CN101668749A

CN101668749A - Novel pyrimidine derivatives 698

Info

Publication number: CN101668749A
Application number: CN200880014048A
Authority: CN
Inventors: S·E·阿什顿; B·C·巴拉姆; D·A·E·克罗斯; R·杜克雷; S·J·伊斯特; J·G·凯特勒; M·A·皮尔逊; S·C·珀基斯; S·R·韦奇
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2007-02-28
Filing date: 2008-02-27
Publication date: 2010-03-10

Abstract

The invention concerns compounds of Formula (I), or a pharmaceutically acceptable salt thereof, where R<1>, n, R<2>, R<3>, and R<4> are as defined in the description. The present invention also relates to processes for the preparation of such compounds, pharmaceutical compositions containing them and their use in the manufacture of a medicament for use as an antiproliferative agent in the prevention or treatment of tumours or other proliferative conditions which are sensitive to the inhibition of EphB4 kinases.

Description

New pyrimidine derivatives 698

Background of invention

The present invention relates to new pyrimidine derivatives, contain the pharmaceutical composition of these derivatives and in therapy particularly the prevention and the treatment warm-blooded animal (for example people) cancer in purposes.

The many existing treatment plan that is used for cell proliferation disorders (for example psoriatic and cancer) has all used inhibition DNA synthetic compound.This compounds is generally all toxic to all cells, but their toxic action then may be useful for quick splitted cell (for example tumour cell).

Discovered in recent years, cell may since its part DNA change into oncogene (promptly the time causing forming the gene of malignant cell) in activation take place canceration (Bradshaw, Mutagenesis, 1986, 1, 91).This some class oncogenes causes producing the peptide as growth factor receptors.The activation of growth factor receptors causes cell proliferation to increase.For example, existing known some oncogenes coding Tyrosylprotein kinases, and some growth factor receptors also be Tyrosylprotein kinase (Yarden etc., Ann. Rev.Biochem., 1988, 57, 443; Larsen etc., Ann.Reports in Med.Chem., 1989, the 13 chapters).

Receptor tyrosine kinase plays an important role in the transmission of biochemical signals, and it starts various cell responses, comprises cell proliferation, survival and migration.They are large-scale enzymes of cross-cell membrane, and it is outer in conjunction with the territory to have born of the same parents of somatomedin (for example Urogastron (EGF)), thereby and play a role as kinases and to make tyrosine amino acid phosphorylation in the protein influence part in the born of the same parents of cell proliferation.Existing known multiple receptor tyrosine kinase (Wilks, Advances in Cancer Research,1993, 6043-73), and according to classifying with extracellular domain bonded growth factor family.This classification comprises I receptoroid Tyrosylprotein kinase, II receptoroid Tyrosylprotein kinase and III receptoroid Tyrosylprotein kinase, and wherein I receptoroid Tyrosylprotein kinase comprises the EGF family of receptor tyrosine kinase, for example EGF, TGF α, Neu and erbB acceptor; II receptoroid Tyrosylprotein kinase comprises the Regular Insulin family of receptor tyrosine kinase, for example Regular Insulin and IGF1 acceptor and Regular Insulin associated receptor (IRR); III receptoroid Tyrosylprotein kinase comprises Thr6 PDGF BB (PDGF) family of receptor tyrosine kinase, for example PDGF α, PDGF β and colony-stimulating factor 1 (CSF1) acceptor.

Known Eph family is maximum receptor tyrosine kinase family, in Mammals, identify 14 acceptors and 8 related livers join protein ligands (relevant summary is seen Kullander and Klein, Nature Reviews Molecular Cell Biology, 2002, 3, 475-486).Receptor family further is subdivided into mainly by the homology of extracellular domain with to two subfamilies that avidity defined of specific ligand type.Generally speaking, all Eph acceptors all contain the interior tyrosine kinase domain of born of the same parents and have the outer Ig spline structure territory of the born of the same parents of being rich in halfcystine district and 2 fibronectin III type structural domains that contain 19 conservative halfcystines.Category-A Eph acceptor is made up of 8 acceptors that are called EphA1-8, this receptor generally be referred to as liver and join the related liver of albumin A 1-5 and join the combination of albumin A class part.Category-B is made up of 6 acceptors that are called EphB1-6, and this receptor is called liver with it and joins the related liver of protein B 1-3 and join the combination of protein B part.The Eph receptors ligand is unusual, and is with the difference of most other receptor tyrosine kinase part: they are joined the whole film district of striding that glycosyl-phosphatidyl inositol joint on the albumin A part or liver join on the protein B part by liver and combine with cell.The zygotic induction Eph born of the same parents intracellular domain occurred conformation that liver is joined protein ligands and Eph acceptor changes, make the tyrosine residues that self suppresses in the membrane-proximal region can phosphorylation, this has just removed the inhibition of catalytic site, and can carry out extra phosphorylation is used for downstream signal transduction effector with stabilizing active conformation and generation more stops position.

In addition, evidence suggests that the Eph/ liver joins protein signal transduction and can regulate other cell response, for example breed and survive.

More and more evidences shows that the transduction of Eph receptor signal can act on tumour cell directly or indirectly by regulating vascularization, thereby the tumour in the multiple human cancer is exerted an influence.For example, many Eph acceptors in the kinds of tumors type overexpression (relevant summary is seen Surawska etc., Cytokine ﹠amp; Growth Factor Reviews, 2004, 15, 419-433, Nakamoto and Bergemann, Microscopy Res and Technique, 2002, 59, 58-67).For example being expressed in of EphB acceptor (comprising EphB4) raised in the tumours such as neuroblastoma, leukemia, breast tumor, liver tumor, lung tumor and colon tumor.In addition, particularly studies show that the overexpression of Eph acceptor can produce tumorigenic phenotype in the cancer cells in the various external and body of EphB4, for example breed and attack that this is consistent with tumorigenic effect of inferring.

For example, use interferential RNA or antisense oligodeoxyribonucleotide to suppress EphB4 and express, suppressed in vitro and in vivo xenograft models PC3 prostate cancer cell propagation, survival and invasion and attack (Xia etc., Cancer Res., 2005, 65, 4623-4632).

Except that the Eph acceptor to the noticeable effect of tumour cell, also have admissible evidence to show, EphB4 can form tumor vessel and exert an influence (relevant summary is seen Brantley-Sieders etc., Current Pharmaceutical Design, 2004, 10, 3431-3442, Cheng etc., Cytokine and Growth Factor Reviews, 2002, 13, 75-85).The member of Eph family (comprising EphB4) expresses on endotheliocyte.Transgenic research show destroy EphB4 (Gerety etc., Molecular Cell, 1999, 4, 403-414) or its part liver join protein B 2 (Wang etc., Cell, 1998, 93, cause and the relevant embryonic death of blood vessel modeling defective that 741-753) this is consistent with the keying action in the vascular development.EphB4 activation stimulated in vitro endothelial cell proliferation and migration (Steinle etc., J.Biol.Chem., 2002, 277, 43830-43835).

In addition, heterograft studies show that, uses the solubility ectodomain of EphB4 to suppress the EphB4 signal transduction, suppressed in vivo tumor growth and vasculogenesis (Martiny-Baron etc., Neoplasia, 2004,6,248-257, Kertesz etc., Blood, 2005, issue in advance on the net).

Therefore, what now gained public acceptance is, Eph acceptor (particularly EphB4) inhibitor, or by direct target tumor cell, or the effect that tumor vessel is formed by their, and can become the selective depressant of valuable tumor cell proliferation and survival.Therefore, this class inhibitor can be the valuable curative that is used to control and/or treat tumor disease.

Applicant of the present invention finds that some pyrimidine compound can be used for suppressing EphB4, therefore can be used for treating in the therapy that wherein relates to the active disease that increases of EphB4.

Summary of the invention

Compound or its pharmacy acceptable salt of following formula I are provided according to a first aspect of the invention:

Wherein:

R ¹For by one or more optional (1-4C) alkyl, (3-4C) cycloalkyl or cyclopropyl methyl :-OR that replace of following substituting group that are selected from ⁵(R wherein ⁵Be selected from hydrogen or (1-2C) alkyl), cyano group, halogen or-NR ⁶R ⁷(R wherein ⁶And R ⁷Independently be selected from hydrogen, (1-2C) alkyl or (1-2C) alkyloyl);

N is 0,1,2 or 3;

The R of each existence ²Group independently is selected from (1-2C) alkyl, (1-2C) alkoxyl group, fluorine, chlorine, cyano group, hydroxyl (1-2C) alkyl or following formula group:

-Q-R ⁸

Wherein Q be selected from-CO-,-NR ^a-,-NR ^a-CO-,-NR ^a-COO-, NR ^aCONR ^b,-CONR ^a-,-S (O) _z-(wherein z is 0,1 or 2) ,-SO ₂NR ^a-and-NR ^aSO ₂-, R ^aAnd R ^bIndependently be selected from hydrogen or methyl, R separately ⁸Be hydrogen or (1-2C) alkyl;

R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

(ii) optional (1-6C) alkyl that replaces, (2-6C) thiazolinyl or (2-6C) alkynyl, wherein Ren Xuan substituting group is selected from:

Cyano group;

Halogen;

The following formula group:

-W-R ⁹

Wherein W be selected from-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CO-,-NR ^bCO-,-CONR ^b-,-NR ^bCONR ^b-,-SO ₂NR ^b-,-NR ^bSO ₂-or-NR ^bCOO-;

R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-4C) alkyl;

Or-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independently be selected from hydrogen or by halogen, hydroxyl, cyano group or (1-4C) optional (1-4C) alkyl that replaces of alkoxyl group, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹⁰And R ¹¹Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹⁰And R ¹¹Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl;

(iii) group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen separately or by halogen, hydroxyl, cyano group or (1-4C) optional (1-6C) alkyl that replaces of alkoxyl group, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹²And R ¹³Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl; Perhaps

The (iv) group of following formula (II):

-X-R ¹⁴

Wherein X be selected from-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CO-,-NR ^cCO-,-CONR ^c-,-NR ^cCOO-and-NR ^cSO ₂-,

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For by halogen, hydroxyl, cyano group or (1-4C) optional (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-2C) alkyl, amylene oxide base (oxanyl) or tetrahydrofuran base (oxolanyl), the perhaps R that replaces of alkoxyl group ¹⁴For

-NR ¹⁵R ¹⁶

R wherein ¹⁵And R ¹⁶Independently be selected from hydrogen, (1-2C) alkyloyl or (1-2C) alkyl, perhaps R ¹⁵And R ¹⁶Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹⁵And R ¹⁶Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom is all by the optional replacement of following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl;

R ⁴Be group-NR ¹⁷R ¹⁸, R wherein ¹⁷And R ¹⁸Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹⁷And R ¹⁸Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO or the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl;

Precondition is:

● if n is 1 and R ²Be (1-2C) alkoxyl group, then this alkoxyl group is not positioned at respect to-NR ¹Promptly 4 of the contrapositions of-group:

● if n is 1 and R ²Be oxyethyl group, then this oxyethyl group is not positioned at respect to-NR ¹The position is promptly 3 between-group;

If ● R ²Be formula-Q-R ⁸(wherein Q is NR to group ^a-CO-, R ^aBe hydrogen, R ⁸Be (1-2C) alkyl), R then ⁴It is not 4-methylpiperazine-1-base.

According to a second aspect of the invention, provide compound or its pharmacy acceptable salt of following formula I, wherein:

N is 0,1,2 or 3;

-Q-R ⁸

R ³Be selected from:

(v) hydrogen, halogen, nitro, cyano group or hydroxyl;

(vi) optional (1-6C) alkyl that replaces, (2-6C) thiazolinyl or (2-6C) alkynyl, wherein Ren Xuan substituting group is selected from:

Cyano group;

Halogen;

The following formula group:

-W-R ⁹

R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-4C) alkyl;

(vii) group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen separately or by halogen, hydroxyl, cyano group or (1-4C) optional (1-6C) alkyl that replaces of alkoxyl group, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹²And R ¹³Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl; Perhaps

(the viii) group of following formula (II):

-X-R ¹⁴

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For by halogen, hydroxyl, cyano group or (1-4C) optional (1-4C) alkyl that replaces of alkoxyl group, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹⁴For

-NR ¹⁵R ¹⁶

Precondition is:

If ● R ²Be (1-2C) alkoxyl group, then this alkoxyl group is not positioned at respect to-NR ¹Promptly 4 of the contrapositions of-group;

According to a third aspect of the present invention, provide compound or its pharmacy acceptable salt of following formula I, wherein:

R ¹For by one or more optional (1-4C) alkyl :-OR that replace of following substituting group that are selected from ⁵(R wherein ⁵Be selected from hydrogen or (1-2C) alkyl), cyano group, halogen or-NR ⁶R ⁷(R wherein ⁶And R ⁷Independently be selected from hydrogen, (1-2C) alkyl or (1-2C) alkyloyl);

N is 0,1,2 or 3;

-Q-R ⁸

R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

Cyano group;

Halogen;

The following formula group:

-W-R ⁹

R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-4C) alkyl;

Or-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independently be selected from hydrogen or (1-2C) alkyl, perhaps R ¹⁰And R ¹¹Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹⁰And R ¹¹Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl;

(iii) group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen or (1-6C) alkyl, perhaps R separately ¹²And R ¹³Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl; Perhaps

The (iv) group of following formula (II):

-X-R ¹⁴

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For being chosen wantonly (1-4C) alkyl that replaces, perhaps R by halogen, hydroxyl, cyano group, (1-4C) alkoxyl group ¹⁴For

-NR ¹⁵R ¹⁶

Precondition is:

Description of drawings

Figure A, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methyl alcohol free alkali form 1.

Figure B, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methyl alcohol-benzene sulfonate form 1.

Figure C, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methyl alcohol-benzene sulfonate form 2.

Figure D, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methanol toluene sulfonate form 1.

Figure E, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methanol toluene sulfonate form 2.

Figure F, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methyl alcohol fumarate form 1.

Figure G, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] the X-ray powder diffraction figure of methyl alcohol fumarate form 2.

Figure H, separately or unite and give [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol (embodiment 6) and 4-(the basic oxygen base of 4-fluoro-2 methyl indole-5-)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline (AZD7514) be to the effect of the HT29 tumor average volume of mouse tumor transplantation model.

Detailed Description Of The Invention

It should be understood that since some formula I compound defined above is because one or more asymmetric carbon atoms can exist optically active form or racemic modification, the present invention just comprises any this class optically active form or racemic modification with above-mentioned activity in its definition so. The synthetic of optically active form can be undertaken by organic chemistry standard technique well-known in the art, and be for example, synthetic or split by racemic modification by the optically-active raw material. Equally, can adopt hereinafter described standard laboratory technology assessment activity mentioned above.

It should be understood that some formula I compound defined above can have tautomerism. Tautomerism especially can affect with 1 or 2 substituent any heterocyclic radicals of oxo. To be appreciated that also the present invention comprises any this class dynamic isomer or its mixture with above-mentioned activity in its definition, and not only be confined to adopt in the structural representation or embodiment in any dynamic isomer of naming.

It should be understood that the compound of some following formula I can non-solvent form and solvation form (for example hydrated form) existence. Also to be appreciated that, the present invention includes all these kind solvent forms with anticancer or antitumor activity.

To be appreciated that also some formula I compound can have polymorphism, the present invention includes all the such forms with anticancer or antitumor activity.

Also should further be appreciated that any R that exists at the phenyl moiety of the aniline group that is positioned at 4 of pyrimidine rings²Group can be positioned on any active position of described phenyl moiety, if just n is 1 and R²Except during for (1-2C) alkoxyl, in this case, the contraposition that it then can not be positioned at phenyl moiety i.e. 4 (with respect to the nitrogen on the aniline), if perhaps n is 1 and R²Be ethyoxyl, in this case, ethyoxyl then can not be positioned at phenyl moiety between position i.e. 3 (with respect to the nitrogen on the aniline). When there being a plurality of R²During group, each R²Group can be identical or different.

Also to be appreciated that R⁴Be group-NR as defined above¹⁷R ¹⁸If, but R²Be formula-Q-R⁸(wherein Q is-NR group^a-CO-，R ^aBe hydrogen, R⁸Be (1-2C) alkyl), R then⁴Can not be the 4-methylpiperazine-1-yl.

In this manual, generic term " alkyl " comprises straight chain and branched alkyl, for example propyl group, isopropyl and the tert-butyl group. Yet, mention that indivedual alkyl such as " propyl group ", only refer in particular to the form of straight chain, and mention indivedual branched alkyls such as " isopropyl ", then only refer in particular to the form of side chain. Similarly convention is applicable to other generic term, and for example (1-4C) alkoxyl comprises methoxyl group, ethyoxyl and isopropoxy.

Term " halogen " refers to fluorine, chlorine, bromine or iodine.

Unless otherwise defined, otherwise term " heterocycle " refers to contain saturated, fractional saturation or the unsaturated monocycle of 4,5,6 or 7 annular atomses. In particular compound of the present invention, " heterocycle " be contain 4,5,6 or 7 annular atomses, especially be the saturated monocycle of 5 or 6 annular atomses.

The example of term used herein " heterocycle " and suitable value are pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholine-4-base, high morpholinyl, thiomorpholine-4-base, Isosorbide-5-Nitrae-oxaza heptane-4-base, Diazesuberane base and oxazole alkyl.

R therein³For by group-NR¹⁰R ¹¹(R wherein¹⁰And R¹¹Couple together and form heterocycle) to choose wantonly in the compounds of this invention of (1-4C) alkyl that replaces, formed heterocycle is suitably 5 or 6 yuan of heterocycle ring systems. Work as R¹⁰And R¹¹When coupling together, formed heterocycle is suitably 5 or 6 yuan of saturated heterocyclics.

Suitable-NR¹⁰R ¹¹The example of group comprises pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholine-4-base, thiomorpholine-4-base, Isosorbide-5-Nitrae-oxaza heptane-4-base, Diazesuberane base and oxazole alkyl. Instantiation comprises pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholine-4-base or thiomorpholine-4-base.

R therein³Be group-NR¹²R ¹³(R wherein¹²And R¹³Couple together and form heterocycle) the compounds of this invention in, formed heterocycle is suitably 5,6 or 7 yuan of rings. Work as R¹⁰And R¹¹When coupling together, formed heterocycle is suitably 5,6 or 7 yuan of saturated heterocyclics.

Suitable-NR¹²R ¹³The example of group comprises pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholine-4-base, high morpholinyl, thiomorpholine-4-base, Isosorbide-5-Nitrae-oxaza heptane-4-base, Diazesuberane base and oxazole alkyl. Instantiation comprises pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholine-4-base, high morpholinyl or thiomorpholine-4-base.

R therein¹⁴Be group-NR¹⁵R ¹⁶(R wherein¹⁵And R¹⁶Couple together and form 5 or 6 yuan of heterocycles) the compounds of this invention in, formed heterocycle is suitably 5 or 6 yuan of rings. Work as R¹⁰And R¹¹When coupling together, formed heterocycle is suitably 5 or 6 yuan of saturated heterocyclics.

Suitable-NR¹⁵R ¹⁶The example of group comprises pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholine-4-base, thiomorpholine-4-base, Isosorbide-5-Nitrae-oxaza heptane-4-base, Diazesuberane base and oxazole alkyl. Instantiation comprises pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, morpholine-4-base or thiomorpholine-4-base.

The concrete novel compound of the present invention comprises for example formula I compound or its pharmaceutically acceptable salt, wherein except as otherwise noted, otherwise R¹、n、R ²、R ³Or R⁴In each have above any implication of definition in definition or following paragraph (1)-(41):

(1)R ¹For by one or more being selected from-OR⁵(R wherein⁵Be selected from hydrogen or (1-2C) alkyl) optional (1-4C) alkyl that replaces of substituting group, or be the cyclopropyl methyl;

(2)R ¹For by one or more being selected from-OR⁵(R wherein⁵Be selected from hydrogen or (1-2C) alkyl) optional (1-4C) alkyl that replaces of substituting group;

(2.1)R ¹Be selected from methyl, ethyl, propyl group, isopropyl, 2-methyl-propyl, cyclopropyl methyl or 2-methoxy ethyl;

(2.2)R ¹Be selected from methyl or 2-methoxy ethyl;

(3)R ¹Be (1-4C) alkyl;

(4)R ¹Be selected from methyl, ethyl, propyl group, isopropyl, 2-methyl-propyl or cyclopropyl methyl;

(5)R ¹Be selected from methyl, ethyl, isopropyl or cyclopropyl methyl;

(6)R ¹Be methyl;

(7)R ¹Be isopropyl;

(8)R ¹Be the cyclopropyl methyl;

(9)R ¹Be ethyl;

(10) n is 1,2 or 3;

(11) n is 2 or 3;

(12) n is 1;

(13) n is 2;

(14) n is 3;

(15) R of each existence²Group independently is selected from (1-2C) alkyl, (1-2C) alkoxyl, fluorine, chlorine, cyano group, hydroxyl (1-2C) alkyl or following formula group:

-Q-R ⁸

Wherein Q is selected from-NR^a-CO-、-S(O) _z-(wherein z is 0,1 or 2); R^aBe selected from hydrogen or methyl, R⁸Be hydrogen or (1-2C) alkyl;

(16) R of each existence²Group independently is selected from (1-2C) alkyl, (1-2C) alkoxyl, fluorine, chlorine, cyano group, hydroxyl (1-2C) alkyl or following formula group:

Q-R ⁸

(16.1) R of each existence²Group independently is selected from methyl, fluorine, chlorine, cyano group, methylol, methoxyl group, acetylamino, methyl mercapto, ethanol or ethyl ketone;

(17) R of each existence²Group independently is selected from methyl, fluorine, chlorine, methylol, methoxyl group, acetylamino or methyl mercapto;

(18) R of each existence²Group independently is selected from methyl, fluorine, chlorine, methylol or methoxyl group;

(19) R of each existence²Group independently is selected from fluorine or chlorine;

(20) R of each existence²Group independently is selected from methyl or methylol;

(21) R of each existence²Group is methyl;

(22) R of each existence²Group is methylol;

(23) R of each existence²Group independently is selected from acetylamino or methoxyl group;

(24) R of each existence²Group is methoxyl group;

(25)R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

(ii) optional (1-6C) alkyl that replaces, wherein optional substituting group is selected from cyano group, halogen,

Perhaps following formula group:

-W-R ⁹

Wherein W be selected from-O-,-S (O)_p-(wherein p is 0,1 or 2) ,-CO-,-NR^bCO-or-CONR^b-；R ^bBe selected from hydrogen or (1-2C) alkyl; R⁹Be selected from hydrogen or (1-4C) alkyl;

Or-NR¹⁰R ¹¹, R wherein¹⁰And R¹¹Independently be selected from hydrogen, (1-2C) alkanoyl or (1-2C) alkyl, perhaps R¹⁰And R¹¹Couple together and form 5 or 6 yuan of heterocycles, described ring is except containing R¹⁰And R¹¹Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and be present in any available nitrogen atom in the ring all by (1-4C) alkyl or (1-4C) alkanoyl is optional and replace;

(iii) group-NR¹²R ¹³, R wherein¹²And R¹³Independently be selected from separately hydrogen or (1-6C) alkyl, perhaps R¹²And R¹³Couple together and form 5,6 or 7 yuan of heterocycles, described ring is except containing R¹²And R¹³Outside the nitrogen-atoms that is attached thereto, also contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and be present in any available nitrogen atom in the ring all by (1-4C) alkyl or (1-4C) alkanoyl is optional and replace; Perhaps

(iv) group of following formula (II):

-X-R ¹⁴

Wherein X be selected from-O-,-S (O)_p-(wherein p is 0,1 or 2) ,-CO-,-NR^cCO-、 -CONR ^c-or-NR^cCOO-，

R wherein^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For being chosen wantonly (1-4C) alkyl that replaces, perhaps R by halogen, hydroxyl, cyano group, (1-4C) alkoxyl¹⁴For

-NR ¹⁵R ¹⁶

R wherein¹⁵And R¹⁶Independently be selected from hydrogen, (1-2C) alkanoyl or (1-2C) alkyl, perhaps R¹⁵And R¹⁶Couple together and form 5 or 6 yuan of heterocycles, described ring is except containing R¹⁵And R¹⁶Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and be present in any available nitrogen atom in the ring all by (1-4C) alkyl or (1-4C) alkanoyl is optional and replace;

(26)R ³Be selected from:

(i) hydrogen, halogen, cyano group or hydroxyl;

(ii) optional (1-4C) alkyl that replaces, wherein optional substituting group is selected from:

Cyano group;

Halogen;

The following formula group:

-W-R ⁹

Wherein W be selected from-O-,-S (O)_p-(wherein p is 0,1 or 2) ,-CO-,-NR^bCO-、 -CONR ^b-，

R ^bBe selected from hydrogen or (1-2C) alkyl,

R ⁹Be selected from hydrogen or (1-2C) alkyl;

Or-NR¹⁰R ¹¹, R wherein¹⁰And R¹¹Independently be selected from hydrogen or (1-2C) alkyl, perhaps R¹⁰And R¹¹Couple together and form 5 or 6 yuan of heterocycles, described ring is except containing R¹⁰And R¹¹Beyond the nitrogen-atoms that is attached thereto, also optionally contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two, and following substituting group is optional to be replaced on any effective carbon atom: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkyl-S (O)_a-(wherein a is 0,1 or 2), and any available nitrogen atom is all by (1-4C) alkyl or (1-4C) the optional replacement of alkanoyl;

(iii) group-NR¹²R ¹³, R wherein¹²And R¹³Independently be selected from separately hydrogen or (1-2C) alkyl, perhaps R¹²And R¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein except R¹²And R¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also optional to contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkyl-S (O)_b-(wherein b is 0,1 or 2), and any available nitrogen atom is all by (1-4C) alkyl or (1-4C) the optional replacement of alkanoyl; Perhaps

(iv) group of following formula (II):

-X-R ¹⁴

Wherein X be selected from-O-,-S (O)_q-(wherein Q is 0,1 or 2) or-CO-,

R ¹⁴For by optional (1-4C) alkyl that replaces of halogen, hydroxyl, cyano group, (1-4C) alkoxyl, (3-4C) cycloalkyl or (3-4C) cycloalkyl (1-2C) alkyl, perhaps R¹⁴For

-NR ¹⁵R ¹⁶

R wherein¹⁵And R¹⁶Independently be selected from hydrogen or by optional (1-4C) alkyl that replaces of halogen, hydroxyl, cyano group, (1-4C) alkoxyl, (3-4C) cycloalkyl or (3-4C) cycloalkyl (1-2C) alkyl, perhaps R¹⁵And R¹⁶Couple together and form 5 or 6 yuan of heterocycles, described ring is except containing R¹⁵And R¹⁶Beyond the nitrogen-atoms that is attached thereto, also optionally contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two, and following substituting group is optional to be replaced on any effective carbon atom: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkyl-S (O)_c-(wherein c is 0,1 or 2), and any available nitrogen atom is all by (1-4C) alkyl or (1-4C) the optional replacement of alkanoyl;

(27)R ³Be selected from:

(i) hydrogen, halogen or cyano group;

(ii) optional (1-2C) alkyl that replaces, wherein optional substituting group is selected from cyano group, halogen, following formula group:

-W-R ⁹

Wherein W be selected from-O-,-S (O)_p-(wherein p is 0,1 or 2) ,-CO-,-NR^bCO-、 -CONR ^b-；R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-4C) alkyl;

Or-NR¹⁰R ¹¹, R wherein¹⁰And R¹¹Independently be selected from hydrogen or (1-2C) alkyl), perhaps R¹⁰And R¹¹Couple together and form 5 or 6 yuan of heterocycles, described ring is except containing R¹⁰And R¹¹Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group or (1-4C) alkyl, and any available nitrogen atom that is present in the ring is all replaced by (1-4C) alkyl is optional;

(iii) group-NR¹²R ¹³, R wherein¹²And R¹³Independently be selected from separately hydrogen or (1-6C) alkyl, perhaps R¹²And R¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein except R¹²And R¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also chosen wantonly and is contained the extra hetero atom that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group or (1-4C) alkyl, and any available nitrogen atom that is present in the ring is all replaced by (1-4C) alkyl is optional; Perhaps

(iv) group of following formula (II):

-X-R ¹⁴

Wherein X be selected from-O-,-S (O) _p-(wherein p is 0,1 or 2) or-CONR ^c-,

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For being chosen wantonly (1-4C) alkyl that replaces by halogen, hydroxyl, cyano group, (1-4C) alkoxyl group;

(28) R ³Be group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen or (1-6C) alkyl, perhaps R separately ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and be present in any available nitrogen atom in the ring all by (1-4C) alkyl or (1-4C) alkyloyl is optional and replace;

(29) R ³Be group-NR ¹²R ¹³, R wherein ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and be present in any available nitrogen atom in the ring all by (1-4C) alkyl or (1-4C) alkyloyl is optional and replace;

(30) R ³Be group-NR ¹²R ¹³, R wherein ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S;

(30.1) R ³Be morpholine-4-base, 1,4-oxaza heptane-4-base, 4-methylpiperazine-1-base or 4-hydroxy piperidine-1-base;

(31) R ³Be thiomorpholine-4-base or morpholine-4-base;

(32) R ³Be morpholine-4-base;

(33) R ⁴Be group-NR ¹⁷R ¹⁸, R wherein ¹⁷And R ¹⁸Couple together and form 5 or 6 yuan of heterocycles, described ring removes and contains R ¹⁷And R ¹⁸Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO or the SO of being oxidized to ₂Group, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and any available nitrogen atom is replaced by following group is optional: (1-4C) alkyl, hydroxyl (1-4C) alkyl or (1-4C) alkyloyl;

(34) R ⁴Be group-NR ¹⁷R ¹⁸, R wherein ¹⁷And R ¹⁸Couple together and form 6 yuan of heterocycles, described ring removes and contains R ¹⁷And R ¹⁸Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group or (1-4C) alkyl, and any available nitrogen atom is all replaced by following group is optional: (1-4C) alkyl, hydroxyl (1-4C) alkyl or (1-4C) alkyloyl;

(35) R ⁴Be the following formula group:

Wherein Y is selected from O, S, NR ^yOr CR ^z, R wherein ^yBe selected from hydrogen, (1-2C) alkyl, hydroxyl (1-2C) alkyl, (1-2C) alkoxyl group (1-2C) alkyl or (1-2C) alkyloyl, R ^zBe selected from hydrogen, hydroxyl, (1-2C) alkyl, hydroxyl (1-2C) alkyl, (1-2C) alkoxyl group (1-2C) alkyl or (1-2C) alkyloyl;

(36) R ⁴Be the following formula group:

Wherein Y is selected from O, NR ^yOr CR ^z, R wherein ^yBe selected from hydrogen or (1-2C) alkyl, R ^zBe selected from hydrogen or hydroxyl;

(37) R ⁴Be the following formula group:

Wherein Y is selected from O or NR ^y, R wherein ^yBe selected from hydrogen or methyl;

(38) R ⁴Be the following formula group:

Wherein Y is O;

(39) R ⁴Be selected from morpholine-4-base, 4-methylpiperazine-1-base or 4-hydroxy piperidine-1-base;

(40) R ⁴Be morpholine-4-base;

(41) R ⁴Be selected from morpholine-4-base, (R)-3-methyl-morpholine-4-base, (S)-3-methyl-morpholine-4-base or 4-oxo-piperidine-1-base.

In the formula I compound of a concrete grouping, R ¹Be alkyl as arbitrary section definition in above paragraph (1)-(9).In the The compounds of this invention of further grouping, R ¹Be methyl.

In the formula I compound of further grouping, n is selected from 0,1,2 or 3 integer, each R that may exist ²Arbitrary section definition in group such as above paragraph (15)-(24).In the The compounds of this invention of a concrete grouping, the R of each existence ²The definition of any in group such as above paragraph (18)-(24).

In the formula I compound of further grouping, n is 3, each R ²Group is selected from fluorine or chlorine.

In the formula I compound of further grouping, the aniline on 4 of the pyrimidine rings has following array structure:

R wherein ¹The definition of any in the definition as described herein.

In the formula I compound of further grouping, n is 2, the R of each existence ²Group is selected from methyl or methylol.

R wherein ¹The definition of any in the definition as described herein.

In the formula I compound of further grouping, n is 1, the R of existence ²Group is methoxyl group (precondition is promptly 4 of the contrapositions that this methoxyl group is not positioned at aniline).

R wherein ¹The definition of any in the definition as described herein.

In the formula I compound of further grouping, R ³As any definition in above paragraph (25)-(32), the definition of any especially as in above paragraph (28)-(32).

In the The compounds of this invention of a concrete grouping, R ⁴As any definition in above paragraph (33)-(40).In the The compounds of this invention of further concrete grouping, R ⁴As any definition in paragraph (39) or the paragraph (40).R ⁴Be suitably morpholine-4-base.

In the formula I of grouping compound, n, R ¹And R ³The definition of any in the definition as indicated above, R ⁴Be the following formula group:

Wherein Y is-NR ^y-, and R ^yBe selected from hydrogen or (1-2C) alkyl, the R of each existence ²Group independently is selected from (1-2C) alkyl, (1-2C) alkoxyl group, fluorine, chlorine, cyano group, hydroxyl (1-2C) alkyl or following formula group:

-Q-R ⁸

Wherein Q be selected from-CO-,-NR ^a-or-S (O) _z-(wherein z is 0,1 or 2), R ^aBe selected from hydrogen or methyl, R ⁸Be hydrogen or (1-2C) alkyl.

In the formula I compound of further grouping, n, R ¹And R ³The definition of any in the definition as indicated above, R ⁴Be the following formula group:

Wherein Y is-NR ^y-, and R ^yBe selected from hydrogen or (1-2C) alkyl, the R of each existence ²Group independently is selected from (1-2C) alkyl, (1-2C) alkoxyl group, fluorine, chlorine, cyano group or hydroxyl (1-2C) alkyl.

In the formula I of grouping compound, R ⁴Be the following formula group:

Wherein Y be O or-CR ^z-, and R ^zBe selected from hydrogen or hydroxyl, R ¹, R ², n and R ³The definition of any in the definition as indicated above separately.

