CN101163691A

CN101163691A - 1,3-diaryl substituted ureas as modulators of kinase activity

Info

Publication number: CN101163691A
Application number: CNA200680005024XA
Authority: CN
Inventors: 斯科特·A·米切尔; 米哈埃拉·黛安娜·丹卡; 彼得·A·布洛姆格伦; 罗伯特·W·德西蒙; 道格拉斯·A·I·皮平; 大卫·R·布里泰利
Original assignee: CGI Pharmaceuticals Inc
Current assignee: Gilead Colorado Inc
Priority date: 2005-01-14
Filing date: 2006-01-13
Publication date: 2008-04-16

Abstract

Certain chemical entities chosen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, crystal forms, chelates, non-covalent complexes, prodrugs, and mixtures thereof, are provided herein. Pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle chosen from carriers, adjuvants, and excipients, are also provided herein. Use in treating patients suffering from certain diseases and disorders responsive to angiogenic kinase modulation, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck sguamous cell carcinoma. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with at least one chemical entity under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase.

Description

As 1 of modulators of kinase activity, the urea that the 3-diaryl replaces

The application requires the U.S. Provisional Application submitted on January 14th, 2005 number 60/643,886 and the right of priority of the U.S. Provisional Application submitted on November 2nd, 2005 number 60/732,999.Each of these applications all is combined in this by reference.

The invention provides some replacement urea and related compound, comprise these compound compositions and their using method.

Protein kinase, the maximum family of people's zymoid comprises considerably beyond 500 albumen.Kinases is played the part of pivotal player in vasculogenesis.Vasculogenesis from the vasculogenesis neovascularity of previous existence, at many pathology environment, comprises in cancer, chronic inflammation, diabetic retinopathy, psoriatic, rheumatoid arthritis and the macular degeneration and playing an important role.A kind of potential important channel for the treatment of (dysregulated) vascularization diseases associated of solid tumor and other and imbalance is represented in the treatment of angiogenesis inhibitor.

The process of vasculogenesis is complicated, needs the coordinative role of various angiogenesis modulators and the participation of different cell types.Determined that important vessel generates conditioning agent, comprise: VEGF, FGF and angiogenin (angiopoietin) 1 and 2 (Ang1 and Ang2), described EGF, FGF and angiogenin 1 and 2 (Ang1 and Ang2) are bonded on the isoreceptor (VEGFRs, FGFRs and Tie1 and Tie2 respectively) that they express on endotheliocyte; And thrombocyte-deutero-somatomedin (PDGF), described thrombocyte-deutero-somatomedin (PDGF) is bonded to it on the acceptor (PDGFR α) of expressing on the stroma cell that produces VEGF, or it is on the acceptor of expressing on pericyte and the smooth muscle cell (PDGFR β).Nearest studies show that: the several members in ephrin family and their the acceptor Eph family also are the conditioning agents of vasculogenesis.VEGFRs, FGFRs, Tie1 ,] Tie2, PDGFRs and Eph acceptor all belong to receptor protein tyrosine kinase (RTK) superfamily.Because these RTKs are playing the part of important role in vasculogenesis, their regulating effect will be the pharmacology coideal for treatment cancer and other disease aspect.

The invention provides the chemical entity at least a compound that is selected from formula 1:

(formula 1)

And pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and mixture,

Wherein

R represents 0 to 2 substituting group, and described substituting group is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional carbalkoxy that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base (sulfanyl), sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces;

R ₇And R ₈, the carbon with they connect forms with group-(Z ₁) _mR ₁Condensed 5-to the 7-unit heteroaryl ring that replaces, wherein condensed 5-to 7-unit heteroaryl ring is optional is further replaced, and

Wherein

R ₁Be the optional heteroaryl that replaces;

Z ₁For-CR ₅R ₆-, R wherein ₅And R ₆Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl and halogen; And

M is selected from 0,1 and 2;

R ₂Be the optional aryl that replaces; And

R ₃And R ₄Be selected from hydrogen, the optional C that replaces independently of one another ₁-C ₆Alkyl, the optional aryl that replaces and the optional heteroaryl that replaces,

Condition is

The compound of formula 1 is not selected from 5-(phenyl amino formyl radical amino)-3-(2-(4-pyridyl) ethyl) indoles; 1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(1-(pyridin-4-yl)-1H-indoles-5-yl) urea; And 1-(2-methoxyl group-5-(trifluoromethyl) phenyl)-3-(1-(pyridin-4-yl)-1H-indoles-5-yl) urea.

The present invention also provides a kind of pharmaceutical composition, comprises at least a described chemical entity herein, and at least a medicinal vehicle (vehicle) that is selected from carrier, assistant agent and vehicle.The present invention also provides a kind of pharmaceutical composition of packing, and it is included in the pharmaceutical composition described in the present invention in the container; The disease that the kinase activity that uses combination treatment to suffer to reply one or more Tyrosylprotein kinases is regulated or the patient's of illness specification sheets.

The present invention also provides a kind of method of suffering from the patient who replys disease that kinase activity regulates or illness that is used for the treatment of, and this method comprises: to the chemical entity at least a of the present invention or the pharmaceutical composition of the present invention of patient's administering therapeutic significant quantity.

The present invention also provides a kind of method that is used for the treatment of the female patient of suffering from female reproduction disease or illness, comprises chemical entity at least a of the present invention or pharmaceutical composition of the present invention to female patient administering therapeutic significant quantity.

The present invention also provides a kind of adjusting EphB ₄The method of kinase activity, this method comprise making expresses EphB ₄Cell contact with at least a chemical entity of the present invention, the amount of described chemical entity is enough to the external EphB that suppresses with detecting ₄Kinase activity.

The present invention also provides a kind of method of the VEGFR2 of adjusting kinase activity, and this method comprises that the cell that makes VEGF expression R2 contacts with at least a chemical entity of the present invention, and the amount of described chemical entity is enough to the external VEGFR2 kinase activity that suppresses with detecting.

The present invention also provides a kind of adjusting PDGFR beta kinase active method, and this method comprises that the cell that makes PDGF-B expression R β contacts with at least a chemical entity of the present invention, and the amount of described chemical entity is enough to the external PDGFR beta kinase activity that suppresses with detecting.

The present invention also provides a kind of method of the c-Kit of adjusting kinase activity, and this method comprises makes the cell of expressing c-Kit contact with at least a chemical entity of the present invention, and the amount of described chemical entity is enough to the external c-Kit kinase activity that suppresses with detecting.

The present invention also provides at least a VEGFR2 of being selected from of a kind of adjusting, EphB ₄, the kinase whose active method among PDGFR β and the c-Kit, this method comprises making expresses at least a VEGFR2 of being selected from, EphB ₄, the kinase whose cell among PDGFR β and the c-Kit be enough to external the inhibition at least a VEGFR2 of being selected from, EphB with detecting ₄, the kinase whose active amount among PDGFR β and the c-Kit chemical entity at least a of the present invention contact.

The present invention also provides the application of at least a chemical entity in the preparation medicine, and described medicine is used for the treatment of to suffer from replys at least a VEGFR2 of being selected from, EphB ₄, the kinase whose inhibiting disease among PDGFR β and the c-Kit the patient, wherein at least a chemical entity is a chemical entity of the present invention.

The present invention also provides a kind of and is used for making treatment and suffers from and reply at least a VEGFR of being selected from ₂, EphB ₄, the kinase whose inhibiting disease among PDGFR β and the c-Kit patient's the method for medicine, this method comprises: comprise at least a chemical entity of the present invention in described medicine.

As used at this specification sheets, following speech and phrase are intended to have following meaning usually, except the situation of indication is arranged in the context that uses them in addition.Implication shown in following shortenings and term have in the text:

As used at this specification sheets, following speech and phrase are intended to have following meaning usually, except the situation of indication is arranged in the context that uses them in addition.

Formula 1 comprises the minor that they are all.For example formula 1 comprises the compound of formula 1 to 5.

As used herein, when variable any in the chemical formula occurred more than one time, it was independently in the definition of each time appearance and the definition of its all other times.According to the ordinary meaning in " one (a) " and " being somebody's turn to do (the) " patent, for example, indication " a kind of " kinases or " being somebody's turn to do " kinases comprise one or more kinases interior.

Not that dash ("-") between two letters or symbol is used to refer to substituent tie point.For example ,-CONH ₂Connect by carbon atom.

Incident or situation that " optional " or " randomly " expression is described afterwards may take place or may not take place, and represented situation that this explanation comprises that incident wherein or situation take place and incident or situation situation about not taking place wherein.For example, " the optional alkyl that replaces " comprises simultaneously as following defined " alkyl " and " alkyl of replacement ".Those skilled in the art should understand, and comprises one or more substituent groups relevant for any, these groups are not intended to introduce impracticable on any solid, synthetic infeasible and/or inherent unsettled replacement or the substitute mode.

" alkyl " comprises the carbon atom with indicated number, common 1 to 20 carbon atom, for example 1 to 8 carbon atom, for example straight chain and the side chain of 1 to 6 carbon atom.C for example ₁-C ₆Alkyl comprises the straight chain and the branched-chain alkyl of 1 to 6 carbon atom simultaneously.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl, amyl group, 2-amyl group, isopentyl, neo-pentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl amyl etc.Alkylidene group is another subclass of alkyl, is meant identical with alkyl but has the residue of two tie points.Alkylidene group will have from 2 to 20 carbon atoms usually, for example 2 to 8 carbon atoms, for example from 2 to 6 carbon atoms.For example, C ₀Alkylidene group is indicated a covalent linkage, and C ₁Alkylidene group is a methylene radical.When name has the alkyl residue of carbon of given number, be intended to comprise the geometrical combination that all have the carbon of this number; Therefore, for example, " butyl " expression comprises normal-butyl, sec-butyl, isobutyl-and the tertiary butyl; " propyl group " comprises n-propyl and sec.-propyl." low alkyl group " is meant to have an alkyl to four carbon atom.

" thiazolinyl " is meant that deutero-has the unsaturated side chain or the straight chained alkyl of at least one carbon-to-carbon double bond by removing a hydrogen atom from the single carbon atom of female alkene.This group can be in cis or the transconfiguration about two keys.Typical thiazolinyl includes but not limited to vinyl; The propylene base class is third-1-alkene-1-base, third-1-alkene-2-base, third-2-alkene-1-base (allyl group), third-2-alkene-2-base, ring third-1-alkene-1-base for example; Ring third-2-alkene-1-base; The butylene base class is but-1-ene-1-base, but-1-ene-2-base, 2-methyl-third-1-alkene-1-base, but-2-ene-1-base, but-2-ene-1-base, but-2-ene-2-base, fourth-1 for example, 3-diene-1-base, fourth-1,3-diene-2-base, ring but-1-ene-1-base, ring but-1-ene-3-base, ring fourth-1,3-diene-1-base; Deng.In certain embodiments, thiazolinyl has 2 to 20 carbon atoms, and in other embodiments, 2 to 6 carbon atoms.

" alkynyl " is meant that deutero-has the unsaturated side chain or the straight chained alkyl of at least one carbon-to-carbon three key by removing a hydrogen atom from the single carbon atom of female alkynes.Typical alkynyl includes but not limited to ethynyl; The propine base class is third-1-alkynes-1-base, third-2-alkynes-1-base for example; The butine base class is fourth-1-alkynes-1-base, fourth-1-alkynes-3-base, fourth-3-alkynes-1-base for example; Deng.In certain embodiments, alkynyl has from 2 to 20 carbon atoms, and in other embodiments, from 3 to 6 carbon atoms.

" cycloalkyl " indication non-aromatic carbocyclic ring has from 3 to 7 ring carbon atoms usually.This ring can be for saturated or have one or more carbon-to-carbon double bond.The example of cycloalkyl comprises that the saturated cyclic group example of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and bridging and cage type (caged) group is as norbornane.

The alkyl of a kind of indicated carbonatoms that connects by oxo bridge connection of " alkoxyl group " expression, for example methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, sec-butoxy, tert.-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyl oxygen, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methyl pentyloxy etc.Alkoxyl group will have 1 to 6 carbon atom that connects by the Sauerstoffatom bridging usually." lower alkoxy " is meant the alkoxyl group with one to four carbon.

" single-and two-alkyl carboxylic acid amides " comprises the NR of formula-(C=O) _aR _bGroup, R wherein _aAnd R _bBe independently selected from the alkyl of hydrogen and indicated carbonatoms, condition is R _aAnd R _bNot all be hydrogen.

" acyl group " be meant group (alkyl)-C (O)-; (cycloalkyl)-C (O)-; (aryl)-C (O)-; (heteroaryl)-C (O)-; (Heterocyclylalkyl)-C (O)-, wherein this group is connected to parent structure by the carbonyl functional group, and wherein alkyl, cycloalkyl, aryl, heteroaryl and Heterocyclylalkyl be as described herein.Acyl group has indicated carbonatoms, and wherein the carbon of ketone group is included in the indicated carbon atom.C for example ₂Acyl group is for having formula CH ₃(C=O)-acyl group.

The formula (alkoxyl group) that " carbalkoxy " expression connects by carbonyl carbon (C=O)-group, wherein alkoxyl group has indicated carbonatoms.Therefore, C ₁-C ₆Carbalkoxy is for being connected to the alkoxyl group with 1 to 6 carbon atom of carbonyl joint by its oxygen.

" amino " expression-NH ₂Base.

" single-and two-(alkyl) amino " comprises secondary and tertiary alkyl amino, and wherein alkyl is as above-mentioned definition with have indicated carbonatoms.The tie point of alkylamino is on nitrogen.Single-and the example of two-alkylamino comprise ethylamino, dimethylamino and methyl-propyl group-amino.

" amino (alkyl) " expression is connected to the amino of the alkyl with indicated carbon number.Similarly, " hydroxyalkyl " is for being connected to the hydroxyl of alkyl.

Term " aminocarboxyl " is meant group-CONR ^bR ^c, wherein

R ^bBe selected from H, the optional C that replaces ₁-C ₆Alkyl, the optional cycloalkyl that replaces, the optional Heterocyclylalkyl that replaces, the optional aryl that replaces and the optional heteroaryl that replaces; And

R ^cBe independently selected from hydrogen and the optional C that replaces ₁-C ₄Alkyl; Or

R ^bAnd R ^cWith the nitrogen that they connect, form optional 5-to the 7-member heterocyclic ring containing nitrogen alkyl that replaces, described 5-to 7-member heterocyclic ring containing nitrogen alkyl is chosen wantonly in heterocycloalkyl ring and is comprised 1 or 2 extra heteroatoms that is selected from O, N and S;

Wherein the group of each replacement replaces with one or more substituting groups independently, and described substituting group independently is selected from: C ₁-C ₄Alkyl, aryl, heteroaryl, aryl-C ₁-C ₄Alkyl-, heteroaryl-C ₁-C ₄Alkyl-, C ₁-C ₄Haloalkyl-,-OC ₁-C ₄Alkyl ,-OC ₁-C ₄Alkyl phenyl ,-C ₁-C ₄Alkyl-OH ,-OC ₁-C ₄Haloalkyl, halogen ,-OH ,-NH ₂,-C ₁-C ₄Alkyl-NH ₂,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl phenyl) ,-NH (C ₁-C ₄Alkyl phenyl), cyano group, nitro, oxo (as cycloalkyl, Heterocyclylalkyl, the perhaps substituting group of heteroaryl) ,-CO ₂H ,-C (O) OC ₁-C ₄Alkyl ,-CON (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-CONH (C ₁-C ₄Alkyl) ,-CONH ₂,-NHC (O) (C ₁-C ₄Alkyl) ,-NHC (O) (phenyl) ,-N (C ₁-C ₄Alkyl) C (O) (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) C (O) (phenyl) ,-C (O) C ₁-C ₄Alkyl ,-C (O) C ₁-C ₄Alkyl phenyl ,-C (O) C ₁-C ₄Haloalkyl ,-OC (O) C ₁-C ₄Alkyl ,-SO ₂(C ₁-C ₄Alkyl) ,-SO ₂(phenyl) ,-SO ₂(C ₁-C ₄Haloalkyl) ,-SO ₂NH ₂,-SO ₂NH (C ₁-C ₄Alkyl) ,-SO ₂NH (phenyl) ,-NHSO ₂(C ₁-C ₄Alkyl) ,-NHSO ₂(phenyl) and-NHSO ₂(C ₁-C ₄Haloalkyl).

