CN101528748A

CN101528748A - Imidazopyridazines as PI3K lipid kinase inhibitors

Info

Publication number: CN101528748A
Application number: CNA2007800399058A
Authority: CN
Inventors: H-G·卡普拉罗; P·菲雷; P·因巴赫; F·施陶费尔
Original assignee: Novartis AG
Current assignee: Novartis AG
Priority date: 2006-10-30
Filing date: 2007-10-29
Publication date: 2009-09-09

Abstract

The invention relates to novel compounds of the formula (I), as well as other invention embodiments related to these compounds. The compounds are e.g. useful in the treatment of the animal or human body in view of their ability to inhibit protein kinases such as especially PI3 kinase.

Description

Imidazopyridazines as the PI3K lipid kinase inhibitors

The present invention relates to new 3, the dibasic 2-methyl-imidazo [1 of 6-, 2-b] pyridazine compound, the method for preparing them, these compounds that are used for the treatment of human or animal body, the purposes of disease that it unites separately or with one or more other medicines active compounds and be used for the treatment of (this term comprise prevent and/or treat), described disease is inflammatory or obstructive respiratory disease (for example asthma), with transplanting diseases associated or proliferative disease (for example tumor disease (can be entity or liquid)), particularly one or more inhibition to the kinase activity of PI3-kinases-related protein kinase enzyme family have the above-mentioned disease of response, and described kinases is lipid kinase and/or PI3 kinases (PI3K) and/or mTOR and/or DNA protein kinase and/or ATM and/or ATR and/or hSMG-1 particularly; Also relate in the animal method of this type of disease of treatment among the mankind particularly; And relate to this compounds, separately or with one or more other medicines active compound combined utilization, in the preparation treatment animal purposes in the pharmaceutical preparation of the described disease among the mankind particularly.

3, the dibasic 2-methyl-imidazo of 6-[1,2-b] pyridazine compound is formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically useful) salt preferably:

Wherein

R ¹It is aryl unsubstituted or that replace; The naphthyl of phenyl of Qu Daiing or replacement particularly; And

R ²Be the phenyl of replacement or the naphthyl of replacement.

Unless otherwise indicated, in content of the present disclosure, the general terms that uses in context preferably has following meaning, and the more upper term of all uses can be replaced by definition more specifically or keep independently of one another, thereby defines preferred embodiment of the present invention.

Prefix " rudimentary " or " C ₁-C ₇-" representative has at the most and comprise the group of maximum 7 (particularly at the most and comprise maximum 4) carbon atoms, described group is a straight chain, or has single or multiple ramose side chains.

Low alkyl group (or C ₁-C ₇-alkyl) 1-7 and comprise the alkyl of 1 and 7 (preferred 1-4 and comprise 1 and 4) carbon atom preferably, and be straight or branched; Preferably, low alkyl group is a butyl, for example normal-butyl, sec-butyl, isobutyl-, the tertiary butyl; Propyl group, for example n-propyl or sec.-propyl; Ethyl; Or preferable methyl.

The numbering of the substituent position that is positioned at central 2-methyl-imidazo [1,2-b] pyridazine ring system that (for example among the embodiment) provides in the disclosure provides in formula I by small letter numeral 2,3 and 6.

Halogen (or halo) is in particular fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine or bromine.

In the alkyl that does not replace or replace, alkyl preferably contains at the most 20, more preferably 12 carbon atoms (also like this in alkyl oxy) at the most, and C particularly ₁-C ₇-alkyl; For straight chain or be one or more side chains; And for unsubstituted or be selected from substituent group described in the following aryl and replace (replace in any position, for example terminal position replaces) by one or more, described group is selected from halogen and cyano group especially.

Single-or dibasic amino preferably by the amino of the alkyl that does not replace as defined above or replaces, the following defined cycloalkyl that does not replace or replace or acyl group (preferably only having an acyl group) replacement, described acyl group for example is C ₁-C ₇-alkyloyl, C ₁-C ₇-alkyl oxy carbonyl, phenyl-and/or naphthyl-C ₁-C ₇-alkoxy carbonyl; Preferably N-single-or N, N-two-(C ₁-C ₇-alkyl, hydroxyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkyl, naphthyl-C ₁-C ₇-alkyl, C ₃-C ₈-cycloalkyl, C ₃-C ₈-cycloalkyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkyloyl, C ₁-C ₇-alkyl oxy carbonyl, phenyl-and/or naphthyl-C ₁-C ₇-alkoxy carbonyl)-amino.

Single-or two-formamyl of replacing is not preferably by alkyl that does not replace as defined above or replaces or following defined the replacement or the formamyl of the cycloalkyl substituted of replacement; Preferably N-single-or N, N-two-(C ₁-C ₇-alkyl, hydroxyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkyl, naphthyl-C ₁-C ₇-alkyl, C ₃-C ₈-cycloalkyl and/or C ₃-C ₈-cycloalkyl-C ₁-C ₇-alkyl)-formamyl.

In the heterocyclic radical that does not replace or replace (also in the heterocyclic radical carbonyl that does not replace or replace), that heterocyclic radical is preferably is undersaturated (=in ring, carry most probable number MPN purpose conjugated double bond, then heterocyclic radical is a heteroaryl), heterocyclic group saturated or fractional saturation, and preferred monocycle, perhaps with regard to broad aspect of the present invention, preferred dicyclo or three encircles; And have 3-24 (more preferably 4-16, most preferably 4-10) annular atoms, most preferably have 6 annular atomses; The heteroatoms that wherein one or more (preferred 1-4, particularly 1 or 2) carboatomic ring atoms are selected from nitrogen, oxygen and sulphur replaces, and the ring of bonding preferably has 4-12 (particularly 5-7) annular atoms; This heterocyclic group (heterocyclic radical) is by unsubstituted or be selected from independently by one or more (particularly 1-3) that defined substituting group is replaced in the aryl of following replacement; Wherein said heterocyclic radical is in particular the heterocyclic radical group that is selected from following groups: Oxyranyle, aziridinyl, the ethylenimine base, 1,2-oxygen thia cyclopentyl, thienyl (=thienyl), furyl, tetrahydrofuran base, pyranyl, the thiapyran base, thianthrenyl, isobenzofuran-base, benzofuryl, chromenyl, the 2H-pyrryl, pyrryl, pyrrolinyl, pyrrolidyl, imidazolyl, imidazolidyl, benzimidazolyl-, pyrazolyl, pyrazinyl, pyrazolidyl, thiazolyl, isothiazolyl, dithiazole base oxazolyl isoxazolyl, pyridyl, pyrazinyl, pyrimidyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thio-morpholinyl, (S-oxo or S, the S-dioxo)-thio-morpholinyl, the indolizine base, the azepan base, Diazesuberane base (particularly 1,4-Diazesuberane base), pseudoindoyl, the 3H-indyl, indyl, benzimidazolyl-, tonka bean camphor base (cumaryl), indazolyl, triazolyl, tetrazyl, purine radicals, the 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydric quinoline group, tetrahydro isoquinolyl, decahydroquinolyl, the octahydro isoquinolyl, benzofuryl, dibenzofuran group, benzothienyl, the dibenzothiophene base, phthalazinyl, naphthyridinyl, pyrrolo--pyrimidyl is pyrrolo-[2 particularly, 3-d] pyrimidine-(for example 1-) base, 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base, pyrrolo--pyridyl is pyrrolo-[2 for example, 3-c] pyridine-1-base (being 5-azepine-indoles-1-yl), quinoxalinyl, quinazolyl, quinazolyl, the cinnolines base, pteridyl, carbazyl, the β-Ka Lin base, phenanthridinyl, acridyl, perimidinyl, the phenanthroline base, the furazan base, phenazinyl, phenothiazinyl phenoxazinyl, chromenyl, different chromanyl, chromanyl, benzo [1,3] dioxole-5-base and 2,3-dihydro-benzo [1,4] dioxin-6-base, each is unsubstituted naturally or replaced by one or more (preferably at the most three) substituting group for these groups, those that above described substituting group is selected from the aryl that replaces is mentioned and oxo are selected from C especially ₁-C ₇-alkyl, hydroxyl-C ₁-C ₇-alkyl is hydroxymethyl, C for example ₁-C ₇-alkoxy-C ₁-C ₇-alkyl is methoxymethyl, amino-or C for example ₁-C ₇-alkylamino-C ₁-C ₇-alkyl, halogen, oxo, hydroxyl, C ₁-C ₇-alkoxyl group, amino, list-or two-(C ₁-C ₇-alkyl and/or hydroxyl-C ₁-C ₇-alkyl)-amino, benzoyl-amido, amino benzoyl amino, C ₁-C ₇-alkoxycarbonyl amino, (phenyl or naphthyl)-C ₁-C ₇-alkoxycarbonyl amino, N-be single-or N, N-two-(C ₁-C ₇-alkyl and/or phenyl-C ₁-C ₇-alkyl) aminocarboxyl, pyridine-2-,-3-or-4-base aminocarboxyl, phenyl amino carbonyl, thiazolyl aminocarboxyl, N-[N '-list-or N ', N '-two-(C ₁-C ₇Alkyl)-amino-C ₁-C ₇-alkyl]-aminocarboxyl and single-or two-[C ₁-C ₇-alkoxyl group, pyrrolidino, piperidino-(1-position only), Piperazino, thiazolyl (for example thiazole-5-yl), hydroxyl-C ₁-C ₇-alkylamino and/or N '-list-or N ', N '-two-(C ₁-C ₇-alkyl)-amino]-phenyl-aminocarboxyl of replacing is (particularly at the heterocyclic radical R that does not replace or replace ¹Situation in, wherein preferably position or contraposition between with respect to the aminocarboxyl group of bonding of heterocyclic radical substituting group).

The heterocyclic radical that does not replace or replace by the N-atomic linkage preferably as leading portion is defined does not replace or the heterocyclic radical of replacement, it comprises at least one nitrogen-atoms, and (it is preferably uncharged, further not protonated or form the N-oxide compound), by the rest part of each group bonding of this nitrogen-atoms to molecule, one of concrete heterocyclic radical of mentioning in the leading portion particularly, wherein there is ring NH in the heterogeneous ring compound, forms described group by this heterogeneous ring compound by removing hydrogen atom from ring NH.

The N-list-or N, the dibasic sulfamyl of N-is preferably by the sulfamyl of alkyl that does not replace as defined above or replace or the following defined cycloalkyl substituted that does not replace or replace; Preferably N-single-or N, N-two-(C ₁-C ₇)-alkyl, hydroxyl-C ₁-C ₇-alkyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkyl, phenyl-C ₁-C ₇-alkyl, naphthyl-C ₁-C ₇-alkyl, C ₃-C ₈-cycloalkyl, azetidine-and/or C ₃-C ₈-cycloalkyl-C ₁-C ₇-alkyl)-sulfamyl.

The preferably following cycloalkyl of cycloalkyl that does not replace or replace: it contains 3-18, more preferably 3-10,3-8 ring carbon atom most preferably, and be unsubstituted or replaced by one or more (3 especially at the most, more preferably 1 or 2) substituting group, below described substituting group is independently selected to the aryl that replaces described those.

In the aryl that does not replace or replace, aryl preferably has 6-18 carbon atom, and be single-, two-or polynary ring-type (preferred three rings at the most, more preferably dicyclo at the most) undersaturated carbon ring group, it has conjugated two keys, particularly phenyl, naphthyl, biphenylene, indacene base (indacenyl), acenaphthenyl, fluorenyl, non-that thiazolinyl (phenalenyl), phenanthryl or anthryl in ring.Particularly preferably be naphthyl and preferred phenyl.

The phenyl that replaces or the naphthyl of replacement are (particularly as R ²) particularly phenyl or naphthyl, more preferably phenyl, they are replaced the described group of aryl above one or more separately, are more preferably replaced by 1-3 (more preferably 1 or 2 or 3) individual group that independently is selected from following groups: halogen, particularly fluorine or chlorine more; C ₁-C ₇-alkoxyl group (extremely preferred), particularly methoxyl group; Hydroxyl; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, particularly 2-methoxy ethoxy, 2-ethoxy ethoxy, 2-or 3-methoxy propoxy, 2-or 3-oxyethyl group propoxy-or 2-or 3-propoxy-propoxy-; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, for example 2-(2-methoxy ethoxy or 2-ethoxy ethoxy)-oxyethyl group; Amino-C ₁-C ₇-alkoxyl group; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, for example 2-dimethyl-or 2-diethyl-amino-oxyethyl group or 2-or 3-dimethyl-or 2-or 3-diethyl-amino-propoxy-; Pyrrolidyl-C ₁-C ₇-alkoxyl group; Piperidyl-C ₁-C ₇-alkoxyl group, for example piperidino-(1-position only)-C ₁-C ₇-alkoxyl group; Morpholinyl-C ₁-C ₇-alkoxyl group, for example morpholino-C ₁-C ₇-alkoxyl group; Thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example thiomorpholine generation-C ₁-C ₇-alkoxyl group; S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example S-oxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, S for example, S-dioxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; Piperazinyl-C ₁-C ₇-alkoxyl group, for example Piperazino-C ₁-C ₇-alkoxyl group; N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group; C ₃-C ₈-cycloalkyloxy; C ₁-C ₇-alkane-alkylsulfonyl, for example methane-or ethane alkylsulfonyl; And C ₃-C ₈-cycloalkyl-alkylsulfonyl is more especially in a position and/or (the most particularly) para-orientation.

Preferably, aryl R ¹Have at least one substituting group (particularly as epimere defined those) and at the methoxyl group of a position in contraposition.

Usually, at R ¹In the situation, in the aryl, the heterocyclic radical of replacement and the cycloalkyl of replacement that replace is under the situation of 6 yuan of rings, and its substituting group can be positioned at the ortho position, position or contraposition between perhaps being preferably placed at, be generally 2 with respect to the atom that is connected with the molecule other parts, perhaps preferred 3 or (particularly) 4.

The N-oxide derivative or the pharmacologically acceptable salt of each formula I compound are also included within the scope of the present invention.For example, suitable oxygenant (superoxide for example, for example between-chloro-benzoyl hydroperoxide or hydrogen peroxide) exist down, the azo-cycle atom of nitrogen heterocyclic ring (for example heteroaryl) can form the N-oxide compound.

If do not offer some clarification on, when mentioning formula I compound, also be intended to comprise one or more N-oxide compounds of this compound.

Term " its N-oxide compound, its solvate and/or its pharmacologically acceptable salt " is meant especially that formula I compound can exist as described like that or with the form of its N-hopcalite or as pure substantially N-oxide compound, exist as the solvate of described compound or N-oxide compound or as the salt of formula I compound or its N-oxide compound or as the solvate of described salt and/or N-oxide compound, exists or exists as the mixture of itself and one or more other form with in the above-mentioned form of pure substantially form each.

Formula I compound also can be modified by additional suitable functional group, thereby improves the biology selectivity.This type of modification is well known in the art, and comprises that those can increase the modification of the modification of given biology system (for example blood, lymphsystem, central nervous system, testis) permeability, increase bioavailability, increase solubleness with the modification that helps parenteral admin (for example inject, infuse), the modification that changes metabolism and/or change secreting rate.The example of this type of modification includes but not limited to esterification (for example adopting the esterification of polyethylene glycols), adopts valeryl oxygen base or fatty acid substituents derivatize, is converted into heteroatomic hydroxylation in carbamate, aromatic ring and the aromatic ring.When mentioning formula I compound, its N-oxide compound, solvate and/or (particularly pharmaceutically acceptable) salt, it comprises the structural formula of this type of modification, although the preferred formula I molecule of mentioning, its N-oxide compound, solvate and/or (particularly pharmaceutically acceptable) salt.

Because free form and its salt form of new formula I compound (comprise those salt that can be used as intermediate, for example be used for the purifying of new compound or evaluation) between be closely connected, if suitably and easily talk about, any appellation to formula I compound all is interpreted as also comprising one or more salt and one or more solvates such as hydrate in the context.

Solvate means (to small part) crystalline formula I compound or its salt, they with have solvent molecule be included in crystallized form in the crystalline structure exist-the term solvate comprises hydrate (crystal that comprises water molecules) and/or any other (preferably pharmaceutically useful) solvate that forms with one or more other solvents herein.

Salt can preferably be formed with organic or inorganic acid by the formula I compound with basic nitrogen atom, for example forms acid salt, especially pharmacologically acceptable salt.Suitable mineral acid for example is haloid acid example hydrochloric acid, sulfuric acid or phosphoric acid.Suitable organic acid for example is a carboxylic-acid, phosphonic acid based, sulfonic acid class or thionamic acid class, acetate for example, propionic acid, sad, capric acid, dodecylic acid, oxyacetic acid, lactic acid, fumaric acid, succsinic acid, propanedioic acid, hexanodioic acid, pimelic acid, suberic acid, nonane diacid, oxysuccinic acid, tartrate, citric acid, amino acid such as L-glutamic acid or aspartic acid, toxilic acid, hydroxymaleic acid, methyl-maleic acid, naphthenic acid, adamantanecarboxylic acid, phenylformic acid, Whitfield's ointment, the 4-aminosallcylic acid, phthalandione, toluylic acid, amygdalic acid, styracin, methylsulfonic acid or ethyl sulfonic acid, the 2-ethylenehydrinsulfonic acid, ethane-1, the 2-disulfonic acid, Phenylsulfonic acid, the 4-toluenesulphonic acids, the 2-naphthene sulfonic acid, 1,5-naphthalene-disulfonic acid, 2-or 3-toluene sulfonic acide, methylsulfuric acid, ethylsulfuric acid, dodecyl sulphate, N-cyclohexyl thionamic acid, N-methyl-thionamic acid, N-ethyl-thionamic acid or N-propyl group-thionamic acid, or other organic protonic acid, as xitix.

For the isolated or purified purpose, also might use pharmaceutically unacceptable salt, for example picrate or perchlorate.Use for treatment, can only use pharmacologically acceptable salt or free cpds (can use with the form of pharmaceutical preparation), therefore, they are preferred.

Preferably formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically acceptable) salt, wherein

R ¹Be phenyl, its be unsubstituted or by one or more, particularly 1 or 2 or 3, more preferably 2 be selected from following group and replace: the alkyl that replaces or replace, C for example unsubstituted or that replaced by hydroxyl ₁-C ₇-alkyl, or cyano group-C ₁-C ₇-alkyl; Halogen; Hydroxyl; Alkyl oxy, particularly C ₁-C ₇-alkoxyl group, particularly methoxyl group; Amino; Single-dibasic amino, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-amino, particularly N-methylamino; C ₁-C ₇-alkanoylamino; C ₁-C ₇-alkoxy carbonyl-amino; Phenyl-or naphthyl-C ₁-C ₇-alkoxy carbonyl-amino; Formamyl; Single-dibasic formamyl, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-formamyl; Tetramethyleneimine-2-carbonyl-amino; Heterocyclic radical carbonyl (wherein heterocyclic radical is bonded to carbonyl by ring nitrogen), particularly piperidino-(1-position only) carbonyl, morpholino-carbonyl, thiomorpholine generation-carbonyl or S-oxo-or S, S-dioxo thiomorpholine is for carbonyl; C ₁-C ₇-alkane alkylsulfonyl; Sulfamyl; The N-list-or N, the dibasic sulfamyl of N-, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl)-sulfamyl; C ₃-C ₈-cycloalkyl-sulfamyl; Azetidine-sulfamyl; Hydroxyl-(C ₁-C ₇-alkyl)-sulfamyl; Cyano group; Nitro; The heterocyclic radical that does not replace or replace by ring carbon atom or preferred theheterocyclic nitrogen atom bonding; particularly 1; 2; 4-triazol-1-yl, formamyl-1; 2,4-triazol-1-yl, pyrazol-1-yl, 3-trifluoromethyl-pyrazol-1-yl, 3-(halogenophenyl)-pyrazol-1-yl for example 3-(4-chloro-phenyl-)-pyrazol-1-yl, tetramethyleneimine-1-base, 2-oxo-tetramethyleneimine-1-base, piperidines-1-base, 2-oxo-piperidine-1-base, morpholino, pyridyl (it is unsubstituted or by cyano group, C ₁-C ₇-alkyl or amino replace), pyrimidyl, pyrazinyl, benzimidazolyl-, C ₁-C ₇The benzothiazolyl of the benzimidazolyl-of-alkoxyl group-replacement, benzothiazolyl, amino-replacement, pyrrolo--pyrimidyl be pyrrolo-[2,3-d] pyrimidyl, C particularly ₁-C ₇Pyrrolo--the pyrimidyl of-alkyl-replacement is 2-C for example ₁-C ₇-alkyl-pyrrolo-[2,3-d] pyrimidin-4-yl-and 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base, it is unsubstituted or by 1 or 2 substituting group replacement, described substituting group independently is selected from C ₁-C ₇-alkyl and halo-C ₁-C ₇-alkyl, and/or also be selected from not the aryl that replaces or replace, the cycloalkyl that does not replace or replace and the heterocyclic radical that does not replace or replace, particularly be selected from phenyl (its be unsubstituted or by one or more for example at the most 2 independently be selected from halogen, C ₁-C ₇-alkoxyl group and C ₁-C ₇The group of-alkane alkylsulfonyl replaces), tetrazolium-5-base, indyl, indazolyl, C ₁-C ₇-alkyl-indazolyl, pyrrolo--pyridyl and azetidine-2-ketone; And

R ²Be phenyl, it is by 1-3, preferred 1 or 2 substituting group replacement (particularly in a position and/or contraposition), and described substituting group is selected from: halogen is fluorine, C particularly ₁-C ₇-alkoxyl group (extremely preferred) is methoxyl group, hydroxyl, C particularly ₁-C ₇-alkoxyl phenyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, amino-C ₁-C ₇-alkoxyl group, N-be single-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy carbonyl, amino-C ₁-C ₇-alkoxyl group, pyrrolidyl-C ₁-C ₇-alkoxyl group, piperidyl-C ₁-C ₇-alkoxyl group, morpholinyl-C ₁-C ₇-alkoxyl group, thio-morpholinyl-C ₁-C ₇-alkoxyl group, S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, piperazinyl-C ₁-C ₇-alkoxyl group, N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group, C ₃-C ₈-cycloalkyloxy, C ₁-C ₇-alkane-alkylsulfonyl and C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Preferred prerequisite is phenyl R ²In a position by C ₁-C ₇-alkoxyl group particularly methoxyl group replaces, and is replaced by following groups in contraposition: C ₁-C ₇-alkoxyl group is methoxyl group, hydroxyl, C particularly ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, amino-C ₁-C ₇-alkoxyl group, N-be single-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, pyrrolidyl-C ₁-C ₇-alkoxyl group, piperidyl-C ₁-C ₇-alkoxyl group, morpholinyl-C ₁-C ₇-alkoxyl group, thio-morpholinyl-C ₁-C ₇-alkoxyl group, S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, piperazinyl-C ₁-C ₇-alkoxyl group, N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group, C ₃-C ₈-cycloalkyloxy, C ₁-C ₇-alkane-alkylsulfonyl or C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Wherein in a more preferred, R ²Be 3, the 4-Dimethoxyphenyl.