In the The compounds of this invention or its pharmacy acceptable salt of a concrete grouping, described compound has following structural IA:

Wherein:

Y is selected from O, S, NR ^yOr CR ^z, R wherein ^yBe selected from hydrogen, (1-2C) alkyl, hydroxyl (1-2C) alkyl, (1-2C) alkoxyl group (1-2C) alkyl or (1-2C) alkyloyl, R ^zBe selected from hydrogen, hydroxyl, (1-2C) alkyl, hydroxyl (1-2C) alkyl, (1-2C) alkoxyl group (1-2C) alkyl or (1-2C) alkyloyl;

R ¹Be (1-4C) alkyl;

N is 0,1,2 or 3;

-Q-R ⁸

Wherein Q be selected from-CO-,-NR ^a-,-NR ^a-CO-,-CONR ^a-,-S (O) _z-(wherein z is 0,1 or 2), R ^aBe selected from hydrogen or methyl, R ⁸Be hydrogen or (1-2C) alkyl;

R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

(ii) optional (1-4C) alkyl that replaces, wherein Ren Xuan substituting group is selected from cyano group, halogen or following formula group:

-W-R ⁹

Wherein W be selected from-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CO-,-NR ^bCO-,-CONR ^b-;

R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-2C) alkyl;

Or-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independently be selected from hydrogen or (1-2C) alkyl, perhaps R ¹⁰And R ¹¹Couple together and form 5 or 6 yuan of heterocycles, described ring removes and contains R ¹⁰And R ¹¹Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and any available nitrogen atom all by (1-4C) alkyl or (1-4C) alkyloyl is optional replaces;

(iii) group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen or (1-2C) alkyl, perhaps R separately ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and any available nitrogen atom all by (1-4C) alkyl or (1-4C) alkyloyl is optional replaces; Perhaps

The (iv) group of following formula (II):

-X-R ¹⁴

Wherein X be selected from-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CO-,-NR ^cCO-or-CONR ^c-,

R ^cBe selected from hydrogen or (1-2C) alkyl and

-NR ¹⁵R ¹⁶

R wherein ¹⁵And R ¹⁶Independently be selected from hydrogen or (1-2C) alkyl, perhaps R ¹⁵And R ¹⁶Couple together and form 5 or 6 yuan of heterocycles, described ring removes and contains R ¹⁵And R ¹⁶Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and any available nitrogen atom all by (1-4C) alkyl or (1-4C) alkyloyl is optional replaces;

Precondition is:

If ● R ²Be (1-2C) alkoxyl group, then it is not positioned at respect to-NR ¹Promptly 4 of the contrapositions of-group;

If ● R ²Be formula-Q-R ⁸(wherein Q is-NR group ^a-CO-, R ^aBe hydrogen, R ⁸Be (1-2C) alkyl), then Y is not NR ^y, R wherein ^yBe methyl.

Further the The compounds of this invention of concrete grouping is formula IA compound or its pharmacy acceptable salt, wherein:

N is 0,1,2 or 3;

-Q-R ⁸

R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

(ii) optional (1-4C) alkyl that replaces, wherein Ren Xuan substituting group is selected from:

Cyano group;

Halogen;

The following formula group:

-W-R ⁹

Wherein W be selected from-O-,-S (O) _p-(wherein p is 0,1 or 2) ,-CO-,-NR ^bCO-,-CONR ^b-,

R ^bBe selected from hydrogen or (1-2C) alkyl,

R ⁹Be selected from hydrogen or (1-2C) alkyl;

Or-NR ¹⁰R ¹¹, R wherein ¹⁰And R ¹¹Independently be selected from hydrogen or (1-2C) alkyl, perhaps R ¹⁰And R ¹¹Couple together and form 5 or 6 yuan of heterocycles, described ring removes and contains R ¹⁰And R ¹¹Beyond the nitrogen-atoms that is attached thereto, also optionally contain the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two, and following substituting group is optional to be replaced on any effective carbon atom: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkyl-S (O) _a-(wherein a is 0,1 or 2), and any available nitrogen atom is all by (1-4C) alkyl or (1-4C) the optional replacement of alkyloyl;

(iii) group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen separately or by halogen, hydroxyl, cyano group or (1-4C) optional (1-4C) alkyl that replaces of alkoxyl group, (3-4C) cycloalkyl or (3-4C) cycloalkyl (1-2C) alkyl, perhaps R ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also optional to contain the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkyl-S (O) _b-(wherein b is 0,1 or 2), and any available nitrogen atom is all by (1-4C) alkyl or (1-4C) the optional replacement of alkyloyl; Perhaps

The (iv) group of following formula (II):

-X-R ¹⁴

Wherein X be selected from-O-,-S (O) _q-(wherein Q is 0,1 or 2) ,-CO-,-NR ^cCO-,-NR ^cCOO-and-NR ^cSO ₂-;

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For by halogen, hydroxyl, cyano group or (1-4C) optional (1-6C) alkyl that replaces of alkoxyl group, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹⁴For

-NR ¹⁵R ¹⁶

R wherein ¹⁵And R ¹⁶Independently be selected from hydrogen or by optional (1-6C) alkyl that replaces of halogen, hydroxyl, cyano group, (1-4C) alkoxyl group, (3-6C) cycloalkyl or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹⁵And R ¹⁶Couple together and form 5 or 6 yuan of heterocycles, described ring removes and contains R ¹⁵And R ¹⁶Beyond the nitrogen-atoms that is attached thereto, also optionally contain the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two, and following substituting group is optional to be replaced on any effective carbon atom: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkyl-S (O) _c-(wherein c is 0,1 or 2), and any available nitrogen atom is all by (1-4C) alkyl or (1-4C) the optional replacement of alkyloyl; With

Y is selected from O, S, NR ^yOr CR ^z, R wherein ^yBe selected from hydrogen, (1-2C) alkyl, hydroxyl (1-2C) alkyl, (1-2C) alkoxyl group (1-2C) alkyl or (1-2C) alkyloyl, R ^zBe selected from hydrogen, hydroxyl, (1-2C) alkyl, hydroxyl (1-2C) alkyl, (1-2C) alkoxyl group, (1-2C) alkoxyl group (1-2C) alkyl or (1-2C) alkyloyl;

Precondition is:

In the formula IA compound of a concrete grouping, Y is selected from O, NR ^yOr CR ^z, R wherein ^yBe selected from hydrogen or (1-2C) alkyl, R ^zBe selected from hydrogen or hydroxyl.In the formula IA compound of further grouping, Y is selected from O or NR ^y, R wherein ^yBe selected from hydrogen or (1-2C) alkyl.In the formula IA compound of further grouping, Y is O.

In formula IA compound, R ¹Any given definition in above-mentioned paragraph (4)-(9) suits to have.In the formula IA compound of a concrete grouping, R ¹Be methyl.

In the formula IA compound of a concrete grouping, the definition of any in n such as above paragraph (10)-(14), R ²The definition of any in the definition as indicated above, perhaps (precondition is if R for defined any definition in above-mentioned paragraph (15)-(24) ²Be (1-2C) alkoxyl group, then it is not positioned at the contraposition of aniline).

In the formula IA compound of a concrete grouping, R ³As any definition in above paragraph (25) or the paragraph (26).

In the formula IA compound of further grouping, if R ²Be formula-Q-R ⁸(wherein Q is-NR group ^a-CO-, R ^aBe hydrogen, R ⁸Be (1-2C) alkyl), then Y is not NR ^yIn the formula IA compound of further grouping, if R ²Be formula-Q-R ⁸Group, then Y is not NR ^y

In the The compounds of this invention or its pharmacy acceptable salt of further grouping, described compound has structural formula IB as follows:

Wherein:

Y, R ¹, n and R ²The definition that has in the above-mentioned definition relevant any separately with formula I; With

R ¹²And R ¹³Independently be selected from hydrogen or (1-2C) alkyl, perhaps R separately ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S, and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and any available nitrogen atom all by (1-4C) alkyl or (1-4C) alkyloyl is optional replaces;

Precondition is:

If ● R ²Be (1-2C) alkoxyl group, then it is not positioned at contraposition;

In formula IB compound, R ¹²And R ¹³Suitable coupling together forms 5,6 or 7 yuan of heterocycles, and wherein removes R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto; described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S; and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and any available nitrogen atom all by (1-4C) alkyl or (1-4C) alkyloyl is optional replaces.

In the formula IB compound of further grouping, R ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto; described ring is also chosen wantonly and is contained an extra heteroatoms that is selected from O, N or S; and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-2C) alkyl or (1-2C) alkanesulfonyl, and any available nitrogen atom all by (1-2C) alkyl or (1-2C) alkyloyl is optional replaces.

In the formula I compound or its pharmacy acceptable salt of further concrete grouping, described compound has structural formula IC as follows:

Wherein n, R ²And R ³(precondition is if R to have in the above-mentioned definition relevant with formula I any definition ²Be (1-2C) alkoxyl group, then it is not positioned at promptly 4 of contrapositions).

In the The compounds of this invention or its pharmacy acceptable salt of further concrete grouping, described compound has structural formula as follows (ID):

R wherein ¹, R ²(precondition is if R with any definition in the n definition as indicated above ²Be (1-2C) alkoxyl group, then it is not positioned at promptly 4 of contrapositions).

In formula (ID) compound of a concrete grouping, R ¹For (1-4C) alkyl, be in particular methyl.

In the The compounds of this invention or its pharmacy acceptable salt of further concrete grouping, described compound has structural formula as follows (IE):

Wherein:

N is 0,1,2 or 3; With

The R of each existence ²Group independently is selected from (1-2C) alkyl, fluorine, chlorine, cyano group, hydroxyl (1-2C) alkyl or following formula group:

-Q-R ⁸

Wherein Q be selected from-CO-,-NR ^a-,-NR ^a-CO-,-NR ^a-COO-, NR ^aCONR ^b,-CONR ^a-,-S (O) _z-(wherein z is 0,1 or 2) ,-SO ₂NR ^a-and-NR ^aSO ₂-, R ^aAnd R ^bIndependently be selected from hydrogen or methyl, R separately ⁸Be hydrogen or (1-2C) alkyl.

In formula (IE) compound of a concrete grouping, R ¹Be quilt-OR ⁵(R wherein ⁵Be selected from (1-2C) alkyl) optional (1-4C) alkyl that replaces.

In formula (IE) compound of a concrete grouping, R ¹Be methyl or 2-methoxy ethyl.

In formula (IE) compound of another concrete grouping, n is 1,2 or 3.

In formula (IE) compound of another concrete grouping, n is 1 or 2.

In formula (IE) compound of further concrete grouping, the R of each existence ²Group independently is selected from (1-2C) alkyl, fluorine, chlorine, cyano group or hydroxyl (1-2C) alkyl.

Concrete new The compounds of this invention comprises any or its pharmacy acceptable salt in the following compounds:

(1) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-(3-morpholine-4-base-5-thiomorpholine-4-base-phenyl) pyrimidine-2, the 4-diamines;

(2) N '-(3-chloro-2,4-two fluoro-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(3) N '-(3-chloro-2,4-two fluoro-phenyl)-N-(3-fluoro-5-morpholine-4-base-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(4) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-(3-morpholine-4-base phenyl) pyrimidine-2, the 4-diamines;

(5) N '-(3-chloro-2,4-two fluoro-phenyl)-N-(3-methoxyl group-5-morpholine-4-base-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(6) the 3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-cyanobenzene;

(7) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-(3-methyl sulphonyl-5-morpholine-4-base-phenyl) pyrimidine-2, the 4-diamines;

(8) [3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] methyl alcohol;

(9) the 3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-N, N-dimethyl-5-morpholine-4-base-benzamide;

(10) N '-(3-chloro-2,4-two fluoro-phenyl)-N-[3-(2-methoxy ethoxy)-5-morpholine-4-base-phenyl]-N '-methyl-pyrimidine-2, the 4-diamines;

(11) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-morpholine-4-base-5-(1,4-oxaza heptane-4-yl) phenyl] pyrimidine-2, the 4-diamines;

(12) the 1-[3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-5-methyl sulphonyl-phenyl] piperidines-4-alcohol;

(13) the 1-[4-[3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-5-methyl sulphonyl-phenyl] piperazine-1-yl] ethyl ketone;

(14) the 2-[4-[3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-5-methyl sulphonyl-phenyl] piperazine-1-yl] ethanol;

(15) N '-(3-chloro-2,4-two fluoro-phenyl)-N-[3-(methoxymethyl)-5-morpholine-4-base-phenyl]-N '-methyl-pyrimidine-2, the 4-diamines;

(16) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-morpholine-4-base-5-(third-2-base oxygen ylmethyl) phenyl] pyrimidine-2, the 4-diamines;

(17) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-morpholine-4-base-5-(morpholine-4-ylmethyl) phenyl] pyrimidine-2, the 4-diamines;

(18) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-morpholine-4-base-5-(tetramethyleneimine-1-ylmethyl) phenyl] pyrimidine-2, the 4-diamines;

(19) methyl N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-[(4-methylpiperazine-1-yl)]-5-morpholine-4-base-phenyl] pyrimidine-2, the 4-diamines;

(20) the 1-[[3-[[4-[(3-chloro-2,4-two fluoro-phenyl)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] methyl] piperidines-4-alcohol;

(21) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl)-5-methyl sulphonyl-phenyl] pyrimidine-2, the 4-diamines;

(22) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl) phenyl] pyrimidine-2, the 4-diamines;

(23) N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base-phenyl] pyrimidine-2, the 4-diamines;

(24) [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(25) [4-methyl-3-[methyl-[2-[[3-morpholine-4-base-5-(1,4-oxaza heptane-4-yl) phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(26) [4-methyl-3-[methyl-[2-[[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(27) [4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-tetramethyleneimine-1-base-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(28) [4-methyl-3-[methyl-[2-[[3-morpholine-4-base-5-(piperidino) phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(29) [4-methyl-3-[methyl-[2-[[3-morpholine-4-base-5-(morpholine-4-ylmethyl) phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(30) [4-methyl-3-[methyl-[and 2-[(3-methyl sulphonyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(31) 1-[3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] piperidines-4-alcohol;

(32) (3S)-1-[3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] tetramethyleneimine-3-alcohol;

(33) (3R)-1-[3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] tetramethyleneimine-3-alcohol;

(34) 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N, N-dimethyl-5-morpholine-4-base-benzamide;

(35) [the 3-[ethyl-[and 2-[(3-methyl sulphonyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl] amino]-4-methyl-phenyl] methyl alcohol;

(36) [4-methyl-3-[[2-[(3-methyl sulphonyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-third-2-base-amino] phenyl] methyl alcohol;

(37) [4-methyl-3-[2-methyl-propyl-[and 2-[(3-methyl sulphonyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(38) [3-[cyclopropyl methyl-[and 2-[(3-methyl sulphonyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl] amino]-4-methyl-phenyl] methyl alcohol;

(39) N-(3,5-dimorpholine-4-base phenyl)-N '-(3-p-methoxy-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(40) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-(4-aminomethyl phenyl) pyrimidine-2, the 4-diamines;

(41) N '-(3-chloro-phenyl-)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(42) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-phenyl-pyrimidine-2, the 4-diamines;

(43) [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] phenyl] methyl alcohol;

(44) N-(3,5-dimorpholine-4-base phenyl)-N '-(3-fluorophenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(45) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-(3-aminomethyl phenyl) pyrimidine-2, the 4-diamines;

(46) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-(3-methylthio group phenyl) pyrimidine-2, the 4-diamines;

(47) N '-(3, the 5-3,5-dimethylphenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(48) N '-(2, the 5-3,5-dimethylphenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(49) 3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] cyanobenzene;

(50) N '-(3, the 4-dichlorophenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(51) N '-(4-chloro-phenyl-)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(52) N-(3,5-dimorpholine-4-base phenyl)-N '-(5-methoxyl group-2-methyl-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(53) N '-(5-methoxyl group-2-methyl-phenyl)-N '-methyl-N-(3-methyl sulphonyl-5-morpholine-4-base-phenyl) pyrimidine-2, the 4-diamines;

(54) N-[2-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methoxyl group-phenyl] ethanamide;

(55) N-[4-methoxyl group-2-[methyl-[2-[(3-methyl sulphonyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl] amino] phenyl] ethanamide; Perhaps

(56) [3-[[2-[(3-methoxyl group-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(57) [3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] methyl alcohol;

(58) [3-[[2-[[3-(2-methoxy ethoxy)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(59) 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-cyanobenzene;

(60) N-(3,5-dimorpholine-4-base phenyl)-N '-(2-p-methoxy-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(61) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-(2,4, the 6-trimethylphenyl) pyrimidine-2, the 4-diamines;

(62) N '-(2,4 difluorobenzene base)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(63) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-(2-aminomethyl phenyl) pyrimidine-2, the 4-diamines;

(64) N-(3,5-dimorpholine-4-base phenyl)-N '-(2-fluorophenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(65) 4-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] cyanobenzene;

(66) [2-chloro-5-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] phenyl] methyl alcohol;

(67) [4-chloro-3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] phenyl] methyl alcohol;

(68) [3-chloro-5-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] phenyl] methyl alcohol;

(69) [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-5-methoxyl group-phenyl] methyl alcohol;

(70) 1-(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) ethanol;

(71) 3-[[4-[(5-methoxyl group-2-methyl-phenyl)-and methyl-amino] pyrimidine-2-base] amino]-N, N-dimethyl-5-morpholine-4-base-benzamide;

(72) N '-(5-methoxyl group-2-methyl-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base-phenyl] pyrimidine-2, the 4-diamines;

(73) N '-(2, the 3-difluorophenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(74) N '-(2,4 dichloro benzene base)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(75) 4-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-2-methoxyl group-cyanobenzene;

(76) N '-(3, the 4-Dimethoxyphenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(77) N '-(2, the 5-Dimethoxyphenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(78) N '-(3, the 5-Dimethoxyphenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(79) 2-chloro-6-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino] cyanobenzene;

(80) N '-(3, the 4-difluorophenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(81) N '-(2, the 5-difluorophenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(82) N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-N '-(2,3, the 4-trifluorophenyl) pyrimidine-2, the 4-diamines;

(83) N-(3,5-dimorpholine-4-base phenyl)-N '-(3-methoxyl group-4-methyl-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(84) N-(3,5-dimorpholine-4-base phenyl)-N '-(4-methoxyl group-2-methyl-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(85) N-(3,5-dimorpholine-4-base phenyl)-N '-(2-methoxyl group-4-methyl-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(86) N-(3,5-dimorpholine-4-base phenyl)-N '-(2-methoxyl group-5-methyl-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(87) N '-(3-chloro-4-methoxyl group-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(88) N '-(3-chloro-2-fluoro-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(89) N '-(4-chloro-3-fluoro-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(90) N '-(4-chloro-2-fluoro-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(91) N '-(2-chloro-5-methyl-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(92) N '-(3-chloro-4-methyl-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(93) N '-(2-chloro-6-methyl-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(94) N '-(2, the 3-dichlorophenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(95) [3-[[2-[(3-oxyethyl group-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(96) [4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-propoxy--phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(97) [4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-third-2-base oxygen base-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(98) [4-methyl-3-[methyl-[2-[[3-(2-methyl propoxy-)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(99) [3-[[2-[[3-(cyclo propyl methoxy)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(100) [3-[[2-[(3-cyclobutyl oxygen base-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(101) [3-[[2-[[3-(3-methoxyl group butoxy)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(102) [3-[[2-[[3-(2-ethoxy ethoxy)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol;

(103) [3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-morpholine-4-base-ketone;

(104) [3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-tetramethyleneimine-1-base-ketone;

(105) 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N-(2-methyl-propyl)-5-morpholine-4-base-benzamide;

(106) N-ethyl-3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N-methyl-5-morpholine-4-base-benzamide;

(107) N-(cyclopropyl methyl)-3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-benzamide;

(108) 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N-methyl-5-morpholine-4-base-N-third-2-base-benzamide;

(109) 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N-(2-methoxy ethyl)-N-methyl-5-morpholine-4-base-benzamide;

(110) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N, N-dimethyl-5-morpholine-4-base-benzamide;

(111) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(2-hydroxyethyl)-N-methyl-5-morpholine-4-base-benzamide;

(112) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(2-methoxy ethyl)-N-methyl-5-morpholine-4-base-benzamide;

(113) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(3-hydroxypropyl)-N-methyl-5-morpholine-4-base-benzamide;

(114) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-[(2S)-the 2-hydroxypropyl]-N-methyl-5-morpholine-4-base-benzamide;

(115) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-[(2S)-1-hydroxyl third-2-yl]-N-methyl-5-morpholine-4-base-benzamide;

(116) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-ethyl-N-methyl-5-morpholine-4-base-benzamide;

(117) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-methyl-5-morpholine-4-base-N-third-2-base-benzamide;

(118) [the 3-[[4-[(3-chloro-phenyl-)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-tetramethyleneimine-1-base-ketone;

(119) [the 3-[[4-[(3-chloro-phenyl-)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-morpholine-4-base-ketone;

(120) [the 3-[[4-[(3-chloro-phenyl-)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-(4-methylpiperazine-1-yl) ketone;

(121) [the 3-[[4-[(3-chloro-phenyl-)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-(4-hydroxyl-piperidino) ketone;

(122) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-cyclobutyl-5-morpholine-4-base-benzamide;

(123) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-N-third-2-base-benzamide;

(124) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(1-methoxy propyl-2-yl)-5-morpholine-4-base-benzamide;

(125) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(cyclopropyl methyl)-5-morpholine-4-base-benzamide;

(126) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(2-methyl-propyl)-5-morpholine-4-base-benzamide;

(127) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(2-methoxy ethyl)-5-morpholine-4-base-benzamide;

(128) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-(1-hydroxy-2-methyl-third-2-yl)-5-morpholine-4-base-benzamide;

(129) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-the 5-morpholine-4-base-N-tertiary butyl-benzamide;

(130) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-[(2S)-1-hydroxyl third-2-yl]-5-morpholine-4-base-benzamide;

(131) [the 3-[[4-[(3-chloro-phenyl-)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl]-[(3R)-and 3-hydroxyl pyrrolidine-1-yl] ketone;

(132) 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N-[(2R)-1-hydroxyl third-2-yl]-5-morpholine-4-base-benzamide;

(133) N2-(3,5-dimorpholino phenyl)-N4-sec.-propyl-N4-(3-p-methoxy-phenyl) pyrimidine-2, the 4-diamines;

(134) (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (2-methoxy ethyl) amino)-4-aminomethyl phenyl) methyl alcohol;

(135) [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-third-2-base-amino]-4-methyl-phenyl] methyl alcohol;

(136) [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-ethyl-amino]-4-methyl-phenyl] methyl alcohol;

(137) 2-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-[5-(methylol)-2-methyl-phenyl] amino] ethanol;

(138) N-(3,5-dimorpholine-4-base phenyl)-N '-(2-methoxy ethyl)-N '-(5-methoxyl group-2-methyl-phenyl) pyrimidine-2, the 4-diamines;

(139) N-(3,5-dimorpholine-4-base phenyl)-N '-(5-methoxyl group-2-methyl-phenyl)-N '-third-2-base-pyrimidine-2, the 4-diamines;

(140) N-(3,5-dimorpholine-4-base phenyl)-N '-ethyl-N '-(5-methoxyl group-2-methyl-phenyl) pyrimidine-2, the 4-diamines;

(141) 2-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-(5-methoxyl group-2-methyl-phenyl) amino] ethanol; Perhaps

(142) 4-[3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] morpholine-3-ketone;

(143) (S) methyl alcohol-(4-methyl-3-(methyl (2-(3-(3-methylmorpholine generation)-5-morpholino phenylamino) pyrimidine-4-yl) amino) phenyl);

(144) (R) methyl alcohol-(4-methyl-3-(methyl (2-(3-(3-methylmorpholine generation)-5-morpholino phenylamino) pyrimidine-4-yl) amino) phenyl);

(145) 1-(3-(4-((5-(methylol)-2-aminomethyl phenyl) (methyl) amino) pyrimidine-2--amino)-5-morpholino phenyl) piperidin-4-one-;

(146) 1-(3-(4-((5-methoxyl group-2-aminomethyl phenyl) (methyl) amino) pyrimidine-2--amino)-5-morpholino phenyl) piperidines-4-alcohol;

(147) N4-(5-methoxyl group-2-aminomethyl phenyl)-N4-methyl-N2-(3-morpholino-5-(piperazine-1-yl) phenyl) pyrimidine-2, the 4-diamines;

(148) 4-[3-[[4-[(5-methoxyl group-2-methyl-phenyl)-and methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenyl] morpholine-3-ketone;

(149) (S)-and N4-(5-methoxyl group-2-aminomethyl phenyl)-N4-methyl-N2-(3-(3-methylmorpholine generation)-5-morpholino phenyl) pyrimidine-2, the 4-diamines;

(150) N '-(4-fluoro-3-chloro-phenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines;

(151) [4-methyl-3-[methyl-[2-[[3-morpholine-4-base-5-(tetrahydrofuran-3-base oxygen base) phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(152) [4-methyl-3-[methyl-[2-[[3-morpholine-4-base-5-[(3S)-tetrahydrofuran-3-yl] oxygen base phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(153) [4-methyl-3-[methyl-[2-[[3-morpholine-4-base-5-(amylene oxide-4-base oxygen base) phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol;

(154) 3-[[4-[(3-chloro-phenyl-)-and methylamino] pyrimidine-2-base] amino]-5-morpholine-4-base-N-(amylene oxide-4-yl) benzamide;

(155) 3-[[4-[(3-chloro-phenyl-)-and methylamino] pyrimidine-2-base] amino]-N-ethyl-5-morpholine-4-yl-benzamide;

(156) 1-[3-({ 4-[(3-chloro-phenyl-) (methyl) amino] pyrimidine-2-base } amino)-5-morpholine-4-base phenyl] piperidines-4-alcohol;

(157) N4-(3-chloro-phenyl-)-N4-methyl-N2-[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base phenyl] pyrimidine-2, the 4-diamines;

(158) (2-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-3-aminomethyl phenyl) methyl alcohol;

(159) N2-(3,5-dimorpholino phenyl)-N4-(2-methoxyl group-6-aminomethyl phenyl)-N4-methylpyrimidine-2, the 4-diamines;

(160) (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-fluorophenyl) methyl alcohol;

(161) (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-2-fluorophenyl) methyl alcohol;

(162) 1-(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) ethyl ketone;

(163) N2-(3,5-dimorpholino phenyl)-N4-(2-fluoro-5-p-methoxy-phenyl)-N4-methylpyrimidine-2, the 4-diamines;

(164) (2-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-p-methoxy-phenyl) methyl alcohol;

(165) (4-chloro-2-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino) phenyl) methyl alcohol.

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

Form that can also prodrug gives compound of the present invention, and prodrug just decomposes in human body or animal body to discharge the compound of The compounds of this invention.Can use prodrug to change the physical properties and/or the pharmacokinetic property of The compounds of this invention.When compound of the present invention contains proper group that the modification group can be attached thereto or substituting group, just can form prodrug.The example of prodrug comprise the ester derivative of cleavable in the body that can on the carboxyl of formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or hydroxyl, form and the body that can on the carboxyl of formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or amino, form in the amide derivatives of cleavable.

Therefore, the present invention includes can by organic synthesis preparation and can by its prodrug of cracking in the human or animal body resulting as mentioned in formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition.Therefore, the present invention includes formula I, the formula IA, formula IB, formula IC, formula ID or the formula IE compound that prepare by the organic synthesis mode, be also included within human body or the animal body by the resulting formula I of precursor compound metabolism, formula IA, formula IB, formula IC, formula ID or formula IE compound, that is to say that formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound can be the compound of synthetic preparation or the compound that metabolism produces.

The pharmaceutically acceptable prodrug that formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound are suitable is based on rational medical judgment, is fit to give human body or animal body, and does not have bad pharmacologically active also not have the compound of excessive toxicity.

In following document for example, introduced various forms of prodrugs:

A) Methods in Enzymology, the 42nd volume, the 309-396 page or leaf, K.Widder etc. edit (Academic Press, 1985);

B) Design ofPro-drugs, H.Bundgaard edits, (Elsevier, 1985);

C) A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.Bundgaard edit, the 5th chapter, " Design andApplication of Pro-drugs ", H.Bundgaard edits, 113-191 page or leaf (1991);

d)H.Bundgaard， Advanced?Drug?Delivery?Reviews， 8，1-38(1992)；

E) H.Bundgaard etc., Journal of Pharmaceutical Sciences, 77, 285 (1988);

F) N.Kakeya etc., Chem.Pharm.Bull., 32, 692 (1984);

G) T.Higuchi and V.Stella, " Pro-Drugs as Novel DeliverySystems ", A.C.S. disquisition series, the 14th volume; With

H) E.Roche (editor), " Bioreversible Carriers in Drug Design ", Pergamon Press, 1987.

Suitable pharmaceutically acceptable prodrug with formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound of carboxyl is for example ester of its interior cleavable of body.The ester of cleavable is for example pharmaceutically acceptable ester in the body of carboxylic formula I compound, and its cracking in human or animal body produces parent acid.The suitable pharmaceutically acceptable ester of carboxyl comprises (1-6C) alkyl ester (methyl esters for example; the ethyl ester and the tert-butyl ester); (1-6C) alkoxy methyl ester (for example methoxymethyl ester); (1-6C) alkyloyl oxygen ylmethyl ester (for example oxy acid methyl neopentyl ester); 3-benzo [c] furanonyl ester (3-phthalidyl ester); (3-8C) alkyl ester (for example cyclopentylcarbonyl oxygen ylmethyl ester and 1-cyclohexyl-carbonyl oxygen base ethyl ester) of naphthene base carbonyl oxygen base-(1-6C); 2-oxo-1; 3-dioxa cyclopentenyl methyl ester (for example 5-methyl-2-oxo-1,3-Dioxol-4-yl methyl ester) and (1-6C) alkyl ester (for example methoxycarbonyl oxygen ylmethyl ester and 1-methoxycarbonyl oxygen base ethyl ester) of alkoxy-carbonyl oxy-(1-6C).

Suitable pharmaceutically acceptable prodrug with formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound of hydroxyl is for example ester or the ether of its interior cleavable of body.The ester or the ether of cleavable are for example pharmaceutically acceptable ester or ether in the body of the formula I of hydroxyl, formula IA, formula IB, formula IC, formula ID or formula IE compound, and their cracking in human or animal body produce the parent hydroxy compound.The suitable pharmaceutically acceptable ester of hydroxyl forms group and comprises inorganic ester, for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester).The pharmaceutically acceptable ester that other of hydroxyl is suitable forms benzoyl, the phenylacetyl of replacement, (1-10C) alkoxy carbonyl (for example ethoxy carbonyl), the N that group comprises (1-10C) alkyloyl (for example ethanoyl), benzoyl, phenylacetyl, replacement, N-[two-(1-4C) alkyl] formamyl, 2-dialkyl amido ethanoyl and 2-carboxyl ethanoyl.The example of the substitution in ring base on phenylacetyl and the benzoyl comprises amino methyl, N-alkylamino methyl, N, N-dialkyl amino ylmethyl, morpholino methyl, piperazine-1-ylmethyl and 4-(1-4C) alkylpiperazine-1-ylmethyl.The suitable pharmaceutically acceptable ether of hydroxyl forms group and comprises the alpha-acyloxy alkyl, for example acetoxy-methyl and oxy acid methyl neopentyl.

Suitable pharmaceutically acceptable prodrug with amino formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound is for example amide derivatives of its interior cleavable of body.Be derived from amino suitable pharmaceutically acceptable acid amides and for example comprise the acid amides that forms with following group: (1-10C) alkyloyl (for example ethanoyl), benzoyl, phenylacetyl, the benzoyl of replacement and the phenylacetyl of replacement.The example of the substitution in ring base on phenylacetyl and the benzoyl comprises amino methyl, N-alkylamino methyl, N, N-dialkyl amino ylmethyl, morpholino methyl, piperazine-1-ylmethyl and 4-(1-4C) alkylpiperazine-1-ylmethyl.

Formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound can part play a role by one or more metabolites in vivo, and described metabolite forms in human or animal body behind giving construction I, formula IA, formula IB, formula IC, formula ID or formula IE compound.As mentioned above, formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound also can utilize the metabolism of precursor compound (prodrug) to play a role in vivo.

The formula I compound of definition or the pharmaceutical composition of its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier during another aspect of the invention provides and comprises as mentioned.

Composition of the present invention can be the form (for example as tablet, lozenge, hard or soft balsam wafer, water-based or oiliness suspensoid, emulsion, dispersible powder or granule, syrup or elixir) that is suitable for orally using; Be suitable for the local form of using (for example as ointment, ointment, gelifying agent or water-based or oily solution agent or suspensoid); Be suitable for form (for example as fine pulvis or liquid aerosol) through the inhalation administration; Be suitable for form (for example as fine pulvis) through the insufflation administration; Or be suitable for the form (for example as the sterile aqueous or the oily solution agent that are used for intravenously, subcutaneous, intramuscular or intramuscular administration, perhaps as the suppository that is used for rectal administration) of parenteral admin.

Can pass through ordinary method, adopt conventional pharmaceutical excipient well-known in the art, obtain composition of the present invention.Therefore, be intended for use in oral composition and can contain for example one or more tinting materials, sweeting agent, correctives and/or sanitas.

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

The preparation of formula I compound

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

The protecting group that amino or alkylamino are suitable is for example acyl group, for example alkyloyl (for example ethanoyl), alkoxy carbonyl (for example methoxycarbonyl, ethoxy carbonyl or tert-butoxycarbonyl), aryl methoxy carbonyl (for example benzyloxycarbonyl) or aroyl (for example benzoyl).Deprotection condition for above-mentioned protecting group must change with selected protecting group.Therefore, for example can slough alkyloyl or acyl groups such as alkoxy carbonyl or aroyl by with suitable alkali (for example alkali metal hydroxide such as lithium hydroxide or sodium hydroxide) hydrolysis.Perhaps; for example can be by handling with suitable acid (example hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid etc.); slough acyl groups such as tert-butoxycarbonyl; can pass through for example through catalyzer hydrogenations such as palladium on carbon; perhaps, slough aryl methoxy carbonyls such as benzyloxycarbonyl by handling with Lewis acids (Lewis acid) such as three (trifluoroacetic acid) boron.For primary amino, suitable alternative protecting group is for example phthaloyl, can handle with alkylamine such as dimethylaminopropyl amine or with hydrazine and slough.

The protecting group that hydroxyl is suitable is for example acyl group, for example alkyloyl such as ethanoyl, as aroyls such as benzoyls or as arylmethyls such as benzyls.Deprotection condition for above-mentioned protecting group will change with selected protecting group.Therefore, for example can slough acyl groups such as alkyloyl or aroyl with for example alkali metal hydroxide (for example lithium hydroxide or the sodium hydroxide) hydrolysis of suitable alkali.Perhaps for example can slough arylmethyls such as benzyl through the hydrogenization of catalyzer such as palladium on carbon.

The protecting group that carboxyl is suitable is an esterified group; for example methyl or ethyl etc.; it can be by for example with sloughing as basic hydrolysiss such as sodium hydroxide; the perhaps tertiary butyl for example; it can be handled with acid organic acids such as (for example) trifluoroacetic acids and slough; perhaps benzyl for example, it can be by sloughing as catalyzer hydrogenations such as palladium on carbon.

Can be in synthetic any suitable stage, the routine techniques that adopts chemical field to know is sloughed protecting group.

In addition, can adopt organic chemistry standard technique well-known in the art to synthesize optically active form, for example synthetic or split by racemic modification by the optically-active raw material.

Can be by for the chemical technology personnel being conspicuous various ordinary method preparation I compound.Specifically, formula I compound can prepare by following formula (II) compound and following formula (III) compound are reacted:

In the formula (II), R ³And R ⁴If any the definition (condition is that any functional group is protected by optional) of closing among the following formula I, L is suitable leavings group; In the formula (III), R ¹, n and R ²As the definition among the relevant formula I (condition is that any functional group is protected by optional).

Therefore, can adopt ordinary method to slough any protecting group, when needing, can adopt conventional chemical method well-known in the art again, formula I compound is converted into different formula I compounds or its pharmacy acceptable salt.