" aryl " comprises:

6-unit aromatic ring carbon ring, for example, benzene;

Bicyclic system, wherein at least one ring is carbocyclic ring and aromatic series, for example, naphthalene, indane and tetraline; And

Three-ring system, wherein at least one ring is carbocyclic ring and aromatic series, for example, fluorenes.

Aryl comprises being fused to and comprises 1 or the 6-unit aromatic ring carbon ring of heteroatomic 5-to the 7-unit heterocycloalkyl ring of a plurality of N of being selected from, O and S.For example, aryl comprises usefulness-O (C ₁-C ₂Alkyl) phenyl of O-replacement (for example, the phenyl that replaces with methylene-dioxy or ethylenedioxy).For this condensed-bicyclic system, wherein these rings have only one to be the aromatic ring carbon ring, and tie point can be in aromatic ring carbon ring or heterocycloalkyl ring.From benzene derivative deutero-that replaces and the phenylene that has the divalent group called after replacement of free valency at annular atoms.The divalent radical of unit price multi-ring alkyl that ends at " yl " by remove a hydrogen atom from the carbon atom with free valency derived from its name is by naming the name that will " inferior (idene) " adds to corresponding unit price base, for example, the naphthyl with two tie points is called naphthylidene.Yet aryl does not comprise or contains heteroaryl by any way, and it is defined in down dividually.Therefore, defined as the present invention, if one or more aromatic ring carbon ring and Heterocyclylalkyl aromatic ring condense, the ring system that is produced is heteroaryl rather than aryl.

Term " aryloxy " is meant-the O-aryl.

That term " halogen " comprises is fluorine-based, chloro, bromo and iodo, and term " halogen " comprises fluorine, chlorine, bromine and iodine.

" haloalkyl " is meant that it has the carbon atom of defined amount as above-mentioned defined alkyl, and with 1 or a plurality of halogen atom, usually as many as can allow the halogen atom of number to replace.The example of haloalkyl includes but not limited to trifluoromethyl, difluoromethyl, 2-fluoro ethyl and pentafluoroethyl group.

" heteroaryl " comprises:

5-to 7-unit aromatic series monocycle, it comprises one or more for example 1 to 4, or in certain embodiments, 1 to 3 heteroatoms that is selected from N, O and S, and all the other annular atomses are carbon; And

Bicyclic heterocycle alkyl ring, it comprises one or more, and for example 1 to 4, or in certain embodiments, 1 to 3 heteroatoms that is selected from N, O and S, and all the other annular atomses are carbon, and wherein at least one heteroatoms is present in the aromatic ring.

Heteroaryl comprises 5-to 7-unit Heterocyclylalkyl, is fused to the aromatic ring or the heterocycloalkyl ring of 5-to 7-unit cycloalkyl.For example, heteroaryl comprises usefulness-O (C ₁-C ₂Alkyl) pyridyl of O-replacement (for example, the pyridyl that replaces with methylene-dioxy or ethylenedioxy).For this condensed-bicyclic heteroaryl ring system, tie point can be on arbitrary ring.When the sum of S in the heteroaryl and O atom surpassed 1, these heteroatomss were not adjacent to each other.In certain embodiments, total no more than 2 of S in the heteroaryl and O atom.In certain embodiments, total no more than 1 of S in the heteroaromatic and O atom.The example of heteroaryl includes but not limited to, (when preferentially being appointed as 1 link position numbering), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidyl, 3,5-pyrimidyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazoline-3-yl, oxazolinyl, thiazolinyl, Thiadiazoline base, tetrazyl, thienyl, benzothienyl, furyl, benzofuryl, benzimidazoline base, indoline base, pyridazinyl, triazolyl, quinolyl, pyrazolyl and 5,6,7, the 8-tetrahydroisoquinoline.The divalent radical of unit price heteroaryl that ends at " yl " by removing a hydrogen atom from the carbon atom with free valency derived from its name is by adding to " Asia " to naming the unit price base name, for example, the pyridyl with two tie points is called pyridylidene.Defined as the present invention, heteroaryl does not comprise or encompass aryl, cycloalkyl or Heterocyclylalkyl.

The heteroaryl that replaces also comprises through one or more oxide compound (O ^-) member ring systems that replaces of substituting group, for example pyridyl N-oxide compound.

In term " heteroarylalkyl ", heteroaryl and alkyl such as the present invention define, and tie point is on alkyl.This term is including but not limited to pyridylmethyl, thienyl methyl and (pyrryl) 1-ethyl.

The single non-aromatic ring of " Heterocyclylalkyl " expression has 3 to 7 annular atomses usually, except 1-3 is independently selected from oxygen, sulphur and nitrogen heteroatomic, also comprises at least 2 carbon atoms, and comprises at least one aforementioned heteroatomic combination.This ring can be saturated or have one or more carbon-to-carbon double bond.The Heterocyclylalkyl that is fit to comprises, for example (when preferentially being appointed as 1 link position numbering), 2-pyrrolinyl, 2,4-imidazolidyl, 2,3-pyrazolidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl and 2,5-piperazinyl.Also consider morpholinyl, comprise 2-morpholinyl and morpholinyl (wherein oxygen preferentially is appointed as 1 numbering).The Heterocyclylalkyl that replaces also comprise with one or more oxo (=O) or oxide compound (O ^-) member ring systems that replaces of substituting group, for example piperidyl N-oxide compound, morpholinyl-N-oxide compound, 1-oxo-1-parathiazan base and 1,1-dioxo-1-parathiazan base.

" Heterocyclylalkyl " also comprises bicyclic system, one of them non-aromatic ring has 3 to 7 annular atomses usually, except 1-3 is independently selected from oxygen, sulphur and nitrogen heteroatomic, also comprise at least 2 carbon atoms, and comprise at least one aforementioned heteroatomic combination; And other ring has 3 to 7 annular atomses usually, comprises randomly that 1-3 is independently selected from the heteroatoms of oxygen, sulphur and nitrogen and is not aromatic.

As using in the present invention, the kinase activity when " adjusting " is meant with respect to not the existing of compound is directly or indirectly replied the change of kinase activity of the existence of formula 1 compound.Change can be active increase or active minimizing, and can be owing to compound and kinase whose direct interaction, or because the interaction of compound and one or more other factor, described other factor is again to kinase activity generation effect.For example, the existence of compound can be for example by directly being bonded to kinases, by causing that (directly or indirectly) another kind of factor is to increase or to reduce kinase activity, or increase or reduce the kinase whose amount that is present in cell or the organism by (directly or indirectly), and increase or reduce kinase activity.

Term " sulfane base " comprises these groups :-S-(optional (C that replaces ₁-C ₆) alkyl) ,-S-(optional replace aryl) ,-S-(the optional heteroaryl that replaces) and-S-(Heterocyclylalkyl of optional replacement).Therefore, the sulfane base comprises C ₁-C ₆Alkylthio.

Term " sulfinyl " comprises these groups :-S (O)-(optional (C that replaces ₁-C ₆) alkyl) ,-S (O)-optional aryl that replaces) ,-S (O)-optional heteroaryl that replaces) ,-S (O)-(the optional Heterocyclylalkyl that replaces); With-S (O)-(the optional amino that replaces).

Term " alkylsulfonyl " comprises these groups :-S (O ₂Optional (the C that replaces of)-( ₁-C ₆) alkyl) ,-S (O ₂)-optional the aryl that replaces) ,-S (O ₂)-optional the heteroaryl that replaces) ,-S (O ₂The optional Heterocyclylalkyl that replaces of)-() ,-S (O ₂The optional alkoxyl group that replaces of)-() ,-S (O ₂)-optional the aryloxy that replaces) ,-S (O ₂)-optional the heteroaryloxy that replaces) ,-S (O ₂The optional heterocyclic oxy group that replaces of)-(); With-S (O ₂The optional amino that replaces of)-().

Term " replacement " as employed among the present invention, be illustrated in any one or more hydrogen on specified atom or the group and be selected from specified group and replace, and condition is the normal valence mumber that is no more than specified atom.When substituting group be oxo (just ,=O) time, then 2 hydrogen on the atom are substituted.If having only, the combination of substituting group and/or variable when these combination results stable compounds or useful synthetic mesophase product, is only permission.The meaning of stable compound or rock steady structure is that to imply compound enough firm and can be from the separation of reaction mixture and be mixed with subsequently the reagent with actual at least usability under the preservation.Unless otherwise, substituting group is named in core texture.For example, should be appreciated that when (cycloalkyl) alkyl is listed in possible substituting group that this substituting group is connected to the point of core texture at moieties.

Term " replacement " alkyl, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl, unless definition expressly in addition, be meant that respectively wherein one or more (for example maximum 5, for example maximum 3) hydrogen atom is independently selected from the following alkyl that substituting group replaced, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl:

-R ^a,-OR ^b,-SR ^b, guanidine, wherein the guanidine that replaced by rudimentary-alkyl of one or more guanidine hydrogen ,-NR ^bR ^c, halogen, cyano group, nitro, oxo (as the substituting group of cycloalkyl, Heterocyclylalkyl and heteroaryl) ,-COR ^b,-CO ₂R ^b,-CONR ^bR ^c,-OCOR ^b,-OCO ₂R ^a,-OCONR ^bR ^c,-NR ^cCOR ^b,-NR ^cCO ₂R ^a,-NR ^cCONR ^bR ^c,-CO ₂R ^b,-CONR ^bR ^c,-NR ^cCOR ^b,-SOR ^a,-SO ₂R ^a,-SO ₂NR ^bR ^cWith-NR ^cSO ₂R ^a,

R wherein ^aBe selected from the optional C that replaces ₁-C ₆Alkyl, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional aryl that replaces and the optional heteroaryl that replaces;

R ^bAnd R ^c, the nitrogen that is connected with them forms the optional Heterocyclylalkyl that replaces together; And

The wherein optional group that replaces is respectively done for oneself and is replaced or use one or more independently, and for example one, two or three substituting group replaces, and described substituting group is independently selected from: C ₁-C ₄Alkyl, aryl, heteroaryl, aryl-C ₁-C ₄Alkyl-, heteroaryl-C ₁-C ₄Alkyl-, C ₁-C ₄Haloalkyl-,-OC ₁-C ₄Alkyl ,-OC ₁-C ₄Alkyl phenyl ,-C ₁-C ₄Alkyl-OH ,-OC ₁-C ₄Haloalkyl, halogen ,-OH ,-NH ₂,-C ₁-C ₄Alkyl-NH ₂,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl phenyl) ,-NH (C ₁-C ₄Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO ₂H ,-C (O) OC ₁-C ₄Alkyl ,-CON (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-CONH (C ₁-C ₄Alkyl) ,-CONH ₂,-NHC (O) (C ₁-C ₄Alkyl) ,-NHC (O) (phenyl) ,-N (C ₁-C ₄Alkyl) C (O) (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) C (O) (phenyl) ,-C (O) C ₁-C ₄Alkyl ,-C (O) C ₁-C ₄Alkyl phenyl ,-C (O) C ₁-C ₄Haloalkyl ,-OC (O) C ₁-C ₄Alkyl ,-SO ₂(C ₁-C ₄Alkyl) ,-SO ₂(phenyl) ,-SO ₂(C ₁-C ₄Haloalkyl) ,-SO ₂NH ₂,-SO ₂NH (C ₁-C ₄Alkyl) ,-SO ₂NH (phenyl) ,-NHSO ₂(C ₁-C ₄Alkyl) ,-NHSO ₂(phenyl) and-NHSO ₂(C ₁-C ₄Haloalkyl).

Term " acyl group of replacement " is meant group: (alkyl of replacement)-C (O)-; (cycloalkyl of replacement)-C (O)-; (aryl of replacement)-C (O)-; (heteroaryl of replacement)-C (O)-; (Heterocyclylalkyl of replacement)-C (O)-, wherein this group is connected to parent structure by the carbonyl functional group, and wherein the alkyl of Qu Daiing, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl are meant wherein one or more (for example maximum 5 individually, for example, maximum 3) hydrogen atom is independently selected from alkyl, cycloalkyl, aryl, Heterocyclylalkyl and the heteroaryl that following substituting group replaces:

-R ^a,-OR ^b,-SR ^b, guanidine, wherein the guanidine that replaced by rudimentary-alkyl of one or more guanidine hydrogen ,-NR ^bR ^c, halogen, cyano group, nitro ,-COR ^b,-CO ₂R ^b,-CONR ^bR ^c,-OCOR ^b,-OCO ₂R ^a,-OCONR ^bR ^c,-NR ^cCOR ^b,-NR ^cCO ₂R ^a,-NR ^cCONR ^bR ^c,-CO ₂R ^b,-CONR ^bR ^c,-NR ^cCOR ^b,-SOR ^a,-SO ₂R ^a,-SO ₂NR ^bR ^cWith-NR ^cSO ₂R ^a,

The wherein optional group that replaces respectively does for oneself and replaces or use one or more independently, for example one, two or three substituting group replaced, described substituting group is independently selected from C ₁-C ₄Alkyl, aryl, heteroaryl, aryl-C ₁-C ₄Alkyl-, heteroaryl-C ₁-C ₄Alkyl-, C ₁-C ₄Haloalkyl-,-OC ₁-C ₄Alkyl ,-OC ₁-C ₄Alkyl phenyl ,-C ₁-C ₄Alkyl-OH ,-OC ₁-C ₄Haloalkyl, halogen ,-OH ,-NH ₂,-C ₁-C ₄Alkyl-NH ₂,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl phenyl) ,-NH (C ₁-C ₄Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO ₂H ,-C (O) OC ₁-C ₄Alkyl ,-CON (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-CONH (C ₁-C ₄Alkyl) ,-CONH ₂,-NHC (O) (C ₁-C ₄Alkyl) ,-NHC (O) (phenyl) ,-N (C ₁-C ₄Alkyl) C (O) (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) C (O) (phenyl) ,-C (O) C ₁-C ₄Alkyl ,-C (O) C ₁-C ₄Alkyl phenyl ,-C (O) C ₁-C ₄Haloalkyl ,-OC (O) C ₁-C ₄Alkyl ,-SO ₂(C ₁-C ₄Alkyl) ,-SO ₂(phenyl) ,-SO ₂(C ₁-C ₄Haloalkyl) ,-SO ₂NH ₂,-SO ₂NH (C ₁-C ₄Alkyl) ,-SO ₂NH (phenyl) ,-NHSO ₂(C ₁-C ₄Alkyl) ,-NHSO ₂(phenyl) and-NHSO ₂(C ₁-C ₄Haloalkyl).

