CN1294135C

CN1294135C - Pyrrolopyrimidines as protein kinase inhitibors

Info

Publication number: CN1294135C
Application number: CNB028119320A
Authority: CN
Inventors: P·J·考克斯; T·N·马吉德; S·阿门道拉; S·D·德普雷; C·埃德林; B·L·佩德格雷弗特; F·阿莱; M·爱德华兹; B·博杜安; L·M·麦克雷; D·J·奥尔德斯
Original assignee: Aventis Pharmaceuticals Inc
Current assignee: Aventis Pharmaceuticals Inc
Priority date: 2001-06-23
Filing date: 2002-06-21
Publication date: 2007-01-10
Anticipated expiration: 2022-06-21
Also published as: EE200400003A; WO2003000695A8; HUP0400300A3; CA2451932A1; HUP0400300A2; TR200302242T2; ECSP034922A; AU2002314325B2; NZ529766A; JP4344607B2; BR0210652A; RS99203A; RS51698B; SK15882003A3; UA76760C2; WO2003000695A1; EP1404676A1; JP2005508300A; GB0115393D0; OA12632A

Abstract

Compounds of the formula I and N-oxides, prodrugs, acid bioisosteres, pharmaceutically acceptable salts or solvates of such compounds, or N-oxides, prodrugs, or acid bioisosteres of such salts or solvates, to compositions comprising such compounds, and methods of treatment comprising administering, to a patient in need thereof, such compounds and compositions.

Description

Pyrrolopyrimidine as kinases inhibitor

The pyrrolopyrimidine that the present invention relates to replace, they preparation, contain the pharmaceutical usage of the morbid state that the pharmaceutical composition of these compounds and they can regulate by the arrestin kinases in treatment.

The signal event of activation, growth and the differentiation of control cell when protein kinase participates in variation in outer medium of cell response born of the same parents and the environment.Usually, these kinases can be classified as several groups: the kinases of preferential phosphorylation Serine and/or threonine residues and the kinases [S.K.Hanks and T.Hunter, FASEB.J., 1995,9,576-596 page or leaf] of preferential phosphorylated tyrosine residue.Serine/threonine kinase for example comprises, protein kinase C isotype [A.C.Newton, J.Biol.Chem., 1995,270, the 28495-28498 page or leaf] and one group of kinases that cyclin relies on, as cdc2[J.Pines, Trends in BiochemicalSciences, 1995,18, the 195-197 page or leaf].Tyrosylprotein kinase comprises transmembrane growth factor receptor, as EGF-R ELISA [S.Iwashita and M.Kobayashi, Cellular Signalling, 1992,4, the 123-132 page or leaf] and the non-receptor kinase of kytoplasm, as p56tck, p59fYn, ZAP-70 and csk kinases [C.Chan etc., Ann.Rev.Immunol., 1994,12, the 555-592 page or leaf].

Unfavorable high protein kinase activity and many disease-relateds that causes by the abnormal cells function.The following situation of this possible or direct or roundabout appearance, for example the failure owing to the correct controlling mechanism of this kinases causes for example sudden change, the expression or the unsuitable activation excessively of this enzyme; Perhaps because the overproduction or the deficiency of cytokine or somatomedin, and described cytokine or somatomedin also participate in the signal transduction in this kinase whose upstream or downstream.In all these examples, selectivity suppresses this kinase whose effect and has favourable effect.

Syk is the cytoplasmic protein Tyrosylprotein kinase of 72kDa, and it is expressed in multiple hematopoietic cell, and the essential composition in the cascade that to be some get up antigen receptor and cell response reaction bonded.Like this, in the signal of Syk high-affinity IgE acceptor Fc ε R1 in mastocyte and playing the part of the role of hinge in the signal of the receptor antigen in T and the bone-marrow-derived lymphocyte.This signal transduction pathway in mastocyte, T cell and B cell has identical feature.The ligand-binding domain of acceptor lacks inherent tyrosine kinase activity.Yet, they and the transduction subunit interaction [M.Reth, Nature, 1989,338,383-384 page or leaf] that contains based on the immunity receptor activation primitive (ITAM) of tyrosine.These primitives are present in [N.S.van Oers and A.Weiss in the IgG α of the ξ subunit of β among the Fc ε R1 and γ subunit, TXi Baoshouti (TCR) and B-cell receptor (BCR) and the IgG β subunit, Seminars inImmunology, 1995,7, the 227-236 page or leaf].When conjugated antigen and multimerization, the ITAM residue is by the protein tyrosine kinase phosphorylation of Src family.Syk belongs to unique family of a Tyrosylprotein kinase, and this Family Tyrosine Kinases has Src homologue 2 (SH2) district and C-terminal catalytic domain of two polyphones.The Syk in conjunction with ITAM and this SH2 mediation of these SH2 district high-affinities stimulates the Syk kinase activity and Syk is navigated to plasmalemma with combining of activated receptor.

In the mouse of Syk defective, the threshing of mastocyte is suppressed, and shows that Syk is an important target [P.S.Costello, Oncogene, 1996,13,2595-2605 page or leaf] of exploitation mast cell stabilizers.Similarly studies show that the keying action [A.M.Cheng, Nature, 1995,378,303-306 page or leaf, (1995) and D.H.Chu etc., Immunological Reviews, 1998,165,167-180 page or leaf] of Syk in the signal of BCR and TCR.Syk as if also participate in replying the eosinophilic granulocyte among IL-5 and the GM-CSF survival [S.Yousefi etc., J.Exp.Med., 1996,183,1407-1414 page or leaf].Although Syk plays a part crucial in mastocyte, BCR and T cell signal, the mechanism that transmits signals to downstream effect for Syk is also known little about it.Shown that two connect albumen, (the B cell junction protein is respectively the substrate of Syk in B cell and the mastocyte with SLP-76 SLP-65) to BLNK, infers that they are contact surface [M.Ishiai etc. of Syk and downstream effect, Immunity, 1999,10,117-125 page or leaf and L.R.Hendricks-Taylor etc., J.Biol.Chem., 1997,272, the 1363-1367 page or leaf].As if in addition, Syk plays an important role in the CD40 signal path, and the CD40 signal path plays an important role in B cell proliferation [M.Faris etc., J.Exp.Med., 1994,179,1923-1931 page or leaf].

Syk also participates in by low affinity IgG acceptor (Fc γ-RIIA) or the hematoblastic activation of collagen stimulation [F.Yanaga etc., Biochem.J., 1995,311, (Pt.2) 471-478 page or leaf].

Focal adhesion kinase (FAK) is the nonreceptor tyrosine kinase that participates in integral protein Mediated Signal Transduction path.FAK and integral protein co be in the adhesion plaque site, shown that the activation of FAK in many cell types and its tyrosine phosphorylation depend on part outside the born of the same parents that integral protein is attached to them.The result of some researchs supports this hypothesis, and promptly the FAK inhibitor can be used for treatment for cancer.For example, the FAK deficient cells moves relatively poor when replying the chemotactic signal, and the C-terminal district of overexpression FAK has blocked diffusion and chemotactic migration (Sieg etc., J.Cell Science, 1999,112, the 2677-2691 of cell; Richardson A. and Parsons T., Cell, 1997,97,221-231); In addition, the tumour cell of handling with the FAK antisense oligonucleotide lost adhesivity and experience apoptosis (Xu etc., Cell Growth Differ.1996,4,413-418).Reported FAK overexpression in prostate cancer, mammary cancer, thyroid carcinoma, colorectal carcinoma and lung cancer.The expression level of FAK is directly related with the tumour that shows tool aggressiveness phenotype.Take place or the formation of neovascularity takes place extremely important for fetal development and organ by the blood vessel of sprouting from the micro-tubular structure that is pre-existing in.Rheumatic arthritis, diabetic retinopathy and in tumor development, observe unusual enhanced neovascularization (Folkman, Nat.Med., 1995,1,27-31.).Blood vessel is the multistage process of a complexity, comprises activation, migration, propagation and the survival of endotheliocyte.The broad research that at the blood vessel of tumour this field took place in past 20 years has identified many treatments treatment targets, comprise kinases, proteolytic enzyme and integral protein, caused the discovery of many new antiangiogenic agents, these antiangiogenic agents comprise the KDR inhibitor, in them some have been in clinical assessment stage (Jekunen etc. now, Cancer TreatmentRev.1997,23,263-286.).Angiogenesis inhibitor can be used on the appearance of tumour or the line that regrows, complementary or even prophylactic treatment in.

In yeast and fruit bat, identified the albumen of several participation chromosome segregation and spindle body assembling.These proteic destructions cause separation and the single polarization or the destructive spindle body of karyomit(e) mistake.Ipl1 and aurora kinase (aurorakinase) from S.cerevisiae and fruit bat are arranged in these kinases respectively, they be centrosome separately and chromosome segregation needed.People's homologue of a primary yeast Ipl1 has been cloned and identified in the different experiments chamber recently.This kinases is named as Aurora 2, STK15 or BTAK, belongs to serine/threonine kinase family.Proof Aurora such as Bischoff 2 be carcinogenic and in people's colorectal cancer the amplification (EMBO J, 1998,17,3052-3065).Prove that also it is relevant with epithelial tumor (as mammary cancer).

The present invention relates to pyrrolopyrimidine with the replacement of one or more pharmaceutically acceptable carriers or vehicle bonded formula (I), it can suppress one or more protein kinases, suppress FAK, KDR, Syk kinases or Aurora 2, particularly Syk kinases more specifically:

With their corresponding N-oxide compound, prodrug, acid bioisoster (bioisostere); With pharmacy acceptable salt and solvate (for example hydrate) and N-oxide compound and their prodrug and their the acid bioisoster of these compounds, wherein

R ¹Represent hydrogen ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-SO ₂-NY ¹Y ²,-SO ₂-R ⁷,-C (=O) R ⁷, perhaps R ¹Represent alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl or cycloalkylalkyl, each randomly by one or more be selected from aryl, cycloalkyl, cyano group, halogen, heteroaryl, Heterocyclylalkyl ,-CHO (or ring acetal derivant of its 5-, 6-or 7 yuan) ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴,-OR ⁷, C (=O)-R ⁷, hydroxyl, alkoxyl group and carboxyl group replace;

R ²Represent one or more following groups that are selected from: hydrogen, acyl group, alkylene dioxo base, alkenyl, alkenyloxy, alkynyl, aryl, cyano group, halogen, hydroxyl, heteroaryl, Heterocyclylalkyl, nitro, R ⁴,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-C (=O)-OR ⁷,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴,-SO ₂-NY ¹Y ²With-ZR ⁴

R ³Represent H, cyano group, halogen, hydroxyl, nitro, R ⁴,-NY ¹Y ²,-ZR ⁴,-C (=O)-OR ⁵,-C (=O)-R ⁷,-C (=O)-NY ¹Y ²,-N (R ⁸)-C (=O)-R ⁴,-N (R ⁸)-C (=O)-NY ¹Y ²,-N (R ⁸)-C (=O)-OR ⁵,-SO ₂-NY ³Y ⁴Or-N (R ⁸)-SO ₂-R ⁷, perhaps R ³Represent aryl, heteroaryl, alkenyl or alkynyl, each randomly be selected from aryl, cyano group, halogen, hydroxyl, heteroaryl, Heterocyclylalkyl, nitro ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-C (=O)-OR ⁷,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴,-SO ₂-NY ¹Y ²Or-ZR ⁴One or more groups replace;

R ⁴Represent alkyl, cycloalkyl or cycloalkylalkyl, each randomly by one or more be selected from aryl, cycloalkyl, cyano group, halogen, heteroaryl, Heterocyclylalkyl, hydroxyl ,-CHO (or ring acetal derivant of its 5-, 6-or 7 yuan) ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴,-OR ⁷With-C (=O)-R ⁷Group replace; R ⁴Also can randomly be selected from O, S (O) _nAnd NR ⁶Group at interval;

R ⁵Represent hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroaryl or heteroaralkyl;

R ⁶Represent hydrogen or low alkyl group;

R ⁷Represent alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, Heterocyclylalkyl or Heterocyclylalkyl alkyl;

R ⁸Represent hydrogen or low alkyl group;

Y ¹And Y ²Be independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl, randomly by one or more be selected from aryl, halogen, heteroaryl, hydroxyl ,-C (=O)-NY ³Y ⁴,-C (=O)-OR ⁵,-NY ³Y ⁴,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴With-OR ⁷Group replace; Perhaps group-NY ¹Y ²Can form cyclic amine;

Y ³And Y ⁴Be independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; Perhaps group-NY ³Y ⁴Can form cyclammonium;

Z represents O or S (O) _n

N is 0 or integer 1 or 2.