More preferably following formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically acceptable) salt, wherein

R ¹Be phenyl, its be unsubstituted or by one or more, particularly 1 or 2 or 3, more preferably 1 or 2 group replace (preferably the 3-of phenyl () and/or 4-(to) position), described group is selected from: hydroxyl-C ₁-C ₇-alkyl; Cyano group-C ₁-C ₇-alkyl; Halogen; C ₁-C ₇-alkoxyl group; Amino; The N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-amino; C ₁-C ₇-alkanoylamino; C ₁-C ₇-alkoxy carbonyl-amino; Phenyl-or naphthyl-C ₁-C ₇-alkoxy carbonyl-amino; Formamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-formamyl; Tetramethyleneimine-2-carbonyl-amino; The piperidino-(1-position only) carbonyl; Morpholino-carbonyl; Thiomorpholine generation-carbonyl; The S-oxo-or S, S-dioxo thiomorpholine is for carbonyl; C ₁-C ₇-alkane alkylsulfonyl; Sulfamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-sulfamyl; C ₃-C ₈-cycloalkyl-sulfamyl; Azetidine-sulfamyl; Hydroxyl-(C ₁-C ₇-alkyl)-sulfamyl; Cyano group; Nitro; 1,2, the 4-triazol-1-yl; Formamyl-1,2,4-triazol-1-yl, 3-formamyl-1,2 for example, 4-triazol-1-yl; Pyrazol-1-yl; 3-trifluoromethyl-pyrazol-1-yl; 3-(halogenophenyl)-pyrazol-1-yl, for example 3-(4-chloro-phenyl-)-pyrazol-1-yl; Tetramethyleneimine-1-base; 2-oxo-tetramethyleneimine-1-base; Piperidines-1-base; 2-oxo-piperidine-1-base; Morpholino; Pyridine-(2-, 3-or 4-) base, it is unsubstituted or by cyano group, C ₁-C ₇-alkyl or amino replacement; Pyrimidine-(2-, 4-or 5-) base; Pyrazinyl; Benzimidazolyl-; C ₁-C ₇The benzimidazolyl-of-alkoxyl group-replacement; Benzothiazolyl; The benzothiazolyl of amino-replacement; Pyrrolo--pyrimidyl, particularly pyrrolo-[2,3-d] pyrimidin-4-yl-; C ₁-C ₇Pyrrolo--the pyrimidyl of-alkyl-replacement; And 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base, it is unsubstituted or by 1 or 2 substituting group replacement, described substituting group independently is selected from C ₁-C ₇-alkyl and halo-C ₁-C ₇-alkyl, or (it is unsubstituted or by one or more halogen, C of independently being selected from also to be selected from phenyl ₁-C ₇-alkoxyl group and C ₁-C ₇The group replacement of-alkane alkylsulfonyl), tetrazolium-5-base, indyl, indazolyl, C ₁-C ₇-alkyl-indazolyl, pyrrolo--pyridyl and azetidine-2-ketone; And

R ²Be phenyl, it is by 1-3, preferred 1 or 2 substituting group replacement, and described substituting group is selected from halogen, C ₁-C ₇-alkoxyl group, hydroxyl, C ₁-C ₇-alkoxyl phenyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, amino-C ₁-C ₇-alkoxyl group, N-be single-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy carbonyl, amino-C ₁-C ₇-alkoxyl group, pyrrolidyl-C ₁-C ₇-alkoxyl group, piperidyl-C ₁-C ₇-alkoxyl group, morpholinyl-C ₁-C ₇-alkoxyl group, thio-morpholinyl-C ₁-C ₇-alkoxyl group, S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, piperazinyl-C ₁-C ₇-alkoxyl group, N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group, C ₃-C ₈-cycloalkyloxy, C ₁-C ₇-alkane-alkylsulfonyl and C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Preferred prerequisite is phenyl R ²In a position by C ₁-C ₇-alkoxyl group particularly methoxyl group replaces, and is replaced by following groups in contraposition: C ₁-C ₇-alkoxyl group, hydroxyl, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, amino-C ₁-C ₇-alkoxyl group, N-be single-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, pyrrolidyl-C ₁-C ₇-alkoxyl group, piperidyl-C ₁-C ₇-alkoxyl group, morpholinyl-C ₁-C ₇-alkoxyl group, thio-morpholinyl-C ₁-C ₇-alkoxyl group, S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, piperazinyl-C ₁-C ₇-alkoxyl group, N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group, C ₃-C ₈-cycloalkyloxy, C ₁-C ₇-alkane-alkylsulfonyl or C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Wherein in a preferred embodiment, R ²Be 3, the 4-Dimethoxyphenyl.

Even more preferably following formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically useful) salt, wherein

R ¹It is phenyl; (particularly 3-or 4-) halogenophenyl; (particularly 3-or 4-) C ₁-C ₇-alkoxyl phenyl; Halo-and C ₁-C ₇The phenyl of-alkoxyl group-replacement, particularly 3-halo-4-C ₁-C ₇-alkoxyl phenyl or 4-halo-3-C ₁-C ₇-alkoxyl phenyl; Halo-, C ₁-C ₇-alkoxyl group-and C ₁-C ₇The phenyl of-alkyl-replacement, for example 2-halo-4-C ₁C ₇-alkoxyl group-5-C ₁-C ₇-alkyl-phenyl; (particularly 3-or 4-) aminophenyl; Tetramethyleneimine-2-carbonylamino-phenyl; (particularly 3-or 4-) list-or two-(C ₁-C ₇-alkyl) phenyl; (particularly 3-or 4-) C ₁-C ₇-alkane alkylsulfonyl-phenyl; Azetidine-1-alkylsulfonyl-phenyl; (particularly 3-or 4-) sulfamyl-phenyl; (particularly 3-or 4-) N-list-(C ₁-C ₇-alkyl)-sulfamyl-phenyl; Cyclopropyl-sulfamyl-phenyl; 2-hydroxyl-ethyl-sulfamyl-phenyl; (particularly 3-or 4-) cyano-phenyl; (particularly 3-or 4-) nitrophenyl; (particularly 4-) 1,2,4-triazol-1-yl-phenyl; (particularly 4-) pyrazol-1-yl-phenyl; (particularly 4-) (3-trifluoromethyl-pyrazol-1-yl)-phenyl; (particularly 4-) 2-oxo-tetramethyleneimine-1-base-phenyl; (particularly 4-) 2-oxo-piperidine-1-base-phenyl; (particularly 4-) morpholino-phenyl; (particularly 3-or 4-) piperazine-1-base-phenyl; (particularly 3-or 4-) 4-(C ₁-C ₇-alkyl)-piperazine-1-base-phenyl; (particularly 4-) pyridine-(2-, 3-or 4-) base-phenyl; Cyano group-pyridyl-phenyl; Methyl-pyridyl-phenyl; Amino-pyridine base-phenyl; (particularly 4-) pyrimidine-(2-, 4-or 5-) base-phenyl; Pyrazinyl-phenyl; Azetidine-2-ketone-phenyl; Or (particularly 3-or 4-) benzoglyoxaline-1-base-phenyl; And

R ²It is 4-methane-alkylsulfonyl phenyl; 4 '-methoxyl group-xenyl; 4-(3-amino-propoxy-)-3-methoxyl group-phenyl; 3,4-two-C ₁-C ₇-phenalkyloxy-, particularly 3,4-Dimethoxyphenyl or 4-oxyethyl group-3-methoxyl group-phenyl.

The embodiment of the present invention that also is preferably as follows, it relates to as shown in the formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically acceptable) salt, wherein

R ¹Be phenyl, its be unsubstituted or by one or more, particularly 1 or 2 or 3 group replaces, described group is selected from: the alkyl that replaces or replace, C for example unsubstituted or that replaced by hydroxyl ₁-C ₇-alkyl, or cyano group-C ₁-C ₇-alkyl; Halogen; Hydroxyl; Alkyl oxy, particularly C ₁-C ₇-alkoxyl group, particularly methoxyl group; Amino; Single-dibasic amino, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-amino, particularly N-methylamino; C ₁-C ₇-alkanoylamino; C ₁-C ₇-alkoxy carbonyl-amino; Phenyl-or naphthyl-C ₁-C ₇-alkoxy carbonyl-amino; Formamyl; Single-dibasic formamyl, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-formamyl; Heterocyclic radical carbonyl (=heterocyclic radical-C (=O)-), wherein heterocyclic radical is bonded to carbonyl by ring nitrogen, piperidino-(1-position only) carbonyl, morpholino-carbonyl, thiomorpholine generation-carbonyl or S-oxo-or S particularly, S-dioxo thiomorpholine is for carbonyl; C ₁-C ₇-alkane alkylsulfonyl, for example methane sulfonyl; Sulfamyl; The N-list-or N, the dibasic sulfamyl of N-, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl)-sulfamyl; Cyano group; Nitro; The heterocyclic radical that does not replace or replace by ring carbon atom or preferred theheterocyclic nitrogen atom bonding; particularly 1; 2; the 4-triazol-1-yl; formamyl-1; 2; the 4-triazol-1-yl is 3-formamyl-1 for example; 2, the 4-triazol-1-yl; pyrazol-1-yl; 3-trifluoromethyl-pyrazol-1-yl; 3-(halogenophenyl)-pyrazol-1-yl is 3-(4-chloro-phenyl-)-pyrazol-1-yl for example; tetramethyleneimine-1-base; 2-oxo-tetramethyleneimine-1-base; piperidines-1-base; 2-oxo-piperidine-1-base; morpholino; pyridine-(2-; 3-or 4-) base; pyrimidine-(2-; 4-or 5-) base; benzoglyoxaline (base particularly-1-); (for example 5-) C ₁-C ₇The benzoglyoxaline of-alkoxyl group-replacement (particularly pyrrolo-[2,3-d] pyrimidine-(for example 1-) base, C of base, pyrrolo--pyrimidyl particularly-1-) ₁-C ₇Pyrrolo--the pyrimidyl of-alkyl-replacement is 2-C for example ₁-C ₇-alkyl-pyrrolo-[2,3-d] pyrimidine-(for example 1-) base (is 2-C ₁-C ₇-alkyl-5,7-diaza indoles-1-yl) and 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base (being 5-azepine-3,4,5,6-tetrahydrochysene indazole-1-yl), it is unsubstituted or by 1 or 2 substituting group replacement, described substituting group independently is selected from C ₁-C ₇-alkyl (for example methyl, particularly in the 5-position) and halo-C ₁-C ₇-alkyl (trifluoromethyl for example, particularly in the 3-position), and/or also be selected from not the aryl that replaces or replace, the cycloalkyl that does not replace or replace and the heterocyclic radical that does not replace or replace, particularly be selected from phenyl (its be unsubstituted or by one or more for example at the most 2 independently be selected from halogen, C ₁-C ₇-alkoxyl group and C ₁-C ₇The group of-alkane alkylsulfonyl replaces), tetrazolium-5-base, indoles-(for example 5-) base, indazolyl for example indazole-5-base, (for example 3-) C ₁-C ₇-alkyl-indazole-(for example 5-) base and pyrrolo--pyridyl be pyrrolo-[2,3-c] pyridine-1-base (being 5-azepine-indoles-1-yl) for example;

R ²Be phenyl, it is by 1-3, preferred 1 or 2 substituting group replacement (particularly in a position and/or contraposition), and described substituting group is selected from: halogen, particularly fluorine; C ₁-C ₇-alkoxyl group (extremely preferred), particularly methoxyl group; Hydroxyl; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, particularly 2-methoxy ethoxy, 2-ethoxy ethoxy, 2-or 3-methoxy propoxy, 2-or 3-oxyethyl group propoxy-or 2-or 3-propoxy-propoxy-; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, for example 2-(2-methoxy ethoxy or 2-ethoxy ethoxy)-oxyethyl group; Amino-C ₁-C ₇-alkoxyl group; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, for example 2-dimethyl-or 2-diethyl-amino-oxyethyl group or 2-or 3-dimethyl-or 2-or 3-diethyl-amino-propoxy-; Pyrrolidyl-C ₁-C ₇-alkoxyl group; Piperidyl-C ₁-C ₇-alkoxyl group, for example piperidino-(1-position only)-C ₁-C ₇-alkoxyl group; Morpholinyl-C ₁-C ₇-alkoxyl group, for example morpholino-C ₁-C ₇-alkoxyl group; Thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example thiomorpholine generation-C ₁-C ₇-alkoxyl group; S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example S-oxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, S for example, S-dioxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; Piperazinyl-C ₁-C ₇-alkoxyl group, for example Piperazino-C ₁-C ₇-alkoxyl group; N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group; C ₃-C ₈-cycloalkyloxy; C ₁-C ₇-alkane-alkylsulfonyl, for example methane-or ethane alkylsulfonyl; And C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Preferred prerequisite is phenyl R ²In a position by C ₁-C ₇-alkoxyl group particularly methoxyl group replaces, and is replaced by following groups in contraposition: C ₁-C ₇-alkoxyl group, particularly methoxyl group; Hydroxyl; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, particularly 2-methoxy ethoxy, 2-ethoxy ethoxy, 2-or 3-methoxy propoxy, 2-or 3-oxyethyl group propoxy-or 2-or 3-propoxy-propoxy-; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, for example 2-(2-methoxy ethoxy or 2-ethoxy ethoxy)-oxyethyl group; Amino-C ₁-C ₇-alkoxyl group; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, for example 2-dimethyl-or 2-diethyl-amino-oxyethyl group or 2-or 3-dimethyl-or 2-or 3-diethyl-amino-propoxy-; Pyrrolidyl-C ₁-C ₇-alkoxyl group; Piperidyl-C ₁-C ₇-alkoxyl group, for example piperidino-(1-position only)-C ₁-C ₇-alkoxyl group; Morpholinyl-C ₁-C ₇-alkoxyl group, for example morpholino-C ₁-C ₇-alkoxyl group; Thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example thiomorpholine generation-C ₁-C ₇-alkoxyl group; S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example S-oxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, S for example, S-dioxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; Piperazinyl-C ₁-C ₇-alkoxyl group, for example Piperazino-C ₁-C ₇-alkoxyl group; N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group; C ₃-C ₈-cycloalkyloxy; C ₁-C ₇-alkane-alkylsulfonyl, for example methane-or ethane alkylsulfonyl; Or C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Wherein in a preferred embodiment, R ²Be 3, the 4-Dimethoxyphenyl.

Also preferred following embodiment of the present invention, it relates to following formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically acceptable) salt, wherein

R ¹Be phenyl, its be unsubstituted or by one or more, particularly 1 or 2 or 3 group replace (preferably the 3-of phenyl () position and/or 4-(to) position), described group is selected from: hydroxyl-C ₁-C ₇-alkyl, for example 3-hydroxypropyl; Cyano group-C ₁-C ₇-alkyl, for example cyano methyl; Halogen, particularly fluorine, chlorine, bromine or iodine; C ₁-C ₇-alkoxyl group, particularly methoxyl group; Amino; The N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-amino, particularly N-methylamino; C ₁-C ₇-alkanoylamino; C ₁-C ₇-alkoxy carbonyl-amino; Phenyl-or naphthyl-C ₁-C ₇-alkoxy carbonyl-amino; Formamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-formamyl; The piperidino-(1-position only) carbonyl; Morpholino-carbonyl; Thiomorpholine generation-carbonyl; The S-oxo-or S, S-dioxo thiomorpholine is for carbonyl; C ₁-C ₇-alkane alkylsulfonyl, for example methane sulfonyl; Sulfamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-sulfamyl; Cyano group; Nitro; 1,2, the 4-triazol-1-yl; Formamyl-1,2,4-triazol-1-yl, 3-formamyl-1,2 for example, 4-triazol-1-yl; Pyrazol-1-yl; 3-trifluoromethyl-pyrazol-1-yl; 3-(halogenophenyl)-pyrazol-1-yl, for example 3-(4-chloro-phenyl-)-pyrazol-1-yl; Tetramethyleneimine-1-base; 2-oxo-tetramethyleneimine-1-base; Piperidines-1-base; 2-oxo-piperidine-1-base; Morpholino; Pyridine-(2-, 3-or 4-) base; Pyrimidine-(2-, 4-or 5-) base; Benzoglyoxaline (base particularly-1-); (for example 5-) C ₁-C ₇The benzoglyoxaline of-alkoxyl group-replacement (base particularly-1-); Pyrrolo--pyrimidyl, particularly pyrrolo-[2,3-d] pyrimidine-(for example 1-) base; C ₁-C ₇Pyrrolo--the pyrimidyl of-alkyl-replacement, for example 2-C ₁-C ₇-alkyl-pyrrolo-[2,3-d] pyrimidine-(for example 1-) base (is 2-C ₁-C ₇-alkyl-5,7-diaza indoles-1-yl); And 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base (being 5-azepine-3,4,5,6-tetrahydrochysene indazole-1-yl), it is not replace or replaced by 1 or 2 substituting group, described substituting group independently is selected from C ₁-C ₇-alkyl (for example methyl, particularly in the 5-position) and halo-C ₁-C ₇-alkyl (for example trifluoromethyl, particularly in the 3-position), or also be selected from phenyl (its be do not replace or by one or more for example at the most 2 independently be selected from halogen, C ₁-C ₇-alkoxyl group and C ₁-C ₇The group replacement of-alkane alkylsulfonyl), tetrazolium-5-base, indoles-(for example 5-) base, indazolyl, (for example 3-) C ₁-C ₇-alkyl-indazole-(for example 5-) base and pyrrolo--pyridyl be pyrrolo-[2,3-c] pyridine-1-base (being 5-azepine-indoles-1-yl) for example; And

Preferred prerequisite is, phenyl in a position by C ₁-C ₇-alkoxyl group particularly methoxyl group replaces, and is replaced by following groups in contraposition: C ₁-C ₇-alkoxyl group, particularly methoxyl group; Hydroxyl; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, particularly 2-methoxy ethoxy, 2-ethoxy ethoxy, 2-or 3-methoxy propoxy, 2-or 3-oxyethyl group propoxy-or 2-or 3-propoxy-propoxy-; C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxy-C ₁-C ₇-alkoxyl group, for example 2-(2-methoxy ethoxy or 2-ethoxy ethoxy)-oxyethyl group; Amino-C ₁-C ₇-alkoxyl group; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-amino-C ₁-C ₇-alkoxyl group, for example 2-dimethyl-or 2-diethyl-amino-oxyethyl group or 2-or 3-dimethyl-or 2-or 3-diethyl-amino-propoxy-; Pyrrolidyl-C ₁-C ₇-alkoxyl group; Piperidyl-C ₁-C ₇-alkoxyl group, for example piperidino-(1-position only)-C ₁-C ₇-alkoxyl group; Morpholinyl-C ₁-C ₇-alkoxyl group, for example morpholino-C ₁-C ₇-alkoxyl group; Thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example thiomorpholine generation-C ₁-C ₇-alkoxyl group; S-oxo-thio-morpholinyl-C ₁-C ₇-alkoxyl group, for example S-oxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; S, S-dioxo thio-morpholinyl-C ₁-C ₇-alkoxyl group, S for example, S-dioxo thiomorpholine generation-C ₁-C ₇-alkoxyl group; Piperazinyl-C ₁-C ₇-alkoxyl group, for example Piperazino-C ₁-C ₇-alkoxyl group; N '-C ₁-C ₇-alkyl-Piperazino-C ₁-C ₇-alkoxyl group; C ₃-C ₈-cycloalkyloxy; C ₁-C ₇-alkane-alkylsulfonyl, for example methane-or ethane alkylsulfonyl; Or C ₃-C ₈-cycloalkyl-alkylsulfonyl;

Wherein in a preferred embodiment, R ²Be 3, the 4-Dimethoxyphenyl.

R ¹It is phenyl; (particularly 3-or 4-) halogenophenyl; (particularly 3-or 4-) C ₁-C ₇-alkoxyl phenyl; Halo-and C ₁-C ₇The phenyl of-alkoxyl group-replacement, particularly 3-halo-4-C ₁-C ₇-alkoxyl phenyl or 4-halo-3-C ₁-C ₇-alkoxyl phenyl; Halo-, C ₁-C ₇-alkoxyl group and C ₁-C ₇The phenyl of-alkyl-replacement, for example 2-halo-4-C ₁C ₇-alkoxyl group-5-C ₁-C ₇-alkyl-phenyl; (particularly 3-or 4-) aminophenyl; (particularly 3-or 4-) list-or two-(C ₁-C ₇-alkyl) phenyl; (particularly 3-or 4-) C ₁-C ₇-alkane alkylsulfonyl-phenyl; (particularly 3-or 4-) cyano-phenyl; (particularly 3-or 4-) nitrophenyl; (particularly 4-) 1,2,4-triazol-1-yl-phenyl; (particularly 4-) pyrazol-1-yl-phenyl; (particularly 4-) (3-trifluoromethyl-pyrazol-1-yl)-phenyl; (particularly 4-) 2-oxo-tetramethyleneimine-1-base-phenyl; (particularly 4-) 2-oxo-piperidine-1-base-phenyl; (particularly 4-) morpholino-phenyl; (particularly 3-or 4-) piperazine-1-base-phenyl; (particularly 3-or 4-) 4-(C ₁-C ₇-alkyl)-piperazine-1-base-phenyl; (particularly 4-) pyridine-(2-, 3-or 4-) base-phenyl; (particularly 4-) pyrimidine-(2-, 4-or 5-) base-phenyl; Or (particularly 3-or 4-) benzoglyoxaline-1-base-phenyl, and

R ²Be 3,4-two-C ₁-C ₇-phenalkyloxy-, particularly 3, the 4-Dimethoxyphenyl.

Therefore embodiment of the present invention described in also extremely preferred claims, are hereby incorporated by them.

The present invention be more particularly directed to provide among the embodiment below the described formula I compound of title, preferred separately shown in structural formula isomer or its pharmacologically acceptable salt or it is according to purposes of the present invention.

Unexpectedly find now, formula I compound has favourable pharmacological property, can suppress the sharp family of lipid kinase such as PI3-kinases and/or PI3-kinases dependency albumen and (be also referred to as PIKK, comprise DNA-PK, ATM, ATR, hSMG-1 and mTOR) member's activity of DNA protein kinase for example, can be used for treating the disease or the illness that depend on described kinase activity.

Phosphatidylinositols-3 '-OH kinases (PI3K) path is one of maincenter signal transduction pathway, and it brings into play its effect to various kinds of cell function (comprising cell cycle development, propagation, mobility, metabolism and survival).The activation of receptor tyrosine kinase can cause PI3K to make phosphatidylinositols-(4,5)-bisphosphate phosphorylation, produces phosphatidylinositols-(3,4, the 5)-triguaiacyl phosphate of film bonding.The latter can pass through phosphatidylinositols-(3,4,5)-triguaiacyl phosphate and combine and promote the multiple protein kinases to shift to plasma membrane from tenuigenin with kinase whose thrombocyte white corpuscle C kinase substrate homology (PH) structural domain.Kinases as the crucial downstream targets of PI3K comprises phosphoinositide-dependant kinase 1 (PDK1) and AKT (being also referred to as protein kinase B).The kinase whose phosphorylation of this class can make multiple other path activate or inactivation then, comprises medium such as GSK3, mTOR, PRAS40, FKHD, NF-κ B, BAD, Caspase-9 etc.The important negative feedback mechanism of PI3K path is PTEN, and it is that catalysis phosphatidylinositols-(3,4,5)-triguaiacyl phosphate dephosphorylation is the Phosphoric acid esterase of phosphatidylinositols-(4, the 5)-bisphosphate of phosphorylation.In surpassing all solid tumors of 60%, PTEN sports the form of non-activity, makes PI3K path constitutively activate.Because most of cancer is solid tumor, thus this type of observation provides following evidence: PI3K itself or in the PI3K path the independent kinase whose target in downstream can provide and be used for alleviating or even eliminate out of control in the multiple cancer and so recover the method likely of normal cell function and behavior.But this does not get rid of other mechanism of the beneficial effect of PI3K active regulator (for example those conditioning agents in the present invention).

Consider its restraining effect to phosphatidyl-inositol 3-kinase; formula (I) compound free or pharmaceutical acceptable salt can be used for treating the illness that the activation (comprising normal activity or especially excessively active) by one or more members (especially PI3 kinases) of PI3 kinases family is mediated, for example proliferative disease, inflammatory diseases or anaphylactic disease, obstructive respiratory disease and/or with transplant relevant illness.

" treatment " of the present invention can be curative (as symptomatic treatment) and/or preventative.Preferred therapeutic warm-blooded animal, especially people.

Be preferred for treating formula (I) compound and the purposes in the treatment proliferative disease thereof of proliferative disease, described proliferative disease is selected from optimum or malignant tumour, the cancer of the brain, kidney, liver cancer, adrenal carcinoma, bladder cancer, mastocarcinoma, cancer of the stomach, gastric tumor, ovarian cancer, colorectal carcinoma, the rectum cancer, prostate cancer, carcinoma of the pancreas, lung cancer, carcinoma of vagina or thyroid carcinoma, sarcoma, glioblastoma, multiple myeloma or gastrointestinal cancer, especially colorectal carcinoma or colorectal carcinoma or neck tumour, the epidermis hyperplasia, psoriatic, hyperplasia of prostate, tumorigenesis, the tumorigenesis of epithelial character, lymphoma, mammary cancer or leukemia.Other disease comprise cowden's syndrome (Cowden syndrome), Lai Ermi-Du Baisi (Lhermitte-Dudos) disease and Bannayan-Zonana syndrome or wherein the PI3K/PKB path by the disease of abnormal activation.

