with EtOAc, and organic phase discards with 0.1N HCl washing.The oxytropism water layer adds the saturated Na of 250ml then ₂CO ₃Solution is succeeded by extracting with 3 parts of EtOAc.With organic layer salt water washing, dry (Na ₂SO ₄), concentrate, obtain title compound, be oil: [M+1] ⁺=302; ¹H-NMR (CDCl ₃): 6.93 (s, 1H), 6.82 (s, 1H), 6.77 (s, 1H), 3.82 (s, H ₂N), 3.45 (s, 2H), 2.67 (septet, 6.3Hz, 1H), 2.57 (m, 4H), 2.51 (m, 4H), 1.07 (d, 6.3Hz, 6H).

Embodiment 6:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

At N ₂Under the atmosphere, will contain 368mg (0.67mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-the 3ml 33%MeNH of N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea ₂EtOH solution in ice bath, stir 4.5h.Pour mixture into EtOAc and NaHCO ₃In the aqueous solution, isolate water, use the EtOAc extracting twice.With organic layer water and salt solution washed twice, dry (Na ₂SO ₄), concentrate.Reverse-phase chromatography is handled and is obtained title compound: MS:[M+1] ⁺=544; ¹H-NMR (CD ₃OD): 8.15 (s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 7.56 (d, 9Hz, 2H), 7.34 (s, 1H), 7.13 (d, 9Hz, 2H), 5.72 (s, 1H), 3.63 (s, 2H), 2.87 (s, H ₃C), 2.9-2.5 (m, 9H), 1.15 (d, 6.7Hz, 6H).

Embodiment 7:N-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

With 470mg (0.86mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea and 111mg (1.7mMol) NaN ₃Mixture in 7mlDMF stirs 2h at 80 ℃.Then solution is cooled off in ice bath, under vigorous stirring, pour in the 80ml water.Filter the gained suspension, wash with water, obtain title compound: MS:[M+1] ⁺=556; HPLC ^At _Ret=11.2.

Embodiment 8:N-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

Hydrogenase 10 .39g (0.70mMol) N-[4-in the presence of 100mg Pd/C 5%, in 20ml THF (6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-sec.-propyl piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea.Leach catalyzer, concentrated filtrate is dissolved in CH again with resistates in a vacuum ₂Cl ₂/ MeOH adds ≈ 1g SiO ₂After concentrate once more.The gained powder is placed MPLC post (SiO ₂) top, with EtOAc/EtOH (+1%NEt ₃) 19: 1 → 9: 1 → 7: 3 wash-outs, from hexane, obtain title compound after the crystallization: ultimate analysis C ₂₆H ₃₀N ₇F ₃O ₂.0.8H ₂O.0.2EtOAc:C, H, N, H ₂O; MS:[M+1] ⁺=530; ¹H-NMR (CD ₃OD): 8.12 (s, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 7.57 (d, 8.6Hz, 2H), 7.34 (s, 1H), 7.13 (d, 8.6Hz, 2H), 5.79 (s, 1H), 3.62 (s, 2H), 2.8-2.5 (m, 9H), 1.13 (d, 6.7Hz, 6H).

Embodiment 9:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[3-(4-methylpiperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

The 3mlTHF solution and 1.1g (4.0mMol) 3-(4-methylpiperazine-1-the ylmethyl)-30ml ethereal solution of 5-trifluoromethyl-aniline (step 9.3) of 1.00g (4.0mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) are similar to Ex.5 and are converted into title compound: m.p.:291-292 ℃; Ultimate analysis C ₂₄H ₂₄N ₆ClF ₃O ₂0.5H ₂O:C, H, N, Cl, F; MS:[M+1] ⁺=521.

Raw material is prepared as follows:

Step 9.1:(3-nitro-5-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone

Be similar to step 5.1,9.00g (38.3mMol) 3-nitro-5-trifluoromethyl-phenylformic acid with the activation of 5.3ml (61mMol) oxalyl chloride, with the reaction of 8.9ml (80mMol) 1-methylpiperazine, is obtained title compound, be oil; MS:[M+1] ⁺=318; HPLC ^At _Ret=8.7.

Step 9.2:(3-amino-5-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone

As described in step 1.5,, obtain title compound at hydrogenation 11.8g (37mMol) in the presence of the 2g Raney nickel, in 200ml ethanol (3-nitro-5-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone; M.p.:114-115 ℃; MS:[M+1] ⁺=288.

Step 9.3:3-(4-methylpiperazine-1-ylmethyl)-5-trifluoromethyl-aniline

Be similar to step 1.6, with the 9.91g among the 90ml THF (34.5mMol) (3-amino-5-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone BH ₃.Me ₂S is reduced to title compound: m.p.:98-99 ℃; MS:[M+1] ⁺=274; ¹H-NMR (CDCl ₃): 6.94 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 3.82 (s, H ₂N), 3.45 (s, 2H), 2.48 (m, 8H), 2.30 (s, H ₃C).

The Ex.10-13 compound can be similar to prepared described herein:

Embodiment 10:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea

171mg (0.69mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-2ml THF solution of pyrimidine (step 1.3) and the 6ml ethereal solution of 170mg (0.69mMol) 3-(diethylin-methyl)-5-trifluoromethyl-aniline (step 10.3) are similar to Ex.5 are converted into title compound.MS：[M+1] ⁺493.9。

Raw material is prepared as follows:

Step 10.1:(3-nitro-5-trifluoromethyl-phenyl)-(diethylin)-ketone

Be similar to step 5.1,2.40g (10.0mMol) 3-nitro-5-trifluoromethyl-phenylformic acid with the activation of 1.7ml (20.0mMol) oxalyl chloride, with the reaction of 7.3g (100mMol) diethylamine, is obtained title compound, be oil; MS:[M-1]=290; ¹H-NMR (DMSO-d ₆): 8.79 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 3.50 (q, 2H), 3.21 (q, 2H), 1.19 (t, 3H), 1.01 (t, 3H).

Step 10.2:(3-amino-5-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone

As described in step 1.5, at hydrogenation 2.8g (9.6mMol) in the presence of the 140mg Pd-C, in 50ml ethanol (3-nitro-5-trifluoromethyl-phenyl)-(diethylin) ketone, obtain title compound, be yellow solid; MS:[M+1] ⁺261. ¹H-NMR (DMSO-d ₆): 6.89 (s, 1H), 6.78 (s, 1H), 6.60 (s, 1H), 5.79 (s, 2H, NH ₂), 3.50-3.39 (m, 2H), 3.25-3.02 (m, 2H), 1.21-0.99 (m, 6H).

Step 10.3:3-(diethylin methyl)-5-trifluoromethyl-aniline

Be similar to step 1.6, with the 1.04g among the 15ml THF (4.0mMol) (3-amino-5-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone BH ₃-Me ₂S is reduced to title compound: MS:[M+1] ⁺=247; ¹H-NMR (DMSO-d ₆): 6.87 (s, 1H), 6.84 (s, 1H), 6.81 (s, 1H), 5.60 (s, 2H, NH ₂), 2.75-2.65 (m, 4H), 1.28-1.08 (m, 6H).

Embodiment 11:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea

At N ₂Under the atmosphere, will contain 250mg (0.52mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-the 3ml 33%MeNH of N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea ₂EtOH solution stir 2h at 5 ℃.After the water treatment, crude product is through purification by flash chromatography (SiO ₂, gradient CH ₂Cl ₂/ MeOH 0-40%), obtain title compound: m.p.:68-70 ℃; MS:[M+1] ⁺=489; ¹H-NMR (DMSO-d ₆): 9.21 (s, 1H, NH), 8.83 (s, 1H, NH), 8.09 (s, 1H), 7.85 (s, 1H), 7.45 (d, 2H), 7.20 (s, 1H), 7.05 (d, 2H), 5.71 (s, 1H), 3.56 (s, 2H), 2.74 (s, 3), 2.50-2.32 (m, 4H), 1.01-0.95 (m, 6H).

Embodiment 12:N-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea

With 218mg (0.44mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea and 50mg (0.7mMol) NaN ₃Mixture in 6ml DMF stirs 2h at 80 ℃.Then reaction mixture is diluted with ethyl acetate, use the salt water washing.Separate organic layer, drying concentrates, and obtains crude product, through purification by flash chromatography (SiO ₂, gradient CH ₂Cl ₂/ MeOH 0-40%).MS：[M+1] ⁺＝501。

Embodiment 13:N-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea

Hydrogenation 98mg (0.17mMol) N-[4-in the presence of 20mg Pd/C 5%, in 10ml DME (6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-diethylin methyl-5-trifluoromethyl-phenyl)-urea.Leach catalyzer, concentrated filtrate in a vacuum, resistates is through preparation type TLC purifying (SiO ₂, CH ₂Cl ₂/ MeOH 9: 1), obtain title compound: m.p.:63-65 ℃ of .MS:[M+1] ⁺=475.

Embodiment 14:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

To N ₂The 3ml THF solution of ice-cold 687mg (2.77mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) drips the 20ml ethereal solution of 758mg (2.77mMol) 4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-aniline (step 14.4) under the atmosphere.After rt stirs 3h, the gained suspension is filtered, resistates washs with ether, obtains title compound: MS:[M+1] ⁺=521; ¹H-NMR (CDCl ₃): 8.55 (s, 1H), 7.67 (d, 8.6Hz, 1H), 7.56 (d, 8.6Hz, 1H), 7.54 (s, 1H), 7.41 (d, 9Hz, 2H), 7.21 (s, 1H), 7.15 (s, 1H), 7.08 (d, 9Hz, 2H), 6.91 (s, 1H), 3.58 (s, 2H), 2.48 (m, 8H), 2.30 (s, H ₃C).

Raw material is prepared as follows:

Step 14.1:N-(4-methyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides

To N ₂Ice-cold 320g (1.827Mol) the 5-amino-2-methyl phenylfluoroform and the 4.5L CH of 1.47L (18.27Mol) pyridine under the atmosphere ₂Cl ₂Solution drips 284ml (2.01Mol) trifluoroacetic anhydride.Behind the 50min, mixture dilutes with the ice-cold 2N HCl of 5L.Isolate organic phase, with 2L cold 2N HCl washed twice, then with 1L 2N HCl, use the water washing of 2L salt at last.With water layer CH ₂Cl ₂Extracting twice, organic phase drying (Na ₂SO ₄), partial concentration.Add the hexane crystallization, obtain title compound: m.p.:72-73 ℃.

Step 14.2:N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides

To N ₂60.9g under the atmosphere (224.6mMol) N-(4-methyl-3-trifluoromethyl-phenyl)-2,2, the 830ml n-butyl acetate solution of 2-three fluoro-ethanamides adds 44g (247mMol) N-bromine succinimide and 830mg (5mMol) azo isobutyronitrile.Suspension is heated to 60 ℃, uses Philips low voltage bulb (500W then; 10500Im) illumination 30min, temperature rises to 70-75 ℃ thus, generates clarifying brown solution.Still can detect remaining extractive substance, therefore divide 3 parts to add other 22g N-bromine succinimide.After amounting to the 6h illumination, leach the gained solid, discard concentrated filtrate.Make resistates at 2L CH ₂Cl ₂With 1L H ₂Distribute water layer 1L CH between the O ₂Cl ₂Extraction.With organic phase 1L H ₂O, the water washing of 0.5L salt 4 times, dry (Na ₂SO ₄), concentrate.Column chromatography is handled (SiO ₂Hexane/CH ₂Cl ₂2: 1 → 1: 1) and from CH ₂Cl ₂Crystallization in the/hexane obtains title compound: m.p.:119-120 ℃.

Step 14.3:2,2,2-three fluoro-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetyl Amine

In 30min to N ₂The 50ml acetonitrile solution of ice-cold 1.9ml (17.1mMol) N methyl piperazine drips 2.00g (5.71mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 50ml acetonitrile solution of 2-three fluoro-ethanamides under the atmosphere.In addition behind the 20min, concentrated reaction mixture in a vacuum.Gained oil EtOAc and saturated NaHCO ₃Solution/H ₂O dilution in 1: 1.Isolate water layer, use the EtOAc extracting twice.With the saturated NaHCO of organic layer ₃Solution/H ₂O 1: 1, water and salt water washing, dry (Na ₂SO ₄), concentrate, be directly used in step 14.4:MS:[M+1] ⁺=370; HPLC ^At _Ret=9.5.

Step 14.4:4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-aniline

To 1.102g (2.98mMol) 2,2,2-three fluoro-N-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-the solution dropping 14ml 1M K of ethanamide in 26ml boiling methyl alcohol ₂CO ₃The aqueous solution.After stirring 1h, reaction mixture is cooled to rt, with EtOAc and water dilution.Isolate water layer, use the EtOAc extracting twice.With organic phase water and salt water washing, dry (Na ₂SO ₄), concentrate, obtain title compound, be directly used in Ex.14:MS:[M+1] ⁺=274; HPLC=5.4.

Substituting of 4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-aniline is synthetic:

Step 14.4.1:4-nitro-2-trifluoromethyl-phenylformic acid is [referring to J.Gen.Chem.USSR (Engl. Transl.) 33 (1963), 2957]

At N ₂Under the atmosphere, 50g (263mMol) o-trifluoromethyl-phenylformic acid and 307ml H that mechanical stirring ₂SO ₄96% mixture cools off in ice bath.In 75min, drip 105ml HNO then at 5-7 ℃ ₃100%.Remove ice bath, continue to stir 2h at rt.Reaction mixture is poured in the 1.9kg ice, stirred 20min.Filter suspension, use the 100ml cold water washing, dry (0.2mbar, 50 ℃) obtain thick title compound, contain 20% regional isomer.This product is partially soluble in the 0.4L boiling toluene, filters.Concentrated filtrate adds the 0.1L hexane then to half of its volume.After being cooled to rt, title compound crystallizes out, and can leach: m.p.:138-141 ℃; ¹H-NMR (CDCl ₃): 8.71 (d, 2.3Hz, 1H), 8.56 (dd, 2.3Hz, 8.2Hz, 1H), 8.18 (d, 8.2Hz, 1H).

Step 14.4.2:(4-nitro-2-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone

To N ₂Ice-cold 17.99g (76.5mMol) 4-nitro-2-trifluoromethyl-phenylformic acid, 300ml CH under the atmosphere ₂Cl ₂Drip 12.3ml (145mMol) oxalyl chloride with 3ml DMF solution.4.5h after, concentrate gained solution in a vacuum.Resistates is dissolved in 300ml CH ₂Cl ₂, be added drop-wise to the 120ml CH of ice-cold 17.8ml (160mMol) 1-methylpiperazine ₂Cl ₂In the solution.After stirring 3h, with mixture 0.5L CH ₂Cl ₂Dilution is with 3 part of 10% Na ₂CO ₃Solution, water and salt water washing.With organic phase drying (Na ₂SO ₄), concentrate and obtain title compound, be oil: MS:[M+1] ⁺=318; ¹H-NMR (CDCl ₃): 8.62 (d, 2.3Hz, 1H), 8.50 (dd, 2.3Hz, 8.2Hz, 1H), 7.60 (d, 8.2Hz, 1H), 3.90 (m, 1H), 3.84 (m, 1H), 3.21 (t, 5.1Hz, 2H), 2.53 (t, 5.1Hz, 2H), 2.36 (s, 3H), 2.36 (m, 2H).

Step 14.4.3:(4-amino-2-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone

The 400ml ethanolic soln of hydrogenation 24g (76mMol) in the presence of the 4g Raney nickel (4-nitro-2-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl)-ketone reaches 14h.Leach catalyzer, in a vacuum concentrated filtrate.Filtration residue in the 500ml boiling toluene, partial concentration filtrate begins crystallization until product.Be cooled to rt, filter, obtain title compound: m.p.:154-156 ℃; MS:[M+1] ⁺=288.

Step 14.4.4:4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-aniline

In 75min to N ₂The 160ml THF that contains 17.2g (60mMol) (4-amino-2-trifluoromethyl-phenyl)-(4-methylpiperazine-1-yl) ketone under the atmosphere adds 180ml (1M THF solution; 180mMol) BH ₃-THF.Gained solution is stirred 18h at rt, under cooling, add the dense HCl/H of 180ml then ₂O 1: 1 stirs 18h with mixture at rt.With the reaction mixture partial concentration, resistates extracts with EtOAc, separates organic phase, with 0.1N HCl washing, discards.The oxytropism water layer adds the saturated Na of 0.7L then ₂CO ₃Solution (→ pH9-10), succeeded by extracting with 3 parts of EtOAc.With organic phase salt water washing, dry (Na ₂SO ₄), concentrate.Crystallization from boiling toluene obtains title compound: m.p.:119-121 ℃.

Embodiment 15:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

To N ₂The 4ml THF solution of ice-cold 1.251g (5.05mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) drips the 25ml ethereal solution of 1.522g (5.05mMol) 4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-aniline (step 15.2) under the atmosphere.After stirring 2.5h, reaction mixture is diluted with ether, leach solid, wash with ether.Crude product is dissolved in CH again ₂Cl ₂/ MeOH is adsorbed on SiO ₂On, place SiO then ₂The chromatographic column top.Use CH ₂Cl ₂/ MeOH/NH ₃ ^Aq95: 5: 1 wash-outs obtain title compound: ultimate analysis C ₂₆H ₂₈N ₆ClF ₃O ₂0.5H ₂O:C, H, N, F; MS:[M+1] ⁺=549; ¹H-NMR (CDCl ₃): 8.56 (s, 1H), 7.68 (d, 8Hz, 1H), 7.57 (d, 8Hz, 1H), 7.56 (s, 1H), 7.43 (d, 9Hz, 2H), 7.11 (s, 1H), 7.10 (d, 9Hz, 2H), 7.05 (s, 1H), 6.92 (s, 1H), 3.58 (s, 2H), 2.67 (septet, 6.3Hz, 1H), 2.56 (m, 4H), 2.51 (m, 4H), 1.08 (d, 6.3Hz, 6H).

Raw material is prepared as follows:

Step 15.1:2,2,2-three fluoro-N-[4-(4-sec.-propyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-second Acid amides

In 35min to N ₂The 70ml acetonitrile solution of ice-cold 3.46g (27mMol) N-sec.-propyl piperazine drips 3.15g (9.0mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 70ml acetonitrile solution of 2-three fluoro-ethanamides (step 14.2) under the atmosphere.Behind the 5min, as described in step 14.3, handle in addition, obtain title compound, be oil: MS:[M+1] ⁺=398; HPLC ^At _Ret=10.1.

Step 15.2:4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-aniline

To 3.58g (9.0mMol) 2,2,2-three fluoro-N-[4-(4-sec.-propyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-the 90ml boiling methanol solution of ethanamide drips 45ml 1M K ₂CO ₃The aqueous solution.After stirring 110min, reaction mixture is cooled to rt, in a vacuum partial concentration.Resistates with EtOAc and water dilution, is isolated water layer, use the EtOAc extracting twice.With organic phase water and salt water washing, dry (Na ₂SO ₄), partial concentration.With after the hexane dilution, title compound crystallizes out, can filtering separation: m.p.:117-119 ℃; MS:[M+1] ⁺=302.

Embodiment 16:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea trifluoroacetate

At N ₂Under the atmosphere, will contain 450mg (0.82mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-the 4ml 33%MeNH of N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea ₂EtOH solution in ice bath, stir 3h.Pour mixture into EtOAc and 10%NaHCO ₃In the solution, isolate water, use the EtOAc extracting twice.With organic layer water and salt solution washed twice, dry (Na ₂SO ₄), concentrate.Reverse-phase chromatography is handled, and obtains title compound: MS:[M+1] ⁺=544; ¹H-NMR (DMSO-d ₆): 9.16 (s, HN), 9.04 (m, HN ⁺), 8.93 (s, HN), 8.12 (m, 1H), 7.95 (s, 1H), 7.62 (2s, 2H), 7.48 (d, 9Hz, 2H), 7.33 (m, HNMe), 7.05 (d, 9Hz, 2H), 5.73 (s, 1H), 3.65 (s, 2H), 3.47 (m, 1H), 3.39 (m, 2H), 3.00 (m, 2H), 2.95 (m, 2H), 2.76 (m, H ₃C), 2.39 (m, 2H), 1.26 (d, 7Hz, 6H).

