CN1688579A

CN1688579A - Condensed pyridines and pyrimidines with TIE2 (TEK) activity

Info

Publication number: CN1688579A
Application number: CN 03823754
Authority: CN
Inventors: R·W·A·卢克; C·D·琼斯; W·麦库尔; B·R·海特
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2002-08-06
Filing date: 2003-08-01
Publication date: 2005-10-26
Also published as: ZA200500863B; GB0218168D0

Abstract

A compound of the Formula (I), wherein A together with the carbon atoms to which it is attached forms a fused 5-membered heteroaryl ring, wherein said heteroaryl ring contains 1 or 2 heteroatoms selected from O, N and S, and wherein the 5-membered ring containing G is linked to the ring formed by A in the meta position to the bridgehead carbon marked # in Formula (I); G is selected from O, S and NR<5>; Z is selected from N and CR<6>; Q<1> is selected from optionally substituted aryl and heteroaryl, and the substituents R<1> to R<6> are as defined in the text for use in the production of an anti-angiogenic effect in a warm blooded animal such as man.

Description

Have active condensed pyridine of TIE2 (TEK) and pyrimidine

The present invention relates to acceptable salt on a kind of compound or its pharmacology, they have anti-angiogenesis activity, therefore can be used for treating in the method for animal or human's body with the disease of vasculogenesis.The invention still further relates to the described compound of preparation, comprise method, but also relate to the method for utilizing described compound in warm-blooded animal (for example people) body, to produce the medicine of blood vessel formation against function as the medicinal compositions of the compound of effective constituent.

Tie2 receptor tyrosine kinase (being also referred to as TEK) is mainly expressed in endotheliocyte and hematopoietic cell, they are vascularization and safeguard requisite (Jones, N.et al.NatureReviews Molecular Cell Biology.2001:2,257-67).

Vasculogenesis is a kind of primary process that produces neovascularity from existing vascular system.Vasculogenesis is that nearly all organ forms and the essential a kind of important and complicated biological procedures of physiological function.In general, vasculogenesis is essentially a progressive formation, and be subjected to local vascular and generate the factor and the control of blood vessel supressor equilibrated, such multistep process comprises that blood vessel sprouts, branch and endotheliocyte form tubule (comprise for example endotheliocyte (EC) activation, blood vessel suppress to remove, synthetic and discharge degrading enzyme, EC migration, EC hyperplasia, EC and organize structure and differentiation, mature blood vessel).

Normal blood vessels is created in many processes and plays an important role, and is under the strict control.The adult, the physiological vasculogenesis mainly is limited to wound healing and some female reproductive functions and embryo development procedure.In not optimum or pathologic vessels generated, the partial balancing's imbalance between angiogenesis factor and the blood vessel supressor caused improper and/or the textural anomaly vascularization.The disease that generates with pathologic vessels comprises diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi sarcoma and vascular tumor (Fan et al, 1995, Trends Pharmacology.Science.16:57-66; Folkman, 1995, Nature Medicine 1:27-31).In cancer, surpass 1-2mm ³Primary and growth needs vasculogenesis (Folkman, the J.New EnglandJournal of Medicine 1995 of secondary tumor; 33,1757-1763).

Disease progression relies on not in the disease of optimum vasculogenesis (for example cancer), and the retardance vasculogenesis can stop disease progression (Folkman, J.1995, Nature Medicine.1:27-31).Scientific and technical literature has been introduced many in the factor that plays decisive role aspect the regulation and control of vasculogenesis.Two kinds of main angiogenesis factors are vascular endothelial growth factor (VEGF) and angiogenesis hormone.These polypeptide factors and they acceptor (stride the film Tyrosylprotein kinase, be mainly the endothelial cell specific acceptor) separately interacts, through ligand-mediated conversion of signals inducing cell reaction.By inference, in normal blood vessels generation and pathologic vessels generation, VEGF and angiogenesis hormone are by all respects of the signal transduction coordinated regulation angiogenesis of its corresponding acceptor.

Receptor tyrosine kinase (RTK) is striden in the conduction of membrane biochemistry signal at cytolemma and is played an important role.The characteristic of these transmembrane molecules consists of the extracellular ligand that links together according to order in conjunction with territory, plasma membrane section, intracellular tyrosine kinases territory.Part and receptors bind costimulatory receptor tyrosine kinase activity cause the tyrosine residues phosphorylation on the molecule in acceptor and other cell.The cascade of tyrosine phosphorylation initiating signal produces different cell responses.Up to now, identify at least 19 kinds of different RTK subclass by the amino acid sequence homology definition.At present, a kind of member of subclass fms sample tyrosine kinase receptor (being Flt or Flt1) to be arranged, comprise acceptor (being KDR) (being also referred to as Flk-1) and the another kind of fms sample tyrosine kinase receptor that kinases inserts the territory be Flt4.Wherein two kinds of dependency RTK are that Flt and KDR combine (De Vries et al, 1992, Science 255:989-991 with the VEGF high-affinity; Terman et al, 1992, Biochem.Biophys.Res.Comm.1992,187:1579-1586).The receptors bind that VEGF and this two kinds of heterogenous cells are expressed is with cell protein tyrosine phosphorylation and calcium current quantitative changeization.

Identified second family receptors that is mainly endothelial cell specific recently, these receptor modulators blood vessels are removed and are suppressed and mature blood vessel.In normal blood vessels generation and pathologic vessels generation, Tie acceptor and part thereof are angiogenesis hormone and the effect of VEGF close cooperation.Transmembrane receptor Tie1 and Tie2 constitute participation and safeguard the endothelial cell specific tyrosine kinase receptor family that blood vessel is complete, and their participation angiogenics sprout and Revascula rization.Tie1 and Tie2 structurally have many identical characteristics (for example, the cell internal area of these two kinds of acceptors all comprises by the interval disconnected tyrosine kinase domain of kinases insertion), therefore constitute the RTK subfamily of a uniqueness.The whole sequence identity of amino acid levels is 44% between Tie1 and the Tie2 acceptor, and their cell internal area is 76% homology.It is the lethality phenotype (Puri, M.et al.1995EMBOJournal:14:5884-5891) of feature that targeted destruction Tie1 gene causes with profuse bleeding and the complete difference of capillary blood vessel.The transgenic rat of Tie2 defective the blood vessel rudiment occurs and builds defective again, shows the lethality phenotype (E9.5-10.5) (Sato, T.et al.1995Nature 370:70-74) that is caused by embryonic blood vessel system major defect in second trimester of pregnancy.

Up to now, also do not identify the part of Tie1, understand very few yet its signal transduction ability.Yet, it is believed that Tie1 (therefore might regulate and control the ability (Marron of Tie2 autophosphorylation by the signal transduction that the different dimerization with the Tie2 acceptor influences Tie2, M.et al.2000Journal of Biology Chemistry:275,39741-39746), nearest studies show that to chimeric Tie1 acceptor, Tie-1 can pass through PI 3 kinases/Akt signal transduction pathway and suppress apoptosis (Kontos, C.D., et al., 2002Molecular and Cell Biology:22,1704-1713).And identified many parts (being called angiogenesis hormone) of Tie2, wherein angiogenesis hormone-1 (Ang1) has been carried out abundant sign.Ang1 activates its signal transduction pathway through signal transduction then in conjunction with inducing Tie2 receptor tyrosine phosphorylation by autophosphorylation.It is reported, Ang2 in endotheliocyte, rise antagonistic action (Maisonpierre, P.et al.1997Science:277,55-60).The destruction of Tie2 and part thereof and transgeneic procedure show that the time of Tie2 signal transduction and spatiality control are necessary to the normal development of neovasculature.According to another report, other at least two kinds of parts (Ang3 and Ang4) also may produce different dimerization (it has the potential of the activity (excitement/antagonism) when improving with receptors bind) between these two kinds of angiogenesis hormone parts.Ang1 activates the Tie2 acceptor and suppresses apoptosis (Papapetropoulos, A., et al., 2000 Journal of Biology Chemistry:2759102-9105), promote vascular endothelial cell rudiment (Witzenbicher, B., et al., 1998Joumal BiologyChemistry:273,18514-18521), promote mature blood vessel and reduce ripe capillary blood vessel perviousness and seepage (Thurston subsequently during the vasculogenesis in vivo, G.et al., 2000Nature Medicine:6,460-463).Therefore, report that activated Tie2 acceptor participates in branch, rudiment and the maturation of neovascularity, keeping raising and interacting as and if promote that capillary blood vessel stability is consistent of very important periphery sustenticular cell on vascular integrity and the globality.Can not activate Tie2 or suppress the Tie2 autophosphorylation and can cause the disorderly and matrix/cell contact interruption (Brindle of blood vessel structure, N., in press, 2002), cause endotheliocyte then and die off, especially lacking under survival or the growth-stimulating factor situation.Based on the effect of the Tie2 kinase activity of above-mentioned report, suppress the Tie2 kinases and can produce blood vessel formation against function, therefore can be used for treating the disease that generates with pathologic vessels.The neovasculature that Tie2 is expressed in kinds of tumors has demonstrated to adjusted (Peters for example, K.G.et al, (BritishJournal of Cancer 1998; 77,51-56), show that suppressing the Tie2 kinase activity will produce blood vessel formation against function.What support this hypothesis is, soluble T ie2 acceptor (cell foreign lands) studies confirm that anti-tumor activity (Pengnian in the tumor model in vivo, L.et al., 1997, Journal of Clinical Investigation 1997:100,2072-2078 and Pengnian, L.et al., 1998, Proceedings of the National Academy ofSciences 1998:95,8829-8834).In addition, these experiments show that also the Tie2 signal transduction pathway of normal health individuality destroys and can tolerate fully, because do not find toxic side effect in these researchs.

To people's primary breast cancer sample and people and mouse mammary carcinoma cell line (Stratman, A., et al., 2001, International Journal of Cancer:91, studies show that 273-282), the Tie2 dependence approach of knurl vasculogenesis can rely on approach with KDR and exist simultaneously, in fact, can independently play a role (Siemeister G., et al. of these two kinds of approach, 1999 CancerResearch:59,3185-3191) also each other co-action (for example, report VEGF A and Angl unite and bring out vasculogenesis and produce the ripe blood vessel of non-seepage, Thurston, G, etal., 1999Science:286,2511-2514).Very possible such vasculogenesis combined process even be present in the tumour.

Also confirm Tie2 in the aberrant angiogenesis that is called venous malformation (VM), work (Mulliken, J.B.﹠amp; Young, A.E.1998, Vascular Birthmarks:W.B.Saunders, Philadelphia).This class defective can be genetic, also can be sporadic.VM is common in skin or mucous membrane, but also can influence any other organ.Typical cytopathic is the blood vessel group of spongy indigo plant to purple, and blood vessel group is the blood vessel of the liner endotheliocyte of a large amount of expansions.In heredity VM, modal defective is Tie2 kinase mutant C2545T (Calvert, the J.T. in the Tie2 encoding sequence, et al., 1999Human Molecular genetics:8,1279-1289), this sudden change produces the R849W aminoacid replacement in the kinases territory.To the analysis revealed of this Tie2 mutant, even lacking under the situation of part, its also by the composition activation (Vikkula, M., et al., 1996 Cell:87,1181-1190).

The rise that Tie2 expresses also sees the vascular synovial joint screen that the person joint connects, and it is consistent with the effect of bad neovascularization.

Such example further shows, suppresses the various illnesss that Tie2 phosphorylation and signal transduction subsequently thereof can be used for treating bad neovascularization.Up to now, the only known several Tie2 inhibitor in this area.Therefore need to identify other Tie2 inhibitor, utilize the treatment potentiality of its inhibition/adjusting Tie2 signal transduction pathway.

Common pending application WO 03/035065 discloses has active benzoglyoxaline of Tie2 and analogue.Common pending application WO 03/00194 discloses thienopyridine and Thienopyrimidine, and they are the inhibitor of KDR/VEGF and erbB family protein Tyrosylprotein kinase (for example EGFR, erbB2HER3 or HER4).Common pending application WO03/22852 discloses furo-and thieno-pyrimidine derivative, and they are as Tie2 and/or VEGFR2 inhibitor.WO 95/10513 and EP 716855 disclose thionaphthene and the related compound as estrogen agonist.WO 97/12615 discloses benzimidizole derivatives, and they are 15-lipoxidase inhibitors.WO 00/17202, WO 00/17203 and WO01/72751 disclose pyrrolopyrimidine, and they are inhibitor of serine/threonine and tyrosine kinase activity.WO 99/62908 and WO 00/75145 disclose thienopyridine and Thienopyrimidine, and they are cell adhesion inhibition anti-inflammatory compound.WO 00/59449 and WO01/49688 disclose purine derivative.EP 1162196 discloses benzoglyoxaline and relevant ring system with US 2003/0050320, and they have the anti-hepatitis c virus activity.JP2002/105081 discloses Thienopyrimidine and related compound, and they are the TNF alpha inhibitor.WO 00/59902 discloses the arylsulfonyl based compound, and they are the X factor inhibitors.US2002/0091116 and WO 01/19798 disclose the benzothienyl pyrazoles, and they are the X factor inhibitors.

We find that some compound has the inhibition activity to the Tie2 receptor tyrosine kinase, and therefore treatment is with the value of the disease of pathologic vessels generation, for example cancer, rheumatoid arthritis and other bad reactivity vasculogenesis disease.

First aspect the invention provides acceptable salt on following structural formula I compound or its pharmacology:

Structural formula I

Wherein:

The connected carbon atom of A constitutes together and condenses 5-unit hetero-aromatic ring, and wherein said hetero-aromatic ring comprises 1-2 heteroatoms that is selected from O, N and S,

And in structural formula I, the 5-unit ring that comprises G is connected with respect to position between # mark end of the bridge carbon with the ring that A forms;

G is selected from O, S and NR ⁵

Z is selected from N and CR ⁶

Q ¹Be selected from aryl and heteroaryl,

And Q wherein ¹Can choose wantonly by one or more identical or different substituting groups and replace, described substituting group be selected from halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) alkanesulfonyl amino, 3-(1-6C) alkyl urea groups, (1-6C) alkoxycarbonyl amino of alkyl-(1-6C) is selected from the group of following formula:

-X ¹-R ⁷

X wherein ¹Be a chemical bond or be selected from O and N (R ⁸), R wherein ⁸Be hydrogen or (1-6C) alkyl, and R ⁷For alkyl or two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl

And described substituting group is selected from the group of following formula:

-X ²-Q ²

X wherein ²Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ⁹), CO, CH (OR ⁹), CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-6C) alkyl, and Q ²Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ²Optional have a 1-3 identical or different substituting group, described substituting group be selected from trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl is amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C), perhaps described substituting group is selected from the group of following formula:

-X ³-R ¹⁰

X wherein ³Be a chemical bond or be selected from O and N (R ¹¹), R wherein ¹¹Be hydrogen or (1-6C) alkyl, and R ¹⁰For alkyl or two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl

And Q ²In any heterocyclic radical optional have 1-2 oxo or a sulfo-substituting group;

R ¹Be selected from hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, sulfydryl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C),

R ²Be selected from hydrogen, amino, hydroxyl, halogen, (1-6C) alkyl, (1-6C) alkoxyl group, formyl radical, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

R ³Independent is R ⁴And R ⁶Group in the definition, precondition are R ³Be not hydrogen, and work as R ³When nitrogen-atoms among the A is connected, R then ³It is not halogen;

R ⁵Independent is R ⁴And R ⁶Group in the definition, precondition are R ⁵It is not halogen;

R ⁴And R ⁶Can be identical or different and be selected from hydrogen; halogen; trifluoromethyl; trifluoromethoxy; cyano group; isocyano-; nitro; hydroxyl; sulfydryl; amino; formyl radical; carboxyl; formamyl; sulfamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) perhaps is selected from the group of following formula:

Q ⁴-X ⁵-

X wherein ⁵Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹²), CO, CH (OR ¹²), CON (R ¹²), N (R ¹²) CO, SO ₂N ( ¹²), N (R ¹²) SO ₂, OC (R ¹²) ₂, SC (R ¹²) ₂And N (R ¹²) C (R ¹²) ₂, R wherein ¹²Be hydrogen or (1-6C) alkyl, and Q ⁴Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-11C) cycloalkyl, (3-11C) cycloalkyl-(1-6C), (3-11C) cycloalkenyl group, (3-11C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, the optional insertion of the adjacent carbons on any (2-6C) alkylidene chain is selected from following group and is separated out: O, S, SO, SO ₂, N (R ¹³), CO, CH (OR ¹³), CON (R ¹³), N (R ¹³) CO, SO ₂N (R ¹³), N (R ¹³) SO ₂, CH=CH and C ≡ C, wherein R ¹³Be hydrogen or (1-6C) alkyl,

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any CH ₂=CH-or HC ≡ C-group are chosen wantonly in terminal CH ₂=or HC ≡ position have and be selected from following substituting group: halogen, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl, perhaps be selected from the group of following formula:

Q ⁵-X ⁶-

X wherein ⁶Be a chemical bond or be selected from CO and N (R ¹⁴) CO, wherein R ¹⁴Be hydrogen or (1-6C) alkyl, and Q ⁵Be the alkyl of the alkyl of aryl, aryl-(1-6C), (3-11C) cycloalkyl, heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any CH ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent or be selected from following substituting group on the group: oxo, hydroxyl, cyano group, amino, carboxyl, formamyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) alkanesulfonyl amino, (1-6C) alkoxycarbonyl amino, amino-sulfonyl amino, (1-6C) alkyl amino sulfonyl amino, two-[(1-6C) alkyl] amino-sulfonyl amino of alkyl-(1-6C),

Perhaps be selected from the group of following formula:

-X ⁷-Q ⁶

X wherein ⁷Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹⁵), CO, CH (OR ¹⁵), CON (R ¹⁵), N (R ¹⁵) CO, SO ₂N (R ¹⁵), N (R ¹⁵) SO ₂, C (R ¹⁵) ₂O, C (R ¹⁵) ₂S and N (R ¹⁵) C (R ¹⁵) ₂, R wherein ¹⁵Be hydrogen or (1-6C) alkyl, and Q ⁶Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-11C) cycloalkyl, (3-11C) cycloalkyl-(1-6C), (3-11C) cycloalkenyl group, (3-11C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any aryl; heteroaryl; heterocyclic radical; cycloalkyl or cycloalkenyl group be optional to have one or more and identical or different is selected from following substituting group: halogen; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) is selected from the group of following formula:

-X ⁸-R ¹⁶

X wherein ⁸Be a chemical bond or be selected from O and N (R ¹⁷), R wherein ¹⁷Be hydrogen or (1-6C) alkyl, and R ¹⁶For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl, (2-6C) alkanoyl amino-(1-6C) alkyl or (1-6C) alkoxycarbonyl amino-(1-6C) alkyl, and the group that is selected from following formula:

-X ⁹-Q ⁷

X wherein ⁹Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹⁸), CO, CH (OR ¹⁸), CON (R ¹⁸), N (R ¹⁸) CO, SO ₂N (R ¹⁸), N (R ¹⁸) SO ₂, C (R ¹⁸) ₂O, C (R ¹⁸) ₂S and N (R ¹⁸) C (R ¹⁸) ₂, R wherein ¹⁸Be hydrogen or (1-6C) alkyl, and Q ⁷Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-11C) cycloalkyl, (3-11C) cycloalkyl-(1-6C), (3-11C) cycloalkenyl group, (3-11C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ⁷Optional have 1-2 and identical or different be selected from following substituting group: halogen; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C),

Perhaps working as G is NR ⁵The time, R ⁴And R ⁵The atom that connects with their constitutes and condenses 5-or 6-unit's hetero-aromatic ring or heterocycle, and the wherein said 5-of condensing or 6-unit ring are optional has one or more R ⁴Substituting group in the definition,

And any formation like this condense that 5-or 6-unit heterocycle is optional to have 1-2 oxo or a sulfo-substituting group,

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any heterocyclic radical is chosen wantonly has 1-2 oxo or sulfo-substituting group;

M is 0,1 or 2, and each R wherein ³Group can be identical or different.

Second aspect the invention provides acceptable salt on following compound in structural formula I or its pharmacology:

Structural formula I

Wherein:

G is selected from O, S and NR ⁵

Z is selected from N and CR ⁶

Q ¹Be selected from aryl and heteroaryl,

And Q wherein ¹Optional replaced by one or more identical or different substituting groups, described substituting group be selected from halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) is selected from the group of following formula:

-X ¹-R ⁷

X wherein ¹Be a chemical bond or be selected from O and N (R ⁸), R wherein ⁸Be hydrogen or (1-6C) alkyl, and R ⁷Be alkyl or two-[(1-6C) alkyl] amino-(1-6C) alkyl, and the group that is selected from following formula of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C):

-X ²-Q ²

X wherein ²Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ⁹), CO, CH (OR ⁹), CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-6C) alkyl, and Q ²Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ²Optional have a 1-3 identical or different substituting group, described substituting group be selected from trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl is amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) perhaps is selected from the group of following formula:

-X ³-R ¹⁰

R ²Be selected from hydrogen, amino, hydroxyl, halogen, (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylamino and two-[(1-6C) alkyl] amino;

Q ⁴-X ⁵-

X wherein ⁵Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹²), CO, CH (OR ¹²), CON (R ¹²), N (R ¹²) CO, SO ₂N (R ¹²), N (R ¹²) SO ₂, OC (R ¹²) ₂, SC (R ¹²) ₂And N (R ¹²) C (R ¹²) ₂, R wherein ¹²Be hydrogen or (1-6C) alkyl, and Q ⁴Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, the adjacent carbons insertion on any (2-6C) alkylidene chain is selected from following group and is separated out: O, S, SO, SO ₂, N (R ¹³), CO, CH (OR ¹³), CON (R ¹³), N (R ¹³) CO, SO ₂N (R ¹³), N (R ¹³) SO ₂, CH=CH and C ≡ C, wherein R ¹³Be hydrogen or (1-6C) alkyl,

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any CH ₂=CH-or HC ≡ C-group are in terminal CH ₂=or HC ≡ position optional have be selected from following substituting group: halogen, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl, perhaps be selected from the group of following formula:

Q ⁵-X ⁶-

X wherein ⁶Be a chemical bond or be selected from CO and N (R ¹⁴) CO, wherein R ¹⁴Be hydrogen or (1-6C) alkyl, and Q ⁵Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C),

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any CH ₂Or CH ₃Group is at each described CH ₂Or CH ₃Optional on the group have one or more halogens or (1-6C) alkyl substituent or be selected from following substituting group: hydroxyl, cyano group, amino, carboxyl, formamyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C),

Perhaps be selected from the group of following formula:

-X ⁷-Q ⁶

X wherein ⁷Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹⁵), CO, CH (OR ¹⁵), CON (R ¹⁵), N (R ¹⁵) CO, SO ₂N (R ¹⁵), N (R ¹⁵) SO ₂, C (R ¹⁵) ₂O, C (R ¹⁵) ₂S and N (R ¹⁵) C (R ¹⁵) ₂, R wherein ¹⁵Be hydrogen or (1-6C) alkyl, and Q ⁶Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

-X ⁸-R ¹⁶

X wherein ⁸Be a chemical bond or be selected from O and N (R ¹⁷), R wherein ¹⁷Be hydrogen or (1-6C) alkyl, and R ¹⁶For alkyl, two-[(1-6C) alkyl] of the alkyl of the alkyl of the alkyl of the alkyl of the alkyl of halo-(1-6C), hydroxyl-(1-6C), (1-6C) alkoxyl group-(1-6C), cyano group-(1-6C), amino-(1-6C), (1-6C) alkylamino-(1-6C) amino-(1-6C) alkyl of alkyl, (2-6C) alkanoyl amino-(1-6C) or (1-6C) alkyl of alkoxycarbonyl amino-(1-6C)

And the group that is selected from following formula:

-X ⁹-Q ⁷

X wherein ⁹Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹⁸), CO, CH (OR ¹⁸), CON (R ¹⁸), N (R ¹⁸) CO, SO ₂N (R ¹⁸), N (R ¹⁸) SO ₂, C (R ¹⁸) ₂O, C (R ¹⁸) ₂S and N (R ¹⁸) C (R ¹⁸) ₂, R wherein ¹⁸Be hydrogen or (1-6C) alkyl, and Q ⁷Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ⁷Optional have 1-2 and identical or different be selected from following substituting group: halogen; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C),

Perhaps working as G is NR ⁵The time, R ⁴And R ⁵The atom that connects with their constitutes and condenses 5-or 6-unit's hetero-aromatic ring or heterocycle, and the wherein said 5-of condensing or 6-unit ring are optional has one or more and a R ⁴Define identical substituting group,

M is 0,1 or 2, and each R wherein ³Group can be identical or different.

In this manual, generic type term " alkyl " comprises straight chain and branched-chain alkyl, for example propyl group, sec.-propyl and the tertiary butyl.Yet when mentioning concrete alkyl (for example " propyl group "), only refer to specific straight chain type, when mentioning concrete branched-chain alkyl (for example " sec.-propyl "), only refer to specific branched chain type.Similar convention is applicable to other generic type term, and for example, (1-6C) alkoxyl group comprises methoxyl group, oxyethyl group, and (1-6C) alkylamino comprises methylamino and ethylamino, and two-[(1-6C) alkyl] amino comprise dimethylamino and diethylamino.

When some the structural formula I compound that should be known in above-mentioned definition can exist optically active form or racemize type because having one or more unsymmetrical carbons, comprise having above-mentioned active any such optically active form or racemize type in the present invention's definition.The optically active form compound is synthesized in available organic chemistry standard method well known in the art, and is for example, synthetic or by the resolution of racemic type with the optically-active raw material.Equally, the available standard laboratory method of hereinafter mentioning is estimated above-mentioned activity.

The proper group of above-mentioned generic group comprises following group.

As any one ' Q ' group (Q ¹-Q ⁷) when the aryl or the aryl in ' Q ' group, suitable aryl be for example phenyl or naphthyl, preferably phenyl.

As any one ' Q ' group (Q ⁴, Q ⁶Or Q ⁷) when (3-11C) cycloalkyl in ' Q ' group or (3-11C) cycloalkyl, suitable (3-11C) cycloalkyl is for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or dicyclo [2.2.1] heptyl; Any one ' Q ' group (Q ⁴, Q ⁶Or Q ⁷) when (3-11C) cycloalkenyl group or (3-11C) cycloalkenyl group in ' Q ' group, suitable (3-11C) cycloalkenyl group is for example cyclobutene base, cyclopentenyl, cyclohexenyl or cycloheptenyl.Should know that such cycloalkyl and cycloalkenyl group can be monocycle, dicyclo or three cyclic groups, and can be the bridge joint group and/or the group that is spirally connected.

Any one ' Q ' group (Q ¹, Q ²Or Q ⁴-Q ⁷) when the heteroaryl or the heteroaryl in ' Q ' group, their proper group is for example 5-or 6-unit's aromatic monocyclic or (except as otherwise noted) 9-or 10-unit aromatics dicyclo, it has 5 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most, (except as otherwise noted, otherwise) described heteroaryl can be that carbon connects or nitrogen connects.Preferred heteroaryl is 5-or 6-unit aromatic monocyclic, and it has 5 ring hetero atoms that are selected from oxygen, nitrogen and sulphur at the most, and (except as otherwise noted, otherwise) described ring hetero atom can be and connects carbon or nitrogen.Suitable hetero-aromatic ring comprises, for example furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, 1,3,5-three azatropylidene bases (1,3,5-triazenyl), benzofuryl, indyl, benzothienyl, benzoxazolyl, benzimidazolyl-, benzothiazolyl, indazolyl, benzo furazan base, quinolyl, isoquinolyl, quinazolyl, quinoxalinyl, cinnolines base or naphthyridinyl.Preferred furyl, pyrryl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazole base, thiadiazolyl group, triazolyl, tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl or 1,3,5-three azatropylidene bases.

The proper group that the connected carbon atom of A forms together condenses 5-unit hetero-aromatic ring comprises, for example furo, pyrrolo-, thieno-, oxazole also, imidazo or thiazole also.Be clear that, the ring that A forms condenses the formation fused 6 with the pyridine/pyrimidine ring among the structural formula I, and 5-dicyclo hetero-aromatic ring is, and for example [1,3] thiazole also [5,4-d] pyrimidyl, [1,3] oxazole is [5,4-d] pyrimidyl, 9H-purine radicals, 7H-purine radicals, furo [3 also, 2-d] pyrimidyl, furo [2,3-d] pyrimidyl, thieno-[3,2-d] pyrimidyl or thieno-[2,3-d] pyrimidyl.The fused rings that A forms is chosen wantonly has one or more R ³Substituting group, this substituting group can be positioned on ring carbon or the theheterocyclic nitrogen atom (precondition be described nitrogen not therefore by quaternized).

As any one ' Q ' group (Q ²-Q ⁷) when being heterocyclic radical or the heterocyclic radical in ' Q ' group, proper group is for for example non-aromatics is saturated or the 3-10 of fractional saturation unit's monocycle or the bridge joint and/or the dicyclo that is spirally connected, it has 5 heteroatomss that are selected from oxygen, nitrogen and sulphur at the most, (except as otherwise noted, otherwise) described heterocyclic radical can be the carbon connection or nitrogen connects, wherein the epithio atom is oxidable is the S-oxide compound.Preferred heterocyclic radical is saturated or fractional saturation 5 or 6 yuan of monocycles of non-aromatics, and it has 1-4 heteroatoms that is selected from oxygen, nitrogen and sulphur, (except as otherwise noted, otherwise) described heterocyclic radical can be the carbon connection or nitrogen connects, wherein the epithio atom is oxidable is the S-oxide compound.Suitable heterocyclic radical comprises for example Oxyranyle, oxetanyl, tetrahydrofuran base, THP trtrahydropyranyl, 2,3-dihydro-1, the 3-thiazolyl, 1, the 3-thiazolidyl, 1, the 3-oxazolidinyl, the oxepane alkyl, pyrrolinyl, pyrrolidyl, morpholinyl, thiomorpholine (perhydro-1, the 4-thiazinyl), (8-oxa--3-azabicyclo [3.2.1] octyl group), (7-oxa--3-azabicyclo [3.1.1] heptyl), perhydro azepines base, perhydro oxa-English in heptan 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, morpholino, 1,1-dioxo tetrahydrochysene-4H-1,4-thiazine-4-base, piperidino-(1-position only), piperidin-4-yl or piperazine-1-base.Proper group with 1-2 oxo or substituent this class 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.

When ' Q ' was the alkyl of heteroaryl-(1-6C), its proper group was, for example, and heteroaryl methyl, 2-heteroaryl ethyl and 3-heteroaryl propyl group.When ' Q ' group is the alkyl of non-heteroaryl-(1-6C), for example ' Q ' group is the alkyl of aryl-(the 1-6C) (alkyl of phenyl-(1-6C) for example, as benzyl or styroyl), during the alkyl of the alkyl of the alkyl of (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group-(1-6C) or heterocyclic radical-(1-6C), the present invention includes corresponding proper group.

For " Q " group that comprises at least 1 nitrogen-atoms, when G is NR ⁵And R ⁴And R ⁵The atom that connects with their constitutes when condensing 5-or 6-unit's heteroaryl or heterocyclic ring, proper group comprises for example above-mentioned 5-and 6-unit's hetero-aromatic ring and heterocyclic divalent derivative, for example thiazole also, isothiazole also, 1,3-thiazoles alkane also, tetramethyleneimine also, pyrroline Bing, oxazole and, isoxazole also, pyrazoline also, pyrido, Mi Dingbing or pyridazine also.Should be known in R equally ⁴And R ⁵The ring that comprises G among ring that forms and the structural formula I condenses and forms 5,5 or 5,6 twin nucleis, for instance, and R ⁴And R ⁵But with atom configuration example such as imidazo [2,1-b] [1,3] thiazolyl, 2 that they connect, the 3-glyoxalidine is [2,1-b] [1,3] thiazolyl condensed-bicyclic or imidazo [1,2-a] pyridyl condensed-bicyclic also.

Obscure for fear of any, this specification sheets does not comprise mark X ⁴Or Q ³Substituting group.

Any ' R ' group (R ¹-R ¹⁸) or R ¹-R ⁶Various groups of substituting group or Q ¹The proper group of various groups is :-

Halogens fluorine, chlorine, bromine and iodine;

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

(2-8C) alkenyl: vinyl, pseudoallyl, allyl group and but-2-ene base;

(2-8C) alkynyl group: ethynyl, 2-propynyl and fourth-2-alkynyl;

(1-6C) alkoxyl group: methoxyl group, oxyethyl group, propoxy-, isopropoxy and fourth

The oxygen base;

(2-6C) alkenyl oxy: vinyl oxygen base and allyl group oxygen base;

(2-6C) alkynyl group oxygen base: ethynyl oxygen base and 2-propynyl oxygen base;

(1-6C) alkylthio: methylthio group, ethylmercapto group and rosickyite base;

(1-6C) alkyl sulphinyl: methylsulfinyl and ethyl sulfinyl;

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

(1-6C) alkylamino: methylamino, ethylamino, propyl group amino, sec.-propyl

Amino and butyl amino;

Two-[(1-6C) alkyl] amino: dimethylamino, diethylamino, N-ethyl- N-methyl

Amino and diisopropylaminoethyl;

(1-6C) alkoxy carbonyl: methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and

Tert-butoxycarbonyl;

N-(1-6C) alkyl carbamoyl N-methylamino formyl radical, N-ethylamino formyl radical and

Base: N-propyl group formamyl;

N, N-two-[(1-6C) alkyl] ammonia N, N-formyl-dimethylamino, N-ethyl- N-methyl

The base formyl radical: formamyl and N, N-diethylamino formyl radical;

(2-6C) alkanoyl: ethanoyl and propionyl;

(2-6C) alkanoyloxy: acetoxyl group and propionyloxy;

(2-6C) alkanoyl amino: kharophen and propionamido;

N-(1-6C) chain of alkyl-(2-6C) N-methyl kharophen and N-methyl-prop amido;

Alkanoylamino:

N-(1-6C) alkyl sulphonamide N-methyl sulfamyl and N-ethyl sulfamyl;

Base:

N, N-two-[(1-6C) alkyl] ammonia N, N-dimethylamino alkylsulfonyl;

Alkylsulfonyl:

(1-6C) alkanesulfonyl ammonia methylsulfonyl amino and ethylsulfonylamino;

Base:

N-(1-6C) chain of alkyl-(1-6C) N-ethyl methylsulfonyl amino and N-methyl ethylsulfonyl ammonia

Alkane sulfuryl amino: base;

(3-6C) alkenoyl amino: acrylamido, methacryloyl amino and crotonoyl amino;

N-(1-6C) chain of alkyl-(3-6C) N-methacrylamido and N-tiglyl amino;

Enoyl-amino:

(3-6C) alkyne acyl amino: propiolyl amino;

N-(1-6C) chain of alkyl-(3-6C) N-methyl propine amido;

The alkynes acyl amino:

Amino-(1-6C) alkyl: amino methyl, 2-amino-ethyl, 1-amino-ethyl and 3-

Aminopropyl;

(1-6C) methylamino methyl, ethylamino methyl, the 1-methyl ammonia of alkylamino-(1-6C)

Alkyl: basic ethyl, 2-methylamino ethyl, 2-ethylamino second

Base and 3-ethylamino propyl group;

Two-[(1-6C) alkyl] amino-(1-dimethylaminomethyl, diethylamino methyl, 1-two

6C) alkyl: methylamino ethyl, 2-dimethyl aminoethyl and 3-two

The methylamino propyl group;

The alkyl of halo-(1-6C): chloromethyl, 2-chloroethyl, 1-chloroethyl and 3-chloropropyl;

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

(1-6C) the alkane methoxymethyl of alkoxyl group-(1-6C), ethoxyl methyl, 1-methoxy ethyl,

Base: 2-methoxy ethyl, 2-ethoxyethyl group and 3-methoxyl group

Propyl group;

The alkyl of cyano group-(1-6C): cyano methyl, 2-cyano ethyl, 1-cyano ethyl and 3-

The cyano group propyl group;

(1-6C) the alkane methylthiomethyl of alkylthio-(1-6C), ethylmercapto group methyl, 2-methylmercaptoethyl,

Base: 1-methylmercaptoethyl and 3-methylthio group propyl group;

(1-6C) alkyl sulphinyl-(1-methylsulfinyl methyl, ethyl sulfinyl methyl, 2-

6C) alkyl: methylsulfinyl ethyl, 1-methylsulfinyl ethyl

With 3-methylsulfinyl propyl group;

(1-6C) alkyl sulphonyl-(1-methylsulfonyl methyl, ethylsulfonyl methyl, 2-methylsulfonyl

6C) alkyl: basic ethyl, 1-methylsulfonyl ethyl and 3-methylsulfonyl third

Base;

(2-6C) alkanoyl amino-(1-acetylamino methyl, propionamido methyl and 2-acetyl ammonia

6C) alkyl: basic ethyl; With

(1-6C) alkoxycarbonyl amino-methoxycarbonyl amino methyl, the amino first of ethoxy carbonyl

(1-6C) alkyl: base, tert-butoxycarbonyl amino methyl and 2-methoxyl group carbonyl

The base amino-ethyl.

As R defined above ⁶Group forms structural formula Q ⁴-X ⁵-group, and X for example ⁵Be OC (R ¹²) ₂When connecting base, that be connected with pyridine ring is OC (R ¹²) ₂Connect the carbon atom of base but not Sauerstoffatom, Sauerstoffatom then with Q ⁴Group connects.Similarly, as for example R ³, R ⁴, R ⁵Or R ⁶CH in the substituting group ₃Has structural formula-X ⁷-Q ⁶Group, and X for example ⁷Be C (R ¹⁵) ₂When O connects base, with CH ₃That connect is C (R ¹⁵) ₂O connects the carbon atom of base but not Sauerstoffatom, Sauerstoffatom then with Q ⁶Group connects.

Definition as mentioned, R ³, R ⁴, R ⁵Or R ⁶The adjacent carbons of any in the substituting group (2-6C) alkylidene chain can be chosen wantonly and independently insert for example O, CON (R ¹³) or C ≡ C group.For example, the ethylidene chain with C ≡ C group insertion 2-morpholino oxyethyl group produce 4-morpholino fourth-2-alkynyloxy base, and for example CONH inserts ethylidene chain in the 3-methoxy propoxy, produces for example 2-(2-methoxyl group kharophen) oxyethyl group.

Definition as mentioned, R ³, R ⁴, R ⁵Or R ⁶Any CH in the substituting group ₂=CH-or HC ≡ C-group are in terminal CH ₂=or HC ≡ C-position is optional has a for example structural formula Q of substituting group ⁵-X ⁶-group, X wherein ⁶Be for example NHCO and Q ⁵Be heterocyclic radical-(1-6C) alkyl, the suitable R of Xing Chenging so ³, R ⁴, R ⁵Or R ⁶Substituting group comprises, for example, N-[heterocyclic radical-(1-6C) alkyl] formamyl vinyl as N-(2-tetramethyleneimine-1-base ethyl) formamyl vinyl or N-[heterocyclic radical-(1-6C) alkyl] formamyl ethynyl as N-(2-tetramethyleneimine-1-base ethyl) formamyl ethynyl.

R is worked as in definition as mentioned ³, R ⁴, R ⁵Or R ⁶Any CH in the substituting group ₂Or CH ₃Group is in each described CH ₂Or CH ₃Optional on the group have one or more halogens or (1-6C) during alkyl substituent, each described CH ₂Group is fit to have 1-2 halogen or (1-6C) alkyl substituent and each described CH ₃Group is fit to have 1-3 halogen or (1-6C) alkyl substituent.

Definition as mentioned, R ³, R ⁴, R ⁵Or R ⁶Any CH in the substituting group ₂Or CH ₃In each described CH ₂Or CH ₃Choose wantonly on the group and have substituting group defined above; so the suitable substituent that forms comprises; for example, the alkoxyl group (as 2-hydroxyl-3-piperidino-(1-position only) propoxy-and 2-hydroxyl-3-morpholino propoxy-) of the heterocyclic radical of hydroxyl-replacement-(1-6C); the alkoxyl group (as 3-amino-2-hydroxyl propoxy-) of the amino of hydroxyl-replacement-(2-6C); the alkoxyl group of (1-6C) alkylamino of hydroxyl-replacement-(2-6C) (as the amino propoxy-of 2-hydroxy-3-methyl); two of hydroxyl-replacement-[(1-6C) alkyl] be amino-(2-6C) alkoxyl group (as 3-dimethylamino-2-hydroxyl propoxy-); the alkylamino of the heterocyclic radical of hydroxyl-replacement-(1-6C) (amino and 2-hydroxyl-3-morpholino propyl group amino) as 2-hydroxyl-3-piperidino-(1-position only) propyl group; the alkylamino (as 3-amino-2-hydroxypropyl amino) of the amino of hydroxyl-replacement-(2-6C); the alkylamino (as 2-hydroxy-3-methyl amino propyl amino) of (1-6C) alkylamino of hydroxyl-replacement-(2-6C); two of hydroxyl-replacement-[(1-6C) alkyl] be amino-(2-6C) alkylamino (as 3-dimethylamino-2-hydroxypropyl amino); (1-6C) alkoxyl group (as the 2-hydroxyl-oxethyl) of hydroxyl-replacement; (1-6C) (1-6C) alkoxyl group of alkoxyl group-replacement (as 2-methoxy ethoxy and 3-oxyethyl group propoxy-); (1-6C) alkyl of (1-6C) alkylamino of (1-6C) alkoxyl group of alkyl sulphonyl-replacement (as 2-methylsulfonyl oxyethyl group) and heterocyclic radical-replacement-(1-6C) is (as 2-morpholino ethylamino methyl; 2-piperazine-1-base ethylamino methyl and 3-morpholino propyl group amino methyl).

Definition as mentioned, R ³, R ⁴, R ⁵Or R ⁶Any cycloalkyl or cycloalkenyl group are optional in the substituting group has one or more substituting groups defined above, and described substituting group can be present in the CH of any cycloalkyl or cycloalkenyl group ₂Or on the CH group.So the suitable substituent that forms comprises, for example, the alkyl (as 2-(1-hydroxyl hexamethylene-1-yl) ethyl, 2-(1-hydroxyl hexamethylene-4-yl) ethyl, 3-(1-hydroxyl hexamethylene-1-yl) propyl group or 3-(1-hydroxycyclopent-1-yl) propyl group) of (3-7C) cycloalkyl of hydroxyl-replacement (as 1-hydroxyl hexamethylene-1-base or 1-hydroxyl ring third-1-yl), (3-7C) cycloalkyl-(1-6C), the perhaps alkoxyl group (as 2-(1-hydroxyl hexamethylene-1-yl) oxyethyl group or 3-(1-hydroxyl hexamethylene-1-yl) propoxy-) of (3-7C) cycloalkyl-(1-6C).

Obscure for fear of any, should be known in as mentioned definition, when the ring that comprises G among the structural formula I is connected with respect to position between # mark end of the bridge carbon with the ring that A forms, a position be meant work as from the end of the bridge carbon of mark # along encircle A with counter-clockwise direction to carry R ¹The adjacent bridge carbon atom of carbon atom when moving, A forms second atom of ring.For instance, when the connected carbon atom of A constituted the thieno-ring together, the ring that comprises G was connected as follows with the thieno-loop section on the carbon atom of mark " 2 ":

Acceptable salt is the acid salt of structural formula I compound for example on the suitable pharmacology of structural formula I compound, for example with mineral acid or organic acid acid salt, described mineral acid or organic acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, trifluoracetic acid, citric acid or toxilic acid; The perhaps abundant salt of tart structural formula I compound for example, for example basic metal or alkaline earth salt, for example calcium or magnesium salts or ammonium salt, perhaps with the salt of organic bases, described organic bases such as methylamine, dimethylamine, Trimethylamine 99, piperidines, morpholine or three-(2-hydroxyethyl) amine.