In this manual, term " The compounds of this invention " and statement of equal value thereof are meant that this statement comprises prodrug, pharmaceutically useful salt and the solvate that content based on context may exist, as hydrate as the compound of previously described general formula (I) herein.Similarly, no matter whether described intermediate is required protection, include salt and solvate that content based on context may exist.For the sake of clarity, when context allows, specific example is described in this article sometimes, but these examples are pure illustrative rather than want to get rid of other examples when context allows.

As mentioned above and in the application's entire description, unless otherwise indicated, following term will be interpreted as to have the following meaning:

" patient " comprises people and other Mammalss.

" acid bioisoster " refer to can to produce in a broad sense with the similar biological property of carboxyl have chemistry and the homophylic group of physics (is seen Lipinski, Annual Reports in MedicinalChemistry, 1986,21, p283 " Bioisosterism In Drug Design "; Yun HwahakSekye, 1993,33,576-579 page or leaf " Application of Bioisosterism To New DrugDesin "; Zhao, Huaxue Tongbao, 1995,34-38 page or leaf; " Bioisosteric ReplacementAnd Development of Lead Compounds In Drug Design "; Graham, Theochem, 1995,343,105-109 page or leaf " Theoretical Studies Applied To DrugDesign:ab Initio Electronic Distributions In Bioisosteres ").The example of suitable acid bioisoster comprises :-C (=O)-NHOH ,-C (=O)-CH ₂OH ,-C (=O)-CH ₂SH ,-C (=O)-NH-CN, sulfo-, phosphono, alkyl sulfonyl-amino formyl radical, tetrazyl, aryl-sulfonyl-amino-carbonyl, heteroarylsulfonyl formamyl, N-methoxyl group formamyl, 3-hydroxyl-3-cyclobutene-1; 2-diketone, 3; 5-dioxy-1; 2; 4- two oxazolidinyls or heterocycle phenolic group are as 3-hydoxyisoxazole base and 3-hydroxyl-1-methylpyrazole base.

" acyl group " refers to H-CO-or alkyl-CO-group, and wherein alkyl is as described herein.

" amido " refers to acyl group-NH-group, and wherein acyl group as described here.

" alkenyl " refers to a kind of aliphatic hydrocarbon groups, and it contains a carbon-to-carbon double bond, can be straight or branched, has an appointment 2 to about 15 carbon atoms in chain; Have about 12 carbon atoms of 2-in the preferred alkenyl chain, more preferably, in chain, have 2 to about 6 carbon atoms (for example, 2 to 4 carbon atoms).Used " side chain " refers to one or more low alkyl groups in full, is connected on the linear chain as methyl, ethyl or propyl group, is meant the linear chain alkenylene chain here." low-grade alkenyl " refers to have an appointment 2 to about 4 carbon atoms in chain, this chain can be straight chain or side chain.Typical alkenyl comprises vinyl, propenyl, n-butene base, isobutenyl, 3-methyl but-2-ene base, positive pentenyl, heptenyl, octenyl, cyclohexyl butenyl and decene base.

" alkenyloxy " is alkenyl-O-group, and wherein the alkenyl definition as above.Typical alkenyloxy comprises allyloxy.

" alkoxyl group " refers to alkyl-O-group, and wherein alkyl is as definition herein.Typical alkoxyl group comprise difluoro-methoxy, methoxyl group, trifluoromethoxy, oxyethyl group, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.

" alkoxy carbonyl " refers to alkyl-O-CO-group, and wherein alkyl is as definition herein.Typical alkoxy carbonyl comprises methoxycarbonyl and ethoxy carbonyl.

Unless otherwise indicated, " alkyl " refers to a kind of aliphatic hydrocarbon groups, and it can be a straight or branched, and 1 to 15 carbon atom of having an appointment in the chain is randomly replaced by one or more halogen atoms.Specific alkyl has 1 to about 6 carbon atoms.Unless otherwise indicated; " low alkyl group " group itself or be meant a kind of aliphatic hydrocarbon groups as " low alkyl group " of lower alkoxy, lower alkylthio, low alkyl group sulfinyl, a low alkyl group alkylsulfonyl part; it can be a straight or branched, has 1 in the chain to about 4 carbon atoms.Typical alkyl comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, n-pentyl, 3-amyl group, heptyl, octyl group, nonyl, decyl and dodecyl.Typically the alkyl that is replaced by one or more halogen atoms comprises trifluoromethyl.

" alkylidene group " refers to that wherein alkyl as described here from straight or branched alkyl deutero-aliphatics divalent radical.Typical alkylidene group comprises methylene radical, ethylene and trimethylene.

" alkylene dioxo base " refers to-O-alkylidene group-O-group, and wherein the alkylidene group definition as above.Typical alkylene dioxo base comprises methylene-dioxy and ethylenedioxy.

" alkyl sulphinyl " refers to alkyl-SO-group, and wherein alkyl as previously described.Preferred alkyl sulphinyl is C for alkyl wherein _1-4Those alkyl sulphinyls of alkyl.

" alkyl sulphonyl " refers to alkyl-SO ₂-group, wherein alkyl as previously described.Preferred alkyl sulphonyl is C for alkyl wherein _1-4Those alkyl sulphonyls of alkyl.

" alkyl sulfonyl-amino formyl radical " refers to alkyl-SO ₂-NH-C (=O)-and group, wherein alkyl is as previously described.Preferred alkyl sulfonyl-amino formyl radical is that those alkyl are C _1-4The alkyl sulfonyl-amino formyl radical of alkyl.

" alkylthio " refers to alkyl-S-group, and wherein alkyl as described above.Typical alkylthio comprise methylthio group, ethylmercapto group, iprotiazem base and heptan sulfenyl.

" alkynyl " refers to contain the aliphatic alkyl of carbon-to-carbon triple bond, and it can be a straight or branched, has an appointment 2 in the chain to about 15 carbon atoms.Preferred alkynyl has 2 to about 12 carbon atoms in chain; Preferred, in chain, have 2 to about 6 carbon atoms (for example 2 to 4 carbon atoms).Typical alkynyl comprises ethynyl, proyl, positive butynyl, isobutyl alkynyl, 3-methyl fourth-2-alkynyl and positive pentynyl.

" aroyl " refers to aryl-CO-group, and wherein aryl as described here.Typical aroyl comprises benzoyl and 1-naphthoyl base and 2-naphthoyl base.

" aroylamino " is aroyl-NH-group, and wherein aryl as described above.

" aryl " as the part of a group or group refers to: (i) about 6 monocycle that randomly replaces or the fragrant isocyclic parts of many cyclophanes to about 14 carbon atoms, as phenyl or naphthyl; Or the fragrant isocyclic part of many cyclophanes of the fractional saturation that (ii) randomly replaces, wherein aryl and cycloalkyl or cycloalkenyl group condense and form ring texture together, as tetralyl, indenyl or 2, and 3-indane basic ring.Unless otherwise defined; aryl can replace with one or more aryl substituents; this substituting group can be identical or different; and " aryl substituent " comprises; for example, acyl group; amido; alkoxyl group; alkoxy carbonyl; alkylene dioxo base; alkyl sulphinyl; alkyl sulphonyl; alkylthio; aroyl; aroylamino; aryl; alkoxy aryl; aryl-alkoxy carbonyl; alkylthio-aryl; aryloxy; aryloxycarbonyl; aryl sulfonyl kia; aryl sulfonyl; arylthio; carboxyl (or acid isostere); cyano group; halogen; 4-hetaroylpyrazol; heteroaryl; the heteroaryl alkoxyl group; heteroaroylamino; heteroaryloxy; hydroxyl; nitro; trifluoromethyl;-NY ³Y ⁴,-CONY ³Y ⁴,-SO ₂NY ³Y ⁴,-NY ³-C (=O) alkyl ,-NY ³SO ₂Alkyl or randomly use aryl, heteroaryl, hydroxyl or-NY ³Y ⁴The alkyl that replaces.

" arylalkyl " refers to aryl-alkyl-group, and wherein aryl and moieties are as described above.The preferred aryl groups alkyl contains C _1-4Moieties.Typical arylalkyl comprises benzyl, 2-styroyl and menaphthyl.

" alkoxy aryl " refers to arylalkyl-O-group, and wherein arylalkyl as described above.Typical alkoxy aryl comprises benzyloxy and 1-naphthyl methoxyl group or 2-naphthyl methoxyl group.

" aryl-alkoxy carbonyl " refers to arylalkyl-O-CO-group, and wherein arylalkyl as described above.Typical aryl-alkoxy carbonyl is a benzyloxycarbonyl.

" alkylthio-aryl " refers to arylalkyl-S-group, and wherein arylalkyl as described above.Typical alkylthio-aryl is a benzylthio-.

" aryloxy " refers to aryl-O-group, and wherein aryl as described above.Typical aryloxy comprises phenoxy group and naphthyloxy, and what each was optional is substituted.

" aryloxycarbonyl " refers to aryl-O-C, and (=O) group, wherein aryl as described above.Typical aryloxycarbonyl comprises phenyloxycarbonyl and naphthyloxy carbonyl.

" aryl sulfonyl kia " refers to aryl-SO-group, and wherein aryl as described above.

" aryl sulfonyl " refers to aryl-SO ₂-group, wherein aryl as described above.

" aryl-sulfonyl-amino-carbonyl " refers to aryl-SO ₂-NH-C (=O)-and group, wherein aryl is as described above.

" arylthio " refers to aryl-S-group, and wherein aryl as described above, typically arylthio comprises thiophenyl and naphthalene sulfenyl.

" azepine aryl " refers to the about 5 aromatic carbocyclic parts to about 10 annular atomses, and one of them annular atoms is a nitrogen, and other annular atomses are selected from carbon, oxygen, sulphur and nitrogen.Typical azepine aryl comprises benzimidazolyl-, imidazolyl, indazole quinoline base, indyl, isoquinolyl, pyridyl, pyrimidyl, pyrryl, quinolyl, quinazolyl and tetrahydrochysene indolizine base.

" cyclic amine " refers to 3 to 8 yuan monocyclic cycloalkyl ring system, and one of them ring carbon atom is replaced by nitrogen and (i) can also contain and be selected from O, S, SO ₂And NY ⁵(Y wherein ⁵For hydrogen, alkyl, aryl, arylalkyl ,-C (=O)-R ⁷,-C (=O)-OR ⁷Or-SO ₂R ⁷) contain heteroatomic group; (ii) can condense and form two rings or three ring ring systems with other aryl (for example phenyl), heteroaryl (for example pyridyl), Heterocyclylalkyl or cycloalkyl ring.Typical cyclic amine comprises groups such as tetramethyleneimine, piperidines, morpholine, piperazine, indoline, pyrido indoline (pyrindoline), tetrahydroquinoline.

" cycloalkenyl group " refers to containing at least one carbon-to-carbon double bond and having an appointment 3 monocycle or multi-loop systems to about 10 carbon atoms of non-aromatic.Typical monocycle cyclenes basic ring comprises cyclopentenyl, cyclohexenyl and cycloheptenyl.

" cycloalkyl " refer to have about 3 to about 10 carbon atoms and the saturated monocycle or the second cycle line system that are optionally replaced by oxygen.Typical monocyclic cycloalkyl ring comprises C _3-8Cycloalkyl ring is as cyclopropyl, cyclopentyl, cyclohexyl and suberyl.

" cycloalkylalkyl " finger ring alkyl-alkyl-group, wherein cycloalkyl and moieties are as described above.Typical monocycle alkyl-alkyl comprises cyclopropyl methyl, cyclopentyl-methyl, cyclohexyl methyl and suberyl methyl.

" halo " or " halogen " refers to fluorine, chlorine, bromine or iodine.Be preferably fluorine and chlorine.

" 4-hetaroylpyrazol " refer to heteroaryl-C (=O)-group, wherein 4-hetaroylpyrazol as described here.Typical 4-hetaroylpyrazol comprises the pyridine carbonyl.

" heteroaroylamino " refers to 4-hetaroylpyrazol-NH-group, and wherein the 4-hetaroylpyrazol part as described above.