Embodiment 17:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl-4-oxygen base piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea trifluoroacetate

During the reverse-phase chromatography of the reaction mixture of Ex.16 is handled, can separate title compound, be the by product that moves more slowly: MS:[M+1] ⁺=560; ¹H-NMR (DMSO-d ₆): 11.48 (s, HN), 9.14 (s, HN), 8.92 (s, HN), 8.11 (m, 1H), 7.95 (s, 1H), 7.63 (m, 2H), 7.47 (d, 8Hz, 2H), 7.30 (m, HNMe), 7.05 (d, 8Hz, 2H), 5.73 (s, 1H), 3.95 (septets, 7Hz, 1H), 3.69 (s, 2H), 3.60 (m, 4H), 2.87 (m, 2H), 2.76 (m, H ₃C), 2.7 (m, 2H), 1.35 (d, 7Hz, 6H).

Embodiment 18:N-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

As described in Ex.7, from 647mg (1.18mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea prepares title compound: MS:[M+1] ⁺=556; HPLC ^At _Ret=11.4.

Embodiment 19:N-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

Hydrogenase 10 .66g (1.18mMol) N-[4-in the presence of 0.12g Pd/C 10% (" Engelhard 4505 "), in 25ml THF (6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea, filter, concentrated filtrate, chromatography [MPLC:CH ₂Cl ₂/ MeOH (+1%NH ₃ ^Aq) 199: 1 → 93: 7 → 82: 18], obtain title compound: ultimate analysis C ₂₆H ₃₀N ₇F ₃O ₂0.8H ₂O:C, H, N, F; MS:[M+1] ⁺=530; ¹H-NMR (CDCl ₃): 8.25 (s, 1H), 7.86 (s, 1H), 7.65 (d, 8.2Hz, 1H), 7.56 (m, 3H), 7.25 (d, 8Hz, 2H), 6.97 (d, 8Hz, 2H), 5.64 (s, 1H), 5.26 (s, H ₂N), 3.57 (s, 2H), 2.64 (septet, 6.7Hz, 1H), 2.53 (m, 4H), 2.49 (m, 4H), 1.06 (d, 6.7Hz, 6H).

Be similar to technology described herein, can prepare Ex.19-1 and 19-2 compound:

Embodiment 19-1:N-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-4-(4-H-piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

Hydrogenase 10 .33g (0.68mMol) N-[4-in the presence of 0.05g Pd/C 10% (" Engelhard 4505 "), in 10ml DME (6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-benzoyloxy carbonyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea, filter, concentrated filtrate, chromatography [C18:CH ₃CN/H ₂O (+0.1%TFA)], obtain title compound: m.p.:153-155 ℃ of .MS:[M+1] ⁺=488; ¹H-NMR (DMSO-d ₆): 9.39 (s, 1H), 9.17 (s, 1H), 8.59 (s, 2H, NH), 8.18 (s, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.42 (d, 2H), 7.01 (d, 2H); 5.62 (s, 2H), 3.17-3.08 (m, 4H), 2.62-2.52 (m, 4H).

Raw material is prepared as follows:

Step 19-1.1:2,2,2-three fluoro-N-[4-(4-benzoyloxy carbonyl-piperazine-1-ylmethyl)-3-fluoroform Base-phenyl]-ethanamide

At N ₂Under the atmosphere, the 10ml EtOH solution to 1.57g (7.1mMol) N-benzyl-1-piperazinecarboxylic acid ester in 35min drips 1.0g (2.8mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 5ml EtOH solution of 2-three fluoro-ethanamides (step 14.2).Stir other 30min, after handling as described in the step 14.3, obtain title compound, be oil: MS:[M+1] ⁺=491; ¹H-NMR (CDCl ₃): 8.15 (s, 1H, NH), 7.81-6.99 (m, 3H), 7.39-7.28 (m, 5H), 5.15 (s, 2H), 3.59 (s, 2H), 3.52-3.43 (m, 4H), 2.44-2.39 (m, 4H).

Step 19-1.2:4-(4-benzoyloxy carbonyl-piperazine-1-ylmethyl)-3-trifluoromethyl-aniline

To 1.31g (2.67mMol) 2,2,2-three fluoro-N-[4-(4-carbobenzoxy-(Cbz)-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-the 20ml boiling methanol solution of ethanamide drips 13ml 1M K ₂CO ₃The aqueous solution.After stirring 1h, reaction mixture is cooled to rt, with EtOAc and water dilution.Isolate water layer, use the EtOAc extracting twice.With organic phase water and salt water washing, dry (Na ₂SO ₄), concentrate, obtain title compound, be directly used in step 19-1.3:[M+1] ⁺=394; ¹H-NMR (DMSO-d ₆): 7.39-7.21 (m, 6H), 6.82 (s, 1H), 6.75 (d, 1H), 5.41 (s, 2H), 5.01 (s, 2H), 3.40-3.29 (m, 6H), 2.31-2.24 (m, 4H).

Step 19-1.3:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-benzoyloxy carbonyl piperazine Piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

To N ₂The 5ml THF solution of ice-cold 0.38g (1.52mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) drips the 15ml ethereal solution of 0.60g (1.52mMol) 4-(4-benzoyloxy carbonyl piperazine-1-ylmethyl)-3-trifluoromethyl-aniline (step 15.2) under the atmosphere.After stirring 1.5h, reaction mixture is diluted with ether, leach solid, wash with ether.Crude product is dissolved in CH again ₂Cl ₂/ MeOH is adsorbed on SiO ₂On, place SiO then ₂The chromatographic column top.Use CH ₂Cl ₂/ MeOH (gradient 0-3%MeOH) wash-out obtains title compound: MS:[M+1] ⁺=642.7; ¹H-NMR (CDCl ₃): 8.59 (s, 1H), 7.62 (d, 1H), 7.59-7.51 (m, 2H), 7.41 (d, 2H), 7.35-7.30 (m, 3H), 7.18 (s, 1H), 7.15 (d, 2H), 7.05 (s, 1H), 6.90 (s, 1H), 5.19 (s, 2H), 3.62 (s, 2H), 3.59-3.40 (m, 4H), 2.51-2.38 (m, 4H).

Step 19-1.4:N-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-benzoyloxy carbonyl Base piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

As described in Ex.7, from 300mg (0.46mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-carbobenzoxy-(Cbz) piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea prepares title compound: MS:[M+1] ⁺=648; ¹H-NMR (CDCl ₃): 8.58 (s, 1H), 8.01 (s, 1H), 7.69-7.59 (m, 3H), 7.41 (d, 1H), 7.39-7.35 (m, 5H), 7.20 (s, 1H), 7.09 (d, 2H), 6.25 (s, 1H), 5.17 (s, 2H), 3.61 (s, 2H), 3.59-3.42 (m, 4H), 2.43-2.38 (m, 4H).

Embodiment 19-2:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-H-piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea

Hydrogenation 88.0mg (0.14mMol) N-[4-in the presence of 15mg Pd/C 10% (" Engelhard 4505 "), in 5ml MeOH (6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-benzoyloxy carbonyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea, filter, concentrated filtrate, chromatography [C18:CH ₃CN/H ₂O (+0.1%TFA), obtain title compound: m.p.:197-198 ℃; MS:[M+1] ⁺=502; ¹H-NMR (DMSO-d ₆): 8.80 (s, 1H, NH), 8.52 (s, 1H, NH), 8.06 (s, 1H), 7.89 (s, 1H), 7.63 (d, 1H), 7.58 (d, 1H), 7.49 (d, 2H), 7.05 (d, 2H), 5.79 (s, 1H), 3.18-3.09 (m, 4H), 2.80 (s, 3H), 2.69-2.59 (m, 4H).

Raw material is prepared as follows:

Step 19-2.1:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-benzoyloxy carbonyl Base piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

At N ₂Under the atmosphere, will contain 122mg (0.19mMol) N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-the 4ml 33%MeNH of N '-[4-(4-benzoyloxy carbonyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea (Ex.20-1) ₂EtOH solution in ice bath, stir 2h.Pour mixture into EtOAc and 10%NaHCO ₃In the solution, isolate water, use the EtOAc extracting twice.With organic layer water and salt solution washed twice, dry (Na ₂SO ₄), concentrate.Flash chromatography is handled (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-5%MeOH), obtain title compound: MS:[M+1] ⁺=636; ¹H-NMR (CDCl ₃): 8.21 (s, 1H), 7.61-7.44 (m, 3H), 7.39-7.31 (m, 5H), 7.17-6.99 (m, 3H), 6.51 (d, 1H), 5.75 (s, 1H), 5.12 (s, 2H), 3.59 (s, 3H), 3.48-3.41 (m, 4H), 2.91 (s, 2H), 2.41-2.35 (m, 4H).

Embodiment 20:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-tertiary butyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation.Crude product is through purification by flash chromatography (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-10%MeOH), obtain title compound, be yellow foam.C ₂₇H ₃₀ClF ₃N ₆O ₂；MS(ES+)，M+H＝563.6； ¹H-NMR(300MHz，CDCl ₃)：8.59(s，1H)，7.62(d，1H)，7.60-7.56(m，2H)，7.42(d，2H)，7.18-7.11(m，3H)，7.02(s，1H)，3.79(s，2H)，2.78-2.54(m，4H)，2.51-2.40(m，4H)，1.04(s，9H)。

Raw material is prepared as follows:

Step 20.1: two-(2-chloro-ethyl)-carboxylamine ethyl ester

According to document technology [J.Pharmaceutical.Sci.61 (1972), 1316], prepare title compound from two-(2-chloroethyl) amine.C ₇H ₁₃Cl ₂NO ₂；MS(ES+)，M+H＝216.4； ¹H-NMR(300MHz，CDCl ₃)：4.19(q，2H)，3.75-3.58(m，8H)，1.14(t，3H)。

The step 20.2:4-tertiary butyl-piperazine-1-formic acid ethyl ester

With step 20.1 compound (10g 46mmol) is dissolved in the trimethyl carbinol, subsequently rt add NaI (280mg, 1.8mmol) and TERTIARY BUTYL AMINE (5.12g, 70mmol).Then the yellow reaction mixture is heated to 130 ℃ in oil bath, stirs 13h.Be cooled to rt once more, add K ₂CO ₃(6.9g, 50mmol).Then reaction is exposed to microwave irradiation (130 ℃/6min).Filter and collect product, be dissolved in EtOAc,, obtain title compound, be xanchromatic oil (2.54g, 32mMol, 26%) through peracid/neutralizing treatment purifying.C ₁₁H ₂₂N ₂O ₂；MS(ES+)，M+H＝215.5； ¹H-NMR(300MHz，CDCl ₃)：4.15(q，2H)，3.51-3.40(m，4H)，2.58-2.41(m，4H)1.12(t，3H)，1.02(s，9H)。

The step 20.3:1-tertiary butyl-piperazine

(1g 4.6mmol) is dissolved in ethanol (15ml) with step 20.2 compound.(1.2g 201mmol), is heated to backflow with reaction and reaches 12h to add KOH.Be cooled to rt, under reduced pressure concentrate.Resistates is dissolved in EtOAc, uses the salt water washing.With organic layer through Na ₂SO ₄Drying concentrates, and is dry under high vacuum, obtains title compound, is xanchromatic oil (546mg, 3.7mMol, 82%).C ₈H ₁₈N ₂；MS(ES+)，M+H＝143.5； ¹H-NMR(300MHz，CDCl ₃)：2.91-2.84(m，4H)，2.59-2.48(m，4H)，1.02(s，9H)。

Step 20.4:N-[4-(the 4-tertiary butyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-2,2,2-three fluoro-second Acid amides

(540mg 3.8mmol) is dissolved in EtOH (3ml), adds 532mg (1.5mmol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides (step 14.2) at rt with step 20.3 compound.To be reflected at envrionment temperature and stir 1.5 hours until finishing.Concentrate, remaining crude product is through purification by flash chromatography (SiO ₂CH ₂Cl ₂/ MeOH, gradient 0-8%MeOH), obtain title compound, be xanchromatic oil (654mg, 1.5mMol, 42%).C ₁₈H ₂₃F ₆N ₃O；MS(ES+)，M+H＝412.0。

Step 20.5:4-(the 4-tertiary butyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl-amine

(650mg 1.5mmol) is dissolved in MeOH (15ml), in rt K with step 20.4 compound ₂CO ₃(the 7.9ml 1N aqueous solution) is handled.Reaction is heated to backflow reaches 1h until finishing, rt is got back in cooling, concentrates.The oil of remnants is dissolved in EtOAc, uses the salt water washing.With organic layer through Na ₂SO ₄Drying is filtered, and under reduced pressure concentrates.Dry under high vacuum, obtain title compound, for xanchromatic oil (496mg, 1.5mmol).C ₁₆H ₂₄F ₃N ₃；MS(ES+)，M+H＝316.1； ¹H-NMR(300MHz，CDCl ₃)：7.44(d，1H)，6.91(d，1H)，6.79(d，d，1H)，3.79(bs，2H)，3.51(s，2H)，2.67-2.59(m，4H)，2.58-2.40(m，4H)，1.01(s，9H)。

Be similar to technology described herein, can prepare Ex.20-1 to 20-8 compound:

Embodiment 20-1:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-benzoyloxy carbonyl-piperazine Piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation, start from 600mg (1.5Mmol) 4-(4-amino-2-trifluoromethyl-benzyl)-piperazine-1-formic acid benzyl ester.Crude product is through purification by flash chromatography (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-10%MeOH).MS(ES+)，M+H＝643； ¹H-NMR(300MHz，CDCl ₃)：8.57(s，1H)，7.64(d，1H，J＝8.2Hz)，7.59-7.55(m，2H)，7.43(d，J＝8.7Hz)，7.36-7.32(m，3H)，7.17(s，1H)，7.08(d，J＝8.7Hz)，7.04(s，1H)，6.91(s，1H)，5.17(s，2H)，3.60(s，2H)，3.57-3.45(m，4H)，2.49-2.33(m，4H)。

Raw material is prepared as follows:

Step 20-1.1:4-[4-(2,2,2-three fluoro-kharophens)-2-trifluoromethyl-benzyl]-piperazine-1-formic acid benzyl Ester

With 1.0g (2.8mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 15ml EtOH solution of 2-three fluoro-ethanamides (step 14.2) is handled with 1.57g (7.1mMol) benzyl-1-piperazine-manthanoate at rt.To be reflected at rt and stir 1h.After finishing, concentrate, remaining crude product is through purification by flash chromatography (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-10%MeOH), obtain title compound, be yellow solid.MS(ES+)，M+H＝491； ¹H-NMR(300MHz，CDCl ₃)：8.19(s，1H，NH)，7.92-7.89(m，3H)，7.40-7.38(m，5H)，5.18(s，2H)，3.60(s，2H)，3.58-3.52(m，4H)，2.49-2.38(m，4H)。

Step 20-1.2:4-(4-amino-2-trifluoromethyl-benzyl)-piperazine-1-formic acid benzyl ester

With 1.3g (2.6mMol) 4-[4-(2,2,2-three fluoro-kharophens)-2-trifluoromethyl-benzyl]-the 20ml MeOH solution of piperazine-1-formic acid benzyl ester at rt with 13.4ml 1M K ₂CO ₃The aqueous solution is handled.Then reaction is heated to backflow, stirs 2h.After finishing, MeOH is removed in distillation, and the residual water suspension extracts (3x) with EtOAc.Merge organic extract liquid, through Na ₂SO ₄Drying after filtering and concentrating in a vacuum, obtains title compound, is yellow solid.MS(ES+)，M+H＝394； ¹H-NMR(300MHz，DMSO-d ₆)：7.39-7.29(m，6H)，6.82(s，1H)，6.74(d，1H)；5.41(s，2H；NH ₂)，5.02(s，2H)，3.42(s，2H)，3.40-3.31(m，4H)，2.31-2.24(m，4H)。

Embodiment 20-2:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(N, N-dimethylamino-methyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation, start from 110mg (0.5mMol) 4-(4-(N, N-dimethylamino-methyl)-3-trifluoromethyl-phenyl-amine and 125mg (0.5mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3).Crude product is through purification by flash chromatography (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-10%MeOH), obtain title compound, be yellow foam.m.p.：98-105℃。MS(ES+)，M+H＝466。 ¹H-NMR(300MHz，DMSO-d ₆)：9.02(s，1H)，8.92(s，1H)，8.60(s，1H)，7.97(s，1H)，7.59-7.54(m，2H)，7.49(d，2H)，7.38(s，1H)，7.12(d，2H)，3.41(s，2H)，2.19(s，6H)。

Raw material is prepared as follows:

Step 20-2.1:4-(4-(N, N-dimethylamino-methyl)-3-trifluoromethyl-phenyl-2,2,2-three fluoro-ethanamides

With 501mg (1.5mmol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides (step 14.2) join in the EtOH solution (33%) of 5ml dimethylamine at rt.To be reflected at envrionment temperature and stir 0.5h until finishing.Concentrate, remaining crude product is through purification by flash chromatography (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-5%MeOH), obtain title compound, be xanchromatic oil.MS(ES+)，M+H＝315。

Step 20-2.2:4-(4-(N, N-dimethylamino-methyl)-3-trifluoromethyl-phenyl-amine

(359mg 1.2mmol) is dissolved in MeOH (12ml), at rt K with step 20-1.1 compound ₂CO ₃(the 6ml 1N aqueous solution) is handled.Reaction is heated to backflow reaches 1.5h until finishing, rt is got back in cooling, concentrates.The oil of remnants is dissolved in EtOAc, uses the salt water washing.With organic layer through Na ₂SO ₄Drying is filtered, and under reduced pressure concentrates.Dry under high vacuum, obtain title compound, be xanchromatic oil.M+H＝219。

Embodiment 20-3:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(N, N-diethylin-methyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation, start from 370mg (1.5mMol) 4-(4-(N, N-diethylin-methyl)-3-trifluoromethyl-phenyl-amine and 371mg (1.5mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3).Crude product is through purification by flash chromatography (SiO ₂, CH ₂Cl ₂/ MeOH, gradient 0-10%MeOH), obtain title compound: MS (ES+), M+H=494.

Embodiment 20-4:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-[(3-dimethylamino-propyl group)-methyl-amino-methyl]]-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation; start from 600mg (2.2mMol) 4-[(3-dimethylamino-propyl)-methyl-amino-methyl]]-3-trifluoromethyl-phenyl-amine and 539mg (2.2mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3); obtain title compound: MS (ES+), M+H=523.

Embodiment 20-5:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-[(4-cyano group-benzyl)-amino-methyl]-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation; start from 440mg (1.4mMol) 4-[(4-cyano group-benzyl)-amino-methyl]]-3-trifluoromethyl-phenyl-amine and 375mg (1.4mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3); obtain title compound: MS (ES+), M+H=553.

Embodiment 20-6:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(1-morpholinyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation, start from 260mg (1.0mMol) 4-(morpholine-4-ylmethyl)-3-trifluoromethyl-phenyl amine and 248mg (1.0mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3), obtain title compound: MS (ES+), M+H=508; ¹H-NMR (300MHz, DMSO-d ₆): 8.82 (s, 1H, NH), 8.79 (s, 1H, NH), 8.69 (s, 1H), 7.91 (s, 1H), 7.75-7.65 (2 * d, 2H), 7.50 (d, 2H), 7.15 (d, 2H), 7.12 (s, 1H), 3.74 (s, 2H), 3.71-3.61 (m, 4H), 2.62-2.52 (m, 4H).