Term " alkoxyl group of replacement " is meant alkoxyl group, wherein moieties for replace (just,-O-(alkyl of replacement)), wherein " alkyl of replacement " is meant wherein one or more (for example maximum 5, for example, maximum 3) hydrogen atom is independently selected from the alkyl that following substituting group replaces:

The wherein optional group that replaces respectively does for oneself and replaces or use one or more independently, for example one, two or three substituting group replaced, described substituting group is independently selected from C ₁-C ₄Alkyl, aryl, heteroaryl, aryl-C ₁-C ₄Alkyl-, heteroaryl-C ₁-C ₄Alkyl ,-C ₁-C ₄Haloalkyl ,-OC ₁-C ₄Alkyl ,-OC ₁-C ₄Alkyl phenyl ,-C ₁-C ₄Alkyl-OH ,-OC ₁-C ₄Haloalkyl, halogen ,-OH ,-NH ₂,-C ₁-C ₄Alkyl-NH ₂,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl phenyl) ,-NH (C ₁-C ₄Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO ₂H ,-C (O) OC ₁-C ₄Alkyl ,-CON (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-CONH (C ₁-C ₄Alkyl) ,-CONH ₂,-NHC (O) (C ₁-C ₄Alkyl) ,-NHC (O) (phenyl) ,-N (C ₁-C ₄Alkyl) C (O) (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) C (O) (phenyl) ,-C (O) C ₁-C ₄Alkyl ,-C (O) C ₁-C ₄Alkyl phenyl ,-C (O) C ₁-C ₄Haloalkyl ,-OC (O) C ₁-C ₄Alkyl ,-SO ₂(C ₁-C ₄Alkyl) ,-SO ₂(phenyl) ,-SO ₂(C ₁-C ₄Haloalkyl) ,-SO ₂NH ₂,-SO ₂NH (C ₁-C ₄Alkyl) ,-SO ₂NH (phenyl) ,-NHSO ₂(C ₁-C ₄Alkyl) ,-NHSO ₂(phenyl) and-NHSO ₂(C ₁-C ₄Haloalkyl).In some embodiments, the alkoxyl group of replacement be " many alkoxyl groups " or-O-(optional replace alkylidene group)-(the optional alkoxyl group that replaces), and comprise that group is for example :-OCH ₂CH ₂OCH ₃And glycol ether for example polyoxyethylene glycol residue and-O (CH ₂CH ₂O) _xCH ₃, wherein x is 2-20, for example 2-10 and for example integer of 2-5.The another kind of alkoxyl group that replaces be the hydroxy alkoxy base or-OCH ₂(CH ₂) _yOH, wherein y is 1-10, for example the integer of 1-4.

Term " carbalkoxy of replacement " be meant group (alkyl of replacement)-O-C (O)-, wherein this group is connected to parent structure by the carbonyl functional group, and wherein the alkyl of Qu Daiing is meant that wherein one or more (for example maximum 5, for example maximum 3) hydrogen atom is independently selected from the alkyl that following substituting group replaces:

-R ^a,-OR ^b,-SR ^b, guanidine, wherein the guanidine that replaced by rudimentary-alkyl of one or more guanidine hydrogen ,-NR ^bR ^c, halogen, cyano group, nitro ,-COR ^b,-CO ₂R ^b,-CONR ^bR ^c,-OCOR ^b,-OCO ₂R ^a,-OCONR ^bR ^c,-NR ^cCOR ^b,-NR ^cCO ₂R ^a,-NR ^cCONR ^bR ^c,-CO ₂R ^b,-CONR ^bR ^c,-NR ^cCOR ^b,-SOR ^a,-SO ₂R ^a, SO ₂NR ^bR ^cWith-NR ^cSO ₂R ^a,

Term " amino of replacement " is meant group-NHR ^dOr-NR ^dR ^e, R wherein ^dFor being selected from: hydroxyl, the optional alkoxyl group that replaces, the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional acyl group that replaces, aminocarboxyl, the optional aryl that replaces, the optional heteroaryl that replaces, the optional Heterocyclylalkyl that replaces, optional carbalkoxy, sulfinyl and the alkylsulfonyl that replaces, and R wherein ^eBe selected from: the optional alkyl that replaces, the optional cycloalkyl that replaces, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces, and wherein the alkyl of Qu Daiing, cycloalkyl, aryl, Heterocyclylalkyl and heteroaryl are meant that individually wherein one or more (for example maximum 5, for example maximum 3) hydrogen atom is independently selected from alkyl, cycloalkyl, aryl, Heterocyclylalkyl and the heteroaryl that following substituting group replaces:

R wherein ^aBe selected from the optional C that replaces ₁-C ₆Alkyl, the optional alkenyl that replaces, the optional alkynyl that replaces, the optional aryl that replaces and the optional heteroaryl that replaces replace;

The wherein optional group that replaces respectively does for oneself unsubstituted or uses one or more independently, for example one, two or three substituting group replaced, described substituting group is independently selected from C ₁-C ₄Alkyl, aryl, heteroaryl, aryl-C ₁-C ₄Alkyl-, heteroaryl-C ₁-C ₄Alkyl-, C ₁-C ₄Haloalkyl-,-OC ₁-C ₄Alkyl ,-OC ₁-C ₄Alkyl phenyl ,-C ₁-C ₄Alkyl-OH ,-OC ₁-C ₄Haloalkyl, halogen ,-OH ,-NH ₂,-C ₁-C ₄Alkyl-NH ₂,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-NH (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl phenyl) ,-NH (C ₁-C ₄Alkyl phenyl), cyano group, nitro, oxo (as the substituting group of cycloalkyl, Heterocyclylalkyl or heteroaryl) ,-CO ₂H ,-C (O) OC ₁-C ₄Alkyl ,-CON (C ₁-C ₄Alkyl) (C ₁-C ₄Alkyl) ,-CONH (C ₁-C ₄Alkyl) ,-CONH ₂,-NHC (O) (C ₁-C ₄Alkyl) ,-NHC (O) (phenyl) ,-N (C ₁-C ₄Alkyl) C (O) (C ₁-C ₄Alkyl) ,-N (C ₁-C ₄Alkyl) C (O) (phenyl) ,-C (O) C ₁-C ₄Alkyl ,-C (O) C ₁-C ₄Alkyl phenyl ,-C (O) C ₁-C ₄Haloalkyl ,-OC (O) C ₁-C ₄Alkyl ,-SO ₂(C ₁-C ₄Alkyl) ,-SO ₂(phenyl) ,-SO ₂(C ₁-C ₄Haloalkyl) ,-SO ₂NH ₂,-SO ₂NH (C ₁-C ₄Alkyl) ,-SO ₂NH (phenyl) ,-NHSO ₂(C ₁-C ₄Alkyl) ,-NHSO ₂(phenyl) and-NHSO ₂(C ₁-C ₄Haloalkyl); And

The wherein optional acyl group that replaces, optional carbalkoxy, sulfinyl and alkylsulfonyl such as the present invention who replaces define.

Term " amine of replacement " also refers to aforesaid separately group-NHR ^dAnd NR ^dR ^dThe N-oxide compound.The N-oxide compound can by with for example hydrogen peroxide or-chloroperoxybenzoic acid handles corresponding amino the preparation.Those skilled in the art are afamiliar with the reaction conditions that carries out the N-oxidation.

The compound of formula 1 includes but not limited to optical isomer, racemoid and its other mixture of the compound of formula 1.In addition, the compound of formula 1 comprises the Z-of the compound with carbon-to-carbon double bond and E-form (or cis-and trans-form).In these cases, single enantiomer or diastereomer, just, the optical activity form can obtain by asymmetric synthesis or the fractionation by racemoid.The fractionation of racemoid can be passed through for example for example crystallization in the presence of resolving agent of ordinary method, or chromatography, for example uses chirality high pressure liquid chromatography (HPLC) post to finish.Under the situation that formula 1 compound exists with various tautomeric forms, chemical entity of the present invention comprises all tautomeric forms of compound.

Chemical entity of the present invention includes but not limited to formula 1 compound and whole medicinal forms thereof.The medicinal forms of compound of the present invention comprises pharmaceutical salts, solvate, crystalline form (comprising polymorphic form and inclusion compound), inner complex, non-covalent title complex, prodrug and composition thereof.In certain embodiments, compound of the present invention is the form of pharmaceutical salts.Therefore, term " a kind of chemical entity " and " number of chemical individuality " also comprise pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and mixture.

" pharmaceutical salts " includes but not limited to the salt with mineral acid, for example hydrochloride, phosphoric acid salt, diphosphate, bromate, vitriol,-sulfinate, nitrate and similar salt; With with organic acid salt, for example malate, maleic acid ester, fumarate, tartrate, succinate, Citrate trianion, acetate, lactic acid salt, mesylate, tosilate, 2-isethionate, benzoate, salicylate, stearate and alkyl salt acetate for example, HOOC-(CH ₂) n-COOH, wherein n is 0-4 and similar salt.Similarly, medicinal cation comprises (but being not limited to) sodium, potassium, calcium, aluminium, lithium and ammonium.

In addition, if the compound of formula 1 obtains with acid salt, free alkali can obtain by the solution of this hydrochlorate that alkalizes.On the contrary, if product is a free alkali, additive salt, particularly medicinal additive salt can make by free alkali being dissolved in the suitable organic solvent and with this solution of acid treatment according to the conventional steps that is used for preparing from alkali cpd acid salt.It will be apparent to those skilled in the art that the various synthetic methods that can be used to prepare atoxic medicinal additive salt.

As implied above, prodrug also drops in the scope of chemical entity, for example the ester or the amide derivatives of formula 1 compound.Term " prodrug " comprises when the patient is given in administration, for example becomes any compound of formula 1 compound after the old metabolic process of prodrug.The example of prodrug includes but not limited to acetate, formate and benzoate etc., and the like derivatives of the functional group in formula 1 compound (for example alcohol or amino).

Term " solvate " is meant the chemical entity that the interaction by solvent and compound forms.The appropriate solvent thing is the medicinal solvent thing, and for example hydrate comprises monohydrate and semihydrate.

Term " inner complex " is meant the chemical entity that forms at individual some coordination to metal ion of two (or more) by compound.

Term " non-covalent title complex " is meant the chemical entity that the interaction by compound and another kind of molecule forms, and does not wherein form covalent linkage between compound and molecule.For example, coordination can take place by Van der Waals interaction, hydrogen bonding and electrostatic interaction (being also referred to as ionic bonding).

Term " promoting agent " is used to refer to the chemical entity of biologically active.In certain embodiments, " promoting agent " is a kind of compound with medical effectiveness.For example promoting agent can be anticancer therapeutic agent.

The term of chemical entity of the present invention " treatment significant quantity " expression treatment disease when to people or non-human patients administration is effectively measured, and for example, treating significant quantity and can being be enough to treat the disease of replying kinase inhibitory activity or the amount of illness.The treatment significant quantity can for example be passed through the haemoconcentration of analytical chemistry individuality experimentally, or determines by calculating bioavailability in theory.

" significantly " is illustrated in the canonical parameter test case Ru Sishi T check of statistical significance, and wherein p＜0.05 is statistically evident any change that detects.

" patient " is meant animal, Mammals for example, and people for example, it has been will be treatment maybe, observe or the object of experiment.Method of the present invention can be used in human treatment and the animal doctor's application.In some embodiments, the patient is a Mammals, and in some embodiments, the patient behaves.

" vasculogenesis kinases " expression participates in the kinases of vasculogenesis, and includes but not limited to be selected from EphB ₄, VEGFR2 and PDGFR β kinases.

" carinogenicity kinases " is illustrated in the cell signal approach that causes cell transformation has direct acting kinases.When having served as expression or unconventionality expression, these kinases can have the carinogenicity activity.The carinogenicity kinases includes but not limited to c-Kit.

Any treatment of " treatment " expression patient disease comprises:

A) preventing disease that is to say, the disease clinical symptom is not developed;

B) suppress disease;

C) slow down or stop the development of (arresting) clinical symptom; And

D) palliate a disease, that is, make the degeneration of clinical symptom.

" reply disease or illness that kinases is regulated " and be meant the pathological symptom that relies on one or more protein kinase activities at least in part, described protein kinase is vasculogenesis kinases and/or carinogenicity kinases for example.Kinases directly or is indirectly participated in the active signal transduction path of various kinds of cell that comprises cell proliferation, differentiation and intrusion.The disease of replying the kinases adjusting includes but not limited to the vasculogenesis of tumor growth, the growth of support entity knurl and it is characterized in that the disease that excessive local vascular forms, for example diabetic retinopathy, macular degeneration and inflammation.

" change of vasculogenesis " is meant the blood vessel network of vascular system or the change of character.The change of vasculogenesis can by many parameter measurements and, for example, can assess by the delay appearance of new vessel structure, the development of slowing down of new vessel structure, the minimizing generation of new vessel structure, the change of blood vessel impregnability, the change of blood flow, the seriousness that slows down or reduce of angiogenesis-dependent disease effect, the angiogenic growth of prevention or the degeneration of previous angiogenic growth.

The invention provides at least a chemical entity of the compound that is selected from following formula 1:

(formula 1)

Wherein

R represents 0 to 2 substituting group, and described substituting group is independently selected from: hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional carbalkoxy that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces;

R ₇And R ₈, the carbon with they connect forms with group-(Z ₁) _mR ₁What replace condenses 5-to 7-unit heteroaryl ring, condenses wherein that 5-to 7-unit heteroaryl ring is optional further to be replaced, and wherein

R ₁Be the optional heteroaryl that replaces;

M is selected from 0,1 and 2;

R ₂Be the optional aryl that replaces; And

Condition is

The compound of formula 1 is not to be selected from 5-(phenyl amino formyl radical amino)-3-(2-(4-pyridyl) ethyl) indoles; 1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(1-(pyridin-4-yl)-1H-indoles-5-yl) urea; And 1-(2-methoxyl group-5-(trifluoromethyl) phenyl)-3-(1-(pyridin-4-yl)-1H-indoles-5-yl) urea.

In certain embodiments, R represents that 1 or 2 is independently selected from halogen, C ₁-C ₂Alkyl and C ₁-C ₂The substituting group of alkoxyl group.

In certain embodiments, R represents 1 or 2 substituting group that is independently selected from halogen, methyl and methoxyl group.

In certain embodiments, R represents to be selected from the substituting group of halogen, methyl and methoxyl group.

In certain embodiments, R does not exist.

In certain embodiments, R ₇And R ₈, the carbon with they connect forms with group-(Z ₁) _mR ₁What replace condenses 5-unit heteroaryl ring, and wherein heteroaryl ring comprises at least one nitrogen and the optional one or more other heteroatoms that is selected among N, O and the S that comprises in ring.

In certain embodiments, R ₇And R ₈,, form and be selected from each personal group-(Z with the carbon that they connect ₁) _mR ₁The fused rings of pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl group, triazolyl and the pyrryl that replaces.In certain embodiments, R ₇And R ₈,, form and be selected from each personal group-(Z with the carbon that they connect ₁) _mR ₁The fused rings of pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl and the pyrryl that replaces.

In certain embodiments, R ₇And R ₈,, form and be selected from each personal group-(Z with the carbon that they connected ₁) _mR ₁The 1H-pyrryl that replaces and the condensed heteroaryl ring of 1H-pyrazolyl.

In certain embodiments, R ₅And R ₆In at least one be hydrogen.In certain embodiments, R ₅And R ₆All be hydrogen.

In certain embodiments, m is 1, and R ₅And R ₆In at least one for for hydrogen.In certain embodiments, R ₅And R ₆All be hydrogen.

In certain embodiments, m is 0.

