CN101137652A

CN101137652A - Pyrimidine compounds having tie2 (tek) inhibitory activity

Info

Publication number: CN101137652A
Application number: CNA2006800078550A
Authority: CN
Inventors: C·D·琼斯; R·W·A·卢克; W·麦克考尔
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-02-01
Filing date: 2006-01-27
Publication date: 2008-03-05
Also published as: GB0501984D0

Abstract

The invention relates to a compound of the Formula (I) or salt thereof wherein R<x>, R<y>, R<z>, R<5>, R<6>, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.

Description

Have TIE2(TEK) suppress active pyrimidine compound

The present invention relates to compound or its pharmacy acceptable salt, they have anti-angiogenic activity and can be used in view of the above in the methods of treatment of animal or the human body morbid state relevant with vascularization.The invention still further relates to the method for the described compound of preparation, contain described compound as the pharmaceutical composition of activeconstituents be used for producing the method for the described compound of use in the medicine of anti-angiogenic formation effect in manufacturing warm blooded animal (such as the mankind).

Tie2 receptor tyrosine kinase (being called TEK again) is mainly expressed in endotheliocyte and hematopoietic cell, for vascularization and keep most important (Jones, people such as N., NatureReviewsMolecular Cell Biology.2001:2,257-67).

Vasculogenesis is defined as the primary process that produces neovascularity from existing vascular system.It forms and the necessary bioprocess of physiological function for important and complicated in fact all organs.It is actually of short duration under the normal circumstances, and is related to angiogenesis factor in the multistep process that the blood vessel sprouting that causes by endotheliocyte, branch and tubule form (relating to for example endotheliocyte (EC) activation, blood vessel instability, synthetic and discharge degrading enzyme, EC migration, EC propagation, EC machineization and differentiation and mature blood vessel process) and the partial balancing of Angiostatin controls.

Normal vasculogenesis plays an important role in a plurality of processes and is subjected to strict control.In the grownup, physiological vasculogenesis major limitation is at the several sections of wound healing and women's reproductive function and fetal development.In unwanted or pathologic vessels generated, the partial balancing's imbalance between angiogenesis factor and the Angiostatin caused unsuitable and/or cacoplastic vascularization.Pathologic vessels generates and comprises diabetic retinopathy, psoriatic, cancer, rheumatoid arthritis, sebaceous cyst, Kaposi sarcoma and vascular tumor relevant (Fan etc., 1995, TrendsPharmacology.Science.16:57-66 with disease; Folkman, 1995, Nature Medicine 1:27-31).In cancer, surpass the primary tumor of 1-2mm3 and growth needs vasculogenesis (Folkman, the J.New England Journal of Medicine1995 of secondary tumor; 33,1757-1763).

In disorders such as cancers, its development depends on that abnormal vascular generates, and blocks the development (Folkman, J.1995, Nature Medicine.1:27-31) that can cause warding off disease of this process.Believe that many factor pair modulating vasculars generations of describing in the scientific literature have important effect.Two main class angiogenesis factors are vascular endothelial growth factor (VEGF) and angiogenin.These polypeptide portions and its acceptor (road film tyrosine kinase receptor is endotheliocyte high degree of specificity acceptor) separately interacts, by ligand-mediated signal conduction causing cell response.VEGF and angiogenin reach its acceptor separately, all respects of common modulating vascular generative process by sending signal during normal and pathologic vessels generate by inference.

Receptor tyrosine kinase (RTK) is in that biochemical signals is passed through in the transmission of cytoplasmic membrane is very important.These transmembrane molecules are characterised in that it is connected to intracellular tyrosine kinases territory by the plasma membrane segment by extracellular ligand-form in conjunction with the territory.Part and receptors bind produce to the stimulation of tyrosine kinase activity associated receptor, cause the tyrosine residues phosphorylation on the molecule in acceptor and other born of the same parents.These variations in tyrosine phosphorylation cause the signal cascade reaction that produces the various kinds of cell reaction.Up to now, at least 19 different RTK subtribes by the amino acid sequence homology definition have obtained evaluation.One of them of these subtribes at present by fms sample tyrosine kinase receptor Flt or Flt1, contain kinases and insert fragment domain receptor, KDR (being called Flk-1 again) and another kind of fms sample tyrosine kinase receptor Flt4 and form.Shown that among RTK, Flt that these are relevant and the KDR two combine (De Vries etc., 1992, Science255:989-991 with high-affinity with VEGF; Terman etc., 1992, Biochem.Biophys.Res.Comm.1992,187:1579-1586).VEGF is relevant with the tyrosine phosphorylation state and the effusive variation of calcium of cell protein with the combination of these acceptors of expressing in heterogenous cell.

Recently determined to regulate unstable and sophisticated second the endotheliocyte high degree of specificity receptor family of blood vessel.Tie acceptor and part thereof, angiogenin and VEGF acting in conjunction nearly during normal and pathologic vessels generate.Transmembrane receptor Tie1 and Tie2 constitute endothelial cell specific tyrosine kinase receptor family, and it relates to the integrity of keeping blood vessel, and the integrity of blood vessel relates to the vasculogenesis generation and blood vessel forms again.Tie1 and Tie2 have multiple same structure feature (born of the same parents' internal area of two kinds of these acceptors for example, each acceptor comprise the tyrosine kinase domain that is inserted the segment area blocking-up by kinases), therefore constitute different RTK subtribes.Tie1 and the Tie2 acceptor overall sequence homogeny on amino acid levels is 44%, and its born of the same parents' internal area has 76% homology.Target destruction to the Tie1 gene causes the phenotype that causes death, and it is characterized by extensively hemorrhage and capillary blood vessel integrity poor (Puri, 1995EMBO Journal:14:5884-5891 such as M.).Because the defective that embryonic blood vessel system major defect causes the transgenic mice of Tie2 defective angiogenic growth to occur and form, and the phenotype (E9.5-10.5) (Sato, 1995Nature370:70-74 such as T.) that causes death appears in midtrimester of pregnancy.

Up to now, do not prove conclusively the part of Tie1, its signal capabilities is almost known nothing.But believe that Tie1 is by influencing the Tie2 signal capabilities with Tie2 acceptor heterology dimerization, ability (the Marron of therefore potential adjusting Tie2 autophosphorylation, M. wait 2000Journal ofBiologicalChemistry:275,39741-39746), and recently chimeric Tie1 acceptor be studies show that Tie-1 can pass through PI3 kinases/Akt signal transduction path and suppress apoptosis (Kontos, C.D. etc., 2002Molecular and Cellular Biology:22,1704-1713).On the contrary, proved conclusively the multiple part of Tie2, the called after angiogenin, wherein angiogenin 1 (Ang1) is for preferably characterizing.Combine with Ang1 and to cause that the Tie2 receptor tyrosine is by the autophosphorylation phosphorylation with activate its signal pathway by the signal conduction subsequently.It is reported Ang2 these effects of antagonism in endotheliocyte (Maisonpierre, 1997Science:277 such as P., 55-60).It is necessary to the correct growth of neovasculature that the separation of Tie2 and part thereof and transgenosis are handled the strict space of prompting and temporary transient control Tie2 signal.Also have report to point out, has the possibility of heterology dimerization between other at least two kinds of parts (Ang3 and Ang4) and the angiogenin part, the angiogenin part has the potentiality of modification itself and receptor-binding activity (excitement/antagonism).In vascular endothelial cell, suppressed apoptosis (Papapetropoulos by Ang1 activated Tie2 acceptor, A. etc., 2000Journal of Biological Chemistry:2759102-9105), promote growth (Witzenbicher, B. etc., 1998Joumal of Biological Chemistry:273,18514-18521), promote mature blood vessel in vivo during the vasculogenesis and reduce ripe microvascular permeability and seepage (Thurston subsequently, G. etc., 2000Nature Medicine:6,460-463).Therefore report, activate branch, sprouting and formation that the Tie2 acceptor will be referred to neovascularity, and on every side the endothelium sustenticular cell raise that to keep the integrity of blood vessel very important with interaction partners, and all obviously consistent with the microvascular stability of raising.Un-activation Tie2 or inhibition Tie2 autophosphorylation can cause the loss (Thurston of blood vessel structure and matrix/cells contacting, G., CellTissue Res. (2003), 314:61-69), thereby can cause endotheliocyte death, especially when lacking existence or growth-stimulating.According to above report because of the effect of Tie2 kinase activity, suppressing the Tie2 kinases can provide blood vessel formation against function, therefore has the purposes that treatment and pathologic vessels generate relative disease.Proved that in the new vessel system of kinds of tumors Tie2 expresses and raised (Peters for example, K.G. etc., (British Journal of Cancer1998; 77,51-56), this prompting suppresses the Tie2 kinase activity will cause anti-angiogenesis activity.For supporting this hypothesis, research (extracellular domain) (Pengnian to soluble T ie2 acceptor, L etc., 1997, Journal ofClinicalInvestigation 1997:100,2072-2078 and Pengnian, L etc., 1998, Proceedingsof the National Academy of Sciences1998:95,8829-8834) show its in vivo tumor model have anti-tumor activity.In addition, these experiments are further illustrated in blocking-up Tie2 signal pathway in the normal health individuality, and tolerance is good, because find no harmful toxicity in these researchs

Inspection (Stratmann to people's primary breast cancer sample and people and mouse breast cancer cell line, A. etc., 2001, International Journal ofCancer:91,273-282) the Tie2 dependent pathway that shows tumor-blood-vessel growth can exist with the KDR dependent pathway, but the two independent operating (Siemeister G. etc. in fact, 1999Cancer Research:59,3185-3191), and collaboratively each other (for example it is reported VEGF A and Ang1 co-induction vasculogenesis, and produce the ripe blood vessel Thurston of non-leakage, G, Deng, 1999Science:286,2511-2514).The mixing of this angiogenesis even probably be present in the single tumour.

Also show Tie2 in the aberrant angiogenesis that is called vein distortion (VM), work (Mulliken, J.B.﹠amp; Young, A.E.1998, Vascular Birthmarks:W.B.Saunders, Philadelphia).This defective can heredity or accidental the generation.VM finds in skin or mucous membrane usually, but can influence any organ.Usually damage for the blue look of sponge shape to the purple vascular plaque, this patch is made up of the blood vessel access that many expansible endotheliocytes are arranged in.In the various genotypes of this disease, modal defective is that the Tie2 kinases is at the sudden change C2545T of Tie2 encoding sequence (Calvert, J.T. etc., 1999Human Molecular genetics:8,1279-1289), the R849W aminoacid replacement takes place in it in the kinases territory.Even this Tie2 mutant analysis revealed part does not exist, its still be activated basically (Vikkula, M. etc., 1996Cell:87,1181-1190).

Also find in the blood vessel synovial membrane pannus of suffering from arthritic person joint, the up-regulated of Tie2, this generates consistent with unsuitable neovascularity.

This example provides further evidence to show, suppresses the conduction of Tie2 phosphorylation and signal subsequently and can be used for treating disease and other incident that unsuitable neovascularity generates.Up to now, only known in the art minority Tie2 inhibitor.For example, international application No:WO04/013141 has described condensed pyridine and pyrimidine group and international application No:WO04/058776 and has described pyridine and pyrimidine compound group.Therefore need to seek the Tie2 inhibitor of the other treatment potentiality of utilizing all inhibition/adjusting Tie2 signal pathway.

We have found that some compound has the activity that suppresses the Tie2 receptor tyrosine kinase, and therefore the value of the following disease of treatment arranged: generate relevant disorders such as cancers, rheumatoid arthritis and have other disease of not wishing active vasculogenesis with pathologic vessels.

According to the present invention, provide formula I compound:

Formula I

R wherein ^yBe group NR ¹R ², R ^xBe radicals R ^3aAnd R ^zBe radicals R ^4a,

Perhaps R ^xBe group NR ¹R ²And R ^yBe radicals R ^4bAnd R ^zBe radicals R ^3b, wherein

R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _v-(wherein v is 0,1,2,3,4,5 or 6) or 5 yuan or 6 yuan of heteroaryl rings, perhaps R ¹And R ²The nitrogen-atoms that is connected with them is represented optional 3～7 yuan of heterocycles of heteroatomic saturated or fractional saturation that another is selected from N or O that contain altogether;

Wherein any (1-6C) alkyl; (1-6C) alkoxyl group; (1-6C) alkyloyl is independently selected from following group replacement with (3-6C) group of naphthene base is optional by one or more: fluorine; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl group; (1-6C) alkoxyl group (1-6C) alkoxyl group; (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group; amino; single (1-6C) alkylamino or two (1-6C) alkylamino; formamyl; single (1-6C) alkyl-carbamoyl; two-[(1-6C) alkyl] formamyls; N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) alkyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation;

Wherein (1-6C) alkoxyl group, (1-6C) alkoxyl group (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group, and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] formamyl of single (1-6C) alkylamino, two-[(1-6C) alkyl] and/or N (R ^d) (1-6C) (1-6C) alkyl of alkyl is optional is replaced by one or more hydroxyl for C (O);

R wherein ¹And/or R ²Interior any phenyl is optional to be independently selected from following group replacement by one or more: halogen, (1-6C) alkyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino or two (1-6C) alkylamino, and wherein (1-6C) alkyl is independently selected from group replacement of hydroxyl, amino, list (1-6C) alkylamino or two-(1-6C) alkylaminos with (1-6C) alkoxyl group is optional by one or more;

R wherein ¹And/or R ²In any heterocycle and heteroaryl ring is optional is replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkylamino, two-[(1-6C) alkyl] is amino, saturated or 3～7 yuan of heterocycles of fractional saturation or-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3 and Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, amino, list (1-6C) alkylamino, two-[(1-6C) alkyl] is amino or 3～7 yuan of heterocycles of saturated or fractional saturation;

With condition is to work as R ¹And/or R ²During for (1C) alkyloyl group, (1C) alkyloyl is not replaced by fluorine or hydroxyl so;

R ^3aAnd R ^4aBe independently selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group,

Wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino, single (1-6C) alkylamino or two (1-6C) alkylamino, formamyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, 3～7 yuan of heterocycles of single (1-6C) alkylamino or two (1-6C) alkylamino or saturated or fractional saturation;

Perhaps R ^3aAnd R ^4aIn one of represent group-NR as defined above with another as defined above ¹R ²,

R ^3bBe selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino, single (1-6C) alkylamino, two (1-6C) alkylamino, formamyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, 3～7 yuan of heterocycles of single (1-6C) alkylamino or two (1-6C) alkylamino or saturated or fractional saturation;

Perhaps R ^3bRepresent group-NR as defined above ¹R ²

R ^4bBe selected from hydrogen, (1-6C) alkyl, (1-6C) alkoxyl group or (3-7C) cycloalkyl;

A represents aryl or is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3, the 5-triazinyl;

R ⁵Be selected from cyclopropyl, cyano group, halogen, (1-6C) alkoxyl group or (1-6C) alkyl, wherein (1-6C) alkyl and (1-6C) alkoxyl group is optional replaces by cyano group or by one or more fluorine;

N is 0,1,2 or 3;

L with respect to the tie point of ethynyl group be connected ring A between in position or the contraposition, and expression-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-,

Wherein Z be direct key ,-O-or-N (R ⁸)-,

Wherein x and y are 0,1,2 or 3 independently, and condition is x+y〉0 and＜4,

R wherein ⁸And R ⁹Represent hydrogen or (1-6C) alkyl independently,

R wherein ^aAnd R ^bRepresent hydrogen or (1-6C) alkyl, perhaps R independently ^aAnd R ^bThe carbon atom that is connected with them is represented (3-6C) cycloalkyl altogether; With

R wherein ^aAnd R ^bIn (1-6C) alkyl optional by 3～7 yuan of heterocyclic substituted of halogen, cyano group, hydroxyl or saturated or fractional saturation;

B represents 3～7 yuan of heterocycles, aryl or 5 or 6 yuan of heteroaryl rings of (3-7C) cycloalkyl ring, saturated or fractional saturation; Perhaps optionally contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S and be 8,9 or 10 yuan of bicyclic groups of saturated, fractional saturation or aromaticity;

R ⁶Be selected from halogen, hydroxyl, amino, list (C1-6 alkyl) amino, two-(C1-6 alkyl) amino, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles and-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

Perhaps R ⁶Be selected from (1-6C) alkyl, S (O) _p(1-6C) alkyl (wherein p is 0,1 or 2) or (1-6C) alkoxyl group,

Wherein (1-6C) alkyl, S (O) _p(1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: 3～7 yuan of heterocycles of cyano group, fluorine, hydroxyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino, two (1-6C) alkylamino, (3-7C) cycloalkyl ring or saturated or fractional saturation; With

The optional group that is selected from (1-6C) alkyl or hydroxyl (1-6C) alkyl independently by one or more of 3～7 yuan of heterocycles of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation replaces; With

M is 0,1,2 or 3;

When as B being 8,9 or 10 yuan of bicyclic groups of 3～7 yuan of heterocycles of (3-7C) cycloalkyl ring, saturated or fractional saturation or saturated or fractional saturation, described ring and bicyclic groups be optional to have 1 or 2 oxos or sulfo-substituting group;

And salt or solvate.

Particularly, in formula (I), work as R ⁶When existing, it be selected from halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles and-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

The optional group that is selected from (1-6C) alkyl or hydroxyl (1-6C) alkyl independently by one or more of 3～7 yuan of heterocycles of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation replaces.

Additionally, R ⁶Be hydroxyl.

Additionally, R ⁶Can be amino, single (C1-6 alkyl) amino, two-(C1-6 alkyl) amino.

In specific embodiments, R wherein ^yBe group NR ¹R ², R ^xBe radicals R ^3aAnd R ^zBe radicals R ^4a, R ⁶Be selected from halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles and-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

The optional group that is selected from (1-6C) alkyl independently by one or more of 3～7 yuan of heterocycles of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation replaces.

The specific examples of formula (I) compound is formula (IA) compound

Formula IA

Wherein:

R ¹, R ², R ^3a, R ^4a, A, R ⁵, L, B, n and m as above defines about formula (I) and

R ⁶Be selected from hydroxyl, halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles and-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

Perhaps R6 is selected from (1-6C) alkyl, S (O) _p(1-6C) alkyl (wherein p is 0,1 or 2) or (1-6C) alkoxyl group,

The optional group that is selected from (1-6C) alkyl independently by one or more of 3～7 yuan of heterocycles of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation replaces; With

And salt or solvate.

Formula IA examples for compounds is following compound, wherein:

R ¹, R ², A, R ⁵, L, n and m as above define about formula (I),

Wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino, single (1-6C) alkylamino or two [(1-6C) alkyl] amino, formamyl, single (1-6C) alkyl-carbamoyl or two-[(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, 3～7 yuan of heterocycles of single (1-6C) alkylamino or two [(1-6C) alkyl] amino or saturated or fractional saturation;

B represents (3-7C) cycloalkyl ring, 3～7 yuan of heterocycles of saturated or fractional saturation, aryl, be selected from furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5 or 6 yuan of heteroaryl rings of 5-triazinyl perhaps optionally contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S and are 8,9 or 10 yuan of bicyclic groups of saturated, fractional saturation or aromaticity;

R ⁶Be selected from halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles or-N (R ^a) C (O) (1-6C) alkyl, wherein R ^aBe hydrogen or (1-6C) alkyl; Perhaps

R ⁶Be selected from (1-6C) alkyl, S (O) _p(1-6C) alkyl (wherein p is 0,1 or 2) or (1-6C) alkoxyl group, wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: 3～7 yuan of heterocycles of cyano group, fluorine, hydroxyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino, two (1-6C) alkylamino, (3-7C) cycloalkyl ring or saturated or fractional saturation;

When B was 8,9 or 10 yuan of bicyclic groups of 3～7 yuan of heterocycles of (3-7C) cycloalkyl ring, saturated or fractional saturation or saturated or fractional saturation, described ring and bicyclic groups be optional to have 1 or 2 oxos or sulfo-substituting group;

And salt or solvate.

According to a further aspect in the invention, provide formula IB compound:

Formula IB

Wherein:

R ¹, R ², R ^3b, R ^4b, A, R ⁵, L, B, n and m as above define about formula (I),

R ⁶Be selected from halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles ,-S (O) _p(1-6C) alkyl (wherein p is 0,1 or 2) and-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps

R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl ,-S (O) p (1-6C) alkyl and (1-6C) alkoxyl group is optional is independently selected from following group by one or more and replaces: 3～7 yuan of heterocycles of cyano group, fluorine, hydroxyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation;

And salt or solvate.

The specific examples of formula IB compound is following compound, wherein:

R ¹, R ², R ^4b, A, R ⁵, L, n and m as above define about formula (I),

R ^3bBe selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino, single (1-6C) alkylamino or two [(1-6C) alkyl] amino, formamyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, 3～7 yuan of heterocycles of single (1-6C) alkylamino or two (1-6C) alkylamino or saturated or fractional saturation;

R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl ,-S (O) _p(1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: 3～7 yuan of heterocycles of cyano group, fluorine, hydroxyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino, two [(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation;

When B was 8,9 or 10 yuan of bicyclic groups of 3～7 yuan of heterocycles of (3-7C) cycloalkyl ring or saturated or fractional saturation or saturated or fractional saturation, described ring and bicyclic groups be optional to have 1 or 2 oxos or sulfo-substituting group;

And salt or solvate.

Additionally, formula IB examples for compounds is a formula IB ' compound:

Formula IB '

Wherein:

R ¹, R ², R ^4b, A, R ⁵, L, n and m as above define about formula (I),

R ⁶Be selected from halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles ,-S (O) _p(1-6C) alkyl (wherein p is 0,1 or 2) ,-(1-6C) alkyl of N (Rc) C (O), wherein Rc is hydrogen or (1-6C) alkyl; Perhaps

When B was 8,9 or 10 yuan of bicyclic groups of 3～7 yuan of heterocycles of (3-7C) cycloalkyl ring or saturated or fractional saturation or saturated or fractional saturation, described ring and bicyclic groups be optional to have 1 or 2 oxos or sulfo-substituting group; With

R ¹⁰And R ¹¹Be independently selected from hydrogen or (1-6C) alkyl;

And salt or solvate, particularly its pharmacy acceptable salt.

For fear of suspection, when showing when having L, the left-hand side of the formula of its representative is connected on the ring A and right-hand side is connected on the ring B.Thus, for example, when L is group-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-time, this part

Be following secondary pole type group

Wherein variable as defined above.

In this specification sheets, generic term " alkyl " comprises straight chain and branched-chain alkyl simultaneously, such as propyl group, sec.-propyl and the tertiary butyl.Yet, about single alkyl, such as " propyl group " the clear and definite linear form that only is meant, about branched-chain alkyl, such as " sec.-propyl " the clear and definite side chain form that only is meant.Can other generic term will be given for similarly, for example (1-6C) alkoxyl group comprises methoxyl group, oxyethyl group and isopropoxy, (1-6C) alkylamino comprises that methylamino, isopropylamino and ethylamino and two-[(1-6C) alkyl] amino comprises dimethylamino, diethylamino and N-methyl-N-isopropyl propyl group amino.The generic term aryl is meant phenyl or naphthyl, particularly phenyl.

Be to be understood that, formula I compound may be because one or more unsymmetrical carbon and existing with optically active or racemization form as defined above can be sure of some, and the present invention will have above-mentioned active any described optically active or the racemization form is included in its definition.The synthetic of optically active form can be synthesized by organic chemistry standard technique well known in the art, for example synthesized by the optically active raw material or synthesizes by splitting the racemization form.Similarly, above-mentioned activity can utilize the standard test technology of hereinafter mentioning to estimate.

The suitable value of above-mentioned general group comprises following those values of enumerating.

5 or 6 yuan of suitable heteroaryl rings comprise, for example furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, 1,4,5-triazinyl or pyrazinyl.5 or 6 yuan of concrete heteroaryl rings comprise imidazolyl, pyridyl, thiazolyl, thiadiazolyl group, pyrimidyl, isoxazolyl, isothiazolyl and pyrazolyl.

Suitable saturated or 3～7 yuan of heterocycles of fractional saturation comprise, for example, Oxyranyle, the oxa-cyclobutyl, tetrahydrofuran base, THP trtrahydropyranyl, 2,3-dihydro-1, the 3-thiazolyl, 1, the 3-thiazolidyl, 1, the 3-oxazolidinyl, oxepanyl, pyrrolinyl, pyrrolidyl, morpholinyl, thio-morpholinyl, (perhydro-1, the 4-thiazinyl), (8-oxa--3-azabicyclo [3.2.1] octyl group), (7-oxa--3-azabicyclo [3.1.1] heptyl), perhydro azepine  base, perhydro oxygen azepine  base, tetrahydrochysene-1, the 4-thiazinyl, 1-oxo tetrahydro-thienyl, 1,1-dioxo tetrahydrochysene-1, the 4-thiazinyl, piperidyl, homopiperidinyl, piperazinyl, high piperazinyl, the dihydropyridine base, tetrahydro pyridyl, dihydro-pyrimidin base or tetrahydro-pyrimidine base, preferred tetrahydrofuran base, THP trtrahydropyranyl, pyrrolidyl, morpholinyl, 1,1-dioxo tetrahydrochysene-4H-1, the 4-thiazinyl, piperidyl or piperazinyl, more preferably tetrahydrofuran (THF)-3-base, tetrahydropyran-4-base, tetramethyleneimine-3-base, morpholinyl, 1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-base, piperidino-(1-position only), piperidin-4-yl or piperazine-1-base.The described suitable value that has 1 or 2 oxos or the substituent group of sulfo-is, for example, 2-oxo-pyrrolidine base, 2-sulfo-pyrrolidyl, 2-oxo-imidazole alkyl, 2-thiocarbamoyl imidazole alkyl, 2-oxo-piperidine base, 2,5-dioxo pyrrolidyl, 2,5-dioxo alkyl imidazole base or 2,6-dioxopiperidine base.Described 3～7 yuan of heterocycles saturated or fractional saturation are optional to be replaced by one or more (C1-6) alkyl and/or by one or more hydroxyls.For fear of suspection, should be appreciated that this definition comprises that hydroxyl tautomerism wherein becomes the tautomer of the ring system that the hydroxyl of oxo group replaces.

Suitable 8,9 or 10 yuan of bicyclic groups comprise thieno-[2,3-b] furyl, imidazo [2,1-b] thiazolyl, dihydro pentamethylene benzothiazolyl, tetrahydro cyclopentyl alkane is [c] pyrazolyl also, furo [3,2-b] furyl, pyrrolopyrrole, the thieno-pyrazolyl, thieno-[2,3-b] thienyl (thiophenyl), the indolizine base, indyl, pseudoindolyl, the 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thiophene phenyl, the 1H-indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, isoquinolyl, the cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl, chromanyl, the isochroman base, indenyl, naphthyl, 2,3-dihydro-1,4-Ben Bing dioxine base, 1,3-benzodioxole-5-base, perhydronaphthalene and norbornane.Concrete 8,9 or 10 yuan of bicyclic groups comprise thieno-[2,3-b] furyl, the indolizine base, indyl, pseudoindolyl, the 3H-indyl, indolinyl, benzo [b] furyl, benzo [b] thienyl, the 1H-indazolyl, benzimidazolyl-, benzothiazolyl, purine radicals, the 4H-quinolizinyl, quinolyl, isoquinolyl, the cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, 1, the 8-naphthyridinyl, pteridyl, chromanyl, the isochroman base, indenyl, naphthyl, 2,3-dihydro-1,4-Ben Bing dioxine base and 1,3-benzodioxole-5-base.

Described bicyclic groups is optional by one or more radicals R as defined above ⁶Replace.

Described group A can be connected on the ethynyl group through the carbon atom in aryl or the 5 or 6 yuan of heteroaryl rings especially.Described group B can be connected on the group L through carbon atom especially.

Any substituent suitable value herein, for example ' R ' group (R ¹～R ⁶) or A, B or L group in the suitable value of multiple group comprise

For halogen: fluorine, chlorine, bromine and iodine;

For (1-6C) alkyl: methyl, ethyl, propyl group, sec.-propyl and the tertiary butyl;

For (1-6C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-, isopropoxy and butoxy;

For (1-6C) alkyl sulphonyl: methylsulfonyl and ethylsulfonyl;

For (1-6C) alkylamino: methylamino-, ethylamino, third amino, isopropylamino and fourth amino;

For two-[(1-6C) alkyl] amino: dimethylamino, diethylamino, N-ethyl-N-methylamino and diisopropylaminoethyl;

For (1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxycarbonyl, third oxygen carbonyl and the tertbutyloxycarbonyl;

For (1-6C) alkyloyl: formyl radical, ethanoyl and propionyl;

For (1-6C) alkoxy carbonyl: methoxycarbonyl, the third oxygen carbonyl, the different third oxygen carbonyl, tertbutyloxycarbonyl;

For hydroxyl (1-6C) alkyl: methylol, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl;

For (1-6C) alkoxyl group (1-6C) alkyl:

Methoxymethyl, ethoxyl methyl, 1-methoxy ethyl, 2-methoxyl group

Ethyl, 2-ethoxyethyl group and 3-methoxy-propyl;

For (3-7C) cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and suberyl;

For (1-6C) alkoxyl group (1-6C) alkoxyl group:

Methoxymethoxy, methoxy ethoxy, methoxy propoxy, methoxy

Base butoxy, methoxyl group hexyloxy, ethoxy ethoxy, ethoxy-c

Oxygen base, oxyethyl group butoxy, propoxy-propoxy-and propoxy-fourth oxygen

Base;

For (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group:

Methoxymethoxy methoxyl group, methoxy ethoxy oxyethyl group, methoxyl group

Propoxy-methoxyl group, methoxyl group butoxy oxyethyl group, methoxyl group hexyloxy

Methoxyl group, ethoxy ethoxy ethoxy, oxyethyl group propoxy-ethoxy

Base, oxyethyl group butoxy methoxyl group, propoxy-propoxy-methoxyl group and third

Oxygen base butoxy methoxyl group;

For list (1-6C) alkyl-carbamoyl:

N-methylamino formyl radical, N-ethylamino formyl radical and N-propyl group ammonia

The base formyl radical; With

For two [(1-6C) alkyl] formamyl:

N, N-formyl-dimethylamino, N-ethyl-N-methylamino formyl radical

And N, N-diethylamino formyl radical.