Particularly, novel cpd of the present invention for example comprises, acceptable salt on structural formula I compound or its pharmacology, and (except as otherwise noted, otherwise) be R wherein ¹, R ², R ³, R ⁴, R ⁵, R ⁶, G, Z and Q ¹Have group defined above or any group (a)-(ggg) separately:

(a) A is selected from-CH=C ^*-O-,-O-C ^*=CH-,-CH=C ^*-S-,-S-C ^*=CH-,-CH=C ^*-NH-,-NH-C ^*=CH-,-N=C ^*-NH-,-NH-C ^*=N-,-O-C ^*=N-,-N=C ^*-O-,-S-C ^*=N-and-N=C ^*-S-, wherein ^*Represent that the ring that comprises G among this atom and the structural formula I forms key, and wherein A goes up at any available carbon or nitrogen-atoms (precondition is that this nitrogen is not therefore by quaternized) optional by R ³Replace, wherein R ³With above define identical;

(b) A is selected from-CH=C ^*-O-,-O-C ^*=CH-,-CH=C ^*-S-,-S-C ^*=CH-,-NH-C ^*=CH-,-N=C ^*-NH-,-NH-C ^*=N-,-O-C ^*=N-,-N=C ^*-O-,-S-C ^*=N-and-N=C ^*-S-, wherein ^*Represent that the ring that comprises G among this atom and the structural formula I forms key, and wherein A goes up at any available carbon or nitrogen-atoms (precondition is that this nitrogen is not therefore by quaternized) optional by R ³Replace, wherein R ³With above define identical;

(c) A is selected from-CH=C ^*-O-,-CH=C ^*-S-,-CH=C ^*-NH-,-N=C ^*-NH-,-N=C ^*-O-and-N=C ^*-S,

Wherein ^*The ring of representing to comprise among this atom and the structural formula I G forms key, and wherein A is optional by R on-NH-group ³Substituting group replaces, wherein R ³With above define identical;

(d) A is selected from-CH=C ^*-O-,-CH=C ^*-S-,-S-C ^*=CH-,-CH=C ^*-NH-,-N=C ^*-NH-,-N=C ^*-O-and-N=C ^*-S-,

Wherein ^*Represent that the ring that comprises G among this atom and the structural formula I forms key;

(e) A is selected from-CH=C ^*-S-,-S-C ^*=CH-,-N=C ^*-S-,-S-C ^*=N-,-CH=C ^*-O-,-O-C ^*=CH-,-NH-C ^*=N-and-N=C ^*-NH-,

Wherein ^*Represent that the ring that comprises G among this atom and the structural formula I forms key; And wherein A is optional by R on any CH or NH group ³Replace, wherein R ³With above define identical;

(f) A is selected from-CH=C ^*-S-,-S-C ^*=CH-,-N=C ^*-S-,-S-C ^*=N-,-CH=C ^*-O-,-O-C ^*=CH-,-NH-C ^*=N-and-N=C ^*-NH-

Wherein ^*Represent that the ring that comprises G among this atom and the structural formula I forms key, and wherein A is optional by R on the NH group ³Replace, wherein R ³With above define identical;

(g) A is selected from-CH=C ^*-S-,-N=C ^*-NH-and-N=C ^*-S-,

Wherein ^*Represent that the ring that comprises G among this atom and the structural formula I forms key; And wherein A is optional by R on any NH group ³Replace, wherein R ³With above define identical;

(h) A is selected from-CH=C ^*-O-and-O-C ^*=CH-,

(i) fused 6 that forms together of the connected pyridine/pyrimidine ring of A, 5-dicyclo heteroaromatic rings is the group of following structural formula:

R wherein ¹, R ²With Z with above define identical,

X is selected from CH and N,

Y is selected from O, S and NH,

And wherein any CH, NH group of X or Y representative are optional has and above defines identical R ³Substituting group;

(j) Z is N;

(k) Z is CR ⁶, R wherein ⁶With above define identical;

(l) R ¹Be selected from hydrogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, sulfydryl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino and N-(1-6C) alkyl-carbamoyl;

(m) R ¹Be selected from hydrogen, cyano group, hydroxyl, amino, sulfydryl, (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl and (1-6C) alkylamino;

(n) R ¹Be selected from hydrogen, hydroxyl, amino, sulfydryl, (1-3C) alkyl, (1-3C) alkoxyl group, (1-3C) alkylthio and (1-3C) alkylamino;

(o) R ¹Be selected from amino, sulfydryl, (1-3C) alkylthio and (1-3C) alkylamino;

(p) R ¹Be selected from hydrogen, amino, sulfydryl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, methylthio group, ethylmercapto group, methylamino-and ethylamino;

(q) R ¹Be selected from hydrogen, amino and methylamino-;

(r) R ¹Be hydrogen;

(s) R ¹Be amino;

(t) R ²Be selected from hydrogen, amino, hydroxyl, (1-3C) alkyl, (1-3C) alkoxyl group, (1-3C) alkylamino and two-[(1-3C) alkyl] amino;

(u) R ²Be selected from hydrogen and (1-3C) alkyl;

(v) R ²Be hydrogen;

(w) R ¹Be selected from hydrogen, hydroxyl, amino, sulfydryl, (1-3C) alkyl, (1-3C) alkoxyl group, (1-3C) alkylthio and (1-3C) alkylamino, and R ²Be selected from hydrogen and (1-3C) alkyl;

(x) R ¹Be selected from hydrogen, hydroxyl, amino, sulfydryl, (1-3C) alkyl, (1-3C) alkoxyl group, (1-3C) alkylthio and (1-3C) alkylamino, and R ²Be hydrogen;

(y) R ¹Be selected from hydrogen, sulfydryl, methylthio group, amino and methylamino, and R ²Be hydrogen;

(x) R ¹Be selected from amino, methylamino-and methylthio group and R ²Be hydrogen;

(y) G is NR ⁵

(z) G is selected from O and S;

(aa) Q ¹Be selected from phenyl, naphthyl and thienyl, it is optional to be replaced by 1-3 the identical or different following substituting group that is selected from: halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) the amino and group that is selected from following formula of the alkanesulfonyl of alkyl-(1-6C):

-X ²-Q ²

X wherein ²Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ⁹), CO, CH (OR ⁹), CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-6C) alkyl, and Q ²Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ²Optional have 1-3 and identical or different be selected from following substituting group: trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) alkyl-(1-6C) alkanesulfonyl amino, and Q ²In any heterocyclic radical optional have 1-2 oxo or a sulfo-substituting group;

(bb) Q ¹Be selected from phenyl and naphthyl, it is optional to be replaced by 1-3 the identical or different following substituting group that is selected from: halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) the amino and group that is selected from following formula of the alkanesulfonyl of alkyl-(1-6C):

-X ²-Q ²

X wherein ²Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ⁹), CO, CH (OR ⁹), CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-6C) alkyl, and Q ²Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C), Q ²Optional have 1-3 and identical or different be selected from following substituting group: trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C);

(cc) Q ¹Group for following formula:

-Q ^1a-X ²-Q ²

Q wherein ^1aBe selected from phenyl and naphthyl, it is optional to be replaced by 1-3 the identical or different following substituting group that is selected from: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-3C) alkyl, (2-3C) alkenyl, (2-3C) alkynyl group, (1-3C) alkoxyl group, (2-3C) alkenyl oxy, (2-3C) alkynyl group oxygen base, (1-3C) alkylthio, (1-3C) alkyl sulphinyl, (1-3C) alkyl sulphonyl, (1-3C) alkylamino, two-[(1-3C) alkyl] amino, (1-3C) alkoxy carbonyl, N-(1-3C) alkyl-carbamoyl, N, N-two-[(1-3C) alkyl] formamyls, (2-3C) alkanoyl, (2-3C) alkanoyloxy, (2-3C) alkanoyl amino, N-(1-3C) alkyl (2-3C) alkanoyl amino, N-(1-3C) alkylsulfamoyl group, N, N-two-[(1-3C) alkyl] sulfamyl, (1-3C) alkanesulfonyl amino and N-(1-3C) the alkanesulfonyl amino of alkyl-(1-3C), X ²Be a chemical bond or be selected from O, S, SO ₂, N (R ⁹), CO, CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-6C) alkyl, and Q ²Be the alkyl of the alkyl of the alkyl, isoxazolyl of the alkyl, oxazolyl of the alkyl of the alkyl of phenyl, phenyl-(1-6C), furyl, thienyl, oxazolyl, isoxazolyl, pyridyl, furyl-(1-6C), thienyl-(1-6C)-(1-6C)-(1-6C) or pyridyl-(1-6C), and Q wherein ²Optional have 1-3 and identical or different be selected from following substituting group: trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-3C) alkyl, (2-3C) alkenyl, (2-3C) alkynyl group, (1-3C) alkoxyl group, (1-3C) alkylthio, (1-3C) alkyl sulphinyl, (1-3C) alkyl sulphonyl, (1-3C) alkylamino, two-[(1-3C) alkyl] amino, (1-3C) alkoxy carbonyl, N-(1-3C) alkyl-carbamoyl, N, N-two-[(1-3C) alkyl] formamyls, (2-3C) alkanoyl, (2-3C) alkanoyloxy, (2-3C) alkanoyl amino, N-(1-3C) the alkanoyl amino of alkyl-(2-3C), N-(1-3C) alkylsulfamoyl group, N, N-two-[(1-3C) alkyl] sulfamyl, (1-3C) alkanesulfonyl amino and N-(1-3C) the alkanesulfonyl amino of alkyl-(1-3C);

(dd) Q ¹Group for following formula:

-Q ^1a-X ²-Q ²

Q wherein ^1aBe phenyl, it is optional to be replaced by 1-2 the identical or different following substituting group that is selected from: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-3C) alkyl, (1-3C) alkoxyl group, (1-3C) alkylamino, two-[(1-3C) alkyl] be amino, N-(1-3C) alkyl-carbamoyl, N, N-two-[(1-3C) alkyl] formamyls, N-(1-3C) alkylsulfamoyl group and N, N-two-[(1-3C) alkyl] sulfamyl, X ²Be a chemical bond or be selected from O, S, SO ₂, N (R ⁹), CO, CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-3C) alkyl, and Q ²Be the alkyl of phenyl, phenyl-(1-3C) alkyl, thienyl or thienyl-(1-3C), and Q wherein ²Optional have 1-3 and identical or different be selected from following substituting group: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-3C) alkyl, (1-3C) alkoxyl group, (1-3C) alkylamino, two-[(1-3C) alkyl] be amino, N-(1-3C) alkyl-carbamoyl, N, N-two-[(1-3C) alkyl] formamyls, N-(1-3C) alkylsulfamoyl group and N, N-two-[(1-3C) alkyl] sulfamyl;

(ee) Q ¹Be selected from phenyl and naphthyl, it is optional to be replaced by 1-3 the identical or different following substituting group that is selected from: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-3C) alkyl, (2-3C) alkenyl, (2-3C) alkynyl group, (1-3C) alkoxyl group, (2-3C) alkenyl oxy, (2-3C) alkynyl group oxygen base, (1-3C) alkylthio, (1-3C) alkyl sulphinyl, (1-3C) alkyl sulphonyl, (1-3C) alkylamino, two-[(1-3C) alkyl] amino, (1-3C) alkoxy carbonyl, N-(1-3C) alkyl-carbamoyl, N, N-two-[(1-3C) alkyl] formamyls, (2-3C) alkanoyl, (2-3C) alkanoyloxy, (2-3C) alkanoyl amino, N-(1-3C) the alkanoyl amino of alkyl-(2-3C), N-(1-3C) alkylsulfamoyl group, N, N-two-[(1-3C) alkyl] sulfamyl, (1-3C) alkanesulfonyl amino and N-(1-3C) the alkanesulfonyl amino of alkyl-(1-3C);

(ff) Q ¹Be selected from phenyl and naphthyl, it is chosen wantonly by 1-3 and is selected from following substituting group replacement: fluorine, chlorine, bromine, methyl, ethyl, methoxyl group and oxyethyl group;

(gg) Q ¹Be selected from 4-fluorophenyl, 2-fluorophenyl, 2,4 difluorobenzene base, 4-p-methoxy-phenyl, 3-p-methoxy-phenyl, 2-naphthyl and 6-methoxyl group-2-naphthyl;

(hh) Q ¹Be phenyl;

(ii) m is 0 or 1, and R ⁵With any R that is connected with A ring nitrogen ³Substituting group can be identical or different and also be selected from trifluoromethyl, hydroxyl, sulfydryl, formyl radical, formamyl, sulfamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkyl sulphonyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl or be selected from the group of following formula:

Q ⁴-X ⁵-

X wherein ⁵Be a chemical bond or be selected from SO ₂, N (R ¹²), CO, CH (OR ¹²), CON (R ¹²), N (R ¹²) CO, N (R ¹²) SO ₂, OC (R ¹²) ₂, SC (R ¹²) ₂And N (R ¹²) C (R ¹²) ₂, R wherein ¹²Be hydrogen or (1-6C) alkyl, and Q ⁴Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And R ³, R ⁴, R ⁵Or R ⁶The optional insertion of the adjacent carbons of any in the substituting group (2-6C) alkylidene chain is selected from following group chain and is separated out: O, S, SO, SO ₂, N (R ¹³), CO, CH (OR ¹³), CON (R ¹³), N (R ¹³) CO, SO ₂N (R ¹³), N (R ¹³) SO ₂, CH=CH and C ≡ C, wherein R ¹³Be hydrogen or (1-6C) alkyl,

And R ³Or R ⁵Any CH in the substituting group ₂=CH-or HC ≡ C-group are in terminal CH ₂=or HC ≡ position optional have be selected from following substituting group: halogen, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl, two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl and the group that is selected from following formula:

Q ⁵-X ⁶-

And R ³Or R ⁵Any CH in the substituting group ₂Or CH ₃Group is at each described CH ₂Or CH ₃Optional on the group have one or more halogens or (1-6C) alkyl substituent or be selected from following substituting group: hydroxyl, cyano group, amino, carboxyl, formamyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) group of the alkanesulfonyl amino of alkyl-(1-6C) and following formula:

-X ⁷-Q ⁶

And R ³Or R ⁵Any aryl in the substituting group; heteroaryl; heterocyclic radical; cycloalkyl or cycloalkenyl group be optional to have one or more and identical or different is selected from following substituting group: halogen; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) is selected from the group of following formula:

-X ⁸-R ¹⁶

And the group that is selected from following formula:

-X ⁹-Q ⁷

X wherein ⁹Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹⁸), CO, CH (OR ¹⁸), CON (R ¹⁸), N (R ¹⁸) CO, SO ₂N (R ¹⁸), N (R ¹⁸) SO ₂, C (R ¹⁸) ₂O, C (R ¹⁸) ₂S and N (R ¹⁸) C (R ¹⁸) ₂, R wherein ¹⁸Be hydrogen or (1-6C) alkyl, and Q ⁷Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-7C) cycloalkyl, (3-7C) cycloalkyl-(1-6C), (3-7C) cycloalkenyl group, (3-7C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ⁷Optional have 1-2 and identical or different be selected from following substituting group: halogen; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyl oxygen base, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C),

And R wherein ⁵Also can be hydrogen;

(jj) m is 0 or 1, and R ³(when existing) is arranged in the ortho position of structural formula I with respect to the end of the bridge carbon of mark #;

(kk) m is 0 or 1, and R ³(when existing) be selected from cyano group, nitro, fluorine, chlorine, bromine, hydroxyl, sulfydryl, amino, formamyl, sulfamyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-, ethanoyl, propionyl, methylthio group, ethylmercapto group, methylsulfonyl, ethylsulfonyl, methylamino, ethylamino, two-methylamino, two-ethylamino, N-methylamino formyl radical, N, N-two-methylamino formyl radical, N-methyl sulfamyl, N, N-two-methyl sulfamyl, methylsulfonyl amino and N-methyl-methylsulfonyl amino or be selected from the group of following formula:

Q ⁴-X ⁵-

X wherein ⁵Be a chemical bond or be selected from O, S, SO ₂, NH, N (methyl), CO, CONH, NHCO, SO ₂NH, NHSO ₂, OCH ₂, SCH ₂And NHCH ₂, Q ⁴Be phenyl, benzyl, the 2-phenylethyl, cyclopropyl, cyclopentyl, cyclohexyl, the cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl, 2-(cyclopropyl) ethyl, 2-(cyclopentyl) ethyl, 2-(cyclohexyl) ethyl, pyrrolinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, the pyrrolinyl methyl, the pyrrolidyl methyl, piperidino methyl, the piperazinyl methyl, the morpholinyl methyl, tetrahydrochysene-1,4-thiazinyl methyl, 2-pyrrolinyl ethyl, 2-pyrrolidyl ethyl, 2-piperidyl ethyl, 2-piperazinyl ethyl, 2-morpholinyl ethyl, 2-tetrahydrochysene-1,4-thiazinyl ethyl, 3-pyrrolinyl propyl group, 3-pyrrolidyl propyl group, 3-piperidyl propyl group, 3-piperazinyl propyl group, morpholinyl propyl group or 3-tetrahydrochysene-1,4-thiazinyl propyl group

And R ³Any CH in the substituting group ₂Or CH ₃Group is in each described CH ₂Or CH ₃Optional on the group have one or more fluorine, chlorine, methyl or ethyl substituting group or be selected from following substituting group: hydroxyl, cyano group, amino, methylamino, two-methylamino, ethanoyl, acetoxyl group, methylsulfonyl,

And R ³Substituent any heterocyclic radical or cycloalkyl be optional to be had one or more and identical or different is selected from following substituting group: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, methyl, ethyl, methoxyl group, methylamino and two-methylamino

And R ³Substituent any heterocyclic radical is optional to have 1-2 oxo substituting group, and precondition is to work as R ³When being present on the nitrogen-atoms of A, R then ³Be not fluorine, chlorine or bromine;

(ll) m is 0 or 1, and R ³(when existing) be connected with the carbon atom of A and be selected from halogen, cyano group, hydroxyl, nitro, amino, formamyl, (1-4C) alkyl, (1-4C) alkoxyl group, (2-4C) alkanoyl, (2-4C) alkanoyloxy, (1-4C) alkoxy carbonyl, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, N-(1-4C) alkyl-carbamoyl and N, N-two-[(1-4C) alkyl] formamyls;

(mm) m is 0 or 1, and R ³(when existing) be connected with the carbon atom of A and be selected from fluorine, chlorine, bromine, cyano group, nitro, hydroxyl, amino, formamyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-, methylamino, ethylamino, two-methylamino, two-ethylamino, N-methylamino formyl radical and N, N-two-methylamino formyl radical;

(nn) m is 0 or 1, and R ³(when existing) is connected with the nitrogen-atoms of A, precondition be the ring that forms of A not therefore by quaternized, and R wherein ³Be selected from hydroxyl, formamyl, (1-4C) alkyl, (1-4C) alkyl sulphonyl, (1-4C) alkoxy carbonyl, N-(1-4C) alkyl-carbamoyl, N, N-two-[(1-4C) alkyl] formamyls and (2-4C) alkanoyl;

(oo) m is 0 or 1, and R ³(when existing) is connected with the nitrogen-atoms of A, precondition be the ring that forms of A not therefore by quaternized, and R wherein ³Be selected from hydroxyl, formamyl, methyl, ethyl, propyl group, sec.-propyl, ethanoyl, propionyl, methoxycarbonyl, ethoxy carbonyl, methylsulfonyl, N-methylamino formyl radical and N, N-two-methylamino formyl radical;

(pp) m is 0 or 1, and R ³(when existing) is (1-6C) alkyl;

(qq) m is 0,1 or 2, and R ³Can be identical or different (1-4C) alkyl;

(rr) R ⁵Be selected from trifluoromethyl, hydroxyl, formyl radical, formamyl, sulfamyl, (1-6C) alkyl, (2-6C) alkenyl, (2-6C) alkynyl group, (1-6C) alkyl sulphonyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, N-(1-6C) alkylsulfamoyl group and N, N-two-[(1-6C) alkyl] sulfamyl;

(ss) R ⁵Be selected from hydrogen, hydroxyl, formamyl, sulfamyl, methyl, ethyl, propyl group, sec.-propyl, methoxyl group, oxyethyl group, propoxy-, ethanoyl, propionyl, methoxycarbonyl, methylsulfonyl, ethylsulfonyl, N-methylamino formyl radical, N, N-two-methylamino formyl radical, N-methyl sulfamyl, N, N-two-methyl sulfamyl or be selected from the group of following formula:

Q ⁴-X ⁵-

X wherein ⁵Be a chemical bond or be selected from O, S, SO ₂, NH, N (methyl), CO, CONH, NHCO, SO ₂NH, NHSO ₂, OCH ₂, SCH ₂And NHCH ₂, Q ⁴Be phenyl, benzyl, the 2-phenylethyl, cyclopropyl, cyclopentyl, cyclohexyl, the cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl, 2-(cyclopropyl) ethyl, 2-(cyclopentyl) ethyl, 2-(cyclohexyl) ethyl, pyrrolinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydrochysene-1, the 4-thiazinyl, the pyrrolinyl methyl, the pyrrolidyl methyl, piperidino methyl, the piperazinyl methyl, the morpholinyl methyl, tetrahydrochysene-1,4-thiazinyl methyl, 2-pyrrolinyl ethyl, 2-pyrrolidyl ethyl, 2-piperidyl ethyl, 2-piperazinyl ethyl, 2-morpholinyl ethyl, 2-tetrahydrochysene-1,4-thiazinyl ethyl, 3-pyrrolinyl propyl group, 3-pyrrolidyl propyl group, 3-piperidyl propyl group, 3-piperazinyl propyl group, 3-3-morpholinyl propyl or 3-tetrahydrochysene-1,4-thiazinyl propyl group

And R ⁴Any CH in the substituting group ₂Or CH ₃Group is in each described CH ₂Or CH ₃Optional on the group have one or more fluorine, chlorine, methyl or ethyl substituting group or be selected from following substituting group: hydroxyl, cyano group, ethanoyl, amino, methylamino and two-methylamino,

And R ³Any heterocyclic radical in the substituting group or cycloalkyl be optional to be had one or more and identical or different is selected from following substituting group: fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, methyl, ethyl, methoxyl group, methylamino and two-methylamino

And R ³Any heterocyclic radical in the substituting group is chosen wantonly has 1-2 oxo substituting group;

(tt) R ⁵Be selected from hydrogen, hydroxyl, (1-6C) alkyl, phenyl and phenyl-(1-6C) alkyl, wherein R ⁵In phenyl optional have 1-3 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group;

(uu) R ⁵Be selected from hydroxyl, (1-6C) alkyl, phenyl and phenyl-(1-6C) alkyl, wherein R ⁵In phenyl optional have 1-3 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group;

(vv) R ⁵Be selected from methyl, ethyl, benzyl and 2-phenylethyl, wherein R ⁵In phenyl optional have a 1-3 substituting group that is selected from methyl, ethyl, methoxyl group and oxyethyl group;

(ww) R ⁴And R ⁶Can be identical or different and be selected from hydrogen, cyano group, nitro, hydroxyl, halogen, sulfydryl, amino, formamyl, sulfamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C);

(xx) R ⁴And R ⁶Can be identical or different and be selected from hydrogen, cyano group, nitro, hydroxyl, amino, formamyl, sulfamyl, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl group, (1-4C) alkoxyl group, (1-4C) alkylamino, two-[(1-4C) alkyl] amino, N-(1-4C) alkyl-carbamoyl and N, N-two-[(1-4C) alkyl] formamyls;

(yy) R ⁴Be selected from hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl group and (1-4C) alkoxyl group;

(zz) R ⁴Be hydrogen;

(aaa) R ⁶Be selected from hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl group and (1-4C) alkoxyl group;

(bbb) R ⁶Be hydrogen;

(ccc) R ²Be selected from hydrogen and (1-3C) alkyl;

M is 0,1 or 2, and R ³Be identical or different (1-4C) alkyl; And

R ⁴And R ⁶Can be identical or different and be selected from hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl group and (1-4C) alkoxyl group;

(ddd) R ²Be selected from hydrogen and (1-3C) alkyl;

M is 0 or 1, and R ³With above define identical;

R ⁵Be selected from hydrogen, hydroxyl and (1-4C) alkyl;

(eee) R ²Be selected from hydrogen and (1-3C) alkyl;

M is 0 or 1, and R ³Be (1-3C) alkyl;

R ⁴And R ⁶Can be identical or different and be selected from hydrogen, (1-4C) alkyl, (2-4C) alkenyl, (2-4C) alkynyl group and (1-4C) alkoxyl group; And

R ⁵Be selected from hydrogen, hydroxyl and (1-6C) alkyl;

(fff) m is 0; And

(ggg) R ⁵Be not hydrogen.

Should be known at above-mentioned (a)-(h) of this specification sheets and hereinafter, be close among the left atom in the A chain and the structural formula I and carry R ¹The bridge carbon atom of carbon connect, and the bridge carbon atom that is close to Z among the right side atom in the A chain and the structural formula I is connected.Therefore working as A is-N=C ^*During-S-, the connected pyridine/pyrimidyl of A constitutes the group of following structural formula together:

One embodiment of the invention provide acceptable salt on structural formula (I) compound or its pharmacology, wherein:

A is selected from-N=C ^*-O-,-O-C ^*=N-,-N=C ^*-S-,-S-C ^*=N-,-N=C ^*-NH-,-NH-C ^*=NH=,-CH=C ^*-S-,-S-C ^*=CH-,-O-C ^*=CH-,-CH=C ^*-O-,-CH=C ^*-NH-and-NH-C ^*=CH-,

Wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, and wherein A goes up optional by R at any available carbon or nitrogen-atoms (precondition is that this nitrogen is not therefore by quaternized) ³Replace;

G is NR ⁵

Z is N;

Q ¹Be the optional phenyl that is replaced by following substituting group: halogen, (1-4C) alkoxyl group, (1-4C) alkyl, trifluoromethyl or trifluoromethoxy (preferred fluorine, chlorine, bromine, methyl, methoxyl group or trifluoromethyl;

R ¹Be selected from hydrogen, amino, hydroxyl, (1-3C) alkoxyl group, sulfydryl, (1-3C) alkylthio and (1-3C) alkylamino;

R ²Be hydrogen;

R ³Be (1-6C) alkyl;

R ⁴Be selected from hydrogen and (1-6C) alkyl;

R ⁵Be selected from hydrogen, hydroxyl, (1-6C) alkyl, phenyl and phenyl (1-6C) alkyl, wherein R ⁵In phenyl optional have 1-3 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group; And m is 0 or 1.

Another embodiment of the invention provides acceptable salt on structural formula (I) compound or its pharmacology, wherein:

A is selected from-N=C ^*-S-,-S-C ^*=N-,-CH=C ^*-S-,-S-C ^*=CH-,-NH-C ^*=N-,-N=C ^*-NH-,-CH=C ^*-O-and-O-C ^*=CH-;

Wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, and wherein A is optional by R on any NH group ³Replace;

G is NR ⁵

Z is N;

Q ¹Be phenyl;

R ¹Be selected from amino and (1-3C) alkylthio;

R ²Be hydrogen;

R ³Be (1-4C) alkyl;

R ⁴Be selected from hydrogen and (1-3C) alkyl;

R ⁵Be selected from (1-3C) alkyl, phenyl and benzyl, wherein R ⁵In phenyl optional have 1-2 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group;

M is 0 or 1.

Another embodiment of the present invention provides structural formula (I) compound, and wherein: A is selected from-N=C ^*-S-or-CH=C ^*-S-, R ²Be H, Z is N, and m is 0, and G is NR ⁵And R ¹, R ⁴, R ⁵And Q ¹With aforementioned definition.

Another one embodiment of the present invention provides acceptable salt on structural formula (I) compound or its pharmacology, wherein:

A is-CH=C ^*-O-,

Wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, and wherein A is optional by R on any available carbon atom ³Replace;

G is NR ⁵

Z is N;

Q ¹Be phenyl;

R ¹Be selected from hydrogen, sulfydryl, amino and (1-3C) alkylthio;

R ²Be hydrogen;

R ⁴Be selected from hydrogen and (1-3C) alkyl;

R ⁵Be selected from hydrogen, (1-3C) alkyl, phenyl and benzyl, wherein R ⁵In phenyl optional have 1-2 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group; And m is 0.

Another embodiment of the present invention provides acceptable salt on structural formula (I) compound or its pharmacology, wherein:

A is selected from-N=C ^*-S-and-S-C ^*=N-

G is NR ⁵

Z is N;

Q ¹Be phenyl;

R ¹Be selected from hydrogen, sulfydryl, amino and (1-3C) alkylthio;

R ²Be hydrogen;

R ⁴Be selected from hydrogen and (1-3C) alkyl;

A is-N=C ^*-S-or-CH=C ^*-S-;

G is NR ⁵

Z is N;

R ¹Be selected from hydrogen, hydroxyl, sulfydryl, amino, (1-6C) alkylamino, two (1-6C) alkylamino, (1-6C) alkanoyl amino, aryl (1-6C) alkylamino, (1-6C) alkoxyl group or (1-6C) alkylthio;

R ²Be hydrogen;

M is 0;

R ⁴Be selected from hydrogen, halogen, amino, (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylthio, aryl, heteroaryl, heterocyclic radical, aryl carbonyl, the heteroaryl carbonyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl, heterocyclic radical (1-6C) alkyl, aryl (1-6C) alkylthio, heteroaryl (1-6C) alkylthio, (3-7C) cycloalkyl (1-6C) alkyl, (3-7C) cycloalkyl (1-6C) alkylthio, wherein each (1-6C) alkyl is optional is replaced by one or more following substituting groups: hydroxyl, (1-6C) alkoxyl group, (1-6C) alkylthio, amino, (1-6C) alkylamino, two (1-6C) alkylamino; Perhaps R ⁴Be optional (2-8C) alkynyl group that is replaced by following substituting group: amino, (1-6C) alkylamino, two (1-6C) alkylamino, hydroxyl, (1-6C) alkoxyl group, heteroaryl or (3-7C) cycloalkyl (wherein cycloalkyl is optional by one or more amino or hydroxyl replacement);

R ⁵Be selected from hydrogen; (1-6C) alkyl; (2-6C) alkenyl; (3-11C) cycloalkyl; (3-11C) cycloalkenyl group; (3-11C) cycloalkyl (1-6C) alkyl; phenyl (1-6C) alkyl; [6-(8-oxa--3-azabicyclo [3.2.1] oct-3-yl) hexyl]; (tetrahydrochysene-1; 1-titanium dioxide-3-thienyl) amino] ethyl; piperidyl; pyrrolidyl; morpholinyl; piperazinyl or tetrahydrochysene-2H-pyranyl; 2-(benzyloxycarbonyl group amino) ethyl; 2-[(2-chloropyridine-3-yl) oxygen ylmethyl carbonylamino] ethyl; 2-(N; N-dimethylamino sulfuryl amino) ethyl; (2-(2; 4-dichlorobenzene sulfonamido)-and phenyl) methyl; 2-(tert-butoxycarbonyl amino) ethyl; 4-(tert-butoxycarbonyl amino) butyl; 2-(2-propenyl amino) ethyl and 5-(morpholino carbonyl amino) penta-1-base, wherein R ⁵In phenyl optional have 1-2 and be selected from following substituting group: (1-3C) alkyl; (1-3C) alkoxyl group; halogen; trifluoromethyl; piperidyl; piperazinyl (optional) by the replacement of (1-4C) alkyl; pyridyl oxygen base; amino; (1-6C) alkylamino; two (1-6C) alkylamino or morpholinoes; and wherein any (1-6C) alkyl or (3-11C) cycloalkyl is optional is selected from following substituting group by one or more and replaces: hydroxyl; oxo; fluorine; amino; (1-6C) alkylamino; two (1-6C) alkylamino; phenylamino; methylsulfonyl; trifluoromethyl; the carboxyl methyl; (1-3C) alkoxyl group; (1-3C) alkylthio; pyridyl; pyrazolyl; imidazolyl; imidazo [1; 2-a] pyridyl; pyrrolidyl; morpholinyl; piperidyl; piperazinyl; 1; 3-benzo dioxine base; 1; 4-benzo dioxine base; (3; 4-dihydro-1H-2-benzopyranyl); 1; 4-dioxane base or tetrahydrofuran base, and R ⁵In any heterocycle optional replaced by one or more following substituting groups: (1-4C) alkyl, halogen, hydroxyl or phenyl;

Q ¹Be phenyl, naphthyl, benzothienyl, indyl, wherein Q ¹In any CH optional is replaced by the substituting group below one or more: halogen, hydroxyl, cyano group, choose (1-6C) alkyl, (1-6C) alkoxyl group, (1-3C) alkyl sulfonyl-amino, methylsulfonyl amino, benzyloxy, thiophenyl, the radicals R that are replaced by one or more fluorine wantonly ^tNHCONH-(R wherein ^tBe selected from phenyl, phenyl (1-6C) alkyl or (1-6C) alkyl) or radicals R ^s-O-CO-NH-(R wherein ^sBe selected from (1-6C) alkyl, phenyl or phenyl (1-6C) alkyl), wherein the phenyl ring of benzyloxy or thiophenyl is optional by one or more (1-6C) alkyl or (1-6C) alkoxyl group replacement.

Preferred A is-N=C ^*-S-.

More preferably A is-N=C ^*-S-, R ²Be H, Z is N, and m is 0, and G is NR ⁵, and R ¹, R ⁴, R ⁵And Q ¹With aforementioned definition.

Another embodiment of the present invention provides acceptable salt on structural formula (A) compound or its pharmacology, wherein:

R ⁵Be selected from hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl (1-6C) alkyl and phenyl (1-6C) alkyl, wherein R ⁵In phenyl optional have 1-2 substituting group that is selected from halogen, (1-3C) alkyl, (1-3C) alkoxyl group and morpholino, and R ⁵In any alkyl or cycloalkyl optional be selected from following substituting group by 1-2 and replace: hydroxyl, oxo, (1-3C) alkoxyl group, (1-3C) alkylthio, pyridyl, pyrrolidyl, morpholinyl, piperidyl, piperazinyl, tetrahydrochysene-2H-pyranyl, tetrahydrofuran base (it is optional by methyl substituted);

Q ¹Be phenyl or naphthyl, Q ¹Optional by one or more following substituting groups replacements: halogen, cyano group, (1-6C) alkoxyl group, (1-3C) alkyl sulfonyl-amino, (1-4C) alkyl-O-CO-NH-or benzyloxy or thiophenyl, wherein the phenyl ring of benzyloxy or thiophenyl is optional by one or more (1-6C) alkyl or (1-6C) alkoxyl group replacement.

Now provide substituent R ¹, R ⁴, R ⁵And Q ¹Concrete group.Should be known in any definition, claim or the embodiment of such group applicable to above or hereinafter definition.

In one embodiment, R ⁵Represent phenyl (1-6C) alkyl or heteroaryl (1-6C) alkyl, wherein said phenyl ring or hetero-aromatic ring are optional on carbon to be replaced by one or more following substituting groups: halogen, (1-3C) alkyl, (1-3C) alkoxyl group, heterocyclic radical (optional by one or more (1-3C) alkyl replacements), or group (CH ₂) _zNR ^jR ^k, wherein z is 0,1,2,3,4,5 or 6, and R ^jAnd R ^kIndependent be H or (1-4C) alkyl, and (1-4C) alkyl is optional by one or more (1-3C) alkoxyl groups replacements, perhaps R ⁵Representative (3-11C) cycloalkyl (1-6C) alkyl, wherein said cycloalkyl is optional to be replaced by one or more following substituting groups: halogen, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl, oxo, heterocyclic radical (optional by one or more (1-3C) alkyl replacements) or group (CH ₂) _zNR ^jR ^k, wherein z is 0,1,2,3,4,5 or 6, and R ^jAnd R ^kIndependent be H or (1-4C) alkyl, and (1-4C) alkyl is optional by one or more (1-3C) alkoxyl groups replacements.

In a further embodiment, R ⁵Represent phenyl (1-6C) alkyl, wherein said phenyl ring is optional to be replaced by one or more following substituting groups: halogen, (1-3C) alkyl, (1-3C) alkoxyl group, heterocyclic radical (optional by one or more (1-3C) alkyl replacements) or group (CH ₂) _zNR ^jR ^k, wherein z is 0,1,2,3,4,5 or 6, and R ^jAnd R ^kIndependent be H or (1-4C) alkyl, and (1-4C) alkyl is optional by one or more (1-3C) alkoxyl groups replacements.

R ¹Be selected from hydrogen, hydroxyl, sulfydryl, methoxyl group, amino, methylamino, diisopropylaminoethyl, acetylamino, benzylamino or methylthio group.

R ⁴Be selected from hydrogen, bromine, methoxyl group, amino, phenyl, the 4-pyridyl, the 3-thienyl, the rosickyite base, 2-methoxyl group ethylmercapto group, the 2-methoxy ethyl, ethyl, hydroxyl (2-thienyl) methyl, (2-thienyl) carbonyl, the 2-furyl carbonyl, hydroxyl (2-furyl) methyl, 5-methyl-isoxazole-3-base carbonyl, hydroxyl (5-methyl-isoxazole-3-yl) methyl, hydroxyl (1,3-dimethyl-1H-pyrazoles-5-yl) methyl, (1,3-dimethyl-1H-pyrazoles-5-yl) carbonyl, 2-(dimethylamino) ethylmercapto group, the 2-[(methylthio group) methyl] sulfenyl, (1H-imidazoles-1-yl) ethyl] sulfenyl, (pyridin-3-yl methyl) sulfenyl, the cyclopropyl methylthio group, the benzyl sulfenyl, 4-methylpiperazine-1-base, 2-(1-aminocyclohexyl) ethynyl, 3-hydroxyl fourth-1-alkynes-1-base, 2-(1-hydroxy-cyclohexyl) ethynyl, pyridine-2-ethyl-acetylene base, 3-amino-3-methyl fourth-1-alkynes-1-base, (3-methoxy propyl-1-alkynes-1-yl), morpholine-4-base, pyrimidine-5-base, 3-(dimethylamino) third-1-alkynes-1-base, 1 (2H)-(tert-butoxycarbonyl)-3,6-dihydropyridine-4-base, (1,2,3,6-tetrahydropyridine-4-yl), hydroxyl (phenyl) methyl, cyclopropyl (hydroxyl) methyl, (1,3-benzodioxole-4-yl) (hydroxyl) methyl, 1-hydroxy-3-methyl fourth-1-base or (1-methyl isophthalic acid H-imidazoles-2-yl) (hydroxyl) methyl.

R ⁵Be selected from hydrogen, methyl, ethyl, butyl, cyclohexyl methyl, 2-hydroxyethyl, 2-methoxy ethyl, 2-(hydroxymethyl) third-1-base, 4-oxo hexamethylene-1-ylmethyl, 4-hydroxyl hexamethylene-1-ylmethyl, 1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-ylmethyl, 2-(morpholine-4-yl) benzyl or (2-(morpholine-4-yl) cyclohexyl) methyl.

Q ¹Be phenyl.

On preferred structure formula A compound or its pharmacology in the acceptable salt:

R ¹Be selected from hydroxyl, amino, sulfydryl or (1-6C) alkoxyl group or (1-6C) alkylthio;

R ⁴Be selected from hydrogen, halogen, amino, (1-6C) alkyl, (1-6C) alkoxyl group, (1-6C) alkylthio, aryl, heteroaryl, aryl carbonyl, heteroaryl carbonyl, aryl (1-6C) alkyl, heteroaryl (1-6C) alkyl or heterocyclic radical (1-6C) alkyl, wherein each (1-6C) alkyl is optional by one or more following hydroxyls, (1-6C) alkoxyl group or (1-6C) alkylthio replacement;

R ⁵Be selected from hydrogen, (1-6C) alkyl, (2-6C) alkenyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl (1-6C) alkyl and phenyl (1-6C) alkyl, wherein R ⁵In phenyl optional have 1-2 substituting group that is selected from (1-3C) alkyl, (1-3C) alkoxyl group and morpholino, and wherein any (1-6C) alkyl or (3-7C) cycloalkyl is optional is selected from following substituting group by 1-2 and replaces: hydroxyl, oxo, (1-3C) alkoxyl group, (1-3C) alkylthio, pyridyl, pyrrolidyl, morpholinyl, piperidyl or piperazinyl or dioxine or tetrahydrofuran base (it is optional by methyl substituted);

Q ¹Be phenyl or naphthyl; it is optional by one or more following substituting groups replacements: halogen, cyano group, (1-6C) alkoxyl group, (1-3C) alkyl sulfonyl-amino, (1-4C) alkyl-O-CO-NH-or benzyloxy or thiophenyl, wherein the phenyl ring of benzyloxy or thiophenyl is optional by one or more (1-6C) alkyl or (1-6C) alkoxyl group replacement.

In the preferred construction formula A compound, R ⁵Be selected from hydrogen, (1-6C) alkyl (3-7C) cycloalkyl or (3-7C) cycloalkyl (1-6C) alkyl, wherein each CH ₂Optional by one or more hydroxyls, (1-6C) alkoxyl group or oxo replacement.

In the preferred construction formula A compound, Q ¹Be phenyl.

A is selected from-S-C ^*=CH-and-CH=C ^*-S-

G is NR ⁵

Z is N;

Q ¹Be phenyl;

R ¹Be selected from hydrogen, sulfydryl, amino and (1-3C) alkylthio;

R ²Be hydrogen;

R ⁴Be selected from hydrogen and (1-3C) alkyl;

R ⁵Be selected from hydrogen, (1-3C) alkyl, phenyl and benzyl, wherein R ⁵Phenyl optional have 1-2 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group; And m is 0.

Preferred A is selected from-CH=C ^*-S-.

More preferably A is-CH=C ^*-S-, R ²Be H, Z is N, and m is 0, and G is NR ⁵And R ¹, R ⁴, R ⁵And Q ¹With aforementioned definition.

Another embodiment of the present invention provides acceptable salt on structural formula (B) compound or its pharmacology, wherein:

R ¹Be selected from hydrogen, hydroxyl, amino, (1-6C) alkylamino, two (1-6C) alkylamino benzylamino, (1-6C) alkanoyl amino, (1-3C) alkylthio;

R ⁴Be hydrogen; And

R ⁵Be selected from hydrogen; (1-6C) alkyl; (2-6C) alkenyl; (3-11C) cycloalkyl; (3-11C) cycloalkenyl group; (3-11C) cycloalkyl (1-6C) alkyl; phenyl (1-6C) alkyl; [6-(8-oxa--3-azabicyclo [3.2.1] oct-3-yl) hexyl]; (tetrahydrochysene-1; 1-titanium dioxide-3-thienyl) amino] ethyl; piperidyl; pyrrolidyl; morpholinyl; piperazinyl or tetrahydrochysene-2H-pyranyl; 2-(benzyloxycarbonyl group amino) ethyl; 2-[(2-chloropyridine-3-yl) oxygen ylmethyl carbonylamino] ethyl; 2-(N; N-dimethylamino sulfuryl amino) ethyl; (2-(2; 4-dichlorobenzene sulfonamido)-and phenyl) methyl; 2-(tert-butoxycarbonyl amino) ethyl; 4-(tert-butoxycarbonyl amino) butyl; 2-(2-propenyl amino) ethyl and 5-(morpholino carbonyl amino) penta-1-base, wherein R ⁵Phenyl optional have 1-2 and be selected from following substituting group: (1-3C) alkyl; (1-3C) alkoxyl group; halogen; trifluoromethyl; piperidyl; piperazinyl (optional) by the replacement of (1-4C) alkyl; pyridyl oxygen base; amino; (1-6C) alkylamino; two (1-6C) alkylamino or morpholinoes; and wherein any (1-6C) alkyl or (3-11C) cycloalkyl is optional is selected from following substituting group by one or more and replaces: hydroxyl; oxo; fluorine; amino; (1-6C) alkylamino; two (1-6C) alkylamino; phenylamino; methylsulfonyl; trifluoromethyl; the carboxyl methyl; (1-3C) alkoxyl group; (1-3C) alkylthio; pyridyl; pyrazolyl; imidazolyl; imidazo [1; 2-a] pyridyl; pyrrolidyl; morpholinyl; piperidyl; piperazinyl; 1; 3-benzo dioxine base; 1; 4-benzo dioxine base; (3; 4-dihydro-1H-2-benzopyranyl); 1; 4-dioxane base or tetrahydrofuran base, and R wherein ⁵In any heterocycle optional be selected from following substituting group by one or more and replace: (1-4C) alkyl, halogen, hydroxyl or phenyl;

Q ¹Be phenyl, naphthyl, benzothienyl, indyl, wherein Q ¹In any CH optional by one or more halogens, hydroxyl, cyano group, optional (1-6C) alkyl, (1-6C) alkoxyl group, (1-3C) alkyl sulfonyl-amino, methylsulfonyl amino, benzyloxy, thiophenyl, the radicals R that is replaced by one or more fluorine ^tNHCONH-(R wherein ^tBe selected from phenyl, phenyl (1-6C) alkyl or (1-6C) alkyl) or radicals R ^s-O-CO-NH-(R wherein ^sBe selected from (1-6C) alkyl, phenyl or phenyl (1-6C) alkyl).

On structural formula B compound or its pharmacology in the particular compound of acceptable salt:

Q ¹Be the optional phenyl or naphthyl that is replaced by one or more following substituting groups: halogen, cyano group, (1-6C) alkoxyl group, (1-3C) alkyl sulfonyl-amino, (1-4C) alkyl-O-CO-NH-or benzyloxy or thiophenyl, wherein the phenyl ring in benzyloxy or the thiophenyl is optional by one or more (1-6C) alkyl or (1-6C) alkoxyl group replacement;

R ¹Be selected from amino, kharophen and (1-3C) alkylthio;

R ⁴Be hydrogen; And

R ⁵Be selected from (1-6C) alkyl, (2-6C) alkenyl, (3-7C) cycloalkyl, (3-7C) cycloalkyl (1-6C) alkyl and phenyl (1-6C) alkyl, wherein R ⁵In phenyl optional have 1-2 substituting group that is selected from (1-3C) alkyl, (1-3C) alkoxyl group and morpholino, and wherein any (1-6C) alkyl or (3-7C) cycloalkyl is optional is selected from following substituting group by 1-2 and replaces: hydroxyl, (1-3C) alkoxyl group, (1-3C) alkylthio, pyridyl, pyrrolidyl, morpholinyl, piperidyl or piperazinyl or dioxine or tetrahydrofuran base (it is optional by methyl substituted).

Now provide substituent R ¹, R ⁴, R ⁵And Q ¹Concrete group.Should know that such group is applicable to above or any definition, claim or the embodiment of hereinafter definition.