Embodiment 20-7:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(tetramethyleneimine-1-base-amino-methyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation.MS(ES+)，M+H＝493； ¹H-NMR(300MHz，CDCl ₃)：8.59(s，1H)，7.71(d，2H)，7.51-7.39(m，3H)，7.17(s，1H)，7.02(d，2H)，6.93(s，1H)，3.79(s，2H)，2.62-2.58(m，4H)，2.93-2.72(m，4H)。

Embodiment 20-8:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-(4-methoxy-benzyl) piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

Be similar to the Ex.14 preparation, start from 878mg (2.3mMol) 4-[4-(4-methoxyl group-benzyl)-piperazinyl]-3-trifluoromethyl-phenyl amine and 573mg (2.3mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3), obtain title compound: MS (ES+), M+H=628; ¹H-NMR (300MHz, CDCl ₃): 8.59 (s, 1H), 7.75 (d, 1H), 7.41 (d, 2H), 7.20 (d, 2H), 7.17 (d, 2H), 6.98 (s, 1H), 6.83 (d, 3H), 6.79 (s, 1H), 3.80 (s, 3H), 3.59 (s, 2H), 3.42 (s, 2H), 2.58-2.37 (m, 8H).

Embodiment 21:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(methyl-tertiary butyl-amino-methyl)-3-trifluoromethyl-phenyl]-urea

Be similar to Ex.14; the 3ml THF solution of 1.0g (4.0mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and the 30ml ethereal solution of 1.1g (4.2mMol) 4-(methyl-tertiary butyl-amino-methyl)-3-trifluoromethyl-aniline (step 21.2) are reacted, obtain title compound: ultimate analysis C ₂₄H ₂₅N ₅ClF ₃O ₂: C, H, N, Cl, F; MS:[M+1] ⁺=508; ¹H-NMR (CDCl ₃): 8.61 (s, 1H), 7.94 (d, 8.2Hz, 1H), 7.63 (d, 2Hz, 1H), 7.54 (dd, 8Hz, 2Hz, 1H), 7.47 (d, 9Hz, 2H), 7.14 (d, 9Hz, 2H), 6.95 (s, 1H), 6.93 (s, 1H), 6.91 (s, 1H), 3.69 (s, 2H), 2.13 (s, H ₃C), 1.17 (s, the tertiary butyls).

Raw material is prepared as follows:

Step 21.1:2,2,2-three fluoro-N-[4-(methyl-tertiary butyl-amino-methyl)-3-trifluoromethyl-phenyl]-second Acid amides

In 30min to N ₂The 80ml acetonitrile solution of ice-cold 2.05ml (17mMol) methyl-tertiary butyl-amine drips 2.0g (5.7mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 80ml acetonitrile solution of 2-three fluoro-ethanamides (step 14.2) under the atmosphere.Behind the 30min, as described in step 14.3, handle in addition, obtain title compound, be oil: MS:[M+1] ⁺=357; HPLC ^At _Ret=10.0.

Step 21.2:4-(methyl-tertiary butyl-amino-methyl)-3-trifluoromethyl-aniline

As saponification 2.55g (7.2mMol) 2,2 as described in the step 15.2,2-three fluoro-N-[4-(methyl-tertiary butyl-amino-methyl)-3-trifluoromethyl-phenyl]-ethanamide, obtain title compound, be oil: MS:(M+1) ⁺=261; HPLC ^At _Ret=8.3.

Embodiment 22:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(azetidine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

Be similar to Ex.14, the 2ml THF solution of 431mg (1.7mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and the 10ml ethereal solution of 400mg (1.7mMol) 4-(azetidine-1-ylmethyl)-3-trifluoromethyl-aniline (step 22.2) are reacted, obtain title compound: MS:[M+1]=478; HPLC ^At _Ret=11.3.

Raw material is prepared as follows:

Step 22.1:2,2,2-three fluoro-N-[4-(azetidine-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetyl Amine

In 65min to N ₂The 100ml acetonitrile solution of ice-cold 1.74ml (25.7mMol) azetidine drips 3.0g (8.5mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 100ml acetonitrile solution of 2-three fluoro-ethanamides (step 14.2) under the atmosphere.Behind the 75min, as described in step 14.3, handle in addition, obtain title compound, be oil: MS:[M+1] ⁺=327; HPLC ^At _Ret=9.1.

Step 22.2:4-(azetidine-1-ylmethyl)-3-trifluoromethyl-aniline

As saponification 2.67g (8.2mMol) 2,2 as described in the step 15.2,2-three fluoro-N-[4-(azetidine-1-ylmethyl)-3-trifluoromethyl-phenyl]-ethanamide, obtain title compound, be oil: MS:[M+1] ⁺=231; ¹H-NMR (CDCl ₃): 7.37 (d, 8.2Hz, 1H), 6.90 (d, 2Hz, 1H), 6.79 (dd, 8Hz, 2Hz, 1H), 3.75 (s, H ₂N), 3.64 (s, 2H), 3.25 (t, 6.8Hz, 4H), 2.10 (quintet, 6.8Hz, 2H).

Embodiment 23:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4,5-methylimidazole-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

At N ₂Under the atmosphere, 238mg (0.96mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 246mg (0.91mMol) 4-(4,5-methylimidazole-1-ylmethyl)-3-trifluoromethyl-aniline (step 23.2) are dissolved in 5ml THF.Behind the 15min, add 10ml DIPE (having precipitation to generate), continue to stir 2h.Filter and wash, obtain title compound: m.p.:195-196 ℃ with DIPE; Anal.C ₂₄H ₂₀N ₆ClF ₃O ₂0.4DIPE0.1THF:C, H, N, Cl, F; MS:[M+1] ⁺=517; ¹H-NMR (CDCl ₃): 9.23 (s, 1H), 8.99 (s, 1H), 8.52 (s, 1H), 8.46 (d, 2Hz, 1H), 7.55 (d, 9.0Hz, 2H), 7.45 (s, 1H), 7.03 (d, 9Hz, 2H), 6.83 (s, 1H), 6.34 (dd, 8.6Hz, 2Hz, 1H), 6.12 (d, 8.6Hz, 1H), 5.15 (s, 2H), 2.20 (s, H ₃C), 2.02 (s, H ₃C).

Raw material is prepared as follows:

Step 23.1:2,2,2-three fluoro-N-[4-(4,5-methylimidazole-1-ylmethyl)-3-trifluoromethyl-phenyl]-second Acid amides

In 30min to N ₂Ice-cold 1.81g (18.8mMol) 4 under the atmosphere, the 70ml acetonitrile solution of 5-methylimidazole drips 2.2g (6.3mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 70ml acetonitrile solution of 2-three fluoro-ethanamides (step 14.2).Behind the 5h, suspension is filtered resistates CH ₃CN washing obtains title compound (as concentrated filtrate as described in the step 14.3, extraction can be separated to more product): m.p.:238-239 ℃; MS:[M+1] ⁺=366.

Step 23.2:4-(4,5-methylimidazole-1-ylmethyl)-3-trifluoromethyl-aniline

As saponification 2.67g (7.3mMol) 2,2 as described in the step 15.2,2-three fluoro-N-[4-(4,5-methylimidazole-1-ylmethyl)-3-trifluoromethyl-phenyl]-ethanamide, through chromatography (SiO ₂, EtOAc/Et ₃N99: 1 → EtOAc/EtOH/Et ₃N 97: 2: 1), crystallization from EtOAc obtains title compound: m.p.:185-186 ℃; MS:[M+1] ⁺=270.

Embodiment 24:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(glyoxal ethyline-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

At N ₂Under the atmosphere, 1.00g (4.04mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 1.03g (4.04mMol) 4-(glyoxal ethyline-1-ylmethyl)-3-trifluoromethyl-aniline (step 24.2) are dissolved in 40ml THF.During rt stirs 4h, generate suspension, can leach title compound: m.p.:228 ℃; Anal.C ₂₃H ₁₈N ₆CIF ₃O ₂: C, H, N, Cl; MS:[M+1] ⁺=503; ¹H-NMR (DMSO-d ₆): 9.15 (s, 1H), 8.93 (s, 1H), 8.67 (s, 1H), 8.14 (d, 2Hz, 1H), 7.55 (d, 9.0Hz, 2H), 7.54 (m, 1H), 7.36 (s, 1H), 7.19 (d, 9Hz, 2H), 7.08 (s, 1H), 6.84 (s, 1H), 6.66 (d, 8.6Hz, 1H), 5.27 (s, 2H), 2.20 (s, H ₃C).

Raw material is prepared as follows:

Step 24.1:2,2,2-three fluoro-N-[4-(glyoxal ethyline-1-ylmethyl)-3-trifluoromethyl-phenyl]-acetyl Amine

In 30min to N ₂The 80ml acetonitrile suspension of ice-cold 1.85g (22.5mMol) glyoxal ethyline drips 2.64g (7.5mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2, the 80ml acetonitrile solution of 2-three fluoro-ethanamides (step 14.2) under the atmosphere.After rt stirs 5h, generate solution, concentrate in a vacuum then.Resistates EtOAc and saturated NaHCO ₃Solution/H ₂O dilution in 1: 1.Isolate water layer, use the EtOAc extracting twice.With the saturated NaHCO of organic layer ₃Solution/H ₂O 1: 1, water and salt water washing, dry (Na ₂SO ₄), concentrate.Handle (SiO through column chromatography ₂, EtOAc/EtOH 19: 1 → 9: 1), obtain title compound: m.p.:229-230 ℃; MS:[M+1] ⁺=352.

Step 24.2:4-(glyoxal ethyline-1-ylmethyl)-3-trifluoromethyl-aniline

As saponification 2.0g (5.69mMol) 2,2 as described in the step 15.2,2-three fluoro-N-[4-(glyoxal ethyline-1-ylmethyl)-3-trifluoromethyl-phenyl]-ethanamide, from EtOAc, obtain title compound: m.p.:146-147 ℃ after the crystallization; MS:[M+1] ⁺=256.

Embodiment 25:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(2,4-methylimidazole-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

Can be similar to Ex.23 or 24 preparations.

Embodiment 26:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-ethyl piperazidine-1-ylmethyl)-3-methyl-phenyl]-urea

Be similar to Ex.14; the 2ml THF solution of 467mg (1.88mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and the 8ml ether suspension of 440mg (1.88mMol) 4-(4-ethyl piperazidine-1-ylmethyl)-3-methyl-aniline (step 26.4) are reacted, obtain title compound: MS:[M+1] ⁺=481; ¹H-NMR (DMSO-d ₆): 8.77 (s, 1H), 8.67 (s, 1H), 8.60 (s, 1H), 7.53 (d, 9.0Hz, 2H), 7.35 (d, 0.8Hz, 1H), 7.21-7.27 (m, 2H), 7.17 (d, 9.0Hz, 2H), 7.10 (d, 8.2Hz, 1H), 3.34 (s, 2H), 2.36 (m, 10H), 2.30 (s, H ₃C), 0.98 (t, 7.2Hz, H ₃C).

Raw material is prepared as follows:

Step 26.1:4-nitro-2-methyl-phenylformic acid

The mixture of 3.04g (18.7mMol) 2-methyl-4-nitrobenzonitrile [preparation is referring to J.Med.Chem.44 (2001), 3856], the dense HCl of 26ml and 26ml acetate is heated 8h to 150 ℃ in the test tube of sealing.Reaction mixture is filtered, and washes with water, obtains title compound: m.p.:151-155 ℃; MS:[M-1] ⁺=180.

Step 26.2:(4-nitro-2-methyl-phenyl)-(4-ethyl piperazidine-1-yl)-ketone

Be similar to step 5.1,8.72g (48.1mMol) 4-nitro-2-methyl-phenylformic acid with the activation of 6.52ml (77mMol) oxalyl chloride, with the reaction of 13.45ml (106mMol) 1-ethyl piperazidine, is obtained title compound: m.p.:96-99 ℃; MS:[M+1] ⁺=278.

Step 26.3:(4-amino-2-methyl-phenyl)-(4-ethyl piperazidine-1-yl)-ketone

As described in step 1.5, at hydrogenation 12.6g (45.5mMol) in the presence of the 2g Raney nickel, in 200ml ethanol (4-nitro-2-methyl-phenyl)-(4-ethyl piperazidine-1-yl)-ketone, obtain title compound, be oil: [M+1] ⁺=248.

Step 26.4:4-(4-ethyl piperazidine-1-ylmethyl)-3-methyl-aniline

Be similar to step 5.3,11.12g (45mMol) (4-amino-2-methyl-phenyl)-(4-ethyl piperazidine-1-yl)-ketone is used 135ml BH in 100ml THF ₃(1M THF solution) reduction.Through chromatography (SiO ₂, CH ₂Cl ₂/ MeOH/NH ₃ ^Aq97: 3: 1), obtain oiliness title compound: MS:[M+1] ⁺=234; ¹H-NMR (CDCl ₃): 7.04 (d, 8.2Hz, 1H), 6.54 (d, 2.4Hz, 1H), 6.51 (dd, 8Hz, 2.4Hz, 1H), 3.59 (s, H ₂N), 3.39 (s, 2H), 2.5 (m, 8H), 2.43 (q, 7.2Hz, 2H), 2.31 (s, H ₃C), 1.11 (t, 7.2Hz, H ₃C).

Embodiment 27:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-ethyl piperazidine-1-ylmethyl)-phenyl]-urea

230mg (0.93mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 200mg (0.91mMol) 4-(4-ethyl piperazidine-1-the ylmethyl)-solution of aniline in 8ml THF are stirred 40min at rt.Add ≈ 15ml DIPE crystallization, filter,, obtain title compound: m.p.:203-204 ℃ with the DIPE washing; MS:[M+1] ⁺=467; ¹H-NMR (CDCl ₃): 8.62 (s, 1H), 7.48 (d, 9.0Hz, 2H), 7.33 (m, 4H), 7.13 (d, 9.0Hz, 2H), 6.95 (s, 1H), 6.88 (s, 1H), 6.75 (s, 1H), 3.52 (s, 2H), 2.53 (m, 8H), 2.45 (q, 7.0Hz, 2H), 1.12 (t, 7.0Hz, H ₃C).

Raw material is prepared as follows:

Step 27.1:4-(4-ethyl piperazidine-1-ylmethyl)-aniline

Be similar to step 5.3,7.8g (33.4mMol) (4-aminophenyl)-(4-ethyl piperazidine-1-yl)-ketone [synthetic as mentioned above or referring to J.Pharmaceutical Sci.57 (1968), 2073] used 100ml BH in 105ml THF at 65 ℃ ₃(1M THF solution) reduction: MS:[M+1] ⁺=220; ¹H-NMR (CDCl ₃): 7.13 (d, 8.2Hz, 2H), 6.68 (d, 8.2Hz, 2H), 3.67 (s, H ₂N), 3.47 (s, 2H), 2.6 (m, 8H), 2.53 (q, 7.3Hz, 2H), 1.16 (t, 7.3Hz, H ₃C).

Embodiment 28:1-(4-[1,4 '] connection piperidines-1 '-Ji-3-trifluoromethyl-phenyl)-3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea

With 248mg (1.0mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 327mg (1.0mMol) 4-[1,4 '] connection piperidines-1 '-Ji-solution of 3-trifluoromethyl-phenyl amine (step 28.2) in 8mlTHF stirs 30min at rt.Add 15ml DIPE crystallization, filter,, obtain title compound: MS:[M+1] with the DIPE washing ⁺=575; HPLC ^Bt _Ret=2.06.

Raw material is prepared as follows:

Step 28.1:1 '-(4-nitro-2-trifluoromethyl-phenyl)-1-[1,4 '] the connection piperidines

With 1.0ml (7.27mMol) 1-fluoro-4-nitro-2-trifluoromethyl-benzene, 1.47g (8.73mMol) [1,4 '] connection piperidines and 1.51g (10.9mMol) K ₂CO ₃Solution is at stirring at room 17h in 15ml DMF.Behind the vapourisation under reduced pressure DMF, with reaction mixture 80ml H ₂The O dilution extracts 3x with 60mlEtOAc.Merge organic phase, use 30ml H ₂O and the water washing of 30ml salt, dry (MgSO ₄), under reduced pressure concentrate, handle (SiO through flash chromatography ₂, 4.0 * 24cm, MeOH/CH ₂Cl ₂1: 19), obtain title compound, be oil: ¹H-NMR (400MHz, CDCl ₃): 8.45 (dd, 1H), 8.25 (dd, 1H), 7.20 (dd, 1H), 3.45 (m, 2H), 2.88 (m, 2H), 2.58 (m, 4H), 2.40 (m, 1H), 1.60 (m, 10H).

Step 28.2:4-[1,4 '] connection piperidines-1 '-Ji-3-trifluoromethyl-phenyl amine

As described in step 1.5, at hydrogenation 2.14g (5.99mMol) 1 ' in the presence of the 220mg 10%Pd/C, in 25ml ethanol-(4-nitro-2-trifluoromethyl-phenyl)-[1,4 '] connection piperidines, obtain title compound, be oil: MS:[M+1] ⁺=328.

Embodiment 29:1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-{4-[4-(2,2-dimethyl-propyl group)-piperazine-1-ylmethyl]-3-trifluoromethyl-phenyl }-urea

With 112mg (0.45mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 150mg (0.45mMol) 4-[4-(2,2-dimethyl-propyl group)-piperazine-1-ylmethyl]-solution of 3-trifluoromethyl-phenyl amine (step 29.4) in 8ml THF stirs 30min at rt.Add ≈ 15ml DIPE crystallization, filter,, obtain title compound: MS:[M+1] with the DIPE washing ⁺=578; HPLC ^Bt _Ret=2.18; ¹H-NMR (d ₆-DMSO): 9.00 (bs, 1H), 8.82 (bs, 1H), 8.60 (s, 1H), 7.94 (s, 1H), 7.5 (m, 4H), 7.30 (s, 1H), 7.10 (m, 2H), 3.46 (bs, 2H), 2.45 (m, 4H), 2.35 (m, 4H), 2.00 (s, 2H), 0.80 (s, 9H).

Raw material is prepared as follows:

Step 29.1:3-[2-(2,2-dimethyl-propyl group amino)-ethyl]-oxazolidines-2-ketone

With 5g (17.5mMol) toluene-4-sulfonic acid 2-(2-oxo-oxazolidines-3-yl)-ethyl ester, 1.68g (19.2mMol) 2,2-dimethyl-propyl group amine and 3.63g (26.3mMol) K ₂CO ₃Solution in 35ml MeCN stirs 12h at 40 ℃.Behind the vapourisation under reduced pressure MeOH, with reaction mixture 80mlH ₂The O dilution is with 60ml EtOAc extraction 3x.Merge organic phase, use 30ml H ₂O and the water washing of 30ml salt, dry (MgSO ₄), under reduced pressure concentrate, obtain the title crude compound, be oil.MS：[M+1] ⁺＝201； ¹H-NMR(CDCl ₃)：4.30(dd，2H)，3.65(dd，2H)，3.35(t，2H)，2.80(t，2H)，2.35(s，2H)，0.90(s，9H)。

Step 29.2:1-(2,2-dimethyl-propyl group)-piperazine two hydrobromates

According to document technology (Tetrahedron Letters, 40,7331,1994), use 3-[2-(2,2-dimethyl-propyl group amino)-ethyl]-oxazolidine-2-ketone prepares 1-(2,2-dimethyl-propyl group)-piperazine two hydrobromates: MS:[M+1] ⁺=157.

Step 29.3:N-{4-[4-(2,2-dimethyl-propyl group)-piperazine-1-ylmethyl]-3-trifluoromethyl-benzene Base }-2,2,2-three fluoro-ethanamides

With 1.0g (3.14mMol) 1-(2,2-dimethyl-propyl group)-piperazine two hydrobromates, 440mg (1.25mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides (step 14.2) and 0.53ml (3.77mMol) triethylamine are dissolved in 10ml DMF, stir 3h at rt.Behind the vapourisation under reduced pressure acetonitrile, with reaction mixture 80ml H ₂The O dilution is with 70ml EtOAc extraction 3 times.Merge organic phase, use 30ml NaHCO ₃Solution and 30ml salt solution washed twice, dry (MgSO ₄), under reduced pressure concentrate, handle (MeOH/CH through flash chromatography ₂Cl ₂1: 19), obtain yellow solid: MS:[M+1] ⁺=426; HPLC ^Bt _Ret=2.13.