When relating to (1-4C) alkyl in this manual, should be appreciated that described group is meant contains the alkyl that is up to 4 carbon atoms.Those skilled in the art can recognize, the representative example of described group is abovely to be up to those cited groups of 4 carbon atoms (1-4C) alkyl about containing, such as methyl, ethyl, propyl group, sec.-propyl, butyl and the tertiary butyl.Similarly, (1-3C) alkyl of mentioning is meant and contains the alkyl that is up to 3 carbon atoms, such as methyl, ethyl, propyl group and sec.-propyl.Similarly regulation is applicable to above other group of enumerating, such as (1-4C) alkoxyl group, (2-4C) thiazolinyl, (2-4C) alkynyl and (1-4C) alkyloyl.

Should be appreciated that some formula (I) compound can with solvate and not the solvation form (such as, for example be hydrated form) exist.Should be appreciated that the present invention includes all demonstrates inhibiting all solvate forms to the Tie2 receptor tyrosine kinase.

It is also understood that some formula I compound may show polymorphism, and the present invention includes all the Tie2 receptor tyrosine kinase is demonstrated inhibiting form.

It is also understood that and the present invention relates to all demonstrate inhibiting formula I compound to the Tie2 receptor tyrosine kinase tautomeric form.

The pharmacy acceptable salt of preferred The compounds of this invention, but other non-pharmacy acceptable salt of The compounds of this invention also is useful, for example, in the preparation of the pharmacy acceptable salt of The compounds of this invention.

The pharmacy acceptable salt of suitable formula I compound is, the acid salt of formula I compound for example, for example acid salt that forms with mineral acid or organic acid (such as spirit of salt, Hydrogen bromide, sulfuric acid, trifluoroacetic acid, citric acid or toxilic acid); Perhaps, the abundant salt of tart formula I compound for example, for example basic metal or alkaline earth salt (such as calcium or magnesium salts) or ammonium salt or the salt that forms with organic bases (such as methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three (2-hydroxyethyl) amine).

As another aspect of the present invention, the prodrug of the The compounds of this invention that the present invention also provides before this or defined after this.The compounds of this invention can carry out administration with the prodrug forms that cracking in the mankind or animal body provides formula (I) compound.The example of prodrug comprises the interior hydrolyzable ester of the body of formula (I) compound.

Multiple prodrug forms all is known in the art.For example, described prodrug derivant referring to:

A) Design of Prodrugs, editor H.Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, editor K.Widder waits people (Academic Press, 1985);

B) A Textbook of Drug Design and Development, editor Krogsgaard-Larsen and H.Bundgaard, Chapter5 " Design and Application of Prodrugs ", editor H.Bundgaard is (1991) p.113-191;

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

D) H.Bundgaard waits people Journal of Pharmaceutical Sciences, 77,285 (1988); With

E) N.Kakeya waits people Chem Pharm Bull, 32,692 (1984).

The interior hydrolyzable ester of body that contains formula (I) compound of hydroxyl is that for example, hydrolysis produces the pharmaceutically acceptable ester of parent acid or alcohol in the mankind or animal body.The suitable pharmaceutically acceptable ester of carboxyl comprises C _1-6Alkoxy methyl ester (for example methoxymethyl ester), C _1-6Alkanoyloxymethyl ester (for example oxy acid methyl neopentyl ester), phthalidyl ester,

C _3-8Cyclo alkoxy carbonyl oxygen base C _1-6Alkyl ester (for example 1-cyclohexyl-carbonyl oxygen base ethyl ester); 1,3-dioxole-2-ketone group methyl esters, for example, 5-methyl isophthalic acid, 3-dioxole-2-ketone group methyl esters; And C _1-6The alkoxy-carbonyl oxy ethyl ester.

Contain in the body of formula (I) compound of hydroxyl hydrolyzable ester and comprise inorganic ester (such as, phosphoric acid ester (comprising the phosphoramidic acid cyclic ester)) and alpha-acyloxy alkyl oxide and because the interior hydrolysis of the body of ester and cracking provides the related compound of parent hydroxy.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxy-ether.The selection of hydrolyzable ester formation group comprises benzoyl and phenylacetyl, alkoxy carbonyl (to provide alkyl carbonate), dialkyl amido formyl radical and N-(dialkyl amido ethyl)-N-alkyl-carbamoyl (to provide carbamate), dialkyl amido ethanoyl and the carboxyl ethanoyl of alkyloyl, benzoyl, phenylacetyl and replacement in the body of hydroxyl.

Concrete compounds of the present invention comprises, for example, and formula I compound or its salt, particularly its pharmacy acceptable salt, wherein except as otherwise noted, R ¹, R ², R ^3a, R ^4a, R ⁵, R ⁶, A, B, L, m and n have any implication of above definition or defined any implication in the paragraph (a)～(mmmmm) hereinafter separately :-

(a) with respect to the tie point of ethynyl group, L be connected ring A between on the position;

(b) with respect to the tie point of ethynyl group, L is connected in the contraposition of ring A;

(c) L is-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-, wherein x and y as defined above and Z be-O-or-N (H)-, and R ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ^a, R ^b, R ⁸And R ⁹All be hydrogen);

(d) L is-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-O-(CR ^aR ^b) _y-, wherein x and y as defined above, and R ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ^a, R ^b, R ⁸And R ⁹All be hydrogen);

(e) L is-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-N (R ⁸)-(CR ^aR ^b) _y-, R wherein ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ^a, R ^b, R ⁸And R ⁹All be hydrogen);

(f) L is-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-O-, wherein x as defined above, and R ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ^a, R ^b, R ⁸And R ⁹All be hydrogen);

(g) L is-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-N (H)-, wherein x as defined above, and R ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ^a, R ^b, R ⁸And R ⁹All be hydrogen);

(g ') L is-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-, x (particularly x is 1 or 2) and R wherein as defined above wherein ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ^a, R ^b, R ⁸And R ⁹All be hydrogen);

(g ") L is-N (R ⁸) C (O) N (R ⁹)-CH ₂-, R wherein ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl (R particularly ⁸And R ⁹All be hydrogen);

(h) R ^aAnd R ^bExpression hydrogen;

(h ') R ^aAnd R ^bRepresent hydrogen or (1-6C) alkyl independently,

R wherein ^aAnd R ^bIn (1-6C) alkyl optional by 3～7 yuan of heterocyclic substituted of hydroxyl or saturated or fractional saturation;

(h ") R ^aAnd R ^bRepresent hydrogen or (1-6C) alkyl independently,

R wherein ^aAnd R ^bIn (1-6C) alkyl optional by 5～6 yuan of heterocyclic substituted of hydroxyl or saturated or fractional saturation;

(h " ') R ^aAnd R ^bRepresent hydrogen, methyl or ethyl independently,

R wherein ^aAnd R ^bIn (1-6C) alkyl optional replaced by hydroxyl or pyrroline-1-base;

(i) A is selected from phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and 1,3, the 5-triazinyl;

(i ') A is selected from phenyl, thiazolyl, thiadiazolyl group, pyridyl and pyrimidyl;

(j) A is phenyl or pyridyl

(k) A is phenyl or pyridyl, and wherein with respect to acetylene bond, the pyridyl nuclear nitrogen is positioned at the 3-position.

(l) A is phenyl or thiazolyl;

(l ') A is phenyl, pyridyl, thiazolyl or thiadiazolyl group;

(l ") A is a phenyl;

(m) A is a pyridyl;

(m ') A is a thiazolyl;

(m ") A is a thiadiazolyl group;

(n) A is that phenyl or pyridyl and n are 0;

(n ') A is that phenyl or thiazolyl and n are 0;

(o) A be phenyl and n be 0 or n be 1, and R ⁵Be (1-4C) alkyl;

(p) A be pyridyl and n be 0 or n be 1, and R ⁵Be (1-4C) alkyl;

(p ') A be thiazolyl and n be 0 or n be 1, and R ⁵Be (1-4C) alkyl;

(q) A is selected from phenyl, oxazolyl, imidazolyl, pyrryl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrazinyl and pyrimidyl.

(r) when B was (3-7C) cycloalkyl ring, B was selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl so;

(s) when B is 3～7 yuan of heterocycles of saturated or fractional saturation, B is selected from oxa-cyclobutyl, azetidinyl, thietanyl, pyrrolidyl, morpholinyl, 1 so, 3-dioxolanyl, tetrahydrofuran base, piperidyl, piperazinyl, thio-morpholinyl, THP trtrahydropyranyl, high piperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, tetrahydro pyridyl, 1,2,4-oxadiazole base and dihydro thiapyran base;

(t) when B is 5 or 6 yuan of heteroaryl rings, B is selected from furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1 so, 3, the 5-triazinyl;

(u) contain 1 for optional as B, 2,3 or 4 are independently selected from N, the heteroatoms of O and S and be saturated, fractional saturation or aromaticity 8, during 9 or 10 yuan of bicyclic groups, B is selected from 2 so, 3-dihydro-1H-indenyl, Ben Bing dioxine base, 1,2,3, the 4-tetralyl, 1,2,3,4-tetrahydrochysene pentalene, benzofuryl, 2, the 3-dihydro benzo furyl, benzimidazolyl-, benzothienyl, benzothiazolyl, benzisothiazole base benzoxazolyl, the benzoisoxazole base, the pyridine-imidazole base, the Mi Dingbing imidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolyl, phthalazinyl, the cinnolines base, indyl and naphthyridinyl.

Perhaps B is the group of following formula:

Wherein W is 5～7 yuan of rings (comprising bridging atom), and described W encircles to contain carbon atom or choose wantonly and further contains the heteroatoms that is independently selected from oxygen, nitrogen and sulphur, and wherein said dicyclo contains no more than altogether 4 heteroatomss.The example of described ring comprises: pyrazolo [1,5-a] pyridyl, pyrazolo [1,5-c] pyrimidyl, pyrazolo [1,5-a] [1,3,5] triazinyl, 4,5-dihydro-pyrazolo [1,5-a] pyridyl, 4H-pyrazolo [5,1-c] [1,4] thiazinyl, 4H-pyrazolo [5,1-c] [1,4] oxazinyl, 1,2-benzoisoxazole base isoxazole also [5,4-b] pyridyl isoxazole also [5,4-d] pyrimidyl, 4H-sulfo-pyrans also [3,4-d] isoxazolyl, the 4H-pyrans also [3,4-d] isoxazolyl, the 7aH-indyl, 7aH-pyrrolo-[2,3-b] pyridyl, 7aH-pyrrolo-[2,3-d] pyrimidyl, 4,7a-dihydrogen phosphorothioate pyrans is [4,3-b] pyrryl and 4 also, the 7a-dihydropyrane is [4,3-b] pyrryl also.

(v) B is aryl, particularly phenyl;

(w) B is 3～7 yuan of (particularly 4～6 yuan) heterocycles of saturated or fractional saturation that contain one or two heteroatomss (particularly heteroatoms) that are selected from oxygen and nitrogen;

(x) B is 5 or 6 yuan of heteroaryl rings;

(y) B contains 1,2 or 3 (particularly 1 or 2) and is independently selected from the heteroatoms of N and O and is 8,9 or 10 yuan of bicyclic groups of saturated, fractional saturation or aromaticity for optional;

(z) B is selected from 4～6 yuan of heterocycles of saturated or fractional saturation, aryl, be selected from furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5～6 yuan of heteroaryl rings of 5-triazinyl perhaps optionally contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S and are 8,9 or 10 yuan of bicyclic groups of saturated, fractional saturation or aromaticity;

(aa) B is selected from 4～6 yuan of heterocycles of saturated or fractional saturation, aryl, perhaps be selected from furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5 or 6 yuan of heteroaryl rings of 5-triazinyl;

(bb) B is selected from 4～6 yuan of heterocycles of saturated or fractional saturation, perhaps be selected from furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5 or 6 yuan of heteroaryl rings of 5-triazinyl;

(cc) B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, piperidyl, tetrahydrofuran base, THP trtrahydropyranyl, 1,4-alkyl dioxin, morpholinyl, pyrrolidyl, piperidyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-1,4-Ben Bing dioxine base and 1,3-benzodioxole-5-base;

(dd) B is selected from phenyl, THP trtrahydropyranyl, tetrahydrofuran base, morpholinyl, thio-morpholinyl, furyl, pyrrolidyl, pyridyl and pyrimidyl;

(dd ') B is selected from phenyl, cyclobutyl, THP trtrahydropyranyl, tetrahydrofuran base, 1,4-alkyl dioxin, morpholinyl, furyl, pyrrolidyl, piperidyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl and pyridazinyl;

(dd ") B is selected from cyclohexyl, phenyl, THP trtrahydropyranyl, tetrahydrofuran base, morpholinyl, thio-morpholinyl, furyl, pyrrolidyl, pyridyl and pyrimidyl;

(dd " ') B is selected from phenyl, imidazolyl, thienyl He isoxazolyl;

(ee) B is selected from phenyl, cyclobutyl, 2,3-dihydro indenyl, THP trtrahydropyranyl, tetrahydrofuran base, piperidyl, 1,4-alkyl dioxin, morpholinyl, thio-morpholinyl, pyrrolidyl, piperidyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl group, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, Ben Bing dioxine base, benzodioxole base or THP trtrahydropyranyl.

(ee ') B is selected from phenyl, cyclohexyl, cyclobutyl, 2,3-dihydro indenyl, THP trtrahydropyranyl, tetrahydrofuran base, piperidyl, 1,4-alkyl dioxin, morpholinyl, thio-morpholinyl, pyrrolidyl, piperidyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl group, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, Ben Bing dioxine base, benzodioxole base or THP trtrahydropyranyl.

(ff) B is selected from piperidyl, phenyl, isoxazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl and pyridyl;

(gg) B is selected from phenyl, pyrazolyl, thiadiazolyl group He isoxazolyl;

(hh) B is selected from isoxazolyl, thiadiazolyl group and pyrazolyl;

(ii) B is selected from isoxazolyl and pyrazolyl;

(jj) B is a phenyl;

(kk) B is an isoxazolyl;

(ll) B is a pyrazolyl;

(mm) R ¹And R ²Be independently selected from hydrogen, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

(1-6C) alkyl wherein; (1-6C) alkyloyl is with (3-6C) group of naphthene base is optional by one or more (for example 1 or 2); can be identical or different; being selected from following group replaces: fluorine; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl group; (1-6C) alkoxyl group (1-6C) alkoxyl group; (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group; amino; single (1-6C) alkylamino; two-[(1-6C) alkyl] amino; formamyl; single (1-6C) alkyl-carbamoyl; two [(1-6C) alkyl] formamyls or-N (R ^d) (1-6C) alkyl (R wherein of C (O) ^dBe hydrogen or (1-6C) alkyl) or 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said (1-6C) alkoxyl group, (1-6C) alkoxyl group (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] formamyl of single (1-6C) alkylamino, two-[(1-6C) alkyl] and/or-N (R ^d) (1-6C) (1-6C) alkyl of alkyl is optional is replaced by one or more (for example 1 or 2) hydroxyl for C (O);

Wherein phenyl optional by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: halogen, (1-6C) alkyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino or two-[(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxyl group is optional by one or more (for example 1 or 2), group replacement can be identical or different, that be selected from hydroxyl, amino, list (1-6C) alkylamino or two [(1-6C) alkyl] amino;

R wherein ¹And/or R ²Interior any heterocycle and heteroaryl ring are optional independently by one or more (for example 1 or 2), can be identical or different, being selected from following group replaces: (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl, amino, single (1-6C) alkylamino or two-[(1-6C) alkyl] amino, 3～7 yuan of heterocycles of perhaps saturated or fractional saturation or-(CH2) zY of C (O), wherein z is 0,1,2 or 3 and Y be selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, amino, single (1-6C) alkylamino, 3～7 yuan of heterocycles of two [(1-6C) alkyl] amino or saturated or fractional saturation;

With condition is to work as R ¹And/or R ²During for (1C) alkyloyl group, should do not replaced by (1C) alkyloyl so by fluorine or hydroxyl;

(nn) R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH2) v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein (1-6C) alkyl, (1-6C) alkyloyl and (3-6C) group of naphthene base optional by one or more (for example 1 or 2), can be identical or different, as above defined group replaces in (mm);

Wherein any heterocycle in R1 and/or the R2 and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (mm);

(oo) R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

Wherein (1-6C) alkyl and (1-6C) alkyloyl group optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (mm);

R wherein ¹And/or R ²In any heterocycle and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different replace as defined group in above (mm);

(pp) R ¹Be hydrogen, and R ²Be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein (1-6C) alkyl, (1-6C) alkyloyl and (1-6C) group of naphthene base optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (mm);

Wherein phenyl optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (mm);

Wherein any heterocycle in the R2 and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (mm);

(qq) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (mm);

(rr) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

(ss) R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH2) v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein (1-6C) alkyl, (1-6C) alkyloyl and (3-6C) group of naphthene base optional by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: hydroxyl, (1-6C) alkoxyl group, (1-6C) alkoxyl group (1-6C) alkoxyl group, amino, list (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl, list (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] formamyls or-N (R ^d) C (O) (1-6C) 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of alkyl (wherein Rd is hydrogen or (1-6C) alkyl) or saturated or fractional saturation, wherein said (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] formamyl of described list (1-6C) alkylamino, two-[(1-6C) alkyl] and/or-N (R ^d) (1-6C) described (1-6C) alkyl of alkyl is optional is replaced by one or more (for example 1 or 2) hydroxyl for C (O);

Wherein phenyl optional by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: halogen, (1-6C) alkyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino or two-[(1-6C) alkyl] amino, wherein said (1-6C) alkyl or (1-6C) alkoxyl group is optional by one or more (for example 1 or 2), group replacement can be identical or different, that be selected from hydroxyl, amino, list (1-6C) alkylamino or two-[(1-6C) alkyl] amino;

Wherein any heterocycle in R1 and/or the R2 and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkylamino or two-[(1-6C) alkyl] is amino or 3～7 yuan of heterocycles of saturated or fractional saturation or-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3 and Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, amino, list (1-6C) alkylamino, two [(1-6C) alkyl] are amino or 3～7 yuan of heterocycles of saturated or fractional saturation;

(tt) R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl or (3-6C) cycloalkyl (CH ₂) _v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein (1-6C) alkyl, (1-6C) alkyloyl and (3-6C) group of naphthene base optional by one or more (for example 1 or 2), can be identical or different, as above defined group replaces in (ss);

R wherein ¹And/or R ²In any heterocycle and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (ss);

(uu) R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

Wherein (1-6C) alkyl and (1-6C) alkyloyl group optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (ss);

(vv) R ¹Be hydrogen, and R ²Be selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-(wherein u is 0,1,2,3,4,5 or 6), (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH2) v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

Wherein phenyl optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (ss);

Wherein any heterocycle in the R2 and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (ss);

(ww) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _v-(wherein v is 0,1,2,3,4,5 or 6) or 5 or 6 yuan of heteroaryl rings;

R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (ss);

(xx) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-6C) alkyloyl, (1-6C) alkyl or 5 or 6 yuan of heteroaryl rings;

(yy) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-6C) alkyloyl and (1-6C) alkyl;

(zz) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-6C) alkyloyl and (1-6C) alkyl,

Wherein (1-6C) alkyl and (1-6C) alkyloyl group optional by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: hydroxyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkoxyl group, amino, list (1-3C) alkylamino, two (1-3C) alkylamino, formamyl or-N (R ^d) (1-3C) alkyl (R wherein of C (O) ^dBe hydrogen or (1-3C) alkyl) or saturated 5 or 6 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings, wherein (1-4C) alkoxyl group and (1-4C) alkoxyl group (1-4C) alkoxyl group and single (1-3C) alkylamino, two-[(1-3C) alkyl] amino and/or N (R ^d) (1-6C) (1-3C) alkyl of alkyl is optional is replaced by one or more (for example 1 or 2) hydroxyl for C (O);

R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl, amino, list (1-3C) alkylamino or two-[(1-3C) alkyl] is amino or 3～7 yuan of heterocycles of saturated or fractional saturation or-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3 and Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, amino, list (1-6C) alkylamino, two [(1-6C) alkyl] are amino or 3～7 yuan of heterocycles of saturated or fractional saturation;

(aaa) R ¹Be hydrogen and R ²Be selected from hydrogen, (1-3C) alkyloyl and (1-3C) alkyl;

Wherein (1-3C) alkyl and (1-3C) alkyloyl group optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (zz);

R wherein ²In any heterocycle and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (zz);

(bbb) R ¹Be hydrogen, and R ²Be selected from hydrogen and (1-6C) alkyl (particularly (1-3C) alkyl);

Wherein (1-6C) alkyl (particularly (1-3C) alkyl) group optional by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (zz);

Wherein any heterocycle in the R2 and heteroaryl ring optional independently by one or more (for example 1 or 2), can be identical or different, replace as defined group in above (zz);

(ccc) R ¹Be hydrogen, and R ²Be (1-6C) alkyl (particularly (1-3C) alkyl),

(ccc ') R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen and R ²Be (1-6C) alkyl,

Wherein (1-6C alkyl) is optional by amino, single (1-6C) alkylamino or two (1-6C) alkylamino or saturated 3～7 yuan of heterocyclic substituted;

(ccc ") R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen and R ²Be (1-6C) alkyl,

Wherein (1-6C alkyl) is optional by two (1-6C) alkylaminos or saturated 3～7 yuan of heterocyclic substituted;

(ccc " " ') R ¹Be hydrogen and R ²Be selected from hydrogen, 3-(dimethylamino) propyl group and 3-piperidines-1-base propyl group;

(ccc " " ") R ¹Be hydrogen, and R ²Be selected from hydrogen, 3-(dimethylamino) propyl group, 2-piperidines-1-base ethyl and 3-piperidines-1-base propyl group;

(ddd) R ¹And R ²All be hydrogen, perhaps R ¹Be hydrogen or (1-6C) alkyl and R ²Be (1-6C) alkyl,

Wherein (1-6C alkyl) optional by hydroxyl, amino, list (1-6C) alkylamino or two (1-6C) alkylamino, formamyl, (1-6C) alkoxyl group, (1-6C) alkoxyl group (1-6C) alkoxyl group ,-N (R ^d) (1-6C) alkyl (R wherein of C (O) ^dBe hydrogen or (1-6C) alkyl), aryl (particularly phenyl), 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings saturated or fractional saturation replace;

Wherein (1-6C) alkoxyl group, list (1-6C) alkylamino and-N (R ^d) (1-6C) alkyl is optional is replaced by hydroxyl for C (O);

Wherein 3～7 yuan of heterocycles of aromatic ring, saturated or fractional saturation or 5 or 6 yuan of heteroaryl rings optional by (1-4C) alkyl, (1-4C) alkoxyl group or-C (O) CH2Y replaces, wherein Y is selected from hydroxyl or two (1-6C) alkylamino.

(eee) R ¹And R ²Be independently selected from hydrogen, methyl, ethyl, propyl group, the 2-hydroxyethyl, the 3-hydroxypropyl, the 2-methoxy ethyl, the 3-methoxy-propyl, the 2-amino-ethyl, 3-aminopropyl 2-(isopropylamino) ethyl, 3-(isopropylamino) propyl group, 2-(dimethylamino) ethyl, 3-(dimethylamino) propyl group, the carbamyl ylmethyl, 2-formamyl ethyl, 3-formamyl propyl group, 2-(2-methoxy ethoxy) ethanoyl, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 3-(4-methylpiperazine-1-yl) propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-(1H-imidazol-4 yl) ethyl, 2-pyridine-2-base ethyl, 3-(1H-imidazoles-1-yl) propyl group, 2-pyridin-4-yl ethyl, 2,4-dimethoxy-benzyl and 5-Shu butyl isoxazole-3-base;

(fff) R ¹Be hydrogen, and R ²Be selected from hydrogen, methyl, ethyl, propyl group, the 2-hydroxyethyl, the 3-hydroxypropyl, the 2-methoxy ethyl, the 3-methoxy-propyl, the 2-amino-ethyl, the 3-aminopropyl, 2-(isopropylamino) ethyl, 3-(isopropylamino) propyl group, 2-(dimethylamino) ethyl, 3-(dimethylamino) propyl group, the carbamyl ylmethyl, 2-formamyl ethyl, 3-formamyl propyl group, 2-(2-methoxy ethoxy) ethanoyl, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 3-(4-methylpiperazine-1-yl) propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-(1H-imidazol-4 yl) ethyl, 2-pyridine-2-base ethyl, 3-(1H-imidazoles-1-yl) propyl group, 2-pyridin-4-yl ethyl, 2,4-dimethoxy-benzyl and 5-Shu butyl isoxazole-3-base;

(ggg) R ¹Be hydrogen, and R ²Be selected from hydrogen, methyl, ethyl, propyl group, 3-(isopropylamino) propyl group, 2-tetramethyleneimine-1-base ethyl, 5-Shu butyl isoxazole-3-base, 3-piperidines-1-base propyl group, 2-morpholino-4-base-ethyl, 2-tetramethyleneimine-1-base ethyl, 3-(dimethylamino) propyl group, 2-hydroxyethyl and 2-piperidines-1-base ethyl;

(ggg ') R ¹Be hydrogen, and R ²Be selected from (1-6C) alkyl (particularly (1-3C) alkyl),

Wherein (1-6C) alkyl (particularly (1-3C) alkyl) group is by saturated 5 or 6 yuan of heterocyclic substituted;

(ggg ") R ¹Be hydrogen, and R ²Be selected from 2-morpholine-4-base-ethyl or morpholinyl-4-base propyl group;

(hhh) R ²Be hydrogen or methyl, and R ^3aBe selected from hydrogen, methyl, the 2-hydroxyethyl, the 2-methoxy ethyl, the 3-methoxy-propyl, 2-(2-hydroxyl-oxethyl) ethyl, 2-methoxy ethoxy methyl, the 2-amino-ethyl, the 3-aminopropyl, the amino butyl of 4-, 2-(isopropylamino) ethyl, 3-(isopropylamino) propyl group, 2-(dimethylamino) ethyl, 3-(dimethylamino) propyl group, 4-(dimethylamino) butyl, 2-(dimethylamino)-1-methylethyl, the carbamyl ylmethyl, 2-formamyl ethyl, 2-(2-methoxy ethoxy) ethanoyl, 2-(2-glycoloyl amido) ethyl, 3-[N-(2-hydroxyethyl) amino] propyl group, 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 2-[(1-methyl-2-morpholine-4-base ethyl), 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group, 1-glycoloyl tetramethyleneimine-2-yl] methyl, 1-(N, N-dimethyl glycyl) tetramethyleneimine-2-base, 2-piperazine-1-base ethyl, 3-piperazine-1-base propyl group, 3-(4-methylpiperazine-1-yl) propyl group, 3-piperidines-1-base propyl group, 2-(1H-imidazol-4 yl) ethyl, 2-pyridine-2-base ethyl, 3-(1H-imidazoles-1-yl) propyl group, 5-Shu butyl isoxazole-3-base, 2-pyridin-4-yl ethyl and 2, the 4-dimethoxy-benzyl;

(iii) R ¹Be hydrogen, and R ²Be selected from 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-tetramethyleneimine-1-base ethyl, 4-methylpiperazine-1-base propyl group and 3-tetramethyleneimine-1-base propyl group;

(jjj) R ¹Be hydrogen, and R ²Be selected from 2-morpholine-4-base ethyl, 3-morpholine-4-base propyl group, 3-piperidines-1-base propyl group, 2-piperidines-1-base ethyl, 2-tetramethyleneimine-1-base ethyl, 3-tetramethyleneimine-1-base propyl group and 4-methyl-piperazine-1-base;

(kkk) R ¹And R ²All be (1-6C) alkyl (particularly (1-3C) alkyl);

(lll) R ¹Be hydrogen and R ²Be methyl;

(mmm) R ¹And R ²All be hydrogen;

(mmm) R ^3aPerhaps R ^3bBe selected from hydrogen, (1-3C) alkyl or (1-3C) alkoxyl group,

Wherein (1-3C) alkyl is with (1-3C) alkoxyl group is optional by one or more (for example 1 or 2), can be identical or different, being selected from following group replaces: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino single (1-6C) alkylamino, two [(1-6C) alkyl] amino, formamyl, single (1-6C) alkyl-carbamoyl or two-[(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional independently by one or more (for example 1 or 2), can be identical or different, be selected from (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, 3～7 yuan of heterocyclic substituted of single (1-6C) alkylamino or two [(1-6C) alkyl] amino or saturated or fractional saturation;

Perhaps R ^3aPerhaps R ^3bRepresent group-NR as defined above ¹R ²

(nnn) R ^3aPerhaps R ^3bBe selected from hydrogen or (1-6C) alkyl,

Wherein (1-6C) alkyl is optional by one or more (for example 1 or 2), can be identical or different, being selected from following group replaces: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino, single (1-6C) alkylamino, two-[(1-6C) alkyl] amino, formamyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional independently by one or more (for example 1 or 2), can be identical or different, be selected from (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, single (1-6C) alkylamino or two-[(1-6C) alkyl] 3～7 yuan of heterocyclic groups amino or saturated or fractional saturation replace;

Perhaps R ^3aPerhaps R ^3bRepresent group-NR as defined above ¹R ²

(ooo) R ^3aPerhaps R ^3bBe selected from hydrogen and group-NR as defined above ¹R ²(particularly-NH ₂);

(ppp) R ^3aPerhaps R ^3bBe hydrogen;

(qqq) R ^3aPerhaps R ^3bBe group-NR as defined above ¹R ²(particularly-NH ₂);

(qqq ') R ^3aPerhaps R ^3bBe selected from hydrogen or group-NR as defined above ¹R ²(particularly-NH ₂);

(qqq ") R ^3aPerhaps R ^3bBe selected from hydrogen or-NH ₂

(rrr) R ^4aPerhaps R ^4bBe independently selected from hydrogen and (1-6C) alkyl (particularly (1-3C) alkyl);

(sss) R ^4aPerhaps R ^4bBe hydrogen;

(ttt) R ^3aAnd R ^4aPerhaps R ^3bAnd R ^4bAll be hydrogen;

(uuu) R ^3aPerhaps R ^3bBe group-NR as defined above ¹R ²(particularly-NH ₂), and R ^4aPerhaps R ^4bBe respectively hydrogen;

(uuu ') R ⁵Be selected from (1-6C) alkyl and (1-6C) alkoxyl group;

(uuu ") R ⁵Be selected from (1-4C) alkyl and (1-4C) alkoxyl group;

(uuu " ') R ⁵Be selected from methyl and methoxyl group;

(vvv) n is 0,1 or 2 (particularly 0 or 1, more especially 0);

(vvv ') n is 0 or 1;

(www) n is 1 or 2, and R ⁵Be independently selected from halogen, (1-6C) alkoxyl group and (1-6C) alkyl, wherein (1-6C) alkyl and (1-6C) alkoxyl group is optional is replaced by cyano group or one or more fluorine;

(xxx) n be 1 or 2 and R5 be independently selected from cyano group, halogen, (1-6C) alkoxyl group and (1-6C) alkyl, (1-6C) alkyl and (1-6C) alkoxyl group is optional is replaced by cyano group or one or more fluorine wherein;

(yyy) n is 0 or 1 and when n is 1, R ⁵Be (1-4C) alkyl (particularly methyl);

(zzz) n is 1 or 2, and R ⁵Be independently selected from cyclopropyl and (1-6C) alkyl, wherein (1-6C) alkyl is optional is replaced by cyano group or one or more fluorine;

(aaaa) n is 1, and R ⁵Be (1-6C) alkyl, particularly (1-3C) alkyl;

(bbbb) n is 0,

(cccc) n is 1;

(dddd) R ⁶Be independently selected from halogen, cyano group, (3-4C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl and (1-6C) alkoxyl group optional by one or more (for example 1 or 2), can be identical or different, be selected from following group and replace: 3～7 yuan of heterocycles of cyano group, fluorine, hydroxyl, (1-6C) alkoxyl group, amino, list (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (3-7C) cycloalkyl ring or saturated or fractional saturation;

(eeee) R ⁶Be independently selected from halogen, cyano group, saturated or fractional saturation 3～7 yuan of heterocycles or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl group, wherein said (1-6C) alkyl is replaced by one or more (for example 1 or 2), group can be identical or different, that be selected from cyano group, fluorine, hydroxyl and amino (particularly fluorine) with (1-6C) alkoxyl group is optional;

(ffff) R ⁶Be independently selected from halogen, cyano group, saturated or fractional saturation 3～7 yuan of heterocycles or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-3C) alkyl; Perhaps R ⁶Be selected from (1-4C) alkyl or (1-4C) alkoxyl group, wherein said (1-4C) alkyl is replaced by one or more (for example 1 or 2), group can be identical or different, that be selected from cyano group, fluorine, hydroxyl and amino (particularly fluorine) with (1-4C) alkoxyl group is optional;

(ggg) R ⁶Be selected from fluorine, chlorine, cyano group, kharophen, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, oxyethyl group, propoxy-, butoxy and morpholine-4-base;

(hhhh) R ⁶Be selected from fluorine, chlorine, kharophen, methyl, propyl group, the tertiary butyl, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group and morpholine-4-base;

(iiii) R ⁶Be independently selected from (1-6C) alkyl, (1-6C) alkoxyl group or saturated 3～7 yuan of heterocycles (particularly morpholine-4-base or piperidines-1-yl),

Wherein (1-6C) alkyl and (1-6C) alkoxyl group is optional is replaced by 1～3 halogen, particularly fluorine,

The first heterocycle of wherein saturated 3-7 is optional to be replaced by hydroxyl (1-2C) alkyl;

(iiii ') R ⁶Be independently selected from hydroxyl, halogen (particularly chlorine or fluorine), (1-6C) alkyl, (1-6C) alkoxyl group, two-(1-6C) alkylaminos or saturated 3～7 yuan of heterocycles (particularly morpholine-4-base, piperidines-1-base or piperazine-1-yl),

Wherein saturated 3-7 unit's heterocycle optional quilt (1-2C) alkyl or hydroxyl (1-2C) alkyl replace;

(iiii ") R ⁶Be independently selected from (1-6C) alkyl (optional replaced, particularly fluorine), halogen or (1-6C) alkoxyl group by 1～3 group that is independently selected from halogen;

(jjjj) R ⁶Be independently selected from methyl, trifluoromethyl, morpholine-4-base or piperidines-1-base, 4-hydroxymethyl piperidines-1-base;

(jjjj ') R ⁶Be independently selected from methyl, methoxyl group, two-methylamino, hydroxyl, oxo, chlorine, fluorine, trifluoromethyl, morpholine-4-base or piperidines-1-base, 4-hydroxymethyl piperidines-1-base, 4-methylpiperazine-1-base;

(jjjj ") R ⁶Be independently selected from chlorine, fluorine, trifluoromethyl, methyl or methoxyl group;

(kkkk) R ⁶Be independently selected from halogen, trifluoromethyl, methyl, the tertiary butyl, methoxyl group, kharophen or morpholino.