In one embodiment, R ⁵Represent phenyl (1-6C) alkyl or heteroaryl (1-6C) alkyl, wherein phenyl ring or hetero-aromatic ring are optional on carbon is selected from following substituting group replacement by one or more: halogen, (1-3C) alkyl, (1-3C) alkoxyl group, heterocyclic radical (optional by one or more (1-3C) alkyl replacements), or group (CH ₂) _zNR ^jR ^k, wherein z is 0,1,2,3,4,5 or 6, and R ^jAnd R ^kIndependent be H or (1-4C) alkyl, and (1-4C) alkyl is optional by one or more (1-3C) alkoxyl groups replacements, perhaps R ⁵Representative (3-11C) cycloalkyl (1-6C) alkyl, wherein cycloalkyl is optional is replaced by one or more following substituting groups: halogen, (1-3C) alkyl, (1-3C) alkoxyl group, hydroxyl, oxo, heterocyclic radical (optional by one or more (1-3C) alkyl replacements) or group (CH ₂) _zNR ^jR ^k, wherein z is 0,1,2,3,4,5 or 6, and R ^jAnd R ^kIndependent be H or (1-4C) alkyl, and (1-4C) alkyl is optional by one or more (1-3C) alkoxyl groups replacements.

In a further embodiment, R ⁵Represent phenyl (1-6C) alkyl, wherein phenyl ring is optional is replaced by one or more following substituting groups: halogen, (1-3C) alkyl, (1-3C) alkoxyl group, heterocyclic radical (optional by one or more (1-3C) alkyl replacements) or group (CH ₂) _zNR ^jR ^k, wherein z is 0,1,2,3,4,5 or 6, and R ^jAnd R ^kIndependent be H or (1-4C) alkyl, and (1-4C) alkyl is optional by one or more (1-3C) alkoxyl groups replacements.

R ¹Be selected from hydrogen, hydroxyl, amino, methylamino, acetylamino, benzylamino or methylthio group.

R ⁴Be hydrogen.

R ⁵Be selected from hydrogen; methyl; ethyl; the 1-methylethyl; the 1-methyl-propyl; 1; the 2-dimethyl propyl; butyl; isobutyl-; the 2-methyl butyl; 1; the 3-dimethylbutyl; the 2-hydroxyethyl; 2-hydroxyl-1-methylethyl; 2-hydroxyl third-1-base; 3-hydroxyl third-1-base; 2; 3-dihydroxyl-third-1-base; 3; 3; 3-three fluoro-2-hydroxyls third-1-base; the 1-hydroxyl oneself-the 2-base; 1-hydroxyl fourth-2-base; the 2-methoxy ethyl; 2-methoxyl group-1-methylethyl; 2; the 2-dimethoxy-ethyl; the 3-methoxy-propyl; 2-methoxyl group-2-methyl-propyl; the 2-fluoro ethyl; 2-(methylsulfonyl) ethyl; the amino butyl of 4-; 4-(diethylamino)-1-methyl butyl; 2-(phenyl amino) ethyl; 3-(dimethylamino)-2; the 2-dimethyl propyl; cyclopropyl; 4-hydroxyl hexamethylene-1-base; 2-hydroxyl hexamethylene-1-ylmethyl; cyclohexyl methyl; the suberyl methyl; spiral shell [dicyclo [2.2.1] hept-2-ene"-7; 1 '-cyclopropane]-the 5-ylmethyl; [(1S; 5S)-6; 6-dimethyl dicyclo [3.1.1] heptan-2-yl] methyl; 2-(carboxyl methyl) hexamethylene-1-ylmethyl; the 2-propenyl; 2-methyl-2-propenyl; 2-(2-propenyl amino) ethyl; (3-methyl but-2-ene-1-yl); benzyl; 3; the 4-dimethoxy-benzyl; (2-fluorophenyl) methyl; (2-aminomethyl phenyl) methyl; (3-fluorophenyl) methyl; phenyl methyl; (2-p-methoxy-phenyl) methyl; [[2-(piperidino) phenyl] methyl]; [[2-(2-pyridyl oxygen base) phenyl] methyl]; 2-(morpholine-4-yl) benzyl; [2-(4-methyl isophthalic acid-piperazinyl) phenyl] methyl; (2-aminophenyl) methyl; 2-hydroxyl-2-(4-trifluoromethyl) ethyl; the pyridin-3-yl methyl; (1H-imidazoles-2-ylmethyl); (imidazo [1; 2-a] pyridine-2-ylmethyl); 2-(methylpiperazine-1-yl) ethyl; 3-(4-methyl isophthalic acid-piperazinyl) propyl group; 3-(hexahydro-1 H-azepines-1-yl) propyl group; (tetrahydrochysene-2-furyl) methyl; 2-(4-morpholinyl) ethyl; 2-(3; 5-dimethyl-1H-pyrazoles-4-yl) ethyl; 2-(1H-imidazoles-1-yl) ethyl; (3; 4-dihydro-1H-2-chromene-1-yl) methyl; (1; 4-diox-2-ylmethyl); [6-(8-oxa--3-azabicyclo [3.2.1] oct-3-yl) hexyl]; [[2-(4-morpholinyl) phenyl] methyl]; [(6-fluoro-4H-1; 3-benzo dioxine-8-yl) methyl]; [3-[4-(2-p-methoxy-phenyl)-1-piperazinyl] propyl group]; 2-(2; 3-dihydro-1; 4-benzo dioxine-6-yl)-2 hydroxyethyls; tetramethyleneimine-3-base; tetrahydrochysene-2; 2-dimethyl-2H-pyrans-4-base; 2; 2; 6; 6-tetramethyl--4-piperidyl; 2-(4-(hydroxymethyl) piperidines-1-yl); (1-methylpyrrolidin-3-yl); the 2-[[(4-fluorophenyl) methyl] amino] ethyl; 2-[(tetrahydrochysene-1; 1-titanium dioxide-3-thienyl) amino] ethyl; 2-(benzyloxycarbonyl group amino) ethyl; 2-[(2-chloropyridine-3-yl) oxygen ylmethyl carbonylamino] ethyl; 2-(N; N-dimethylamino sulfuryl amino) ethyl; (2-(2,4 dichloro benzene sulfonamido)-phenyl) methyl; 2-(tert-butoxycarbonyl amino) ethyl; 4-(tert-butoxycarbonyl amino) butyl or 5-(morpholino carbonyl amino) penta-1-base.

Q ¹Be selected from phenyl; the 2-chloro-phenyl-; the 3-chloro-phenyl-; the 4-chloro-phenyl-; the 3-fluorophenyl; the 4-fluorophenyl; the 3-iodophenyl; the 3-bromophenyl; 2; the 5-dichlorophenyl; 2; the 5-difluorophenyl; the 2-aminomethyl phenyl; the 3-butoxy phenyl; 3-(4-methylbenzene sulfenyl) phenyl; 4-(benzyloxy) phenyl; the 4-butoxy phenyl; 4-methylsulfonyl aminophenyl; the 1-naphthyl; the 2-naphthyl; 1-thionaphthene-2-base; 1H-indoles-5-base; 4-(benzyloxy)-2-aminomethyl phenyl; 3-(benzyloxy) phenyl; the 3-hydroxy phenyl; the 3-cyano-phenyl; 4-[(3, the 4-dichloro benzyl) the oxygen base] phenyl; 3-(tert-butoxycarbonyl amino) phenyl; 3-(phenyl amino carbonylamino) phenyl; 3-(benzylamino carbonylamino) phenyl; 4-(phenyl amino carbonylamino) phenyl; 4-(benzylamino carbonylamino) phenyl; 3-[2-fluoro-5-(trifluoromethyl) phenyl amino carbonylamino] phenyl; 4-[2-fluoro-5-(trifluoromethyl) phenyl amino carbonylamino] phenyl; 4-(benzyloxycarbonyl group aminophenyl) phenyl; 3-(benzyloxycarbonyl group aminophenyl) phenyl; 3-(benzyloxycarbonyl amino) phenyl; 3-(butoxy carbonyl amino) phenyl or 3-(phenyloxycarbonyl amino) phenyl.

A is selected from-NH-C ^*=N-and-N=C ^*-NH-

G is NR ⁵

Z is N;

Q ¹Be phenyl;

R ¹Be selected from hydrogen, sulfydryl, amino and (1-3C) alkylthio;

R ²Be hydrogen;

R ³Be (1-3C) alkyl;

R ⁴Be selected from hydrogen and (1-3C) alkyl;

R ⁵Be selected from hydrogen, (1-3C) alkyl, phenyl and benzyl, wherein R ⁵In phenyl optional have 1-2 and be selected from (1-3C) alkyl and (1-3C) substituting group of alkoxyl group; And m is 0 or 1.

Particular compound of the present invention is acceptable salt on any compound of introducing among the embodiment or its pharmacology.Such compound of concrete kind is described below.

Be selected from acceptable salt on following a kind of compound or its pharmacology:

8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

9-methyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

7-methyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7H-purine-6-amine or

8-(4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine.

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[3,2-d] pyrimidine

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[3,2-d] pyrimidine-4-amine or

5-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-1H-imidazoles-1-alcohol.

5-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-1H-imidazoles-1-alcohol or

9-cyclohexyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine.

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine-4-amine or

6-[1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] furo [2,3-d] pyrimidine.

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7H-pyrrolo-[2,3-d] pyrimidine

6-(4-phenyl-1H-imidazoles-5-yl) thieno-[3,2-d] pyrimidine

[1,3] oxazole is [5,4-d] pyrimidine-7-amine also for 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)

2-[1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] furo [3,2-c] pyridine

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine.

Be selected from following one or more structural formula A compound or its pharmacology on acceptable salt:

(1) 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(2) 2-(4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(3) 2-(4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine also

(4) 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(5) 2-(2-amino-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(6) 2-(2-methoxyl group-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also.

(7) 2-(1-methyl-2,4-phenylbenzene-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also.

(8) 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-mercaptan also

(9) 7-methoxyl group-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine also

(10) 2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(11) 2-(1-methyl-4-phenyl-2-pyridin-4-yl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(12) 2-(2-ethyl-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(13) 2-[1-methyl-4-phenyl-2-(rosickyite base)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(14) sulfenyl 2-{2-[(methoxymethyl)]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole pyrimidine-7-amine also-[5,4-d]

(15) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (5-methyl-isoxazole-3-yl) ketone

(16) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (5-methyl-isoxazole-3-yl) methyl alcohol

(17) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-furyl) ketone

(18) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-furyl) methyl alcohol

(19) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-dimethyl-1H-pyrazoles-5-yl) ketone

(20) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-dimethyl-1H-pyrazoles-5-yl) methyl alcohol or

(21) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-thienyl) methyl alcohol

(22) 2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(23) 2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(24) 7-(diisopropylaminoethyl)-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-5-formaldehyde also

(25) 2-(2-{[2-(dimethylamino) ethyl] sulfenyl }-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(26) 2-(1-methyl-2-{[(methylthio group) methyl] sulfenyl }-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(27) 2-(2-{[2-(1H-imidazoles-1-yl) ethyl] sulfenyl }-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(28) sulfenyl 2-{1-methyl-4-phenyl-2-[(pyridin-3-yl methyl)]-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(29) sulfenyl 2-{2-[(cyclopropyl methyl)]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(30) 2-[2-(benzyl sulfenyl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(31) 2-[1-methyl-2-(4-methylpiperazine-1-yl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(32) 2-{2-[(1-aminocyclohexyl) ethynyl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(33) 4-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] fourth-3-alkynes-2-alcohol

(34) 1-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] ethynyl } hexalin

(35) 2-[1-methyl-4-phenyl-2-(pyridine-2-ethyl-acetylene base)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(36) 2-[2-(3-amino-3-methyl fourth-1-alkynes-1-yl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(37) 2-[2-(3-methoxy propyl-1-alkynes-1-yl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(38) 2-(1-methyl-2-morpholine-4-base-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(39) 2-(1-methyl-4-phenyl-2-pyrimidine-5-base-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(40) 2-{2-[3-(dimethylamino) third-1-alkynes-1-yl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(41) 4-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester

(42) 2-[1-methyl-4-phenyl-2-(1,2,3,6-tetrahydropyridine-4-yl)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(43) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl alcohol

(44) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (cyclopropyl) methyl alcohol

(45) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-benzodioxole-4-yl) methyl alcohol

(46) 1-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl]-3-methyl fourth-1-alcohol

(47) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1-methyl isophthalic acid H-imidazoles-2-yl) methyl alcohol

(48) 2-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also]-4-phenyl-1H-imidazoles-1-yl) ethanol

(49) 2-[1-(2-methoxy ethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(50) 2-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-Ji Ding-1-alcohol

(51) 2-(1-butyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(52) 2-[1-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-ylmethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(53) 4-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl } hexalin

(54) 4-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl pimelinketone or

(55) 2-[1-(2-morpholine-4-base benzyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also.

Be selected from following one or more structural formula B compound or its pharmacology on acceptable salt:

(1) 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine

(2) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine

(3) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(4) 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

(5) 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(6) N-methyl-6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(7) N-[6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-yl] ethanamide

(8) 6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(9) 6-(1-benzyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine

(10) 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(11) 6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(12) 6-[4-(3-butoxy phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(13) 6-{1-methyl-4-[3-(4-methylbenzene sulfenyl) phenyl]-1H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(14) 6-{4-[4-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(15) 6-{4-[4-butoxy phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(16) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl } Toluidrin

(17) 6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(18) 6-[1-(3-methoxy-propyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(19) 6-(1-isobutyl--4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(20) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethanol

(21) 6-(1-cyclopropyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(22) 6-[1-(2-methoxy ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(23) 6-(1-butyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(24) 6-[4-phenyl-1-(pyridin-3-yl methyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(25) 6-[1-(2, the 2-dimethoxy-ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(26) 6-(4-phenyl-1-tetramethyleneimine-3-base-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(27) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] oneself-1-alcohol

(28) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] fourth-1-alcohol

(29) 6-{1-[2-(4-methylpiperazine-1-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(30) 2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(31) 2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(32) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [3,2-d] pyrimidine-4-amine

(33) 6-[1-(2-fluoro ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(34) 6-[4-(2-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(35) 6-[4-(3-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(36) 6-[4-(4-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(37) 6-[1-methyl-4-(2-naphthyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(38) 6-[4-(1-thionaphthene-2-yl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(39) 6-[4-(3-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(40) 6-[1-methyl-4-(2-aminomethyl phenyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(41) 6-[4-(2, the 5-difluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(42) 6-[4-(2, the 5-dichlorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(43) 6-[1-methyl-4-(1-naphthyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(44) 6-[4-(1H-indoles-5-yl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(45) 6-{4-[4-(benzyloxy)-2-aminomethyl phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(46) 6-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(47) 6-[1-[3-(4-methyl isophthalic acid-piperazinyl) propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(48) 6-[1-[3-(hexahydro-1 H-azepines-1-yl) propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-alcohol

(49) 6-[4-phenyl-1-(tetrahydrochysene-2,2-dimethyl-2H-pyrans-4-yl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(50) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-Beta-methyl-4-phenyl-1H-imidazoles-1-ethanol

(51) 6-[1-(2-methoxyl group-1-methylethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(52) 6-[1-(1-methylethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(53) 6-[1-(1, the 2-dimethyl propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(54) 6-[1-(1, the 3-dimethylbutyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(55) 6-[4-phenyl-1-(2-propenyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(56) 6-[4-phenyl-1-(2,2,6,6-tetramethyl--4-piperidyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(57) 6-[1-(1-methyl-propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(58) 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl]-hexalin

(59) methyl 6-[4-phenyl-1-[(tetrahydrochysene-2-furyl)]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(60) 6-[1-[2-(4-morpholinyl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(61) 6-[1-[4-(diethylamino)-1-methyl butyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(62) methyl 6-[1-[(2-fluorophenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(63) methyl 6-[1-[(2-aminomethyl phenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(64) methyl 6-[1-[(3-fluorophenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(65) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-Alpha-Methyl-4-phenyl-1H-imidazoles-1-ethanol

(66) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl]-1, the 2-propylene glycol

(67) 6-[1-(2-methyl butyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(68) 6-[4-phenyl-1-[2-(phenyl amino) ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(69) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-propyl alcohol

(70) 6-[1-[3-(dimethylamino)-2, the 2-dimethyl propyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(71) 6-[1-(2-methyl-2-propenyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(72) N-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-4-hydroxyl-phenylacetamide

(73) 6-[1-(2-methoxyl group-2-methyl-propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(74) 6-[4-phenyl-1-(spiral shell [dicyclo [2.2.1] hept-2-ene"-7,1 '-cyclopropane]-5-ylmethyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(75) 6-[1-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(76) 6-[1-[2-(1H-imidazoles-1-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(77) methyl 6-[1-[2-[[(4-fluorophenyl)] amino] ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(78) 6-[1-[(3,4-dihydro-1H-2-chromene-1-yl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(79) 6-[1-[2-(methylsulfonyl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(80) N-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-2-[(2-chloro-3-pyridyl) the oxygen base]-ethanamide

(81) 6-[4-phenyl-1-[2-[(tetrahydrochysene-1,1-titanium dioxide-3-thienyl) amino] ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(82) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-α-(trifluoromethyl)-1H-imidazoles-1-ethanol

(83) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-α-[3-(trifluoromethyl) phenyl]-1H-imidazoles-1-ethanol

(84) 6-[4-phenyl-1-[2-(2-propenyl amino) ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(85) N-[5-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] amyl group]-4-morpholine methane amide

(86) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-α-(2,3-dihydro-1,4-benzo dioxine-6-yl)-4-phenyl-1H-imidazoles-1-ethanol

(87) 6-[1-[3-[4-(2-p-methoxy-phenyl)-1-piperazinyl] propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(88) N '-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-N, N-dimethyl-sulphonamide

(89) 6-[1-[6-(8-oxa--3-azabicyclo [3.2.1] oct-3-yl) hexyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(90) 6-[1-[[2-(4-morpholinyl) phenyl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(91) 6-[1-(1,4-diox-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(92) 2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl]-, (1S, 2R)-hexalin

(93) 6-[1-(suberyl methyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(94) 6-[1-[[(1S, 5S)-6,6-dimethyl dicyclo [3.1.1] heptan-2-yl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(95) 1-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl]-Cyclohexaneacetic acid

(96) 6-[4-phenyl-1-(phenyl methyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(97) methyl 6-[1-[(2-p-methoxy-phenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(98) 6-[4-phenyl-1-[[2-(piperidino) phenyl] methyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(99) 6-[4-phenyl-1-[[2-(2-pyridyl oxygen base) phenyl] methyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(100) 6-[1-[[2-(4-methyl isophthalic acid-piperazinyl) phenyl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(101) 1-[2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl] phenyl]-the 4-piperidine carbinols

(102) methyl 6-[1-[(2-aminophenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(103) N-[2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl] phenyl]-2,4-two chloro-benzsulfamides

(104) 6-[1-(1H-imidazoles-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(105) 6-[1-[(6-fluoro-4H-1,3-benzo dioxine-8-yl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(106) 6-[1-(imidazo [1,2-a] pyridine-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(107) N-benzyl-6 (1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(108) 6-[1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(109) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] and ethyl } t-butyl carbamate

(110) 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also]-4-phenyl-1H-imidazoles-1-yl) butyl] t-butyl carbamate

(111) 6-{4-[3-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(112) 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenol

(113) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] benzonitrile

(114) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } t-butyl carbamate

(115) 6-(4-{4-[(3,4-dichloro benzyl) oxygen base] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(116) N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-phenylurea

(117) N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-benzylurea

(118) N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

(119) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-phenylurea

(120) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-benzylurea

(121) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

(122) 6-[1-(the amino butyl of 4-)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(123) 6-[1-(3-methyl but-2-ene-1-yl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(124) 6-[4-(4-fluorophenyl)-1 (2-morpholine-4-base benzyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(125) { 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl } phenyl carbamate or

(126) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } benzyl carbamate

Acceptable salt can be by any known method preparation that is suitable for preparing related compound on structural formula I compound or its pharmacology.Such method provides as further aspect of the present invention when being used to prepare structural formula I compound, and illustrates by following exemplary process variant.Essential raw material can obtain by vitochemical standard method.The preparation of this class raw material is in conjunction with following exemplary process variant and be introduced in the embodiment of back.Obtain the essential raw material of alternate by being similar to method for example, this belongs to organic chemistry ordinary skill category.

Again on the one hand, the invention provides acceptable salt on preparation structural formula I compound or its pharmacology (except as otherwise noted, otherwise wherein A, R ¹, R ², R ³, R ⁴, Q ¹, G is identical with the definition among the structural formula I with m) method, this method may further comprise the steps:

(a) for the such structural formula I compound of preparation: wherein G is NR ⁵, the suitable alkali that exists, the compound reaction of the imines of following structural formula II and structural formula II I:

Wherein A, R ¹, R ², R ³, R ⁵, Z and m with above define identical, exception be, if necessary, functional group is protected, and wherein imines and A the position is connected between the end of the bridge carbon of # being labeled as, described structural formula II I compound is:

Q wherein ¹With above define identical, exception be if necessary, functional group to be protected;

(b) for the such structural formula I compound of preparation: wherein Z is N, R ¹For amino and the connected carbon atom of A Gou Cheng oxazole ring together, with following structural formula IV compound and amidine or its reactant salt,

Wherein A is-NH=C ^*-O-, ^*The ring that comprises G among expression and the structural formula IV forms the atom of key and R ³, R ⁴, G, Q ¹With m with above define identical, exception be if necessary, functional group is protected, and the position to be connected between the ring that wherein comprises G and the amino of A in structural formula IV;

(c) for the such compound in structural formula I of preparation: wherein A is-N=C ^*-S-or-S-C ^*=N-, wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, in the presence of suitable vulcanizing agent, thus following structural formula V compound sulfuration of heating and cyclized structure formula V compound:

R wherein ¹, R ²With Z with above define identical, exception be, if necessary, functional group is protected,

G ¹Group G for following structural formula VI ²Be OH, perhaps

G ¹Be OH G ²Group for following structural formula VI:

Q wherein ¹, G and R ⁴With above define identical, exception be if necessary, functional group to be protected;

(d) for the so such structural formula I compound of preparation: wherein A is-N=C ^*-NH-or-NH-C ^*=N-, wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, in the presence of suitable dewatering agent, following structural formula VII compound is dewatered and cyclisation:

G ³Group G for structural formula VI defined above ⁴Be amino;

(e) for the such structural formula I compound of preparation: wherein G is N-OH, under acidic conditions, and with ketoxime and ammonium acetate and the polyformaldehyde reaction of following structural formula VIII, the suitable Lewis acid that exists:

Wherein A, R ¹, R ², R ³, Z, Q ¹With m with above define identical, exception be if necessary, functional group is protected, and the group that wherein carries ketoxime among the structural formula VIII and A position between with respect to the end of the bridge carbon that is labeled as # to be connected;

(f) for the such structural formula I compound of preparation: wherein A is-CH=C ^*-NH-,-NH-C ^*=CH-,-CH=C ^*-O-,-O-C ^*=CH-,-CH=C ^*-S-or-S-C ^*=CH-, wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, and the alkynes of following structural formula IX is carried out cyclisation:

Structural formula IX

R wherein ¹, R ²With Z with above define identical, exception be, if necessary, functional group is protected, and

G ⁵Group G for following structural formula X ⁶Be amino, perhaps

G ⁵Be amino G ⁶Be the group of structural formula X, perhaps

G ⁵Group G for structural formula X ⁶Be hydroxyl, perhaps

G ⁵Be hydroxyl G ⁶Be the group of structural formula X, perhaps

G ⁵Group G for structural formula X ⁶Be sulfydryl, perhaps

G ⁵Be sulfydryl G ⁶Be the group of structural formula X,

Structural formula X

(g) a kind of compound in structural formula I is converted into another kind of structural formula I compound; Or

(h) for the such structural formula I compound of preparation: wherein A is-N=C ^*-S-or-S-C ^*=N-, wherein ^*The ring that comprises G among expression and the structural formula I forms the atom of key, in the presence of suitable acid or dewatering agent, thus the following structural formula XXVI of heating arrangement formula XVI compound cyclisation compound:

G ⁷Group G for structural formula VI ⁸Be SH, perhaps

G ⁷Be SH G ⁸Group for structural formula VI;

Wherein structural formula VI compound with above define identical; And

(if desired) removed any protecting group and/or formed acceptable salt on its pharmacology then.

Method (a)

The suitable alkali that exists of the carrying out of method (a).The appropriate base of method (a) for for example organic amine alkali (as piperazine, pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11 carbon-7-alkene), perhaps for example basic metal or alkaline earth metal carbonate or oxyhydroxide (as yellow soda ash, salt of wormwood, cesium carbonate, lime carbonate, sodium hydroxide or potassium hydroxide), perhaps for example alkalimetal hydride (as sodium hydride) or metal alkoxide (as sodium ethylate).

Method (a) suit suitable inert solvent or thinner for example ether (as tetrahydrofuran (THF) or 1, the 4-diox), ester (as ethyl acetate), alcohol or alcohol-water solution (as methyl alcohol, ethanol or Virahol) or dipolar aprotic solvent (as N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or N, the N-methyl-sulphoxide) in carry out.Preferred method (a) is being lower than (for example 0-30 ℃) under 50 ℃ the temperature, is being preferable under the ambient temperature and carries out.

The structural formula II compound can be by aldehyde and the formula R of following structural formula XI ⁵NH ₂The amine prepared in reaction:

Structural formula XI

Wherein A, R ¹, R ², R ³, Z and m with above define identical, exception be if necessary, functional group to be protected formula R ⁵NH ₂Middle R ⁵With above define identical, exception be if necessary, functional group to be protected.

The aldehyde of structural formula XI preferably for example reacts in the presence of the chlorinated solvent (as methylene dichloride) at suitable inert solvent.Reaction is suitable under refluxad to be carried out.This reaction can be carried out in the presence of suitable molecular sieve (for example 4 molecular sieves).

With the variant of method (a), the comprehensive processing step of above introducing but do not separate the imines of structural formula XI, (wherein G is NR can be directly to begin to prepare compound in structural formula I from the aldehyde of structural formula XI ⁵); That is, the aldehyde of said structure formula XI and formula R ⁵NH ₂Amine reaction, then with the structural formula II compound defined above of gained and the structural formula II I compound direct reaction relevant with aforesaid method (a).

The aldehyde of structural formula XI can prepare with ordinary method.For example, as the R of structural formula I ¹For hydrogen or (1-6C) during alkylthio, the aldehyde of structural formula XI (R wherein ¹Be hydrogen or (1-6C) alkylthio) can be according to reaction process 1 preparation:

Reaction process 1

Wherein Z and A with above define identical, R ¹Be hydrogen or (1-6C) alkylthio, and R is suitable displaceable group, for example (1-6C) alkyl or benzyl.

In the step (i) of reaction process 1, the ester of structural formula XIa and methoxyl group (methyl) amine reacts in the presence of suitable alkali (for example isopropylmagnesium chloride).This reaction suits for example to carry out in the ether (as tetrahydrofuran (THF)) at inert solvent.

The step of reaction process (i) (ii) in, methane amide is reduced to the aldehyde of structural formula XI with appropriate reductant (for example lithium aluminium hydride).

Any stage in reaction can be with other substituting group (R for example ²And R ³) add compound shown in the reaction process 1 or improve one's methods with conventional chemical, for example this paper method (g) is described, and (a) carries out according to method.

Structural formula XIa and XIb compound can be gone into business and be sold acquisition, perhaps are known compound in the document, perhaps by standard method preparation known in the art.For example prepare R ¹For the structural formula XIa of (1-6C) alkylthio and XIb compound can be by suitable following structural formula XIc or XId compound and suitable basic metal sulfo-(1-6C) alkoxide (R for example ¹Use sodium methyl mercaptide during for methylthio group) reaction:

Wherein L is a displaceable group, and A, Z and R with above define identical.The suitable displaceable group of L representative comprises for example halogen (preferred chlorine or bromine) or phenoxy group.

Method (b)

Method (b) is suitable carries out with suitable amidine or its salt (for example formamidine acetate).This method suits to carry out under anhydrous condition, preferably suitable inert solvent or thinner for example dipolar aprotic solvent (as N, dinethylformamide, N, the N-N,N-DIMETHYLACETAMIDE, N-methylpyrrolidin-2-ketone or methyl-sulphoxide) in carry out.The optimal temperature scope that reaction is carried out is for example 30-150 ℃, preferred 50-120 ℃.

With for example ordinary method of reaction process 2 introductions, but structural formula (IV) compound that preparation method (b) uses, and wherein A is-N=C ^*-O-, and ^*The ring that comprises G among expression and the structural formula IV forms the atom of key:

Reaction process 2

In reaction process 2, the carbonyl chloride of structural formula XII and amino propane dinitrile p-toluenesulfonic esters are at suitable inert solvent or thinner (for example N-2-methyl-2-pyrrolidone) reaction in.

Structural formula XII compound can prepare with conventional steps.For example, when the G of structural formula XII be NR ⁵The time, the imdazole derivatives of structural formula XII can prepare with for example reaction process 3:

Reaction process 3

In reaction process 3, the iso-cyano compound of structural formula XIIa and methylamine and the reaction of hydroxyl acetaldehyde dimer form imidazoles-5-base carbinol derivatives.With weak oxidant (for example Manganse Dioxide), alcohol is oxidized to corresponding aldehyde.Optionally then there is suitable alkali (for example salt of wormwood), aldehyde further is oxidized to carboxylic acid with suitable oxygenant (for example potassium permanganate or Manganse Dioxide).With carboxylic acid and suitable chloride of acid (for example oxalyl chloride) reaction, acquisition G is NR then ⁵Structural formula XII compound.

Perhaps, in reaction process 3, can be aldehyde with imidazoles-5-base carbinol derivatives direct oxidation, with suitable oxygenant (for example potassium permanganate), preferably there is above-mentioned alkali during oxidation.

Structural formula XIIa compound can be gone into business and be sold acquisition, perhaps is known compound in the document, perhaps prepares (for example referring to Org.React. by standard method known in the art 77198-205).

Wherein G is that the structural formula XII compound of O or S is a known compound, the preparation of perhaps available currently known methods (J.Org.Chem.2000 for example, 65, 1516-1524).

Method (c)

The spendable suitable vulcanizing agent of method (c) is (for example thiophosphoric anhydride, LawessonShi reagent or a DavyShi reagent) well known in the art.Reaction preferably under anhydrous condition, inert solvent for example carries out in the hydrocarbon cosolvent (as toluene or dimethylbenzene).Yet preferred reaction is carried out in alkaline inert organic solvents (for example pyridine or picoline).Method (c) is preferable under 50-120 ℃ the temperature (for example 80-110 ℃) carries out.

The structural formula V compound that available ordinary method preparation method (c) uses, for example R wherein ¹Be amino R ²For the structural formula V compound of H can be by making following structural formula XIII aniline and structural formula XII compound (with above define identical) prepared in reaction:

Structural formula XIII

G wherein ^1aBe amino G ^2aBe hydroxyl, perhaps

G ^1aBe hydroxyl G ^3aBe amino.

This reaction at inert solvent or thinner (for example suits N-methyl-2-pyrrolidone) carries out in, under the preferred anhydrous condition.

This reaction suits to carry out in the presence of alkali.Appropriate base is introduced alkali (for example triethylamine or pyridine) for method (a) above.

Structural formula XIII compound can be gone into business and be sold acquisition, perhaps is known compound in the document, perhaps by standard method preparation known in the art.

Method (d)

The suitable dewatering agent that can be used for method (d) is for for example, Vanadium Pentoxide in FLAKES, phosphoryl chloride, Tripyrophosphoric acid, phosphoric acid and/or strong acid.Suitable strong acid comprises, for example the concentrated hydrochloric acid or the vitriol oil.In embodiments, can use the mixture of dewatering agent, for example Vanadium Pentoxide in FLAKES and acid (as Vanadium Pentoxide in FLAKES and phosphoric acid).

Method (d) suits, and for example water or inert organic solvents (carry out in for example suitable hydrocarbon cosolvent (as toluene or dimethylbenzene) at suitable inert solvent.

Method (d) is suitable for carrying out under-10 to 200 ℃ temperature, preferably is in or near ambient temperature.

The structural formula VII compound that method (d) is used can prepare with ordinary method.R wherein for example ¹Be amino R ²For the structural formula I compound of hydrogen by following structural formula XIV compound and structural formula XII compound (with above define identical) reaction prepares,

Structural formula XIV

G wherein ^3aAnd G ^4aAll for amino Z with above define identical.

This reaction at inert solvent or thinner (for example suits N-methyl-2-pyrrolidone) carries out in, preferably under anhydrous condition.

This reaction suits to carry out in the presence of suitable alkali.Suitable alkali for example comprises the above alkali of method (a) introduction.

Structural formula XIV compound can be gone into business and be sold acquisition, perhaps is known compound in the document, perhaps by standard method preparation known in the art.

Should be known in purine compound that method (c) forms can be between 7-H and 9-H purine isomer tautomerism.If desired, use R ³The NH group of substituting group substituted purin mixture is for example used for example haloalkane (as methyl iodide) alkanisation of suitable alkylating agent, the gained isomer can be fixed as a kind of concrete isomeric form.Can use routine techniques (for example HPLC) with these two kinds of isomer segregations then.

Method (e)

Method (e) is suitable for carrying out under 90-150 ℃ temperature.This reaction suits to carry out in (for example about 2 hours) at 1-48 hour.Preferably react like this: the ketoxime to structural formula VIII adds ammonium acetate post-heating gained mixture.Add Paraformaldehyde 96 to reaction mixture then.In this reaction, the ketoxime of structural formula VIII is converted into corresponding imines oxime, and then with the Paraformaldehyde 96 reaction in, generating wherein, G is the structural formula I compound of N-OH.

The acidic conditions that method (e) needs can produce like this, is reflected at suitable acid and for example carries out under mineral acid (for example HCl) existence, perhaps preferably carries out in the presence of organic acid (for example acetate).

Available ordinary method prepares the ketoxime of structural formula VIII.Structural formula I compound (R wherein for example ¹Be methylthio group, R ²Be hydrogen, A is-S-C ^*=CH-, and ^*The ring that comprises G among expression and the structural formula I forms the atom of key) can prepare according to reaction process 4:

Reaction process 4

Wherein Z and Q ¹With above define identical, and L be replaceable group (with above define identical), halogen (as chlorine or bromine) for example.

In reaction process 4, structural formula XV compound and basic metal sulfo-methylate (for example sodium methyl mercaptide) reaction.Then with the Weinreb acid amides (Q of gained compound and aryl acid or heteroaryl acid ¹-CON (OMe) Me) reaction generates ketone.Preferably in the presence of suitable alkali (for example two (trimethyl silyl) acid amides lithium or LDA), carry out with the reaction of Weinreb acid amides.This reaction is preferably for example carried out in the ether (as tetrahydrofuran (THF)) at suitable inert solvent or thinner.The optimal temperature of this reaction is-78 ℃ to 10 ℃ (for example about 0 ℃).

By reacting with Sodium Nitrite, be ketoxime with the gained oxidation of ketones, obtain structural formula VIII compound.

Structural formula XV compound can be gone into business and be sold acquisition, perhaps is known compound in the document, perhaps by standard method preparation known in the art.

Should be known in that with suitable following structural formula compound as starting raw material, the available method that is similar to reaction process 4 prepares other structural formula I compound (wherein A is non-thieno-ring):

Wherein L, A and Z with above define identical.Such compound can be gone into business and be sold acquisition, perhaps is known compound in the document, perhaps can be by standard method preparation known in the art.

Method (f)

When the connected carbon atom of A constituted furo or thieno-fused rings together, method (f) was suitable to heating arrangement formula IX compound (G wherein ⁵Group G for structural formula X ⁶Be hydroxyl, perhaps G ⁵Be hydroxyl G ⁶Be the group of structural formula X, G ⁵Group G for structural formula X ⁶Be sulfydryl, perhaps G ⁵Be sulfydryl G ⁶Group for structural formula X) carries out.Suitable reaction temperature is for example 0-80 ℃, preferred 20-50 ℃.

When the connected carbon atom of A constituted the pyrrolo-fused rings together, method (f) is suitable carried out (G wherein by heating arrangement formula IX compound ⁵Group G for structural formula X ⁶Be amino, perhaps G ⁵Be amino G ⁶Group for structural formula X), there is suitable alkali in this reaction, the alkali introduced of method (a) above for example, preferred as alkali alkoxide (for example potassium tert.-butoxide) or hydride (for example potassium hydride KH or sodium hydride).Suitable reaction temperature is for example 0-80 ℃, preferred 20-65 ℃.

Method (f) suit suitable inert solvent or thinner (for example dipolar aprotic solvent (as N, N-dimethyl formamide, N, N-N,N-DIMETHYLACETAMIDE or N-methylpyrrolidin-2-ketone)) carry out in.

Should also be appreciated that, as any G ⁵Or G ⁶During for sulfydryl or hydroxyl, structural formula IX compound can be corresponding oxo (=O) or sulfo-(=S) tautomeric forms.

Structural formula IX compound can prepare with ordinary method, for example, and with the alkine compounds coupling of following structural formula XVI compound and structural formula XVII,

Structural formula XVI

R wherein ¹, R ²With Z with above define identical,

G ^5aBe replaceable group G ^6aBe selected from amino, hydroxyl or sulfydryl, perhaps

G ^6aBe replaceable group G ^5aBe selected from amino, hydroxyl or sulfydryl,

Described structural formula XVII alkine compounds is:

Structural formula XVII

(Org.Prep.Proc.Int.1995 129-160) finishes the suitable use of this coupling process Sonogashira couling process.This coupling process is carried out under monovalence copper (I) ionic compound (for example cuprous iodide) and suitable alkali (for example organic amine alkali, as triethylamine) exist.Suitable metal catalyst (for example two (triphenylphosphine) palladium chloride, tetra-triphenylphosphine palladium (0) or acid chloride (II)) is used in described reaction.This reaction can for example dipolar aprotic solvent be (for example at suitable inert solvent or thinner N, N-dimethyl formamide) carries out in.The suitable temperature of reaction is 0-150 ℃, preferred 20-80 ℃.G ^5aAnd G ^6aThe suitable displaceable group of representative comprises for example halogen (as chlorine, bromine and iodine).

Structural formula XVII compound can be converted into the aldehyde of following formula XVIII the alkine compounds of corresponding structure formula XVII by for example following method preparation:

Structural formula XVIII

Q wherein ¹, G and R ⁴With above definition.

This conversion can use known method for transformation to carry out, for example use the Ohira method (Chem.Commun.1992,721-722), wherein structural formula XVIII compound and n-Butyl Lithium and trimethyl silyl diazomethane reaction.This reaction suits for example to carry out in hydrocarbon cosolvent (as pentane or hexane) or the ether (as tetrahydrofuran (THF)) at suitable inert solvent or thinner.Temperature of reaction for example can be-78 to 30 ℃.

Structural formula XVI and XVIII compound can be gone into business and be sold acquisition, perhaps are known compound in the document, perhaps by standard method preparation known in the art.For example use the initial step of reaction process 3, generate the aldehyde of required structural formula XVIII, can preparing wherein, G is NR ⁵Structural formula XVIII compound.

Method (g)

Use improved conventional chemical method, a kind of structural formula I compound is converted into another kind of structural formula I compound can prepares structural formula I compound.For example work as R ¹During for alkylthio (for example methylthio group), use suitable oxygenant (for example-chlorine peroxybenzoic acid (m-CPBA)), it can be oxidized to corresponding alkyl sulphonyl.Use suitable nucleophilic reagent (for example ammoniacal liquor or amine) then,, obtain R by the replaceable alkyl sulphonyl of nucleophilic substitution ¹Be amino amino or that replace.Perhaps, alkylthio can directly be replaced with suitable nucleophilic reagent (for example ammoniacal liquor) reaction.For example in suitable inert solvent (for example N-Methyl pyrrolidone), heat R ¹Compound and ammonium chloride solution for methylthio group.R in structural formula I ¹During for (1-6C) alkylthio or halogen, reducible R ¹Obtain R ¹Structural formula I compound for hydrogen.The conditions suitable of this reduction reaction is known, for example hydrogenation in the presence of Raney nickel catalyst.The 1-hydroxyl imidazoles that method (e) generates can be converted into corresponding imidazoles by reduction.For example heat three-alkyl phosphorous acid ester, perhaps hydrogenation in the presence of appropriate catalyst (for example Raney nickel catalyst).Substituent R ³Or R ⁵Can use in the NH group of ordinary method guiding structure formula I compound.For example use suitable alkylating agent (as alkylogen, alkyl sulfonic ester (as tosylate or methanesulfonates)), the optional existence under suitable alkali and the suitable inert solvent carried out alkylation.

Method (h)

Cyclization suits to carry out under 50-120 ℃ temperature (for example 80-110 ℃).The acid that is suitable for this reaction comprises, for example aqueous hydrochloric acid.Spendable suitable dewatering agent comprises, for example POCl ₃Reaction suits for example to carry out in the hydrocarbon cosolvent (as toluene or dimethylbenzene) at inert organic solvents.

The used structural formula XVIX compound of method (h) can use the ordinary method preparation.For example use the method that aforesaid method (c) prepares structural formula V compound that is similar to, just utilization structure formula XIII compound, wherein G ^1aBe amino G ^2aBe sulfydryl, perhaps G ^1aBe sulfydryl G ^2aBe amino.

When on the pharmacology that needs structural formula I compound during acceptable salt, for example acid salt can use ordinary method, for example by structural formula I compound and suitable acid (example hydrochloric acid) reaction acquisition.When needing the free alkali form of structural formula I compound, can handle the acid salt of structural formula I compound, suitable alkali is used in described processing, for example organic amine alkali (as pyridine, 2,6-lutidine, trimethylpyridine, 4-dimethylaminopyridine, triethylamine, morpholine, N-methylmorpholine or diazabicyclo [5.4.0] 11 carbon-7-alkene) or for example basic metal or alkaline earth metal carbonate or oxyhydroxide (as yellow soda ash, salt of wormwood, lime carbonate, sodium hydroxide or potassium hydroxide).

Some structural formula I compound can be stereoisomer form.Should be understood that the geometrical isomer that the present invention includes all structural formula I compounds and optical isomer and composition thereof (comprising racemic modification).Tautomer and composition thereof also belongs to integral part of the present invention.

Isomer can pass through ordinary method (for example chromatography or fractional crystallization) fractionation or segregation.Other mixture that can use ordinary method (for example chiral hplc (HPLC)) segregation racemic compound or described compound is to separate enantiomer.In addition, required optical isomer can be by suitable optically-active raw material reaction preparation under the condition that does not produce racemization, perhaps by using for example homochiral acid derivation, use ordinary method (for example HPLC, silica gel chromatography) to separate non-enantiomer derivative then and prepare, perhaps available achirality raw material and chiral reagent preparation.All steric isomers belong to category of the present invention.

The compounds of this invention can use ordinary method to separate from their reaction mixture.

Should be understood that in this paper mentions some reactions, any sensitive group of protection compound be essential/desirable.Be that the proper method of protection is well known by persons skilled in the art under essential/desirable situation at blocking group.But the secundum legem working specification is used GPF (General Protection False base (for example referring to T.W.Green, Protective Groups in Organic synthesis, John Wiley and Sons, 1991).Therefore, if reactant comprises for example groups such as amino, carboxyl or hydroxyl, must in some reactions that this paper mentions, protect described group so.Protecting group can be removed by the method that any ordinary method or this area chemist of document introduction are known, and method selected should be suitable for removing the protection of goal base and disturb minimum to other group of molecule.

For convenience's sake, provide the specific examples of protecting group below, when wherein " rudimentary " for example was used for low alkyl group, the group of expression indication preferably had 1-4 carbon atom.Should be known in that these examples are non-limit example.Hereinafter the concrete grammar example that provides for the removal protecting group is non-limit example equally.Certainly, the use of protecting group and de-protected method though do not mention especially, belong to category of the present invention.

Carboxyl-protecting group can be Fatty Alcohol(C12-C14 and C12-C18) or the aryl alcohols residue that forms ester, perhaps is the residue (described alcohol or silanol preferably comprise 1-20 carbon atom) that forms the silanol of ester.The example of carboxyl-protecting group comprises straight or branched (1-12C) alkyl (for example sec.-propyl and the tertiary butyl); Lower alkoxy-low alkyl group (for example methoxymethyl, ethoxyl methyl and isobutoxy methyl); Low-grade acyloxy-low alkyl group, (for example acetoxy-methyl, propionyloxy methyl, butyryl acyloxy methyl and oxy acid methyl neopentyl); Elementary alkoxy carbonyl oxygen base-low alkyl group (for example-methoxycarbonyl oxygen base ethyl and 1-ethoxy carbonyl oxygen base ethyl); Aryl lower alkyl (for example benzyl, 4-methoxy-benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-methyl and phthalidyl); Three (low alkyl group) silyl (for example trimethyl silyl and t-butyldimethylsilyl); Three (low alkyl group) silyl-low alkyl group (for example trimethyl silyl ethyl); And (2-6C) alkenyl (for example allyl group).The concrete appropriate method of removing carboxyl-protecting group comprise for example acid-, alkali-, metal-or enzyme catalysis cracking.

The example of hydroxyl protecting group comprises low alkyl group (for example tertiary butyl); Low-grade alkenyl (for example allyl group); Lower alkane acyl group (for example ethanoyl); Elementary alkoxy carbonyl (for example tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl (for example allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (for example benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Three (low alkyl group) silyl (for example trimethyl silyl and t-butyldimethylsilyl) and aryl lower alkyl (for example benzyl).