Step 29.4:4-[4-(2,2-dimethyl-propyl group)-piperazine-1-ylmethyl]-3-trifluoromethyl-phenyl amine

To 445mg (1.04mMol) N-{4-[4-(2,2-dimethyl-propyl group)-piperazine-1-ylmethyl]-3-trifluoromethyl-phenyl }-2,2, the solution of 2-three fluoro-ethanamides in 18ml boiling methyl alcohol drips 5.2ml 1MK ₂CO ₃The aqueous solution.After stirring 1h, reaction mixture is cooled to rt, with EtOAc and water dilution.Isolate water layer, use the EtOAc extracting twice.With organic phase water and salt water washing, dry (Na ₂SO ₄), concentrate, obtain title compound, be directly used in Ex.29:MS:[M+1] ⁺=330; HPLC ^Dt _Ret=1.73.

Embodiment 30:1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-{4-[4-(2,2-dimethyl-propyl group)-piperazine-1-yl]-3-trifluoromethyl-phenyl }-urea

With 141mg (0.57mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 180mg (0.57mMol) 4-[4-(2,2-dimethyl-propyl group)-piperazine-1-yl]-solution of 3-trifluoromethyl-phenyl amine (step 30.2) in 8ml THF stirs 30min at rt.Add ≈ 15ml DIPE crystallization, filter,, obtain title compound: MS:[M+1] with the DIPE washing ⁺=563; HPLC ^Dt _Ret=2.28.

Raw material is prepared as follows:

Step 30.1:1-(2,2-dimethyl-propyl group)-4-(4-nitro-2-trifluoromethyl-phenyl)-piperazine

With 0.36ml (2.62mMol) 1-fluoro-4-nitro-2-trifluoromethyl-benzene, 1.0g (3.14mMol) 1-(2,2-dimethyl-propyl group)-piperazine two hydrobromates and 1.08g (7.86mMol) K ₂CO ₃Solution in 8mlDMF is at stirring at room 17h.Behind the vapourisation under reduced pressure DMF, with reaction mixture 80ml H ₂The O dilution is with 60ml EtOAc extraction 3x.Merge organic phase, use 30ml H ₂O and the water washing of 30ml salt, dry (MgSO ₄), under reduced pressure concentrate, handle (SiO through flash chromatography ₂, MeOH/CH ₂Cl ₂1: 19), obtain title compound, be oil: MS:[M+1] ⁺=346; HPLC ^Dt _Ret=2.39; ¹H-NMR (300MHz, CDCl ₃): 8.50 (dd, 1H), 8.30 (dd, 1H), 7.25 (dd, 1H), 3.15 (m, 4H), 2.70 (m, 4H), 2.10 (s, 2H), 0.90 (s, 9H).

Step 30.2:4-[4-(2,2-dimethyl-propyl group)-piperazine-1-yl]-3-trifluoromethyl-phenyl amine

As described in step 1.5, hydrogenation 210mg (0.63mMol) 1-(2,2-dimethyl-propyl group) in the presence of 40mg 10% Pd/C, in 10ml ethanol-4-(4-nitro-2-trifluoromethyl-phenyl)-piperazine obtains title compound, is oil: MS:[M+1] ⁺=316.

Embodiment 31:1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(1-methyl-piperidin-4-yl methoxyl group)-3-trifluoromethyl-phenyl]-urea

248mg (1.00mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 288mg (1.00mMol) 4-(1-methyl-piperidin-4-yl the methoxyl group)-solution of 3-trifluoromethyl-phenyl amine (step 31.2) in 8ml THF are stirred 30min at rt.Add ≈ 15ml DIPE crystallization, filter,, obtain title compound: MS:[M+1] with the DIPE washing ⁺=535; HPLC ^At _Ret=1.98.

Raw material is prepared as follows:

Step 31.1:1-methyl-4-(4-nitro-2-trifluoromethyl-phenoxymethyl)-piperidines

With 1.00ml (7.27mMol) 1-fluoro-4-nitro-2-trifluoromethyl-benzene, 1.88g (14.5mMol) (1-methyl-piperidin-4-yl)-methyl alcohol and 470mg (1.45mMol) Tetrabutyl amonium bromide 6ml toluene and 6ml 25%KOH ^AqIn solution stir 17h at 60 ℃.Behind the cooling solution, with reaction mixture 80ml H ₂The O dilution is with 60ml EtOAc extraction 3 times.Merge organic phase, use 30mlNaHCO ₃Solution and 30ml salt solution washed twice, dry (MgSO ₄), under reduced pressure concentrate, handle (MeOH/CH through flash chromatography ₂Cl ₂1: 19), obtain title compound: MS:[M+1] ⁺=319.

Step 31.2:4-(1-methyl-piperidin-4-yl methoxyl group)-3-trifluoromethyl-phenyl amine

As described in step 1.5, hydrogenation 1.86g (5.84mMol) 1-methyl-4-(4-nitro-2-trifluoromethyl-phenoxymethyl)-piperidines obtains title compound in the presence of 190mg 10% Pd/C, in 20ml ethanol, is oil: MS:[M+1] ⁺=289.

Embodiment 32:1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(1-methyl-piperidin-4-yl oxygen base)-3-trifluoromethyl-phenyl]-urea

248mg (1.00mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 274mg (1.00mMol) 4-(1-methyl-piperidin-4-yl oxygen the base)-solution of 3-trifluoromethyl-phenyl amine (step 32.2) in 8ml THF are stirred 30min at rt.Add ≈ 15ml DIPE crystallization, filter,, obtain title compound: MS:[M+1] with the DIPE washing ⁺=522; HPLC ^At _Ret=1.96.

Raw material is prepared as follows:

Step 32.1:1-methyl-4-(4-nitro-2-trifluoromethyl-phenoxy group)-piperidines

With 1.00ml (7.27mMol) 1-fluoro-4-nitro-2-trifluoromethyl-benzene, 1.71ml (14.5mMol) 1-methyl-piperidines-4-alcohol and 470mg (1.45mMol) Tetrabutyl amonium bromide at 6ml toluene and 6ml25%KOH _AqIn solution stir 17h at 60 ℃.Behind the cooling solution, with reaction mixture 80mlH ₂The O dilution is with 60ml EtOAc extraction 3 times.Merge organic phase, use 30ml NaHCO ₃Solution and 30ml salt solution washed twice, dry (MgSO ₄), under reduced pressure concentrate, handle (MeOH/CH through flash chromatography ₂Cl ₂1: 19), obtain title compound: MS:[M+1] ⁺=305.

Step 32.2:4-(1-methyl-piperidin-4-yl oxygen base)-3-trifluoromethyl-phenyl amine

As described in step 1.5, hydrogenation 1.74g (5.72mMol) 1-methyl-4-(4-nitro-2-trifluoromethyl-phenoxy group)-piperidines obtains title compound in the presence of 180mg 10% Pd/C, in 20ml ethanol, is oil: MS:[M+1] ⁺=275.

Embodiment 33:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-4-[2-(4-ethyl-piperazine-1-yl)-ethyl]-3-trifluoromethyl-phenyl }-urea

At N ₂Under the atmosphere; with 370mg (1.49mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) and 450mg (1.49mMol) 4-[2-(4-ethyl-piperazine-1-yl)-ethyl]-3-trifluoromethyl-phenyl amine (step 33.3) is dissolved in 1.4ml THF and 7.4ml ether, stirs 1h.Concentrate and reverse-phase chromatography processing (Gilson System), obtain title compound: HPLC ^At _Ret=11.1; MS:[M+1] ⁺=549; ¹H-NMR (CDCl ₃): 8.60 (s, 1H), 7.58 (d, 1H), 7.57 (s, 1H), 7.46 (d, 9.0Hz, 2H), 7.30 (m, 1H), 7.12 (m, 4H), 6.95 (s, 1H), 2.94 (m, 2H), 2.6 (m, 12H), 1.13 (t, 7.2Hz, H ₃C).

Raw material is prepared as follows:

Step 33.1:2-(4-nitro-2-trifluoromethyl-phenyl)-1-(4-ethyl-piperazine-1-yl)-ethyl ketone

To ice-cold 11.4g (45.9mMol) (4-nitro-2-trifluoromethyl-phenyl)-acetate at 200mlCH ₂Cl ₂With drip 7.36ml (87.2mMol) oxalyl chloride in the solution among the 2ml DMF.Concentrated reaction mixture in a vacuum behind the 20min.Resistates is dissolved in 200ml CH again ₂Cl ₂, the 80ml CH of dropping 12.2ml (96mMol) N-ethyl-piperazine ₂Cl ₂Solution.Behind the 1h, with mixture 0.4L 10%Na ₂CO ₃Solution and 0.4L CH ₂Cl ₂Water layer is isolated in dilution, uses CH ₂Cl ₂Extracting twice.With organic phase 10%Na ₂CO ₃Solution, water and salt solution washed twice, dry (Na ₂SO ₄), concentrate, obtain title compound: HPLC ^At _Ret=9.2; MS:[M+1] ⁺=346.

Step 33.2:2-(4-amino-2-trifluoromethyl-phenyl)-1-(4-ethyl-piperazine-1-yl)-ethyl ketone

Hydrogenation 15.35g (44.5mMol) 2-(4-nitro-2-trifluoromethyl-phenyl) in the presence of 2.46g Raney nickel (B113W Degussa), in 245ml ethanol-1-(4-ethyl-piperazine-1-yl)-ethyl ketone.Filter, concentrated filtrate is handled (SiO through column chromatography ₂, EtOAc/EtOH+1%NH ₃ ^Aq4: 1), obtain title compound: MS:[M+1] ⁺=316; R _f(EtOAc/EtOH+1%NH ₃ ^Aq4: 1): 0.11.

Step 33.3:4-[2-(4-ethyl-piperazine-1-yl)-ethyl]-3-trifluoromethyl-phenyl amine

35ml THF solution to 3.47g (11.0mMol) 2-(4-amino-2-trifluoromethyl-phenyl)-1-(4-ethyl-piperazine-1-yl)-ethyl ketone in 30min drips 46.8ml1M BH ₃THF solution.After stirring 20h, at 30 ℃ of 1: 1 mixtures that in 20min, drips dense HCl of 60ml and water of ≈.Mixture is stirred 16h at rt, then partial concentration in a vacuum.Resistates is extracted 3 times with EtOAc, and organic layer discards then with 0.1N HCl washing.The oxytropism water adds saturated Na ₂CO ₃Solution is to alkalescence, with EtOAc extraction 3 times.With organic layer salt water washing, dry (Na ₂SO ₄), concentrate.Handle (CH through the Combi flash chromatography ₂Cl ₂/ MeOH+1%NH ₃ ^Aq99: 1 → 95: 5), obtain title compound: MS:[M+1] ⁺=302.

Embodiment 34: be similar to described technology, can prepare following compounds:

^*) educt A synthetic referring to Ex.65

^*) be similar to Ex.16, respectively from MeNH ₂And EtNH ₂The THF formulations prepared from solutions, 4-10d under rt

^{* *}) educt step 69.1

$) ^Dt _Ret

Be similar to technology described herein and can prepare the Ex.35-44 compound:

Embodiment 35:3-{3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide

Be similar to Ex.14; 250mg (1.0mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) is dissolved in 2ml THF; with 204mg (1.0mMol) 3-amino-5-trifluoromethyl)-reaction of the 6ml ethereal solution of benzamide (step 35.2), obtain title compound: MS:[M+1] ⁺=452; ¹H-NMR (DMSO-d ₆): 9.41 (s, 1H, NH), 9.05 (s, 1H, NH), 8.62 (s, 1H), 8.16 (s, 2H, NH ₂), 8.14 (s, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.55-7.52 (m, 3H), 7.32 (s, 1H), 7.17 (d, 2H).

Raw material is prepared as follows:

Step 35.1:(3-nitro-5-trifluoromethyl)-benzamide

Be similar to step 1.4 preparation, from 2.35g (10.0mMol) 3-nitro-5-trifluoromethyl-phenylformic acid (Lancaster) and 20ml NH ₃(25% aqueous solution) obtains title compound.MS：[M+1] ⁺＝233。

Step 35.2:(3-amino-5-trifluoromethyl)-benzamide

Be similar to step 1.5 preparation, with 250mg Pd-C (the 10% Engelhard 4505) hydrogenation of 2.34g (10mmol) (3-nitro-5-trifluoromethyl)-benzamide.MS：[M+1] ⁺＝205。 ¹H-NMR(400MHz，DMSO-d ₆)：7.99(s，1H)，7.31(s，1H)，7.19(s，2H，NH ₂)，6.89(s，1H)，5.78(s，2H，NH ₂)。m.p.：94-98℃。

Embodiment 36:3-{3-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide

Be similar to Ex.16, by 45mg (0.1mMol) 3-{3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide and 0.8ml methylamine (33%EtOH solution) preparation.MS：[M+1] ⁺＝447；HPLC ^Bt _Ret：2.31。

Embodiment 37:3-{3-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide

As described in Ex.7, from 150mg (0.33mMol) 3-{3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide prepares title compound, directly as the raw material of Ex.38.MS：[M+1] ⁺＝459。

Embodiment 38:3-{3-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide

Hydrogenase 10 .15g (0.33mMol) 3-{3-[4-in the presence of 20mg Pd/C 10% (" Engelhard 4505 "), in 10ml DME (6-azido--pyrimidine-4-base oxygen base)-phenyl]-urea groups }-5-trifluoromethyl-benzamide, filter, concentrated filtrate is through chromatography (preparation type TLC:CH ₂Cl ₂/ MeOH 9: 1), obtain title compound: MS:[M+1] ⁺=433; ¹H-NMR (DMSO-d ₆): 9.72 (s, 1H, NH), 9.43 (s, 1H, NH), 8.18 (s, 1H), 8.16 (s, 1H), 8.06 (s, 2H), 7.78 (s, 1H), 7.52 (d, 2H), 7.05 (d, 2H), 6.82 (s, 2H, NH ₂).

Embodiment 39:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-aminomethyl-5-trifluoromethyl-phenyl)-urea

Embodiment 40:3-{3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl-benzamide

Be similar to Ex.14; 250mg (1.5mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3) is dissolved in 3ml THF; 6ml ethereal solution reaction with 218mg (1.5mMol) 3-amino-N-methyl-5-(trifluoromethyl)-benzamide (step 35.2) obtains title compound: MS:[M+1] ⁺=466; HPLC ^Bt _Ret: 2.31.

Raw material is prepared as follows:

Step 40.1:N-methyl-(3-nitro-5-trifluoromethyl)-benzamide

Be similar to step 1.4 preparation, from 2.35g (10.0mMol) 3-nitro-5-trifluoromethyl-phenylformic acid (Lancaster) and 40ml NH ₃(40% aqueous solution) obtains title compound.MS：[M-1]＝247。 ¹H-NMR(400MHz，DMSO-d ₆)：9.09(q，1H，NH)，8.89(s，1H)，8.39(s，1H)，8.38(s，1H)，2.81(d，3H)。

Step 40.2:3-amino-N-methyl-5-(trifluoromethyl)-benzamide

Be similar to step 1.5 preparation, with 240mg Pd-C (10%Engelhard 4505) hydrogenation of 2.34g (10mmol) N-methyl-(3-nitro-5-trifluoromethyl) benzamide.MS：[M+1] ⁺＝219。 ¹H-NMR(400MHz，DMSO-d ₆)：8.41(q，1H，NH)，7.24(s，1H)，7.19(s，1H)，6.98(s，1H)，3.41(s，2H，NH ₂)，2.78(d，3H)。

Embodiment 41:3-{3-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl-benzamide

Be similar to Ex.16, by 83mg (0.18mMol) 3-{3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl-benzamide and 1.5ml methylamine (33%EtOH solution) preparation.MS：[M+1] ⁺ 461； ¹H-NMR(400MHz，DMSO-d ₆)：9.19(s，1H，NH)，8.87(s，1H，NH)，8.65(q，1H，NH)，8.13(s，1H)，8.03(s，1H)，7.75(s，1H)，7.5(d，2H)，7.26(s，1H)，7.07(d，2H)，5.72(s，1H)，3.59(s，3H)，2.82(d，3H)。

Embodiment 42:3-{3-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl-benzamide

As described in Ex.7, from 300mg (0.64mMol) 3-{3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl-benzamide prepares title compound, directly as the raw material of Ex.43.MS：[M+1] ⁺＝473。

Embodiment 43:3-{3-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl benzamide

Hydrogenase 10 .3g (0.64mMol) 3-{3-[4-in the presence of 60mg Pd/C 10% (" Engelhard 4505 "), in 10ml DME (6-azido--pyrimidine-4-base oxygen base)-phenyl]-urea groups }-N-methyl-5-trifluoromethyl-benzamide, filter, concentrated filtrate obtains title compound: MS:[M+1] ⁺=447; ¹H-NMR (DMSO-d ₆): 9.17 (s, 1H, NH), 8.82 (s, 1H, NH), 8.60 (q, 1H, NH), 8.12 (s, 1H), 8.03 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.50 (d, 2H), 7.05 (d, 2H), 6.80 (s, 1H), 5.68 (s, 1H), 3.57 (s, 3H), 2.80 (d, 3H).HPLC ^Bt _Ret：1.82。

Embodiment 44:N-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-(3-methylamino-methyl-5-trifluoromethyl-phenyl)-urea

It is synthetic to be similar to compound described herein.

Embodiment 45:N-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

To N ₂Under the atmosphere in ice bath the 11ml CH of refrigerative 98mg (0.33mMol) triphosgene ₂Cl ₂Solution drips 302mg (1.00mMol) 4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-aniline (step 15.2) and 0.14ml (1.0mMol) NEt ₃5ml CH ₂Cl ₂Solution.In ice bath, stir 10min, stir 30min, in 5min, add 202mg (1.0mMol) 4-(4-amino-phenoxy group)-pyrimidine-2-base amine (step 45.3) and 0.14ml (1.0mMol) NEt then at rt ₃5ml CH ₂Cl ₂Suspension.After rt stirred 15min, concentrated reaction mixture was dissolved in CH again with resistates in a vacuum ₂Cl ₂/ MeOH adds SiO ₂After concentrate once more.The gained powder is placed MPLC chromatographic column top, use CH ₂Cl ₂/ methyl alcohol (+1%NH ₃ ^Aq) 19: 1 → 9: 1 wash-out title compounds, last freeze-drying Cong diox: ultimate analysis C ₂₆H ₃₀N ₇F ₃O ₂1.2H ₂O0.1C ₄H ₈O ₂: C, H, N, F; MS:[M+1] ⁺=530; ¹H-NMR (DMSO-d ₆): 9.06 (s, HN), 8.86 (s, HN), 8.10 (d, 5.5Hz, 1H), 7.98 (d, 2.3Hz, 1H), 7.65 (d, 8.6Hz, 1H), 7.59 (dd, 8.6Hz, 2.3Hz, 1H), 7.50 (d, 9.0Hz, 2H), 7.10 (d, 9.0Hz, 2H), 6.62 (s, H ₂N), 6.09 (d, 5.5,1H), 3.54 (s, 2H), 2.67 (m, 1H), 2.50 (m, 4H), 2.41 (m, 4H), 0.99 (d, 6.7Hz, 6H).