Compound of the present invention also can be used for treating inflammatory or obstructive airway (respiratory tract) disease, thereby for example reduces tissue injury, airway inflammation, bronchial hyperreactivity, reinvent or disease progression.Inflammatory that the present invention is suitable for or obstructive respiratory disease comprise the asthma of any kind or cause, comprise endogenous (nonallergic) asthma and exogenous (supersensitivity) asthma, for example the asthma of bringing out behind mild asthma, moderate bronchial asthma, severe asthma, segmental bronchus inflammatory asthma, exercise induced type asthma, occupational asthma and the infectation of bacteria.Treatment of asthma be will also be understood that to be to comprise for example less than the treatment of the individuality of 4 years old or 5 years old, these individualities show the symptom and diagnosed or diagnosable for " infant of stridulating (wheezyinfants) " of stridulating, this is a kind of patient's classification of medically very paying close attention to of having established, is accredited as initial stage or early stage asthma at present usually.(for simplicity, this specific asthma is called " the infant's syndrome of stridulating ".)

Prevention effects in the treating asthma can be confirmed by frequency or the reduction of severity, the improvement of pulmonary function or the improvement of respiratory tract hyperergy such as the paresthesia epilepsy of acute asthma or bronchoconstriction outbreak.This effect can further be confirmed by the minimizing to other allopathic demand, described other symptomatic therapy promptly is used for or is intended to be used for limiting paresthesia epilepsy or make its therapy that stops when symptom taking place, for example antiphlogiston (for example reflunomide) or bronchodilator.The beneficial effect of prevention of asthma is obvious especially in the individuality that tends to " falling (morning dipping) morning "." fall morning " is a kind of generally acknowledged asthma syndrome, very common and be characterised in that asthma attack between several hours of 4 to 6 of about mornings for example in the asthma of suitable vast scale, promptly asthma is leaving one's post usually what gave in advance and is suiting the medicine to the illness asthma therapies time point outbreak all quite far away.

Formula I compound can be used for other inflammatory or obstructive respiratory disease and the illness that the present invention is suitable for, comprise acute lung injury (ALI), adult/adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, respiratory tract disease or lung disease (COPD, COAD or COLD), comprise chronic bronchitis or associated expiratory dyspnea, pulmonary emphysema and the respiratory tract hyperergy that causes because of other medicines treatment (particularly other sucks pharmacological agent) aggravate.

The present invention also is applicable to the bronchitis of treatment any kind or cause, comprises for example acute, Semen arachidis hypogaeae imbedibility, Catarrhal, croup (croupus), chronic or phthinoid bronchitis.The present invention is applicable to that no matter other inflammatory of treatment or the pneumokoniosis that obstructive respiratory disease comprises any kind or cause (be chronic or acute, this disease often is attended by respiratory tract obstruction and causes because of sucking dust repeatedly, be a kind of inflammatory and be generally professional tuberculosis), for example comprise aluminosis, anthracosis, asbestosis, chalicosis, ostrich hair pneumoconiosis, siderosis, silicosis, tabacism and byssinosis.

Consider its anti-inflammatory activity, especially suppress relevant anti-inflammatory activity with the eosinophilic granulocyte activatory, it is diseases related that compound of the present invention also can be used for treating eosinophilic granulocyte, eosinophilia for example, especially the respiratory tract disease that eosinophilic granulocyte is relevant (the ill eosinophilic granulocyte that for example comprises lung tissue soaks into), comprise oxyphie too much (because it influences respiratory tract and/or lung), and for example by

Syndrome cause or concurrent with it respiratory tract oxyphie diseases related, the eosinophilic pneumonia, parasite (particularly metazoan) infect (comprising tropical eosinophilosis's disease), bronchopneumonic aspergillosis, polyarteritis nodosa (comprising Qiu-Si syndrome), the oxyphie that influences respiratory tract that oxyphie granuloma and drug reaction cause is diseases related.

Compound of the present invention also can be used for treating the inflammatory or the supersensitivity illness of skin, for example psoriatic, contact dermatitis, atopic dermatitis, alopecia circumscripta, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita and other skin inflammatory or skin hypersensitivity illness.

Compound of the present invention can also be used for the treatment of other disease or illness, for example has the disease or the illness of inflammatory component, for example is used for the treatment of eye disease and illness, for example conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis; Influence the disease of nose, comprise allergic rhinitis; Relevant with autoimmune response or have the inflammatory diseases of the immunizing composition or the cause of disease, comprise autoimmunity hematologic disease (for example hemolytic anemia, aplastic anemia, pure red-cell anemia and Te Fa thrombopenia); Systemic lupus erythematous; Polychondritis; Sclerosis (sclerodoma); Wegner granulomatosis; Dermatomyositis; Chronic active hepatitis; Myasthenia gravis; Si-Qiong (Steven-Johnson) syndrome; The special property sent out sprue; Autoimmunity inflammatory bowel (for example ulcerative colitis and crohn); Endocrine ophthalmopathy; Graves disease; Sarcoidosis; Dentoalveolitis; The chronic anaphylaxis pneumonia; Multiple sclerosis; Primary biliary cirrhosis; Uveitis (preceding and back uveitis); Keratoconjunctivitis sicca and vernal keratoconjunctivitis; Interstitial pulmonary fibrosis; Psoriasis arthropathica; Glomerulonephritis (with or without nephrotic syndrome, for example comprise idiopathic nephrotic syndrome or subtle change ephrosis).

In addition, the invention provides the compound or pharmaceutically acceptable salt thereof of this paper definition or its hydrate or solvate is used for the treatment of proliferative disease, inflammatory diseases, obstructive respiration systemic disease or follows purposes in the medicine of transplanting the disease that takes place usually in preparation.

The invention particularly relates to the purposes of the formula I compound pharmaceutical preparation of formula I compound (or contain) in the disease that one or more contexts of treatment are mentioned, wherein said disease has response (in useful mode to the inhibition of one or more kinases (the most particularly PI3 kinases (PI3K)) in the PI3-kinases dependency protein kinase family, for example by partially or completely eliminating one or more its symptoms) until curing fully or alleviating, especially wherein kinases demonstrates (under the situation of other regulation mechanism) not high enough activity, or more preferably is higher than normal (for example composition) activity.

No matter term " purposes " or " use " are referred wherein; all be intended to comprise and be used for preventing and/or treating the especially formula I compound (being also included within the compound of being got rid of in the protection of above-mentioned and claim compound itself) of human diseases (preferably one or more contexts mention disease) of warm-blooded animal; comprise the using method or the methods of treatment that formula I compound are awarded the people who needs this treatment with the significant quantity that prevents and/or treats the disease of mentioning as context; the preparation or the preparation method that comprise the pharmaceutical preparation that is used to prevent and treat the disease that context mentions; especially comprise formula I compound (as the therapeutic activity composition) and at least a pharmaceutically acceptable carrier material mixing, comprise making it be used for this treatment (for example add specification sheets inset (as package insert etc.) easily; prescription; suitable preparation; be suitable for special purpose; according to customer requirement customization etc.) and be used for the purposes of formula I compound of this type of preparation and/or all other prevention or the therepic use that context is mentioned.All these aspects all are embodiment of the present invention.

Can followingly prove as the formula I compound of PI3 kinase inhibitor and the usefulness of salt thereof:

In the long-pending COSTAR (96 orifice plate) of demifacet, carry out kinase reaction with the final volume in 50 μ l/ holes.The final concentration of ATP and phosphatidylinositols is respectively 5 μ M and 6 μ g/mL in the analysis.Add for example PI3 kinases p110 β initiation reaction of PI3 kinases.

Component is analyzed in the following adding in every hole:

The 2-1 row, the 5%DMSO solution of every hole 10 μ L test-compounds.

In back 4 holes of the 1st preceding 4 holes that are listed as and the 12nd row, add 10 μ L 5%v/vDMSO and measure gross activity.

In preceding 4 holes of the 1st back 4 holes that are listed as and the 12nd row, add 10 μ M control compounds and measure background.

Every block of plate prepares 2ml " analysis of mixtures ":

1.912ml HEPES analysis buffer

8.33 μ L 3mM ATP storing solution, every hole final concentration is 5 μ M

1 μ L be in the active phase [ ³³P] ATP, every hole is 0.05 μ Ci

30 μ L 1mg/mL PI storing solutions, every hole final concentration is 6 μ g/mL

5 μ L 1M MgCl ₂Storing solution, every hole final concentration is 1mM

Every hole adds 20 μ L analysis of mixtures.

Every block of plate prepares 2ml " enzyme mixture " (containing x* μ L PI3 kinases p110 β in 2ml kinase buffer liquid).During joining analysis plates, " enzyme mixture " placed on ice.

Every hole adds 20 μ l " enzyme mixture " to begin reaction.

Then with plate in room temperature incubation 90 minutes.

Add 50 μ L WGA-SPA pearls (wheat germ agglutinin bag quilt get close to scintillation analysis pearl) suspension termination reaction to every hole.

Adopt TopSeal-S (sealant of polystyrene micro plate, PerkinElmerLAS (Deutschland) GmbH, Rodgau, Germany) sealing analysis plates, in room temperature incubation at least 60 minutes.

Adopt Jouan desk centrifuge (Jouan Inc., Nantes, France) with analysis plates centrifugal 2 minutes then in 1500rpm.

Adopt Packard TopCount that analysis plates is counted, every hole counting 20 seconds.

^*The enzyme volume will depend on used batch enzymic activity.

Some compound exhibits goes out the selectivity at different symbiosis homology (paralogs) PI3K α, β, γ and δ of certain level.

Field of activity during these are analyzed preferably at 150nM between about 5 μ M.

The description of DNA-PK biochemical analysis:

In the enzyme prepared product of purifying and nucleus extract, adopt and to carry out quantitative test kit V7870 (Signa to DNA-deopendent protein kinase activity available from Promega

DNA-deopendent protein kinase system comprises DNA-PK, biotinylation peptide substrates and other composition, Promega, and Madison, Wisconsin USA) analyzes.DNA-PK is a kind of nuclear serine/threonine protein kitase, and it needs double-stranded DNA (dsDNA) for activity.DsDNA causes the formation of organized enzyme with combining of enzyme, and makes substrate more approach enzyme, thereby helps the carrying out of phosphorylation reaction.

With DNA-PK * 5 reaction buffers (250mM HEPES, 500mM KCl, 50mMMgCl ₂, 1mM EGTA, 0.5mM EDTA, 5mM DTT, adopting KOH to make pH is 7.5) in deionized water with 1/5 dilution, (storing solution=10mg/ml) to final concentration is 0.1mg/ml to add BSA.

Adopt 100 μ g/ml calf thymus DNAs preparation activation damping fluid in contrast damping fluid (10mM Tris-HCl (pH 7.4), 1mM EDTA (pH 8.0)).In every test tube, reaction mixture is made up of following material: 2.5 μ l activation or contrast damping fluid, 5 μ l * 5 reaction buffers, 2.5 μ l p53-deutero-biotinylation peptide substrates (storing solution=4mM), 0.2 μ l BSA (storing solution, 10mg/ml) and 5 μ l[γ- ³²P] ATP (5 μ l 0.5mM refrigerative ATP+0.05 μ l Redivue [γ- ³²P] ATP=Amersham AA0068-250 μ Ci, 3000Ci/mmol, 10 μ Ci/ μ l (present GEGealthcare Biosciences AB), Uppsala, Sweden).

DNA-PK enzyme (Promega V5811, concentration=100U/ μ L) is diluted in * 1 reaction buffer with 1/10, place standby on ice.The enzyme and 1.2 μ l, the 100 μ M compounds (being diluted with 1/100 in water by the 10mM storing solution in pure DMSO) of 10.8 μ l dilution were arised from the room temperature incubation 10 minutes.During this period, in the nut test tube behind Perspex glass, add 15.2 μ l reaction mixtures.Then 9.8 μ l enzymes are transferred in the test tube that contains reaction mixture, in 30 ℃ hatch 5 minutes after, add 12.5 μ l stop buffer (7.5M Guanidinium hydrochloride) termination reactions.

Behind the thorough mixing, every pipe is got 10 μ l aliquots containigs and is existed

(Wisconsin USA) goes up point sample to the vitamin H capture membrane, and it was placed dry several minutes for Promega, Madison.Then with the film thorough washing with remove excessive free [γ- ³²P] ATP and not biotinylated protein: in 200ml 2MNaCl one time 30 seconds; In 200ml 2M NaCl 3 times, each 2 minutes; 1%H at 2M NaCl ₃PO ₄In the solution 4 times, each 2 minutes; In the 100ml deionized water 2 times, each 30 seconds.Then film was placed under the room temperature air-dry 30 to 60 minutes.

Adopt tweezers and scissors that each piece film is cut into square, put into the flicker bottle, add 8ml scintillation solution (Flo-Scint 6013547, available from Perkin-Elmer) then.Measure by liquid scintillation counting(LSC) then and be incorporated in the DNA-PK biotinylation peptide substrates ³²The amount of P.In this experimental system, formula I compound can demonstrate have 10nM to the 50 μ M IC of (for example 10nM to 10 μ M) ₅₀Value.

The effect of The compounds of this invention in the activation of blocking-up PI3K/PKB path can followingly prove in cell is provided with:

Detect the scheme of phosphoric acid-PKB in the U87MG cell by Elisa

Make U87MG cell (people's glioblastoma, ATCC preserving number HTB-14) through tryptic digestion, the CASY cell counter (

System,

Germany) counting in, with the high dextrose culture-medium dilution of fresh complete DMEM, every hole is loaded and is contained 4 * 10 ⁴150 μ L cell suspensions of individual cell were with test board incubation 18 hours.Abreast, 50 μ L coated antibodies are loaded into the desired concn in PBS/O in each hole of elisa plate, plate were kept 2 hours in room temperature.Plate sealing agent (Costar-Corning, query ID: 3095) the flat 96 orifice plate (Microtest of Mi Feng black are being used in this ELISA test ^TM, Falcon Becton-Dickinson, query ID: carry out 353941).Substratum in the plate is discarded, replace with the high dextrose culture-medium of complete DMEM that contains 0.1%DMSO or 0.1% inhibitor (titre in the DMSO of 10mM to 0.156mM is (7)).Contact after 30 minutes, substratum is removed rapidly, then plate is placed on ice, immediately cell is dissolved with 70 μ L dissolving damping fluid by suction.Abreast, will with coated antibody (in PBS/O with anti--Akt1C-20 (goat) of 1/250 dilution, Santa-Cruz-1618, Santa Cruz Biotechnology, Inc., Santa Cruz, California, USA) Zhi Bei 96 orifice plates are with containing 0.05% polysorbas20 and 0.1%Top-

(derivative of gelatin, lip-deep non-specific binding capable of blocking position; Sigma-Aldrich, Fluka, Buchs, Switzerland, query ID: 3 times (1 minute) of 37766) PBS/O washing, under room temperature with containing 3%Top 200 μ L PBS with remaining protein binding position blocking-up 2 hours to stop non-specific interaction.The hole content used available from the 50 μ L samples of handling cell replaces, in 4 ℃ with plate incubation 3 hours.The ELISA test always is to use the following contrast same form to carry out abreast for 6 parts: U87MG (undressed contrast) or independent dissolving damping fluid (LB).Wash after 3 * 15 minutes, in all holes, add 50 μ L secondary antibody (in 3%Top Block with anti--S473P-PKB (rabbit) of 1/250 dilution, cell signaling (Cell Signaling)-9271, Cell Signaling Technologies Inc., Danvers, Massachusetts USA), was hatched 16 hours in 4 ℃.After washing 3 times, under the room temperature with plate and three grades and conjugated antibody anti-rabbit (HRP) the Jackson Immuno Research111-035-144 of 1/1000 dilution (in the 3%TopBlock with) incubation 2 hours.At last, immunocomplex with PBS/O/ polysorbas20/top Block washing 2 times 15 seconds, with 200 μ l water washings 1 time, is left 200 μ l water at last in each test holes, then incubation 45 minutes in the dark.Use (Super then

ELISA pik chemical luminous substrate, Pierce, query ID: 27070, Pierce Biotechnology, Inc., Rockford, Illinois USA) measures plate.Add 100 μ L substrates, with plate jolting 1 minute.On Top-Count NXT (Packard Bioscience) luminometer, read luminous immediately.Use this pilot system, can find IC as the formula I compound of experimental compound ₅₀Value is in the scope of 10 μ M to 5nM (more preferably 5 μ M to 10nM).

Also there is the active experiment of anti-tumor in vivo of provable formula (I) compound.

For example, (USA) athymia naked (nu/nu) mouse can be used to measure the anti-tumor activity of PI3 kinase inhibitor to the female Harlan of subcutaneous implantation people glioblastoma U87MG tumour for Indianapolis, Indiana.The 0th day, that animal via is oral

(1-chloro-2,2,2-trifluoroethyl difluoro methyl ether, Abbot, Wiesbaden, Germany) anaesthetizes, and about 25mg tumor fragment is placed under the side of body skin of an animal left side, with the closed little incision wound of closing clamp.When gross tumor volume reaches 100mm ³The time, with the mouse random packet, every group of 6-8 animal, begin treatment.Treatment is carried out 2-3 week, gives the compound of the formula (I) in appropriate medium according to dosage per os, intravenously or the intraperitoneal of defined, uses every day once (or more low frequency).Use the kind of calliper tumour, measure twice weekly, calculate tumor size.

As the alternative of clone U87MG, also can use other clone in the same manner, for example:

MDA-MB 468 breast cancer cell lines (ATCC No.HTB 132; Also referring to InVitro 14, 911-15[1978]);

MDA-MB 231 breast cancer cell lines (ATCC No.HTB-26; Also referring to OnVitro 12, 331[1976]);

MDA-MB 453 breast cancer cell lines (ATCC No.HTB-131);

Colo 205 colon carcinoma cell lines (ATCC No.CCL 222; Also referring to Cancer Res. 38, 1345-55[1978]);

DU145 prostate cancer cell line DU 145 (ATCC No.HTB 81; Also referring to Cancer Res. 37, 4049-58[1978]),

PC-3 is (particularly preferred for the PC-3 prostate cancer cell line; ATCC No.CRL 1435; Also referring to Cancer Res. 40, 524-34[1980]) and the PC-3M prostate cancer cell line;

A549 human lung adenocarcinoma (ATCC No.CCL 185; Also referring to Int.J.Cancer 17, 62-70[1976]),

NCI-H596 clone (ATCC No.HTB 178; Also referring to Science 246, 491-4[1989]);

Pancreatic cancer cell be SUIT-2 (referring to people such as Tomioka, Cancer Res. 61, 7518-24[2001]).

Compound exhibits of the present invention goes out the T cell inhibitory activity.More specifically, The compounds of this invention stops activation and/or the propagation of T cell in aqueous solution for example, for example according to following experimental technique proved like that.According to standard method carry out two-way MLR (J.Immunol.Methods, 1973,2,279 and Meo T. etc., Immunological Methods (immunological method), New York, the academic press, 1979,227-39).In brief, will (in every hole of flat tissue culture micro plate, contain 1.6 * 10 available from the splenocyte of CBA and BALB/c mouse ⁵Individual cell from each strain system, altogether 3.2 * 10 ⁵) in the RPMI substratum, cultivate, described RPMI substratum contains the compound of 10%FCS, 100U/ml penicillin, 100 μ g/ml Streptomycin sulphates (Gibco BRL, Basel, Switzerland), 50 μ M 2 mercapto ethanols (Fluka, Buchs, Switzerland) and serial dilution.Every kind of test-compound carries out 7 three times of dilution step, carries out in duplicate.Cultivate after 4 days, add 1 μ Ci ³The H-thymidine.Cultivate collecting cell after 5 hours in addition, mixed according to standard method mensuration ³The H-thymidine.The background values of MLR (low contrast) is the propagation of BALB/c cell just.From all numerical value, deduct low contrast.Height contrast without any sample is bred as 100%.The inhibition percentage ratio of calculation sample is measured 50% and is suppressed required concentration (IC ₅₀Value).In this is analyzed, the IC of The compounds of this invention ₅₀The scope of value is preferably 10nM to 5 μ M, preferred 10nM to 500nM.

Formula (I) compound can also advantageously be used in combination with other anti-proliferative compounds.This type of anti-proliferative compounds includes but not limited to aromatase inhibitor; Antiestrogen; The topoisomerase I inhibitor; The topoisomerase II inhibitor; The microtubule active compound; Alkylated compound; Histone deacetylase inhibitor; The compound of inducing cell atomization; Cyclooxygenase inhibitors; The MMP inhibitor; The mTOR inhibitor; The antitumor activity metabolic antagonist; Platinic compound; Target in/reduce the compound of protein kinase or the active compound of lipid kinase and other angiogenesis inhibitor; Target is in the compound of, reduction or arrestin Phosphoric acid esterase or lipid phosphatase activity; The gonadorelin agonist; Antiandrogen; The methionine(Met) aminopeptidase inhibitor; Bisphosphonates; The biological response conditioning agent; Anti proliferative antibody; Heparanase (heparanase) inhibitor; The carcinogenic isoform inhibitor of Ras; Telomerase inhibitor; Proteasome inhibitor; The compound that is used for the treatment of malignant hematologic disease; Target in, reduce or suppress the active compound of Flt-3; Hsp90 inhibitor such as 17-AAG (17-allyl amino geldanamycin mycin, NSC330507), 17-DMAG (17-dimethyl aminoethyl amino-17-de-methoxy geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, available from ConformaTherapeutics; Temozolomide (

); Kinesin spindle body albumen (kinesinspindle protein) inhibitor, as SB715992 or SB743921 available from GlaxoSmithKline, or available from pentamidine/chlorpromazine of CombinatoRx; Mek inhibitor is as available from the ARRY142886 of Array PioPharma, available from the AZD6244 of AstraZeneca, PD181461, folinic acid, EDG wedding agent, antileukemie compound, ribonucleotide reductase inhibitor, S-ademetionine decarboxylase inhibitor, anti proliferative antibody or other chemotherapy compound available from Pfizer.And, alternatively or additionally, they can be used in combination with other tumor therapeuticing method, and described other tumor therapeuticing method comprises operation, ionizing radiation, photodynamic therapy, implant as containing the implant of reflunomide or hormone, and perhaps they can be used as radiosensitizer.Equally, in anti-inflammatory and/or anti proliferative treatment, also comprise combination with anti-inflammatory drug.Combination also might be the combination with antihistamine drug, bronchodilator, NSAID or chemokine receptor anagonists.

Term used herein " aromatase inhibitor " refers to suppress the compound that oestrogenic hormon generates (be about to Androstenedione and testosterone substrate and be separately converted to oestrone and estradiol).This term includes but not limited to steroid, especially Atamestane, Exemestane and formestane, particularly non-steroid, especially aminoglutethimide, Rogletimide (roglethimide), Racemic pyridoglutethimide, Win-24540, testolactone, KETOKONAZOL, vorozole, fadrozole, Anastrozole and letrozole.Exemestane can be for example with its commercial form (for example trade mark is AROMASIN) administration.Formestane can be for example with its commercial form (for example trade mark is LENTARON) administration.Fadrozole can be for example with its commercial form (for example trade mark is AFEMA) administration.Anastrozole can be for example with its commercial form (for example trade mark is ARIMIDEX) administration.Letrozole can be for example with its commercial form (for example trade mark is FEMARA or FEMAR) administration.Aminoglutethimide can be for example with its commercial form (for example trade mark is ORIMETEN) administration.The combination of the present invention that is included as the chemotherapeutics of aromatase inhibitor is particularly useful for treating hormone receptor positive tumour, for example breast tumor.