The example of amino protecting group comprises formyl radical, aryl lower alkyl (for example the benzyl of benzyl and replacement, 4-methoxy-benzyl, 2-nitrobenzyl and 2,4-dimethoxy-benzyl and trityl group); Two-4-anisyl methyl and furyl methyl; Elementary alkoxy carbonyl (for example tert-butoxycarbonyl); Low-grade alkenyl oxygen base carbonyl (for example allyl group oxygen base carbonyl); Aryl-lower alkoxy carbonyl (for example benzyloxycarbonyl, 4-methoxyl group benzyloxy base carbonyl, 2-nitro benzyloxycarbonyl and 4-nitro benzyloxycarbonyl); Trialkylsilkl (for example trimethyl silyl and t-butyldimethylsilyl); The benzylidene of alkylidene group (for example methylene radical) and benzylidene and replacement.

The method that is suitable for removing hydroxyl and amino protecting group for example comprise acid at groups such as 2-nitro benzyloxycarbonyl-, alkali-, metal-or enzymatic hydrolysis method, be applicable to the hydride process of group such as benzyl for example and be applicable to for example photodissociation method of group such as 2-nitro benzyloxycarbonyl.

Some the different rings substituting group that should be known in The compounds of this invention can import or before carrying out aforesaid method or carry out producing by conventional modified with functional group immediately behind the aforesaid method, these class methods comprise in the method for the invention by the substitution reaction of standard aromatics.This class reaction and modifying method comprise, for example, import substituting group, reduction substituting group, alkanisation substituting group and oxidation substituting group by aromatics substitution reaction method.The reagent of these class methods and reaction conditions are that chemical field is known.The specific examples of aromatics substitution reaction comprises and uses concentrated nitric acid to import nitro, for example uses that acyl halide and Lewis acid (for example aluminum chloride) import acyl group under Friedel Crafts condition; Use alkylogen and Lewis acid (for example aluminum chloride) under Friedel Crafts condition, to import alkyl; And importing halogen.It is amino that the specific examples of modifying method comprises nitroreduction, and for example heating is simultaneously handled with the nickel catalyzator catalytic hydrogenation or with iron in the presence of hydrochloric acid; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.

The midbody compound of some structural formula II-XXVI is a novel cpd, and is claimed on the other hand as the present invention in this article.Some midbody compound 1-108 also be considered to novel cpd and these midbody compounds one or more advance claimed on the one hand in this article as the present invention.

Biology is measured

Following mensuration can be used for measuring the effect that The compounds of this invention is used as external Tie2 inhibitor and is used as the Tie2 autophosphorylation inhibitor of intact cell.

A. extracorporeal receptor tyrosine-kinase EIA

Test compounds is to measure the ability that test compounds arrestin tyrosine phosphorylation contains the peptide substrate of tyrosine with the acellular protein kinase to the effect of Tie2 receptor tyrosine kinase, and measuring method is an ELISA type micro plate assay method.Under this particular condition, measure three kinds of different recombinant human Tyrosylprotein kinase Tie2, KDR and the IC of Flt ₅₀Value.

Use standard molecular biology clone and induced-mutation technique to produce the recombinant receptor gene to promote to produce Tyrosylprotein kinase.The recombinant protein fragment of encoding in these genes only is the interior C-terminal portions of the cell of every kind of acceptor, wherein has the kinases territory.Clones coding comprises the segmental recombination in kinases territory, expresses with standard baculovirus/Sf21 system (or alternate coordinator).

With host insect cell preparation cytolysis thing, method is with ice-cold dissolving 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 behind the protein expression ₂, 1mM ethylene glycol-two (beta-amino ether) N ', N ', N ', N '-tetraacethyl (EGTA)) add that proteinase inhibitor handles, pass through centrifugal clarification then.

With Tie2, KDR and Flt1 cytolysis thing five equilibrium in-80 ℃ of storages.

By the synthetic peptide of these recombinant protein phosphorylations ability of (randomcopolymer by L-glutamic acid, L-Ala and the tyrosine of 6: 3: 1 ratios is formed), determine their composition kinase activity.Specifically, wrap by Nunc Maxisorb with the synthetic peptide Sigma P3899 of 100 microlitres (with PBS (1: 500) dilution 1mg/ml mother liquor, wrapping by plate then earlier) ^TMBe incubated overnight in 4 ℃ behind the 96-hole immunity plate.In 50mM HEPES (pH7.4) in room temperature washing immunity plate to remove any excessive not binding synthetic peptide.

The activity of test Tie2, KDR or Flt1, method is to contain the cytolysis thing (be respectively 1: 200,1: 400 and 1: 1000) of suitable fresh dilution in the room temperature incubation at the peptide bag in by plate, and the reaction solution of cytolysis thing comprises 100mM HEPES pH7.4, Triphosaden (ATP) 5 micromoles (or Km concentration of corresponding enzyme), 10mM MnCl ₂, 0.1mM Na ₃VO ₄, 0.2mMDL-dithiothreitol (DTT) (DTT), 0.1%Triton X-100 and test-compound DMSO solution (ultimate density 2.5%), final compound simmer down to 0.05 micromole-100 micromole, the incubation time is respectively 60 minutes (Tie2) or 20 minutes (KDR, Flt).Remove the liquid component termination reaction of this mensuration, use PBS-T (phosphate-buffered saline that contains 0.5% polysorbas20) or the equal lavation buffer solution of alternate to wash this plate then.

Detect the fixedly phospho-peptide product of this reaction by immunological method.At first, with plate in room temperature and mouse monoclonal anti-phospho tyrosine-HRP (horseradish peroxidase) binding antibody (4G10, Upstate Biotechnology UBI 16-105) incubation 4 hours.Thoroughly wash with PBS-T then, every hole HRP activity of this plate of colorimetric estimation, use 22 '-azino-two-[3-ethyl benzo thiazole phenanthroline sulfonate (6)] di-ammonium salts crystal ABTS (Sigma P4922-prepares according to product description) to be substrate, colour developing adds 100ul 1M H then after incubation 30-45 minute ₂SO ₄Stopped reaction.

Quantitative colour developing is also measured absorbancy with 405nm and is measured enzymic activity on Molecular Devices ThermoMax micro plate reader.The kinase inhibitory activity of certain specific compound is with IC ₅₀Value representation, its measuring method are to calculate the test-compound concentration that suppresses 50% phosphorylation in this mensuration.With positive (solvent and ATP) control value and feminine gender (solvent and do not have ATP) control value calculating phosphorylation degree.

B. Cell Tie2 autophosphorylation

This is measured based on measuring the ability that compound suppresses Tie2 acceptor autophosphorylation, and this causes producing " activation " acceptor usually, then " activation " receptor promoter relevant with function of receptors the signal specific transduction pathway.

Autophosphorylation can be finished by several different methods.The expression in reorganization kinases territory can produce the phosphorylation activated receptor in the known baculovirus system.Report is also arranged, and under the situation of disappearance part, the overexpression of acceptor itself just can cause acceptor autophosphorylation (HeldinC-H.1995 Cell:80,213-223 in the recombinant cell lines; Blume-J.P, Hunter is Nature:411 T.2001,355-65).In addition, in the lot of documents example, made up the mosaic acceptor.In these cases, the natural exterior cell surface territory of acceptor is replaced by a kind of structural domain, known this structural domain is easy to dimerization (for example, TrkA-Tie2/NGF part (Marron, M.B. because add suitable part, et al., 2000 Journal of Biological Chemistry:275:39741-39746) or C-fms-Tie-1/CSF-1 part (Kontos, C.D., et al., 2002Molecular and Cellular Biology:22,1704-1713).Therefore, when Chimerical receptor is expressed and add separately part, bring out the kinases territory autophosphorylation of mosaic acceptor in host cell system.The advantage of this method is the part that allows to use known (and usually obtaining easily) usually, and needn't identify and the native ligand that separates every kind of target recipient.

Certainly, if can obtain part, then can use known expression target recipient and easily with the n cell system or the primary cell of ligand stimulation with the phosphorylation that reaches part and bring out.Compound suppresses the ability of Tie2 acceptor autophosphorylation can measure measurement by this, wherein at EA.hy926/B3 cell for example (by J.McLean/B.Tuchi, Univ.of N.Carolina atChapel Hill, CB-4100,300 Bynum Hall, Chapel Hill, N.C.27599-41000, USA provides) or the middle Tie2 expression of receptor of former generation HUVEC (Human umbilical vein endothelial cells-merchant sells acquisition).

Use standard purification techniques can be from oncocyte supernatant liquor separating natural Ang1 part, and perhaps using standard molecular biological technique and expressing is can clone and recombinant expressed Ang1 gene.In this case, can attempt production state of nature part or as the part of recombinant protein, described recombinant protein for example heredity make up and comprise other purification mark (for example poly Histidine peptide, antibody Fc territory) to promote this process.

With ligand stimulation EA.hy926/B3 or HUVEC cell Tie2 acceptor is example, can make up the cell receptor phosphorylation assay of Ang1 ligand stimulation, can use it for the potential that the analysis to measure compound suppresses this process.For example on 6 orifice plates, initial inoculum density is 5 * 10 ⁵Cells/well adds in 10% foetal calf serum (FCS) growth two days with the EA.hy926/B3 cell at suitable tissue culture medium (TCM).The 3rd day, replace aforementioned substratum with the substratum that only contains 1%FCS, allow cell serum starvation 2 hours altogether.After 1 hour 40 minutes, remove substratum at serum starvation, replace with 1ml test-compound diluent (with low blood serum medium preparation, and DMSO concentration keeps below 0.8%).After 1.5 hours, add the ultimate density of ortho-vanadate (orthovanidate) to 0.1mM at serum starvation, serum starvation continues last 10 minutes.

Then serum starvation is altogether after 2 hours, add part and ortho-vanadate with irritation cell Tie2 acceptor autophosphorylation (can add part as purified feed stock, it is with low blood serum medium dilution or comprise non-purifying cells supernatant liquor when recombinant expressed mammalian cell (for example when) of part).In 37 ℃ with part incubation after 10 minutes, at the cooled on ice cell, the cold PBS that contains the 1mM ortho-vanadate with about 5ml washs, and adds the ice-cold dissolving damping fluid of 1ml to cell then and (places 10-20 minute on ice after (20mM Tris pH7.6,150mM NaCl, 50mM NaF, 0.1%SDS, 1%NP40,0.5%DOC, 1mM ortho-vanadate, 1mM EDTA, 1mMPMSF, 30 μ l/ml Trypsin inhibitor,Trasylols, 10 μ g/ml pepstatins, 10 μ g/ml leupeptins).Remove and move into 1.5 blood Eppendorf pipe behind the cytolysis thing, in 4 ℃ with 13000 commentaries on classics/per minutes centrifugal 3 minutes.Every kind of cytolysis thing of 800 μ l is moved into new 2ml Eppendorf pipe be used for immunoprecipitation.The anti-phosphotyrosine antibody of 3mg=15 μ l (Santa Cruz PY99-sc-7020) is added behind the cytolysis thing in 4 ℃ of incubations 2 hours.600 μ l washing MagnaBind pearls (goat anti-mouse IgG, Pierce 21354) are added the cytolysis thing, the test tube rotation is spent the night in 4 ℃.

Handle sample 1 minute with magnet, carefully remove the dissolving supernatant liquor then.Then 1ml being dissolved damping fluid adds described pearl and repeats this step twice.Described pearl is suspended in 2 * Laemmli sample loading buffer (containing β-mercaptoethanol) of 25 μ l94 ℃ temperatures, placed 15 minutes in room temperature.

Test tube is positioned over magnet 1 minute to remove bead, the whole liquid application of samples that bead separated acquisition with immunoprecipitation to polyacrylamide/SDS protein gelatin (prefabricated 4-12%BisTrisNuPAGE/MOPS 12 hole gels, Novex).With 200V electrophoresis protein gelatin, then with the 50V/250mA trace in 30 minutes last 1 hours of NC film.All traces are put in room temperature and are handled 1 hour to reduce the non-specific binding that detects antibody with the PBS-tween of 5%Marvel.With the 0.5%Marvel/PBS tween with rabbit anti--Tie2 (Santa Cruz sc-324) adds with 1: 500 extent of dilution, is incubated overnight in 4 ℃.Wash down the trace point with the strictness of PBS-tween, use the 0.5%Marvel/PBS-tween to add goat antirabbit-POD binding substances (Dako P0448) then with 1: 5000 extent of dilution.Antibody was placed 1 hour in room temperature, washed down the trace point with the PBS-tween subsequently.The western blotting point of different immunoprecipitation matter samples LumiGLO (NEB 7003) development trace.Move into the X-Ray magazine then, with film exposure 15sec/30sec and 60sec.Use FluorS BioRad image dissector system evaluation to belong to the protein band relative intensity of the Tie2 acceptor of phosphorylation.Determine the phosphorylation percentage of every kind of test-compound dilution system, use suitable control sample calculating for referencial use IC by standard method with it ₅₀Value.

Although the change with structure as expecting of the pharmacological property of structural formula I compound changes, in general, active available following concentration that structural formula I compound has or dosage utilize one or more above-mentioned tests (a) and (b) confirmation:

1 (a) :-IC ₅₀The value scope, for example,＜100 μ M;

Test (b) :-IC ₅₀The value scope, for example,＜50 μ M;

For example the test (b) in, the IC of embodiment 2 ₅₀Value is 2.7 μ M, and the IC of embodiment 7 ₅₀Value is 2.2 μ M.

Again on the one hand, of the present inventionly provide a kind of medicinal compositions, it comprises on structural formula I compound defined above or its pharmacology acceptable diluent or carrier on acceptable salt and the pharmacology.

The present composition can be and is suitable for oral formulation (tablet for example, lozenge, hard capsule or soft capsule, water suspension or oil suspension, emulsion, but dispersion powder or granule, syrup or elixir), be suitable for the local formulation of using (emulsifiable paste for example, ointment, gel, perhaps watery or oily solution agent or suspensoid), be suitable for the formulation (for example pulvis subtilis or liquid aerosol) of inhalation, be suitable for being blown into the formulation (for example pulvis subtilis) of administration or be suitable for the formulation (vein for example of administered parenterally, subcutaneous, the suppository of the aseptic aqueous solution of intramuscular or intramuscular administration or oil solution or rectal administration).

The present composition can use conventional pharmaceutical excipient well known in the art to obtain by ordinary method.Therefore, oral composition can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

Effective constituent and one or more mixed with excipients are prepared into the concrete approach of host that the dosage of single formulation should treat with the need and administration and change.For example, the prescription of human oral administration comprises usually with the promoting agent of suitable convention amount vehicle preparation 0.5mg-0.5g (0.5-100mg is more suitable, for example 1-30mg) for example, and vehicle accounts for about 5-98% of composition total weight.

With regard to treatment or prevention purpose, the dosage size of structural formula I compound should change by the medical science principle of knowing according to character and severity, animal or patient's age and the sex and the route of administration of disease.

With regard to treatment or prevention purpose, usually can accept the structural formula I compound that gives like this: per daily dose 0.1mg/kg-75mg/kg (body weight) for example, if desired, with the divided dose administration.When administered parenterally, generally give lower dosage.Therefore, for example the common dose of intravenously administrable is for example 0.1mg/kg-30mg/kg (body weight).Equally, the common dose of inhalation is for example 0.05mg/kg-25mg/kg (body weight).Yet preferred oral administration, especially tablet.In general, unit dosage should comprise the The compounds of this invention of about 0.5mg-0.5g.

The The compounds of this invention of this paper definition mainly is its blood vessel formation against function.The disease that expection The compounds of this invention wide model is used for the treatment of or prevent to generate with bad vasculogenesis or pathologic vessels comprises cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, lymphedema, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune disorder, acute inflammation, excessive cicatrization and adhesion, endometriosis, dysfunctional uterine bleeding and retinal vessel hyperplasia eye disease.Cancer can be attacked any tissue, comprises leukemia, multiple myeloma and lymphoma.Specifically, this class The compounds of this invention helps slowing down the growth of primary and recurrent solid tumor, for example colon knurl, mastadenoma, prostate tumor, lung cancer and skin carcinoma.

We think that the angiogenesis inhibitor character of The compounds of this invention is from their Tie2 receptor tyrosine kinase inhibition activity.Correspondingly, The compounds of this invention is used in and produces the Tie2 restraining effect in the warm-blooded animal body that needs this treatment.Therefore, by suppressing the Tie2 receptor tyrosine kinase alone or partly, The compounds of this invention can be used for producing blood vessel formation against function.

More particularly, the expection The compounds of this invention can suppress any type of cancer relevant with Tie2.For example, primary relevant and the growth of recurrent solid tumor with Tie2, especially those mainly rely on the tumour of growth of Tie2 receptor tyrosine kinase and diffusion.

Again on the one hand, the invention provides as acceptable salt on the structural formula I compound defined above of medicine or its pharmacology.

Again on the one hand, the invention provides on structural formula I compound defined above or its pharmacology acceptable salt in preparation as the purposes on the medicine of warm-blooded animal (for example people) Tie2 receptor tyrosine kinase inhibitors.

Again on the one hand, the invention provides acceptable salt on structural formula I compound defined above or its pharmacology is used for warm-blooded animal (for example people) in preparation and produces purposes on the blood vessel formation against function medicine.

Again on the one hand, the invention provides purposes on acceptable salt on structural formula I compound defined above or its pharmacology is used for the treatment of warm-blooded animal (for example people) cancer in preparation the medicine.

Again on the one hand, the invention provides acceptable salt on structural formula I compound defined above or its pharmacology is used for the treatment of the following cancer of warm-blooded animal (for example people) in preparation purposes: leukemia, breast 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.

Again on the one hand, the invention provides inhibition needs the method for Tie2 receptor tyrosine kinase of the warm-blooded animal (for example people) of this treatment, and this method comprises and gives acceptable salt on the structural formula I compound defined above of significant quantity or its pharmacology to described animal.

Again on the one hand, produce the method for blood vessel formation against function in warm-blooded animal (for example people) body that the invention provides in this treatment of needs, this method comprises and gives acceptable salt on the structural formula I compound defined above of significant quantity or its pharmacology to described animal.

Again on the one hand, the invention provides the method for cancer that treatment needs the warm-blooded animal (for example people) of this treatment, this method comprises and gives acceptable salt on the structural formula I compound defined above of significant quantity or its pharmacology to described animal.

Again on the one hand, the invention provides treatment needs the following method for cancer of the warm-blooded animal (for example people) of this treatment: leukemia, breast 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, this method comprise and give acceptable salt on the structural formula I compound defined above of significant quantity or its pharmacology to described animal.

Again on the one hand, the invention provides that acceptable salt is used to suppress warm-blooded animal (for example people) Tie2 receptor tyrosine kinase on structural formula I compound defined above or its pharmacology.

Again on the one hand, the invention provides on structural formula I compound defined above or its pharmacology acceptable salt is used for warm-blooded animal (for example people) and produces blood vessel formation against function.

Again on the one hand, the invention provides that acceptable salt is used for the treatment of cancer on structural formula I compound defined above or its pharmacology.

Again on the one hand, the invention provides that acceptable salt is used for the treatment of following cancer on structural formula I compound defined above or its pharmacology: leukemia, breast 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.

As mentioned above, The compounds of this invention also has anti-other bad or the pathologic vessels generation is disease mediated activity, and these diseases comprise psoriasis, rheumatoid arthritis, Kaposi sarcoma, vascular tumor, lymphedema, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune disorder, acute inflammation, excessive cicatrization and adhesion, endometriosis, dysfunctional uterine bleeding and retinal vessel hyperplasia eye disease.

The anti-angiogenesis activity of this paper definition can be used as independent treatment or can comprise a kind or various other materials and/or treatment except that The compounds of this invention.This combination therapy can be by simultaneously, sequential or treat various treatments separately and finish.At the internal medicine tumor area, using each cancer patients of conjoint therapy of multi-form treatment is conventional practice.At the internal medicine tumor area, except that cell cycle suppression therapy defined above, the other therapies of this class conjoint therapy can be: surgery, radiotherapy or chemotherapy.This kind chemotherapy can comprise a kind or multiple following antitumor drug:

(i) anti-invasion agent (for example inhibitor of inhibitors of metalloproteinase (as Marimastat) and urokinase profibr(in)olysin activator receptor function);

Anti-hyperplasia/the antitumor drug and the conjoint therapy thereof that (ii) are used for tumour, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Antimetabolite (for example antifol such as fluorine pyrimidine such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, perhaps for example, disclosed a kind of antimetabolite (2S)-2-{ for example in the preferred European Patent Application No. 562734 Adjacent-fluoro- Right-[ N-{ 2,7-dimethyl-4-oxo-3,4-dihydroquinazoline-6-ylmethyl }- N-(Propargyl) amino] benzoyl amino }-4-(tetrazolium-5-yl) butyric acid); Antitumor antibiotics (for example anthracycline such as Zorubicin, bleomycin, Dx, daunomycin, epirubicin, idarubicin, Mitomycin-C, gengshengmeisu and Plicamycin); Antimitotic agent (for example Changchun alkaloid such as vincristine(VCR), vinblastine, vindesine and Vinorelbine, and Japanese yew class medicine such as safe element and taxotere); And topoisomerase enzyme inhibitor (for example epipodophyllotoxin such as Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);

(iii) cytostatics estrogen antagonist (tamoxifen for example for example, toremifene, raloxifene, droloxifene and idoxifene), androgen antagonist (bicalutamide for example, flutamide, Nilutamide and cyproterone acetate), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example Magace), aromatase inhibitor (Anastrozole for example, letrozole, vorozole and Exemestane) and 5 inhibitor finasteride for example;

(iv) somatomedin depressant of functions; for example this class inhibitor comprises growth factor antibodies, growth factor receptor antibody, method Buddhist nun's inhibitors, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, for example epidermal growth factor family inhibitor (EGFR tyrosine kinase inhibitor for example N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (ZD 1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (CP 358774) and 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)), for example Thr6 PDGF BB man group inhibitor and for example pHGF man group inhibitor;

(the angiogenesis inhibitor medicine that v) mechanism of action is different with medicine defined above for example suppresses vascular endothelial growth factor medicine for example disclosed compound and the medicine (for example linomide, integral protein α ν β 3 depressant of functions and angiostatin) by other mechanism effect among International Patent Application WO 97/22596, WO97/30035, WO 97/32856 and the WO 98/13354;

(vi) the biotechnological formulation therapeutics is for example used shielding receptors ligand, retardance part bind receptor or is reduced the peptide or the albumen (for example antibody or soluble outer receptor domain construction) of receptor signal transduction (for example owing to strengthening the acceptor degraded or reducing expression level).

(for example ISIS 2503, a kind of anti-ras antisense drug for vii) antisense therapy method, the antisense drug of directed above-mentioned target for example;

(viii) gene therapy comprises method, GDEPT (treatment of the gene pacemaker enzyme prodrug) method (for example using the method for cytosine(Cyt) deaminase, thymidine kinase or bacterium nitroreductase) of for example replacing aberrant gene (for example unusual p53 or unusual BRCA1 or BRCA2) and strengthens the method (for example multi-medicine resistance gene therapy) of patient to chemotherapy or radiotherapeutic tolerance; With

(ix) immunotherapy method, comprise strengthening the immunogenic method of patient's oncocyte in for example external and body, for example use cytokine (for example interleukin-22, interleukin 4 or granulocyte-macrophage colony stimulating factor) transfection method, reduce the anergic method of T-cell, use the method for the immunocyte (for example dendritic cell of cytokine transfection) of transfection, the method for oncocyte system of using cytokine transfection and the method for using antiidiotypic antibody.

This combination therapy can be finished by while, each treatment component sequential or that treat separately.This class combination medicine product uses the The compounds of this invention of above-mentioned dosage range and ratifies other medical active medicine of dosage range.

The present invention provides a kind of medicinal product according to this respect, and it comprises structural formula I compound defined above and other antitumor drug defined above is used for the combination therapy cancer.

Except that the treatment pharmaceutical use, on structural formula I compound and its pharmacology acceptable salt also can be used as exploitation and stdn with laboratory animal for example cat, dog, rabbit, monkey, rat and mouse estimate the pharmacological tool of external and body build-in test system of the cell cycle active function of various inhibitor, described test system is the integral part of searching novel therapeutic medicine.

The present invention is existing to be illustrated by following limiting examples, except as otherwise noted, otherwise:

(i) provide temperature for degree centigrade (℃); Operate promptly 18-25 ℃ in room temperature or ambient temperature;

(ii) organic solution anhydrous magnesium sulfate drying; Use rotatory evaporator decompression (600-4000 pascal; 4.5-30 mmhg) and bath temperature evaporating solvent 60 ℃ time the at the most;

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

(iv) in general, monitor with TLC and/or analytical LC-MS after the reaction process, and the reaction times that provides only illustrates;

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

(vi) the output of giving only illustrates and not necessarily can both obtain by tight technological process; More if desired materials then repeat preparation;

(vii) when NMR data that provide during for the main δ value form of identifying proton, to provide with respect to interior target ppm of tetramethylsilane (TMS) (ppm), except as otherwise noted, otherwise with regard to full deuterium methyl-sulphoxide (DMSO-d ₆) make solvent and measure in 300MHz; Use following abbreviation: s, unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; B, broad peak;

(viii) chemical symbol is its implication commonly used; Use SI units and symbol;

(ix) solvent ratio is a volume: volume (v/v); And

(x) carry out mass spectrum (MS) in chemi-ionization (CI) mode with 70 electron-volts electronic energy with directly exposing probe to the open air; Wherein the ionization of Xian Shiing is finished by electronic impact (EI), fast atom bombardment (FAB) or electron spray(ES) (ESP); Provide the m/z value; In general, report is the ion of only indicating the parent quality; Except as otherwise noted, otherwise the mass ion that provides is MH ⁺

(xi) except as otherwise noted, otherwise folding divides the compound that comprises asymmetric replacement carbon and/or sulphur atom;

(xii) synthetic when being similar to synthetic that front embodiment introduces when what introduce, the mmole of usage quantity is than the mmole ratio that equals front embodiment use;

(xvi) use following abbreviation:

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

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

ⁱThe PrMgCl isopropylmagnesium chloride

LDA diisopropylaminoethyl lithium

LHMDS two (trimethyl silyl) lithium amide

The m-CPBA metachloroperbenzoic acid

MeOH methyl alcohol

The MeCN acetonitrile

MCX mixed-cation exchange resin

The MTBE methyl tertiary butyl ether

The LCMS C/MS (liquid chromatography-mass spectrography)

The NMP 1-Methyl-2-Pyrrolidone

PhTosMIC α-tosyl group benzyl isocyanides

POCl ₃Phosphoryl chloride

The RPHPLC reversed-phased high performace liquid chromatographic

The TFA trifluoracetic acid

The THF tetrahydrofuran (THF)

Xvii) when the synthetic generation acid salt (for example HCl salt) introduced, the stechiometry of undeclared this salt.Except as otherwise noted, otherwise all MR data of report are free base material, characterize after being converted into free alkali form with isolating salt.

Embodiment 1

2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3]Evil Azoles is [5,4-d] pyrimidine-7-amine also

To contain 5-amino-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-1,3-oxazole-4-formonitrile HCN (intermediate 5) dry DMF (2.0mL) (650mg) added dry DMF (20mL) suspension that contains formamidine acetate (2.55g), in 100 ℃ of heating 0.5 hour.Behind the evaporating solvent, purify with the fast silica gel chromatogram method, and DCM: the MeOH of elder generation (100: 0-95: 5) wash-out, use DCM: MeOH: NH then ₃(94: 5: 1) wash-out obtains beige solid title compound (221mg, 31%);

¹H?NMR(DMSO-d ₆)δ3.95(s，3H)，7.24-7.41(m，3H)，7.63-7.69(m，4H)，8.02(s，1H)，8.2(s，1H)；

MS?m/e?MH ⁺293。

The raw material that uses is prepared as follows:

Intermediate 1

(1-methyl-4-phenyl-1H-imidazoles-5-yl) methyl alcohol

(33% industrial methylated spirits 60.3mL) adds the solution that glycolaldehyde dimer (2.7g) is dissolved in THF (320mL) with methylamine.After 75 minutes, add 1-1{[isocyano-(phenyl) methyl] alkylsulfonyl }-4-toluene (PhTosMIC) (Org.Syn., 77,198-205) (10.8g), cooling makes this reaction keep below 30 ℃.Stirring reaction 90 minutes, evaporating solvent is to volume 100mL.Add entry (500mL), filter and collect white solid title compound (4.94g, 66%).Extract filtrate with EtOAc, dry final vacuum removes and desolvates.Use the EtOAc grinding residues, obtain other white solid 1.06g (14%).

¹H?NMR(DMSO-d ₆)δ3.66(s，3H)，4.53(d，2H)，5.16(t，1H)，7.25(t，1H)，7.36(d，2H)，7.61-7.64(m，3H)。

MS?m/e?MH ⁺189。

Intermediate 2

1-methyl-4-phenyl-1H-imidazoles-5-formaldehyde

Manganse Dioxide (11.5g) is added (1-methyl-4-phenyl-1H-imidazoles-5-yl) methyl alcohol (intermediate 1) dioxane (100mL) suspension (5.75g),, be cooled to ambient temperature then and spend the night gained mixture heating up to 80 ℃ 8 hours.Heated mixt to 80 ℃ once more is through diatomite filtration, with the thorough washing leaching cake of acetone.Purify with the fast silica gel chromatogram method, use EtOAc: (50: 50-100: 0) wash-out obtains pale solid title compound (4.90g, 86%) to hexane.

¹H?NMR(DMSO-d ₆)δ3.89(s，3H)，7.43-7.50(m，3H)，7.72(d，2H)，8.03(s，1H)，9.83(s，1H)。

MS?m/e?MH ⁺187。

Intermediate 3

1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid

Salt of wormwood (3.13g) is added 1-methyl-4-phenyl-1H-imidazoles-5-formaldehyde (intermediate 2) (2.33g) be dissolved in the solution of acetone (125mL) and water (25mL).The dissolving back adds potassium permanganate (4.23g), stirs the mixture 24 hours.Mixture is through diatomite filtration, water (2 * 20mL) washing leaching cakes.Behind filtrate evaporation acetone, with EtOAc (50mL) extraction.To pH5, reduce volume with acetate acidifying water layer, filter faint yellow precipitation,, obtain faint yellow solid title compound (1.74g, 69%) in 60 ℃ of vacuum-dryings to half

¹H?NMR(DMSO-d ₆)δ3.8(s，3H)，7.3-7.4(m，3H)，7.65(m，2H)，7.9(s，1H)；

MS?m/e?MH ⁺203。

Intermediate 4

1-methyl-4-phenyl-H-imidazoles-5-carbonyl chloride

Oxalyl chloride (0.35mL) and a DMF added successively contain 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (intermediate 3) anhydrous DCM (6mL) suspension (732mg).Inert atmosphere stirred down after 1 hour, and evaporating mixture directly uses and need not further purification (800mg, 100%) to doing.

Intermediate 5

5-amino-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-1,3-Evil Azoles-4-formonitrile HCN

1-methyl-4-phenyl-1H-imidazoles-5-carbonyl chloride (intermediate 4) anhydrous NMP (2mL) suspension (0.80g) is added the anhydrous NMP (10mL) that contains amino propane dinitrile tosilate (0.92g).Stirred the gained mixture 24 hours.Pour mixture into water (10mL), with EtOAc (3 * 20mL) extractions, further washing of water (10mL), sodium bicarbonate aqueous solution (10mL) and salt solution (10mL) successively behind the merging organism.Dry (MgSO ₄) evaporate behind the organism, obtain canescence natural gum.Grind with isohexane (5mL), obtain white solid title compound (650mg, 68%);

¹H?NMR(DMSO-d ₆)δ3.74(s，3H)，7.3-7.4(m，3H)，7.6(m，2H)，7.9(bs，3H)；

MS?m/e?MH ⁺266。

Embodiment 2

2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

Thiophosphoric anhydride (411mg) adding under inert atmosphere is contained N-(4-amino-6-hydroxy pyrimidine-5-yl)-1-methyl-4-phenyl-1H-imidazoles-5-methane amide (intermediate 6) anhydrous pyridine (1.0mL) suspension (0.185g), in 110 ℃ of heating 24 hours.Evaporating solvent, resistates preadsorption are purified with column chromatography on silica gel, use earlier DCM: MeOH (100: 0-90: 10) wash-out, back DCM: MeOH: NH ₃(89: 10: 1) wash-out.Water grinds the back in 60 ℃ of vacuum-dryings, obtains yellow solid title compound (32mg, 19%);

¹H?NMR(DMSO-d ₆)δ3.92(s，3H)，7.35-7.42(m，3H)，7.48-7.52(m，2H)，7.74(bs，2H)，7.99(s，1H)，8.26(s，1H)；

MS?m/e?MH ⁺309。

The raw material that uses is prepared as follows:

Intermediate 6

N-(4-amino-6-hydroxy pyrimidine-5-yl)-1-methyl-4-phenyl-1H-imidazoles-5-methane amide

To contain anhydrous NMP (1mL) adding (0.50g) of 1-methyl-4-phenyl-1H-imidazoles-5-carbonyl chloride (intermediate 4) and contain 4, the anhydrous NMP (5mL) of 5-diamino-6-hydroxyl-pyrimidine (312mg) stirred 24 hours.Pour reaction mixture into water (15mL), use NH ₃The aqueous solution is adjusted to pH9, stirs 15 minutes until the precipitation end.Leach solid, wash the back with water, obtain white solid title compound (185mg, 24%) in 60 ℃ of vacuum-dryings;

¹H?NMR(DMSO-d ₆)δ3.76(s，3H)，6.17(bs，2H)，7.19-7.33(m，3H)，7.73(s，1H)，7.78(s，1H)，7.94(dd，2H)，8.70(s，1H)，11.72(bs，1H)。

Embodiment 3

8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

Vanadium Pentoxide in FLAKES (1.06g) is added N-(4,6-di-amino-pyrimidine-5-yl)-1-methyl-4-phenyl-1H-imidazoles-5-methane amide (intermediate 7) (171mg), add then phosphoric acid (85%, 0.76mL), in 160 ℃ of heating 72 hours.To ice adding refrigerative mixture, use NH then ₃The aqueous solution is adjusted to pH 5, leaches the gained precipitation, washes the back with water in 60 ℃ of vacuum-dryings, obtains faint yellow solid title compound (156mg, 89%);

¹H?NMR(DMSO-d ₆+AcOH-d ₄)δ3.64(s，3H)，7.15-7.28(m，3H)，7.43(dd，2H)，7.89(s，1H)，8.14(s，1H)；

MS?m/e?MH ⁺292。

The raw material that uses is prepared as follows:

Intermediate 7

N-(4,6-di-amino-pyrimidine-5-yl)-1-methyl-4-phenyl-1H-imidazoles-5-methane amide

To contain anhydrous NMP (1mL) the suspension adding (0.30g) of 1-methyl-4-phenyl-1H-imidazoles-5-carbonyl chloride (intermediate 4) and contain 4,5, the anhydrous NMP (2mL) of 6-Triaminopyrimidine (358mg).Stir the gained mixture 24 hours, and poured in the water (10mL), use NH ₃The aqueous solution is adjusted to pH 9, stirs 10 minutes then until precipitating fully.Leach solid, wash the back with water, obtain faint yellow solid title compound (171mg, 37%) in 60 ℃ of vacuum-dryings

¹H?NMR(DMSO-d ₆)δ3.77(s，3H)，5.79(s，4H)，7.26-7.38(m，3H)，7.68(dd，2H)，7.76(s，1H)，7.78(s，1H)，8.75(s，1H)；

MS?m/e?MH ⁺309。

Embodiment 4 and 5

9-methyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine and

7-methyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7H-purine-6-amine

Sodium hydride (60% oily dispersion liquid) (0.026g) is added 8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine (embodiment 3) in 30 ℃ (0.18g) be dissolved in the solution of DMF (25ml).After 1 hour, add methyl iodide (0.088g), reaction stirred 5 hours in 30 ℃ of stirrings.Evaporating solvent adds saturated aqueous sodium carbonate (20mL) and chloroform (20mL).In chloroform (aqueous layer extracted once more in 3 * 20mL), dry (MgSO ₄) organism that merges, filter the final vacuum evaporation, obtain brown oil.Purify with the fast silica gel chromatogram method, use DCM: MeOH (99: 1) wash-out obtains isolating white solid title compound:

Higher R _fIsomer; 0.081g, 43%.

¹H?NMR(CDCl ₃)δ3.28(s，3H)，3.75(s，3H)，5.72(s，b，2H)，7.27(m，3H)，7.38(d，2H)，7.71(s，1H)，8.41(s，1H)；

MS?m/e?MH ⁺306。

Low R _fIsomer; 0.004g, 2%.

¹H?NMR(CDCl ₃)δ3.42(s，3H)，3.83(s，3H)，5.05(s，b，2H)，7.31(m，3H)，7.41(m，2H)，7.75(s，1H)，8.55(s，1H)；

MS?m/e?MH ⁺306。

Do not identify the higher and low specific isomer that keeps part.

Embodiment 6

6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine

To contain N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14) (76mg), the THF (5mL) of PhTosMIC (99mg) and piperazine (31mg) stirred 6 days down in inert atmosphere.With EtOAc and water diluted reaction mixture.Separate organic layer, with EtOAc (2 * 15mL) aqueous layer extracted.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate.Purify by the fast silica gel chromatogram method, use hexane: EtOAc (1: 4) wash-out obtains faint yellow solid title compound (50mg, 48%);

¹H?NMR(CDCl ₃)δ3.74(s，3H)，3.87(s，3H)，5.07(s，2H)，6.53-6.60(m，2H)，6.76-6.79(m，1H)，7.15(s，1H)，7.22-7.30(m，3H)，7.56-7.59(m，2H)，7.74(s，1H)，9.08(s，1H)，9.12(s，1H)；

MS?m/e?MH ⁺429。

The raw material that uses is prepared as follows:

Intermediate 8

4,6-two-chloropyrimide-5-formaldehyde

DMF (7mL) is added dropwise to the POCl that internal temperature keeps below 30 ℃ ₃(22mL).Add 4,6-dihydroxy-pyrimidine (5.0g), temperature keeps below 30 ℃.Stirred reaction mixture 20 minutes is heated to then and refluxed 4 hours.Excessive POCl is removed in evaporation ₃, the gained viscous mixt is poured into the ice solution of stirring.With diethyl ether (6 * 50mL) extraction products.The organism that vacuum concentration merges is purified with the fast silica gel chromatogram method then, uses hexane: (7: 1-2: 1) wash-out obtains white crystalline solid title compound (4.42g, 56%) to EtOAc;

¹H?NMR(CDCl ₃)δ8.89(s，1H)，10.46(s，1H)。

Intermediate 9

[(6-chloro-5-formyl radical pyrimidine-4-yl) sulfenyl] methyl acetate

DIPEA (4.1mL) is down added 4 in inert atmosphere, and 6-dichloro pyrimidine-5-formaldehyde (intermediate 8) (4.2g) is dissolved in the solution of DCM (85mL).Solution is cooled to-10 ℃, is added dropwise to the DCM (40mL) that contains thin guanidine-acetic acid methyl esters (2.1mL) in 30 minutes.Reaction mixture was warming up to ambient temperature about 2 hours, water (4 * 50mL) washings, dry (MgSO ₄), filter final vacuum and concentrate, obtain the orange oily title compound of solidified (5.4g, 92%) subsequently;

¹H?NMR(CDCl ₃)δ3.75(s，3H)，3.99(s，2H)，8.76(s，1H)，10.56(s，1H)。

Intermediate 10

The 4-chlorothiophene is [2,3-d] pyrimidine-6-carboxylate methyl ester also

DIPEA (2.1mL) adding under inert atmosphere is contained [(6-chloro-5-formyl radical pyrimidine-4-yl) sulfenyl] methyl acetate (intermediate 9) hexalin (50mL) (2.9g).In 120 ℃ of reacting by heating mixtures 90 minutes.Evaporating solvent, with fast silica gel chromatogram method purified product, use hexane: diethyl ether (4: 1) wash-out obtains faint yellow solid title compound (1.45g, 53%);

¹H?NMR(CDCl ₃)δ4.01(s，3H)，8.13(s，1H)，8.94(s，1H)。

Intermediate 11

Thieno-[2,3-d] pyrimidine-6-carboxylate methyl ester

Also [2,3-d] pyrimidine-6-carboxylate methyl ester (intermediate 10) (114mg), the Virahol (10mL) of magnesium oxide (40mg) and Pd/C (12mg) stirred 48 hours down in hydrogen will to contain the 4-chlorothiophene.Solution is through diatomite filtration, with DCM (3 * 10mL) washing, vacuum concentration then.Purify with the fast silica gel chromatogram method, use hexane: EtOAc (2: 1) wash-out obtains white crystalline solid title compound (76mg, 78%);

¹H?NMR(CDCl ₃)δ4.00(s，3H)，8.07(s，1H)，9.19(s，1H)，9.25(s，1H)；

MS?m/e?MH ⁺195。

Intermediate 12

N-methoxyl group-N-thiotolene is [2,3-d] pyrimidine-6-methane amide also

Will ⁱPrMgCl (THF that contains 2M, 1.1mL) in-20 ℃, internal temperature keep below-5 ℃ be added dropwise to thieno-[2,3-d] pyrimidine-6-carboxylate methyl ester (intermediate 11) (138mg) and N-methoxyl group-N-methane amide (104mg) be dissolved in the solution of THF.In-10 ℃ of reaction stirred 30 minutes, use NH then ₄Cl (saturated aqueous solution) quencher reaction.Use the EtOAc diluting soln, separate organic layer.With EtOAc (2 * 15mL) aqueous layer extracted, dry then (MgSO ₄) organism that merges, filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use hexane: (1: 1-1: 4) wash-out obtains faint yellow solid title compound (107mg, 67%) to EtOAc;

¹H?NMR(CDCl ₃)δ3.46(s，3H)，3.86(s，3H)，8.22(s，1H)，9.19(s，1H)，9.26(s，1H)。

Intermediate 13

Thieno-[2,3-d] pyrimidine-6-formaldehyde

Under the inert atmosphere with LiAlH ₄(THF of 1M 0.26mL) is added dropwise in-78 ℃ and contains also [2,3-d] pyrimidine-6-methane amide (intermediate 12) THF (6mL) (117mg) of N-methoxyl group-N-thiotolene.In-78 ℃ of reaction stirred 30 minutes, be warming up to 0 ℃ then.Adding saturated aqueous ammonium chloride (2mL) back stirred 10 minutes in 0 ℃.Separate organic layer, (2 * 15mL) extract water layer with diethyl ether.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use hexane: EtOAc (1: 4) wash-out obtains white solid title compound (60mg, 70%);

¹H?NMR(CDCl ₃)δ8.06(s，1H)，9.22(s，1H)，9.33(s，1H)，10.15(s，1H)；

MS?m/e?MH ⁺165。

Intermediate 14

N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine

With thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 13) (40mg), 3,4-dimethoxybenzylamine (0.04ml) and 4 molecular sieves (150mg) in DCM (5ml) under inert atmosphere reflux 3 hours.Remove by filter molecular sieve, evaporating solvent obtains faint yellow solid title compound (76mg, 100%);

¹H?NMR(CDCl ₃)δ3.87-3.90(m，6H)，4.84(s，2H)，6.84-6.88(m，3H)，7.51(s，1H)，8.50(s，1H)，9.10(s，1H)，9.11(s，1H)。

Embodiment 7

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, only be to use N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-and N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14).Obtain Off-white solid title compound (105mg, 81%);

¹H?NMR(CDCl ₃)δ2.73(s，3H)，3.65(s，3H)，7.19-7.30(m，3H)，7.57-7.61(m，2H)，7.66(s，1H)，8.86(s，1H)；

MS?m/e?MH ⁺339。

The raw material that uses is prepared as follows:

Intermediate 15

4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde

To contain 4-(methylthio group) thieno-[2,3-d] pyrimidine (J.Heterocycl.Chem.1975,12,921-924) THF of (1g) (5mL) in-78 ℃ add LDA[BuLi (hexane of 1.6M, 3.8mL) and Diisopropylamine (0.85mL)] be dissolved in the prefabricated solution of THF (20mL).In-78 ℃ of stirred reaction mixtures 1 hour, add DMF (1.1mL) then.In-78 ℃ of stirred reaction mixtures 30 minutes, be warming up to ambient temperature then, stirred once more 3 hours.The dilute with water reaction mixture is with EtOAc (4 * 30mL) extraction products.The organic extract that merges washs with salt solution (30mL), dry (MgSO ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use the DCM wash-out, obtain white solid title compound (1.17g, 51%);

¹H?NMR(CDCl ₃)δ2.76(s，3H)，8.03(s，1H)，8.90(s，1H)，10.10(s，1H)；

MS?m/e?MH ⁺211。

Intermediate 16

N-[4-(methylthio group thieno-[2,3-d[pyrimidine-6-methylene] methylamine

Prepare title compound by being similar to the method for preparing intermediate 14 introductions, only be to use 4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 15) replacement thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 13) and replace 3 with methylamine (33% methylated spirits), the 4-dimethoxybenzylamine.Obtain colorless solid title compound (73mg, 98%);

¹H?NMR(CDCl ₃)δ2.73(s，3H)，3.57(s，3H)，7.48(s，1H)，8.45(s，1H)，8.83(s，1H)。

Embodiment 8

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

With 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17) (30mg) and dense NH ₃(0.75mL) 1, stirred 1 hour in the 4-diox (3mL).Evaporating solvent, the gained resistates is dissolved in a small amount of DCM.Add isohexane then, filter gained solid after drying vacuum, obtain faint yellow solid title compound (25mg, 100%);