Raw material is prepared as follows:

Step 45.1:2-chloro-4-(4-nitro-phenoxy group)-pyrimidine

With 18g (130mMol) 2, the 4-dichloro pyrimidine is dissolved in 100ml acetone, at 0 ℃ of 100ml H that slowly joins 5.32g (130mMol) NaOH and 16.64g (118.4mMol) 4-nitrophenols ₂In the O solution.Behind 80 ℃ of stirring 23h, under reduced pressure concentrated reaction mixture cools off, and leaches sedimentary crude product, uses H ₂The O washing, dry in a vacuum.Carry out purification by flash chromatography (SiO ₂4.5 * 46cm, hexane/EtOAc 2: 1): MS:[M+1] ⁺=252; ¹H-NMR (400MHz, DMSO-d ₆): 8.67 (d, 4.5Hz, 1H, pyrimidyl), 8.33 (d, 8.5Hz, 2H, phenyl), 7.56 (d, 8.5Hz, 2H, phenyl), 7.31 (d, 4.5Hz, 1H, pyrimidyl), R _f(hexane/EtOAc=1: 1): 0.38, HPLC ^Bt _Ret: 5.97.

Step 45.2:4-(4-nitro-phenoxy group)-pyrimidine-2-base amine

4g (15.9mMol) 2-chloro-4-(4-nitro-phenoxy group)-pyrimidine is dissolved in 100ml EtOH and 100ml NH ₃The aqueous solution (25%) stirs 2h in 100 ℃ of autoclaves (2bar).Under reduced pressure behind the concentrated reaction mixture, precipitated product is dissolved in MeOH, handles (SiO through flash chromatography ₂4.5 * 26cm, EtOAc/ hexane/NH ₃50: 50: 1.5 → 100: 50: 1.5), obtain title compound, be white solid: R _f(EtOAc/ hexane/NH ₃: 100: 50: 1.5): 0.10; MS:[M+1] ⁺=233.

Step 45.3:4-(4-amino-phenoxy group)-pyrimidine-2-base amine

1.68g (6.7mMol) 4-(4-nitro-phenoxy group)-pyrimidine-2-base amine is dissolved in 50ml MeOH, hydrogenation 4h in the presence of the 500mg Raney nickel.Filter through Hyflo, with 40ml EtOH washed twice, under reduced pressure concentrated reaction solution is handled (SiO through flash chromatography ₂4.5 * 26cm, EtOAc/ hexane/NH ₃100: 50: 1.5 → 200: 50: 1.5), obtain title compound, be beige solid: R _f(EtOAc/ hexane/NH ₃: 100: 50: 1.5): 0.10; MS:[M+1] ⁺=203.

Embodiment 46:N-[4-(2-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

To N ₂Under the atmosphere in ice bath the 7ml CH of refrigerative 60mg (0.20mMol) triphosgene ₂Cl ₂Solution drips 181mg (0.60mMol) 4-(4-sec.-propyl piperazine-1-ylmethyl)-3-trifluoromethyl-aniline (step 15.2) and 83 μ l (0.6mMol) NEt ₃3ml CH ₂Cl ₂Solution.In ice bath, stir 10min, stir 30min, in 5min, add 130mg (0.60mMol) [4-(4-amino-phenoxy group)-pyrimidine-2-base]-methyl-amine (step 46.2) and 83 μ l (0.6mMol) NEt then at rt ₃3mlCH ₂Cl ₂Suspension.After rt stirred 90min, concentrated reaction mixture was dissolved in CH again with resistates in a vacuum ₂Cl ₂/ MeOH adds SiO ₂After concentrate once more.The gained powder is placed MPLC chromatographic column top, use CH ₂Cl ₂/ methyl alcohol (+1%NH ₃ ^Aq) 97: 3 → 93: 7 wash-out title compound: MS:[M+1] ⁺=544; ¹H-NMR (CD ³OD/CDCl ₃): 7.99 (d, 5Hz, 1H), 7.67 (d, 2Hz, 1H), 7.60 (dd, 8.6Hz, 2Hz, 1H), 7.55 (d, 8.6Hz, 1H), 7.43 (d, 9.0Hz, 2H), 7.03 (d, 9.0Hz, 2H), 5.96 (d, 5Hz, 1H), 3.59 (s, 2H), 2.99 (m, 1H), 2.83 (s, H ₃C), 2.70 (m, 4H), 2.58 (m, 4H), 1.12 (d, 6.3Hz, 6H).

Raw material is prepared as follows:

Step 46.1: methyl-[4-(4-nitro-phenoxy group)-pyrimidine-2-base]-amine

2g (7.95mMol) 2-chloro-4-(4-nitro-phenoxy group)-pyrimidine is dissolved in 40ml MeNH ₂(30%EtOH solution) stirs 50min at rt.Behind the evaporating solvent, crude product is handled (SiO through flash chromatography ₂4.5 * 30cm, hexane/EtOAc 1: 1), obtain title compound, be white solid: R _f(hexane/EtOAc 2: 1): 0.18; MS:[M+1] ⁺=247; ¹H-NMR (400MHz, CDCl ₃): 8.33 (d, 8.5Hz, 2H, phenyl), 8.24 (d/ broad peak, 1H, pyrimidyl), 7.35 (d, 8.5Hz, 2H, phenyl), 6.22 (d, 6.0Hz, 1H, pyrimidyl), 2.90 (s/ broad peak, 3H, CH ₃).

Step 46.2:[4-(4-amino-phenoxy group)-pyrimidine-2-base]-methyl-amine

Hydrogenation in the presence of Raney nickel prepares title compound from methyl-[4-(4-nitro-phenoxy group)-pyrimidine-2-base]-amine: R _f(hexane/EtOAc 1: 1): 0.13; MS:[M+1] ⁺=217; ¹H-NMR (400MHz, DMSO-d ₆): 8.04 (s/ broad peak, 1H, pyrimidyl), 6.95 (the s/ broad peak, 1H, HN), 6.76 (d, 8.5Hz, 2H, phenyl), 6.54 (d, 8.5Hz, 2H, phenyl), 5.90 (s/ broad peak, 1H, pyrimidyl), 5.00 (s, 2H, NH ₂), 2.70 (s/ broad peak, 3H, CH ₃).

Embodiment 47:N-[4-(2-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(dimethylamino-methyl)-3-trifluoromethyl-phenyl]-urea

Prepare title compound from 2-chloro-4-(4-isocyanide acyl group-phenoxy group)-pyrimidine and 4-(dimethylamino-methyl)-3-trifluoromethyl-phenyl amine.

Be similar to technology described herein, can prepare the Ex.48-50 compound:

Embodiment 48:N-[4-(2-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-dimethylamino-methyl)-3-trifluoromethyl-phenyl]-urea

According to the Ex.45 preparation, start from 101mg (0.43mMol) 4-(N, N-dimethylamino methyl)-3-trifluoromethyl-aniline (step 20.1-2) and 100mg (0.43mMol) [4-(4-amino-phenoxy group)-pyrimidine-2-base]-methyl-amine (step 46.2).After rt stirred 3h, concentrated reaction mixture was dissolved in CH again with resistates in a vacuum ₂Cl ₂/ MeOH, crude product is through preparation type TLC purifying (CH ₂Cl ₂/ MeOH 9: 1), obtain title compound: MS:[M+1] ⁺=461; HPLC ^Bt _Ret: 2.03, R _f(CH ₂Cl ₂/ MeOH 9: 1): 0.65.

Embodiment 49:N-[4-(2-methylamino--pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-tertiary butyl piperazinyl-methyl)-3-trifluoromethyl-phenyl]-urea

Prepare according to Ex.45, start from 146mg (0.43mMol) 4-(the 4-tertiary butyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl-amine (step 20.5) and 100mg (0.43mMol) [4-(4-amino-phenoxy group)-pyrimidine-2-base]-methyl-amine (step 46.2), in 5min, add 83 μ l (0.6mMol) NEt ₃3ml CH ₂Cl ₂Solution.After rt stirs 0.5h, the sedimentary product of filtering separation.MS：[M+1] ⁺＝558；m.p.257-258℃， ¹H-NMR(400MHz，DMSO-d ₆)：9.60(bs，1H，NH)，9.09(s，1H，NH)，8.78(s，1H，NH)，8.10(d，1H，)，7.86(s，1H)，7.69-7.55(m，2H)，7.48(d，2H)，7.08(d，2H)，6.50(bs，1H，NH)，6.04(d，1H)，3.70(s，2H)，3.49-3.37(m，4H)，3.10-2.87(m，4H)，2.85(s，3H)，1.37(s，9H)。

Embodiment 50:N-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-tertiary butyl piperazinyl-methyl)-3-trifluoromethyl-phenyl]-urea

According to the Ex.45 preparation, start from 312mg (0.98mMol) 4-(the 4-tertiary butyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl-amine (step 20.5) and 200mg (0.98mMol) 4-(4-amino-phenoxy group)-pyrimidine-2-base amine (step 45.3).After rt stirs 30min, the sedimentary product of filtering separation, dry in a vacuum with cold THF washing, obtain title compound, be white solid.MS：[M+1] ⁺＝548； ¹H-NMR(DMSO-d ₆)：9.41(s，1H，HN)，9.17(s，1H，NH)，8.03(d，1H)，7.97(s，1H)，7.62-7.58(m，2H)，7.43(d，2H)，7.02(d，2H)，6.59(bs，2H)，6.01(d，1H)，3.62(s，2H)，3.49-3.39(m，2H)，2.99-2.82(m，4H)，2.61-2.48(m，2H)，1.17(s，9H)。

Raw material (amine component) is as preparation as described in the embodiment 20 step 1-5.

Embodiment 51: can prepare following compounds similarly:

1) is similar to the Ex.45 preparation; 2) be similar to the Ex.46 preparation

Embodiment 52: be similar to embodiment 45 preparation following compounds:

Step 52c.1:N-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-2,2,2-three fluoro-acetyl Amine

With 2g (5.71mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides (step 14.2) and 2.22ml (17.14mMol) N-ethyl piperazidine are dissolved in the 55ml acetonitrile, stir 45min at rt.Behind the vapourisation under reduced pressure acetonitrile, with reaction mixture 80ml H ₂The O dilution is with 70mlEtOAc extraction 3 times.Merge organic phase, use 30ml NaHCO ₃Solution and 30ml salt solution washed twice, dry (MgSO ₄), under reduced pressure concentrate, handle (SiO through flash chromatography ₂4.0 * 24cm, MeOH/CH ₂Cl ₂1: 19), obtain yellow solid: R _f(MeOH/CH ₂Cl ₂1: 4): 0.42; MS:[M+1] ⁺=384; ¹H-NMR (400MHz, DMSO-d ₆): 11.40 (the s/ broad peak, 1H, NH), 8.02 (s, 1H), 7.90 (d, 7.5Hz, 1H), 7.74 (d, 7.5Hz, 1H), 3.56 (s, 2H, CH ₂-aryl), 2.30 (m, 10H), 2.51 (t, 7.5Hz, 3H, CH ₃).

Step 52c.2:4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl amine

Under Ar, with 1.59g (4.1mMol) N-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-2,2,2-three fluoro-ethanamides are at 41ml MeOH and 20.5ml 1M K ₂CO ₃H ₂Solution in the O solution stirs 1.5h at 70 ℃.Behind the vapourisation under reduced pressure MeOH, with reaction mixture 80mlH ₂The O dilution is with 60ml EtOAc extraction 3x.Merge organic phase, use 30ml H ₂O and the water washing of 30ml salt, dry (MgSO ₄), under reduced pressure concentrate, handle (SiO through flash chromatography ₂4.0 * 24cm, MeOH/CH ₂Cl ₂1: 19), obtain title compound, be yellow solid: R _f(MeOH/CH ₂Cl ₂1: 4): 0.42; MS:[M+1] ⁺=288; ¹H-NMR (400MHz, DMSO-d ₆): 7.24 (d, 7.5Hz, 1H), 6.81 (s, 1H), 6.73 (d, 7.5Hz, 1H), 5.41 (s, 2H, CH ₂-aryl), 3.35 (m, 2H, CH ₂-CH ₃), 2.30 (m, 8H, piperazinyls), 2.51 (t, 6.5Hz, 3H, CH ₃).

Step 52d.1:3-pyridine-2-base-5-trifluoromethyl-phenyl amine

According to [Lam F, Chan KS (1995), Synthesis of acyclic dinucleating Schiffbase-pyridine and Schiff base-phosphine ligands.Tetrahedron Lett; 36 (6): 919-922] technology synthesising title compound, 600mg (2.44mMol) 3-amino-5-5 bromine benzotrifluoride, 1g (2.69mMol) 2-(tributyl stannyl)-pyridine and 285mg four (triphenyl phosphine) palladium are dissolved in 10ml THF, under Ar, stir 7d at 90 ℃.Through chromatographic separation (SiO ₂4.5 * 19cm, EtOAc/ hexane 1: 2 → 2: 3), obtain title compound, be light brown solid: R _f(hexane/EtOAc2: 1): 0.17; MS:[M+1] ⁺=239; ¹H-NMR (400MHz, DMSO-d ₆): 8.81 (d, 4.5Hz, 1H, pyridyl), 7.88 (m, 2H, pyridyl), 7.53 (s, 1H, phenyl-CF ₃), 7.43 (s, 1H, phenyl-CF ₃), 7.37 (m, 1H, pyridyl), 6.89 (s, 1H, phenyl-CF ₃), 5.73 (s, 2H, NH ₂).

Embodiment 53: be similar to embodiment 46 preparation following compounds:

^*Corresponding trifluoromethyl amine member synthetic respectively as described under step 53b.3 and the 53d.1.

Step 53b.1:(3-bromo-5-trifluoromethyl-phenyl)-the carboxylamine tertiary butyl ester

With 25g (104mMol) 3-bromo-5-trifluoromethyl-aniline, 24g (110mMol) (Boc) ₂The 200ml MeCN solution of O and 1.2g (10mMol) DMAP stirs 10h at 60 ℃.Behind the vapourisation under reduced pressure solvent, resistates is handled (SiO through flash chromatography ₂Hexane/EtOAc 10: 1), crystallization from hexane obtains title compound, is white crystal: R _f(hexane/EtOAc 1: 5): 0.23; MS:[M+1] ⁺=341.

Step 53b.2:[3-(4-methyl-piperazine-1-yl)-5-trifluoromethyl-phenyl]-the carboxylamine tertiary butyl ester

With 6.8g (20mMol) (3-bromo-5-trifluoromethyl-phenyl)-carboxylamine tertiary butyl ester, 2.6ml (24mMol) 1-methyl-piperazine, 2.7g (28mMol) NaOtBu, 6ml tri-butyl phosphine (10% hexane solution, 3mMol) and 0.5g (1mMol) three-(dibenzalacetone)-two-palladium be dissolved in 100ml toluene, under Ar, stir 6h at 70 ℃.Reaction soln with 200ml EtOAc dilution, is filtered through Hyflo.After the water washing of 50ml salt, with filtrate drying (MgSO ₄), under reduced pressure concentrating, crystallization from the EtOAc/ hexane obtains title compound again, is the oil of brown: R _f(MeOH/CH ₂Cl ₂1: 5): 0.45; MS:[M+1] ⁺=360.

Step 53b.3:3-(4-methyl-piperazine-1-yl)-5-trifluoromethyl-phenyl amine

3.2g (8.9mMol) [3-(4-methyl-piperazine-1-yl)-5-trifluoromethyl-phenyl]-carboxylamine tertiary butyl ester is dissolved in the 2-propanol solution of 60ml 2.5N HCl, stirs 5.5h at 60 ℃.Behind the vapourisation under reduced pressure solvent, make resistates at 200ml EtOAc and 100ml NaHCO ₃Distribute between the solution.With organic phase 50ml salt water washing, dry (MgSO ₄), evaporating solvent obtains title compound, is the oil of brown: MS:[M+1] ⁺=260; R _f(MeOH/CH ₂Cl ₂1: 5): 0.18; ¹N-NMR (400MHz, DMSO-d ₆): 6.31 (s, 1H), 6.27 (s, 1H), 5.34 (s, 1H), 3.32 (s/ broad peak, 2H, NH ₂), 3.70/2.42 (m/m, 4H/4H, CH ₂-piperazinyl), 2.20 (s, 3H, CH ₃).

Step 53d.1:4-(4-methyl-piperazine-1-yl)-3-trifluoromethyl-phenyl amine

Title compound is following synthetic: 1-bromo-4-nitro-2-trifluoromethyl-benzene and 1-methyl-piperazine carry out nucleophilic substitution reaction (140 ℃ 4h), are amine: m.p.:121-123 ℃ by Raney nickel hydro-reduction nitro functions further; R _f(MeOH/CH ₂Cl ₂=1: 5): 0.17; MS:[M+1] ⁺=260; ¹H-NMR (400MHz, DMSO-d ₆): 7.21 (d, 9Hz, 1H), 6.74 (m, 2H), 5.35 (s/ broad peak, 2H, NH ₂), 2.70 (m/ broad peak, 4H, CH ₂), 2.36 (s/ broad peak, 4H, CH ₂), 2.18 (s, 3H, CH ₃).

Embodiment 54:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[3-(6-methyl-pyridine-2-yl)-5-trifluoromethyl-phenyl]-urea

At 0 ℃, with 252mg (1mMol) 3-(6-methyl-pyridine-2-yl)-5-trifluoromethyl-phenyl amine (step 54.2) and 0.12ml NEt ₃4.5ml CH ₂Cl ₂Solution joins the 9ml CH of 99mg (0.33mMol) triphosgene ₂Cl ₂In the solution.After rt stirs 15min, add 202mg (1mMol) 4-(4-amino-phenoxy group)-pyrimidine-6-base amine (step 54.3) and 0.12ml NEt ₃At 4.5ml CH ₂Cl ₂With the solution among the 0.5ml DMF.After rt stirred 3.5h, the vapourisation under reduced pressure solvent was handled (SiO through flash chromatography with browning reaction solution ₂2.5 * 18cm, MeOH/CH ₂Cl ₂/ NH ₃5: 95: 0.5), obtain title compound, be beige solid: R _f(MeOH/CH ₂Cl ₂/ NH ₃5: 95: 0.5): 0.06; MS:[M+1] ⁺=481; ¹H-NMR (DMSO-d ₆): 9.21/8.83 (s/s, 1H/1H, urea), 8.29 (s, 1H, pyrimidyl), 8.06 (m, 2H, pyridyl), 7.93 (s, 1H, phenyl-CF ₃), 7.80 (s, 1H, phenyl-CF ₃), 7.79 (s, 1H, phenyl-CF ₃), 7.51 (d, 9.0Hz, 2H, phenyl), 7.26 (m, 1H, pyridyl), 7.06 (d, 9.0Hz, 2H, phenyl), 6.77 (s, 2H, NH ₂), 5.66 (s, 1H, pyrimidyl), 2.51 (s, 3H, CH ₃).

Step 54.1:6-methyl-2-(tributyl stannyl)-pyridine

Be similar to the technology synthesising title compound of people such as Zhang (Synthetic Communications 31 (2001), 1129).Under Ar, at-78 ℃, slowly add 13.9ml nBuLi (1.6N hexane solution to the 7ml THF solution of 3.83g (22.2mMol) 2-bromo-6-methyl-pyridine; 22.2mMol).Behind-78 ℃ of stirring 1.5h, slowly add 6ml (22.2mMol) tributyl stannyl chlorine, reaction soln is stirred other 30min at-78 ℃.Behind the filter reaction mixture, flash chromatography separates title compound (SiO ₂5 * 16cm, EtOAc/ hexane 1: 9): colourless oil: R _f(hexane/EtOAc 3: 2): 0.42; MS:[M+1] ⁺=380.

Step 54.2:3-(6-methyl-pyridine-2-yl)-5-trifluoromethyl-phenyl amine

1g (4.19mMol) 3-amino-5-5 bromine benzotrifluoride, 1g (2.60mMol) 6-methyl-2-(tributyl stannyl)-pyridine and 30mg four (triphenyl phosphine) palladium are dissolved in 1.5ml THF, in the test tube of sealing, at microwave oven (Emrys Optimizer, personal chemistry, Sweden) in, under Ar, stirred 1000 seconds at 140 ℃.Chromatographic separation (SiO ₂5 * 18cm, EtOAc/ hexane 1: 9 → 2: 3), obtain title compound, be colourless oil: R _f(hexane/EtOAc 3: 2): 0.42; MS:[M+1] ⁺=253; ¹H-NMR (400MHz, DMSO-d ₆): 7.62 (t, 6.5Hz, 1H, pyridyl), 7.74/7.70 (s/s, 1H/1H, phenyl-CF ₃), 7.69 (d, 6.5Hz, 1H, pyridyl), 7.12 (d, 6.5Hz, 1H, pyridyl), 6.91 (s, 1H, phenyl-CF ₃), 3.95 (s/ broad peak, 2H, NH ₂), 2.63 (s, 3H, CH ₃).