Term used herein " antiestrogen " refers to the compound of antagonism estrogen effect on the estrogen receptor level.This term includes but not limited to tamoxifen, fulvestrant, raloxifene and RALOXIFENE HCL.Tamoxifen can be for example with its commercial form (for example trade mark is NOLVADEX) administration.RALOXIFENE HCL can be for example with its commercial form (for example trade mark is EVISTA) administration.Fulvestrant can be as US 4,659, disclosed prepare like that or can be for example with its commercial form (for example trade mark is FASLODEX) administration in 516.The combination of the present invention that is included as the chemotherapeutics of antiestrogen is particularly useful for treating estrogen receptor positive tumors, for example breast tumor.

Term used herein " antiandrogen " refers to any material that can suppress the male hormone biological effect, includes but not limited to bicalutamide (CASODEX), and it can be for example according to US 4,636, disclosedly in 505 prepares like that.

Term " gonadorelin agonist " includes but not limited to abarelix, goserelin and acetate goserelin as used herein.Goserelin is disclosed in US 4,100,274, can be for example with its commercial form (for example trade mark is ZOLADEX) administration.Abarelix can be for example as US 5,843, disclosedly in 901 prepares like that.

Term used herein " topoisomerase I inhibitor " includes but not limited to Hycamtin, gefitinib (gimatecan), irinotecan, camptothecine and analogue thereof, 9-nitrocamptothecin and macromole camptothecine conjugate PNU-166148 (compd A 1 among the WO 99/17804).Irinotecan can be for example with its commercial form (for example trade mark is CAMPTOSAR) administration.Hycamtin can be for example with its commercial form (for example trade mark is HYCAMTIN) administration.

Term used herein " topoisomerase II inhibitor " includes but not limited to the anthracene nucleus class, as Dx (comprising Liposomal formulation, for example CAELYX), daunorubicin, epirubicin, idarubicin and Nemorubicin; The mitoxantrone of anthraquinone class and losoxantrone; And the Etoposide of podophillotoxines and teniposide.Etoposide can be for example with its commercial form (for example trade mark is ETOPOPHOS) administration.Teniposide can be for example with its commercial form (for example trade mark is VM26-BRISTOL) administration.Dx can be for example with its commercial form (for example trade mark is ADRIBLASTIN or ADRIAMYCIN) administration.Epirubicin can be for example with its commercial form (for example trade mark is FARMORUBICIN) administration.Idarubicin can be for example with its commercial form (for example trade mark is ZAVEDOS) administration.Mitoxantrone can be for example with its commercial form (for example trade mark is NOVANTRON) administration.

Term " microtubule active compound " refers to microtubule stable compound, microtubule stabilization removal compound and tubulin polymerization inhibitor, includes but not limited to taxanes, for example taxol and Docetaxel; Vinca alkaloids, vincaleucoblastine (especially Vinblastine Sulfate) for example, vincristin (especially sulfuric acid vincristin) and vinorelbine; Wash rice suberite lactone (discodermolides); Colchicine; With epothilones and derivative thereof, for example epothilone B or D or derivatives thereof.Taxol can be with for example its commercial form (for example with TAXOL) administration.Docetaxel can be for example with its commercial form (for example trade mark is TAXOTERE) administration.Vinblastine Sulfate can be for example with its commercial form (for example trade mark is VINBLASTIN R.P.) administration.The sulfuric acid vincristin can be for example with its commercial form (for example trade mark is FARMISTIN) administration.Wash rice suberite lactone can be for example as US5, disclosed such acquisition in 010,099.Also comprise disclosed esperamicin derivatives among WO 98/10121, US 6,194,181, WO98/25929, WO 98/08849, WO 99/43653, WO 98/22461 and the WO 00/31247.Especially preferred is Epothilones A and/or B.

Term used herein " alkylated compound " includes but not limited to endoxan, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel).Endoxan can be for example with its commercial form (for example trade mark is CYCLOSTIN) administration.Ifosfamide can be for example with its commercial form (for example trade mark is HOLOXAN) administration.

Term " histone deacetylase inhibitor " or " hdac inhibitor " refer to can the inhibition of histone deacetylase and have a compound of antiproliferative activity.This comprises disclosed compound among the WO 02/22577, especially N-hydroxyl-3-[4-[[(2-hydroxyethyl) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl]-amino] methyl] phenyl]-2E-2-acrylamide and pharmacologically acceptable salt thereof.Also particularly including suberoyl aniline (suberoylanilide) hydroxamic acid (SAHA).

Term " antitumor activity metabolic antagonist " includes but not limited to 5 FU 5 fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compound such as 5-azacytidine and Decitabine, methotrexate and edatrexate and antifol such as pemetrexed.Capecitabine can be for example with its commercial form (for example trade mark is XELODA) administration.Gemcitabine can be for example with its commercial form (for example trade mark is GEMZAR) administration.

Term used herein " platinic compound " includes but not limited to carboplatin, suitable-platinum, cis-platinum and oxaliplatin.Carboplatin can be for example with its commercial form (for example trade mark is CARBOPLAT) administration.Oxaliplatin can be for example with its commercial form (for example trade mark is ELOXATIN) administration.

Term used herein " target in/reduce protein kinase or the active compound of lipid kinase ", " target in/reduce the compound of phosphoprotein phosphatase or lipid phosphatase activity " or " other angiogenesis inhibitor compound " include but not limited to protein tyrosine kinase and/or Serine and/or threonine kinase enzyme inhibitors or lipid kinase inhibitors, for example:

A) target in, reduce or suppress the active compound of platelet derived growth factor receptor (PDGFR), for example target in, reduce or suppress the active compound of PDGFR, especially the compound that suppresses pdgf receptor, for example N-phenyl-2-pyrimidine-amine derivatives, for example imatinib, SU101, SU6668 and GFB-111;

B) target in, reduce or be suppressed to the active compound of bfgf receptor (FGFR);

C) target in, reduce or suppress the active compound of IGF-1 I (IGF-IR), for example target in, reduce or suppress the active compound of IGF-IR, especially the compound that suppresses the kinase activity of IGF-I acceptor, for example public those compounds of being opened among the WO 02/092599; Perhaps target is in the antibody of IGF-I receptor extracellular domain or its somatomedin;

D) target in, reduce or suppress the compound of Trk receptor tyrosine kinase family active; Or liver is joined albumen (ephrin) B4 inhibitor;

E) target in, reduce or suppress the compound of Axl receptor tyrosine kinase family active;

F) target in, reduce or suppress the compound of Ret receptor tyrosine kinase activity;

G) target in, reduce or suppress the compound of Kit/SCFR receptor tyrosine kinase activity; As imatinib;

H) target in, reduce or suppress the active compound of C-kit receptor tyrosine kinase (PDGFR family member), for example target in, reduce or suppress the compound of c-Kit receptor tyrosine kinase family active, especially the compound that suppresses the c-Kit acceptor, for example imatinib;

I) target in, reduce or suppress c-Abl family member, their gene-fusion product (for example BCR-Abl kinases) and the active compound of mutant, for example target in, reduce or suppress the compound of c-Abl family member and their gene fusion its lytic activity, N-phenyl-2-pyrimidine-amine derivatives for example, for example imatinib or nilotinib (nilotinib) are (AMN107); PD180970; AG957; NSC 680410; PD173955 available from ParkeDavis; Or Dasatinib (dasatinib) (BMS-354825);

J) target is in, reduction or arrestin kinase c (PKC) and serine/threonine kinase Raf family member and MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family member and/or the active compound of the member of cell cycle protein dependent kinase family (CDK), especially US 5,093, disclosed those staurosporine derivatives, for example midostaurin in 330; Other examples for compounds comprises for example UCN-01, Safingol, BAY 43-9006, bryostatin 1, Perifosine; Thio ALP; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; Isoquinoline compound, for example among the WO 00/09495 disclosed those; FTIs; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor);

K) target is in, reduction or the active compound of arrestin tyrosine kinase inhibitor, for example target comprises imatinib mesylate (GLEEVEC) or tyrphostin (tyrphostin) in, reduction or the active compound of arrestin tyrosine kinase inhibitor.Tyrphostin is preferably lower molecular weight (Mr＜1500) compound or pharmaceutically acceptable salt thereof, particularly be selected from benzylidene propane dinitrile class or S-aryl phenylpropyl alcohol dintrile or Double bottom thing quinolines, more especially be selected from down any compound of group: Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; TyrphostinAG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrph ostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxy phenyl) methyl] amino }-the phenylformic acid adamantane esters; NSC680410, adaphostin);

L) target in, reduce or suppress the epidermal growth factor family (EGFR of receptor tyrosine kinase, ErbB2, ErbB3, ErbB4, be homodimer or heterodimer) and their the active compound of mutant, for example target in, reduce or the active compound of inhibition Epidermal Growth Factor Receptor Family, especially can suppress for example EGF acceptor of EGF receptor tyrosine kinase family member, ErbB2, ErbB3 and ErbB4 or can with EGF or EGF dependency part bonded compound, protein or antibody, those disclosed compound briefly and particularly in following document particularly, protein or monoclonal antibody: WO 97/02266, the compound of embodiment 39 for example, perhaps EP 0564409, WO 99/03854, EP 0520722, EP 0566226, EP 0787722, EP 0837063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO97/38983, particularly WO 96/30347 (compound that for example is called as CP 358774), WO96/33980 (for example compound ZD 1839) and WO 95/03283 (for example compound ZM105180); Trastuzumab (Herceptin for example ^TM), Cetuximab (Erbitux ^TM), disclosed 7H-pyrrolo-[2,3-d] pyrimidine derivatives among Iressa (Iressa), Te Luokai (Tarceva), OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and the WO 03/013541; With

M) target in, reduce or suppress the compound of c-Met receptor active, for example target in, reduce or suppress the active compound of c-Met, especially the compound that suppresses the kinase activity of c-Met acceptor, perhaps target in the extracellular domain of c-Met or with HGF bonded antibody.

Other angiogenesis inhibitor compound comprises and has other activity mechanism the compound of (for example with protein kinase or the irrelevant mechanism of lipid kinase restraining effect), for example Thalidomide (THALOMID) and TNP-470.

Target comprises for example inhibitor of phosphatase 1, Phosphoric acid esterase 2A or CDC25 in the compound of, reduction or arrestin Phosphoric acid esterase or lipid phosphatase activity, for example okadaic acid (okadaic acid) or derivatives thereof.

The compound of inducing cell atomization for example comprise vitamin A acid, α-, γ-or Delta-Tocopherol or α-, γ-or δ-tocotrienols.

Term used herein " cyclooxygenase inhibitors " includes but not limited to the 2-arylamino phenylacetic acid and the derivative thereof of for example cox 2 inhibitor, the replacement of 5-alkyl, for example celecoxib (CELEBREX), rofecoxib (VIOXX), L-791456, valdecoxib or 5-alkyl-2-arylamino phenylacetic acid (for example 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid), Prexige (lumiracoxib).

Term used herein " bisphosphonates " includes but not limited to etidronic acid (etridonic acid), clodronic acid, tiludronic acid, pamidronic acid, clinic effect of alendronate, Ibandronic acid, risedronic acid and Zoledronic acid." etidronic acid " can be for example with its commercial form (for example trade mark is DIDRONEL) administration." clodronic acid " can be for example with its commercial form (for example trade mark is BONEFOS) administration." tiludronic acid " can be for example with its commercial form (for example trade mark is SKELID) administration." pamidronic acid " can for example (for example trade mark be AREDIA with its commercial form ^TM) administration." clinic effect of alendronate " can be for example with its commercial form (for example trade mark is FOSAMAX) administration." Ibandronic acid " can be for example with its commercial form (for example trade mark is BONDRANAT) administration." risedronic acid " can be for example with its commercial form (for example trade mark is ACTONEL) administration." Zoledronic acid " can be for example with its commercial form (for example trade mark is ZOMETA) administration.

The compound that term " mTOR inhibitor " refers to suppress the Mammals target (mTOR) of rapamycin and has antiproliferative activity, for example sirolimus (

), everolimus (Certican ^TM), CCI-779 and ABT578.

Term used herein " heparanase inhibitors " be meant target in, reduce or suppress the compound of heparin sulfate degraded.This term includes but not limited to PI-88.

Term used herein " biological response conditioning agent " is meant lymphokine or Interferon, rabbit, for example interferon-gamma.

Term used herein " the carcinogenic isoform inhibitor of Ras " (as H-Ras, K-Ras or N-Ras) be meant target in, reduce or suppress the compound of the carcinogenic activity of Ras, for example " farnesyl transferase inhibitor ", for example L-744832, DK8G557 or R115777 (Zarnestra).

Term used herein " telomerase inhibitor " be meant target in, reduce or suppress the compound of telomerase activation.Target in, reduce or the compound that suppresses telomerase activation particularly suppresses the compound of Telomerase acceptor, for example telomestatin (for Mo Meitating).

Term used herein " methionine(Met) aminopeptidase inhibitor " be meant target in, reduce or suppress the active compound of methionine(Met) aminopeptidase.Target in, reduce or suppress the active compound of methionine(Met) aminopeptidase and comprise for example bengamide (than Ge Maide) or derivatives thereof.

Term used herein " proteasome inhibitor " is meant that target is in, reduction or the active compound of arrestin enzyme body.Target comprises for example Bortezomid (Velcade) (Velcade in, reduction or the active compound of arrestin enzyme body ^TM) and MLN 341.

Term used herein " matrix metallo-proteinase inhibitor " or " MMP inhibitor " include but not limited to that collagen intends peptide and non-plan inhibitor peptides, tetracycline derivant, but for example hydroxamic acid is intended analogue Marimastat (BB-2516), prinomastat (AG3340), metastat (Ma Tasita) (NSC 683551) BMS-279251, BAY 12-9566, TAA211, MMI270B or the AAJ996 of inhibitor peptides Batimastat and oral biological utilisation thereof.

Term used herein " compound that is used for the treatment of the hematology malignant disease " includes but not limited to FMS-sample tyrosine kinase inhibitor, for example target in, reduce or suppress the active compound of FMS-sample tyrosine kinase receptor (Flt-3R); Interferon, rabbit, 1-b-D-arbinofuranose base cytosine(Cyt) (ara-c) and busulfan (bisulfan); The ALK inhibitor, for example target in, reduce or suppress the compound of Nucleophosmin-anaplastic lymphoma kinase.

Target in, reduce or suppress the active compound of FMS-sample tyrosine kinase receptor (Flt-3R), especially the compound, protein or the antibody that suppress Flt-3R receptor kinase family member, for example PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

Term used herein " HSP90 inhibitor " include but not limited to target in, reduce or suppress the compound of the endogenous atpase activity of HSP90; By ubiquitin protein enzyme body path degrade, target in, reduce or suppress the compound of HSP90 client's albumen (client protein).Target in, reduce or the compound that suppresses the endogenous atpase activity of HSP90 especially suppresses compound, protein or the antibody of the atpase activity of HSP90, for example 17-allyl amino, 17-de-methoxy geldanamycin (17AAG)---geldanamycin derivant; The compound that other is relevant with geldanamycin; Radicicol and hdac inhibitor.

Term used herein " anti proliferative antibody " includes but not limited to trastuzumab (Herceptin ^TM), trastuzumab-DM1, Erbitux (erbitux), rhuMAb-VEGF (Avastin ^TM), Rituximab (

), PRO64553 (anti-CD 40) and 2C4 antibody.Multi-specificity antibody and antibody fragment that antibody is meant for example complete monoclonal antibody, polyclonal antibody, is formed by at least 2 complete antibodies are as long as they show required biologic activity.

For the treatment of acute myeloid leukaemia (AML), formula (I) compound can be used in combination with standard leukemia therapy, especially is used in combination with the therapy that is used for the treatment of AML.Particularly, formula (I) compound can be used for treating medicine (for example daunorubicin, Zorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and the PKC412) combination medicine-feeding of AML with for example farnesyl transferase inhibitor and/or other.

Term " antileukemie compound " comprises for example pyrimidine analogue Ara-C, it be 2 of Deoxyribose cytidine '-Alpha-hydroxy ribose (cytosine arabinoside) derivative.Also comprise purine analogue xanthoglobulin, Ismipur (6-MP) and fludarabine phosphate.

Target in the compound (as Sodium propanecarboxylate and Vorinostat (SAHA)) of, reduction or inhibition of histone deacetylase (HDAC) inhibitor activity can the inhibition of histone deacetylase activity.Concrete hdac inhibitor comprises MS275, SAHA, FK228 (being called FR901228 in the past), Trichostatin A and US6,552, disclosed compound in 065, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl)-ethyl particularly]-amino] methyl] phenyl]-2E-2-acrylamide or its pharmacologically acceptable salt and N-hydroxyl-3-[4-[(2-hydroxyethyl) 2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-acrylamide or its pharmacologically acceptable salt, especially lactic acid salt.

The somatostatin receptor antagonist used herein refer to target in, reduce or suppress the compound of the somatostatin receptor, for example Sostatin and SOM230 (pasireotide (SOM230)).

The tumor cell destruction method is meant such as methods such as ionizing radiations.Mentioned term " ionizing radiation " means the ionizing radiation that carries out with electromagnetic radiation (as X-ray and gamma-rays) or particle (as α and beta-particle) form in the context.Ionizing radiation provides in radiotherapy, but is not limited thereto, and is known in the art.Referring to Hellman, Principles of Radiation Therapy, Cancer, Principles and Practice of Oncology (radiotherapy principle, cancer, the oncology principle with put into practice), people such as Devita edit, the 4th edition, the 1st volume, 248-275 page or leaf (1993).

The immunosuppressor class that term used herein " EDG wedding agent " refers to regulate lymphocyte recirculation is as FTY720.

Term " ribonucleotide reductase inhibitor " refers to pyrimidine or purine nucleoside analogs, includes but not limited to fludarabine and/or cytosine arabinoside (ara-C), 6-Tioguanine, 5 FU 5 fluorouracil, CldAdo, Ismipur (especially being used for anti-ALL with the ara-C combination) and/or pentostatin.The ribonucleotide reductase inhibitor is in particular hydroxyurea or 2-hydroxyl-1H-isoindole-1, the 3-derovatives, people such as Nandy for example, Acta Oncologica, the 33rd volume, the 8th phase, PL-1, the PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or the PL-8 that mention in the 953-961 page or leaf (1994).

Term used herein " S-ademetionine decarboxylase inhibitor " includes but not limited to US5, disclosed compound in 461,076.

The monoclonal antibody of disclosed those compounds, protein or VEGF in the WO98/35958 also, 1-(4-chlorobenzene amino)-4-(4-pyridylmethyl) phthalazines or its pharmacologically acceptable salt for example, for example succinate, perhaps those disclosed in WO00/09495, WO00/27820, WO00/59509, WO98/11223, WO00/27819 and EP0769947; Described in following document those: Prewett etc., Cancer Res, the 59th volume, 5209-5218 page or leaf (1999); Yuan etc., Proc Natl Acad Sci USA, the 93rd volume, 14765-14770 page or leaf (1996); Zhu etc., Cancer Res, the 58th volume, 3209-3214 page or leaf (1998); With Mordenti etc., ToxicolPathol, the 27th volume, the 1st phase, 14-21 page or leaf (1999); WO00/37502 and WO94/10202; Angiostatin (ANGIOSTATIN), O ' Reilly etc., Cell, the 79th volume, 315-328 page or leaf (1994); Endostatin (ENDOSTATIN), O ' Reilly etc., Cell, the 88th volume, 277-285 page or leaf (1997); The anthranilic acid acid amides; ZD4190; ZD6474; SU5416; SU6668; RhuMAb-VEGF; Or anti-VEGF antibodies or anti-VEGF receptor antibody, as rhuMAb and RHUFab, VEGF is fit as Macugon; FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2IgG1 antibody, Angiozyme (RPI 4610) and rhuMAb-VEGF (Avastin ^TM).

" photodynamic therapy " refers to that the chemical preparations that adopts some to be called as light-sensitive compound is treated or the therapy of preventing cancer as used herein.The example of photodynamic therapy comprises uses the treatment of carrying out such as the compound of tieing up fast Da Er (VISUDYNE) and porfimer sodium.

" steroid that suppresses blood vessel " used herein refers to block or suppress the compound of vasculogenesis, as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, deoxidation cortisone, 17 α-hydroxyprogesterone, Kendall compound, Doca, testosterone, oestrone and dexamethasone.

The implant that contains reflunomide relates to the compound such as fluocinolone acetonide and dexamethasone.

" other chemotherapy compound " includes but not limited to plant alkaloid, hormonal compounds and antagonist; The biological response conditioning agent, preferred lymphokine or Interferon, rabbit; Antisense oligonucleotide or oligonucleotide derivative; ShRNA or siRNA; Or mixed compounds (miscellaneous compounds) or have other mechanism of action or the compound of unknown role mechanism.

Compound of the present invention also can be used as the assisting therapy compound and other medicines (as antiphlogiston, bronchodilator or antihistaminic) are used in combination, especially for treatment obstructive or inflammatory respiratory disease, for example mentioned above those are for example as the active synergistic agent of such pharmacological agent or as the means that reduce required dosage of such medicine or possibility side effect.Compound of the present invention can mix with other medicines in the fixed drug composition, perhaps can be before the other medicines administration, administration simultaneously or administration respectively after the administration.Therefore, the present invention includes the combination of compound of the present invention and antiphlogiston, bronchodilator, antihistaminic or cough medicine mentioned above, wherein said compound of the present invention and described medicine can be included in the identical or different pharmaceutical composition.

Suitable anti-inflammatory drug comprises steroid, particularly glucocorticoids such as budesonide, beclometasone (beclamethasone), fluticasone propionate, ciclesonide or furoic acid momisone, or the steroid described in the following document: WO 02/88167, WO 02/12266, WO02/100879, (particularly embodiment 3 for WO 02/00679,11,14,17,19,26,34,37,39,51,60,67,72,73,90, in 99 and 101 those), WO 03/035668, WO03/048181, WO 03/062259, WO 03/064445, WO 03/072592, the non-steroid glucocorticoid receptor agonist, those described in for example following document: WO 00/00531, WO02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; The LTB4 antagonist, those described in LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO 4057, SB 209247 and US 5451700; The LTD4 antagonist is as Singulair and Zafirlukast; The PDE4 inhibitor, as cilomilast ( GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arofylline (AlmirallProdesfarma), PD189659/PD168787 (Parke-Davis), AWD-12-281 (AstaMedica), CDC-801 (Celgene), SelCID (TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), described in KW-4490 (Kyowa Hakko Kogyo) and the following document those: WO 92/19594, WO 93/19749, WO 93/19750, WO 93/19751, WO 98/18796, WO 99/16766, WO 01/13953, WO 03/104204, WO 03/104205, WO 03/39544, WO 04/000814, WO 04/000839, WO 04/005258, WO 04/018450, WO 04/018451, WO 04/018457, WO 04/018465, WO 04/018431, WO 04/018449, WO 04/018450, WO 04/018451, WO04/018457, WO 04/018465, WO 04/019944, WO 04/019945, WO 04/045607 and WO 04/037805; The A2a agonist, those described in for example following document: EP409595A2, EP 1052264, EP 1241176, WO 94/17090, WO 96/02543, WO96/02553, WO 98/28319, WO 99/24449, WO 99/24450, WO 99/24451, WO 99/38877, WO 99/41267, WO 99/67263, WO 99/67264, WO 99/67265, WO 99/67266, WO 00/23457, WO 00/77018, WO 00/78774, WO01/23399, WO 01/27130, WO 01/27131, WO 01/60835, WO 01/94368, WO02/00676, WO 02/22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO 04/046083; A2b antagonist, for example those described in the WO02/42298; With the beta-2-adrenoceptor agonist, as Aerolin (salbutamol), Orciprenaline, terbutaline, Salmeterol, Partusisten, procaterol, especially formoterol and pharmacologically acceptable salt thereof, and the formula I compound of WO0075114 (free or salt or solvate form thereof), the document is incorporated herein by reference, compound, especially following formula: compound and the pharmacologically acceptable salt thereof of preferred embodiment: And the compound of the formula I compound of WO04/16601 (free or salt or solvate form thereof) and WO04/033412.

Suitable bronchodilator comprises anticholinergic or antimuscarinic compounds, particularly ipratropium bromide, oxitropium bromide, tiotropium salt and CHF 4226 (Chiesi), Glycopyrronium Bromide also have described in WO01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, US 5171744, US 3714357, WO 03/33495 and the WO 04/018422 those.