¹H?NMR(CDCl ₃)δ3.61(s，3H)，5.44(bs，2H)，7.10(s，1H)，7.21-7.31(m，3H)，7.58-7.61(m，2H)，7.66(s，1H)，8.53(s，1H)；

MS?m/e?MH ⁺308。

The raw material that uses is prepared as follows:

Intermediate 17

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

(70-75% 105mg) adds 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7) and (72mg) is dissolved in the stirred solution of DCM (5mL), stirs after 6 hours, adds 2M Na with m-CPBA ₂S ₂O ₃(2.5mL).Use DCM (2 * 15mL) aqueous layer extracted after separating organic layer.The saturated NaHCO of organism that merges ₃The aqueous solution (10mL) washing, dry (MgSO ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use hexane: EtOAc (1: 4) wash-out obtains yellow solid title compound (44mg, 56%);

¹H?NMR(CDCl ₃)δ3.45(s，3H)，3.73(s，3H)，7.25-7.34(m，3H)，7.54-7.57(m，2H)，7.70(s，1H)，8.04(s，1H)，9.16(s，1H)；

MS?m/e?MH ⁺371。

Embodiment 9

6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3- D] pyrimidine

The step that use is similar to preparation embodiment 6 introductions prepares title compound (55% productive rate), just with raw material N-(3, the 4-dimethoxy-benzyl)-N-{[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-yl] methylene radical } amine (intermediate 18) (76mg) replaces N-(3, the 4-dimethoxy-benzyl)-and N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14);

¹H?NMR(CDCl ₃)δ2.71(s，3H)，3.75(s，3H)，3.87(s，3H)，5.05(s，2H)，6.54-6.62(m，2H)，6.79(d，1H)，7.11(s，1H)，7.22-7.30(m，3H)，7.58-7.61(m，2H)，7.74(s，1H)，8.84(s，1H)；

MS?m/e?MH ⁺475。

The raw material that uses is prepared as follows:

Intermediate 18

N-(3, the 4-dimethoxy-benzyl)-N-{[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-yl] methylene radical } Amine

Prepare title compound by being similar to the method for preparing intermediate 14 introductions, just replace thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 13) with 4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 15).Obtain white solid title compound (76mg, 97%);

¹H?NMR(CDCl ₃)δ2.71(s，3H)，3.87-3.89(m，6H)，4.81(d，2H)，6.83-6.87(m，3H)，7.50(s，1H)，8.45(t，1H)，8.82(s，1H)。

Embodiment 10

6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-[1-(3; the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl]-4-(methylsulfonyl)-thieno-[2; 3-d] pyrimidine (intermediate 19) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain white solid title compound (35mg, 91%);

¹H?NMR(CDCl ₃)δ3.72(s，3H)，3.84(s，3H)，4.96(s，2H)，5.47(bs，2H)，6.49-6.50(m，1H)，6.54-6.58(m，1H)，6.75(d，1H)，6.83(s，1H)，7.32-7.51(m，3H)，7.57-7.60(m，2H)，7.69(s，1H)，8.49(s，1H)；

MS?m/e?MH ⁺444。

The raw material that uses is prepared as follows:

Intermediate 19

6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl]-4-(methylsulfonyl) thieno- [2,3-d] pyrimidine

Prepare title compound (75% productive rate) with being similar to the method for preparing intermediate 17 introductions, just with raw material 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 9) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7);

¹H?NMR(CDCl ₃)δ3.41(s，3H)，3.74(s，3H)，3.84(s，3H)，5.11(s，2H)，6.54-6.60(m，2H)，6.77(d，1H)，7.12-7.31(m，3H)，7.53-7.56(m，2H)，7.74(s，1H)，7.91(s，1H)，9.12(s，1H)；

MS?m/e?MH ⁺507。

Embodiment 11

(THF of 2M 2.5mL) adds 4-(methylthio group) thieno-[3,2-d] pyrimidine-6-formaldehyde (intermediate 21) and (105mg) is dissolved in the solution of the DCM (10mL) that contains 4 molecular sieves (1g) with methylamine.Stirred reaction mixture 2.5 hours adds PhTosMIC (149mg) and piperazine (90mg) then.Reaction stirred is 72 hours once more, and then adds PhTosMIC (30mg).Stir once more after 1.5 hours and pour mixture into water, with DCM extraction, water and salt water washing, dry back is removed and is desolvated.Purify with the fast silica gel chromatogram method, use EtOAc: (25: 75-0: 100) wash-out obtains pale solid spumescence title compound (95mg, 56%) to hexane;

¹H?NMR(CDCl ₃)δ2.77(s，3H)，3.66(s，3H)，7.22-7.28(m，3H)，7.47(s，1H)，7.55(dd，2H)，7.67(s，1H)，8.99(s，1H)。

MS?m/e?MH ⁺339。

The raw material that uses is prepared as follows:

Intermediate 20

4-(methylthio group) thieno-[3,2-d] pyrimidine

With sodium methyl mercaptide (9.1g) add the 4-chlorothiophene also [3,2-d] pyrimidine (WO 9849899, embodiment 3A; WO 9924440, embodiment 1C) (17.0g) be dissolved in the solution of DMF (100mL).Stir after 90 minutes, pour mixture into water (400mL),, wash with water, dry (MgSO with the EtOAc extraction ₄) back except that desolvating.Purify with the fast silica gel chromatogram method, use DCM: EtOAc (4: 1) wash-out obtains faint yellow solid title compound (16.5g, 69%);

¹H?NMR(CDCl ₃)δ2.76(s，3H)，7.50(d，1H)，7.85(d，1H)，8.97(s，1H)。

MS?m/e?MH ⁺182。

Intermediate 21

4-(methylthio group) thieno-[3,2-d] pyrimidine-6-formaldehyde

Prepare title compound by being similar to the method for preparing intermediate 15 introductions, just replace 4-(methylthio group) thieno-[2,3-d] pyrimidine with 4-(methylthio group) thieno-[3,2-d] pyrimidine (intermediate 20).Obtain yellow solid title compound (434mg, 38%);

¹H?NMR(DMSO-d ₆)δ3.76(s，3H)，8.52(s，1H)，9.09(s，1H)，10.25(s，1H)。

MS?m/e?MH ⁺211。

Embodiment 12

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[3,2-d] pyrimidine-4-amine

With dense NH ₃The aqueous solution (0.5mL) and saturated ammonium chloride solution (1) add 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[3,2-d] pyrimidine (embodiment 11) and (40mg) are dissolved in the solution of NMP (2mL).Behind the sealed tube, (the CEM detector, 200-210 ℃, 110W) heating is 35 minutes for microwave.Water (1.5mL) dilution is used MeCN: H after RPHPLC purifies ₂(2: 98-40: 60) wash-out obtains light brown solid title compound (24mg, 67%) to O;

¹H?NMR(DMSO-d ₆)δ3.73(s，3H)，7.30-7.50(m，5H)，7.78(s，1H)，8.74(s，b，2H)，9.03(s，b，2H)。

MS?m/e?MH ⁺308。

Embodiment 13

5-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-1H-imidazoles-1-alcohol

With 1-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-2-phenylethane-1,2-diketone-1-oxime (intermediate 23) (300mg), neutralized verdigris (290mg) and the mixture heating up to 95 of ammonium acetate (690mg) in acetate (20mL) ℃.In 4 hours, add the acetate (0.9M) that contains Paraformaldehyde 96 gradually.After adding 1.2mL Paraformaldehyde 96 stock solution, finish reaction.Evaporating solvent is suspended in residual solid the mixture after-filtration of acetonitrile (8mL) and water (8mL).Obtain the brown solid title compound, water (10mL) and diethyl ether (20mL) washing, dry air (189mg, 62%).Filtrate obtains white solid title compound sample (47mg, 15%) through preparation type RPHPLC (with MeCN and water+0.1%TFA gradient elution) after scouring;

¹H?NMR(CDCl ₃)δ2.72(s，3H)，7.4(m，3H)，7.56(d，2H)，7.59(s，1H)，8.36(s，1H)，8.95(s，1H)。

MS?m/e?MH ⁺341。

The raw material that uses is prepared as follows:

Intermediate 22

6-methyl-4-(methylthio group) thieno-[3,2-d] pyrimidine

With sodium methyl mercaptide (245mg) and 6-methyl-4-chlorothiophene also [3,2-d] pyrimidine (Acta Pol.Pharm. (1986), 43 (2), 97-100) (650mg) solution stirring of being dissolved in acetonitrile (50mL) is spent the night.Wash solid with acetonitrile behind the filtering mixt.Filtrate and washing lotion that evaporation merges obtain white solid title compound (665mg, 97%);

MS?m/e?MH ⁺197。

Intermediate 23

1-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-2-phenylethane-1,2-diketone 1-oxime

6-methyl-4-(methylthio group) thieno-[3,2-d] pyrimidine (intermediate 22) (665mg) is dissolved in THF (10mL), slowly adds LHMDS in-78 ℃ in 15 minutes and be dissolved in THF (1M, stirred solution 3.39mL).After 10 minutes, add N-methoxyl group-N-methyl-benzamide (616mg), reaction mixture is warming up to 0 ℃.In 0 ℃ after 2 hours, gained solution 2-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-1-phenylethane ketone is with acetate (10mL) acidifying, is cooled to 0 ℃ once more after water (10mL) dilution.Add Sodium Nitrite (280mg), stir the mixture and spend the night.Behind the evaporating solvent, water solid collected by filtration resistates, dry back obtains brown solid title compound (959mg, 86%);

MS?m/e?MH ⁺330。

Embodiment 14

6-(4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine

To contain the 5-[4 methylthio group] furo [2,3-d] pyrimidine-6-yl]-4-phenyl-1H-imidazoles-1-alcohol (intermediate 25) is (375mg) and Raney nickel (Aldrich, the stirring that under the hydrogen capsule, refluxes of aqeous suspension, the suspension of ethanol 0.5mL) (75mL) and water (75mL).After 4 days, mixture filters through Celite pad, with the mixture washing solid of second alcohol and water.Filtrate and washing lotion that evaporation merges, resistates is purified through preparation type RPHPLC (with MeCN and water+0.1%TFA gradient elution), obtains white solid title compound (105mg, 35%);

¹H?NMR(DMSO-d ₆)δ7.16(s，1H)，7.5(m，3H)7.6(d，2H)，8.5(s，1H)，8.9(s，1H)，9.13(s，1H)；

MS?m/e?MH ⁺263。

The raw material that uses is prepared as follows:

Intermediate 24

6-methyl-4 (methylthio group) furo 12,3-d] pyrimidine

6-methyl-4-chlorine furo [2,3-d] pyrimidine (US 3577420, example I G) (219mg) was dissolved in the solution of acetonitrile (25mL) and sodium methyl mercaptide (190mg) reflux 16 hours.Wash solid with acetonitrile behind the filtering mixt.Evaporating solvent obtains white solid title compound (230mg, 90%);

MS?m/e?MH ⁺181。

Intermediate 25

5-[4-(methylthio group) furo [2,3-d] pyrimidine-6-yl]-4-phenyl-1H-imidazoles-1-alcohol

Use is similar to the method for preparing intermediate 23 introductions and prepares title compound (35% productive rate), use behind the aforesaid method to be similar to and prepare the method that embodiment 13 introduces, just with raw material 6-methyl-4 (methylthio group) furo [2,3-d] pyrimidine (intermediate 24) (230mg) replaces 6-methyl-4-(methylthio group) thieno-[3,2-d] pyrimidine (intermediate 22).Title compound is no longer purified and is directly used;

MS?m/e?MH ⁺325。

Embodiment 15

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine

With cuprous iodide (I) (2mg), two (triphenylphosphine) palladium chloride (4mg) and 4-hydroxyl-5-iodine pyrimidine (Coll.Czech.Chem.Commun., 1962,27,2550-2560) (51.9mg) is at DMF (6mL) and NEt ₃Stir in the mixture (2mL), then with the nitrogen degassing 30 minutes.Add 5-ethynyl-1-methyl-4-phenyl-1H-imidazoles (intermediate 26) (42.6mg), stirred reaction mixture was 16 hours then, in 50 ℃ of heating 8 hours.(3 * 10mL) extraction mixtures, the organism of merging is with salt solution (2 * 10mL) and water (4 * 10mL) washings, drying (MgSO with DCM to add entry (10mL) back ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method,, obtain white solid title compound (17.1mg, 26%) with DCM-MeOH (40: 1) wash-out;

¹H?NMR(CDCl ₃)δ3.87(s，3H)，6.78(s，1H)，7.29-7.40(m，3H)，7.60-7.66(m，2H)，8.97(s，1H)，9.00(s，1H)；

MS?m/e?MH ⁺277。

The raw material that uses is prepared as follows:

Intermediate 26

5-ethynyl-1-methyl-4-phenyl-1H-imidazoles

(pentane of 2M, 650 μ L) are added dropwise to the THF (1mL) that contains trimethyl silyl diazomethane (hexane of 2M, 750 μ L) with n-Butyl Lithium, stir 30 minutes after being cooled to-78 ℃.In 5 minutes, be added dropwise to 1-methyl-4-phenyl-1H-imidazoles-5-formaldehyde (intermediate 2) (186mg), continue to stir 30 minutes, in 30 minutes, be warming up to 0 ℃ then, stirred once more 30 minutes in 0 ℃ in-78 ℃.Add saturated aqueous ammonium chloride (3mL), with diethyl ether (3 * 5mL) extraction mixtures, dry (MgSO ₄) organism that merges, filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use DCM: MeOH (50: 1) wash-out obtains yellow solid title compound (61.3mg, 34%);

¹H?NMR(DMSO-d ₆)δ3.68(s，3H)，5.00(bs，1H)，7.27-7.32(m，1H)，7.40-7.49(m，2H)，7.81(bs，1H)，8.04-8.06(m，2H)；

MS?m/e?MH ⁺183。

Embodiment 16

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine-4-amine

Prepare title compound (13% productive rate) with the method that is similar to the foregoing description 15 introductions, just replace 4-hydroxyl-5-iodine pyrimidine with raw material 4-amino-5-iodo-6-hydroxy pyrimidine (intermediate 27);

¹H?NMR(CDCl ₃)δ3.80(s，3H)，5.25(bs，2H)，6.61(s，1H)，7.29-7.38(m，3H)，7.61-7.64(m，3H)，8.42(s，1H)；

MS?m/e?MH ⁺292。

The raw material that uses is prepared as follows:

Intermediate 27

4-amino-5-iodo-6-hydroxy pyrimidine

(1.5N stirs post-heating to 60 in 12.7mL) ℃ 30 minutes at aqueous sodium hydroxide solution with 4-amino-6-hydroxy pyrimidine (1.77g).After being cooled to ambient temperature, added iodine (4.04g) back backflow mixture 2 hours.The ice bath cooling mixture filters, and with ice cold water (10mL) washing, passes through P in 60 ℃ then ₂O ₅Vacuum oven suction dried 16 hours obtains white solid title compound (886mg, 23%);

¹H?NMR(DMSO-d ₆)δ6.65(bs，1H)，7.76(s，1H)，11.34(bs，2H)；

MS?m/e?MH ⁺238。

Embodiment 17

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7H-pyrrolo-[2,3-d] pyrimidine

Potassium tert.-butoxide (84mg) is added 5-[(1-methyl-4-phenyl-1H-imidazoles-5-yl) ethynyl] (41mg) back stirring among NMP (2mL) of pyrimidine-4-amine (intermediate 28), be heated to 60 ℃ 5 hours.After being cooled to ambient temperature, add entry (3mL) and DCM (10mL) successively.Water (4 * 10mL) washing reaction mixtures, dry (MgSO ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use DCM: (20: 1-10: 1) wash-out obtains white solid title compound (13.6mg, 33%) to MeOH;

¹H?NMR(CDCl ₃)δ3.70(s，3H)，6.70(s，1H)，7.27-7.30(m，3H)，7.47-7.52(m，2H)，7.66(s，1H)，8.83(s，1H)，9.03(s，1H)，9.40(s，1H)；

MS?m/e?MH ⁺276。

The raw material that uses is prepared as follows:

Intermediate 28

5-[(1-methyl-4-phenyl-1H-imidazoles-5-yl) ethynyl] pyrimidine-4-amine

With cuprous iodide (I) (4mg) and two (triphenylphosphine) palladium chloride (8mg) at DMF (6mL) and NEt ₃Stir in the mixture (2mL), then with the nitrogen degassing 30 minutes.Add 4-amino-5-iodine pyrimidine (Heterocycles, 1984,22,1195-1210) (122mg) and 5-ethynyl-1-methyl-4-phenyl-1H-imidazoles (intermediate 26) (101mg), stirred reaction mixture 30 minutes.Add entry (20mL), (3 * 15mL) extraction mixtures merge organism, dry (MgSO with EtOAc ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use DCM: (40: 1-20: 1) wash-out obtains Off-white solid title compound (63.6mg, 42%) to MeOH;

¹H?NMR(CDCl ₃)δ3.77(s，3H)，5.48(bs，1H)，7.30-7.45(m，3H)，7.58(s，1H)，8.08-8.11(m，2H)，8.40(s，1H)，8.59(s，1H)；

MS?m/e?MH ⁺276。

Embodiment 18

6-(4-phenyl-1H-imidazoles-5-yl) thieno-[3,2-d] pyrimidine

Use is similar to the method for preparing embodiment 14 introductions and prepares title compound, and just the compound with embodiment 13 is a raw material.Obtain white solid title compound (25mg, 50%);

MS?m/e?MH ⁺279。

Embodiment 19

N-methyl-6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

Use is similar to the method for preparing embodiment 8 introductions and prepares title compound, just replaces NH with the ethanol (33%w/v) that contains methylamine ₃Obtain white solid title compound (74mg, 90%);

MS?m/e?MH ⁺322。

Embodiment 20

N-[6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-yl] ethanamide

With 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine (embodiment 8) (29mg), DMA (2mL), DIPEA (0.05mL) and acetic anhydride (0.01mL) be in 82 ℃ of heating 1 day.Reaction mixture adds entry (2mL) to ambient temperature, through preparation type RPHPLC (with MeCN and water+0.1%TFA gradient elution), obtains colorless solid title compound (25mg, 76%) then;

MS?m/e?MH ⁺350。

Embodiment 21

6-[1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] furo [2,3-d] pyrimidine

The method of introducing by embodiment 15 prepares title compound, just replaces 5-ethynyl-1-methyl-4-phenyl-1H-imidazoles (intermediate 26) with 5-ethynyl-1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles (intermediate 31).Obtain white solid title compound (110mg, 40%);

¹H?NMR(DMSO-d ₆)δ3.66(s，3H)，5.26(s，2H)，6.78(d，2H)，6.99(d，2H)，7.17(s，1H)，7.23-7.35(m，3H)，7.5(d，2H)，8.2(s，1H)，8.97(s，1H)，9.16(s，1H)。

MS?m/e?MH ⁺383。

The raw material that uses is prepared as follows:

Intermediate 29

5-(dimethoxy-methyl)-1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles

Prepare title compound by being similar to the method for preparing intermediate 1 introduction, just replace methylamine, and dimethoxy acetaldehyde replaces hydroxy-acetaldehyde with the 4-methoxybenzylamine.Obtain colorless oil title compound (1.5g, 74%);

MS?m/e?MH ⁺339。

Intermediate 30

1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-formaldehyde

5-(dimethoxy-methyl)-1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles (intermediate 29) (1.5g) is dissolved in formic acid (10mL) and water (10mL), stirred 16 hours in ambient temperature.Vacuum evaporating solvent, resistates (passes through P behind 2 * 10mL) azeotropic with toluene ₂O ₅The vacuum-drying irreducible oil obtains colorless oil title compound (1.29g, 100%);

MS?m/e?MH ⁺293。

Intermediate 31

5-ethynyl-1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles

Prepare title compound by being similar to the method for preparing intermediate 26 introductions, just replace 1-methyl-4-phenyl-1H-imidazoles-5-formaldehyde (intermediate 2) with 1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-formaldehyde (intermediate 30).Obtain colorless oil title compound (420mg, 33%);

MS?m/e?MH ⁺289。

Embodiment 22

2-[1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] furo [3,2-c] pyridine

Prepare title compound by the method for preparing embodiment 15 introductions, just replace 4-hydroxyl-5-iodine pyrimidine with 3-iodine pyridine-4 (1H)-ketone (SPECS chemical company).Obtain white solid title compound (115mg, 58%);

MS?m/e?MH ⁺382。

Embodiment 23

2-(4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

Thiophosphoric anhydride (175mg) is added down N-(4-amino-6-hydroxy pyrimidine-5-yl)-4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group in inert atmosphere] methyl }-1H-imidazoles-5-methane amide and N-(4-amino-6-hydroxy pyrimidine-5-yl)-5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-4-methane amide (intermediate 34) (0.11g) is suspended in the suspension of anhydrous pyridine (0.41mL), then in 110 ℃ of heating 24 hours.Evaporating solvent, water (10mL) grinding residues, filtering separation throw out.Purify through RPHPLC chromatography (water: MeCN, 95: 5-30: in 70,12 minutes), obtain yellow gummy title compound (22mg, 30%);

¹H?NMR(DMSO-d ₆)δ7.4-7.48(m，2H)，7.52-7.58(m，2H)，8.0(s，1H)，8.08-8.12(d，2H)，8.32(s，1H)；

MS?m/e?MH ⁺295。

The raw material that uses is prepared as follows.

Intermediate 32

4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl-1H-imidazole-5-carboxylic acid ethyl ester and 5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-4-carboxylic acid, ethyl ester

The solution that ethyl-4-phenyl-1H-imidazole-5-carboxylic acid ester (J.Chem.Soc.1925,127,576) (1g) is dissolved in THF (5mL) contains sodium hydride (60%) THF (5mL) (0.20g) in 0 ℃ of adding.Add 2-(trimethyl silyl) ethoxyl methyl chlorine (0.90mL), reaction stirred 2 hours adds entry (10mL) then, with EtOAc (3 * 20mL) extractions.Dry organic extract final vacuum removes and desolvates, and obtains 2: 1 mixtures (1.52g, 95%) of colourless gummy title compound;

MS?m/e?MH ⁺347。

Intermediate 33

4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazole-5-carboxylic acid and 5-benzene Base-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-4-carboxylic acid

2M NaOH solution (3.62mL) and several MeOH addings are contained 2: 1 mixture 4-phenyl-1-{[2-(trimethyl silyl) oxyethyl groups] methyl }-1H-imidazole-5-carboxylic acid ethyl ester and 5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-4-carboxylic acid, ethyl ester (intermediate 32) THF (7mL) (1.0g), reflux reactant 48 hours.Vacuum-evaporation THF adds entry (25mL), with EtOAc (20mL) extraction.To pH4, filter the white precipitate after drying with AcOH acidifying water layer, obtain 2: 1 mixtures (0.52g, 56%) of white solid title compound;

MS?m/e?MH ⁺319。

Intermediate 34

N-(4-amino-6-hydroxy pyrimidine-5-yl)-4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] first Base }-1H-imidazoles-5-methane amide and N-(4-amino-6-hydroxy pyrimidine-5-yl)-5-phenyl-1-{[2-(three The methyl-silicane base) oxyethyl group] methyl }-1H-imidazoles-4-methane amide

With 4,5-diamino-6-hydroxyl-pyrimidine (119mg) adds contain mixtures 4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazole-5-carboxylic acid and 5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-4-carboxylic acid (intermediate 33) dry DMF (4mL) (0.20g).Add DMTMM (0.26g), heated the gained solution 24 hours in 50 ℃.Pour reaction mixture into water (15mL), stir 15 minutes, leach solid, wash with water,, obtain faint yellow solid title compound (111mg, 41%) in 60 ℃ of vacuum-dryings until precipitating fully;

¹H?NMR(DMSO-d ₆)δ0.81-0.86(m，2H)，3.41-3.48(m，2H)，5.27(s，2H)，6.36(bs，2H)，7.48-7.5(m，3H)，7.56-7.58(M，2H)，7.82(s，1H)，8.15(s，1H)，8.89(s，1H)，11.93(bs，1H)。

MS?m/e?MH ⁺427。

Embodiment 24

2-(4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine also

Thiophosphoric anhydride (109mg) added contains N-(4-hydroxy pyrimidine-5-yl)-4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl-1H-imidazoles-5-methane amide and N-(4-hydroxy pyrimidine-5-yl)-5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl-suspension of 1H-imidazoles-4-methane amide (intermediate 35) anhydrous pyridine (0.26mL) (65mg), under the inert atmosphere in 110 ℃ of heating 24 hours.Evaporating solvent, resistates is purified through RPHPLC chromatography (water: MeCN, 95: 5-30: in 70,12 minutes), obtains yellow gummy title compound (9mg, 20%);

¹H?NMR(DMSO-d ₆)δ7.42-7.48(m，1H)，7.5-7.58(m，2H)，7.9-8.4(m，2H)，9.05(s，1H)，9.1-9.15(d，1H)，9.23(s，1H)；

MS?m/e?MH ⁺280。

The raw material that uses is prepared as follows.

Intermediate 35

N-(4-hydroxy pyrimidine-5-yl)-4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }- 1H-imidazoles-5-methane amide and N-(4-hydroxy pyrimidine-5-yl)-5-phenyl-1-{[2-(trimethylammonium first silicon Alkyl) oxyethyl group] methyl }-1H-imidazoles-4-methane amide

With 5-aminopyrimidine-4-alcohol (Collect.Czech.Chem.Commun.; EN, 1986,551,1,215-233) (105mg) and DMTMM (0.26g) add contain mixtures 4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazole-5-carboxylic acid and 5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-4-carboxylic acid (intermediate 33) dry DMF (4mL) (0.20g).The gained mixture was in 50 ℃ of heating 24 hours.Pour reaction mixture into water (15mL), stir 15 minutes until precipitating fully.Leach solid, wash the back with water, obtain yellow solid title compound (65mg, 25%) in 60 ℃ of vacuum-dryings;

MS?m/e?MH ⁺412。

Embodiment 25

8-(4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

With P ₂O ₅(0.29g) and H ₃PO ₄(0.21mL) add mixture N-(4,6-di-amino-pyrimidine-5-yl)-and 4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl }-1H-imidazoles-5-methane amide and N-(4,6-di-amino-pyrimidine-5-yl)-5-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl-1H-imidazoles-4-methane amide (intermediate 36) (65mg) in, in 160 ℃ the heating 24 hours.After being cooled to ambient temperature, add ice, use NH ₃Solution conditioned reaction mixture is to pH5.Vacuum evaporating solvent obtains yellow oil.Purify by preparation type RPHPLC (MeCN: water: TFA, 90: 10: 0.1), obtain colorless solid title compound (2.6mg, 6%);

¹H?NMR(DMSO-d ₆)δ7.15(d，1H)，7.45(m，3H)，7.98(m，2H)，8.10(s，1H)，8.45(s，1H)，13.10(bs，2H)；

MS?m/e?MH ⁺278。

The raw material that uses is prepared as follows:

Intermediate 36

N-(4,6-di-amino-pyrimidine-5-yl)-4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] first Base }-1H-imidazoles-5-methane amide and N-(4,6-di-amino-pyrimidine-5-yl)-5-phenyl-1-{[2-(front three The base silyl) oxyethyl group] methyl }-1H-imidazoles-4-methane amide

DIPEA (0.09mL) is added contain mixtures 4-phenyl-1-{[2-(trimethyl silyl) oxyethyl group] methyl-1H-imidazole-5-carboxylic acid and 5-phenyl-1-{[3-(trimethyl silyl) propoxy-] methyl-1H-imidazoles-4-carboxylic acid (intermediate 33) (40mg), 4,5, the DMF (1mL) of 6-Triaminopyrimidine sulfate hydrate (42mg) and HATU (114mg).The gained mixture stirred 24 hours in ambient temperature.Pour reaction mixture into water (5mL), (3 * 10mL) extractions, with salt solution (10mL) washing, dry final vacuum evaporating solvent obtains yellow oil with EtOAc.Purify with the fast silica gel chromatogram method, use DCM: MeOH (99: 1) wash-out, 2: 1 mixtures (53mg, 99%) of acquisition yellow solid title compound;

MS?m/e?MH ⁺426。

Embodiment 26

2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylsulfonyl) [1; 3] thiazole also [5; 4-d] pyrimidine (intermediate 38) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain yellow solid title compound (52mg, 61%);

¹H?NMR(CDCl ₃)δ3.95(s，3H)，5.71(bs，2H)，7.37(m，3H)，7.50(m，2H)，8.43(s，1H)。

MS?m/e?MH ⁺387、389。

The raw material that uses is prepared as follows:

Intermediate 37

2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] is phonetic Pyridine

With 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] also [5,4-d] pyrimidine (intermediate 42) (0.25g), N-bromine succinimide (0.26g) and the mixture of AIBN (37mg) in tetracol phenixin (30mL) be in 70 ℃ of heating 18 hours for thiazole.Filtering suspension liquid, resistates CCl ₄Thoroughly washing.Vacuum evaporating solvent obtains yellow solid.Purify with the fast silica gel chromatogram method, use EtOAC: hexane (1: 9) wash-out obtains white solid title compound (0.12g, 39%);

¹H?NMR(CDCl ₃)δ2.71(s，3H)，4.08(s，3H)，7.42(m，3H)，7.51(m，2H)，8.77(s，1H)。

MS?m/e?MH ⁺418、420。

Intermediate 38

2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylsulfonyl) [1,3] thiazole is [5,4-d] also Pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine (intermediate 37) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain yellow oily title compound (0.1g, 93%);

MS?m/e?MH ⁺450、452。

Embodiment 27

2-(2-amino-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3]-thiazole also [5,4-d] pyrimidine (intermediate 37) (24mg) is dissolved in dense NH ₃The aqueous solution (1mL), 1, the solution of 4-diox (1mL) and aqueous ammonium chloride solution (2) is in microwave condition (the CEM detector, continues 90 minutes by 170 ℃) heating down.Vacuum evaporating solvent obtains yellow solid.Purify with the fast silica gel chromatogram method, use DCM: MeOH (9: 1) wash-out obtains yellow solid title compound (2mg, 9%);

¹H?NMR(CDCl ₃)δ3.83(s，3H)，4.60(bs，2H)，5.65(bs，2H)，7.40(m，3H)，7.51(m，2H)，8.38(s，1H)；

MS?m/e?MH ⁺324。

Embodiment 28

2-(2-methoxyl group-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

With sodium methylate (31mg) add 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 26) (22mg) be dissolved in the solution of MeOH (1mL).Reaction stirred refluxed 4 days and adds sodium methylate (31mg) every day.Add entry (5mL) behind the vacuum evaporating solvent.With DCM (2 * 5mL) extractions, MgSO ₄The dry organism that merges filters the final vacuum evaporating solvent, obtains white solid title compound (15mg, 78%);

¹H?NMR(CDCl ₃)δ3.79(s，3H)，4.18(s，3H)，7.40(m，3H)，7.53(m，2H)，8.38(s，1H)。

MS?m/e?MH ⁺339。

Embodiment 29

2-(1-methyl-2,4-phenylbenzene-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 2-(1-methyl-2; 4-phenylbenzene-1H-imidazoles-5-yl)-7-(methylsulfonyl) [1; 3] thiazole also [5; 4-d] pyrimidine (intermediate 40) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain yellow solid title compound (21mg, 91%);

¹H?NMR(CDCl ₃)δ3.98(s，3H)，5.77(bs，2H)，7.39(m，3H)，7.52(m，3H)，7.60(m，2H)，7.77(m，2H)，8.42(s，1H)。

MS?m/e?MH ⁺385。

The raw material that uses is prepared as follows:

Intermediate 39

2-(1-methyl-2,4-phenylbenzene-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole is [5,4-d] pyrimidine also

With 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group)-[1,3] thiazole also [5,4-d] pyrimidine (intermediate 37) (50mg), tetrakis triphenylphosphine palladium (0) (28mg), yellow soda ash (33mg) and the mixture of phenyl-boron dihydroxide (14mg) in DME (2mL) and water (1mL) be in 90 ℃ of heating 2 hours.After being cooled to ambient temperature, (3 * 5mL) extractions, the dry organism that merges filters the final vacuum evaporating solvent, obtains brown oil with DCM.Purify with the fast silica gel chromatogram method, use EtOAC: hexane (1: 9) wash-out obtains yellow solid title compound (25mg, 50%);

¹H?NMR(CDCl ₃)δ2.71(s，3H)，4.10(s，3H)，7.43(m，3H)，7.50(m，3H)，7.60(m，2H)，7.75(m，2H)，8.77(s，1H)。

MS?m/e?MH ⁺416。

Intermediate 40

2-(1-methyl-2,4-phenylbenzene-1H-imidazoles-5-yl)-7-(methylsulfonyl) [1,3] thiazole also [5,4-d] is phonetic Pyridine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 2-(1-methyl-2,4-phenylbenzene-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine (intermediate 39) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain yellow solid title compound (26mg, 97%);

MS?m/e?MH ⁺448。

Embodiment 30

9-cyclohexyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

With diisopropyl azo-2-carboxylic acid (0.1mL) under inert atmosphere, add 8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine (embodiment 3) (75mg), hexalin (0.07mL) and triphenylphosphine (0.14g) be dissolved in the solution of THF (4mL).After ambient temperature stirs 48 hours, reaction mixture in 40 ℃ of heating 48 hours, was heated 24 hours in 55 ℃ then.Vacuum evaporating solvent obtains brown oil.Purify by preparation type LCMS, obtain white solid title compound (11mg, 11%);

¹H?NMR(CDCl ₃)δ1.25(m，4H)，1.50(m，2H)，1.64(m，2H)，2.26(m，2H)，3.62(s，3H)，3.77(m，1H)，5.82(bs，2H)，7.27(m，3H)，7.40(m，2H)，7.72(s，1H)，8.37(s，1H)。

MS?m/e?MH ⁺374

Embodiment 31

2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-mercaptan also

With 5-aminopyrimidine-4,6-two mercaptan (intermediate 41) (1.26g) and 1-methyl-4-phenyl-1H-imidazole-5-carboxylic acid (intermediate 3) (1.6g) be dissolved in/be suspended in the pyridine (30mL), under the inert atmosphere in 55 ℃ of heating.Be added dropwise to POCl in 5 minutes ₃(1.55mL), 2 hours final vacuum concentrated reaction mixtures carefully add 2M NaOH (15mL).Stir after 15 minutes, add dense HCl and be acidified to pH5, the solid of filtering-depositing, water (40mL), diethyl ether (50mL) washing, dry under high vacuum then, obtain yellow solid title compound (1.83g, 71%);

¹H?NMR(DMSO-d ₆)δ3.93(s，3H)，7.35-7.43(m，3H)，7.50-7.55(m，2H)，8.00(s，1H)，8.24(s，1H)；

MS?m/e?MH ⁺326。

The raw material that uses is prepared as follows:

Intermediate 41

5-aminopyrimidine-4,6-two mercaptan

The suspension returning heating in water (700mL) with dichloro aminopyrimidine (28.9g) and sodium sulfhydrate monohydrate (52.1g) under the inert atmosphere.After 3 hours, add sodium sulfhydrate monohydrate (19.5g) once more, continue heating 3 hours, be cooled to ambient temperature then.Add dense HCl with pH regulator to 6-7, leach the faint yellow precipitation of generation, then with the filtrate vacuum concentration to about 500mL.Cooling filtrate (ice bath) adds 2M HCl with pH regulator to 3, filters the precipitation that produces, and is dry down in 60 ℃ of high vacuums with the ice cold water washing, obtains yellow solid title compound (24g, 86%);

MS?m/e?MH ⁺160。

Embodiment 32

2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidin-7-ones also

With 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine (intermediate 42) (1.26g) be dissolved in DCM (60mL), be cooled to 0 ℃, in 10 minutes, add mCPBA (2.29g) then in batches.Reaction mixture is warming up to ambient temperature about 2 hours, uses saturated NaHCO then ₃The aqueous solution (1 * 40mL), salt solution (1 * 30mL) washing, dry (MgSO ₄), filter final vacuum and concentrate, obtain brown spumescence sulfone.Impure sulfone is dissolved in 1, and the 4-diox adds dense NH ₃The aqueous solution (50mL) stirred 1 hour in ambient temperature then.The vacuum concentration reaction mixture is used saturated NaHCO ₃(60mL) dilution is with DCM (2 * 50mL) extractions.(1 * 30mL) washing final vacuum concentrates organic extract, obtains yellow solid with salt solution.Purify with the fast silica gel chromatogram method, use the 5%MeOH/DCM wash-out, obtain the compound (0.65g, 57%) (data of reporting previously) of colorless solid embodiment 2.Filter water layer, with the diethyl ether washing, high vacuum is dry down, obtains faint yellow solid title compound (0.09g, 8%);

¹H?NMR(DMSO-d ₆)δ3.84(s，3H)，7.31-7.40(m，3H)，7.46-7.51(m，2H)，7.95(s，1H)，8.18(s，1H)。

MS?m/e?MH ⁺310。

The raw material that uses is prepared as follows:

Intermediate 42

2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole is [5,4-d] pyrimidine also

With 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-mercaptan (embodiment 31) (2.91g) be dissolved in 2M NaOH (50mL), then under inert atmosphere, ambient temperature adds methyl iodide (0.67mL).2.5 hour after-filtration reaction mixture washes with water, high vacuum is dry down, obtains light brown solid title compound (2.9g, 95%);

¹H?NMR(DMSO-d ₆)δ2.66(s，3H)，3.96(s，3H)，7.39-7.45(m，3H)，7.51-7.56(m，2H)，8.05(s，1H)，8.84(s，1H)。

Embodiment 33

7-methoxyl group-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine also

With 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine (intermediate 42) (2.88g) be dissolved in DCM (120mL), be cooled to 0 ℃, in 15 minutes, add mCPBA (5.23g) then in batches.Reaction mixture is warming up to ambient temperature about 4 hours, uses saturated NaHCO then ₃The aqueous solution (2 * 60mL), salt solution (60mL) washing, dry (MgSO ₄), filter final vacuum and concentrate, obtain brown spumescence sulfone.Impure sulfone is dissolved in 7N NH ₃/ MeOH spends the night in the ambient temperature stirring, filters then and obtains the colorless solid title compound.Vacuum concentrated filtrate is dissolved in DCM (150mL) with resistates, uses saturated NaHCO ₃The aqueous solution (100mL), salt solution (40mL) washing, dry (MgSO ₄) after-filtration.Vacuum concentrated filtrate is purified with the fast silica gel chromatogram method then, uses the 5%MeOH/DCM wash-out, obtains other a collection of title compound (total amount 1.40g, 50%);

¹H?NMR(DMSO-d ₆)δ3.91(s，3H)，4.14(s，3H)，7.37-7.42(m，3H)，7.46-7.52(m，2H)，8.01(s，1H)，8.68(s，1H)。

MS?m/e?MH ⁺324。

Embodiment 34

2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazoles-5-yl] [1,3] thiazole also [5,4-d] pyrimidine- 7-amine

With 7-methoxyl group-2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazoles-5-yl] [1,3] thiazole also [5,4-d] pyrimidine (intermediate 44) (26mg) be dissolved in and contain 0.5M NH ₃1,4-diox (3mL)/dense NH ₃The aqueous solution (0.6mL), (the CEM detector, 150W) heated 1 hour down sealing back microwave condition by 150 ℃.The vacuum concentration reaction mixture is dissolved in EtOAc (20mL) then, use successively 2M NaOH (2 * 10mL), salt solution (1 * 15mL) washing, dry (MgSO ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use the 4%MeOH/DCM wash-out, obtain Off-white solid title compound (17mg, 68%);

¹H?NMR(DMSO-d ₆)δ4.00(s，3H)，7.34-7.44(m，3H)，7.53-7.59(m，2H)，7.62(m，1H)，7.75(m，1H)，7.77(bs，2H)，8.01(s，1H)，8.68(s，1H)。

MS?m/e?MH ⁺391。

The raw material that uses is prepared as follows:

Intermediate 43

2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-methoxyl group [1,3] thiazole is [5.4-d] pyrimidine also

Prepare title compound by being similar to the method for preparing intermediate 37 introductions, just with 7-methoxyl group-2-(1-methyl-4-phenyl-1H) imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine (embodiment 33) replacement 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole [5,4-d] pyrimidine (intermediate 42) also.Obtain light brown solid title compound (0.47g, 45%);

¹H?NMR(DMSO-d ₆)δ3.87(s，3H)，4.15(s，3H)，7.37-7.42(m，3H)，7.45-7.50(m，2H)，8.72(s，1H)；

MS?m/e?MH ⁺402、404。

Intermediate 44

7-methoxyl group-2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazoles-5-yl] [1,3] thiazole is also [5,4-d] pyrimidine

Under the inert atmosphere with 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-methoxyl group [1,3] thiazole also [5,4-d] pyrimidine (intermediate 43) (50mg), [1,1 '-two (diphenylphosphine) ferrocene] dichloro palladium (II) (14mg), thiophene-3-boric acid (17mg) and 2M salt of wormwood (0.25mL) in toluene (5mL)/MeOH (1mL) in 100 ℃ of heating.After 90 minutes, reaction mixture adds MgSO to ambient temperature ₄, filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method,, obtain colorless solid title compound (40mg, 82%) with 35%EtOAc/ isohexane wash-out;

¹H?NMR(DMSO-d ₆)δ4.01(s，3H)，4.16(s，3H)，7.38-7.43(m，3H)，7.50-7.55(m，2H)，7.61(m，1H)，7.74(m，1H)，8.10(s，1H)，8.71(s，1H)；

MS?m/e?MH ⁺406。

Embodiment 35

2-(1-methyl-4-phenyl-2-pyridin-4-yl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-also Amine

Under the inert atmosphere with 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 26) (20mg), PdCl ₂Dppf (8mg), pyridine-4-boric acid (8mg) and 2M yellow soda ash (2.0mL) in DMF (2.0mL) in 100 ℃ of heating.After 3 hours, reaction mixture adds EtOAc (25mL) to ambient temperature, then water (15mL), salt solution (2 * 10mL) washings, dry (MgSO ₄), filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use the 6%MeOH/DCM wash-out, obtain dark brown solid,, obtain light brown solid title compound (6mg, 31%) with diethyl ether washing back high vacuum drying;

¹H?NMR(CDCl ₃)δ4.06(s，3H)，5.78(bs，2H)，7.35-7.42(m，3H)，7.54-7.59(m，3H)，7.74(m，2H)，8.45(s，1H)，8.82(m，1H)；

MS?m/e?MH ⁺386。

Embodiment 36

2-(2-ethyl-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

With 10% carbon carry palladium (6mg) in inert atmosphere add down 2-(2-ethynyl-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (intermediate 46) (6mg) be dissolved in the solution of EtOAc (20mL).Stirred reaction mixture 11 hours under nitrogen atmosphere filters final vacuum and concentrates then.Grind impure product after-filtration with diethyl ether, obtain colorless solid title compound (2mg, 30%);

MS?m/e?MH ⁺337。

The raw material that uses is prepared as follows:

Intermediate 45

2-{1-methyl-4-phenyl-2-[(trimethyl silyl) ethynyl]-1H-imidazoles-5-yl } [1,3] thiophene Azoles is [5,4-d] pyrimidine-7-amine also

With 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 26) (52mg), PdCl ₂Dppf (10mg), cuprous iodide (I) (2mg), under trimethyl silyl acetylene (0.11mL) and triethylamine (0.2mL) inert atmosphere in DMF (4mL) in 80 ℃ of heating 1 hour.The vacuum concentration reaction mixture adds EtOAc (20mL)/MeOH (0.3mL)/water (10mL), removes water layer.Dry (MgSO ₄) organic layer, filter final vacuum and concentrate, purify with the fast silica gel chromatogram method then, use the 4%MeOH/DCM wash-out, obtain light brown solid title compound (48mg, 100%);

¹H?NMR(DMSO-d ₆)δ0.30(s，9H)，3.96(s，3H)，7.37-7.42(m，3H)，7.48-7.52(m，2H)，7.78(bs，2H)，8.27(s，1H)；

MS?m/e?MH ⁺405

Intermediate 46

2-(2-ethynyl-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

With 2-{1-methyl-4-phenyl-2-[(trimethyl silyl) ethynyl]-1H-imidazoles-5-yl } [1,3] thiazole also [5,4-d] pyrimidine-7-amine (intermediate 45) (48mg) is dissolved in/is suspended in MeOH (3mL)/water (1mL), add salt of wormwood (50mg), stirred 90 minutes in ambient temperature then.With 2M HCl neutralization reaction mixture, vacuum concentration, water (10mL) dilution resistates is with DCM (3 * 10mL) extractions.Dry (MgSO ₄) organic extract, to filter final vacuum and concentrate, the fast silica gel chromatogram method is purified, and uses the 4%MeOH/DCM wash-out, obtains yellow solid title compound (10mg, 25%);

¹H?NMR(DMSO-d ₆)δ3.99(s，3H)，4.89(s，1H)，7.37-7.45(m，3H)，7.49-7.54(m，2H)，7.79(bs，2H)，8.30(s，1H)。

MS?m/e?MH ⁺333

Embodiment 37

2-[1-methyl-4-phenyl-2-(propyl group sulfenyl)-1H-imidazoles-5-yl] [1,3] thiazole also [5,4-d] pyrimidine- 7-amine