" heteroaryl " as the part of group or group refers to: (i) have an appointment 5 to the aromatic series monocycle of the optional replacement of about 10 annular atomses or encircle organic moiety more, wherein the one or more of annular atoms are not carbon, for example be nitrogen, (example of these groups comprises benzimidazolyl-for oxygen or sulphur, benzothiazolyl, furyl, imidazolyl, indyl, the indolizine base, different  azoles base, isoquinolyl, isothiazolyl, the  di azoly, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidyl, pyrryl, quinazolyl, quinolyl, 1,3, the 4-thiadiazolyl group, thiazolyl, thienyl and triazolyl are randomly replaced by one or more aryl substituent of (in addition to additional definitions) as defined above); (ii) choose the assorted isocyclic part of many rings of the fractional saturation that replaces wantonly, one of them heteroaryl and cycloalkyl or cycloalkenyl group condense and form ring texture (example of these groups comprises pyrido indanyl (pyrindanyl) group, is randomly replaced by one or more above-mentioned defined (in addition to additional definitions) " aryl substituents ").Optional substituting group comprises (unless otherwise defined) one or more " aryl substituents " as defined above.

" heteroarylalkyl " refers to heteroaryl-alkyl-group, and wherein heteroaryl and moieties are as described above.Preferred heteroarylalkyl comprises C _1-4Moieties.Typical heteroarylalkyl comprises pyridylmethyl.

" heteroaryl alkoxyl group " refers to heteroarylalkyl-O-group, and wherein heteroarylalkyl as described above.Typical heteroaryl alkoxyl group comprises the optional pyridine methoxyl group that replaces.

" heteroaryloxy " refers to heteroaryl-O-group, and wherein heteroaryl as described above.Typical heteroaryloxy comprises the optional pyridyloxy that replaces.

" heteroarylsulfonyl formamyl " refers to heteroaryl-SO ₂(=O) group, wherein heteroaryl as described above for-NH-C.

" Heterocyclylalkyl " refers to: (i) contain and be selected from O, S and NY ⁵One or more heteroatomss or contain heteroatomic group and the cycloalkyl of 3 to 7 annular atomses can be randomly being replaced by oxygen; The (ii) assorted isocyclic part of the polycyclic of fractional saturation, wherein virtue (or assorted virtue) ring (each is randomly replaced by one or more " aryl substituent ") and Heterocyclylalkyl condense the formation ring texture.(example of this group comprises chromanyl, dihydro benzo furyl, indolinyl and pyrido indolinyl).

" Heterocyclylalkyl alkyl " refers to Heterocyclylalkyl-alkyl-group, and wherein Heterocyclylalkyl and moieties are as described above.

" prodrug " refers to by metabolic way (for example by hydrolysis) but changes the compound of an accepted way of doing sth (I) compound in the body, comprise its N-oxide compound.The ester that for example contains formula (I) compound of hydroxyl can be transformed into parent molecule by hydrolysis in the body.Alternatively, the ester that contains formula (I) compound of carboxyl can be transformed into parent molecule by hydrolysis in the body.

The suitable ester that contains formula (I) compound of hydroxyl is, for example acetic ester, citrate, lactate, tartrate, malonic ester, barkite, salicylate, propionic ester, succinate, fumaric acid esters, maleic acid ester, methylene radical-two-β-Qiang Jinaijiasuan ester, rough gentian acid esters, isethionic acid ester, two-p-toluyl tartrate, methanesulfonates, esilate, benzene sulfonate, p-tosylate, cyclohexyl sulfamate and quinate.

The ester of the suitable formula that contains carboxyl (I) compound is, for example, F.J.Leinweber, DrugsMetab.Res., 1987, 18, 379 pages described those.

The suitable ester that not only contains carboxyl but also contain formula (I) compound of hydroxyl in-L1-Y part comprises the lactone that forms by dehydration between described carboxyl and hydroxyl.The example of these lactones comprises caprolactone and butyrolactone.

The useful especially ester that contains formula (I) compound of hydroxyl of one class can be from being selected from by Bundgaard etc., J.Med.Chem., 1989,32, the described acid moieties of 2503-2507 page or leaf forms, and (amino methyl) benzoic ether that comprises replacement, dialkyl amido-methyl benzoic acid ester for example, wherein two alkyl can link together and/or by Sauerstoffatom or the nitrogen-atoms that is optionally substituted (alkylation nitrogen-atoms for example, more particularly, (morpholinyl methyl) benzoic ether, for example, 3-or 4-(morpholinyl methyl)-benzoic ether and (4-alkylpiperazine-1-yl) benzoic ether) institute interrupts, 3-or 4-(4-alkylpiperazine-1-yl) benzoic ether for example.

When The compounds of this invention contains carboxyl or enough acid isosteres, can form alkali addition alkali salt, and they are a kind of types of service more easily; In the practice, the use of salt form is suitable with the use of free acid form.The alkali that can be used for preparing base addition salt comprise preferably those when and free acid in conjunction with the time form the alkali of pharmacy acceptable salt, that is to say, in the pharmaceutical dosage scope of described salt, positively charged ion in the salt is nontoxic to the patient, and the inherent useful restraining effect of free alkali can not destroyed by cationic side effect like this.Pharmacy acceptable salt (comprising those salt derived from basic metal or alkaline-earth metal) comprises the salt derived from following alkali in the scope of the invention: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, quadrol, N-methyl-glucosamine, Methionin, arginine, ornithine, choline, N, N '-dibenzyl-ethylenediamin, chloro PROCAINE HCL, PHARMA GRADE, diethanolamine, PROCAINE HCL, PHARMA GRADE, N-benzyl-1-phenylethylamine, diethylamine, piperazine, three (methylol) aminomethane, tetramethyl ammonium hydroxide, or the like.

Compounds more of the present invention are alkaline, these compounds can free alkali form or the form of its pharmaceutically-acceptable acid addition use.

Acid salt is a kind of form of more convenient use; In the practice, use the form of salt and use the form of free alkali suitable.The acid that can be used for preparing acid salt comprise preferably when and alkali in conjunction with the time produce pharmacy acceptable salt those acid, the negatively charged ion of salt that is pharmaceutical dosage is nontoxic to patient, thereby the favourable restraining effect of organic bases intrinsic can not destroyed by anionic side effect.Although the pharmacy acceptable salt of preferred described basic cpd, but all acid salt all can be used as the source of free alkali form, even itself only can be used as intermediate product this specific salts, for example, be used for purifying and evaluation when generating this salt, perhaps when its when preparing the intermediate of pharmacy acceptable salt by ion-exchange techniques.Pharmacy acceptable salt comprises derived from mineral acid or organic acid salt in the scope of the invention, comprises hydrohalogen (for example hydrochloride and hydrobromate), vitriol, phosphoric acid salt, nitrate, sulfamate, acetate, Citrate trianion, lactic acid salt, tartrate, malonate, oxalate, salicylate, propionic salt, succinate, fumarate, maleate, methylene radical-two-β-Qiang Jinaijiasuan salt, gentisate, isethionate, two-p-toluyl tartrate, mesylate, esilate, benzene sulfonate, the p-tosylate, cyclohexyl-n-sulfonate and quinate.

The salt of The compounds of this invention itself can be used as the active ingredient beyond the region of objective existence except them, for example also can be used for, and utilizes the different solubility purifying compounds of salt and parent compound, by product and/or initial substance by technology well known to those skilled in the art.

For top formula (I), concrete preferred following definition:

R ¹Specifically can represent:

(i) hydrogen;

(ii) C _1-4Alkyl [for example-CH ₃Or-CH ₂CH ₃];

(iii) halo C _1-4Alkyl [for example-CH ₂CF ₃];

The (iv) C that replaces of hydroxyl _1-4Alkyl [for example-CH ₂OH ,-CH ₂CH ₂OH or-CH ₂CH ₂CH ₂OH];

(v)-N (R ⁶) C (=O)-R ⁷The C that replaces _1-4Alkyl [for example-CH ₂CH ₂CH ₂NHC (=O) CH ₃];

(vi)-C (=O)-NY ¹Y ²The C that replaces _1-4Alkyl [for example

Or

(vii) the cycloalkylalkyl of hydroxyl replacement [for example

Preferred especially R ¹Represent hydrogen ,-CH ₃, CH ₂CH ₃-CH ₂CF ₃Or

Formula (I) compound.R ¹More particularly represent hydrogen.

R ²Can represent especially:

(i) carboxyl or acid isostere are (for example

(ii) hydroxyl;

(iii) the alkyl of carboxyl substituted [for example-CH ₂CH ₂CO ₂H];

(iv) heteroaryl [for example Or pyridyl];

(v)-OR ⁴, R wherein ⁴For alkyl [for example-OCH ₃];

(vi)-OR ⁴, R wherein ⁴For the alkyl or cycloalkyl alkyl that replaced by one or more hydroxyls [for example-OCH ₂CH ₂OH ,-OCH ₂CH ₂CH ₂OH ,-OCH (CH ₃) CH ₂OH ,-OCH ₂CH (OH) CH ₃,

Or-OCH ₂CH (OH) CH ₂OH];

(vii)-OR ⁴, R wherein ⁴The alkyl that is replaced by one or more alkoxyl groups [for example-OCH (CH ₃) CH ₂OCH ₃];

(viii)-OR ⁴, R wherein ⁴By the alkyl or cycloalkyl of one or more carboxyl substituted [for example-OCH ₂CO ₂H ,-OCH (CH ₃) CO ₂H or

(ix)-OR ⁴, R wherein ⁴By-C (=O)-NY ¹Y ²The cycloalkyl that replaces [for example

(x)-C (=O)-R, wherein R be alkyl [for example-C (=O)-CH ₃];

(xi)-C (=O)-NY ¹Y ²[for example-CONH ₂,-CONHCH ₃,-CONHCH (CH ₂OH) ₂,-CONHCH ₂CH ₂OH ,-CONHC (CH ₃) ₂CH ₂OH ,-CONHCH ₂CH ₂OCH ₃,-CONHCH ₂CH ₂CONH ₂,-CONHCH ₂C (CH ₃) ₂OH or

Or

(xii)-N (R ⁶)-C (=O)-R ⁷[for example-NHC (=O) CH ₃].

Preferred especially R ²Representative-OCH ₃Or-CONHC (CH ₃) ₂CH ₂The formula of OH (I) compound.R ²Representative-OCH more preferably ₃

R ³Can represent especially:

(i) hydrogen;

(ii) cyano group;

The (iii) optional aryl (for example phenyl) that replaces;

The (iv) optional heteroaryl that replaces (for example optional pyridyl that replaces or the optional indyl that replaces, especially

(v) alkyl (for example methyl or ethyl);

(the vi) alkyl that is replaced by one or more halogen atoms (as trifluoromethyl);

(vii) by-C (=O)-NY ¹Y ², particularly by-CH ₂-CH ₂-C (=O) NHCH ₃The alkyl that replaces;

(viii) by-OR ⁷The alkyl that replaces (for example-CH ₂-CH ₂-OCH ₃);

(ix) ZR ⁴, particularly-OCH ₃,-OCH ₂CH ₃,-OCF ₂H or-OCH ₂-CH ₂-OCH ₃

(x)-C (=O)-OR ⁵, particularly-C (=O)-OH;

(xi)-C (=O)-NY ¹Y ², in particular-C (=O) NHCH ₃Or-C (=O)-NH-C (CH ₃) ₂-CH ₂OH; With

(xii)-NY ¹Y ², especially

Preferred R ³Represent hydrogen, cyano group, pyridyl, trifluoromethyl ,-CH ₂-CH ₂-C (=O) NHCH ₃,-OCF ₂H ,-C (=O)-NH-C (CH ₃) ₂-CH ₂OH or

Formula (I) compound.More particularly, R ³Representative-OCH ₃

R ²Preferably be connected in 5 of indole ring.

Group Preferably be connected in 3 of indole ring.

Should be appreciated that all suitable combinations specific and preferred group that reach mentioned herein are contained in the present invention.

The particularly preferred compound of the present invention is:

And corresponding N-oxide compound, and their prodrug, the pharmacy acceptable salt of these compounds and N-oxide compound and prodrug and solvate (for example, hydrate).

Particularly preferred The compounds of this invention is:

4-methoxyl group-6-(5-methoxyl group-1H-indol-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine;

Therefore the pharmacologically active that The compounds of this invention shows one's usefulness can add in the pharmaceutical composition, is used for the treatment of the patient who suffers from some disease.Like this, according to other one side, the invention provides The compounds of this invention that is used for the treatment of and the composition that contains The compounds of this invention.