Suitable leavings group L is halogen, for example chlorine.This reaction suits at organic solvent C for example _1-6Carry out in alkanol (for example propyl carbinol, Virahol or 2-amylalcohol), N,N-DIMETHYLACETAMIDE (DMA) or N-crassitude (NMP) or its mixture.Suitable to acid, particularly mineral acid (for example hydrochloric acid) is added in the reaction mixture.This reaction suits to carry out under high temperature (for example 80-150 ℃), the reflux temperature at solvent preferably.

Perhaps, (II) and the available transition metal complex of the reaction (III) (for example palladium catalyst) carry out catalysis.The example of suitable palladium catalyst comprises Pd ₂(dba) ₃(three (dibenzalacetones) close two palladiums), Pd (PPh ₃) ₄And Pd (OAc) ₂The catalytic reaction of this palladium suits in suitable alkali (for example salt of wormwood, cesium carbonate, potassiumphosphate, sodium tert-butoxide) or 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) carries out under existing.The suitable solvent that is used for this reaction comprises toluene, diox or glycol dimethyl ether (DME).The suitable ligand that is used for this reaction comprises Xantphos (4, two (diphenyl phosphine)-9 of 5-, 9-dimethyl xanthene), BINAP (2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene) or DPPF (1,1 '-two (diphenyl phosphine) ferrocene).This reaction is suitable at high temperature to be carried out, and generally carries out under the reflux temperature of used concrete solvent.Typical temperature can be 90-140 ℃.

Can pass through prepared in various methods formula (II) compound, comprise for example when L is halogen, by making following formula (IV) compound and suitable halogenating agent (for example phosphoryl chloride) reaction:

R wherein ⁴As the definition among the relevant formula I.

Carry out this reaction under the reaction conditions of the halogenating agent that adopts being suitable for.For example, it can carry out in organic solvent (for example acetonitrile or DCM (DCM)) under high temperature (for example 50-100 ℃ high temperature).

Suitable to making down formula V compound and following formula (VI) compound react preparation formula (IV) compound:

In the formula (VI), R ³And R ⁴As the definition among the relevant formula I.

This reaction suits in organic solvent (for example diglyme), carries out under high temperature (for example 120-180 ℃) equally, preferablyly carries out under the reflux temperature of solvent.

Wherein L is formula (II) compound of chlorine, can also following formula (XIII) compound and 4-chloro-2-sulfonyloxy methyl yl pyrimidines be reacted prepare in the presence of suitable alkali (for example sodium hydride):

R wherein ³And R ⁴As the definition among the relevant formula I.

Perhaps, can react preparation I compound by making following formula (VII) compound and formula (VI) compound as defined above:

R wherein ¹, n and R ²As the definition among the relevant formula I, condition is that any functional group all can be protected, and L is suitable leavings group, for example halogen or-SO ₂Me.

Equally, any protecting group all can adopt ordinary method to slough, and when needing, also available conventional chemical method makes formula I compound be converted into different formula I compound or salt.

Be used for (VII) and (VI) between the conditions suitable of reaction with above-mentioned compound (II) with the reaction conditions (III).

It is suitable that formula (III) compound and following formula (VIII) compound react preparation formula (VII) compound by making as defined above:

L wherein ¹And L ²Be leavings group, for example halogen, particularly chlorine.

This reaction suits to carry out in the presence of organic bases (for example triethylamine).This reaction also suits under high temperature (for example between 80 ℃ and 120), at appropriate organic solvent (C such as ethanol for example _1-6Alkanol) carries out in.This reaction also can be carried out in organic solvent (for example DMA) in the presence of highly basic (for example sodium hydride).When adopting basic reaction conditions, the suitable low temperature that adopts (for example-20 ℃ to 20 ℃, is about 0 ℃ preferablyly.

Can be suitable leavings group (for example halogen) and R also by making following formula (IX) compound and X wherein ¹The following formula: compound that defines among the relevant as mentioned formula I reacts preparation formula (VII) compound:

R ¹-X

In the formula (IX), L is the middle as mentioned leavings group that defines, R ²With the definition among n such as the relevant formula I.

Suit in suitable solvent (for example dimethyl formamide), to carry out this reaction with alkali (for example cesium carbonate).

The another kind of method that is used for preparation I compound comprises that making following formula (X) compound and X wherein is suitable leavings group (for example halogen), R ¹The following formula: compound reaction of the appropriate protection base (for example 4-methoxy-benzyl) that definition among the relevant as mentioned formula I and P are this reaction:

R ¹-X

In the formula (X), R ², n, R ³And R ⁴The definition of relevant formula I as mentioned.

Suit in suitable solvent (for example dimethyl formamide), to carry out this reaction with highly basic (for example sodium hydride).

The another kind of method that is used for preparation I compound comprises makes following formula (XI) compound and the reaction of following formula (XII) compound:

In the formula (XI), R ¹, R ³And R ⁴The definition of relevant formula I as mentioned;

In the formula (XII), R ²With n as mentioned in the definition of relevant formula I, L is halogen, for example bromine.

This reaction suits to carry out in the presence of appropriate catalyst (for example palladium catalyst).The example of suitable palladium catalyst comprises Pd ₂(dba) ₃(three (dibenzalacetones) close two palladiums), Pd (PPh ₃) ₄And Pd (OAc) ₂The catalytic reaction of this palladium suits in suitable alkali (for example salt of wormwood, cesium carbonate, potassiumphosphate, sodium tert-butoxide) or 1, and 8-diazabicylo [5.4.0] 11 carbon-7-alkene (DBU) carries out under existing.The suitable solvent that is used for this reaction comprises toluene, diox or glycol dimethyl ether (DME).The suitable ligand that is used for this reaction comprises Xantphos (4, two (diphenyl phosphine)-9 of 5-, 9-dimethyl xanthene), BINAP (2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene) or DPPF (1,1 '-two (diphenyl phosphine) ferrocene).This reaction is suitable at high temperature to be carried out, and generally carries out under the reflux temperature of used concrete solvent.Typical temperature can be 90-140 ℃.

Formula (III) compound is a compound known, and perhaps can adopt skilled chemical technology personnel is that conspicuous similar approach is prepared by known compound.

Can adopt the standard method of this area routine that some formula I compounds are changed into other formulas I compound.Can be used to the example that a kind of formula I compound changes into different formula I conversion of compounds reaction types comprised by aromatics substitution reaction or nucleophilic substitution reaction and introduce substituting group, substituent reduction, substituent alkylation and substituent oxidation.The reagent and the reaction conditions that are used for these methods are that chemical field is well-known.

The specific examples of aromatics substitution reaction comprises and uses alkyl halide and Lewis acid (Lewisacid) (for example aluminum chloride) to introduce alkyl under Friedel Crafts condition; And introducing halogen group.The specific examples of nucleophilic substitution reaction comprises use standard conditions introducing alkoxyl group or an alkylamino, dialkyl amido or contains the N heterocycle.The specific examples of reduction reaction comprises with sodium borohydride makes carbonyl reduction become hydroxyl, perhaps also heats with iron with the nickel catalyzator catalytic hydrogenation or in the presence of hydrochloric acid and handles, and makes nitroreduction become amino;

Use the concrete formula I compound of method for preparing, for example formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound constitute another aspect of the present invention.

Biological experiment

A) external EphB4 enzyme assay

This assay method adopts Alphascreen ^TMLuminescent detection techniques, the inhibitor of the peptide substrate phosphorylation of detection EphB4 mediation.Briefly, in the presence of magnesium-ATP, the EphB4 that will recombinate is with biotinylation-peptide substrate (incubation of vitamin H-poly-GAT).By adding EDTA, come termination reaction together with the donor bead of streptavidin bag quilt, this donor bead combines with the vitamin H-substrate of the tyrosine residues that contains any phosphorylation.The anti-phosphotyrosine antibody that exists on the acceptor bead combines with the substrate of phosphorylation, therefore, donor bead and acceptor bead closely is close together.Donor bead excites under 680nm immediately, and the interactional singlet oxygen intermediate of chemiluminescent substance (chemiluminescer) on generation and the acceptor bead causes the light emission under 520-620nm.This strength of signal is directly proportional with the substrate phosphorylation level, thereby suppressing to reduce by signal measures.

Test compound is prepared into the 10mM mother liquor in DMSO (Sigma-Aldrich Company Ltd, Gillingham, Dorset SP8 4XT catalog number (Cat.No.) 154938), uses the 5%DMSO serial dilution, obtain the various experimental concentration of the required final concentration of 6x.Each diluted chemical compound liquid of 2 μ l aliquot is moved on in the appropriate well of low volume white 384 hole assay plate (Greiner, Stroudwater Business Park, Stonehouse, Gloucestershire, GL 10 3SX, catalog number (Cat.No.) 784075) in duplicate.Every plate also contains control wells: use the hole of containing 2 μ l 5%DMSO to produce peak signal, use the hole of containing 2 μ l 0.5M EDTA (Sigma-AldrichCompany Ltd, catalog number (Cat.No.) E7889) to produce and be equivalent to 100% minimum signal that suppresses.

For this assay method, except that 2 μ l compounds or 2 μ l contrast, assay plate also contains in each hole: 10 μ l contain final damping fluid (10mM Tris, 100 μ M EGTA, 10mM magnesium acetate, 4 μ M ATP, 500 μ M DTT, 1mg/ml BSA), 0.25ng active EphB4 (the amino acid 563-987 that recombinates; Swiss-Prot searching number P54760) (ProQinase GmbH, BreisacherStr.117, D-79106 Freiburg, Germany, catalog number (Cat.No.) 0178-0000-3) and 5nM poly-GAT substrate (CisBio International, BP 84175,30204 Bagnols/Ceze Cedex, France, catalog number (Cat.No.) 61GATBLB) experimental mixture.Then with assay plate incubation 1 hour at room temperature.Contain donor bead (the Perkin Elmer of 0.25ng AlphaScreen anti-Tyrosine O-phosphate-100 acceptor bead and streptavidin bag quilt respectively by adding 5 μ l/ holes, catalog number (Cat.No.) 6760620M) stop buffer (10mM Tris, 495mM EDTA, 1mg/ml BSA) termination reaction.At natural lighting condition lower seal, with behind the aluminium foil parcel, lucifuge is incubation 20 hours again with every plate.

Adopt Perkin Elmer En Vision to read the plate instrument and measure resulting experimental signal.All numerical value are all deducted minimum value, signal is mapped to compound concentration, draw IC ₅₀Data.In external EphB4 enzyme assay, compound of the present invention is measured resulting IC ₅₀The value A that sees the following form.

Table A

The embodiment numbering	EphB4 enzyme assay IC ₅₀Value
The embodiment numbering	EphB4 enzyme assay IC ₅₀Value	??1	??0.763
??2.1	??0.829	??1	??0.763
??2.1	??0.829	??2.2	??2.18
??2.3	??0.304	??2.2	??2.18
??2.3	??0.304	??2.4	??0.348
??2.5	??0.937	??2.4	??0.348
??2.5	??0.937	??2.6	??0.447
??2.7	??0.117	??2.6	??0.447
??2.7	??0.117	??2.8	??0.335
??2.9	??0.781	??2.8	??0.335
??2.9	??0.781	??2.10	??1.27
??2.11	??0.106	??2.10	??1.27
??2.11	??0.106	??2.12	??0.189
??2.13	??0.0697	??2.12	??0.189
??2.13	??0.0697	??2.14	??0.653
??2.15	??1.11	??2.14	??0.653
??2.15	??1.11	??2.16	??0.307
??2.17	??0.0289	??2.16	??0.307
??2.17	??0.0289	??2.18	??0.0461
??2.19	??0.0596	??2.18	??0.0461
??2.19	??0.0596	??3	??0.0651
??4	??0.0638	??3	??0.0651
??4	??0.0638	??5	??0.424
??6	??0.052	??5	??0.424
??6	??0.052	??7.1	??0.361
??7.2	??0.0431	??7.1	??0.361
??7.2	??0.0431	??7.3	??0.657
??7.4	??0.51	??7.3	??0.657
??7.4	??0.51	??7.5	??0.113
??7.7	??0.144	??7.5	??0.113
??7.7	??0.144	??7.8	??0.0759
??7.9	??0.151	??7.8	??0.0759
??7.9	??0.151	??7.10	??0.0135
??7.11	??0.0601	??7.10	??0.0135

??7.12	??0.116
??7.12	??0.116	??7.13	??0.0326
??7.14	??0.0659	??7.13	??0.0326
??7.14	??0.0659	??7.15	??0.195
??7.16	??0.0222	??7.15	??0.195
??7.16	??0.0222	??7.17	??0.00313
??7.18	??0.00645	??7.17	??0.00313
??7.18	??0.00645	??7.19	??0.00973
??8.1	??0.414	??7.19	??0.00973
??8.1	??0.414	??8.2	??0.32
??8.3	??0.917	??8.2	??0.32
??8.3	??0.917	??8.4	??1.07
??9	??0.0565	??8.4	??1.07
??9	??0.0565	??10.1	??0.402
??10.2	??0.0453	??10.1	??0.402
??10.2	??0.0453	??10.3	??0.0758
??10.4	??0.0481	??10.3	??0.0758
??10.4	??0.0481	??10.5	??0.34
??10.6	??0.511	??10.5	??0.34
??10.6	??0.511	??10.7	??0.638
??10.8	??1.1	??10.7	??0.638
??10.8	??1.1	??10.9	??0.543
??10.10	??0.527	??10.9	??0.543
??10.10	??0.527	??10.11	??0.66
??10.12	??0.107	??10.11	??0.66
??10.12	??0.107	??10.13	??0.811
??10.14	??0.381	??10.13	??0.811
??10.14	??0.381	??10.15	??0.116
??10.16	??0.237	??10.15	??0.116
??10.16	??0.237	??10.17	??9.78
??10.18	??0.0968	??10.17	??9.78
??10.18	??0.0968	??10.19	??0.15
??10.20	??0.338	??10.19	??0.15
??10.20	??0.338	??10.21	??0.147
??10.22	??0.055	??10.21	??0.147
??10.22	??0.055	??11

??12.1	??0.0175
??12.1	??0.0175	??12.2	??0.0294
??12.3	??0.455	??12.2	??0.0294
??12.3	??0.455	??12.4	??0.171
??12.5	??0.00295	??12.4	??0.171
??12.5	??0.00295	??12.6	??0.0034
??12.7	??0.305	??12.6	??0.0034
??12.7	??0.305	??12.8	??0.00582
??13.1	??0.47	??12.8	??0.00582
??13.1	??0.47	??13.2	??0.426
??14	??0.37	??13.2	??0.426
??14	??0.37	??15.1	??34.1
??15.2	??0.206	??15.1	??34.1
??15.2	??0.206	??15.3	??1
??15.4	??0.68	??15.3	??1
??15.4	??0.68	??15.5	??1.12
??15.6	??0.417	??15.5	??1.12
??15.6	??0.417	??15.7	??0.707
??15.8	??0.338	??15.7	??0.707
??15.8	??0.338	??15.9	??0.602
??15.10	??7.73	??15.9	??0.602
??15.10	??7.73	??15.11	??1.32
??15.12	??1.4	??15.11	??1.32
??15.12	??1.4	??15.13	??0.722
??15.14	??0.5	??15.13	??0.722
??15.14	??0.5	??15.15	??0.696
??15.16	??0.634	??15.15	??0.696
??15.16	??0.634	??15.17	??1.15
??15.18	??1.39	??15.17	??1.15
??15.18	??1.39	??15.19	??1.73
??15.20	??1.75	??15.19	??1.73
??15.20	??1.75	??15.21	??1.31
??15.22	??0.316	??15.21	??1.31
??15.22	??0.316	??16	??0.132
??17.1	??0.265	??16	??0.132
??17.1	??0.265	??17.2	??0.171

??17.3	??1.91
??17.3	??1.91	??17.4	??1.09
??17.5	??0.951	??17.4	??1.09
??17.5	??0.951	??17.6	??1.21
??17.7	??0.639	??17.6	??1.21
??17.7	??0.639	??17.8	??0.481
??17.9	??0.443	??17.8	??0.481
??17.9	??0.443	??17.10	??0.0646
??18.1	??0.0338	??17.10	??0.0646
??18.1	??0.0338	??18.2	??0.0623
??18.3	??0.246	??18.2	??0.0623
??18.3	??0.246	??18.4	??0.0753
??18.5	??0.477	??18.4	??0.0753
??18.5	??0.477	??18.6	??0.342
??18.7	??0.118	??18.6	??0.342
??18.7	??0.118	??19.1	??0.419
??19.2	??0.395	??19.1	??0.419
??19.2	??0.395	??19.3	??0.571
??19.4	??0.295	??19.3	??0.571
??19.4	??0.295	??19.5	??0.181
??19.6	??0.339	??19.5	??0.181
??19.6	??0.339	??19.7	??0.648
??19.8	??1.45	??19.7	??0.648
??19.8	??1.45	??19.9	??0.754
??19.10	??0.656	??19.9	??0.754
??19.10	??0.656	??19.11	??0.207
??19.12	??0.234	??19.11	??0.207
??19.12	??0.234	??19.13	??2.08
??19.14	??1.18	??19.13	??2.08
??19.14	??1.18	??19.15	??1.1
??19.16	??1.97	??19.15	??1.1
??19.16	??1.97	??19.17	??2.83
??19.18	??0.614	??19.17	??2.83
??19.18	??0.614	??19.19	??1.05
??19.20	??3.09	??19.19	??1.05
??19.20	??3.09	??19.21	??0.527

??19.22	??0.119
??19.22	??0.119	??19.23	??1.31
??19.24	??1	??19.23	??1.31
??19.24	??1	??19.25	??0.875
??20	??0.912	??19.25	??0.875
??20	??0.912	??21	??0.0532
??21.1	??0.0433	??21	??0.0532
??21.1	??0.0433	??21.2	??0.0274
??21.3	??0.025	??21.2	??0.0274
??21.3	??0.025	??22.1	??1.48
??22.2	??1.86	??22.1	??1.48
??22.2	??1.86	??22.3	??1.19
??22.4	??0.802	??22.3	??1.19
??22.4	??0.802	??23	??0.00171
??24	??0.000581	??23	??0.00171
??24	??0.000581	??25.1	??0.0528
??25.2	??0.0769	??25.1	??0.0528
??25.2	??0.0769	??25.3	??0.0115
??25.4	??0.0116	??25.3	??0.0115
??25.4	??0.0116	??25.5	??0.127
??25.6	??0.00788	??25.5	??0.127
??25.6	??0.00788	??25.7	??0.0103
??25.8	??0.00639	??25.7	??0.0103

B) external EphB4 raji cell assay Raji

This assay method by measuring the reduction value of EphB4 phosphorylation, identifies the inhibitor of cell EphB4 after using the compound treatment cell.End assay method adopts sandwich ELISA to detect the phosphorylation state of EphB4.Briefly, on elisa plate, derive from the EphB4 of the band Myc label of handling cell lysate by anti-c-Myc antibody capture.Then, use the general phosphotyrosine antibody of puting together with HRP, by by the catalytic colorimetric output valve of HRP, measure the phosphorylation state of the EphB4 that is captured, wherein the level of EphB4 phosphorylation is directly proportional with colour intensity.Under 450nm, measure absorbancy with spectrophotometry.

The application standard technology clones total length people EphB4 (Swiss-Prot searching number P54760) by the cDNA that adopts RT-PCR by the HUVEC preparation.Then with this cDNA fragment subclone to the pcDNA3.1 expression vector that contains Myc-His epi-position label, be created in the total length EphB4 that C end contains the Myc-His label (Invitrogen Ltd.Paisley, UK).At 37 ℃ and 5%CO ₂Down, with CHO-K1 cell (LGC Promochem, Teddington, Middlesex, UK, catalog number (Cat.No.) CCL-61) keep cultivation at HAM F12 substratum (Sigma-Aldrich Company Ltd, Gillingham, Dorset SP8 4XT, catalog number (Cat.No.) N4888) in, this substratum contains 10% heat-inactivated fetal bovine serum (PAA lab GmbH, Pasching, Austria catalog number (Cat.No.) PAA-A15-043) and 1%glutamax-1 (InvitrogenLtd., catalog number (Cat.No.) 35050-038).Employing standard stable transfection technology is carried out engineeredly with stably express EphB4-Myc-His construct to the CHO-K1 cell, obtain the cell of EphB4-CHO hereinafter referred to as.

For each mensuration, with 10, the 000EphB4-CHO cell inoculation is in (the Fisher Scientific UK of Costar 96 hole tissue culturing plates, Loughborough, Leicestershire, UK., catalog number (Cat.No.) 3598) in each hole, overnight incubation in perfect medium.The 2nd day,, contain 0.1% serum deprivation Hyclone (FisherScientific UK, catalog number (Cat.No.) SH30068.02) in the substratum with cell overnight incubation in 90 μ l/ hole substratum.Test compound is prepared into the 10mM mother liquor in DMSO (Sigma-Aldrich Company Ltd, Gillingham, Dorset SP8 4XT catalog number (Cat.No.) 154938), and uses the serum free medium serial dilution, obtain the various experimental concentration of the required final concentration of 10x.Every kind of diluted chemical compound liquid of 10 μ l aliquot is moved on in each hole of cell plate in duplicate, cell was hatched under 37 ℃ 1 hour.Every plate also contains control wells: peak signal produces with untreated cell, is equivalent to 100% minimum signal that suppresses and produces with the hole of containing the active reference compound of known elimination EphB4.

The liver of will recombinating is joined albumen-B2-Fc (R﹠amp; D Systems, Abingdon Science Park, Abingdon, Oxon OX14 3NB UK, catalog number (Cat.No.) 496-EB), the related part of EphB4 of band Fc label form is with the concentration of 3 μ g/ml and anti-human IgG (Fc fragments specific) (the Jackson ImmunoResearch Labs of 0.3 μ g/ml, Northfield Business Park, Soham, Cambridgeshire, UK CB7 5UE, catalog number (Cat.No.) 109-005-008) together, in serum free medium, clustered in advance 30 minutes in 4 ℃, during stir frequently.After compound treatment, cell is joined albumen-B2 with the liver that clusters to stimulate 20 minutes down at 37 ℃ with the final concentration of 1 μ g/ml, to induce the EphB4 phosphorylation.After stimulation, discard substratum, with cell cracking in the lysis buffer (25mM Tris HCl, 3mM EDTA, 3mM EGTA, 50mM NaF, 2mM ortho-vanadate, 0.27M sucrose, 10mM β-Phosphoric acid glycerol esters, 5mM trisodium phosphate, 2% triton x-100, pH 7.4) in 100 μ l/ holes.

Under 4 ℃, with ELISA Maxisorp 96 orifice plate (Nunc; Fisher Scientific UK, Loughborough, Leicestershire, UK., catalog number (Cat.No.) 456537) each hole with phosphate buffered saline(PBS) (the 10 μ g/ml of the anti-c-Myc antibody of 100 μ l; AstraZeneca produces) wrap and spent the night.Each plate at room temperature sealed minimum 2 hours with 250 μ l/ hole 3%TopBlock (Fluka) (Sigma-Aldrich Company Ltd, Gillingham, Dorset SP84XT, catalog number (Cat.No.) 37766) with after containing the PBS washed twice of 0.05% tween 20.Each plate with PBS/0.05% tween 20 washed twice after, be incubated overnight under 4 ℃ with the cell lysate in 100 μ l/ holes.After elisa plate washs four times with the PBS/0.05% tween 20, anti-phosphotyrosine antibody (the Upstate of 4G10 that puts together by the HRP that in 3%TopBlock, dilutes at 1: 6000 with 100 μ l/ holes, DundeeTechnology Park, Dundee, UK, DD2 1SW, catalog number (Cat.No.) 16-105) incubation 1 hour at room temperature.Elisa plate develops the color with 100 μ l/ hole tmb substrates (Sigma-Aldrich Company Ltd, catalog number (Cat.No.) T0440) after washing four times with the PBS/0.05% tween 20.Add 25 μ l/ hole 2M sulfuric acid termination reactions after 15 minutes.Adopt Tecan SpectraFluor Plus under 450nm, to measure absorbancy.All numerical value are all deducted minimum value, compound concentration is mapped, draw IC with signal ₅₀Data.

In said determination, compound of the present invention has activity, for example, in assay method A, IC ₅₀Value is generally less than 3 μ M, in assay method B less than 0.3 μ M.The preferred IC of The compounds of this invention in assay method B ₅₀Value is generally less than 0.1 μ M.For the cited selected compound of the application, adopt the resulting more exemplary IC of assay method B ₅₀The value B that can see the following form.

Table B-adopts and measures the average IC that B obtained ₅₀ Value

The embodiment numbering	Average IC ₅₀(μM)
The embodiment numbering	Average IC ₅₀(μM)	??2.2	??0.074
??2.10	??0.011	??2.2	??0.074
??2.10	??0.011	??2.15	??0.017
??2.17	??0.021	??2.15	??0.017
??2.17	??0.021	??4	??1.71
??7.2	??＜0.032	??4	??1.71

C) in-vivo tumour transplantation model

With human colorectal cancer cell (HT295x10 ⁶(ATCC HTB-38)) to implant the right side of body of male nude mouse (nu/nu:Alpk) subcutaneous.Selection is roughly 0.2-0.3cm ³The tumour and the random packet of active growth.Adopt gavage, formulation with U.S. many elegant (Methocel)+0.1% of 0.5% (weight/volume) (weight/volume) poly-(HPMC/ tween), give [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl by 100mg/kg oral administration continuous 16 days of every day 2 times]-methyl-amino]-4-methyl-phenyl] methyl alcohol.[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol gives as the independent medicine that uses, perhaps unites to give with vegf receptor tyrosine kinase inhibitors 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline (AZD7514) (unitary dose (dose u.d)).Measure tumour twice weekly, calculate volume (cm ³) (π/6x (the wide x of long x is wide)/1000).Measure tumour in the last day of administration, calculate growth-inhibiting per-cent (((GMDVT-GMDVC)/(GMDVC-1)) * 100) then with respect to contrast, wherein GMDV has carried out the T-check to determine significance for handling how much δ volumes of (T) or contrast (C).

Figure H shows and to give separately [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol and with the effect of 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline (AZD7514) Combined Preparation to mean tumour volume.

Because the active and [3-[[2-[(3 of described selected compound, 5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol reduces the effect of the gross tumor volume of above-mentioned tumour transplatation model in vivo, therefore expect that compound of the present invention can be used for treating separately or partly by the disease or the medical conditions of the mediation of EphB4 enzymic activity, promptly described compound is used in and produces the EphB4 restraining effect in the warm-blooded animal body that needs this treatment.Therefore, compound of the present invention is provided for treating the method for the malignant cell propagation that it is characterized in that suppressing the EphB4 enzyme, and promptly described compound can be used for producing by suppressing EphB4 separately or the antiproliferative effect of part mediation.

Formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of definition were used for the method by the therapy for treating human or animal body during the present invention provided as mentioned on the other hand.

Therefore, another aspect of the invention provides formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of middle definition as mentioned as medicine.

Formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition or its pharmacy acceptable salt were used for producing the purposes of the inhibiting medicine of EphB4 during another aspect of the invention provided as mentioned in warm-blooded animal (for example people) body in preparation.

The further feature in this aspect of the present invention provides and produces the inhibiting method of EphB4 in warm-blooded animal (for example people) body that is used in this treatment of needs, and this method comprises formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of middle definition as mentioned that gives described animal effective dose.

Formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition or its pharmacy acceptable salt were used for producing the purposes of the medicine of blood vessel formation against function during another aspect of the invention provided as mentioned in warm-blooded animal (for example people) body in preparation.

The further feature in this aspect of the present invention provides the method that produces blood vessel formation against function in warm-blooded animal (for example people) body that is used in this treatment of needs, and this method comprises formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of middle definition as mentioned that gives described animal effective dose.

The further feature of this aspect of the present invention provides the method for cancer that treatment needs the warm-blooded animal (for example people) of this treatment, and this method comprises formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of middle definition as mentioned that gives described animal effective dose.

Formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition or its pharmacy acceptable salt were used for the treatment of purposes in the medicine of cancer in preparation during further aspect of the present invention provided as mentioned.

The further feature of this aspect of the present invention provides formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of middle definition as mentioned that is used for the treatment of cancer.

Formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition or its pharmacy acceptable salt were in the purposes that is used for preparing the medicine for the treatment of cancer during the further feature of this aspect of the present invention provided as mentioned.

Formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of definition were used for the treatment of solid tumor disease in preparation during another aspect of the present invention provided as mentioned, particularly the purposes in neuroblastoma, mammary cancer, liver cancer, lung cancer and the rectum cancer or the leukemic medicine.

Neuroblastoma, mammary cancer, liver cancer, lung cancer and the rectum cancer or leukemic method that another aspect of the present invention provides treatment to need the warm-blooded animal (for example people) of this treatment, this method comprise formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound or its pharmacy acceptable salt of middle definition as mentioned that gives described animal effective dose.

Anticancer therapy defined above can be used as independent therapy and uses, and perhaps except that compound of the present invention, also can comprise routine operation or radiotherapy or chemotherapy.Can be by simultaneously, each component sequential or that separately give therapy realizes this class combination therapy.In the medical oncology field, adopting the combination of multi-form treatment is conventional way to treat each cancer patients.In medical oncology, except that angiogenesis inhibitor treatment defined above, other component of this class conjoint therapy can be operation, radiotherapy or chemotherapy.This class chemotherapy can comprise the antitumor drug of one or more following classifications:

(i) other antiproliferative/antitumor drug and the combination thereof used in the medical oncology, for example alkylating agent (for example cis-platinum (cis-platin), oxaliplatin (oxaliplatin), carboplatin (carboplatin), endoxan (cyclophosphamide), mustargen (nitrogen mustard), melphalan (melphalan), Chlorambucil (chlorambucil), busulfan (busulphan), Temozolomide (temozolamide) and nitrosourea (nitrosoureas)); Antimetabolite (for example antifolic (antifolate), for example 5 FU 5 fluorouracil fluorine miazines (fluoropyrimidines) and Tegafur (tegafur), Raltitrexed (raltitrexed), methotrexate (methotrexate), cytosine arabinoside (cytosine arabinoside) and hydroxyurea (hydroxyurea) and gemcitabines (gemcitabine) such as (5-fluorouracil)); Antitumor antibiotics (for example anthracene nucleus class (anthracyclines), as Zorubicin (adriamycin), bleomycin (bleomycin), Dx (doxorubicin), daunomycin (daunomycin), epirubicin (epirubicin), idarubicin (idarubicin), ametycin (mitomycin-C), dactinomycin (dactinomycin) and mithramycin (mithramycin)); (for example catharanthus alkaloid (vinca alkaloid) is as vincristine(VCR) (vincristine), vinealeucoblastine(VLB) (vinblastine), vindesine (vindesine) and vinorelbine (vinorelbine) for antimitotic drug, taxanes (taxoids) is as safe plain (taxol) and taxotere (taxotere) and polo kinase inhibitor); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin class (epipodophyllotoxins) is as Etoposide (etoposide) and teniposide (teniposide), amsacrine (amsacrine), Hycamtin (topotecan) and camptothecine (camptothecin));

(ii) cytostatic agent, anti-estrogens medicine (tamoxifen (tamoxifen) for example for example, fulvestrant (fulvestrant), toremifene (toremifene), raloxifene (raloxifene), droloxifene (droloxifene) and idoxifene (iodoxyfene)), anti-androgens medicine (bicalutamide (bicalutamide) for example, flutamide (flutamide), Nilutamide (nilutamide) and cyproterone acetate (cyproterone acetate)), lhrh antagonist or LHRH agonist (goserelin (goserelin) for example, Leuprolide (leuprorelin) and buserelin (buserelin)), progestogens medicine (for example Magace (megestrol acetate)), aromatase inhibitor (Anastrozole (anastrozole) for example, letrozole (letrozole), vorozole (vorazole) and Exemestane (exemestane)) and 5 inhibitor, for example finasteride (finasteride);

(iii) anti-invasion medicine [for example c-Src kinases man group inhibitor such as 4-(6-chloro-2,3-methylene dioxo group aniline base)-7-[2-(4-methylpiperazine-1-yl) oxyethyl group]-5-tetrahydropyran-4-base oxygen base quinazoline (AZD0530; International Patent Application WO 01/94341) and ripple relax for Buddhist nun (bosutinib) (SKI-606), inhibitors of metalloproteinase such as Marimastat (marimastat) and upar depressant of functions];

(iv) somatomedin depressant of functions: for example, this class inhibitor comprises growth factor antibodies and growth factor receptor antibody [for example anti-erbB 2 antibody Herceptin (trastuzumab) and anti-erbB1 antibody Cetuximab (cetuximab) (C225) and handkerchief Buddhist nun monoclonal antibody (panitumumab)]; This class inhibitor for example also comprises tyrosine kinase inhibitor, and [for example (for example for example Gefitinib (gefitinib) is (ZD1839) for EGFR family tyrosine kinase inhibitor for the epidermal growth factor family inhibitor, erlotinib (erlotinib) (OSI-774) and CI 1033) and erbB2 tyrosine kinase inhibitor lapatinibditosylate (lapatinib) for example), pHGF man group inhibitor, the insulin-like growth factor acceptor inhibitor, Thr6 PDGF BB man group inhibitor and/or bcr/abl kinase inhibitor (imatinib (imatinib) for example, Dasatinib (dasatinib) (BMS-354825) replaces Buddhist nun (nilotinib) (AMN107) with the Buddhist nun Lip river), pass through MEK, AKT, PI3, c-kit, Flt3, the kinase whose cell signalling inhibitor of CSF-1R and/or aurora]; This class inhibitor also comprises cell cycle protein dependent kinase inhibitor, comprises CDK2 and CDK4 inhibitor; And this class inhibitor for example also comprise the serine/threonine kinase inhibitor (Ras/Raf signal transduction inhibitor farnesyl transferase inhibitor for example for example, for example Xarelto (sorafenib) (BAY 43-9006), Zarnestra (tipifarnib) (R115777) and chlorine Na Fani (lonafarnib) (SCH66336);

(v) angiogenesis inhibitor medicine for example suppresses medicine [anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF (the bevacizumab) (Avastin for example for example of vascular endothelial growth factor effect ^TM) or for example vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors for example ZD6474 (vandetanib) (ZD6474), cut down Ta Lani (vatalanib) (PTK787), Sutent (sunitinib) (SU11248), Ah former times for Buddhist nun (axitinib) (AG-013736), handkerchief azoles handkerchief Buddhist nun (pazopanib) (GW 786034), 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline (AZD2171; Embodiment 240 in the WO 00/47212) and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(the basic propoxy-of 3-piperidines-1-) quinazoline (AZD7514; Embodiment 238 in the WO 00/47212) or the compound (for example linomide (linomide), beta 2 integrin alpha v β 3 depressant of functions and angiostatin) that for example works by other mechanism];

(vi) angiolysis medicine, for example combretastatin A4 (Combretastatin A4);

(vii) antisense therapy, for example at the compound of above-mentioned target, for example ISIS 2503, and this is a kind of anti-ras antisense therapy;

(viii) gene therapy, comprise the method for for example replacing aberrant gene (for example unusual p53, unusual BRCA1 or unusual BRCA2), the method that GDEPT (gene targeting enzyme prodrug therapy) for example adopts Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, and the raising patient is to the method for chemotherapy or radiotherapy tolerance, for example multidrug resistance gene therapy; With

(ix) immunotherapy comprises (in vivo) method (for example using cytokine such as interleukin-22, interleukin 4 or rHuGM-CSF transfection) in (exvivo) method that exsomatizes that for example improves the patient tumors cell immunogenicity and the body, reduces the method for T cell anergy, the method for utilizing transfection immunocyte (for example dendritic cell of cytokine transfection), the method for tumor cell line of utilizing cytokine transfection and the method for utilizing antiidiotypic antibody.