Step 54.3:4-(4-amino-phenoxy group)-pyrimidine-6-base amine

2.0g (9.725mMol) 4-(6-chloro-pyrimidine-4-base-oxygen base)-aniline (step 1.2) is dissolved in 80mlNH ₃Water (25%) and 60ml EtOH are in the test tube of sealing, at 80 ℃ of stirring 23h.Under reduced pressure, behind evaporating solvent in 40 ℃ of water-baths, resistates is handled (SiO through flash chromatography ₂5.5 * 65cm; CH ₂Cl ₂/ MeOH 9: 1), obtains title compound, be white solid: R _f(CH ₂Cl ₂/ MeOH=9: 1): 0.37; MS:[M+1] ⁺=203; ¹H-NMR (400MHz, DMSO-d ₆): 8.01 (s, 1H, pyrimidyl), 6.74 (d, 9Hz, 2H, phenyl), 6.70 (s, 2H, NH ₂), 6.57 (d, 9Hz, 2H, phenyl), 5.51 (s, 1H, pyrimidyl), 5.03 (s, 2H, NH ₂).

Embodiment 55: be similar to the preparation of embodiment 54 compounds, synthesize additional compounds via the generation of urea:

^*The OH group of phenol type amine is protected by TBDMS.After generating urea, remove the TBDMS blocking group of phenol type oxygen by pyridine solution (30%) cracking of HF.

Step 55a.1a:4-[6-(4-nitro-phenoxy group)-pyrimidine-4-base is amino]-phenol

3g (11.9mMol) 4-chloro-6-(4-nitro-phenoxy group)-pyrimidine (step 1.1), 1.95g (17.9mMol) 4-amino-phenol and 3.04ml (17.9mMol) DIPEA are dissolved in 50ml 2-propyl alcohol, stir 18h at 85 ℃.Under reduced pressure behind the concentrated reaction mixture, the product precipitation is colourless micro-solid: R _f(EtOAc/ hexane 2: 1): 0.48; MS:[M+1] ⁺=245; ¹H-NMR (400MHz, DMSO-d ₆): 9.40/9.25 (s/s, 2H, NH/OH), 8.28 (d, 7.5Hz, 2H, phenyl-NO ₂), 8.26 (s, 1H, pyrimidyl), 7.40 (d, 7.5Hz, 2H, phenyl-NO ₂), 7.24 (d, 8.0Hz, 2H, phenyl-OH), 6.77 (d, 8.0Hz, 2H, phenyl-OH), 6.15 (s, 1H, pyrimidyl).

Step 55a.1b:[4-(tertiary butyl-dimethyl-siloxy-)-phenyl]-[6-(4-nitro-phenoxy group)-phonetic Pyridine-4-yl]-amine

1.5g (4.63mMol) 4-[6-(4-nitro-phenoxy group)-pyrimidine-4-base is amino]-phenol, 1.39g (9.26mMol) tertiary butyl-dimethyl-silyl chloride, 1.29ml (9.26mMol) NEt ₃Be dissolved in 20mlDMF, stir 3.5h.Concentrated reaction mixture under reduced pressure, be dissolved in phosphate buffered saline buffer (50ml, pH=7) after, product is with 10ml EtOAc extraction, through purification by flash chromatography (SiO ₂3.0 * 17cm, EtOAc/ hexane 1: 1 → 4: 1), obtain title compound, be colorless solid: MS:[M+1] ⁺=439; ¹H-NMR (400MHz, DMSO-d ₆): 9.56 (s, 1H, NH), 8.28 (m, 3H, pyrimidyl, phenyl-NO ₂), 7.40 (m, 4H, phenyl-OTBS, phenyl-NO ₂), 6.81 (d, 8.8Hz, 2H, phenyl-OTBS), 6.20 (s, 1H, pyrimidyl), 0.93 (s, 9H, TBS), 0.18 (s, 6H, TBS).

Step 55a.1c:[6-(4-amino-phenoxy group)-pyrimidine-4-yl]-[4-(tertiary butyl-dimethyl-silicomethane oxygen Base)-phenyl]-amine

Reach 3h at hydrogenation 1.8g (4.1mMol) in the presence of the 0.4g Raney nickel, in 50ml EtOH/THF (35/15) [4-(tertiary butyl-dimethyl-siloxy-)-phenyl]-[6-(4-nitro-phenoxy group)-pyrimidine-4-yl]-amine, through purification by flash chromatography (SiO ₂3.0 * 18cm, EtOAc/ hexane 1: 1 → 4: 1), obtain title compound, be colorless solid: R _f(EtOAc/ hexane=2: 1): 0.22; MS:[M+1] ⁺=409; ¹H-NMR (400MHz, DMSO-d ₆): 9.22 (s, 1H, NH), 8.20 (s, 1H, pyrimidyl), 7.37 (d, 8.8Hz, 2H, phenyl-OTBS), 6.77 (d, 8.8Hz, 2H, phenyl-NH ₂), 6.70 (d, 8.8Hz, 2H, phenyl-OTBS), 6.55 (8.8Hz, 2H, phenyl-NH ₂), 5.79 (s, 1H, pyrimidyl), 5.02 (s, 2H, NH ₂), 0.90 (s, 9H, TBS), 0.12 (s, 6H, TBS).

Step 55b.2:4-dimethylamino methyl-3-trifluoromethyl-phenyl amine

With 1.8g (5.14mMol) N-(4-brooethyl-3-trifluoromethyl-phenyl)-2,2,2-three fluoro-ethanamides (step 14.2) are dissolved in 25ml HNMe ₂(30%EtOH solution) stirs 1h at rt, and (with regard to 2,2, the saponification of 2-trifluoroacetyl amine functional group) stir 3h at 50 ℃ in addition then.Behind the vapourisation under reduced pressure solvent, resistates is through purification by flash chromatography (SiO ₂5.5 * 17cm, acetone/CH ₂Cl ₂/ NH ₃5: 94: 1 → 50: 49: 1), obtain xanchromatic oil: R _f(acetone/CH ₂Cl ₂/ NH ₃50: 49: 1): 0.73; MS:[M+1] ⁺=219; ¹H-NMR (400MHz, DMSO-d ₆): 7.32 (d, 8.5Hz, 1H), 6.88 (d, 4.5Hz, 1H), 6.76 (d, 8.5Hz, 1H), 5.44 (s, 2H, CH ₂), 3.33 (s, 2H, NH ₂), 2.12 (s, 6H, CH ₃).

Step 55c.1a:(3-methoxyl group-phenyl)-[6-(4-nitro-phenoxy group)-pyrimidine-4-yl]-amine

5g (19.9mMol) 4-chloro-6-(4-nitro-phenoxy group)-pyrimidine (step 1.1) and 4.88ml (43.8mMol) m-methyl oxyaniline are dissolved in 7.4ml DIPEA and 85ml 2-propyl alcohol, backflow 162h.Under reduced pressure during the concentrated reaction mixture, the resistates precipitation obtains title compound, is white crystal, with cold MeOH washing: MS:[M+1] ⁺=339; ¹H-NMR (400MHz, DMSO-d ₆): 9.69 (s, 1H, NH), 8.40 (s, 1H, pyrimidyl), (8.31 d, 9.5Hz, 2H, phenyl), 7.44 (d, 9.5Hz, 2H, phenyl), 7.29 (s/ broad peak, 1H, MeO-phenyl), 7.23 (t, 8.5Hz, 1H, MeO-phenyl), 7.16 (d, 8.5Hz, 1H, the MeO-phenyl), 6.62 (d/ broad peak, 8.5Hz, 1H, MeO-phenyl), 7.97 (s/ broad peaks, 1H, pyrimidyl), 5.11 (s, 2H, NH ₂), 3.74 (s, 3H, CH ₃).

Step 55c.1b:[6-(4-amino-phenoxy group)-pyrimidine-4-yl]-(3-methoxyl group-phenyl)-amine

5.4g (16mMol) (3-methoxyl group-phenyl)-[6-(4-nitro-phenoxy group)-pyrimidine-4-yl]-amine is dissolved in 160ml MeOH/THF 2: 1, hydrogenation 16h in the presence of Raney nickel.After will reacting suspension process Hyflo filtration ice concentrated reaction mixture, be settled out title compound, be white crystal: MS:[M+1] ⁺=309; ¹H-NMR (400MHz, DMSO-d ₆): 9.47 (s, 1H, NH), 8.36 (s, 1H, pyrimidyl), (7.31 s/ broad peak, 1H, MeO-phenyl), 7.19 (t, 8.5Hz, 1H, the MeO-phenyl), 7.14 (d, 8.5Hz, 1H, MeO-phenyl), 6.88 (d, 9.5Hz, 2H, phenyl), 6.63 (d, 9.5Hz, 2H, phenyl), 6.58 (d/ broad peak, 8.5Hz, 1H, MeO-phenyl), 7.97 (s/ broad peaks, 1H, pyrimidyl), 5.06 (s/ broad peak, 2H, NH ₂), 5.11 (s, 2H, NH ₂), 3.73 (s, 3H, CH ₃); HPLC ^Bt _Ret: 3.82.

Step 55c.2:4-morpholine-4-base-3-trifluoromethyl-phenyl amine

Title compound is following synthetic: 1-bromo-4-nitro-2-trifluoromethyl-benzene and morpholine carry out nucleophilic substitution reaction (140 ℃ 4h), are amine: m.p.:149-151 ℃ by Raney nickel hydro-reduction nitro functions further; R _f(hexane/EtOAc 1: 1): 0.30; MS:[M+1] ⁺=247.1, ¹H-NMR (400MHz, DMSO-d ₆): 7.22 (d, 9Hz, 1H), 6.77 (m, 2H), 5.37 (s/ broad peak, 2H, NH ₂), 3.62 (m/ broad peak, 4H, CH ₂), 2.67 (m, broad peak 4H, CH ₂).

Step 55d.1a:4-[6-(4-nitro-phenoxy group)-pyrimidine-4-base is amino]-hexalin

300mg (1.19mMol) 4-chloro-6-(4-nitro-phenoxy group)-pyrimidine (step 1.1) and 184mg (1.60mMol) 4-amino-hexalin are dissolved in 0.5ml DIPEA and 30ml 2-propyl alcohol, backflow 3h.Behind the evaporating solvent, resistates is handled twice (SiO through flash chromatography ₂2.5 * 12cm, hexane/EtOAc1: 1 → MeOH/EtOAc 5: 95.SiO ₂2 * 15cm, the CH of 5 → 10%MeOH ₂Cl ₂Solution), obtain colourless oil: R _f(MeOH/CH ₂Cl ₂1: 9): 0.50; MS:[M+1] ⁺=331, ¹H-NMR (400MHz, DMSO-d ₆): 8.30 (d, 10.5Hz, 2H, phenyl), 8.14 (s/ broad peak, 1H, pyrimidyl), 7.43 (d, 8.5Hz, 1H, NH), 7.38 (d, 10.5Hz, 2H, phenyl), 5.95 (s/ broad peak, 1H, pyrimidyl), 5.06 (s/ broad peak, 2H, NH ₂), 4.55 (d, 4.5Hz, 1H, OH), 3.76 (the s/ broad peak, 1H, CH), 3.41 (the m/ broad peak, 1H, CH), 1.92-1.80 (m, 4H, CH ₂), 1.25 (m, 4H, CH ₂).

Step 55d.1b:4-[6-(4-amino-phenoxy group)-pyrimidine-4-base is amino]-hexalin

100mg (0.30mMol) 4-[6-(4-nitro-phenoxy group)-pyrimidine-4-base is amino]-hexalin is dissolved in 15ml MeOH, hydrogenation 3h in the presence of Raney nickel.After will reacting Hyflo filtration of suspension process and evaporating solvent, crude product is through purification by flash chromatography (SiO ₂2 * 20cm, acetone/CH ₂Cl ₂/ NH ₃5: 94: 1 → 50: 49: 1), obtain title compound, be xanchromatic oil: R _f(MeOH/CH ₂Cl ₂/ NEt ₃15: 84: 1): 0.12; MS:[M+1] ⁺=301; ¹H-NMR (400MHz, DMSO-d ₆): 8.09 (s, 1H, pyrimidyl), 7.13 (d, 8.5Hz, 1H, NH), 6.76 (d, 9.5Hz, 2H, phenyl), 6.56 (d, 9.5Hz, 2H, phenyl), 5.55 (s/ broad peak, 1H, pyrimidyl), 5.06 (the s/ broad peak, 2H, NHa), 4.56 (d, 4.0Hz, 1H, OH), 3.64 (the s/ broad peak, 1H, CH), 3.38 (m/ broad peaks, 1H, CH), 1.79 (m, 4H, CH ₂), 1.23 (m, 4H, CH ₂).

Embodiment 56: can prepare following compounds similarly:

Embodiment 57:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-(4-pyridine-2-base-3-trifluoromethyl-phenyl)-urea

In the test tube of sealing, under argon atmospher, with 150mg (0.320mMol) 1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-(4-bromo-3-trifluoromethyl-phenyl)-urea (step 57.3), 590mg (1.602mMol) 2-(tributyl stannyl)-pyridine and 97mg (0.084mMol) four (triphenyl phosphine) palladium be suspended in 1, in the 4-diox.Behind 150 ℃ of stirring 2.5h, under reduced pressure remove and desolvate.Handle (SiO through column chromatography ₂CH ₂Cl ₂/ MeOH 95: 5), crystallization from ether obtains title compound, is white powder: m.p.:188-192 ℃; R _f(CH ₂Cl ₂/ MeOH 9: 1): 0.19; MS:[M+1] ⁺=470; HPLC ^Ct _Ret=5.49.

Raw material is prepared as follows:

Step 57.1:1-(4-bromo-3-trifluoromethyl-phenyl)-3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea

To N ₂(4-isocyanide acyl group-phenoxy group)-(embodiment 1 for pyrimidine for 4.0g under the atmosphere (16.15mMol) 4-chloro-6-; Step 1.3) 13ml THF solution adds the 85ml ethereal solution of 3.88g (16.15mMol) 4-bromo-3-trifluoromethyl-aniline.After rt stirs 27h, leach product, wash with ether.After the drying, obtain title compound, be white crystal: m.p.:179-182 ℃; R _f(EtOAc): 0.55; MS:[M+1] ⁺489; HPLC ^Ct _Ret=7.46.

Step 57.2:1-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-3-(4-bromo-3-trifluoromethyl-phenyl)- Urea

With 4.13g (8.47mMol) 1-(4-bromo-3-trifluoromethyl-phenyl)-3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea and 1.1g (16.94mMol) NaN ₃Mixture in 65ml DMF stirs 19h at 50 ℃, stirs 6h at 60 ℃.Reaction mixture is poured in the 150ml water, with EtOAc extraction (3 * 350ml).With organic layer water and salt water washing, dry (Na ₂SO ₄), concentrate.Crude product is directly used in the step of hydrogenation (step 57.3) of back.R _f(EtOAc)：0.58；MS：[M+1] ⁺＝494；HPLC ^Ct _Ret＝7.58。

Step 57.3:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-(4-bromo-3-trifluoromethyl-phenyl)-urea

With 4.1g (8.3mMol) 1-[4-(6-azido--pyrimidine-4-base oxygen base)-phenyl]-3-(4-bromo-3-trifluoromethyl-phenyl)-urea is dissolved in 80ml EtOH, in the presence of the 1g Raney nickel, at rt hydrogenation 15h.Reaction soln is filtered, concentrate.Handle (SiO through column chromatography ₂EtOAc), crystallization from ether obtains title compound: m.p.:186-188 ℃; R _f(EtOAc): 0.18; MS:[M+1] ⁺=469; HPLC ^Ct _Ret=5.49.

Embodiment 58:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-(4-pyridin-3-yl-3-trifluoromethyl-phenyl)-urea

As preparation title compound as described in the embodiment 57, use 3-(1,1,1-tributyl stannyl) pyridine: m.p.:132-135 ℃; MS:[M+1] ⁺=467; HPLC ^Ct _Ret=3.54.

Embodiment 59:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-(4-pyridin-4-yl-3-trifluoromethyl-phenyl)-urea

As preparation title compound as described in the embodiment 57, use 4-(1,1,1-tributyl stannyl) pyridine: m.p.:131-135 ℃; MS:[M+1] ⁺=467; HPLC ^Ct _Ret=3.51.

Embodiment 60:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(6-methyl-pyridine-2-yl)-3-trifluoromethyl-phenyl]-urea

As preparation title compound as described in the embodiment 57, use 2-methyl-6-tributyl stannyl-pyridine (step 54.1): m.p.:130-133 ℃; MS:[M+1] ⁺=481; HPLC ^Ct _Ret=3.66.

Embodiment 61:1-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-(4-pyridine-2-base-3-trifluoromethyl-phenyl)-urea

In the test tube of sealing, under argon atmospher, with 136mg (0.282mMol) 1-(4-bromo-3-trifluoromethyl-phenyl)-3-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-urea (step 61.1), 129mg (0.35mMol) 2-(tributyl stannyl)-pyridine and 36mg (0.031mMol) four (triphenyl phosphine) palladium be suspended among the 0.5ml THF.With reaction mixture in microwave oven (Emrys Optimizer), 140 ℃ the heating 85min.After the filtration, mother liquid evaporation is through chromatography (SiO ₂CH ₂Cl ₂/ MeOH 95: 5).By preparation type TLC (SiO ₂CH ₂Cl ₂/ MeOH 9: 1), obtains title compound, be white powder: m.p.:114-118 ℃; R _f(CH ₂Cl ₂/ MeOH 9: 1): 0.32; MS:[M+1] ⁺=481; HPLC ^Ct _Ret=3.78.

Raw material is prepared as follows:

Step 61.1:1-(4-bromo-3-trifluoromethyl-phenyl)-3-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]- Urea

With 3g (6.15mMol) 1-(4-bromo-3-trifluoromethyl-phenyl)-3-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-urea (step 57.1) is dissolved in 35.5ml 33%MeNH ₂EtOH solution, in ice bath, stir 4h.Under reduced pressure except that after desolvating, resistates is through chromatography (SiO ₂EtOAc), crystallization from ether obtains title compound, is white crystal: m.p.:161-164 ℃; R _f(EtOAc): 0.26; MS:[M+1] ⁺=482; HPLC ^Ct _Ret=5.64.

Embodiment 62:1-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-(4-pyridin-3-yl-3-trifluoromethyl-phenyl)-urea

As preparation title compound as described in the embodiment 61, use 3-(1,1,1-tributyl stannyl) pyridine: m.p.:118-123 ℃; MS:[M+1] ⁺=481; HPLC ^Ct _Ret=3.67.

Embodiment 63:1-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-(4-pyridin-4-yl-3-trifluoromethyl-phenyl)-urea

As preparation title compound as described in the embodiment 61, use 4-(1,1,1-tributyl stannyl) pyridine: m.p.:127-130 ℃; MS:[M+1] ⁺=481; HPLC ^Ct _Ret=3.64.

Embodiment 64:1-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-[4-(6-methyl-pyridine-2-yl)-3-trifluoromethyl-phenyl]-urea

As preparation title compound as described in the embodiment 61, use 2-methyl-6-tributyl stannyl-pyridine (step 54.1): m.p.:106-109 ℃; MS:[M+1] ⁺=495; HPLC ^Ct _Ret=3.80.