According to test of describing in the document and the in vitro method that describes below, find that the compound in the scope of the invention can be blocked kinase catalytic activity, and believe that test-results and the mankind are relevant with pharmacological activities in other Mammalss.Like this, in a further embodiment, the invention provides the The compounds of this invention that is used for the treatment of the patient and the composition that contains The compounds of this invention, the symptom that described patient suffers from or easily suffers from can by use protein kinase (for example Syk, FAK, KDR or Aurora 2) inhibitor, particularly the Syk kinase inhibitor improves.For example, The compounds of this invention can be used for treating inflammatory diseases, for example, and asthma, inflammatory dermatosis (for example, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis and skin vasculitis, bulla disease); Allergic rhinitis and anaphylaxis conjunctivitis; The joint inflammation comprises sacroiliitis, rheumatoid arthritis and other arthritic symptoms such as rheumatoid spondylitis, urarthritis, traumatic arthritis, rubella arthritis, arthritic psoriasis and osteoarthritis.These compounds also can be used for treating chronic obstructive disease of lung (COPD), acute synovitis, autoimmune diabetes, the autoimmunity encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disorder, multiple sclerosis, restenosis, myocarditis, B cell lymphoma, systemic lupus erythematous, graft versus host disease is transplanted relevant rejection with other, cancer and tumour are (as colorectal cancer, prostate cancer, mammary cancer, thyroid carcinoma, colorectal carcinoma and lung cancer) and inflammatory bowel disease.In addition, these compounds can be used as the tumour anti-angiogenic agent.

A particular of methods of treatment of the present invention is a treatment asthma.

Another particular of methods of treatment of the present invention is the treatment psoriasis.

Another particular of methods of treatment of the present invention is a treatment of arthritis disease.

Another particular of methods of treatment of the present invention is the treatment inflammatory bowel disease.

Another particular of methods of treatment of the present invention is treatment cancer and tumour.

According to a further aspect of the invention, the method that provides treatment to suffer from or easily suffer from human or animal patient that can be by using the symptom (for example previously described symptom of this paper) that protein kinase (for example Syk, FAK, KDR or Aurora 2) inhibitor improves, this method comprise to be used the The compounds of this invention of significant quantity or contains the composition of The compounds of this invention the patient." significant quantity " refers to the amount of The compounds of this invention of the catalytic activity of effective arrestin kinases such as Syk, FAK, KDR or Aurora 2, therefore can produce useful result of treatment.

Should be appreciated that the treatment of indication herein comprises prophylactic treatment and the treatment of the symptom made a definite diagnosis.

The present invention also comprises pharmaceutical composition, and this pharmaceutical composition contains at least a The compounds of this invention and pharmaceutically acceptable carrier or vehicle.

Can use The compounds of this invention by proper method.In the practice, The compounds of this invention can the stomach other places, partly, rectum ground, oral or suck and use, particularly Orally administered.

Can be according to composition of the present invention according to conventional process, with one or more pharmaceutically acceptable auxiliarys or vehicle preparation.Auxiliary itself comprises thinner, sterile aqueous media and various nonpoisonous organic solvent.Composition can provide with the form of tablet, pill, powder, pulvis, aqueous solution or suspension, injection liquid, elixir or syrup, and can contain the material that one or more are selected from sweeting agent, correctives, tinting material and stablizer, obtain pharmaceutically acceptable preparation thus.The regulation that content of active substance is observed according to needs in the solubleness of active compound and chemical property, specific application pattern and the pharmacy practice in the selection of carrier and the carrier is determined.For example, vehicle (as lactose, Trisodium Citrate, lime carbonate, Lin Suanergai) and disintegrating agent (as starch, alginic acid and some silicate composites) can be used for preparing tablet with lubricant (as Magnesium Stearate, sodium lauryl sulphate and talcum powder).In order to prepare capsule, advantageously use lactose and high-molecular weight polyoxyethylene glycol.When using aqueous suspension, they can contain emulsifying agent or be beneficial to the reagent of suspension.Also can use thinner such as sucrose, ethanol, polyoxyethylene glycol, propylene glycol, glycerine and chloroform or their mixture.

For parenteral administration, can adopt emulsion, suspensoid and the solution of the product of the present invention in the sterile aqueous solution that is dissolved in vegetables oil (for example sesame oil, peanut oil or sweet oil) or water-containing organic solvent solution (as water and propylene glycol), injection organic ester (as ethyl oleate) and pharmacy acceptable salt.Be particularly suitable for intramuscular or subcutaneous injection is used according to the salts solution of product of the present invention.Aqueous solution (also comprising the salts solution that is dissolved in pure distilled water) can be used for intravenously and uses, condition is that their pH is suitably regulated, so that they by the glucose of q.s or sodium-chlor cushion well and make its etc. ooze, can make them aseptic by heating, irradiation or micro-filtration.

For topical application, can use the gelifying agent (based on water or alcohol), creme or the ointment that contain The compounds of this invention.The compounds of this invention also can add in gel or the matrix with the patch form and uses, and this will make compound controlledly discharge through skin barrier.

Use for imbedibility, The compounds of this invention can be dissolved in or be suspended in suitable carriers to be used for atomizer or suspension agent or aerosol or absorption or to be adsorbed in suitable solid phase carrier to be used for Diskus.

The solid compositions of rectal administration comprises the suppository for preparing and contain at least a The compounds of this invention according to currently known methods.

The per-cent of activeconstituents can change in the present composition, and this per-cent should be is enough to obtain the necessary ratio of proper dosage.Obviously, can use several unit dosage in the roughly the same time.Employed dosage will be determined by the doctor, and depend on required result of treatment, route of administration and treatment time and patient status.

For the grownup, inhalation dose is generally and arrives about 5mg/kg body weight to about 50, preferred about 0.001 every day about 0.001, Orally administered is every day about 0.01 to about 100, preferred 0.1 to 70, more preferably 0.5 to the 10mg/kg body weight, intravenously is used to about 0.001 to about 10, preferred 0.01 and is arrived the 1mg/kg body weight.For each specific case, will determine as age, body weight, general health state and other features that can influence the effect of this pharmaceutical prod according to the different factors of the object that will treat.

Can use The compounds of this invention to obtain required curative effect as required regularly.Some patient may to or high or low dose response rapid, and use lower maintenance dose just enough subsequently.And, may need long periods of treatment for other patients, according to the psychological need of each given patient, but give 1 to 4 dosage every day.Usually, this active result can be Orally administered, every day 1 to 4 time.Certainly, for some patient, may need every day and be no more than 1 to 2 dosage.

Can be by implementing or revise known method to prepare The compounds of this invention, these methods refer to use so far or document in the method described, for example R.C.Larock is at Comprehensive OrganicTransformations, VCH publishers, the method described in 1989.

In the reaction of Miao Shuing, may need reactive functional group hereinafter, for example hydroxyl, amino, imino-, sulfo-or carboxyl (these groups are required in the end product) are protected to avoid them to participate in unwanted reaction.Can use protectiveness group commonly used according to standard convention, for example, see " Protective Groups in Organic Chemistry " John Wiley and Sons of T.W.Greene and P.G.M.Wuts, 1991.

Through type (XXVIII) compound (R ³As preceding definition, X ¹Be halogen atom (preferred iodine) or trifluoromethanesulfonic acid root)

With formula (XXIX) compound (R wherein ¹And R ²As preceding definition)

Prepared in reaction formula (I) compound (wherein, R ¹, R ²And R ³Define as the front).In the presence of for example composite metal catalyst such as tetrakis triphenylphosphine palladium (0) and sodium bicarbonate, in moisture dimethyl formamide, be to carry out this coupled reaction easily under the reflux temperature in top temperature.With the pyrroles NH in the protection compound of tosyl group for example (XXVIII), can carry out this reaction easily with the indoles NH in the tert-butoxycarbonyl protection compound (XXIX) for example.

By corresponding formula (I) compound (R wherein ²And R ³As preceding definition, R ¹Be hydrogen) and suitable alkyl halide R ²-X ²(R wherein ²Be the optional alkyl that replaces, X ²Be halogen) prepared in reaction formula (I) compound (R wherein ²And R ³As preceding definition, R ¹Be the optional alkyl that replaces).This reaction is particularly suitable for preparation formula (I) compound (R wherein ¹Be the morpholinyl ethanoyl).

Also can prepare The compounds of this invention by the change of other compounds of the present invention.

Like this, for example, contain formula (I) compound of carboxyl by the hydrolysis preparation of corresponding esters.(use alkali by alkaline hydrolysis, as alkali metal hydroxide, for example lithium hydroxide or alkaline carbonate, yellow soda ash for example) in the presence of water/ORGANIC SOLVENT MIXTURES, with organic solvent as two  alkane, tetrahydrofuran (THF) or methyl alcohol, under temperature, can be hydrolyzed easily from about envrionment temperature to about reflux temperature.Also can be in the presence of water/inert organic solvents mixture, as two  alkane or tetrahydrofuran (THF)s, carry out the hydrolysis of ester with mineral acid (example hydrochloric acid) acidic hydrolysis from about 50 ℃ down to about 80 ℃ with organic solvent in temperature.

Can be by with standard reaction condition (for example with trifluoroacetic acid when about room temperature) as another example of the formula that contains carboxyl (I) compound, the tertiary butyl that acid catalysis is removed corresponding tertiary butyl ester prepares.

Another example as the formula that contains carboxyl (I) compound can prepare by the corresponding benzyl ester of hydrogenation.Can ammonium formiate be carried on suitable metal catalyst (for example palladium) on the inert support (as carbon) in the presence of, preferably in solvent (as methyl alcohol or ethanol), under about reflux temperature, carry out this reaction.Perhaps, also can optional be carried on suitable metal catalyst (for example platinum or palladium) on the inert support (as carbon) in the presence of, preferably in solvent (as methyl alcohol or ethanol), carry out this reaction.

Another example as the change method, can be by the standard peptide couling process (O-in being dissolved in tetrahydrofuran (THF) (or dimethyl formamide) (7-azepine benzo triazol-1-yl)-1 for example, 1,3, under the existence of 3-tetramethyl-urea hexafluorophosphate and triethylamine (or diisopropylethylamine), in the room temperature coupling), will contain formula (I) compound and the formula HNY of carboxyl ¹Y ²The amine coupling obtain amido bond, thereby preparation contain-C (=O)-NY ¹Y ²The formula of group (I) compound.This method is particularly suitable for preparation: (i) formula (I) compound, wherein R ³Representative-C (=O)-NY ¹Y ², or (ii) formula (I) compound, wherein R ²Representative-C (=O)-NY ¹Y ²Also can be by making formula (I) compound and N-{ (the dimethylamino) (1H-1 that contains carboxyl, 2,3-triazolo [4,5-b] pyridine-1-yl) methylene radical }-N-methyl first ammonium hexafluorophosphate N-oxide compound, in the presence of the suitable alkali (as diisopropylethylamine), in inert solvent (as dimethyl formamide), under about room temperature, react, then with formula HNY ¹Y ²Amine reaction (ammonium chloride can be used for preparation and contains-C (=O)-NH ₂The formula of group (I) compound) this coupled reaction is carried out in reaction.Also can be by making formula (I) compound and the 2-(1H-benzotriazole-1-yl) 1,1,3 that contains carboxyl, 3-tetramethyl-urea hexafluorophosphate reacts in dry dimethyl formamide, then in the presence of diisopropylethylamine with formula HNY ¹Y ²Amine reaction carry out this coupled reaction.

As another example of change method, can contain by reduction-CHO or-CO ₂R ⁷(R wherein ⁷Be low alkyl group) corresponding formula (I) compound, prepare and contain-CH ₂The formula of OH (I) compound.For example, by in inert solvent (as tetrahydrofuran (THF)), from about room temperature under about reflux temperature, make the reaction of itself and lithium aluminum hydride carry out reduction reaction easily.

As another example of change method, can be by in inert solvent (as methylene dichloride), from about 0 ℃ under the temperature of about room temperature, make corresponding formula (I) compound (R wherein ¹Be methoxyl group) with Lewis acid (as boron tribromide) prepared in reaction formula (I) compound (R wherein ²Be hydroxyl).

As another example of change method, can adopt the standard alkylation conditions by make corresponding formula (I) compound (R wherein with formula (XXX) compound ²Be hydroxyl) alkylation:

R ⁴-X ³ (XXX)

R wherein ⁴As preceding definition, X ³Be halogen atom (preferred bromine) or tosyl group) preparation formula (I) compound, wherein R ²For-OR ⁴(R wherein ⁴Be optional alkyl, cycloalkyl, cycloalkylalkyl, Heterocyclylalkyl or the Heterocyclylalkyl alkyl that replaces).Can be in the presence of for example alkali (as alkaline carbonate (for example salt of wormwood or cesium carbonate) and alkali metal alcoholates (for example potassium tert.-butoxide) or alkalimetal hydride (for example sodium hydride)), in dimethyl formamide or methyl-sulphoxide, under about 100 ℃ temperature, carrying out this alkylated reaction from about 0 ℃.