In certain embodiments, R ₁Be selected from the pyridyl of pyridyl and replacement; wherein the pyridyl of Qu Daiing be selected from single-, two-and the three-pyridyl that replaces, and wherein the substituting group on the pyridyl that replaces is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional carbalkoxy that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₈Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

In certain embodiments, the substituting group on the pyridyl that replaces is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, halogen, carboxyl, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylthio, C ₁-C ₆Acyl group, C ₁-C ₆Carbalkoxy, optional heteroaryl and the Heterocyclylalkyl that replaces.

In certain embodiments, the substituting group on the pyridyl that replaces is independently selected from hydroxyl, cyano group, halogen, the optional C that replaces ₁-C ₂Alkyl, the optional C that replaces ₁-C ₂Alkoxyl group and-NHR ₁₀, R wherein ₁₀Be selected from hydrogen and the optional acyl group that replaces.

In certain embodiments, R ₁Be selected from the pyridin-4-yl of pyridin-4-yl and replacement; wherein the pyridin-4-yl of Qu Daiing be selected from single-, two-and the three-pyridin-4-yl that replaces, and wherein the substituting group on the pyridin-4-yl that replaces is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional carbalkoxy that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

In certain embodiments, the substituting group on the pyridin-4-yl that replaces is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, halogen, carboxyl, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylthio, C ₁-C ₆Acyl group, C ₁-C ₆Carbalkoxy, optional heteroaryl and the Heterocyclylalkyl that replaces.

In certain embodiments, the substituting group on the pyridin-4-yl that replaces is independently selected from hydroxyl, cyano group, halogen, the optional C that replaces ₁-C ₂Alkyl, the optional C that replaces ₁-C ₂Alkoxyl group and-NHR ₁₀, R wherein ₁₀Be selected from hydrogen and the optional acyl group that replaces.

In certain embodiments, R ₁Be pyridin-4-yl.

In certain embodiments, R ₂Be selected from the phenyl of phenyl and replacement; wherein the phenyl of Qu Daiing be selected from single-, two-and the three-phenyl that replaces, and wherein the substituting group on the phenyl that replaces is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional carbalkoxy that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, the optional aryloxy that replaces, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

In certain embodiments, the substituting group on the phenyl that replaces is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, halogen, carboxyl, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, the optional phenyl that replaces, optional phenoxy group, the C that replaces ₁-C ₆Alkylthio, C ₁-C ₆Acyl group, C ₁-C ₆Carbalkoxy, optional heteroaryl and the Heterocyclylalkyl that replaces.

In certain embodiments, the substituting group on the phenyl of replacement is independently selected from hydroxyl, cyano group, halogen, the optional C that replaces ₁-C ₂Alkyl, phenoxy group and the optional C that replaces ₁-C ₂Alkoxyl group.

In certain embodiments, the substituting group on the phenyl that replaces is independently selected from halogen, methyl, ethyl, methoxyl group, oxyethyl group, difluoromethyl, trifluoromethyl, difluoro-methoxy and trifluoromethoxy.

In certain embodiments, R ₃And R ₄From being independently selected from hydrogen and methyl.

In certain embodiments, R ₃And R ₄Be hydrogen.

The invention provides at least a chemical entity of the compound of the formula of being selected from 2

(formula 2)

And pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and mixture, wherein R ₁, m, Z ₁, R, R ₂, R ₃And R ₄As described in for the compound of formula 1, and wherein

X and Y are independently selected from CH and N; And

R ₉Be selected from hydrogen and the optional alkyl that replaces.

In certain embodiments, R ₉Be selected from hydrogen and the optional low alkyl group that replaces.In certain embodiments, R ₉Be selected from hydrogen and low alkyl group.In certain embodiments, R ₉Be hydrogen.

In certain embodiments, X and Y are N.

In certain embodiments, Y is N, and X is CH.

The invention provides few a kind of chemical entity to the compound that is selected from formula 3:

(formula 3)

Wherein R, R ₂, R ₃And R ₄As described in for the compound of formula 1, wherein X, Y and R ₉As described in for the compound of formula 2, and wherein

R ₂₀Represent 0 to 3 substituting group, described substituting group is independently selected from hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional carbalkoxy that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

In certain embodiments, R ₂₀Be the optional amino that replaces.In certain embodiments, R ₂₀Be amino.

The invention provides at least a chemical entity of the compound of the formula of being selected from 4

(formula 4)

Wherein R, R ₂, R ₃And R ₄As described in for the compound of formula 1, wherein X, Y and R ₉As described in for the compound of formula 2, and R wherein ₂₀For as described in for the compound of formula 3.

At least a chemical entity of the compound of the formula of being selected from 5 also is provided

(formula 5)

And pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and mixture, wherein R, R ₃And R ₄As described in for the compound of formula 1, wherein X, Y and R ₉As described in for the compound of formula 2, R wherein ₂₀For as described in for the compound of formula 3; , and wherein

R ₂₁Be selected from hydrogen, halogen and the optional low alkyl group that replaces;

R ₂₂Be selected from hydrogen, halogen, lower alkoxy and low alkyl group; And

R ₂₃Be selected from hydrogen, low alkyl group, the optional phenoxy group that replaces, optional lower alkoxy and the halogen that replaces.

In certain embodiments, R ₂₁Be selected from hydrogen, halogen, methyl and trifluoromethyl.

In certain embodiments, R ₂₂Be selected from hydrogen, halogen, methoxyl group and methyl.

In certain embodiments, R ₂₂Be hydrogen.

In certain embodiments, R ₂₃Be selected from hydrogen, methyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group and halogen.

In certain embodiments, R ₂₁, R ₂₂And R ₂₃In at least one be not hydrogen.

At least a chemical entity also is provided, and it is selected from

1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-6-yl)-urea;

1-(4-chloro-2-methoxyl group-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2,4-dimethoxy-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2,4-dimethyl-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-oxyethyl group-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl methyl isophthalic acid H-indazole-4-yl)-urea;

1-(5-bromo-2-oxyethyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-5-yl)-urea;

1-(4-methyl-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(4-chloro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-5-yl)-urea;

1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-5-yl)-urea;

1-(4-chloro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-5-yl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-5-yl)-urea;

1-(2-chloro-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-5-yl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-(3-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-(3-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(3-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-3-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-3-yl Methyl-1H-indole-5-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(5-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(7-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-(5-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-(5-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-(5-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(4-methoxyl group-xenyl-3-yl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-methoxyl group-5-trifluoromethyl-phenyl)-3-(7-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-(7-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-(7-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

4-{4-[3-(2-methoxyl group-5-trifluoromethyl-phenyl)-urea groups]-5-methyl-indoles-1-ylmethyl }-the pyridine-2-carboxylic acids methyl nitrosourea;

1-(7-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-3-(4-methyl-3-trifluoromethyl-phenyl)-urea;

1-(4-chloro-3-trifluoromethyl-phenyl)-3-(7-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-[5-chloro-2-([1,3] dioxolane-2-ylmethoxy)-phenyl]-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-[5-chloro-2-(3-hydroxyl-propoxy-)-phenyl]-3-(5-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-chloro-4-methoxyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(4-methoxyl group-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2-methoxyl group-4-methyl-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-bromo-4-methyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(4-fluoro-3-trifluoromethyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-4-methyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(2-fluoro-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(2-methyl-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(3-bromo-4-methoxyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(3-fluoro-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-[1-(3-fluoro-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(4-methyl-3-trifluoromethyl-phenyl)-urea;

1-(3-chloro-4-fluoro-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

1-(3,4-dimethoxy-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-chloro-4-methyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-chloro-2-methoxyl group-4-methyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-4-methyl-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(3-chloro-4-methyl-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(5-chloro-2-methoxyl group-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(5-chloro-2,4-dimethoxy-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(2,4-dimethyl-5-trifluoromethyl-phenyl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(5-methoxyl group-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(2-methoxyl group-5-trifluoromethyl-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(2,4-dimethoxy-5-trifluoromethyl-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(2-methoxyl group-4-methyl-5-trifluoromethyl-phenyl)-urea;

1-benzo [1,3] dioxole-5-base-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(6-methyl isophthalic acid-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-Urethylane;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(3-chloro-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(5-fluoro-2,4-dimethoxy-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-bromo-4-fluoro-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

1-(5-ethylsulfonyl-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2,4-two fluoro-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;

N-(4-{4-[3-(5-chloro-2-methoxyl group-4-methyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

1-(5-bromo-2-methoxyl group-phenyl)-3-(7-fluoro-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-chloro-2-methoxyl group-4-methyl-phenyl)-3-(7-fluoro-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-hydroxyl-ethanamide;

2-amino-N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-methane amide;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(3-bromo-4-methoxyl group-phenyl)-urea;

N-(4-{4-[3-(3-chloro-4-methyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

1-(5-bromo-2-methoxyl group-phenyl)-3-(7-methoxyl group-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(2,4-dimethoxy-5-trifluoromethyl-phenyl)-3-(7-methoxyl group-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(5-fluoro-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

1-methyl isophthalic acid H-imidazoles-2-carboxylic acid (4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-acid amides;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-propionic acid amide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-isobutyramide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-morpholine-4-base-ethanamide;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(2-methylamino-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-{1-[2-(2-methoxyl group-ethylamino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(2-morpholine-4-base-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(2-methoxyl group-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-[1-(2-hydroxyl-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

N-(4-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-morpholine-4-base-ethanamide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-methoxyl group-ethanamide;

1-(5-chloro-2-methoxyl group-phenyl)-3-[1-(3-methyl-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

Cyclopropane-carboxylic acid (4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-acid amides;

1-[1-(2-amino-pyridine-4-ylmethyl)-1H-indoles-4-yl]-3-(5-bromo-2-difluoro-methoxy-phenyl)-urea;

N-(4-{4-[3-(5-bromo-2-difluoro-methoxy-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-ethanamide;

N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-3-diethylamino-propionic acid amide;

1-(5-bromo-2-methoxyl group-phenyl)-3-(7-chloro-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-{1-[2-(2-hydroxyl-ethylamino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-(5-chloro-1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-tetramethyleneimine-1-base-ethanamide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-dimethylamino-ethanamide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-methylamino-ethanamide;

1-[1-(2-amino-pyridine-4-ylmethyl)-5-fluoro-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

Cyclopropane-carboxylic acid (4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-acid amides;

Cyclopropane-carboxylic acid (4-{4-[3-(2-methoxyl group-5-trifluoromethyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-acid amides;

Cyclopropane-carboxylic acid (4-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-acid amides;

1-[1-(2-amino-pyridine-4-ylmethyl)-5-fluoro-1H-indoles-4-yl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-5-fluoro-1H-indoles-4-yl]-3-(2-methoxyl group-5-trifluoromethyl-phenyl)-urea;

Cyclopropane-carboxylic acid (4-{4-[3-(3-chloro-4-methyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-acid amides;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-Toluidrin;

N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-Toluidrin;

1-[1-(2-amino-pyridine-4-ylmethyl)-5-fluoro-1H-indoles-4-yl]-3-(2,5-two chloro-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-5-fluoro-1H-indoles-4-yl]-3-(5-chloro-2-methoxyl group-phenyl)-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(pyrazine-2-base is amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(thiazol-2-yl amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-7-fluoro-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-methylamino-ethanamide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-3-diethylamino-propionic acid amide;

1-[1-(2-amino-pyridine-4-ylmethyl)-7-fluoro-1H-indoles-4-yl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-{1-[2-(pyridine-2-base is amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-(5-bromo-2-methoxyl group-phenyl)-3-{1-[2-(3-sec.-propyl-urea groups)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

3-(ethanoyl-methyl-amino)-N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-propionic acid amide;

N-(4-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-2-methylamino-ethanamide;

1-[1-(2-allyl amino-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

3-amino-N-(4-{4-[3-(5-chloro-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyridine-2-yl)-propionic acid amide;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-{1-[2-(pyridin-3-yl amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-[1-(2-amino-5-fluoro-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

1-[1-(2-amino-pyridine-4-ylmethyl)-5-chloro-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

1-[1-(2-amino-3-methyl-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(5-bromo-2-methoxyl group-phenyl)-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-{1-[2-(1H-tetrazolium-5-yl)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-{1-[2-(pyrimidine-2--amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-[1-(2-bromo-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(5-chloro-2-methoxyl group-phenyl)-urea;

1-[1-(2-bromo-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;

1-[1-(2-cyano group-pyridin-4-yl methyl)-1H-indoles-4-yl]-3-(2-fluoro-5-trifluoromethyl-phenyl)-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-[1-(2-cyano group-pyridin-4-yl methyl)-1H-indoles-4-yl]-urea;

1-(2-fluoro-5-trifluoromethyl-phenyl)-3-{1-[2-(1H-imidazoles-2-yl)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(4-cyano group-phenyl amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea; And

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(6-cyano group-pyridin-3-yl amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea;

And pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and mixture.

The method that obtains novel cpd of the present invention will be conspicuous to those of ordinary skill in the art, and proper step is described in for example following reaction scheme and example, and be described in the document that the present invention quotes.

Reference reaction scheme 1 step 1, with excessive, for example about 3 normal alkali for example the sodium hydride compound (wherein Y is NH, and X is CH or N) that joins formula 101 at inert solvent for example in the cooling solution among the THF.Stirred the gained reaction mixture about 30 minutes down at about 0 ℃, and with excessive, for example about 1.5 normal formula R ₁-(Z ₁) _mThe compound of-X (wherein X is a for example bromine of leaving group) is handled.About 16 hours of stirred reaction mixture is warmed to room temperature simultaneously.With product, the compound of formula 103 separates, and optional purifying.

Reference reaction scheme 1 step 2, the compound that the Pd/C of catalytic amount is joined formula 103 be at polar aprotic solvent for example in the solution among the EtOH/EtOAc, and reaction mixture is placed in the Pa Er shaker with hydrogen.After about 3 hours, stop H ₂Gas feeds, and reaction mixture is filtered through Celite pad.With product, the compound of formula 105 separates, and optional purifying.

Reference reaction scheme 1 step 3 is with the formula R of about monovalent ₂The compound that the isocyanic ester of-NCO joins formula 105 is at inert solvent CH for example ₂Cl ₂In solution.With product, the compound of formula 107 separates, and optional purifying.

In some embodiments, with chemical entity of the present invention with pharmaceutical composition or preparation administration.Therefore, the invention provides pharmaceutical preparation, it comprises at least a chemical entity and pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and the mixture that is selected from formula 1 compound, and at least a medicinal vehicle that is selected from carrier, assistant agent and the vehicle.

Medicinal vehicle must have sufficiently high purity and sufficiently hypotoxicity, causes them to be suitable for to patient's administration of being treated.Vehicle can be inert, or it can have medical benefit.The vectorial amount system that is used in combination with chemical entity is enough to be provided for the actual amount of material of administration of the chemical entity of per unit dosage.

Exemplary pharmaceutical carrier or its composition are for example lactose, dextrose plus saccharose of sugar; Starch is W-Gum and yam starch for example; Mierocrystalline cellulose and derivative thereof, for example Xylo-Mucine, ethyl cellulose and methylcellulose gum; Tragacanth gum powder; Fructus Hordei Germinatus; Gelatin; Talcum; Solid lubricant is stearic acid and Magnesium Stearate for example; Calcium sulfate; Synthetic oils; Vegetables oil is peanut oil, Oleum Gossypii semen, sesame oil, sweet oil and Semen Maydis oil for example; Polyvalent alcohol is propylene glycol, glycerine, Sorbitol Powder, N.F,USP MANNITOL and polyoxyethylene glycol for example; Alginic acid; Phosphate buffer soln; Emulsifying agent is tween for example; Wetting agent, for example Sodium Lauryl Sulphate BP/USP; Colorant; Seasonings; System lozenge; Stablizer; Antioxidant; Sanitas; Apirogen water; Isotonic saline solution; And phosphate buffer soln.