Can be by simultaneously, sequential or separately give respectively to treat component, implement this class conjoint therapy.This class joint product adopts The compounds of this invention and other the interior active medicine of approval dosage range in the above-mentioned dosage range of this paper.

This aspect of the present invention provides the combined prod that is applicable to treatment cell proliferation disorders (for example solid tumor disease), the other antitumour drug of definition during formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition reached as mentioned during this combined prod comprised as mentioned.

This aspect of the present invention also provides the combined prod that is applicable to treatment cell proliferation disorders (for example solid tumor disease), formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition and other angiogenesis inhibitor medicine during this combined prod comprises as mentioned.

In the embodiment of the present invention aspect this, the combined prod that is applicable to treatment cell proliferation disorders (for example solid tumor disease) is provided, the formula I of definition during this combined prod comprises as mentioned, formula IA, formula IB, formula IC, formula ID or formula IE compound and vegf receptor tyrosine kinase inhibitor, for example 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt, perhaps 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline or its pharmacy acceptable salt.

In the further embodiment of the present invention aspect this, the combined prod that is applicable to treatment cell proliferation disorders (for example solid tumor disease) is provided, this combined prod comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol or its pharmacy acceptable salt and vegf receptor tyrosine kinase inhibitor, for example 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt, perhaps 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline or its pharmacy acceptable salt.

In the specific embodiments of the present invention aspect this, the combined prod that is applicable to treatment cell proliferation disorders (for example solid tumor disease) is provided, this combined prod comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol or its pharmacy acceptable salt and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt.

4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) preferred salt of quinazoline (AZD2171) is maleate (AZD2171 maleate), can be referring to international application published WO 05/061488.The AZD2171 maleate can be synthetic according to method described in the WO05/061488.

Therefore, in the embodiment of the present invention aspect this, the combined prod that is applicable to treatment cell proliferation disorders (for example solid tumor disease) is provided, this combined prod comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] maleate of methyl alcohol or its pharmacy acceptable salt and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline.

This aspect of the present invention also provides a kind of medicament production, formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition and other angiogenesis inhibitor medicine during this medicament production comprises as mentioned.

In the embodiment of the present invention aspect this, a kind of medicament production is provided, formula I, formula IA, formula IB, formula IC, formula ID or formula IE compound and the vegf receptor tyrosine kinase inhibitor of definition during this medicament production comprises as mentioned, for example 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt, perhaps 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline or its pharmacy acceptable salt.

In the further embodiment of the present invention aspect this, a kind of medicament production is provided, this medicament production comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol or its pharmacy acceptable salt and vegf receptor tyrosine kinase inhibitor, for example 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt, perhaps 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-piperidines-1-base-propoxy-)-quinazoline or its pharmacy acceptable salt.

In the specific embodiments of the present invention aspect this, a kind of medicament production is provided, this medicament production comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol or its pharmacy acceptable salt and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt.

In the embodiment of the present invention aspect this, provide a kind of medicament production, this medicament production comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] maleate of methyl alcohol or its pharmacy acceptable salt and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline.

This aspect of the present invention also is provided for the medicament production of combination therapy cancer, formula I, formula IA, formula IB, formula IC, formula ID or the formula IE compound of definition and the middle as mentioned other antitumour drug that defines during this medicament production comprises as mentioned.

As mentioned above, required therapeutic of concrete cell proliferation disorders or the big young pathbreaker of prophylactic treatment dosage change with the severity of subject host, route of administration and disease to be treated.The scope of expection unitary dose is for example 1-100mg/kg, preferred 1-50mg/kg.

Combination therapy of the present invention as defined herein can be of value to its angiogenesis inhibitor and/or vascular permeability effects.Vasculogenesis and/or vascular permeability raising are present in the multiple disease, comprise cancer (comprising leukemia, multiple myeloma and lymphoma), diabetes, psoriatic, rheumatoid arthritis, Kaposi sarcoma (Kaposi ' s sarcoma), vascular tumor, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune disease, acute inflammation, asthma, lymphedema, endometriosis, dysfunctional uterine bleeding and the outgrowth ophthalmic diseases of the retinal vessel that occurs together, comprise age-related macular degeneration.

Expect that combination therapy of the present invention is used in particular for for example prevention and treatment of diseases such as cancer and Kaposi sarcoma.Specifically, expect that this class combination therapy of the present invention can be used for treating cancer, for example lung cancer, incidence cancer, the cancer of the brain, colorectal carcinoma, the rectum cancer, the esophageal carcinoma, cancer of the stomach, liver cancer, cholangiocarcinoma, thyroid carcinoma, kidney, cervical cancer, ovarian cancer, uterus carcinoma, skin carcinoma, mammary cancer, bladder cancer, prostate cancer, carcinoma of the pancreas, and comprise the blood malignant disease, for example leukemia, multiple myeloma and lymphoma.

Specifically, expection this class combination therapy of the present invention growth of helping slowing down primary and recurrent solid tumor.

More particularly, expect that this class combination therapy of the present invention suppresses any cancer form relevant with VEGF, comprise leukemia, multiple myeloma and lymphoma, and also suppress for example relevant primary and the growth of recurrent solid tumor with VEGF, especially its growth and diffusion significantly depend on the tumour of VEGF, comprise for example some colon tumor, rectal neoplasm, pancreatic neoplasm, cerebral tumor, tumor of bladder, ovarian tumor, breast tumor, tumor of prostate, lung tumor, external genital tumor, liver tumor and dermatoma.

Except that their purposes in medicine, formula I, formula IA or formula IB compound and pharmacy acceptable salt thereof also are used as pharmacological tool in the exploitation of test system and the stdn in vitro and in vivo, be used to estimate of the effect of anti-angiogenesis activity inhibitor, as the integral part of exploring the novel therapeutic medicine to laboratory animal (for example cat, dog, rabbit, monkey, rat and mouse).

Now, the present invention will be described by the following example, wherein generally speaking:

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

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

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

(iv) generally speaking, reaction process is followed the tracks of with TLC and/or analysis mode LC-MS, and the reaction times only is used for explanation; Retention time (t _R) be equipped with Waters Symmetry post (C18,3.5 μ M, 4.6x50mm) or Waters Sunfire post (C18,3.5 μ M, 4.6x50mm), detect the LC/MS Waters 2790/ZMD Micromass systematic survey of UV 254nM and MS; Wash-out: flow velocity 2.5ml/ minute, the linear gradient in 3 minutes was 5% methyl alcohol to 40% water-55% acetonitrile-contain, 5% methyl alcohol of 5% formic acid of 95% water-contain, 5% formic acid; Linear gradient in 1 fen clock time is 95% acetonitrile-contain, 5% methyl alcohol of 5% formic acid then;

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

(vi) given yield only is used for explanation, not necessarily by too much testing obtainable yield; Can repeat preparation as the more raw materials of needs;

(vii) when the NMR data that provide are the δ value form of principal character proton, to provide with respect to interior target ppm of tetramethylsilane (TMS) (ppm), except as otherwise noted, otherwise just with full deuterium methyl-sulphoxide (DMSO-d ₆) make solvent and under 500MHz, measure; Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak.

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

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

(x) adopt 70 electron-volts electronic energy in the mass spectrum operation, chemi-ionization (CI) pattern is used directly to expose probe; Wherein said ionization realizes by electronic impact (EI), fast atom bombardment (FAB) or electron spray(ES) (ESP); Provided the m/z value; In general, only report the ion of indication parent quality; Except as otherwise noted, otherwise the mass ion that provides is (MH) ⁺, it is meant protonated mass ion; Mention M ⁺Be meant and lose the mass ion that an electron institute produces; Mention M-H ⁺Shi Ze is meant and loses a mass ion that proton produced;

(xi) except as otherwise noted, otherwise the compound that contains asymmetric alternate c atoms and/or sulphur atom split;

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

(xiii) all microwave reactions are all at Personal Chemistry EMRYS ^TMCarry out in the OptimizerEXP microwave synthesizer;

(xiv) adopt following condition, in the Waters instrument, be prepared type high performance liquid chromatography (HPLC):

Post: 30mmx15cm Xterra Waters, C18,5mm

Solvent orange 2 A: water and 1% acetate or 2g/l volatile salt

Solvent B: acetonitrile

Flow velocity: 40ml/ minute

Spend the post time: 15 minutes, wherein gradient 5-95%B was 10 minutes

Wavelength: 254nm

Volume injected 2.0-4.0ml;

In addition, if needed, use following abbreviation:

The DMSO methyl-sulphoxide

The NMP 1-Methyl-2-Pyrrolidone

The DMA N,N-dimethylacetamide

The DCM methylene dichloride

The THF tetrahydrofuran (THF)

The DEAD diethyl azodiformate

DMF N, dinethylformamide

The DTAD tert-butyl azodicarboxylate

The DIPEA diisopropylethylamine

The IPA Virahol

The Ether ether

TBTU Tetrafluoroboric acid O-benzotriazole-1-base-N, N, N ', N '-tetramethyl-urea

The TFA trifluoroacetic acid

NH ₄The OH ammonium hydroxide aqueous solution

The AcOEt ethyl acetate

Embodiment 1

N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-(3-morpholine-4-base-5-thiomorpholine-4-base-phenyl) pyrimidine-2, the 4-diamines

With 2-chloro-N-(3-chloro-2,4-two fluoro-phenyl)-N-methyl-pyrimidine-4-amine is (referring to method 1,100mg, 0.34mmol), 3-morpholine-4-base-5-thiomorpholine-4-base-aniline is (referring to method 9,95mg, 0.34mmol), the mixture of 4N HCl/ diox (100 μ l) and 2-propyl alcohol (5ml) is 90 ℃ of heating 3 hours down.After making reaction mixture be cooled to room temperature, reduction vaporization.After resistates is dissolved in methylene dichloride, wash with saturated solution of sodium bicarbonate.After the evaporation, crude product obtains title compound (107mg, yield 58%) with silica gel chromatography purifying (0-20%EtOAc/DCM).NMR composes (500MHz, DMSOd ₆) 2.60-2.68 (m, 4H), 2.97-3.06 (m, 4H), 3.38 (s, 3H), and 3.40-3.47 (m, 4H), 3.67-3.75 (m, 4H), 5.81 (bs, 1H), 6.07 (dd, 1H), 6.89 (s, 1H), 6.91 (s, 1H), 7.46 (dd, 1H), 7.59 (ddd, 1H), 7.95 (d, 1H), 8.87 (s, 1H); Mass spectrum: MH ⁺533.

Embodiment 2

Use suitable aniline, repeat method described in the embodiment 1, thereby obtain following compound.

^aReaction mixture was heated 16 hours down at 80 ℃.

^bUse the 2-amylalcohol to be solvent, reaction mixture was heated 3 hours down at 110 ℃.

^cReaction mixture was heated 15 minutes in 120 ℃ in microwave oven.

Embodiment 3

N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl)-5-methyl sulphonyl-phenyl] pyrimidine-2, the 4-diamines

With 2-chloro-N-(3-chloro-2,4-two fluoro-phenyl)-N-methyl-pyrimidine-4-amine (method 1,120mg, 0.41mmol), 3-methyl sulphonyl-5-morpholine-4-base-aniline (method 11,110mg, 0.41mmol), salt of wormwood (571mg, 4.14mmol), Pd ₂Dba ₃(three (dibenzalacetones) close two palladiums) (24mg, 0.041mmol) and Xantphos (48mg 0.083mmol) refluxed 16 hours with mixture with the toluene (3ml) of argon-degassed.Solvent removed in vacuo, resistates is dissolved in DMF after, with preparation HPLC-MS system purifying (post: C18,5 microns, diameter 19mm, long 100mm, water carries out gradient elution with the acetonitrile that contains the 2g/l volatile salt).The flow point of collecting obtains title compound (101mg, yield 46%) after evaporation; NMR composes (500MHz, DMSOd ₆) 2.24 (s, 3H), 2.43-2.51 (m, 4H), 3.14 (s, 3H), 3.16-3.23 (m, 4H), 3.41 (s, 3H), 5.88 (bs, 1H), 6.96 (s, 1H), 7.47 (ddd, 1H), 7.50 (s, 1H), 7.61 (ddd, 1H), 8.01 (d, 1H), 8.05 (bs, 1H), 8.43 (s, 1H).Mass spectrum: MH ⁺523.

Embodiment 4

N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl) phenyl] pyrimidine-2, the 4-diamines

Use 3-(4-methylpiperazine-1-yl) aniline (J.Med.Chem.2005, the 48th volume, 8261-8269 page or leaf) as initial aniline, according to embodiment 3 preparations (yield 33%); NMR composes (500MHz, DMSOd ₆) 2.21 (s, 3H), 2.40-2.47 (m, 4H), 3.02-3.10 (m, 4H), 3.37 (s, 3H), 5.99 (bs, 1H), 6.48 (dd, 1H), 6.91 (dd, 1H), 7.08 (d, 1H), 7.17 (bs, 1H), 7.46 (ddd, 1H), 7.58 (ddd, 1H), 8.02 (d, 1H), 9.00 (s, 1H).Mass spectrum: MH ⁺445.

Embodiment 5

N '-(3-chloro-2,4-two fluoro-phenyl)-N '-methyl-N-[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base-phenyl] pyrimidine-2, the 4-diamines

Use 3-(4-methylpiperazine-1-yl)-5-morpholine-4-base-aniline (method 9) to be alkali as aniline, cesium carbonate, Pd (OAc) ₂/ BINAP is a catalyst system, according to embodiment 3 preparations (yield 9%); NMR composes (500MHz, DMSOd ₆) 2.21 (s, 3H), 2.39-2.46 (m, 4H), 2.97-3.04 (m, 4H), 3.04-3.10 (m, 4H), 3.39 (s, 3H), 3.67-3.76 (m, 4H), 5.81 (bs, 1H), 6.10 (dd, 1H), 6.90 (s, 1H), 6.92 (s, 1H), 7.46 (ddd, 1H), 7.60 (ddd, 1H), 7.96 (d, 1H), 8.86 (s, 1H).Mass spectrum: MH ⁺530.

Embodiment 6

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol

Will [3-[(2-chloropyrimide-4-yl)-methyl-amino]-4-methyl-phenyl] methyl alcohol (method 2,700mg, 2.6mmol), 3,5-dimorpholine-4-base aniline (method 9,700mg, 2.6mmol), the mixture of 4N HCl/ diox (200 μ l) and 2-propyl alcohol (15ml) is at Personal ChemistryEMRYS ^TMHeated 15 minutes in 140 ℃ in the Optimizer EXP microwave synthesizer.After making reaction mixture be cooled to room temperature, reduction vaporization.After in the mixture (regulator solution is to pH 8) of resistates is water-soluble, ethyl acetate and ammonium hydroxide, organic layer water and salt water washing.After the evaporation, crude product silica gel purification (1-7%MeOH/DCM).The flow point of collecting grinds with ether and sherwood oil after evaporation, obtains title compound (810mg, yield 62%, white solid); NMR composes (500MHz, DMSOd ₆) 2.08 (s, 3H), 3.07 (bs, 8H), 3.37 (s, 3H), 3.68-3.77 (m, 8H), 4.49 (d, 2H), 5.22 (t, 1H), 5.25 (bs, 1H), 6.11 (s, 1H), 7.03 (bs, 2H), 7.18 (s, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.78 (bs, 1H), 8.85 (bs, 1H). Mass spectrum: MH ⁺491.

Embodiment 6.1

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1

While stirring with amorphous [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol (about 20mg) in ether in lasting 5 days of 25 ℃ of making beating.With resulting crystal [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol is as crystal seed, Same Way amplifies in proportion and repeats, obtain [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1 crystallized product.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methyl alcohol free alkali form 1 provides the X-ray powder diffraction figure shown in figure A substantially.The peak value B that sees the following form.

Therefore, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1 can also provide at least one 2 following θ value to characterize by using the CuKa radiation measurement: 7.47 °, 22.21 °, 22.67 ° and 24.69 °.

Table B

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??7.472	??94.3
??10.12	??32.7	??7.472	??94.3
??10.12	??32.7	??11.884	??20.8
??12.337	??16.6	??11.884	??20.8
??12.337	??16.6	??12.962	??8.7
??13.587	??42.6	??12.962	??8.7
??13.587	??42.6	??15.15	??37.9
??16.274	??71	??15.15	??37.9
??16.274	??71	??16.614	??24
??17.353	??16.5	??16.614	??24
??17.353	??16.5	??18.02	??58.9
??18.562	??51.3	??18.02	??58.9
??18.562	??51.3	??19.008	??59.1
??19.76	??12.9	??19.008	??59.1
??19.76	??12.9	??20.166	??53.2
??20.59	??51.1	??20.166	??53.2
??20.59	??51.1	??21.051	??17.1
??22.214	??100	??21.051	??17.1
??22.214	??100	??22.675	??73.6
??23.808	??27.1	??22.675	??73.6
??23.808	??27.1	??24.15	??19.8
??24.69	??90.2	??24.15	??19.8
??24.69	??90.2	??25.152	??44
??26.162	??12.2	??25.152	??44
??26.162	??12.2	??26.672	??33.3
??27.57	??12.4	??26.672	??33.3
??27.57	??12.4	??28.13	??16.9
??28.836	??9	??28.13	??16.9
??28.836	??9	??29.4	??13.7
??31.499	??11.9	??29.4	??13.7
??31.499	??11.9	??32.338	??10.6
??33.956	??6.6	??32.338	??10.6
??33.956	??6.6	??35.55	??6.7
??36.249	??6.7	??35.55	??6.7
??36.249	??6.7	??37.542	??12.8
??38.102	??9.9	??37.542	??12.8

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure has at least one specific peak value at 7.5 ° ± 0.5 ° 2 θ place more precisely near 2 θ=7.5 °.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure has at least one specific peak value near 2 θ=22.2 °.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure has at least one specific peak value near 2 θ=22.7 °.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is near 2 θ=24.7 °, have at least one specific peak value at 24.7 ° ± 0.5 ° 2 θ place more precisely.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure has specific peak value near 2 θ=7.5 °, 22.2 °, 22.7 ° and 24.7 °, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=7.5 °, 10.1 °, 11.9 °, 12.3 °, 13.0 °, 13.6 °, 15.2 °, 16.3 °, 16.6 °, 17.4 °, 18.0 °, 18.6 °, 19.0 °, 19.8 °, 20.2 °, 20.6 °, 21.1 °, 22.2 °, 22.7 °, 23.8 °, 24.2 °, 24.7 °, 25.2 °, 26.2 °, 26.7 °, 27.6 °, 28.1 °, 28.8 °, 29.4 °, 31.5 °, 32.3 °, 34.0 °, 35.6 °, 36.2 °, 37.5 ° and 38.1 ° locate to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol free alkali form 1, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure A.

Dsc analysis shows, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1 begins to melt in the time of 179.01 ℃, reaches peak value in the time of 182.29 ℃.Observe [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] heat of fusion of methyl alcohol free alkali form 1 is 71.28J/g.

Salt is synthetic

Embodiment 6.2

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate

With Phenylsulfonic acid (395mg, acetonitrile 2.45mmol) (2ml) drips of solution be added to (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol (1200mg, 2.45mmol) with the stirred solution of hot acetonitrile in.This solution is stirred down at 20 ℃, after salt is precipitated out after 30 minutes, the mixture stirring is spent the night.After collecting white solid after filtration, spend the night, obtain required benzene sulfonate (1.315g) 45 ℃ of following vacuum-dryings.Fusing point: 224.6-224.8 ℃.

NMR composes (500MHz, DMSOd ₆) 2.12 (s, 3H), 3.08-3.17 (m, 8H), 3.45 (s, 3H), 3.70-3.77 (m, 8H), 4.52 (s, 2H), 5.28 (bs, 1H), 6.39 (s, 1H), 6.63 (bs, 2H), 7.26 (s, 1H), 7.28-7.38 (m, 4H), 7.41 (d, 1H), 7.57-7.63 (m, 2H), 7.70 (d, 1H), 10.17 (bs, 1H).

Ultimate analysis: measured value: C, 60.29; H, 6.24; N, 12.81;

C ₂₇H ₃₄N ₆O ₃H ₂O 0.36mol, C ₆H ₅SO ₃H 1.0mol, desired value: C, 60.49; H, 6.26; N, 12.83%.

Embodiment 6.3

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 1

The 1ml acetonitrile is added to about 50mg[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] form solution in the methyl alcohol.About 18.5mg Phenylsulfonic acid is dissolved in the 1ml acetonitrile.With 3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol/acetonitrile solution is added in the counter ion solution, the gained mixture heating up vibrated.After about 1 hour, solution precipitates, and throw out after filtration and analyze obtains [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 1.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methyl alcohol-benzene sulfonate form 1 provides basically as schemes the X-ray powder diffraction figure as shown in the B.The peak value C that sees the following form.

Therefore, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 1 can also provide at least one 2 following θ value to characterize by using the CuKa radiation measurement: 5.56 °, 8.70 °, 16.39 °, 18.15 °, 18.97 °, 20.35 ° and 22.98 °.

Table C

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??5.569	??74.9
??8.701	??72.5	??5.569	??74.9
??8.701	??72.5	??9.505	??25.1
??10.325	??5.3	??9.505	??25.1
??10.325	??5.3	??11.002	??8.9
??11.265	??12.8	??11.002	??8.9
??11.265	??12.8	??12.858	??8.3
??14.798	??8.9	??12.858	??8.3
??14.798	??8.9	??15.14	??9.9
??15.38	??8.3	??15.14	??9.9
??15.38	??8.3	??15.858	??8.3
??16.349	??61.1	??15.858	??8.3
??16.349	??61.1	??17.333	??35.8
??18.152	??40.9	??17.333	??35.8
??18.152	??40.9	??18.972	??39.3
??19.566	??16.2	??18.972	??39.3
??19.566	??16.2	??20.358	??38.7
??20.794	??12.5	??20.358	??38.7

??21.061	??13.4
??21.061	??13.4	??21.376	??13.2
??22.106	??25.7	??21.376	??13.2
??22.106	??25.7	??22.983	??100
??23.7	??12.6	??22.983	??100
??23.7	??12.6	??24.319	??28.5
??24.58	??9.9	??24.319	??28.5
??24.58	??9.9	??25.232	??10.9
??26.118	??10.7	??25.232	??10.9
??26.118	??10.7	??26.671	??9.1
??27.662	??9.5	??26.671	??9.1
??27.662	??9.5	??28.54	??7.9
??30.054	??8.3	??28.54	??7.9
??30.054	??8.3	??31.008	??8.7
??31.909	??5.9	??31.008	??8.7
??31.909	??5.9	??33.752	??6.3

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol-benzene sulfonate form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure has specific peak value near 2 θ=5.6 °, 8.7 °, 16.3 °, 18.2 °, 19.0 °, 20.4 ° and 23.0 °, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol-benzene sulfonate form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=5.6 °, 8.7 °, 9.5 °, 10.3 °, 11.0 °, 11.3 °, 12.9 °, 14.8 °, 15.1 °, 15.4 °, 15.9 °, 16.3 °, 17.3 °, 18.2 °, 19.0 °, 19.6 °, 20.4 °, 20.8 °, 21.1 °, 21.4 °, 22.1 °, 23.0 °, 23.7 °, 24.3 °, 24.6 °, 25.2 °, 26.1 °, 26.7 °, 27.7 °, 28.5 °, 30.1 °, 31.0 °, 31.9 ° and 33.8 ° locate to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol-benzene sulfonate form 1, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure B.

Dsc analysis shows, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 1 begins to melt in the time of 225.38 ℃, reaches peak value in the time of 228.26 ℃.Observe [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] heat of fusion of methyl alcohol-benzene sulfonate form 1 is 64.40J/g.

Embodiment 6.4

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 2

Under nitrogen atmosphere, (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol (2g, 4.08mmol) (1 molar equivalent) and the acetonitrile (20ml) (10rel vol) of in 100ml three neck round-bottomed flasks, packing into.With this soup compound reflux but can't dissolve, therefore add more acetonitrile (10ml) (5rel vol) then, finally be dissolved in this volume.By transfer pipet, in this solution, drip Phenylsulfonic acid (0.645g, 4.08mmol) acetonitrile solution (10ml) (5rel vol) of (1 molar equivalent) then.This moment as do not observe precipitation, then further under refluxing, stir, and then make solution slowly cool to room temperature spend the night.Solid precipitation gets off, and obtains thick soup compound, no longer need firmly stir.It is leached, with MeCN (2x10ml, 2x5rel vol) washing, after blotting with filter paper, in vacuum oven in about 40 ℃ of dryings.

Yield: 2.2g (theoretical value 83.2%) is white solid.

d ₆Among-the DMSO ¹The required product of H-NMR analysis revealed is synthesized out.

Lcms analysis shows that required product purity is 99%.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methyl alcohol-benzene sulfonate form 2 provides basic with the X-ray powder diffraction figure shown in the figure C.The peak value D that sees the following form.

Therefore, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 2 can also provide at least one 2 following θ value to characterize by using the CuKa radiation measurement: 5.58 °, 8.64 °, 15.98 °, 17.26 °, 20.87 °, 23.33 ° and 23.94 °.

Table D

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??5.581	??52.6
??8.645	??100	??5.581	??52.6
??8.645	??100	??9.815	??9.9
??11.074	??8.2	??9.815	??9.9
??11.074	??8.2	??15.988	??21
??16.661	??17	??15.988	??21
??16.661	??17	??17.261	??40.3
??17.675	??13.6	??17.261	??40.3
??17.675	??13.6	??18.614	??15.6
??20.871	??18.8	??18.614	??15.6
??20.871	??18.8	??23.331	??47.7
??23.946	??26.7	??23.331	??47.7
??23.946	??26.7	??25.961	??13.4
??27.748	??9.9	??25.961	??13.4

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol-benzene sulfonate form 2, when using the CuKa radiation measurement, its X-ray powder diffraction figure has specific peak value near 2 θ=5.6 °, 8.6 °, 16.0 °, 17.3 °, 20.9 °, 23.3 ° and 23.9 °, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol-benzene sulfonate form 2, when using the CuKa radiation measurement, its X-ray powder diffraction figure in 2 θ=5.6 °, 8.6 °, 9.8 °, 11.1 °, 16.0 °, 16.7 °, 17.3 °, 17.7 °, 18.6 °, 20.9 °, 23.3 °, 23.9 °, 26.0 ° and 27.7 ° locate to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol-benzene sulfonate form 2, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure C.

Dsc analysis shows, [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 2 begins to melt in the time of 226.12 ℃, reaches peak value in the time of 229.01 ℃.[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] measured value of heat of fusion of methyl alcohol-benzene sulfonate form 2 is 76.55J/g.

Embodiment 6.5

(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methanol toluene sulfonate

Under slightly heated (45 ℃), with tosic acid (441mg, 2.32mmol) be added to slowly with the hot solution of ethyl acetate (5ml) that (((2-(3 for 3-, 5-dimorpholino phenylamino) (methyl) amino pyrimidine-4-yl))-the 4-aminomethyl phenyl) methyl alcohol (1100mg, 2.24mmol) with the stirred solution of ethyl acetate (11ml) in.This solution is stirred down at 20 ℃, when salt precipitates after 30 minutes, the mixture stirring is spent the night.After collecting white solid after filtration,, obtain required tosilate (1.3g) 50 ℃ of following vacuum-dryings 24 hours.Fusing point: 202.2-202.3 ℃.

NMR composes (500MHz, DMSOd ₆) 2.12 (s, 3H), 2.29 (s, 3H), 3.9-3.17 (m, 8H), 3.45 (s, 3H), 3.70-3.77 (m, 8H), 4.51 (s, 2H), 5.30 (bs, 1H), 5.51 (d, 1H), 6.40 (s, 1H), 6.63 (bs, 2H), 7.11 (d, 2H), 7.27 (s, 1H), 7.35 (d, 1H), 7.41 (d, 1H), 7.47 (d, 2H), 7.70 (d, 1H), 10.17 (bs, 1H).

Ultimate analysis: measured value: C, 60.96; H, 6.56; N, 12.43;

C ₂₇H ₃₄N ₆O ₃H ₂O 0.17mol, C ₇H ₈O ₃S 1.02mol, desired value: C, 61.26; H, 6.41; N, 12.54%.

Embodiment 6.6

(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methanol toluene sulfonate form 1

Under slightly heated (45 ℃), with tosic acid (80mg, 0.42mmol) be added to the hot solution of ethyl acetate (1ml) that (((2-(3 for 3-, 5-dimorpholino phenylamino) (methyl) amino pyrimidine-4-yl))-the 4-aminomethyl phenyl) methyl alcohol (200mg, 0.41mmol) with the stirred solution of ethyl acetate (2ml) in.This solution is stirred down at 20 ℃, and salt precipitates after 30 minutes.Mixed crystal was stirred into pasty material in 4 hours.White solid is filtered, after joining ethanol (2ml), the mixture stirring is spent the night, filter, 50 ℃ of following vacuum-dryings 24 hours, obtain (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methanol toluene sulfonate form 1, m=170mg, fusing point: 147.8-149.7 ℃.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methanol toluene sulfonate form 1 provides basic as schemes the X-ray powder diffraction figure as shown in the D.The peak value E that sees the following form.

Table E

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??5.601	??100
??8.338	??65.4	??5.601	??100
??8.338	??65.4	??9.335	??66.3
??10.576	??17.1	??9.335	??66.3
??10.576	??17.1	??11.135	??20
??13.667	??43.8	??11.135	??20
??13.667	??43.8	??15.753	??63.3
??16.71	??75	??15.753	??63.3
??16.71	??75	??17.024	??39.2
??17.532	??30	??17.024	??39.2
??17.532	??30	??18.559	??55.4
??18.788	??44.6	??18.559	??55.4
??18.788	??44.6	??19.228	??32.9
??19.828	??61.3	??19.228	??32.9
??19.828	??61.3	??20.415	??34.2
??21.139	??58.8	??20.415	??34.2
??21.139	??58.8	??22.109	??87.5
??22.367	??55.8	??22.109	??87.5
??22.367	??55.8	??23.193	??74.6
??24.768	??31.7	??23.193	??74.6
??24.768	??31.7	??25.871	??22.9
??26.746	??22.9	??25.871	??22.9
??26.746	??22.9	??27.923	??30.4
??29.877	??20.8	??27.923	??30.4

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methanol toluene sulfonate form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=5.6 °, 8.3 °, 9.3 °, 10.6 °, 11.1 °, 13.7 °, 15.8 °, 16.7 °, 17.0 °, 17.5 °, 18.6 °, 18.8 °, 19.2 °, 19.8 °, 20.4 °, 21.1 °, 22.1 °, 22.4 °, 23.2 °, 24.8 °, 25.9 °, 26.7 °, 27.9 ° and 29.9 ° locate to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methanol toluene sulfonate form 1, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure D.

Embodiment 6.7

(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methanol toluene sulfonate form 2

Under slightly heated (45 ℃), with tosic acid (441mg, 2.32mmol) be added to slowly with the hot solution of ethyl acetate (5ml) that (((2-(3 for 3-, 5-dimorpholino phenylamino) (methyl) amino pyrimidine-4-yl))-the 4-aminomethyl phenyl) methyl alcohol (1100mg, 2.24mmol) with the stirred solution of ethyl acetate (11ml) in.Stirring is after 30 minutes down at 20 ℃ with this solution, and salt precipitates.Mixed crystal is stirred the pulp material that spends the night.White solid is filtered,, obtain (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methanol toluene sulfonate form 2 50 ℃ of following vacuum-dryings 24 hours, m=1.3g, fusing point: 202.2-202.3 ℃.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methanol toluene sulfonate form 2 provides basically as schemes the X-ray powder diffraction figure as shown in the E.The peak value F that sees the following form.

Table F

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??7.141	??59.2
??8.586	??100	??7.141	??59.2
??8.586	??100	??10.163	??28.3
??10.983	??13.6	??10.163	??28.3
??10.983	??13.6	??11.413	??22.7
??13.292	??11.6	??11.413	??22.7
??13.292	??11.6	??14.206	??18.7

??16.125	??26.9
??16.125	??26.9	??17.071	??41.1
??17.58	??33.1	??17.071	??41.1
??17.58	??33.1	??18.931	??24.4
??19.327	??16.1	??18.931	??24.4
??19.327	??16.1	??19.59	??32.3
??19.821	??26.9	??19.59	??32.3
??19.821	??26.9	??20.275	??19
??21.013	??12.5	??20.275	??19
??21.013	??12.5	??21.808	??22.9
??22.306	??34.8	??21.808	??22.9
??22.306	??34.8	??22.54	??26.9
??22.88	??13	??22.54	??26.9
??22.88	??13	??23.807	??16.7
??25.345	??29.2	??23.807	??16.7
??25.345	??29.2	??25.757	??15.3
??26.716	??11	??25.757	??15.3
??26.716	??11	??27.072	??9.3
??29.365	??12.5	??27.072	??9.3
??29.365	??12.5	??29.837	??12.5
??34.58	??10.2	??29.837	??12.5

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methanol toluene sulfonate form 2, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=7.1 °, 8.6 °, 10.2 °, 11.0 °, 11.4 °, 13.3 °, 14.2 °, 16.1 °, 17.1 °, 17.6 °, 18.9 °, 19.3 °, 19.6 °, 19.8 °, 20.3 °, 21.0 °, 21.8 °, 22.3 °, 22.5 °, 22.9 °, 23.8 °, 25.3 °, 25.8 °, 26.7 °, 27.1 °, 29.4 °, 29.8 and 34.6 ° located to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methanol toluene sulfonate form 2, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure E.

Embodiment 6.8

(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol fumarate form 1

The 1ml acetonitrile is added in about 50mg (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol forms solution.About 12.22mg fumaric acid is dissolved in the 1ml acetonitrile.(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol/acetonitrile solution is added in the counter ion solution, the gained mixture heating up is vibrated.Solution precipitates immediately, analyzes after throw out is filtered.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methyl alcohol fumarate form 1 provides basically as schemes the X-ray powder diffraction figure as shown in the F.The peak value G that sees the following form.

Table G

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??6.845	??56.2
??7.211	??75.2	??6.845	??56.2
??7.211	??75.2	??8.837	??30.2
??11.689	??33.4	??8.837	??30.2
??11.689	??33.4	??14.621	??65.9
??15.569	??42.9	??14.621	??65.9
??15.569	??42.9	??16.132	??62.2
??17.176	??55.7	??16.132	??62.2
??17.176	??55.7	??17.723	??49.3
??18.241	??78.6	??17.723	??49.3
??18.241	??78.6	??19.706	??36
??21.126	??57.1	??19.706	??36
??21.126	??57.1	??22.8	??48.4
??24.012	??41.7	??22.8	??48.4
??24.012	??41.7	??24.48	??48.3
??25.928	??40.5	??24.48	??48.3
??25.928	??40.5	??28.735	??100
??29.313	??19.3	??28.735	??100

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol fumarate form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=6.8 °, 7.2 °, 8.8 °, 11.7 °, 14.6 °, 15.6 °, 16.1 °, 17.2 °, 17.7 °, 18.2 °, 19.7 °, 21.1 °, 22.8 °, 24.0 °, 24.5 °, 25.9 °, 28.7 ° and 29.3 ° locate to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol fumarate form 1, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure F.