As another example of change method, can pass through use-case those standard alkylation conditions as described previously, use suitable formula (XXXI) halogenide:

R ¹-X ⁴ (XXXI)

R wherein ¹Be alkyl, alkenyl, cycloalkyl, Heterocyclylalkyl, or quilt-C (=O) NY ¹Y ²,-OR ⁷,-C (=O)-OR ⁷,-NY ¹Y ¹The alkyl that replaces, X ⁴Be halogen atom, preferred bromine is with corresponding formula (Ia) compound (R wherein ¹Be hydrogen) alkylation, come preparation formula (I) compound, wherein R ¹Be alkyl, alkenyl, cycloalkyl, Heterocyclylalkyl, or quilt-C (=O) NY ¹Y ²,-OR ⁷,-C (=O)-OR ⁷,-NY ¹Y ¹The alkyl that replaces.

As another example of change method, can contain by oxidation-preparation of the respective compound of S-key contains formula (I) compound of sulfoxide.For example, by preferably in inert solvent (for example methylene dichloride), preferably or near under the room temperature, with peroxy acid (for example 3-chlorine peroxybenzoic acid) reaction, perhaps by being dissolved in medium (as aqueous methanol, be buffered to pH and be about 5) permonosulphuric acid hydrogen potassium, between the temperature of about 0 ℃ and room temperature, react, carry out oxidizing reaction easily.For the compound that contains acid variable group, the preferred a kind of method in back that adopts.

As another example of change method, can contain by oxidation-the respective compound preparation of S-or sulfoxide key contains formula (I) compound of sulfone key.For example, preferably in inert solvent (for example methylene dichloride), preferably or near under the room temperature with peroxy acid (for example, 3-chlorine peroxybenzoic acid) reaction, carry out oxidizing reaction easily.

As another example of change method, can pass through in the presence of triethylamine, to contain by making-C (=O)-NH ₂Formula (I) compound that corresponding formula (I) compound of group and phosphorus pentachloride prepared in reaction contain cyano group.Can under about reflux temperature, carry out this reaction easily at inert solvent (as tetrahydrofuran (THF)).

As another example of change method, can make corresponding formula (I) compound and the hydroperoxidation that contain cyano group by in the presence of sodium hydroxide, prepare contain-C (=O)-NH ₂The formula of group (I) compound.Can under the temperature of about room temperature, in methyl alcohol, carry out this reaction easily.

As another example of change method, can be by making corresponding formula (I) compound (R wherein ³Be halogen (for example chlorine) and formula HNY ¹Y ²Amine (Y wherein ¹And Y ²Reaction as described above) comes preparation formula (I) compound (R wherein ³For-NY ¹Y ²(Y wherein ¹And Y ²As preceding definition)).

Another example as the change method, can pass through at zinc powder, [1 ' 1-two (diphenylphosphino) ferrocene] dichloro palladium (II) mixture and methylene dichloride (catalytic amount) and N, the N-N,N-DIMETHYLACETAMIDE exists down, under the highest about 150 ℃, makes formula (I) compound (X wherein ¹Be halogen, preferred chlorine) and zinc cyanide prepared in reaction formula (I) compound (R wherein ³Be cyano group).

As another example of change method, can contain by making-C (=O)-corresponding formula (I) compound and the formula R of OH group ⁵The pure prepared in reaction of-OH contains-C (=O)-OR ⁵Group (R wherein ⁵As front definition) formula (I) compound.For example, work as R ⁵During for the tertiary butyl, can be 1,1 '-carbonyl dimidazoles and 1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene exist down, carry out this reaction under the temperature of about room temperature easily.

Be appreciated that The compounds of this invention may contain asymmetric center.These asymmetric centers can independently be R or S configuration.Some The compounds of this invention also can demonstrate geometric isomerism, and this is conspicuous to those skilled in the art.Should be appreciated that, the present invention includes independent geometrical isomer and the steric isomer and their mixture of top formula (I) compound herein, comprise racemic mixture.By implementing or revise currently known methods, for example chromatographic technique can separate these isomer with recrystallization technology from their mixture, perhaps can prepare them respectively by their the suitable isomer of intermediate.

According to a further aspect of the invention, can make free alkali and suitable acid-respons, prepare the acid salt of The compounds of this invention by implementing or revising known method.For example, can be by free alkali being dissolved in the water or aqueous alcohol solutions or other suitable solvents that contains suitable acid, and by the evaporating solns separated salt, perhaps, prepare the acid salt of The compounds of this invention by making free alkali and acid reaction in organic solvent (salt can directly separate or can obtain by concentrated solution at this moment).

By implementing or revise currently known methods, the acid salt of the The compounds of this invention of can from salt, regenerating.For example, by handling the parent compound of the present invention of from acid salt, to regenerate with alkali (for example, sodium bicarbonate or ammonia soln).

By implementing or revise currently known methods, the The compounds of this invention of can from their base addition salt, regenerating.For example, by handle the parent compound of the present invention of from their base addition salt, to regenerate with acid (for example hydrochloric acid).

In the methods of the invention, can prepare or form the The compounds of this invention of solvate (for example hydrate) form easily.As two  alkane, tetrahydrofuran (THF) or methyl alcohol, from moisture/ORGANIC SOLVENT MIXTURES, prepare the hydrate of The compounds of this invention with organic solvent easily by recrystallization.

Another aspect according to the present invention by implementing or revising currently known methods, makes free acid and suitable alkali reaction, the base addition salt of preparation The compounds of this invention.For example, by with acid dissociable dissolution in the water that contains suitable alkali or aqueous alcohol solutions or other suitable solvent, the evaporating solns separated salt, perhaps, prepare the base addition salt of The compounds of this invention by making free bronsted lowry acids and bases bronsted lowry in organic solvent, react (this moment directly separated salt or obtain salt) by concentrated solution.

By implementing or revising currently known methods (method of for example in reference example, describing or their tangible chemical equivalent processes), can prepare initial substance and intermediate.

Can be shown in scheme 1 intermediate (the R wherein of preparation formula (XXVIII) ³Definition so, X ¹Be iodo, pyrroles NH protects with tosyl group).

Scheme 1

Like this, for example, preparation formula (XXXIV) compound through the following steps:

(i) under the room temperature, in inert solvent (as toluene), in the presence of sodium hydroxide and tetrabutyl ammonium sulfate solution, make the reaction of formula (XXXII) compound and tosylation chlorine;

(ii) then approximately under-78 ℃, in tetrahydrofuran (THF), handle formula (XXXIII) compound that produces with butyllithium;

Make the anionic reactive of iodine and generation.

By making formula (XXXIII) compound (R wherein ³Be halogen, for example chlorine) and formula R ³BEt ₂Borine (R wherein ³Be heteroaryl) reaction, preparation formula (XXXIII) intermediate (R wherein ³Be heteroaryl).Can be under the reflux temperature, in the presence of tetrakis triphenylphosphine palladium (0) and salt of wormwood, in tetrahydrofuran (THF) also, carry out this reaction easily in top temperature.This reaction is particularly suitable for preparation formula (XXXIII) (R wherein ³Be pyridyl) compound.

Can be under the reflux temperature, in the presence of tetrakis triphenylphosphine palladium (0) and sodium bicarbonate aqueous solution, in dimethyl formamide also, make formula (XXXIII) compound (R wherein in top temperature ³Be halogen, for example chlorine) and formula R ³B (OH) ₂The heteroaryl acid reaction, preparation formula (XXXIII) intermediate (R wherein ³Be heteroaryl).This reaction is particularly suitable for preparation formula (XXXIII) compound (R wherein ³Be the optional indyl that replaces).

Can be under the highest about 65 ℃ of temperature, make formula (XXXIII) compound (R wherein ³Be halogen, for example chlorine) and formula R ⁴ONa compound (through type R ⁴The alcohol of OH and sodium prepared in reaction) reaction, preparation formula (XXXIII) intermediate (R wherein ³Be OR ⁴, R ⁴Definition so).This reaction is particularly suitable for preparation formula (XXXIII) (R wherein ³Be OMe) compound.

With following illustrative embodiment and reference example the present invention is further illustrated, but scope of the present invention is not subjected to any restriction of these embodiment and reference example.

Determine retention time (R _T) the condition of high pressure liquid chromatography (HPLC)-mass spectrum (LC-MS) as follows:

Method A:Hypersil BDS C-18 post (operated in anti-phase of 4.6mm * 50mm), condition of gradient elution is: the mixture that (A) contains the water of 0.05% trifluoroacetic acid and (B) contain the acetonitrile of 0.05% trifluoroacetic acid carries out gradient elution as moving phase: 0.00 minute 100%A:0%B; Linear gradient is to 100%B in the time of 2 minutes; Keep then up to 3.5 minutes; Flow velocity 1mL/min, about 0.25ml/min shunting enters mass spectrograph; Volume injected 10 μ L; Hewlett Packard Model HP1100 series UV detector, wavelength 200nm; 46 ℃ of evaporat light scattering (ELS) detection-temperature, nitrogen pressure 4 crust.

Method B: (4.6mm * 50mm) Gilson 215 injector types are operated, and condition of gradient elution is: (A) contain the water of 0.05% trifluoroacetic acid and carry out gradient elution with the mixture that (B) contains the acetonitrile of 0.05% trifluoroacetic acid as moving phase: 0.00 minute 95%A:5%B with HyPURITY C-18-5 μ post; Linear gradient is to 95%B in the time of 4 minutes; 4.5 minute time to 5%, keep then then up to 6 minutes; Volume injected 5 μ L; Flow velocity 1mL/min enters UV (DAD) detector, and about 0.100ml/min shunting enters mass spectrograph (positivity electron spray(ES)), the remaining ELS detector that enters.

Method C: the Micromass LCT type that is connected with HP 1100 types.With HP G1315A type photodiode array detector in 200-600nm wavelength region and Sedex 65 type light scattering detector detection compound abundance.In 180 to 800 scopes, obtain mass spectrum.Adopt MicromassMassLynx software analysis data.At Hypersil BDS C18,3 μ m particle posts (separate on 50 * 4.6mm), with the aqueous solution linear gradient elution that contains 0.05% (v/v) trifluoroacetic acid of 5 to 90% acetonitriles that contain 0.05% (v/v) trifluoroacetic acid 3.5 minutes, flow velocity was 1ml/min.Total run time (time that comprises the post reequilibrate) is 7 minutes.

Embodiment 1

2-[5-methoxyl group-3-(4-trifluoromethyl-7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-indoles-1-base-morpholine-4-base-ethyl ketone

By following formula (II)

Formula (I) compound of representative (R wherein ¹For

R ²For-OMe, R ³For-CF ₃, group

Be connected in 3 of indole ring, radicals R ²Be connected to 5 of indole ring) according to following scheme preparation:

(i) about 0 ℃, in methylene dichloride, handle 7-H-pyrrolo-[2,3-b] pyrimidines (1) with 3-chlorine peroxybenzoic acid, obtain 7H-pyrrolo-[2,3-b] pyrimidine-N-oxide compound (2);

(ii), make phosphorus oxybromide and (2) reaction, obtain 4-bromo-7H-pyrrolo-[2,3-b] pyrimidines (3) at about 50 ℃;

(iii) in the presence of tetrabutyl ammonium sulfate and aqueous sodium hydroxide solution, in toluene, make the reaction of (3) and 4-tolylsulfonyl-chlorine, obtain 4-bromo-7H-pyrrolo-[2,3-b] pyrimidines (4);

(iv) in the presence of Potassium monofluoride and cupric iodide (I), in dimethyl formamide, under about 60 ℃, make the reaction of (4) and trifluoromethyl trimethyl silane, obtain 7-(toluene-4-alkylsulfonyl)-4-trifluoromethyl-7H-pyrrolo-[2,3-b] pyrimidines (5);

(v)-78 ℃ approximately, in tetrahydrofuran (THF), handle (5) with the di-isopropyl lithamide, make gained negatively charged ion and Iod R then, obtain 6-iodo-7-(toluene-4-alkylsulfonyl)-4-trifluoromethyl-7H-pyrrolo-[2,3-b] pyrimidines (6).