Suitable antihistamine drug comprises cetrizine hcl, paracetamol, clemastine fumarate, promethazine, Loratadine, Desloratadine, diphenhydramine and fexofenadine hydrochloride, acrivastine (activastine), astemizole, nitrogen

Among Si Ting, ebastine, epinastine, mizolastine and Te Fennading and WO 03/099807, WO 04/026841 and the JP 2004107299 disclosed those.

The useful combination of other of The compounds of this invention and antiphlogiston is and Chemokine Receptors (CCR-1 for example, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5) combination of antagonist, described antagonism is the antagonist of CCR-5 particularly, the antagonist SC-351125 of Schering-Plough for example, SCH-55700 and SCH-D, the antagonist of Takeda such as N-[[4-[[[6,7-dihydro-2-(4-aminomethyl phenyl)-5H-benzepine-8-yl] carbonyl] amino] phenyl] methyl] tetrahydrochysene-N, the CCR-5 antagonist described in N-dimethyl-2H-pyrans-4-ammonium chloride (TAK-770) and the following document: US 6166037 (particularly claim 18 and 19), WO 00/66558 (particularly claim 8), WO 00/66559 (particularly claim 9), WO 04/018425 and WO 04/026873.

The structure of the activeconstituents of determining by Code Number, popular name or trade(brand)name can collect from standard " the Merck index " current edition or from database for example Patents International (for example IMSWorld Publications) obtain.

The above-claimed cpd that can be used in combination with formula (I) compound can be according to being prepared and administration described in the state of the art (for example document of above being quoted) like that.

" combination " means a kind of fixed combination of dosage unit form, the complete medicine box that perhaps is used for combination medicine-feeding, its Chinese style (I) compound and medicinal composition can be distinguished administration at one time, perhaps administration respectively in certain time interval, the described timed interval should make that especially each medicinal composition demonstrates the cooperation effect, for example synergy.

The present invention also provides pharmaceutical preparation, and it comprises pharmacologically acceptable salt or its hydrate or solvate and at least a pharmaceutically acceptable carrier of formula I compound defined herein or its N-oxide compound or tautomer or this compounds.

Formula I compound can be individually dosed or with one or more other therapeutic compound combination medicine-feedings, possible combined therapy is taked the form of fixed combination, perhaps adopt compound of the present invention and one or more other therapeutic (comprising preventative) compound alternately or the form of separate administration, the perhaps combination medicine-feeding of fixed combination and one or more other therapeutic compounds.In addition or additionally, formula I compound can get involved with amic therapy method, radiotherapy, immunotherapy, actinotherapy, operation or the combinatorial association of these methods be used, and is used in particular for oncotherapy.Long-term treatment is possible equally, as the adjuvant therapy in aforesaid other treatment plan.Other possible treatment is the treatment of keeping patient's states behind tumor regression, perhaps or even chemoprophylaxis treatment, for example treatment in patient on the line.

The dosage of activeconstituents depends on multiple factor, comprises patient's type, kind, age, body weight, sex and medical condition; Sanatory seriousness; Route of administration; Patient's hepatic and renal function; And used particular compound.Doctor, clinicist or animal doctor with common skill can easily determine and leave prevention, antagonism or stop the required effective amount of drug of condition worse.Best accurately acquisition can produce the drug level area requirement of effect based on the dynamic (dynamical) scheme of medicine to the availability of target position.This comprises distribution, balance and the removing of considering medicine.

The dosage that formula I compound or pharmaceutically acceptable salt thereof delivers medicine to warm-blooded animal (for example body weight is the people of about 70kg) is preferably about for each person every day 3mg to about 5g, more preferably from about 10mg is to about 1.5g, preferably be subdivided into 1 to 3 single dose, this dosage can for example be identical size.Usually, child dose can be half of adult's dosage.

Compound of the present invention can pass through any conventional route administration, particularly through following form administration: outside the gi tract, for example with Injectable solution or suspensoid form; Through intestines, for example oral, for example with tablet or Capsule form; The part is for example with lotion, gelifying agent, ointment or emulsion form or with nose or suppository form.Topical application is for example to be applied to skin.The another kind of form of topical is to deliver medicine to eye.The pharmaceutical composition that comprises The compounds of this invention and at least a pharmaceutically acceptable carrier or thinner can be with ordinary method by preparing with pharmaceutically acceptable carrier or mixing diluents.

The invention still further relates to the formula I compound that comprises significant quantity (the especially effectively amount of one of above-mentioned disease of treatment) or the pharmaceutical composition of its N-oxide compound or tautomer and one or more pharmaceutically acceptable carrier, described carrier is suitable for the part, through intestines such as oral or rectum or gi tract external administration, and can be inorganic or organic, solid or liquid.For orally using, can use the tablet or the gelatine capsule that particularly comprise activeconstituents and thinner (as lactose, glucose, N.F,USP MANNITOL and/or glycerine) and/or lubricant and/or polyoxyethylene glycol.Tablet can also comprise tackiness agent, as neusilin, starch such as W-Gum, wheat starch or rice starch, gelatin, methylcellulose gum, Xylo-Mucine and/or polyvinylpyrrolidone, if necessary, can also comprise disintegrating agent (as starch, agar, Lalgine or its salt such as sodium alginate) and/or effervescent mixture or sorbent material, dyestuff, correctives and sweeting agent.Also might use can be through the composition forms of gi tract external administration or the compound of the present invention with pharmacologically active of infusion solution form.This pharmaceutical composition can be salt and/or buffer reagent sterilization and/or that can comprise vehicle such as sanitas, stablizer, wettability compound and/or emulsifying agent, solubilizing agent, adjusting osmotic pressure.Pharmaceutical composition of the present invention (if necessary, can comprise the material that other has pharmacologically active) can be according to known method preparation, for example by conventional mixing, granulation, moulding, dissolving or freeze-drying method preparation, it comprises about 1% to 99% (weight), especially about 1% to about 60% activeconstituents.

In addition, the invention provides the pharmacologically acceptable salt of formula I compound or its N-oxide compound or tautomer or this compounds, they are used for the methods of treatment of human body or animal body, in particular for the disease that treatment this paper mentions, needing more particularly to be used for the patient of this type of treatment.

The pharmacologically acceptable salt that the invention still further relates to formula I compound or its tautomer or this compounds is used for the treatment of proliferative disease, inflammatory diseases or obstructive respiratory disease or follows purposes in the medicine of transplanting the disease that takes place usually in preparation.

In addition, the present invention relates to treatment lipid kinase and/or the active inhibition of PI3-kinase-associated protein kinases (particularly PI3 kinases and/or mTOR and/or DNA protein kinase) are had the method for the proliferative disease of response, this method comprises that the amount with the described disease of effective antagonism needs the warm-blooded animal formula I compound or pharmaceutically acceptable salt thereof of this type of treatment, and wherein group and symbol are as hereinbefore defined.

And, the present invention relates to be used for the treatment of the solid tumor of the warm-blooded animal that comprises the people or the pharmaceutical composition of liquid tumor, it comprises the aforesaid formula I compound of effective antagonism dose,tumor or the pharmacologically acceptable salt and the pharmaceutical carrier of this compound.

The preparation method:

The invention still further relates to the method for preparation I compound, its N-oxide compound, its solvate and/or its salt.

Formula I compound is methods known in the art or according to similar method and adopt other educt, intermediate and/or end product preparation with it on can be on principle, particularly prepares by following novel method according to the present invention, and this method comprises:

A) make formula II compound

R wherein ²Suc as formula defining in the I compound, and X is the preferred chlorine of halogen, bromine or iodine, or trifyl oxygen base,

Boric acid or boric acid ester with formula III under the cross-coupling condition react,

R ¹-D (III)

R wherein ¹Suc as formula defining in the I compound and be bonded to D by carbon atom, and D is free form or esterified form-B (OH ₂), for example be the dialkoxy ester or be the group of formula A,

Or

B) make boric acid or the boric acid ester compound of formula IV,

R wherein ²Suc as formula defining in the I compound, and D is free form or esterified form-B (OH ₂), for example be the formula A group shown in a),

Under the cross-coupling condition, react with formula V compound,

R ¹-X (V)

R wherein ¹Suc as formula defining in the I compound, and X is particularly chlorine, bromine or iodine of halogen, or trifyl oxygen base, or

C) make formula VI compound

R wherein ¹Suc as formula defining in the I compound, and X is particularly chlorine, bromine or iodine of halogen, or trifyl oxygen base,

Boric acid or boric acid ester with formula VII under the cross-coupling condition react,

R ²-D (VII)

R wherein ²Suc as formula defining in the I compound, and D is free form or esterified form-B (OH ₂), for example be the formula A group shown in a), or

D) make the pyridazine compound of formula VIII

R wherein ²Suc as formula defining in the I compound,

With the halogenated ketone reaction of formula IX,

R wherein ¹Suc as formula defining in the I compound, and Y is particularly chlorine or bromine of halogen,

And, if necessary, can with according to above-mentioned reaction a) to d) in the obtainable formula I compound of arbitrary reaction be converted into different formula I compounds, the salt of obtainable formula I compound is converted into its different salt, obtainable free type I compound is converted into its salt, and/or the isomer of obtainable formula I compound is separated from one or more different obtainable formula I isomer.

In the more detailed description below the preferred alternative (variants) of described method, selectable reaction and conversion, raw material and intermediate synthetic etc., in each case if not otherwise specified, R ¹And R ²Implication described in the compound that has formula I compound or specifically mention, and D in the formula III compound definition, X is suc as formula defining in the II compound, Y is suc as formula defining in the IX compound, Het is suc as formula defining in the X compound, and Hyl is suc as formula defining in the XI compound.

Useful or when needing, reaction can for example be carried out under nitrogen or the argon gas atmosphere at rare gas element.

Alternative a), b) and c) in the reaction that provides preferably carry out respectively in following condition: under the Suzuki reaction conditions, preferably at polar aprotic solvent for example in the mixture of dimethyl formamide (DMF) and optional water, the cross-coupling catalyzer particularly noble metal catalyst (preferred palladium catalyst is palladium (II) complex compound for example, for example two (triphenylphosphine) palladium chlorides (II)) exist down, at alkali for example in the presence of salt of wormwood, sodium hydroxide or the yellow soda ash, under 80 ℃ to 130 ℃ preferred temperature; Or carry out in following condition: in cyclic ether solvents for example in the tetrahydrofuran (THF) according to another preferred method, at cross-coupling catalyzer noble metal catalyst (preferred palladium (0) complex compound particularly, three (dibenzalacetones), two palladiums (0) for example) or as two (benzylidene-acetone) palladium of precursor exist down, at suitable part 2-dicyclohexyl phosphino--2 ' for example, 6 '-dimethoxy-biphenyl (SPhos) or 2-dicyclohexyl phosphino--2 '-(N, the N-dimethylamino)-existence of biphenyl (P1) under, and in the presence of alkali alkali for example recited above or potassiumphosphate, and under 80 to 150 ℃ preferred temperature; When temperature surpasses the boiling point of reaction mixture and particularly when heating with microwave radiation (as preferred embodiment) carries out described reaction if necessary in sealed vessel (for example sealed reactor).When needs, can add for example (PdCl of other or another catalyzer ₂(PPh ₂) FeCH ₂Cl ₂).

Reaction between formula VIII compound and the formula IX compound (above-mentioned flexible reaction d)) preferably appropriate solvent for example alcohol as ethanol in, the temperature of rising for example under 80-180 ℃ preferred 100-170 ℃, do not exist or exist (if useful) tertiary nitrogen alkali for example to carry out under the condition of three-(low alkyl group)-amine such as triethylamine.

Blocking group

In raw material; in for example described below any one or a plurality of formula II or III raw material or other raw material, intermediate and the educt; if one or more other functional groups (for example carboxyl, hydroxyl, amino or sulfydryl) are protected or need protection (because they should not participate in reaction or disturbance reponse), then they are these type of groups of synthetic that are generally used for peptide compounds, cephalosporins and penicillins and nucleic acid derivative and sugar.Protecting group is such group: in a single day they just be removed and no longer be present in the final compound; on meaning used herein; the group that keeps as substituting group is not a blocking group, and the blocking group on the meaning used herein is to introduce and be removed to obtain the group of final compound in a certain intermediate stage.For example, be substituting group if tert.-butoxy is retained in the formula I compound, and if it is removed to obtain final formula I compound, then it is a blocking group.

Blocking group Already in the precursor, can protect relevant functional group to avoid taking place undesirable secondary reactions, as acidylate, etherificate, esterification, oxidation, solvolysis and similar reaction.Blocking group is characterised in that they are easy to be released out; undesirable secondary reactions does not promptly take place; usually can remove by acetolysls, protonolysis, solvolysis, reduction, photodissociation or by enzymic activity (for example being similar under the condition of physiological conditions), thereby they are not present in the end product.The professional knows or can easily establish which blocking group and is suitable for the mentioned reaction of context.

This type of blocking group is removed for example to be reflected at and in the canonical reference works description is arranged the protection of this type of functional group, blocking group self and they, J.F.W.McOmie for example, " blocking group in the organic chemistry " " Protective Groups in Organic Chemistry ", Plenum Press, London and New York, 1973; T.W.Greene, " blocking group in the organic synthesis " " ProtectiveGroups in Organic Synthesis ", the 3rd edition, Wiley, New York 1999; " peptide " " Peptides ", the 3rd volume (editor: E.Gross and J.Meienhofer), Academic Press, London and New York, 1981; " organic chemistry method " " Methoden der organischen Chemie ", Houben Weyl, the 4th edition, the 15/I volume, Georg Thieme Verlag, Stuttgart 1974; H.-D.Jakubke and H.Jescheit, " amino acid, peptide and protein " "

Peptide, Proteine ", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982; And JochenLehmann, " carbohydrate chemistry: monose and derivative " " Chemie der Kohlenhydrate:Monosaccharide und Derivate ", Georg Thieme Verlag, Stuttgart, 1974.

Selectable reaction and conversion

According to the standard reaction method, formula I compound can be converted into different formula I compounds.

For example, R therein ¹By halogen particularly chlorine or bromine for example at the aryl of para-orientation for example in the formula I compound of phenyl, described halogen can not replaced or replace comprises ring nitrogen and through the unsaturated heterocycle base displacement of theheterocyclic nitrogen atom bonding, this displacement is to realize by reacting down at Ullman type reaction conditions (for example as in the reference mentioned among the embodiment 1) with formula X compound

H-Het (X)

Wherein Het is a unsaturated heterocycle base group that do not replace or replace, by theheterocyclic nitrogen atom and hydrogen bonding, for example 1,2, and 4-triazole, pyrazoles, benzoglyoxaline, 3-trifluoromethyl-pyrazoles,

Preferably make corresponding formula I compound and formula X compound at Cu ₂O, part for example salicylic aldehyde hydrazone, alkali for example cesium carbonate and solvent for example acetonitrile exist down, 100-180 ℃ as 160-150 ℃ preferred temperature under, for example in microwave oven, react.This causes and obtains wherein R ¹The aryl that comprises ring nitrogen and replace through the unsaturated heterocycle base of theheterocyclic nitrogen atom bonding that is not replaced or replace is the formula I compound of phenyl for example.

Perhaps, for example, R therein ¹By halogen particularly chlorine or bromine for example at the aryl of para-orientation for example in the formula I compound of phenyl, the saturated heterocyclyl displacement that comprises theheterocyclic nitrogen atom that described halogen can not replaced or replace, this displacement is to realize by reaction under those reaction conditionss described in the reference of for example mentioning in embodiment 14 with formula XI compound

H-Hyl (XI)

Wherein Hyl is that do not replace or replace and saturated heterocyclyl group by theheterocyclic nitrogen atom and hydrogen bonding, for example Valerolactim, morpholine, 2-Pyrrolidone or N methyl piperazine,

The heterogeneous ring compound that for example makes formula XI and corresponding formula I compound CuI, alkali for example carbonic acid first and proline(Pro) in the presence of, appropriate solvent for example dimethyl sulfoxide (DMSO), preferably 80-130 ℃ of reaction down.

By with azide salt for example sodiumazide preferably ammonium salt for example in the presence of the ammonium chloride in for example 120-160 ℃ of reaction down, can be with R wherein ¹The aryl that is replaced by the cyano group for example formula I compound of phenyl is converted into wherein said cyano group by 1H-tetrazolium-displaced corresponding formula I compound of 5-base group.

Can be with R wherein ¹The aryl that is replaced by the nitro for example formula I compound of phenyl is reduced to wherein said nitro by the displaced corresponding formula I compound of amino group, the hydro-reduction by following condition for example: hydrogenation catalyst for example noble metal catalyst for example palladium (its can be preferably with carrier for example charcoal combine) in the presence of, at appropriate solvent alcohol for example in the methyl alcohol, preferably for example at room temperature for example at 0-50 ℃.As by product, may obtain the alkylate that produces by alcohol, for example in the methyl alcohol situation, obtain the methylamino compound of corresponding formula I, this compound can according to standard method for example chromatography separate and obtain.

R therein ¹The aryl that is replaced by chlorine, bromine or iodine is for example in the formula I compound of phenyl, described chlorine, bromine or iodine can be converted into the group D described in top formula III compound, for example by at first with n-Butyl Lithium reaction (replacing chlorine, bromine or iodine) with Li, and subsequently with for example triisopropyl borine reaction of corresponding tri-alkoxy borine; Or by described chlorine, bromine or iodine compound are reacted in the presence of transition-metal catalyst (PdCl (dppf) that for example has alkoxyl group two boron) etc.Perhaps, replace triflate (the trifluoromethane sulfonyl group oxygen base) substituting group of halogen in corresponding raw material, to be substituted like that as described above.For example can obtain free boric acid class (nonesterified) by for example carrying out aftertreatment in the presence of the hydrochloric acid at mineral acid.

Can make aforesaid formula I compound that has a group D and aryl or undersaturated heterocyclyl compounds in the above to a) (cross-coupling for example of reaction then, for example Suzuki coupling) reacts under the described condition, obtain wherein original chlorine, bromine or iodine by aryl or the displaced corresponding formula I compound of undersaturated heterocyclic radical substituting group (they can be substituted separately as mentioned above like that).

Imidazo [1,2-b] pyridazine nuclear or the substituent azo-cycle atom of nitrogen heterocycle can for example form the N-oxide compound under the superoxide situation that for example metachloroperbenzoic acid or hydrogen peroxide exist in the suitable oxidizing agent.

And; in the optional method steps that " if necessary " carries out; the functional group of the starting compound that should participate in reacting can not exist with unprotected form, perhaps can be protected, for example protected by one or more blocking groups of above in " blocking group ", mentioning.Remove blocking group whole or in part according to one of wherein said method then.

Salt with formula I compound of salt forming group can prepare according to known method itself.Thus, the acid salt of formula I compound can obtain by handling with acid or with suitable anionresin reagent.

Salt can be converted into free cpds usually, for example by handling with suitable basic cpd (for example alkaline carbonate, alkali metal hydrocarbonate or alkali metal hydroxide, normally salt of wormwood or sodium hydroxide).

The mixture of the mixture of constitutional isomer or product and by product can for example separate by distribution, chromatography etc. according to standard method.

The mixture of steric isomer (as the mixture of diastereomer) can be separated into their corresponding isomer by suitable separation method according to known mode itself.Non-enantiomer mixture for example can be separated into their single diastereomer by fractional crystallization, chromatography, solvent distribution and similar approach.This separation can be carried out in the starting compound level or on the level of formula I compound itself.Enantiomer can be separated by forming diastereoisomeric salt, for example by forming salt with the chiral acid of enantiomer-pure, or separates by the chromatography (for example HPLC) that employing has a chromatogram material of chiral ligand.

Should emphasize that the reaction that is similar to the conversion reaction that these chapters and sections mention also can on the level of suitable intermediate (thereby can be used for preparing corresponding raw material) take place.

Raw material:

Other raw material midbody that the raw material of formula II, III, IV, V, VI, VII, VIII, IX and X and this paper (for example) mention or educt can be according to methods known in the art or similar approach preparations, these raw materials are known in the art and/or commercial obtainable, perhaps by or the method described in the embodiment that is similar to obtain.New raw material is (for example in embodiment 29; the compound 3-bromo-6-(3 of step 29.1; 4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine or wherein bromine by chlorine or iodine or the displaced analogue of trifyl oxygen base) and preparation method thereof be embodiment of the present invention equally.In preferred embodiments, use this type of raw material and select selected reaction to allow to obtain preferred compound.

The raw material of formula II is well known in the art, can derives from commerce or can prepare according to methods known in the art or similar approach.

For example, formula II compound can followingly obtain: make formula XII compound

Halide reagent for example the N-iodo-, the N-bromo-or N-chloro-succinimide (preferred N-bromosuccinimide) down, at for example alkylating acid amides of appropriate solvent for example in dimethyl formamide or the halogenide (methylene dichloride, chloroform) etc.s, for example to react down at-20 to 50 ℃, obtaining wherein, X is corresponding formula (II) compound of halogen (preferably bromine).

Formula XII compound can for example following acquisition: the halogenation acetone that makes formula VIII compound and formula XIII

Wherein Hal is a halogen, chlorine particularly,

In those conditions (at alternative d) of describing with the reaction of top halogenated ketone compound to formula VIII and formula IX) similarly react under the condition.

Formula VIII compound can for example following acquisition: the pyridazine compound that makes formula XV

Wherein Hal is a particularly chlorine or bromine of halogen,

With the boric acid of above mentioned formula VII or boric acid ester with top reaction (for alternative c) to formula VI compound and formula VII compound) react under those similar conditions of mentioning.

Formula IV compound for example can by formula II compound by with group D with free form (can acid for example in the presence of the hydrochloric acid by the form acquisition of esterification) or the group-B (OH) of esterified form ₂Replace and obtain, this for example be with R wherein ¹The aryl that is replaced by chlorine, the bromine or iodine for example formula I conversion of compounds of phenyl is that wherein said chlorine, bromine or iodine are by the group-B (OH) of free form or preferred esterified form ₂Carry out under the similar condition of the condition of mentioning in the respective compound of replacing.

Formula VI compound preferably can followingly obtain: make above-mentioned formula XV compound and alternative d) described in formula IX compound with top reaction (to alternative d) to formula VIII compound and formula IX compound) react under the similar condition of those conditions of mentioning.

Formula IX compound can for example be prepared as follows: make formula XVI compound

Halide reagent for example mineral acid halogenide for example in the presence of the preferred SULPHURYL CHLORIDE of alkylsulfonyl halogenide, appropriate solvent for example in the methylene dichloride, for example-20 to 50 ℃ of reactions down.

Formula XVI compound can for example following acquisition: make formula XVII compound

R ¹-Br (XVII)

With Isoamyl Acetate FCC at methoxy tributyl tin, catalyzer Pd for example ₂(dba) ₃Exist down, for example for example react under the reflux conditions in the temperature that raises in the toluene with 2-dicyclohexyl phosphino--2 '-(N, N-dimethylamino)-biphenyl at appropriate solvent.

Perhaps, formula XVI compound can followingly obtain: the aldehyde that makes formula XVIII

R ¹-CHO (XVIII)

In the presence of nitroethane and ammonium acetate, in for example 60 to 130 ℃ of reactions down of the temperature that raises, subsequently the 2-nitro propenyl intermediate that obtains (is added with or is not added with FeCl at iron powder ₃) and acid for example hydrogenchloride or acetate exist down, in water-containing solvent, for example the temperature that raises for example 50 ℃ to the reflux temperature of reaction mixture, transform.

All remaining raw materials for example raw material of formula III, V, VII, X, XI, XIV, XV, XVII or XVIII are known, that can prepare according to currently known methods or commercial can buying; Particularly, they can prepare with method described in the embodiment or method similar with it.

Embodiment:

The following example is used to illustrate the present invention, and does not limit its scope.

Temperature with degree centigrade (℃) provide.When not providing temperature, reaction is at room temperature carried out.The ratio of solvent or eluent provides with solvent ratio (v/v).