Embodiment 65:N-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-N '-[4-(4-ethyl piperazidine-1-ylmethyl)-3-chloro-phenyl]-urea

To N ₂The 30ml THF solution of the 720mg under the atmosphere (2.8mMol) 4-(4-ethyl piperazidine-1-ylmethyl)-3-chloro-aniline (step 65.3) adds 710mg (2.86mMol) 4-chloro-6-(4-isocyanide acyl group-phenoxy group)-pyrimidine (step 1.3).After stirring 18h, reaction mixture is filtered, partial concentration filtrate adds the DIPE crystallization and goes out title compound: MS:[M+1] ⁺=501; ¹H-NMR (DMSO-d ₆): 8.91 (s, 1H), 8.88 (s, 1H), 8.66 (s, 1H), 7.72 (d, 2Hz, 1H), 7.54 (d, 9Hz, 2H), 7.36 (d, 8Hz, 1H), 7.35 (s, 1H), 7.28 (dd, 8Hz, 2Hz, 1H), 7.18 (d, 9Hz, 2H), 3.49 (s, 2H), 2.43 (m, 8H), 2.32 (q, 7.1Hz, 2H), 0.99 (t, 7.1Hz, H ₃C).

Raw material is prepared as follows:

Step 65.1:(4-nitro-2-chloro-phenyl)-(4-ethyl piperazidine-1-yl)-ketone

Be similar to step 5.1,5.0g (24.8mMol) 4-nitro-2-chloro-phenylformic acid with the activation of 6.0ml (71mMol) oxalyl chloride, with the reaction of 6.6ml (52mMol) 1-ethyl piperazidine, is obtained title compound: MS:[M+1] ⁺=298; HPLC ^At _Ret=7.3.

Step 65.2:(4-amino-2-chloro-phenyl)-(4-ethyl piperazidine-1-yl)-ketone

As described in step 1.5, at hydrogenation 7.29g (24.5mMol) in the presence of the 1.3g Raney nickel, in 130ml ethanol (4-nitro-2-chloro-phenyl)-(4-ethyl piperazidine-1-yl)-ketone, crystallization from toluene obtains title compound: m.p.:123-124 ℃; MS:[M+1] ⁺=268.

Step 65.3:4-(4-ethyl piperazidine-1-ylmethyl)-3-chloro-aniline

Be similar to step 5.3,5.06g (18.9mMol) (4-amino-2-chloro-phenyl)-(4-ethyl piperazidine-1-yl)-ketone is used 57ml BH in 60ml THF ₃(1M THF solution) reduction.Through chromatography (SiO ₂CH ₂Cl ₂/ MeOH/NH ₃ ^Aq95: 5: 1 → 80: 20: 1), obtain title compound: MS:[M+1] ⁺=254; ¹H-NMR (CDCl ₃): 7.21 (d, 8Hz, 1H), 6.72 (d, 2.3Hz, 1H), 6.58 (dd, 8Hz, 2.3Hz, 1H), 3.70 (s, H ₂N), 3.57 (s, 2H), 2.6 (m, 8H), 2.47 (q, 7.2Hz, 2H), 1.13 (t, 7.2Hz, H ₃C).

Embodiment 66:1-[4-(2-amino-pyrimidine-4-base oxygen base-phenyl]-3-(4-piperazine-1-ylmethyl-3-trifluoromethyl-phenyl)-urea

At 20mg Pd/C (10%; Engelhard 4505) existence under, in 6ml methyl alcohol hydrogenation 107mg (0.172mMol) 4-(4-{3-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-urea groups-2-trifluoromethyl-benzyl)-piperazine-1-formic acid benzyl ester (Ex.51.h.1), filter, handle (CH through the Combi flash chromatography ₂Cl ₂/ MeOH+1%NH ₃ ^Aq95: 5 → 4: 1), obtain title compound: R _f(CH ₂Cl ₂/ MeOH/NH ₃ ^Aq80: 20: 1): 0.10; HPLC ^At _Ret=7.6; MS:[M+1] ⁺=488; ¹H-NMR (CD ₃OD): 8.09 (d, 5.9Hz, 1H), 7.90 (m, 1H), 7.74 (d, 8.2Hz, 1H), 7.64 (d, 8.2Hz, 1H), 7.53 (d, 9.0Hz, 2H), 7.12 (d, 9.0Hz, 2H), 6.18 (d, 5.9Hz, 1H), 3.63 (s, 2H), 2.88 (m, 4H), 2.48 (m, 4H).

Embodiment 67:1-[4-(2-methylamino--pyrimidine-4-base oxygen base-phenyl]-3-(4-piperazine-1-ylmethyl-3-trifluoromethyl-phenyl)-urea

Can be similar to prepared described herein.

Embodiment 68:N-(6-{4-[3-(3-trifluoromethyl-phenyl)-urea groups]-phenoxy group }-pyrimidine-4-yl) ethanamide

Under Ar, with N-(4-(4-chloropyrimide-6-yl)-oxygen base phenyl)-N '-(3-trifluoromethyl)-urea (step 68.1) (100mg, 0.245mmol), ethanamide (40mg, 0.68mmol), Pd ₂(dba) ₃(three (dibenzalacetones), two palladiums (0)) (6mg), 4, two (diphenyl phosphine)-9 of 5-, 9-dimethyl xanthene (9mg) and Cs ₂CO ₃(160mg) in THF (3ml), stir 8h at 55 ℃.Behind filtration and the evaporating solvent, by preparative thin-layer chromatography separated product (4 20 * 20cm flat boards, acetone/CH ₂Cl ₂=3: 7): white solid, M+H=431.9, ¹H-NMR (400MHz, DMSO-d ₆): 10.85 (s, 1H, pyrimidyl), 9.03/8.84 (s/s, 1H/1H, urea), 8.45 (s, 1H, NH), (7.98 s, 1H, pyrimidyl), 7.56 (d, 8.5Hz, 1H), 7.56 (d/s, 9.0Hz, 2H/1H), 7.29 (d, 8.5Hz, 1H), 7.06 (d, 9.0Hz, 2H), 2.09 (s, 3H, CH ₃), R _f(acetone/CH ₂Cl ₂=3: 7): 0.34.

Step 68.1N-(4-(4-chloropyrimide-6-yl)-oxygen base phenyl)-N '-(3-trifluoromethyl)-urea

With 3-trifluoromethyl-phenyl isocyanate (412mg, 2.2mmol), 4-(6-chloro-pyrimidine-4-base-oxygen base)-aniline (step 68.2; 0.25g, 1.1mmol) and pyridine (0.18ml) be dissolved in THF (3ml), stir spend the night after, under reduced pressure concentrated reaction solution is handled (silica gel, 2.5 * 17cm through flash chromatography; Acetone/CH ₂Cl ₂=5: 95 → 1: 9), obtain title compound, be colorless solid: M+H=408.9/410.9, ¹H-NMR (400MHz, DMSO-d ₆): 9.07 (s, 1H, NH), 8.89 (s, 1H, NH), 8.63 (d, 2.0Hz, 1H, pyridyl), 8.01 (s, 1H, 3-CF ₃-phenyl), 7.57 (d/ broad peak, 8.0Hz, 1H, CF ₃-phenyl), 7.52 (d, 9.5Hz, 2H, oxo-phenyl-amine), 7.50 (m, 1H, 3-CF ₃-phenyl), 7.32 (d, 2.0Hz, 1H, pyridyl), 7.29 (d/ broad peak, 8.0Hz, 1H ,-CF ₃-phenyl), 7.15 (d, 9.5Hz, 2H, oxo-phenyl-amine), (d, 6.5Hz, 2H, pyridyl); R _f(acetone/CH ₂Cl ₂=1: 9): 0.54; M.p.=187.4-189.7 ℃.

Raw material is prepared as follows:

Step 68.2:4-(6-chloro-pyrimidine-4-base-oxygen base)-aniline

With 4-chloro-6-(4-nitro-phenoxy group)-pyrimidine (step 68.3; 3.6g, 14.3mmol) be dissolved in MeOH (250ml), in the presence of Raney nickel (3g), at 40 ℃ of hydrogenation 3d.Reaction soln is filtered, under reduced pressure concentrate, crystallization from the EtOAc/ hexane obtains 4-chloro-6-(4-amino-phenoxy group)-pyrimidine: M+H=222/224; ¹H-NMR (400MHz, DMSO-d ₆): 8.62 (s, 1H, piperidyls), 7.13 (s, 1H, piperidyls), 6.83 (d, 9Hz, 2H, phenyl), 6.56 (d, 9Hz, 2H, phenyl), 5.12 (s, 2H, NH ₂); M.p.=135.5-138.1 ℃.

Step 68.3:4-chloro-6-(4-nitro-phenoxy group)-pyrimidine

With the 4-nitrophenols (2.8g, 20.1mMol), 2,4-two chloro-pyrimidines (3g, 20.1mMol), (0.8g 20.1mmol) is dissolved in H to NaOH ₂O/ acetone (80ml; 1: 1), stir 1h at 60-65 ℃.Under reduced pressure concentrated reaction solution is handled (silica gel, 4.5 * 22cm, EtOAc/ hexane=1: 4) through flash chromatography, obtains title compound, is colorless solid: M+H=252/254; ¹H-NMR (400MHz, DMSO-d ₆): 8.67 (s, 1H, pyrimidyl), 8.34 (d, 9Hz, 2H, phenyl), 7.58 (d, 9Hz, 2H, phenyl), 7.53 (s, 1H, pyrimidyl); R _f(EtOAc/ hexane=1: 1): 0.16; M.p.=125.4-126.6 ℃.

Embodiment 69:N-(6-{4-[3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea groups]-phenoxy group }-pyrimidine-4-yl)-ethanamide

Be similar to the synthetic of embodiment 68 compounds, from 1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea (step 69.1) preparation title compound: beige solid, M+H=516.9, HPLC[20 → 100%CH ₃CN (0.1%TFA) and H ₂O (0.1%TFA) 7min keeps 100%CH ₃CN (0.1%TFA) 2min]: t _Ret=7.72min, R _f(MeOH/CH ₂Cl ₂=1: 9): 0.42.

Step 69.1:1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-(4-morpholine-4-base-3-trifluoromethyl-benzene Base)-urea

What be similar to embodiment 1 compound synthesizes, starts from step 55c.2 compound title compound: white solid, M-H=491.9, HPLC[20-100%CH ₃CN (0.1%TFA) and H ₂O (0.1%TFA) 7min keeps 100%CH ₃CN (0.1%TFA) 2min]: t _Ret=7.52min, R _f(MeOH/CH ₂Cl ₂=3: 97): 0.17.

Embodiment 70:[6-(4-{3-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea groups } phenoxy group)-pyrimidine-4-yl]-the carboxylamine methyl ester

787 μ l (10.2mMol) methyl-chloroformates are dissolved in 10ml CH ₂Cl ₂, slowly join 160mg (0.31mMol) 1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl at rt]-3-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-the 16ml CH of urea (step 70.1), 5.6ml pyridine and 20mg DMAP ₂Cl ₂In the solution.After stirring 2h, the gained suspension is filtered, filtrate is used H with 100ml EtOAc dilution ₂O and salt solution washed twice.With water layer EtOAc extracting twice, organic phase drying (Na ₂SO ₄), under reduced pressure concentrate.Handle (CH through the Combi flash chromatography ₂Cl ₂/ NH ₃ ^Aq/ MeOH96: 1: 3 → 90: 1: 9), obtain white crystal: m.p.:191-193 ℃; Ultimate analysis C ₂₇H ₃₀N ₇F ₃O ₄: C, H, N; MS:[M+1] ⁺=574.

Step 70.1:1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-ethyl-piperazine-1-Ji Jia Base)-3-trifluoromethyl-phenyl]-urea

Be similar to the synthetic preparation title compound of Ex.19 compound: ultimate analysis C ₂₅H ₂₈N ₇F ₃O ₂0.86H ₂O:C, H, N, F, H ₂O; MS:[M+1] ⁺=516; HPLC ^At _Ret=8.0.

Embodiment 71:1-[4-(2-acetylaminohydroxyphenylarsonic acid pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

119 μ l (1.67mMol) Acetyl Chloride 98Min.s are dissolved in 7ml CH ₂Cl ₂, in 2.5h, join 250mg (0.50mMol) 1-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-the 6.5ml pyridine solution of urea (Ex.52a) and 10mg DMAP in.After stirring other 1 hour, mixture dilutes with 200ml water and 250ml EtOAc.Separate water layer, strip twice with EtOAc.With organic phase water and salt water washing, dry (Na ₂SO ₄), concentrate in a vacuum.Handle (Gilson System) through reverse-phase chromatography, obtain title compound: acetone/EtOH+1%Et ₃N 95: 5 → 4: 1; MS:[M+1] ⁺=544; R _f(acetone/EtOH/Et ₃N 80: 20: 1): 0.11; HPLC ^At _Ret=7.8.

Embodiment 72: be similar to described technology and can prepare following compounds:

Embodiment 73:3-[3-(4-{6-[4-(tertiary butyl-dimethyl-siloxy-)-phenyl amino]-pyrimidine-4-base oxygen base }-phenyl)-urea groups]-5-trifluoromethyl-benzamide

Be similar to the preparation of Ex.54 compound, prepare title compound from [6-(4-amino-phenoxy group)-pyrimidine-4-yl]-[4-(tertiary butyl-dimethyl-siloxy-)-phenyl]-amine and 3-amino-5-trifluoromethyl-benzamide (step 73.1) through the generation of urea: MS:[M+1] ⁺=639; R _f(MeOH/CH ₂Cl ₂=1: 9): 0.49.

Step 73.1:[6-(4-amino-phenoxy group)-pyrimidine-4-yl]-[4-(tertiary butyl-dimethyl-siloxy-)- Phenyl] amine

Title compound is as preparation as described in the WO 2003/099771.

Embodiment 74:1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl }-urea

With 3 '-(48mg is 0.18mMol) with DIPEA (67 μ L, 0.38mMol, CH 2.2equiv) for chloro-2-trifluoromethyl-biphenyl-4-amine ₂Cl ₂(0.6ml) drips of solution is added to triphosgene (19mg, CH 0.07mMol) of cold (0 ℃) ₂Cl ₂(0.6ml) in the solution.Add N-[4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base to reaction mixture then]-N ', N '-dimethyl-butane-1, (56mg is 0.18mMol) with DIPEA (66 μ L, 0.38mMol, CH 2.2equiv) for the 4-diamines ₂Cl ₂(1.1ml) solution.Make mixture be warming up to rt, stir 10min, concentrate in a vacuum.Crude product is through MPLC purifying (CH ₃CN/H ₂O/TFA) obtain title compound, be yellow solid: MS:613.9[M] ⁺HPLC ^Dt _Ret=4.2.

Step 74.1:N-[4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4- Diamines

Will [4-(2-chloro-pyrimidine-4-base oxygen base)-2-methyl-phenyl amine (808mg, 3.43mMol), 4-dimethylamino butylamine (438mg, 3.77mMol, 1.1equiv) and K ₂CO ₃(2.7equiv) mixture in DMF (8ml) stirs 1h at 100 ℃ for 1.3g, 9.26mMol.Make reaction mixture be cooled to rt, filter by the glass sintering funnel.Concentrated filtrate in a vacuum.Crude product is through silica gel chromatography (CH ₂Cl ₂9: 1 → CH of/MeOH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq9: 1), obtain title compound, be xanchromatic oil: MS:316.1[M] ⁺R _f=0.23 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 4: 1).

Step 74.2:4-(2-chloro-pyrimidine-4-base oxygen base)-2-methyl-phenyl amine

Under rt, nitrogen atmosphere, (992mg, 3.73mMol) (3: 1,40ml) mixture in stirred 7h at MeOH/THF with Raney nickel (700mg) with 2-chloro-4-(3-methyl-4-nitro-phenoxy group)-pyrimidine.Reaction mixture is filtered by Celite pad, and concentrated filtrate obtains title compound in a vacuum, is yellow solid: MS:236.0[M+1] ⁺HPLC ^Dt _Ret=2.2.

Step 74.3:2-chloro-4-(3-methyl-4-nitro-phenoxy group)-pyrimidine

With 2, (3.7g, 25.17mMol 2equiv) disposablely join 4-nitro-m-cresols (1.9g, 12.59mMol) (0.605g, 15.11mMol are 1.2equiv) in the mixture in DMF (25ml) with powdery NaOH the 4-dichloro pyrimidine.Reaction mixture is stirred 1h at rt, use H ₂O (300ml) dilution is with EtOAc (600ml) extraction.Water layer is saturated with NaCl, use CH ₂Cl ₂/ MeOH extraction (9: 1,2 * 300ml).Merge organic phase, dry (Na ₂SO ₄), filter, concentrate.Gained yellow crystal product obtains title compound through silica gel chromatography (hexane → hexane/EtOAc 6: 1 → 4: 1), is white crystal: HPLC ^Dt _Ret=4.7; Rf=0.17 (hexane/EtOAc, 3: 1).

Step 74.4:3 '-chloro-2-trifluoromethyl-biphenyl-4-amine

With 5-amino-2-5 bromine benzotrifluoride (500mg, 2.1mMol), the 3-chloro-phenyl-for boric acid (970mg, 6.2mMol, 3equiv), Pd (PPh ₃) ₄(70mg, 0.018mMol, 0.03equiv), Na ₂CO ₃(2MH ₂O solution, 5ml, 10mMol, 4.76equiv) mixture with toluene (14ml) stirs 1h under refluxing.Make reaction mixture be cooled to rt, filter, use CH by Celite pad ₂Cl ₂And H ₂The O washing leaching cake.Separate each layer, water CH ₂Cl ₂Extraction (2 * 60ml).Merge organic phase, use the salt water washing, dry (Na ₂SO ₄), filter, concentrate in a vacuum.Crude product is through MPLC purifying (CH ₃CN/H ₂O/TFA) obtain title compound: MS:270.0[M-2] ^-HPLC ^Dt _Ret=4.9.

Embodiment 75:1-(3 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl }-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use 3 '-bromo-2-trifluoromethyl-biphenyl-4-amine.Title compound: MS:658.8 (M+1) ⁺HPLC ^Dt _Ref=4.3; R _f=0.47 (CH ₂Cl ₂/ MeOH, 99: 1).

Step 75.1:3 '-bromo-2-trifluoromethyl-biphenyl-4-amine

As Ex.74 (step 74.4) about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use the 3-bromophenyl for boric acid.Title compound: MS:315.9 (M-1) ^-HPLC ^Dt _Ref=4.9; R _f=0.16 (hexane/EtOAc, 4: 1).

Embodiment 76:1-(4 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl }-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use 4 '-chloro-2-trifluoromethyl-biphenyl-4-amine.Title compound: MS:612.9 (M) ⁺HPLC ^Dt _Ref=4.3; R _f=0.13 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Step 76.1:4 '-chloro-2-trifluoromethyl-biphenyl-4-amine

As Ex.74 (step 74.4) about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use the 4-chloro-phenyl-for boric acid.Title compound: MS:270.0[M-2] ^-HPLC ^Dt _Ref=4.9.

Embodiment 77:1-(4 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl }-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use 4 '-bromo-2-trifluoromethyl-biphenyl-4-amine.Title compound: MS:658.8[M+1] ⁺HPLC ^Dt _Ref=4.4; R _f=0.07 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Step 77.1:4 '-bromo-2-trifluoromethyl-biphenyl-4-amine

As Ex.74 (step 74.4) about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use the 4-bromophenyl for boric acid.Title compound: MS:315.9[M-1] ^-HPLC ^Dt _Ref=4.9; R _f=0.14 (hexane/EtOAc, 4: 1).

Embodiment 78:1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-2-trifluoromethyl-phenyl }-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-3-trifluoromethyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1, the 4-diamines.Title compound: MS:668.8[M+1] ⁺HPLC ^Dt _Ref=4.4; R _f=0.01 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Step 78.1:N-[4-(4-amino-3-trifluoromethyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane -1, the 4-diamines

As Ex.74 (step 74.1) about N-[4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1, the described preparation title compound of 4-diamines, but be to use 4-(2-chloro-pyrimidine-4-base oxygen base)-2-trifluoromethyl-phenyl amine.Title compound: MS:370.1[M] ⁺HPLC ^Dt _Ref=2.6; R _f=0.14 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 4: 1).