(llll) R ⁶Be independently selected from halogen, cyano group, oxo, (3-7C) cycloalkyl, saturated 3～7 yuan of heterocycles (optional replaced) by (1-4C) alkyl or hydroxyl (1-4C) alkyl ,-N (R ^c) (1-6C) alkyl (R wherein of C (O) ^cBe hydrogen or (1-6C) alkyl (particularly (1-4C) alkyl)), (1-6C) alkyl (optionally is up to three groups that are independently selected from halogen and replaced, fluorine particularly) or (1-6C) alkoxyl group (optional be up to three groups that are independently selected from halogen and replace, particularly fluorine).

(ll1l ') R ⁶Be independently selected from hydroxyl, halogen, cyano group, oxo, (3-7C) cycloalkyl, saturated 3～7 yuan of heterocycles (optional replaced) by (1-4C) alkyl or hydroxyl (1-4C) alkyl ,-N (R ^c) (1-6C) alkyl (R wherein of C (O) ^cAlkyl (particularly (1-4C) alkyl), (1-6C) alkyl (are chosen wantonly by saturated 3～7 yuan of heterocycles or are up to three groups that are independently selected from halogen and replace for hydrogen or (1-6C), fluorine particularly), (1-6C) alkoxyl group (optional be up to three groups that are independently selected from halogen and replace, particularly fluorine) or two-(1-6C) alkylaminos;

(mmmm) R ⁶Be independently selected from halogen, trifluoromethyl, trifluoromethoxy, cyano group, methyl, sec.-propyl, the tertiary butyl, methoxyl group, kharophen, oxo, cyclopropyl, morpholine-4-base, piperidines-1-base, 4-(methylol) piperidines-1-base and 4-methylpiperazine-1-base.

(mmmm ') R ⁶Be independently selected from hydroxyl, halogen, trifluoromethyl, trifluoromethoxy, cyano group, methyl, sec.-propyl, the tertiary butyl, 1-cyanoethyl, methoxyl group, isopropoxy, dimethylamino, kharophen, oxo, cyclopropyl, morpholine-4-base, piperidines-1-base, 4-(methylol) piperidines-1-base, 4-methylpiperazine-1-base and 4-methylpiperazine-1-ylmethyl;

(mmmm ") R ⁶Be independently selected from halogen (such as chlorine), trifluoromethyl, methoxyl group, dimethylamino, morpholine-4-base or piperidines-1-base.

(mmmm " ') at least one R ⁶Group is selected from amino, amino, two-(C1-6 alkyl) amino of list (C1-6 alkyl), such as dimethylamino.

(nnnn) m is 1 or 2;

(oooo) m is 1;

(pPPP) m is 2;

(qqqq) ring B-R ⁶Wherein m is 1 or 2, is selected from: 2-(trifluoromethyl) phenyl, 2-(trifluoromethoxy) phenyl, 2-oxo-pyrrolidine-1-base, 2-morpholine-4-base phenyl, 2-(piperidines-1-yl) phenyl, 2-[4-(methylol) piperidines-1-yl)] phenyl, 5-methyl furan-2-base and 4-morpholine-4-yl pyrimidines-5-base;

(qqqq ') ring B-R ⁶Wherein m is 1 or 2, is selected from: 2-hydroxy-cyclohexyl, 2-aminomethyl phenyl, 2-p-methoxy-phenyl, 2-chloro-phenyl-, 3-chloro-phenyl-, 2-(dimethylamine) phenyl, 2-(trifluoromethyl) phenyl, 2-(trifluoromethoxy) phenyl, 2-oxo-pyrrolidine-1-base, 2-morpholine-4-base phenyl, 3-morpholine-4-base phenyl, morpholine-4-base-5-fluorophenyl, 2-(piperidines-1-yl) phenyl, 2-[4-(methylol) piperidines-1-yl] phenyl, 5-methyl furan-2-base, 2-(4-methylpiperazine-1-yl) phenyl and 4-morpholine-4-yl pyrimidines-5-base;

(qqqq " ') ring B-R ⁶Wherein m is 1 or 2, is selected from 2-chloro-phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3,6-difluorophenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 2-chloro-thiophene-5-base, 1-Methylimidazole-4-base, 3-p-methoxy-phenyl and 3,5-dimethyl isoxazole-4-base;

(qqqq " ") ring B-R ⁶Wherein m is 1 or 2, be selected from 2-chloro-phenyl, 2,3-dichlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 3,6-difluorophenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 2-chloro-thiophene-5-base, 1-Methylimidazole-4-base, 3-p-methoxy-phenyl and 3,5-dimethyl isoxazole-4-base;

(rrrr) ring B-R ⁶Wherein m is 1 or 2, be selected from 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2, the 3-dichlorophenyl, 3, the 4-dichlorophenyl, 2, the 5-difluorophenyl, 3, the 4-difluorophenyl, 4, the 5-difluorophenyl, 3, the 6-difluorophenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 3-cyano-phenyl, 2-(trifluoromethyl) phenyl, 2-(trifluoromethoxy) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, the 3-acetylamino phenyl, 2-morpholine-4-base phenyl, 3-fluoro-5-(4-methylpiperazine-1-yl) phenyl, 2-morpholine-4-base phenyl, 2-(piperidines-1-yl) phenyl, 2-(4-hydroxymethyl piperidines-1-yl) phenyl, 2-oxo-pyrrolidine-1-base, 2-oxo-piperidine-3-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 2,2-dimethyl tetrahydro pyrans-4-base, 5-methyl furan-2-base, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, the 5-tertiary butyl-1,3,4-thiadiazoles-2-base, the 5-Trifluoromethyl-1,3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 5-ethyl-1,3,4-thiadiazoles-2-base, 5-sec.-propyl-1,3,4-thiadiazoles-2-base, 5-ethylenebis dithiocarbamate-1,3,4-thiadiazoles-2-base, 3-methyl-isoxazole-5-base, 4-methyl-isoxazole-3-base, 5-methyl-isoxazole-3-base, 5-Shu butyl isoxazole-3-base, 3,5-dimethyl isoxazole-4-base, 4-tertiary butyl thiazole-2-base, 3-methyl isothiazole-5-base, 4-methyl isothiazole-2-base, 1-methyl isophthalic acid H-imidazol-4 yl, 2-chloro-thiophene-5-base, 1-methyl-3-the tertiary butyl-pyrazoles-5-base, 1-methyl-3-cyclopropyl-pyrazoles-5-base, 1-methyl-3-one sec.-propyl-pyrazoles-5-base, the 1-tertiary butyl-pyrazoles-4-base, the 1-tertiary butyl-3-cyclopropyl-pyrazoles-5-base, 1-ethyl-pyrazole-3-yl, 1-sec.-propyl-pyrazole-3-yl, 5-sec.-propyl-1,3,4-oxadiazole-2-base, 4-three fluoro-pyridine-2-base, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base; 5-methyl-pyrazine-2-base and 4-morpholine-4-yl pyrimidines-5-base;

(rrrr ') ring B-R ⁶, wherein m is 1 or 2, is selected from

The 2-hydroxy-cyclohexyl, phenyl, the 2-aminomethyl phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-two chloro-phenyl, 3,4-two chloro-phenyl, 2,5-two fluoro-phenyl, 3,4-two fluoro-phenyl, 4, the 5-difluorophenyl, 3, the 6-difluorophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 3-isopropyl phenyl, 3-cyano group-phenyl, 3-(1-cyano ethyl) phenyl, 2-(trifluoromethyl) phenyl, 2-(trifluoromethoxy) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, 2-(dimethylamine) phenyl, the 3-acetylamino phenyl, 2-morpholine-4-base phenyl, 3-morpholine-4-base phenyl, 2-morpholine-4-base-5-fluorophenyl, 2-(4-methylpiperazine-1-yl) phenyl, 3-fluoro-5-(4-methylpiperazine-1-yl) phenyl, 2-(piperidines-1-yl) phenyl, 2-(4-hydroxymethyl piperidines-1-yl) phenyl, 2-oxo-pyrrolidine-1-base, 2-oxo-piperidine-3-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 4-methyl-piperazine-1-ylmethyl phenyl, 2,2-dimethyl tetrahydro pyrans-4-base, 5-methyl furan-2-base, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, the 5-tertiary butyl-1,3,4-thiadiazoles-2-base, the 5-Trifluoromethyl-1,3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 5-ethyl-1,3,4-thiadiazoles-2-base, 5-sec.-propyl-1,3,4-thiadiazoles-2-base, 5-ethylenebis dithiocarbamate-1,3,4-thiadiazoles-2-base, 3-methyl-isoxazole-5-base, 4-methyl-isoxazole-3-base, 5-methyl-isoxazole-3-base, 5-Shu butyl isoxazole-3-base, 3,5-dimethyl isoxazole-4-base, the 4-tertiary butyl-thiazol-2-yl, 3-methyl-isothiazole-5-base, 4-methyl-isothiazole-2-base, 1-methyl isophthalic acid H-imidazol-4 yl, 2-chloro-thiophene-5-base, 1-methyl-3-the tertiary butyl-pyrazoles-5-base, 1-methyl-3-cyclopropyl-pyrazoles-5-base, 1-methyl-3-sec.-propyl-pyrazoles-5-base, the 1-tertiary butyl-pyrazoles-4-base, the 1-tertiary butyl-3-cyclopropyl-pyrazoles-5-base, 1-ethyl-pyrazole-3-yl, 1-sec.-propyl-pyrazole-3-yl, 5-sec.-propyl-1,3,4-oxadiazole-2-base, 4-three fluoro-pyridine-2-base, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base;

5-methylpyrazine-2-base and 4-morpholine-4-yl pyrimidines-5-base; The benzodioxole base;

(rrrr ") ring B-R ⁶, wherein m is 1 or 2, is selected from

The 2-hydroxy-cyclohexyl, phenyl, the 2-aminomethyl phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-two chloro-phenyl, 3,4-two chloro-phenyl, 2,5-two fluoro-phenyl, 3,4-two fluoro-phenyl, 4, the 5-difluorophenyl, 3, the 6-difluorophenyl, the 2-aminomethyl phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 3-isopropyl phenyl, 3-cyano group-phenyl, 3-(1-cyano ethyl) phenyl, 2-(trifluoromethyl) phenyl, 2-(trifluoromethoxy) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, 2-(dimethylamine) phenyl, the 3-acetylamino phenyl, 2-morpholine-4-base phenyl, 3-morpholine-4-base phenyl, 2-morpholine-4-base-5-fluorophenyl, 2-(4-methylpiperazine-1-yl) phenyl, 3-fluoro-5-(4-methylpiperazine-1-yl) phenyl, 2-(piperidines-1-yl) phenyl, 2-(4-hydroxymethyl piperidines-1-yl) phenyl, 2-oxo-pyrrolidine-1-base, 2-oxo-piperidine-3-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 4-methyl-piperazine-1-ylmethyl phenyl, 2,2-dimethyl tetrahydro pyrans-4-base, 5-methyl furan-2-base, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, the 5-tertiary butyl-1,3,4-thiadiazoles-2-base, the 5-Trifluoromethyl-1,3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 5-ethyl-1,3,4-thiadiazoles-2-base, 5-sec.-propyl-1,3,4-thiadiazoles-2-base, 5-ethylenebis dithiocarbamate-1,3,4-thiadiazoles-2-base, 3-methyl-isoxazole-5-base, 4-methyl-isoxazole-3-base, 5-methyl-isoxazole-3-base, 5-Shu butyl isoxazole-3-base, 3,5-dimethyl isoxazole-4-base, the 4-tertiary butyl-thiazol-2-yl, 3-methyl-isothiazole-5-base, 4-methyl-isothiazole-2-base, 1-methyl isophthalic acid H-imidazol-4 yl, 2-chloro-thiophene-5-base, 1-methyl-3-the tertiary butyl-pyrazoles-5-base, 1-methyl-3-cyclopropyl-pyrazoles-5-base, 1-methyl-3-sec.-propyl-pyrazoles-5-base, the 1-tertiary butyl-pyrazoles-4-base, the 1-tertiary butyl-3-cyclopropyl-pyrazoles-5-base, 1-ethyl-pyrazole-3-yl, 1-sec.-propyl-pyrazole-3-yl, 5-sec.-propyl-1,3,4-oxadiazole-2-base, 4-three fluoro-pyridine-2-base, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base; 5-methylpyrazine-2-base, 4-morpholine-4-yl pyrimidines-5-base; Benzodioxole base and 2-(dimethylamino) phenyl;

(ssss) A is selected from phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl group, pyridyl and pyrimidyl);

N is 0; With

With respect to the tie point of acetylene group, L be connected ring A between on the position, and expression-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-, wherein Z be-O-or-N (R ⁸)-, perhaps L represents-N (R ⁸) C (O) N (R ⁹)-CH ₂-or-N (R ⁸) C (O) N (R ⁹)-CH ₂-CH ₂-;

R ⁸, R ⁹, R ^aAnd R ^bRepresent hydrogen or (1-6C) alkyl (particularly hydrogen or (1-3C) alkyl, more especially hydrogen) independently;

X and y are 0,1 or 2 independently, and condition is x+y〉0 and x+y＜3,

(tttt) A is selected from phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl group, pyridyl and pyrimidyl);

N is 0; With

X and y are 0,1 or 2 independently, and condition is x+y〉0 and x+y＜3,

(uuuu) A is a phenyl;

N is 0; With

B is selected from 4～6 yuan of heterocycles of saturated or fractional saturation, aryl, be selected from furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5～6 yuan of heteroaryl rings of 5-triazinyl perhaps optionally contain 1,2,3 or 4 heteroatoms that is independently selected from N, O and S and are 8,9 or 10 yuan of bicyclic groups of saturated, fractional saturation or aromaticity;

(vvvv) A is a phenyl;

N is 0; With

B is selected from phenyl, pyrazolyl, thiadiazolyl group He isoxazolyl;

(wwww) A is selected from phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl group, pyridyl and pyrimidyl);

N is 0;

With respect to the tie point of ethynyl group, L be connected ring A between on the position, and expression-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-, wherein Z be-O-or-N (R ⁸)-, perhaps L represents-N (R ⁸) C (O) N (R ⁹)-CH ₂-or-N (R ⁸) C (O) N (R ⁹)-CH ₂-CH ₂-;

Wherein x and y are 0,1 or 2 independently, and condition is x+y〉0 and x+y＜3,

B is selected from phenyl, pyrazolyl, thiadiazolyl group He isoxazolyl;

(xxxx) A is selected from phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl group, pyridyl and pyrimidyl);

N is 0;

B is selected from phenyl, pyrazolyl, thiadiazolyl group He isoxazolyl;

(yyyy) m is 0,1 or 2 (particularly 1 or 2);

(zzzz) B is selected from cyclopentyl, cyclohexyl, piperidyl, THP trtrahydropyranyl, phenyl, furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-1,4-Ben Bing dioxine base and 1,3-benzodioxole-5-base;

M is 1 or 2; With

R ⁶Be independently selected from fluorine, chlorine, cyano group, kharophen, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, oxyethyl group, propoxy-, butoxy and morpholine-4-base;

(aaaaa) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl and pyridyl;

M is 1 or 2; With

R ⁶Be independently selected from halogen, cyano group, (3-4C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles or-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps R ⁶Be selected from (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl is replaced by one or more (for example 1 or 2), group can be identical or different, that be selected from cyano group, fluorine, hydroxyl and amino (particularly fluorine) with (1-6C) alkoxyl group is optional;

(bbbbb) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl group, pyrazolyl and pyridyl;

M is 1 or 2; With

(ccccc) B is a phenyl;

M is 1 or 2; With

R ⁶Be independently selected from fluorine, chlorine, cyano group, kharophen, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, oxyethyl group, propoxy-, butoxy and morpholine-4-base;

(ddddd) B is a phenyl;

M is 1 or 2; With

R ⁶Be independently selected from fluorine and trifluoromethyl;

(eeeee) B is an isoxazolyl;

M is 1 or 2; With

R ⁶Be independently selected from fluorine, chlorine, cyano group, kharophen, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, trifluoromethyl, cyclopropyl, cyclopropyl methyl, methoxyl group, oxyethyl group, propoxy-and butoxy;

(fffff) B is an isoxazolyl;

M is 1 or 2; With

R ⁶Be independently selected from methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl (the particularly methyl and the tertiary butyl, the more especially tertiary butyl);

(ggggg) B is a pyrazolyl;

M is 1 or 2; With

(hhhhh) B is a pyrazolyl;

M is 1 or 2; With

(iiiii) B is a thiadiazolyl group;

M is 1 or 2; With

R ⁶Be independently selected from fluorine, chlorine, cyano group, kharophen, methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, trifluoromethyl, cyclopropyl, methoxyl group, oxyethyl group, propoxy-and butoxy;

(jjjjj) B is a thiadiazolyl group;

M is 1 or 2; With

(cccc) wherein m is 0,1 or 2 ring B-R ⁶Be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, phenyl, the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, 2, the 5-difluorophenyl, 3, the 4-difluorophenyl, 3, the 5-difluorophenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 2, the 5-dichlorophenyl, 3, the 4-dichlorophenyl, 3, the 5-dichlorophenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 2-cyano-phenyl, the 3-cyano-phenyl, the 4-cyano-phenyl, the 2-acetylamino phenyl, the 3-acetylamino phenyl, the 4-acetylamino phenyl, the 5-tertiary butyl-1,3,4-thiadiazoles-2-base, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 1-methyl-3-cyclopropyl-pyrazoles-5-base, the 1-tertiary butyl-3-cyclopropyl-pyrazoles-5-base, 3-methyl-isothiazole-5-base, 3-methyl-isoxazole-5-base, 5-methyl-isoxazole-3-base, the 5-tertiary butyl-isoxazole-3-bases, 4-(trifluoromethyl)-pyridine-2-base, 2-oxo-piperidine-3-base, 2,2-dimethyl tetrahydro-2H-pyrans-4-base, 2,3-dihydro-1,4-Ben Bing dioxine base, 1,3-benzodioxole-5-base, 2-morpholine-4-base phenyl, 3-morpholine-4-base phenyl, 4-morpholine-4-base phenyl, 1-methyl-piperidin-4-yl, 1-ethyl piperidine-4-base and 1-propyl group piperidin-4-yl; With

(kkkkk) wherein m is 1 or 2 ring B-R ⁶Be selected from the 2-fluorophenyl, the 3-fluorophenyl, the 4-fluorophenyl, 2,5-two-fluorophenyl, 3, the 4-difluorophenyl, 3, the 5-difluorophenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, the 2-chloro-phenyl-, the 3-chloro-phenyl-, the 4-chloro-phenyl-, 2, the 5-dichlorophenyl, 3, the 4--dichlorophenyl, 3, the 5-dichlorophenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, the 4-p-methoxy-phenyl, the 2-cyano-phenyl, the 3-cyano-phenyl, the 4-cyano-phenyl, the 2-acetylamino phenyl, the 3-acetylamino phenyl, the 4-acetylamino phenyl, the 5-tertiary butyl-1,3,4-thiadiazoles-2-base, the 5-methyl isophthalic acid, 3,4-thiadiazoles-2-base, 5-cyclopropyl-1,3,4-thiadiazoles-2-base, 3-cyclopropyl-pyrazoles-5-base, the 1-tertiary butyl-3-cyclopropyl-pyrazoles-5-base, 3-methyl isothiazole-5-base, 3-methyl-isoxazole-5-base, 5-methyl-isoxazole-3-base, 5-Shu butyl isoxazole-3-base, 4-(trifluoromethyl)-pyridine-2-base, 2-oxo-piperidine-3-base, 2,2-dimethyl tetrahydro-2H-pyrans-4-base, 2-morpholine-4-base phenyl, 3-morpholine-4-base phenyl, 4-morpholine-4-base phenyl, 1-methyl piperidine-4-base, 1-ethyl piperidine-4-base and 1-propyl group piperidin-4-yl.

(lllll) R ¹And R ²All be hydrogen, R ^3aAnd R ^4aPerhaps R ^3bAnd R ^4bAll be hydrogen, n is 0, and L is-NHC (O) NH-CH ₂-and wherein m be 1 or 2 ring B-R ⁶Be selected from the 3-acetylamino phenyl, 2-(trifluoromethyl) phenyl, 3-(trifluoromethyl) phenyl, 4-(trifluoromethyl) phenyl, the 2-p-methoxy-phenyl, the 3-p-methoxy-phenyl, 2-fluoro-5-(trifluoromethyl) phenyl, 3, the 4-dichlorophenyl, 2-morpholine-4-base phenyl, the 5-tertiary butyl-1,3,4-thiadiazoles-2-base, 3-methyl isothiazole-5-base, 3-methyl-isoxazole-5-base, 5-Shu butyl isoxazole-3-base, 1-methyl-3-tertiary butyl pyrazoles-5-base, 1-methyl piperidine-4-base, 1-propyl group piperidin-4-yl, 4-(trifluoromethyl) pyridin-3-yl and 4-(trifluoromethyl) pyridine-2-base;

(mmmmm) R ^yBe group-NR ¹R ², R ^xBe radicals R ^3aAnd R ^zBe radicals R ^4a, and R ^3aAnd R ^4aBe hydrogen, ring A is phenyl or pyridyl, and n is 0 or 1 and when n is 1, R ⁵Be methyl, L is-NHC (O) NH-CH ₂-, ring B-R ⁶Be selected from 2-chloro-phenyl, 2-(trifluoromethyl) phenyl, 2-p-methoxy-phenyl, 3-methoxyl group-phenyl, 2-methylamino phenyl, 2-morpholine-4-base phenyl or 2-piperin-1-base phenyl.

The specific embodiments of formula IA compound is formula IA (i) compound:

Formula IA (i)

R wherein ¹, R ², R ^3a, R ^4a, R ⁵, R ⁶, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

Another specific embodiments of formula I compound is a (ii) compound of formula IA:

Formula IA (ii)

R wherein ¹, R ², R ^3a, R ^4a, R ⁵, R ⁶, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

Another specific embodiments of formula I compound is a (iii) compound of formula IA:

Formula IA (iii)

R wherein ¹, R ², R ^3a, R ^4a, R ⁵, R ⁶, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

Another specific embodiments of formula I compound is a (iv) compound of formula IA:

Formula IA (iv)

R wherein ¹, R ², R ^3a, R ^4a, R ⁵, R ⁶, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

The specific embodiments of formula IB compound is formula IB (i) compound:

Formula IB (i)

R wherein ¹, R ², R ^3b, R ^4b, R ⁵, Ru, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

Another specific embodiments of formula I compound is a (ii) compound of formula IB:

Formula IB (ii)

R wherein ¹, R ², R ^3b, R ^4b, R ⁵, R ⁶, L, B, n and m as defined above, and salt, particularly its pharmacy acceptable salt.

Another specific embodiments of formula I compound is a (iii) compound of formula IB:

Formula IB (iii)

Wherein:

R wherein ¹, R ², R ^3b, R ^4b, R ⁵, R ⁶, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

Another specific embodiments of formula I compound is a (iv) compound of formula IB:

Formula IB (iv)

R wherein ¹, R ², R ^3b, R ^4b, R ⁵, R ⁶, L, B, n and m as defined above,

And salt, particularly its pharmacy acceptable salt.

Formula I compound or its pharmacy acceptable salt can be prepared by any known method of the compound that the chemical aspect of preparation is relevant that is applicable to.Described method when being used for preparation I compound, is provided as another feature of the present invention and with following representational method variant illustrations.Necessary raw material can obtain by vitochemical standard method.The preparation of described raw material is described and is described in the related embodiment in conjunction with following representational method variant.Additionally, raw material can obtain by the method that is similar to the diagram method necessarily, and described similar approach is in the those of ordinary skill limit of power of organic chemistry filed.

According to a further aspect in the invention, provide preparation I compound or its pharmacy acceptable salt (R wherein except as otherwise noted, ¹, R ², R ^3a, R ^4a, R ⁵, R ⁶, R ⁷, R ⁸, R ⁹, R ¹⁰, R ¹¹, L, ring A and ring B, n and m be suc as formula defining among the I) method, following signal description.

Method (a)Make formula II compound:

R wherein ^x, R ^y, R ^z, R ⁵, R ⁸, n and A have any implication of above definition, but in case of necessity any functional group is protected and the isocyanate reaction of formula IV:

Wherein Z, R ⁶, R ^a, R ^b, x, y, m and B have any implication of above definition, but in case of necessity any functional group protected;

Perhaps

Method (b)Make the aryl carbamate reaction of formula II compound and formula III as defined above:

Wherein Ar is suitable aryl, for example phenyl and Z, R ⁶, R ^a, R ^b, x, y, m and B have any implication of above definition, but in case of necessity any functional group protected;

Perhaps

Method (c)For Z wherein be-O-or-N (R ^a)-formula I compound, make formula IX compound

R wherein ^x, R ^y, R ^z, R ⁵, R ⁸, R ⁹, R ^a, R ^b, x, n and A have any implication of above definition, but in case of necessity any functional group is protected, with the reaction of formula XI compound,

Lg wherein ¹Be suitable replaceable group, for example halogen (such as fluorine, chlorine, bromine), O-tosyl group, O-methylsulfonyl or trifluoro sulfonyloxy, and R ^a, R ^b, R ⁶, y, m and B have any implication of above definition, but in case of necessity any functional group protected;

Method (d)For Z wherein be-O-or-N (R ^a)-formula I compound, make formula XIV compound

Lg wherein ²Be suitable replaceable group, for example halogen (such as chlorine, bromine), O-tosyl group, O-methylsulfonyl or trifluoro sulfonyloxy, and R ^x, R ^y, R ^z, R ⁵, R ⁸, R ⁹, R ^a, R ^b, n, x and A have any implication of above definition, but in case of necessity any functional group is protected, with the reaction of formula XV compound,

R wherein ^a, R ^b, R ⁶, y, m and B have any implication of above definition, but in case of necessity any functional group protected;

Perhaps

Method (e)For L wherein be-N (R ⁸) C (O) N (H)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-formula I compound, make the trichloroacetamide reaction of formula II compound and formula XIII as defined above:

Perhaps

Method (f)Make formula XVI or XVIA compound:

Lg wherein ³Be suitable replaceable group, for example halogen (such as fluorine, chlorine, bromine or iodine), methylsulfonyl, methylsulfinyl (being methyl sulfoxide), methylthio group or aryloxy (such as phenoxy group), and R ^3a, R ^4a, R ^3b, R ^4b, R ⁵, R ⁶, n, m, A, B and L have any implication of above definition, but in case of necessity any group is protected, with formula HNR ¹R ²Amine reaction, R wherein ¹And R ²Any implication with above definition, but in case of necessity any functional group is protected;

Perhaps

Method (g)Make formula XVII compound:

Lg wherein ⁴Be suitable replaceable group, for example halogen (such as chlorine, bromine or iodine) or sulfonyloxy (such as the trifluoromethyl sulfonyloxy), and R ⁵, R ⁶, n, m, A, B and L have any implication of above definition, but in case of necessity any functional group is protected and the alkyne reaction of formula XVIII:

R wherein ^x, R ^yAnd R ^zAny implication with above definition, but in case of necessity any functional group is protected;

Perhaps

Method (h) makes the compound of formula XVIIa:

R wherein ⁵, R ⁶, n, m, A, B and L have any implication of above definition, but in case of necessity any functional group is protected and the pyrimidine reaction of formula XVIIIa:

Lg wherein ⁵Be suitable replaceable group, for example halogen (such as chlorine, bromine or iodine) or sulfonyloxy (such as the trifluoromethyl sulfonyloxy), and R ^x, R ^yAnd R ^zAny implication with above definition, but in case of necessity any functional group is protected;

Perhaps

Method (i)L is-N (H) C (O) N (R to doing wherein ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-formula I compound, make the isocyanic ester of formula XIX:

R wherein ^x, R ^y, R ^z, R ⁵, n and A have any implication of above definition, but in case of necessity any functional group is protected, with the amine reaction of formula XV;

R wherein ⁹, R ^a, R ^b, Z, B, R ⁶, x, y and m as defined above.