Optional promoting agent can be included in the pharmaceutical composition, and it does not disturb the activity of chemical entity of the present invention basically.

With treating at least a chemical entity and pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and the mixture of the formula that is selected from 1 compound of significant quantity, mix with suitable medicinal vehicle.Show at chemical entity under the situation of not enough solubleness, can use the method that is used for the solubilize compound.These methods it is known to those skilled in the art that, and include but not limited to use cosolvent, for example methyl-sulphoxide (DMSO), use for example tween of tensio-active agent, or be dissolved in the sodium bicarbonate aqueous solution.

In case mix or add chemical entity of the present invention, the gained mixture can be solution, suspension, emulsion etc.The form of gained mixture relies on many factors, comprises mode of administration and the solubleness of chemical entity in selected vehicle wanted.The chemical entity of treatment significant quantity can rule of thumb determine.

Chemical entity of the present invention can be oral, local, parenteral, intravenously, by intramuscularly, by suction or spraying, hypogloeeis, transdermal, through cheek administration, rectum, as medicament for the eyes solution or by other method, with the dosage unit preparations administration.

The dosage particles that is suitable for orally using comprises for example tablet, tablet, lozenge, water or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule or syrup or elixir.The composition that is intended to orally use can be according to the known any method preparation in the field of making pharmaceutical composition, and these compositions can comprise one or more reagent, for example sweeting agent, seasonings, colorant and sanitas are so that provide pharmaceutically graceful and delicious preparation.In some embodiments, oral preparations comprises 0.1 to 99% chemical entity at least a of the present invention.In some embodiments, oral preparations comprises the chemical entity at least a of the present invention of at least 5% (weight %).Some embodiments comprise 25% to 50% or 5% to 75% chemical entity at least a of the present invention.

Liquid preparations for oral administration also comprises liquor agent, emulsion, suspension, pulvis, granula, elixir, tincture, syrup etc.The pharmaceutical carrier that is suitable for preparing these compositions is well known in the art.Oral preparations can comprise sanitas, seasonings, sweeting agent, for example sucrose or asccharin, taste masked agent and colorant.

Syrup, elixir, emulsion and suspension comprise ethanol, glycerine, propylene glycol, polyoxyethylene glycol, liquid sugar, sorbose alcohol and water with the typical composition of carrier.Syrup and elixir can be prepared pleasantly sweet dose of for example glycerine, propylene glycol, Sorbitol Powder or sucrose.These preparations also can comprise negative catalyst.

For example, chemical entity of the present invention can be incorporated into oral liquid for example water or oil suspension, solution, emulsion, syrup or elixir agent.In addition, the preparation that comprises these chemical entitys can be used as desciccate and exists, and is used for preparing with water or other suitable vehicle before use.These liquid preparations can comprise conventional additives, for example suspension agent (for example, Sorbitol Powder syrup, methylcellulose gum, glucose/sugar, syrup, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel and hydrogenation edible fat), emulsifying agent (for example, Yelkin TTS, sorbitan mono-oleic acid ester or gum arabic), non-aqueous vehicle, it (for example can comprise edible oils, Prunus amygdalus oil, fractionated coconut oil, silyl ester, propylene glycol and ethanol)) and sanitas is (for example, methyl p-hydroxybenzoate or propyl ester, and Sorbic Acid).

For suspension, typical suspension agent comprises methylcellulose gum, Xylo-Mucine, Microcrystalline Cellulose RC-591 (AVICEL RC-591), tragacanth gum and sodiun alginate; Typical wetting agent comprises Yelkin TTS and Polysorbate 80; And typical preservatives comprises methyl p-hydroxybenzoate and Sodium Benzoate.

Aqeous suspension comprises and is suitable for making one or more active substances of the vehicle blending of waterborne suspension.These vehicle are selected from suspension agent, for example the plain sodium of carboxymethyl dimension dimension, methylcellulose gum, Vltra tears, sodiun alginate, polyethylene Pyrrolizidine ketone, tragacanth gum and gum arabic; Disperse or wetting agent; Naturally occurring phosphatide, Yelkin TTS for example, with the condensation product of oxirane and lipid acid, the condensation product of polyoxyethylene stearic acid ester and oxyethane and long chain aliphatic for example, for example, 17 ethyleneoxy group hexadecanols and oxyethane and derived from the condensation product of the partial ester of lipid acid and hexose alcohol, for example polyoxyethylene sorbitol alternative, or oxyethane and derived from the condensation product of the partial ester of lipid acid and hexose alcohol acid anhydride, for example polyethylene anhydrous sorbitol alternative.These waterborne suspensions also can comprise one or more sanitas, for example ethyl p-hydroxybenzoate or n-propyl.

Oil suspension can be by being suspended in vegetables oil with activeconstituents, for example peanut oil, sweet oil, sesame oil or Oleum Cocois or at mineral oil for example in the whiteruss and prepare.These oil suspensions can comprise thickening material, for example beeswax, paraffinum durum or hexadecanol.Can add for example aforesaid sweeting agent of sweeting agent and seasonings so that good to eat oral preparations to be provided.These compositions can by add antioxidant for example xitix preserve.

Pharmaceutical composition of the present invention also can be the form of oil-in-water emulsion.Oil phase can be vegetables oil for example sweet oil or peanut oil, or mineral oil for example whiteruss or these mixture.Suitable emulsifying agent can be naturally occurring glue, for example gum arabic or tragacanth gum, naturally occurring phosphatide, for example soybean, Yelkin TTS and derived from the ester or the partial ester of lipid acid and hexose alcohol, acid anhydrides, sorbitan mono-oleic acid ester for example, with the condensation product of this partial ester and oxyethane, for example polyoxyethylene 20 sorbitan monooleate.

But be adapted to pass through and add water and prepare the dispersion powder of aqeous suspension and granula activeconstituents with dispersion or wetting agent, suspension agent and the blending of one or more sanitas is provided.Suitable dispersion or wetting agent and suspension agent are by top those examples of having described.

Tablet typically comprises the conventional medicinal adjuvant as inert diluent, for example lime carbonate, yellow soda ash, N.F,USP MANNITOL, lactose and Mierocrystalline cellulose; Tackiness agent is starch, gelatin and sucrose for example; Disintegrating agent is starch, alginic acid and croscarmellose for example; Lubricant is Magnesium Stearate, stearic acid and talcum for example.Can with glidant for example silicon-dioxide be used for improving the flow characteristics of powder mixture.For outward appearance, can add colorant, for example FD﹠amp; The C dyestuff.Sweeting agent and seasonings be aspartame, asccharin, menthol, lavender and flavoring agent of fruit for example, can be the useful assistant agent of chewable tablets.Capsule (comprising that the time discharges and extended release preparation) typically comprises disclosed solid diluent above one or more.Usually depend on less important consideration during the selection of carrier components, as taste, cost and package stability.

These compositions also can pass through ordinary method, typically with the pH value or time-dependency coating material dressing so that discharge near the gi tract of chemical entity in want topical application, or discharge to extend desired effect in the various times and to discharge.These dosage forms typically include but not limited to one or more Cellacefate, polyvinyl acetate phthalic ester, Hydroxypropyl Methylcellulose Phathalate, ethyl cellulose, acrylic resin coating material, wax and shellac.

The preparation that is used to orally use also can exist with hard gelatin capsule, wherein for example lime carbonate, calcium phosphate or kaolin mix for activeconstituents and inert solid diluent, or there be for example peanut oil, whiteruss or mixed with olive oil of activeconstituents and water or oily medium wherein with soft gelatin capsule.

Pharmaceutical composition can be the form of sterile injectable water-based or oleagenous suspension.This suspension can use suitable dispersion described above or wetting agent and suspension preparation according to known technology.Sterile injectable preparation also can be the solution or the suspension of the sterile injectable in the acceptable vehicle of atoxic parenteral, for example solution in the 1,3 butylene glycol.Wherein spendable acceptable vehicle is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, routine is used as solvent or suspension medium with aseptic expressed oil.For this purpose, can use the expressed oil of any gentleness, comprise synthetic list-or two-glycerate.In addition, lipid acid for example oleic acid can be used in the injectable preparation.

Chemical entity of the present invention can be through parenteral admin in sterile media.Parenteral admin comprises subcutaneous injection, intravenously, intramuscular, intrathecal injection or perfusion technique.Chemical entity of the present invention according to used vehicle and concentration, can suspend or be dissolved in the vehicle.Advantageously, for example local anesthetic, sanitas and buffer reagent may be dissolved in the vehicle assistant agent.In the composition of parenteral admin, carrier accounts at least 90 weight % of total composition many, and in some embodiments, the carrier that is used for parenteral admin is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.

Chemical entity of the present invention also can be used for the form administration of the suppository of medicine rectal administration.These compositions can prepare by medicine is mixed with suitable non-irritating excipient, and described vehicle is a solid at normal temperature, but are liquid in rectal temperature, therefore will be in the rectum fusing and the release medicine.These materials comprise cocoa cream and macrogol class.

Chemical entity of the present invention can be mixed with zone or topical application, and for example the form with gelifying agent, ointment and lotion locally applies to skin and mucous membrane, for example in eyes, and is applied to eyes.Topical composition can be any form, comprises that for example solution, ointment, ointment, gelifying agent, lotion, breast are washed, sanitising agent, moisturizing agent, spraying are washed, transdermal patches etc.

These solutions can be mixed with the 0.01%-10% isotonic solution with suitable salt, pH value from 2 to 12, for example from 5 to 7.Chemical entity of the present invention also can be mixed with the percutaneous plaster that is used for transdermal administration.

Comprise at least a chemical entity of the present invention topical composition can for example water, alcohol, Aloe gel, wallantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 propionic acid myristin etc. mix with variety carrier material known in the art.

Other material that is suitable for topical carrier comprises for example lubricant, solvent, wetting Agent for Printing Inks, thickening material and powder.Example is as follows separately for these types of materials that can use separately or use with the mixture of one or more materials:

Representational lubricant comprises stearyl alcohol, single ricinolic acid glyceryl ester, glyceryl monostearate, the third-1, the 2-glycol, fourth-1, the 3-glycol, ermine oil, hexadecanol, the Unimac 5680 isopropyl ester, stearic acid, the palmitinic acid isobutyl ester, Standamul 7061, oleyl alcohol, isopropyl laurate, lauric acid hexyl ester, decyl oleate, octadecane-2-alcohol, different hexadecanol, cetin, dimethicone, n-butyl sebacate, Isopropyl myristate, Wickenol 111, isopropyl stearate, butyl stearate, polyoxyethylene glycol, triglycol, lanolin, sesame oil, Oleum Cocois, peanut oil, Viscotrol C, Acetylated lanolin alcohols, oil, mineral oil, butyl myristate, Unimac 5680, palmitinic acid, the linolic acid isopropyl ester, Lauryl lactate, Tetradecyl lactate, decyl oleate and Tetradecyl tetradecanoate; Propelling agent, for example propane, butane, Trimethylmethane, dme, carbonic acid gas and Nitrous Oxide; Solvent, for example ethanol, methylene dichloride, Virahol, Viscotrol C, ethylene glycol monomethyl ether, diglycol monotertiary butyl ether, diethylene glycol monoethyl ether, methyl-sulphoxide, dimethyl formamide, tetrahydrofuran (THF); Wetting Agent for Printing Inks, for example glycerine, Sorbitol Powder, 2-Pyrrolidone-5-carboxylic acid sodium, soluble collagen, dibutyl phthalate and gelatin; And powder, for example magnesium aluminum silicate of chalk, talcum, Fuller's earth, kaolin, starch, glue, colloid silica, sodium polyacrylate, tetra-allkylammonium terre verte, trialkyl aryl terre verte, chemical modification, organically-modified montmorillonitic clay, hydrated aluminium silicate, pyrogenic silica, carboxy vinyl polymer, Xylo-Mucine and ethylene glycol monostearate.

Chemical entity of the present invention also can the liposome delivery system form by administration partly, for example little liposome of individual layer, the big liposome of individual layer and multilayer liposome.Liposome can be from multiple phosphatide, and for example cholesterol, stearylamine or phosphatidylcholine form.

Can be used for realizing that other composition that the system of chemical entity sends comprises the dosage form of hypogloeeis, cheek and nose.The solubility weighting agent material that these compositions typically comprise one or more is for example gum arabic, Microcrystalline Cellulose, carboxymethyl cellulose and Vltra tears of sucrose, Sorbitol Powder and N.F,USP MANNITOL and tackiness agent for example.Also can comprise above-mentioned disclosed glidant, lubricant, sweeting agent, colorant, antioxidant and seasonings.

The composition that is used to suck typically can be with the form of solution, suspension or the emulsion of dry powder administration, or provides with the form of the aerosol that uses conventional propellant (for example, Refrigerant 12 or trichlorofluoromethane).

Composition of the present invention also can randomly comprise active reinforcing agent.Active reinforcing agent can be selected from molecule widely, and its function is to improve by different way the result of treatment of chemical entity of the present invention or has nothing to do with this effect.The special kind of active reinforcing agent comprises skin penetration enhancer and absorption enhancer.

Pharmaceutical composition of the present invention also can comprise other promoting agent, and it can be selected from molecule widely, and its function is to improve by different way the result of treatment of at least a chemical entity of the present invention.Other promoting agent that these are optional when existing, typically is used in the composition of the present invention with the content in 0.01% to 15% scope.Some embodiments comprise 0.1 weight % of composition to 10 weight %.The composition of other embodiment from 0.5 weight % to 5 weight %.

The present invention can comprise the pharmaceutical preparation of packing.The preparation of these packings is included in the pharmaceutical composition in the container and uses the specification sheets of said composition treatment Mammals (typically human patients), and described pharmaceutical composition comprises at least a chemical entity and pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and the mixture of the formula of being selected from 1 compound.In some embodiments, these specification sheetss are used to use this medicine composite for curing to suffer from the patient of the disease of replying kinase inhibitory activity.The present invention includes provides prescription information; For example, offer patient or health care supplier, or as the label in the pharmaceutical preparation of packing.Prescription information can comprise effect, dosage and the administration that for example belongs to this pharmaceutical preparation, contraindication and side reaction information.

In all are aforementioned, these chemical entitys can be individually, with mixture or with other promoting agent combination ground administration.

Compound of the present invention can be used for the treatment of replys disease and the illness that kinases is regulated.

In certain embodiments, compound of the present invention is the conditioning agent of protein kinase.In certain embodiments, compound of the present invention is the inhibitor of protein kinase.In certain embodiments, these compounds suppress to be selected from EphB ₄, at least a kinases in c-Kit, PDGFR β and the VEGFR2 kinases.In certain embodiments, these compounds suppress to be selected from EphB ₄, in c-Kit, PDGFR β and the VEGFR2 kinases more than a kind of kinases.

Therefore, the present invention includes a kind of be used for the treatment of to suffer from reply the disease that kinases regulates or the patient of illness, the method for human patients for example, this method comprises: the chemical entity at least a of the present invention that will treat significant quantity is administered into the patient.

The invention provides a kind of being used for the treatment of suffers from the kinases of replying and regulates, and the patient's of VEGFR2 disease of regulating or illness method particularly, this method comprise that the compound administration of one or more formula 1 that will the treatment significant quantity is to the patient.