Step 78.2:4-(2-chloro-pyrimidine-4-base oxygen base)-2-trifluoromethyl-phenyl amine

About preparation title compound as described in 4-(2-chloro-pyrimidine-4-base oxygen base)-2-methyl-phenyl amine, but be to use 2-chloro-4-(4-nitro-3-trifluoromethyl-phenoxy group)-pyrimidine as Ex.74 (step 74.2).Title compound: MS:288.0[M-1] ^-HPLC ^Dt _Ref=4.6.

Step 78.3:2-chloro-4-(4-nitro-3-trifluoromethyl-phenoxy group)-pyrimidine

About preparation title compound as described in 2-chloro-4-(3-methyl-4-nitro-phenoxy group)-pyrimidine, but be to use 4-nitro-3-(trifluoromethyl)-phenol as Ex.74 (step 74.3).Reaction mixture is stirred 3h at rt.Title compound: MS:317.9[M-1] ^-HPLC ^Dt _Ref=4.8.

Embodiment 79:1-(3 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-2-trifluoromethyl-phenyl }-urea

As Ex.75 about 1-(3 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-3-trifluoromethyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4-diamines (Ex.78, step 78.1).Title compound: MS:712.7[M+1] ⁺HPLC ^Dt _Ref=4.5; R _f=0.04 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Embodiment 80:1-(4 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-trifluoromethyl-phenyl }-urea

As Ex.76 about 1-(4 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-3-trifluoromethyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4-diamines (Ex.78, step 78.1).Title compound: MS:668.8[M+1] ⁺HPLC ^Dt _Ref=4.5; R _f=0.08 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Embodiment 81:1-(4 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-2-trifluoromethyl-phenyl }-urea

As Ex.77 about 1-(4 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-3-trifluoromethyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4-diamines (Ex.78, step 78.1).Title compound: MS:712.7[M+1] ⁺HPLC ^Dt _Ref=4.5; R _f=0.07 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Embodiment 82:1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-phenyl }-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1, the 4-diamines.Title compound: MS:600.9[M+1] ⁺HPLC ^Dt _Ref=4.3; R _f=0.02 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Step 82.1:N-[4-(4-amino-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4-diamines

As Ex.74 (step 74.1) about N-[4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1, the described preparation title compound of 4-diamines, but be to use 4-(2-chloro-pyrimidine-4-base oxygen base)-phenyl amine.Title compound: MS:302.2[M] ⁺R _f=0.27 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 4: 1).

Step 82.2:4-(2-chloro-pyrimidine-4-base oxygen base)-phenyl amine

As Ex.74 (step 74.2) about [preparation title compound as described in 4-(2-chloro-pyrimidine-4-base oxygen base)-2-methyl-phenyl amine, but be to use 2-chloro-4-(4-nitro-phenoxy group)-pyrimidine (Ex.45, step 45.1).Title compound: MS:223.9[M+1] ⁺HPLC ^Dt _Ref=1.6; R _f=0.62 (CH ₂Cl ₂/ MeOH, 95: 5).

Embodiment 83:1-(4 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-phenyl }-urea

As Ex.76 about 1-(4 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4-diamines (Ex.82, step 82.1).Title compound: MS:598.9[M] ⁺HPLC ^Dt _Ref=4.3; R _f=0.10 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Embodiment 84:1-(4 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino butyl amino)-pyrimidine-4-base oxygen base]-phenyl }-urea

As Ex.77 about 1-(4 '-bromo-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use N-[4-(4-amino-phenoxy group)-pyrimidine-2-base]-N ', N '-dimethyl-butane-1,4-diamines (Ex.82, step 82.1).Title compound: MS:644.8[M+1] ⁺HPLC ^Dt _Ref=4.3; R _f=0.10 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Embodiment 85:1-{4-[2-(3-methoxyl group-phenyl amino)-pyrimidine-4-base oxygen base]-phenyl }-3-[4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use [4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-(3-methoxyl group-phenyl)-amine and 4-(4-methylpiperazine-1-ylmethyl)-3-trifluoromethyl-aniline (Ex.14, step 14.4).Title compound: MS:622.0[M+1] ⁺HPLC ^Dt _Ref=3.5; R _f=0.33 (CH ₂Cl ₂/ MeOH+1%NH ₃ ^Aq, 9: 1).

Step 85.1:[4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-(3-methoxyl group-phenyl)-amine

Under rt, nitrogen atmosphere, (400mg, 1.14mMol) (3: 1,40ml) mixture in stirred 2h at MeOH/THF with Raney nickel (200mg) with (3-methoxyl group-phenyl)-[4-(3-methyl-4-nitro-phenoxy group)-pyrimidine-2-base]-amine.Reaction mixture is filtered by Celite pad, and concentrated filtrate obtains title compound in a vacuum, is yellow-brown solid: MS:323.1[M+1] ⁺HPLC ^Dt _Ret=2.6.

Step 85.2:(3-methoxyl group-phenyl)-[4-(3-methyl-4-nitro-phenoxy group)-pyrimidine-2-base]-amine

With 2-chloro-4-(3-methyl-4-nitro-phenoxy group)-pyrimidine (Ex.74, step 74.3) (700mg, 2.63mMol), (357mg, 2.90mMol 1.1equiv) stir 1h with the mixture of 2-propyl alcohol (10.5ml) at 100 ℃ to the m-methyl oxyaniline.Make reaction mixture be cooled to rt, use H ₂CH is used in O (90ml) dilution ₂Cl ₂(350ml) extraction.With organic phase salt water washing, dry (Na ₂SO ₄), filter, concentrate.Title compound: MS:353.3[M+1] ⁺HPLC ^Dt _Ref=4.6; R _f=0.08 (hexane/EtOAc, 3: 1).

Embodiment 86:1-(2-methyl-4-{2-[4-(4-methyl-piperazine-1-yl)-phenyl amino]-pyrimidine-4-base oxygen base }-phenyl)-3-(3-trifluoromethyl-phenyl)-urea

As Ex.74 about 1-(3 '-chloro-2-trifluoromethyl-biphenyl-4-yl)-3-{4-[2-(4-dimethylamino-butyl amino)-pyrimidine-4-base oxygen base]-2-methyl-phenyl-urea as described in the preparation title compound, but be to use [4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine and 3-5 amido benzotrifluoride.Title compound: MS:577.9[M] ⁺HPLC ^Dt _Ref=3.7; R _f=0.29 (CH ₂Cl ₂/ MeOH, 9: 1).

Step 86.1:[4-(4-amino-3-methyl-phenoxy group)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-benzene Base]-amine

Under rt, nitrogen atmosphere, (133mg 0.32mMol) stirs 6h with the mixture of Raney nickel (50mg) in MeOH (10ml) with [4-(3-methyl-4-nitro-phenoxy group)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-phenyl]-amine.Reaction mixture is filtered by Celite pad, and concentrated filtrate obtains title compound in a vacuum, is redness-brown solid: MS:391.1[M] ⁺HPLC ^Dt _Ret=1.3.

Step 86.2:[4-(3-methyl-4-nitro-phenoxy group)-pyrimidine-2-base]-[4-(4-methyl-piperazine-1-yl)-benzene Base] amine

With 2-chloro-4-(3-methyl-4-nitro-phenoxy group)-pyrimidine (Ex.74, step 74.3) (400mg, 1.51mMol), 4-(4-methyl-piperazine-1-yl)-phenyl amine (318mg, 1.66mMol, 1.1equiv), 4NHCl (1.1ml, 4.8mMol 2.7equiv) mixture with 2-propyl alcohol (6ml) stirs 1h at 100 ℃.Make reaction mixture be cooled to rt, use H ₂CH is used in O (30ml) dilution ₂Cl ₂(120ml) extraction.With organic phase salt water washing, dry (Na ₂SO ₄), filter, concentrate.Title compound: MS:421.1[M+1] ⁺HPLC ^Dt _Ref=3.1; R _f=0.39 (CH ₂Cl ₂/ MeOH, 9: 1).

Embodiment 87:1-{4-[6-(5-chloro-2-methoxyl group-phenyl amino)-pyrimidine-4-base oxygen base]-phenyl }-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea

To 1-[4-(6-chloro-pyrimidine-4-base oxygen base)-phenyl]-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea (step 69.1) (34mg, 68 μ mol) 3ml Virahol ∶ diox (1: 1, v/v) solution adds 5-chloro-2-methoxyl group-phenyl amine (54mg, 340 μ mol; Fluka, Buchs is Switzerland) with dense HCl (5 μ l).With mixture at microwave oven (Emrys Optimizer, Personal Chemistry; Uppsala, Sweden) middle heating is finished until reaction.Reaction mixture with EtOAc (50ml) dilution, is extracted with 0.1NNaOH (x2) and water (x2).Aqueous phase discarded is with organic phase drying (Na ₂SO ₄), filter, be concentrated into dried.Handle (CH through silica gel chromatography ₂Cl ₂: MeOH 98: 2, v/v), obtains title compound: MS:615.2,616.4,617.4; HPLC t _Ret ^New=8.67 (new gradient: MeCN/0.09%TFA and H ₂O/0.1%TFA detects wavelength 215nm from 1: 49 to 1: 0 linear gradient 7min and 1: 03min, flow velocity 2.0ml/min, pillar Nucleosil C18-post (250 * 4.6mm, 5 μ m, 100A)).

Use suitable sulfonamide derivatives, as preparation following compounds as described in the embodiment 87:

Embodiment	The compound title	ES-MS (M+H) +	t Ret new [min]
				88	1-{4-[6-(4-methyl-piperazine-1-yl)-pyrimidine-4-base oxygen base]-phenyl }-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea	558.2	6.69
89	1-[4-(6-dimethylamino-pyrimidine-4-base oxygen base)-phenyl]-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea	503.3	7.14
				90	N, N-dimethyl-4-(6-{4-[3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea groups]-phenoxy group }-pyrimidine-4-base is amino)-benzamide	622.4	7.68
91	1-{4-[6-(2-methoxyl group-5-methyl-phenyl amino)-pyrimidine-4-base oxygen base]-phenyl }-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea	595.6	8.17
				92	1-{4-[6-(2-methoxyl group-5-nitro-phenyl amino)-pyrimidine-4-base oxygen base]-phenyl }-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea	626.5	8.50
93	1-{4-[6-(2,5-dimethoxy-phenyl amino)-pyrimidine-4-base oxygen base]-phenyl }-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea	611.5	8.10
				94	N, N-diethyl-4-methoxyl group-3-(6-{4-[3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea groups]-phenoxy group }-pyrimidine-4-base is amino)-benzsulfamide	716.4	8.39
95	1-{4-[6-(2-methoxyl group-phenyl amino)-pyrimidine-4-base oxygen base]-phenyl }-3-(4-morpholine-4-base-3-trifluoromethyl-phenyl)-urea	581.3	7.91

The restraining effect of embodiment 96:RET protein tyrosine kinase activity

Carry out the restraining effect test as mentioned above.Following table provides the IC of some formula I compounds ₅₀Value:

The compound title	IC 50RET[μM]
		1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-(3-azetidine-1-ylmethyl-5-trifluoromethyl-phenyl)-urea	0.083
1-(3-dimethylamino methyl-5-trifluoromethyl-phenyl)-3-[4-(6-methylamino-pyrimidine-4-base oxygen base)-phenyl]-urea	0.11
		1-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-methyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea	0.18
1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[3-(4-methyl-piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea	0.26
		1-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea	0.31
1-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(2-methylamino--pyrimidine-4-base oxygen base)-phenyl]-urea	0.35
		1-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-sec.-propyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea	0.4
1-[4-(2-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-methyl-piperazine-1-yl)-3-trifluoromethyl-phenyl]-urea	0.45
		1-[4-(2-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-[3-(4-methyl-piperazine-1-yl)-5-trifluoromethyl-phenyl]-urea	0.45
1-[4-(6-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4-sec.-propyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea	0.55
		1-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(the 4-tertiary butyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-urea	0.56
1-[4-(4-ethyl-piperazine-1-ylmethyl)-3-trifluoromethyl-phenyl]-3-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-urea	0.58
		1-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-3-[3-(4-methyl-piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-urea	0.59
1-[4-(2-amino-pyrimidine-4-base oxygen base)-phenyl]-3-[4-(4,5-dimethyl-imidazoles-1-ylmethyl)-3-	0.85

Trifluoromethyl-phenyl]-urea
		1-[3-(4-sec.-propyl-piperazine-1-ylmethyl)-5-trifluoromethyl-phenyl]-3-[4-(6-methylamino--pyrimidine-4-base oxygen base)-phenyl]-urea	0.96

The restraining effect of embodiment 97:Flt-3 protein tyrosine kinase activity

Carry out the restraining effect test as mentioned above.Following table provides the IC of some formula I compounds ₅₀Value:

Example I C 50 Flt-3 No. [μM]	Example I C 50 Flt-3 No. [μM]	Example I C 50 Flt-3 No. [μM]
			1 0.905 2 1.2 4 0.153 5 0.54 6 0.4 8 0.51 9 0.32 11 0.23 13 0.34 14 0.36 15 0.6 16 0.36 17 0.94 19 0.25 19-1 0.038 19-2 0.08 21 1.8 23 1.3 24 0.17 34a.1 1.1 34a.3 0.83 34b.1 0.36 34b.3 0.37 34c.1 0.54 34c.3 0.35	34d.1 0.67 34d.3 0.29 34e.1 0.16 34e.3 0.079 34g.1 0.3 34g.3 0.378 34j.1 0.25 34j.3 0.283 34k.1 0.13 34k.3 0.1 34l.1 0.62 34m.1 0.4 34m.3 0.2 34n.1 0.31 34n.3 0.2 34p.1 0.59 34s.2 0.24 34t.2 0.29 34u.2 1.5 34w.2 0.14 38 0.354 41 0.42 43 0.16 48 0.58 50 0.12	51a.1 0.085 51a.2 0.12 51b.1 0.13 51b.2 0.17 51d.1 0.091 51d.2 0.135 51e.1 0.25 51e.2 0.91 52a 0.12 52b 0.08 52c 0.029 52d 0.26 53b 0.12 53d 0.19 55c 0.37 55d 0.97 57 0.118 58 0.12 59 0.076 60 0.16 61 0.49 62 0.16 63 0.14 64 0.34

The effect of embodiment 98:Flt-3 dependent cell inhibition of proliferation

Carry out restraining effect as mentioned above and measure, using and expressing the kinase whose wild-type IL-3-dependency of composing type activatory Flt-3 hematopoietic cell is Ba/F3 and mutant subbreed ITD-Ba/F3 or D835Y-Ba/F3.Following table provides the ED of some embodiment compounds ₅₀Value:

Embodiment 99: the tablet that comprises the embodiment compound

Abide by standard technology, utilize following composition to prepare tablet, comprise any one embodiment 1 to 95 compound of 100mg as activeconstituents:

Form

Activeconstituents 100mg

Crystallinity lactose 240mg

Avicel 80mg

PVPPXL 20mg

Aerosil 2mg

Magnesium Stearate 5mg

447mg

Preparation: activeconstituents is mixed with solid support material, suppress by tabletting machine (Korsch EKO, Stempeldurchmesser 10mm).

Avicel be Microcrystalline Cellulose (FMC, Philadelphia, USA).

PVPPXL is a crosslinked polyethylene polypyrrole alkane ketone (BASF, Germany).

Aerosil is silicon-dioxide (Degussa, German y).

Embodiment 100: capsule

Prepare the capsule of following composition according to standard technology, comprise any one embodiment 1 to 95 compound of 100mg as activeconstituents:

Form

Activeconstituents 100mg

Avicel 200mg

PVPPXL 15mg

Aerosil 2mg

Magnesium Stearate 1.5mg

318.5mg

Preparation: mix each component, be filled in No. 1 hard gelatin capsule.

Claims (12)

1, formula I compound is used for the treatment of purposes in the pharmaceutical composition of RET dependence disease in preparation,

Wherein G does not exist or low-grade alkylidene or C ₃-C ₅Cycloalkylidene, Z are formula Ia groups

Perhaps G does not exist, and Z is a formula Ib group

A is CH, N or N → O, and A ' is N or N → O, and its condition is that to be no more than one can be N → O for A and A ';

N is 1 or 2;

M is 0,1 or 2;

P is 0,2 or 3;

R is 0 to 5;

If p is 0, X is NR, and wherein R is hydrogen or organic moiety, if perhaps p is 2 or 3, X is a nitrogen, it and (CH ₂) _pAnd the key of dotted line (intermittent line) representative, comprise that the atom of their institute's bondings constitutes a ring together, perhaps

X is CHK, and wherein K is low alkyl group or hydrogen, and p is zero, and its condition is that the key of dotted line representative does not exist if p is zero;

Y ₁Be O, S or CH ₂

Y ₂Be O, S or NH;

Its condition is (Y ₁) _n-(Y ₂) _mDo not comprise O-O, S-S, NH-O, NH-S or S-O group;

Each R ₁, R ₂, R ₃And R ₅Be hydrogen or inorganic or organic moiety independently of one another, perhaps any two rudimentary alkylene dioxo base bridges that constitute together via the Sauerstoffatom bonding, one of all the other of these parts are hydrogen or inorganic or organic moiety;

R ₄(if present, if promptly r is not zero) is inorganic or organic moiety;

Or its tautomer;

Or its pharmacy acceptable salt.

2, according to the purposes of claim 1, wherein this RET dependence disease is a RET dependent tumors disease.

3, according to the purposes of claim 2, wherein this RET dependent tumors disease is selected from colorectal carcinoma, lung cancer, breast cancer, pancreas cancer and thyroid carcinoma.

4, according to the purposes of claim 3, wherein this cancer is a thyroid carcinoma.

5, be selected from N-[4-as the described embodiment 1-67 of specification sheets, 68-70 or 71-95 compound (pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives or its salt.

6, pharmaceutical composition comprises N-[4-(pyrimidine-4-base oxygen the base)-phenyl that is selected from as the described embodiment 1-67 of specification sheets, 68-70 or 71-95 compound]-N '-phenyl-urea derivatives or its pharmacy acceptable salt and pharmaceutically acceptable carrier.

7, be used for the treatment of animal or human's body, especially treat protein kinase dependent diseases be selected from N-[4-as the described embodiment 1-67 of specification sheets, 68-70 or 71-95 compound (pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives or its pharmacy acceptable salt.

8, according to the compound of claim 7, wherein the protein kinase dependent diseases that will treat is the protein tyrosine kinase dependence disease, especially depend on the hyperplasia of any one or multiple following protein tyrosine kinase: c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R and/or Tek, especially Flt-3.

9, be selected from N-[4-as the described embodiment 1-67 of specification sheets, 68-70 or 71-95 compound (pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives or its pharmacy acceptable salt be used for the treatment of the purposes of protein kinase dependent diseases.

10, be selected from N-[4-as the described embodiment 1-67 of specification sheets, 68-70 or 71-95 compound (pyrimidine-4-base oxygen base)-phenyl]-N '-phenyl-urea derivatives or its pharmacy acceptable salt be used for the treatment of purposes in the pharmaceutical composition of protein kinase dependent diseases in preparation.

11, according to the purposes of claim 9 or 10, wherein this protein kinase dependent diseases is the protein tyrosine kinase dependence disease, especially depend on the hyperplasia of any one or multiple following protein tyrosine kinase: c-Abl, Bcr-Abl, Flt-3, RET, VEGF-R and/or Tek, especially Flt-3.

12, the method for the disease that suppresses in response to (especially tyrosine) protein kinase of treatment, comprise warm-blooded animal, for example people to this class treatment of needs give preventative or especially the therapeutic significant quantity be selected from N-[4-(pyrimidine-4-base oxygen base)-phenyl as the described embodiment 1-67 of specification sheets, 68-70 or 71-95 compound]-N '-phenyl-urea derivatives or its pharmacy acceptable salt.