5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-mercaptan (intermediate 47) (10mg) is dissolved in 2M NaOH (0.5mL), adds n-propyl iodide (2), then in 60 ℃ of heating 5 hours.Reaction mixture is filtered solid precipitation to ambient temperature, and water (2mL) and diethyl ether (2mL) washing back high vacuum drying obtain colorless solid title compound (5mg, 43%);

MS?m/e?MH ⁺383。

The raw material that uses is prepared as follows:

Intermediate 47

5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-mercaptan

To contain under the inert atmosphere 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 26) (80mg) and the DMF (5mL) of sodium methyl mercaptide (58mg) in 80 ℃ the heating 2 hours.After being cooled to ambient temperature, the vacuum concentration reaction mixture is dissolved in 2M NaOH (5mL) then, with DCM (5mL) washing.To pH4, water (5mL), diethyl ether (10mL) wash solid precipitation successively with 2M HCl acidifying water layer, and the high vacuum drying obtains yellow solid title compound (44mg, 65%);

¹H?NMR(DMSO-d ₆)δ3.86(s，3H)，7.46-7.54(m，5H)，7.76(bs，2H)，8.26(s，1H)，13.15(bs，1H)。

MS?m/e?MH ⁺341。

Embodiment 38

The 2-{2-[(methoxy ethyl) sulfenyl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

Use is similar to the method for above introducing for preparing embodiment 37, just replaces n-propyl iodide with 2-bromotrifluoromethane methyl ether, obtains colorless solid title compound (8mg, 40%);

¹H?NMR(DMSO-d ₆)δ3.28(s，3H)，3.42(t，2H)，3.66(t，2H)，3.86(s，3H)，7.37-7.42(m，3H)，7.48-7.55(m，2H)，7.74(bs，2H)，8.25(s，1H)。

MS?m/e?MH ⁺399。

Embodiment 39

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (the 5-methyl is differentEvil Azoles-3-yl) ketone

With 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 2) (50mg) and 5-methyl-isoxazoles-3-carbonyl chloride (140mg) in MeCN (4mL), stirred 15 minutes, add triethylamine (0.14mL) then, stirred 3.5 days in ambient temperature under the inert atmosphere.The vacuum concentration reaction mixture adds and contains 7N NH ₃MeOH (5mL)/dense NH ₃The aqueous solution (5mL) is then in 55 ℃ of heating 2.5 hours.The vacuum concentration reaction mixture obtains faint yellow solid title compound (12mg, 18%) after RPHPLC purifies;

¹H?NMR(DMSO-d ₆)δ2.56(s，3H)，4.19(s，3H)，7.01(s，1H)，7.40-7.45(m，3H)，7.63-7.68(m，2H)，8.01(bs，2H)，8.37(s，1H)；

MS?m/e?MH ⁺418。

Embodiment 40

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (the 5-methyl is differentEvil Azoles-3-yl) methyl alcohol

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (5-methyl-isoxazole-3-yl) ketone (embodiment 39) (6mg) is dissolved in MeOH (2mL), adds sodium borohydride (3mg), stirred then 1 hour.Add entry (1mL), continue to stir 20 minutes, then vacuum concentration.Water (5mL) dilution resistates is with DCM (2 * 6mL) extractions, dry (MgSO ₄) organic extract, filter final vacuum and concentrate, obtain faint yellow solid title compound (3.6mg, 60%);

MS?m/e?MH ⁺420。

Embodiment 41

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (2-furyl) ketone

Use is similar to and prepares the method that embodiment 39 introduces, and just 5-methyl-isoxazoles-3-carbonyl chloride is replaced by furans-2-carbonyl chloride, obtains faint yellow solid title compound (5mg, 8%);

¹H?NMR(DMSO-d ₆)δ4.15(s，3H)，6.86(m，1H)，7.38-7.47(m，3H)，7.57-7.63(m，2H)，7.96(bs，2H)，8.15(d，1H)，8.19(m，1H)，8.36(s，1H)。

MS?m/e?MH ⁺403。

Embodiment 42

5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (2-furyl) methyl alcohol

Use is similar to the ketone method of reducing that the foregoing description 40 is introduced, and just with the compound of embodiment 41, obtains faint yellow solid title compound (3.4mg, 68%);

MS?m/e?MH ⁺405。

Embodiment 43

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (1,3-dimethyl-1H-pyrazoles-5-yl) ketone

Use is similar to and prepares the method that embodiment 39 introduces, and just 5-methyl-isoxazoles-3-carbonyl chloride is replaced by 1, and 3-dimethyl-1H-pyrazoles-5-carbonyl chloride obtains faint yellow solid title compound (21mg, 31%);

¹H?NMR(DMSO-d ₆)δ2.27(s，3H)，4.11(s，3H)，4.14(s，3H)，7.38(s，1H)，7.40-7.47(m，3H)，7.56-7.61(m，2H)，7.98(bs，2H)，8.36(s，1H)；

MS?m/e?MH ⁺431。

Embodiment 44

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (1,3-dimethyl-1H-pyrazoles-5-yl) methyl alcohol

Use is similar to the ketone method of reducing that the foregoing description 40 is introduced, and just with the compound of the foregoing description 43, obtains faint yellow solid title compound (10mg, 65%);

MS?m/e?MH ⁺433。

Embodiment 45

6-[1-(2-fluoro ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Use the universal method of preparation embodiment 65 to prepare title compound, just the 3-amino-pyrrolidine is replaced into 2-fluorine ethamine.Obtain colorless solid title compound (30mg, 44%);

¹H?NMR(DMSO-d ₆)4.35(dt，2H)，4.67(dt，2H)，7.30(t，1H)，7.36(t，2H)，7.51(d，2H)，7.77(s，1H)，7.86(bs，2H)，8.38(s，1H)，8.56(s，1H)；

MS?m/e?MH ⁺340。

Embodiment 46

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (2-thienyl) methyl alcohol

Use is similar to the ketone method of reducing that the foregoing description 40 is introduced, just with [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-thienyl) ketone (intermediate 48), obtain colorless solid title compound (9mg, 89%);

¹H NMR (DMSO-d ₆) δ 3.79 (s, 3H), 6.25 (d, 1H), 6.75 (d, 1H (commutative)), 6.95 (m, 1H), 7.01 (m, 1H), 7.30-7.39 (m, 3H), 7.45-7.50 (m, 3H), 7.77 (bs, 2H), 8.26 (s, 1H);

MS?m/e?MH ⁺421。

The raw material that uses is prepared as follows:

Intermediate 48

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (2-thienyl) ketone

The method of using the similar embodiment of preparation 39 to introduce just is replaced by 2 thiophen carbonyl chloride with 5-methyl-isoxazoles-3-carbonyl chloride, obtains faint yellow solid title compound (19mg, 66%);

¹H?NMR(DMSO-d ₆)δ4.12(s，3H)，7.32(dd，1H)，7.37-7.45(m，3H)，7.55-7.62(m，2H)，7.92(bs，2H)，8.13(d，1H)，8.34(s，1H)，8.47(m，1H)；

MS?m/e?MH ⁺419。

Embodiment 47

6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 50) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain white solid title compound (53mg, 75%);

¹H?NMR(CDCl ₃)δ3.61(s，3H)，5.43(br?s，2H)，6.93-7.00(m，2H)，7.09(s，1H)，7.52-7.59(m，2H)，7.63(s，1H)，8.54(s，1H)；

MS?m/e?MH ⁺326。

The raw material that uses is prepared as follows:

Intermediate 49

6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just with N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14), replace PhTosMIC with 4-fluorophenyl-toluene sulfo group methyl carbylamine.Obtain faint yellow solid title compound (105mg, 67%);

¹H?NMR(CDCl ₃)δ2.74(s，3H)，3.65(s，3H)，6.94-7.00(m，2H)，7.31(s，1H)，7.53-7.57(m，2H)，7.65(s，1H)，8.87(s，1H)；

MS?m/e?MH ⁺357。

Intermediate 50

6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 49) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain yellow solid title compound (80mg, 73%);

¹H?NMR(CDCl ₃)δ3.45(s，3H)，3.73(s，3H)，6.96-7.04(m，2H)，7.48-7.55(m，2H)，7.69(s，1H)，8.03(s，1H)，9.16(s，1H)；

MS?m/e?MH ⁺389。

Embodiment 48

6-(1-benzyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just with N-benzyl-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 51) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14).Obtain faint yellow solid title compound (26mg, 26%);

¹H?NMR(CDCl ₃)δ5.13(s，2H)，7.00-7.03(m，2H)，7.10(s，1H)，7.21-7.32(m，6H)，7.55-7.58(m，2H)，7.75(s，1H)，9.03(s，1H)，9.10(s，1H)；

MS?m/e?MH ⁺429。

The raw material that uses is prepared as follows:

Intermediate 51

N-benzyl-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine

Prepare title compound by being similar to the method for preparing intermediate 14 introductions, just replace 3, the 4-dimethoxybenzylamine with benzylamine.Obtain faint yellow solid title compound (69mg, 100%), it is no longer purified and directly uses.

Embodiment 49

6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 55) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain white solid title compound (136mg, 78%);

¹H?NMR(DMSO-d ₆)δ3.58(s，3H)，7.06(t，1H)，7.42(d，1H)，7.56(d，1H)，7.65(m，3H)，7.95(m，2H，8.32(s，1H)。

MS?m/e?MH ⁺434。

The raw material that uses is prepared as follows:

Intermediate 52

{ (3-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide

Trimethylsilyl chloride (9.1mL) is added the stirred solution that 3-benzaldehyde iodine (15.1g) and methane amide (6.5mL) are dissolved in MeCN (34mL) and toluene (34mL) down in inert atmosphere.Then in 50 ℃ of reacting by heating things 5 hours.Add toluenesulfinic acid (15.3g), in 50 ℃ of reacting by heating mixtures 5 hours once more.Reaction mixture adds methyl tert-butyl ether (55mL) back and stirred 5 minutes to ambient temperature.Add entry (275mL), stirred 1 hour behind the cooling reactant to 0 ℃.Cross filter solid, (2 * 35mL) washing reaction flasks are poured on the filter cake with MTBE.In 60 ℃ of drying solids 10 hours, obtain impure solid title compound (14g, 51%) in vacuum drying oven, this compound is no longer purified and is directly used.Small amount of sample is by the EtOH crystallization;

Main (6: 1) rotational isomer ¹H NMR (DMSO-d ₆) δ; 2.43 (s, 3H), 6.42 (d, 1H), 7.15-8.00 (m, 9H), 9.73 (d, 1H).

MS?m/e?MH ⁺416。

Intermediate 53

(3-iodophenyl) (isocyano-) methyl 4-methyl phenyl sulfone

With POCl ₃(3.05mL) after (6.23g) being dissolved in the stirred solution of anhydrous THF (35mL), stirred 5 minutes 25 ℃ of addings { (3-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 52).Reaction mixture to 0 ℃ was added dropwise to Et in 45 minutes ₃N (13.7mL) keeps internal temperature to be lower than 10 ℃.In 5-10 ℃ of stirred reaction mixture 45 minutes once more.Add EtOAc (140mL) and water (140mL), stirred then 5 minutes.Organic phase successively water (2 * 140mL), NaHCO ₃(saturated aqueous solution, 140mL) and salt solution (140mL) washing.The vacuum concentration organic phase obtains dark-brown natural gum.Should filter with silicagel pad by natural gum then, concentrate, obtain dark-brown natural gum (3.5g of about 70% purity, 58%) with DCM washing final vacuum;

¹H?NMR(CDCl ₃)δ2.42(s，3H)，5.45(s，1H)，7.00-7.75(m，8H)；

MS?m/e(M-H) ^-396。

Intermediate 54

6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just with N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14), replace PhTosMIC with (3-iodophenyl) (isocyano-) methyl 4-methyl phenyl sulfone (intermediate 53).Obtain faint yellow solid title compound (1.50g, 71%);

¹H?NMR(DMSO-d ₆)δ2.68(s，3H)，3.60(s，3H)，7.04(t，1H)，7.37(d，1H)，7.55(d，1H)，7.70(s，1H)，7.94(m，2H)，8.89(s，1H)；

MS?m/e?MH ⁺465。

Intermediate 55

6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 54) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain yellow solid title compound (220mg, 68%);

¹H?NMR(DMSO-d ₆)δ3.50(s，3H)，3.66(s，3H)，7.04(t，1H)，7.38(d，1H)，7.59(d，1H)，8.00(m，3H)，9.34(s，1H)；

MS?m/e?MH ⁺497。

Embodiment 50

6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 59) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain solid title compound (357mg, 58%);

¹H?NMR(DMSO-d ₆)δ3.60(s，3H)，7.26(t，1H)，7.40(m，2H)，7.65(s，2H)，7.69(s，1H)，7.77(s，1H)，7.95(s，1H)，8.33(s，1H)；

MS?m/e?MH ⁺386、388。

The raw material that uses is prepared as follows:

Intermediate 56

{ (3-bromophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide

Prepare title compound by being similar to the method for preparing intermediate 52 introductions, just replace the 3-benzaldehyde iodine with the 3-bromobenzaldehyde.Obtain solid title compound (11g, 28%);

Main (5: 1) rotational isomer ¹H NMR (DMSO-d ₆) δ 2.40 (s, 3H), 6.45 (d, 1H), 7.30-7.95 (m, 9H), 9.73 (d, 1H);

MS?m/e?MNa ⁺?390、392。

Intermediate 57

(3-bromophenyl) (isocyano-) methyl 4-methyl phenyl sulfone

Prepare title compound by being similar to the method for preparing intermediate 53 introductions, just replace { (3-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 52) with { (3-bromophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 56).Obtain light brown solid title compound (3.2g, 30%);

¹H?NMR(DMSO-d ₆)δ2.43(s，3H)，6.98(s，1H)，7.33-7.77(m，8H)；

MS?m/e?(M-H) ^-348、350

Intermediate 58

6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just with N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14), with ((3-bromophenyl) (isocyano-) methyl 4-methyl phenyl sulfone (intermediate 57) replaces PhTosMIC.Obtain spumescence title compound (1.9g, 91%);

¹H?NMR(DMSO-d ₆)δ2.68(s，3H)，3.61(s，3H)，7.20(t，1H)，7.37(m，2H)，7.72(m，2H)，7.96(s，1H)，8.89(s，1H)；

MS?m/e?MH ⁺417、419。

Intermediate 59

6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 58) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain weak yellow foam shape title compound (740mg, 82%);

¹H?NMR(DMSO-d ₆)δ3.50(s，3H)，3.66(s，3H)，7.20(t，1H)，7.40(m，2H)，7.77(s，1H)，8.01(s，1H)，8.03(s，1H)，9.34(s，1H)；

MS?m/e?MH ⁺451、449。

Embodiment 51

6-[4-(3-butoxy phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

To contain 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl under the inert atmosphere] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49) (43mg), 1, the positive BuOH (1mL) of 10-phenanthroline (4mg), cesium carbonate (49mg) and CuI (4mg) in 110 ℃ the heating 17 hours.Reaction mixture is used the dilution of EtOAc (10mL) and water (10mL) then.Organic layer water (10mL) washing is filtered, and application of sample is in MCX (1g) post then.This post is used DCM: MeOH (1: 1) wash-out earlier, then with containing 5% dense NH ₃DCM: MeOH (1: 1) wash-out.The evaporate cut is purified with the fast silica gel chromatogram method, is the EtOAc/DCM wash-out of 0-100% with gradient, uses the 0-20%MeOH/DCM wash-out then, obtains gummy title compound (5mg, 13%);

¹H?NMR(CDCl ₃)δ0.90(t，3H)，1.38(m，2H)，1.65(m，2H)，3.56(s，3H)，3.84(t，2H)，5.60(s，2H)，6.75(d，1H)，7.10(m，3H)，7.20(s，1H)，7.63(s，1H)，8.50(s，1H)；

MS?m/e?MH ⁺380。

Embodiment 52

6-{1-methyl-4-[3-(4-methylbenzene sulfenyl) phenyl]-1H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine- 4-amine

To contain 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49) (43mg), DMF (0.5mL) degassing of SPTS (50mg) and CuI (29mg), under the inert atmosphere in 110 ℃ of heating 17 hours.Reaction mixture is used the dilution of EtOAc (10mL) and water (10mL) then.Organic layer water (10mL) washing back concentrates.Resistates is dissolved in DMSO after preparation type RPHPLC purifies, obtains solid title compound (9mg, 20%);

¹H?NMR(CDCl ₃)δ2.30(s，3H)，3.52(s，3H)，5.60(s，2H)，6.95(m，3H)，7.14(m，4H)，7.43(m，2H)，7.60(s，1H)，8.52(s，1H)；

MS?m/e?MH ⁺430。

Embodiment 53

6-{4-[4-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 51 introductions, just with 6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 64) replacement 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49), replace positive BuOH with benzylalcohol.Obtain solid title compound (19mg, 23%);

¹H?NMR(CDCl ₃)δ3.51(s，3H)，5.02(s，2H)，5.60(s，2H)，6.87(d，2H)，7.03(s，1H)，7.35(m，5H)，7.50(d，2H)，7.59(s，1H)，8.51(s，1H)；

MS?m/e?MH ⁺414。

The raw material that uses is prepared as follows:

Intermediate 60

{ (4-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide

Prepare title compound by being similar to the method for preparing intermediate 52 introductions, just replace the 3-benzaldehyde iodine with the 4-benzaldehyde iodine.Obtain solid title compound (12.7g, 57%);

Main (5: 1) rotational isomer ¹H NMR (DMSO-d ₆) δ 2.43 (s, 3H), 6.40 (d, 1H), 7.1-8.3 (m, 9H), 9.74 (d, 1H);

Intermediate 61

(4-iodophenyl) (isocyano-) methyl 4-methyl phenyl sulfone

Prepare title compound by being similar to the method for preparing intermediate 53 introductions, just replace { (3-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 52) with { (4-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 60).Obtain brown gummy title compound (3.1g, 20%);

¹H?NMR(CDCl ₃)δ2.41(s，3H)，5.47(s，1H)，7.01(d，2H)，7.28(d，2H)，7.57(d，2H)，7.67(d，2H)；

MS?m/e(M-H) ^-396。

Intermediate 62

6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just with N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14), replace PhTosMIC with (4-iodophenyl) (isocyano-) methyl 4-methyl phenyl sulfone (intermediate 61).Obtain solid title compound (0.8g, 37%);

¹H?NMR(DMSO-d ₆)δ2.68(s，3H)，3.60(s，3H)，7.27(d，2H)，7.62(d，2H)，7.68(s，1H)，7.94(s，1H)，8.90(s，1H)；

MS?m/e?MH ⁺465。

Intermediate 63

6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] close pyridine (intermediate 62) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain solid title compound (200mg, 100%);

¹H?NMR(DMSO-d ₆)δ3.50(s，3H)，3.66(s，3H)，7.29(d，2H)，7.64(d，2H)，8.02(s，2H)，9.34(s，1H)；

MS?m/e?MH ⁺497。

Intermediate 64

6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 63) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain solid title compound (116mg, 74%);

¹H?NMR(DMSO-d ₆)δ3.58(s，3H)，7.32(d，2H)，7.65(m，5H)，7.93(s，1H)，8.32(s，1H)；

MS?m/e?MH ⁺434。

Embodiment 54

The 6-{4-[4-butoxy phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 51 introductions, just with 6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 64) replacement 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49).Obtain gummy title compound (5mg, 13%);

¹H?NMR(CDCl ₃)δ0.95(t，3H)，1.47(m，2H)，1.73(m，2H)，3.52(s，3H)，3.91(t，2H)，5.62(s，2H)，6.78(d，2H)，7.02(s，1H)，7.48(d，2H)，7.58(s，1H)，8.50(s，1H)；

MS?m/e?MH ⁺380。

Embodiment 55

N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl-H-imidazol-4 yl] phenyl } first Sulphonamide

To contain 6-[4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 69) (38mg), anti-form-1,2-cyclohexane diamine (11mg), K ₃PO ₄(42mg), dioxane (2mL) degassing of Toluidrin (19mg) and CuI (10mg), under the inert atmosphere in 100 ℃ of heating 12 hours.The cooling reactant adds MeOH, DCM and water then to ambient temperature.With the solution application of sample in the MCX post.This post is used DCM: MeOH (1: 1) wash-out earlier, then with containing 5% dense NH ₃DCM: MeOH (1: 1) wash-out.The evaporate cut is purified through preparation type LCMS, obtains gummy title compound (11mg, 27%);

MS?m/e?MH ⁺401。

The raw material that uses is prepared as follows:

Intermediate 65

{ (4-bromophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide

Prepare title compound by being similar to the method for preparing intermediate 52 introductions, just replace the 3-benzaldehyde iodine with the 4-bromobenzaldehyde.Obtain solid title compound (31g, 80%;

Main (4: 1) rotational isomer ¹H NMR (DMSO-d ₆) δ 2.40 (s, 3H), 6.42 (d, 1H), 7.2-8.3 (m, 9H), 9.73 (d, 1H);

MS?m/e?MNa ⁺390、392。

Intermediate 66

(4-bromophenyl) (isocyano-) methyl 4-methyl phenyl sulfone

Prepare title compound by being similar to the method for preparing intermediate 53 introductions, just replace { (3-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 52) with { (4-bromophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 65).Obtain brown solid title compound (3.1g, 29%);

¹H?NMR(DMSO-d ₆)δ2.43(s，3H)，6.98(s，1H)，7.28(d，2H)，7.51(d，2H)，7.68(m，4H)；

MS?m/e?(M-H) ^-348、350。

Intermediate 67

6-[4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just with N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14), replace PhTosMIC with (4-bromophenyl) (isocyano-) methyl 4-methyl phenyl sulfone (intermediate 66).Obtain faint yellow solid title compound (1.7g, 81%);

¹H?NMR(DMSO-d ₆)δ2.68(s，3H)，3.60(s，3H)，7.43(m，4H)，7.68(s，1H)，7.95(s，1H)，8.89(s，1H)；

MS?m/e?MH ⁺417、419。

Intermediate 68

6-[4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-[4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 67) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain faint yellow solid title compound (715mg, 79%);

¹H?NMR(DMSO-d ₆)δ3.51(s，3H)，3.67(s，3H)，7.45(m，4H)，7.99(s，1H)，8.02(s，1H)，9.34(s，1H)；

MS?m/e?MH ⁺449、451。

Intermediate 69

6-[4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions, just with 6-[4-(4-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 68) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17); Obtain solid title compound (568mg, 95%);

¹H?NMR(DMSO-d ₆)δ3.58(s，3H)，7.48(m，4H)，7.66(m，3H)，7.94(s，1H)，8.33(s，1H)；

MS?m/e?MH ⁺386、388。

Embodiment 56

6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(70-75% 160mg) adds 6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 70) and (91mg) is dissolved in the stirred solution of DCM (8mL), stirs 45 minutes in ambient temperature with mCPBA.Add NH then ₃(dioxane of 0.5M) (10mL), reaction stirred 2 days adds NH once more ₃(dioxane of 0.5M) (5mL) back stirred 16 hours.The vacuum concentration reaction mixture with fast silica gel chromatogram method purification crude product, uses isohexane: EtOAc (1: 1) to use 0-10% (7M NH then earlier ₃MeOH) the EtOAc wash-out, obtain solid title compound (40mg, 48%);

¹H?NMR(DMSO-d ₆)δ1.28(t，3H)，3.95(q，2H)，7.19(t，1H)，7.28(t，2H)，7.51(d，2H)，7.60(s，2H)，7.67(s，1H)，7.98(s，1H)，8.32(s，1H)。

MS?m/e?MH ⁺322。

The raw material that uses is prepared as follows:

Intermediate 70

6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine

To contain 4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 15) (105mg) and the THF (5mL) of ethamine (70%aq.) (80 μ L) stirred 24 hours in ambient temperature.Added PhTosMIC (203mg) and piperazine (100mg) back reaction stirred 3 days.Adding PhTosMIC (70mg) back once more stirred 3 days.The vacuum concentration reaction mixture, with fast silica gel chromatogram method purification crude product, use Hex: (4: 1-100%EtOAc) wash-out obtains yellow gummy title compound (91mg, 52%) (the 1-ethyl-4 that comprises 33mol%, 5-phenylbenzene-1H-imidazoles) to EtOAc;

MS?m/e?MH ⁺353。

Use the universal method for preparing embodiment 56 and intermediate 70 to prepare the compound of embodiment 57-59, just replace ethamine with suitable amine.

Embodiment 57

6-[1-(3-methoxy-propyl)-4-phenyl-H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Yellow solid title compound (40mg, 51% productive rate); MS m/e MH ⁺366

¹H?NMR(DMSO-d ₆)δ1.86(m，2H)，3.15(s，3H)，3.25-3.31(m，4H)，3.98(t，2H)，6.30(s，2H)，7.18(t，1H)，7.28(t，2H)，7.52(d，2H)，7.67(s，1H)，7.93(s，1H)，8.32(s，1H)；

Embodiment 58

6-(1-isobutyl--4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

Yellow solid title compound (60mg, 51% productive rate); MS m/e MH ⁺350

¹H?NMR(DMSO-d ₆)δ0.80(d，6H)，1.83-1.95(m，1H)，3.76(d，2H)，7.18(t，1H)，7.27(t，2H)，7.52(d，2H)，7.60(s，2H)，7.65(s，1H)，7.92(s，1H)，8.32(s，1H)；

Embodiment 59

2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethanol

Yellow solid title compound (30mg, 19% productive rate); MS m/e MH ⁺338

¹H?NMR(DMSO-d ₆)δ3.56-3.60(m，2H)，3.95(t，2H)，4.99(t，1H)，7.18(t，1H)，7.28(t，2H)，7.52(d，2H)，7.60(s，2H)，7.64(s，1H)，7.91(s，1H)，9.31(s，1H)；

Embodiment 60

6-(1-cyclopropyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

To contain 6-(1-cyclopropyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 71) (25mg), NH ₃(concentrated aqueous solutions) and NH ₄The dioxane (2mL) of Cl (saturated aqueous solution) is in microwave condition (CEM detector, 170 ℃, 4 hours) heating down.With DCM and water diluted reaction mixture.Water layer extracts with DCM, concentrates the organism that merges then.Crude product is purified with the fast silica gel chromatogram method, uses Hex: (1: 1-100%EtOAc, MeOH then: EtOAc95: 5) wash-out obtains solid title compound (8mg, 35%) to EtOAc;

¹H?NMR(DMSO-d ₆)δ0.87-0.93(m，2H)，0.98-1.02(m，2H)，3.30-3.45(m，1H)，7.20(t，1H)，7.29(t，2H)，752(d，2H)，7.58(s，2H)，7.70(s，1H)，7.91(s，1H)，8.31(s，1H)；

MS?m/e?MH ⁺334。

The raw material that uses is prepared as follows:

Intermediate 71

6-(1-cyclopropyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 70 introductions, just replace ethamine with cyclopropylamine.Obtain solid title compound (25mg, 14%) (comprising 30% 1-cyclopropyl-4,5-phenylbenzene-1H-imidazoles);

MS?m/e?MH ⁺365。

Use the universal method for preparing embodiment 60 and intermediate 70 to prepare the compound of embodiment 61-64, just with suitable amine displacement ethamine, final compound is purified with preparation type LCMS replacement silica gel chromatography.

Embodiment 61

6-[1-(2-methoxy ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amineYellow solid title compound (11mg, 16% productive rate); MS m/e MH ⁺352.

Embodiment 62

6-(1-butyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amineYellow solid title compound (9mg, 11% productive rate); MS m/e MH ⁺350.

Embodiment 63

6-[4-phenyl-1-(pyridin-3-yl methyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amineYellow solid title compound (6mg, 18% productive rate); MS m/e MH ⁺385.

Embodiment 64

6-[1-(2, the 2-dimethoxy-ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amineYellow solid title compound (5mg, 7% productive rate); MS m/e MH ⁺382.

Embodiment 65

6-(4-phenyl-1-tetramethyleneimine-3-base-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

The THF (1mL) that will contain 3-amino-pyrrolidine (26mg) adds the 4-aminothiophene, and also [2,3-d] pyrimidine-6-formaldehyde (intermediate 73) (18mg).In ambient temperature stirred reaction mixture 1.5 hours, add the solution that PhTosMIC (30mg) and morpholine (20 μ L) are dissolved in THF (1mL) then.In ambient temperature reaction stirred 6 days, solvent removed in vacuo then.Crude product is purified with the fast silica gel chromatogram method, uses EtOAc: 7N NH ₃MeOH (100: 0-90: 10) wash-out obtains faint yellow solid title compound (5mg, 14%);

MS?m/e?MH ⁺363。

The raw material that uses is prepared as follows:

Intermediate 72

6-(diethoxymethyl)-4-(methylthio group) thieno-[2,3-d] pyrimidine

With 4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 15) (3.06g), dense H ₂SO ₄(0.25mL) and MgSO ₄(7.6g) be dissolved in EtOH (100mL), then in 60 ℃ of heating 3 hours.The cooling reactant is then through anhydrous K ₂CO ₃Filter, wash with EtOH.The vacuum concentration reaction mixture obtains crude product (3.95g, 95%) (no longer purify and directly use);

¹H?NMR(CDCl ₃)δ1.28(t，6H)，3.60-6.75(m，4H)，5.78(s，1H)，7.30(s，1H)，8.79(s，1H)；

MS?m/e?MH ⁺285。

Intermediate 73

The 4-aminothiophene is [2,3-d] pyrimidine-6-formaldehyde also

With NaHCO ₃(7.75g) add crude product 6-(diethoxymethyl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 72) (3.95g) and MCPBA (7.5g) be dissolved in the solution of DCM (125mL).In ambient temperature stirred reaction mixture 3 hours, and then add MCPBA (4.0g) and NaHCO ₃(4.0g), stirring is spent the night.Filter reaction mixture thoroughly washs with DCM, then vacuum concentration.Resistates is dissolved in dioxane (75mL), adds dense NH ₃(100mL).Spend the night in the ambient temperature stirred reaction mixture.The concentration response volume is used HCl (5mL) acidifying then to about 100mL.In ambient temperature stirred reaction mixture 1.5 hours, use DCM (250mL) and saturated NaHCO then ₃The aqueous solution (50mL) dilution.Use DCM (3 * 50mL) aqueous layer extracted after separating organic layer.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate.Product grinds with ether, obtains faint yellow solid title compound (1.74g, 69%);

¹H?NMR(DMSO-d ₆)δ8.16(s，2H)，8.48(s，1H)，8.59(s，1H)，10.11(s，1H)；

MS?m/e?MH ⁺180。

Use the universal method of preparation embodiment 65 to prepare the compound of embodiment 66 and 67, just with suitable amine displacement 3-amino-pyrrolidine, final compound replaces silica gel chromatography to purify with preparation type LCMS.

Embodiment 66

2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] oneself-1-alcohol

Yellow solid title compound (6mg, 15% productive rate); MS m/e MH ⁺394.

Embodiment 67

2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] fourth-1-alcohol

Yellow solid title compound (5mg, 14% productive rate); MS m/e MH ⁺366

Embodiment 68

6-{1-[2-(4-methylpiperazine-1-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl } thieno-[2,3-d] is phonetic Pyridine-4-amine

With [5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] acetaldehyde (intermediate 74) (100mg) and N methyl piperazine (100 μ L) in AcOH (1mL), stirred 15 minutes.Add Na (AcO) ₃BH (70mg) back reaction stirred is spent the night.With 2M NaOH (50mL) reactant is made alkalescence, use DCM (3 * 50mL) extraction products then.Organism water (30mL), salt solution (30mL) washing, dry (MgSO ₄) final vacuum concentrates.Product is purified with the fast silica gel chromatogram method, uses DCM: 7N NH ₃MeOH (95: 5) wash-out, obtain solid title compound (32mg, 28%);

¹H NMR (DMSO-d ₆) (s, 3H), (m, 8H), 3.30 (m, 2H is because of H for 2.20-2.40 for δ 2.12 ₂O is fuzzy), 4.00 (t, 2H); 7.18 (t, 1H), 7.28 (t, 2H), 7.52 (d, 2H), 7.60 (s, 2H), 7.66 (s, 1H), 7.93 (s, 1H), 8.32 (s, 1H);

MS?m/e?MH ⁺420。

The raw material that uses is prepared as follows:

Intermediate 74

[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] acetaldehyde

With 2M HCl (8mL) and dense H ₂SO ₄(0.5mL) adding 6-[1-(2, the 2-dimethoxy-ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 64) (1.54g) is dissolved in the solution of THF (20mL).In 60 ℃ of reacting by heating things 72 hours, be cooled to ambient temperature, pour NaHCO then into ₃(50% saturated aqueous solution) (100mL).Filtration gained precipitation obtains faint yellow solid title compound (1g, 74%) (no longer purify and directly use);

MS?m/e?MH ⁺354。

Embodiment 69

2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) [, 3] thiazole is [5,4-d] pyrimidine-7-amine also

Prepare title compound by being similar to the method for preparing embodiment 56 introductions, just with 2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine (intermediate 78) replacement 6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 70).Obtain yellow solid title compound (60mg, 64%);

¹H?NMR(DMSO-d ₆)δ1.30(t，3H)，4.39(q，2H)，7.35-7.42(m，3H，7.50(d，2H)，7.74(s，2H)，8.02(s，1H)，8.29(s，1H)；

MS?m/e?MH ⁺323。

The raw material that uses is prepared as follows:

Intermediate 75

(7-sulfydryl [1,3] thiazole is [5,4-d] pyrimidine-2-base also) methyl alcohol

To contain 5-aminopyrimidine-4,6-two mercaptan (intermediate 41) pyridine (500mL) cooling (ice bath) suspension (40.0g) stirs down in inert atmosphere.Add alpha-Acetoxyacetyl chloride (38mL) in 10 minutes, removing behind the ice bath stirs the mixture in ambient temperature spends the night.Vacuum concentrated mixture is used toluene (200mL) azeotropic 3 times.Resistates is suspended in 2N HCl,, is cooled to ambient temperature and spends the night in 115 ℃ of heating 5 hours.Filter gained suspension, water (200mL) and ether (200mL) washing obtain light brown solid title compound (48.3g, 97%) (comprising (7-sulfydryl [1,3] thiazole is [5,4-d] pyrimidine-2-base also) methyl acetate of 10%);

¹H?NMR(DMSO-d ₆)δ4.81(d，2H)，6.38(s，br，1H)，8.36(s，1H)，14.15(s，br，5H)；

MS?m/e(MH) ⁺200。

Intermediate 76

[7-(methylthio group) [1,3] thiazole is [5,4-d] pyrimidine-2-base also] methyl alcohol

Will (7-sulfydryl [1,3] thiazole is [5,4-d] pyrimidine-2-base also] methyl alcohol (intermediate 75) (48.3g) and methyl iodide (16.6mL) be dissolved in 2M NaOH (450mL) solution in ambient temperature stirring 5 hours.Filter to collect crude product, add 2N HCl acidifying after being suspended in water.Filter and collect the flocculence solid, Vanadium Pentoxide in FLAKES vacuum-drying is used in water (200mL) and ether (200mL) washing, obtains light brown solid title compound (27.5g, 53%);

¹H?NMR(DMSO-d ₆)δ2.66(s，3H)，4.90(d，2H)，6.47(s，br，1H)，8.90(s，1H)；

MS?m/e(MH) ⁺214。

Intermediate 77

7-(methylthio group) [1,3] thiazole is [5,4-d] pyrimidine-2-formaldehyde also

To contain [7-(methylthio group) [1,3] thiazole is [5,4-d] pyrimidine-2-base also] methyl alcohol (intermediate 76) (25.0g) and dioxane (1200mL) suspension of activated manganese dioxide (40.7g) in 100 ℃ the heating 24 hours.Mixture filters through Celite, concentrates with THF (2000mL) washing final vacuum, obtains yellow solid title compound (22.5g, 91%);

¹H?NMR(DMSO-d ₆)δ2.84(s，3H)，9.16(s，1H)，10.19(s，1H)；

MS?m/e(MH+H ₂O) ⁺230。

Intermediate 78

2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole is [5,4-d] pyrimidine also

Prepare title compound by being similar to the method for preparing intermediate 70 introductions, just use also [5,4-d] pyrimidine-2-formaldehyde (intermediate 77) replacement 4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 15) of 7-(methylthio group) [1,3] thiazole.Obtain yellow solid title compound (103mg, 58%);

MS?m/e?MH ⁺354。

Embodiment 70

2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

Prepare title compound by being similar to the method for preparing embodiment 56 introductions, just with 2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl]-7-(methylthio group) [1,3]-thiazole also [5,4-d] pyrimidine (intermediate 79) replacement 6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 70), use NH ₃Gas replaces NH ₃Solution (dioxane of 0.5M).Obtain solid title compound (160mg, 25%);

¹H?NMR(DMSO-d ₆)δ0.90-1.20(6H，m)，1.40(5H，m)，4.34(d，2H)，7.40-7.48(m，3H)，7.51-7.57(m，2H)，7.86(s，br，2H)，8.33(s，1H)，8.42(s，1H)；

MS?m/e?MH ⁺391。

The raw material that uses is prepared as follows:

Intermediate 79

2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl]-7-(methylthio group) [1,3] thiazole also [5,4-d] Pyrimidine

Prepare title compound by being similar to the method for preparing embodiment 65 introductions, just with 7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine-2-formaldehyde (intermediate 77) replaces 4-aminothiophene also [2,3-d] pyrimidine-6-formaldehyde (intermediate 73), replace the 3-amino-pyrrolidine with the cyclohexyl methylamine.Obtain yellow solid title compound (542mg) (product comprises 33% 1-(cyclohexyl methyl)-4, and 5-phenylbenzene-1H-imidazoles is directly used in next step but no longer purify);

MS?m/e?MH ⁺422。

Embodiment 71

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [3,2-d] pyrimidine-4-amine

With 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) furo [3,2-d] pyrimidine (intermediate 87) (50mg) and saturated aqueous ammonium chloride (2) at dense NH ₃The aqueous solution (1mL) and 1, the mixture in the 4-diox (2mL) is in microwave condition (CEM detector, 170 ℃, 150 minutes) heating down.Add entry (10mL), at EtOAc (extraction mixture in 2 * 20mL).The dry organic phase final vacuum that merges concentrates.Purify with fast silica gel chromatogram method (EtOAc of 0-5%MeOH), obtain Off-white solid title compound (38mg, 84%);

¹H?NMR(DMSO-d ₆)δ3.69(s，3H)，7.10(s，1H)，7.20-7.34(m，4H)，7.53(d，1H)，7.93(s，1H)，8.25(s，1H)；

MS?m/e?MH ⁺292。

The raw material that uses is prepared as follows:

Intermediate 80

3-furyl t-butyl carbamate

Two phenoxy group phosphoryl azides (78.9mL) are added dropwise to 3-furancarboxylic acid (Aldrich) (27.2g) are dissolved in the solution of mixed toluene (400mL), triethylamine (52.5mL) and the trimethyl carbinol (35.1mL).Heated solution adds entry (500mL) to refluxing 6 hours after the cool overnight.(3 * 500mL) extractions, decolorizing with activated carbon is used in the organism water (400mL) of merging, salt solution (400mL) washing to mixture, dry (MgSO with EtOAc ₄) back except that desolvating, obtain the 73g brown solid.Grind with 1: 1 DCM/ isohexane, obtain white solid title compound (31.5g, 71%);

¹H?NMR(CDCl ₃)δ1.50(s，9H)，6.22(s，br，1H)，6.27(s，1H)，7.26(d，1H)，7.69(s，br，1H)；

MS?m/e?MH ⁺184。

Intermediate 81

The 3-[(tert-butoxycarbonyl) amino]-the 2-furancarboxylic acid

(hexane solution of 1.6M 45mL) slowly adds 3-furyl t-butyl carbamates (intermediate 80) in-40 ℃ and (5.49g) is dissolved in the solution of THF (60mL), keeps internal reaction temperature to be lower than-35 ℃ with butyllithium.In-40 ℃ of reaction stirred 4 hours, pour the solid CO that covers diethyl ether (300mL) then into ₂(100mL).After being warming up to ambient temperature, pour in the water (300mL) mixture and stirring, add the 100mL diethyl ether once more.The separation solution phase, water (2 * 100mL) extracted organic phase once more.The organic phase that merges is washed with ether, adds the HCl acidified aqueous solution, with EtOAc (4 * 250mL) extractions.Evaporate behind the dry extract that merges, obtain faint yellow solid (7.5g).Grind with hexanaphthene, obtain white solid title compound (4.80g, 70%);

¹H?NMR(DMSO-d ₆)δ1.46(s，9H)，7.05(s，1H)，7.76(s，1H)，8.27(s，1H)，13.36(s，br，1H)；

MS?m/e(M-H) ^-226。

Intermediate 82

2-(aminocarboxyl)-3-furyl t-butyl carbamate

Diisopropylethylamine (14.75mL) adding is contained PyBOP (10.4g), ammonium chloride (1.81g) and 3-[(tert-butoxycarbonyl) amino]-2-furancarboxylic acid (intermediate 81) DMF (50mL) suspension (3.83g).Stirred the gained mixture 90 minutes in ambient temperature, (3 * 100mL) extract with DCM to pour 0.4M HCl (250mL) back into.Organism water (80mL) that merges and salt solution (80mL) washing, dry (MgSO ₄) the back evaporation.With fast silica gel chromatogram method purified product,, obtain white solid title compound (3.38g, 89%) with the isohexane wash-out of 20-70%EtOAc;

¹H?NMR(DMSO-d ₆)δ1.51(s，9H)，5.67(s，br，2H)，7.21(s，1H)，7.27(d，1H)，7.26(s，1H)，8.56(s，1H)；

MS?m/e?MH ⁺227。

Intermediate 83

Furo [3,2-d] pyrimidines-4 (3H)-ketone

To contain 2-(aminocarboxyl)-3-furyl t-butyl carbamate (intermediate 82) TFA (25mL) and DCM (25mL) (3.38g) stirred 30 minutes.Remove and desolvate, crude product heated 30 minutes in triethyl orthoformate (20mL) in 80 ℃.Cooling mixture is poured in the ether (100mL), filters and collects the back with the ether washing, obtains first faint yellow solid title compound (1.31g, 65%).Grind with EtOAc behind the evaporated filtrate, obtain second batch of product (296mg, 15%);

¹H?NMR(DMSO-d ₆)δ6.96(d，1H)，8.03(s，1H)，8.19(d，1H)，12.54(s，br，1H)；

MS?m/e(M+MeCN) ⁺187。

Intermediate 84

4-chlorine furo [3,2-d] pyrimidine

With furo [3,2-d] pyrimidines-4 (3H)-ketone (intermediate 83) (1.49g) and phosphoryl chloride (15mL) be heated to 120 ℃ 45 minutes, be cooled to high vacuum evaporation down behind the ambient temperature.Resistates is added 50% saturated sodium carbonate solution (100mL), with DCM (3 * 100mL) extractions.Remove behind the dry organism that merges and desolvate, obtain orange solids title compound (1.32g, 78%);

¹H?NMR(CDCl ₃)δ7.07(d，1H)，8.03(d，1H)，8.88(s，1H)；

MS?m/e(M+OH) ^-171、173。

Intermediate 85

4-(methylthio group) furo [3,2-d] pyrimidine

Sodium methyl mercaptide (1.2g) is added 4-chlorine furo [3,2-d] pyrimidine (intermediate 84) (1.32g) be dissolved in the solution of MeCN (100mL).Heated mixt to 90 ℃ 60 minutes, the cooling back adds 50% sodium carbonate solution (100mL).(3 * 100mL) extract the gained mixture with EtOAc.Dry (MgSO ₄) remove behind the organism that merges and desolvate, obtain greenish orange look solid title compound (1.21g, 85%);

¹H?NMR(CDCl ₃)δ2.74(s，3H)，6.95(d，1H)，7.87(d，1H)，8.86(s，1H)；

MS?m/e?MH ⁺167。

Intermediate 86

4-(methylthio group) furo [3,2-d] pyrimidine-6-formaldehyde

(hexane solution of 1.6M 7mL) adds 4-(methylthio group) furo [3,2-d] pyrimidines (intermediate 85) in-70 ℃ and (1.21g) is dissolved in the solution of THF (25mL) with butyllithium.Reaction stirred 5 minutes adds DMF (5mL), and reaction mixture is warming up to ambient temperature.(3 * 50mL) extract mixtures with EtOAc to add 30% saturated ammonium chloride solution (50mL) back.With the organism that 50% saturated sodium carbonate solution (50mL), water (50mL) washing merge, dry back is removed and is desolvated, and obtains faint yellow solid title compound (1.02g) (this product comprises 20% unreacting material, is directly used in next step but no longer purify);

¹H?NMR(DMSO-d ₆)δ2.74(s，3H)，8.09(s，1H)，8.98(s，1H)，10.02(s，1H)；

MS?m/e(M+MeOH+H) ⁺227。

Intermediate 87

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) furo [3,2-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 70 introductions, just with 4-(methylthio group) furo [3,2-d] pyrimidine-6-formaldehyde (intermediate 86) replacement 4-(methylthio group) thieno-[2,3-d] pyrimidine-6-formaldehyde (intermediate 15), replace ethamine with methylamine.Obtain faint yellow solid title compound (105mg, 54%);

¹H?NMR(DMSO-d ₆)δ2.62(s，3H)，3.77(s，3H)，7.25-7.38(m，4H)，7.53(d，2H)，7.99(s，1H)，8.84(s，1H)。