Perhaps

Method (j)For L wherein be-N (H) C (O) N (R ⁹)-formula I compound, make the compound of formula XX:

Wherein Ar is suitable aryl, for example phenyl, and R ^x, R ^y, R ^z, R ⁵, n and A have any implication of above definition, but in case of necessity any functional group is protected, with the amine reaction of formula XV as defined above.

After this if necessary:

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

Ii) remove any protecting group;

Iii) form salt.

The reaction conditions of method (a)

The reaction of method (a) is desirably carried out in the presence of suitable inert solvent or thinner, for example halide reagent (such as methylene dichloride, chloroform or tetracol phenixin), ether are (such as tetrahydrofuran (THF) or 1, the 4-dioxane), amine (such as pyridine) or dipolar aprotic solvent are (such as N, dinethylformamide or N,N-dimethylacetamide).This reaction is desirably carried out in following temperature range, and for example, envrionment temperature～about 60 ℃ is preferably envrionment temperature or near envrionment temperature.

The reaction conditions of method (b)

The reaction of method (b) is desirably carried out in the presence of suitable alkali.Suitable alkali is that for example, organic amine alkali is such as pyridine or trialkylamine (such as triethylamine or diisopropylethylamine).

The reaction of method (b) is desirably carried out in the presence of suitable inert solvent or thinner, for example ether is (such as tetrahydrofuran (THF) or 1, the 4-dioxane) or dipolar aprotic solvent (such as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or methyl-sulphoxide).This reaction is desirably carried out in following temperature range, and for example, envrionment temperature～about 120 ℃ is preferably about 80 ℃～about 100 ℃.

This reaction can also be desirably by utilizing suitable well heater (such as microwave heater) reacting by heating thing to carry out in sealed vessel.

The reaction conditions of method (c)

The reaction of method (c) is desirably carried out in the presence of suitable alkali.Suitable alkali is, for example, organic amine alkali, such as pyridine or trialkylamine (such as triethylamine or diisopropylethylamine), perhaps for example basic metal or alkaline earth metal carbonate (such as yellow soda ash or salt of wormwood).

The reaction of method (c) is desirably carried out in the presence of The suitable solvent or thinner, tetrahydrofuran (THF), 1 for example, 4-dioxane or dipolar aprotic solvent (such as dimethyl formamide or N,N-DIMETHYLACETAMIDE).This reaction desirably in following temperature range, for example, 100 ℃ of envrionment temperatures～about and under barometric point, carrying out.

The reaction conditions of method (d)

The reaction of method (d) is desirably carried out under as above about the described condition of method (c).

The reaction conditions of method (e)

The reaction of method (e) is desirably carried out in the presence of suitable alkali.Suitable alkali is that for example, organic amine alkali is such as pyridine or trialkylamine (such as triethylamine or diisopropylethylamine).

The reaction of method (e) is desirably carried out in the presence of suitable inert solvent or thinner, for example ether is (such as tetrahydrofuran (THF) or 1, the 4-dioxane) or dipolar aprotic solvent (such as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or methyl-sulphoxide).This reaction is desirably carried out in following temperature range, and for example, envrionment temperature～about 120 ℃ is preferably about 100 ℃～about 120 ℃.

The reaction conditions of method (f)

The reaction of method (f) is desirably carried out in the presence of the suitable acid of catalytic amount.Suitable acid is, for example, and hydrogenchloride.

The reaction of method (f) can be desirably carried out not existing or exist under suitable inert solvent or the thinner.When using, suitable inert solvent or thinner are that for example, alcohol (such as ethanol, Virahol or butanols) or dipolar aprotic solvent are (such as acetonitrile, N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or methyl-sulphoxide).This reaction is desirably carried out in following temperature range, and for example, envrionment temperature～about 120 ℃ is preferably about 80 ℃～about 90 ℃.

The reaction conditions of method (g)

The reaction of method (g) is desirably carried out in the presence of suitable palladium catalyst, the suitable copper catalyst of optional coupling.Suitable palladium catalyst is, for example, and two (triphenylphosphine) palladium chloride, [1,1 '-two (diphenyl phosphine) ferrocene] palladium chloride or tetrakis triphenylphosphine palladium (0).Suitable copper catalyst is, for example, and copper(I) iodide (I).

The reaction of method (g) is desirably carried out in the presence of suitable alkali.Suitable alkali is that for example, organic amine alkali is such as trialkylamine (for example triethylamine) or tetramethyl guanidine.

The reaction of method (g) can be desirably carried out not existing or exist under suitable inert solvent or the thinner, for example ester (such as ethyl acetate), ether are (such as tetrahydrofuran (THF) or 1, the 4-dioxane) or dipolar aprotic solvent (such as N, dinethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-ketone or methyl-sulphoxide).This reaction desirably in following temperature range, for example, is made an appointment with-20 ℃～about 100 ℃.

The reaction conditions of method (h)

The reaction of method (h) is desirably carried out under as above about the described condition of method (g).

The reaction conditions of method (i)

The reaction of method (i) is desirably carried out under as above about the described condition of method (a).

The reaction conditions of method (j)

The reaction of method (j) is desirably carried out under as above about the described condition of method (b).

The raw material of method (a)

Formula II compound can obtain by ordinary method.For example, pyrimidine that formula II compound can be by making formula VI and the alkyne reaction of formula VII obtain, as 1 diagram of reaction scheme:

Reaction scheme 1

Lg wherein ⁴Be aforesaid suitable replaceable group, and R ^x, R ^y, R ^z, R ⁵, R ⁸, n and A have any implication of above definition, but in case of necessity any functional group protected.

The reaction of reaction scheme 1 is desirably carried out under as above about the described condition of method (h).

Additionally, pyrimidine that formula II compound can be by making formula VI and the shielded alkyne reaction of formula VIa, the amine reaction with formula VIb obtains then, as institute's diagram in the reaction scheme 2:

Reaction scheme 2

Lg in its Chinese style VI and the VIb compound ⁴The aforesaid suitable replaceable group of respectively doing for oneself, Pg is suitable protecting group, for example trialkylsilkl (such as trimethyl silyl or t-butyldimethylsilyl) or Me ₂(OH) C-, and R ^x, R ^y, R ^z, R ⁵R ⁸, n and A have any implication of above definition, but in case of necessity any functional group protected.

The step of reaction scheme 2 (i) is that the protected alkynes with formula VIa is coupled on the pyrimidine of formula VI.Step (i) is carried out under as above about the described condition of method (h).The step of reaction scheme 2 (ii) is under alkalescence or acidic conditions gained alkynes to be gone protection, thereby not protected alkynes is provided.Those skilled in the art can be chosen in step easily and carry out de-protected felicity condition in (ii).The step of reaction scheme 2 (iii) is that alkynes is coupled on the amine of formula VIb.The step of reaction scheme 2 is (iii) carried out under as above about the described condition of method (h).

Additionally, formula II compound can obtain by following reaction: make formula VIc or Vic ' compound, wherein Lg ³Be aforesaid suitable replaceable group, and R ³, R ⁴, R ⁵, R ⁸, n and A have any implication of above definition, but in case of necessity any functional group is protected, with formula HNR ¹R ²The amine utilization as above react about the described reaction conditions of method (g).

Formula VI, VII, VIa and VIb and amine HNR ¹R ²Raw material can market buy or they are known in the literature, perhaps they can be prepared by standard method known in the art.The raw material of formula VIc and VIc ' can be prepared by standard method known in the art.

The isocyanic ester of formula IV can market buys or they are known in document, and perhaps they can be prepared by standard method known in the art.For example, those skilled in the art are appreciated that described isocyanic ester can be desirably obtained through the Curtis prepared in reaction by corresponding acid or acyl chlorides and for example trinitride or diphenyl phosphoryl azide.Additionally, described isocyanic ester can be desirably by corresponding amine and phosgene or phosgene Equivalent (for example triphosgene, trichloromethylchloroformate or N, N '-N,N'-carbonyldiimidazole) reaction obtains preparation (March J., Adv.Org.Chem., 4th edition, 1992, page1290, Wiley Interscience).

The raw material of method (b)

Formula II compound can obtain by aforesaid ordinary method.

The aryl carbamate of formula III can market buys or they are known in document, and perhaps they can be prepared by standard method known in the art.For example, described aryl carbamate can amine and the reaction of chloroformic acid aryl ester by making formula V obtain preparation, as institute's diagram in the reaction scheme 3:

Reaction scheme 3

R wherein ⁶, R ^a, R ^b, m, x, y, B, Z and Ar have any implication of above definition, but in case of necessity any functional group protected.

The reaction of reaction scheme 3 is desirably carried out in the presence of suitable alkali.Suitable alkali is that for example, organic amine alkali is such as pyridine or trialkylamine (such as triethylamine).

This reaction is desirably carried out in the presence of suitable inert solvent or thinner, ether for example, and such as tetrahydrofuran (THF) or 1, the 4-dioxane.This reaction for example ,-20 ℃～about 100 ℃ approximately, is preferably 0 ℃ or near 0 ℃ desirably in following temperature range.

The raw material of formula V and chloroformic acid aryl ester can market buy or they are known in the literature, and perhaps they can be prepared by standard method known in the art.

The raw material of method (c)

The ordinary method that formula IX compound is used for the method for preparation formula II compound in can above by being similar to " raw material of method (a) " obtains.

Formula XI compound can market buys or they are known in the literature, and perhaps they can be prepared by standard method known in the art.

The raw material of method (d)

The ordinary method that formula XIV compound is used for the method for preparation formula II compound in can above by being similar to " raw material of method (a) " obtains.

The raw material of method (e)

Formula II compound can obtain by aforesaid ordinary method.

The trichloroacetamide of formula XIII can market buys or they are known in the literature, and perhaps they can be prepared by standard method known in the art.

The raw material of method (f)

Those skilled in the art should be appreciated that formula XVI compound can utilize with the similar method of method as mentioned above and use suitable raw material to be prepared that for example, wherein raw material has the group L g of optional protection ³0 replacement-NR ¹R ²Group.

Formula HNR ¹R ²Amine can market buy or they are known in the literature, perhaps they can be prepared by standard method known in the art.

The raw material of method (g)

Formula XVII compound can market buys or they are known in the literature, perhaps understand as those skilled in the art, they can utilize with as mentioned above similarly the suitable raw material of method utilization be prepared.For example, wherein L is-N (R ⁸) C (O) N (H)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-formula XVII compound can be desirably amine by making formula XVIIa and the aryl carbamate reaction of formula XVIIb obtain, as institute's diagram in the reaction scheme 4:

Reaction scheme 4

Lg wherein ⁴Be aforesaid suitable replaceable group, L is-N (R ⁸) C (O) N (H)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-, and R ⁵, R ⁶, R ⁸, n, m, A and B have any implication of above definition, but in case of necessity any functional group protected.

The reaction of reaction scheme 4 is desirably carried out under as above about the described condition of method (b).

The raw material of formula XVIIa and XVIIb can market buys or they are known in the literature, and perhaps they can be prepared by standard method known in the art.

The alkynes of formula XVIII can market buys or understands as those skilled in the art, they can utilize with as mentioned above similarly method use suitable raw material to be prepared.For example, formula XVIII compound can desirably obtain by following reaction, makes the pyrimidine of formula XVIIIa:

Lg wherein ⁴Be aforesaid suitable replaceable group, and R ¹, R ², R ³And R ⁴Has any implication defined above; but in case of necessity any functional group is protected; desirably under as above about the described condition of method (h), react, utilize standard method known in the art to remove protecting group subsequently with trimethyl silyl acetylene or 2-methyl-3-butyne-2-alcohol.

The raw material of method (h)

Formula XVIIa compound can utilize the method that is similar to aforesaid method (a)～(e) and method (i)～(j) to be prepared.

Formula XVIIIa compound can market buys or understands as those skilled in the art, they can utilize with as mentioned above similarly method use suitable raw material to be prepared.

The raw material of method (i)

Understand as those skilled in the art, the isocyanic ester of formula XIX can be desirably obtained through the Curtis prepared in reaction by corresponding acid or acyl chlorides and for example trinitride or diphenyl phosphoryl azide.Additionally, described isocyanic ester can be desirably by corresponding amine and phosgene or phosgene Equivalent (for example triphosgene, trichloromethylchloroformate or N, N '-N,N'-carbonyldiimidazole) reaction obtains preparation (March J., Adv.Org.Chem., 4th edition, 1992, page1290, WileyInterscience).

The amine of formula XV can market buys or they are known in the literature, and perhaps they can be prepared by standard method known in the art.

The raw material of method (j)

Formula XX compound can market buys or they are known in the literature, perhaps understand as those skilled in the art, they can utilize with as mentioned above similarly the suitable raw material of method utilization be prepared.

Utilize the conventional criteria method of this area, formula I compound can be converted into other formula I compound.

The example of the type of operable conversion reaction comprises, introduces substituting group, reduction substituting group, alkylation substituting group and oxidation substituting group by fragrant substitution reaction or nucleophilic substitution reaction.The reagent and the reaction conditions that are used for aforesaid method are that chemical field is known.

The specific examples of fragrance substitution reaction comprises, under Friedel Crafts condition, utilizes alkyl halide and Lewis acid (such as aluminum chloride) to introduce alkyl; With the introducing halogen group.The specific examples of nucleophilic substitution reaction comprises, utilizes standard conditions introducing alkoxyl group or alkyl monosubstituted amino group, dialkyl amino group or contains the N heterocycle.The specific examples of described reduction reaction comprises, is hydroxyl with sodium borohydride with carbonyl reduction, perhaps by carrying out catalytic hydrogenation with nickel catalyzator or being amino by handling with heating nitroreduction with iron in the presence of hydrochloric acid.

The example of suitable conversion reaction is with R wherein ^x, R ^y, R ^z, R ⁵, R ⁶, n, m, A, B and L as defined in claim 1 with R1 and/or R ²For the formula I compound of hydrogen is converted into wherein R ¹And/or R ²Be for example formula I compound of optional (1-6C) alkoxycarbonyl groups that replaces.Described conversion can utilize standard method to realize, for example, and by with R ¹And/or R ²One of in the hydrogen atom or all be substituted by expectation, optional (1-6C) alkoxycarbonyl groups that replaces.

Some formula I compound can exist with stereoisomeric forms in any ratio.Should be appreciated that the present invention includes formula I compound all how much and optically active isomer and composition thereof (comprising racemoid).Tautomer and composition thereof has also constituted an aspect of of the present present invention.

Isomer can utilize ordinary method (for example chromatography or fractional crystallization) to split or separate.Enantiomer can be separated by racemize or other mixture that utilizes ordinary method (for example chiral hplc (HPLC)) separating compound.Additionally, the optically active isomer of expectation can be by making suitable optically active raw material under the condition that can not cause racemization or pass through derivatization, for example with chiral acid react, subsequently by ordinary method (HPLC for example, at the enterprising circumstances in which people get things ready for a trip spectrometry of silicon-dioxide) separate non-enantiomer derivative and obtain preparation, perhaps can be prepared with achirality raw material and chiral reagent.All steric isomers all are included in the scope of the present invention.

The compounds of this invention can utilize routine techniques to separate from their reaction mixture.

Should be appreciated that any sensitive group that in reactions more described herein, may need/wish in the protection compound.Situation that needs or desirably protect and the proper method of protecting are that those skilled in the art are known.Can use conventional blocking group (for example referring to, T.W.Green, Protective Groups in Organic Synthesis, JohnWiley and Sons, 1991) according to standard practices.Thus, if reactant contains the group such as amino, carboxyl or hydroxyl, can desirably in reactions more described herein, protect described group so.Protecting group can be removed by ordinary method described in document or the skilled known ordinary method of chemist; depend on the circumstances; in order to remove described protecting group; can select aforesaid method, thereby realize removing of protecting group in the mode that other position of molecule is produced lowest interference.

For convenience's sake, below provided the specific examples of protecting group, wherein, for example " rudimentary " in low alkyl group represents that its applied group preferably has 1～4 carbon atom.Should be appreciated that these examples are not exhaustive.Being used for of providing hereinafter removed the specific examples of the method for protecting group, and these methods are not exhaustive equally.Clearly the use and the de-protected method of the protecting group of record are not included in the scope of the present invention certainly.

It should also be understood that, multiple ring substituents can obtain introducing by carrying out the substitution reaction of standard fragrance before carrying out aforesaid method or after carrying out immediately in the The compounds of this invention, perhaps can obtain forming by conventional functional group modification, this be included in the aspect of the inventive method equally.Described reaction and modification comprise, for example, introduce substituting group, reduction substituting group, alkylation substituting group and oxidation substituting group by fragrant substitution reaction.The reagent and the reaction conditions that are used for aforesaid method are that chemical field is known.The specific examples of fragrance substitution reaction comprises, utilizes concentrated nitric acid to introduce nitro; Utilize that for example acyl halide and Lewis acid (such as aluminum chloride) are introduced acyl group under Friedel Crafts condition; Utilize alkyl halide and Lewis acid (such as aluminum chloride) under Friedel Crafts condition, to introduce alkyl; With the introducing halogen group.The specific examples of described modification comprises, by for example handling with iron in the presence of hydrochloric acid with the nickel catalyzator catalytic hydrogenation or in heating, is amino with nitroreduction; The alkyl sulfenyl is oxidized to alkyl sulphinyl or alkyl sulphonyl.

Can believe that some formula II, XIV, XVI, XVIA, XIX, XX, VIc and VIc ' midbody compound are novel, and require to be another aspect of the present invention in this article.

Biology is measured

Below measure and to be used for measuring The compounds of this invention as the in vitro effects of Tie2 inhibitor with as the effect of Tie2 autophosphorylation inhibitor at full cell.

A. extracorporeal receptor tyrosine-kinase EIA

Be the inhibition of test to the Tie2 receptor tyrosine kinase, in not testing based on the protein kinase of cell, the ability that will contain the tyrosine phosphorylation of peptide substrate by their arrestin kinases in based on the test of ELISA microtiter plate is come assessing compound.In this particular case, determine three kinds of different recombinant human Tyrosylprotein kinase Tie2, KDR and the IC of Flt with this test ₅₀

For ease of producing Tyrosylprotein kinase, prepare the recombinant receptor gene with standard molecular biology clone and induced-mutation technique.These recombinant protein fragments of encoding in these genes only are made up of part C-terminal portions in the born of the same parents of corresponding acceptor, find the kinases territory therein.The recombination that coding is contained segmental kinases territory is cloned and is expressed in standard baculovirus/Sf21 system (perhaps other equivalent system).

Behind the protein expression, from the host insect cell, prepare lysate by the following method: with freezing molten born of the same parents' damping fluid (20mM N-2-hydroxyethyl piperazine-N '-2-ethanesulfonic acid (HEPES) pH7.5,150mM NaCl, 10% glycerine, 1%Triton X-100,1.5mM MgCl ₂, 1mM ethylene glycol-two (beta-aminoethyl ether) N ', N ', N ', N '-tetraacethyl (EGTA) add proteinase inhibitor to be handled, and passes through centrifugal clarification then.

Tie2, KDR and Fltl lysate are stored down at-80 ℃ with sample aliquot.

Determine the basic kinase activity of these recombinant proteins by measuring its ability that makes synthetic polypeptide (forming in the random copolymer of 6: 3: 1 ratios) phosphorylation by L-glutamic acid, L-Ala and tyrosine.Specifically, immunity plate in Nunc Maxisorb TM96 hole is applied with the synthetic peptide SigmaP3899 of 100 μ l (1mg/ml PBS storing solution is diluted to 1: 500 with PBS before applying to plate), under 4 ℃, be incubated overnight then.At room temperature with 50mM HEPES pH7.4 wash plate to remove any excessive unconjugated synthetic peptide.

By estimating Tie2, KDR or Flt1 activity in the plate that peptide applies the lysate (being respectively 1: 200,1: 400 and 1: 1000) of fresh suitable dilution being tested by following incubation: condition is at room temperature, in 100mM HEPES pH7.4,5 μ mol Triphosadens (ATP) (or the Km concentration of corresponding enzyme, 10mM MnCl ₂, among the 0.1mM Na3VO4,0.2mMDL-dithiothreitol (DTT) (DTT), 0.1%Triton X-100 and test compounds is dissolved among the DMSO (final concentration is 2.5%) together and the compound final concentration is 0.05 μ mol-100 μ mol, (Tie2) incubation 60 minutes or incubation (KDR, Flt) are 20 minutes.By removing liquid ingredient termination reaction in the test, use PBS-T (phosphate buffered saline (PBS) and 0.5% tween 20) or lavation buffer solution wash plate of equal value subsequently.

Immobilization phosphoric acid-peptide prod with the immunological method detection reaction.At first, at room temperature with plate and mouse monoclonal anti Tyrosine O-phosphate-HRP (horseradish peroxidase) binding antibody (4G10 of UpstateBiotechnology UBI16-105) incubation 4 hours.Behind the PBS-T thorough washing, measure the HR activity in each hole on the plate with colorimetry, make substrate with 22 '-azino-two-[3-ethyl benzo thiazole phenanthroline sulfonic acid (6)] di-ammonium salts crystalline A BTS (Sigma P4922-is by preparation explanation preparation), make colour developing in incubation 30-45 minute, and added 100 μ l1M H then ₂SO ₄Termination reaction.

By with Molecular Devices ThermoMax micro plate reader, measure absorbancy at the 405nm place and finish the quantitative enzymic activity that also therefore obtains of colour developing.The compound that provides to kinase whose inhibition with IC ₅₀Value representation.This value is determined by calculating the compound concentration that generation 50% phosphorylation need to suppress in this test.Scope from positive (vehicle adds ATP) and negative (vehicle subtracts ATP) control value calculating phosphorylation.

B. cell Tie2 autophosphorylation is measured

This test is based on measuring the ability that compound suppresses Tie2 acceptor autophosphorylation, and autophosphorylation causes producing " activation " acceptor usually, and this has caused the concrete signal pathway relevant with function of receptors.

Can pass through the accomplished in many ways autophosphorylation.Known in rhabdovirus system express recombinant kinases territory can cause producing phosphorylation and activated receptor.Also report and do not have overexpression acceptor in recombinant cell lines part to exist and itself can cause acceptor autophosphorylation (HeldinC-H.1995Cell:80,213-223 down; Blume-J.P, Hunter T.2001Nature:411,355-65).In addition, there is lot of documents example proof to make up Chimerical receptor.In these examples, the natural outer cell surface territory of acceptor by known by adding suitable part (TrkA-Tie2/NGF part (Marron for example, M B. etc., 2000Journal of BiologicalChemistry:275:39741-39746) or C-fms-Tie-1/CSF-1 part (Kontos, C.D. etc., 2002Molecularand Cellular Biology:22,1704-1713) easy two polymeric territories displacement.Therefore express and during separately part of adding, this just causes the autophosphorylation in Chimerical receptor kinases territory in host cell system when Chimerical receptor.This method has the part that known (and obtaining easily usually) used in common permission, and need not differentiate the advantage with the native ligand that separates each target recipient.

If nature has part to use, then available known selective expression's acceptor and n cell system or primary cell with ligand stimulation acquisition part inductive phosphorylation.Available this experimental measurement compound suppresses the ability of Tie2 acceptor autophosphorylation, the Tie2 acceptor at EA.hy926/B3 cell for example (by J.McLean/B.Tuchi, Univ.of N.Carolina at ChapelHill, CB-4100,300BynumHall, Chapel Hill, N.C.27599-41000, USA provides) or primary HUVEC (Human umbilical vein endothelial cells-can obtain) from various commercial sources express.

The available standards purification technique is separating natural Ang1 part from the tumour cell supernatant liquor, or available standards Protocols in Molecular Biology and expression system clone and regroup expression Ang1 gene.In this case, can attempt producing the part of native state or produce part as recombinant protein, the genetic engineering of this albumen is to contain other purifying tail (for example polyhistidine peptide, antibody Fc territory) to promote this process.

With ligand stimulation EA.hy926/B3 or HUVEC cell Tie2 acceptor is example, can set up the test of Ang1 ligand stimulation cell receptor phosphorylation, can be used for analyzing, determining that compound suppresses the potentiality of this process.For example in 6 orifice plates, begin to make the EA.hy926/B3 cell in the suitable tissue culture medium (TCM) that adds 10% foetal calf serum (FCS), to grow 2 days with initial inoculation density 5 * 105 cells/well.At the 3rd day, made the cell serum starvation totally 2 hours by replacing previous substratum with the substratum that only contains 1%FCS.Serum starvation is removed substratum after carrying out 1 hour 40 minutes, replaces with lml test compounds diluent (with the diluted chemical compound liquid of serum starvation medium preparation, but its DMSO concentration keeps below 0.8%).Behind the serum starvation 1.5 hours, add ortho-vanadate (orthovanidate) final concentration, carry out last 10 minutes serum starvation to 0.1mM.

Behind totally 2 hours serum starvations, add part and ortho-vanadate irritation cell Tie2 acceptor autophosphorylation (can add purifying ligand material, or add the not purifying cells supernatant liquor when containing for example recombinant expressed mammalian cell of part) with the dilution of serum starvation substratum.

Under 37 ℃ with the part incubation after 10 minutes, with cell in cooled on ice, with the cold PBS washing of the about 5ml that contains the 1mM ortho-vanadate, ((20mM Tris pH7.6,150mM NaCl, 50mM NaF, 0.1%SDS, 1%NP40,0.5%DOC, 1mM ortho-vanadate, 1mM EDTA, 1mM PMSF, 30 μ l/ml press down enzyme peptide, 10 μ g/ml pepstatins, 10 μ g/ml leupeptins) adds cell, places on ice 10-20 minute with the freezing molten born of the same parents' damping fluid of 1ml then.The molten thing of born of the same parents is pipetted and is transferred in the 1.5ml Eppendorf pipe, under 4 ℃ centrifugal 3 minutes with 13000rpm.The molten thing of 800 each born of the same parents of μ l moved in the new 2ml Eppendorf pipe carry out immunoprecipitation.Anti-phosphoric acid-tyrosine antibody (Santa Cruz PY99-sc-7020) of 3mg=15 μ l is added in the molten thing of born of the same parents, 4 ℃ of following incubations 2 hours.(goat anti-mouse IgG Pierce21354) adds in the molten thing of born of the same parents the MagnaBind pearl that 600 μ l are washed, and pipe is rotated through night under 4 ℃.

Sample was handled in magnetic field 1 minute, carefully removed the molten thing supernatant liquor of born of the same parents then.Then the molten born of the same parents' damping fluid of 1ml is added in the pearl, this step further repeats 2 times.2 * Laemmli the sample loading buffer that pearl is suspended in 25 μ l94 ℃ heat adds in the beta-mercaptoethanol, at room temperature leaves standstill 15 minutes.

Remove pearl by pipe is exposed 1 minute in magnetic field, will load on polyacrylamide/SDS protein gelatin (the prefabricated 4-12%BisTrisNuPAGE/MOPS12 hole gel of Novex) from the isolating all liquid of the strain of each immunoprecipitation.Protein gelatin moves under 200V, and under 50V/250mA, trace is 1 hour 30 minutes on the NC film then.All traces were at room temperature handled 1 hour with the PBS-tween solution of 5%Marvel, to reduce and the non-specific binding of surveying antibody.The anti-Tie2 of rabbit (Santa Cruz sc-324) is added in the solution (1: 500) that dilutes with the 0.5%Marvel/PBS-tween, under 4 ℃, be incubated overnight.Acutely wash trace with the PBS-tween, add then in the solution (1: 5000) with the dilution of 0.5%Marvel/PBS-tween of goat antirabbit-POD conjugates (Dako P0448).Antibody was at room temperature placed 1 hour, subsequently with PBS-tween washing trace.Make the western blotting colour developing of various immunoprecipitation samples with LumiGLO (NEB7003).Move to X-ray magazine then, with exposure 15 seconds/30 seconds and 60 seconds.Relative intensity with the FluorSBioRad image dissector system evaluation protein belt relevant with the Tie2 acceptor of phosphorylation.Calculate IC by the standard method of doing reference with suitable control sample ₅₀Be worth, determine the phosphorylation per-cent of each test compounds dilution series.

Although the pharmacological properties of formula I compound is different with structural changes as expecting, generally speaking, the activity that the formula I compound of following concentration or dosage has can more than one or more, test (a) and (b) in confirm:

1 (a) :-IC ₅₀Scope is at μ M for example＜100;

Test (b) :-IC ₅₀Scope is at μ M for example＜50;

For example, Table A has illustrated the activity according to representative compounds of the present invention.The 2nd hurdle of Table A has shown the IC of the test (a) of vitro inhibition Tie2 receptor tyrosine kinase ₅₀Data and the 3rd hurdle have shown the IC of the test (b) that suppresses Tie2 receptor tyrosine kinase autophosphorylation ₅₀Data.