(vi) under about reflux temperature, in the dimethyl formamide aqueous solution, in the presence of tetrakis triphenylphosphine palladium (0) and sodium bicarbonate, make (6) and uncle 1--butoxy carbonyl-5-methoxyl group-1H-indoles-3-boric acid coupling, after removing uncle-butoxy carbonyl blocking group, in the presence of sodium hydride, in tetrahydrofuran (THF), handle with methyl iodide, obtain 6-(5-methoxyl group-1H-indol-3-yl)-7-(toluene-4-alkylsulfonyl)-4-trifluoromethyl-7H-pyrrolo-[2,3-b] pyrimidines (7);

(vii) in methyl alcohol, remove tosyl group blocking group in (7), obtain 6-(5-methoxyl group-1H-indol-3-yl)-4-trifluoromethyl-7H-pyrrolo-[2,3-b] pyrimidines (8) with potassium hydroxide treatment; With

(viii) in the presence of sodium hydride, in dimethyl formamide; make (8) alkylation with 4-(2-chloracetyl) morpholine; obtain 2-[5-methoxyl group-3-(4-trifluoromethyl-7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-indoles-1-yl]-1-morpholine-4-base-ethyl ketone (II).

Embodiment 2

1-methyl-3-(7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-1H-indole-5-carboxylic acid (2-hydroxyl-1,1-dimethyl-ethyl)-acid amides

By formula (III):

Formula (I) compound of expression (R wherein ¹For-CH ₃, R ²For

R ³For-H, group

Be connected to 3 of indole ring, radicals R ²Be connected to 5 of indole ring) according to following scheme preparation:

(i) in the presence of tetrabutyl ammonium sulfate and aqueous sodium hydroxide solution, in toluene, make the reaction of (9) and 4-toluene sulfonyl chloride, obtain (10);

(ii) approximately under-78 ℃, in tetrahydrofuran (THF), handle (10) with the di-isopropyl lithamide, make gained negatively charged ion and Iod R then, obtain (11);

(iii) under about reflux temperature, in the dimethyl formamide aqueous solution, in the presence of tetrakis triphenylphosphine palladium (0) and sodium bicarbonate, make (11) and uncle 1--butoxy carbonyl-5-methoxyl group-1H-indoles-3-boric acid (12) coupling, after removing uncle-butoxy carbonyl blocking group, in the presence of sodium hydride, in tetrahydrofuran (THF), handle with methyl iodide, obtain 6-[(1-methyl-5-methoxycarbonyl indoles)-the 3-yl]-7H-pyrrolo-[2,3-b] pyrimidines (13);

(iv), handle (13), obtain 6-[(1-methyl-5-methoxyl group indoles with aqueous methanol hydrogen manufacturing potassium oxide in refluxing down)-the 3-yl]-7H-pyrrolo-[2,3-b] pyrimidines (14); With

(v) at O-(7-azepine benzo triazol-1-yl)-1,1,3, under 3-tetramethyl-urea hexafluorophosphate and diisopropylethylamine exist, in dimethyl formamide, make (14) and 2-hydroxyl-1, the coupling of 1-dimethyl amine obtains 1-methyl-3-(7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-1H-indole-5-carboxylic acid (2-hydroxyl-1,1-dimethyl-ethyl)-acid amides (III).

Embodiment 3

2-{[5-methoxyl group-3-(7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-indoles-1-yl]-morpholine-4-yl }-ethyl ketone

By formula (IV):

Formula (I) compound of expression (R wherein ¹For

, R ²For-OMe, R ³For-H, group

(i) under about reflux temperature, in the dimethyl formamide aqueous solution, in the presence of tetrakis triphenylphosphine palladium (0) and sodium bicarbonate, make 6-iodo-7-(toluene-4-alkylsulfonyl)-7H-pyrrolo-[2,3-b] pyrimidine (11) and uncle 1--butoxy carbonyl-5-methoxyl group indoles-3-boric acid (15) coupling, remove uncle-butoxy carbonyl blocking group, obtain 6-[(5-methoxyl group indoles)-the 3-yl]-7-(toluene-4-alkylsulfonyl)-7H-pyrrolo-[2,3-b] pyrimidines (16);

(ii) under refluxing, handle (16), obtain 6-[(5-methoxyl group indoles with aqueous methanol hydrogen manufacturing potassium oxide)-the 3-yl]-7H-pyrrolo-[2,3-b] pyrimidines (17); With

(iii) in dimethyl formamide, make (17) and sodium hydride reaction, with the reaction of 2-bromoacetic acid morpholine acid amides, obtain 2-{[5-methoxyl group-3-(7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-indoles-1-yl then]-1-morpholine-4-yl }-ethyl ketone (IV).

Embodiment 4

By formula (VII):

Formula (I) compound of expression (R wherein ¹For-CH ₂CF ₃, R ²For-OMe, R ³For-CN, group

(i) in the presence of salt of wormwood and sodium iodide, make (18) and (19) reaction, obtain (20);

(ii) in the presence of sodium ethylate, in ethanol, make (20) and thiocarbamide the reaction, obtain (21);

(iii) under refluxing approximately, in toluene, heating makes (21) cyclisation, obtains (22);

(iv) make the reaction of (22) and phosphorus oxybromide, obtain 4-bromo-7H-pyrrolo-[2,3-b] pyrimidines (23);

(v) in the presence of tetrabutyl ammonium sulfate and aqueous sodium hydroxide solution, in toluene, make (23) and 4-toluene sulfonyl chloride the reaction, obtain (24);

(vi)-78 ℃ approximately, in tetrahydrofuran (THF), handle (24) with the di-isopropyl lithamide, make gained negatively charged ion and Iod R then, obtain (25);

(vii) under about reflux temperature, in the dimethyl formamide aqueous solution, in the presence of tetrakis triphenylphosphine palladium (0) and sodium bicarbonate, make (25) and uncle 1--butoxy carbonyl-5-methoxyl group indoles-3-boric acid (15) coupling, remove uncle-butoxy carbonyl blocking group, obtain 4-bromo-6-[(5-methoxyl group indoles)-the 3-yl]-7-(toluene-4-alkylsulfonyl)-7H-pyrrolo-[2,3-b] pyrimidines (26);

(viii) in tetrahydrofuran (THF), make the reaction of (26) and sodium hydride, with the reaction of 2-three fluoro-iodic ethers, obtain (27) then;

(ix) in the presence of palladium, at N ', in the accelerine, under about 140 ℃, make the reaction of (27) and zinc cyanide, obtain (28); With

(x) under refluxing, handle (28) with aqueous methanol hydrogen manufacturing potassium oxide, obtain (VII).

Embodiment 5

By formula (IX):

Formula (I) compound of expression (R wherein ¹For-CH ₃, R ²For-OMe, R ³For

Group

(i) in tetrahydrofuran (THF), make the reaction of (26) and sodium hydride, with the methyl iodide reaction, obtain (29) then;

(ii), make (29) and reaction of carbon monoxide, obtain (30) in the presence of the palladium, in methyl alcohol, under refluxing;

(iii), handle (30), obtain (31) with aqueous methanol hydrogen manufacturing sodium oxide in refluxing down; With

(iv) at O-(7-azepine benzo triazol-1-yl)-1,1,3, under 3-tetramethyl-urea hexafluorophosphate and di-isopropyl ethanamide exist, in dimethyl formamide, make (31) and 2-hydroxyl-1, the coupling of 1-dimethyl amine obtains (IX).

Embodiment 6

By formula V:

Formula (I) compound of expression (R wherein ¹For

, R ²For-OMe, R ³For

Group

(i) in the presence of acid chloride, triphenylphosphine and the triethylamine, under about 110 ℃, make the reaction of (26) and methyl acrylate, obtain (32);

(ii) in the presence of palladium carbon, hydrogenation (32) obtains (33);

(iii), handle (33), obtain acid (34) with aqueous methanol hydrogen manufacturing potassium oxide in refluxing down;

(iv), under 3-tetramethyl-urea hexafluorophosphate and diisopropylethylamine exist, in dimethyl formamide, make (34) and methylamine coupling, obtain (35) at O-(7-azepine benzo triazol-1-yl)-1,1,3; With

(v) in the presence of sodium hydride, in dimethyl formamide, make (35) alkylation with 4-(2-chloracetyl) morpholine, obtain (V).

Embodiment 7

By formula (VI):

Formula (I) compound of expression (R wherein ¹For

, R ²For-OMe, R ³For

, group

(i) under about reflux temperature, in the presence of tetrakis triphenylphosphine palladium (0) and sodium bicarbonate aqueous solution, in the dimethyl formamide aqueous solution, make (26) and pyridine-3-boric acid coupling, obtain 4-(pyridin-3-yl)-6-[(5-methoxyl group indoles)-the 3-yl]-7-(toluene-4-alkylsulfonyl)-7H-pyrrolo-[2,3-b] pyrimidines (36);

(ii), handle (36), obtain (37, embodiment 9) with aqueous methanol hydrogen manufacturing sodium oxide in refluxing down; With

(iii) in the presence of sodium hydride, in dimethyl formamide; make (37 with 4-(2-chloracetyl) morpholine; embodiment 9) alkylation, obtain 2-[5-methoxyl group-3-(4-(pyridin-3-yl)-7H-pyrrolo-[2,3-b] pyrimidine-6-yl)-indoles-1-yl]-1-morpholine-4-base-ethyl ketone (VI).

Embodiment 8

By formula (VIII):

Formula (I) compound of expression (R wherein ¹For-CH ₂CH ₃, R ²For-OMe, R ³For

, group

(i) in the presence of sodium hydride, in dimethyl formamide, make (26) alkylation with iodoethane, obtain (38);

(ii) in microwave oven, under about 200 ℃, in α, α, in α-phenylfluoroform, make (38) and morpholine the reaction, obtain (39); With

(iii), handle (39), obtain (VIII) with aqueous methanol hydrogen manufacturing potassium oxide in refluxing down.

Embodiment 9

6-(5-methoxyl group-1H-indol-3-yl)-4-pyridin-3-yl-7H-pyrrolo-[2,3-d] pyrimidine

Handle the 6-iodo-7-[(4-aminomethyl phenyl that is dissolved in dimethyl formamide (10mL) with tetrakis triphenylphosphine palladium (13mg) and sodium bicarbonate (8mg)) alkylsulfonyl]-4-pyridin-3-yl-7H-pyrrolo-[2; 3-d] pyrimidine [260mg; reference example 1] and 1-tert-butyl-carboxyl-5-methoxyl group-1H-indoles-3-boric acid [178mg, reference example 12] solution.In refluxing down, stirred reaction mixture 2 hours is cooled to room temperature.Reduction vaporization solution, residue distributes between water and ethyl acetate.Organic phase separated and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (95: 5, v/v) wash-out obtained 6-(5-methoxyl group-1H-indol-3-yl)-4-pyridin-3-yl-7H-pyrrolo-[2,3-d] pyrimidine of amorphous solid with ethyl acetate and methanol mixture.MS:342[MH] ⁺, LCMS (method A) R _T=2.57 minutes.

Embodiment 10

4-methoxyl group-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine

Be dissolved in 4-methoxyl group-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7-[(4-aminomethyl phenyl in the methyl alcohol (20mL)) alkylsulfonyl]-solution of 7H-pyrrolo-[2,3-d] pyrimidine [361mg, reference example 4] handles with potassium hydroxide (1.53g).At room temperature stirred reaction mixture is 16 hours, and refluxes 1 hour.Reduction vaporization solution, residue distributes between water and ethyl acetate.Separate organic phase, through dried over mgso and reduction vaporization.Grind residue with ether, obtain solid-state 4-methoxyl group-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7H-pyrrolo-[2,3-d] pyrimidines (155mg), fusing point=184 ℃.MS：309[MH] ⁺。

Embodiment 11

4-methoxyl group-6-(5-methoxyl group-1H-indol-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine

Be dissolved in 4-methoxyl group-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7-[(4-aminomethyl phenyl in the methyl alcohol (15mL)) alkylsulfonyl]-solution of 7H-pyrrolo-[2,3-d] pyrimidine [448mg, reference example 5] handles with potassium hydroxide (1.96g).At room temperature stirred reaction mixture 2 hours and reduction vaporization solution, residue distributes between water and ethyl acetate.Separate organic phase, through dried over mgso and reduction vaporization.Residue is dodged column chromatography on silica gel, with the mixture of ethyl acetate and hexanaphthene (80: 20, v/v) wash-out obtains yellow solid-state 4-methoxyl group-6-(5-methoxyl group-1H-indol-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine (320mg), fusing point＞260 ℃.MS：295[MH] ⁺。

Embodiment 12

4-(5-methoxyl group-1H-indol-3-yl)-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7H-pyrrolo-[2,3-d] pyrimidine

Be dissolved in 4-(5-methoxyl group-1-[(4-aminomethyl phenyl) alkylsulfonyl in the methyl alcohol (5mL)]-the 1H-indol-3-yl)-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] solution of pyrimidine [93mg, reference example 9] handles with potassium hydroxide (249mg).Stirring at room reaction mixture 16 hours.Reduction vaporization solution, residue distributes between ethyl acetate and water.Separate organic phase, then through dried over mgso, reduction vaporization then.With HPLC purifying residue, obtain gluey 4-(5-methoxyl group-1H-indol-3-yl)-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7H-pyrrolo-[2,3-d] pyrimidines (9mg).MS：424[MH] ⁺。LCMS (method B) R _T=3.15 minutes.