The present invention also provides the application of at least a chemical entity of the present invention in the preparation medicine, and described medicine is used for the treatment of to suffer from replys kinases adjusting, the disease of particularly VEGFR2 adjusting or the patient of illness.Also provide at least a chemical entity of the present invention to be used for making the application of the medicine for the treatment of the patient who suffers from vasculogenesis in preparation.

In some embodiments, the compound of formula 1 suppresses to be selected from EphB ₄, at least a kinases among c-Kit, PDGFR β and the VEGFR2, and can be used for the treatment of and reply disease and the illness that at least a these kinases are regulated.In some embodiments, disease or illness is characterized in that the vasculogenesis of support entity knurl growth or (dysregulated) local vascular of imbalance form.

Methods of treatment also comprise by suppress ATP in conjunction with or reply disease that kinases regulates or the patient of illness in vivo regulates kinase activity by the kinases hydrolysis or by some other mechanism suffering from, at least a of the present invention chemical entity of this method by the drug treatment significant quantity is with the vitro inhibition kinase activity.

In some embodiments, replying the situation that kinases regulates is cancer or is characterised in that disease or the illness that vasculogenesis changes.

The present invention includes and a kind ofly give few a kind of chemical entity of the present invention by administration, treatment suffers from cancer or is characterised in that disease that vasculogenesis changes or the patient's of illness method.The invention provides a kind of methods of treatment, compound wherein of the present invention is the unique promoting agent that gives the patient, and also comprises methods of treatment, and the combination of at least a chemical entity wherein of the present invention and one or more other promoting agent gives to the patient.

Some compound of the present invention can be used for the treatment of to suffer from replys the disease that kinases regulates or the patient of illness.

In certain embodiments, the compound of use formula I and the symptom that comprises these compound compositions influences, disease and/or illness include but not limited to: psoriatic, vasculogenesis, cancer (for example, chronic granulocytic leukemia, the gastrointestinal stromal knurl, nonsmall-cell lung cancer, mammary cancer, ovarian cancer, recurrent ovarian carcinoma, prostate cancer is hormone intractable (hormone refractory) prostate cancer for example, kidney, head and neck cancer or colorectal cancer), immunomodulatory (transplant rejection), atherosclerosis, rheumatoid arthritis, Parkinson's disease, alzheimer's disease, diabetes (for example insulin resistance or diabetic retinopathy), septic shock, etc.

In certain embodiments, using at least a chemical entity of the present invention and symptom, disease and/or the illness of the composition influence that comprises these chemical entitys is female genital female reproduction illness and symptom.In certain embodiments, female reproduction illness and symptom are selected from: endometriosis, carcinoma of endometrium, gynecological and hemorrhage illness, menstrual cycle are irregular, ovulation, premenstrual syndrome (PMS) and menopause dysfunction.

Because kinases plays active function at vasculogenesis, so some compound of the present invention can be used to regulate vasculogenesis.Vasculogenesis, neovascularity, comprise in cancer, chronic inflammation, diabetic retinopathy and the macular degeneration playing a decisive role at many pathology environment from the formation of the blood vessel of previous existence.Vasculogenesis is comprised by the approach of cell kinase control and regulating by the various kinds of cell signal pathway.Therefore, by the adjusting of cell kinase, the blocking-up vasculogenesis can be represented for example effective way of cancer of treatment disease.The method of these treatments comprises the of the present invention at least a chemical entity of drug treatment significant quantity to treat these diseases or illness, for example, reduces the progress of symptom or slow down these diseases or illness by the speed that suppresses the vasculogenesis in the tissue.

The present invention further comprises the method for medicinal composition treatment, and compound of the present invention gives the patient with one or more other promoting agent.Therefore, in one embodiment, the invention provides a kind of treatment method for cancer, this method comprises the of the present invention at least a chemical entity of significant quantity and second promoting agent that can be used for the treatment of cancer administration together given needs its patient.For example, second kind of medicament can be antineoplastic agent.Can be before with the treatment of second promoting agent with chemical entity of the present invention, simultaneously, or afterwards.

In certain embodiments, be selected from least a chemical entity and pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and the mixture of the compound of formula 1, with the synthetic single dose form of at least a second active groups.The radiotherapy antineoplastic agent also can use separately or be used in combination with chemotherapeutic.The antitumor treatment agent that is fit to can be used in combination with at least a chemical entity of the present invention.The example of antitumor treatment agent generally includes: microtubule stabilizer (for example taxol (also be known as safe plain), docetaxel (also being known as taxotere), Epothilones A, epothilone B, NSC-703147 A, NSC-703147 B or derivatives thereof; Microtubule-agent interfering; Alkylating agent, metabolic antagonist; She the holder this (epidophyllotoxin); Antitumor enzyme; The topology isomerase inhibitors; Procarbazine; Mitoxantrone; Iridium-platinum complex; Biological response modifier and growth inhibitor; Hormone/anti--hormonotherapy agent and hemopoieticgrowth factor.

The example kind of antitumor treatment agent comprises, for example the pyridine family that talks endlessly of the anthracycline family of medicine, Vinca medicine, mitomycin, bleomycin class, cytotoxin ucleosides, taxanes, epothilones, dish suberite lactone, medicine, treat Buddhist nun's class (diynenes) and podophillotoxines.The useful especially member of these classifications for example comprises: Dx, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin-A (methopterin), two chloro-methotrexates, ametycin, porfiromycin, trastuzumab, 5 FU 5 fluorouracil, Ismipur, gemcitabine, cytosine arabinoside, podophyllotoxin or podophyllotoxin derivative be Etoposide for example, Etoposide phosphoric acid salt or teniposide, melphalan, vinealeucoblastine(VLB), vincristine(VCR), leurosidine, vindesine, leurosine, taxol etc.Other useful antineoplastic agent comprises that estramustine, cis-platinum, carboplatin, endoxan, bleomycin, tamoxifen, ifosfamide, melphalan, altretamine, plug are for group, cytosine arabinoside, Yi Da Qu Sha (idatrexate), trimetrexate, Dacarbazine, 1-Asparaginase, camptothecine, CPT-11, Hycamtin, cytosine arabinoside (ara-C), bicalutamide, flutamide, bright third Reed, pyrido benzindole derivative, interferons and interleukin class.

In certain embodiments, be selected from least a chemical entity and pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and the mixture of the compound of formula 1, can with the anti-inflammatory agent combination medicine-feeding.Anti-inflammatory agent comprises: nonsteroidal anti-inflammatory agent, non-specific and COX-2 specificity cyclo-oxygenase enzyme inhibitors, gold-containing compound, reflunomide, methotrexate, tumour necrosis factor (TNF) receptor antagonist, immunosuppressor and methotrexate.The example of nonsteroidal anti-inflammatory agent comprises Ibuprofen BP/EP, flurbiprofen, Naproxen Base and naproxen sodium, diclofenac, the combination by diclofenac sodium and Misoprostol, sulindac, Evil promazine, diflunisal, piroxicam, indomethacin, R-ETODOLAC, fenoprofen calcium, Ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and Oxychloroquine.The example of nonsteroidal anti-inflammatory agent also comprises COX-2 specific inhibitor (that is IC, ₅₀IC than COX-1 ₅₀The compound of low 50-at least inhibition COX-2 doubly) for example celecoxib, valdecoxib, Rumi draw and examine former times (lumiracoxib), Yi Takao former times (etoricoxib) and/or rofecoxib.In certain embodiments, anti-inflammatory agent can be salicylate.Salicylate comprises acetylsalicylic acid salt or Aspirin, sodium salicylate and choline and magnesium salicylate.Anti-inflammatory agent also can be reflunomide.For example, reflunomide can be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone phosphate disodium and prednisone.In certain embodiments, anti-inflammatory agent can be gold-containing compound for example gold, thiomalic acid sodium (sodium thiomalate) or auranofin.In certain embodiments, anti-inflammatory agent can be metabolic poison, for example dihydrofolate reductase inhibitor, for example methotrexate or dhodh inhibitors, for example leflunomide.Some embodiment of the present disclosure comprises: composition, wherein at least a anti-inflammatory compound can be anti--C5 monoclonal antibody (for example Yi Kali monoclonal antibody (eculizumab) or Pei Si power monoclonal antibody (pexelizumab), TNF antagonist, for example etanercept (entanercept) or infliximab, it is the anti-TNF alpha monoclonal antibody, and composition, wherein at least a promoting agent is for example methotrexate, leflunomide, S-Neoral, tacrolimus, azathioprine or a mycophenolate mofetil of immunosuppressive compounds.

About 0.1 milligram to the 140 milligrams dosage content of per kilogram of body weight every day, for example per kilogram is 1 to 50 milligram, the symptom shown in above can being used for the treatment of (every patient every day 0.5 milligram to 7 grams).The amount that can merge with carrier substance and produce the activeconstituents of single dose form will depend on the concrete pattern of the host that treated and administration and change.Dosage unit form will comprise 1 milligram to 500 milligrams activeconstituents usually.

The frequency of dosage also can change according to the disease specific of employed compound and treatment.In certain embodiments, use every day 4 times or lower treatment plan.In certain embodiments, use the treatment plan of every day 1 or 2 times.

Yet, should understand, any concrete patient's concrete dosage level will depend on multiple factor, comprise the activity of employed particular compound, the patient's age for the treatment of, body weight, general health, sex, diet, administration time, route of administration and discharge rate, drug regimen and disease specific seriousness.

Embodiment

Further specify the present invention with following unrestricted embodiment.

In the following example, following abbreviation has following meaning.Undefined if abridge, then it has its meaning of accepting usually.

The DME=dme

Eagle ' the s substratum of DMEM=Dulbecco ' s modification

DMF=N, dinethylformamide

The DMSO=methyl-sulphoxide

The g=gram

H=hour

The mg=milligram

Min=minute

The mL=milliliter

The mmol=mmole

The mM=millimolar concentration

The ng=nanogram(ng)

The nm=millimicron

NM=nanomole concentration

The PBS=phosphate buffered saline (PBS)

μ L=microlitre

μ M=micro-molar concentration

Embodiment 1

4-nitro-1-pyridin-4-yl Methyl-1H-indole: (19mmol, NaH 3eq.) (95% is anhydrous) join 1.0g (6.2mmol, the cooling solution of 4-nitroindoline in 25 milliliters THF 1eq.) with 0.44g.At 0 ℃ of reaction mixture 30min that stirs down gained, and with the 4-bromo methyl cycloheptapyridine hydrobromate processing of 2.3g (9.3mmol, 1.5 equivalents), and stirred reaction mixture 16 hours, be warming to room temperature simultaneously.Add water, and, merge these organic layers, and use anhydrous MgSO with EtOAc (3 * 75 milliliters) aqueous layer extracted ₄Dry.(5%MeOH: the 95%EtOAc) solid that purifying produced so that 4-nitro-1-pyridin-4-yl Methyl-1H-indole to be provided, is yellow solid by column chromatography then.

1-pyridin-4-yl Methyl-1H-indole-4-base amine: the Pd/C of catalytic amount is joined 1.2g (4.7mmol, 1eq.) 4-nitro-1-pyridin-4-yl Methyl-1H-indole (20 milliliters of EtOH/EtOAc, 1: 1) in solution, and reaction mixture is placed in the Pa Er hydrogenation apparatus.After 3 hours, stop H ₂Gas feeds, and reaction mixture filters through Celite pad.Under reduced pressure concentrate thick solution then, and (5%MeOH: the thick material that 95%DCM) purifying produced so that 1-pyridin-4-yl Methyl-1H-indole-4-base amine to be provided, is pale solid by column chromatography.

The preparation of urea: the phenylcarbimide of 1eq. is joined 1-pyridin-4-yl Methyl-1H-indole-4-base amine (1eq.) at CH ₂Cl ₂In solution in, and by the LCMS monitoring reaction.Under the sedimentary situation of urea, use Et ₂The O diluted reaction mixture, filtration product and do not need further purifying.Otherwise the thick material that is produced is by using CH ₂Cl ₂The column chromatography purifying of/MeOH is wanted urea to provide, and is white solid.

4-nitro-1-pyridin-4-yl methyl isophthalic acid H-indazole: with NaH (0.44g, 95%, 18.0mmol) join 4-nitro indazole (1.0g, 6.10mmol) cooling solution in THF (25 milliliters).Stir the reaction mixture 30min that is produced down at 0 ℃, (1.5eq.) processing, and stirred reaction mixture 16 hours is warming to room temperature simultaneously for 2.3g, 9.2mmol to use 4-bromo methyl cycloheptapyridine hydrobromate then.Add water (25 milliliters), and, merge these organic layers and use anhydrous MgSO with EtOAc (3 * 75 milliliters) aqueous layer extracted ₄Dry.Then, (5%MeOH: the thick material that 95%EtOAc) purifying produced so that 4-nitro-1-pyridin-4-yl methyl isophthalic acid H-indazole to be provided, is yellow solid by column chromatography.

1-pyridin-4-yl methyl isophthalic acid H-indazole-4-base amine: the Pd/C of catalytic amount is joined 4-nitro-1-pyridin-4-yl methyl isophthalic acid H-indazole (0.90g, 3.60mmol, 1.0 equivalent) (20 milliliters of EtOH/EtOAc, 1: 1) in solution in, and reaction mixture is placed in the Pa Er hydrogenation apparatus.After 4 days, stop H ₂Gas feeds, and produces and the filtration of reaction mixture process Celite pad.Under reduced pressure concentrate thick solution then, and (5%MeOH: the thick material that 95%DCM) purifying produced so that 1-pyridin-4-yl methyl isophthalic acid H-indazole-4-base amine to be provided, is orange by column chromatography.

1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl methyl isophthalic acid H-indazole-4-yl)-urea: with isocyanic acid 5-bromo-2-methoxy phenyl ester (0.06g, 0.3mmol, 1eq.) join 1-pyridin-4-yl methyl isophthalic acid H-indazole-4-base amine (0.06g, 0.3mmol, 1eq.) solution in DCM (2.0 milliliters), and stirred reaction mixture 16 hours.Then, under reduced pressure remove and desolvate, and (5%MeOH: 95%DCM) purifying crude samples so that 1-(5-bromo-2-methoxyl group-phenyl)-3-(1-pyridin-4-yl methyl isophthalic acid H-indazole-4-yl)-urea to be provided, is white solid by column chromatography.

[4-(4-nitro-indoles-1-ylmethyl)-pyridine-2-yl]-t-butyl carbamate: with NaH (0.44g, 95%, 19.0mmol 3.0eq.) joins 4-nitroindoline (1.0g, 6.2mmol, 1eq.) cooling solution in THF (25 milliliters).Stir the reaction mixture 30min that is produced down at 0 ℃, and (1.5eq.) processing, and stirred reaction mixture 16 hours is warming to RT simultaneously for 2.30g, 9.3mmol with (4-brooethyl-pyridine-2-yl)-t-butyl carbamate.Add water (50 milliliters), and, merge these organic layers then, and use anhydrous MgSO with EtOAc (3 * 75 milliliters) aqueous layer extracted ₄Dry.(5%MeOH: the 95%EtOAc) crude samples that purifying produced so that [4-(4-nitro-indoles-1-ylmethyl)-pyridine-2-yl]-t-butyl carbamate to be provided, is yellow solid by column chromatography.

[4-(4-amido-indoles-1-ylmethyl)-pyridine-2-yl]-t-butyl carbamate: the Pd/C of catalytic amount is joined [4-(4-nitro-indoles-1-ylmethyl)-pyridine-2-yl]-t-butyl carbamate (1.2g, 4.7mmol, 1eq.) at EtOH/EtOAc (20mL, 1: 1) solution, and reaction mixture is placed in the Pa Er hydrogenation apparatus.After 3 hours, stop H ₂Gas passes through, and reaction mixture filters through Celite pad.(5%MeOH: the 95%DCM) crude samples that purifying produced so that [4-(4-amido-indoles-1-ylmethyl)-pyridine-2-yl]-t-butyl carbamate to be provided, is Off-white solid by column chromatography.