Table A

The embodiment numbering	IC ₅₀(μ M) tests (a): vitro inhibition Tie2 receptor tyrosine kinase	IC ₅₀(μ M) tests (b): suppress Tie2 receptor tyrosine kinase autophosphorylation
The embodiment numbering			6	20	1.7
12	25	1.3	6	20	1.7
12	25	1.3	14	20	0.38
45	3.3	0.2	14	20	0.38
45	3.3	0.2	47	1.5	1.9
50	9.0	3.6	47	1.5	1.9

Relate to formula I compound hereinafter in the paragraph, also relate to aforesaid subgroup of the present invention, for example, in other subgroup of the present invention, also will be suitable for formula Ia, Ib, Ic and Id compound.

Pharmaceutical composition is provided according to a further aspect in the invention, and described pharmaceutical composition comprises (I) compound of formula as defined above or its pharmacy acceptable salt that uses with pharmaceutically acceptable thinner or carrier.

Composition of the present invention can (for example be tablet for the form that is applicable to oral application, lozenge, hard capsule or soft capsule, aqueous suspensions or contain oil suspension, emulsion, dispersible powder or granula, syrup or elixir), the form that is used for topical application (for example is ointment, paste, gelifying agent, perhaps moisture or oily soln agent or suspensoid), the form (for example being pulvis or liquid aerosol in small, broken bits) that is used for inhalation, the form that is used to be blown into the form (for example for pulvis in small, broken bits) of administration or is used for parenteral admin is (for example for being used for intravenously, subcutaneous, the aseptic moisture or oil-containing liquor of intramuscular or intramuscular dosage or for being used for the suppository of rectal dose administration).

The present composition can pass through ordinary method, utilizes conventional medicine vehicle well known in the art to obtain.Thus, the composition that is designed for oral application can contain, for example, and one or more tinting materials, sweeting agent, sweetener and/or sanitas.

Depend on the main body handled and concrete route of administration, uniting use with one or more vehicle will inevitably be different with the amount of the activeconstituents that forms single formulation.For example, being designed for the preparation that is administered orally to the mankind will contain usually, for example, with suitably and the 0.5mg～0.5g promoting agent of the mixed with excipients of sufficient quantity (be preferably 0.5～100mg, for example 1～30mg), based on the weight of whole compositions, described vehicle can change between about 5～about 98%.

According to character and severity, animal or patient's age and the sex and the route of administration of situation, according to the principle of knowing of medicine, the dosage size nature that is used for the treatment of the formula I compound of or prophylactic purpose can change.

For therapeutics or prophylactic purpose use formula I compound the time, usually it is carried out administration, make for example for the per daily dose scope of 0.1mg/kg～75mg/kg body weight is accepted, if desired, carry out administration with the dosage that separates.When using the parenteral route, usually with administration than low dosage.Thus, for example,, will use usually, for example the dosage range of 0.1mg/kg～30mg/kg body weight for intravenous administration.Similarly, for by inhalation, will use, for example the dosage range of 0.05mg/kg～25mg/kg body weight.Yet the preferred oral administration particularly is administered orally in the form of tablets.Usually, unit dosage will contain the 0.5mg that has an appointment～0.5g The compounds of this invention.

As defined herein be their anti-angiogenic formation effect according to the usefulness of The compounds of this invention.The expection The compounds of this invention can be used for the treatment of or prevent multiple with do not expect or pathological angiogenesis form relevant morbid state, comprise cancer, diabetes, psoriasis, rheumatic arthritis, Kaposi ' s sarcoma, vascular tumor, lymphedema, acute and chronic nephropathy, sebaceous cyst, artery postoperative restenosis, autoimmune disease, acute inflammation, too much scar and adhesion, endometriosis, dysfunctional uterine bleeding and have the eye disease that retinal vessel is bred.Cancer can influence any tissue, and cancer comprises leukemia, multiple myeloma and lymphoma.Particularly, expect that compound of the present invention will advantageously reduce starting property and for example growth of the solid tumor of colon, breast, prostate gland, lung and skin of recidivity.

We believe, come from their Tie2 receptor tyrosine kinase rejection according to the anti-angiogenic formation performance of The compounds of this invention.In view of the above, the expection The compounds of this invention can be used for producing the Tie2 restraining effect the warm-blooded animal of the described treatment of needs.Thus, The compounds of this invention only can produce or partly pass through the anti-angiogenic formation effect of the restraining effect mediation of Tie2 receptor tyrosine kinase.

More especially, the expection The compounds of this invention can suppress any cancer form relevant with Tie2.For example, the growth of starting property that those are relevant with Tie2 and recurrent solid tumor is particularly grown and is spread those tumours that significantly depend on the Tie2 receptor tyrosine kinase.

(I) compound of formula as defined above or its pharmacy acceptable salt as medicine are provided according to a further aspect in the invention.

According to a further aspect in the invention, provide purposes in formula I compound as defined above or its pharmacy acceptable salt be used as the Tie2 receptor tyrosine kinase inhibitors in being manufactured on warm-blooded animal (such as the mankind) the medicine.

According to a further aspect in the invention, provide formula I compound as defined above or its pharmacy acceptable salt to be used for producing purposes in the medicine of anti-angiogenic formation effect warm-blooded animal (such as the mankind) in manufacturing.

According to a further aspect in the invention, provide formula I compound as defined above or its pharmacy acceptable salt to be used for purposes in the medicine of warm-blooded animal (such as the mankind) treatment cancer in manufacturing.

According to a further aspect in the invention, provide as defined above formula I compound or its pharmacy acceptable salt making the purposes for the treatment of in the warm-blooded animal (such as the mankind) in the medicine that is selected from following cancer: leukemia, mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, prostate cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, lymphoma, carcinoma of testis, neuroblastoma, liver cancer, cholangiocarcinoma, renal cell carcinoma, uterus carcinoma, thyroid carcinoma and skin carcinoma with doing.

According to a further aspect in the invention, the method that the Tie2 receptor tyrosine kinase is provided in the warm-blooded animal (such as the mankind) that provides in the described treatment of needs comprises the I compound of formula as defined above or its pharmacy acceptable salt of the described animal effective dose of administration.

According to a further aspect in the invention, produce the method for anti-angiogenic formation effect in the warm blooded animal (such as the mankind) that provides in the described treatment of needs, comprise the I compound of formula as defined above or its pharmacy acceptable salt of the described animal effective dose of administration.

According to a further aspect in the invention, treat method for cancer in the warm-blooded animal (such as the mankind) that provides in the described treatment of needs, comprise the I compound of formula as defined above or its pharmacy acceptable salt of the described animal effective dose of administration.

According to a further aspect in the invention, treatment is selected from the method for cancer of leukemia, mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, prostate cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, lymphoma, carcinoma of testis, neuroblastoma, liver cancer, cholangiocarcinoma, renal cell carcinoma, uterus carcinoma, thyroid carcinoma or skin carcinoma in the warm-blooded animal (such as the mankind) that provides in the described treatment of needs, comprises the I compound of formula as defined above or its pharmacy acceptable salt of the described animal effective dose of administration.

According to a further aspect in the invention, provide the I compound of formula as defined above or its pharmacy acceptable salt that is used for suppressing the Tie2 receptor tyrosine kinase warm-blooded animal (such as the mankind).

According to a further aspect in the invention, provide the I compound of formula as defined above or its pharmacy acceptable salt that is used for producing anti-angiogenic formation effect warm-blooded animal (such as the mankind).

According to a further aspect in the invention, provide the I compound of formula as defined above or its pharmacy acceptable salt that is used for the treatment of cancer.

According to a further aspect in the invention, provide the I compound of formula as defined above or its pharmacy acceptable salt that is used for the treatment of the cancer that is selected from leukemia, mammary cancer, lung cancer, colorectal carcinoma, the rectum cancer, cancer of the stomach, prostate cancer, bladder cancer, carcinoma of the pancreas, ovarian cancer, lymphoma, carcinoma of testis, neuroblastoma, liver cancer, cholangiocarcinoma, renal cell carcinoma, uterus carcinoma, thyroid carcinoma or skin carcinoma.

As above put down in writing, further contemplate that The compounds of this invention will have activity to other disease of the mediation of the vascularization by undesirable or pathology, described other disease comprises psoriasis, rheumatic arthritis, Kaposi ' s sarcoma, vascular tumor, lymphedema, acute and chronic nephropathy, sebaceous cyst, artery postoperative restenosis, autoimmune disease, acute inflammation, too much scar and adhesion, endometriosis, dysfunctional uterine bleeding and eye disease with retinal vessel propagation.

Ding Yi anti-angiogenic activity can also may relate to one or more other material and/or treatments as independent therapy or except The compounds of this invention in this article.Described combination therapy can be by the single therapy component time, order or separation administration are accomplished.In medical oncology, can use each cancer patients of combined therapy of different form of therapy usually.In medical oncology, except the cell cycle suppression therapy of above definition, other composition of described combination therapy can be: operation, radiotherapy or chemotherapy.Described chemotherapy can comprise the anti-tumor agent comprising salmosin of one or more following classifications:

(i) the anti-reagent (for example inhibitor of inhibitors of metalloproteinase (such as marimastat) and the former activator function of receptors of urokinase plasmin) of invading;

(ii) be used for the antiproliferative/antitumour drug and the combination thereof of medical oncology, such as alkylating reagent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, Myelosan and nitrosourea); Metabolic antagonist (antifolate for example, such as fluorinated pyrimidine, such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, perhaps, disclosed a kind of preferred metabolic antagonist among the european patent application No.562734 for example, such as (2S)-2-{ neighbour-fluoro-right-[N-{2,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-ylmethyl } N-(Propargyl) amino] benzo amide group-4-(tetrazolium-5-yl) butyric acid); Antitumor antibiotics (for example anthracycline, such as adriamycin, bleomycin, Zorubicin, daunomycin, epirubicin, idarubicin, Mitomycin-C, actinomycin and mithramycin); Antimitotic agent (for example vinca alkaloids (such as vincristine(VCR), vincaleucoblastine, desacetyl vinblastine amide and vinorelbine) and taxoids (such as taxol and taxotere)); With local isomerase inhibitors (for example epipodophyllotoxin (such as etoposide and teniposide), SN-11841, topotecan and camptothecine);

(iii) cytostatic agent is such as estrogen antagonist (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), androgen antagonist (for example bicalutamide, Drogenil, Nilutamide and acetate Sai Pulong), lhrh antagonist or LHRH agonist (for example goserelin, Leuprolide and buserelin), progestogen (for example megestrol), aromatase inhibitor (for example Anastrozole, letrozole, vorazole and Exemestane) and 5 inhibitor (such as finasteride);

(iv) somatomedin depressant of functions, for example described inhibitor comprises growth factor antibodies, growth factor receptor antibody, farnesyl transferase inhibitor, tyrosine kinase inhibitor and serine-threonine kinase inhibitor, epidermal growth factor family inhibitor (EGFR tyrosine kinase inhibitor N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholine subbase propoxy-) quinazoline-4-amine (ZD1839) for example for example, N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (CP358774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholine subbase propoxy-) quinazoline-4-amine (CI1033)), for example platelet-derived growth factor man group inhibitor and for example pHGF man group inhibitor;

(the v) anti-angiogenic formation reagent of the different mechanisms work by above definition, suppress the reagent of vascular endothelial growth factor such as those, such as being disclosed in compound among International Patent Application WO 97/22596, WO97/30035, WO97/32856 and the WO98/13354 and those reagent (for example linomide, beta 2 integrin alpha v β 3 functions and angiogenesis inhibitor) by other mechanism works;

(vi) biotherapy therapeutics method, for example peptide of those uses or alignable receptors part, block ligand bind receptor or reduction receptor signal (for example because the expression level of degraded of enhanced acceptor or reduction) or the method for protein (such as antibody or solubility external receptors domain structure);

(vii) antisense therapy is for example at those therapies of above-mentioned target body, such as ISIS2503, anti-ras antisense;

(viii) gene therapy method, comprise, for example use such as Isocytosine deaminase, thymidine kinase or bacterium nitroreductase and replace the method for aberrant gene (such as unusual p53 or unusual BRCA1 or BRCA2, the GDEPT treatment of enzyme prodrug of gene (directly at) method) and strengthen the patient the method for chemotherapy or radiotherapy tolerance (such as, many drug resistance genes therapy); With

(ix) immunotherapy method, comprise method in the external and body that strengthens the patient tumors cell immunogenicity (such as, use such as the cytokine of interleukin 2, interleukin 4 or rHuGM-CSF and carry out transfection), reduce the anergic method of T cell, use transfection immunocyte (such as transfectional cell factor dendritic cell) method, use transfectional cell factor tumor cell line method and utilize anti-spy to answer the method for antibody.

Described combination therapy can be by the single therapy component time, order or separate dose administration are accomplished.Described combined prod uses interior The compounds of this invention and the another kind of forms of pharmacologically active agents in its approval dosage range of dosage range as mentioned above.

According to this aspect of the invention, provide the medicament production that comprises formula I compound as defined above and be used for other antitumorigenic substance as defined above of cancer combination therapy.

Except their purposes in the therapeutics medicine, formula I compound and their pharmacy acceptable salts can also be as effective pharmacological tools outside exploitation and standardization body and in the in vivo test system, described pilot system is used for estimating the effect of cell cycle activity inhibitor laboratory animal (such as cat, dog, rabbit, monkey, rat and mouse), as the part of novel treatment exploitation.

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

(i) temperature with centigradetemperature provide (℃); Operate under room temperature or the envrionment temperature and carry out, that is, in 18～25 ℃ temperature range, carry out;

(ii) organic solution is all carried out drying with anhydrous sodium sulphate; Rotatory evaporator (600～4000 pascals are under reduced pressure used in solvent evaporation; 4.5-30mmHg) carry out, bathe 60 ℃ of Wen Gaoda;

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

(iv) common, reaction process is carried out TLC and/or analysis LC-MS and reaction times afterwards and is provided as just example;

(v) the finished product have gratifying proton magnetic resonance (PMR) (NMR) spectrum and/or mass-spectrometric data;

(vi) productive rate only is used for illustrations, must not be that those can be by making great efforts to carry out the value that process exploitation obtains; More if desired material then repeats preparation;

(vii) when providing, the NMR data are the main form of measuring the δ value of proton, with respect to providing with 1,000,000/(ppm) as interior target tetramethylsilane (TMS), except as otherwise noted, use full deuterated dimethyl sulfoxide (methyl-sulphoxide-d ₆) determine under 300MHz as solvent; Use following shortenings: s, unimodal; D, doublet; T, triplet; Q, quartet; M, multiplet; B, wide;

(viii) chemical symbol has their implication commonly used, uses SI units and symbol;

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

(x) mass spectrum (MS) uses the probe that directly exposes, in the mode of chemi-ionization (CI), with 70 electron-volts electron energy operation; Wherein represented ionization is to realize by electronic impact (EI), fast atom bombardment (FAB) or electrospray (ESP); If provide the m/z value, only report the ion of expression parent quality usually; And the mass ion of listing except as otherwise noted, is MH ⁺

(xi) except as otherwise noted, containing the carbon of asymmetric replacement and/or the compound of sulphur atom splits;

(xii) wherein be called be similar to previous embodiment described synthetic in, the amount of use is the mmole ratio that is equivalent to previous embodiment usage quantity.

(xvi) use following shortenings:

AcOH acetate

AIBN 2,2 '-Diisopropyl azodicarboxylate

The DCM methylene dichloride

The DIPEA diisopropylethylamine

The DMA N,N-dimethylacetamide

DMF N, dinethylformamide

The DMSO methyl-sulphoxide

DMTMM 4-(4,6-dimethoxy-1,3,5-triazines-2-yl)-4-methylmorpholine-4-muriate

Dppf 1,1 '-two (diphenyl phosphine) ferrocene

The EtOAc ethyl acetate

HATU O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea hexafluorophosphate

The iPrMgCl isopropylmagnesium chloride

The LDA lithium diisopropylamine

Two (trimethyl silyl) Lithamides of LHMDS

The m-CPBA metachloroperbenzoic acid

MeOH methyl alcohol

The MeCN acetonitrile

MCX mixed-cation exchange resin

The MTBE methyl tertiary butyl ether

The LCMS liquid chromatography-mass spectrography

The NMP 1-Methyl-2-Pyrrolidone

POCl ₃Phosphorus oxychloride

The RPHPLC reversed-phased high performace liquid chromatographic

The TFA trifluoroacetic acid

The THF tetrahydrofuran (THF)

The SM raw material

Xvii) when synthetic when being described to cause acid salt (for example HCl salt), the stoichiometry to this salt does not describe.Except as otherwise noted, all NMR data are all reported free alkali, before characterizing isolating salt are converted into free alkali form.

Embodiment 1

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[(4-morpholine-4-yl pyrimidines-5-yl) methyl] urea

Under 80 ℃, will { 3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl } phenyl carbamate (intermediate 2) (50mg), heated 24 hours among the THF (2mL) in 1-(4-morpholine-4-yl pyrimidines-5-yl) methylamine (58mg) and the triethylamine (0.06mL).In a vacuum above-mentioned reaction mixture is concentrated, the gained solid is ground with ether and under 60 ℃, it is carried out drying in a vacuum, thereby obtain being solid title compound (22mg, 34%);

¹H?NMR(DMSO-d ₆)3.37-3.44(m，4H)，3.66-3.73(m，4H)，4.24-4.30(d，2H)，6.67-6.73(t，1H)，7.01-7.06(m，1H)，7.09(s，2H)，7.21-7.31(m，2H)，7.67(s，1H)，8.30(s，1H)，8.40(s，1H)，8.57(s，1H)，8.74(s，1H)；

MS?m/e?MH ⁺431.

Intermediate 1

The 5-[(3-aminophenyl) ethynyl] pyrimidine-2-amine

In DMF (100mL)-triethylamine (20mL), 2-amino-5-iodine pyrimidine (2.21g), two (triphenylphosphine) palladium chloride (350mg) and copper(I) iodide (I) (40mg) are stirred, and outgased 10 minutes with nitrogen.3-ethynyl aniline (1.29g) is added wherein, and, kept 2 hours gained mixture heating up to 95 ℃.With solvent evaporation and by grinding the gained resistates is carried out purifying, thereby obtain title compound (1.25g, 60%) into brown solid with DCM (20mL);

¹H?NMR(DMSO-d ₆)5.21(bs，2H)，6.58-6.70(m，3H)，7.03-7.07(m，3H)，8.40(s，2H)；

MS?m/e?MH ⁺211.

Intermediate 2

3-[(2-aminopyrimidine-5-yl) and ethynyl] phenyl } phenyl carbamate

Under 0 ℃, (1.79mL) is added to the 5-[(3-aminophenyl with phenyl chloroformate) ethynyl] pyrimidine-2-amine (intermediate 1) is (2.0g) and in the THF solution of pyridine (1.54mL).After 2 hours, water (20mL) is with the reaction mixture quencher and in a vacuum it is concentrated.The solid that forms is leached, washes with water then with the ether washing, thereby obtain being beige solid title compound (2.95g, 94%);

¹H?NMR(DMSO-d ₆)7.15(s，2H)，7.20-7.32(m，4H)，7.36-7.55(m，4H)，7.69(s，1H)，8.45(s，2H)，10.37(s，1H)；

MS?m/e?MH ⁺331

Following examples utilize intermediate 2 and suitable amine to be prepared in the mode that is similar to embodiment 1:

Embodiment 2

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[3-(2-oxo-pyrrolidine-1-yl) propyl group] urea

SM: intermediate 2,1-(3-aminopropyl)-2-Pyrrolidone

¹H?NMR(DMSO-d ₆)1.54-1.66(qn，2H)，1.85-1.97(qn，2H)，2.18-2.25(t，2H)，2.99-3.08(q，2H)，3.16-3.24(t，2H)，3.26-3.37(m，2H)，6.20(t，1H)，6.98-7.04(m，1H)，7.09(bs，2H)，7.18-7.29(m，2H)，7.67(s，1H)，8.40(s，2H)，8.68(s，1H)；

MS?m/e?MH ⁺379.

Embodiment 3

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(tetrahydrochysene-2H-pyrans-4-ylmethyl) urea

SM: intermediate 2,4-amino methyl tetrahydropyrans

¹H?NMR(DMSO-d ₆)1.08-1.24(m，2H)，1.49-1.72(m，3H)，2.94-3.02(t，2H)，3.19-3.30(m，2H)，3.79-3.89(m，2H)，6.22-6.30(t，1H)，6.98-7.03(m，1H)，7.09(bs，2H)，7.21-7.26(m，2H)，7.66(s，1H)，8.40(s，2H)，8.50(bs，1H)；

MS?m/e?MH ⁺352.

Embodiment 4

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(tetrahydrofuran (THF)-2-ylmethyl) urea

SM: intermediate 2, tetrahydrofurfuryl amine

¹H?NMR(DMSO-d ₆)1.45-1.58(m，1H)，1.76-1.94(m，3H)，3.03-3.13(m，1H)，3.18-3.28(m，1H)，3.58-3.67(m，1H)，3.72-3.90(m，2H)，6.20-6.26(t，1H)，6.98-7.03(m，1H)，7.09(bs，2H)，7.21-7.27(m，2H)，7.64(s，1H)，8.41(s，2H)，8.63(bs，1H)；

MS?m/e?MH ⁺338.

Embodiment 5

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(2-pyridin-3-yl ethyl) urea

SM: intermediate 2,3-(2-aminoethyl) pyridine

¹H?NMR(DMSO-d ₆)2.74-2.79(t，2H)，3.32-3.39(m，2H)，6.17-6.24(t，1H)，6.99-7.04(m，1H)，7.09(bs，2H)，7.20-7.27(m，2H)，7.29-7.35(m，1H)，7.63-7.68(m，2H)，8.37-8.47(m，4H)，8.56(bs，1H)；

MS?m/e?MH ⁺359.

Embodiment 6

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[(5-methyl-2-furyl) methyl] urea

SM: intermediate 2,5-methyl furfuryl group amine

¹H?NMR(DMSO-d ₆)2.22(s，3H)，4.19-4.25(d，2H)，5.96-5.99(m，1H)，6.09-6.13(m，1H)，6.51-6.59(t，1H)，6.99-7.06(m，1H)，7.09(bs，2H)，7.19-7.30(m，2H)，7.65(s，1H)，8.41(s，2H)，8.59(bs，1H)；

MS?m/e?MH ⁺348.

Embodiment 7

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(2-morpholine-4-base benzyl) urea

SM: intermediate 2,1-(2-morpholine-4-base phenyl) methylamine

¹H?NMR(DMSO-d ₆)2.79-2.90(m，4H)，3.70-3.79(m，4H)，4.34-4.42(m，2H)，6.54-6.61(m，1H)，6.98-7.18(m，5H)，7.20-7.34(m，4H)，7.69(s，1H)，8.40(s，2H)，8.69(bs，1H)；

MS?m/e?MH ⁺429.

Embodiment 8

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-and 2-[4-(hydroxymethyl) piperidines-1-yl] benzyl } urea

SM: intermediate 2, [1-[2-(aminomethyl) phenyl]-4-piperidyl] methyl alcohol

¹H?NMR(DMSO-d ₆)1.24-1.54(m，4H)，1.69-1.80(m，2H)，2.55-2.68(m，2H)，2.96-3.06(m，2H)，3.29-3.32(m，1H)，4.31-4.37(d，2H)，4.43-4.49(t，1H)，6.48-6.55(t，1H)，6.98-7.30(m，9H)，7.69(s，1H)，8.40(s，2H)，8.67(bs，1H)；

MS?m/e?MH ⁺457.

Embodiment 9

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(2-piperidines-1-base benzyl) urea

SM; Intermediate 2, (2-piperidino-(1-position only) phenyl) methylamine

¹H?NMR(DMSO-d ₆)1.48-1.58(m，2H)，1.62-1.72(m，4H)，2.76-2.82(m，4H)，4.30-4.38(d，2H)，649-6.55(t，1H)，6.98-7.31(m，9H)，7.69(s，1H)，8.40(s，2H)，8.67(bs，1H)；

MS?m/e?MH ⁺427.

Embodiment 10

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(trifluoromethyl) benzyl] urea

SM: intermediate 2,2-(trifluoromethyl) benzylamine

¹H?NMR(DMSO-d ₆)4.46-4.52(d，2H)，6.73-6.79(t，1H)，7.01-7.05(m，1H)，7.11(bs，2H)，7.19-7.31(m，2H)，7.42-7.50(m，1H)，7.56-7.61(m，1H)，7.63-7.74(m，3H)，8.40(s，2H)，8.84(bs，1H)；

MS?m/e?MH ⁺412.

Embodiment 11

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(trifluoromethoxy) benzyl] urea

SM: intermediate 2,2-(trifluoromethoxy) benzylamine

¹H?NMR(DMSO-d ₆)4.34-4.40(d，2H)，6.67-6.73(t，1H)，7.00-7.06(m，1H)，7.09(bs，2H)，7.20-7.29(m，2H)，7.31-7.42(m，3H)，7.43-7.49(m，1H)，7.68(s，1H)，8.40(s，2H)，8.77(bs，1H)；

MS?m/e?MH ⁺428.

Embodiment 12

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(3-hydroxyl-1-phenyl propyl) urea

SM: intermediate 2,3-amino-3-phenyl-1-propyl alcohol

¹H?NMR(DMSO-d ₆)1.78-1.89(m，2H)，3.36-3.45(m，2H)，4.53-4.59(t，1H)，4.78-4.87(m，1H)，6.71-6.77(d，1H)，6.97-7.03(m，1H)，7.08(bs，2H)，7.17-7.25(m，3H)，7.28-7.35(m，4H)，7.64(s，1H)，8.39(s，2H)，8.55(bs，1H)；

MS?m/e?MH ⁺388.

Embodiment 13

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(1-phenyl-2-tetramethyleneimine-1-base ethyl) urea

SM: intermediate 2,1-phenyl-2-pyrrolidyl ethamine

¹H?NMR(DMSO-d ₆)1.62-1.70(m，4H)，2.41-2.81(m，6H)，4.69-4.79(m，1H)，6.62-6.67(d，1H)，6.96-7.02(m，1H)，7.08(bs，2H)，7.16-7.26(m，3H)，7.28-7.34(m，4H)，7.66(s，1H)，8.39(s，2H)，8.77(bs，1H)；

MS?m/e?MH ⁺427.

Embodiment 14

N-[(5-methyl-2-furyl) methyl]-N '-[3-(2-[(3-piperidines-1-base propyl group) and amino] pyrimidine-5-yl } ethynyl) phenyl] urea

Under 0～5 ℃, phenyl chloroformate (103mg) is added to the 5-[(3-aminophenyl of stirring) ethynyl]-N-(3-piperidines-1-base propyl group) pyrimidine-2-amine (intermediate 4) is (202mg) and in THF (5mL) solution of pyridine (95mg).Above-mentioned reaction mixture is stirred and makes it be warming up to envrionment temperature.Be dissolved in THF (10mL) and the triethylamine (115mg) with solvent evaporation with products obtained therefrom.5-methyl furfuryl group amine (0.5mL) is added wherein, and 75 ℃ under, will react stirring and heated 3 hours.With solvent evaporation, and the DCM solution that utilizes 1-12% methyl alcohol/NH3 carries out purifying by flash chromatography to products obtained therefrom as elutriant on silica gel.The finished product are ground with methyl alcohol, thereby obtain title compound into pale solid.(196mg)；

¹H NMR (DMSO-d ₆) 1.30-1.41 (m, 2H), 1.42-1.53 (m, 4H), 1.66 (quintet, 2H), 2.22 (s, 3H), 2.24-2.35 (m, 6H), 3.24-3.37 (m, 2H), 4.21 (d, 2H), 5.95-6.00 (m, 1H), 6.11 (d, 1H), 6.56 (t, 1H), 6.99-7.05 (m, 1H), 7.22-7.27 (m, 2H), 7.66 (s, 1H), 7.71 (t, 1H), 8.44 (s, 2H), 8.60 (s, 1H);

MS?m/e?MH ⁺473

Intermediate 3

3-[(2-chloropyrimide-5-yl) and ethynyl] phenyl } amine

Under inert atmosphere, will join at the palladium (10wt.%) on the activated carbon (1.5g) in DIPEA (120mL) solution of the 5-bromo-2-chloropyrimide (12.76g) of stirring and 3-ethynyl aniline (9.28g).Under 80 ℃, above-mentioned reaction mixture was stirred 4 hours.Wash with gained reaction mixture filtration over celite and with DCM.The DCM that utilizes 0-30%EtOAc carries out purifying by flash chromatography to gained filtrate as elutriant on silicon-dioxide.The gained solid is ground with ether, thereby obtain being paste solid title compound (4.28g, 28%);

¹H?NMR(DMSO-d ₆)5.31(s，2H)，6.64(dd，1H)，6.69-6.76(m，2H)，7.08(dd，1H)，8.94(s，2H)；

MS?m/e(MH+MeCN) ⁺271.

Intermediate 4

The 5-[(3-aminophenyl) ethynyl]-N-(3-piperidines-1-base propyl group) pyrimidine-2-amine

In MeCN (15mL) to { 3-[(2-chloropyrimide-5-yl) ethynyl] phenyl } amine (intermediate 3) (1.2g) and 3-(piperidino) propylamine (3.7g) stir, and HCl (1.0M diethyl ether solution) (6.3mL) is dripped and adds wherein.Under 80 ℃, above-mentioned reaction mixture is stirred and heated 1 hour.With solvent evaporation, and the DCM solution that uses 0-10% methyl alcohol/NH3 carries out purifying by flash chromatography to products obtained therefrom, thereby obtains the title compound (1.2g, 69%) into pale solid as elutriant on silicon-dioxide;

¹H NMR (DMSO-d ₆) 1.31-1.42 (m, 2H), 1.42-1.53 (m, 4H), 1.66 (quintet, 2H), 2.19-2.37 (m, 6H), 3.25-3.35 (m, 2H), 5.19 (s, 2H), 6.53-6.63 (m, 2H), 6.67 (s, 1H), 7.01 (t, 1H), 7.64 (t, 1H), 8.40 (s, 2H)

MS?m/e?MH ⁺336.