Reference example 1

6-iodo-7-[(4-aminomethyl phenyl) alkylsulfonyl]-4-pyridin-3-yl-7H-pyrrolo-[2,3-d] pyrimidine

-78 ℃, in inert environments; 7-[(4-aminomethyl phenyl in being dissolved in tetrahydrofuran (THF) (20mL)) alkylsulfonyl]-4-pyridin-3-yl-7H-pyrrolo-[2; 3-d] pyrimidine [1g, reference example 2] dropwise add the butyl lithium solution that is dissolved in hexane (2mL, 1.6M).Under this temperature, stirred 1.5 hours, add iodine (796mg) then.-78 ℃ of following restir reaction mixtures 1 hour, make it reach room temperature.Reaction mixture distributes between ethyl acetate and sodium sulfite aqueous solution.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (50: 50-100, v/v) gradient elution obtains the title compound (260mg) of amorphous solid with the mixture of ethyl acetate and hexanaphthene.MS：477[MH] ⁺。LCMS (method B) R _T=3.26 minutes.

Reference example 2

The 7-[(4-aminomethyl phenyl) alkylsulfonyl]-4-pyridin-3-yl-7H-pyrrolo-[2,3-d] pyrimidine

To be dissolved in the 4-chloro-7-[(4-aminomethyl phenyl in the tetrahydrofuran (THF) (180mL)) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] pyrimidine [4g, reference example 3] and diethyl-3-pyridyl-borine (2.1g) solution tetrakis triphenylphosphine palladium (0.65g) and salt of wormwood (3.59g) processing.In stirred solution 24 hours and the reduction vaporization down of refluxing.Residue distributes between ethyl acetate and salt solution.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is carried out dodging for twice column chromatography on silica gel, (90: 10, v/v) (50: 50, v/v) wash-out obtained the title compound (2.5g) of amorphous solid with the mixture of ethyl acetate and hexanaphthene with ethyl acetate and methanol mixture.MS：351[MH] ⁺。LCMS (method B) R _T=3.05 minutes.

Reference example 3

4-chloro-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

To be dissolved in 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (reference: Gerster, JohnF. in the toluene (1L); Hinshaw, Barbara C.; Robins, Roland K.; Townsend, Leroy B.Study ofelectrophylic substitution in the pyrrolo[2,3-d] pyrimidine ring.J.Heterocycl.Chem. (1969),-(2), 207-213) solution of (20g) and p-toluenesulfonyl chloride (28.6g) is handled with sodium hydroxide (50g) solution in water-soluble (800mL) and tetrabutyl ammonium sulfate (462mg).At room temperature vigorous stirring solution is 2 hours, and solution distributes between ethyl acetate and salt solution.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (50: 50, v/v) gradient elution obtained solid-state title compound (2.5g) to the mixture of usefulness ethyl acetate and hexanaphthene.Fusing point=143 ℃.LCMS (method B) R _T=2.78 minutes.

Reference example 4

4-methoxyl group-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

In inert environments; 4-methoxyl group-6-in being dissolved in dimethyl formamide (20mL) (5-methoxyl group-1H-indol-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] pyrimidine [448mg; reference example 5] solution adding sodium hydride (44mg, 60% is scattered in the oil) and methyl iodide (156mg).Stirred solution 1 hour and solvent evaporated under reduced pressure under the room temperature.Residue distributes between water and ethyl acetate.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (30: 70, v/v) wash-out obtained amorphous solid title compound (260mg) to the mixture of usefulness ethyl acetate and hexanaphthene.MS：464[MH] ⁺。LCMS (method B) R _T=4.39 minutes.

Reference example 5

4-methoxyl group-6-(5-methoxyl group-1H-indol-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

To be dissolved in the 6-iodo-4-methoxyl group-7-[(4-aminomethyl phenyl in the dimethyl formamide (40mL)) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] pyrimidine [1.98g; reference example 6] and 1-tert-butyl-carboxyl-5-methoxyl group-1H-indoles-3-boric acid [1.26g, reference example 12] solution handle successively with saturated sodium bicarbonate aqueous solution (10mL) and tetrakis triphenylphosphine palladium (165mg).Stirred reaction mixture is 3 hours under refluxing, solvent evaporated under reduced pressure, and residue distributes between water and ethyl acetate.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (50: 50, v/v) wash-out obtained the solid-state title compound of grey (1.8g) to the mixture of usefulness ethyl acetate and hexanaphthene.Fusing point=131 ℃.MS：450[MH] ⁺。

Reference example 6

6-iodo-4-methoxyl group-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

In inert environments, under-78 ℃; 4-methoxyl group-7-[(4-aminomethyl phenyl in being dissolved in tetrahydrofuran (THF) (35mL)) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] pyrimidine [2.23g, reference example 7] solution dropwise add the butyl lithium solution that is dissolved in hexane (5mL, 1.6M).-70 ℃ of following stirred solutions 1 hour and add iodine (2.05g).-70 ℃ of following restir reaction mixtures 1 hour, make it rise to room temperature and between ethyl acetate and sodium sulfite aqueous solution, distribute.Separate organic phase and through dried over mgso, reduction vaporization obtains amorphous solid title compound (2.64g) then.MS：430[MH] ⁺。LCMS (method B) R _T=4.15 minutes.

Reference example 7

4-methoxyl group-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

4-methoxyl group-7H-pyrrolo-[2, the 3-d] pyrimidine [1.2g, reference example 8] and the Tosyl chloride (1.77g) that will be dissolved in the toluene (60mL) are handled with sodium hydroxide (3.2g) solution and the tetrabutyl ammonium sulfate (27mg) of water-soluble (30mL).Vigorous stirring solution is 4 hours under the room temperature, and solution distributes between ethyl acetate and salt solution.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (50: 50 to 80: 20, v/v) wash-out obtained amorphous solid title compound (2.23g) to the mixture gradient of usefulness ethyl acetate and hexanaphthene.MS：304[MH] ⁺。LCMS (method B) R _T=3.88 minutes.

Reference example 8

4-methoxyl group-7H-pyrrolo-[2,3-d] pyrimidine

In inert environments, in methyl alcohol (100mL),, in this solution, add 4-chloro-7H-pyrrolo-[2,3-d] pyrimidine (reference: Gerster, John F. by part adding sodium (2g) preparation sodium methoxide solution; Hinshaw, Barbara C.; Robins, Roland K.; Townsend, Leroy B.Study of electrophylicsubstitution in the pyrrolo[2,3-d] pyrimidine ring.J.Heterocycl.Chem.(1969)，-(2)，207-13.)(3.5g)。Solution was stirred 16 hours down at 65 ℃, and solution distributes between ethyl acetate and salt solution.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (50: 50, v/v) wash-out obtained amorphous solid title compound (1.2g) to the mixture of usefulness ethyl acetate and hexanaphthene.MS：150[MH] ⁺。LCMS (method B) R _T=2.39 minutes.

Reference example 9

4-(5-methoxyl group-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-indol-3-yl)-6-(5-methoxyl group-1-Methyl-1H-indole-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

In inert environments; to the 4-that is dissolved in dimethyl formamide (10mL) (5-methoxyl group-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-indol-3-yl)-6-(5-methoxyl group-1H-indol-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] pyrimidine [270mg; reference example 10] solution adding sodium hydride (10mg, 60% is scattered in the oil) and methyl iodide (0.025mL).Stirring at room solution 16 hours and solvent evaporated under reduced pressure.Residue distributes between water and ethyl acetate.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (50: 50, v/v) wash-out obtained amorphous solid title compound (93mg) to the mixture of usefulness ethyl acetate and hexanaphthene.MS：732[MH] ⁺。LCMS (method B) R _T=4.68 minutes.

Reference example 10

4-(5-methoxyl group-1-[(4-aminomethyl phenyl) alkylsulfonyl]-the 1H-indol-3-yl)-6-(5-methoxyl group-1H-indol-3-yl)-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

To be dissolved in the 4-chloro-6-iodo-7-[(4-aminomethyl phenyl of dimethyl formamide (36.5mL)) alkylsulfonyl]-7H-pyrrolo-[2; 3-d] pyrimidine [1.72g; reference example 11] and 1-tert-butyl-carboxyl-5-methoxyl group-1H-indoles-3-boric acid [1.26g, reference example 12] solution use saturated sodium bicarbonate aqueous solution (9.1mL) and tetrakis triphenylphosphine palladium (0.3g) to handle successively.Stirred reaction mixture 2 hours and solvent evaporated under reduced pressure down reflux.Residue distributes between ethyl acetate and water.Separate organic phase and through dried over mgso, then reduction vaporization.Residue is dodged column chromatography on silica gel, (30: 70, v/v) wash-out obtained gluey title compound (270mg) to the mixture of usefulness ethyl acetate and hexanaphthene.MS：718[MH] ⁺。LCMS (method B) R _T=4.44 minutes.

Reference example 11

4-chloro-6-iodo-7-[(4-aminomethyl phenyl) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine

In inert environments, under-78 ℃, to the 4-chloro-7-[(4-aminomethyl phenyl that is dissolved in tetrahydrofuran (THF) (96mL)) alkylsulfonyl]-7H-pyrrolo-[2,3-d] pyrimidine [5.4g, reference example 3] dropwise add the butyllithium that is dissolved in the hexane (12.1mL, 1.6M).-78 ℃ of following stirred solutions 3 hours also add iodine (8.9g).-78 ℃ of following stirred reaction mixtures 2 hours make it reach room temperature.Reaction mixture distributes in ethyl acetate and sodium sulfite aqueous solution, with reaction mixture through dried over mgso and reduction vaporization.Residue is dodged column chromatography on silica gel, (v/v) wash-out obtained amorphous solid title compound (1.52g) to the mixture of usefulness ethyl acetate and hexanaphthene to 100 in 50: 50.MS：434[MH] ⁺。LCMS (method B) R _T=4.26 minutes.

Reference example 12

1-tert-butyl-carboxyl-5-methoxyl group-1H-indoles-3-boric acid

Under nitrogen, to be dissolved in the 3-bromo-5-methoxyl group-indoles-1-t-butyl formate [50g of tetrahydrofuran (THF) (800mL), reference example 13] solution boric acid tributyl ester (49.5mL) processing, be cooled to-100 ℃ then, subsequently be dissolved in hexane just-butyl lithium solution (94mL, 2.5M) handle, maintain the temperature at simultaneously below-90 ℃.In case add and to finish, make mixture return to room temperature gradually with 1 hour, add then and ice (10g) and make its quenching.Organism is removed in decompression, and residue distributes between ethyl acetate (500mL) and water (400mL).Through the dried over mgso organic layer, evaporation obtains creamy solid-state title compound (28g) then.MS：314[M+Na] ⁺。LCMS (method C) R _T=4.07 minutes.

Reference example 13

3-bromo-5-methoxyl group-indoles-1-t-butyl formate

Under room temperature, 5-methoxyl group indoles (10g) solution that will be dissolved in anhydrous dimethyl formamide (150mL) is handled by dropwise adding bromine (4mL), guarantees that temperature does not rise to more than 30 ℃.Use triethylamine (28mL) and 4-dimethylaminopyridine (0.5g) treating mixture at once,, continue to stir 4 hours then with two carbonic acid, two-tert-butyl ester (18g) solution-treated that is dissolved in anhydrous dimethyl formamide (80mL).Evaporation reaction mixture, residue distribute between ethyl acetate (250mL) and water (200mL).With ethyl acetate (100mL) aqueous layer extracted.Water (100mL), use salt solution (100mL) washing blended organic phase then, with after dried over mgso, then evaporation.Residue is dodged column chromatography on silica gel, (19/1, v/v) wash-out obtains colourless solid-state title compound (23.4g) to the mixture of usefulness pentane and ethyl acetate, fusing point 111-112 ℃.