Abbreviation:

Abs is absolute

Aq is aqueous

The Boc tert-butoxycarbonyl

Salt solution is at the saturated nacl aqueous solution of RT

The DMA N,N-dimethylacetamide

DMF N, N '-dimethyl formamide

The DMSO dimethyl sulfoxide (DMSO)

Emrys Optimizer Emrys ^TMOptimizer, from Personal Chemistry,

Biotage AB, Uppsala, the microwave oven of Sweden

Eq. equivalent

The ether ether

EtOH ethanol

The EtOAc ethyl acetate

The DCM methylene dichloride

H hour

The HPLC high performance liquid chromatography

Hyflo

Super Cel is the hyflo that uses in filtration treatment, can get

From for example Fluka, Buchs, Switzerland

K ₃PO ₄Tripotassium phosphate

The LC-MS liquid chromatograph mass spectrography

Min minute

The mL milliliter

The MS-ES electron spray mass spectrometry

The MW microwave

NEt ₃Triethylamine

The NMP 1-Methyl-2-Pyrrolidone

P1 2-dicyclohexyl phosphino--2 '-(N, N-dimethylamino)-biphenyl

Pd (dba) ₂Two (benzylidene-acetone) palladium

Pd ₂(dba) ₃Three (benzylidene-acetones), two palladiums

The Ph phenyl

The rotavap Rotary Evaporators

The RT room temperature

Sat is saturated

Sphos 2-dicyclohexyl phosphino--2 ', 6 '-dimethoxy-biphenyl

TBME butyl methyl ether

The TFA trifluoroacetic acid

The THF tetrahydrofuran (THF)

The TLC tlc

t _RRetention time

The UV ultraviolet

The boric acid raw material of mentioning among the embodiment can followingly obtain:

3, and 4-dimethoxy benzene ylboronic acid (Frontier Scientific, Inc., Logan, UT, USA)

3-pyridine boric acid (=pyridine-3-boric acid) (Flurochem Ltd., Derbyshire, Britain)

5-pyrimidyl boric acid (=pyrimidine-5-ylboronic acid) (Flurochem Ltd., Derbyshire, Britain)

4-(aminocarboxyl)-phenyl-boric acid, 4-(morpholine-4-carbonyl) phenyl-boron dihydroxide, 4-(N, N-dimethylamino alkylsulfonyl phenyl) boric acid and 4-ethylsulfonyl phenyl) and boric acid (Combi-Blocks Inc., San Diego, California, USA)

Embodiment 1:6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-[1,2,4] triazol-1-yl-phenyl)-imidazo [1,2-b] pyridazine

(about the reference of the general Ullmann-type arylation of nucleophile, referring to for example Chem.Eur.J. (2004), 10,5607).Use in the 2ml bottle at the microwave that has crown cap (crown cap) and magnetic stirring bar, with 50mg (0.118mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine, 12.2mg (0.177mmol) 1,2,4-triazole, 0.24mg Cu ₂O, 3.2mg salicylic aldehyde hydrazone and 77.6mg (0.236mmol) Cs ₂CO ₃2ml acetonitrile mixture in microwave oven (Emrys Optimizer), 160 ℃ the heating 20h.Reaction mixture is diluted with methylene dichloride, filter through hyflo, and with solvent evaporation.Add methylene dichloride again, and with organic phase water (2 *) and salt solution (2 *) washing.Use MgSO ₄After the drying, with the reaction mixture vapourisation under reduced pressure.With crude product chromatography purifying (CH on silica gel ₂Cl ₂-EtOAc; Gradient, 100/0 to 20/80), obtain pure products.LC-MS：t _R＝1.63min；(M+1)＝143；MS-ES.：143(M+1).

Raw material is prepared as follows:

Step 1.1: 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

Should be noted that this compound also is a formula I compound of the present invention.

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar, with 270mg (1.17mmol) 6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine and 433mg (crude product; About 1.15mmol) the 2ml alcohol mixture of 1-(4-bromo-phenyl)-1-chloro-third-2-ketone is in microwave oven (Emrys Optimizer), at 170 ℃ of heating 2h.In reaction mixture, add NaHCO ₃After this saturated solution extracts with EtOAc.With organic phase salt water washing and dry (MgSO ₄).Evaporating solvent, and with residue chromatography purifying (solvent systems: CH on silica gel ₂Cl ₂-EtOAc 100: 0 (beginning) was to 80: 20 (end).The yellow solid that obtains is suspended in the ether, filters and, obtain title compound at 50 ℃ of dry 2h.LC-MS:t _R=1.86min; (M+1)=425; HPLC:t _R=5.53min. (same 2-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-3-methyl-imidazo [1, the 2-b] pyridazine that separates the isomer that obtains a small amount of (about 3%) in chromatographic process.LC-MS：t _R＝1.86min；(M+1)＝425；HPLC：t _R＝5.46min.)

Step 1.2:6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine

In round-bottomed flask, with 500mg (3.86mmol) 3-amino-6-chlorine pyridazine, 840mg (2.78mmol) 3,4-dimethoxy benzene ylboronic acid, 97.5mg Pd-catalyzer [PdCl ₂(PPh ₃) ₂] and 5.8ml1M K ₂CO ₃The aqueous solution heats 20h down at 105 ℃ in 10ml DMF under inert conditions.Afterwards, add NaHCO ₃Saturated solution, and with mixture CH ₂Cl ₂Extraction.With the organic phase drying, and evaporating solvent.With residue chromatography purifying on silica gel.Light brown solid further is suspended in the methyl alcohol, and filtration is also dry under high vacuum, obtains title compound.MS-ES.：(M+1)＝232；(M-1)＝230；HPLC：t _R＝2.76min.；LC-MS：t _R＝1.41min；(M+1)＝232.

Step 1.3: 1-(4-bromo-phenyl)-1-chloro-third-2-ketone

This compound use with document in similarly method preparation of currently known methods (referring to J.Org.Chem. (2001), 66,3617).10ml CH to 3.5g (16.4mmol) 4-bromophenyl acetone ₂Cl ₂In the solution, at 0 ℃ of 10ml CH that slowly adds 1.58ml (19.7mmol) SULPHURYL CHLORIDE ₂Cl ₂Solution.Reaction mixture stirred under this temperature spend the night.For the cancellation reaction, add entry and separate two-phase.With water CH ₂Cl ₂Washed twice merges organic phase, with salt water washing and dry.Behind the evaporating solvent, title compound need not to be further purified and can directly use.

HPLC；t _R＝6.5min.

Embodiment 2:6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-nitro-phenyl)-imidazo [1,2-b] pyridazine

Use in the 20ml bottle at the microwave that has crown cap and magnetic stirring bar, with 250mg (0.866mmol) 6-chloro-2-methyl-3-(4-nitro-phenyl)-imidazo [1,2-b] pyridazine, 211mg (1.13mmol) 3,4-dimethoxy phenylo boric acid, 20mg (0.0346mmol) Pd (dba) ₂, 551mg (2.6mmol) K ₃PO ₄And the anhydrous THF mixture of 10ml of 28mg (0.0693mmol) SPhos heats 1h at 110 ℃ in microwave oven (Emrys Optimizer) under inert conditions.Reaction mixture is poured in the water, and used CH ₂Cl ₂Extraction.With organic phase salt water washing, drying, and evaporate to dryness.Adopt CH with silica gel chromatography ₂Cl ₂-EtOAc (100/0 to 50/50, gradient) carries out purifying as solvent systems, obtains title compound.MS-ES：(M+1)＝391；LC-MS：t _R＝1.84min，(M+1)＝391.

Raw material is prepared as follows:

Step 2.1.6-chloro-2-methyl-3-(4-nitro-phenyl)-imidazo [1,2-b] pyridazine

In having the 6ml microwave bottle of crown cap and magnetic stirring bar, with 1.1g (8.49mmol) 6-chlorine pyridazine-3-amine and 2.38g (crude product; About 11.1mmol) the 3.5ml alcohol mixture of 1-chloro-1-(4-nitro-phenyl)-third-2-ketone stirs 1h at 170 ℃ in microwave oven (Emrys Optimizer).Afterwards, reactant is poured into saturated NaHCO ₃In-the solution, and extract with EtOAc.Merge organic phase and use salt water washing, evaporating solvent then.With residue chromatography purification (CH ₂Cl ₂-EtOAc: gradient, 100: 0 to 80: 20.Product is suspended in the methyl alcohol, filters, and dry under high vacuum.MS-ES.：M+＝289.HPLC：t _R＝5.2min.

Step 2.2: 1-chloro-1-(4-nitro-phenyl)-third-2-ketone

Be similar to embodiment 1.3, title compound by 1g (5.58mmol) 4-nitrophenyl acetone and SULPHURYL CHLORIDE at CH ₂Cl ₂In 0 ℃ of acquisition.Need not to be further purified crude product is directly used in next step.

Embodiment 3:6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyrazol-1-yl-phenyl)-imidazo [1,2-b] pyridazine

Be similar to embodiment 1, title compound is by 50mg (0.118mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (step 1.1), 12.0mg (0.177mmol) pyrazoles, about 1mg Cu ₂O, about 4mg salicylic aldehyde hydrazone (part) and 77.6mg (0.236mmol) Cs ₂CO ₃In the 2ml acetonitrile, prepare.Reaction times in microwave oven is at 160 ℃ of reaction 6h.MS-ES：412.LC-MS：t _R＝1.70min.

Embodiment 4:3-(4-benzoglyoxaline-1-base-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

Be similar to embodiment 1, title compound is by 75mg (0.177mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (step 1.1), 31.3mg (0.177mmol) benzoglyoxaline, about 1.2mg Cu ₂O, about 5mg salicylic aldehyde hydrazone and 116mg (0.0.354mmol) Cs ₂CO ₃In the 2ml acetonitrile, prepare.Reaction times in microwave oven is at 160 ℃ of reaction 6h.MS-ES：(M+1)＝462；.LC-MS：t _R＝1.65min.，(M+1)＝462.

Embodiment 5:4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzonitrile

Use in the 20ml bottle at the microwave that has crown cap and magnetic stirring bar, with 500mg (1.86mmol) 4-(6-chloro-2-methyl-imidazo [1,2-b] pyridazine-3-yl)-benzonitrile, 779mg (4.28mmol adds at twice) 3,4-dimethoxy benzene ylboronic acid, 42.8mg Pd (dba) ₂, 1.18g (5.58mmol) K ₃PO ₄Heat at 110 ℃ (2h), 120 ℃ (2h), 130 ℃ (5h) in microwave oven (EmrysOptimizer) with the anhydrous THF mixture of the 15ml of 61.1mg SPhos, after adding the described boric acid of 1 equivalent again, 110 ℃ of heating 2 hours, heat 11 hours (with HPLC monitoring reaction) altogether again.Reaction mixture is poured in the water, and extracted with EtOAc.Organic phase is with salt solution and water washing, dry then, and evaporating solvent.With residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂100: 0 to 230: 70 (gradients of-EtOAc; Chromatography first) and CH ₂Cl ₂-MeOH 95: 5 (chromatography for the second time).LC-MS：t _R＝1.81min.，(M+1)＝371.

Step 5.1: 4-(6-chloro-2-methyl-imidazo [1,2-b] pyridazine-3-yl)-benzonitrile

Use in the 20ml bottle, at the microwave that has crown cap and magnetic stirring bar 0.98g (7.56mmol) 6-chlorine pyridazine-3-amine and 1.9g (crude product; About 9.81mmol) the anhydrous EtOH mixture of 5ml of 4-(1-chloro-2-oxo-propyl group)-benzonitrile in 100 ℃ (3h 15min), 120 ℃ (2h) and 140 ℃ (6h) heating, heats 7.5h altogether in microwave oven.Afterwards, pour reaction mixture into NaHCO ₃In the aqueous solution, and extract with EtOAc.With organic phase salt solution and water washing.With crude product chromatography purification (solvent systems: CH ₂Cl ₂-EtOAC=100/0 to 50/50; Gradient) .LC-MS:t _R=1.84min., (M+1)=269; HPLC:t _R=4.65min.

Step 5.2:4-(1-chloro-2-oxo-propyl group)-benzonitrile.

Be similar to embodiment 1.3, title compound by 1.95g (12.2mmol) 4-(2-oxo-propyl group)-benzonitrile and 1.13ml (14mmol) SULPHURYL CHLORIDE at 9.7ml CH ₂Cl ₂In stir down the 3h preparation at 0 ℃.HPLC:t _R=5.35min. crude product need not to be further purified and is directly used in next step.

Step 5.3: 4-(2-oxo-propyl group)-benzonitrile

(about the document of general method referring to Bull.Chem.Soc.Jpn. (1984), 57,242.).In being equipped with the round-bottomed flask of reflux exchanger, with 10g (52.2mmol) 4-bromobenzyl nitrile, 9.02ml methylvinyl acetate, 24ml methoxy tributyl tin, 502mg (0.548mmol) Pd ₂(dba) ₃And the 27.5ml toluene mixture of 865mg (2.2mmol) P1 stirs 16h under reflux temperature.Reaction mixture is poured in the water, and separated two-phase.Organic phase is washed with water, and use CH ₂Cl ₂Aqueous phase extracted.Two parts of organic phases are merged, and evaporate to dryness.Use the silica gel chromatography purified product.Solvent systems: hexane-EtOAc 80: 20 to 50: 50.Can from impure stream part, isolate other material with reverse-phase chromatography.Obtain title compound, be faint yellow solid.LC-MS：t _R＝1.70min.，(M+1)＝160；HPLC：t _R＝4.4min.

Embodiment 6:6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyridin-3-yl-phenyl)-imidazo [1,2-b] pyridazine

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar, with 50mg (0.118mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine, 21.7mg (0.177mmol) 3-pyridine boric acid, 2.71mg Pd (dba) ₂With 75mg K ₃PO ₄, 3.87mg

The anhydrous THF mixture of the 2ml of SPhos stirs 2h down inert atmosphere, 110 ℃ in microwave oven (Emrys Optimizer).Afterwards, reaction mixture is poured in the water, and used CH ₂Cl ₂Extraction.With organic phase salt water washing, use MgSO ₄Drying, and be concentrated into dried.With residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc 50: 50 to 100: 0.Obtain title compound, be yellow solid.MS-ES：(M+1)＝423；HPLC：t _R＝3.4min.；LC-MS：t _R＝1.65min.，(M+1)＝423.

Embodiment 7:6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(1H-tetrazolium-5-yl)-phenyl]-imidazo [1,2-b] pyridazine

(about the document of general method referring to J.Heteroc.Chem. (1999), 36,1129.) use in the 3ml bottle at the microwave that has crown cap and magnetic stirring bar, with 50mg (0.135mmol) 4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzonitrile, altogether 106mg (1.63mmol) sodiumazide and altogether the 2ml DMF mixture of 88.5mg (1.65mmol) ammonium chloride in microwave oven (Emrys Optimizer) at 150 ℃ of heating 8h.With HPLC monitoring reaction process, and added 2 equivalent sodiumazide and ammonium chlorides in per 2 hours again, intact up to cyano group raw material consumption.With the reaction mixture concentrating under reduced pressure, and be suspended in 2N HCl and CH ₂Cl ₂In.Title compound precipitates with yellow powder, with its filtration, washes with water, and dry under 70 ℃, high vacuum.HPLC：t _R＝2.89min；ES-MS：414(M+1)；LC-MS：t _R＝1.33min，(M+1)＝414.

Embodiment 8:6-(3,4-dimethoxy-phenyl)-3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

Title reaction is carried out in the 2ml bottle at the microwave that has crown cap and magnetic stirring bar with two parts; In bracket, provide relative quantity.With 112mg (50 and 62mg; 0.48mmol) 6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine, 181mg (63 and 118mg; 0.587mmol) 1-chloro-1-(4-methane sulfonyl-phenyl)-third-2-ketone and 109 μ l (38 and 71 μ l) NEt ₃1.5ml (0.5 and 1ml) EtOH mixture under argon gas (Ar) atmosphere, in microwave oven (Emrys Optimizer) 170 ℃ of reactions 30 minutes down.HPLC and TLC demonstration no longer include raw material.Pour reaction mixture into CH ₂Cl ₂In, water and salt water washing, and use Na ₂SO ₄Dry.Carry out purifying with silica gel chromatography.Solvent systems: CH ₂Cl ₂-MeOH 100/0 to 0/100 (gradient).By with ether from CH ₂Cl ₂Middle precipitation is further purified title compound.HPLC：t _R＝4.06min.；ES-MS：424(M+1).

Raw material is prepared as follows:

Step 8.1: 4-methane sulfonyl-phenyl aldehyde

Under argon gas atmosphere, with the 25ml DMSO mixture of 2.5g (17.4mmol) 4-chloro-phenyl aldehyde and 2.62g (21.8mmol) methane-sulfinic acid sodium at 150 ℃ of heating 18h.HPLC shows only a small amount of raw material.Reaction mixture is cooled to RT, and pours in the frozen water.Generate precipitation, and stir 30min.Cross filter solid, wash with water, and under 50 ℃, high vacuum dry 20h.Title compound need not to be further purified and is directly used in next step.HPLC：t _R＝3.04min.；ES-MS：183(M-1).

Step 8.2:1-(4-methane sulfonyl-phenyl)-third-2-ketone

With 4-methane sulfonyl-phenyl aldehyde (1.75g; 9.02mmol), nitroethane (5.24ml; 72.2mmol) and ammonium acetate (211mg; 2.71mmol) at 125 ℃ of heating 5h.By in Rotary Evaporators, evaporating, remove excess reagent, add CH then ₂Cl ₂, and with mixture water and salt water washing.Use Na ₂SO ₄After the drying, remove and to desolvate, then with 1-methane sulfonyl-2-nitro-propenyl)-the benzene intermediate is suspended in the 11ml water.Add iron powder (1.98g; 35.2mmol) and FeCl ₃6H ₂O (48.8mg; 0.18mmol), mixture heating up is extremely refluxed.Under this temperature, go through 1h and slowly add 5ml 2M HCl, and make that being reflected at refluxes carries out 7h down again.In cold reaction mixture, add CH ₂Cl ₂And filter through hyflo.Separate organic phase, water and salt water washing, and use Na ₂SO ₄Dry.Behind the evaporating solvent, obtain title compound.HPLC：t _R＝3.21min.；ES-MS：211(M-1).

Step 8.3: 1-chloro-1-(4-methane sulfonyl-phenyl)-third-2-ketone

Be similar to embodiment 1.3, title compound by 150mg (0.67mmol) 1-(4-methane sulfonyl-phenyl)-third-2-ketone and 66 μ l (0.8mmol) SULPHURYL CHLORIDE at 3ml CH ₂Cl ₂In stir down the 22h preparation at 0 ℃.HPLC:t _R=4.42min.; ES-MS:245 (M-1). crude product need not to be further purified and is directly used in next step.

Embodiment 9:6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyrimidine-5-base-phenyl)-imidazo [1,2-b] pyridazine

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar, with 50mg (0.118mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine, 21.9mg (0.177mmol) 5-pyrimidyl boric acid, 2.71mg Pd (dba) ₂, 75mg K ₃PO ₄With the anhydrous THF mixture of the 3ml of 3.87mgSPhos in microwave oven (Emrys Optimizer), stir 2h down inert atmosphere, 110 ℃.Afterwards, reacted, added alkali (K again ₂CO ₃49.4mg) and another catalyzer (PdCl ₂(PPh ₂) FeCH ₂Cl ₂), with mixture at 110 ℃ of reheat 20h.Mixture is poured in the water, and used CH ₂Cl ₂Extraction.With organic phase Na ₂SO ₄Drying, and be concentrated into dried.With residue combi-flash chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc obtained title compound in 100: 0 to 50: 50., was the glassy yellow solid.MS-ES.:(M+1)=424; HPLC:t _R=4.134min. can find the raw material of trace debrominate.

Embodiment 10:6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

Use in the 20ml bottle at the microwave that has crown cap and magnetic stirring bar, with 0.6g ((2.59mmol) 6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine, 2.46g 1-chloro-1-(4-iodo-phenyl)-third-2-ketone (crude product; About 5.19mmol) and 1.09ml (7.78mmol) Et ₃The 10ml alcohol mixture of N heats 30min at 170 ℃ in microwave oven (Emrys Optimizer).Pour reaction mixture into NaHCO ₃In the saturated solution, and use dichloromethane extraction.With organic phase salt water washing, dry (Na ₂SO ₄), filter and under reduced pressure concentrate.Product is passed through the combi-flash chromatography purification.Solvent systems: gradient CH ₂Cl ₂/ MeOH 100: 0 to 95: 5.Collection contains stream part of title compound and under reduced pressure concentrates.Residue is suspended in the ether, filter and under high vacuum 50 ℃ of dryings 1 hour.Obtain light brown solid.MS：(M+1)＝472；HPLC：t _R＝5.667min.

The following acquisition of raw material:

Step 10.1: 1-chloro-1-(4-iodo-phenyl)-third-2-ketone

Title compound is similar to the chloro-acetone of preparation in the step 1.3 by 2g (7.69mmol) 1-(4-iodo-phenyl)-third-2-ketone, 1.85ml (23.1mmol) SULPHURYL CHLORIDE and 15ml CH ₂Cl ₂Preparation.Product need not purifying and is directly used in next step.HPLC；t _R＝6.78min.

Step 10.2: 1-(4-iodo-phenyl)-third-2-ketone

Under argon gas atmosphere, with 7.51ml nitroethane mixture stirring 15h under 125 ℃ of 3g (12.8mmol) 4-benzaldehyde iodine (Pfaltz-Bauer) and 302mg (3.88mmol) ammonium acetate.Then reaction mixture is concentrated under reduced pressure.Residue is dissolved in CH ₂Cl ₂In, and with organic phase water and salt water washing.Dry (Na ₂SO ₄) after, evaporating solvent, and residue is dissolved in a few ml Glacial acetic acid.In 60 ℃ of 8ml Glacial acetic acid soup compounies that this solution slowly added to 2.9g (51.7mmol) iron powder.Reactant is spent the night 100 ℃ of stirrings.Cold reaction mixture is poured in the frozen water.Brown suspension is filtered through hyflo, and with the residue on the filter with enough CH ₂Cl ₂Washing.Separate mutually filterable, organic phase is used 1M hydrochloric acid, saturated NaHCO continuously ₃Solution, water and salt water washing.Use MgSO ₄After the drying, evaporating solvent, and with the residue purified by flash chromatography.Solvent systems: hexane-ethyl acetate=90: 10.HPLC; t _R=6.14min.

Embodiment 11:6-(3,4-dimethoxy-phenyl)-3-(3-fluoro-4-methoxyl group-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

Title compound, be similar to the compound described in the embodiment 8, at microwave (at 170 ℃, 30min) by 100mg (0.411mmol) 6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine (preparation is referring to step 1.2), 167mg (0.616mmol) 1-chloro-1-(3-fluoro-4-methoxyl group-phenyl)-third-2-ketone and 0.115ml (0.822mmol) Et ₃N prepares in 1.5ml ethanol.With silica gel chromatography purifying crude product.The solvent gradient: hexane-ethyl acetate 50: 50 (beginning) is to 100% ethyl acetate (end).Title compound, is suspended in it in ethyl acetate (a few ml) and the hexane from obtaining with ochre shape solids constituent, and stirs and cool off with frozen water simultaneously.Yellow solid is filtered and drying, obtain pure title compound.MS：(M+1)＝394；HPLC：t _R＝4.92min.

Raw material is prepared as follows:

Step 11.1: 1-chloro-1-(3-fluoro-4-methoxyl group-phenyl)-third-2-ketone

Title compound is similar to the chloro-acetone for preparing in the step 1.3, by 150mg (0.69mmol) 1-(3-fluoro-4-methoxyl group-phenyl)-third-2-ketone, 0.068ml (0.83mmol) SULPHURYL CHLORIDE and 3mlCH ₂Cl ₂Preparation.Product need not purifying and is directly used in next step.