MS?m/e?MH ⁺323。

Embodiment 72

6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine

To contain 6-[(1-methyl-4-phenyl-1H-imidazoles-5-yl under the inert atmosphere) ethynyl] pyrimidine-4,5-diamines (intermediate 90) (50mg) and the DMF (2mL) of CuI (3mg) in 110 ℃ the heating 4 hours.With the reaction mixture application of sample in using DCM: on the 1g SCX post of MeOH (3: 1) pre-wash.Earlier use this post of DCM: MeOH (3: 1) wash-out, use 7NNH then ₃/ MeOH: DCM: MeOH (1: 3: 1) eluted product.The enriched product cut is purified with the fast silica gel chromatogram method then, uses DCM: MeOH (9: 1) wash-out obtains yellow solid title compound (3mg, 6%);

¹H?NMR(DMSO-d ₆)δ3.60(s，3H)，6.65-6.66(m，3H)，7.17-7.31(m，3H)，7.47-7.49(m，2H)，7.92(s，1H)，8.18(s，1H)，11.19(s，1H)。

m/e?MH ⁺291。

The raw material that uses is prepared as follows:

Intermediate 88

6-chloropyrimide-4, the 5-diamines

To contain 4, the POCl of 5-diamino-6-hydroxy pyrimidine (1g) and xylidene(s) (1mL) ₃(10mL) reflux 4 hours under inert atmosphere.The vacuum concentration reaction mixture carefully dilutes with frozen water, uses NaHCO then ₃Neutralization.(4 * 30mL) extract product, dry then (MgSO with EtOAc ₄) organism, filter final vacuum and concentrate.Crude product grinds with DCM, obtains light gray solid title compound product (168mg, 15%);

¹H?NMR(CDCl ₃)δ4.95(br?s，2H)，6.73(s，2H)，7.65(s，1H)；

m/e(MH+MeCN) ⁺186。

Intermediate 89

6-iodine pyrimidine-4, the 5-diamines

With 6-chloropyrimide-4,5-diamines (intermediate 88) (90mg) slowly adds HI (57%, the aqueous solution) (2mL) in 0 ℃.In 0 ℃ of stirred reaction mixture 30 minutes, stirred 24 hours in ambient temperature then.Be added dropwise to NaHCO ₃(saturated aqueous solution) is until reaction mixture pH8.(3 * 15mL) extract product with EtOAc.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate, obtain gray solid title compound (144mg, 98%);

¹H?NMR(CDCl ₃)δ4.81(bs，2H)，6.66(s，2H)，7.61(s，1H)；

MS?m/e?MH ⁺237。

Intermediate 90

6-[(1-methyl-4-phenyl-1H-imidazoles-5-yl) ethynyl] pyrimidine-4, the 5-diamines

To contain 6-iodine pyrimidine-4,5-diamines (intermediate 89) (50mg), CuI (2mg), PdCl ₂Dppf (16mg), 5-ethynyl-1-methyl-4-phenyl-1H-imidazoles (intermediate 26) (77mg) and the DMF (7mL) of triethylamine (0.33mL) be mixed together the back degassing.Under inert atmosphere, reaction mixture was stirred 24 hours in ambient temperature.Reaction mixture thoroughly washs with MeCN with DCM earlier then through diatomite filtration.Concentrate organism, resistates is purified on silica gel with chromatography, uses DCM: MeOH (9: 1) wash-out obtains yellow solid title compound (47mg, 76%);

¹H?NMR(CDCl ₃)δ3.79(s，3H)，5.29(s，2H)，6.85(s，2H)，7.29-7.34(m，1H)，7.41-7.46(m，2H)，7.87(s，1H)，7.92(s，1H)，8.10-8.12(m，2H)；

MS?m/e?MH ⁺291。

Embodiment 73

6-[4-(2-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

With 6-(4-iodo-1-methyl isophthalic acid H-imidazoles-5--yl) thieno-[2,3-d] pyrimidine-4-amine (intermediate 95) (50mg), 2-chlorophenylboronic acid (44mg) and PdCl ₂Dppf (10mg) is at Na ₂CO ₃(2M, the aqueous solution) (0.21mL), the mixture degassing in EtOH (1.2mL) and toluene (2mL) solution, then under inert atmosphere in 80 ℃ of heating 30 hours.Evaporating solvent, resistates DCM (10mL) and saturated NaHCO ₃The aqueous solution (10mL) dilution.Use DCM (10mL) aqueous layer extracted after separating organic layer.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate.Crude product is purified with the fast silica gel chromatogram method, uses DCM: MeOH (9: 1) wash-out obtains yellow solid title compound (15mg, 31%);

¹H?NMR(CDCl ₃)δ3.80(s，3H)，5.52(bs，2H)，7.01(s，1H，)，7.22-7.27(m，2H)，7.34-7.42(m，2H)，7.66(s，1H)，8.43(s，1H)；

MS?m/e?MH ⁺342。

The raw material that uses is prepared as follows:

Intermediate 91

4-methylthio group-6-iodo-thieno-[2,3-d] pyrimidine

(hexane of 1.6M 32.8mL) is added dropwise to the stirred solution that Diisopropylamine (7.36mL) is dissolved in THF (170mL) in-78 ℃ under inert atmosphere with butyllithium.Reaction mixture is warming up to 0 ℃, stirred 20 minutes, be cooled to-78 ℃ once more, add and contain 4-(methylthio group) thieno-[2,3-d] pyrimidine (J.Heterocycl.Chem.1975,12, the 921-924) THF of (9.11g) (17mL).Obtain purple solution, add the THF (20mL) that contains iodine (19.0g) then, continue to stir 1 hour, be warming up to behind the ambient temperature restir 1.5 hours in-78 ℃.Add saturated NH successively ₄The Cl aqueous solution (3mL) and water (500mL) are with DCM (500mL) extractive reaction mixture, organic layer Na ₂S ₂O ₃(2M, the aqueous solution) (2 * 50mL), water (2 * 200mL) washings, dry (MgSO ₄), filter final vacuum and concentrate.Crude product grinds with DCM (50mL), obtains brown solid title compound (11.8g, 77%);

¹H?NMR(CDCl ₃)δ2.70(s，3H)，7.60(s，1H)，8.74(s，1H)；

MS?m/e?MH ⁺309。

Intermediate 92

5-tributyl stannyl-4-iodo-1-methyl isophthalic acid H-imidazoles

With 4,5-two iodo-1-methyl isophthalic acid H-imidazoles (40.0g) stir in ambient temperature in anhydrous THF (560mL), in 20 minutes in inert atmosphere add down ethylmagnesium bromide (ether of 3M, 42.0mL).Stir the gained white precipitate 30 minutes, and be added dropwise to tributyltin chloride (34.2mL) then.Stir the gained clear solution 1 hour, and added saturated NH then ₄The Cl aqueous solution (50mL) and water (300mL).(3 * 300mL) wash reaction mixture, dry (MgSO with DCM (500mL) extraction, water ₄), filter final vacuum and concentrate.Crude product is purified with the fast silica gel chromatogram method, uses hexane: EtOAc (1: 1) wash-out obtains colorless oil title compound (45.1g, 76%);

¹H?NMR(CDCl ₃)δ0.89-0.95(m，9H)，1.21-1.29(m，6H)，1.30-1.40(m，6H)，1.51-1.60(m，6H)，3.66(s，3H)，7.45(s，1H)；

MS?m/e?MH ⁺499( ¹²⁰Sn)、497( ¹¹⁸Sn)、495( ¹¹⁶Sn)。

Intermediate 93

6-(4-iodo-1-methyl isophthalic acid H-imidazoles-5-yl)-4-methylthio group-thieno-[2,3-d] pyrimidine

With 4-methylthio group-6-iodo-thieno-[2,3-d] pyrimidine (intermediate 91) (949mg), 5-tributyl stannyl-4-iodo-1-methyl isophthalic acid H-imidazoles (intermediate 92) (2.76g) and tetrakis triphenylphosphine palladium (0) (178mg) in dry DMF (50mL), stir, with the nitrogen degassing 10 minutes, under inert atmosphere, be heated to then 100 ℃ 18 hours.The vacuum concentration reaction mixture, crude product grinds with DCM (20mL), obtains yellow solid title compound (805mg, 67%);

¹H?NMR(CDCl ₃)δ2.75(s，3H)，3.75(s，3H)，7.42(s，1H)，7.59(s，1H)，8.86(s，1H)；

MS?m/e?MH ⁺389。

Intermediate 94

6-(4-iodo-1-methyl isophthalic acid H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-(4-iodo-1-methyl isophthalic acid H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 93) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain yellow solid title compound (273mg, 85%);

¹HNMR(CDCl ₃)δ3.46(s，3H)，3.82(s，3H)，7.63(s，1H，)，8.10(s，1H)，9.20(s，1H)；

MS?m/e?MH ⁺421。

Intermediate 95

6-(4-iodo-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-(4-iodo-1-methyl isophthalic acid H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 94) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2,3-d] pyrimidine (intermediate 17).Obtain beige solid title compound (143mg, 85%);

¹H?NMR(DMSO-d ₆)δ3.72(s，3H)，7.66(s，2H)，7.73(s，1H)，7.88(s，1H)，8.32(s，1H)；

MS?m/e?MH ⁺358。

Preparation embodiment 74-84 uses the universal method of preparation embodiment 73, just replaces the 2-chlorophenylboronic acid with suitable boric acid.

Embodiment 74

6-[4-(3-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (15mg, 31%);

¹H?NMR(CDCl ₃)δ3.61(s，3H)，5.43(br?s，2H)，7.11(1H，s)，7.15-7.18(m，2H)，7.35-7.38(m，1H)，7.65(s，1H)，7.70(s，1H)，8.54(s，1H)；

MS?m/e?MH ⁺342。

Embodiment 75

6-[4-(4-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (12mg, 25%);

¹H?NMR(CDCl ₃)δ3.58(s，3H)，5.63(br?s，2H)，7.09(1H，s)，7.22(d，2H)，7.51(d，2H)，7.64(s，1H)，8.53(s，1H)；

MS?m/e?MH ⁺342。

Embodiment 76

6-[1-methyl-4-(2-naphthyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Brown solid title compound (18mg, 36%);

¹H?NMR(CDCl ₃)δ3.55(s，3H)，5.63(br?s，2H)，7.11(1H，s)，7.39-7.76(m，7H)，8.14(s，1H)，8.53(s，1H)；

MS?m/e?MH ⁺358。

Embodiment 77

6-[4-(1-thionaphthene-2-yl)-1-methyl-H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (16mg, 31%);

¹H?NMR(DMSO-d ₆)δ3.61(s，3H)，7.25-7.32(m，2H)，7.38(s，1H)，7.68(br?s，2H)，7.73-7.75(m，1H)，7.82(s，1H)，7.87-7.89(m，1H)，7.97(s，1H)，8.37(s，1H)；

MS?m/e?MH ⁺364。

Embodiment 78

6-[4-(3-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (23mg, 50%);

¹H?NMR(CDCl ₃)δ3.59(s，3H)，5.53(br?s，2H)，6.88-6.93(m，1H)，7.11(s，1H)，7.21(td，1H)，7.32-7.35(m，2H)，7.65(s，1H)，8.54(s，1H)；

MS?m/e?MH ⁺326。

Embodiment 79

6-[1-methyl-4-(2-aminomethyl phenyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (17mg, 38%);

¹H?NMR(CDCl ₃)δ2.19(s，3H)，3.79(s，3H)，5.36(br?s，2H)，6.86(1H，s)，7.11-7.14(m，1H)，7.18-7.26(m，3H)，7.64(s，1H)，8.43(s，1H)；

MS?m/e?MH ⁺322。

Embodiment 80

6-[4-(2, the 5-difluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amineBeige solid title compound (11mg, 23%);

¹H?NMR(CDCl ₃)δ3.73(s，3H)，5.35(br?s，2H)，6.91-6.97(m，2H)，7.01(1H，s)，7.29-7.34(m，1H)，7.69(s，1H)，8.49(s，1H)；

MS?m/e?MH ⁺344。

Embodiment 81

6-[4-(2, the 5-dichlorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Green solid title compound (9mg, 17%);

¹H?NMR(CDCl ₃)δ3.80(s，3H)，5.41(br?s，2H)，6.94(1H，s)，7.22-7.30(m，2H)，7.48(s，1H)，7.68(s，1H)，8.46(s，1H)；

MS?m/e?MH ⁺376。

Embodiment 82

6-[1-methyl-4-(1-naphthyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (18mg, 36%);

¹H?NMR(CDCl ₃)δ3.79(s，3H)，5.39(br?s，2H)，6.87(1H，s)，7.33-7.47(m，4H)，7.71(s，1H)，7.78-7.84(m，2H)，8.07-8.10(m，1H)，8.46(s，1H)；

MS?m/e?MH ⁺358。

Embodiment 83

6-[4-(1H-indoles-5-yl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Beige solid title compound (5mg, 10%);

¹H?NMR(CDCl ₃)δ3.64(s，3H)，5.30(br?s，2H)，6.49(s，1H)，7.10(s，1H)，7.18(t，1H)，7.30(s，1H)，7.41(dt，1H)，7.66(s，1H)，7.90(s，1H)，8.12(s，1H)，8.52(s，1H)；

MS?m/e?MH ⁺347。

Embodiment 84

6-{4-[4-(benzyloxy)-2-aminomethyl phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine -4-amine

Beige solid title compound (14mg, 23%);

¹H?NMR(CDCl ₃)δ2.15(s，3H)，3.76(s，3H)，5.04(s，2H)，5.50(brs，2H)，6.73(dd，1H，)，6.82(d，1H)，6.90(s，1H)，7.15(d，1H)，7.31-7.43(m，5H)，7.61(s，1H)，8.42(s，1H)；

MS?m/e?MH ⁺428。

Embodiment 85

7-(diisopropylaminoethyl)-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] also Pyrimidine-5-formaldehyde

Under the inert atmosphere with 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7-(methylthio group) [1,3] thiazole also [5,4-d] pyrimidine (intermediate 42) solution of (0.1g) being dissolved in THF (4mL) add the solution that LDA (2.2eq) are dissolved in THF (6mL) in-78 ℃.In-78 ℃ of stirred reaction mixtures 1 hour, add DMF (0.4mL) then.In-78 ℃ of stirred reaction mixtures 1 hour once more, pour into then in the water (10mL), (3 * 10mL) extractions, with salt solution (10mL) washing, dry final vacuum evaporating solvent obtains brown oil with EtOAc.Purify with the fast silica gel chromatogram method, use EtOAc: hexane (1: 9) wash-out obtains yellow oily title compound (14mg, 11%);

¹H?NMR(CDCl ₃)δ1.32(m，12H)，3.65(sept，1H)，4.19(s，3H)，4.61(sept，1H)，7.35(m，3H)，7.57(m，2H)，7.68(s，1H)，9.91(s，1H)；

MS?m/e?MH ⁺421。

Embodiment 86

2-(2-{[2-(dimethylamino) ethyl] sulfenyl }-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiophene Azoles is [5,4-d] pyrimidine-7-amine also

With 5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-mercaptan (intermediate 47) (10mg), N, the mixture of N-dimethyl-2-chloroethyl amine hydrochloride (9mg) and 2MNaOH (1mL) in 60 ℃ the heating 6 hours.Reaction mixture is to ambient temperature then, and filtering separation obtains yellow solid title compound (6mg, 50%);

¹H?NMR(CDCl ₃)δ2.30(s，6H)，2.71(t，2H)，3.46(t，2H)，3.89(s，3H)，5.71(bs，2H)，7.38(m，3H)，7.51(m，2H)，8.39(s，1H)；

MS?m/e?MH ⁺412。

Embodiment 87

2-(1-methyl-2-{[(methylthio group) methyl] sulfenyl }-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

Also [5,4-d] pyrimidine-7-amine (embodiment 26) (0.2g), the mixture of sodium methyl mercaptide (0.14g) and DMF (12mL) is in 80 ℃ of heating 2 hours with 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole under the inert atmosphere.Vacuum evaporating solvent is dissolved in 1MNaOH (10mL) with resistates, uses DCM (3 * 10mL) extractions then.Water layer is acidified to pH4, with EtOAc (3 * 10mL) extractions.Merge organic layer, dry final vacuum evaporating solvent obtains brown oil.Purify with the fast silica gel chromatogram method, use DCM: MeOH (9: 1) wash-out obtains yellow solid title compound (26mg, 15%);

¹H?NMR(CDCl ₃)δ2.30(s，3H)，3.92(s，3H)，4.41(s，2H)，5.70(bs，2H)，7.40(m，3H)，7.52(m，2H)，8.41(s，1H)；

MS?m/e?MH ⁺401。

Use the universal method of preparation embodiment 86 to prepare embodiment 88-91, just replace N, N-dimethyl-2-chloroethyl amine hydrochloride with suitable halogenated alkyl.

Embodiment 88

2-(2-{[2-(1H-imidazoles-1-yl] ethyl) sulfenyl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] Thiazole is [5,4-d] pyrimidine-7-amine also

Yellow solid title compound (9mg, 99%); MS m/e MH ⁺435.

Embodiment 89

2-{1-methyl-4-phenyl-2-[(pyridin-3-yl methyl) sulfenyl]-1H-imidazoles-5-yl } [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

Yellow solid title compound (8.5mg, 99%); MS m/e MH ⁺432.

Embodiment 90

2-{2-[(cyclopropyl methyl) sulfenyl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

Yellow solid title compound (6.5mg, 79%); MS m/e MH ⁺395.

Embodiment 91

2-[2-(benzylthio-)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-also Amine

Yellow solid title compound (8.2mg, 95%); MS m/e MH ⁺431.

Embodiment 92

2-[1-methyl-2-(4-methylpiperazine-1-yl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole also [5,4-d] Pyrimidine-7-amine

With 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 26) (0.02g) and the mixture of N methyl piperazine (1mL) in down heating of microwave condition (CEM detector, 195 ℃, 1 hour).Behind the vacuum evaporating solvent resistates is dissolved in EtOAc (10mL), (2 * 10mL) washings, dry final vacuum evaporating solvent obtains yellow solid title compound (10mg, 48%) to water

¹H?NMR(CDCl ₃)δ2.39(s，3H)，2.63(m，4H)，3.29(m，4H)，3.78(s，3H)，5.72(bs，2H)，7.37(m，3H)，7.51(m，2H)，8.38(s，1H)；

MS?m/e?MH ⁺401。

Embodiment 93

The 2-{2-[(1-aminocyclohexyl) ethynyl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole And [5,4-d] pyrimidine-7-amine

Under the inert atmosphere with 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 26) (0.02g), PdCl ₂Dppf (3.5mg), triethylamine (0.1mL), DMF (5mL), cuprous iodide (I) (1mg) and the mixture of 1-ethynyl hexahydroaniline (0.034mL) in 90 ℃ of heating 1.5 hours.Vacuum evaporating solvent is purified with the fast silica gel chromatogram method then, uses DCM: MeOH (9: 1) wash-out obtains beige solid title compound (9mg, 41%).

¹H?NMR(CDCl ₃)δ1.30-2.10(m，10H)，4.08(s，3H)，5.80(bs，2H)，7.40(m，3H)，7.51(m，2H)，8.41(s，1H)；

MS?m/e?MH ⁺430。

Use the universal method of preparation embodiment 93 to prepare embodiment 94-98, just replace 1-ethynyl hexahydroaniline with the alkynes that suitably replaces.

Embodiment 94

4-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] Fourth-3-alkynes-2-alcohol

Yellow solid title compound (2mg, 9%);

¹H?NMR(CDCl ₃)δ1.61(d，3H)，2.25(bs，1H)，4.01(s，3H)，4.83(m，1H)，5.73(bs，2H)，7.40(m，3H)，7.51(m，2H)，8.42(s，1H)；

MS?m/e?MH ⁺377。

Embodiment 95

1-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] ethynyl } hexalin

Beige solid title compound (7mg, 29%);

¹H?NMR(CDCl ₃)δ1.50-1.81(m，8H)，2.09(m，2H)，2.54(bs，1H)，4.01(s，3H)，5.81(bs，2H)，7.38(m，3H)，7.51(m，2H)，8.41(s，1H)；

MS?m/e?MH ⁺431。

Embodiment 96

2-[1-methyl-4-phenyl-2-(pyridine-2-ethyl-acetylene base)-1H-imidazoles-5-yl] [1,3] thiazole also [5,4- D] pyrimidine-7-amine

Beige solid title compound (9.4mg, 44%);

¹H?NMR(CDCl ₃)δ4.17(s，3H)，5.81(bs，2H)，7.32(m，1H)，7.39(m，3H)，7.57(m，2H)，7.62(d，1H)，7.75(t，1H)，8.42(s，1H)，8.68(s，1H)；

MS?m/e?MH ⁺410。

Embodiment 97

2-[2-(3-amino-3-methyl fourth-1-alkynes-1-yl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiophene Azoles is [5,4-d] pyrimidine-7-amine also

Yellow solid title compound (7mg, 33%);

¹H?NMR(CDCl ₃)δ1.40(s，6H)，4.01(s，3H)，5.76(bs，2H)，7.40(m，3H)，7.52(m，2H)，8.42(s，1H)；

MS?m/e?MH ⁺390。

Embodiment 98

2-[2-(3-methoxy propyl-1-alkynes-1-yl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

Beige solid title compound (9mg, 45%;

¹H?NMR(CDCl ₃)δ3.51(s，3H)，4.04(s，3H)，4.43(s，2H)，5.91(bs，2H)，7.39(m，3H)，7.54(m，2H)，8.42(s，1H)；

MS?m/e?MH ⁺377。

Embodiment 99

2-(1-methyl-2-morpholine-4-base-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-also Amine

Prepare title compound by being similar to the method for preparing embodiment 92 introductions, just replace N methyl piperazine with morpholino.Obtain white solid title compound (7mg, 33%);

¹H?NMR(CDCl ₃)δ3.25(m，4H)，3.81(s，3H)，3.90(m，4H)，5.63(bs，2H)，7.39(m，3H)，7.52(m，2H)，8.39(s，1H)；

MS?m/e?MH ⁺394。

Embodiment 100

2-(1-methyl-4-phenyl-2-pyrimidine-5-base-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-also Amine

Prepare title compound by being similar to the method for preparing embodiment 35 introductions, just replace pyridine-4-boric acid with 5-pyrimidyl boric acid.Obtain colorless solid title compound (6mg, 15%);

MS?m/e?MH ⁺387。

Embodiment 101

2-{2-[3-(dimethylamino) third-1-alkynes-1-yl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] Thiazole is [5,4-d] pyrimidine-7-amine also

Prepare title compound by being similar to the method for preparing intermediate 45 introductions, just replace trimethyl silyl acetylene with 1-dimethylamino-2-propine.Obtain colorless solid title compound (25mg, 64%);

¹H?NMR(DMSO-d ₆)δ2.28(s，6H)，3.54(s，2H)，3.89(s，3H)，7.31-7.40(m，3H)，7.42-7.50(m，2H)，7.74(bs，2H)，8.23(s，1H)。

MS?m/e?MH ⁺390。

Embodiment 102

4-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-H-imidazoles-2- Base]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester

Prepare title compound by being similar to the method for preparing embodiment 35 introductions, just with 4-(4,4,5,5-tetramethyl--1,3, the 2-luxuriant alkane of two oxa-boron (dioxaborolan)-2-yl)-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (Tetrahedron Lett., 2000,41,3705) replace pyridine-4-boric acid.Obtain weak yellow foam shape title compound (60mg, 56%);

¹H?NMR(DMSO-d ₆)δ1.46(s，9H)，2.58(bs，2H)，3.58(m，2H)，3.85(s，3H)，4.10(bs，2H)，6.23(bs，1H)，7.31-7.41(m，3H)，7.47-7.53(m，2H)，7.78(bs，2H)，8.29(s，1H)。

MS?m/e?MH ⁺490。

Embodiment 103

2-[1-methyl-4-phenyl-2-(1,2,3,6-tetrahydropyridine-4-yl)-1H-imidazoles-5-yl] [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

With 4-[5-(7-amino [1,3] thiazole also [5,4-d] pyrimidine-2-base)-1-methyl-4-phenyl-1H-imidazoles-2-yl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (embodiment 102) (20mg) is dissolved in DCM (0.5mL), add TFA (2mL), stir 2 hours final vacuums in ambient temperature and concentrate.Resistates dilutes with saturated sodium bicarbonate aqueous solution, and (2 * 5mL) extractions, dry organism filter final vacuum and concentrate with DCM.Purify with the fast silica gel chromatogram method, use the 10%MeOH/DCM wash-out, obtain colorless solid title compound (11mg, 69%);

MS?m/e?MH ⁺390。

Embodiment 104

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (phenyl) methyl alcohol

With [5-(7-amino [1,3] thiazole also [5,4-d] pyrimidine-2-base)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl dimethoxy aminocarbamic acid ester (intermediate 97) (25mg) is dissolved in THF (4mL), add TFA (0.1mL) and water (0.1mL), reflux under inert atmosphere then.After 2 hours, be cooled to ambient temperature,, use saturated NaHCO with EtOAc (10mL) dilution ₃The aqueous solution (10mL) washing, dry (MgSO ₄) organic layer, filter final vacuum and concentrate.Resistates is purified with the fast silica gel chromatogram method, uses the 4%MeOH/DCM wash-out, obtains colourless foam shape title compound (21mg, 99%);

¹H NMR (DMSO-d ₆) δ 3.72 (s, 3H), 6.06 (d, 1H), 6.47 (d, 1H (replaceable)), 7.24-7.76 (m, 9H), 7.74 (bs, 2H), 7.85 (m, 1H), 8.26 (s, 1H).

MS?m/e?MH ⁺415。

The raw material that uses is prepared as follows:

Intermediate 96

The N-benzoyl-N-[2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] is phonetic Pyridine-7-yl] benzamide

With 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 2) (0.56g) is dissolved in pyridine (10mL), adds Benzoyl chloride (0.44mL) and triethylamine (0.28mL), under inert atmosphere, stir then in ambient temperature.After 4 hours, add saturated NaHCO ₃The aqueous solution (10mL), filter reaction mixture, water, EtOAc and diethyl ether washing successively, high vacuum is dry down, obtains colorless solid title compound (0.63g, 68%);

¹H?NMR(DMSO-d ₆)δ3.66(s，3H)，7.56-7.68(m，9H)，7.71-7.79(m，2H)，7.95(m，4H)，8.08(s，1H)，8.89(s，1H)。

Intermediate 97

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2 Base] (phenyl) methyl dimethoxy aminocarbamic acid ester

With N-benzoyl-N-[2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1; 3] thiazole also [5; 4-d] pyrimidin-7-yl] benzamide (intermediate 96) (0.05g) is dissolved in/is suspended in MeCN (5mL), adds dimethylcarbamyl chloride (0.015mL), phenyl aldehyde (16mg) and DIPEA (0.05mL) successively.Reflux reaction mixture 24 hours.Add dimethylcarbamyl chloride (0.015mL), phenyl aldehyde (16mg) and DIPEA (0.05mL) then successively.Heat after 5 days, the vacuum concentration reaction mixture is used saturated NaHCO ₃DCM (2 * 10mL) extractions are used in solution (5mL) dilution then.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate, will obtain brown resistates and be dissolved in MeOH (2mL)/dense NH ₃The aqueous solution (2mL).In 55 ℃ of reacting by heating mixtures 1 hour, vacuum concentration then was with 2M NaOH (8mL) dilution, with DCM (1 * 20mL) extraction.Dry (MgSO ₄) organic layer, filtering, vacuum concentration obtains resistates, purifies (2%MeOH/DCM) with the fast silica gel chromatogram method, obtains colorless solid title compound (0.033g, 68%);

¹H?NMR(DMSO-d ₆)δ2.84(s，3H)，2.99(s，3H)，3.81(s，3H)，6.96(s，1H)，7.26-7.53(m，8H)，7.78(bs，2H)，7.85(m，2H)，8.26(s，1H)。

MS?m/e?MH ⁺486。

Embodiment 105

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (cyclopropyl) methyl alcohol

Prepare title compound by being similar to the method for preparing embodiment 104 introductions, just with [5-(7-amino [1,3] thiazole also [5,4-d] pyrimidine-2-base)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (cyclopropyl) methyl dimethoxy aminocarbamic acid ester (intermediate 98) replacement [5-(7-amino [1,3] thiazole [5,4-d] pyrimidine-2-base also)-and 1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl dimethoxy aminocarbamic acid ester (intermediate 97).Obtain colorless solid title compound (6mg, 66%);

MS?m/e?MH ⁺379。

The raw material that uses is prepared as follows:

Intermediate 98

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (cyclopropyl) methyl dimethoxy aminocarbamic acid ester

Prepare title compound by being similar to the method for preparing intermediate 97 introductions, just replace phenyl aldehyde with cyclopanecarboxaldehyde.Obtain colourless gummy title compound (14mg, 68%);

¹H?NMR(CDCl ₃)δ0.42-0.50(m，1H)，0.61-0.76(m，3H)，1.86(m，1H)，2.83(s，3H)，2.98(s，3H)，3.96(s，3H)，5.26(d，1H)，5.74(bs，2H)，7.31-7.38(m，3H)，7.49-7.56(m，2H)，8.43(s，1H)。

MS?m/e?MH ⁺450。

Embodiment 106

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (1,3-benzodioxole-4-yl) methyl alcohol

Prepare title compound by being similar to the method for preparing embodiment 104 introductions, just with [5-(7-amino [1,3] thiazole also [5,4-d] pyrimidine-2-base)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-benzodioxole-4-yl) methyl dimethoxy aminocarbamic acid ester (intermediate 99) replaces [5-(7-amino [1,3] thiazole [5,4-d] pyrimidine-2-base also)-and 1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl dimethoxy aminocarbamic acid ester (intermediate 97).Obtain colorless solid title compound (5mg, 54%);

MS?m/e?MH ⁺459。

The raw material that uses is prepared as follows:

Intermediate 99

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (1,3-benzodioxole-4-yl) methyl dimethoxy aminocarbamic acid ester

Prepare title compound by being similar to the method for preparing intermediate 97 introductions, just with 2,3-(methylene radical dioxy base) phenyl aldehyde replaces phenyl aldehyde.Obtain faint yellow oily title compound (65mg, 82%);

¹H?NMR(CDCl ₃)δ2.95(s，3H)，3.06(s，3H)，4.01(s，3H)，5.74(bs，2H)，5.99(d，2H)，6.80(m，1H)，6.87(m，1H)，7.13(s，1H)，7.20(d，1H)，7.29-7.35(m，3H)，7.32-7.53(m，2H)，8.42(s，1H)。

MS?m/e?MH ⁺530。

Embodiment 107

1-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base]-3-methyl fourth-1-alcohol

Prepare title compound by being similar to the method for preparing embodiment 104 introductions, just with 1-[5-(7-amino [1,3] thiazole also [5,4-d] pyrimidine-2-base)-1-methyl-4-phenyl-1H-imidazoles-2-yl]-3-methyl butyl dimethylcarbamate (intermediate 100) replacement [5-(7-amino [1,3] thiazole [5,4-d] pyrimidine-2-base also)-and 1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl dimethoxy aminocarbamic acid ester (intermediate 97).Obtain colorless solid title compound (5mg, 63%);

MS?m/e?MH ⁺394。

The raw material that uses is prepared as follows:

Intermediate 100

1-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base]-3-methyl butyl dimethylcarbamate

Prepare title compound by being similar to the method for preparing intermediate 97 introductions, just replace phenyl aldehyde with isovaleric aldehyde.Obtain faint yellow oily title compound (54mg, 77%);

MS?m/e?MH ⁺466。

Embodiment 108

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (1-methyl isophthalic acid H-imidazoles-2-yl) methyl alcohol

Prepare title compound by being similar to the method for preparing embodiment 104 introductions, just with [5-(7-amino [1,3] thiazole also [5,4-d] pyrimidine-2-base)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1-methyl isophthalic acid H-imidazoles-2-yl) methyl dimethoxy aminocarbamic acid ester (intermediate 101) replacement [5-(7-amino [1,3] thiazole [5,4-d] pyrimidine-2-base also)-and 1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl dimethoxy aminocarbamic acid ester (intermediate 97).Obtain colorless solid title compound (20mg, 82%);

¹H?NMR(DMSO-d ₆)δ3.77(s，3H)，3.92(s，3H)，6.24(s，1H)，6.93(m，1H)，7.26(m，1H)，7.31-7.39(m，3H)，7.41-7.47(m，2H)，7.82(bs，2H)，8.27(s，1H)。

MS?m/e?MH ⁺419。

The raw material that uses is prepared as follows:

Intermediate 101

[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2- Base] (1-methyl isophthalic acid H-imidazoles-2-yl) methyl dimethoxy aminocarbamic acid ester

Prepare title compound by being similar to the method for preparing intermediate 97 introductions, just replace phenyl aldehyde with 1-methyl-2-imidazole formaldehyde.Obtain faint yellow oily title compound (33mg, 46%);

¹H?NMR(DMSO-d ₆)δ2.86(s，3H)，2.97(s，3H)，3.77(s，3H)，3.93(s，3H)，6.86(s，1H)，7.08(s，1H)，7.30-7.39(m，3H)，7.40-7.47(m，2H)，7.82(bs，2H)，8.29(s，1H)。

MS?m/e?MH ⁺491。

Embodiment 109

6-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

Use the universal method of preparation embodiment 56 and intermediate 70 to prepare title compound, just with cyclohexyl methylamine displacement ethamine.Obtain solid title compound (20mg, 19%);

¹H?NMR(DMSO-d ₆)δ0.70-1.70(m，11H)，3.77(d，2H)，7.18(t，1H)，7.26(t，2H)，7.50(d，2H)，7.60(s，br，2H)，7.61(s，1H)，7.92(s，1H)，8.32(s，1H)；

MS?m/e?MH ⁺390。

Embodiment 110

6-[1-[3-(4-methyl isophthalic acid-piperazinyl) propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] is phonetic Pyridine-4-amine

Use the universal method of preparation embodiment 65 to prepare title compound, just, replace morpholine with piperazine with 1-(3-aminopropyl)-4-methylpiperazine displacement 3-amino-pyrrolidine.Obtain solid title compound (38mg, 35%);

MS?m/e?MH ⁺434。

Embodiment 111

6-[1-[3-(hexahydro-1 H-azepines-1-yl) propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno- [2,3-d] pyrimidine-4-alcohol

Use the universal method of preparation embodiment 65 to prepare title compound, just, replace morpholine with piperazine with 3-hexamethyleneimino-1-propylamine displacement 3-amino-pyrrolidine.Obtain solid title compound (17mg, 16%);

MS?m/e?MH ⁺434。

Use the universal method of preparation embodiment 65 to prepare embodiment 112-169, just, make solvent (sol.) with THF, DMA or DMSO with suitable amine displacement 3-amino-pyrrolidine.

Embodiment	The compound title	??sol.	??MH ⁺	?? ¹H?NMR(DMSO-d ₆)
Embodiment	The compound title	??sol.	??MH ⁺	?? ¹H?NMR(DMSO-d ₆)	Embodiment 112	6-[4-phenyl-1-(tetrahydrochysene-2,2-dimethyl-2H-pyrans-4-yl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??406
Embodiment 113	5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-Beta-methyl-4-phenyl-1H-imidazoles-1-ethanol	??THF	??352		Embodiment 112		??THF	??406
Embodiment 113		??THF	??352		Embodiment 114	6-[1-(2-methoxyl group-1-methylethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine	??THF	??366
Embodiment 115	6-[1-(1-methylethyl)-4-phenyl-1H-imidazoles-5-yl]-	??THF	??336		Embodiment 114		??THF	??366

	Thieno-[2,3-d] pyrimidine-4-amine
	Thieno-[2,3-d] pyrimidine-4-amine			Embodiment 116	6-[1-(1, the 2-dimethyl propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??364
Embodiment 117	6-[1-(1, the 3-dimethylbutyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??378	Embodiment 116		??THF	??364
Embodiment 117		??THF	??378	Embodiment 118	6-[1-(1-methyl-propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??350
Embodiment 119	6-[4-phenyl-1-(2-propenyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??334	Embodiment 118		??THF	??350
Embodiment 119		??THF	??334	Embodiment 120	6-[4-phenyl-1-(2,2,6,6-tetramethyl--4-piperidyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??433
Embodiment 121	4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl]-hexalin	??THF	??392	Embodiment 120		??THF	??433
Embodiment 121		??THF	??392	Embodiment 122	6-[4-phenyl-1-[(tetrahydrochysene-2-furyl) methyl]-1H-imidazoles-5-yl]-thieno-[2,3-	??THF	??378

	D] pyrimidine-4-amine
	D] pyrimidine-4-amine			Embodiment 123	6-[1-[2-(4-morpholinyl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??407
Embodiment 124	6-[1-[4-(diethylamino)-1-methyl butyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??435	Embodiment 123		??THF	??407
Embodiment 124		??THF	??435	Embodiment 125	The 6-[1-[(2-fluorophenyl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??402
Embodiment 126	The 6-[1-[(2-aminomethyl phenyl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??398	Embodiment 125		??THF	??402
Embodiment 126		??THF	??398	Embodiment 127	The 6-[1-[(3-fluorophenyl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??402
Embodiment 128	5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-Alpha-Methyl-4-phenyl-1H-imidazoles-1-ethanol	??THF	??352	Embodiment 127		??THF	??402
Embodiment 128		??THF	??352	Embodiment 129	3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl]-1,2-	??THF	??368

	Propylene glycol
	Propylene glycol			Embodiment 130	6-[1-(2-methyl butyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??364
Embodiment 131	6-[4-phenyl-1-[2-(phenyl amino) ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??413	Embodiment 130		??THF	??364
Embodiment 131		??THF	??413	Embodiment 132	5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-propyl alcohol	??THF	??352
Embodiment 133	6-[1-[3-(dimethylamino)-2, the 2-dimethyl propyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??407	Embodiment 132		??THF	??352
Embodiment 133		??THF	??407	Embodiment 134	6-[1-(2-methyl-2-propenyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??348
Embodiment 135	N-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-4-hydroxyl-phenylacetamide	??THF	??471	Embodiment 134		??THF	??348
Embodiment 135		??THF	??471	Embodiment 136	6-[1-(2-methoxyl group-2-methyl-propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??380

Embodiment 137	6-[4-phenyl-1-(spiral shell [dicyclo [2.2.1] hept-2-ene"-7,1 '-cyclopropane]-the 5-ylmethyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??426
Embodiment 137		??THF	??426	Embodiment 138	6-[1-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??416
Embodiment 139	6-[1-[2-(1H-imidazoles-1-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??388	Embodiment 138		??THF	??416
Embodiment 139		??THF	??388	Embodiment 140	The 6-[1-[2-[[(4-fluorophenyl) methyl] amino] ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??446
Embodiment 141	6-[1-[(3,4-dihydro-1H-2-chromene-1-yl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??440	Embodiment 140		??THF	??446
Embodiment 141		??THF	??440	Embodiment 142	6-[1-[2-(methylsulfonyl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??400
Embodiment	N-[2-[5-(4-aminothiophene	??THF	??505	Embodiment 142		??THF	??400

??143	And [2,3-d] pyrimidine-6-yl)-and 4-phenyl-1H-imidazoles-1-yl] ethyl]-2-[(2-chloro-3-pyridyl) the oxygen base]-ethanamide		?507
??143			?507	Embodiment 144	6-[4-phenyl-1-[2-[(tetrahydrochysene-1,1-titanium dioxide-3-thienyl) amino] ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	?455
Embodiment 145	5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-α-(trifluoromethyl)-1H-imidazoles-1-ethanol	??THF	?406	Embodiment 144		??THF	?455
Embodiment 145		??THF	?406	Embodiment 146	5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-α-[3-(trifluoromethyl) phenyl]-1H-imidazoles-1-ethanol	??THF	?482
Embodiment 147	6-[4-phenyl-1-[2-(2-propenyl amino) ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	?377	Embodiment 146		??THF	?482
Embodiment 147		??THF	?377	Embodiment 148	N-[5-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] amyl group]-4-morpholine methane amide	??THF	?492
Embodiment 149	5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-α-(2,3-dihydro-1,4-benzo dioxane	??THF	?472	Embodiment 148		??THF	?492

	Hexene-6-yl)-4-phenyl-1H-imidazoles-1-ethanol
	Hexene-6-yl)-4-phenyl-1H-imidazoles-1-ethanol				Embodiment 150	6-[1-[3-[4-(2-p-methoxy-phenyl)-1-piperazinyl] propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??526
Embodiment 151	N '-[2-[5-(4-aminothiophene also [2,3-d] pyrimidine-6-yl)-4-phenyl-1H-imidazoles-1-yl] ethyl]-N, N-dimethyl-sulphonamide	??THF	??444		Embodiment 150		??THF	??526
Embodiment 151		??THF	??444		Embodiment 152	6-[1-[6-(8-oxa--3-azabicyclo [3.2.1] oct-3-yl) hexyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??489
Embodiment 153	6-[1-[[2-(4-morpholinyl) phenyl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	??THF	??469	??2.45-2.50(m，4H)， ??4.06-4.10(m，4H)， ??5.36(s，2H)，6.90(dd， ??1H)，6.96(d，1H)， ??7.03(t，1H)，7.21- ??7.38(m，4H)，7.44(s， ??1H)，7.46-7.52(m，2H)， ??7.83(s，br，2H)，8.29(s， ??1H)，8.96(s，1H)；	Embodiment 152		??THF	??489
Embodiment 153		??THF	??469		Embodiment 154	6-[1-(1,4-diox-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d]	??THF	??394	??3.17(dd，1H)，3.43(dt， ??1H)，3.53(dt，1H)， ??3.63(dd，2H)，3.69- ??3.76(m，2H)，3.90-

	Pyrimidine-4-amine			??4.00(m，2H)，7.19(t， ??1H)，7.27(t，2H)， ??7.50(d，2H)，7.61(s， ??br，2H)，7.65(s，1H)， ??7.91(s，1H)，8.33(s，1H)
	Pyrimidine-4-amine				Embodiment 155	2-[[5-(4-aminothiophene also [2,3-d] pyrimidine-6-yl)-4-phenyl-1H-imidazoles-1-yl] methyl]-, (1S, 2R)-hexalin	?THF	??406	??0.70-1.20(m，5H)， ??1.32-1.54(m，3H)， ??1.64-1.70(m，1H)， ??2.92-2.96(m，1H)， ??3.58(dd，1H)，4.24(dd， ??1H)，4.53(s，br，1H)， ??7.07(t，1H)，7.16(t， ??2H)，7.40(d，2H)， ??7.48(s，br，2H)，7.53(s， ??1H)，7.78(s，1H)， ??7.78(s，1H)，8.21(s， ??1H)；
Embodiment 156	6-[1-(suberyl methyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?THF	??404	??1.03-1.85(m，13H)， ??3.76(d，2H)，7.18(t， ??1H)，7.27(t，2H)， ??7.51(d，2H)，7.61(s， ??br，2H)，7.64(s，1H)， ??7.94(s，1H)，8.32(s， ??1H)；	Embodiment 155		?THF	??406
Embodiment 156		?THF	??404		Embodiment 157	6-[1-[[(1S, 5S)-6,6-dimethyl dicyclo [3.1.1] heptan-2-yl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?THF	??430	??0.70-2.30(m，17H)， ??3.92(d，2H)，7.18(t， ??1H)，7.28(t，2H)， ??7.51(d，2H)，7.60(s， ??br，2H)，6.76(s，1H)， ??8.00(s，1H)，8.32(s， ??1H)；
Embodiment	(the 4-aminothiophene also for 1-[[5-	?THF	??448	??1.07-1.51(m，10H)， ??2.25(s，2H)，4.23(s，	Embodiment 157		?THF	??430

??158	[2,3-d] pyrimidine-6-yl)-and 4-phenyl-1H-imidazoles-1-yl] methyl]-Cyclohexaneacetic acid			2H), 7.26 (t, 1H), 7.35 (t, 2H), 7.56 (d, 2H), 7.68 (s, br, 2H), 7.76 (s, 1H), 8.12 (s, 1H), 8.39 (s, 1H), CO2H exchanges into baseline;
??158					Embodiment 159	6-[4-phenyl-1-(phenyl methyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?DMS ?O	??384	??5.33(s，2H)，7.07(dd， ??2H)，7.26-7.38(m，6H)， ??7.51(d，2H)，7.66(s， ??1H)，7.87(s，br，2H)， ??8.35(s，1H)，8.79(s， ??1H)；
Embodiment 160	The 6-[1-[(2-p-methoxy-phenyl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?DMA	??414	??3.65(s，3H)，5.22(s， ??2H)，6.84-6.87(m，2H)， ??6.96(d，1H)，7.26- ??7.40(m，4H)，7.50- ??7.57(m，2H)，7.65(s， ??1H)，7.78(s，br，2H)， ??8.34(s，1H)，8.59(s， ??1H)；	Embodiment 159		?DMS ?O	??384
Embodiment 160		?DMA	??414		Embodiment 161	6-[4-phenyl-1-[[2-(piperidino) phenyl] methyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?DMA	??467
Embodiment 162	6-[4-phenyl-1-[[2-(2-pyridyl oxygen base) phenyl] methyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?DMA	??477		Embodiment 161		?DMA	??467
Embodiment 162		?DMA	??477		Embodiment 163	6-[1-[[2-(4-methyl isophthalic acid-piperazinyl) phenyl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thiophene	?DMA	??482

	Fen is [2,3-d] pyrimidine-4-amine also
	Fen is [2,3-d] pyrimidine-4-amine also			Embodiment 164	1-[2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl] phenyl]-the 4-piperidine carbinols	?DMA	??497
Embodiment 165	The 6-[1-[(2-aminophenyl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?DMA	??399	Embodiment 164		?DMA	??497
Embodiment 165		?DMA	??399	Embodiment 166	N-[2-[[5-(4-aminothiophene also [2,3-d] pyrimidine-6-yl)-4-phenyl-1H-imidazoles-1-yl] methyl] phenyl]-2,4-two chloro-benzsulfamides	?DMA	?607 ?， ??609 ?，611	??5.37(s，2H)，6.56(d， ??1H)，6.83(d，1H)， ??7.14-7.36(m，5H)， ??7.46-7.51(m，3H)， ??7.57(s，1H)，7.73(d， ??1H)，7.77-7.81(m，3H)， ??8.31(s，1H)，8.48(s，br， ??1H)，9.87(s，br，1H)；
Embodiment 167	6-[1-(1H-imidazoles-2-ylmethyl-4-phenyl-1H-imidazoles-5-yl)-thieno-[2,3-d] pyrimidine-4-amine	?DMA	??374	Embodiment 166		?DMA	?607 ?， ??609 ?，611
Embodiment 167		?DMA	??374	Embodiment 168	6-[1-[(6-fluoro-4H-1,3-benzo dioxine-8-yl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine	?DMA	??460
Embodiment 169	6-[1-(imidazo [1,2-a] pyridine-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-	?DMA	??424	Embodiment 168		?DMA	??460

[2,3-d] pyrimidine-4-amine

Embodiment 170

N-benzyl-6 (1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions, just replace NH with benzylamine ₃Obtain colorless solid title compound (7mg, 18%);

MS?m/e?MH ⁺398。

Embodiment 171

6-[1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4- Amine

THF (the 1M that will contain lithium aluminium hydride, 0.1mL), THF (2mL) and 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] tetramethyleneimine-1-carboxylic acid tert-butyl ester (intermediate 102) mixture (31mg) refluxed 4 hours down in inert atmosphere.After adding entry and TFA (1), evaporating mixture, resistates is purified with preparation type RPHPLC (with MeCN and water+0.1%TFA gradient elution), obtains colorless solid title compound (5mg, 28%).