In vitro tests method to Syk

1. compound is to the kinase whose restraining effect of Syk

Differentiate (time-resolved) fluorometry with the time and measure compound the kinase whose restraining effect of Syk.

The kinase whose catalytic domain of Syk (A340-N635 residue) with fusion protein form expression, is purified to homogeneous in yeast cell.Containing 50mM NaCl, 5mM MgCl ₂, 5mM MnCl ₂, the synthetic peptide vitamin H of 1 μ M Triphosaden and 10 μ M-(Beta-alanine) 3-DEEDYEIPP-NH ₂50mM Tris-HCl damping fluid (pH 7.0) in measure the kinases vigor.Add and to contain 0.4M KF, 133mM EDTA, pH7.0, the damping fluid that contains streptavidin-XL665 conjugate and be attached to the mono-clonal phosphorus specific antibody of europium kryptofix 222 (Eu-K) stop enzyme reaction.The feature of two kinds of fluorophore XL-665 and Eu-K is at G.Mathis etc., Anticancer Research, and 1997,17, the 3011-3014 page or leaf provides.The special long-time signal of XL-665 (have only when synthetic peptide just produce during by the Syk phosphorylation) is read to measure on the plate instrument at LJL Biosystems Analyst AD microdetermination plate.The compounds of this invention is represented with the inhibition percentage ratio of contrast vigor under the situation that does not add test compounds the inhibition of Syk vigor.The concrete preferred compound of the present invention suppresses the IC of Syk vigor ₅₀In 100mM arrives the scope of 100nM.The particularly preferred compound of the present invention suppresses the IC of Syk vigor ₅₀In 1mM arrives the scope of 100nM.

2. the threshing of the antigen induction of rat basophilic leukemia (RBL) cell

2.1 the mark of cell cultures, RBL-2H3 cell and analysis

The RBL-2H3 cell is kept at 37 ℃, 5%CO ₂The T75 flask in, and went down to posterity once in every 3-4 days.For harvested cell, wash flask once with 5ml trypsinase-EDTA, add 5ml trypsinase then in every flask and incubated at room 2 minutes.With the 14ml nutrient solution with cell transfer in test tube, with 1100rpm RT rotation 5 minutes, with 2 * 10 ⁵/ ml suspends again.In every 10ml cell, add the special IgE of 1 μ l DNP-and make cell sensitization.In every hole of flat 96 orifice plates, add 200 μ l cells (40,000 cells/well), with flat board at 37 ℃ and 5%CO ₂Following overnight incubation.Second day, the 100%DMSO solution of preparation 10mM compound.With analysis buffer every kind of compound was diluted with 1: 100, in the 1%DMSO analysis buffer, further dilute then so that final concentration is 0.03-30 μ M.In every hole, add 80 μ l analysis buffer, add the compound of 10 μ l dilution then.Then hatched 5 minutes.In every hole, add 10 μ l DNP-HAS (100ng/ml) and at 37 ℃ of (no CO ₂) hatched 30 minutes.As a contrast, in one group of hole, only add 1%DMSO (no compound) to measure total release.As another contrast, in another group hole, add DNP-HAS damping fluid determination and analysis background.After hatching 30 minutes, supernatant liquor is transferred in the 96 new orifice plates.In each hole of analysis plates, add 50 μ l supernatant liquors.In every hole, add 100 μ l substrate solutions and hatched 90 minutes at 37 ℃.Add 50 μ l 0.4M glycine solution stopped reactions, flat board is read to measure in 405nm on the plate instrument at Molecular Devices SpectraMax 250 flat boards.

2.2 the result calculates

(i) calculate mean value ± SD of three parts every group.

(ii) maximum replying is to contain antigen (100ng/ml) but the positive control hole of not having compound.

(iii) minimum replying is to contain damping fluid (no antigen) but the control wells of not having compound.

(iv) utilize these values as maximum value (100%) and minimum value (0%) respectively, the experiment with computing data obtain producing the percentage (being called contrast %) that maximum is replied.

(v) draw the IC that dose response curve is also used Prism GraphPad software and nonlinear least square regression analysis computerized compound ₅₀

The EC of the threshing of the antigen induction of The compounds of this invention inhibition rat basophilic leukemia (RBL) cell ₅₀For 100mM arrives 1mM.

Claims

1. the compound of following formula or its ester prodrugs, pharmacy acceptable salt or solvate; The ester prodrugs of perhaps this salt or solvate:

R wherein ¹Represent hydrogen ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-SO ₂-NY ¹Y ²,-SO ₂-R ⁷,-C (=O) R ⁷, perhaps R ¹Represent alkenyl, alkenyloxy, alkyl, alkynyl, aryl, heteroaryl, Heterocyclylalkyl, cycloalkyl or cycloalkylalkyl, each randomly by one or more be selected from aryl, cycloalkyl, cyano group, halogen, heteroaryl, Heterocyclylalkyl ,-CHO or its 5-, 6-or 7 yuan of ring acetal derivants ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴,-OR ⁷,-C (=O)-R ⁷, hydroxyl, alkoxyl group and carboxyl group replace;

R ²Represent hydrogen ,-OR ⁴, R wherein ⁴Be alkyl; Perhaps representative-C (=O)-NY ¹Y ²

R ³Represent H, cyano group, halogen, hydroxyl, nitro, R ⁴,-NY ¹Y ²,-ZR ⁴,-C (=O)-O ^R5,-C (=O)-R ⁷,-C (=O)-NY ¹Y ²,-N (R ⁸)-C (=O)-R ⁴,-N (R ⁸)-C (=O)-NY ¹Y ²,-N (R ⁸)-C (=O)-OR ⁵,-SO ₂-NY ³Y ⁴Or-N (R ⁸)-SO ₂-R ⁷, perhaps

R ³Represent aryl, heteroaryl, alkenyl or alkynyl, each randomly is selected from following group and replaces by one or more: aryl, cyano group, halogen, hydroxyl, heteroaryl, Heterocyclylalkyl, nitro ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-C (=O)-OR ⁷,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂NY ³Y ⁴,-SO ₂-NY ¹Y ²Or-ZR ⁴

R ⁴Represent alkyl, cycloalkyl or cycloalkylalkyl, each randomly is selected from following group and replaces by one or more: aryl, cycloalkyl, cyano group, halogen, heteroaryl, Heterocyclylalkyl, hydroxyl ,-CHO or its 5-, 6-or 7 yuan of ring acetal derivants ,-C (=O)-NY ¹Y ²,-C (=O)-OR ⁵,-NY ¹Y ²,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴,-OR ⁷With-C (=O)-R ⁷R wherein ⁴Randomly be selected from O, S (O) _nAnd NR ⁶Group at interval;

R ⁶Represent hydrogen or C ₁-C ₄Alkyl;

R ⁸Represent hydrogen or C ₁-C ₄Alkyl;

Y ¹And Y ²Be hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl or alkyl independently, randomly be selected from following group and replace by one or more: aryl, halogen, heteroaryl, hydroxyl ,-C (=O)-NY ³Y ⁴,-C (=O)-OR ⁵,-NY ³Y ⁴,-N (R ⁶)-C (=O)-R ⁷,-N (R ⁶)-C (=O)-NY ³Y ⁴,-N (R ⁶)-SO ₂-R ⁷,-N (R ⁶)-SO ₂-NY ³Y ⁴With-OR ⁷Perhaps group-NY ¹Y ²Form cyclic amine;

Y ³And Y ⁴Be hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl independently; Perhaps group-NY ³Y ⁴Form cyclic amine;

Z represents O or S (O) _n

N is 0 or integer 1 or 2.

2. according to the compound of claim 1, R wherein ¹Be hydrogen, C _1-4Alkyl, halo C _1-4The C that alkyl, hydroxyl replace _1-4Alkyl ,-N (R ⁶) C (=O)-R ⁷The C that replaces _1-4Alkyl ,-C (=O)-NY ¹Y ²The C that replaces _1-4The cycloalkylalkyl that alkyl or hydroxyl replace.

3. according to the compound of claim 1, R wherein ¹For hydrogen ,-CH ₃, CH ₂CH ₃,-CH ₂CF ₃

Or

4. according to the compound of claim 1, R wherein ¹Be hydrogen.

5. according to each compound in the claim 1 to 4, wherein R ²For-OR ⁴, R wherein ⁴Be alkyl; Perhaps R ²For-C (=O)-NY ¹Y ²

6. according to each compound in the claim 1 to 4, wherein R ²For-OCH ₃Or-CONHC (CH ₃) ₂CH ₂OH.

7. according to each compound in the claim 1 to 4, wherein R ²For-OCH ₃

8. according to each compound in the claim 1 to 7, wherein R ³The alkyl that replaces for hydrogen, cyano group, the optional aryl that replaces, the optional heteroaryl that replaces, alkyl, by one or more halogen atoms, quilt-C (=O)-NY ¹Y ²The alkyl, the quilt-OR that replace ⁷The alkyl that replaces; Perhaps R ³Be ZR ⁴,-C (=O)-OR ⁵,-C (=O)-NY ¹Y ²Or-NY ¹Y ²

9. according to each compound in the claim 1 to 7, wherein R ³For hydrogen, cyano group, pyridyl, fluoroform alkyl ,-CH ₂-CH ₂-C (=O) NHCH ₃,-OCF ₂H ,-C (=O)-NH-C (CH ₃) ₂-CH ₂OH or

10. according to each compound in the claim 1 to 7, wherein R ³For-OCH ₃

11. according to each compound in the claim 1 to 10, wherein R ²Be connected to 5 of indole ring.

12. according to each compound in the claim 1 to 11, wherein group

Be connected to 3 of indole ring.

13. according to the compound of claim 1, described compound is

Or its ester prodrugs, pharmacy acceptable salt or solvate; The ester prodrugs of perhaps this salt or solvate.

14. according to the compound of claim 1, described compound is

15. pharmaceutical composition, this pharmaceutical composition contain medicinal significant quantity according to each compound and one or more pharmaceutically acceptable carrier or vehicle in the claim 1 to 14.

16. suffer from or easily suffer from purposes in patient's that can be by using the symptom that Syk catalysis activity inhibitor improves the medicine according to each compound or being used for the treatment of in preparation of medicinal significant quantity in the claim 1 to 14 according to the composition of claim 15.

17. according in the claim 1 to 14 each compound or medicinal significant quantity be used for the treatment of purposes in the medicine of patient's inflammatory diseases according to the composition of claim 15 in preparation.

18. suffer from or easily suffer from purposes in patient's that can be by using the symptom that FAK catalysis activity inhibitor improves the medicine according to each compound or being used for the treatment of in preparation of medicinal significant quantity in the claim 1 to 14 according to the composition of claim 15.

19. suffer from or easily suffer from purposes in patient's that can be by using the symptom that KDR catalysis activity inhibitor improves the medicine according to each compound or being used for the treatment of in preparation of medicinal significant quantity in the claim 1 to 14 according to the composition of claim 15.

20. suffer from or easily suffer from purposes in patient's that can be by using the symptom that Aurora 2 catalysis activity inhibitor improve the medicine according to each compound or being used for the treatment of in preparation of medicinal significant quantity in the claim 1 to 14 according to the composition of claim 15.

21. according in the claim 1 to 14 each compound or medicinal significant quantity be used for the treatment of purposes in the medicine of patient's cancer according to the composition of claim 15 in preparation.

22. according to the purposes of claim 17, wherein said inflammatory diseases is asthma, inflammatory dermatosis, allergic rhinitis, anaphylaxis conjunctivitis or joint inflammation.

23. according to the purposes of claim 17, wherein said inflammatory diseases is asthma, psoriasis, dermatitis herpetiformis, eczema, necrotizing vasculitis, skin vasculitis, bulla disease, allergic rhinitis, anaphylaxis conjunctivitis, sacroiliitis, rheumatoid arthritis, rubella arthritis, arthritic psoriasis or osteoarthritis.

24. according in the claim 1 to 14 each compound or medicinal significant quantity be used for the treatment of purposes in the medicine of patient's chronic obstructive disease of lung according to the composition of claim 15 in preparation.

25. according to the purposes of claim 21, wherein the cancer of being treated is colorectal cancer, prostate cancer, mammary cancer, thyroid carcinoma, skin carcinoma, the rectum cancer or lung cancer.