Step 11.2: 1-(3-fluoro-4-methoxyl group-phenyl)-third-2-ketone

Part A:

The 9.32ml nitroethane mixture of 2.5g (16.1mmol) 3-fluoro-4-methoxyl group-phenyl aldehyde (SynChem) and 375mg (4.82mmol) ammonium acetate is heated 24h at 125 ℃.In Rotary Evaporators, evaporate, remove excess reagent, add CH ₂Cl ₂, and with mixture water and salt water washing.Use Na ₂SO ₄After the drying, remove and desolvate, then the nitro intermediate that obtains is suspended in the 18ml water.Add iron powder (3.51g; 62.6mmol) and FeCl ₃6H ₂O (86.8mg; 0.32mmol), and with extremely backflow of mixture heating up.Under this temperature, go through 1h and slowly add 8.83ml 1M HCl, reactant is under refluxad carried out 8h again.In cold reaction mixture, add CH ₂Cl ₂, mixture is filtered through hyflo.Separate organic phase, water and salt water washing, and use Na ₂SO ₄Dry.Behind the evaporating solvent, the product of acquisition is accredited as 2-fluoro-1-methoxyl group-4-((E)-2-nitro-propenyl)-benzene intermediate, shows reduction MS:(M+1 does not take place)=212; HPLC:t _R=6.42min.

Part B:

The unreduced substance dissolves that 1g (4.5mmol) is obtained above and at 60 ℃, adds in 1h in the 15ml Glacial acetic acid suspension of 2.52g iron powder in the 7ml Glacial acetic acid.After this, reaction mixture is stirred 22h at 100 ℃.Cold reaction mixture is poured in the frozen water, and stirred 15min.Add CH ₂Cl ₂And water, and mixture filtered through hyflo.Separate each phase, water is used CH once more ₂Cl ₂Extraction, and with the organic phase 1M HCl (1 *), saturated sodium bicarbonate (1 *), water (2 *) and salt solution (1 *) washing that merge.Behind the dry also evaporating solvent, with crude product chromatography purifying on silica gel.Solvent: hexane-ethyl acetate 90: 10.MS:(M+1)=183; HPLC:t _R=4.93min.

Embodiment 12a and 12b:4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl amine 12a4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-methyl-amine 12b

With the 10ml methanol solution of 200mg 6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-nitro-phenyl)-imidazo [1,2-b] pyridazine (preparation referring to embodiment 2) in the presence of Pd-10%C, at RT hydrogenation 37h (hydrogen balloon).Mixture is filtered and evaporating solvent through hyflo.With residue chromatography purifying on silica gel-C18.Solvent gradient: acetonitrile-water.Amine 12aAnalytical data: MS:(M+1)=361; HPLC:t _R=3.22min.; The analytical data of methyl-amine 12b: MS:(M+1)=375; HPLC:t _RThe suitable weight ratio of 12a that=3.87min. obtains and 12b is 4: 3.

Embodiment 13:6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-imidazo [1,2-b] pyridazine

Be similar to embodiment 1, title compound is by 75mg (0.177mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to step 1.1), 36mg (0.265mmol) 3-(trifluoromethyl)-pyrazoles (Fluka, Buchs, Switzerland), 1.5mgCu ₂O, 5.5mg salicylic aldehyde hydrazone (Aldrich, Sigma-Aldrich, Buchs, Switzerland)) and 120mg (0.364mmol) Cs ₂CO ₃In the 2ml acetonitrile, prepare.Reaction times in microwave oven is 4h: at 160 ℃ (1h) and 150 ℃ (3h).MS-ES(M+1)：480.HPLC?t _R＝5.86min.

Embodiment 14:1-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-piperidines-2-ketone

(about general method referring to J.Org.Chem. (2005), 70,5164.).With 50mg (0.106mmol) 6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to embodiment 10), 13.7mg (0.138mmol) Valerolactim, 2.02mg CuI, 29.6mg (0.212mmol) K ₂CO ₃Stir 24h with the 2ml DMSO mixture of 3.05mg L-proline(Pro) at 130 ℃.With the refrigerative mixture at water and CH ₂Cl ₂Between distribute, and filter through hyflo.Separate each phase, and with water CH ₂Cl ₂Extraction.With the organic phase salt water washing that merges, through Na ₂SO ₄Dry also evaporate to dryness.With crude product combi-flash chromatography purification.Solvent systems: hexane-ethyl acetate 100/0 (beginning) is to 0/100 (end).Isolating solid is suspended in the ether, and filtration is also dry under high vacuum, obtains title compound, is yellow solid.LC-MS：443(M+1)；t _R＝1.43min.HPLC：t _R＝4.2min.

Embodiment 15:6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-morpholine-4-base-phenyl)-imidazo [1,2-b] pyridazine

Title compound uses the method that is similar to embodiment 14 by 50mg 6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation is referring to embodiment 10), 19mg morpholine, 2mg CuI, 30mg K ₂CO ₃Prepare in 2ml DMSO with 3mg L-proline(Pro).Reaction times: at 100 ℃, 15h.MS:431 (M+1) .HPLC:t _R=4.59min.

Embodiment 16:1-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-pyrrolidin-2-one

Title compound uses the method that is similar to embodiment 14 by 50mg 6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation is referring to embodiment 10), 18mg 2-Pyrrolidone, 2mg CuI, 30mg K ₂CO ₃Prepare in 2ml DMSO with 3mg L-proline(Pro).Reaction times: at 100 ℃, 15h.MS:429 (M+1) .HPLC:t _R=4.31min.

Embodiment 17:6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(4-methyl-piperazine-1-yl)-phenyl]-imidazo [1,2-b] pyridazine

Title compound is with being similar to the method for embodiment 14 by 50mg 6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] and pyridazine (preparation referring to embodiment 10), 0.024mlN-methylpiperazine (Fluka, Buchs, Schweiz), 2mg CuI, 30mg K ₂CO ₃Prepare in 2ml DMSO with 3mg L-proline(Pro).Reaction times: at 100 ℃, 15h.MS:444 (M+1) .HPLC:t _R=3.27min.

The compound of describing among the following embodiment can be used with the similar method preparation of method described in the literary composition or prepare as described in concrete:

Embodiment 18:

Embodiment 19:

Embodiment 20:

Embodiment 21:

Embodiment 22:

Embodiment 23:

Embodiment 24:{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-morpholine-4-base-ketone.

Be similar to embodiment 27, title compound is by 80mg (0.207mmol) 3-bromo-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to embodiment 29), 58.9mg (0.248mmol) 4-(morpholino-4-carbonyl) phenyl-boron dihydroxide (from Combi-Blocks) and 0.41ml 1MK ₂CO ₃The aqueous solution, 11.9mg (0.0103mmol) four (triphenylphosphine) close palladium and prepare in 2ml DMA.Bottle is heated 20min (100 ℃ of reaction generations) at 150 ℃ in microwave oven.Behind the purifying, obtain yellow crystals.MS.：459(M+1).-HPLC.：tR＝3.878min.

Embodiment 25:

Embodiment 26:4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N, N-dimethyl-benzsulfamide

Be similar to embodiment 27; title compound is by 80mg (0.207mmol) 3-bromo-6-(3; 4-dimethoxy-phenyl)-2-methyl-imidazo [1; 2-b] pyridazine (preparation referring to embodiment 29), 71.8mg (0.31mmol) 4-(N, N-dimethylamino alkylsulfonyl phenyl) boric acid (deriving from Combi-Blocks), 0.52ml 1MK ₂CO ₃The aqueous solution, 11.9mg (0.0103mmol) four (triphenylphosphine) close palladium and prepare in 2ml DMA.Bottle is heated 40min at 100 ℃ in microwave oven.Behind the purifying, obtain yellow crystals.MS.：453(M+1).-HPLC.：t _R＝4.691min.

Embodiment 27:4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzamide

Use in the 3ml bottle at the microwave that has crown cap and magnetic stirring bar, with 80mg (0.207mmol) 3-bromo-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to embodiment 29), 41.3mg (0.248mmol) 4-(aminocarbonyl-phenyl) boric acid (from Combi-Blocks), 0.52ml1M K ₂CO ₃The mixture argon-degassed 5min of the aqueous solution and 2ml DMA (dimethyl formamide).Afterwards, add 11.9mg (0.0103mmol) four (triphenylphosphines) and close palladium, and bottle is heated 55min (100 ℃ of reaction generations) at 150 ℃ in microwave oven.Afterwards, no longer can detect raw material with HPLC.Reaction mixture is evaporated to dried, residue is dissolved in EtOAc and the water.Separate each phase, with water with EtOAc extracting twice again.Use Na ₂SO ₄After the drying, evaporating solvent.With the thick material (CombiFlash of chromatography purification; Solvent systems: from 100%CH ₂Cl ₂/ MeOH 98: 2 is to 100%CH ₂Cl ₂/ MeOH 95: 5).Pure compound is suspended among the EtOAc, adds hexane, behind about 5 ℃ of placement 1h, suspension is filtered,, obtain title compound with hexane wash and dry.MS.：389(M+1).-HPLC.：t _R＝3.461min.

Embodiment 28:

Embodiment 29:

By using formula R ¹-B (OH) ₂Boric acid replace the 3-bromine group, following raw materials according can be used for synthetic compound of formula i:

Step 29.1: 3-bromo-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

In the 3ml DMF solution of ice-cold 300mg (1.06mmol) 6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine, add 178mg (1.02mmol) N-bromosuccinimide.Continue to stir 2h at 0-5 ℃, then at RT restir 1h.Afterwards,, residue is dissolved in the ethyl acetate the reaction mixture evaporate to dryness, and with organic phase water (2 *) and salt solution (1x) washing.Use Na ₂SO ₄After the drying, evaporating solvent.Title compound is crystallization from ethyl acetate-hexanes mixtures.MS-ES.：348/350.Rf(CH ₂Cl ₂-MeOH＝95∶5)＝0.56.

Step 29.2: 6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar, with 500mg (2.05mmol) 6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine, 0.364ml (4.11mmol) monochloroacetone (Fluka) and 0.716ml Et ₃The 4ml alcohol mixture of N heats 30min at 170 ℃ in microwave (Emrys Optimizer).With the reaction mixture evaporate to dryness, and residue is dissolved in CH ₂Cl ₂In.With organic phase water (2 *) and salt solution (1x) washing.Use Na ₂SO ₄After the drying, evaporating solvent is with residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂(100%; Beginning) to CH ₂Cl ₂-MeOH98: 2 (end).MS：(M+1)＝270；HPLC：t _R＝3.37min.

Embodiment 30:3-(2-chloro-4-methoxyl group-5-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine.

Title compound, be similar to the compound of describing among the embodiment 8, by 300mg (1.297mmol) 6-(3,4-dimethoxy-phenyl)-pyridazine-3-base amine (referring to step 1.2), 1.6g (crude product, about 1.95mmol), 1-chloro-1-(2-chloro-4-methoxyl group-5-methyl-phenyl)-third-2-ketone and 0.602ml (4.324mmol) NEt ₃In the dry EtOH of 3ml, prepare.Mixture is heated 30min at 170 ℃ in microwave oven.Behind aftertreatment and purifying, obtain yellow solid.MS.：424(M+1).-HPLC.：t _R＝5.477min.

The following acquisition of raw material:

Step 30.1:1-chloro-2-chloromethyl-5-methoxyl group-4-methyl-benzene

For synthetic to the compound of step 30.4. of the synthetic and step 14.2. of title compound, J.Chem.Soc.Perkin Trans.I (1984), 1913. referring to people such as Carvalho

Described compound according to the method that provides in the top document by 50g (319mmol) 5-chloro-2-methyl phenylmethylether (Apollo Chemicals Co., Burlington, North Carolina, USA), 6.22g (44.7mmol) ZnCl ₂, 0.466g NaCl, 41.4ml formaldehyde (37% the aqueous solution) and the preparation of HCl gas.The product that forms need not to be further purified and is directly used in next step.HPLC.：t _R＝5.252min.

Step 30.2.Acetate 2-chloro-4-methoxyl group-5-methyl-benzyl ester

React in 300ml DMF by 62g (about 287mmol) 1-chloro-2-chloromethyl-5-methoxyl group-4-methyl-benzene (referring to step 30.1), 250g (3.02Mol) NaOAc, obtain title compound, be oily matter, it need not to be further purified and is directly used in next step.HPLC.：t _R＝6.779min.

Step 30.3: 2-chloro-4-methoxyl group-5-methyl-phenyl)-methyl alcohol

By 70g (crude product; About 275mmol) acetate 2-chloro-4-methoxyl group-5-methyl-benzyl ester (referring to step 30.2), 29g (0.71mmol) NaOH sheet, 70ml H ₂O and 350ml MeOH react, with among the 4N HCl and after, obtain title compound.After the drying, obtain product into white powder.HPLC.：t _R＝5.255min.

Step 30.4:2-chloro-4-methoxyl group-5-methyl-phenyl aldehyde

By 58.5g (crude product, about 160mmol) (2-chloro-4-methoxyl group-5-methyl-phenyl)-methyl alcohol (referring to step 24.3), 139g (1.6Mol) activatory MnO ₂(Merck-Schuchard, Darmsatadt Germany) react in 1L toluene, obtain title compound.With analytic sample chromatography purifying (solvent systems: hexane-EtOAc 100: 1 to 50: 50) .MS.:185 (M+1) .-HPLC.:t on silica gel _R=6.496min.

Step 30.5:1-(2-chloro-4-methoxyl group-5-methyl-phenyl)-third-2-ketone

Title compound with step 8.2 in the slightly different method of the compound preparation of preparation: with 5g (13.5mmol) 2-chloro-4-methoxyl group-5-methyl-phenyl aldehyde (referring to step 30.4.) and 316mg (4.06mmol) NH ₄The 7.86ml nitroethane mixture of OAc is 125 ℃ of heated overnight.Reaction mixture is under reduced pressure concentrated.Residue is dissolved in CH ₂Cl ₂In, and use H ₂The O extraction.With water CH ₂Cl ₂Washing.With the organic phase salt water washing that merges, dry and evaporate to dryness.In 5-neck bottle, add 3.04g (54.2mmol) iron powder and 8.5ml HOAc.This flask is assembled condenser, and mixture is stirred the formation grey slurry at 60 ℃.In this soup compound, slowly add the suspension of above-mentioned intermediate in Glacial acetic acid, spend the night 105 ℃ of stirrings then.Make the reactant cooling, and pour H into ₂Among the O.Suspension is filtered through hyflo.Separate each layer, and with organic phase 1N HCl, saturated NaHCO ₃, water and salt water washing.Evaporating solvent is with residue purified by flash chromatography (solvent systems: hexane-EtOAc 100: 0 to 50: 50).Separate the product that obtains to oily matter.MS.：213(M+1).-HPLC.：t _R＝6.29min.

Step 30.6:1-(2-chloro-4-methoxyl group-5-methyl-phenyl)-third-2-ketone

Title compound is similar to the compound for preparing among the step 8.3., by 1.3g (3.97mmol) 1-(2-chloro-4-methoxyl group-5-methyl-phenyl)-third-2-ketone (referring to step 30.5.) and 0.958ml SO ₂Cl ₂At 10ml CH ₂Cl ₂In 0 ℃ of preparation.Product need not to be further purified and can use in embodiment 30.

Embodiment 31:6-(3,4-dimethoxy-phenyl)-3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine.

Be similar to embodiment 19; title compound is by 80mg (0.207mmol) 3-bromo-6-(3; 4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to embodiment 14), 53.6mg (0.248mmol) (4-ethylsulfonyl phenyl) boric acid (from Combi-Blocks), 0.52ml 1M K ₂CO ₃The aqueous solution, 11.9mg (0.0103mmol) four (triphenylphosphine) close palladium and prepare in 2ml DMA.Bottle is heated 40min (100 ℃ of reaction generations) at 150 ℃ in microwave oven.Behind the purifying, obtain yellow crystals.MS.：438(M+1).-HPLC.：t _R＝4.359min.

Embodiment 32:

Embodiment 33:

Embodiment 34:

Embodiment 35:3-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N, N-dimethyl-benzsulfamide

Use in the 3ml bottle at the microwave that has crown cap and magnetic stirring bar; with 80mg (0.207mmol) 3-bromo-6-(3; 4-dimethoxy-phenyl)-2-methyl-imidazo [1; 2-b] pyridazine (preparation referring to step 29.1), 72.5mg (0.31mmol) 3-(N, N-dimethylamino alkylsulfonyl phenyl) boric acid (Combi-Blocks) and 0.52ml 1M K ₂CO ₃The 2ml DMA mixture argon-degassed 5min of the aqueous solution.Add 11.9mg four triphenylphosphines then and close palladium, and mixture is heated 40min at 150 ℃ in microwave oven.Pour reaction soln into CH ₂Cl ₂In, and with organic phase water and salt water washing.Separate each phase, with organic phase drying (Na ₂SO ₄) and evaporate to dryness.With residue chromatography purifying on silica gel.Solvent systems: A=EtOAc; B=EtOAc-MeOH=98: 2. from 100%A, then in 30min to 100%B.Separate obtaining title compound, be the glassy yellow solid.MS.：453.1(M+1).-HPLC.：t _R＝4.635min.

Compound in the following table prepares with the method that is similar to embodiment 35:

Embodiment 50:5-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-the cigarette nitrile

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar, with 142mg (0.301mmol) 6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-imidazo [1,2-b] pyridazine, 50mg 5-bromo-3-cyanopyridine (Aldrich), 151mgK ₂CO ₃With 12mg PdCl ₂(dppf) 3ml toluene and 2ml are dry, and the EtOH mixture heats l h at 110 ℃ in microwave oven.Pour reaction mixture into CH ₂Cl ₂In, water and salt water washing, and dry (Na ₂SO ₄).Behind the evaporating solvent, with residue chromatography purifying on silica gel.Solvent systems: from CH ₂Cl ₂-EtOAc-MeOH=100-0-0 begins, and finishes to 80-1.6-0.4.Separate obtaining title compound, be yellow solid.LC-MS：448(M+1).-

HPLC.：t _R＝4.867min.

Step 50.1:6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(4,4,5,5-tetramethyl--[1,3,2] dioxo bora pentamethylene-2-yl)-phenyl]-imidazo [1,2-b] pyridazine

The method for preparing this boric acid ester is found in document, for example WO2005123687.

Use in the 20ml bottle at the microwave that has crown cap and magnetic stirring bar, with 3.5g (8.249mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to step 1.1.), triethylamine (triethyamin puriss) that 3.8ml is pure (Fluka), 2.8g connection boric acid pinacol ester (bis (pinacolato) diboron) 20ml dioxane solution argon-degassed (Aldrich).Add 371mg PdCl ₂(PPh ₂) Fe.CH ₂Cl ₂With several ionic liquids (1-butyl-3-methyl imidazolium tetrafluoroborate; Fluka), and with mixture in microwave oven, stir 4h (extremely slow) 130 ℃ of reactions at 150 ℃.Pour reactant into CH ₂Cl ₂In, wash with water and dry (Na ₂SO ₄).Evaporating solvent is with residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc=100-0 (beginning) is to 70-30 (end).Separate obtaining title compound, be yellow solid.MS：472(M+1).-HPLC.：t _R＝6.014min.

The following table compound prepares with the method that is similar to embodiment 50:

Embodiment 55:3-(4-benzothiazole-2-base-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

For similar reaction referring to J.Org.Chem. (2005), 70,5164.

With 100mg (0.212mmol) 6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to embodiment 10), 0.04ml (1.74mmol) benzothiazole (Aldrich), 6mg CuI (Fluka), 64mg K ₂CO ₃, 6mg L-proline(Pro) (Fluka) the 5mlDMSO mixture in oil bath, heat 18h.Pour reaction mixture into CH ₂Cl ₂In, wash with water, and dry (Na ₂SO ₄).Evaporating solvent through dual chromatography purifying on silica gel and C18-silica gel, obtains title compound with residue, is yellow solid.MS：479(M+1)；HPLC.：t _R＝6.154min

Compound in the following table prepares with the method that is similar to embodiment 55:

Embodiment 60:5-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-pyridine-2-base amine

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar, with 100mg (0.236mmol) 3-(4-bromo-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation referring to step 1.1.), 70mg (0.305mmol) 2-aminopyridine-5-boric acid pinacol ester (Aldrich), 130mgK ₂CO ₃With 10mg PdCl ₂(dppf) 3ml toluene and 2ml are dry, and the EtOH mixture heats 8h at 10 ℃ in microwave oven.Pour reaction mixture into CH ₂Cl ₂In, wash with water and dry (Na ₂SO ₄).Behind the evaporating solvent, with residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc-MeOH=100-0-0 (beginning) is to 50-40-10 (end).Separate obtaining title compound, be yellow solid.MS：438(M+1)；HPLC.：t _R＝3.498min.

Embodiment 61:3,6-pair-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

With 50mg (0.203mmol) 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine (BKS422; Preparation is referring to step 61.1), 92mg (0.446mmol) (4-methyl sulphonyl) phenyl-boron dihydroxide (Combi-Blocks), 0.51ml 1M K ₂CO ₃The aqueous solution, 8mg Pd (PPh ₃) ₂Cl ₂The 1.5mlDMF mixture in oil bath 105 ℃ the heating 5h.Pour reaction mixture into CH ₂Cl ₂In, wash with water and dry (Na ₂SO ₄).Behind the evaporating solvent, with residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc=100-0 (beginning) is to 0/100 (end).Separate obtaining title compound, be yellow solid.MS：442(M+1)；HPLC.：t _R＝3.710min.

Step 61.1:3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine

With 6-chloro-2-methyl-imidazo [1,2-b] pyridazine (NVP-BKS419; Preparation is referring to the step 13.6. of application example P2 (Beispiele P2 Anmeldung)) (2.4g; 14.3mmol) be dissolved among the DMF (25mL), and be cooled to 0 ℃.Under this temperature, add N-bromosuccinimide (2.82g; 15mmol), yellow solution is stirred 2h at 0 ℃, stir 1h at RT then.Yellow solution is extracted among the EtOAc (200mL), and water (2 * 100mL) washings, then with water layer with EtOAc (1 * 200mL) back extraction.With the organic layer drying (Na that merges ₂SO ₄), under reduced pressure concentrate, then chromatographic separation (120g Redisep, ISCO Sg-100; Use the TBME wash-out), obtain being light brown crystalline title compound; Mp.146-148 ℃;

MS:247.9 (M+1); HPLC.:t _R=5.81min. structure is determined by the analysis of x light.

Embodiment 62:3,6-pair-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine

Title compound, be similar to the compound of preparation among the embodiment 61, by 100mg (0.406mmol) 3-bromo-6-chloro-2-methyl-imidazo [1,2-b] pyridazine (step 61.1) and 400mg (1.754mmol) 4 '-methoxyl biphenyl-4-ylboronic acid (Combi-Blocks) preparation.Yellow solid.

MS：498(M+1)；HPLC.：t _R＝6.989min.

Embodiment 63:6-(4-oxyethyl group-3-methoxyl group-phenyl)-3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

With 50mg (0.138mmol) 3-bromo-6-(4-oxyethyl group-3-methoxyl group-phenyl)-2-methyl-imidazo [1,2-b] pyridazine (preparation is referring to the step 13.1. in application example P2 (Beispiele Anmeldung P2)), 40mg (0.194mmol) (4-methyl sulphonyl) phenyl-boron dihydroxide (Combi-Blocks), 0.35ml 1M K ₂CO ₃The aqueous solution and 6mg Pd (PPh ₃) ₂Cl ₂1.5ml DMF mixture in oil bath 105 ℃ the heating 4 ¹/ ₂H.Pour reaction mixture into CH ₂Cl ₂In, organic phase is washed with water and dry (Na ₂SO ₄).Organic solution is concentrated, and with chromatography purifying residue on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc=100-0 (beginning) is to 30-70 (end).Separate obtaining title compound, be colorless solid.LC-MS：438(M+1)；HPLC.：t _R＝4.499min.

Embodiment 64:4-[6-(4-oxyethyl group-3-methoxyl group-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-methyl-benzsulfamide

Except with microwave oven as the thermal source, title compound use with embodiment 63 in method preparation like the compounds of preparation.Colorless solid.LC-MS：453(M+1)；HPLC.：t _R＝4.531min.