Embodiment 6.9

(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol fumarate form 2

With about 20mg (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) methyl alcohol fumarate form 1 furnishing soup compound in EtOAc, in MeOH, stir 2 days furnishing soup compounies down equally at 25 ℃.Products therefrom is air-dry and analyze, be shown as form 2 separately.

[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] feature of methyl alcohol fumarate form 2 provides basically as schemes the X-ray powder diffraction figure as shown in the G and characterize.The peak value H that sees the following form.

Table H

Angle 2 θ ° (2 θ)	Intensity %
Angle 2 θ ° (2 θ)	Intensity %	??7.581	??47.8
??7.66	??57.5	??7.581	??47.8
??7.66	??57.5	??10.644	??56.7
??11.083	??71.1	??10.644	??56.7
??11.083	??71.1	??13.23	??57.5
??13.292	??56	??13.23	??57.5
??13.292	??56	??15.007	??79.3
??15.479	??75.9	??15.007	??79.3
??15.479	??75.9	??15.693	??75.6
??16.538	??46.6	??15.693	??75.6
??16.538	??46.6	??17.163	??41.2

??17.822	??65.9
??17.822	??65.9	??17.953	??73.3
??18.399	??100	??17.953	??73.3
??18.399	??100	??19.627	??68.8
??20.535	??40.1	??19.627	??68.8
??20.535	??40.1	??20.763	??48.9
??21.046	??47.4	??20.763	??48.9
??21.046	??47.4	??21.74	??58.2
??22.515	??92	??21.74	??58.2
??22.515	??92	??23.265	??53
??26.215	??44.8	??23.265	??53

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol fumarate form 2, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=7.6 °, 7.7 °, 10.6 °, 11.1 °, 13.2 °, 13.3 °, 15.0 °, 15.5 °, 15.7 °, 16.5 °, 17.2 °, 17.8 °, 18.0 °, 18.4 °, 19.6 °, 20.5 °, 20.8 °, 21.0 °, 21.7 °, 22.5 °, 23.3 ° and 26.2 ° locate to have specific peak value, wherein said more precisely value can be ± 0.5 ° of 2 θ.

Therefore, the invention provides [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] a kind of crystal formation of methyl alcohol fumarate form 2, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure G.

X-ray powder diffraction (XRPD)

The crystalline material sample is put into single silicon wafer (the single silicon crystal of Siemens, SSC) on the wafer (wafer mount), by microslide sample diffusion is become very thin one deck, measure the X-ray powder diffraction figure of the polymorphic form of the free alkali of embodiment 6 and salt.With sample with 30 rev/mins centrifugal (to improve the counting statistics value), adopt Bruker D5000 powder x-ray diffraction meter (Bruker AXS, Banner Lane Coventry CV4 9GH), under 40kV and 40mA, operate elongated copper by wavelength 1.5418 dusts (Angstroms) and assemble the x-ray bombardment sample that pipe (copperlong-fine focus tube) is produced.Behind the divergent slit of the automatic variation of X source by being set to V20 of calibration, reflected radiation detects slit by anti-scatter slit of 2mm and 0.2mm.Press θ-θ pattern, in 2 ° of-40 ° of 2 θ scopes, 0.02 ° of 2 θ of every increase (continuous sweep pattern) just makes sample expose for 1 second.This apparatus preparation the flicker reader as detector.Control and data capture by Dell Optiplex 686 NT 4.0 workstations with the Diffrac+ running software.

(note,, use the BrukerD8 X-ray diffractometer, sample is analyzed for the form 1 and the form 2 of the fumarate of embodiment 6.Press θ-θ pattern, in the scope of 5 ° of-40 ° of 2 θ, make the per 0.0071 ° of θ of sample expose for 0.2 second) by continuous sweep.

The technician is clear, can obtain to have the X-ray powder diffraction figure of one or more measuring error, and this depends on measuring condition (for example employed instrument, specimen preparation or machine).Specifically, generally be appreciated that the intensity of X-ray powder diffraction figure can fluctuate according to measuring condition and specimen preparation.For example, the technician will be appreciated that the relative intensity of peak value for example can be subjected to size to surpass the influence of the crystal grain of about 30 microns and non-single long-width ratio, and this can influence the analysis of sample.The technician it should also be appreciated that reflection position may be subjected to sample to be arranged in the definite height of diffractometer and the influence of diffractometer zero calibration.The sample surfaces Flatness also has the small part influence.Therefore, those skilled in the art should be appreciated that, it is that absolute (relevant more information can be referring to Jenkins, R and Snyder, R.L. ' Introduction to X-Ray Powder Diffractometry ' John Wiley ﹠amp that the diffractogram data that this paper provided shall not be construed as; Sons, 1996).Therefore, should be appreciated that, described crystal formation is not limited to provides X-ray powder diffraction figure and the identical crystal of X-ray powder diffraction figure shown in the figure A-G, provides with any crystal of scheming the essentially identical X-ray powder diffraction figure of the figure of X-ray powder diffraction shown in the A-G all to fall within the scope of the present invention.The X-ray powder diffraction those skilled in the art can judge the essential characteristic (substantial identity) of X-ray powder diffraction figure.

Differential scanning calorimetry (DSC)

With Thermal Analysis Q1000 system log (SYSLOG) DSC.The material that will be no more than 5mg is usually packed into and is equipped with in the aluminum pot of sealing cover, in 25 ℃-325 ℃ temperature range, with the constant rate of heating heating of 10 ℃ of per minutes.Use flow velocity to be 50ml/ minute nitrogen purging gas.

Embodiment 7

Use suitable aniline, repeat method described in the embodiment 6.Thereby obtain following compound.

^aMixture was heated 18 hours in 85 ℃ in oil bath.The cooling back adds 7N methyl alcohol/ammonia.Make solvent vacuum-evaporation.After the solvent evaporation, resistates is injected on the HPLC post (C18,5 microns, diameter 19mm, long 100mm) of preparation HPLC-MS system water and acetonitrile mixture (gradient) wash-out that contains the 2g/l volatile salt.

^bNotice that just compound is by using NaHCO ₃Water law is handled and is separated, and after the DCM extraction, handles (50-100%EtOAc/DCM) with silica gel chromatography.

^c: stirred 2 hours down at 80 ℃.After reaction mixture being concentrated into do, use DCM: methyl alcohol/ammonia 7N (95: 5,10ml) dilute.The gained throw out washs with DCM after removing after filtration.After filtrate is concentrated, with flash chromatography on silica gel method purifying (with the mixture wash-out of 0-5% methyl alcohol gradient/1: 1 ethyl acetate: DCM).

Be prepared as follows 4-(3-amino-5-morpholino phenyl) morpholine-3-ketone as raw material:

With 1-fluoro-3-iodo-5-oil of mirbane (10.486g, 39.27mmol) and morpholine (7.21ml, DMSO 82.48mmol) (28ml) solution stir down at 90 ℃ and spend the night.Reaction mixture is poured in the water (70ml), and throw out is collected after filtration, washes after drying with water, obtains 4-(3-iodo-5-nitrophenyl) morpholine (12.90g, 98%), is yellow solid, need not to be further purified just and can use. Mass spectrum: M+H ⁺335. The NMR spectrum(CDCl ₃): 3.22-3.27 (m, 4H), 3.84-3.89 (m, 4H), 7.46 (dd, 1H), 7.66 (dd, 1H), 7.98 (dd, 1H).

With potassium permanganate (4.26g, 26.94mmol) be added in batches 4-(the 3-iodo-5-nitrophenyl) morpholine that is dissolved in DCM (40ml) (3g, 8.98mmol) and benzyltriethylammoinium chloride (5.93g, 26.04mmol) in.Descend stirring after 1 hour at 25 ℃ the gained soup compound, reflux 4 hours.(2.84g 17.96mmol), stirs reaction mixture 8 hours under refluxing again to add potassium permanganate under 25 ℃ again.Under agitation make reaction mixture be cooled to room temperature, after water (90ml) quencher, under 5 ℃, add in batches S-WAT (18.11g, 143.67mmol).Mixture is after Celite pad filters, and water extracts with DCM, and after the merging organic phase, water, salt water washing concentrate after dried over mgso.Crude product obtains 4-(3-iodo-5-nitrophenyl) morpholine-3-ketone (0.418g, 13.37%) with flash chromatography on silica gel method purifying (with 0-15% ethyl acetate/DCM wash-out), is beige solid. Mass spectrum: M+H ⁺349. NMR composes (DMSOd ₆ ): 3.81-3.87 (m, 2H), 3.96-4.01 (m, 2H), 4.25 (s, 2H), 8.28 (dd, 1H), 8.36 (dd, 1H), 8.39 (dd, 1H).

With 4-(3-iodo-5-nitrophenyl) morpholine-3-ketone (395mg, 1.13mmol), cesium carbonate (1109mg, 3.40mmol), acid chloride (II) (12.74mg, 0.06mmol) and 2,2 '-two (diphenyl phosphine)-1,1 '-(35.3mg is 0.06mmol) with the mixture argon-degassed of toluene (4ml) for dinaphthalene, (0.199ml 2.27mmol) stirred 6 hours under refluxing with morpholine then.Reactant dilutes with DCM, removes insolubles after filtration.Make filtrate concentrating.Crude product flash chromatography on silica gel method purifying (with 0-100% ethyl acetate/DCM wash-out).Make solvent evaporation to doing, obtain 4-(3-morpholino-5-nitrophenyl) morpholine-3-ketone (243mg, 69.7%), be yellow solid. Mass spectrum: M+H ⁺308. The NMR spectrum(CDCl ₃): 3.25-3.29 (m, 4H), 3.79-3.83 (m, 2H), 3.85-3.89 (m, 4H), 4.04-4.09 (m, 2H), 4.36 (s, 2H), 7.28 (dd, 1H), 7.60 (dd, 1H), 7.64 (dd, 1H).

With 4-(3-morpholino-5-nitrophenyl) morpholine-3-ketone (245mg, 0.80mmol) and Adam's Si platinum oxide (ADAMS ' platinum oxide) (18.10mg, ethyl acetate 0.08mmol) (2ml) and ethanol (2ml) solution hydrogenation 1 hour under room temperature, 55psi.Gained solution is after Celite pad filters, and it is dried that filtrate is concentrated into, and obtains crude product 4-(3-amino-5-morpholino phenyl) morpholine-3-ketone (235mg, 106%), is the canescence foam. Mass spectrum: M+H ⁺278. NMR Spectrum(CDCl ₃): 3.10-3.16 (m, 4H), 3.67-3.72 (m, 2H), 3.73 (bs, 2H), 3.80-3.85 (m, 4H), 3.97-4.02 (m, 2H), 4.31 (s, 2H), 6.15 (dd, 1H), 6.16 (dd, 1H), 6.26 (dd, 1H).

^d: the method that is adopted is similar to method described in the note (c).Be prepared as follows (S)-3-(3-methylmorpholine generation)-5-morpholino aniline as raw material:

With 4-(3-iodo-5-nitrophenyl) morpholine (670mg, 2.01mmol), (S)-3-methylmorpholine (406mg, 4.01mmol), cesium carbonate (1960mg, 6.02mmol), acid chloride (II) (22.51mg, 0.10mmol) and 2,2 '-two (diphenyl phosphine)-1,1 '-(62.4mg, 0.10mmol) mixture with toluene (6ml) stirred 5 hours under refluxing dinaphthalene.Reactant dilutes with DCM, removes insolubles after filtration.Make filtrate concentrating.Crude product flash chromatography on silica gel method purifying (with 0-5% ethyl acetate/DCM wash-out).Make solvent evaporation to doing, obtain (S)-3-methyl-4-(3-morpholino-5-nitrophenyl) morpholine (350mg, 53.9%), be the deep yellow solid.It contains 5mol%4,4 '-(5,5 '-dinitrobenzene biphenyl-3,3 '-two bases) dimorpholine. Mass spectrum: M+H ⁺308. The NMR spectrum(CDCl ₃): 1.14 (d, 3H), 3.15 (ddd, 1H), 3.18-3.25 (m, 5H), 3.69 (ddd, 1H), 3.76 (d, 1H), 3.79-3.90 (m, 6H), 4.02 (ddd, 1H), 6.60 (dd, 1H), 7.22-7.25 (m, 2H).

The reduction of nitro functions is carried out according to method described in the note (c).Crude product flash chromatography on silica gel method purifying (with DCM/ ethyl acetate (1/1) eluant solution of 0-5% methyl alcohol).Make solvent evaporation to doing, obtain (S)-3-(3-methylmorpholine generation)-5-morpholino aniline (250mg, 70.6%), be white foam shape thing. Mass spectrum: M+H ⁺278. The NMR spectrum(CDCl ₃): 1.07 (s, 3H), 3.03 (ddd, 1H), 3.07-3.19 (m, 5H), 3.58 (bs, 2H), 3.61-3.74 (m, 3H), 3.79-3.86 (m, 5H), 3.93 (ddd, 1H), 5.84 (bs, 2H), 5.92 (bs, 1H).

^e: use the S enantiomer of the R enantiomer replacement 3-methylmorpholine of 3-methylmorpholine, adopt to be similar to the preparation of method described in the embodiment 7.17.The R enantiomer prepares in accordance with the following methods: Bettoni, G.; Franchini, C.; Perrone, R. and TortorellaTetrahedron 1980,36,409.The S enantiomer is commercially available.

^f: with ((((3-morpholino-5-(1 for 2-for methyl for 4-methyl-3-, 4-two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-yl) methyl alcohol (166mg phenyl amino pyrimidine-4-yl phenylamino)))), 0.30mmol) and tosic acid (63.5mg, water 0.33mmol) (0.750ml) and acetone (1ml) solution stirred 12 hours down at 70 ℃.Make reaction mixture be cooled to room temperature, water (5ml) quencher is with saturated aqueous solution of sodium bicarbonate (5ml) alkalization.The gained throw out is collected after filtration, washes after drying with water, obtains crude product, and it is used flash chromatography on silica gel method purifying (with DCM/ ethyl acetate (1/1) eluant solution of 0-5% methyl alcohol).Make solvent evaporation to doing, obtain product, be jelly, it is further purified with preparation HPLC, adopts Waters X-Terra reversed-phase column (5 microns in silica gel, diameter 30mm, long 150mm), the water (containing 0.2% volatile salt) that successively decreases of polarity and the mixture of acetonitrile are elutriant.Flow point is evaporated to dried, obtains 1-(3-(4-((5-(methylol)-2-aminomethyl phenyl) (methyl) amino) pyrimidine-2--amino)-5-morpholino phenyl) piperidin-4-one-(50mg, 0.10mmol, 32.8%), be pale solid.

Be prepared as follows (4-methyl-3-(methyl (2-(3-morpholino-5-(1,4-two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-yl) phenylamino) pyrimidine-4-yl) amino) phenyl) methyl alcohol as raw material:

Described in note (c), make 4-(3-iodo-5-nitrophenyl) morpholine (600mg, 1.80mmol), 1,4-two oxa-s-8-azaspiro [4.5] decane (0.460ml, 3.59mmol) mixture react, just refluxing only kept 5 hours, and used toluene to replace DMSO.After under agitation making reaction mixture be cooled to room temperature, add DCM.After insolubles is removed after filtration, make filtrate concentrating.Crude product flash chromatography on silica gel method purifying (with 0-10% ethyl acetate/DCM wash-out).Make solvent evaporation, obtain 8-(3-morpholino-5-nitrophenyl)-1,4-two oxa-s-8-azaspiro [4.5] decane (404mg, 64.4%) are the deep yellow jelly. Mass spectrum: M+H ⁺349. NMR Spectrum(CDCl ₃): 1.81-1.86 (m, 4H), 3.18-3.24 (m, 4H), 3.37-3.42 (m, 4H), 3.84-3.89 (m, 4H), 4.00 (s, 4H), 6.67 (dd, 1H), 7.21 (dd, 1H), 7.29 (dd, 1H).

^g: described in note (c), make 8-(3-morpholino-5-nitrophenyl)-1,4-two oxa-s-8-azaspiro [4.5] decane (260mg, 0.74mmol) hydrogenation.Crude product flash chromatography on silica gel method purifying (with 0-5% methyl alcohol/DCM wash-out).Make solvent evaporation to doing.Foam grinds after crystallization with EtOAc, and solid is collected after filtration, with the ether washing, obtains 3-morpholino-5-(1,4-two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-yl) aniline (230mg, 97%). Mass spectrum: M+H ⁺320. The NMR spectrum(CDCl ₃): 1.78-1.87 (m, 4H), 3.07-3.15 (m, 4H), 3.23-3.31 (m, 4H), 3.57 (bs, 2H), 3.79-3.87 (m, 4H), 3.98 (s, 4H), 5.81 (s, 1H), 5.88 (s, 1H), 5.97 (s, 1H).

Carry out coupled reaction with being similar to condition described in the note (c) (embodiment 7.16), just in 6 hours, keep heating. Mass spectrum: M+H ⁺547. The NMR spectrum(CDCl ₃): 1.64-1.74 (m, 4H), 2.08 (s, 3H), 3.06 (m, 4H), 3.23 (m, 4H), 3.37 (s, 3H), 3.67-3.75 (m, 4H), 3.90 (s, 4H), 4.49 (d, 2H), 5.22 (t, 1H), 5.25 (bs, 1H), 6.11 (s, 1H), 7.00 (s, 1H), 7.04 (s, 1H), 7.18 (s, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.77 (bs, 1H), 8.81 (s, 1H).

Embodiment 8

Use corresponding chloropyrimide (method 3,100mg, 0.33mmol) and aniline (method 11 0.33mmol), repeats the method for embodiment 6, obtains following compounds.

Embodiment 9

N-(3,5-dimorpholine-4-base phenyl)-N '-(3-p-methoxy-phenyl)-N '-methyl-pyrimidine-2, the 4-diamines

(0.19mmol) (25 μ l 0.22mmol) mix in 2-amylalcohol (1ml) pyrimidine-2-amine with N-methyl m-anisidine for method 21,70mg with 4-chloro-N-(3,5-dimorpholine-4-base phenyl).Add 4M HCl De dioxane solution (100 μ l), mixture was heated 15 hours down at 100 ℃.After the solvent removed in vacuo, resistates is dissolved in DMF (1ml) after, with preparation HPLC-MS system purifying (post: C18,5 microns, diameter 19mm, long 100mm, water carries out gradient elution with the acetonitrile that contains the 2g/l volatile salt).The flow point of collecting obtains title compound (62mg, yield 68%) after evaporation; NMR composes (500MHz, DMSOd ₆) 3.04-3.06 (m, 8H), 3.44 (s, 3H), 3.71-3.73 (m, 8H), 3.77 (s, 3H), 5.78 (d, 1H), 6.11 (s, 1H), 6.91 (s, 1H), 6.93 (s, 2H), 6.99 (s, 2H), 7.38 (t, 1H), 7.85 (d, 1H), 8.85 (s, 1H).Mass spectrum: MH ⁺477.

Embodiment 10

Use suitable aniline, repeat method described in the embodiment 9.Thereby obtain following compound.

^aUse the 2-propyl alcohol as solvent.

^bWith reaction mixture at Personal Chemistry EMRYS ^TMIn the Optimizer EXP microwave synthesizer in 120 ℃ the heating 15 minutes, except as otherwise noted.

^cFor initial aniline referring to method 22.

^dMixture was heated 30 minutes down at 120 ℃.

^eMixture is following 45 minutes at 140 ℃.

^fMixture was heated 20 minutes down at 150 ℃.

^gMixture was heated 90 minutes down at 150 ℃.

^hMixture was heated 45 minutes down at 150 ℃.

ⁱBe reflected under the level of 0.45mmol and carry out (for the preparation of initial aniline referring to method 22).Mixture was heated 2 hours in 120 ℃ in oil bath.Make solvent evaporation after the cooling, resistates is dissolved in DCM (10ml), and add 7N methyl alcohol/ammonia (1ml).After the filtration, filtrate is concentrated, (behind 2% methyl alcohol/DCM), grind with ether/pentane with the silica gel chromatography purifying.

^jSame i is just with reactant heating 18 hours.

^kWith reactant in Virahol (20ml)-DMA (5ml) in 120 ℃ the heating 11 hours, then at PersonalChemistry EMRYS ^TMHeated 30 minutes in 140 ℃ in the Optimizer EXP microwave synthesizer.

Be prepared as follows 1-(4-methyl-3-(methylamino) phenyl) ethanol as raw material:

At room temperature, successively with imidazoles (3.16g, 46.36mmol) and TERT-BUTYL DIMETHYL CHLORO SILANE (3.97ml, 23.18mmol) disposable be added to 1-(4-methyl-3-nitro phenyl) ethanol (2.1g, 11.59mmol) with the stirred solution of DMF (10ml) in.Gained solution was at room temperature stirred 2 hours.It is dried that reaction mixture is concentrated into, and with methyl alcohol (5ml) quencher, with the ether dilution, water (2x15ml), salt solution (15ml) washing concentrate after dried over mgso, obtain crude product, are oily matter.Crude product flash chromatography on silica gel method purifying (with 0%-10% DCM/ sherwood oil wash-out).Make solvent evaporation to doing, obtain tertiary butyl dimethyl (1-(4-methyl-3-nitro phenyl) oxyethyl group) silane (3.15g, 92%), be light brown oily matter.

Make tertiary butyl dimethyl (1-(4-methyl-3-nitro phenyl) oxyethyl group) silane (3.15g, 10.66mmol) and platinum oxide (IV) (310mg, ethanol 1.37mmol) (30ml) solution hydrogenation 90 minutes under 1 hydrogen-pressure, room temperature.Gained solution is filtered, and it is dried that filtrate is concentrated into, and obtains crude product 5-(1-(t-butyldimethylsilyl oxygen base) ethyl)-2-aminotoluene (2.67g, 94%), is light brown oily matter.

With 5-(1-(t-butyldimethylsilyl oxygen base) ethyl)-2-aminotoluene (2.5g, 9.42mmol) and tert-Butyl dicarbonate (2.60ml, acetonitrile solution 11.30mmol) (5ml) at room temperature stirred 18 hours.After reaction mixture being concentrated into do, crude product is with flash chromatography on silica gel method purifying (using the DCM wash-out).Make solvent evaporation to doing, obtain 5-(1-(t-butyldimethylsilyl oxygen base) ethyl)-2-aminomethyl phenyl t-butyl carbamate (3.40g, 99%), be white solid.

Under argon atmospher, 0 ℃, with the 60% (0.263g of the sodium hydride in the oil, 6.56mmol) (1-(t-butyldimethylsilyl oxygen base) ethyl)-(2g is in stirred solution 5.47mmol) for 2-aminomethyl phenyl t-butyl carbamate to be added to the 5-that is dissolved in DMF (30ml).Gained solution was at room temperature stirred 90 minutes.With methyl-iodide (0.409ml, 6.56mmol) disposable being added in the mixture.The gained mixture was at room temperature stirred 5 hours.Reaction mixture ammonium chloride saturated aqueous solution quencher, water (150ml) dilutes, and extracts with ether (2x40ml).The organic phase water that merges, saturated brine solution washing concentrate after dried over mgso.Crude product flash chromatography on silica gel method purifying (with 40-100%DCM/ sherwood oil wash-out).Make solvent evaporation to doing, obtain 5-(1-(t-butyldimethylsilyl oxygen base) ethyl)-2-aminomethyl phenyl (methyl) t-butyl carbamate (1.6g, 77%), be colorless oil.

(6.45ml, (1-(t-butyldimethylsilyl oxygen base) ethyl)-(1.4g is in stirred solution 3.69mmol) for 2-aminomethyl phenyl (methyl) t-butyl carbamate 12.9mmol) to be added to the 5-that is dissolved in methyl alcohol (15ml) with the 2N aqueous hydrochloric acid.Gained solution was stirred 60 minutes down at 50 ℃.Vacuum is removed organic solvent, and aqueous residue neutralizes with the 4N aqueous sodium hydroxide solution.Mixture extracts with ethyl acetate (3x15ml).The organic phase salt water washing that merges concentrates after dried over mgso.Resistates flash chromatography on silica gel method purifying (with 0-4% methyl alcohol/DCM wash-out).Make solvent evaporation to doing, obtain 1-(4-methyl-3-(methylamino) phenyl) ethanol (0.595g, 98%), be colorless oil. Mass spectrum: MH ⁺166.

Embodiment 11

N '-(4-chloro-phenyl-)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines

In pressurized vessel, pack into 4-chloro-N-(3,5-dimorpholine-4-base phenyl) pyrimidine-2-amine (method 21,500mg, 1.3mmol) and the methanol solution of 10ml 6N methylamine.Reaction mixture is made the gained solution evaporation in heating under 140 ℃ after 20 hours.Resistates obtains N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2,4-diamines (370mg, 75%, white solid) with silica gel purification (5%MeOH/DCM).NMR composes (500MHz, CDCl ₃) 2.97 (d, 3H), 3.15-3.17 (m, 8H), 3.84-3.86 (m, 8H), 4.80 (bs, 1H), 5.85 (d, 1H), 6.15 (s, 1H), 6.83 (s, 2H), 7.10 (bs, 1H), 7.90 (bs, 1H).Mass spectrum: MH ⁺371.

Under nitrogen atmosphere, in the dry toluene of 3ml with the nitrogen degassing, with N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines (37mg, 0.10mmol), 4-chloro-bromobenzene (57mg, 0.30mmol), salt of wormwood (276mg, 2.0mmol), Pd ₂Dba ₃(3mg, 0.005mmol) and Xantphos (6mg 0.01mmol) mixes.Reaction mixture 120 ℃ of down heating 20 hours, is filtered then and evaporates.Resistates preparation HPLC-MS system purifying (post: C18,5 microns, diameter 19mm, long 100mm, water carries out gradient elution with the acetonitrile that contains the 2g/l volatile salt), obtain 10mg (yield 21%) title compound.NMR spectrum (500MHz, DMSO) 3.01-3.03 (m, 8H), 3.42 (s, 3H), 3.70-3.72 (m, 8H), 5.81 (d, 1H), 6.10 (s, 1H), 6.94 (s, 2H), 7.39 (d, 2H), 7.51 (d, 2H), 7.89 (d, 2H), 8.86 (s, 1H).Mass spectrum: MH ⁺481.

Embodiment 12

Method prepares following compounds described in the employing embodiment 6.

Note:

(a): (280mg, 0.47mmol) solution with DCM (3ml) and HCl/ Virahol 7N (1ml) stirred 2 hours down at 25 ℃ with 4-(3-(4-((5-methoxyl group-2-aminomethyl phenyl) (methyl) amino) pyrimidine-2--amino)-5-morpholino phenyl) piperazine-1-t-butyl formate.Mixture is dissolved in DMF and NH after evaporation ₄The OH aqueous solution (0.5ml) is used preparation HPLC purifying (using wherein, acetonitrile and ammonium carbonate solution are the reversed-phase column of elutriant) then.The flow point that will contain required compound is evaporated to dried.The gained foam grinds with ether and pentane.The gained solid is dry under 50 ℃, obtain N4-(5-methoxyl group-2-aminomethyl phenyl)-N4-methyl-N2-(3-morpholino-5-(piperazine-1-yl) phenyl) pyrimidine-2,4-diamines (105mg, 45.2%) is beige solid. The NMR spectrum (DMSOd ₆ ): 2.01 (s, 3H), 2.57 (bs, 1H), 2.77-2.83 (m, 4H), 3.00 (bs, 4H), 3.05 (bs, 4H), 3.37 (s, 3H), 3.68-3.74 (m, 4H), 3.74 (s, 3H), 5.29 (bs, 1H), 6.07 (s, 1H), 6.85 (d, 1H), 6.91 (dd, 1H), 6.98 (bs, 1H), 7.01 (bs, 1H), 7.28 (d, 1H), 7.79 (bs, 1H), 8.80 (bs, 1H).

4-above (3-(4-((5-methoxyl group-2-aminomethyl phenyl) (methyl) amino) pyrimidine-2--amino)-5-morpholino phenyl) piperazine-1-t-butyl formate is prepared as follows:

To be dissolved in 4-(the 3-iodo-5-nitrophenyl) morpholine (1g of toluene (25ml), 2.99mmol), piperazine-1-t-butyl formate (1.115g, 5.99mmol), cesium carbonate (4.88g, 14.97mmol), acid chloride (II) (0.067g, 0.30mmol) and 2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene (0.093g, 0.15mmol) mixture with after the nitrogen degassing, reflux 2 hours.After reaction is finished, cooling at room temperature, suspension dilutes with DCM (20ml).Insolubles is filtered.It is dried that filtrate is concentrated into, and obtains orange solids, it is dissolved in DCM after, with flash chromatography on silica gel method purifying (with DCM and 3%AcOEt/DCM wash-out).Make solvent evaporation to doing, obtain 4-(3-morpholino-5-nitrophenyl) piperazine-1-t-butyl formate (0.920g, 78%), be orange solids. Mass spectrum: [M-H] ^-392.

The NMR spectrum(CDCl ₃): 1.49 (s, 9H), (m, 8H), (m, 4H), (m, 4H), 6.65 (dd, 1H), (m is by CHCl for 7.25-7.27 for 3.84-3.90 for 3.56-3.63 for 3.17-3.26 ₃The peak part is sheltered, 2H).

Make 4-(3-morpholino-5-nitrophenyl) piperazine-1-t-butyl formate (870mg, 2.22mmol), (50.3mg, EtOH 0.22mmol) (30ml) the suspension hydrogenation 2 hours 30 minutes under 1100 millibars of Adam's Si platinum oxide.Form white depositions.Gained suspension is dissolved with AcOEt.After catalyzer filtered, it is dried that filtrate is concentrated into, and obtains crude product 4-(3-amino-5-morpholino phenyl) piperazine-1-t-butyl formate (783mg, 97%), is beige solid. Mass spectrum: M+H ⁺363. The NMR spectrum(CDCl ₃): 1.48 (s, 9H), 3.02-3.16 (m3.50-3.58 (m, 4H), 3.60 (bs, 2H), 3.78-3.87 (m, 4H), 5.83-5.87 (m, 2H), 5.94 (dd, 1H).

With 2-chloro-N-(5-methoxyl group-2-aminomethyl phenyl)-N-methylpyrimidine-4-amine (180mg, 0.68mmol), 4-(3-amino-5-morpholino phenyl) piperazine-1-t-butyl formate (260mg, 0.72mmol) and HCl/ diox 4N (5.97 μ l, 2-amylalcohol (2ml) suspension 0.02mmol) stirred 1 hour 30 minutes down at 120 ℃.It is dried that mixture is concentrated into, with DCM (10ml) and 5N NH ₃Methanol solution (2ml) dilution.Insolubles is filtered, after filtrate being concentrated into do, be dissolved in DCM, with flash chromatography on silica gel method purifying (using the 40%AcOEt/DCM wash-out), obtain 4-(3-(4-((5-methoxyl group-2-aminomethyl phenyl) (methyl) amino) pyrimidine-2--amino)-5-morpholino phenyl) piperazine-1-t-butyl formate (280mg, 69.6%), is foam. Mass spectrum: M+H ⁺590.

^bStirred 2 hours down at 80 ℃.After reaction mixture being concentrated into do, use DCM: methyl alcohol/ammonia 7N (95: 5,10ml) dilute.The gained throw out washs with DCM after removing after filtration.Filtrate is concentrated, be dissolved in DCM after, with flash chromatography on silica gel method purifying (with 0-5% methyl alcohol/DCM wash-out). The NMR spectrum(DMSOd ₆Under 323 ° of K): 2.01 (s, 3H), 3.05-3.13 (m, 4H), 3.34 (s, 3H), 3.65 (bs, 2H), 3.70-3.77 (m, 4H), 3.76 (s, 3H), 3.92-3.97 (m, 2H), 4.16 (s, 2H), 5.42 (bs, 1H), 6.50 (s, 1H), 6.82 (d, 1H), 6.90 (dd, 1H), 7.27 (d, 1H), 7.30 (bs, 1H), 7.32 (bs, 1H), 7.82 (d, 1H), 8.89 (s, 1H).

^c: prepare according to method described in 7.17 synthesis methods.

Embodiment 13

Adopt method described in the embodiment 6, just be reflected in the 2-amylalcohol in 120 ℃ and carried out 1 hour, prepare following compounds.Crude product preparation HPLC-MS system purifying (post: C18,5 microns, diameter 19mm, long 100mm, water carries out gradient elution with the acetonitrile that contains the 2g/l volatile salt).

Embodiment 14

N '-(2, the 3-difluorophenyl)-N-(3,5-dimorpholine-4-base phenyl)-N '-methyl-pyrimidine-2, the 4-diamines

With 4-chloro-N-(3,5-dimorpholine-4-base phenyl)-and the N-[(4-p-methoxy-phenyl) methyl] pyrimidine-2-amine (120mg, 0.24mmol, method 25), 2, the mixture of 3-difluoroaniline (0.27mmol) and 4M hydrogenchloride/diox (0.11ml) and 2-amylalcohol (1.5ml) in sealed tube in 120 ℃ of heating 3 hours.After the cooling, make solvent evaporation to doing.Resistates is dissolved in DCM (3ml).Add 7N methyl alcohol/ammonia (0.3ml).After insolubles is removed after filtration, make the gained solution evaporation to doing.

Resistates is dissolved in DMF (0.5ml).DMF (1ml) slurries that add sodium hydride (20mg) after 1 hour, add the DMF solution (500 μ l) of methyl-iodide (10 μ l) with the mixture stirring.With the gained mixture at room temperature stir be evaporated to after 24 hours dried.Resistates is dissolved in trifluoroacetic acid (1ml) and phenylmethylether (3).Mixture was at room temperature stirred 24 hours.It is dried that mixture is evaporated to, and slowly adds 7N methyl alcohol/ammonia (1ml), after insolubles is removed after filtration, makes the gained solution evaporation to doing.Mixture is directly injected in the HPLC post (C18,5 microns, diameter 19mm, long 100mm) of preparation HPLC-MS system, water and the acetonitrile mixture wash-out (gradient) that contains the 2g/l volatile salt obtain title compound (46mg).

The NMR spectrum: (DMSOd ₆) 2.97-3.08 (m, 8H), 3.41 (s, 3H), 3.67-3.75 (m, 8H), 5.82 (d, 1H), 6.11 (t, 1H), 6.93 (d, 2H), 7.31-7.37 (m, 2H), 7.47 (ddd, 1H), 7.97 (d, 1H), 8.90 (s, 1H); Mass spectrum: MH ⁺483.

Embodiment 15

Use suitable aniline, repeat method described in the embodiment 14, thereby obtain following compound.

^aBe reflected under the level of 200mg and carry out.Deprotection steps with TFA was carried out under 130 ℃ 15 minutes.