Following examples utilize intermediate 4 and suitable amine to be prepared in the mode that is similar to embodiment 14:

Embodiment 15

N-(2-morpholine-4-base benzyl)-N '-[3-(2-[(3-piperidines-1-base propyl group) and amino] pyrimidine-5-yl } ethynyl) phenyl] urea

SM: intermediate 4, (2-morpholine-4-base benzyl) amine

¹H NMR (DMSO-d ₆) 1.31-1.41 (m, 2H), 1.42-1.54 (m, 4H), 1.66 (quintets, 2H), and 2.24-2.37 (m, 6H), 2.80-2.88 (m, 4H), 3.27-3.35 (m, 2H), 3.71-3.78 (m, 4H), 4.38 (d, 2H), 6.58 (t, 1H), 6.97-7.17 (m, 3H), 7.18-7.34 (m, 4H), 8.44 (s, 2H), 8.44 (s, 2H), 8.70 (s, 1H)

MS?m/e?MH ⁺554.

Embodiment 16

N-{5-[(2-aminopyrimidine-5-yl) ethynyl]-1,3-thiazoles-2-yl }-N '-[(5-methyl-2-furyl) methyl] urea

In dry DMF (3mL), to 2-amino-5-ethynyl pyrimidine (intermediate 6) (119mg), N-(5-bromo-1, the 3-thiazol-2-yl)-N '-[(5-methyl-2-furyl) methyl] urea (intermediate 8) (316mg), 1,1,3,3-tetramethyl guanidine (138mg) and copper(I) iodide (I) mixture (10mg) stir, and with nitrogen it are outgased.Tetrakis triphenylphosphine palladium (0) (116mg) is added wherein, and under 60 ℃ with gained mixture heating up 3 hours.To the gained mixture concentrate, cool off, stirring and water (20mL) dilution.The solid that forms is leached and it is carried out drying.The DCM solution that utilizes 0-40% methyl alcohol carries out purifying by flash chromatography as elutriant on silicon-dioxide, grind with DCM then, thereby obtain being solid title compound (33mg, 9%);

¹H?NMR(DMSO-d ₆)2.23(s，3H)，4.29(d，2H)，6.00(d，1H)，6.17(d，1H)，6.93(t，1H)，7.12(s，2H)，7.59(s，1H)，8.41(s，2H)10.70(s，1H)；

MS?m/e?MH ⁺355.

Intermediate 5

The 5-[(trimethyl silyl) ethynyl] pyrimidine-2-amine

Under 20 ℃, under inert atmosphere, with PdCl ₂Dppf (146mg) joins in EtOAc (5mL) solution of 2-amino-5-iodine pyrimidine (221mg), trimethyl silyl acetylene (491mg), CuI (57mg) and DIPEA (259mg).Make above-mentioned reaction mixture be warming up to envrionment temperature and it was stirred 6 hours.Water (10mL) dilutes above-mentioned reaction mixture.Organic layer is separated, carries out drying (MgSO ₄), filter and concentrate.The thick product of gained need not be further purified and can use (191mg, 100%);

¹H?NMR(CDCl ₃)0.26(s，9H)，5.19(bs，2H)，8.39(s，2H)；

MS?m/e?MH ⁺+MeCN233.

Intermediate 6

5-ethynyl pyrimidine-2-amine

(276mg) joins the 5-[(trimethyl silyl with salt of wormwood) ethynyl] pyrimidine-2-amine (intermediate 5) MeOH (40mL) (191mg): in the water (20mL).Under inert atmosphere, at ambient temperature above-mentioned reaction mixture was stirred 24 hours, neutralize with 1M HCI then.Then the gained reaction mixture is concentrated, and the gained resistates is dissolved among the DCM (30mL).Gained DCM phase water (15mL) washs, washs, carries out drying (MgSO with salt solution (15mL) ₄), filter and concentrate.The thick product of gained need not be further purified and can use (119mg, 100%);

¹H?NMR(CDCl ₃)3.19(s，1H)，5.26(bs，2H)，8.41(s，2H)；

MS?m/e?MH ⁺+MeCN161.

Intermediate 7

(5-bromo-1,3-thiazoles-2-yl) phenyl carbamate

Under inert atmosphere, the 2-amino-5-bromo thiazole (6.27g) of cooling (ice bath) and anhydrous DCM (120mL) solution of pyridine (3.22mL) are stirred.DCM (20mL) solution of phenyl chloroformate (4.4mL) is dripped adding wherein, then it was stirred 2 hours.Said mixture is concentrated, and it is diluted with isohexane and water.The solid that forms leached, washes with water use isohexane: DCM washing then, and at ambient temperature it is carried out drying.The gained solid is absorbed among the THF (400mL), carries out drying (MgSO ₄) and with solvent evaporation, thereby obtain product (9.5g, 88%).

¹H?NMR(DMSO-d ₆)7.27(m，3H)，7.44(m，2H)，7.52(s，1H)；

MS?m/e?MH ⁺301，299(1x?Br).

Intermediate 8

N-(5-bromo-1,3-thiazoles-2-yl)-N '-[(5-methyl-2-furyl) methyl] urea

Under 80 ℃, under inert atmosphere, anhydrous 1, in the 4-dioxane (10mL), (5-bromo-1,3-thiazoles-2-yl) phenyl carbamate (intermediate 7) (1.79g) was stirred 1 hour with [(5-methyl-2-furyl) methyl] amine (0.67g) and triethylamine (1.0mL).It is concentrated, and the DCM solution that utilizes the DCM solution of 0-100%EtOAc then and use 0-10%MeOH subsequently carries out purifying by flash chromatography to it as elutriant on silicon-dioxide, thereby obtains being solid product (0.9g, 47%);

¹H?NMR(DMSO-d ₆)2.22(s，3H)，4.25(d，2H)，5.98(d，1H)，6.12(d，1H)，6.87(t，1H)，7.37(s，1H)，10.60(bs，1H)；

MS?m/e?MH ⁺318，316(1x?Br).

Embodiment 17

N-{5-[(2-aminopyrimidine-5-yl) ethynyl]-1,3-thiazoles-2-yl }-N '-(2-morpholine-4-base benzyl) urea

Be prepared in the mode that is similar to embodiment 16.

SM:2-amino-5-ethynyl pyrimidine (intermediate 6), N-(5-bromo-1,3-thiazoles-2-yl)-N '-(2-morpholine-4-base benzyl) urea (intermediate 9)

¹H?NMR(DMSO-d ₆)2.83(m，4H)，3.75(m，4H)，4.42(d，2H)，6.91(m，1H)，7.05-7.32(m，6H)，7.57(s，1H)，8.38(s，2H)，10.83(bs，1H)；

MS?m/e?MH ⁺436.

Intermediate 9

N-(5-bromo-1,3-thiazoles-2-yl)-N '-(2-morpholine-4-base benzyl) urea

Be prepared in the mode that is similar to intermediate 8.

SM:(5-bromo-1,3-thiazoles-2-yl) phenyl carbamate (intermediate 7), (2-morpholine-4-base benzyl) amine

¹H?NMR(DMSO-d ₆)2.82(m，4H)，3.74(m，4H)，4.41(d，2H)，6.88(t，1H)，7.05-7.32(m，4H)，7.37(s，1H)，10.76(bs，1H)；

MS?m/e?MH ⁺399，397(1x?Br).

Following examples are prepared in the mode that is similar to embodiment 1

Embodiment 18

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(2-morpholine-4-base ethyl) urea

SM: intermediate 2,4-(2-amino-ethyl) morpholine

¹H?NMR(DMSO-d ₆)2.36-2.42(m，6H)，3.23(q，2H)，3.60-3.63(m，4H)，6.13(t，1H)，7.02-7.05(m，1H)，7.12(s，2H)，7.23-7.30(m，2H)，7.69(s，1H)，8.44(s，2H)，8.74(s，1H)；

MS?m/e?MH ⁺367.

Embodiment 20

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(2-tetramethyleneimine-1-base ethyl) urea

SM: intermediate 2,1-(2-amino-ethyl) tetramethyleneimine

¹H?NMR(DMSO-d ₆)1.70-1.73(m，4H)，2.48-2.50(m，6H)，3.22(q，2H)，6.17(t，1H)，7.03(dt，1H)，7.12(s，2H)，7.22-7.30(m，2H)，7.68(s，1H)，8.44(s，2H)，8.75(s，1H)；

MS?m/e?MH ⁺351.

Embodiment 21

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(pyridine-2-base is amino) ethyl] urea

SM: intermediate 2, N1-pyridine-2-base-ethane-1,2-diamines

¹H?NMR(DMSO-d ₆)3.28-3.35(m，4H)，6.33-6.35(m，1H)，6.51-6.56(m，3H)，7.03-7.05(m，1H)，7.12(s，2H)，7.23-7.32(m，2H)，7.35-7.41(m，1H)，7.69(s，1H)，7.97-7.99(m，1H)，8.44(s，2H)，8.65(s，1H)；

MS?m/e?MH ⁺374.

Embodiment 22

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(3-tetramethyleneimine-1-base propyl group) urea

SM: intermediate 2,1-(3-aminopropyl) tetramethyleneimine

¹H?NMR(DMSO-d ₆)1.59-1.72(m，6H)，2.40-2.44(m，6H)，3.15(q，2H)，6.22(t，1H)，7.01-7.05(m，1H)，7.12(s，2H)，7.22-7.30(m，2H)，7.69(s，1H)，8.44(s，2H)，8.55(s，1H)；

MS?m/e?MH ⁺365.

Following examples need be passed through RPHPLC (H ₂O:MeCN0-70%) be further purified, thereby be provided as the title compound of tfa salt.

Embodiment 24

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(2-thiomorpholine-4-base ethyl) urea

SM: intermediate 2,4-(2-amino-ethyl) thiomorpholine

¹H?NMR(DMSO-d ₆)2.89-3.05(m，4H)，3.14-3，39(m，4H)，3.50(q，2H)，3.80-3.84(m，2H)，6.61(s，1H)，7.06-7.15(m，3H)，7.26-7.37(m，2H)，7.70(s，1H)，8.43(s，2H)，9.09(s，1H)；

MS?m/e?MH ⁺383.

Embodiment 25

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(benzylamino) ethyl] urea

SM: intermediate 2,2-benzylamino ethamine

¹H?NMR(DMSO-d ₆)3.01-3.12(m，2H)，3.41-3.44(m，2H)，4.20-4.22(m，2H)，6.48-6.56(m，1H)，7.06-7.14(m，3H)，7.26-7.36(m，2H)，7.41-7.54(m，5H)，7.69(s，1H)，8.43(s，2H)，8.81(s，1H)，8.92(s，1H)；

MS?m/e?MH ⁺387.

Embodiment 26

N-{3-[(2-{[3-(dimethylamino) propyl group] amino } pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-morpholine-4-base benzyl) urea

Under 50 ℃, with 2-(4-morpholino) benzylamine (0.167mg), triethylamine (0.12mL) and 3-[(2-{[3-(dimethylamino) propyl group] amino pyrimidine-5-yl) ethynyl] and phenylcarbamic acid phenyl ester (intermediate 11) (300mg) in THF (10mL) heating 16 hours.In a vacuum the gained reaction mixture is concentrated and the gained resistates is ground, thereby obtain being beige solid title compound (332mg, 89%) with ether;

¹H?NMR(DMSO-d ₆)1.66-1.79(m，2H)，2.27(s，6H)，2.31-2.35(m，2H)，2.86(t，4H)，3.30-3.40(m，2H)，3.76(t，4H)，4.39(d，2H)，6.58(s，1H)，7.02-7.05(m，1H)，7.10(t，1H)，7.15(d，1H)，7.23-7.35(m，4H)，7.68(t，1H)，7.72(s，1H)，8.47(s，2H)，8.70(s，1H)；

MS?m/e?MH ⁺514.

Intermediate 10

N '-and the 5-[(3-aminophenyl) ethynyl] pyrimidine-2-base }-N, N-dimethylpropane-1,3-diamines

With 3-[(2-chloropyrimide-5-yl) ethynyl] aniline (intermediate 3) (2.23g), N, N-dimethylpropane-1, the ethereal solution (11.7mL) of 3-diamines (6.11mL) and 1.0M HCl are dissolved among the MeCN (10ml) and are heated and refluxed 4 hours.The DCM solution that concentrates in a vacuum and use 1-10% (the MeOH solution of 10%7N NH3) carries out purifying by flash chromatography, thereby obtains being beige solid title compound (2.70g, 94%) as elutriant on silicon-dioxide;

¹H?NMR(DMSO-d ₆)1.59-1.69(m，2H)，2.11(s，6H)，2.24(t，2H)，3.30(t，2H)，5.19(s，2H)，6.56(dd，1H)，6.61(d，1H)，6.67(s，1H)，7.01(t，1H)，7.62(t，1H)，8.40(s，2H

MS?m/e?MH ⁺296.

Intermediate 11

3-[(2-{[3-(dimethylamino) propyl group] amino } pyrimidine-5-yl) ethynyl] the phenylcarbamic acid phenyl ester

With N '-{ 5-[(3-aminophenyl) ethynyl] pyrimidine-2-base }-N, N-dimethylpropane-1,3-diamines (intermediate 10) (1.5g) and pyridine (0.41mL) be dissolved among the THF (200mL) and and be cooled to 0 ℃ it.Phenyl chloroformate (0.89mL) is dripped adding wherein and in 1 hour time makes gained solution be warming up to envrionment temperature.In a vacuum above-mentioned reaction mixture is concentrated and the gained resistates is dissolved in the ethyl acetate, with aqueous sodium carbonate, water and salt water washing, in a vacuum it is concentrated and grind, thereby obtain title compound (2.28g) into colorless solid with ether.

¹H?NMR(DMSO-d ₆)1.60-1.79(m，2H)，2.12(s，6H)，2.26(t，2H)，3.30-3.40(m，2H)，7.15-7.51(m，8H)，7.66-7.70(m，2H)，8.45(s，2H)，10.33(s，1H)；

MS?m/e?MH ⁺416.

Following examples use intermediate 2 and suitable amine to be prepared in the mode that is similar to embodiment 1:

Embodiment 27

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[(1R, 2R)-the 2-hydroxy-cyclohexyl] methyl } urea

SM: intermediate 2, cis-2-aminomethyl-1-hexalin

¹H?NMR(DMSO-d ₆)1.20-1.73(m，9H)，2.99-3.15(m.2H)，3.79(s，1H)，4.38(d，1H)，6.22(t，1H)，7.03(d，1H)，7.11(s，2H)，7.22-7.27(m，2H)，7.68(s，1H)，8.44(s，2H)，8.63(s，1H)；

MS?m/e?MH ⁺366.

Embodiment 28

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[(1S, 2R)-the 2-hydroxy-cyclohexyl] methyl } urea

SM: intermediate 2, trans-2-aminomethyl-1-hexalin

¹H?NMR(DMSO-d ₆)0.97-1.26(m，6H)，1.60-1.86(m，3H)，3.09-3.18(m，2H)，3.23-3.29(m，1H)，4.70(d，1H)，6.24(t，1H)，7.02-7.05(m，1H)，7.11(s，2H)，7.22-7.28(m，2H)，7.69(s，1H)，8.44(s，2H)，8.64(s，1H)；

MS?m/e?MH ⁺366.

Embodiment 29

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-(5-fluoro-2-morpholine-4-base benzyl) urea

SM: intermediate 2,5-fluoro-2-morpholine-4-base benzonitrile (intermediate 13)

¹H?NMR(DMSO-d ₆)2.80(t，4H)，3.73(t，4H)，4.38(d，2H)，6.65(t，1H)，7.01-7.69(m，8H)，7.68(s，1H)，8.40(s，2H)，8.72(s，1H)；

MS?m/e?MH ⁺447.

Intermediate 12

5-fluoro-2-morpholine-4-base benzonitrile

With 2, DMSO (150mL) suspension of 5-difluoro benzonitrile (13.9g), salt of wormwood (27.6g) and morpholine (13.2mL) heating 18 hours is cooled off and is poured in the water (500mL) it under 100 ℃.With ether to the gained water extract, water and salt water washing and in a vacuum it is concentrated.The isohexane solution that uses 10-50%EtOAc carries out purifying by flash chromatography to gained oily solid, thereby obtains the title compound (10.9g) into pale solid as elutriant on silicon-dioxide;

¹H?NMR(CDCl ₃)3.14(t，4H)，3.90(t，4H)，7.02(dd，1H)，7.20-7.36(m，2H)；

MS?m/e?MH ⁺207.

Intermediate 13

1-(5-fluoro-2-morpholine-4-base phenyl) methylamine

At room temperature, with ethanol (200mL) and the hydrogenation 24 hours under 50psi of the suspension of the dense HCl aqueous solution (10mL) (10.9g) of 10%Pd/C (1.0g) and 5-fluoro-2-morpholine-4-base benzonitrile (intermediate 12).Make gained mixture filtration over celite, concentrate and use the isohexane solution of 10-100%EtOAc as elutriant in a vacuum, on silicon-dioxide, it is carried out purifying, thereby obtain title compound (4.0g) into yellow oil by flash chromatography.

¹H?NMR(CDCl ₃)2.87(t，4H)，3.84(t，4H)，3.90(s，2H)，6.92(dt，1H)，7.05-7.12(m，2H)；

MS?m/e?MH ⁺211.

Embodiment 30

N-{3-[(2-aminopyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(4-methylpiperazine-1-yl) benzyl] urea

SM: intermediate 2,1-[2-(4-methylpiperazine-1-yl) phenyl] methylamine (intermediate 14)

¹H NMR (DMSO-d ₆) 2.30 (s, 3H), 2.54 (4H is covered by DMSO), 2.84 (t, 4H), 4.34 (d, 2H), 6.53 (t, 1H), 6.99-7.14 (m, 5H), 7.18-7.31 (m, 4H), 7.69 (s, 1H), 8.41 (s, 2H), 8.69 (s, 1H);

MS?m/e?MH ⁺442.

Intermediate 14

1-[2-(4-methylpiperazine-1-yl) phenyl] methylamine

80 ℃ and 20 the crust under, with 2-(4-methylpiperazine-1-yl) benzonitrile (J.Med.Chem., 1983,1116-1122) ethanol (200mL) of (18.0g) and 10%Pd/C (1.0g) and the hydrogenation of liquefied ammonia (20mL) suspension are 24 hours.Make gained mixture filtration over celite, concentrate and use 1-12%MeOH/NH in a vacuum ₃DCM solution as elutriant, on silicon-dioxide, it is carried out purifying, thereby obtains title compound (2.7g) into yellow oil by flash chromatography.

¹H?NMR(CDCl ₃)1.76(s，br，2H)，2.58(s，br，4H)，2.96(t，4H)，3.88(s，2H)，7.05-7.30(m，4H)；

MS?m/e?MH ⁺205

Following examples use intermediate 6 and intermediate 16 to be prepared in the mode that is similar to embodiment 16.

Embodiment 31

N-{5-[(2-aminopyrimidine-5-yl) ethynyl]-1,3,4-thiadiazoles-2-yl }-N '-(2-morpholine-4-base benzyl) urea

SM:2-amino-5-ethynyl pyrimidine (intermediate 6), N-(5-bromo-1,3,4-thiadiazoles-2-yl)-N '-(2-morpholine-4-base benzyl) urea (intermediate 16)

¹H?NMR(DMSO-d ₆)2.83(m，4H)，3.75(m，4H)，4.46(d，2H)，7.00-7.40(m，7H)，8.51(s，2H)，11.28(bs，1H)；

MS?m/e?MH ⁺437.

Intermediate 15

(5-bromo-1,3,4-thiadiazoles-2-yl) phenyl carbamate

DCM (20mL) solution of phenyl chloroformate (4.4mL) is joined 2-amino-5-bromo-1,3 that refrigerative stirs on ice bath, and the 4-thiadiazoles is { in pyridine (100mL) solution of EurJ.Med.Chem.Chim.Ther. (1975) 121} (6.3g).After 3 hours, the gained mixture is concentrated water (400mL) dilution then.The solid that forms is leached and at ambient temperature it is carried out drying in a vacuum.Use acetone as elutriant, on silicon-dioxide, it is carried out purifying, grind with ether/isohexane then, thereby obtain being solid product (5.3g, 51%) by flash chromatography;

¹H?NMR(DMSO-d ₆)7.29(m，3H)，7.44(m，2H)，13.10(bs，1H)；

MS?m/e?MH ⁺300，302(1x?Br).

Following intermediate replaces intermediate 7 to be prepared in the mode that is similar to intermediate 9 by using intermediate 15.

Intermediate 16

N-(5-bromo-1,3,4-thiadiazoles-2-yl)-N '-(2-morpholine-4-base benzyl) urea

¹H?NMR(DMSO-d ₆)2.78-2.87(m，4H)，3.71-3.77(m，4H)，4.41-4.46(m，2H)，7.00-7.10(m，2H)，7.13-7.18(m，1H)，7.22-7.30(2H，m)；

MS?m/e?MH ⁺397，399(1x?Br)

Embodiment 32

N-{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl }-N '-(2-morpholine-4-base benzyl) urea

Under 80 ℃, will 5-[(2-aminopyrimidine-5-yl) ethynyl]-pyridin-2-yl-phenyl carbamate (intermediate 21) (331mg), (2-morpholine-4-base benzyl) amine (230mg) and triethylamine (303mg) be 1, heated 3 hours in the 4-dioxane (10mL).In a vacuum reaction mixture is concentrated on a small quantity and it is diluted with ether.The solid that forms is leached and under 60 ℃, in a vacuum it is carried out drying, thereby obtain being solid title compound (417mg, 97%);

¹H?NMR(DMSO-d ₆)2.87(m，4H)，3.77(m，4H)，4.41(d，2H)，6.78(t，1H)，7.05-7.35(m，6H)，8.12(m，1H)，8.25(m，1H)，8.51(m，3H)，8.91(s，1H)；

MS?m/e(M-H) ^-428.

Intermediate 17

(5-bromopyridine-3-yl) t-butyl carbamate

Triethylamine (7mL) is joined DPPA (10.9mL) subsequently in toluene (100mL) solution of 5-bromo-nicotinic acid (10.1g) and t-BuOH (7.1mL), and under inert atmosphere, should react reflux 1.5 hours.With EtOAc (100mL) and water (100mL) the gained reaction mixture is diluted.Organic layer is separated, uses NaHCO ₃(3 * 50mL) wash, carry out drying (Mg ₂SO ₄), filter and in a vacuum it concentrated.The DCM solution that uses 0-4%EtOAc carries out purifying by flash chromatography to products obtained therefrom, thereby obtains being beige solid title compound (9.82g, 72%) as elutriant on silicon-dioxide;

¹H?NMR(DMSO-d ₆)1.50(s，9H)，8.19(t，1H)，8.30(d，1H)，8.57(d，1H)，9.80(s，1H)；

MS?m/e?MH ⁺273/275.

Intermediate 18

(5-iodine pyridine-3-yl) t-butyl carbamate

Under inert atmosphere, with (5-bromopyridine-3-yl) t-butyl carbamate (intermediate 17) (14.9g), CuI (520mg), NaI (16.35g) and N, N-dimethyl-ethylenediamine (481mg) in dioxane (300mL) 110 ℃ of heating 24 hours down.In a vacuum reaction mixture is concentrated into about 100mL, then water (400mL) is added wherein.The gained solid is filtered, it is dissolved among the DCM, carries out drying (MgSO ₄), filter and concentrate, thereby obtain being beige solid title compound (15.18g, 87%);

MS?m/e?MH ⁺321.

Intermediate 19

5-[(2-aminopyrimidine-5-yl) and ethynyl] pyridin-3-yl } t-butyl carbamate

With PdCl ₂Dppf (907mg) join the degassing (5-iodine pyridine-3-yl) t-butyl carbamate (intermediate 18) (7.94g), 5-ethynyl pyrimidine-2-amine (intermediate 6) (3.7g), CuI (94mg) and Et ₃In DMF (250mL) solution of N (63mL).At ambient temperature, under inert atmosphere, will react stirring 24 hours.Silicon-dioxide is joined in the reaction mixture, then evaporating solvent in a vacuum.The DCM solution that uses 0-10%MeOH is as elutriant, on silicon-dioxide, gained preadsorption product is carried out purifying by flash chromatography, wash then and in a vacuum it is carried out drying subsequently, thereby obtain being beige solid title compound (5.3g, 69%);

¹H?NMR(DMSO-d ₆)1.51(s，9H)，7.20(s，2H)，8.05(s，1H)，8.31(s，1H)，8.48(s，2H)，8.57(s，1H)，9.74(s，1H)；

MS?m/e(M-H+)-310.

Intermediate 20

5-[(5-aminopyridine-3-yl) ethynyl] pyrimidine-2-amine

Under inert atmosphere, TFA (25mL) is joined in { 5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl } t-butyl carbamate (intermediate 19) DCM (150mL) solution (2.92g).At ambient temperature, above-mentioned reaction was stirred 3 hours.Water (100mL) dilutes and in a vacuum DCM is removed then.Use NaHCO ₃In and the aqueous solution, gained precipitation is filtered, is washed with water and in a vacuum it carried out drying then, thereby obtain title compound (2.00g, 66%);

¹H?NMR(DMSO-d ₆)5.49(s，2H)，7.00(s，1H)，7.88(s，2H)，8.44(s，2H)；

MS?m/e?MH ⁺212.

Following intermediate replaces intermediate 1 to be prepared in the mode that is similar to intermediate 2 by using intermediate 20.

Intermediate 21

5-[(2-aminopyrimidine-5-yl) and ethynyl] pyridin-3-yl } phenyl carbamate

¹H?NMR(DMSO-d ₆)7.19(br.s，2H)，7.25-7.33(m，3H)，7.41-7.50(m，2H)，8.04(s，1H)，8.39(s，1H)，8.48(s，2H)，8.65-8.68(m，1H)，11.6(br.S，1H)；

MS?m/e?MH ⁺332.

Following examples use intermediate 21 and suitable amine to be prepared in the mode that is similar to embodiment 32.

Embodiment 33

N-{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl }-N '-(2-methoxy-benzyl) urea

SM:{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl } phenyl carbamate (intermediate 21) and 2-methoxybenzylamine.

¹H?NMR(DMSO-d ₆)3.83(s，3H)，4.25(d，2H)，6.67(t，1H)，6.91(t，1H)，6.98(d，1H)，7.15(s，2H)7.23(m，2H)8.08(t，1H)，8.21(d，1H)，8.41(d，1H)，8.44(s，2H)，8.90(s，1H)；

MS?m/e?MH ⁺375.

Embodiment 34

N-{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl }-N '-[2-(trifluoromethyl) benzyl] urea

SM:{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl } phenyl carbamate (intermediate 21) and 2-(trifluoromethyl) benzylamine.This product carries out purifying by reverse-phase chromatography.

¹H?NMR(DMSO-d ₆)4.50(d，2H)，6.93(t，1H)，7.16(s，2H)7.40-7.77(m，4H)8.09(t，1H)，8.23(d，1H)，8.43(m，3H)，9.05(s，1H)；

MS?m/e?MH ⁺413.

Embodiment 35

N-{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl }-N '-(2-methyl-benzyl) urea

SM:{5-[(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl } phenyl carbamate (intermediate 21) and 2-methylbenzylamine.This product carries out purifying by reverse-phase chromatography.

¹H?NMR(DMSO-d ₆)2.30(s，3H)，4.28(d，2H)，6.74(t，1H)，7.10-7.30(m，6H)8.09(t，1H)，8.22(d，1H)，8.43(m，3H)，8.82(s，1H)；

MS?m/e?MH ⁺359.

Embodiment 36

1-{4-methyl-3-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-phenyl }-3-(2-morpholine-4-base-benzyl)-urea

Will { 4-methyl-3-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-phenyl }-phenyl carbamate (intermediate 26) (0.25g), TEA (0.23mL) and 2-morpholine-4-base-benzylamine (113mg) join in the dioxane (6mL), and under 60 ℃, be heated and spend the night.In a vacuum solvent is removed and the gained resistates is carried out purifying through RPHPLC.Make required component by the SCX post and in a vacuum solvent is removed, thereby obtain pale solid (210mg, 70%);

¹H?NMR(400.132MHz，DMSO)δ8.57(s，1H)，8.47(s，2H)，7.66(s，1H)，7.48(t，1H)，7.31(d，1H)，7.25(t，1H)，7.20(d，1H)，7.16-7.14(m，2H)，7.10(t，1H)，6.53(t，1H)，4.39(d，2H)，3.76(t，4H)，3.57(t，4H)，3.44(q，2H)，2.86-2.84(m，4H)，2.48(t，2H)，2.42-2.40(m，4H)，2.35(s，3H)；

MS?m/e?MH ⁺557.

Intermediate 22

4-(5-amino-2-methyl-phenyl)-2-methyl-Ding-3-alkynes-2-alcohol

With 3-iodo-4-monomethylaniline (100g), two (triphenylphosphine) Palladous chloride (II) (6.0g), triphenylphosphine (112g) and 2-methyl-Ding-3-alkynes-2-alcohol (83mL) joins in the piperidines (600mL), and under inert atmosphere, it is refluxed and stirred 4 hours.In a vacuum piperidines is removed, thereby obtained the viscosity black sludge.In ether (300ml), the gained slurry is stirred, use aqueous citric acid solution (500mL) afterwards its acidifying.With another part ether (150mL) washing aqueous solution, with gained ether laminated and and extract again with aqueous citric acid solution (500mL), the water layer that is combined with salt of wormwood alkalizes then, (3 * 500mL) extract, carry out drying (MgSO with ether ₄) and remove in a vacuum and desolvate, thereby obtain black viscous oil.Be dissolved in gained oil in 80% ether/isohexane and make it pass through 4 inches silicon-dioxide plugs, with 80% ether/isohexane wash-out.Desolvate by removing, obtain orange oil, the curing (87g) of spending the night; MS m/eMH ⁺190.

Intermediate 23

3-ethynyl-4-methyl-aniline

4-(5-amino-2-methyl-phenyl)-2-methyl-Ding-3-alkynes-2-alcohol (intermediate 22) (81g) is joined in the toluene, then atomizing NaOH (25.8g) is added wherein, and will react reflux 6 hours.In a vacuum toluene is removed, with NaHCO ₃The aqueous solution (300mL) adds wherein, extracts, carries out drying (MgSO with ether (3x400mL) ₄) and in a vacuum solvent is removed, thereby obtain black oil.Under 120 ℃, under 0.30mbar, compound is carried out purifying through the bulb-to-bulb distillation.Obtain slight xanchromatic oil (47g, two steps are 84%);

¹H?NMR(300.072MHz，cdcl ₃)δ6.97(d，1H)，6.80(s，1H)，6.60(d，1H)，3.53(brs，1H)，3.20(s，1H)，2.33(s，3H).