MS?m/e?MH ⁺377。

Prepare intermediate 102 and embodiment 172 and 173 with being similar to the method for preparing embodiment 65 introductions, just replace the 3-amino-pyrrolidine, purify with preparation type RPHPLC then with suitable amine.

Intermediate 102

3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl) tetramethyleneimine-1- Carboxylic acid tert-butyl ester

Colorless solid title compound (96mg, 14%); MS m/e MH ⁺463.

Embodiment 172

2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] and ethyl } amino T-butyl formate

Colorless solid title compound (30mg, 65%); MS m/e MH ⁺437.

Embodiment 173

4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] and butyl } amino T-butyl formate

Colorless solid title compound (35mg, 75%); MS m/e MH ⁺465.

Embodiment 174

2-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] ethanol

MCPBA (50mg) is added 2-[5-(7-methylthio group [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] ethanol (intermediate 103) (52mg) is dissolved in through MgSO ₄(0.5g) solution of exsiccant DCM (40mL).After 16 hours, filtering mixt is with DCM (2 * 10mL) washing solids.Filtrate and washing lotion that evaporation merges are dissolved in 1 with rough resistates sulfone, use NH behind the 4-diox (20mL) ₃Gas is saturated.After 48 hours, evaporating mixture by preparation type RPHPLC, obtains colorless solid title compound (34mg, 72%);

MS?m/e?MH ⁺339。

The raw material that uses is prepared as follows:

Intermediate 103

2-[5-(7-methylthio group [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1 base] ethanol

Prepare title compound by being similar to the method for preparing intermediate 70 introductions, just use also [5,4-d] pyrimidine-2-formaldehyde (intermediate 78) replacement 4-(methylthio group) thieno-[2 of 7-(methylthio group) [1,3] thiazole, 3-d] pyrimidine-6-formaldehyde (intermediate 15), replace ethamine with thanomin.Obtain colorless solid title compound (52mg, 56%);

MS?m/e?MH ⁺370。

Use the universal method for preparing embodiment 174 and intermediate 103 to prepare the title compound of embodiment 175-178, just replace thanomin with suitable amine.

Embodiment 175

2-[1-(2-methoxy ethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-also Amine

Obtain colorless solid title compound (46mg, 90%); MS m/e MH ⁺353.

Embodiment 176

2-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-Ji Ding-1-alcohol

Obtain colorless solid title compound (20mg, 56%); MS m/e MH ⁺367.

Embodiment 177

2-(1-butyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole is [5,4-d] pyrimidine-7-amine also

Obtain colorless solid title compound (42mg, 80%); MS m/e MH ⁺351.

Embodiment 178

2-[1-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-ylmethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole is also [5,4-d] pyrimidine-7-amine

Obtain colorless solid title compound (1.35g, 88%); MS m/e MH ⁺449.

Embodiment 179

4-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl } Pimelinketone

With 2-[1-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-ylmethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole also [5,4-d] pyrimidine-7-amine (embodiment 178) (634mg) be dissolved in MeCN (10mL), add entry (10mL) and TFA (0.5mL).After 48 hours,, obtain colorless solid title compound (570mg, 99%) in ambient temperature by preparation type RPHPLC (water and MeCN+0.1%TFA gradient elution);

MS?m/e?MH ⁺405。

Embodiment 180

4-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl } Hexalin

With 4-{[5-(7-amino [1,3] thiazole [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl pimelinketone (embodiment 179) (100mg) with the MeCN (20mL) that contains three-acetoxyl group sodium borohydride (160mg) and 1-methylpiperazine (150mg) in ambient temperature processing 4 days.(2 * 5mL) wash solids with MeCN behind the filtering mixt.Filtrate and washing lotion that evaporation merges, resistates is purified with preparation type RPHPLC (water and MeCN+0.1%TFA gradient elution), obtains colorless solid title alcohol (15mg, 16%;

MS?m/e?MH ⁺407。

Embodiment 181

6-{4-[3-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 51 introductions, just replace propyl carbinol with benzylalcohol.Obtain gummy title compound (20mg);

¹H?NMR(CDCl ₃)δ3.55(s，3H)，4.95(s，2H)，5.50(bs，2H)，6.85(m，1H)，7.06(s，1H)，7.15(m，2H)，7.35(m，6H)，7.62(s，1H)，8.52(s，1H)。

MS?m/e?MH ⁺414。

Embodiment 182

4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenol

With 6-{4-[4-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine (embodiment 53) is (19mg) with TFA (3mL) and water (0.05mL) backflow 6 hours.Mixture is with 1: 1DCM/MeOH dilutes after peracidity column extractor (Waters Oasis  MCX 1g).With 1: 1DCM/MeOH washs described post, uses dense NH then ₃4: 48: 48 aqueous solution wash-outs of the aqueous solution/DCM/MeOH.Evaporated fraction obtains solid title compound (10mg, 67%);

¹H?NMR(DMSO-d ₆)δ3.56(s，3H)，6.68(d，2H)，7.32(d，2H)，7.55(bs，2H)，7.62(s，1H)，7.82(s，1H)，8.30(s，1H)，9.36(bs，1H)。

MS?m/e?MH ⁺324。

Embodiment 183

3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] benzonitrile

With 6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 50) (192mg) stirs with the DMF (7mL) that contains zinc cyanide (118mg), tetrakis triphenylphosphine palladium (116mg), the degassing was heated 20 hours in 80 ℃ under inert atmosphere then.Evaporating solvent, resistates is purified with the fast silica gel chromatogram method, uses the DCM wash-out of 0-20%MeOH earlier then with the DCM of 0-100%EtOAc.RPHPLC further purifies by the preparation type, with MeCN/ water/formic acid gradient elution, obtains solid title compound (28mg, 16%);

¹H?NMR(DMSO-d ₆)δ3.60(s，3H)，7.50(m，1H)，7.60(bs，2H)，7.66(m，1H)，7.70(s，1H)，7.76(m，1H)，7.94(m，1H)，7.99(s，1H)，8.33(s，1H)。

MS?m/e?MH ⁺333。

Embodiment 184

3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } amino T-butyl formate

With 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49) (43mg) with contain t-butyl carbamate (24mg), N, N '-dimethyl-ethylenediamine (9mg), cuprous iodide (I) (10mg) and potassiumphosphate (42mg) 1,4-diox (2mL) stirs, the degassing was heated 24 hours in 100 ℃ under the inert atmosphere.Mixture is at EtOAc and rare NH ₃Distribute between the aqueous solution, evaporate after the dry organic phase.Resistates is purified with the fast silica gel chromatogram method, and the DCM with 0-100%EtOAc uses the DCM gradient of 0-20%MeOH as eluent then earlier.Evaporated fraction obtains gummy title compound (4mg, 9%);

MS?m/e?MH ⁺423。

Embodiment 185

6-(4-{4-[(3,4-dichloro benzyl) oxygen base] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] Pyrimidine-4-amine

To containing 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenol (intermediate 108) MeCN (2mL) suspension adding 4-chlorine bromotoluene (14mg), salt of wormwood (53mg) and 1,4 (25mg), 7,10,13,16-hexaoxacyclooctadecane-6 (7mg).Reacting by heating mixture under microwave condition (CEM detector, 140 ℃, 10 minutes) is used EtOAc (10mL) and H then successively ₂O (10mL) dilution.Separate organic layer, with salt solution (10mL) washing, dry final vacuum concentrates, and crude product is purified with the fast silica gel chromatogram method, uses DCM: MeOH (0-10%) wash-out obtains title compound (42mg, 56%);

¹H?NMR(DMSO-d ₆)δ3.56(s，3H)，5.1(s，2H)，6.92-6.96(d，2H)，7.4-7.46(m，3H)，7.58(bs，2H)，7.61-7.65(m，2H)，7.68(s，1H)，7.85(s，1H)，8.30(s，1H)；

m/e?MH ⁺482。

The raw material that uses is prepared as follows:

Intermediate 104

Isocyano-(4-p-methoxy-phenyl) methyl 4-methyl phenyl sulfone

Prepare title compound by being similar to the method for preparing intermediate 53 introductions; just with (4-p-methoxy-phenyl) (phenyl sulfonyl) methylformamide (Tetrahedron Lett.; 1996; 37 (45), 8113) replace { (3-iodophenyl) [(4-aminomethyl phenyl) alkylsulfonyl] methyl } methane amide (intermediate 52).Obtain tawny solid title compound (26.15g, 97%)

¹H?NMR(CDCl ₃)δ2.56(s，3H)，3.92(s，3H)，5.62(s，1H)，6.97-7.00(d，2H)，7.31-7.36(d，2H)，7.40-7.44(d，2H)，7.70-7.73(d，2H)。

Intermediate 105

6-[4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] is phonetic Pyridine

Prepare title compound by being similar to the method for preparing embodiment 6 introductions, just replace PhTosMIC with isocyano-(4-p-methoxy-phenyl) methyl 4-methyl phenyl sulfone (intermediate 104), with N-[4-(methylthio group) thieno-[2,3-d] pyrimidine-6-methylene] methylamine (intermediate 16) replacement N-(3, the 4-dimethoxy-benzyl)-N-[thieno-[2,3-d] pyrimidine-6-methylene] amine (intermediate 14), obtain solid title compound (2.69g, 39%);

¹H?NMR(CDCl ₃)δ2.72(s，3H)，3.63(s，3H)，3.78(s，3H)，6.79-6.84(d，2H)，7.30(s，1H)，7.49-7.53(d，2H)，7.63(s，1H)，8.85(s，1H)；

MS?m/e?MH ⁺369。

Intermediate 106

6-[4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2,3-d] Pyrimidine

Prepare title compound by being similar to the method for preparing intermediate 17 introductions, just with 6-[4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine (intermediate 105) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine (embodiment 7).Obtain brown gummy title compound (3.13g, 100%);

¹H?NMR(CDCl ₃)δ3.44(s，3H)，3.72(s，3H)，3.81(s，3H)，6.83-6.87(d，2H)，7.46-7.48(d，2H)，7.69(s，1H)，8.02(s，1H)，9.15(s，1H)；

MS?m/e?MH ⁺401。

Intermediate 107

6-[4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing embodiment 8 introductions; just with 6-[4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl]-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 106) replacement 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylsulfonyl) thieno-[2; 3-d] pyrimidine (intermediate 17); purify with the fast silica gel chromatogram method then, use DCM: MeOH (0-10%) to use 1%NH then earlier ₃Wash-out.Obtain tawny solid title compound (0.91g, 36%);

¹H?NMR(DMSO-d ₆)δ3.56(s，3H)，3.70(s，3H)，6.77-6.87(d，2H)，7.41-7.44(d，2H)，7.57(bs，2H)，7.63(s，1H)，7.84(s，1H)，8.29(s，1H)；

MS?m/e?MH ⁺338。

Intermediate 108

With boron tribromide (DCM of 1.0M) (10.1mL) be added dropwise to contain 6-[4-(4-p-methoxy-phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 107) DCM (20mL) (0.91g), stirred 5 days in ambient temperature then.The vacuum concentration reaction mixture, resistates distributes between DCM and water.(dense NH is used in 3 * 20mL) extractions then with DCM after separating water layer ₃The aqueous solution is regulated water layer to pH9, filters gained solid final vacuum drying, obtains brown solid title compound (623mg, 71%);

¹H?NMR(DMSO-d ₆)δ3.56(s，3H)，6.65-6.67(d，2H)，7.29-7.33(d，2H)，7.55-7.58(bs，2H)，7.61(s，1H)，7.82(s，1H)，8.29(s，1H)，9.36(s，1H)；

MS?m/e?MH ⁺324。

Embodiment 186

N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }- N '-phenylurea

Phenylcarbimide (28mg) adding under inert atmosphere is contained 6-[4-(3-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 110) THF (6mL) stirred suspension (40mg).After 30 minutes, add methyl ethylenediamine-polystyrene (200mg), filter reaction mixture, the filtrate application of sample on the MCX post, with DCM/MeOH (1: 1) washing, is used DCM/MeOH (1: the 1) wash-out that contains 5% triethylamine then, obtain colorless solid title compound (35mg, 67%);

¹H?NMR(DMSO-d ₆)δ3.59(s，3H)，6.93-6.97(m，1H)，7.09-7.11(m，1H)，7.15-7.19(m，1H)，7.24-7.32(m，3H)，7.36-7.39(m，2H)，7.57(bs，2H)，7.66(s，1H)，7.74-7.75(m，1H)，7.90(s，1H)，8.32(s，1H)，8.53(s，1H)，8.57(s，1H)；

MS?m/e?MH ⁺442。

The raw material that uses is prepared as follows:

Intermediate 109

6-(4-{3-[(phenylbenzene methylene radical) amino] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) and thieno-[2,3- D] pyrimidine-4-amine

To contain 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49), benzophenone imines (549mg), 1, the degassing of the dioxane (40mL) of 1 '-two (diphenylphosphine) ferrocene (120mg), two (benzylidene-acetone) palladium (100mg) and sodium tert-butoxide (960mg), then under inert atmosphere in 90 ℃ of heating.After 17 hours, reaction mixture, water (50mL) dilution, (drying is filtered final vacuum and is concentrated for 2 * 30mL) extractions, organic extract salt water washing with EtOAc.Purify with the fast silica gel chromatogram method,, obtain title compound (0.48g, 50%) with DCM/MeOH (0-10%) wash-out;

¹H?NMR(CDCl ₃)δ3.32(s，3H)，5.75(bs，2H)，6.40-6.45(m，1H)，6.85-6.94(m，4H)，6.83-7.15(m，5H)，7.28-7.32(m，2H)，7.35-7.40(m，1H)，7.48(s，1H)，7.57-7.62(m，2H)，8.40(s，1H)；

MS?m/e?MH ⁺487。

Intermediate 110

6-[4-(3-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

With 2M HCl (0.75mL) add 6-(4-{3-[(phenylbenzene methene amido] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine (intermediate 109) (0.45g) is dissolved in the solution of THF (15mL), stirred 10 minutes, and between water and EtOAc, distributed then.Separate water layer, use dense NH ₃The aqueous solution is adjusted to pH9, and (3 * 30mL) extractions, the dry organism that merges filter final vacuum and concentrate, and obtain colorless solid title compound (0.33g, 100%) with DCM;

¹H?NMR(DMSO-d ₆)δ3.54(s，3H)，4.96(bs，2H)，6.36-6.39(m，1H)，6.55-6.57(m，1H)，6.83-6.88(m，2H)，7.56(bs，2H)，7.59(s，1H)，7.82(s，1H)，8.28(s，1H)；

MS?m/e?MH ⁺323。

Embodiment 187

N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }- N '-benzylurea

Prepare title compound by being similar to the method for preparing embodiment 186 introductions, just replace phenylcarbimide with benzyl mustard oil.Obtain colorless solid title compound (16mg, 57%);

¹H?NMR(DMSO-d ₆)δ3.56(s，3H)，4.26(d，2H)，6.50(t，1H)，6.95-6.99(m，1H)，7.10(t，1H)，7.22-7.36(m，6H)，7.57(bs，2H)，7.63-7.65(m，2H)，7.89(s，1H)，8.30(s，1H)，8.46(s，1H)；

MS?m/e?MH ⁺456。

Embodiment 188

N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }- N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

Prepare title compound by being similar to the method for preparing embodiment 186 introductions, just replace phenylcarbimide with isocyanic acid 2-fluoro-5-trifluoromethyl phenyl ester.Obtain colorless solid title compound (59mg, 90%);

¹H?NMR(DMSO-d ₆)δ3.57(s，3H)，7.06-7.09(m，1H)，7.15-7.21(m，1H)，7.33-7.38(m，2H)，7.43-7.50(m，1H)，7.57(bs，2H)，7.65(s，1H)，7.71-7.73(m，1H)，7.90(s，1H)，8.29(s，1H)，8.54-8.58(m，1H)，8.76-8.78(s，1H)，9.09(s，1H)；

MS?m/e?MH ⁺527。

Embodiment 189

N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }- N '-phenylurea

Prepare title compound by being similar to the method for preparing embodiment 186 introductions, just with 6-[4-(4-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 112) replacement 6-[4-(3-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 110).Obtain yellow solid title compound (15mg, 56%);

¹H?NMR(DMSO-d ₆)δ3.57(s，3H)，6.94-6.98(m，1H)，7.18-7.55(m，8H)，7.56-7.65(m，3H)，7.87(s，1H)，8.31(s，1H)，8.67(s，1H)，8.69(s，1H)；

MS?m/e?MH ⁺442。

The raw material that uses is prepared as follows:

Intermediate 111

6-(4-{4-[(phenylbenzene methylene radical) amino] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) and thieno-[2,3- D] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing intermediate 109 introductions, just with 6-[4-(4-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 64) replacement 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (embodiment 49).Obtain colorless solid title compound (31mg, 64%);

¹H?NMR(CDCl ₃)δ3.53(s，3H)，6.52-6.50(m，2H)，6.62(bs，2H)，7.01-7.03(m，1H)，7.17-7.20(m，3H)，7.31-7.34(m，4H)，7.38-7.39(m，1H)，7.44-7.45(m，2H)，7.55(s，1H)，7.62-7.64(m，2H)，8.33(s，1H)；

MS?m/e?MH ⁺487。

Intermediate 112

6-[4-(4-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

Prepare title compound by being similar to the method for preparing intermediate 110 introductions, just with 6-(4-{4-[(phenylbenzene methylene radical) amino] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine (intermediate 111) replacement 6-(4-{3-[(phenylbenzene methylene radical) amino] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine (intermediate 109).Obtain colorless solid title compound (276mg, 87%);

¹H?NMR(DMSO-d ₆)δ3.54(s，3H)，5.04(bs，2H)，6.42-6.47(m，2H)，7.15-7.19(m，2H)，7.54(bs，2H)，7.59(s，1H)，7.77(s，1H)，8.28(s，1H)；

MS?m/e?MH ⁺323。

Embodiment 190

Prepare title compound by being similar to the method for preparing embodiment 186 introductions, just with 6-[4-(4-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 112) replacement 6-[4-(3-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 110), replace phenylcarbimide with benzyl mustard oil.Obtain yellow solid title compound (10mg, 36%);

¹H?NMR(DMSO-d ₆)δ3.57(s，3H)，4.26-4.29(m，2H)，6.56-6.59(m，1H)，7.19-7.39(m，9H)，7.58(s，2H)，7.63(s，1H)，7.85(s，1H)，8.28(s，1H)，8.50(s，1H)；

MS?m/e?MH ⁺456。

Embodiment 191

N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }- N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

Prepare title compound by being similar to the method for preparing embodiment 186 introductions, just with 6-[4-(4-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 112) replacement 6-[4-(3-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 110), replace phenylcarbimide with isocyanic acid 2-fluoro-5-trifluoromethyl phenyl ester.Obtain colorless solid title compound (48mg, 73%);

¹H?NMR(DMSO-d ₆)δ3.57(s，3H)，7.36-7.47(m，6H)，7.58(bs，2H)，7.64(s，1H)，7.86(s，1H)，8.30(s，1H)，8.57-8.62(m，1H)，8.86-8.89(m，1H)，9.12(s，1H)；

MS?m/e?MH ⁺527。

Following compounds prepares with similar approach:

Embodiment 192

6-[1-(the amino butyl of 4-)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

Will 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] fourth Base } t-butyl carbamate (embodiment 173)(23mg) add blended TFA, water and tri isopropyl silane (5: 5: 1) (5ml), stirred 1 hour in ambient temperature.The vacuum concentration reaction mixture, resistates is purified through preparation type RPHPLC (with MeCN and water+0.1%TFA gradient elution), obtains colorless solid title compound (18mg, 90%);

MS?m/e?MH ⁺365。

Embodiment 193

6-[1-(3-methyl but-2-ene-1-yl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4- Amine

Use the universal method of preparation embodiment 65 to prepare title compound, just with 3-methyl but-2-ene-1-amine displacement 3-amino-pyrrolidine.Obtain colorless solid title compound (45mg, 62%);

¹H?NMR(DMSO-d ₆)δ1.48(s，3H)，1.65(s，3H)，4.65(d，2H)，5.25(t，1H)，7.33(t，1H)，7.38(t，2H)，7.50(d，2H)，7.76(s，1H)，7.80(s，br，2H)，8.36(s，1H)，8.69(s，1H)；

MS?m/e?MH ⁺362。

Embodiment 194

2-[1-(2-morpholine-4-base benzyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole also [5,4-d] pyrimidine- 7-amine

Embodiment 195

6-[4-(4-fluorophenyl)-1 (2-morpholine-4-base benzyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine- 4-amine

Prepare title compound by the universal method of using preparation embodiment 65, just with suitable reagent displacement 3-amino-pyrrolidine and PhTosMIC.Obtain colorless solid title compound (24mg, 25%);

¹H?NMR(DMSO-d ₆)2.40-2.50(m，4H)，3.50-3.60(m，4H)，5.23(s，2H)，6.78(d，1H)，6.94(d，1H)，7.02(t，1H)，7.09(t，2H)，7.21(t，1H)，7.35(s，1H)，7.49(s，br，2H)，7.53(dd，2H)，8.13(s，1H)，8.22(s，1H)；

MS?m/e?MH ⁺487。

Embodiment 196

3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } amino Benzyl formate

Chloroformic acid benzyl ester (0.027mL) is added 6-[4-(3-aminophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine (intermediate 110) (40mg) and pyridine (0.02mL) be dissolved in the solution of THF (7mL).Under inert atmosphere, stirred the mixture 1 hour, and used H then ₂(3 * 10mL) extract with EtOAc after O (10mL) quencher.Dry (MgSO ₄) organism that merges, filter final vacuum and concentrate.Purify with the fast silica gel chromatogram method, use CH ₂Cl ₂: MeOH (0-10%) wash-out obtains gummy title compound (16mg, 28%);

¹H?NMR(DMSO-d ₆)δ3.47-3.57(m，3H)，5.035.12(m，2H)，7.05-7..23(m，2H)，7.29-7.40(m，6H)，7.55(bs，2H)，7.63(s，1H)，7.75-7.77(m，1H)，7.87(s，1H)，8.29(s，1H)，9.68(bs，1H)；

MS?m/e?MH ⁺457。

Embodiment 197

3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } amino Phenyl formate

Prepare title compound by being similar to the method for preparing embodiment 196 introductions, just replace chloroformic acid benzyl ester with phenyl chloroformate.Obtain faint yellow solid title compound (9mg, 16%);

¹H?NMR(DMSO-d ₆)δ3.58(s，3H)，6.7-6.75(d，1H)，7.1-7.25(m，3H)，7.37-7.50(m，5H)，7.55-7.6(bs，2H)，7.65(s，1H)，7.87(s，1H)，8.30(s，1H)，10.2(bs，1H)；

MS?m/e?MH ⁺443。

Claims

1. acceptable salt on a following compound in structural formula I or its pharmacology:

Structural formula I

Wherein:

G is selected from O, S and NR ⁵

Z is selected from N and CR ⁶

Q ¹Be selected from aryl and heteroaryl,

And Q wherein ¹Optional replaced by one or more identical or different substituting groups, described substituting group be selected from halogen, trifluoromethyl, trifluoromethoxy, cyano group, nitro, hydroxyl, amino, carboxyl, formamyl, (1-6C) alkyl, (2-8C) alkenyl, (2-8C) alkynyl group, (1-6C) alkoxyl group, (2-6C) alkenyl oxy, (2-6C) alkynyl group oxygen base, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), (3-6C) alkenoyl amino, N-(1-6C) the alkenoyl amino of alkyl-(3-6C), (3-6C) alkyne acyl amino, N-(1-6C) the alkyne acyl amino of alkyl-(3-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) alkanesulfonyl amino, 3-(1-6C) alkyl urea groups, (1-6C) alkoxycarbonyl amino of alkyl-(1-6C) is selected from the group of following formula:

-X ¹-R ⁷

And the group that is selected from following formula:

-X ²-Q ²

X wherein ²Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ⁹), CO, CH (OR ⁹), CON (R ⁹), N (R ⁹) CO, N (R ⁹) CON (R ⁹), SO ₂N (R ⁹), N (R ⁹) SO ₂, C (R ⁹) ₂O, C (R ⁹) ₂S and N (R ⁹) C (R ⁹) ₂, R wherein ⁹Be hydrogen or (1-6C) alkyl, and Q ²Be the alkyl of the alkyl of aryl, aryl-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C), Q ²Optional have 1-3 identical or different substituting group and described substituting group and be selected from trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl is amino and N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) perhaps is selected from the group of following formula:

-X ³-R ¹⁰

R ³Independent is R ⁴And R ⁶Group in the definition, precondition are R ³Be not hydrogen, and work as R ³With

When the nitrogen-atoms among the A connects, R ³It is not halogen;

Q ⁴-X ⁵-

X wherein ⁵Be a chemical bond or be selected from O, S, SO, SO ₂, N (R ¹²), CO, CH (OR ¹²), CON (R ¹²), N (R ¹²) CO, SO ₂N (R ¹²), N (R ¹²) SO ₂, OC (R ¹²) ₂, SC (R ¹²) ₂And N (R ¹²) C (R ¹²) ₂, R wherein ¹²Be hydrogen or (1-6C) alkyl, and Q ⁴Be the alkyl of the alkyl of the alkyl of the alkyl of aryl, aryl-(1-6C), (3-11C) cycloalkyl, (3-11C) cycloalkyl-(1-6C), (3-11C) cycloalkenyl group, (3-11C) cycloalkenyl group-(1-6C), heteroaryl, heteroaryl-(1-6C) alkyl, heterocyclic radical or heterocyclic radical-(1-6C)

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, the optional insertion of the adjacent carbons on any (2-6C) alkylidene chain is selected from following group chain and is separated out: O, S, SO, SO ₂, N (R ¹³), CO, CH (OR ¹³), CON (R ¹³), N (R ¹³) CO, SO ₂N (R ¹³), N (R ¹³) SO ₂, CH=CH and C ≡ C, wherein R ¹³Be hydrogen or (1-6C) alkyl,

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any CH ₂=CH-or HC ≡ C-group are chosen the CH in end wantonly ₂=or HC ≡ position have and be selected from following substituting group: halogen, carboxyl, formamyl, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, NAlkyl and two-[(1-6C) alkyl] of the alkyl of-two-[(1-6C) alkyl] formamyls, amino-(1-6C), (1-6C) alkylamino-(1-6C) be amino-(1-6C) alkyl or be selected from the group of following formula:

Q ⁵-X ⁶-

And at R ³, R ⁴, R ⁵Or R ⁶In the substituting group, any CH ₂Or CH ₃Group is chosen wantonly at each described CH ₂Or CH ₃Have one or more halogens or (1-6C) alkyl substituent or be selected from following substituting group on the group: oxo, hydroxyl, cyano group, amino, carboxyl, formamyl, (1-6C) alkoxyl group, (1-6C) alkylthio, (1-6C) alkyl sulphinyl, (1-6C) alkyl sulphonyl, (1-6C) alkylamino, two-[(1-6C) alkyl] amino, (1-6C) alkoxy carbonyl, N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino and N-(1-6C) alkanesulfonyl amino, (1-6C) alkoxycarbonyl amino, amino-sulfonyl amino, (1-6C) alkyl amino sulfonyl amino, two-[(1-6C) alkyl] amino-sulfonyl amino of alkyl-(1-6C) perhaps is selected from the group of following formula:

-X ⁷-Q ⁶

And at R ³, R ⁴, R ⁵Or R ⁶On substituting group in, any aryl; heteroaryl; heterocyclic radical; cycloalkyl or cycloalkenyl group be optional to have one or more and identical or different is selected from following substituting group: halogen; trifluoromethyl; trifluoromethoxy; cyano group; nitro; hydroxyl; amino; carboxyl; formamyl; (1-6C) alkyl; (2-8C) alkenyl; (2-8C) alkynyl group; (1-6C) alkoxyl group; (2-6C) alkenyl oxy; (2-6C) alkynyl group oxygen base; (1-6C) alkylthio; (1-6C) alkyl sulphinyl; (1-6C) alkyl sulphonyl; (1-6C) alkylamino; two-[(1-6C) alkyl] amino; (1-6C) alkoxy carbonyl; N-(1-6C) alkyl-carbamoyl, N, N-two-[(1-6C) alkyl] formamyls, (2-6C) alkanoyl, (2-6C) alkanoyloxy, (2-6C) alkanoyl amino, N-(1-6C) the alkanoyl amino of alkyl-(2-6C), N-(1-6C) alkylsulfamoyl group, N, N-two-[(1-6C) alkyl] sulfamyl, (1-6C) alkanesulfonyl amino, N-(1-6C) the alkanesulfonyl amino of alkyl-(1-6C) is selected from the group of following formula:

-X ⁸-R ¹⁶

And the group that is selected from following formula:

-X ⁹-Q ⁷

And so any 5-of condensing that forms or 6-unit heterocycle is chosen wantonly and is had 1-2 oxo or sulfo-substituting group,

M is 0,1 or 2, and each R wherein ³Group can be identical or different.

2. the compound of claim 1, wherein A is-N=C*-S-, R ²Be H, Z is N, and m is 0 and G is NR ⁵

3. the compound of claim 1, wherein A is-CH=C*-S-, R ²Be H, Z is N, and m is 0 and G is NR ⁵

4. compound, it is selected from acceptable salt on following one or more following compounds or its pharmacology:

(1) 8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

(2) 9-methyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

(3) 7-methyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7H-purine-6-amine

(4) 8-(4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

(5) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[3,2-d] pyrimidine

(6) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[3,2-d] pyrimidine-4-amine

(7) 5-[4-(methylthio group) thieno-[3,2-d] pyrimidine-6-yl]-1H-imidazoles-1-alcohol

(8) 9-cyclohexyl-8-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-9H-purine-6-amine

(9) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine

(10) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [2,3-d] pyrimidine-4-amine

(11) 6-[1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] furo [2,3-d] pyrimidine

(12) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-7H-pyrrolo-[2,3-d] pyrimidine

(13) 6-(4-phenyl-1H-imidazoles-5-yl) thieno-[3,2-d] pyrimidine

(14) [1,3] oxazole is [5,4-d] pyrimidine-7-amine also for 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl)

(15) 2-[1-(4-methoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] furo [3,2-c] pyridine

(16) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-5H-pyrrolo-[3,2-d] pyrimidine-4-amine

(17) 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(18) 2-(4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(19) 2-(4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine also

(20) 2-(2-bromo-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(21) 2-(2-amino-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(22) 2-(2-methoxyl group-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(23) 2-(1-methyl-2,4-phenylbenzene-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(24) 2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-mercaptan also

(25) 7-methoxyl group-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine also

(26) 2-[1-methyl-4-phenyl-2-(3-thienyl)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(27) 2-(1-methyl-4-phenyl-2-pyridin-4-yl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(28) 2-(2-ethyl-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(29) 2-[1-methyl-4-phenyl-2-(rosickyite base)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(30) sulfenyl 2-{2-[(methoxymethyl)]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(31) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (5-methyl-isoxazole-3-yl) ketone

(32) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (5-methyl-isoxazole-3-yl) methyl alcohol

(33) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-furyl) ketone

(34) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-furyl) methyl alcohol

(35) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-dimethyl-1H-pyrazoles-5-yl) ketone

(36) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-dimethyl-1H-pyrazoles-5-yl) methyl alcohol or

(37) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (2-thienyl) methyl alcohol

(38) 2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(39) 2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(40) 7-(diisopropylaminoethyl)-2-(1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-5-formaldehyde also

(41) 2-(2-{[2-(dimethylamino) ethyl] sulfenyl }-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(42) 2-(1-methyl-2-{[(methylthio group) methyl] sulfenyl }-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(43) 2-(2-{[2-(1H-imidazoles-1-yl) ethyl] sulfenyl }-1-methyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(44) sulfenyl 2-{1-methyl-4-phenyl-2-[(pyridin-3-yl methyl)]-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(45) sulfenyl 2-{2-[(cyclopropyl methyl)]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(46) 2-[2-(benzyl sulfenyl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(47) 2-[1-methyl-2-(4-methylpiperazine-1-yl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(48) 2-{2-[(1-aminocyclohexyl) ethynyl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(49) 4-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] fourth-3-alkynes-2-alcohol

(50) 1-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] ethynyl } hexalin

(51) 2-[1-methyl-4-phenyl-2-(pyridine-2-ethyl-acetylene base)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(52) 2-[2-(3-amino-3-methyl fourth-1-alkynes-1-yl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(53) 2-[2-(3-methoxy propyl-1-alkynes-1-yl)-1-methyl-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(54) 2-(1-methyl-2-morpholine-4-base-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(55) 2-(1-methyl-4-phenyl-2-pyrimidine-5-base-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(56) 2-{2-[3-(dimethylamino) third-1-alkynes-1-yl]-1-methyl-4-phenyl-1H-imidazoles-5-yl } [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(57) 4-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl]-3,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester

(58) 2-[1-methyl-4-phenyl-2-(1,2,3,6-tetrahydropyridine-4-yl)-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(59) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (phenyl) methyl alcohol

(60) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (cyclopropyl) methyl alcohol

(61) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1,3-benzodioxole-4-yl) methyl alcohol

(62) 1-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl]-3-methyl fourth-1-alcohol

(63) [5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-1-methyl-4-phenyl-1H-imidazoles-2-yl] (1-methyl isophthalic acid H-imidazoles-2-yl) methyl alcohol

(64) 2-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] ethanol

(65) 2-[1-(2-methoxy ethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(66) 2-[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-Ji Ding-1-alcohol

(67) 2-(1-butyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(68) 2-[1-(1,4-dioxo spiro [4,5] last of the ten Heavenly stems-8-ylmethyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(69) 4-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl } hexalin

(70) 4-{[5-(7-amino [1,3] thiazole is [5,4-d] pyrimidine-2-base also)-4-phenyl-1H-imidazoles-1-yl] methyl } pimelinketone

(71) 2-[1-(2-morpholine-4-base benzyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(72) 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine

(73) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl)-4-(methylthio group) thieno-[2,3-d] pyrimidine

(74) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(75) 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl]-4-(methylthio group) thieno-[2,3-d] pyrimidine

(76) 6-[1-(3, the 4-dimethoxy-benzyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(77) N-methyl-6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(78) N-[6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-yl] ethanamide

(79) 6-[4-(4-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(80) 6-(1-benzyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine

(81) 6-[4-(3-iodophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(82) 6-[4-(3-bromophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(83) 6-[4-(3-butoxy phenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(84) 6-{1-methyl-4-[3-(4-methylbenzene sulfenyl) phenyl]-1H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(85) 6-{4-[4-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(86) 6-{4-[4-butoxy phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(87) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl } Toluidrin

(88) 6-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(89) 6-[1-(3-methoxy-propyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(90) 6-(1-isobutyl--4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(91) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethanol

(92) 6-(1-cyclopropyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(93) 6-[1-(2-methoxy ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(94) 6-(1-butyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(95) 6-[4-phenyl-1-(pyridin-3-yl methyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(96) 6-[1-(2, the 2-dimethoxy-ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(97) 6-(4-phenyl-1-tetramethyleneimine-3-base-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(98) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] oneself-1-alcohol

(99) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] fourth-1-alcohol

(100) 6-{1-[2-(4-methylpiperazine-1-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(101) 2-(1-ethyl-4-phenyl-1H-imidazoles-5-yl) [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(102) 2-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl] [1,3] thiazole [5,4-d] pyrimidine-7-amine also

(103) 6-(1-methyl-4-phenyl-1H-imidazoles-5-yl) furo [3,2-d] pyrimidine-4-amine

(104) 6-[1-(2-fluoro ethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(105) 6-[4-(2-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(106) 6-[4-(3-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(107) 6-[4-(4-chloro-phenyl-)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(108) 6-[1-methyl-4-(2-naphthyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(109) 6-[4-(1-thionaphthene-2-yl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(110) 6-[4-(3-fluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(111) 6-[1-methyl-4-(2-aminomethyl phenyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(112) 6-[4-(2, the 5-difluorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(113) 6-[4-(2, the 5-dichlorophenyl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(114) 6-[1-methyl-4-(1-naphthyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(115) 6-[4-(1H-indoles-5-yl)-1-methyl isophthalic acid H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(116) 6-{4-[4-(benzyloxy)-2-aminomethyl phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(117) 6-[1-(cyclohexyl methyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(118) 6-[1-[3-(4-methyl isophthalic acid-piperazinyl) propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(119) 6-[1-[3-(hexahydro-1 H-azepines-1-yl) propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-alcohol

(120) 6-[4-phenyl-1-(tetrahydrochysene-2,2-dimethyl-2H-pyrans-4-yl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(121) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-Beta-methyl-4-phenyl-1H-imidazoles-1-ethanol

(122) 6-[1-(2-methoxyl group-1-methylethyl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(123) 6-[1-(1-methylethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(124) 6-[1-(1, the 2-dimethyl propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(125) 6-[1-(1, the 3-dimethylbutyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(126) 6-[4-phenyl-1-(2-propenyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(127) 6-[4-phenyl-1-(2,2,6,6-tetramethyl--4-piperidyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(128) 6-[1-(1-methyl-propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(129) 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl]-hexalin

(130) methyl 6-[4-phenyl-1-[(tetrahydrochysene-2-furyl)]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(131) 6-[1-[2-(4-morpholinyl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(132) 6-[1-[4-(diethylamino)-1-methyl butyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(133) methyl 6-[1-[(2-fluorophenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(134) methyl 6-[1-[(2-aminomethyl phenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(135) methyl 6-[1-[(3-fluorophenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(136) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-Alpha-Methyl-4-phenyl-1H-imidazoles-1-ethanol

(137) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl]-1, the 2-propylene glycol

(138) 6-[1-(2-methyl butyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(139) 6-[4-phenyl-1-[2-(phenyl amino) ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(140) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-propyl alcohol

(141) 6-[1-[3-(dimethylamino)-2, the 2-dimethyl propyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(142) 6-[1-(2-methyl-2-propenyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(143) N-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-4-hydroxyl-phenylacetamide

(144) 6-[1-(2-methoxyl group-2-methyl-propyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(145) 6-[4-phenyl-1-(spiral shell [dicyclo [2.2.1] hept-2-ene"-7,1 '-cyclopropane]-5-ylmethyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(146) 6-[1-[2-(3,5-dimethyl-1H-pyrazoles-4-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(147) 6-[1-[2-(1H-imidazoles-1-yl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(148) methyl 6-[1-[2-[[(4-fluorophenyl)] amino] ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(149) 6-[1-[(3,4-dihydro-1H-2-chromene-1-yl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(150) 6-[1-[2-(methylsulfonyl) ethyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(151) N-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-2-[(2-chloro-3-pyridyl) the oxygen base]-ethanamide

(152) 6-[4-phenyl-1-[2-[(tetrahydrochysene-1,1-titanium dioxide-3-thienyl) amino] ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(153) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-α-(trifluoromethyl)-1H-imidazoles-1-ethanol

(154) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-α-[3-(trifluoromethyl) phenyl]-1H-imidazoles-1-ethanol

(155) 6-[4-phenyl-1-[2-(2-propenyl amino) ethyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(156) N-[5-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] amyl group]-4-morpholine methane amide

(157) 5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-α-(2,3-dihydro-1,4-benzo dioxine-6-yl)-4-phenyl-1H-imidazoles-1-ethanol

(158) 6-[1-[3-[4-(2-p-methoxy-phenyl)-1-piperazinyl] propyl group]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(159) N '-[2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] ethyl]-N, N-dimethyl-sulphonamide

(160) 6-[1-[6-(8-oxa--3-azabicyclo [3.2.1] oct-3-yl) hexyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(161) 6-[1-[[2-(4-morpholinyl) phenyl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(162) 6-[1-(1,4-diox-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(163) 2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl]-, (1S, 2R)-hexalin

(164) 6-[1-(suberyl methyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(165) 6-[1-[[(1S, 5S)-6,6-dimethyl dicyclo [3.1.1] heptan-2-yl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(166) 1-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl]-Cyclohexaneacetic acid

(167) 6-[4-phenyl-1-(phenyl methyl)-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(168) methyl 6-[1-[(2-p-methoxy-phenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(169) 6-[4-phenyl-1-[[2-(piperidino) phenyl] methyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(170) 6-[4-phenyl-1-[[2-(2-pyridyl oxygen base) phenyl] methyl]-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(171) 6-[1-[[2-(4-methyl isophthalic acid-piperazinyl) phenyl] methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(172) 1-[2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl] phenyl]-the 4-piperidine carbinols

(173) methyl 6-[1-[(2-aminophenyl)]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(174) N-[2-[[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] methyl] phenyl]-2,4-two chloro-benzsulfamides

(175) 6-[1-(1H-imidazoles-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(176) 6-[1-[(6-fluoro-4H-1,3-benzo dioxine-8-yl) methyl]-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(177) 6-[1-(imidazo [1,2-a] pyridine-2-ylmethyl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(178) N-benzyl-6 (1-methyl-4-phenyl-1H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(179) 6-[1-(1-methylpyrrolidin-3-yl)-4-phenyl-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(180) 2-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] and ethyl } t-butyl carbamate

(181) 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-4-phenyl-1H-imidazoles-1-yl] and butyl } t-butyl carbamate

(182) 6-{4-[3-(benzyloxy) phenyl]-1-methyl isophthalic acid H-imidazoles-5-yl } thieno-[2,3-d] pyrimidine-4-amine

(183) 4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenol

(184) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] benzonitrile

(185) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } t-butyl carbamate

(186) 6-(4-{4-[(3,4-dichloro benzyl) oxygen base] phenyl }-1-methyl isophthalic acid H-imidazoles-5-yl) thieno-[2,3-d] pyrimidine-4-amine

(187) N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-phenylurea

(188) N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-benzylurea

(189) N-{3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

(190) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-phenylurea

(191) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-benzylurea

(192) N-{4-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl }-N '-[2-fluoro-5-(trifluoromethyl) phenyl] urea

(193) 6-[1-(the amino butyl of 4-)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(194) 6-[1-(3-methyl but-2-ene-1-yl)-4-phenyl-1H-imidazoles-5-yl]-thieno-[2,3-d] pyrimidine-4-amine

(195) 6-[4-(4-fluorophenyl)-1 (2-morpholine-4-base benzyl)-1H-imidazoles-5-yl] thieno-[2,3-d] pyrimidine-4-amine

(196) { 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] phenyl } phenyl carbamate or

(197) 3-[5-(the 4-aminothiophene is [2,3-d] pyrimidine-6-yl also)-1-methyl isophthalic acid H-imidazol-4 yl] and phenyl } benzyl carbamate.

5. medicinal compositions, it comprises on the structural formula I compound of each definition of claim 1-4 or its pharmacology acceptable diluent or carrier on acceptable salt and the pharmacology.

6. as acceptable salt on the structural formula I compound of each definition of claim 1-4 of medicine or its pharmacology.

On the structural formula I compound of each definition of claim 1-4 or its pharmacology acceptable salt in preparation as the warm-blooded animal purposes on the people Tie2 receptor tyrosine kinase inhibitors medicine for example.

On the structural formula I compound of each definition of claim 1-4 or its pharmacology acceptable salt in preparation as the purposes that for example produces in the human body warm-blooded animal on the blood vessel formation against function medicine.