Embodiment 65:3-(4-methane sulfonyl-phenyl)-6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine

With 50mg (0.127mmol) 3-bromo-6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine (preparation is referring to step 65.1), 36mg (0.18mmol) (4-methyl sulphonyl) phenyl-boron dihydroxide (Combi-Blocks), 0.32ml1M K ₂CO ₃The aqueous solution and 5mg Pd (PPh ₃) ₂Cl ₂1.5ml DMF mixture in oil bath 105 ℃ the heating 2 ¹/ ₂H.Evaporating solvent is dissolved in CH with residue ₂Cl ₂In, and organic phase washed with water and dry (Na ₂SO ₄).Evaporating solvent, and with residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-EtOAc=100-0 (beginning) is to 0-100 (end).Separate obtaining title compound, be yellow solid.MS：470(M+1)；HPLC.：t _R＝5.437min.

Step 65.1:3-bromo-6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine

490mg (1.554mmol) 6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine (preparation is referring to step 65.2) is dissolved among the dry DMF of 50ml.Solution is cooled to 0-5 ℃, adds 297mg (1.58mmol) N-bromosuccinimide.At 0-5 ℃, continue to stir 2h, then at RT restir 2h.Reaction mixture is under reduced pressure concentrated, add CH ₂Cl ₂, and with organic phase water and salt solution extraction.Separate and dry (Na ₂SO ₄) after the organic phase, evaporating solvent is with the residue chromatography purification.Solvent systems: CH ₂Cl ₂-EtOAc=100-0 (beginning) is to 70-30 (end).Separate obtaining title compound, be yellow solid.MS：396(M+1)；HPLC.：t _R＝6.988min.

Step 65.2.6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine

Use in the 20ml bottle at the microwave that has crown cap and magnetic stirring bar, with 300mg (1.79mmol) 6-chloro-2-methyl-imidazo [1,2-b] pyridazine (preparation is referring to the step 13.6. among the application example P2 (BeispieleP2-Anmeldung)), 500mg (2.192mmol) 4 '-methoxyl biphenyl-4-base-boric acid (Combi-Blocks), 41mg Pd (dba) ₂, 1.15g (5.418mmol) K ₃PO ₄In microwave oven, heat 30min with the 15ml dry THF mixture of 59mgSPhos at 110 ℃.Pour reaction mixture into CH ₂Cl ₂In and wash with water.With organic phase drying (Na ₂SO ₄) and evaporate to dryness.With the residue chromatography purification.Solvent systems: CH ₂Cl ₂-EtOAc=100-0 (beginning) is to 0-100 (end).Separate obtaining title compound, be yellow solid.MS：316(M+1)；HPLC.：t _R＝5.124min.

Embodiment 66:4-(6-(4 '-methoxyl biphenyl-4-yl)-glyoxal ethyline is [1,2-b] pyridazine-3-yl also)-N-methyl benzenesulfonamide

Title compound, be similar to the compound of preparation among the embodiment 65, by 50mg (0.127mmol) 3-bromo-6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine (step 65.1) and 38mg (0.177mmol) methyl-4-borono-benzsulfamide (Combi-Blocks) preparation.Separate obtaining product, be yellow solid.MS：485(M+1)；HPLC.：t _R＝5.437min.

Embodiment 67:4-[6-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-methyl-benzsulfamide

Title compound, be similar among the embodiment 65 compound of preparation and be similar to step 65.1. and step 65.2. in the intermediate for preparing, by boric acid class preparation separately.Yellow solid.MS：457(M+1)；HPLC.：t _R＝3.796min.

Embodiment 68:3-{4-[3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-propyl group amine

With 115mg (0.193mmol) (3-{4-[3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group-propyl group)-t-butyl carbamate (step 68.1) is dissolved in 2ml CH ₂Cl ₂In.Under RT and argon gas atmosphere, added 0.5ml TFA-water 9: 1.Reaction mixture is stirred 90min (with HPLC and MS monitoring).With solution CH ₂Cl ₂Dilution, and with the saturated NaHCO of organic phase ₃Solution, water and salt water washing.Use Na ₂SO ₄After the dry organic phase, evaporating solvent is with residue chromatography purifying on silica gel.Solvent systems: CH ₂Cl ₂-MeOH-NH ₄OH 32%=90: 10: 1.MS:467.1 (M+1); HPLC.:t _R=2.989min.

Step 68.1.(3-{4-[3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-propyl group)-t-butyl carbamate

Use in the 6ml bottle at the microwave that has crown cap and magnetic stirring bar; with 150mg (0.29mmol) { 3-[4-(3-bromo-2-methyl-imidazo [1,2-b] pyridazine-6-yl)-2-methoxyl group-phenoxy group]-propyl group }-t-butyl carbamate (preparation is referring to the step 25.2. among the application example P2), 71mg (0.348mmol) (4-methyl sulphonyl phenyl) boric acid (Combi-Blocks), 0.72ml 1M K ₂CO ₃The 4ml DMA mixture that the aqueous solution and 16.8mg four-triphenylphosphine close palladium heats 40min at 150 ℃ in microwave oven.With the reactant vaporising under vacuum, residue is dissolved in CH ₂Cl ₂In, and water and salt solution extraction.With organic phase drying (Na ₂SO ₄) and evaporating solvent.With residue chromatography purifying on silica gel.Solvent systems: EtOAc=A; EtOAc-MeOH:98-2=B; Operation: 100%A, 20min; Then in the 10min to 100%B, 100%B then, 20min.Separate obtaining title compound, be colorless solid.MS：567.1(M+1)；HPLC.：t _R＝5.077min.

Compound in the following table use with embodiment 68 and step 68.1 in method preparation like the compounds of preparation:

Embodiment 73:2-{4-[3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-ethylamine

Title compound; be similar to the compound of preparation among the embodiment 68; by 112mg (0.178mmol) (2-{4-[3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-] pyridazine-6-yl]-2-methoxyl group-phenoxy group-ethyl)-the mixture preparation in 9: 1 of t-butyl carbamate (step 73.1) and 0.25ml TFA-water.Reaction times: 5h is at RT.Yellow solid.MS：467.1(M+1)；HPLC.：t _R＝3.092min.

Step 73.1:(2-{4-[3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-ethyl)-t-butyl carbamate

Title compound; be similar to the compound for preparing among the step 68.1.; prepare by 156mg (0.31mmol) { 2-[4-(3-bromo-2-methyl-imidazo [1,2-b] pyridazine-6-yl)-2-methoxyl group-phenoxy group]-ethyl }-t-butyl carbamate (preparation is referring to the step 24.2. among the application example P2) and 102mg (0.466mmol) (4-ethylsulfonyl phenyl) boric acid (Combi-Blocks).Reaction times: 40min is in 150 ℃, microwave oven.Yellow (Yelloy) crystal.MS：567.1(M+1)；HPLC.：t _R＝5.062min.

Compound in the following table use with embodiment 73 and step 73.1 in method preparation like the compounds of preparation:

Embodiment 78: soft capsule

5000 soft capsules (each capsule comprises one of formula I compound of mentioning in 0.05g the foregoing description as activeconstituents) are prepared as follows:

Form

Activeconstituents 250g

Lauroglycol 2L

Preparation method: pulverous activeconstituents is suspended in (the propylene glycol laurate,

S.A., Saint Priest, France) in, and in wet crushing mill, grind, to produce the granularity of about 1 to 3 μ m.With the capsule loading machine 0.419g mixture is incorporated in the soft gelatin capsule then.

Claims

1. formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically useful) salt:

Wherein

R ¹It is aryl unsubstituted or that replace; And

R ²Be the phenyl of replacement or the naphthyl of replacement.

2. according to formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically useful) salt of claim 1, wherein

R ¹Be phenyl, its be unsubstituted or by one or more, particularly 1 or 2 or 3, more preferably 2 be selected from following group and replace: the alkyl that replaces or replace, C for example unsubstituted or that replaced by hydroxyl ₁-C ₇-alkyl, or cyano group-C ₁-C ₇-alkyl; Halogen; Hydroxyl; Alkyl oxy, particularly C ₁-C ₇-alkoxyl group, particularly methoxyl group; Amino; Single-dibasic amino, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-amino, particularly N-methylamino; C ₁-C ₇-alkanoylamino; C ₁-C ₇-alkoxy carbonyl-amino; Phenyl-or naphthyl-C ₁-C ₇-alkoxy carbonyl-amino; Formamyl; Single-dibasic formamyl, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-formamyl; Tetramethyleneimine-2-carbonyl-amino; Wherein heterocyclic radical is bonded to heterocyclic radical carbonyl, particularly piperidino-(1-position only) carbonyl, morpholino-carbonyl, thiomorpholine generation-carbonyl or the S-oxo of carbonyl-or S by ring nitrogen, and S-dioxo thiomorpholine is for carbonyl; C ₁-C ₇-alkane alkylsulfonyl; Sulfamyl; The N-list-or N, the dibasic sulfamyl of N-, preferred N-list-or N, N-two-(C ₁-C ₇-alkyl)-sulfamyl; C ₃-C ₈-cycloalkyl-sulfamyl; Azetidine-sulfamyl; Hydroxyl-(C ₁-C ₇-alkyl)-sulfamyl; Cyano group; Nitro; The heterocyclic radical that does not replace or replace by ring carbon atom or preferred theheterocyclic nitrogen atom bonding; particularly 1; 2; 4-triazol-1-yl, formamyl-1; 2; 4-triazol-1-yl, pyrazol-1-yl, 3-trifluoromethyl-pyrazol-1-yl, 3-(halogenophenyl)-pyrazol-1-yl be 3-(4-chloro-phenyl-)-pyrazol-1-yl, tetramethyleneimine-1-base, 2-oxo-tetramethyleneimine-1-base, piperidines-1-base, 2-oxo-piperidine-1-base, morpholino, pyridyl for example, and it is unsubstituted or by cyano group, C ₁-C ₇-alkyl or amino that replace, pyrimidyl, pyrazinyl, benzimidazolyl-, C ₁-C ₇The benzothiazolyl of the benzimidazolyl-of-alkoxyl group-replacement, benzothiazolyl, amino-replacement, pyrrolo--pyrimidyl be pyrrolo-[2,3-d] pyrimidyl, C particularly ₁-C ₇Pyrrolo--the pyrimidyl of-alkyl-replacement is 2-C for example ₁-C ₇-alkyl-pyrrolo-[2,3-d] pyrimidin-4-yl-and 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base, it is unsubstituted or by 1 or 2 substituting group replacement, described substituting group independently is selected from C ₁-C ₇-alkyl and halo-C ₁-C ₇-alkyl, and/or also be selected from not the aryl that replaces or replace, the cycloalkyl that does not replace or replace and the heterocyclic radical that does not replace or replace particularly is selected from: phenyl, its be unsubstituted or by one or more for example at the most 2 independently be selected from halogen, C ₁-C ₇-alkoxyl group and C ₁-C ₇That the group of-alkane alkylsulfonyl replaces, tetrazolium-5-base, indyl, indazolyl, C ₁-C ₇-alkyl-indazolyl, pyrrolo--pyridyl and azetidine-2-ketone; And

Wherein in a more preferred, R ²Be 3, the 4-Dimethoxyphenyl.

3. according to formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically useful) salt of claim 1, wherein

R ¹Be phenyl, its be unsubstituted or by one or more, particularly 1 or 2 or 3, more preferably 1 or 2 group replace (preferably the 3-of phenyl () position and/or 4-(to) position), described group is selected from: hydroxyl-C ₁-C ₇-alkyl; Cyano group-C ₁-C ₇-alkyl; Halogen; C ₁-C ₇-alkoxyl group; Amino; The N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-amino; C ₁-C ₇-alkanoylamino; C ₁-C ₇-alkoxy carbonyl-amino; Phenyl-or naphthyl-C ₁-C ₇-alkoxy carbonyl-amino; Formamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl and/or C ₃-C ₈-cycloalkyl)-formamyl; Tetramethyleneimine-2-carbonyl-amino; The piperidino-(1-position only) carbonyl; Morpholino-carbonyl; Thiomorpholine generation-carbonyl; The S-oxo-or S, S-dioxo thiomorpholine is for carbonyl; C ₁-C ₇-alkane alkylsulfonyl; Sulfamyl; The N-list-or N, N-two-(C ₁-C ₇-alkyl)-sulfamyl; C ₃-C ₈-cycloalkyl-sulfamyl; Azetidine-sulfamyl; Hydroxyl-(C ₁-C ₇-alkyl)-sulfamyl; Cyano group; Nitro; 1,2, the 4-triazol-1-yl; Formamyl-1,2,4-triazol-1-yl, 3-formamyl-1,2 for example, 4-triazol-1-yl; Pyrazol-1-yl; 3-trifluoromethyl-pyrazol-1-yl; 3-(halogenophenyl)-pyrazol-1-yl, for example 3-(4-chloro-phenyl-)-pyrazol-1-yl; Tetramethyleneimine-1-base; 2-oxo-tetramethyleneimine-1-base; Piperidines-1-base; 2-oxo-piperidine-1-base; Morpholino; Pyridine-(2-, 3-or 4-) base, it is unsubstituted or by cyano group, C ₁-C ₇-alkyl or amino replacement; Pyrimidine-(2-, 4-or 5-) base; Pyrazinyl; Benzimidazolyl-; C ₁-C ₇The benzimidazolyl-of-alkoxyl group-replacement; Benzothiazolyl; The benzothiazolyl of amino-replacement; Pyrrolo--pyrimidyl, particularly pyrrolo-[2,3-d] pyrimidin-4-yl-; C ₁-C ₇Pyrrolo--the pyrimidyl of-alkyl-replacement; And 1H, 4H, 5H-three hydrogen pyrazolos [2,3-c] piperidines-1-base, it is unsubstituted or by 1 or 2 substituting group replacement, described substituting group independently is selected from C ₁-C ₇-alkyl and halo-C ₁-C ₇-alkyl, or also be selected from: phenyl, it is unsubstituted or by one or more halogen, C of independently being selected from ₁-C ₇-alkoxyl group and C ₁-C ₇That the group of-alkane alkylsulfonyl replaces, tetrazolium-5-base, indyl, indazolyl, C ₁-C ₇-alkyl-indazolyl, pyrrolo--pyridyl and azetidine-2-ketone; And

Wherein in a preferred embodiment, R ²Be 3, the 4-Dimethoxyphenyl.

4. according to formula I compound or its N-oxide compound, solvate and/or its (preferably pharmaceutically useful) salt of claim 1, wherein

R ¹It is phenyl; (particularly 3-or 4-) halogenophenyl; (particularly 3-or 4-) C ₁-C ₇-alkoxyl phenyl; Halo-and C ₁-C ₇The phenyl of-alkoxyl group-replacement, particularly 3-halo-4-C ₁-C ₇-alkoxyl phenyl or 4-halo-3-C ₁-C ₇-alkoxyl phenyl; Halo-, C ₁-C ₇-alkoxyl group-and C ₁-C ₇The phenyl of-alkyl-replacement, for example 2-halo-4-C ₁-C ₇-alkoxyl group-5-C ₁-C ₇-alkyl-phenyl; (particularly 3-or 4-) aminophenyl; Tetramethyleneimine-2-carbonylamino-phenyl; (particularly 3-or 4-) list-or two-(C ₁-C ₇-alkyl) phenyl; (particularly 3-or 4-) C ₁-C ₇-alkane alkylsulfonyl-phenyl; Azetidine-1-alkylsulfonyl-phenyl; (particularly 3-or 4-) sulfamyl-phenyl; (particularly 3-or 4-) N-list-(C ₁-C ₇-alkyl)-sulfamyl-phenyl; Cyclopropyl-sulfamyl-phenyl; 2-hydroxyl-ethyl-sulfamyl-phenyl; (particularly 3-or 4-) cyano-phenyl; (particularly 3-or 4-) nitrophenyl; (particularly 4-) 1,2,4-triazol-1-yl-phenyl; (particularly 4-) pyrazol-1-yl-phenyl; (particularly 4-) (3-trifluoromethyl-pyrazol-1-yl)-phenyl; (particularly 4-) 2-oxo-tetramethyleneimine-1-base-phenyl; (particularly 4-) 2-oxo-piperidine-1-base-phenyl; (particularly 4-) morpholino-phenyl; (particularly 3-or 4-) piperazine-1-base-phenyl; (particularly 3-or 4-) 4-(C ₁-C ₇-alkyl)-piperazine-1-base-phenyl; (particularly 4-) pyridine-(2-, 3-or 4-) base-phenyl; Cyano group-pyridyl-phenyl; Methyl-pyridyl-phenyl; Amino-pyridine base-phenyl; (particularly 4-) pyrimidine-(2-, 4-or 5-) base-phenyl; Pyrazinyl-phenyl; Azetidine-2-ketone-phenyl; Or (particularly 3-or 4-) benzoglyoxaline-1-base-phenyl; And

5. according to formula I compound or its N-oxide compound, solvate and/or its pharmacologically acceptable salt of claim 1, described compound is selected from the compound with following title:

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-[1,2,4] triazol-1-yl-phenyl)-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-nitro-phenyl)-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyrazol-1-yl-phenyl)-imidazo [1,2-b] pyridazine;

3-(4-benzoglyoxaline-1-base-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzonitrile;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyridin-3-yl-phenyl)-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(1H-tetrazolium-5-yl)-phenyl]-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyrimidine-5-base-phenyl)-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-3-(4-iodo-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-3-(3-fluoro-4-methoxyl group-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl amine;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-methyl-amine;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(3-trifluoromethyl-pyrazol-1-yl)-phenyl]-imidazo [1,2-b] pyridazine;

1-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-piperidines-2-ketone;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-morpholine-4-base-phenyl)-imidazo [1,2-b] pyridazine;

1-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-pyrrolidin-2-one;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(4-methyl-piperazine-1-yl)-phenyl]-imidazo [1,2-b] pyridazine;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-morpholine-4-base-ketone;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N, N-dimethyl-benzsulfamide;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzamide;

3-(2-chloro-4-methoxyl group-5-methyl-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

6-(3,4-dimethoxy-phenyl)-3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

3-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N, N-dimethyl-benzsulfamide;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-methyl-benzsulfamide;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzsulfamide;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-acetonitrile;

3-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo-[1,2-b] pyridazine-3-yl]-phenyl }-third-1-alcohol;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-ethyl-benzsulfamide;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(propane-2-alkylsulfonyl)-phenyl]-imidazo [1,2-b] pyridazine;

N-cyclopropyl-4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzsulfamide;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N, N-diethyl-benzsulfamide;

3-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-methyl-benzamide;

3-[4-(azetidine-1-alkylsulfonyl)-phenyl]-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine

6-(3,4-dimethoxy-phenyl)-3-(3-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b]-pyridazine;

4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b]-pyridazine-3-yl]-N-(2-hydroxyl-ethyl)-benzsulfamide;

3-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-benzamide;

5-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-the cigarette nitrile;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-(4-pyrazine-2-base-phenyl)-imidazo [1,2-b] pyridazine;

4 '-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-biphenyl-4-yl }-acetonitrile;

5-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-pyridine-2-formonitrile HCN;

6-(3,4-dimethoxy-phenyl)-2-methyl-3-[4-(3-methyl-pyridine-2-yl)-phenyl]-imidazo [1,2-b] pyridazine;

3-(4-benzothiazole-2-base-phenyl)-6-(3,4-dimethoxy-phenyl)-2-methyl-imidazoles [1,2-b] pyridazine;

1-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-azetidine-2-ketone;

(R)-tetramethyleneimine-2-formic acid 4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-acid amides;

1-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-1H-[1,2,4] triazole-3-methane amide;

2-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-benzothiazole-5-base amine;

5-{4-[6-(3,4-dimethoxy-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-phenyl }-pyridine-2-base amine;

3,6-pair-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

3,6-pair-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine;

6-(4-oxyethyl group-3-methoxyl group-phenyl)-3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine;

4-[6-(4-oxyethyl group-3-methoxyl group-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-methyl-benzsulfamide;

3-(4-methane sulfonyl-phenyl)-6-(4 '-methoxyl group-biphenyl-4-yl)-2-methyl-imidazo [1,2-b] pyridazine;

4-(6-(4 '-methoxyl biphenyl-4-yl)-glyoxal ethyline is [1,2-b] pyridazine-3-yl also)-N-methyl benzenesulfonamide;

4-[6-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-3-yl]-N-methyl-benzsulfamide;

3-{4-[3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-propyl group amine;

(3-{4-[3-(4-dimethylamino alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-propyl group)-t-butyl carbamate;

4-{6-[4-(3-amino-propoxy-)-3-methoxyl group-phenyl]-2-methyl-imidazo [1,2-b] pyridazine-3-yl }-N, N-dimethyl-benzsulfamide;

3-{4-[3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-propyl group amine;

(3-{4-[3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-propyl group)-t-butyl carbamate;

2-{4-[3-(4-ethane alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-ethylamine;

2-{4-[3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-ethylamine;

(2-{4-[3-(4-methane sulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-ethyl)-t-butyl carbamate;

4-{6-[4-(2-amino-oxyethyl group)-3-methoxyl group-phenyl]-2-methyl-imidazo [1,2-b] pyridazine-3-yl }-N, N-dimethyl-benzsulfamide;

(2-{4-[3-(4-dimethylamino alkylsulfonyl-phenyl)-2-methyl-imidazo [1,2-b] pyridazine-6-yl]-2-methoxyl group-phenoxy group }-ethyl)-t-butyl carbamate.

6. according to formula I compound or its N-oxide compound, solvate and/or its pharmacologically acceptable salt of claim 1, described compound is selected from the compound with following structural formula:

7. according to formula I compound any among the claim 1-6, its N-oxide compound, its tautomer and/or its pharmacologically acceptable salt, they are used for the treatment of and comprise that the prophylactic treatment warm-blooded animal is particularly human.

8. according to the formula I compound of claim 7, its N-oxide compound, its tautomer and/or its pharmacologically acceptable salt, wherein they are used to resist one or more diseases, described disease is selected from proliferative, inflammatory diseases, anaphylactic disease, obstructive respiratory disease and the disease of following transplanting to take place usually, particularly one or more have the disease of response to the PI3-kinases-kinase whose active inhibition of related protein kinase enzyme family, and described kinases is lipid kinase and/or PI3 kinases (PI3K) and/or mTOR and/or DNA protein kinase and/or ATM and/or ATR and/or hSMG-1 particularly.

9. pharmaceutical preparation, this pharmaceutical preparation comprises according to formula I compound any among the claim 1-8, its N-oxide compound, its tautomer and/or its pharmacologically acceptable salt and at least a pharmaceutically acceptable carrier.

10. the method for useful in preparing drug formulations, this method comprise according to formula I compound any among the claim 1-8, its N-oxide compound, its tautomer and/or its pharmacologically acceptable salt and at least a pharmaceutically acceptable carrier material mixing.

11. preparation is according to the method for compound any among the claim 1-6, described method comprises

A) make formula II compound

R wherein ²Define in the formula I compound as claimed in claim 1, and X is the preferred chlorine of halogen, bromine or iodine, or trifyl oxygen base,

R ¹-D (III)

R wherein ¹Define in the formula I compound as claimed in claim 1 and be bonded to D, and D is free form or esterified form-B (OH by carbon atom ₂), for example be the group of formula A,

Or

B) make boric acid or the boric acid ester compound of formula IV

R wherein ²Define in the formula I compound as claimed in claim 1, and D is free form or esterified form-B (OH ₂), for example be the formula A group shown in a),

Under the cross-coupling condition, react with formula V compound,

R ¹-X (V)

R wherein ¹Define in the formula I compound as claimed in claim 1, and X is particularly chlorine, bromine or iodine of halogen, or trifyl oxygen base,

Or

C) make formula VI compound

R ²-D (VII)

Or

D) make the pyridazine compound of formula VIII

R wherein ²Define in the formula I compound as claimed in claim 1,

With the halogenated ketone reaction of formula IX,

R wherein ¹Define in the formula I compound as claimed in claim 1, and Y is particularly chlorine or bromine of halogen,

And, when needs, will be according to above-mentioned reaction a) to d) in the obtainable formula I compound of arbitrary reaction be converted into different formula I compounds, the salt of obtainable formula I compound is converted into its different salt, obtainable free type I compound is converted into its salt, and/or the isomer of obtainable formula I compound is separated from one or more different obtainable formula I isomer.