Embodiment 16

[3-[[2-[(3-oxyethyl group-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol

With triphenyl phosphine (414mg, 1.58mmol) and DEAD (0.246ml 1.58mmol) at room temperature stirred 1 hour with the mixture of THF (3ml).Make mixture then after cooling under 0 ℃, and adding ethanol (92 μ l, 1.58mmol).After at room temperature stirring 30 minutes, add [3-[[2-[ethanoyl-(3-hydroxyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl acetate (200mg), at room temperature stirred mixture 2 hours.Water is added in the mixture, makes THF vacuum-evaporation.The gained mixture extracts with DCM.After making organic layer vacuum-evaporation, with silica gel chromatography purifying (elutriant: 0-100%EtOAc/DCM), obtain white foam shape thing (144mg).This solid is dissolved in methyl alcohol (4ml)-water (4ml), and adding sodium hydroxide (108mg, 2.7mmol).Mixture was at room temperature stirred 24 hours.After making solvent vacuum-evaporation, mixture dilutes with sodium bicarbonate aqueous solution, and extracts with DCM.After making organic layer vacuum-evaporation, with silica gel chromatography purifying (elutriant: 0-100%EtOAc/DCM), obtain title compound (100mg, 56%, white foam shape thing).

The NMR spectrum: (DMSOd ₆) 1.30 (t, 3H), 2.08 (s, 3H), 3.06 (bs, 4H), 3.37 (s, 3H), 3.67-3.77 (m, 4H), 3.77 (bs, 2H), 4.49 (d, 2H), 5.22 (t, 1H), 5.27 (bs, 1H), 6.06 (s, 1H), 7.02 (s, 2H), 7.18 (s, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.79 (d, 1H), 8.96 (s, 1H); Mass spectrum: 450MH ⁺

[3-[[2-[ethanoyl-(3-hydroxyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl acetate is prepared as follows:

The mixture of 4-(3-methoxyl group-5-nitro-phenyl) morpholine (5.52g, 21.8mmol, method 8) with 48% hydrobromic acid aqueous solution (91ml) heated 12 hours down at 130 ℃.After the cooling,, slowly add ammoniacal liquor making mixture simultaneously at 0 ℃ of refrigerative.It is dried that mixture is concentrated into.Resistates grinds with EtOAc, through the dried over mgso after-filtration.After the filtrate evaporation, handle (elutriant: 0%-30%EtOAc/DCM), obtain 3-morpholine-4-base-5-nitro-phenol (3.76g, 77%), be yellow solid with silica gel chromatography. The NMR spectrum: (DMSOd ₆) 3.17 (m, 4H), 3.72 (m, 4H), 6.71 (s, 1H), 7.01 (s, 1H), 7.19 (s, 1H); Mass spectrum: MH ⁺225.

With 3-morpholine-4-base-5-nitro-phenol (3.76g, 16.8mmol), bromotoluene (2.19ml, 18.4mmol) and cesium carbonate (6.55g, 20.1mmol) with the mixture of DMF (40ml) 90 ℃ of heating 2 hours down.After the cooling, the mixture dilute with water.Formed throw out is filtered, wash after drying with water, (5.32g quantitatively), is yellow solid to obtain 4-(3-nitro-5-phenyl methoxyl group-phenyl) morpholine. The NMR spectrum: (DMSOd ₆) 3.23 (m, 4H), 3.73 (m, 4H), 5.21 (s, 2H), 6.99 (s, 1H), 7.24 (s, 1H), 7.48-7.33 (m, 6H); Mass spectrum: MH ⁺315.

Make 4-(3-nitro-5-phenyl methoxyl group-phenyl) morpholine (5g, 15.9mmol), platinum oxide (IV) (500mg), the hydrogenation 3 hours under 50PSI, room temperature of the mixture of salt of wormwood (830mg) and EtOAc (70ml)-ethanol (70ml).Behind the solid filtering, evaporating solvent obtains 3-morpholine-4-base-5-phenyl methoxyl group-aniline (4.49g, 99%), is light brown jelly. The NMR spectrum: (DMSOd ₆) 2.98 (m, 4H), 3.68 (m, 4H), 4.96-4.90 (m, 4H), 5.76 (s, 2H), 5.80 (s, 1H), 7.42-7.28 (m, 5H); Mass spectrum: MH ⁺285.

According to method described in the embodiment 1, make 3-morpholine-4-base-5-phenyl methoxyl group-aniline (4.12g, 14.5mmol) and [3-[(2-chloropyrimide-4-yl)-methyl-amino]-4-methyl-phenyl] methyl alcohol (3.43g, 13mmol, method 2) reacts, obtain [4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-phenyl methoxyl group-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol (5.96g, 80%), be white foam shape thing. Mass spectrum: MH ⁺512.

Will [4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-phenyl methoxyl group-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol (2.15g, 4.20mmol) and pyridine (0.75ml, solution of acetic anhydride 9.25mmol) (9.32ml) is 70 ℃ of down heating 2 hours.After the solvent evaporation, add saturated aqueous solution of sodium bicarbonate.Mixture extracts with EtOAc.After the organic layer evaporation; resistates silica gel chromatography purifying (elutriant: EtOAc); obtain [3-[[2-[ethanoyl-(3-morpholine-4-base-5-phenyl methoxyl group-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl acetate (2.23g, 89%). Mass spectrum: MH ⁺596.

At 10% palladium charcoal (400mg) when existing; make [3-[[2-[ethanoyl-(3-morpholine-4-base-5-phenyl methoxyl group-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] (1.1g is 1.85mmol) with the hydrogenation 3 hours under 50PSI, room temperature of the mixture of ethanol (15ml)-EtOAc (15ml)-DMF (8) for methyl acetate.Behind the solid filtering; it is dried that mixture is concentrated into; with silica gel chromatography purifying (elutriant: 0-3% methyl alcohol/EtOAc); obtain [3-[[2-[ethanoyl-(3-hydroxyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl acetate (636mg; 68%), is white foam shape thing. The NMR spectrum: (DMSOd ₆) 2.06 (s, 3H), 2.07 (s, 3H), 2.24 (s, 3H), 2.97-3.08 (m, 4H), 3.29 (s, 3H), 3.64-3.75 (m, 4H), 5.06 (s, 2H), 5.67 (s, 1H), 6.12 (s, 1H), 6.25 (s, 1H), 6.29 (s, 1H), 7.30 (s, 1H), 7.34 (d, 1H), 7.42 (d, 1H), 7.99 (s, 1H), 9.33 (s, 1H); Mass spectrum: MH ⁺506.

Embodiment 17

According to method described in the embodiment 16; make [3-[[2-[ethanoyl-(3-hydroxyl-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl acetate and corresponding alcohol reacts; obtain following compounds; the triphenyl phosphine (3mmol/g) that only is to use polymkeric substance to support; the first step is not carried out purifying; after deprotection steps; compound is injected the HPLC post (C18 of preparation HPLC-MS system; 5 microns; diameter 19mm; long 100mm) in, water and the acetonitrile mixture wash-out (gradient) that contains the 2g/l volatile salt.

Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum
Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum	??17.1	[4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-propoxy--phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol	??Pr	??464	??0.96(t，3H)，1.75-1.76(m，??2H)，2.08(s，3H)，3.06(bs，??4H)，3.37(s，3H)，3.68-3.75??(m，4H)，3.87(bs，2H)，4.49??(d，2H)，5.22(t，1H)，5.27??(bs，1H)，6.07(s，1H)，7.06??(s，1H)，7.10(s，1H)，7.18(s，??1H)，7.26(d，1H)，7.34(d，??1H)，7.79(s，1H)，8.96(s，??1H)
??17.2	[4-methyl-3-[methyl-[and 2-[(3-morpholine-4-base-5-third-2-base oxygen base-phenyl) amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol	??iPr	??464	??1.25(d，6H)，2.08(s，3H)，??3.05(bs，4H)，3.37(s，3H)，??3.67-3.75(m，4H)，4.49(d，??2H)，4.52(bs，1H)，5.22(t，??1H)，5.27(bs，1H)，6.04(s，??1H)，7.02(bs，1H)，7.09(bs，??1H)，7.18(s，1H)，7.26(d，??1H)，7.34(d，1H)，7.79(bs，??1H)，8.94(bs，1H)	??17.1		??Pr	??464

Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum
Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum	??17.3	[4-methyl-3-[methyl-[2-[[3-(2-methyl propoxy-)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl] amino] phenyl] methyl alcohol	??iBu	??478	0.97 (s, 6H), (m, 1H), 2.09 (s, 3H), 3.07 (bs, 4H), 3.38 (s is by H for 1.95-2.05 ₂O peak part is sheltered, 3H), 3.66-3.77 (m, 6H), 4.50 (d, 2H), 5.23 (t, 1H), 5.28 (bs, 1H), 6.08 (s, 1H), 7.03 (bs, 1H), 7.15 (bs, 1H), 7.19 (s, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.80 (bs, 1H), 8.96 (bs, 1H)
??17.4	[3-[[2-[[3-(cyclo propyl methoxy)-5-morpholine-4-base-phenyl] amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol	??CH ₂cPr	??476	0.23-0.36 (m, 2H), (m, 2H), (m, 1H), 2.02 (s, 3H), 3.07 (bs, 4H), 3.38 (s is by H for 1.15-1.27 for 0.50-0.62 ₂O peak part is sheltered, 3H), 3.72 (bs, 4H), 3.77 (d, 2H), 4.50 (d, 2H), 5.23 (t, 1H), 5.28 (bs, 1H), 6.08 (s, 1H), 7.06 (bs, 1H), 7.09 (bs, 1H), 7.19 (s, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.80 (bs, 1H), 8.96 (bs, 1H)	??17.3		??iBu	??478
??17.4		??CH ₂cPr	??476		??17.5	[3-[[2-[(3-cyclobutyl oxygen base-5-morpholine-4-base-phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol	??cBu	??476	(DMSOd6 is under 323 ° of K) 1.59-1.70 (m, 1H), 1.75-1.84 (m, 1H), 1.98-2.12 (m, 2H), 2.10 (s, 3H), 2.39-2.48 (m, 2H), 3.03-3.12 (m, 4H), 3.38 (s, 3H), 3.70-3.77 (m, 4H), 4.51 (d, 2H), 4.57-4.67 (m, 1H), 5.09 (bs, 1H), 5.36 (bs, 1H), 5.78 (s, 1H), 6.89 (s, 1H), 7.10 (bs, 1H), 7.19 (s, 1H), 7.27 (d, 1H), 7.34 (d, 1H), 7.82 (d, 1H), 8.76 (bs, 1H)

Embodiment 18

With 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenylformic acid (120mg, 0.27mmol), corresponding amine (1.07mmol), diisopropylethylamine (61 μ l, 0.35mmol) and TBTU (112mg 0.35mmol) stirred 18 hours down at 30 ℃ with the mixture of DMF (1.5ml).After the solvent evaporation, resistates is directly injected in the HPLC post (C18,5 microns, diameter 21mm, long 100mm) of preparation HPLC-MS system, water and the acetonitrile mixture wash-out (gradient) that contains the 2g/l volatile salt obtain corresponding amide after the solvent evaporation.

Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum
Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum	??18.4	N-ethyl-3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N-methyl-5-morpholine-4-base-benzamide	??N(Me)Et	??491	(DMSO-d6 is under 323 ° of K) 1.11 (t, 3H), 2.10 (s, 3H), 2.92 (s, 3H), 3.11 (bs, 4H), 3.29 (bs, 2H), 3.36 (s, 3H), 3.71-3.80 (m, 4H), 4.51 (d, 2H), 5.09 (t, 1H), 5.38 (bs, 1H), 6.44 (s, 1H), 7.18 (s, 1H), 7.26 (d, 1H), 7.31 (bs, 1H), 7.33 (d, 1H), 7.49 (s, 1H), 7.84 (d, 1H), 8.97 (s, 1H)
??18.5	N-(cyclopropyl methyl)-3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-benzamide	??NHCH ₂cPr	??503	(DMSO-d6 is under 323 ° of K) 0.20-0.25 (m, 2H), 0.39-0.46 (m, 2H), 0.96-1.07 (m, 1H), 2.10 (s, 3H), 3.11-3.16 (m, 4H), 3.38 (s, 3H), 3.73-3.80 (m, 4H), 4.50 (d, 2H), 5.08 (t, 1H), 5.35 (bs, 1H), 6.94 (s, 1H), 7.17 (s, 1H), 7.25 (d, 1H), 7.33 (d, 1H), 7.52 (s, 1H), 7.80 (d, 1H), 7.84 (s, 1H), 8.20 (bs, 1H), 8.93 (s, 1H)	??18.4		??N(Me)Et	??491
??18.5		??NHCH ₂cPr	??503		??18.6	3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-N-methyl-5-morpholine-4-base-N-third-2-base-benzamide	??N(Me)iPr	??505	(DMSO-d6 is under 323 ° of K) 1.13 (d, 6H), 2.10 (s, 3H), 2.79 (s, 3H), 3.08-3.16 (m, 4H), 3.36 (s, 3H), 3.72-3.79 (m, 4H), 3.99 (bs, 1H), 4.51 (d, 2H), 5.09 (t, 1H), 5.37 (bs, 1H), 6.42 (s, 1H), 7.19 (s, 1H), 7.26 (d, 1H), 7.30 (bs, 1H), 7.34 (d, 1H), 7.50 (bs, 1H), 7.83 (d, 1H), 8.97 (s, 1H)

Be prepared as follows 3-[[4-[[5-(methylol)-2-methyl-phenyl as raw material]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenylformic acid:

With 3-fluoro-5-ethyl nitrobenzoate (7g, 32.8mmol) and morpholine (5.7ml, 66mmol) with the mixture of DMSO (5ml) 120 ℃ of heating 6 hours down.After the cooling, the mixture dilute with water.Formed throw out is filtered, wash after drying with water.With silica gel chromatography be further purified (elutriant: DCM), obtain 3-morpholine-4-base-5-nitro-ethyl benzoate (6.73g, 73%), be yellow solid: The NMR spectrum: (DMSOd ₆) 1.35 (t, 3H), 3.32 (m, 4H), 3.76 (m, 4H), 4.36 (q, 2H), 7.81 (s, 1H), 7.90 (s, 1H), 8.01 (s, 1H); Mass spectrum: MH ⁺281.

Employing method 9 makes 3-morpholine-4-base-5-nitro-ethyl benzoate hydrogenation, only is to use platinum oxide (IV), obtains 3-amino-5-morpholine-4-base-ethyl benzoate (6g, 100%), is white solid. The NMR spectrum: (DMSOd ₆) 1.28 (t, 3H), 3.03 (m, 4H), 3.71 (m, 4H), 4.23 (q, 2H), 5.21 (s, 2H), 6.38 (s, 1H), 6.70 (s, 2H); Mass spectrum: MH ⁺251.

Make 3-amino-5-morpholine-4-base-ethyl benzoate (3g according to embodiment 1,12mmol) and [3-[(2-chloropyrimide-4-yl)-methyl-amino]-4-methyl-phenyl] methyl alcohol (2.64g, 10mmol) react, obtain 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-ethyl benzoate (4.43g, 93%), be white foam shape thing, just reactant heated 18 hours down at 85 ℃. Mass spectrum: MH ⁺478.

With sodium hydroxide (3.18g, 79.6mmol) and 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-(3.8g, 7.96mmol) mixture with methyl alcohol (40ml)-water (20ml) at room temperature stirred 2 hours 5-morpholine-4-base-ethyl benzoate.After the solvent evaporation, add 2N hydrochloric acid and regulate pH to 3.Formed throw out is filtered after drying, obtains 3-[[4-[[5-(methylol)-2-methyl-phenyl]-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenylformic acid (3.21g, 90%), be solid. The NMR spectrum: (DMSOd ₆) 2.09 (s, 3H), 3.06-3.19 (m, 4H), 3.39 (s, 1H), 3.70-3.81 (m, 4H), 4.50 (s, 2H), 5.23 (bs, 1H), 5.32 (bs, 1H), 7.08 (s, 1H), 7.19 (s, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.66 (s, 1H), 7.79 (bs, 1H), 8.06 (s, 1H), 8.31 (bs, 1H); Mass spectrum: MH ⁺450.

Embodiment 19

According to method described in the embodiment 18, make the 3-[[4-[(3-chloro-phenyl-)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenylformic acid (100mg, 0.23mmol) reaction obtains corresponding amide:

Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum
Embodiment	Title	??R	Molion (MH ⁺)	The NMR spectrum	??19.1	The 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-N, N-dimethyl-5-morpholine-4-base-benzamide	??NMe ₂	??467	??2.89(bs，3H)，2.95(bs，??3H)，3.03-3.09(m，4H)，??3.42(s，3H)，3.69-3.75(m，??4H)，5.90(d，1H)，6.45(s，??1H)，7.25(s，1H)，7.35(d，??1H)，7.38(d，1H)，7.43(s，??1H)，7.45-7.51(m，2H)，??7.95(d，1H)，9.17(s，1H)

Be prepared as follows 3-[[4-[(3-chloro-phenyl-as raw material)-methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-phenylformic acid:

With sodium hydride (4.89g, 73.4mmol, 60% oil solution) be added in batches N-methyl-3-chloroaniline (8g, 56.5mmol) with the ice-cold solution of DMF (40ml) in.Then this mixture is added to 2, the 4-dichloro pyrimidine (16.8g, 113mmol) with the ice-cold solution of DMF (40ml) in.The gained mixture was heated 18 hours down at 70 ℃.After adding sodium hydride (extremely excessive) again, mixture was heated 2 hours down at 100 ℃.After the cooling, mixture is poured in the saturated aqueous solution of sodium bicarbonate, extracted with DCM.Organic layer is through the dried over mgso after-filtration.After the solvent evaporation, resistates is with silica gel chromatography purifying (elutriant: 0-20%EtOAc/DCM, 10% methyl alcohol/EtOAc), obtain the 4-[(3-chloro-phenyl-then)-methyl-amino]-1H-pyrimid-2-one (4g, 30%, light brown solid). The NMR spectrum: (DMSOd ₆And CF ₃CO ₂D) 3.53 (s, 3H), 7.46 (m, 1H), 7.67-7.60 (m, 3H), 7.78 (m, 1H); Mass spectrum: MH ⁺236.

DMF (5) is added to the 4-[(3-chloro-phenyl-)-methyl-amino]-the 1H-pyrimid-2-one (3.08g, 13.1mmol) with the mixture of phosphoryl chloride (30ml) in.Mixture was stirred 1.5 hours down at 100 ℃.After the solvent evaporation, resistates dilutes with DCM, and slowly is added in the refrigerative saturated aqueous solution of sodium bicarbonate.Mixture extracts with DCM.Organic layer is concentrated.Resistates silica gel chromatography purifying (elutriant: DCM), obtain 2-chloro-N-(3-chloro-phenyl-)-N-methyl-pyrimidine-4-amine (2.56g, 77%), be white solid. The NMR spectrum: (DMSOd ₆) 3.38 (s, 3H), 6.40 (d, 1H), 7.38 (m, 1H), 7.45 (m, 1H), 7.54 (m, 2H), 8.05 (d, 1H); Matter Spectrum: MH ⁺254.

According to method described in the embodiment 18, raw material, make 3-amino-5-morpholine-4-base-ethyl benzoate (embodiment 18, raw material) and 2-chloro-N-(3-chloro-phenyl-)-N-methyl-pyrimidine-4-amine react, obtain:

The 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-5-morpholine-4-base-ethyl benzoate (3.15g, 89%), be white solid. Mass spectrum: MH ⁺468.

The 3-[[4-[(3-chloro-phenyl-)-and methyl-amino] pyrimidine-2-base] amino]-(3.18g quantitatively), is white solid to 5-morpholine-4-base-phenylformic acid. The NMR spectrum: (DMSOd ₆) 3.09 (m, 4H), 3.46 (s, 3H), 3.74 (m, 4H), 5.87 (d, 1H), 7.08 (s, 1H), 7.42-7.35 (m, 2H), 7.50 (m, 2H), 7.59 (s, 1H), 7.93 (d, 1H), 7.99 (s, 1H), 9.38 (m, 1H); Mass spectrum: MH ⁺440.

Embodiment 20

N2-(3,5-dimorpholino phenyl)-N4-sec.-propyl-N4-(3-p-methoxy-phenyl) pyrimidine-2, the 4-diamines

With N2-(3,5-dimorpholino phenyl)-N4-sec.-propyl-N2-(4-methoxy-benzyl)-N4-(3-p-methoxy-phenyl) pyrimidine-2, the 4-diamines (170mg, 0.23mmol) and phenylmethylether (126 μ l, TFA solution (5ml) 1.16mmol) stirred 7 hours down at 130 ℃.It is dried that reaction mixture is concentrated into, and with DCM (30ml) dilution, with saturated aqueous solution of sodium bicarbonate (1x70ml) washing, concentrates after dried over mgso, obtains crude product, is the canescence jelly.Crude product flash chromatography on silica gel method purifying (using eluent ethyl acetate).Make solvent evaporation to doing, obtain N2-(3,5-dimorpholino phenyl)-N4-sec.-propyl-N4-(3-p-methoxy-phenyl) pyrimidine-2,4-diamines (76mg, 65.1%) is white foam shape thing. The NMR spectrum: (DMSOd ₆) 1.09 (s, 6H), 3.03-3.11 (m, 8H), 3.70-3.77 (m, 8H), 3.78 (s, 3H), 5.19 (d, 1H), 5.31-5.41 (m, 1H), 6.11 (t, 1H), 6.77 (dd, 1H), 6.79 (d, 1H), 6.98 (d, 2H), 7.04 (dd, 1H), 7.45 (dd, 1H), 7.73 (dd, 1H), 8.82 (s, 1H); Mass spectrum: MH ⁺505.

Be prepared as follows N2-(3,5-dimorpholino phenyl)-N4-sec.-propyl-N2-(4-methoxy-benzyl)-N4-(3-p-methoxy-phenyl) pyrimidine-2, the 4-diamines as raw material:

Under nitrogen atmosphere, with 4N hydrogenchloride De dioxane solution (0.050ml, 0.20mmol) be added to 4-chloro-N-(3,5-dimorpholino phenyl)-N-(4-methoxy-benzyl) pyrimidine-2-amine (2g, 4.03mmol) and the 3-anisidine (0.473ml, 4.23mmol) with the stirred suspension of 2-propyl alcohol (20ml) in.Gained suspension was stirred 1 hour down at 80 ℃.

After making reaction mixture be cooled to room temperature, make solvent evaporation.Resistates is dissolved in DCM, uses the saturated aqueous solution of sodium bicarbonate quencher, with DCM (1x30ml) extraction.Organic phase concentrates after dried over mgso, obtains crude product, is light yellow gluey thing.Crude product flash chromatography on silica gel method purifying (with 0-50% ethyl acetate/DCM wash-out).Make solvent evaporation to doing, obtain N2-(3,5-dimorpholino phenyl)-N2-(4-methoxy-benzyl)-N4-(3-p-methoxy-phenyl) pyrimidine-2,4-diamines (2.28g, 97%) is the transparent whites foam. Mass spectrum: MH ⁺583.

Under argon atmospher, 25 ℃, with sodium hydride (13.8mg, 0.34mmol, 60% oil solution) the disposable N2-(3 that is dissolved in DMF (3ml) that is added to, 5-dimorpholino phenyl)-N2-(4-methoxy-benzyl)-N4-(3-p-methoxy-phenyl) pyrimidine-2, the 4-diamines (134mg, 0.23mmol) and 2 cbloropropane isopropyl chloride (0.069ml is in the stirring the mixture 0.69mmol).Gained suspension was stirred 3 hours down at 90 ℃.Add successively again another part sodium hydride (28mg, 0.68mmol) and 2 cbloropropane isopropyl chloride (0.14ml, 1.4mmol).The gained mixture was stirred 18 hours down at 90 ℃.After under agitation making reaction mixture be cooled to room temperature, use the ammonium chloride saturated aqueous solution quencher.The gained throw out is collected after filtration, after water (100ml) washing, is dried to constant weight, obtain N2-(3,5-dimorpholino phenyl)-N4-sec.-propyl-N2-(4-methoxy-benzyl)-N4-(3-p-methoxy-phenyl) pyrimidine-2,4-diamines (145mg, quantitatively), be beige solid. Mass spectrum: MH ⁺625.

Embodiment 21

(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (2-methoxy ethyl) amino)-4-aminomethyl phenyl) methyl alcohol

Under 25 ℃, (0.103ml 1.10mmol) is added drop-wise to (3-(2-chloropyrimide-4-base is amino)-4-aminomethyl phenyl) methyl alcohol (250mg, 1.00mmol with the 2-bromo-ethyl-methyl ether, method 2) and cesium carbonate (652mg, 2.00mmol) with the stirred suspension of DMF (4ml) in.The stirring under 25 ℃ of gained suspension is spent the night.Reaction mixture after filtering, it is dried that filtrate is concentrated into.With 3, after 5-dimorpholine-4-base aniline (264mg, 1.00mmol, method 9) and hydrochloric acid 4N De dioxane solution (2) are suspended in 2-propyl alcohol (3ml), in microwave tube, seal.With reactant at PersonalChemistry EMRYS ^TMBe heated to 140 ℃ in the Optimizer EXP microwave synthesizer and reach 10 minutes.Remove and desolvate, resistates is dissolved in DMF (1.5ml).Add ammoniacal liquor (100 μ l), mixture preparation HPLC purifying adopts Waters X-Terra reversed-phase column (5 microns silica gel, diameter 30mm, long 150mm), and the mixture of water that polarity is successively decreased (containing 0.2% volatile salt) and acetonitrile is an elutriant.Flow point is evaporated to dried, obtains (3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (2-methoxy ethyl) amino)-4-aminomethyl phenyl) methyl alcohol (192mg, 36%), be pink solid. The NMR spectrum: (DMSOd ₆Under 297 ° of K) 2.07 (s, 3H), 3.01-3.13 (m, 8H), 3.20 (s, 3H), 3.40-3.51 (m, 2H), 3.68-3.78 (m, 8H), 3.94-4.04 (m, 1H), 4.18-4.28 (m, 1H), 4.50 (d, 2H), 5.18 (d, 1H), 5.22 (t, 1H), 6.11 (s, 1H), 6.97 (s, 2H), 7.18 (s, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.78 (d, 1H), 8.83 (s, 1H); Mass spectrum: MH ⁺535.

Adopt method above, prepare following compounds with corresponding halogenide:

Embodiment	Title	R (initial halogenide)	Molion (MH ⁺)	NMR composes (DMSOd ₆)
Embodiment	Title	R (initial halogenide)	Molion (MH ⁺)	NMR composes (DMSOd ₆)	??21.1	[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-third-2-base-amino]-4-methyl-phenyl] methyl alcohol	IPr (2-N-PROPYLE BROMIDE)	??519	(DMSOd6 is under 297 ° of K) 0.94 (d, 3H), 1.28 (d, 3H), 2.07 (s, 3H), 3.01-3.15 (m, 8H), 3.69-3.80 (m, 8H), 4.52 (d, 2H), 5.04 (bs, 1H), 5.25 (t, 1H), 5.28 (bs, 1H), 6.11 (s, 1H), 7.00 (s, 2H), 7.11 (s, 1H), 7.29 (d, 1H), 7.36 (d, 1H), 7.74 (d, 1H), 8.82 (s, 1H)
??21.2	[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-ethyl-amino]-4-methyl-phenyl] methyl alcohol	Et (2-monobromethane)	??505	(DMSOd6 is under 297 ° of K) 1.14 (t, 3H), 2.08 (s, 3H), 2.98-3.14 (m, 8H), and 3.66-3.82 (m, 9H), 4.07-4.21 (m, 1H), 4.51 (d, 2H), 5.18 (bs, 1H), 5.23 (t, 1H), 6.11 (s, 1H), 7.00 (s, 2H), 7.16 (s, 1H), 7.27 (d, 1H), 7.35 (d, 1H), 7.77 (d, 1H), 8.83 (s, 1H)	??21.1		IPr (2-N-PROPYLE BROMIDE)	??519

Embodiment	Title	R (initial halogenide)	Molion (MH ⁺)	NMR composes (DMSOd ₆)
Embodiment	Title	R (initial halogenide)	Molion (MH ⁺)	NMR composes (DMSOd ₆)	??21.3 ^a	2-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-[5-(methylol)-2-methyl-phenyl] amino] ethanol	??CH ₂CH ₂OH (2-ethyl bromoacetate)	??521	(DMSOd6 is under 297 ° of K) 2.07 (s, 3H), 2.99-3.17 (m, 8H), 3.53-3.64 (m, 2H), 3.65-3.81 (m, 9H), 4.14-4.27 (m, 1H), 4.51 (d, 2H), 4.68 (t, 1H), 5.17 (s, 1H), 5.23 (t, 1H), 6.11 (s, 1H), 6.98 (s, 2H), 7.22 (s, 1H), 7.26 (d, 1H), 7.33 (d, 1H), 7.77 (d, 1H), 8.81 (s, 1H)

^aWith 3,5-dimorpholine-4-base aniline reaction and make the mixture cooling after, (0.661ml 1.32mmol), at room temperature stirs reaction mixture and to spend the night to add the 2N aqueous sodium hydroxide solution.Separating compound as previously mentioned then.

Embodiment 22

Adopt method described in the embodiment 21, with 2-chloro-N-(5-methoxyl group-2-methyl-phenyl)-N-methyl-pyrimidine-4-amine (200mg, 0.8mmol) and corresponding halogenide together, the preparation following compounds:

^aWith 3,5-dimorpholine-4-base aniline reaction and make the mixture cooling after, (0.481ml 0.96mmol), at room temperature stirs reaction mixture and to spend the night to add the 2N aqueous sodium hydroxide solution.Separating compound as previously mentioned then.

Embodiment 23

1-[3-(the 4-[(3-chloro-phenyl-) and (methyl) amino] pyrimidine-2-base } amino)-5-morpholine-4-base phenyl] piperidines-4-alcohol

With 2-chloro-N-(3-chloro-phenyl-)-N-methylpyrimidine-4-amine (180mg, 0.71mmol), 1-(3-amino-5-morpholino phenyl) piperidines-4-alcohol (196mg, 0.71mmol) and HCl/ diox 4N (0.195ml 0.78mmol) stirred 1.5 hours in 120 ℃ in sealed tube with the suspension of 2-amylalcohol (4ml).Formed throw out is at room temperature cooled off.Throw out after filtering, and is also dry with the washing of 2-amylalcohol.Solid DCM (10ml) and 5N NH ₃Methanol solution (2ml) dissolving.Remove insolubles after filtration.It is dried that filtrate is concentrated into, and is dissolved in DCM, is concentrated into dried after the filtration.The gained foam grinds with ether and pentane, obtains 1-[3-({ 4-[(3-chloro-phenyl-) (methyl) amino] pyrimidine-2-base } amino)-5-morpholine-4-base phenyl] piperidines-4-alcohol (190mg, 54.2%), be pink solid. Mass spectrum: M+H ⁺495.

NMR composes (DMSOd ₆ ): 1.39-1.50 (m, 2H), 1.74-1.84 (m, 2H), 2.71-2.81 (m, 2H), 2.96-3.05 (m, 4H), 3.41-3.50 (m, 5H), 3.54-3.63 (m, 1H), 3.66-3.74 (m, 4H), 4.65 (d, 1H), 5.82 (d, 1H), 6.08 (s, 1H), 6.90 (s, 1H), 6.95 (s, 1H), 7.35 (dd, 1H), 7.38 (dd, 1H), 7.49 (s, 1H), 7.50 (dd, 1H), 7.90 (d, 1H), 8.85 (s, 1H).

Be prepared as follows 2-chloro-N-(3-chloro-phenyl-)-N-methylpyrimidine-4-amine as raw material:

With 2, the 4-dichloro pyrimidine (4g, 26.85mmol), the 3-chloroaniline (2.84ml, 26.85mmol) and triethylamine (4.49ml, EtOH 32.22mmol) (40ml) solution is 80 ℃ of following heated overnight.Make solvent evaporation.Resistates dilutes with AcOEt and 1M aqueous hydrochloric acid.Organic phase water, saturated aqueous solution of sodium bicarbonate and saturated brine solution washing concentrate after dried over mgso, obtain crude product, are beige solid.Crude product grinds with AcOEt (40ml), filters, and uses CH ₂Cl ₂The washing after drying obtains 00150-62-01 (3g), is white solid. Mass spectrum: M+H ⁺240 and 242. NMR composes (DMSOd ₆ ): 6.80 (d, 1H), 7.14 (dd, 1H), 7.40 (dd, 1H), 7.51 (dd, 1H), 7.82 (s, 1H), 8.22 (d, 1H), 10.20 (s, 1H).

With 2-chloro-N-(3-chloro-phenyl-) pyrimidine-4-amine (2.5g, 10.41mmol) and cesium carbonate (6.79g, DMF 20.83mmol) (15ml) suspension 25 ℃ down stir 10 minutes after, add methyl-iodide (0.648ml, 10.41mmol).25 ℃ assign 3 hours after, remove insolubles after filtration.It is dried that filtrate is concentrated into, with AcOEt and water dilution.Organic phase salt water washing is concentrated into dried after dried over mgso.Solid grinds with ether (20ml), filters, and drying obtains 2-chloro-N-(3-chloro-phenyl-)-N-methylpyrimidine-4-amine (1.5g, 56.7%), is white solid. Mass spectrum: M+H ⁺254 and 256. The NMR spectrum(CDCl ₃): 3.48 (s, 3H), 6.20 (d, 1H), 7.15 (ddd, 1H), 7.26 (dd, 1H), 7.36 (ddd, 1H), 7.42 (dd, 1H), 7.94 (d, 1H).

Embodiment 24

N4-(3-chloro-phenyl-)-N4-methyl-N2-[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base phenyl] pyrimidine-2, the 4-diamines

Employing is similar to method described in the embodiment 23, make 2-chloro-N-(3-chloro-phenyl-)-N-methylpyrimidine-4-amine (180mg, 0.71mmol) and 3-(4-methylpiperazine-1-yl)-5-morpholino aniline (196mg, 0.71mmol) reaction, obtain N4-(3-chloro-phenyl-)-N4-methyl-N2-[3-(4-methylpiperazine-1-yl)-5-morpholine-4-base phenyl] pyrimidine-2,4-diamines (213mg, 60.9%) is white solid. Mass spectrum: M+H ⁺494. NMR composes (DMSOd ₆ ): 2.21 (s, 3H), 2.38-2.45 (m, 4H), 2.98-3.04m (m, 4H), 3.04-3.09 (m, 4H), 3.44 (s, 3H), 3.67-3.74 (m, 4H), 5.83 (d, 1H), 6.08 (s, 1H), 6.94 (d, 1H), 7.35 (dd, 1H), 7.38 (dd, 1H), 7.48 (dd, 1H), 7.49 (s, 1H), 7.90 (d, 1H), 8.85 (s, 1H).