The Boc deprotection: the solution of urea (1eq.) in 4N HCl (20 milliliters) and EtOH (20 milliliters) of backflow Boc-protection, and by the LCMS monitoring reaction.In case deprotection makes the solution alkalize with 2N NaOH, and extracts with EtOAc (3 * 50 milliliters) fully.With organic solution and Na ₂SO ₄Thick solid is filtered and under reduced pressure be concentrated to drying.By the purification of column chromatography (MeOH:DCM), desired urea is provided, be pale solid.

[4-(4-nitro-indoles-1-ylmethyl)-pyridine-2-yl]-pyrazine-2-base-amine: at RT, with CsCO ₃(175mg, 0.538mmol) (51mg 0.538mmol) joins 1-(2-bromo-pyridin-4-yl methyl)-4-nitro-1H-indoles (119mg, 0.358mmol the) solution in the Zai diox (10 milliliters) with 2-amido pyrazine.By argon gas is blown into mixture, under supersound process, with mixture degasification 15min.Sequentially add Pd ₂(DBA) ₃(16mg, 0.018mmol) and Xantphos (31mg, 0.054mmol), and with solution be heated to 120 ℃ 6 hours.Crude reaction product is adsorbed on the silica gel, and carries out chromatogram (hexane/ethyl acetate),, be yellow solid so that [4-(4-nitro-indoles-1-ylmethyl)-pyridine-2-yl]-pyrazine-2-base-amine to be provided.

1-[2-(pyrazine-2-base is amino)-pyridin-4-yl methyl]-1H-indoles-4-base amine: [4-(4-nitro-indoles-1-ylmethyl)-pyridine-2-yl]-pyrazine-2-base-amine and ethanol (5 milliliters), water (5 milliliters) and DMF (3 milliliters) form slurries.Add iron (90 milligrams) and ammonium chloride, and heated mixt is to backflow 30min.Filter crude mixture, and crude product be adsorbed on the silica gel, by column chromatography (DCM/MeOH) purifying, so that 1-[2-(pyrazine-2-base is amino)-pyridin-4-yl methyl to be provided]-1H-indoles-4-base amine, be pale solid.

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(pyrazine-2-base amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea: with 1-[2-(pyrazine-2-base is amino)-pyridin-4-yl methyl]-1H-indoles-4-base amine (45mg) is dissolved among the DCM (5.0 milliliters), and add 4-chloro-2-isocyanato--1-methoxyl group-benzene (30mg), and stirred 1 hour.Ether (20 milliliters) is added in the mixture, and collects the solid of Shen Dian, so that 1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(pyrazine-2-base is amino)-pyridin-4-yl methyl to be provided by vacuum filtration]-1H-indoles-4-yl }-urea, be white solid.

Embodiment 2.

Following compounds is to use and is similar to above-mentioned step preparation.When changing initial substance or reaction conditions when obtaining desired compound, the those of ordinary skill in organic synthesis field should will be recognized.

The MS data that following acquisition is reported in this embodiment:

The MS condition: electrospray MS is used in installation carrying out on the MICROMASS LCT in the LockSpray source that exact mass measures.At the positive ion mode of 100-1000Da,,, obtain spectrum with scanning delay in the 0.1s in 1 spectrum/0.9s pick-up rate.Instrument is tuned to 5000 resolving power (FWHM).Obtain each the 5th scanning from the reference position in Lockspray source.Leucine enkephalin (556.2771[M+H] ⁺) conduct is used with reference to thing, or lock peak quality (lock mass).

Embodiment 3.EphB ₄The analysis of kinase activity

Classify a kind of EphB that can be used for testing disclosed compound among the application down as ₄The step of the standard biochemical analysis of kinase activity.

Material:

The 96-hole, 1/2 area is flat, white polystyrene board, available from Costar, catalogue #3693.

Has C-end V5-(his) ₆The reorganization EphB of label ₄Kinases (amino acid 596-987, Homosapiens EphB ₄, GENBANK registration number AY056047.1) the cytoplasmic structure territory from the Sf9 cell purification.＞95% purity is by the Sypro-Ruby dyeing assessment of sds gel.

PTK biotinylation peptide substrates 2 is available from Promega, catalogue #V288A.

The anti-phosphotyrosine antibody (PT66) of LANCE Eu-W1024 mark is available from Perkin-Elmer, catalogue #AD0068.Kinase buffer liquid is available from Cell Signaling, catalogue #9802.

The dilution of compound is that the last concentration of wanting in 20X is carried out in 100%DMSO.Compound in 100%DMSO (1.25 μ l) is transferred to 96 hole analysis plates.The main mixture (EphB that comprises ultimate density 0.01%BSA, 1X Cell Signaling kinase buffer liquid, 0.5 μ M PTK biotinylation peptide substrates 2 and the 18.6ng/ hole of (in 25 μ l) with 18.75 μ l volumes ₄Kinases) be added to institute porose in, except four negative control holes (it does not comprise kinases), and mix.For initiation reaction, the 550 μ M ATP of 5 μ l are added in each hole.(ultimate density of ATP=110 μ M).Reacted at room temperature incubation 1 hour.After incubation, the 4X SA-APC detection mixture that 8.35 μ l are measured adds in each hole.The ultimate density of the PT66 antibody of Eu-mark is 1nM, and SA-APC is 20nM (based on the SA part).Add SA-APC and detect after the mixture, Sptting plate was room temperature incubation at least 15 minutes.Then, Sptting plate utilizes Envision to read plate meter (Perkin-Elmer) under 605nm excites situation, reads in the reading under 605nM and the 640nM emission wavelength.Proofread and correct fluorescent value at enzyme in the presence of not, and use Luo Jite (Logit) fitting of a curve rule, will suppress curve and data and carry out match.Suppress curve by these and determine IC ₅₀Value.

Embodiment 4.EphB ₄Cell analysis

Classify the EphB that can be used for testing disclosed compound among the application down as ₄The step of the standard biochemical analysis of kinase activity.

The EphB of V5-epi-position label will stably be expressed ₄The HEK293 cell grow into～75% converge, incubation 90 minutes in 37 ℃ of low blood serum mediums (Optimem) that comprising test compounds then.Cell is used 500ng/ml EphrinB in 37 ℃ ₂/ Fc mosaic and the anti-IgG of 50ng/ml goat (FC-specificity) were the low blood serum medium moderate stimulation that comprises test compounds 10 minutes.Cell washs in ice-cold PBS, cracking, and on the split product of removing, carry out analysis of protein.With anti-Tyrosine O-phosphate (phosphotyrosine) antibody or anti-V5 antibody, each sample that equates protein content is carried out SDS-PAGE and Western blotting, to control the EphB of the V5-epi-position mark in each split product ₄Total amount

Embodiment 5

Biochemical analysis

Classify as down can be used for testing the present invention disclosed compound as the step of the standard biochemical analysis of the inhibitor of c-Kit, PDGFR β and VEGFR2 kinase activity.

From 1: 20 test compounds of original 200 μ M DMSO storing solutions dilution, and c-Kit (10ng) with reorganization, or VEGFR2 (1ng) enzyme (ProQinase GmbH, Germany), biotinylation peptide (PTK peptide 2, Promega) incubation 60 minutes at room temperature in the ATP of Cell Signalling kinase buffer liquid (c-Kit) or Upstate kinase buffer liquid (VEGFR2) and 5 μ l (it is 150 μ M that ultimate density: c-Kit analyzes, and VEGFR2 to analyze be 85 μ M).For PDGFR β, from 1: 20 test compounds of original 200 μ MDMSO storing solutions dilution, and with reorganization PDGFR β (2ng) (ProQinaseGmbH, Germany), the biotinylation peptide (PTK peptide 2, Promega), 1 μ M poly-L-Lysine (Sigma) is in the ATP of Upstate kinase buffer liquid and 5 μ l (ultimate density: incubation at least 15 minutes at room temperature 2.5 μ M).The ultimate analysis volume is 25 μ l.After cultivating, add and detect mixture, it comprises the anti-phosphotyrosine antibody PT66 (Perkin-Elmer, catalogue #AD0068) and the 20nM SA-APC (based on the SA part) of 1nM LANCE Eu-W1024 mark.After SA-APC detected the mixture adding, Sptting plate was at room temperature cultivated 15 minutes at least.Then, Sptting plate utilizes Envision to read plate meter (Perkin-Elmer) under the situation that 605nm excites, and reads the reading under 615nM and the 640nM emission wavelength.

For negative control, just the not repressed data of kinases are read, and analyze and carry out under the situation that does not add any test compounds.Staurosporin (Staurosporine), a kind of common kinase inhibitor is as using over against shining.

IC ₅₀Value is to determine from the full binding curve that closes of the 11-point of the remarkable inhibiting test compounds that shows one of Tyrosylprotein kinase.In these were analyzed, the concentration range of test compounds was that 10 μ M are to 20nM.The balance incorporating parametric is by by means of computer program FitP for example ^TM(MO) match allosteric Hill equation to observed value is measured for BIOSOFT, Ferguson.

Embodiment 6. test results

Some at the compound described in the embodiment 2 at EphB ₄The analysis of kinase activity (such as in embodiment 3 and 4 general introduction) in test, and find to show 1 micro-molar concentration or lower IC ₅₀Some these compound shows 500nM or lower IC in these are analyzed ₅₀Some these compound shows 50nM or lower IC in these are analyzed ₅₀

The compound of some embodiment 2 is test in the active analysis of PDGFR beta kinase (in as embodiment 5 general introduction), and finds to show 1 micro-molar concentration or lower IC ₅₀Some these compound shows 500nM or lower IC in the active analysis of PDGFR beta kinase ₅₀Some these compound shows 100nM or lower IC in this analyzes ₅₀

Some is in the test in the analysis of c-Kit kinase activity (in as embodiment 5 general introduction) of the compound described in the embodiment 2, and finds to show 1 micro-molar concentration or lower IC ₅₀Some these compound shows 500nM or lower IC in the analysis of c-Kit kinase activity ₅₀Some these compound shows 50nM or lower IC in this analyzes ₅₀

Some is at the compound described in the embodiment 2 also test in the analysis of VEGFR2 kinase activity (in as embodiment 5 general introduction), and finds to show 1 micro-molar concentration or lower IC ₅₀Some these compound shows 100nM or lower IC in this analyzes ₅₀Some these compound shows 50nM or lower IC in this analyzes ₅₀

Some is also tested in analysis of the present invention at the compound described in the embodiment 2, and finds to show at being selected from EphB ₄, two or more kinase whose 1 micro-molar concentration or lower IC among PDGFR β, c-Kit and the VEGFR2 ₅₀Some is also tested in analysis of the present invention at the compound described in the embodiment 2, and finds to show at being selected from EphB ₄, two or more kinase whose 100nM or lower IC among PDGFR β, c-Kit and the VEGFR2 ₅₀

Some is also tested in analysis of the present invention at the compound described in the embodiment 2, and finds to show at being selected from EphB ₄, three kinds or more kinds of kinase whose 1 micro-molar concentrations or lower IC among PDGFR β, c-Kit and the VEGFR2 ₅₀Some is also tested in analysis of the present invention at the compound described in the embodiment 2, and finds to show at being selected from EphB ₄, three kinds or more kinds of kinase whose 100nM or lower IC among PDGFR β, c-Kit and the VEGFR2 ₅₀

Some is also tested in analysis of the present invention at the compound described in the embodiment 2, and finds to show at EphB ₄, 1 micro-molar concentration of every kind of PDGFR β, c-Kit and VEGFR2 or lower IC ₅₀Some is also tested in analysis of the present invention at the compound described in the embodiment 2, and finds to show at EphB ₄, the 100nm of every kind of PDGFR β, c-Kit and VEGFR2 or lower IC ₅₀

Though illustrated and described some embodiment, various modifications and replace and to carry out not leaving under the spirit and scope of the present invention.Therefore, should understand, explanation rather than restrictive mode are described by way of example in the present invention.

Claims

1. be selected from least a chemical entity of following formula 1 compound:

Formula 1

And pharmaceutical salts, solvate, crystalline form, inner complex, non-covalent title complex, prodrug and mixture, wherein:

R represents 0 to 2 substituting group, and described substituting group is independently selected from: hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional alkoxy carbonyl that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces;

R ₇And R ₈, the carbon with they connect forms with group-(Z ₁) _mR ₁Condensed 5-to the 7-unit heteroaryl ring that replaces, the first heteroaryl ring of wherein said condensed 5-to 7-is optional further to be replaced, and wherein

R ₁Be the optional heteroaryl that replaces;

M is selected from 0,1 and 2;

R ₂Be the optional aryl that replaces; And

Condition is

2. at least a chemical entity of claim 1, wherein R ₇And R ₈, the carbon with they connect forms with group-(Z ₁) _mR ₁The 5 yuan of heteroaryl rings of condensed that replace, wherein said heteroaryl ring contain at least one nitrogen and in ring optional comprising be selected from N, the one or more other heteroatoms among O and the S.

3. at least a chemical entity of claim 2, wherein R ₇And R ₈,, form and be selected from each personal group-(Z with the carbon that they connect ₁) _mR ₁The pyrazolyl that replaces, imidazolyl ， isoxazolyl ， oxazolyl, thiazolyl, the condensed ring of triazolyl and pyrryl.

4. at least a chemical entity of claim 3, wherein R ₇And R ₈,, form and be selected from each personal group-(Z with the carbon that they connect ₁) _mR ₁The 1H-pyrryl that replaces and the condensed heteroaryl ring of 1H-pyrazolyl.

5. at least a chemical entity of claim 1, the compound of its Chinese style 1 is selected from the compound of formula 2:

(formula 2)

Wherein

X and Y are independently selected from CH and N; And

R ₉Be selected from hydrogen and the optional alkyl that replaces.

6. at least a chemical entity of any one, wherein R in the claim 1 to 5 ₁The pyridyl that is selected from the fixed base of piperazine and replaces; wherein the pyridyl of Qu Daiing be selected from single-, two-and the three-pyridyl that replaces, and wherein the substituting group on the pyridyl that replaces is independently selected from: hydroxyl, nitro; cyano group; the optional amino that replaces, aminocarboxyl, halogen; carboxyl; the optional acyl group that replaces, the optional alkoxy carbonyl that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

7. at least a chemical entity of claim 6, wherein the substituting group on the pyridyl that replaces is independently selected from: hydroxyl, nitro, cyano group, the optional amino that replaces, halogen, carboxyl, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylthio, C ₁-C ₆Acyl group, C ₁-C ₆Alkoxy carbonyl, the optional heteroaryl that replaces, and Heterocyclylalkyl.

8. at least a chemical entity of claim 7, wherein the substituting group on the pyridyl that replaces is independently selected from: hydroxyl, cyano group, halogen, the optional C that replaces ₁-C ₂Alkyl, the optional C that replaces ₁-C ₂Alkoxyl group and-NHR ₁₀, R wherein ₁₀Be selected from hydrogen and the optional acyl group that replaces.