Intermediate 24

(5-bromo-pyrimidine-2-base)-(2-morpholine-4-base-ethyl)-amine

2-chloro-5-bromo pyrimi piperidine (100g) is joined in propan-2-ol (700mL), DIPEA (184mL) and the amino-ethyl morpholine (80.8g), under 80 ℃, be heated 7 hours then.Make above-mentioned reaction cooling and in a vacuum solvent is removed, thereby obtain orange jelly, water (200mL) is with its quencher, extract, carry out drying (MgSO with ether (3x600mL) ₄) and in a vacuum solvent is removed, thereby obtain yellow viscous oil.Grind with ether (100mL), thereby obtain solid, in isohexane (200mL), it was stirred 20 minutes, then it is filtered and drying.Obtain white solid (118g, 79%);

¹H?NMR(300.072MHz，cdcl ₃)δ8.28(s，2H)，5.73(s，1H)，3.72(t，4H)，3.46(q，2H)，2.59(t，2H)，2.49(t，4H)；

MS?m/e?MH ⁺288.

Intermediate 25

[5-(5-amino-2-methyl-phenylacetylene base)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl)-amine

With (5-bromo-pyrimidine-2-base)-(2-morpholine-4-base-ethyl)-amine (intermediate 24) (15g), PdCl ₂(PPh3) 2 (0.37g), triphenylphosphine (0.7g) and 3-ethynyl-4-methyl-phenyl amine (intermediate 23) (8.2mL) join in the piperidines (150mL), and are heated backflow 2 hours.In a vacuum piperidines is removed then, thereby obtained yellow solid.Water (200mL) is added wherein, this is extracted, it is carried out drying (MgSO with DCM (2x250mL) ₄) and in a vacuum solvent is removed, thereby obtain yellow solid.The gained solid is dissolved among the small amount of thermal DCM, then the ether adding wherein is settled out solid, cooling obtains yellow solid.The DCM solution that uses 2.5-10%MeOH carries out purifying by flash chromatography to remaining liq, thereby obtains the title compound (13.5g, 77%) into white solid as elutriant on silicon-dioxide;

¹H?NMR(300.132MHz，CDCl ₃)δ8.41(s，2H)，7.00(d，1H)，6.82(s，1H)，6.60(d，1H)，5.85(brs，1H)，3.72(t，4H)，3.60-3.50(m，4H)，2.61(t，2H)，2.50(t，4H)，2.36(s，3H)；

MS?m/e?MH ⁺338.

Intermediate 26

4-methyl-3-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-phenyl }-phenyl carbamate

With [5-(5-amino-2-methyl-phenylacetylene base)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl) amine (intermediate 25) (3.0g) and NaHCO ₃(1.1g) join among the THF (40mL), and it is cooled to 0 ℃.In 10 fens clock times, will slowly join in the reaction at the phenyl chloroformate (1.1mL) among the THF (10mL).After the adding, make reaction be warming up to envrionment temperature and it was stirred 1 hour.Water (100mL) will react quencher, extract, carries out drying (MgSO with DCM (2x200mL) ₄) and in a vacuum solvent is removed, thereby obtain yellow solid.The gained solid is dissolved among a small amount of DCM, then ether is added wherein, subsequently isohexane is added wherein, thereby be settled out solid.

¹H?NMR(300.074MHz，dmso)δ8.46(s，2H)，7.62(s，1H)，7.49(t，1H)，7.45-7.37(m，3H)，7.27-7.20(m，5H)，3.55(t，4H)，3.42(q，2H)，2.46(t，2H)，2.41-2.37(m，7H)；

MS?m/e?MH ⁺458.

Embodiment 37

N-[6-methyl-5-(2-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } ethynyl) pyridin-3-yl]-N '-(3-morpholine-4-base benzyl) urea

Will { 6-methyl-5-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-phenyl carbamate (intermediate 31) (0.17g), TEA (0.2mL) and 3-morpholine-4-base-benzylamine (93mg) join in the dioxane (6mL), and under 60 ℃, be heated and spend the night.In a vacuum solvent is removed and the gained resistates is carried out purifying through RPHPLC.The component that makes merging is by the SCX post and in a vacuum solvent is removed, thereby obtains pale solid (111mg, 54%);

¹H?NMR(400.132MHz，DMSO)δ8.73(s，1H)，8.50(s，2H)，8.32(s，1H)，8.04(s，1H)，7.54(t，1H)，7.19(t，1H)，6.89(s，1H)，6.83(d，1H)，6.78-6.73(m，2H)，4.26(d，2H)，3.74(t，4H)，3.57(t，4H)，3.44(q，2H)，3.10(t，4H)，2.54(s，3H)，2.48(t，2H)，2.43-2.39(m，4H)；

MS?m/e?MH ⁺557.

Intermediate 27

5-bromo-2-methyl-3-nitro-pyridine

Sodium hydride (13.4g) is joined among the DMF (500mL), under inert atmosphere, in this mixture, slowly add diethyl malonic ester (45mL).Finish in case add, will react and stir 10 minutes.Then 2-chloro-3-iodo-5-nitropyridine (61g) is slowly joined in the negatively charged ion, form dark solution (showing temperature rise).Above-mentioned reaction was stirred 1 hour, use 2.0N HCl (300mL) with its quencher, extract, carry out drying (MgSO afterwards with ether (3x300mL) ₄) and in a vacuum solvent is removed, thereby obtain dark oil (2-(3-iodo-5-nitro-pyridine-2-yl)-diethyl malonate) (87g).This material need not be further purified and can use, it is joined among the 7.0N HCl (300mL) and it was refluxed 4 hours, reaction is cooled off and extracted with ether (3x200mL), with 10N NaOH water is alkalized to pH10, use ether (3x200mL) that it is extracted, carries out drying (MgSO more then ₄) and in a vacuum solvent is removed, thereby obtain black oil, place and solidify.The isohexane solution that uses 30% ether carries out purifying by flash chromatography as elutriant on silicon-dioxide, thereby obtains the title compound into white solid.In 50% ether/isohexane, carry out recrystallization, obtain yellow solid.Repeat to handle, till not having solid to produce (33g, two steps were 60%);

¹H?NMR(300.072MHz，cdcl ₃)δ9.26(s，1)，8.82(s，1)，2.87(s，3H)；

MS?m/e?MH ⁺264

Intermediate 28

5-iodo-6-methyl-pyridin-3-yl amine

With 5-bromo-2-methyl-3-nitro-pyridine (intermediate 27) (33g) and iron (21g) join in the acetate (200mL), and under 60 ℃, will react the heating 2 hours.In a vacuum acetate is removed, remaining black viscous oil is alkalized with wet chemical (250mL).Then, with ether (3x300mL) said system is extracted, it is carried out drying (MgSO ₄) and in a vacuum solvent is removed, thereby obtain solid.The isohexane solution that uses the 80-100% ether carries out purifying by flash chromatography, thereby obtains the title compound (25g, 86%) into white solid as elutriant on silicon-dioxide;

¹H?NMR(300.072MHz，cdcl ₃)δ7.96(s，1H)，7.43(s，1H)，3.59(brs，2H)，2.62(s，3H)；

MS?m/e?MH ⁺236.

Intermediate 29

5-ethynyl-6-methyl-pyridin-3-yl amine

With 5-iodo-6-methyl-pyridin-3-yl amine (intermediate 28) (22g), PdCl ₂(PPh3) ₂(0.7g), triphenylphosphine (24g) and 2-methyl-Ding-3-alkynes-2-alcohol (17mL) joins in the piperidines (180mL), and be heated and refluxed 4 hours.In a vacuum piperidines is removed, residual resistates is carried out acidifying and extract with ether (300mL) with aqueous citric acid solution (300mL).Gained ether layer extracts with aqueous citric acid solution (100mL) again, water layer is merged and alkalizes to pH12 with salt of wormwood, uses then that ether (3x300mL) extracts, dry (MgSO ₄) and in a vacuum solvent is removed, thereby obtain viscosity black oil (4-(5-amino-2-methyl-pyridin-3-yl)-2-methyl-Ding-3-alkynes-2-alcohol).Above-mentioned thick product is dissolved in the toluene (300mL), NaOH (5.6g) is added wherein, will react then and reflux 5 hours.Above-mentioned reaction is cooled off and in a vacuum solvent removed.Remaining black viscous oil is joined NaHCO ₃In the aqueous solution (300mL), extract, carry out drying (MgSO with ether (3x300mL) ₄) and in a vacuum solvent is removed, thereby obtain brown solid.The isohexane solution that uses the 70-100% ether carries out purifying by flash chromatography as elutriant on silicon-dioxide, thereby obtains the title compound (9.8g, two steps were 80%) into pale solid;

¹H?NMR(300.072MHz，cdcl ₃)δ7.97(s，1H)，7.05(s，1H)，3.59(brs，2H)，3.32(s，1H)，2.56(s，3H)；

MS?m/e?MH ⁺+MeCN174.

Intermediate 30

[5-(5-amino-2-methyl-pyridin-3-yl ethynyl)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl)-amine

With (5-bromo-pyrimidine-2-base)-(2-morpholine-4-base-ethyl)-amine (intermediate 24) (7.0g), PdCl ₂(PPh3) ₂(0.17g), triphenylphosphine (0.2g) and 3-ethynyl-4-methyl-aniline (intermediate 29) (3.54g) joins in the piperidines (70mL), and be heated and refluxed 2 hours.In a vacuum piperidines is removed then, thereby obtained yellow jelly.With in the above-mentioned jelly water-soluble (200mL), extract, carry out drying (MgSO with DCM (2x250mL) ₄) and in a vacuum solvent is removed, thereby obtain yellow jelly.The gained jelly is dissolved among the hot DCM, grinds, be settled out yellow solid with ether.The DCM solution that uses 2.5-10%MeOH carries out purifying by flash chromatography to remaining liq, thereby obtains the title compound (6.5g, 78%) into yellow solid as elutriant on silicon-dioxide;

¹H?NMR(300.132MHz，CDCl ₃)δ8.41(s，2H)，7.00(d，1H)，6.81(s，1H)，6.59(d，1H)，5.84(brs，1H)，3.72(t，4H)，3.56-3.50(m，4H)，2.60(t，2H)，2.49(t，4H)，2.36(s，3H)；

MS?m/e?MH ⁺339

Intermediate 31

6-methyl-5-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-phenyl carbamate

With [5-(5-amino-2-methyl-pyridin-3-yl ethynyl)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl)-amine (intermediate 3) (3.0g) and NaHCO ₃(1.1g) join among the THF (40mL), and it is cooled to 0 ℃.In 10 fens clock times, will slowly join in the reaction at the phenyl chloroformate (1.1mL) among the THF (10mL).After the adding, make reaction be warming up to envrionment temperature and it was stirred 1 hour.Water (100mL) will react quencher, extract, carries out drying (MgSO with DCM (2x200mL) ₄) and in a vacuum solvent is removed, thereby obtain yellow solid.The gained solid is dissolved among a small amount of DCM, then ether is added wherein, subsequently isohexane is added wherein, till solid is separated out.The solid that forms is filtered and drying.The DCM solution that uses 1.0-10%MeOH carries out purifying by flash chromatography to remaining liq, thereby obtains the title compound (1.1g, 27%) into white solid as elutriant on silicon-dioxide;

MS?m/e?MH ⁺459.

Embodiment 38

N-(2-benzyl chloride base)-N '-[5-(2-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } ethynyl) pyridin-3-yl] urea

In dioxane, [5-(5-amino-pyridine-3-ethyl-acetylene base)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl)-amine (intermediate 34) (180mg) is carried out pre-mixing with 1-chloro-2-isocyanato methyl-benzene (120mg), and under 80 ℃, be heated 24 hours.In a vacuum solvent is removed and the gained resistates is carried out purifying (60 peak method) through HPLC.With the component that obtains merge, with the salt of wormwood alkalization and in a vacuum acetonitrile is removed, thereby obtain solid, this is filtered and drying (120mg, 44%);

¹H?NMR(400.132MHz，DMSO)δ9.49(vbrs，1H)，8.54-8.44(m，3H)，8.22(s，1H)，8.11(s，1H)，7.53(brs，1H)，7.45-7.41(m，2H)，7.35-7.27(m，3H)，4.38(s，2H)，3.56(t，4H)，3.44(t，2H)，2.48(t，2H)，2.44-2.38(m，4H)；

MS?m/e?MH ⁺493.

Intermediate 32

4-(5-amino-pyridine-3-yl)-2-methyl-Ding-3-alkynes-2-alcohol

With 5-iodo-pyridin-3-yl amine (50g), PdCl ₂(PPh ₃) ₂(1.6g), triphenylphosphine (12g) and 2-methyl-Ding-3-alkynes-2-alcohol (44mL) joins in the piperidines (300mL), and be heated and refluxed 2 hours.In a vacuum piperidines is removed, thereby obtained the black jelly, water (200mL) and isohexane (200mL) adding wherein and under 50 ℃ are stirred the gained jelly 20 minutes.Solid is separated out, and isohexane is removed, and other a isohexane (100mL) is added wherein and under 50 ℃ it is added, and is removed equally.Above-mentioned reaction is filtered and the solid that obtains is carried out drying;

MS?m/e?MH ⁺177.

Intermediate 33

5-ethynyl-pyridin-3-yl amine

4-(5-amino-pyridine-3-yl)-2-methyl-Ding-3-alkynes-2-alcohol (intermediate 32) (40g) is joined in the toluene (350mL), it is carried out reflux, then the NaOH (13.8g) that pulverizes is slowly added wherein, above-mentioned reaction was refluxed 5 hours, after this in a vacuum solvent is removed, thereby obtained black viscous oil.Use NaHCO ₃The aqueous solution (300mL) is handled, is extracted, carries out drying (MgSO with ether (3x300mL) above-mentioned viscous oil ₄) and in a vacuum solvent is removed, thereby obtain the black jelly.Under 0.32mmHg, under 140 ℃, this is carried out purifying through kulgohlor bulb to bulb distillation.Obtain white solid (15.5g, two steps were 58%);

¹H?NMR(300.072MHz，cdcl ₃)δ8.13(s，1H)，8.03(s，1H)，7.05(s，1H)，3.76(brs，2H)，3.14(s，1H)；

MS?m/e?MH ⁺+MeCN160.

Intermediate 34

[5-(5-amino-pyridine-3-ethyl-acetylene base)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl)-amine

With (5-bromo-pyrimidine-2-base)-(2-morpholine-4-base-ethyl)-amine (intermediate 24) (13g), PdCl ₂(PPh ₃) ₂(0.32g), triphenylphosphine (0.3g) and 5-ethynyl-pyridin-3-yl amine (intermediate 33) (5.3g) joins in the piperidines (100mL), and be heated and refluxed 2 hours.In a vacuum piperidines is removed then, thereby obtained the black jelly.In above-mentioned jelly water-soluble (200mL) and DCM (200mL), extract, carry out drying (MgSO with DCM (2x250mL) ₄) and in a vacuum solvent is removed, thereby obtain the black jelly.The gained jelly is dissolved among the small amount of thermal DCM.The DCM solution that uses 2.5-10%MeOH carries out purifying by flash chromatography, thereby obtains the title compound (10.3g, 71%) into yellow solid as elutriant on silicon-dioxide;

¹H?NMR(300.072MHz，cdcl ₃)δ8.44(s，2H)，8.16(s，1H)，8.04(s，1H)，7.07(s，1H)，5.92(brs，1H)，3.75-3.72(m，6H)，3.55(q，2H)，2.63(t，2H)，2.53-2.50(m，4H)；

MS?m/e?MH ⁺325.

Embodiment 39

N-[2-(dimethylamino) benzyl]-N '-[5-(2-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } ethynyl) pyridin-3-yl] urea

Will { 5-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-carboxylamine 4-chloro-phenyl ester (intermediate 35) (0.22g), TEA (0.19mL) and (2-amino-methyl-phenyl)-dimethyl-amine (77mg) joins in the dioxane (6mL), and be heated 1 hour under 50 ℃.In a vacuum solvent is removed and the gained resistates is carried out purifying through RPHPLC.Merge component, alkalize and in a vacuum acetonitrile is removed with salt of wormwood, thereby obtain white solid.Solid is filtered and dry (160mg, 70%);

¹H?NMR(400.132MHz，DMSO)δ9.07(brs，1H)，8.50(s，2H)，8.45(s，1H)，8.23(s，1H)，8.13(s，1H)，7.55(t，1H)，7.28(d，1H)，7.22(t，1H)，7.13(d，1H)，7.04(t，1H)，6.92(brs，1H)，4.39(s，2H)，3.57(t，4H)，3.44(q，2H)，2.66(s，6H)，2.48(t，2H)，2.42-2.40(m，4H)；

MS?m/e?MH ⁺501.

Intermediate 35

5-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-carboxylamine 4-chloro-phenyl ester

Under inert atmosphere, with [5-(5-amino-pyridine-3-ethyl-acetylene base)-pyrimidine-2-base]-(2-morpholine-4-base-ethyl)-amine (intermediate 34) (2.0g) and TEA (1.0mL) join in the anhydrous dioxane (60mL).Slowly add chloroformic acid to chlorobenzene ester (0.91mL) and will react stirring 10 minutes in above-mentioned solution, water (50mL) is with its quencher then.In a vacuum solvent is removed, thereby obtained solid, DCM (30mL) is joined in this solid, to this supersound process 10 minutes, filter and it is carried out drying.Obtain pale solid (1.7g, 57%);

¹H?NMR(400.132MHz，DMSO)δ10.66(s，1H)，8.65(s，1H)，8.52(s，2H)，8.41(s，1H)，8.04(s，1H)，7.58(s，1H)，7.51(d，2H)，7.32(d，2H)，3.61-3.54(m，4H)，3.49-3.40(m，2H)，2.51-2.35(m，6H)；

MS?m/e?MH ⁺479.

Embodiment 40

N-(3-benzyl chloride base)-N '-[5-(2-[(2-morpholine-4-base ethyl) and amino] pyrimidine-5-yl } ethynyl) pyridin-3-yl] urea

Will { 5-[2-(2-morpholine-4-base-ethylamino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-carboxylamine 4-chloro-phenyl ester (intermediate 35) (0.22g), TEA (0.19mL) and 3-chloro-benzylamine (72mg) join in the dioxane (6mL), and be heated 1 hour under 50 ℃.In a vacuum solvent is removed and the gained resistates is carried out purifying through RPHPLC.Merge component, alkalize and in a vacuum acetonitrile is removed with salt of wormwood, thereby obtain white solid.Solid is filtered and dry (154mg, 68%);

¹H?NMR(400.132MHz，DMSO)δ9.32(vbrs，1H)，8.53-8.48(m，3H)，8.22(s，1H)，8.10(s，1H)，7.54(s，1H)，7.38-7.34(m，2H)，7.31-7.27(m，3H)，4.31(s，2H)，3.57(t，4H)，3.44(q，2H)，2.48(t，2H)，2.42-2.40(m，4H)；

MS?m/e?MH ⁺493.

Embodiment 41

N-(2-methoxy-benzyl)-N '-[5-(2-[(3-morpholine-4-base propyl group) and amino] pyrimidine-5-yl } ethynyl) pyridin-3-yl] urea

Will { 5-[2-(2-morpholine-4-base-propyl group amino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-carboxylamine 4-chloro-phenyl ester (intermediate 38) (0.20g), TEA (0.17mL) and 2-methoxyl group-benzylamine (87mg) join in the dioxane (6mL), and be heated 1 hour under 50 ℃.In a vacuum solvent is removed and the gained resistates is carried out purifying through RPHPLC.Merge component, alkalize and in a vacuum acetonitrile is removed with salt of wormwood, thereby obtain white solid.The solid that forms is filtered and dry (138mg, 67%);

¹H NMR (400.132MHz, DMSO) δ 8.94 (s, 1H), 8.49 (s, 2H), 8.42 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.74 (t, 1H), 7.28-7.23 (m, 2H), 7.00 (d, 1H), 6.93 (t, 1H), 6.70 (t, 1H), 4.28 (d, 2H), 3.84 (s, 3H), 3.57 (t, 4H), 3.34 (q, 2H), 2.36-2.32 (m, 6H), 1.69 (quintet, 2H);

MS?m/e?MH ⁺502.

Intermediate 36

(5-bromo-pyrimidine-2-base)-(3-morpholine-4-base-propyl group)-amine

2-chloro-5-bromo pyrimi piperidine (50g) is joined in propan-2-ol (300mL), DIPEA (92mL) and the aminopropyl morpholine (46mL), and under 80 ℃, will react heating 3 hours.Make above-mentioned reaction cooling and in a vacuum solvent is removed, thereby obtain orange jelly, water (200mL) is with its quencher, extract, carry out drying (MgSO with ether (3x600mL) ₄) and in a vacuum solvent is removed, thereby obtain yellow viscous oil.Ether (100mL) joined rapidly grind wiping (scratching) in the jelly simultaneously, till solid is separated out, this is filtered.Repeat filtering mother liquor is handled, till not having solid to separate out.The solid that obtains is merged and in isohexane (200mL), it was stirred 20 minutes, afterwards it is filtered and dry.Obtain white solid (67g, 86%);

¹H NMR (300.072MHz, cdcl ₃) δ 8.25 (s, 2H), 6.02 (s, 1H), 3.73 (t, 4H), 3.45 (q, 2H), 2.49-2.44 (m, 6H), 1.78 (quintet, 2H);

MS?m/e?MH ⁺302.

Intermediate 37

[5-(5-amino-pyridine-3-ethyl-acetylene base)-pyrimidine-2-base]-(3-morpholine-4-base-propyl group)-amine

With (5-bromo-pyrimidine-2-base)-(2-morpholine-4-base-propyl group)-amine (intermediate 36) (7g), PdCl ₂(PPh ₃) ₂(0.33g), triphenylphosphine (6.1g) and 5-ethynyl-pyridin-3-yl amine (intermediate 33) (2.7g) joins in the piperidines (100mL), and be heated and refluxed 4 hours.In a vacuum piperidines is removed then, thereby obtained the black jelly.(200mL) handles this with aqueous citric acid solution, extracts with ether (100mL), uses salt of wormwood (pH12) that water layer is alkalized then, and (2 * 250mL) extract, carry out drying (MgSO with DCM ₄) and remove in a vacuum and desolvate, thereby obtain the dark yellow solid.The DCM solution that uses 3.5-10%MeOH carries out purifying by flash chromatography, thereby obtains the title compound into brown solid as elutriant on silicon-dioxide.The gained solid is joined in the hot acetonitrile, the gained slurries were stirred 10 minutes, afterwards it is filtered and drying.Obtain pale solid (4.6g, 59%);

¹H NMR (300.132MHz, DMSO) δ 8.46 (s, 2H), 7.91 (d, 1H), 7.84 (d, 1H), 7.70 (t, 1H), 6.99 (t, 1H), 5.47 (s, 2H), 3.57 (t, 4H), 3.37-3.28 (m, 2H), 2.35-2.31 (m, 6H), 1.69 (quintet, 2H); MS m/e MH ⁺339.

Intermediate 38

5-[2-(2-morpholine-4-base-propyl group amino)-pyrimidine-5-ethyl-acetylene base]-pyridin-3-yl }-carboxylamine 4-chloro-phenyl ester

Under inert atmosphere, with [5-(5-amino-pyridine-3-ethyl-acetylene base)-pyrimidine-2-base]-(2-morpholine-4-base-propyl group)-amine (intermediate 37) (0.9g) and TEA (0.5mL) join in the anhydrous dioxane (60mL).Slowly add chloroformic acid to chlorobenzene ester (0.45mL) and will react stirring 10 minutes in above-mentioned solution, water (50mL) is with its quencher then.In a vacuum solvent is removed, thereby obtained solid, DCM (30mL) is joined in this solid, to this supersound process 10 minutes, filter and it is carried out drying.Obtain yellow solid (0.7g, 54%);

¹H NMR (300.074MHz, dmso) δ 10.64 (s, 1H), 8.63 (s, 1H), 8.49 (s, 2H), 8.38 (s, 1H), 8.01 (s, 1H), 7.76 (t, 1H), 7.49 (d, 2H), 7.30 (d, 2H), 3.59-3.54 (m, 4H), 3.32 (q, 2H), 2.39-2.26 (m, 6H), 1.68 (quintet, 2H);

MS?m/e?MH ⁺394

Embodiment 42

N-{3-[(4,6 di-amino-pyrimidines-5-yl) ethynyl] phenyl }-N '-(1,4-diox-2-ylmethyl) urea

Under 80 ℃, will { 3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl } phenyl carbamate (intermediate 2) (50mg), C-[1,4] diox-2-base methylamine (35mg) and triethylamine (0.06mL) heated 24 hours in THF (2mL).In a vacuum above-mentioned reaction mixture is concentrated, the gained solid is ground, in 60 ℃ vacuum it carried out drying with ether, thereby obtain being solid title compound (41mg, 77%);

¹H?NMR(DMSO-d ₆)2.99-3.11(m，1H)，3.13-3.27(m，1H)，3.39-3.78(m，7H)，6.25-6.31(t，1H)，6.50(bs，4H)，7.16-7.26(m，2H)，7.32-7.38(m，1H)，7.60(s，1H)，7.83(s，1H)，8.52(bs，1H)；

MS?m/e?MH ⁺369.

The preparation of intermediate 38

The 5-[(3-aminophenyl) ethynyl] pyrimidine-4, the 6-diamines

In DMF (100mL)/triethylamine (20mL) to 4,6-diamino-5-iodine pyrimidine (J.Med.Chem., 2001,44,2133-2138) (2.36g), two (triphenylphosphine) palladium chloride (350mg) and cupric iodide (I) (40mg) stir, and outgas 10 minutes with nitrogen.3-ethynyl aniline (1.29g) is added wherein, and under 95 ℃, said mixture was heated 20 hours.With solvent evaporation, the DCM solution that utilizes 1-10% (the MeOH solution of 7M ammonia) carries out purifying by flash chromatography to the gained resistates as elutriant on silicon-dioxide.By grinding it be further purified, thereby obtain title compound (970mg, 43%) into brown solid with DCM (20mL);

¹H?NMR(DMSO-d ₆)3.72(bs，2H)，5.17(bs，4H)，6.67-6.71(m，1H)，6.80-6.82(m，1H)，6.88-6.92(m，1H)，7.11-7.17(m，1H)，8.08(s，1H)；

MS?m/e?MH ⁺226.

The preparation of intermediate 39

3-[(4,6-di-amino-pyrimidine-5-yl) and ethynyl] phenyl } phenyl carbamate

Under 0 ℃, phenyl chloroformate (2.51mL) is added to the 5-[(3-aminophenyl of stirring) ethynyl] pyrimidine-4,6-diamines (intermediate 1) is (3.0g) and in THF (200mL) solution of pyridine (2.15mL).After 2 hours, water (10mL) is added wherein, above-mentioned reaction mixture was stirred 10 minutes, in a vacuum it is concentrated then.With the solid that obtains with water and grind with ether subsequently, the DCM solution that uses 0-10%MeOH carries out purifying by flash chromatography as elutriant on silicon-dioxide, grind with MeOH then, thereby obtain title compound (2.51g, 55%) into light yellow solid;

¹H?NMR(DMSO-d ₆)6.53(s，4H)，7.17-7.46(m，8H)，7.77(s，1H)，7.83(s，1H)，10.24(bs，1H)；

MS?m/e?MH ⁺346.

Embodiment 43

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[(5-methylpyrazine-2-yl) methyl] urea

SM: intermediate 2,2-(aminomethyl)-5-methylpyrazine

¹H?NMR(DMSO-d ₆)4.38-4.44(d，2H)，6.48(bs，4H)，6.77-6.84(t，1H)，7.16-7.26(m，2H)，7.30-7.38(m，1H)，7.63(s，1H)，7.83(s，1H)，8.48(s，2H)，8.74(s，1H)；

MS?m/e?MH ⁺375.

Embodiment 44

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(tetrahydrochysene-2H-pyrans-4-ylmethyl) urea

SM: intermediate 2,4-amino methyl tetrahydropyrans

¹H?NMR(DMSO-d ₆)1.09-1.25(m，2H)，1.49-1.70(m，3H)，2.94-3.04(t，2H)，3.20-3.30(m，2H)，3.78-3.89(m，2H)，6.21-6.30(t，1H)，6.50(bs，4H)，7.16-7.24(m，2H)，7.31-7.39(m，1H)，7.61(s，1H)，7.83(s，1H)，8.38(bs，1H)；

MS?m/e?MH ⁺367.

Embodiment 45

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(pyridin-3-yl methyl) urea

SM: intermediate 2,3-(aminomethyl) pyridine

¹H?NMR(DMSO-d ₆)4.29-4.34(d，2H)，6.50(bs，4H)，6.72-6.78(t，1H)，7.17-7.26(m，2H)，7.32-7.39(m，2H)，7.62-7.66(m，1H)，7.67-7.72(m，1H)，7.82(s，1H)，8.42-8.46(m，1H)，8.50-8.53(m，1H)，8.60(bs，1H)；

MS?m/e?MH ⁺360.

Embodiment 46

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[3-(1H-pyrazol-1-yl) propyl group] urea

SM: intermediate 2, [3-(1H-pyrazol-1-yl) propyl group] amine hydrate

¹H?NMR(DMSO-d ₆)1.85-1.98(m，2H)，3.00-3.09(m，2H)，4.10-4.18(m，2H)，6.20-6.23(m，1H)，6.24-6.33(t，1H)，6.50(bs，4H)，7.18-7.26(m，2H)，7.32-7.39(m，1H)，7.41-7.45(m，1H)，7.62(s，1H)，7.70-7.73(m，1H)，7.82(s，1H)，8.46(bs，1H)；

MS?m/e?MH ⁺377.

Embodiment 47

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(tetrahydrofuran (THF)-2-ylmethyl) urea

SM: intermediate 2, tetrahydrofurfuryl amine

¹H?NMR(DMSO-d ₆)1.44-1.58(m，1H)，1.73-1.96(m，3H)，3.01-3.30(m，2H)，3.55-3.68(m，1H)，3.73-3.90(m，2H)，6.21-6.28(t，1H)，6.50(bs，4H)，7.16-7.25(m，2H)，7.33-7.39(m，1H)，7.59(s，1H)，7.82(s，1H)，8.50(bs，1H)；

MS?m/e?MH ⁺353.