Embodiment 25

According to preparing following compounds described in embodiment 6 synthesis methods:

^a: be prepared as follows (2-((2-chloropyrimide-4-yl) (methyl) amino)-3-aminomethyl phenyl) methyl alcohol as raw material:

According to Method 1Described in, with 2, the 4-dichloro pyrimidine (1.5g, 10.07mmol), 2-amino-3-methylbenzyl alcohol (commercially available) (1.285g, 9.36mmol) and triethylamine (1.544ml 11.08mmol) stirred 20 hours under refluxing with the mixture of ethanol (13ml).Behind aftertreatment and the purifying, obtain (2-(2-chloropyrimide-4-base is amino)-3-aminomethyl phenyl) methyl alcohol (0.477g, 18.97%), be cream-coloured foam. Mass spectrum: M+H ⁺250. The NMR spectrum(DMSOd ₆Under 323 ° of K): 2.12 (s, 3H), 4.40 (bs, 2H), 4.97 (bs, 1H), 7.22 (s, 1H), 7.26 (s, 1H), 7.39 (d, 1H), 8.02 (s, 1H), 9.19 (bs, 1H).

According to Method 1Described in, with (2-(2-chloropyrimide-4-base is amino)-3-aminomethyl phenyl) methyl alcohol (470mg, 1.88mmol), cesium carbonate (1227mg, 3.76mmol) and methyl-iodide (129 μ l 2.07mmol) stirred 20 hours down argon atmospher, 22 ℃ with the suspension of DMF (5ml).Behind aftertreatment and the purifying, obtain (2-((2-chloropyrimide-4-yl) (methyl) amino)-3-aminomethyl phenyl) methyl alcohol (386mg, 78%), be light yellow solid.

Mass spectrum: M+H ⁺264. The NMR spectrum(DMSOd ₆Under 323 ° of K): 2.05 (s, 3H), 3.27 (s, 3H), 4.22 (dd, 1H), 4.36 (dd, 1H), 5.25 (t, 1H), 5.70 (d, 1H), 7.31 (d, 1H), 7.37 (dd, 1H), 7.45 (d, 1H), 7.91 (d, 1H).

^b: be prepared as follows 2-chloro-N-(2-methoxyl group-6-aminomethyl phenyl)-N-methylpyrimidine-4-amine as raw material:

According to Method 1Described in, with 2, and the 4-dichloro pyrimidine (1.5g, 10.07mmol), (1.285g, 9.36mmol) and N, (1.929ml, propyl carbinol 11.08mmol) (13ml) solution stirred 15 hours under refluxing the N-diisopropylethylamine 2-methoxyl group-6-monomethylaniline.Behind aftertreatment and the purifying, obtain 2-chloro-N-(2-methoxyl group-6-aminomethyl phenyl) pyrimidine-4-amine (1.450g, 57.7%), be beige solid. Mass spectrum: M+H ⁺250. The NMR spectrum(DMSOd ₆Under 323 ° of K): 2.14 (s, 3H), 3.73 (s, 3H), 6.16 (bs, 1H), 6.89 (d, 1H), 6.95 (d, 1H), 7.21 (dd, 1H), 7.99 (d, 1H), 9.10 (s, 1H).

Employing is similar to the method for note (a), and above-mentioned product is methylated.Crude product flash chromatography on silica gel method purifying (with 10-30% ethyl acetate/petroleum ether wash-out).Make solvent evaporation to doing, obtain 2-chloro-N-(2-methoxyl group-6-aminomethyl phenyl)-N-methylpyrimidine-4-amine (816mg, 97%), be colourless jelly. Mass spectrum: M+H ⁺264. NMR composes (DMSOd ₆ ): DMSOd ₆: 2.08 (s, 3H), 3.23 (s, 3H), 3.74 (s, 3H), 5.77 (d, 1H), 6.98 (d, 1H), 7.04 (d, 1H), 7.34 (dd, 1H), 7.91 (d, 1H).

^c: be prepared as follows (3-((2-chloropyrimide-4-yl) (methyl) amino)-4-fluorophenyl) methyl alcohol as raw material:

Make (4-fluoro-3-nitrophenyl) methyl alcohol (2.5g, 14.61mmol) and 10% palladium/C (0.25g, ethanol 2.35mmol) (70ml) suspension was 1 hydrogen-pressure, 21 ℃ of following hydrogenation 1 hour.Gained suspension after filtering, it is dried that filtrate is concentrated into, and obtains crude product (3-amino-4-fluorophenyl) methyl alcohol (1.900g, 92%), is the oldlace solid. Mass spectrum: M+H ⁺142. NMR composes (DMSOd ₆ ): 4.32 (d, 2H), 5.00-5.07 (m, 3H), 6.43 (ddd, 1H), 6.73 (dd, 1H), 6.88 (dd, 1H).

According to Method 1Described in, with 2,4-dichloro pyrimidine (1.5g, 10.07mmol), (3-amino-4-fluorophenyl) methyl alcohol (1.421g, 10.07mmol) and N, (1.929ml, 11.08mmol) solution with propyl carbinol (13ml) stirred 15 hours under refluxing the N-diisopropylethylamine.Behind aftertreatment and the purifying, obtain (3-(2-chloropyrimide-4-base is amino)-4-fluorophenyl) methyl alcohol (1.170g, 45.8%), be beige solid. Mass spectrum: M+H ⁺254. NMR composes (DMSOd ₆ ): 4.48 (d, 2H), 5.29 (t, 1H), 6.72 (d, 1H), 7.18 (ddd, 1H), 7.27 (dd, 1H), 7.60 (d, 1H), 8.17 (d, 1H), 9.81 (bs, 1H).

Employing is similar to the method for note (a), and above-mentioned product is methylated, and obtains (3-((2-chloropyrimide-4-yl) (methyl) amino)-4-fluorophenyl) methyl alcohol (60%), is white solid. Mass spectrum: M+H ⁺268. The NMR spectrum(DMSOd ₆Under 323 ° of K): 3.37 (s, 3H), 4.17 (d, 2H), 5.20 (t, 1H), 6.32 (bs, 1H), 7.34 (dd, 1H), 7.37-7.42 (m, 2H), 8.07 (d, 1H).

^d: be prepared as follows (3-((2-chloropyrimide-4-yl) (methyl) amino)-2-fluorophenyl) methyl alcohol as raw material:

NMR composes (DMSOd ₆ ): 4.85 (d, 2H), 5.72 (t, 1H), 7.38 (ddd, 1H), 7.60 (dd, 1H), 8.21 (dd, 1H).

Under 0 ℃, with commercially available BH ₃Solution (22.7ml; 22.7mmol; The THF solution of 1N) be added drop-wise to 2-fluoro-3-nitrobenzoic acid (2.8g; 15.14mmol) THF solution (30ml) in.Add when finishing, remove ice bath, continue to stir 3 days.After making reaction mixture be cooled to 0 ℃, slowly add methyl alcohol.In case stop to emit gas, just solvent removed in vacuo, resistates dilutes with ethyl acetate, after the salt water washing, through dried over mgso.Filtrate is adsorbed on the silica gel, is poured on the flash chromatography column top, and use the methylene dichloride wash-out.After the solvent evaporation, obtain (3-nitro-2-fluorophenyl) methyl alcohol (2.4g; 93%).

NMR composes (DMSOd ₆ ): 4.34 (d, 2H), 4.74 (bs, 2H), 5.12 (t, 1H), 6.59 (dd, 1H), 6.77 (ddd, 1H), 6.91 (dd, 1H).

In the presence of Pt/C, make (3-nitro-2-fluorophenyl) methyl alcohol (2.1g, AcOEt solution reduction 12.28mmol) 1 hour with hydrogen (30Psi).Catalyzer makes solvent evaporation after removing after filtration, obtains (3-amino-2-fluorophenyl) methyl alcohol (1.64g, 95%, yellow solid).

According to Method 1Described in, with 2, the 4-dichloro pyrimidine (300mg, 2.01mmol), (3-amino-2-fluorophenyl) methyl alcohol (256mg, 1.81mmol) and triethylamine (309 μ l, 2-propyl alcohol (5ml) solution 2.22mmol) stirred 15 hours down at 90 ℃.Behind aftertreatment and the purifying, obtain (3-(2-chloropyrimide-4-base is amino)-2-fluorophenyl) methyl alcohol (206mg, 40.3%), be white solid. Mass spectrum: M+H ⁺254.

NMR composes (DMSOd ₆ ): 4.44 (s, 2H), 5.39 (bs, 1H), 6.51 (bs, 1H), 7.13 (ddd, 1H), 7.30 (dd, 1H), 7.36 (dd, 1H), 8.09 (d, 1H), 9.41 (bs, 1H).

Employing is similar to the method for note (a), and above-mentioned product is methylated, and obtains (3-((2-chloropyrimide-4-yl) (methyl) amino)-2-fluorophenyl) methyl alcohol (73%), is white solid. Mass spectrum: M+H ⁺268. The NMR spectrum(DMSOd ₆Under 323 ° of K): 3.28 (s, 3H), 4.23 (dd, 1H), 4.37 (dd, 1H), 5.25 (t, 1H), 5.86 (bs, 1H), 7.22 (dd, 1H), 7.33 (dd, 1H), 7.38 (d, 1H), 7.96 (bs, 1H).

^e: with 3,5-dimorpholino aniline (87mg, 0.31mmol), 1-(3-((2-chloropyrimide-4-yl) (methyl) amino)-4-aminomethyl phenyl) ethyl ketone (81mg, 0.29mmol) and hydrochloric acid (4M De dioxane solution) (3.67 μ l 0.01mmol) stirred 6 hours down at 80 ℃ with the mixture of iPrOH (1ml).After reaction mixture being concentrated into do, use DCM: methyl alcohol/ammonia 7N (95: 5,5ml) dilute.The gained throw out washs with DCM after removing after filtration.After filtrate is concentrated, with flash chromatography on silica gel method purifying (with 0-100% ethyl acetate/DCM wash-out), obtain 1-(3-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-aminomethyl phenyl) ethyl ketone (106mg, 71.8%) blush solid.

Be prepared as follows 1-(3-((2-chloropyrimide-4-yl) (methyl) amino)-4-aminomethyl phenyl) ethyl ketone as raw material:

Under room temperature, 1.3 normal atmosphere, make 4-methyl-3-nitro phenyl methyl ketone (500mg, 2.79mmol) and Adam's Si platinum oxide (44mg is 0.2mmol) with the solution hydrogenation of ethyl acetate (5ml) and ethanol (5.00ml) 30 minutes.Gained solution is after Celite pad filters, and it is dried that filtrate is concentrated into, and obtains yellow oil, need not to be further purified just to use. Mass spectrum: M+H ⁺150. NMR Spectrum(CDCl ₃): 2.22 (s, 3H), 2.55 (s, 3H), 3.72 (bs, 2H), 7.12 (d, 1H), 7.24 (d, 1H), 7.29 (dd, 1H).

With 2, and the 4-dichloro pyrimidine (200mg, 1.34mmol), (200mg, 1.34mmol) and N, (0.257ml, 2-propyl alcohol (2ml) solution 1.48mmol) stirred 3 days down at 80 ℃ the N-diisopropylethylamine 1-(3-amino-4-aminomethyl phenyl) ethyl ketone.It is dried that reaction mixture is concentrated into, with the DCM dilution, with the washing of 10% aqueous citric acid solution, through MgSO ₄After the drying, in the presence of silica gel, concentrate.Crude product flash chromatography on silica gel method purifying (with 20-50% ethyl acetate/petroleum ether wash-out).Make solvent evaporation to doing, obtain 1-(3-(2-chloropyrimide-4-base is amino)-4-aminomethyl phenyl) ethyl ketone (181mg, 51.5%), be white solid. Mass spectrum: M+H ⁺262. The NMR spectrum(CDCl ₃): 2.34 (s, 3H), 2.60 (s, 3H), 6.33 (d, 1H), 6.87 (bs, 1H), 7.42 (d, 1H), 7.81 (dd, 1H), 7.74 (d, 1H), 8.13 (d, 1H).

Employing is similar to the method for note (a), and above-mentioned product is methylated, and obtains 1-(3-((2-chloropyrimide-4-yl) (methyl) amino)-4-aminomethyl phenyl) ethyl ketone (90%), is white solid. Mass spectrum: M+H ⁺276. The NMR spectrum(CDCl ₃): 2.21 (s, 3H), 2.60 (s, 3H), 3.44 (s, 3H), 5.76 (d, 1H), 7.47 (d, 1H), 7.76 (d, 1H), 7.88 (d, 1H), 7.91 (d, 1H).

^f: described in note (e), make 3,5-dimorpholino aniline (144mg, 0.51mmol) (2-fluoro-5-p-methoxy-phenyl)-(130mg 0.49mmol) carries out coupling to N-methylpyrimidine-4-amine, obtains N2-(3 with 2-chloro-N-, 5-dimorpholino phenyl)-N4-(2-fluoro-5-p-methoxy-phenyl)-N4-methylpyrimidine-2,4-diamines (197mg, 82%) is the glassy yellow foam.

Be prepared as follows 2-chloro-N-(2-fluoro-5-p-methoxy-phenyl)-N-methylpyrimidine-4-amine as raw material:

With 2,6-two bromo-4-fluorophenols (5g, 18.53mmol), salt of wormwood (3.84g, 27.79mmol) and methyl-sulfate (1.928ml 20.38mmol) stirred 6 hours under refluxing with the suspension of acetone (110ml).Make reaction mixture be cooled to room temperature, salt is filtered, it is dried that filtrate is concentrated into, and with the ether dilution, water and salt water washing concentrate after dried over mgso, obtain product 1, and 3-two bromo-5-fluoro-2-anisoles (5.20g, 99%) are white solid. The NMR spectrum(CDCl ₃): 3.86 (s, 3H), 7.28 (d, 2H).

Temperature keep 0 ℃ and+5 ℃ between in, in 10 minutes, the HNO that will smolder ₃90% (0.35ml)/dense H ₂SO ₄(6.5ml) drips of solution is added to 1, and (2g is 7.04mmol) with dense H for 3-two bromo-5-fluoro-2-anisoles ₂SO ₄In the stirred suspension (8.5ml).Gained suspension was stirred in ice bath 2 hours, and quencher in ice (30g) is with methylene dichloride (2x20ml) extraction.Organic phase concentrates after dried over mgso with saturated aqueous solution of sodium bicarbonate (x2) washing, obtains requiredly 1, and 3-two bromo-5-fluoro-2-methoxyl group-4-oil of mirbane (2.100g, 91%) are light yellow oil.Crude product need not to be further purified and just can be used for next step. The NMR spectrum(CDCl ₃): 3.92 (s, 3H), 7.53 (d, 1H).

Under 60psi, 21 ℃, make 1,3-two bromo-5-fluoro-2-methoxyl group-4-oil of mirbane (2.1g, 6.38mmol) and 10% palladium/C 50% wet pulp (0.5g is 4.70mmol) with the hydrogenation 25 hours in Pa Er reactor (500ml) of the suspension of ethanol (60ml).Gained suspension after filtering, it is dried that filtrate is concentrated into.The gained solid dilutes with methyl alcohol, adds 7N NH ₃Methanol solution.It is dried that mixture is concentrated into, and with the methylene dichloride dilution, solid makes solvent evaporation after removing after filtration.Product is used the methylene dichloride wash-out with flash chromatography on silica gel method purifying (15-40 μ m).Make solvent evaporation to doing, obtain 2-fluoro-5-anisidine (0.720g, 80%), be white solid. Mass spectrum: M+H ⁺142. The NMR spectrum(CDCl ₃): 3.71 (bs, 2H), 3.74 (s, 3H) 6.20 (ddd, 1H), 6.32 (dd, 1H), 6.88 (dd, 1H).

According to Method 1Described in, with 2, and the 4-dichloro pyrimidine (200mg, 1.34mmol), (189mg, 1.34mmol) and N, (0.257ml, 2-propyl alcohol (1.5ml) suspension 1.48mmol) stirred 3 days under refluxing the N-diisopropylethylamine 2-fluoro-5-anisidine.Behind aftertreatment and the purifying, obtain 2-chloro-N-(2-fluoro-5-p-methoxy-phenyl) pyrimidine-4-amine (220mg, 64.6%), be oily matter, crystallization when leaving standstill. Mass spectrum: M+H ⁺254.

The NMR spectrum(CDCl ₃): 3.82 (s, 3H), 3.58 (d, 1H), 3.67 (ddd, 1H), 6.90 (bs, 1H), 7.08 (dd, 1H), 7.49 (bs, 1H), 8.20 (d, 1H).

Employing is similar to the method for note (a), and above-mentioned product is methylated, and obtains 2-chloro-N-(2-fluoro-5-p-methoxy-phenyl)-N-methylpyrimidine-4-amine (92%), is colorless oil. Mass spectrum: M+H ⁺268. The NMR spectrum(CDCl ₃): 3.45 (s, 3H), 3.80 (s, 3H), 6.11 (d, 1H), 6.77 (ddd, 1H), 6.89 (ddd, 1H), 7.15 (dd, 1H), 7.95 (d, 1H).

^g: with 3,5-dimorpholino aniline (254mg, 0.97mmol), (2-((2-chloropyrimide-4-yl) (methyl) amino)-4-p-methoxy-phenyl) methyl alcohol (180mg, 0.64mmol) and the mixture of hydrogenchloride 5N/iPrOH (5) and 2-amylalcohol (5ml) stirred 3 hours down at 100 ℃.It is dried that reactant is concentrated into, resistates is dissolved in DMF (1.5ml) after, add NH ₃7N/MeOH (100 μ l).After the solution filtration, (adopt Waters X-Bridge reversed-phase column (C-18,5 microns in silica gel with the preparation HPLC purifying, diameter 19mm, long 100mm, flow velocity 40ml/ minute), the mixture of water that polarity is successively decreased (containing 0.2% volatile salt) and acetonitrile is an elutriant).It is dried that the flow point that contains required compound is evaporated to, and obtains the Vandyke brown solid, and it is further purified (with 0-5% ethanol/methylene wash-out) with the flash chromatography on silica gel method.Make solvent evaporation to doing, obtain (2-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino)-4-p-methoxy-phenyl) methyl alcohol, be light brown foam.After this foam grinds with ether, with sherwood oil dilution, 10 minutes after-filtration of supersound process, obtain that (((2-(3 for 2-, 5-dimorpholino phenylamino) (methyl) amino pyrimidine-4-yl))-and the 4-p-methoxy-phenyl) methyl alcohol (125mg, 38.3%), be beige solid.

Be prepared as follows (2-((2-chloropyrimide-4-yl) (methyl) amino)-4-p-methoxy-phenyl) methyl alcohol as raw material:

With (2-amino-4-p-methoxy-phenyl) methyl alcohol (555mg, 3.62mmol), 2, (1080mg, 7.25mmol) (1.893ml, EtOH solution (10ml) 10.87mmol) stirred weekend at 80 ℃ the 4-dichloro pyrimidine with N-ethyl-N-sec.-propyl third-2-amine (DIPEA).After reaction mixture being concentrated into do, between ethyl acetate (30ml) and water, distribute.Water extracts with ethyl acetate (2x30ml), and the salt water washing of the organic phase of merging concentrates after dried over mgso, obtains crude product, is yellow oil.Crude product flash chromatography on silica gel method purifying (with 0-50% ethyl acetate/dichloromethane wash-out).Make solvent evaporation to doing, obtain (2-(2-chloropyrimide-4-base is amino)-4-p-methoxy-phenyl) methyl alcohol (340mg, 35.3%), be light yellow solid.

Mass spectrum: [M-H] ^-264. The NMR spectrum(DMSOd ₆): 3.75 (s, 3H), 4.41 (s, 2H), 5.14 (bs, 1H), 6.60 (d, 1H), 6.84 (dd, 1H), 7.02 (s, 1H), 7.39 (d, 1H), 8.10 (d, 1H), 9.40 (bs, 1H).

Under nitrogen atmosphere, 0 ℃, with methyl iodide (0.082ml, 1.32mmol) be added to (2-(2-chloropyrimide-4-base is amino)-4-p-methoxy-phenyl) methyl alcohol (320mg, 1.20mmol) and salt of wormwood (250mg is 1.81mmol) and in the stirred suspension of DMF (10ml).Gained suspension at room temperature stirred spend the night.Reaction mixture after filtration, be concentrated into do after, distribution between ethyl acetate (20ml) and water (20ml).Water extracts with ethyl acetate (2x10ml), and the salt water washing of the organic phase of merging concentrates after dried over mgso, obtains crude product, is yellow jelly.Crude product flash chromatography on silica gel method purifying (with 0-40% ethyl acetate/dichloromethane wash-out).Make solvent evaporation to doing, obtain (2-((2-chloropyrimide-4-yl) (methyl) amino)-4-p-methoxy-phenyl) methyl alcohol (200mg, 59.4%), be light yellow gluey thing.

Mass spectrum: M+H ⁺280.

NMR composes (DMSOd ₆ ): 3.32 (s is by H ₂O peak part is sheltered, 3H), 3.76 (s, 3H), 4.18 (d, 1H), 4.28 (d, 1H), 5.09 (bs, 1H), 5.85 (d, 1H), 6.90 (s, 1H), 7.04 (d, 1H), 7.51 (d, 1H), 7.91 (d, 1H).

^h: will (4-chloro-2-(2-chloropyrimide-4-base amino) phenyl) methyl alcohol (35mg, 0.13mmol), methyl iodide (8.87 μ l, 0.14mmol) and salt of wormwood (26.9mg, 0.19mmol) and the mixture of DMF (1ml) under nitrogen atmosphere, room temperature, stir and spend the night.After reactant being concentrated into do, between ethyl acetate and water, distribute.The water ethyl acetate extraction, the organic phase of merging is washed with saturated brine solution, is concentrated into driedly after dried over mgso, obtains rough intermediate, is yellow jelly.

With above-mentioned intermediate 3, (51.2mg, 0.19mmol) the iPrOH solution (3) with hydrogenchloride 5N is suspended in the 2-amylalcohol (1ml) 5-dimorpholino aniline, and seals in microwave tube.Make reactant in microwave reactor, be heated to 140 ℃ and reach 15 minutes.After reaction mixture being concentrated into do, between ethyl acetate and saturated aqueous solution of sodium bicarbonate, distribute.The water ethyl acetate extraction, the organic phase of merging is washed with saturated brine solution, is concentrated into driedly after dried over mgso, obtains crude product, with it with flash chromatography on silica gel method purifying (with 0-5% ethanol/methylene wash-out).Make solvent evaporation to doing, obtain (4-chloro-2-((2-(3,5-dimorpholino phenylamino) pyrimidine-4-yl) (methyl) amino) phenyl) methyl alcohol (20.00mg, 30.2%), be orange solids.

Be prepared as follows (4-chloro-2-(2-chloropyrimide-4-base is amino) phenyl) methyl alcohol as raw material:

Under 1300 millibars, room temperature, make (4-chloro-2-nitrophenyl) methyl alcohol (1g, 5.33mmol, ALDRICH) and platinum oxide (IV) (100mg, ethanol 0.44mmol) (100ml) suspension hydrogenation 1 hour.With the gained suspension filtered, after washing with alcohol, it is dried that filtrate is concentrated into, and obtains crude product (2-amino-4-chloro-phenyl-) methyl alcohol, is the light orange solid.Crude product flash chromatography on silica gel method purifying (with 0-3% ethanol/methylene wash-out).Make solvent evaporation to doing, obtain (2-amino-4-chloro-phenyl-) methyl alcohol (0.650g, 77%), be the light orange solid.

NMR composes (DMSOd ₆ ): 4.34 (d, 2H), 5.06 (t, 1H), 5.20 (s, 2H), 6.51 (dd, 1H), 6.64 (d, 1H), 7.05 (d, 1H).

With (2-amino-4-chloro-phenyl-) methyl alcohol (100mg, 0.63mmol), 2, (99mg, 0.67mmol) (0.221ml, 2-amyl alcohol solution (2ml) 1.27mmol) stirred 3.5 days down at 100 ℃ the 4-dichloro pyrimidine with N-ethyl-N-sec.-propyl third-2-amine (DIPEA).After reaction mixture being concentrated into do, between ethyl acetate and water, distribute.The water ethyl acetate extraction, the salt water washing of the organic phase of merging concentrates after dried over mgso, obtains crude product, is orange.Crude product flash chromatography on silica gel method purifying (with 0-50% ethyl acetate/dichloromethane wash-out).Make solvent evaporation to doing, obtain (4-chloro-2-(2-chloropyrimide-4-base is amino) phenyl) methyl alcohol (38.0mg, 22%), be colorless oil, crystallization when leaving standstill. Mass spectrum: M+H ⁺270.

NMR composes (DMSOd ₆ ): 4.46 (s, 2H), 5.36 (bs, 1H), 6.67 (d, 1H), 7.32 (dd, 1H), 7.51 (d, 1H), 7.55 (d, 1H), 8.15 (d, 1H), 9.47 (bs, 1H).

The method part

Method 1

2-chloro-N-(3-chloro-2,4-two fluoro-phenyl) pyrimidine-4-amine

With 2, the 4-dichloro pyrimidine (6.0g, 40.5mmol), 3-chloro-2,4 difluorobenzene amine (6.28g, 38.5mmol), diisopropylethylamine (9.16ml, 52.7mmol) and the mixture of amylalcohol (20ml) refluxed 24 hours.Behind the concentrating under reduced pressure, resistates is dissolved in ethyl acetate, the solution with water washing, dry back concentrates.Crude product grinds with methylene dichloride, collects white solid after filtration, obtains the required product of 2.1g.Make filtrate concentrating,, obtain other 1.9g product (ultimate production: 4.0g, 36%) with silica gel purification (10-50%EtOAc/ sherwood oil). The NMR spectrum(500MHz, DMSOd ₆) 6.80 (d, 1H), 7.38 (ddd, 1H), 7.74 (ddd, 1H), 8.21 (d, 1H), 9.95 (bs, 1H); Mass spectrumMH ⁺276.

2-chloro-N-(3-chloro-2,4-two fluoro-phenyl)-N-methyl-pyrimidine-4-amine

To 2-chloro-N-(3-chloro-2,4-two fluoro-phenyl) pyrimidine-4-amine (2.45g, 8.91mmol) and Cs ₂CO ₃(5.79g, (0.55ml 8.91mmol), spends the night the mixture stirring to drip methyl iodide in 15ml acetonitrile suspension 17.8mmol).Reduction vaporization is dissolved in methylene dichloride with resistates, and solution is filtered the back evaporation.Resistates obtains 2-chloro-N-(3-chloro-2,4-two fluoro-phenyl)-N-methyl-pyrimidine-4-amine (2.20g, 86%) with silica gel purification (10-30%EtOAc/ sherwood oil), is oily matter, solidifies when leaving standstill.

The NMR spectrum(500MHz, DMSOd ₆) 3.36 (s, 3H), 6.53 (bs, 1H), 7.49 (ddd, 1H), 7.62 (ddd, 1H), 8.15 (bs, 1H); Mass spectrumMH ⁺290.

Method 2

[3-[(2-chloropyrimide-4-yl) amino]-4-methyl-phenyl] methyl alcohol

With 2, the 4-dichloro pyrimidine (4g, 27mmol), (3-amino-4-aminomethyl phenyl) methyl alcohol (3.7g, 27mmol), (4.13ml's triethylamine 29.7mmol) refluxed 18 hours with the mixture of ethanol (20ml).Behind the concentrating under reduced pressure, resistates is dissolved in ethyl acetate, the solution with water washing, dry back concentrates.Crude product silica gel chromatography purifying (elutriant: 5% methyl alcohol/DCM).After collecting flow point, make solvent evaporation, resistates is stirred in DCM (60ml), filter the final vacuum drying, obtain title compound (2.6g, 39%). The NMR spectrum(500MHz, DMSOd ₆) 2.15 (s, 3H), 4.46 (d, 2H), 5.18 (t, 1H), 6.44 (m, 1H), 7.14 (d, 1H), 7.22 (s, 1H), 7.25 (d, 1H), 8.07 (d, 1H), 9.55 (bs, 1H);

Mass spectrum

MH

⁺250.

[3-[(2-chloropyrimide-4-yl)-methyl-amino]-4-methyl-phenyl] methyl alcohol

At room temperature, with methyl iodide (1.37ml, 22.1mmol) be added drop-wise to [3-[(2-chloropyrimide-4-yl) amino]-4-methyl-phenyl] and methyl alcohol (5.0g, 20.1mmol) and Cs ₂CO ₃(13.1g, 40.2mmol) with the suspension of DMF (30ml) in.Mixture at room temperature stirred spend the night.Reduction vaporization is dissolved in DCM with resistates, and solution is filtered the back evaporation.Resistates silica gel chromatography purifying (20-100%EtOAc/ sherwood oil), obtain [3-[(2-chloropyrimide-4-yl)-methyl-amino]-4-methyl-phenyl] methyl alcohol (3.2g, 61%), be solid.

The NMR spectrum(500MHz, DMSOd ₆) 2.06 (s, 3H), 3.32 (s, 3H), 4.50 (d, 2H), 5.25 (t, 1H), 5.80 (d, 1H), 7.20 (s, 1H), 7.31 (m, 1H), 7.38 (m, 1H), 7.94 (d, 1H); Mass spectrumMH ⁺264.

Method 3

At room temperature, corresponding br-derivatives (6.02mmol) is added drop-wise to [3-[(2-chloropyrimide-4-yl) amino]-4-methyl-phenyl] and methyl alcohol (method 2,1.5g, 6.02mmol), Cs ₂CO ₃(2.94g 9.04mmol) and in the suspension of tetrabutylammonium iodide (100mg) reaches 48 hours.Behind the solid filtering, make filtrate evaporated under reduced pressure, resistates is dissolved in DCM, gained solution is filtered the back evaporation.Resistates silica gel chromatography purifying (10-50%EtOAc/ sherwood oil) obtains required compound:

Title	Initial bromoalkane	Yield	??MH ⁺	??NMR(500MHz，??DMSOd ₆)
Title	Initial bromoalkane	Yield	??MH ⁺	??NMR(500MHz，??DMSOd ₆)	[3-[(2-chloropyrimide-4-yl)-third-2-base-amino]-4-methyl-phenyl] methyl alcohol	The 2-N-PROPYLE BROMIDE	??26％	??292	??0.96(d，3H)，1.28(d，3H)，??2.04(s，3H)，4.51(d，2H)，??4.97(m，1H)，5.26(t，1H)，??5.59(m，1H)，7.10(s，1H)，??7.33(d，1H)，7.39(d，1H)，??7.91(m，1H)
[3-[(2-chloropyrimide-4-yl)-(2-methyl-propyl) amino]-4-methyl-phenyl] methyl alcohol	1-bromo-2-methylpropane	??37％	??306	??0.92(d，3H)，0.93(d，3H)，??1.90(m，1H)，2.05(s，3H)，??3.30(m，1H)，4.02(m，1H)，??4.50(br?d，2H)，5.25(br?s，??1H)，5.73(m，1H)，7.17(s，??1H)，7.30(d，1H)，7.38(d，??1H)，7.93(m，1H)		The 2-N-PROPYLE BROMIDE	??26％	??292

Title	Initial bromoalkane	Yield	??MH ⁺	??NMR(500MHz，??DMSOd ₆)
Title	Initial bromoalkane	Yield	??MH ⁺	??NMR(500MHz，??DMSOd ₆)	[3-[(2-chloropyrimide-4-yl)-(cyclopropyl methyl) amino]-4-methyl-phenyl] methyl alcohol	Brooethyl-cyclopropane	??71％	??304	??0.15(m，2H)，0.42(m，2H)，??1.05(m，1H)，2.09(s，3H)，??3.65(m，1H)，3.75(m，1H)，??4.50(d，1H)，5.24(brt，2H)，??5.73(d，1H)，7.22(s，1H)，??7.30(d，1H)，7.37(d，1H)，??7.93(d，1H)
[3-[(2-chloropyrimide-4-yl)-ethyl-amino]-4-methyl-phenyl] methyl alcohol	Monobromethane	??57％	??278	??1.14(t，3H)，2.06(s，3H)，??3.65(m，1H)，4.04(m，1H)，??4.50(d，2H)，5.24(br?t，1H)，??5.73(d，1H)，7.16(s，1H)，??7.32(d，1H)，7.39(d，1H)，??7.92(d，1H)		Brooethyl-cyclopropane	??71％	??304

Method 4

4-(3-morpholine-4-base-5-nitro-phenyl) morpholine

With 3, (50g, 314mmol) (164ml, mixture 1.89mol) heated 24 hours down at 160 ℃ 5-two fluoro-1-oil of mirbane with morpholine with anhydrous DMSO (25ml).Add anhydrous DMSO (12.5ml) again, mixture is added heat 66 hours under 160 ℃.After the cooling, mixture is diluted in DCM, after water and the salt water washing, through MgSO ₄Dry.After the solvent evaporation, resistates silica gel chromatography purifying (elutriant: 5%EtOAc/DCM), obtain 4-(3-morpholine-4-base-5-nitro-phenyl) morpholine (53.3g, 58%), be orange solids.

The NMR spectrum: (DMSOd ₆) 3.21 (m, 8H), 3.73 (m, 8H), 6.84 (s, 1H), 7.15 (s, 2H); Mass spectrum: MH ⁺294.

Method 5

4-(3-iodo-5-nitro-phenyl) morpholine

With 1-fluoro-3-iodo-5-oil of mirbane (0.97g, 3.63mmol), morpholine (3.16ml, 36.3mmol) and the mixture of DMSO (3ml) 90 ℃ of down heating 4 hours.After the cooling, add entry, collect gained yellow mercury oxide (1.12g, 93%) after filtration. The NMR spectrum(500MHz, DMSOd ₆) 3.24-3.26 (m, 4H), 3.71-3.73 (m, 4H), 6.64 (s, 1H), 7.67 (s, 1H), 7.83 (s, 1H). Mass spectrum: MH ⁺335.

Method 6

4-(3-nitro-5-thiomorpholine-4-base-phenyl) morpholine

With 4-(3-iodo-5-nitro-phenyl) morpholine (method 5,300mg, 1.0mmol), cesium carbonate (1.66g, 5.1mmol), Pd (OAc) ₂(11mg, 0.051mmol), BINAP (12mg, 0.02mmol) and thiomorpholine (205 μ l 2.0mmol) refluxed 3 hours with mixture heating up with the toluene (10ml) of argon-degassed.After the cooling, solvent removed in vacuo is dissolved in ethyl acetate with resistates, through diatomite filtration, and filtrate water washing, dry and evaporation.Crude product obtains 140mg (44%) yellow solid with silica gel purification (100% methylene dichloride). The NMR spectrum(500MHz, DMSOd ₆) 2.65-2.66 (m, 4H), 3.19-3.21 (m, 4H), 3.63-3.65 (m, 4H), 3.72-3.74 (m, 4H), 6.80 (s, 1H), 7.10 (s, 1H), 7.12 (s, 1H).

Adopt and use the same method, replace morpholine, obtain following compounds with suitable amine:

Method 7

1-iodo-3-(2-methoxy ethoxy)-5-nitro-benzene

With sodium hydride (60%, 408mg, (2.68ml is in DMA 34mmol) (8ml) solution 10.2mmol) to be added to 2-methyl cellosolve.After at room temperature 5 minutes, add 1-iodo-3, (2.0g 6.8mmol), heats mixture 3 hours down at 100 ℃ the 5-dinitrobenzene.After the cooling, add entry, gained mixture extracted with diethyl ether.Organic phase is evaporated after drying, and resistates obtains orange (1.3g, 59%) with silica gel purification (100%DCM). The NMR spectrum(500MHz, DMSOd ₆) 3.30 (s, 3H), 3.66 (t, 2H), 4.24 (t, 2H), 7.72 (s, 1H), 7.78 (s, 1H), 8.06 (s, 1H).