9. at least a chemical entity of claim 6, wherein R ₁Be selected from the pyridin-4-yl of pyridin-4-yl and replacement; wherein the pyridin-4-yl of Qu Daiing be selected from single-, two-and the three-pyridin-4-yl that replaces, and wherein the substituting group on the pyridin-4-yl that replaces is independently selected from: hydroxyl, nitro; cyano group; the optional amino that replaces, aminocarboxyl, halogen; carboxyl; the optional acyl group that replaces, the optional alkoxy carbonyl that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

10. at least a chemical entity of claim 9, wherein the substituting group on the pyridin-4-yl that replaces is independently selected from: hydroxyl, nitro, cyano group, the optional amino that replaces, halogen, carboxyl, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, C ₁-C ₆Alkylthio, C ₁-C ₆Acyl group, C ₁-C ₆Alkoxy carbonyl, the optional heteroaryl that replaces, and Heterocyclylalkyl.

11. at least a chemical entity of claim 10, wherein the substituting group on the pyridin-4-yl that replaces is independently selected from: hydroxyl, cyano group, halogen, the optional C that replaces ₁-C ₂Alkyl, the optional C that replaces ₁-C ₂Alkoxyl group and-NHR ₁₀, R wherein ₁₀Be selected from hydrogen and the optional acyl group that replaces.

12. at least a chemical entity of claim 9, wherein R ₁It is pyridin-4-yl.

13. at least a chemical entity of any one, wherein R in the claim 1 to 12 ₅And R ₆In at least one be hydrogen.

14. at least a chemical entity of claim 13, wherein R ₅And R ₆All be hydrogen.

15. at least a chemical entity of any one in the claim 1 to 12, wherein m is 1, and R ₅And R ₆In at least one be hydrogen.

16. at least a chemical entity of claim 13, wherein R ₅And R ₆All be hydrogen.

17. at least a chemical entity of any one in the claim 1 to 12, wherein m is 0.

18. at least a chemical entity of claim 5, the compound of its Chinese style 2 is selected from the compound of formula 3:

(formula 3)

Wherein

R ₂₀Represent 0 to 3 substituting group, described substituting group is independently selected from: hydroxyl, nitro, cyano group, the optional amino that replaces, aminocarboxyl, halogen, carboxyl, the optional acyl group that replaces, the optional alkoxy carbonyl that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

19. at least a chemical entity of claim 18, the compound of its Chinese style 3 is selected from the compound of formula 4:

(formula 4).

20. at least a chemical entity of any one in the claim 5 to 19, wherein X and Y are N.

21. at least a chemical entity of any one in the claim 5 to 19, wherein Y is N, and X is CH.

22. at least a chemical entity of any one, wherein R in the claim 1 to 21 ₂Be selected from the phenyl of phenyl and replacement; wherein the phenyl of Qu Daiing be selected from single-, two-and the three-phenyl that replaces, and the substituting group on the phenyl that replaces is independently selected from: hydroxyl, nitro; cyano group; the optional amino that replaces, aminocarboxyl, halogen; carboxyl; the optional acyl group that replaces, the optional alkoxy carbonyl that replaces, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, the optional aryloxy that replaces, sulfane base, sulfinyl, alkylsulfonyl, the optional aryl that replaces, the optional heteroaryl that replaces and the optional Heterocyclylalkyl that replaces.

23. at least a chemical entity of claim 22, wherein the substituting group on the phenyl that replaces is independently selected from: hydroxyl, nitro, cyano group, the optional amino that replaces, halogen, carboxyl, the optional C that replaces ₁-C ₆Alkyl, the optional C that replaces ₁-C ₆Alkoxyl group, the optional phenyl that replaces, the optional phenoxy group that replaces, C ₁-C ₆Alkylthio, C ₁-C ₆Acyl group, C ₁-C ₆Alkoxy carbonyl, optional heteroaryl and the Heterocyclylalkyl that replaces.

24. at least a chemical entity of claim 23, wherein the substituting group on the phenyl that replaces is independently selected from: hydroxyl, cyano group, halogen, the optional C that replaces ₁-C ₂Alkyl, phenoxy group and the optional C that replaces ₁-C ₂Alkoxyl group.

25. at least a chemical entity of claim 24, wherein the substituting group on the phenyl that replaces is independently selected from: halogen, methyl, ethyl, methoxyl group, oxyethyl group, difluoromethyl, trifluoromethyl, difluoro-methoxy, and trifluoromethoxy.

26. at least a chemical entity of claim 19, the compound of its Chinese style 4 is selected from the compound of formula 5:

(formula 5)

Wherein

R ₂₂Be selected from hydrogen, halogen, lower alkoxy, and low alkyl group; And

R ₂₃Be selected from hydrogen, low alkyl group, the optional phenoxy group that replaces, the optional lower alkoxy that replaces, and halogen.

27. at least a chemical entity of claim 26, wherein R ₂₁Be selected from hydrogen, halogen, methyl and trifluoromethyl.

28. at least a chemical entity of claim 26 or 27, wherein R ₂₂Be selected from hydrogen, halogen, methoxyl group and methyl.

29. at least a chemical entity of claim 28, wherein R ₂₂Be hydrogen.

30. any one at least a chemical entity of claim 26 to 28, wherein R ₂₃Be selected from hydrogen, methyl, methoxyl group, difluoro-methoxy, trifluoromethoxy, oxyethyl group and halogen.

31. any one at least a chemical entity of claim 18 to 30, wherein R ₂₀Be the optional amino that replaces.

32. any one at least a chemical entity of claim 5 to 31, wherein R ₉Be selected from hydrogen and the optional low alkyl group that replaces.

33. at least a chemical entity of claim 32, wherein R ₉Be selected from hydrogen and low alkyl group.

34. at least a chemical entity of claim 33, wherein R ₉Be hydrogen.

35. any one at least a chemical entity of claim 1 to 34, wherein R represents 1 or 2 substituting group, and described substituting group is independently selected from: halogen, C ₁-C ₂Alkyl and C ₁-C ₂Alkoxyl group.

36. at least a chemical entity of claim 35, wherein R represents 1 or 2 substituting group, and described substituting group is independently selected from: halogen, methyl and methoxyl group.

37. at least a chemical entity of claim 36, wherein R represents to be selected from halogen, the substituting group in methyl and the methoxyl group.

38. any one at least a chemical entity of claim 1 to 37, wherein R does not exist.

39. any one at least a chemical entity of claim 1 to 38, wherein R ₃And R ₄Be selected from hydrogen and methyl independently of one another.

40. at least a chemical entity of claim 39, wherein R ₃And R ₄Be hydrogen.

41. any one at least a chemical entity of claim 1 to 40 is wherein at EphB ₄In the standard external test of kinase activity, described at least a chemical entity shows 1 micro-molar concentration or lower IC ₅₀

42. at least a chemical entity of claim 41 is wherein at EphB ₄In the standard external test of kinase activity, described at least a chemical entity shows 500 nanomole concentration or lower IC ₅₀

43. at least a chemical entity of claim 42 is wherein at EphB ₄In the standard external test of kinase activity, described at least a chemical entity shows 50 nanomole concentration or lower IC ₅₀

44. any one at least a chemical entity of claim 1 to 43, wherein in the active standard external test of PDGFR beta kinase, described at least a chemical entity shows 1 micro-molar concentration or lower IC ₅₀

45. at least a chemical entity of claim 44, wherein in the active standard external test of PDGFR beta kinase, described at least a chemical entity shows 500 nanomole concentration or lower IC ₅₀

46. at least a chemical entity of claim 45, wherein in the active standard external test of PDGFR beta kinase, described at least a chemical entity shows 100 nanomole concentration or lower IC ₅₀

47. any one at least a chemical entity of claim 1 to 46, wherein in the standard external test of VEGFR2 kinase activity, described at least a chemical entity shows 1 micro-molar concentration or lower IC ₅₀

48. at least a chemical entity of claim 47, wherein in the standard external test of VEGFR2 kinase activity, described at least a chemical entity shows 500nM or lower IC ₅₀

49. at least a chemical entity of claim 48, wherein in the standard external test of VEGFR2 kinase activity, described at least a chemical entity shows 50nM or lower IC ₅₀

50. any one at least a chemical entity of claim 1 to 49, wherein in the standard external test of c-Kit kinase activity, described at least a chemical entity shows 1 micro-molar concentration or lower IC ₅₀

51. at least a chemical entity of claim 50, wherein in the standard external test of c-Kit kinase activity, described at least a chemical entity shows 500 nanomole concentration or lower IC ₅₀

52. at least a chemical entity of claim 51, wherein in the standard external test of c-Kit kinase activity, described at least a chemical entity shows 50 nanomole concentration or lower IC ₅₀

53. any one at least a chemical entity of claim 1 to 40, wherein said at least a chemical entity is at EphB ₄Show 1 micro-molar concentration or lower IC in the standard external test of kinase activity ₅₀In the active standard external test of PDGFR beta kinase, show 1 micro-molar concentration or lower IC ₅₀And in the standard external test of VEGFR2 kinase activity, show 1 micro-molar concentration or lower IC ₅₀

54. at least a chemical entity of claim 1, its Chinese style 1 compound is selected from:

1-(4-methoxyl group-xenyl-3-yl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-bromo-4-methyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-chloro-4-fluoro-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3,4-dimethoxy-phenyl)-3-(1-pyridin-4-yl methyl isophthalic acid H-indoles-4-yl)-urea;

1-(3-chloro-4-methyl-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-benzo [1,3] dioxole-5-base-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

1-(3-bromo-4-fluoro-phenyl)-3-(1-pyridin-4-yl Methyl-1H-indole-4-yl)-urea;

N-(4-{4-[3-(2-fluoro-5-trifluoromethyl-phenyl)-urea groups]-indoles-1-ylmethyl }-than pyridine-2-yl)-ethanamide;

N-(4-{4-[3-(5-bromo-2-methoxyl group-phenyl)-urea groups]-indoles-1-ylmethyl }-pyrrole is than pyridine-2-yl)-2-tetramethyleneimine-1-base-ethanamide;

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(4-cyano group-phenyl amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea; With

1-(5-chloro-2-methoxyl group-phenyl)-3-{1-[2-(6-cyano group-pyridin-3-yl amino)-pyridin-4-yl methyl]-1H-indoles-4-yl }-urea.

55. a pharmaceutical composition, it comprises in the claim 1 to 54 any one at least a chemical entity and at least a medicinal vehicle, and described medicinal vehicle is selected from carrier, assistant agent and vehicle.

56. the pharmaceutical composition of claim 55, wherein said composition is formulated into and is selected from: the form of injection liquid, aerosol, ointment, gelifying agent, tablet, pill, capsule, syrup, ophthalmic solution and transdermal patch.

57. one kind is used for the treatment of the method for suffering from the patient who replys disease that kinase activity regulates or illness, this method comprises: to patient's drug treatment significant quantity according to any one at least a chemical entity or claim 55 or 56 any one pharmaceutical compositions in the claim 1 to 54.

58. the method for claim 57, wherein said patient is the people.

59. the method for claim 57, wherein said patient is selected from cat and dog.

60. the method for any one in the claim 57 to 59, the disease or the illness of wherein replying the kinase activity adjusting are selected from cancer and are characterised in that the disease that vasculogenesis changes.

61. the method for claim 60, the wherein said disease that is characterised in that vasculogenesis changes is selected from cancerous tumour, macular degeneration and diabetic retinopathy.

62. the method for any one in the claim 57 to 61, wherein said at least a chemical entity is by being selected from intravenously, intramuscular and parenteral method administration.

63. the pharmaceutical composition of a packing, it is included in interior claim 55 of container or 56 pharmaceutical composition, with the specification sheets that uses described composition to treat the patient who suffers from disease or illness, described disease or illness are replied the kinase activity of one or more Tyrosylprotein kinases and are regulated.

64. the pharmaceutical composition of the packing of claim 63, the disease or the illness of wherein replying the kinase activity adjusting are selected from cancer or are characterised in that the disease that vasculogenesis changes.

65. the pharmaceutical composition of the packing of claim 64, the wherein said disease that is characterised in that vasculogenesis changes is selected from cancerous tumour, macular degeneration and diabetic retinopathy.

66. regulate EphB for one kind ₄The method of kinase activity, this method comprises: with expressing EphB ₄Cell be enough to external with detecting the inhibition EphB ₄At least a chemical entity contact of any one in the claim 41 to 43 of the amount of kinase activity.

67. a method of regulating the VEGFR2 kinase activity, this method comprises: with the cell of VEGF expression R2 be enough to that at least a chemical entity of any one contacts with detecting in the claim 47 to 49 of the external amount that suppresses the VEGFR2 kinase activity.

68. a method of regulating the c-Kit kinase activity, this method comprises: with the cell of expressing c-Kit be enough to that at least a chemical entity of any one contacts with detecting in the claim 50 to 52 of the amount of external inhibition c-Kit kinase activity.

69. regulate the active method of PDGFR beta kinase for one kind, this method comprises: with the cell of PDGF-B expression R β be enough to that at least a chemical entity of any one contacts with detecting in the claim 44 to 46 of the active amount of external inhibition PDGFR beta kinase.

70. an adjusting is selected from VEGFR2, EphB ₄, at least a kinase whose active method among PDGFR β and the c-Kit, this method comprises: be selected from VEGFR2, EphB with expressing ₄, at least a kinase whose cell among PDGFR β and the c-Kit be enough to be selected from VEGFR2, EphB in external inhibition with detecting ₄, at least a chemical entity of any one contacts in the claim 1 to 54 of at least a kinase whose active amount among PDGFR β and the c-Kit.

71. being used for the treatment of to suffer to reply, the application of at least a chemical entity in the preparation medicine, described medicine be selected from VEGFR2, EphB ₄, the patient of the disease of at least a kinase whose inhibition among PDGFR β and the c-Kit, wherein said at least a chemical entity is any one a chemical entity in the claim 1 to 54.

72. the application of claim 71, wherein said disease of replying at least a kinase whose inhibition is replied the inhibition of VEGFR2 kinase activity.

73. the application of claim 72, the disease of the inhibition of the wherein said VEGFR2 of replying kinase activity are selected from cancer or are characterised in that the disease that vasculogenesis changes.

74. the application of claim 73, the wherein said disease that is characterised in that vasculogenesis changes is selected from cancerous tumour, macular degeneration and diabetic retinopathy.

75. being used for the treatment of to suffer to reply, a method that is used to prepare medicine, described medicine be selected from VEGFR2, EphB ₄, the patient of the disease of at least a kinase whose inhibition among PDGFR β and the c-Kit, this method is included at least a chemical entity that comprises in the claim 1 to 54 any one in the described medicine.

76. the method for claim 75, wherein said disease of replying at least a kinase whose inhibition is replied the inhibition of VEGFR2 kinase activity.

77. the method for claim 76, the disease of the inhibition of the wherein said VEGFR2 of replying kinase activity are selected from cancer or are characterised in that the disease that vasculogenesis changes.

78. the method for claim 77, the wherein said disease that is characterised in that vasculogenesis changes is selected from cancerous tumour, macular degeneration and diabetic retinopathy.

79. a method that is used for the treatment of the female patient of suffering from female reproduction illness or symptom, this method comprises: to female patient drug treatment significant quantity according to any one at least a chemical entity or claim 55 or 56 any one pharmaceutical compositions in the claim 1 to 54.

80. the method for claim 79, wherein said female reproduction illness or symptom are selected from: endometriosis, carcinoma of endometrium, gynecological and hemorrhage illness, menstrual cycle are irregular, ovulation, premenstrual syndrome (PMS) and menopause dysfunction.

81. the method for claim 79 or 80, wherein said at least a chemical entity is by being selected from intravenously, intramuscular and parenteral method administration.

82. the method for any one in the claim 79 to 80, wherein the described at least a chemical entity of significant quantity is an oral administration.