Embodiment 48

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-pyridin-3-yl ethyl) urea

SM: intermediate 2,3-(2-amino-ethyl) pyridine

¹H?NMR(DMSO-d ₆)2.73-2.81(t，2H)，3.31-3.40(q，2H)，6.17-6.23(t，1H)，6.50(bs，4H)，7.17-7.26(m，2H)，7.29-7.37(m，1H)，7.58-7.68(m，2H)，7.82(s，1H)，8.39-8.47(m，3H)；

MS?m/e?MH ⁺374.

Embodiment 49

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[(4-methyl isophthalic acid, 3-thiazol-2-yl) methyl] urea

SM: intermediate 2, C-(4-methylthiazol-2-yl) methylamine

¹H?NMR(DMSO-d ₆)2.32(s，3H)，4.49-4.56(d，2H)，6.51(bs，4H)，6.91-6.98(t，1H)，7.10-7.13(m，1H)，7.19-7.28(m，2H)，7.36-7.40(m，1H)，7.65(s，1H)，7.82(s，1H)，8.76(bs，1H)；

MS?m/e?MH ⁺380.

Embodiment 50

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[(4-methyl-isoxazole-3-yl) methyl] urea

SM: intermediate 2, (4-methyl-3-isoxazolyl) methylamine

¹H?NMR(DMSO-d ₆)2.36(s，3H)，4.27-4.32(d，2H)，6.13(s，1H)，6.71-6.79(t，1H)，7.22-7.40(m，3H)，7.76-7.79(m，1H)，7.87(bs，4H)，8.16(s，1H)，8.74(bs，1H)；

MS?m/e?MH ⁺364.

Embodiment 51

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(3-methoxy-benzyl) urea

SM: intermediate 2,3-methoxybenzylamine

¹H?NMR(DMSO-d ₆)3.73(s，3H)，4.24-4.29(d，2H)，6.50(bs，4H)，6.61-6.68(t，1H)，6.76-6.89(m，3H)，7.17-7.27(m，3H)，7.35-7.40(m，1H)，7.62-7.65(m，1H)，7.82(s，1H)，8.54(bs，1H)；

MS?m/e?MH ⁺389.

Embodiment 52

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[(5-methyl-2-furyl) methyl] urea

SM: intermediate 2,5-methyl furfuryl group amine

¹H?NMR(DMSO-d ₆)2.23(s，3H)，4.19-4.24(d，2H)，5.95-5.98(m，1H)，6.18-6.23(m，1H)，6.43-6.58(m，5H)，7.18-7.27(m，2H)，7.33-7.39(m，1H)，7.62(s，1H)，7.82(s，1H)，8.48(bs，1H)；

MS?m/e?MH ⁺363.

Embodiment 53

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-morpholine-4-base benzyl) urea

SM: intermediate 2,1-(2-morpholine-4-base phenyl) methylamine

¹H?NMR(DMSO-d ₆)2.81-2.87(m，4H)，3.72-3.77(m，4H)，4.35-4.41(d，2H)，6.46-6.60(m，5H)，7.04-7.16(m，2H)，7.20-7.32(m，4H)，7.34-7.41(m，1H)，7.64(s，1H)，7.83(s，1H)，8.57(bs，1H)；

MS?m/e?MH ⁺444.

Following compound embodiment is prepared in the mode that is similar to embodiment 42, but by water, grinds with ether then it is carried out purifying.

Embodiment 54

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(3,5-dimethyl-1H-pyrazol-1-yl) ethyl] urea

SM: intermediate 2,1-aminomethyl-3,5-ethyl pyrazole hydrochloride

¹H?NMR(DMSO-d ₆)2.08(s，3H)，2.17(s，3H)，3.35-3.45(q，2H)，3.95-4.01(t，2H)，5.78(s，1H)，6.19-6.27(t，1H)，6.50(bs，4H)，7.16-7.27(m，2H)，7.33-7.39(m，1H)，7.61(s，1H)，7.82(s，1H)，8.58(bs，1H)；

MS?m/e?MH ⁺391.

Embodiment 55

N-(3-cyano group benzyl)-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl } urea

SM: intermediate 2,3-cyanobenzyamine of derivative hydrochlorate

¹H?NMR(DMSO-d ₆)4.35-4.40(d，2H)，6.50(bs，4H)，6.78-6.84(t，1H)，7.17-7.27(m，2H)，7.33-7.39(m，1H)，7.46(s，1H)，7.49(s，1H)，7.64(s，1H)，7.77(s，1H)，7.80(s，1H)，7.83(s，1H)，8.67(bs，1H)；

MS?m/e?MH ⁺384.

Embodiment 56

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(pyridazine-3-base oxygen base) ethyl] urea

SM: intermediate 2,2-(pyridazine-3-base oxygen base) ethamine

¹H?NMR(DMSO-d ₆)3.50-3.58(q，2H)，4.43-4.52(t，2H)，6.42-6.50(t，1H)，6.65(bs，4H)，7.17-7.27(m，3H)，7.32-7.40(m，1H)，7.57-7.66(m，2H)，7.86(s，1H)，8.57(bs，1H)，8.87-8.90(m，1H)；

MS?m/e?MH ⁺391.

Following examples are prepared in the mode that is similar to embodiment 42, but carry out purifying by RPHPLC:

Embodiment 57

N-(cyclopropyl methyl)-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl } urea

SM: intermediate 2, (aminomethyl) cyclopropane

¹H?NMR(DMSO-d ₆)0.00-0.06(m，2H)，0.24-0.31(m，2H)，0.70-0.85(s，1H)，2.78-2.88(t，2H)，6.10-6.19(t，1H)，7.04-7.25(m，3H)，7.60(s，1H)，7.71(bs，4H)，8.01(s，1H)，8.36(bs，1H)；

MS?m/e?MH ⁺323.

Embodiment 58

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-pyrimidine-4-base ethyl) urea

SM: intermediate 2,2-pyrimidine-4-base ethamine hydrogen chlorate

¹H?NMR(DMSO-d ₆)2.77-2.83(t，2H)，3.31-3.39(m，2H)，6.25-6.28(t，1H)，7.21-7.32(m，3H)，7.78(bs，4H)，8.15(s，1H)，8.52(s，1H)，8.68(s，2H)，9.05(bs，1H)；

MS?m/e?MH ⁺375.

Following examples are prepared in the mode that is similar to embodiment 42, but the DCM solution that is to use 1-10%MeOH carries out purifying by flash chromatography as elutriant on silicon-dioxide.

Embodiment 59

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[3-(2-oxo-pyrrolidine-1-yl) propyl group] urea

SM: intermediate 2,1-(3-aminopropyl)-2-Pyrrolidone

¹H?NMR(DMSO-d ₆)1.54-1.66(qn，2H)，1.85-1.98(qn，2H)，2.16-2.27(t，2H)，2.99-3.09(q，2H)，3.15-3.25(t，2H)，3.26-3.38(m，2H)，6.17-6.24(t，1H)，6.49(bs，4H)，7.18-7.25(m，2H)，7.31-7.38(m，1H)，7.62(s，1H)，7.83(s，1H)，8.55(s，1H)；

MS?m/e?MH ⁺394.

Embodiment 60

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl] urea

SM: intermediate 2,2-(3,5-dimethyl-1h-pyrazoles-4-yl) ethamine

¹H?NMR(DMSO-d ₆)2.09(s，6H)，2.40-2.49(t，2H)，3.06-3.17(q，2H)，6.06-6.12(t，1H)，6.50(bs，4H)，7.18-7.24(m，2H)，7.33-7.39(m，1H)，7.61(s，1H)，7.83(s，1H)，8.45(bs，1H)，11.89(bs，1H)；

MS?m/e?MH ⁺391.

Embodiment 61

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[(4-morpholine-4-yl pyrimidines-5-yl) methyl] urea

SM: intermediate 2,1-(4-morpholine-4-yl pyrimidines-5-yl) methylamine

¹H?NMR(DMSO-d ₆)3.38-3.45(m，4H)，3.63-3.73(m，4H)，4.25-4.30(d，2H)，6.50(bs，4H)，6.65-6.73(t，1H)，7.17-7.29(m，2H)，7.34-7.40(m，1H)，7.63(s，1H)，7.82(s，1H)，8.30(s，1H)，8.56(s，1H)，8.62(bs，1H)；

MS?m/e?MH ⁺446.

Following examples are prepared in the mode that is similar to embodiment 42

Embodiment 62

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-morpholine-4-base ethyl) urea

SM: intermediate 2,4-(2-amino-ethyl) morpholine

¹H?NMR(DMSO-d ₆)2.39-2.45(m，6H)，3.23(q，2H)，3.61(t，4H)，6.15(t，1H)，6.52(s，4H)，7.23-7.25(m，2H)，7.39-7.45(m，1H)，7.64-7.65(m，1H)，7.86(s，1H)，8.64(s，1H)；

MS?m/e?MH ⁺382.

Embodiment 63

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(3-morpholine-4-base propyl group) urea

SM: intermediate 2,4-(3-aminopropyl) morpholine

¹H?NMR(DMSO-d ₆)1.61(t，2H)，2.27-2.37(m，6H)，3.13(q，2H)，3.55-3.61(m，4H)，6.21(t，1H)，6.52(s，4H)，7.22-7.26(m，2H)，7.36-7.40(m，1H)，7.64(d，1H)，7.86(s，1H)，8.44(s，1H)；

MS?m/e?MH ⁺396.

Embodiment 64

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-tetramethyleneimine-1-base ethyl) urea

SM: intermediate 2,1-(2-amino-ethyl) tetramethyleneimine

¹H?NMR(DMSO-d ₆)1.70-1.74(m，4H)，2.40-2.50(m，6H)，3.22(q，2H)，6.18(t，1H)，6.52(s，4H)，7.22-7.26(m，2H)，7.35-7.39(m，1H)，7.64(d，1H)，7.86(s，1H)，8.63(s，1H)；

MS?m/e?MH ⁺366.

Embodiment 65

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[2-(pyridine-2-base is amino) ethyl] urea

SM: intermediate 2, N1-pyridine-2-base-ethane-1,2-diamines

¹H?NMR(DMSO-d ₆)3.25-3.42(m，4H)，6.32-6.36(m，1H)，6.48-6.52(m，6H)，7.23-7.25(m，2H)，7.35-7.40(m，2H)，7.65(s，1H)，7.86(s，1H)，7.97(d，1H)，8.54(s，1H)；

MS?m/e?MH ⁺389.

Embodiment 66

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(3-tetramethyleneimine-1-base propyl group) urea

SM: intermediate 2,1-(3-aminopropyl) tetramethyleneimine

¹H?NMR(DMSO-d ₆)1.59-1.71(m，6H)，2.40-2.45(m，6H)，3.14(q，2H)，6.22(t，1H)，6.53(s，4H)，7.22-7.26(m，2H)，7.36-7.40(m，1H)，7.63-7.64(m，1H)，7.86(s，1H)，8.44(s，1H)；

MS?m/e?MH ⁺380.

Embodiment 67

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-(2-piperidines-1-base ethyl) urea

SM: intermediate 2,1-(2-amino-ethyl) piperidines

¹H?NMR(DMSO-d ₆)1.35-1.48(m，2H)，1.50-1.57(m，4H)，2.34-2.38(m，6H)，3.21(q，2H)，6.11(t，1H)，6.52(s，4H)，7.22-7.26(m，2H)，7.36-7.40(m，1H)，7.65(d，1H)，7.86(s，1H)，8.66(s，1H)；

MS?m/e?MH ⁺380.

Following compound need pass through RPHPLC (H ₂O:MeCN0-70%) be further purified, thereby obtain title compound into tfa salt.

Embodiment 68

N-[2-(benzylamino) ethyl]-N '-and 3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl } urea

SM: intermediate 2,2-benzylamino ethamine

¹H?NMR(DMSO-d ₆)3.07-3.12(m，2H)，3.44(q，2H)，4.18-4.26(m，2H)，6.76(t，1H)，7.26-7.35(m，2H)，7.42-7.55(m，6H)，7.76(s，1H)，7.80-8.00(m，4H)，8.21(s，1H)，8.87-9.01(m，2H)，8.99(s，1H)；

MS?m/e?MH ⁺402

Embodiment 69

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-[(1,5-dimethyl-1H-pyrazole-3-yl) methyl] urea

SM: intermediate 2, (1,5-dimethyl-1h-pyrazole-3-yl) methylamine

¹H?NMR(DMSO-d ₆)2.22(s，3H)，3.65(s，3H)，4.16(d，2H)，5.94(d，1H)，6.45(t，1H)，6.52(s，4H)，7.21-7.27(m，2H)，7.38-7.41(m，1H)，7.64(s，1H)，7.86(s，1H)，8.53(s，1H)；

MS?m/e?MH ⁺377.

Embodiment 70

N-{3-[(4,6-di-amino-pyrimidine-5-yl) ethynyl] phenyl }-N '-benzylurea

In THF to the 5-[(3-aminophenyl) ethynyl] pyrimidine-4,6-diamines (intermediate 1) (45mg) stirs, and benzyl mustard oil (37mg) drip is added wherein.After 30 minutes, further benzyl mustard oil (37mg) is added wherein.After 30 minutes, methyl ethylenediamine-polystyrene (400mg) added wherein and continue stirred 30 minutes.Above-mentioned reaction mixture is filtered and concentrates, thereby obtain yellow solid, grind, thereby obtain beige solid (22mg, 31%) with DCM (7mL);

¹H?NMR(DMSO-d ₆)4.35(d，2H)，6.44-6.57(bs，4H)，6.65-6.72(m，1H)，7.21-7.44(m，8H)，7.67(s，1H)，7.86(s，1H)，8.57(s，1H)；

MSm/e?MH ⁺359

Embodiment 71

1-[5-[2-(2-aminopyrimidine-5-yl) ethynyl] pyridin-3-yl]-3-[[2-(piperidino) phenyl] methyl] urea

Under 80 ℃, will 5-[(2-aminopyrimidine-5-yl) ethynyl]-pyridin-3-yl phenyl carbamate (intermediate 21) (463mg), (2-piperidines-1-base benzyl) amine (475mg) and triethylamine (252mg) heated 3 hours in DMF (4mL).By the RPHPLC purifying, obtain solid phase prod (97mg, 16%).

¹H?NMR(DMSO-d ₆)1.53(m，2H)，1.66(m，4H)，2.80(m，4H)，4.37(d，2H)，6.70(t，1H)，7.0-7.3(m，6H)，8.11(m，1H)，8.23(m，1H)，8.44(m，3H)，8.92(s，1H).

MS?m/e?MH ⁺428.

Following examples use intermediate 31 and suitable amine to be prepared in the mode that is similar to embodiment 37.

Embodiment 72

The 1-[(2-p-methoxy-phenyl) methyl]-3-[6-methyl-5-[2-[2-(2-morpholine-4-base ethylamino) pyrimidine-5-yl] ethynyl] pyridin-3-yl]-urea

SM: intermediate 31,2-methoxyl group-benzylamine

¹H?NMR(DMSO-d ₆)δ8.77(s，1H)，8.50(s，2H)，8.30(s，1H)，8.04(s，1H)，7.54(t，1H)，7.28-7.22(m，2H)，7.00(d，1H)，6.92(t，1H)，6.60(t，1H)，4.27(d，2H)，3.84(s，3H)，3.57(t，4H)，3.44(q，2H)，2.54(s，3H)，2.48(t，2H)，2.42-2.40(m，4H)；

MS?m/e?MH ⁺502.

Embodiment 73

The 1-[(2-dimethylaminophenyl) methyl]-3-[6-methyl-5-[2-[2-(2-morpholine-4-base ethylamino) pyrimidine-5-yl] ethynyl] pyridin-3-yl]-urea

SM: intermediate 31,2-dimethylamino-benzylamine

MS?m/e?MH ⁺515.

Following examples use intermediate 31 and suitable isocyanic ester to be prepared in the mode that is similar to embodiment 38.

Embodiment 74

The 3-[(2-chloro-phenyl-) methyl]-1-[6-methyl-5-[2-[2-(2-morpholine-4-base ethylamino) pyrimidine-5-yl] ethynyl] pyridin-3-yl]-urea

SM: intermediate 31,2-chloro-benzyl isocyanate ester

¹H?NMR(DMSO-d ₆)δ8.49(s，2H)，8.38(s，1H)，8.03(s，1H)，7.62(vbrs，1H)，7.44-7.41(m，2H)，7.34-7.26(m，2H)，4.36(s，2H)，3.57(t，4H)，3.44(t，2H)，2.53(s，3H)，2.48(t，2H)，2.42-2.40(m，4H).

MS?m/e?MH ⁺506.

Claims

1. formula I compound:

R wherein ^yBe group NR ¹R ², R ^xBe radicals R ^3aAnd R ^zBe radicals R ^4a,

R ¹And R ²Be independently selected from hydrogen, (1-6C) alkyl sulphonyl, phenyl (CH ₂) _u-, wherein u be 0,1,2,3,4,5 or 6, (1-6C) alkyloyl, (1-6C) alkyl, (1-6C) alkoxy carbonyl, (3-6C) cycloalkyl (CH ₂) _v-, wherein v is 0,1,2,3,4,5 or 6, perhaps 5 yuan or 6 yuan of heteroaryl rings, perhaps R ¹And R ²The nitrogen-atoms that is connected with them is represented optional 3～7 yuan of heterocycles of heteroatomic saturated or fractional saturation that another is selected from N or O that contain altogether;

Wherein any (1-6C) alkyl; (1-6C) alkoxyl group; (1-6C) alkyloyl is independently selected from following group replacement with (3-6C) group of naphthene base is optional by one or more: fluorine; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl group; (1-6C) alkoxyl group (1-6C) alkoxyl group; (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group; amino; single (1-6C) alkylamino or two (1-6C) alkylamino; formamyl; single (1-6C) alkyl-carbamoyl; two-[(1-6C) alkyl] formamyls;-N (R ^d) C (O) (1-6C) alkyl, wherein R ^dBe hydrogen or (1-6C) 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of alkyl, saturated or fractional saturation;

Wherein (1-6C) alkoxyl group, (1-6C) alkoxyl group (1-6C) alkoxyl group and (1-6C) alkoxyl group (1-6C) alkoxyl group (1-6C) alkoxyl group, and amino, single (1-6C) alkyl-carbamoyl, two [(1-6C) alkyl] formamyl of single (1-6C) alkylamino, two-[(1-6C) alkyl] and/or-N (R ^d) (1-6C) (1-6C) alkyl of alkyl is optional is replaced by one or more hydroxyl for C (O);

R wherein ¹And/or R ²In any heterocycle or heteroaryl ring is optional is replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, (1-4C) alkoxyl group (1-4C) alkyl, hydroxyl, amino, list (1-6C) alkylamino, two-[(1-6C) alkyl] is amino, saturated or 3～7 yuan of heterocycles of fractional saturation or-C (O) (CH ₂) _zY, wherein z is 0,1,2 or 3 and Y is selected from hydrogen, hydroxyl, (1-4C) alkoxyl group, amino, list (1-6C) alkylamino, two-[(1-6C) alkyl] is amino or 3～7 yuan of heterocycles of saturated or fractional saturation;

R ^3aBe selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group, wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine, hydroxyl, (1-6C) alkyl, (1-6C) alkoxyl group, amino, single (1-6C) alkylamino, two (1-6C) alkylamino, formamyl, single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] formamyl, 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl, (1-4C) alkoxyl group, hydroxyl, amino, 3～7 yuan of heterocycles of single (1-6C) alkylamino or two (1-6C) alkylamino or saturated or fractional saturation;

Perhaps R ^3bRepresent group-NR as defined above ¹R ²

A represents aryl or is selected from 5 or 6 yuan of following heteroaryl rings: furyl, pyrryl, thienyl,  azoles base, different  azoles base, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,  di azoly, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3, the 5-triazinyl;

N is 0,1,2 or 3;

Wherein Z be direct key ,-O-or-N (R ⁸)-,

Wherein x and y are 0,1,2 or 3 independently, condition be x+y＞0 and＜4,

R wherein ⁸And R ⁹Represent hydrogen or (1-6C) alkyl independently,

R wherein ^aAnd R ^bIn (1-6C) alkyl optional by 3～7 yuan of heterocyclic substituted of halogen, cyano group, hydroxyl or saturated or fractional saturation,

M is 0,1,2 or 3;

And salt or solvate.

2. according to the compound of claim 1, be formula (IA)

Wherein:

R ¹, R ², R ^3a, R ^4a, A, R ⁵, L, B, n and m as defined in claim 1, and R ⁶Be selected from hydroxyl, halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles and-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl;

Perhaps R ⁶Be selected from (1-6C) alkyl, S (O) _p(1-6C) alkyl wherein p be 0,1 or 2 or (1-6C) alkoxyl group,

The optional group that is selected from (1-6C) alkyl independently by one or more of 3～7 yuan of heterocycles of wherein said (3-7C) cycloalkyl ring and saturated or fractional saturation replaces;

And salt or solvate.

3. according to the compound of claim 2, R wherein ^3aAnd R ^4aBe independently selected from hydrogen, (1-6C) alkyl or (1-6C) alkoxyl group,

Wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl group; amino; single (1-6C) alkylamino; two (1-6C) alkylamino; formamyl; single (1-6C) alkyl-carbamoyl or two-[(1-6C) alkyl] formamyl; 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl; (1-4C) alkoxyl group; hydroxyl; amino; 3～7 yuan of heterocycles of single (1-6C) alkylamino or two [(1-6C) alkyl] amino or saturated or fractional saturation.

4. according to the compound of claim 1, be formula IB:

Wherein:

R ¹, R ², R ^3b, R ^4b, A, R ⁵, L, B, n and m as defined in claim 1,

R ⁶Be selected from halogen, cyano group, oxo, (3-7C) cycloalkyl ring, saturated or fractional saturation 3～7 yuan of heterocycles ,-S (O) _p(1-6C) alkyl wherein p be 0,1 or 2 ,-N (R ^c) C (O) (1-6C) alkyl, wherein R ^cBe hydrogen or (1-6C) alkyl; Perhaps

And salt or solvate.

5. according to the compound of claim 4, R wherein ^3bBe selected from hydrogen; (1-6C) alkyl or (1-6C) alkoxyl group; wherein (1-6C) alkyl is independently selected from following group replacement with (1-6C) alkoxyl group is optional by one or more: fluorine; hydroxyl; (1-6C) alkyl; (1-6C) alkoxyl group; amino; single (1-6C) alkylamino or two [(1-6C) alkyl] amino; formamyl; single (1-6C) alkyl-carbamoyl or two [(1-6C) alkyl] formamyl; 3～7 yuan of heterocycles or 5 or 6 yuan of heteroaryl rings of saturated or fractional saturation, wherein said heterocycle and heteroaryl ring are optional to be replaced by one or more following group independently: (1-4C) alkyl; (1-4C) alkoxyl group; hydroxyl; amino; 3～7 yuan of heterocycles of single (1-6C) alkylamino or two [(1-6C) alkyl] amino or saturated or fractional saturation.

6. according to the compound of claim 4, its Chinese style IB compound is a formula IB ' compound:

Wherein:

R ¹, R ², R ^4b, R ⁵, R ⁶, L, n, m, A and B as defined in claim 4 and

R ¹⁰And R ¹¹Be independently selected from hydrogen or (1-6C) alkyl;

And salt or solvate.

7. according to the compound of previous each claim, wherein L is group-N (R ⁸) C (O) N (R ⁹)-(CR ^aR ^b) _x-, wherein x is 1 or 2 and R wherein ^a, R ^b, R ⁸And R ⁹Be independently selected from hydrogen and (1-6C) alkyl.

8. according to the compound of claim 7, R wherein ^a, R ^b, R ⁸And R ⁹All be hydrogen.

9. according to the compound of previous each claim, wherein A is phenyl or pyridyl.

10. according to the compound of previous each claim, wherein B is a phenyl.

11. according to the compound of previous each claim, wherein n is 0 or 1.

12. according to the compound of previous each claim, wherein n is not 0, and R ⁵Be selected from (1-6C) alkyl and (1-6C) alkoxyl group.

13. according to the compound of previous each claim, wherein m is 1 or 2.

14. preparation is according to the method for compound or its pharmacy acceptable salt of claim 1; This method comprises

Method (a)Make formula II compound:

R wherein ^x, R ^y, R ^z, R ⁵, R ⁸, n and A as defined in claim 1, but in case of necessity any functional group is protected and the isocyanate reaction of formula IV:

Wherein Z, R ⁶, R ^a, R ^b, x, y, m and B as defined in claim 1, but in case of necessity any functional group is protected;

Perhaps

Wherein Ar is aryl and Z, R ⁶, R ^a, R ^b, x, y, m and B as defined in claim 1, but in case of necessity any functional group is protected;

Perhaps

R wherein ^x, R ^y, R ^z, R ⁵, R ⁸, R ⁹, R ^a, R ^b, x, n and A as defined in claim 1, but in case of necessity any functional group is protected, with the reaction of formula XI compound,

Lg wherein ¹Be suitable replaceable group, and R ^a, R ^b, R ⁶, y, m and B as defined in claim 1, but in case of necessity any functional group is protected; Perhaps

Lg wherein ²Be suitable replaceable group, and R ^x, R ^y, R ^z, R ⁵, R ⁸, R ⁹, R ^a, R ^b, n, x and A as defined in claim 1, but in case of necessity any functional group is protected,

With the reaction of formula XV compound,

R wherein ^a, R ^b, R ⁶, y, m and B as defined in claim 1, but in case of necessity any functional group is protected;

Perhaps

R wherein ⁶, R ^a, R ^b, x, y, m and B as defined in claim 1, but in case of necessity any functional group is protected;

Perhaps

Method (f)Make formula XVI or XVIA compound:

Lg wherein ³Be suitable replaceable group, and R ^3a, R ^4a, R ^3b, R ^4b, R ⁵, R ⁶, n, m, A, B and L as defined in claim 1, but in case of necessity any functional group is protected, with formula HNR ¹R ²Amine reaction, R wherein ¹And R ²As defined in claim 1, still in case of necessity any functional group is protected;

Perhaps

Method (g)Make formula XVII compound:

Lg wherein ⁴Be suitable replaceable group, and R ⁵, R ⁶, n, m, A, B and L as defined in claim 1, but in case of necessity any functional group is protected and the alkyne reaction of formula XVIII:

R wherein ^x, R ^yAnd R ^zAs defined in claim 1, still in case of necessity any functional group is protected;

Perhaps

Method (h)Make the compound of formula XVIIa:

R wherein ⁵, R ⁶, n, m, A, B and L as defined in claim 1, but in case of necessity any functional group is protected and the pyrimidine reaction of formula XVIIIa:

Lg wherein ⁵Be suitable replaceable group, and R ^x, R ^yAnd R ^zAs defined in claim 1, still in case of necessity any functional group is protected;

Perhaps

Method (i)For L wherein be-N (H) C (O) N (R ⁹)-(CR ^aR ^b) _x-Z-(CR ^aR ^b) _y-formula I compound, make the isocyanic ester of formula XIX:

R wherein ^x, R ^y, R ^z, R ⁵, n and A as defined in claim 1, but in case of necessity any functional group is protected, with the amine reaction of formula XV;

R wherein ⁹, R ^a, R ^b, Z, R ⁶, B, x, y and m as defined in claim 1;

Perhaps

Method (i)For L wherein be-N (H) C (O) N (R ⁹)-formula I compound, make the compound of formula XX:

Wherein Ar is an aryl, and R ^x, R ^y, R ^z, R ⁵, n and A as defined in claim 1, but in case of necessity any functional group is protected, with the amine reaction of formula XV as defined above,

After this if necessary:

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

Ii) remove any protecting group;

Iii) form salt.

15. a pharmaceutical composition, comprise with pharmaceutically acceptable thinner or carrier coupling according to each compound or its pharmacy acceptable salt of claim 1～13.

16. according to each compound or its pharmacy acceptable salt of claim 1～13, as medicine.

17. according to claim 1～13 each compound or its pharmacy acceptable salt in being manufactured on warm-blooded animal, be used as the Tie2 receptor tyrosine kinase inhibitors medicine in purposes.

18. be used for producing purposes in the medicine of anti-angiogenic formation effect in manufacturing warm-blooded animal according to each compound or its pharmacy acceptable salt of claim 1～13.

19. be used for purposes in the medicine of warm-blooded animal treatment cancer in manufacturing according to each compound or its pharmacy acceptable salt of claim 1～13.

20. suppress the method for Tie2 receptor tyrosine kinase among the warm-blooded animal in the described treatment of needs, for example people, comprise the described animal effective dose of administration according to each compound or its pharmacy acceptable salt of claim 1～13.

21. method that in the warm blooded animal of the described treatment of needs, produces anti-angiogenic formation effect, comprise the described animal effective dose of administration according to each compound or its pharmacy acceptable salt of claim 1～13, wherein said warm-blooded animal is such as the mankind.

22. in the warm-blooded animal of the described treatment of needs, treat method for cancer for one kind, comprise the described animal effective dose of administration according to each compound or its pharmacy acceptable salt of claim 1～13.

23. formula (II) compound,

R wherein ^x, R ^y, R ^z, R ⁵, R ⁸, n and A as defined in claim 1, but any functional group is optional protected.

24. formula XIV compound,

Lg wherein ²Be suitable replaceable group, and R ^x, R ^y, R ^z, R ⁵, R ⁸, R ⁹, R ^a, R ^b, n, x and A as defined in claim 1, but any functional group is optional protected.

25. formula XVI or XVIA compound:

Lg wherein ³Be suitable replaceable group, and R ^3a, R ^4a, R ^3b, R ^4b, R ⁵, R ⁶, n, m, A, B and L as defined in claim 1, but any functional group is optional protected.

26. formula XIX compound

R wherein ^x, R ^y, R ^z, R ⁵, n and A as defined in claim 1, but any functional group is optional protected.

27. formula XX compound

Wherein Ar is an aryl, and R ^x, R ^y, R ^z, R ⁵, n and A as defined in claim 1, but any functional group is optional protected.

28. formula VIc or VIc ' compound:

Lg wherein ³Be suitable replaceable group, and R ⁵, R ⁸, n and A as defined in claim 1, R ^3aAnd R ^4aAs defined in claim 2, and R ^3bAnd R ^4bAs defined in claim 4, still any functional group is optional protected.