Method 8

4-(3-methoxyl group-5-nitro-phenyl) morpholine

With 1.0g (3.4mmol) 1-iodo-3-methoxyl group-5 oil of mirbane (J.Med.Chem.2000, the 43rd volume, 1670-1683 page or leaf), cesium carbonate (5.54g, 17mmol), Pd (OAc) ₂(38mg, 0.17mmol), BINAP (42mg, 0.068mmol) and morpholine (355 μ l 4.1mmol) refluxed 3 hours with mixture heating up with the toluene (40ml) of argon-degassed.After the cooling, solvent removed in vacuo is dissolved in ethyl acetate with resistates, through diatomite filtration, and filtrate water washing, dry and evaporation.Crude product obtains 775mg (96%) yellow solid with silica gel purification (100% methylene dichloride). The NMR spectrum(500MHz, DMSOd ₆) 3.21-3.23 (m, 4H), 3.72-3.74 (m, 4H), 3.84 (s, 3H), 6.88 (t, 1H), 7.14 (t, 1H), 7.32 (t, 1H). Mass spectrum: MH ⁺239.

4-[3-(2-methoxy ethoxy)-5-nitro-phenyl] morpholine

According to the method same, prepare title compound (method 7, yield 71%) by 1-iodo-3-(2-methoxy ethoxy)-5-nitro-benzene with aforesaid method. The NMR spectrum(500MHz, DMSOd ₆) 3.21-3.23 (m, 4H), 3.30 (s, 3H), 3.66 (t, 2H), 3.72-3.74 (m, 4H), 4.19 (t, 2H), 6.90 (t, 1H), 7.15 (t, 1H), 7.32 (t, 1H). Mass spectrum: MH ⁺283.

Method 9

3,5-dimorpholine-4-base aniline

In the presence of 10% palladium charcoal (5g), make 4-(3-morpholine-4-base-5-nitro-phenyl) morpholine (method 4,53.3g, ethanolic soln 182mmol) (700ml) hydrogenation 17 hours under normal atmosphere and room temperature.Behind the solid filtering, with the DMF washing, with gained filtrate vacuum concentration.After resistates grinds with ether, vacuum-drying.This solid is dissolved in DCM.Gained solution is filtered, add ether.The gained solid is high vacuum dry after filtering, obtains 3, and 5-dimorpholine-4-base aniline (46.5g, 97%) is beige solid.

The NMR spectrum: (DMSOd ₆) 2.97 (m, 8H), 3.68 (m, 8H), 4.74 (s, 2H), 5.69 (s, 2H), 5.73 (s, 1H); Mass spectrum: MH ⁺264.

After the same method, obtain following compounds:

^aUse platinum oxide (IV) to replace palladium charcoal as catalyzer.

Method 10

4-(3-methyl sulphonyl-5-nitro-phenyl) morpholine

With 1-fluoro-3-iodo-5-oil of mirbane (8.36g, 31.3mmol), cuprous iodide I (11.9g, 62.6mmol) and methane-sulfinic acid sodium (5.65g, purity 85%, 47mmol) with the mixture of DMF (50ml) 110 ℃ of following heated overnight.After the cooling, mixture is poured into after-filtration in the mixture of ethyl acetate and water.Separate organic layer, dry final vacuum concentrates.Resistates silica gel chromatography purifying (elutriant: DCM), obtain 1-fluoro-3-methyl sulphonyl-5-oil of mirbane (4.49g, 65%), be light solid; The NMR spectrum(500MHz, DMSOd ₆) 3.42 (s, 3H), 8.33 (m, 1H), 8.52 (m, 2H).

With 1-fluoro-3-methyl sulphonyl-5-oil of mirbane (2.42g, 15.2mmol) and morpholine (5.3ml, 60.9mmol) with the mixture of DMSO (5ml) 110 ℃ of heating 30 minutes down.After the cooling, add entry.The gained throw out is filtered, wash the back high vacuum dry with water, obtain 4-(3-methyl sulphonyl-5-nitro-phenyl) morpholine (2.91g, 67%), be orange solids. The NMR spectrum(500MHz, DMSOd ₆) 3.30-3.42 (m+s, 7H), 3.77 (m, 4H), 7.77 (m, 1H), 7.94 (m, 2H).

Adopt and use the same method, replace the morpholine of second step, obtain following compounds with suitable amine:

^aProduct silica gel purification (0-5%MeOH/EtOAc).

^bProduct silica gel purification (0-2%MeOH/DCM).

^cProduct preparation HPLC system purifying.

Method 11

3-methyl sulphonyl-5-morpholine-4-base-aniline

At 10% palladium charcoal (1g) when existing, make 4-(3-methyl sulphonyl-5-nitro-phenyl) morpholine (method 10,4.85g, ethanolic soln 16.9mmol) (70ml) hydrogenation 3 hours under 1.4 bar pressures, room temperature.Behind the solid filtering, with the DMF washing, with gained filtrate vacuum concentration.Resistates silica gel chromatography purifying (elutriant: 50%-70%EtOAc/DCM), obtain 3-methyl sulphonyl-5-morpholine-4-base-aniline (4.12g, 95%), be yellow solid.

The NMR spectrum: (DMSOd ₆) 3.08 (m, 7H), 3.72 (m, 4H), 5.49 (s, 2H), 6.37 (s, 1H), 6.56 (m, 2H); Mass spectrum: MH ⁺257.

After the same method, obtain following compounds:

Title	Yield	??MH+	??NMR(500MHz)
Title	Yield	??MH+	??NMR(500MHz)	3-(4-methylpiperazine-1-yl)-5-methyl sulphonyl-aniline	??100％ ^a	??270	??(DMSO)2.21(s，3H)，2.42-2.44(m，4H)，3.08??(s，3H)，3.10-3.12(m，4H)，5.45(s，2H)，6.37??(s，1H)，6.52(s，1H)，6.55(s，1H).
2-[4-(3-amino-5-methyl sulphonyl-phenyl) piperazine-1-yl] ethanol	??87％ ^b	??300	??(CDCl3)2.60-2.63(m，2H)，2.65-6.7(m，4H)，??3.02(s，3H)，3.24-3.26(m，4H)，3.66-3.68(m，??2H)，6.37(s，1H)，6.68(s，1H)，6.85(s，1H).	3-(4-methylpiperazine-1-yl)-5-methyl sulphonyl-aniline	??100％ ^a	??270

1-[4-(3-amino-5-methyl sulphonyl-phenyl) piperazine-1-yl] ethyl ketone	??51％ ^b	??298	??(DMSO-d6)2.03(s，3H)，3.08-3.10(m+s，??5H)，3.14-3.16(m，2H)，3.55-3.57(m，4H)，??5.50(s，2H)，6.38(s，1H)，6.55(s，1H)，6.57??(s，1H).
	??51％ ^b	??298		1-(3-amino-5-methyl sulphonyl-phenyl) piperidines-4-alcohol	??72％	??271	??(DMSO-d6)1.41-1.44(m，2H)，1.77-1.81(m，??2H)，2.82-2.87(m，2H)，3.07(s，3H)，3.47-??3.50(m，2H)，3.61-3.64(m，1H)，4.69(d，1H)，??5.42(s，2H)，6.37(t，1H)，6.47(t，1H)，6.54(t，??1H).

^aThe crude product yield.

^bUse PtO ₂As catalyzer.

Method 12

4-[3-(brooethyl)-5-nitro-phenyl] morpholine

Under argon atmospher, (7.14ml, the THF solution of 1M 7.14mmol) are added to 3-morpholine-4-base-5-nitro-phenylformic acid (1.2g, 4.76mmol in batches with the THF solution of borane-THF complex compound; Glaxo International Patent Application WO 2003101959 embodiment 327 a parts, the 228th page) ice-cold solution in.Make mixture be warming up to room temperature, stir after 18 hours, slowly add the methyl alcohol quencher.After the solvent evaporation, resistates dilutes with salt solution, uses twice of ethyl acetate extraction.Organic layer water and salt water washing are through MgSO ₄Dry.Behind the evaporating solvent, obtain (3-morpholine-4-base-5-nitro-phenyl) methyl alcohol (1.1g, 97%), be yellow solid. The NMR spectrum(500MHz, DMSOd ₆) 3.23 (m, 4H), 3.75 (m, 4H), 4.56 (d, 2H), 5.44 (t, 1H), 7.33 (s, 1H), 7.54 (s, 1H), 7.60 (s, 1H).

At room temperature, with triphenylphosphine (3.96g, 15.1mmol) and carbon tetrabromide (5g, (1.8g is in DCM 7.56mmol) (130ml) solution 15.1mmol) to be added to (3-morpholine-4-base-5-nitro-phenyl) methyl alcohol.Mixture was at room temperature stirred 18 hours.After the solvent evaporation, and resistates silica gel chromatography purifying (elutriant: DCM), obtain 4-[3-(brooethyl)-5-nitro-phenyl] morpholine (1.6g, 70%), be yellow solid. The NMR spectrum(500MHz, DMSOd ₆) 3.25 (m, 4H), 3.75 (m, 4H), 4.76 (s, 2H), 7.51 (s, 1H), 7.60 (s, 1H), 7.71 (s, 1H).

Method 13

4-[3-(methoxymethyl)-5-nitro-phenyl] morpholine

At room temperature, with 4-[3-(brooethyl)-5-nitro-phenyl] morpholine (method 12,800mg, 2.66mmol) be added to the THF solution of sodium methylate (7.44mmol) [by with methyl alcohol (0.301ml, 7.44mmol) be added to sodium hydride (298mg, 60% oil solution 7.44mmol) and in the ice-cold suspension of THF (15ml) prepares] in.Mixture was at room temperature stirred 18 hours.After the solvent evaporation, residue diluted with water extracts with DCM.Organic layer evaporates through the dried over mgso final vacuum.Resistates silica gel chromatography purifying (elutriant: 0%-7%EtOAc/DCM), obtain 4-[3-(methoxymethyl)-5-nitro-phenyl] morpholine (582mg, 87%), be oily matter, crystallization when leaving standstill. The NMR spectrum(500MHz, DMSOd ₆) 3.24 (m, 4H), 3.33 (s, 3H), 3.75 (m, 4H), 4.48 (s, 2H), 7.33 (s, 1H), 7.56 (s, 1H), 7.59 (s, 1H); Mass spectrum: MH ⁺253.

4-[3-nitro-5-(third-2-base oxygen ylmethyl) phenyl] morpholine

Adopt method same as described above, make 4-[3-(brooethyl)-5-nitro-phenyl] and morpholine (700mg 2.33mmol) with the sodium isopropylate reaction, obtains 4-[3-nitro-5-(third-2-base oxygen ylmethyl) phenyl] morpholine (375mg, 58%), be oily matter. The NMR spectrum(500MHz, DMSOd ₆) 1.16 (d, 6H), 3.23 (m, 4H), 3.65 (m, 1H), 3.75 (m, 4H), 4.52 (s, 2H), 7.33 (s, 1H), 7.57 (s, 2H); Mass spectrum: MH ⁺281.

Method 14

With 4-[3-(brooethyl)-5-nitro-phenyl] morpholine (method 12,325mg, 1.08mmol), corresponding amine (1.3mmol), salt of wormwood (298mg, 2.2mmol) and the mixture of tetrabutylammonium iodide (30mg) and acetonitrile (4ml) heated 3 hours down at 45 ℃.After the cooling, mixture dilutes with DCM.The gained solid is leached.

Make filtrate concentrating, obtain corresponding amine, be solid:

Method 15

N, N-dimethyl-3-morpholine-4-base-5-nitro-benzamide

With oxalyl chloride (4.03ml, 47.6mmol) and DMF (1) be added to 3-morpholine-4-base-5-nitro-phenylformic acid successively (800mg be in DCM 3.17mmol) (4ml) suspension.Mixture was refluxed 30 minutes.After the cooling, it is dried that mixture is concentrated into, dilution in DCM (2ml), obtain 3-morpholine-4-base-5-nitro-Benzoyl chloride solution, with its be added drop-wise to dimethylamine hydrochloride (517mg, 6.34mmol) and diisopropylethylamine (1.66ml, 9.52mmol) with the ice-cold solution of DCM (4ml) in.Stirring is after 20 minutes down at 0 ℃, and the mixture dilute with water extracts with DCM.Organic layer evaporates through the dried over mgso final vacuum.Resistates silica gel chromatography purifying (elutriant: 0%-20%EtOAc/DCM), obtain N, N-dimethyl-3-morpholine-4-base-5-nitro-benzamide (847mg, 96%).

The NMR spectrum(500MHz, DMSO _d6) 2.90 (s, 3H), 2.99 (4H), 3.74 (m, 4H), 7.37 (s, 1H), 7.54 (s, 1H), 7.69 (s, 1H). Mass spectrum: MH ⁺280.

Method 16

3-morpholine-4-base-5-nitro-cyanobenzene

With 3-morpholine-4-base-5-nitro-phenylformic acid (1.5g, 5.95mmol) and 7N methyl alcohol/ammonia (1.7ml) replacement dimethylamine hydrochloride, method described in the repetition methods 15, obtain 3-morpholine-4-base-5-nitro-benzamide (961mg, 64%), be yellow solid, just the mixture of compound water and DCM grinds and separates, and filters after drying. The NMR spectrum(500MHz, DMSOd ₆) 3.30 (m, 4H), 3.77 (m, 4H), 7.64 (s, 1H), 7.78 (s, 1H), 7.82 (s, 1H), 8.08 (s, 1H), 8.26 (s, 1H); Mass spectrum: MH ⁺252.

With superpalite (2.77ml, 23mmol) be added drop-wise to 3-morpholine-4-base-5-nitro-benzamide (961mg, 3.83mmol) with the ice-cold mixture of trimethyl phosphite 99 (5ml) in.Mixture was heated 24 hours down at 60 ℃.After the cooling, water is added in the mixture.The gained throw out washes after drying with water after filtration.This solid silica gel chromatography purifying (elutriant: DCM), obtain 3-morpholine-4-base-5-nitro-cyanobenzene (693mg, 78%). The NMR spectrum(500MHz, DMSOd ₆) 3.34 (m, 4H), 3.74 (m, 4H), 7.83 (s, 1H), 7.91 (s, 1H), 7.99 (s, 1H).

Method 17

3-(methoxymethyl)-5-morpholine-4-base-aniline

Platinum oxide (IV) (60mg) in the presence of, with 4-[3-(methoxymethyl)-5-nitro-phenyl] (method 13,580mg, ethanolic soln 2.30mmol) (15ml) stir up to stopping to absorb hydrogen under hydrogen-pressure (normal atmosphere), room temperature morpholine.After catalyzer filtered, evaporating solvent obtained 3-(methoxymethyl)-5-morpholine-4-base-aniline (510mg, 100%), is oily matter, crystallization when leaving standstill; The NMR spectrum(500MHz, DMSOd ₆) 2.99 (m, 4H), 3.23 (s, 3H), 3.70 (m, 4H), 4.19 (s, 2H), 4.89 (m, 2H), 6.05 (m, 3H); Mass spectrum: MH ⁺223.

Adopt and use the same method, obtain following aniline:

^aUse palladium charcoal to replace platinum oxide as catalyzer.

Method 18

3-amino-N, N-dimethyl-5-morpholine-4-base-benzamide

In the presence of 10% palladium charcoal (200mg), with N, (ethyl acetate 2.98mmol) (20ml)-ethanol (20ml) solution stirs up to stopping to absorb hydrogen under nitrogen atmosphere (40psi), room temperature N-dimethyl-3-morpholine-4-base-5-nitro-benzamide for method 15,833mg.After catalyzer filtered, evaporating solvent obtained 3-amino-N, and N-dimethyl-5-morpholine-4-base-benzamide (510mg, 100%) is white solid. The NMR spectrum(500MHz, DMSOd ₆) 2.50 (s, 3H), 3.01 (s, 3H), 3.34 (m, 4H), 3.70 (m, 4H), 5.07 (m, 2H), 6.01 (s, 1H), 6.06 (s, 1H), 6.17 (s, 1H). Mass spectrum: MH ⁺250.

Method 19

3-amino-5-morpholine-4-base-cyanobenzene

With 3-morpholine-4-base-5-nitro-cyanobenzene (method 16,693mg, 2.97mmol), ammonium formiate (1.87g, 29.7mmol) and the mixture heating up of 10% palladium charcoal (150mg) and THF (15ml) refluxed 3 hours.Make solvent evaporation after the cooling, mixture is distributed in water and ethyl acetate mixture.After catalyzer filtered, organic layer was through MgSO ₄Dry also vacuum-evaporation obtains 3-amino-5-morpholine-4-base-cyanobenzene (527mg, 87%), is white solid.

The NMR spectrum(500MHz, DMSOd ₆) 3.05 (m, 4H), 3.70 (m, 4H), 5.41 (m, 2H), 6.33 (s, 1H), 6.39 (s, 1H), 6.49 (s, 1H); Mass spectrum: MH ⁺204.

Method 20

1-(3-amino-5-morpholine-4-base-phenyl) piperidines-4-alcohol

With 3, (500mg, 3.1mmol) (317mg, DMSO 3.1mmol) (3ml) solution heated 2 hours down at 100 ℃ 5-two fluoro-oil of mirbane with the 4-hydroxy piperidine.Add morpholine (1.3ml) then, mixture was heated 16 hours down at 155 ℃.Add DMSO (1ml) and morpholine (1ml), again mixture was stirred 3 hours down at 177 ℃.Reaction mixture is distributed between ether and water, and organic layer washs with saturated solution of sodium bicarbonate, dry and evaporation.Crude product obtains 116mg (yield 12%) 1-(3-morpholine-4-base-5-nitro-phenyl) piperidines-4-alcohol with silica gel purification (0-100% dichloromethane/ethyl acetate), is orange solids. The NMR spectrum(500MHz, DMSOd ₆) 1.42-1.46 (m, 2H), 1.79-1.82 (m, 2H), 2.92-2.98 (m, 2H), 3.18-3.20 (m, 4H), 3.60-3.67 (m, 3H), 3.72-3.74 (m, 4H), 4.69 (d, 1H), 6.82 (s, 1H), 7.08 (s, 1H), 7.13 (s, 1H). Mass spectrum: MH ⁺308.

Platinum oxide (IV) (80mg) in the presence of, (106mg, 0.34mmol) solution with ethyl acetate (3ml) and ethanol (3ml) stirs up to stopping to absorb hydrogen under nitrogen atmosphere (50psi), room temperature with 1-(3-morpholine-4-base-5-nitro-phenyl) piperidines-4-alcohol.After catalyzer filtered, evaporating solvent obtained title compound (96mg, 100%). Mass spectrum: MH ⁺278.

Method 21

4-chloro-N-(3,5-dimorpholine-4-base phenyl) pyrimidine-2-amine

With sodium hydride (60%, 0.99g, 24.7mmol) be added to N-(3 in batches, 5-dimorpholine-4-base phenyl) methane amide (4.5g, 15mmol) [preparation method is as follows: with 3,5-dimorpholine-4-base aniline (method 9, formic acid 10g) (100ml) vlil 3 hours, after making solvent evaporation, distribute, handle (1-4%MeOH/DCM) with silica gel chromatography with ethyl acetate/sodium bicarbonate aqueous solution] with the ice-cold solution of THF (130ml) in.Mixture was at room temperature stirred 15 minutes, then 0 ℃ of cooling down.4-chloro-2-sulfonyloxy methyl yl pyrimidines (3.26g, 17mmol, L.Xu etc., J.Org.Chem.2003,68,5388) is added in the mixture in batches.Reactant is warming up to stirs after the room temperature and spend the night.Add aqueous sodium hydroxide solution (2N, 14ml) and methyl alcohol (20ml), with mixture stirring 1 hour.Behind the vacuum concentration, resistates is dissolved in methylene dichloride, washes with water, dry and evaporation after the ether grinding, obtains beige solid (4.2g, 73%). The NMR spectrum(500MHz, DMSO) 3.05-3.07 (m, 8H), 3.72-3.73 (m, 8H), 6.19 (s, 1H), 6.88 (s, 2H), 6.91 (d, 1H), 8.41 (d, 1H), 9.73 (s, 1H); Mass spectrumMH ⁺376.

Method 22

(3-methylamino phenyl) methyl alcohol

(1.0g 8.1mmol) refluxed 2 hours in formic acid (15ml) to make 3-amino-benzene methyl alcohol.Vacuum is dissolved in ethyl acetate with resistates, and uses saturated solution of sodium bicarbonate and salt water washing successively after removing formic acid removal, and dry back concentrates, and obtains (3-formamido group phenyl) methyl-formiate (1.28g, 88%), is oily matter.

Mass spectrum

MH

⁺180.

(1.7g, (0.64g, in DMF 3.5mmol) (15ml) solution, (0.24ml 3.9mmol), at room temperature stirred mixture 3 hours to add methyl-iodide then 5.3mmol) to be added to (3-formamido group phenyl) methyl-formiate with cesium carbonate.After making the reaction mixture vacuum concentration, resistates is dissolved in methylene dichloride.Precipitated solid is filtered, and concentrated filtrate obtains [3-(formyl radical-methyl-amino) phenyl] methyl-formiate, is oily matter.After this product is dissolved in methyl alcohol (3ml), add 4N aqueous sodium hydroxide solution (3ml).Reaction mixture was heated 2 hours down at 70 ℃, make solution concentration afterwards, and neutralize with the ammonium chloride saturated solution.The salt water washing of aqueous solution extracted with diethyl ether, organic layer, dry and evaporation obtains (3-methylamino phenyl) methyl alcohol, is oily matter (400mg, the yield 82% of two steps). The NMR spectrum(500MHz, DMSO) 2.65 (d, 3H), 4.37 (d, 2H), 4.99 (t, 1H), 5.54 (d, 1H), 6.38 (d, 1H), 6.47 (d, 1H), 6.50 (s, 1H), 7.00 (t, 1H); Mass spectrumMH ⁺138.

The following aniline of same preparation:

^aAdopt methyl alcohol (20ml) as solvent, at room temperature use the aqueous isopropanol (4ml) of 5N hydrogenchloride to carry out deprotection steps.

Method 23

2-chloro-N-(5-methoxyl group-2-methyl-phenyl) pyrimidine-4-amine

According to the method identical, adopt 2-methyl-5-anisidine preparation with method 2.Crude product obtains title compound, yield 40% with silica gel purification (10-40% ethyl acetate/petroleum ether). The NMR spectrum(500MHz, DMSOd ₆) 2.11 (s, 3H), 3.72 (s, 3H), 6.52 (bs, 1H), 6.78 (dd, 1H), 6.95 (s, 1H), 7.19 (d, 1H), 8.08 (d, 1H), 9.49 (bs, 1H).

2-chloro-N-(5-methoxyl group-2-methyl-phenyl)-N-methyl-pyrimidine-4-amine

According to the method identical, adopt 2-chloro-N-(5-methoxyl group-2-methyl-phenyl) pyrimidine-4-amine preparation with method 2. The NMR spectrum(500MHz, DMSOd ₆) 2.00 (s, 3H), 3.30 (s, 3H), 3.74 (s, 3H), 5.84 (d, 1H), 6.91 (s, 1H), 6.95 (d, 1H), 7.33 (d, 1H), 7.93 (d, 1H); Mass spectrumMH ⁺264.

Method 24

N-[2-[(2-chloropyrimide-4-yl) amino]-4-methoxyl group-phenyl] ethanamide

According to the method identical with method 2, adopt the preparation of N-(2-amino-4-methoxyl group-phenyl) ethanamide, carried out 15 hours in 110 ℃ but be reflected among the DMF. The NMR spectrum(500MHz, DMSOd ₆) 1.99 (s, 3H), 3.74 (s, 3H), 6.64 (d, 1H), 6.80 (dd, 1H), 7.13 (s, 1H), 7.40 (d, 1H), 8.12 (d, 1H), 9.24 (s, 1H), 9.34 (s, 1H).

N-[2-[(2-chloropyrimide-4-yl)-methyl-amino]-4-methoxyl group-phenyl] ethanamide

According to the method identical, adopt 2-chloro-N-(5-methoxyl group-2-methyl-phenyl) pyrimidine-4-amine preparation with method 2. The NMR spectrum(500MHz, DMSOd ₆) 1.91 (s, 3H), 3.27 (s, 3H), 3.74 (s, 3H), 5.96 (bs, 1H), 6.94-6.98 (m, 2H), 7.66 (d, 1H), 7.94 (bs, 1H), 9.25 (bs, 1H); Mass spectrumMH ⁺307.

Method 25

4-chloro-N-(3,5-dimorpholine-4-base phenyl)-N-[(4-p-methoxy-phenyl) methyl] pyrimidine-2-amine

With sodium hydride (1.66g, 41.6mmol, 60% oil solution) be added in batches 4-chloro-N-(3,5-dimorpholine-4-base phenyl) pyrimidine-2-amine (13g, 34.6mmol) with the ice-cold solution of THF (100ml) in.After at room temperature stirring 2 hours, with 4-methoxy-benzyl bromine (6.57ml, 45.1mmol) and potassiumiodide (100mg) be added in the mixture back and add DMF (10ml).The gained mixture was at room temperature stirred 15 hours.Mixture distributes with ammonium chloride saturated aqueous solution and ethyl acetate, further extracts with ethyl acetate.After merging organic layer, through dried over mgso.Make solvent evaporation, resistates silica gel chromatography purifying (elutriant: the 40%-100% ethyl acetate/petroleum ether), after ether/sherwood oil grinding, obtain title compound (12.37g, 72%), be white solid. The NMR spectrum: (DMSOd ₆) 3.01 (m, 8H), 3.70 (m, 11H), 5.05 (s, 2H), 6.23 (s, 2H), 6.33 (s, 1H), 6.82 (m, 3H), 7.17 (d, 2H), 8.29 (d, 1H); Mass spectrum: MH ⁺496.

Claims

1. the compound of a following formula I or its pharmacy acceptable salt:

Wherein:

N is 0,1,2 or 3;

-Q-R ⁸

R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

Cyano group;

Halogen;

The following formula group:

-W-R ⁹

R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-4C) alkyl;

(iii) group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen separately or by halogen, hydroxyl, cyano group or (1-4C) optional (1-6C) alkyl (3-6C) cycloalkyl that replaces of alkoxyl group or (3-6C) cycloalkyl (1-2C) alkyl, perhaps R ¹²And R ¹³Couple together and form 4,5,6 or 7 yuan of heterocycles, described ring removes and contains R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto, also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S, and any S atom that wherein exists all can be by optional SO and the SO of being oxidized to ₂Group, and any carbon atom that wherein is present in the ring is all chosen wantonly replacement by following group: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-4C) alkoxyl group, (1-2C) alkyl of alkoxyl group-(1-4C), (1-4C) alkyloyl, (1-4C) alkanesulfonyl, (1-4C) alkoxy carbonyl, (1-6C) alkyl amino-carbonyl or two-(1-6C) alkyl amino-carbonyls, and any available nitrogen atom that is present in the ring is all chosen wantonly replacement by following group: (1-4C) alkyl, hydroxyl (1-4C) alkyl, (1-2C) alkoxyl group-(1-4C) alkyl or (1-4C) alkyloyl; Perhaps

The (iv) group of following formula (II):

-X-R ¹⁴

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

R ¹⁴For by halogen, hydroxyl, cyano group or (1-4C) optional (1-4C) alkyl, (3-6C) cycloalkyl, (3-6C) cycloalkyl (1-2C) alkyl, amylene oxide base or tetrahydrofuran base, the perhaps R that replaces of alkoxyl group ¹⁴For

-NR ¹⁵R ¹⁶

Precondition is:

If n is 1 and R ²Be (1-2C) alkoxyl group, then this alkoxyl group is not positioned at respect to-NR ¹Promptly 4 of the contrapositions of-group:

If n is 1 and R ²Be oxyethyl group, then this oxyethyl group is not positioned at respect to-NR ¹The position is promptly 3 between-group;

If R ²Be formula-Q-R ⁸Group, then R ⁴Be not 4-methylpiperazine-1-base, wherein Q is NR ^a-CO-, R ^aBe hydrogen, R ⁸Be (1-2C) alkyl.

2. the I compound of a following formula:

Wherein:

N is 0,1,2 or 3;

-Q-R ⁸

R ³Be selected from:

(i) hydrogen, halogen, nitro, cyano group or hydroxyl;

(ii) optional (1-6C) alkyl that replaces, (2-6C) thiazolinyl or (2-6C) alkynyl, wherein Ren Xuan substituting group is selected from: cyano group, halogen, following formula group:

-W-R ⁹

R ^bBe selected from hydrogen or (1-2C) alkyl;

R ⁹Be selected from hydrogen or (1-4C) alkyl;

The (iv) group of following formula (II):

-X-R ¹⁴

R wherein ^cBe selected from hydrogen or (1-2C) alkyl;

-NR ¹⁵R ¹⁶

Precondition is:

If R ²Be (1-2C) alkoxyl group, then this alkoxyl group is not positioned at respect to-NR ¹Promptly 4 of the contrapositions of-group;

3. the compound of claim 1 or claim 2 or its pharmacy acceptable salt, wherein R ¹For by one or more being selected from-OR ⁵(R wherein ⁵Be selected from hydrogen or (1-2C) alkyl) optional (1-4C) alkyl that replaces of substituting group.

4. each compound or its pharmacy acceptable salt, the wherein R of each existence among the claim 1-3 ²Group independently is selected from (1-2C) alkyl, (1-2C) alkoxyl group, fluorine, chlorine, cyano group, hydroxyl (1-2C) alkyl or following formula group:

-Q-R ⁸

Wherein Q be selected from-CO-,-NR ^a-CO-,-S (O) _z-(wherein z is 0,1 or 2), R ^aBe selected from hydrogen or methyl, R ⁸Be hydrogen or (1-2C) alkyl.

5. each compound or its pharmacy acceptable salt, wherein R among the claim 1-4 ³Be group-NR ¹²R ¹³, R wherein ¹²And R ¹³Independently be selected from hydrogen or (1-6C) alkyl, perhaps R separately ¹²And R ¹³Couple together and form 5,6 or 7 yuan of heterocycles, and wherein remove R ¹²And R ¹³Beyond the nitrogen-atoms that is attached thereto; described ring is also chosen wantonly and is contained the extra heteroatoms that one or two is selected from O, N or S; and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group, (1-4C) alkyl or (1-4C) alkanesulfonyl, and be present in any available nitrogen atom in the ring all by (1-4C) alkyl or (1-4C) alkyloyl is optional and replace.

6. each compound or its pharmacy acceptable salt, wherein R among the claim 1-5 ⁴Be group-NR ¹⁷R ¹⁸, R wherein ¹⁷And R ¹⁸Couple together and form 6 yuan of heterocycles, described ring removes and contains R ¹⁷And R ¹⁸Beyond the nitrogen-atoms that is attached thereto; also choose wantonly and contain the extra heteroatoms that one or two is selected from O, N or S; and wherein said ring is selected from by one or two on any effective carbon atom, and following substituting group is optional to be replaced: oxo, halogen, hydroxyl, cyano group or (1-4C) alkyl, and any available nitrogen atom is all replaced by following group is optional: (1-4C) alkyl, hydroxyl (1-4C) alkyl or (1-4C) alkyloyl.

7. the compound of claim 1 or its pharmacy acceptable salt, it is among the embodiment 1-25 any.

8. the compound of claim 1 or its pharmacy acceptable salt, described compound are [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidines-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol.

9. the compound of claim 8, described compound is:

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] free alkali form of methyl alcohol;

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] benzene sulfonate of methyl alcohol; Perhaps

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] tosylate of methyl alcohol.

10. the compound of claim 8 or claim 9, described compound is crystal formation.

11. the compound of claim 10, described compound is [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure has specific peak value near 2 θ=7.5 °, 22.2 °, 22.7 ° and 24.7 °.

12. the compound of claim 10, described compound is:

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=7.5 °, 10.1 °, 11.9 °, 12.3 °, 13.0 °, 13.6 °, 15.2 °, 16.3 °, 16.6 °, 17.4 °, 18.0 °, 18.6 °, 19.0 °, 19.8 °, 20.2 °, 20.6 °, 21.1 °, 22.2 °, 22.7 °, 23.8 °, 24.2 °, 24.7 °, 25.2 °, 26.2 °, 26.7 °, 27.6 °, 28.1 °, 28.8 °, 29.4 °, 31.5 °, 32.3 °, 34.0 °, 35.6 °, 36.2 °, 37.5 ° and 38.1 ° locate to have specific peak value;

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 1, when using the CuKa radiation measurement, its X-ray powder diffraction figure is in 2 θ=5.6 °, 8.7 °, 9.5 °, 10.3 °, 11.0 °, 11.3 °, 12.9 °, 14.8 °, 15.1 °, 15.4 °, 15.9 °, 16.3 °, 17.3 °, 18.2 °, 19.0 °, 19.6 °, 20.4 °, 20.8 °, 21.1 °, 21.4 °, 22.1 °, 23.0 °, 23.7 °, 24.3 °, 24.6 °, 25.2 °, 26.1 °, 26.7 °, 27.7 °, 28.5 °, 30.1 °, 31.0 °, 31.9 ° and 33.8 ° locate to have specific peak value; Perhaps

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 2, when using the CuKa radiation measurement, its X-ray powder diffraction figure in 2 θ=5.6 °, 8.6 °, 9.8 °, 11.1 °, 16.0 °, 16.7 °, 17.3 °, 17.7 °, 18.6 °, 20.9 °, 23.3 °, 23.9 °, 26.0 ° and 27.7 ° locate to have specific peak value.

13. the compound of claim 10, described compound is:

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol free alkali form 1, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure A;

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 1, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure B; Perhaps

-[3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol-benzene sulfonate form 2, its X-ray powder diffraction figure is basic identical with the X-ray powder diffraction figure shown in the figure C.

14. a medicament production, described medicament production comprise as formula I compound or its pharmacy acceptable salt and the vegf receptor tyrosine kinase inhibitor defined in each among the claim 1-13.

15. the medicament production of claim 14, described medicament production comprises [3-[[2-[(3,5-dimorpholine-4-base phenyl) amino] pyrimidine-4-yl]-methyl-amino]-4-methyl-phenyl] methyl alcohol or its pharmacy acceptable salt and 4-(4-fluoro-2 methyl indole-5-base oxygen base)-6-methoxyl group-7-(3-tetramethyleneimine-1-base propoxy-) quinazoline or its pharmacy acceptable salt.

16. a pharmaceutical composition, described pharmaceutical composition comprise among the claim 1-13 each compound or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.

17. as each compound or its pharmacy acceptable salt among the claim 1-13 of medicine.

18. be used for the treatment of among the claim 1-13 of cancer each compound or its pharmacy acceptable salt.

19. each compound or its pharmacy acceptable salt are used for the treatment of purposes in the medicine of cancer in preparation among the claim 1-13.

All can be protected by optional 20. a method for preparing the formula I compound defined in the claim 1, condition are any functional groups, L is suitable leavings group, and this method comprises makes following formula (VII) compound and the reaction of following formula (VI) compound:

And, thereafter if needed:

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

(ii) slough any protecting group; And/or

(iii) form its salt.